5	33300026	It is estimated that ~70 000 lesions occur in genomic DNA in each human cell per day, most of which (75%) originate from oxidation reactions with endogenous byproducts of metabolism and base hydrolysis.	('human', 'Species', '9606', (66, 71))	('lesions', 'Var', (29, 36))	('originate from', 'Reg', (106, 120))
6	33300026	To counteract the continuous threat these lesions pose to genome stability, cells have evolved a wide-ranging arsenal of repair programs, including DNA base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), translesion synthesis (TLS) and strand break repair (homologous recombination and various non-homologous end joining pathways), which together act upon particular types of lesion or at specific phases of the cell cycle to prevent mutations in DNA and cell death.	('mutations', 'Var', (467, 476))	('death', 'Disease', 'MESH:D003643', (493, 498))	('death', 'Disease', (493, 498))	('DNA', 'Gene', (480, 483))
10	33300026	Indeed, despite the fact that replication-associated mutations have been linked to high frequencies of single base-pair substitutions (SBSs) in human cancers, mutational landscapes in cancer genomes are highly heterogeneous.	('cancer', 'Disease', (184, 190))	('human', 'Species', '9606', (144, 149))	('single base-pair substitutions', 'Var', (103, 133))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('replication-associated', 'Disease', (30, 52))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
14	33300026	We showed that NEIL1 becomes stabilized on chromatin after site-specific (Lys296-298) acetylation, and accumulates almost exclusively at highly transcribed genomic regions as well as the transcription start sites (TSS) of weakly expressed genes, some of which are associated with poor prognosis when overexpressed in cancer.	('acetylation', 'Var', (86, 97))	('accumulates', 'PosReg', (103, 114))	('NEIL1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('Lys296-298) acetylation', 'Var', (74, 97))	('Lys296', 'Chemical', '-', (74, 80))	('acetyl', 'Chemical', '-', (86, 92))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
15	33300026	Bioinformatic analyses using cancer genome datasets and human germline population mutation datasets provide, with unprecedented resolution, information on the relationship between local variations in single base substitution (SBS) rates and ChIP-seq AcNEIL1 occupancy, both in cancer genomes and the germline.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('human', 'Species', '9606', (56, 61))	('variations', 'Var', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
79	33300026	For XRCC1, we downloaded the original fastq file from the GEO (https://www.ncbi.nlm.nih.gov/geo/) repository (GSE95302, file SRR5282040) and processed it according to the pipeline we used here.	('GSE95302', 'Var', (110, 118))	('XRCC1', 'Gene', (4, 9))	('XRCC1', 'Gene', '7515', (4, 9))
81	33300026	The file for OGG1 was GSM2357433_CP-Sample_Flag-OGG1-Con-2.tdf from the GEO record GSM2357433; the file was first converted to a bedGraph format using the 'igvtools tdftobedgraph'and then to bigWig.	('OGG1', 'Gene', '4968', (48, 52))	('GSM2357433', 'Var', (83, 93))	('OGG1', 'Gene', (13, 17))	('OGG1', 'Gene', '4968', (13, 17))	('OGG1', 'Gene', (48, 52))
88	33300026	To this end we divided patients with each tumor type into two groups: group 1, with expression of gene x above the mean; and group 2, with expression of gene x below or at the mean value.	('tumor', 'Disease', (42, 47))	('above', 'PosReg', (105, 110))	('patients', 'Species', '9606', (23, 31))	('gene x', 'Var', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('expression', 'MPA', (84, 94))	('below', 'NegReg', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
101	33300026	We recently showed that p300 acetylates NEIL1 (herein referred to as AcNEIL1) at residues Lys296, Lys297 and Lys298, which serves to increase DG activity and stabilize the enzyme on chromatin-bound complexes.	('Lys298', 'Var', (109, 115))	('Lys297', 'Chemical', '-', (98, 104))	('Lys296', 'Var', (90, 96))	('p300', 'Gene', (24, 28))	('Lys296', 'Chemical', '-', (90, 96))	('NEIL1', 'Gene', (40, 45))	('DG activity', 'MPA', (142, 153))	('Lys297', 'Var', (98, 104))	('p300', 'Gene', '2033', (24, 28))	('increase', 'PosReg', (133, 141))	('Lys298', 'Chemical', '-', (109, 115))	('acetyl', 'Chemical', '-', (29, 35))	('stabilize', 'MPA', (158, 167))
104	33300026	STED of human colorectal adenocarcinoma HCT116 cells labeled with anti-AcNEIL1 or anti-total-NEIL1 antibodies showed strong AcNEIL1 nuclear localization, as opposed to diffuse staining in nuclei and cytoplasm for non-acetylated NEIL1.	('anti-total-NEIL1', 'Var', (82, 98))	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('AcNEIL1', 'Gene', (124, 131))	('colorectal adenocarcinoma', 'Disease', (14, 39))	('nuclear localization', 'MPA', (132, 152))	('acetyl', 'Chemical', '-', (217, 223))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('human', 'Species', '9606', (8, 13))	('TE', 'Chemical', 'MESH:D013691', (1, 3))
114	33300026	H3K27Ac (Figure 1Dii) colocalized with AcNEIL1 on condensed chromosomes to a greater extent than total histone H3 (Figure 1Diii) and, likewise, AcNEIL1 yielded stronger fluorescent signal than total NEIL1 in nuclei (Supplementary Figure S2A, green trace).	('H3K27Ac', 'Protein', (0, 7))	('H3K27Ac', 'Chemical', '-', (0, 7))	('AcNEIL1', 'Var', (144, 151))	('fluorescent signal', 'MPA', (169, 187))	('stronger', 'PosReg', (160, 168))
163	33300026	We therefore analyzed ~25.4 million SBSs specific to tumor samples, including 5.6 million coding region mutations and 19.8 million non-coding variants.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
164	33300026	We conclude that transcription is an intrinsically mutagenic process, and that chromatin-bound AcNEIL1 is the active DG form of NElL1 in the context of BERosomes, which is responsible for the repair of oxidative DNA damage and the prevention of base-pair change accumulations, particularly transversion mutations at A:T base pairs.	('NElL1', 'Gene', (128, 133))	('transversion mutations', 'Var', (290, 312))	('NElL1', 'Gene', '4745', (128, 133))
165	33300026	After establishing that the local variations in mutation rates observed in cancer genomes coincide with segmental AcNEIL1 occupancy, we next addressed whether similar patterns exist for genetic variations between populations.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
166	33300026	We selected SweGen, a database of single nucleotide polymorphisms (SNPs) in the Swedish population, which is comparable in size (~23 million SNPs) to the cancer dataset.	('single nucleotide polymorphisms', 'Var', (34, 65))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
167	33300026	No qualitative differences were observed in the genome-wide distribution of SNPs as a function of AcNEIL1 ICS compared with those observed for cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SNPs', 'Disease', (76, 80))	('AcNEIL1 ICS', 'Var', (98, 109))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
168	33300026	Quantitatively, the frequency of incurring base changes at low AcNEIL1 (<500 000 ICS) was greater in cancer than in the germline, particularly for A>T and A>C transversions (Supplementary Figure S9C).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('A>C transversions', 'Var', (155, 172))	('A>T', 'Var', (147, 150))	('cancer', 'Disease', (101, 107))	('base changes', 'MPA', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
169	33300026	We surveyed the Human Gene Mutation Database (HGMD) to assess the frequency of variants at G4 DNA motifs in 5'-UTRs known to cause or predispose toward inherited disease.	('Human', 'Species', '9606', (16, 21))	('variants', 'Var', (79, 87))	('inherited disease', 'Disease', (152, 169))	('cause', 'Reg', (125, 130))	('G4 DNA', 'Gene', (91, 97))	('inherited disease', 'Disease', 'MESH:D030342', (152, 169))
174	33300026	The AcNEIL1 acetyl acceptors, Lys296, Lys297 and Lys298, are embedded within an intrinsically unstructured carboxyl-terminal (C-ter) domain (Supplementary Figure S10B), whose disordered nature has been well-conserved (Supplementary Figure S10B-D) despite the high degree of ordered protein folds expected among thermophilic lifeforms.	('acetyl', 'Chemical', '-', (12, 18))	('Lys297', 'Chemical', '-', (38, 44))	('Lys298', 'Chemical', '-', (49, 55))	('S10B', 'SUBSTITUTION', 'None', (162, 166))	('S10B', 'Var', (239, 243))	('Lys298', 'Var', (49, 55))	('Lys297', 'Var', (38, 44))	('Lys296', 'Var', (30, 36))	('S10B', 'SUBSTITUTION', 'None', (239, 243))	('Lys296', 'Chemical', '-', (30, 36))	('S10B', 'Var', (162, 166))
180	33300026	The observed loading and stabilization of AcNEIL1 on chromatin is critically dependent upon PTM at three consecutive lysine residues (Lys297-299), an acetylation center that appears to be the result of consolidation among variable amino acids in protostomes, probably occurring during the Cambrian explosion, ~540 million years ago, during a transition from sulfur to oxygen as an energy source.	('AcNEIL1', 'Gene', (42, 49))	('sulfur', 'Chemical', 'MESH:D013455', (358, 364))	('acetyl', 'Chemical', '-', (150, 156))	('oxygen', 'Chemical', 'MESH:D010100', (368, 374))	('Lys297-299', 'Var', (134, 144))	('Lys297', 'Chemical', '-', (134, 140))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
182	33300026	C>T (G>A) substitutions occur frequently at methylated CpG dinucleotides, particularly in single-stranded DNA where deamination of 5-methylcytosine to thymine, which produces G:T mismatches resulting in mutations (i.e.	('C>T (G>A', 'Gene', (0, 8))	('G:T mismatches', 'Var', (175, 189))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (131, 147))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (55, 72))	('mismatches', 'Var', (179, 189))	('thymine', 'Chemical', 'MESH:D013941', (151, 158))	('mutations', 'Var', (203, 212))	('substitutions', 'Var', (10, 23))
184	33300026	C>T transitions also arise from stable cytosine oxidation products, such as 5-hydroxycytosine.	('5-hydroxycytosine', 'Chemical', 'MESH:C017400', (76, 93))	('cytosine oxidation', 'MPA', (39, 57))	('5-hydroxycytosine', 'MPA', (76, 93))	('C>T', 'Var', (0, 3))	('cytosine', 'Chemical', 'MESH:D003596', (39, 47))	('cytosine', 'Chemical', 'MESH:D003596', (85, 93))	('arise', 'Reg', (21, 26))
190	33300026	Regarding transcription-associated mutagenesis, the tumor suppressor TP53, the most commonly mutated gene associated with cancer, strikingly resides within the most highly transcribed 1-Mb domain in the human genome, raising the intriguing possibility that susceptibility to human cancer may stem, in part, from intrinsic genome architecture.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutagenesis', 'Var', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('human', 'Species', '9606', (203, 208))	('tumor', 'Disease', (52, 57))	('TP53', 'Gene', (69, 73))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (281, 287))	('human', 'Species', '9606', (275, 280))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
192	33300026	Studies on the mutagenic potential of formamidopyrimidines have suggested that direct base misincorporation can generate both transition and transversion mutations.	('transversion mutations', 'CPA', (141, 163))	('misincorporation', 'Var', (91, 107))	('formamidopyrimidines', 'Chemical', '-', (38, 58))	('transition', 'MPA', (126, 136))
193	33300026	TG blocks DNA replication and its bypass, aided by translesion synthesis polymerases, can yield mutations when Poltheta is utilized.	('yield', 'Reg', (90, 95))	('TG', 'Chemical', 'MESH:C029389', (0, 2))	('DNA replication', 'CPA', (10, 25))	('mutations', 'Var', (96, 105))
198	33300026	Our analysis that Hox overexpression, and especially AcNEIL1-containing Hox gene reactivation in low grade glioma, contributes to poor survival strengthens the growing support for their key role in tumorigenesis.	('Hox', 'Gene', '42536', (72, 75))	('Hox', 'Gene', (72, 75))	('overexpression', 'PosReg', (22, 36))	('survival', 'MPA', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('poor', 'NegReg', (130, 134))	('reactivation', 'Var', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Hox', 'Gene', (18, 21))	('tumor', 'Disease', (198, 203))	('glioma', 'Disease', (107, 113))	('Hox', 'Gene', '42536', (18, 21))
199	33300026	Neil1-/- (or Neil2-/-) mouse embryoid bodies display neural defects, the downregulation of key developmental genes, including Hox genes, elevated levels of reactive oxygen species (ROS) and a pro-apoptotic TP53-associated DNA damage response.	('pro-apoptotic', 'PosReg', (192, 205))	('neural defects', 'CPA', (53, 67))	('Neil2', 'Gene', (13, 18))	('Neil1-/-', 'Var', (0, 8))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (156, 179))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('elevated', 'PosReg', (137, 145))	('TP53-associated', 'CPA', (206, 221))	('mouse', 'Species', '10090', (23, 28))	('levels of reactive oxygen species', 'MPA', (146, 179))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (137, 179))	('Hox', 'Gene', '42536', (126, 129))	('downregulation', 'NegReg', (73, 87))	('Neil2', 'Gene', '382913', (13, 18))	('Hox', 'Gene', (126, 129))
202	33300026	The altered expression and mutations associated with polycomb complexes have also been linked to cancer, and it will be of interest to determine the extent to which escape from NEIL1 damage repair beyond the early developmental stages may contribute to tumorigenesis.	('mutations', 'Var', (27, 36))	('NEIL1', 'Gene', (177, 182))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('contribute', 'Reg', (239, 249))	('linked', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (253, 258))	('expression', 'MPA', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
226	33184301	According to a 2016 report of World Health Organization (WHO), classification of tumors in the CNS is based on both phenotype and genotype (i.e., IDH mutation and 1p/19q codeletion status).	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('IDH', 'Gene', (146, 149))	('IDH', 'Gene', '3417', (146, 149))	('1p/19q codeletion status', 'Var', (163, 187))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
228	33184301	Tumor subtypes include diffuse astrocytoma, IDH-wild/-mutant type, oligodendroglioma, IDH-mutant and 1p/19q-codeleted, glioblastoma, IDH-wildtype, etc..	('astrocytoma', 'Disease', 'MESH:D001254', (31, 42))	('glioblastoma', 'Disease', (119, 131))	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (133, 136))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('astrocytoma', 'Disease', (31, 42))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('1p/19q-codeleted', 'Var', (101, 117))	('IDH', 'Gene', '3417', (86, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('astrocytoma', 'Phenotype', 'HP:0009592', (31, 42))	('oligodendroglioma', 'Disease', (67, 84))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (133, 136))	('IDH', 'Gene', '3417', (44, 47))	('oligodendroglioma', 'Disease', 'MESH:D009837', (67, 84))
293	33184301	This study considers three tumor subtypes: lower grade astrocytoma, IDH-mutant (A), oligodendroglioma, IDH-mutant, 1p/19q codeleted (O), and glioblastoma and diffuse astrocytic glioma with molecular features of glioblastoma, IDH-wildtype (G).	('IDH', 'Gene', '3417', (68, 71))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('astrocytoma', 'Disease', 'MESH:D001254', (55, 66))	('astrocytoma', 'Disease', (55, 66))	('IDH', 'Gene', '3417', (225, 228))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Disease', (211, 223))	('astrocytic glioma', 'Disease', 'MESH:D001254', (166, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('astrocytic glioma', 'Disease', (166, 183))	('tumor', 'Disease', (27, 32))	('IDH', 'Gene', (103, 106))	('1p/19q', 'Var', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('IDH', 'Gene', '3417', (103, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('oligodendroglioma', 'Disease', 'MESH:D009837', (84, 101))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('IDH', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('IDH', 'Gene', (225, 228))	('oligodendroglioma', 'Disease', (84, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (211, 223))
308	33184301	For tumor classification, there are three subtypes: lower grade astrocytoma with IDH-mutant (Grade II or III), oligodendroglioma with IDH-mutant, 1p/19q codeleted (Grade II or III), and glioblastoma and diffuse astrocytic glioma with molecular features of globlastoma, IDH-wildtype (Grade IV).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('IDH', 'Gene', '3417', (81, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('IDH', 'Gene', (269, 272))	('globlastoma', 'Disease', (256, 267))	('globlastoma', 'Disease', 'None', (256, 267))	('oligodendroglioma', 'Disease', 'MESH:D009837', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('glioblastoma', 'Disease', (186, 198))	('IDH', 'Gene', (134, 137))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (64, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('astrocytic glioma', 'Disease', (211, 228))	('oligodendroglioma', 'Disease', (111, 128))	('astrocytic glioma', 'Disease', 'MESH:D001254', (211, 228))	('IDH', 'Gene', '3417', (269, 272))	('1p/19q', 'Var', (146, 152))	('IDH', 'Gene', '3417', (134, 137))	('IDH', 'Gene', (81, 84))	('astrocytoma', 'Disease', 'MESH:D001254', (64, 75))	('astrocytoma', 'Disease', (64, 75))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
326	32599896	NG2/CSPG4 expression was significantly associated with EGFR gene amplification (p = 0.0005) and poor prognosis (p = 0.016) in astrocytic tumors.	('EGFR', 'Gene', '1956', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('NG2', 'Gene', '1464', (0, 3))	('EGFR', 'Gene', (55, 59))	('CSPG4', 'Gene', '1464', (4, 9))	('associated', 'Reg', (39, 49))	('amplification', 'Var', (65, 78))	('astrocytic tumors', 'Disease', (126, 143))	('CSPG4', 'Gene', (4, 9))	('NG2', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('astrocytic tumors', 'Disease', 'MESH:D001254', (126, 143))
345	32599896	It is co-expressed with PDGFRalpha, the high levels and gene mutations of which are regarded as features of the proneural subtype of GB.	('GB', 'Phenotype', 'HP:0012174', (133, 135))	('gene mutations', 'Var', (56, 70))	('PDGFRalpha', 'Gene', '5156', (24, 34))	('PDGFRalpha', 'Gene', (24, 34))
374	32599896	Cell line authentication from the matched primary tumor was verified by short tandem repeat profiling.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('short tandem repeat', 'Var', (72, 91))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
391	32599896	The search for mutations in IDH1 (exon 4) (GenBank sequence NM_005896), IDH2 (exon 4) (GenBank sequence NM_002168), the TERT gene promoter region (GenBank accession no.	('IDH2', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (28, 32))	('TERT', 'Gene', (120, 124))	('IDH2', 'Gene', '3418', (72, 76))	('mutations', 'Var', (15, 24))	('TERT', 'Gene', '7015', (120, 124))	('IDH1', 'Gene', (28, 32))
425	32599896	The mean percentage of NG2/CSPG4-positive cells at x400 HPF varied from 75.8% (25/33) for the former to 84.9% (45/53) for the latter.	('CSPG4', 'Gene', '1464', (27, 32))	('NG2', 'Gene', (23, 26))	('CSPG4', 'Gene', (27, 32))	('NG2', 'Gene', '1464', (23, 26))	('x400 HPF', 'Var', (51, 59))
432	32599896	TERT promoter mutations were detected in 20 out of 41 (48.8%) gliomas.	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('detected', 'Reg', (29, 37))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('gliomas', 'Disease', (62, 69))	('mutations', 'Var', (14, 23))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
435	32599896	Point mutations at codons Arg132 of the IDH1 gene and Arg172 of the IDH2 genes were identified in 25 out of 60 (41.7%) gliomas.	('Arg132', 'Chemical', '-', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('IDH1', 'Gene', (40, 44))	('IDH2', 'Gene', (68, 72))	('identified', 'Reg', (84, 94))	('IDH1', 'Gene', '3417', (40, 44))	('gliomas', 'Disease', (119, 126))	('Point mutations at codons', 'Var', (0, 25))	('IDH2', 'Gene', '3418', (68, 72))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('Arg172', 'Chemical', '-', (54, 60))	('Arg172', 'Var', (54, 60))
436	32599896	The missense mutation c.395G > A (p.Arg132His) accounted for 23/25 (92%) and c.516G > T (p.Arg172Ser) and c.515G > A (p.Arg172Lys) accounted for 1/25 (4%) each.	('p.Arg132His', 'Mutation', 'rs121913500', (34, 45))	('c.395G > A', 'Mutation', 'rs121913500', (22, 32))	('c.515G > A', 'Var', (106, 116))	('c.395G > A', 'Var', (22, 32))	('c.516G > T', 'Var', (77, 87))	('c.515G > A', 'Mutation', 'rs1064795056', (106, 116))	('c.516G > T', 'Mutation', 'rs11575996', (77, 87))	('p.Arg172Lys', 'Mutation', 'rs121913503', (118, 129))	('p.Arg172Ser', 'Mutation', 'rs1057519736', (89, 100))
438	32599896	All mutations detected in the TERT, IDH1/2, and TP53 genes were somatic changes.	('TP53', 'Gene', '7157', (48, 52))	('IDH1/2', 'Gene', (36, 42))	('TERT', 'Gene', (30, 34))	('TP53', 'Gene', (48, 52))	('TERT', 'Gene', '7015', (30, 34))	('mutations', 'Var', (4, 13))	('IDH1/2', 'Gene', '3417;3418', (36, 42))
439	32599896	EGFR gene amplification occurred in 19/45 (42.2%) malignant gliomas.	('EGFR', 'Gene', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('malignant gliomas', 'Disease', (50, 67))	('amplification', 'Var', (10, 23))	('malignant gliomas', 'Disease', 'MESH:D005910', (50, 67))	('EGFR', 'Gene', '1956', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('occurred', 'Reg', (24, 32))
440	32599896	The MGMT promoter hypermethylation was detected in 19 out of 46 (41.3%) tumors.	('MGMT', 'Gene', '4255', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('hypermethylation', 'Var', (18, 34))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('MGMT', 'Gene', (4, 8))
441	32599896	Malignant gliomas showed LOH on 10q in 42 out of 46 (91.3%) cases and LOH on 9p in 35 out of 46 (76.1%) cases.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('Malignant gliomas', 'Disease', 'MESH:D005910', (0, 17))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('LOH', 'Var', (70, 73))	('Malignant gliomas', 'Disease', (0, 17))	('LOH on 10q', 'Var', (25, 35))
450	32599896	NG2/CSPG4 immunoreactivity was significantly associated with EGFR gene amplification (p = 0.0005, Fisher's exact test) in malignant gliomas and with 1p/19q-codeletion in oligodendroglial tumors (p = 0.0297, Fisher's exact test) (Table 3).	('malignant gliomas', 'Disease', 'MESH:D005910', (122, 139))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (170, 193))	('oligodendroglial tumors', 'Disease', (170, 193))	('NG2', 'Gene', '1464', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('1p/19q-codeletion', 'Var', (149, 166))	('CSPG4', 'Gene', '1464', (4, 9))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('associated', 'Reg', (45, 55))	('EGFR', 'Gene', '1956', (61, 65))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('CSPG4', 'Gene', (4, 9))	('NG2', 'Gene', (0, 3))	('malignant gliomas', 'Disease', (122, 139))	('EGFR', 'Gene', (61, 65))
456	32599896	However, NG2/CSPG4 immunoreactivity was significantly associated with a poor prognosis (p = 0.016, log-rank test) after stratification for the malignancy grade (Figure 4).	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('immunoreactivity', 'Var', (19, 35))	('malignancy', 'Disease', (143, 153))	('NG2', 'Gene', (9, 12))	('rat', 'Species', '10116', (122, 125))	('NG2', 'Gene', '1464', (9, 12))	('CSPG4', 'Gene', '1464', (13, 18))	('CSPG4', 'Gene', (13, 18))	('associated', 'Reg', (54, 64))
480	32599896	In the present study, we confirm an inter-grade NG2/CSPG4 variability in gliomas and its correlation with the malignancy grade, in agreement with previous findings.	('CSPG4', 'Gene', (52, 57))	('NG2', 'Gene', (48, 51))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('CSPG4', 'Gene', '1464', (52, 57))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('variability', 'Var', (58, 69))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('NG2', 'Gene', '1464', (48, 51))	('malignancy', 'Disease', (110, 120))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', (73, 80))
496	32599896	By IF, we could confirm that NG2/CSPG4 positivity marks immature progenitor cells that represent the majority of cells under in vitro culture conditions.	('CSPG4', 'Gene', '1464', (33, 38))	('CSPG4', 'Gene', (33, 38))	('NG2', 'Gene', (29, 32))	('positivity', 'Var', (39, 49))	('NG2', 'Gene', '1464', (29, 32))
501	32599896	There is an apparent inconsistency between the predominant NG2/CSPG4 positivity of NS and the negativity of most tumor cells in GB.	('tumor', 'Disease', (113, 118))	('NG2', 'Gene', (59, 62))	('NG2', 'Gene', '1464', (59, 62))	('positivity', 'Var', (69, 79))	('GB', 'Phenotype', 'HP:0012174', (128, 130))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CSPG4', 'Gene', '1464', (63, 68))	('CSPG4', 'Gene', (63, 68))
512	32599896	Finally, the significant association between NG2/CSPG4 immunoreactivity and EGFR gene amplification (a well-known negative prognostic marker) in both astrocytic and oligodendroglial tumors is in line with previous findings.	('CSPG4', 'Gene', (49, 54))	('amplification', 'Var', (86, 99))	('NG2', 'Gene', (45, 48))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (150, 188))	('CSPG4', 'Gene', '1464', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('NG2', 'Gene', '1464', (45, 48))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
521	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))	('loss', 'Var', (72, 76))	('hallmark of many cancers', 'Disease', (151, 175))	('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))
525	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))
526	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))
528	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))
539	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))
540	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))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('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))
543	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))	('low-density lipoprotein receptor', 'Gene', '3949', (171, 203))	('human', 'Species', '9606', (85, 90))	('LDLR', 'Gene', '3949', (205, 209))	('de novo cholesterol synthesis', 'MPA', (7, 36))
556	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))	('cholesterol', 'Chemical', 'MESH:D002784', (79, 90))	('GBM', 'Phenotype', 'HP:0012174', (177, 180))	('dysregulation of cholesterol homeostasis', 'MPA', (62, 102))	('CYP46A1/24OHC', 'Var', (129, 142))
567	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))
569	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))
570	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))
572	31777202	The intra-tumoral expression pattern of CYP46A1 in GBMs was further determined using the IVY GBM RNA-seq data (http://glioblastoma.alleninstitute.org/).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('tumor', 'Disease', (10, 15))	('CYP46A1', 'Var', (40, 47))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('glioblastoma', 'Disease', (118, 130))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))
573	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))
574	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).	('rat', 'Species', '10116', (63, 66))	('tumour', 'Disease', (194, 200))	('CYP46A1', 'Var', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (194, 200))
581	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))
582	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))
584	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).	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('high CYP46A1', 'Var', (18, 30))	('CYP46A1', 'Var', (23, 30))	('progression-free survival', 'CPA', (135, 160))	('patients', 'Species', '9606', (4, 12))	('overall survival', 'CPA', (102, 118))	('better', 'PosReg', (95, 101))
585	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))
586	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))
587	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))
588	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))	('CYP46A1', 'Var', (37, 44))	('glioma', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('S5B', 'Gene', (156, 159))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
590	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))
591	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))	('caspase-3', 'Gene', '836', (143, 152))	('rat', 'Species', '10116', (67, 70))	('levels of the proliferation marker PCNA', 'MPA', (46, 85))	('increased', 'PosReg', (90, 99))	('reduced', 'NegReg', (38, 45))	('expression', 'MPA', (100, 110))	('caspase-3', 'Gene', (143, 152))
592	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))
596	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))
601	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', (44, 49))	('LN229', 'CellLine', 'CVCL:0393', (122, 127))	('caspase-3', 'Gene', (20, 29))	('elevated', 'PosReg', (11, 19))	('24OHC', 'Var', (0, 5))
604	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))
606	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))
610	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))
613	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))	('PARP', 'Gene', '1302', (110, 114))	('LN229', 'CellLine', 'CVCL:0393', (62, 67))	('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))
614	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))
616	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))	('depleting', 'NegReg', (78, 87))	('GBM growth', 'CPA', (64, 74))	('cellular cholesterol', 'MPA', (88, 108))	('24OHC', 'Var', (47, 52))	('cholesterol', 'Chemical', 'MESH:D002784', (97, 108))	('24OHC', 'Chemical', 'MESH:C496310', (47, 52))
619	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))
621	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))	('negatively', 'NegReg', (100, 110))	('positive', 'PosReg', (53, 61))	('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))
627	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))
628	31777202	Based on the RNA-seq data, 24OHC was also found to suppress SREBP signalling (Fig 5D and E).	('suppress', 'NegReg', (51, 59))	('24OHC', 'Chemical', 'MESH:C496310', (27, 32))	('24OHC', 'Var', (27, 32))	('SREBP signalling', 'MPA', (60, 76))
632	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))	('decrease', 'NegReg', (79, 87))	('LDLR', 'Gene', (168, 172))	('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))
637	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))	('binding', 'Interaction', (222, 229))	('GBM growth', 'CPA', (44, 54))	('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))
643	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))
645	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))	('PARP', 'Gene', '1302', (109, 113))	('ABCA1', 'Gene', '19', (70, 75))	('SREBP1', 'Gene', (142, 148))	('LDLR', 'Gene', (153, 157))	('ABCA1', 'Gene', (70, 75))	('SOX2', 'Gene', '6657', (179, 183))	('PARP', 'Gene', (109, 113))	('LDLR', 'Gene', '3949', (153, 157))	('decreased', 'NegReg', (122, 131))	('SOX2', 'Gene', (179, 183))
646	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))
653	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))
654	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))
655	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).	('caspase-3', 'Gene', (155, 164))	('S10A', 'Var', (179, 183))	('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))
661	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))
664	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))
666	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))
669	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))
671	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))
672	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))
675	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))
676	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))
677	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))
678	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))	('24OHC', 'Chemical', 'MESH:C496310', (9, 14))	('cholesterol', 'Chemical', 'MESH:D002784', (182, 193))	('modulates', 'Reg', (22, 31))
683	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))
685	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))	('GBM growth', 'CPA', (76, 86))	('EFV', 'Var', (39, 42))	('tumour cell death', 'Disease', 'MESH:D003643', (99, 116))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
687	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))
692	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))
716	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))
717	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))
745	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-H3K4me3', 'Var', (73, 85))	('anti-H3K27ac', 'Var', (36, 48))	('H3K4me3', 'Chemical', 'MESH:C024755', (78, 85))	('rabbit', 'Species', '9986', (120, 126))
778	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))
780	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))
782	31777202	EFV increased 24OHC levels in GBM cells and suppressed GBM cell growth.	('suppressed', 'NegReg', (44, 54))	('EFV', 'Var', (0, 3))	('increased', 'PosReg', (4, 13))	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('24OHC', 'Chemical', 'MESH:C496310', (14, 19))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('GBM cell growth', 'CPA', (55, 70))	('24OHC levels', 'MPA', (14, 26))
788	29991527	LINC00152 knockdown alters the transcription of genes important to epithelial-to-mesenchymal transition (EMT).	('LINC00152', 'Gene', (0, 9))	('alters', 'Reg', (20, 26))	('transcription of genes', 'MPA', (31, 53))	('LINC00152', 'Gene', '112597', (0, 9))	('knockdown', 'Var', (10, 19))
790	29991527	Point mutations in the stem-loop suggest that stem formation in the hairpin is essential for LINC00152 function.	('Point mutations', 'Var', (0, 15))	('LINC00152', 'Gene', '112597', (93, 102))	('LINC00152', 'Gene', (93, 102))
791	29991527	LINC00152 has a nearly identical homolog, MIR4435-2HG, which encodes a near identical hairpin, is equally expressed in low-grade glioma (LGG) and GBM, predicts poor patient survival in these tumors and is also reduced by LINC00152 knockdown.	('reduced', 'NegReg', (210, 217))	('GBM', 'Disease', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('MIR4435-2HG', 'Gene', '541471', (42, 53))	('GBM', 'Disease', 'MESH:D005909', (146, 149))	('tumors', 'Disease', (191, 197))	('LINC00152', 'Gene', (0, 9))	('LINC00152', 'Gene', (221, 230))	('glioma', 'Disease', (129, 135))	('MIR4435-2HG', 'Gene', (42, 53))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('poor', 'NegReg', (160, 164))	('knockdown', 'Var', (231, 240))	('patient', 'Species', '9606', (165, 172))	('LINC00152', 'Gene', '112597', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('LINC00152', 'Gene', '112597', (221, 230))	('predicts', 'Reg', (151, 159))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
797	29991527	These efforts have identified commonly altered signaling pathways in GBMs, including mutations in EGFR, p53 and mTOR signaling.	('EGFR', 'Gene', (98, 102))	('signaling pathways', 'Pathway', (47, 65))	('p53', 'Gene', (104, 107))	('GBM', 'Disease', (69, 72))	('p53', 'Gene', '7157', (104, 107))	('GBM', 'Disease', 'MESH:D005909', (69, 72))	('mutations', 'Var', (85, 94))	('mTOR', 'Gene', '2475', (112, 116))	('EGFR', 'Gene', '1956', (98, 102))	('mTOR', 'Gene', (112, 116))	('altered', 'Reg', (39, 46))
815	29991527	Furthermore, we find that LINC00152 is overexpressed in 10 other tumor types compared to matched normal tissue and high LINC00152 expression is associated with a poor prognosis in 7 of these tumors.	('LINC00152', 'Gene', (26, 35))	('high', 'Var', (115, 119))	('expression', 'MPA', (130, 140))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('LINC00152', 'Gene', '112597', (120, 129))	('tumor', 'Disease', (191, 196))	('LINC00152', 'Gene', '112597', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumors', 'Disease', (191, 197))	('LINC00152', 'Gene', (120, 129))
816	29991527	U87 cells were maintained in MEM supplemented with 1% non-essential amino acids solution (cat # 11140-050, Gibco), 1mM sodium pyruvate (cat # 11360070, Gibco), 0.15% sodium bicarbonate (cat # 25080094, Gibco), 10% FBS and 1% P/S.	('cat # 11360070', 'Var', (136, 150))	('U87', 'CellLine', 'CVCL:0022', (0, 3))	('FBS', 'Disease', 'MESH:D005198', (214, 217))	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (166, 184))	('FBS', 'Disease', (214, 217))	('sodium pyruvate', 'Chemical', 'MESH:D011773', (119, 134))	('cat # 25080094', 'Var', (186, 200))	('cat # 11140-050', 'Var', (90, 105))
819	29991527	500etag of LINC00152 or LINC00152 mutants pCDNA3-flag vectors were transfected into U87 cells using 2muL of Lipofectamine 2000 (Thermo Fisher).	('mutants', 'Var', (34, 41))	('LINC00152', 'Gene', (24, 33))	('LINC00152', 'Gene', (11, 20))	('pCDNA3-flag', 'Gene', (42, 53))	('U87', 'CellLine', 'CVCL:0022', (84, 87))	('LINC00152', 'Gene', '112597', (24, 33))	('LINC00152', 'Gene', '112597', (11, 20))
839	29991527	Aligned reads were then processed to identify gapped mapping to LINC00152 and visualized with IGV.	('LINC00152', 'Gene', '112597', (64, 73))	('gapped mapping', 'Var', (46, 60))	('LINC00152', 'Gene', (64, 73))
850	29991527	In GBMs, patients who had high expression of LINC00152 had a poor prognosis (p = 0.02) compared to the patients expressing low level of LINC00152, with a median survival of 11.9 and 15.4 months, respectively (Fig 2A).	('LINC00152', 'Gene', '112597', (45, 54))	('GBM', 'Disease', (3, 6))	('patients', 'Species', '9606', (9, 17))	('LINC00152', 'Gene', (136, 145))	('high expression', 'Var', (26, 41))	('GBM', 'Disease', 'MESH:D005909', (3, 6))	('LINC00152', 'Gene', '112597', (136, 145))	('LINC00152', 'Gene', (45, 54))	('patients', 'Species', '9606', (103, 111))
852	29991527	LGG patients with high expression of LINC00152 had a median survival of 62.1 months, while the low expressing group had a median survival of 98.2 months (p < 0.0001) (Fig 2B).	('LINC00152', 'Gene', (37, 46))	('high expression', 'Var', (18, 33))	('LINC00152', 'Gene', '112597', (37, 46))	('patients', 'Species', '9606', (4, 12))
864	29991527	Interestingly, even among these tumors, LINC00152 expression was associated with poor patient outcome in pancreatic adenocarcinoma when we compare the tumors in the top third and bottom third (Sup Fig 1D), and acute myeloid leukemia, with the top quartile and bottom quartile for LINC00152 expression (Sup Fig 1E).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (210, 232))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (210, 232))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (105, 130))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('LINC00152', 'Gene', '112597', (280, 289))	('tumors', 'Disease', (151, 157))	('patient', 'Species', '9606', (86, 93))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('LINC00152', 'Gene', (40, 49))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (105, 130))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('expression', 'Var', (50, 60))	('acute myeloid leukemia', 'Disease', (210, 232))	('leukemia', 'Phenotype', 'HP:0001909', (224, 232))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (216, 232))	('LINC00152', 'Gene', '112597', (40, 49))	('LINC00152', 'Gene', (280, 289))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('pancreatic adenocarcinoma', 'Disease', (105, 130))
873	29991527	These findings suggest that LINC00152 knockdown decreases invasion of GBM cells, while upregulation in GBMs promotes the invasive phenotype that is commonly seen in patient tumors.	('invasive', 'CPA', (121, 129))	('decreases', 'NegReg', (48, 57))	('LINC00152', 'Gene', (28, 37))	('GBM', 'Disease', (103, 106))	('GBM', 'Disease', (70, 73))	('patient', 'Species', '9606', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('GBM', 'Disease', 'MESH:D005909', (103, 106))	('GBM', 'Disease', 'MESH:D005909', (70, 73))	('promotes', 'PosReg', (108, 116))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('LINC00152', 'Gene', '112597', (28, 37))	('knockdown', 'Var', (38, 47))	('upregulation', 'PosReg', (87, 99))
874	29991527	In order to better understand how LINC00152 affects cellular invasion we performed RNA-seq on U87 following knockdown of LINC00152 using a combination of two different siRNAs.	('LINC00152', 'Gene', '112597', (121, 130))	('knockdown', 'Var', (108, 117))	('LINC00152', 'Gene', (34, 43))	('LINC00152', 'Gene', (121, 130))	('U87', 'CellLine', 'CVCL:0022', (94, 97))	('LINC00152', 'Gene', '112597', (34, 43))
878	29991527	More interestingly, six of the genes that were downregulated by LINC00152 knockdown were conversely upregulated by overexpression of the lncRNA: TPM2 (Tropomyosin 2), PTX3 (Pentraxin 3), IGFBP4 (Insulin growth factor binding protein 4), TGM2 (Transglutaminase 2), SPP1 (Secreted phosphoprotein 1) and LUM (Lumican)] (Sup Table 1).	('Secreted phosphoprotein 1', 'Gene', '6696', (270, 295))	('IGFBP4', 'Gene', '3487', (187, 193))	('upregulated', 'PosReg', (100, 111))	('ncRNA', 'Gene', (138, 143))	('Insulin growth factor binding protein 4', 'Gene', (195, 234))	('ncRNA', 'Gene', '220202', (138, 143))	('Insulin growth factor binding protein 4', 'Gene', '3487', (195, 234))	('TPM2', 'Gene', (145, 149))	('TPM2', 'Gene', '7169', (145, 149))	('knockdown', 'Var', (74, 83))	('TGM2', 'Gene', (237, 241))	('LINC00152', 'Gene', '112597', (64, 73))	('LINC00152', 'Gene', (64, 73))	('downregulated', 'NegReg', (47, 60))	('PTX3', 'Gene', (167, 171))	('LUM', 'Gene', (301, 304))	('PTX3', 'Gene', '5806', (167, 171))	('SPP1', 'Gene', (264, 268))	('Transglutaminase 2', 'Gene', (243, 261))	('TGM2', 'Gene', '7052', (237, 241))	('IGFBP4', 'Gene', (187, 193))	('Secreted phosphoprotein 1', 'Gene', (270, 295))	('Pentraxin 3', 'Gene', '5806', (173, 184))	('Pentraxin 3', 'Gene', (173, 184))	('SPP1', 'Gene', '6696', (264, 268))	('Tropomyosin 2', 'Gene', '7169', (151, 164))	('Transglutaminase 2', 'Gene', '7052', (243, 261))	('LUM', 'Gene', '4060', (301, 304))	('Tropomyosin 2', 'Gene', (151, 164))
883	29991527	If LINC00152 acts as a miRNA sponge in U87 cells we would expect that the targets of these microRNAs would be repressed upon knockdown of the lncRNA and the subsequent release of the microRNAs from interaction with the lncRNA.	('knockdown', 'Var', (125, 134))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('LINC00152', 'Gene', (3, 12))	('U87', 'CellLine', 'CVCL:0022', (39, 42))	('ncRNA', 'Gene', (143, 148))	('ncRNA', 'Gene', (220, 225))	('LINC00152', 'Gene', '112597', (3, 12))	('ncRNA', 'Gene', '220202', (143, 148))	('interaction', 'Interaction', (198, 209))	('ncRNA', 'Gene', '220202', (220, 225))
884	29991527	However, we find that there is a statistically significant up-regulation of the targets of these six microRNAs compared with non-targets when LINC00152 is knocked down ruling out the possibility of LINC00152 acting as a ceRNA for these miRNAs (Fig 4C).	('miR', 'Gene', '220972', (236, 239))	('miR', 'Gene', (236, 239))	('LINC00152', 'Gene', '112597', (198, 207))	('knocked down', 'Var', (155, 167))	('LINC00152', 'Gene', (142, 151))	('LINC00152', 'Gene', (198, 207))	('up-regulation', 'PosReg', (59, 72))	('LINC00152', 'Gene', '112597', (142, 151))
893	29991527	In order to determine whether this newly identified, potentially protein bound, stem-loop plays a role in LINC00152 function, we created a series of LINC00152 deletion mutants (Fig 5B and Sup Fig 5A).	('LINC00152', 'Gene', (106, 115))	('LINC00152', 'Gene', '112597', (149, 158))	('LINC00152', 'Gene', '112597', (106, 115))	('LINC00152', 'Gene', (149, 158))	('deletion mutants', 'Var', (159, 175))
895	29991527	We assessed whether independent overexpression of the mutants was able to stimulate U87 cell invasion.	('mutants', 'Var', (54, 61))	('U87 cell invasion', 'CPA', (84, 101))	('stimulate', 'PosReg', (74, 83))	('U87', 'CellLine', 'CVCL:0022', (84, 87))
897	29991527	On the other hand, the mutant M4 (which removed the 3' end but preserved the stem-loop) or M7 (which removed the extreme 3' end, and also preserved the stem-loop) increased U87 cell invasion.	('U87 cell invasion', 'CPA', (173, 190))	("extreme 3' end", 'MPA', (113, 127))	('increased', 'PosReg', (163, 172))	('U87', 'CellLine', 'CVCL:0022', (173, 176))	("3' end", 'MPA', (52, 58))	('stem-loop', 'MPA', (77, 86))	('mutant', 'Var', (23, 29))
898	29991527	Other deletion mutants that removed regions of LINC00152 5' to the stem loop (M5 or M6) stimulated cellular invasion to a similar extent as full-length LINC00152.	('LINC00152', 'Gene', '112597', (152, 161))	('stimulated', 'PosReg', (88, 98))	('cellular invasion', 'CPA', (99, 116))	('LINC00152', 'Gene', (152, 161))	('deletion mutants', 'Var', (6, 22))	('LINC00152', 'Gene', '112597', (47, 56))	('LINC00152', 'Gene', (47, 56))
899	29991527	Finally, overexpression of M8, containing only the protein bound stem-loop (nucleotides 280-401) was sufficient to stimulate invasion of U87 cells (Fig 5D).	('U87', 'CellLine', 'CVCL:0022', (137, 140))	('invasion', 'CPA', (125, 133))	('stimulate', 'PosReg', (115, 124))	('nucleotides 280-401', 'Var', (76, 95))
910	29991527	Thus, the phenotype that we observe with siRNA directed towards LINC00152 is also likely through knocking down the highly similar MIR4435-2HG.	('MIR4435-2HG', 'Gene', (130, 141))	('LINC00152', 'Gene', (64, 73))	('knocking', 'Var', (97, 105))	('LINC00152', 'Gene', '112597', (64, 73))	('MIR4435-2HG', 'Gene', '541471', (130, 141))
915	29991527	Moreover, the Kaplan Meier plot to estimate survival showed that expression of either RNA is associated with poor patient survival (Fig 7G and H).	('patient', 'Species', '9606', (114, 121))	('expression', 'Var', (65, 75))	('patient survival', 'CPA', (114, 130))	('poor', 'NegReg', (109, 113))
917	29991527	GWAS and high throughput sequencing studies have found that many of the genomic lesions and expression alterations seen in cancer and other pathologies fall within non-protein coding regions of the genome and may lead to dysregulation of ncRNAs.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ncRNA', 'Gene', (238, 243))	('alterations', 'Var', (103, 114))	('dysregulation', 'MPA', (221, 234))	('lead to', 'Reg', (213, 220))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('ncRNA', 'Gene', '220202', (238, 243))	('cancer', 'Disease', (123, 129))	('fall', 'Phenotype', 'HP:0002527', (152, 156))	('expression', 'MPA', (92, 102))
937	29991527	GSEA of RNA-seq from LINC00152 knocked down cells also supports the idea that LINC00152 is involved in promoting invasion.	('promoting', 'PosReg', (103, 112))	('invasion', 'CPA', (113, 121))	('LINC00152', 'Gene', (21, 30))	('knocked down', 'Var', (31, 43))	('LINC00152', 'Gene', '112597', (78, 87))	('LINC00152', 'Gene', '112597', (21, 30))	('LINC00152', 'Gene', (78, 87))
969	27072750	For subtotal resections, the volume of residual tumor is predictive of disease progression.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('subtotal', 'Var', (4, 12))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
984	27072750	A subset of pilocytic astrocytomas arise in patients with neurofibromatosis type 1 due to germline NF1 mutation that is accompanied by loss of heterozygosity of the remaining wild-type NF1 allele in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('neurofibromatosis type 1', 'Gene', '4763', (58, 82))	('patients', 'Species', '9606', (44, 52))	('neurofibromatosis type 1', 'Gene', (58, 82))	('NF1', 'Gene', (99, 102))	('NF1', 'Gene', '4763', (99, 102))	('pilocytic astrocytomas', 'Disease', (12, 34))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('mutation', 'Var', (103, 111))	('NF1', 'Gene', (185, 188))	('astrocytoma', 'Phenotype', 'HP:0009592', (22, 33))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (12, 34))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (58, 75))	('NF1', 'Gene', '4763', (185, 188))
986	27072750	On the other hand, the vast majority of sporadic pilocytic astrocytomas arising in the posterior fossa/cerebellum of non-NF1 patients harbor a duplication of the 3' portion of the BRAF gene encoding the C-terminal kinase domain.	('patients', 'Species', '9606', (125, 133))	('BRAF', 'Gene', (180, 184))	('NF1', 'Gene', '4763', (121, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('sporadic pilocytic astrocytomas', 'Disease', (40, 71))	('duplication', 'Var', (143, 154))	('sporadic pilocytic astrocytomas', 'Disease', 'MESH:D001254', (40, 71))	('BRAF', 'Gene', '673', (180, 184))	('NF1', 'Gene', (121, 124))
988	27072750	Other less common fusion partners for the duplicated BRAF kinase domain have been described including FAM131B, RNF130, CLCN6 and GNAI1.	('CLCN6', 'Gene', '1185', (119, 124))	('FAM131B', 'Gene', (102, 109))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('CLCN6', 'Gene', (119, 124))	('FAM131B', 'Gene', '9715', (102, 109))	('GNAI1', 'Gene', '2770', (129, 134))	('RNF130', 'Gene', '55819', (111, 117))	('RNF130', 'Gene', (111, 117))	('GNAI1', 'Gene', (129, 134))	('duplicated', 'Var', (42, 52))
989	27072750	Outside of the posterior fossa BRAF duplication and gene fusion is less common, being found in approximately half of cases centered in the diencephalon and cerebral hemispheres.	('found', 'Reg', (86, 91))	('duplication', 'Var', (36, 47))	('diencephalon', 'Disease', 'None', (139, 151))	('diencephalon', 'Disease', (139, 151))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
990	27072750	Pilocytic astrocytomas lacking BRAF duplication and gene fusion occasionally harbor the BRAFV600E activating missense mutation (6%), somatic mutations in NF1 (3%) or PTPN11 (2%), activating mutations within the kinase domain of FGFR1 (6%), and gene fusions involving NTRK2 (3%).	('Pilocytic astrocytomas', 'Disease', (0, 22))	('FGFR1', 'Gene', '2260', (228, 233))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('PTPN11', 'Gene', (166, 172))	('NTRK2', 'Gene', (267, 272))	('gene fusions', 'Var', (244, 256))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('NF1', 'Gene', '4763', (154, 157))	('PTPN11', 'Gene', '5781', (166, 172))	('BRAF', 'Gene', '673', (31, 35))	('FGFR1', 'Gene', (228, 233))	('BRAF', 'Gene', (31, 35))	('activating', 'Reg', (179, 189))	('mutations', 'Var', (141, 150))	('NF1', 'Gene', (154, 157))	('activating', 'PosReg', (98, 108))	('NTRK2', 'Gene', '4915', (267, 272))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (88, 97))
991	27072750	Indeed, it appears that virtually all pilocytic astrocytomas harbor genetic alterations that activate the Ras-Raf-MEK-ERK signaling pathway.	('alterations', 'Var', (76, 87))	('pilocytic astrocytomas', 'Disease', (38, 60))	('ERK', 'Gene', '2048', (118, 121))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (38, 60))	('ERK', 'Gene', (118, 121))	('Raf', 'Gene', '22882', (110, 113))	('MEK', 'Gene', (114, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('MEK', 'Gene', '5609', (114, 117))	('activate', 'PosReg', (93, 101))	('Raf', 'Gene', (110, 113))
992	27072750	BRAF mutations and the resultant signaling aberrations will be discussed in greater detail below.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('mutations', 'Var', (5, 14))
1005	27072750	Pediatric-type diffuse astrocytomas are genetically distinct from diffuse astrocytomas arising in adult patients, though older teenagers with diffuse astrocytomas arising within the cerebral hemispheres may sometimes have genetic alterations similar to those found in adults.	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('astrocytoma', 'Phenotype', 'HP:0009592', (23, 34))	('astrocytomas', 'Disease', 'MESH:D001254', (150, 162))	('astrocytomas', 'Disease', (23, 35))	('astrocytomas', 'Disease', (74, 86))	('astrocytomas', 'Disease', (150, 162))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))	('genetic alterations', 'Var', (222, 241))	('patients', 'Species', '9606', (104, 112))	('astrocytomas', 'Disease', 'MESH:D001254', (74, 86))	('astrocytomas', 'Disease', 'MESH:D001254', (23, 35))
1006	27072750	The vast majority of grade II and III infiltrative gliomas arising in adult patients harbor IDH1 or IDH2 mutation (most commonly the R132H substitution in IDH1), thought to be an early transforming event during gliomagenesis.	('IDH1', 'Gene', '3417', (155, 159))	('glioma', 'Disease', (211, 217))	('IDH2', 'Gene', (100, 104))	('IDH2', 'Gene', '3418', (100, 104))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('gliomas', 'Disease', (51, 58))	('glioma', 'Disease', (51, 57))	('grade II', 'Disease', (21, 29))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('R132H', 'Mutation', 'rs121913500', (133, 138))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('patients', 'Species', '9606', (76, 84))	('IDH1', 'Gene', (92, 96))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('IDH1', 'Gene', (155, 159))	('IDH1', 'Gene', '3417', (92, 96))	('R132H', 'Var', (133, 138))
1007	27072750	However, IDH mutations are rare in pediatric low-grade astrocytomas, highlighting one of the distinct differences in pathobiology between these adult and pediatric gliomas,.	('pediatric gliomas', 'Disease', 'MESH:D005910', (154, 171))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('astrocytomas', 'Disease', 'MESH:D001254', (55, 67))	('IDH', 'Gene', (9, 12))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('pediatric gliomas', 'Disease', (154, 171))	('IDH', 'Gene', '3417', (9, 12))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('astrocytomas', 'Disease', (55, 67))	('mutations', 'Var', (13, 22))
1008	27072750	Recent genetic analyses of diffuse astrocytomas arising in the cerebral hemispheres of pediatric patients have found rearrangement of MYB or MYBL1 genes, BRAFV600E mutation, and FGFR1 alterations including missense mutations, duplications of the kinase domain, and gene fusions.	('astrocytomas', 'Disease', 'MESH:D001254', (35, 47))	('astrocytoma', 'Phenotype', 'HP:0009592', (35, 46))	('duplications', 'Var', (226, 238))	('missense mutations', 'Var', (206, 224))	('FGFR1', 'Gene', '2260', (178, 183))	('MYB', 'Gene', '4602', (141, 144))	('MYB', 'Gene', (141, 144))	('gene fusions', 'Var', (265, 277))	('astrocytomas', 'Disease', (35, 47))	('MYB', 'Gene', '4602', (134, 137))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))	('MYBL1', 'Gene', (141, 146))	('MYB', 'Gene', (134, 137))	('BRAFV600E mutation', 'Var', (154, 172))	('patients', 'Species', '9606', (97, 105))	('MYBL1', 'Gene', '4603', (141, 146))	('FGFR1', 'Gene', (178, 183))	('rearrangement', 'Var', (117, 130))	('kinase domain', 'MPA', (246, 259))
1009	27072750	MYB and MYBL1 encode transcriptional activator proteins, and the rearrangements of these genes in pediatric gliomas typically lead to truncation of their C-terminal negative regulatory domains causing constitutive activation and altered gene transcription,.	('MYB', 'Gene', (0, 3))	('MYBL1', 'Gene', (8, 13))	('pediatric gliomas', 'Disease', 'MESH:D005910', (98, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('MYB', 'Gene', '4602', (8, 11))	('truncation', 'MPA', (134, 144))	('gene transcription', 'MPA', (237, 255))	('MYB', 'Gene', (8, 11))	('pediatric gliomas', 'Disease', (98, 115))	('rearrangements', 'Var', (65, 79))	('MYBL1', 'Gene', '4603', (8, 13))	('lead to', 'Reg', (126, 133))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('altered', 'Reg', (229, 236))	('MYB', 'Gene', '4602', (0, 3))	('constitutive activation', 'MPA', (201, 224))	('C-terminal negative regulatory domains', 'MPA', (154, 192))
1010	27072750	The rearrangements of MYB and MYBL1 genes have only been found in PLGGs within the cerebral hemispheres and have not been found in pediatric high-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('rearrangements', 'Var', (4, 18))	('gliomas', 'Disease', (152, 159))	('PLGGs', 'Disease', (66, 71))	('found', 'Reg', (57, 62))	('MYB', 'Gene', '4602', (22, 25))	('MYBL1', 'Gene', (30, 35))	('MYB', 'Gene', '4602', (30, 33))	('MYB', 'Gene', (30, 33))	('MYB', 'Gene', (22, 25))	('MYBL1', 'Gene', '4603', (30, 35))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
1012	27072750	thalamus, pons, and spinal cord) frequently harbor missense mutations at codon 27 in either of the H3F3A or HIST1H3B genes, encoding the histone H3 variants, H3.3 and H3.1, respectively,,,,,.	('H3F3A', 'Gene', '3020', (99, 104))	('H3F3A', 'Gene', (99, 104))	('HIST1H3B', 'Gene', (108, 116))	('HIST1H3B', 'Gene', '8358', (108, 116))	('missense mutations', 'Var', (51, 69))
1013	27072750	These missense mutations cause a lysine to methionine substitution, altering a critical site of post-translational modification within these histone H3 variants that leads to altered gene expression profiles thought to contribute to tumorigenesis,.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('methionine', 'Chemical', 'MESH:D008715', (43, 53))	('tumor', 'Disease', (233, 238))	('lysine', 'Chemical', 'MESH:D008239', (33, 39))	('missense mutations', 'Var', (6, 24))	('contribute', 'Reg', (219, 229))	('lysine', 'Var', (33, 39))	('cause', 'Reg', (25, 30))	('histone H3', 'Protein', (141, 151))	('variants', 'Var', (152, 160))	('altering', 'Reg', (68, 76))	('critical site of post-translational modification', 'MPA', (79, 127))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('gene expression profiles', 'MPA', (183, 207))	('altered', 'Reg', (175, 182))
1014	27072750	A mutant-specific antibody for histone H3-K27M mutant protein has been developed for immunohistochemical use and is now routinely used in surgical neuropathology for the identification of the diffuse midline gliomas with this important molecular alteration,,.	('midline gliomas', 'Disease', 'MESH:D005910', (200, 215))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('K27M', 'Mutation', 'p.K27M', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('midline gliomas', 'Disease', (200, 215))	('H3-K27M', 'Var', (39, 46))
1015	27072750	Though only 2% of PLGG as a whole harbor histone H3-K27M mutation, this alteration occurs in a significant subset of low-grade and high-grade diffuse gliomas arising in midline structures where it has significant prognostic implications.	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('K27M', 'Mutation', 'p.K27M', (52, 56))	('histone H3-K27M mutation', 'Var', (41, 65))	('low-grade', 'Disease', (117, 126))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
1016	27072750	In a recent study of diffuse midline gliomas, seven of the nine (78%) pediatric cases that displayed low-grade histologic features at time of initial biopsy were found to have histone H3-K27M mutation.	('histone H3-K27M mutation', 'Var', (176, 200))	('midline gliomas', 'Disease', (29, 44))	('midline gliomas', 'Disease', 'MESH:D005910', (29, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('K27M', 'Mutation', 'p.K27M', (187, 191))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
1019	27072750	Amongst the five patients with K27M+ pontine gliomas that displayed only low-grade histologic features, all experienced disease course typical of diffuse intrinsic pontine glioma (i.e.	('experienced', 'Reg', (108, 119))	('K27M+', 'Var', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('K27M', 'Mutation', 'p.K27M', (31, 35))	('patients', 'Species', '9606', (17, 25))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('glioma', 'Disease', (172, 178))	('glioma', 'Disease', (45, 51))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
1023	27072750	With the exception of a couple rare case reports of children with K27M+ gliomas with indolent behavior,, the vast majority of K27M+ gliomas in children have aggressive clinical course regardless of the grade of histologic features observed in biopsy specimens.	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('children', 'Species', '9606', (52, 60))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('K27M', 'Mutation', 'p.K27M', (126, 130))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('K27M+', 'Var', (126, 131))	('K27M', 'Mutation', 'p.K27M', (66, 70))	('children', 'Species', '9606', (143, 151))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
1024	27072750	This is in contrast to K27M+ gliomas located in the thalamus of adult patients, where histone H3 status does not uniformly appear to portend worse prognosis,.	('patients', 'Species', '9606', (70, 78))	('K27M+', 'Var', (23, 28))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('portend', 'Reg', (133, 140))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('K27M', 'Mutation', 'p.K27M', (23, 27))
1027	27072750	SEGA is virtually always associated with the genetic syndrome tuberous sclerosis, resulting from germline mutations in TSC1 or TSC2, and up to 20% of children with tuberous sclerosis develop SEGAs.	('TSC2', 'Gene', (127, 131))	('SEGA', 'Phenotype', 'HP:0009718', (191, 195))	('associated', 'Reg', (25, 35))	('TSC1', 'Gene', '7248', (119, 123))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (164, 182))	('TSC1', 'Gene', (119, 123))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (62, 80))	('genetic syndrome tuberous sclerosis', 'Disease', (45, 80))	('TSC2', 'Gene', '7249', (127, 131))	('mutations', 'Var', (106, 115))	('SEGAs', 'Disease', (191, 196))	('SEGA', 'Phenotype', 'HP:0009718', (0, 4))	('children', 'Species', '9606', (150, 158))	('tuberous sclerosis', 'Disease', (164, 182))	('genetic syndrome tuberous sclerosis', 'Disease', 'MESH:D014402', (45, 80))
1032	27072750	Whereas virtually all oligodendrogliomas in adult patients have mutation of the IDH1 or IDH2 genes, co-deletion of chromosomes 1p and 19q, TERT promoter mutation, and mutations in CIC or FUBP1, these alterations are uncommon in their pediatric counterpart, being only present in tumors arising in older teenagers.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('mutations', 'Var', (167, 176))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('tumors', 'Disease', (279, 285))	('IDH1', 'Gene', (80, 84))	('CIC', 'Gene', (180, 183))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('FUBP1', 'Gene', '8880', (187, 192))	('TERT', 'Gene', (139, 143))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (22, 40))	('TERT', 'Gene', '7015', (139, 143))	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (50, 58))	('IDH1', 'Gene', '3417', (80, 84))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('CIC', 'Gene', '23152', (180, 183))	('IDH2', 'Gene', (88, 92))	('co-deletion', 'Var', (100, 111))	('oligodendrogliomas', 'Disease', (22, 40))	('IDH2', 'Gene', '3418', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('FUBP1', 'Gene', (187, 192))
1033	27072750	Whole-genome sequencing has found a duplication of the 3' portion of the FGFR1 gene encoding the intracellular kinase domain portion of the protein in 3 of 5 pediatric oligodendrogliomas.	('duplication', 'Var', (36, 47))	('FGFR1', 'Gene', '2260', (73, 78))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (168, 186))	('pediatric oligodendroglioma', 'Disease', (158, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('FGFR1', 'Gene', (73, 78))	('pediatric oligodendroglioma', 'Disease', 'MESH:D009837', (158, 185))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('oligodendrogliomas', 'Disease', (168, 186))
1034	27072750	Other smaller series corroborate the lack of 1p19q co-deletion in pediatric-type oligodendroglioma, with the presence of 1p19q co-deletion occurring only in the "adult-type" usually in older teenagers and young adults,,,.	('oligodendroglioma', 'Disease', 'MESH:D009837', (81, 98))	('1p19q', 'Var', (121, 126))	('1p19q', 'Var', (45, 50))	('oligodendroglioma', 'Disease', (81, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
1039	27072750	The BRAFV600E mutation is present in 15-51% of DNT, and FGFR1 alterations are present in 58-82%.	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('FGFR1', 'Gene', (56, 61))	('FGFR1', 'Gene', '2260', (56, 61))	('DNT', 'Chemical', '-', (47, 50))
1057	27072750	Recently, the MYB-QKI gene fusion was found to be a specific genetic alteration in angiocentric gliomas and was demonstrated to be the single genetic driver of these rare glial tumors.	('MYB', 'Gene', (14, 17))	('glial tumors', 'Disease', (171, 183))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (83, 103))	('fusion', 'Var', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('angiocentric gliomas', 'Disease', (83, 103))	('QKI', 'Gene', (18, 21))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('glial tumors', 'Disease', 'MESH:D005910', (171, 183))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('QKI', 'Gene', '9444', (18, 21))	('MYB', 'Gene', '4602', (14, 17))
1064	27072750	The NF1 syndrome results from mutation of neurofibromin 1 (NF1), a tumor suppressor gene residing on chromosome 17q.	('NF1', 'Gene', '4763', (4, 7))	('neurofibromin 1', 'Gene', (42, 57))	('mutation', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('results from', 'Reg', (17, 29))	('NF1', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('NF1', 'Gene', (4, 7))	('neurofibromin 1', 'Gene', '4763', (42, 57))	('tumor', 'Disease', (67, 72))	('NF1', 'Gene', '4763', (59, 62))
1065	27072750	The majority of NF1 mutations result in protein truncation, causing disruption of its functional domain, Ras-GAP related-domain (Ras-GRD).	('NF1', 'Gene', (16, 19))	('NF1', 'Gene', '4763', (16, 19))	('protein truncation', 'MPA', (40, 58))	('result in', 'Reg', (30, 39))	('functional domain', 'MPA', (86, 103))	('disruption', 'NegReg', (68, 78))	('Ras-GAP related-domain', 'MPA', (105, 127))	('mutations', 'Var', (20, 29))
1067	27072750	Truncation of NF1 and disruption of Ras-GRD results in dysregulation of the Raf and PI3K pathways and promotion of cellular proliferation,.	('PI3', 'Gene', '5266', (84, 87))	('dysregulation', 'MPA', (55, 68))	('NF1', 'Gene', '4763', (14, 17))	('cellular proliferation', 'CPA', (115, 137))	('disruption', 'Var', (22, 32))	('Truncation', 'Var', (0, 10))	('PI3', 'Gene', (84, 87))	('Raf', 'Gene', '22882', (76, 79))	('promotion', 'PosReg', (102, 111))	('Ras-GRD', 'Protein', (36, 43))	('NF1', 'Gene', (14, 17))	('Raf', 'Gene', (76, 79))
1068	27072750	Indeed, dysregulation of the Ras-Raf-MAP kinase pathway plays an important role in the molecular pathogenesis of PLGG.	('dysregulation', 'Var', (8, 21))	('Raf', 'Gene', (33, 36))	('PLGG', 'Disease', (113, 117))	('Raf', 'Gene', '22882', (33, 36))
1071	27072750	There have been two major BRAF genomic alterations characterized in PLGG, the BRAFV600E missense mutation and BRAF gene duplication/fusions.	('gene duplication/fusions', 'Var', (115, 139))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', (26, 30))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('BRAF', 'Gene', '673', (110, 114))	('missense mutation', 'Var', (88, 105))	('BRAF', 'Gene', (110, 114))
1072	27072750	The BRAFV600E mutation results from replacement of valine by glutamic acid within the activation loop of the enzyme.	('BRAFV600E', 'Var', (4, 13))	('results from', 'Reg', (23, 35))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('valine', 'Chemical', 'MESH:D014633', (51, 57))	('glutamic acid', 'Chemical', 'MESH:D018698', (61, 74))	('glutamic', 'Protein', (61, 69))	('valine', 'MPA', (51, 57))
1074	27072750	The BRAFV600E mutation is sufficient for NIH3T3 fibroblast transformation in vitro.	('NIH3T3', 'CellLine', 'CVCL:0594', (41, 47))	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('NIH3T3 fibroblast transformation', 'CPA', (41, 73))
1075	27072750	Interestingly, BRAFV600E also promotes proliferative transformation of human neural stem cells followed by senescence, and it has been hypothesized that this "oncogene-induced senescence" may be one underlying mechanism for the low-grade pathogenesis of pilocytic astrocytomas,.	('pilocytic astrocytomas', 'Disease', (254, 276))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (254, 276))	('promotes', 'PosReg', (30, 38))	('proliferative transformation', 'CPA', (39, 67))	('BRAFV600E', 'Var', (15, 24))	('BRAFV600E', 'Mutation', 'rs113488022', (15, 24))	('astrocytoma', 'Phenotype', 'HP:0009592', (264, 275))	('senescence', 'CPA', (107, 117))	('human', 'Species', '9606', (71, 76))
1076	27072750	In the whole-genome sequencing study by Zhang and colleagues, BRAFV600E mutations were detected in 70% of pleomorphic xanthoastrocytomas, 23% of diffuse astrocytomas, 33% of gangliogliomas, and 6% of pilocytic astrocytomas.	('astrocytomas', 'Disease', (153, 165))	('astrocytomas', 'Disease', 'MESH:D001254', (210, 222))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('astrocytoma', 'Phenotype', 'HP:0009592', (153, 164))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('mutations', 'Var', (72, 81))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (62, 71))	('pleomorphic xanthoastrocytomas', 'Disease', (106, 136))	('ganglioglioma', 'Disease', 'MESH:D018303', (174, 187))	('astrocytomas', 'Disease', (124, 136))	('astrocytomas', 'Disease', 'MESH:D001254', (153, 165))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('pilocytic astrocytomas', 'Disease', (200, 222))	('astrocytomas', 'Disease', (210, 222))	('BRAFV600E mutations', 'Var', (62, 81))	('detected', 'Reg', (87, 95))	('ganglioglioma', 'Disease', (174, 187))	('astrocytomas', 'Disease', 'MESH:D001254', (124, 136))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (200, 222))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('gliomas', 'Disease', (181, 188))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (106, 136))
1077	27072750	In addition to the BRAFV600E missense mutation, genetic duplication/fusion mutations are common in PLGG.	('BRAFV600E', 'Var', (19, 28))	('BRAFV600E', 'Mutation', 'rs113488022', (19, 28))	('PLGG', 'Disease', (99, 103))	('common', 'Reg', (89, 95))	('genetic duplication/fusion mutations', 'Var', (48, 84))
1080	27072750	Over 90% of pilocytic astrocytomas arising in the cerebellum in children without NF1 have BRAF-KIAA1549 gene fusions, whereas approximately half of pilocytic astrocytomas arising outside the cerebellum have the BRAF-KIAA1549 fusion,.	('BRAF-KIAA1549', 'Disease', 'None', (90, 103))	('BRAF-KIAA1549', 'Disease', (90, 103))	('BRAF-KIAA1549', 'Disease', 'None', (211, 224))	('BRAF-KIAA1549', 'Disease', (211, 224))	('NF1', 'Gene', (81, 84))	('fusions', 'Var', (109, 116))	('NF1', 'Gene', '4763', (81, 84))	('pilocytic astrocytomas', 'Disease', (148, 170))	('pilocytic astrocytomas', 'Disease', (12, 34))	('children', 'Species', '9606', (64, 72))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (148, 170))	('astrocytoma', 'Phenotype', 'HP:0009592', (22, 33))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (12, 34))	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))
1082	27072750	Tuberous sclerosis results from germline mutations in either of the genes hamartin (TSC1) or tuberin (TSC2),,, and SEGA is strongly associated with tuberous sclerosis.	('TSC2', 'Gene', (102, 106))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('TSC1', 'Gene', '7248', (84, 88))	('Tuberous sclerosis', 'Disease', (0, 18))	('results from', 'Reg', (19, 31))	('germline mutations', 'Var', (32, 50))	('tuberin', 'Gene', (93, 100))	('SEGA', 'Phenotype', 'HP:0009718', (115, 119))	('tuberous sclerosis', 'Disease', (148, 166))	('TSC1', 'Gene', (84, 88))	('TSC2', 'Gene', '7249', (102, 106))	('associated', 'Reg', (132, 142))	('tuberin', 'Gene', '7249', (93, 100))	('hamartin', 'Gene', '7248', (74, 82))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (148, 166))	('hamartin', 'Gene', (74, 82))
1085	27072750	Mutations in TSC1 or TSC2 can result in loss of function of the protein complex, resulting in unopposed activation of Rheb-GTP.	('Rheb', 'Gene', (118, 122))	('activation', 'PosReg', (104, 114))	('TSC2', 'Gene', (21, 25))	('TSC1', 'Gene', '7248', (13, 17))	('protein complex', 'Protein', (64, 79))	('Mutations', 'Var', (0, 9))	('Rheb', 'Gene', '6009', (118, 122))	('TSC1', 'Gene', (13, 17))	('loss of function', 'NegReg', (40, 56))	('TSC2', 'Gene', '7249', (21, 25))	('GTP', 'Chemical', 'MESH:D006160', (123, 126))
1087	27072750	Sporadic mutations within the mTOR signaling pathway in children without tuberous sclerosis have also been shown to be important in the pathogenesis in PLGG.	('important', 'Reg', (119, 128))	('tuberous sclerosis', 'Disease', (73, 91))	('PLGG', 'Disease', (152, 156))	('children', 'Species', '9606', (56, 64))	('mutations', 'Var', (9, 18))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (73, 91))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))
1092	27072750	Approximately half of PLGG show enhanced expression of phospho-S6 and phospho-EBP1, and expression of these two proteins is associated with worse progression-free survival.	('EBP1', 'Gene', (78, 82))	('EBP1', 'Gene', '4790', (78, 82))	('expression', 'MPA', (41, 51))	('progression-free survival', 'CPA', (146, 171))	('enhanced', 'PosReg', (32, 40))	('PLGG', 'Gene', (22, 26))	('phospho-S6', 'Var', (55, 65))
1096	27072750	Akt phosphorylation is associated with a more clinically aggressive pilocytic astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (78, 89))	('aggressive pilocytic astrocytoma', 'Disease', 'MESH:D001254', (57, 89))	('aggressive pilocytic astrocytoma', 'Disease', (57, 89))	('Akt', 'Gene', '207', (0, 3))	('associated', 'Reg', (23, 33))	('Akt', 'Gene', (0, 3))	('phosphorylation', 'Var', (4, 19))
1097	27072750	Both the Ras-Raf-MAP kinase and mTOR pathways are affected by alterations of the FGFR1 gene that encodes the transmembrane receptor tyrosine kinase fibroblast growth factor receptor 1.	('FGFR1', 'Gene', (81, 86))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('Raf', 'Gene', (13, 16))	('FGFR1', 'Gene', '2260', (81, 86))	('Raf', 'Gene', '22882', (13, 16))	('alterations', 'Var', (62, 73))	('affected', 'Reg', (50, 58))
1098	27072750	A variety of FGFR1 alterations have been found in PLGG including somatic missense mutations, duplication of the 3' portion of the gene encoding the kinase domain, and rearrangement usually involving fusion with TACC genes.	('found', 'Reg', (41, 46))	('PLGG', 'Disease', (50, 54))	('FGFR1', 'Gene', (13, 18))	('duplication', 'Var', (93, 104))	('alterations', 'Var', (19, 30))	('FGFR1', 'Gene', '2260', (13, 18))	('missense mutations', 'Var', (73, 91))	('rearrangement', 'Var', (167, 180))
1099	27072750	These alterations in FGFR1 lead to its constitutive activation of downstream signaling pathways including both Ras-Raf-MEK-ERK and PI3K-Akt-mTOR.	('MEK', 'Gene', (119, 122))	('alterations', 'Var', (6, 17))	('MEK', 'Gene', '5609', (119, 122))	('PI3', 'Gene', (131, 134))	('Raf', 'Gene', (115, 118))	('FGFR1', 'Gene', (21, 26))	('Akt', 'Gene', '207', (136, 139))	('PI3', 'Gene', '5266', (131, 134))	('Raf', 'Gene', '22882', (115, 118))	('ERK', 'Gene', (123, 126))	('ERK', 'Gene', '2048', (123, 126))	('FGFR1', 'Gene', '2260', (21, 26))	('mTOR', 'Gene', (140, 144))	('Akt', 'Gene', (136, 139))	('mTOR', 'Gene', '2475', (140, 144))	('downstream signaling pathways', 'Pathway', (66, 95))	('activation', 'PosReg', (52, 62))
1100	27072750	Elucidation of oncogenic mutations within the Ras-Raf-MAP kinase and PI3-kinase-AKT-mTOR pathways has led to the development of agents that specifically target oncogenic proteins within these pathways for the treatment of pediatric gliomas.	('mutations', 'Var', (25, 34))	('Raf', 'Gene', (50, 53))	('AKT', 'Gene', '207', (80, 83))	('pediatric gliomas', 'Disease', (222, 239))	('gliomas', 'Phenotype', 'HP:0009733', (232, 239))	('mTOR', 'Gene', '2475', (84, 88))	('PI3-kinase', 'Gene', '5293', (69, 79))	('AKT', 'Gene', (80, 83))	('mTOR', 'Gene', (84, 88))	('PI3-kinase', 'Gene', (69, 79))	('Raf', 'Gene', '22882', (50, 53))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('pediatric gliomas', 'Disease', 'MESH:D005910', (222, 239))
1102	27072750	The enzyme inhibitor vemurafenib specifically inhibits BRAFV600E from activating MEK, and has been shown to have strong clinical activity in BRAFV600E positive melanoma.	('BRAFV600E positive', 'Var', (141, 159))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('vemurafenib', 'Chemical', 'MESH:D000077484', (21, 32))	('melanoma', 'Disease', (160, 168))	('BRAFV600E', 'Var', (55, 64))	('BRAFV600E', 'Mutation', 'rs113488022', (141, 150))	('activating', 'MPA', (70, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('inhibits', 'NegReg', (46, 54))	('MEK', 'Gene', (81, 84))	('MEK', 'Gene', '5609', (81, 84))
1104	27072750	A multicenter trial under the auspices of the Pacific Pediatric Neuro-Oncology Consortium (PNOC002) is enrolling children with recurrent or refractory BRAFV600E gliomas to evaluate the safety and pharmacokinetic characteristics of vemurafenib.	('BRAFV600E', 'Var', (151, 160))	('BRAFV600E', 'Mutation', 'rs113488022', (151, 160))	('Oncology', 'Phenotype', 'HP:0002664', (70, 78))	('PNOC', 'Gene', '5368', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('children', 'Species', '9606', (113, 121))	('gliomas', 'Disease', (161, 168))	('vemurafenib', 'Chemical', 'MESH:D000077484', (231, 242))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('PNOC', 'Gene', (91, 95))
1105	27072750	Dabrafenib is a selective ATP-competitive inhibitor of the BRAFV600E kinase, approved in unresectable or metastatic melanoma with the BRAFV600E mutation.	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('ATP', 'Chemical', 'MESH:D000255', (26, 29))	('BRAFV600E', 'Gene', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('BRAFV600E', 'Var', (134, 143))	('BRAFV600E', 'Mutation', 'rs113488022', (134, 143))
1106	27072750	NCT01677741 is currently enrolling children with BRAFV600E positive relapsed or refractory solid tumors, including high-grade and low-grade gliomas (Table 1).	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('solid tumors', 'Disease', 'MESH:D009369', (91, 103))	('BRAFV600E', 'Var', (49, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('solid tumors', 'Disease', (91, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))	('high-grade', 'Disease', (115, 125))	('children', 'Species', '9606', (35, 43))
1110	27072750	A proportion of BRAF mutated tumors have BRAF mutations other than the V600E missense mutation, including alternative missense mutations, duplications, fusions, and deletions that have been shown to decrease the efficacy of BRAFV600E-targeted inhibition.	('BRAFV600E', 'Mutation', 'rs113488022', (224, 233))	('fusions', 'Var', (152, 159))	('V600E', 'Mutation', 'rs113488022', (228, 233))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('deletions', 'Var', (165, 174))	('decrease', 'NegReg', (199, 207))	('BRAF', 'Gene', '673', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('BRAF', 'Gene', (224, 228))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', (41, 45))	('duplications', 'Var', (138, 150))	('tumors', 'Disease', (29, 35))	('BRAF', 'Gene', '673', (224, 228))
1111	27072750	For instance, in cells expressing KIAA1549-BRAF, these fusion kinases function as homodimers that are resistant to PLX4720 (a research analog of vemurafenib), and PLX4720 leads to paradoxical activation of MEK and ERK.	('KIAA1549', 'Gene', (34, 42))	('MEK', 'Gene', (206, 209))	('KIAA1549', 'Gene', '57670', (34, 42))	('BRAF', 'Gene', '673', (43, 47))	('vemurafenib', 'Chemical', 'MESH:D000077484', (145, 156))	('MEK', 'Gene', '5609', (206, 209))	('BRAF', 'Gene', (43, 47))	('ERK', 'Gene', (214, 217))	('activation', 'PosReg', (192, 202))	('ERK', 'Gene', '2048', (214, 217))	('PLX4720', 'Var', (163, 170))
1112	27072750	However, some tumors harboring BRAF alteration do have sensitivity to MEK inhibition.	('alteration', 'Var', (36, 46))	('sensitivity', 'MPA', (55, 66))	('MEK', 'Gene', (70, 73))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('BRAF', 'Gene', '673', (31, 35))	('MEK', 'Gene', '5609', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BRAF', 'Gene', (31, 35))
1114	27072750	Selumetinib (AZD6244), another MEK inhibitor, has been shown to have activity against a pilocytic astrocytoma xenograft harboring the BRAFV600E mutation.	('astrocytoma', 'Phenotype', 'HP:0009592', (98, 109))	('activity', 'MPA', (69, 77))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (88, 109))	('AZD6244', 'Chemical', 'MESH:C517975', (13, 20))	('BRAFV600E', 'Var', (134, 143))	('BRAFV600E', 'Mutation', 'rs113488022', (134, 143))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('pilocytic astrocytoma', 'Disease', (88, 109))
1119	27072750	A clinical response to sirolimus in a tuberous sclerosis child with SEGA harboring a TSC2 gene mutation was first reported in 2008.	('tuberous sclerosis', 'Disease', 'MESH:D014402', (38, 56))	('child', 'Species', '9606', (57, 62))	('SEGA', 'Phenotype', 'HP:0009718', (68, 72))	('sirolimus', 'Chemical', 'MESH:D020123', (23, 32))	('tuberous sclerosis', 'Disease', (38, 56))	('TSC2', 'Gene', (85, 89))	('TSC2', 'Gene', '7249', (85, 89))	('mutation', 'Var', (95, 103))
1152	27072750	Sporadic pilocytic astrocytomas arising in the posterior fossa harbor BRAF duplication and gene fusion.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('Sporadic pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 31))	('Sporadic pilocytic astrocytomas', 'Disease', (0, 31))	('BRAF', 'Gene', '673', (70, 74))	('gene fusion', 'Var', (91, 102))	('BRAF', 'Gene', (70, 74))
1153	27072750	Outside the posterior fossa sporadic pilocytic astrocytomas lacking BRAF duplication and gene fusion may harbor the BRAFV600E missense mutation, NF1 or PTPN11 somatic mutations, activating FGFR1 mutations, and gene fusions involving NTRK2.	('PTPN11', 'Gene', '5781', (152, 158))	('NTRK2', 'Gene', '4915', (233, 238))	('sporadic pilocytic astrocytomas', 'Disease', 'MESH:D001254', (28, 59))	('FGFR1', 'Gene', (189, 194))	('BRAFV600E', 'Mutation', 'rs113488022', (116, 125))	('sporadic pilocytic astrocytomas', 'Disease', (28, 59))	('NF1', 'Gene', '4763', (145, 148))	('BRAF', 'Gene', '673', (68, 72))	('BRAF', 'Gene', '673', (116, 120))	('gene fusions', 'Var', (210, 222))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', (116, 120))	('NTRK2', 'Gene', (233, 238))	('mutations', 'Var', (195, 204))	('NF1', 'Gene', (145, 148))	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('activating', 'PosReg', (178, 188))	('FGFR1', 'Gene', '2260', (189, 194))	('PTPN11', 'Gene', (152, 158))
1154	27072750	Virtually all pilocytic astrocytomas harbor genetic alterations that activate the Ras-Raf-MEK-ERK signaling pathway.	('ERK', 'Gene', (94, 97))	('pilocytic astrocytomas', 'Disease', (14, 36))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (14, 36))	('activate', 'PosReg', (69, 77))	('Raf', 'Gene', '22882', (86, 89))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('genetic alterations', 'Var', (44, 63))	('MEK', 'Gene', (90, 93))	('MEK', 'Gene', '5609', (90, 93))	('Raf', 'Gene', (86, 89))	('ERK', 'Gene', '2048', (94, 97))
1157	27072750	Immunohistochemistry for histone H3-K27M mutant protein plays an important role in the diagnosis of midline diffuse gliomas, as this mutation is associated with a poor prognosis.	('midline diffuse gliomas', 'Disease', 'MESH:D005910', (100, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('K27M', 'Mutation', 'p.K27M', (36, 40))	('H3-K27M', 'Var', (33, 40))	('midline diffuse gliomas', 'Disease', (100, 123))
1160	27072750	IDH1/IDH2 mutations, co-deletion of chromosomes 1p and 19q, TERT promoter mutation, and mutations in CIC or FUBP1 are rare in children.	('CIC', 'Gene', '23152', (101, 104))	('IDH1', 'Gene', '3417', (0, 4))	('IDH2', 'Gene', (5, 9))	('TERT', 'Gene', '7015', (60, 64))	('CIC', 'Gene', (101, 104))	('mutations', 'Var', (88, 97))	('FUBP1', 'Gene', '8880', (108, 113))	('children', 'Species', '9606', (126, 134))	('FUBP1', 'Gene', (108, 113))	('IDH2', 'Gene', '3418', (5, 9))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('TERT', 'Gene', (60, 64))	('co-deletion', 'Var', (21, 32))
1161	27072750	Up to 60% of ganglioglioma tumors harbor the BRAFV600E mutation.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('BRAFV600E', 'Var', (45, 54))	('BRAFV600E', 'Mutation', 'rs113488022', (45, 54))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('ganglioglioma tumors', 'Disease', (13, 33))	('ganglioglioma tumors', 'Disease', 'MESH:D018303', (13, 33))
1165	27072750	Majority of NF1 mutations result in protein truncation, causing disruption in its ability to regulate the Ras-Raf-MEK-ERK signaling pathway.	('ERK', 'Gene', '2048', (118, 121))	('NF1', 'Gene', (12, 15))	('ERK', 'Gene', (118, 121))	('NF1', 'Gene', '4763', (12, 15))	('result in', 'Reg', (26, 35))	('ability', 'MPA', (82, 89))	('mutations', 'Var', (16, 25))	('MEK', 'Gene', (114, 117))	('regulate', 'MPA', (93, 101))	('MEK', 'Gene', '5609', (114, 117))	('Raf', 'Gene', '22882', (110, 113))	('disruption', 'NegReg', (64, 74))	('protein', 'Protein', (36, 43))	('Raf', 'Gene', (110, 113))
1168	27072750	Tuberous sclerosis results from germline mutations in TSC1 or TSC2.	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('Tuberous sclerosis', 'Disease', (0, 18))	('results from', 'Reg', (19, 31))	('germline mutations', 'Var', (32, 50))	('TSC1', 'Gene', '7248', (54, 58))	('TSC2', 'Gene', '7249', (62, 66))	('TSC2', 'Gene', (62, 66))	('TSC1', 'Gene', (54, 58))
1169	27072750	Mutations in TSC1 or TSC2 lead to disinhibited activation of the PI3-Akt-mTOR signaling cascade, promoting SEGA  tumorigenesis.	('Akt', 'Gene', (69, 72))	('tumor', 'Disease', (113, 118))	('mTOR', 'Gene', '2475', (73, 77))	('SEGA', 'Phenotype', 'HP:0009718', (107, 111))	('SEGA', 'Disease', (107, 111))	('TSC2', 'Gene', (21, 25))	('mTOR', 'Gene', (73, 77))	('TSC1', 'Gene', '7248', (13, 17))	('promoting', 'PosReg', (97, 106))	('PI3', 'Gene', '5266', (65, 68))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('TSC1', 'Gene', (13, 17))	('Akt', 'Gene', '207', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TSC2', 'Gene', '7249', (21, 25))	('PI3', 'Gene', (65, 68))
1172	27072750	Vemurafenib specifically inhibits BRAFV600E from activating MEK.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('MEK', 'Gene', '5609', (60, 63))	('inhibits', 'NegReg', (25, 33))	('activating', 'MPA', (49, 59))	('BRAFV600E', 'Var', (34, 43))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('MEK', 'Gene', (60, 63))
1176	27072750	Genome sequencing and identification of genetic alterations in PLGG subtypes are changing the way these tumors are diagnosed, prognosticated, and managed.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PLGG', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('changing', 'Reg', (81, 89))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('genetic alterations', 'Var', (40, 59))
1180	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))
1181	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))
1185	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))
1213	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-503', 'Gene', '574506', (68, 75))	('miR-196a', 'Var', (58, 66))
1215	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))
1216	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))
1217	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))
1218	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))
1220	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))
1221	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))
1225	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))	('snail family transcriptional repressor 2', 'Gene', '6591', (43, 83))	('SNAI2', 'Gene', '6591', (124, 129))	('JAK2', 'Gene', '3717', (204, 208))	('SUZ12', 'Gene', (132, 137))	('targeting', 'Reg', (114, 123))	('Janus kinase 2', 'Gene', (188, 202))
1255	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))
1267	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))
1287	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))	('TGF-beta', 'Gene', (73, 81))	('induce', 'PosReg', (161, 167))	('mesenchymal transition', 'CPA', (172, 194))	('T7039', 'Var', (0, 5))
1298	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))
1314	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))
1350	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))
1353	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))
1366	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))
1368	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))
1375	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))
1385	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))
1387	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))	('U87mg cells', 'Var', (40, 51))	('CD66b', 'Gene', (91, 96))	('CD45', 'Gene', '5788', (78, 82))
1395	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))
1399	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))
1425	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))
1431	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))
1436	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))
1438	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))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (36, 64))	('RB1', 'Gene', (96, 99))	('Patient', 'Species', '9606', (0, 7))	('mutation', 'Var', (80, 88))
1439	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))
1440	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))
1442	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))
1444	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))
1445	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))
1446	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))
1448	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))
1449	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))
1450	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))
1451	31466397	Consequently, neuroblastoma patients with ALK mutations show poorer overall survival.	('neuroblastoma', 'Disease', (14, 27))	('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))	('patients', 'Species', '9606', (28, 36))	('poorer', 'NegReg', (61, 67))	('overall', 'MPA', (68, 75))
1452	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))	('p.R1275 mutations', 'Var', (116, 133))	('neuroblastoma', 'Disease', (81, 94))	('ALK', 'Gene', (159, 162))	('ALK', 'Gene', '238', (53, 56))	('crizotinib', 'Chemical', 'MESH:C551994', (183, 193))	('sensitivity', 'MPA', (139, 150))
1453	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))
1458	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))
1459	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))
1478	31316099	Wide-field fluorescence guided brain tumor surgery, most notably with 5-aminolevulinic acid (5-ALA), has been shown to improve extent of resection for patients with glioblastoma and is easily incorporated into a standard surgical workflow.	('improve', 'PosReg', (119, 126))	('extent of resection', 'CPA', (127, 146))	('5-aminolevulinic acid', 'Var', (70, 91))	('glioblastoma', 'Disease', (165, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (165, 177))	('patients', 'Species', '9606', (151, 159))	('brain tumor', 'Disease', 'MESH:D001932', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('brain tumor', 'Disease', (31, 42))	('5-ALA', 'Chemical', 'MESH:C000614854', (93, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (165, 177))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (70, 91))	('brain tumor', 'Phenotype', 'HP:0030692', (31, 42))
1613	28116517	The water frequency shift due to field inhomogeneity was measured in a separate scan using the water saturation shift referencing method with 21 offset frequencies ranging from -1.25 ppm to 1.25 ppm at a step of 0.125 ppm (16 Hz) and one reference scan without a saturation RF pulse resulting in a full z spectrum within the offset range.	('water', 'Chemical', 'MESH:D014867', (4, 9))	('water', 'Chemical', 'MESH:D014867', (95, 100))	('full z spectrum', 'MPA', (298, 313))	('1.25 ppm', 'Var', (190, 198))
1621	28116517	The data for the offsets (+4, +3.5, +3 ppm) and (-3, -3.5, -4 ppm) for each voxel were interpolated to 385 points over a frequency offset range from +5 to +2 ppm and from -2 to -5 ppm, respectively, and shifted using the fitted water saturation shift referencing central frequency offset at the same voxel.	('+4', 'Var', (26, 28))	('water', 'Chemical', 'MESH:D014867', (228, 233))	('-3', 'Var', (49, 51))
1687	25062303	Recurrence after gross-total resection of low-grade pediatric brain tumors: the frequency and timing of postoperative imaging Low-grade glial and glioneuronal brain tumors are frequently encountered in the pediatric population and can be effectively treated by resection.	('brain tumors', 'Disease', (62, 74))	('Low-grade', 'Var', (126, 135))	('brain tumor', 'Phenotype', 'HP:0030692', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('brain tumor', 'Phenotype', 'HP:0030692', (62, 73))	('brain tumors', 'Disease', 'MESH:D001932', (159, 171))	('brain tumors', 'Disease', 'MESH:D001932', (62, 74))	('brain tumors', 'Phenotype', 'HP:0030692', (62, 74))	('brain tumors', 'Phenotype', 'HP:0030692', (159, 171))	('brain tumors', 'Disease', (159, 171))	('glial and glioneuronal brain tumors', 'Phenotype', 'HP:0025170', (136, 171))
1745	25062303	Among the patients in whom recurrence was observed, we found that nodular FLAIR signal in the tumor cavity on the immediate postoperative MR image that persisted to the first interval postoperative MR image might be a useful marker for recurrence.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('nodular', 'Var', (66, 73))	('patients', 'Species', '9606', (10, 18))
1790	25062303	An earlier report by Dorward and colleagues described early nodular enhancement at 3-6 months, high Ki 67 labeling index, and CD68 positivity as potential predictors of recurrence in patients with JPA following GTR.	('CD68', 'Gene', (126, 130))	('JPA', 'Disease', (197, 200))	('positivity', 'Var', (131, 141))	('enhancement', 'PosReg', (68, 79))	('GTR', 'Chemical', '-', (211, 214))	('patients', 'Species', '9606', (183, 191))	('CD68', 'Gene', '968', (126, 130))
1873	26410079	Duration of surgery, measured from skin incision to wound closure, was significantly longer in the iMRI group (median 540 min (range 300-840)) than it was in the conventional group (median 300 min (range 240-720)), due to further removal of residual tumor and preparing and scanning time needed in the iMRI group (p < 0.001; Fig.	('longer', 'PosReg', (85, 91))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('iMRI', 'Var', (99, 103))
1878	26410079	Permanent deficits developed in 4 patients (10.3 %) in the iMRI group, compared with 2 patients (16.7 %) in the conventional group (p = 0.928).	('iMRI', 'Var', (59, 63))	('Permanent deficits', 'Disease', 'MESH:D003638', (0, 18))	('Permanent deficits', 'Disease', (0, 18))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (87, 95))
1894	26410079	Since surgery is the first therapeutic option to consider in LGG, the impact of surgery has been studied in numerous literature, supporting the significant effect of EOR on overall survival (OS) by delaying anaplastic transformation, even in incomplete tumor removal.	('anaplastic transformation', 'CPA', (207, 232))	('EOR', 'Var', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('overall survival', 'MPA', (173, 189))	('OS', 'Chemical', '-', (191, 193))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('delaying', 'NegReg', (198, 206))
1938	26410079	Further, some studies reported similar seizure outcome between groups regarding the resection of hippocampus and amygdala.	('seizure', 'Disease', 'MESH:D012640', (39, 46))	('resection', 'Var', (84, 93))	('seizure', 'Disease', (39, 46))	('seizure', 'Phenotype', 'HP:0001250', (39, 46))
1944	26410079	Reducing an epileptogenic mass involving these regions was more likely to include excision of the mesial temporal structures and the insular cortex and might possibly resulting in disconnection of critical seizure propagation pathways.	('excision', 'Var', (82, 90))	('seizure', 'Disease', (206, 213))	('seizure', 'Disease', 'MESH:D012640', (206, 213))	('epileptogenic', 'Disease', (12, 25))	('seizure', 'Phenotype', 'HP:0001250', (206, 213))	('disconnection', 'NegReg', (180, 193))
2073	32640583	Image parameters according to IDH mutation status.	('IDH', 'Gene', '3417', (30, 33))	('mutation', 'Var', (34, 42))	('IDH', 'Gene', (30, 33))
2078	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))
2079	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))
2080	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))
2081	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))
2089	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))
2090	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))
2093	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))
2118	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))	('IDH1', 'Gene', '3417', (13, 17))	('IDH', 'Gene', '3417', (22, 25))	('glioblastomas', 'Disease', 'MESH:D005909', (146, 159))	('IDH', 'Gene', '3417', (13, 16))
2119	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))
2128	30926639	Eighty-five per cent of mutations found by T200 were also detected on T200.1.	('T200', 'Gene', '5788', (43, 47))	('T200', 'Gene', (70, 74))	('mutations', 'Var', (24, 33))	('T200', 'Gene', (43, 47))	('T200', 'Gene', '5788', (70, 74))
2129	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))
2131	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))	('1p/19q', 'Var', (40, 46))	('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))	('IDH', 'Gene', (85, 88))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))
2133	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))
2134	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))
2135	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))
2136	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))
2138	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))
2139	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))
2144	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))
2145	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))
2147	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))
2148	30926639	We found EGFR mutations evenly distributed across the groups.	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
2149	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))
2151	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))
2154	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))
2156	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))
2159	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))
2160	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))
2163	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))	('IDH', 'Gene', '3417', (42, 45))	('IDH2', 'Gene', '3418', (97, 101))	('R172', 'Var', (89, 93))	('R332', 'Var', (73, 77))	('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))
2164	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))
2165	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))
2168	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))
2171	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))
2175	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))
2177	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))
2178	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))
2180	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))
2190	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))
2208	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))
2209	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))
2213	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))
2215	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))
2216	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))	('facilitate', 'PosReg', (55, 65))	('elicit', 'Reg', (106, 112))	('immune cell infiltration', 'CPA', (122, 146))	('neoantigens', 'MPA', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('more', 'PosReg', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
2222	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))
2227	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', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
2239	29896307	Image-guided paclitaxel injection after nanoagonist-mediated BBB modulation more efficiently attenuated tumor growth and extended survival than in animal models treated with paclitaxel or temozolomide alone.	('temozolomide', 'Chemical', 'MESH:D000077204', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('modulation', 'Var', (65, 75))	('attenuated tumor', 'Disease', (93, 109))	('survival', 'CPA', (130, 138))	('attenuated tumor', 'Disease', 'MESH:C538265', (93, 109))	('paclitaxel', 'Chemical', 'MESH:D017239', (174, 184))	('extended', 'PosReg', (121, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (13, 23))
2247	29896307	However, non-selective BBB disruption results in complications such as epileptic seizures and brain edema.	('edema', 'Phenotype', 'HP:0000969', (100, 105))	('non-selective', 'Var', (9, 22))	('seizures', 'Phenotype', 'HP:0001250', (81, 89))	('results in', 'Reg', (38, 48))	('brain edema', 'Phenotype', 'HP:0002181', (94, 105))	('brain edema', 'Disease', (94, 105))	('epileptic seizures', 'Disease', (71, 89))	('brain edema', 'Disease', 'MESH:D001929', (94, 105))	('epileptic seizures', 'Disease', 'MESH:D004827', (71, 89))
2280	29896307	Nanoagonists induced ASF assembly more efficiently than regadenoson.	('induced', 'Reg', (13, 20))	('Nanoagonists', 'Var', (0, 12))	('ASF', 'Gene', '110809', (21, 24))	('regadenoson', 'Chemical', 'MESH:C430916', (56, 67))	('ASF', 'Gene', (21, 24))
2284	29896307	Phosphorylation of myosin light chain (MLC) protein triggers the formation of ASF from short F-actins to elicit cytoskeletal contraction.	('elicit', 'Reg', (105, 111))	('Phosphorylation', 'Var', (0, 15))	('MLC', 'Gene', '170790', (39, 42))	('MLC', 'Gene', (39, 42))	('ASF', 'Gene', '110809', (78, 81))	('ASF', 'Gene', (78, 81))	('myosin light chain', 'Gene', (19, 37))	('cytoskeletal contraction', 'CPA', (112, 136))	('short F-actins', 'Protein', (87, 101))	('myosin light chain', 'Gene', '170790', (19, 37))
2288	29896307	injection (39.3 mg/mouse) in mice bearing orthotopic U87MG glioma xenografts (Figure S4).	('glioma xenograft', 'Disease', (59, 75))	('glioma xenograft', 'Disease', 'MESH:D005910', (59, 75))	('U87MG', 'CellLine', 'CVCL:0022', (53, 58))	('U87MG', 'Var', (53, 58))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('mouse', 'Species', '10090', (19, 24))	('mice', 'Species', '10090', (29, 33))
2298	29896307	Compared with the Ktrans map post treatment with Gd3+-DTPA alone, the combined treatment of nanoagonist followed by Gd3+-DTPA remarkably enhanced the Ktrans signal in both the glioma parenchyma and margin but not in the normal brain tissue (Figure 4B).	('enhanced', 'PosReg', (137, 145))	('glioma parenchyma', 'Disease', 'MESH:D005910', (176, 193))	('glioma parenchyma', 'Disease', (176, 193))	('Gd3+-DTPA', 'Chemical', '-', (116, 125))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('Ktrans', 'Chemical', '-', (18, 24))	('Ktrans signal', 'MPA', (150, 163))	('Gd3+-DTPA', 'Chemical', '-', (49, 58))	('Ktrans', 'Chemical', '-', (150, 156))	('Gd3+-DTPA', 'Var', (116, 125))
2320	29896307	However, the non-specific BBB breakdown leads to potential risks such as epileptic seizures and vasogenic edema.	('edema', 'Disease', (106, 111))	('epileptic seizures', 'Disease', (73, 91))	('seizures', 'Phenotype', 'HP:0001250', (83, 91))	('breakdown', 'Var', (30, 39))	('edema', 'Disease', 'MESH:D004487', (106, 111))	('epileptic seizures', 'Disease', 'MESH:D004827', (73, 91))	('edema', 'Phenotype', 'HP:0000969', (106, 111))
2328	29896307	Both regadenoson and nanoagonist led to an increased F/G-actin ratio and MLC phosphorylation level but reduced TJ-associated protein level in the endothelial monolayer.	('MLC', 'Gene', '170790', (73, 76))	('MLC', 'Gene', (73, 76))	('reduced', 'NegReg', (103, 110))	('TJ-associated protein level', 'MPA', (111, 138))	('nanoagonist', 'Var', (21, 32))	('increased', 'PosReg', (43, 52))	('F/G-actin ratio', 'MPA', (53, 68))	('regadenoson', 'Chemical', 'MESH:C430916', (5, 16))
2344	29896307	Overall, nanoagonist-mediated BBB permeability enhancement followed by image-guided drug injection holds promise to improve the response of multiple therapeutics to glioma and minimize their side effects.	('response', 'MPA', (128, 136))	('improve', 'PosReg', (116, 123))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('nanoagonist-mediated', 'Var', (9, 29))	('BBB permeability', 'CPA', (30, 46))	('enhancement', 'PosReg', (47, 58))	('glioma', 'Disease', (165, 171))
2354	29896307	Nine mice bearing orthotropic glioma xenografts were randomly divided into three groups (three mice in each group): Den-PEG, Den-Reg and Den-RGD-Reg.	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('glioma xenograft', 'Disease', 'MESH:D005910', (30, 46))	('mice', 'Species', '10090', (95, 99))	('Den-Reg', 'Chemical', '-', (125, 132))	('Den-RGD-Reg', 'Var', (137, 148))	('Den-PEG', 'Var', (116, 123))	('Den-PEG', 'Chemical', '-', (116, 123))	('mice', 'Species', '10090', (5, 9))	('Den-RGD-Reg', 'Chemical', '-', (137, 148))	('glioma xenograft', 'Disease', (30, 46))
2388	28473657	IE86 staining positively correlates with the staining of activating transcription factor 5 (ATF5) which is essential for glioma cell viability and proliferation suggesting that HCMV IE86 could have important implications in glioma biology.	('HCMV IE86', 'Var', (177, 186))	('rat', 'Species', '10116', (154, 157))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('glioma', 'Disease', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('activating transcription factor 5', 'Gene', '22809', (57, 90))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('activating transcription factor 5', 'Gene', (57, 90))	('HCMV', 'Species', '10359', (177, 181))	('glioma', 'Disease', (224, 230))
2390	28473657	We demonstrate that IE86 protein physically interacts with, and acetylates ATF5 thereby promoting glioma cell survival.	('acetylates', 'Var', (64, 74))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('protein', 'Protein', (25, 32))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('IE86', 'Gene', (20, 24))	('interacts', 'Interaction', (44, 53))	('promoting', 'PosReg', (88, 97))	('glioma', 'Disease', (98, 104))	('ATF5', 'Protein', (75, 79))	('rat', 'Species', '10116', (10, 13))
2418	28473657	Disturbance on ATF5 function or expression drives apoptosis of glioma cell lines while not affecting survival of nonneoplastic brain cells.	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('Disturbance', 'Var', (0, 11))	('ATF5', 'Gene', (15, 19))	('expression', 'MPA', (32, 42))	('apoptosis', 'CPA', (50, 59))	('glioma', 'Disease', (63, 69))
2427	28473657	We found IE86 positive reactivity in the GBM tumor cells nuclei and partly in the perinuclear cytoplasm (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('IE86', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('reactivity', 'MPA', (23, 33))
2451	28473657	To determine which part of ATF5 interacts with IE86, we performed immunoprecipitation analysis using C6 cells transfected with a construct expressing GFP-ATF5 or GFP-dnATF5.	('GFP-ATF5', 'Var', (150, 158))	('GFP-dnATF5', 'Var', (162, 172))	('C6', 'CellLine', 'CVCL:X905', (101, 103))
2456	28473657	These results suggest that ATF5 acetylation induced by IE86 is subject to p300-dependent manner.	('p300', 'Gene', (74, 78))	('p300', 'Gene', '2033', (74, 78))	('ATF5 acetylation', 'MPA', (27, 43))	('IE86', 'Var', (55, 59))
2459	28473657	To exam whether the K29 in ATF5 GK motif is the acetylation site of IE86 as well, we transfected IE86 plasmid and wild-type (WT) ATF5 or ATF5 (K29R) to C6 cells, in which K29 was mutated into arginine.	('arginine', 'Chemical', 'MESH:D001120', (192, 200))	('C6', 'CellLine', 'CVCL:X905', (152, 154))	('K29R', 'Var', (143, 147))	('K29', 'Gene', (171, 174))	('K29R', 'SUBSTITUTION', 'None', (143, 147))	('mutated', 'Var', (179, 186))
2460	28473657	Immunoblotting analysis displayed that WT ATF5 but not ATF5 (K29R) acetylated by IE86 (Figure 6).	('K29R', 'Var', (61, 65))	('IE86', 'Gene', (81, 85))	('K29R', 'SUBSTITUTION', 'None', (61, 65))	('acetylated', 'MPA', (67, 77))
2462	28473657	Our in vitro results showed that IE86 could enhance tumor survivability.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('IE86', 'Var', (33, 37))	('enhance', 'PosReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
2466	28473657	At the endpoint, the tumor volume and weight of vector group was significantly smaller than that of IE group (Figure 7).	('vector', 'Var', (48, 54))	('tumor', 'Disease', (21, 26))	('smaller', 'NegReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
2481	28473657	IE86 has the ability to form a complex with several cellular regulators, including the TATA box-binding protein (TBP), TFIIB, Sp1,Tef-1, c-Jun, JunB, p53, and P300.	('TBP', 'Gene', '6908', (113, 116))	('IE86', 'Var', (0, 4))	('P300', 'Gene', (159, 163))	('Tef-1', 'Gene', (130, 135))	('c-Jun', 'Gene', '3725', (137, 142))	('JunB', 'Gene', '3726', (144, 148))	('TFIIB', 'Gene', (119, 124))	('TATA box-binding protein', 'Gene', (87, 111))	('P300', 'Gene', '2033', (159, 163))	('complex', 'Interaction', (31, 38))	('p53', 'Gene', (150, 153))	('Tef-1', 'Gene', '7003', (130, 135))	('TFIIB', 'Gene', '2959', (119, 124))	('p53', 'Gene', '7157', (150, 153))	('TATA box-binding protein', 'Gene', '6908', (87, 111))	('c-Jun', 'Gene', (137, 142))	('JunB', 'Gene', (144, 148))	('TBP', 'Gene', (113, 116))
2482	28473657	The IE86 protein is reported to inhibit the induction of apoptosis by TNF-alpha.	('TNF-alpha', 'Gene', (70, 79))	('TNF-alpha', 'Gene', '7124', (70, 79))	('IE86', 'Var', (4, 8))	('inhibit', 'NegReg', (32, 39))
2495	28473657	Immunoblotting of the immunoprecipitated IE with an anti-ATF5 antibody from C6 cell transfected with a construct expressing GFP-ATF5 or GFP-dnATF5 showed that ATF5 but not dnATF5 associated with IE, indicating that IE specifically interacts with the N-terminal proline-rich domain of ATF5.	('GFP-dnATF5', 'Var', (136, 146))	('GFP-ATF5', 'Var', (124, 132))	('interacts', 'Interaction', (231, 240))	('C6', 'CellLine', 'CVCL:X905', (76, 78))	('proline', 'Chemical', 'MESH:D011392', (261, 268))	('associated', 'Interaction', (179, 189))
2537	28473657	Antibodies used were anti-ATF5 (Abcam), anti-P300 (Santa Cruz), anti-IE (Virostat), anti-FLAG (Stratagene) and anti-beta-actin (Santa Cruz).	('rat', 'Species', '10116', (97, 100))	('anti-ATF5', 'Var', (21, 30))	('P300', 'Gene', '2033', (45, 49))	('beta-actin', 'Gene', '728378', (116, 126))	('beta-actin', 'Gene', (116, 126))	('anti-FLAG', 'Var', (84, 93))	('P300', 'Gene', (45, 49))	('anti-IE', 'Var', (64, 71))
2538	28473657	For cell death analysis, gating was adjusted using 7-aminoactinomycin D (7-AAD) staining with dot plots displaying FL3-7-AAD on the y-axis and FL2- annexin V-PE on the x-axis and 5,000 events were collected for each sample.	('FL2-', 'Var', (143, 147))	('annexin V', 'Gene', '308', (148, 157))	('7-aminoactinomycin D', 'Chemical', 'MESH:C025942', (51, 71))	('annexin V', 'Gene', (148, 157))	('7-AAD', 'Chemical', 'MESH:C025942', (119, 124))	('FL3-7-AAD', 'Chemical', '-', (115, 124))	('FL3-7-AAD', 'Var', (115, 124))	('7-AAD', 'Chemical', 'MESH:C025942', (73, 78))
2600	26337080	Finally, dynamic 1H-MRS showed that, at high grade glioma, the [NAA] reduced greatly to almost to the noise level and the noise will have relatively more effect on the small NAA peak, therefore, make the [Cho/NAA] change greatly from 0 to 6 min.	('Cho', 'Chemical', 'MESH:D002794', (205, 208))	('high grade', 'Var', (40, 50))	('glioma', 'Disease', (51, 57))	('NAA', 'Chemical', 'MESH:C000179', (64, 67))	('NAA', 'Chemical', 'MESH:C000179', (209, 212))	('[Cho/NAA', 'MPA', (204, 212))	('reduced', 'NegReg', (69, 76))	('NAA', 'Chemical', 'MESH:C000179', (174, 177))	('1H', 'Chemical', '-', (17, 19))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('make', 'Reg', (195, 199))	('small NAA', 'Phenotype', 'HP:0000430', (168, 177))	('[NAA]', 'MPA', (63, 68))	('change', 'Reg', (214, 220))
2661	26050591	The study was halted on the assumption that results with radiotherapy alone would be inferior to radiotherapy and temozolomide) Finally, EORTC 22033/26033, NCIC CE5, accrued patients with LGGs who "required treatment" defined as several unfavorable factors such as age >=40, but additional prognostic factors that were not solely identified by the Pignatti analysis.	('patients', 'Species', '9606', (174, 182))	('EORTC', 'Var', (137, 142))	('temozolomide', 'Chemical', 'MESH:D000077204', (114, 126))	('LGGs', 'Disease', (188, 192))
2662	26050591	Patients were randomized to either radiotherapy or temozolomide alone, but were stratified by loss of chrososome 1p in tumor DNA which is a favorable molecular factor (results discussed below).	('tumor', 'Disease', (119, 124))	('chrososome 1p', 'Var', (102, 115))	('loss', 'NegReg', (94, 98))	('temozolomide', 'Chemical', 'MESH:D000077204', (51, 63))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
2663	26050591	Loss of chromosomes 1p and 19q, O6-Methylguanine-DNA-methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase (IDH) mutations are among the best-understood biomarkers, although several others are emerging.	('isocitrate dehydrogenase', 'Gene', '3417', (104, 128))	('IDH', 'Gene', '3417', (130, 133))	('MGMT', 'Gene', '4255', (72, 76))	('MGMT', 'Gene', (72, 76))	('mutations', 'Var', (135, 144))	('O6-Methylguanine-DNA-methyltransferase', 'Gene', '4255', (32, 70))	('Loss', 'NegReg', (0, 4))	('O6-Methylguanine-DNA-methyltransferase', 'Gene', (32, 70))	('isocitrate dehydrogenase', 'Gene', (104, 128))	('IDH', 'Gene', (130, 133))
2664	26050591	1p19q co-deletion is clearly prognostic in both anaplastic oligodendroglial tumors  and LGGs, although it is less well studied in the latter.	('prognostic', 'Reg', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('1p19q co-deletion', 'Var', (0, 17))	('LGGs', 'Disease', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (48, 82))	('anaplastic oligodendroglial tumors', 'Disease', (48, 82))
2669	26050591	In addition, IDH mutation induces methylation of many genes (G-CIMP), which may partially explain the effect of MGMT methylation at specific sites in the promoter.	('induces', 'Reg', (26, 33))	('IDH', 'Gene', '3417', (13, 16))	('mutation', 'Var', (17, 25))	('MGMT', 'Gene', (112, 116))	('MGMT', 'Gene', '4255', (112, 116))	('IDH', 'Gene', (13, 16))	('methylation', 'MPA', (34, 45))
2670	26050591	Tumors with 1p19q co-deletion appear to represent a subset of those with IDH mutation.	('1p19q co-deletion', 'Var', (12, 29))	('IDH', 'Gene', (73, 76))	('Tumors', 'Disease', (0, 6))	('IDH', 'Gene', '3417', (73, 76))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
2671	26050591	Surprisingly, one study suggested that in the natural history of a low grade astrocytoma, untreated patients with tumors harboring methylated MGMT promoters had a shorter PFS than untreated patients without MGMT methylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patients', 'Species', '9606', (190, 198))	('tumors', 'Disease', (223, 229))	('MGMT', 'Gene', '4255', (207, 211))	('patients', 'Species', '9606', (100, 108))	('shorter', 'NegReg', (163, 170))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('astrocytoma', 'Disease', 'MESH:D001254', (77, 88))	('astrocytoma', 'Disease', (77, 88))	('MGMT', 'Gene', '4255', (142, 146))	('PFS', 'MPA', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('MGMT', 'Gene', (207, 211))	('methylated', 'Var', (131, 141))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (77, 88))	('MGMT', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Disease', (114, 120))
2677	26050591	In fact, both patients treated with radiotherapy and PCV and those treated with radiotherapy alone experienced improved cognition (as measured by mini mental status examination) over time, suggesting improved tumor control results in improved symptoms.	('improved', 'PosReg', (234, 242))	('tumor', 'Disease', (209, 214))	('symptoms', 'MPA', (243, 251))	('radiotherapy', 'Var', (36, 48))	('improved', 'PosReg', (111, 119))	('PCV', 'Var', (53, 56))	('improved', 'PosReg', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('patients', 'Species', '9606', (14, 22))	('cognition', 'CPA', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
2690	26050591	The updated results from RTOG 9802 demonstrated improved PFS in the subset of patients with low grade astrocytomas (median 3.7 years vs. 1.7 years, HR = 0.58) by adding PCV to radiotherapy vs. radiotherapy alone).	('astrocytomas', 'Disease', 'MESH:D001254', (102, 114))	('PFS', 'MPA', (57, 60))	('PCV', 'Var', (169, 172))	('improved', 'PosReg', (48, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('patients', 'Species', '9606', (78, 86))	('astrocytomas', 'Disease', (102, 114))
2693	26050591	On first glance, it appears mysterious why patients with low grade astrocytomas benefited from adding PCV to radiotherapy in RTOG 9802, as astrocytomas are considered less chemo-sensitive than oligodendrogliomas, and they rarely harbor 1p19q co-deletion which is typically linked with response to chemotherapy.	('astrocytomas', 'Disease', 'MESH:D001254', (67, 79))	('astrocytomas', 'Disease', (139, 151))	('oligodendrogliomas', 'Disease', (193, 211))	('patients', 'Species', '9606', (43, 51))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('astrocytomas', 'Disease', (67, 79))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('astrocytomas', 'Disease', 'MESH:D001254', (139, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (139, 150))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (193, 211))	('1p19q', 'Var', (236, 241))
2697	26050591	Looking at the data from trials of anaplastic oligodendroglial tumors, it appears that IDH mutant or MGMT methylated tumors benefit from PCV when added to radiotherapy, even in the absence of 1p19q co-deletion.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MGMT', 'Gene', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('benefit', 'PosReg', (124, 131))	('IDH', 'Gene', (87, 90))	('MGMT', 'Gene', '4255', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('IDH', 'Gene', '3417', (87, 90))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (35, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutant', 'Var', (91, 97))	('anaplastic oligodendroglial tumors', 'Disease', (35, 69))
2698	26050591	IDH mutation is far more common in LGGs than anaplastic tumors, and MGMT methylation is linked with and possibly dependent on IDH mutation, regardless of histologic subtype.	('common', 'Reg', (25, 31))	('IDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('IDH', 'Gene', '3417', (126, 129))	('anaplastic tumors', 'Disease', 'MESH:D002277', (45, 62))	('LGGs', 'Disease', (35, 39))	('IDH', 'Gene', '3417', (0, 3))	('linked', 'Reg', (88, 94))	('mutation', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('anaplastic tumors', 'Disease', (45, 62))	('MGMT', 'Gene', '4255', (68, 72))	('MGMT', 'Gene', (68, 72))	('IDH', 'Gene', (126, 129))
2700	26050591	In summary, similar to patients with anaplastic oligodendroglial tumors, those with LGGs harboring both 1p19q co-deletion and IDH mutation may benefit most from PCV, explaining the clear improvement in oligodendrogliomas which are typically 1p19q co-deleted.	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (37, 71))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('IDH', 'Gene', '3417', (126, 129))	('anaplastic oligodendroglial tumors', 'Disease', (37, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('patients', 'Species', '9606', (23, 31))	('mutation', 'Var', (130, 138))	('improvement', 'PosReg', (187, 198))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (202, 220))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('oligodendrogliomas', 'Disease', (202, 220))	('1p19q', 'Var', (104, 109))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('IDH', 'Gene', (126, 129))
2714	26050591	Chemotherapy alone (generally temozolomide) with deferred radiotherapy is the treatment recommended most frequently among neuro-oncologists for patients with 1p19q co-deleted anaplastic oligodendroglial tumors which are even more aggressive than lower grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('1p19q co-deleted', 'Var', (158, 174))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('temozolomide', 'Chemical', 'MESH:D000077204', (30, 42))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Disease', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (175, 209))	('anaplastic oligodendroglial tumors', 'Disease', (175, 209))	('patients', 'Species', '9606', (144, 152))
2719	26050591	The frequency of grade 3 treated related toxicities was lower in RTOG 0424 than among patients treated with radiotherapy and PCV in RTOG 9802.	('toxicities', 'Disease', (41, 51))	('lower', 'NegReg', (56, 61))	('RTOG 0424', 'Var', (65, 74))	('toxicities', 'Disease', 'MESH:D064420', (41, 51))	('patients', 'Species', '9606', (86, 94))
2732	26050591	The "CODEL" trial, for patients with newly diagnosed anaplastic oligodendroglial tumors harboring 1p19q codeletion, will compare radiotherapy with either PCV or temozolomide.	('anaplastic oligodendroglial tumors', 'Disease', (53, 87))	('temozolomide', 'Chemical', 'MESH:D000077204', (161, 173))	('patients', 'Species', '9606', (23, 31))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (53, 87))	('1p19q codeletion', 'Var', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
2743	33986244	Interfering with hyaluronic acid metabolism suppresses glioma cell proliferation by regulating autophagy The tumor microenvironment plays an important role in tumor progression.	('Interfering', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (159, 164))	('hyaluronic acid metabolism suppresses glioma', 'Disease', 'MESH:D005910', (17, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('hyaluronic acid metabolism suppresses glioma', 'Disease', (17, 61))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('autophagy', 'CPA', (95, 104))	('regulating', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (109, 114))
2747	33986244	Silencing HAS3 expression or blocking CD44 inhibited glioma cell proliferation in vitro and in vivo.	('glioma', 'Disease', (53, 59))	('inhibited', 'NegReg', (43, 52))	('blocking', 'NegReg', (29, 37))	('HAS3 expression', 'Protein', (10, 25))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('CD44', 'Gene', (38, 42))	('Silencing', 'Var', (0, 9))
2763	33986244	For instance, HMW-HA possesses antiangiogenic and immunosuppressive activities, whereas LMW-HA induces inflammation and is related to the angiogenesis, survival, growth, and metastasis of tumors.	('metastasis of tumors', 'Disease', 'MESH:D009362', (174, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('inflammation', 'Disease', (103, 115))	('metastasis of tumors', 'Disease', (174, 194))	('inflammation', 'Disease', 'MESH:D007249', (103, 115))	('HA', 'Chemical', 'MESH:D006820', (18, 20))	('LMW-HA', 'Var', (88, 94))	('antiangiogenic', 'CPA', (31, 45))	('related', 'Reg', (123, 130))	('immunosuppressive activities', 'CPA', (50, 78))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('angiogenesis', 'CPA', (138, 150))	('induces', 'PosReg', (95, 102))	('HA', 'Chemical', 'MESH:D006820', (92, 94))
2768	33986244	Inhibition of CD44 activity induces the apoptosis of invasive tumors.	('invasive tumors', 'Disease', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('apoptosis', 'CPA', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CD44', 'Protein', (14, 18))	('activity', 'MPA', (19, 27))	('invasive tumors', 'Disease', 'MESH:D009361', (53, 68))	('Inhibition', 'Var', (0, 10))
2779	33986244	Alterations in HA metabolism induced by silencing HAS3, blocking its binding with the receptor CD44, or administering 4-MU inhibited autophagy flux, arrested the cell cycle at G1 phase, and subsequently inhibited glioma cell proliferation in the present study.	('4-MU', 'Chemical', 'MESH:D006923', (118, 122))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('HAS3', 'Gene', (50, 54))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('HA', 'Chemical', 'MESH:D006820', (50, 52))	('blocking', 'NegReg', (56, 64))	('arrest', 'Disease', (149, 155))	('cell cycle at G1 phase', 'CPA', (162, 184))	('binding', 'Interaction', (69, 76))	('inhibited', 'NegReg', (123, 132))	('autophagy flux', 'CPA', (133, 147))	('inhibited', 'NegReg', (203, 212))	('silencing', 'Var', (40, 49))	('glioma', 'Disease', (213, 219))	('HA', 'Chemical', 'MESH:D006820', (15, 17))
2788	33986244	Moreover, in view of HAS1, HAS2, and HAS3 expression in glioma, we over-expressed HAS1 and knocked down HAS2 in glioma cell lines, the results demonstrated the over-expression of HAS1 or the silencing of HAS2 did not significantly affect the viability of glioma cells (Supplementary Fig.	('silencing', 'Var', (191, 200))	('HAS1', 'Gene', '3036', (21, 25))	('HAS2', 'Gene', (104, 108))	('HAS1', 'Gene', (179, 183))	('HAS2', 'Gene', '3037', (204, 208))	('glioma', 'Disease', (112, 118))	('HAS2', 'Gene', '3037', (27, 31))	('HAS1', 'Gene', '3036', (179, 183))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('HAS1', 'Gene', (82, 86))	('glioma', 'Disease', (255, 261))	('glioma', 'Disease', (56, 62))	('knocked', 'Var', (91, 98))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('HAS1', 'Gene', '3036', (82, 86))	('HAS2', 'Gene', '3037', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('HAS2', 'Gene', (204, 208))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('HAS2', 'Gene', (27, 31))	('HAS1', 'Gene', (21, 25))
2796	33986244	The results confirmed the relative expression levels of HA, HAS3, and CD44 in glioma were higher than those in HUVEC cells (Supplementary Fig.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('HA', 'Chemical', 'MESH:D006820', (56, 58))	('HAS3', 'Gene', (60, 64))	('HUVEC', 'CellLine', 'CVCL:2959', (111, 116))	('expression levels', 'MPA', (35, 52))	('glioma', 'Disease', (78, 84))	('CD44', 'Var', (70, 74))	('higher', 'PosReg', (90, 96))	('HA', 'Chemical', 'MESH:D006820', (60, 62))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
2800	33986244	Exogenous HA reversed this effect of HAS3 knockdown.	('HAS3', 'Gene', (37, 41))	('HA', 'Chemical', 'MESH:D006820', (37, 39))	('knockdown', 'Var', (42, 51))	('HA', 'Chemical', 'MESH:D006820', (10, 12))
2803	33986244	Moreover, inhibition of HAS3 or treatment with the CD44 antibody decreased the expression of Ki67 in U251 or LN229 glioma cells, respectively (Fig.	('Ki67', 'Gene', (93, 97))	('glioma', 'Disease', (115, 121))	('expression', 'MPA', (79, 89))	('decreased', 'NegReg', (65, 74))	('Ki67', 'Gene', '17345', (93, 97))	('U251', 'CellLine', 'CVCL:0021', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('HAS3', 'Protein', (24, 28))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('CD44', 'Gene', (51, 55))	('inhibition', 'Var', (10, 20))	('LN229', 'CellLine', 'CVCL:0393', (109, 114))
2808	33986244	2E, HAS3 and CD44 expression were significantly decreased in glioma cells transfected with the HAS3 siRNA and CD44 siRNA, respectively, compared with control glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('HAS3', 'Var', (95, 99))	('decreased', 'NegReg', (48, 57))	('glioma', 'Disease', (61, 67))	('CD44', 'Gene', (13, 17))	('glioma', 'Disease', (158, 164))	('expression', 'MPA', (18, 28))	('HAS3', 'Gene', (4, 8))	('CD44 siRNA', 'Var', (110, 120))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
2810	33986244	The inhibition of HAS3 or CD44 in vivo significantly decreased the glioma volumes, extended the survival time of mice, and downregulated Ki67 expression compared with controls (Fig.	('Ki67', 'Gene', '17345', (137, 141))	('glioma', 'Disease', (67, 73))	('downregulated', 'NegReg', (123, 136))	('Ki67', 'Gene', (137, 141))	('inhibition', 'Var', (4, 14))	('survival time', 'CPA', (96, 109))	('CD44', 'Gene', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('extended', 'PosReg', (83, 91))	('expression', 'MPA', (142, 152))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('decreased', 'NegReg', (53, 62))	('mice', 'Species', '10090', (113, 117))	('HAS3', 'Gene', (18, 22))
2811	33986244	As expected, silencing of HAS3 also reduced the production of HA in vivo (Fig.	('HA', 'Chemical', 'MESH:D006820', (62, 64))	('HAS3', 'Gene', (26, 30))	('reduced', 'NegReg', (36, 43))	('production of HA', 'MPA', (48, 64))	('HA', 'Chemical', 'MESH:D006820', (26, 28))	('silencing', 'Var', (13, 22))
2817	33986244	HAS3 silencing or treatment with the CD44 antibody increased the number of autophagic vesicles in glioma cells (Fig.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('increased', 'PosReg', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('CD44', 'Gene', (37, 41))	('silencing', 'Var', (5, 14))	('HAS3', 'Protein', (0, 4))	('glioma', 'Disease', (98, 104))
2824	33986244	Based on these results, treatments interfering with HA metabolism by silencing HAS3 or the application of an antibody against CD44 blocks autophagy flux.	('HA', 'Chemical', 'MESH:D006820', (52, 54))	('HA', 'Chemical', 'MESH:D006820', (79, 81))	('HAS3', 'Protein', (79, 83))	('CD44', 'Gene', (126, 130))	('blocks', 'NegReg', (131, 137))	('autophagy flux', 'CPA', (138, 152))	('silencing', 'Var', (69, 78))
2825	33986244	CQ, an inhibitor of autophagy flux, was used to measure autophagy flux in glioma cells and our research further confirmed that interfering with HA metabolism inhibits cell proliferation by inhibiting autophagy flux.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('inhibits', 'NegReg', (158, 166))	('HA', 'Chemical', 'MESH:D006820', (144, 146))	('interfering', 'Var', (127, 138))	('inhibiting', 'NegReg', (189, 199))	('glioma', 'Disease', (74, 80))	('CQ', 'Chemical', 'MESH:D002738', (0, 2))	('HA metabolism', 'MPA', (144, 157))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('autophagy flux', 'CPA', (200, 214))	('cell proliferation', 'CPA', (167, 185))
2829	33986244	Therefore, we investigated the effect of silencing HAS3 or treatment with CD44 antibodies on glioma cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (100, 117))	('glioma', 'Disease', (93, 99))	('silencing', 'Var', (41, 50))	('arrest', 'Disease', 'MESH:D006323', (111, 117))	('CD44', 'Gene', (74, 78))	('arrest', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('HAS3', 'Gene', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
2831	33986244	More importantly, silencing HAS3 or treatment with the anti-CD44 antibodies decreased the levels of the cell cycle-related proteins cyclin B1 and cyclin D1 in glioma cells, and CQ treatment further enhanced this effect (Fig.	('cyclin D1', 'Gene', (146, 155))	('glioma', 'Disease', (159, 165))	('silencing', 'Var', (18, 27))	('cyclin D1', 'Gene', '595', (146, 155))	('cyclin B1', 'Gene', '891', (132, 141))	('cyclin B1', 'Gene', (132, 141))	('decreased', 'NegReg', (76, 85))	('CQ', 'Chemical', 'MESH:D002738', (177, 179))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('antibodies', 'Var', (65, 75))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('anti-CD44', 'Gene', (55, 64))	('HAS3', 'Gene', (28, 32))
2832	33986244	Inhibition of HAS3 or treatment with the CD44 antibody combined with autophagy inhibitors exerted synergistic inhibitory effects on glioma proliferation through a molecular mechanism that involves arresting the cell cycle in G1 phase.	('glioma', 'Disease', (132, 138))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('CD44', 'Gene', (41, 45))	('HAS3', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('cell cycle', 'CPA', (211, 221))	('arrest', 'Disease', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
2834	33986244	In addition, 4-MU inhibited HA synthesis in glioma cells (Supplementary Fig.	('4-MU', 'Chemical', 'MESH:D006923', (13, 17))	('HA', 'Chemical', 'MESH:D006820', (28, 30))	('4-MU', 'Var', (13, 17))	('glioma', 'Disease', (44, 50))	('HA synthesis', 'MPA', (28, 40))	('inhibited', 'NegReg', (18, 27))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
2838	33986244	Moreover, 4-MU increased the number of autophagic vesicles in vitro (Fig.	('increased', 'PosReg', (15, 24))	('4-MU', 'Chemical', 'MESH:D006923', (10, 14))	('number of autophagic vesicles in vitro', 'CPA', (29, 67))	('4-MU', 'Var', (10, 14))
2840	33986244	GFP-RFP-LC3 fluorescence assays showed that 4-MU blocked the autophagy flux of glioma cells (Fig.	('4-MU', 'Chemical', 'MESH:D006923', (44, 48))	('glioma', 'Disease', (79, 85))	('4-MU', 'Var', (44, 48))	('LC3', 'Gene', '84557', (8, 11))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('LC3', 'Gene', (8, 11))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('blocked', 'NegReg', (49, 56))
2844	33986244	3G-H, 4-MU decreased the volume of glioma tissues, and the levels of HA and Ki67 were also decreased.	('Ki67', 'Gene', (76, 80))	('decreased', 'NegReg', (11, 20))	('Ki67', 'Gene', '17345', (76, 80))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('HA', 'Chemical', 'MESH:D006820', (69, 71))	('4-MU', 'Chemical', 'MESH:D006923', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('levels of HA', 'MPA', (59, 71))	('4-MU', 'Var', (6, 10))	('decreased', 'NegReg', (91, 100))	('glioma', 'Disease', (35, 41))
2846	33986244	Overall, 4-MU suppressed the proliferation of glioma cells in vitro and in vivo by blocking autophagy flux.	('blocking', 'NegReg', (83, 91))	('autophagy flux', 'CPA', (92, 106))	('4-MU', 'Var', (9, 13))	('glioma', 'Disease', (46, 52))	('proliferation', 'CPA', (29, 42))	('suppressed', 'NegReg', (14, 24))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('4-MU', 'Chemical', 'MESH:D006923', (9, 13))
2849	33986244	Previous studies have confirmed that the abnormal accumulation of HA is related to the dysregulated expression of HA synthases and HA degradation enzymes in patients with many pathological conditions, such as cancer, injury, and inflammation.	('dysregulated', 'Var', (87, 99))	('inflammation', 'Disease', 'MESH:D007249', (229, 241))	('HA', 'Chemical', 'MESH:D006820', (66, 68))	('injury', 'Disease', (217, 223))	('HA', 'Chemical', 'MESH:D006820', (131, 133))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('inflammation', 'Disease', (229, 241))	('expression', 'MPA', (100, 110))	('patients', 'Species', '9606', (157, 165))	('HA', 'Chemical', 'MESH:D006820', (114, 116))	('cancer', 'Disease', (209, 215))	('accumulation', 'PosReg', (50, 62))	('injury', 'Disease', 'MESH:D014947', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
2857	33986244	Moreover, glioma cell viability was not significantly affected when HAS2 was knocked down or HAS1 was overexpressed.	('knocked down', 'Var', (77, 89))	('HAS1', 'Gene', '3036', (93, 97))	('HAS2', 'Gene', (68, 72))	('HAS1', 'Gene', (93, 97))	('HAS2', 'Gene', '3037', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('glioma', 'Disease', (10, 16))
2863	33986244	For example, the interaction of LMW-HA with CD44 and TLR enhanced the production of IL-1beta/IL-8 via the subsequent activation of MyD88/NF-kappaB and finally promoted the invasiveness of breast cancer cells.	('NF-kappaB', 'Gene', '4790', (137, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('LMW-HA', 'Var', (32, 38))	('IL-8', 'Gene', '3576', (93, 97))	('enhanced', 'PosReg', (57, 65))	('IL-1beta', 'Gene', (84, 92))	('MyD88', 'Gene', (131, 136))	('HA', 'Chemical', 'MESH:D006820', (36, 38))	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (172, 201))	('TLR', 'Gene', (53, 56))	('IL-1beta', 'Gene', '3552', (84, 92))	('activation', 'PosReg', (117, 127))	('IL-8', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('interaction', 'Interaction', (17, 28))	('NF-kappaB', 'Gene', (137, 146))	('CD44', 'Gene', (44, 48))	('invasiveness of breast cancer', 'Disease', (172, 201))	('MyD88', 'Gene', '4615', (131, 136))	('promoted', 'PosReg', (159, 167))
2877	33986244	4-MU inhibits HA synthesis through the depletion of cellular UDP, which finally leads to changes in the tumor microenvironment and the inhibition of tumor growth.	('inhibition', 'NegReg', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('changes', 'Reg', (89, 96))	('tumor', 'Disease', (104, 109))	('HA', 'Chemical', 'MESH:D006820', (14, 16))	('UDP', 'Chemical', 'MESH:D014530', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('depletion of cellular UDP', 'MPA', (39, 64))	('4-MU', 'Chemical', 'MESH:D006923', (0, 4))	('tumor', 'Disease', (149, 154))	('HA synthesis', 'MPA', (14, 26))	('leads', 'Reg', (80, 85))	('inhibits', 'NegReg', (5, 13))	('4-MU', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
2879	33986244	Recently, research has demonstrated that dietary supplementation of 4-MU can serve as an effective chemotherapeutic for prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('4-MU', 'Chemical', 'MESH:D006923', (68, 72))	('4-MU', 'Var', (68, 72))	('prostate cancer', 'Disease', (120, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))
2880	33986244	4-MU can also decrease the growth of pancreatic cancer by inhibiting HA synthesis.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('inhibiting', 'NegReg', (58, 68))	('HA', 'Chemical', 'MESH:D006820', (69, 71))	('pancreatic cancer', 'Disease', (37, 54))	('HA synthesis', 'MPA', (69, 81))	('decrease', 'NegReg', (14, 22))	('4-MU', 'Chemical', 'MESH:D006923', (0, 4))	('growth', 'MPA', (27, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('4-MU', 'Var', (0, 4))
2881	33986244	The BBB is known to be a major obstacle for glioma treatment; Fortunately, 4-MU has the characteristic of relatively small molecular weight and ability to penetrate the BBB.	('4-MU', 'Chemical', 'MESH:D006923', (75, 79))	('4-MU', 'Var', (75, 79))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
2915	33986244	The main antibodies utilized in the present study were as follows: HAS3 (BF0681, Affinity), CD44 (A0340, Abclonal), HA (Ab53842, Abcam), and Ki67 (A2094-100, Abclonal).	('Ki67', 'Gene', '17345', (141, 145))	('A0340', 'Var', (98, 103))	('HA', 'Chemical', 'MESH:D006820', (67, 69))	('Ki67', 'Gene', (141, 145))	('HA', 'Chemical', 'MESH:D006820', (116, 118))
2936	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))
2938	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))
2958	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))
2959	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))	('COAD', 'Disease', 'MESH:D029424', (135, 139))	('CTSL', 'Gene', '1514', (12, 16))	('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))
2960	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))
2961	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))
2964	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))
2969	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))
3004	31968004	T2 FLAIR features also showed distinct characteristics between IDH wildtype and mutant tumors,1p/19q co-deleted and 1p/19q intact tumors, MGMT methylated and unmethylated tumors respectively, which could useful in molecular classification of patients with grade II/III glioma.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('patients', 'Species', '9606', (242, 250))	('MGMT', 'Gene', (138, 142))	('mutant', 'Var', (80, 86))	('IDH', 'Gene', (63, 66))	('III glioma', 'Disease', 'MESH:D005910', (265, 275))	('tumors', 'Disease', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Disease', (171, 177))	('IDH', 'Gene', '3417', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('MGMT', 'Gene', '4255', (138, 142))	('useful', 'Reg', (204, 210))	('III glioma', 'Disease', (265, 275))
3054	31968004	It can be seen that the Ki-67 and CD34 models were slightly inferior performed to the other two models.	('CD34', 'Gene', '947', (34, 38))	('Ki-67', 'Var', (24, 29))	('CD34', 'Gene', (34, 38))
3080	31968004	For example, modifications in the level of S100A3 protein expression level could help identify the pilocytic astrocytomas from WHO grade II-IV astrocytic tumors.	('astrocytic tumors', 'Disease', 'MESH:D001254', (143, 160))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (99, 121))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('S100A3', 'Gene', (43, 49))	('S100A3', 'Gene', '6274', (43, 49))	('astrocytic tumors', 'Disease', (143, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('pilocytic astrocytomas', 'Disease', (99, 121))	('modifications', 'Var', (13, 26))
3083	31968004	Another study reported that S100A4 played a crucial role in neutrophil-promoting tumor progression and S100A4 depletion could increase the effectiveness of anti-VEGF therapy in glioma.	('VEGF', 'Gene', '7422', (161, 165))	('glioma', 'Disease', (177, 183))	('S100A4', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('S100A4', 'Gene', '6275', (28, 34))	('S100A4', 'Gene', '6275', (103, 109))	('S100A4', 'Gene', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('increase', 'PosReg', (126, 134))	('depletion', 'Var', (110, 119))	('VEGF', 'Gene', (161, 165))	('tumor', 'Disease', (81, 86))	('effectiveness', 'MPA', (139, 152))
3104	31968004	CD34 staining were also associated with hypoxia-induced angiogenesis and may play a role in glioblastoma hemorrhage.	('hypoxia', 'Disease', (40, 47))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('associated', 'Reg', (24, 34))	('glioblastoma hemorrhage', 'Disease', (92, 115))	('play', 'Reg', (77, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('CD34', 'Gene', '947', (0, 4))	('staining', 'Var', (5, 13))	('role', 'Reg', (84, 88))	('glioblastoma hemorrhage', 'Disease', 'MESH:D005909', (92, 115))	('CD34', 'Gene', (0, 4))
3171	31968004	Ki-67: The nuclear protein Ki-67 has been widely used as an indicator of cell proliferation in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('Ki-67', 'Var', (27, 32))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))
3191	31968004	Another study reported that S100A4 played a crucial role in neutrophil-promoting tumor progression and S100A4 depletion could increase the effectiveness of anti-VEGF therapy in glioma [56]."	('VEGF', 'Gene', '7422', (161, 165))	('glioma', 'Disease', (177, 183))	('S100A4', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('S100A4', 'Gene', '6275', (28, 34))	('S100A4', 'Gene', '6275', (103, 109))	('S100A4', 'Gene', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('increase', 'PosReg', (126, 134))	('depletion', 'Var', (110, 119))	('VEGF', 'Gene', (161, 165))	('tumor', 'Disease', (81, 86))	('effectiveness', 'MPA', (139, 152))
3205	31968004	And we have made some revision for this discussion part from two aspects including: (a)Why we want to have a try to use radiomics for identifying the four biomarkers of Ki-67, vimentin, S-100 and CD34.	('vimentin', 'Gene', '7431', (176, 184))	('S-100', 'Gene', '6271', (186, 191))	('CD34', 'Gene', '947', (196, 200))	('vimentin', 'Gene', (176, 184))	('CD34', 'Gene', (196, 200))	('Ki-67', 'Var', (169, 174))	('S-100', 'Gene', (186, 191))
3206	31968004	(a) Why we want to have a try to use radiomics for identifying the four biomarkers of Ki-67, vimentin, S-100 and CD34?	('vimentin', 'Gene', '7431', (93, 101))	('S-100', 'Gene', '6271', (103, 108))	('CD34', 'Gene', (113, 117))	('CD34', 'Gene', '947', (113, 117))	('vimentin', 'Gene', (93, 101))	('Ki-67', 'Var', (86, 91))	('S-100', 'Gene', (103, 108))
3232	31968004	T2 FLAIR features also showed distinct characteristics between IDH wildtype and mutant tumors,1p/19q co-deleted and 1p/19q intact tumors, MGMT methylated and unmethylated tumors respectively, which could useful in molecular classification of patients with grade II/III glioma [32].	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('patients', 'Species', '9606', (242, 250))	('MGMT', 'Gene', (138, 142))	('mutant', 'Var', (80, 86))	('IDH', 'Gene', (63, 66))	('III glioma', 'Disease', 'MESH:D005910', (265, 275))	('tumors', 'Disease', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Disease', (171, 177))	('IDH', 'Gene', '3417', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('MGMT', 'Gene', '4255', (138, 142))	('III glioma', 'Disease', (265, 275))
3242	31968004	The clinical relevance for the respective marker was described in detail as follows: Ki-67: The nuclear protein Ki-67 has been widely used as an indicator of cell proliferation in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('Ki-67', 'Var', (112, 117))
3244	31968004	Another study reported that S100A4 played a crucial role in neutrophil-promoting tumor progression and S100A4 depletion could increase the effectiveness of anti-VEGF therapy in glioma [56].	('VEGF', 'Gene', '7422', (161, 165))	('glioma', 'Disease', (177, 183))	('S100A4', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('S100A4', 'Gene', '6275', (28, 34))	('S100A4', 'Gene', '6275', (103, 109))	('S100A4', 'Gene', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('increase', 'PosReg', (126, 134))	('depletion', 'Var', (110, 119))	('VEGF', 'Gene', (161, 165))	('tumor', 'Disease', (81, 86))	('effectiveness', 'MPA', (139, 152))
3269	28921173	Although independent factors, i.e., age, preoperative Karnofsky performance scale (KPS), molecular markers (IDH-1 mutation, O6-methylguanin-DNA-methyltransferase, MGMT, promoter methylation), and tumor location, might play a role in influencing OS, EoR is the variable that we as neurosurgeons can influence.	('influencing', 'Reg', (233, 244))	('tumor', 'Disease', (196, 201))	('MGMT', 'Gene', (163, 167))	('IDH-1', 'Gene', '3417', (108, 113))	('IDH-1', 'Gene', (108, 113))	('MGMT', 'Gene', '4255', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('OS', 'Chemical', '-', (245, 247))	('mutation', 'Var', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
3279	28921173	5-Aminolevulinic acid, a prodrug and a precursor in heme biosynthesis, leads to accumulation of fluorescent protoporphyrin IX (PPIX) in certain glioma tumor cells, enabling their visualization with the use of commercially available microscopes equipped with a special filter system.	('glioma tumor', 'Disease', 'MESH:D005910', (144, 156))	('PPIX', 'Chemical', 'MESH:C028025', (127, 131))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('5-Aminolevulinic acid', 'Chemical', 'MESH:C000614854', (0, 21))	('protoporphyrin IX', 'Chemical', 'MESH:C028025', (108, 125))	('5-Aminolevulinic acid', 'Var', (0, 21))	('accumulation', 'PosReg', (80, 92))	('glioma tumor', 'Disease', (144, 156))	('heme', 'Chemical', 'MESH:D006418', (52, 56))
3334	28921173	Furthermore, in 44-55% of cases where lesions in the preoperative MRI are suggestive of low-grade glioma, an anaplastic focus could still be discovered.	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('lesions', 'Var', (38, 45))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Disease', (98, 104))
3341	28921173	Thus, studies applying high-field iMRI report much higher resection rates for non-fluorescing and enhancing gliomas, which is probably more suitable for low-grade glioma surgery.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('enhancing', 'PosReg', (98, 107))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('glioma', 'Disease', (163, 169))	('glioma', 'Disease', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('non-fluorescing', 'Var', (78, 93))	('higher', 'PosReg', (51, 57))	('resection', 'CPA', (58, 67))
3374	30766494	This genetic susceptibility can in part be explained by variants of complement factor 4 (C4), possibly linked to increased synaptic pruning during brain development.	('variants', 'Var', (56, 64))	('complement factor 4', 'Gene', (68, 87))	('C4', 'Gene', '720', (89, 91))	('complement factor 4', 'Gene', '720', (68, 87))
3410	30766494	Binding of IL-1 can initiate and strengthen the acute phase response by inducing fever that increases migration of leucocytes, by stimulating the acute phase proteins such as CRP, by activation of the hypothalamus-pituitary-adrenal (HPA) axis with cortisol regulating innate inflammation, and by inducing adhesion molecules that increase leucocyte recruitement.	('acute phase proteins', 'MPA', (146, 166))	('inducing', 'Reg', (296, 304))	('fever', 'Phenotype', 'HP:0001945', (81, 86))	('leucocyte recruitement', 'CPA', (338, 360))	('cortisol', 'Chemical', 'MESH:D006854', (248, 256))	('inflammation', 'Disease', (275, 287))	('migration of leucocytes', 'CPA', (102, 125))	('inducing', 'Reg', (72, 80))	('Binding', 'Var', (0, 7))	('CRP', 'Gene', '1401', (175, 178))	('stimulating', 'PosReg', (130, 141))	('activation', 'PosReg', (183, 193))	('IL-1', 'Gene', '3552', (11, 15))	('adhesion molecules', 'Protein', (305, 323))	('increase', 'PosReg', (329, 337))	('hypothalamus-pituitary-adrenal (HPA) axis', 'Disease', 'MESH:D007029', (201, 242))	('fever', 'Disease', 'MESH:D005334', (81, 86))	('fever', 'Disease', (81, 86))	('IL-1', 'Gene', (11, 15))	('CRP', 'Gene', (175, 178))	('inflammation', 'Disease', 'MESH:D007249', (275, 287))	('increases', 'PosReg', (92, 101))
3421	30766494	There is a growing body of evidence implicating dysregulated immunity in schizophrenia from both in-vitro and in-vivo studies.	('dysregulated', 'Var', (48, 60))	('schizophrenia', 'Phenotype', 'HP:0100753', (73, 86))	('schizophrenia', 'Disease', 'MESH:D012559', (73, 86))	('schizophrenia', 'Disease', (73, 86))
3437	30766494	They included 99 studies with 8,234 participants and found that peripheral levels of the following cytokines differed between patients with schizophrenia and healthy controls in more than 50% of the included studies, listed according to falling prevalence among the studies: IL-6, TNF-alpha, IL-10, IFN-gamma, IL-1beta, IL-8, IL-2, IL-1RA, furthermore the gene polymorphisms for TNF-alpha 1800629, IL-6 rs1800795, and IL-1beta rs16944, and elevated expression levels of IL-6, TNFR1, TNFR2, and IL-1beta mRNAs.	('participants', 'Species', '9606', (36, 48))	('IL-1beta', 'Gene', (310, 318))	('IL-1RA', 'Gene', (332, 338))	('TNF-alpha', 'Gene', '7124', (379, 388))	('rs1800795', 'Var', (403, 412))	('IL-1beta', 'Gene', (418, 426))	('schizophrenia', 'Disease', (140, 153))	('elevated', 'PosReg', (440, 448))	('patients', 'Species', '9606', (126, 134))	('TNF-alpha', 'Gene', (379, 388))	('IL-6', 'Gene', (275, 279))	('IL-1RA', 'Gene', '3557', (332, 338))	('IL-2', 'Gene', '3558', (326, 330))	('IL-8', 'Gene', (320, 324))	('falling', 'Phenotype', 'HP:0002527', (237, 244))	('IFN-gamma', 'Gene', '3458', (299, 308))	('IFN-gamma', 'Gene', (299, 308))	('rs16944', 'Var', (427, 434))	('rs1800795', 'Mutation', 'rs1800795', (403, 412))	('IL-10', 'Gene', '3586', (292, 297))	('schizophrenia', 'Disease', 'MESH:D012559', (140, 153))	('expression levels', 'MPA', (449, 466))	('IL-10', 'Gene', (292, 297))	('TNF-alpha', 'Gene', '7124', (281, 290))	('IL-6', 'Gene', '3569', (470, 474))	('IL-2', 'Gene', (326, 330))	('schizophrenia', 'Phenotype', 'HP:0100753', (140, 153))	('TNF-alpha', 'Gene', (281, 290))	('TNFR1', 'Gene', '7132', (476, 481))	('IL-1beta', 'Gene', '3553', (494, 502))	('rs16944', 'Mutation', 'rs16944', (427, 434))	('IL-6', 'Gene', (470, 474))	('TNFR1', 'Gene', (476, 481))	('TNFR2', 'Gene', (483, 488))	('IL-8', 'Gene', '3576', (320, 324))	('IL-6', 'Gene', '3569', (398, 402))	('IL-1beta', 'Gene', '3553', (310, 318))	('TNFR2', 'Gene', '7133', (483, 488))	('elevated expression levels of IL-6', 'Phenotype', 'HP:0030783', (440, 474))	('IL-1beta', 'Gene', '3553', (418, 426))	('IL-1beta', 'Gene', (494, 502))	('IL-6', 'Gene', (398, 402))	('IL-6', 'Gene', '3569', (275, 279))
3511	30766494	Also antibodies to gliadin have been found elevated in studies comparing patients with schizophrenia to healthy controls, but this was not the case for antibodies more specific to coeliac disease.	('schizophrenia', 'Phenotype', 'HP:0100753', (87, 100))	('elevated', 'PosReg', (43, 51))	('coeliac disease', 'Disease', (180, 195))	('antibodies', 'Var', (5, 15))	('coeliac disease', 'Phenotype', 'HP:0002608', (180, 195))	('gliadin', 'Protein', (19, 26))	('schizophrenia', 'Disease', (87, 100))	('patients', 'Species', '9606', (73, 81))	('coeliac disease', 'Disease', 'MESH:D004194', (180, 195))	('schizophrenia', 'Disease', 'MESH:D012559', (87, 100))
3574	30766494	In another study by the same group 20 stable outpatients with CRP >5 mg/L will be randomized to receive treatment with tocilizumab or placebo for 12 weeks.	('>5 mg/L', 'Var', (66, 73))	('CRP', 'Gene', (62, 65))	('CRP', 'Gene', '1401', (62, 65))	('tocilizumab', 'Chemical', 'MESH:C502936', (119, 130))	('patients', 'Species', '9606', (48, 56))
3577	30766494	NAC interacts with a wide range of physiological pathways, and has anti-oxidative and anti-inflammatory effects.	('NAC', 'Var', (0, 3))	('NAC', 'Chemical', 'MESH:D000111', (0, 3))	('interacts', 'Reg', (4, 13))	('anti-inflammatory effects', 'CPA', (86, 111))	('anti-oxidative', 'MPA', (67, 81))
3578	30766494	A recent systematic review and meta-analysis summarizing the results from 3 RCTs with schizophrenia patients found that NAC improved total psychopathology.	('schizophrenia', 'Disease', 'MESH:D012559', (86, 99))	('schizophrenia', 'Phenotype', 'HP:0100753', (86, 99))	('improved', 'PosReg', (124, 132))	('NAC', 'Var', (120, 123))	('total psychopathology', 'MPA', (133, 154))	('NAC', 'Chemical', 'MESH:D000111', (120, 123))	('patients', 'Species', '9606', (100, 108))	('schizophrenia', 'Disease', (86, 99))
3579	30766494	A recent RCT including 63 early psychosis patients found that NAC had no effects on positive and negative symptoms or functional outcome, but a significant effect on processing speed.	('effect', 'Reg', (156, 162))	('psychosis', 'Phenotype', 'HP:0000709', (32, 41))	('NAC', 'Chemical', 'MESH:D000111', (62, 65))	('psychosis', 'Disease', (32, 41))	('patients', 'Species', '9606', (42, 50))	('psychosis', 'Disease', 'MESH:D011605', (32, 41))	('processing speed', 'MPA', (166, 182))	('NAC', 'Var', (62, 65))
3600	30766494	Also in this meta-analysis minocycline was superior to placebo in improving PANSS total, negative and general subscale, and here also for the positive subscale.	('minocycline', 'Chemical', 'MESH:D008911', (27, 38))	('minocycline', 'Var', (27, 38))	('improving', 'PosReg', (66, 75))	('PANSS total', 'MPA', (76, 87))
3646	27835581	Similar to other cancers, malignant glioma is a pathological outcome resulted from genetic mutations, epigenetic aberrations, environmental stress, malfunctioned metabolism, and immunological dysfunctions.	('immunological dysfunctions', 'Disease', 'MESH:D007154', (178, 204))	('immunological dysfunctions', 'Disease', (178, 204))	('epigenetic aberrations', 'Var', (102, 124))	('malfunctioned', 'Var', (148, 161))	('malignant glioma', 'Disease', (26, 42))	('malignant glioma', 'Disease', 'MESH:D005910', (26, 42))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('genetic mutations', 'Var', (83, 100))	('resulted from', 'Reg', (69, 82))
3647	27835581	For GBM patients received gross total resection in surgery and adjuvant treatments, the 5-year survival rate is merely 0.05% to 4.7% after the first diagnosis, which imperatively necessitates in-depth and comprehensive understanding of the glioma etiology.	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('GBM', 'Gene', (4, 7))	('glioma', 'Disease', (240, 246))	('gross total', 'Var', (26, 37))	('patients', 'Species', '9606', (8, 16))
3648	27835581	Although epigenetic aberration has been uncovered as a driving force in a variety of human diseases, its mechanistic relation to malignant glioma has been less explored.	('malignant glioma', 'Disease', 'MESH:D005910', (129, 145))	('malignant glioma', 'Disease', (129, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('epigenetic aberration', 'Var', (9, 30))	('human', 'Species', '9606', (85, 90))
3649	27835581	As a core epigenetic modulator, DNA methylation (mainly the addition of a methyl-group to the 5-carbon of cytosine) is able to turn off the downstream gene transcription when accumulating at the CpG islands of promoter.	('cytosine', 'Chemical', 'MESH:D003596', (106, 114))	('carbon', 'Chemical', 'MESH:D002244', (96, 102))	('turn', 'Reg', (127, 131))	('methylation', 'Var', (36, 47))
3657	27835581	We further uncover that depleting MBD3 enhances the transcription of the oncogenic miR-17-92 cluster at chromosome 13, therefore promoting tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('depleting', 'Var', (24, 33))	('miR-17-92', 'Gene', (83, 92))	('enhances', 'PosReg', (39, 47))	('transcription', 'MPA', (52, 65))	('tumor', 'Disease', (139, 144))	('MBD3', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('promoting', 'PosReg', (129, 138))	('miR-17-92', 'Gene', '407975', (83, 92))
3667	27835581	Hence, we proposed that the deregulated MBD3 may join other oncogenic events (e.g., global DNA hypohydroxymethylation) to promote gliomagenesis and metastasis.	('glioma', 'Disease', (130, 136))	('promote', 'PosReg', (122, 129))	('global DNA hypohydroxymethylation', 'MPA', (84, 117))	('deregulated', 'Var', (28, 39))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('MBD3', 'Gene', (40, 44))
3674	27835581	The top-matched gene ontology (GO) term in the down-regulated DEGs by MBD3-KD is the "MHC II protein complex" - a surface protein complex presenting antigens to the CD4+ T cells (Figure S3).	('MBD3-KD', 'Var', (70, 77))	('DEGs', 'Gene', '8560', (62, 66))	('down-regulated', 'NegReg', (47, 61))	('DEGs', 'Gene', (62, 66))
3676	27835581	Other up-regulated DEGs by MBD3-KD include transport proteins (e.g., ion channel proteins and solute carrier family), cytochrome P450 family, growth factors (e.g., FGF and IGF), and dynein proteins, all of which are hallmarks for active cell metabolism and proliferation.	('DEGs', 'Gene', '8560', (19, 23))	('transport proteins', 'MPA', (43, 61))	('DEGs', 'Gene', (19, 23))	('ion channel proteins', 'MPA', (69, 89))	('cytochrome P450 family', 'Enzyme', (118, 140))	('dynein proteins', 'Protein', (182, 197))	('up-regulated', 'PosReg', (6, 18))	('MBD3-KD', 'Var', (27, 34))
3677	27835581	Moreover, the MBD3-KD induced DEG-dependent cell functions and diseases, as revealed by Ingenuity Pathway Analysis (IPA), mainly point to "gliomagenesis", "inflammatory responses", "metabolism", and "signaling" in the central nervous system (CNS) (Figure 3).	('MBD3-KD', 'Var', (14, 21))	('point', 'Reg', (129, 134))	('glioma', 'Disease', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))
3683	27835581	Transcription of CIITA is subjected to epigenetic inactivation, especially by DNA methylation in the promoter IV region.	('methylation', 'Var', (82, 93))	('CIITA', 'Gene', (17, 22))	('epigenetic inactivation', 'MPA', (39, 62))	('CIITA', 'Gene', '4261', (17, 22))	('DNA methylation', 'Var', (78, 93))
3684	27835581	With methylation-specific PCR (MSP), the methylation level of the CIITA promoter IV was also found to rapidly increase by ~20% after 72 hours of MBD3-KD (Figure S6B), which supports an epigenetic control on the CIITA gene expression by MBD3.	('CIITA', 'Gene', (211, 216))	('increase', 'PosReg', (110, 118))	('MBD3-KD', 'Var', (145, 152))	('CIITA', 'Gene', '4261', (211, 216))	('CIITA', 'Gene', (66, 71))	('CIITA', 'Gene', '4261', (66, 71))	('methylation level', 'MPA', (41, 58))
3697	27835581	Among all the variants, the full-length (WT), Delta(9, 10), Delta(11q), and Delta(9, 10, 11q) are four predominant BRCA1 gene products.	('Delta(11q', 'Var', (60, 69))	('BRCA1', 'Gene', '672', (115, 120))	('variants', 'Var', (14, 22))	('Delta(9, 10, 11q', 'Var', (76, 92))	('BRCA1', 'Gene', (115, 120))
3698	27835581	The Delta(11q) and Delta(9, 10, 11q) variants respectively give rise to the functional isoforms of BRCA1a and BRCA1b proteins.	('BRCA1', 'Gene', (99, 104))	('BRCA1', 'Gene', '672', (110, 115))	('Delta(11q', 'Var', (4, 13))	('proteins', 'Protein', (117, 125))	('functional isoforms', 'MPA', (76, 95))	('give rise', 'Reg', (59, 68))	('BRCA1', 'Gene', (110, 115))	('Delta(9, 10, 11q', 'Var', (19, 35))	('BRCA1', 'Gene', '672', (99, 104))
3699	27835581	In light of this knowledge, we next evaluated the quantities of these four major BRCA1 variants after MBD3 knockdown.	('BRCA1', 'Gene', '672', (81, 86))	('variants', 'Var', (87, 95))	('BRCA1', 'Gene', (81, 86))
3702	27835581	As a result, the disturbed equilibrium in BRCA1 expression would exacerbate the glioma progression, as supported by the Kaplan-Meier survival data in the NCI REMBRANDT database (https://caintegrator.nci.nih.gov/rembrandt, Figure S9).	('glioma', 'Disease', (80, 86))	('BRCA1', 'Gene', '672', (42, 47))	('exacerbate', 'PosReg', (65, 75))	('BRCA1', 'Gene', (42, 47))	('expression', 'MPA', (48, 58))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('disturbed', 'Var', (17, 26))
3734	27835581	Nevertheless, by epigenetically regulating the CIITA gene and relevant lncRNAs on chromosome 6, MBD3 may be able to reactivate MHC class II molecules and hence serve as a therapeutic target to advance the current wave of immunotherapies.	('CIITA', 'Gene', (47, 52))	('CIITA', 'Gene', '4261', (47, 52))	('MHC class II molecules', 'Protein', (127, 149))	('MBD3', 'Gene', (96, 100))	('reactivate', 'NegReg', (116, 126))	('epigenetically regulating', 'Var', (17, 42))	('advance', 'PosReg', (193, 200))
3742	27835581	In our study, the up-regulation of miR-17-92 in GBM rather than in low-grade gliomas, can be primarily attributed to the significantly higher expression of n-Myc (up by 4.46-fold) and E2Fs (Figure S14).	('up-regulation', 'PosReg', (18, 31))	('gliomas', 'Disease', (77, 84))	('GBM', 'Disease', (48, 51))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('n-Myc', 'Gene', (156, 161))	('miR-17-92', 'Gene', (35, 44))	('n-Myc', 'Gene', '4613', (156, 161))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('E2Fs', 'Var', (184, 188))	('expression', 'MPA', (142, 152))	('higher', 'PosReg', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('miR-17-92', 'Gene', '407975', (35, 44))
3743	27835581	As a control mechanism, MBD3 and its associated Mi-2/NuRD complex could epigenetically fine-tune the transactivation activity of Myc proteins.	('fine-tune', 'Reg', (87, 96))	('Myc', 'Gene', (129, 132))	('transactivation activity', 'MPA', (101, 125))	('epigenetically', 'Var', (72, 86))	('MBD3', 'Gene', (24, 28))	('Myc', 'Gene', '4609', (129, 132))
3751	27835581	Although BRCA1 is a tumor suppressor gene responding to DNA damage, the disequilibrium among its spliced variants may adversely abrogate the therapeutic benefits from the DNA damage-inducing agents, such as temozolomide and platinum drugs.	('abrogate', 'NegReg', (128, 136))	('disequilibrium', 'MPA', (72, 86))	('therapeutic', 'MPA', (141, 152))	('BRCA1', 'Gene', '672', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('variants', 'Var', (105, 113))	('temozolomide', 'Chemical', 'MESH:D000077204', (207, 219))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BRCA1', 'Gene', (9, 14))	('tumor', 'Disease', (20, 25))
3752	27835581	With an over-activation of Gomafu by depleting MBD3, the full-length BRCA1 increases at the cost of two major spliced variants BRCA1a and BRCA1b.	('BRCA1', 'Gene', '672', (138, 143))	('BRCA1', 'Gene', '672', (127, 132))	('BRCA1', 'Gene', '672', (69, 74))	('Gomafu', 'Gene', '440823', (27, 33))	('BRCA1', 'Gene', (138, 143))	('BRCA1', 'Gene', (127, 132))	('BRCA1', 'Gene', (69, 74))	('Gomafu', 'Gene', (27, 33))	('depleting', 'Var', (37, 46))	('increases', 'PosReg', (75, 84))
3754	27835581	Clinically, the altered ratio of BRCA1 variants would undermine the survival of glioma patients who need standard temozolomide treatment.	('glioma', 'Disease', (80, 86))	('survival', 'CPA', (68, 76))	('undermine', 'NegReg', (54, 63))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('BRCA1', 'Gene', '672', (33, 38))	('temozolomide', 'Chemical', 'MESH:D000077204', (114, 126))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('patients', 'Species', '9606', (87, 95))	('BRCA1', 'Gene', (33, 38))	('variants', 'Var', (39, 47))
3771	27835581	The difference of whole-genome transcriptome between low-grade glioma and GBM, as well as the DEGs before and after knocking down MBD3 in human SF767 GBM cells were investigated by the SurePrint G3 Human Gene Expression 8 x 60K Microarray Kit (Design ID: 028004, Agilent) that covers 27,958 Entrez Gene RNAs and 7,419 lncRNAs.	('DEGs', 'Gene', '8560', (94, 98))	('SF767', 'CellLine', 'CVCL:6950', (144, 149))	('DEGs', 'Gene', (94, 98))	('human', 'Species', '9606', (138, 143))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('Human', 'Species', '9606', (198, 203))	('knocking', 'Var', (116, 124))	('glioma', 'Disease', (63, 69))
3777	27835581	PCR amplifications for BRCA1 variants, p53, p21 and Caspase3 were performed in a StepOnePlus system (Applied Biosystems) with SYBR Green PCR Master Mix (Life Technologies).	('Caspase3', 'Gene', (52, 60))	('Caspase3', 'Gene', '836', (52, 60))	('variants', 'Var', (29, 37))	('p53', 'Gene', (39, 42))	('p21', 'Gene', '1026', (44, 47))	('p53', 'Gene', '7157', (39, 42))	('p21', 'Gene', (44, 47))	('BRCA1', 'Gene', '672', (23, 28))	('BRCA1', 'Gene', (23, 28))
3837	22937526	A mutation in the NF-1 gene results in an absence of a protein called neurofibromin.	('neurofibromin', 'Gene', '4763', (70, 83))	('mutation', 'Var', (2, 10))	('absence', 'NegReg', (42, 49))	('neurofibromin', 'Gene', (70, 83))	('NF-1', 'Gene', (18, 22))
3844	22937526	Patients with Turcot's syndrome typically have a defect in the adenomatous polyposis coli (APC) gene and/or a mutation in DNA mismatch repair (MMR) genes predisposing them to the development of multiple colorectal adenomas, colorectal adenocarcinoma, and primary brain tumors.	('adenomatous polyposis coli', 'Disease', (63, 89))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (63, 89))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (224, 249))	('multiple colorectal adenomas', 'Disease', 'MESH:C563924', (194, 222))	('brain tumors', 'Disease', 'MESH:D001932', (263, 275))	('brain tumors', 'Phenotype', 'HP:0030692', (263, 275))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('defect', 'NegReg', (49, 55))	("Turcot's syndrome", 'Disease', (14, 31))	("Turcot's syndrome", 'Disease', 'MESH:C536928', (14, 31))	('Patients', 'Species', '9606', (0, 8))	('brain tumor', 'Phenotype', 'HP:0030692', (263, 274))	('APC', 'Phenotype', 'HP:0005227', (91, 94))	('APC', 'Disease', 'MESH:D011125', (91, 94))	('APC', 'Disease', (91, 94))	('brain tumors', 'Disease', (263, 275))	('multiple colorectal adenomas', 'Disease', (194, 222))	('mutation', 'Var', (110, 118))	('colorectal adenocarcinoma', 'Disease', (224, 249))	('MMR', 'Gene', (143, 146))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (63, 89))
3845	22937526	The MMR mutations are thought to be associated with the development of HGG in these patients whereas the APC defects are more closely associated with medulloblastoma development.	('medulloblastoma', 'Phenotype', 'HP:0002885', (150, 165))	('APC defects', 'Disease', 'MESH:D011125', (105, 116))	('patients', 'Species', '9606', (84, 92))	('HGG', 'Disease', (71, 74))	('APC defects', 'Disease', (105, 116))	('mutations', 'Var', (8, 17))	('medulloblastoma', 'Disease', (150, 165))	('APC', 'Phenotype', 'HP:0005227', (105, 108))	('associated with', 'Reg', (36, 51))	('MMR', 'Gene', (4, 7))	('medulloblastoma', 'Disease', 'MESH:D008527', (150, 165))
3880	22937526	An analysis of p53 revealed that those patients with overexpression of p53 and/or a mutation in the TP53 gene had significantly lower PFS as compared to children who had neither of these findings.	('TP53', 'Gene', '7157', (100, 104))	('patients', 'Species', '9606', (39, 47))	('overexpression', 'PosReg', (53, 67))	('TP53', 'Gene', (100, 104))	('PFS', 'MPA', (134, 137))	('children', 'Species', '9606', (153, 161))	('p53', 'Gene', (15, 18))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', '7157', (71, 74))	('lower', 'NegReg', (128, 133))	('mutation', 'Var', (84, 92))
3881	22937526	Abnormalities of p53 were most commonly seen in WHO grade IV tumors; however, p53 was shown to be an independent prognostic factor regardless of histologic grade.	('Abnormalities', 'Var', (0, 13))	('IV tumors', 'Disease', 'MESH:D009369', (58, 67))	('p53', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('p53', 'Gene', '7157', (78, 81))	('IV tumors', 'Disease', (58, 67))
3908	22937526	Unfortunately, numerous subsequent combination studies completed over the last 40 years have never reached the outcomes achieved by the CCG-943 trial, suggesting that the addition of LGGs in this cohort skewed the survivals reported.	('addition', 'Var', (171, 179))	('CCG', 'Chemical', '-', (136, 139))	('survivals', 'MPA', (214, 223))
3968	22937526	One of the most common genetic abnormalities in adult HGG is the amplification of epidermal growth factor receptor (EGFR).	('epidermal growth factor receptor', 'Gene', (82, 114))	('genetic abnormalities', 'Disease', (23, 44))	('adult HGG', 'Disease', (48, 57))	('epidermal growth factor receptor', 'Gene', '1956', (82, 114))	('amplification', 'Var', (65, 78))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('genetic abnormalities', 'Disease', 'MESH:D030342', (23, 44))
3971	22937526	Mutations in the p53 pathway are a much more common finding in pediatric HGG.	('common', 'Reg', (45, 51))	('pediatric HGG', 'Disease', (63, 76))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
3972	22937526	Both overexpression of p53 and mutations in the TP53 suppressor gene can lead to defects in this pathway and tumorigenesis.	('mutations', 'Var', (31, 40))	('TP53', 'Gene', '7157', (48, 52))	('defects', 'NegReg', (81, 88))	('TP53', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
3973	22937526	Many of the alteration/abnormalities identified in adult HGG such as retinoblastoma gene mutation, amplifications of MYC, MYCN, CDK6, CCND2, deletion of CDKN2C and PTEN mutations are less well understood and overall seemingly less prevalent among children.	('MYCN', 'Gene', '4613', (122, 126))	('retinoblastoma', 'Disease', 'MESH:D012175', (69, 83))	('children', 'Species', '9606', (247, 255))	('PTEN', 'Gene', (164, 168))	('CDK6', 'Gene', (128, 132))	('MYC', 'Gene', '4609', (117, 120))	('MYC', 'Gene', (122, 125))	('CDKN2C', 'Gene', '1031', (153, 159))	('retinoblastoma', 'Phenotype', 'HP:0009919', (69, 83))	('PTEN', 'Gene', '5728', (164, 168))	('MYCN', 'Gene', (122, 126))	('deletion', 'Var', (141, 149))	('retinoblastoma', 'Disease', (69, 83))	('CCND2', 'Gene', (134, 139))	('MYC', 'Gene', '4609', (122, 125))	('CCND2', 'Gene', '894', (134, 139))	('MYC', 'Gene', (117, 120))	('CDKN2C', 'Gene', (153, 159))	('CDK6', 'Gene', '1021', (128, 132))
3974	22937526	Among the numerous focal genetic alterations elucidated in pediatric HGG, platelet-derived growth factor receptor A (PDGFRA) amplification is by far the most common genomic event identified.	('amplification', 'Var', (125, 138))	('PDGFRA', 'Gene', (117, 123))	('PDGFRA', 'Gene', '5156', (117, 123))	('platelet-derived growth factor receptor A', 'Gene', '5156', (74, 115))	('common', 'Reg', (158, 164))	('platelet-derived growth factor receptor A', 'Gene', (74, 115))
3976	22937526	Another mutation observed in about 10% of pediatric HGG is the V600E point mutation in BRAF.	('V600E point', 'Var', (63, 74))	('BRAF', 'Gene', '673', (87, 91))	('BRAF', 'Gene', (87, 91))	('V600E', 'Mutation', 'rs113488022', (63, 68))
3978	22937526	Distinct from the BRAFV600E mutation in many LGG, however, CDKN2A/CDKN2B mutations are more common in these HGG which may help explain why these lesions behave more malignant compared to their LGG counterparts.	('HGG', 'Disease', (108, 111))	('CDKN2B', 'Gene', '1030', (66, 72))	('common', 'Reg', (92, 98))	('CDKN2A', 'Gene', (59, 65))	('CDKN2B', 'Gene', (66, 72))	('mutations', 'Var', (73, 82))	('CDKN2A', 'Gene', '1029', (59, 65))
3980	22937526	PDGFRA was the predominant target of focal amplification in childhood HGG as mentioned above.	('PDGFRA', 'Gene', (0, 6))	('PDGFRA', 'Gene', '5156', (0, 6))	('child', 'Species', '9606', (60, 65))	('childhood HGG', 'Disease', (60, 73))	('focal amplification', 'Var', (37, 56))
3981	22937526	Specific gene expression analyses identified a possible role for disrupted PDGFRalpha signaling in pediatric HGG.	('pediatric HGG', 'Disease', (99, 112))	('PDGFRalpha', 'Gene', '5156', (75, 85))	('PDGFRalpha', 'Gene', (75, 85))	('disrupted', 'Var', (65, 74))
3982	22937526	This group also did not identify a significant number of isocitrate dehydrogenase I (IDHI) mutations in pediatric HGG which have been shown to be quite prevalent and prognostic among adult HGG patients.	('patients', 'Species', '9606', (193, 201))	('mutations', 'Var', (91, 100))	('IDHI', 'Gene', (85, 89))
3989	22937526	Mutations in H3F3A were observed in 31%, which was identified to effect key regulatory post-translational modifications.	('H3F3A', 'Gene', '3020', (13, 18))	('Mutations', 'Var', (0, 9))	('H3F3A', 'Gene', (13, 18))
3990	22937526	Mutations in ATRX (alpha-thalassemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), were identified in 31% of tumor samples and TP53 mutations were found in 54% of all cases.	('DAXX', 'Gene', '1616', (79, 83))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (25, 73))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ATRX', 'Gene', (13, 17))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (25, 73))	('identified', 'Reg', (124, 134))	('mental retardation', 'Phenotype', 'HP:0001249', (37, 55))	('ATRX', 'Gene', '546', (13, 17))	('TP53', 'Gene', '7157', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('DAXX', 'Gene', (79, 83))	('tumor', 'Disease', (145, 150))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (163, 167))
3991	22937526	TP53 mutations were found at a higher percent in samples that also had H3F3A and/or ATRX mutations.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('H3F3A', 'Gene', (71, 76))	('ATRX', 'Gene', '546', (84, 88))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (89, 98))	('H3F3A', 'Gene', '3020', (71, 76))	('ATRX', 'Gene', (84, 88))
4054	22394548	cellularity, pleomorphism, vessel hyperplasia and degree of mitosis, and lowers the proliferating cell nuclear antigen, a marker for late G1- and S-phases of the cell cycle.	('hyperplasia', 'Disease', 'MESH:D006965', (34, 45))	('cellularity', 'CPA', (0, 11))	('mitosis', 'Disease', (60, 67))	('proliferating cell nuclear antigen', 'MPA', (84, 118))	('pleomorphism', 'Var', (13, 25))	('lowers', 'NegReg', (73, 79))	('mitosis', 'Disease', 'None', (60, 67))	('hyperplasia', 'Disease', (34, 45))
4116	22394548	Moreover, the effects of an oligodendroglial differentiation, as well as recently discovered molecular genetic markers (such as LOH1p/19q, TP53 mutations, MGMT promoter methylation and IDH1 mutations), on the efficiency of interstitial brachytherapy, have not been evaluated yet.	('IDH1', 'Gene', '3417', (185, 189))	('MGMT', 'Gene', '4255', (155, 159))	('mutations', 'Var', (190, 199))	('LOH1p/19q', 'Gene', (128, 137))	('MGMT', 'Gene', (155, 159))	('TP53', 'Gene', '7157', (139, 143))	('TP53', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('IDH1', 'Gene', (185, 189))
4125	22394548	found a 5-year survival rate as high as 93% in patients with low activity temporary iodine-125 implants (54Gy, 10cGy/h).	('activity', 'MPA', (65, 73))	('iodine-125', 'Chemical', 'MESH:C000614960', (84, 94))	('low', 'NegReg', (61, 64))	('patients', 'Species', '9606', (47, 55))	('54Gy', 'Var', (105, 109))
4130	22394548	Target volume and radiation dose showed a direct correlation with the risk of radionecrosis with critical values being 35 cm3 and 100Gy for permanent and 50Gy at 42cGy/h for temporary implants.	('necrosis', 'Disease', 'MESH:D009336', (83, 91))	('100Gy', 'Var', (130, 135))	('necrosis', 'Disease', (83, 91))	('50Gy', 'Var', (154, 158))
4143	22394548	Factors associated with improved survival were age <= 45-50 years, KPS >= 80-90, superficial location, decreasing volume of implanted tumour, chemotherapy at recurrence and reoperation at the original site in case of tumour recurrence.	('KPS >= 80-90', 'Var', (67, 79))	('improved', 'PosReg', (24, 32))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('survival', 'MPA', (33, 41))	('tumour', 'Disease', (134, 140))	('tumour', 'Disease', (217, 223))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
4155	22394548	Iodine-125 has improved the survival most demonstrably in poorer prognostic classes so that a selection bias does not account for the survival benefit.	('improved', 'PosReg', (15, 23))	('survival', 'MPA', (28, 36))	('Iodine-125', 'Chemical', 'MESH:C000614960', (0, 10))	('Iodine-125', 'Var', (0, 10))
4173	22394548	For metastases, good prognostic factors are KPS >= 70, solitary metastasis, no extracerebral metastases, long time interval between primary diagnosis and diagnosis of metastases.	('metastases', 'Disease', 'MESH:D009362', (4, 14))	('metastases', 'Disease', (93, 103))	('KPS >= 70', 'Var', (44, 53))	('metastases', 'Disease', (167, 177))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('solitary', 'Disease', (55, 63))	('metastases', 'Disease', 'MESH:D009362', (167, 177))	('metastases', 'Disease', (4, 14))
4198	22394548	Late radiation necrosis is a severe side effect which seems to occur in 40% of the low-dose-rate implantations and is correlated with total radiation dose, implanted activity and the velocity of tumour shrinkage.	('low-dose-rate', 'Var', (83, 96))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Disease', (195, 201))	('radiation necrosis', 'Disease', 'MESH:D004194', (5, 23))	('radiation necrosis', 'Disease', (5, 23))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
4369	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))
4370	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))
4376	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', 'MESH:D005909', (158, 161))	('MATH', 'Var', (0, 4))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', (116, 122))	('recurrence-free survival', 'CPA', (62, 86))	('negatively', 'NegReg', (17, 27))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('GBM', 'Disease', (158, 161))
4387	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))
4416	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))
4417	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))
4419	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))
4422	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))
4425	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))
4428	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))
4429	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))
4441	31788085	Patients with GBM and IDH1/2-wt glioma had higher MATH levels than the other patients with glioma.	('higher', 'PosReg', (43, 49))	('GBM', 'Disease', (14, 17))	('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))
4442	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))
4449	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))
4451	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))
4452	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))
4455	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))	('effect', 'Reg', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('gene', 'Var', (56, 60))	('glioma', 'Disease', (179, 185))
4456	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))
4461	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.	('GBM', 'Disease', (206, 209))	('IDH1/2-wt', 'Var', (188, 197))	('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))
4462	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))
4465	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))
4466	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))	('PTEN', 'Gene', '5728', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('ATRX', 'Gene', '546', (70, 74))	('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))
4469	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))
4470	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))
4473	31788085	In addition, MATH values do not comprehensively describe glioma ITH, which results from epigenetic regulation and the tumor microenvironment and needs to be analyzed using advanced methods.	('results from', 'Reg', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('epigenetic', 'Var', (88, 98))	('glioma', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
4476	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))	('tumor', 'Disease', (87, 92))	('glioblastoma', 'Disease', (4, 16))	('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))
4493	31601888	Approximately 80% of LGG harbor driver mutations in isocitrate dehydrogenase (IDH) 1 or 2 genes, while HGG are mostly IDH wildtype.	('LGG', 'Disease', (21, 24))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (52, 84))	('mutations', 'Var', (39, 48))
4512	31601888	Since the observed differences in quantity and location of CD8 T cells could be due to different levels in antigenicity, we have determined the quantity of: (i) neo-antigens that may arise from expressed somatic mutations and (ii) cancer germline antigens (CGAs) that may arise from loss of epigenetic silencing.	('CGA', 'Gene', (257, 260))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('loss', 'NegReg', (283, 287))	('CD8', 'Gene', (59, 62))	('CGA', 'Gene', '1113', (257, 260))	('CD8', 'Gene', '925', (59, 62))	('mutations', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('epigenetic silencing', 'Var', (291, 311))
4513	31601888	Importantly, on average only two of these expressed mutations per tumor scored sufficiently high according to MHC class I binding, proteasomal C terminal cleavage and TAP transport efficiency to be considered a neo-epitope.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('binding', 'Interaction', (122, 129))	('tumor', 'Disease', (66, 71))	('MHC', 'Gene', '3107', (110, 113))	('proteasomal C terminal cleavage', 'MPA', (131, 162))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TAP', 'Gene', (167, 170))	('TAP', 'Gene', '23541', (167, 170))	('MHC', 'Gene', (110, 113))
4531	31601888	For example, in a murine model for LGG, the introduction of mutant IDH1 or treatment with 2HG reduced protein levels of CXCL10 likely through decreased production of STAT1, and suppressed the accumulation of T cells at tumor sites.	('suppressed', 'NegReg', (177, 187))	('accumulation', 'CPA', (192, 204))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('protein levels of CXCL10', 'MPA', (102, 126))	('STAT1', 'Gene', '20846', (166, 171))	('reduced', 'NegReg', (94, 101))	('STAT1', 'Gene', (166, 171))	('tumor', 'Disease', (219, 224))	('IDH1', 'Gene', (67, 71))	('decreased', 'NegReg', (142, 151))	('mutant', 'Var', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('murine', 'Species', '10090', (18, 24))
4532	31601888	A different study showed that 2HG reduced proliferation of human T cells cultured in vitro.	('human', 'Species', '9606', (59, 64))	('reduced', 'NegReg', (34, 41))	('proliferation of human T cells cultured in vitro', 'CPA', (42, 90))	('2HG', 'Var', (30, 33))
4536	31601888	A recent study analyzed PD-1+ T cell infiltration and also PD-L1 tumor cell expression in 57 IDH mutant and 117 IDH wildtype gliomas and found that IDH wildtype HGG gliomas display more prominent PD-1+ T cells and higher PD-L1 expression when compared to IDH mutant LGG cases.	('gliomas', 'Disease', (125, 132))	('higher', 'PosReg', (214, 220))	('IDH', 'Var', (148, 151))	('PD-L1 tumor', 'Disease', 'MESH:C536029', (59, 70))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('PD-L1', 'Protein', (221, 226))	('PD-1+ T cells', 'CPA', (196, 209))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('expression', 'MPA', (227, 237))	('HGG', 'Disease', (161, 164))	('gliomas', 'Disease', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('PD-L1 tumor', 'Disease', (59, 70))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
4537	31601888	Garber and colleagues also showed a positive correlation between PD-1+ T cells and high but not low tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('high', 'CPA', (83, 87))	('PD-1+ T cells', 'Var', (65, 78))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
4541	31601888	Studies on melanoma and non-small-cell lung carcinoma have shown that response to checkpoint inhibitors is associated with a high mutational load.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('non-small-cell lung carcinoma', 'Disease', (24, 53))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (24, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('high mutational load', 'Var', (125, 145))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
4543	31601888	In most HGG and LGG mutational burden is more than an order of magnitude lower than in melanomas and lung adenocarcinomas.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('HGG', 'Disease', (8, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('lung adenocarcinomas', 'Disease', (101, 121))	('melanomas', 'Disease', (87, 96))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (101, 121))	('LGG', 'Disease', (16, 19))	('lower', 'NegReg', (73, 78))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('mutational', 'Var', (20, 30))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (101, 121))	('melanomas', 'Disease', 'MESH:D008545', (87, 96))
4549	31601888	Indeed, there is preclinical evidence for the immunogenicity of a number of neo-epitopes arising from hallmark glioma mutations, including EGFRvIII (an intragenic deletion of exons 2-7 of the epidermal growth factor receptor), IDH1R132H and H3.3K27M .	('deletion', 'Var', (163, 171))	('EGFRvIII', 'Gene', (139, 147))	('H3.3K27M', 'Var', (241, 249))	('mutations', 'Var', (118, 127))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('hallmark glioma', 'Disease', (102, 117))	('IDH1R132H', 'Var', (227, 236))	('hallmark glioma', 'Disease', 'MESH:D005910', (102, 117))
4561	31601888	We performed sanger sequencing on DNA isolated from FFPE tumor tissue samples in case of unknown IDH1 mutation status.	('IDH1', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
4570	31601888	Live T cells (7AAD-, CD14-, CD3+) were quantified on a FACS Canto (BD Biosciences) and flow cytometric data was analyzed using FlowJo V10.	('CD14', 'Gene', '929', (21, 25))	('CD3+', 'Var', (28, 32))	('CD14', 'Gene', (21, 25))
4574	31601888	The sections were washed in PBS and incubated for 1 hour with one of the following mouse anti-human primary antibodies: anti-CD3 clone F7.2.38, 1:100; anti-CD8 clone C8/144B, 1:200, anti-CD31 clone JC70A, 1:30 (all from Agilent Technologies, Amstelveen, the Netherlands); and, subsequently, with goat anti-mouse biotinylated, 1:200 (Agilent Technologies).	('JC70A', 'Var', (198, 203))	('CD31', 'Gene', '5175', (187, 191))	('mouse', 'Species', '10090', (83, 88))	('mouse', 'Species', '10090', (306, 311))	('human', 'Species', '9606', (94, 99))	('CD8', 'Gene', '925', (156, 159))	('goat', 'Species', '9925', (296, 300))	('CD8', 'Gene', (156, 159))	('CD31', 'Gene', (187, 191))
4588	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))
4592	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))
4593	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))
4600	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))
4618	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))
4621	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))
4628	25558448	Univariate Cox regression models, with activity entered either as a dichotomous variable using median activity as the cut point or as a continuous variable, revealed an inverse association between MGMT activity and PFS in 91 GBMs and in 84 AGs.	('GBM', 'Phenotype', 'HP:0012174', (225, 228))	('AGs', 'Chemical', '-', (240, 243))	('MGMT', 'Gene', (197, 201))	('MGMT', 'Gene', '4255', (197, 201))	('PFS', 'Var', (215, 218))	('inverse', 'NegReg', (169, 176))
4630	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))	('MGMT', 'Gene', (41, 45))	('PFS', 'MPA', (82, 85))
4636	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))
4722	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))
4728	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))	('MGMT', 'Gene', '4255', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('MGMT', 'Gene', (136, 140))	('tumors', 'Disease', (169, 175))
4732	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))
4739	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))
4746	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))
4747	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))
4755	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))
4773	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.	('promoter methylation', 'Var', (83, 103))	('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))
4774	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))
4775	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))
4776	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))
4782	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))
4783	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))
4784	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))	('MGMT', 'Gene', (33, 37))	('methylation', 'Var', (47, 58))	('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))
4785	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))
4802	33652578	Indeed, mutations, chromosomal alterations and the deregulation of teneurins expression have been associated with several tumor types and patient survival.	('teneurins', 'Protein', (67, 76))	('expression', 'MPA', (77, 87))	('deregulation', 'Var', (51, 63))	('teneurins', 'Chemical', '-', (67, 76))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patient', 'Species', '9606', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('chromosomal alterations', 'Var', (19, 42))	('rat', 'Species', '10116', (35, 38))	('associated', 'Reg', (98, 108))	('tumor', 'Disease', (122, 127))
4827	33652578	This trans-homodimerization of teneurins has been reported to allow the correct matching between axons and their targets to occur, thus contributing to correct circuit-wiring in the nervous system.	('circuit-wiring', 'CPA', (160, 174))	('contributing to', 'Reg', (136, 151))	('trans-homodimerization', 'Var', (5, 27))	('matching', 'MPA', (80, 88))	('teneurins', 'Chemical', '-', (31, 40))
4828	33652578	Upon homodimerization, teneurins' intracellular domains are cleaved close to the plasma membrane and translocate into the nucleus, where they regulate gene expression via direct and indirect interactions with transcription factors.	('gene expression', 'MPA', (151, 166))	('teneurins', 'Chemical', '-', (23, 32))	('interactions', 'Interaction', (191, 203))	('regulate', 'Reg', (142, 150))	('homodimerization', 'Var', (5, 21))
4833	33652578	The different teneurins' alternative variants interact with different ligands, mediating either teneurin homodimerization or heterodimerization with latrophilins, leading to the activation of different biological functions.	('biological functions', 'MPA', (202, 222))	('teneurin', 'Chemical', '-', (96, 104))	('teneurins', 'Gene', (14, 23))	('activation', 'PosReg', (178, 188))	('teneurin', 'Protein', (96, 104))	('mediating', 'Reg', (79, 88))	('teneurin', 'Chemical', '-', (14, 22))	('teneurins', 'Chemical', '-', (14, 23))	('variants', 'Var', (37, 45))	('heterodimerization', 'MPA', (125, 143))	('homodimerization', 'MPA', (105, 121))
4844	33652578	Recent data have demonstrated a role for TENM1 in the establishment of olfactory circuits; indeed, TENM1 deletion in mice affects their ability to detect odors and TENM1 mutations in humans are correlated with congenital anosmia.	('deletion', 'Var', (105, 113))	('ability to detect odors', 'MPA', (136, 159))	('TENM1', 'Gene', (99, 104))	('TENM1', 'Gene', (164, 169))	('congenital anosmia', 'Disease', (210, 228))	('humans', 'Species', '9606', (183, 189))	('mutations', 'Var', (170, 179))	('anosmia', 'Phenotype', 'HP:0000458', (221, 228))	('affects', 'Reg', (122, 129))	('mice', 'Species', '10090', (117, 121))	('rat', 'Species', '10116', (24, 27))	('correlated with', 'Reg', (194, 209))	('congenital anosmia', 'Disease', 'MESH:C535983', (210, 228))
4854	33652578	Indeed, in vivo studies in rodents have demonstrated that TCAP-1 administration impacts upon CRF-associated behavior, such as anxiety and depression, and increases glucose levels in rat brains.	('increases', 'PosReg', (154, 163))	('anxiety', 'Phenotype', 'HP:0000739', (126, 133))	('impacts', 'Reg', (80, 87))	('increases glucose levels', 'Phenotype', 'HP:0003074', (154, 178))	('depression', 'Disease', 'MESH:D000275', (138, 148))	('depression', 'Phenotype', 'HP:0000716', (138, 148))	('CRF-associated', 'Disease', (93, 107))	('rat', 'Species', '10116', (47, 50))	('depression', 'Disease', (138, 148))	('TCAP', 'Gene', (58, 62))	('rat', 'Species', '10116', (182, 185))	('glucose levels', 'MPA', (164, 178))	('TCAP', 'Gene', '8557', (58, 62))	('anxiety', 'Disease', 'MESH:D001007', (126, 133))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('anxiety', 'Disease', (126, 133))	('administration', 'Var', (65, 79))	('rat', 'Species', '10116', (73, 76))
4855	33652578	Besides congenital general anosmia, TENM1 deregulation has also been associated with several tumors.	('TENM1', 'Gene', (36, 41))	('deregulation', 'Var', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('associated', 'Reg', (69, 79))	('congenital general anosmia', 'Disease', 'MESH:C535983', (8, 34))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('congenital general anosmia', 'Disease', (8, 34))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('anosmia', 'Phenotype', 'HP:0000458', (27, 34))
4859	33652578	However, data on the association between TENM1 deregulation and tumor progression are scarce and confined to a few tumor types, such as thyroid carcinoma, pituitary tumor and glioblastoma.	('tumor', 'Disease', (115, 120))	('pituitary tumor', 'Disease', (155, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('deregulation', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (136, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (175, 187))	('thyroid carcinoma', 'Disease', (136, 153))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', (64, 69))	('TENM1', 'Gene', (41, 46))	('glioblastoma', 'Disease', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (136, 153))	('pituitary tumor', 'Disease', 'MESH:D010911', (155, 170))
4860	33652578	Further support for TENM1's functional contribution to carcinogenesis, TENM1 mutations and chromosomal alterations have occasionally been found in tumors of differing origins.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('rat', 'Species', '10116', (107, 110))	('mutations', 'Var', (77, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('TENM1', 'Gene', (71, 76))	('carcinogenesis', 'Disease', (55, 69))
4873	33652578	Recent data show that TENM1 is also up-regulated in a follicular variant of papillary thyroid cancer, and it is significantly more highly expressed and mutated in thyroid malignant nodules than in benign ones.	('papillary thyroid cancer', 'Disease', (76, 100))	('expressed', 'MPA', (138, 147))	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('mutated', 'Var', (152, 159))	('more highly', 'PosReg', (126, 137))	('up-regulated', 'PosReg', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TENM1', 'Gene', (22, 27))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (76, 100))	('follicular', 'Disease', (54, 64))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (76, 100))
4875	33652578	Another tumor in which TENM1 seems to play an oncogenic role is glioblastoma, where it promotes the cell proliferation, the cytoskeletal remodeling of tumor cells and the invasion of the surrounding environment, both in vitro and in vivo, via the Myc-dependent transcriptional up-regulation of ras homolog family member A (RhoA) and consequent rho-associated protein kinase (ROCK) activation.	('ras homolog family member A', 'Gene', '387', (294, 321))	('rho-associated', 'Enzyme', (344, 358))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TENM1', 'Var', (23, 28))	('ras homolog family member A', 'Gene', (294, 321))	('rat', 'Species', '10116', (112, 115))	('RhoA', 'Gene', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Myc', 'Gene', '4609', (247, 250))	('up-regulation', 'PosReg', (277, 290))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('RhoA', 'Gene', '387', (323, 327))	('tumor', 'Disease', (8, 13))	('activation', 'PosReg', (381, 391))	('glioblastoma', 'Disease', (64, 76))	('Myc', 'Gene', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (151, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('cell proliferation', 'CPA', (100, 118))	('promotes', 'PosReg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
4876	33652578	Indeed, the absence of TENM1, achieved via gene deletion or down-regulation by small interfering RNA (siRNA), drastically reduces the invasive capacity of glioblastoma cells.	('absence', 'NegReg', (12, 19))	('reduces', 'NegReg', (122, 129))	('glioblastoma', 'Disease', (155, 167))	('down-regulation', 'NegReg', (60, 75))	('TENM1', 'Gene', (23, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('gene deletion', 'Var', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
4880	33652578	Moreover, TENM1 mRNA up-regulation in response to hypoxia increases cell migration capacity in glioblastoma cells, while the blockade of TENM1 expression results in reduces hypoxia-induced glioblastoma cell migration.	('hypoxia', 'Disease', (50, 57))	('glioblastoma', 'Disease', (189, 201))	('glioblastoma cell migration', 'Disease', 'MESH:D005909', (189, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('increases', 'PosReg', (58, 67))	('glioblastoma cell migration', 'Disease', (189, 216))	('hypoxia', 'Disease', (173, 180))	('TENM1', 'Gene', (10, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('mRNA', 'MPA', (16, 20))	('rat', 'Species', '10116', (210, 213))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('up-regulation', 'PosReg', (21, 34))	('glioblastoma', 'Disease', (95, 107))	('reduces', 'NegReg', (165, 172))	('rat', 'Species', '10116', (76, 79))	('TENM1', 'Gene', (137, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('blockade', 'Var', (125, 133))
4887	33652578	Interestingly, a single-cell analysis of circulating tumor cells, performed on a lung cancer patient, highlighted the presence of an acquired TENM1 single nucleotide variation in circulating tumor cells, whose function has not been elucidated.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TENM1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('single nucleotide variation', 'Var', (148, 175))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
4897	33652578	It has been shown that the intracellular domain of TENM2, cleaved and released after TENM2 dimerization, translocate into the nucleus, where it represses Zic-1 mediated transcription, promoting cellular differentiation.	('represses', 'NegReg', (144, 153))	('TENM2', 'Gene', (85, 90))	('dimerization', 'Var', (91, 103))	('promoting', 'PosReg', (184, 193))	('TENM2', 'Gene', (51, 56))	('Zic-1', 'Gene', (154, 159))	('cellular differentiation', 'CPA', (194, 218))	('Zic-1', 'Gene', '7545', (154, 159))
4901	33652578	The possible tumor suppressor role of TENM2 is also suggested by the observation that hepatitis B virus-related insertional mutagenesis, leading to TENM2 gene disruption, is frequently associated with hepatocarcinogenesis.	('tumor', 'Disease', (13, 18))	('hepatitis B virus', 'Species', '10407', (86, 103))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (201, 221))	('hepatitis', 'Phenotype', 'HP:0012115', (86, 95))	('TENM2', 'Gene', (148, 153))	('insertional mutagenesis', 'Var', (112, 135))	('associated with', 'Reg', (185, 200))	('hepatocarcinogenesis', 'Disease', (201, 221))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('gene disruption', 'Var', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hepatitis B virus-related', 'Disease', (86, 111))
4912	33652578	A conflicting trend can be observed in urothelial, endometrial, head and neck, renal, stomach and thyroid cancers, as well as in glioma and melanoma, in which low levels of TENM2 expression are correlated with better patients' overall survival.	('endometrial', 'Disease', (51, 62))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('low levels', 'Var', (159, 169))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('renal', 'Disease', (79, 84))	('better', 'PosReg', (210, 216))	('glioma', 'Disease', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('thyroid cancers', 'Disease', 'MESH:D013964', (98, 113))	('overall survival', 'CPA', (227, 243))	('thyroid cancer', 'Phenotype', 'HP:0002890', (98, 112))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('patients', 'Species', '9606', (217, 225))	('stomach', 'Disease', (86, 93))	('urothelial', 'Disease', (39, 49))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('TENM2', 'Gene', (173, 178))	('thyroid cancers', 'Disease', (98, 113))
4915	33652578	Accordingly, an analysis of triple negative breast cancer (TNBC) patient samples has suggested that there is a significant correlation between high TENM2 expression and reduced patient metastatic-free survival time.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('patient metastatic-free survival time', 'CPA', (177, 214))	('breast cancer', 'Disease', (44, 57))	('high', 'Var', (143, 147))	('reduced', 'NegReg', (169, 176))	('TENM2', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patient', 'Species', '9606', (65, 72))	('patient', 'Species', '9606', (177, 184))	('expression', 'MPA', (154, 164))
4918	33652578	A possible link between TENM2 deregulation and the drug sensitivity of cancer cells has also been proposed, again with contradictory results.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('TENM2', 'Gene', (24, 29))	('cancer', 'Disease', (71, 77))	('drug sensitivity', 'CPA', (51, 67))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('drug sensitivity', 'Phenotype', 'HP:0020174', (51, 67))	('deregulation', 'Var', (30, 42))
4926	33652578	Further evidence supporting a possible role for TENM2 deregulation in the tumor microenvironment comes from whole-genome single nucleotide polymorphism profiling, which compared the progressive passages of tumor-derived endothelial cells.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TENM2', 'Gene', (48, 53))	('tumor', 'Disease', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('deregulation', 'Var', (54, 66))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
4931	33652578	Proof of the importance of TENM3 in visual system circuit connectivity has been found in behavioral studies that show that TENM3 KO mice lack binocular vision.	('vision', 'Disease', 'MESH:D015354', (152, 158))	('TENM3', 'Var', (123, 128))	('mice', 'Species', '10090', (132, 136))	('vision', 'Disease', (152, 158))	('lack', 'NegReg', (137, 141))
4946	33652578	Data from different tumor types has suggested that TENM3 may possibly contribute to cancer metastasization.	('cancer metastasization', 'Disease', (84, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TENM3', 'Var', (51, 56))	('contribute', 'Reg', (70, 80))	('tumor', 'Disease', (20, 25))	('cancer metastasization', 'Disease', 'MESH:D009362', (84, 106))
4949	33652578	Increased TENM3 copy numbers and expressions have also been found in glioblastoma patients with leptomeningeal dissemination, compared to patients who do not present this pattern of metastasization.	('TENM3', 'Gene', (10, 15))	('leptomeningeal dissemination', 'Disease', (96, 124))	('patients', 'Species', '9606', (82, 90))	('Increased', 'PosReg', (0, 9))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('expressions', 'MPA', (33, 44))	('patients', 'Species', '9606', (138, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('copy numbers', 'Var', (16, 28))
4950	33652578	The possible pro-metastatic role of TENM3 can also be hypothesized in lung tumors in which patients' circulating tumor cells display TENM3 mutations that are also maintained in metastasis, suggesting that these mutations are important for the migration process.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (91, 99))	('rat', 'Species', '10116', (246, 249))	('mutations', 'Var', (139, 148))	('lung tumors', 'Disease', 'MESH:D008175', (70, 81))	('TENM3', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lung tumors', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('lung tumors', 'Phenotype', 'HP:0100526', (70, 81))	('tumor', 'Disease', (75, 80))
4951	33652578	Interestingly, a gene-based query at the Human Protein Atlas displayed a correlation between worst survival and high TENM3 expression in most of the tumors analyzed, including endometrial, lung, ovarian, stomach, thyroid, urothelial cancer and glioma.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('expression', 'MPA', (123, 133))	('glioma', 'Disease', (244, 250))	('high', 'Var', (112, 116))	('stomach', 'Disease', (204, 211))	('Human', 'Species', '9606', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('thyroid', 'Disease', (213, 220))	('ovarian', 'Disease', (195, 202))	('endometrial', 'Disease', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('tumors', 'Disease', (149, 155))	('TENM3', 'Gene', (117, 122))	('lung', 'Disease', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('ovarian', 'Disease', 'MESH:D010049', (195, 202))	('urothelial cancer', 'Disease', 'MESH:D014523', (222, 239))	('urothelial cancer', 'Disease', (222, 239))
4958	33652578	Although no translocations have been reported for TENM3, a high frequency of TENM3 mutation has been found in skin cutaneous melanoma and pancreatic adenocarcinoma, suggesting that TENM3 may also play a role in carcinogenesis in these tumor types, and in others that have not yet been investigated.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('found', 'Reg', (101, 106))	('carcinogenesis', 'Disease', (211, 225))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (138, 163))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('play', 'Reg', (196, 200))	('mutation', 'Var', (83, 91))	('pancreatic adenocarcinoma', 'Disease', (138, 163))	('tumor', 'Disease', (235, 240))	('TENM3', 'Gene', (77, 82))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (138, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('skin cutaneous melanoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('role', 'Reg', (203, 207))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))
4962	33652578	Interestingly, a specific TENM3-mutated epitope CD8+ T cell response was observed when peripheral blood mononuclear cells were re-stimulated.	('CD8', 'Gene', (48, 51))	('TENM3-mutated', 'Var', (26, 39))	('CD8', 'Gene', '925', (48, 51))
4970	33652578	The TENM4 protein bears a phenylalanine in the third residue of the fifth EGF repeat in the extracellular domain, and, in the intracellular domain, two SH3-binding domains and one nuclear localization sequence.	('phenylalanine in', 'Var', (26, 42))	('EGF', 'Gene', (74, 77))	('EGF', 'Gene', '1950', (74, 77))	('TENM4', 'Gene', (4, 9))	('phenylalanine', 'Chemical', 'MESH:D010649', (26, 39))	('SH3-binding', 'Protein', (152, 163))
4971	33652578	Lastly, TENM4 lacks the predicted furin cleavage sequence just outside the plasma membrane.	('lacks', 'NegReg', (14, 19))	('furin', 'Gene', '5045', (34, 39))	('TENM4', 'Var', (8, 13))	('furin', 'Gene', (34, 39))
4973	33652578	Indeed, TENM4 KO neuroblastoma cells of mouse origin display decreased neurite length and ability to generate filopodia-like protrusions through FAK, Cdc42 and Rac1, whereas TENM4 overexpression in neuroblastoma cells promotes protrusion formation.	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('FAK', 'Protein', (145, 148))	('Rac1', 'Gene', (160, 164))	('neurite length', 'CPA', (71, 85))	('TENM4', 'Var', (174, 179))	('neuroblastoma', 'Disease', 'MESH:D009447', (198, 211))	('rat', 'Species', '10116', (105, 108))	('TENM4 KO', 'Var', (8, 16))	('protrusion formation', 'CPA', (227, 247))	('neuroblastoma', 'Disease', (198, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (17, 30))	('Cdc42', 'Gene', '12540', (150, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (198, 211))	('neuroblastoma', 'Disease', (17, 30))	('decreased', 'NegReg', (61, 70))	('mouse', 'Species', '10090', (40, 45))	('Cdc42', 'Gene', (150, 155))	('Rac1', 'Gene', '19353', (160, 164))
4974	33652578	Here, its disruption limits the generation of normal oligodendrocyte processes, leading to lower axon myelination, which results in the essential tremor phenotype in mice.	('lower', 'NegReg', (91, 96))	('axon myelination', 'Disease', (97, 113))	('essential tremor', 'Phenotype', 'HP:0030186', (136, 152))	('rat', 'Species', '10116', (36, 39))	('results in', 'Reg', (121, 131))	('axon myelination', 'Disease', 'MESH:D003711', (97, 113))	('tremor', 'Disease', 'MESH:D014202', (146, 152))	('mice', 'Species', '10090', (166, 170))	('tremor', 'Phenotype', 'HP:0001337', (146, 152))	('disruption', 'Var', (10, 20))	('tremor', 'Disease', (146, 152))	('limits', 'NegReg', (21, 27))
4975	33652578	Moreover, a similar phenotype, which is related to TENM4 missense mutations, has been identified in humans, although contrasting results have been obtained in a study performed in the Canadian population.	('missense mutations', 'Var', (57, 75))	('TENM4', 'Gene', (51, 56))	('humans', 'Species', '9606', (100, 106))
4978	33652578	This suggests that TENM4 is down-regulated following the activation and proliferation of satellite cells, probably in response to NOTCH signaling, and that TENM4 has a pivotal role in suppressing myogenic differentiation.	('TENM4', 'Gene', (19, 24))	('down-regulated', 'NegReg', (28, 42))	('myogenic differentiation', 'CPA', (196, 220))	('rat', 'Species', '10116', (79, 82))	('TENM4', 'Var', (156, 161))	('suppressing', 'NegReg', (184, 195))
4983	33652578	Recently, a missense mutation of the gene has been found to co-segregate with schizophrenia, suggesting that TENM4 has a potential role in this pathology.	('schizophrenia', 'Phenotype', 'HP:0100753', (78, 91))	('schizophrenia', 'Disease', 'MESH:D012559', (78, 91))	('schizophrenia', 'Disease', (78, 91))	('missense mutation', 'Var', (12, 29))
4984	33652578	A TENM4 risk variant has also been associated with mood disorders, and with the early onset of bipolar disorders.	('bipolar disorders', 'Phenotype', 'HP:0007302', (95, 112))	('TENM4', 'Gene', (2, 7))	('associated', 'Reg', (35, 45))	('bipolar disorder', 'Phenotype', 'HP:0007302', (95, 111))	('mood disorders', 'Disease', (51, 65))	('bipolar disorders', 'Disease', (95, 112))	('variant', 'Var', (13, 20))	('bipolar disorders', 'Disease', 'MESH:D001714', (95, 112))	('mood disorders', 'Disease', 'MESH:D019964', (51, 65))
4992	33652578	Interestingly, in the breast cancer cell line MDA-MB-175, TENM4 is involved in a translocation that generates the TENM4-neureguilin-1 fusion gene, resulting in Upsilon-heregulin fusion protein production.	('TENM4-neureguilin-1', 'Var', (114, 133))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Upsilon-heregulin fusion protein production', 'MPA', (160, 203))	('MDA-MB-175', 'CellLine', 'CVCL:1400', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TENM4', 'Gene', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('rat', 'Species', '10116', (104, 107))
5003	33652578	Significantly lower amounts of TENM4 mRNA transcripts, compared to normal tissues, can also be observed in ovarian serous cystadenocarcinoma, in skin cutaneous melanoma and in testicular germ cell tumors (Figure 5).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lower', 'NegReg', (14, 19))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 168))	('TENM4', 'Var', (31, 36))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (107, 140))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('skin cutaneous melanoma', 'Disease', (145, 168))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('germ cell tumors', 'Phenotype', 'HP:0100728', (187, 203))	('ovarian serous cystadenocarcinoma', 'Disease', (107, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('tumors', 'Disease', (197, 203))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (107, 140))
5007	33652578	Indeed, TENM4 peptides have been identified in a proteomic study using human urine, and TENM4 was detected as one of the most abundant proteins in the secretome and in the exosomes derived from a neuroblastoma cell line.	('neuroblastoma', 'Phenotype', 'HP:0003006', (196, 209))	('TENM4', 'Var', (88, 93))	('neuroblastoma', 'Disease', 'MESH:D009447', (196, 209))	('neuroblastoma', 'Disease', (196, 209))	('human', 'Species', '9606', (71, 76))
5010	33652578	Current findings suggest that teneurins deregulation is associated with cancer cells proliferation, migration and invasion.	('rat', 'Species', '10116', (103, 106))	('teneurins', 'Protein', (30, 39))	('migration', 'CPA', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (56, 66))	('rat', 'Species', '10116', (92, 95))	('teneurins', 'Chemical', '-', (30, 39))	('deregulation', 'Var', (40, 52))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('invasion', 'CPA', (114, 122))	('cancer', 'Disease', (72, 78))
5016	33652578	However, it has to be noted that an oncogenic role for TENM2 cannot be excluded, since in TNBC, a significant correlation between high TENM2 expression and reduced patient metastatic-free survival time has been demonstrated.	('TNBC', 'Disease', (90, 94))	('high', 'Var', (130, 134))	('patient', 'Species', '9606', (164, 171))	('TENM2', 'Gene', (135, 140))	('reduced', 'NegReg', (156, 163))	('rat', 'Species', '10116', (218, 221))	('expression', 'MPA', (141, 151))	('patient metastatic-free survival time', 'CPA', (164, 201))
5022	33652578	The data mining of publicly available data sets derived from large cohorts of oncologic patients provides interesting evidence about the presence of somatic mutations and chromosomal alterations (e.g., translocations, copy number variations, chromothripsis, and viral genome integration) leading to both teneurins' inactivation or overexpression in human tumors.	('viral genome integration', 'Var', (262, 286))	('inactivation', 'NegReg', (315, 327))	('rat', 'Species', '10116', (187, 190))	('human', 'Species', '9606', (349, 354))	('overexpression', 'PosReg', (331, 345))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('copy number variations', 'Var', (218, 240))	('teneurins', 'Chemical', '-', (304, 313))	('patients', 'Species', '9606', (88, 96))	('rat', 'Species', '10116', (280, 283))	('chromothripsis', 'Disease', (242, 256))	('tumors', 'Disease', (355, 361))	('tumors', 'Disease', 'MESH:D009369', (355, 361))	('tumors', 'Phenotype', 'HP:0002664', (355, 361))	('chromothripsis', 'Disease', 'MESH:D000072837', (242, 256))	('teneurins', 'Protein', (304, 313))	('translocations', 'Var', (202, 216))
5029	33652578	; Writing:Original Draft Preparation: G.P., R.R., M.A., F.R., G.B.	('M.A.', 'Var', (50, 54))	('F.R.', 'Var', (56, 60))	('rat', 'Species', '10116', (30, 33))
5033	32426049	Predicting STAT1 as a prognostic marker in patients with solid cancer Aberrant activities of signal transducer and activator of transcription 1 (STAT1) have been implicated in cancer development.	('implicated', 'Reg', (162, 172))	('STAT1', 'Gene', (11, 16))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('STAT1', 'Gene', (145, 150))	('STAT1', 'Gene', '6772', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('signal transducer and activator of transcription 1', 'Gene', '6772', (93, 143))	('Aberrant activities', 'Var', (70, 89))	('STAT1', 'Gene', '6772', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (63, 69))
5038	32426049	Pooled data showed that overexpressed STAT1 favored long overall survival (OS) (HR = 0.604, 95% CI = 0.431-0.846, p = 0.003) and disease-specific survival (DSS) (HR = 0.650, 95% CI = 0.512-0.825, p = 0.000).	('disease-specific survival', 'CPA', (129, 154))	('STAT1', 'Gene', (38, 43))	('DSS', 'Chemical', '-', (156, 159))	('favored', 'PosReg', (44, 51))	('overexpressed', 'Var', (24, 37))
5059	32426049	Patients with STAT1 or phospho-STAT1 at a high expression level have a worse outcome compared with patients with STAT1 at a low expression level.	('phospho-STAT1 at', 'Var', (23, 39))	('STAT1', 'Var', (14, 19))	('patients', 'Species', '9606', (99, 107))	('Patients', 'Species', '9606', (0, 8))
5081	32426049	Our analysis revealed that highly expressed STAT1 was a positive predictor for OS among cancer patients (HR = 0.604, 95% CI = 0.431-0.846, p = 0.003) (Figure 3).	('highly expressed', 'Var', (27, 43))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('STAT1', 'Gene', (44, 49))
5085	32426049	The pooled results indicated a positive correlation between highly expressed STAT1 and longer DSS (HR = 0.650, 95% CI = 0.512-0.825, p = 0.000) (Figure 4B).	('highly expressed', 'Var', (60, 76))	('DSS', 'Chemical', '-', (94, 97))	('longer DSS', 'Disease', (87, 97))	('STAT1', 'Gene', (77, 82))
5086	32426049	The first subgroup analyses by region revealed that the pooled HRs were 0.630 (95% CI = 0.337-1.178, p = 0.148) for Asian patients (five studies) and 0.666 (95% CI = 0.431-0.846, p = 0.000) for Non-Asian patients (six studies).	('Asian patients', 'Disease', (116, 130))	('patients', 'Species', '9606', (204, 212))	('0.666', 'Var', (150, 155))	('0.630', 'Var', (72, 77))	('patients', 'Species', '9606', (122, 130))
5087	32426049	The fourth subgroup analyses by cancer types displayed that highly expressed STAT1 was associated with favorable OS of patients with high-grade serous ovarian cancer (HR = 0.683, 95% CI = 0.497-0.938, p = 0.019) (2 studies), oral squamous cell carcinoma (HR = 0.486, 95% CI = 0.241-0.980, p = 0.044) (two studies), and another five cancers (pooled HR = 0.542, 95% CI = 0.361-0.813, p = 0.003), but not in lung cancer (HR = 1.223, 95% CI = 0.996-1.501, p = 0.055) (two studies).	('oral squamous cell carcinoma', 'Disease', (225, 253))	('lung cancer', 'Disease', (405, 416))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('serous ovarian cancer', 'Disease', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (405, 416))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (405, 416))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('cancer', 'Disease', (332, 338))	('cancers', 'Disease', (332, 339))	('STAT1', 'Gene', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (144, 165))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Disease', (410, 416))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('highly expressed', 'Var', (60, 76))
5104	32426049	The outcomes after analyses indicate that expression of STAT1 is associated with survival of patients based on their cancer type.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('STAT1', 'Gene', (56, 61))	('associated with', 'Reg', (65, 80))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('expression', 'Var', (42, 52))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (93, 101))
5110	32426049	The tumor-suppressive role of STAT1 is driven by findings that the reconstitution of STAT1 in STAT1-deficient murine fibrosarcoma cells significantly suppressed tumorigenicity and metastasis in nude mice.	('STAT1-deficient', 'Gene', (94, 109))	('tumor', 'Disease', (4, 9))	('fibrosarcoma', 'Disease', 'MESH:D005354', (117, 129))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (117, 129))	('nude mice', 'Species', '10090', (194, 203))	('suppressed', 'NegReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('reconstitution', 'Var', (67, 81))	('STAT1', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('fibrosarcoma', 'Disease', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (161, 166))	('murine', 'Species', '10090', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
5111	32426049	The high expression of STAT1 is reported to have a good prognosis compared with the low or negative expression of STAT1 in some cancer patients.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (4, 8))	('STAT1', 'Gene', (23, 28))	('cancer', 'Disease', (128, 134))
5112	32426049	However, on the other hand, two studies have identified high STAT1 mRNA levels associated with poor prognosis, tumor progression, and worse survival in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('tumor', 'Disease', (111, 116))	('breast cancer', 'Disease', (152, 165))	('STAT1 mRNA levels', 'MPA', (61, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('high', 'Var', (56, 60))
5115	32426049	The survival analysis of TCGA data revealed that highly expressed STAT1 was associated with longer OS in ovarian cancer, rectum adenocarcinoma, sarcoma, and skin cutaneous melanoma.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('highly expressed', 'Var', (49, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('skin cutaneous melanoma', 'Disease', (157, 180))	('STAT1', 'Gene', (66, 71))	('longer OS in ovarian cancer', 'Disease', (92, 119))	('rectum adenocarcinoma', 'Disease', (121, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('associated', 'Reg', (76, 86))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (121, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('longer OS in ovarian cancer', 'Disease', 'MESH:C567932', (92, 119))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 180))
5125	32426049	For instance, STAT1 can arrest the cell cycle in response to IFNgamma through direct interaction with cyclin D1 and CDK4 proteins.	('arrest', 'Disease', (24, 30))	('cell cycle', 'CPA', (35, 45))	('IFNgamma', 'Gene', '3458', (61, 69))	('IFNgamma', 'Gene', (61, 69))	('CDK4', 'Gene', (116, 120))	('CDK4', 'Gene', '1019', (116, 120))	('cyclin D1', 'Gene', '595', (102, 111))	('cyclin D1', 'Gene', (102, 111))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('interaction', 'Interaction', (85, 96))	('STAT1', 'Var', (14, 19))
5131	32426049	Full-length STAT1alpha isoform has traditionally been considered as the physiologically active form of STAT1 after phosphorylation at Tyr701 and Ser727 residues, and the truncated STAT1beta isoform is considered as a physiological inhibitor of STAT1.	('Tyr701', 'Chemical', '-', (134, 140))	('Ser727', 'Var', (145, 151))	('Ser727', 'Chemical', '-', (145, 151))	('Tyr701', 'Var', (134, 140))
5132	32426049	The expression and activation ratio of STAT1alpha and STAT1beta in different cancer types may impact cancer progression and promote a 'switch' from tumor cell proliferation to a death phenotype.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('STAT1beta', 'Var', (54, 63))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (77, 83))	('tumor', 'Disease', (148, 153))	('death', 'Disease', 'MESH:D003643', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('death', 'Disease', (178, 183))	("'switch'", 'PosReg', (134, 142))	('STAT1alpha', 'Gene', (39, 49))	('promote', 'PosReg', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('impact', 'Reg', (94, 100))
5134	32426049	Interestingly, another study shows that STAT1beta protects STAT1alpha from degradation and enhances STAT1 function in esophageal squamous cell carcinoma.	('STAT1alpha', 'Protein', (59, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('STAT1 function', 'MPA', (100, 114))	('enhances', 'PosReg', (91, 99))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('STAT1beta', 'Var', (40, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('degradation', 'MPA', (75, 86))	('esophageal squamous cell carcinoma', 'Disease', (118, 152))
5145	31514337	However, significantly increased TGFBI was predominantly found in muscle invasive (14,411.7 pg/mg creatinine), high-grade (8190.7 pg/mg) and de novo UC (1856.7 pg/mg; all p < 0.0001).	('TGFBI', 'Gene', '7045', (33, 38))	('TGFBI', 'Gene', (33, 38))	('muscle invasive', 'Disease', (66, 81))	('8190.7', 'Var', (123, 129))	('increased', 'PosReg', (23, 32))	('1856.7', 'Var', (153, 159))	('creatinine', 'Chemical', 'MESH:D003404', (98, 108))
5202	31514337	Therefore, we investigated the role of TGFBI on tumor cell proliferation by siRNA mediated gene silencing of TGFBI.	('TGFBI', 'Gene', '7045', (39, 44))	('tumor', 'Disease', (48, 53))	('gene silencing', 'Var', (91, 105))	('TGFBI', 'Gene', (39, 44))	('TGFBI', 'Gene', '7045', (109, 114))	('investigated', 'Reg', (14, 26))	('TGFBI', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('rat', 'Species', '10116', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
5208	31514337	Knockdown of TGFBI resulted in a significant decrease of TGFBI concentration in the cell supernatant in comparison to negative control (Figure 5B).	('rat', 'Species', '10116', (70, 73))	('TGFBI', 'Gene', '7045', (57, 62))	('Knockdown', 'Var', (0, 9))	('TGFBI', 'Gene', (57, 62))	('TGFBI', 'Gene', '7045', (13, 18))	('decrease', 'NegReg', (45, 53))	('TGFBI', 'Gene', (13, 18))
5210	31514337	On day 4 (96 h) TGFBI-siRNA transfected cells significantly increased their G1 and G2/M phase populations by 19.9% (p = 0.0273) and 7.6% (p <= 0.0066) compared to negative control.	('transfected', 'Var', (28, 39))	('TGFBI', 'Gene', (16, 21))	('increased', 'PosReg', (60, 69))	('TGFBI', 'Gene', '7045', (16, 21))
5212	31514337	Together, these results indicate that TGFBI-deficient 5637 bladder cancer cells have a disrupted cell cycle with, most likely, erroneous G1/S transitioning and S phase regulation.	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('disrupted', 'Reg', (87, 96))	('TGFBI', 'Gene', (38, 43))	('TGFBI', 'Gene', '7045', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('cell cycle', 'CPA', (97, 107))	('erroneous', 'Var', (127, 136))	('S phase regulation', 'CPA', (160, 178))	('bladder cancer', 'Disease', (59, 73))
5220	31514337	Incubation of the cells for 48 h with 10 microM inhibitor caused a significant decrease of TGFBI concentration in the cell supernatant (Figure 7A; p <= 0.032).	('TGFBI', 'Gene', '7045', (91, 96))	('TGFBI', 'Gene', (91, 96))	('decrease', 'NegReg', (79, 87))	('inhibitor', 'Var', (48, 57))	('concentration in the cell supernatant', 'MPA', (97, 134))	('rat', 'Species', '10116', (104, 107))
5263	31514337	The silencing of TGFBI in glioma and gastrointestinal cancer decreased local tumor growth and metastasis.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (37, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TGFBI', 'Gene', '7045', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGFBI', 'Gene', (17, 22))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('silencing', 'Var', (4, 13))	('glioma and gastrointestinal cancer decreased local tumor', 'Disease', 'MESH:D005770', (26, 82))
5345	26829751	MYB-QKI rearrangements in Angiocentric Glioma drive tumorigenicity through a tripartite mechanism Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers.	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('QKI', 'Gene', (4, 7))	('Angiocentric gliomas', 'Disease', (98, 118))	('rearrangements', 'Var', (8, 22))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('QKI', 'Gene', '9444', (4, 7))	('Angiocentric Glioma', 'Disease', (26, 45))	('MYB', 'Gene', (0, 3))	('Angiocentric gliomas', 'Disease', 'MESH:D005910', (98, 118))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MYB', 'Gene', '17863', (0, 3))	('gliomas', 'Disease', (143, 150))	('Glioma', 'Phenotype', 'HP:0009733', (39, 45))	('gliomas', 'Disease', (111, 118))	('tumorigenicity', 'MPA', (52, 66))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (26, 45))
5347	26829751	We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas.	('MYB-QKI', 'Gene', (14, 21))	('fusions', 'Var', (22, 29))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (81, 101))	('Angiocentric Gliomas', 'Disease', (81, 101))	('Glioma', 'Phenotype', 'HP:0009733', (94, 100))	('Gliomas', 'Phenotype', 'HP:0009733', (94, 101))
5348	26829751	In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('MYB-QKI', 'Gene', (45, 52))	('promote', 'PosReg', (68, 75))	('tumor', 'Disease', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('activation', 'PosReg', (120, 130))	('expression', 'Species', '29278', (194, 204))	('MYB-QKI', 'Gene', (186, 193))	('truncation', 'Var', (134, 144))	('expression', 'MPA', (194, 204))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('hemizygous loss of the tumor', 'Disease', 'MESH:C564097', (210, 238))	('rearrangements', 'Var', (53, 67))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('enhancer', 'Var', (146, 154))	('MYB', 'Gene', (116, 119))	('hemizygous loss of the tumor', 'Disease', (210, 238))
5349	26829751	This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.	('cells', 'CPA', (95, 100))	('transforming', 'Reg', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('rearrangement', 'Var', (53, 66))
5352	26829751	We previously identified one Angiocentric Glioma with deletion of the 3' region of MYB and one other Angiocentric Glioma has been reported to harbor a MYB-QKI rearrangement.	('MYB', 'Gene', (83, 86))	('Angiocentric Glioma', 'Disease', (29, 48))	('deletion', 'Var', (54, 62))	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (29, 48))	('Angiocentric Glioma', 'Disease', (101, 120))	('Glioma', 'Phenotype', 'HP:0009733', (42, 48))	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (101, 120))	('Glioma', 'Phenotype', 'HP:0009733', (114, 120))
5355	26829751	We found MYB-QKI rearrangements to be the most common event involving a MYB family member and to be specific to Angiocentric Gliomas.	('rearrangements', 'Var', (17, 31))	('Angiocentric Gliomas', 'Disease', (112, 132))	('MYB', 'Gene', (72, 75))	('MYB-QKI', 'Gene', (9, 16))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (112, 132))	('Glioma', 'Phenotype', 'HP:0009733', (125, 131))	('Gliomas', 'Phenotype', 'HP:0009733', (125, 132))
5358	26829751	Rearrangements or structural alterations were observed in 129 tumors (83%; Figure 1a, Supplementary Table 1).	('Rearrangements', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('observed', 'Reg', (46, 54))	('structural alterations', 'CPA', (18, 40))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))
5359	26829751	Rearrangements involving MYB family members (MYB, MYBL1) were the second-most recurrent alteration, affecting 16 tumors (10%), predominantly Diffuse Astrocytomas and Angiocentric Gliomas (Figure 1a and Supplementary Figure 1).	('MYB', 'Gene', (45, 48))	('Astrocytomas and Angiocentric Gliomas', 'Disease', 'MESH:D005910', (149, 186))	('Rearrangements', 'Var', (0, 14))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('MYBL1', 'Gene', (50, 55))	('Glioma', 'Phenotype', 'HP:0009733', (179, 185))	('Astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('Gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('affecting', 'Reg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
5361	26829751	The other Angiocentric Glioma, which was not centrally reviewed, contained a MYB-ESR1 rearrangement.	('Angiocentric Glioma', 'Disease', (10, 29))	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (10, 29))	('Glioma', 'Phenotype', 'HP:0009733', (23, 29))	('rearrangement', 'Var', (86, 99))	('contained', 'Reg', (65, 74))	('MYB-ESR1', 'Gene', (77, 85))
5362	26829751	Although MYB rearrangements have been described in PLGGs, we were struck by two novel findings: QKI was the most frequent fusion partner, and MYB-QKI fusions were near-universal in Angiocentric Gliomas.	('MYB-QKI', 'Gene', (142, 149))	('Gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('fusions', 'Var', (150, 157))	('Angiocentric Gliomas', 'Disease', (181, 201))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (181, 201))	('Glioma', 'Phenotype', 'HP:0009733', (194, 200))
5364	26829751	Nine Angiocentric Gliomas were analyzed by FISH to detect MYB rearrangement or deletion (Figure 1b), and three Angiocentric Gliomas were analyzed by WES and/or aCGH (Supplementary Figure 2).	('Gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('Angiocentric Gliomas', 'Disease', (111, 131))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (111, 131))	('Angiocentric Gliomas', 'Disease', (5, 25))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (5, 25))	('rearrangement', 'Var', (62, 75))	('Glioma', 'Phenotype', 'HP:0009733', (18, 24))	('Glioma', 'Phenotype', 'HP:0009733', (124, 130))	('Gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('deletion', 'Var', (79, 87))	('MYB', 'Gene', (58, 61))
5367	26829751	MYB-QKI rearrangements appeared specific to Angiocentric Glioma.	('MYB-QKI', 'Gene', (0, 7))	('Angiocentric Glioma', 'Disease', (44, 63))	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (44, 63))	('rearrangements', 'Var', (8, 22))	('Glioma', 'Phenotype', 'HP:0009733', (57, 63))
5373	26829751	In the WGS/RNA-seq cohort we also observed rearrangements involving QKI but not MYB in three supratentorial Pilocytic Astrocytomas (PAs), and rearrangements involving MYB or MYBL1 but not QKI in nine tumors, seven of which were Diffuse Astrocytomas.	('Astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('QKI but', 'Gene', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Astrocytomas', 'Disease', 'MESH:D001254', (118, 130))	('Astrocytomas', 'Disease', (118, 130))	('rearrangements', 'Var', (142, 156))	('MYBL1', 'Gene', (174, 179))	('tumors', 'Disease', (200, 206))	('supratentorial Pilocytic Astrocytomas', 'Disease', (93, 130))	('supratentorial Pilocytic Astrocytomas', 'Disease', 'MESH:D001254', (93, 130))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('MYB', 'Gene', (167, 170))	('Astrocytoma', 'Phenotype', 'HP:0009592', (236, 247))	('rearrangements', 'Var', (43, 57))	('Astrocytomas', 'Disease', 'MESH:D001254', (236, 248))	('Astrocytomas', 'Disease', (236, 248))
5381	26829751	Deletions of QKI have been suggested to be oncogenic in a number of cancers including glioblastoma, prostate cancer, and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('QKI', 'Gene', (13, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('glioblastoma', 'Disease', (86, 98))	('prostate cancer', 'Disease', (100, 115))	('gastric cancer', 'Disease', (121, 135))	('Deletions', 'Var', (0, 9))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
5382	26829751	In copy-number analyses of 10,570 cancers within the Cancer Genome Atlas, QKI was one of two genes in a deletion peak in adult glioblastomas (Figure 2l), renal clear cell, and cervical squamous cell carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer Genome Atlas', 'Disease', (53, 72))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cervical squamous cell carcinomas', 'Disease', (176, 209))	('QKI', 'Gene', (74, 77))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (53, 72))	('adult glioblastomas', 'Disease', (121, 140))	('cancers within the Cancer', 'Disease', (34, 59))	('adult glioblastomas', 'Disease', 'MESH:D005909', (121, 140))	('glioblastomas', 'Phenotype', 'HP:0012174', (127, 140))	('cancers within the Cancer', 'Disease', 'MESH:D001929', (34, 59))	('renal clear cell', 'Disease', (154, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('cervical squamous cell carcinomas', 'Disease', 'MESH:D002294', (176, 209))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (185, 209))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('deletion', 'Var', (104, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))
5384	26829751	Focal QKI deletions were observed in over 10% of glioblastomas.	('Focal', 'Gene', (0, 5))	('glioblastomas', 'Disease', (49, 62))	('deletions', 'Var', (10, 19))	('glioblastomas', 'Phenotype', 'HP:0012174', (49, 62))	('observed', 'Reg', (25, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('glioblastomas', 'Disease', 'MESH:D005909', (49, 62))
5386	26829751	We therefore characterized mechanisms through which MYB-QKI rearrangements may contribute to aberrant MYB-QKI expression and evaluated the oncogenic potential of both genes.	('rearrangements', 'Var', (60, 74))	('MYB-QKI', 'Gene', (52, 59))	('contribute', 'Reg', (79, 89))	('expression', 'Species', '29278', (110, 120))	('aberrant', 'Var', (93, 101))	('expression', 'MPA', (110, 120))	('MYB-QKI', 'Gene', (102, 109))
5388	26829751	Relative to eGFP-expressing cells, those expressing MYB-QKI5 and MYB-QKI6 exhibited significantly different expression of 1621 and 1947 genes, respectively, with 1029 genes overlapping (p<0.0001; Supplementary Table 4).	('expression', 'Species', '29278', (108, 118))	('different', 'Reg', (98, 107))	('MYB-QKI6', 'Var', (65, 73))	('expression', 'MPA', (108, 118))
5389	26829751	Gene-set enrichment analysis revealed expression of either MYBtrExon1-9 or MYB-QKI was associated with enrichment of signatures of MYB pathway activation (p<0.0001, Supplementary Table 5).	('MYB pathway', 'Pathway', (131, 142))	('expression', 'Species', '29278', (38, 48))	('MYB-QKI', 'Gene', (75, 82))	('MYBtrExon1-9', 'Var', (59, 71))	('activation', 'PosReg', (143, 153))
5393	26829751	We observed a slight induction of mim-1 promoter activity with transfection with full length MYB compared to the control vector.	('mim-1', 'Gene', '100073347', (34, 39))	('mim-1', 'Gene', (34, 39))	('transfection', 'Var', (63, 75))
5397	26829751	Angiocentric Gliomas with MYB-QKI exhibit significantly higher MYB expression relative to normal pediatric cortical brain (p=0.0062) or to PLGGs with BRAF or FGFR alterations (p=0.03) (Figure 4a and Supplementary Note 2).	('MYB-QKI', 'Var', (26, 33))	('Glioma', 'Phenotype', 'HP:0009733', (13, 19))	('MYB', 'Protein', (63, 66))	('Gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('expression', 'Species', '29278', (67, 77))	('Angiocentric Gliomas', 'Disease', (0, 20))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (0, 20))	('expression', 'MPA', (67, 77))	('higher', 'PosReg', (56, 62))
5398	26829751	Three Angiocentric Gliomas harbored MYB-QKI rearrangement breakpoints between exons 9 and 10 of MYB.	('MYB', 'Gene', (96, 99))	('Gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('rearrangement breakpoints', 'Var', (44, 69))	('MYB-QKI', 'Gene', (36, 43))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (6, 26))	('Angiocentric Gliomas', 'Disease', (6, 26))	('Glioma', 'Phenotype', 'HP:0009733', (19, 25))
5400	26829751	These data support the selective, aberrant regulation of expression of truncated MYB via MYB-QKI.	('MYB', 'Gene', (81, 84))	('expression', 'Species', '29278', (57, 67))	('MYB-QKI', 'Gene', (89, 96))	('truncated', 'Var', (71, 80))
5401	26829751	Aberrant oncogene expression can result from enhancer translocation.	('oncogene', 'Protein', (9, 17))	('Aberrant', 'Var', (0, 8))	('enhancer translocation', 'CPA', (45, 67))	('expression', 'Species', '29278', (18, 28))	('expression', 'MPA', (18, 28))	('result', 'Reg', (33, 39))
5407	26829751	Normal human cortical brain is not associated with H3K27ac MYB-related enhancers, and indeed we did not observe formation of H3K27ac MYB enhancer peaks in the Pilocytic Astrocytoma (Supplementary Figure 5).	('human', 'Species', '9606', (7, 12))	('H3K27ac', 'Var', (125, 132))	('Astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('Pilocytic Astrocytoma', 'Disease', 'MESH:D001254', (159, 180))	('Pilocytic Astrocytoma', 'Disease', (159, 180))
5409	26829751	RNA-seq revealed expression of the first nine exons of MYB corresponding to those retained in the rearrangement, suggesting that the aberrant M5E1 enhancer is regulating expression of truncated MYB from the rearranged allele.	('aberrant', 'Var', (133, 141))	('expression', 'Species', '29278', (17, 27))	('MYB', 'Gene', (55, 58))	('M5E1', 'Gene', (142, 146))	('expression', 'Species', '29278', (170, 180))	('expression', 'MPA', (170, 180))
5410	26829751	The lack of full-length MYB expression indicates the aberrant enhancer does not regulate the remaining wild-type MYB allele.	('aberrant', 'Var', (53, 61))	('MYB', 'Gene', (24, 27))	('expression', 'Species', '29278', (28, 38))
5412	26829751	We observed significant induction of MYB promoter activity in U87 cells stably expressing MYB-QKI with MYB-luc as compared to U87 cells containing MYB-luc or the promoter-less control luciferase construct alone (Figure 5c).	('U87', 'CellLine', 'CVCL:0022', (62, 65))	('U87', 'CellLine', 'CVCL:0022', (126, 129))	('MYB-luc', 'Var', (103, 110))	('induction', 'PosReg', (24, 33))	('MYB-QKI', 'Var', (90, 97))	('MYB', 'Protein', (37, 40))
5416	26829751	Baseline activity of the Q3E1-MYB-luc promoter construct was higher than with MYB-luc alone in U87 glioma cells (Figure 5c), increasing activation by approximately 1.5 fold, a level of activation shown to harbor biological relevance in other diseases.	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('higher', 'PosReg', (61, 67))	('glioma', 'Disease', (99, 105))	('U87', 'CellLine', 'CVCL:0022', (95, 98))	('Baseline', 'MPA', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('Q3E1-MYB-luc', 'Var', (25, 37))	('activation', 'MPA', (136, 146))
5417	26829751	Expression of MYB-QKI with Q3E1-MYB-luc led to even higher activity, again consistent with an auto-regulatory feedback loop in the presence of the fusion protein (Figure 5c).	('activity', 'MPA', (59, 67))	('Expression', 'Species', '29278', (0, 10))	('Q3E1-MYB-luc', 'Var', (27, 39))	('higher', 'PosReg', (52, 58))
5418	26829751	Expression of truncated MYB has previously been reported to be oncogenic.	('truncated', 'Var', (14, 23))	('Expression', 'Species', '29278', (0, 10))	('MYB', 'Protein', (24, 27))
5420	26829751	Furthermore mNSCs expressing MYBtr induced diffuse gliomas on average 100 days post intracranial injection (Figure 6e, f).	('gliomas', 'Disease', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('induced', 'Reg', (35, 42))	('MYBtr', 'Gene', (29, 34))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('mNSCs', 'Var', (12, 17))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
5424	26829751	Similarly both isoforms induced anchorage-independent growth in NIH-3T3 cells (Supplementary Figure 7a); in vivo, overexpression of both MYB-QKI5 and MYB-QKI6, but not full-length MYB, led to tumor formation as flank xenografts (Figure 6b).	('overexpression', 'PosReg', (114, 128))	('tumor', 'Disease', (192, 197))	('NIH-3T3', 'CellLine', 'CVCL:0594', (64, 71))	('led to', 'Reg', (185, 191))	('MYB-QKI6', 'Var', (150, 158))	('MYB-QKI5', 'Var', (137, 145))	('expression', 'Species', '29278', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('flank xenografts', 'CPA', (211, 227))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
5425	26829751	Intracranial injections of mNSCs overexpressing MYB-QKI5 or MYB-QKI6 formed gliomas with infiltrating tumor cells with some evidence of enhanced growth around vessels and a clustered growth pattern, features similar to Angiocentric Glioma and distinct from the histology seen adult glioblastoma models (e.g.	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (219, 238))	('MYB-QKI5', 'Var', (48, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (282, 294))	('enhanced', 'PosReg', (136, 144))	('tumor', 'Disease', (102, 107))	('clustered growth pattern', 'CPA', (173, 197))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('growth around vessels', 'CPA', (145, 166))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('glioblastoma', 'Disease', (282, 294))	('glioblastoma', 'Disease', 'MESH:D005909', (282, 294))	('Angiocentric Glioma', 'Disease', (219, 238))	('Glioma', 'Phenotype', 'HP:0009733', (232, 238))	('MYB-QKI6', 'Var', (60, 68))
5433	26829751	We were interested in understanding how disruption of QKI may contribute to oncogenicity in tumors that harbor MYB-QKI.	('QKI', 'Gene', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('disruption', 'Var', (40, 50))	('MYB-QKI', 'Gene', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('contribute', 'Reg', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
5434	26829751	Exon-specific RNA-seq analysis of Angiocentric Gliomas with MYB-QKI (n=4) showed reduced expression of QKI compared to PLGGs that harbor BRAF alterations (n=5) (Figure 7a and Supplementary Note 2).	('Glioma', 'Phenotype', 'HP:0009733', (47, 53))	('expression', 'MPA', (89, 99))	('MYB-QKI', 'Var', (60, 67))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('Gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('Angiocentric Gliomas', 'Disease', (34, 54))	('reduced', 'NegReg', (81, 88))	('Angiocentric Gliomas', 'Disease', 'MESH:D005910', (34, 54))	('QKI', 'Gene', (103, 106))	('expression', 'Species', '29278', (89, 99))
5438	26829751	Suppression of Qk by shRNAs in mNSCs expressing MYB-QKI6 led to differential expression of 309 genes relative to shLacZ (q<0.25, Supplementary Table 6).	('MYB-QKI6', 'Var', (48, 56))	('expression', 'MPA', (77, 87))	('expression', 'Species', '29278', (77, 87))	('Suppression', 'NegReg', (0, 11))
5445	26829751	Thus disruption of both MYB and QKI appear to contribute to tumor formation in a co-operative manner.	('contribute', 'Reg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MYB', 'Protein', (24, 27))	('disruption', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('QKI', 'Gene', (32, 35))
5447	26829751	It also represents the first example of a single driver translocation of two genes resulting in the aberrant expression of an activated oncogenic fusion protein which then participates in an auto-regulatory feedback loop, proximal translocation of enhancer elements regulating fusion-gene expression, and simultaneous functional loss of a tumor suppressor gene.	('tumor', 'Disease', (339, 344))	('participates in', 'Reg', (172, 187))	('expression', 'MPA', (109, 119))	('translocation', 'Var', (56, 69))	('expression', 'Species', '29278', (289, 299))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('auto-regulatory feedback loop', 'MPA', (191, 220))	('loss', 'NegReg', (329, 333))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('expression', 'Species', '29278', (109, 119))
5451	26829751	This could aid in distinction of Angiocentric Glioma from tumors with higher potential for recurrence or require further treatment, such as IDH-mutant diffuse gliomas or ependymomas.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('IDH-mutant', 'Var', (140, 150))	('gliomas', 'Disease', (159, 166))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('Angiocentric Glioma', 'Disease', (33, 52))	('ependymomas', 'Disease', 'MESH:D004806', (170, 181))	('Angiocentric Glioma', 'Disease', 'MESH:D005910', (33, 52))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('ependymomas', 'Disease', (170, 181))	('Glioma', 'Phenotype', 'HP:0009733', (46, 52))	('aid', 'Reg', (11, 14))
5458	26829751	Like MYB-QKI, MYB-NFIB also results in high levels of MYB expression, although the mechanism underlying this, the functional role of NFIB, and oncogenicity of MYB-NFIB remain undefined.	('expression', 'Species', '29278', (58, 68))	('expression', 'MPA', (58, 68))	('results', 'Reg', (28, 35))	('MYB-NFIB', 'Var', (14, 22))	('MYB', 'Protein', (54, 57))
5466	26829751	Pediatric tumors are characterized by simple genomes with single driver alterations.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('alterations', 'Var', (72, 83))	('Pediatric tumors', 'Disease', 'MESH:D063766', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Pediatric tumors', 'Disease', (0, 16))
5473	26829751	FISH was performed as previously described using five micron FFPE tissue sections and Homebrew probes RP11-63K22 (5' to MYB; directly labeled in SpectrumOrange) and RP11-170P19 (3' to MYB; directly labeled in SpectrumGreen) that map to 6q23.3.	('RP11-170P19', 'Disease', (165, 176))	('RP11-63K22', 'Var', (102, 112))	('RP11-170P19', 'Disease', 'MESH:C563991', (165, 176))
5484	26829751	Anchorage-independent growth of NIH3T3 cells was assayed as previously described with the following modifications: NIH3T3 cells expressing each of the MYB-QKI5, MYB-QKI6, MYBtr, full-length MYB and full length QKI proteins and retroviral vector control were plated in 0.7% agar with DMEM and DBS in 96 well plates (in triplicates).	('agar', 'Chemical', 'MESH:D000362', (273, 277))	('MYB-QKI6', 'Var', (161, 169))	('NIH3T3', 'CellLine', 'CVCL:0594', (115, 121))	('DBS', 'Chemical', 'MESH:C007323', (292, 295))	('DMEM', 'Chemical', '-', (283, 287))	('MYB-QKI5', 'Gene', (151, 159))	('NIH3T3', 'CellLine', 'CVCL:0594', (32, 38))
5490	26829751	The reporter construct was designed using the core MYB recognition element (MRE) consensus sequence PyAAC(G/T)G which is present in the mim-1 gene promoter, a previously described MYB target.	('PyAAC', 'Var', (100, 105))	('mim-1', 'Gene', (136, 141))	('mim-1', 'Gene', '100073347', (136, 141))
5503	26829751	Target mNSC underwent infection using a spin protocol (2000rpm for 120 minutes at 30C with no polybrene).	('underwent', 'Reg', (12, 21))	('2000rpm', 'Var', (55, 62))	('polybrene', 'Chemical', 'MESH:D006583', (94, 103))
5525	24267971	We retrospectively evaluated the incidence of PP in adult patients with sGBM treated with chemoradiation therapy (CRTx) using temozolomide (TMZ) and sought to assess if there was an association between PP and MGMT promoter methylation status, IDH mutations status, or 1p/19q codeletion.	('1p/19q codeletion', 'Var', (268, 285))	('temozolomide', 'Chemical', 'MESH:D000077204', (126, 138))	('TMZ', 'Chemical', 'MESH:D000077204', (140, 143))	('IDH', 'Gene', (243, 246))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('patients', 'Species', '9606', (58, 66))	('MGMT', 'Gene', (209, 213))	('MGMT', 'Gene', '4255', (209, 213))	('CRTx', 'Chemical', '-', (114, 118))	('IDH', 'Gene', '3417', (243, 246))
5530	24267971	Based on this small series of sGBM patients treated with CRTx (concomitantly or sequentially) the frequency of PP appears to be very low in sGBM, even in those patients with methylated MGMT promoter or IDH mutations.	('IDH', 'Gene', (202, 205))	('MGMT', 'Gene', '4255', (185, 189))	('MGMT', 'Gene', (185, 189))	('methylated', 'Var', (174, 184))	('patients', 'Species', '9606', (160, 168))	('IDH', 'Gene', '3417', (202, 205))	('low', 'NegReg', (133, 136))	('CRTx', 'Chemical', '-', (57, 61))	('GBM', 'Phenotype', 'HP:0012174', (141, 144))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('patients', 'Species', '9606', (35, 43))	('sGBM', 'Disease', (140, 144))
5554	24267971	Status of 1p/19q codeletion was detected by fluorescence in situ hybridization analysis, using samples of paraffin-embedded tumor tissues, by using probes to detect 1p36.1 to 36.3 (target, red) and 1q25.1 to 25.3 (control, green) for 1p detection, and 19p13.1 to 13.30 (green, control) and 19q13.1 to 13.4 (red, target) for 19q detection (Vysis; Abbot Laboratories, Abbot Park, IL), following the recommendations of the manufacturer.	('1q25.1 to 25.3', 'Var', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('1p36.1 to 36.3', 'Var', (165, 179))	('paraffin', 'Chemical', 'MESH:D010232', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
5579	24267971	Of 71 patients with pGBM (26 patients with methylated and 45 with unmethylated MGMT promoter), 19 patients (26.7%) had evidence of PP during the first 6 months after concomitant CRTx with TMZ (Fig.	('MGMT', 'Gene', (79, 83))	('patients', 'Species', '9606', (29, 37))	('pGBM', 'Gene', (20, 24))	('patients', 'Species', '9606', (98, 106))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('CRTx', 'Chemical', '-', (178, 182))	('pGBM', 'Chemical', '-', (20, 24))	('TMZ', 'Chemical', 'MESH:D000077204', (188, 191))	('patients', 'Species', '9606', (6, 14))	('methylated', 'Var', (43, 53))	('MGMT', 'Gene', '4255', (79, 83))
5580	24267971	Of those, 26 patients had methylated MGMT and 6 had unmethylated MGMT promoter status.	('MGMT', 'Gene', (65, 69))	('methylated', 'Var', (26, 36))	('MGMT', 'Gene', '4255', (65, 69))	('patients', 'Species', '9606', (13, 21))	('MGMT', 'Gene', '4255', (37, 41))	('MGMT', 'Gene', (37, 41))
5583	24267971	Retrospective data suggested that PP may occur more commonly in GBM patients with a methylated MGMT promoter (>90%) than in those with unmethylated promoter (approximately 40%) and is associated even more with improved survival.	('improved', 'PosReg', (210, 218))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('patients', 'Species', '9606', (68, 76))	('methylated', 'Var', (84, 94))	('MGMT', 'Gene', '4255', (95, 99))	('MGMT', 'Gene', (95, 99))
5584	24267971	However, as shown in our study, despite the fact that most of the patients in our series had a methylated MGMT promoter (66.6%), none of them showed any sign of PP.	('MGMT', 'Gene', (106, 110))	('methylated', 'Var', (95, 105))	('patients', 'Species', '9606', (66, 74))	('MGMT', 'Gene', '4255', (106, 110))
5589	24267971	In contrast, our series of 10 sGBM patients harboring an IDH mutation, including 2 patients with oligodendroglial components exhibiting 1p/19q codeletions, did not support the latter hypothesis, as none of them had PP.	('IDH', 'Gene', '3417', (57, 60))	('mutation', 'Var', (61, 69))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (83, 91))	('IDH', 'Gene', (57, 60))
5590	24267971	Thus, we conclude that IDH mutations are not associated with PP in sGBM.	('mutations', 'Var', (27, 36))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (23, 26))
5662	31435515	With the disease progression, tumor cells initially possessing common initiating mutations start accumulating additional somatic mutations leading to highly heterogeneous cell populations.	('leading to', 'Reg', (139, 149))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (81, 90))	('highly heterogeneous cell populations', 'MPA', (150, 187))	('tumor', 'Disease', (30, 35))
5684	31435515	The importance of glioma molecular profiling was underscored by the WHO in 2016, when it issued a new glioma classification based on certain mutations in the genes coding for isocitrate dehydrogenases (IDH1, IDH2) and 1p/19q codeletion.	('isocitrate', 'Chemical', 'MESH:C034219', (175, 185))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glioma', 'Disease', (18, 24))	('IDH2', 'Gene', (208, 212))	('mutations', 'Var', (141, 150))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('IDH2', 'Gene', '3418', (208, 212))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH1', 'Gene', (202, 206))	('glioma', 'Disease', (102, 108))	('IDH1', 'Gene', '3417', (202, 206))
5685	31435515	Specifically, gliomas are divided into IDH-mutant (IDHmt) and IDH-wild type (IDHwt), IDHmt further subdivided to the ones bearing 1p/19q codeletion and ones with the ATRX (ATP-dependent helicase ATRX, X-linked helicase II) mutation.	('IDH', 'Gene', '3417', (51, 54))	('X-linked helicase II', 'Gene', '546', (201, 221))	('1p/19q codeletion', 'Var', (130, 147))	('IDH', 'Gene', (62, 65))	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('ATRX', 'Gene', (195, 199))	('IDH', 'Gene', (77, 80))	('ATRX', 'Gene', '546', (195, 199))	('IDH', 'Gene', (39, 42))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('IDH', 'Gene', (85, 88))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('IDH', 'Gene', '3417', (62, 65))	('IDH', 'Gene', '3417', (77, 80))	('ATP-dependent helicase ATRX', 'Gene', '546', (172, 199))	('IDH', 'Gene', '3417', (39, 42))	('IDH', 'Gene', '3417', (85, 88))	('IDH', 'Gene', (51, 54))	('ATP-dependent helicase ATRX', 'Gene', (172, 199))	('ATRX', 'Gene', (166, 170))	('gliomas', 'Disease', (14, 21))	('X-linked helicase II', 'Gene', (201, 221))	('ATRX', 'Gene', '546', (166, 170))
5686	31435515	Thus, tumors carrying mutations in the IDH gene concurrently with 1p/19q codeletion are classified as oligodendrogliomas, while those bearing mutations in IDH and ATRX are referred to as astrocytomas, and IDHwt tumors are identified as primary glioblastomas.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('IDHwt tumors', 'Disease', 'MESH:D009369', (205, 217))	('primary glioblastomas', 'Disease', (236, 257))	('glioblastoma', 'Phenotype', 'HP:0012174', (244, 256))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (102, 120))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('primary glioblastomas', 'Disease', 'MESH:D005909', (236, 257))	('IDH', 'Gene', (205, 208))	('IDH', 'Gene', (39, 42))	('ATRX', 'Gene', (163, 167))	('astrocytomas', 'Disease', (187, 199))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('ATRX', 'Gene', '546', (163, 167))	('IDH', 'Gene', (155, 158))	('oligodendrogliomas', 'Disease', (102, 120))	('tumors', 'Disease', (6, 12))	('IDH', 'Gene', '3417', (205, 208))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('IDH', 'Gene', '3417', (39, 42))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('glioblastomas', 'Phenotype', 'HP:0012174', (244, 257))	('astrocytomas', 'Disease', 'MESH:D001254', (187, 199))	('IDH', 'Gene', '3417', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (187, 198))	('IDHwt tumors', 'Disease', (205, 217))
5689	31435515	Among patients with diffuse gliomas, the best prognosis is associated with IDHmt and 1p/19q codeletion as well as with the ATRX loss of function.	('ATRX', 'Gene', (123, 127))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('diffuse gliomas', 'Disease', 'MESH:D005910', (20, 35))	('ATRX', 'Gene', '546', (123, 127))	('loss of function', 'NegReg', (128, 144))	('patients', 'Species', '9606', (6, 14))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('diffuse gliomas', 'Disease', (20, 35))	('1p/19q codeletion', 'Var', (85, 102))
5690	31435515	Furthermore, the mutation of the TERT gene promoter is unfavorable in IDHwt tumors but beneficial in IDHmt tumors.	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('IDHwt tumors', 'Disease', 'MESH:D009369', (70, 82))	('mutation', 'Var', (17, 25))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('IDHmt tumors', 'Disease', (101, 113))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('IDHwt tumors', 'Disease', (70, 82))	('IDHmt tumors', 'Disease', 'MESH:D009369', (101, 113))
5692	31435515	Thus, 90% of the primary glioblastomas are IDHwt and carry mutations in the genes involved in molecular pathways involving p53, retinoblastoma 1 (Rb1), and tyrosine kinase receptor (RTK/RAS/PI3K).	('primary glioblastomas', 'Disease', (17, 38))	('IDH', 'Gene', '3417', (43, 46))	('retinoblastoma 1', 'Gene', (128, 144))	('Rb1', 'Gene', (146, 149))	('glioblastomas', 'Phenotype', 'HP:0012174', (25, 38))	('retinoblastoma 1', 'Gene', '5925', (128, 144))	('Rb1', 'Gene', '5925', (146, 149))	('p53', 'Gene', (123, 126))	('primary glioblastomas', 'Disease', 'MESH:D005909', (17, 38))	('mutations', 'Var', (59, 68))	('retinoblastoma', 'Phenotype', 'HP:0009919', (128, 142))	('carry', 'Reg', (53, 58))	('IDH', 'Gene', (43, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('p53', 'Gene', '7157', (123, 126))
5693	31435515	Secondary glioblastomas are almost invariably IDHmt and carry TP53 and ATRX mutations, pointing to their most probable source of origin - low-grade astrocytomas.	('TP53', 'Gene', '7157', (62, 66))	('mutations', 'Var', (76, 85))	('ATRX', 'Gene', '546', (71, 75))	('glioblastomas', 'Phenotype', 'HP:0012174', (10, 23))	('carry', 'Reg', (56, 61))	('TP53', 'Gene', (62, 66))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (46, 49))	('glioblastomas', 'Disease', 'MESH:D005909', (10, 23))	('astrocytomas', 'Disease', 'MESH:D001254', (148, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (148, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))	('astrocytomas', 'Disease', (148, 160))	('glioblastomas', 'Disease', (10, 23))	('ATRX', 'Gene', (71, 75))
5695	31435515	Additionally, several studies have separately investigated some heritable genomic variants that could be utilized for glioma risk prognosis, for instance, the mutation in CCDC26 is associated with the oligodendroglioma and astrocytoma development, CDKN2B mutation is linked with low-grade astrocytomas; VTI1A, ZBTB16, PHLDB1 rs12230172 (noncoding), and ETFA defects could be considered as risk markers for low-grade IDHmt gliomas; while RTEL1 alteration can be common for all gliomas.	('rat', 'Species', '10116', (447, 450))	('CDKN2B', 'Gene', (248, 254))	('CCDC26', 'Gene', '137196', (171, 177))	('IDHmt gliomas', 'Disease', (416, 429))	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('ETFA', 'Gene', (353, 357))	('VTI1A', 'Gene', (303, 308))	('RTEL1', 'Gene', (437, 442))	('oligodendroglioma', 'Disease', (201, 218))	('astrocytomas', 'Disease', 'MESH:D001254', (289, 301))	('gliomas', 'Phenotype', 'HP:0009733', (476, 483))	('astrocytoma', 'Phenotype', 'HP:0009592', (289, 300))	('ZBTB16', 'Gene', (310, 316))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('CCDC26', 'Gene', (171, 177))	('variants', 'Var', (82, 90))	('associated', 'Reg', (181, 191))	('CDKN2B', 'Gene', '1030', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('astrocytoma', 'Phenotype', 'HP:0009592', (223, 234))	('mutation', 'Var', (255, 263))	('rat', 'Species', '10116', (39, 42))	('ETFA', 'Gene', '2108', (353, 357))	('mutation', 'Var', (159, 167))	('gliomas', 'Disease', (422, 429))	('glioma', 'Disease', (422, 428))	('rs12230172', 'Mutation', 'rs12230172', (325, 335))	('astrocytoma', 'Disease', 'MESH:D001254', (289, 300))	('RTEL1', 'Gene', '51750', (437, 442))	('ZBTB16', 'Gene', '7704', (310, 316))	('glioma', 'Disease', 'MESH:D005910', (422, 428))	('VTI1A', 'Gene', '143187', (303, 308))	('gliomas', 'Disease', (476, 483))	('glioma', 'Disease', (476, 482))	('astrocytoma', 'Disease', (289, 300))	('linked', 'Reg', (267, 273))	('glioma', 'Disease', 'MESH:D005910', (476, 482))	('astrocytomas', 'Disease', (289, 301))	('astrocytoma', 'Disease', 'MESH:D001254', (223, 234))	('gliomas', 'Disease', 'MESH:D005910', (422, 429))	('rs12230172', 'Var', (325, 335))	('glioma', 'Phenotype', 'HP:0009733', (422, 428))	('glioma', 'Disease', (118, 124))	('astrocytoma', 'Disease', (223, 234))	('PHLDB1', 'Gene', (318, 324))	('gliomas', 'Disease', 'MESH:D005910', (476, 483))	('oligodendroglioma', 'Disease', 'MESH:D009837', (201, 218))	('PHLDB1', 'Gene', '23187', (318, 324))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('IDHmt gliomas', 'Disease', 'MESH:D005910', (416, 429))	('glioma', 'Phenotype', 'HP:0009733', (476, 482))	('gliomas', 'Phenotype', 'HP:0009733', (422, 429))	('glioma', 'Disease', (212, 218))
5696	31435515	Meanwhile, the most morbid IDHwt primary glioblastomas, with the poorest prognoses, could also be predicted in advance using such genomic variants as 3q26.2 near TERC, 7p11.2 near EGFR, and 12q23.33 near POLR3B.	('IDH', 'Gene', (27, 30))	('TERC', 'Gene', '7012', (162, 166))	('glioblastomas', 'Phenotype', 'HP:0012174', (41, 54))	('primary glioblastomas', 'Disease', 'MESH:D005909', (33, 54))	('3q26.2', 'Var', (150, 156))	('IDH', 'Gene', '3417', (27, 30))	('POLR3B', 'Gene', '55703', (204, 210))	('primary glioblastomas', 'Disease', (33, 54))	('POLR3B', 'Gene', (204, 210))	('7p11.2', 'Var', (168, 174))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('TERC', 'Gene', (162, 166))	('12q23.33 near', 'Var', (190, 203))
5697	31435515	While significant correlations of these genomic variants with the probability of further acquisition of the specific glioma subtypes needs to be addressed in more detail, the aforementioned markers can be clinically assessed in people with family glioma history.	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('variants', 'Var', (48, 56))	('people', 'Species', '9606', (228, 234))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Disease', (247, 253))	('glioma', 'Disease', (117, 123))
5698	31435515	While the role of IDH mutation as a diagnostic marker and predictor of glioma development has been investigated, specific mechanisms determining lower disease grade in the case of this mutation remain unclear.	('mutation', 'Var', (22, 30))	('IDH', 'Gene', (18, 21))	('glioma', 'Disease', (71, 77))	('IDH', 'Gene', '3417', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
5700	31435515	It was shown that the introduction of mutant IDH1 in human primary astrocytes causes the hypermethylation of histones and DNA sites linked to terminal differentiation, which can lead to locking cell in the embryonic state associated with unlimited self-renewing capacity.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (45, 49))	('causes', 'Reg', (78, 84))	('lead to', 'Reg', (178, 185))	('histones', 'Protein', (109, 117))	('hypermethylation', 'MPA', (89, 105))	('human', 'Species', '9606', (53, 58))	('introduction', 'Var', (22, 34))	('IDH1', 'Gene', (45, 49))
5701	31435515	At the same time, mutations in stem cells are considered to be the most malignant, since they are the alleged progenitors of the whole tumor.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mutations', 'Var', (18, 27))
5703	31435515	Possible explanations could be either different glioma-initiating progenitor cells for IDHmt and IDHwt glioma types, or distinct secondary epigenetic perturbations of chromatin blocking the final differentiation and determining different transcriptional cellular profiles.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('IDH', 'Gene', (97, 100))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('epigenetic perturbations', 'Var', (139, 163))	('IDH', 'Gene', (87, 90))	('perturbations', 'Var', (150, 163))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('IDH', 'Gene', '3417', (97, 100))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('IDH', 'Gene', '3417', (87, 90))	('blocking', 'NegReg', (177, 185))	('glioma', 'Disease', (103, 109))	('glioma', 'Disease', (48, 54))
5704	31435515	In the latter case, glioma CSC molecular phenotyping and tracking their changes in culture should help unravelling the effects of different DNA mutations on tumor fate and delineating factors responsible for the glioma development on case-to-case basis.	('tumor', 'Disease', (157, 162))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('glioma', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutations', 'Var', (144, 153))	('glioma', 'Disease', (212, 218))
5713	31435515	U87 was generated in 1960`s from patient with a glioblastoma, but the recently performed whole genome sequencing revealed a great number of indels and translocations, most of which were acquired over decades of cell cultivation.	('translocations', 'Var', (151, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('U87', 'Gene', '641648', (0, 3))	('patient', 'Species', '9606', (33, 40))	('rat', 'Species', '10116', (12, 15))	('indels', 'Var', (140, 146))	('U87', 'Gene', (0, 3))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))
5721	31435515	It is widely accepted that primary glioma cells should be passaged as little as possible preventing epigenetic or genetic alteration, while cultured without serum.	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('rat', 'Species', '10116', (126, 129))	('genetic alteration', 'Var', (114, 132))	('epigenetic', 'Var', (100, 110))	('glioma', 'Disease', (35, 41))
5741	31435515	This was revealed by the introduction of the same mutations in the OPs and NSCs, that, however, caused the formation of different glioma types, thus indicating the interaction between the activated oncogenic molecular pathway and the epigenetic status of the cell at the certain stage of differentiation.	('caused', 'Reg', (96, 102))	('mutations', 'Var', (50, 59))	('glioma', 'Disease', (130, 136))	('NSCs', 'Gene', (75, 79))	('oncogenic molecular pathway', 'Pathway', (198, 225))	('OPs', 'Gene', (67, 70))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
5742	31435515	On the other hand, the activation of different mutations in the same progenitor cells led to the formation of histologically different gliomas.	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('mutations', 'Var', (47, 56))	('gliomas', 'Disease', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))
5748	31435515	Predominantly researchers focus on finding mutations causing the development of the malignant processes, yet often missing the effect of concomitant mutations, transcriptional profiles, epigenetic regulators and microenvironment of the tumor cells.	('missing', 'NegReg', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('causing', 'Reg', (53, 60))	('mutations', 'Var', (43, 52))	('malignant processes', 'CPA', (84, 103))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('development', 'CPA', (65, 76))	('tumor', 'Disease', (236, 241))
5808	31245283	Molecular mechanistic investigation demonstrated that both LRIG3 and sLRIG3 inhibit the growth and invasion capabilities of GL15, U87, and PriGBM cells and tumor xenografts in nude mice through regulating the MET/phosphatidylinositol 3-kinase/Akt signaling pathway.	('inhibit', 'NegReg', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('sLRIG3', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('U87', 'Gene', (130, 133))	('tumor', 'Disease', (156, 161))	('U87', 'Gene', '641648', (130, 133))	('nude mice', 'Species', '10090', (176, 185))	('regulating', 'Reg', (194, 204))
5826	31245283	The amplification and activation of EGFR, platelet derived growth factor receptor alpha (PDGFRalpha), and mesenchymal-epithelial transition factor (MET) promote the proliferation and invasion of glioma cells and are correlated with recurrence and therapeutic resistance.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('PDGFRalpha', 'Gene', (89, 99))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (42, 87))	('platelet derived growth factor receptor alpha', 'Gene', (42, 87))	('EGFR', 'Gene', (36, 40))	('activation', 'PosReg', (22, 32))	('EGFR', 'Gene', '1956', (36, 40))	('amplification', 'Var', (4, 17))	('glioma', 'Disease', (195, 201))	('PDGFRalpha', 'Gene', '5156', (89, 99))	('promote', 'PosReg', (153, 160))	('invasion', 'CPA', (183, 191))	('proliferation', 'CPA', (165, 178))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
5921	31245283	Although phosphorylation of PDGFRalpha was not affected by the status of LRIG3 in GL15 and PriGBM cells, MET and Akt phosphorylation was inhibited by overexpression of LRIG3 and sLRIG3 compared with that in the control group (Figures 5A,B).	('expression', 'Species', '29278', (154, 164))	('inhibited', 'NegReg', (137, 146))	('PDGFRalpha', 'Gene', (28, 38))	('overexpression', 'PosReg', (150, 164))	('PDGFRalpha', 'Gene', '5156', (28, 38))	('Akt', 'Pathway', (113, 116))	('MET and', 'MPA', (105, 112))	('LRIG3', 'Var', (168, 173))	('sLRIG3', 'Var', (178, 184))
5931	31245283	These findings are consistent with the results that LRIG3 inhibited the phosphorylation of the components of the MET/PI3K/Akt pathway in glioma cell lines.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('LRIG3', 'Var', (52, 57))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('phosphorylation', 'MPA', (72, 87))	('glioma', 'Disease', (137, 143))	('MET/PI3K/Akt pathway', 'Pathway', (113, 133))	('inhibited', 'NegReg', (58, 67))
5933	31245283	After demonstrating that si-2-LRIG3 and si-3-LRIG3 effectively silenced LRIG3 expression in A172 cell lines (Figure 6A), growth curves and migration assays indicated that knockdown of LRIG3 protein facilitated the proliferation and migration of A172 cells (Figures 6B,C).	('expression', 'MPA', (78, 88))	('facilitated', 'PosReg', (198, 209))	('LRIG3', 'Gene', (184, 189))	('A172 cells', 'CPA', (245, 255))	('knockdown', 'Var', (171, 180))	('proliferation', 'CPA', (214, 227))	('migration', 'CPA', (232, 241))	('protein', 'Protein', (190, 197))	('A172', 'CellLine', 'CVCL:0131', (245, 249))	('A172', 'CellLine', 'CVCL:0131', (92, 96))	('silenced', 'NegReg', (63, 71))	('expression', 'Species', '29278', (78, 88))	('LRIG3', 'Gene', (72, 77))
5940	31245283	As shown in Figure 7C, the phosphorylation levels of MET and Akt were lower in tumors overexpressing LRIG3 and sLRIG3 than in the control group.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('MET', 'MPA', (53, 56))	('LRIG3', 'Var', (101, 106))	('lower', 'NegReg', (70, 75))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('phosphorylation levels', 'MPA', (27, 49))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Akt', 'Pathway', (61, 64))
5943	31245283	Our aforementioned study demonstrated that sLRIG3 existed in serum samples from glioma patients through western blotting, and overexpression of sLRIG3 inhibited the proliferation and invasion of glioma cells.	('glioma', 'Disease', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('sLRIG3', 'Gene', (144, 150))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('inhibited', 'NegReg', (151, 160))	('glioma', 'Disease', (195, 201))	('patients', 'Species', '9606', (87, 95))	('expression', 'Species', '29278', (130, 140))	('overexpression', 'Var', (126, 140))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
5953	31245283	Previous studies have shown that growth factor pathways are constitutively activated in malignant gliomas through gene mutations and overexpression or genetic amplification of growth factor receptor genes.	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('activated', 'PosReg', (75, 84))	('gene mutations', 'Var', (114, 128))	('growth factor pathways', 'Pathway', (33, 55))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('overexpression', 'PosReg', (133, 147))	('malignant gliomas', 'Disease', (88, 105))	('genetic amplification', 'Var', (151, 172))	('malignant gliomas', 'Disease', 'MESH:D005910', (88, 105))	('expression', 'Species', '29278', (137, 147))
5965	31245283	However, this agent only prolongs progression-free survival and does not affect overall survival, due to aberrant MET expression and activation, which may contribute to bevacizumab resistance.	('bevacizumab', 'Chemical', 'MESH:D000068258', (169, 180))	('activation', 'MPA', (133, 143))	('progression-free survival', 'CPA', (34, 59))	('MET expression', 'MPA', (114, 128))	('expression', 'Species', '29278', (118, 128))	('prolongs', 'PosReg', (25, 33))	('aberrant', 'Var', (105, 113))	('contribute', 'Reg', (155, 165))
5967	31245283	Although there are many preclinical and clinical studies about small molecular inhibitors or antibodies against MET in glioblastoma, their usefulness is limited.	('MET', 'Gene', (112, 115))	('glioblastoma', 'Disease', (119, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('small molecular inhibitors', 'Var', (63, 89))
5970	31245283	Additionally, coexpression of MET and its ligand HGF occur frequently in cancers, including glioblastoma, and have been associated with increased malignancy and decreased patient survival.	('cancers', 'Disease', (73, 80))	('glioblastoma', 'Disease', (92, 104))	('patient survival', 'CPA', (171, 187))	('decreased', 'NegReg', (161, 170))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('patient', 'Species', '9606', (171, 178))	('HGF', 'Gene', (49, 52))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('coexpression', 'Var', (14, 26))	('expression', 'Species', '29278', (16, 26))	('increased', 'PosReg', (136, 145))	('malignancy', 'Disease', (146, 156))	('HGF', 'Gene', '3082', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('MET', 'Gene', (30, 33))
5979	31245283	Previous analysis of glioma samples showed that aberrant regulations of RTK/PI3K pathway played important roles in the events of tumor formation, progression and therapeutic resistance.	('RTK', 'Gene', (72, 75))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('aberrant regulations', 'Var', (48, 68))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('RTK', 'Gene', '5979', (72, 75))	('glioma', 'Disease', (21, 27))	('tumor', 'Disease', (129, 134))
6030	29967940	We would likely see such a score as a suggestion that a case may be in some way related to a certain methylation class and would try to find further evidence of such a relation [e.g., sequencing of BRAF in a case with a methylation class (anaplastic) pleomorphic xanthoastrocytoma (PXA) calibrated score of 0.75].	('related', 'Reg', (80, 87))	('BRAF', 'Gene', '673', (198, 202))	('sequencing', 'Var', (184, 194))	('BRAF', 'Gene', (198, 202))	('astrocytoma', 'Phenotype', 'HP:0009592', (269, 280))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (251, 280))	('pleomorphic xanthoastrocytoma', 'Disease', (251, 280))
6033	29967940	1a, e) and homozygous deletions (e.g., CDKN2A/B, Figs.	('CDKN2A/B', 'Gene', '1029;1030', (39, 47))	('deletions', 'Var', (22, 31))	('CDKN2A/B', 'Gene', (39, 47))
6039	29967940	5a) and the high-level amplification of C19MC on Chr.19 in embryonal tumors with multilayered rosettes (ETMR; Fig.	('Chr', 'Gene', (49, 52))	('rosettes', 'Phenotype', 'HP:0031925', (94, 102))	('embryonal tumors', 'Phenotype', 'HP:0002898', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Chr', 'Gene', '1125', (49, 52))	('embryonal tumors', 'Disease', (59, 75))	('embryonal tumors', 'Disease', 'MESH:D009373', (59, 75))	('rosette', 'Phenotype', 'HP:0031925', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('embryonal tumor', 'Phenotype', 'HP:0002898', (59, 74))	('MC', 'Chemical', 'MESH:D008748', (43, 45))	('C19MC', 'Var', (40, 45))
6041	29967940	Based on this algorithm which is also underlying the MGMT promoter methylation analysis provided by our webpage for uploaded cases, we receive the readouts "methylated", unmethylated, or "not determinable".	('MGMT', 'Gene', (53, 57))	('unmethylated', 'Var', (170, 182))	('MGMT', 'Gene', '4255', (53, 57))
6058	29967940	Of note, the "A IDH, HG" group also contains most of the IDH mutant glioblastomas.	('IDH', 'Gene', '3417', (57, 60))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('IDH', 'Gene', (16, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (68, 81))	('mutant', 'Var', (61, 67))	('IDH', 'Gene', '3417', (16, 19))	('IDH', 'Gene', (57, 60))	('glioblastomas', 'Disease', (68, 81))
6060	29967940	However, recent data provide evidence that grading of IDH mutant astrocytoma by assessing copy-number alterations is more powerful than grading by DNA methylation analysis only.	('astrocytoma', 'Disease', 'MESH:D001254', (65, 76))	('astrocytoma', 'Disease', (65, 76))	('copy-number alterations', 'Var', (90, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('IDH', 'Gene', (54, 57))	('IDH', 'Gene', '3417', (54, 57))
6065	29967940	We have so far analyzed one case of a dual genotype astrocytoma/oligodendroglioma and, indeed, observed a different methylation class of A IDH and O IDH, respectively, in different macrodissected tumor areas and an exclusive 1p/19q codeletion in the oligodendroglial tumor regions.	('methylation', 'MPA', (116, 127))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('astrocytoma/oligodendroglioma', 'Disease', 'MESH:D009837', (52, 81))	('IDH', 'Gene', (149, 152))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('IDH', 'Gene', '3417', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (267, 272))	('IDH', 'Gene', (139, 142))	('1p/19q', 'Var', (225, 231))	('oligodendroglial tumor', 'Disease', 'MESH:D009369', (250, 272))	('astrocytoma/oligodendroglioma', 'Disease', (52, 81))	('IDH', 'Gene', '3417', (139, 142))	('oligodendroglial tumor', 'Disease', (250, 272))
6068	29967940	Consensus of the critique is the demonstration of mutational profiles in these tumors that closely match those of glioblastoma (or, rarely, a more pediatric-type diffuse glioma).	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('glioma', 'Disease', (170, 176))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('mutational', 'Var', (50, 60))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('glioblastoma', 'Disease', (114, 126))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
6080	29967940	In some instances, this may result in a higher score for an astrocytoma despite a 1p/19q codeletion.	('astrocytoma', 'Disease', 'MESH:D001254', (60, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('astrocytoma', 'Disease', (60, 71))	('1p/19q codeletion', 'Var', (82, 99))
6086	29967940	In case the CNV shows prototypic glioblastoma changes (in particular amplification of EGFR or other amplifications, combined gain of Chr.7, and loss of Chr.10), we would consider the case a glioblastoma, IDH wt.	('glioblastoma', 'Disease', 'MESH:D005909', (190, 202))	('glioblastoma', 'Disease', (33, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (190, 202))	('EGFR', 'Gene', '1956', (86, 90))	('gain', 'PosReg', (125, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('Chr', 'Gene', '1125', (152, 155))	('Chr', 'Gene', (152, 155))	('EGFR', 'Gene', (86, 90))	('IDH', 'Gene', (204, 207))	('Chr', 'Gene', (133, 136))	('IDH', 'Gene', '3417', (204, 207))	('Chr', 'Gene', '1125', (133, 136))	('amplification', 'Var', (69, 82))	('loss', 'NegReg', (144, 148))	('glioblastoma', 'Disease', (190, 202))
6107	29967940	In case a BRAF V600 mutation is detected and the CNV shows a focal deletion of CDKN2A/B but no additional complex chromosomal changes we consider the case as PXA (and would grade according to WHO by counting mitotic figures).	('CDKN2A/B', 'Gene', (79, 87))	('deletion', 'Var', (67, 75))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('CDKN2A/B', 'Gene', '1029;1030', (79, 87))
6118	29967940	Duplication of the BRAF locus is frequent among pilocytic astrocytomas and can be observed as a focal low-level gain indicative for a duplication on Chr.7q (Fig.	('pilocytic astrocytomas', 'Disease', (48, 70))	('BRAF', 'Gene', '673', (19, 23))	('Chr', 'Gene', '1125', (149, 152))	('Chr', 'Gene', (149, 152))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (48, 70))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('BRAF', 'Gene', (19, 23))	('Duplication', 'Var', (0, 11))	('gain', 'PosReg', (112, 116))	('low-level', 'MPA', (102, 111))
6120	29967940	The copy-number pattern of these tumors occasionally also demonstrates BRAF duplications but much more frequently harbor CDKN2A/B deletions and further chromosomal changes (Fig.	('CDKN2A/B', 'Gene', '1029;1030', (121, 129))	('deletions', 'Var', (130, 139))	('BRAF', 'Gene', '673', (71, 75))	('CDKN2A/B', 'Gene', (121, 129))	('BRAF', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('duplications', 'Var', (76, 88))
6122	29967940	The presence of a BRAF V600E mutation seen in approximately 70% of pleomorphic xanthoastrocytomas is not a requirement for classification of these tumors into this class.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('pleomorphic xanthoastrocytomas', 'Disease', (67, 97))	('tumors', 'Disease', (147, 153))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', '673', (18, 22))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (67, 97))	('BRAF', 'Gene', (18, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (85, 96))
6123	29967940	An established but usually underestimated feature of pleomorphic xanthoastrocytoma is homozygous deletion of CDKN2A previously reported in 50%.	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (53, 82))	('CDKN2A', 'Gene', (109, 115))	('pleomorphic xanthoastrocytoma', 'Disease', (53, 82))	('CDKN2A', 'Gene', '1029', (109, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('deletion', 'Var', (97, 105))
6124	29967940	Among cases falling into this methylation, class CDKN2A/B deletions are seen in around 70% of cases (Fig.	('CDKN2A/B', 'Gene', (49, 57))	('falling', 'Phenotype', 'HP:0002527', (12, 19))	('deletions', 'Var', (58, 67))	('CDKN2A/B', 'Gene', '1029;1030', (49, 57))	('fall', 'Phenotype', 'HP:0002527', (12, 16))
6129	29967940	If the mutation is present and the tumor, additionally, harbors a CDKN2A/B deletion, we would consider the case as a molecular PXA with unusual histological features.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CDKN2A/B', 'Gene', '1029;1030', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('deletion', 'Var', (75, 83))	('CDKN2A/B', 'Gene', (66, 74))	('tumor', 'Disease', (35, 40))
6132	29967940	In our experience, detection of a BRAF duplication in the form of the typical focal low-level gain on Chr.7q representing a 7q34 tandem duplication (Fig.	('duplication', 'Var', (39, 50))	('gain', 'PosReg', (94, 98))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))	('Chr', 'Gene', '1125', (102, 105))	('Chr', 'Gene', (102, 105))
6139	29967940	If these cases, additionally, harbor a CDKN2A/B deletion and/or immunohistochemical ATRX loss (frequent in "anaplastic astrocytoma with piloid features", likely never present in PA), we would consider the case as "anaplastic astrocytoma with piloid features".	('astrocytoma', 'Phenotype', 'HP:0009592', (119, 130))	('anaplastic astrocytoma', 'Disease', (108, 130))	('ATRX', 'Gene', '546', (84, 88))	('CDKN2A/B', 'Gene', '1029;1030', (39, 47))	('anaplastic astrocytoma', 'Disease', (214, 236))	('CDKN2A/B', 'Gene', (39, 47))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (108, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (225, 236))	('deletion', 'Var', (48, 56))	('ATRX', 'Gene', (84, 88))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (214, 236))	('loss', 'NegReg', (89, 93))
6150	29967940	CNV in "ependymoma, spine" are also frequent, with the dominating alteration being chromosome 22 loss (Fig.	('loss', 'NegReg', (97, 101))	('"ependymoma', 'Disease', (7, 18))	('"ependymoma', 'Disease', 'MESH:D004806', (7, 18))	('chromosome 22', 'Var', (83, 96))	('ependymoma', 'Phenotype', 'HP:0002888', (8, 18))
6161	29967940	The "ependymoma, YAP1 fusion" tumors on average have fewer alterations, with loss close to the YAP1 locus on Chr.11q and loss of Chr.22 being most frequent (Fig.	('YAP1', 'Gene', (17, 21))	('tumors', 'Disease', (30, 36))	('YAP1', 'Gene', (95, 99))	('YAP1', 'Gene', '10413', (17, 21))	('YAP1', 'Gene', '10413', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('"ependymoma', 'Disease', (4, 15))	('loss', 'Var', (121, 125))	('ependymoma', 'Phenotype', 'HP:0002888', (5, 15))	('Chr', 'Gene', (109, 112))	('Chr', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('loss', 'NegReg', (77, 81))	('Chr', 'Gene', '1125', (109, 112))	('Chr', 'Gene', '1125', (129, 132))	('"ependymoma', 'Disease', 'MESH:D004806', (4, 15))
6169	29967940	Along the same lines, all so far analyzed subependymoma/ependymoma composition tumors (n = 4) scored as methylation class subependymoma in both tumor areas and we consider the ependymoma parts as a more compact growth pattern of subependymoma.	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('subependymoma', 'Disease', 'MESH:D018315', (229, 242))	('subependymoma', 'Disease', (229, 242))	('ependymoma', 'Phenotype', 'HP:0002888', (125, 135))	('subependymoma/ependymoma composition tumors', 'Disease', (42, 85))	('ependymoma', 'Phenotype', 'HP:0002888', (45, 55))	('subependymoma/ependymoma composition tumors', 'Disease', 'MESH:D018315', (42, 85))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (79, 84))	('ependymoma parts', 'Disease', 'MESH:D004806', (176, 192))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('ependymoma parts', 'Disease', (176, 192))	('ependymoma', 'Phenotype', 'HP:0002888', (176, 186))	('subependymoma', 'Disease', 'MESH:D018315', (122, 135))	('subependymoma', 'Disease', 'MESH:D018315', (42, 55))	('subependymoma', 'Disease', (122, 135))	('ependymoma', 'Phenotype', 'HP:0002888', (232, 242))	('subependymoma', 'Disease', (42, 55))	('methylation', 'Var', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ependymoma', 'Phenotype', 'HP:0002888', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
6176	29967940	A more conservative approach might designate these tumors as "ependymoma with methylation profile of myxopapillary ependymoma", although this would neglect the additional and independent data from the copy-number profiles pointing to myxopapillary ependymoma.	('myxopapillary ependymoma', 'Disease', 'MESH:D004806', (234, 258))	('myxopapillary ependymoma', 'Disease', (234, 258))	('methylation', 'Var', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('"ependymoma', 'Disease', 'MESH:D004806', (61, 72))	('ependymoma', 'Phenotype', 'HP:0002888', (115, 125))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('myxopapillary ependymoma', 'Disease', 'MESH:D004806', (101, 125))	('myxopapillary ependymoma', 'Disease', (101, 125))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('ependymoma', 'Phenotype', 'HP:0002888', (248, 258))	('"ependymoma', 'Disease', (61, 72))	('ependymoma', 'Phenotype', 'HP:0002888', (62, 72))
6183	29967940	All cases investigated also harbored the recently published PRKCA hotspot mutation.	('mutation', 'Var', (74, 82))	('PRKCA', 'Gene', (60, 65))	('harbored', 'Reg', (28, 36))	('PRKCA', 'Gene', '5578', (60, 65))
6187	29967940	By methylation analysis, a substantial part of astroblastomas are classified as "CNS high-grade neuroepithelial tumor with MN1 alteration".	('MN1', 'Gene', (123, 126))	('astroblastomas', 'Disease', 'MESH:D018302', (47, 61))	('MN1', 'Gene', '4330', (123, 126))	('neuroepithelial tumor', 'Disease', (96, 117))	('astroblastomas', 'Disease', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('alteration', 'Var', (127, 137))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (96, 117))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (96, 117))
6188	29967940	Likely, the remaining cases are not a single tumor entity but rather harbor genetic alterations that suggest classification as other tumor entities.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('genetic alterations', 'Var', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
6193	29967940	Here, we would be more cautious to downgrade the tumor and would remain with the diagnosis of a "not further classifiable pediatric glioma with alterations of MYB/MYBL1 and additional complex chromosomal changes".	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MYB', 'Gene', '4602', (163, 166))	('glioma', 'Disease', (132, 138))	('MYBL1', 'Gene', '4603', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MYB', 'Gene', (159, 162))	('MYB', 'Gene', (163, 166))	('tumor', 'Disease', (49, 54))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('MYB', 'Gene', '4602', (159, 162))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('alterations', 'Var', (144, 155))	('MYBL1', 'Gene', (163, 168))
6221	29967940	CNV profiles show no recurrent chromosomal imbalances (Supplementary file 1), while initial data suggest that BRAF mutations may be relatively common in this group.	('imbalances', 'Phenotype', 'HP:0002172', (43, 53))	('BRAF', 'Gene', (110, 114))	('mutations', 'Var', (115, 124))	('BRAF', 'Gene', '673', (110, 114))
6233	29967940	In particular, familial paraganglioma may carry germline SDH mutations associated with a CpG island methylator phenotype (CIMP).	('familial paraganglioma', 'Disease', (15, 37))	('SDH', 'Gene', (57, 60))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('familial paraganglioma', 'Disease', 'MESH:D010235', (15, 37))	('mutations', 'Var', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('CIMP', 'Chemical', '-', (122, 126))	('SDH', 'Gene', '10993', (57, 60))	('associated', 'Reg', (71, 81))
6234	29967940	Paraganglioma without SDH mutations constitute the vast majority of sporadic tumors form the "paraganglioma, spinal non-CIMP" methylation class.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Paraganglioma', 'Disease', (0, 13))	('sporadic tumors', 'Disease', 'MESH:D009369', (68, 83))	('paraganglioma', 'Disease', 'MESH:D010235', (94, 107))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paraganglioma', 'Disease', 'MESH:D010235', (0, 13))	('CIMP', 'Chemical', '-', (120, 124))	('mutations', 'Var', (26, 35))	('SDH', 'Gene', '10993', (22, 25))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('sporadic tumors', 'Disease', (68, 83))	('SDH', 'Gene', (22, 25))	('paraganglioma', 'Disease', (94, 107))
6236	29967940	Repeatedly, we have observed cases with a high score for "low-grade glioma, ganglioglioma" methylation class but without clear histologic evidence for ganglionic differentiation.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('methylation', 'Var', (91, 102))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Disease', (68, 74))
6244	29967940	We observe cases scored as methylation class "diffuse leptomeningeal glioneuronal tumor" more frequently than anticipated.	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (69, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('methylation', 'Var', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
6257	29967940	Typical CNV in "pineoblastoma group A/intracranial retinoblastoma" are gain of Chr.1q, gain of 6p and loss of 16q (Fig.	('pineoblastoma', 'Disease', 'MESH:D010871', (16, 29))	('intracranial retinoblastoma', 'Disease', (38, 65))	('Chr', 'Gene', '1125', (79, 82))	('gain', 'PosReg', (87, 91))	('pineoblastoma', 'Phenotype', 'HP:0030408', (16, 29))	('intracranial retinoblastoma', 'Disease', 'MESH:D012175', (38, 65))	('pineoblastoma', 'Disease', (16, 29))	('retinoblastoma', 'Phenotype', 'HP:0009919', (51, 65))	('loss', 'Var', (102, 106))	('gain', 'PosReg', (71, 75))	('Chr', 'Gene', (79, 82))
6260	29967940	"Papillary tumor of the pineal region group A" exhibits a high number of CNV with gains of 4, 5, 11, and 12 and loss of Chr.10 being most frequent (Fig.	('Papillary tumor', 'Disease', 'MESH:D002291', (1, 16))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('gains', 'PosReg', (82, 87))	('Papillary tumor', 'Disease', (1, 16))	('loss', 'Var', (112, 116))	('Chr', 'Gene', '1125', (120, 123))	('Chr', 'Gene', (120, 123))
6272	29967940	Tumors in both methylation classes frequently show an isochromosome 17q, approximately 60% in group 3 and 80% in group 4.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('isochromosome 17q', 'Var', (54, 71))
6273	29967940	Group 3 medulloblastoma tend to have a higher number of alterations, most frequently gain of 1q and, 7 and loss of 10q (Fig.	('gain', 'PosReg', (85, 89))	('medulloblastoma', 'Disease', (8, 23))	('loss of 10q', 'Var', (107, 118))	('medulloblastoma', 'Phenotype', 'HP:0002885', (8, 23))	('medulloblastoma', 'Disease', 'MESH:D008527', (8, 23))
6274	29967940	Besides isochromosome 17q, most abundant in group 4 medulloblastomas is gain of 7p and loss of 8 (Fig.	('loss', 'Var', (87, 91))	('medulloblastomas', 'Disease', 'MESH:D008527', (52, 68))	('gain', 'PosReg', (72, 76))	('medulloblastomas', 'Disease', (52, 68))	('medulloblastoma', 'Phenotype', 'HP:0002885', (52, 67))
6276	29967940	Embryonal tumor with multilayered rosettes, C19MC-altered is another genetically defined WHO entity.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('MC', 'Chemical', 'MESH:D008748', (47, 49))	('Embryonal tumor', 'Disease', (0, 15))	('rosette', 'Phenotype', 'HP:0031925', (34, 41))	('Embryonal tumor', 'Disease', 'MESH:D009373', (0, 15))	('Embryonal tumor', 'Phenotype', 'HP:0002898', (0, 15))	('C19MC-altered', 'Var', (44, 57))	('rosettes', 'Phenotype', 'HP:0031925', (34, 42))
6279	29967940	The very few cases that we have so far observed of the exceedingly rare non-19q13 amplified embryonal tumors with multilayered rosettes also fall into this group.	('embryonal tumors', 'Disease', 'MESH:D009373', (92, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('rosettes', 'Phenotype', 'HP:0031925', (127, 135))	('embryonal tumor', 'Phenotype', 'HP:0002898', (92, 107))	('non-19q13 amplified', 'Var', (72, 91))	('fall', 'Phenotype', 'HP:0002527', (141, 145))	('embryonal tumors', 'Phenotype', 'HP:0002898', (92, 108))	('embryonal tumors', 'Disease', (92, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('rosette', 'Phenotype', 'HP:0031925', (127, 134))
6286	29967940	Besides "CNS neuroblastoma with FOXR2 activation" the three classes of "CNS high-grade neuroepithelial tumor with BCOR alteration", "CNS Ewing sarcoma family tumor with CIC alteration", and the previously mentioned "CNS high-grade neuroepithelial tumor with MN1 alteration" may frequently present with primitive embryonal histology.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (87, 108))	('MN1', 'Gene', (258, 261))	('BCOR', 'Gene', '54880', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('BCOR', 'Gene', (114, 118))	('FOXR2', 'Gene', (32, 37))	('MN1', 'Gene', '4330', (258, 261))	('FOXR2', 'Gene', '139628', (32, 37))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (231, 252))	('neuroblastoma', 'Disease', (13, 26))	('neuroepithelial tumor', 'Disease', (231, 252))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (87, 108))	('Ewing sarcoma family tumor', 'Disease', 'MESH:C563168', (137, 163))	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('alteration', 'Var', (119, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (231, 252))	('neuroepithelial tumor', 'Disease', (87, 108))	('neuroblastoma', 'Disease', 'MESH:D009447', (13, 26))	('Ewing sarcoma family tumor', 'Disease', (137, 163))
6287	29967940	CNV profiles of "CNS Ewing sarcoma family tumor with CIC alteration" and "CNS high-grade neuroepithelial tumor with BCOR alteration" exhibit no characteristic features, whereas "CNS high-grade neuroepithelial tumor with MN1 alteration" very frequently shows extensive alterations on Chr.X reminiscent of chromothripsis (Chr.X not shown in the summary CNV plots).	('MN1', 'Gene', '4330', (220, 223))	('Chr', 'Gene', '1125', (283, 286))	('Ewing sarcoma family tumor', 'Disease', 'MESH:C563168', (21, 47))	('alterations', 'Reg', (268, 279))	('Chr', 'Gene', '1125', (320, 323))	('Ewing sarcoma family tumor', 'Disease', (21, 47))	('alteration', 'Var', (57, 67))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (193, 214))	('Chr', 'Gene', (283, 286))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (89, 110))	('BCOR', 'Gene', '54880', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('Chr', 'Gene', (320, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('MN1', 'Gene', (220, 223))	('neuroepithelial tumor', 'Disease', (193, 214))	('neuroepithelial tumor', 'Disease', (89, 110))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (193, 214))	('BCOR', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (89, 110))
6295	29967940	A constellation that may lower the score of an SHH medulloblastoma below the threshold of 0.9 is the rare case of an IDH1 R132 mutant SHH medulloblastomas (score expected in the range of ~ 0.4 to 0.7), so testing for IDH point mutation may be of help in some instances.	('SHH medulloblastoma', 'Disease', 'MESH:D008527', (47, 66))	('SHH medulloblastomas', 'Disease', 'MESH:D008527', (134, 154))	('IDH1', 'Gene', '3417', (117, 121))	('IDH', 'Gene', (217, 220))	('IDH', 'Gene', (117, 120))	('lower', 'NegReg', (25, 30))	('R132 mutant', 'Var', (122, 133))	('score', 'MPA', (35, 40))	('SHH medulloblastoma', 'Disease', (47, 66))	('IDH', 'Gene', '3417', (217, 220))	('IDH', 'Gene', '3417', (117, 120))	('medulloblastoma', 'Phenotype', 'HP:0002885', (51, 66))	('medulloblastoma', 'Phenotype', 'HP:0002885', (138, 153))	('SHH medulloblastoma', 'Disease', 'MESH:D008527', (134, 153))	('SHH medulloblastomas', 'Disease', (134, 154))	('IDH1', 'Gene', (117, 121))
6311	29967940	Such tumors may likely represent not yet defined tumor entities, as proposed for one rare tumor class with recurrent amplification of Chr.6q24.2.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', (5, 11))	('Chr', 'Gene', '1125', (134, 137))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (117, 130))	('Chr', 'Gene', (134, 137))
6315	29967940	The most frequent CNV in "schwannoma" is loss of 22q seen in approximately 60% of tumors (Fig.	('schwannoma', 'Disease', 'MESH:D009442', (26, 36))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('loss of 22q', 'Var', (41, 52))	('schwannoma', 'Phenotype', 'HP:0100008', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('schwannoma', 'Disease', (26, 36))
6323	29967940	These epigenetic sub-groups, their mutational characteristics, CNV, and the association with histology and outcome have been previously reported: Cases of MC ben-1 have typically no aberrations besides 22q deletion and NF2 mutation.	('MC ben-1', 'Gene', (155, 163))	('NF2', 'Gene', (219, 222))	('22q deletion', 'Var', (202, 214))	('MC', 'Chemical', 'MESH:D008748', (155, 157))	('NF2', 'Gene', '4771', (219, 222))
6324	29967940	MC ben-2 is characterized by flat CNPs and an enrichment for KLF4/TRAF7, AKT1/TRAF7, and SMO mutations.	('KLF4', 'Gene', '9314', (61, 65))	('mutations', 'Var', (93, 102))	('KLF4', 'Gene', (61, 65))	('AKT1', 'Gene', '207', (73, 77))	('MC', 'Chemical', 'MESH:D008748', (0, 2))	('TRAF7', 'Gene', (78, 83))	('TRAF7', 'Gene', '84231', (66, 71))	('AKT1', 'Gene', (73, 77))	('SMO', 'Gene', '6608', (89, 92))	('SMO', 'Gene', (89, 92))	('TRAF7', 'Gene', '84231', (78, 83))	('TRAF7', 'Gene', (66, 71))
6326	29967940	If needed, detection of the exact AKT1 or SMO mutation holds potential for targeted therapy in case of a biologically low grade but not resectable meningioma.	('AKT1', 'Gene', '207', (34, 38))	('SMO', 'Gene', '6608', (42, 45))	('SMO', 'Gene', (42, 45))	('AKT1', 'Gene', (34, 38))	('meningioma', 'Disease', (147, 157))	('meningioma', 'Phenotype', 'HP:0002858', (147, 157))	('mutation', 'Var', (46, 54))	('meningioma', 'Disease', 'MESH:D008577', (147, 157))
6327	29967940	MC ben-3 is the only sub-group harboring many gains of chromosomes, with or without 22q loss and NF2 mutation.	('gains', 'PosReg', (46, 51))	('22q', 'Gene', (84, 87))	('MC', 'Chemical', 'MESH:D008748', (0, 2))	('NF2', 'Gene', '4771', (97, 100))	('NF2', 'Gene', (97, 100))	('mutation', 'Var', (101, 109))
6329	29967940	The intermediate and malignant MCs mostly have 22q deletion and NF2 mutations, with the number of losses of whole chromosomes (10, 14) or chromosomal arms (1p) increasing with malignancy.	('malignancy', 'Disease', 'MESH:D009369', (176, 186))	('22q deletion', 'Var', (47, 59))	('NF2', 'Gene', '4771', (64, 67))	('MC', 'Chemical', 'MESH:D008748', (31, 33))	('malignancy', 'Disease', (176, 186))	('mutations', 'Var', (68, 77))	('NF2', 'Gene', (64, 67))
6330	29967940	These groups, particularly MC mal, can also carry TERT promoter mutations and show CDKN2A deletion.	('deletion', 'Var', (90, 98))	('CDKN2A', 'Gene', '1029', (83, 89))	('TERT', 'Gene', '7015', (50, 54))	('MC', 'Chemical', 'MESH:D008748', (27, 29))	('TERT', 'Gene', (50, 54))	('CDKN2A', 'Gene', (83, 89))
6331	29967940	For example, cases with BAP1 mutations can have no or only focal chromosomal alterations but still be identified as MC mal, in line with their aggressive behavior.	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('aggressive behavior', 'Phenotype', 'HP:0000718', (143, 162))	('MC', 'Chemical', 'MESH:D008748', (116, 118))	('BAP1', 'Gene', '8314', (24, 28))
6350	29967940	The corresponding CNV profiles are inconspicuous (Supplementary file 1), but these tumors are characterized by either CTNNB1 or BRAF V600E mutations, respectively.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BRAF', 'Gene', '673', (128, 132))	('CTNNB1', 'Gene', '1499', (118, 124))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('V600E', 'Var', (133, 138))	('CTNNB1', 'Gene', (118, 124))	('BRAF', 'Gene', (128, 132))
6356	29967940	Interestingly, in a recent series of 66 institutionally diagnosed olfactory neuroblastomas/esthesioneuroblastomas, only 42 (64%) of cases were classified as DNA methylation esthesioneuroblastoma, subclass A or B.	('neuroblastoma', 'Phenotype', 'HP:0003006', (181, 194))	('neuroblastoma', 'Disease', (76, 89))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('olfactory neuroblastomas/esthesioneuroblastomas', 'Disease', 'MESH:D018304', (66, 113))	('olfactory neuroblastomas/esthesioneuroblastomas', 'Disease', (66, 113))	('neuroblastoma', 'Disease', 'MESH:D009447', (99, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (181, 194))	('neuroblastoma', 'Disease', (99, 112))	('DNA methylation', 'Var', (157, 172))	('neuroblastoma', 'Disease', (181, 194))	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
6407	29967940	However, we fully agree that an adamantinous craniopharyngioma with a CTNBB1 mutation is not in need of additional DNA methylation analysis.	('CTNBB1', 'Gene', (70, 76))	('craniopharyngioma', 'Phenotype', 'HP:0030062', (45, 62))	('adamantinous craniopharyngioma', 'Disease', 'MESH:D003397', (32, 62))	('mutation', 'Var', (77, 85))	('adamantinous craniopharyngioma', 'Disease', (32, 62))
6411	29967940	The latter group frequently turns out to be oligodendroglioma with evident 1p/19q codeletion.	('1p/19q codeletion', 'Var', (75, 92))	('oligodendroglioma', 'Disease', 'MESH:D009837', (44, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('oligodendroglioma', 'Disease', (44, 61))
6416	29967940	Amplifications such as EGFR or MDM2 and homozygous deletions of CDKN2A are even more robust when present in the tumor.	('CDKN2A', 'Gene', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('EGFR', 'Gene', '1956', (23, 27))	('CDKN2A', 'Gene', '1029', (64, 70))	('deletions', 'Var', (51, 60))	('tumor', 'Disease', (112, 117))	('MDM2', 'Gene', '4193', (31, 35))	('EGFR', 'Gene', (23, 27))	('MDM2', 'Gene', (31, 35))
6417	29967940	Importantly, we find such tumors to carry multiple chromosomal losses or gains.	('gains', 'PosReg', (73, 78))	('tumors', 'Disease', (26, 32))	('chromosomal losses', 'Var', (51, 69))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
6423	28710497	The performance of DLR for predicting the mutation status of isocitrate dehydrogenase 1 (IDH1) was validated in a dataset of 151 patients with low-grade glioma.	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('isocitrate dehydrogenase 1', 'Gene', '3417', (61, 87))	('glioma', 'Disease', (153, 159))	('patients', 'Species', '9606', (129, 137))	('isocitrate dehydrogenase 1', 'Gene', (61, 87))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', (89, 93))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('IDH1', 'Gene', '3417', (89, 93))
6447	28710497	IDH1 mutation status accounts for more than 50% of the predictive value in low-grade glioma.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('glioma', 'Disease', (85, 91))	('mutation status', 'Var', (5, 20))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('IDH1', 'Gene', '3417', (0, 4))
6449	28710497	Therefore, accurate prediction of IDH1 mutation status via noninvasive methods has been widely explored.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', (34, 38))	('mutation', 'Var', (39, 47))
6450	28710497	Here, we used DLR to determine IDH1 mutation status in a low-grade glioma cohort composed of 151 patients.	('IDH1', 'Gene', '3417', (31, 35))	('glioma', 'Disease', (67, 73))	('low-grade', 'Disease', (57, 66))	('patients', 'Species', '9606', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('mutation', 'Var', (36, 44))	('IDH1', 'Gene', (31, 35))
6451	28710497	We demonstrate that DLR is a useful and accurate tool for predicting IDH1 mutation status in low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('mutation', 'Var', (74, 82))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('IDH1', 'Gene', '3417', (69, 73))	('gliomas', 'Disease', (103, 110))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('IDH1', 'Gene', (69, 73))
6462	28710497	Two typical IDH1 mutation and wild-type cases were used as examples.	('IDH1', 'Gene', '3417', (12, 16))	('mutation', 'Var', (17, 25))	('IDH1', 'Gene', (12, 16))
6468	28710497	The feature maps of IDH1 mutant gliomas showed a more uniform distribution.	('IDH1', 'Gene', '3417', (20, 24))	('mutant', 'Var', (25, 31))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('IDH1', 'Gene', (20, 24))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
6489	28710497	Despite the diagnostic significance of glioma according to the new version the WHO criterion, the IDH1 mutation status was used to tailor personalized treatment regimens, including surgical extent and chemo-sensitivity.	('glioma', 'Disease', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('IDH1', 'Gene', (98, 102))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('mutation', 'Var', (103, 111))	('IDH1', 'Gene', '3417', (98, 102))
6490	28710497	Patients with IDH1 mutations tend to have a positive prognosis.	('IDH1', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (19, 28))	('IDH1', 'Gene', '3417', (14, 18))
6493	28710497	Several noninvasive methods to predict IDH1 mutation status have been explored and reported during the last few years.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
6495	28710497	reported that tumor necrosis area and tumor blood flow are useful for predicting IDH1 mutation status.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (14, 19))	('tumor necrosis', 'Disease', 'MESH:D009336', (14, 28))	('tumor necrosis', 'Disease', (14, 28))	('IDH1', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutation', 'Var', (86, 94))	('IDH1', 'Gene', '3417', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
6500	28710497	Our group also examined the possibility of predicting IDH1 mutation status using a radiomics method.	('mutation', 'Var', (59, 67))	('IDH1', 'Gene', '3417', (54, 58))	('IDH1', 'Gene', (54, 58))
6504	28710497	Therefore, DLR outperforms other methods for IDH1 mutation prediction.	('IDH1', 'Gene', '3417', (45, 49))	('IDH1', 'Gene', (45, 49))	('mutation', 'Var', (50, 58))
6505	28710497	Alternatively, the second method involves detecting metabolic changes caused by IDH1 mutation using MRS technology.	('IDH1', 'Gene', (80, 84))	('MRS', 'Disease', 'MESH:D008556', (100, 103))	('IDH1', 'Gene', '3417', (80, 84))	('metabolic changes', 'MPA', (52, 69))	('mutation', 'Var', (85, 93))	('MRS', 'Disease', (100, 103))
6506	28710497	When a tumor harbors an IDH1 mutation, it produces 2-hydroxyglutarate (2-HG), which is reflected in the MRS results.	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (24, 28))	('tumor', 'Disease', (7, 12))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (51, 69))	('MRS', 'Disease', 'MESH:D008556', (104, 107))	('2-hydroxyglutarate', 'MPA', (51, 69))	('IDH1', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('MRS', 'Disease', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
6510	28710497	predicted the presence of IDH1 mutations based on 2-HG concentrations in the plasma and urine of 84 patients.	('IDH1', 'Gene', '3417', (26, 30))	('patients', 'Species', '9606', (100, 108))	('mutations', 'Var', (31, 40))	('IDH1', 'Gene', (26, 30))
6514	28710497	In medical imaging applications, our method is able to noninvasively predict IDH1 mutation status with high accuracy by using routinely collected MR image modalities.	('mutation', 'Var', (82, 90))	('IDH1', 'Gene', (77, 81))	('IDH1', 'Gene', '3417', (77, 81))	('predict', 'Reg', (69, 76))
6515	28710497	Noninvasive prediction of other important glioma biomarkers, such as 1p19q and TERT, will be considered for future work.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('1p19q', 'Var', (69, 74))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('glioma', 'Disease', (42, 48))
6549	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.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('PDGFR', 'Gene', '5159', (106, 111))	('alterations', 'Var', (49, 60))	('ATRX', 'Gene', (82, 86))	('IDH1', 'Gene', '15926', (70, 74))	('H3F3A', 'Gene', '3020', (94, 99))	('tumor', 'Disease', (139, 144))	('PTEN', 'Gene', (113, 117))	('rat', 'Species', '10116', (53, 56))	('EGFR', 'Gene', '1956', (88, 92))	('PDGFR', 'Gene', (106, 111))	('PTEN', 'Gene', '5728', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('TP53', 'Gene', (64, 68))	('H3F3A', 'Gene', (94, 99))	('EGFR', 'Gene', (88, 92))	('IDH1', 'Gene', (70, 74))	('PI3K', 'Gene', (76, 80))
6550	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))
6551	31959027	Almost 50% of adult glioma patients harbor mutations in IDH1, usually at arginine 132 (R132H).	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('R132H', 'Mutation', 'rs1034749666', (87, 92))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('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))
6553	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))
6555	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))
6556	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))
6557	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))	('associated', 'Reg', (95, 105))	('TERTp', 'Gene', (66, 71))	('TERT', 'Gene', (51, 55))	('oligodendroglioma', 'Disease', (111, 128))	('TERTp', 'Gene', '7015', (66, 71))	('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))	('IDH1', 'Gene', (7, 11))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
6559	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))
6560	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))
6568	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))
6569	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))
6572	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))
6587	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))
6595	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))
6621	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))	('increase', 'PosReg', (50, 58))	('modifications', 'Var', (16, 29))	('persistence', 'CPA', (81, 92))	('CAR', 'Gene', '19674', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
6648	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))
6665	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))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('R132H', 'Mutation', 'rs1034749666', (37, 42))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('IDH1', 'Gene', '15926', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
6669	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))	('metabolic', 'CPA', (51, 60))	('IDH1 glioma', 'Disease', (25, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
6673	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))
6674	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))	('delaying', 'NegReg', (130, 138))	('IDH1', 'Gene', (33, 37))	('blocks', 'NegReg', (38, 44))	('mutant', 'Var', (149, 155))	('growth', 'CPA', (139, 145))	('IDH1', 'Gene', '15926', (156, 160))	('decreases', 'NegReg', (100, 109))	('2-HG', 'Chemical', '-', (84, 88))	('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))
6675	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))
6677	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))	('IDH1', 'Gene', (21, 25))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('Disruption', 'Var', (0, 10))
6678	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))
6681	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))
6685	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))
6688	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))
6689	31959027	Deletion or amplification of mutant IDH1 locus led to reduced 2HG and transformation to more aggressive grade IV glioblastoma.	('glioblastoma', 'Disease', (113, 125))	('2HG', 'CPA', (62, 65))	('IDH1', 'Gene', (36, 40))	('transformation', 'Reg', (70, 84))	('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))
6690	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))	('tumor', 'Disease', (62, 67))	('IDH1', 'Gene', (137, 141))	('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))
6691	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))
6693	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))
6694	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))
6701	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))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rat', 'Species', '10116', (43, 46))	('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))
6715	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))	('mice', 'Species', '10090', (149, 153))	('GMX-1778', 'Chemical', 'MESH:C401312', (41, 49))	('IDH1', 'Gene', '15926', (106, 110))	('intracerebral', 'Disease', (85, 98))	('suppression', 'NegReg', (66, 77))
6735	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))
6753	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))
6777	31410219	The expression of EGFR in serum EVs can accurately differentiate high-grade and low-grade glioma patients, and EGFR in EVs positively correlates with ki-67 LI in the tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('EGFR', 'Var', (111, 115))	('glioma', 'Disease', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('tumor', 'Disease', (166, 171))	('EGFR', 'Gene', (18, 22))	('rat', 'Species', '10116', (44, 47))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('high-grade', 'Disease', (65, 75))	('patients', 'Species', '9606', (97, 105))
6789	31410219	For instance, changes (e.g., mutation and methylation) in the serum DNAs (ctDNAs), such as MGMT, EGFR, and PTEN, have been proven to be effective biomarkers of glioma and may have the potential for the diagnosis of glioma.	('mutation', 'Var', (29, 37))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('PTEN', 'Gene', (107, 111))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('PTEN', 'Gene', '5728', (107, 111))	('MGMT', 'Gene', (91, 95))	('glioma', 'Disease', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('glioma', 'Disease', (215, 221))	('changes', 'Reg', (14, 21))	('methylation', 'Var', (42, 53))	('MGMT', 'Gene', '4255', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
6813	31410219	Some evidence also showed that the expression of EGFR has some relationship with glioma patient prognosis, although this conclusion has been contradicted by other studies, and the prognostic value of EGFR for glioma has not been demonstrated to date.	('patient', 'Species', '9606', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('rat', 'Species', '10116', (236, 239))	('EGFR', 'Gene', (49, 53))	('glioma', 'Disease', (81, 87))	('glioma', 'Disease', (209, 215))	('relationship', 'Reg', (63, 75))	('expression', 'Var', (35, 45))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
6848	31410219	Then, 100 muL of secondary antibody (anti-rat, ab150157, Abcam, dilution 1/1000 or anti-goat, ab150127, Abcam, dilution 1/1000) was added and incubated for 30 min with steady rotation (rotating speed 220 rpm/min) at room temperature.	('goat', 'Species', '9925', (88, 92))	('ab150127', 'Var', (94, 102))	('ab150157', 'Var', (47, 55))	('steady rotation', 'Disease', 'MESH:D009069', (168, 183))	('rat', 'Species', '10116', (226, 229))	('steady rotation', 'Disease', (168, 183))	('rat', 'Species', '10116', (42, 45))
6859	31410219	Anti-CD81, CST, sc166029, 1/500.	('CD81', 'Gene', (5, 9))	('CD81', 'Gene', '975', (5, 9))	('sc166029', 'Var', (16, 24))
6864	31410219	Forward primer sequence for NLGN3 mRNAs: F- 5'-GGGAGTCCCCTTTCTGAAGC-3', reverse primer for all NLGN3 mRNAs: R-5'-CCTTCATGGCCACACTGACT-3'.	('NLGN3', 'Gene', (95, 100))	('NLGN3', 'Gene', '54413', (95, 100))	('NLGN3', 'Gene', (28, 33))	('NLGN3', 'Gene', '54413', (28, 33))	("R-5'-CCTTCATGGCCACACTGACT-3", 'Var', (108, 135))
6865	31410219	Forward primer sequence for GAPDH mRNAs: F-5'- GAGAAGGCTGGGGCTCATTT-3', reverse primer for all GADPH mRNAs: R-5'-AGTGATGGCATGGACTGTGG-3'.	('GAPDH', 'Gene', '2597', (28, 33))	("R-5'-AGTGATGGCATGGACTGTGG-3", 'Var', (108, 135))	('GAPDH', 'Gene', (28, 33))
6873	31410219	Different quantities of EVs were bound on the beads, and captured EVs were labeled with FMTM4-64FX, a dye to label EV membranes.	('bound', 'Interaction', (33, 38))	('FMTM4-64FX', 'Chemical', '-', (88, 98))	('FMTM4-64FX', 'Var', (88, 98))
6878	31410219	As expected, the expression of EGFR was significantly higher in the glioma cell lines U87MG (unpaired Student's t-test, ***P < 0.0001) and U251 (unpaired Student's t-test, ***P < 0.0001) than in the normal HA cell line (Figure 2A, 2B), which was in line with the previous studies showing that EGFR was highly expressed in glioma cells.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('higher', 'PosReg', (54, 60))	('U251', 'Var', (139, 143))	('expression', 'MPA', (17, 27))	('EGFR', 'Gene', (31, 35))	('glioma', 'Disease', (322, 328))	('glioma', 'Disease', (68, 74))	('U87MG', 'CellLine', 'CVCL:0022', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (322, 328))	('glioma', 'Phenotype', 'HP:0009733', (322, 328))	('U87MG', 'Var', (86, 91))
6879	31410219	Similarly, the expression of EGFR in the cell-derived EVs was significantly higher in the glioma cells U87MG (unpaired Student's t-test, **P < 0.01) and U251 (unpaired Student's t-test, **P < 0.01) than in the normal HA cells (Figure 2C, 2D), in the same tendency as the expression of EGFR in the parental cell lines, indicating that the expression of EGFR in the EVs was associated with the expression in the parental cells.	('U87MG', 'Var', (103, 108))	('glioma', 'Disease', (90, 96))	('U251', 'Var', (153, 157))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('expression', 'MPA', (338, 348))	('EGFR', 'Gene', (29, 33))	('expression', 'MPA', (15, 25))	('higher', 'PosReg', (76, 82))	('U87MG', 'CellLine', 'CVCL:0022', (103, 108))
6880	31410219	These differences were further verified by Western blot analyses showing a significant band of EGFR in EVs extracted from U87MG and U251 and a negligible band in HA cells (Figure 2E).	('U87MG', 'Var', (122, 127))	('U251', 'Var', (132, 136))	('U87MG', 'CellLine', 'CVCL:0022', (122, 127))	('EGFR', 'Gene', (95, 99))
6904	31410219	Ki-67 LI, the percentage of ki-67-positive cells examined normally by immunohistochemical (IHC) staining, has been shown to be associated with the high malignancy and poor outcome of tumors.	('Ki-67', 'Var', (0, 5))	('associated', 'Reg', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('malignancy', 'Disease', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumors', 'Disease', (183, 189))
6906	31410219	Moreover, a high value of ki-67 LI has also been reported to be correlated with EGFR mutations in NSCL patients and to be a prognostic indicator for NSCLC.	('NSCL', 'Disease', 'None', (149, 153))	('NSCL', 'Disease', (149, 153))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Disease', (149, 154))	('NSCL', 'Disease', 'None', (98, 102))	('EGFR', 'Gene', (80, 84))	('NSCL', 'Disease', (98, 102))	('mutations', 'Var', (85, 94))	('correlated', 'Reg', (64, 74))	('patients', 'Species', '9606', (103, 111))
6967	31306418	They are slowly growing, infiltrative tumors with isocitrate dehydrogenase 1 or 2 mutations and codeletion of chromosomal arms 1p and 19q.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (82, 91))
7017	31306418	Uniform distributions were taken for the parameters in the most representative region of the parameter space obtained from Table 1: rho   [0.5 x 10-3, 2.5 x 10-3] day- 1, alpha1   [0.01, 1.0] cm3/mug day, alpha2   [0.1, 0.75] cm3/mug day, P(0)   [20, 200], K   [300, 550] cm3.	('alpha1', 'Gene', '146', (171, 177))	('alpha1', 'Gene', (171, 177))	('alpha2   [0.1', 'Var', (205, 218))
7088	31306418	The induction of persisters in glioma cells has been known to be partially reverted by 'drug wash-out' suggesting the contribution of epigenetic mechanisms in drug resistance and supporting the possibility of TMZ rechallenge in glioma patients after prior drug exposure, provided there is a sufficiently long waiting time between treatments.	('glioma', 'Disease', (228, 234))	('patients', 'Species', '9606', (235, 243))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (159, 174))	('TMZ', 'Chemical', 'MESH:D000077204', (209, 212))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('epigenetic', 'Var', (134, 144))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('glioma', 'Disease', (31, 37))
7164	27229157	Pilocytic astrocytomas were found to have a distinctive signature at 315 CpG sites, of which 312 were hypomethylated and 3 were hypermethylated.	('Pilocytic astrocytomas', 'Disease', (0, 22))	('hypomethylated', 'Var', (102, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))
7171	27229157	Pilocytic astrocytomas typically contain a BRAF fusion but occasionally a BRAFV600E mutation, RAF1 fusion, intragenic duplication of FGFR1, or other rarer alterations are present.	('RAF1', 'Gene', (94, 98))	('fusion', 'Var', (99, 105))	('Pilocytic astrocytomas', 'Disease', (0, 22))	('RAF1', 'Gene', '5894', (94, 98))	('FGFR1', 'Gene', (133, 138))	('FGFR1', 'Gene', '2260', (133, 138))	('BRAF', 'Gene', '673', (43, 47))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('BRAF', 'Gene', (43, 47))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (74, 83))	('contain', 'Reg', (33, 40))	('mutation', 'Var', (84, 92))
7173	27229157	Various genetic alterations have been identified in diffuse astrocytomas, including BRAFV600E mutations, intragenic duplication of FGFR1, structural alterations of the MYB oncogene and gene fusions involving FGFR1, FGFR3, MYB and MYBL1.	('structural alterations', 'Var', (138, 160))	('FGFR3', 'Gene', (215, 220))	('MYB', 'Gene', '4602', (168, 171))	('FGFR3', 'Gene', '2261', (215, 220))	('MYB', 'Gene', (168, 171))	('FGFR1', 'Gene', '2260', (131, 136))	('MYBL1', 'Gene', (230, 235))	('BRAFV600E', 'Mutation', 'rs113488022', (84, 93))	('MYBL1', 'Gene', '4603', (230, 235))	('MYB', 'Gene', '4602', (230, 233))	('MYB', 'Gene', (230, 233))	('astrocytomas', 'Disease', (60, 72))	('FGFR1', 'Gene', '2260', (208, 213))	('mutations', 'Var', (94, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('MYB', 'Gene', '4602', (222, 225))	('MYB', 'Gene', (222, 225))	('FGFR1', 'Gene', (131, 136))	('BRAFV600E', 'Gene', (84, 93))	('gene fusions', 'Var', (185, 197))	('astrocytomas', 'Disease', 'MESH:D001254', (60, 72))	('FGFR1', 'Gene', (208, 213))
7174	27229157	Virtually all the key genetic alterations in pilocytic and diffuse astrocytomas give rise to constitutive activation of the ERK/MAPK pathway, but these tumour types exhibit significant biological and clinical heterogeneity.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('ERK', 'Gene', (124, 127))	('tumour', 'Disease', (152, 158))	('astrocytomas give rise', 'Disease', 'MESH:D001254', (67, 89))	('pilocytic', 'Disease', (45, 54))	('clinical', 'Species', '191496', (200, 208))	('genetic alterations', 'Var', (22, 41))	('alterations', 'Var', (30, 41))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))	('activation', 'PosReg', (106, 116))	('ERK', 'Gene', '2048', (124, 127))	('astrocytomas give rise', 'Disease', (67, 89))
7193	27229157	The linear model with the factor of interest (tumour type - pilocytic, diffuse, control) was computed, with other varying factors: bead chip number (1-5), BRAF status (fusion, V600E mutation, WT), sample location (infratentorial/supratentorial), age group (foetal/HNSC, <3 years, > = 3 years, >16 years) and gender included.	('BRAF', 'Gene', (155, 159))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('fusion', 'Var', (168, 174))	('V600E mutation', 'Var', (176, 190))	('V600E', 'Mutation', 'rs113488022', (176, 181))	('BRAF', 'Gene', '673', (155, 159))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
7214	27229157	Unlike other cancers where changes are mainly identified in the shores, the majority of the differentially methylated CpGs were found to be located in open sea regions.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('CpGs', 'Gene', (118, 122))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('differentially methylated', 'Var', (92, 117))	('cancers', 'Disease', (13, 20))
7217	27229157	The majority of these sites are hypomethylated in pilocytic astrocytomas and the distinctive signature was not present in normal brain controls (Fig.	('pilocytic astrocytomas', 'Disease', (50, 72))	('hypomethylated', 'Var', (32, 46))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (50, 72))
7226	27229157	The hypomethylation signature was not present in other low-grade astrocytomas (adult gliomas -TCGA), paediatric and adult glioblastomas (GSE36278), medulloblastomas or ependymomas (GSE45353; Additional file 3: Figures S9 and S10; Additional file 9: Table S8).	('medulloblastomas or ependymomas', 'Disease', (148, 179))	('glioblastomas', 'Phenotype', 'HP:0012174', (122, 135))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('GSE45353', 'Var', (181, 189))	('gliomas', 'Disease', (85, 92))	('adult glioblastomas', 'Disease', 'MESH:D005909', (116, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('S10', 'Gene', '9861', (225, 228))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('GSE36278', 'Var', (137, 145))	('adult glioblastomas', 'Disease', (116, 135))	('S10', 'Gene', (225, 228))	('astrocytomas', 'Disease', (65, 77))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('medulloblastomas or ependymomas', 'Disease', 'MESH:D008527', (148, 179))	('medulloblastoma', 'Phenotype', 'HP:0002885', (148, 163))
7238	27229157	Interestingly, the SNP rs9344 (G870A), which is located within a CpG site at the splice site at exon 4 - intron 4, is abolished in the presence of the A-allele and has been reported to be associated with expression of CCND1b (Fig.	('associated', 'Reg', (188, 198))	('CCND1', 'Gene', (218, 223))	('G870A', 'Mutation', 'rs9344', (31, 36))	('rs9344', 'Mutation', 'rs9344', (23, 29))	('rs9344 (G870A', 'Var', (23, 36))	('abolished', 'NegReg', (118, 127))	('expression', 'MPA', (204, 214))	('CCND1', 'Gene', '595', (218, 223))
7240	27229157	Differential methylation was identified at the adjacent CpG site to the SNP showing hypomethylation in pilocytic astrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (103, 125))	('pilocytic astrocytomas', 'Disease', (103, 125))	('hypomethylation', 'Var', (84, 99))
7253	27229157	Of the genes that have differential methylation, expression of the down-regulated genes in the pilocytic astrocytomas are involved in neuronal differentiation and brain function, with the up-regulated genes involved in the inflammatory response, apoptosis, metabolic processes and MAPK pathway (Additional file 19: Table S18).	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (95, 117))	('S18', 'Gene', (321, 324))	('pilocytic astrocytomas', 'Disease', (95, 117))	('S18', 'Gene', '6222', (321, 324))	('neuronal differentiation', 'CPA', (134, 158))	('up-regulated', 'PosReg', (188, 200))	('brain function', 'CPA', (163, 177))	('down-regulated', 'NegReg', (67, 81))	('methylation', 'Var', (36, 47))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
7255	27229157	All 72 CpG sites were also hypomethylated in the infratentorial pilocytic astrocytomas compared to the diffuse astrocytomas.	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (64, 86))	('astrocytomas', 'Disease', (74, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))	('astrocytomas', 'Disease', (111, 123))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('pilocytic astrocytomas', 'Disease', (64, 86))	('astrocytomas', 'Disease', 'MESH:D001254', (74, 86))	('hypomethylated', 'Var', (27, 41))
7267	27229157	High expression of the oncogenic variant CCND1b may therefore be critical for tumorigenesis in diffuse astrocytomas, and suggests that defective splicing mechanisms may be present in these tumours, as shown for other malignancies.	('astrocytomas', 'Disease', (103, 115))	('tumours', 'Disease', (189, 196))	('tumorigenesis', 'CPA', (78, 91))	('CCND1', 'Gene', '595', (41, 46))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('astrocytomas', 'Disease', 'MESH:D001254', (103, 115))	('variant', 'Var', (33, 40))	('tumours', 'Disease', 'MESH:D009369', (189, 196))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('malignancies', 'Disease', (217, 229))	('CCND1', 'Gene', (41, 46))
7275	27229157	Distinct outputs of the MAPK pathway have been identified in melanoma and other malignancies with BRAFV600E and receptor tyrosine kinase mutations.	('MAPK pathway', 'Pathway', (24, 36))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('BRAFV600E', 'Var', (98, 107))	('receptor tyrosine kinase', 'MPA', (112, 136))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('BRAFV600E', 'Mutation', 'rs113488022', (98, 107))	('malignancies', 'Disease', (80, 92))
7276	27229157	Additionally, genetic alterations in mouse models of brain tumours often interfere with normal differentiation processes and give rise to tumours in a manner that is dependent on the tumour cell of origin, as reviewed recently.	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('brain tumours', 'Disease', (53, 66))	('rise to tumours', 'Disease', (130, 145))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('mouse', 'Species', '10090', (37, 42))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (59, 65))	('tumour', 'Disease', (138, 144))	('brain tumours', 'Disease', 'MESH:D001932', (53, 66))	('brain tumours', 'Phenotype', 'HP:0030692', (53, 66))	('interfere', 'NegReg', (73, 82))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('genetic alterations', 'Var', (14, 33))	('tumour', 'Disease', (183, 189))	('normal differentiation processes', 'CPA', (88, 120))	('rise to tumours', 'Disease', 'MESH:D009369', (130, 145))
7283	27229157	Our findings highlight epigenetic differences between pilocytic and diffuse astrocytoma, in addition to the well-documented genomic alterations.	('astrocytoma', 'Disease', 'MESH:D001254', (76, 87))	('epigenetic differences', 'Var', (23, 45))	('astrocytoma', 'Disease', (76, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('pilocytic', 'Disease', (54, 63))
7307	32635409	In BraTS2015, there are four MRI sequences available for every patient: FLAIR, T1-weighted (T1), T2-weighted (T2), and T1-weighted (T1c).	('T2-weighted', 'Var', (97, 108))	('T1-weighted', 'Var', (79, 90))	('BraTS2015', 'Gene', (3, 12))	('patient', 'Species', '9606', (63, 70))	('T1-weighted', 'Var', (119, 130))
7350	31786124	Patients with non-metastatic >5 cm, high-grade or unresectable tumor of any grade or size have an approximately 50% survival rate and constituted the intermediaterisk group, whereas patients with metastatic disease have a less than 20% survival rate and comprised the high-risk group.	('tumor', 'Disease', (63, 68))	('Patients', 'Species', '9606', (0, 8))	('high-grade', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
7401	31786124	Initiation of each chemotherapy cycle required an absolute neutrophil count >= 750/microliter, platelet count >= 75,000/microliter, total bilirubin <= 1 5x the upper limit of normal, and for doxorubicin-containing cycles except at week 4, a shortening fraction 24% or ejection fraction 50% on echocardiogram or multigated acquisition scan.	('total bilirubin', 'MPA', (132, 147))	('doxorubicin', 'Chemical', 'MESH:D004317', (191, 202))	('ejection fraction', 'MPA', (268, 285))	('bilirubin', 'Chemical', 'MESH:D001663', (138, 147))	('platelet', 'MPA', (95, 103))	('shortening fraction 24%', 'Var', (241, 264))
7437	31786124	Since intermediate-risk patients could undergo tumor resection prior to study entry or in a delayed fashion, we also evaluated whether the timing of surgery and the extent of resection (R0/R1 vs. R2/no resection, R0 vs. R1) influenced EFS/OS.	('influenced', 'Reg', (224, 234))	('R0/R1', 'Var', (186, 191))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('EFS/OS', 'MPA', (235, 241))	('R0 vs. R1', 'Var', (213, 222))	('tumor', 'Disease', (47, 52))	('EFS/OS', 'CellLine', 'CVCL:5I29', (235, 241))
7473	31786124	Isolated local recurrence/progression occurred in 4 of 103 low-grade R0 tumors (4%), 4 of 22 low-grade R1 tumors (18%), 5 of 80 <=5 cm high-grade R0 tumors (9%), and 2 of 17 <=5 cm high-grade R1 tumors (18%).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('local recurrence/progression', 'CPA', (9, 37))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('low-grade R0', 'Var', (59, 71))
7479	31786124	As shown in Table 3, unresectable disease in intermediate-risk patients predicted poor EFS [29 6% (95% CI 9 7-49 5%) for R2/no resection vs. 70 5% (95% CI 63 5-77 4%) for R0/R1 resection, p<0 0001] and OS [58 0% (95% CI 37 6-78 5%) for R2/no resection vs. 82 5% (95% CI 76 7-88 2%) for R0/R1 resection, p<0 0001].	('R2/no', 'Var', (121, 126))	('EFS', 'MPA', (87, 90))	('patients', 'Species', '9606', (63, 71))
7565	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))
7602	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))
7611	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))
7624	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))
7641	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))
7649	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))
7654	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))
7655	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))
7669	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))
7676	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))	('stomach', 'Disease', (104, 111))	('kidney', 'Disease', (120, 126))	('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))
7677	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))
7743	30577835	The study that concluded this gene set observed the aberration in NSCLC with oncogenic form of KRAS and inactivated PTEN, in which condition resulted in shorter survival.	('KRAS', 'Gene', '3845', (95, 99))	('NSCLC', 'Disease', (66, 71))	('aberration', 'Var', (52, 62))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('shorter', 'NegReg', (153, 160))	('KRAS', 'Gene', (95, 99))	('PTEN', 'Gene', (116, 120))	('survival', 'MPA', (161, 169))
7911	27744512	Since it is not always possible to predict which patients will suffer from progressive neurocognitive deficits, or when, it is advisable to build proxy assessments into study designs from the start of brain tumor clinical trials as is currently the case in EORTC studies 26101 (NCT01290939) and 26091 (NCT01164189).	('cognitive deficits', 'Phenotype', 'HP:0100543', (92, 110))	('NCT01290939', 'Var', (278, 289))	('brain tumor', 'Phenotype', 'HP:0030692', (201, 212))	('neurocognitive deficits', 'Disease', 'MESH:D019965', (87, 110))	('brain tumor', 'Disease', 'MESH:D001932', (201, 212))	('neurocognitive deficits', 'Phenotype', 'HP:0100543', (87, 110))	('neurocognitive deficits', 'Disease', (87, 110))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('patients', 'Species', '9606', (49, 57))	('brain tumor', 'Disease', (201, 212))	('men', 'Species', '9606', (158, 161))
7991	32536040	The variable association between expression and methylation of estrogen receptors and the survival of patients with different tumors Estrogen receptor (ER) is essential in reproductive development and is also the primary driver of breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (231, 245))	('tumors', 'Disease', (126, 132))	('breast cancers', 'Disease', (231, 245))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('ER', 'Gene', '2099', (152, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (231, 245))	('methylation', 'Var', (48, 59))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))
7992	32536040	Deregulation of ER may also be involved in tumorigenesis of other organs.	('Deregulation', 'Var', (0, 12))	('involved', 'Reg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ER', 'Gene', '2099', (16, 18))	('tumor', 'Disease', (43, 48))
8001	32536040	Deregulation of ERs are involved in tumorigenesis of different organs.	('Deregulation', 'Var', (0, 12))	('involved', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ER', 'Gene', '2099', (16, 18))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
8003	32536040	The expression/methylation of ESR1/2 were associated with survival of patients.	('ESR1/2', 'Gene', (30, 36))	('patients', 'Species', '9606', (70, 78))	('associated', 'Reg', (42, 52))	('expression/methylation', 'MPA', (4, 26))	('expression/methylation', 'Var', (4, 26))	('ESR1/2', 'Gene', '2099;2100', (30, 36))
8015	32536040	16  ESR1 mutations are frequently detected in ER+ metastatic breast cancer and may be associated with endocrine therapy resistance.	('detected', 'Reg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('ESR1', 'Gene', (4, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('mutations', 'Var', (9, 18))	('associated', 'Reg', (86, 96))	('ER', 'Gene', '2099', (46, 48))	('ESR1', 'Gene', '2099', (4, 8))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
8032	32536040	We downloaded eight microarrays set from four different cancers, including GSE63514 and GSE63678 of cervical cancer; GSE73360 and GSE74602 of colorectal cancer; GSE76297 of cholangiocarcinoma; GSE87630, GSE112790, and GSE121248 of hepatocellular cancer.	('hepatocellular cancer', 'Disease', (231, 252))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (231, 252))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (56, 62))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (231, 252))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('GSE74602', 'Var', (130, 138))	('cancer', 'Disease', (246, 252))	('GSE63678', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('GSE76297', 'Var', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancers', 'Disease', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (109, 115))	('GSE112790', 'Var', (203, 212))	('GSE121248', 'Var', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (173, 191))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('GSE73360', 'Var', (117, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('GSE63514', 'Var', (75, 83))	('GSE87630', 'Var', (193, 201))	('cholangiocarcinoma', 'Disease', (173, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (173, 191))
8042	32536040	Methylation is a crucial epigenetic regulation mechanism; the DNA methylation in promoter regions is strongly associated with gene expression and could be a predictor of patients' prognosis.	('patients', 'Species', '9606', (170, 178))	('methylation', 'Var', (66, 77))	('associated', 'Reg', (110, 120))	('gene expression', 'MPA', (126, 141))	('DNA methylation', 'Var', (62, 77))
8061	32536040	We compared the expression of estrogen receptor gene in eight microarray expression datasets of four tumors (Cervical cancer: GSE63514 and GSE63678; Colorectal cancer: GSE73360 and GSE74602; Cholangiocarcinoma: GSE76297; Hepatocellular cancer: GSE87630, GSE112790 and GSE121248).	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('GSE63678', 'Var', (139, 147))	('GSE76297', 'Var', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('Hepatocellular cancer', 'Disease', 'MESH:D006528', (221, 242))	('GSE112790', 'Var', (254, 263))	('GSE121248', 'Var', (268, 277))	('cancer', 'Disease', (160, 166))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('GSE63514', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('GSE73360', 'Var', (168, 176))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (236, 242))	('GSE87630', 'Var', (244, 252))	('Colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (191, 209))	('Hepatocellular cancer', 'Disease', (221, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Colorectal cancer', 'Disease', (149, 166))	('GSE74602', 'Var', (181, 189))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 209))	('Cholangiocarcinoma', 'Disease', (191, 209))	('Hepatocellular cancer', 'Phenotype', 'HP:0001402', (221, 242))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
8071	32536040	We also noticed that IDH-mutant or IDH-like LIHC and PRAD samples belonged to subtypes with low ESR1 expression, while high ESR1 subtype was exclusively IDH-wild-type in glioma (GBM and LGG), and the expression of ESR1 was lower in IDH1 mutated samples (Figure S6).	('IDH1', 'Gene', (232, 236))	('ESR1', 'Gene', (124, 128))	('IDH', 'Gene', '3417', (35, 38))	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', '3417', (232, 235))	('glioma', 'Disease', (170, 176))	('IDH1', 'Gene', '3417', (232, 236))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('ESR1', 'Gene', '2099', (96, 100))	('IDH', 'Gene', '3417', (153, 156))	('IDH', 'Gene', (21, 24))	('ESR1', 'Gene', (96, 100))	('lower', 'NegReg', (223, 228))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (21, 24))	('low', 'NegReg', (92, 95))	('ESR1', 'Gene', '2099', (214, 218))	('IDH', 'Gene', (232, 235))	('expression', 'MPA', (101, 111))	('ESR1', 'Gene', (214, 218))	('mutated', 'Var', (237, 244))	('ESR1', 'Gene', '2099', (124, 128))
8078	32536040	Besides, compared with low ESR2 mRNA level, high mRNA level ESR2 was ascertained worse prognosis in KIRC and STAD (Figure 7C,D).	('high', 'Var', (44, 48))	('ESR2', 'Gene', '2100', (27, 31))	('ESR2', 'Gene', (60, 64))	('STAD', 'Disease', (109, 113))	('KIRC', 'Disease', (100, 104))	('ESR2', 'Gene', (27, 31))	('ESR2', 'Gene', '2100', (60, 64))
8081	32536040	Survival differences between high- and low-methylation of ESR1/2 group patients were compared.	('patients', 'Species', '9606', (71, 79))	('low-methylation', 'Var', (39, 54))	('ESR1/2', 'Gene', '2099;2100', (58, 64))	('ESR1/2', 'Gene', (58, 64))
8082	32536040	Moreover, we found that the overall and progression-free survival was longer in the high ESR1 methylation group in BLCA, BRCA, LAML, LGG, and STAD, but shorter in KIRC and KIRP (Figure S9A-G).	('ESR1', 'Gene', (89, 93))	('high', 'Var', (84, 88))	('BRCA', 'Gene', '672', (121, 125))	('BRCA', 'Gene', (121, 125))	('longer', 'PosReg', (70, 76))	('shorter', 'NegReg', (152, 159))	('progression-free survival', 'CPA', (40, 65))	('ESR1', 'Gene', '2099', (89, 93))	('methylation', 'Var', (94, 105))
8083	32536040	In the ESR2 high-methylation group, the overall and progression-free survival was significantly longer in LGG and STAD (Figure S9H,I).	('LGG', 'Disease', (106, 109))	('ESR2', 'Gene', '2100', (7, 11))	('progression-free survival', 'CPA', (52, 77))	('STAD', 'Disease', (114, 118))	('high-methylation', 'Var', (12, 28))	('longer', 'PosReg', (96, 102))	('ESR2', 'Gene', (7, 11))
8088	32536040	Overall, these data demonstrated that higher expression of ERalpha or over-phosphorylation of ERalpha in the S118 site should protect and prolong tumor patient life, except for a little particular type.	('over-phosphorylation', 'Var', (70, 90))	('prolong', 'PosReg', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ERalpha', 'Gene', (59, 66))	('tumor', 'Disease', (146, 151))	('ERalpha', 'Gene', '2099', (59, 66))	('ERalpha', 'Gene', '2099', (94, 101))	('expression', 'MPA', (45, 55))	('ERalpha', 'Gene', (94, 101))	('higher', 'PosReg', (38, 44))	('patient', 'Species', '9606', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
8101	32536040	The cellular biological processes suggest a negative correlation between DNA methylation and mRNA expression, a positive correlation between mRNA and protein expression, as we observed in most cancers.	('mRNA expression', 'MPA', (93, 108))	('methylation', 'Var', (77, 88))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('DNA', 'MPA', (73, 76))	('negative', 'NegReg', (44, 52))
8105	32536040	Recent studies have verified tissues ESR1 mutations in most tumor patients, especially with metastatic breast cancer, and some of them to activate the estrogen-independent receptor, 18 ,  39 ,  40  whereas ESR1 and ESR2 expression not only express in breast cancer but also have been shown in other cancer types.	('ESR2', 'Gene', (215, 219))	('ESR1', 'Gene', '2099', (37, 41))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (103, 116))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('ESR1', 'Gene', (37, 41))	('tumor', 'Disease', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('activate', 'PosReg', (138, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('cancer', 'Disease', (110, 116))	('estrogen-independent receptor', 'MPA', (151, 180))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (251, 264))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ESR1', 'Gene', '2099', (206, 210))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', (299, 305))	('patients', 'Species', '9606', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('ESR1', 'Gene', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('ESR2', 'Gene', '2100', (215, 219))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
8113	32536040	6 ,  7  Moreover, the low ESR1 expression subtypes enriched IDH1 mutations in glioma, liver cancer, and prostate adenocarcinoma.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('prostate adenocarcinoma', 'Disease', (104, 127))	('IDH1', 'Gene', (60, 64))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (104, 127))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('liver cancer', 'Disease', 'MESH:D006528', (86, 98))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('ESR1', 'Gene', '2099', (26, 30))	('liver cancer', 'Disease', (86, 98))	('glioma', 'Disease', (78, 84))	('IDH1', 'Gene', '3417', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (65, 74))	('ESR1', 'Gene', (26, 30))
8116	32536040	ER methylation has previously been reported to be associated with the progression and prognosis of female tumors.	('ER', 'Gene', '2099', (0, 2))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('methylation', 'Var', (3, 14))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('associated', 'Reg', (50, 60))
8117	32536040	Promoter methylation of ESR1 in breast cancer was related to worse overall survival and associated with a lack of response to endocrine treatment.	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('ESR1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Promoter methylation', 'Var', (0, 20))	('overall', 'MPA', (67, 74))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('ESR1', 'Gene', '2099', (24, 28))	('worse', 'NegReg', (61, 66))
8118	32536040	26 ,  33  Both primary tumors and paired ctDNA detected methylated ESR1 and the presence of ESR1 methylation correlated with better clinical outcome in ovarian cancer.	('tumors', 'Disease', (23, 29))	('ovarian cancer', 'Disease', (152, 166))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (152, 166))	('methylated', 'Var', (56, 66))	('presence', 'Var', (80, 88))	('better', 'PosReg', (125, 131))	('ESR1', 'Gene', '2099', (92, 96))	('ESR1', 'Gene', (67, 71))	('ESR1', 'Gene', '2099', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('ESR1', 'Gene', (92, 96))	('methylation', 'Var', (97, 108))
8119	32536040	14  Methylation of the ESR1 promoter correlated with tumor grade, while unmethylated ESR1 predicted for chemoradiation resistance in cervical carcinoma.	('ESR1', 'Gene', (85, 89))	('Methylation', 'Var', (4, 15))	('cervical carcinoma', 'Disease', (133, 151))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ESR1', 'Gene', '2099', (23, 27))	('correlated', 'Reg', (37, 47))	('unmethylated', 'Var', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('predicted', 'Reg', (90, 99))	('ESR1', 'Gene', '2099', (85, 89))	('cervical carcinoma', 'Disease', 'MESH:D002583', (133, 151))	('tumor', 'Disease', (53, 58))	('chemoradiation', 'MPA', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('ESR1', 'Gene', (23, 27))
8120	32536040	21 ,  36  Our study showed the ESR1 methylation difference and its association with survival in BLCA, BRCA, and KIRC.	('methylation difference', 'Var', (36, 58))	('BRCA', 'Gene', (102, 106))	('ESR1', 'Gene', (31, 35))	('BLCA', 'Disease', (96, 100))	('association', 'Interaction', (67, 78))	('ESR1', 'Gene', '2099', (31, 35))	('BRCA', 'Gene', '672', (102, 106))
8121	32536040	Both ESR1 and ESR2 showed the correlation between promoter methylation and survival in LGG and STAD.	('STAD', 'Disease', (95, 99))	('survival', 'CPA', (75, 83))	('ESR1', 'Gene', '2099', (5, 9))	('promoter methylation', 'Var', (50, 70))	('ESR2', 'Gene', '2100', (14, 18))	('LGG', 'Disease', (87, 90))	('correlation', 'Reg', (30, 41))	('ESR1', 'Gene', (5, 9))	('ESR2', 'Gene', (14, 18))
8123	32536040	3  The phosphorylation of ERalpha further activates the hormone signal pathway and then unique coactivator complexes to specific genes.	('ERalpha', 'Gene', '2099', (26, 33))	('activates', 'PosReg', (42, 51))	('phosphorylation', 'Var', (7, 22))	('hormone signal pathway', 'Pathway', (56, 78))	('ERalpha', 'Gene', (26, 33))
8125	32536040	Shrivastav et al showed that the p-S118, p-S167, and p-S282 of the ERalpha were positively correlated with breast cancer.	('ERalpha', 'Gene', '2099', (67, 74))	('p-S118', 'Var', (33, 39))	('p-S167', 'Var', (41, 47))	('correlated', 'Reg', (91, 101))	('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))	('p-S282', 'Var', (53, 59))	('ERalpha', 'Gene', (67, 74))
8135	32536040	As the prognostic significance of ESR1 in an eight genes assessment model in liver cancer, and ER-beta expression in colorectal cancer and ESR2 polymorphisms in advanced gastric cancer.	('liver cancer', 'Disease', 'MESH:D006528', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('liver cancer', 'Phenotype', 'HP:0002896', (77, 89))	('liver cancer', 'Disease', (77, 89))	('polymorphisms', 'Var', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ESR1', 'Gene', '2099', (34, 38))	('gastric cancer', 'Disease', (170, 184))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('ESR1', 'Gene', (34, 38))	('ER-beta', 'Gene', (95, 102))	('colorectal cancer', 'Disease', (117, 134))	('ESR2', 'Gene', '2100', (139, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('ER-beta', 'Gene', '2099', (95, 102))	('ESR2', 'Gene', (139, 143))
8140	32536040	32  Estrogen receptor knockout enhanced immune cell infiltration and liver tumorigenesis in the mouse tumor model.	('enhanced', 'PosReg', (31, 39))	('mouse', 'Species', '10090', (96, 101))	('immune cell infiltration', 'CPA', (40, 64))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('knockout', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('liver tumorigenesis', 'Disease', (69, 88))	('liver tumorigenesis', 'Disease', 'MESH:D063646', (69, 88))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
8141	32536040	41  While our study found the correlation between estrogen receptors and immune cell differentiation, immune cell signaling, and inflammation pathways in multiple tumors, target estrogen receptor in combination with immunotherapy may potentially benefit patients.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('target', 'Var', (171, 177))	('inflammation', 'Disease', (129, 141))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Disease', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('benefit', 'PosReg', (246, 253))	('patients', 'Species', '9606', (254, 262))
8142	32536040	Overall, our findings revealed DNA methylation and mRNA expression of ESR1 and ESR2, proteins expression of ESR1 in different tumor tissues, and ESR1 and ESR2 participated in some critical cancer development and progression as they associated with tumor subtypes, pathological features, and patients' survival.	('ESR1', 'Gene', '2099', (108, 112))	('ESR1', 'Gene', '2099', (70, 74))	('ESR2', 'Gene', '2100', (79, 83))	('ESR1', 'Gene', (108, 112))	('ESR1', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mRNA expression', 'MPA', (51, 66))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('ESR2', 'Gene', (79, 83))	('tumor', 'Disease', (248, 253))	('participated', 'Reg', (159, 171))	('patients', 'Species', '9606', (291, 299))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('ESR1', 'Gene', '2099', (145, 149))	('methylation', 'Var', (35, 46))	('ESR1', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', (126, 131))	('cancer', 'Disease', (189, 195))	('ESR2', 'Gene', '2100', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ESR2', 'Gene', (154, 158))	('associated', 'Reg', (232, 242))
8143	32536040	This pan-cancer analysis work showed that the expression and methylation of ESR genes are significantly associated with overall survival or progression-free survival of some tumor types, which may suggest that ESR genes are potential prognosis markers of these tumors.	('tumor', 'Disease', (174, 179))	('progression-free survival', 'CPA', (140, 165))	('cancer', 'Disease', (9, 15))	('expression', 'MPA', (46, 56))	('methylation', 'Var', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('overall survival', 'CPA', (120, 136))	('ESR genes', 'Gene', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
8153	30429891	Results: Overexpressing HOXC10 enhanced the capacity of glioma cells to induce tube formation, migration and proliferation of HUVECs, and neovascularization in CAMs, while silencing HOXC10 had the opposite result.	('tube formation', 'CPA', (79, 93))	('glioma', 'Disease', (56, 62))	('enhanced', 'PosReg', (31, 39))	('HOXC10', 'Gene', (24, 30))	('neovascularization', 'CPA', (138, 156))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('migration', 'CPA', (95, 104))	('induce', 'PosReg', (72, 78))	('proliferation', 'CPA', (109, 122))	('silencing', 'Var', (172, 181))
8154	30429891	We observed that CD31 staining was significantly increased in tumors formed by HOXC10-overexpressing U251MG cells but reduced in HOXC10-silenced tumors.	('U251MG', 'Var', (101, 107))	('HOXC10-silenced tumors', 'Disease', 'MESH:D009369', (129, 151))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('staining', 'MPA', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (62, 68))	('CD31', 'Gene', (17, 21))	('increased', 'PosReg', (49, 58))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('HOXC10-overexpressing', 'Var', (79, 100))	('HOXC10-silenced tumors', 'Disease', (129, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('CD31', 'Gene', '5175', (17, 21))	('U251MG', 'CellLine', 'CVCL:0021', (101, 107))
8158	30429891	Conclusions: This study suggests that HOXC10 induces glioma angiogenesis by transcriptionally upregulating VEGFA expression, and may represent a potential target for antiangiogenic therapy in gliomas.	('VEGFA', 'Protein', (107, 112))	('expression', 'MPA', (113, 123))	('HOXC10', 'Var', (38, 44))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('induces', 'PosReg', (45, 52))	('glioma', 'Disease', (53, 59))	('gliomas', 'Disease', (192, 199))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('upregulating', 'PosReg', (94, 106))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma', 'Disease', (192, 198))
8174	30429891	Zhai and colleagues reported that elevated HOXC10 is associated with increased invasiveness of cervical cancer-derived cell lines and that knockdown of HOXC10 markedly impaired cervical cancer cell invasiveness.	('impaired cervical cancer cell invasiveness', 'Disease', 'MESH:D002583', (168, 210))	('increased', 'PosReg', (69, 78))	('HOXC10', 'MPA', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('knockdown', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('invasiveness of cervical cancer', 'Disease', (79, 110))	('invasiveness of cervical cancer', 'Disease', 'MESH:D002583', (79, 110))	('elevated', 'PosReg', (34, 42))	('impaired cervical cancer cell invasiveness', 'Disease', (168, 210))	('HOXC10', 'Gene', (152, 158))
8180	30429891	Furthermore, we demonstrated that HOXC10 upregulated VEGFA expression via directly binding to the VEGFA promoter, eventually promoting angiogenesis in glioma.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('binding', 'Interaction', (83, 90))	('promoting', 'PosReg', (125, 134))	('upregulated', 'PosReg', (41, 52))	('VEGFA', 'Gene', (53, 58))	('expression', 'MPA', (59, 69))	('HOXC10', 'Var', (34, 40))	('glioma', 'Disease', (151, 157))	('angiogenesis', 'CPA', (135, 147))
8189	30429891	Western blotting (WB) was performed as previously described, using anti-HOXC10, anti-Flag, anti-protein arginine methyltransferase 5 (PRMT5), anti-glutathione-s-transferase (GST), anti-hemagluttinin (HA), anti-VEGFA and anti-WD repeat domain 5 (WDR5) antibodies (Abcam, Cambridge, MA, USA).	('anti-protein arginine methyltransferase 5', 'Gene', '10419', (91, 132))	('WD repeat domain 5', 'Gene', (225, 243))	('WDR5', 'Gene', (245, 249))	('WD repeat domain 5', 'Gene', '11091', (225, 243))	('anti-protein arginine methyltransferase 5', 'Gene', (91, 132))	('WDR5', 'Gene', '11091', (245, 249))	('anti-HOXC10', 'Var', (67, 78))
8220	30429891	Therefore, we verified whether HOXC10 was upregulated in gliomas via analyzing public glioma datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO; GSE13276 and GSE4290).	('Cancer Genome Atlas', 'Disease', (111, 130))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (111, 130))	('GSE4290', 'Var', (189, 196))	('public glioma', 'Disease', 'MESH:D005910', (79, 92))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('HOXC10', 'Gene', (31, 37))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('upregulated', 'PosReg', (42, 53))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('public glioma', 'Disease', (79, 92))
8222	30429891	Furthermore, Kaplan-Meier analysis of data from the TCGA and HG-UG133A dataset indicated that GBM or low-grade gliomas (LGG) patients with higher HOXC10 expression presented shorter overall survival than those with lower HOXC10 expression (Figure S1D-F).	('patients', 'Species', '9606', (125, 133))	('gliomas', 'Disease', (111, 118))	('UG133A', 'Mutation', 'c.133UG>A', (64, 70))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('HOXC10', 'Var', (146, 152))	('higher HOXC10', 'Var', (139, 152))	('overall survival', 'MPA', (182, 198))	('shorter', 'NegReg', (174, 181))
8226	30429891	We also performed western blotting analysis and real-time PCR analysis in NHAs and multiple glioma cell lines, including A-172, U87, LN229, T98G, LN-18, and U251MG.	('U251MG', 'CellLine', 'CVCL:0021', (157, 163))	('U251MG', 'Var', (157, 163))	('glioma', 'Disease', (92, 98))	('LN229', 'CellLine', 'CVCL:0393', (133, 138))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
8233	30429891	Importantly, univariate and multivariate analysis indicated that HOXC10 might serve as a prognostic factor in gliomas (Table S3).	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('HOXC10', 'Var', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))
8238	30429891	Tumors formed by HOXC10-overexpressing U251MG cells were significantly larger than those formed by the control cells, as indicated by luminescence and H&E staining (Figure 1A-C).	('U251MG', 'Var', (39, 45))	('H&E', 'Chemical', '-', (151, 154))	('larger', 'PosReg', (71, 77))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('U251MG', 'CellLine', 'CVCL:0021', (39, 45))
8239	30429891	Conversely, silencing HOXC10 yielded smaller tumors than the control shRNA vector (Figure 1A-C).	('smaller', 'NegReg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('HOXC10', 'Var', (22, 28))	('silencing HOXC10', 'Var', (12, 28))
8240	30429891	Furthermore, overexpression of HOXC10 shortened, while silencing HOXC10 prolonged the survival of tumor-bearing mice compared to the control shRNA group (Figure 1D).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('silencing', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('prolonged', 'PosReg', (72, 81))	('HOXC10', 'Gene', (65, 71))	('survival', 'CPA', (86, 94))	('tumor', 'Disease', (98, 103))	('mice', 'Species', '10090', (112, 116))
8242	30429891	Consistent with the in vivo results, overexpressing HOXC10 significantly promoted, but silencing HOXC10 prominently inhibited, the capability of tube formation, migration ability, and proliferation of HUVECs (Figure S3B-E and Figure S4A-D) and the formation of second- and third-order vessels in the chicken CAM assay (Figure 1G).	('silencing', 'Var', (87, 96))	('migration ability', 'CPA', (161, 178))	('inhibited', 'NegReg', (116, 125))	('proliferation', 'CPA', (184, 197))	('tube formation', 'CPA', (145, 159))	('chicken', 'Species', '9031', (300, 307))	('HOXC10', 'Gene', (97, 103))	('promoted', 'PosReg', (73, 81))
8243	30429891	Gene set enrichment analysis (GSEA) results also revealed that angiogenesis gene signatures (LU_TUMOR_ ANGIOGENESIS_UP, ANGIOGENESIS, HALLMARK_ANGIOGENESIS, GO_ ANGIOGENESIS) were significantly elevated in the higher HOXC10 expression group compared to the lower HOXC10 expression group (Figure 1H).	('elevated', 'PosReg', (194, 202))	('higher HOXC10 expression', 'Var', (210, 234))	('ANGIOGENESIS', 'CPA', (120, 132))	('GSEA', 'Chemical', '-', (30, 34))	('angiogenesis', 'MPA', (63, 75))
8246	30429891	As expected, the expression of VEGFA, at both mRNA and protein levels, was consistently upregulated in HOXC10-overexpressing glioma cells, and downregulated in HOXC10-silenced glioma cells compared to control cells (Figure S5B-D).	('glioma', 'Disease', (125, 131))	('glioma', 'Disease', (176, 182))	('VEGFA', 'Gene', (31, 36))	('upregulated', 'PosReg', (88, 99))	('downregulated', 'NegReg', (143, 156))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('expression', 'MPA', (17, 27))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('HOXC10-silenced glioma', 'Disease', 'MESH:D005910', (160, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('HOXC10-overexpressing', 'Var', (103, 124))	('HOXC10-silenced glioma', 'Disease', (160, 182))
8247	30429891	Importantly, silencing VEGFA or treatment with bevacizumab, a monoclonal antibody against VEGFA, could reverse the effects of HOXC10 overexpression-mediated tube formation, migration, and proliferation of HUVECs (Figure S5E-M).	('tube formation', 'CPA', (157, 171))	('VEGFA', 'Protein', (23, 28))	('migration', 'CPA', (173, 182))	('bevacizumab', 'Chemical', 'MESH:D000068258', (47, 58))	('proliferation', 'CPA', (188, 201))	('silencing', 'Var', (13, 22))
8249	30429891	Mice bearing VEGFA-silenced U251MG/HOXC10 cells had longer survival than those bearing control-shRNA-transduced cells (Figure 2C).	('U251MG/HOXC10', 'CellLine', 'CVCL:0021', (28, 41))	('longer', 'PosReg', (52, 58))	('survival', 'CPA', (59, 67))	('U251MG/HOXC10 cells', 'Var', (28, 47))	('Mice', 'Species', '10090', (0, 4))
8253	30429891	To identify the site that HOXC10 binds to in the VEGFA promoter, fragments of the VEGFA promoter, namely P1(nucleotides -2056 to +176), P2 (nucleotides -1751 to +176), P3 (nucleotides -931 to +176), P4 (nucleotides -226 to +176), P5 (nucleotides -2056 to -907) and P6 (nucleotides -732 to -208), were inserted into the luciferase reporter pGL3 vector, respectively (Figure 3B).	('nucleotides -2056 to -907', 'Var', (234, 259))	('nucleotides -2056 to +176', 'Var', (108, 133))	('nucleotides -1751 to +176', 'Var', (140, 165))	('pGL3', 'Gene', '6391', (339, 343))	('nucleotides -931 to +176', 'Var', (172, 196))	('nucleotides -226 to +176', 'Var', (203, 227))	('pGL3', 'Gene', (339, 343))
8255	30429891	Moreover, a chromatin immunoprecipitation (CHIP) assay showed that HOXC10 bound to region 3 within the VEGFA promoter region (Figure 3G), which agreed with the luciferase assay results and suggested that HOXC10 upregulates VEGFA expression by binding to the VEGFA promoter.	('binding', 'Interaction', (243, 250))	('VEGFA', 'Gene', (223, 228))	('CHIP', 'Disease', 'None', (43, 47))	('upregulates', 'PosReg', (211, 222))	('HOXC10', 'Var', (204, 210))	('expression', 'MPA', (229, 239))	('CHIP', 'Disease', (43, 47))
8256	30429891	Furthermore, we found that recruitment of PRMT5 to the VEGFA promoter was significantly enhanced in HOXC10-overexpressing glioma cells, but markedly suppressed in HOXC10-silenced glioma cells (Figure 4B).	('recruitment', 'MPA', (27, 38))	('HOXC10-silenced glioma', 'Disease', 'MESH:D005910', (163, 185))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Disease', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('HOXC10-silenced glioma', 'Disease', (163, 185))	('PRMT5', 'Gene', (42, 47))	('suppressed', 'NegReg', (149, 159))	('glioma', 'Disease', (179, 185))	('enhanced', 'PosReg', (88, 96))	('HOXC10-overexpressing', 'Var', (100, 121))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
8259	30429891	Overexpressing HOXC10-FL and HOXC10-F1 markedly promoted the luciferase activity of VEGFA, while overexpressing HOXC10-F2, HOXC10-F3, HOXC10-F4, all of which lacked the PRMT5 binding site or homeobox, could not activate the VEGFA promoter-dependent luciferase activity (Figure 4I).	('promoted', 'PosReg', (48, 56))	('HOXC10-F1', 'CellLine', 'CVCL:9089', (29, 38))	('luciferase', 'Enzyme', (61, 71))	('HOXC10-F1', 'Var', (29, 38))	('HOXC10-FL', 'Var', (15, 24))
8260	30429891	Consistently, VEGFA expression, at both mRNA and protein levels, was significantly increased in the HOXC10-FL- and HOXC10-F1-overexpressing cells but decreased in the cells transfected with HOXC10-F2, or HOXC10-F3 (Figure S6A-B).	('HOXC10-FL-', 'Var', (100, 110))	('increased', 'PosReg', (83, 92))	('expression', 'MPA', (20, 30))	('HOXC10-F1', 'CellLine', 'CVCL:9089', (115, 124))	('VEGFA', 'Protein', (14, 19))	('decreased', 'NegReg', (150, 159))
8261	30429891	As shown in Figure S7A-B and Figure 5A-B, knockdown of PRMT5 significantly reduced VEGFA expression and inhibited the occupancy of H3R2me1 and H3R2me2s on VEGFA in HOXC10-overexpressing glioma cells, with no change in control marker H3.	('glioma', 'Disease', (186, 192))	('PRMT5', 'Gene', (55, 60))	('expression', 'MPA', (89, 99))	('H3R2me1', 'Protein', (131, 138))	('reduced', 'NegReg', (75, 82))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('occupancy', 'MPA', (118, 127))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('H3R2me2s', 'Protein', (143, 151))	('inhibited', 'NegReg', (104, 113))	('VEGFA', 'Protein', (83, 88))	('knockdown', 'Var', (42, 51))
8262	30429891	PRMT5-methylated H3R2me1 may lead to WDR5-induced H3K4 methylation and transcriptional activation of target genes.	('H3K4', 'Protein', (50, 54))	('PRMT5-methylated', 'Var', (0, 16))	('lead to', 'Reg', (29, 36))	('H3R2me1', 'Var', (17, 24))	('WDR5', 'Gene', (37, 41))	('transcriptional', 'MPA', (71, 86))	('methylation', 'MPA', (55, 66))	('WDR5', 'Gene', '11091', (37, 41))
8264	30429891	As expected, overexpressing HOXC10 strongly increased, while silencing HOXC10 prominently decreased, the abundance of H3K4me3, Polymerase II, and WDR5 on the VEGFA promoter in U251MG and LN229 cells (Figure 5C-D).	('abundance', 'MPA', (105, 114))	('H3K4me3', 'Protein', (118, 125))	('decreased', 'NegReg', (90, 99))	('LN229', 'CellLine', 'CVCL:0393', (187, 192))	('U251MG', 'CellLine', 'CVCL:0021', (176, 182))	('WDR5', 'Gene', '11091', (146, 150))	('silencing', 'Var', (61, 70))	('increased', 'PosReg', (44, 53))	('HOXC10', 'Gene', (71, 77))	('WDR5', 'Gene', (146, 150))
8266	30429891	Furthermore, silencing WDR5 profoundly impaired the stimulatory effect of overexpressing HOXC10 (Figure S7D-F).	('WDR5', 'Gene', '11091', (23, 27))	('stimulatory effect', 'MPA', (52, 70))	('WDR5', 'Gene', (23, 27))	('impaired', 'NegReg', (39, 47))	('overexpressing', 'PosReg', (74, 88))	('silencing', 'Var', (13, 22))
8267	30429891	Importantly, OICR-9429, an inhibitor of WDR5 interaction with the H3 tail, markedly decreased the expression of VEGFA and the occupancy of H3K4me3 and Polymerase II on the VEGFA promoter (Figure 5F-G).	('WDR5', 'Gene', (40, 44))	('WDR5', 'Gene', '11091', (40, 44))	('occupancy', 'MPA', (126, 135))	('OICR-9429', 'Var', (13, 22))	('VEGFA', 'Protein', (112, 117))	('H3K4me3', 'Protein', (139, 146))	('decreased', 'NegReg', (84, 93))	('expression', 'MPA', (98, 108))
8268	30429891	These results suggested that HOXC10 interacts with PRMT5, which promotes H3R2me1 and H3R2me2s enrichment on the VEGFA promoter and recruits WDR5 for subsequent methylation of H3K4 at the VEGFA promoter, eventually resulting in VEGFA transcription.	('resulting in', 'Reg', (214, 226))	('promotes', 'PosReg', (64, 72))	('H3R2me2s', 'Var', (85, 93))	('WDR5', 'Gene', '11091', (140, 144))	('H3K4', 'Protein', (175, 179))	('H3R2me1', 'Var', (73, 80))	('WDR5', 'Gene', (140, 144))	('methylation', 'MPA', (160, 171))	('VEGFA transcription', 'MPA', (227, 246))
8275	30429891	Therefore, inhibiting the angiogenic process might be used as a potential therapy to prevent tumor growth and metastasis.	('inhibiting', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('angiogenic process', 'CPA', (26, 44))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
8282	30429891	reported that HOXB7 is overexpressed in more than 40% myeloma cell lines compared to normal plasma cells, and knockdown of HOXB7 expression in multiple myeloma cells represses the production of angiogenic factors and impairs their pro-angiogenic properties.	('knockdown', 'Var', (110, 119))	('myeloma', 'Disease', (152, 159))	('HOXB7', 'Gene', (14, 19))	('HOXB7', 'Gene', (123, 128))	('myeloma', 'Disease', (54, 61))	('impairs', 'NegReg', (217, 224))	('represses', 'NegReg', (166, 175))	('myeloma', 'Disease', 'MESH:D009101', (152, 159))	('production of angiogenic factors', 'MPA', (180, 212))	('HOXB7', 'Gene', '3217', (123, 128))	('multiple myeloma', 'Phenotype', 'HP:0006775', (143, 159))	('myeloma', 'Disease', 'MESH:D009101', (54, 61))	('pro-angiogenic properties', 'CPA', (231, 256))	('HOXB7', 'Gene', '3217', (14, 19))
8300	30429891	Furthermore, PRMT5 is recruited through interaction with Sp1 and activates the androgen receptor by symmetrically dimethylating H4R3, which significantly enhanced the growth of prostate xenograft tumors in mice.	('H4R3', 'Protein', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('enhanced', 'PosReg', (154, 162))	('mice', 'Species', '10090', (206, 210))	('prostate xenograft tumors', 'Disease', (177, 202))	('growth', 'CPA', (167, 173))	('PRMT5', 'Gene', (13, 18))	('androgen receptor', 'Gene', '11835', (79, 96))	('interaction', 'Interaction', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('androgen receptor', 'Gene', (79, 96))	('prostate xenograft tumors', 'Disease', 'MESH:D011471', (177, 202))	('activates', 'PosReg', (65, 74))	('dimethylating', 'Var', (114, 127))
8301	30429891	Our results showed that HOXC10 interacted with PRMT5, leading to enrichment of H3R2me1, H3R2me2s, and H3K4me3 on the VEGFA promoter, which eventually resulted in increased VEGFA expression and enhances growth of gliomas.	('growth', 'CPA', (202, 208))	('increased', 'PosReg', (162, 171))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('expression', 'MPA', (178, 188))	('H3K4me3', 'Var', (102, 109))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('H3R2me1', 'Var', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('gliomas', 'Disease', (212, 219))	('H3R2me2s', 'Var', (88, 96))	('VEGFA', 'Protein', (172, 177))	('enhances', 'PosReg', (193, 201))
8306	30429891	Herein, we demonstrated that HOXC10 transcriptionally upregulates VEGFA expression by binding to its promoter and silencing HOXC10, which significantly decreased VEGFA expression and angiogenesis, implicating that HOXC10 may regulate expression of various splicing VEGF isoforms, which needs to be further investigated in future studies.	('VEGF', 'Gene', (66, 70))	('angiogenesis', 'CPA', (183, 195))	('VEGF', 'Gene', (265, 269))	('VEGF', 'Gene', (162, 166))	('expression', 'MPA', (168, 178))	('binding', 'Interaction', (86, 93))	('silencing', 'Var', (114, 123))	('upregulates', 'PosReg', (54, 65))	('VEGF', 'Gene', '7422', (66, 70))	('expression', 'MPA', (72, 82))	('decreased', 'NegReg', (152, 161))	('VEGF', 'Gene', '7422', (162, 166))	('HOXC10', 'Gene', (124, 130))	('VEGF', 'Gene', '7422', (265, 269))
8319	29371935	And knockdown of UCH-L5 expression improved both mRNA expression and protein level of SNRPF.	('protein level', 'MPA', (69, 82))	('improved', 'PosReg', (35, 43))	('knockdown', 'Var', (4, 13))	('SNRPF', 'Gene', '6636', (86, 91))	('UCH-L5', 'Gene', '51377', (17, 23))	('mRNA expression', 'MPA', (49, 64))	('SNRPF', 'Gene', (86, 91))	('UCH-L5', 'Gene', (17, 23))
8353	29371935	These results indicated that low UCH-L5 expression was positively correlated with the occurrence of gliomas, but there was no difference between low-grade gliomas and high-grade gliomas (Figure 1C).	('expression', 'MPA', (40, 50))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('correlated', 'Reg', (66, 76))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('UCH-L5', 'Gene', '51377', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('low', 'Var', (29, 32))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('UCH-L5', 'Gene', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('gliomas', 'Disease', (178, 185))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', (100, 107))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
8361	29371935	We found that knockdown of UCH-L5 promoted the cell capability to migrate and invade in both U87MG and U251 cells.	('UCH-L5', 'Gene', (27, 33))	('U251', 'CellLine', 'CVCL:0021', (103, 107))	('UCH-L5', 'Gene', '51377', (27, 33))	('promoted', 'PosReg', (34, 42))	('knockdown', 'Var', (14, 23))	('cell capability', 'CPA', (47, 62))	('U87MG', 'CellLine', 'CVCL:0022', (93, 98))
8375	29371935	These data indicated that knockdown of SNRPF, SNRPN and CKLF inhibits migration and invasion of U87MG cell in vitro.	('SNRPF', 'Gene', (39, 44))	('CKLF', 'Gene', (56, 60))	('SNRPN', 'Gene', (46, 51))	('knockdown', 'Var', (26, 35))	('CKLF', 'Gene', '51192', (56, 60))	('SNRPF', 'Gene', '6636', (39, 44))	('SNRPN', 'Gene', '6638', (46, 51))	('U87MG', 'CellLine', 'CVCL:0022', (96, 101))	('inhibits', 'NegReg', (61, 69))
8376	29371935	To find the targeting gene of UCH-L5, firstly, we found that mRNA level of SNRPF was higher in U87MG cells treated with UCH-L5-siRNA than the control treated with scramble-siRNA, but mRNA level of SNRPN or CKLF do not change significantly (Figure 6A), *P < 0.05.	('UCH-L5', 'Gene', (30, 36))	('UCH-L5', 'Gene', '51377', (30, 36))	('CKLF', 'Gene', (206, 210))	('UCH-L5', 'Gene', '51377', (120, 126))	('SNRPN', 'Gene', '6638', (197, 202))	('SNRPF', 'Gene', (75, 80))	('higher', 'PosReg', (85, 91))	('CKLF', 'Gene', '51192', (206, 210))	('U87MG', 'CellLine', 'CVCL:0022', (95, 100))	('U87MG', 'Var', (95, 100))	('SNRPF', 'Gene', '6636', (75, 80))	('SNRPN', 'Gene', (197, 202))	('UCH-L5', 'Gene', (120, 126))	('mRNA level', 'MPA', (61, 71))
8380	29371935	And after transfecting Flag-UCH-L5, we also found endogenous protein level of SNRPF decreased in 293T cells (Figure 6D).	('transfecting', 'Var', (10, 22))	('SNRPF', 'Gene', (78, 83))	('UCH-L5', 'Gene', '51377', (28, 34))	('293T', 'CellLine', 'CVCL:0063', (97, 101))	('SNRPF', 'Gene', '6636', (78, 83))	('decreased', 'NegReg', (84, 93))	('endogenous protein level', 'MPA', (50, 74))	('UCH-L5', 'Gene', (28, 34))
8387	29371935	In stable UCH-L5 knockdown and stable UCH-L5 overexpressing U87MG cells, we found that knockdown UCH-L5 expression upregulated mRNA level of Sm genes except for SNRPN (Supplementary Figure 1A), while UCH-L5 overexpression downregulates mRNA level of Sm genes in U87MG cells (Supplementary Figure 1B).	('mRNA level', 'MPA', (127, 137))	('UCH-L5', 'Gene', (10, 16))	('UCH-L5', 'Gene', (38, 44))	('SNRPN', 'Gene', (161, 166))	('UCH-L5', 'Gene', '51377', (38, 44))	('UCH-L5', 'Gene', (200, 206))	('SNRPN', 'Gene', '6638', (161, 166))	('U87MG', 'CellLine', 'CVCL:0022', (60, 65))	('UCH-L5', 'Gene', '51377', (10, 16))	('UCH-L5', 'Gene', (97, 103))	('UCH-L5', 'Gene', '51377', (200, 206))	('UCH-L5', 'Gene', '51377', (97, 103))	('U87MG', 'CellLine', 'CVCL:0022', (262, 267))	('upregulated', 'PosReg', (115, 126))	('knockdown', 'Var', (87, 96))
8413	29371935	Furthermore, we found that knockdown of UCH-L5 expression promotes the migration and invasion of U87MG and U251 cells.	('UCH-L5', 'Gene', '51377', (40, 46))	('U87MG', 'CellLine', 'CVCL:0022', (97, 102))	('knockdown', 'Var', (27, 36))	('promotes', 'PosReg', (58, 66))	('migration', 'CPA', (71, 80))	('U251', 'CellLine', 'CVCL:0021', (107, 111))	('invasion', 'CPA', (85, 93))	('UCH-L5', 'Gene', (40, 46))
8419	29371935	It has been reported that the disruption of components and the formation steps of spliceosome will increase the occurrence of cancers and other diseases.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('disruption', 'Var', (30, 40))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('increase', 'PosReg', (99, 107))
8425	29371935	In our study, the scratch and invasion assay results showed that SNRPF, SNRPN, and CKLF could inhibit the migration and invasion of U87MG cells, and knockdown of UCH-L5 expression only unregulated the gene level of SNRPF but not mRNA expression of SNRPN or CKLF in U87MG cells.	('SNRPF', 'Gene', (215, 220))	('U87MG', 'CellLine', 'CVCL:0022', (132, 137))	('SNRPF', 'Gene', '6636', (65, 70))	('SNRPN', 'Gene', (248, 253))	('knockdown', 'Var', (149, 158))	('CKLF', 'Gene', '51192', (257, 261))	('CKLF', 'Gene', (83, 87))	('UCH-L5', 'Gene', '51377', (162, 168))	('SNRPN', 'Gene', (72, 77))	('CKLF', 'Gene', '51192', (83, 87))	('U87MG', 'CellLine', 'CVCL:0022', (265, 270))	('SNRPF', 'Gene', (65, 70))	('UCH-L5', 'Gene', (162, 168))	('SNRPN', 'Gene', '6638', (248, 253))	('SNRPF', 'Gene', '6636', (215, 220))	('SNRPN', 'Gene', '6638', (72, 77))	('inhibit', 'NegReg', (94, 101))	('CKLF', 'Gene', (257, 261))
8426	29371935	We also found that knockdown of UCH-L5 could upregulate the mRNA and protein level of SNRPF, while overexpression of UCH-L5 downregulated the mRNA and protein level of SNRPF in U87MG cells infected by Lentivirus.	('UCH-L5', 'Gene', (117, 123))	('SNRPF', 'Gene', '6636', (168, 173))	('SNRPF', 'Gene', '6636', (86, 91))	('knockdown', 'Var', (19, 28))	('UCH-L5', 'Gene', '51377', (32, 38))	('U87MG', 'CellLine', 'CVCL:0022', (177, 182))	('downregulated', 'NegReg', (124, 137))	('SNRPF', 'Gene', (168, 173))	('UCH-L5', 'Gene', '51377', (117, 123))	('UCH-L5', 'Gene', (32, 38))	('SNRPF', 'Gene', (86, 91))	('upregulate', 'PosReg', (45, 55))
8428	29371935	Considering the function of UCH-L5 regulates DNA transcription and mRNA expression of the spliceosome components, the possible reason is that knockdown of UCH-L5 expression upregulates mRNA level of SNRPF which promots the splicing of downstream oncogenes, causing a promotion of oncogenic genes and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('upregulates', 'PosReg', (173, 184))	('tumor', 'Disease', (300, 305))	('UCH-L5', 'Gene', (155, 161))	('UCH-L5', 'Gene', '51377', (28, 34))	('SNRPF', 'Gene', '6636', (199, 204))	('oncogenic genes', 'Gene', (280, 295))	('SNRPF', 'Gene', (199, 204))	('splicing', 'MPA', (223, 231))	('UCH-L5', 'Gene', '51377', (155, 161))	('promotion', 'PosReg', (267, 276))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('mRNA', 'MPA', (185, 189))	('knockdown', 'Var', (142, 151))	('UCH-L5', 'Gene', (28, 34))
8443	29371935	Endogenous catalase activity was inactivated by H2O2.	('inactivated', 'NegReg', (33, 44))	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('H2O2', 'Var', (48, 52))	('Endogenous catalase activity', 'MPA', (0, 28))
8520	28446876	According to, the lack of sensitivity in skin tests could be explained by the fact that the molecular weight of carboplatin (373.272 g/mol) is low and it is not immunogenic in the native form.	('molecular weight', 'MPA', (92, 108))	('carboplatin', 'Chemical', 'MESH:D016190', (112, 123))	('low', 'NegReg', (143, 146))	('373.272 g/mol', 'Var', (125, 138))
8543	28446876	Despite its effectiveness, however, cisplatin is more ototoxic and nephrotoxic than carboplatin.	('ototoxic', 'Disease', (54, 62))	('nephrotoxic', 'Disease', 'MESH:D007674', (67, 78))	('carboplatin', 'Chemical', 'MESH:D016190', (84, 95))	('cisplatin', 'Var', (36, 45))	('ototoxic', 'Disease', 'MESH:D006311', (54, 62))	('nephrotoxic', 'Disease', (67, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))
8545	28446876	In patients receiving cumulative cisplatin doses of <=200 mg/m2, 200-400 mg/m2, and >=400 mg/m2, the incidence increases to 59, 68, and 65%, respectively.	('>=400 mg/m2', 'Var', (84, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('patients', 'Species', '9606', (3, 11))	('<=200 mg/m2', 'Var', (52, 63))
8633	20708548	By combining both MRSI and perfusion MRI, a sensitivity of 72.2% and specificity of 91.7% in differentiating tumors from nonneoplastic lesions was achieved with cutoff points of NAA/Cho <=0.61 and rCBV >=1.50 corresponding to tumor diagnosis.	('NAA', 'Chemical', 'MESH:C000179', (178, 181))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('rCBV', 'Chemical', '-', (197, 201))	('tumor', 'Disease', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('Cho', 'Chemical', 'MESH:D002794', (182, 185))	('nonneoplastic lesions', 'Disease', 'MESH:D004194', (121, 142))	('NAA/Cho', 'Var', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (124, 142))	('MRSI', 'Disease', (18, 22))	('MRSI', 'Disease', 'None', (18, 22))	('nonneoplastic lesions', 'Disease', (121, 142))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumor', 'Disease', (226, 231))
8663	20708548	In another study of children with recurrent gliomas, a high Cho/NAA ratio was associated with decreased survival.	('NAA', 'Chemical', 'MESH:C000179', (64, 67))	('survival', 'MPA', (104, 112))	('Cho', 'Chemical', 'MESH:D002794', (60, 63))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('decreased', 'NegReg', (94, 103))	('high', 'Var', (55, 59))	('children', 'Species', '9606', (20, 28))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
8693	20708548	In nine patients with T2-hyperintense lesions without contrast enhancement suggestive of low-grade glioma on conventional MRI, 1H MRSI was performed presurgically and the area of the highest Cho intensity (or, if not apparent, area from the center of the lesion) was chosen as a biopsy target using a frameless stereotactic system.	('MRSI', 'Disease', (130, 134))	('Cho', 'Chemical', 'MESH:D002794', (191, 194))	('1H', 'Chemical', '-', (127, 129))	('MRSI', 'Disease', 'None', (130, 134))	('glioma', 'Disease', (99, 105))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('T2-hyperintense lesions', 'Var', (22, 45))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('patients', 'Species', '9606', (8, 16))
8746	20708548	At relapse, 82% of the 17 voxels with Cho/NAA>=2 at baseline exhibited either continuing or new contrast enhancement (as compared to 15% of 323 voxels with normal Cho/NAA ratio).	('NAA', 'Chemical', 'MESH:C000179', (167, 170))	('enhancement', 'PosReg', (105, 116))	('NAA', 'Chemical', 'MESH:C000179', (42, 45))	('Cho', 'Chemical', 'MESH:D002794', (38, 41))	('Cho/NAA', 'Var', (38, 45))	('Cho', 'Chemical', 'MESH:D002794', (163, 166))	('contrast', 'MPA', (96, 104))
8778	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))
8785	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))
8787	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))
8795	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))
8806	32894165	MiR-342-3p is reported to exert tumor inhibiting effects in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('MiR-342-3p', 'Var', (0, 10))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('MiR-342-3p', 'Chemical', '-', (0, 10))
8815	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))
8854	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))
8857	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))
8866	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))
8870	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))
8872	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))	('VEGFA', 'Gene', (89, 94))	('GSC205', 'Chemical', '-', (179, 185))	('GSC406', 'Gene', (129, 135))	('VEGFA', 'Gene', '7422', (89, 94))	('silencing', 'Var', (116, 125))	('secretion', 'MPA', (76, 85))	('expression', 'MPA', (61, 71))
8874	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))
8876	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))	('decreased', 'NegReg', (59, 68))	('VEGFA', 'Gene', (49, 54))	('silencing', 'NegReg', (77, 86))	('GSC205', 'Chemical', '-', (131, 137))	('increased', 'PosReg', (98, 107))	('enrichment', 'MPA', (35, 45))	('VEGFA', 'Gene', '7422', (49, 54))
8879	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))
8880	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))
8881	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))
8883	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))	('GSC205', 'Chemical', '-', (145, 151))	('GSC406-GCM', 'Var', (112, 122))	('VEGFA', 'Gene', '7422', (38, 43))
8889	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))
8891	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))
8892	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))
8893	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))
8894	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))
8895	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))
8896	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))
8897	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))
8898	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))	('decreased', 'NegReg', (86, 95))	('secretion', 'MPA', (62, 71))	('miR-342-3p', 'Chemical', '-', (134, 144))	('VEGFA', 'Gene', (75, 80))	('expression', 'MPA', (47, 57))
8900	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))
8901	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))
8902	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))
8904	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))
8906	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))
8907	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))
8911	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))
8912	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))
8918	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))
8919	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))
8922	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))	('angiogenesis of hBMECs', 'CPA', (144, 166))	('expression', 'MPA', (172, 182))	('VEGFA', 'Gene', (200, 205))	('proliferation', 'CPA', (115, 128))	('GSC406', 'Var', (209, 215))	('miR-342-3p', 'Chemical', '-', (81, 91))	('secretion', 'MPA', (187, 196))	('VEGFA', 'Gene', '7422', (200, 205))
8925	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))
8926	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))
8931	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))
8932	32894165	However, the opposite results were also obtained after ISL2 knockdown combined with cARF1 overexpression in GSC205 (Fig.	('cARF1', 'Gene', (84, 89))	('GSC205', 'Chemical', '-', (108, 114))	('knockdown', 'Var', (60, 69))	('overexpression', 'PosReg', (90, 104))
8935	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))
8937	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))	('enrichment', 'MPA', (110, 120))	('U2AF2', 'Gene', (67, 72))	('knockdown', 'Var', (6, 15))	('U2AF2', 'Gene', (0, 5))	('decreased', 'NegReg', (16, 25))	('GSC205', 'Chemical', '-', (133, 139))
8938	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))
8941	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))
8944	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))
8946	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))
8947	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))
8949	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))
8950	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))
8951	32894165	Taken together, these results suggested that U2AF2 promoted glioma angiogenesis via upregulating cARF1 expression in GSCs.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('expression', 'MPA', (103, 113))	('glioma', 'Disease', (60, 66))	('promoted', 'PosReg', (51, 59))	('cARF1', 'Gene', (97, 102))	('GSCs', 'Chemical', '-', (117, 121))	('upregulating', 'PosReg', (84, 96))	('U2AF2', 'Var', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
8953	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))	('activity', 'MPA', (104, 112))	('ISL2', 'Gene', (135, 139))	('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))
8954	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))
8957	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.	('miR-342-3p', 'Chemical', '-', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('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))
8958	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', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR-342-3p mimic', 'Var', (48, 64))
8964	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))
8972	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))	('GSCs', 'Chemical', '-', (106, 110))	('ERK', 'Gene', '5594', (208, 211))	('ERK', 'Gene', (208, 211))	('promoted', 'PosReg', (78, 86))	('proliferation', 'CPA', (152, 165))	('expression', 'MPA', (63, 73))	('invasion', 'CPA', (167, 175))	('VEGFA', 'Gene', (57, 62))	('VEGFA', 'Gene', '7422', (87, 92))	('angiogenesis', 'CPA', (181, 193))
8975	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))
8978	32894165	Circular RNA MAPK4 (circ-MAPK4) inhibits glioma cell apoptosis via the MAPK signaling pathway by sponging miR-125a-3p in glioma.	('MAPK signaling pathway', 'Pathway', (71, 93))	('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', 'Phenotype', 'HP:0009733', (121, 127))	('-3p', 'Chemical', '-', (114, 117))	('MAPK4', 'Gene', (13, 18))	('inhibits', 'NegReg', (32, 40))	('glioma', 'Disease', (41, 47))	('MAPK4', 'Gene', '5596', (13, 18))	('glioma', 'Disease', (121, 127))
8979	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))
8982	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))
8983	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))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('miR-342-3p', 'Chemical', '-', (68, 78))	('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))
8984	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))
8985	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))
8986	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))
8987	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))	('inhibited', 'NegReg', (83, 92))	('miR-342-3p', 'Var', (30, 40))	('GSCs', 'Chemical', '-', (74, 78))	('miR-342-3p', 'Chemical', '-', (30, 40))	('ISL2', 'Gene', (55, 59))
8989	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))
8990	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))	('ablation', 'Var', (71, 79))	('tumor', 'Disease', (93, 98))	('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))
9000	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))
9006	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))
9010	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))
9018	29765148	As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (67, 76))
9021	29765148	We show that, for most cancer types, de-sparsified mutation data associate with phenotypic data.	('de-sparsified mutation', 'Var', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
9022	29765148	We identify poor prognostic subtypes in three cancer types, which are associated with mutations in signal transduction pathways for which targeted treatment options are available.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('signal transduction pathways', 'Pathway', (99, 127))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
9023	29765148	Finally, we perform a pan-cancer subtyping analysis and identify nine pan-cancer subtypes, which associate with mutations in four overarching sets of biological pathways.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
9030	29765148	Since the onset of large-scale genomic experiments, cancer subtypes have been identified in multiple cancers, using mRNA and microRNA expression levels, methylation data, copy number alterations and combinations of different 'omics data types, but few studies have subtyped patients based on somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('multiple cancers', 'Disease', 'MESH:D009369', (92, 108))	('cancer', 'Disease', (101, 107))	('patients', 'Species', '9606', (274, 282))	('copy', 'Var', (171, 175))	('multiple cancers', 'Disease', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
9033	29765148	However, subtype classification using somatic mutations in cancer is challenging, mainly because the data are very sparse: many tumours only have a handful of mutations in coding regions yet the total number of mutations within a population is typically substantial.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('mutations', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
9034	29765148	Often, frequent cancer drivers:such as TP53:are mutated, as well as so-called "passenger" events that are considered mutational noise yet which may still influence tumour properties.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('mutated', 'Var', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('influence', 'Reg', (154, 163))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', (39, 43))
9044	29765148	While these studies have improved our understanding of the genes and pathways that are recurrently mutated in cancer, data are now available for many more samples and cancer types, increasing the power to detect new mutational patterns and cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('increasing', 'PosReg', (181, 191))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (240, 246))	('mutational', 'Var', (216, 226))
9065	29765148	For each cancer type, we clustered the pathway mutation scores using hierarchical clustering with binomial distance.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutation', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
9080	29765148	We divided the cell lines into two groups: those that had mutations in all 94 "Set 1" pathways (n = 156), and those that did not (n = 845), and performed a t-test to identify significant differences in response to drugs targeting phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/MTOR) signalling (Benjamini-Hochberg adjusted p-values <0.05).	('mutations', 'Var', (58, 67))	('MTOR', 'Gene', '2475', (292, 296))	('Set 1"', 'Gene', '9739', (79, 85))	('Set 1"', 'Gene', (79, 85))	('mammalian', 'Species', '9606', (256, 265))	('MTOR', 'Gene', (292, 296))
9082	29765148	We repeated this analysis on cell lines that had mutations in all 38 "Set 2" pathways (n = 681) and those that did not (n = 320) and drugs targeting DNA replication.	('Set 2"', 'Gene', (70, 76))	('Set 2"', 'Gene', '29072', (70, 76))	('mutations', 'Var', (49, 58))
9083	29765148	We note that we identified a relatively high number of cell lines with mutations in all "Set 2" pathways compared to the number we identified in primary tumours.	('Set 2"', 'Gene', (89, 95))	('primary tumours', 'Disease', 'MESH:D009369', (145, 160))	('Set 2"', 'Gene', '29072', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (71, 80))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('primary tumours', 'Disease', (145, 160))
9094	29765148	As expected, we observed a larger number of mutated pathways than of mutated cancer-associated genes across all samples (median = 103).	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutated', 'Var', (44, 51))
9098	29765148	These percentages were lower for mutations in cancer-associated genes, with an average of 54.8% of all cancer-associated genes being mutated in a cancer type (minimum of 6.1% for KICH, maximum of 95.1% for UCEC).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (46, 52))	('UCEC', 'Disease', (206, 210))	('mutated', 'Var', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
9109	29765148	Additionally, technical variability (batch number) appears to associate with pathway mutation scores in a number of cancers.	('associate', 'Reg', (62, 71))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('pathway', 'PosReg', (77, 84))	('mutation scores', 'Var', (85, 100))
9118	29765148	In addition to these known cancer-driver pathways, we identified mutations in neurotrophin signalling, which plays a role in neuron development and differentiation, in the poor prognosis subtype.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('neurotrophin signalling', 'Gene', (78, 101))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (65, 74))
9122	29765148	In addition to these pathways, DNA damage response pathways, which included p53 and ATM signalling, were mutated in the poor prognostic subtype of LAML.	('ATM', 'Gene', (84, 87))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('ATM', 'Gene', '472', (84, 87))	('mutated', 'Var', (105, 112))	('DNA damage response pathways', 'Pathway', (31, 59))
9124	29765148	Tumours assigned to this subtype had higher mutation scores in multiple epidermal growth factor receptor (EGFR) family pathways, in cell-cell contact and cellular structure ("adherens junction", "gap junction"), the immune system ("cytokine-cytokine receptor interaction") and in brain tissue-associated pathways (including "gonadotropin-releasing hormone signalling").	('mutation', 'Var', (44, 52))	('higher', 'PosReg', (37, 43))	('epidermal growth factor receptor', 'Gene', (72, 104))	('EGFR', 'Gene', '1956', (106, 110))	('gonadotropin-releasing hormone', 'Gene', (325, 355))	('epidermal growth factor receptor', 'Gene', '1956', (72, 104))	('gonadotropin-releasing hormone', 'Gene', '2796', (325, 355))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('EGFR', 'Gene', (106, 110))
9125	29765148	Mutations in cell-cell contact genes could be important for metastasis, and immune cells are known to play a critical role into transforming low-grade glioma into glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('Mutations', 'Var', (0, 9))	('glioblastoma', 'Disease', (163, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))	('glioma', 'Disease', (151, 157))
9127	29765148	However, while this gene was mutated in 15/17 patients, other genes belonging to EGFR family pathways, including EGF, GNAS and PTRB, were also mutated in tumours belonging to this subtype and might not have been detected if we had focussed on EGFR alone.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('patients', 'Species', '9606', (46, 54))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('PTRB', 'Gene', (127, 131))	('EGF', 'Gene', (113, 116))	('tumours belonging', 'Disease', 'MESH:D009369', (154, 171))	('EGFR', 'Gene', '1956', (81, 85))	('GNAS', 'Gene', '2778', (118, 122))	('mutated', 'Var', (143, 150))	('EGFR', 'Gene', '1956', (243, 247))	('tumours belonging', 'Disease', (154, 171))	('EGFR', 'Gene', (243, 247))	('GNAS', 'Gene', (118, 122))	('EGFR', 'Gene', (81, 85))
9129	29765148	For each of the significant cancer types, we performed 10,000 sample label permutations and found that the original log-rank tests were more significant than those on the permuted null background (Benjamini-Hochberg adjusted p-values p < 0.01), indicating that the poor prognostic subtypes were not identified by chance but were detected based on mutations in specific biological pathways (see Supplemental Fig.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (347, 356))
9136	29765148	This was not unexpected, as we found specific mutations in p53 pathways in this subtype.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutations', 'Var', (46, 55))
9143	29765148	In total, the subtypes that were enriched for mutations in drug targets from CMap account for 12% (689/5805) of all primary tumours from TCGA.	('mutations', 'Var', (46, 55))	('primary tumours', 'Disease', 'MESH:D009369', (116, 131))	('primary tumours', 'Disease', (116, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('CMap', 'Gene', (77, 81))
9159	29765148	All of the subtypes, except S5, which had no subtype-specific pathway mutations, had frequent mutations in Kyoto Encyclopedia of Genes and Genomes "pathways in cancer".	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', (160, 166))	('Kyoto Encyclopedia of Genes', 'Gene', (107, 134))	('Genomes "pathways', 'Pathway', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
9161	29765148	Using hierarchical clustering (binomial distance) on average mutation scores in these 202 pathways, we identified four overarching "sets" of pathways that were differentially mutated in the pan-cancer subtypes (see Fig.	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutation', 'Var', (61, 69))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
9167	29765148	Most of the sets are either mutated alone (such as Set 2 in pan-cancer subtypes S4 and S6) or in combination with other sets (for example, Sets 2-4 in pan-cancer subtype S8).	('mutated', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Set 2', 'Gene', (51, 56))	('Set 2', 'Gene', '29072', (51, 56))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
9174	29765148	We identified significantly higher protein activation scores in tumours from patients belonging to the subtypes that had higher levels of mutations in these pathways.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('protein activation scores', 'MPA', (35, 60))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('higher', 'PosReg', (28, 34))	('patients', 'Species', '9606', (77, 85))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (138, 147))
9176	29765148	This indicates that the pan-cancer subtypes we had identified based on pathway mutation scores also corresponded to higher protein levels in these pathways.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('higher', 'PosReg', (116, 122))	('mutation scores', 'Var', (79, 94))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('protein levels', 'MPA', (123, 137))
9177	29765148	Second, we wanted to determine whether cell lines with mutations in the overarching sets of pathways we had identified in the pan-cancer subtypes were more sensitive to drugs targeting those pathways.	('sensitive', 'MPA', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
9178	29765148	We identified which cell lines had mutations in all "Set 1" pathways and compared how these cells responded to PI3K/MTOR inhibitors compared to other cell lines (Methods).	('MTOR', 'Gene', (116, 120))	('Set 1"', 'Gene', '9739', (53, 59))	('Set 1"', 'Gene', (53, 59))	('MTOR', 'Gene', '2475', (116, 120))	('mutations', 'Var', (35, 44))
9181	29765148	We repeated this analysis for cell lines with mutations in all "Set 2" pathways and compared how these cell lines responded to drugs interfering with DNA replication.	('Set 2"', 'Gene', '29072', (64, 70))	('Set 2"', 'Gene', (64, 70))	('mutations', 'Var', (46, 55))
9187	29765148	We showed that SAMBAR helps identifying mutational patterns associated with clinical phenotypes and prognosis and potential targeted treatment options for cancer-specific subtypes, as well as mutational patterns that are manifested across multiple cancer types.	('cancer', 'Disease', (248, 254))	('SAMBAR', 'Species', '662561', (15, 21))	('multiple cancer', 'Disease', (239, 254))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('multiple cancer', 'Disease', 'MESH:D009369', (239, 254))	('mutational', 'Var', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', (155, 161))	('associated', 'Reg', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
9190	29765148	For example, we identified MDM2 inhibitors as potential targets for treatment of the poor prognosis subtype in ACC by integrating subtype-specific mutations with a drug-targeting database.	('mutations', 'Var', (147, 156))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('ACC', 'Disease', (111, 114))	('MDM2', 'Gene', '4193', (27, 31))	('MDM2', 'Gene', (27, 31))
9194	29765148	By generating patient-specific "pathway mutation profiles", we may not only identify patients who could benefit from specific targeted therapeutics but we will also obtain a clearer picture of the cellular processes that are altered through mutation in a specific tumour.	('tumour', 'Disease', (264, 270))	('mutation', 'Var', (40, 48))	('patient', 'Species', '9606', (85, 92))	('patients', 'Species', '9606', (85, 93))	('patient', 'Species', '9606', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('mutation', 'Var', (241, 249))
9199	29765148	In addition, one of the pan-cancer mutational patterns we identified was enriched for several growth factor pathways, including EGF receptor family genes, and FGFR and nerve growth factor signalling.	('mutational', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('growth factor pathways', 'Pathway', (94, 116))	('EGF receptor family genes', 'Gene', (128, 153))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FGFR', 'Gene', (159, 163))	('cancer', 'Disease', (28, 34))	('nerve growth factor signalling', 'Pathway', (168, 198))
9200	29765148	Because these pathways are mutated in a large set of the primary tumours we analysed, we believe that these treatment options are worthy of further investigation and may lead to better treatment options for a large numbers of patients.	('mutated', 'Var', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('patients', 'Species', '9606', (226, 234))	('primary tumours', 'Disease', 'MESH:D009369', (57, 72))	('primary tumours', 'Disease', (57, 72))
9202	29765148	Our framework to classify cancers based on mutational patterns in biological pathways could help expand precision medicine applications both by identifying groups of patients who may or may not respond to particular therapies and by identifying pathways that might be useful targets for therapeutic intervention.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('mutational', 'Var', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('patients', 'Species', '9606', (166, 174))
9227	26948360	In one study of 222 patients with meningiomas, seizures were the presenting symptoms in 26% of cases, were more frequently seen with convexity-based lesion than with tumors in other regions, and were common with lesions associated with marked peritumoral edema.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('edema', 'Disease', (255, 260))	('meningioma', 'Phenotype', 'HP:0002858', (34, 44))	('convexity-based', 'Var', (133, 148))	('meningiomas', 'Disease', 'MESH:D008577', (34, 45))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('meningiomas', 'Phenotype', 'HP:0002858', (34, 45))	('patients', 'Species', '9606', (20, 28))	('meningiomas', 'Disease', (34, 45))	('tumors', 'Disease', (166, 172))	('tumor', 'Disease', (247, 252))	('seizures', 'Disease', (47, 55))	('tumor', 'Disease', (166, 171))	('seizure', 'Phenotype', 'HP:0001250', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('seizures', 'Disease', 'MESH:D012640', (47, 55))	('edema', 'Phenotype', 'HP:0000969', (255, 260))	('seizures', 'Phenotype', 'HP:0001250', (47, 55))	('edema', 'Disease', 'MESH:D004487', (255, 260))
9240	26948360	Mutation of the isocitrate dehydrogenase 1 (IDH1) enzyme, which takes part in the Krebs cycle, causes conversion of isocitrate into 2-hydroxyglutarate.	('isocitrate into 2-hydroxyglutarate', 'MPA', (116, 150))	('causes', 'Reg', (95, 101))	('isocitrate dehydrogenase 1', 'Gene', (16, 42))	('Krebs', 'Chemical', '-', (82, 87))	('isocitrate dehydrogenase 1', 'Gene', '3417', (16, 42))	('IDH1', 'Gene', (44, 48))	('Mutation', 'Var', (0, 8))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (132, 150))	('IDH1', 'Gene', '3417', (44, 48))	('conversion', 'MPA', (102, 112))	('isocitrate', 'Chemical', 'MESH:C034219', (16, 26))	('isocitrate', 'Chemical', 'MESH:C034219', (116, 126))
9242	26948360	In low-grade gliomas, the presence of IDH1 mutations shows a strong association with seizures as initial clinical symptom, frontal-lobe tumor location, and longer survival.	('IDH1', 'Gene', '3417', (38, 42))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('frontal-lobe tumor', 'Disease', 'MESH:D001932', (123, 141))	('seizures', 'Disease', 'MESH:D012640', (85, 93))	('seizures', 'Disease', (85, 93))	('seizure', 'Phenotype', 'HP:0001250', (85, 92))	('seizures', 'Phenotype', 'HP:0001250', (85, 93))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('IDH1', 'Gene', (38, 42))	('gliomas', 'Disease', (13, 20))	('frontal-lobe tumor', 'Disease', (123, 141))	('presence', 'Var', (26, 34))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
9245	26948360	Disturbances in chloride balance may play a role as well, secondary to changes in chloride co-transporters, suggesting accompanying changes in GABA metabolism and chloride transport.	('changes', 'Reg', (132, 139))	('changes', 'Reg', (71, 78))	('chloride', 'Chemical', 'MESH:D002712', (163, 171))	('GABA', 'Chemical', 'MESH:D005680', (143, 147))	('Disturbances', 'Var', (0, 12))	('chloride co-transporters', 'MPA', (82, 106))	('chloride transport', 'MPA', (163, 181))	('chloride', 'Chemical', 'MESH:D002712', (82, 90))	('chloride', 'Chemical', 'MESH:D002712', (16, 24))	('GABA metabolism', 'MPA', (143, 158))	('chloride balance', 'MPA', (16, 32))
9266	26948360	Seizure freedom was observed in 96% of patients with gross total lesionectomy, but in only 54% of those with subtotal resection.	('gross total lesionectomy', 'Var', (53, 77))	('patients', 'Species', '9606', (39, 47))	('Seizure', 'Disease', 'MESH:D012640', (0, 7))	('Seizure', 'Disease', (0, 7))	('Seizure', 'Phenotype', 'HP:0001250', (0, 7))
9267	26948360	While tumor progression was noted in 38% of cases involving subtotal resection, this occurred in only 8% of patients who received gross total resection.	('subtotal resection', 'Var', (60, 78))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
9269	26948360	As with gangliogliomas, seizure freedom was significantly more common with gross total resection, which was achieved in about 80% of surgeries, and seizure freedom remained resilient at a median follow-up of more than 5 years.	('gangliogliomas', 'Disease', (8, 22))	('seizure', 'Phenotype', 'HP:0001250', (148, 155))	('gangliogliomas', 'Disease', 'MESH:D018303', (8, 22))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('seizure', 'Disease', (24, 31))	('seizure', 'Disease', (148, 155))	('seizure', 'Disease', 'MESH:D012640', (24, 31))	('seizure', 'Disease', 'MESH:D012640', (148, 155))	('gross total', 'Var', (75, 86))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('seizure', 'Phenotype', 'HP:0001250', (24, 31))
9271	26948360	In this study, seizure freedom was approximately 30% more likely with gross total resection than after subtotal excision, and was predicted by early surgical therapy and an absence of generalized seizures.	('seizure', 'Disease', (196, 203))	('seizure', 'Phenotype', 'HP:0001250', (15, 22))	('seizure', 'Disease', 'MESH:D012640', (196, 203))	('seizures', 'Phenotype', 'HP:0001250', (196, 204))	('seizures', 'Disease', (196, 204))	('gross total', 'Var', (70, 81))	('seizure', 'Phenotype', 'HP:0001250', (196, 203))	('generalized seizure', 'Phenotype', 'HP:0002197', (184, 203))	('seizure', 'Disease', (15, 22))	('generalized seizures', 'Phenotype', 'HP:0002197', (184, 204))	('seizure', 'Disease', 'MESH:D012640', (15, 22))	('seizures', 'Disease', 'MESH:D012640', (196, 204))
9279	26948360	Therefore, similar to glioneuronal tumors, gross total resection and early surgery are associated with improved seizure outcomes in epilepsy caused by low-grade gliomas, with other positive predictors described in the literature, including localized electroencephalogram and less severe seizure profile .	('epilepsy', 'Phenotype', 'HP:0001250', (132, 140))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (22, 40))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (22, 41))	('epilepsy', 'Disease', (132, 140))	('glioneuronal tumors', 'Disease', (22, 41))	('seizure', 'Disease', 'MESH:D012640', (287, 294))	('seizure', 'Disease', 'MESH:D012640', (112, 119))	('seizure', 'Phenotype', 'HP:0001250', (287, 294))	('improved', 'PosReg', (103, 111))	('seizure', 'Phenotype', 'HP:0001250', (112, 119))	('gliomas', 'Disease', (161, 168))	('seizure', 'Disease', (112, 119))	('seizure', 'Disease', (287, 294))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('low-grade', 'Var', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('epilepsy', 'Disease', 'MESH:D004827', (132, 140))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (22, 41))
9324	26948360	Across all tumor pathologies and patient populations, the most consistent finding in surgical studies of brain tumor-related epilepsy is that gross total resection is associated with dramatically improved seizure outcomes compared to subtotal resection.	('brain tumor', 'Disease', 'MESH:D001932', (105, 116))	('brain tumor', 'Disease', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('patient', 'Species', '9606', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('seizure', 'Phenotype', 'HP:0001250', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (11, 16))	('epilepsy', 'Disease', 'MESH:D004827', (125, 133))	('brain tumor', 'Phenotype', 'HP:0030692', (105, 116))	('epilepsy', 'Phenotype', 'HP:0001250', (125, 133))	('tumor', 'Disease', (111, 116))	('gross total resection', 'Var', (142, 163))	('seizure', 'Disease', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('seizure', 'Disease', 'MESH:D012640', (205, 212))	('epilepsy', 'Disease', (125, 133))	('improved', 'PosReg', (196, 204))
9375	26948360	Carbamazepine-induced Stevens-Johnson syndrome occurs in almost all patients carrying the human leukocyte antigen (HLA) 1 allele B*1502 with a prevalence of 8.6% of the population at large.	('Stevens-Johnson syndrome', 'Disease', 'MESH:D013262', (22, 46))	('patients', 'Species', '9606', (68, 76))	('human', 'Species', '9606', (90, 95))	('Stevens-Johnson syndrome', 'Disease', (22, 46))	('B*1502', 'Var', (129, 135))	('Carbamazepine', 'Chemical', 'MESH:D002220', (0, 13))
9376	26948360	Presence of the HLA-A*3101 allele increases the risk of developing carbamazepine-induced hypersensitivity from 5% to 26%.	('HLA-A', 'Gene', '3105', (16, 21))	('HLA-A', 'Gene', (16, 21))	('hypersensitivity', 'Disease', 'MESH:D004342', (89, 105))	('carbamazepine', 'Chemical', 'MESH:D002220', (67, 80))	('Presence', 'Var', (0, 8))	('hypersensitivity', 'Disease', (89, 105))
9377	26948360	Lacosamide undergoes moderate hepatic metabolism through 2C19, 40% is excreted unchanged in urine, and it does not invoke drug interactions.	('Lacosamide', 'Chemical', 'MESH:D000078334', (0, 10))	('2C19', 'Var', (57, 61))	('hepatic metabolism', 'MPA', (30, 48))
9393	26948360	In a prospective study, switching from phenytoin to levetiracetam monotherapy during the perioperative period, ataxia was seen in more than half of the phenytoin group, though not in patients on levetiracetam.	('levetiracetam', 'Chemical', 'MESH:D000077287', (195, 208))	('phenytoin', 'Chemical', 'MESH:D010672', (39, 48))	('levetiracetam', 'Chemical', 'MESH:D000077287', (52, 65))	('ataxia', 'Phenotype', 'HP:0001251', (111, 117))	('phenytoin', 'Chemical', 'MESH:D010672', (152, 161))	('ataxia', 'Disease', 'MESH:D001259', (111, 117))	('phenytoin', 'Var', (152, 161))	('ataxia', 'Disease', (111, 117))	('patients', 'Species', '9606', (183, 191))
9433	22331519	Evidence accumulates that loss of optimal neural network architecture negatively impacts complex cerebral functioning and also decreases the threshold to develop epileptic seizures.	('decreases', 'NegReg', (127, 136))	('negatively', 'NegReg', (70, 80))	('epileptic seizures', 'Disease', (162, 180))	('impacts', 'Reg', (81, 88))	('seizure', 'Phenotype', 'HP:0001250', (172, 179))	('epileptic seizures', 'Disease', 'MESH:D004827', (162, 180))	('loss', 'Var', (26, 30))	('seizures', 'Phenotype', 'HP:0001250', (172, 180))	('complex cerebral functioning', 'MPA', (89, 117))
9518	21844184	Loss of cdk4 blocked tumor development, but loss of cyclin D1 did not prevent gliomas from developing.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('cdk4', 'Gene', (8, 12))	('blocked', 'NegReg', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('cdk4', 'Gene', '12567', (8, 12))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
9519	21844184	Instead, loss of cyclin D1 impeded progression to higher stages of malignancy.	('cyclin D1', 'Protein', (17, 26))	('loss', 'Var', (9, 13))	('malignancy', 'Disease', 'MESH:D009369', (67, 77))	('impeded', 'NegReg', (27, 34))	('malignancy', 'Disease', (67, 77))
9521	21844184	In contrast, restoration of cdk4 in the cdk4 deficient animals restored cell proliferation and tumor formation, although at lower tumor grades.	('cdk4', 'Gene', (28, 32))	('restored', 'PosReg', (63, 71))	('cdk4', 'Gene', '12567', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cell proliferation', 'CPA', (72, 90))	('lower', 'NegReg', (124, 129))	('deficient', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cdk4', 'Gene', (40, 44))	('cdk4', 'Gene', '12567', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (95, 100))
9522	21844184	Notably, the failure of tumors in the cyclin D1 and cdk4 deficient animals to progress to higher grades was correlated with a failure to fully activate microglia in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('deficient', 'Var', (57, 66))	('cyclin D1', 'Protein', (38, 47))	('tumors', 'Disease', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('cdk4', 'Gene', (52, 56))	('microglia', 'CPA', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cdk4', 'Gene', '12567', (52, 56))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
9536	21844184	We show that deletion of cdk4 abolishes glioma-associated morbidity and tumor formation, whereas ablation of cyclin D1 impedes tumor progression to higher grades.	('cdk4', 'Gene', (25, 29))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('impedes', 'NegReg', (119, 126))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (72, 77))	('cdk4', 'Gene', '12567', (25, 29))	('abolishes', 'NegReg', (30, 39))	('deletion', 'Var', (13, 21))	('glioma', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
9539	21844184	Histological examination pointed to a defect in the activation of tumor associated microglia (TAMs) in both cyclin D1 and cdk4 deficient mice as well as when tumor cells were transplanted into cyclin D1 knockout mice.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cdk4', 'Gene', (122, 126))	('tumor', 'Disease', (158, 163))	('mice', 'Species', '10090', (212, 216))	('cyclin', 'Gene', (108, 114))	('cdk4', 'Gene', '12567', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (66, 71))	('deficient', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('TAMs', 'Chemical', '-', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('mice', 'Species', '10090', (137, 141))	('activation', 'PosReg', (52, 62))
9555	21844184	The absence of cyclin D1 reduced the onset of glioma-associated morbidity in a dose-dependent manner (Fig.	('reduced', 'NegReg', (25, 32))	('glioma', 'Disease', (46, 52))	('cyclin D1', 'Protein', (15, 24))	('absence', 'Var', (4, 11))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
9562	21844184	The difference in proliferation remained apparent even when comparing the low-grade gliomas arising in cyclin D1 knockout animals to the few low-grade gliomas observed in wild-type animals (data not shown).	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Disease', (84, 91))	('knockout', 'Var', (113, 121))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('cyclin D1', 'Gene', (103, 112))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
9565	21844184	To assess if cdk4 contributes to glioma formation, we challenged nestin-tvA wild type and cdk4 knockout animals with RCAS-PDGF and monitored them for symptoms of glial tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('cdk4', 'Gene', '12567', (13, 17))	('glioma', 'Disease', (33, 39))	('knockout', 'Var', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('cdk4', 'Gene', (90, 94))	('cdk4', 'Gene', (13, 17))	('RCAS', 'Chemical', '-', (117, 121))	('glial tumors', 'Disease', 'MESH:D005910', (162, 174))	('cdk4', 'Gene', '12567', (90, 94))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glial tumors', 'Disease', (162, 174))
9566	21844184	Strikingly, removal of cdk4 abolished glioma-associated morbidity (Fig.	('cdk4', 'Gene', '12567', (23, 27))	('abolished', 'NegReg', (28, 37))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('removal', 'Var', (12, 19))	('glioma', 'Disease', (38, 44))	('cdk4', 'Gene', (23, 27))
9583	21844184	One of the mechanisms by which cyclin D1-cdk4 facilitates proliferation is through sequestration of the cell-cycle inhibitor, p27.	('proliferation', 'CPA', (58, 71))	('cdk4', 'Gene', (41, 45))	('sequestration', 'MPA', (83, 96))	('cdk4', 'Gene', '12567', (41, 45))	('p27', 'Gene', (126, 129))	('p27', 'Gene', '12576', (126, 129))	('facilitates', 'PosReg', (46, 57))	('cyclin', 'Var', (31, 37))
9584	21844184	Thus, we asked whether removal of p27 in cdk4 knockout mice would similarly re-establish PDGF-driven gliomagenesis.	('cdk4', 'Gene', (41, 45))	('cdk4', 'Gene', '12567', (41, 45))	('p27', 'Gene', (34, 37))	('glioma', 'Disease', (101, 107))	('mice', 'Species', '10090', (55, 59))	('p27', 'Gene', '12576', (34, 37))	('removal', 'Var', (23, 30))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
9585	21844184	Whereas p27 deficiency enhanced glioma formation and associated morbidity in this model, ablation of one or both alleles of p27 in a cdk4 knockout background does not restore gliomagenesis, and no readily identifiable tumors were found in any mouse in this cohort (data not shown).	('p27', 'Gene', '12576', (8, 11))	('p27', 'Gene', (124, 127))	('glioma', 'Disease', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('deficiency', 'Var', (12, 22))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('enhanced', 'PosReg', (23, 31))	('glioma', 'Disease', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('tumors', 'Disease', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('mouse', 'Species', '10090', (243, 248))	('p27', 'Gene', '12576', (124, 127))	('p27', 'Gene', (8, 11))	('cdk4', 'Gene', (133, 137))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('cdk4', 'Gene', '12567', (133, 137))
9588	21844184	However, deletion of cdk2 did not profoundly affect morbidity, glial tumor formation or grade (Supplemental Fig.	('cdk2', 'Gene', '12566', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glial tumor', 'Disease', (63, 74))	('deletion', 'Var', (9, 17))	('glial tumor', 'Disease', 'MESH:D005910', (63, 74))	('cdk2', 'Gene', (21, 25))
9591	21844184	For these experiments, we made use of a nuclear-stabilized and activated mutant of cyclin D1, D1T286A, in which mutation of threonine 286 to alanine prevents its phosphorylation and nuclear export by GSK3beta.	('prevents', 'NegReg', (149, 157))	('nuclear export', 'MPA', (182, 196))	('threonine 286', 'Var', (124, 137))	('mutation', 'Var', (112, 120))	('GSK3beta', 'Gene', (200, 208))	('phosphorylation', 'MPA', (162, 177))	('GSK3beta', 'Gene', '56637', (200, 208))	('threonine 286 to alanine', 'Mutation', 'p.T286A', (124, 148))
9603	21844184	Collectively, this further enforces the notion that tumor cell specific expression of either cyclin D1 or cdk4 was insufficient to correct the defects in morbidity and malignancy in the respective knockout animals, leading us to consider the possibility that the absence of these genes might perturb some aspect of the microenvironment in which glioma arise.	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('glioma', 'Disease', (345, 351))	('cdk4', 'Gene', '12567', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('malignancy', 'Disease', (168, 178))	('perturb', 'Reg', (292, 299))	('tumor', 'Disease', (52, 57))	('absence', 'Var', (263, 270))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('glioma', 'Disease', 'MESH:D005910', (345, 351))	('glioma', 'Phenotype', 'HP:0009733', (345, 351))	('insufficient', 'Disease', 'MESH:D000309', (115, 127))	('cdk4', 'Gene', (106, 110))	('insufficient', 'Disease', (115, 127))
9604	21844184	The development of cancer relies on the dynamic interplay between the mutant tumor cell and other normal cells in the microenvironment.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mutant', 'Var', (70, 76))	('cancer', 'Disease', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', (77, 82))
9605	21844184	Since glial cell-specific expression of either cyclin D1 or cdk4 was insufficient to correct the defects in morbidity and malignancy in the respective knockout animals, it was possible that the absence of these genes affected recruitment or activation of another cell type in the tumor microenvironment.	('malignancy', 'Disease', (122, 132))	('absence', 'Var', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('insufficient', 'Disease', (69, 81))	('affected', 'Reg', (217, 225))	('insufficient', 'Disease', 'MESH:D000309', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('cdk4', 'Gene', (60, 64))	('tumor', 'Disease', (280, 285))	('malignancy', 'Disease', 'MESH:D009369', (122, 132))	('cdk4', 'Gene', '12567', (60, 64))
9607	21844184	Angio- and vasculogenesis are critical determinants for the transition of tumors, including glioma, to higher grade, and the loss of cell-cycle regulators in endothelial cells and stem cell progenitors will impair tumor neoangiogenesis and haematopoietic cell proliferation.	('haematopoietic cell proliferation', 'CPA', (240, 273))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('loss', 'Var', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('glioma', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (214, 219))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('impair', 'NegReg', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
9609	21844184	4C), indicating that the absence of cyclin D1 did not prevent the establishment of a coherent tumor vasculature.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('absence', 'Var', (25, 32))	('tumor', 'Disease', (94, 99))
9612	21844184	However, whereas the number and intensity of the GFAP- and NeuN- positive cells in tumors was comparable between wild type and mutant mice, the morphology and intensity of the Iba1 stained cells was very different.	('mutant', 'Var', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mice', 'Species', '10090', (134, 138))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('GFAP', 'Gene', '14580', (49, 53))	('GFAP', 'Gene', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
9616	21844184	The intensity of each of these markers was reduced in the tumors arising in cyclin D1 knockout mice compared to that seen in wild type mice (Fig.	('knockout', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mice', 'Species', '10090', (95, 99))	('cyclin D1', 'Gene', (76, 85))	('tumors', 'Disease', (58, 64))	('intensity', 'MPA', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mice', 'Species', '10090', (135, 139))	('reduced', 'NegReg', (43, 50))
9631	21844184	Whereas cdk4 knockout mice were completely refractory to glioma, tumors formed in cyclin D1 knockout animals.	('knockout', 'Var', (92, 100))	('glioma', 'Disease', (57, 63))	('cyclin D1', 'Gene', (82, 91))	('tumors', 'Disease', (65, 71))	('cdk4', 'Gene', (8, 12))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cdk4', 'Gene', '12567', (8, 12))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('mice', 'Species', '10090', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
9633	21844184	Likewise, the stroma of cyclin D1 deficient mice was unable to support progression of transplanted tumor cells.	('tumor', 'Disease', (99, 104))	('deficient', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('unable', 'NegReg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mice', 'Species', '10090', (44, 48))
9636	21844184	The traditional view of cancer as an autonomously growing aggregation of mutant cells has been superseded by one in which the tumor acts more insidiously, actively subverting the surrounding tissue to support its growth and proliferation.	('subverting', 'NegReg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('mutant', 'Var', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('growth', 'CPA', (213, 219))	('tumor', 'Disease', (126, 131))
9646	21844184	Furthermore, other markers of TAM activation, including cathepsin X, H and S and CSF1R expression were reduced in knockout tumors relative to wild-type gliomas.	('cathepsin X', 'Gene', (56, 67))	('CSF1R', 'Gene', '12978', (81, 86))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('reduced', 'NegReg', (103, 110))	('CSF1R', 'Gene', (81, 86))	('TAM', 'Chemical', 'MESH:D013629', (30, 33))	('expression', 'MPA', (87, 97))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('cathepsin X', 'Gene', '64138', (56, 67))	('knockout', 'Var', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
9650	21844184	Toogood, Chin, and Waldman independently demosntrated that the cdk4 inhibitor drug, PD0332991, currently in phase II clinical trials, may be effective in halting the progression of glioma cell lines and xenografts.	('cdk4', 'Gene', (63, 67))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('PD0332991', 'Chemical', 'MESH:C500026', (84, 93))	('cdk4', 'Gene', '12567', (63, 67))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('halting', 'NegReg', (154, 161))	('PD0332991', 'Var', (84, 93))	('glioma', 'Disease', (181, 187))	('progression', 'CPA', (166, 177))
9651	21844184	We are in the process of addressing whether PD0332991 can inhibit disease progression or reduce tumor burden in mice that have developed oligodendroglioma in situ and whether this is due to effects in the tumor cell, the microglia, or both.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (96, 101))	('disease progression', 'CPA', (66, 85))	('reduce', 'NegReg', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('inhibit', 'NegReg', (58, 65))	('PD0332991', 'Chemical', 'MESH:C500026', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('oligodendroglioma', 'Disease', (137, 154))	('oligodendroglioma', 'Disease', 'MESH:D009837', (137, 154))	('PD0332991', 'Var', (44, 53))	('mice', 'Species', '10090', (112, 116))
9652	21844184	Current therapeutic strategies typically focus on direct inhibition of glial tumor proliferation and growth, even though compromising macrophage activity can also enhance chemotherapeutic efficiencies in other systems (reviewed in Nature 272: 303-4, 2011).	('glial tumor', 'Disease', 'MESH:D005910', (71, 82))	('macrophage activity', 'CPA', (134, 153))	('compromising', 'Var', (121, 133))	('inhibition', 'NegReg', (57, 67))	('glial tumor', 'Disease', (71, 82))	('enhance', 'PosReg', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('growth', 'CPA', (101, 107))
9658	33576304	More intriguingly, CD155 expression had a significant interaction with immune function in several tumors by analyzing Tumor mutational burden and microsatellite in stability, immune score and stromal score.	('tumors', 'Disease', (98, 104))	('CD155', 'Gene', '5817', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('microsatellite', 'Var', (146, 160))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('CD155', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Tumor', 'Phenotype', 'HP:0002664', (118, 123))	('interaction', 'Reg', (54, 65))
9720	33576304	There is also evidence that CD155/CD226 interaction can attenuate the generation of CD8+ T cells by regulating NK T-cell differentiation.	('CD8', 'Gene', '925', (84, 87))	('attenuate', 'NegReg', (56, 65))	('CD226', 'Gene', '10666', (34, 39))	('CD155', 'Gene', '5817', (28, 33))	('interaction', 'Var', (40, 51))	('regulating', 'Reg', (100, 110))	('NK T-cell differentiation', 'CPA', (111, 136))	('CD155', 'Gene', (28, 33))	('CD8', 'Gene', (84, 87))	('CD226', 'Gene', (34, 39))
9731	33576304	ACC Adrenocortical carcinoma BLCA Bladder Urothelial Carcinoma BRCA Breast invasive carcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CHOL Cholangio carcinoma COAD Colon adenocarcinoma DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma ESCA Esophageal carcinoma GBM Glioblastoma multiforme HNSC Head and Neck squamous cell carcinoma KICH Kidney Chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LAML Acute Myeloid Leukemia LGG Brain Lower Grade Glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma TME tumor microenvironment OS overall survival DSS Disease-specific survival LUSC Lung squamous cell carcinoma MESO Mesothelioma OV Ovarian serous cystadenocarcinoma PAAD Pancreatic adenocarcinoma PCPG Pheochromocytoma and Paraganglioma PRAD Prostate adenocarcinoma READ Rectum adenocarcinoma SARC Sarcoma SKCM Skin Cutaneous Melanoma STAD Stomach adenocarcinoma TGCT Testicular Germ Cell Tumors THCA Thyroid carcinoma THYM Thymoma UCEC Uterine Corpus Endometrial Carcinoma UCS Uterine Carcinosarcoma UVM Uveal Melanoma TMB Tumor mutational burden MSI microsatellite in stability DFI Disease-free interval PFI Progression-free interval	('Tumor', 'Phenotype', 'HP:0002664', (978, 983))	('carcinoma', 'Disease', 'MESH:D009369', (179, 188))	('carcinoma', 'Disease', (845, 854))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (394, 427))	('Kidney renal papillary cell carcinoma', 'Disease', (433, 470))	('KICH', 'Disease', (365, 369))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (990, 1007))	('tumor', 'Phenotype', 'HP:0002664', (593, 598))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('Sarcoma', 'Disease', (887, 894))	('Kidney Chromophobe', 'Disease', (370, 388))	('serous cystadenocarcinoma', 'Disease', (729, 754))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (1034, 1062))	('Breast invasive carcinoma', 'Disease', 'MESH:D001943', (68, 93))	('Paraganglioma', 'Phenotype', 'HP:0002668', (812, 825))	('carcinoma', 'Disease', (998, 1007))	('carcinoma', 'Disease', (776, 785))	('carcinoma', 'Disease', (579, 588))	('CHOL', 'Disease', 'None', (164, 168))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (68, 93))	('Urothelial Carcinoma', 'Disease', (42, 62))	('carcinoma', 'Disease', (554, 563))	('Acute Myeloid Leukemia', 'Disease', (476, 498))	('Neck squamous cell carcinoma', 'Disease', (336, 364))	('Melanoma', 'Disease', 'MESH:D008545', (915, 923))	('carcinoma', 'Disease', 'MESH:D009369', (461, 470))	('Pheochromocytoma and Paraganglioma', 'Disease', 'MESH:D010673', (791, 825))	('Melanoma', 'Disease', (1100, 1108))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (760, 785))	('carcinoma', 'Disease', 'MESH:D009369', (284, 293))	('carcinoma', 'Disease', (179, 188))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (990, 1007))	('Cholangio carcinoma', 'Phenotype', 'HP:0030153', (169, 188))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (760, 785))	('Pancreatic adenocarcinoma', 'Disease', (760, 785))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (194, 214))	('Rectum adenocarcinoma', 'Disease', 'MESH:D012004', (860, 881))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (831, 854))	('CHOL', 'Disease', (164, 168))	('carcinoma', 'Disease', 'MESH:D009369', (872, 881))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', 'MESH:D009369', (418, 427))	('Melanoma', 'Phenotype', 'HP:0002861', (915, 923))	('Head and Neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (327, 364))	('squamous cell carcinoma', 'Disease', (108, 131))	('Cholangio carcinoma', 'Disease', (169, 188))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (671, 699))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Breast invasive carcinoma', 'Disease', (68, 93))	('Kidney Chromophobe', 'Disease', 'MESH:D000238', (370, 388))	('carcinoma', 'Disease', (461, 470))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (136, 163))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (569, 588))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (482, 498))	('carcinoma', 'Disease', (872, 881))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('Mesothelioma', 'Disease', (705, 717))	('Kidney renal clear cell carcinoma', 'Disease', (394, 427))	('Thymoma', 'Disease', (1013, 1020))	('Corpus Endometrial Carcinoma', 'Disease', (1034, 1062))	('ACC', 'Gene', '31', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (539, 563))	('Liver hepatocellular carcinoma', 'Disease', (533, 563))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (533, 563))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('Rectum adenocarcinoma', 'Disease', (860, 881))	('tumor', 'Disease', (593, 598))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (336, 364))	('carcinoma', 'Disease', (418, 427))	('KICH', 'Disease', 'None', (365, 369))	('TME', 'Chemical', '-', (589, 592))	('Stomach adenocarcinoma', 'Disease', (929, 951))	('DSS', 'Gene', '5376', (636, 639))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('tumor', 'Disease', 'MESH:D009369', (593, 598))	('clear cell carcinoma KIRP Kidney', 'Phenotype', 'HP:0006770', (407, 439))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('Prostate adenocarcinoma', 'Disease', (831, 854))	('Lymphoma', 'Phenotype', 'HP:0002665', (259, 267))	('Skin Cutaneous Melanoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D009369', (355, 364))	('carcinoma', 'Disease', 'MESH:D009369', (942, 951))	('serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (729, 754))	('carcinoma', 'Disease', 'MESH:D009369', (690, 699))	('Thymoma', 'Disease', 'MESH:D013945', (1013, 1020))	('Leukemia', 'Phenotype', 'HP:0001909', (490, 498))	('carcinoma', 'Disease', 'MESH:D009369', (745, 754))	('carcinoma', 'Disease', 'MESH:D009369', (84, 93))	('TMB', 'Chemical', '-', (1109, 1112))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (791, 807))	('Stomach adenocarcinoma', 'Disease', 'MESH:D000230', (929, 951))	('carcinoma', 'Disease', (19, 28))	('Carcinoma', 'Phenotype', 'HP:0030731', (1053, 1062))	('COAD', 'Disease', 'MESH:D029424', (189, 193))	('carcinoma', 'Disease', 'MESH:D009369', (19, 28))	('Glioma', 'Disease', (521, 527))	('MESO Mesothelioma', 'Phenotype', 'HP:0100001', (700, 717))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (341, 364))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (252, 267))	('Tumors', 'Disease', 'MESH:D009369', (978, 984))	('Cholangio carcinoma', 'Disease', 'MESH:D009369', (169, 188))	('carcinoma', 'Disease', 'MESH:D009369', (154, 163))	('Glioblastoma', 'Phenotype', 'HP:0012174', (298, 310))	('Melanoma', 'Disease', 'MESH:D008545', (1100, 1108))	('Lung squamous cell carcinoma', 'Disease', (671, 699))	('carcinoma', 'Disease', (284, 293))	('Ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (721, 754))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (476, 498))	('DSS', 'Gene', (636, 639))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (900, 923))	('carcinoma', 'Disease', (942, 951))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (1075, 1089))	('carcinoma', 'Disease', (745, 754))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (341, 364))	('Colon adenocarcinoma', 'Disease', (194, 214))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (1067, 1089))	('Neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (298, 321))	('carcinoma', 'Disease', 'MESH:D009369', (998, 1007))	('ACC', 'Gene', (0, 3))	('Tumors', 'Phenotype', 'HP:0002664', (978, 984))	('Thyroid carcinoma', 'Disease', (990, 1007))	('Melanoma', 'Phenotype', 'HP:0002861', (1100, 1108))	('Germ Cell Tumors', 'Phenotype', 'HP:0100728', (968, 984))	('carcinoma', 'Disease', 'MESH:D009369', (554, 563))	('THCA', 'Chemical', '-', (985, 989))	('endocervical adenocarcinoma', 'Disease', (136, 163))	('Melanoma', 'Disease', (915, 923))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', 'MESH:D016403', (220, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (676, 699))	('carcinoma', 'Disease', (154, 163))	('Glioma', 'Phenotype', 'HP:0009733', (521, 527))	('carcinoma', 'Disease', 'MESH:D009369', (205, 214))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (905, 923))	('BRCA', 'Gene', (63, 67))	('Tumors', 'Disease', (978, 984))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (1041, 1062))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (273, 293))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (676, 699))	('Thymoma', 'Phenotype', 'HP:0100522', (1013, 1020))	('carcinoma', 'Disease', 'MESH:D009369', (122, 131))	('Sarcoma', 'Phenotype', 'HP:0100242', (887, 894))	('Glioblastoma multiforme', 'Disease', (298, 321))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (569, 588))	('mutational', 'Var', (1119, 1129))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (433, 470))	('carcinoma', 'Disease', 'MESH:D009369', (845, 854))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (42, 62))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (1094, 1108))	('Mesothelioma', 'Disease', 'MESH:D008654', (705, 717))	('COAD', 'Disease', (189, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', (355, 364))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (476, 498))	('carcinoma', 'Disease', (690, 699))	('carcinoma', 'Disease', (205, 214))	('carcinoma', 'Disease', (84, 93))	('Glioma', 'Disease', 'MESH:D005910', (521, 527))	('UCEC Uterine Corpus', 'Phenotype', 'HP:0000139', (1021, 1040))	('BRCA', 'Gene', '672', (63, 67))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (671, 699))	('Tumor', 'Phenotype', 'HP:0002664', (1113, 1118))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', (220, 267))	('carcinoma', 'Disease', 'MESH:D009369', (776, 785))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (440, 470))	('carcinoma', 'Disease', 'MESH:D009369', (579, 588))	('Lung adenocarcinoma', 'Disease', (569, 588))	('Carcinosarcoma', 'Disease', (1075, 1089))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma', 'Disease', (122, 131))	('Sarcoma', 'Disease', 'MESH:D012509', (887, 894))
9775	30066053	Correlation for VT in the tumour regions as derived from 2T4kVb and 1T2kVb was very high (r = 0.99); however, agreement analysis showed a significant difference for estimated VT of 0.08 (9%), as shown in the Bland Altman plot in Additional file 1: Figure S2.	('1T2kVb', 'Var', (68, 74))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('VT', 'Disease', 'MESH:D017180', (16, 18))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('VT', 'Disease', 'MESH:D017180', (175, 177))
9777	30066053	There was no correlation between K1 values of [18F]FET and CBF in the tumour regions (r = - 0.018, p = 0.93), Additional file 1: Figure S4.	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('[18F]', 'Var', (46, 51))
9821	28600641	Predicting Deletion of Chromosomal Arms 1p/19q in Low-Grade Gliomas from MR Images Using Machine Intelligence Several studies have linked codeletion of chromosome arms 1p/19q in low-grade gliomas (LGG) with positive response to treatment and longer progression-free survival.	('arms 1p', 'Gene', '3075', (163, 170))	('Deletion', 'Var', (11, 19))	('Gliomas', 'Disease', 'MESH:D005910', (60, 67))	('arms 1p', 'Gene', (163, 170))	('Gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('Arms 1p', 'Gene', '3075', (35, 42))	('Gliomas', 'Disease', (60, 67))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('gliomas', 'Disease', (188, 195))	('Arms 1p', 'Gene', (35, 42))
9822	28600641	Our method consists of three main steps: image registration, tumor segmentation, and classification of 1p/19q status using CNN.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('1p/19q', 'Var', (103, 109))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
9824	28600641	Multi-scale CNN with their self-learning capability provides promising results for predicting 1p/19q status non-invasively based on T1C and T2 images.	('T1C', 'Mutation', 'c.1T>C', (132, 135))	('1p/19q status', 'Var', (94, 107))	('predicting', 'Reg', (83, 93))
9833	28600641	Several studies have shown that codeletion of 1p/19q chromosome arms is a strong prognostic molecular marker for positive tumor response to chemotherapy and radiotherapy in LGG and associated with longer survival.	('associated', 'Reg', (181, 191))	('longer', 'PosReg', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('LGG', 'Disease', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('codeletion', 'Var', (32, 42))	('1p/19q chromosome arms', 'Var', (46, 68))	('tumor', 'Disease', (122, 127))
9835	28600641	presented detection of 1p/19q status from [18F] fluoroethyltyrosine-PET (FET-PET) images.	('detection', 'Reg', (10, 19))	('fluoroethyltyrosine', 'Chemical', '-', (48, 67))	('1p/19q status', 'Var', (23, 36))
9837	28600641	studied detection of 1p/19q codeletion from 11C-methionine PET images and concluded that 11C-methionine PET might help discriminate tumors with and without 1p/19q codeletion preoperatively.	('1p/19q codeletion', 'Var', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('11C-methionine', 'Chemical', '-', (44, 58))	('11C-methionine', 'Chemical', '-', (89, 103))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
9842	28600641	One hundred fifty nine (n = 159) consecutive (01 October 2002-01 August 2011) pre-operative LGG patients, with stereotactic MRI images, who had biopsy proven 1p/19q status consisting either no deletion or co-deletion, were identified from our brain tumor patient database at Mayo Clinic for this study.	('deletion', 'Var', (193, 201))	('Mayo', 'Species', '162683', (275, 279))	('brain tumor', 'Disease', (243, 254))	('brain tumor', 'Disease', 'MESH:D001932', (243, 254))	('co-deletion', 'Var', (205, 216))	('patient', 'Species', '9606', (96, 103))	('patient', 'Species', '9606', (255, 262))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('brain tumor', 'Phenotype', 'HP:0030692', (243, 254))	('patients', 'Species', '9606', (96, 104))
9914	28197403	Considering glioma surgery as "brain networks surgery" has led not only to a dramatic decrease of permanent neurologic impairment (<2% in series using intraoperative cortico-subcortical mapping) but also to improvement of higher order functions such as working memory, neurocognitive functions, and emotions and behavior, as evidenced by postoperative neuropsychological assessments following surgery.	('neurologic impairment', 'Disease', 'MESH:D009422', (108, 129))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('behavior', 'CPA', (312, 320))	('glioma', 'Disease', (12, 18))	('improvement', 'PosReg', (207, 218))	('working memory', 'CPA', (253, 267))	('neurologic impairment', 'Disease', (108, 129))	('surgery', 'Var', (46, 53))	('higher order functions', 'MPA', (222, 244))	('decrease', 'NegReg', (86, 94))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('permanent neurologic impairment', 'Phenotype', 'HP:0002344', (98, 129))	('neurocognitive functions', 'CPA', (269, 293))
9928	25040262	Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low grade gliomas The majority of pediatric low grade gliomas (LGGs) are characterized by constitutive activation of the mitogen activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions.	('KIAA1549-BRAF', 'Disease', (343, 356))	('BRAF', 'Gene', '673', (352, 356))	('BRAF', 'Gene', (352, 356))	('deletions', 'Var', (21, 30))	('KIAA1549-BRAF', 'Disease', 'None', (44, 57))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('FAM131B', 'Gene', (361, 368))	('BRAF', 'Gene', '673', (302, 306))	('FAM131B', 'Gene', '9715', (361, 368))	('BRAF', 'Gene', (302, 306))	('activation', 'PosReg', (199, 209))	('KIAA1549-BRAF', 'Disease', 'None', (343, 356))	('BRAF', 'Gene', '673', (70, 74))	('gliomas', 'Disease', (106, 113))	('BRAF', 'Gene', (70, 74))	('mutations', 'Var', (307, 316))	('BRAF', 'Gene', '673', (53, 57))	('FAM131B', 'Gene', (62, 69))	('BRAF', 'Gene', (53, 57))	('gliomas', 'Disease', (150, 157))	('FAM131B', 'Gene', '9715', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('inactivation', 'Var', (318, 330))	('KIAA1549-BRAF', 'Disease', (44, 57))	('BRAF', 'Gene', '673', (369, 373))	('NF1', 'Gene', '4763', (334, 337))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('BRAF', 'Gene', (369, 373))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('NF1', 'Gene', (334, 337))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
9929	25040262	The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34.	('results from', 'Reg', (35, 47))	('KIAA1549-BRAF', 'Disease', 'None', (4, 17))	('tandem duplication', 'Var', (57, 75))	('KIAA1549-BRAF', 'Disease', (4, 17))
9930	25040262	In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion.	('resulted in', 'Reg', (130, 141))	('BRAF', 'Gene', '673', (144, 148))	('deletions', 'Var', (107, 116))	('7q34', 'Gene', (120, 124))	('BRAF', 'Gene', (144, 148))
9931	25040262	Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon15-9 KIAA1549-BRAF fusion.	('astrocytoma', 'Phenotype', 'HP:0009592', (30, 41))	('KIAA1549-BRAF', 'Disease', (95, 108))	('pilocytic astrocytoma', 'Disease', (20, 41))	('deletions', 'Var', (58, 67))	('7q33q34', 'Gene', (71, 78))	('KIAA1549-BRAF', 'Disease', 'None', (95, 108))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (20, 41))
9934	25040262	BRAF fusions can result from multiple non-overlapping deletions suggesting various complex mechanisms of formation.	('result from', 'Reg', (17, 28))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('deletions', 'Var', (54, 63))	('fusions', 'Disease', (5, 12))
9939	25040262	A recent whole genome sequencing (WGS) study of 96 PAs identified molecular alterations leading to MAPK activation in 100% of cases.	('alterations', 'Var', (76, 87))	('activation', 'PosReg', (104, 114))	('MAPK', 'Gene', (99, 103))	('PAs', 'Disease', (51, 54))	('PAs', 'Disease', 'MESH:D011471', (51, 54))
9941	25040262	To date, the most common mechanism of MAPK pathway activation in sporadic LGGs is a 2.0 Mb tandem duplication in 7q34 that results in production of a KIAA1549-BRAF fusion transcript.	('KIAA1549-BRAF', 'Disease', (150, 163))	('tandem duplication', 'Var', (91, 109))	('results in', 'Reg', (123, 133))	('KIAA1549-BRAF', 'Disease', 'None', (150, 163))	('7q34', 'Gene', (113, 117))	('LGGs', 'Disease', (74, 78))	('activation', 'PosReg', (51, 61))	('MAPK pathway', 'Pathway', (38, 50))
9944	25040262	Fusion of BRAF to another gene, FAM131B has also been identified in at least five tumors to date, including four PAs and one DA.	('Fusion', 'Var', (0, 6))	('PAs', 'Disease', (113, 116))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('PAs', 'Disease', 'MESH:D011471', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BRAF', 'Gene', (10, 14))	('FAM131B', 'Gene', (32, 39))	('identified', 'Reg', (54, 64))	('BRAF', 'Gene', '673', (10, 14))	('FAM131B', 'Gene', '9715', (32, 39))
9945	25040262	This fusion results from a deletion in 7q34, fusing the first several exons of FAM131B to the activation domain of BRAF.	('BRAF', 'Gene', '673', (115, 119))	('BRAF', 'Gene', (115, 119))	('FAM131B', 'Gene', (79, 86))	('deletion', 'Var', (27, 35))	('FAM131B', 'Gene', '9715', (79, 86))	('results from', 'Reg', (12, 24))
9949	25040262	BRAF mutations have also been implicated in pediatric LGG, specifically p.V600E, and are most frequently found in the PXA, DA and GG subtypes.	('LGG', 'Disease', (54, 57))	('mutations', 'Var', (5, 14))	('p.V600E', 'Mutation', 'rs113488022', (72, 79))	('BRAF', 'Gene', '673', (0, 4))	('implicated', 'Reg', (30, 40))	('BRAF', 'Gene', (0, 4))	('p.V600E', 'Var', (72, 79))
9950	25040262	Notably there are mechanisms in addition to BRAF alterations that lead to MAPK activation in LGG including RAF1 and NTRK2 gene fusions, MYB deletions, KRAS mutations and FGFR1 alterations which include both mutations and internal tandem duplications.	('deletions', 'Var', (140, 149))	('RAF1', 'Gene', '5894', (107, 111))	('MAPK', 'Gene', (74, 78))	('FGFR1', 'Gene', '2260', (170, 175))	('internal tandem duplications', 'Var', (221, 249))	('NTRK2', 'Gene', (116, 121))	('activation', 'PosReg', (79, 89))	('MYB', 'Gene', '4602', (136, 139))	('RAF1', 'Gene', (107, 111))	('MYB', 'Gene', (136, 139))	('KRAS', 'Gene', '3845', (151, 155))	('BRAF', 'Gene', '673', (44, 48))	('alterations', 'Var', (49, 60))	('mutations', 'Var', (156, 165))	('BRAF', 'Gene', (44, 48))	('alterations', 'Var', (176, 187))	('FGFR1', 'Gene', (170, 175))	('KRAS', 'Gene', (151, 155))	('LGG', 'Gene', (93, 96))	('fusions', 'Var', (127, 134))	('NTRK2', 'Gene', '4915', (116, 121))
9951	25040262	For the most part, these MAPK alterations are mutually exclusive, with only a few reports of multiple hits in this pathway occurring within the same tumor.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('MAPK', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('alterations', 'Var', (30, 41))	('tumor', 'Disease', (149, 154))
9954	25040262	We herein describe three LGGs in which SNP array studies showed deletions in 7q34 that were suggestive of the rare FAM131B-BRAF fusion, or of a KIAA1549-BRAF fusion.	('BRAF', 'Gene', (153, 157))	('KIAA1549-BRAF', 'Disease', (144, 157))	('deletions', 'Var', (64, 73))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('7q34', 'Gene', (77, 81))	('FAM131B', 'Gene', (115, 122))	('KIAA1549-BRAF', 'Disease', 'None', (144, 157))	('BRAF', 'Gene', '673', (153, 157))	('FAM131B', 'Gene', '9715', (115, 122))
9958	25040262	Screening for mutations in BRAF exons 11 and 15 was performed using PCR and Sanger sequencing as previously described.	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', (27, 31))	('BRAF', 'Gene', '673', (27, 31))
9960	25040262	FAM131B-BRAF fusions were detected using a FAM131B forward primer as described in Cin et al and a reverse primer located in exons 11/12 of BRAF (5'-TTTCACTGCCACATCACCAT-3').	('FAM131B', 'Gene', (43, 50))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (139, 143))	('FAM131B', 'Gene', (0, 7))	('BRAF', 'Gene', (8, 12))	('Cin', 'Gene', '57026', (82, 85))	('FAM131B', 'Gene', '9715', (43, 50))	('FAM131B', 'Gene', '9715', (0, 7))	('fusions', 'Var', (13, 20))	('Cin', 'Gene', (82, 85))	('BRAF', 'Gene', '673', (139, 143))
9981	25040262	The B-allele frequency (BAF) of rs10229557 was close to 1 (BAF = 0.99), indicating homozygosity at this locus, and was therefore uninformative regarding copy number.	('BAF', 'Gene', '8815', (24, 27))	('BAF', 'Gene', '8815', (59, 62))	('BAF', 'Gene', (59, 62))	('rs10229557', 'Var', (32, 42))	('BAF', 'Gene', (24, 27))	('rs10229557', 'Mutation', 'rs10229557', (32, 42))
9985	25040262	An additional SNP located in intron 1 (rs1267621) was potentially deleted (LogR = -0.172), and would thus result in inclusion of BRAF exon 2 in the deletion (Figure 3E).	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('rs1267621', 'Var', (39, 48))	('rs1267621', 'Mutation', 'rs1267621', (39, 48))	('result in inclusion', 'Reg', (106, 125))
9988	25040262	RT-PCR and sequencing analyses demonstrated the presence of a fusion transcript between exon 15 of KIAA1549 and exon 9 of BRAF (Figure 4A).	('KIAA1549', 'Gene', '57670', (99, 107))	('BRAF', 'Gene', '673', (122, 126))	('KIAA1549', 'Gene', (99, 107))	('fusion', 'Var', (62, 68))	('BRAF', 'Gene', (122, 126))
10002	25040262	The distal end of the 2.6 Mb deletion resulted in deletion of exons 1-20 of the CLCN1 gene.	('CLCN1', 'Gene', '1180', (80, 85))	('resulted in', 'Reg', (38, 49))	('CLCN1', 'Gene', (80, 85))	('deletion', 'Var', (50, 58))
10003	25040262	If the deletion included the next two SNP probes, rs7802536 and rs4236482, it would result in deletion of a portion of or the entire FAM131B gene (Figure 3E).	('rs7802536', 'Var', (50, 59))	('FAM131B', 'Gene', (133, 140))	('deletion', 'Var', (94, 102))	('FAM131B', 'Gene', '9715', (133, 140))	('rs4236482', 'Mutation', 'rs4236482', (64, 73))	('result in', 'Reg', (84, 93))	('rs4236482', 'Var', (64, 73))	('rs7802536', 'Mutation', 'rs7802536', (50, 59))
10007	25040262	The BAF of rs4236482 was equal to 0.99, indicating homozygosity at this SNP, which was uninformative in determining copy number.	('rs4236482', 'Var', (11, 20))	('BAF', 'Gene', (4, 7))	('rs4236482', 'Mutation', 'rs4236482', (11, 20))	('BAF', 'Gene', '8815', (4, 7))
10008	25040262	RT-PCR yielded an approximately 500 bp product (data not shown) and sequence analysis demonstrated a fusion between exon 2 of FAM131B and exon 9 of BRAF (Figure 4B).	('fusion', 'Var', (101, 107))	('FAM131B', 'Gene', (126, 133))	('FAM131B', 'Gene', '9715', (126, 133))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (148, 152))
10018	25040262	Considering the radiographic findings together with the pathology of both the initial and recurrent lesions, the final diagnosis of 3A/B/C was consistent with monophasic PA.	('monophasic', 'Disease', (159, 169))	('3A/B', 'SUBSTITUTION', 'None', (132, 136))	('3A/B', 'Var', (132, 136))
10026	25040262	SNP array analysis of the recurrent tumor (3C) displayed 4 deletions in chromosome band 7q34 (Table 1 and Figure 3D).	('deletions', 'Var', (59, 68))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
10029	25040262	The proximal end of this deletion may also have included BRAF exons 8-10 because two probes within intron 7 (rs1733826 and rs17161714) had LogR values less than zero (-0.17 and -0.06 respectively) (Figure 3E).	('rs17161714', 'Var', (123, 133))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('rs1733826', 'Mutation', 'rs1733826', (109, 118))	('rs17161714', 'Mutation', 'rs17161714', (123, 133))	('rs1733826', 'Var', (109, 118))
10030	25040262	The BAF values of these probes were non-contributory to the copy number analysis due to the fact that they were homozygous (rs1733826, BAF = 1; rs17161714, BAF = 0.002).	('rs1733826', 'Mutation', 'rs1733826', (124, 133))	('BAF', 'Gene', '8815', (156, 159))	('BAF', 'Gene', (4, 7))	('BAF', 'Gene', '8815', (135, 138))	('rs1733826', 'Var', (124, 133))	('BAF', 'Gene', (156, 159))	('rs17161714', 'Mutation', 'rs17161714', (144, 154))	('BAF', 'Gene', (135, 138))	('BAF', 'Gene', '8815', (4, 7))
10033	25040262	It was difficult to determine if a SNP (rs13244040) located in intron 1 of FAM131B was included in the deletion.	('FAM131B', 'Gene', (75, 82))	('FAM131B', 'Gene', '9715', (75, 82))	('rs13244040', 'Var', (40, 50))	('rs13244040', 'Mutation', 'rs13244040', (40, 50))
10034	25040262	The LogR value of rs13244040 was very close to zero (LogR = -0.097) and the BAF was equal to 0.50 indicating two alleles present in fairly equal copy number at this locus.	('rs13244040', 'Var', (18, 28))	('rs13244040', 'Mutation', 'rs13244040', (18, 28))	('BAF', 'Gene', '8815', (76, 79))	('BAF', 'Gene', (76, 79))
10036	25040262	If rs13244040 was included, the entire FAM131B gene could have been deleted (Figure 3E).	('rs13244040', 'Mutation', 'rs13244040', (3, 13))	('FAM131B', 'Gene', (39, 46))	('FAM131B', 'Gene', '9715', (39, 46))	('rs13244040', 'Var', (3, 13))
10039	25040262	Given that the SNP array results for cases 3B and 3C indicated a deletion involving at least part of the FAM131B gene, we performed RT-PCR and sequence analyses on case 3B (there was not sufficient material to perform these studies in the recurrent tumor).	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('FAM131B', 'Gene', '9715', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('indicated', 'Reg', (53, 62))	('tumor', 'Disease', (249, 254))	('deletion', 'Var', (65, 73))	('FAM131B', 'Gene', (105, 112))
10041	25040262	Finally, the recurrent tumor (3C) did not demonstrate a mutation in BRAF exon 15.	('BRAF', 'Gene', '673', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('BRAF', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutation', 'Var', (56, 64))
10054	25040262	The KIAA1549-BRAF fusion protein is typically the result of a 2.0 Mb tandem duplication in 7q34.	('tandem duplication', 'Var', (69, 87))	('KIAA1549-BRAF', 'Disease', 'None', (4, 17))	('KIAA1549-BRAF', 'Disease', (4, 17))	('result', 'Reg', (50, 56))
10055	25040262	In contrast to the typical 7q34 duplication, case 1 had three non-overlapping 7q33q34 deletions detected by SNP array analysis that resulted in formation of a KIAA1549-BRAF fusion.	('KIAA1549-BRAF', 'Disease', 'None', (159, 172))	('7q33q34', 'Gene', (78, 85))	('KIAA1549-BRAF', 'Disease', (159, 172))	('deletions', 'Var', (86, 95))	('resulted in', 'Reg', (132, 143))
10056	25040262	Given that KIAA1549 and BRAF are both transcribed from the lagging strand, creation of the fusion product could result from an insertion into one of the adjacent deletions, as shown in model 1 and model 2 in Figure 5.	('result from', 'Reg', (112, 123))	('KIAA1549', 'Gene', '57670', (11, 19))	('insertion', 'Var', (127, 136))	('KIAA1549', 'Gene', (11, 19))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))
10061	25040262	Repair of the single interstitial deletion would result in this fusion given the genomic order and direction of transcription of the BRAF and FAM131B genes, as shown in Figure 5C.	('result in', 'Reg', (49, 58))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('FAM131B', 'Gene', (142, 149))	('deletion', 'Var', (34, 42))	('FAM131B', 'Gene', '9715', (142, 149))
10062	25040262	Case 3B and the recurrent tumor from the same patient (3C) both demonstrated multiple non-overlapping deletions in 7q34 by SNP array analysis.	('patient', 'Species', '9606', (46, 53))	('deletions', 'Var', (102, 111))	('7q34', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
10064	25040262	Given the orientation of BRAF and FAM131B, fusion formation in case 3B would result from juxtaposing the two outer segments of chromosome 7 that remained after the deletions (Figure 5D).	('result from', 'Reg', (77, 88))	('deletions', 'Var', (164, 173))	('FAM131B', 'Gene', (34, 41))	('FAM131B', 'Gene', '9715', (34, 41))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
10067	25040262	Both FAM131B-BRAF fusions identified in this series resulted from fusion of FAM131B exon 2 to BRAF exon 9 similar to what has been previously reported in PA.	('BRAF', 'Gene', (94, 98))	('fusions', 'Var', (18, 25))	('resulted from', 'Reg', (52, 65))	('BRAF', 'Gene', '673', (13, 17))	('FAM131B', 'Gene', '9715', (5, 12))	('fusion', 'Var', (66, 72))	('BRAF', 'Gene', (13, 17))	('FAM131B', 'Gene', '9715', (76, 83))	('FAM131B', 'Gene', (76, 83))	('BRAF', 'Gene', '673', (94, 98))	('FAM131B', 'Gene', (5, 12))
10069	25040262	The KIAA1549-BRAF and SRGAP3-RAF1 fusions typically result from tandem duplications in chromosomes 7 and 3, respectively.	('RAF1', 'Gene', (29, 33))	('KIAA1549-BRAF', 'Disease', (4, 17))	('RAF1', 'Gene', '5894', (29, 33))	('SRGAP3', 'Gene', (22, 28))	('SRGAP3', 'Gene', '9901', (22, 28))	('tandem duplications', 'Var', (64, 83))	('KIAA1549-BRAF', 'Disease', 'None', (4, 17))	('result from', 'Reg', (52, 63))	('fusions', 'Var', (34, 41))
10071	25040262	Translocations between chromosomes 1 and 7 or between chromosomes 5 and 7 lead to CLCN6-BRAF and RNF130-BRAF fusions, respectively.	('CLCN6', 'Gene', (82, 87))	('RNF130', 'Gene', (97, 103))	('Translocations', 'Var', (0, 14))	('BRAF', 'Gene', (88, 92))	('lead to', 'Reg', (74, 81))	('BRAF', 'Gene', '673', (88, 92))	('CLCN6', 'Gene', '1185', (82, 87))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))	('RNF130', 'Gene', '55819', (97, 103))
10072	25040262	The BRAF-AKAP9 fusion in thyroid cancer is the result of a pericentric inversion on chromosome 7.	('fusion', 'Var', (15, 21))	('thyroid cancer', 'Phenotype', 'HP:0002890', (25, 39))	('thyroid cancer', 'Disease', 'MESH:D013964', (25, 39))	('AKAP9', 'Gene', '10142', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('AKAP9', 'Gene', (9, 14))	('thyroid cancer', 'Disease', (25, 39))
10077	25040262	Case 2 had a larger deletion, and thus would demonstrate one fusion and one signal for the 3' end of BRAF.	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', '673', (101, 105))	('deletion', 'Var', (20, 28))	('fusion', 'MPA', (61, 67))
10079	25040262	The BRAF fusions identified in this study were detected due to deletions in 7q33q34.	('deletions in', 'Var', (63, 75))	('7q33q34', 'Gene', (76, 83))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
10080	25040262	A MKRN1-BRAF fusion which is the result of a tandem duplication in 7q34 would also be detected with this platform, as would fusions involving RAF1 and MYB, which have also been associated with copy number alterations.	('BRAF', 'Gene', '673', (8, 12))	('fusion', 'Var', (13, 19))	('BRAF', 'Gene', (8, 12))	('MKRN1', 'Gene', (2, 7))	('MKRN1', 'Gene', '23608', (2, 7))	('7q34', 'Gene', (67, 71))	('MYB', 'Gene', (151, 154))	('MYB', 'Gene', '4602', (151, 154))	('RAF1', 'Gene', (142, 146))	('fusions', 'Var', (124, 131))	('RAF1', 'Gene', '5894', (142, 146))
10081	25040262	In contrast, BRAF fusions involving RNF130, CLCN6, GNAI1, FXR1, and MACF1 were not noted to have associated copy number alterations and thus may best be identified by whole genome sequencing or RNA-sequencing strategies.	('RNF130', 'Gene', '55819', (36, 42))	('CLCN6', 'Gene', '1185', (44, 49))	('fusions', 'Var', (18, 25))	('RNF130', 'Gene', (36, 42))	('BRAF', 'Gene', '673', (13, 17))	('CLCN6', 'Gene', (44, 49))	('FXR1', 'Gene', (58, 62))	('BRAF', 'Gene', (13, 17))	('GNAI1', 'Gene', (51, 56))	('GNAI1', 'Gene', '2770', (51, 56))	('MACF1', 'Gene', (68, 73))	('MACF1', 'Gene', '23499', (68, 73))	('FXR1', 'Gene', '8087', (58, 62))
10090	25040262	Inhibitors of MEK (U0126) or general tyrosine kinases (TKs) (Sorafenib) were shown to block oncogenic phenotypes that are mediated by BRAF or RAF fusions in an in vitro model of prostate cancer cells.	('oncogenic phenotypes', 'CPA', (92, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (178, 193))	('block', 'NegReg', (86, 91))	('RAF', 'Gene', '22882', (142, 145))	('RAF', 'Gene', (142, 145))	('BRAF', 'Gene', '673', (134, 138))	('Inhibitors', 'Var', (0, 10))	('RAF', 'Gene', (135, 138))	('MEK', 'Gene', (14, 17))	('prostate cancer', 'Disease', (178, 193))	('BRAF', 'Gene', (134, 138))	('RAF', 'Gene', '22882', (135, 138))	('Sorafenib', 'Chemical', 'MESH:D000077157', (61, 70))	('U0126', 'Chemical', 'MESH:C113580', (19, 24))	('MEK', 'Gene', '5609', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('prostate cancer', 'Disease', 'MESH:D011471', (178, 193))
10092	25040262	demonstrate that cells expressing KIAA1549-BRAF are resistant to the research analog of vemurafenib (PLX4720; Plexxikon/Genentech), an inhibitor of the BRAF V600E mutation.	('vemurafenib', 'Chemical', 'MESH:D000077484', (88, 99))	('BRAF', 'Gene', (152, 156))	('resistant', 'MPA', (52, 61))	('BRAF', 'Gene', '673', (43, 47))	('KIAA1549-BRAF', 'Disease', (34, 47))	('BRAF', 'Gene', (43, 47))	('V600E', 'Mutation', 'rs113488022', (157, 162))	('KIAA1549-BRAF', 'Disease', 'None', (34, 47))	('V600E', 'Var', (157, 162))	('BRAF', 'Gene', '673', (152, 156))
10096	25040262	Identification of KIAA1549-BRAF or FAM131B-BRAF fusions in low grade glial tumors as well as PA suggests that molecular classification of pediatric LGGs, perhaps independent of pathologic subtype, will ultimately be useful for selecting therapies based on MAPK activation in these patients.	('low', 'Disease', (59, 62))	('fusions', 'Var', (48, 55))	('LGGs', 'Disease', (148, 152))	('BRAF', 'Gene', '673', (43, 47))	('KIAA1549-BRAF', 'Disease', (18, 31))	('patients', 'Species', '9606', (281, 289))	('BRAF', 'Gene', (43, 47))	('glial tumors', 'Disease', 'MESH:D005910', (69, 81))	('FAM131B', 'Gene', (35, 42))	('BRAF', 'Gene', '673', (27, 31))	('FAM131B', 'Gene', '9715', (35, 42))	('glial tumors', 'Disease', (69, 81))	('BRAF', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('KIAA1549-BRAF', 'Disease', 'None', (18, 31))
10120	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))
10121	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))
10158	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))
10363	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))
10379	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', (184, 189))	('RNU48', 'Gene', '26801', (184, 189))	('P/N 4373383', 'SUBSTITUTION', 'None', (191, 202))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))
10405	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))
10408	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))
10418	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-139-3p', 'Gene', (41, 51))	('miR', 'Gene', (77, 80))	('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-342', 'Gene', (77, 84))	('miR', 'Gene', (14, 17))	('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))
10426	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))
10432	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))
10433	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))
10497	29098169	Comparisons included high-grade versus low-grade with noncancer (G4+ versus G3 and NC), high-grade versus low-grade (G4+ versus G3), G4CG versus NC, G4CG versus G3 and NC, and G4CG versus G3, limited to the PZ.	('G4CG', 'Var', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('G4+', 'Var', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('G4CG', 'Var', (176, 180))	('G4CG', 'Var', (149, 153))
10498	29098169	Comparisons of annotated lesions within the entire prostate included G5 versus G3 cancer versus noncancer (G3+ versus NC), G4FG versus NCG5 versus NC, G4FG versus G3 and NC, G5 versus G3 and NC, and G4FG versus G3.	('G4FG', 'Chemical', '-', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('G4FG', 'Chemical', '-', (199, 203))	('G4FG', 'Var', (123, 127))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('G4FG', 'Var', (151, 155))	('G4FG', 'Var', (199, 203))	('G4FG', 'Chemical', '-', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
10500	29098169	This included 210 regions considered normal prostate tissue, 25 of seminal vesicles, 692 atrophies, 77 HGPIN, 252 G3, 81 G4FG, 24 G4CG, and 8 G5.	('G4FG', 'Chemical', '-', (121, 125))	('G4FG', 'Var', (121, 125))	('atrophies', 'Disease', (89, 98))	('atrophies', 'Disease', 'MESH:D001284', (89, 98))
10501	29098169	When limited to the PZ, a total of 802 annotated pathological regions including 207 regions considered normal prostate tissue, 9 of seminal vesicles, 376 atrophies, 23 HGPIN, 127 G3, 38 G4FG, 16 G4CG, and 6 G5.	('atrophies', 'Disease', 'MESH:D001284', (154, 163))	('G4FG', 'Chemical', '-', (186, 190))	('G4FG', 'Var', (186, 190))	('atrophies', 'Disease', (154, 163))
10507	29098169	6 and Table 3, G5 versus G3 cancer versus noncancer (G3+ versus NC), G4FG versus NCG5 versus NC, G4FG versus G3 and NC, G5 versus G3 and NC, and G4FG versus G3.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('G4FG', 'Chemical', '-', (69, 73))	('cancer', 'Disease', (28, 34))	('G4FG', 'Chemical', '-', (97, 101))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('G4FG', 'Var', (69, 73))	('G4FG', 'Chemical', '-', (145, 149))	('cancer', 'Disease', (45, 51))	('G4FG', 'Var', (97, 101))	('G4FG', 'Var', (145, 149))
10513	29098169	We found that mean ADC values for G4FG, G4CG, and G5 are not significantly different from one another although all three were significantly different from low-grade cancer in the higher performing -value combinations (Fig.	('different', 'Reg', (140, 149))	('G4CG', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('G4FG', 'Chemical', '-', (34, 38))	('G4FG', 'Var', (34, 38))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
10526	27716027	Identification of gene-drug interactions that impact patient survival in TCGA With the advent of large scale biological data collection for various diseases, data analysis pipelines and workflows need to be established to build frameworks for integrative analysis.	('impact', 'Reg', (46, 52))	('drug interaction', 'Phenotype', 'HP:0020172', (23, 39))	('interactions', 'Var', (28, 40))	('TCGA', 'Disease', (73, 77))	('patient', 'Species', '9606', (53, 60))
10530	27716027	Several gene-drug interactions are identified, where the copy number of a gene is associated to survival of a patient exposed to a certain drug.	('copy number', 'Var', (57, 68))	('patient', 'Species', '9606', (110, 117))	('drug interaction', 'Phenotype', 'HP:0020172', (13, 29))	('associated to', 'Reg', (82, 95))
10535	27716027	Here a pipeline is implemented for integrative analysis of CNV data, drug treatment and survival data, for the purpose of identifying beneficial gene-drug interactions, where the copy number of a gene is associated to survival of patients exposed to a certain drug.	('patients', 'Species', '9606', (230, 238))	('drug interaction', 'Phenotype', 'HP:0020172', (150, 166))	('copy number', 'Var', (179, 190))	('associated to', 'Reg', (204, 217))
10538	27716027	Variation in levels of gene expression between patient profiles and obtaining the necessary number of patients for sufficient statistical power are just a few of the hurdles that need to be addressed with any study of this nature.	('patient', 'Species', '9606', (47, 54))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('levels', 'MPA', (13, 19))	('Variation', 'Var', (0, 9))
10569	27716027	CNV data was used to place patients into three categories of CNV based on full or partial deletion, no change in copy number, or increased copy number.	('partial deletion', 'Var', (82, 98))	('patients', 'Species', '9606', (27, 35))	('copy', 'MPA', (139, 143))	('increased', 'PosReg', (129, 138))
10577	27716027	Following one identified gene-drug interaction, HAS2 and Irinotecan, shows that among patients treated with Irinotecan, normal or elevated copy number of HAS2 correlates with increased survival.	('copy number', 'Var', (139, 150))	('Irinotecan', 'Chemical', 'MESH:D000077146', (108, 118))	('HAS2', 'Gene', '3037', (154, 158))	('drug interaction', 'Phenotype', 'HP:0020172', (30, 46))	('HAS2', 'Gene', (154, 158))	('elevated', 'PosReg', (130, 138))	('Irinotecan', 'Chemical', 'MESH:D000077146', (57, 67))	('HAS2', 'Gene', (48, 52))	('increased', 'PosReg', (175, 184))	('HAS2', 'Gene', '3037', (48, 52))	('survival', 'MPA', (185, 193))	('patients', 'Species', '9606', (86, 94))
10578	27716027	Looking at all LGG and GBM patients, the Kaplan-Meier curves show no difference between patients with normal and elevated copy number of HAS2, and a marked decrease in survival in patients with low copy number of HAS2 (Fig.	('low copy number', 'Var', (194, 209))	('HAS2', 'Gene', (137, 141))	('patients', 'Species', '9606', (88, 96))	('HAS2', 'Gene', '3037', (137, 141))	('copy number', 'Var', (122, 133))	('patients', 'Species', '9606', (27, 35))	('HAS2', 'Gene', (213, 217))	('HAS2', 'Gene', '3037', (213, 217))	('decrease', 'NegReg', (156, 164))	('survival', 'MPA', (168, 176))	('patients', 'Species', '9606', (180, 188))
10583	27716027	2b where no expression difference was observed among patients with different copy number of HAS2, when focusing on patients exposed to Irinotecan in Fig.	('patients', 'Species', '9606', (115, 123))	('HAS2', 'Gene', '3037', (92, 96))	('Irinotecan', 'Chemical', 'MESH:D000077146', (135, 145))	('patients', 'Species', '9606', (53, 61))	('HAS2', 'Gene', (92, 96))	('copy number', 'Var', (77, 88))
10584	27716027	2d, we observed a significant (p = .045) expression difference between the low and normal/increased copy number patients.	('expression', 'MPA', (41, 51))	('patients', 'Species', '9606', (112, 120))	('low', 'Var', (75, 78))
10585	27716027	This shows that the HAS2-Irinotecan interaction identified based on copy number also manifests at the gene expression level.	('HAS2', 'Gene', (20, 24))	('Irinotecan', 'Chemical', 'MESH:D000077146', (25, 35))	('HAS2', 'Gene', '3037', (20, 24))	('copy', 'Var', (68, 72))
10595	27716027	This interaction was explored in cell lines and the loss of PGAM1 was shown to decrease the effects of hypoxia on the tumor by inhibiting the ability of the cell to regulate balance between glycolysis and biosynthesis allowing tumor growth that would be inhibited in a hypoxic state.	('effects', 'MPA', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', (227, 232))	('loss', 'Var', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inhibiting', 'NegReg', (127, 137))	('decrease', 'NegReg', (79, 87))	('PGAM1', 'Gene', (60, 65))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('hypoxia', 'Disease', (103, 110))	('ability', 'MPA', (142, 149))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))	('PGAM1', 'Gene', '5223', (60, 65))
10597	27716027	While loss of COL22A1 copy number can be linked to lowered survival over the entire pool of patients (Fig.	('loss', 'NegReg', (6, 10))	('copy number', 'Var', (22, 33))	('COL22A1', 'Gene', '169044', (14, 21))	('patients', 'Species', '9606', (92, 100))	('lowered', 'NegReg', (51, 58))	('survival', 'MPA', (59, 67))	('COL22A1', 'Gene', (14, 21))
10611	27716027	Therefore, for patients with increased copy number or expression of a target gene, the drug is more likely to show an effect.	('expression', 'MPA', (54, 64))	('patients', 'Species', '9606', (15, 23))	('copy number', 'Var', (39, 50))	('increased', 'PosReg', (29, 38))
10647	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))
10651	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))
10659	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))
10819	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))
11013	27899997	The frequency of hypermethylation of CpG dinucleotides varies significantly between different malignancy grades of gliomas.	('gliomas', 'Disease', (115, 122))	('malignancy', 'Disease', 'MESH:D009369', (94, 104))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('CpG', 'Gene', (37, 40))	('malignancy', 'Disease', (94, 104))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (37, 54))	('hypermethylation', 'Var', (17, 33))
11020	27899997	Promoter methylation is closely associated with the loss of TES expression in glioblastoma cell lines.	('glioblastoma', 'Disease', (78, 90))	('expression', 'MPA', (64, 74))	('loss', 'NegReg', (52, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('TES', 'Gene', (60, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('TES', 'Gene', '26136', (60, 63))	('Promoter methylation', 'Var', (0, 20))
11059	27899997	Promoter hypermethylation was detected in 57.25% (79/138) of all analysed astrocytoma tumours, but not in normal brain tissue.	('astrocytoma tumours', 'Disease', (74, 93))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('detected', 'Reg', (30, 38))	('Promoter hypermethylation', 'Var', (0, 25))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))	('astrocytoma tumours', 'Disease', 'MESH:D001254', (74, 93))
11060	27899997	The results revealed that the TES gene methylation frequency increases with the degree of malignancy of the tumour (Fig.	('malignancy of the tumour', 'Disease', 'MESH:D009369', (90, 114))	('methylation', 'Var', (39, 50))	('TES', 'Gene', (30, 33))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('TES', 'Gene', '26136', (30, 33))	('increases', 'PosReg', (61, 70))	('malignancy of the tumour', 'Disease', (90, 114))
11062	27899997	Grade III astrocytoma TES promoter methylation was detected in 65.52% (19/29) of samples, and the highest methylation degree of the TES gene was observed in glioblastoma samples [79.59% (39/49)].	('detected', 'Reg', (51, 59))	('astrocytoma', 'Disease', 'MESH:D001254', (10, 21))	('TES', 'Gene', (132, 135))	('glioblastoma', 'Disease', (157, 169))	('astrocytoma', 'Disease', (10, 21))	('TES', 'Gene', (22, 25))	('TES', 'Gene', '26136', (132, 135))	('TES', 'Gene', '26136', (22, 25))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('methylation', 'Var', (35, 46))
11064	27899997	The TES gene methylation status differed significantly between astrocytomas of different malignancy grades (P<0.001).	('malignancy', 'Disease', (89, 99))	('methylation', 'Var', (13, 24))	('astrocytomas', 'Disease', 'MESH:D001254', (63, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('astrocytomas', 'Disease', (63, 75))	('TES', 'Gene', (4, 7))	('differed', 'Reg', (32, 40))	('TES', 'Gene', '26136', (4, 7))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))
11067	27899997	In addition, methylation of TES was significantly associated with patient survival.	('TES', 'Gene', (28, 31))	('methylation', 'Var', (13, 24))	('patient survival', 'CPA', (66, 82))	('patient', 'Species', '9606', (66, 73))	('associated', 'Reg', (50, 60))	('TES', 'Gene', '26136', (28, 31))
11068	27899997	Patients who survived <24 months after resection tended to have a methylated TES allele (P=0.001).	('TES', 'Gene', '26136', (77, 80))	('Patients', 'Species', '9606', (0, 8))	('methylated', 'Var', (66, 76))	('TES', 'Gene', (77, 80))
11071	27899997	Promoter methylation of TES was noticed to be closely associated with shorter survival (long-rank test, P<0.001).	('TES', 'Gene', (24, 27))	('shorter', 'NegReg', (70, 77))	('Promoter methylation', 'Var', (0, 20))	('TES', 'Gene', '26136', (24, 27))
11087	27899997	Furthermore, in addition to methylation, TES down-regulation could be caused by other molecular mechanisms, including mutation, loss of heterozygosity and microRNA regulation, which may affect the correlation between gene expression and methylation.	('methylation', 'MPA', (237, 248))	('affect', 'Reg', (186, 192))	('microRNA regulation', 'MPA', (155, 174))	('loss of heterozygosity', 'Var', (128, 150))	('mutation', 'Var', (118, 126))	('correlation', 'Interaction', (197, 208))	('TES', 'Gene', (41, 44))	('down-regulation', 'NegReg', (45, 60))	('TES', 'Gene', '26136', (41, 44))
11093	27899997	Epigenetic changes, including aberrant DNA methylation, are important in the pathogenesis of glial tumours.	('glial tumours', 'Disease', 'MESH:D009369', (93, 106))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('aberrant', 'Var', (30, 38))	('glial tumours', 'Disease', (93, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
11108	27899997	Aggressive and invasive astrocytomas (WHO grades IV and III) exhibited a higher frequency of methylated TES promoter compared with low-grade tumours.	('tumours', 'Disease', (141, 148))	('TES', 'Gene', '26136', (104, 107))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('Aggressive and invasive astrocytomas', 'Disease', 'MESH:D001254', (0, 36))	('methylated', 'Var', (93, 103))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('TES', 'Gene', (104, 107))
11115	27899997	Using western blotting, a decreased protein level of TES in glioblastomas was detected, compared with lower grade astrocytomas, thus indicating that aberrant expression of TES may be associated with malignant progression of astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (114, 126))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('decreased', 'NegReg', (26, 35))	('TES', 'Gene', '26136', (172, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('astrocytomas', 'Disease', 'MESH:D001254', (224, 236))	('astrocytoma', 'Phenotype', 'HP:0009592', (224, 235))	('glioblastomas', 'Disease', (60, 73))	('TES', 'Gene', '26136', (53, 56))	('associated with', 'Reg', (183, 198))	('TES', 'Gene', (172, 175))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('expression', 'MPA', (158, 168))	('TES', 'Gene', (53, 56))	('protein level', 'MPA', (36, 49))	('aberrant', 'Var', (149, 157))	('astrocytomas', 'Disease', (114, 126))	('astrocytomas', 'Disease', (224, 236))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))
11118	31563982	Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration.	('astrocytoma', 'Phenotype', 'HP:0009592', (193, 204))	('glioma', 'Disease', (287, 293))	('glioma', 'Disease', (19, 25))	('gene fusions', 'Var', (101, 113))	('glioma', 'Disease', 'MESH:D005910', (287, 293))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('astrocytoma', 'Disease', 'MESH:D001254', (193, 204))	('astrocytoma', 'Disease', (193, 204))	('MYBL1', 'Gene', (117, 122))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('MYB', 'Gene', '4602', (126, 129))	('MYBL1', 'Gene', '4603', (117, 122))	('tumour', 'Disease', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('MYB', 'Gene', (126, 129))	('MYB', 'Gene', '4602', (117, 120))	('MYB', 'Gene', (117, 120))	('diffuse brain infiltration', 'Phenotype', 'HP:0002283', (344, 370))
11124	31563982	Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%).	('copy number alterations', 'Var', (43, 66))	('MYB', 'Gene', (79, 82))	('MYBL1', 'Gene', '4603', (70, 75))	('MYB', 'Gene', '4602', (70, 73))	('MYB', 'Gene', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('MYBL1', 'Gene', (70, 75))	('MYB', 'Gene', '4602', (79, 82))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
11138	31563982	In a more recent analysis of the same tumours, then termed "isomorphic neuroepithelial tumours" (INET), all isomorphic diffuse gliomas were IDH1 R132H-negative, suggesting that they differ from diffuse astrocytoma, IDH-mutant.	('IDH1', 'Gene', '3417', (140, 144))	('neuroepithelial tumours', 'Disease', (71, 94))	('IDH', 'Gene', '3417', (140, 143))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('astrocytoma', 'Phenotype', 'HP:0009592', (202, 213))	('R132H', 'Mutation', 'rs121913500', (145, 150))	('IDH', 'Gene', (215, 218))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('R132H-negative', 'Var', (145, 159))	('IDH', 'Gene', '3417', (215, 218))	('astrocytoma', 'Disease', 'MESH:D001254', (202, 213))	('astrocytoma', 'Disease', (202, 213))	('tumours', 'Disease', (87, 94))	('neuroepithelial tumour', 'Phenotype', 'HP:0030063', (71, 93))	('neuroepithelial tumours', 'Disease', 'MESH:D018302', (71, 94))	('IDH1', 'Gene', (140, 144))	('gliomas', 'Disease', (127, 134))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('IDH', 'Gene', (140, 143))	('tumours', 'Disease', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
11144	31563982	Some recurrent genomic alterations in glioma subgroups and glio-neuronal tumours are well established such as IDH-mutations and BRAF mutations and fusions.	('glio-neuronal tumours', 'Disease', (59, 80))	('IDH', 'Gene', (110, 113))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH', 'Gene', '3417', (110, 113))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('fusions', 'Var', (147, 154))	('glio-neuronal tumours', 'Disease', 'MESH:D009369', (59, 80))	('mutations', 'Var', (133, 142))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('BRAF', 'Gene', '673', (128, 132))	('glioma', 'Disease', (38, 44))	('BRAF', 'Gene', (128, 132))
11146	31563982	These include gene fusions of FGFR1-3, NTRK2, PRKCA and MYB/MYBL1 with different fusion partners, or different rearrangements and mutations of these genes.	('NTRK2', 'Gene', (39, 44))	('MYB', 'Gene', '4602', (56, 59))	('PRKCA', 'Gene', (46, 51))	('gene fusions', 'Reg', (14, 26))	('FGFR1-3', 'Gene', (30, 37))	('rearrangements', 'Var', (111, 125))	('MYBL1', 'Gene', (60, 65))	('FGFR1-3', 'Gene', '2260;2263;2261', (30, 37))	('MYB', 'Gene', (56, 59))	('MYB', 'Gene', '4602', (60, 63))	('MYBL1', 'Gene', '4603', (60, 65))	('NTRK2', 'Gene', '4915', (39, 44))	('mutations', 'Var', (130, 139))	('MYB', 'Gene', (60, 63))	('PRKCA', 'Gene', '5578', (46, 51))
11164	31563982	Reference cases for an unsupervised hierarchical cluster analysis and a t-SNE-analysis included well-characterized cases belonging to the following methylation classes of the DNA methylation-based brain tumour classifier [ and www.molecularneuropathology.org/mnp/classifier/2]: hemispheric cortex (n = 9); white matter (n = 9); low grade glioma, dysembryoplastic neuroepithelial tumour (n = 13); low grade glioma, ganglioglioma (n = 15); low grade glioma, subclass hemispheric pilocytic astrocytoma and ganglioglioma (n = 10); low grade glioma, subclass midline pilocytic astrocytoma (n = 15); low grade glioma, subclass posterior fossa pilocytic astrocytoma (n = 11); (anaplastic) pleomorphic xanthoastrocytoma (n = 15); anaplastic astrocytoma with piloid features (n = 15); diffuse midline glioma H3 K27M mutant (n = 14); glioblastoma, IDH wildtype, H3.3 G34 mutant (n = 10); glioblastoma, IDH wildtype, subclass mesenchymal (n = 15); glioblastoma, IDH wildtype, subclass midline (n = 10); glioblastoma, IDH wildtype, subclass RTK I (n = 15); glioblastoma, IDH wildtype, subclass RTK II (n = 8).	('ganglioglioma', 'Disease', 'MESH:D018303', (414, 427))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('glioma', 'Disease', (537, 543))	('IDH', 'Gene', '3417', (1059, 1062))	('glioblastoma', 'Phenotype', 'HP:0012174', (824, 836))	('H3 K27M mutant', 'Var', (799, 813))	('astrocytoma', 'Phenotype', 'HP:0009592', (487, 498))	('glioblastoma', 'Disease', (878, 890))	('midline glioma', 'Disease', (784, 798))	('glioma', 'Phenotype', 'HP:0009733', (448, 454))	('IDH', 'Gene', (1006, 1009))	('astrocytoma', 'Phenotype', 'HP:0009592', (572, 583))	('glioblastoma', 'Disease', 'MESH:D005909', (937, 949))	('glioblastoma', 'Disease', 'MESH:D005909', (992, 1004))	('IDH', 'Gene', '3417', (951, 954))	('dysembryoplastic neuroepithelial tumour', 'Disease', (346, 385))	('glioma', 'Disease', 'MESH:D005910', (421, 427))	('glioma', 'Disease', 'MESH:D005910', (406, 412))	('glioma', 'Phenotype', 'HP:0009733', (510, 516))	('IDH', 'Gene', (838, 841))	('glioblastoma', 'Disease', 'MESH:D005909', (824, 836))	('glioma', 'Disease', 'MESH:D005910', (792, 798))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (682, 711))	('midline pilocytic astrocytoma', 'Disease', 'MESH:D001254', (554, 583))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (562, 583))	('glioma', 'Disease', 'MESH:D005910', (448, 454))	('glioblastoma', 'Disease', (1045, 1057))	('astrocytoma', 'Phenotype', 'HP:0009592', (733, 744))	('glioblastoma', 'Phenotype', 'HP:0012174', (878, 890))	('glioma', 'Phenotype', 'HP:0009733', (338, 344))	('glioma', 'Disease', 'MESH:D005910', (510, 516))	('glioma', 'Disease', (421, 427))	('glioma', 'Disease', (406, 412))	('IDH', 'Gene', '3417', (1006, 1009))	('brain tumour', 'Disease', (197, 209))	('glioma', 'Disease', (792, 798))	('IDH', 'Gene', (892, 895))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (477, 498))	('glioblastoma', 'Disease', 'MESH:D005909', (878, 890))	('IDH', 'Gene', '3417', (838, 841))	('glioma', 'Disease', 'MESH:D005910', (338, 344))	('pilocytic astrocytoma', 'Disease', (477, 498))	('glioblastoma', 'Phenotype', 'HP:0012174', (1045, 1057))	('astrocytoma', 'Phenotype', 'HP:0009592', (700, 711))	('glioma', 'Disease', (510, 516))	('pleomorphic xanthoastrocytoma', 'Disease', (682, 711))	('cluster', 'Species', '100569', (49, 56))	('glioma', 'Disease', 'MESH:D005910', (604, 610))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (722, 744))	('midline glioma', 'Disease', 'MESH:D005910', (784, 798))	('brain tumour', 'Disease', 'MESH:D001932', (197, 209))	('glioblastoma', 'Disease', (937, 949))	('neuroepithelial tumour', 'Phenotype', 'HP:0030063', (363, 385))	('glioblastoma', 'Disease', (992, 1004))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (637, 658))	('IDH', 'Gene', (1059, 1062))	('tumour', 'Phenotype', 'HP:0002664', (379, 385))	('glioma', 'Phenotype', 'HP:0009733', (421, 427))	('pilocytic astrocytoma', 'Disease', (637, 658))	('glioblastoma', 'Disease', 'MESH:D005909', (1045, 1057))	('glioma', 'Disease', (338, 344))	('glioma', 'Disease', (448, 454))	('glioblastoma', 'Disease', (824, 836))	('K27M', 'Mutation', 'p.K27M', (802, 806))	('glioma', 'Disease', 'MESH:D005910', (537, 543))	('ganglioglioma', 'Disease', (503, 516))	('anaplastic astrocytoma', 'Disease', (722, 744))	('IDH', 'Gene', '3417', (892, 895))	('IDH', 'Gene', (951, 954))	('glioma', 'Disease', (604, 610))	('ganglioglioma', 'Disease', (414, 427))	('pilocytic astrocytoma and ganglioglioma', 'Disease', 'MESH:D001254', (477, 516))	('brain tumour', 'Phenotype', 'HP:0030692', (197, 209))	('ganglioglioma', 'Disease', 'MESH:D018303', (503, 516))	('midline pilocytic astrocytoma', 'Disease', (554, 583))	('glioblastoma', 'Phenotype', 'HP:0012174', (937, 949))	('dysembryoplastic neuroepithelial tumour', 'Disease', 'MESH:D018302', (346, 385))	('glioblastoma', 'Phenotype', 'HP:0012174', (992, 1004))	('astrocytoma', 'Phenotype', 'HP:0009592', (647, 658))	('glioma', 'Phenotype', 'HP:0009733', (406, 412))
11209	31563982	However, the analysis revealed that 10/25 tumours (40%) had focal copy number alterations affecting the MYBL1-locus (8q13.1; Fig.	('MYBL1', 'Gene', '4603', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('copy number alterations', 'Var', (66, 89))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))	('MYBL1', 'Gene', (104, 109))
11210	31563982	1) and 3/25 (12%) showed copy number alterations of the MYB-locus (6q23.3; Fig.	('MYB', 'Gene', '4602', (56, 59))	('copy number alterations', 'Var', (25, 48))	('MYB', 'Gene', (56, 59))
11212	31563982	Of the tumours with rearrangements of the MYB-locus, one tumour had a MYB-gain (Fig.	('tumour', 'Disease', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('MYB', 'Gene', '4602', (70, 73))	('MYB', 'Gene', (70, 73))	('rearrangements', 'Var', (20, 34))	('MYB', 'Gene', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))	('tumours', 'Disease', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('MYB', 'Gene', '4602', (42, 45))
11217	31563982	Of all cases with CNP alterations of MYBL1 or MYB, eleven cases (85%) had broader gains/losses of MYBL1 or MYB and adjacent loci which were evident from a low resolution CNP.	('MYB', 'Gene', '4602', (107, 110))	('gains/losses', 'NegReg', (82, 94))	('MYBL1', 'Gene', (37, 42))	('MYB', 'Gene', '4602', (46, 49))	('MYB', 'Gene', (107, 110))	('MYBL1', 'Gene', (98, 103))	('gains/losses', 'PosReg', (82, 94))	('MYBL1', 'Gene', '4603', (37, 42))	('MYB', 'Gene', '4602', (37, 40))	('MYBL1', 'Gene', '4603', (98, 103))	('MYB', 'Gene', (46, 49))	('MYB', 'Gene', '4602', (98, 101))	('MYB', 'Gene', (37, 40))	('MYB', 'Gene', (98, 101))	('CNP alterations', 'Var', (18, 33))
11219	31563982	The same holds true for the case with alterations of both MYBL1 and MYB.	('MYB', 'Gene', '4602', (58, 61))	('MYBL1', 'Gene', (58, 63))	('MYB', 'Gene', '4602', (68, 71))	('MYB', 'Gene', (68, 71))	('alterations', 'Var', (38, 49))	('MYBL1', 'Gene', '4603', (58, 63))	('MYB', 'Gene', (58, 61))
11222	31563982	Altogether, we detected alterations of the MYBL1- or MYB-loci in 13/25 (52%) of the isomorphic diffuse gliomas analysed (Supplementary Fig.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('alterations', 'Var', (24, 35))	('MYBL1', 'Gene', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('MYB', 'Gene', '4602', (43, 46))	('MYBL1', 'Gene', '4603', (43, 48))	('MYB', 'Gene', '4602', (53, 56))	('MYB', 'Gene', (53, 56))	('MYB', 'Gene', (43, 46))
11223	31563982	MYBL1 fusions were detected in 8/22 tumours (36%; Fig.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumours', 'Disease', (36, 43))	('MYBL1', 'Gene', (0, 5))	('detected', 'Reg', (19, 27))	('MYBL1', 'Gene', '4603', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('fusions', 'Var', (6, 13))
11229	31563982	Some fusions were associated with corresponding changes of the CNP: The MYBL1-MMP16 fused cases showed corresponding duplications in the CNP (Fig.	('MYBL1', 'Gene', '4603', (72, 77))	('MMP16', 'Gene', '4325', (78, 83))	('MMP16', 'Gene', (78, 83))	('CNP', 'MPA', (137, 140))	('duplications', 'Var', (117, 129))	('MYBL1', 'Gene', (72, 77))
11231	31563982	However, there was only a partial overlap of the cases with MYBL1 fusions in RNA sequencing and those with copy number alterations of MYBL1 (Fig.	('MYBL1', 'Gene', (134, 139))	('MYBL1', 'Gene', (60, 65))	('MYBL1', 'Gene', '4603', (60, 65))	('MYBL1', 'Gene', '4603', (134, 139))	('fusions', 'Var', (66, 73))
11235	31563982	4c), we detected two MYB-HMG20A fusions with two different breakpoints in MYB, likely representing splice variants.	('fusions', 'Var', (32, 39))	('HMG20A', 'Gene', (25, 31))	('HMG20A', 'Gene', '10363', (25, 31))	('MYB', 'Gene', '4602', (74, 77))	('MYB', 'Gene', '4602', (21, 24))	('MYB', 'Gene', (74, 77))	('MYB', 'Gene', (21, 24))
11237	31563982	4c) While some of the fusions resulted in a truncation of MYB before the negative regulatory C-myb domain reminiscent of the MYBL1 fusions, others resulted in a truncation downstream of the C-myb domain leading to a loss of the 3' miRNA-binding sites of MYB.	('MYBL1', 'Gene', '4603', (125, 130))	('MYB', 'Gene', (254, 257))	('C-myb', 'Gene', (190, 195))	('truncation', 'MPA', (44, 54))	('MYB', 'Gene', '4602', (125, 128))	('C-myb', 'Gene', '4602', (190, 195))	('MYB', 'Gene', '4602', (254, 257))	('fusions', 'Var', (131, 138))	('MYB', 'Gene', (125, 128))	('fusions', 'Var', (22, 29))	('truncation', 'MPA', (161, 171))	("3' miRNA-binding sites", 'MPA', (228, 250))	('loss', 'NegReg', (216, 220))	('MYB', 'Gene', '4602', (58, 61))	('MYBL1', 'Gene', (125, 130))	('C-myb', 'Gene', (93, 98))	('C-myb', 'Gene', '4602', (93, 98))	('MYB', 'Gene', (58, 61))
11239	31563982	In sum, we detected MYBL1 or MYB fusions in 11/22 (50%) of the cases analysed by RNA sequencing (Fig.	('MYB', 'Gene', (20, 23))	('detected', 'Reg', (11, 19))	('fusions', 'Var', (33, 40))	('MYB', 'Gene', '4602', (29, 32))	('MYBL1', 'Gene', (20, 25))	('MYBL1', 'Gene', '4603', (20, 25))	('MYB', 'Gene', (29, 32))	('MYB', 'Gene', '4602', (20, 23))
11241	31563982	Deletion of the C-terminal regions of MYBL1 or MYB has been shown to result in an upregulation of the corresponding gene.	('MYB', 'Gene', (38, 41))	('MYB', 'Gene', '4602', (47, 50))	('MYBL1', 'Gene', (38, 43))	('upregulation', 'PosReg', (82, 94))	('MYBL1', 'Gene', '4603', (38, 43))	('MYB', 'Gene', (47, 50))	('MYB', 'Gene', '4602', (38, 41))	('Deletion', 'Var', (0, 8))
11246	31563982	The isomorphic diffuse glioma with a rearrangement with breakpoint 5' of MYBL1 (#3) also had an increased MYBL1 expression.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('increased', 'PosReg', (96, 105))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	("rearrangement with breakpoint 5'", 'Var', (37, 69))	('MYBL1', 'Gene', '4603', (73, 78))	('glioma', 'Disease', (23, 29))	('MYBL1', 'Gene', (106, 111))	('MYBL1', 'Gene', '4603', (106, 111))	('MYBL1', 'Gene', (73, 78))	('expression', 'MPA', (112, 122))
11255	31563982	It is possible that these cases have fusions of a MYB-family gene that are not evident from the CNP.	('MYB', 'Gene', (50, 53))	('MYB', 'Gene', '4602', (50, 53))	('fusions', 'Var', (37, 44))
11296	31563982	MYB or MYBL1 fusions result in an activation and overexpression of the respective gene through loss of the C-terminal negative regulatory domain (C-myb).	('MYB', 'Gene', (0, 3))	('loss', 'NegReg', (95, 99))	('MYBL1', 'Gene', '4603', (7, 12))	('C-myb', 'Gene', (146, 151))	('MYB', 'Gene', '4602', (0, 3))	('fusions', 'Var', (13, 20))	('activation', 'PosReg', (34, 44))	('C-terminal negative regulatory domain', 'MPA', (107, 144))	('MYB', 'Gene', '4602', (7, 10))	('overexpression', 'PosReg', (49, 63))	('MYBL1', 'Gene', (7, 12))	('MYB', 'Gene', (7, 10))	('C-myb', 'Gene', '4602', (146, 151))
11297	31563982	MYB fusions also lead to a loss of the 3' UTR binding sites for several microRNAs that also negatively regulate MYB mRNA stability and translation.	('MYB', 'Gene', (0, 3))	("3' UTR", 'MPA', (39, 45))	('fusions', 'Var', (4, 11))	('translation', 'MPA', (135, 146))	('negatively', 'NegReg', (92, 102))	('MYB', 'Gene', '4602', (112, 115))	('regulate', 'Reg', (103, 111))	('MYB', 'Gene', '4602', (0, 3))	('MYB', 'Gene', (112, 115))	('loss', 'NegReg', (27, 31))	('mRNA stability', 'MPA', (116, 130))
11298	31563982	MYB/MYBL1 fusions have been detected in a variety of tumour entities such as adenoid cystic carcinoma, haematological neoplasias and, in the CNS, angiocentric glioma and paediatric diffuse gliomas/astrocytomas.	('MYB', 'Gene', (4, 7))	('adenoid cystic carcinoma', 'Disease', (77, 101))	('haematological neoplasias', 'Disease', 'MESH:D009369', (103, 128))	('haematological neoplasias', 'Disease', (103, 128))	('detected', 'Reg', (28, 36))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('MYB', 'Gene', '4602', (0, 3))	('gliomas/astrocytomas', 'Disease', 'MESH:D005910', (189, 209))	('gliomas/astrocytomas', 'Disease', (189, 209))	('MYB', 'Gene', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('haematological neoplasias', 'Phenotype', 'HP:0004377', (103, 128))	('tumour entities', 'Disease', 'MESH:D009369', (53, 68))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (77, 101))	('astrocytoma', 'Phenotype', 'HP:0009592', (197, 208))	('angiocentric glioma', 'Disease', (146, 165))	('fusions', 'Var', (10, 17))	('angiocentric glioma', 'Disease', 'MESH:D005910', (146, 165))	('MYBL1', 'Gene', '4603', (4, 9))	('MYBL1', 'Gene', (4, 9))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('tumour entities', 'Disease', (53, 68))	('neoplasias', 'Phenotype', 'HP:0002664', (118, 128))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('MYB', 'Gene', '4602', (4, 7))
11301	31563982	However, in isomorphic diffuse gliomas, MYBL1 fusions were the most abundant, while fusions in previously-published paediatric diffuse astrocytomas primarily affected MYB.	('astrocytomas', 'Disease', (135, 147))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('fusions', 'Var', (46, 53))	('MYBL1', 'Gene', (40, 45))	('MYB', 'Gene', '4602', (40, 43))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('affected', 'Reg', (158, 166))	('MYBL1', 'Gene', '4603', (40, 45))	('astrocytoma', 'Phenotype', 'HP:0009592', (135, 146))	('MYB', 'Gene', (40, 43))	('abundant', 'Reg', (68, 76))	('MYB', 'Gene', '4602', (167, 170))	('MYB', 'Gene', (167, 170))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('astrocytomas', 'Disease', 'MESH:D001254', (135, 147))	('gliomas', 'Disease', (31, 38))
11305	31563982	We expect that for the other two cases and also further cases with MYB/MYBL1-copy number alterations but without detected MYB or MYBL1 fusion, technical reasons due to low RNA quality extracted from the FFPE material may have hindered the identification of alterations.	('MYBL1', 'Gene', (129, 134))	('MYBL1', 'Gene', (71, 76))	('MYB', 'Gene', '4602', (67, 70))	('MYB', 'Gene', '4602', (71, 74))	('MYBL1', 'Gene', '4603', (129, 134))	('MYB', 'Gene', (67, 70))	('MYB', 'Gene', '4602', (129, 132))	('MYB', 'Gene', (71, 74))	('MYBL1', 'Gene', '4603', (71, 76))	('MYB', 'Gene', (129, 132))	('MYB', 'Gene', '4602', (122, 125))	('alterations', 'Var', (89, 100))	('MYB', 'Gene', (122, 125))
11323	31563982	In summary, isomorphic diffuse glioma is a morphologically recognizable and molecularly distinct IDH-wildtype glioma with alterations of the MYBL1- and, less frequently, the MYB-gene that exists both in paediatric and in adult patients.	('MYB', 'Gene', (141, 144))	('glioma', 'Disease', (110, 116))	('MYBL1', 'Gene', '4603', (141, 146))	('IDH', 'Gene', (97, 100))	('MYB', 'Gene', '4602', (141, 144))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH', 'Gene', '3417', (97, 100))	('patients', 'Species', '9606', (227, 235))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('MYB', 'Gene', '4602', (174, 177))	('alterations', 'Var', (122, 133))	('MYBL1', 'Gene', (141, 146))	('glioma', 'Disease', (31, 37))	('MYB', 'Gene', (174, 177))
11326	29232556	MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8.	('promoting', 'PosReg', (143, 152))	('Glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('Glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('autophagosome formation', 'CPA', (153, 176))	('ATG8', 'Gene', (212, 216))	('Tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MST4', 'Gene', '51765', (0, 4))	('Glioblastoma', 'Disease', (100, 112))	('ATG4B', 'Gene', '66615', (113, 118))	('stimulates', 'PosReg', (119, 129))	('ATG4B', 'Gene', '66615', (24, 29))	('Tumorigenicity', 'CPA', (61, 75))	('autophagy', 'CPA', (130, 139))	('Autophagic Activity', 'CPA', (40, 59))	('MST4', 'Gene', (0, 4))	('ATG4B', 'Gene', (113, 118))	('ATG4B', 'Gene', (24, 29))	('modification', 'Var', (196, 208))	('Radioresistance', 'CPA', (81, 96))	('ATG8', 'Gene', '11345', (212, 216))
11329	29232556	Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ATG4B', 'Gene', (83, 88))	('glioblastoma', 'Disease', (136, 148))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('autophagy', 'CPA', (100, 109))	('inhibitor', 'Var', (70, 79))	('suppresses', 'NegReg', (89, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('tumor', 'Disease', (118, 123))
11331	29232556	Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Inhibiting', 'Var', (0, 10))	('ATG4B', 'Gene', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('slows', 'NegReg', (108, 113))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Disease', (114, 119))	('survival benefit', 'CPA', (154, 170))
11333	29232556	MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383 Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models  Huang et al.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('enhances', 'PosReg', (267, 275))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (285, 290))	('S383', 'Var', (163, 167))	('phosphorylation', 'CPA', (214, 229))	('MST4', 'Gene', (188, 192))	('expression', 'MPA', (193, 203))	('expression', 'Species', '29278', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
11335	29232556	Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.	('glioblastoma', 'Disease', (60, 72))	('autophagy', 'CPA', (28, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('tumor', 'Disease', (42, 47))	('ATG4B', 'Gene', (14, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('reduces', 'NegReg', (20, 27))	('mice', 'Species', '10090', (142, 146))	('Inhibition', 'Var', (0, 10))	('improves', 'PosReg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('impact', 'MPA', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
11372	29232556	These results support epigenetic silencing as a mechanism by which STK26 expression is suppressed in PN-like GSCs.	('PN-like', 'Disease', (101, 108))	('STK26', 'Gene', '51765', (67, 72))	('expression', 'Species', '29278', (73, 83))	('expression', 'MPA', (73, 83))	('epigenetic silencing', 'Var', (22, 42))	('suppressed', 'NegReg', (87, 97))	('STK26', 'Gene', (67, 72))
11374	29232556	shRNA knockdown inhibited GSC glioma cell growth and sphere-forming ability in vitro (Figures 2A, 2B, and S2B-S2D) and markedly suppressed intracranial tumor growth in athymic nude mice (Figures 2C, S2E, and S2F), thereby significantly prolonging animal subject survival (Figure 2D).	('inhibited', 'NegReg', (16, 25))	('nude mice', 'Species', '10090', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('sphere-forming ability', 'CPA', (53, 75))	('intracranial tumor', 'Disease', (139, 157))	('animal subject survival', 'CPA', (247, 270))	('prolonging', 'PosReg', (236, 246))	('glioma', 'Disease', (30, 36))	('suppressed', 'NegReg', (128, 138))	('knockdown', 'Var', (6, 15))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('intracranial tumor', 'Disease', 'MESH:D001932', (139, 157))	('shRNA', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
11375	29232556	We found that rescue with exogenous MST4, but not an empty vector control, restored GSC cell growth and sphere-forming frequency in vitro and tumorigenicity in the brains of athymic mice (Figures 2E-2G, S2H, and S2I).	('GSC cell growth', 'CPA', (84, 99))	('restored', 'PosReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MST4', 'Gene', (36, 40))	('tumor', 'Disease', (142, 147))	('mice', 'Species', '10090', (182, 186))	('sphere-forming frequency', 'CPA', (104, 128))	('exogenous', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
11376	29232556	To further investigate the effects of modulating MST4 expression, we transduced cells with constructs to express exogenous WT MST4 or kinase-dead (KD) MST4 mutants K53E and T178A in GSC 23, 528, and JK42 with low endogenous MST4 (Figures 1B and S2J).	('T178A', 'Mutation', 'c.178T>A', (173, 178))	('K53E', 'Mutation', 'rs770534113', (164, 168))	('mutants K53E', 'Var', (156, 168))	('T178A', 'Var', (173, 178))	('MST4', 'Gene', (151, 155))	('expression', 'Species', '29278', (54, 64))	('K53E', 'Var', (164, 168))
11377	29232556	Ectopic expression of WT but not KD MST4 mutants promoted GSC growth and sphere-forming frequency in vitro (Figures 2H, 2I, S2K, and S2L).	('mutants', 'Var', (41, 48))	('GSC growth', 'CPA', (58, 68))	('MST4', 'Gene', (36, 40))	('expression', 'Species', '29278', (8, 18))	('promoted', 'PosReg', (49, 57))	('sphere-forming frequency', 'CPA', (73, 97))
11381	29232556	With respect to the identified phosphorylated proteins, we found ATG4B, a major cysteine protease that cleaves LC3 and catalyzes the lipidation and delipidation of LC3, to be highly phosphorylated at serine residue 383 (S383) in GSCs expressing MST4 (Figures 3A and S3A).	('LC3', 'Gene', '84557', (164, 167))	('MST4', 'Var', (245, 249))	('LC3', 'Gene', (164, 167))	('ATG4B', 'Gene', (65, 70))	('S383', 'Var', (220, 224))	('serine', 'Chemical', 'MESH:D012694', (200, 206))	('LC3', 'Gene', '84557', (111, 114))	('LC3', 'Gene', (111, 114))
11384	29232556	Next, we examined whether MST4 directly phosphorylates ATG4B by co-expressing Myc-tagged MST4 with FLAG-tagged WT ATG4B or with a non-phosphorylatable S383A ATG4B mutant.	('S383A', 'Mutation', 'p.S383A', (151, 156))	('Myc', 'Gene', (78, 81))	('Myc', 'Gene', '17869', (78, 81))	('S383A', 'Var', (151, 156))	('MST4', 'Gene', (89, 93))
11386	29232556	To confirm these findings, we generated an antibody that specifically detects p-S383 of endogenous ATG4B (p-ATG4B) in JK83 cells and in GSC 17 modified for overexpression of MST4, but not for GFP control (Figure S3G).	('p-ATG4B', 'Gene', (106, 113))	('p-S383', 'Var', (78, 84))	('expression', 'Species', '29278', (160, 170))	('ATG4B', 'Gene', (99, 104))	('p-ATG4B', 'Gene', '23192', (106, 113))
11387	29232556	Moreover, p-S383 of endogenous ATG4B was also detected in GBM tumor sections using the anti-p-ATG4B antibody.	('p-S383', 'Var', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ATG4B', 'Gene', (31, 36))	('GBM tumor', 'Disease', 'MESH:D005910', (58, 67))	('GBM tumor', 'Disease', (58, 67))	('detected', 'Reg', (46, 54))	('p-ATG4B', 'Gene', '23192', (92, 99))	('p-ATG4B', 'Gene', (92, 99))
11388	29232556	Binding of the anti-p-ATG4B antibody was blocked by treating specimens with phosphorylated ATG4B peptide RLERFFD(pS)EDEDFEI, but not with the non-phosphorylated peptide RLERFFDSEDEDFEI (Figure S3H).	('p-ATG4B', 'Gene', '23192', (20, 27))	('p-ATG4B', 'Gene', (20, 27))	('blocked', 'NegReg', (41, 48))	('ATG4B', 'Gene', (91, 96))	('peptide RLERFFD', 'Var', (97, 112))	('Binding', 'Interaction', (0, 7))
11390	29232556	To further confirm ATG4B S383 phosphorylation by MST4, we carried out an in vitro kinase assay using purified recombinant proteins of MST4-WT, a KD MST4 mutant (K53E), ATG4B-WT, and the non-phosphorylatable ATG4B-S383A mutant.	('K53E', 'Mutation', 'rs770534113', (161, 165))	('MST4', 'Gene', (148, 152))	('K53E', 'Var', (161, 165))	('S383A', 'Mutation', 'p.S383A', (213, 218))
11393	29232556	We additionally determined that exogenously expressed WT and KD MST4 associated with WT and S383A ATG4B (Figure 3F), suggesting that neither MST4 kinase activity nor S383 was required for MST4-ATG4B interaction.	('S383A', 'Var', (92, 97))	('interaction', 'Interaction', (199, 210))	('MST4', 'Gene', (64, 68))	('S383A', 'Mutation', 'p.S383A', (92, 97))	('associated', 'Interaction', (69, 79))
11397	29232556	When endogenous MST4 or ATG4B were knocked down by specific shRNAs in GSC 1123 and JK83, the associated reductions in p-ATG4B resulted in a corresponding decrease in LC3-II conversion (LC3B-II/I ratio) and increased p62/SQSTM1, an established autophagy substrate (Figure 4A).	('reductions', 'NegReg', (104, 114))	('LC3', 'Gene', '84557', (185, 188))	('ATG4B', 'Gene', (24, 29))	('increased', 'PosReg', (206, 215))	('LC3', 'Gene', (185, 188))	('decrease', 'NegReg', (154, 162))	('p-ATG4B', 'Gene', (118, 125))	('p-ATG4B', 'Gene', '23192', (118, 125))	('LC3', 'Gene', '84557', (166, 169))	('MST4', 'Gene', (16, 20))	('LC3', 'Gene', (166, 169))	('JK83', 'Var', (83, 87))	('p62/SQSTM1', 'MPA', (216, 226))
11398	29232556	MST4 overexpression induced p-S383 of ATG4B, increased LC3-II conversion, LC3B puncta, autophagosome formation, and YFP-CFP-LC3B cleavage (Figures S4A-S4C).	('ATG4B', 'Gene', (38, 43))	('autophagosome formation', 'CPA', (87, 110))	('increased', 'PosReg', (45, 54))	('LC3', 'Gene', '84557', (55, 58))	('LC3', 'Gene', '84557', (124, 127))	('expression', 'Species', '29278', (9, 19))	('LC3', 'Gene', (124, 127))	('increased LC3', 'Phenotype', 'HP:0003141', (45, 58))	('LC3', 'Gene', (55, 58))	('LC3', 'Gene', '84557', (74, 77))	('LC3', 'Gene', (74, 77))	('MST4', 'Gene', (0, 4))	('p-S383', 'Var', (28, 34))
11399	29232556	To demonstrate whether MST4-induced p-S383 of ATG4B is critical in MST4-enhanced GSC tumorigenicity, we re-expressed exogenous WT or a phosphomimic S383D mutant ATG4B in GSC 1123 cells, in which endogenous MST4 was knocked down by shRNA (Figure 4E).	('tumor', 'Disease', (85, 90))	('S383D', 'Mutation', 'p.S383D', (148, 153))	('S383D', 'Var', (148, 153))	('p-S383', 'Var', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('ATG4B', 'Gene', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
11400	29232556	Exogenous phosphomimic S383D ATG4B markedly rescued the MST4 knockdown-inhibited GSC cell growth and sphere-forming frequency in vitro (Figures 4F, S4D, and S4E) and tumorigenicity of orthotopic GBM xenografts (Figures 4G, 4H, and S4F).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('GSC cell growth', 'CPA', (81, 96))	('rescued', 'PosReg', (44, 51))	('MST4', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('S4E', 'Mutation', 'p.S4E', (157, 160))	('knockdown-inhibited', 'Var', (61, 80))	('tumor', 'Disease', (166, 171))	('S383D', 'Mutation', 'p.S383D', (23, 28))	('S383D', 'Var', (23, 28))	('sphere-forming frequency', 'CPA', (101, 125))
11401	29232556	Next, we expressed exogenous WT or the S383D mutant ATG4B in GSC JK16 cells with low levels of endogenous ATG4B but with high levels of endogenous MST4 (Figure S3I).	('S383D', 'Var', (39, 44))	('ATG4B', 'Gene', (52, 57))	('S383D', 'Mutation', 'p.S383D', (39, 44))
11402	29232556	Expression of exogenous WT ATG4B but not a vector control in unmodified JK16 cells, or the S383D but not WT ATG4B in JK16 cells modified with knockdown of MST4, increased autophagic activity and sphere-forming frequency (Figures 4I-4K and S4G).	('MST4', 'Gene', (155, 159))	('S383D', 'Var', (91, 96))	('autophagic activity', 'CPA', (171, 190))	('sphere-forming frequency', 'CPA', (195, 219))	('Expression', 'Species', '29278', (0, 10))	('increased', 'PosReg', (161, 170))	('S383D', 'Mutation', 'p.S383D', (91, 96))	('knockdown', 'Var', (142, 151))
11403	29232556	To further evaluate of the importance of ATG4B S383 phosphorylation in autophagic response, we overexpressed WT, S383A, or a non-catalytic mutant C74S ATG4B in JK16 cells.	('ATG4B', 'Gene', (151, 156))	('C74S', 'Mutation', 'rs1470862162', (146, 150))	('C74S', 'Var', (146, 150))	('S383A', 'Var', (113, 118))	('S383A', 'Mutation', 'p.S383A', (113, 118))
11404	29232556	We found that WT, but not C74S or S383A mutant ATG4B, markedly increased LC3-II conversion and LC3B puncta (Figures S4H and S4I).	('increased', 'PosReg', (63, 72))	('increased LC3', 'Phenotype', 'HP:0003141', (63, 76))	('LC3', 'Gene', '84557', (73, 76))	('S383A', 'Var', (34, 39))	('LC3', 'Gene', (73, 76))	('LC3', 'Gene', '84557', (95, 98))	('C74S', 'Var', (26, 30))	('S383A', 'Mutation', 'p.S383A', (34, 39))	('ATG4B', 'Gene', (47, 52))	('C74S', 'Mutation', 'rs1470862162', (26, 30))	('LC3', 'Gene', (95, 98))
11405	29232556	WT, but not S383A or C74S mutant ATG4B, also increased the cleavage of FRET-LC3B (Figure S4J).	('C74S', 'Var', (21, 25))	('C74S', 'Mutation', 'rs1470862162', (21, 25))	('S383A', 'Var', (12, 17))	('increased', 'PosReg', (45, 54))	('FRET-LC3B', 'Protein', (71, 80))	('S383A', 'Mutation', 'p.S383A', (12, 17))	('cleavage', 'MPA', (59, 67))	('ATG4B', 'Gene', (33, 38))
11406	29232556	Furthermore, ATG4B-WT but not its mutants significantly elevated GSC JK16 sphere formation, survival, and proliferation (Figures S4K and S4L).	('elevated', 'PosReg', (56, 64))	('survival', 'CPA', (92, 100))	('S4L', 'Mutation', 'p.S4L', (137, 140))	('ATG4B-WT', 'Var', (13, 21))	('GSC JK16', 'Gene', (65, 73))	('proliferation', 'CPA', (106, 119))
11407	29232556	Consistent with these observations, in M83 cells with endogenous ATG4B depleted, expression of exogenous WT or S383D, but not C74S or S383A ATG4B, restored ATG4B S383 phosphorylation, LC3-I/II conversion, and LC3B puncta (Figures S4M and S4N).	('C74S', 'Mutation', 'rs1470862162', (126, 130))	('LC3', 'Gene', (209, 212))	('restored', 'PosReg', (147, 155))	('S383D', 'Mutation', 'p.S383D', (111, 116))	('S383D', 'Var', (111, 116))	('S383', 'Var', (162, 166))	('LC3', 'Gene', '84557', (184, 187))	('LC3', 'Gene', (184, 187))	('expression', 'Species', '29278', (81, 91))	('S383A', 'Mutation', 'p.S383A', (134, 139))	('LC3', 'Gene', '84557', (209, 212))	('ATG4B', 'Gene', (156, 161))
11408	29232556	Conversely, in GSC 528 cells having non-detectable MST4 (Figure 1B), expression of exogenous MST4 induced p-ATG4B, LC3-II conversion, autophagosome formation, and increased sphere-forming frequency while decreasing p62.	('p-ATG4B', 'Gene', (106, 113))	('LC3', 'Gene', (115, 118))	('MST4', 'Gene', (93, 97))	('increased', 'PosReg', (163, 172))	('expression', 'Species', '29278', (69, 79))	('induced', 'PosReg', (98, 105))	('LC3', 'Gene', '84557', (115, 118))	('p-ATG4B', 'Gene', '23192', (106, 113))	('p62', 'MPA', (215, 218))	('sphere-forming frequency', 'CPA', (173, 197))	('autophagosome formation', 'CPA', (134, 157))	('decreasing', 'NegReg', (204, 214))	('expression', 'Var', (69, 79))
11410	29232556	Lastly, we examined whether knockdown or overexpression of MST4, and knockdown of ATG4B affect the ERK- and AKT-signaling pathways, which regulate the onset of autophagy and autophagic activity.	('AKT', 'Gene', '207', (108, 111))	('affect', 'Reg', (88, 94))	('AKT', 'Gene', (108, 111))	('expression', 'Species', '29278', (45, 55))	('ATG4B', 'Gene', (82, 87))	('knockdown', 'Var', (69, 78))
11413	29232556	Finally, PD98059, a MEK1 inhibitor, reduced p-ERK but had no effects on p-ATG4B and autophagic activity in GSCs (Figure S5E).	('PD98059', 'Chemical', 'MESH:C093973', (9, 16))	('p-ERK', 'MPA', (44, 49))	('p-ATG4B', 'Gene', '23192', (72, 79))	('p-ATG4B', 'Gene', (72, 79))	('autophagic activity', 'CPA', (84, 103))	('reduced', 'NegReg', (36, 43))	('PD98059', 'Var', (9, 16))
11416	29232556	We found that ATG4B-WT or phosphomimic S383D, but not the non-catalytic C74S or non-phosphorylatable S383A mutant, rescued GSC cell proliferation and sphere formation in vitro as well as tumorigenicity in vivo (Figures 6G-6K and S6C-S6I).	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('S383A', 'Mutation', 'p.S383A', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('sphere formation', 'CPA', (150, 166))	('C74S', 'Mutation', 'rs1470862162', (72, 76))	('tumor', 'Disease', (187, 192))	('GSC cell proliferation', 'CPA', (123, 145))	('S383D', 'Var', (39, 44))	('S383D', 'Mutation', 'p.S383D', (39, 44))	('rescued', 'PosReg', (115, 122))
11419	29232556	However, inhibition of ATG5 or ATG7 had a minimal effect on inhibition of cell growth resulting from ATG4B knockdown (Figure S6K).	('knockdown', 'Var', (107, 116))	('ATG7', 'Gene', '74244', (31, 35))	('ATG7', 'Gene', (31, 35))	('ATG4B', 'Gene', (101, 106))	('cell growth', 'CPA', (74, 85))	('ATG5', 'Gene', '11793', (23, 27))	('ATG5', 'Gene', (23, 27))
11425	29232556	NSC did not enhance the effects of STK26 knockout (KO) on M83 xenograft growth and autophagic activity in vivo (Figures S7F-S7I).	('STK26', 'Gene', '51765', (35, 40))	('knockout', 'Var', (41, 49))	('STK26', 'Gene', (35, 40))	('autophagic activity', 'CPA', (83, 102))
11433	29232556	On the other hand, IR on GSC JK83, JK42, and JK18 cells, which are not yet molecularly classified, increased endogenous MST4 and p-ATG4B, but only at a higher IR dose (5 Gy) and at later time points subsequent to IR (>=6 days, Figure S7M).	('GSC JK83', 'Var', (25, 33))	('JK42', 'Var', (35, 39))	('MST4', 'Protein', (120, 124))	('p-ATG4B', 'Gene', (129, 136))	('increased', 'PosReg', (99, 108))	('p-ATG4B', 'Gene', '23192', (129, 136))	('endogenous', 'MPA', (109, 119))
11441	29232556	Apoptosis indicators gammaH2AX and cleaved caspase-3 were also markedly increased 6 hr following completion of IR when compared with control (p < 0.001, Figures S7S-S7V).	('increased', 'PosReg', (72, 81))	('cleaved caspase-3', 'MPA', (35, 52))	('Apoptosis', 'CPA', (0, 9))	('gammaH2AX', 'Chemical', '-', (21, 30))	('gammaH2AX', 'Var', (21, 30))
11445	29232556	The clinical implications of these findings are highlighted by the determination of patient survival being inversely correlated with MST4, p-ATG4B, and LC3B staining (Figure 8C).	('p-ATG4B', 'Gene', (139, 146))	('MST4', 'Gene', (133, 137))	('patient', 'Species', '9606', (84, 91))	('p-ATG4B', 'Gene', '23192', (139, 146))	('inversely', 'NegReg', (107, 116))	('LC3B staining', 'Var', (152, 165))
11449	29232556	Pharmacologic inhibition of ATG4B using NSC185058 markedly attenuates autophagic activity, decreases GBM cell tumorigenicity, and enhances the anti-tumor activity of RT when applied to orthotopic GBM xenograft models.	('ATG4B', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('NSC185058', 'Var', (40, 49))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('attenuates', 'NegReg', (59, 69))	('enhances', 'PosReg', (130, 138))	('decreases', 'NegReg', (91, 100))	('autophagic activity', 'CPA', (70, 89))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
11458	29232556	Although phosphorylation of serine 383 (p-S383) and p-S392 on ATG4B is important for ATG4B in controlling the autophagic process, this study describes MST4 as the authentic kinase for S383 phosphorylation that is critical in stimulating autophagy and tumorigenicity in GBM.	('autophagy', 'CPA', (237, 246))	('tumor', 'Disease', (251, 256))	('serine', 'Chemical', 'MESH:D012694', (28, 34))	('p-S392', 'Var', (52, 58))	('S383', 'Var', (184, 188))	('MST4', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('stimulating', 'PosReg', (225, 236))
11472	29232556	In conclusion, this study not only describes a signaling relationship by which MST4 phosphorylation of ATG4B promotes autophagy, contributes to GBM malignancy, and lessens tumor response to RT, but also reveals a clinical opportunity involving combined ATG4B inhibitor and RT for treating patients with GBM.	('lessens tumor', 'Disease', 'MESH:D009369', (164, 177))	('contributes', 'Reg', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('GBM', 'Disease', (144, 147))	('ATG4B', 'Gene', (103, 108))	('lessens tumor', 'Disease', (164, 177))	('autophagy', 'CPA', (118, 127))	('MST4 phosphorylation', 'Var', (79, 99))	('malignancy', 'Disease', 'MESH:D009369', (148, 158))	('malignancy', 'Disease', (148, 158))	('promotes', 'PosReg', (109, 117))	('patients', 'Species', '9606', (289, 297))
11508	29232556	Human cDNAs for ATG4B and its variants were cloned by PCR and then sub-cloned into pET-28a for expression in E. coli.	('Human', 'Species', '9606', (0, 5))	('variants', 'Var', (30, 38))	('E. coli', 'Species', '562', (109, 116))	('expression', 'Species', '29278', (95, 105))	('ATG4B', 'Gene', (16, 21))
11509	29232556	Lentiviral vectors expressing non-target control shRNA, specific shRNA constructs (MST4, ATG4B, ATG5 or ATG7), or full-length MST4, ATG4B or their mutant cDNAs were transfected into 293T using Lipofectamine 2000 in accordance to the manufacturer's instructions.	('ATG7', 'Gene', (104, 108))	('ATG5', 'Gene', '11793', (96, 100))	('293T', 'CellLine', 'CVCL:0063', (182, 186))	('ATG5', 'Gene', (96, 100))	('MST4', 'Var', (126, 130))	('ATG4B', 'Var', (132, 137))	('ATG7', 'Gene', '74244', (104, 108))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (193, 211))
11517	29232556	In brief, dissociated cells from glioma spheres seeded in 96-well plates at density of 1, 5, 10, 20 or 50 for GSC M83, 1123, JK83, 528 and 23 cells, and 5, 10, 20, 50 or 100 for JK16 and JK42 cells per well.	('JK83', 'Var', (125, 129))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Disease', (33, 39))
11518	29232556	After 7 days for GSC M83 and 1123, and 14 days for GSC JK16, JK42, JK83, 528 and 23, each well was examined for formation of tumor spheres.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('JK83', 'Var', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('JK42', 'Var', (61, 65))
11551	29232556	Sensitivities of each antibody such as the anti-MST4, anti-p-S383-ATG4B and anti-LC3B antibodies used in this study on detection of corresponding protein expression on GBM tumor sample sections are variable.	('expression', 'Species', '29278', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('GBM tumor', 'Disease', 'MESH:D005910', (168, 177))	('anti-MST4', 'Var', (43, 52))	('GBM tumor', 'Disease', (168, 177))	('anti-p-S383-ATG4B', 'Var', (54, 71))
11624	29156720	The n-6 PUFA linoleic acid content in terms of total lipids composition was significantly greater in tumor tissue than in normal one.	('total lipids composition', 'MPA', (47, 71))	('n-6', 'Var', (4, 7))	('greater', 'PosReg', (90, 97))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('n-6 PUFA', 'Chemical', '-', (4, 12))	('lipids', 'Chemical', 'MESH:D008055', (53, 59))	('linoleic acid', 'Chemical', 'MESH:D019787', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
11626	29156720	Figure 3 shows distribution of lipids and proteins in the human normal brain tissue (P17) obtained from the basis analysis in the high frequency region and fingerprint region with the following spectral filters: (a) two filters 2800-2920 cm-1 (lipids) and 2900-3010 cm-1 (proteins) for the high frequency region, and (b) two filters for the fingerprint region 1400-1515 (lipids), 1605-1695 (proteins).	('lipids', 'Chemical', 'MESH:D008055', (371, 377))	('2900-3010 cm-1', 'Var', (256, 270))	('human', 'Species', '9606', (58, 63))	('P17', 'Gene', (85, 88))	('lipids', 'Chemical', 'MESH:D008055', (31, 37))	('lipids', 'Chemical', 'MESH:D008055', (244, 250))	('P17', 'Gene', '653820', (85, 88))	('2800-2920 cm-1', 'Var', (228, 242))
11631	29156720	Detailed inspection into Figure 4 and Table 2 demonstrates that the Raman spectra of the human normal brain tissue provide information about proteins (alpha-helix proteins at ~1658 cm-1 (Amide I), ~1276 cm-1 (Amide III); beta-sheet proteins at ~1667-1680 cm-1 (Amide I), 1558 cm-1 (Amide II), 1238 cm-1 (Amide III), 2940 cm-1 (CH3 stretching)), lipids (cell membrane phospholipids at ~1080-1158, 1248 cm-1 (symmetric and antisymmetric P=O stretching), fatty acids, triglycerides at ~1437-1444 cm-1 (CH2 deformation(bending)), at ~1658 (C=C stretching), at ~1742 cm-1 (C=0 stretching), ~2845-2940 cm-1 (CH2, CH3 stretching)), (H3C)N+) choline group can at ~721 cm-1), nucleic acids (~751 cm-1, 1080-1158 cm-1, 1584 cm-1), and metabolites (glycogen at 840 cm-1, lactic acid at 917 cm-1).	('C', 'Chemical', 'MESH:D002244', (536, 537))	('C', 'Chemical', 'MESH:D002244', (568, 569))	('~751', 'Var', (682, 686))	('phospholipids', 'Chemical', 'MESH:D010743', (367, 380))	('choline', 'Chemical', 'MESH:D002794', (634, 641))	('lactic acid', 'Chemical', 'MESH:D019344', (760, 771))	('glycogen', 'Chemical', 'MESH:D006003', (738, 746))	('C', 'Chemical', 'MESH:D002244', (607, 608))	('human', 'Species', '9606', (89, 94))	('C', 'Chemical', 'MESH:D002244', (327, 328))	('CH2 deformation', 'Disease', (499, 514))	('lipids', 'Chemical', 'MESH:D008055', (345, 351))	('triglycerides', 'Chemical', 'MESH:D014280', (465, 478))	('C', 'Chemical', 'MESH:D002244', (628, 629))	('C', 'Chemical', 'MESH:D002244', (602, 603))	('C', 'Chemical', 'MESH:D002244', (538, 539))	('fatty acids', 'Chemical', 'MESH:D005227', (452, 463))	('lipids', 'Chemical', 'MESH:D008055', (374, 380))	('C', 'Chemical', 'MESH:D002244', (499, 500))	('CH2 deformation', 'Disease', 'MESH:D009140', (499, 514))	('lactic acid', 'MPA', (760, 771))
11633	29156720	Figure 5 shows the MRI image, the H&E-stained and non-stained microscopic image, Raman images, and vibrational Raman spectra in the fingerprint region and high frequency regions of the tumor tissue (medulloblastoma, grade WHO IV).	('tumor', 'Disease', (185, 190))	('medulloblastoma', 'Disease', 'MESH:D008527', (199, 214))	('tissue', 'Var', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('medulloblastoma', 'Phenotype', 'HP:0002885', (199, 214))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('medulloblastoma', 'Disease', (199, 214))
11634	29156720	One can see that the Raman images of the tumor tissue (Figure 5E and 5F) are dominated by proteins (red region in the Raman images) reflected by Raman peak at 1585 cm-1 and 2935 cm-1 in Figure 5G in Figure 5J, respectively (detailed analysis of the secondary structure will be discussed below).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('proteins', 'Protein', (90, 98))	('2935 cm-1', 'Var', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
11641	29156720	Detailed inspection shows notable differences at 751 cm-1 (nucleic acids, Trp), 992 cm-1 (tyrosine, proline, glycogen, carbohydrates, collagen, glucose, lactic acid), 1080 cm-1, 1130/1170 cm-1 (phospholipids), 1338cm-1 (tryptophan), Calpha-H def), 1369 cm-1, 1392 cm-1, 1448 cm-1 (fatty acids, triglycerides, CH2 or CH3 deformations), 1551 cm-1, 1584 cm-1, 1658/1667 cm-1 (amide II and amide I, nucleic acids), and 1740- 1759 cm-1 (triglycerides).	('1551 cm-1', 'Var', (335, 344))	('tryptophan', 'Chemical', 'MESH:D014364', (220, 230))	('tyrosine', 'Chemical', 'MESH:D014443', (90, 98))	('triglycerides', 'Chemical', 'MESH:D014280', (432, 445))	('1740- 1759 cm-1', 'Var', (415, 430))	('glucose', 'Chemical', 'MESH:D005947', (144, 151))	('amide', 'Chemical', 'MESH:D000577', (386, 391))	('CH2 or CH3 deformations', 'Disease', 'MESH:D009140', (309, 332))	('phospholipids', 'Chemical', 'MESH:D010743', (194, 207))	('proline', 'Chemical', 'MESH:D011392', (100, 107))	('carbohydrates', 'Chemical', 'MESH:D002241', (119, 132))	('Calpha-H', 'Chemical', '-', (233, 241))	('triglycerides', 'Chemical', 'MESH:D014280', (294, 307))	('amide', 'Chemical', 'MESH:D000577', (373, 378))	('glycogen', 'Chemical', 'MESH:D006003', (109, 117))	('CH2 or CH3 deformations', 'Disease', (309, 332))	('lactic acid', 'Chemical', 'MESH:D019344', (153, 164))	('fatty acids', 'Chemical', 'MESH:D005227', (281, 292))
11642	29156720	The most spectacular changes can be observed for Raman bands at 1584 cm-1 and 1658/1667 cm-1 attributed to proteins/nucleic acids, and amide I, respectively.	('amide', 'Chemical', 'MESH:D000577', (135, 140))	('1658/1667 cm-1', 'Var', (78, 92))	('proteins/nucleic', 'Protein', (107, 123))	('changes', 'Reg', (21, 28))	('Raman bands', 'MPA', (49, 60))
11645	29156720	A further inspection into Figure 6C shows also an increase in Raman signal intensity between 1230-1250 cm-1 in the region of amide III vibrations attributed to beta-sheet conformation and an decrease in the region around 1270-1280 cm-1 attributed to alpha-helix conformation.	('amide', 'Chemical', 'MESH:D000577', (125, 130))	('Raman signal intensity', 'MPA', (62, 84))	('beta-sheet conformation', 'Var', (160, 183))	('increase', 'PosReg', (50, 58))	('amide III vibrations', 'MPA', (125, 145))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('decrease', 'NegReg', (191, 199))
11659	29156720	Our Raman results for choline level correlate quite well with the proton magnetic resonance spectroscopy (MRS) results, but also clearly demonstrate that the Raman signals at 1437-1444 cm-1 and 2845-2854 cm-1 that reflect global level of saturated bonds in lipids (not only choline specific) decreases significantly in high grade brain tumors.	('brain tumor', 'Phenotype', 'HP:0030692', (330, 341))	('choline', 'Chemical', 'MESH:D002794', (274, 281))	('lipids', 'Chemical', 'MESH:D008055', (257, 263))	('brain tumors', 'Disease', 'MESH:D001932', (330, 342))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('decreases', 'NegReg', (292, 301))	('brain tumors', 'Phenotype', 'HP:0030692', (330, 342))	('MRS', 'Disease', (106, 109))	('2845-2854 cm-1', 'Var', (194, 208))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('brain tumors', 'Disease', (330, 342))	('choline', 'Chemical', 'MESH:D002794', (22, 29))	('MRS', 'Disease', 'MESH:D008556', (106, 109))
11748	29156720	The low-grade astrocytoma does not exhibit spectacular conformational modifications indicating that alpha-helix structure is not modified to beta-sheet as a result of low grade brain tumor as it was observed for the high grade brain tumors.	('low grade', 'Var', (167, 176))	('brain tumor', 'Disease', 'MESH:D001932', (177, 188))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('astrocytoma', 'Disease', 'MESH:D001254', (14, 25))	('brain tumor', 'Phenotype', 'HP:0030692', (177, 188))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('astrocytoma', 'Disease', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('astrocytoma', 'Phenotype', 'HP:0009592', (14, 25))	('brain tumors', 'Phenotype', 'HP:0030692', (227, 239))	('brain tumor', 'Disease', 'MESH:D001932', (227, 238))	('brain tumors', 'Disease', 'MESH:D001932', (227, 239))	('brain tumor', 'Phenotype', 'HP:0030692', (227, 238))	('brain tumor', 'Disease', (177, 188))	('brain tumors', 'Disease', (227, 239))
11766	28966829	The histological diagnosis was an LGG, WHO II, molecularly characterized by the absence of: IDH1/2 mutation, 1p/19q codeletion, or MGMT promotor hypermethylation.	('LGG', 'Disease', (34, 37))	('IDH1/2', 'Gene', (92, 98))	('MGMT', 'Gene', '4255', (131, 135))	('MGMT', 'Gene', (131, 135))	('mutation', 'Var', (99, 107))	('1p/19q codeletion', 'Var', (109, 126))	('IDH1/2', 'Gene', '3417;3418', (92, 98))	('absence', 'NegReg', (80, 87))
11776	28966829	Every LGG is characterized according to the presence or the absence of mutations in the isocitrate dehydrogenase 1 or 2 genes (IDH) and complete or incomplete deletion of both the short arm of chromosome 1 and of the long arm of chromosome 19 (1p/19q co-deletion).	('short arm', 'Phenotype', 'HP:0009824', (180, 189))	('absence', 'NegReg', (60, 67))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('isocitrate', 'Chemical', 'MESH:C034219', (88, 98))	('mutations', 'Var', (71, 80))	('deletion', 'Var', (159, 167))
11777	28966829	The first segregation of diffuse LGG is based on the presence of IDH1/2 gene mutation [Figure 4].	('presence', 'Var', (53, 61))	('diffuse LGG', 'Disease', (25, 36))	('IDH1/2', 'Gene', (65, 71))	('IDH1/2', 'Gene', '3417;3418', (65, 71))
11778	28966829	These mutations occur at a single amino acid residue of IDH1, arginine 132, which is most commonly mutated to histidine (R132H).	('R132H', 'Mutation', 'rs121913500', (121, 126))	('IDH1', 'Gene', '3417', (56, 60))	('arginine', 'Chemical', 'MESH:D001120', (62, 70))	('arginine 132', 'Var', (62, 74))	('histidine', 'Chemical', 'MESH:D006639', (110, 119))	('IDH1', 'Gene', (56, 60))
11780	28966829	A mutation in the IDH1 gene (IDHmut) allows the homodimeric enzyme to reduce alpha-ketoglutarate in 2-hydroxygluterate (2-HG).	('reduce alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (70, 96))	('mutation', 'Var', (2, 10))	('IDH', 'Gene', (18, 21))	('IDH1', 'Gene', '3417', (18, 22))	('IDH', 'Gene', '3417', (18, 21))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (77, 96))	('2-hydroxygluterate', 'Chemical', '-', (100, 118))	('IDH', 'Gene', (29, 32))	('IDH', 'Gene', '3417', (29, 32))	('IDH1', 'Gene', (18, 22))
11782	28966829	In addition, an IDH gene mutation causes hypermethylation of specific DNA loci (CpG islands), resulting in a significantly different gene expression profile compared to wild type IDH LGG.	('IDH', 'Gene', (179, 182))	('different', 'Reg', (123, 132))	('IDH', 'Gene', '3417', (179, 182))	('mutation', 'Var', (25, 33))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', '3417', (16, 19))	('hypermethylation', 'MPA', (41, 57))	('gene expression profile', 'MPA', (133, 156))
11783	28966829	Specifically, hypermethylation of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) promotor gene downregulates the expression of this enzyme, and therefore increases tumor susceptibility to alkylating agents such as temozolomide.	('tumor', 'Disease', (185, 190))	('MGMT', 'Gene', '4255', (96, 100))	('hypermethylation', 'Var', (14, 30))	('expression', 'MPA', (134, 144))	('downregulates', 'NegReg', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('temozolomide', 'Chemical', 'MESH:D000077204', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('MGMT', 'Gene', (96, 100))	('increases', 'PosReg', (175, 184))
11784	28966829	IDH mutations are present in almost 90% of the diffuse LGG and are correlated with a favorable, therapy independent, survival compared to IDHwt LGG: 13.1 years compared to 5.1 years.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', (138, 141))	('LGG', 'Disease', (55, 58))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (138, 141))	('mutations', 'Var', (4, 13))
11785	28966829	Furthermore, an IDH mutation is predictive for the response of the LGG to multimodal treatment strategies, as was recently shown that the addition of chemotherapy to radiotherapy increases progression-free and overall survival in diffuse LGG compared to radiotherapy alone.	('increases', 'PosReg', (179, 188))	('overall survival', 'CPA', (210, 226))	('mutation', 'Var', (20, 28))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', '3417', (16, 19))	('progression-free', 'CPA', (189, 205))	('diffuse LGG', 'Disease', (230, 241))
11786	28966829	Subsequent to IDHmut/IDHwt segregation, LGGs are classified according to the presence or absence of 1p/19q codeletion.	('IDH', 'Gene', (21, 24))	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (21, 24))	('IDH', 'Gene', '3417', (14, 17))	('1p/19q codeletion', 'Var', (100, 117))
11787	28966829	A strong correlation exists between the presence an IDH mutation and 1p/19q codeletion with the histological oligodendroglioma with a correspondence rate of 95% for WHO II tumors.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('II tumors', 'Disease', (169, 178))	('II tumors', 'Disease', 'MESH:D009369', (169, 178))	('1p/19q codeletion', 'Var', (69, 86))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('oligodendroglioma', 'Disease', (109, 126))	('mutation', 'Var', (56, 64))	('oligodendroglioma', 'Disease', 'MESH:D009837', (109, 126))
11788	28966829	Strikingly, mutations in the coding gene for TElomerase Reverse Transcriptase (TERT) is found in 96% of this subclass.	('mutations', 'Var', (12, 21))	('TElomerase Reverse Transcriptase', 'Gene', '7015', (45, 77))	('TERT', 'Gene', (79, 83))	('TElomerase Reverse Transcriptase', 'Gene', (45, 77))	('TERT', 'Gene', '7015', (79, 83))
11789	28966829	TERT gene mutations cause an activation of this enzyme.	('mutations', 'Var', (10, 19))	('activation', 'PosReg', (29, 39))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (0, 4))
11793	28966829	Almost all diffuse LGGs without a 1p/19q codeletion harbor mutations in the Tumor protein (TP) 53 coding gene and the majority harbor inactivating mutations in the ATRX gene.	('Tumor protein (TP) 53', 'Gene', (76, 97))	('ATRX', 'Gene', (164, 168))	('Tumor protein (TP) 53', 'Gene', '7157', (76, 97))	('Tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ATRX', 'Gene', '546', (164, 168))	('mutations', 'Var', (59, 68))	('diffuse LGGs', 'Disease', (11, 23))	('harbor', 'Reg', (52, 58))
11794	28966829	Dysfunction of the TP-53 gene, as known for the Li-Fraumeni syndrome, causes a loss of tumor suppressive capabilities of TP-53.	('loss', 'NegReg', (79, 83))	('TP-53', 'Gene', (121, 126))	('Dysfunction', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('Li-Fraumeni syndrome', 'Disease', (48, 68))	('TP-53', 'Gene', (19, 24))	('TP-53', 'Gene', '7157', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (48, 68))	('TP-53', 'Gene', '7157', (19, 24))
11795	28966829	For LGG, it is hypothesized that, after the acquisition of an IDH mutation, a tumor cell either acquires a 1p/19q codeletion or a mutation in TP-53.	('1p/19q codeletion', 'MPA', (107, 124))	('TP-53', 'Gene', (142, 147))	('IDH', 'Gene', '3417', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', (78, 83))	('TP-53', 'Gene', '7157', (142, 147))	('acquires', 'Reg', (96, 104))	('IDH', 'Gene', (62, 65))
11796	28966829	This theory is further supported by the observation that TERT and ATRX mutation are mutually exclusive and result in different subclasses: IDHmut with (TERT) or without (ATRX) 1p/19q codeletion.	('ATRX', 'Gene', '546', (170, 174))	('TERT', 'Gene', '7015', (152, 156))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('mutation', 'Var', (71, 79))	('ATRX', 'Gene', (66, 70))	('ATRX', 'Gene', (170, 174))	('IDH', 'Gene', (139, 142))	('ATRX', 'Gene', '546', (66, 70))	('TERT', 'Gene', (152, 156))	('IDH', 'Gene', '3417', (139, 142))	('result in', 'Reg', (107, 116))
11797	28966829	Interestingly, not TERT but ATRX mutations were associated with increased telomere length in a pan-glioma analysis, suggesting an alternative lengthening of telomeres.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('increased telomere length', 'Phenotype', 'HP:0031413', (64, 89))	('ATRX', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('ATRX', 'Gene', '546', (28, 32))	('glioma', 'Disease', (99, 105))	('increased', 'PosReg', (64, 73))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('telomere length', 'MPA', (74, 89))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
11800	28966829	Mutations in the genes encoding for EGFR, PTEN, and NF1 are observed in both LGG-IDHwt and GBM.	('NF1', 'Gene', (52, 55))	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('NF1', 'Gene', '4763', (52, 55))	('observed', 'Reg', (60, 68))	('EGFR', 'Gene', '1956', (36, 40))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (81, 84))	('EGFR', 'Gene', (36, 40))	('IDH', 'Gene', '3417', (81, 84))
11801	28966829	Moreover, numerical and structural chromosomal abnormalities such as a trisomy of chromosome 7 and a loss of chromosome 10 are more frequently observed in high-grade glial tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('loss', 'NegReg', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('observed', 'Reg', (143, 151))	('chromosomal abnormalities', 'Disease', (35, 60))	('glial tumors', 'Disease', 'MESH:D005910', (166, 178))	('trisomy', 'Var', (71, 78))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (35, 60))	('glial tumors', 'Disease', (166, 178))
11803	28966829	Further research will have to show whether the identified subclass-specific genetic aberrations, such as EGFR amplification, will aid to the development of targeted therapy for low-grade gliomas.	('gliomas', 'Disease', (187, 194))	('amplification', 'Var', (110, 123))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('EGFR', 'Gene', '1956', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('EGFR', 'Gene', (105, 109))	('aid', 'Reg', (130, 133))
11824	26474389	Previous genetic studies demonstrated the loss of 16q in HG1 IDC and the possibility of micro-deletions in 16q in HG3 IDC.	('HG1', 'Gene', '339044', (57, 60))	('HG3', 'Gene', (114, 117))	('IDC', 'Gene', '4000', (61, 64))	('16q', 'Protein', (50, 53))	('micro-deletions', 'Var', (88, 103))	('IDC', 'Gene', (61, 64))	('HG1', 'Gene', (57, 60))	('HG3', 'Gene', '339039', (114, 117))	('IDC', 'Gene', '4000', (118, 121))	('IDC', 'Gene', (118, 121))	('loss', 'NegReg', (42, 46))
11865	26474389	According to our data driven grouping (DDG) prognosis analysis (see Methods), all 22g-TAG genes were significant for patient survival (log-rank test FDR < 0.05) and showed consistent pattern (oncogene-like/tumor suppressor-like) in at least three of four independent validation cohorts (obtained from GEO dataset IDs: GSE1456 (Stockholm), GSE4922 (Singapore and Uppsala), and GSE21653 (Marseille)).	('GSE21653', 'Var', (376, 384))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('significant', 'Reg', (101, 112))	('GSE4922', 'Chemical', '-', (339, 346))	('tumor', 'Disease', (206, 211))	('GSE1456', 'Chemical', '-', (318, 325))	('patient', 'Species', '9606', (117, 124))	('GSE4922', 'Var', (339, 346))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
11899	26474389	Our results revealed 1,214 DAG (925 protein-coding, 242 ncRNA, 32 pseudo, 14 snoRNA, and 1 snRNA, Supplementary Table S9).	('ncRNA', 'Gene', (56, 61))	('925', 'Var', (32, 35))	('DAG', 'Chemical', '-', (27, 30))	('ncRNA', 'Gene', '220202', (56, 61))
11901	26474389	Specifically in HG1-like tumors, there is a deletion of part of 16q.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HG1', 'Gene', (16, 19))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('deletion of', 'Var', (44, 55))	('HG1', 'Gene', '339044', (16, 19))
11902	26474389	In contrast, HG3-like tumors showed gains in 8q, 17q, and 20q and losses in 8p, 11q, and 17p (Table 2A).	('losses', 'NegReg', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('17q', 'Var', (49, 52))	('HG3', 'Gene', '339039', (13, 16))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('gains', 'PosReg', (36, 41))	('HG3', 'Gene', (13, 16))	('tumors', 'Disease', (22, 28))
11924	26474389	Similarly, for HG3-like and HG3 tumors, we found 680 significant DAG enriched primarily in chromosomes 11, 16, and 17 (Table 2C).	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('DAG', 'Chemical', '-', (65, 68))	('tumors', 'Disease', (32, 38))	('DAG', 'Var', (65, 68))	('HG3-like and HG3', 'Gene', '339039', (15, 31))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
11931	26474389	Overall, these findings suggest multi-layered molecular dichotomization of IDC into LGG and HGG classes, predetermined by 22g-TAG classifier, specific patterns of DNA alterations and point mutations.	('IDC', 'Gene', (75, 78))	('alterations', 'Var', (167, 178))	('point mutations', 'Var', (183, 198))	('IDC', 'Gene', '4000', (75, 78))
11954	26474389	Visualization of the copy number variation status across the chromosome arms showed that in LGG, there is a gain of 16p and deletion of 16q whereas HGG tumors showed gain of 8q and loss of 8p and 17p (Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('HGG tumors', 'Disease', 'MESH:D009369', (148, 158))	('16p', 'MPA', (116, 119))	('gain', 'PosReg', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('gain', 'PosReg', (166, 170))	('HGG tumors', 'Disease', (148, 158))	('loss', 'NegReg', (181, 185))	('16q', 'Gene', (136, 139))	('deletion', 'Var', (124, 132))	('LGG', 'Disease', (92, 95))
11956	26474389	In particular, the deletion of 16q in the LGG tumors and the lack of deletion of 16q in the HGG tumors support the model of independent tumor progression into low or high grades.	('LGG tumors', 'Disease', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('deletion', 'Var', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('LGG tumors', 'Disease', 'MESH:D009369', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HGG tumors', 'Disease', (92, 102))	('HGG tumors', 'Disease', 'MESH:D009369', (92, 102))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
11960	26474389	The mutation status of TP53 and PIK3CA show a significant correlation with the new classification into two major genetic classes (Fisher's exact test p-value for TP53 = 8.3 x 10-15, and for PIK3CA = 6.1 x 10-7).	('PIK3CA', 'Gene', '5290', (190, 196))	('PIK3CA', 'Gene', '5290', (32, 38))	('correlation', 'Interaction', (58, 69))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('mutation', 'Var', (4, 12))	('TP53', 'Gene', '7157', (23, 27))	('PIK3CA', 'Gene', (190, 196))	('TP53', 'Gene', (23, 27))	('PIK3CA', 'Gene', (32, 38))
11961	26474389	For TP53, the frequency of mutations in this gene consists of the 10% (14/130) in the LGG tumors and the 48% (137/284) in the HGG tumors.	('mutations', 'Var', (27, 36))	('HGG tumors', 'Disease', 'MESH:D009369', (126, 136))	('LGG tumors', 'Disease', (86, 96))	('TP53', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('LGG tumors', 'Disease', 'MESH:D009369', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('TP53', 'Gene', '7157', (4, 8))	('HGG tumors', 'Disease', (126, 136))
11962	26474389	Inversely, for PIK3CA the frequency of mutations in the gene consists of the 48%(62/130) in the LGG tumors and 23%(67/284) in the HGC tumors, suggesting the negative correlation relatively HGC.	('HGC tumors', 'Disease', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('HGC tumors', 'Disease', 'MESH:D009369', (130, 140))	('LGG tumors', 'Disease', (96, 106))	('PIK3CA', 'Gene', '5290', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('LGG tumors', 'Disease', 'MESH:D009369', (96, 106))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PIK3CA', 'Gene', (15, 21))
11964	26474389	Specifically, the high mutation rate of the genes in specific regions of LGG tumor cells with respect to HGG tumor cells supports the independence of the oncogenic pathways hypothesis for LGG and HGG tumors.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('HGG tumors', 'Disease', (196, 206))	('mutation', 'Var', (23, 31))	('HGG tumors', 'Disease', 'MESH:D009369', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (109, 114))
11967	26474389	Moreover, the DAG (1,845 genes) have stronger correlation with their gene expression profile compared with non-differentially altered genes (non-DAG).	('stronger', 'PosReg', (37, 45))	('gene expression profile', 'MPA', (69, 92))	('DAG', 'Chemical', '-', (14, 17))	('DAG', 'Chemical', '-', (145, 148))	('correlation', 'MPA', (46, 57))	('DAG', 'Var', (14, 17))
11970	26474389	Generally, a loss of genetic material in low grade tumors but not in high grade represents the striking evidence for the independence of the low- and high-grade oncogenic pathways (e.g.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('loss', 'NegReg', (13, 17))	('genetic material', 'Var', (21, 37))
11975	26474389	Therefore, 5 genes (LOC286114 for 8p, MYC for 8q, POLR3E for 16p, HERPUD1 for 16q, and ZNF18 for 17p) were selected for subsequent class discovery analysis.	('ZNF18', 'Gene', (87, 92))	('MYC', 'Gene', (38, 41))	('HERPUD1', 'Gene', (66, 73))	('LOC286114', 'Var', (20, 29))	('POLR3E', 'Gene', '55718', (50, 56))	('POLR3E', 'Gene', (50, 56))	('HERPUD1', 'Gene', '9709', (66, 73))	('ZNF18', 'Gene', '7566', (87, 92))	('MYC', 'Gene', '4609', (38, 41))
11983	26474389	Interestingly, all gene lists related to the 21 stem cell were over-represented in the up-regulated genes in HG3-like tumors (Benjamini p-value <8.3 x 10-24, Supplementary Table S15A).	('up-regulated', 'PosReg', (87, 99))	('HG3', 'Gene', '339039', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('HG3', 'Gene', (109, 112))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Disease', (118, 124))	('S15A', 'Var', (178, 182))	('S15A', 'SUBSTITUTION', 'None', (178, 182))	('over-represented', 'PosReg', (63, 79))
11993	26474389	DNA copy number variations and point mutations are the major genetic changes that drive tumor development.	('point mutations', 'Var', (31, 46))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
11997	26474389	Our gene-centric based copy number variation analysis helps to highlight candidate genes of which copy number alterations give a survival advantage to tumor cells during tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('copy number alterations', 'Var', (98, 121))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('survival advantage', 'CPA', (129, 147))
11999	26474389	However, it was reported that the loss of 16q in HG3 tumors is followed by mitotic recombination.	('HG3', 'Gene', (49, 52))	('loss', 'Var', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('HG3', 'Gene', '339039', (49, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mitotic recombination', 'CPA', (75, 96))	('16q', 'Protein', (42, 45))	('tumors', 'Disease', (53, 59))
12005	26474389	Overall, LGG tumors have fewer mutations than HGG tumors.	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('LGG tumors', 'Disease', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HGG tumors', 'Disease', (46, 56))	('HGG tumors', 'Disease', 'MESH:D009369', (46, 56))	('LGG tumors', 'Disease', 'MESH:D009369', (9, 19))
12007	26474389	Our analysis demonstrated that a relatively higher count of PIK3CA mutations is associated with HG1-like tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('PIK3CA', 'Gene', (60, 66))	('HG1', 'Gene', '339044', (96, 99))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (67, 76))	('associated', 'Reg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HG1', 'Gene', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
12008	26474389	As PIK3CA mutations frequently occurs in IDC and are known to activate the PI3K/AKT/mTOR pathway, these mutations could be considered as potential predictive biomarkers of HG1-like tumors.	('HG1', 'Gene', '339044', (172, 175))	('AKT', 'Gene', '207', (80, 83))	('tumors', 'Disease', (181, 187))	('PIK3CA', 'Gene', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('IDC', 'Gene', '4000', (41, 44))	('activate', 'PosReg', (62, 70))	('PIK3CA', 'Gene', '5290', (3, 9))	('occurs', 'Reg', (31, 37))	('mTOR', 'Gene', '2475', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('AKT', 'Gene', (80, 83))	('IDC', 'Gene', (41, 44))	('mTOR', 'Gene', (84, 88))	('mutations', 'Var', (10, 19))	('HG1', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
12009	26474389	High mutation rate of PIK3CA in LGG with respect to HGG indicates that PIK3CA hotspot mutations could have the potential to predict intrinsic tamoxifen resistance in the adjuvant treatment of LGG ER+ BC patients.	('mutations', 'Var', (86, 95))	('PIK3CA', 'Gene', '5290', (71, 77))	('predict', 'Reg', (124, 131))	('PIK3CA', 'Gene', '5290', (22, 28))	('intrinsic tamoxifen resistance', 'MPA', (132, 162))	('LGG ER+ BC', 'Disease', (192, 202))	('patients', 'Species', '9606', (203, 211))	('tamoxifen', 'Chemical', 'MESH:D013629', (142, 151))	('PIK3CA', 'Gene', (22, 28))	('PIK3CA', 'Gene', (71, 77))
12015	26474389	Interestingly, these DNA variations do not result in any functional transcriptomic discrimination between HG3 and HG3-like sub-classes of IDC.	('HG3', 'Gene', (114, 117))	('variations', 'Var', (25, 35))	('HG3', 'Gene', '339039', (106, 109))	('HG3', 'Gene', (106, 109))	('IDC', 'Gene', '4000', (138, 141))	('HG3', 'Gene', '339039', (114, 117))	('IDC', 'Gene', (138, 141))
12041	26474389	Alternatively, the IDC patient population dichotomization based on the multiple key cancer-associated molecular factors and mechanisms, were characterized by the 5691 DEGs and by the 1858 DAGs reported in this study.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('IDC', 'Gene', '4000', (19, 22))	('5691 DEGs', 'Var', (162, 171))	('IDC', 'Gene', (19, 22))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('DAGs', 'Chemical', 'MESH:C011439', (188, 192))	('patient', 'Species', '9606', (23, 30))
12045	26474389	Clinical information and gene expression data for the Uppsala, Stockholm, Singapore and Marseille BC cohorts were obtained from the NCBI/GEO database series GSE4922, GSE1456, GSE4922 and GSE21653, respectively.	('GSE1456', 'Var', (166, 173))	('GSE1456', 'Chemical', '-', (166, 173))	('GSE4922', 'Chemical', '-', (157, 164))	('GSE4922', 'Chemical', '-', (175, 182))	('GSE21653', 'Var', (187, 195))	('GSE4922', 'Var', (157, 164))	('GSE4922', 'Var', (175, 182))
12198	29740389	Ig gene rearrangement of the dural tumor detected a kappa light chain clone of the same size (Jk) as that seen in the peripheral blood.	('dural tumor', 'Disease', (29, 40))	('dural tumor', 'Disease', 'MESH:D020785', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('rearrangement', 'Var', (8, 21))
12199	29740389	Although these lymphomas were phenotypically different and also presented at different sites, the analysis of Ig gene rearrangement raised the possibility that the two of them shared the same clonal origin.	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('Ig gene', 'Gene', (110, 117))	('lymphomas', 'Disease', (15, 24))	('lymphomas', 'Disease', 'MESH:D008223', (15, 24))	('lymphomas', 'Phenotype', 'HP:0002665', (15, 24))	('rearrangement', 'Var', (118, 131))
12203	29740389	A second smaller cell population represented 6.3% of all cells and consisted of small cells with the following immunophenotype: CD45+, CD19+, CD20+, CD5+, CD10-, CD23+, CD38-, and surface kappa weakly+.	('CD19', 'Gene', (135, 139))	('surface kappa weakly+', 'Var', (180, 201))	('CD45', 'Gene', (128, 132))	('CD10', 'Gene', (155, 159))	('CD19', 'Gene', '930', (135, 139))	('CD5', 'Gene', (149, 152))	('CD10', 'Gene', '4311', (155, 159))	('CD23', 'Gene', (162, 166))	('CD45', 'Gene', '5788', (128, 132))	('CD38', 'Gene', (169, 173))	('CD20', 'Gene', '54474', (142, 146))	('CD20', 'Gene', (142, 146))	('CD5', 'Gene', '921', (149, 152))	('CD38', 'Gene', '952', (169, 173))	('CD23', 'Gene', '2208', (162, 166))
12221	29740389	Moreover, MYD88 gene mutation is detected in 90% of WM patients, while being rarely found in MZL.	('MYD88', 'Gene', '4615', (10, 15))	('MYD88', 'Gene', (10, 15))	('WM', 'Phenotype', 'HP:0005508', (52, 54))	('mutation', 'Var', (21, 29))	('patients', 'Species', '9606', (55, 63))
12227	29740389	Trisomy of chromosomes 3, 7, 12, and 18 can be found in all types of MZL, but their effect on lymphomagenesis is still unclear.	('MZL', 'Disease', (69, 72))	('lymphoma', 'Disease', 'MESH:D008223', (94, 102))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('Trisomy', 'Var', (0, 7))	('lymphoma', 'Disease', (94, 102))
12228	29740389	In our review of dural MZL, we observed that trisomy 3 is the most common chromosomal aberration, followed by t(14;18)(q32;q21).	('t(14;18)(q32;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (110, 127))	('trisomy', 'Disease', (45, 52))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (74, 96))	('t(14;18)(q32;q21', 'Var', (110, 126))
12295	27227746	The B0 map was created from dual-echo gradient-echo images (DeltaTE = 1 ms) according to the following equation;  , where Phase [TEi](x) indicates image phases of the images with echo times TE1 or TE2 at position x in radian, and B0(x) is the resulting B0 map measured in Hz.	('TE2', 'Gene', '8260', (197, 200))	('Phase [', 'Var', (122, 129))	('TE2', 'Gene', (197, 200))
12324	27227746	Both MTRasym (3.5ppm) and DeltaMTRasym (3.5ppm) were significantly higher (P < 0.0001 for all comparisons) in HGG than in LGG with all the three saturation pulse lengths.	('HGG', 'Disease', (110, 113))	('DeltaMTRasym', 'Var', (26, 38))	('higher', 'PosReg', (67, 73))	('rat', 'Species', '10116', (149, 152))
12367	33634261	One of the important aspects of updated WHO classification in 2016 has been dividing some of the glial tumor according to IDH1 (isocitrate dehydrogenase 1) mutation.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('isocitrate dehydrogenase 1', 'Gene', (128, 154))	('glial tumor', 'Disease', (97, 108))	('isocitrate dehydrogenase 1', 'Gene', '3417', (128, 154))	('IDH1', 'Gene', (122, 126))	('IDH1', 'Gene', '3417', (122, 126))	('glial tumor', 'Disease', 'MESH:D005910', (97, 108))	('mutation', 'Var', (156, 164))
12369	33634261	For 5 years (2013-2018), 50 cases of clinically documented reactive gliosis and 50 cases of low-grade astrocytoma were evaluated for the presence or absence of IDH1 and P53 mutation by immunohistochemistry.	('P53', 'Gene', '7157', (169, 172))	('astrocytoma', 'Disease', (102, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('IDH1', 'Gene', (160, 164))	('gliosis', 'Disease', 'MESH:D005911', (68, 75))	('gliosis', 'Disease', (68, 75))	('IDH1', 'Gene', '3417', (160, 164))	('gliosis', 'Phenotype', 'HP:0002171', (68, 75))	('astrocytoma', 'Disease', 'MESH:D001254', (102, 113))	('P53', 'Gene', (169, 172))	('mutation', 'Var', (173, 181))
12374	33634261	P53 mutation can be a good marker for differential diagnosis of reactive gliosis from low-grade astrocytoma; however, some controversies are still present and, in some studies, P53 mutation has been reported in reactive gliosis as well as in low-grade astrocytoma.	('P53', 'Gene', '7157', (177, 180))	('astrocytoma', 'Disease', 'MESH:D001254', (96, 107))	('gliosis', 'Phenotype', 'HP:0002171', (73, 80))	('astrocytoma', 'Disease', (96, 107))	('reported', 'Reg', (199, 207))	('gliosis', 'Disease', 'MESH:D005911', (220, 227))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('gliosis', 'Disease', 'MESH:D005911', (73, 80))	('astrocytoma', 'Disease', 'MESH:D001254', (252, 263))	('P53', 'Gene', (0, 3))	('mutation', 'Var', (181, 189))	('astrocytoma', 'Disease', (252, 263))	('gliosis', 'Disease', (220, 227))	('gliosis', 'Disease', (73, 80))	('P53', 'Gene', '7157', (0, 3))	('gliosis', 'Phenotype', 'HP:0002171', (220, 227))	('P53', 'Gene', (177, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (252, 263))
12375	33634261	Recently, isocitrate dehydrogenase (IDH) has been introduced to be mutated in low-grade gliomas.	('isocitrate dehydrogenase', 'Gene', '3417', (10, 34))	('gliomas', 'Disease', (88, 95))	('IDH', 'Gene', (36, 39))	('mutated', 'Var', (67, 74))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('IDH', 'Gene', '3417', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('isocitrate dehydrogenase', 'Gene', (10, 34))
12376	33634261	The first introduction of IDH mutation has been reported by Parsons et al in 2008 in 12% of brain tumors with the diagnosis of glioblastoma multiforme.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (92, 104))	('mutation', 'Var', (30, 38))	('brain tumors', 'Phenotype', 'HP:0030692', (92, 104))	('brain tumors', 'Disease', (92, 104))	('glioblastoma multiforme', 'Disease', (127, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH', 'Gene', (26, 29))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (127, 150))	('IDH', 'Gene', '3417', (26, 29))
12377	33634261	In that study, the authors showed that all of these cases with IDH mutation also harbor P53 mutation.	('P53', 'Gene', (88, 91))	('mutation', 'Var', (67, 75))	('P53', 'Gene', '7157', (88, 91))	('IDH', 'Gene', (63, 66))	('harbor', 'Reg', (81, 87))	('IDH', 'Gene', '3417', (63, 66))
12381	33634261	Majority of IDH1 mutations occur in exon 4 at codon 132, where a transition changes a single amino acid from arginine to histidine (R132H).	('arginine', 'Chemical', 'MESH:D001120', (109, 117))	('IDH1', 'Gene', (12, 16))	('R132H', 'Var', (132, 137))	('IDH1', 'Gene', '3417', (12, 16))	('R132H', 'SUBSTITUTION', 'None', (132, 137))	('mutations', 'Var', (17, 26))	('histidine', 'Chemical', 'MESH:D006639', (121, 130))
12383	33634261	In this study, we are trying to evaluate the role of IDH1 mutation in combination with P53 mutation by immunohistochemistry (IHC) method to differentiate reactive gliosis from low-grade astrocytoma (grade II).	('gliosis', 'Phenotype', 'HP:0002171', (163, 170))	('gliosis', 'Disease', 'MESH:D005911', (163, 170))	('IDH1', 'Gene', (53, 57))	('astrocytoma', 'Phenotype', 'HP:0009592', (186, 197))	('mutation', 'Var', (58, 66))	('astrocytoma', 'Disease', 'MESH:D001254', (186, 197))	('IDH1', 'Gene', '3417', (53, 57))	('astrocytoma', 'Disease', (186, 197))	('gliosis', 'Disease', (163, 170))	('P53', 'Gene', (87, 90))	('P53', 'Gene', '7157', (87, 90))
12388	33634261	The slides were reviewed and the best representative block was selected for IHC with mouse monoclonal anti-R132H-IDH1 antibody (H09, Dianova, dilution 1:50, citrate-EDTA for antigen retrieval) and P53 antibody (Dako, clone DO-7, dilution 1:100, citrate-EDTA [Ethylenediamine tetraacetic acid] for antigen retrieval).	('R132H', 'Var', (107, 112))	('Ethylenediamine tetraacetic acid', 'Chemical', 'MESH:D004492', (259, 291))	('IDH1', 'Gene', (113, 117))	('P53', 'Gene', '7157', (197, 200))	('R132H', 'SUBSTITUTION', 'None', (107, 112))	('citrate', 'Chemical', 'MESH:D019343', (157, 164))	('IDH1', 'Gene', '3417', (113, 117))	('EDTA', 'Chemical', 'MESH:D004492', (253, 257))	('citrate', 'Chemical', 'MESH:D019343', (245, 252))	('EDTA', 'Chemical', 'MESH:D004492', (165, 169))	('P53', 'Gene', (197, 200))
12391	33634261	The immunohistochemical positivity for IDH1 was considered strong with 3+ positivity and weak with 1-2+ positivity.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('3+ positivity', 'Var', (71, 84))
12404	33634261	Immunohistochemistry for P53 mutation is a marker which is seen in diffuse astrocytoma and can be useful for the differential diagnosis.	('mutation', 'Var', (29, 37))	('P53', 'Gene', (25, 28))	('astrocytoma', 'Disease', 'MESH:D001254', (75, 86))	('P53', 'Gene', '7157', (25, 28))	('astrocytoma', 'Disease', (75, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))
12405	33634261	In our study, we detected P53 mutation in 90% of the cases with the diagnosis of low-grade astrocytoma and 4% of the reactive astrocytosis.	('astrocytosis', 'Disease', (126, 138))	('P53', 'Gene', (26, 29))	('mutation', 'Var', (30, 38))	('P53', 'Gene', '7157', (26, 29))	('astrocytosis', 'Disease', 'MESH:D005911', (126, 138))	('astrocytoma', 'Disease', 'MESH:D001254', (91, 102))	('detected', 'Reg', (17, 25))	('astrocytoma', 'Disease', (91, 102))	('astrocytosis', 'Phenotype', 'HP:0002446', (126, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
12406	33634261	Another genetic change common in low-grade astrocytomas is IDH1 gene mutations which have not been reported in reactive gliosis, so it seems specific for astrocytoma.	('astrocytoma', 'Disease', (154, 165))	('mutations', 'Var', (69, 78))	('astrocytoma', 'Disease', (43, 54))	('IDH1', 'Gene', '3417', (59, 63))	('gliosis', 'Disease', 'MESH:D005911', (120, 127))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (154, 165))	('astrocytomas', 'Disease', (43, 55))	('gliosis', 'Disease', (120, 127))	('astrocytoma', 'Disease', 'MESH:D001254', (154, 165))	('astrocytoma', 'Disease', 'MESH:D001254', (43, 54))	('gliosis', 'Phenotype', 'HP:0002171', (120, 127))	('IDH1', 'Gene', (59, 63))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))
12407	33634261	Majority of IDH1 mutations involve substitution of arginine by histidine at codon 132 (R132H).	('R132H', 'Var', (87, 92))	('IDH1', 'Gene', (12, 16))	('R132H', 'SUBSTITUTION', 'None', (87, 92))	('arginine by histidine at codon 132', 'Mutation', 'rs121913500', (51, 85))	('substitution', 'Var', (35, 47))	('IDH1', 'Gene', '3417', (12, 16))	('mutations', 'Var', (17, 26))
12409	33634261	If IHC for mutant R132H IDH1 protein and sequencing for IDH1 codon 132 and IDH2 codon 172 gene mutations are both negative, or if sequencing for IDH1 codon 132 and IDH2 codon 172 gene mutations alone is negative, then the lesion can be diagnosed as IDH wildtype.	('IDH1', 'Gene', (145, 149))	('IDH', 'Gene', '3417', (145, 148))	('IDH1', 'Gene', (24, 28))	('IDH', 'Gene', '3417', (249, 252))	('IDH1', 'Gene', (56, 60))	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', (56, 59))	('IDH1', 'Gene', '3417', (145, 149))	('IDH2', 'Gene', (164, 168))	('IDH', 'Gene', (164, 167))	('IDH2', 'Gene', '3418', (164, 168))	('R132H', 'Var', (18, 23))	('IDH1', 'Gene', '3417', (24, 28))	('IDH2', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (56, 60))	('IDH', 'Gene', '3417', (24, 27))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', (75, 78))	('protein', 'Protein', (29, 36))	('IDH2', 'Gene', '3418', (75, 79))	('IDH', 'Gene', '3417', (164, 167))	('IDH', 'Gene', (145, 148))	('R132H', 'SUBSTITUTION', 'None', (18, 23))	('IDH', 'Gene', '3417', (75, 78))	('IDH', 'Gene', (249, 252))
12411	33634261	The study by Camelo-Piragua et al showed that the combination of P53 and mutant IDH1 by IHC provides a sensitivity of 71.4% which is significantly higher than either test alone (47.8%).	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('mutant', 'Var', (73, 79))	('P53', 'Gene', (65, 68))	('higher', 'PosReg', (147, 153))	('P53', 'Gene', '7157', (65, 68))
12412	33634261	IDH1 mutation has been reported in 64.6% and 45.4% of low- and high-grade gliomas of adult patients.	('patients', 'Species', '9606', (91, 99))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
12415	33634261	In our experience in this study, more than 90% of low-grade astrocytomas have shown mutant IDH1 (R132H) and the IHC for IDH1 was positive; this marker was only positive in 4% of reactive cases.	('astrocytomas', 'Disease', (60, 72))	('R132H', 'Var', (97, 102))	('IDH1', 'Gene', (91, 95))	('mutant', 'Var', (84, 90))	('IDH1', 'Gene', (120, 124))	('R132H', 'SUBSTITUTION', 'None', (97, 102))	('IDH1', 'Gene', '3417', (91, 95))	('astrocytomas', 'Disease', 'MESH:D001254', (60, 72))	('IDH1', 'Gene', '3417', (120, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))
12422	33634261	Isocitrate dehydrogenase gene mutation assessment has been reported as highly specific marker for low-grade diffuse glioma and is recommended as an additional test not only for classification and prognosis but also for differentiating of these tumors from their mimics.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('mutation', 'Var', (30, 38))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('glioma', 'Disease', (116, 122))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
12432	31341789	Multivariate analyses showed improved mortality of the fMRI group and the fMRI+ECM group compared to the No-fMRI group, with age and tumor grade being the most significant influencers.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('fMRI', 'Var', (55, 59))	('tumor', 'Disease', (133, 138))	('improved', 'PosReg', (29, 37))	('mortality', 'CPA', (38, 47))
12433	31341789	Furthermore, patients with high-grade tumors showed significant survival benefits in the fMRI group, while patients with low-grade tumors did not (controlling for age and ECM).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('benefits', 'PosReg', (73, 81))	('survival', 'CPA', (64, 72))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('fMRI', 'Var', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('patients', 'Species', '9606', (107, 115))
12434	31341789	There was also a significant difference in the two groups with respect to morbidity, with patients receiving fMRI showing improved outcomes in the motor and language domains.	('fMRI', 'Var', (109, 113))	('patients', 'Species', '9606', (90, 98))	('motor', 'CPA', (147, 152))	('improved', 'PosReg', (122, 130))
12435	31341789	This study analyzing a large retrospective series of brain tumor patients with and without the use of fMRI in the preoperative planning has resulted in improved mortality and morbidity outcomes with the use of fMRI.	('brain tumor', 'Phenotype', 'HP:0030692', (53, 64))	('fMRI', 'Var', (210, 214))	('improved', 'PosReg', (152, 160))	('patients', 'Species', '9606', (65, 73))	('brain tumor', 'Disease', 'MESH:D001932', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('brain tumor', 'Disease', (53, 64))
12473	31341789	The differences become notable in the high-grade tumors (50.8% survival with fMRI and 27.8% survival with No-fMRI).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('fMRI', 'Var', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
12493	31341789	However, there was a significant increase in 3-year survival of high-grade tumor patients who received a preoperative fMRI compared to the No-fMRI group (50.8% vs 27.8%, respectively).	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('increase', 'PosReg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('fMRI', 'Var', (118, 122))
12499	31341789	This would be consistent with the reported improvement in 6 month progression free survival for high grade gliomas patients who underwent 5-aminolevulinic acid fluorescence-guided surgery, and improved median survival due to ECM and more aggressive tumor resection in low-grade tumors by Chang et al.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('patients', 'Species', '9606', (115, 123))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('tumors', 'Disease', (278, 284))	('gliomas', 'Disease', (107, 114))	('ECM', 'Var', (225, 228))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('improved', 'PosReg', (193, 201))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('aggressive tumor', 'Disease', 'MESH:D001523', (238, 254))	('median survival', 'MPA', (202, 217))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (138, 159))	('aggressive tumor', 'Disease', (238, 254))	('improvement', 'PosReg', (43, 54))
12520	31341789	We posit that the survival benefit conferred by fMRI is primarily due to accurate spatial localization of functional brain regions leading to maximal tumor resection while minimizing functional deficits.	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('fMRI', 'Var', (48, 52))	('survival', 'CPA', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
12590	26524630	Genomic dynamics associated with malignant transformation in IDH1 mutated gliomas The genomic mechanism responsible for malignant transformation remains an open question for glioma researchers, where differing conclusions have been drawn based on diverse study conditions.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('mutated', 'Var', (66, 73))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('associated', 'Reg', (17, 27))	('gliomas', 'Disease', (74, 81))	('glioma', 'Disease', (174, 180))	('IDH1', 'Gene', (61, 65))	('glioma', 'Disease', (74, 80))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('IDH1', 'Gene', '3417', (61, 65))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
12596	26524630	The alterations in genetic regulatory mechanisms may be the key factor for the major phenotypic changes in IDH1 mutated gliomas.	('IDH1', 'Gene', (107, 111))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH1', 'Gene', '3417', (107, 111))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('mutated', 'Var', (112, 119))	('alterations', 'Reg', (4, 15))	('gliomas', 'Disease', (120, 127))
12598	26524630	One of the classic concepts of cancer progression includes an evolutionary process that results from stepwise mutations with sequential subclonal selection.	('results from', 'Reg', (88, 100))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
12602	26524630	Furthermore, once a genetic alteration is identified as a driver in one tumor type, that event can be more reliably interpreted even if it is infrequent.	('tumor', 'Disease', (72, 77))	('genetic alteration', 'Var', (20, 38))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
12610	26524630	Strong evidence shows that somatic mutation of isocitrate dehydrogenase 1 (IDH1) is related to a better prognosis in LGGs.	('somatic mutation', 'Var', (27, 43))	('LGGs', 'Disease', (117, 121))	('isocitrate dehydrogenase 1', 'Gene', (47, 73))	('isocitrate dehydrogenase 1', 'Gene', '3417', (47, 73))	('IDH1', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (75, 79))
12612	26524630	However, IDH1 mutation itself may not be the driving force for malignant transformation.	('mutation', 'Var', (14, 22))	('IDH1', 'Gene', '3417', (9, 13))	('IDH1', 'Gene', (9, 13))
12615	26524630	We studied 3 pairs of IDH1 mutated low grade gliomas and their high grade phenotype transformed after the lapse of time (Figure 1).	('mutated', 'Var', (27, 34))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
12616	26524630	Case 1 is histologically classified as astrocytoma with IDH1 mutation and intact 1p19q status, which progressed to anaplastic astrocytoma followed by glioblastoma.	('IDH1', 'Gene', (56, 60))	('astrocytoma', 'Disease', 'MESH:D001254', (126, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (39, 50))	('astrocytoma', 'Disease', (126, 137))	('glioblastoma', 'Disease', (150, 162))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('glioblastoma', 'Disease', 'MESH:D005909', (150, 162))	('mutation', 'Var', (61, 69))	('IDH1', 'Gene', '3417', (56, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('astrocytoma', 'Disease', 'MESH:D001254', (39, 50))	('astrocytoma', 'Disease', (39, 50))	('progressed', 'PosReg', (101, 111))
12617	26524630	Case 2 and 3 are oligodendrogliomas with IDH1 mutation and 1p19q co-deletion, which progressed to anaplastic oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('oligodendroglioma', 'Disease', (17, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('oligodendroglioma', 'Disease', 'MESH:D009837', (109, 126))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (17, 35))	('oligodendroglioma', 'Disease', 'MESH:D009837', (17, 34))	('1p19q co-deletion', 'Var', (59, 76))	('oligodendrogliomas', 'Disease', (17, 35))	('oligodendroglioma', 'Disease', (109, 126))	('IDH1', 'Gene', (41, 45))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('mutation', 'Var', (46, 54))	('IDH1', 'Gene', '3417', (41, 45))	('progressed', 'PosReg', (84, 94))
12622	26524630	The segments with heterozygous deletion are of primary interest because they can be further utilized for inferring clonal dynamics of tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('deletion', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
12630	26524630	Among 262 cases from lower-grade glioma and 235 cases from glioblastoma with complete sequencing and CNA data, a total of 216 cases with an IDH1 mutation and available information about histological grade were analyzed (Table S2).	('IDH1', 'Gene', '3417', (140, 144))	('glioma', 'Disease', (33, 39))	('glioblastoma', 'Disease', (59, 71))	('IDH1', 'Gene', (140, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('mutation', 'Var', (145, 153))
12631	26524630	As verified recently, TP53 and ATRX mutations were the hallmark of 1p19q intact IDH1-mutated gliomas, while CIC and FUBP1 mutations were found in 1p19q co-deleted gliomas.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', (163, 170))	('ATRX', 'Gene', (31, 35))	('ATRX', 'Gene', '546', (31, 35))	('FUBP1', 'Gene', '8880', (116, 121))	('TP53', 'Gene', (22, 26))	('IDH1', 'Gene', (80, 84))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('CIC', 'Gene', (108, 111))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('IDH1', 'Gene', '3417', (80, 84))	('TP53', 'Gene', '7157', (22, 26))	('CIC', 'Gene', '23152', (108, 111))	('1p19q', 'Var', (67, 72))	('FUBP1', 'Gene', (116, 121))	('mutations', 'Var', (36, 45))
12632	26524630	However, it is worth noting that TP53 and ATRX mutations were observed only in a small fraction of 1p19q co-deleted gliomas of high grade, which implies that these types of trans-lineage mutations can contribute to the malignant transformation that was also observed in Case 2.	('contribute', 'Reg', (201, 211))	('malignant transformation', 'CPA', (219, 243))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('TP53', 'Gene', '7157', (33, 37))	('ATRX', 'Gene', (42, 46))	('ATRX', 'Gene', '546', (42, 46))	('gliomas', 'Disease', (116, 123))	('TP53', 'Gene', (33, 37))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('1p19q co-deleted', 'Var', (99, 115))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
12633	26524630	Recent observation of changes in TP53 expression in sequential samples of oligodendrogliomas supports that the de novo TP53 mutation or the proliferation of a subset of cells with nuclear expression of TP53 could lead to tumor progression in some IDH1-mutated oligodendroglial tumors.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (74, 92))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('TP53', 'Gene', '7157', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('IDH1', 'Gene', '3417', (247, 251))	('TP53', 'Gene', '7157', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('TP53', 'Gene', (202, 206))	('oligodendrogliomas', 'Disease', (74, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('tumor', 'Disease', (221, 226))	('oligodendroglial tumors', 'Disease', (260, 283))	('TP53', 'Gene', (33, 37))	('tumor', 'Disease', (277, 282))	('TP53', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('TP53', 'Gene', '7157', (202, 206))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (260, 283))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('lead to', 'Reg', (213, 220))	('IDH1', 'Gene', (247, 251))	('mutation', 'Var', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
12636	26524630	U2AF2 had a copy number loss in case 3 from the low-grade stage and developed additional missense mutations at the high-grade stage.	('U2AF2', 'Gene', '11338', (0, 5))	('U2AF2', 'Gene', (0, 5))	('missense mutations', 'Var', (89, 107))	('copy number loss', 'Var', (12, 28))
12637	26524630	And in TCGA samples, 5.9% of grade 3 gliomas with IDH1 mutation/1p19q co-deletion harbored mutations in U2AF2 while no mutations were found in grade 2 gliomas with the same molecular signature (Figure 6).	('harbored', 'Reg', (82, 90))	('IDH1', 'Gene', (50, 54))	('mutation/1p19q co-deletion', 'Var', (55, 81))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('U2AF2', 'Gene', (104, 109))	('IDH1', 'Gene', '3417', (50, 54))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('mutations', 'Var', (91, 100))	('gliomas', 'Disease', (37, 44))	('U2AF2', 'Gene', '11338', (104, 109))	('gliomas', 'Disease', (151, 158))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
12639	26524630	A novel frameshift deletion in TCF12 was found in the high grade sample of case 1, and mutations were observed in 4.7% of grade 2 and 5.9% of grade 3 of IDH1 mutation/1p19q co-deletion samples in TCGA (Figure 6).	('IDH1', 'Gene', (153, 157))	('TCF12', 'Gene', '6938', (31, 36))	('frameshift deletion', 'Var', (8, 27))	('IDH1', 'Gene', '3417', (153, 157))	('mutation/1p19q', 'Var', (158, 172))	('TCF12', 'Gene', (31, 36))
12640	26524630	Although a mutation in low grade phase was already present, newly developed copy number loss of ARID1A was found in the high grade sample of case 1.	('ARID1A', 'Gene', '8289', (96, 102))	('ARID1A', 'Gene', (96, 102))	('copy number loss', 'Var', (76, 92))
12641	26524630	TCGA data shows that increase in mutation rate in high grade phenotype was observed in both 1p19q co-deleted and intact gliomas with IDH1 mutation (Figure 6).	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH1', 'Gene', (133, 137))	('mutation', 'Var', (138, 146))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('1p19q co-deleted', 'Var', (92, 108))	('gliomas', 'Disease', (120, 127))	('increase', 'PosReg', (21, 29))	('IDH1', 'Gene', '3417', (133, 137))
12642	26524630	Moreover, copy number loss was accompanied by 1p19q co-deleted tumors, but there was no mutation in grade 4 GBMs as observed previously.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('1p19q co-deleted', 'Var', (46, 62))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('copy number loss', 'Var', (10, 26))
12650	26524630	Interestingly, the DEG from the high grade phenotype share a common genetic signature with a proneural type of glioblastoma (Gene set: VERHAAK_GLIOBLASTOMA_PRONEURAL), which is distinguished from other glioblastomas by lower age, better prognosis, PDGFRA expression, and frequent IDH1 mutation (Figure S4).	('proneural type', 'Disease', (93, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('IDH1', 'Gene', (280, 284))	('glioblastomas', 'Phenotype', 'HP:0012174', (202, 215))	('PDGFRA', 'Gene', (248, 254))	('glioblastoma', 'Disease', (202, 214))	('IDH1', 'Gene', '3417', (280, 284))	('PDGFRA', 'Gene', '5156', (248, 254))	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('glioblastomas', 'Disease', 'MESH:D005909', (202, 215))	('mutation', 'Var', (285, 293))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('glioblastomas', 'Disease', (202, 215))	('glioblastoma', 'Disease', (111, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))
12653	26524630	U2AF2 is a core member of the spliceosome machinery, so mutations in this gene can affect the normal function of spliceosomes resulting in the formation of aberrant mature mRNAs by misunderstanding of splice site recognition.	('misunderstanding', 'Var', (181, 197))	('mutations', 'Var', (56, 65))	('aberrant mature mRNAs', 'MPA', (156, 177))	('affect', 'Reg', (83, 89))	('formation', 'MPA', (143, 152))	('U2AF2', 'Gene', '11338', (0, 5))	('normal function of spliceosomes', 'MPA', (94, 125))	('U2AF2', 'Gene', (0, 5))
12654	26524630	Mutations to spliceosome genes are related to hematological malignancy and its prognosis and can act as a driver of oncogenesis in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colon cancer', 'Disease', 'MESH:D015179', (131, 143))	('spliceosome genes', 'Gene', (13, 30))	('colon cancer', 'Disease', (131, 143))	('hematological malignancy', 'Disease', 'MESH:D019337', (46, 70))	('Mutations', 'Var', (0, 9))	('related', 'Reg', (35, 42))	('hematological malignancy', 'Phenotype', 'HP:0004377', (46, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (131, 143))	('hematological malignancy', 'Disease', (46, 70))
12658	26524630	Interestingly, significant differences in TCF12 expression between 1p19q co-deleted tumors and intact tumors (higher with 1q19q codeletion) as well as among WHO grades (highest in grade 2 and lowest in grade 4) were reported previously.	('TCF12', 'Gene', '6938', (42, 47))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('1q19q codeletion', 'Var', (122, 138))	('expression', 'MPA', (48, 58))	('differences', 'Reg', (27, 38))	('1p19q co-deleted', 'Var', (67, 83))	('TCF12', 'Gene', (42, 47))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('higher', 'PosReg', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
12669	26524630	Moreover, expression changes resulting from genomic alterations appear to activate genes associated with the restoration of stemness in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('expression', 'MPA', (10, 20))	('cancer', 'Disease', (136, 142))	('genomic alterations', 'Var', (44, 63))	('genes', 'Gene', (83, 88))	('activate', 'PosReg', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
12681	26524630	However, we found that the ASCAT algorithm overestimated the ploidy of the high grade sample from Case 2 because the algorithm prefers to assign integer copy numbers to segments with heterozygous deletion in chromosomes 2 and 18, even though they are only likely to be altered in just under half of the cancer cells from the sample (Figure S8).	('cancer', 'Disease', (303, 309))	('deletion', 'Var', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('ploidy', 'MPA', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
12684	26524630	1) We identified segments with heterozygous deletions whose size is greater than 10Mb in each tumor sample.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('deletions', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))
12686	26524630	For each tumor sample, we calculated the fraction of a subclone harboring a segment with heterozygous deletion by utilizing two types of information: a) the normalized read count ratio between the normal and tumor sample within the segment, and b) the altered allele frequencies of germline heterozygous SNVs in a tumor sample within the segments.	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (314, 319))	('deletion', 'Var', (102, 110))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (208, 213))	('SNVs', 'Gene', (304, 308))
12719	33093452	Moreover, we found that miR-504 exerted an antitumor effect in vitro and in vivo and in addition, inhibited the stemness and mesenchymal transit of GSCs.	('miR-504', 'Var', (24, 31))	('inhibited', 'NegReg', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('GSCs', 'Chemical', '-', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
12729	33093452	Lentivirus vectors (System Biosciences, Mountain View, CA) expressing the miR-504 reporter, pre-miR-504, miR-504 antagomiR, Grb10, or control and Grb10 shRNAs were packaged and used to transduce the cells according to the manufacturer's protocol and as previously described.	('Grb10', 'Gene', (124, 129))	('Grb10', 'Gene', (146, 151))	('Grb10', 'Gene', '2887', (146, 151))	('Grb10', 'Gene', '2887', (124, 129))	('miR-504', 'Var', (105, 112))	('transduce', 'Reg', (185, 194))	('miR-504', 'Gene', (74, 81))	('pre-miR-504', 'Var', (92, 103))
12758	33093452	Since miR-504 was one of the most downregulated miRNAs in GSCs compared with hNSCs (Fig.	('GSCs', 'Disease', (58, 62))	('miR-504', 'Var', (6, 13))	('GSCs', 'Chemical', '-', (58, 62))	('downregulated', 'NegReg', (34, 47))
12772	33093452	3SA) and found that pre-miR-504 markedly decreased the expression of the stemness markers Oct4 and Nanog and increased the expression of the astrocytic marker GFAP in both GSC-1 and GSC-2 (Fig.	('Oct4', 'Gene', '5460', (90, 94))	('GSC', 'Chemical', '-', (172, 175))	('expression', 'MPA', (123, 133))	('decreased', 'NegReg', (41, 50))	('GFAP', 'Gene', '2670', (159, 163))	('expression', 'MPA', (55, 65))	('GSC-2', 'Gene', (182, 187))	('Nanog', 'Gene', '79923', (99, 104))	('GSC-2', 'Gene', '2928', (182, 187))	('Oct4', 'Gene', (90, 94))	('Nanog', 'Gene', (99, 104))	('increased', 'PosReg', (109, 118))	('pre-miR-504', 'Var', (20, 31))	('GSC', 'Chemical', '-', (182, 185))	('GFAP', 'Gene', (159, 163))
12786	33093452	Using the Grb10 3'-UTR- tagged to luciferase, we demonstrated a direct targeting of Grb10 by miR-504 (Fig.	('targeting', 'Reg', (71, 80))	('Grb10', 'Gene', (10, 15))	('miR-504', 'Var', (93, 100))	('Grb10', 'Gene', (84, 89))	('Grb10', 'Gene', '2887', (84, 89))	('Grb10', 'Gene', '2887', (10, 15))
12796	33093452	These results demonstrate that targeting Grb10 by miR-504 mediates at least in part the inhibitory effects of miR-504 on the stemness and mesenchymal phenotypes of GSCs.	('miR-504', 'Var', (110, 117))	('Grb10', 'Gene', '2887', (41, 46))	('miR-504', 'Gene', (50, 57))	('GSCs', 'Chemical', '-', (164, 168))	('stemness', 'CPA', (125, 133))	('Grb10', 'Gene', (41, 46))
12803	33093452	In contrast, transduction of the GSCs with pre-miR-504 (Fig.	('pre-miR-504', 'Var', (43, 54))	('transduction', 'MPA', (13, 25))	('GSCs', 'Chemical', '-', (33, 37))
12807	33093452	5G, microglia that were co-cultured with GSCs overexpressing pre-miR-504 exhibited decreased luciferase activity indicating that miR-504 was transferred by the cocultured GSCs.	('luciferase', 'Enzyme', (93, 103))	('activity', 'MPA', (104, 112))	('GSCs', 'Chemical', '-', (171, 175))	('decreased', 'NegReg', (83, 92))	('overexpressing', 'Var', (46, 60))	('GSCs', 'Chemical', '-', (41, 45))	('pre-miR-504', 'Var', (61, 72))
12810	33093452	Finally, we demonstrated that overexpression of miR-504 in microglial cells upregulated the relative expression of the M1 markers CD86 and TNF-alpha (Fig.	('miR-504', 'Var', (48, 55))	('CD86', 'Gene', (130, 134))	('overexpression', 'PosReg', (30, 44))	('TNF-alpha', 'Gene', '7124', (139, 148))	('TNF-alpha', 'Gene', (139, 148))	('upregulated', 'PosReg', (76, 87))	('expression', 'MPA', (101, 111))
12815	33093452	We found that EVs isolated from GSC-1 overexpressing miR-504 expressed significantly higher levels of miR-504 compared with EVs isolated from GSC-1 expressing a control pre-miR (Figs.	('higher', 'PosReg', (85, 91))	('GSC', 'Chemical', '-', (142, 145))	('miR-504', 'Var', (53, 60))	('miR-504', 'MPA', (102, 109))	('GSC', 'Chemical', '-', (32, 35))	('levels', 'MPA', (92, 98))
12822	33093452	These results indicate that the transfer of miR-504 by GSC-derived EVs mediated, at least partly, the increased M1 phenotypes of the microglial cells induced by the cocultured GSCs.	('transfer', 'Var', (32, 40))	('M1 phenotypes', 'MPA', (112, 125))	('GSC', 'Chemical', '-', (55, 58))	('miR-504', 'Gene', (44, 51))	('GSC', 'Chemical', '-', (176, 179))	('increased', 'PosReg', (102, 111))	('GSCs', 'Chemical', '-', (176, 180))
12831	33093452	These findings indicate that alterations in miRNA expression are associated with deregulation in pathways which contribute to the tumorigenic phenotypes of GSCs.	('GSCs', 'Disease', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('alterations', 'Var', (29, 40))	('associated', 'Reg', (65, 75))	('deregulation', 'MPA', (81, 93))	('miRNA', 'Protein', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('pathways', 'Pathway', (97, 105))	('GSCs', 'Chemical', '-', (156, 160))	('tumor', 'Disease', (130, 135))
12836	33093452	In agreement with the lower expression of miR-504 in more high grade tumors and in the mesenchymal subtype, we found that overexpression of miR-504 inhibited the self-renewal and mesenchymal phenotypes of GSCs, Collectively, the current results highlight miR-504 as a potential tumor suppressor miRNA and as a negative regulator of the tumorigenicity of GBM and GSCs.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', (278, 283))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('GSCs', 'Chemical', '-', (362, 366))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('GBM', 'Phenotype', 'HP:0012174', (354, 357))	('GSCs', 'Chemical', '-', (205, 209))	('inhibited', 'NegReg', (148, 157))	('miR-504', 'Var', (255, 262))	('tumor', 'Disease', (336, 341))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
12855	33093452	Since miR-504 decreased the stemness and mesenchymal differentiation of GSCs, it is possible that other factors or miRNAs that are secreted by the transduced GSCs can also contribute to the induction of this change in the microglial phenotype.	('miR-504', 'Var', (6, 13))	('GSCs', 'Chemical', '-', (72, 76))	('GSCs', 'Chemical', '-', (158, 162))	('decreased', 'NegReg', (14, 23))
12860	33093452	miR-504 is downregulated in GSCs and exerts inhibitory effects on the functions of these cells via the targeting of Grb10 that acts as an oncogene in GBM and GSCs.	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('GSCs', 'Chemical', '-', (158, 162))	('downregulated', 'NegReg', (11, 24))	('Grb10', 'Gene', (116, 121))	('GSCs', 'Chemical', '-', (28, 32))	('miR-504', 'Gene', (0, 7))	('targeting', 'Var', (103, 112))	('Grb10', 'Gene', '2887', (116, 121))	('GSCs', 'Disease', (28, 32))
12865	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))	('SIX3', 'Gene', '6496', (26, 30))	('human', 'Species', '9606', (141, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
12868	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))
12870	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))
12871	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))	('epigenetic', 'CPA', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('DNA', 'MPA', (121, 124))	('hypermethylation', 'Var', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
12872	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))
12875	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))
12876	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))
12877	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))
12879	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))
12880	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))
12881	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.	('signaling networks', 'Pathway', (228, 246))	('activation', 'PosReg', (214, 224))	('mutations', 'Var', (46, 55))	('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))
12883	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))
12888	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))
12892	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))
12897	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))
12904	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))
12920	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))	('ZNF263', 'Gene', (36, 42))	('H3K9me3', 'Protein', (161, 168))	('enrichment', 'MPA', (147, 157))	('ZNF263', 'Gene', '10127', (36, 42))	('knockdown', 'Var', (26, 35))	('reduced', 'NegReg', (135, 142))	('SIX3', 'Gene', '6496', (104, 108))	('decreased', 'NegReg', (43, 52))	('SIX3', 'Gene', (104, 108))
12925	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))
12927	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))
12936	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))
12942	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))
12950	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))
12956	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))
12959	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))	('erlotinib', 'Chemical', 'MESH:D000069347', (111, 120))	('Trametinib', 'Chemical', 'MESH:C560077', (124, 134))	('SIX3', 'Gene', '6496', (64, 68))	('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))	('SIX3', 'Gene', (143, 147))	('epigenetic silencing', 'Var', (40, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
12975	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))
12976	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))
12978	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))
12979	32051553	These results suggested that inhibiting EGF/MAPK pathway promotes ZNF263 degradation through the ubiquitin-proteasome pathway.	('degradation', 'MPA', (73, 84))	('EGF', 'Gene', (40, 43))	('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))
12987	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))
12988	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))
12994	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.	('vIII', 'Gene', (5, 9))	('malignant progression', 'CPA', (191, 212))	('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))
13001	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))
13005	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))
13009	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))
13010	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))
13015	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))
13016	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))
13017	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))
13019	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))
13022	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))	('mutations', 'Var', (84, 93))	('results from', 'Reg', (41, 53))	('extensive abnormalities', 'Disease', (125, 148))	('extensive abnormalities', 'Disease', 'MESH:D054908', (125, 148))	('causes', 'Reg', (118, 124))	('TETs', 'Chemical', 'MESH:C010349', (106, 110))
13023	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))
13025	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))
13027	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))
13028	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))
13030	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))
13034	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))
13039	32051553	S11), suggesting that DNA hypermethylation, but not H3K27me3, is responsible for epigenetic silencing of SIX3 in glioma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('epigenetic silencing', 'Var', (81, 101))	('SIX3', 'Gene', '6496', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('SIX3', 'Gene', (105, 109))	('glioma', 'Disease', (113, 119))
13042	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))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('IDH1', 'Gene', '3417', (52, 56))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (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))	('occurs', 'Reg', (73, 79))	('IDH1', 'Gene', (52, 56))
13043	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))	('mutation', 'Var', (81, 89))	('mutant R132H', 'Var', (5, 17))	('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))
13044	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))	('IDH1', 'Gene', (17, 21))	('mutant R132H', 'Var', (22, 34))	('R132H', 'Var', (29, 34))	('alpha-KG', 'Chemical', '-', (129, 137))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (209, 227))	('R132H', 'Mutation', 'rs121913500', (29, 34))	('a-ketoglutarate', 'Chemical', '-', (139, 154))	('catalyze', 'MPA', (88, 96))	('IDH1', 'Gene', '3417', (17, 21))	('ability', 'MPA', (77, 84))
13046	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))
13048	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))
13050	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))
13051	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))
13052	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))
13053	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))
13054	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))
13055	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))
13057	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))	('SIX3', 'Gene', (36, 40))	('affect', 'Reg', (29, 35))	('expression', 'Species', '29278', (57, 67))	('IDH1', 'Gene', (11, 15))
13058	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))
13059	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))	('binding', 'Interaction', (257, 264))	('transcription factor', 'MPA', (236, 256))	('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))
13071	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.	('protein phosphatases', 'Enzyme', (48, 68))	('binding', 'Interaction', (69, 76))	('dephosphorylated', 'MPA', (120, 136))	('degradation', 'MPA', (150, 161))	('c-Myc', 'MPA', (165, 170))	('PP2A', 'Var', (108, 112))	('promoted', 'PosReg', (141, 149))	('ZNF263', 'Gene', '10127', (82, 88))	('ZNF263', 'Gene', (82, 88))
13072	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))
13073	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))	('phosphorylation', 'Var', (105, 120))	('ZNF263', 'Gene', (59, 65))	('stabilizes', 'PosReg', (140, 150))	('ZNF263', 'Gene', (124, 130))	('MAPKs', 'Gene', (134, 139))
13079	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))
13115	32762688	TOX was down-regulated in malignant gliomas compared to low grade gliomas, and upregulated in the proneural and IDH mutant subtypes of GBM.	('malignant gliomas', 'Disease', 'MESH:D005910', (26, 43))	('down-regulated', 'NegReg', (8, 22))	('gliomas', 'Disease', (36, 43))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('TOX', 'Gene', '9760', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (135, 138))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('TOX', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('mutant', 'Var', (116, 122))	('IDH', 'Gene', (112, 115))	('upregulated', 'PosReg', (79, 90))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('malignant gliomas', 'Disease', (26, 43))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('IDH', 'Gene', '3417', (112, 115))
13116	32762688	TOXlow tumours are associated with the loss of PTEN and amplification of EGFR, while TOXhigh tumours harbor frequent mutations in IDH1 (91%).	('mutations', 'Var', (117, 126))	('EGFR', 'Gene', '1956', (73, 77))	('TOXlow tumours', 'Disease', (0, 14))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('EGFR', 'Gene', (73, 77))	('IDH1', 'Gene', (130, 134))	('TOXhigh tumours', 'Disease', 'MESH:D009369', (85, 100))	('TOXlow tumours', 'Disease', 'MESH:D009369', (0, 14))	('loss', 'NegReg', (39, 43))	('PTEN', 'Gene', (47, 51))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('amplification', 'MPA', (56, 69))	('TOXhigh tumours', 'Disease', (85, 100))	('IDH1', 'Gene', '3417', (130, 134))	('PTEN', 'Gene', '5728', (47, 51))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))
13133	32762688	Deregulation of TOX expression in cancer can be roughly attributed to two mechanisms: genetic alteration and epigenetic events.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('TOX', 'Gene', '9760', (16, 19))	('TOX', 'Gene', (16, 19))	('expression', 'MPA', (20, 30))	('epigenetic events', 'Var', (109, 126))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Deregulation', 'MPA', (0, 12))	('cancer', 'Disease', (34, 40))
13156	32762688	Isocitrate dehydrogenase (IDH) mutation, which is associated with better clinical outcomes, has a tight association with a high expression level of TOX (Fig.	('TOX', 'Gene', (148, 151))	('TOX', 'Gene', '9760', (148, 151))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('mutation', 'Var', (31, 39))	('association', 'Interaction', (104, 115))	('IDH', 'Gene', (26, 29))	('high expression level', 'MPA', (123, 144))	('IDH', 'Gene', '3417', (26, 29))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
13158	32762688	The ROC curve further suggested that TOX could be a valuable predictor for IDH mutation across glioma types, in LGG cases, and in GBM cases respectively (AUC value = 0.878, P < 0.001; value = 0.841, P < 0.001; value = 0.814, P < 0.001, respectively Fig.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('TOX', 'Gene', '9760', (37, 40))	('TOX', 'Gene', (37, 40))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('glioma', 'Disease', (95, 101))	('mutation', 'Var', (79, 87))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
13160	32762688	Additionally, TOX was up-regulated with 1p/19q codeletion in pan-glioma analysis in both TCGA and CGGA cohorts (Fig.	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('TOX', 'Gene', '9760', (14, 17))	('TOX', 'Gene', (14, 17))	('up-regulated', 'PosReg', (22, 34))	('1p/19q codeletion', 'Var', (40, 57))
13161	32762688	Notably, in LGG samples, IDH mutation together with 1p/19q codeletion is related to higher expression of TOX in both TCGA and CGGA cohorts (Fig.	('TOX', 'Gene', '9760', (105, 108))	('mutation', 'Var', (29, 37))	('expression', 'MPA', (91, 101))	('IDH', 'Gene', (25, 28))	('TOX', 'Gene', (105, 108))	('IDH', 'Gene', '3417', (25, 28))	('higher', 'PosReg', (84, 90))
13182	32762688	In univariate analysis, TOX, WHO Grade, age at diagnosis, 1p19q codeletion, and IDH mutation were significantly related to OS in both TCGA and CGGA databases (Tables 1, 2).	('related', 'Reg', (112, 119))	('IDH', 'Gene', (80, 83))	('TOX', 'Gene', '9760', (24, 27))	('IDH', 'Gene', '3417', (80, 83))	('TOX', 'Gene', (24, 27))	('1p19q codeletion', 'Var', (58, 74))
13187	32762688	Chromosome 7 amplification and chromosome 10 deletion, the two most common genomic events in GBM, were frequently associated with the TOXlow cluster (Fig.	('cluster (Fig', 'Species', '100569', (141, 153))	('TOX', 'Gene', '9760', (134, 137))	('chromosome 10', 'Gene', (31, 44))	('Chromosome', 'Var', (0, 10))	('TOX', 'Gene', (134, 137))	('associated', 'Reg', (114, 124))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('deletion', 'Var', (45, 53))
13188	32762688	The genomic hallmark of oligodendroglioma, deletion of 1p and 19q, was more frequently occurring in the TOXhigh cluster (Fig.	('oligodendroglioma', 'Disease', (24, 41))	('oligodendroglioma', 'Disease', 'MESH:D009837', (24, 41))	('cluster (Fig', 'Species', '100569', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('TOX', 'Gene', '9760', (104, 107))	('deletion of', 'Var', (43, 54))	('TOX', 'Gene', (104, 107))
13193	32762688	Notably, a 4q12 peak was detected in both TOXhigh and TOXlow samples.	('TOX', 'Gene', '9760', (54, 57))	('TOX', 'Gene', (54, 57))	('4q12', 'Var', (11, 15))	('TOX', 'Gene', '9760', (42, 45))	('TOX', 'Gene', (42, 45))
13195	32762688	Based on TOX expression levels, the somatic mutation profiles revealed that mutations in IDH1 (91%), CIC (28%), and ATRX (37%) were significantly enriched in GBM samples with high TOX expression (Fig.	('TOX', 'Gene', (9, 12))	('CIC', 'Disease', 'None', (101, 104))	('mutations', 'Var', (76, 85))	('ATRX', 'Gene', (116, 120))	('ATRX', 'Gene', '546', (116, 120))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('TOX', 'Gene', '9760', (180, 183))	('CIC', 'Disease', (101, 104))	('IDH1', 'Gene', (89, 93))	('TOX', 'Gene', (180, 183))	('TOX', 'Gene', '9760', (9, 12))	('IDH1', 'Gene', '3417', (89, 93))
13196	32762688	In addition, frequently observed mutations to EGFR (27%), IDH1 (20%), PTEN (18%), and MUC16 (16%) were present in gliomas with low TOX expression (n = 158; Fig.	('gliomas', 'Disease', (114, 121))	('MUC16', 'Gene', (86, 91))	('IDH1', 'Gene', '3417', (58, 62))	('PTEN', 'Gene', (70, 74))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('PTEN', 'Gene', '5728', (70, 74))	('EGFR', 'Gene', '1956', (46, 50))	('present', 'Reg', (103, 110))	('mutations', 'Var', (33, 42))	('MUC16', 'Gene', '94025', (86, 91))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('EGFR', 'Gene', (46, 50))	('TOX', 'Gene', '9760', (131, 134))	('IDH1', 'Gene', (58, 62))	('TOX', 'Gene', (131, 134))
13220	32762688	Altogether, our data reveal that high expression of TOX is associated with reduced infiltration of immune cells in the microenvironment of gliomas.	('high expression', 'Var', (33, 48))	('gliomas', 'Disease', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('reduced', 'NegReg', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('infiltration', 'MPA', (83, 95))	('TOX', 'Gene', '9760', (52, 55))	('TOX', 'Gene', (52, 55))
13234	32762688	Moreover, high expression of TOX was associated with better survival in pan-glioma analysis, LGG alone, and GBM alone.	('glioma', 'Disease', (76, 82))	('TOX', 'Gene', '9760', (29, 32))	('TOX', 'Gene', (29, 32))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('high expression', 'Var', (10, 25))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('better', 'PosReg', (53, 59))
13240	32762688	Given that genomic alternations may promote the progression of tumor through transforming the tumor microenvironment, these results suggest that TOX expression is associated with benign biological processes.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('promote', 'PosReg', (36, 43))	('genomic alternations', 'Var', (11, 31))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('transforming', 'Reg', (77, 89))	('tumor', 'Disease', (94, 99))	('associated', 'Reg', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('progression', 'CPA', (48, 59))	('TOX', 'Gene', '9760', (145, 148))	('TOX', 'Gene', (145, 148))
13264	30880007	Here we employed a computational approach to uncover mechanisms underlying cancer mutational burden by focusing upon relationships between 1) translocation breakpoints and the thousands of G4 DNA-forming sequences within retrotransposons impacting transcription and exemplifying probable non-B DNA structures and 2) transcriptome profiling and cancer mutations.	('cancer', 'Disease', (344, 350))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('transcription', 'MPA', (248, 261))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('sequences', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('transposons', 'Species', '2387', (226, 237))	('impacting', 'Reg', (238, 247))
13266	30880007	By analyzing >97,000 unique translocation breakpoints from the Catalogue Of Somatic Mutations In Cancer (COSMIC), we found that breakpoints are overrepresented at G4 DNA-forming sequences within hominid-specific SVA retrotransposons, and generally occur in tumors with mutations in tumor suppressor genes, such as TP53.	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (257, 262))	('Mutations', 'Var', (84, 93))	('mutations', 'Var', (269, 278))	('occur', 'Reg', (248, 253))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Disease', (282, 287))	('TP53', 'Gene', '7157', (314, 318))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('transposons', 'Species', '2387', (221, 232))	('TP53', 'Gene', (314, 318))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
13269	30880007	Thus, correlation analyses of DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate processes shaping genomic instability in cancer.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutation loads', 'Var', (69, 83))	('cancer', 'Disease', (188, 194))
13271	30880007	Genomic instability, increased proliferation and escape from apoptosis are hallmarks of cancer.	('increased', 'PosReg', (21, 30))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('proliferation', 'CPA', (31, 44))	('escape', 'CPA', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Genomic', 'Var', (0, 7))
13272	30880007	A recent survey of >11000 tumor samples identified ~300 genes (cancer-driver genes) whose somatic mutations in terms of base substitutions are directly linked to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('linked', 'Reg', (152, 158))	('base substitutions', 'Var', (120, 138))	('malignancy', 'Disease', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('cancer', 'Disease', (63, 69))
13273	30880007	Another ~1100 genes may support tumorigenesis through alterations in their expression profiles as a consequence of copy-number alterations, gene fusions, and other types of genomic rearrangements.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('expression profiles', 'MPA', (75, 94))	('alterations', 'Reg', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('copy-number alterations', 'Var', (115, 138))	('support', 'PosReg', (24, 31))
13277	30880007	Such genomic alterations are seen not only in adult but also in pediatric tumors, implicating DNA mutations and epigenetic changes in steering a normal cell into a malignant phenotype.	('epigenetic changes', 'Var', (112, 130))	('DNA', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('steering', 'PosReg', (134, 142))	('tumors', 'Disease', (74, 80))
13278	30880007	Somatic mutations in driver genes are often instigated by predisposing germline variants, such as in BRCA1 and BRCA2, and impinge on 8 major cellular processes, with alterations in genes involved in maintaining genome integrity, such as the Fanconi anemia pathway, and in 10 signaling pathways (RTK/RAS, Nrf2, PI3K, TGFbeta, Wnt, Myc, TP53, cell cycle, Hippo, Notch) as being among the most commonly altered.	('alterations', 'Reg', (166, 177))	('TGFbeta', 'Gene', (316, 323))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (241, 255))	('impinge', 'Reg', (122, 129))	('TP53', 'Gene', '7157', (335, 339))	('BRCA2', 'Gene', (111, 116))	('TGFbeta', 'Gene', '7039', (316, 323))	('Nrf2', 'Gene', (304, 308))	('Myc', 'Gene', (330, 333))	('mutations', 'Var', (8, 17))	('cell cycle', 'CPA', (341, 351))	('BRCA2', 'Gene', '675', (111, 116))	('signaling pathways', 'Pathway', (275, 293))	('variants', 'Var', (80, 88))	('Fanconi anemia', 'Disease', (241, 255))	('anemia', 'Phenotype', 'HP:0001903', (249, 255))	('TP53', 'Gene', (335, 339))	('BRCA1', 'Gene', '672', (101, 106))	('Fanconi anemia', 'Disease', 'MESH:D005199', (241, 255))	('Myc', 'Gene', '4609', (330, 333))	('altered', 'Reg', (400, 407))	('BRCA1', 'Gene', (101, 106))	('Nrf2', 'Gene', '4780', (304, 308))
13280	30880007	By extracting patterns of base changes in cancer genomes, ~30 distinct signatures have been catalogued, which inform on molecular processes likely to lead to mutations from either extrinsic (ultraviolet light, smoking, chemicals) or intrinsic (APOBEC misediting, DNA repair deficiencies, defective polymerase epsilon) sources.	('mutations', 'Var', (158, 167))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
13281	30880007	Patterns of base substitutions have also been associated with direct damage to DNA bases by oxidants, such as reactive oxygen and nitrogen species (ROS and RNS respectively), which rise in tumor cells following glucose deprivation, deregulation of the mitochondrial electron transport chain and other organelles (endoplasmic reticulum, lysosomes and peroxisomes).	('rise', 'PosReg', (181, 185))	('tumor', 'Disease', (189, 194))	('base substitutions', 'Var', (12, 30))	('deregulation', 'Reg', (232, 244))	('glucose', 'Chemical', 'MESH:D005947', (211, 218))	('nitrogen', 'Chemical', 'MESH:D009584', (130, 138))	('RNS', 'Chemical', 'MESH:D011886', (156, 159))	('mitochondrial', 'Enzyme', (252, 265))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
13282	30880007	This sustained proliferation contributes to a condition referred to as "replication stress", a potent inducer of genomic instability triggered by a buildup of ssDNA from RPA depletion, the accumulation of secondary DNA structures, R-loops, collisions between replication and transcription, and other factors.	('RPA', 'Gene', '6117', (170, 173))	('collisions', 'Var', (240, 250))	('R-loops', 'Var', (231, 238))	('accumulation', 'PosReg', (189, 201))	('stress', 'Disease', 'MESH:D000079225', (84, 90))	('RPA', 'Gene', (170, 173))	('secondary DNA structures', 'Protein', (205, 229))	('stress', 'Disease', (84, 90))
13287	30880007	Tumor samples with translocation breakpoints at G4 DNA-forming sequences are also more likely to carry mutations in TP53 and less likely to harbor pathologic mutations in KRAS and CTNNB1, supporting a role for TP53 mutations in G4 DNA-induced instability.	('mutations', 'Var', (103, 112))	('TP53', 'Gene', (116, 120))	('CTNNB1', 'Gene', '1499', (180, 186))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', (210, 214))	('G4 DNA-forming', 'Var', (48, 62))	('CTNNB1', 'Gene', (180, 186))	('KRAS', 'Gene', (171, 175))	('TP53', 'Gene', '7157', (116, 120))	('KRAS', 'Gene', '3845', (171, 175))	('TP53', 'Gene', '7157', (210, 214))
13290	30880007	Thus, correlation analyses of G4 DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate sources of genomic instability in cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutation loads', 'Var', (72, 86))
13307	30880007	single base substitutions and small insertion/deletions in exons genome-wide specific to the tumor but not the matched normal samples.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('insertion/deletions', 'Var', (36, 55))	('single base substitutions', 'Var', (0, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
13321	30880007	In conclusion, our analysis shows that translocation breakpoints in cancer occur at G4 DNA-forming repeats more often than expected by chance alone.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('translocation breakpoints', 'Var', (39, 64))	('cancer', 'Disease', (68, 74))
13323	30880007	First, we assessed the genome-wide load of translocations in each patient; we found that the group of patients with G4-associated breakpoints carried more translocations than the group of patients without G4-associated breakpoints (57.9 +- 59.7 vs. 17.3 +- 20.7; Fig.	('G4-associated', 'Var', (116, 129))	('breakpoints', 'Var', (130, 141))	('patient', 'Species', '9606', (188, 195))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('patient', 'Species', '9606', (66, 73))	('patients', 'Species', '9606', (188, 196))	('translocations', 'MPA', (155, 169))
13324	30880007	Second, even though tumor samples with and without G4-associated breakpoints carried pathologic mutations in cancer-related genes, such as TP53, KRAS, PIK3CA, etc.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('pathologic', 'Reg', (85, 95))	('KRAS', 'Gene', (145, 149))	('PIK3CA', 'Gene', (151, 157))	('cancer', 'Disease', (109, 115))	('TP53', 'Gene', '7157', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('KRAS', 'Gene', '3845', (145, 149))	('PIK3CA', 'Gene', '5290', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', (20, 25))
13325	30880007	(Figs 2C and D), samples with G4-containing breakpoints displayed a greater frequency of mutations at TP53, PTPRD and GATA3 than the alternate group.	('TP53', 'Gene', (102, 106))	('GATA3', 'Gene', (118, 123))	('PTPRD', 'Gene', '5789', (108, 113))	('PTPRD', 'Gene', (108, 113))	('mutations', 'Var', (89, 98))	('GATA3', 'Gene', '2625', (118, 123))	('TP53', 'Gene', '7157', (102, 106))	('G4-containing', 'Var', (30, 43))
13326	30880007	By contrast, the likelihood of harboring pathologic mutations at KRAS and CTNNB1 was significantly reduced (Fig.	('mutations', 'Var', (52, 61))	('CTNNB1', 'Gene', (74, 80))	('KRAS', 'Gene', '3845', (65, 69))	('CTNNB1', 'Gene', '1499', (74, 80))	('reduced', 'NegReg', (99, 106))	('KRAS', 'Gene', (65, 69))
13327	30880007	3E), in accordance with the expectation that mutations in the TP53, RTK/RAS and Wnt pathways are mutually exclusive.	('RTK/RAS', 'Pathway', (68, 75))	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('Wnt pathways', 'Pathway', (80, 92))
13328	30880007	We conclude that strand breaks at or near G4 DNA-forming sequences occur generally in tumors with high genetic instability, which is promoted in part by mutations in tumor suppressor genes, such as TP53.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (153, 162))	('tumor', 'Disease', (86, 91))	('strand', 'Var', (17, 23))	('tumors', 'Disease', (86, 92))	('tumor', 'Disease', (166, 171))	('TP53', 'Gene', '7157', (198, 202))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('TP53', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
13337	30880007	In conclusion, translocation breakpoints are more likely to be found at G4 DNA located in SVA elements than in L1 transposons; furthermore, it is possible that a subset of SVA elements in the human genome might be particularly unstable, yielding recurrent strand breaks in cancer.	('cancer', 'Disease', (273, 279))	('human', 'Species', '9606', (192, 197))	('transposons', 'Species', '2387', (114, 125))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('yielding', 'Reg', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('SVA', 'Gene', (172, 175))	('elements', 'Var', (176, 184))	('strand breaks', 'MPA', (256, 269))	('recurrent strand breaks', 'Phenotype', 'HP:0040012', (246, 269))
13338	30880007	Recognizing that G4 DNA likely impacts transcription, we employed a separate set of analyses to assess the extent to which the cellular transcriptome and its regulation are associated with mutation loads in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('G4 DNA', 'Var', (17, 23))	('mutation loads', 'Var', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('associated', 'Reg', (173, 183))	('impacts', 'Reg', (31, 38))	('transcription', 'MPA', (39, 52))
13340	30880007	Thus, an S-plot of all P-values allowed for a direct comparison across all tumors, which revealed a strong variability on tissue-dependent origin in the extent to which gene expression correlates with mutation loads.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('gene expression', 'MPA', (169, 184))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (201, 209))	('tumors', 'Disease', (75, 81))
13348	30880007	Of the 10 top genes most negatively correlated with mutation loads, the strongest association was found for MLH1 in ESCA (Fig.	('ESCA', 'Disease', (116, 120))	('MLH1', 'Gene', '4292', (108, 112))	('MLH1', 'Gene', (108, 112))	('mutation', 'Var', (52, 60))
13349	30880007	Mutations in MLH1 or its low expression are known for their role in tumorigenesis, however none of the other 9 genes were listed in the COSMIC cancer gene census.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MLH1', 'Gene', (13, 17))	('MLH1', 'Gene', '4292', (13, 17))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
13352	30880007	In summary, the top genes most strongly correlated with mutations loads reveal strong associations between deregulation of gene expression and poor survival in cancer.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('poor survival', 'CPA', (143, 156))	('cancer', 'Disease', (160, 166))	('deregulation', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
13353	30880007	To further explore the involvement of the top genes correlated with mutations in tumorigenesis, we focused on two genes: MYBL2 for the positive correlations and SDHAF3 for the negative correlations.	('MYBL2', 'Gene', '4605', (121, 126))	('SDHAF3', 'Gene', '57001', (161, 167))	('MYBL2', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (68, 77))	('SDHAF3', 'Gene', (161, 167))	('tumor', 'Disease', (81, 86))
13359	30880007	Poor prognosis was associated with high MYBL2 expression in 11/32 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('MYBL2', 'Gene', '4605', (40, 45))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('MYBL2', 'Gene', (40, 45))
13367	30880007	In PRAD, where SDHAF3 displayed the strongest negative correlation between expression and mutation of all tumors, the gene was overexpressed relative to matched controls (not shown); however, SDHD was strongly downregulated.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('SDHAF3', 'Gene', '57001', (15, 21))	('tumors', 'Disease', (106, 112))	('overexpressed', 'PosReg', (127, 140))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('PRAD', 'Disease', (3, 7))	('SDHAF3', 'Gene', (15, 21))	('SDHD', 'Gene', (192, 196))	('SDHD', 'Gene', '6392', (192, 196))	('downregulated', 'NegReg', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('negative', 'NegReg', (46, 54))	('mutation', 'Var', (90, 98))	('expression', 'MPA', (75, 85))
13371	30880007	Having established the validity of our analyses in uncovering genes whose deregulation seem to predict poor clinical outcome, we then conducted a systematic assessment of gene enrichment for a pool of genes with strong correlations in each tumor type.	('deregulation', 'Var', (74, 86))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (240, 245))
13378	30880007	We also conducted the gene enrichment analysis for the 270 genes (in each tumor type), whose expression was most negatively correlated with mutations, but did not find any enriched term.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (140, 149))	('negatively', 'NegReg', (113, 123))
13380	30880007	Therefore, our correlation analysis of gene expression versus mutation loads identified pathways that are commonly altered in different types of cancer.	('cancer', 'Disease', (145, 151))	('pathways', 'Pathway', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutation', 'Var', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
13381	30880007	In LUAD, although not in KICH and PRAD, the main pathways for the repair of base mismatch and base lesions, i.e.	('KICH', 'Disease', 'None', (25, 29))	('base mismatch', 'Var', (76, 89))	('KICH', 'Disease', (25, 29))
13383	30880007	In addition, ALKBH3 (R = -0.22, P = 4.0x10-7) for alkylation damage reversal, RRM2B (R = -0.24, P = 2.7 x 10-8), which supplies dNTPs during DNA repair synthesis, POLK (R = -0.22, P = 3.9 x 10-7) for translesion DNA synthesis and UBE2B (R = -0.22, P = 4.9 x 10-7), involved in ubiquitination of PCNA also displayed negative correlations with mutational loads (Fig.	('RRM2B', 'Gene', (78, 83))	('ALKBH3', 'Gene', (13, 19))	('ALKBH3', 'Gene', '221120', (13, 19))	('PCNA', 'Gene', (295, 299))	('negative', 'NegReg', (315, 323))	('UBE2B', 'Gene', '7320', (230, 235))	('RRM2B', 'Gene', '50484', (78, 83))	('mutational', 'Var', (342, 352))	('PCNA', 'Gene', '5111', (295, 299))	('POLK', 'Gene', (163, 167))	('POLK', 'Gene', '51426', (163, 167))	('UBE2B', 'Gene', (230, 235))
13386	30880007	Translocation breakpoints were enriched at sequences with the potential to form G4 DNA structures in tumor samples that were characterized by elevated genetic instability and frequent mutations in tumor suppressor genes, such as TP53.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('mutations', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TP53', 'Gene', '7157', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('TP53', 'Gene', (229, 233))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
13390	30880007	Genes whose expression is positively correlated with mutations were enriched in selected KEGG terms in more than one cancer type, which provides a platform for addressing the contribution of specific pathways to somatic mutation in cancer.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (232, 238))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('expression', 'MPA', (12, 22))
13393	30880007	Nevertheless, our estimates are in line with determinations of mutations at non-B DNA-forming motifs in cancer genomes and strengthens the concept, both from genome-wide and targeted studies, that non-B DNA structures contribute to mutagenesis, both in cancer and in genetic disease.	('mutations', 'Var', (63, 72))	('genetic disease', 'Disease', (267, 282))	('non-B DNA', 'Var', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('mutagenesis', 'MPA', (232, 243))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genetic disease', 'Disease', 'MESH:D030342', (267, 282))
13394	30880007	The prevalence of G4-associated translocation breakpoints with tumor samples carrying extensive genomic alterations is consistent with reports that TP53 mutant tumors are associated with high rates of genomic instability (reviewed in).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', (63, 68))	('translocation breakpoints', 'Var', (32, 57))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('mutant', 'Var', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('G4-associated', 'Gene', (18, 31))	('tumor', 'Disease', (160, 165))	('genomic instability', 'MPA', (201, 220))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
13395	30880007	TP53 mutants have been reported to sequester DNA repair factors, such as MRE11, away from double-strand breaks and at stalled replication forks, leading to an accumulation of translocations.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('MRE11', 'Gene', '4361', (73, 78))	('accumulation', 'PosReg', (159, 171))	('MRE11', 'Gene', (73, 78))	('translocations', 'MPA', (175, 189))	('mutants', 'Var', (5, 12))
13397	30880007	Changes in gene expression, which we show here are extensive and impact cancer mutagenesis, are also likely to influence G4 DNA structure-induced genetic instability.	('influence', 'Reg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Changes', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('impact', 'Reg', (65, 71))	('cancer', 'Disease', (72, 78))
13398	30880007	We are also learning how replication and repair proteins, such as FEN1, can act in trans to greatly impact mutations so molecular mechanisms are expected to be key to improve predictions.	('impact', 'Reg', (100, 106))	('FEN1', 'Gene', (66, 70))	('FEN1', 'Gene', '2237', (66, 70))	('mutations', 'Var', (107, 116))
13405	30880007	MLH1 mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal.	('protein-protein', 'Protein', (14, 29))	('MLH1', 'Gene', '4292', (0, 4))	('strand discrimination', 'Var', (72, 93))	('mediates', 'Reg', (5, 13))	('MLH1', 'Gene', (0, 4))	('mismatch recognition', 'Var', (50, 70))
13406	30880007	In colon and rectal cancers hypermutation has been linked in part to MLH1 hypermethylation, and in esophageal squamous cell carcinoma MLH1 promoter methylation correlates with weak expression and poor survival.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('expression', 'MPA', (181, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('linked', 'Reg', (51, 57))	('esophageal squamous cell carcinoma', 'Disease', (99, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('weak', 'NegReg', (176, 180))	('MLH1', 'Gene', '4292', (134, 138))	('MLH1', 'Gene', (134, 138))	('MLH1', 'Gene', '4292', (69, 73))	('hypermethylation', 'Var', (74, 90))	('MLH1', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('hypermutation', 'Var', (28, 41))	('colon and rectal cancers', 'Disease', 'MESH:D015179', (3, 27))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (99, 133))
13411	30880007	The polymeric immunoglobulin receptor (the PIGR gene product) pIgR plays an important role in protecting small airways of the lung from airborne antigens and microorganisms; PIGR-/- mice develop chronic obstructive pulmonary disease (COMP)-like pathology with age and persistent activation of innate immune response to the lung microbiome.	('chronic obstructive pulmonary disease', 'Disease', (195, 232))	('pIgR', 'Gene', (62, 66))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (195, 232))	('mice', 'Species', '10090', (182, 186))	('PIGR-/-', 'Var', (174, 181))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (203, 232))	('pIgR', 'Gene', '18703', (62, 66))	('develop', 'Reg', (187, 194))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (195, 232))
13412	30880007	Loss of PIGR is an early event in lung tumorigenesis, and it is plausible that the association of low PIGR with high mutation rates we observe reflects a role for the ensuing inflammation in mutagenesis, in part through the release of ROS and reactive nitrogen intermediates.	('nitrogen', 'Chemical', 'MESH:D009584', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('low', 'NegReg', (98, 101))	('PIGR', 'Gene', (8, 12))	('PIGR', 'Gene', (102, 106))	('reactive nitrogen intermediates', 'MPA', (243, 274))	('ROS', 'MPA', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('inflammation', 'Disease', 'MESH:D007249', (175, 187))	('inflammation', 'Disease', (175, 187))	('Loss', 'Var', (0, 4))	('release', 'MPA', (224, 231))	('ROS', 'Chemical', 'MESH:D017382', (235, 238))
13420	30880007	A causal association between MYBL2 expression and mutation loads has recently been reported, and involves transactivation of the APOBEC3B gene whose product (apolipoprotein B mRNA cytosine deaminase, A3B) generates ectopic C>U>T transitions and genomic hypermutation when overproduced.	('APOBEC3B', 'Gene', (129, 137))	('genomic hypermutation', 'CPA', (245, 266))	('apolipoprotein B', 'Gene', (158, 174))	('APOBEC3B', 'Gene', '9582', (129, 137))	('MYBL2', 'Gene', '4605', (29, 34))	('apolipoprotein B', 'Gene', '338', (158, 174))	('A3B', 'Gene', '9582', (200, 203))	('ectopic C', 'MPA', (215, 224))	('MYBL2', 'Gene', (29, 34))	('mutation', 'Var', (50, 58))	('A3B', 'Gene', (200, 203))
13421	30880007	The strong correlation of the SDH accessory factor SDHAF3 with mutations was of particular interest since a germline c.157T>C (p.Phe53Leu) substitution in this gene was recently associated with increased prevalence of familiar and sporadic pheochromocytoma and paraganglioma, which are characteristic of SDH-deficiency.	('SDHAF3', 'Gene', (51, 57))	('associated with', 'Reg', (178, 193))	('SDH', 'Gene', (51, 54))	('c.157T>C', 'Mutation', 'rs62624461', (117, 125))	('sporadic pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (231, 274))	('SDH', 'Gene', (304, 307))	('c.157T>C', 'Var', (117, 125))	('paraganglioma', 'Phenotype', 'HP:0002668', (261, 274))	('p.Phe53Leu', 'Mutation', 'rs62624461', (127, 137))	('familiar', 'Disease', (218, 226))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('SDH', 'Gene', '6390', (30, 33))	('SDH-deficiency', 'Disease', 'MESH:D007153', (304, 318))	('SDH-deficiency', 'Disease', (304, 318))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (240, 256))	('SDH', 'Gene', '6390', (51, 54))	('SDH', 'Gene', (30, 33))	('SDH', 'Gene', '6390', (304, 307))	('SDHAF3', 'Gene', '57001', (51, 57))
13423	30880007	The fundamental importance of Fe-S clusters and control of superoxide support the observed connections of the SDHB subunit with mutational load.	('SDHB', 'Gene', (110, 114))	('superoxide', 'Chemical', 'MESH:D013481', (59, 69))	('Fe-S', 'Chemical', 'MESH:D007501', (30, 34))	('mutational load', 'Var', (128, 143))	('SDHB', 'Gene', '6390', (110, 114))	('connections', 'Interaction', (91, 102))
13426	30880007	Thus, anticorrelation between SDHAF3 expression and mutations may stem from SDH deficiency.	('stem from', 'Reg', (66, 75))	('mutations', 'Var', (52, 61))	('SDH deficiency', 'Disease', 'MESH:D007153', (76, 90))	('SDHAF3', 'Gene', '57001', (30, 36))	('SDHAF3', 'Gene', (30, 36))	('expression', 'MPA', (37, 47))	('SDH deficiency', 'Disease', (76, 90))
13428	30880007	The clustering encompassing KICH, LUAD, PRAD and LGG is centered on cell cycle, DNA replication and DNA repair genes, and the positive correlations with mutations likely arise from replication stress, excessive DNA damage (such as A3B activation) and its escape from repair.	('A3B', 'Gene', (231, 234))	('DNA', 'MPA', (211, 214))	('mutations', 'Var', (153, 162))	('KICH', 'Disease', (28, 32))	('stress', 'Disease', 'MESH:D000079225', (193, 199))	('A3B', 'Gene', '9582', (231, 234))	('stress', 'Disease', (193, 199))	('KICH', 'Disease', 'None', (28, 32))	('arise from', 'Reg', (170, 180))
13430	30880007	Thus, we propose that the association of mitochondrial gene expression with mutations likely stems from direct damage to DNA by increased ROS and other oxidants.	('ROS', 'MPA', (138, 141))	('mutations', 'Var', (76, 85))	('mitochondrial gene', 'Gene', (41, 59))	('increased', 'PosReg', (128, 137))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))
13433	30880007	The ectopic expression and upregulation of olfactory receptors in melanoma (SKCM) is a potential source of malignant transformation, and it will be useful to assess their role in mutagenesis.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('olfactory receptors', 'Protein', (43, 62))	('upregulation', 'PosReg', (27, 39))	('ectopic expression', 'Var', (4, 22))
13438	30880007	We found that G4 DNA-forming sequences are enriched twofold at translocation breakpoints, strengthening the view that G4 DNA structures contribute to genomic instability in cancer; many such structures are likely to originate from L1 and SVA retrotransposons and contribute to instability.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('genomic instability', 'MPA', (150, 169))	('contribute', 'Reg', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('transposons', 'Species', '2387', (247, 258))	('G4 DNA', 'Var', (118, 124))
13439	30880007	Mutations in TP53 increase the chance of G4 DNA-induced translocations, possibly through defects in homologous recombination following replication fork stalling at G4 DNA.	('TP53', 'Gene', (13, 17))	('homologous', 'MPA', (100, 110))	('defects', 'NegReg', (89, 96))	('Mutations', 'Var', (0, 9))	('translocations', 'MPA', (56, 70))	('TP53', 'Gene', '7157', (13, 17))
13441	30880007	Transcriptome analyses identify two distinct branches though which alterations in gene expression may lead to an accumulation of single base substitutions in cancer: 1) activation of cell cycle/DNA repair; and 2) loss of homeostatic control of mitochondrial respiration.	('homeostatic control of mitochondrial respiration', 'MPA', (221, 269))	('cell cycle/DNA repair', 'CPA', (183, 204))	('activation', 'PosReg', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('alterations', 'Var', (67, 78))	('cancer', 'Disease', (158, 164))	('single base substitutions', 'Var', (129, 154))	('loss', 'NegReg', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
13444	30880007	Tumor-specific alterations in gene expression associated with mutation loads also include the ectopic expression of olfactory receptor genes in skin cancer, exacerbation of the ER unfolded protein response in breast cancer and altered HLA gene expression in cervical cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('alterations', 'Reg', (15, 26))	('HLA', 'Protein', (235, 238))	('cancer', 'Disease', (216, 222))	('ER unfolded protein', 'MPA', (177, 196))	('gene expression', 'MPA', (30, 45))	('skin cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutation loads', 'Var', (62, 76))	('cancer', 'Disease', (149, 155))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('cancer', 'Disease', (267, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('ectopic expression', 'MPA', (94, 112))	('olfactory receptor genes', 'Gene', (116, 140))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('altered', 'Reg', (227, 234))	('breast cancer', 'Disease', (209, 222))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('exacerbation', 'PosReg', (157, 169))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
13446	30880007	The second is to clarify how deregulation of the mitochondrial respiratory chain and its link to the TCA cycle through the SDH complex elicits mutations.	('SDH', 'Gene', (123, 126))	('mitochondrial respiratory chain', 'Enzyme', (49, 80))	('deregulation', 'Var', (29, 41))	('elicits', 'Reg', (135, 142))	('SDH', 'Gene', '6390', (123, 126))	('TCA', 'Chemical', 'MESH:D014233', (101, 104))	('mutations', 'Var', (143, 152))
13512	26115094	 Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (226, 239))	('II gliomas', 'Disease', 'MESH:D005910', (201, 211))	('gliomas', 'Disease', (204, 211))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('Gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('Glioma', 'Phenotype', 'HP:0009733', (93, 99))	('Isocitrate dehydrogenase 1', 'Gene', (101, 127))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('Associated', 'Reg', (45, 55))	('glioblastomas', 'Disease', (226, 239))	('mutations', 'Var', (133, 142))	('Gliomas', 'Disease', (93, 100))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (1, 27))	('glioblastomas', 'Disease', 'MESH:D005909', (226, 239))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('II gliomas', 'Disease', (201, 211))	('Isocitrate dehydrogenase 1', 'Gene', (1, 27))	('glioma', 'Disease', (204, 210))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (101, 127))	('Gliomas', 'Disease', 'MESH:D005910', (93, 100))
13514	26115094	Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database.	('TP53', 'Gene', (175, 179))	('Glioma Genome Atlas', 'Disease', 'MESH:D005910', (246, 265))	('TP53', 'Gene', '7157', (175, 179))	('Glioma Genome Atlas', 'Disease', (246, 265))	('O 6-methylguanine DNA methyltransferase', 'Gene', '4255', (85, 124))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('low-grade gliomas', 'Disease', (196, 213))	('O 6-methylguanine DNA methyltransferase', 'Gene', (85, 124))	('loss', 'NegReg', (165, 169))	('Glioma', 'Phenotype', 'HP:0009733', (246, 252))	('mutation', 'Var', (180, 188))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))
13516	26115094	Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas.	('oligodendrogliomas', 'Disease', (110, 128))	('astrocytoma', 'Disease', 'MESH:D001254', (155, 166))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('astrocytoma', 'Disease', (155, 166))	('astrocytomas', 'Disease', 'MESH:D001254', (155, 167))	('astrocytoma', 'Phenotype', 'HP:0009592', (155, 166))	('patient', 'Species', '9606', (96, 103))	('patient', 'Species', '9606', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('patients', 'Species', '9606', (96, 104))	('astrocytomas', 'Disease', (155, 167))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (110, 128))	('patients', 'Species', '9606', (141, 149))	('mutation', 'Var', (36, 44))	('isocitrate dehydrogenase 1', 'Gene', (9, 35))
13517	26115094	Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p < 0.001), but not 1p/19q loss (p = 0.834), occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Disease', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Disease', (271, 277))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('isocitrate dehydrogenase 1-mutated', 'Disease', (184, 218))	('tumor', 'Disease', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('TP53', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('mutation', 'Var', (95, 103))
13518	26115094	Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation.	('frontal lobe location', 'Disease', (36, 57))	('isocitrate dehydrogenase 1', 'Gene', (105, 131))	('frontal lobe location', 'Disease', 'MESH:D001927', (36, 57))	('correlated', 'Reg', (89, 99))	('mutation', 'Var', (132, 140))
13521	26115094	Recent genome-wide mutational analyses have demonstrated the presence of isocitrate dehydrogenase 1 (IDH1) mutations in more than 70% of WHO grade II and III astrocytomas, oligodendrogliomas, and secondary glioblastomas (GBMs), whereas fewer than 5% of primary GBMs harbor this mutation.	('IDH1', 'Gene', (101, 105))	('mutations', 'Var', (107, 116))	('IDH1', 'Gene', '3417', (101, 105))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('secondary glioblastomas', 'Disease', (196, 219))	('glioblastomas', 'Phenotype', 'HP:0012174', (206, 219))	('oligodendrogliomas', 'Disease', (172, 190))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))
13522	26115094	A few studies have suggested that IDH1 mutation is associated with better outcome and sensitivity to temozolomide; however, evidence of its predictive value for response to alkylating agents, 1-(2-chloroethyl)-3-cyclohexyl-L-nitrosourea, and vincristine chemotherapy is lacking.	('mutation', 'Var', (39, 47))	('sensitivity', 'MPA', (86, 97))	('temozolomide', 'Chemical', 'MESH:D000077204', (101, 113))	('vincristine', 'Chemical', 'MESH:D014750', (242, 253))	('IDH1', 'Gene', (34, 38))	('1-(2-chloroethyl)-3-cyclohexyl-L-nitrosourea', 'Chemical', '-', (192, 236))
13523	26115094	Many previous studies have suggested that the prevalence of IDH1 mutations is particularly high in LGGs with 1p/19q deletion, TP53 mutation, and O 6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, which has been shown to play a role in predicting survival in patients with newly diagnosed GBM.	('TP53', 'Gene', (126, 130))	('IDH1', 'Gene', (60, 64))	('O 6-methylguanine-DNA methyltransferase', 'Gene', '4255', (145, 184))	('MGMT', 'Gene', (186, 190))	('O 6-methylguanine-DNA methyltransferase', 'Gene', (145, 184))	('MGMT', 'Gene', '4255', (186, 190))	('high', 'Reg', (91, 95))	('LGGs', 'Disease', (99, 103))	('mutations', 'Var', (65, 74))
13532	26115094	Of the 417 grade II gliomas examined, mutations at codon 132 of the IDH1 gene were detected in 309 tumors (74%) including 304 R132H mutations (arginine to histidine substitution [CGT to CAT]) and 5 R132G mutations (arginine to glycine substitution [CGT to GGT]), which resulted in amino acid sequence alterations.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('detected', 'Reg', (83, 91))	('R132G', 'Mutation', 'rs121913499', (198, 203))	('glycine', 'Chemical', 'MESH:D005998', (227, 234))	('histidine', 'Chemical', 'MESH:D006639', (155, 164))	('R132G', 'Var', (198, 203))	('CAT]', 'Gene', '847', (186, 190))	('arginine', 'Chemical', 'MESH:D001120', (143, 151))	('IDH1', 'Gene', (68, 72))	('CAT]', 'Gene', (186, 190))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutations', 'Var', (38, 47))	('arginine', 'Var', (143, 151))	('R132H', 'Mutation', 'rs121913500', (126, 131))	('arginine', 'Chemical', 'MESH:D001120', (215, 223))
13533	26115094	IDH1 mutation was associated with better OS in patients with oligoastrocytomas or oligodendrogliomas (p = 0.047; Fig 1E), but not in patients with astrocytomas (p = 0.124; Fig 1F).	('oligoastrocytomas or oligodendrogliomas', 'Disease', 'MESH:D001254', (61, 100))	('better', 'PosReg', (34, 40))	('oligoastrocytomas or oligodendrogliomas', 'Disease', (61, 100))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('astrocytoma', 'Phenotype', 'HP:0009592', (66, 77))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
13535	26115094	reported that more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas had mutations in amino acid position 132 of IDH1.	('IDH1', 'Gene', (132, 136))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (52, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('mutations in amino acid position 132', 'Var', (92, 128))
13536	26115094	Notably, our study is the first to demonstrate the prognostic significance of IDH1 mutation in patients with oligodendroglioma or oligoastrocytoma, but not in patients with astrocytoma.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH1', 'Gene', (78, 82))	('oligodendroglioma or oligoastrocytoma', 'Disease', 'MESH:D001254', (109, 146))	('mutation', 'Var', (83, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('astrocytoma', 'Phenotype', 'HP:0009592', (135, 146))	('oligodendroglioma or oligoastrocytoma', 'Disease', (109, 146))
13539	23450706	Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies.	('neurotoxicity', 'Disease', (95, 108))	('neurotoxicity', 'Disease', 'MESH:D020258', (95, 108))	('GBM', 'Gene', (74, 77))	('pediatric', 'Var', (64, 73))
13551	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))
13557	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))
13565	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))	('stage-specific embryonic antigen 1', 'Gene', (133, 167))	('CD15', 'Gene', (127, 131))	('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))
13592	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))
13600	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))
13615	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))
13620	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))
13635	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))
13642	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))	('selective', 'CPA', (98, 107))	('deletion', 'Var', (13, 21))	('glioma', 'Disease', (123, 129))	('gamma134.5', 'Gene', (54, 64))
13643	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))
13646	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))
13651	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))	('PKR', 'Gene', (173, 176))	('limiting', 'NegReg', (106, 114))	('PKR', 'Gene', (67, 70))	('deleted', 'Var', (15, 22))
13653	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))	('Mutant', 'Var', (0, 6))	('PKR', 'Gene', (244, 247))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('defective', 'NegReg', (117, 126))	('activating', 'PosReg', (193, 203))
13655	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))
13657	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))
13658	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))
13665	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))
13675	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))
13691	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))
13692	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.	('viral replication', 'MPA', (285, 302))	('improves', 'PosReg', (276, 284))	('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))
13694	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))	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('nectin-1', 'Gene', (180, 188))	('hypoxic', 'Disease', 'MESH:D000860', (122, 129))	('D456MG', 'Var', (241, 247))	('D456MG', 'Chemical', '-', (241, 247))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('hypoxia', 'Disease', (74, 81))	('increased', 'PosReg', (200, 209))	('increase', 'PosReg', (229, 237))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('expression', 'MPA', (189, 199))	('D456MG', 'Chemical', '-', (50, 56))	('nectin-1', 'Gene', '5818', (180, 188))	('glioma', 'Disease', (147, 153))
13696	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))	('diminished', 'NegReg', (121, 131))	('replication', 'CPA', (72, 83))	('hypoxia', 'Disease', (175, 182))	('gamma134.5-deleted', 'Var', (34, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))	('nectin-1', 'Gene', (24, 32))
13698	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))
13700	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))
13712	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))
13716	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))
13719	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))
13720	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))
13721	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))
13722	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))
13731	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))
13734	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))	('antiangiogenesis', 'CPA', (177, 193))	('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))	('reduced', 'NegReg', (199, 206))
13738	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))
13745	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.	('oHSV', 'Chemical', '-', (10, 14))	('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))	('Akt', 'Gene', '207', (223, 226))	('MG18L', 'Chemical', '-', (0, 5))	('Akt', 'Gene', (185, 188))
13759	32525984	Pan-cancer analysis of TCGA data showed widespread single/double copy loss of RP genes, without significantly affecting survival.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('RP genes', 'Gene', (78, 86))	('cancer', 'Disease', (4, 10))	('single/double copy loss', 'Var', (51, 74))
13760	32525984	In several cancer cell lines, CRISPR-Cas9 knockout of RP genes did not affect cell viability.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('RP genes', 'Gene', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('knockout', 'Var', (42, 50))	('cancer', 'Disease', (11, 17))
13764	32525984	One of the strongest evidence for existence of 'specialized ribosomes' comes from a study in mice, where loss of function mutation in Rpl38 selectively perturbs translation of subsets of Hox mRNA, while maintaining global protein synthesis.	('Rpl38', 'Gene', '67671', (134, 139))	('mutation', 'Var', (122, 130))	('mice', 'Species', '10090', (93, 97))	('perturbs', 'NegReg', (152, 160))	('Rpl38', 'Gene', (134, 139))	('global protein synthesis', 'MPA', (215, 239))	('translation of subsets of Hox mRNA', 'MPA', (161, 195))	('maintaining', 'PosReg', (203, 214))
13768	32525984	In yeast, growth-defective 60S mutants increased synthesis of proteins involved in proteasome-mediated degradation, and 40S mutants had increased translation of ribosome biogenesis genes.	('translation', 'MPA', (146, 157))	('mutants', 'Var', (31, 38))	('mutants', 'Var', (124, 131))	('ribosome biogenesis genes', 'Gene', (161, 186))	('increased', 'PosReg', (39, 48))	('yeast', 'Species', '4932', (3, 8))	('increased', 'PosReg', (136, 145))
13769	32525984	The effects of alterations in RPs have also been noted in cancers, with both germline and somatic mutations in RP genes found in 10-30% of tumors.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('RPs', 'Gene', (30, 33))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('rat', 'Species', '10116', (19, 22))	('alterations', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (58, 65))
13770	32525984	Ribosomopathies, which are congenital dysfunctions in heart, bone, and kidney, derive from mutations in different RPs, and make patients susceptible to cancers later in life.	('congenital dysfunctions in heart', 'Phenotype', 'HP:0001627', (27, 59))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('congenital dysfunctions', 'Disease', (27, 50))	('congenital dysfunctions', 'Disease', 'MESH:D009358', (27, 50))	('susceptible', 'Reg', (137, 148))	('Ribosomopathies', 'Disease', 'None', (0, 15))	('derive from', 'Reg', (79, 90))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (128, 136))	('Ribosomopathies', 'Disease', (0, 15))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('RPs', 'Gene', (114, 117))
13782	32525984	GISTIC2 copy number variation (CNV) data for the 78 RP genes in 10 845 tumors from 33 cancer types in the TCGA dataset was compiled from 'all_thresholded.by_genes.txt' files downloaded from Broad GDAC (http://gdac.broadinstitute.org), and the entries -2 and -1 were interpreted as double deletion (aka deep deletion) and single deletion (aka shallow deletion) respectively.	('double deletion', 'Var', (281, 296))	('single deletion', 'Var', (321, 336))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (86, 92))
13795	32525984	transcripts being translated in ribosomes) data sets were downloaded from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=): human (GSE60426, GSE62247, GSE65885), mouse (GSE60426, GSE41246, GSE72064, GSE89108, rat (GSE66715).	('GSE60426', 'Var', (169, 177))	('GSE65885', 'Var', (189, 197))	('GSE41246', 'Var', (217, 225))	('GSE89108', 'Var', (237, 245))	('GSE72064', 'Var', (227, 235))	('GSE66715', 'Var', (252, 260))	('mouse', 'Species', '10090', (200, 205))	('GSE62247', 'Var', (179, 187))	('rat', 'Species', '10116', (247, 250))	('human', 'Species', '9606', (162, 167))	('GSE60426', 'Var', (207, 215))
13824	32525984	In these six cancer types, the RP genes over-expressed in the better prognosis RP subtypes (Supplementary Table S1e) were intolerant of loss-of-function (LoF) variation, as measured by the 'probability of loss of intolerance' (pLI) score (Figure 4C).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('RP genes', 'Gene', (31, 39))	('loss-of-function', 'NegReg', (136, 152))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('variation', 'Var', (159, 168))	('over-expressed', 'PosReg', (40, 54))
13826	32525984	The RP genes over-expressed in the worse prognosis RP subtypes in the six cancer types described above were more tolerant of loss-of-function (LoF) variation, i.e.	('over-expressed', 'PosReg', (13, 27))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('loss-of-function', 'NegReg', (125, 141))	('variation', 'Var', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RP genes', 'Gene', (4, 12))
13827	32525984	The LGG-worse survival RP mRNA subtype was enriched in the 'IDH-mutant 1p/19q non-co-deletion tumors', 'IDH-wildtype tumors', and tumors with 'astrocytoma histology', while the LGG-better survival RP mRNA subtype was enriched in the 'IDH-mutant 1p/19q co-deletion tumors', and tumors with 'oligodendroglioma histology' as defined in the literature.	('astrocytoma', 'Disease', (143, 154))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumors', 'Disease', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('rat', 'Species', '10116', (341, 344))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('oligodendroglioma', 'Disease', 'MESH:D009837', (290, 307))	('tumors', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('oligodendroglioma', 'Disease', (290, 307))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('glioma', 'Phenotype', 'HP:0009733', (301, 307))	('astrocytoma', 'Disease', 'MESH:D001254', (143, 154))	('non-co-deletion', 'Var', (78, 93))	("'IDH-mutant", 'Disease', (59, 70))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
13832	32525984	Pan-Cancer analysis of TCGA CNV data showed that 1,272 (11.7%) tumors had double deletion of one or more of the 78 RP genes, and both copies of each of the 78 RP genes were deleted in at least one tumor in the TCGA data (Figure 5A, B).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('RP genes', 'Gene', (115, 123))	('Cancer', 'Disease', (4, 10))	('tumors', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('double deletion', 'Var', (74, 89))	('tumor', 'Disease', (197, 202))
13833	32525984	RPL13 and RPL29 had double deletions in more than 100 samples (Figure 5A, B) and both copies of up to 16 RPs were lost in one sample (Figure 5C).	('RPL13', 'Gene', '6137', (0, 5))	('RPL13', 'Gene', (0, 5))	('double deletions', 'Var', (20, 36))	('RPL29', 'Gene', '6159', (10, 15))	('RPL29', 'Gene', (10, 15))
13834	32525984	Double deletions of RP genes were observed in all 33 cancer types (Figure 5D), but were more frequent in some cancer types than others (Supplementary Figure S13, Table S1f).	('cancer', 'Disease', (110, 116))	('RP genes', 'Gene', (20, 28))	('cancer', 'Disease', (53, 59))	('Double deletions', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('observed', 'Reg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('frequent', 'Reg', (93, 101))
13835	32525984	DLBC was at one extreme, where over 25% of tumors had double deletion of some RP gene, and KICH was at the other extreme, where <2% tumors had double deletion of some RP genes.	('double deletion', 'Var', (54, 69))	('RP gene', 'Gene', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('KICH', 'Disease', 'None', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Disease', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('KICH', 'Disease', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
13837	32525984	Overall, 8,910 (82.2%) tumors had single/double deletion of one or more of the 78 RP genes in the TCGA dataset.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('single/double deletion', 'Var', (34, 56))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('RP genes', 'Gene', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
13838	32525984	Individual RP genes had single/double deletion in 392-4,013 tumors (Supplementary Figure S14ab), and up to 55 RPs had single/double deletions in the same sample (Supplementary Figure S14c).	('single/double deletion', 'Var', (24, 46))	('RP genes', 'Gene', (11, 19))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
13839	32525984	Single/double deletions of RP genes were abundant in all 33 cancer types (Supplementary Figure S14d) but were more frequent in some cancer types than others (Supplementary Figure S15, Table S1g).	('RP genes', 'Gene', (27, 35))	('cancer', 'Disease', (132, 138))	('Single/double deletions', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('frequent', 'Reg', (115, 123))
13840	32525984	OV was at one extreme, with over 99% of tumors showing single/double deletion of some RP genes, and LAML was at the other extreme, with <20% of tumors showing single/double deletion of some RP genes.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('RP genes', 'Gene', (86, 94))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('single/double deletion', 'Var', (55, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Disease', (40, 46))
13841	32525984	Highly recurrent single/double deletion of a RP gene was quite common (Supplementary Figure S15, Table S1g), and there were even examples of RP genes single/double deleted in over 85% of tumors in a given cancer type, such as RPS15 in OV, RPL29 in LUSC, RPS24 in GBM, RPL17 in READ; and RPL14, RPL15, RPL29, RPL32, RPSA in KIRC.	('RPS15', 'Gene', (226, 231))	('RPSA', 'Gene', (315, 319))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('RPL17', 'Gene', (268, 273))	('RP genes', 'Gene', (141, 149))	('RPL29', 'Gene', (301, 306))	('RPSA', 'Gene', '3921', (315, 319))	('RPS24', 'Gene', (254, 259))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('RPL29', 'Gene', '6159', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (205, 211))	('RPL15', 'Gene', (294, 299))	('tumors', 'Disease', (187, 193))	('RPL32', 'Gene', '6161', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('RPL15', 'Gene', '6138', (294, 299))	('RPL32', 'Gene', (308, 313))	('RPS24', 'Gene', '6229', (254, 259))	('RPL29', 'Gene', '6159', (301, 306))	('RPL17', 'Gene', '6139', (268, 273))	('single/double deletion', 'Var', (17, 39))	('RPS15', 'Gene', '6209', (226, 231))	('RPL14', 'Gene', (287, 292))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('RP gene', 'Gene', (45, 52))	('RPL14', 'Gene', '9045', (287, 292))	('RPL29', 'Gene', (239, 244))
13842	32525984	In most cancer types, there was no significant association between the number of double-deleted RP genes in tumors and patient survival (Supplementary Figure S16), showing that RP loss did not reduce tumor fitness.	('patient', 'Species', '9606', (119, 126))	('double-deleted', 'Var', (81, 95))	('cancer', 'Disease', (8, 14))	('RP genes', 'Gene', (96, 104))	('tumor fitness', 'Disease', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('RP loss', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('RP loss', 'Disease', 'MESH:C538365', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('tumor fitness', 'Disease', 'MESH:D012640', (200, 213))
13845	32525984	Instead, 73 of the 74 RPs (all except RPS20), had gDS >-1 in one or more cell lines (Figure 6A, B; Supplementary Table S1h).	('RPS20', 'Gene', '6224', (38, 43))	('gDS >-1', 'Var', (50, 57))	('RPS20', 'Gene', (38, 43))
13846	32525984	Every cell-line, irrespective of the cancer type, had some RP genes with gDS >-1, and the minimum/maximum number of RPs with gDS >-1 in a single cell line varied from 21 to 62, with a mode of 35 (Figure 6C).	('gDS >-1', 'Var', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('RP genes', 'Gene', (59, 67))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
13847	32525984	RP genes with gDS >-1 were abundant in every cancer type, as between 51 and 68 RPs had gDS >-1 in different cancer types (Figure 6D).	('gDS >-1', 'Var', (14, 21))	('gDS >-1', 'Var', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
13848	32525984	Supplementary Figure S17 and Table S1i show the frequency (%) of gDS >-1 for each RP (shown in rows) in various cancer types (shown in columns).	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('gDS', 'Var', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (112, 118))
13852	32525984	These differences in the essentiality of RP genes in cell lines versus RP copy number loss in tumors is in accordance with the tissue-specific clustering seen in tumors but not seen in cell lines.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('loss', 'NegReg', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('copy number', 'Var', (74, 85))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (162, 168))	('essentiality', 'MPA', (25, 37))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
13864	32525984	Finally, double copy losses of RPs in tumors, and CRISPR-Cas9 knockout of several RPs in cell lines, do not lead to loss of ribosome function.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('double copy losses', 'Var', (9, 27))	('loss', 'NegReg', (116, 120))	('ribosome function', 'MPA', (124, 141))	('RPs', 'Gene', (31, 34))
13867	32525984	Fact I: TCGA CNV data showed that double deletion of each of the 78 non-sex-specific RP genes is found in one or more tumors (Figure 5A and B).	('found', 'Reg', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('double deletion', 'Var', (34, 49))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
13868	32525984	Nearly 12 percent of tumors had double deletion of an RP gene while retaining ribosome functionality.	('RP gene', 'Gene', (54, 61))	('ribosome functionality', 'MPA', (78, 100))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('double deletion', 'Var', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
13870	32525984	Furthermore, there was no correlation between number of double deleted RPs in tumors and patient survival (Supplementary Figure S16) in most cancer types, suggesting that ribosome function is not compromised by such losses of RP genes.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('patient', 'Species', '9606', (89, 96))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('double deleted RPs', 'Var', (56, 74))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
13871	32525984	Speculation I: These copy number variations would suggest that at least in tumors, the ribosome can function without all its RP components, which would suggest that the ribosomal protein stoichiometry in tumors is not necessarily 1:1:1... for all RPs.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('variations', 'Var', (33, 43))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
13875	32525984	These results show that not all RPs are essential in cancer cell lines, and several RPs can be knocked out without complete loss of ribosome function.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('RPs', 'Gene', (84, 87))	('knocked', 'Var', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
13877	32525984	Moreover, CERES analysis corrects for association between copy number effects and sgRNA scores improving false discovery rates associated with CRISPR screens.	('copy number effects', 'Var', (58, 77))	('CRISPR', 'Disease', (143, 149))	('improving', 'PosReg', (95, 104))	('false discovery rates', 'MPA', (105, 126))	('sgRNA scores', 'Gene', (82, 94))	('rat', 'Species', '10116', (121, 124))
13892	32525984	In LGG, UVM, and BLCA, the majority of the difference in RP mRNA levels among the RP subtypes were due to copy number alteration of RP genes (Supplementary Figure S12).	('RP mRNA levels', 'MPA', (57, 71))	('RP genes', 'Gene', (132, 140))	('copy number alteration', 'Var', (106, 128))	('rat', 'Species', '10116', (122, 125))	('difference', 'Reg', (43, 53))	('due to', 'Reg', (99, 105))
13896	32525984	Speculation VII: In most cancers, loss of both copies of some RPs seems to have no effect on survival (Supplementary Figure S16).	('loss', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('RPs', 'Gene', (62, 65))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
13905	32525984	is supported by NHGRI [U01CA232161, U41HG001715, P50HG004233 to M.V.]	('U41HG001715', 'Var', (36, 47))	('U01', 'CellLine', 'CVCL:2220', (23, 26))	('P50HG004233 to', 'Var', (49, 63))
13920	32408867	However, the histopathological result depends on biopsy or surgical resection, which is not only invasive, but also affected by the intratumoral histological heterogeneity and sampling erros, which may lead to underestimation of the true grades.	('tumor', 'Disease', (137, 142))	('affected', 'Reg', (116, 124))	('erros', 'Var', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
13937	32408867	The patients' histological types of gliomas were as follows: 6 diffuse astrocytomas (3 IDH-mutant, 3 IDH wild-type), 3 oligodendrogliomas (3 IDH-mutant and 1p19q-codeleted), 2 anaplastic astrocytomas (1 IDH wild-type, 1 IDH-mutant), 1 anaplastic oligodendroglioma (IDH-mutant and 1p19q-codeleted), 1 anaplastic oligoastrocytoma (NOS) and 14 glioblastoma multiforme (GBM, 14 IDH wild-type).	('glioblastoma', 'Phenotype', 'HP:0012174', (341, 353))	('1p19q-codeleted', 'Var', (280, 295))	('IDH', 'Gene', '3417', (203, 206))	('gliomas', 'Disease', (36, 43))	('IDH', 'Gene', '3417', (265, 268))	('gliomas', 'Disease', (130, 137))	('glioblastoma multiforme', 'Disease', (341, 364))	('IDH', 'Gene', (374, 377))	('IDH', 'Gene', (141, 144))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (119, 137))	('astrocytomas', 'Disease', (71, 83))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (341, 364))	('IDH', 'Gene', (87, 90))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (235, 263))	('anaplastic oligoastrocytoma', 'Disease', 'MESH:D001254', (300, 327))	('patients', 'Species', '9606', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('astrocytomas', 'Disease', (187, 199))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('anaplastic oligoastrocytoma', 'Disease', (300, 327))	('IDH', 'Gene', (220, 223))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('anaplastic oligodendroglioma', 'Disease', (235, 263))	('IDH', 'Gene', '3417', (374, 377))	('IDH', 'Gene', '3417', (141, 144))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('oligodendrogliomas', 'Disease', (119, 137))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (87, 90))	('astrocytomas', 'Disease', 'MESH:D001254', (71, 83))	('IDH', 'Gene', (203, 206))	('IDH', 'Gene', (265, 268))	('IDH', 'Gene', '3417', (220, 223))	('astrocytomas', 'Disease', 'MESH:D001254', (187, 199))	('IDH', 'Gene', '3417', (101, 104))
13963	32408867	Medium diagnostic performance was achieved by all the parameters, with the area under the ROC curve (AUC) of 0.877 for ADC 20th and 0.858 for the ADC mean, and by the APT values, with the AUC of 0.833 for the APT 90th and 0.840 for the APT mean, and by the rCBF values, with the AUC of 0.735 for the ASL 90th and 0.722 for the ASL mean.	('ADC', 'Chemical', '-', (146, 149))	('rCBF', 'Gene', (257, 261))	('0.858', 'Var', (132, 137))	('ADC', 'Chemical', '-', (119, 122))	('0.840', 'Var', (222, 227))	('rCBF', 'Gene', '362686', (257, 261))
14023	31702614	For example, knockdown of lncRNA PEG10 significantly inhibited the malignant behavior, such as growth, migration, and invasion in gastric and esophageal cancer.	('inhibited', 'NegReg', (53, 62))	('malignant behavior', 'CPA', (67, 85))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (130, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('knockdown', 'Var', (13, 22))	('PEG10', 'Gene', '23089', (33, 38))	('PEG10', 'Gene', (33, 38))	('invasion', 'CPA', (118, 126))	('growth', 'CPA', (95, 101))	('migration', 'CPA', (103, 112))
14027	31702614	Together these evidences suggest important functions for aberrant expression of PEG10 in tumor malignancy progression.	('functions', 'Reg', (43, 52))	('tumor malignancy', 'Disease', 'MESH:D009369', (89, 105))	('PEG10', 'Gene', '23089', (80, 85))	('PEG10', 'Gene', (80, 85))	('tumor malignancy', 'Disease', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('aberrant expression', 'Var', (57, 76))
14114	31702614	In addition, PEG10 was also identified as a biomarker for predicting early recurrence and patients with high expression of PEG10 have shorter recurrence-free survival in HCC.	('PEG10', 'Gene', '23089', (123, 128))	('recurrence-free survival', 'CPA', (142, 166))	('PEG10', 'Gene', (123, 128))	('HCC', 'Disease', (170, 173))	('PEG10', 'Gene', (13, 18))	('high expression', 'Var', (104, 119))	('patients', 'Species', '9606', (90, 98))	('shorter', 'NegReg', (134, 141))	('PEG10', 'Gene', '23089', (13, 18))
14148	31092699	Additionally, patients with ring-like enhancement exhibited significantly longer 5-year PFS time in the Kaplan-Meier survival curves (100 vs 67.2 +- 7.7%, P=0.049).	('longer', 'PosReg', (74, 80))	('PFS', 'CPA', (88, 91))	('patients', 'Species', '9606', (14, 22))	('ring-like enhancement', 'Var', (28, 49))
14158	31092699	Furthermore, combined loss of 1p and 19q is independent prognosis factor of prolonged survival in LGG patient which originated from oligodendrocytes.	('patient', 'Species', '9606', (102, 109))	('loss', 'Var', (22, 26))	('prolonged', 'PosReg', (76, 85))	('LGG', 'Disease', (98, 101))
14159	31092699	IDH mutation was also found to be related to the prognosis of LGGs.	('IDH', 'Gene', (0, 3))	('LGGs', 'Disease', (62, 66))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('related', 'Reg', (34, 41))
14223	31092699	In addition, the study pointed that heterogeneously enhancing tumors appear to have poorer outcomes when compared with ring-like enhancing and nodular enhancing tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('heterogeneously', 'Var', (36, 51))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))
14227	31092699	The present study found that patients with ring-like enhancement exhibited significantly longer PFS time in the Kaplan-Meier survival curves.	('patients', 'Species', '9606', (29, 37))	('longer', 'PosReg', (89, 95))	('ring-like enhancement', 'Var', (43, 64))	('PFS time', 'CPA', (96, 104))
14242	31092699	Radiotherapy can cause adverse long-term effects such as late neurocognitive toxicity and leukoencephalopathy.	('leukoencephalopathy', 'Disease', (90, 109))	('late neurocognitive toxicity', 'Disease', 'MESH:D002493', (57, 85))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (90, 109))	('Radiotherapy', 'Var', (0, 12))	('late neurocognitive toxicity', 'Disease', (57, 85))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (90, 109))
14252	29541392	The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors.	('glioma', 'Disease', (83, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('glioma', 'Disease', (169, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioma tumors', 'Disease', (169, 182))	('hypo-methylated', 'Var', (113, 128))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma tumors', 'Disease', 'MESH:D005910', (169, 182))	('upregulated', 'PosReg', (14, 25))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('glioblastoma', 'Disease', (29, 41))
14254	29541392	Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype.	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('glioblastoma subtype', 'Disease', 'MESH:D005909', (94, 114))	('high', 'Var', (13, 17))	('decreased', 'NegReg', (63, 72))	('glioblastoma subtype', 'Disease', (94, 114))
14260	29541392	There are known monogenic GBM biomarkers that include mutations in the IDH1 and PDGFRalpha loci.	('PDGFRalpha', 'Gene', '5156', (80, 90))	('mutations', 'Var', (54, 63))	('IDH1', 'Gene', (71, 75))	('PDGFRalpha', 'Gene', (80, 90))	('IDH1', 'Gene', '3417', (71, 75))
14281	29541392	The correlations in Brain M0257, which is enriched for GBM, were compared to matching correlations found by KINC using only the normal brain datasets in the Brain GEM.	('GEM', 'Gene', (163, 166))	('GEM', 'Gene', '2669', (163, 166))	('M0257', 'Var', (26, 31))
14306	29541392	The mutual exclusivity of PIK3R1 mutations in GBM is of particular interest; PIK3R1 knockdown decreases invasion, proliferation, and migration in GBM.	('knockdown', 'Var', (84, 93))	('decreases', 'NegReg', (94, 103))	('mutations', 'Var', (33, 42))	('migration', 'CPA', (133, 142))	('PIK3R1', 'Gene', '5295', (26, 32))	('invasion', 'CPA', (104, 112))	('PIK3R1', 'Gene', '5295', (77, 83))	('PIK3R1', 'Gene', (26, 32))	('PIK3R1', 'Gene', (77, 83))
14307	29541392	IDH1 mutations were neither mutually exclusive nor co-occurring with alterations in the 22 shared genes.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
14308	29541392	This is consistent with Figure 7; the proneural GBM subtype, which exhibits low expression for these 22 genes, is often defined by IDH1 or PDGFRA mutation.	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', '3417', (131, 135))	('PDGFRA', 'Gene', '5156', (139, 145))	('PDGFRA', 'Gene', (139, 145))	('proneural', 'Disease', (38, 47))	('mutation', 'Var', (146, 154))
14326	29541392	Transcript counts were indexed as 209086 Ensembl hg38 transcript IDs resulted in a 209086 x 204 GEM.	('GEM', 'Gene', (96, 99))	('hg38', 'Gene', (49, 53))	('hg38', 'Gene', '8549', (49, 53))	('209086', 'Var', (83, 89))	('GEM', 'Gene', '2669', (96, 99))
14331	29541392	The KS test (DN > 0.15) removed 211 datasets, resulting in a 209086 x 1793 GEM.	('GEM', 'Gene', (75, 78))	('209086 x 1793', 'Var', (61, 74))	('GEM', 'Gene', '2669', (75, 78))	('KS', 'Chemical', '-', (4, 6))
14332	29541392	From this 209086 x 1793 preprocessed GEM, 49 transcripts mapped to the genes present in Module 0214 identified in the TCGA Network.	('209086', 'Var', (10, 16))	('GEM', 'Gene', (37, 40))	('GEM', 'Gene', '2669', (37, 40))
14530	33184974	Postoperative and prognostic follow-up-related indicators were T1S1 distance (cm) (coronal), T1S1 distance (cm) (sagittal), major curve (Cobb) (coronal), C7CSVL (cm) (coronal), apical vertebra translation (cm), kyphosis angle (Cobb), sagittal vertical axis (SVA), and postoperative spinal nerve function (Frankel grade).	('apical vertebra translation', 'CPA', (177, 204))	('kyphosis', 'Phenotype', 'HP:0002808', (211, 219))	('sagittal vertical axis', 'CPA', (234, 256))	('kyphosis angle', 'Disease', (211, 225))	('T1S1', 'Var', (63, 67))	('major', 'Disease', (124, 129))	('kyphosis angle', 'Disease', 'MESH:D007738', (211, 225))
14543	33184974	The operation time, the intraoperative bleeding volume, and the hospital stay of the low-grade surgical treatment group were lower than those of the high-grade surgical treatment group.	('hospital stay', 'CPA', (64, 77))	('lower', 'NegReg', (125, 130))	('intraoperative bleeding', 'Disease', 'MESH:D016063', (24, 47))	('intraoperative bleeding', 'Disease', (24, 47))	('low-grade', 'Var', (85, 94))
14549	33184974	The detection indexes were T1S1 distance (cm) (coronal), T1S1 distance (cm) (Sagittal), major curve (Cobb) (Coronal), C7CSVL (cm) (coronal), AVT (cm), kyphosis angle (Cobb), and SVA (sagittal vertical axis).	('kyphosis angle', 'Disease', (151, 165))	('SVA', 'Disease', (178, 181))	('AVT', 'Disease', (141, 144))	('T1S1 distance', 'Var', (27, 40))	('kyphosis angle', 'Disease', 'MESH:D007738', (151, 165))	('major curve', 'Disease', (88, 99))	('kyphosis', 'Phenotype', 'HP:0002808', (151, 159))	('T1S1 distance', 'Var', (57, 70))
14560	33184974	An 18-year-old male patient with scoliosis T11-L3 110  and kyphosis T11-L2 70  before the operation had scoliosis 51  and kyphosis 14  after the operation.	('scoliosis', 'Phenotype', 'HP:0002650', (104, 113))	('kyphosis', 'Disease', (122, 130))	('kyphosis', 'Disease', 'MESH:D007738', (122, 130))	('kyphosis', 'Disease', (59, 67))	('scoliosis', 'Phenotype', 'HP:0002650', (33, 42))	('patient', 'Species', '9606', (20, 27))	('kyphosis', 'Disease', 'MESH:D007738', (59, 67))	('T11-L2', 'Var', (68, 74))	('scoliosis', 'Disease', 'MESH:D012600', (104, 113))	('scoliosis', 'Disease', (104, 113))	('kyphosis', 'Phenotype', 'HP:0002808', (122, 130))	('scoliosis', 'Disease', 'MESH:D012600', (33, 42))	('scoliosis', 'Disease', (33, 42))	('kyphosis', 'Phenotype', 'HP:0002808', (59, 67))
14618	31995621	We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient.	('patient', 'Species', '9606', (140, 147))	('genetic alterations', 'Var', (12, 31))	('detected', 'Reg', (3, 11))
14626	31995621	In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG.	('pLGG', 'Disease', (74, 78))	('GOPC', 'Gene', '57120', (29, 33))	('ROS1', 'Gene', (34, 38))	('ROS1', 'Gene', '6098', (34, 38))	('GOPC', 'Gene', (29, 33))	('fusion', 'Var', (39, 45))
14644	31995621	In this study, we sought to illustrate how correlating genetic alterations with histologic and clinical features can improve pLGG classification and treatment decisions for patients in Saudi Arabia (SA).	('genetic alterations', 'Var', (55, 74))	('improve', 'PosReg', (117, 124))	('pLGG', 'Disease', (125, 129))	('patients', 'Species', '9606', (173, 181))
14676	31995621	GOPC-ROS1 fusions have been identified in a "not otherwise specified" (NOS) single case of glioblastoma (deemed to be neither pLGG nor pHGG) in which the tumor also harbored mutations in other glioma-associated genes, including TP53 and PTPN11, and in one case of pHGG.	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('PTPN11', 'Gene', (237, 243))	('TP53', 'Gene', (228, 232))	('glioblastoma', 'Disease', (91, 103))	('tumor', 'Disease', (154, 159))	('PTPN11', 'Gene', '5781', (237, 243))	('glioma', 'Disease', (193, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutations', 'Var', (174, 183))	('ROS1', 'Gene', (5, 9))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('harbored', 'Reg', (165, 173))	('TP53', 'Gene', '7157', (228, 232))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('GOPC', 'Gene', '57120', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('GOPC', 'Gene', (0, 4))	('fusions', 'Var', (10, 17))	('identified', 'Reg', (28, 38))	('ROS1', 'Gene', '6098', (5, 9))
14679	31995621	We detected a likely pathogenic GOPC-ROS1 fusion in a pLGG patient who also harbored a RAD15C variant of uncertain significance.	('variant', 'Var', (94, 101))	('RAD15C', 'Gene', (87, 93))	('ROS1', 'Gene', '6098', (37, 41))	('GOPC', 'Gene', '57120', (32, 36))	('fusion', 'Var', (42, 48))	('GOPC', 'Gene', (32, 36))	('patient', 'Species', '9606', (59, 66))	('ROS1', 'Gene', (37, 41))	('pathogenic', 'Reg', (21, 31))
14692	31995621	The majority of tumors harboring BRAF fusions were located in the cerebellum/posterior fossa (Fig 1C, S2 Table), which was consistent with the association between tumor location and BRAF fusions reported in other cohorts.	('BRAF', 'Gene', '673', (33, 37))	('BRAF', 'Gene', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('BRAF', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('BRAF', 'Gene', '673', (182, 186))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', (16, 22))	('fusions', 'Var', (38, 45))
14694	31995621	We observed higher rates of recurrence (12 of 37 patients, 32.43%), raising the possibility that BRAF fusions may not be directly associated with an improved outcome in SA pLGGs, as reported in previous studies.	('fusions', 'Var', (102, 109))	('BRAF', 'Gene', (97, 101))	('patients', 'Species', '9606', (49, 57))	('BRAF', 'Gene', '673', (97, 101))
14695	31995621	Because KIAA1549-BRAF is rarely detected in pHGGs, including anaplastic astrocytoma and glioblastoma, BRAF fusions can genetically distinguish pLGG from pHGG in the Saudi cohort.	('glioblastoma', 'Disease', (88, 100))	('fusions', 'Var', (107, 114))	('distinguish', 'Reg', (131, 142))	('pLGG', 'Disease', (143, 147))	('astrocytoma', 'Disease', 'MESH:D001254', (72, 83))	('BRAF', 'Gene', '673', (102, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('astrocytoma', 'Disease', (72, 83))	('BRAF', 'Gene', '673', (17, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('BRAF', 'Gene', (102, 106))	('KIAA1549', 'Gene', (8, 16))	('BRAF', 'Gene', (17, 21))	('KIAA1549', 'Gene', '57670', (8, 16))
14696	31995621	We suggest that in the future, the identification of BRAF fusions can guide patient treatment as targeted molecular therapies are discovered.	('patient', 'Species', '9606', (76, 83))	('fusions', 'Var', (58, 65))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (53, 57))
14697	31995621	Regarding gene variants, mutations in the Notch genes were most frequent (Fig 3C, S2 Table).	('mutations', 'Var', (25, 34))	('frequent', 'Reg', (64, 72))	('Notch', 'Gene', (42, 47))	('variants', 'Var', (15, 23))	('Notch', 'Gene', '4851;4853;4854', (42, 47))
14700	31995621	The frequency of these mutations is perhaps surprising since higher expression of ASCL1, Dll1, Notch1, -3, -4 have been shown to correlate with a higher glioma grade and poorer prognosis, implicating Notch signaling in more undifferentiated and aggressive tumor phenotypes.	('aggressive tumor', 'Disease', (245, 261))	('expression', 'MPA', (68, 78))	('Notch', 'Gene', '4851;4853;4854', (95, 100))	('ASCL1', 'Gene', '429', (82, 87))	('glioma', 'Disease', (153, 159))	('higher', 'PosReg', (61, 67))	('Dll1', 'Gene', (89, 93))	('mutations', 'Var', (23, 32))	('Dll1', 'Gene', '28514', (89, 93))	('Notch', 'Gene', (200, 205))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('ASCL1', 'Gene', (82, 87))	('Notch1', 'Gene', (95, 101))	('Notch1', 'Gene', '4851', (95, 101))	('aggressive tumor', 'Disease', 'MESH:D001523', (245, 261))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('higher', 'PosReg', (146, 152))	('Notch', 'Gene', (95, 100))	('Notch', 'Gene', '4851;4853;4854', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))
14701	31995621	We observed no association between Notch mutants and relapse/disease progression in our cohort, indeed a patient with co-occurring Notch2/3 mutations did not relapse following surgical intervention (S2 Table).	('patient', 'Species', '9606', (105, 112))	('Notch2', 'Gene', '4853', (131, 137))	('Notch', 'Gene', '4851;4853;4854', (35, 40))	('Notch', 'Gene', '4851;4853;4854', (131, 136))	('Notch', 'Gene', (35, 40))	('Notch', 'Gene', (131, 136))	('Notch2', 'Gene', (131, 137))	('mutations', 'Var', (140, 149))
14702	31995621	Among the less frequent mutations, we observed alterations in RAD51C, a component of the DNA double-strand repair pathway, the E3 ubiquitin ligase RNF43, and the central checkpoint gene ATM that is involved in the repair of DNA damage after ionizing irradiation to be associated with the risk of brain tumors.	('brain tumors', 'Phenotype', 'HP:0030692', (296, 308))	('brain tumors', 'Disease', (296, 308))	('ATM', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('RAD51C', 'Gene', '5889', (62, 68))	('associated', 'Reg', (268, 278))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('ATM', 'Gene', '472', (186, 189))	('mutations', 'Var', (24, 33))	('RNF43', 'Gene', '54894', (147, 152))	('brain tumors', 'Disease', 'MESH:D001932', (296, 308))	('alterations', 'Var', (47, 58))	('RNF43', 'Gene', (147, 152))	('RAD51C', 'Gene', (62, 68))
14704	31995621	Regarding RNF43, mutations affecting this gene were loss-of function mutations, likely leading to the activation of pro-oncogenic Wnt signaling by interfering with the RNF43-mediated ubiquitination of the frizzled receptor.	('interfering', 'NegReg', (147, 158))	('pro-oncogenic Wnt signaling', 'MPA', (116, 143))	('loss-of function', 'NegReg', (52, 68))	('activation', 'PosReg', (102, 112))	('RNF43', 'Gene', '54894', (168, 173))	('RNF43', 'Gene', '54894', (10, 15))	('RNF43', 'Gene', (168, 173))	('RNF43', 'Gene', (10, 15))	('mutations', 'Var', (17, 26))
14713	31995621	We identified a rare GOPC-ROS1 fusion in pLGG patients lacking BRAF alterations, which may represent a genomically-distinct subgroup of pLGGs that could be targeted with crizotinib.	('crizotinib', 'Chemical', 'MESH:C551994', (170, 180))	('ROS1', 'Gene', (26, 30))	('patients', 'Species', '9606', (46, 54))	('pLGG', 'Disease', (41, 45))	('ROS1', 'Gene', '6098', (26, 30))	('fusion', 'Var', (31, 37))	('GOPC', 'Gene', '57120', (21, 25))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('GOPC', 'Gene', (21, 25))
14737	31995621	They found one patient with a a GOPC-ROS1 mutation, and suggested possible clinical implications if the tumor recurs.	('patient', 'Species', '9606', (15, 22))	('ROS1', 'Gene', '6098', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('GOPC', 'Gene', '57120', (32, 36))	('GOPC', 'Gene', (32, 36))	('tumor', 'Disease', (104, 109))	('mutation', 'Var', (42, 50))	('ROS1', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
14750	31995621	In the results section (Lines 182-197), a 4 year old Paediatric High Grade Glioma (pHGG) patient with the GOPC-ROS1 fusion mutation received the same treatment and achieved the same outcome (previously reported in reference 39), whereas an 8-year old patient with the GOPC-ROS1 fusion mutation received a gross resection with no adjuvant chemotherapy.	('Glioma', 'Phenotype', 'HP:0009733', (75, 81))	('ROS1', 'Gene', (273, 277))	('GOPC', 'Gene', (268, 272))	('patient', 'Species', '9606', (89, 96))	('ROS1', 'Gene', '6098', (273, 277))	('Glioma', 'Disease', (75, 81))	('patient', 'Species', '9606', (251, 258))	('GOPC', 'Gene', '57120', (106, 110))	('ROS1', 'Gene', (111, 115))	('fusion mutation', 'Var', (116, 131))	('GOPC', 'Gene', (106, 110))	('ROS1', 'Gene', '6098', (111, 115))	('Glioma', 'Disease', 'MESH:D005910', (75, 81))	('GOPC', 'Gene', '57120', (268, 272))
14777	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))
14785	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))
14798	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-10b', 'Gene', (139, 146))	('miR-10a', 'Gene', (130, 137))	('let-7a', 'Var', (114, 120))	('tumor', 'Disease', (79, 84))	('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))	('miR-10b', 'Gene', '406903', (139, 146))	('patients', 'Species', '9606', (351, 359))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('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))
14820	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))
14825	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))	('astrocytomas', 'Disease', 'MESH:D001254', (104, 116))	('miR-196b', 'Gene', '442920', (24, 32))	('expression levels', 'MPA', (50, 67))	('GBM', 'Disease', (71, 74))	('patients', 'Species', '9606', (247, 255))	('higher', 'PosReg', (216, 222))	('increased', 'PosReg', (40, 49))	('miR-196a', 'Var', (11, 19))	('GBM', 'Disease', (243, 246))	('non-tumor', 'Disease', (266, 275))	('astrocytomas', 'Disease', (104, 116))	('GBM', 'Disease', 'MESH:D005909', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('non-tumor', 'Disease', 'MESH:C580335', (266, 275))
14827	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))
14946	30952038	The four D95 outliers belong to subjects where small regions in the brain were erroneously segmented as tumor core by our method, for some cases because of co-occurring pathologies.	('D95', 'Var', (9, 12))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
14986	30952038	Although the method we propose is demonstrated to be applicable across data with various image contrast properties without retraining, it does rely on contrast-specific settings to constrain and to initialize tumor-specific appearance parameters, especially in the MR-sequences FLAIR and T1c (see Table 3 and Table 4, respectively).	('T1c', 'Var', (288, 291))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('FLAIR', 'Var', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
15008	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))
15010	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))
15012	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))	('IDH1', 'Gene', (71, 75))	('IDH', 'Gene', (80, 83))	('gliomas', 'Disease', (89, 96))	('IDH', 'Gene', (229, 232))	('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))	('IDH1', 'Gene', '3417', (71, 75))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('IDH', 'Gene', '3417', (80, 83))	('IDH', 'Gene', '3417', (229, 232))	('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))
15014	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))
15015	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))
15020	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))	('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))	('HDAC-1', 'Gene', (217, 223))	('targeting', 'Reg', (164, 173))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('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))	('c-Myc', 'Gene', (207, 212))
15022	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))
15025	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))
15026	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))
15030	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))
15031	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))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('human', 'Species', '9606', (3, 8))	('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))
15038	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))
15039	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))
15040	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))
15042	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))
15046	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))
15049	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))
15056	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))
15058	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))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('increased', 'PosReg', (97, 106))	('rat', 'Species', '10116', (115, 118))	('inhibition', 'Var', (47, 57))	('slowed down', 'NegReg', (164, 175))	('migration', 'CPA', (176, 185))	('Rb/p53', 'Gene', (84, 90))	('miR-449', 'Gene', '723868', (61, 68))	('tumour invasion', 'Disease', 'MESH:D009361', (24, 39))	('miR-449', 'Gene', (131, 138))	('cell migration', 'CPA', (107, 121))	('expression', 'MPA', (70, 80))	('rat', 'Species', '10116', (179, 182))	('miR-449', 'Gene', (61, 68))	('miR-449', 'Gene', '723868', (131, 138))	('tumour invasion', 'Disease', (24, 39))
15060	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))	('slower', 'NegReg', (60, 66))	('rat', 'Species', '10116', (154, 157))	('invasion', 'CPA', (165, 173))	('rat', 'Species', '10116', (143, 146))	('proliferation', 'CPA', (136, 149))	('grow', 'CPA', (55, 59))	('suppressive', 'NegReg', (104, 115))	('miR-449ahigh', 'Var', (36, 48))
15061	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))
15069	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', (165, 168))	('rat', 'Species', '10116', (152, 155))	('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))
15070	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))
15071	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))	('Gpr158', 'Gene', (71, 77))	('Rb/p53', 'Gene', '7157', (100, 106))	('Rb/p53', 'Gene', (100, 106))	('reduction', 'NegReg', (151, 160))
15073	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))
15075	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.	('Ptn', 'Gene', '5764', (188, 191))	('Map2', 'Gene', (60, 64))	('Filamin A', 'Gene', (135, 144))	('Netrin 1', 'Gene', '9423', (153, 161))	('Ntn1', 'Gene', '9423', (163, 167))	('Netrin 1', 'Gene', (153, 161))	('Flna', 'Gene', '2316', (146, 150))	('Ptn', 'Gene', (188, 191))	('Flna', 'Gene', (146, 150))	('Filamin A', 'Gene', '2316', (135, 144))	('Ntn1', 'Gene', (163, 167))	('Pleiotrophin', 'Gene', (174, 186))	('Gpr158', 'Gene', (218, 224))	('knock-down', 'Var', (225, 235))	('up-regulation', 'PosReg', (21, 34))	('Sox2', 'Gene', (66, 70))	('Pleiotrophin', 'Gene', '5764', (174, 186))	('Pdgfra', 'Gene', (76, 82))	('downregulation', 'NegReg', (198, 212))
15077	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))
15079	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))
15080	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))
15083	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))
15084	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))
15086	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))
15096	29720725	5d4) conspicuously retained their expression of DCX, suggesting a direct effect of miR-449a to suppress neural differentiation.	('suppress', 'NegReg', (95, 103))	('DCX', 'Gene', (48, 51))	('DCX', 'Gene', '1641', (48, 51))	('miR-449a', 'Var', (83, 91))	('neural differentiation', 'CPA', (104, 126))
15099	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))
15101	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))	('Ccnd1', 'Gene', '595', (42, 47))	('downregulation', 'NegReg', (24, 38))	('miR-449a-induced', 'Var', (61, 77))	('Ccnd1', 'Gene', (42, 47))
15102	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))
15103	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))
15109	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))
15111	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))
15114	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).	('gain', 'PosReg', (41, 45))	('IDH', 'Gene', (0, 3))	('TERT', 'Gene', (80, 84))	('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))	('loss', 'NegReg', (51, 55))	('EGFR', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (80, 84))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
15119	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))
15124	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))
15130	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))
15132	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))
15134	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))
15135	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))
15136	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))	('longer', 'PosReg', (110, 116))	('IDH', 'Gene', '3417', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('GPR158high', 'Var', (61, 71))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))
15137	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))	('IDH', 'Gene', (16, 19))	('GPR158high', 'Var', (37, 47))	('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))
15138	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))
15139	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))	('patients', 'Species', '9606', (167, 175))	('tumour', 'Phenotype', 'HP:0002664', (285, 291))	('better', 'PosReg', (146, 152))	('GPR158low tumours', 'Disease', (275, 292))	('higher', 'PosReg', (76, 82))	('GPR158low tumours', 'Disease', 'MESH:D009369', (275, 292))	('patients', 'Species', '9606', (261, 269))	('GPR158high', 'Var', (181, 191))	('IDH', 'Gene', (192, 195))
15141	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))
15144	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))
15147	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))
15148	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))
15152	29720725	4k-o, and Supplementary Figure 2), whilst miR-449a antagomir restores a neural phenotype (Fig.	('mir', 'Gene', '220972', (57, 60))	('restores', 'PosReg', (61, 69))	('miR-449a', 'Var', (42, 50))	('mir', 'Gene', (57, 60))
15153	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))	('promoting', 'PosReg', (90, 99))	('GPR158', 'Var', (46, 52))
15155	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))
15156	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))	('tumour', 'Disease', (24, 30))	('hepatocellular carcinoma', 'Disease', (75, 99))	('cancer', 'Disease', (58, 64))	('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))	('cancers', 'Disease', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('breast or colorectal cancer', 'Disease', 'MESH:D015179', (201, 228))
15160	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))
15162	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))
15163	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))
15166	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))
15169	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))
15174	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))
15183	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))
15184	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))
15190	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))
15205	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).	('Rb/p53', 'Gene', '7157', (163, 169))	('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))	('brain tumour', 'Disease', 'MESH:D001932', (132, 144))	('Rb/p53', 'Gene', (163, 169))
15207	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))
15355	22748659	For example, mutations in TP53 are commonly found in astrocytomas (50%-90%) and oligoastrocytomas (40%-50%) but are infrequent in oligodendrogliomas (5%-10%).	('TP53', 'Gene', (26, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (130, 148))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('astrocytomas', 'Disease', 'MESH:D001254', (85, 97))	('astrocytomas', 'Disease', (53, 65))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('found', 'Reg', (44, 49))	('oligodendrogliomas', 'Disease', (130, 148))	('oligoastrocytomas', 'Disease', (80, 97))	('astrocytomas', 'Disease', (85, 97))	('TP53', 'Gene', '7157', (26, 30))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (80, 97))	('mutations', 'Var', (13, 22))	('astrocytomas', 'Disease', 'MESH:D001254', (53, 65))
15356	22748659	On the other hand, 1p19q deletions are frequent in oligodendrogliomas (50%-70%) and less common to rare in oligoastrocytomas (30%-50%) and astrocytomas (0%-15%).	('oligodendrogliomas', 'Disease', (51, 69))	('1p19q deletions', 'Var', (19, 34))	('astrocytomas', 'Disease', (139, 151))	('astrocytomas', 'Disease', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('oligoastrocytomas', 'Disease', (107, 124))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (107, 124))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (51, 69))	('astrocytomas', 'Disease', 'MESH:D001254', (139, 151))	('astrocytomas', 'Disease', 'MESH:D001254', (112, 124))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
15357	22748659	Although both TP53 mutations and 1p19q codeletions have been associated with improved prognosis, these mutations are mutually exclusive in gliomas, providing molecular evidence to support the histologic stratification of these tumors.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('gliomas', 'Disease', (139, 146))	('1p19q codeletions', 'Var', (33, 50))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('mutations', 'Var', (19, 28))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('improved', 'PosReg', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
15358	22748659	Recently, a sentinel paper by Parsons and colleagues demonstrated the existence of a novel glioma-associated mutation in isocitrate dehydrogenase-1 (IDH1) in 12% of patients with glioblastoma (GBM) via high-throughput gene expression analysis of 20,661 protein coding genes.	('IDH1', 'Gene', (149, 153))	('glioblastoma', 'Disease', (179, 191))	('glioma', 'Disease', (91, 97))	('isocitrate dehydrogenase-1', 'Gene', '3417', (121, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('IDH1', 'Gene', '3417', (149, 153))	('isocitrate dehydrogenase-1', 'Gene', (121, 147))	('patients', 'Species', '9606', (165, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('GBM', 'Phenotype', 'HP:0012174', (193, 196))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('mutation', 'Var', (109, 117))
15360	22748659	Mutations in IDH1 were found to be associated with younger age, secondary GBMs (grade IV tumors that arise from biopsy-proven lower-grade predecessors), and increased overall survival (OS).	('tumors', 'Disease', (89, 95))	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('secondary GBMs', 'Disease', (64, 78))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('increased', 'PosReg', (157, 166))	('IDH1', 'Gene', '3417', (13, 17))	('overall', 'MPA', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
15367	22748659	A critical structure in the enzymatic interaction with the substrate isocitrate is the arginine 132 (R132) found within the active site of IDH1 (arginine is conserved in the functionally analogous R172 of IDH2).	('IDH1', 'Gene', (139, 143))	('R132', 'Var', (101, 105))	('R132', 'Chemical', '-', (101, 105))	('IDH2', 'Gene', '3418', (205, 209))	('isocitrate', 'Chemical', 'MESH:C034219', (69, 79))	('IDH1', 'Gene', '3417', (139, 143))	('arginine', 'Chemical', 'MESH:D001120', (87, 95))	('arginine', 'Chemical', 'MESH:D001120', (145, 153))	('IDH2', 'Gene', (205, 209))
15370	22748659	Mutations in IDH1 and IDH2 are generally mutually exclusive, and there has only been one report of simultaneous IDH1 and IDH2 mutations to date.	('IDH2', 'Gene', '3418', (121, 125))	('IDH1', 'Gene', (112, 116))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('IDH1', 'Gene', '3417', (112, 116))	('IDH2', 'Gene', (121, 125))
15371	22748659	Interestingly, apart from rare case reports, the mutations of IDH1 and IDH2 occur exclusively at these arginine residues (most commonly replaced by histidine, R132H in IDH1), which are highly conserved across species and malignancies that involve the mutation of isocitrate dehydrogenase.	('IDH1', 'Gene', '3417', (168, 172))	('malignancies', 'Disease', (221, 233))	('mutations', 'Var', (49, 58))	('IDH1', 'Gene', '3417', (62, 66))	('R132H', 'Var', (159, 164))	('IDH2', 'Gene', (71, 75))	('isocitrate', 'Chemical', 'MESH:C034219', (263, 273))	('hydrogen', 'Chemical', 'MESH:D006859', (276, 284))	('R132H', 'Mutation', 'rs121913500', (159, 164))	('occur', 'Reg', (76, 81))	('IDH2', 'Gene', '3418', (71, 75))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('arginine', 'Chemical', 'MESH:D001120', (103, 111))	('IDH1', 'Gene', (62, 66))	('IDH1', 'Gene', (168, 172))	('histidine', 'Chemical', 'MESH:D006639', (148, 157))
15372	22748659	This slight modification in the active site of the enzyme disrupts the aforementioned hydrogen bonding of the critical R132 and results in a shift in the enzymatic equilibrium to favor the closed configuration and subsequently increased affinity for nicotinamide adenine dinucleotide phosphate (NADPH).	('increased', 'PosReg', (227, 236))	('NADPH', 'Chemical', 'MESH:D009249', (295, 300))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (250, 293))	('disrupts', 'NegReg', (58, 66))	('shift', 'Reg', (141, 146))	('hydrogen', 'Chemical', 'MESH:D006859', (86, 94))	('hydrogen bonding', 'MPA', (86, 102))	('closed configuration', 'MPA', (189, 209))	('R132', 'Chemical', '-', (119, 123))	('modification', 'Var', (12, 24))	('enzymatic equilibrium', 'MPA', (154, 175))
15374	22748659	As a result of these changes, R132 mutations result in a greater than 80% reduction in activity compared with the wild-type (wt) enzyme.	('R132', 'Chemical', '-', (30, 34))	('R132 mutations', 'Var', (30, 44))	('activity', 'MPA', (87, 95))	('reduction', 'NegReg', (74, 83))	('changes', 'Var', (21, 28))
15375	22748659	Following the first report that IDH1 mutations were found more frequently in secondary GBMs (sGBM) compared with primary GBMs (pGBM), other studies showed similar findings and elucidated other associations between IDH1 mutation status and WHO classification (Table 1).	('found', 'Reg', (52, 57))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', (214, 218))	('IDH1', 'Gene', '3417', (32, 36))	('mutations', 'Var', (37, 46))	('IDH1', 'Gene', '3417', (214, 218))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('secondary GBMs', 'Disease', (77, 91))
15376	22748659	Indeed, IDH1 mutations are more frequently found in sGBMs, with reported frequencies ranging from 50% to 86% compared with pGBMs, which contain the mutation only 4% to 21% of the time.	('sGBMs', 'Disease', (52, 57))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('IDH1', 'Gene', (8, 12))	('found', 'Reg', (43, 48))	('IDH1', 'Gene', '3417', (8, 12))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))	('mutations', 'Var', (13, 22))
15377	22748659	sGBMs were frequently cited as being associated with younger patients; prognostically favorable genetic alterations, including 1p19q deletions and TP53 mutations; and an improved clinical course.	('GBM', 'Phenotype', 'HP:0012174', (1, 4))	('TP53', 'Gene', (147, 151))	('mutations', 'Var', (152, 161))	('1p19q deletions', 'Var', (127, 142))	('patients', 'Species', '9606', (61, 69))	('sGBMs', 'Gene', (0, 5))	('TP53', 'Gene', '7157', (147, 151))	('clinical', 'Species', '191496', (179, 187))
15378	22748659	The association between IDH1 mutations and favorable overall prognosis was so striking that some groups argued that sGBMs lacking these characteristics may in fact be pGBMs that were underdiagnosed as anaplastic tumors on initial discovery; the molecular similarities with pGBMs of these IDH1 mutation-negative sGBMs and the fact that all said tumors were initially found as anaplastic gliomas supported this assertion.	('gliomas', 'Disease', (386, 393))	('IDH1', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('GBM', 'Phenotype', 'HP:0012174', (274, 277))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('gliomas', 'Disease', 'MESH:D005910', (386, 393))	('glioma', 'Phenotype', 'HP:0009733', (386, 392))	('IDH1', 'Gene', '3417', (24, 28))	('GBM', 'Phenotype', 'HP:0012174', (312, 315))	('GBM', 'Phenotype', 'HP:0012174', (168, 171))	('tumors', 'Disease', (212, 218))	('mutations', 'Var', (29, 38))	('gliomas', 'Phenotype', 'HP:0009733', (386, 393))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('IDH1', 'Gene', (288, 292))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumors', 'Disease', (344, 350))
15379	22748659	The reported rates of IDH1 mutation in low-grade gliomas (LGG) are comparable with those of sGBMs, ranging from 59% to 100% in diffuse astrocytomas, 67% to 93% in oligodendrogliomas, and 50% to 100% in oligoastrocytomas.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('oligodendrogliomas', 'Disease', (163, 181))	('astrocytomas', 'Disease', (207, 219))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('mutation', 'Var', (27, 35))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('astrocytomas', 'Disease', (135, 147))	('astrocytomas', 'Disease', 'MESH:D001254', (207, 219))	('gliomas', 'Disease', (49, 56))	('IDH1', 'Gene', (22, 26))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (163, 181))	('gliomas', 'Disease', (174, 181))	('astrocytomas', 'Disease', 'MESH:D001254', (135, 147))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))	('oligoastrocytomas', 'Disease', (202, 219))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (202, 219))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1', 'Gene', '3417', (22, 26))
15380	22748659	WHO grade III tumors seem to share a similar rate of IDH1 mutations (0%-100% in anaplastic astrocytomas, 49%-86% in anaplastic oligodendrogliomas, and 63%-100% in anaplastic oligoastrocytomas); however, when calculated and compared across numerous series, they seem to have a lower overall frequency (see Table 1).	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('mutations', 'Var', (58, 67))	('astrocytomas', 'Disease', (91, 103))	('anaplastic oligodendrogliomas', 'Disease', (116, 145))	('oligoastrocytomas', 'Disease', (174, 191))	('astrocytomas', 'Disease', 'MESH:D001254', (179, 191))	('IDH1', 'Gene', (53, 57))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (174, 191))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('IDH1', 'Gene', '3417', (53, 57))	('astrocytomas', 'Disease', (179, 191))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('astrocytomas', 'Disease', 'MESH:D001254', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (116, 145))
15381	22748659	The ubiquitous nature of the mutation across histologic grades and traditionally dichotomized tumor groups (eg, oligodendroglial and astrocytic tumors) separated it from previously described genetic alterations and sparked great interest in elucidating its role in tumorigenesis and its value as a prognostic marker.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (29, 37))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('oligodendroglial and astrocytic tumors', 'Disease', 'MESH:D001254', (112, 150))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
15386	22748659	Although initial work reported elevated levels of HIF-1a in IDH1 mutant tumors, subsequent studies involving genome array, immunohistochemical, and fluorodeoxyglucose positron emission tomography analyses did not find significantly elevated levels of HIF-1a in IDH1 mutated gliomas.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (72, 78))	('HIF-1a', 'Gene', (50, 56))	('gliomas', 'Disease', (274, 281))	('HIF-1a', 'Gene', '3091', (251, 257))	('mutant', 'Var', (65, 71))	('mutated', 'Var', (266, 273))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('gliomas', 'Disease', 'MESH:D005910', (274, 281))	('IDH1', 'Gene', (261, 265))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('IDH1', 'Gene', (60, 64))	('HIF-1a', 'Gene', '3091', (50, 56))	('gliomas', 'Phenotype', 'HP:0009733', (274, 281))	('elevated', 'PosReg', (31, 39))	('HIF-1a', 'Gene', (251, 257))	('IDH1', 'Gene', '3417', (261, 265))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('IDH1', 'Gene', '3417', (60, 64))
15387	22748659	Moreover, because the tumors associated with the loss of succinate dehydrogenase and fumarate hydratase are vascular because of the activated angiogenesis pathways, the lack of vascularity in IDH1-mutated LGG (tumors most frequently carrying the mutation) further argues against this as an underlying mechanism in their gliomagenesis.	('vascularity', 'MPA', (177, 188))	('fumarate hydratase', 'Gene', (85, 103))	('hydrogen', 'Chemical', 'MESH:D006859', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('IDH1', 'Gene', '3417', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('glioma', 'Disease', (320, 326))	('activated', 'PosReg', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (320, 326))	('lack', 'NegReg', (169, 173))	('angiogenesis pathways', 'Pathway', (142, 163))	('tumors', 'Disease', (22, 28))	('fumarate hydratase', 'Gene', '2271', (85, 103))	('LGG', 'Gene', (205, 208))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('glioma', 'Phenotype', 'HP:0009733', (320, 326))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('loss', 'Var', (49, 53))	('tumors', 'Disease', (210, 216))	('IDH1', 'Gene', (192, 196))
15388	22748659	Other biochemical arguments against the role of reduced alpha-KG in gliomagenesis stem from the reasoning that a significant percentage of IDH1 molecules would need to exist as heterodimers in order for this mutation to exert dominant negative activity in vivo.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('activity', 'MPA', (244, 252))	('IDH1', 'Gene', (139, 143))	('mutation', 'Var', (208, 216))	('alpha-KG', 'Chemical', 'MESH:D007656', (56, 64))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('alpha-KG', 'Protein', (56, 64))	('reduced', 'NegReg', (48, 55))	('IDH1', 'Gene', '3417', (139, 143))	('glioma', 'Disease', (68, 74))
15389	22748659	A study by Jin and colleagues demonstrated that although IDH1 R132 mutants have equal binding affinity for IDH1 wt proteins, IDH2 R172 mutants (which exhibit the same clinical and molecular profiles as IDH1 mutants) have little affinity for their IDH2-wt counterparts.	('IDH1', 'Gene', (107, 111))	('R132', 'Chemical', '-', (62, 66))	('IDH2', 'Gene', '3418', (125, 129))	('R172 mutants', 'Var', (130, 142))	('IDH1', 'Gene', '3417', (107, 111))	('IDH2', 'Gene', (247, 251))	('binding', 'Interaction', (86, 93))	('IDH1', 'Gene', (57, 61))	('mutants', 'Var', (67, 74))	('mutants', 'Var', (135, 142))	('IDH1', 'Gene', (202, 206))	('clinical', 'Species', '191496', (167, 175))	('IDH2', 'Gene', '3418', (247, 251))	('IDH1', 'Gene', '3417', (57, 61))	('IDH2', 'Gene', (125, 129))	('IDH1', 'Gene', '3417', (202, 206))
15391	22748659	Notwithstanding the controversial role of diminished oxidative decarboxylation of isocitrate to alpha-KG, IDH1/2 mutants do gain a neomorphic ability to convert alpha-KG to D-2-hydroxyglutarate (2-HG).	('alpha-KG', 'Chemical', 'MESH:D007656', (96, 104))	('isocitrate', 'Chemical', 'MESH:C034219', (82, 92))	('oxidative decarboxylation', 'MPA', (53, 78))	('IDH1/2', 'Gene', '3417;3418', (106, 112))	('gain', 'PosReg', (124, 128))	('2-HG', 'Chemical', 'MESH:C019417', (195, 199))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (173, 193))	('IDH1/2', 'Gene', (106, 112))	('alpha-KG', 'Chemical', 'MESH:D007656', (161, 169))	('convert alpha-KG to D-2-hydroxyglutarate', 'MPA', (153, 193))	('mutants', 'Var', (113, 120))
15392	22748659	This ability is likely secondary to the newly developed high affinity for NADPH by the R132/R172 mutant enzyme, which changes the equilibrium of the active site state to kinetically allow, and even favor, the conversion of alpha-KG to 2-HG.	('R132/R172', 'Var', (87, 96))	('R132', 'Chemical', '-', (87, 91))	('2-HG', 'Chemical', 'MESH:C019417', (235, 239))	('favor', 'PosReg', (198, 203))	('equilibrium of the active site state', 'MPA', (130, 166))	('NADPH', 'Chemical', 'MESH:D009249', (74, 79))	('conversion', 'MPA', (209, 219))	('alpha-KG', 'Chemical', 'MESH:D007656', (223, 231))
15393	22748659	Assays of 2-HG have shown increases in its concentration from 100- to 300-fold in glioma cells harboring IDH1 mutations.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutations', 'Var', (110, 119))	('IDH1', 'Gene', (105, 109))	('2-HG', 'Chemical', 'MESH:C019417', (10, 14))	('IDH1', 'Gene', '3417', (105, 109))	('concentration', 'MPA', (43, 56))	('glioma', 'Disease', (82, 88))	('increases', 'PosReg', (26, 35))
15394	22748659	Furthermore, the addition of 2-HG alone into glioma cells has been shown to decrease proliferation without inducing apoptosis as was found in IDH1 R132 mutant cells; the addition of this metabolite also induced global metabolic changes in IDH1-wt glioma on metabolomic analysis, akin to those found in IDH1-R132H expressing cells.	('R132', 'Chemical', '-', (307, 311))	('IDH1', 'Gene', (239, 243))	('global metabolic changes', 'MPA', (211, 235))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('2-HG', 'Chemical', 'MESH:C019417', (29, 33))	('IDH1', 'Gene', (142, 146))	('R132', 'Chemical', '-', (147, 151))	('IDH1', 'Gene', (302, 306))	('addition', 'Var', (170, 178))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('mutant', 'Var', (152, 158))	('IDH1', 'Gene', '3417', (239, 243))	('glioma', 'Disease', (247, 253))	('decrease', 'NegReg', (76, 84))	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('IDH1', 'Gene', '3417', (142, 146))	('IDH1', 'Gene', '3417', (302, 306))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('R132H', 'Mutation', 'rs121913500', (307, 312))	('induced', 'Reg', (203, 210))	('glioma', 'Disease', (45, 51))
15395	22748659	The existence of a highly conserved mutation site without complete inactivation of the gene product, combined with data showing that the knockdown of IDH1-wt does not produce downstream changes shared by 2-HG-injected or IDH1-R132 mutant glioma, gives further credence to the idea that the isocitrate dehydrogenase gene serves as an oncogene with gain of function through its mutation.	('IDH1', 'Gene', (221, 225))	('IDH1', 'Gene', (150, 154))	('glioma', 'Disease', (238, 244))	('isocitrate dehydrogenase', 'Gene', (290, 314))	('IDH1', 'Gene', '3417', (221, 225))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('2-HG', 'Chemical', 'MESH:C019417', (204, 208))	('gain of function', 'PosReg', (347, 363))	('mutation', 'Var', (376, 384))	('hydrogen', 'Chemical', 'MESH:D006859', (303, 311))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('isocitrate', 'Chemical', 'MESH:C034219', (290, 300))	('R132', 'Chemical', '-', (226, 230))	('IDH1', 'Gene', '3417', (150, 154))
15396	22748659	The notion that 2-HG may serve as an oncogenic metabolite in IDH1/2 mutated gliomas was appealing given the existence of congenital conditions, such as L-2HG aciduria whereby germ-line mutations of IDH result in the accumulation of the L-enantiomer of 2-HG, with some of these patients developing malignant brain tumors.	('2-HG', 'Chemical', 'MESH:C019417', (16, 20))	('IDH', 'Gene', '3417', (61, 64))	('L-2HG aciduria', 'Phenotype', 'HP:0040144', (152, 166))	('developing', 'PosReg', (286, 296))	('patients', 'Species', '9606', (277, 285))	('IDH1/2', 'Gene', '3417;3418', (61, 67))	('2-HG', 'Chemical', 'MESH:C019417', (252, 256))	('aciduria', 'Phenotype', 'HP:0012072', (158, 166))	('malignant brain tumors', 'Disease', (297, 319))	('gliomas', 'Disease', (76, 83))	('accumulation', 'PosReg', (216, 228))	('IDH1/2', 'Gene', (61, 67))	('L-enantiomer of 2-HG', 'MPA', (236, 256))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('IDH', 'Gene', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('malignant brain tumors', 'Disease', 'MESH:D001932', (297, 319))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('brain tumors', 'Phenotype', 'HP:0030692', (307, 319))	('IDH', 'Gene', (61, 64))	('IDH', 'Gene', '3417', (198, 201))	('brain tumor', 'Phenotype', 'HP:0030692', (307, 318))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('mutations', 'Var', (185, 194))
15400	22748659	With mounting evidence that IDH1 mutations in glioma are associated with favorable molecular profiles and clinical outcomes, many studies began reporting on its association with other known significant genetic aberrations in human brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (231, 243))	('brain tumors', 'Phenotype', 'HP:0030692', (231, 243))	('association', 'Interaction', (161, 172))	('brain tumors', 'Disease', (231, 243))	('genetic aberrations', 'Disease', 'MESH:D030342', (202, 221))	('IDH1', 'Gene', '3417', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('glioma', 'Disease', (46, 52))	('mutations', 'Var', (33, 42))	('brain tumor', 'Phenotype', 'HP:0030692', (231, 242))	('genetic aberrations', 'Disease', (202, 221))	('human', 'Species', '9606', (225, 230))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('clinical', 'Species', '191496', (106, 114))	('IDH1', 'Gene', (28, 32))
15401	22748659	Traditionally, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, TP53 mutation, and deletions of 1p19q have been associated with improved outcomes in patients with glial tumors.	('TP53', 'Gene', '7157', (83, 87))	('mutation', 'Var', (88, 96))	('MGMT', 'Gene', '4255', (55, 59))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (15, 53))	('MGMT', 'Gene', (55, 59))	('glial tumors', 'Disease', 'MESH:D005910', (182, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('TP53', 'Gene', (83, 87))	('deletions', 'Var', (102, 111))	('glial tumors', 'Disease', (182, 194))	('O6-methylguanine-DNA methyltransferase', 'Gene', (15, 53))	('patients', 'Species', '9606', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('1p19q', 'Gene', (115, 120))	('improved', 'PosReg', (147, 155))
15402	22748659	IDH1 mutations were found to be strongly associated with 1p19q codeletions in numerous studies, although a few others did not find any significant relationship between the two.	('1p19q codeletions', 'Disease', (57, 74))	('associated', 'Reg', (41, 51))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
15403	22748659	Most of the published work to date regarding the association between these two genetic phenomena have indicated a high incidence of co-occurrence, with reported rates of 90% to 100% of IDH mutations in gliomas that have 1p19q deletions.	('IDH', 'Gene', '3417', (185, 188))	('IDH', 'Gene', (185, 188))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('gliomas', 'Disease', (202, 209))	('gliomas', 'Disease', 'MESH:D005910', (202, 209))	('gliomas', 'Phenotype', 'HP:0009733', (202, 209))	('mutations', 'Var', (189, 198))
15404	22748659	The correlation between TP53 and IDH1 mutations is not as robust; however, the trend of evidence does suggest a high rate of simultaneous mutations in gliomas that have been studied to date.	('TP53', 'Gene', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('IDH1', 'Gene', (33, 37))	('TP53', 'Gene', '7157', (24, 28))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('IDH1', 'Gene', '3417', (33, 37))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('mutations', 'Var', (138, 147))
15405	22748659	MGMT promoter methylation was similarly found to be associated with IDH1 mutation in numerous studies, although others did not find any significant relationship.	('MGMT', 'Gene', (0, 4))	('associated', 'Reg', (52, 62))	('IDH1', 'Gene', (68, 72))	('IDH1', 'Gene', '3417', (68, 72))	('mutation', 'Var', (73, 81))	('MGMT', 'Gene', '4255', (0, 4))
15406	22748659	The overwhelming presence of IDH1 mutations with 1p19q deletion and TP53 mutation, 2 events that have been classically dichotomized with distinct histologic and molecular groups, namely oligodendroglial and astrocytic tumors, alluded to an early genetic event that occurred before the differentiation of neural progenitor cells into these various tissue types.	('oligodendroglial and astrocytic tumors', 'Disease', 'MESH:D001254', (186, 224))	('TP53', 'Gene', (68, 72))	('IDH1', 'Gene', (29, 33))	('1p19q deletion', 'Var', (49, 63))	('IDH1', 'Gene', '3417', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('TP53', 'Gene', '7157', (68, 72))	('mutation', 'Var', (73, 81))	('mutations', 'Var', (34, 43))
15408	22748659	In many cases, IDH1 mutations were found to be simultaneously present with TP53 mutations or 1p19q deletions, whereas in others, IDH1 mutations preceded them.	('1p19q', 'Gene', (93, 98))	('IDH1', 'Gene', (129, 133))	('mutations', 'Var', (80, 89))	('IDH1', 'Gene', (15, 19))	('IDH1', 'Gene', '3417', (15, 19))	('IDH1', 'Gene', '3417', (129, 133))	('TP53', 'Gene', '7157', (75, 79))	('mutations', 'Var', (20, 29))	('TP53', 'Gene', (75, 79))
15409	22748659	In no case did TP53 mutations or 1p19q deletions precede the mutation of IDH1, indicating that this was indeed an early event in the development of glioma.	('IDH1', 'Gene', '3417', (73, 77))	('glioma', 'Disease', (148, 154))	('TP53', 'Gene', '7157', (15, 19))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('TP53', 'Gene', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('IDH1', 'Gene', (73, 77))	('mutations', 'Var', (20, 29))	('1p19q deletions', 'Var', (33, 48))
15410	22748659	Watanabe and colleagues analyzed a series of glioma from patients with Li-Fraumeni syndrome, who on account of their disease have germ-line TP53 mutations, and found that 71% of their patients had an IDH1 mutation.	('IDH1', 'Gene', (200, 204))	('TP53', 'Gene', (140, 144))	('patients', 'Species', '9606', (184, 192))	('mutations', 'Var', (145, 154))	('IDH1', 'Gene', '3417', (200, 204))	('patients', 'Species', '9606', (57, 65))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (71, 91))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', (45, 51))	('Li-Fraumeni syndrome', 'Disease', (71, 91))	('mutation', 'Var', (205, 213))	('TP53', 'Gene', '7157', (140, 144))
15411	22748659	Of note, 100% of these mutations were R132C substitutions, a rarer form of mutation (3.6%-4.6%) compared with R132H (~90%), suggesting that this mutation may be the favored gliomagenic pathway in patients with preexisting mutations of TP53.	('R132C', 'Var', (38, 43))	('glioma', 'Disease', (173, 179))	('R132C', 'Mutation', 'rs121913499', (38, 43))	('patients', 'Species', '9606', (196, 204))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (235, 239))	('R132H', 'Mutation', 'rs121913500', (110, 115))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('TP53', 'Gene', (235, 239))
15412	22748659	These findings indicate that although there seems to be a predilection for IDH1 mutations to be an early step in the formation of glioma, it is not the exclusive pathway in IDH1 mutation based gliomagenesis.	('mutations', 'Var', (80, 89))	('glioma', 'Disease', (193, 199))	('glioma', 'Disease', (130, 136))	('IDH1', 'Gene', (173, 177))	('IDH1', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (173, 177))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('IDH1', 'Gene', '3417', (75, 79))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
15413	22748659	In addition to isolated changes in chromosome copy and gene mutations, some studies have investigated the relationship between IDH1 mutations and glioma genetics on a genome level.	('investigated', 'Reg', (89, 101))	('glioma', 'Disease', (146, 152))	('mutations', 'Var', (132, 141))	('IDH1', 'Gene', (127, 131))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('IDH1', 'Gene', '3417', (127, 131))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))
15416	22748659	Noushmehr and colleagues analyzed more than 200 gliomas for their glioma-CpG island methylator phenotype (G-CIMP) to ascertain if there was any relationship between IDH1 mutations and overall DNA methylation profiles.	('glioma', 'Disease', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('mutations', 'Var', (170, 179))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('IDH1', 'Gene', (165, 169))	('G-CIMP', 'Chemical', '-', (106, 112))	('IDH1', 'Gene', '3417', (165, 169))	('glioma', 'Disease', (48, 54))	('gliomas', 'Disease', (48, 55))
15419	22748659	Similarly, Christensen and colleagues clustered gliomas into separate groups based on their methylation status and found that only 2 distinct methylation classes had IDH1 or IDH2 mutants and that more than 98% of the tumors in these 2 classes possessed the mutation.	('IDH1', 'Gene', (166, 170))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('IDH1', 'Gene', '3417', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('IDH2', 'Gene', (174, 178))	('IDH2', 'Gene', '3418', (174, 178))	('mutants', 'Var', (179, 186))	('gliomas', 'Disease', (48, 55))
15420	22748659	Moreover, these methylation profiles were stable across the evolution of the tumor into more malignant grades, suggesting that these changes occurred early during gliomagenesis, giving further credence to the idea that the mutation of IDH1 may have a role in the epigenetic modulation of gene expression.	('glioma', 'Disease', (163, 169))	('IDH1', 'Gene', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('IDH1', 'Gene', '3417', (235, 239))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('mutation', 'Var', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('epigenetic modulation of gene expression', 'MPA', (263, 303))	('tumor', 'Disease', (77, 82))
15422	22748659	Finally, recent reports have described the association between IDH1 mutation and internexin-alpha, a proneural gene encoding a neurofilament interacting protein that has previously been shown to be tightly related to 1p19q codeletions and a predictor of favorable outcomes in anaplastic oligoastrocytomas and anaplastic oligodendrogliomas.	('oligoastrocytomas', 'Disease', (287, 304))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (287, 304))	('association', 'Interaction', (43, 54))	('IDH1', 'Gene', '3417', (63, 67))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (309, 338))	('mutation', 'Var', (68, 76))	('anaplastic oligodendrogliomas', 'Disease', (309, 338))	('gliomas', 'Phenotype', 'HP:0009733', (331, 338))	('related', 'Reg', (206, 213))	('internexin-alpha', 'Gene', (81, 97))	('glioma', 'Phenotype', 'HP:0009733', (331, 337))	('IDH1', 'Gene', (63, 67))
15423	22748659	Further studies will likely help add to the list of IDH1 mutation-associated genetic changes that interact in the oncogenesis of these unique tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('IDH1', 'Gene', '3417', (52, 56))	('mutation-associated', 'Var', (57, 76))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('IDH1', 'Gene', (52, 56))
15424	22748659	Since the publication of the first report on improved survival in patients with GBM with IDH1 mutations (45.6 vs 13.2 months in IDH1-mutations vs IDH1-wt respectively) by Parsons and colleagues, numerous groups have been able to replicate similar findings.	('IDH1', 'Gene', (146, 150))	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('IDH1', 'Gene', '3417', (128, 132))	('mutations', 'Var', (94, 103))	('improved', 'PosReg', (45, 53))	('IDH1', 'Gene', '3417', (146, 150))	('survival', 'MPA', (54, 62))	('patients', 'Species', '9606', (66, 74))	('IDH1', 'Gene', (89, 93))	('IDH1', 'Gene', (128, 132))	('IDH1', 'Gene', '3417', (89, 93))
15425	22748659	In addition to improved OS, Sanson and colleagues were able to demonstrate improved progression free survival (PFS) as well in their set of patients with GBM, with 55 months PFS in patients with IDH1 mutation versus 8.8 months PFS in those without it.	('improved', 'PosReg', (75, 83))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('progression', 'MPA', (84, 95))	('IDH1', 'Gene', (195, 199))	('patients', 'Species', '9606', (181, 189))	('patients', 'Species', '9606', (140, 148))	('mutation', 'Var', (200, 208))	('IDH1', 'Gene', '3417', (195, 199))
15426	22748659	The analysis was extended to anaplastic (WHO grade III) tumors because many groups were readily able to show an improved OS in grade III tumors that harbored the IDH mutation compared with those that did not in both univariate and multivariate analyses.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('IDH', 'Gene', (162, 165))	('tumors', 'Disease', (56, 62))	('IDH', 'Gene', '3417', (162, 165))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
15427	22748659	In a prospective analysis, Wick and colleagues found that grade III astrocytomas that possessed the IDH1 mutation were associated with greater PFS regardless of the treatment arm and conferred a stronger risk reduction than any other factor in multivariate analysis, including histology.	('mutation', 'Var', (105, 113))	('PFS', 'MPA', (143, 146))	('IDH1', 'Gene', '3417', (100, 104))	('astrocytomas', 'Disease', (68, 80))	('reduction', 'NegReg', (209, 218))	('IDH1', 'Gene', (100, 104))	('greater', 'PosReg', (135, 142))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))
15428	22748659	The evidence for LGG and the prognostic value of IDH1 mutations is slightly more controversial.	('IDH1', 'Gene', '3417', (49, 53))	('mutations', 'Var', (54, 63))	('IDH1', 'Gene', (49, 53))	('LGG', 'Disease', (17, 20))
15429	22748659	Two independent groups found that IDH1 mutations in LGG were associated with significantly improved OS, whereas others could not find any significant association.	('IDH1', 'Gene', '3417', (34, 38))	('LGG', 'Gene', (52, 55))	('mutations', 'Var', (39, 48))	('improved', 'PosReg', (91, 99))	('IDH1', 'Gene', (34, 38))
15430	22748659	Weller and colleagues found improved PFS with IDH1 mutation in univariate and multivariate analyses but no significant improvement in OS in multivariate analysis.	('improved', 'PosReg', (28, 36))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('mutation', 'Var', (51, 59))	('PFS', 'MPA', (37, 40))
15431	22748659	It is still unclear if IDH1 mutational status is a prognostic indicator or a predictive measure of response to treatment.	('mutational', 'Var', (28, 38))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', (23, 27))
15432	22748659	Houillier and colleagues stratified a cohort of LGG into 3 groups based on prognostic factors based on the presence of 1p19q deletion, IDH1 mutation, or both together.	('IDH1', 'Gene', (135, 139))	('mutation', 'Var', (140, 148))	('IDH1', 'Gene', '3417', (135, 139))	('1p19q deletion', 'Var', (119, 133))
15433	22748659	They found that each of these factors was an independent predictor of improved clinical outcome in response to treatment with the chemotherapeutic agent temozolomide and that the group of patients with both mutations had the best treatment response (objective response in 80% with both mutations, 61% of IDH1-mutants without 1p19q deletion, 17% without either mutation).	('clinical outcome', 'MPA', (79, 95))	('mutations', 'Var', (286, 295))	('IDH1', 'Gene', (304, 308))	('improved', 'PosReg', (70, 78))	('response to treatment with', 'MPA', (99, 125))	('patients', 'Species', '9606', (188, 196))	('IDH1', 'Gene', '3417', (304, 308))	('temozolomide', 'Chemical', 'MESH:D000077204', (153, 165))	('clinical', 'Species', '191496', (79, 87))
15434	22748659	In a similar fashion, Hartman and colleagues found that in their cohort of patients that received adjuvant therapies, IDH1 mutation status was the single most important predictor of PFS and OS; this was not seen in their cohort of patients that did not receive adjuvant therapy.	('mutation', 'Var', (123, 131))	('IDH1', 'Gene', (118, 122))	('patients', 'Species', '9606', (231, 239))	('patients', 'Species', '9606', (75, 83))	('IDH1', 'Gene', '3417', (118, 122))	('OS', 'Disease', (190, 192))	('PFS', 'Disease', (182, 185))
15435	22748659	These findings support the notion that IDH1 mutations may be an important predictor to treatment response.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))
15438	22748659	There are 6 amino acid base pair substitutions at R132 of IDH1 that have been identified to date in human glioma: R132H (88.2%-92.7%), R132C (3.6%-4.6%), R132L (0.4%-4.3%), R132 G (0.6%-3.8%), R132S (0.8%-2.5%), and R132P (0.4%).	('R132H', 'Mutation', 'rs121913500', (114, 119))	('R132C', 'Var', (135, 140))	('R132L', 'Var', (154, 159))	('R132C', 'Mutation', 'rs121913499', (135, 140))	('R132', 'Chemical', '-', (173, 177))	('R132S', 'Var', (193, 198))	('R132S', 'Mutation', 'rs121913499', (193, 198))	('IDH1', 'Gene', '3417', (58, 62))	('R132', 'Chemical', '-', (193, 197))	('R132 G', 'Mutation', 'rs121913499', (173, 179))	('R132', 'Chemical', '-', (50, 54))	('glioma', 'Disease', (106, 112))	('R132', 'Chemical', '-', (154, 158))	('R132L', 'Mutation', 'rs121913500', (154, 159))	('R132', 'Chemical', '-', (216, 220))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('R132 G', 'Var', (173, 179))	('R132', 'Chemical', '-', (114, 118))	('R132H', 'Var', (114, 119))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('human', 'Species', '9606', (100, 105))	('R132P', 'Var', (216, 221))	('R132', 'Chemical', '-', (135, 139))	('R132P', 'Mutation', 'rs121913500', (216, 221))	('IDH1', 'Gene', (58, 62))
15440	22748659	The R132C substitution has been found in greater frequency in astrocytomas and gliomas associated with Li-Fraumeni syndrome, which were diffuse and anaplastic astrocytomas.	('gliomas', 'Disease', (79, 86))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (103, 123))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('R132C', 'Var', (4, 9))	('R132C', 'Mutation', 'rs121913499', (4, 9))	('astrocytomas', 'Disease', 'MESH:D001254', (159, 171))	('astrocytomas', 'Disease', 'MESH:D001254', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('Li-Fraumeni syndrome', 'Disease', (103, 123))	('astrocytomas', 'Disease', (159, 171))	('astrocytomas', 'Disease', (62, 74))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
15441	22748659	Recently Pusch and colleagues identified 3 cases of R100Q substitutions within the IDH1 gene.	('R100Q substitutions', 'Var', (52, 71))	('R100Q', 'Mutation', 'p.R100Q', (52, 57))	('IDH1', 'Gene', '3417', (83, 87))	('IDH1', 'Gene', (83, 87))
15442	22748659	In line with the preexisting dogma that it was the conformational alteration of the IDH1 protein that allowed neomorphic enzymatic activity, R100 is within the active site involved in binding isocitrate.	('R100', 'Var', (141, 145))	('IDH1', 'Gene', '3417', (84, 88))	('IDH1', 'Gene', (84, 88))	('isocitrate', 'Chemical', 'MESH:C034219', (192, 202))
15443	22748659	Regardless of the location of the amino acid substituted, each of the identified IDH1 mutations seems to share the same molecular and clinical properties.	('mutations', 'Var', (86, 95))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (81, 85))	('clinical', 'Species', '191496', (134, 142))
15444	22748659	Given the increasing importance of IDH1 mutation status in glioma research, there has been considerable effort to develop novel ways to quickly and reliably detect this mutation in tissue specimens.	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('glioma', 'Disease', (59, 65))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))
15447	22748659	Pyrosequencing is an alternative to traditional sequencing that allows for rapid high-throughput analysis of IDH1 mutations.	('mutations', 'Var', (114, 123))	('IDH1', 'Gene', '3417', (109, 113))	('IDH1', 'Gene', (109, 113))
15448	22748659	This method has been recently used to detect IDH1 mutations in gliomas and demonstrated an advantage over classic Sanger sequencing in that it can detect mutated allele frequencies down to 5%.	('IDH1', 'Gene', '3417', (45, 49))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('mutations', 'Var', (50, 59))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', (45, 49))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
15449	22748659	However, because the technique requires the new mutation to have a Tm that is lower than IDH1-wt, it theoretically may not be able to detect R132 G mutations.	('IDH1', 'Gene', (89, 93))	('R132 G', 'Mutation', 'rs121913499', (141, 147))	('R132 G mutations', 'Var', (141, 157))	('IDH1', 'Gene', '3417', (89, 93))
15451	22748659	Other antibodies for R132H followed, including IMab-1 and DIAH09, with one report indicating that DIA-H09 was superior to IMab-1 in that it was generally crisper with better signal-to-noise ratio.	('R132H', 'Mutation', 'rs121913500', (21, 26))	('DIA-H09', 'Var', (98, 105))	('R132H', 'Var', (21, 26))
15452	22748659	Proponents of immunohistochemistry-based antibody staining argue that the use of these antibodies to identify IDH1 mutations may even be superior to direct sequencing because there are reported cases in which these antibodies detect mutations missed by direct sequencing, likely because of poor tissue preservation of samples.	('mutations', 'Var', (233, 242))	('IDH1', 'Gene', '3417', (110, 114))	('IDH1', 'Gene', (110, 114))	('mutations', 'Var', (115, 124))
15454	22748659	However, because the antibodies are mutation specific, it can be expected that those designed to bind R132H will fail to detect IDH1 mutants approximately 10% of the time.	('R132H', 'Mutation', 'rs121913500', (102, 107))	('IDH1', 'Gene', '3417', (128, 132))	('R132H', 'Var', (102, 107))	('mutants', 'Var', (133, 140))	('IDH1', 'Gene', (128, 132))
15456	22748659	Multiple studies have reported the rate of IDH1 mutations in tumors other than glioma.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('IDH1', 'Gene', (43, 47))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', '3417', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (48, 57))
15457	22748659	In regard to central nervous system (CNS) tumors, IDH1 mutations do seem to favor glial tumors because the highest frequencies of mutations are found in astrocytic and oligodendroglial tumors of WHO grades II, III, and IV, as mentioned previously.	('IDH1', 'Gene', (50, 54))	('glial tumors', 'Disease', 'MESH:D005910', (179, 191))	('glial tumors', 'Disease', (82, 94))	('mutations', 'Var', (55, 64))	('favor', 'PosReg', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('IDH1', 'Gene', '3417', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('central nervous system (CNS) tumors', 'Disease', 'MESH:D016543', (13, 48))	('glial tumors', 'Disease', (179, 191))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (153, 191))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('glial tumors', 'Disease', 'MESH:D005910', (82, 94))
15458	22748659	Juvenile pilocytic astrocytomas do not seem to fall under the predilection of IDH1 mutations because there have been no reports of this gene mutation in this tumor type to date.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (158, 163))	('fall', 'Phenotype', 'HP:0002527', (47, 51))	('IDH1', 'Gene', (78, 82))	('IDH1', 'Gene', '3417', (78, 82))	('Juvenile pilocytic astrocytomas', 'Disease', (0, 31))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Juvenile pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 31))
15460	22748659	Other CNS tumors that conspicuously lack IDH1 mutations include medulloblastomas, dysembryoplastic neuroepithelial tumors, schwannomas, meningiomas, pleomorphic xanthoastrocytomas,  subependymal giant cell astrocytomas,  and ependymomas.	('subependymal giant cell astrocytomas', 'Disease', 'MESH:D001254', (182, 218))	('tumors', 'Disease', (10, 16))	('schwannomas', 'Phenotype', 'HP:0100008', (123, 134))	('IDH1', 'Gene', '3417', (41, 45))	('ependymomas', 'Disease', (225, 236))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('dysembryoplastic neuroepithelial tumors', 'Disease', (82, 121))	('meningiomas', 'Disease', 'MESH:D008577', (136, 147))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('medulloblastomas', 'Disease', 'MESH:D008527', (64, 80))	('meningiomas', 'Phenotype', 'HP:0002858', (136, 147))	('medulloblastomas', 'Disease', (64, 80))	('schwannomas', 'Disease', 'MESH:D009442', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('meningiomas', 'Disease', (136, 147))	('tumors', 'Disease', (115, 121))	('subependymal giant cell astrocytomas', 'Disease', (182, 218))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (149, 179))	('schwannomas', 'Disease', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (82, 121))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (99, 121))	('IDH1', 'Gene', (41, 45))	('ependymomas', 'Disease', 'MESH:D004806', (225, 236))	('subependymal giant cell astrocytomas', 'Phenotype', 'HP:0009718', (182, 218))	('pleomorphic xanthoastrocytomas', 'Disease', (149, 179))
15461	22748659	IDH1 mutations have been found with moderate frequency within gangliogliomas, and have been shown to confer a poorer prognosis in these patients.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (136, 144))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
15462	22748659	In a large-scale multi-institutional analysis of 98 gangliogliomas, Horbinski and colleagues found that 8.2% (8/98) of the gangliogliomas harbored the R132H IDH1 mutation, and that these patients were older (46.1 vs 25.5 years of age), had greater risks of adverse outcomes (high-grade transformation or death), and shorter recurrence-free survival.	('patients', 'Species', '9606', (187, 195))	('death', 'Disease', 'MESH:D003643', (304, 309))	('death', 'Disease', (304, 309))	('R132H', 'Var', (151, 156))	('R132H', 'Mutation', 'rs121913500', (151, 156))	('shorter', 'NegReg', (316, 323))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('harbored', 'Reg', (138, 146))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH1', 'Gene', (157, 161))	('gliomas', 'Disease', (59, 66))	('recurrence-free survival', 'CPA', (324, 348))	('IDH1', 'Gene', '3417', (157, 161))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
15463	22748659	On multivariate analysis, the presence of the IDH1 mutation was found to be the most powerful risk factor after age.	('IDH1', 'Gene', (46, 50))	('presence', 'Var', (30, 38))	('IDH1', 'Gene', '3417', (46, 50))
15464	22748659	Pediatric gliomas have been reported to possess IDH mutations less frequently than their adult counterparts.	('mutations', 'Var', (52, 61))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('Pediatric gliomas', 'Disease', (0, 17))	('IDH', 'Gene', (48, 51))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('IDH', 'Gene', '3417', (48, 51))	('Pediatric gliomas', 'Disease', 'MESH:D005910', (0, 17))
15466	22748659	This finding was highlighted in a study by Pollack and colleagues whereby 100% of their IDH mutations were in children aged older than 14 years (7/20, 35%), whereas none of their patients aged younger than 14 years were positive for the mutation.	('children', 'Species', '9606', (110, 118))	('mutations', 'Var', (92, 101))	('IDH', 'Gene', (88, 91))	('patients', 'Species', '9606', (179, 187))	('IDH', 'Gene', '3417', (88, 91))	('Pollack', 'Species', '185739', (43, 50))
15467	22748659	Given the paucity of studies, further reports will be needed before the exact frequency and prognostic value of IDH1 mutations in the pediatric population can be determined.	('mutations', 'Var', (117, 126))	('IDH1', 'Gene', (112, 116))	('IDH1', 'Gene', '3417', (112, 116))
15468	22748659	The discovery of IDH1/2 mutations in gliomas was arguably one of the most significant breakthroughs in our understanding of the oncogenesis and classification of gliomas in the past decade.	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('gliomas', 'Disease', (162, 169))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('IDH1/2', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
15469	22748659	The presence of the mutation in both astrocytic and oligodendroglial tumor types suggests that it is an early event in the pathogenesis of brain tumors and has added novel insight in the way we view gliomas and their origins.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('brain tumors', 'Disease', 'MESH:D001932', (139, 151))	('brain tumors', 'Phenotype', 'HP:0030692', (139, 151))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('brain tumor', 'Phenotype', 'HP:0030692', (139, 150))	('oligodendroglial tumor', 'Disease', (52, 74))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutation', 'Var', (20, 28))	('oligodendroglial tumor', 'Disease', 'MESH:D009369', (52, 74))	('brain tumors', 'Disease', (139, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (199, 206))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))
15474	22748659	Isocitrate dehydrogenase-1 (IDH1) mutations are highly conserved to R132 within the enzyme's active site, suggesting that the mutation may have an oncogenic gain of function.	('IDH1', 'Gene', '3417', (28, 32))	('gain of function', 'PosReg', (157, 173))	('Isocitrate dehydrogenase-1', 'Gene', '3417', (0, 26))	('Isocitrate dehydrogenase-1', 'Gene', (0, 26))	('R132', 'Chemical', '-', (68, 72))	('mutations', 'Var', (34, 43))	('IDH1', 'Gene', (28, 32))
15475	22748659	IDH1 mutations are associated with other prognostically favorable alterations (TP53 mutations and 1p19q codeletions) and certain gene cluster profiles (proneural).	('associated', 'Reg', (19, 29))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
15476	22748659	IDH1 mutations are found across different molecular and histologic brain tumor subtypes, suggesting they are early genetic alterations in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (138, 143))	('brain tumor', 'Phenotype', 'HP:0030692', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (73, 78))	('IDH1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('brain tumor', 'Disease', 'MESH:D001932', (67, 78))	('brain tumor', 'Disease', (67, 78))	('IDH1', 'Gene', '3417', (0, 4))
15494	22833841	The loss of either of these cell types could ultimately produce white matter necrosis, but the loss of glial cells was thought to cause necrosis earlier than the loss of vascular endothelial cells.	('necrosis', 'Disease', (136, 144))	('produce', 'Reg', (56, 63))	('necrosis', 'Disease', 'MESH:D009336', (77, 85))	('necrosis', 'Disease', 'MESH:D009336', (136, 144))	('white matter necrosis', 'Disease', (64, 85))	('white matter necrosis', 'Disease', 'MESH:D056784', (64, 85))	('necrosis', 'Disease', (77, 85))	('loss', 'Var', (4, 8))
15495	22833841	However, there is a growing awareness that patients receiving fWBI can have significant cognitive impairment at >6 months post-irradiation even when they do not have detectable anatomic abnormalities.	('cognitive impairment', 'Disease', (88, 108))	('fWBI', 'Var', (62, 66))	('patients', 'Species', '9606', (43, 51))	('cognitive impairment', 'Disease', 'MESH:D003072', (88, 108))	('cognitive impairment', 'Phenotype', 'HP:0100543', (88, 108))	('WBI', 'Chemical', '-', (63, 66))
15525	22833841	However, the anti-inflammatory agent, L-158, 809, has no effect on microglial activation, but still prevents radiation-induced cognitive impairment.	('microglial activation', 'CPA', (67, 88))	('cognitive impairment', 'Phenotype', 'HP:0100543', (127, 147))	('cognitive impairment', 'Disease', (127, 147))	('L-158', 'Var', (38, 43))	('cognitive impairment', 'Disease', 'MESH:D003072', (127, 147))	('prevents', 'NegReg', (100, 108))	('L-158', 'Chemical', '-', (38, 43))
15543	22833841	The majority of >6 month survivors of partial or whole brain irradiation have a symptom cluster consisting of fatigue, changes in mood, and cognitive dysfunction.	('fatigue', 'Disease', 'MESH:D005221', (110, 117))	('changes in mood', 'MPA', (119, 134))	('cognitive dysfunction', 'Disease', 'MESH:D003072', (140, 161))	('fatigue', 'Disease', (110, 117))	('fatigue', 'Phenotype', 'HP:0012378', (110, 117))	('cognitive dysfunction', 'Disease', (140, 161))	('partial or whole brain irradiation', 'Var', (38, 72))
15560	22833841	The NCI published a study on 15 SCLC patients who were long-term survivors after PCI and found that 12 of these exhibited abnormalities on neuropsychiatric testing, while seven performed below the normal range on the MMSE test.	('psychiatric', 'Disease', (144, 155))	('SCLC', 'Disease', (32, 36))	('patients', 'Species', '9606', (37, 45))	('SCLC', 'Disease', 'MESH:D018288', (32, 36))	('abnormalities', 'Var', (122, 135))	('PCI', 'Chemical', '-', (81, 84))	('exhibited', 'Reg', (112, 121))	('psychiatric', 'Disease', 'MESH:D001523', (144, 155))
15569	22833841	In a seminal publication by, cognitive outcomes of patients with low-grade glioma were compared to both patients with indolent lymphomas that had no CNS disease and healthy controls.	('lymphomas', 'Disease', 'MESH:D008223', (127, 136))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('low-grade', 'Var', (65, 74))	('lymphomas', 'Phenotype', 'HP:0002665', (127, 136))	('glioma', 'Disease', (75, 81))	('patients', 'Species', '9606', (51, 59))	('lymphomas', 'Disease', (127, 136))	('patients', 'Species', '9606', (104, 112))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
15584	22833841	Prior studies have suggested that partial brain irradiation may not cause the same degree of cognitive impairment as WBI.	('WBI', 'Chemical', '-', (117, 120))	('partial brain irradiation', 'Var', (34, 59))	('cognitive impairment', 'Phenotype', 'HP:0100543', (93, 113))	('cognitive impairment', 'Disease', (93, 113))	('cognitive impairment', 'Disease', 'MESH:D003072', (93, 113))
15619	22833841	Gln and mI are predominantly glial cell markers; changes in their concentrations have been associated with glial damage after fWBI.	('mI', 'Chemical', 'MESH:D007294', (8, 10))	('glial damage', 'Disease', 'MESH:D004194', (107, 119))	('glial damage', 'Disease', (107, 119))	('associated with', 'Reg', (91, 106))	('WBI', 'Chemical', '-', (127, 130))	('changes', 'Var', (49, 56))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))	('rat', 'Species', '10116', (73, 76))	('concentrations', 'MPA', (66, 80))
15678	22833841	When young adult mice received 10 Gy of focal irradiation to the hippocampus, a significant decrease in neurogenesis and cell proliferation was detected 3 months post-irradiation; this reduction correlated to a decline in cognitive function as assessed by the Barnes maze.	('mice', 'Species', '10090', (17, 21))	('decrease', 'NegReg', (92, 100))	('decline', 'NegReg', (211, 218))	('rat', 'Species', '10116', (133, 136))	('cell proliferation', 'CPA', (121, 139))	('focal irradiation', 'Var', (40, 57))	('decline in cognitive function', 'Phenotype', 'HP:0001268', (211, 240))	('cognitive function', 'CPA', (222, 240))	('neurogenesis', 'CPA', (104, 116))
15719	22833841	It is hypothesized that blocking this receptor blocks ischemia-induced NMDA excitation and thus, may be neuroprotective if radiation-induced ischemia occurs after fWBI.	('ischemia', 'Disease', (54, 62))	('NMDA', 'Chemical', 'MESH:D016202', (71, 75))	('blocks', 'NegReg', (47, 53))	('ischemia', 'Disease', 'MESH:D007511', (141, 149))	('ischemia', 'Disease', 'MESH:D007511', (54, 62))	('blocking', 'Var', (24, 32))	('WBI', 'Chemical', '-', (164, 167))	('NMDA excitation', 'MPA', (71, 86))	('ischemia', 'Disease', (141, 149))
15753	20626198	Rsize = 2* Vsmallest /(V1t +V2t) where V1t is the averaged size of the activated volume for threshold, t, in scan1 and V2t is the averaged size of the activated volume for threshold, t, in the corresponding scan 2.	('scan1', 'Gene', '124583', (109, 114))	('scan1', 'Gene', (109, 114))	('V1t', 'Var', (39, 42))
15785	31040521	Tc-99m GHA has shown high accuracy in discriminating tumor recurrence from treatment-related changes.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Tc-99m', 'Var', (0, 6))	('Tc-99', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (53, 58))
15814	31040521	For semiquantitative analysis, ROIs were drawn surrounding the abnormal uptake/primary tumor site/CT lesion in the consequent SPECT-CT slices spanning the full extent of the abnormal uptake/primary tumor site/CT lesion but excluding the first and last slices.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('abnormal', 'Var', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (198, 203))	('S', 'Chemical', 'MESH:D013455', (126, 127))
15838	31040521	On subgroup analysis, Tc-99m GHA SPECT-CT was positive in 17/37 low-grade glioma patients (with 2 false positives) and 11/18 high-grade glioma patients (with 2 false positives).	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('Tc-99m', 'Var', (22, 28))	('Tc-99', 'Chemical', '-', (22, 27))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (143, 151))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('glioma', 'Disease', (74, 80))	('glioma', 'Disease', (136, 142))	('positive', 'Reg', (46, 54))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
15851	31040521	Both N-13 NH3 PET-CT and Tc-99m GHA SPECT-CT had high overall diagnostic accuracies of 83.6% and 85.5%, respectively, the difference being not statistically significant on McNemar test (P = 0.508).	('N', 'Chemical', 'MESH:D009584', (5, 6))	('N-13 NH3', 'Chemical', '-', (5, 13))	('N-13', 'Var', (5, 9))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('Tc-99m', 'Var', (25, 31))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('Tc-99', 'Chemical', '-', (25, 30))
15855	31040521	The patient with false-positive finding on N-13 NH3 PET-CT only (anaplastic astrocytoma) had diffuse uptake in the occipitotemporal lobes without any CT lesion or significant edema, which was subsequently proven as radiation necrosis on reoperation [Figure 3].	('edema', 'Disease', (175, 180))	('N-13 NH3', 'Var', (43, 51))	('astrocytoma', 'Disease', 'MESH:D001254', (76, 87))	('N-13 NH3', 'Chemical', '-', (43, 51))	('astrocytoma', 'Disease', (76, 87))	('patient', 'Species', '9606', (4, 11))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('edema', 'Disease', 'MESH:D004487', (175, 180))	('edema', 'Phenotype', 'HP:0000969', (175, 180))	('radiation necrosis', 'Disease', 'MESH:D004194', (215, 233))	('radiation necrosis', 'Disease', (215, 233))
15864	31040521	Of the 4 patients with false-negative finding on N-13 NH3 PET-CT only, one patient with astrocytoma was found to have recurrent tumor on reoperation with change in grade to anaplastic astrocytoma and patient subsequently received radiotherapy.	('N-13', 'Var', (49, 53))	('patients', 'Species', '9606', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('astrocytoma', 'Phenotype', 'HP:0009592', (184, 195))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('astrocytoma', 'Disease', 'MESH:D001254', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('astrocytoma', 'Disease', (184, 195))	('astrocytoma', 'Disease', 'MESH:D001254', (88, 99))	('tumor', 'Disease', (128, 133))	('patient', 'Species', '9606', (9, 16))	('N-13 NH3', 'Chemical', '-', (49, 57))	('astrocytoma', 'Disease', (88, 99))	('patient', 'Species', '9606', (200, 207))	('patient', 'Species', '9606', (75, 82))	('NH3', 'Gene', (54, 57))
15876	31040521	In the other patient, active disease was detected only on N-13 NH3 PET-CT (baseline MRI was also negative).	('patient', 'Species', '9606', (13, 20))	('active disease', 'Disease', 'OMIM:612348', (22, 36))	('N-13 NH3', 'Var', (58, 66))	('active disease', 'Disease', (22, 36))	('N-13 NH3', 'Chemical', '-', (58, 66))
15879	31040521	On the other hand, Tc-99m GHA SPECT-CT had high accuracies in both low-grade and high-grade tumors with a better performance inclining toward the latter subgroup (low grade, 83.8% and high grade, 88.9%).	('Tc-99m', 'Var', (19, 25))	('Tc-99', 'Chemical', '-', (19, 24))	('low-grade', 'Disease', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
15890	31040521	In the present study, N-13 NH3 PET-CT was found to have high diagnostic accuracy (overall, 83.6%; low grade, 89.2%; high grade, 72.2%).	('N-13 NH3', 'Chemical', '-', (22, 30))	('N-13', 'Var', (22, 26))	('NH3', 'Gene', (27, 30))
15896	31040521	The false-negative findings of N-13 NH3 PET-CT in 6 patients could be due to the high normal background activity in the brain rendering the target-to-background ratio suboptimal.	('NH3', 'Gene', (36, 39))	('N-13', 'Var', (31, 35))	('patients', 'Species', '9606', (52, 60))	('N-13 NH3', 'Chemical', '-', (31, 39))
15902	31040521	The possibility of intact BBB in low-grade astrocytomas could be an explanation for the absence of uptake in these patients on the modality as disruption of BBB is the main mechanism for the uptake of Tc-99m GHA.	('Tc-99m', 'Var', (201, 207))	('patients', 'Species', '9606', (115, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('BBB', 'Protein', (157, 160))	('Tc-99', 'Chemical', '-', (201, 206))	('astrocytomas', 'Disease', (43, 55))	('disruption', 'Var', (143, 153))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))
15923	31040521	The authors reported the superiority of N-13 NH3 PET-CT over F-18 FDG PET-CT in detecting high-grade glioma.	('N-13 NH3', 'Var', (40, 48))	('F-18', 'Gene', '10046', (61, 65))	('glioma', 'Disease', (101, 107))	('N-13 NH3', 'Chemical', '-', (40, 48))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('F-18', 'Gene', (61, 65))
15930	31040521	reported superiority of N-13 NH3 PET over F-18 FDG PET in differentiating recurrent astrocytoma from radiation necrosis.	('F-18', 'Gene', (42, 46))	('astrocytoma', 'Disease', 'MESH:D001254', (84, 95))	('radiation necrosis', 'Disease', (101, 119))	('F-18', 'Gene', '10046', (42, 46))	('radiation necrosis', 'Disease', 'MESH:D004194', (101, 119))	('astrocytoma', 'Disease', (84, 95))	('N-13 NH3 PET', 'Var', (24, 36))	('N-13 NH3', 'Chemical', '-', (24, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (84, 95))
15939	31040521	Despite being highly accurate in detecting recurrent glioma, N-13 NH3 has the drawback of short half-life (10 min) and hence the need for an onsite cyclotron which might not be available in every center.	('glioma', 'Disease', (53, 59))	('NH3', 'Gene', (66, 69))	('N-13 NH3', 'Chemical', '-', (61, 69))	('N-13', 'Var', (61, 65))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
15943	31040521	has shown Tc-99m GHA SPECT as superior to F-18 FDG PET-CT in detecting glioma recurrence.	('S', 'Chemical', 'MESH:D013455', (21, 22))	('glioma', 'Disease', (71, 77))	('F-18', 'Gene', (42, 46))	('F-18', 'Gene', '10046', (42, 46))	('Tc-99m', 'Var', (10, 16))	('Tc-99', 'Chemical', '-', (10, 15))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
15945	31040521	has highlighted the equivalent efficacies of Tc-99m GHA SPECT-CT and F-18 fluorodopa PET-CT.	('S', 'Chemical', 'MESH:D013455', (56, 57))	('fluorodopa', 'Chemical', 'MESH:C043437', (74, 84))	('F-18', 'Gene', (69, 73))	('F-18', 'Gene', '10046', (69, 73))	('Tc-99m', 'Var', (45, 51))	('Tc-99', 'Chemical', '-', (45, 50))
15949	31040521	An active transport mechanism for the uptake of Tc-99m GHA in brain tumors has been suggested, as it is a structural analog to glucose.	('brain tumors', 'Disease', (62, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Tc-99', 'Chemical', '-', (48, 53))	('glucose', 'Chemical', 'MESH:D005947', (127, 134))	('Tc-99m', 'Var', (48, 54))	('brain tumors', 'Phenotype', 'HP:0030692', (62, 74))	('brain tumors', 'Disease', 'MESH:D001932', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('active transport', 'MPA', (3, 19))
15968	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))
16016	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))
16018	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))
16038	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))
16039	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))
16072	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))
16073	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))
16087	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))
16090	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))
16102	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))
16103	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))
16104	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))
16108	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))
16110	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))
16111	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))
16112	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))
16113	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))	('RPA', 'Gene', (138, 141))	('Chk1', 'Gene', (133, 137))	('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))
16115	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))	('increased', 'PosReg', (71, 80))	('RPA', 'Gene', (44, 47))
16118	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))	('human', 'Species', '9606', (52, 57))	('RPA', 'Gene', '6117', (171, 174))	('cancer', 'Disease', (102, 108))	('PC3', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('RPA', 'Gene', '6117', (38, 41))	('RPA', 'Gene', (171, 174))
16121	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))
16122	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))
16127	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))
16129	27845331	To exclude the possibility that this decrease in RRM2 levels is just a consequence of cell cycle arrest invoked by BRCA1 knockdown, we have performed additional analysis of RRM2 protein levels in individual cell cycle phases using flow cytometry analysis.	('knockdown', 'Var', (121, 130))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('RRM2', 'Gene', '6241', (49, 53))	('RRM2', 'Gene', (49, 53))	('BRCA1', 'Gene', (115, 120))	('RRM2', 'Gene', '6241', (173, 177))	('RRM2', 'Gene', (173, 177))
16131	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))
16137	27845331	Intriguingly, BRCA1 knockdown did not result in RRM2 protein level changes in either NHA-DRB or BJ cells (Supplementary Fig.	('changes', 'Reg', (67, 74))	('RRM2', 'Gene', (48, 52))	('BRCA1', 'Gene', (14, 19))	('RRM2', 'Gene', '6241', (48, 52))	('BJ', 'CellLine', 'CVCL:6573', (96, 98))	('knockdown', 'Var', (20, 29))
16142	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))
16143	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))
16145	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))	('transcriptional', 'MPA', (167, 182))	('RRM2', 'Gene', (197, 201))	('reduced', 'NegReg', (36, 43))	('BRCA1', 'Gene', (149, 154))	('BRCA1', 'Protein', (44, 49))
16147	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))
16155	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', (94, 102))	('triapine', 'Chemical', 'MESH:C078157', (225, 233))	('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))
16163	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))	('Ola', 'Chemical', '-', (71, 74))	('olaparib', 'Chemical', 'MESH:C531550', (56, 64))	('Ola', 'Chemical', '-', (84, 87))	('EC50-Tria', 'Disease', (41, 50))	('triapine', 'Chemical', 'MESH:C078157', (31, 39))
16176	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))	('BRCA1', 'Gene', (4, 9))	('overall survival', 'MPA', (146, 162))	('patients', 'Species', '9606', (245, 253))	('patients', 'Species', '9606', (294, 302))	('shorter', 'NegReg', (138, 145))	('patients', 'Species', '9606', (178, 186))	('high', 'Var', (10, 14))
16180	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))
16189	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))
16197	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))
16200	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))	('positivity', 'Var', (65, 75))	('BRCA1', 'Gene', (59, 64))	('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))
16204	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))
16207	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))
16208	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))
16209	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))
16210	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))
16211	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))
16223	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))	('Ectopic expression', 'Var', (0, 18))	('rescued', 'PosReg', (27, 34))	('RS', 'Chemical', '-', (66, 68))	('RRM2', 'Gene', (22, 26))	('RRM2', 'Gene', '6241', (22, 26))
16226	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))
16228	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))
16232	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))
16234	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))
16297	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))
16324	25368772	However, PWI showed increased relative cerebral blood volume, relative cerebral blood flow, and permeability of nonenhanced brain tumor compared with contralateral normal brain parenchyma, suggesting a high-grade glioma.	('brain tumor', 'Phenotype', 'HP:0030692', (124, 135))	('increased', 'PosReg', (20, 29))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('relative', 'MPA', (30, 38))	('permeability', 'MPA', (96, 108))	('PWI', 'Var', (9, 12))	('brain tumor', 'Disease', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('glioma', 'Disease', (213, 219))	('brain tumor', 'Disease', 'MESH:D001932', (124, 135))
16404	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))
16508	27120204	In patients with SVZ involvement, those with tumors exhibiting a CS <=30 mm from the SVZ were found to have a significantly shorter OS compared to patients with tumor centroids located further away from the SVZ (CS >30 mm; p = 0.022) (Fig 4A); there was no significant difference in PFS between these same patient groups (p = 0.056) (Fig 4B).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('patient', 'Species', '9606', (147, 154))	('tumor', 'Disease', (45, 50))	('shorter', 'NegReg', (124, 131))	('patient', 'Species', '9606', (3, 10))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (3, 11))	('CS <=30 mm', 'Var', (65, 75))	('CS', 'Chemical', 'MESH:D002586', (212, 214))	('CS', 'Chemical', 'MESH:D002586', (65, 67))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patient', 'Species', '9606', (306, 313))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
16569	26634437	It contains over 10,000 pretreatment samples across 30 cancer types and includes measurements such as RNA sequencing (RNA-seq), DNA methylation, copy-number variation and more.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('copy-number variation', 'Var', (145, 166))	('cancer', 'Disease', (55, 61))
16614	26634437	The only significant non-pathological associations of purity we found were a history of thyroid gland disorder in THCA and presence of IDH1 mutation in LGG (Supplementary Fig.	('thyroid gland disorder', 'Disease', (88, 110))	('IDH1', 'Gene', (135, 139))	('THCA', 'Phenotype', 'HP:0002895', (114, 118))	('mutation', 'Var', (140, 148))	('IDH1', 'Gene', '3417', (135, 139))	('thyroid gland disorder', 'Disease', 'MESH:D013959', (88, 110))	('thyroid gland disorder', 'Phenotype', 'HP:0000820', (88, 110))
16615	26634437	The latter association likely results from the fact that LGG tumours with wild-type IDH1 are molecularly and clinically similar to GBM, which have lower purity levels.	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('wild-type', 'Var', (74, 83))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('IDH1', 'Gene', (84, 88))	('LGG tumours', 'Disease', 'MESH:D009369', (57, 68))	('LGG tumours', 'Disease', (57, 68))	('IDH1', 'Gene', '3417', (84, 88))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
16618	26634437	This result could also be explained by clinical outcomes associated with IDH1 mutation, which is also associated with purity, as shown above.	('IDH1', 'Gene', (73, 77))	('mutation', 'Var', (78, 86))	('IDH1', 'Gene', '3417', (73, 77))
16665	26634437	Another finding reported here was a strong association between tumour purity and mutational burden (Fig.	('tumour purity', 'Disease', 'MESH:D009369', (63, 76))	('tumour purity', 'Disease', (63, 76))	('mutational', 'Var', (81, 91))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))
16682	26634437	We obtained DNA methylation profiles (HumanMethylation450) for 10 immune cells (whole blood, peripheral blood mononuclear cell, granulocytes, neutrophils, eosinophils, CD4+, CD8+, CD14+, CD19+ and CD56+ cells) with six replicates each.	('CD56', 'Gene', (197, 201))	('CD19', 'Gene', '930', (187, 191))	('eosin', 'Chemical', 'MESH:D004801', (155, 160))	('CD4+', 'Var', (168, 172))	('CD14', 'Gene', (180, 184))	('CD56', 'Gene', '4684', (197, 201))	('CD8+', 'Var', (174, 178))	('CD14', 'Gene', '929', (180, 184))	('CD19', 'Gene', (187, 191))
16726	24179806	Evaluation at the individual tumor cell level is only possible by IDH1R132 immunostaining in IDH1 mutated gliomas in adults.	('IDH1', 'Gene', (93, 97))	('gliomas', 'Disease', (106, 113))	('IDH1', 'Gene', '3417', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('IDH1', 'Gene', '3417', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('mutated', 'Var', (98, 105))	('IDH1', 'Gene', (66, 70))
16807	33745419	However, when bilateral defects in the vestibular system and its related connections occur, physiologic nystagmus is not elicited.	('nystagmus', 'Disease', (104, 113))	('defects in the vestibular system', 'Phenotype', 'HP:0001751', (24, 56))	('nystagmus', 'Disease', 'MESH:D009759', (104, 113))	('nystagmus', 'Phenotype', 'HP:0000639', (104, 113))	('defects', 'Var', (24, 31))
16822	33745419	Tyrosine kinases trigger cell proliferation, differentiation, migration, and metabolic changes via numerous signaling cascades (Schlessinger and Ullrich).	('metabolic changes', 'CPA', (77, 94))	('migration', 'CPA', (62, 71))	('Tyrosine', 'Var', (0, 8))	('differentiation', 'CPA', (45, 60))	('rat', 'Species', '10116', (37, 40))	('cell proliferation', 'CPA', (25, 43))	('trigger', 'Reg', (17, 24))	('rat', 'Species', '10116', (65, 68))
16823	33745419	Dysregulation (mutation) of tyrosine kinases induces uncontrolled cell proliferation and differentiation.	('Dysregulation', 'Var', (0, 13))	('induces', 'Reg', (45, 52))	('uncontrolled cell proliferation', 'CPA', (53, 84))	('rat', 'Species', '10116', (78, 81))	('tyrosine kinases', 'Enzyme', (28, 44))	('tyrosine', 'Chemical', 'MESH:D014443', (28, 36))
16832	33745419	Although combination therapy with hydroxyurea and imatinib was used, imatinib was initially associated with an improvement in neurological clinical signs.	('improvement', 'PosReg', (111, 122))	('hydroxyurea', 'Chemical', 'MESH:D006918', (34, 45))	('imatinib', 'Chemical', 'MESH:D000068877', (50, 58))	('neurological clinical signs', 'MPA', (126, 153))	('imatinib', 'Var', (69, 77))	('imatinib', 'Chemical', 'MESH:D000068877', (69, 77))
16865	32158691	Therefore, our study investigated whether histogram profiling of ADC distinguishes grade I from grade II glioma, reflects the proliferation index Ki-67, as well as the IDH (isocitrate dehydrogenase) mutation and MGMT (methylguanine-DNA methyl-transferase) promotor methylation status.	('isocitrate dehydrogenase', 'Gene', '3417', (173, 197))	('IDH', 'Gene', '3417', (168, 171))	('methylguanine-DNA methyl-transferase', 'Gene', (218, 254))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('grade', 'Disease', (83, 88))	('glioma', 'Disease', (105, 111))	('mutation', 'Var', (199, 207))	('methylguanine-DNA methyl-transferase', 'Gene', '4255', (218, 254))	('MGMT', 'Gene', '4255', (212, 216))	('MGMT', 'Gene', (212, 216))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('isocitrate dehydrogenase', 'Gene', (173, 197))	('IDH', 'Gene', (168, 171))
16871	32158691	Furthermore, minimum ADC value (ADCmin) was significantly associated with MGMT promotor methylation status as well as ADC entropy with IDH-1 mutation status.	('ADC entropy', 'MPA', (118, 129))	('minimum ADC value', 'MPA', (13, 30))	('associated', 'Reg', (58, 68))	('IDH-1', 'Gene', '3417', (135, 140))	('MGMT', 'Gene', (74, 78))	('IDH-1', 'Gene', (135, 140))	('MGMT', 'Gene', '4255', (74, 78))	('mutation', 'Var', (141, 149))
16872	32158691	Conclusions: ADC histogram-profiling is a valuable radiomic approach, which helps differentiating tumor grade, estimating growth kinetics and probably prognostic relevant genetic as well as epigenetic alterations in LGG.	('epigenetic alterations', 'Var', (190, 212))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('LGG', 'Gene', (216, 219))
16881	32158691	On the contrary, several studies in recent years indicated better prognosis and overall survival of patients after partial or total resection, which has partially led to a paradigm shift in therapy from "watchful waiting" toward early tumor surgery.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('better', 'PosReg', (59, 65))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', (235, 240))	('partial', 'Var', (115, 122))
16899	32158691	All regions of interest (ROIs) were then automatically co-registered with the corresponding ADC maps and the whole lesion histogram profile was consecutively calculated, providing the following set of parameters: ADCmean, ADCmin, ADCmax, ADCp10, ADCp25, ADCp75, ADCp90, ADCmodus, ADCmedian, ADC standard deviation (SD), Skewness, Kurtosis, and Entropy.	('Skewness, Kurtosis', 'Disease', 'MESH:D015835', (320, 338))	('p25', 'Gene', '11076', (249, 252))	('p90', 'Gene', (265, 268))	('p90', 'Gene', '7037', (265, 268))	('Entropy', 'MPA', (344, 351))	('p75', 'Gene', (257, 260))	('p10', 'Gene', (241, 244))	('p75', 'Gene', '7133', (257, 260))	('p25', 'Gene', (249, 252))	('ADCmax', 'Var', (230, 236))	('p10', 'Gene', '6281', (241, 244))
16910	32158691	Also, normally distributed DWI histogram profiling parameters between IDH mutated and IDH wildtype gliomas as well as between MGMT promotor methylated and unmethylated gliomas were compared using unpaired T-test.	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (86, 89))	('IDH', 'Gene', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('gliomas', 'Disease', (99, 106))	('IDH', 'Gene', '3417', (70, 73))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('mutated', 'Var', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('gliomas', 'Disease', (168, 175))	('MGMT', 'Gene', (126, 130))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('MGMT', 'Gene', '4255', (126, 130))
16916	32158691	Statistical significant differences between grade I and grade II astrocytomas were identified for the following set of ADC histogram parameters: ADCmean, ADCmax, ADCp25, ADCp75, ADCp90, ADCmedian, ADC SD, and Entropy (all p < 0.05).	('p75', 'Gene', (173, 176))	('p75', 'Gene', '7133', (173, 176))	('p90', 'Gene', '7037', (181, 184))	('p25', 'Gene', (165, 168))	('ADC', 'MPA', (197, 200))	('p90', 'Gene', (181, 184))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('p25', 'Gene', '11076', (165, 168))	('II astrocytoma', 'Disease', (62, 76))	('II astrocytoma', 'Disease', 'MESH:D001254', (62, 76))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('ADCmax', 'Var', (154, 160))	('ADCmean', 'Var', (145, 152))	('astrocytomas', 'Disease', (65, 77))	('ADCmedian', 'MPA', (186, 195))	('Entropy', 'MPA', (209, 216))
16921	32158691	Comparison of ADC histogram profiles of IDH-1 mutated and IDH-1 wildtype astrocytomas revealed significant differences for Entropy, with higher values in case of muted IDH-1.	('IDH-1', 'Gene', '3417', (58, 63))	('IDH-1', 'Gene', '3417', (168, 173))	('IDH-1', 'Gene', (168, 173))	('astrocytomas', 'Disease', (73, 85))	('IDH-1', 'Gene', (58, 63))	('higher', 'PosReg', (137, 143))	('mutated', 'Var', (46, 53))	('astrocytomas', 'Disease', 'MESH:D001254', (73, 85))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('IDH-1', 'Gene', '3417', (40, 45))	('differences', 'Reg', (107, 118))	('Entropy', 'MPA', (123, 130))	('IDH-1', 'Gene', (40, 45))
16936	32158691	Low-grade gliomas (LGG) often harbor mutations in one of both genes for IDH.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('IDH', 'Gene', '3417', (72, 75))	('harbor', 'Reg', (30, 36))	('mutations', 'Var', (37, 46))	('IDH', 'Gene', (72, 75))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
16937	32158691	A growing body of evidence indicates that these mutations are at least co-causative for glioma-genesis and therefore represent promising future therapeutic targets.	('glioma-genesis', 'Disease', (88, 102))	('glioma-genesis', 'Disease', 'MESH:D005910', (88, 102))	('mutations', 'Var', (48, 57))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
16938	32158691	So far, IDH mutation status is a well-established and important prognostic factor in low-grade glioma with better prognosis and survival in case of mutated IDH genes compared to wild-type genes.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH', 'Gene', (8, 11))	('mutated', 'Var', (148, 155))	('better', 'PosReg', (107, 113))	('glioma', 'Disease', (95, 101))	('IDH', 'Gene', (156, 159))	('IDH', 'Gene', '3417', (8, 11))	('IDH', 'Gene', '3417', (156, 159))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
16942	32158691	Its expression may be silenced by methylation of its promotor during tumor development, which in turn increases the anti-proliferative effect of alkylating chemotherapeutics.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('methylation', 'Var', (34, 45))	('tumor', 'Disease', (69, 74))	('expression', 'MPA', (4, 14))	('anti-proliferative effect', 'MPA', (116, 141))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('increases', 'PosReg', (102, 111))
16954	32158691	Furthermore, our results indicate that ADC histogram profiling enables to draw conclusions about the prognostic relevant IDH mutation status and MGMT promotor methylation status in LGG.	('LGG', 'Disease', (181, 184))	('MGMT', 'Gene', '4255', (145, 149))	('IDH', 'Gene', (121, 124))	('MGMT', 'Gene', (145, 149))	('IDH', 'Gene', '3417', (121, 124))	('mutation', 'Var', (125, 133))
16958	27852048	IGFBP2 expression predicts IDH-mutant glioma patient survival Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas.	('IDH', 'Gene', '3417', (27, 30))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('IDH', 'Gene', '3417', (105, 108))	('IGFBP2', 'Gene', '3485', (0, 6))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (79, 117))	('lower-grade', 'Disease', (141, 152))	('IGFBP2', 'Gene', (0, 6))	('patient', 'Species', '9606', (45, 52))	('glioma', 'Disease', (182, 188))	('glioma', 'Disease', (38, 44))	('Mutations', 'Var', (62, 71))	('gliomas', 'Disease', (182, 189))	('IDH', 'Gene', (27, 30))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('occur', 'Reg', (124, 129))	('IDH', 'Gene', (105, 108))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))
16959	27852048	Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis.	('IDH', 'Gene', (7, 10))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (20, 42))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('drives', 'PosReg', (94, 100))	('DNA hypermethylation', 'MPA', (58, 78))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('induces', 'Reg', (50, 57))
16960	27852048	Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear.	('glioma', 'Disease', (70, 76))	('improved', 'PosReg', (49, 57))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('mutations', 'Var', (19, 28))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('patients', 'Species', '9606', (77, 85))	('IDH', 'Gene', (15, 18))	('survival', 'MPA', (58, 66))
16963	27852048	Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients.	('expressiondisplay', 'Var', (83, 100))	('disease-free survival', 'CPA', (134, 155))	('IGFBP2', 'Gene', (76, 82))	('patients', 'Species', '9606', (243, 251))	('advantage', 'PosReg', (109, 118))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('overall', 'CPA', (122, 129))	('IGFBP2', 'Gene', '3485', (181, 187))	('patients', 'Species', '9606', (58, 66))	('low', 'NegReg', (72, 75))	('IGFBP2', 'Gene', (181, 187))	('IGFBP2', 'Gene', '3485', (76, 82))
16965	27852048	We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2.	('glioma', 'Disease', (83, 89))	('IDH', 'Gene', (66, 69))	('promoting', 'PosReg', (127, 136))	('mutations', 'Var', (70, 79))	('tumor-suppressor', 'Gene', '7248', (137, 153))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('patient survival', 'CPA', (107, 123))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('tumor-suppressor', 'Gene', (137, 153))	('IGFBP2', 'Gene', '3485', (213, 219))	('ameliorate', 'PosReg', (96, 106))	('patient', 'Species', '9606', (107, 114))	('IGFBP2', 'Gene', (213, 219))	('inhibiting', 'NegReg', (170, 180))
16967	27852048	Single somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, predominantly R132H, occurred in ~80% of LGGs as well as in secondary glioblastomas.	('isocitrate dehydrogenase 1', 'Gene', '3417', (32, 58))	('occurred', 'Reg', (93, 101))	('isocitrate dehydrogenase 1', 'Gene', (32, 58))	('IDH1', 'Gene', (60, 64))	('R132H', 'Var', (86, 91))	('glioblastomas', 'Phenotype', 'HP:0012174', (142, 155))	('R132H', 'Mutation', 'rs121913500', (86, 91))	('LGGs', 'Disease', (113, 117))	('glioblastomas', 'Disease', 'MESH:D005909', (142, 155))	('IDH1', 'Gene', '3417', (60, 64))	('glioblastomas', 'Disease', (142, 155))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
16970	27852048	The most striking biochemical finding from IDH1 and IDH2 mutations is the acquired neomorphic activity to catalyze the reduction of 2-oxoglutarate to the (R)-enantiomer of 2-hydroxyglutarate [(R)-HG].	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (132, 146))	('IDH2', 'Gene', '3418', (52, 56))	('IDH1', 'Gene', (43, 47))	('mutations', 'Var', (57, 66))	('IDH1', 'Gene', '3417', (43, 47))	('reduction', 'MPA', (119, 128))	('IDH2', 'Gene', (52, 56))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (172, 190))
16972	27852048	In keeping with this, mutant IDH1 inhibits histone demethylation and induces DNA hypermethylation in cell culture and animal model, thereby blocking cell differentiation.	('blocking', 'NegReg', (140, 148))	('inhibits', 'NegReg', (34, 42))	('DNA hypermethylation', 'MPA', (77, 97))	('IDH1', 'Gene', (29, 33))	('cell differentiation', 'CPA', (149, 169))	('IDH1', 'Gene', '3417', (29, 33))	('induces', 'Reg', (69, 76))	('mutant', 'Var', (22, 28))	('histone demethylation', 'MPA', (43, 64))
16973	27852048	Likewise, glioblastomas and LGGs harboring IDH mutations manifest a CpG island methylator phenotype.	('glioblastomas', 'Phenotype', 'HP:0012174', (10, 23))	('mutations', 'Var', (47, 56))	('glioblastomas', 'Disease', 'MESH:D005909', (10, 23))	('IDH', 'Gene', (43, 46))	('glioblastomas', 'Disease', (10, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
16974	27852048	Although pharmacological targeting of mutant IDH1 or IDH2 induces tumor cell differentiation through reduction of (R)2-HG production, the inhibitory effect on glioma growth remains less clear, and there are no appreciable changes in genome-wide DNA methylation.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('reduction', 'NegReg', (101, 110))	('IDH2', 'Gene', (53, 57))	('tumor', 'Disease', (66, 71))	('induces', 'Reg', (58, 65))	('IDH2', 'Gene', '3418', (53, 57))	('glioma growth', 'Disease', (159, 172))	('glioma growth', 'Disease', 'MESH:D005910', (159, 172))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('IDH1', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
16982	27852048	It should be noted that mutations of NF1 and PTEN were almost exclusive to IDH-wildtype glioma (Table S1), indicating the functional importance of increased NF1 and PTEN expression in IDH-mutant glioma.	('NF1', 'Gene', '4763', (157, 160))	('mutations', 'Var', (24, 33))	('PTEN', 'Gene', '5728', (45, 49))	('expression', 'MPA', (170, 180))	('PTEN', 'Gene', '5728', (165, 169))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (195, 201))	('NF1', 'Gene', '4763', (37, 40))	('NF1', 'Gene', (157, 160))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('IDH-wildtype glioma', 'Disease', 'MESH:D005910', (75, 94))	('increased', 'PosReg', (147, 156))	('NF1', 'Gene', (37, 40))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('IDH-mutant', 'Gene', (184, 194))	('IDH-wildtype glioma', 'Disease', (75, 94))	('glioma', 'Disease', (195, 201))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', (165, 169))	('IDH-mutant', 'Gene', '3418', (184, 194))
16993	27852048	Because sustaining proliferative signaling is another hallmark of cancer, we explored the receptor tyrosine kinase (RTK) signal pathways by analyzing genes known to promote the EGFR, FGFR, and PDGFR signaling commonly seen in malignant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('RTK', 'Gene', '5979', (116, 119))	('receptor tyrosine kinase', 'Gene', (90, 114))	('malignant gliomas', 'Disease', 'MESH:D005910', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('genes', 'Var', (150, 155))	('receptor tyrosine kinase', 'Gene', '5979', (90, 114))	('PDGFR', 'Gene', (193, 198))	('gliomas', 'Phenotype', 'HP:0009733', (236, 243))	('PDGFR', 'Gene', '5159', (193, 198))	('FGFR', 'Gene', (183, 187))	('promote', 'PosReg', (165, 172))	('EGFR', 'Gene', '1956', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('RTK', 'Gene', (116, 119))	('EGFR', 'Gene', (177, 181))	('cancer', 'Disease', (66, 72))	('malignant gliomas', 'Disease', (226, 243))
17004	27852048	Of note, high expression of PDGFRA seemed rather associated, if at all, with improved overall survival.	('PDGFRA', 'Gene', '5156', (28, 34))	('PDGFRA', 'Gene', (28, 34))	('overall', 'MPA', (86, 93))	('improved', 'PosReg', (77, 85))	('high', 'Var', (9, 13))
17007	27852048	Unexpectedly, high ERBB3 abundance and Tyr-1289 phosphorylation correlated with improved overall and disease-free survival (Figure 3B; Figure S3B).	('overall', 'CPA', (89, 96))	('improved', 'PosReg', (80, 88))	('disease-free survival', 'CPA', (101, 122))	('Tyr', 'Chemical', 'MESH:D014443', (39, 42))	('ERBB3', 'Gene', '2065', (19, 24))	('Tyr-1289', 'Var', (39, 47))	('ERBB3', 'Gene', (19, 24))
17018	27852048	Patients with low expression of IGFBP2 and WWTR but not YAP1 had essentially the same median overall and disease-free survival as IDH-mutant patients (Figure 4B and 4C; Tables S2 and S3).	('IGFBP2', 'Gene', '3485', (32, 38))	('YAP1', 'Gene', (56, 60))	('IGFBP2', 'Gene', (32, 38))	('IDH-mutant', 'Gene', (130, 140))	('IDH-mutant', 'Gene', '3418', (130, 140))	('Patients', 'Species', '9606', (0, 8))	('low expression', 'Var', (14, 28))	('YAP1', 'Gene', '10413', (56, 60))	('disease-free', 'CPA', (105, 117))	('patients', 'Species', '9606', (141, 149))
17020	27852048	It is noteworthy, however, that patients with high IGFBP2 mRNA levels were the only group that showed worse survival than IDH-wildtype patients.	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (32, 40))	('IGFBP2', 'Gene', (51, 57))	('mRNA levels', 'MPA', (58, 69))	('IGFBP2', 'Gene', '3485', (51, 57))
17021	27852048	Furthermore, within the IDH-mutant group, IGFBP2 was the only gene that was still prognostic at the mRNA levels; the median overall survival of IDH-mutant gliomas with high IGFBP2 expression was ~25% worse than that of IDH-wildtype (Figure 5A and 5B; Table S2).	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('IGFBP2', 'Gene', '3485', (173, 179))	('IGFBP2', 'Gene', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('high', 'Var', (168, 172))	('worse', 'NegReg', (200, 205))	('IDH-mutant', 'Gene', (24, 34))	('IDH-mutant', 'Gene', (144, 154))	('IGFBP2', 'Gene', '3485', (42, 48))	('IDH-mutant', 'Gene', '3418', (24, 34))	('IDH-mutant', 'Gene', '3418', (144, 154))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('IGFBP2', 'Gene', (42, 48))
17027	27852048	Again, not only were IGFBP2 mRNA levels statistically much lower in the IDH1R132H-positive than in the IDH1R132H-negative group, but low IGFBP2 mRNA levels also correlated with improved survival whereas high IGFBP2 mRNA levels exhibited worse survival than the IDH1R132H-negative group (Figure 5C and 5D).	('IGFBP2', 'Gene', '3485', (208, 214))	('IGFBP2', 'Gene', (21, 27))	('low', 'NegReg', (133, 136))	('IGFBP2', 'Gene', (208, 214))	('lower', 'NegReg', (59, 64))	('improved', 'PosReg', (177, 185))	('high', 'Var', (203, 207))	('IGFBP2', 'Gene', '3485', (137, 143))	('mRNA levels', 'MPA', (144, 155))	('IGFBP2', 'Gene', '3485', (21, 27))	('IGFBP2', 'Gene', (137, 143))	('IDH1R132H-positive', 'Var', (72, 90))	('survival', 'CPA', (186, 194))
17028	27852048	Importantly, the survival benefit of low IGFBP2 expression held true within the IDH1R132H-positive group (Figure 5E).	('low', 'Var', (37, 40))	('IGFBP2', 'Gene', (41, 47))	('expression', 'MPA', (48, 58))	('IGFBP2', 'Gene', '3485', (41, 47))
17036	27852048	The latest classification of IDH-mutant glioma groups into two subtypes: one with 1p/19q co-deletion also harboring mutations in CIC, FUBP1, and NOTCH1, and the other without 1p/19q co-deletion but with extreme high frequencies of mutations in TP53 and ATRX.	('ATRX', 'Gene', (253, 257))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('IDH-mutant', 'Gene', (29, 39))	('IDH-mutant', 'Gene', '3418', (29, 39))	('FUBP1', 'Gene', (134, 139))	('TP53', 'Gene', (244, 248))	('ATRX', 'Gene', '546', (253, 257))	('glioma', 'Disease', (40, 46))	('mutations', 'Var', (116, 125))	('FUBP1', 'Gene', '8880', (134, 139))	('CIC', 'Gene', (129, 132))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('NOTCH1', 'Gene', '4851', (145, 151))	('NOTCH1', 'Gene', (145, 151))	('TP53', 'Gene', '7157', (244, 248))
17038	27852048	Furthermore, no statistical differences in IGFBP2 expression were observed between subtypes with and without CIC, FUBP1, and/or NOTCH1 mutations, nor between those with and without TP53 and/or ATRX mutations, which further disputes the possibility of IGFBP2 association with specific glioma subtypes.	('glioma', 'Phenotype', 'HP:0009733', (284, 290))	('glioma subtypes', 'Disease', 'MESH:D005910', (284, 299))	('ATRX', 'Gene', '546', (193, 197))	('TP53', 'Gene', (181, 185))	('IGFBP2', 'Gene', '3485', (43, 49))	('mutations', 'Var', (135, 144))	('IGFBP2', 'Gene', (43, 49))	('CIC', 'Gene', (109, 112))	('FUBP1', 'Gene', '8880', (114, 119))	('IGFBP2', 'Gene', '3485', (251, 257))	('ATRX', 'Gene', (193, 197))	('glioma subtypes', 'Disease', (284, 299))	('FUBP1', 'Gene', (114, 119))	('TP53', 'Gene', '7157', (181, 185))	('NOTCH1', 'Gene', '4851', (128, 134))	('NOTCH1', 'Gene', (128, 134))	('IGFBP2', 'Gene', (251, 257))
17043	27852048	However, this advantage reduced by half and lost statistical significance when the only 7 IDH-mutant cases were subtracted from the analysis, further supporting an intimate relationship between IDH mutations and IGFBP2 in glioblastoma prognosis.	('IDH-mutant', 'Gene', '3418', (90, 100))	('glioblastoma', 'Disease', (222, 234))	('IGFBP2', 'Gene', (212, 218))	('glioblastoma', 'Disease', 'MESH:D005909', (222, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (222, 234))	('mutations', 'Var', (198, 207))	('IDH', 'Gene', (194, 197))	('IGFBP2', 'Gene', '3485', (212, 218))	('IDH-mutant', 'Gene', (90, 100))
17049	27852048	Furthermore, these changes in gene expression are associated statistically with improved patient survival.	('patient survival', 'CPA', (89, 105))	('gene expression', 'MPA', (30, 45))	('patient', 'Species', '9606', (89, 96))	('changes', 'Var', (19, 26))	('improved', 'PosReg', (80, 88))
17053	27852048	Whereas mutations that are causally implicated in oncogenesis are defined as driver mutations, the rest are grouped as passenger mutations for the lack of clear contributions to cancer development.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (8, 17))
17054	27852048	Although IDH mutations are believed to drive glioma initiation by producing (R)2-HG, which results in DNA hypermethylation and metabolic reprograming, expression of mutant Idh1 in the mouse brain has yet to induce glioma formation despite robust production of (R)2-HG.	('mutant', 'Var', (165, 171))	('glioma', 'Disease', (214, 220))	('DNA', 'MPA', (102, 105))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('Idh1', 'Gene', (172, 176))	('glioma initiation', 'Disease', (45, 62))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('mouse', 'Species', '10090', (184, 189))	('induce', 'Reg', (207, 213))	('glioma initiation', 'Disease', 'MESH:D005910', (45, 62))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('glioma', 'Disease', (45, 51))	('Idh1', 'Gene', '15926', (172, 176))
17055	27852048	To the contrary, our results show strong correlation between increased DNA methylation and suppression of oncogenic signaling, suggesting that the effects of DNA hypermethylation in IDH-mutant glioma are unexpectedly anti-oncogenic, which is consistent with a newly identified subtype of IDH-mutant glioma featuring DNA demethylation associated with poor survival.	('oncogenic signaling', 'Pathway', (106, 125))	('glioma', 'Disease', (299, 305))	('anti-oncogenic', 'CPA', (217, 231))	('glioma', 'Disease', (193, 199))	('hypermethylation', 'Var', (162, 178))	('IDH-mutant', 'Gene', (288, 298))	('IDH-mutant', 'Gene', '3418', (288, 298))	('glioma', 'Disease', 'MESH:D005910', (299, 305))	('glioma', 'Phenotype', 'HP:0009733', (299, 305))	('IDH-mutant', 'Gene', (182, 192))	('IDH-mutant', 'Gene', '3418', (182, 192))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('glioma', 'Disease', 'MESH:D005910', (193, 199))
17056	27852048	Our hypothesis is also supported by the strong correlations between IDH mutations and increased tumor-suppressor gene expression that correlates with patient survival.	('mutations', 'Var', (72, 81))	('patient', 'Species', '9606', (150, 157))	('increased', 'PosReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor-suppressor', 'Gene', '7248', (96, 112))	('IDH', 'Gene', (68, 71))	('expression', 'MPA', (118, 128))	('tumor-suppressor', 'Gene', (96, 112))
17057	27852048	Likewise, targets of epigenetic silencing identified in IDH1-mutant gliomas, including glycolytic genes, retinol binding protein 1, and microRNA miR148a, were all associated with reduced cell proliferation and improved survival.	('improved', 'PosReg', (210, 218))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('epigenetic silencing', 'Var', (21, 41))	('miR148a', 'Gene', (145, 152))	('survival', 'CPA', (219, 227))	('IDH1', 'Gene', '3417', (56, 60))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('miR148a', 'Gene', '406940', (145, 152))	('cell proliferation', 'CPA', (187, 205))	('retinol binding protein 1', 'Gene', (105, 130))	('retinol binding protein 1', 'Gene', '5947', (105, 130))	('reduced', 'NegReg', (179, 186))	('IDH1', 'Gene', (56, 60))
17058	27852048	Furthermore, introduction of mutant IDH1 in glioblastoma cells and transformed astrocytes inhibited cell proliferation, reduced tumor growth, and improved mouse survival (Tiburcio et al., manuscript in preparation).	('glioblastoma', 'Disease', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('IDH1', 'Gene', (36, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('mutant', 'Var', (29, 35))	('mouse survival', 'CPA', (155, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('mouse', 'Species', '10090', (155, 160))	('improved', 'PosReg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cell proliferation', 'CPA', (100, 118))	('IDH1', 'Gene', '3417', (36, 40))	('tumor', 'Disease', (128, 133))	('inhibited', 'NegReg', (90, 99))	('reduced', 'NegReg', (120, 127))
17059	27852048	Thus, taken together, the evidence indicates that IDH mutations in glioma may represent a different category, i.e., beneficial mutations, resulting from an aberrant cellular response that counteracts glioma progression, even though the mechanism by which transformed cells acquire this type of mutations necessitates further investigation.	('glioma', 'Disease', (200, 206))	('glioma', 'Disease', (67, 73))	('mutations', 'Var', (54, 63))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('IDH', 'Gene', (50, 53))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
17061	27852048	Given the fact that IDH mutations are early events ("founder mutation") in LGG development, it stands to reason that the early gain of IDH mutations prevents glioma from acquiring additional malignant traits seen in IDH-wildtype glioma, whereas functional loss of IDH mutations, such as the loss of DNA hypermethylation in the newly identified IDH-mutant glioma subtype, results in unfavorable clinical outcome.	('IDH-mutant', 'Gene', (344, 354))	('prevents', 'NegReg', (149, 157))	('IDH-mutant', 'Gene', '3418', (344, 354))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Disease', (355, 361))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('mutations', 'Var', (139, 148))	('IDH-wildtype glioma', 'Disease', 'MESH:D005910', (216, 235))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('glioma subtype', 'Disease', (355, 369))	('glioma', 'Disease', 'MESH:D005910', (355, 361))	('glioma', 'Disease', (229, 235))	('glioma subtype', 'Disease', 'MESH:D005910', (355, 369))	('glioma', 'Phenotype', 'HP:0009733', (355, 361))	('glioma', 'Disease', (158, 164))	('glioma', 'Disease', 'MESH:D005910', (229, 235))	('IDH-wildtype glioma', 'Disease', (216, 235))	('gain', 'PosReg', (127, 131))
17064	27852048	Although pharmacological targeting of IDH mutations induces tumor cell differentiation by reducing (R)2-HG production, the inhibitory effect on glioma growth remains less clear.	('glioma growth', 'Disease', 'MESH:D005910', (144, 157))	('glioma growth', 'Disease', (144, 157))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('reducing', 'NegReg', (90, 98))	('induces', 'Reg', (52, 59))	('tumor', 'Disease', (60, 65))	('mutations', 'Var', (42, 51))
17065	27852048	Additionally, a recent study suggests that IDH1-mutant inhibitors may alter oxidative stress responses in glioma patients and therefore diminish the therapeutic efficacy of irradiation.	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('patients', 'Species', '9606', (113, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('IDH1', 'Gene', (43, 47))	('diminish the therapeutic efficacy of irradiation', 'Phenotype', 'HP:0011133', (136, 184))	('oxidative stress responses', 'MPA', (76, 102))	('diminish', 'NegReg', (136, 144))	('therapeutic efficacy of irradiation', 'CPA', (149, 184))	('glioma', 'Disease', (106, 112))	('alter', 'Reg', (70, 75))	('inhibitors', 'Var', (55, 65))	('IDH1', 'Gene', '3417', (43, 47))
17066	27852048	Our results not only suggest that targeting of mutant IDH in glioma patients could be counterproductive but also raise concerns about the selection of molecular targets for malignant glioma treatment.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('malignant glioma', 'Disease', 'MESH:D005910', (173, 189))	('glioma', 'Disease', (183, 189))	('malignant glioma', 'Disease', (173, 189))	('glioma', 'Disease', (61, 67))	('patients', 'Species', '9606', (68, 76))	('IDH', 'Gene', (54, 57))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('mutant', 'Var', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
17073	27852048	There were 53 cases of IDH-wildtype gliomas and 233 cases with either IDH1 or IDH2 mutations, which were grouped into a single group, IDH-mutant.	('mutations', 'Var', (83, 92))	('IDH-wildtype gliomas', 'Disease', (23, 43))	('IDH2', 'Gene', (78, 82))	('IDH-mutant', 'Gene', (134, 144))	('IDH-mutant', 'Gene', '3418', (134, 144))	('IDH1', 'Gene', '3417', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('IDH2', 'Gene', '3418', (78, 82))	('IDH-wildtype gliomas', 'Disease', 'MESH:D005910', (23, 43))	('IDH1', 'Gene', (70, 74))
17083	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))
17086	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))
17087	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))
17088	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))
17110	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))
17121	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))
17188	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))
17198	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))	('mice', 'Species', '10090', (52, 56))	('xenograft tumors', 'Disease', 'MESH:D009369', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('DFO', 'Chemical', 'MESH:D003676', (5, 8))	('MT1-MMP+ GBM', 'Var', (108, 120))	('xenograft tumors', 'Disease', (67, 83))
17202	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))
17208	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))
17213	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))
17216	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))
17227	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))
17230	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))
17235	27462980	Biodistribution studies with the U251 murine model revealed specific MT1-MMP driven uptake of 89Zr-DFO LEM2/15 in GBM tumors (about 30%ID/g at 24h), declining in a time-dependent manner up to 15% ID/g at 7 days p.i.	('uptake', 'MPA', (84, 90))	('GBM tumors', 'Disease', 'MESH:D005910', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('GBM tumors', 'Disease', (114, 124))	('89Zr', 'Chemical', 'MESH:C000615502', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('89Zr-DFO LEM2/15', 'Var', (94, 110))	('murine', 'Species', '10090', (38, 44))	('DFO', 'Chemical', 'MESH:D003676', (99, 102))
17241	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))
17247	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))
17249	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', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('minituarized', 'Var', (4, 16))	('enhance', 'PosReg', (32, 39))	('BBB penetration', 'CPA', (40, 55))
17313	33098284	[10] compared DWI using high b-value (b = 3000 s/mm2) to standard b-value (b = 1000 s/mm2) in the preoperative grading of supratentorial gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('b = 3000 s/mm2', 'Var', (38, 52))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))
17343	26091668	DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis.	('gliomas', 'Disease', (250, 257))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('IDH', 'Gene', '3417', (145, 148))	('tumor', 'Disease', (282, 287))	('IDH', 'Gene', (191, 194))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('chromothripsis', 'MPA', (114, 128))	('Isocitrate dehydrogenase', 'Gene', '3417', (165, 189))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('Isocitrate dehydrogenase', 'Gene', (165, 189))	('gliomas', 'Disease', 'MESH:D005910', (250, 257))	('IDH', 'Gene', '3417', (191, 194))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('gliomas', 'Phenotype', 'HP:0009733', (250, 257))	('mutation', 'Var', (196, 204))	('IDH', 'Gene', (145, 148))	('gliomas', 'Disease', (54, 61))	('mutation', 'Var', (149, 157))
17350	26091668	Functional analyses showed that IDHwt gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('receptor tyrosine kinase pathways', 'Pathway', (94, 127))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (32, 45))	('chromosome gains', 'Var', (55, 71))	('IDHwt gliomas', 'Disease', (32, 45))
17351	26091668	In contrast, IDHmut gliomas more commonly demonstrated amplification of cyclins and cyclin dependent kinase genes.	('IDH', 'Gene', '3417', (13, 16))	('amplification', 'Var', (55, 68))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('cyclin dependent kinase genes', 'Gene', (84, 113))	('cyclins', 'Gene', (72, 79))	('IDH', 'Gene', (13, 16))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
17361	26091668	Recently, large scale efforts have been made to identify the major genetic and epigenetic alterations and to define important molecular subtypes in GBM and lower grade gliomas.	('epigenetic alterations', 'Var', (79, 101))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('GBM', 'Disease', (148, 151))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('gliomas', 'Disease', (168, 175))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))
17362	26091668	The strongest prognostic factor for all glioma histologies is mutation in one of the isocitrate dehydrogenase genes (IDH1 or IDH2), and mutation of these genes is seen at higher frequencies in lower grade gliomas and secondary GBMs.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('IDH2', 'Gene', '3418', (125, 129))	('IDH1', 'Gene', '3417', (117, 121))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Disease', (205, 212))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('secondary GBMs', 'Disease', (217, 231))	('glioma', 'Disease', (205, 211))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('mutation', 'Var', (62, 70))	('isocitrate dehydrogenase', 'Gene', (85, 109))	('GBM', 'Phenotype', 'HP:0012174', (227, 230))	('IDH2', 'Gene', (125, 129))	('isocitrate dehydrogenase', 'Gene', '3417', (85, 109))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('IDH1', 'Gene', (117, 121))
17364	26091668	A summary of over 400 GBMs showed gains in EGFR (7p12) in 30 %, GLI/CDK4/MDM2 (12q13-14) in 13 %, PIK3C2B/MDM4 (1q32) in 8 %, PDGFRA (4q12) in 8 %, and MET (7q31) in 4 % with deletions in CDKN2A/2B (9p21) in 47 %, PTEN (10q23) in 10 %, and RB1 (13q14) in 6 %.	('PDGFRA', 'Gene', (126, 132))	('MDM4', 'Gene', (106, 110))	('CDK4', 'Gene', (68, 72))	('RB1', 'Gene', '5925', (240, 243))	('PTEN', 'Gene', '5728', (214, 218))	('EGFR', 'Gene', (43, 47))	('CDKN2A/2B', 'Gene', '1029', (188, 197))	('GLI', 'Gene', (64, 67))	('CDK4', 'Gene', '1019', (68, 72))	('MDM2', 'Gene', (73, 77))	('deletions', 'Var', (175, 184))	('PIK3C2B', 'Gene', (98, 105))	('CDKN2A/2B', 'Gene', (188, 197))	('EGFR', 'Gene', '1956', (43, 47))	('MDM2', 'Gene', '4193', (73, 77))	('GLI', 'Gene', '2735', (64, 67))	('RB1', 'Gene', (240, 243))	('PIK3C2B', 'Gene', '5287', (98, 105))	('PTEN', 'Gene', (214, 218))	('MDM4', 'Gene', '4194', (106, 110))	('PDGFRA', 'Gene', '5156', (126, 132))	('GBM', 'Phenotype', 'HP:0012174', (22, 25))
17367	26091668	Although some groups have found worse prognosis in GBMs with either EGFR or chromosome 7 amplifications, others, including the largest study (n = 532), found no association with outcome.	('amplifications', 'Var', (89, 103))	('EGFR', 'Gene', '1956', (68, 72))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('EGFR', 'Gene', (68, 72))	('chromosome 7', 'Gene', (76, 88))
17368	26091668	One reason for this inconsistency may be confounding due to the association of EGFR amplification with other known prognostic factors, such as age, G-CIMP status, or IDH mutation status.	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('amplification', 'Var', (84, 97))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', '3417', (166, 169))	('association', 'Interaction', (64, 75))
17369	26091668	Only one study has looked at the prognosis of copy nuber alterations (CNAs) within subgroups defined by IDH status, suggesting that chromosome 7p gain and TP53 loss are prognostic in grade III gliomas with IDH mutation.	('IDH', 'Gene', (206, 209))	('IDH', 'Gene', (104, 107))	('gliomas', 'Disease', (193, 200))	('TP53', 'Gene', '7157', (155, 159))	('loss', 'NegReg', (160, 164))	('chromosome', 'Gene', (132, 142))	('IDH', 'Gene', '3417', (206, 209))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('IDH', 'Gene', '3417', (104, 107))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('TP53', 'Gene', (155, 159))	('mutation', 'Var', (210, 218))	('gain', 'PosReg', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))
17381	26091668	BioDiscovery's SNP-Rank Segmentation algorithm with Quadratic Wave Correction, a statistically based algorithm similar to Circular Binary Segmentation (CBS), was used to make copy number and loss of heterozygosity (LOH) calls.	('copy number', 'Var', (175, 186))	('Circular Binary Segmentation', 'Disease', 'MESH:C537538', (122, 150))	('loss of heterozygosity', 'NegReg', (191, 213))	('Circular Binary Segmentation', 'Disease', (122, 150))
17382	26091668	In order to assess the significance of the genomic alterations, Genomic Identification of Significant Targets in Cancer (GISTIC) was used to define deletions and gains and to calculate the q-value, taking into account the frequency, amplitude and focality of the observed gains and deletions.	('deletions', 'Var', (148, 157))	('Cancer', 'Disease', 'MESH:D009369', (113, 119))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Cancer', 'Disease', (113, 119))
17389	26091668	1b Due to their distinct chromosomal abnormalities and clinical characteristics, the lower grade oligodendroglial tumors with 1p/19q co-deletion (n = 5) were analyzed separately (Fig.	('1p/19q', 'Var', (126, 132))	('oligodendroglial tumors', 'Disease', (97, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('chromosomal abnormalities', 'Disease', (25, 50))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (25, 50))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (97, 120))
17398	26091668	The CNA alterations seen most frequently across all grades of IDHwt gliomas were broad gain of chromosome 7 and loss of chromosome 10 (Arrows, Fig.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('gain', 'PosReg', (87, 91))	('IDHwt gliomas', 'Disease', (62, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('loss', 'Var', (112, 116))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (62, 75))
17402	26091668	Rather, there were several chromosomal regions, which are listed in Additional file 3: Table S3, that were less likely to be gained in grade IV (IDHwt) gliomas than in lower grade IDHmut gliomas.	('grade IV', 'Var', (135, 143))	('gliomas', 'Disease', (187, 194))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('IDH', 'Gene', (180, 183))	('IDH', 'Gene', '3417', (180, 183))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
17404	26091668	The fact that no CNAs were more common in high grade IDHwt gliomas than in lower grade IDHwt gliomas supports the concept that the recurring copy number aberrations seen in IDHwt GBM are likely to be present in grade II-III precursor tumors.	('IDHwt gliomas', 'Disease', (53, 66))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('copy number aberrations', 'Var', (141, 164))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (87, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDHwt gliomas', 'Disease', (87, 100))	('IDH', 'Gene', '3417', (173, 176))	('IDH', 'Gene', '3417', (87, 90))	('IDH', 'Gene', (53, 56))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('tumors', 'Disease', (234, 240))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (53, 66))	('IDH', 'Gene', '3417', (53, 56))
17413	26091668	The most significant difference (P = 5 x 10-5) between the two largest clusters was loss of the terminal end of the q arm of chromosome 10 including MGMT, which occurred in 80 % of the cluster with most of the GBMs and 9 % of the cluster with primarily lower grade gliomas (Additional file 4: Table S4).	('MGMT', 'Gene', (149, 153))	('loss', 'NegReg', (84, 88))	('MGMT', 'Gene', '4255', (149, 153))	('glioma', 'Phenotype', 'HP:0009733', (265, 271))	('GBM', 'Phenotype', 'HP:0012174', (210, 213))	('GBMs', 'Var', (210, 214))	('gliomas', 'Disease', 'MESH:D005910', (265, 272))	('gliomas', 'Phenotype', 'HP:0009733', (265, 272))	('gliomas', 'Disease', (265, 272))
17434	26091668	We hypothesized that loss of function of p53 would predispose to chromothripsis because of the inability of p53 deficient cells to undergo apoptosis in the face of chromosome shattering.	('p53', 'Gene', '7157', (41, 44))	('chromothripsis', 'Disease', (65, 79))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('deficient', 'Var', (112, 121))	('loss of function', 'NegReg', (21, 37))	('inability', 'NegReg', (95, 104))	('p53', 'Gene', (41, 44))
17435	26091668	Indeed, gliomas with chromosome loss at the TP53 locus or LOH at the TP53 locus were more likely to have chromothripsis than those with no alteration of TP53 (Fig.	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('gliomas', 'Disease', (8, 15))	('LOH', 'Var', (58, 61))	('TP53', 'Gene', '7157', (69, 73))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('TP53', 'Gene', (69, 73))	('chromothripsis', 'MPA', (105, 119))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (153, 157))	('chromosome loss', 'Var', (21, 36))	('TP53', 'Gene', (44, 48))
17444	26091668	These findings suggest that loss of PTEN or genes near it on chromosome 10q may be a key and unique factor associated with progression of IDHmut tumors to grade IV.	('loss', 'Var', (28, 32))	('IDHmut tumors', 'Disease', 'MESH:D009369', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('associated', 'Reg', (107, 117))	('PTEN', 'Gene', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('PTEN', 'Gene', '5728', (36, 40))	('IDHmut tumors', 'Disease', (138, 151))
17447	26091668	IDHwt gliomas had significantly more chromosome alterations affecting RTK signaling than IDHmut gliomas.	('chromosome alterations', 'Var', (37, 59))	('IDH', 'Gene', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))	('affecting', 'Reg', (60, 69))	('IDHwt gliomas', 'Disease', (0, 13))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('RTK signaling', 'MPA', (70, 83))	('IDH', 'Gene', (89, 92))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (0, 13))	('gliomas', 'Disease', (6, 13))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('IDH', 'Gene', '3417', (89, 92))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
17448	26091668	PI3K pathway activation also differed based on IDH status: upstream changes such as PTEN deletion or AKT gain were more common in IDHwt gliomas and MTOR gain was significantly less common (p = 2 x 10-7, 0.002, and 1 x 10-5, respectively).	('MTOR', 'Gene', (148, 152))	('IDH', 'Gene', '3417', (130, 133))	('IDH', 'Gene', '3417', (47, 50))	('AKT', 'Gene', '207', (101, 104))	('IDHwt gliomas', 'Disease', (130, 143))	('MTOR', 'Gene', '2475', (148, 152))	('PTEN', 'Gene', (84, 88))	('AKT', 'Gene', (101, 104))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('PTEN', 'Gene', '5728', (84, 88))	('deletion', 'Var', (89, 97))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (130, 143))	('gain', 'PosReg', (105, 109))	('IDH', 'Gene', (130, 133))	('IDH', 'Gene', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
17454	26091668	Although univariate analysis identified distinct copy number alterations in each subgroup that were significantly associated with survival in our cohort, none were significantly associated with survival when we attempted to validate them using 433 GBM and 181 lower grade glioma samples from the TCGA obtained via Nexus premier.	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('copy number alterations', 'Var', (49, 72))	('GBM', 'Phenotype', 'HP:0012174', (248, 251))	('associated', 'Reg', (114, 124))	('glioma', 'Disease', (272, 278))
17459	26091668	In contrast, among IDHmut tumors, clustering based on copy number demonstrates that lower grade and grade IV gliomas with IDH mutations are distinct biologic entities; they also have distinct prognosis.	('IV gliomas', 'Disease', 'MESH:D005910', (106, 116))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('IDHmut tumors', 'Disease', (19, 32))	('IDHmut tumors', 'Disease', 'MESH:D009369', (19, 32))	('lower grade', 'Disease', (84, 95))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('IDH', 'Gene', (19, 22))	('mutations', 'Var', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('IDH', 'Gene', '3417', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('IV gliomas', 'Disease', (106, 116))
17463	26091668	Amplification of EGFR has been shown to separate GBM into distinct clusters.	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('Amplification', 'Var', (0, 13))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
17464	26091668	Although IDH mutation status was not reported in these clustering papers, alterations seen in the non-EGFR amplified group, such as losses on chromosome 13, mirror those seen in our IDHmut glioblastomas.	('IDH', 'Gene', '3417', (182, 185))	('losses on chromosome', 'Var', (132, 152))	('glioblastomas', 'Phenotype', 'HP:0012174', (189, 202))	('IDH', 'Gene', (9, 12))	('glioblastomas', 'Disease', 'MESH:D005909', (189, 202))	('IDH', 'Gene', '3417', (9, 12))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('glioblastomas', 'Disease', (189, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('IDH', 'Gene', (182, 185))
17468	26091668	We found an unexpectedly large number of intrachromosomal breakpoints, also known as chromothripsis, in our IDHmut GBM tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('intrachromosomal breakpoints', 'Var', (41, 69))	('IDH', 'Gene', (108, 111))	('GBM tumors', 'Disease', (115, 125))	('GBM tumors', 'Disease', 'MESH:D005910', (115, 125))	('IDH', 'Gene', '3417', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('GBM', 'Phenotype', 'HP:0012174', (115, 118))
17469	26091668	Upon closer inspection, we observed that chromothripsis is more likely when TP53 is altered through deletion and/or LOH, and others have found that astrocytes lacking p53 have more chromosome breaks and medulloblastoma due to inherited TP53 mutations have increased chromothripsis.	('p53', 'Gene', (167, 170))	('TP53', 'Gene', '7157', (236, 240))	('LOH', 'Var', (116, 119))	('chromothripsis', 'MPA', (266, 280))	('TP53', 'Gene', '7157', (76, 80))	('medulloblastoma', 'Disease', 'MESH:D008527', (203, 218))	('chromosome breaks', 'Phenotype', 'HP:0040012', (181, 198))	('medulloblastoma', 'Phenotype', 'HP:0002885', (203, 218))	('p53', 'Gene', '7157', (167, 170))	('TP53', 'Gene', (76, 80))	('deletion', 'Var', (100, 108))	('increased', 'PosReg', (256, 265))	('chromosome breaks', 'CPA', (181, 198))	('TP53', 'Gene', (236, 240))	('medulloblastoma', 'Disease', (203, 218))	('mutations', 'Var', (241, 250))
17473	26091668	In conclusion, we have shown that IDH and grade define four distinct groups of 1p/19q non-co-deleted gliomas determined by functionally important CNAs and unique prognostic factors.	('1p/19q non-co-deleted', 'Var', (79, 100))	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
17474	26091668	IDHwt lower grade gliomas and grade IV gliomas are closely related and driven by common and well known alterations including EGFR amplification and PTEN deletion, while IDHmut lower grade gliomas remain functionally distinct from grade IV gliomas.	('PTEN', 'Gene', (148, 152))	('deletion', 'Var', (153, 161))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('IDH', 'Gene', '3417', (169, 172))	('IDH', 'Gene', (0, 3))	('PTEN', 'Gene', '5728', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('EGFR', 'Gene', '1956', (125, 129))	('amplification', 'Var', (130, 143))	('IV gliomas', 'Disease', (236, 246))	('IV gliomas', 'Disease', 'MESH:D005910', (236, 246))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('gliomas', 'Disease', (18, 25))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', (239, 246))	('IV gliomas', 'Disease', (36, 46))	('IV gliomas', 'Disease', 'MESH:D005910', (36, 46))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('IDH', 'Gene', (169, 172))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('gliomas', 'Disease', (39, 46))	('EGFR', 'Gene', (125, 129))	('gliomas', 'Disease', (188, 195))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
17475	26091668	The transition of IDHmut lower grade gliomas to grade IV gliomas involves loss of PTEN and dysregulation of cell cycle regulators, in addition to an apparent higher frequency of chromosomal instability and/or chromothripsis.	('IDH', 'Gene', (18, 21))	('dysregulation', 'MPA', (91, 104))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('IDH', 'Gene', '3417', (18, 21))	('loss', 'NegReg', (74, 78))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('IV gliomas', 'Disease', (54, 64))	('IV gliomas', 'Disease', 'MESH:D005910', (54, 64))	('PTEN', 'Gene', (82, 86))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (57, 64))	('PTEN', 'Gene', '5728', (82, 86))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('chromosomal instability', 'Var', (178, 201))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('chromothripsis', 'Disease', (209, 223))
17494	25050814	Loss of PTEN, amplification of EGFR and alterations of TP53, PDGFRA and CDKN2A/P16 are frequently found to be associated with GBM pathogenesis.	('GBM', 'Disease', (126, 129))	('EGFR', 'Gene', '1956', (31, 35))	('TP53', 'Gene', '7157', (55, 59))	('CDKN2A', 'Gene', '1029', (72, 78))	('TP53', 'Gene', (55, 59))	('PTEN', 'Gene', (8, 12))	('P16', 'Gene', (79, 82))	('EGFR', 'Gene', (31, 35))	('alterations', 'Var', (40, 51))	('Loss', 'NegReg', (0, 4))	('associated', 'Reg', (110, 120))	('PTEN', 'Gene', '5728', (8, 12))	('P16', 'Gene', '1029', (79, 82))	('PDGFRA', 'Gene', (61, 67))	('PDGFRA', 'Gene', '5156', (61, 67))	('CDKN2A', 'Gene', (72, 78))	('amplification', 'Var', (14, 27))
17540	25050814	Highest positive correlations ( Figure 2C  , red) were found to occur between HBA and HBD; CN37 and TBA1B; CN37 and LDHB; ALDOC and ESTD; CN37 and DEST; CN37 and RAN; ALDOC and NFM; TBA1B and DEST.	('ALDOC', 'Gene', '230', (122, 127))	('HBD', 'Gene', '100187828', (86, 89))	('RAN', 'Gene', '5901', (162, 165))	('ALDOC', 'Gene', (122, 127))	('NFM', 'Gene', (177, 180))	('ALDOC', 'Gene', '230', (167, 172))	('HBD', 'Gene', (86, 89))	('NFM', 'Gene', '4741', (177, 180))	('CN37', 'Gene', (107, 111))	('CN37', 'Var', (138, 142))	('TBA1B', 'Gene', (100, 105))	('ALDOC', 'Gene', (167, 172))	('CN37', 'Gene', (91, 95))	('RAN', 'Gene', (162, 165))	('HBA', 'Gene', (78, 81))	('LDHB', 'Gene', (116, 120))	('LDHB', 'Gene', '3945', (116, 120))	('CN37', 'Var', (153, 157))	('HBA', 'Gene', '85340', (78, 81))
17594	25050814	Huntingtin, whose mutations are responsible for the neurodegenerative disorders of Huntington's disease, is found in neurites and at synapses, has anti-apoptotic functions and is neuroprotective in brain cells exposed to apoptotic stimuli, such as serum deprivation, mitochondrial toxins or death-inducing genes.	('neurites', 'Disease', 'MESH:D058225', (117, 125))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (52, 79))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (52, 79))	('neurodegenerative disorders', 'Disease', (52, 79))	('anti-apoptotic functions', 'CPA', (147, 171))	('neurites', 'Disease', (117, 125))	('Huntingtin', 'Gene', (0, 10))	('Huntingtin', 'Gene', '3064', (0, 10))	("Huntington's disease", 'Disease', (83, 103))	("Huntington's disease", 'Disease', 'MESH:D006816', (83, 103))	('mutations', 'Var', (18, 27))
17595	25050814	Notably, pathogenic Huntingtin affects the expression, redox state, disulfide bonding of antioxidant proteins identified here, among them SODC, and PRDX2, together with PRDXI, thus supporting a shared functional link.	('PRDX2', 'Gene', '7001', (148, 153))	('Huntingtin', 'Gene', '3064', (20, 30))	('pathogenic', 'Var', (9, 19))	('Huntingtin', 'Gene', (20, 30))	('PRDX2', 'Gene', (148, 153))	('disulfide bonding', 'MPA', (68, 85))	('affects', 'Reg', (31, 38))	('expression', 'MPA', (43, 53))	('redox state', 'MPA', (55, 66))	('disulfide', 'Chemical', 'MESH:D004220', (68, 77))
17599	25050814	Both HNF4alpha and c-Myc proteins compete for control of the P21/CDKN1A gene transcription, and deletion of HNF4A in hepatocellular carcinoma cells results in significant up-regulation of c-Myc and enhanced cell proliferation rates.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (117, 141))	('P21', 'Gene', '1026', (61, 64))	('c-Myc', 'Gene', '4609', (19, 24))	('P21', 'Gene', (61, 64))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (117, 141))	('HNF4alpha', 'Gene', (5, 14))	('HNF4alpha', 'Gene', '3172', (5, 14))	('enhanced', 'PosReg', (198, 206))	('CDKN1A', 'Gene', (65, 71))	('CDKN1A', 'Gene', '1026', (65, 71))	('cell proliferation rates', 'CPA', (207, 231))	('hepatocellular carcinoma', 'Disease', (117, 141))	('HNF4A', 'Gene', '3172', (108, 113))	('HNF4A', 'Gene', (108, 113))	('up-regulation', 'PosReg', (171, 184))	('c-Myc', 'Gene', (188, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('deletion', 'Var', (96, 104))	('c-Myc', 'Gene', (19, 24))	('c-Myc', 'Gene', '4609', (188, 193))
17601	25050814	Deregulation of MYC is a frequent driver of cancer.	('MYC', 'Gene', '4609', (16, 19))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('MYC', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
17609	25050814	Glioma development is frequently associated with mutations of the isocitrate dehydrogenase IDH1 and IDH2 genes, whereas mutations of IDH3 have never been observed in GBM.	('IDH', 'Gene', (100, 103))	('IDH', 'Gene', '3417', (133, 136))	('IDH', 'Gene', '3417', (91, 94))	('mutations', 'Var', (49, 58))	('citrate', 'Chemical', 'MESH:D019343', (69, 76))	('IDH', 'Gene', '3417', (100, 103))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH1', 'Gene', (91, 95))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('IDH2', 'Gene', (100, 104))	('IDH', 'Gene', (91, 94))	('associated', 'Reg', (33, 43))	('Glioma', 'Disease', (0, 6))	('IDH1', 'Gene', '3417', (91, 95))	('IDH', 'Gene', (133, 136))	('IDH2', 'Gene', '3418', (100, 104))
17610	25050814	Our analysis discovered IDH3A quantitative variations in low-grade samples versus high-grade tumors.	('IDH3A', 'Gene', '3419', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('IDH3A', 'Gene', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('variations', 'Var', (43, 53))
17619	25050814	GBM type II are linked to mutations of TP53, whereas GBM type I are thought to be driven by EGFR amplification/disregulation.	('mutations', 'Var', (26, 35))	('GBM type II', 'Disease', (0, 11))	('TP53', 'Gene', '7157', (39, 43))	('linked', 'Reg', (16, 22))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('TP53', 'Gene', (39, 43))
17649	23862163	For example, mutations of the gene encoding isocitrate dehydrogenase 1 (IDH1) are very common in low-grade astrocytomas, anaplastic astrocytomas, oligodendrogliomas, anaplastic oligodendrogliomas, and secondary glioblastomas but very rare in de novo glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (250, 262))	('common', 'Reg', (87, 93))	('astrocytomas', 'Disease', 'MESH:D001254', (107, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('glioblastoma', 'Disease', (211, 223))	('glioblastoma', 'Disease', (250, 262))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('IDH1', 'Gene', (72, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('oligodendrogliomas', 'Disease', (146, 164))	('glioblastomas', 'Disease', (211, 224))	('oligodendrogliomas', 'Disease', (177, 195))	('isocitrate dehydrogenase 1', 'Gene', (44, 70))	('isocitrate dehydrogenase 1', 'Gene', '3417', (44, 70))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (250, 262))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('astrocytomas', 'Disease', (132, 144))	('glioblastomas', 'Disease', 'MESH:D005909', (211, 224))	('IDH1', 'Gene', '3417', (72, 76))	('mutations', 'Var', (13, 22))	('astrocytomas', 'Disease', (107, 119))	('astrocytomas', 'Disease', 'MESH:D001254', (132, 144))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (166, 195))	('anaplastic oligodendrogliomas', 'Disease', (166, 195))	('glioblastomas', 'Phenotype', 'HP:0012174', (211, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (132, 143))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (146, 164))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (177, 195))	('glioblastoma', 'Disease', 'MESH:D005909', (211, 223))
17651	23862163	In addition to mutations of IDH1, low-grade astrocytomas usually have TP53 mutation while oligodendrogliomas typically show 1p/19q loss.	('astrocytoma', 'Phenotype', 'HP:0009592', (44, 55))	('oligodendrogliomas', 'Disease', (90, 108))	('astrocytomas', 'Disease', (44, 56))	('IDH1', 'Gene', '3417', (28, 32))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (90, 108))	('TP53', 'Gene', (70, 74))	('astrocytomas', 'Disease', 'MESH:D001254', (44, 56))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH1', 'Gene', (28, 32))
17652	23862163	The most common genetic alteration in de novo glioblastomas is loss of heterozygosity (LOH) on chromosome 10.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('glioblastomas', 'Disease', (46, 59))	('loss of heterozygosity', 'Var', (63, 85))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('rat', 'Species', '10116', (28, 31))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))
17725	23862163	Until recently, advances in molecular biology have shed light on the development of anti-VEGF monoclonal antibodies as a novel therapy for high-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('anti-VEGF', 'Var', (84, 93))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
17760	33614475	Utilizing mass cytometry (CyTOF), we performed an analysis of immune cells from 5 patients with anaplastic astrocytoma, IDH-mutant (AAmut) and 10 patients with anaplastic oligodendroglioma, IDH-mutant and 1p/19q codeletion (AOD) and their paired peripheral blood mononuclear cells (PBMCs).	('anaplastic oligodendroglioma', 'Disease', (160, 188))	('IDH', 'Gene', '3417', (120, 123))	('patients', 'Species', '9606', (82, 90))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (96, 118))	('IDH', 'Gene', (190, 193))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (160, 188))	('1p/19q', 'Var', (205, 211))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('IDH', 'Gene', '3417', (190, 193))	('patients', 'Species', '9606', (146, 154))	('IDH', 'Gene', (120, 123))	('anaplastic astrocytoma', 'Disease', (96, 118))
17767	33614475	Based on the mutation of isocitrate dehydrogenase (IDH) and the codeletion of chromosome 1p/19q, AGs can be divided into three main distinct subgroups: 1) anaplastic astrocytoma, IDH-mutant (AAmut); 2) anaplastic astrocytoma IDH-wild-type (AAwt); and 3) anaplastic oligodendroglioma, IDH-mutant and 1p/19q codeletion (AOD).	('anaplastic astrocytoma', 'Disease', (202, 224))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (254, 282))	('IDH', 'Gene', '3417', (179, 182))	('IDH', 'Gene', '3417', (51, 54))	('IDH', 'Gene', '3417', (225, 228))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (155, 177))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('anaplastic oligodendroglioma', 'Disease', (254, 282))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (202, 224))	('IDH', 'Gene', (284, 287))	('isocitrate dehydrogenase', 'Gene', '3417', (25, 49))	('astrocytoma', 'Phenotype', 'HP:0009592', (213, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('IDH', 'Gene', '3417', (284, 287))	('anaplastic astrocytoma', 'Disease', (155, 177))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', (51, 54))	('mutation', 'Var', (13, 21))	('1p/19q codeletion', 'Var', (299, 316))	('IDH', 'Gene', (225, 228))	('isocitrate dehydrogenase', 'Gene', (25, 49))
17837	33614475	It has been reported that the prognosis between WHO grade III AAmuts and AODs is significantly different, and AOD patients have a better overall survival time than AAmuts patients.	('better', 'PosReg', (130, 136))	('AODs', 'Disease', (73, 77))	('patients', 'Species', '9606', (171, 179))	('AOD', 'Var', (110, 113))	('patients', 'Species', '9606', (114, 122))	('AODs', 'Disease', 'None', (73, 77))
17849	33221817	Current biomarker-associated procedures of cancer modeling-a reference in the context of IDH1 mutant glioma Isocitrate dehydrogenases (IDH1/2) are central molecular markers for glioblastoma.	('glioblastoma', 'Disease', (177, 189))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('IDH1', 'Gene', (135, 139))	('cancer', 'Disease', (43, 49))	('glioma', 'Disease', (101, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (177, 189))	('mutant', 'Var', (94, 100))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1/2', 'Gene', '3417;3418', (135, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('IDH1', 'Gene', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH1/2', 'Gene', (135, 141))	('IDH1', 'Gene', '3417', (89, 93))
17850	33221817	Providing in vitro or in vivo models with mutated IDH1/2 can help prepare facilities to understand the biology of these mutated genes as glioma markers, as well as help, improve therapeutic strategies.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('mutated', 'Var', (42, 49))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('IDH1/2', 'Gene', (50, 56))	('glioma', 'Disease', (137, 143))	('IDH1/2', 'Gene', '3417;3418', (50, 56))
17851	33221817	In this review, we first summarize the biology principles of IDH and its mutations and outline the core primary findings in the clinical context of neuro-oncology.	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))	('mutations', 'Var', (73, 82))	('oncology', 'Phenotype', 'HP:0002664', (154, 162))
17854	33221817	Mutations in IDH genes represent the first central genomic markers to guide clinical diagnosis in neuro-oncology.	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', '3417', (13, 16))	('Mutations', 'Var', (0, 9))	('oncology', 'Phenotype', 'HP:0002664', (104, 112))
17855	33221817	The involvement of IDH mutations in various processes of glioma cell biology opens an opportunity for new treatment and diagnostic strategies, with several clinical trials underway.	('glioma', 'Disease', (57, 63))	('mutations', 'Var', (23, 32))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', (19, 22))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('involvement', 'Reg', (4, 15))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
17859	33221817	Since IDH1 mutations occur in other cancers than brain tumor, can the progress of understanding the glioma IDH1 mutation cell biology translate into tumor-agnostic approaches?	('glioma', 'Disease', (100, 106))	('mutations', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('IDH1', 'Gene', '3417', (107, 111))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('brain tumor', 'Phenotype', 'HP:0030692', (49, 60))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('brain tumor', 'Disease', 'MESH:D001932', (49, 60))	('brain tumor', 'Disease', (49, 60))	('IDH1', 'Gene', (6, 10))	('IDH1', 'Gene', '3417', (6, 10))	('IDH1', 'Gene', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
17860	33221817	Mutations in the DNA encoding for isocitrate dehydrogenases (IDH) mutations are recognized as one of the main molecular markers in 70-80% of stage II or III astrocytomas, oligodendrogliomas, and secondary GBMs, as opposed to primary tumors.	('mutations', 'Var', (66, 75))	('DNA', 'Gene', (17, 20))	('isocitrate', 'Chemical', 'MESH:C034219', (34, 44))	('III astrocytomas', 'Disease', (153, 169))	('IDH', 'Gene', '3417', (61, 64))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (171, 189))	('tumors', 'Disease', (233, 239))	('secondary GBMs', 'Disease', (195, 209))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('oligodendrogliomas', 'Disease', (171, 189))	('Mutations', 'Var', (0, 9))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('III astrocytomas', 'Disease', 'MESH:D001254', (153, 169))	('IDH', 'Gene', (61, 64))
17861	33221817	In the WHO classification, expressions of mutated IDH1/2, TP53, chromatin remodeling, and a loss of alpha-thalassemia/mental retardation, X-linked (ATRX) has been seen in astrocytoma.	('astrocytoma', 'Disease', (171, 182))	('mutated', 'Var', (42, 49))	('mental retardation', 'Phenotype', 'HP:0001249', (118, 136))	('IDH1/2', 'Gene', (50, 56))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (171, 182))	('loss', 'NegReg', (92, 96))	('alpha-thalassemia/mental retardation, X-linked (ATRX)', 'Gene', '546', (100, 153))	('alpha-thalassemia/mental retardation, X-linked (ATRX', 'Gene', (100, 152))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('astrocytoma', 'Disease', 'MESH:D001254', (171, 182))
17862	33221817	In contrast, oligodendrogliomas carry mutated IDH1/2 cells associated with 1p/19q co-deletion and TERT promoter mutations.	('mutated', 'Var', (38, 45))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('TERT', 'Gene', (98, 102))	('IDH1/2', 'Gene', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (13, 31))	('TERT', 'Gene', '7015', (98, 102))	('oligodendrogliomas', 'Disease', (13, 31))	('IDH1/2', 'Gene', '3417;3418', (46, 52))
17871	33221817	The role of mutated IDH1/2 has been reported in low-grade gliomas (LGG).	('IDH1/2', 'Gene', '3417;3418', (20, 26))	('mutated', 'Var', (12, 19))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1/2', 'Gene', (20, 26))	('reported', 'Reg', (36, 44))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
17872	33221817	According to the authors' knowledge, no study shows the IDH3 mutation related to any kind of cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('IDH', 'Gene', (56, 59))	('mutation', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('IDH', 'Gene', '3417', (56, 59))	('related', 'Reg', (70, 77))
17875	33221817	Mutated IDH1, as a common mutation, was then reported in glioma, acute myeloid leukemia (AML), cholangiocarcinoma, melanoma, and cartilaginous tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('cartilaginous tumors', 'Disease', (129, 149))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('AML', 'Disease', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (71, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (65, 87))	('IDH1', 'Gene', (8, 12))	('glioma', 'Disease', (57, 63))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (129, 149))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (65, 87))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('IDH1', 'Gene', '3417', (8, 12))	('Mutated', 'Var', (0, 7))	('cholangiocarcinoma', 'Disease', (95, 113))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('reported', 'Reg', (45, 53))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('acute myeloid leukemia', 'Disease', (65, 87))
17876	33221817	IDH mutations in gliomas are normally heterozygous missense mutations.	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('gliomas', 'Disease', (17, 24))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('mutations', 'Var', (4, 13))
17877	33221817	In addition to the R132H mutation, other IDH1 mutations in glioma are R132L, R132C, R132G, R132S, R132V, and IDH2-R172K or R140Q which all of these mutations show identical output.	('IDH', 'Gene', (41, 44))	('R132S', 'Mutation', 'rs121913499', (91, 96))	('R132L', 'Mutation', 'rs121913500', (70, 75))	('R132V', 'Var', (98, 103))	('R132G', 'Mutation', 'rs121913499', (84, 89))	('IDH1', 'Gene', '3417', (41, 45))	('R132G', 'Var', (84, 89))	('glioma', 'Disease', (59, 65))	('IDH', 'Gene', '3417', (41, 44))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('IDH', 'Gene', (109, 112))	('R132C', 'Var', (77, 82))	('R132C', 'Mutation', 'rs121913499', (77, 82))	('R140Q', 'Mutation', 'p.R140Q', (123, 128))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('R172K', 'Mutation', 'rs121913503', (114, 119))	('R140Q', 'Var', (123, 128))	('IDH', 'Gene', '3417', (109, 112))	('R132V', 'Mutation', 'p.R132V', (98, 103))	('R132L', 'Var', (70, 75))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('IDH1', 'Gene', (41, 45))	('R132S', 'Var', (91, 96))
17878	33221817	However, a mutation in IDH1 or IDH2 is considered an early event in gliomagenesis; they are not classic oncogenes.	('gliomagenesis', 'Disease', 'None', (68, 81))	('IDH', 'Gene', (31, 34))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (31, 34))	('IDH1', 'Gene', (23, 27))	('gliomagenesis', 'Disease', (68, 81))	('IDH1', 'Gene', '3417', (23, 27))	('mutation', 'Var', (11, 19))	('IDH', 'Gene', '3417', (23, 26))
17879	33221817	It seems that these genes can facilitate pro-oncogene mutations, such as TP53 in IDH1-R132H astrocytoma, or downregulation of the expression of the genes related to immune response, which was observed in IDH1-R132H gliomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('expression', 'MPA', (130, 140))	('R132H', 'Mutation', 'rs121913500', (209, 214))	('TP53', 'Gene', '7157', (73, 77))	('IDH1', 'Gene', (81, 85))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('mutations', 'Var', (54, 63))	('astrocytoma', 'Disease', 'MESH:D001254', (92, 103))	('downregulation', 'NegReg', (108, 122))	('IDH1', 'Gene', '3417', (81, 85))	('astrocytoma', 'Disease', (92, 103))	('IDH1', 'Gene', (204, 208))	('TP53', 'Gene', (73, 77))	('gliomas', 'Disease', (215, 222))	('R132H', 'Mutation', 'rs121913500', (86, 91))	('IDH1', 'Gene', '3417', (204, 208))	('gliomas', 'Disease', 'MESH:D005910', (215, 222))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('facilitate', 'PosReg', (30, 40))
17883	33221817	Any mutation in IDH1 or IDH2 forces the cells to convert a-KG into the D isomer of 2-hydroxyglutarate (D2HG).	('D2HG', 'Chemical', '-', (103, 107))	('convert a-KG', 'MPA', (49, 61))	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', (16, 19))	('mutation', 'Var', (4, 12))	('IDH1', 'Gene', (16, 20))	('IDH', 'Gene', '3417', (24, 27))	('IDH', 'Gene', '3417', (16, 19))	('IDH1', 'Gene', '3417', (16, 20))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (83, 101))
17885	33221817	Among IDH1 mutations, R132H is the most common mutation (90%) in glioma.	('IDH1', 'Gene', '3417', (6, 10))	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('R132H', 'Var', (22, 27))	('common', 'Reg', (40, 46))	('IDH1', 'Gene', (6, 10))	('R132H', 'Mutation', 'rs121913500', (22, 27))
17886	33221817	In this mutation, adenine is replaced with guanine at nucleotide 395 (c.395G>A), which converts to histidine instead of arginine in protein sequencing (p.Arg132His).	('p.Arg132His', 'Var', (152, 163))	('converts', 'Reg', (87, 95))	('c.395G>A', 'Var', (70, 78))	('adenine', 'Chemical', 'MESH:D000225', (18, 25))	('arginine', 'Chemical', 'MESH:D001120', (120, 128))	('histidine', 'Chemical', 'MESH:D006639', (99, 108))	('p.Arg132His', 'Mutation', 'rs121913500', (152, 163))	('guanine', 'Chemical', 'MESH:D006147', (43, 50))	('c.395G>A', 'Mutation', 'rs121913500', (70, 78))
17887	33221817	clarified that this event is due to the fact that human glioma cells with R132G, R132C, and R132S produce higher concentrations of D2HG as compared to those with R132H.	('R132C', 'Mutation', 'rs121913499', (81, 86))	('glioma', 'Disease', (56, 62))	('R132G', 'Var', (74, 79))	('R132H', 'Mutation', 'rs121913500', (162, 167))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('D2HG', 'Chemical', '-', (131, 135))	('higher', 'PosReg', (106, 112))	('R132G', 'Mutation', 'rs121913499', (74, 79))	('R132S', 'Var', (92, 97))	('human', 'Species', '9606', (50, 55))	('D2HG', 'MPA', (131, 135))	('R132C', 'Var', (81, 86))	('R132S', 'Mutation', 'rs121913499', (92, 97))
17888	33221817	A high concentration of D2HG is toxic for the glioma cells and induces biological alternations such as inhibiting the proliferation and migration of these cells.	('D2HG', 'Chemical', '-', (24, 28))	('D2HG', 'Var', (24, 28))	('glioma', 'Disease', (46, 52))	('induces', 'Reg', (63, 70))	('inhibiting', 'NegReg', (103, 113))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
17891	33221817	In addition to glioma cells, D2HG can be found in the non-neoplastic cells around the tumors in the patients carrying IDH1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (123, 131))	('IDH1', 'Gene', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('IDH1', 'Gene', '3417', (118, 122))	('glioma', 'Disease', (15, 21))	('patients', 'Species', '9606', (100, 108))	('D2HG', 'Chemical', '-', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
17892	33221817	detected around 100 mM of D2HG in the circulating cerebrospinal fluid (CSF) of LGG patient.	('LGG', 'Disease', (79, 82))	('circulating cerebrospinal fluid', 'Phenotype', 'HP:0002922', (38, 69))	('patient', 'Species', '9606', (83, 90))	('D2HG', 'Chemical', '-', (26, 30))	('D2HG', 'Var', (26, 30))
17893	33221817	This amount of D2HG can cause oxidative stress, inhibition of expression of pro-apoptotic proteins, reduction of pro-inflammatory signaling, and changing cellular metabolism in these patients.	('reduction', 'NegReg', (100, 109))	('cellular metabolism', 'MPA', (154, 173))	('changing', 'Reg', (145, 153))	('pro-inflammatory signaling', 'MPA', (113, 139))	('cause', 'Reg', (24, 29))	('expression', 'MPA', (62, 72))	('oxidative stress', 'Phenotype', 'HP:0025464', (30, 46))	('D2HG', 'Chemical', '-', (15, 19))	('D2HG', 'Var', (15, 19))	('oxidative stress', 'MPA', (30, 46))	('inhibition', 'NegReg', (48, 58))	('patients', 'Species', '9606', (183, 191))
17894	33221817	have shown that the level of the D2HG cells carrying IDH1 mutation depends on the wild-type (wt) allele, however; this level in IDH2 mutated cells is related to the site of mutation.	('IDH', 'Gene', (128, 131))	('IDH1', 'Gene', (53, 57))	('D2HG', 'Chemical', '-', (33, 37))	('mutation', 'Var', (58, 66))	('IDH', 'Gene', '3417', (128, 131))	('IDH1', 'Gene', '3417', (53, 57))	('IDH', 'Gene', (53, 56))	('IDH', 'Gene', '3417', (53, 56))
17899	33221817	A study of DNA-methylation of the patient samples with glioma demonstrated that from 365,092 analyzed CpG sites, 70,591 (19%) were hypermethylated in gliomas carrying IDH1wt/R132H, compared to wild-type gliomas.	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('IDH1', 'Gene', (167, 171))	('patient', 'Species', '9606', (34, 41))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('gliomas', 'Disease', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('IDH1', 'Gene', '3417', (167, 171))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('R132H', 'Mutation', 'rs121913500', (174, 179))	('gliomas', 'Disease', (150, 157))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Disease', (55, 61))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Disease', (203, 209))	('hypermethylated', 'Var', (131, 146))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
17900	33221817	The ratio of hypermethylation changes during differentiation leads to suppression of tissue development and differentiation of glioma cells.	('suppression', 'NegReg', (70, 81))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('differentiation', 'CPA', (108, 123))	('tissue development', 'CPA', (85, 103))	('glioma', 'Disease', (127, 133))	('hypermethylation', 'Var', (13, 29))
17901	33221817	In addition, this mutation can hypermethylate and modify important glioma-related genes, such as EGFR and PDGFRA.	('PDGFRA', 'Gene', '5156', (106, 112))	('glioma', 'Disease', (67, 73))	('EGFR', 'Gene', '1956', (97, 101))	('modify', 'Reg', (50, 56))	('hypermethylate', 'Var', (31, 45))	('EGFR', 'Gene', (97, 101))	('mutation', 'Var', (18, 26))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('PDGFRA', 'Gene', (106, 112))
17902	33221817	On the other hand, IDH1Mut decreases self-renewal and proliferation rate in vitro and in vivo in glioma cells.	('self-renewal', 'CPA', (37, 49))	('decreases', 'NegReg', (27, 36))	('glioma', 'Disease', (97, 103))	('proliferation rate', 'CPA', (54, 72))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH1Mut', 'Var', (19, 26))
17903	33221817	This can be explained by hypermethylation and downregulation of PROM1 that encodes for CD133, the bona fide stem cell marker of glioma.	('CD133', 'Gene', (87, 92))	('downregulation', 'NegReg', (46, 60))	('hypermethylation', 'Var', (25, 41))	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('PROM1', 'Gene', (64, 69))	('PROM1', 'Gene', '8842', (64, 69))
17906	33221817	IDH1Mut inhibits the PIK3/AKT signaling in human glioma cells.	('IDH1Mut', 'Var', (0, 7))	('human', 'Species', '9606', (43, 48))	('inhibits', 'NegReg', (8, 16))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('PIK3', 'Gene', '5294', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('PIK3', 'Gene', (21, 25))	('glioma', 'Disease', (49, 55))
17912	33221817	have revealed that overexpression of the P53 mutation can rescue these dysfunctions.	('P53', 'Gene', (41, 44))	('mutation', 'Var', (45, 53))	('P53', 'Gene', '7157', (41, 44))
17916	33221817	Downregulation of PDPN has been observed in glioma carrying IDH1 mutations, which can increase chances for survival in patients carrying IDH1Mut .	('PDPN', 'Gene', '10630', (18, 22))	('IDH1', 'Gene', (60, 64))	('Downregulation', 'NegReg', (0, 14))	('PDPN', 'Gene', (18, 22))	('patients', 'Species', '9606', (119, 127))	('IDH1', 'Gene', (137, 141))	('glioma', 'Disease', (44, 50))	('IDH1', 'Gene', '3417', (60, 64))	('IDH1', 'Gene', '3417', (137, 141))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('mutations', 'Var', (65, 74))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
17917	33221817	Moreover, an IDH1Mut enhances AKT/mTOR activity.	('mTOR', 'Gene', '2475', (34, 38))	('IDH1Mut', 'Var', (13, 20))	('enhances', 'PosReg', (21, 29))	('mTOR', 'Gene', (34, 38))
17919	33221817	The IDH1 mutation, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p 19q deletion have been introduced as markers for a low-grade glioma, anaplastic oligoastrocytoma, and glioblastoma, respectively, to predict sensitivity to chemotherapy and develop the appropriate prognosis.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('anaplastic oligoastrocytoma', 'Disease', (163, 190))	('astrocytoma', 'Phenotype', 'HP:0009592', (179, 190))	('glioblastoma', 'Disease', (196, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (196, 208))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('MGMT', 'Gene', '4255', (59, 63))	('O6-methylguanine-DNA methyltransferase', 'Gene', (19, 57))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('IDH1', 'Gene', (4, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('MGMT', 'Gene', (59, 63))	('anaplastic oligoastrocytoma', 'Disease', 'MESH:D001254', (163, 190))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (19, 57))	('glioma', 'Disease', (155, 161))
17922	33221817	concluded that IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations mostly occur in oligodendroglial tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('IDH', 'Gene', '3417', (96, 99))	('IDH1', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('IDH1', 'Gene', '3417', (15, 19))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (127, 150))	('IDH', 'Gene', '3417', (15, 18))	('IDH', 'Gene', (15, 18))	('oligodendroglial tumors', 'Disease', (127, 150))	('R132C', 'Mutation', 'rs121913499', (37, 42))	('astrocytoma', 'Phenotype', 'HP:0009592', (77, 88))	('astrocytoma', 'Disease', 'MESH:D001254', (77, 88))	('R132C', 'Var', (37, 42))	('associated', 'Reg', (61, 71))	('astrocytoma', 'Disease', (77, 88))	('mutations', 'Var', (20, 29))	('IDH', 'Gene', (96, 99))
17923	33221817	In addition, the IDH1 mutation occurs in younger patients which can be considered a predictor for grades 2 and 3, but not grade 4, glioma with a favorable prognosis, especially with radiation or alkylating therapy.	('glioma', 'Disease', (131, 137))	('mutation', 'Var', (22, 30))	('IDH1', 'Gene', (17, 21))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('patients', 'Species', '9606', (49, 57))	('IDH1', 'Gene', '3417', (17, 21))
17924	33221817	In this regard, the clinical trial demonstrated that patients with IDH1 mutations in grade 3 have a better response to chemotherapy, although chemo-radiotherapy may have a more positive effect on grades 2 and 3 tumors.	('mutations', 'Var', (72, 81))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('patients', 'Species', '9606', (53, 61))	('IDH1', 'Gene', (67, 71))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('better', 'PosReg', (100, 106))	('IDH1', 'Gene', '3417', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('response', 'MPA', (107, 115))
17925	33221817	IDH1-R132H is expressed in almost all slow-growing tumors, so the preparation of a vaccine targeting mutant IDH1 could be a novel therapeutic assay.	('IDH1', 'Gene', '3417', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('mutant', 'Var', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', (108, 112))	('IDH1', 'Gene', '3417', (0, 4))
17931	33221817	transplanted murine glioma cells containing the IDH1 mutation in the brains of mice and then immunized them to different peptides encompassing the IDH1 mutation.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('mutation', 'Var', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('IDH1', 'Gene', '3417', (48, 52))	('mice', 'Species', '10090', (79, 83))	('murine', 'Species', '10090', (13, 19))	('glioma', 'Disease', (20, 26))	('IDH1', 'Gene', (147, 151))	('IDH1', 'Gene', (48, 52))	('IDH1', 'Gene', '3417', (147, 151))
17933	33221817	It has been shown that increasing the number of T cells may be due to a reduction of the expression of programmed death-ligand 1 (PD-L1) in mutant IDH.	('reduction', 'NegReg', (72, 81))	('IDH', 'Gene', '3417', (147, 150))	('expression', 'MPA', (89, 99))	('programmed death-ligand 1', 'Gene', (103, 128))	('programmed death-ligand 1', 'Gene', '29126', (103, 128))	('PD-L1', 'Gene', (130, 135))	('PD-L1', 'Gene', '29126', (130, 135))	('IDH', 'Gene', (147, 150))	('mutant', 'Var', (140, 146))
17934	33221817	have found that reduction of PD-L1 may not result in a stronger T cell response, because D2HG inhibits ATP-dependent T cell receptor signaling, which in turn leads to suppression of T cell anti-tumor immunity.	('D2HG', 'Chemical', '-', (89, 93))	('PD-L1', 'Gene', (29, 34))	('D2HG', 'Var', (89, 93))	('ATP-dependent T cell receptor signaling', 'MPA', (103, 142))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('T cell response', 'CPA', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('inhibits', 'NegReg', (94, 102))	('PD-L1', 'Gene', '29126', (29, 34))	('tumor', 'Disease', (194, 199))	('ATP', 'Chemical', 'MESH:D000255', (103, 106))	('suppression', 'NegReg', (167, 178))
17937	33221817	There are many studies about the role of IDH1 and R132H mutation in glioma.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('R132H', 'Var', (50, 55))	('IDH1', 'Gene', (41, 45))	('glioma', 'Disease', (68, 74))	('R132H', 'Mutation', 'rs121913500', (50, 55))	('IDH1', 'Gene', '3417', (41, 45))
17938	33221817	However, a more complete understanding of the contribution of this mutation in tumorigenesis, the identification of interconnecting pathways, and the exploitation of IDHMut-associated molecular and cellular alterations for diagnostic and therapeutic strategies have been hindered largely due to the lack of an appropriate model.	('mutation', 'Var', (67, 75))	('tumor', 'Disease', (79, 84))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', '3417', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
17944	33221817	Glioma models carrying the IDH1Mut, in vitro, can be based on the establishment of primary patient cells or generating IDH1 mutated cell lines via gene engineering or editing.	('mutated', 'Var', (124, 131))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH1', 'Gene', (119, 123))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('IDH1', 'Gene', '3417', (119, 123))	('IDH1', 'Gene', (27, 31))	('patient', 'Species', '9606', (91, 98))	('IDH1', 'Gene', '3417', (27, 31))
17949	33221817	Sequencing of the genome of U87 revealed an enormous number of indels, copy number variations, and translocations, which are most likely due to the condition of the serum culture.	('U87', 'Gene', '641648', (28, 31))	('copy number variations', 'Var', (71, 93))	('translocations', 'Var', (99, 113))	('indels', 'Var', (63, 69))	('U87', 'Gene', (28, 31))
17952	33221817	U87 and U251 have also been used to overexpress IDH1 wt and R132H, as well as to study the mechanism in glioma and the behavior of the cells.	('R132H', 'Mutation', 'rs121913500', (60, 65))	('U87', 'Gene', '641648', (0, 3))	('IDH1', 'Gene', '3417', (48, 52))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('R132H', 'Var', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('IDH1', 'Gene', (48, 52))	('U87', 'Gene', (0, 3))	('overexpress', 'PosReg', (36, 47))	('glioma', 'Disease', (104, 110))
17954	33221817	Overexpressed IDH1-R132H cells were more sensitive to 5-FU, meaning that this medication could increase apoptosis in mutated IDH1 due to the decreasing expression of NADPH and CGH as antioxidants.	('mutated', 'Var', (117, 124))	('increase', 'PosReg', (95, 103))	('IDH1', 'Gene', '3417', (125, 129))	('decreasing', 'NegReg', (141, 151))	('NADPH', 'Gene', (166, 171))	('NADPH', 'Gene', '1666', (166, 171))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('IDH1', 'Gene', (14, 18))	('apoptosis', 'CPA', (104, 113))	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))	('expression', 'MPA', (152, 162))	('IDH1', 'Gene', (125, 129))	('IDH1', 'Gene', '3417', (14, 18))
17955	33221817	also overexpressed IDH1 Wt and R132H (ligated in pLenti6.3-MCS-IRES2-EGFP) by lentivirus in the U87 and U251 cell lines and showed the correlation between IDH1 mutations and B-catenin/Wnt pathways.	('IDH1', 'Gene', (155, 159))	('mutations', 'Var', (160, 169))	('correlation', 'Reg', (135, 146))	('IDH1', 'Gene', '3417', (155, 159))	('IDH1', 'Gene', (19, 23))	('R132H', 'Var', (31, 36))	('R132H', 'Mutation', 'rs121913500', (31, 36))	('B-catenin', 'Gene', '1499', (174, 183))	('B-catenin', 'Gene', (174, 183))	('overexpressed', 'PosReg', (5, 18))	('IDH1', 'Gene', '3417', (19, 23))	('EGF', 'Gene', (69, 72))	('U87', 'Gene', (96, 99))	('EGF', 'Gene', '1950', (69, 72))	('U87', 'Gene', '641648', (96, 99))
17957	33221817	Overexpression of Wnt/beta-Catenin in U87-IDH1-R132H and tumor samples carrying the R132H mutation restored a decline of proliferation and a high apoptosis ratio, reducing both invasion and migration in vitro and in vivo in the mutated cells.	('R132H', 'Mutation', 'rs121913500', (84, 89))	('decline', 'NegReg', (110, 117))	('invasion', 'CPA', (177, 185))	('migration', 'CPA', (190, 199))	('IDH1', 'Gene', '3417', (42, 46))	('proliferation', 'CPA', (121, 134))	('U87', 'Gene', '641648', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('beta-Catenin', 'Gene', (22, 34))	('R132H', 'Var', (84, 89))	('beta-Catenin', 'Gene', '1499', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('reducing', 'NegReg', (163, 171))	('IDH1', 'Gene', (42, 46))	('tumor', 'Disease', (57, 62))	('U87', 'Gene', (38, 41))	('R132H', 'Mutation', 'rs121913500', (47, 52))	('apoptosis ratio', 'CPA', (146, 161))
17958	33221817	They concluded that mutant IDH1 can play an anti-tumor role in glioma.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('mutant', 'Var', (20, 26))	('glioma', 'Disease', (63, 69))
17962	33221817	tried to expand primary glioma cells carrying IDH1 mutations.	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('mutations', 'Var', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('glioma', 'Disease', (24, 30))
17963	33221817	They reported that glioma cells with IDH1 mutations cannot be cultured in vitro because of their death in standard cell culture condition.	('IDH1', 'Gene', (37, 41))	('glioma', 'Disease', (19, 25))	('IDH1', 'Gene', '3417', (37, 41))	('death', 'Disease', 'MESH:D003643', (97, 102))	('death', 'Disease', (97, 102))	('mutations', 'Var', (42, 51))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
17964	33221817	The neurosphere assay is the gold standard for keeping stem cells in brain tissue and can help achieve better cultivation of mutant IDH glioma cells.	('mutant', 'Var', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('IDH glioma', 'Disease', 'MESH:D005910', (132, 142))	('IDH glioma', 'Disease', (132, 142))
17970	33221817	They could generate organoids for 96.4% IDH1-wt and 66.7% with IDH1 mutations for over 48 weeks with a similar gene expression of parental tumor markers.	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mutations', 'Var', (68, 77))	('parental tumor', 'Disease', (130, 144))	('IDH1', 'Gene', (63, 67))	('parental tumor', 'Disease', 'MESH:D063129', (130, 144))
17971	33221817	Although they were successful in generating and testing glioma cells derived from patients, the efficiency for mutated IDH1 was low in comparison to LGG with IDH1 wt.	('IDH1', 'Gene', '3417', (119, 123))	('glioma', 'Disease', (56, 62))	('mutated', 'Var', (111, 118))	('patients', 'Species', '9606', (82, 90))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH1', 'Gene', (119, 123))	('IDH1', 'Gene', (158, 162))	('low', 'NegReg', (128, 131))	('IDH1', 'Gene', '3417', (158, 162))
17972	33221817	They concluded that more optimization is required to establish IDH1 mutated organoids.	('mutated', 'Var', (68, 75))	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (63, 67))
17974	33221817	overexpressed Yamanaka's transcription factors in LGG cells BTO1 (carrying the R132C mutation), BTO3 (carrying the R132H mutation), and BT-142 (ATCC #ACS-1018) that originated from a grade III oligoastrocytoma carrying the mono-allelic R132H mutation.	('R132C', 'Var', (79, 84))	('R132C', 'Mutation', 'rs121913499', (79, 84))	('R132H', 'Var', (115, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (198, 209))	('R132H', 'Mutation', 'rs121913500', (115, 120))	('R132H', 'Var', (236, 241))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (193, 209))	('oligoastrocytoma', 'Disease', (193, 209))	('R132H', 'Mutation', 'rs121913500', (236, 241))
17975	33221817	Their results demonstrate that cells containing the IDH1 mutation are resistant to reprogramming.	('mutation', 'Var', (57, 65))	('IDH1', 'Gene', '3417', (52, 56))	('IDH1', 'Gene', (52, 56))
17976	33221817	Their explanation is the high sensitivity of the pluripotent stem cells to D2HG because when human embryonic stem cells (hESCs) were treated with D2HG for 24 h, the hESCs could not tolerate D2HG and die.	('D2HG', 'Chemical', '-', (146, 150))	('D2HG', 'Var', (146, 150))	('human', 'Species', '9606', (93, 98))	('D2HG', 'Chemical', '-', (190, 194))	('not', 'NegReg', (177, 180))	('die', 'CPA', (199, 202))	('D2HG', 'Chemical', '-', (75, 79))
17977	33221817	Analysis of tumor cells derived from LGG samples in a serum-free medium showed that they carry Xq23, 7q31 amplification, 1p 19q deletion, and the IDH1Mut, from which it can be concluded that these amplifications or deletions in primary patient cells carrying the IDH1Mut are perhaps early mutational events associated with the manifestation of the IDH1Mut.	('deletions', 'Var', (215, 224))	('IDH1Mut', 'Gene', (263, 270))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('amplifications', 'Var', (197, 211))	('patient', 'Species', '9606', (236, 243))
17978	33221817	Cell lines expressing mutated IDH1 can be generated by gene targeting methods such as zinc finger (ZFN), TALEN (Transcription activator-like effector nuclease), or clustered, regularly interspaced short palindromic repeats (CRISPR) or by overexpressing of wild-type and IDH1-R132H in various cell lines.	('IDH1', 'Gene', (270, 274))	('R132H', 'Mutation', 'rs121913500', (275, 280))	('mutated', 'Var', (22, 29))	('IDH1', 'Gene', (30, 34))	('IDH1', 'Gene', '3417', (270, 274))	('IDH1', 'Gene', '3417', (30, 34))
17979	33221817	The background of different experimental strategies, such as cellular background, mutation strategy, model validation, and core principal observations to model gliomas carrying the IDH1 mutation is summarized in Tables 2-4, respectively.	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('gliomas', 'Disease', (160, 167))	('IDH1', 'Gene', (181, 185))	('mutation', 'Var', (186, 194))	('IDH1', 'Gene', '3417', (181, 185))
17982	33221817	They induced hiPSC-NPCs by a lentiviral construct containing the R132H mutation under the EF1 promoter.	('hiPSC-NPCs', 'Disease', 'None', (13, 23))	('R132H', 'Mutation', 'rs121913500', (65, 70))	('induced', 'Reg', (5, 12))	('hiPSC-NPCs', 'Disease', (13, 23))	('R132H', 'Var', (65, 70))
17986	33221817	demonstrated that induction of immortalized human astrocytes (by pLNCX2in packaged in lentivirus) to overexpress IDH1-wt and R132H can reshape methylome in the induced cells but in two different manners.	('human', 'Species', '9606', (44, 49))	('methylome', 'MPA', (143, 152))	('IDH1', 'Gene', (113, 117))	('R132H', 'Var', (125, 130))	('IDH1', 'Gene', '3417', (113, 117))	('R132H', 'Mutation', 'rs121913500', (125, 130))	('overexpress', 'PosReg', (101, 112))	('reshape', 'Reg', (135, 142))
17988	33221817	They showed histone modification, such as hypermethylation of H3K9me2, H3K27me3 involved in hypermethylation of DNA, and declination of TET2-dependent 5-hydroxymethylcytosine (5hmC) levels.	('5hmC', 'Chemical', 'MESH:C011865', (176, 180))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (151, 174))	('hypermethylation', 'Var', (42, 58))	('H3K9me2', 'Protein', (62, 69))	('H3K27me3', 'Var', (71, 79))	('hypermethylation', 'MPA', (92, 108))	('TET2', 'Gene', '54790', (136, 140))	('declination', 'MPA', (121, 132))	('TET2', 'Gene', (136, 140))	('involved', 'Reg', (80, 88))
17991	33221817	This result not only emphasized the effect of heterozygosity of IDH1 in D2HG production but also confirmed that the IDH1 mutation in glioma can have an anti-oncogenic role, which is an early phenomenon in glioma development.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('anti-oncogenic role', 'CPA', (152, 171))	('D2HG', 'Chemical', '-', (72, 76))	('IDH1', 'Gene', (64, 68))	('glioma', 'Disease', (205, 211))	('IDH1', 'Gene', (116, 120))	('IDH1', 'Gene', '3417', (64, 68))	('glioma', 'Disease', (133, 139))	('mutation', 'Var', (121, 129))	('IDH1', 'Gene', '3417', (116, 120))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
17992	33221817	New recombinant genomic techniques, TALEN and CRISPR, have been used to generate IDH1 mutant cell lines or study the behavior of IDH1 mut.	('IDH1', 'Gene', (129, 133))	('mutant', 'Var', (86, 92))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', '3417', (81, 85))
17994	33221817	In this regard, many metabolic enzymes were downregulated via hypermethylation of the promoter, including acyl-CoA dehydrogenase (ACADS), Aldehyde Dehydrogenase 2 Family (ALDH2), and Aldehyde Oxidase 1 (AOX1), indicating the involvement of IDH1 in multiple energy pathways.	('IDH1', 'Gene', '3417', (240, 244))	('acyl-CoA dehydrogenase', 'Gene', (106, 128))	('Aldehyde Oxidase 1', 'Gene', (183, 201))	('AOX1', 'Gene', (203, 207))	('hypermethylation', 'Var', (62, 78))	('downregulated', 'NegReg', (44, 57))	('acyl-CoA dehydrogenase', 'Gene', '35', (106, 128))	('ACADS', 'Gene', '35', (130, 135))	('Aldehyde Oxidase 1', 'Gene', '316', (183, 201))	('AOX1', 'Gene', '316', (203, 207))	('ACADS', 'Gene', (130, 135))	('IDH1', 'Gene', (240, 244))	('metabolic enzymes', 'Enzyme', (21, 38))
17995	33221817	In addition, they showed that hypermethylation of the promoter can lead to histone modification and declination of histone markers such as H3K27me3, H3K36me3, and H3K4me3 in IDH1-R132H cells.	('declination', 'MPA', (100, 111))	('lead to', 'Reg', (67, 74))	('R132H', 'Mutation', 'rs121913500', (179, 184))	('IDH1', 'Gene', '3417', (174, 178))	('H3K27me3', 'Var', (139, 147))	('IDH1', 'Gene', (174, 178))	('H3K4me3', 'Var', (163, 170))	('histone modification', 'MPA', (75, 95))	('hypermethylation', 'Var', (30, 46))	('H3K36me3', 'Var', (149, 157))
17996	33221817	also demonstrated increasing migration of cells by upregulation of integrin beta4 (ITGB4) and inhibition of the proliferation of mutant cells.	('upregulation', 'PosReg', (51, 63))	('inhibition', 'NegReg', (94, 104))	('ITGB4', 'Gene', (83, 88))	('ITGB4', 'Gene', '3691', (83, 88))	('integrin beta4', 'Gene', '3691', (67, 81))	('integrin beta4', 'Gene', (67, 81))	('migration of cells', 'CPA', (29, 47))	('proliferation', 'CPA', (112, 125))	('increasing', 'PosReg', (18, 28))	('mutant', 'Var', (129, 135))
18002	33221817	Due to the toxicity of D2HG on hiPSCs, scientists should investigate ways to by-pass this issue.	('iPSC', 'Chemical', '-', (32, 36))	('toxicity', 'Disease', 'MESH:D064420', (11, 19))	('toxicity', 'Disease', (11, 19))	('D2HG', 'Chemical', '-', (23, 27))	('D2HG', 'Var', (23, 27))
18004	33221817	have shown that the spheroid culture of glioma primary cells expresses new genes related to malignancy and may help to culture primary cells carrying the IDH1 mutation.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('glioma', 'Disease', (40, 46))	('mutation', 'Var', (159, 167))	('IDH1', 'Gene', (154, 158))	('malignancy', 'Disease', 'MESH:D009369', (92, 102))	('IDH1', 'Gene', '3417', (154, 158))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('malignancy', 'Disease', (92, 102))
18009	33221817	reported the gene modification of IDH1-R132H in hiPSC by CRISPR/Cas9 (efficiency 1%).	('gene modification', 'Var', (13, 30))	('IDH1', 'Gene', '3417', (34, 38))	('hiPSC', 'Disease', (48, 53))	('iPSC', 'Chemical', '-', (49, 53))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('IDH1', 'Gene', (34, 38))
18011	33221817	Initial results show that cerebral organoids from gene-modified iPSC-R132H are not affected in cell differentiation in the maturation of cerebral organoids.	('R132H', 'Mutation', 'rs121913500', (69, 74))	('gene-modified iPSC-R132H', 'Var', (50, 74))	('iPSC-R132H', 'Var', (64, 74))	('iPSC', 'Chemical', '-', (64, 68))
18015	33221817	Most of our knowledge about the effect of IDH mutations in glioma were obtained from clinical studies or overexpression of the IDH1/2 mutation in various types of cells.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (42, 45))	('glioma', 'Disease', (59, 65))	('mutations', 'Var', (46, 55))	('IDH1/2', 'Gene', '3417;3418', (127, 133))	('IDH', 'Gene', '3417', (42, 45))	('mutation', 'Var', (134, 142))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH1/2', 'Gene', (127, 133))
18017	33221817	They induced mutated IDH1 in nestin-expressing cells and showed that this led to the death of mice directly after birth.	('induced', 'Reg', (5, 12))	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('led to', 'Reg', (74, 80))	('IDH1', 'Gene', (21, 25))	('mice', 'Species', '10090', (94, 98))	('mutated', 'Var', (13, 20))	('IDH1', 'Gene', '3417', (21, 25))
18018	33221817	Brain hemorrhage associated with accumulation of D2HG, high levels of hypoxia-inducible transcription factor-1a (HIF1alpha), reduction of ROS level, impaired collagen maturation, and disruption of basement formation were observed in mutant mice.	('reduction', 'NegReg', (125, 134))	('mutant', 'Var', (233, 239))	('basement formation', 'CPA', (197, 215))	('D2HG', 'Chemical', '-', (49, 53))	('HIF1alpha', 'Gene', (113, 122))	('Brain hemorrhage', 'Disease', 'MESH:D020300', (0, 16))	('Brain hemorrhage', 'Phenotype', 'HP:0001342', (0, 16))	('impaired', 'NegReg', (149, 157))	('mice', 'Species', '10090', (240, 244))	('hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('Brain hemorrhage', 'Disease', (0, 16))	('ROS level', 'MPA', (138, 147))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('hypoxia', 'Disease', (70, 77))	('D2HG', 'Protein', (49, 53))	('collagen maturation', 'CPA', (158, 177))	('accumulation', 'PosReg', (33, 45))	('HIF1alpha', 'Gene', '15251', (113, 122))
18023	33221817	generated a mouse model expressing IDH1-R132H associated with the deletion of p53 and ATRX.	('IDH1', 'Gene', (35, 39))	('IDH1', 'Gene', '3417', (35, 39))	('p53', 'Gene', (78, 81))	('mouse', 'Species', '10090', (12, 17))	('associated', 'Reg', (46, 56))	('deletion', 'Var', (66, 74))	('R132H', 'Mutation', 'rs121913500', (40, 45))
18025	33221817	In addition, this study demonstrated hypermethylation of histone 3, which can cause epigenetic reprogramming and upregulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway that leads to DNA damage response (DDR) as observed in the human glioma cells from surgical biopsies.	('leads to', 'Reg', (192, 200))	('cause', 'Reg', (78, 83))	('ataxia-telangiectasia-mutated', 'Gene', (133, 162))	('ataxia', 'Phenotype', 'HP:0001251', (133, 139))	('glioma', 'Disease', (252, 258))	('upregulation', 'PosReg', (113, 125))	('ATM', 'Gene', (164, 167))	('glioma', 'Disease', 'MESH:D005910', (252, 258))	('epigenetic reprogramming', 'CPA', (84, 108))	('histone 3', 'Protein', (57, 66))	('human', 'Species', '9606', (246, 251))	('hypermethylation', 'Var', (37, 53))	('telangiectasia', 'Phenotype', 'HP:0001009', (140, 154))	('ataxia-telangiectasia-mutated', 'Gene', '472', (133, 162))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))	('ATM', 'Gene', '472', (164, 167))	('DNA damage response', 'Disease', (201, 220))
18026	33221817	Moreover, the IDH1 mutation in this model resulted in radiotherapy resistance that could be restored by pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR.	('mutation', 'Var', (19, 27))	('checkpoint kinases 1 and 2', 'Gene', '1111;11200', (141, 167))	('radiotherapy', 'MPA', (54, 66))	('ATM', 'Gene', (134, 137))	('IDH1', 'Gene', (14, 18))	('resulted in', 'Reg', (42, 53))	('ATM', 'Gene', '472', (134, 137))	('IDH1', 'Gene', '3417', (14, 18))
18029	33221817	Since IDH1 mutations relate to both astrocytoma and oligodendroglioma, selecting the correct medium is essential to keep the IDH1 mutated model similar to the patient's condition, because using an inaccurate medium can change the sensitivity of cells to different drugs.	('IDH1', 'Gene', '3417', (6, 10))	('mutations', 'Var', (11, 20))	('change', 'Reg', (219, 225))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (36, 69))	('IDH1', 'Gene', '3417', (125, 129))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('relate', 'Reg', (21, 27))	('patient', 'Species', '9606', (159, 166))	('IDH1', 'Gene', (6, 10))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))	('IDH1', 'Gene', (125, 129))
18035	33221817	Generating in vitro models by overexpression of the wild-type or mutated IDH1 can be a way to establish the glioma model containing IDH1-R132H, although this is not an accurate model for disease modeling.	('IDH1', 'Gene', (132, 136))	('R132H', 'Mutation', 'rs121913500', (137, 142))	('glioma', 'Disease', (108, 114))	('IDH1', 'Gene', '3417', (73, 77))	('IDH1', 'Gene', '3417', (132, 136))	('overexpression', 'PosReg', (30, 44))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1', 'Gene', (73, 77))	('mutated', 'Var', (65, 72))
18036	33221817	Reprogramming of glioma cells derived from patients and established isogenic clones is an alternative way to generate disease models for glioma:with or without IDH1 mutations.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('IDH1', 'Gene', (160, 164))	('patients', 'Species', '9606', (43, 51))	('IDH1', 'Gene', '3417', (160, 164))	('glioma', 'Disease', (17, 23))	('glioma', 'Disease', (137, 143))	('mutations', 'Var', (165, 174))
18037	33221817	Since D2HG production from mutated IDH1/2 can be a factor in inhibiting the reprogramming process, designing small molecules that can attach to the active catalytic site of mutated IDH1/2 may inhibit the mutated enzyme from producing D2HG instead of alpha-KG.	('mutated', 'Var', (27, 34))	('IDH1/2', 'Gene', '3417;3418', (181, 187))	('mutated', 'Var', (173, 180))	('alpha-KG', 'Chemical', 'MESH:D007656', (250, 258))	('inhibit', 'NegReg', (192, 199))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('IDH1/2', 'Gene', (181, 187))	('D2HG', 'Chemical', '-', (234, 238))	('reprogramming process', 'CPA', (76, 97))	('D2HG', 'Chemical', '-', (6, 10))	('IDH1/2', 'Gene', (35, 41))
18038	33221817	In this regard, IDH1 inhibitors (AG-120 ML 309, AG-120, and AGI-5198), and IDH2 inhibitors (AG-221, AGI-6780) have shown that they can restore the IDH1 mutation effects.	('IDH', 'Gene', '3417', (147, 150))	('AGI-6780', 'Chemical', 'MESH:C581155', (100, 108))	('IDH1', 'Gene', '3417', (147, 151))	('AG-120', 'Var', (48, 54))	('IDH', 'Gene', (16, 19))	('IDH1', 'Gene', (16, 20))	('AG-120 ML 309', 'Var', (33, 46))	('IDH', 'Gene', '3417', (16, 19))	('IDH', 'Gene', (75, 78))	('IDH1', 'Gene', (147, 151))	('IDH', 'Gene', '3417', (75, 78))	('IDH1', 'Gene', '3417', (16, 20))	('IDH', 'Gene', (147, 150))	('mutation', 'Var', (152, 160))	('restore', 'PosReg', (135, 142))
18042	33221817	The high tendency of the cells carrying mutated IDH1 to grow as a sphere makes organoids a suitable model for understanding the pathophysiology of this mutation in glioma and may help us develop patient-specific therapies.	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('IDH1', 'Gene', '3417', (48, 52))	('patient', 'Species', '9606', (195, 202))	('mutated', 'Var', (40, 47))	('IDH1', 'Gene', (48, 52))	('glioma', 'Disease', (164, 170))
18044	33221817	Brain organoids may be able to fuse with glioma neurospheres or single glioma cells carrying the IDH1 mutation.	('IDH1', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Disease', (71, 77))	('IDH1', 'Gene', '3417', (97, 101))	('glioma neurospheres', 'Disease', (41, 60))	('glioma neurospheres', 'Disease', 'MESH:D005910', (41, 60))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', (41, 47))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
18049	33221817	Co-cultures of patients, healthy T cells, or microglial or innate immune cells with fused organoids or organoid carrying mutated IDH1 can recapitulate cell infiltration in the brain.	('patients', 'Species', '9606', (15, 23))	('IDH1', 'Gene', (129, 133))	('mutated', 'Var', (121, 128))	('cell infiltration in the brain', 'CPA', (151, 181))	('IDH1', 'Gene', '3417', (129, 133))
18058	32708419	Finally, an efficient deep feature learning method, multi-stream convolutional autoencoder (CAE) and feature fusion, is proposed for the prediction of molecular subtypes (1p/19q-codeletion and IDH mutation).	('1p/19q-codeletion', 'Var', (171, 188))	('IDH', 'Gene', '3417', (193, 196))	('IDH', 'Gene', (193, 196))
18064	32708419	Oligodendrogliomas contain IDH mutation and 1p19q codeletion, while astrocytomas have no codeletion and are further subclassified if they are IDH mutated or not.	('IDH', 'Gene', (27, 30))	('1p19q codeletion', 'Var', (44, 60))	('IDH', 'Gene', '3417', (27, 30))	('astrocytomas', 'Disease', (68, 80))	('IDH', 'Gene', (142, 145))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('IDH', 'Gene', '3417', (142, 145))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))
18074	32708419	also used SVM based approach for prediction of IDH mutation.	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', (47, 50))	('mutation', 'Var', (51, 59))
18095	32708419	Moreover, the data used in this work is raw clinical data for the prediction of 1p/19q codeletion and IDH genotype without annotations (tumor segmentation masks) obtained from multiple hospitals.	('IDH', 'Gene', '3417', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('1p/19q codeletion', 'Var', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('IDH', 'Gene', (102, 105))	('tumor', 'Disease', (136, 141))
18143	32708419	False positive (FP): the 1p/19q non-codeletion/IDH wild-type gliomas, but were incorrectly classified as 1p/19q codeltion/IDH mutation.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('1p/19q', 'Var', (25, 31))	('IDH', 'Gene', '3417', (47, 50))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('IDH', 'Gene', (47, 50))
18144	32708419	True negative (TN): the 1p/19q non-codeletion/IDH wild-type gliomas, and were correctly classified as 1p/19q non-codeltion/IDH wild-type.	('1p/19q', 'Var', (24, 30))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('IDH', 'Gene', (46, 49))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('IDH', 'Gene', '3417', (46, 49))	('IDH', 'Gene', (123, 126))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('IDH', 'Gene', '3417', (123, 126))
18161	32708419	The accuracy was obtained after the refined training stage with 820 and 420 MRIs for IDH mutation and wild-type, respectively.	('IDH', 'Gene', '3417', (85, 88))	('IDH', 'Gene', (85, 88))	('mutation', 'Var', (89, 97))
18165	32708419	Unlike the previous case, the class distribution in Case-B for IDH mutation and IDH wild-type is uneven.	('mutation', 'Var', (67, 75))	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (80, 83))	('IDH', 'Gene', '3417', (80, 83))
18166	32708419	Precision (81.96%) indicates here that how many patients predicted as IDH mutated are actually mutated.	('mutated', 'Var', (95, 102))	('IDH', 'Gene', (70, 73))	('patients', 'Species', '9606', (48, 56))	('IDH', 'Gene', '3417', (70, 73))
18168	32708419	To further evaluate the proposed scheme, we compare our performance with several state-of-the-art results on prediction of 1p/19q deletion/non-codeletion and IDH1 mutation/wild-type.	('IDH1', 'Gene', '3417', (158, 162))	('1p/19q', 'Gene', (123, 129))	('mutation/wild-type', 'Var', (163, 181))	('IDH1', 'Gene', (158, 162))
18178	32708419	Moreover, increasing the number of classes by combining IDH genotype and 1p/19q codeletion status into one classifier would also be desirable for the clinical usage.	('1p/19q codeletion', 'Var', (73, 90))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', (56, 59))
18179	32708419	The results obtained on the test dataset have shown a noticeable increase in the performance compared to when the dataset was not mapped (74.81%, improved by 7.78% on 1p/19q codeletion status) and (81.19%, improved by 8.81% on IDH mutation status).	('increase', 'PosReg', (65, 73))	('IDH', 'Gene', (227, 230))	('1p/19q codeletion status', 'Var', (167, 191))	('IDH', 'Gene', '3417', (227, 230))	('improved', 'PosReg', (146, 154))
18186	30661193	Using machine-learning algorithms, high accuracy was achieved in the prediction of IDH genotype in gliomas and moderate accuracy in a three-group prediction including IDH genotype and 1p19q codeletion.	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('1p19q', 'Var', (184, 189))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
18190	30661193	IDH1 mutations, specifically involving the amino acid arginine at position 132, were first described in 12% of glioblastomas, followed by observation that they are present in 50-80% of LGG patients.	('glioblastomas', 'Disease', (111, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('amino acid arginine', 'Chemical', '-', (43, 62))	('mutations', 'Var', (5, 14))	('glioblastomas', 'Phenotype', 'HP:0012174', (111, 124))	('IDH1', 'Gene', (0, 4))	('patients', 'Species', '9606', (189, 197))	('glioblastomas', 'Disease', 'MESH:D005909', (111, 124))	('IDH1', 'Gene', '3417', (0, 4))
18191	30661193	Gliomas with the IDH1 mutation (or its homolog IDH2) is associated with a significantly more favorable survival outcomes than the IDH1/2 wild-type tumors, independent of histological grade.	('type tumor', 'Disease', 'MESH:D009369', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mutation', 'Var', (22, 30))	('IDH2', 'Gene', (47, 51))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('IDH1/2', 'Gene', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('IDH1', 'Gene', (130, 134))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('type tumor', 'Disease', (142, 152))	('IDH1', 'Gene', (17, 21))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('IDH1', 'Gene', '3417', (130, 134))	('IDH2', 'Gene', '3418', (47, 51))	('Gliomas', 'Disease', (0, 7))	('IDH1', 'Gene', '3417', (17, 21))	('IDH1/2', 'Gene', '3417;3418', (130, 136))
18192	30661193	Due to the prognostic significance of the IDH mutation, the World Health Organization (WHO) updated its classification criteria in 2016 to integrate IDH1/2 status as a molecular parameter for classifying gliomas.	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('IDH1/2', 'Gene', '3417;3418', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('mutation', 'Var', (46, 54))	('IDH1/2', 'Gene', (149, 155))
18193	30661193	IDH mutants are driven by specific epigenetic alterations, which may make them susceptible to therapeutic interventions (such as temozolomide) that are less effective against IDH wild type tumor.	('temozolomide', 'Chemical', 'MESH:D000077204', (129, 141))	('mutants', 'Var', (4, 11))	('IDH', 'Disease', (0, 3))	('type tumor', 'Disease', (184, 194))	('type tumor', 'Disease', 'MESH:D009369', (184, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('epigenetic alterations', 'Var', (35, 57))
18195	30661193	Targeted therapy against IDH mutation has been shown to be associated with a favorable safety profile and prolonged stable disease in Phase I study of cholangiocarcinoma and glioma.	('mutation', 'Var', (29, 37))	('IDH', 'Gene', (25, 28))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('Targeted', 'Var', (0, 8))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('cholangiocarcinoma and glioma', 'Disease', 'MESH:D005910', (151, 180))
18196	30661193	Codeletion of 1p19q has also been proven to be a prognostic molecular marker for positive tumor response to radiation and chemotherapy and associated with better survival.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Codeletion of 1p19q', 'Var', (0, 19))	('tumor', 'Disease', (90, 95))	('1p19q', 'Var', (14, 19))	('better', 'PosReg', (155, 161))	('associated', 'Reg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
18197	30661193	The Cancer Genome Atlas Research Network classified LGGs into three molecular categories: gliomas with IDH mutation and 1p19q codeletion (IDHmut-codel), gliomas with IDH mutation and no 1pI19q codeletion (IDHmut-non-codel) and gliomas with wild-type IDH (IDHwt).	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', (227, 234))	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('1p19q codeletion', 'Var', (120, 136))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('IDH', 'Disease', (103, 106))	('Cancer Genome Atlas', 'Disease', (4, 23))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
18198	30661193	LGGs with an IDH mut-codel are more sensitive to radiation and chemotherapy and associated with longer survival than other types of diffuse gliomas.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('sensitive', 'MPA', (36, 45))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('longer', 'PosReg', (96, 102))	('survival', 'CPA', (103, 111))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('IDH mut-codel', 'Var', (13, 26))	('gliomas', 'Disease', (140, 147))	('more', 'PosReg', (31, 35))
18199	30661193	The early identification of IDH and 1p19q status may benefit the prediction of patient's prognosis and predictive of responsiveness to chemotherapy and radiation.	('IDH', 'Gene', (28, 31))	('benefit', 'PosReg', (53, 60))	('patient', 'Species', '9606', (79, 86))	('1p19q status', 'Var', (36, 48))
18200	30661193	Several advanced imaging techniques have been shown to predict IDH and/or 1p19q status in gliomas.	('gliomas', 'Disease', (90, 97))	('1p19q status', 'Var', (74, 86))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH', 'Var', (63, 66))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
18210	30661193	For the BWH cohort, IDH1/2 mutations were determined using IHC, mass spectrometry-based mutation genotyping (OncoMap), or capture-based sequencing (OncoPanel), depending on the available genotyping technology at the time of diagnosis.	('mutations', 'Var', (27, 36))	('IDH1/2', 'Gene', '3417;3418', (20, 26))	('IDH1/2', 'Gene', (20, 26))
18212	30661193	For this retrospective study, only gliomas with absence of IDH1/2 mutations as determined by full sequencing assay were included in our analyses as IDH-WT gliomas.	('mutations', 'Var', (66, 75))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('gliomas', 'Disease', (155, 162))	('IDH-WT gliomas', 'Disease', 'MESH:D005910', (148, 162))	('IDH1/2', 'Gene', '3417;3418', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('gliomas', 'Disease', (35, 42))	('IDH1/2', 'Gene', (59, 65))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('IDH-WT gliomas', 'Disease', (148, 162))
18234	30661193	demonstrated that IDH mutants have a characteristic appearance on imaging, including sharp tumor margins and homogenous signal intensity.	('IDH', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('homogenous signal intensity', 'MPA', (109, 136))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutants', 'Var', (22, 29))	('tumor', 'Disease', (91, 96))
18235	30661193	built a model predictive of IDH1 mutation with AUC of 0.859 and 0.788 in the discovery and validation sets.	('mutation', 'Var', (33, 41))	('IDH1', 'Gene', '3417', (28, 32))	('IDH1', 'Gene', (28, 32))
18237	30661193	built a radiomic model to predict IDH mutation in grade II gliomas using only T2-weighted imaging and reported an accuracy of 80% in the primary cohort and 83% on the validation cohort.	('II gliomas', 'Disease', 'MESH:D005910', (56, 66))	('IDH', 'Gene', (34, 37))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('II gliomas', 'Disease', (56, 66))	('mutation', 'Var', (38, 46))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
18238	30661193	used routine preoperative MRIs of 165 patients from the TCGA/TCIA to generate texture features predicting IDH mutation and 1p19q status with an accuracy of 0.86 and 0.96 within the same data set.	('patients', 'Species', '9606', (38, 46))	('mutation', 'Var', (110, 118))	('IDH', 'Gene', (106, 109))	('1p19q status', 'Var', (123, 135))
18240	30661193	In the current study, using data from multiple institutions, a random forest model integrating preoperative multimodal automated imaging features and age was constructed to predict IDH and 1p19q genotype in grade II-IV gliomas.	('IV gliomas', 'Disease', (216, 226))	('IV gliomas', 'Disease', 'MESH:D005910', (216, 226))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('1p19q', 'Var', (189, 194))	('IDH', 'Var', (181, 184))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))
18241	30661193	The only non-imaging feature included in the final model is patient age which is available to the radiologists preoperative and remains a strong feature correlating with IDH mutation and 1p19q status.	('IDH', 'Gene', (170, 173))	('patient', 'Species', '9606', (60, 67))	('1p19q status', 'Var', (187, 199))
18246	30661193	Although the precise relationship between automated imaging features and the biology of IDH mutations remains unclear, our results provided quantitative insight into intratumor heterogeneity and behavior of tumor margins.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (207, 212))
18249	30661193	In conclusion, using machine-learning algorithms, high accuracy was achieved in the prediction of IDH genotype in gliomas and moderate accuracy in a three-group prediction including IDH genotype and 1p19q codeletion.	('gliomas', 'Disease', (114, 121))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('1p19q', 'Var', (199, 204))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))
18271	27613707	If myeloid cells are also particularly susceptible to these factors, this could explain the association between low birthweight and AML.	('low birthweight', 'Var', (112, 127))	('AML', 'Disease', (132, 135))	('low birthweight', 'Phenotype', 'HP:0001518', (112, 127))	('AML', 'Disease', 'MESH:D015470', (132, 135))	('association', 'Interaction', (92, 103))
18274	27613707	Whereas pre-pregnancy underweight and insufficient gestational weight gain, which have been linked to restricted fetal growth, will result in an increased risk of childhood cancers that have been associated with lower birthweight.	('restricted fetal growth', 'Phenotype', 'HP:0001558', (102, 125))	('-pregnancy underweight and insufficient gestational weight', 'Phenotype', 'HP:0001622', (11, 69))	('underweight', 'Var', (22, 33))	('insufficient gestational weight gain', 'Disease', (38, 74))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('childhood cancers', 'Disease', 'MESH:C536928', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('childhood cancers', 'Disease', (163, 180))	('insufficient gestational weight', 'Phenotype', 'HP:0001518', (38, 69))	('lower birthweight', 'Phenotype', 'HP:0001518', (212, 229))	('weight gain', 'Phenotype', 'HP:0004324', (63, 74))	('insufficient gestational weight gain', 'Disease', 'MESH:D000078064', (38, 74))
18283	27613707	We also excluded children that were missing sex (n=3), births that were likely not viable (gestational age <20 weeks and/or birthweight <500g) (n=169), and children diagnosed with Down syndrome (n=151).	('children', 'Species', '9606', (156, 164))	('Down syndrome', 'Disease', (180, 193))	('birthweight <500g', 'Phenotype', 'HP:0001518', (124, 141))	('missing sex', 'Phenotype', 'HP:0008187', (36, 47))	('<500g', 'Var', (136, 141))	('children', 'Species', '9606', (17, 25))
18295	27613707	Pre-pregnancy BMI was categorized according to the World Health Organization criteria: <18.5 kg/m2 (underweight), 18.5-24.9 kg/m2 (normal), 25-29.9 kg/m2 (overweight), >=30 kg/m2 (obese).	('obese', 'Disease', (180, 185))	('BMI', 'Disease', (14, 17))	('<18.5 kg/m2', 'Var', (87, 98))	('25-29.9 kg/m2', 'Var', (140, 153))	('obese', 'Disease', 'MESH:D009765', (180, 185))	('overweight', 'Phenotype', 'HP:0025502', (155, 165))
18345	27613707	In contrast, underweight appeared to increase the risk of germ cell tumors.	('germ cell tumor', 'Phenotype', 'HP:0100728', (58, 73))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('cell tumors', 'Disease', (63, 74))	('germ cell tumors', 'Phenotype', 'HP:0100728', (58, 74))	('germ', 'Disease', (58, 62))	('underweight', 'Var', (13, 24))	('cell tumors', 'Disease', 'MESH:D005935', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
18366	27613707	Errors in pre-pregnancy weight seem to be the main source of misclassification of pre-pregnancy BMI and gestational weight gain, which is plausible since pre-pregnancy weight recorded on the birth certificate is typically ascertained by maternal recall at delivery.	('gestational weight gain', 'Disease', (104, 127))	('weight gain', 'Phenotype', 'HP:0004324', (116, 127))	('Errors', 'Var', (0, 6))	('gestational weight gain', 'Disease', 'MESH:D000078064', (104, 127))	('BMI', 'Disease', (96, 99))
18379	25849605	Radiological and Pathological Features Associated with IDH1-R132H Mutation Status and Early Mortality in Newly Diagnosed Anaplastic Astrocytic Tumours Glioblastoma can occur either de novo or by the transformation of a low grade tumour; the majority of which harbor a mutation in isocitrate dehydrogenase (IDH1).	('R132H', 'Mutation', 'rs121913500', (60, 65))	('Glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('IDH1', 'Gene', (306, 310))	('Glioblastoma', 'Disease', (151, 163))	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('Anaplastic Astrocytic Tumours', 'Disease', 'MESH:D065646', (121, 150))	('IDH1', 'Gene', '3417', (55, 59))	('tumour', 'Disease', (229, 235))	('IDH1', 'Gene', '3417', (306, 310))	('Glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('mutation', 'Var', (268, 276))	('isocitrate', 'Chemical', 'MESH:C034219', (280, 290))	('Tumours', 'Phenotype', 'HP:0002664', (143, 150))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('Anaplastic Astrocytic Tumours', 'Disease', (121, 150))	('IDH1', 'Gene', (55, 59))
18387	25849605	Patients with IDH1-R132H-positive tumours were less likely to die within 12 months of diagnosis (17% vs. 47%; p=0.046), more likely to have tumours located in the frontal lobe (55% vs. 16%; p=0.015), and have a higher minimum apparent diffusion coefficient (1.115 x 10-3 mm2/sec vs. 0.838 x 10-3 mm2/sec; p=0.016), however, these variables demonstrated only moderate strength for predicting the IDH1-R132H mutation status (AUC=0.735 and 0.711, respectively).	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('mm2', 'Gene', '10687', (296, 299))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('mm2', 'Gene', '10687', (271, 274))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('R132H', 'Var', (400, 405))	('R132H', 'Var', (19, 24))	('mm2', 'Gene', (296, 299))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('Patients', 'Species', '9606', (0, 8))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('IDH1', 'Gene', (395, 399))	('IDH1', 'Gene', (14, 18))	('mm2', 'Gene', (271, 274))	('higher', 'PosReg', (211, 217))	('less', 'NegReg', (47, 51))	('R132H', 'SUBSTITUTION', 'None', (400, 405))	('R132H', 'SUBSTITUTION', 'None', (19, 24))	('IDH1', 'Gene', '3417', (395, 399))	('IDH1', 'Gene', '3417', (14, 18))	('R132H', 'Mutation', 'rs121913500', (400, 405))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('tumours', 'Disease', (140, 147))
18388	25849605	The Ki-67 index was significantly lower in IDH1-R132H-positive tumours (0.13 vs. 0.21; p=0.034).	('R132H', 'Var', (48, 53))	('Ki-67', 'CPA', (4, 9))	('R132H', 'SUBSTITUTION', 'None', (48, 53))	('lower', 'NegReg', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))
18389	25849605	An increased risk of death was associated with contrast-enhancement >= 5 cm3 in patients with IDH1-R132H-positive tumours while edema >= 1 cm beyond the tumour margin and < 5 mitoses/mm2 were associated with an increased risk of death in patients with IDH1-R132H-negative tumours.	('R132H', 'Mutation', 'rs121913500', (99, 104))	('tumours', 'Disease', (114, 121))	('patients', 'Species', '9606', (80, 88))	('edema', 'Disease', 'MESH:D004487', (128, 133))	('R132H', 'Mutation', 'rs121913500', (257, 262))	('death', 'Disease', 'MESH:D003643', (21, 26))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('edema', 'Disease', (128, 133))	('death', 'Disease', (229, 234))	('tumours', 'Disease', (272, 279))	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumour', 'Phenotype', 'HP:0002664', (272, 278))	('contrast-enhancement', 'MPA', (47, 67))	('tumour', 'Disease', 'MESH:D009369', (272, 278))	('mm2', 'Gene', '10687', (183, 186))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumours', 'Phenotype', 'HP:0002664', (272, 279))	('tumour', 'Disease', (272, 278))	('R132H', 'Var', (99, 104))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('tumours', 'Disease', 'MESH:D009369', (272, 279))	('tumour', 'Disease', (114, 120))	('tumour', 'Disease', (153, 159))	('IDH1', 'Gene', (94, 98))	('R132H', 'Var', (257, 262))	('IDH1', 'Gene', (252, 256))	('death', 'Disease', (21, 26))	('mm2', 'Gene', (183, 186))	('death', 'Disease', 'MESH:D003643', (229, 234))	('patients', 'Species', '9606', (238, 246))	('R132H', 'SUBSTITUTION', 'None', (99, 104))	('R132H', 'SUBSTITUTION', 'None', (257, 262))	('IDH1', 'Gene', '3417', (94, 98))	('edema', 'Phenotype', 'HP:0000969', (128, 133))	('>= 5 cm3', 'Var', (68, 76))	('IDH1', 'Gene', '3417', (252, 256))
18396	25849605	Important recent discoveries have shown that most secondary glioblastomas arise from lower grade astrocytic tumours that harbor a mutation in the gene for isocitrate dehydrogenase (IDH1); of these, 90% posses the R132H mutation.	('astrocytic tumours', 'Disease', (97, 115))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('R132H', 'Mutation', 'rs121913500', (213, 218))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('mutation in', 'Var', (130, 141))	('isocitrate', 'Chemical', 'MESH:C034219', (155, 165))	('glioblastomas', 'Disease', (60, 73))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('IDH1', 'Gene', (181, 185))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('astrocytic tumours', 'Disease', 'MESH:D001254', (97, 115))	('IDH1', 'Gene', '3417', (181, 185))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))	('R132H', 'Var', (213, 218))
18398	25849605	Anaplastic astrocytic tumours (anaplastic astrocytoma [AA] and anaplastic oligoastrocytoma [AOA]) exist at the interface between these two entities with just over half of tumours harboring an IDH1 mutation.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('IDH1', 'Gene', '3417', (192, 196))	('astrocytoma', 'Phenotype', 'HP:0009592', (42, 53))	('Anaplastic astrocytic tumours', 'Disease', (0, 29))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (74, 90))	('anaplastic astrocytoma', 'Disease', (31, 53))	('tumours', 'Disease', (22, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('mutation', 'Var', (197, 205))	('oligoastrocytoma', 'Disease', (74, 90))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('IDH1', 'Gene', (192, 196))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (31, 53))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumours', 'Disease', (171, 178))	('Anaplastic astrocytic tumours', 'Disease', 'MESH:D065646', (0, 29))
18403	25849605	Recent evidence has shown that IDH1 mutant diffuse gliomas and glioblastomas demonstrate unique radiological features that correlated with outcome.	('gliomas', 'Disease', (51, 58))	('IDH1', 'Gene', '3417', (31, 35))	('glioblastomas', 'Phenotype', 'HP:0012174', (63, 76))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioblastomas', 'Disease', 'MESH:D005909', (63, 76))	('mutant', 'Var', (36, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('glioblastomas', 'Disease', (63, 76))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('IDH1', 'Gene', (31, 35))
18404	25849605	Specifically, a study examining diffuse gliomas demonstrated that IDH1 mutant tumours were smaller and less infiltrative.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('IDH1', 'Gene', '3417', (66, 70))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('mutant', 'Var', (71, 77))	('IDH1', 'Gene', (66, 70))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
18405	25849605	In contrast, a study examining glioblastoma found that IDH1 mutant tumours were more likely to be non-CE, larger, and in the frontal lobe.	('IDH1', 'Gene', '3417', (55, 59))	('non-CE', 'Disease', (98, 104))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('mutant', 'Var', (60, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('IDH1', 'Gene', (55, 59))
18428	25849605	IDH1 mutation status was assessed by immunohistochemistry using an antibody specific for the R132H mutation (clone H09, 1:100 dilution; Dianova).	('IDH1', 'Gene', (0, 4))	('R132H', 'Mutation', 'rs121913500', (93, 98))	('R132H', 'Var', (93, 98))	('IDH1', 'Gene', '3417', (0, 4))
18429	25849605	Consequently, for the purpose of this study, the designation of a tumour as 'IDH1 positive' refers only to the R132H mutation.	('R132H', 'Var', (111, 116))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('IDH1', 'Gene', (77, 81))	('R132H', 'Mutation', 'rs121913500', (111, 116))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('IDH1', 'Gene', '3417', (77, 81))	('tumour', 'Disease', (66, 72))
18442	25849605	Receiver operating characteristics (ROC) were used to assess the predictive power of each radiological feature for the IDH1 mutation status of the tumour.	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('IDH1', 'Gene', (119, 123))	('mutation', 'Var', (124, 132))	('IDH1', 'Gene', '3417', (119, 123))	('tumour', 'Disease', (147, 153))
18451	25849605	Indeed, 72% of patients with IDH1-R132H positive tumours were younger than 50 years old whereas 68% of patients with IDH1-R132H negative tumours were older than 50 years.	('patients', 'Species', '9606', (15, 23))	('R132H', 'Mutation', 'rs121913500', (122, 127))	('R132H', 'Mutation', 'rs121913500', (34, 39))	('tumours', 'Disease', (137, 144))	('tumours', 'Disease', (49, 56))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('R132H', 'Var', (122, 127))	('R132H', 'Var', (34, 39))	('IDH1', 'Gene', (117, 121))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('IDH1', 'Gene', (29, 33))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('R132H', 'SUBSTITUTION', 'None', (122, 127))	('IDH1', 'Gene', '3417', (117, 121))	('R132H', 'SUBSTITUTION', 'None', (34, 39))	('IDH1', 'Gene', '3417', (29, 33))	('patients', 'Species', '9606', (103, 111))
18453	25849605	Patients with IDH1-R132H positive tumours were less likely to die within 12 months of the initial diagnosis (17% vs. 47%; p = 0.046).	('less', 'NegReg', (47, 51))	('R132H', 'Var', (19, 24))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('Patients', 'Species', '9606', (0, 8))	('R132H', 'SUBSTITUTION', 'None', (19, 24))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
18459	25849605	Although IDH1-R132H positive tumours tended to be larger than IDH1-R132H negative tumours, the difference was not statistically significant (62.2 +- 50.0 cm3 vs. 37.9 +- 29.6; p = NS).	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('R132H', 'Var', (14, 19))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (62, 66))	('R132H', 'SUBSTITUTION', 'None', (14, 19))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('R132H', 'Mutation', 'rs121913500', (14, 19))	('tumours', 'Disease', (29, 36))	('IDH1', 'Gene', '3417', (9, 13))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('R132H', 'Var', (67, 72))	('IDH1', 'Gene', (62, 66))	('R132H', 'SUBSTITUTION', 'None', (67, 72))	('R132H', 'Mutation', 'rs121913500', (67, 72))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
18461	25849605	Relative to IDH1-R132H negative tumours, IDH1-R132H positive tumours demonstrated a significantly higher minimum ADC (1.115 x 10-3 +- 0.326 x 103 mm2/sec vs. 0.838 x 10-3 +- 0.266 x 103 mm2/sec; p = 0.016) (Fig 1C and 1D).	('R132H', 'SUBSTITUTION', 'None', (17, 22))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('mm2', 'Gene', '10687', (146, 149))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('R132H', 'SUBSTITUTION', 'None', (46, 51))	('IDH1', 'Gene', '3417', (12, 16))	('mm2', 'Gene', '10687', (186, 189))	('IDH1', 'Gene', '3417', (41, 45))	('tumours', 'Disease', (32, 39))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('R132H', 'Mutation', 'rs121913500', (46, 51))	('mm2', 'Gene', (146, 149))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('mm2', 'Gene', (186, 189))	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('R132H', 'Var', (17, 22))	('IDH1', 'Gene', (12, 16))	('R132H', 'Var', (46, 51))	('ADC', 'MPA', (113, 116))	('higher', 'PosReg', (98, 104))	('tumours', 'Disease', (61, 68))	('IDH1', 'Gene', (41, 45))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
18465	25849605	Compared to IDH1-R132H negative tumours, IDH1-R132H positive tumours demonstrated a significantly lower Ki67 LI (0.14 +- 0.10 vs. 0.24 +- 0.15; p = 0.034).	('R132H', 'SUBSTITUTION', 'None', (17, 22))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('R132H', 'SUBSTITUTION', 'None', (46, 51))	('IDH1', 'Gene', '3417', (12, 16))	('Ki67 LI', 'CPA', (104, 111))	('IDH1', 'Gene', '3417', (41, 45))	('lower', 'NegReg', (98, 103))	('tumours', 'Disease', (32, 39))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('R132H', 'Mutation', 'rs121913500', (46, 51))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('R132H', 'Var', (17, 22))	('IDH1', 'Gene', (12, 16))	('R132H', 'Var', (46, 51))	('tumours', 'Disease', (61, 68))	('IDH1', 'Gene', (41, 45))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
18469	25849605	Among patients with IDH1-R132H positive tumours, age >= 50 years and volume of CE tumour >= 5 cm3 were associated with death within 12 months (Fig 1E and 1F).	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('CE tumour', 'Disease', (79, 88))	('R132H', 'Var', (25, 30))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('R132H', 'SUBSTITUTION', 'None', (25, 30))	('associated with', 'Reg', (103, 118))	('patients', 'Species', '9606', (6, 14))	('CE tumour', 'Disease', 'MESH:D009369', (79, 88))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
18473	25849605	Up to half will harbour a mutation in IDH1 which suggests that they arose from a previously undiagnosed low-grade tumour.	('tumour', 'Disease', (114, 120))	('IDH1', 'Gene', '3417', (38, 42))	('mutation', 'Var', (26, 34))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('IDH1', 'Gene', (38, 42))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('arose from', 'Reg', (68, 78))
18476	25849605	Patient age is the demographic parameter most robustly associated with IDH1 mutation status and also a strong predictor of outcome.	('associated', 'Reg', (55, 65))	('IDH1', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (71, 75))	('Patient', 'Species', '9606', (0, 7))	('mutation status', 'Var', (76, 91))
18479	25849605	Indeed, Lai and colleagues found that the probability of a tumour harbouring the IDH1 mutation abruptly increases at 20 years of age only to decrease again later in life.	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('IDH1', 'Gene', (81, 85))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('IDH1', 'Gene', '3417', (81, 85))	('mutation', 'Var', (86, 94))	('tumour', 'Disease', (59, 65))
18484	25849605	Subsequent mutations in the tumour suppressor genes PTEN and p53 then appear to drive the development of IDH1-negative tumours.	('mutations', 'Var', (11, 20))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('PTEN', 'Gene', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('PTEN', 'Gene', '5728', (52, 56))	('IDH1', 'Gene', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('IDH1', 'Gene', '3417', (105, 109))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('development', 'CPA', (90, 101))	('drive', 'Reg', (80, 85))	('tumours', 'Disease', (119, 126))	('tumour', 'Disease', (28, 34))	('tumour', 'Disease', (119, 125))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
18485	25849605	However, as our results show, IDH1-R132H negative tumours can occur in young adults just as IDH1-R132H positive tumours can occur in older adults.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('R132H', 'Var', (35, 40))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('R132H', 'Var', (97, 102))	('IDH1', 'Gene', (92, 96))	('R132H', 'Mutation', 'rs121913500', (35, 40))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumours', 'Disease', (50, 57))	('IDH1', 'Gene', (30, 34))	('tumours', 'Disease', (112, 119))	('IDH1', 'Gene', '3417', (92, 96))	('R132H', 'Mutation', 'rs121913500', (97, 102))	('R132H', 'SUBSTITUTION', 'None', (35, 40))	('R132H', 'SUBSTITUTION', 'None', (97, 102))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('IDH1', 'Gene', '3417', (30, 34))
18486	25849605	These uncommon cases are informative in the context of disentangling the relative contributions of IDH1 mutation status and age as older adults do poorly despite IDH1 mutation positivity and favourable pathology.	('IDH1', 'Gene', '3417', (162, 166))	('mutation', 'Var', (167, 175))	('IDH1', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (99, 103))	('IDH1', 'Gene', (162, 166))
18488	25849605	In a study looking at low-grade gliomas, Metellus and colleagues demonstrated that tumours harbouring the IDH1 mutation are smaller and less likely to have an infiltrative pattern on MRI.	('infiltrative pattern', 'CPA', (159, 179))	('tumours', 'Disease', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('less', 'NegReg', (136, 140))	('IDH1', 'Gene', (106, 110))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('mutation', 'Var', (111, 119))	('IDH1', 'Gene', '3417', (106, 110))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
18490	25849605	Recently, MR spectroscopy has been used to identify mutant tumours through the non-invasive detection of the 2-hydroxyglutarate.	('mutant', 'Var', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('2-hydroxyglutarate', 'Protein', (109, 127))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (109, 127))	('tumours', 'Disease', (59, 66))
18492	25849605	The presence of the IDH1-mutation in most low grade gliomas but relatively few primary glioblastomas and the predilection for the frontal lobe raises the possibility that the tumour progenitors susceptible to IDH1 mutation normally reside in this region or migrate there prior to tumourigenesis.	('IDH1', 'Gene', '3417', (20, 24))	('IDH1', 'Gene', '3417', (209, 213))	('gliomas', 'Disease', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (280, 286))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('tumour', 'Disease', 'MESH:D009369', (280, 286))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('tumour', 'Disease', (280, 286))	('tumour', 'Disease', (175, 181))	('glioblastomas', 'Phenotype', 'HP:0012174', (87, 100))	('IDH1', 'Gene', (20, 24))	('primary glioblastomas', 'Disease', (79, 100))	('mutation', 'Var', (214, 222))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH1', 'Gene', (209, 213))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('primary glioblastomas', 'Disease', 'MESH:D005909', (79, 100))
18493	25849605	In contrast to the previously described study, one-third of the IDH1-R132H positive tumours in the present study demonstrated large areas of avid CE.	('R132H', 'Var', (69, 74))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('R132H', 'SUBSTITUTION', 'None', (69, 74))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('avid CE', 'CPA', (141, 148))
18496	25849605	Another novel finding of the present study is that IDH1-R132H positive tumours have a higher minimum ADC (optimal cut-point >= 0.950 x 10-3 mm2/sec) when compared to IDH1-R132H negative tumours although this feature only had moderate power for predicting the status of the tumour.	('IDH1', 'Gene', '3417', (51, 55))	('tumours', 'Disease', (186, 193))	('R132H', 'SUBSTITUTION', 'None', (56, 61))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('higher', 'PosReg', (86, 92))	('R132H', 'Var', (171, 176))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('tumour', 'Disease', (186, 192))	('IDH1', 'Gene', (166, 170))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('mm2', 'Gene', (140, 143))	('tumour', 'Disease', (273, 279))	('R132H', 'Mutation', 'rs121913500', (56, 61))	('tumours', 'Disease', (71, 78))	('R132H', 'SUBSTITUTION', 'None', (171, 176))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('ADC', 'MPA', (101, 104))	('IDH1', 'Gene', '3417', (166, 170))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('IDH1', 'Gene', (51, 55))	('R132H', 'Mutation', 'rs121913500', (171, 176))	('tumour', 'Disease', 'MESH:D009369', (71, 77))	('R132H', 'Var', (56, 61))	('tumour', 'Disease', (71, 77))	('mm2', 'Gene', '10687', (140, 143))
18504	25849605	A mutation in either IDH1 or IDH2 has been shown to be a very early event in the development of low-grade gliomas.	('mutation', 'Var', (2, 10))	('IDH2', 'Gene', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('IDH2', 'Gene', '3418', (29, 33))	('IDH1', 'Gene', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('IDH1', 'Gene', '3417', (21, 25))
18505	25849605	A mutation in either gene confers upon the mutant enzyme a neo-function, resulting in the production of the onco-metabolite D-2-hydroxyglutarate (D2H) which through genome-wide histone and DNA modification results in a hypermethylated phenotype.	('mutation', 'Var', (2, 10))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (124, 144))	('D2H', 'Gene', (146, 149))	('mutant', 'Var', (43, 49))	('hypermethylated phenotype', 'MPA', (219, 244))	('results in', 'Reg', (206, 216))	('D2H', 'Gene', '6519', (146, 149))
18507	25849605	For example, in vitro studies have shown that the accumulation of DH2 in tumour cells decreases cell proliferation through inhibition of the cell cycle and depletion of metabolic substrates.	('tumour', 'Disease', (73, 79))	('DH2', 'Chemical', '-', (66, 69))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('cell proliferation', 'CPA', (96, 114))	('cell cycle', 'CPA', (141, 151))	('decreases', 'NegReg', (86, 95))	('depletion of metabolic substrates', 'MPA', (156, 189))	('inhibition', 'NegReg', (123, 133))	('accumulation', 'Var', (50, 62))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('DH2', 'Gene', (66, 69))
18508	25849605	Indeed, in cells expressing the IDH1 mutation, cell proliferation decreased in a dose dependent manner as the concentration D2H increased and this effect was associated with decreased activity of AKT, an enzyme linked to several cell survival pathways.	('decreased', 'NegReg', (174, 183))	('AKT', 'Gene', (196, 199))	('D2H', 'Gene', (124, 127))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('decreased', 'NegReg', (66, 75))	('activity', 'MPA', (184, 192))	('IDH1', 'Gene', '3417', (32, 36))	('AKT', 'Gene', '207', (196, 199))	('D2H', 'Gene', '6519', (124, 127))	('cell proliferation', 'CPA', (47, 65))
18509	25849605	In the present study we show for the first time that IDH1-R132H positive tumours have a lower rate of proliferation as measured by expression of the cell cycle antigen Ki67.	('R132H', 'Var', (58, 63))	('R132H', 'SUBSTITUTION', 'None', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('lower', 'NegReg', (88, 93))
18511	25849605	Taken together, these results suggest that while mutation of the IDH1 gene may initially drive tumourigenesis, it actually slows tumour growth by reducing cell proliferation.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('slows', 'NegReg', (123, 128))	('IDH1', 'Gene', '3417', (65, 69))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('drive', 'PosReg', (89, 94))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('mutation', 'Var', (49, 57))	('tumour', 'Disease', (95, 101))	('cell proliferation', 'CPA', (155, 173))	('tumour', 'Disease', (129, 135))	('reducing', 'NegReg', (146, 154))	('IDH1', 'Gene', (65, 69))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
18513	25849605	Previous studies have demonstrated that the IDH1 mutation is a favourable prognostic factor in patients with high grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('patients', 'Species', '9606', (95, 103))	('IDH1', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))	('IDH1', 'Gene', '3417', (44, 48))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))
18515	25849605	Similarly, IDH1 mutation and MGMT methylation status have been shown to predict survival in patients with AA treated with chemoradiation.	('predict', 'Reg', (72, 79))	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('MGMT', 'Gene', '4255', (29, 33))	('patients', 'Species', '9606', (92, 100))	('MGMT', 'Gene', (29, 33))	('IDH1', 'Gene', (11, 15))
18517	25849605	First, we found that patients with IDH1-R132H positive tumours and a volume of CE greater than 5 cm3 were more likely to die within the first 12 months compared to patients with IDH1-R132H positive tumours and less CE.	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('R132H', 'Var', (183, 188))	('patients', 'Species', '9606', (21, 29))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (164, 172))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('R132H', 'Var', (40, 45))	('R132H', 'SUBSTITUTION', 'None', (183, 188))	('R132H', 'SUBSTITUTION', 'None', (40, 45))
18539	25849605	Third, IDH1 mutant tumours were identified by immunohistochemical analysis using an antibody that is specific for the R132H mutation.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('IDH1', 'Gene', '3417', (7, 11))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('mutant', 'Var', (12, 18))	('R132H', 'Var', (118, 123))	('R132H', 'Mutation', 'rs121913500', (118, 123))	('IDH1', 'Gene', (7, 11))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
18540	25849605	While this mutation is responsible for approximately 90% of all IDH1 mutant tumours, our study may have underestimated the actual number of IDH1-positive tumours by as much as 10%.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('IDH1', 'Gene', '3417', (140, 144))	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('mutant', 'Var', (69, 75))	('IDH1', 'Gene', (64, 68))	('tumours', 'Disease', (76, 83))	('responsible', 'Reg', (23, 34))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('IDH1', 'Gene', '3417', (64, 68))	('IDH1', 'Gene', (140, 144))	('IDH1-positive tumours', 'Disease', 'MESH:D009369', (140, 161))	('IDH1-positive tumours', 'Disease', (140, 161))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
18635	33912442	Abnormalities in HLA expression and expression of checkpoint molecules would suggest potential escape mechanisms utilized by chondrosarcoma cells to avoid immune recognition and destruction.	('chondrosarcoma', 'Disease', 'MESH:D002813', (125, 139))	('Abnormalities', 'Var', (0, 13))	('chondrosarcoma', 'Disease', (125, 139))	('expression', 'MPA', (21, 31))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (125, 139))	('expression', 'MPA', (36, 46))	('HLA', 'Protein', (17, 20))
18717	33912442	Positive staining of PD-L1 was associated with a significantly shorter time to metastasis (p=0.019) (excluding the patients with metastasized disease at the time of presentation).	('patients', 'Species', '9606', (115, 123))	('metastasized disease', 'Disease', 'MESH:D009362', (129, 149))	('metastasized disease', 'Disease', (129, 149))	('time to metastasis', 'CPA', (71, 89))	('shorter', 'NegReg', (63, 70))	('PD-L1', 'Gene', (21, 26))	('Positive staining', 'Var', (0, 17))
18729	33912442	In chondrosarcoma, the frequency of defects is significantly lower in subtypes with an aggressive phenotype and poor clinical course than in those with a benign phenotype and with a more favourable clinical course.	('lower', 'NegReg', (61, 66))	('chondrosarcoma', 'Disease', (3, 17))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (3, 17))	('defects', 'Var', (36, 43))	('chondrosarcoma', 'Disease', 'MESH:D002813', (3, 17))
18734	33912442	Several mechanisms can be envisioned for the association between defective HLA class I antigen expression and favourable course of the disease we have unexpectedly found in chondrosarcoma.	('HLA class I antigen', 'Gene', (75, 94))	('defective', 'Var', (65, 74))	('chondrosarcoma', 'Disease', 'MESH:D002813', (173, 187))	('HLA class I antigen', 'Gene', '100507436', (75, 94))	('chondrosarcoma', 'Disease', (173, 187))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (173, 187))
18739	33912442	In this case high HLA class I antigen expression would represent a defensive mechanism for malignant cells, since it would very effectively inhibit the ability of NK cells to eliminate malignant cells.	('high', 'Var', (13, 17))	('inhibit', 'NegReg', (140, 147))	('HLA class I antigen', 'Gene', '100507436', (18, 37))	('HLA class I antigen', 'Gene', (18, 37))
18886	29792149	Inhibition of Mutated Isocitrate Dehydrogenase 1 in Cancer R132H mutation of isocitrate dehydrogenase 1 (IDH1) are found in ~75% of low-grade gliomas and secondary glioblastomas as well as in several other types of cancer.	('found', 'Reg', (115, 120))	('Inhibition', 'NegReg', (0, 10))	('isocitrate dehydrogenase 1', 'Gene', (77, 103))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('isocitrate dehydrogenase 1', 'Gene', '3417', (77, 103))	('glioblastomas', 'Phenotype', 'HP:0012174', (164, 177))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (22, 48))	('R132H', 'Var', (59, 64))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('cancer', 'Disease', (215, 221))	('Isocitrate Dehydrogenase 1', 'Gene', (22, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('glioblastomas', 'Disease', (164, 177))	('R132H', 'SUBSTITUTION', 'None', (59, 64))	('glioblastomas', 'Disease', 'MESH:D005909', (164, 177))	('gliomas', 'Disease', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('IDH1', 'Gene', (105, 109))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))
18887	29792149	More chemotypes of inhibitors of IDH1(R132H) are therefore needed.	('R132H', 'Var', (38, 43))	('IDH1', 'Gene', '3417', (33, 37))	('IDH1', 'Gene', (33, 37))	('R132H', 'SUBSTITUTION', 'None', (38, 43))
18888	29792149	To develop a new class of IDH1(R132H) inhibitors as potent antitumor agents.	('tumor', 'Disease', (63, 68))	('R132H', 'Var', (31, 36))	('IDH1', 'Gene', (26, 30))	('R132H', 'SUBSTITUTION', 'None', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('IDH1', 'Gene', '3417', (26, 30))
18889	29792149	A biochemical assay was developed to find inhibitors of IDH1(R132H) mutant enzyme.	('IDH1', 'Gene', '3417', (56, 60))	('R132H', 'SUBSTITUTION', 'None', (61, 66))	('R132H', 'Var', (61, 66))	('IDH1', 'Gene', (56, 60))
18892	29792149	A series of aromatic sulfonamide compounds were found to be novel, potent inhibitors of IDH1(R132H) with Ki values as low as 0.6 muM.	('aromatic', 'Chemical', '-', (12, 20))	('R132H', 'Var', (93, 98))	('muM', 'Gene', (129, 132))	('IDH1', 'Gene', (88, 92))	('R132H', 'SUBSTITUTION', 'None', (93, 98))	('IDH1', 'Gene', '3417', (88, 92))	('muM', 'Gene', '56925', (129, 132))	('sulfonamide', 'Chemical', 'MESH:D013449', (21, 32))
18895	29792149	Two potent inhibitors exhibited strong activity against proliferation of BT142 glioma cells with IDH1 R132H mutation, while these compounds did not significantly affect growth of glioma cells without IDH1 mutation.	('BT142', 'CellLine', 'CVCL:D718', (73, 78))	('IDH1', 'Gene', (200, 204))	('IDH1', 'Gene', (97, 101))	('glioma', 'Disease', (79, 85))	('IDH1', 'Gene', '3417', (200, 204))	('IDH1', 'Gene', '3417', (97, 101))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('proliferation', 'CPA', (56, 69))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('activity', 'MPA', (39, 47))	('R132H', 'Var', (102, 107))	('glioma', 'Disease', (179, 185))	('R132H', 'SUBSTITUTION', 'None', (102, 107))
18896	29792149	This novel series of IDH1(R132H) inhibitors have potential to be further developed for the treatment of glioma with IDH1 mutation.	('R132H', 'SUBSTITUTION', 'None', (26, 31))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('IDH1', 'Gene', (116, 120))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('mutation', 'Var', (121, 129))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (116, 120))	('R132H', 'Var', (26, 31))	('IDH1', 'Gene', '3417', (21, 25))	('glioma', 'Disease', (104, 110))
18897	29792149	Point mutations of isocitrate dehydrogenase (IDH) 1 and 2, located in cytoplasm and mitochondria, respectively, have been frequently found in cancer including glioma, leukemia and sarcomas.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('leukemia', 'Disease', 'MESH:D007938', (167, 175))	('glioma', 'Disease', (159, 165))	('leukemia', 'Disease', (167, 175))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('found', 'Reg', (133, 138))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (19, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('sarcomas', 'Disease', (180, 188))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))	('Point mutations', 'Var', (0, 15))	('cancer', 'Disease', (142, 148))
18898	29792149	In particular, mutations of IDH1 have been identified in ~75% low-grade gliomas (grade II and III), which grow slowly but eventually develop to become secondary glioblastoma multiforme (GBM), which is highly invasive grade IV glioma with a very low 5-year survival rate of <10%.	('IDH1', 'Gene', '3417', (28, 32))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('IV glioma', 'Disease', 'MESH:D005910', (223, 232))	('mutations', 'Var', (15, 24))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (161, 184))	('glioblastoma multiforme', 'Disease', (161, 184))	('IV glioma', 'Disease', (223, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (161, 173))	('identified', 'Reg', (43, 53))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))	('IDH1', 'Gene', (28, 32))
18899	29792149	R132H (Arg132His) is the predominant (~90%) form of mutation in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('R132H', 'SUBSTITUTION', 'None', (0, 5))	('Arg132His', 'Var', (7, 16))	('Arg132His', 'SUBSTITUTION', 'None', (7, 16))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('R132H', 'Var', (0, 5))
18902	29792149	Mutant IDH enzymes including IDH1(R132H) almost lose the function of the wild-type (WT) enzyme.	('IDH', 'Gene', (7, 10))	('function', 'MPA', (57, 65))	('lose', 'NegReg', (48, 52))	('IDH1', 'Gene', (29, 33))	('IDH', 'Gene', '3417', (7, 10))	('R132H', 'SUBSTITUTION', 'None', (34, 39))	('IDH1', 'Gene', '3417', (29, 33))	('IDH', 'Gene', (29, 32))	('IDH', 'Gene', '3417', (29, 32))	('R132H', 'Var', (34, 39))
18903	29792149	However, these mutant proteins can reduce alpha-KG to D-2-hydroxyglutaric acid (D2HG), using NADPH as the cofactor (Figure 1B).	('D-2-hydroxyglutaric acid', 'Chemical', '-', (54, 78))	('proteins', 'Protein', (22, 30))	('NADPH', 'Gene', (93, 98))	('alpha-KG', 'MPA', (42, 50))	('NADPH', 'Gene', '1666', (93, 98))	('reduce', 'NegReg', (35, 41))	('mutant', 'Var', (15, 21))	('alpha-KG', 'Chemical', 'MESH:D007656', (42, 50))
18904	29792149	This new function leads to a high cellular level of D2HG, which is an inhibitor of alpha-KG dependent histone demethylases as well as DNA methyl hydroxylases, causing a genome-wide histone/DNA hypermethylation phenotype.	('histone/DNA hypermethylation phenotype', 'MPA', (181, 219))	('causing', 'Reg', (159, 166))	('ethyl', 'Chemical', '-', (139, 144))	('D2HG', 'Var', (52, 56))	('alpha-KG', 'Chemical', 'MESH:D007656', (83, 91))	('ethyl', 'Chemical', '-', (199, 204))	('ethyl', 'Chemical', '-', (113, 118))
18905	29792149	Recent studies showed introducing R132H IDH1 mutation recapitulated the phenotype and blocked cell differentiation of the recipient cells.	('IDH1', 'Gene', (40, 44))	('R132H', 'SUBSTITUTION', 'None', (34, 39))	('IDH1', 'Gene', '3417', (40, 44))	('cell differentiation of the recipient cells', 'CPA', (94, 137))	('blocked', 'NegReg', (86, 93))	('R132H', 'Var', (34, 39))
18906	29792149	These lines of evidence have indicated that IDH mutation is a key step towards oncogenesis and a potential drug target for intervention.	('mutation', 'Var', (48, 56))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', (44, 47))
18907	29792149	There has been a significant amount of interest in discovering inhibitors of mutant IDH during the past few years.	('IDH', 'Gene', '3417', (84, 87))	('mutant', 'Var', (77, 83))	('IDH', 'Gene', (84, 87))
18908	29792149	Figure 1C shows structurally distinct inhibitors of mutant IDH.	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', (59, 62))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('mutant', 'Var', (52, 58))
18910	29792149	Given the limited number of available inhibitors as well as the high potential to become potential therapeutics for these cancers, more chemotypes of inhibitors of mutant IDH are needed.	('mutant', 'Var', (164, 170))	('IDH', 'Gene', '3417', (171, 174))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('IDH', 'Gene', (171, 174))
18911	29792149	Here, we report the discovery and structure activity relationships (SAR) of aromatic sulfonamides as a new class of inhibitors of IDH1(R132H).	('aromatic', 'Chemical', '-', (76, 84))	('R132H', 'Var', (135, 140))	('IDH1', 'Gene', (130, 134))	('R132H', 'SUBSTITUTION', 'None', (135, 140))	('IDH1', 'Gene', '3417', (130, 134))	('sulfonamides', 'Chemical', 'MESH:D013449', (85, 97))
18912	29792149	Antitumor activities of selected compounds are also reported against primary tumor cells from GBM patients bearing IDH1 R132H mutation.	('tumor', 'Disease', (4, 9))	('R132H', 'SUBSTITUTION', 'None', (120, 125))	('IDH1', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('IDH1', 'Gene', '3417', (115, 119))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('R132H', 'Var', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (77, 82))
18966	29792149	Inhibitory activities of compounds were tested against mutant and wild-type IDH1 using our previous methods.	('IDH1', 'Gene', (76, 80))	('tested', 'Reg', (40, 46))	('mutant', 'Var', (55, 61))	('IDH1', 'Gene', '3417', (76, 80))
18967	29792149	Steady-state kinetic inhibition experiment was performed by determining initial velocities of reactions catalyzed by IDH1(R132H) with varying the concentrations of compound 9, alpha-KG and NADPH.	('R132H', 'SUBSTITUTION', 'None', (122, 127))	('alpha-KG', 'Chemical', 'MESH:D007656', (176, 184))	('IDH1', 'Gene', '3417', (117, 121))	('NADPH', 'Gene', (189, 194))	('NADPH', 'Gene', '1666', (189, 194))	('R132H', 'Var', (122, 127))	('IDH1', 'Gene', (117, 121))
18971	29792149	A biochemical assay was used to screen for new inhibitors of IDH1(R132H), which was expressed in E. coli and purified using our previous methods.	('E. coli', 'Species', '562', (97, 104))	('R132H', 'Var', (66, 71))	('R132H', 'SUBSTITUTION', 'None', (66, 71))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (61, 65))
18974	29792149	We performed compound screening at 50 muM followed by IC50 (concentration at which a compound can inhibit the enzyme activity by 50%) and Ki (inhibition constant) determination for active hits, compound 1 (Figure 2) was found to be a novel inhibitor of IDH1(R132H) with a Ki value of 8.2 muM.	('muM', 'Gene', (288, 291))	('R132H', 'Var', (258, 263))	('muM', 'Gene', '56925', (38, 41))	('activity', 'MPA', (117, 125))	('IDH1', 'Gene', (253, 257))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('R132H', 'SUBSTITUTION', 'None', (258, 263))	('muM', 'Gene', (38, 41))	('inhibit', 'NegReg', (98, 105))	('muM', 'Gene', '56925', (288, 291))	('IDH1', 'Gene', '3417', (253, 257))
18985	29792149	Compound 5 bearing a carboxylethyl group showed reduced activity with Ki of 17.5 muM, as compared with compounds 1 and 2.	('activity', 'MPA', (56, 64))	('reduced', 'NegReg', (48, 55))	('ethyl', 'Chemical', '-', (29, 34))	('muM', 'Gene', '56925', (81, 84))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('carboxylethyl', 'Var', (21, 34))	('muM', 'Gene', (81, 84))
18988	29792149	2-Bromo compounds 8 - 11 with different aromatic sulfonyl groups were synthesized and tested for their activities inhibiting IDH1(R132H).	('2-Bromo compounds 8 - 11', 'Chemical', '-', (0, 24))	('aromatic', 'Chemical', '-', (40, 48))	('IDH1', 'Gene', '3417', (125, 129))	('inhibiting', 'NegReg', (114, 124))	('R132H', 'Var', (130, 135))	('IDH1', 'Gene', (125, 129))	('R132H', 'SUBSTITUTION', 'None', (130, 135))
18992	29792149	These results suggest that electron-donating and/or bulky aromatic groups are more favored at this position.	('aromatic', 'Chemical', '-', (58, 66))	('bulky aromatic', 'Var', (52, 66))	('electron-donating', 'Var', (27, 44))
18993	29792149	Compound 12 (Ki = 6.8 muM, Figure 2) is ~6-fold less active than compound 9, showing the 2-Br group in 9 is significantly more favorable than the 2-H.	('2-Br', 'Var', (89, 93))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('muM', 'Gene', '56925', (22, 25))	('muM', 'Gene', (22, 25))
18997	29792149	However, compound 17 having a 1-OH showed enhanced activity (Ki = 7.3 muM), which is considerably more active than 16 with a 1-OMe.	('activity', 'MPA', (51, 59))	('enhanced', 'PosReg', (42, 50))	('muM', 'Gene', '56925', (70, 73))	('1-OMe', 'Chemical', '-', (125, 130))	('1-OH', 'Chemical', '-', (30, 34))	('1-OH', 'Var', (30, 34))	('muM', 'Gene', (70, 73))
18999	29792149	Compound 20 having a smaller -Cl at this position is a weaker inhibitor of IDH1(R132H) (Ki = 16.1 muM), although it is possible that the -F group also contributes to the inhibition.	('muM', 'Gene', (98, 101))	('R132H', 'Var', (80, 85))	('IDH1', 'Gene', (75, 79))	('R132H', 'SUBSTITUTION', 'None', (80, 85))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('IDH1', 'Gene', '3417', (75, 79))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('muM', 'Gene', '56925', (98, 101))
19000	29792149	Initial velocities of IDH1(R132H) were determined with increasing concentrations of 9, the substrate alpha-KG and cofactor NADPH.	('R132H', 'Var', (27, 32))	('alpha-KG', 'Chemical', 'MESH:D007656', (101, 109))	('NADPH', 'Gene', (123, 128))	('R132H', 'SUBSTITUTION', 'None', (27, 32))	('IDH1', 'Gene', (22, 26))	('NADPH', 'Gene', '1666', (123, 128))	('IDH1', 'Gene', '3417', (22, 26))
19004	29792149	Finally, we tested antitumor activities of potent inhibitors 9 and 10 against proliferation of BT142 glioma cells harboring R132H IDH1 mutation (Figure 5).	('tested', 'Reg', (12, 18))	('glioma', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('R132H', 'Var', (124, 129))	('BT142', 'CellLine', 'CVCL:D718', (95, 100))	('IDH1', 'Gene', (130, 134))	('R132H', 'SUBSTITUTION', 'None', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('IDH1', 'Gene', '3417', (130, 134))	('tumor', 'Disease', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
19005	29792149	In the meantime, activity of these compounds against BXD-3752 glioma cells without an IDH1 mutation was also evaluated.	('mutation', 'Var', (91, 99))	('IDH1', 'Gene', (86, 90))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH1', 'Gene', '3417', (86, 90))	('activity', 'MPA', (17, 25))	('glioma', 'Disease', (62, 68))
19010	29792149	As shown in Figure 5A, compounds 9 and 10 at 5 muM strongly inhibited the growth of BT142 glioma cells with R132H IDH1 mutation, while these two compounds did not show activity against BXD-3752 cells.	('IDH1', 'Gene', (114, 118))	('glioma', 'Disease', (90, 96))	('muM', 'Gene', (47, 50))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('R132H', 'Var', (108, 113))	('inhibited', 'NegReg', (60, 69))	('muM', 'Gene', '56925', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1', 'Gene', '3417', (114, 118))	('R132H', 'SUBSTITUTION', 'None', (108, 113))	('growth', 'CPA', (74, 80))	('BT142', 'CellLine', 'CVCL:D718', (84, 89))
19012	29792149	These results show that potent inhibitors of IDH1(R132H) have selective activity against glioma cells containing the IDH1 mutation.	('IDH1', 'Gene', '3417', (45, 49))	('R132H', 'SUBSTITUTION', 'None', (50, 55))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('IDH1', 'Gene', '3417', (117, 121))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('mutation', 'Var', (122, 130))	('glioma', 'Disease', (89, 95))	('R132H', 'Var', (50, 55))	('IDH1', 'Gene', (45, 49))	('IDH1', 'Gene', (117, 121))
19013	29792149	In summary, a series of aromatic sulfonamide compounds have been found to be novel, potent inhibitors of R132H mutant IDH1 with Ki values as low as 0.6 muM.	('IDH1', 'Gene', (118, 122))	('sulfonamide', 'Chemical', 'MESH:D013449', (33, 44))	('IDH1', 'Gene', '3417', (118, 122))	('muM', 'Gene', '56925', (152, 155))	('R132H', 'Var', (105, 110))	('aromatic', 'Chemical', '-', (24, 32))	('muM', 'Gene', (152, 155))	('inhibitors', 'NegReg', (91, 101))	('R132H', 'SUBSTITUTION', 'None', (105, 110))
19015	29792149	For the aromatic amine moiety, 1-hydroxy and 2-bromo groups have been found to be critical to the inhibition of IDH1(R132H).	('R132H', 'Var', (117, 122))	('IDH1', 'Gene', (112, 116))	('inhibition', 'NegReg', (98, 108))	('R132H', 'SUBSTITUTION', 'None', (117, 122))	('aromatic amine', 'Chemical', '-', (8, 22))	('IDH1', 'Gene', '3417', (112, 116))
19018	29792149	Enzyme kinetics studies showed that compound 9 is a competitive inhibitor of IDH1(R132H) against the substrate alpha-KG and a non-competitive inhibitor against the cofactor NADPH.	('alpha-KG', 'Chemical', 'MESH:D007656', (111, 119))	('IDH1', 'Gene', (77, 81))	('R132H', 'Var', (82, 87))	('IDH1', 'Gene', '3417', (77, 81))	('NADPH', 'Gene', (173, 178))	('NADPH', 'Gene', '1666', (173, 178))	('R132H', 'SUBSTITUTION', 'None', (82, 87))
19019	29792149	In addition, potent sulfonamide inhibitors of IDH1(R132H) are highly selective, showing no or negligible inhibitory activity against WT or R132C IDH1 (Table 1).	('IDH1', 'Gene', (145, 149))	('IDH1', 'Gene', (46, 50))	('R132H', 'Var', (51, 56))	('IDH1', 'Gene', '3417', (145, 149))	('IDH1', 'Gene', '3417', (46, 50))	('R132H', 'SUBSTITUTION', 'None', (51, 56))	('R132C', 'Mutation', 'rs121913499', (139, 144))	('R132C', 'Var', (139, 144))	('sulfonamide', 'Chemical', 'MESH:D013449', (20, 31))
19020	29792149	Potent inhibitors 9 and 10 exhibited strong activity against proliferation of BT142 glioma cells with IDH1 R132H mutation, while these compounds did not significantly affect growth of BXD-3752 cells without IDH1 mutation.	('IDH1', 'Gene', (207, 211))	('R132H', 'Var', (107, 112))	('BT142', 'CellLine', 'CVCL:D718', (78, 83))	('glioma', 'Disease', (84, 90))	('R132H', 'SUBSTITUTION', 'None', (107, 112))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('IDH1', 'Gene', '3417', (207, 211))	('IDH1', 'Gene', (102, 106))	('activity', 'MPA', (44, 52))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('IDH1', 'Gene', '3417', (102, 106))	('proliferation', 'CPA', (61, 74))
19021	29792149	These results suggest further characterization and optimization of these compounds are warranted with a goal to find a clinically useful drug targeting IDH1 mutated gliomas.	('IDH1', 'Gene', (152, 156))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('IDH1', 'Gene', '3417', (152, 156))	('mutated', 'Var', (157, 164))	('gliomas', 'Disease', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
19028	21559010	In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.	('arms 1p', 'Gene', (220, 227))	('chromosomal', 'Gene', (208, 219))	('R132H', 'Mutation', 'rs121913500', (165, 170))	('losses', 'NegReg', (198, 204))	('tumours', 'Phenotype', 'HP:0002664', (252, 259))	('R132H protein', 'Protein', (165, 178))	('oligodendrocytic tumours', 'Disease', 'MESH:D009369', (235, 259))	('oligodendrocytic tumours', 'Disease', (235, 259))	('isocitrate dehydrogenase 1', 'Gene', (138, 164))	('mutated', 'Var', (130, 137))	('isocitrate dehydrogenase 1', 'Gene', '3417', (138, 164))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('arms 1p', 'Gene', '3075', (220, 227))
19070	21559010	Mutated isocitrate dehydrogenase 1 (IDH1) R132H protein was detected using a monoclonal mouse antibody targeting the mutated IDH1 R132H protein, known as mIDH1R132, as described previously.	('R132H', 'Mutation', 'rs121913500', (130, 135))	('IDH1', 'Gene', (155, 159))	('isocitrate dehydrogenase 1', 'Gene', (8, 34))	('IDH1', 'Gene', (36, 40))	('mutated', 'Var', (117, 124))	('R132H', 'Mutation', 'rs121913500', (42, 47))	('isocitrate dehydrogenase 1', 'Gene', '3417', (8, 34))	('IDH1', 'Gene', '3417', (155, 159))	('IDH1', 'Gene', '3417', (125, 129))	('IDH1', 'Gene', '3417', (36, 40))	('mouse', 'Species', '10090', (88, 93))	('R132H', 'Var', (130, 135))	('IDH1', 'Gene', (125, 129))
19077	21559010	Evaluation of immunostaining with mIDH1R132 was performed by one of the neuropathologists (AvD) as previously reported, and samples were classified as either positive or negative for mutated IDH1 protein.	('IDH1', 'Gene', (35, 39))	('IDH1', 'Gene', (191, 195))	('mutated', 'Var', (183, 190))	('IDH1', 'Gene', '3417', (35, 39))	('IDH1', 'Gene', '3417', (191, 195))
19083	21559010	Established clinical prognostic factors for LGG were used in the model, as well as contrast enhancement, extent of resection, radiotherapy and the molecular markers Ki-67, mutated IDH1 R132H protein and combined loss of 1p/19q.	('IDH1', 'Gene', (180, 184))	('R132H', 'Mutation', 'rs121913500', (185, 190))	('IDH1', 'Gene', '3417', (180, 184))	('LGG', 'Disease', (44, 47))	('loss', 'NegReg', (212, 216))	('mutated', 'Var', (172, 179))
19094	21559010	Table 3 shows the molecular tumour profiles, summarising the results of PROX1 protein expression, mutated IHD1 R132 protein, combined losses of chromosomal arms 1p and 19q, that is, loss of heterozygosity (LOH) 1p/19q, and Ki-67.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('loss of heterozygosity', 'Var', (182, 204))	('Ki-67', 'Var', (223, 228))	('arms 1p', 'Gene', '3075', (156, 163))	('losses', 'NegReg', (134, 140))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('arms 1p', 'Gene', (156, 163))	('chromosomal', 'Protein', (144, 155))	('IHD1 R132', 'Gene', (106, 115))	('tumour', 'Disease', (28, 34))	('mutated', 'Var', (98, 105))	('PROX1 protein', 'Protein', (72, 85))
19102	21559010	Ninety tumour samples were found to stain for the mutated IDH1 R132H protein (Table 3).	('R132H', 'Var', (63, 68))	('IDH1', 'Gene', '3417', (58, 62))	('R132H', 'Mutation', 'rs121913500', (63, 68))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('protein', 'Protein', (69, 76))	('mutated', 'Var', (50, 57))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))	('IDH1', 'Gene', (58, 62))
19103	21559010	In general, most cells stained positively for mIDH1R132 in tumours that harboured the mutated IDH1 R132H protein.	('R132H', 'Mutation', 'rs121913500', (99, 104))	('mutated', 'Var', (86, 93))	('stained positively', 'Reg', (23, 41))	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', (47, 51))	('IDH1', 'Gene', '3417', (94, 98))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('IDH1', 'Gene', '3417', (47, 51))	('tumours', 'Disease', (59, 66))
19106	21559010	Twenty-five oligodendrogliomas showed combined losses of chromosomal arms 1p/19q.	('arms 1p', 'Gene', (69, 76))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('arms 1p', 'Gene', '3075', (69, 76))	('chromosomal', 'Var', (57, 68))	('oligodendrogliomas', 'Disease', (12, 30))	('losses', 'NegReg', (47, 53))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (12, 30))
19108	21559010	Eight oligoastrocytomas showed combined 1p/19q loss.	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (6, 23))	('1p/19q loss', 'Var', (40, 51))	('oligoastrocytomas', 'Disease', (6, 23))
19113	21559010	Analysis of the prognostic significance of PROX1 using the Kaplan-Meier model showed that high PROX1 expression (>30% of the tumour cells) correlated with shorter overall survival, compared with lower PROX1 expression (10-30%, respectively, <10% of the tumour cells) (Figure 2A).	('overall survival', 'MPA', (163, 179))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('PROX1', 'Gene', (95, 100))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('high', 'Var', (90, 94))	('shorter', 'NegReg', (155, 162))	('tumour', 'Disease', (253, 259))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('expression', 'MPA', (101, 111))	('tumour', 'Disease', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))
19118	21559010	The variable IDH1 mutation was identified as an independent predictor for longer overall survival in the full model.	('longer', 'PosReg', (74, 80))	('IDH1', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', '3417', (13, 17))	('overall survival', 'MPA', (81, 97))
19124	21559010	PROX1 emerged as an independent marker for survival in the multivariate analysis, together with established molecular prognostic factors such as LOH 1p/19q and mutated IDH1 R132H protein.	('IDH1', 'Gene', '3417', (168, 172))	('mutated', 'Var', (160, 167))	('R132H', 'Var', (173, 178))	('R132H', 'Mutation', 'rs121913500', (173, 178))	('IDH1', 'Gene', (168, 172))
19133	21559010	We found a strong correlation between favourable outcome and LOH 1p/19q in oligodendrocytic tumours, confirming the importance of this biomarker for survival.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('oligodendrocytic tumours', 'Disease', 'MESH:D009369', (75, 99))	('oligodendrocytic tumours', 'Disease', (75, 99))	('LOH 1p/19q', 'Var', (61, 71))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
19135	21559010	In addition, the presence of mutated IDH R132H protein was identified as an independent marker for longer survival in our study sample.	('longer', 'PosReg', (99, 105))	('protein', 'Protein', (47, 54))	('R132H', 'Mutation', 'rs121913500', (41, 46))	('mutated', 'Var', (29, 36))	('IDH', 'Gene', (37, 40))
19136	21559010	Mutations in IDH1 and the clinical implications of this biomarker for gliomas have received considerable attention lately.	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
19137	21559010	Heterozygous point mutations in codon 132 are frequently present in LGG, anaplastic gliomas and secondary glioblastomas, that is, highly malignant tumours that evolve from previously confirmed LGG.	('LGG', 'Disease', (68, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (106, 119))	('codon 132', 'Gene', (32, 41))	('Heterozygous point mutations', 'Var', (0, 28))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('glioblastomas', 'Disease', 'MESH:D005909', (106, 119))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('gliomas', 'Disease', (84, 91))	('malignant tumours', 'Disease', 'MESH:D009369', (137, 154))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('glioblastomas', 'Disease', (106, 119))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('malignant tumours', 'Disease', (137, 154))	('present', 'Reg', (57, 64))
19138	21559010	In the vast majority of cases, IDH1 mutations affect codon 132 and in 93% of all cases they are of the R132H type.	('IDH1', 'Gene', '3417', (31, 35))	('R132H', 'Mutation', 'rs121913500', (103, 108))	('mutations', 'Var', (36, 45))	('affect', 'Reg', (46, 52))	('codon 132', 'MPA', (53, 62))	('IDH1', 'Gene', (31, 35))
19139	21559010	The development of an IDH1 R132H mutation-specific antibody suitable for immunohistochemistry has largely facilitated detection of mutated IDH1 protein in clinical practice.	('R132H', 'Var', (27, 32))	('IDH1', 'Gene', (139, 143))	('protein', 'Protein', (144, 151))	('R132H', 'Mutation', 'rs121913500', (27, 32))	('mutated', 'Var', (131, 138))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (139, 143))	('facilitated', 'PosReg', (106, 117))	('IDH1', 'Gene', '3417', (22, 26))	('detection', 'MPA', (118, 127))
19140	21559010	As both PROX1 protein expression and mutated IDH1 R132 protein were identified as prognostic factors in our study, we searched for a possible correlation between the two biomarkers but did not find any evidence for this (data not shown).	('IDH1', 'Gene', '3417', (45, 49))	('protein', 'Protein', (55, 62))	('PROX1', 'Protein', (8, 13))	('IDH1', 'Gene', (45, 49))	('mutated', 'Var', (37, 44))
19143	21559010	Inactivation of PROX1 in the developing eye lens leads to the downregulation of the cell cycle inhibitors p27 and p57 and deregulation of E-cadherin.	('p27', 'Gene', '3429', (106, 109))	('PROX1', 'Gene', (16, 21))	('p27', 'Gene', (106, 109))	('p57', 'Gene', '1028', (114, 117))	('downregulation', 'NegReg', (62, 76))	('cell cycle', 'CPA', (84, 94))	('deregulation', 'MPA', (122, 134))	('p57', 'Gene', (114, 117))	('Inactivation', 'Var', (0, 12))	('E-cadherin', 'Gene', (138, 148))	('E-cadherin', 'Gene', '999', (138, 148))
19157	33472598	The diagnostic value of lower glucose consumption for IDH1 mutated gliomas on FDG-PET Non-invasive diagnosis of IDH1 mutation for gliomas has great clinical significance, and PET has natural advantage to detect metabolism, as IDH mutated gliomas share lower glucose consumption.	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('gliomas', 'Disease', (67, 74))	('IDH1', 'Gene', (112, 116))	('glucose consumption', 'MPA', (258, 277))	('gliomas', 'Disease', (130, 137))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glucose', 'Chemical', 'MESH:D005947', (258, 265))	('gliomas', 'Disease', (238, 245))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('lower', 'NegReg', (24, 29))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('glucose consumption', 'MPA', (30, 49))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('mutation', 'Var', (117, 125))	('lower', 'NegReg', (252, 257))
19159	33472598	The glucose consumption was investigated with U251 cells expressing wild-type or mutated IDH1 by glucose assay.	('IDH1', 'Gene', (89, 93))	('mutated', 'Var', (81, 88))	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('glucose', 'Chemical', 'MESH:D005947', (4, 11))
19162	33472598	Seventy-one glioma cases were enrolled, including 30 carrying IDH1 mutation.	('mutation', 'Var', (67, 75))	('glioma', 'Disease', (12, 18))	('IDH1', 'Gene', (62, 66))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
19163	33472598	Glucose consumption of U251 IDH1 mutant cells (0.209 +- 0.0472 mg/ml) was obviously lower than IDH1wild-type cells (0.978 +- 0.0773 mg/ml, P = 0.0001) and astrocyte controls (0.335 +- 0.0592 mg/ml, P = 0.0451).	('Glucose consumption', 'Disease', (0, 19))	('U251', 'Var', (23, 27))	('Glucose consumption', 'Disease', 'MESH:D014397', (0, 19))	('mutant', 'Var', (33, 39))	('lower', 'NegReg', (84, 89))	('IDH1', 'Gene', (28, 32))
19164	33472598	Meanwhile, the glucose quantity in IDH1mutant glioma samples were significantly lower than those in IDH1 wild-type tissues (1.033 +- 1.19608 vs 6.361 +- 4.3909 mg/g, P = 0.0051).	('glioma', 'Disease', (46, 52))	('glucose', 'Chemical', 'MESH:D005947', (15, 22))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('IDH1mutant', 'Var', (35, 45))	('lower', 'NegReg', (80, 85))	('glucose quantity', 'MPA', (15, 31))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
19165	33472598	Silico analysis and western blot confirmed that HK1 and PKM2 in IDH1 wild-type gliomas were significantly higher than in IDH1 mutant group, while PC was significantly higher in IDH1 mutant gliomas.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('IDH1', 'Gene', (64, 68))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('HK1', 'Enzyme', (48, 51))	('mutant', 'Var', (126, 132))	('higher', 'PosReg', (106, 112))	('gliomas', 'Disease', (189, 196))	('PKM2', 'Enzyme', (56, 60))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
19166	33472598	SUVmax on PET can predict IDH1 mutation with adequate sensitivity and specificity, as is supported by reduced glucose consumption in IDH1 mutant gliomas.	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('mutation', 'Var', (31, 39))	('mutant', 'Var', (138, 144))	('IDH1', 'Gene', (26, 30))	('IDH1', 'Gene', (133, 137))	('glucose consumption', 'MPA', (110, 129))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('reduced', 'NegReg', (102, 109))	('gliomas', 'Disease', (145, 152))
19167	33472598	Recent genomic investigation has been updating the molecular profiling for adult gliomas, as isocitrate dehydrogenase (IDH) mutated gliomas showed better clinical prognosis.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('adult gliomas', 'Disease', 'MESH:D005910', (75, 88))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('better', 'PosReg', (147, 153))	('mutated', 'Var', (124, 131))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('adult gliomas', 'Disease', (75, 88))
19168	33472598	Mutated IDH induces abnormal 2-hydroxyglutarate (2-HG) accumulation, which affects the epigenetics and promotes tumorigenesis.	('affects', 'Reg', (75, 82))	('abnormal 2-hydroxyglutarate', 'Phenotype', 'HP:0012401', (20, 47))	('IDH', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (29, 47))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('promotes', 'PosReg', (103, 111))	('epigenetics', 'MPA', (87, 98))	('tumor', 'Disease', (112, 117))	('induces', 'Reg', (12, 19))	('Mutated', 'Var', (0, 7))
19178	33472598	PET images could reveal metabolic differences among gliomas, providing a possible non-invasive preoperative molecular diagnosis with FDG, 11C-choline(CHO), or 11C-methionine(MET).	('11C-choline', 'Chemical', '-', (138, 149))	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('MET', 'Chemical', 'MESH:D008715', (174, 177))	('FDG', 'Var', (133, 136))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('11C-choline', 'MPA', (138, 149))	('FDG', 'Chemical', 'MESH:D019788', (133, 136))	('11C-methionine', 'Var', (159, 173))	('11C-methionine', 'Chemical', '-', (159, 173))
19181	33472598	Moreover, several studies revealed an association between the FDG uptake and the status of IDH mutation or the prognosis of glioma, as SUVmax or different ratio based on SUV showed its diagnostic value.	('glioma', 'Disease', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('IDH', 'Gene', (91, 94))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('FDG', 'Chemical', 'MESH:D019788', (62, 65))	('mutation', 'Var', (95, 103))
19182	33472598	Here, we reported a simple calculation of the maximum uptake of FDG (SUVmax) on PET showed good prediction of IDH mutation from a cohort of 71 glioma patients.	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('IDH', 'Disease', (110, 113))	('glioma', 'Disease', (143, 149))	('mutation', 'Var', (114, 122))	('FDG', 'Chemical', 'MESH:D019788', (64, 67))
19183	33472598	ROC analysis also showed that SUVmax might serve as a predictor to differentiate IDH1mut vs IDH1wt gliomas, and also GBM (grade IV) vs LGG (grade II and grade III).	('IDH1mut', 'Var', (81, 88))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
19184	33472598	Non-invasive and accurate prediction of IDH1 mutation in glioma has great potential in routine clinical application.	('IDH1', 'Gene', (40, 44))	('glioma', 'Disease', (57, 63))	('mutation', 'Var', (45, 53))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
19185	33472598	Additionally, the consumption of glucose was reduced in IDH1mut gliomas, as demonstrated by cell line-based experiments and silico analysis.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('reduced', 'NegReg', (45, 52))	('glucose', 'Chemical', 'MESH:D005947', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('IDH1mut', 'Var', (56, 63))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('consumption of glucose', 'MPA', (18, 40))
19186	33472598	So, a simple index of FDG PET here was demonstrated to predict IDH mutation in gliomas.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('mutation', 'Var', (67, 75))	('IDH', 'Gene', (63, 66))	('predict', 'Reg', (55, 62))	('FDG', 'Chemical', 'MESH:D019788', (22, 25))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
19212	33472598	SUVmax of FDG uptake in IDH1mut gliomas was around 2.761 +- 1.275 on FDG-PET analysis, which is significantly lower than 7.656 +- 5.780 in IDH1wt gliomas (P<0.0001, Fig.	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('FDG', 'Chemical', 'MESH:D019788', (69, 72))	('gliomas', 'Disease', (146, 153))	('gliomas', 'Disease', (32, 39))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('IDH1mut', 'Var', (24, 31))	('lower', 'NegReg', (110, 115))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('FDG', 'Chemical', 'MESH:D019788', (10, 13))
19215	33472598	ROC analysis suggested that SUVmax of 3.85 could serve as a threshold for predicting IDH1mutation (AUC = 0.831, 95%CI 0.736 to 0.927, P<0.0001), and the sensitivity of differentiating IDH1mut and IDH1wt gliomas reaches 73.2%, while the specificity reaches 86.7% (Fig.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('IDH1mutation', 'Var', (85, 97))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('IDH1mut', 'Var', (184, 191))	('gliomas', 'Disease', (203, 210))
19216	33472598	The effect of IDH1 mutation on glucose uptake were investigated with U251 expressing IDH1wt or IDH1mut as well as normal astrocytes lines (NHA).	('IDH1', 'Gene', (14, 18))	('IDH1mut', 'Var', (95, 102))	('IDH1wt', 'Var', (85, 91))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))
19218	33472598	The quantitation of glucose by HPLC in clinical glioma samples (8 IDH1mut, 8 IDH1wt, and 7 normal brain) were also analyzed, and the results showed that the level of glucose in IDH1wt samples were significantly higher than those in IDH1mut ones (6.361 +- 4.3909 mg/g vs 1.033 +- 1.19608 mg/g, P = 0.0051, Fig.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('IDH1wt', 'Var', (177, 183))	('glucose', 'Chemical', 'MESH:D005947', (166, 173))	('higher', 'PosReg', (211, 217))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('glioma', 'Disease', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (20, 27))
19221	33472598	Silico analysis showed that HK1 and PKM2 in IDH1wt gliomas were significantly higher than those in IDH1mut group (P = 0.0002 and P<0.0001, respectively), while PC was significantly higher in IDH1mut than in IDH1wt gliomas (P<0.0001, Fig.	('gliomas', 'Disease', (51, 58))	('PKM2', 'Enzyme', (36, 40))	('higher', 'PosReg', (78, 84))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('IDH1wt', 'Var', (44, 50))	('gliomas', 'Disease', (214, 221))	('higher', 'PosReg', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('HK1', 'Gene', (28, 31))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('IDH1mut', 'Var', (191, 198))
19222	33472598	Western blot also confirmed the up-regulation of HK1 and PKM2 in IDH1wt gliomas (P = 0.0004 and P = 0.0003, respectively).	('PKM2', 'Enzyme', (57, 61))	('HK1', 'Enzyme', (49, 52))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('up-regulation', 'PosReg', (32, 45))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))	('IDH1wt', 'Var', (65, 71))
19223	33472598	Instead, the expression of PC was higher in IDH1mut gliomas than in IDH1wt group (P = 0.0046).	('IDH1mut', 'Var', (44, 51))	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('expression', 'MPA', (13, 23))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('higher', 'PosReg', (34, 40))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))
19224	33472598	No difference of PC expression was observed between IDH1mut gliomas and normal brain tissues (P = 0.1536, Fig.	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('IDH1mut', 'Var', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
19225	33472598	These findings indicate that the glycolysis is inhibited, while glycogenesis is stimulated by IDH1 mutation, which is in line with reduced glucose consumption in IDH1mut gliomas.	('stimulated', 'PosReg', (80, 90))	('IDH1', 'Gene', (94, 98))	('inhibited', 'NegReg', (47, 56))	('glycolysis', 'MPA', (33, 43))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('glycogenesis', 'MPA', (64, 76))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('gliomas', 'Disease', (170, 177))	('mutation', 'Var', (99, 107))	('glucose', 'Chemical', 'MESH:D005947', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))
19226	33472598	Previous studies suggested that IDH1 mutation is a powerful prognostic marker for gliomas, and it is also considered as a predictive biomarker for extensive surgical resection, radiotherapy and chemotherapy in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (210, 217))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
19227	33472598	So, IDH1 mutation has been applied in molecular typing and comprehensive diagnosis for gliomas.	('mutation', 'Var', (9, 17))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('IDH1', 'Gene', (4, 8))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('gliomas', 'Disease', (87, 94))
19234	33472598	FDG-PET could predict IDH1 mutation non-invasively and pre-operatively, and it could also identify LGG and GBM hereby.	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('FDG', 'Chemical', 'MESH:D019788', (0, 3))
19237	33472598	Since IDH1 mutation have a great impact on glucose metabolism, which is also supported by cell line and bioinformatics analysis.	('glucose metabolism', 'Disease', (43, 61))	('glucose metabolism', 'Disease', 'MESH:D044882', (43, 61))	('mutation', 'Var', (11, 19))	('IDH1', 'Gene', (6, 10))	('impact', 'Reg', (33, 39))
19238	33472598	IDH1 mutation might contribute to the lower glucose metabolism and good prediction of malignancy in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('lower', 'NegReg', (38, 43))	('malignancy in gliomas', 'Disease', 'MESH:D005910', (86, 107))	('glucose metabolism', 'Disease', (44, 62))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glucose metabolism', 'Disease', 'MESH:D044882', (44, 62))	('IDH1', 'Gene', (0, 4))	('malignancy in gliomas', 'Disease', (86, 107))	('mutation', 'Var', (5, 13))
19239	33472598	analyzed a cohort o 59 gliomas and found that the ratio of SUVmax of glioma to SUVmean of the contralateral cortex (G/C ratio) was correlated with IDH1 mutation, which also supported our conclusion.	('glioma', 'Disease', (69, 75))	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('correlated', 'Reg', (131, 141))	('gliomas', 'Disease', (23, 30))	('glioma', 'Disease', (23, 29))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('IDH1', 'Gene', (147, 151))	('mutation', 'Var', (152, 160))
19241	33472598	In order to clarify the influence of IDH1 mutation on glucose consumption and the level of glucose in gliomas, we compared the expression of key gluconeogenesis and glycolysis enzymes in clinical tissues.	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('IDH1', 'Gene', (37, 41))	('glucose', 'Chemical', 'MESH:D005947', (91, 98))	('mutation', 'Var', (42, 50))	('gliomas', 'Disease', (102, 109))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))
19242	33472598	Both bioinformatics analysis and clinical validation have shown that IDH1 mutation could significantly alter gluconeogenesis and glycolysis, which contributes to the lower glucose consumption in IDH1mut gliomas.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('mutation', 'Var', (74, 82))	('IDH1', 'Gene', (69, 73))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('gluconeogenesis', 'MPA', (109, 124))	('glucose consumption', 'MPA', (172, 191))	('IDH1mut', 'Var', (195, 202))	('glycolysis', 'MPA', (129, 139))	('lower', 'NegReg', (166, 171))	('alter', 'Reg', (103, 108))	('glucose', 'Chemical', 'MESH:D005947', (172, 179))	('gliomas', 'Disease', (203, 210))
19243	33472598	Chen et al found that cell growth was significantly inhibited either by IDH1 knockout or mutant, which could be restored after the reintroduction of IDH1, and glucose transport is the key pivot during this event.	('IDH1', 'Gene', (72, 76))	('glucose', 'Chemical', 'MESH:D005947', (159, 166))	('glucose transport', 'MPA', (159, 176))	('knockout', 'Var', (77, 85))	('cell growth', 'CPA', (22, 33))	('inhibited', 'NegReg', (52, 61))	('mutant', 'Var', (89, 95))
19244	33472598	IDH1 mutation could dramatically affect tumor metabolism and epigenetics, as proline is upregulated simultaneously with 2-HG in IDH1mut gliomas in our previous study.	('2-HG', 'Chemical', 'MESH:C019417', (120, 124))	('epigenetics', 'MPA', (61, 72))	('tumor metabolism', 'Disease', (40, 56))	('upregulated', 'PosReg', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor metabolism', 'Disease', 'MESH:D008659', (40, 56))	('affect', 'Reg', (33, 39))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('gliomas', 'Disease', (136, 143))	('proline', 'MPA', (77, 84))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('proline', 'Chemical', 'MESH:D011392', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
19245	33472598	Glutamate dehydrogenase 2 (GLUD2) also could compensate to synthesize alpha-KG in IDH1mut gliomas, thereby resisting the growth inhibition caused by IDH1 mutation.	('gliomas', 'Disease', (90, 97))	('IDH1mut', 'Var', (82, 89))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('IDH1', 'Gene', (149, 153))	('resisting', 'NegReg', (107, 116))	('mutation', 'Var', (154, 162))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('growth inhibition', 'MPA', (121, 138))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
19246	33472598	So, there might be multiple manners that IDH1 mutation could affect glucose consumption.	('affect', 'Reg', (61, 67))	('glucose', 'Chemical', 'MESH:D005947', (68, 75))	('IDH1', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('glucose consumption', 'MPA', (68, 87))
19247	33472598	In conclusion, SUVmax on FDG-PET showed adequate sensitivity and specificity in predicting IDH1 mutation.	('FDG', 'Chemical', 'MESH:D019788', (25, 28))	('predicting', 'Reg', (80, 90))	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))
19248	33472598	IDH2 mutation contribute a small population of gliomas, which cannot be identified by PET analysis now.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('gliomas', 'Disease', (47, 54))	('IDH2', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('mutation', 'Var', (5, 13))
19253	29628290	Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers.	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('TP53', 'Gene', '7157', (89, 93))	('IDH1', 'Gene', '3417', (66, 70))	('CTNNB1', 'Gene', '1499', (49, 55))	('lower', 'NegReg', (42, 47))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (16, 25))	('leukocyte levels', 'MPA', (105, 121))	('higher', 'PosReg', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('CTNNB1', 'Gene', (49, 55))	('BRAF', 'Gene', '673', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', (83, 87))	('CASP8', 'Gene', '841', (98, 103))	('TP53', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (57, 61))	('IDH1', 'Gene', (66, 70))	('CASP8', 'Gene', (98, 103))
19254	29628290	Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('copy', 'Var', (103, 107))	('involved', 'Reg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
19262	29628290	Antibodies against CTLA-4, PD-1, and PD-L1 are effective in treating a variety of malignancies.	('Antibodies', 'Var', (0, 10))	('PD-L1', 'Gene', (37, 42))	('CTLA-4', 'Gene', '1493', (19, 25))	('malignancies', 'Disease', (82, 94))	('PD-1', 'Gene', (27, 31))	('effective', 'Reg', (47, 56))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('CTLA-4', 'Gene', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
19277	29628290	The six resulting clusters "Immune Subtypes", C1-C6 (with 2416, 2591, 2397, 1157, 385 and 180 cases, respectively) were characterized by a distinct distribution of scores over the five representative signatures (Figure 1A, bottom panel), and showed distinct immune signatures based on the dominant sample characteristics of their tumor samples (Figure 1B-C).	('C1-C6', 'Var', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
19287	29628290	IDH mutations were enriched in C5 over C4 (80% of IDH mutations, p<2x10-16, Fisher's exact test), suggesting an association of IDH-mutations with favorable immune composition.	('association', 'Interaction', (112, 123))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', (50, 53))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (50, 53))
19300	29628290	The spatial fraction of tumor regions with tumor infiltrating lymphocytes (TILs), estimated by analysis of digitized TCGA H&E stained slides, varied by immune subtype, with C2 the highest (p<10-16, Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('with', 'Var', (168, 172))	('H&E', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
19313	29628290	The immune infiltrate was related to measures of DNA damage, including copy number variation (CNV) burden (both in terms of number of segments and fraction of genome alterations), aneuploidy, loss of heterozygosity (LOH), homologous recombination deficiency (HRD), and intratumor heterogeneity (ITH) (Figure 4A).	('aneuploidy', 'Disease', (180, 190))	('loss of heterozygosity', 'Var', (192, 214))	('homologous recombination deficiency', 'Disease', (222, 257))	('copy number variation', 'MPA', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('HRD', 'Disease', (259, 262))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('HRD', 'Disease', 'None', (259, 262))	('men', 'Species', '9606', (137, 140))
19314	29628290	LF correlated negatively with CNV segment burden, with strongest correlation in C6 and C2, and positively with aneuploidy, LOH, HRD, and mutation load, particularly in C3.	('HRD', 'Disease', (128, 131))	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('negatively', 'NegReg', (14, 24))	('HRD', 'Disease', 'None', (128, 131))	('men', 'Species', '9606', (37, 40))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('CNV segment burden', 'MPA', (30, 48))	('mutation load', 'Var', (137, 150))
19315	29628290	Chromosome 1p (including TNFRS9 and VTCN1) amplification associated with higher LF, while its deletion did the opposite.	('VTCN1', 'Gene', '79679', (36, 41))	('TNFRS9', 'Gene', (25, 31))	('amplification', 'Var', (43, 56))	('VTCN1', 'Gene', (36, 41))	('higher', 'PosReg', (73, 79))
19317	29628290	Amplification of chr2, 20q, and 22q (including CTLA4, CD40, and ADORA2 respectively), and deletions of 5q, 9p, and chr19 (including IL13 and IL4, IFNA1 and IFNA2, and ICAM1 respectively) associated with changes in macrophage polarity (Figure S4A).	('macrophage polarity', 'CPA', (214, 233))	('IFNA1', 'Gene', '3439', (146, 151))	('ADORA2', 'Gene', (64, 70))	('chr19', 'Gene', (115, 120))	('CTLA4', 'Gene', (47, 52))	('chr2', 'Gene', (17, 21))	('IL13', 'Gene', (132, 136))	('ICAM1', 'Gene', (167, 172))	('deletions', 'Var', (90, 99))	('ICAM1', 'Gene', '3383', (167, 172))	('IFNA2', 'Gene', (156, 161))	('CD40', 'Gene', (54, 58))	('IFNA2', 'Gene', '3440', (156, 161))	('associated', 'Reg', (187, 197))	('changes', 'Reg', (203, 210))	('ADORA2', 'Gene', '135', (64, 70))	('IFNA1', 'Gene', (146, 151))	('CD40', 'Gene', '958', (54, 58))	('IL4', 'Gene', '3565', (141, 144))	('IL4', 'Gene', (141, 144))	('IL13', 'Gene', '3596', (132, 136))	('CTLA4', 'Gene', '1493', (47, 52))
19318	29628290	IL-13 influences macrophage polarization, implying a possible basis for our observation that IL13 deletions associated with altered M0 macrophage fractions.	('IL-13', 'Gene', '3596', (0, 5))	('influences', 'Reg', (6, 16))	('IL13', 'Gene', (93, 97))	('IL13', 'Gene', '3596', (93, 97))	('macrophage polarization', 'CPA', (17, 40))	('IL-13', 'Gene', (0, 5))	('deletions', 'Var', (98, 107))
19321	29628290	We correlated mutations in 299 cancer driver genes with immune subtypes, and found 33 significant associations (q<0.1) (Figure 4C, Table S2).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('associations', 'Interaction', (98, 110))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (14, 23))
19322	29628290	C1 was enriched in mutations in driver genes, such as TP53, PIK3CA, PTEN or KRAS.	('PIK3CA', 'Gene', (60, 66))	('KRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (76, 80))	('PTEN', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (54, 58))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', (54, 58))
19324	29628290	C3 was enriched in BRAF, CDH1 and PBRM1 mutations, a finding of note since patients with PBRM1 mutations respond particularly well to IM therapy.	('BRAF', 'Gene', '673', (19, 23))	('CDH1', 'Gene', '999', (25, 29))	('BRAF', 'Gene', (19, 23))	('PBRM1', 'Gene', (89, 94))	('PBRM1', 'Gene', (34, 39))	('patients', 'Species', '9606', (75, 83))	('PBRM1', 'Gene', '55193', (89, 94))	('PBRM1', 'Gene', '55193', (34, 39))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (95, 104))	('CDH1', 'Gene', (25, 29))
19325	29628290	C4 was enriched in CTNNB1, EGFR, and IDH1 mutations.	('CTNNB1', 'Gene', (19, 25))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('IDH1', 'Gene', (37, 41))	('CTNNB1', 'Gene', '1499', (19, 25))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (42, 51))
19327	29628290	C6 only showed an enrichment in KRAS G12 mutations.	('mutations', 'Var', (41, 50))	('men', 'Species', '9606', (24, 27))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))
19328	29628290	Mutations in 23 driver genes associated with increased LF either in specific tumor types or across them, including TP53, HLA-B, BRAF, PTEN, NF1, APC and CASP8.	('BRAF', 'Gene', '673', (128, 132))	('HLA-B', 'Gene', '3106', (121, 126))	('HLA-B', 'Gene', (121, 126))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', '5728', (134, 138))	('tumor type', 'Disease', (77, 87))	('NF1', 'Gene', (140, 143))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (115, 119))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('tumor type', 'Disease', 'MESH:D009369', (77, 87))	('NF1', 'Gene', '4763', (140, 143))	('CASP8', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CASP8', 'Gene', '841', (153, 158))	('APC', 'Disease', (145, 148))	('PTEN', 'Gene', (134, 138))	('BRAF', 'Gene', (128, 132))
19329	29628290	Twelve other events were associated with lower LF, including the IDH1 R132H mutation, GATA3, KRAS, NRAS, CTNNB1 and NOTCH1 (Figure 4D).	('IDH1', 'Gene', '3417', (65, 69))	('GATA3', 'Gene', (86, 91))	('R132H', 'Var', (70, 75))	('KRAS', 'Gene', (93, 97))	('NOTCH1', 'Gene', '4851', (116, 122))	('NOTCH1', 'Gene', (116, 122))	('R132H', 'Mutation', 'rs121913500', (70, 75))	('GATA3', 'Gene', '2625', (86, 91))	('lower', 'NegReg', (41, 46))	('KRAS', 'Gene', '3845', (93, 97))	('CTNNB1', 'Gene', '1499', (105, 111))	('NRAS', 'Gene', (99, 103))	('NRAS', 'Gene', '4893', (99, 103))	('IDH1', 'Gene', (65, 69))	('CTNNB1', 'Gene', (105, 111))
19331	29628290	PI3K, NOTCH and RTK/RAS pathway disruptions showed variable, tumor type specific effects on immune factors, while TGF-beta pathway disruptions more consistently associated with lower LF (most prominently in C2 and C6; Figure S4C), higher eosinophils (C2), and increased macrophages.	('lower', 'NegReg', (177, 182))	('TGF-beta', 'Gene', '7040', (114, 122))	('disruptions', 'Var', (131, 142))	('disruptions', 'Var', (32, 43))	('RTK/RAS pathway', 'Gene', (16, 31))	('increased', 'PosReg', (260, 269))	('eosinophils', 'MPA', (238, 249))	('higher', 'PosReg', (231, 237))	('TGF-beta', 'Gene', (114, 122))	('tumor type', 'Disease', (61, 71))	('eosin', 'Chemical', 'MESH:D004801', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor type', 'Disease', 'MESH:D009369', (61, 71))	('macrophages', 'CPA', (270, 281))
19333	29628290	Thus, TGF-beta pathway disruption has context-dependent effects on LF, but may promote increased macrophages, particularly M1.	('TGF-beta', 'Gene', (6, 14))	('disruption', 'Var', (23, 33))	('promote increased', 'PosReg', (79, 96))	('macrophages', 'CPA', (97, 108))	('TGF-beta', 'Gene', '7040', (6, 14))
19339	29628290	No single cis-eQTL significantly correlated with PD-L1 expression, although the SNP rs822337, approximately 1KB upstream of CD274 transcription start, correlated weakly (p=0.074;1.3x10-4 unadjusted; Figure S4G).	('CD274', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (49, 54))	('CD274', 'Gene', '29126', (124, 129))	('rs822337', 'Var', (84, 92))	('PD-L1', 'Gene', (49, 54))	('rs822337', 'Mutation', 'rs822337', (84, 92))
19340	29628290	Lymphocyte fractions tended to be lower in people of Asian ancestry, particularly in UCEC and BLCA (Figure S4H).	('BLCA', 'Disease', (94, 98))	('lower', 'NegReg', (34, 39))	('Asian ancestry', 'Var', (53, 67))	('Lymphocyte fractions', 'CPA', (0, 20))	('UCEC', 'Disease', (85, 89))	('BLCA', 'Chemical', '-', (94, 98))	('people', 'Species', '9606', (43, 49))
19341	29628290	Peptides predicted to bind with MHC proteins (pMHCs) and induce antitumor adaptive immunity were identified from SNV and indel mutations.	('tumor', 'Disease', (68, 73))	('MHC proteins', 'Protein', (32, 44))	('indel mutations', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('bind', 'Interaction', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('induce', 'PosReg', (57, 63))
19343	29628290	Neoantigen load also associated with higher content of CD8 T cells, M1 macrophages, and CD4 memory T cells, and lower Tregs, mast, dendritic, and memory B cells in multiple tumor types (Figure S4K).	('content', 'MPA', (44, 51))	('CD8', 'Gene', '925', (55, 58))	('higher', 'PosReg', (37, 43))	('CD4 memory T cells', 'CPA', (88, 106))	('tumor type', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor type', 'Disease', 'MESH:D009369', (173, 183))	('CD8', 'Gene', (55, 58))	('Neoantigen load', 'Var', (0, 15))	('multiple tumor', 'Disease', 'MESH:D009369', (164, 178))	('multiple tumor', 'Disease', (164, 178))	('Tregs', 'CPA', (118, 123))	('lower', 'NegReg', (112, 117))
19351	29628290	In a regression model of all tumors, high load of each virus type associated with immune features (Figure S5C, cancer-type adjusted).	('tumors', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (66, 76))	('immune', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high load', 'Var', (37, 46))
19370	29628290	CD40 (Figure 6C), IL10 and IDO1, inversely correlated with gene expression, suggesting epigenetic silencing.	('CD40', 'Gene', (0, 4))	('IDO1', 'Gene', (27, 31))	('IL10', 'Gene', (18, 22))	('IL10', 'Gene', '3586', (18, 22))	('correlated', 'Reg', (43, 53))	('gene expression', 'MPA', (59, 74))	('epigenetic silencing', 'Var', (87, 107))	('IDO1', 'Gene', '3620', (27, 31))	('CD40', 'Gene', '958', (0, 4))
19373	29628290	In particular, IMs SLAMF7, SELP, TNFSF4 (OX40L), IL10, and CD40 were amplified less frequently in C5 relative to all samples, while TGFB1, KIR2DL1, and KIR2DL3 deletions were enriched in C5 (Figure 6D), consistent with our observation of lower immune infiltration with TGFB1 deletion (Figure S4A).	('CD40', 'Gene', (59, 63))	('IL10', 'Gene', '3586', (49, 53))	('TGFB1', 'Gene', '7040', (269, 274))	('TGFB1', 'Gene', (269, 274))	('SELP', 'Gene', '6403', (27, 31))	('CD40', 'Gene', '958', (59, 63))	('TNFSF4', 'Gene', '7292', (33, 39))	('SELP', 'Gene', (27, 31))	('TGFB1', 'Gene', '7040', (132, 137))	('deletion', 'Var', (275, 283))	('KIR2DL1', 'Gene', '3802', (139, 146))	('TGFB1', 'Gene', (132, 137))	('OX40L', 'Gene', (41, 46))	('KIR2DL3', 'Gene', (152, 159))	('TNFSF4', 'Gene', (33, 39))	('KIR2DL3', 'Gene', '3804', (152, 159))	('lower', 'NegReg', (238, 243))	('IL10', 'Gene', (49, 53))	('SLAMF7', 'Gene', '57823', (19, 25))	('KIR2DL1', 'Gene', (139, 146))	('OX40L', 'Gene', '7292', (41, 46))	('SLAMF7', 'Gene', (19, 25))
19387	29628290	Some T cell associated ligands were subtype specific, such as CD276 (C2, C6), IL1B (C6), and VEGFB (C4).	('VEGFB', 'Gene', '7423', (93, 98))	('IL1B', 'Gene', (78, 82))	('VEGFB', 'Gene', (93, 98))	('IL1B', 'Gene', '3553', (78, 82))	('CD276', 'Var', (62, 67))
19392	29628290	Somatic alterations in AKAP9, HRAS, KRAS and PREX2 were inferred to modulate the activity of IMs according to both the MR- and SYGNAL-PanImmune, a significant overlap (p=1.6x10-7, Fisher's exact test).	('HRAS', 'Gene', (30, 34))	('PREX2', 'Gene', (45, 50))	('alterations', 'Var', (8, 19))	('KRAS', 'Gene', (36, 40))	('modulate', 'Reg', (68, 76))	('KRAS', 'Gene', '3845', (36, 40))	('AKAP9', 'Gene', '10142', (23, 28))	('activity', 'MPA', (81, 89))	('AKAP9', 'Gene', (23, 28))	('HRAS', 'Gene', '3265', (30, 34))	('PREX2', 'Gene', '80243', (45, 50))
19397	29628290	Conversely, causal mutations shared across tumor types may associate with different tumor-specific downstream regulators.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor type', 'Disease', (43, 53))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor type', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Disease', (43, 48))	('associate', 'Reg', (59, 68))
19402	29628290	C3 was regulated by KLF15 and miR-141-3p.	('KLF15', 'Gene', (20, 25))	('miR-141-3p', 'Var', (30, 40))	('KLF15', 'Gene', '28999', (20, 25))
19405	29628290	In SYGNAL-PanImmune, the increased expression of biclusters enriched with IMs from KIRC, LGG, LUSC, and READ was associated with worse patient survival (CoxPH BH adjusted p-value <= 0.05).	('BH', 'Chemical', '-', (159, 161))	('patient', 'Species', '9606', (135, 142))	('increased', 'PosReg', (25, 34))	('expression', 'MPA', (35, 45))	('biclusters', 'Var', (49, 59))	('worse', 'NegReg', (129, 134))	('patient survival', 'CPA', (135, 151))	('Cox', 'Gene', '1351', (153, 156))	('Cox', 'Gene', (153, 156))
19422	29628290	For example, KRAS mutations were enriched in C1 and but infrequent in C5, suggesting that mutations in driver oncogenes alter pathways that affect immune cells.	('mutations', 'Var', (90, 99))	('alter', 'Reg', (120, 125))	('pathways', 'Pathway', (126, 134))	('affect', 'Reg', (140, 146))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
19423	29628290	Driver mutations such as TP53, by inducing genomic instability, may alter the immune landscape via the generation of neoantigens.	('inducing', 'Reg', (34, 42))	('TP53', 'Gene', (25, 29))	('alter', 'Reg', (68, 73))	('genomic instability', 'MPA', (43, 62))	('immune landscape', 'MPA', (78, 94))	('TP53', 'Gene', '7157', (25, 29))	('neoantigens', 'MPA', (117, 128))	('mutations', 'Var', (7, 16))
19424	29628290	Our findings confirmed previous work showing that mutations in BRAF enhance the immune infiltrate while those in IDH1 diminish it.	('diminish', 'NegReg', (118, 126))	('immune infiltrate', 'CPA', (80, 97))	('IDH1', 'Gene', (113, 117))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', '3417', (113, 117))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('enhance', 'PosReg', (68, 75))
19432	29628290	Predicted intracellular networks implied that seven immune related TFs(including interferon and STAT-family transcription factors) may play an active role in transcriptional events related to leukocyte infiltration, and that mutations in six genes (including Ras-family proteins) may influence immune infiltration.	('influence', 'Reg', (284, 293))	('mutations', 'Var', (225, 234))	('STAT', 'Disease', (96, 100))	('immune infiltration', 'CPA', (294, 313))	('STAT', 'Disease', 'None', (96, 100))
19500	29628290	Comparing functional annotations of these clusters, we found that overlap to be reflected in the concordant distribution of mean scores of IFN-gamma, TGF-beta, mutation load and overall leukocyte infiltrate among the overlapping clusters.	('IFN-gamma', 'Gene', '3458', (139, 148))	('IFN-gamma', 'Gene', (139, 148))	('TGF-beta', 'Gene', '7040', (150, 158))	('mutation load', 'Var', (160, 173))	('TGF-beta', 'Gene', (150, 158))
19530	29628290	All clonality calls for quantifying intratumoral heterogeneity (ITH) were also determined by ABSOLUTE, which models tumor copy number alterations and mutations as mixtures of subclonal and clonal components of varying ploidy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
19532	29628290	Scores for copy number burden, aneuploidy, loss of heterozygosity, and homologous recombination deficiency (HRD) were derived.	('aneuploidy', 'Disease', (31, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (31, 41))	('HRD', 'Disease', 'None', (108, 111))	('copy number burden', 'Var', (11, 29))	('loss of heterozygosity', 'Var', (43, 65))	('HRD', 'Disease', (108, 111))
19533	29628290	Copy number burden scores frac_altered and n_segs ("fraction altered", and "number of segments", respectively) represent the fraction of bases deviating from baseline ploidy (defined as above 0.1 or below - 0.1 in log2 relative copy number (CN) space), and the total number of segments in each sample's copy number profile, respectively.	('men', 'Species', '9606', (89, 92))	('deviating', 'NegReg', (143, 152))	('frac_altered', 'Var', (26, 38))	('men', 'Species', '9606', (280, 283))
19534	29628290	LOH_n_seg and LOH_frac_altered are the number of segments with LOH events and fraction of bases with LOH events, respectively.	('LOH_n_seg', 'Var', (0, 9))	('men', 'Species', '9606', (52, 55))	('LOH_frac_altered', 'Var', (14, 30))
19535	29628290	HRD score is a measure quantifying defects in homologous recombination that sums 3 separate metrics of genomic scarring: large (>15 Mb) non-arm-level regions with LOH, large-scale state transitions (breaks between adjacent segments of >10 Mb), and subtelomeric regions with allelic imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (282, 291))	('HRD', 'Disease', 'None', (0, 3))	('scarring', 'Phenotype', 'HP:0100699', (111, 119))	('defects', 'Var', (35, 42))	('HRD', 'Disease', (0, 3))	('LOH', 'NegReg', (163, 166))	('men', 'Species', '9606', (226, 229))
19536	29628290	Aneuploidy scores were calculated as the sum total of amplified or deleted (collectively "altered") arms.	('deleted', 'Var', (67, 74))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('Aneuploidy', 'Disease', (0, 10))
19537	29628290	To call arm alterations, sample chromosome arms were first stratified by sample tumor type, type of alteration being tested (amplification or deletion), and chromosome arm (1p, 1q, etc.).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (12, 23))	('tumor type', 'Disease', 'MESH:D009369', (80, 90))	('tumor type', 'Disease', (80, 90))	('deletion', 'Var', (142, 150))
19543	29628290	Furthermore, for each gene, we similarly computed significances of differences of CIBERSORT-estimated relative immune cell subtype levels from their expected levels first in "amplified" and then in "deleted" samples in order to identify the effects of copy number amplification and deletion respectively on immune infiltrate composition while controlling for cancer disease type.	('cancer disease', 'Disease', 'MESH:D009369', (359, 373))	('deletion', 'Var', (282, 290))	('effects', 'Reg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('cancer disease', 'Disease', (359, 373))	('copy number amplification', 'Var', (252, 277))
19544	29628290	Contributors: Galen Gao, Andrew Cherniack We focused our analysis on genes identified as drivers by the TCGA PanCancer Atlas Driver Mutation Working Group (the CGAT list; TCGA Research Network, "Comprehensive Discovery and Characterization of Driver Genes and Mutations in Human Cancers", unpublished data) that were identified as 1) having 10 or more mutations overall and 2) mutated in two or more tissues.	('CGAT', 'Gene', (160, 164))	('Human', 'Species', '9606', (273, 278))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (352, 361))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancers', 'Disease', (279, 286))	('Cancer', 'Disease', (279, 285))	('Cancers', 'Disease', 'MESH:D009369', (279, 286))	('Cancers', 'Phenotype', 'HP:0002664', (279, 286))	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('CGAT', 'Gene', '6570', (160, 164))
19547	29628290	Contributor: Eduard Porta Pardo We used domainXplorer to identify driver genes and mutations that correlate with the leukocyte fraction of the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
19548	29628290	The algorithm uses a linear model that takes into account potential biases caused by differences in the immune responses between the tissues of origin of the tumors, the gender of the patient, the total number of missense mutations in the sample or the patient's age as covariates.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('patient', 'Species', '9606', (253, 260))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('missense mutations', 'Var', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (184, 191))
19552	29628290	For each pathway, samples from each of 30 tumor types were divided into two groups of altered and intact cases based on acquisition of non-silent or frameshift mutations, heterozygous or homozygous deletions, or amplifications, in at least one member of the pathway.	('tumor type', 'Disease', (42, 52))	('amplifications', 'Var', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor type', 'Disease', 'MESH:D009369', (42, 52))
19562	29628290	To perform association analyses with single nucleotide polymorphisms (SNPs) at the PDL1 locus, we imputed the genotype data using the Haplotype Reference Consortium as a reference.	('PDL1', 'Gene', '29126', (83, 87))	('single nucleotide polymorphisms', 'Var', (37, 68))	('PDL1', 'Gene', (83, 87))
19571	29628290	Variation in sequencing coverage and tumor purity require careful consideration in order to mitigate the risk of impacting mutation calls and on pMHC, and prior to pMHC calling, sequencing data was subjected to rigorous harmonization efforts, performed by the PanCancer MC3 Consortium.	('Cancer', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impacting', 'Reg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation calls', 'Var', (123, 137))	('Cancer', 'Disease', 'MESH:D009369', (263, 269))
19598	29628290	Using output from a PanCan GISTIC2.0 run on ISAR-corrected Affymetrix genome-wide human SNP6.0 array data, deep amplifications, shallow amplifications, non-alterations, shallow deletions, and deep deletions of each immunomodulator gene were called as described in "Genomic Correlations with Immune Phenotype" above for 8461 tumors that both were immune subtyped and had ABSOLUTE purity and ploidy calls.	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('non-alterations', 'Var', (152, 167))	('human', 'Species', '9606', (82, 87))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('shallow deletions', 'Var', (169, 186))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('deep deletions', 'Var', (192, 206))	('shallow amplifications', 'Var', (128, 150))
19614	29628290	Mutation or copy-number events identified by the domainXplorer algorithm were tested for statistical association with the 32 cMRs identified, using the DIGGIT algorithm (above), and retained if associated with one or more of the 32 cMRs in at least one tumor-specific context.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('copy-number', 'Var', (12, 23))
19652	28924174	investigated the prognostic relevance of four prominent molecular markers in WHO grade II gliomas, including TP53 mutation, 1p/19q deletion, O6-methylguanylmethyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation.	('isocitrate dehydrogenase 1', 'Gene', (207, 233))	('IDH1', 'Gene', (235, 239))	('II gliomas', 'Disease', 'MESH:D005910', (87, 97))	('mutation', 'Var', (114, 122))	('isocitrate dehydrogenase 1', 'Gene', '3417', (207, 233))	('IDH1', 'Gene', '3417', (235, 239))	('TP53', 'Gene', '7157', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('TP53', 'Gene', (109, 113))	('mutation', 'Var', (241, 249))	('II gliomas', 'Disease', (87, 97))	('MGMT', 'Gene', (175, 179))	('MGMT', 'Gene', '4255', (175, 179))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
19653	28924174	The results showed that 1p/19q codeletion and IDH1 mutation are prognostic markers following the administration of radiotherapy or chemotherapy.	('IDH1', 'Gene', (46, 50))	('1p/19q codeletion', 'Var', (24, 41))	('mutation', 'Var', (51, 59))	('IDH1', 'Gene', '3417', (46, 50))
19654	28924174	TP53 mutations have been most commonly identified in A, whereas 1p/19q codeletion is more common in OD.	('TP53', 'Gene', '7157', (0, 4))	('common', 'Reg', (90, 96))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('identified', 'Reg', (39, 49))	('1p/19q codeletion', 'Var', (64, 81))
19655	28924174	OAs appear to be heterogeneous and typically show either TP53 mutations or 1p/19q deletion.	('1p/19q', 'Disease', (75, 81))	('show', 'Reg', (45, 49))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
19656	28924174	The 2016 WHO classification of CNS tumours defines tumour entities based on histology and a combination of molecular aberrations, such as IDH mutation, ATRX mutation, 1p/19q deletion, and TP53 mutation.	('1p/19q deletion', 'Var', (167, 182))	('IDH', 'Gene', (138, 141))	('TP53', 'Gene', '7157', (188, 192))	('IDH', 'Gene', '3417', (138, 141))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('CNS tumours defines tumour', 'Disease', (31, 57))	('CNS tumour', 'Phenotype', 'HP:0100006', (31, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('ATRX', 'Gene', (152, 156))	('TP53', 'Gene', (188, 192))	('CNS tumours defines tumour', 'Disease', 'MESH:D009369', (31, 57))	('ATRX', 'Gene', '546', (152, 156))
19660	28924174	A total of 7 studies from the Gene Expression Omnibus (GEO) dataset were included: GSE68848, GSE16011, GSE4290, GSE12657, GSE21354, GSE2223, and GSE70231.	('GSE70231', 'Var', (145, 153))	('GSE4290', 'Chemical', '-', (103, 110))	('GSE4290', 'Var', (103, 110))	('GSE21354', 'Var', (122, 130))	('GSE12657', 'Var', (112, 120))	('GSE16011', 'Var', (93, 101))	('GSE2223', 'Chemical', '-', (132, 139))	('GSE2223', 'Var', (132, 139))	('GSE68848', 'Var', (83, 91))
19663	28924174	For this purpose, five datasets containing information on A and OD (GSE4290, GSE16011, GSE21354, GSE68848, and CGGA) were selected to compare mRNA expression signatures among low-grade glioma subtypes; these datasets included a total of 148A and 98 OD samples.	('GSE68848', 'Var', (97, 105))	('GSE4290', 'Chemical', '-', (68, 75))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('GSE21354', 'Var', (87, 95))	('GSE4290', 'Var', (68, 75))	('glioma', 'Disease', (185, 191))	('GSE16011', 'Var', (77, 85))
19688	28924174	The 2016 version of the WHO classification criteria for glioma combined genotypic parameters with traditional histology and included IDH mutation, ATRX mutation, 1p/19q deletion, and TP53 mutation as classification factors.	('IDH', 'Gene', '3417', (133, 136))	('glioma', 'Disease', (56, 62))	('ATRX', 'Gene', (147, 151))	('TP53', 'Gene', '7157', (183, 187))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('TP53', 'Gene', (183, 187))	('1p/19q deletion', 'Var', (162, 177))	('ATRX', 'Gene', '546', (147, 151))	('IDH', 'Gene', (133, 136))	('mutation', 'Var', (152, 160))
19689	28924174	With the continued development of high-throughput genomics technology, many studies have explored genetic alterations associated with low-grade gliomas, such as telomerase reverse transcriptase (TERT) promoter mutation, CpG island methylator phenotypes (CIMP), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and changes in nestin expression.	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (261, 300))	('MGMT', 'Gene', '4255', (302, 306))	('telomerase reverse transcriptase', 'Gene', '7015', (161, 193))	('TERT', 'Gene', (195, 199))	('nestin', 'Protein', (345, 351))	('MGMT', 'Gene', (302, 306))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('mutation', 'Var', (210, 218))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (261, 300))	('TERT', 'Gene', '7015', (195, 199))	('changes', 'Reg', (334, 341))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('expression', 'MPA', (352, 362))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('telomerase reverse transcriptase', 'Gene', (161, 193))
19702	28924174	Overexpression of MTHFD2 has been associated with poor prognosis in patients with breast cancer, and knockdown of MTHFD2 in breast cancer cell lines reduced cell viability; increased apoptosis; decreased migration, invasion, and metastasis; and increased the expression of cancer stem cell markers.	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('cancer', 'Disease', (89, 95))	('increased', 'PosReg', (173, 182))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('migration', 'CPA', (204, 213))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('patients', 'Species', '9606', (68, 76))	('MTHFD2', 'Gene', '10797', (114, 120))	('breast cancer', 'Disease', (124, 137))	('MTHFD2', 'Gene', (114, 120))	('invasion', 'CPA', (215, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('reduced', 'NegReg', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('MTHFD2', 'Gene', '10797', (18, 24))	('expression', 'MPA', (259, 269))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Disease', (131, 137))	('breast cancer', 'Disease', (82, 95))	('cell viability', 'CPA', (157, 171))	('cancer', 'Disease', (273, 279))	('MTHFD2', 'Gene', (18, 24))	('increased', 'PosReg', (245, 254))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('decreased', 'NegReg', (194, 203))	('apoptosis', 'CPA', (183, 192))	('knockdown', 'Var', (101, 110))
19703	28924174	reported that knockdown of MTHFD2 decreased cell growth, induced differentiation, and impaired colony formation in primary acute myeloid leukaemia (AML) blasts.	('decreased', 'NegReg', (34, 43))	('acute myeloid leukaemia', 'Disease', (123, 146))	('MTHFD2', 'Gene', '10797', (27, 33))	('differentiation', 'CPA', (65, 80))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (129, 146))	('induced', 'Reg', (57, 64))	('AML', 'Disease', (148, 151))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (123, 146))	('impaired colony', 'Disease', 'MESH:D009422', (86, 101))	('cell growth', 'CPA', (44, 55))	('knockdown', 'Var', (14, 23))	('impaired colony', 'Disease', (86, 101))	('AML', 'Disease', 'MESH:D015470', (148, 151))	('MTHFD2', 'Gene', (27, 33))
19712	28924174	reported that inhibition of STX1A reduced glioblastoma tumour proliferation and cell invasion.	('reduced', 'NegReg', (34, 41))	('glioblastoma tumour', 'Disease', (42, 61))	('cell invasion', 'CPA', (80, 93))	('glioblastoma tumour', 'Disease', 'MESH:D005909', (42, 61))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('STX1A', 'Gene', (28, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('STX1A', 'Gene', '6804', (28, 33))	('inhibition', 'Var', (14, 24))
19728	28924174	APP mutations cause Alzheimer's disease, and over-expression of APP has a link with shortened survival in patients with breast cancer.	('APP', 'Gene', (0, 3))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (20, 39))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('cause', 'Reg', (14, 19))	("Alzheimer's disease", 'Disease', (20, 39))	('patients', 'Species', '9606', (106, 114))	('over-expression', 'Var', (45, 60))	('mutations', 'Var', (4, 13))	('shortened', 'NegReg', (84, 93))	('APP', 'Gene', (64, 67))
19731	28924174	In a report by Sooman et al., high PTPN6 expression was found to contribute to worse prognosis in patients with anaplastic glioma, and there was an association between high PTPN6 expression and worse survival in a subgroup of patients with anaplastic oligodendroglioma (p = 0.053).	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('anaplastic glioma', 'Disease', 'MESH:D005910', (112, 129))	('PTPN6', 'Gene', (35, 40))	('expression', 'MPA', (179, 189))	('PTPN6', 'Gene', '5777', (35, 40))	('expression', 'MPA', (41, 51))	('PTPN6', 'Gene', (173, 178))	('PTPN6', 'Gene', '5777', (173, 178))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (240, 268))	('patients', 'Species', '9606', (98, 106))	('high', 'Var', (30, 34))	('high', 'Var', (168, 172))	('patients', 'Species', '9606', (226, 234))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('anaplastic oligodendroglioma', 'Disease', (240, 268))	('anaplastic glioma', 'Disease', (112, 129))
19772	25609475	Many researchers have reported increased diagnostic value when using DWI and/or DTI, and/or DSCI for tumor differentiation; however the number of studies reporting otherwise remains significant.	('increased', 'PosReg', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('DWI', 'Var', (69, 72))	('DT', 'Chemical', 'MESH:D013936', (80, 82))	('diagnostic value', 'MPA', (41, 57))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
19784	25609475	Since the measured signal is a summation of tiny signals from all individual spins, the misalignment, or "dephasing", caused by the gradient pulses results in a drop in signal intensity; the longer the diffusion distance, the lower the signal (more dephasing).	('spin', 'Gene', (77, 81))	('signal', 'MPA', (236, 242))	('lower', 'NegReg', (226, 231))	('spin', 'Gene', '10927', (77, 81))	('diffusion', 'MPA', (202, 211))	('misalignment', 'Var', (88, 100))	('signal intensity', 'MPA', (169, 185))	('drop', 'NegReg', (161, 165))
20003	33912452	In this report, we identified two novel tumor types from TCGA with LINC00460 deregulation.	('LINC00460', 'Gene', '728192', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('LINC00460', 'Gene', (67, 76))	('deregulation', 'Var', (77, 89))
20019	33912452	Several reports have shown that sponge lncRNAs play a pivotal role in various cancer types, including BRCA and abnormal expression of lncRNAs can significantly contribute to BRCA initiation and progression.	('BRCA', 'Gene', (174, 178))	('BRCA', 'Gene', '672', (174, 178))	('BRCA', 'Gene', (102, 106))	('BRCA initiation', 'Disease', (174, 189))	('BRCA initiation', 'Disease', 'MESH:D007319', (174, 189))	('contribute', 'Reg', (160, 170))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('abnormal expression', 'Var', (111, 130))	('BRCA', 'Gene', '672', (102, 106))
20032	33912452	We identified two novel (not previously reported) tumor types from the TCGA cohort with LINC00460 deregulation.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('deregulation', 'Var', (98, 110))	('tumor', 'Disease', (50, 55))	('LINC00460', 'Gene', '728192', (88, 97))	('LINC00460', 'Gene', (88, 97))
20068	33912452	GAPDH (Hs99999905) and SCARNA5 (Hs03391742_cn) transcripts were used as endogenous controls.	('SCARNA5', 'Gene', '677775', (23, 30))	('SCARNA5', 'Gene', (23, 30))	('GAPDH', 'Gene', '2597', (0, 5))	('Hs03391742_cn', 'Var', (32, 45))	('Hs99999905', 'Var', (7, 17))	('GAPDH', 'Gene', (0, 5))
20116	33912452	These data strongly suggest that LINC00460 might play a dual prognostic role across different tumors, as high LINC00460 expression predicts an increased OS, RFS and DMFS in the BRCA model, but it is also a marker for poor prognosis in at least eight distinct solid tumors (see  Figure 3C ).	('increased', 'PosReg', (143, 152))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('LINC00460', 'Gene', '728192', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LINC00460', 'Gene', (110, 119))	('DMFS', 'MPA', (165, 169))	('tumors', 'Disease', (94, 100))	('DMFS', 'Chemical', '-', (165, 169))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('BRCA', 'Gene', '672', (177, 181))	('LINC00460', 'Gene', '728192', (110, 119))	('high', 'Var', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumors', 'Disease', (265, 271))	('LINC00460', 'Gene', (33, 42))	('RFS', 'CPA', (157, 160))	('BRCA', 'Gene', (177, 181))
20121	33912452	Analysis with LINC00460 predicted an increased OS in the TNBC GEO derived cohort GSE16446 (using all TNBC samples; n= 107; HR = 0.26; 95% CI [0.09 - 0.72]; logrank p = 0.0053) ( Figure 5D ).	('LINC00460', 'Gene', (14, 23))	('LINC00460', 'Gene', '728192', (14, 23))	('TNBC', 'Gene', (57, 61))	('GSE16446', 'Var', (81, 89))
20127	33912452	Interestingly, in aggressive BRCA subtypes, high LINC00460 expression is able to predict a favorable clinical course, further strengthening the dual role for this lncRNA in OS and RFS prediction in cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('high', 'Var', (44, 48))	('cancer', 'Disease', (198, 204))	('BRCA', 'Gene', '672', (29, 33))	('LINC00460', 'Gene', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('BRCA', 'Gene', (29, 33))	('LINC00460', 'Gene', '728192', (49, 58))
20162	33912452	We have also confirmed LINC00460 deregulation in BRCA using two independent cohorts.	('BRCA', 'Gene', '672', (49, 53))	('BRCA', 'Gene', (49, 53))	('deregulation', 'Var', (33, 45))	('LINC00460', 'Gene', '728192', (23, 32))	('LINC00460', 'Gene', (23, 32))
20166	33912452	In addition, we describe here that LINC00460 high expression is significantly associated with poor survival in three different tumors (GBM, LGG and SARC) but related with a favorable survival rate in BRCA, i.e., its association to clinical outcome varies between tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('BRCA', 'Gene', '672', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('BRCA', 'Gene', (200, 204))	('LINC00460', 'Gene', (35, 44))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('LINC00460', 'Gene', '728192', (35, 44))	('high expression', 'Var', (45, 60))	('tumors', 'Disease', (263, 269))	('poor', 'NegReg', (94, 98))
20169	33912452	For example, high MALAT-1 expression has been reported as a marker for poor prognosis in various tumors, including COAD, NSCLC, STAD, PAAD, ESCA, among others, but also as a good prognosis factor for BRCA, acting as a metastasis suppressor.	('expression', 'MPA', (26, 36))	('COAD', 'Disease', 'MESH:D029424', (115, 119))	('MALAT-1', 'Gene', (18, 25))	('ESCA', 'Disease', (140, 144))	('high', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRCA', 'Gene', '672', (200, 204))	('NSCLC', 'Disease', (121, 126))	('STAD', 'Disease', (128, 132))	('PAAD', 'Disease', (134, 138))	('BRCA', 'Gene', (200, 204))	('COAD', 'Disease', (115, 119))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('MALAT-1', 'Gene', '378938', (18, 25))
20171	33912452	It has been shown that high expression of this lncRNA is related to poor clinical outcome in different cancers, but in another study, authors demonstrate that high XIST expression is related to an increased brain metastasis-free survival in BRCA patients.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('brain metastasis-free survival', 'CPA', (207, 237))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (246, 254))	('BRCA', 'Gene', '672', (241, 245))	('XIST', 'Gene', '7503', (164, 168))	('BRCA', 'Gene', (241, 245))	('increased', 'PosReg', (197, 206))	('XIST', 'Gene', (164, 168))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('high', 'Var', (159, 163))	('cancers', 'Disease', (103, 110))
20183	33912452	High expression of SFRP5 is significantly associated with a better prognosis in PAAD and BRCA.	('PAAD', 'Disease', (80, 84))	('SFRP5', 'Gene', '6425', (19, 24))	('BRCA', 'Gene', (89, 93))	('High', 'Var', (0, 4))	('associated', 'Reg', (42, 52))	('SFRP5', 'Gene', (19, 24))	('BRCA', 'Gene', '672', (89, 93))
20190	33912452	It has been previously shown that the presence of TILs improves prognosis as it modulates cancer progression and enhances chemotherapy response in TNBC, conferring a protective immunity in these patients.	('presence', 'Var', (38, 46))	('chemotherapy response', 'CPA', (122, 143))	('enhances', 'PosReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('modulates', 'Reg', (80, 89))	('prognosis', 'CPA', (64, 73))	('cancer', 'Disease', (90, 96))	('patients', 'Species', '9606', (195, 203))	('improves', 'PosReg', (55, 63))	('TILs', 'Gene', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
20198	33912452	In this regard, although there have been reports that suggest that WNT7A is an oncoprotein, it has also been shown that loss of WNT7A expression is significantly associated with poor RFS in BRCA and it is also involved in tumor cell differentiation.	('WNT7A', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('involved', 'Reg', (210, 218))	('RFS', 'MPA', (183, 186))	('WNT7A', 'Gene', '7476', (128, 133))	('BRCA', 'Gene', '672', (190, 194))	('associated', 'Reg', (162, 172))	('BRCA', 'Gene', (190, 194))	('tumor', 'Disease', (222, 227))	('WNT7A', 'Gene', '7476', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('loss', 'Var', (120, 124))	('WNT7A', 'Gene', (128, 133))
20204	33912452	This finding further strengthens the beneficial role of both transcripts in patient's prediction and prognosis as, it has been demonstrated that ER-negative breast cancers with high levels of TILs have heightened sensitivity to anthracycline-based chemotherapy, and that TILs are an independent predictor of good response to anthracycline/taxane neoadjuvant chemotherapy.	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('breast cancers', 'Disease', 'MESH:D001943', (157, 171))	('heightened', 'PosReg', (202, 212))	('breast cancers', 'Disease', (157, 171))	('high', 'Var', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('ER', 'Gene', '2099', (145, 147))	('patient', 'Species', '9606', (76, 83))	('anthracycline', 'Chemical', 'MESH:D018943', (228, 241))	('anthracycline', 'Chemical', 'MESH:D018943', (325, 338))	('sensitivity to anthracycline-based chemotherapy', 'MPA', (213, 260))	('taxane', 'Chemical', 'MESH:C080625', (339, 345))
20210	33912452	In gastric cancer patients, high expression of miR-103 was significantly associated with poor overall survival and disease-free survival and is a key factor that contributes to tumor progression.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('overall survival', 'CPA', (94, 110))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('poor', 'NegReg', (89, 93))	('contributes', 'Reg', (162, 173))	('disease-free survival', 'CPA', (115, 136))	('expression', 'MPA', (33, 43))	('miR-103', 'Var', (47, 54))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
20216	33912452	LINC00460:WNT7A ratio is a composite marker that can predict a favorable OS and DMFS in TNBC, and combination of LINC00460 and WNT7A over-expression is associated with complete pathological response (pCR) after anthracycline therapy in ER- BRCA patients.	('over-expression', 'PosReg', (133, 148))	('LINC00460', 'Gene', (0, 9))	('BRCA', 'Gene', '672', (240, 244))	('combination', 'Var', (98, 109))	('LINC00460', 'Gene', '728192', (113, 122))	('LINC00460', 'Gene', (113, 122))	('WNT7A', 'Gene', '7476', (127, 132))	('BRCA', 'Gene', (240, 244))	('LINC00460', 'Gene', '728192', (0, 9))	('DMFS', 'Chemical', '-', (80, 84))	('anthracycline', 'Chemical', 'MESH:D018943', (211, 224))	('patients', 'Species', '9606', (245, 253))	('WNT7A', 'Gene', (10, 15))	('WNT7A', 'Gene', (127, 132))	('ER', 'Gene', '2099', (236, 238))	('associated with', 'Reg', (152, 167))	('WNT7A', 'Gene', '7476', (10, 15))	('complete pathological response', 'Disease', (168, 198))
20278	26216736	However, using intra-operative MRI on these 'non-eloquent' tumors did non-significantly (p > 0,05) increased the mean EOR to a sub-total resection of 97%, when compared with a partial resection of 90% with the use of neuronavigation only.	('EOR', 'MPA', (118, 121))	('MRI', 'Var', (31, 34))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('increased', 'PosReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
20348	26454818	Sixty-eight percent (n = 34) of surgeons state that the isocitrate dehydrogenase (IDH) or 1p19q status did not alter their decision for surgical management.	('IDH', 'Gene', '3417', (82, 85))	('isocitrate dehydrogenase', 'Gene', '3417', (56, 80))	('IDH', 'Gene', (82, 85))	('1p19q status', 'Var', (90, 102))	('isocitrate dehydrogenase', 'Gene', (56, 80))
20349	26454818	1p19q loss of heterozygosity (LOH) status was the most routinely determined molecular marker requested (96 %, n = 47), followed by p53 mutation (45 %, n = 22), MGMT methylation status (39 %, n = 19), IDH1 mutation (37 %, n = 18) and finally EGFR mutation (14 %, n = 7).	('loss', 'NegReg', (6, 10))	('IDH1', 'Gene', (200, 204))	('EGFR', 'Gene', '1956', (241, 245))	('1p19q', 'Var', (0, 5))	('MGMT', 'Gene', (160, 164))	('IDH1', 'Gene', '3417', (200, 204))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('EGFR', 'Gene', (241, 245))	('MGMT', 'Gene', '4255', (160, 164))	('mutation', 'Var', (135, 143))
20356	26454818	Of note is the recent recognition of molecular subtypes of LGG, including IDH mutation and 1p/19q co-deletion, which are of increasing clinical relevance.	('1p/19q co-deletion', 'Var', (91, 109))	('IDH', 'Gene', (74, 77))	('LGG', 'Disease', (59, 62))	('IDH', 'Gene', '3417', (74, 77))
20367	26454818	The rate of permanent neurological deficits have been shown to be significantly reduced with awake mapping with less than 2 % in a recent series using intraoperative stimulation, in comparison with 15-20 % of severe worsening in series with no mapping.	('neurological deficits', 'Disease', 'MESH:D009461', (22, 43))	('permanent neurological deficits', 'Phenotype', 'HP:0002344', (12, 43))	('neurological deficit', 'Phenotype', 'HP:0000707', (22, 42))	('reduced', 'NegReg', (80, 87))	('awake mapping', 'Var', (93, 106))	('neurological deficits', 'Disease', (22, 43))	('neurological deficits', 'Phenotype', 'HP:0000707', (22, 43))
20447	31179222	The densities of neuropil obtained in THG images of histologically low-grade glioma tissue and normal white matter were higher than that obtained in THG images of high-grade glioma tissue and normal gray matter, respectively (Figure 2F,G).	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('THG', 'Chemical', '-', (149, 152))	('THG', 'Chemical', '-', (38, 41))	('higher', 'PosReg', (120, 126))	('glioma', 'Disease', (174, 180))	('densities', 'MPA', (4, 13))	('glioma', 'Disease', (77, 83))	('low-grade', 'Var', (67, 76))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
20486	31179222	The apparent diffusion coefficient (ADC) of the four samples, recorded from diffusion MRI,40 suggested that the cell density of sample 3 (0.0015400 mm2 s-1) and sample 4 (0.0013200 mm2 s-1) was on an average  40% higher than sample 1 (0.0012290 mm2 s-1) and sample 2 (0.0008282 mm2 s-1), which quantitatively agreed with THG imaging.	('0.0013200 mm2 s-1', 'Var', (171, 188))	('higher', 'PosReg', (213, 219))	('THG', 'Chemical', '-', (321, 324))	('apparent diffusion coefficient', 'MPA', (4, 34))	('cell density', 'CPA', (112, 124))	('0.0015400 mm2 s-1', 'Var', (138, 155))
20532	31179222	In case of imaging with THG and HOE three-photon fluorescence, the narrow-band filter for SHG was replaced by a broad-band filter (430-570 nm, Chroma, HQ500/140 M-2P) for collection of HOE signals.	('Chroma', 'Disease', (143, 149))	('HOE', 'Chemical', 'MESH:C017807', (32, 35))	('THG', 'Chemical', '-', (24, 27))	('Chroma', 'Disease', 'None', (143, 149))	('HOE', 'Chemical', 'MESH:C017807', (185, 188))	('430-570', 'Var', (131, 138))
20645	30873074	reviewed 72 articles focused on cancer; they reported PTG resulted inversely associated with depressive and anxious symptoms and directly related to hope, optimism, spirituality and meaning.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('inversely', 'NegReg', (67, 76))	('depressive and anxious symptoms', 'Disease', 'MESH:D000275', (93, 124))	('cancer', 'Disease', (32, 38))	('depressive and anxious symptoms', 'Phenotype', 'HP:0000716', (93, 124))	('anxious symptoms', 'Phenotype', 'HP:0000739', (108, 124))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('related', 'Reg', (138, 145))	('PTG', 'Var', (54, 57))	('associated', 'Reg', (77, 87))
20706	28717417	Consent for CSF collection was approved by the institutional review board (IRB) at each institution (Control, UCSD IRB 080012; AD, OHSU IRB 6845; PD, OHSU IRB 8122; LGG, UCSD IRB 120345X; GBM, UCSD IRB 120345X; SAH, TGen IRB 20110058).	('SAH', 'Disease', 'MESH:D013345', (211, 214))	('SAH', 'Disease', (211, 214))	('IRB 120345X', 'Var', (198, 209))	('AD', 'Disease', 'MESH:D000544', (127, 129))	('AD', 'Disease', (127, 129))	('PD', 'Disease', 'MESH:D010300', (146, 148))	('IRB 120345X', 'Var', (175, 186))
20798	26967252	Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy.	('glioma', 'Disease', (79, 85))	('IDH1', 'Gene', '3417', (42, 46))	('mutation', 'Var', (47, 55))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('positive', 'Reg', (56, 64))	('IDH1', 'Gene', (42, 46))	('patients', 'Species', '9606', (86, 94))
20800	26967252	Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors.	('tumors', 'Disease', (254, 260))	('activity', 'MPA', (200, 208))	('creatine pathway', 'Pathway', (78, 94))	('IDH', 'Gene', '3417', (232, 235))	('IDH', 'Gene', (127, 130))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('levels of intermediate metabolites', 'MPA', (40, 74))	('proline', 'Chemical', 'MESH:D011392', (20, 27))	('IDH', 'Gene', '3417', (127, 130))	('mutation positive', 'Var', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('creatine', 'Chemical', 'MESH:D003401', (78, 86))	('creatine', 'Chemical', 'MESH:D003401', (212, 220))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('positive', 'Var', (140, 148))	('increased', 'PosReg', (190, 199))	('IDH', 'Gene', (232, 235))	('arginine', 'Chemical', 'MESH:D001120', (7, 15))	('lower', 'NegReg', (118, 123))	('patients', 'Species', '9606', (166, 174))
20805	26967252	The results from The Cancer Genome Atlas (TCGA) Research Network and several other studies have pinpointed phosphoinositide 3-kinase (PI3K), RTK/RAS/PI3K, EGF receptors (EGFR), p53, retinoblastoma (RB), and PTEN signaling alterations as driving forces for high-grade glioma tumorigenesis.	('retinoblastoma', 'Gene', '5925', (182, 196))	('p53', 'Gene', (177, 180))	('retinoblastoma', 'Phenotype', 'HP:0009919', (182, 196))	('phosphoinositide 3-kinase', 'Gene', '5293', (107, 132))	('RB', 'Gene', '5925', (198, 200))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('glioma tumor', 'Disease', 'MESH:D005910', (267, 279))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (21, 40))	('phosphoinositide 3-kinase', 'Gene', (107, 132))	('retinoblastoma', 'Gene', (182, 196))	('PTEN', 'Gene', (207, 211))	('glioma tumor', 'Disease', (267, 279))	('Cancer Genome Atlas', 'Disease', (21, 40))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('RB', 'Phenotype', 'HP:0009919', (198, 200))	('p53', 'Gene', '7157', (177, 180))	('PTEN', 'Gene', '5728', (207, 211))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('alterations', 'Var', (222, 233))
20844	26967252	Levels of plasma N-acetylputrescine were 2.96-fold lower in IDH mutation positive relative to the negative glioma patients.	('Levels of plasma N-acetylputrescine', 'MPA', (0, 35))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('lower', 'NegReg', (51, 56))	('N-acetylputrescine', 'Chemical', 'MESH:C026212', (17, 35))	('IDH', 'Gene', (60, 63))	('positive', 'Var', (73, 81))	('patients', 'Species', '9606', (114, 122))	('IDH', 'Gene', '3417', (60, 63))	('mutation positive', 'Var', (64, 81))	('glioma', 'Disease', (107, 113))
20845	26967252	On the other hand, levels of plasma Methionine were 2.08-fold higher in IDH mutation positive than negative glioma patients.	('patients', 'Species', '9606', (115, 123))	('Methionine', 'Chemical', 'MESH:D008715', (36, 46))	('glioma', 'Disease', (108, 114))	('positive', 'Var', (85, 93))	('mutation positive', 'Var', (76, 93))	('levels of plasma Methionine', 'MPA', (19, 46))	('IDH', 'Gene', (72, 75))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('IDH', 'Gene', '3417', (72, 75))	('higher', 'PosReg', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))
20855	26967252	However, we did identify metabolic pathways that significantly differed by IDH mutation status (Table 4) such as, tryptophan metabolism, D-arginine and D-ornithine metabolism, and arginine and proline metabolism pathways.	('metabolic pathways', 'Pathway', (25, 43))	('D-ornithine', 'Chemical', 'MESH:D009952', (152, 163))	('D-ornithine metabolism', 'MPA', (152, 174))	('tryptophan', 'Chemical', 'MESH:D014364', (114, 124))	('differed', 'Reg', (63, 71))	('D-arginine', 'Chemical', '-', (137, 147))	('mutation', 'Var', (79, 87))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('arginine', 'Chemical', 'MESH:D001120', (180, 188))	('proline', 'Chemical', 'MESH:D011392', (193, 200))	('arginine', 'Chemical', 'MESH:D001120', (139, 147))	('tryptophan metabolism', 'MPA', (114, 135))
20860	26967252	In a recent publication by Eckel-Passow et al., gliomas could be classified into five principal groups on the basis of three tumor markers, including chromosome 1p/19q co-deletion, IDH mutation, and TERT promoter mutations in tumors.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('IDH', 'Gene', (181, 184))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('TERT', 'Gene', (199, 203))	('IDH', 'Gene', '3417', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('co-deletion', 'Var', (168, 179))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('TERT', 'Gene', '7015', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))	('gliomas', 'Disease', (48, 55))
20881	26967252	IDH mutation is not restricted to a specific histopathological type of glioma but instead was associated with a distinctive tumor-cell metabolism.	('IDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', (71, 77))	('tumor', 'Disease', (124, 129))	('mutation', 'Var', (4, 12))	('associated with', 'Reg', (94, 109))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
20883	26967252	In the current study, we identified 6 plasma metabolites that differed significantly by IDH mutation status.	('differed', 'Reg', (62, 70))	('IDH', 'Gene', (88, 91))	('IDH', 'Gene', '3417', (88, 91))	('mutation', 'Var', (92, 100))
20887	26967252	In the pathway analysis, we found tryptophan metabolism, D-arginine and D-ornithine metabolism, and arginine and proline metabolism were significantly different based on IDH mutation status.	('mutation', 'Var', (174, 182))	('different', 'Reg', (151, 160))	('tryptophan metabolism', 'MPA', (34, 55))	('D-arginine', 'Chemical', '-', (57, 67))	('IDH', 'Gene', (170, 173))	('arginine', 'Chemical', 'MESH:D001120', (100, 108))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('IDH', 'Gene', '3417', (170, 173))	('D-ornithine', 'Chemical', 'MESH:D009952', (72, 83))	('tryptophan', 'Chemical', 'MESH:D014364', (34, 44))	('proline', 'Chemical', 'MESH:D011392', (113, 120))
20888	26967252	Within the arginine and proline metabolism pathway, we found levels of intermediate metabolites in the creatine pathway, from guanidoacetic acid, creatine, and creatinine, were all significantly lower in IDH mutation positive than in negative patients.	('guanidoacetic acid', 'Chemical', 'MESH:C004946', (126, 144))	('creatinine', 'Chemical', 'MESH:D003404', (160, 170))	('creatine', 'Chemical', 'MESH:D003401', (103, 111))	('creatine pathway', 'Pathway', (103, 119))	('patients', 'Species', '9606', (243, 251))	('lower', 'NegReg', (195, 200))	('creatine', 'Chemical', 'MESH:D003401', (146, 154))	('levels of intermediate metabolites', 'MPA', (61, 95))	('creatinine', 'MPA', (160, 170))	('positive', 'Var', (217, 225))	('creatine', 'MPA', (146, 154))	('mutation positive', 'Var', (208, 225))	('IDH', 'Gene', (204, 207))	('proline', 'Chemical', 'MESH:D011392', (24, 31))	('arginine', 'Chemical', 'MESH:D001120', (11, 19))	('IDH', 'Gene', '3417', (204, 207))	('from guanidoacetic acid', 'MPA', (121, 144))
20889	26967252	However, levels of sarcosine, the downstream metabolite in the pathway, were higher in IDH mutation positive than in negative patients.	('higher', 'PosReg', (77, 83))	('positive', 'Var', (100, 108))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (87, 90))	('patients', 'Species', '9606', (126, 134))	('levels of sarcosine', 'MPA', (9, 28))	('sarcosine', 'Chemical', 'MESH:D012521', (19, 28))	('mutation positive', 'Var', (91, 108))
20892	26967252	Our results may suggest an increased activity of creatine pathway in IDH mutation positive patients, which is in line with the findings that creatine tended to be low in the high-grade tumors.	('creatine', 'Chemical', 'MESH:D003401', (49, 57))	('increased', 'PosReg', (27, 36))	('creatine pathway', 'Pathway', (49, 65))	('patients', 'Species', '9606', (91, 99))	('IDH', 'Gene', (69, 72))	('creatine', 'Chemical', 'MESH:D003401', (141, 149))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('IDH', 'Gene', '3417', (69, 72))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('activity', 'MPA', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('mutation', 'Var', (73, 81))
20894	26967252	Thus, although survival data are not available in this study yet because of short follow-up time, the plasma metabolites that significantly differed by IDH mutation status may potentially have prognostic relevance.	('plasma metabolites', 'MPA', (102, 120))	('mutation status', 'Var', (156, 171))	('differed', 'Reg', (140, 148))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', '3417', (152, 155))
20896	26967252	Mutated IDH protein leads to the generation of excessive amount of the metabolite 2-hydrocyglutarate (2-HG) in glioma tumor cells.	('glioma tumor', 'Disease', (111, 123))	('IDH', 'Gene', (8, 11))	('glioma tumor', 'Disease', 'MESH:D005910', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('generation', 'MPA', (33, 43))	('IDH', 'Gene', '3417', (8, 11))	('protein', 'Protein', (12, 19))	('2-HG', 'Chemical', '-', (102, 106))	('2-hydrocyglutarate', 'Chemical', '-', (82, 100))	('Mutated', 'Var', (0, 7))
20904	26967252	In summary, our study showed distinct signatures of plasma metabolite levels by glioma grade (high vs low) and IDH mutation status.	('glioma', 'Disease', (80, 86))	('IDH', 'Gene', (111, 114))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('IDH', 'Gene', '3417', (111, 114))	('plasma metabolite levels', 'MPA', (52, 76))	('mutation', 'Var', (115, 123))
20921	16404364	In addition, an inverse correlation of cytoplasmc Survivin positivity with GBM apoptotic index, and a positive association between cytoplasmic Survivin and size of the tumours were observed.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('positive', 'PosReg', (102, 110))	('positivity', 'Var', (59, 69))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('tumours', 'Disease', (168, 175))	('inverse', 'NegReg', (16, 23))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))
20926	16404364	In addition, in glioblastoma multiform (GBM, WHO, grade IV), patients with detectable Survivin expression by Western blot analysis have been observed to have significantly shorter overall survival times compared with those without detectable expression (Chakravarti et al, 2002).	('GBM', 'Phenotype', 'HP:0012174', (40, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('detectable', 'Var', (75, 85))	('shorter', 'NegReg', (172, 179))	('patients', 'Species', '9606', (61, 69))	('overall', 'MPA', (180, 187))	('Survivin', 'Protein', (86, 94))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
20927	16404364	Primary GBM may arise from de novo after a short clinical history without an identifiable less-malignant precursor lesion and frequently contains EGFR amplification/overexpression, PTEN mutation, homozygous p16 deletion, and loss of heterozygosity (LOH) on chromosome 19q.	('PTEN', 'Gene', '5728', (181, 185))	('EGFR', 'Gene', '1956', (146, 150))	('loss', 'Var', (225, 229))	('EGFR', 'Gene', (146, 150))	('p16', 'Gene', '1029', (207, 210))	('GBM', 'Phenotype', 'HP:0012174', (8, 11))	('Primary GBM', 'Disease', (0, 11))	('amplification/overexpression', 'PosReg', (151, 179))	('contains', 'Reg', (137, 145))	('p16', 'Gene', (207, 210))	('PTEN', 'Gene', (181, 185))	('mutation', 'Var', (186, 194))
20929	16404364	P53 mutations and LOH on chromosome 10q are often observed, while amplification/overexpression of EGFR is most often lacking (Watanabe et al, 1996; Nakamura et al, 2000).	('EGFR', 'Gene', (98, 102))	('LOH', 'Var', (18, 21))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (4, 13))
20974	16404364	Moreover, knockout or inhibition of Survivin has been shown to result in multinucleated and polyploid cells, which is a characteristic of mitotic arrest (Speliotes et al, 2000).	('inhibition', 'NegReg', (22, 32))	('mitotic arrest', 'Disease', (138, 152))	('knockout', 'Var', (10, 18))	('mitotic arrest', 'Disease', 'MESH:D006323', (138, 152))	('Survivin', 'Gene', (36, 44))	('result in', 'Reg', (63, 72))
20975	16404364	In our GBM studies, the majority of GBMs showed an aneuploid DNA content (Xie et al, 2005), and, furthermore, a close association between nuclear Survivin positivity and tumour aneuploidy was observed (data not shown).	('aneuploid', 'Var', (51, 60))	('tumour aneuploidy', 'Disease', 'MESH:D000782', (170, 187))	('positivity', 'Var', (155, 165))	('GBM', 'Phenotype', 'HP:0012174', (7, 10))	('nuclear Survivin', 'Protein', (138, 154))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour aneuploidy', 'Disease', (170, 187))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
20976	16404364	It is known that genetic instability can cause cytogenetic heterogeneity within a number of tumour types, including gliomas (Harada et al, 1998).	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('cause', 'Reg', (41, 46))	('genetic instability', 'Var', (17, 36))	('gliomas', 'Disease', (116, 123))	('cytogenetic', 'MPA', (47, 58))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
20979	16404364	Recently, nuclear Survivin positivity has been reported to be predictive of poor survival in patients with oesophageal carcinoma and non-small-cell lung cancer (Grabowski et al, 2003; Lu et al, 2004).	('poor', 'NegReg', (76, 80))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (107, 128))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (133, 159))	('positivity', 'Var', (27, 37))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (133, 159))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (107, 128))	('non-small-cell lung cancer', 'Disease', (133, 159))	('nuclear Survivin', 'Protein', (10, 26))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('patients', 'Species', '9606', (93, 101))	('oesophageal carcinoma', 'Disease', (107, 128))
20980	16404364	In contrast, high nuclear Survivin expression has been shown to be an independent indicator of a favourable prognosis in osteosarcoma, breast cancer, and gastric carcinomas (Okada et al, 2001; Kennedy et al, 2003; Trieb et al, 2003) and, moreover, it has been associated with a less-progressive cytologic grade in pediatric ependymomas and choroid plexus tumours of the brain (Altura et al, 2003).	('expression', 'MPA', (35, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (121, 133))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('high nuclear', 'Var', (13, 25))	('ependymomas', 'Disease', 'MESH:D004806', (324, 335))	('choroid plexus tumours of the brain', 'Disease', (340, 375))	('tumours of the brain', 'Phenotype', 'HP:0030692', (355, 375))	('Survivin', 'Protein', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('osteosarcoma', 'Disease', (121, 133))	('ependymomas', 'Disease', (324, 335))	('osteosarcoma', 'Disease', 'MESH:D012516', (121, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('tumour', 'Phenotype', 'HP:0002664', (355, 361))	('gastric carcinomas', 'Disease', 'MESH:D013274', (154, 172))	('gastric carcinomas', 'Disease', (154, 172))	('choroid plexus tumours of the brain', 'Disease', 'MESH:D020288', (340, 375))	('tumours', 'Phenotype', 'HP:0002664', (355, 362))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
21018	31996727	This consist in a fitting process of the fluorescence spectrum to retrieve the relative contribution of the two states of PpIX, PpIX620 and PpIX634 for each excitation wavelength.	('PpIX', 'Chemical', 'MESH:C028025', (140, 144))	('PpIX', 'Chemical', 'MESH:C028025', (128, 132))	('PpIX634', 'Var', (140, 147))	('PpIX620', 'Var', (128, 135))	('PpIX634', 'Chemical', 'MESH:C002489', (140, 147))	('PpIX', 'Chemical', 'MESH:C028025', (122, 126))
21055	31235820	For example, dysregulated miRNAs play an important role in the development and progression of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('dysregulated', 'Var', (13, 25))
21092	31235820	Furthermore, the differential expression genes in the tissue are mainly involved in "Glioma", "Signalling pathways regulating pluripotency of stem cells" and "Pathways in cancer" pathways.	('differential expression genes', 'Var', (17, 46))	('Glioma', 'Phenotype', 'HP:0009733', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('pluripotency of stem', 'MPA', (126, 146))	('cancer', 'Disease', (171, 177))	('involved', 'Reg', (72, 80))	('"Glioma', 'Disease', 'MESH:D005910', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('"Glioma', 'Disease', (84, 91))
21098	31235820	Meanwhile, the dysregulated miRNAs also play a vital function in the occurrence and development of gliomas.	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('miR', 'Gene', '220972', (28, 31))	('dysregulated', 'Var', (15, 27))	('miR', 'Gene', (28, 31))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
21130	31235820	This indicates that the dysregulation of hsa-miR-196b-5p plays an important role in regulating physiological function as well as pathology.	('physiological', 'MPA', (95, 108))	('miR', 'Gene', (45, 48))	('dysregulation', 'Var', (24, 37))	('miR', 'Gene', '220972', (45, 48))
21141	31235820	Consistent with these outcomes, our results also indicated that Salmonella infection pathway may play a crucial role in the self-destruction of SCG via genetic modification.	('Salmonella infection', 'Disease', 'MESH:D012480', (64, 84))	('Salmonella infection', 'Disease', (64, 84))	('genetic modification', 'Var', (152, 172))
21172	28202508	Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas.	('IDH1', 'Gene', '3417', (20, 24))	('IDH', 'Gene', '3417', (20, 23))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('Mutations', 'Var', (91, 100))	('gliomas', 'Disease', (195, 202))	('PARP1', 'Gene', (65, 70))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('IDH', 'Gene', '3417', (130, 133))	('genetic abnormalities', 'Disease', 'MESH:D030342', (158, 179))	('genetic abnormalities', 'Disease', (158, 179))	('gliomas', 'Disease', 'MESH:D005910', (195, 202))	('isocitrate dehydrogenase', 'Gene', '3417', (104, 128))	('prevalent', 'Reg', (148, 157))	('gliomas', 'Disease', (33, 40))	('IDH1', 'Gene', (20, 24))	('PARP1', 'Gene', '142', (65, 70))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('IDH', 'Gene', (20, 23))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('isocitrate dehydrogenase', 'Gene', (104, 128))	('IDH', 'Gene', (130, 133))
21173	28202508	The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival.	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('mutations', 'Var', (22, 31))	('patient', 'Species', '9606', (97, 104))	('glioma', 'Disease', (35, 41))
21175	28202508	In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells.	('temozolomide', 'Chemical', 'MESH:D000077204', (13, 25))	('glioma', 'Disease', (101, 107))	('apoptotic changes', 'CPA', (73, 90))	('mutant', 'Var', (94, 100))	('greater', 'PosReg', (50, 57))	('DNA damage', 'MPA', (58, 68))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('TMZ', 'Chemical', 'MESH:D000077204', (27, 30))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
21176	28202508	The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability.	('NAD+ availability', 'MPA', (101, 118))	('mutant', 'Var', (71, 77))	('compromised', 'NegReg', (56, 67))	('NAD+', 'Chemical', 'MESH:D009243', (101, 105))	('PARP1', 'Gene', '142', (4, 9))	('decreased', 'NegReg', (91, 100))	('PARP1', 'Gene', (4, 9))
21180	28202508	Mutations in isocitrate dehydrogenase (IDH1/2) are common genetic abnormalities in grade II and III diffusive astrocytomas and oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (127, 145))	('IDH1/2', 'Gene', (39, 45))	('genetic abnormalities', 'Disease', 'MESH:D030342', (58, 79))	('isocitrate dehydrogenase', 'Gene', (13, 37))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('astrocytomas', 'Disease', 'MESH:D001254', (110, 122))	('Mutations', 'Var', (0, 9))	('genetic abnormalities', 'Disease', (58, 79))	('isocitrate dehydrogenase', 'Gene', '3417', (13, 37))	('oligodendrogliomas', 'Disease', (127, 145))	('astrocytomas', 'Disease', (110, 122))	('IDH1/2', 'Gene', '3417;3418', (39, 45))
21182	28202508	In glioma, IDH mutations cluster in an arginine residue at the center of the catalytic domain (IDH1 R132, IDH2 R172).	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (106, 109))	('arginine', 'Chemical', 'MESH:D001120', (39, 47))	('IDH', 'Gene', '3417', (11, 14))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('mutations', 'Var', (15, 24))	('IDH2', 'Gene', (106, 110))	('IDH1', 'Gene', (95, 99))	('IDH', 'Gene', '3417', (95, 98))	('glioma', 'Disease', (3, 9))	('IDH', 'Gene', (95, 98))	('IDH2', 'Gene', '3418', (106, 110))	('IDH1', 'Gene', '3417', (95, 99))	('IDH', 'Gene', (106, 109))	('cluster in', 'Reg', (25, 35))
21183	28202508	Mutant IDH confers neomorphic enzymatic activity that, catalyzes alpha-ketoglutarate (alpha-KG) into 2-hydroxyglutarate (2-HG), an oncometabolite closely related to the deactivation of alpha-KG-dependent deoxygenases.	('IDH', 'Gene', (7, 10))	('alpha-KG', 'Chemical', 'MESH:D007656', (86, 94))	('comet', 'Species', '302767', (133, 138))	('IDH', 'Gene', '3417', (7, 10))	('oxygen', 'Chemical', 'MESH:D010100', (206, 212))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (101, 119))	('alpha-KG', 'Chemical', 'MESH:D007656', (185, 193))	('Mutant', 'Var', (0, 6))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (65, 84))
21184	28202508	For example, IDH1 mutant derived 2-HG promotes hypoxia signaling by perturbing the catalytic activity of prolyl hydroxylase, resulting in constitutive activation of hypoxia-inducible factor 1alpha (HIF-1alpha).	('HIF-1alpha', 'Gene', '3091', (198, 208))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (165, 196))	('mutant', 'Var', (18, 24))	('hypoxia', 'Disease', (47, 54))	('promotes', 'PosReg', (38, 46))	('perturbing', 'NegReg', (68, 78))	('IDH1', 'Gene', (13, 17))	('HIF-1alpha', 'Gene', (198, 208))	('catalytic activity', 'MPA', (83, 101))	('hypoxia', 'Disease', 'MESH:D000860', (165, 172))	('hypoxia-inducible factor 1alpha', 'Gene', (165, 196))	('hypoxia', 'Disease', (165, 172))	('IDH1', 'Gene', '3417', (13, 17))	('activation', 'PosReg', (151, 161))
21185	28202508	Additionally, 2-HG has also been found to affect collagen maturation and basement membrane function, which may facilitate cancer cell infiltration and promote glioma progression.	('affect', 'Reg', (42, 48))	('glioma', 'Disease', (159, 165))	('collagen maturation', 'CPA', (49, 68))	('facilitate', 'PosReg', (111, 121))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('promote', 'PosReg', (151, 158))	('2-HG', 'Var', (14, 18))	('basement membrane function', 'CPA', (73, 99))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))
21186	28202508	Clinically, the occurrence of IDH mutations predicts longer survival and greater sensitivity to chemotherapy in low-grade gliomas and secondary glioblastomas.	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioblastomas', 'Phenotype', 'HP:0012174', (144, 157))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('greater', 'PosReg', (73, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (144, 157))	('IDH', 'Gene', (30, 33))	('gliomas', 'Disease', (122, 129))	('glioblastomas', 'Disease', (144, 157))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('IDH', 'Gene', '3417', (30, 33))	('mutations', 'Var', (34, 43))	('longer', 'PosReg', (53, 59))	('sensitivity to chemotherapy', 'MPA', (81, 108))
21187	28202508	A phase III clinical trial has provided the direct link between IDH mutation and survival benefit from chemotherapy.	('mutation', 'Var', (68, 76))	('IDH', 'Gene', '3417', (64, 67))	('survival benefit', 'CPA', (81, 97))	('IDH', 'Gene', (64, 67))
21188	28202508	Combined with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, IDH mutations serve as an important prognostic marker for gliomas treated with radiation and chemotherapy.	('MGMT', 'Gene', '4255', (55, 59))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('MGMT', 'Gene', (55, 59))	('gliomas', 'Disease', (148, 155))	('IDH', 'Gene', (90, 93))	('mutations', 'Var', (94, 103))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('IDH', 'Gene', '3417', (90, 93))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (14, 53))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (14, 53))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))
21189	28202508	Although there has been increasing awareness of the correlation between IDH mutations and chemo-sensitivity, the molecular mechanism that determines the vulnerability that results from IDH mutations remains unanswered.	('mutations', 'Var', (76, 85))	('IDH', 'Gene', '3417', (185, 188))	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('mutations', 'Var', (189, 198))
21194	28202508	The IDH1 mutations resulted in the metabolic reprogramming and cytotoxic effects via 2-HG production.	('cytotoxic effects', 'CPA', (63, 80))	('IDH1', 'Gene', '3417', (4, 8))	('resulted in', 'Reg', (19, 30))	('2-HG production', 'MPA', (85, 100))	('mutations', 'Var', (9, 18))	('IDH1', 'Gene', (4, 8))	('metabolic reprogramming', 'CPA', (35, 58))
21195	28202508	In addition, cells with mutant IDH failed to form the poly (ADP-ribose) polymer (pADPR), and therefore were unable to maintain genomic integrity.	('mutant', 'Var', (24, 30))	('IDH', 'Gene', (31, 34))	('unable', 'NegReg', (108, 114))	('IDH', 'Gene', '3417', (31, 34))	('ADP', 'Chemical', 'MESH:D000244', (60, 63))	('ADP', 'Chemical', 'MESH:D000244', (82, 85))	('failed', 'NegReg', (35, 41))	('poly (ADP-ribose)', 'Chemical', 'MESH:D011064', (54, 71))
21197	28202508	Taken together, our findings indicate a potential molecular mechanism of chemo-sensitization in IDH mutant gliomas and, suggests a novel therapeutic strategy for clinical therapies.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('IDH', 'Gene', '3417', (96, 99))	('gliomas', 'Disease', (107, 114))	('mutant', 'Var', (100, 106))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH', 'Gene', (96, 99))
21203	28202508	U87 and U251 stable cell lines ectopically expressing wild type IDH1, R132C or R132H variants, as well as HT1080 cells with stable IDH1 gene knockdown were created.	('U87', 'Gene', '641648', (0, 3))	('IDH1', 'Gene', (131, 135))	('R132H', 'Mutation', 'rs121913500', (79, 84))	('IDH1', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (131, 135))	('HT1080', 'Gene', (106, 112))	('R132C', 'Var', (70, 75))	('IDH1', 'Gene', '3417', (64, 68))	('R132C', 'Mutation', 'rs121913499', (70, 75))	('U87', 'Gene', (0, 3))	('U251', 'CellLine', 'CVCL:0021', (8, 12))	('R132H', 'Var', (79, 84))	('HT1080', 'Gene', '8872', (106, 112))
21227	28202508	IDH mutations appear to be associated with a better response to chemotherapies such as TMZ.	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('TMZ', 'Chemical', 'MESH:D000077204', (87, 90))
21229	28202508	We found that IDH1 mutant cells were more vulnerable to TMZ treatment in vitro.	('TMZ', 'Chemical', 'MESH:D000077204', (56, 59))	('mutant', 'Var', (19, 25))	('IDH1', 'Gene', (14, 18))	('vulnerable', 'MPA', (42, 52))	('IDH1', 'Gene', '3417', (14, 18))
21232	28202508	TMZ-induced apoptosis was enhanced in IDH mutant cells, as Annexin-V labeled cells were more abundant in IDH1R132H cells (Figure 1B, Annexin-V+ cells IDH1WT=22.5%; Annexin-V+ cells IDH1R132H=34.2%).	('mutant', 'Var', (42, 48))	('Annexin-V', 'Gene', (133, 142))	('IDH1', 'Gene', '3417', (105, 109))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', '3417', (105, 108))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('enhanced', 'PosReg', (26, 34))	('more', 'PosReg', (88, 92))	('IDH1', 'Gene', (181, 185))	('Annexin-V', 'Gene', (164, 173))	('Annexin-V', 'Gene', (59, 68))	('IDH1', 'Gene', (150, 154))	('IDH', 'Gene', '3417', (150, 153))	('apoptosis', 'CPA', (12, 21))	('IDH', 'Gene', (181, 184))	('IDH', 'Gene', (38, 41))	('Annexin-V', 'Gene', '308', (133, 142))	('IDH1', 'Gene', '3417', (150, 154))	('IDH1', 'Gene', '3417', (181, 185))	('IDH1', 'Gene', (105, 109))	('IDH', 'Gene', '3417', (181, 184))	('IDH', 'Gene', '3417', (38, 41))	('Annexin-V', 'Gene', '308', (164, 173))	('IDH', 'Gene', (105, 108))	('Annexin-V', 'Gene', '308', (59, 68))
21234	28202508	We demonstrated impaired cell cycle progression with G2/M arrest in both IDH1WT and IDH1R132H cells treated with TMZ, which is consistent with the finding that TMZ induces G2/M arrest in glioma cells.	('TMZ', 'Var', (160, 163))	('cell cycle progression', 'CPA', (25, 47))	('IDH1', 'Gene', '3417', (73, 77))	('glioma', 'Disease', (187, 193))	('IDH1', 'Gene', (84, 88))	('G2/M arrest', 'CPA', (53, 64))	('TMZ', 'Chemical', 'MESH:D000077204', (160, 163))	('impaired', 'NegReg', (16, 24))	('IDH1', 'Gene', '3417', (84, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (113, 116))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('IDH1', 'Gene', (73, 77))
21235	28202508	Notably, the population of cells in G2/M arrest was markedly increased in IDH1 mutant cells (for U251 cells, G2/M IDH1WT=26.6%; G2/M IDH1R132H=56.8%), suggesting a greater incidence of failed cell cycle progression in mutant cells during treatment.	('IDH1', 'Gene', (114, 118))	('IDH1', 'Gene', (74, 78))	('mutant', 'Var', (79, 85))	('U251', 'CellLine', 'CVCL:0021', (97, 101))	('IDH1', 'Gene', (133, 137))	('increased', 'PosReg', (61, 70))	('IDH1', 'Gene', '3417', (114, 118))	('IDH1', 'Gene', '3417', (74, 78))	('IDH1', 'Gene', '3417', (133, 137))	('G2/M arrest', 'MPA', (36, 47))	('cell cycle progression', 'CPA', (192, 214))
21239	28202508	The increase in G2/M arrest is a common phenomenon when cells fail to proceed to the DNA damage checkpoint, suggesting that the chemo-sensitivity of IDH1 mutant cells is linked to their vulnerability to DNA damage.	('IDH1', 'Gene', (149, 153))	('G2/M arrest', 'CPA', (16, 27))	('mutant', 'Var', (154, 160))	('IDH1', 'Gene', '3417', (149, 153))
21240	28202508	To test this hypothesis, we evaluated TMZ-induced DNA damage in IDH1 mutant cells by measuring gammaH2A.X (Figure 2A).	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('mutant', 'Var', (69, 75))	('IDH1', 'Gene', (64, 68))	('H2A.X', 'Gene', (100, 105))	('IDH1', 'Gene', '3417', (64, 68))	('H2A.X', 'Gene', '3014', (100, 105))
21243	28202508	Interestingly, the baseline H2A.X phosphorylation in mutant cells was also elevated, indicating severe intrinsic dysfunction in DNA repair machinery (0.21 AU and 0.57 AU for IDH1WT and IDH1R132C, respectively).	('IDH1', 'Gene', '3417', (185, 189))	('phosphorylation', 'MPA', (34, 49))	('IDH1', 'Gene', '3417', (174, 178))	('intrinsic dysfunction', 'Disease', 'MESH:D020919', (103, 124))	('H2A.X', 'Gene', (28, 33))	('elevated', 'PosReg', (75, 83))	('intrinsic dysfunction', 'Disease', (103, 124))	('H2A.X', 'Gene', '3014', (28, 33))	('IDH1', 'Gene', (174, 178))	('mutant', 'Var', (53, 59))	('IDH1', 'Gene', (185, 189))
21245	28202508	Consistent with previous findings, the baseline DNA damage was also elevated in mutant cells (0.0036 AU, 0.018 AU and 0.032 AU for IDH1WT, IDH1R132C and IDH1R132H, respectively).	('IDH1', 'Gene', (153, 157))	('IDH1', 'Gene', (139, 143))	('IDH1', 'Gene', (131, 135))	('mutant', 'Var', (80, 86))	('IDH1', 'Gene', '3417', (153, 157))	('0.032 AU', 'Var', (118, 126))	('IDH1', 'Gene', '3417', (131, 135))	('elevated', 'PosReg', (68, 76))	('IDH1', 'Gene', '3417', (139, 143))	('0.0036 AU', 'Var', (94, 103))	('0.018 AU', 'Var', (105, 113))	('DNA damage', 'MPA', (48, 58))
21246	28202508	To better understand the integrity of genomic DNA in IDH1 mutant cells, we analyzed the proportion of fragmented DNA through comet assay (Figure 2C).	('mutant', 'Var', (58, 64))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))	('comet', 'Species', '302767', (125, 130))
21247	28202508	We confirmed the baseline DNA damage by increased fragmented DNA in IDH1R132C and IDH1R132H cells without any treatment, as shown by elongated comet tail under electric field.	('comet', 'Species', '302767', (143, 148))	('comet tail', 'CPA', (143, 153))	('fragmented', 'Var', (50, 60))	('increased', 'PosReg', (40, 49))
21248	28202508	TMZ treatment resulted in significant DNA fragmentation, and the fragmented DNA is more abundant in IDH1R132C and IDH1R132H cells.	('IDH1R132H', 'Var', (114, 123))	('IDH1R132C', 'Var', (100, 109))	('more', 'PosReg', (83, 87))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('DNA fragmentation', 'CPA', (38, 55))
21249	28202508	Quantitative analysis confirmed more DNA damage occurred in IDH1 mutant cells (Figure 2D).	('IDH1', 'Gene', (60, 64))	('IDH1', 'Gene', '3417', (60, 64))	('mutant', 'Var', (65, 71))	('DNA damage', 'MPA', (37, 47))
21250	28202508	Mutations in IDH1 establishes neomorphic catalytic activity, which redirects carbon metabolites away from the Kreb cycle towards 2-HG production.	('2-HG production', 'MPA', (129, 144))	('carbon metabolites away from the Kreb cycle', 'MPA', (77, 120))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('Kreb', 'Chemical', '-', (110, 114))	('carbon', 'Chemical', 'MESH:D002244', (77, 83))
21252	28202508	To test this, we studied the oxidative metabolism in IDH1 mutant cells through the Seahorse metabolic assay (Figure 3A).	('mutant', 'Var', (58, 64))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))
21254	28202508	The 2-HG production could be reversed by treatment with AGI-5198, a specific chemical inhibitor targeting the R132H variant of IDH1 enzyme.	('R132H', 'Var', (110, 115))	('IDH1', 'Gene', (127, 131))	('2-HG production', 'MPA', (4, 19))	('R132H', 'Mutation', 'rs121913500', (110, 115))	('IDH1', 'Gene', '3417', (127, 131))	('AGI-5198', 'Chemical', 'MESH:C581156', (56, 64))
21256	28202508	Taken together, our findings demonstrate that the capacity for oxidative metabolism is greatly limited in the presence of IDH1 mutation, suggesting a significant shift in energy metabolism in IDH1 mutant cells.	('mutation', 'Var', (127, 135))	('energy metabolism', 'MPA', (171, 188))	('IDH1', 'Gene', (122, 126))	('IDH1', 'Gene', (192, 196))	('mutant', 'Var', (197, 203))	('IDH1', 'Gene', '3417', (122, 126))	('IDH1', 'Gene', '3417', (192, 196))	('shift', 'Reg', (162, 167))
21259	28202508	We found that the 2-HG levels correlated with their vulnerability to chemotherapy, as the introduction of 2-HG potentiated the cytotoxic effect of TMZ.	('potentiated', 'PosReg', (111, 122))	('cytotoxic effect', 'CPA', (127, 143))	('introduction', 'Var', (90, 102))	('2-HG', 'Var', (106, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (147, 150))
21263	28202508	To further test the role of IDH1 mutation in chemo-sensitivity, we investigated the cell viability of HT-1080, a colon cancer cell line with an intrinsic IDH1R132H variant, with TMZ treatment (Figure 3G to H).	('HT-1080', 'CellLine', 'CVCL:0317', (102, 109))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('mutation', 'Var', (33, 41))	('IDH1', 'Gene', '3417', (28, 32))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('colon cancer', 'Disease', (113, 125))	('IDH1', 'Gene', (154, 158))	('variant', 'Var', (164, 171))	('TMZ', 'Chemical', 'MESH:D000077204', (178, 181))	('IDH1', 'Gene', '3417', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('IDH1', 'Gene', (28, 32))
21266	28202508	In sum, our findings suggested an important role of 2-HG centered metabolic reprogramming in chemo-sensitization in IDH1 mutant cells.	('mutant', 'Var', (121, 127))	('IDH1', 'Gene', '3417', (116, 120))	('IDH1', 'Gene', (116, 120))
21267	28202508	A seminal study indicated that the metabolic defects in NAD+ productivity, prompted the vulnerability of IDH1 mutant cells.	('IDH1', 'Gene', (105, 109))	('mutant', 'Var', (110, 116))	('IDH1', 'Gene', '3417', (105, 109))	('NAD+', 'Chemical', 'MESH:D009243', (56, 60))	('metabolic defects', 'MPA', (35, 52))
21271	28202508	To test this hypothesis, we treated IDH1 mutant cells with TMZ, and olaparib (Ola), a PARP inhibitor.	('Ola', 'Chemical', 'MESH:C531550', (78, 81))	('IDH1', 'Gene', (36, 40))	('olaparib', 'Chemical', 'MESH:C531550', (68, 76))	('mutant', 'Var', (41, 47))	('PARP', 'Gene', '142', (86, 90))	('IDH1', 'Gene', '3417', (36, 40))	('PARP', 'Gene', (86, 90))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
21274	28202508	Consistent with this, the comet assay demonstrated a significantly elongated tail formation in both IDH1WT and IDH1R132H cells demonstrating that the fragmented DNA is more abundant in mutant cells in either TMZ treatment or combination treatment involving TMZ and Ola (Figure 4C and D).	('elongated', 'PosReg', (67, 76))	('tail formation', 'CPA', (77, 91))	('mutant', 'Var', (185, 191))	('IDH1', 'Gene', '3417', (100, 104))	('IDH1', 'Gene', '3417', (111, 115))	('TMZ', 'Chemical', 'MESH:D000077204', (208, 211))	('Ola', 'Chemical', 'MESH:C531550', (265, 268))	('more', 'PosReg', (168, 172))	('IDH1', 'Gene', (100, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (257, 260))	('comet', 'Species', '302767', (26, 31))	('IDH1', 'Gene', (111, 115))
21275	28202508	To better understand whether PARP-associated DNA repair is a key factor that defines the difference in chemo-sensitivity in IDH1 mutant cells, we measured the quantity of ADP-ribose-conjugated PARP (pADPR) through immunoblotting (Figure 4E).	('PARP', 'Gene', (29, 33))	('PARP', 'Gene', '142', (193, 197))	('ribose', 'Chemical', 'MESH:D012266', (175, 181))	('IDH1', 'Gene', '3417', (124, 128))	('PARP', 'Gene', '142', (29, 33))	('ADP', 'Chemical', 'MESH:D000244', (171, 174))	('ADP', 'Chemical', 'MESH:D000244', (200, 203))	('PARP', 'Gene', (193, 197))	('IDH1', 'Gene', (124, 128))	('mutant', 'Var', (129, 135))
21282	28202508	Finally, we confirmed this hypothesis by measuring changes in NAD+ in mutant cells (Figure 4F and S2).	('NAD+', 'Chemical', 'MESH:D009243', (62, 66))	('mutant', 'Var', (70, 76))	('NAD+', 'MPA', (62, 66))
21283	28202508	The total and nuclear NAD+ quantity was slightly lower in IDH1R132C and IDH1R132H cells without treatment.	('NAD+', 'Chemical', 'MESH:D009243', (22, 26))	('lower', 'NegReg', (49, 54))	('IDH1R132C', 'Var', (58, 67))
21286	28202508	The quantity of NAD+ was significantly reduced in mutant cells after washing off TMZ, suggesting that the NAD+ deficiency is the key factor causing a malfunction of BER repair (-32.6% and -25.7% in IDH1R132C and IDH1R132H, respectively).	('NAD+', 'Chemical', 'MESH:D009243', (16, 20))	('NAD+', 'Gene', (106, 110))	('BER repair', 'CPA', (165, 175))	('NAD+', 'Chemical', 'MESH:D009243', (106, 110))	('IDH1R132H', 'Var', (212, 221))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('deficiency', 'Var', (111, 121))	('mutant', 'Var', (50, 56))	('IDH1R132C', 'Var', (198, 207))
21287	28202508	The significantly enhanced DNA damage in IDH1 mutant cells that occurs as a consequence of inhibiting the PARP-associated DNA repair pathway suggested that a combination therapy could be more effective than current chemotherapy options, potentially generating a better tumor-inhibiting effect but at a lower dosage of chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('inhibiting', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('PARP', 'Gene', (106, 110))	('tumor', 'Disease', (269, 274))	('enhanced', 'PosReg', (18, 26))	('mutant', 'Var', (46, 52))	('IDH1', 'Gene', (41, 45))	('PARP', 'Gene', '142', (106, 110))	('DNA damage', 'MPA', (27, 37))	('IDH1', 'Gene', '3417', (41, 45))
21289	28202508	We found that Ola potently enhanced the cytotoxic effect of TMZ regardless of the IDH1 mutation status (Figure 5A), as the dose-response curves were shifted leftwards in all genotypes.	('enhanced', 'PosReg', (27, 35))	('TMZ', 'Chemical', 'MESH:D000077204', (60, 63))	('Ola', 'Chemical', 'MESH:C531550', (14, 17))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (82, 86))	('mutation', 'Var', (87, 95))	('cytotoxic effect', 'CPA', (40, 56))
21291	28202508	Consistent with the findings above, the IC50 of TMZ was significantly smaller for IDH1R132C and IDH1R132H cells (Table S1).	('TMZ', 'Chemical', 'MESH:D000077204', (48, 51))	('smaller', 'NegReg', (70, 77))	('IC50', 'MPA', (40, 44))	('IDH1R132H cells', 'Var', (96, 111))	('IDH1R132C', 'Var', (82, 91))
21293	28202508	Similar to previous findings, quantitative analysis showed that TMZ induced more apoptosis in IDH1 mutant cells.	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', '3417', (94, 98))	('apoptosis', 'CPA', (81, 90))	('TMZ', 'Chemical', 'MESH:D000077204', (64, 67))	('mutant', 'Var', (99, 105))
21294	28202508	The population of apoptotic cells was significantly increased in both cell lines with the presence of Ola; however, IDH1 mutation predicted a more extensive cellular apoptosis (Figure 5C).	('Ola', 'Chemical', 'MESH:C531550', (102, 105))	('IDH1', 'Gene', (116, 120))	('cellular apoptosis', 'CPA', (157, 175))	('mutation', 'Var', (121, 129))	('IDH1', 'Gene', '3417', (116, 120))
21295	28202508	In the present study, we confirmed that pathogenic IDH1 mutations result in metabolic reprogramming and compromised oxidative metabolism.	('IDH1', 'Gene', '3417', (51, 55))	('mutations', 'Var', (56, 65))	('IDH1', 'Gene', (51, 55))	('oxidative metabolism', 'MPA', (116, 136))	('compromised', 'NegReg', (104, 115))	('metabolic reprogramming', 'CPA', (76, 99))	('result in', 'Reg', (66, 75))
21296	28202508	Production of 2-HG by the mutant enzyme activity confers a vulnerability to TMZ treatment.	('mutant', 'Var', (26, 32))	('TMZ', 'Chemical', 'MESH:D000077204', (76, 79))	('Production of 2-HG', 'MPA', (0, 18))	('vulnerability', 'MPA', (59, 72))
21298	28202508	As a consequence of these molecular changes, IDH1-mutated cells are sensitized to therapies such as TMZ and Ola (Figure 6).	('IDH1', 'Gene', '3417', (45, 49))	('changes', 'Var', (36, 43))	('Ola', 'Chemical', 'MESH:C531550', (108, 111))	('IDH1', 'Gene', (45, 49))	('TMZ', 'Chemical', 'MESH:D000077204', (100, 103))	('sensitized', 'Reg', (68, 78))
21301	28202508	Although the prognostic value of an IDH mutation in glioma has been widely accepted, little is known about the unique molecular features that defines the chemo-sensitivity in IDH1 mutant cells.	('mutation', 'Var', (40, 48))	('IDH', 'Gene', '3417', (175, 178))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('mutant', 'Var', (180, 186))	('IDH', 'Gene', (36, 39))	('IDH1', 'Gene', (175, 179))	('IDH', 'Gene', '3417', (36, 39))	('glioma', 'Disease', (52, 58))	('IDH', 'Gene', (175, 178))	('IDH1', 'Gene', '3417', (175, 179))
21302	28202508	In the present study, we established cell line models by introducing IDH1 mutation in a glioma biologic background.	('mutation', 'Var', (74, 82))	('IDH1', 'Gene', '3417', (69, 73))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('introducing', 'Reg', (57, 68))	('IDH1', 'Gene', (69, 73))
21303	28202508	Our cell lines recapitulate the molecular signatures of IDH1 mutant gliomas, such as expression of mutant enzyme, 2-HG production, as well as an increase in histone 3 methylation (Figure S4).	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('increase', 'PosReg', (145, 153))	('IDH1', 'Gene', '3417', (56, 60))	('histone 3 methylation', 'MPA', (157, 178))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('2-HG production', 'MPA', (114, 129))	('mutant', 'Var', (61, 67))	('mutant', 'Var', (99, 105))	('IDH1', 'Gene', (56, 60))
21304	28202508	Moreover, we confirmed that IDH1 mutant cells are more vulnerable to TMZ treatment, which replicated the clinically observed increased chemo-sensitivity in IDH1 mutant cells (Figure 1A).	('vulnerable', 'MPA', (55, 65))	('mutant', 'Var', (161, 167))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('IDH1', 'Gene', (156, 160))	('IDH1', 'Gene', '3417', (28, 32))	('IDH1', 'Gene', '3417', (156, 160))	('mutant', 'Var', (33, 39))	('IDH1', 'Gene', (28, 32))
21305	28202508	Additionally, analysis of apoptosis confirmed increased sensitivity to TMZ in IDH1 mutant cells (Figure 1B to D).	('mutant', 'Var', (83, 89))	('increased', 'PosReg', (46, 55))	('IDH1', 'Gene', (78, 82))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('IDH1', 'Gene', '3417', (78, 82))	('sensitivity', 'MPA', (56, 67))
21307	28202508	We believe that our models are more suitable than several recently developed cell lines from individual patient with intrinsic IDH1 mutation.	('mutation', 'Var', (132, 140))	('patient', 'Species', '9606', (104, 111))	('IDH1', 'Gene', '3417', (127, 131))	('IDH1', 'Gene', (127, 131))
21308	28202508	Because we introduced IDH1 mutants to cell lines with the same genetic background, as such the bias from genomic/transcriptomic variation is extensively reduced.	('IDH1', 'Gene', '3417', (22, 26))	('IDH1', 'Gene', (22, 26))	('mutants', 'Var', (27, 34))
21309	28202508	To validate the observed increase in chemo-sensitivity, we carefully measured DNA damage in IDH1 mutant cells by measuring gammaH2A.X as well as DNA fragmentation (Figure 2).	('IDH1', 'Gene', (92, 96))	('mutant', 'Var', (97, 103))	('IDH1', 'Gene', '3417', (92, 96))	('H2A.X', 'Gene', (128, 133))	('H2A.X', 'Gene', '3014', (128, 133))
21316	28202508	Currently, only IDH1 and IDH2 mutations have been found in glioma cells.	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH1', 'Gene', (16, 20))	('mutations', 'Var', (30, 39))	('IDH2', 'Gene', (25, 29))	('IDH1', 'Gene', '3417', (16, 20))	('IDH2', 'Gene', '3418', (25, 29))
21317	28202508	Neomorphic changes in IDH redirect carbon-based metabolites into unusable 2-HG.	('carbon-based metabolites', 'MPA', (35, 59))	('carbon', 'Chemical', 'MESH:D002244', (35, 41))	('redirect', 'Reg', (26, 34))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', '3417', (22, 25))	('changes', 'Var', (11, 18))
21319	28202508	The adjustment in cellular metabolism may limit physiologically important metabolic routes, such as ATP generation and macromolecule synthetic pathways, and therefore result in the increased vulnerability of IDH1 mutant cells.	('vulnerability', 'MPA', (191, 204))	('macromolecule synthetic pathways', 'Pathway', (119, 151))	('IDH1', 'Gene', (208, 212))	('cellular metabolism', 'MPA', (18, 37))	('ATP generation', 'MPA', (100, 114))	('increased', 'PosReg', (181, 190))	('limit', 'NegReg', (42, 47))	('IDH1', 'Gene', '3417', (208, 212))	('adjustment', 'Reg', (4, 14))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))	('physiologically important metabolic routes', 'MPA', (48, 90))	('mutant', 'Var', (213, 219))	('result', 'Reg', (167, 173))
21320	28202508	Moreover, introducing 2-HG to native U87 cells mimics the introduction of IDH1 mutant enzyme, as shown by increased cell death and chemo-sensitivity (Figure 3E).	('cell death', 'CPA', (116, 126))	('IDH1', 'Gene', (74, 78))	('mutant', 'Var', (79, 85))	('U87', 'Gene', (37, 40))	('IDH1', 'Gene', '3417', (74, 78))	('U87', 'Gene', '641648', (37, 40))	('increased', 'PosReg', (106, 115))	('chemo-sensitivity', 'CPA', (131, 148))
21323	28202508	Indeed, Molenaar et al has reported that targeting IDH1 mutation confer radioprotection.	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))	('radioprotection', 'CPA', (72, 87))	('IDH1', 'Gene', '3417', (51, 55))
21327	28202508	For example, ATRX/RAD54 is frequently mutated in IDH1-mutated glioma, whereas other DNA repair enzymes, such as ATM, CHEK1, CHEK2, and RAD52, are amplified in the genome of IDH1-mutated glioma (Figure S5).	('glioma', 'Disease', (186, 192))	('ATRX', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('ATRX', 'Gene', '546', (13, 17))	('CHEK2', 'Gene', (124, 129))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('mutated', 'Var', (38, 45))	('CHEK1', 'Gene', '1111', (117, 122))	('IDH1', 'Gene', '3417', (49, 53))	('RAD52', 'Gene', (135, 140))	('RAD54', 'Gene', '546', (18, 23))	('CHEK2', 'Gene', '11200', (124, 129))	('ATM', 'Gene', (112, 115))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('RAD54', 'Gene', (18, 23))	('IDH1', 'Gene', (173, 177))	('CHEK1', 'Gene', (117, 122))	('RAD52', 'Gene', '5893', (135, 140))	('glioma', 'Disease', (62, 68))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('IDH1', 'Gene', '3417', (173, 177))	('ATM', 'Gene', '472', (112, 115))	('IDH1', 'Gene', (49, 53))
21330	28202508	highlighted the essential role of NAD+ in IDH1-mutated glioma, suggesting that impairment of NAD+ synthesis could be one of the key metabolic defects in IDH mutant cells.	('glioma', 'Disease', (55, 61))	('IDH', 'Gene', (42, 45))	('NAD+', 'Chemical', 'MESH:D009243', (93, 97))	('mutant', 'Var', (157, 163))	('IDH1', 'Gene', '3417', (42, 46))	('NAD+', 'Chemical', 'MESH:D009243', (34, 38))	('IDH', 'Gene', '3417', (42, 45))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH', 'Gene', (153, 156))	('NAD+ synthesis', 'MPA', (93, 107))	('IDH1', 'Gene', (42, 46))	('IDH', 'Gene', '3417', (153, 156))
21332	28202508	IDH1 mutant deplete NAD in all subcellular compartment due to inhibition of Naprt1 activity.	('activity', 'MPA', (83, 91))	('Naprt1', 'Gene', (76, 82))	('NAD', 'Chemical', 'MESH:D009243', (20, 23))	('Naprt1', 'Gene', '93100', (76, 82))	('mutant', 'Var', (5, 11))	('IDH1', 'Gene', (0, 4))	('deplete NAD in all subcellular compartment', 'MPA', (12, 54))	('inhibition', 'NegReg', (62, 72))	('IDH1', 'Gene', '3417', (0, 4))
21333	28202508	Targeting the damaged NAD synthetic pathway by Nampt inhibitors FK866 or GMX1778 further limit the availability of NAD.	('GMX1778', 'Chemical', 'MESH:C401312', (73, 80))	('limit', 'NegReg', (89, 94))	('GMX1778', 'Gene', (73, 80))	('NAD', 'Chemical', 'MESH:D009243', (22, 25))	('NAD', 'Chemical', 'MESH:D009243', (115, 118))	('FK866', 'Var', (64, 69))	('FK866', 'Chemical', 'MESH:C480543', (64, 69))	('NAD synthetic pathway', 'Pathway', (22, 43))
21336	28202508	Interestingly, we observed a significant reduction in NAD+ in IDH1 mutant cells (Figure 4F), which confirmed that the limited DNA repair capacity in IDH1 mutant cells is caused by insufficient substrate for the biological function of PARP.	('IDH1', 'Gene', '3417', (62, 66))	('DNA repair', 'MPA', (126, 136))	('IDH1', 'Gene', (149, 153))	('PARP', 'Gene', (234, 238))	('limited', 'NegReg', (118, 125))	('IDH1', 'Gene', '3417', (149, 153))	('NAD+', 'Chemical', 'MESH:D009243', (54, 58))	('mutant', 'Var', (67, 73))	('IDH1', 'Gene', (62, 66))	('PARP', 'Gene', '142', (234, 238))	('mutant', 'Var', (154, 160))
21337	28202508	Additionally, we observed pADPR, the intermediate molecule that represents active PARP DNA repair, is depleted in IDH1 mutant cells (Figure 4D).	('ADP', 'Chemical', 'MESH:D000244', (27, 30))	('depleted', 'NegReg', (102, 110))	('PARP', 'Gene', (82, 86))	('IDH1', 'Gene', (114, 118))	('pADPR', 'MPA', (26, 31))	('IDH1', 'Gene', '3417', (114, 118))	('PARP', 'Gene', '142', (82, 86))	('mutant', 'Var', (119, 125))
21338	28202508	TMZ treatment led to an induction of pADPR formation in cells with wild type IDH1, but not the mutant cells, suggesting a significantly reduced DNA repair mechanism in IDH1 mutant cells.	('IDH1', 'Gene', '3417', (168, 172))	('DNA repair mechanism', 'MPA', (144, 164))	('IDH1', 'Gene', (77, 81))	('mutant', 'Var', (173, 179))	('pADPR formation', 'MPA', (37, 52))	('reduced', 'NegReg', (136, 143))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', (168, 172))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('ADP', 'Chemical', 'MESH:D000244', (38, 41))
21339	28202508	Interestingly, the amount of total PARP remained stable within all the treatments, suggesting the vulnerability based on functional ablation of DNA repair, but not changes in the level of expression.	('DNA repair', 'Gene', (144, 154))	('PARP', 'Gene', (35, 39))	('PARP', 'Gene', '142', (35, 39))	('ablation', 'Var', (132, 140))
21340	28202508	Notably, several recent findings showed PARP inhibition further damages energy metabolism, which may exert synergistic effect with genotoxic agents.	('PARP', 'Gene', '142', (40, 44))	('energy metabolism', 'MPA', (72, 89))	('inhibition', 'Var', (45, 55))	('damages', 'NegReg', (64, 71))	('PARP', 'Gene', (40, 44))
21353	28202508	The synergistic effects between TMZ and Olaparib in patients with the IDH mutation provides the possibility to achieve better cytotoxic effect with less amount of alkylating agent, which leads to the reduced toxicities and improved patients' quality of life.	('mutation', 'Var', (74, 82))	('Olaparib', 'Chemical', 'MESH:C531550', (40, 48))	('quality of life', 'CPA', (242, 257))	('improved', 'PosReg', (223, 231))	('better', 'PosReg', (119, 125))	('toxicities', 'Disease', (208, 218))	('cytotoxic effect', 'MPA', (126, 142))	('IDH', 'Gene', (70, 73))	('patients', 'Species', '9606', (232, 240))	('TMZ', 'Chemical', 'MESH:D000077204', (32, 35))	('reduced', 'NegReg', (200, 207))	('IDH', 'Gene', '3417', (70, 73))	('toxicities', 'Disease', 'MESH:D064420', (208, 218))	('patients', 'Species', '9606', (52, 60))
21372	26449838	Moreover, several studies on experimental glioma models have confirmed the tumor-inhibition effect of GRPR antagonists.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('antagonists', 'Var', (107, 118))	('GRPR', 'Gene', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('GRPR', 'Gene', '2925', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('glioma', 'Disease', (42, 48))	('tumor', 'Disease', (75, 80))
21375	26449838	BBN, with the amino acid sequence Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, has been labeled with various radionuclides and used extensively to develop molecular probes for imaging GRPR.	('GRPR', 'Gene', (176, 180))	('Ala-Val', 'Chemical', '-', (42, 49))	('GRPR', 'Gene', '2925', (176, 180))	('Trp', 'Chemical', 'MESH:D014364', (38, 41))	('radionuclide', 'Chemical', 'MESH:D011868', (101, 113))	('BBN', 'Gene', (0, 3))	('Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2', 'Var', (34, 69))	('BBN', 'Gene', '2922', (0, 3))	('Leu', 'Chemical', 'MESH:D007930', (58, 61))	('His', 'Chemical', 'MESH:D006639', (54, 57))	('Gln', 'Chemical', 'MESH:D005973', (34, 37))	('Gly', 'Chemical', 'MESH:D005998', (50, 53))
21419	26449838	Because of the 67.6-min physical half-life of 68Ga, patients may be exposed to less radiation with 68Ga than with longer-lived PET isotopes, but overall radiation exposure is also affected by biologic half-life, distribution profile, and positron energy.	('PET', 'Gene', '22095', (127, 130))	('68Ga', 'Var', (46, 50))	('PET', 'Gene', (127, 130))	('68Ga', 'Var', (99, 103))	('affected', 'Reg', (180, 188))	('patients', 'Species', '9606', (52, 60))
21467	26752735	Moreover, variations within a single tumor can cause marked differences among its imaging features:like necrosis or contrast enhancement; being primarily caused by changes in blood flow (or perfusion).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('changes', 'Reg', (164, 171))	('necrosis', 'Disease', (104, 112))	('contrast enhancement', 'CPA', (116, 136))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('variations', 'Var', (10, 20))	('necrosis', 'Disease', 'MESH:D009336', (104, 112))	('caused', 'Reg', (154, 160))
21509	26752735	It may also be noted that T1C suppresses the edema region in Fig 4(e) and 4(f), while T2 also illuminates the CSF in Fig 4(c) and 4(d).	('edema', 'Disease', 'MESH:D004487', (45, 50))	('edema', 'Phenotype', 'HP:0000969', (45, 50))	('suppresses', 'NegReg', (30, 40))	('T1C', 'Var', (26, 29))	('edema', 'Disease', (45, 50))	('T1C', 'Mutation', 'c.1T>C', (26, 29))
21531	25609060	Detection, characterization and inhibition of FGFR-TACC fusions in IDH wild type glioma Oncogenic fusions consisting of FGFR and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets.	('fusions', 'Var', (56, 63))	('FGFR', 'Gene', (120, 124))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('human', 'Species', '9606', (192, 197))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('glioma', 'Disease', (81, 87))	('IDH', 'Gene', (67, 70))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('glioblastoma', 'Disease', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('IDH', 'Gene', '3417', (67, 70))	('FGFR-TACC', 'Gene', (46, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))	('TACC', 'Gene', (129, 133))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
21534	25609060	The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (43, 55))	('glioma', 'Disease', (81, 87))	('JNJ-42756493', 'Var', (43, 55))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
21535	25609060	Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response.	('JNJ-42756493', 'Var', (61, 73))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (61, 73))	('FGFR3-TACC3-positive', 'Gene', (27, 47))	('patients', 'Species', '9606', (4, 12))
21537	25609060	They are mutually exclusive with IDH1/2 mutations and EGFR amplification whereas co-occur with CDK4 amplification.	('IDH1/2', 'Gene', (33, 39))	('CDK4', 'Gene', (95, 99))	('mutations', 'Var', (40, 49))	('EGFR', 'Gene', '1956', (54, 58))	('CDK4', 'Gene', '1019', (95, 99))	('EGFR', 'Gene', (54, 58))
21538	25609060	JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo.	('JNJ-42756493', 'Var', (0, 12))	('glioma', 'Disease', (33, 39))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (0, 12))	('inhibited', 'NegReg', (13, 22))	('FGFR3-TACC3', 'Gene', (56, 67))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('growth', 'CPA', (23, 29))
21539	25609060	The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.	('rearrangements', 'Var', (34, 48))	('improvement', 'PosReg', (95, 106))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (62, 74))	('FGFR3-TACC3', 'Gene', (22, 33))	('man', 'Species', '9606', (75, 78))	('patients', 'Species', '9606', (8, 16))
21541	25609060	FGFR3-TACC3 fusions are associated with uniform intra-tumor expression of the fusion protein.	('expression', 'MPA', (60, 70))	('fusions', 'Var', (12, 19))	('FGFR3-TACC3', 'Gene', (0, 11))	('intra-tumor', 'Disease', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('intra-tumor', 'Disease', 'MESH:D009369', (48, 59))
21543	25609060	The history of successful targeted therapy of cancer largely coincides with the inactivation of recurrent, oncogenic and addicting gene fusions in hematological malignancies and recently in some types of epithelial cancer.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('hematological malignancies', 'Phenotype', 'HP:0004377', (147, 173))	('epithelial cancer', 'Phenotype', 'HP:0031492', (204, 221))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (46, 52))	('hematological malignancies', 'Disease', (147, 173))	('epithelial cancer', 'Disease', (204, 221))	('epithelial cancer', 'Disease', 'MESH:D000077216', (204, 221))	('hematological malignancies', 'Disease', 'MESH:D019337', (147, 173))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('inactivation', 'Var', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
21548	25609060	The majority of grade II-III glioma (but only a small subgroup of GBM) harbor mutations in IDH genes (IDH1 or IDH2), which confer a more favorable clinical outcome.	('IDH', 'Gene', '3417', (102, 105))	('IDH2', 'Gene', '3418', (110, 114))	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', '3417', (110, 113))	('mutations', 'Var', (78, 87))	('IDH1', 'Gene', (102, 106))	('IDH', 'Gene', (91, 94))	('IDH1', 'Gene', '3417', (102, 106))	('IDH2', 'Gene', (110, 114))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('IDH', 'Gene', (102, 105))	('IDH', 'Gene', '3417', (91, 94))	('II-III glioma', 'Disease', 'MESH:D005910', (22, 35))	('II-III glioma', 'Disease', (22, 35))
21549	25609060	Conversely, the absence of IDH mutations is associated with the worst prognosis.	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (31, 40))	('IDH', 'Gene', '3417', (27, 30))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('absence', 'NegReg', (16, 23))
21550	25609060	We have recently identified FGFR-TACC gene fusions (mostly FGFR3-TACC3, and rarely FGFR1-TACC1) as the first example of highly oncogenic and recurrent gene fusions in GBM.	('gene fusions', 'Var', (151, 163))	('FGFR3-TACC3', 'Gene', (59, 70))	('TACC1', 'Gene', (89, 94))	('FGFR-TACC', 'Gene', (28, 37))	('FGFR1', 'Gene', (83, 88))	('GBM', 'Gene', (167, 170))	('TACC1', 'Gene', '6867', (89, 94))	('FGFR1', 'Gene', '2260', (83, 88))
21552	25609060	We also tested tumor dependency on FGFR-TACC fusions in preclinical mouse models of FGFR-TACC glioma and observed marked anti-tumor effects by FGFR inhibition.	('tested', 'Reg', (8, 14))	('mouse', 'Species', '10090', (68, 73))	('tumor dependency', 'Disease', 'MESH:D019966', (15, 31))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('glioma', 'Disease', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('tumor', 'Disease', (15, 20))	('tumor dependency', 'Disease', (15, 31))	('FGFR-TACC', 'Var', (84, 93))	('tumor', 'Disease', (126, 131))
21553	25609060	After our report, FGFR3-TACC3 fusions have been identified in pediatric and adult glioma, bladder carcinoma, squamous lung carcinoma and head and neck carcinoma, thus establishing FGFR-TACC fusions as one of the chromosomal translocation most frequently found across multiple types of human cancers.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (90, 107))	('fusions', 'Var', (30, 37))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (137, 160))	('bladder carcinoma', 'Disease', 'MESH:D001749', (90, 107))	('identified', 'Reg', (48, 58))	('adult glioma', 'Disease', (76, 88))	('squamous lung carcinoma', 'Phenotype', 'HP:0030359', (109, 132))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('FGFR3-TACC3', 'Gene', (18, 29))	('bladder carcinoma', 'Disease', (90, 107))	('adult glioma', 'Disease', 'MESH:D005910', (76, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('human', 'Species', '9606', (285, 290))	('squamous lung carcinoma', 'Disease', 'MESH:D002294', (109, 132))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('neck carcinoma', 'Disease', (146, 160))	('squamous lung carcinoma', 'Disease', (109, 132))	('neck carcinoma', 'Disease', 'MESH:D006258', (146, 160))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cancers', 'Disease', (291, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
21554	25609060	From a mechanistic standpoint, we discovered the unexpected capacity of FGFR-TACC fusions to trigger aberrant chromosome segregation during mitosis, thus initiating chromosome instability (CIN) and aneuploidy, two hallmarks of cancer.	('initiating', 'Reg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('aneuploidy', 'Disease', (198, 208))	('aberrant chromosome segregation', 'CPA', (101, 132))	('CIN', 'Disease', (189, 192))	('fusions', 'Var', (82, 89))	('chromosome', 'Disease', (165, 175))	('mitosis', 'Disease', 'None', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('mitosis', 'Disease', (140, 147))	('CIN', 'Disease', 'MESH:D007674', (189, 192))	('FGFR-TACC', 'Gene', (72, 81))	('cancer', 'Disease', (227, 233))	('chromosome instability', 'Phenotype', 'HP:0040012', (165, 187))	('trigger', 'Reg', (93, 100))	('aberrant chromosome segregation', 'Phenotype', 'HP:0002916', (101, 132))	('aneuploidy', 'Disease', 'MESH:D000782', (198, 208))
21555	25609060	However, we still have an incomplete understanding of the full repertoire of the structural variants of FGFR-TACC fusions occurring in GBM and lower grade glioma Furthermore, it remains unknown whether FGFR-TACC fusions mark distinct grades of glioma and GBM subtypes.	('fusions', 'Var', (114, 121))	('glioma', 'Disease', (244, 250))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('FGFR-TACC', 'Gene', (104, 113))	('glioma', 'Disease', (155, 161))
21556	25609060	Here we report a screening method for FGFR-TACC fusions that includes a RT-PCR assay designed to identify the known and novel FGFR3-TACC3 fusion transcripts, followed by confirmation of the in-frame breakpoint by Sanger sequencing.	('C', 'Chemical', 'MESH:D002244', (45, 46))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('FGFR3-TACC3', 'Gene', (126, 137))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('fusion', 'Var', (138, 144))	('C', 'Chemical', 'MESH:D002244', (134, 135))
21558	25609060	A crucial question with fundamental clinical relevance for any novel candidate target mutation is the frequency of the alteration in the cancer cell population, thus discriminating between a clonal or sub-clonal origin of the mutation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutation', 'Var', (86, 94))
21561	25609060	In this study, we determine that brain tumors harboring FGFR-TACC fusions manifest strong and homogeneous intra-tumor expression of the FGFR3 and TACC3 component invariably included in the fusion protein, when analyzed by immunostaining.	('brain tumors', 'Phenotype', 'HP:0030692', (33, 45))	('man', 'Species', '9606', (74, 77))	('brain tumors', 'Disease', 'MESH:D001932', (33, 45))	('brain tumors', 'Disease', (33, 45))	('brain tumor', 'Phenotype', 'HP:0030692', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('FGFR-TACC', 'Gene', (56, 65))	('intra-tumor', 'Disease', 'MESH:D009369', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('fusions', 'Var', (66, 73))	('intra-tumor', 'Disease', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
21562	25609060	We also report a significant clinical benefit following treatment with a specific inhibitor of FGFR-TK in two GBM patients who harbored FGFR3-TACC3 rearrangement.	('benefit', 'PosReg', (38, 45))	('FGFR-TK', 'Gene', (95, 102))	('inhibitor', 'NegReg', (82, 91))	('rearrangement', 'Var', (148, 161))	('clinical', 'MPA', (29, 37))	('patients', 'Species', '9606', (114, 122))	('FGFR3-TACC3', 'Gene', (136, 147))
21591	25609060	IDH1 and IDH2 gene mutations were identified by Sanger sequencing in 464 and 388 gliomas, respectively.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH2', 'Gene', (9, 13))	('IDH2', 'Gene', '3418', (9, 13))	('mutations', 'Var', (19, 28))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
21592	25609060	IDH wild-type tumors are defined according to the absence of IDH1-R132H immunopositivity and/or mutations in IDH1 and IDH2 genes.	('IDH', 'Gene', '3417', (61, 64))	('R132H', 'Mutation', 'rs121913500', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (96, 105))	('IDH2', 'Gene', (118, 122))	('IDH', 'Gene', (0, 3))	('IDH1', 'Gene', (109, 113))	('IDH', 'Gene', (118, 121))	('IDH2', 'Gene', '3418', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('IDH', 'Gene', (109, 112))	('IDH', 'Gene', '3417', (0, 3))	('tumors', 'Disease', (14, 20))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (109, 113))	('IDH', 'Gene', '3417', (118, 121))	('IDH', 'Gene', (61, 64))	('IDH', 'Gene', '3417', (109, 112))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('IDH1', 'Gene', '3417', (61, 65))
21597	25609060	Additional analyses of 193 tumor specimens were performed by SNP array, using Illumina Omni (N=110), Illumina HumCore (N=32), Illumina 370K (N=27), or Illumina 610K (N=24), as previously described.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Illumina HumCore', 'Var', (101, 117))	('tumor', 'Disease', (27, 32))	('Illumina', 'Var', (126, 134))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('Illumina 610K', 'Var', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
21598	25609060	Copy number alterations (CAN) magnitudes called log-R ratio (LRR) were classified using simple thresholds: deletion (x <= -1), loss (-1< x <= -0.2), gain (0.2 <= x < 1) or amplification (x >= 1) according to default Nexus 7.5 software.	('C', 'Chemical', 'MESH:D002244', (0, 1))	('deletion', 'Var', (107, 115))	('gain', 'PosReg', (149, 153))	('C', 'Chemical', 'MESH:D002244', (25, 26))
21599	25609060	For additional 56 gliomas, 10q loss was assessed on tumor and blood DNA by microsatellite analysis, while amplification of EGFR, MDM2 and CDK4, and deletion of CDKN2A gene, were determined by qPCR, as previously reported.	('EGFR', 'Gene', (123, 127))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('loss', 'NegReg', (31, 35))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('tumor', 'Disease', (52, 57))	('C', 'Chemical', 'MESH:D002244', (194, 195))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CDK4', 'Gene', (138, 142))	('MDM2', 'Gene', (129, 133))	('EGFR', 'Gene', '1956', (123, 127))	('CDK4', 'Gene', '1019', (138, 142))	('deletion', 'Var', (148, 156))	('gliomas', 'Disease', (18, 25))	('MDM2', 'Gene', '4193', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CDKN2A', 'Gene', (160, 166))	('C', 'Chemical', 'MESH:D002244', (160, 161))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('CDKN2A', 'Gene', '1029', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))
21606	25609060	The CNV magnitudes, called log-R ratio (LRR), were classified using the following thresholds: deletion (x < -1), loss (-1 <= x <= -0.2), gain (0.2 <= x <= 1) or amplification (x > 1), according to the Atlas-TCGA.	('deletion', 'Var', (94, 102))	('amplification', 'MPA', (161, 174))	('C', 'Chemical', 'MESH:D002244', (208, 209))	('gain', 'PosReg', (137, 141))	('C', 'Chemical', 'MESH:D002244', (4, 5))
21625	25609060	To determine the frequency and molecular features of FGFR-TACC fusions in human glioma patients, we screened a cohort of 584 GBM and 211 grade II-III glioma treated at five Neuro-oncology centers (Table 1).	('glioma', 'Disease', (80, 86))	('II-III glioma', 'Disease', (143, 156))	('FGFR-TACC', 'Gene', (53, 62))	('II-III glioma', 'Disease', 'MESH:D005910', (143, 156))	('oncology', 'Phenotype', 'HP:0002664', (179, 187))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioma', 'Disease', (150, 156))	('human', 'Species', '9606', (74, 79))	('patients', 'Species', '9606', (87, 95))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('fusions', 'Var', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
21627	25609060	We also established the IDH mutational status of 333 GBM and determined that 303 harbored wild type IDH1/2 and 30 were mutated at codon 132 of IDH1.	('IDH', 'Gene', (100, 103))	('IDH1', 'Gene', '3417', (100, 104))	('IDH', 'Gene', '3417', (143, 146))	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', '3417', (100, 103))	('IDH1/2 and 30', 'Gene', '3417;3418', (100, 113))	('IDH1', 'Gene', (143, 147))	('IDH', 'Gene', '3417', (24, 27))	('IDH1', 'Gene', (100, 104))	('IDH1', 'Gene', '3417', (143, 147))	('mutated at codon', 'Var', (119, 135))	('IDH', 'Gene', (143, 146))
21628	25609060	We designed a RT-PCR assay for the detection of all known and possibly new variants of FGFR1-TACC1 and FGFR3-TACC3 fusions that retain the mRNA sequences coding for the key FGFR-TK and TACC domains required for the oncogenic activity of the fusion protein (Fig.	('C', 'Chemical', 'MESH:D002244', (188, 189))	('fusions', 'Var', (115, 122))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('TACC1', 'Gene', '6867', (93, 98))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('FGFR1', 'Gene', (87, 92))	('FGFR3-TACC3', 'Gene', (103, 114))	('FGFR1', 'Gene', '2260', (87, 92))	('TACC1', 'Gene', (93, 98))	('variants', 'Var', (75, 83))
21629	25609060	Overall, we found 20 tumors with an FGFR3-TACC3 fusion, of which 17 were GBM (2.9% positives) and 3 lower grade glioma harboring wild type IDH1/2 genes (3.5% positives).	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('tumors', 'Disease', (21, 27))	('fusion', 'Var', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('glioma', 'Disease', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('FGFR3-TACC3', 'Gene', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
21630	25609060	The size of the FGFR3-TACC3 RT-PCR amplicons ranged from 928 bp (for FGFR3ex18-TACC3ex13) to 1706 bp (for FGFR3ex18-TACC3ex4).	('C', 'Chemical', 'MESH:D002244', (118, 119))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('FGFR3ex18-TACC3ex13', 'Var', (69, 88))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('C', 'Chemical', 'MESH:D002244', (119, 120))	('FGFR3-TACC3', 'Gene', (16, 27))	('C', 'Chemical', 'MESH:D002244', (24, 25))	('C', 'Chemical', 'MESH:D002244', (25, 26))
21631	25609060	The FGFR1-TACC1 fusion was detected in one grade II IDH wild type glioma (Fig.	('type glioma', 'Disease', 'MESH:D005910', (61, 72))	('TACC1', 'Gene', '6867', (10, 15))	('FGFR1', 'Gene', (4, 9))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('FGFR1', 'Gene', '2260', (4, 9))	('TACC1', 'Gene', (10, 15))	('type glioma', 'Disease', (61, 72))	('fusion', 'Var', (16, 22))	('detected', 'Reg', (27, 35))
21638	25609060	Notably, IF using an antibody that recognizes an epitope at the C-terminus of TACC3, which is invariably retained within FGFR3-TACC3 variants (TACC3-C), reproduced the staining pattern of the FGFR3-N antibody in FGFR3-TACC3 positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('TACC3', 'Gene', (78, 83))	('tumors', 'Disease', (233, 239))	('C', 'Chemical', 'MESH:D002244', (220, 221))	('C', 'Chemical', 'MESH:D002244', (145, 146))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('C', 'Chemical', 'MESH:D002244', (149, 150))	('C', 'Chemical', 'MESH:D002244', (80, 81))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('staining', 'MPA', (168, 176))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('variants', 'Var', (133, 141))
21640	25609060	Consistently, quantitative RT-PCR of GBM harboring FGFR3-TACC3 fusions showed that the expression of the N-terminal coding region of FGFR3 and the C-terminal coding region of TACC3 (which are included in the fusion genes) is markedly higher than the expression of the C-terminal coding region of FGFR3 and the N-terminal coding region of TACC3, which are excluded from the fusion transcripts (Supplementary Fig.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('C', 'Chemical', 'MESH:D002244', (268, 269))	('FGFR3', 'Gene', (133, 138))	('TACC3', 'Gene', (175, 180))	('C', 'Chemical', 'MESH:D002244', (59, 60))	('C', 'Chemical', 'MESH:D002244', (341, 342))	('C', 'Chemical', 'MESH:D002244', (147, 148))	('C', 'Chemical', 'MESH:D002244', (177, 178))	('expression', 'MPA', (87, 97))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('higher', 'PosReg', (234, 240))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (340, 341))	('fusions', 'Var', (63, 70))	('C', 'Chemical', 'MESH:D002244', (178, 179))
21643	25609060	Clinical and molecular profiling data were available for 591 patients including 380 GBM (9 with FGFR3-TACC3 fusions) and all 211 lower grade glioma (3 with FGFR3-TACC3 fusions).	('glioma', 'Disease', (141, 147))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('FGFR3-TACC3', 'Gene', (96, 107))	('patients', 'Species', '9606', (61, 69))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('C', 'Chemical', 'MESH:D002244', (164, 165))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('fusions', 'Var', (108, 115))
21647	25609060	Patients with FGFR3-TACC3 fusions displayed unique characteristics (Table 2).	('fusions', 'Var', (26, 33))	('Patients', 'Species', '9606', (0, 8))	('FGFR3-TACC3', 'Gene', (14, 25))
21648	25609060	FGFR3-TACC3 fusions were mutually exclusive with EGFR amplification (0/16 vs. 166/411; p=0.0004, FDR q-value corrected for multiple comparisons=0.0012) and showed a clear trend against the presence of the EGFRvIII transcript variant (0/16 vs. 37/219; p=0.083).	('EGFR', 'Gene', '1956', (49, 53))	('fusions', 'Var', (12, 19))	('FGFR3-TACC3', 'Gene', (0, 11))	('EGFR', 'Gene', (49, 53))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))
21649	25609060	Conversely, CDK4 amplification was significantly more frequent in FGFR3-TACC3-positive tumors (7/16 vs 41/408, p=0.0008; FDR q-value= 0.0024).	('FGFR3-TACC3-positive', 'Gene', (66, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('amplification', 'Var', (17, 30))	('CDK4', 'Gene', (12, 16))	('C', 'Chemical', 'MESH:D002244', (12, 13))	('CDK4', 'Gene', '1019', (12, 16))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('C', 'Chemical', 'MESH:D002244', (75, 76))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
21650	25609060	A less significant association of FGFR3-TACC3 fusions was also seen with amplification of MDM2, which as CDK4, maps to chromosome 12q (4/16 vs 24/408, p=0.016; FDR q-value= 0.048).	('FGFR3-TACC3', 'Gene', (34, 45))	('CDK4', 'Gene', (105, 109))	('fusions', 'Var', (46, 53))	('CDK4', 'Gene', '1019', (105, 109))	('MDM2', 'Gene', '4193', (90, 94))	('MDM2', 'Gene', (90, 94))	('amplification', 'Var', (73, 86))
21651	25609060	We found no statistical association between FGFR3-TACC3 fusions and other genetic and epigenetic alterations that commonly occur in gliomas harboring wild type IDH genes (CDKN2A deletion, TERT promoter mutations, gain of chromosome 7p, loss of chromosome 10q and methylation of the MGMT promoter, Table 2).	('gain', 'PosReg', (213, 217))	('MGMT', 'Gene', (282, 286))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('TERT', 'Gene', (188, 192))	('MGMT', 'Gene', '4255', (282, 286))	('gliomas', 'Disease', (132, 139))	('TERT', 'Gene', '7015', (188, 192))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('CDKN2A', 'Gene', (171, 177))	('loss', 'NegReg', (236, 240))	('deletion', 'Var', (178, 186))	('IDH', 'Gene', (160, 163))	('CDKN2A', 'Gene', '1029', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('IDH', 'Gene', '3417', (160, 163))	('mutations', 'Var', (202, 211))
21652	25609060	When compared with the IDH wild type patient population of grade II and grade III glioma and GBM, there was no significant difference in progression free survival (PFS) or overall survival (OS) between patients positive or negative for FGFR3-TACC3 (Supplementary Fig.	('overall', 'MPA', (172, 179))	('III glioma', 'Disease', 'MESH:D005910', (78, 88))	('III glioma', 'Disease', (78, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('patient', 'Species', '9606', (37, 44))	('patient', 'Species', '9606', (202, 209))	('negative', 'NegReg', (223, 231))	('patients', 'Species', '9606', (202, 210))	('IDH', 'Gene', (23, 26))	('FGFR3-TACC3', 'Gene', (236, 247))	('positive', 'Var', (211, 219))	('IDH', 'Gene', '3417', (23, 26))
21653	25609060	Finally, we sought to establish whether the CNV analysis of the FGFR3 and TACC3 genomic loci could be used to predict positivity for FGFR3-TACC3 fusions.	('FGFR3-TACC3', 'Gene', (133, 144))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('FGFR3', 'Gene', (64, 69))	('TACC3', 'Gene', (74, 79))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('fusions', 'Var', (145, 152))	('C', 'Chemical', 'MESH:D002244', (142, 143))
21654	25609060	The analysis of high-density SNP6.0 arrays of the 158 GBM samples from the Atlas-TCGA revealed that 10 samples displayed different degrees of copy number gains encompassing the entire FGFR3 and TACC3 loci (Supplementary Fig.	('C', 'Chemical', 'MESH:D002244', (197, 198))	('gains', 'PosReg', (154, 159))	('TACC3', 'Gene', (194, 199))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('FGFR3', 'Gene', (184, 189))	('C', 'Chemical', 'MESH:D002244', (196, 197))	('copy number', 'Var', (142, 153))
21657	25609060	JNJ-42756493 is a potent, oral pan-FGFR tyrosine kinase inhibitor with IC50 values in the low nanomolar range for all members of the FGFR family.	('JNJ-42756493', 'Var', (0, 12))	('C', 'Chemical', 'MESH:D002244', (72, 73))	('tyrosine kinase', 'Gene', (40, 55))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (0, 12))	('tyrosine kinase', 'Gene', '7294', (40, 55))
21658	25609060	It has demonstrated potent antitumor activities in nonclinical models with FGFR aberrations including squamous non-small cell lung cancer, gastric, breast, hepatocellular cancer (HCC), endometrial, and bladder.	('non-small cell lung cancer', 'Disease', (111, 137))	('endometrial', 'Disease', (185, 196))	('breast, hepatocellular cancer', 'Disease', 'MESH:D006528', (148, 177))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('aberrations', 'Var', (80, 91))	('FGFR', 'Gene', (75, 79))	('tumor', 'Disease', (31, 36))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (156, 177))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (111, 137))	('bladder', 'Disease', (202, 209))	('gastric', 'Disease', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
21659	25609060	To ask whether JNJ-42756493 is effective in targeting specifically FGFR-TACC-positive cells, we treated with JNJ-42756493 mouse astrocytes expressing FGFR3-TACC3, FGFR3-TACC3 containing a mutation that inactivates the kinase activity of FGFR3 (FGFR3-TACC3-KD), or the empty vector.	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (15, 27))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (109, 121))	('mutation', 'Var', (188, 196))	('FGFR3', 'Gene', (237, 242))	('kinase activity', 'MPA', (218, 233))	('inactivates', 'NegReg', (202, 213))	('mouse', 'Species', '10090', (122, 127))
21661	25609060	These experiments revealed that both mouse astrocytes and GIC-1123 that express FGFR3-TACC3 but not cells expressing the KD mutant fusion or the empty vector are highly sensitive to FGFR inhibition by JNJ-42756493 with an IC50 of 3.03 nM and 1.55 nM, respectively (Fig.	('C', 'Chemical', 'MESH:D002244', (223, 224))	('FGFR3-TACC3', 'Var', (80, 91))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('mouse', 'Species', '10090', (37, 42))	('JNJ-42756493', 'Var', (201, 213))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (201, 213))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('sensitive', 'MPA', (169, 178))
21662	25609060	Next, we tested whether oral treatment with JNJ-42756493 of mice bearing xenografts of human GIC-1123 affects tumor growth.	('mice', 'Species', '10090', (60, 64))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (44, 56))	('human', 'Species', '9606', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('JNJ-42756493', 'Var', (44, 56))	('tested', 'Reg', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
21664	25609060	Mirroring the in vitro results, JNJ-42756493 elicited a potent growth inhibition of GIC-1123 tumor xenografts (Fig.	('C', 'Chemical', 'MESH:D002244', (86, 87))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('JNJ-42756493', 'Var', (32, 44))	('growth inhibition', 'CPA', (63, 80))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
21666	25609060	The above findings provide a strong foundation for the treatment of GBM patients harboring FGFR-TACC rearrangements with JNJ-42756493.	('FGFR-TACC', 'Gene', (91, 100))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (121, 133))	('rearrangements', 'Var', (101, 115))	('patients', 'Species', '9606', (72, 80))
21667	25609060	Two patients with recurrent GBM harboring FGFR3-TACC3 fusions were treated with JNJ-42756493 in a first-in-man phase I trial.	('fusions', 'Var', (54, 61))	('FGFR3-TACC3', 'Gene', (42, 53))	('patients', 'Species', '9606', (4, 12))	('man', 'Species', '9606', (107, 110))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (80, 92))
21680	25609060	The tumor was positive for FGFR3-TACC3 gene fusion by RT-PCR-sequencing and showed diffuse FGFR3 expression in most tumor cells (Figure 2A, 2C, 2E, sample 4620).	('tumor', 'Disease', (4, 9))	('FGFR3', 'Gene', (91, 96))	('fusion', 'Var', (44, 50))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('FGFR3-TACC3', 'Gene', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (116, 121))	('expression', 'MPA', (97, 107))	('C', 'Chemical', 'MESH:D002244', (58, 59))
21688	25609060	FGFR-TACC fusions are potent oncogenic events that when present in brain tumor cells confer sensitivity to FGFR inhibitors.	('FGFR-TACC', 'Gene', (0, 9))	('brain tumor', 'Phenotype', 'HP:0030692', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('brain tumor', 'Disease', (67, 78))	('brain tumor', 'Disease', 'MESH:D001932', (67, 78))	('fusions', 'Var', (10, 17))
21689	25609060	Since our original identification of recurrent FGFR-TACC fusions in GBM, small subgroups of patients harboring FGFR-TACC translocations have been identified in several other tumor types.	('tumor', 'Disease', (174, 179))	('FGFR-TACC', 'Gene', (47, 56))	('patients', 'Species', '9606', (92, 100))	('fusions', 'Var', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('GBM', 'Disease', (68, 71))
21690	25609060	Here, we report an unbiased RT-PCR-sequencing analysis for the identification of all possible functional FGFR-TACC fusion transcripts.	('FGFR-TACC', 'Gene', (105, 114))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('fusion', 'Var', (115, 121))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('C', 'Chemical', 'MESH:D002244', (113, 114))
21691	25609060	The screening of a large glioma dataset from multiple Institutions not only confirmed that FGFR-TACC rearrangements occur in ~3% of human GBM but also revealed that FGFR-TACC fusions are present in the subgroup of IDH wild type lower grade glioma (grade II-III) with prevalence similar to that of GBM.	('FGFR-TACC', 'Gene', (91, 100))	('human', 'Species', '9606', (132, 137))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('rearrangements', 'Var', (101, 115))	('IDH', 'Gene', (214, 217))	('IDH', 'Gene', '3417', (214, 217))	('fusions', 'Var', (175, 182))	('glioma', 'Disease', (25, 31))	('glioma', 'Disease', (240, 246))
21693	25609060	Our finding that FGFR-TACC fusions occur in IDH wild type but not IDH mutant glioma provides an important clue for the molecular characterization of this glioma subtype.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('IDH', 'Gene', (66, 69))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH', 'Gene', '3417', (66, 69))	('glioma', 'Disease', (154, 160))	('FGFR-TACC', 'Gene', (17, 26))	('glioma', 'Disease', (77, 83))	('glioma subtype', 'Disease', 'MESH:D005910', (154, 168))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))	('fusions', 'Var', (27, 34))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma subtype', 'Disease', (154, 168))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
21695	25609060	While we showed that FGFR-TACC fusions cluster within the poor clinical outcome subgroup of IDH wild type glioma, these translocations do not seem to carry prognostic value within the IDH wild type subgroup of glioma patients.	('IDH', 'Gene', '3417', (184, 187))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('FGFR-TACC', 'Gene', (21, 30))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('IDH', 'Gene', (184, 187))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('glioma', 'Disease', (106, 112))	('IDH', 'Gene', (92, 95))	('type glioma', 'Disease', (101, 112))	('type glioma', 'Disease', 'MESH:D005910', (101, 112))	('patients', 'Species', '9606', (217, 225))	('fusions', 'Var', (31, 38))	('IDH', 'Gene', '3417', (92, 95))	('glioma', 'Disease', (210, 216))
21696	25609060	However, the sample size of patients harboring FGFR-TACC fusions is too small to draw definitive conclusions with respect to the impact on survival and larger studies will be necessary to clarify the prognostic role of FGFR-TACC fusions in IDH wild type glioma.	('IDH', 'Gene', (240, 243))	('type glioma', 'Disease', 'MESH:D005910', (249, 260))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('IDH', 'Gene', '3417', (240, 243))	('fusions', 'Var', (57, 64))	('patients', 'Species', '9606', (28, 36))	('type glioma', 'Disease', (249, 260))
21697	25609060	Beside mutual exclusivity between IDH1 mutations and FGFR-TACC fusions, our results showed that patients with FGFR3-TACC3 rearrangements lack EGFR amplification and EGFRvIII but are significantly enriched for amplification of CDK4 (and MDM2 to a lesser extent).	('EGFR', 'Gene', (165, 169))	('IDH1', 'Gene', '3417', (34, 38))	('MDM2', 'Gene', '4193', (236, 240))	('EGFR', 'Gene', '1956', (165, 169))	('lack', 'NegReg', (137, 141))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('MDM2', 'Gene', (236, 240))	('CDK4', 'Gene', (226, 230))	('FGFR3-TACC3', 'Gene', (110, 121))	('CDK4', 'Gene', '1019', (226, 230))	('patients', 'Species', '9606', (96, 104))	('IDH1', 'Gene', (34, 38))	('rearrangements', 'Var', (122, 136))
21698	25609060	Knowledge of these molecular characteristics will help select those patients who most likely harbor FGFR-TACC rearrangements and design combinatorial targeted therapies that might be more effective in the FGFR-TACC-positive glioma subgroup.	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('rearrangements', 'Var', (110, 124))	('patients', 'Species', '9606', (68, 76))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('FGFR-TACC', 'Gene', (100, 109))	('glioma', 'Disease', (224, 230))
21708	25609060	Therefore, it was essential to determine whether such heterogeneity was also present in gliomas harboring FGFR-TACC translocations.	('FGFR-TACC', 'Gene', (106, 115))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('translocations', 'Var', (116, 130))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
21712	25609060	The strong antitumor effects obtained with JNJ-42756493 in glioma cells harboring FGFR3-TACC3 fusions have built a compelling rationale for the treatment of glioma patients positive for FGFR-TACC rearrangements.	('glioma', 'Disease', (59, 65))	('FGFR3-TACC3', 'Gene', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (43, 55))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Disease', (15, 20))	('glioma', 'Disease', (157, 163))	('patients', 'Species', '9606', (164, 172))	('JNJ-42756493', 'Var', (43, 55))	('fusions', 'Var', (94, 101))
21713	25609060	JNJ-42756493 is an oral ATP-competitive pan-FGFR selective inhibitor that inhibits tyrosine phosphorylation of activated FGFR at nanomolar concentrations.	('JNJ-42756493', 'Var', (0, 12))	('tyrosine', 'Chemical', 'MESH:D014443', (83, 91))	('tyrosine phosphorylation', 'MPA', (83, 107))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (0, 12))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('inhibits', 'NegReg', (74, 82))
21716	25609060	In conclusion, we have shown the importance and feasibility of prospective genotyping for FGFR-TACC fusions in glioma patients and provided a preliminary evidence of clinical response that warrants the investigation of the sensitivity of gliomas harboring FGFR-TACC rearrangements to FGFR kinase inhibition in clinical trials.	('fusions', 'Var', (100, 107))	('glioma', 'Disease', (111, 117))	('FGFR-TACC', 'Gene', (256, 265))	('glioma', 'Disease', (238, 244))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('gliomas', 'Disease', (238, 245))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('patients', 'Species', '9606', (118, 126))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('FGFR-TACC', 'Gene', (90, 99))	('rearrangements', 'Var', (266, 280))
21717	25609060	This manuscript reports an unbiased screening assay for FGFR-TACC fusions in glioma that overcomes the great variability of variants that are generated by FGFR-TACC chromosomal translocation in human cancer.	('man', 'Species', '9606', (5, 8))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('man', 'Species', '9606', (196, 199))	('FGFR-TACC', 'Gene', (56, 65))	('human', 'Species', '9606', (194, 199))	('glioma', 'Disease', (77, 83))	('fusions', 'Var', (66, 73))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('cancer', 'Disease', (200, 206))
21718	25609060	FGFR-TACC fusions occur in grade II and III glioma harboring wild-type IDH1 with frequency similar to glioblastoma (GBM), therefore providing a clue to the aggressive clinical behavior of this glioma subtype.	('fusions', 'Var', (10, 17))	('glioblastoma', 'Disease', (102, 114))	('glioma subtype', 'Disease', 'MESH:D005910', (193, 207))	('FGFR-TACC', 'Gene', (0, 9))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (156, 184))	('IDH1', 'Gene', (71, 75))	('glioma subtype', 'Disease', (193, 207))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('IDH1', 'Gene', '3417', (71, 75))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('III glioma', 'Disease', 'MESH:D005910', (40, 50))	('III glioma', 'Disease', (40, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
21722	25609060	These findings validate the treatment with FGFR inhibitors of glioma patients harboring FGFR-TACC chromosomal translocations.	('FGFR-TACC', 'Gene', (88, 97))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('chromosomal translocations', 'Var', (98, 124))	('patients', 'Species', '9606', (69, 77))	('glioma', 'Disease', (62, 68))
21726	32001707	In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma.	('N', 'Chemical', 'MESH:D009584', (32, 33))	('attenuated', 'NegReg', (52, 62))	('glioma', 'Disease', (160, 166))	('TMZ', 'Chemical', 'MESH:C047246', (146, 149))	('enhanced', 'PosReg', (86, 94))	('TMZ', 'Chemical', 'MESH:C047246', (67, 70))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('TMZ sensitivity', 'MPA', (67, 82))	('DNA damage repair', 'MPA', (31, 48))	('TTP', 'Gene', (139, 142))	('E2F1', 'Gene', (122, 126))	('BIP-MPC-NP', 'Var', (19, 29))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('TTP', 'Gene', '7538', (139, 142))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('down-regulation', 'NegReg', (103, 118))
21727	32001707	In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ.	('mice', 'Species', '10090', (116, 120))	('repression', 'NegReg', (61, 71))	('TMZ', 'Chemical', 'MESH:C047246', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('survival', 'CPA', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BIP-MPC-NP', 'Var', (144, 154))	('tumor', 'Disease', (75, 80))
21737	32001707	Crosstalk between EGFR and MET contributes to the poor efficacy in the clinical treatment and malignant progresses such as alternative DNA damage repair.	('alternative DNA damage repair', 'CPA', (123, 152))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('Crosstalk', 'Var', (0, 9))	('EGFR', 'Gene', (18, 22))
21742	32001707	Inherbin3 has exhibited the reduction of the EGFR signaling in tumor cells and the suppression of tumor growth in vivo via targeting EGFR and inhibits the EGFR phosphorylation.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (98, 103))	('EGFR', 'Protein', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('inhibits', 'NegReg', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('targeting', 'Var', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('EGFR', 'Protein', (133, 137))	('EGFR signaling', 'MPA', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('reduction', 'NegReg', (28, 37))	('Inherbin3', 'Gene', (0, 9))
21748	32001707	In vitro and in vivo results show that BIP-MPC-NP downregulates E2F1 via ARE motifs with tristetraprolin (TTP) mediated by phosphorylated p38 and significantly reduces its reduction of transcriptional activity on DNA damage repair modules to enhance the TMZ therapy effect.	('TTP', 'Gene', (106, 109))	('tristetraprolin', 'Gene', '7538', (89, 104))	('p38', 'Gene', (138, 141))	('transcriptional activity', 'MPA', (185, 209))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('TTP', 'Gene', '7538', (106, 109))	('TMZ', 'Chemical', 'MESH:C047246', (254, 257))	('BIP-MPC-NP', 'Var', (39, 49))	('tristetraprolin', 'Gene', (89, 104))	('E2F1', 'Gene', (64, 68))	('enhance', 'PosReg', (242, 249))	('reduction', 'NegReg', (172, 181))	('p38', 'Gene', '1432', (138, 141))	('reduces', 'NegReg', (160, 167))	('downregulates', 'NegReg', (50, 63))	('N', 'Chemical', 'MESH:D009584', (214, 215))
21752	32001707	According to our previous work, we established TMZ-resistant GBM cells named LN229R, U87MGR and HG9R through TMZ treatment on LN229, U87MG and patient-derived GBM cell HG9 (Supplementary Fig.	('LN229', 'Var', (126, 131))	('U87MG', 'CellLine', 'CVCL:0022', (133, 138))	('patient', 'Species', '9606', (143, 150))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('U87MG', 'Var', (133, 138))	('U87MG', 'CellLine', 'CVCL:0022', (85, 90))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('LN229', 'CellLine', 'CVCL:0393', (77, 82))	('LN229R', 'CellLine', 'CVCL:0393', (77, 83))	('TMZ', 'Chemical', 'MESH:C047246', (109, 112))	('LN229', 'CellLine', 'CVCL:0393', (126, 131))	('TMZ', 'Chemical', 'MESH:C047246', (47, 50))
21753	32001707	Gene expression profiling was performed for the LN229R and the parental cells LN229 and RTK genes had higher expression levels in LN229R cells than in LN229 cells, especially for EGFR and MET (Supplementary Fig.	('LN229', 'CellLine', 'CVCL:0393', (48, 53))	('LN229', 'CellLine', 'CVCL:0393', (151, 156))	('LN229R', 'CellLine', 'CVCL:0393', (48, 54))	('higher', 'PosReg', (102, 108))	('RTK', 'Gene', (88, 91))	('LN229R', 'CellLine', 'CVCL:0393', (130, 136))	('LN229', 'CellLine', 'CVCL:0393', (78, 83))	('LN229', 'CellLine', 'CVCL:0393', (130, 135))	('expression levels', 'MPA', (109, 126))	('LN229R', 'Var', (130, 136))	('RTK', 'Gene', '5979', (88, 91))
21754	32001707	LN229R exhibited higher levels of EGFR and MET expression and phosphorylation in mouse orthotopic models bearing GBM xenografts (Supplementary Fig.	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('LN229R', 'CellLine', 'CVCL:0393', (0, 6))	('LN229R', 'Var', (0, 6))	('phosphorylation', 'MPA', (62, 77))	('MET expression', 'MPA', (43, 57))	('EGFR', 'MPA', (34, 38))	('higher', 'PosReg', (17, 23))	('mouse', 'Species', '10090', (81, 86))
21756	32001707	3, Supplementary Table 1), simultaneous reduction of EGFR and MET could significantly downregulate the phosphorylation levels of the downstream proteins (p-AKT, p-p38, p-STAT3 and p-p65) compared with single knockdown of EGFR or MET (Supplementary Fig.	('MET', 'Var', (62, 65))	('AKT', 'Gene', '207', (156, 159))	('p38', 'Gene', (163, 166))	('STAT3', 'Gene', '6774', (170, 175))	('p-p65', 'Protein', (180, 185))	('STAT3', 'Gene', (170, 175))	('AKT', 'Gene', (156, 159))	('reduction', 'NegReg', (40, 49))	('phosphorylation levels', 'MPA', (103, 125))	('p38', 'Gene', '1432', (163, 166))	('EGFR', 'Gene', (53, 57))	('downregulate', 'NegReg', (86, 98))
21766	32001707	Then different nanoinhibitors were labeled with FITC (green) and in vitro fluorescence images showed the localization of EBP-MPC-NP, MBP-MPC-NP and BIP-MPC-NP on the surface of LN229R cells (red), while the MPC-NP without peptides showed negligible colocalization (Fig.	('N', 'Chemical', 'MESH:D009584', (156, 157))	('MBP-MPC-NP', 'Gene', '4155', (133, 143))	('N', 'Chemical', 'MESH:D009584', (211, 212))	('MP', 'Chemical', 'MESH:D008775', (137, 139))	('pep', 'Gene', (222, 225))	('EBP-MPC-NP', 'Gene', '10682', (121, 131))	('BIP-MPC-NP', 'Var', (148, 158))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('MP', 'Chemical', 'MESH:D008775', (125, 127))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('pep', 'Gene', '5047', (222, 225))	('EBP-MPC-NP', 'Gene', (121, 131))	('MP', 'Chemical', 'MESH:D008775', (152, 154))	('LN229R', 'CellLine', 'CVCL:0393', (177, 183))	('MBP-MPC-NP', 'Gene', (133, 143))	('MP', 'Chemical', 'MESH:D008775', (207, 209))	('FITC', 'Chemical', 'MESH:D016650', (48, 52))	('N', 'Chemical', 'MESH:D009584', (141, 142))
21767	32001707	Flow cytometric analysis showed that compared with cells treated with MPC-NP, those treated with EBP-MPC-NP, MBP-MPC-NP or BIP-MPC-NP had stronger fluorescent intensities (Fig.	('MP', 'Chemical', 'MESH:D008775', (113, 115))	('MP', 'Chemical', 'MESH:D008775', (101, 103))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('MP', 'Chemical', 'MESH:D008775', (127, 129))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('fluorescent intensities', 'MPA', (147, 170))	('stronger', 'PosReg', (138, 146))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('MP', 'Chemical', 'MESH:D008775', (70, 72))	('MBP-MPC-NP', 'Gene', (109, 119))	('EBP-MPC-NP', 'Gene', '10682', (97, 107))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('MBP-MPC-NP', 'Gene', '4155', (109, 119))	('BIP-MPC-NP', 'Var', (123, 133))	('EBP-MPC-NP', 'Gene', (97, 107))
21768	32001707	With 5-h incubation, 5.2% of BIP-MPC-NP (4 muM) penetrated through the bEnd.3 layer (Fig.	('muM', 'Gene', (43, 46))	('BIP-MPC-NP', 'Var', (29, 39))	('muM', 'Gene', '56925', (43, 46))
21772	32001707	6d, e), the fluorescence signal of Cy5.5-labeled BIP-MPC-NP was observed clearly in the mouse brains and showed a 3.2-fold higher increase than BIP-NP, indicating effective BBB permeability.	('higher increase', 'PosReg', (123, 138))	('N', 'Chemical', 'MESH:D009584', (148, 149))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('Cy5.5-labeled', 'Var', (35, 48))	('fluorescence', 'MPA', (12, 24))	('mouse', 'Species', '10090', (88, 93))
21773	32001707	The ex vivo fluorescence images of the sliced tumor-bearing brain tissues showed the enhanced distribution of Cy5.5-labeled BIP-NP with MPC (Supplementary Fig.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('BIP-NP', 'Var', (124, 130))	('MP', 'Chemical', 'MESH:D008775', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('enhanced', 'PosReg', (85, 93))	('distribution', 'MPA', (94, 106))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
21774	32001707	These results demonstrated that the nanoinhibitors were internalized into glioma tissues in vivo and BIP-MPC-NP had a more effective BBB permeability than BIP-NP.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('BIP-MPC-NP', 'Var', (101, 111))	('glioma', 'Disease', (74, 80))	('BBB permeability', 'MPA', (133, 149))	('N', 'Chemical', 'MESH:D009584', (159, 160))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
21776	32001707	With nanoinhibitors as treatments on TMZ-resistant glioma cells, BIP-MPC-NP simultaneously attenuated p-EGFR and p-MET in cells with EGF and HGF incubation (Supplementary Fig.	('EGF', 'Gene', '1950', (104, 107))	('p-MET', 'MPA', (113, 118))	('glioma', 'Disease', (51, 57))	('BIP-MPC-NP', 'Var', (65, 75))	('EGF', 'Gene', (133, 136))	('TMZ', 'Chemical', 'MESH:C047246', (37, 40))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('EGF', 'Gene', '1950', (133, 136))	('HGF', 'Gene', (141, 144))	('EGF', 'Gene', (104, 107))	('attenuated', 'NegReg', (91, 101))	('HGF', 'Gene', '3082', (141, 144))
21779	32001707	BIP-MPC-NP was also found to significantly decrease the dimer formation of EGFR or MET, the key step of EGFR or MET activation, in the EGF- and HGF-dependent (Supplementary Fig.	('BIP-MPC-NP', 'Var', (0, 10))	('decrease', 'NegReg', (43, 51))	('EGF', 'Gene', (135, 138))	('EGF', 'Gene', '1950', (104, 107))	('EGF', 'Gene', (75, 78))	('EGF', 'Gene', '1950', (135, 138))	('EGF', 'Gene', '1950', (75, 78))	('dimer formation', 'MPA', (56, 71))	('HGF', 'Gene', (144, 147))	('EGF', 'Gene', (104, 107))	('HGF', 'Gene', '3082', (144, 147))	('MET', 'MPA', (83, 86))
21780	32001707	The crosstalk signaling molecules of EGFR and MET pathways (p-AKT, p-p38, p-STAT3 and p-p65) were also mitigated by BIP-MPC-NP in TMZ-resistant glioma cells (Supplementary Fig.	('STAT3', 'Gene', '6774', (76, 81))	('AKT', 'Gene', (62, 65))	('crosstalk signaling molecules', 'MPA', (4, 33))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('mitigated', 'NegReg', (103, 112))	('TMZ', 'Chemical', 'MESH:C047246', (130, 133))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('STAT3', 'Gene', (76, 81))	('p-p65', 'Var', (86, 91))	('MET pathways', 'Pathway', (46, 58))	('p38', 'Gene', '1432', (69, 72))	('glioma', 'Disease', (144, 150))	('AKT', 'Gene', '207', (62, 65))	('BIP-MPC-NP', 'Var', (116, 126))	('EGFR', 'Pathway', (37, 41))	('p38', 'Gene', (69, 72))
21781	32001707	Through the analysis of TCGA datasets, we observed that the upregulated proteins in the samples with high EGFR and MET copy numbers included EGFR, p-EGFR, p-MET and several DNA damage repair molecules such as CHK1, MERE11, RAD51, p53, RAD50 and p-CHK1 (Fig.	('CHK1', 'Gene', (247, 251))	('RAD51', 'Gene', (223, 228))	('CHK1', 'Gene', (209, 213))	('upregulated', 'PosReg', (60, 71))	('RAD51', 'Gene', '5888', (223, 228))	('proteins', 'Protein', (72, 80))	('p-MET', 'Var', (155, 160))	('CHK1', 'Gene', '1111', (247, 251))	('p53', 'Gene', '7157', (230, 233))	('EGFR', 'Gene', (141, 145))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('CHK1', 'Gene', '1111', (209, 213))	('MET copy numbers', 'Var', (115, 131))	('RAD50', 'Gene', (235, 240))	('RAD50', 'Gene', '10111', (235, 240))	('p-EGFR', 'Var', (147, 153))	('p53', 'Gene', (230, 233))	('EGFR', 'Gene', (106, 110))
21783	32001707	We detected the expression levels of the DNA damage repair molecules and observed that BIP-MPC-NP reduced the expression levels of CHK1, CHK2, RAD51, RAD50 and p53, and increased the expression levels of gammaH2AX induced by TMZ compared with EBP-MPC-NP or MBP-MPC-NP (Fig.	('EBP-MPC-NP', 'Gene', '10682', (243, 253))	('CHK2', 'Gene', (137, 141))	('p53', 'Gene', '7157', (160, 163))	('N', 'Chemical', 'MESH:D009584', (251, 252))	('expression levels', 'MPA', (183, 200))	('reduced', 'NegReg', (98, 105))	('TMZ', 'Chemical', 'MESH:C047246', (225, 228))	('CHK1', 'Gene', '1111', (131, 135))	('MBP-MPC-NP', 'Gene', '4155', (257, 267))	('EBP-MPC-NP', 'Gene', (243, 253))	('BIP-MPC-NP', 'Var', (87, 97))	('expression levels', 'MPA', (110, 127))	('p53', 'Gene', (160, 163))	('CHK2', 'Gene', '11200', (137, 141))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('N', 'Chemical', 'MESH:D009584', (265, 266))	('RAD51', 'Gene', (143, 148))	('RAD50', 'Gene', (150, 155))	('increased', 'PosReg', (169, 178))	('RAD51', 'Gene', '5888', (143, 148))	('RAD50', 'Gene', '10111', (150, 155))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('CHK1', 'Gene', (131, 135))	('MBP-MPC-NP', 'Gene', (257, 267))	('gammaH2AX', 'Protein', (204, 213))
21784	32001707	Immunofluorescence (IF) assays further confirmed that CHK1, CHK2, RAD51, RAD50 and p53 expression were reduced in the TMZ + BIP (TMZ combined with BIP-MPC-NP) group compared with those in the TMZ + EBP (TMZ combined with EBP-MPC-NP) or TMZ + MBP (TMZ combined with MBP-MPC-NP) group in TMZ-resistant glioma cells (Supplementary Figs.	('EBP-MPC-NP', 'Gene', (221, 231))	('MBP-MPC-NP', 'Gene', (265, 275))	('TMZ', 'Chemical', 'MESH:C047246', (203, 206))	('p53', 'Gene', (83, 86))	('RAD51', 'Gene', (66, 71))	('glioma', 'Phenotype', 'HP:0009733', (300, 306))	('RAD51', 'Gene', '5888', (66, 71))	('CHK2', 'Gene', '11200', (60, 64))	('TMZ', 'Chemical', 'MESH:C047246', (129, 132))	('TMZ', 'Chemical', 'MESH:C047246', (192, 195))	('TMZ', 'Chemical', 'MESH:C047246', (247, 250))	('EBP', 'Gene', '10682', (221, 224))	('EBP', 'Gene', '10682', (198, 201))	('MBP-MPC-NP', 'Gene', '4155', (265, 275))	('RAD50', 'Gene', (73, 78))	('MBP', 'Gene', '4155', (242, 245))	('CHK1', 'Gene', (54, 58))	('MBP', 'Gene', (242, 245))	('TMZ + BIP', 'Var', (118, 127))	('reduced', 'NegReg', (103, 110))	('MBP', 'Gene', '4155', (265, 268))	('RAD50', 'Gene', '10111', (73, 78))	('TMZ', 'Chemical', 'MESH:C047246', (286, 289))	('expression', 'MPA', (87, 97))	('MBP', 'Gene', (265, 268))	('TMZ', 'Chemical', 'MESH:C047246', (118, 121))	('TMZ', 'Chemical', 'MESH:C047246', (236, 239))	('EBP', 'Gene', (221, 224))	('glioma', 'Disease', (300, 306))	('EBP-MPC-NP', 'Gene', '10682', (221, 231))	('EBP', 'Gene', (198, 201))	('p53', 'Gene', '7157', (83, 86))	('CHK2', 'Gene', (60, 64))	('CHK1', 'Gene', '1111', (54, 58))	('glioma', 'Disease', 'MESH:D005910', (300, 306))
21785	32001707	Comet assays also illustrated that BIP-MPC-NP enhanced the DNA damage induced by TMZ compared with EBP-MPC-NP or MBP-MPC-NP in TMZ-resistant glioma cells (Fig.	('EBP-MPC-NP', 'Gene', '10682', (99, 109))	('MBP-MPC-NP', 'Gene', '4155', (113, 123))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('TMZ', 'Chemical', 'MESH:C047246', (127, 130))	('BIP-MPC-NP', 'Var', (35, 45))	('glioma', 'Disease', (141, 147))	('EBP-MPC-NP', 'Gene', (99, 109))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('Comet', 'Species', '302767', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('enhanced', 'PosReg', (46, 54))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('MBP-MPC-NP', 'Gene', (113, 123))	('TMZ', 'Chemical', 'MESH:C047246', (81, 84))	('DNA damage', 'MPA', (59, 69))
21787	32001707	The lower ability of DNA replication could be observed in the TMZ + BIP group than in the other groups (Fig.	('TMZ', 'Chemical', 'MESH:C047246', (62, 65))	('DNA replication', 'CPA', (21, 36))	('lower', 'NegReg', (4, 9))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('TMZ + BIP', 'Var', (62, 71))
21788	32001707	The clone formation assay and CCK-8 assay also validated that BIP-MPC-NP exhibited a greater proliferative inhibition effect induced by TMZ compared with EBP-MPC-NP or MBP-MPC-NP (Fig.	('proliferative', 'CPA', (93, 106))	('BIP-MPC-NP', 'Var', (62, 72))	('TMZ', 'Chemical', 'MESH:C047246', (136, 139))	('EBP-MPC-NP', 'Gene', '10682', (154, 164))	('MBP-MPC-NP', 'Gene', '4155', (168, 178))	('EBP-MPC-NP', 'Gene', (154, 164))	('TMZ', 'Var', (136, 139))	('MBP-MPC-NP', 'Gene', (168, 178))
21789	32001707	The rate of apoptotic cells and the population of cells arrested in S phase of the cell cycle in the TMZ+BIP group were increased compared with those in other groups (Fig.	('arrest', 'Disease', (56, 62))	('apoptotic cells', 'CPA', (12, 27))	('TMZ', 'Chemical', 'MESH:C047246', (101, 104))	('increased', 'PosReg', (120, 129))	('TMZ+BIP', 'Var', (101, 108))	('arrest', 'Disease', 'MESH:D006323', (56, 62))
21790	32001707	These results demonstrated the potentiation of BIP-MPC-NP on TMZ-induced DNA damage and cytotoxicity effects in TMZ-resistant glioma cells.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('TMZ', 'Chemical', 'MESH:C047246', (112, 115))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('cytotoxicity', 'Disease', (88, 100))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('DNA damage', 'MPA', (73, 83))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('potentiation', 'PosReg', (31, 43))	('BIP-MPC-NP', 'Var', (47, 57))	('glioma', 'Disease', (126, 132))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('TMZ', 'Chemical', 'MESH:C047246', (61, 64))
21793	32001707	Chromatin immunoprecipitation followed by polymerase chain reaction (ChIP-PCR) assays showed that BIP-MPC-NP could significantly downregulate the enrichment of E2F1 in the promoter regions of CHEK1, CHEK2, RAD50, RAD51 and TP53 genes compared with EBP-MPC-NP or MBP-MPC-NC in LN229R (Fig.	('MP', 'Chemical', 'MESH:D008775', (252, 254))	('CHEK1', 'Gene', '1111', (192, 197))	('MBP', 'Gene', '4155', (262, 265))	('MP', 'Chemical', 'MESH:D008775', (102, 104))	('MBP', 'Gene', (262, 265))	('MP', 'Chemical', 'MESH:D008775', (266, 268))	('E2F1', 'Var', (160, 164))	('TP53', 'Gene', '7157', (223, 227))	('CHEK1', 'Gene', (192, 197))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('EBP-MPC-NP', 'Gene', '10682', (248, 258))	('enrichment', 'MPA', (146, 156))	('RAD51', 'Gene', (213, 218))	('CHEK2', 'Gene', (199, 204))	('RAD51', 'Gene', '5888', (213, 218))	('downregulate', 'NegReg', (129, 141))	('RAD50', 'Gene', (206, 211))	('N', 'Chemical', 'MESH:D009584', (256, 257))	('BIP-MPC-NP', 'Var', (98, 108))	('EBP-MPC-NP', 'Gene', (248, 258))	('CHEK2', 'Gene', '11200', (199, 204))	('N', 'Chemical', 'MESH:D009584', (270, 271))	('RAD50', 'Gene', '10111', (206, 211))	('N', 'Chemical', 'MESH:D009584', (277, 278))	('TP53', 'Gene', (223, 227))	('LN229R', 'CellLine', 'CVCL:0393', (276, 282))
21794	32001707	With the treatment of BIP-MPC-NP, the expression of E2F1 mRNA as well as protein was lower compared with that in the EBP-MPC-NP or MBP-MPC-NP group (Supplementary Fig.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('E2F1', 'Gene', (52, 56))	('lower', 'NegReg', (85, 90))	('expression', 'MPA', (38, 48))	('MBP-MPC-NP', 'Gene', (131, 141))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('EBP-MPC-NP', 'Gene', '10682', (117, 127))	('MBP-MPC-NP', 'Gene', '4155', (131, 141))	('EBP-MPC-NP', 'Gene', (117, 127))	('BIP-MPC-NP', 'Var', (22, 32))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('protein', 'MPA', (73, 80))
21796	32001707	In our results, E2F1 mRNA was attenuated accompanied by increased TTP expression in cells treated with BIP-MPC-NP compared to those in the EBP-MPC-NP or MBP-MPC-NP groups (Fig.	('EBP-MPC-NP', 'Gene', (139, 149))	('BIP-MPC-NP', 'Var', (103, 113))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('TTP', 'Gene', (66, 69))	('MBP-MPC-NP', 'Gene', (153, 163))	('increased', 'PosReg', (56, 65))	('TTP', 'Gene', '7538', (66, 69))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('E2F1', 'Gene', (16, 20))	('MBP-MPC-NP', 'Gene', '4155', (153, 163))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('mRNA', 'MPA', (21, 25))	('EBP-MPC-NP', 'Gene', '10682', (139, 149))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('attenuated', 'NegReg', (30, 40))
21798	32001707	16a), we cloned the wild-type (AUUUA) or mutant-type (AGUGA) ARE motifs derived from E2F1 mRNA 3'-UTR into the downstream of the luciferase reporter gene in the luciferase expression vector to investigate the role of TTP in post-transcriptional regulation of E2F1 expression.	('N', 'Chemical', 'MESH:D009584', (92, 93))	('TTP', 'Gene', (217, 220))	('TTP', 'Gene', '7538', (217, 220))	('E2F1', 'Gene', (85, 89))	('mutant-type', 'Var', (41, 52))
21799	32001707	As downstream of the EGFR and MET signaling pathways, phosphorylated p38 (p-p38), which could be significantly attenuated by BIP-MPC-NP as previously described, is responsible for multiple biological processes, such as TTP downregulation.	('TTP', 'Gene', (219, 222))	('TTP', 'Gene', '7538', (219, 222))	('p38', 'Gene', (76, 79))	('attenuated', 'NegReg', (111, 121))	('p38', 'Gene', '1432', (69, 72))	('p38', 'Gene', '1432', (76, 79))	('phosphorylated', 'Var', (54, 68))	('p38', 'Gene', (69, 72))
21801	32001707	With the incubation of SB203580, p-p38 was attenuated with increasing TTP compared to that in cells treated with DMSO as a control group.	('SB203580', 'Chemical', 'MESH:C093642', (23, 31))	('SB203580', 'Var', (23, 31))	('DMSO', 'Chemical', 'MESH:D004121', (113, 117))	('TTP', 'Gene', (70, 73))	('TTP', 'Gene', '7538', (70, 73))	('p38', 'Gene', '1432', (35, 38))	('attenuated', 'NegReg', (43, 53))	('p38', 'Gene', (35, 38))
21802	32001707	In cells treated with SB203580, E2F1 mRNA and protein expression was synergistically decreased by the mitigation of p-p38 levels (Supplementary Fig.	('SB203580', 'Var', (22, 30))	('decreased', 'NegReg', (85, 94))	('SB203580', 'Chemical', 'MESH:C093642', (22, 30))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('E2F1', 'Gene', (32, 36))	('p38', 'Gene', (118, 121))	('mitigation', 'NegReg', (102, 112))	('p38', 'Gene', '1432', (118, 121))
21803	32001707	We also validated that SB230580, similar to BIP-MPC-NP, led to decreased luciferase reporter activity in cells containing wild-type ARE fragments instead of in cells containing mutant-type ARE fragments.	('luciferase', 'Enzyme', (73, 83))	('SB230580', 'Var', (23, 31))	('decreased', 'NegReg', (63, 72))	('SB230580', 'Chemical', 'MESH:C475340', (23, 31))
21804	32001707	No significant difference in luciferase reporter activity was found in cells containing mutant ARE motifs (Supplementary Fig.	('luciferase', 'Enzyme', (29, 39))	('mutant', 'Var', (88, 94))	('N', 'Chemical', 'MESH:D009584', (0, 1))
21805	32001707	These results demonstrated that BIP-MPC-NP could attenuate phosphorylation of p38 and reduce E2F1 expression mediated by TTP on ARE-containing mRNA to attenuate DNA damage repair in TMZ-resistant glioma cells.	('DNA damage repair', 'MPA', (161, 178))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('attenuate', 'NegReg', (151, 160))	('BIP-MPC-NP', 'Var', (32, 42))	('reduce', 'NegReg', (86, 92))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('p38', 'Gene', '1432', (78, 81))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('TTP', 'Gene', '7538', (121, 124))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('TMZ', 'Chemical', 'MESH:C047246', (182, 185))	('E2F1', 'Gene', (93, 97))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('TTP', 'Gene', (121, 124))	('phosphorylation', 'MPA', (59, 74))	('attenuate', 'NegReg', (49, 58))	('p38', 'Gene', (78, 81))	('glioma', 'Disease', (196, 202))	('expression', 'MPA', (98, 108))
21806	32001707	To expand our investigation to explore whether BIP-MPC-NP exhibited the effective improvement of TMZ sensitivity for TMZ-resistant glioma in vivo, we transplanted LN229R cells into 4-week-old female BALB/c nude mice.	('glioma', 'Disease', (131, 137))	('TMZ', 'Chemical', 'MESH:C047246', (117, 120))	('TMZ', 'Chemical', 'MESH:C047246', (97, 100))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('TMZ sensitivity', 'MPA', (97, 112))	('BIP-MPC-NP', 'Var', (47, 57))	('LN229R', 'CellLine', 'CVCL:0393', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('improvement', 'PosReg', (82, 93))	('nude mice', 'Species', '10090', (206, 215))
21814	32001707	The TMZ + BIP group showed significantly reduced expression levels of p-EGFR and p-MET in glioma tissues by IF and IHC assays (Supplementary Fig.	('reduced', 'NegReg', (41, 48))	('expression levels', 'MPA', (49, 66))	('glioma', 'Disease', (90, 96))	('TMZ', 'Chemical', 'MESH:C047246', (4, 7))	('p-MET', 'Var', (81, 86))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('p-EGFR', 'Var', (70, 76))
21815	32001707	The higher expression of TTP and gammaHAX, and the lower expression of E2F1, CHK1, CHK2, p53, RAD50 and RAD51 in glioma tissues were also observed in the TMZ + BIP group compared with other groups (Supplementary Figs.	('expression', 'MPA', (11, 21))	('CHK1', 'Gene', '1111', (77, 81))	('p53', 'Gene', (89, 92))	('CHK2', 'Gene', '11200', (83, 87))	('expression', 'MPA', (57, 67))	('TTP', 'Gene', '7538', (25, 28))	('RAD51', 'Gene', (104, 109))	('E2F1', 'Gene', (71, 75))	('RAD51', 'Gene', '5888', (104, 109))	('lower', 'NegReg', (51, 56))	('glioma', 'Disease', (113, 119))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('p53', 'Gene', '7157', (89, 92))	('RAD50', 'Gene', (94, 99))	('higher', 'PosReg', (4, 10))	('gammaHAX', 'Gene', (33, 41))	('TTP', 'Gene', (25, 28))	('CHK1', 'Gene', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('RAD50', 'Gene', '10111', (94, 99))	('TMZ + BIP', 'Var', (154, 163))	('CHK2', 'Gene', (83, 87))	('TMZ', 'Chemical', 'MESH:C047246', (154, 157))
21817	32001707	These results demonstrated that BIP-MPC-NP potentiated the TMZ-induced restriction on TMZ-resistant glioma xenografts by attenuating DNA damage repair via mitigation of the EGFR and MET signaling pathways (Fig.	('mitigation', 'NegReg', (155, 165))	('glioma', 'Disease', (100, 106))	('TMZ', 'Chemical', 'MESH:C047246', (59, 62))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('TMZ', 'Chemical', 'MESH:C047246', (86, 89))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('BIP-MPC-NP', 'Var', (32, 42))	('DNA damage repair', 'MPA', (133, 150))	('attenuating', 'NegReg', (121, 132))
21825	32001707	MET alterations, including MET exon 14 skipping (METex14) and PTPRZ1-MET (ZM) fusion, in cell lines and xenografts demonstrated hyper-activation of the MET signaling pathway and acceleration of glioma proliferation.	('PTPRZ1', 'Gene', (62, 68))	('MET signaling pathway', 'Pathway', (152, 173))	('hyper-activation', 'PosReg', (128, 144))	('glioma proliferation', 'Disease', (194, 214))	('glioma proliferation', 'Disease', 'MESH:D005910', (194, 214))	('acceleration', 'PosReg', (178, 190))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('PTPRZ1', 'Gene', '5803', (62, 68))	('MET exon 14 skipping', 'Var', (27, 47))
21830	32001707	MET, as an RTK, was an independent prognostic factor for TMZ chemotherapy.	('TMZ', 'Chemical', 'MESH:C047246', (57, 60))	('TMZ chemotherapy', 'Disease', (57, 73))	('RTK', 'Gene', '5979', (11, 14))	('RTK', 'Gene', (11, 14))	('MET', 'Var', (0, 3))
21840	32001707	However, with the presence of BBB, glioma patients hardly benefit from immunological therapy.	('presence', 'Var', (18, 26))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('patients', 'Species', '9606', (42, 50))	('BBB', 'Protein', (30, 33))	('glioma', 'Disease', (35, 41))
21845	32001707	The transportation assays showed that BIP-MPC-NP had higher permeability on crossing BBB in comparison to BIP-NP.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('higher', 'PosReg', (53, 59))	('BIP-MPC-NP', 'Var', (38, 48))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('permeability', 'MPA', (60, 72))
21847	32001707	Higher average radiance was detected in mouse brain tissues treated with BIP-MPC-NP than with BIP-NP, which indicated that nanoparticles with MPC had a long circulative half-life and remarkable BBB penetration ability.	('N', 'Chemical', 'MESH:D009584', (81, 82))	('BBB penetration ability', 'CPA', (194, 217))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('MPC', 'Var', (142, 145))	('MP', 'Chemical', 'MESH:D008775', (142, 144))	('mouse', 'Species', '10090', (40, 45))	('MP', 'Chemical', 'MESH:D008775', (77, 79))
21848	32001707	BIP-MPC-NP was found to significantly decrease the dimer formation of EGFR or MET, which were reported to be the key step of EGFR or MET activation, in an EGF- and HGF-dependent or independent manner.	('BIP-MPC-NP', 'Var', (0, 10))	('EGF', 'Gene', '1950', (155, 158))	('MET', 'Gene', (78, 81))	('dimer formation', 'MPA', (51, 66))	('HGF', 'Gene', (164, 167))	('EGF', 'Gene', '1950', (70, 73))	('EGF', 'Gene', '1950', (125, 128))	('HGF', 'Gene', '3082', (164, 167))	('decrease', 'NegReg', (38, 46))	('EGF', 'Gene', (155, 158))	('EGF', 'Gene', (70, 73))	('EGF', 'Gene', (125, 128))
21849	32001707	The EGFR and MET activation and the downstream of EGFR and MET signaling pathways, such as p-AKT, p-p38, p-STAT3 and p-p65 in TMZ-resistant glioma cells, were also mitigated by BIP-MPC-NP, as expected.	('p38', 'Gene', (100, 103))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('STAT3', 'Gene', (107, 112))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('TMZ', 'Chemical', 'MESH:C047246', (126, 129))	('AKT', 'Gene', (93, 96))	('MET', 'CPA', (13, 16))	('EGFR', 'Pathway', (4, 8))	('p-p65', 'Var', (117, 122))	('p38', 'Gene', '1432', (100, 103))	('activation', 'PosReg', (17, 27))	('glioma', 'Disease', (140, 146))	('STAT3', 'Gene', '6774', (107, 112))	('AKT', 'Gene', '207', (93, 96))
21856	32001707	With BIP-MPC-NP treatments, the DNA damage repair modules were attenuated, and the cytotoxicity caused by TMZ was enhanced in TMZ-resistant glioma cells.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('cytotoxicity', 'Disease', 'MESH:D064420', (83, 95))	('TMZ', 'Chemical', 'MESH:C047246', (106, 109))	('DNA damage', 'MPA', (32, 42))	('attenuated', 'NegReg', (63, 73))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('TMZ', 'Chemical', 'MESH:C047246', (126, 129))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('enhanced', 'PosReg', (114, 122))	('glioma', 'Disease', (140, 146))	('cytotoxicity', 'Disease', (83, 95))	('BIP-MPC-NP', 'Var', (5, 15))
21858	32001707	Blocking EGFR signaling leads to disrupted E2F1 function, and direct knockdown of MET downregulated the expression of downstream molecules, including E2F1, in retinal pigment epithelia cells.	('retinal pigment epithelia', 'Disease', 'MESH:D012173', (159, 184))	('MET', 'Gene', (82, 85))	('disrupted', 'NegReg', (33, 42))	('function', 'MPA', (48, 56))	('E2F1', 'Gene', (43, 47))	('retinal pigment epithelia', 'Disease', (159, 184))	('downregulated', 'NegReg', (86, 99))	('EGFR', 'Gene', (9, 13))	('expression', 'MPA', (104, 114))	('E2F1', 'Gene', (150, 154))	('knockdown', 'Var', (69, 78))
21859	32001707	In the present study, the peak enrichment of E2F1 in the promoter regions of TP53, CHEK1, CHEK2, RAD50 and RAD51, which were predicted on JASPAR datasets, was significantly downregulated in TMZ-resistant glioma cells with BIP-MPC-NP treatment.	('downregulated', 'NegReg', (173, 186))	('TMZ', 'Chemical', 'MESH:C047246', (190, 193))	('RAD51', 'Gene', (107, 112))	('CHEK2', 'Gene', '11200', (90, 95))	('CHEK1', 'Gene', '1111', (83, 88))	('glioma', 'Disease', (204, 210))	('RAD51', 'Gene', '5888', (107, 112))	('RAD50', 'Gene', (97, 102))	('RAD50', 'Gene', '10111', (97, 102))	('CHEK2', 'Gene', (90, 95))	('CHEK1', 'Gene', (83, 88))	('BIP-MPC-NP', 'Var', (222, 232))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('TP53', 'Gene', '7157', (77, 81))	('E2F1', 'Gene', (45, 49))	('TP53', 'Gene', (77, 81))
21861	32001707	When glioma cells were treated with BIP-MPC-NP, the E2F1 mRNA and protein expression levels were significantly downregulated.	('E2F1', 'Gene', (52, 56))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('glioma', 'Disease', (5, 11))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('downregulated', 'NegReg', (111, 124))	('BIP-MPC-NP', 'Var', (36, 46))	('glioma', 'Disease', 'MESH:D005910', (5, 11))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))
21865	32001707	In our results, BIP-MPC-NP downregulated E2F1 expression by the interaction between TTP and wild-type ARE motifs within the E2F1 mRNA 3'-UTR.	('downregulated', 'NegReg', (27, 40))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('BIP-MPC-NP', 'Var', (16, 26))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('TTP', 'Gene', (84, 87))	('expression', 'MPA', (46, 56))	('interaction', 'Interaction', (64, 75))	('TTP', 'Gene', '7538', (84, 87))	('E2F1', 'Gene', (41, 45))
21867	32001707	TTP could also be modulated by phosphorylated p38, which was found to play a major role in the regulation of mRNA stability.	('TTP', 'Gene', (0, 3))	('TTP', 'Gene', '7538', (0, 3))	('p38', 'Gene', (46, 49))	('phosphorylated', 'Var', (31, 45))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('p38', 'Gene', '1432', (46, 49))	('modulated', 'Reg', (18, 27))
21869	32001707	In the current study, BIP-MPC-NP attenuated p-p38 expression and increased TTP expression.	('increased', 'PosReg', (65, 74))	('p38', 'Gene', (46, 49))	('attenuated', 'NegReg', (33, 43))	('BIP-MPC-NP', 'Var', (22, 32))	('TTP', 'Gene', (75, 78))	('TTP', 'Gene', '7538', (75, 78))	('expression', 'MPA', (50, 60))	('p38', 'Gene', '1432', (46, 49))
21870	32001707	The p38-specific inhibitor SB203580 was also employed to further validate that inhibition of p-p38 decreased E2F1 mRNA and protein levels via the upregulation of TTP.	('p38', 'Gene', '1432', (95, 98))	('decreased', 'NegReg', (99, 108))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('upregulation', 'PosReg', (146, 158))	('SB203580', 'Chemical', 'MESH:C093642', (27, 35))	('p38', 'Gene', (95, 98))	('TTP', 'Gene', (162, 165))	('inhibition', 'Var', (79, 89))	('p38', 'Gene', '1432', (4, 7))	('TTP', 'Gene', '7538', (162, 165))	('p38', 'Gene', (4, 7))
21871	32001707	Intracranial xenograft models further elucidated that BIP-MPC-NP enhanced TMZ chemosensitivity via attenuating the EGFR and MET signaling pathways, including phosphorylation of p38 and reducing E2F1 expression accompanied by elevated TTP in TMZ-resistant gliomas.	('TMZ', 'Chemical', 'MESH:C047246', (241, 244))	('TTP', 'Gene', '7538', (234, 237))	('reducing', 'NegReg', (185, 193))	('enhanced', 'PosReg', (65, 73))	('TMZ', 'Chemical', 'MESH:C047246', (74, 77))	('elevated', 'PosReg', (225, 233))	('expression', 'MPA', (199, 209))	('phosphorylation', 'MPA', (158, 173))	('p38', 'Gene', (177, 180))	('TMZ chemosensitivity', 'MPA', (74, 94))	('BIP-MPC-NP', 'Var', (54, 64))	('gliomas', 'Disease', (255, 262))	('TTP', 'Gene', (234, 237))	('attenuating', 'NegReg', (99, 110))	('p38', 'Gene', '1432', (177, 180))	('gliomas', 'Disease', 'MESH:D005910', (255, 262))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('E2F1', 'Gene', (194, 198))	('gliomas', 'Phenotype', 'HP:0009733', (255, 262))
21872	32001707	The expression of p-EGFR and p-MET decreased in the TMZ+BIP group compared with the other groups.	('p-MET', 'Protein', (29, 34))	('expression', 'MPA', (4, 14))	('decreased', 'NegReg', (35, 44))	('TMZ', 'Chemical', 'MESH:C047246', (52, 55))	('p-EGFR', 'Protein', (18, 24))	('TMZ+BIP', 'Var', (52, 59))
21873	32001707	BIP-MPC-NP had more effective inhibition of E2F1 expression and DNA damage repair modules (CHK1, CHK2, p53, RAD50 and RAD51) than other nanoinhibitors.	('BIP-MPC-NP', 'Var', (0, 10))	('CHK2', 'Gene', '11200', (97, 101))	('CHK1', 'Gene', (91, 95))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('CHK1', 'Gene', '1111', (91, 95))	('expression', 'MPA', (49, 59))	('inhibition', 'NegReg', (30, 40))	('RAD50', 'Gene', (108, 113))	('RAD51', 'Gene', (118, 123))	('E2F1', 'Gene', (44, 48))	('RAD50', 'Gene', '10111', (108, 113))	('RAD51', 'Gene', '5888', (118, 123))	('CHK2', 'Gene', (97, 101))	('N', 'Chemical', 'MESH:D009584', (8, 9))
21876	32001707	BIP-MPC-NP attenuated E2F1 expression by interactions between TTP and ARE motifs within the E2F1 3'-UTR and consequently downregulated DNA damage repair and enhanced TMZ chemosensitivity in TMZ-resistant glioma.	('TTP', 'Gene', (62, 65))	('TMZ', 'MPA', (166, 169))	('attenuated', 'NegReg', (11, 21))	('expression', 'MPA', (27, 37))	('downregulated', 'NegReg', (121, 134))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('BIP-MPC-NP', 'Var', (0, 10))	('interactions', 'Interaction', (41, 53))	('DNA damage repair', 'MPA', (135, 152))	('TTP', 'Gene', '7538', (62, 65))	('enhanced', 'PosReg', (157, 165))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('TMZ', 'Chemical', 'MESH:C047246', (166, 169))	('E2F1', 'Gene', (22, 26))	('E2F1', 'Gene', (92, 96))	('TMZ', 'Chemical', 'MESH:C047246', (190, 193))	('N', 'Chemical', 'MESH:D009584', (8, 9))	('glioma', 'Disease', (204, 210))	('glioma', 'Disease', 'MESH:D005910', (204, 210))
21927	32001707	The mice were randomly divided into two groups (three mice per group) and intravenously injected with 100 muL of Cy5.5-labeled BIP-MPC-NP and BIP-NP, respectively (The concentration was 4 muM.	('mice', 'Species', '10090', (4, 8))	('muM', 'Gene', (188, 191))	('BIP-NP', 'Var', (142, 148))	('N', 'Chemical', 'MESH:D009584', (146, 147))	('mice', 'Species', '10090', (54, 58))	('muM', 'Gene', '56925', (188, 191))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('BIP-MPC-NP', 'Var', (127, 137))
21957	32001707	After injection of cyanine 5.5 (Cy5.5)-labeled BIP-MPC-NP or Cy5.5-labeled BIP-NP for 5 h, the tumor-bearing brains were removed and further fixed, followed by dehydration in 15% sucrose and 30% sucrose at 4  C. Frozen coronal sections of 20 mum in thickness were prepared and processed for fluorescence imaging.	('sucrose', 'Chemical', 'MESH:D013395', (179, 186))	('mum', 'Gene', (242, 245))	('sucrose', 'Chemical', 'MESH:D013395', (195, 202))	('dehydration', 'Disease', (160, 171))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cyanine', 'Chemical', 'MESH:C467359', (19, 26))	('BIP-MPC-NP', 'Var', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('dehydration', 'Disease', 'MESH:D003681', (160, 171))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('Cy5.5-labeled BIP-NP', 'Var', (61, 81))	('dehydration', 'Phenotype', 'HP:0001944', (160, 171))	('tumor', 'Disease', (95, 100))	('mum', 'Gene', '56925', (242, 245))
21986	30675060	Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2 , were shared in all matched ctDNA-positive CSF/tumor pairs, whereas we observed considerable evolution in growth factor receptor signaling pathways.	('mutations', 'Var', (125, 134))	('co-deletion', 'Var', (59, 70))	('IDH1', 'Gene', (186, 190))	('tumor', 'Disease', (248, 253))	('IDH1', 'Gene', '3417', (186, 190))	('IDH2', 'Gene', (195, 199))	('isocitrate dehydrogenase 1', 'Gene', (158, 184))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('isocitrate dehydrogenase 1', 'Gene', '3417', (158, 184))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('IDH2', 'Gene', '3418', (195, 199))	('growth factor receptor signaling pathways', 'Pathway', (307, 348))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', (36, 41))
22001	30675060	Subjects with CSF positivity experienced a four-fold risk of death compared to subjects who were CSF negative (p-value = 0.000024315).	('death', 'Disease', (61, 66))	('positivity', 'Var', (18, 28))	('death', 'Disease', 'MESH:D003643', (61, 66))
22005	30675060	These alterations are viewed as "truncal" events during tumor evolution and are used to define prognostically distinct LGG subtypes .	('alterations', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('LGG', 'Disease', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
22006	30675060	For example, gliomas with IDH mutation and 1p/19q codeletion typically also harbor mutations in telomerase reverse transcriptase (TERT) promoter.	('harbor', 'Reg', (76, 82))	('mutations', 'Var', (83, 92))	('telomerase reverse transcriptase', 'Gene', (96, 128))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('telomerase reverse transcriptase', 'Gene', '7015', (96, 128))	('IDH', 'Gene', (26, 29))	('1p/19q', 'Var', (43, 49))	('gliomas', 'Disease', (13, 20))	('IDH', 'Gene', '3417', (26, 29))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
22007	30675060	In contrast, gliomas with IDH and TP53 mutations (and no 1p/19q codeletion) often contain alterations in alpha-thalassemia/Mental-Retardation-Syndrome-X-linked (ATRX).	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('TP53', 'Gene', (34, 38))	('ATRX', 'Gene', (161, 165))	('Mental-Retardation', 'Phenotype', 'HP:0001249', (123, 141))	('IDH', 'Gene', '3417', (26, 29))	('mutations', 'Var', (39, 48))	('contain alterations', 'Reg', (82, 101))	('IDH', 'Gene', (26, 29))	('ATRX', 'Gene', '546', (161, 165))	('gliomas', 'Disease', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('TP53', 'Gene', '7157', (34, 38))	('alpha-thalassemia/Mental-Retardation-Syndrome-X-linked', 'Gene', '546', (105, 159))
22008	30675060	TERT promoter mutations and ATRX gene alterations both promote telomerase maintenance and are mutually exclusive .	('telomerase maintenance', 'MPA', (63, 85))	('ATRX', 'Gene', (28, 32))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('promote', 'PosReg', (55, 62))	('ATRX', 'Gene', '546', (28, 32))	('mutations', 'Var', (14, 23))	('alterations', 'Var', (38, 49))
22009	30675060	We examined whether these combinations of genetic alterations or "LGG signatures" were detectable in CSF and matched the signature of the original tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('original tumor', 'Disease', (138, 152))	('genetic alterations', 'Var', (42, 61))	('original tumor', 'Disease', 'MESH:D009369', (138, 152))	('CSF', 'Disease', (101, 104))
22013	30675060	Mutations were also shared between CSF and tumor in 20/20 (100%) GBM patients without DNA hypermutation (Extended Data Fig.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Disease', (43, 48))
22015	30675060	The most commonly observed alterations included mutations within the TERT promoter, the protein-coding regions of TP53, and the catalytic domain of IDH1 as well as deletions of CDKN2A/CDKN2B, amplifications of the Epidermal Growth Factor Receptor (EGFR), and the in-frame EGFR-variant III deletion (Fig.	('CDKN2B', 'Gene', '1030', (184, 190))	('amplifications', 'Var', (192, 206))	('deletions', 'Var', (164, 173))	('TP53', 'Gene', '7157', (114, 118))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))	('mutations', 'Var', (48, 57))	('CDKN2A', 'Gene', (177, 183))	('EGFR', 'Gene', (272, 276))	('EGFR', 'Gene', (248, 252))	('IDH1', 'Gene', (148, 152))	('CDKN2A', 'Gene', '1029', (177, 183))	('TP53', 'Gene', (114, 118))	('Epidermal Growth Factor Receptor', 'Gene', (214, 246))	('EGFR', 'Gene', '1956', (272, 276))	('CDKN2B', 'Gene', (184, 190))	('EGFR', 'Gene', '1956', (248, 252))	('IDH1', 'Gene', '3417', (148, 152))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (214, 246))
22022	30675060	This assay, while more targeted than MSK-IMPACT, encompassed at least 1 CSF mutation in each of the 19 patients, and 211 in total.	('patients', 'Species', '9606', (103, 111))	('mutation', 'Var', (76, 84))	('CSF', 'Gene', (72, 75))
22024	30675060	A total of 35 mutations were detected in the remaining three patients, including 32 from a single patient with a hypermutated tumor.	('patient', 'Species', '9606', (61, 68))	('patient', 'Species', '9606', (98, 105))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (126, 131))
22030	30675060	In patients with hypermutated tumors, shared mutations were considerably less common (range: 3%-49%; Figure 2b) with a median 19.6 % shared mutation rate (Supplementary Information Table 5).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('hypermutated', 'Var', (17, 29))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
22031	30675060	The majority of mutations that were clonal in tissue were also present in CSF, even in patients with DNA hypermutation.	('patients', 'Species', '9606', (87, 95))	('CSF', 'Disease', (74, 77))	('mutations', 'Var', (16, 25))	('present', 'Reg', (63, 70))
22037	30675060	For example, the initial tumor biopsy from patient # 25 harbored a high-level EGFR amplification and EGFR missense mutation whereas a later CSF sample revealed amplification and mutation of the Platelet-Derived Growth Factor Receptor (PDGFR) without evidence for the original EGFR alteration (Fig.	('missense mutation', 'Var', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Platelet-Derived Growth Factor Receptor', 'Gene', '5159', (194, 233))	('patient', 'Species', '9606', (43, 50))	('PDGFR', 'Gene', (235, 240))	('tumor', 'Disease', (25, 30))	('mutation', 'Var', (178, 186))	('PDGFR', 'Gene', '5159', (235, 240))	('EGFR', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', '1956', (276, 280))	('Platelet-Derived Growth Factor Receptor', 'Gene', (194, 233))	('EGFR', 'Gene', (276, 280))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
22038	30675060	Similarly, the initial tumor profile of patient #28 showed an activating mutation in PIK3CA (E545K), whereas a later tumor biopsy showed amplifications of MET and PDGFRA and a subsequent CSF sample retained the MET amplification and acquired a MYC amplification while losing the PDGFRA amplification (Extended Data Fig.	('E545K', 'Mutation', 'rs104886003', (93, 98))	('MET amplification', 'MPA', (211, 228))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patient', 'Species', '9606', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('acquired', 'PosReg', (233, 241))	('activating', 'PosReg', (62, 72))	('PDGFRA', 'Gene', '5156', (163, 169))	('PDGFRA', 'Gene', (163, 169))	('E545K', 'Var', (93, 98))	('MYC amplification', 'MPA', (244, 261))	('PIK3CA', 'Gene', '5290', (85, 91))	('tumor', 'Disease', (23, 28))	('losing', 'NegReg', (268, 274))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('PDGFRA', 'Gene', (279, 285))	('PDGFRA', 'Gene', '5156', (279, 285))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('PIK3CA', 'Gene', (85, 91))
22039	30675060	In LGGs, truncal alterations (IDH1, TP53, and ATRX) persisted throughout the disease course, but later samples documented additional mutations in glioma core pathways (Extended Data Fig.	('ATRX', 'Gene', '546', (46, 50))	('TP53', 'Gene', (36, 40))	('glioma', 'Disease', (146, 152))	('TP53', 'Gene', '7157', (36, 40))	('IDH1', 'Gene', (30, 34))	('mutations', 'Var', (133, 142))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('ATRX', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (30, 34))
22073	30675060	For all mutations called in either the tumor or the CSF, a secondary mutation analysis was performed in which less stringent criteria were applied to detect the full compilation of SNVs detectable within our samples.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', (39, 44))
22074	30675060	If these criteria were not met a mutation was marked as "not present" and considered to be private to the tumor or the CSF.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutation', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
22076	30675060	In patients with multiple CSF collections, we prioritized CSF samples that met the following criteria: (1) at least one mutation "called" in CSF; (2) CSF collected through lumbar puncture (i.e., rather than during VP-shunt placement or intra-operatively); (3) highest sequence coverage; (4) shortest interval between CSF and tumor collection.	('-shunt', 'Phenotype', 'HP:0001693', (216, 222))	('mutation', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('patients', 'Species', '9606', (3, 11))	('CSF', 'Disease', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))
22096	30431206	For instance, inhibition of glutaminase (GLS) with siRNA or small molecule inhibitor preferentially slows growth of glioma cells with mutant IDH 1.11 Yue et al12 found that oncogenic MYC selectively activates SLC7A5/SLC43A1 transcription and the MYC-SLC7A5/SLC43A1 signaling circuit promotes essential amino acid transport and tumorigenesis.	('SLC7A5', 'Gene', '8140', (250, 256))	('slows growth', 'Phenotype', 'HP:0001510', (100, 112))	('SLC7A5', 'Gene', '8140', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('promotes', 'PosReg', (283, 291))	('growth', 'CPA', (106, 112))	('MYC', 'Gene', (183, 186))	('tumor', 'Disease', (327, 332))	('MYC', 'Gene', (246, 249))	('SLC43A1', 'Gene', (257, 264))	('IDH 1', 'Gene', '3417', (141, 146))	('SLC43A1', 'Gene', '8501', (257, 264))	('SLC7A5', 'Gene', (250, 256))	('mutant', 'Var', (134, 140))	('SLC7A5', 'Gene', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('glutaminase', 'Gene', '2744', (28, 39))	('SLC43A1', 'Gene', '8501', (216, 223))	('GLS', 'Gene', '2744', (41, 44))	('SLC43A1', 'Gene', (216, 223))	('MYC', 'Gene', '4609', (183, 186))	('slows', 'NegReg', (100, 105))	('MYC', 'Gene', '4609', (246, 249))	('transcription', 'MPA', (224, 237))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('glioma', 'Disease', (116, 122))	('GLS', 'Gene', (41, 44))	('glutaminase', 'Gene', (28, 39))	('essential amino acid transport', 'MPA', (292, 322))	('IDH 1', 'Gene', (141, 146))	('essential amino acid', 'Chemical', 'MESH:D000601', (292, 312))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('activates', 'PosReg', (199, 208))
22116	30431206	Furthermore, OS analysis showed that glioma patients with the Cluster1 subgroup had a better prognosis compared with the Cluster2 subgroup (P < .001, log-rank; Figure 1F).	('patients', 'Species', '9606', (44, 52))	('glioma', 'Disease', (37, 43))	('Cluster1', 'Var', (62, 70))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('OS', 'Chemical', 'MESH:D009992', (13, 15))
22131	30431206	Based on the critical molecular markers IDH and 1p/19q, we investigated the distribution of the 30-gene signature in patients stratified by IDH status among distinct WHO grades (Figure 5B-D and Figure S5B-D) and 1p/19q codeletion status in LGG-IDH mutation patients (Figure 5E and Figure S5E).	('patients', 'Species', '9606', (117, 125))	('mutation', 'Var', (248, 256))	('LGG-IDH', 'Gene', (240, 247))	('patients', 'Species', '9606', (257, 265))
22132	30431206	Verhaak et al34 have identified four clinically relevant subtypes (neural, proneural, classical, mesenchymal) of GBM characterized by abnormalities in platelet derived growth factor receptor alpha (PDGFRA), IDH1, epidermal growth factor receptor (EGFR) and neurofibromin 1 by an integrated genomic analysis.	('IDH1', 'Gene', (207, 211))	('epidermal growth factor receptor', 'Gene', (213, 245))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (151, 196))	('platelet derived growth factor receptor alpha', 'Gene', (151, 196))	('neurofibromin 1', 'Gene', (257, 272))	('IDH1', 'Gene', '3417', (207, 211))	('epidermal growth factor receptor', 'Gene', '1956', (213, 245))	('PDGFRA', 'Gene', '5156', (198, 204))	('PDGFRA', 'Gene', (198, 204))	('abnormalities', 'Var', (134, 147))	('neurofibromin 1', 'Gene', '4763', (257, 272))	('EGFR', 'Gene', '1956', (247, 251))	('EGFR', 'Gene', (247, 251))
22148	30431206	However, for LGG-IDHmut-codel and LGG-IDHmut-noncodel, the OS of high-risk patients tended to be worse, although the difference showed no significance (P > .05) (Figure S4E-G).	('OS', 'Chemical', 'MESH:D009992', (59, 61))	('LGG-IDHmut-noncodel', 'Var', (34, 53))	('worse', 'PosReg', (97, 102))	('patients', 'Species', '9606', (75, 83))	('LGG-IDHmut-codel', 'Var', (13, 29))
22172	27469209	Genetic alterations resulting in constitutive activation of BRAF, a key tyrosine kinase in the mitogen-activated protein kinase (MAPK) pathway, are the defining abnormality in the majority of pediatric low-grade gliomas.	('Genetic alterations', 'Var', (0, 19))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('activation', 'PosReg', (46, 56))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('gliomas', 'Disease', (212, 219))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))
22173	27469209	The most common activating mutations are tandem duplications at chromosomal band 7q34, which generate KIAA1549-BRAF fusions, and BRAF:p.V600E point mutations.	('KIAA1549-BRAF', 'Disease', (102, 115))	('KIAA1549-BRAF', 'Disease', 'None', (102, 115))	('fusions', 'Var', (116, 123))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (129, 141))	('tandem duplications', 'Var', (41, 60))	('activating', 'PosReg', (16, 26))	('BRAF:p.V600E', 'Var', (129, 141))
22181	27469209	One category comprises classic gangliogliomas (70%), which may contain BRAF:p.V600E mutations and are more frequently solid and enhancing.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('BRAF:p.V600E', 'Var', (71, 83))	('contain', 'Reg', (63, 70))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (71, 83))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
22183	27469209	These frequently contain KIAA1549-BRAF fusions, but not a BRAF:p.V600E mutation, and are better characterized as PAs with gangliocytic differentiation (PA-GD).	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (58, 70))	('PAs with', 'Disease', (113, 121))	('PA-GD', 'Chemical', '-', (152, 157))	('contain', 'Reg', (17, 24))	('BRAF:p.V600E', 'Var', (58, 70))	('KIAA1549-BRAF', 'Disease', (25, 38))	('KIAA1549-BRAF', 'Disease', 'None', (25, 38))
22192	27469209	Hematoxylin & eosin stained 4mum formalin-fixed paraffin-embedded sections were supplemented with immunohistochemical analysis with antibodies to glial fibrillary acidic protein (1:400, MO76101, Dako, Carpenteria, CA), Ki67 (1:200, Dako M7240), microtubule-associated protein 2 (MAP2 1:10,000 Sigma M4403), NEU-N (1:5000, Chemicon MAB377), neurofilament protein (1:100, Dako M076229) and synaptophysin (1:400, Leica MCL-L-SYNAP-299).	('MAP2', 'Gene', (279, 283))	('paraffin', 'Chemical', 'MESH:D010232', (48, 56))	('MAP2', 'Gene', '4133', (279, 283))	('formalin', 'Chemical', 'MESH:D005557', (33, 41))	('microtubule-associated protein 2', 'Gene', '4133', (245, 277))	('microtubule-associated protein 2', 'Gene', (245, 277))	('protein', 'Var', (354, 361))	('synaptophysin', 'Gene', (388, 401))	('glial fibrillary acidic protein', 'Gene', (146, 177))	('glial fibrillary acidic protein', 'Gene', '2670', (146, 177))	('synaptophysin', 'Gene', '6855', (388, 401))
22193	27469209	Tumors were screened for the presence or absence of a KIAA1549-BRAF fusion using two complimentary methods: dual-color interphase fluorescence in-situ hybridization (iFISH) for BRAF duplication at 7q34, as a surrogate marker for the presence of fusions, and real-time quantitative reverse-transcription PCR (qRT-PCR) to detect specific KIAA1549-BRAF fusion transcripts.	('BRAF', 'Gene', (345, 349))	('KIAA1549-BRAF', 'Disease', (336, 349))	('BRAF', 'Gene', (177, 181))	('KIAA1549-BRAF', 'Disease', 'None', (54, 67))	('BRAF', 'Gene', '673', (177, 181))	('duplication', 'Var', (182, 193))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BRAF', 'Gene', '673', (63, 67))	('KIAA1549-BRAF', 'Disease', 'None', (336, 349))	('KIAA1549-BRAF', 'Disease', (54, 67))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (345, 349))
22195	27469209	The BRAF:p.V600 mutation hotspot was sequenced in genomic DNA and qRT-PCR was performed using first-strand cDNA synthesized from total RNA, both as previously described.	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('p.V600', 'Var', (9, 15))
22218	27469209	ADC map was provided without trace-weighted DWI for one subject with PA. For the 28 PA and 5 PA-GD with ADC maps, minimum tumor rADC was significantly lower for PA-GD (range 0.81 to 1.20, mean 1.01+-0.17) than for PA (range 1.24 to 2.89, mean 2.01+-0.38), with no overlap in values (p=0.0005).	('PA-GD', 'Chemical', '-', (93, 98))	('rADC', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lower', 'NegReg', (151, 156))	('rADC', 'Gene', '366473', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PA-GD', 'Var', (161, 166))	('PA-GD', 'Chemical', '-', (161, 166))	('tumor', 'Disease', (122, 127))
22223	27469209	No BRAF:p.V600E mutations were identified in 34/41 tumors tested (7 PA-GD, 27 PA).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('BRAF:p.V600E', 'Var', (3, 15))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (3, 15))	('PA-GD', 'Chemical', '-', (68, 73))
22228	27469209	Subjects with KIAA1549-BRAF fusion were more likely to have GTR than those without (p=0.0199), but fusion status alone did not predict improved progression-free survival in the entire cohort (p=0.1165) or in patients whose tumors were incompletely resected (p=0.59).	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patients', 'Species', '9606', (208, 216))	('GTR', 'Disease', (60, 63))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('fusion', 'Var', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('KIAA1549-BRAF', 'Disease', (14, 27))	('GTR', 'Chemical', '-', (60, 63))	('KIAA1549-BRAF', 'Disease', 'None', (14, 27))
22236	27469209	A growing body of literature suggests that activating mutations of BRAF may be tumor and site-specific in the CNS, and have morphologic, prognostic and therapeutic implications.	('BRAF', 'Gene', '673', (67, 71))	('tumor', 'Disease', (79, 84))	('BRAF', 'Gene', (67, 71))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('activating', 'PosReg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
22237	27469209	Most cerebellar PAs carry BRAF duplications in conjunction with a KIAA1549-BRAF fusion, which is highly specific for PA (98.5%) and associated with a well-defined tumor margin and a good prognosis.	('KIAA1549-BRAF', 'Disease', 'None', (66, 79))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', '673', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (26, 30))	('cerebellar PAs', 'Disease', 'MESH:D002528', (5, 19))	('BRAF', 'Gene', (75, 79))	('KIAA1549-BRAF', 'Disease', (66, 79))	('duplications', 'Var', (31, 43))	('tumor', 'Disease', (163, 168))	('cerebellar PAs', 'Disease', (5, 19))
22238	27469209	The BRAF:p.V600E point mutation is a recurring alteration in gangliogliomas (up to 58%) but is rare in pilocytic astrocytoma.	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (103, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('BRAF:p.V600E', 'Var', (4, 16))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('pilocytic astrocytoma', 'Disease', (103, 124))	('gliomas', 'Disease', (68, 75))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (4, 16))
22243	27469209	Presence of residual tumor (NTR) was the strongest predictor of tumor progression (p=0.0002), and was associated with fusion-negative status (p=0.0199), midline involvement (p=0.0187) and PA-GD diagnosis (p=0.0141).	('tumor', 'Disease', (64, 69))	('midline involvement', 'Disease', (153, 172))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('PA-GD', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('midline involvement', 'Disease', 'MESH:D009436', (153, 172))	('fusion-negative status', 'Var', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PA-GD', 'Chemical', '-', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
22255	27469209	BRAF inhibitors such as vemurafenib are effective for BRAF:p.V600E mutation positive tumors, but cause paradoxical activation of the MAPK pathway and tumor progression in tumors with KIAA1549-BRAF fusion or wild-type BRAF.	('tumor', 'Disease', (85, 90))	('activation', 'PosReg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('BRAF', 'Gene', (0, 4))	('KIAA1549-BRAF', 'Disease', (183, 196))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (171, 177))	('tumors', 'Disease', (85, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (24, 35))	('KIAA1549-BRAF', 'Disease', 'None', (183, 196))	('MAPK pathway', 'Pathway', (133, 145))	('tumor', 'Disease', (150, 155))	('BRAF:p.V600E', 'Var', (54, 66))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('BRAF', 'Gene', '673', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('BRAF', 'Gene', '673', (217, 221))	('BRAF', 'Gene', (192, 196))	('BRAF', 'Gene', (217, 221))	('tumor', 'Disease', (171, 176))
22441	27231629	Earlier we reported a penetration depth of zmax > 300 mum in the cortex of young mouse brain while here we show that scattering properties of human tissue result in smaller effective attenuation length.	('effective attenuation length', 'MPA', (173, 201))	('smaller', 'NegReg', (165, 172))	('human', 'Species', '9606', (142, 147))	('zmax', 'Var', (43, 47))	('mouse', 'Species', '10090', (81, 86))
22457	27231629	Theoretically, lateral and axial 2P/3P resolution values can be evaluated for lambda = 1200 nm, n = 1.33 (for water as an immersion liquid) and objective NA = 0.8: Delta2P,lateral = 0.7 mum, Delta2P,axial = 3.4 mum, Delta3P,lateral = 0.6 mum, Delta3P,axial = 2.8 mum.	('water', 'Chemical', 'MESH:D014867', (110, 115))	('Delta3P', 'Var', (243, 250))	('Delta3P', 'Var', (216, 223))	('Delta2P', 'Var', (191, 198))	('Delta2P', 'Var', (164, 171))
22480	26864347	In addition, we detected that IDH1 mutation by DNA sequencing was associated with favorable survival within DA.	('IDH1', 'Gene', (30, 34))	('favorable', 'PosReg', (82, 91))	('IDH1', 'Gene', '3417', (30, 34))	('mutation', 'Var', (35, 43))
22481	26864347	Lastly, we detected that the combination of 5hmC/KI67 was a useful prognostic marker for restratification of DA.	('KI67', 'Chemical', '-', (49, 53))	('5hmC', 'Chemical', 'MESH:C011865', (44, 48))	('5hmC/KI67', 'Gene', (44, 53))	('combination', 'Var', (29, 40))
22485	26864347	For example, molecular biomarkers isocitrate dehydrogenase (IDH1/IDH2) mutation and 1p/19q codeletion were proposed to resolve oligoastrocytoma as either oligodendroglioma or astrocytoma.	('IDH2', 'Gene', '3418', (65, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('mutation', 'Var', (71, 79))	('oligoastrocytoma', 'Disease', (127, 143))	('oligodendroglioma or astrocytoma', 'Disease', (154, 186))	('IDH1', 'Gene', (60, 64))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('astrocytoma', 'Phenotype', 'HP:0009592', (132, 143))	('oligodendroglioma or astrocytoma', 'Disease', 'MESH:D009837', (154, 186))	('IDH2', 'Gene', (65, 69))	('IDH1', 'Gene', '3417', (60, 64))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (127, 143))
22489	26864347	DNA methylation at the 5-carbon position of cytosine (5mC) is the most extensively studied epigenetic modification in human cancer.	('cancer', 'Disease', (124, 130))	('carbon', 'Chemical', 'MESH:D002244', (25, 31))	('cytosine', 'Chemical', 'MESH:D003596', (44, 52))	('5mC', 'Chemical', 'MESH:D044503', (54, 57))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
22494	26864347	Initially, 5hmC loss in gliomas was proposed to be related with IDH1/IDH2 mutations.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('IDH2', 'Gene', '3418', (69, 73))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH1', 'Gene', (64, 68))	('mutations', 'Var', (74, 83))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))	('5hmC', 'MPA', (11, 15))	('loss', 'NegReg', (16, 20))	('IDH1', 'Gene', '3417', (64, 68))	('IDH2', 'Gene', (69, 73))	('gliomas', 'Disease', (24, 31))	('5hmC', 'Chemical', 'MESH:C011865', (11, 15))
22500	26864347	Moreover, we detected that IDH1 mutation by DNA sequencing and the combination of 5hmC/KI67 was associated with prognosis of DA respectively.	('DA respectively', 'Disease', (125, 140))	('KI67', 'Chemical', '-', (87, 91))	('associated with', 'Reg', (96, 111))	('5hmC', 'Chemical', 'MESH:C011865', (82, 86))	('IDH1', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))
22545	26864347	We also examined the mutation status of IDH1/2 by direct DNA sequencing and detected 64% (49/76) of DA bear heterozygous IDH1 mutations (Fig.	('IDH1', 'Gene', (121, 125))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (121, 125))	('IDH1/2', 'Gene', (40, 46))	('IDH1', 'Gene', '3417', (40, 44))	('mutations', 'Var', (126, 135))	('IDH1/2', 'Gene', '3417;3418', (40, 46))
22546	26864347	The predominant amino acid sequence alteration in IDH1 was R132H accounting for 98% (48/49) of the detected mutations.	('R132H', 'Mutation', 'rs121913500', (59, 64))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', (50, 54))	('R132H', 'Var', (59, 64))
22549	26864347	Of 70 samples by both DNA sequencing and immunohistochemistry assays, 45 cases were identified as carrying IDH1 mutation by DNA sequencing.	('IDH1', 'Gene', '3417', (107, 111))	('IDH1', 'Gene', (107, 111))	('mutation', 'Var', (112, 120))
22550	26864347	However, only 78% (35/45) DA with IDH1 mutation by DNA sequencing was positive for IDH1-R132H antibody.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', '3417', (83, 87))	('mutation', 'Var', (39, 47))	('IDH1', 'Gene', (34, 38))	('R132H', 'Mutation', 'rs121913500', (88, 93))	('IDH1', 'Gene', (83, 87))
22556	26864347	Surprisingly, we detected that 5hmC reduction seem to be associated with IDH1 wild type versus mutation cases (Fig.	('5hmC', 'Chemical', 'MESH:C011865', (31, 35))	('IDH1', 'Gene', '3417', (73, 77))	('reduction', 'NegReg', (36, 45))	('5hmC', 'MPA', (31, 35))	('IDH1', 'Gene', (73, 77))	('mutation', 'Var', (95, 103))
22557	26864347	Thus, this result was consistent with previous conclusions that 5hmC reduction didn't result from IDH1 mutation.	('5hmC', 'Chemical', 'MESH:C011865', (64, 68))	('IDH1', 'Gene', (98, 102))	('mutation', 'Var', (103, 111))	('reduction', 'NegReg', (69, 78))	('IDH1', 'Gene', '3417', (98, 102))	('5hmC', 'MPA', (64, 68))
22560	26864347	In addition, univariate Cox regression analyses also revealed that DA patients with either positive immunoreactivity for IDH1-R132H antibody (P = 0.030) or IDH1 mutation by DNA sequencing (P = 0.001) had a better survival (Table 5).	('IDH1', 'Gene', (121, 125))	('patients', 'Species', '9606', (70, 78))	('IDH1', 'Gene', (156, 160))	('Cox', 'Gene', '9377', (24, 27))	('IDH1', 'Gene', '3417', (121, 125))	('mutation', 'Var', (161, 169))	('survival', 'CPA', (213, 221))	('IDH1', 'Gene', '3417', (156, 160))	('better', 'PosReg', (206, 212))	('Cox', 'Gene', (24, 27))	('R132H', 'Mutation', 'rs121913500', (126, 131))
22561	26864347	However, multivariate analyses revealed that IDH1 mutation by DNA sequencing (P = 0.021) versus IDH1 positive immunstaining (P = 0.254) had an prognostic value for DA patients (Table 5).	('IDH1', 'Gene', '3417', (45, 49))	('IDH1', 'Gene', '3417', (96, 100))	('patients', 'Species', '9606', (167, 175))	('IDH1', 'Gene', (45, 49))	('IDH1', 'Gene', (96, 100))	('mutation', 'Var', (50, 58))
22562	26864347	In addition, we found that neither P53 nor KI67 harbored prognostic power by uni- or multivariate analysis (Table 5).	('P53', 'Gene', '7157', (35, 38))	('KI67', 'Chemical', '-', (43, 47))	('KI67', 'Var', (43, 47))	('P53', 'Gene', (35, 38))
22564	26864347	Kaplan-Meier survival analysis revealed combinations of 5hmC/IDH1 (IHC)(Fig.	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', (61, 65))	('5hmC', 'Chemical', 'MESH:C011865', (56, 60))	('combinations', 'Var', (40, 52))
22575	26864347	Within this group, the mean OS for 5hmClow/KI67high, 5hmClow/KI67low, 5hmChigh/KI67high and 5hmChigh/KI67low groups were 22 (95% CI, 6-38), 42 (95% CI, 26-58), 63 (95% CI, 44-82) and 80 (95% CI, 67-94) months respectively.	('KI67', 'Chemical', '-', (79, 83))	('5hmC', 'Chemical', 'MESH:C011865', (70, 74))	('5hmC', 'Chemical', 'MESH:C011865', (35, 39))	('5hmC', 'Chemical', 'MESH:C011865', (92, 96))	('5hmClow/KI67high', 'Var', (35, 51))	('5hmC', 'Chemical', 'MESH:C011865', (53, 57))	('KI67', 'Chemical', '-', (101, 105))	('KI67', 'Chemical', '-', (43, 47))	('KI67', 'Chemical', '-', (61, 65))	('5hmChigh/KI67low', 'Var', (92, 108))
22577	26864347	Even for 5hmC/IDH1 (Seq) combinations, the mean OS for 5hmCLow/IDH1WT, 5hmCLow/IDH1Mut, 5hmCHigh/IDH1WT and 5hmCHigh/IDH1Mut groups were 20 (95% CI, 6-33), 51 (95% CI, 34-68), 51 (95% CI, 30-70) and 79 (95% CI, 67-89) months respectively.	('IDH1', 'Gene', '3417', (79, 83))	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (117, 121))	('5hmC', 'Chemical', 'MESH:C011865', (9, 13))	('combinations', 'Var', (25, 37))	('5hmC', 'Chemical', 'MESH:C011865', (71, 75))	('5hmC', 'Chemical', 'MESH:C011865', (88, 92))	('IDH1', 'Gene', '3417', (97, 101))	('5hmC', 'Chemical', 'MESH:C011865', (108, 112))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', (79, 83))	('5hmC', 'Chemical', 'MESH:C011865', (55, 59))	('IDH1', 'Gene', (63, 67))	('IDH1', 'Gene', (117, 121))	('IDH1', 'Gene', '3417', (14, 18))
22582	26864347	Epigenetic modifications play crucial roles in normal development and frequently alter during carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('alter', 'Reg', (81, 86))	('carcinogenesis', 'Disease', (94, 108))	('Epigenetic modifications', 'Var', (0, 24))
22586	26864347	IDH1/2 mutation has been accepted as a favorable prognostic biomarker for gliomas.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('mutation', 'Var', (7, 15))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
22587	26864347	However, IDH1/2 mutated status can't be used to differentiate AA from DA because both tumors have high rates of IDH1/2 mutation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('IDH1/2', 'Gene', (9, 15))	('mutation', 'Var', (119, 127))	('IDH1/2', 'Gene', (112, 118))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('IDH1/2', 'Gene', '3417;3418', (112, 118))
22599	26864347	Many studies have confirmed an association of IDH1 mutations with favorable outcome for patients with malignant gliomas (WHO III/IV).	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', (46, 50))	('patients', 'Species', '9606', (88, 96))	('association', 'Interaction', (31, 42))	('IDH1', 'Gene', '3417', (46, 50))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('malignant gliomas', 'Disease', (102, 119))	('malignant gliomas', 'Disease', 'MESH:D005910', (102, 119))
22600	26864347	However, prognostic value of IDH1 mutations for low-grade gliomas (LGG, WHO II), especial DA, was subject to debate (supplementary Table S1 and S2).	('IDH1', 'Gene', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1', 'Gene', '3417', (29, 33))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('mutations', 'Var', (34, 43))
22602	26864347	A recent Cancer Genome Atlas Research showed IDH mutations had significant survival prediction in lower grade gliomas (WHO II and III), including oligodendroglioma, oligoastrocytoma and astrocytoma.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('IDH', 'Gene', (45, 48))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('mutations', 'Var', (49, 58))	('oligodendroglioma', 'Disease', (146, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('IDH', 'Gene', '3417', (45, 48))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('oligodendroglioma', 'Disease', 'MESH:D009837', (146, 163))	('Cancer', 'Disease', (9, 15))	('astrocytoma', 'Phenotype', 'HP:0009592', (186, 197))	('oligoastrocytoma and astrocytoma', 'Disease', 'MESH:D001254', (165, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('Cancer', 'Disease', 'MESH:D009369', (9, 15))
22603	26864347	However, the report didn't particularly analyze prognostic value of IDH1 mutations within DA (WHO II).	('IDH1', 'Gene', '3417', (68, 72))	('mutations', 'Var', (73, 82))	('IDH1', 'Gene', (68, 72))
22604	26864347	performed IDH1/2 mutation assays in a series of 100 DAs patients and detected no survival benefit of IDH1 mutations in these patients.	('IDH1', 'Gene', (101, 105))	('patients', 'Species', '9606', (56, 64))	('IDH1', 'Gene', '3417', (10, 14))	('IDH1', 'Gene', '3417', (101, 105))	('IDH1/2', 'Gene', '3417;3418', (10, 16))	('IDH1', 'Gene', (10, 14))	('mutations', 'Var', (106, 115))	('IDH1/2', 'Gene', (10, 16))	('patients', 'Species', '9606', (125, 133))
22606	26864347	In the present study, both univariate and multivariate Cox regression analyses confirmed that IDH1 mutation by DNA sequencing was associated with better survival for DA patients (Table 5).	('IDH1', 'Gene', (94, 98))	('patients', 'Species', '9606', (169, 177))	('Cox', 'Gene', '9377', (55, 58))	('IDH1', 'Gene', '3417', (94, 98))	('survival', 'MPA', (153, 161))	('Cox', 'Gene', (55, 58))	('mutation', 'Var', (99, 107))	('better', 'PosReg', (146, 152))
22607	26864347	Therefore, our results suggested that IDH1 mutation was still a favorable prognostic marker for DA.	('mutation', 'Var', (43, 51))	('IDH1', 'Gene', '3417', (38, 42))	('IDH1', 'Gene', (38, 42))
22615	26864347	Functionally, double-knockout of Tet1 and Tet2 resulted in reduced 5hmC level and delayed brain development.	('reduced', 'NegReg', (59, 66))	('delayed', 'NegReg', (82, 89))	('5hmC level', 'MPA', (67, 77))	('Tet1', 'Gene', '80312', (33, 37))	('delayed brain development', 'Phenotype', 'HP:0001263', (82, 107))	('Tet1', 'Gene', (33, 37))	('brain development', 'CPA', (90, 107))	('5hmC', 'Chemical', 'MESH:C011865', (67, 71))	('Tet2', 'Gene', '54790', (42, 46))	('double-knockout', 'Var', (14, 29))	('Tet2', 'Gene', (42, 46))
22619	26864347	Previously, some reports suggested IDH1 mutations might account for 5hmC reduction in gliomas by means of the presumed role of 2-hydroxyglutarate as an inhibitor of TET oxidases.	('IDH1', 'Gene', (35, 39))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (127, 145))	('5hmC', 'Chemical', 'MESH:C011865', (68, 72))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('TET', 'Chemical', '-', (165, 168))	('mutations', 'Var', (40, 49))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('reduction', 'NegReg', (73, 82))	('gliomas', 'Disease', (86, 93))
22620	26864347	However, this suggestion was challenged by other observations that 5hmC reduction not associated with IDH1 mutations.	('5hmC', 'Chemical', 'MESH:C011865', (67, 71))	('mutations', 'Var', (107, 116))	('IDH1', 'Gene', '3417', (102, 106))	('IDH1', 'Gene', (102, 106))
22621	26864347	In the present study, we detected a higher versus lower level of 5hmC in IDH1 mutated DA compared to IDH1 wild type tumors (Fig.	('IDH1', 'Gene', (101, 105))	('lower', 'NegReg', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('IDH1', 'Gene', '3417', (101, 105))	('IDH1', 'Gene', '3417', (73, 77))	('type tumors', 'Disease', (111, 122))	('5hmC', 'MPA', (65, 69))	('type tumors', 'Disease', 'MESH:D009369', (111, 122))	('level', 'MPA', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutated', 'Var', (78, 85))	('IDH1', 'Gene', (73, 77))	('5hmC', 'Chemical', 'MESH:C011865', (65, 69))
22622	26864347	Therefore, our results didn't support 5hmC reduction was associated with IDH1 mutations.	('IDH1', 'Gene', '3417', (73, 77))	('reduction', 'NegReg', (43, 52))	('mutations', 'Var', (78, 87))	('5hmC', 'Chemical', 'MESH:C011865', (38, 42))	('IDH1', 'Gene', (73, 77))
22624	26864347	3A,B,D), while IDH1 mutations correlated with better survival in DA (Table 5).	('better', 'PosReg', (46, 52))	('mutations', 'Var', (20, 29))	('IDH1', 'Gene', '3417', (15, 19))	('IDH1', 'Gene', (15, 19))
22628	26864347	Indeed, one of TET family genes, TET2, was detected with high mutation rates in some hematologic malignancies, which simultaneously had aberrant levels of 5hmC in their genomes.	('hematologic malignancies', 'Disease', (85, 109))	('TET', 'Chemical', '-', (33, 36))	('TET2', 'Gene', '54790', (33, 37))	('TET2', 'Gene', (33, 37))	('mutation', 'Var', (62, 70))	('hematologic malignancies', 'Disease', 'MESH:D019337', (85, 109))	('5hmC', 'Chemical', 'MESH:C011865', (155, 159))	('TET', 'Chemical', '-', (15, 18))
22631	26864347	Summarizing, our data suggested that the 5hmC level, IDH1 mutation and 5hmC/KI67 combination harbor the value for assessment of prognosis of DA.	('5hmC', 'Chemical', 'MESH:C011865', (71, 75))	('IDH1', 'Gene', (53, 57))	('KI67', 'Chemical', '-', (76, 80))	('mutation', 'Var', (58, 66))	('IDH1', 'Gene', '3417', (53, 57))	('5hmC', 'Chemical', 'MESH:C011865', (41, 45))
22632	26864347	Thus, the prognostic value of 5hmC level, IDH1 mutation and 5hmC/KI67 combination in DA needs further verify.	('IDH1', 'Gene', '3417', (42, 46))	('KI67', 'Chemical', '-', (65, 69))	('5hmC', 'Chemical', 'MESH:C011865', (60, 64))	('mutation', 'Var', (47, 55))	('5hmC', 'Chemical', 'MESH:C011865', (30, 34))	('IDH1', 'Gene', (42, 46))
22657	26864347	For statistical analysis, cutoff value of LI for P53 and KI67 was 10% and 4% respectively according to previous reports.	('P53', 'Gene', '7157', (49, 52))	('KI67', 'Chemical', '-', (57, 61))	('KI67', 'Var', (57, 61))	('P53', 'Gene', (49, 52))
22658	26864347	For IDH1 and IDH2 mutations assays, DNA extraction from formalin fixed paraffin embedded tissue was used.	('IDH1', 'Gene', '3417', (4, 8))	('IDH2', 'Gene', (13, 17))	('IDH1', 'Gene', (4, 8))	('IDH2', 'Gene', '3418', (13, 17))	('paraffin', 'Chemical', 'MESH:D010232', (71, 79))	('formalin', 'Chemical', 'MESH:D005557', (56, 64))	('mutations', 'Var', (18, 27))
22674	24529209	Molecular genetic analysis revealed BRAF duplication and a KIAA1549-BRAF fusion gene in 82% of group II tumors, but in none of the group I tumors, and a BRAF:p.V600E mutation in 43% of group I tumors, but in none of the group II tumors.	('II tumors', 'Disease', (101, 110))	('BRAF', 'Gene', (153, 157))	('group', 'Disease', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('II tumors', 'Disease', (226, 235))	('duplication', 'Var', (41, 52))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (153, 165))	('I tumors', 'Disease', 'MESH:D009369', (227, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('I tumors', 'Disease', 'MESH:D009369', (137, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('I tumors', 'Disease', 'MESH:D009369', (191, 199))	('BRAF:p.V600E', 'Var', (153, 165))	('BRAF', 'Gene', '673', (36, 40))	('I tumors', 'Disease', (137, 145))	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (68, 72))	('KIAA1549-BRAF', 'Disease', (59, 72))	('BRAF', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('I tumors', 'Disease', (191, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('II tumors', 'Disease', 'MESH:D009369', (101, 110))	('I tumors', 'Disease', 'MESH:D009369', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('II tumors', 'Disease', 'MESH:D009369', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('KIAA1549-BRAF', 'Disease', 'None', (59, 72))	('BRAF', 'Gene', '673', (153, 157))
22681	24529209	Genetic alterations in elements of the mitogen-activated protein kinase (MAPK) signaling pathway have been identified in many low-grade neuroepithelial tumors, including pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), and ganglioglioma.	('Genetic alterations', 'Var', (0, 19))	('astrocytoma', 'Phenotype', 'HP:0009592', (216, 227))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (170, 191))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (198, 227))	('identified', 'Reg', (107, 117))	('glioma', 'Disease', (246, 252))	('neuroepithelial tumors', 'Disease', (136, 158))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (136, 158))	('pleomorphic xanthoastrocytoma', 'Disease', (198, 227))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (136, 158))	('astrocytoma', 'Phenotype', 'HP:0009592', (180, 191))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('pilocytic astrocytoma', 'Disease', (170, 191))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
22682	24529209	Recent studies have demonstrated that specific mutations are enriched in certain tumors; for example, KIAA1549-BRAF fusions are found in PAs, and BRAF:p.V600E mutations are frequently detected in PXAs (~70%).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('KIAA1549-BRAF fusions', 'Disease', (102, 123))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (146, 158))	('found', 'Reg', (128, 133))	('PXAs', 'Disease', (196, 200))	('PAs', 'Disease', (137, 140))	('detected', 'Reg', (184, 192))	('KIAA1549-BRAF fusions', 'Disease', 'MESH:D000069337', (102, 123))	('PAs', 'Chemical', 'MESH:D011478', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('BRAF:p.V600E', 'Var', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
22683	24529209	BRAF:p.V600E mutations are also present in about one quarter of gangliogliomas.	('BRAF:p.V600E', 'Var', (0, 12))	('glioma', 'Disease', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (0, 12))
22691	24529209	Antibodies to the following proteins were utilized for routine pathologic evaluation: glial fibrillary acidic protein (1:400, Dako M076101), synaptophysin (1:400, Leica MCL-L-SYNAP-299), NEU-N (1:5000, Chemicon MAB377), neurofilament protein (1:100, Dako M076229), microtubule-associated protein 2 (MAP2 1:10,000, Sigma M4403), and Ki67 (1:200, Dako M7240).	('synaptophysin', 'Gene', (141, 154))	('microtubule-associated protein 2', 'Gene', (265, 297))	('MAP2', 'Gene', (299, 303))	('microtubule-associated protein 2', 'Gene', '4133', (265, 297))	('MAP2', 'Gene', '4133', (299, 303))	('synaptophysin', 'Gene', '6855', (141, 154))	('1:400', 'Var', (156, 161))	('NEU-N', 'Gene', '146713', (187, 192))	('NEU-N', 'Gene', (187, 192))
22693	24529209	BAC clones RP11-96I22 and RP11-837G3 were used to screen for BRAF duplication at 7q34 (control probe on 7p11, RP11-251I15 and RP11-746C13).	('RP11', 'Gene', (11, 15))	('RP11', 'Gene', '26121', (126, 130))	('BRAF', 'Gene', '673', (61, 65))	('RP11', 'Gene', '26121', (110, 114))	('duplication', 'Var', (66, 77))	('RP11', 'Gene', '26121', (11, 15))	('RP11', 'Gene', (26, 30))	('BRAF', 'Gene', (61, 65))	('RP11', 'Gene', (126, 130))	('RP11', 'Gene', '26121', (26, 30))	('RP11', 'Gene', (110, 114))
22696	24529209	BRAF:p.V600, KRAS:p.G12, and KRAS:p.Q61 were sequenced in genomic DNA using previously published primers.	('p.V600', 'Var', (5, 11))	('KRAS', 'Gene', '3845', (13, 17))	('KRAS', 'Gene', (29, 33))	('BRAF', 'Gene', '673', (0, 4))	('KRAS', 'Gene', '3845', (29, 33))	('BRAF', 'Gene', (0, 4))	('KRAS', 'Gene', (13, 17))	('p.G12', 'Var', (18, 23))
22725	24529209	iFISH demonstrated BRAF duplication in 9 of 11 (82%) group II tumors (Figure 3), but in none of the group I tumors (Table 1).	('BRAF', 'Gene', '673', (19, 23))	('I tumors', 'Disease', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('I tumors', 'Disease', 'MESH:D009369', (106, 114))	('BRAF', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('II tumors', 'Disease', (59, 68))	('II tumors', 'Disease', 'MESH:D009369', (59, 68))	('duplication', 'Var', (24, 35))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('I tumors', 'Disease', 'MESH:D009369', (60, 68))
22726	24529209	One group II tumor, GG17, demonstrated BRAF duplication and a potential BRAF fusion, the latter on the basis of a 'break-apart' probe profile that showed one (normal) overlapping pair of signals and one 'split' pair of signals (Figure 3d).	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (39, 43))	('duplication', 'Var', (44, 55))	('II tumor', 'Disease', 'MESH:D009369', (10, 18))	('BRAF', 'Gene', (39, 43))	("'break-apart'", 'Phenotype', 'HP:0001061', (114, 127))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('II tumor', 'Disease', (10, 18))	('BRAF', 'Gene', '673', (72, 76))	('overlapping pair of signals', 'MPA', (167, 194))
22727	24529209	KIAA1549-BRAF fusions were found in all 9 group II tumors with BRAF duplication, but in no other group I or group II tumor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('II tumor', 'Disease', (114, 122))	('duplication', 'Var', (68, 79))	('BRAF', 'Gene', (9, 13))	('KIAA1549-BRAF fusions', 'Disease', (0, 21))	('II tumor', 'Disease', 'MESH:D009369', (114, 122))	('II tumor', 'Disease', 'MESH:D009369', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('KIAA1549-BRAF fusions', 'Disease', 'MESH:D000069337', (0, 21))	('BRAF', 'Gene', '673', (63, 67))	('II tumors', 'Disease', (48, 57))	('II tumors', 'Disease', 'MESH:D009369', (48, 57))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (9, 13))
22728	24529209	Three KIAA1549-BRAF fusion variants were identified; exon16:exon9, exon15:exon9, and exon16:exon11 (Table 1).	('KIAA1549-BRAF', 'Disease', 'None', (6, 19))	('KIAA1549-BRAF', 'Disease', (6, 19))	('exon9', 'Var', (74, 79))	('exon16:exon11', 'Var', (85, 98))	('exon9', 'Var', (60, 65))	('exon15:exon9', 'Var', (67, 79))	('exon16:exon9', 'Var', (53, 65))
22729	24529209	BRAF:p.V600E mutations were detected in 7 of 16 (43%) group I tumors, but in no group II tumor.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('detected', 'Reg', (28, 36))	('BRAF:p.V600E', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('II tumor', 'Disease', (86, 94))	('II tumor', 'Disease', 'MESH:D009369', (86, 94))	('I tumors', 'Disease', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (0, 12))	('I tumors', 'Disease', 'MESH:D009369', (60, 68))
22747	24529209	Alterations in genes involved in the MAPK pathway dominate; KIAA1549-BRAF fusions characterize PAs, occurring in approximately 90% of posterior fossa tumors but at lower frequencies in spinal cord and supratentorial tumors.	('PAs', 'Disease', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('PAs', 'Chemical', 'MESH:D011478', (95, 98))	('Alterations', 'Var', (0, 11))	('fossa tumors', 'Disease', (144, 156))	('supratentorial tumors', 'Disease', (201, 222))	('fossa tumors', 'Disease', 'MESH:D015192', (144, 156))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('supratentorial tumors', 'Disease', 'MESH:D015173', (201, 222))	('KIAA1549-BRAF fusions', 'Disease', 'MESH:D000069337', (60, 81))	('supratentorial tumors', 'Phenotype', 'HP:0030693', (201, 222))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('supratentorial tumor', 'Phenotype', 'HP:0030693', (201, 221))	('occurring', 'Reg', (100, 109))	('KIAA1549-BRAF fusions', 'Disease', (60, 81))
22749	24529209	BRAF:p.V600E mutations occur in PXAs (~70%), gangliogliomas (~25%), and WHO grade II diffuse astrocytomas (~20%).	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (0, 12))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('BRAF:p.V600E', 'Var', (0, 12))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('astrocytomas', 'Disease', 'MESH:D001254', (93, 105))	('occur', 'Reg', (23, 28))	('glioma', 'Disease', (52, 58))	('astrocytomas', 'Disease', (93, 105))	('PXAs', 'Disease', (32, 36))
22750	24529209	Rarely, mutations of KRAS are found in a PA or grade II diffuse glioma, and an ETV6-NTRK3 fusion gene has been reported in a PXA.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('KRAS', 'Gene', '3845', (21, 25))	('mutations', 'Var', (8, 17))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (79, 96))	('glioma', 'Disease', (64, 70))	('ETV6-NTRK3 fusion', 'Gene', (79, 96))	('KRAS', 'Gene', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
22751	24529209	However, such genetic abnormalities were not harbored by those gangliogliomas in which we were unable to show a KIAA1549-BRAF fusion or BRAF:p.V600E mutation.	('glioma', 'Disease', (70, 76))	('BRAF:p.V600E', 'Var', (136, 148))	('genetic abnormalities', 'Disease', 'MESH:D030342', (14, 35))	('KIAA1549-BRAF', 'Disease', 'None', (112, 125))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (136, 148))	('genetic abnormalities', 'Disease', (14, 35))	('KIAA1549-BRAF', 'Disease', (112, 125))
22752	24529209	Low-grade neuroepithelial tumors presenting in childhood rarely contain an IDH1:p.R132H mutation.	('contain', 'Reg', (64, 71))	('IDH1:p.R132H', 'Var', (75, 87))	('neuroepithelial tumors', 'Disease', (10, 32))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (10, 32))	('IDH1:p.R132H', 'SUBSTITUTION', 'None', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (10, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
22755	24529209	Additionally, it is not characterized by KIAA1549-BRAF fusion or BRAF:p.V600E mutation.	('BRAF:p.V600E', 'Var', (65, 77))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (65, 77))	('KIAA1549-BRAF', 'Disease', 'None', (41, 54))	('KIAA1549-BRAF', 'Disease', (41, 54))
22757	24529209	Seven of sixteen (44%) tumors in group I, with features of a classic ganglioglioma, harbored a BRAF:p.V600E mutation.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('glioma', 'Disease', (76, 82))	('tumors', 'Disease', (23, 29))	('BRAF:p.V600E', 'Var', (95, 107))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
22782	21603196	The gene encoding kisspeptin (Kiss1) has been demonstrated to be mutated in some cases of hypogonadotropic hypogonadism and to be upregulated in some instances of precocious puberty.	('upregulated', 'PosReg', (130, 141))	('precocious puberty', 'Phenotype', 'HP:0000826', (163, 181))	('Kiss1', 'Gene', '3814', (30, 35))	('Kiss1', 'Gene', (30, 35))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (90, 119))	('hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (90, 119))	('hypogonadism', 'Phenotype', 'HP:0000135', (107, 119))	('hypogonadotropic hypogonadism', 'Disease', (90, 119))	('mutated', 'Var', (65, 72))
22827	21603196	The clinical sequelae of NF-1 are due to inactivation of the tumor suppressor gene neurofibromin-1, which in turn normally inhibits the Ras gene, an important regulator of cell growth, differentiation, and survival.	('NF-1', 'Gene', '4763', (25, 29))	('NF-1', 'Gene', (25, 29))	('inactivation', 'Var', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('neurofibromin-1', 'Gene', (83, 98))	('Ras gene', 'Gene', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('inhibits', 'NegReg', (123, 131))	('tumor', 'Disease', (61, 66))	('neurofibromin-1', 'Gene', '4763', (83, 98))
22828	21603196	Upregulated Ras activity with or without a clear gene mutation may act in part through activation of the mTOR pathway .	('mutation', 'Var', (54, 62))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('Ras', 'Protein', (12, 15))	('activity', 'MPA', (16, 24))	('Upregulated', 'PosReg', (0, 11))
22864	21603196	These lesions are believed to cause precocious puberty (Figure 4) through endogenous pulsatile release of GnRH, either independently or in concert with the GnRH-secreting neurons of the hypothalamus.	('precocious puberty', 'Disease', (36, 54))	('cause', 'Reg', (30, 35))	('GnRH', 'Gene', (106, 110))	('hypothalamus', 'Disease', (186, 198))	('GnRH', 'Gene', '2796', (106, 110))	('precocious puberty', 'Phenotype', 'HP:0000826', (36, 54))	('endogenous pulsatile release', 'MPA', (74, 102))	('hypothalamus', 'Disease', 'MESH:D007029', (186, 198))	('lesions', 'Var', (6, 13))	('GnRH', 'Gene', (156, 160))	('GnRH', 'Gene', '2796', (156, 160))
22875	21603196	PHS is due to mutations of the zinc-finger transcription factor gene GLI3 on chromosome 7p13.	('GLI3', 'Gene', '2737', (69, 73))	('PHS', 'Disease', (0, 3))	('GLI3', 'Gene', (69, 73))	('due to', 'Reg', (7, 13))	('PHS', 'Disease', 'MESH:D054975', (0, 3))	('mutations', 'Var', (14, 23))
22877	21603196	Disruption of this gene or associated genes may explain some cases of hypothalamic hamartoma.	('hypothalamic hamartoma', 'Phenotype', 'HP:0002444', (70, 92))	('hamartoma', 'Phenotype', 'HP:0010566', (83, 92))	('hypothalamic hamartoma', 'Disease', (70, 92))	('hypothalamic hamartoma', 'Disease', 'MESH:C537158', (70, 92))	('Disruption', 'Var', (0, 10))
22900	21603196	Furthermore, patients who develop precocious puberty following doses of 30 Gray or more have a significant risk of ultimately developing gonadotropin deficiency, while those who receive doses in excess of 50 Gray are at increased risk of delayed puberty (secondary to gonadotropin deficiency).	('doses', 'Var', (63, 68))	('delayed puberty', 'Phenotype', 'HP:0000823', (238, 253))	('deficiency', 'Disease', 'MESH:D007153', (150, 160))	('precocious', 'Disease', (34, 44))	('patients', 'Species', '9606', (13, 21))	('gonadotropin deficiency', 'Phenotype', 'HP:0008213', (268, 291))	('precocious puberty', 'Phenotype', 'HP:0000826', (34, 52))	('gonadotropin deficiency', 'Phenotype', 'HP:0008213', (137, 160))	('deficiency', 'Disease', (150, 160))	('deficiency', 'Disease', (281, 291))	('gonadotropin', 'Disease', (137, 149))	('deficiency', 'Disease', 'MESH:D007153', (281, 291))
22939	33665207	The results showed that ZIC2 also acted as a risk prognostic factor in bladder, breast and lung cancer Table 1.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('bladder', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast and lung cancer', 'Disease', 'MESH:D001943', (80, 102))	('ZIC2', 'Var', (24, 28))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('lung cancer', 'Disease', (91, 102))
22946	33665207	The results revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype in a variety of tumors including complement and coagulation cascades, P53 signaling pathway, basal cell carcinoma, PPAR signaling pathway, tight junction, etc (Figure 10).	('carcinoma', 'Disease', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tight junction', 'Disease', (279, 293))	('P53', 'Gene', (210, 213))	('PPAR', 'Gene', '5465', (255, 259))	('carcinoma', 'Disease', 'MESH:D009369', (244, 253))	('ZIC2', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('P53', 'Gene', '7157', (210, 213))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (233, 253))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (233, 253))	('basal cell carcinoma', 'Disease', (233, 253))	('high', 'Var', (107, 111))	('PPAR', 'Gene', (255, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('enriched', 'Reg', (90, 98))	('low', 'NegReg', (115, 118))
22961	33299035	Mutation in tumor suppressor genes (KEAP1, PBRM1) and genes involved in extrinsic apoptosis (CASP8), antigen-presentation (HLA-A, HLA-B), immune regulation (SMAD4) or DNA repair (BRCA1, BRCA2, TP53BP1) correlated with TLS alteration in multiple tumor types, indicating the interaction between mutation landscape and TLS formation.	('KEAP1', 'Gene', (36, 41))	('PBRM1', 'Gene', (43, 48))	('TP53BP1', 'Gene', (193, 200))	('BRCA1', 'Gene', (179, 184))	('BRCA', 'Phenotype', 'HP:0003002', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('SMAD4', 'Gene', (157, 162))	('BRCA2', 'Gene', '675', (186, 191))	('tumor', 'Disease', (12, 17))	('correlated', 'Reg', (202, 212))	('TLS alteration', 'Disease', (218, 232))	('HLA-B', 'Gene', '3106', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CASP8', 'Gene', '841', (93, 98))	('HLA-A', 'Gene', (123, 128))	('SMAD4', 'Gene', '4089', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CASP8', 'Gene', (93, 98))	('tumor', 'Disease', (245, 250))	('HLA-B', 'Gene', (130, 135))	('BRCA2', 'Gene', (186, 191))	('TP53BP1', 'Gene', '7158', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('HLA-A', 'Gene', '3105', (123, 128))	('PBRM1', 'Gene', '55193', (43, 48))	('Mutation', 'Var', (0, 8))	('KEAP1', 'Gene', '9817', (36, 41))	('BRCA', 'Phenotype', 'HP:0003002', (179, 183))	('BRCA1', 'Gene', '672', (179, 184))
22967	33299035	The presence of TLS had been reported to be associated with favorable prognosis in multiple solid tumors, which might be associated with their capacity in inducing a long-lasting antitumor response.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('inducing', 'Reg', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('TLS', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (98, 103))	('presence', 'Var', (4, 12))
22993	33299035	Among all the tumor sample applied to the viral detection, the presence of viral genome was frequently observed in certain tumor types including BLCA, CESC, CRC, HNSC, LIHC and STAD.	('BLCA', 'Disease', (145, 149))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (123, 128))	('HNSC', 'Disease', (162, 166))	('presence', 'Reg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BLCA', 'Phenotype', 'HP:0002862', (145, 149))	('CRC', 'Disease', (157, 160))	('CESC', 'Disease', (151, 155))	('STAD', 'Disease', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))	('viral genome', 'Var', (75, 87))	('observed', 'Reg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('LIHC', 'Disease', (168, 172))
23004	33299035	Genomic alteration of certain oncogenic pathway of tumor cells can help shape the immune microenvironment as the intrinsic factors.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Genomic alteration', 'Var', (0, 18))	('tumor', 'Disease', (51, 56))	('oncogenic pathway', 'Pathway', (30, 47))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
23006	33299035	We therefore asked whether driver gene mutations were associated with TLS density in tumor microenvironment.	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('associated', 'Reg', (54, 64))
23007	33299035	By focusing on the known driver genes with annotated mutation information (gain-of-function, loss-of-function, switch-of-function), we first identified 35 driver genes whose mutation significantly correlated with alteration in TLS signature expression in pan-cancer (P < 0.01).	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('mutation', 'Var', (174, 182))	('expression', 'MPA', (241, 251))	('correlated', 'Reg', (197, 207))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('TLS signature', 'Gene', (227, 240))	('alteration', 'Reg', (213, 223))	('cancer', 'Disease', (259, 265))
23010	33299035	Higher TLS scoring was also associated with loss-of-function mutations in tumor suppressor genes (KEAP1, PBRM1), genes involved in extrinsic apoptosis (CASP8), antigen-presentation (HLA-A, HLA-B) or immune regulation (SMAD4), indicating the mechanism by which the tumor cells survive or escape the immune surveillance.	('KEAP1', 'Gene', (98, 103))	('PBRM1', 'Gene', '55193', (105, 110))	('CASP8', 'Gene', '841', (152, 157))	('tumor', 'Disease', (74, 79))	('CASP8', 'Gene', (152, 157))	('HLA-B', 'Gene', (189, 194))	('PBRM1', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (264, 269))	('HLA-A', 'Gene', '3105', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('TLS', 'Disease', (7, 10))	('SMAD4', 'Gene', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (61, 70))	('HLA-B', 'Gene', '3106', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('Higher', 'PosReg', (0, 6))	('HLA-A', 'Gene', (182, 187))	('KEAP1', 'Gene', '9817', (98, 103))	('SMAD4', 'Gene', '4089', (218, 223))	('loss-of-function', 'NegReg', (44, 60))
23011	33299035	Mutation in a few genes like IDH1, NRAS, CTNNB1 etc.	('NRAS', 'Gene', (35, 39))	('IDH1', 'Gene', (29, 33))	('Mutation', 'Var', (0, 8))	('CTNNB1', 'Gene', (41, 47))	('IDH1', 'Gene', '3417', (29, 33))	('NRAS', 'Gene', '4893', (35, 39))	('CTNNB1', 'Gene', '1499', (41, 47))
23017	33299035	Tumors with high TLS scoring also exhibited tendency of improved survival in BRCA, LIHC, UCEC, although the association of which failed to achieve statistical significance.	('high', 'Var', (12, 16))	('BRCA', 'Disease', (77, 81))	('improved', 'PosReg', (56, 64))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('UCEC', 'Disease', (89, 93))	('TLS', 'Gene', (17, 20))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BRCA', 'Phenotype', 'HP:0003002', (77, 81))	('LIHC', 'Disease', (83, 87))
23020	33299035	Similarly, tumor with high TLS exhibited significant improved overall survival in LIHC (P = 0.051, Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('high TLS', 'Var', (22, 30))	('tumor', 'Disease', (11, 16))	('LIHC', 'Disease', (82, 86))	('improved', 'PosReg', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
23029	33299035	Patients with high TLS scoring also demonstrated significant improved overall survival (P = 0.024) (Fig.	('improved', 'PosReg', (61, 69))	('overall survival', 'MPA', (70, 86))	('TLS', 'Gene', (19, 22))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
23032	33299035	Also, NSCLC patients with high TLS scoring were associated with significantly prolonged progression-free survival (P < 0.0001) (Fig.	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('high', 'Var', (26, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('progression-free survival', 'CPA', (88, 113))	('TLS', 'Gene', (31, 34))	('NSCLC', 'Disease', (6, 11))	('prolonged', 'PosReg', (78, 87))
23036	33299035	Our findings suggested that neoantigen load, oncovirus infection and diver gene mutations may play a role in the formation of TLS, which in turn also interact with tumor cells and help to shape the oncogene mutation landscape across different tumor types.	('help', 'Reg', (180, 184))	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (80, 89))	('interact', 'Reg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('diver gene', 'Gene', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('oncovirus infection', 'Disease', (45, 64))	('oncovirus infection', 'Disease', 'MESH:D007239', (45, 64))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
23054	33299035	Also, tumor types with high mutation/neoantigen load tend to have higher expression of TLS signature.	('mutation/neoantigen', 'Var', (28, 47))	('TLS signature', 'Protein', (87, 100))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('expression', 'MPA', (73, 83))	('higher', 'PosReg', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
23056	33299035	Certain oncogenic events caused by driver gene mutation like CTNNB1, FGFR3 etc.	('CTNNB1', 'Gene', (61, 67))	('caused', 'Reg', (25, 31))	('FGFR3', 'Gene', '2261', (69, 74))	('mutation', 'Var', (47, 55))	('FGFR3', 'Gene', (69, 74))	('CTNNB1', 'Gene', '1499', (61, 67))
23061	33299035	Of note, a recent study had demonstrated the involvement of caspase-8 (encoded by CASP8) in the cleavage of immune regulator, RIPK1, the accumulation of which can cause autoinflammatory diseases.	('autoinflammatory diseases', 'Disease', (169, 194))	('CASP8', 'Gene', (82, 87))	('caspase-8', 'Gene', (60, 69))	('CASP8', 'Gene', '841', (82, 87))	('caspase-8', 'Gene', '841', (60, 69))	('RIPK1', 'Gene', (126, 131))	('autoinflammatory diseases', 'Disease', 'MESH:D056660', (169, 194))	('cleavage', 'MPA', (96, 104))	('RIPK1', 'Gene', '8737', (126, 131))	('involvement', 'Reg', (45, 56))	('accumulation', 'Var', (137, 149))	('cause', 'Reg', (163, 168))
23062	33299035	Thus, overexpression of TLS signature in tumor with genomic loss in CASP8 could also be associated with its immune dysregulation function.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('immune dysregulation function', 'MPA', (108, 137))	('CASP8', 'Gene', (68, 73))	('tumor', 'Disease', (41, 46))	('CASP8', 'Gene', '841', (68, 73))	('genomic loss', 'Var', (52, 64))	('immune dysregulation', 'Phenotype', 'HP:0002958', (108, 128))	('overexpression', 'PosReg', (6, 20))	('associated', 'Reg', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
23063	33299035	Tumors with high TLS scoring were also frequently correlated with loss of function mutation on genes associated with antigen presentation, like HLA-A, HLA-B, or genes involved in immune regulation like SMAD4, which could be the mechanism by which tumor cells escape the immune surveillance.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('HLA-B', 'Gene', (151, 156))	('HLA-A', 'Gene', '3105', (144, 149))	('SMAD4', 'Gene', '4089', (202, 207))	('tumor', 'Disease', (247, 252))	('HLA-B', 'Gene', '3106', (151, 156))	('mutation', 'Var', (83, 91))	('HLA-A', 'Gene', (144, 149))	('loss of function', 'NegReg', (66, 82))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('SMAD4', 'Gene', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (247, 252))
23064	33299035	Intriguingly, several genes associated with DNA repair, like BRCA1, BRCA2 and TP53BP1, were also frequently mutated (loss-of-function) in tumors with high TLS scoring.	('mutated', 'Var', (108, 115))	('BRCA1', 'Gene', (61, 66))	('BRCA2', 'Gene', '675', (68, 73))	('TP53BP1', 'Gene', '7158', (78, 85))	('TP53BP1', 'Gene', (78, 85))	('loss-of-function', 'NegReg', (117, 133))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('BRCA', 'Phenotype', 'HP:0003002', (68, 72))	('BRCA', 'Phenotype', 'HP:0003002', (61, 65))	('BRCA2', 'Gene', (68, 73))	('BRCA1', 'Gene', '672', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
23065	33299035	We speculated that high TLS density in tumors with mutated BRCA1, BRCA2 or TP53BP1 could be attributed to the genomic instability and the subsequent increase in mutation burden.	('BRCA2', 'Gene', (66, 71))	('BRCA1', 'Gene', '672', (59, 64))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('TP53BP1', 'Gene', (75, 82))	('increase', 'PosReg', (149, 157))	('high', 'PosReg', (19, 23))	('BRCA1', 'Gene', (59, 64))	('TP53BP1', 'Gene', '7158', (75, 82))	('BRCA2', 'Gene', '675', (66, 71))	('TLS density', 'MPA', (24, 35))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutation burden', 'MPA', (161, 176))	('tumors', 'Disease', (39, 45))	('BRCA', 'Phenotype', 'HP:0003002', (59, 63))	('mutated', 'Var', (51, 58))
23071	33299035	We also found that tumor subtypes with copy number alteration (CN low or CN high) demonstrated significantly lower TLS scoring as compared to MSI (hypermutated) subtype and POLE (ultramutated) subtype.	('TLS scoring', 'MPA', (115, 126))	('lower', 'NegReg', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('copy number alteration', 'Var', (39, 61))	('tumor', 'Disease', (19, 24))
23073	33299035	We didn't observe any survival benefit in lung cancers with high TLS scoring, which though had been reported in published studies.	('lung cancers', 'Disease', (42, 54))	('high TLS scoring', 'Var', (60, 76))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('lung cancers', 'Disease', 'MESH:D008175', (42, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancers', 'Phenotype', 'HP:0100526', (42, 54))
23110	31719831	Identification of Dysregulated Competitive Endogenous RNA Networks Driven by Copy Number Variations in Malignant Gliomas Gliomas represent 80% of malignant brain tumors.	('Gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('malignant brain tumors', 'Disease', (146, 168))	('malignant brain tumors', 'Disease', 'MESH:D001932', (146, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Gliomas', 'Disease', 'MESH:D005910', (113, 120))	('brain tumors', 'Phenotype', 'HP:0030692', (156, 168))	('Gliomas', 'Disease', (121, 128))	('Gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('brain tumor', 'Phenotype', 'HP:0030692', (156, 167))	('Gliomas', 'Disease', (113, 120))	('Malignant Gliomas', 'Disease', 'MESH:D005910', (103, 120))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Copy Number Variations', 'Var', (77, 99))	('Malignant Gliomas', 'Disease', (103, 120))	('Gliomas', 'Disease', 'MESH:D005910', (121, 128))
23112	31719831	In this study, we developed a new approach to identify dysregulated competitive endogenous RNA (ceRNA) interactions driven by copy number variation (CNV) in both lower-grade glioma (LGG) and glioblastoma multiforme (GBM).	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioblastoma multiforme', 'Disease', (191, 214))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('GBM', 'Disease', (216, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('copy number variation', 'Var', (126, 147))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('GBM', 'Disease', 'MESH:D005909', (216, 219))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (191, 214))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('glioma', 'Disease', (174, 180))	('driven', 'Reg', (116, 122))	('interactions', 'Interaction', (103, 115))	('dysregulated', 'Reg', (55, 67))
23113	31719831	By analyzing genome and transcriptome data from The Cancer Genome Atlas (TCGA), we first found out the protein coding genes and long non-coding RNAs (lncRNAs) significantly affected by CNVs and further determined CNV-driven dysregulated ceRNA interactions by a customized pipeline.	('N', 'Chemical', 'MESH:D009584', (214, 215))	('N', 'Chemical', 'MESH:D009584', (240, 241))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('CNVs', 'Var', (185, 189))	('affected', 'Reg', (173, 181))
23115	31719831	Our results showed that most of the ceRNA interactions were weakened by CNVs in both LGG and GBM, and many CNV-driven genes shared the same ceRNAs in the dysregulated ceRNA networks.	('N', 'Chemical', 'MESH:D009584', (73, 74))	('ceRNA', 'CPA', (36, 41))	('CNVs', 'Var', (72, 76))	('weakened', 'NegReg', (60, 68))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('GBM', 'Disease', (93, 96))	('interactions', 'Interaction', (42, 54))	('LGG', 'Gene', (85, 88))	('GBM', 'Disease', 'MESH:D005909', (93, 96))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('N', 'Chemical', 'MESH:D009584', (108, 109))
23118	31719831	Moreover, by exploring the association of CNV-driven ceRNAs with prognosis and histological subtype, we found that the copy number status of MTAP, KLHL9, and ELAVL2 related to the overall survival in LGG and showed high correlation with histological subtype.	('N', 'Chemical', 'MESH:D009584', (43, 44))	('ELAVL2', 'Gene', (158, 164))	('related to', 'Reg', (165, 175))	('overall survival', 'MPA', (180, 196))	('MTAP', 'Gene', '4507', (141, 145))	('KLHL9', 'Gene', '55958', (147, 152))	('KLHL9', 'Gene', (147, 152))	('copy number status', 'Var', (119, 137))	('LGG', 'Disease', (200, 203))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('MTAP', 'Gene', (141, 145))	('ELAVL2', 'Gene', '1993', (158, 164))
23123	31719831	Recently, high-throughput studies have proven that copy number variations (CNVs), which are gains or deletions of genomic segments, are considered important risk factors for human cancers.	('human', 'Species', '9606', (174, 179))	('copy number variations', 'Var', (51, 73))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('N', 'Chemical', 'MESH:D009584', (76, 77))
23126	31719831	combined mRNA regulatory relationships with CNV profiles to construct a CNA-driven network using lasso regression and identified driver copy number alterations (CNAs) and explored their effects on transcription in GBM.	('N', 'Chemical', 'MESH:D009584', (73, 74))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('GBM', 'Disease', (214, 217))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('copy number alterations', 'Var', (136, 159))	('GBM', 'Disease', 'MESH:D005909', (214, 217))
23127	31719831	applied a correlation measure to identify significant relationships between copy number variation regions and mRNAs, and characterized the impact of genotypic variations on phenotype in a genome-wide scale.	('N', 'Chemical', 'MESH:D009584', (112, 113))	('mRNAs', 'MPA', (110, 115))	('relationships', 'Interaction', (54, 67))	('copy number variation regions', 'Var', (76, 105))
23132	31719831	Experimental evidence has suggested that the aberration of ceRNA interaction can play important roles in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('aberration', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('tumor', 'Disease', (105, 110))	('ceRNA', 'Protein', (59, 64))
23134	31719831	The existence and strength of ceRNA interactions may vary significantly in different physiological and cellular conditions (e.g., copy number variation).	('interactions', 'Interaction', (36, 48))	('copy number variation', 'Var', (130, 151))	('N', 'Chemical', 'MESH:D009584', (33, 34))
23135	31719831	Most ceRNA studies only considered interactions among ceRNAs and miRNAs while overlooking other important gene regulators, such as transcription factors, DNA methylation, and copy number alteration, which would impede our understanding of ceRNA interactions in cancer.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('N', 'Chemical', 'MESH:D009584', (242, 243))	('interactions', 'Interaction', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('cancer', 'Disease', (261, 267))	('interactions', 'Interaction', (245, 257))	('copy number alteration', 'Var', (175, 197))	('N', 'Chemical', 'MESH:D009584', (155, 156))	('N', 'Chemical', 'MESH:D009584', (8, 9))
23138	31719831	We first got the copy number status of each gene and identified over one hundred protein-coding genes and lncRNAs whose expression levels were significantly affected by CNVs in LGG and GBM.	('GBM', 'Disease', (185, 188))	('affected', 'Reg', (157, 165))	('GBM', 'Disease', 'MESH:D005909', (185, 188))	('CNVs', 'Var', (169, 173))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('expression levels', 'MPA', (120, 137))
23150	31719831	amplification, deletion, and normal), we calculated Pearson correlation coefficient (PCC) between ceRNA pairs as well as mRNA/lncRNA (ceRNA) and miRNA to measure their expression correlations.	('Pearson', 'MPA', (52, 59))	('N', 'Chemical', 'MESH:D009584', (148, 149))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('deletion', 'Var', (15, 23))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('N', 'Chemical', 'MESH:D009584', (101, 102))
23154	31719831	So we compared the correlations of ceRNAs in amplification/deletion samples with normal samples to determine the extent of dysregulation.	('amplification/deletion', 'Var', (45, 67))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('compared', 'Reg', (6, 14))
23157	31719831	(3) Identifying CNV-driven dysregulated ceRNA-ceRNA interactions.	('N', 'Chemical', 'MESH:D009584', (43, 44))	('interactions', 'Interaction', (52, 64))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('dysregulated', 'Var', (27, 39))
23169	31719831	For example, the amplification of PDGFRA was found in 23 patients, and 71 and 28 patients showed EGFR and CDK4 amplification, respectively.	('EGFR', 'Gene', '1956', (97, 101))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (81, 89))	('CDK4', 'Gene', (106, 110))	('EGFR', 'Gene', (97, 101))	('CDK4', 'Gene', '1019', (106, 110))	('amplification', 'Var', (17, 30))	('PDGFRA', 'Gene', '5156', (34, 40))	('PDGFRA', 'Gene', (34, 40))
23171	31719831	The amplification of oncogenes across LGG was not as extensive as GBM, but focal deletions of CDKN2A/B were also found in LGG, which were considered as negative cell cycle regulators in gliomas.	('LGG', 'Disease', (122, 125))	('CDKN2A', 'Gene', '1029', (94, 100))	('deletions', 'Var', (81, 90))	('GBM', 'Disease', (66, 69))	('gliomas', 'Disease', (186, 193))	('GBM', 'Disease', 'MESH:D005909', (66, 69))	('gliomas', 'Disease', 'MESH:D005910', (186, 193))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('CDKN2A', 'Gene', (94, 100))
23174	31719831	While in GBM, 47 protein-coding genes and lncRNAs were significantly associated with copy number status, including 36 protein-coding genes associated with amplifications, and 9 protein-coding genes and 2 lncRNAs associated with deletions.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('copy number', 'Var', (85, 96))	('associated', 'Reg', (69, 79))	('GBM', 'Disease', (9, 12))	('GBM', 'Disease', 'MESH:D005909', (9, 12))	('N', 'Chemical', 'MESH:D009584', (208, 209))
23175	31719831	While our CNV-driven genes were identified between amplification/deletion copy number states and normal state, only several genes were confirmed in previous studies, for example, ELAVL2 in GBM.	('GBM', 'Disease', (189, 192))	('ELAVL2', 'Gene', '1993', (179, 185))	('amplification/deletion', 'Var', (51, 73))	('GBM', 'Disease', 'MESH:D005909', (189, 192))	('ELAVL2', 'Gene', (179, 185))	('N', 'Chemical', 'MESH:D009584', (11, 12))
23179	31719831	It has been reported that the deletion of 9p21.3 is related to the occurrence of GBM.	('9p21.3', 'Gene', (42, 48))	('deletion', 'Var', (30, 38))	('GBM', 'Disease', (81, 84))	('GBM', 'Disease', 'MESH:D005909', (81, 84))	('related', 'Reg', (52, 59))
23182	31719831	The expression levels of genes identified as copy number deletion (amplification) were generally decreased (increased) in both LGG and GBM (Figure 1), which was consistent with previous reports.	('increased', 'PosReg', (108, 117))	('GBM', 'Disease', (135, 138))	('expression levels of genes', 'MPA', (4, 30))	('decreased', 'NegReg', (97, 106))	('copy number deletion', 'Var', (45, 65))	('GBM', 'Disease', 'MESH:D005909', (135, 138))
23187	31719831	If CNV increased the correlation, the ceRNA pair was enhanced by CNV.	('increased', 'PosReg', (7, 16))	('correlation', 'MPA', (21, 32))	('ceRNA pair', 'CPA', (38, 48))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('CNV', 'Var', (3, 6))	('N', 'Chemical', 'MESH:D009584', (4, 5))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('enhanced', 'PosReg', (53, 61))
23188	31719831	Conversely, the ceRNA pair was weakened by CNV.	('CNV', 'Var', (43, 46))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('weakened', 'NegReg', (31, 39))	('ceRNA pair', 'CPA', (16, 26))
23193	31719831	By observing the ceRNA network of GBM, we found most of the ceRNA interactions were weakened because of the CNV-driven ceRNAs, and only a few CNV-driven ceRNAs (ELAVL2 and PDGFRA) showed opposite influence (Figure 2C).	('N', 'Chemical', 'MESH:D009584', (156, 157))	('GBM', 'Disease', (34, 37))	('weakened', 'NegReg', (84, 92))	('PDGFRA', 'Gene', (172, 178))	('GBM', 'Disease', 'MESH:D005909', (34, 37))	('ELAVL2', 'Gene', '1993', (161, 167))	('PDGFRA', 'Gene', '5156', (172, 178))	('ceRNA', 'CPA', (60, 65))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('ELAVL2', 'Gene', (161, 167))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('CNV-driven', 'Var', (108, 118))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('interactions', 'Interaction', (66, 78))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('N', 'Chemical', 'MESH:D009584', (143, 144))
23197	31719831	The interactions between STMN1 and ELAVL2/MARCH9 were weakened by CNV, while in MTMR1 and CECR2 the interactions were weakened by MARCH9 amplification and enhanced by ELAVL2 deletion.	('interactions', 'Interaction', (4, 16))	('deletion', 'Var', (174, 182))	('MTMR1', 'Gene', (80, 85))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('weakened', 'NegReg', (118, 126))	('N', 'Chemical', 'MESH:D009584', (67, 68))	('CECR2', 'Gene', '27443', (90, 95))	('weakened', 'NegReg', (54, 62))	('amplification', 'Var', (137, 150))	('MARCH9', 'Gene', (130, 136))	('MARCH9', 'Gene', '92979', (130, 136))	('MARCH9', 'Gene', (42, 48))	('ELAVL2', 'Gene', '1993', (35, 41))	('STMN1', 'Gene', '3925', (25, 30))	('enhanced', 'PosReg', (155, 163))	('MARCH9', 'Gene', '92979', (42, 48))	('ELAVL2', 'Gene', '1993', (167, 173))	('MTMR1', 'Gene', '8776', (80, 85))	('CECR2', 'Gene', (90, 95))	('interactions', 'Interaction', (100, 112))	('STMN1', 'Gene', (25, 30))	('ELAVL2', 'Gene', (35, 41))	('ELAVL2', 'Gene', (167, 173))
23199	31719831	Some studies have shown that co-deletion of CDKN2A and MTAP could be used as markers for glioma stratification, and the deletion of CDKN2A was associated with the expression of CDK4/6 in various tumors.	('CDKN2A', 'Gene', (132, 138))	('MTAP', 'Gene', (55, 59))	('tumors', 'Disease', (195, 201))	('associated', 'Reg', (143, 153))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('CDKN2A', 'Gene', '1029', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('CDKN2A', 'Gene', (44, 50))	('MTAP', 'Gene', '4507', (55, 59))	('CDK4', 'Gene', '1019', (177, 181))	('CDK4', 'Gene', (177, 181))	('CDKN2A', 'Gene', '1029', (44, 50))	('deletion', 'Var', (120, 128))	('expression', 'MPA', (163, 173))	('glioma', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
23203	31719831	In GBM, dysregulated ceRNAs were primarily enriched in categories related to cell cycle, e.g.	('GBM', 'Disease', (3, 6))	('GBM', 'Disease', 'MESH:D005909', (3, 6))	('dysregulated', 'Var', (8, 20))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('ceRNAs', 'Gene', (21, 27))
23208	31719831	It has been proven that cell cycle was mediated by CDKN2A, its dysregulation driven by copy number deletion could inhibit CDK4 and CDK6 and thus blocked traversal from G1 to S-phase.	('CDKN2A', 'Gene', '1029', (51, 57))	('cell cycle', 'CPA', (24, 34))	('inhibit', 'NegReg', (114, 121))	('traversal from G1 to S-phase', 'CPA', (153, 181))	('CDKN2A', 'Gene', (51, 57))	('CDK4', 'Gene', '1019', (122, 126))	('CDK4', 'Gene', (122, 126))	('copy number deletion', 'Var', (87, 107))	('CDK6', 'Gene', (131, 135))	('CDK6', 'Gene', '1021', (131, 135))	('blocked', 'NegReg', (145, 152))
23212	31719831	The largest community in LGG contained 798 nodes, including some glioma-associated genes like IDH1 and CDK4/6, in which most ceRNA pairs were driven by copy number deletion.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('CDK4', 'Gene', '1019', (103, 107))	('IDH1', 'Gene', (94, 98))	('glioma', 'Disease', (65, 71))	('IDH1', 'Gene', '3417', (94, 98))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('copy number deletion', 'Var', (152, 172))	('CDK4', 'Gene', (103, 107))
23221	31719831	For LGG, our results showed that the deletion of MTAP, CDKN2A, and CDKN2B had the worse prognosis (with hazard ratios of 1.946, 1.992 and 1.984, respectively).	('CDKN2A', 'Gene', '1029', (55, 61))	('deletion', 'Var', (37, 45))	('CDKN2B', 'Gene', (67, 73))	('MTAP', 'Gene', '4507', (49, 53))	('CDKN2B', 'Gene', '1030', (67, 73))	('MTAP', 'Gene', (49, 53))	('CDKN2A', 'Gene', (55, 61))
23222	31719831	The dysregulated ceRNA network driven by the deletion of CDKN2B was enriched in Epac1/Rap1 pathway, which was proved to be important in glioma cell death.	('N', 'Chemical', 'MESH:D009584', (60, 61))	('CDKN2B', 'Gene', (57, 63))	('Epac1', 'Gene', (80, 85))	('Rap1', 'Gene', '5906', (86, 90))	('dysregulated', 'Reg', (4, 16))	('glioma cell death', 'Disease', 'MESH:D003643', (136, 153))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('CDKN2B', 'Gene', '1030', (57, 63))	('glioma cell death', 'Disease', (136, 153))	('deletion', 'Var', (45, 53))	('Epac1', 'Gene', '10411', (80, 85))	('Rap1', 'Gene', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
23223	31719831	By using the Cox proportional hazards regression model, we found that the CNV-driven ceRNAs, such as MTAP, KLHL9, and ELAVL2, whose deletion led to worse overall survival also exhibited significant associations between their expression and survival time (Table 3, univariate Cox hazard analysis, P < 0.05).	('deletion', 'Var', (132, 140))	('MTAP', 'Gene', (101, 105))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('Cox', 'Gene', (13, 16))	('survival', 'CPA', (240, 248))	('ELAVL2', 'Gene', (118, 124))	('MTAP', 'Gene', '4507', (101, 105))	('KLHL9', 'Gene', '55958', (107, 112))	('Cox', 'Gene', (275, 278))	('Cox', 'Gene', '1351', (275, 278))	('worse', 'NegReg', (148, 153))	('ELAVL2', 'Gene', '1993', (118, 124))	('KLHL9', 'Gene', (107, 112))	('CNV-driven', 'Gene', (74, 84))	('overall survival', 'MPA', (154, 170))	('expression', 'MPA', (225, 235))	('Cox', 'Gene', '1351', (13, 16))
23227	31719831	It has been shown that the deletion of 9p21, especially co-deletions of CDKN2A/B and MTAP, could be a marker for different grades of glioma.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('CDKN2A', 'Gene', '1029', (72, 78))	('9p21', 'Gene', (39, 43))	('deletion', 'Var', (27, 35))	('MTAP', 'Gene', (85, 89))	('glioma', 'Disease', (133, 139))	('marker', 'Reg', (102, 108))	('MTAP', 'Gene', '4507', (85, 89))	('CDKN2A', 'Gene', (72, 78))
23232	31719831	Based on the CNV-driven genes and ceRNA triplets, dysregulated ceRNA networks driven by copy number amplification/deletion were identified in LGG and GBM.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('GBM', 'Disease', (150, 153))	('copy number amplification/deletion', 'Var', (88, 122))	('GBM', 'Disease', 'MESH:D005909', (150, 153))
23248	31719831	Additionally, the loss of CDKN2B could cause the dysregulation of its relevant community structures, by affecting the expression of its ceRNA partners, including CDK2 and RBL1, and ultimately resulted in cell-cycle dysregulation.	('RBL1', 'Gene', (171, 175))	('cause', 'Reg', (39, 44))	('dysregulation', 'MPA', (49, 62))	('CDK2', 'Gene', '1017', (162, 166))	('N', 'Chemical', 'MESH:D009584', (139, 140))	('loss', 'Var', (18, 22))	('CDKN2B', 'Gene', (26, 32))	('resulted in', 'Reg', (192, 203))	('CDK2', 'Gene', (162, 166))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('CDKN2B', 'Gene', '1030', (26, 32))	('RBL1', 'Gene', '5933', (171, 175))	('cell-cycle dysregulation', 'Phenotype', 'HP:0011018', (204, 228))	('community structures', 'MPA', (79, 99))	('affecting', 'Reg', (104, 113))	('expression', 'MPA', (118, 128))	('cell-cycle dysregulation', 'CPA', (204, 228))
23251	31719831	By performing a systematic analysis of the CNV-driven ceRNAs with clinical features, we found that the CNVs of some genes (such as MTAP/CDKN2A/CDKN2B/KLHL9) had significant impacts on histological diagnosis and survival in glioma.	('MTAP', 'Gene', (131, 135))	('MTAP', 'Gene', '4507', (131, 135))	('CDKN2B', 'Gene', (143, 149))	('N', 'Chemical', 'MESH:D009584', (146, 147))	('N', 'Chemical', 'MESH:D009584', (139, 140))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('CDKN2A', 'Gene', (136, 142))	('CDKN2B', 'Gene', '1030', (143, 149))	('survival', 'CPA', (211, 219))	('glioma', 'Disease', (223, 229))	('CNVs', 'Var', (103, 107))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('KLHL9', 'Gene', (150, 155))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('CDKN2A', 'Gene', '1029', (136, 142))	('KLHL9', 'Gene', '55958', (150, 155))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('impacts', 'Reg', (173, 180))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('histological diagnosis', 'CPA', (184, 206))
23252	31719831	Functional analysis of CDKN2B through its influenced ceRNA network further revealed that the dysregulation of specific ceRNA networks driven by CNVs could act as prognostic markers of glioma (Figure 6).	('glioma', 'Disease', (184, 190))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('CDKN2B', 'Gene', (23, 29))	('glioma', 'Disease', 'MESH:D005910', (184, 190))	('CDKN2B', 'Gene', '1030', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('CNVs', 'Gene', (144, 148))	('dysregulation', 'Var', (93, 106))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('N', 'Chemical', 'MESH:D009584', (56, 57))
23378	33808106	Another interesting study showed that the cytosine methylation of mature miRNA inhibits their tumor suppressive nature and also provides poor prognosis for the glioblastoma.	('glioblastoma', 'Disease', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('cytosine methylation', 'Var', (42, 62))	('inhibits', 'NegReg', (79, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('cytosine', 'Chemical', 'MESH:D003596', (42, 50))
23399	33808106	For cell culture, T98G, U251, and U87MG glioma cell lines were grown in Dulbecco's modified essential medium (DMEM) and supplemented with 10% fetal bovine serum, 1% Penicillin, and 10% streptomycin after culture in a 5% CO2 humidified incubator at 37  C. After reaching 70% confluency, the samples were treated with a miRNA mimic in 6-well culture plates.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('U251', 'CellLine', 'CVCL:0021', (24, 28))	('DMEM', 'Chemical', '-', (110, 114))	('CO2', 'Chemical', 'MESH:D002245', (220, 223))	('glioma', 'Disease', (40, 46))	('streptomycin', 'Chemical', 'MESH:D013307', (185, 197))	('Penicillin', 'Chemical', 'MESH:D010406', (165, 175))	('U87MG', 'CellLine', 'CVCL:0022', (34, 39))	('T98', 'CellLine', 'CVCL:B368', (18, 21))	('U87MG', 'Var', (34, 39))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	("Dulbecco's modified essential medium", 'Chemical', '-', (72, 108))
23409	33808106	Then, the miR-302-367 cluster down-regulates GB and can also be considered to act as a tumor suppressor miRNA (Figure 2).	('down-regulates', 'NegReg', (30, 44))	('tumor suppressor', 'Gene', '7248', (87, 103))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('GB', 'Phenotype', 'HP:0012174', (45, 47))	('miR-302-367 cluster', 'Var', (10, 29))	('tumor suppressor', 'Gene', (87, 103))
23410	33808106	(3) MicroRNA-7-5p inhibits cell migration and invasion in GB through targeting SATB1 (special AT-rich sequence binding protein 1).	('special AT-rich sequence binding protein 1', 'Gene', '6304', (86, 128))	('GB', 'Phenotype', 'HP:0012174', (58, 60))	('cell migration', 'CPA', (27, 41))	('inhibits', 'NegReg', (18, 26))	('SATB1', 'Gene', (79, 84))	('SATB1', 'Gene', '6304', (79, 84))	('special AT-rich sequence binding protein 1', 'Gene', (86, 128))	('targeting', 'Reg', (69, 78))	('MicroRNA-7-5p', 'Var', (4, 17))	('invasion', 'CPA', (46, 54))
23411	33808106	MicroRNA-7-5p is, therefore, a potential biomarker that might be used for the treatment of glioblastoma.	('glioblastoma', 'Disease', (91, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('MicroRNA-7-5p', 'Var', (0, 13))
23416	33808106	Finally, miR-181 inhibits Bcl-2 and leads to the down-regulation of glioblastoma (Figure 2).	('inhibits', 'NegReg', (17, 25))	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('Bcl-2', 'Gene', (26, 31))	('Bcl-2', 'Gene', '596', (26, 31))	('miR-181', 'Var', (9, 16))	('down-regulation', 'NegReg', (49, 64))	('miR-181', 'Chemical', '-', (9, 16))
23419	33808106	Six miRNAs, miR-4443, miR-422a, miR-494-3p, miR-502-5p, miR-520f-3p, and miR-549a are overexpressed in tumors of glial origin.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR-422a', 'Gene', '494334', (22, 30))	('miR-502', 'Gene', (44, 51))	('miR-549a', 'Gene', (73, 81))	('miR-520f-3p', 'Var', (56, 67))	('overexpressed', 'PosReg', (86, 99))	('miR-4443', 'Gene', '100616407', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('miR-494-3p', 'Var', (32, 42))	('miR-422a', 'Gene', (22, 30))	('miR-549a', 'Gene', '693132', (73, 81))	('miR-4443', 'Gene', (12, 20))	('miR-502', 'Gene', '574504', (44, 51))
23421	33808106	MiRNAs such as miR-4443, miR-422a, miR-494-3p, miR-502-5p, miR-520f-3p, and miR-549a inhibit apoptosis and up-regulate glioblastoma.	('miR-4443', 'Gene', (15, 23))	('glioblastoma', 'Disease', (119, 131))	('miR-502', 'Gene', '574504', (47, 54))	('miR-549a', 'Gene', (76, 84))	('miR-4443', 'Gene', '100616407', (15, 23))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('miR-494-3p', 'Var', (35, 45))	('miR-422a', 'Gene', '494334', (25, 33))	('miR-502', 'Gene', (47, 54))	('up-regulate', 'PosReg', (107, 118))	('inhibit', 'NegReg', (85, 92))	('miR-520f-3p', 'Var', (59, 70))	('miR-549a', 'Gene', '693132', (76, 84))	('miR-422a', 'Gene', (25, 33))	('apoptosis', 'CPA', (93, 102))
23429	33808106	MiR-378a-3p suppresses the progression of GB by reducing TSPAN17 expression, and may thus serve as a potential therapeutic target for treating patients with GB.	('TSPAN17', 'Gene', '26262', (57, 64))	('GB', 'Phenotype', 'HP:0012174', (157, 159))	('suppresses', 'NegReg', (12, 22))	('GB', 'Phenotype', 'HP:0012174', (42, 44))	('reducing', 'NegReg', (48, 56))	('patients', 'Species', '9606', (143, 151))	('MiR-378a-3p', 'Var', (0, 11))	('progression', 'CPA', (27, 38))	('expression', 'MPA', (65, 75))	('TSPAN17', 'Gene', (57, 64))	('MiR-378a-3p', 'Chemical', '-', (0, 11))
23438	33808106	The knockdown of CKS1 significantly induced cell cycle arrest and restrained GB cell proliferation.	('restrained', 'NegReg', (66, 76))	('induced', 'Reg', (36, 43))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('CKS1', 'Gene', '137529', (17, 21))	('CKS1', 'Gene', (17, 21))	('GB cell proliferation', 'CPA', (77, 98))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('GB', 'Phenotype', 'HP:0012174', (77, 79))	('knockdown', 'Var', (4, 13))
23447	33808106	The silencing of Cdh4 is important for inducing a decrease in the infiltrative ability of human glioma cells.	('Cdh4', 'Gene', (17, 21))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('Cdh4', 'Gene', '1002', (17, 21))	('human', 'Species', '9606', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('silencing', 'Var', (4, 13))	('glioma', 'Disease', (96, 102))	('decrease', 'NegReg', (50, 58))
23449	33808106	MicroRNA-Cdh4 transduction induced a strong down-regulation of Cdh4 mRNA in glioma-initiating cells.	('Cdh4', 'Gene', (9, 13))	('Cdh4', 'Gene', '1002', (9, 13))	('glioma', 'Disease', (76, 82))	('transduction', 'Var', (14, 26))	('down-regulation', 'NegReg', (44, 59))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('mRNA', 'MPA', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Cdh4', 'Gene', (63, 67))	('Cdh4', 'Gene', '1002', (63, 67))
23454	33808106	Furthermore, miR-101 directly targets KLF6, thereby inhibiting CHI3L1 expression and blocking the activation of the MEK1/2 and PI3K signaling pathways.	('miR-101', 'Chemical', '-', (13, 20))	('blocking', 'NegReg', (85, 93))	('KLF6', 'Gene', '1316', (38, 42))	('inhibiting', 'NegReg', (52, 62))	('miR-101', 'Var', (13, 20))	('CHI3L1', 'Gene', (63, 69))	('CHI3L1', 'Gene', '1116', (63, 69))	('expression', 'MPA', (70, 80))	('MEK1/2', 'Gene', '5604;5605', (116, 122))	('MEK1/2', 'Gene', (116, 122))	('KLF6', 'Gene', (38, 42))
23457	33808106	Both miR-338-3p and miR-338-5p are differentially expressed in GB and non-tumor brain tissue.	('miR-338-3p', 'Chemical', '-', (5, 15))	('non-tumor', 'Disease', (70, 79))	('GB', 'Phenotype', 'HP:0012174', (63, 65))	('miR-338-3p', 'Var', (5, 15))	('tumor brain', 'Phenotype', 'HP:0030692', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('non-tumor', 'Disease', 'MESH:D009369', (70, 79))	('miR-338-5p', 'Chemical', '-', (20, 30))	('miR-338-5p', 'Var', (20, 30))
23458	33808106	Moreover, miR-338-5p with radiation leads to significantly decreased cell proliferation, increased cell cycle arrest, and apoptosis.	('decreased', 'NegReg', (59, 68))	('arrest', 'Disease', 'MESH:D006323', (110, 116))	('apoptosis', 'CPA', (122, 131))	('miR-338-5p', 'Chemical', '-', (10, 20))	('miR-338-5p', 'Var', (10, 20))	('arrest', 'Disease', (110, 116))	('cell proliferation', 'CPA', (69, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (99, 116))	('increased', 'PosReg', (89, 98))
23460	33808106	MiR-338-5p even inhibited TSHZ3 expression and the promotion of MMP2 expression.	('inhibited', 'NegReg', (16, 25))	('MiR-338-5p', 'Var', (0, 10))	('promotion', 'PosReg', (51, 60))	('MMP2', 'Gene', '4313', (64, 68))	('TSHZ3', 'Gene', '57616', (26, 31))	('expression', 'MPA', (69, 79))	('TSHZ3', 'Gene', (26, 31))	('MiR-338-5p', 'Chemical', '-', (0, 10))	('expression', 'MPA', (32, 42))	('MMP2', 'Gene', (64, 68))
23461	33808106	Because miR-338-5p inhibited glioma growth it may therefore be used as one of the diagnostic markers for high-grade gliomas.	('inhibited', 'NegReg', (19, 28))	('glioma', 'Disease', (29, 35))	('miR-338-5p', 'Chemical', '-', (8, 18))	('miR-338-5p', 'Var', (8, 18))	('glioma', 'Disease', (116, 122))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('gliomas', 'Disease', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
23462	33808106	Notably, miR-338-3p expression is negatively correlated with GB.	('negatively', 'NegReg', (34, 44))	('miR-338-3p', 'Var', (9, 19))	('miR-338-3p', 'Chemical', '-', (9, 19))	('GB', 'Phenotype', 'HP:0012174', (61, 63))
23463	33808106	A low miR-338-3p expression is associated with increased mortality and disease progression in glioblastoma patients.	('mortality', 'Disease', 'MESH:D003643', (57, 66))	('low', 'NegReg', (2, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('disease progression', 'CPA', (71, 90))	('mortality', 'Disease', (57, 66))	('increased', 'PosReg', (47, 56))	('miR-338-3p', 'Chemical', '-', (6, 16))	('miR-338-3p expression', 'Var', (6, 27))	('glioblastoma', 'Disease', (94, 106))	('patients', 'Species', '9606', (107, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
23464	33808106	Therefore, miR-338-3p showed clinically relevant tumor suppressing behaviors in GB (Figure 4).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('GB', 'Phenotype', 'HP:0012174', (80, 82))	('tumor', 'Disease', (49, 54))	('miR-338-3p', 'Chemical', '-', (11, 21))	('miR-338-3p', 'Var', (11, 21))
23471	33808106	Moreover, miR-153 is a regulator of apoptosis as it reduces the protein levels of the anti-apoptotic Bcl-2 and Mcl-1.	('miR-153', 'Var', (10, 17))	('Bcl-2', 'Gene', (101, 106))	('Bcl-2', 'Gene', '596', (101, 106))	('Mcl-1', 'Gene', '4170', (111, 116))	('reduces', 'NegReg', (52, 59))	('miR-153', 'Chemical', '-', (10, 17))	('Mcl-1', 'Gene', (111, 116))
23472	33808106	Additionally, miR-153 inhibited the expression of Bcl-2 and Mcl-1 by directly targeting the 3'UTR regions of their respective mRNAs.	('Mcl-1', 'Gene', (60, 65))	('inhibited', 'NegReg', (22, 31))	('miR-153', 'Var', (14, 21))	('targeting', 'Reg', (78, 87))	('Bcl-2', 'Gene', (50, 55))	('Bcl-2', 'Gene', '596', (50, 55))	('Mcl-1', 'Gene', '4170', (60, 65))	('miR-153', 'Chemical', '-', (14, 21))	('expression', 'MPA', (36, 46))
23473	33808106	Therefore, miR-153 may be further developed as a promising anti-tumor target candidate (Figure 2).	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('miR-153', 'Chemical', '-', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('miR-153', 'Var', (11, 18))
23478	33808106	MicroRNA-199a down-regulates AKT-mTOR pathways leading to the down-regulation of survivin.	('AKT', 'Gene', '207', (29, 32))	('mTOR', 'Gene', '2475', (33, 37))	('mTOR', 'Gene', (33, 37))	('MicroRNA-199a', 'Var', (0, 13))	('down-regulates', 'NegReg', (14, 28))	('down-regulation', 'NegReg', (62, 77))	('AKT', 'Gene', (29, 32))	('survivin', 'Protein', (81, 89))
23483	33808106	MicroRNA-410 transfected into GB results in growth suppression by inhibiting MET expression.	('transfected', 'Var', (13, 24))	('MicroRNA-410', 'Gene', '574434', (0, 12))	('growth suppression', 'MPA', (44, 62))	('inhibiting', 'NegReg', (66, 76))	('MicroRNA-410', 'Gene', (0, 12))	('MET', 'Gene', '79811', (77, 80))	('GB', 'Phenotype', 'HP:0012174', (30, 32))	('MET', 'Gene', (77, 80))
23486	33808106	Silencing OIP5-AS1 is blocking the Wnt-7b/beta-catenin pathway via targeted up-regulating miR-410, inhibiting growth, invasion, and migration while promoting apoptosis in glioma cells and also down-regulation of glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('beta-catenin', 'Gene', (42, 54))	('up-regulating', 'PosReg', (76, 89))	('promoting', 'PosReg', (148, 157))	('miR-410', 'Gene', '574434', (90, 97))	('beta-catenin', 'Gene', '1499', (42, 54))	('glioblastoma', 'Disease', (212, 224))	('apoptosis', 'CPA', (158, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (212, 224))	('Silencing', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('inhibiting', 'NegReg', (99, 109))	('Wnt-7b', 'Gene', '7477', (35, 41))	('growth', 'CPA', (110, 116))	('Wnt-7b', 'Gene', (35, 41))	('miR-410', 'Gene', (90, 97))	('down-regulation', 'NegReg', (193, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (212, 224))	('glioma', 'Disease', (171, 177))	('OIP5-AS1', 'Gene', '729082;11339;5729', (10, 18))	('blocking', 'NegReg', (22, 30))	('OIP5-AS1', 'Gene', (10, 18))
23492	33808106	MiR-181a and miR-181c bind to Notch2 UTRs, down-regulating its expression.	('miR-181c', 'Gene', '406957', (13, 21))	('Notch2', 'Gene', (30, 36))	('MiR-181a', 'Var', (0, 8))	('expression', 'MPA', (63, 73))	('Notch2', 'Gene', '4853', (30, 36))	('MiR-181', 'Chemical', '-', (0, 7))	('down-regulating', 'NegReg', (43, 58))	('bind', 'Interaction', (22, 26))	('miR-181c', 'Gene', (13, 21))
23505	33808106	(20) MicroRNA-26a was first identified in colorectal cancer.	('MicroRNA-26a', 'Var', (5, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('colorectal cancer', 'Disease', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))
23517	33808106	MiR-181may be used as a prognostic biomarker of glioblastoma (Figure 4).	('MiR-181may', 'Var', (0, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('MiR-181', 'Chemical', '-', (0, 7))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))
23522	33808106	The overexpression of miR152-3p increased cisplatin sensitivity in GB cells.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('miR152-3p', 'Var', (22, 31))	('cisplatin sensitivity', 'MPA', (42, 63))	('GB', 'Phenotype', 'HP:0012174', (67, 69))	('increased', 'PosReg', (32, 41))	('overexpression', 'PosReg', (4, 18))
23527	33808106	Transfection of recombinant SOS1 could effectively reverse the increased cisplatin sensitivity induced by miR-152-3p overexpression in GB cells.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('reverse', 'NegReg', (51, 58))	('increased', 'PosReg', (63, 72))	('SOS1', 'Gene', '6654', (28, 32))	('miR-152-3p', 'Chemical', '-', (106, 116))	('cisplatin sensitivity', 'MPA', (73, 94))	('GB', 'Phenotype', 'HP:0012174', (135, 137))	('overexpression', 'PosReg', (117, 131))	('SOS1', 'Gene', (28, 32))	('miR-152-3p', 'Var', (106, 116))
23528	33808106	Thus, miR152-3p acts as a tumor suppressor miRNA in GB (Figure 4).	('tumor suppressor', 'Gene', (26, 42))	('GB', 'Phenotype', 'HP:0012174', (52, 54))	('tumor suppressor', 'Gene', '7248', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('miR152-3p', 'Var', (6, 15))
23530	33808106	MiR-212-3p directly binds to the 3'UTR of SGK3 and inhibits protein expression.	('inhibits', 'NegReg', (51, 59))	('SGK3', 'Gene', (42, 46))	('MiR-212-3p', 'Chemical', '-', (0, 10))	('MiR-212-3p', 'Var', (0, 10))	('protein expression', 'MPA', (60, 78))	('SGK3', 'Gene', '23678', (42, 46))	('binds', 'Interaction', (20, 25))
23531	33808106	MiR-212-3p also suppressed tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('suppressed', 'NegReg', (16, 26))	('tumor', 'Disease', (27, 32))	('MiR-212-3p', 'Chemical', '-', (0, 10))	('MiR-212-3p', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
23532	33808106	MiR-212-3p inhibited the proliferation of GB cells by directly targeting SGK3, and could potentially be used as a new therapeutic target for glioblastoma (Figure 4).	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('proliferation', 'CPA', (25, 38))	('GB', 'Phenotype', 'HP:0012174', (42, 44))	('SGK3', 'Gene', (73, 77))	('targeting', 'Reg', (63, 72))	('MiR-212-3p', 'Chemical', '-', (0, 10))	('MiR-212-3p', 'Var', (0, 10))	('SGK3', 'Gene', '23678', (73, 77))	('inhibited', 'NegReg', (11, 20))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))
23535	33808106	Knockout of fibronectin expression in GB cell lines inhibited proliferation and migration.	('fibronectin', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('inhibited', 'NegReg', (52, 61))	('fibronectin', 'Gene', '2335', (12, 23))	('GB', 'Phenotype', 'HP:0012174', (38, 40))
23549	33808106	MiR-183 is up-regulated in gliomas compared with normal brain tissues.Silencing the expression of miR-183 inhibited cell proliferation, migration, and invasion.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('MiR-183', 'Gene', (0, 7))	('tissues.Silencing', 'Var', (62, 79))	('inhibited', 'NegReg', (106, 115))	('miR-183', 'Gene', (98, 105))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('invasion', 'CPA', (151, 159))	('miR-183', 'Gene', '406959', (98, 105))	('migration', 'CPA', (136, 145))	('MiR-183', 'Gene', '406959', (0, 7))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('gliomas', 'Disease', (27, 34))	('cell proliferation', 'CPA', (116, 134))	('expression', 'MPA', (84, 94))
23551	33808106	(29) MicroRNA-590-3p was up-regulated in glioma tissues and confers resistance to radiotherapy in glioblastoma cells.	('up-regulated', 'PosReg', (25, 37))	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('MicroRNA-590-3p', 'Var', (5, 20))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('glioma', 'Disease', (41, 47))
23552	33808106	The expression of miR-590-3p is higher in high-grade than in low-grade gliomas.	('gliomas', 'Disease', (71, 78))	('higher', 'PosReg', (32, 38))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('expression', 'MPA', (4, 14))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('high-grade', 'Disease', (42, 52))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('miR-590-3p', 'Var', (18, 28))
23553	33808106	Therefore, miR-590-3p is positively correlated with glioblastoma and contributes to the radio-resistance of GB cells by directly targeting immunoglobulin-like domains protein 1 (LRIG1).	('GB', 'Phenotype', 'HP:0012174', (108, 110))	('correlated', 'Reg', (36, 46))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('LRIG1', 'Gene', (178, 183))	('LRIG1', 'Gene', '26018', (178, 183))	('miR-590-3p', 'Var', (11, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('targeting', 'Reg', (129, 138))
23557	33808106	Therefore, both miRNAs miR-221 and miR-222 could be potential therapeutic targets for GB intervention (Figure 3).	('miR-221', 'Gene', '407006', (23, 30))	('miR-222', 'Gene', '407007', (35, 42))	('miRNAs', 'Var', (16, 22))	('GB', 'Phenotype', 'HP:0012174', (86, 88))	('miR-221', 'Gene', (23, 30))	('miR-222', 'Gene', (35, 42))
23572	33808106	(35) MiR-15a-5p is up-regulated in GB and acts as an oncogene by targeting tumor suppressor gene cell adhesion molecule 1 (CADM1).	('CADM1', 'Gene', (123, 128))	('cell adhesion molecule 1', 'Gene', '23705', (97, 121))	('MiR-15a-5p', 'Chemical', '-', (5, 15))	('GB', 'Phenotype', 'HP:0012174', (35, 37))	('tumor suppressor', 'Gene', (75, 91))	('MiR-15a-5p', 'Var', (5, 15))	('CADM1', 'Gene', '23705', (123, 128))	('targeting', 'Reg', (65, 74))	('up-regulated', 'PosReg', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cell adhesion molecule 1', 'Gene', (97, 121))	('tumor suppressor', 'Gene', '7248', (75, 91))
23573	33808106	MiR-15a-5p inhibits CADM1 which stimulates Akt phosphorylation.	('CADM1', 'Gene', (20, 25))	('Akt', 'Gene', '207', (43, 46))	('CADM1', 'Gene', '23705', (20, 25))	('inhibits', 'NegReg', (11, 19))	('Akt', 'Gene', (43, 46))	('MiR-15a-5p', 'Chemical', '-', (0, 10))	('MiR-15a-5p', 'Var', (0, 10))	('stimulates', 'PosReg', (32, 42))
23584	33808106	Collectively, miR-522-3p is a novel therapeutic target for GB treatment via regulating the SFRP2/Wnt/beta-catenin axis, therefore, providing a feasible direction for the development of new strategies for GB treatment (Figure 5).	('SFRP2', 'Gene', (91, 96))	('GB', 'Phenotype', 'HP:0012174', (59, 61))	('beta-catenin', 'Gene', (101, 113))	('miR-522-3p', 'Chemical', '-', (14, 24))	('GB', 'Phenotype', 'HP:0012174', (204, 206))	('miR-522-3p', 'Var', (14, 24))	('Wnt', 'Gene', '7477', (97, 100))	('regulating', 'Reg', (76, 86))	('beta-catenin', 'Gene', '1499', (101, 113))	('SFRP2', 'Gene', '6423', (91, 96))	('Wnt', 'Gene', (97, 100))
23598	33808106	Some miRNAs are gene silencers of anti-apoptotic genes and inhibit the growth and survival of glioblastoma.	('silencer', 'Disease', 'None', (21, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('miRNAs', 'Var', (5, 11))	('silencer', 'Disease', (21, 29))	('inhibit', 'NegReg', (59, 66))	('glioblastoma', 'Disease', (94, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))	('anti-apoptotic genes', 'Gene', (34, 54))
23607	32777166	We characterized the clinicopathological characteristics, including 2016 World Health Organization (WHO) grade, age, sex, location, segment length, resection, pre- and postsurgery, Modified McCormick Scale (MMS), radio- and chemotherapy, and Ki-67 and H3 K27M mutations, in 108 spinal cord astrocytomas through heatmaps.	('astrocytoma', 'Phenotype', 'HP:0009592', (290, 301))	('H3 K27M mutations', 'Var', (252, 269))	('K27M', 'Mutation', 'p.K27M', (255, 259))	('spinal cord astrocytomas', 'Disease', (278, 302))	('spinal cord astrocytomas', 'Disease', 'MESH:D013118', (278, 302))
23619	32777166	9 ,  16 ,  17 ,  18   "Diffused midline glioma, H3 K27M-mutant" has been defined as a new entity in the 2016 World Health Organization (WHO) classification of Central Nervous System (CNS) tumors, corresponding to WHO grade IV.	('midline glioma', 'Disease', 'MESH:D005910', (32, 46))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('K27M', 'Mutation', 'p.K27M', (51, 55))	('midline glioma', 'Disease', (32, 46))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('Central Nervous System', 'Disease', (159, 181))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('H3 K27M-mutant', 'Var', (48, 62))
23620	32777166	Some studies have reported "diffuse midline glioma, H3 K27M-mutant" in the midline structure including spinal cord.	('H3 K27M-mutant', 'Var', (52, 66))	('K27M', 'Mutation', 'p.K27M', (55, 59))	('midline glioma', 'Disease', 'MESH:D005910', (36, 50))	('midline glioma', 'Disease', (36, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
23630	32777166	Routine neuropathologic evaluation of the formalin-fixed and paraffin-embedded tumor samples included hematoxylin and eosin staining and immunohistochemical analysis performed using antibodies against mutant H3 K27M (ABE419; Millipore; 1:800) and Ki-67 (MIB-1; Labvision; 1:50).	('tumor', 'Disease', (79, 84))	('Ki-67', 'Var', (247, 252))	('MIB-1', 'Gene', (254, 259))	('hematoxylin', 'Chemical', 'MESH:D006416', (102, 113))	('mutant H3 K27M', 'Var', (201, 215))	('eosin', 'Chemical', 'MESH:D004801', (118, 123))	('MIB-1', 'Gene', '57534', (254, 259))	('formalin', 'Chemical', 'MESH:D005557', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('K27M', 'Mutation', 'p.K27M', (211, 215))	('paraffin', 'Chemical', 'MESH:D010232', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
23631	32777166	K27M-mutant gliomas were classified as grade IV according to the 2016 WHO Classification of Tumors of the Central Nervous System.	('gliomas', 'Disease', (12, 19))	('K27M-mutant', 'Var', (0, 11))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('Tumors of the Central Nervous System', 'Phenotype', 'HP:0100006', (92, 128))	('Tumors of the Central Nervous', 'Disease', (92, 121))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('Tumors of the Central Nervous', 'Disease', 'MESH:D016543', (92, 121))	('Tumors', 'Phenotype', 'HP:0002664', (92, 98))
23653	32777166	In this study, the positive rate of H3 K27M mutation was 38%, and 31 histological grade II/III gliomas with H3 K27M mutation were diagnosed as WHO grade IV gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('K27M', 'Mutation', 'p.K27M', (39, 43))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('III gliomas', 'Disease', 'MESH:D005910', (91, 102))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('H3 K27M mutation', 'Var', (36, 52))	('gliomas', 'Disease', (156, 163))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('III gliomas', 'Disease', (91, 102))	('K27M', 'Mutation', 'p.K27M', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('H3 K27M mutation', 'Var', (108, 124))
23681	32777166	The tumor site of the patient was located in the cervical enlargement (C4-T1), and the recurrence of the original site may lead to limb paralysis without conscious coma.	('tumor', 'Disease', (4, 9))	('limb', 'Disease', (131, 135))	('lead to', 'Reg', (123, 130))	('paralysis', 'Disease', (136, 145))	('paralysis', 'Phenotype', 'HP:0003470', (136, 145))	('coma', 'Disease', 'MESH:D003128', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('coma', 'Phenotype', 'HP:0001259', (164, 168))	('coma', 'Disease', (164, 168))	('paralysis', 'Disease', 'MESH:D010243', (136, 145))	('recurrence', 'Var', (87, 97))	('patient', 'Species', '9606', (22, 29))
23685	32777166	Compared with previous studies on diffuse intrinsic pontine gliomas (DIPGs), our study revealed an older age at diagnosis (median, 30 years; range, 4-63 years), a lower ratio of H3 K27M mutation (38%), and a longer OS (48.1 months) among patients with spinal cord astrocytomas.	('spinal cord astrocytomas', 'Disease', 'MESH:D013118', (252, 276))	('K27M', 'Mutation', 'p.K27M', (181, 185))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('H3 K27M mutation', 'Var', (178, 194))	('astrocytoma', 'Phenotype', 'HP:0009592', (264, 275))	('lower', 'NegReg', (163, 168))	('spinal cord astrocytomas', 'Disease', (252, 276))	('patients', 'Species', '9606', (238, 246))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
23694	32777166	38  All these findings indicate that spinal cord astrocytomas are different from DIPGs, and the characteristics of H3 K27M-mutant gliomas should be considered separately based on their location.	('H3 K27M-mutant', 'Var', (115, 129))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('spinal cord astrocytomas', 'Disease', 'MESH:D013118', (37, 61))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (49, 60))	('spinal cord astrocytomas', 'Disease', (37, 61))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('K27M', 'Mutation', 'p.K27M', (118, 122))
23697	32777166	11  A study of 561 low-grade (WHO grade I/II) astrocytomas indicated that gross total resection could significantly improve survival (HR, 0.22; P < .001).	('astrocytomas', 'Disease', (46, 58))	('survival', 'MPA', (124, 132))	('improve', 'PosReg', (116, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (46, 57))	('gross', 'Var', (74, 79))	('astrocytomas', 'Disease', 'MESH:D001254', (46, 58))
23698	32777166	15  Meanwhile, our study involved all glioma grades and also demonstrated that EOR had a positive effect on survival among patients with low-grade astrocytomas but not among patients with high-grade astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (147, 159))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('astrocytomas', 'Disease', 'MESH:D001254', (199, 211))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (199, 210))	('patients', 'Species', '9606', (123, 131))	('low-grade', 'Disease', (137, 146))	('positive', 'PosReg', (89, 97))	('astrocytomas', 'Disease', (147, 159))	('patients', 'Species', '9606', (174, 182))	('EOR', 'Var', (79, 82))	('astrocytomas', 'Disease', (199, 211))	('glioma', 'Disease', (38, 44))	('survival', 'MPA', (108, 116))
23721	31856384	According to the World Health Organization (WHO), gliomas can be classified into four grades (I-IV) according to histological features, with grade IV tumours or glioblastoma multiforme (GBM) being associated with the worst prognosis, namely a median survival time of just 12-15 months and a 5-year survival rate < 3% after initial diagnosis (Torre et al., 2015; Wen and Kesari, 2008).	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('gliomas', 'Disease', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('glioblastoma multiforme', 'Disease', (161, 184))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (161, 173))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('grade IV', 'Var', (141, 149))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (161, 184))
23736	31856384	IHC staining was performed with anti-BACE2, anti-N-cadherin and anti-Ki-67.	('Ki-67', 'Gene', (69, 74))	('anti-BACE2', 'Var', (32, 42))	('N-cadherin', 'Gene', (49, 59))	('N-cadherin', 'Gene', '1000', (49, 59))	('Ki-67', 'Gene', '17345', (69, 74))
23740	31856384	The following antibodies were used: BACE2 (ab5670), N-cadherin (#13116), E-cadherin (#3195), beta-catenin (#8480), MMP2 (#40994), Vimentin (#5741), Snail (#3879), Twist (#46702), CDK2 (#2546), CDK4 (#12790), Cyclin D1 (#2978), c-Myc (#13987), p21 (#2947), p27 (#3686), p65 (#8242), p-p65 (#3033), Smad2 (#5339), p-Smad2 (#18338), PP1A (#2582), p-PP1A (#2581), IKKbeta (#8943), p-IKKbeta (#2694), IKBalpha (#11930), p-IKBalpha (#2859) and GAPDH (#5174).	('Smad2', 'Gene', (314, 319))	('Cyclin D1', 'Gene', '595', (208, 217))	('CDK2', 'Gene', (179, 183))	('p-PP1A', 'Gene', '5499', (344, 350))	('Smad2', 'Gene', (297, 302))	('Cyclin D1', 'Gene', (208, 217))	('IKKbeta', 'Gene', (379, 386))	('p65', 'Gene', '5970', (284, 287))	('N-cadherin', 'Gene', (52, 62))	('MMP2', 'Gene', (115, 119))	('#13987', 'Var', (234, 240))	('GAPDH', 'Gene', '2597', (438, 443))	('PP1A', 'Gene', '5499', (330, 334))	('N-cadherin', 'Gene', '1000', (52, 62))	('CDK4', 'Gene', (193, 197))	('#5339', 'Var', (304, 309))	('PP1A', 'Gene', '5499', (346, 350))	('Snail', 'Gene', '6615', (148, 153))	('GAPDH', 'Gene', (438, 443))	('#8943', 'Var', (369, 374))	('IKBalpha', 'Gene', '4792', (396, 404))	('MMP2', 'Gene', '4313', (115, 119))	('PP1A', 'Gene', (330, 334))	('beta-catenin', 'Gene', (93, 105))	('IKKbeta', 'Gene', '1147', (360, 367))	('CDK4', 'Gene', '1019', (193, 197))	('beta-catenin', 'Gene', '1499', (93, 105))	('IKBalpha', 'Gene', (396, 404))	('#2694', 'Var', (388, 393))	('#2582', 'Var', (336, 341))	('#11930', 'Var', (406, 412))	('p65', 'Gene', (269, 272))	('p21', 'Gene', (243, 246))	('PP1A', 'Gene', (346, 350))	('p27', 'Gene', '3429', (256, 259))	('IKBalpha', 'Gene', '4792', (417, 425))	('p21', 'Gene', '644914', (243, 246))	('Smad2', 'Gene', '4087', (314, 319))	('p65', 'Gene', (284, 287))	('#2859', 'Var', (427, 432))	('E-cadherin', 'Gene', (73, 83))	('p27', 'Gene', (256, 259))	('Vimentin', 'Gene', '7431', (130, 138))	('E-cadherin', 'Gene', '999', (73, 83))	('IKKbeta', 'Gene', (360, 367))	('Smad2', 'Gene', '4087', (297, 302))	('c-Myc', 'Gene', (227, 232))	('IKKbeta', 'Gene', '1147', (379, 386))	('CDK2', 'Gene', '1017', (179, 183))	('#2581', 'Var', (352, 357))	('Snail', 'Gene', (148, 153))	('Vimentin', 'Gene', (130, 138))	('IKBalpha', 'Gene', (417, 425))	('p-PP1A', 'Gene', (344, 350))	('c-Myc', 'Gene', '4609', (227, 232))	('p65', 'Gene', '5970', (269, 272))	('#18338', 'Var', (321, 327))
23773	31856384	As stated in several reports, the isocitrate dehydrogenase 1/2 (IDH1/2) mutation, methylation of O-methylguanine-DNA methyltransferase (MGMT) promoter methylation, codeletion of 1p/19q, telomerase reverse transcriptase (TERT) loss and alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) mutation were associated with a better prognosis for glioma patients (Jiang et al., 2016; Yan et al., 2009).	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('mutation', 'Var', (298, 306))	('ATRX', 'Gene', (292, 296))	('IDH1/2', 'Gene', (64, 70))	('TERT', 'Gene', (220, 224))	('telomerase reverse transcriptase', 'Gene', (186, 218))	('TERT', 'Gene', '7015', (220, 224))	('MGMT', 'Gene', '4255', (136, 140))	('ATRX', 'Gene', '546', (292, 296))	('glioma', 'Disease', (351, 357))	('glioma', 'Disease', 'MESH:D005910', (351, 357))	('telomerase reverse transcriptase', 'Gene', '7015', (186, 218))	('O-methylguanine-DNA methyltransferase', 'Gene', (97, 134))	('alpha-thalassaemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (235, 290))	('glioma', 'Phenotype', 'HP:0009733', (351, 357))	('mental retardation', 'Phenotype', 'HP:0001249', (254, 272))	('mutation', 'Var', (72, 80))	('MGMT', 'Gene', (136, 140))	('O-methylguanine-DNA methyltransferase', 'Gene', '4255', (97, 134))	('patients', 'Species', '9606', (358, 366))	('isocitrate', 'Chemical', 'MESH:D007523', (34, 44))
23774	31856384	High BACE2 expression was related to wild-type IDH1 in glioma patients, while low BACE2 expression was associated with other features, including MGMT promoter methylation, 1p/19q codeletion, TERT loss and ATRX mutation.	('1p/19q codeletion', 'Var', (172, 189))	('associated', 'Reg', (103, 113))	('expression', 'MPA', (11, 21))	('MGMT', 'Gene', '4255', (145, 149))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('patients', 'Species', '9606', (62, 70))	('expression', 'MPA', (88, 98))	('IDH1', 'Gene', (47, 51))	('low', 'NegReg', (78, 81))	('MGMT', 'Gene', (145, 149))	('BACE2', 'Gene', (5, 10))	('IDH1', 'Gene', '3417', (47, 51))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('glioma', 'Disease', (55, 61))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('BACE2', 'Gene', (82, 87))	('ATRX', 'Gene', (205, 209))	('ATRX', 'Gene', '546', (205, 209))
23775	31856384	Thus, based on the above results, we suggest that high BACE2 expression indicates a worse prognosis for glioma patients.	('BACE2', 'Gene', (55, 60))	('glioma', 'Disease', (104, 110))	('expression', 'MPA', (61, 71))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('high', 'Var', (50, 54))	('patients', 'Species', '9606', (111, 119))
23776	31856384	We found that the LGG and GBM patients with high BACE2 expression had a worse prognosis than patients with low BACE2 expression in the TCGA database (Fig.	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (44, 48))	('patients', 'Species', '9606', (93, 101))	('BACE2', 'Gene', (49, 54))
23783	31856384	Finally, GSEA revealed that high BACE2 expression was statistically associated with epithelial-mesenchymal transition (EMT), tumour invasion, tumour metastasis and the regulation of the G1-S phase transition in the cell cycle (Fig.	('tumour invasion', 'Disease', (125, 140))	('associated', 'Reg', (68, 78))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('BACE2', 'Gene', (33, 38))	('tumour metastasis', 'Disease', (142, 159))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('epithelial-mesenchymal transition', 'CPA', (84, 117))	('tumour invasion', 'Disease', 'MESH:D009361', (125, 140))	('tumour metastasis', 'Disease', 'MESH:D009362', (142, 159))
23784	31856384	Furthermore, we performed RNA-seq in U87MG cells and BACE2-knockdown U87MG cells.	('U87MG', 'CellLine', 'CVCL:0022', (69, 74))	('U87MG', 'CellLine', 'CVCL:0022', (37, 42))	('BACE2-knockdown', 'Gene', (53, 68))	('BACE2-knockdown', 'Var', (53, 68))
23785	31856384	A total of 451 genes were specifically downregulated, while 623 were specifically upregulated in BACE2-knockdown U87MG cells compared to U87MG cells (Fig.	('upregulated', 'PosReg', (82, 93))	('U87MG', 'CellLine', 'CVCL:0022', (113, 118))	('U87MG', 'CellLine', 'CVCL:0022', (137, 142))	('U87MG', 'Var', (113, 118))	('BACE2-knockdown', 'Gene', (97, 112))	('downregulated', 'NegReg', (39, 52))
23790	31856384	Compared to that in the control group, the invaded area was significantly reduced by knocking down BACE2 with single siRNA in the U87MG and U251 spheroids (Fig.	('U251', 'CellLine', 'CVCL:0021', (140, 144))	('U87MG', 'CellLine', 'CVCL:0022', (130, 135))	('invaded area', 'CPA', (43, 55))	('BACE2', 'Gene', (99, 104))	('reduced', 'NegReg', (74, 81))	('knocking down', 'Var', (85, 98))
23792	31856384	First, BACE2 silencing led to glioma cell morphological transformation.	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('glioma', 'Disease', (30, 36))	('led to', 'Reg', (23, 29))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('silencing', 'Var', (13, 22))	('BACE2', 'Gene', (7, 12))
23794	31856384	Furthermore, BACE2 silencing caused a significant decrease in several mesenchymal subtype markers (N-cadherin, beta-catenin, Vimentin), upstream transcription factors (Snail, Twist) and MMP2 and an increase in an epithelial marker (E-cadherin) compared to the control cells (Fig.	('mesenchymal', 'CPA', (70, 81))	('epithelial', 'MPA', (213, 223))	('N-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', (232, 242))	('beta-catenin', 'Gene', (111, 123))	('N-cadherin', 'Gene', '1000', (99, 109))	('increase', 'PosReg', (198, 206))	('silencing', 'Var', (19, 28))	('Vimentin', 'Gene', (125, 133))	('Snail', 'Gene', '6615', (168, 173))	('Snail', 'Gene', (168, 173))	('E-cadherin', 'Gene', '999', (232, 242))	('MMP2', 'Gene', (186, 190))	('beta-catenin', 'Gene', '1499', (111, 123))	('Vimentin', 'Gene', '7431', (125, 133))	('BACE2', 'Gene', (13, 18))	('MMP2', 'Gene', '4313', (186, 190))	('decrease', 'NegReg', (50, 58))
23797	31856384	First, BACE2 silencing significantly decreased the percentage of positive cells compared with the control group for both the U87MG and U251 cells, and the percentage of positive cells in the BACE2-LentiOV group was higher than that in the BACE2-LentiNC group (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (125, 130))	('U251', 'CellLine', 'CVCL:0021', (135, 139))	('decreased', 'NegReg', (37, 46))	('silencing', 'Var', (13, 22))	('BACE2', 'Gene', (7, 12))
23803	31856384	Based on the GSEA, high BACE2 expression is involved in activating the NF-kappaB signalling pathway (Fig.	('high', 'Var', (19, 23))	('NF-kappaB', 'Gene', (71, 80))	('activating', 'PosReg', (56, 66))	('BACE2', 'Gene', (24, 29))	('NF-kappaB', 'Gene', '4790', (71, 80))
23804	31856384	It is well known that phosphorylation of p65 initiates activation of the canonical NF-kappaB signalling pathway.	('NF-kappaB', 'Gene', '4790', (83, 92))	('phosphorylation', 'Var', (22, 37))	('p65', 'Gene', (41, 44))	('NF-kappaB', 'Gene', (83, 92))	('p65', 'Gene', '5970', (41, 44))	('activation', 'PosReg', (55, 65))
23806	31856384	The levels of p-p65 and p65 were determined in transfected glioma cells, and knocking down BACE2 led to p-p65 downregulation (Fig.	('p65', 'Gene', (16, 19))	('glioma', 'Disease', (59, 65))	('p65', 'Gene', '5970', (16, 19))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('p65', 'Gene', '5970', (106, 109))	('p65', 'Gene', (106, 109))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('BACE2', 'Gene', (91, 96))	('p65', 'Gene', (24, 27))	('downregulation', 'NegReg', (110, 124))	('knocking down', 'Var', (77, 90))	('p65', 'Gene', '5970', (24, 27))
23807	31856384	Next, the BACE2-LentiOV group was treated with IMD0354, an inhibitor of NF-kappaB signalling.	('NF-kappaB', 'Gene', '4790', (72, 81))	('IMD0354', 'Var', (47, 54))	('IMD0354', 'Chemical', 'MESH:C492919', (47, 54))	('NF-kappaB', 'Gene', (72, 81))
23814	31856384	Initially, knocking down BACE2 decreased the expression of NF-kappaB downstream genes, including IKBalpha, A20 and IL-8 (Fig.	('A20', 'Gene', (107, 110))	('BACE2', 'Gene', (25, 30))	('IL-8', 'Gene', (115, 119))	('knocking down', 'Var', (11, 24))	('IKBalpha', 'Gene', '4792', (97, 105))	('NF-kappaB', 'Gene', '4790', (59, 68))	('decreased', 'NegReg', (31, 40))	('IKBalpha', 'Gene', (97, 105))	('expression', 'MPA', (45, 55))	('NF-kappaB', 'Gene', (59, 68))	('A20', 'Gene', '28935', (107, 110))	('IL-8', 'Gene', '3576', (115, 119))
23815	31856384	Furthermore, BACE2 knockdown suppressed the phosphorylation of IKKbeta induced by TNF-alpha in glioma cells (Fig.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('phosphorylation', 'MPA', (44, 59))	('IKKbeta', 'Gene', '1147', (63, 70))	('knockdown', 'Var', (19, 28))	('IKKbeta', 'Gene', (63, 70))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('TNF-alpha', 'Gene', '7124', (82, 91))	('TNF-alpha', 'Gene', (82, 91))	('BACE2', 'Gene', (13, 18))	('suppressed', 'NegReg', (29, 39))
23816	31856384	As IKBalpha and p65 are IKK substrates, we examined the phosphorylation of IKBalpha and p65 and found that knocking down BACE2 inhibited TNF-alpha-induced p-IKBalpha and p-p65 (Fig.	('p65', 'Gene', (16, 19))	('p65', 'Gene', '5970', (172, 175))	('p65', 'Gene', (88, 91))	('IKBalpha', 'Gene', (75, 83))	('knocking down', 'Var', (107, 120))	('BACE2', 'Gene', (121, 126))	('IKBalpha', 'Gene', (157, 165))	('IKBalpha', 'Gene', '4792', (75, 83))	('IKBalpha', 'Gene', (3, 11))	('p65', 'Gene', '5970', (16, 19))	('IKBalpha', 'Gene', '4792', (157, 165))	('inhibited', 'NegReg', (127, 136))	('p65', 'Gene', '5970', (88, 91))	('IKBalpha', 'Gene', '4792', (3, 11))	('p65', 'Gene', (172, 175))	('TNF-alpha', 'Gene', '7124', (137, 146))	('TNF-alpha', 'Gene', (137, 146))
23817	31856384	In agreement with this finding, BACE2 knockdown suppressed TNF-alpha-stimulated import of p65 into the nucleus (Fig.	('TNF-alpha', 'Gene', (59, 68))	('p65', 'Gene', '5970', (90, 93))	('BACE2', 'Gene', (32, 37))	('suppressed', 'NegReg', (48, 58))	('p65', 'Gene', (90, 93))	('knockdown', 'Var', (38, 47))	('TNF-alpha', 'Gene', '7124', (59, 68))
23822	31856384	After BACE2 was knocked down, the expression of p-PP1A decreased in both the U87MG and U251 cell lines (Fig.	('expression', 'MPA', (34, 44))	('U251', 'CellLine', 'CVCL:0021', (87, 91))	('U87MG', 'CellLine', 'CVCL:0022', (77, 82))	('decreased', 'NegReg', (55, 64))	('p-PP1A', 'Gene', (48, 54))	('BACE2', 'Gene', (6, 11))	('knocked down', 'Var', (16, 28))	('p-PP1A', 'Gene', '5499', (48, 54))
23824	31856384	We found that PP1A knockdown reversed BACE2 silencing and prevented TNF-alpha from inducing NF-kappaB activation through the PP1A/IKK pathway (Fig.	('NF-kappaB', 'Gene', (92, 101))	('TNF-alpha', 'Gene', (68, 77))	('PP1A', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('inducing', 'Reg', (83, 91))	('prevented', 'NegReg', (58, 67))	('PP1A', 'Gene', (125, 129))	('activation', 'PosReg', (102, 112))	('PP1A', 'Gene', '5499', (14, 18))	('BACE2', 'Protein', (38, 43))	('silencing', 'NegReg', (44, 53))	('PP1A', 'Gene', '5499', (125, 129))	('TNF-alpha', 'Gene', '7124', (68, 77))	('NF-kappaB', 'Gene', '4790', (92, 101))
23831	31856384	Through western blot analysis, we observed that knocking down BACE2 suppressed EMT stimulated by TGFbeta1 (10 ng mL-1) in both U87MG and U251 cells, which indicated that BACE2 may be stimulated by TGFbeta1 in glioma cells (Fig.	('EMT', 'CPA', (79, 82))	('TGFbeta1', 'Gene', (197, 205))	('knocking down', 'Var', (48, 61))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('suppressed', 'NegReg', (68, 78))	('mL-1', 'Gene', '16728', (113, 117))	('mL-1', 'Gene', (113, 117))	('glioma', 'Disease', (209, 215))	('TGFbeta1', 'Gene', '7040', (97, 105))	('TGFbeta1', 'Gene', (97, 105))	('U87MG', 'CellLine', 'CVCL:0022', (127, 132))	('U251', 'CellLine', 'CVCL:0021', (137, 141))	('TGFbeta1', 'Gene', '7040', (197, 205))	('BACE2', 'Gene', (62, 67))
23841	31856384	The protein levels of N-cadherin, Ki-67 and BACE2 were lower in the sh-BACE2 group (Fig.	('Ki-67', 'Gene', (34, 39))	('protein levels', 'MPA', (4, 18))	('N-cadherin', 'Gene', '1000', (22, 32))	('sh-BACE2', 'Var', (68, 76))	('lower', 'NegReg', (55, 60))	('N-cadherin', 'Gene', (22, 32))	('Ki-67', 'Gene', '17345', (34, 39))	('BACE2', 'MPA', (44, 49))
23845	31856384	In contrast, lower BACE2 expression was associated with active prognostic markers, including IDH mutation, MGMT promoter methylation, 1p/19q codeletion, TERT loss and ATRX mutation.	('ATRX', 'Gene', (167, 171))	('TERT', 'Gene', '7015', (153, 157))	('lower', 'NegReg', (13, 18))	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('expression', 'MPA', (25, 35))	('IDH', 'Gene', (93, 96))	('ATRX', 'Gene', '546', (167, 171))	('BACE2', 'Gene', (19, 24))	('IDH', 'Gene', '3417', (93, 96))	('1p/19q codeletion', 'Var', (134, 151))	('TERT', 'Gene', (153, 157))
23853	31856384	By immunofluorescence, we found that knocking down BACE2 led to F-actin cytoskeletal changes in gliomas.	('BACE2', 'Gene', (51, 56))	('F-actin cytoskeletal changes', 'MPA', (64, 92))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('knocking down', 'Var', (37, 50))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
23854	31856384	This finding suggested that knocking down BACE2 reduced the formation of invadopodia by suppressing the F-actin-rich edge in glioma cells.	('F-actin-rich edge', 'MPA', (104, 121))	('glioma', 'Disease', (125, 131))	('knocking down', 'Var', (28, 41))	('suppressing', 'NegReg', (88, 99))	('formation', 'MPA', (60, 69))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('reduced', 'NegReg', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('BACE2', 'Gene', (42, 47))
23858	31856384	Silencing of BACE2 in glioma cells led to cell cycle arrest at G0-G1 and suppressed tumour growth in xenograft mice, while BACE2 overexpression decreased the proportion of cells in the G0-G1 phase of the cell cycle.	('tumour', 'Disease', (84, 90))	('cell cycle arrest', 'CPA', (42, 59))	('glioma', 'Disease', (22, 28))	('mice', 'Species', '10090', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('suppressed', 'NegReg', (73, 83))	('BACE2', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
23861	31856384	We found that BACE2 knockdown led to significantly decreased levels of p-p65 and key tumour promoters, namely CDK2, CDK4, cyclin D1 and c-Myc.	('p65', 'Gene', '5970', (73, 76))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('c-Myc', 'Gene', '4609', (136, 141))	('tumour', 'Disease', (85, 91))	('CDK2', 'Gene', (110, 114))	('decreased', 'NegReg', (51, 60))	('cyclin D1', 'Gene', '595', (122, 131))	('levels', 'MPA', (61, 67))	('CDK4', 'Gene', (116, 120))	('CDK4', 'Gene', '1019', (116, 120))	('CDK2', 'Gene', '1017', (110, 114))	('cyclin D1', 'Gene', (122, 131))	('knockdown', 'Var', (20, 29))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('BACE2', 'Gene', (14, 19))	('p65', 'Gene', (73, 76))	('c-Myc', 'Gene', (136, 141))
23870	31856384	Moreover, silencing of BACE2 prevented TNF-alpha-induced activation of NF-kappaB.	('NF-kappaB', 'Gene', (71, 80))	('activation', 'PosReg', (57, 67))	('BACE2', 'Gene', (23, 28))	('NF-kappaB', 'Gene', '4790', (71, 80))	('TNF-alpha', 'Gene', (39, 48))	('TNF-alpha', 'Gene', '7124', (39, 48))	('prevented', 'NegReg', (29, 38))	('silencing', 'Var', (10, 19))
23871	31856384	We found that BACE2 knockdown prevented the phosphorylation of IKKbeta and IKBalpha as well as p65 and that the degradation of IKBalpha was induced by TNF-alpha.	('p65', 'Gene', (95, 98))	('IKBalpha', 'Gene', (127, 135))	('phosphorylation', 'MPA', (44, 59))	('IKBalpha', 'Gene', (75, 83))	('prevented', 'NegReg', (30, 39))	('TNF-alpha', 'Gene', '7124', (151, 160))	('IKKbeta', 'Gene', '1147', (63, 70))	('IKKbeta', 'Gene', (63, 70))	('TNF-alpha', 'Gene', (151, 160))	('IKBalpha', 'Gene', '4792', (75, 83))	('p65', 'Gene', '5970', (95, 98))	('IKBalpha', 'Gene', '4792', (127, 135))	('knockdown', 'Var', (20, 29))	('degradation', 'MPA', (112, 123))	('BACE2', 'Gene', (14, 19))
23874	31856384	As expected, the PP1A knockdown reversed the downregulation of BACE2 by inhibiting the TNF-alpha-induced activation of NF-kappaB.	('TNF-alpha', 'Gene', '7124', (87, 96))	('TNF-alpha', 'Gene', (87, 96))	('NF-kappaB', 'Gene', '4790', (119, 128))	('PP1A', 'Gene', '5499', (17, 21))	('inhibiting', 'NegReg', (72, 82))	('NF-kappaB', 'Gene', (119, 128))	('knockdown', 'Var', (22, 31))	('downregulation', 'NegReg', (45, 59))	('BACE2', 'Gene', (63, 68))	('PP1A', 'Gene', (17, 21))	('activation', 'MPA', (105, 115))
23882	31856384	Furthermore, silencing of Smad2 in the presence of TGFbeta1 could also suppress the induction of BACE2 in U87MG and U251 cells.	('Smad2', 'Gene', '4087', (26, 31))	('BACE2', 'Gene', (97, 102))	('Smad2', 'Gene', (26, 31))	('U87MG', 'CellLine', 'CVCL:0022', (106, 111))	('TGFbeta1', 'Gene', '7040', (51, 59))	('TGFbeta1', 'Gene', (51, 59))	('suppress', 'NegReg', (71, 79))	('induction', 'MPA', (84, 93))	('U251', 'CellLine', 'CVCL:0021', (116, 120))	('silencing', 'Var', (13, 22))
23909	32436117	Related studies have found that the loss of mammalian PCL2 leads to increased self-renewal and delayed differentiation of ESCs.	('self-renewal', 'CPA', (78, 90))	('loss', 'Var', (36, 40))	('mammalian', 'Species', '9606', (44, 53))	('delayed differentiation', 'CPA', (95, 118))	('increased', 'PosReg', (68, 77))
23912	32436117	Cases of GBM with H3F3AK27 mutations show high frequency of TP53 mutations, hypomethylation of DNA, midline location and spread of diffuse pontine glioma, and poor prognosis.	('mutations', 'Var', (27, 36))	('H3F3A', 'Gene', '3020', (18, 23))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('hypomethylation', 'Var', (76, 91))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('TP53', 'Gene', '7157', (60, 64))	('H3F3A', 'Gene', (18, 23))	('glioma', 'Disease', (147, 153))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
23913	32436117	Mutations in these genes are closely related to the alternate expansions of specific gene expression profiles, leading to the formation of gliomas.	('leading to', 'Reg', (111, 121))	('gliomas', 'Disease', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))
23966	32436117	In the colony formation experiment, we could obviously see that the number of colonies was reduced after DZNeP treatment (Fig.	('DZNeP treatment', 'Var', (105, 120))	('reduced', 'NegReg', (91, 98))	('DZNeP', 'Chemical', 'MESH:C048460', (105, 110))
23967	32436117	We demonstrated that in U87 cells, DZNeP reduced the increases in the EZH2 protein level caused by hPCL2 expressions and the protein expression of SUZ12 and EED in PRC2 were reduced compared to that in the control (Fig.	('hPCL2', 'Gene', '22823', (99, 104))	('reduced', 'NegReg', (41, 48))	('SUZ12', 'Gene', '23512', (147, 152))	('PRC2', 'Gene', (164, 168))	('hPCL2', 'Gene', (99, 104))	('U87', 'Gene', '641648', (24, 27))	('DZNeP', 'Chemical', 'MESH:C048460', (35, 40))	('SUZ12', 'Gene', (147, 152))	('protein expression', 'MPA', (125, 143))	('increases', 'PosReg', (53, 62))	('EZH2', 'Gene', '2146', (70, 74))	('U87', 'Gene', (24, 27))	('DZNeP', 'Var', (35, 40))	('EZH2', 'Gene', (70, 74))	('reduced', 'NegReg', (174, 181))	('expressions', 'MPA', (105, 116))
23974	32436117	The phenotypes associated with PCL mutations in Drosophila and Xenopus, as well as the colocalization and interaction of PCLs and PRC2, suggest that PCL proteins play a crucial role in PRC2 function.	('Xenopus', 'Species', '8355', (63, 70))	('interaction', 'Interaction', (106, 117))	('PCL', 'Gene', (31, 34))	('Drosophila', 'Species', '7227', (48, 58))	('mutations', 'Var', (35, 44))
23985	32436117	Interestingly, shRNA-mediated inhibition of PRC2 subunit EED, SUZ12, or EZH1/EZH2 causes leukemia cells to stop proliferation and differentiation.	('EZH2', 'Gene', (77, 81))	('inhibition', 'Var', (30, 40))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('leukemia', 'Disease', 'MESH:D007938', (89, 97))	('SUZ12', 'Gene', '23512', (62, 67))	('leukemia', 'Disease', (89, 97))	('SUZ12', 'Gene', (62, 67))	('EZH1', 'Gene', (72, 76))	('EZH2', 'Gene', '2146', (77, 81))	('stop proliferation', 'CPA', (107, 125))	('EZH1', 'Gene', '2145', (72, 76))
23987	32436117	Studies have shown that the absence of EED can lead to abnormal differentiation and functional defects of hematopoietic stem cells (HSPCs).It has been reported in the literature that CRISPR/Cas9-mediated SUZ12 inactivation and mutant JAK3 synergistically drive T cell transformation and T-cell acute lymphoblastic leukemia (T-ALL) development.	('inactivation', 'NegReg', (210, 222))	('mutant', 'Var', (227, 233))	('T cell transformation', 'CPA', (261, 282))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (294, 322))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (287, 322))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (287, 322))	('T-cell acute lymphoblastic leukemia', 'Disease', (287, 322))	('SUZ12', 'Gene', '23512', (204, 209))	('SUZ12', 'Gene', (204, 209))	('drive', 'PosReg', (255, 260))	('leukemia', 'Phenotype', 'HP:0001909', (314, 322))	('JAK3', 'Gene', (234, 238))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (300, 322))	('JAK3', 'Gene', '3718', (234, 238))
23988	32436117	In contrast, in the study of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), it was found that shRNA-mediated SUZ12 knock-down significantly inhibited tumor cell proliferation, migration and invasion.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('head', 'Disease', (29, 33))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (29, 66))	('inhibited', 'NegReg', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('SUZ12', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('SUZ12', 'Gene', '23512', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('non-small cell lung cancer', 'Disease', (79, 105))	('knock-down', 'Var', (154, 164))	('NSCLC', 'Disease', (107, 112))	('neck squamous cell carcinoma', 'Disease', (38, 66))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (38, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('HNSC', 'Disease', 'None', (68, 72))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('tumor', 'Disease', (189, 194))	('invasion', 'CPA', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('HNSC', 'Disease', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
23993	32436117	H3K9 and H3K27 methylation are related to gene silencing, while H3K4 methylation can activate genes.	('gene', 'MPA', (42, 46))	('H3', 'Gene', '126961', (9, 11))	('methylation', 'Var', (15, 26))	('H3', 'Gene', '126961', (64, 66))	('activate', 'PosReg', (85, 93))	('H3', 'Gene', '126961', (0, 2))
23998	32436117	It has been suggested in the latest research that the mutant H3K27, which is a lethal subunit of glioma, appears in the normal H3.	('H3', 'Gene', '126961', (61, 63))	('glioma', 'Disease', (97, 103))	('H3', 'Gene', '126961', (127, 129))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('mutant', 'Var', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
23999	32436117	The ability, recruiting target genes on chromatin by PRC2, does not seem to be affected by the H3K27 mutation, but the transcription will be restricted if the deposition of H3K27me3 and me2 in the whole genome is depleted, and results in affecting gene expression of regulating neurogenesis.	('affecting', 'Reg', (238, 247))	('restricted', 'NegReg', (141, 151))	('regulating neurogenesis', 'CPA', (267, 290))	('me2', 'Gene', '4200', (186, 189))	('deposition', 'MPA', (159, 169))	('H3', 'Gene', '126961', (95, 97))	('me2', 'Gene', (186, 189))	('transcription', 'MPA', (119, 132))	('me3', 'Gene', '109264', (178, 181))	('depleted', 'NegReg', (213, 221))	('gene expression', 'MPA', (248, 263))	('mutation', 'Var', (101, 109))	('H3', 'Gene', '126961', (173, 175))	('me3', 'Gene', (178, 181))
24008	32436117	We found that the expression of PCL2 increased the protein level of EZH2, while DZNeP inhibited the expression of EZH2.	('EZH2', 'Gene', (68, 72))	('DZNeP', 'Chemical', 'MESH:C048460', (80, 85))	('PCL2', 'Gene', (32, 36))	('protein level', 'MPA', (51, 64))	('expression', 'Var', (18, 28))	('increased', 'PosReg', (37, 46))	('EZH2', 'Gene', '2146', (114, 118))	('EZH2', 'Gene', '2146', (68, 72))	('EZH2', 'Gene', (114, 118))
24061	32328184	The strongest association between mutations and expression changes was observed for DRG2 and LRCC41 gene in GBMs and LGGs, respectively.	('LGGs', 'Disease', (117, 121))	('expression', 'MPA', (48, 58))	('DRG2', 'Gene', (84, 88))	('GBMs', 'Disease', (108, 112))	('DRG2', 'Gene', '1819', (84, 88))	('LRCC41', 'Gene', (93, 99))	('mutations', 'Var', (34, 43))
24063	32328184	Conclusion: Our study results revealed the influences of driver gene mutations on global gene expression in diffuse glioma patients.	('mutations', 'Var', (69, 78))	('glioma', 'Disease', (116, 122))	('patients', 'Species', '9606', (123, 131))	('global gene expression', 'MPA', (82, 104))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
24076	32328184	The majority (i.e., 54-83%) of GBMs contain mutations in TERT promoter and are also commonly observed in oligodendrogliomas but rare in grade II or III astrocytomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (105, 123))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('GBMs', 'Gene', (31, 35))	('oligodendrogliomas', 'Disease', (105, 123))	('astrocytomas', 'Disease', 'MESH:D001254', (152, 164))	('mutations', 'Var', (44, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (152, 163))	('contain', 'Reg', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('astrocytomas', 'Disease', (152, 164))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('observed', 'Reg', (93, 101))
24077	32328184	The IDH mutations are commonly observed in secondary GBMs (about 80%) and grade II-III diffuse gliomas (about 65-80%), while only about 5% of primary GBMs carry this type of mutation.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH', 'Gene', '3417', (4, 7))	('mutations', 'Var', (8, 17))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('observed', 'Reg', (31, 39))	('secondary GBMs', 'Disease', (43, 57))	('IDH', 'Gene', (4, 7))
24078	32328184	IDH1 mutations are more commonly (>90%) observed in diffuse gliomas than IDH2 mutations, but are generally mutually exclusive.	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('observed', 'Reg', (40, 48))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', (60, 67))	('IDH2', 'Gene', (73, 77))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('IDH2', 'Gene', '3418', (73, 77))	('IDH1', 'Gene', '3417', (0, 4))
24094	32328184	More specifically, the GBM patients with NF1 and IDH1 mutations were in opposite directions, suggesting the differences in the transcriptomic patterns of these two subtypes of patients (Figure S2a).	('patients', 'Species', '9606', (176, 184))	('IDH1', 'Gene', '3417', (49, 53))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (27, 35))	('NF1', 'Gene', (41, 44))	('differences', 'Reg', (108, 119))	('NF1', 'Gene', '4763', (41, 44))	('IDH1', 'Gene', (49, 53))
24095	32328184	For LGG patients, patients with IDH1 mutations or 1p/19q codeletion have similar PCA projections, indicating the similarity of the transcriptomic pattern (Figure S2b).	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (18, 26))	('1p/19q', 'Var', (50, 56))	('PCA', 'Disease', (81, 84))	('patients', 'Species', '9606', (8, 16))
24097	32328184	The transcriptome of glioma is globally perturbed by genetic and cytogenetic driver mutations.	('transcriptome', 'MPA', (4, 17))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('perturbed', 'Reg', (40, 49))	('mutations', 'Var', (84, 93))	('glioma', 'Disease', (21, 27))
24099	32328184	For GBMs, the strongest association reached R2=72% between mutations and expression changes for the gene DRG2 (Figure 2c).	('DRG2', 'Gene', '1819', (105, 109))	('mutations', 'Var', (59, 68))	('expression', 'MPA', (73, 83))	('DRG2', 'Gene', (105, 109))
24100	32328184	The observed variability can be largely explained by the presence of IDH1 mutations, leading to the downregulation of DRG2 gene expression.	('IDH1', 'Gene', '3417', (69, 73))	('mutations', 'Var', (74, 83))	('DRG2', 'Gene', '1819', (118, 122))	('DRG2', 'Gene', (118, 122))	('downregulation', 'NegReg', (100, 114))	('expression', 'MPA', (128, 138))	('IDH1', 'Gene', (69, 73))
24101	32328184	For LGGs, the strongest association reached R2=76% between mutations and expression changes for the gene LRRC41 (Figure 2d).	('expression', 'MPA', (73, 83))	('LRRC41', 'Gene', '10489', (105, 111))	('LRRC41', 'Gene', (105, 111))	('mutations', 'Var', (59, 68))
24102	32328184	The presence of 1p19q co-deletion might explain the downregulation of LRRC41 gene expression.	('expression', 'MPA', (82, 92))	('LRRC41', 'Gene', '10489', (70, 76))	('downregulation', 'NegReg', (52, 66))	('1p19q co-deletion', 'Var', (16, 33))	('LRRC41', 'Gene', (70, 76))
24103	32328184	For example, IDH1 mutations showed an independent correlation with the expression levels of 804 genes, whereas PTEN mutations showed association only with altered expression levels of 35 genes in GBM samples.	('PTEN', 'Gene', (111, 115))	('PTEN', 'Gene', '5728', (111, 115))	('correlation', 'Reg', (50, 61))	('IDH1', 'Gene', (13, 17))	('IDH1', 'Gene', '3417', (13, 17))	('expression levels', 'MPA', (71, 88))	('mutations', 'Var', (18, 27))
24104	32328184	Similarly, in LGG samples, IDH1 and IDH2 mutations were independently correlated with most of the gene expression level changes (2871 genes and 2713 genes, respectively).	('IDH2', 'Gene', (36, 40))	('mutations', 'Var', (41, 50))	('IDH2', 'Gene', '3418', (36, 40))	('IDH1', 'Gene', (27, 31))	('gene expression level changes', 'MPA', (98, 127))	('IDH1', 'Gene', '3417', (27, 31))	('correlated', 'Reg', (70, 80))
24105	32328184	However, the DEGs induced by EGFR mutations were located on 19 chromosomes (75/241, 31.1%), while those induced by TERT promoter mutations were located on 6 chromosomes (19/47, 40.4%) in GBM samples (Figure S3a).	('TERT', 'Gene', '7015', (115, 119))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('TERT', 'Gene', (115, 119))
24108	32328184	For the driver gene itself, the NF1, RB1, PIK3R1, and TP53 mutants in patients demonstrated significantly lower levels of expression when compared with wild-type in GBM and lower expression levels of FUBP1, NF1, PTEN, and IDH1 in mutant patients in LGG (Figure S4).	('expression', 'MPA', (122, 132))	('NF1', 'Gene', (207, 210))	('NF1', 'Gene', (32, 35))	('PTEN', 'Gene', '5728', (212, 216))	('FUBP1', 'Gene', (200, 205))	('patients', 'Species', '9606', (237, 245))	('patients', 'Species', '9606', (70, 78))	('lower', 'NegReg', (106, 111))	('mutants', 'Var', (59, 66))	('PIK3R1', 'Gene', (42, 48))	('IDH1', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (54, 58))	('RB1', 'Gene', (37, 40))	('expression levels', 'MPA', (179, 196))	('mutant', 'Var', (230, 236))	('FUBP1', 'Gene', '8880', (200, 205))	('IDH1', 'Gene', '3417', (222, 226))	('RB1', 'Gene', '5925', (37, 40))	('PIK3R1', 'Gene', '5295', (42, 48))	('NF1', 'Gene', '4763', (207, 210))	('NF1', 'Gene', '4763', (32, 35))	('PTEN', 'Gene', (212, 216))	('levels', 'MPA', (112, 118))	('lower', 'NegReg', (173, 178))	('LGG', 'Disease', (249, 252))	('TP53', 'Gene', (54, 58))
24109	32328184	In contrast, the expression level of EGFR was highly expressed when mutated (Figure S4).	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutated', 'Var', (68, 75))	('expression level', 'MPA', (17, 33))
24111	32328184	For example, a strong predictive value for purity in GBMs was found and the two strongest predictors included PC1 from gene expression data and presence of Chr7 gain and Chr10 loss (Figure 3a and Figure S5).	('Chr7', 'Gene', (156, 160))	('loss', 'NegReg', (176, 180))	('PC1', 'Gene', (110, 113))	('Chr10', 'Gene', (170, 175))	('PC1', 'Gene', '5167', (110, 113))	('presence', 'Var', (144, 152))	('gain', 'PosReg', (161, 165))
24113	32328184	Consistently, we found the association between the presence of 1p19q codeletion and oligodendroglioma (Figure 3b).	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('oligodendroglioma', 'Disease', (84, 101))	('oligodendroglioma', 'Disease', 'MESH:D009837', (84, 101))	('1p19q codeletion', 'Var', (63, 79))	('presence', 'Var', (51, 59))
24121	32328184	IDH1, and EGFR mutations in the genetics class and the presence of chr7 gain and chr10 loss in the cytogenetics class were also the major contributors of survival risk (Figure S7b).	('loss', 'NegReg', (87, 91))	('EGFR', 'Gene', '1956', (10, 14))	('S7', 'Gene', '6264', (176, 178))	('EGFR', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('gain', 'PosReg', (72, 76))	('chr10', 'Gene', (81, 86))	('IDH1', 'Gene', (0, 4))	('chr7', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (0, 4))
24129	32328184	Indeed, for both GBMs and LGGs, the IDH mutations induced most of the gene expression changes, confirming the core role of IDH mutations in glioma pathogenesis.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('IDH', 'Gene', (123, 126))	('gene expression changes', 'MPA', (70, 93))	('IDH', 'Gene', (36, 39))	('mutations', 'Var', (40, 49))	('IDH', 'Gene', '3417', (36, 39))	('glioma', 'Disease', (140, 146))	('IDH', 'Gene', '3417', (123, 126))
24130	32328184	Moreover, our data revealed a difference in the impact of driver mutations on GBMs or LGGs, which included RB1 mutations for GBMs and PTEN, ATRX, and CIC mutations for LGGs.	('mutations', 'Var', (111, 120))	('ATRX', 'Gene', (140, 144))	('RB1', 'Gene', (107, 110))	('CIC', 'Gene', '23152', (150, 153))	('RB1', 'Gene', '5925', (107, 110))	('CIC', 'Gene', (150, 153))	('ATRX', 'Gene', '546', (140, 144))	('mutations', 'Var', (154, 163))	('PTEN', 'Gene', (134, 138))	('PTEN', 'Gene', '5728', (134, 138))
24133	32328184	Although our methods of model-building did not provide us the exact mechanism on the level of molecular biology as to how the mutation of a certain driver gene affects the expression of other genes, our work showed a connection between mutation and transcriptome, providing a theoretical basis for further experiments in gliomas.	('affects', 'Reg', (160, 167))	('gliomas', 'Disease', 'MESH:D005910', (321, 328))	('gliomas', 'Phenotype', 'HP:0009733', (321, 328))	('gliomas', 'Disease', (321, 328))	('mutation', 'Var', (126, 134))	('expression', 'MPA', (172, 182))	('glioma', 'Phenotype', 'HP:0009733', (321, 327))
24134	32328184	By taking DRG2 as an example, significantly lower expression in GBM patients with IDH1 or TP53 mutation, and significantly lower expression level of LRRC41 were observed when there is 1p/19q co-deletion in LGG patients.	('lower', 'NegReg', (44, 49))	('DRG2', 'Gene', (10, 14))	('LRRC41', 'Gene', (149, 155))	('DRG2', 'Gene', '1819', (10, 14))	('lower', 'NegReg', (123, 128))	('TP53', 'Gene', '7157', (90, 94))	('IDH1', 'Gene', (82, 86))	('patients', 'Species', '9606', (68, 76))	('expression level', 'MPA', (129, 145))	('TP53', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (82, 86))	('patients', 'Species', '9606', (210, 218))	('expression', 'MPA', (50, 60))	('LRRC41', 'Gene', '10489', (149, 155))	('mutation', 'Var', (95, 103))
24135	32328184	Most of the driver genes of glioma showed decreased expression when mutated but not for EGFR.	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('decreased', 'NegReg', (42, 51))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glioma', 'Disease', (28, 34))	('expression', 'MPA', (52, 62))	('EGFR', 'Gene', '1956', (88, 92))	('mutated', 'Var', (68, 75))	('EGFR', 'Gene', (88, 92))
24136	32328184	As a known oncogene of glioma, EGFR overexpression usually occurs as a result of copy number amplification, while in other cases where there is no copy number variation, EGFR has the ability for ligand- independent activation by some point mutations or frame-shifting insertions/deletions.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('EGFR', 'Gene', '1956', (31, 35))	('copy number', 'Var', (81, 92))	('overexpression', 'PosReg', (36, 50))	('activation', 'PosReg', (215, 225))	('frame-shifting insertions/deletions', 'Var', (253, 288))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', (31, 35))	('point mutations', 'Var', (234, 249))	('insertions/deletions', 'Var', (268, 288))	('glioma', 'Disease', (23, 29))	('EGFR', 'Gene', (170, 174))
24138	32328184	Point mutations of EGFR, promoter of TERT, PI3KR1, and KMT2D affects genes on chromosomes 19 and 6, which are not the chromosomes they originated from.	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('affects', 'Reg', (61, 68))	('KMT2D', 'Gene', '8085', (55, 60))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))	('Point mutations', 'Var', (0, 15))	('KMT2D', 'Gene', (55, 60))
24156	30627595	Whole-lesion ADC values ranged 0.225-1.240 x 10-3 mm2/s for ependymal tumors, 0.107-1.571 x 10-3 mm2/s for embryonal tumors, 0.1065-2.37801 x 10-3 mm2/s for diffuse astrocytic and oligodendroglial tumors, 0.5220-0.7840 x 10-3 mm2/s for other astrocytic tumors, and 0.1530-0.8160 x 10-3 mm2/s for meningiomas.	('mm2', 'Gene', '10687', (147, 150))	('mm2', 'Gene', '10687', (226, 229))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('embryonal tumors', 'Phenotype', 'HP:0002898', (107, 123))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('embryonal tumors', 'Disease', (107, 123))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mm2', 'Gene', '10687', (50, 53))	('embryonal tumors', 'Disease', 'MESH:D009373', (107, 123))	('meningioma', 'Phenotype', 'HP:0002858', (296, 306))	('ependymal tumors', 'Disease', (60, 76))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('meningiomas', 'Disease', 'MESH:D008577', (296, 307))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('0.5220-0.7840 x 10-3', 'Var', (205, 225))	('mm2', 'Gene', (147, 150))	('mm2', 'Gene', (226, 229))	('0.107-1.571 x 10-3', 'Var', (78, 96))	('mm2', 'Gene', '10687', (97, 100))	('meningiomas', 'Phenotype', 'HP:0002858', (296, 307))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('meningiomas', 'Disease', (296, 307))	('mm2', 'Gene', (50, 53))	('oligodendroglial tumors', 'Disease', (180, 203))	('0.1530-0.8160', 'Var', (265, 278))	('mm2', 'Gene', '10687', (286, 289))	('mm2', 'Gene', (97, 100))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (180, 203))	('ependymal tumors', 'Disease', 'MESH:D009369', (60, 76))	('astrocytic tumors', 'Disease', (242, 259))	('mm2', 'Gene', (286, 289))	('astrocytic tumors', 'Disease', 'MESH:D001254', (242, 259))
24239	30627595	The diagnosis of oligodendroglioma and anaplastic oligodendroglioma requires the presence of the isocitrate dehydrogenase (IDH) gene family mutation and whole-arm losses of both 1p and 19q.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('isocitrate dehydrogenase', 'Gene', (97, 121))	('oligodendroglioma', 'Disease', (17, 34))	('anaplastic oligodendroglioma', 'Disease', (39, 67))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('losses', 'Var', (163, 169))	('oligodendroglioma', 'Disease', 'MESH:D009837', (17, 34))	('isocitrate dehydrogenase', 'Gene', '3417', (97, 121))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (39, 67))	('mutation', 'Var', (140, 148))	('oligodendroglioma', 'Disease', (50, 67))	('oligodendroglioma', 'Disease', 'MESH:D009837', (50, 67))	('IDH', 'Gene', (123, 126))	('IDH', 'Gene', '3417', (123, 126))
24240	30627595	However, most tumors in childhood that histologically resemble oligodendroglioma often do not demonstrate isocitrate dehydrogenase gene family mutation and 1p/19q codeletion.	('oligodendroglioma', 'Disease', (63, 80))	('oligodendroglioma', 'Disease', 'MESH:D009837', (63, 80))	('1p/19q codeletion', 'Var', (156, 173))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('isocitrate dehydrogenase', 'Gene', (106, 130))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('isocitrate dehydrogenase', 'Gene', '3417', (106, 130))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
24254	28295365	For example, we found that CIC deficiency was associated with disruptions in the expression of genes involved in cell-cell adhesion, and in the development of several cell and tissue types.	('CIC deficiency', 'Disease', 'MESH:D007153', (27, 41))	('expression of', 'MPA', (81, 94))	('CIC deficiency', 'Disease', (27, 41))	('disruptions', 'Var', (62, 73))
24257	28295365	Multiple distinct CIC mutations have also been found within different regions of single lesions 1, indicating that multiple, independently arising CIC mutations may contribute to the progression of a single tumour.	('tumour', 'Disease', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('contribute', 'Reg', (165, 175))	('CIC', 'Gene', (147, 150))	('mutations', 'Var', (151, 160))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('progression', 'CPA', (183, 194))
24266	28295365	Both approaches were designed to produce insertions or deletions within exon 2, which is shared between the short (CIC-S) and long (CIC-L) CIC isoforms 33 (supplementary material, Figure S2B).	('insertions', 'Var', (41, 51))	('deletions', 'Var', (55, 64))	('CIC-S', 'Disease', 'MESH:D018455', (115, 120))	('CIC-S', 'Disease', (115, 120))
24271	28295365	Similarly, signatures significantly enriched for genes underexpressed in CIC KO lines included gene sets whose expression was found to decrease upon activation of KRAS, MEK, or MTOR, and upon knockdown of RB, E2F1, or P53 (supplementary material, Table S5C).	('P53', 'Gene', (218, 221))	('MTOR', 'Gene', (177, 181))	('KRAS', 'Gene', (163, 167))	('P53', 'Gene', '7157', (218, 221))	('expression', 'MPA', (111, 121))	('knockdown', 'Var', (192, 201))	('MEK', 'Gene', (169, 172))	('E2F1', 'Gene', '1869', (209, 213))	('E2F1', 'Gene', (209, 213))	('decrease', 'NegReg', (135, 143))	('activation', 'PosReg', (149, 159))
24279	28295365	CIC aberrations have recently begun to be associated with additional cancer types, such as sarcomas 19, 47, prostate cancer 36, and lung cancer 35.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('sarcomas 19', 'Disease', 'MESH:D012509', (91, 102))	('aberrations', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('associated', 'Reg', (42, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('sarcomas 19', 'Disease', (91, 102))	('lung cancer', 'Disease', (132, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('CIC', 'Gene', (0, 3))	('prostate cancer', 'Disease', (108, 123))
24284	28295365	Disruptions in WNT-beta-catenin signalling and EMT also complement the apparent increase in cell motility conferred by loss of CIC 35.	('Disruptions', 'Var', (0, 11))	('beta-catenin', 'Gene', '1499', (19, 31))	('increase', 'PosReg', (80, 88))	('beta-catenin', 'Gene', (19, 31))	('EMT', 'CPA', (47, 50))	('CIC 35', 'Gene', (127, 133))	('loss', 'Var', (119, 123))	('cell motility', 'CPA', (92, 105))
24292	28295365	Similarly, hypermethylation and associated decreased expression of PCDH10 60, 61, 62, PCDH8 63 and PDCH17 64, 65 have been associated with poor prognosis in gastric cancers.	('PDCH17', 'Gene', (99, 105))	('associated', 'Reg', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('hypermethylation', 'Var', (11, 27))	('gastric cancers', 'Disease', 'MESH:D013274', (157, 172))	('gastric cancers', 'Disease', (157, 172))	('gastric cancers', 'Phenotype', 'HP:0012126', (157, 172))	('PCDH10', 'Gene', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('expression', 'MPA', (53, 63))	('decreased', 'NegReg', (43, 52))	('PCDH8', 'Gene', (86, 91))	('PCDH8', 'Gene', '5100', (86, 91))
24293	28295365	Thus, loss of CIC may affect cell adhesion processes through gene expression dysregulation, which is consistent with a recent report showing that loss of CIC in lung cancer cells leads to increased metastatic potential through elevated expression of ETV4 and matrix metalloproteinase-24 (MMP24) 35.	('gene expression', 'MPA', (61, 76))	('CIC', 'Gene', (14, 17))	('loss', 'Var', (6, 10))	('cell adhesion processes', 'CPA', (29, 52))	('expression', 'MPA', (236, 246))	('loss of CIC in lung cancer', 'Disease', 'MESH:D008175', (146, 172))	('metastatic potential', 'CPA', (198, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('matrix metalloproteinase-24', 'Gene', (259, 286))	('affect', 'Reg', (22, 28))	('MMP24', 'Gene', (288, 293))	('loss of CIC in lung cancer', 'Disease', (146, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('matrix metalloproteinase-24', 'Gene', '10893', (259, 286))	('elevated', 'PosReg', (227, 235))	('increased', 'PosReg', (188, 197))	('ETV4', 'Gene', (250, 254))	('MMP24', 'Gene', '10893', (288, 293))
24294	28295365	These results are consistent with recent reports showing that loss of CIC imparts resistance to MAPK and EGFR inhibitors in various cancer-derived cell lines with activating mutations in upstream members of the pathway, including KRAS, NRAS, BRAF, and EGFR 23, 24.	('BRAF', 'Gene', '673', (242, 246))	('loss', 'Var', (62, 66))	('BRAF', 'Gene', (242, 246))	('NRAS', 'Gene', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('resistance', 'MPA', (82, 92))	('activating', 'PosReg', (163, 173))	('NRAS', 'Gene', '4893', (236, 240))	('mutations', 'Var', (174, 183))
24295	28295365	Our results thus expand on the potential roles of CIC mutations in malignancy, and may provide new insights into the possible mechanisms underlying phenotypic responses recently associated with CIC loss, such as shorter times to recurrence, increased metastatic potential, and resistance to MAPK inhibitors 9, 10, 23, 24, 35.	('increased', 'PosReg', (241, 250))	('mutations', 'Var', (54, 63))	('loss', 'NegReg', (198, 202))	('CIC', 'Gene', (194, 197))	('CIC', 'Gene', (50, 53))	('malignancy', 'Disease', 'MESH:D009369', (67, 77))	('malignancy', 'Disease', (67, 77))	('metastatic potential', 'CPA', (251, 271))
24323	27456199	We aimed to develop novel MR-based clustered images (MRcIs) using our two-level clustering approach with multiple features in conventional MRI, such as T1WI, T1WIce, T2WI, and FLAIR, and to use those images to visualize the regional glioma grading because these conventional MRIs are more familiar to neurosurgeons and are easier to understand.	('glioma', 'Disease', (233, 239))	('glioma', 'Disease', 'MESH:D005910', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('T2WI', 'Var', (166, 170))
24326	27456199	We retrospectively reviewed 36 patients, including 21 patients with HGGs and 15 patients with LGGs (Table 1), who underwent T1WI, T1WIce, T2WI, and FLAIR before tumor resection.	('T1WIce', 'Var', (130, 136))	('T1WI', 'Var', (124, 128))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (54, 62))	('T2WI', 'Var', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
24365	27456199	Further, FLAIR can be used to assess abnormalities in the white matter; however, hyperintensity on FLAIR can indicate edema and/or tumor cell infiltration.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('indicate', 'Reg', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('edema', 'Disease', 'MESH:D004487', (118, 123))	('edema', 'Phenotype', 'HP:0000969', (118, 123))	('tumor', 'Disease', (131, 136))	('hyperintensity', 'Var', (81, 95))	('edema', 'Disease', (118, 123))
24384	27456199	In addition to pathological features, genetics subtypes such as IDH1/2 mutations would be important.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('mutations', 'Var', (71, 80))	('IDH1/2', 'Gene', (64, 70))
24386	27456199	Two of 10 grade IV gliomas who were examined the sequence of the IDH1 gene revealed IDH1 mutation and eight of 10 did not reveal IDH1 mutation.	('IDH1', 'Gene', '3417', (65, 69))	('IDH1', 'Gene', (129, 133))	('revealed', 'Reg', (75, 83))	('mutation', 'Var', (89, 97))	('IDH1', 'Gene', (84, 88))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('IDH1', 'Gene', '3417', (84, 88))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', (65, 69))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
24387	27456199	Two of three grade III gliomas who were examined the sequence of the IDH1 gene revealed IDH1 mutations and one of three did not reveal the IDH1 mutation.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('IDH1', 'Gene', (139, 143))	('mutations', 'Var', (93, 102))	('IDH1', 'Gene', '3417', (69, 73))	('IDH1', 'Gene', (88, 92))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('IDH1', 'Gene', '3417', (139, 143))	('revealed', 'Reg', (79, 87))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('IDH1', 'Gene', '3417', (88, 92))	('IDH1', 'Gene', (69, 73))
24388	27456199	The survival outcomes were as the following: all two grade IV patients with IDH1 mutation lives at least 32 months, whereas one out of two grade III patient without IDH1 mutation only survived 9 months.	('IDH1', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))	('patient', 'Species', '9606', (62, 69))	('IDH1', 'Gene', '3417', (76, 80))	('IDH1', 'Gene', (165, 169))	('patient', 'Species', '9606', (149, 156))	('IDH1', 'Gene', '3417', (165, 169))	('patients', 'Species', '9606', (62, 70))
24389	27456199	Mutation of IDH1 gene would be associated with improved outcome even in our small dataset.	('improved', 'PosReg', (47, 55))	('IDH1', 'Gene', '3417', (12, 16))	('Mutation', 'Var', (0, 8))	('IDH1', 'Gene', (12, 16))
24393	27456199	MRcI-guided tissue sampling stage: We retrospectively reviewed 36 patients (23 men, 13 women) with gliomas who underwent DTI, T1WI, T1WIce, T2WI, and FLAIR sequences in our study.	('men', 'Species', '9606', (79, 82))	('T2WI', 'Var', (140, 144))	('gliomas', 'Disease', (99, 106))	('DTI', 'Chemical', '-', (121, 124))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('women', 'Species', '9606', (87, 92))	('men', 'Species', '9606', (89, 92))	('T1WIce', 'Var', (132, 138))	('T1WI', 'Var', (126, 130))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('patients', 'Species', '9606', (66, 74))
24405	27456199	The results from BLSOM are more consistent than those of the standard sequential SOM due to the independence of the input order, and the KM++ algorithm improves both the speed and accuracy compared with the classic KM algorithm.	('speed', 'MPA', (170, 175))	('KM++', 'Var', (137, 141))	('KM++', 'Chemical', '-', (137, 141))	('improves', 'PosReg', (152, 160))
24415	27456199	Then, we used bootstrapped 95% CIs to analyze the ratios of the normalized intensities on three of the MR sequences, namely T1WI, FLAIR, and T2WI, within the enhanced tumor regions when K revealed the best classification performance.	('T1WI', 'Var', (124, 128))	('FLAIR', 'Var', (130, 135))	('T2WI', 'Var', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
24429	27165745	For example, one of the most frequent arm-level SCNAs is chromosome 9p loss, which is linked to disease progression and worse survival in many types of cancer, including lower grade glioma (LGG; WHO grade II and III).	('linked to', 'Reg', (86, 95))	('cancer', 'Disease', (152, 158))	('chromosome 9p loss', 'Var', (57, 75))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('glioma', 'Disease', (182, 188))
24441	27165745	In fact, across all types of cancer, 9p loss was the third most frequent arm-level deletion and eighth most frequent arm-level SCNA overall.	('cancer', 'Disease', (29, 35))	('9p loss', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (83, 91))	('arm-level', 'Disease', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
24445	27165745	Therefore, 9p loss in LGG provided an ideal model to explore genomic approaches for identifying genetic loci responsible for arm-level SCNA-associated phenotypes in cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LGG', 'Gene', (22, 25))	('9p loss', 'Var', (11, 18))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
24446	27165745	The nature of genetic alterations on 9p and which underlying loci affect survival is an important question in cancer biology that remains controversial.	('survival', 'MPA', (73, 81))	('cancer', 'Disease', (110, 116))	('genetic alterations', 'Var', (14, 33))	('affect', 'Reg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
24455	27165745	We confirmed the presence of several subtype-defining molecular characteristics - CIC and FUBP1 mutation in IDHmut-codel, ATRX and TP53 mutation in IDHmut-non-codel, 7p gain and 10p loss in IDHWT - as well as several unpublished associations of these 3 LGG subtypes (Figure 2C and Table S2).	('loss', 'NegReg', (182, 186))	('CIC', 'Gene', '23152', (82, 85))	('FUBP1', 'Gene', (90, 95))	('mutation', 'Var', (96, 104))	('gain', 'PosReg', (169, 173))	('IDH', 'Gene', (190, 193))	('TP53', 'Gene', (131, 135))	('ATRX', 'Gene', (122, 126))	('IDH', 'Gene', (108, 111))	('mutation', 'Var', (136, 144))	('IDH', 'Gene', (148, 151))	('ATRX', 'Gene', '546', (122, 126))	('FUBP1', 'Gene', '8880', (90, 95))	('associations', 'Interaction', (229, 241))	('IDH', 'Gene', '3417', (190, 193))	('CIC', 'Gene', (82, 85))	('IDH', 'Gene', '3417', (108, 111))	('TP53', 'Gene', '7157', (131, 135))	('IDH', 'Gene', '3417', (148, 151))
24461	27165745	All together, these results suggest that 9p loss may independently predict progression of LGG in IDH mutant tumors, at least when tested against 379 possible confounding variables.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('IDH', 'Gene', (97, 100))	('LGG', 'Disease', (90, 93))	('IDH', 'Gene', '3417', (97, 100))	('mutant', 'Var', (101, 107))	('loss', 'NegReg', (44, 48))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
24462	27165745	We defined a region on chromosome 9p that is lost in more than 90% of LGG patients with broad deletions on this arm (Figure S3A).	('LGG', 'Disease', (70, 73))	('patients', 'Species', '9606', (74, 82))	('deletions', 'Var', (94, 103))
24465	27165745	Specifically, several loci exhibited no change in expression following heterozygous deletion alone, while others such as CDKN2A even had elevated expression in this context (Figure S4A).	('CDKN2A', 'Gene', '1029', (121, 127))	('deletion', 'Var', (84, 92))	('elevated', 'PosReg', (137, 145))	('expression', 'MPA', (146, 156))	('CDKN2A', 'Gene', (121, 127))	('expression', 'MPA', (50, 60))
24466	27165745	In fact, when we examined copy number status of each gene in regard to distance from CDKN2A where homozygous deletions were most prominent, a strong correlation was observed in the entire LGG cohort and in most subtypes (Figures 4B and S4C).	('observed', 'Reg', (165, 173))	('deletions', 'Var', (109, 118))	('CDKN2A', 'Gene', (85, 91))	('CDKN2A', 'Gene', '1029', (85, 91))
24467	27165745	In contrast, mRNA/miRNA expression at each locus was poorly correlated to distance from CDKN2A (Figures 4C and S4C) as well as copy number status at each respective locus (Figure S4D).	('CDKN2A', 'Gene', '1029', (88, 94))	('copy number', 'Var', (127, 138))	('CDKN2A', 'Gene', (88, 94))	('mRNA/miRNA expression', 'MPA', (13, 34))
24469	27165745	Not surprisingly, copy number status was significantly correlated with worse OS at every locus whereas expression was much more variable across all LGG subtypes (Figures 4D and S4E).	('correlated', 'Reg', (55, 65))	('copy number status', 'Var', (18, 36))	('OS', 'Chemical', '-', (77, 79))
24475	27165745	This may be due to inactivation of several genes, likely by some combination of cumulative haploinsuffiency and additional epigenetic downregulation that provides the necessary second "hit(s)" (Figure 5C).	('inactivation', 'Var', (19, 31))	('epigenetic', 'Var', (123, 133))	('haploinsuffiency', 'Disease', (91, 107))	('haploinsuffiency', 'Disease', 'None', (91, 107))
24477	27165745	For many years, CDKN2A deletion has been associated with poor survival in LGG, leading to speculation that it is important for both initiation of high grade disease as well as tumor aggressiveness.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (176, 196))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('deletion', 'Var', (23, 31))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('tumor aggressiveness', 'Disease', (176, 196))	('aggressiveness', 'Phenotype', 'HP:0000718', (182, 196))	('LGG', 'Disease', (74, 77))
24483	27165745	This suggests that any change in survival in the context of CDKN2A heterozygous deletion is likely due to the confounding 9p loss phenotype.	('change', 'Reg', (23, 29))	('loss', 'NegReg', (125, 129))	('deletion', 'Var', (80, 88))	('survival', 'MPA', (33, 41))	('CDKN2A', 'Gene', (60, 66))	('CDKN2A', 'Gene', '1029', (60, 66))
24486	27165745	Additionally, CDKN2A-/- significantly associated with chromosome 7 gain, chromosome 10 loss, EGFR mutation, and PTEN mutation - the defining characteristics of IDHWT subtype tumors (Figure 6C).	('loss', 'NegReg', (87, 91))	('IDHWT subtype tumors', 'Disease', 'MESH:C535673', (160, 180))	('associated', 'Reg', (38, 48))	('mutation', 'Var', (98, 106))	('EGFR', 'Gene', '1956', (93, 97))	('CDKN2A', 'Gene', '1029', (14, 20))	('mutation -', 'Var', (117, 127))	('PTEN', 'Gene', '5728', (112, 116))	('IDHWT subtype tumors', 'Disease', (160, 180))	('EGFR', 'Gene', (93, 97))	('chromosome 10', 'Gene', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('PTEN', 'Gene', (112, 116))	('gain', 'PosReg', (67, 71))	('chromosome 7', 'Gene', (54, 66))	('CDKN2A', 'Gene', (14, 20))
24488	27165745	Since LGG IDHWT carries the worst prognosis of all 3 subtypes, we sought to clarify whether the worse survival observed in patients harboring CDKN2A homozygous deletion was a result of this association.	('IDH', 'Gene', (10, 13))	('homozygous', 'Var', (149, 159))	('CDKN2A', 'Gene', '1029', (142, 148))	('IDH', 'Gene', '3417', (10, 13))	('patients', 'Species', '9606', (123, 131))	('CDKN2A', 'Gene', (142, 148))
24489	27165745	We found that CDKN2A deletion status did not correlate with OS in either IDHWT or IDH mutant (IDHmut-codel and IDHmut-non-codel) patients in both TCGA and REMBRANDT LGG cohorts (Figures 6D, S6E and S6F).	('IDH', 'Gene', '3417', (82, 85))	('CDKN2A', 'Gene', '1029', (14, 20))	('IDH', 'Gene', (94, 97))	('patients', 'Species', '9606', (129, 137))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', (111, 114))	('deletion', 'Var', (21, 29))	('IDH', 'Gene', '3417', (94, 97))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', '3417', (111, 114))	('IDH', 'Gene', (82, 85))	('OS', 'Chemical', '-', (60, 62))	('CDKN2A', 'Gene', (14, 20))
24490	27165745	Although there was a trend toward worse survival following CDKN2A deletion of any type (CDKN2A-/- or CDKN2A+/-), decreased mRNA expression was only observed among samples with CDKN2A-/- (Figures 6E and S6E).	('CDKN2A', 'Gene', (88, 94))	('worse', 'NegReg', (34, 39))	('CDKN2A', 'Gene', (101, 107))	('CDKN2A+/-', 'Gene', (101, 110))	('CDKN2A', 'Gene', '1029', (88, 94))	('mRNA expression', 'MPA', (123, 138))	('CDKN2A', 'Gene', '1029', (101, 107))	('survival', 'MPA', (40, 48))	('CDKN2A', 'Gene', (176, 182))	('CDKN2A', 'Gene', '1029', (59, 65))	('CDKN2A+/-', 'Gene', '1029', (101, 110))	('CDKN2A', 'Gene', (59, 65))	('decreased', 'NegReg', (113, 122))	('deletion', 'Var', (66, 74))	('CDKN2A', 'Gene', '1029', (176, 182))
24509	27165745	Perhaps most surprising was our discovery that CDKN2A inactivation did not promote tumor aggressiveness within any of the 3 LGG cohorts we examined.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('CDKN2A', 'Gene', (47, 53))	('tumor aggressiveness', 'Disease', (83, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('CDKN2A', 'Gene', '1029', (47, 53))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (83, 103))	('inactivation', 'Var', (54, 66))
24511	27165745	We show, however, that only CDKN2A homozygous deletion - not expression - associates with poor OS and that this event almost exclusively occurs in IDHWT tumors, a subset of LGG with dismal prognosis.	('deletion', 'Var', (46, 54))	('occurs', 'Reg', (137, 143))	('CDKN2A', 'Gene', '1029', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('CDKN2A', 'Gene', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('IDHWT tumors', 'Disease', 'MESH:D009369', (147, 159))	('OS', 'Chemical', '-', (95, 97))	('IDHWT tumors', 'Disease', (147, 159))	('poor OS', 'MPA', (90, 97))
24515	27165745	Although many have suggested that CDKN2A inactivation can lead to progression and worse survival in glioma, these early studies were unable to account for subtype-specific confounding alterations and deconvolute copy number status and transcriptional downregulation.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('inactivation', 'Var', (41, 53))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('CDKN2A', 'Gene', '1029', (34, 40))	('CDKN2A', 'Gene', (34, 40))
24528	27165745	Data were assembled from the TCGA LGG dataset for 379 patients that had completed information for the following tiers: clinical, copy number, mRNA expression, miRNA expression, DNA methylation, and somatic mutation.	('miRNA expression', 'MPA', (159, 175))	('patients', 'Species', '9606', (54, 62))	('copy number', 'Var', (129, 140))	('DNA', 'MPA', (177, 180))	('mRNA expression', 'MPA', (142, 157))
24537	27165745	Clinical, expression, and methylation data were obtained for 52 patients with LGG at MSKCC (GEO accession #GSE30336 and #GSE30338).	('patients', 'Species', '9606', (64, 72))	('#GSE30338', 'Var', (120, 129))	('MSKCC', 'Gene', (85, 90))
24538	27165745	Methylation data was derived from Illumina Infinium 450K Methylation Beadchip and were used to construct copy number segmentation for all 52 patient samples via the ChAMP package in R. Inclusion criteria for broad 9p loss were deletion beta value < -0.1 and deletion size > 5 Mb.	('deletion beta value < -0.1', 'Var', (227, 253))	('patient', 'Species', '9606', (141, 148))	('loss', 'NegReg', (217, 221))
24549	27165745	In the 379 patient TCGA LGG cohort, using 1p/19q codeletion along with 10p, 7p and 7q, and CDKN2A status, we achieved > 90% accuracy.	('CDKN2A', 'Gene', (91, 97))	('patient', 'Species', '9606', (11, 18))	('1p/19q', 'Var', (42, 48))	('CDKN2A', 'Gene', '1029', (91, 97))
24593	25250156	The number of cases who could complete the treatment has slightly higher in patients with low-grade tumors compared to those with high-grade tumors (90.6% vs. 85.3%, p=0.47).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('low-grade', 'Var', (90, 99))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))
24596	25250156	We have recorded 28 deaths during the follow-ups, which were significantly higher in cases with high-grade tumors; all deaths were tumor-related.	('high-grade', 'Var', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
24612	25250156	in a study on 63 children with high-grade astrocytoma, whose have managed at John Hopkins Hospital (in years 1997-2004), has shown that performance status <80%, resection less than gross total, bilaterally, parietal lobe location and radiation dose <50 Gy have associated with inferior survival.	('parietal lobe location', 'Disease', (207, 229))	('astrocytoma', 'Disease', 'MESH:D001254', (42, 53))	('inferior', 'NegReg', (277, 285))	('astrocytoma', 'Disease', (42, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (42, 53))	('less', 'NegReg', (171, 175))	('performance', 'MPA', (136, 147))	('children', 'Species', '9606', (17, 25))	('parietal lobe location', 'Disease', 'MESH:C566826', (207, 229))	('resection', 'Var', (161, 170))
24638	33047900	These studies have included not only the well-known IDH1 mutation status, but also some factors discovered in recent years by bioinformatics analysis, such as eukaryotic initiation factor and some N6-methyladenosine (m6A) RNA methylation regulators 3 ,  4 ; however, according to the 2016 WHO brain tumor classification, IDH1 mutation status and 1p/19q are the only universally recognized significant prognostic biomarkers of LGG.	('1p/19q', 'Var', (346, 352))	('LGG', 'Disease', (426, 429))	('IDH1', 'Gene', '3417', (52, 56))	('brain tumor', 'Phenotype', 'HP:0030692', (293, 304))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('as', 'Gene', '112935892', (307, 309))	('as', 'Gene', '112935892', (156, 158))	('IDH1', 'Gene', (321, 325))	('mutation status', 'Var', (326, 341))	('brain tumor', 'Disease', (293, 304))	('IDH1', 'Gene', '3417', (321, 325))	('IDH1', 'Gene', (52, 56))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (197, 215))	('brain tumor', 'Disease', 'MESH:D001932', (293, 304))
24694	33047900	Univariate Cox analysis showed that patient age (p < 0.001), new event (p = 0.001), KPS score (p = 0.001), WHO grade (p < 0.001), pharmaceutical treatment (p < 0.001), IDH1 mutation status (p < 0.001), TP53 mutation status (p < 0.001), and all AS signatures (p < 0.001) were significantly correlated with patient OS.	('TP53', 'Gene', (202, 206))	('IDH1', 'Gene', '3417', (168, 172))	('patient', 'Species', '9606', (305, 312))	('patient OS', 'Disease', (305, 315))	('correlated', 'Reg', (289, 299))	('mutation status', 'Var', (207, 222))	('AS', 'Gene', '112935892', (244, 246))	('TP53', 'Gene', '7157', (202, 206))	('IDH1', 'Gene', (168, 172))	('patient', 'Species', '9606', (36, 43))	('mutation', 'Var', (173, 181))
24695	33047900	Based on the univariate Cox analysis, a multivariate Cox analysis was used to further screen independent factors that could affect the prognosis of patients including age (p = 0.002), new event (p = 0.036), KPS score (p < 0.001), WHO grade (p = 0.002), pharmaceutical treatment (p = 0.009), IDH1 mutation status (p = 0.022), TP53 mutation status (p = 0.006), and integrated AS signature (p < 0.001).	('mutation status', 'Var', (330, 345))	('patients', 'Species', '9606', (148, 156))	('TP53', 'Gene', (325, 329))	('affect', 'Reg', (124, 130))	('IDH1', 'Gene', (291, 295))	('as', 'Gene', '112935892', (67, 69))	('as', 'Gene', '112935892', (1, 3))	('TP53', 'Gene', '7157', (325, 329))	('AS', 'Gene', '112935892', (374, 376))	('IDH1', 'Gene', '3417', (291, 295))	('mutation status', 'Var', (296, 311))
24698	33047900	This scoring system includes age, new event, KPS score, WHO grade, pharmaceutical therapy, IDH1 mutation status, TP53 mutation status, and integrated AS signature (Figure 6A).	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (113, 117))	('IDH1', 'Gene', '3417', (91, 95))	('TP53', 'Gene', (113, 117))	('AS', 'Gene', '112935892', (150, 152))
24708	33047900	Studies have shown that in lung cancer, after aberrant splicing, the expression of BCL2L1, MDM2, MDM4, NUMB, and MET may play an important role in tumorigenesis, which may be due to the effects on cell apoptosis, cell proliferation, and intercellular cohesion-related pathways.	('MET', 'Gene', (113, 116))	('MDM4', 'Gene', '4194', (97, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('MDM4', 'Gene', (97, 101))	('tumor', 'Disease', (147, 152))	('NUMB', 'Gene', (103, 107))	('MDM2', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('play', 'Reg', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('MET', 'Gene', '79811', (113, 116))	('BCL2L1', 'Gene', '598', (83, 89))	('cell proliferation', 'CPA', (213, 231))	('intercellular cohesion-related pathways', 'Pathway', (237, 276))	('lung cancer', 'Disease', (27, 38))	('MDM2', 'Gene', '4193', (91, 95))	('NUMB', 'Gene', '8650', (103, 107))	('aberrant splicing', 'Var', (46, 63))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cell apoptosis', 'CPA', (197, 211))	('effects', 'Reg', (186, 193))	('BCL2L1', 'Gene', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
24721	33047900	25  These factors included tumor grade, age of diagnosis, KPS score, and IDH1 mutation status.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('IDH1', 'Gene', '3417', (73, 77))	('tumor', 'Disease', (27, 32))	('mutation status', 'Var', (78, 93))	('IDH1', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
24745	32545894	Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers.	('roles', 'Reg', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('HOX gene', 'Gene', (51, 59))	('mis-regulation', 'Var', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
24752	32545894	Multiple reports have demonstrated that mis-regulation of HOX genes expression plays key roles in the development of cancers.	('mis-regulation', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('roles', 'Reg', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('HOX genes', 'Gene', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
24807	32545894	The expression correlation observed between HOXB5, HOXB6, and HOXB7 in ESCA, is in line with a previous report that showed that expression changes in the three "midcluster" HOXB genes, namely HOXB5, HOXB6, and HOXB7, can trigger changes in the transcriptional program of adult esophageal cells, with implications to the early stages of esophageal carcinogenesis.	('HOXB', 'Gene', (62, 66))	('HOXB7', 'Gene', '3217', (210, 215))	('HOXB7', 'Gene', (210, 215))	('HOXB', 'Gene', (44, 48))	('HOXB', 'Gene', (173, 177))	('HOXB', 'Gene', '3210', (199, 203))	('HOXB', 'Gene', (51, 55))	('HOXB', 'Gene', (210, 214))	('HOXB6', 'Gene', '3216', (51, 56))	('HOXB6', 'Gene', (51, 56))	('HOXB5', 'Gene', (44, 49))	('HOXB', 'Gene', (192, 196))	('HOXB6', 'Gene', '3216', (199, 204))	('HOXB7', 'Gene', '3217', (62, 67))	('trigger changes', 'Reg', (221, 236))	('esophageal carcinogenesis', 'Disease', (336, 361))	('HOXB7', 'Gene', (62, 67))	('HOXB', 'Gene', '3210', (62, 66))	('changes', 'Var', (139, 146))	('HOXB6', 'Gene', (199, 204))	('HOXB', 'Gene', '3210', (44, 48))	('HOXB', 'Gene', '3210', (173, 177))	('transcriptional program', 'MPA', (244, 267))	('HOXB5', 'Gene', '3215', (44, 49))	('HOXB5', 'Gene', (192, 197))	('HOXB', 'Gene', '3210', (51, 55))	('HOXB', 'Gene', '3210', (210, 214))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (336, 361))	('HOXB', 'Gene', (199, 203))	('HOXB', 'Gene', '3210', (192, 196))	('ESCA', 'Phenotype', 'HP:0011459', (71, 75))	('HOXB5', 'Gene', '3215', (192, 197))
24898	28733365	We applied this model to both a set of germline mutations identified in exomes and to exonic somatic mutations in four types of tumors.	('germline mutations', 'Var', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
24899	28733365	GERMLINE mutations are the source of all heritable variation, including in disease susceptibility, and it is increasingly clear that somatic mutations also play important roles in human diseases, notably cancers.	('play', 'Reg', (156, 160))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('roles', 'Reg', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('human', 'Species', '9606', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('GERMLINE mutations', 'Var', (0, 18))
24900	28733365	Understanding the rate and mechanisms by which mutations occur is therefore of interest to both evolutionary biologists and to human geneticists aiming to identify the underlying causes of genetic diseases.	('human', 'Species', '9606', (127, 132))	('genetic diseases', 'Disease', 'MESH:D030342', (189, 205))	('genetic diseases', 'Disease', (189, 205))	('mutations', 'Var', (47, 56))
24903	28733365	Our knowledge of somatic point mutations, in turn, relies primarily on resequencing tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('point mutations', 'Var', (25, 40))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))
24905	28733365	Because, in this approach, a large population of cells is sequenced, the mutations identified tend to predate the tumorigenesis, and thus are mostly somatic mutations that occurred in normal tissues (see, e.g.,).	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (73, 82))
24906	28733365	Notably, the mutation rate of CpG transitions (henceforth CpG Ti) is an order of magnitude higher than other mutation types (e.g.,).	('henceforth CpG Ti', 'Disease', (47, 64))	('mutation', 'Var', (13, 21))	('CpG transitions', 'Var', (30, 45))	('henceforth CpG Ti', 'Disease', 'MESH:D000072676', (47, 64))
24907	28733365	Most CpG dinucleotides are methylated in the human genome; when the methylated cytosine undergoes spontaneous deamination to thymine and is not corrected by the time of replication, the damage leads to a mutation.	('mutation', 'Var', (204, 212))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (5, 22))	('deamination', 'MPA', (110, 121))	('human', 'Species', '9606', (45, 50))	('leads to', 'Reg', (193, 201))	('cytosine', 'Chemical', 'MESH:D003596', (79, 87))	('thymine', 'Chemical', 'MESH:D013941', (125, 132))
24909	28733365	More generally, tumors vary in their mutation spectrum: analyses of mutations and their two neighboring base pairs (i.e., considering 96 mutation types) point to enrichment of distinct mutational signatures for different types of cancers, a subset of which have been shown to reflect particular mutagens or differences in the efficiency of repair.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))	('mutations', 'Var', (68, 77))	('tumors', 'Disease', (16, 22))
24911	28733365	Similarly, two studies that focused on somatic mutations in noncancerous somatic tissues, normal eyelid tissue, and neurons, found mutations to be enriched in regions of low expression and repressed chromatin.	('mutations', 'Var', (131, 140))	('low', 'NegReg', (170, 173))	('expression', 'MPA', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
24914	28733365	Their findings point to possible differences in their determinants: for instance, the histone mark H3K9me3 accounts for >40% of mutation rate variation at 100 kb in tumors, when a much weaker association is seen in the germline.	('H3K9me3', 'Protein', (99, 106))	('tumors', 'Disease', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutation', 'Var', (128, 136))
24915	28733365	We applied the model to a large set of germline point mutations identified in exomes from recently published studies on developmental disorders and to somatic point mutations in exomes found in four types of tumors and reported by the Cancer Genome Atlas (see Materials and Methods).	('Cancer Genome Atlas', 'Disease', (235, 254))	('Cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (235, 254))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('point mutations', 'Var', (159, 174))	('developmental disorders', 'Disease', (120, 143))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('developmental disorders', 'Disease', 'MESH:D002658', (120, 143))
24922	28733365	What remains are somatic mutations found at high enough frequency to be seen in a large population of cells, which are therefore likely to predate the tumorigenesis, i.e., that occurred in the preneoplastic tissues.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))
24929	28733365	Similarly, in order to ask whether effects differ between CpG Ti and other type of mutations in the same tissue, we included a binary variable C for the two mutation types (see Figure S4 in File S1) where: All variables are set up the same way as in the combined model described previously, except for that beta7, beta8, beta9, beta10, and beta11 are now the differences of the effect sizes for CpG Ti compared to those for all other mutation types.	('beta8', 'Var', (314, 319))	('CpG', 'Disease', (395, 398))	('beta1', 'Gene', (328, 333))	('beta7', 'Var', (307, 312))	('beta1', 'Gene', (340, 345))	('beta1', 'Gene', '10678', (328, 333))	('beta1', 'Gene', '10678', (340, 345))
24930	28733365	CpG methylation data were downloaded from GEO (https://www.ncbi.nlm.nih.gov/geo/), with accession number GSM1010980 for ovary, GSM1127119 for sperm, GSM11217054 for breast myoepithelial cells, GSM1112838 for brain hippocampus cells, GSM916049 for adult liver cells, and GSM429321 for ESC cells.	('breast myoepithelial', 'Disease', (165, 185))	('GSM1112838', 'Var', (193, 203))	('GSM429321', 'Var', (270, 279))	('GSM916049', 'Var', (233, 242))	('GSM11217054', 'Var', (149, 160))	('GSM1127119', 'Var', (127, 137))	('breast myoepithelial', 'Disease', 'MESH:D009208', (165, 185))	('GSM1010980', 'Var', (105, 115))
24931	28733365	A previous study reported that in one set of cases, individuals with CHD, there is an increased number of putatively damaging mutations in the genes most highly expressed in the developing heart and brain.	('CHD', 'Disease', (69, 72))	('CHD', 'Disease', 'None', (69, 72))	('genes', 'Gene', (143, 148))	('mutations', 'Var', (126, 135))
24932	28733365	Since the mutations are thought to be germline mutations (rather than somatic mutations), this association cannot be causal, instead reflecting an enrichment of damaging mutations in important heart developmental genes in CHD patients.	('mutations', 'Var', (10, 19))	('CHD', 'Disease', (222, 225))	('patients', 'Species', '9606', (226, 234))	('CHD', 'Disease', 'None', (222, 225))
24938	28733365	Figure 1 and Figure 2 also hint at a difference between testis (and more tentatively, ovary) and somatic tissues in the magnitude of the effects of replication timing on mutation rates and the direction of the effects of expression levels, with a significant positive effect for germline mutations and a significantly negative effect for somatic tissues (e.g., BRCA: P = 8 x 10-16 for CpG Ti; P < 2 x 10-16 for other mutation types; P < 2 x 10-7 for all somatic tissues and mutation types).	('BRCA', 'Gene', '672', (361, 365))	('CpG Ti', 'Disease', (385, 391))	('germline mutations', 'Var', (279, 297))	('BRCA', 'Gene', (361, 365))
24941	28733365	We compared the determinants of mutation in the soma and the germline, using the same unit of analysis (a coding region) and the same statistical model, and applied it to similar exome data for germline de novo mutations and four types of tumors, in which mutations largely predate tumorigenesis.	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Disease', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Disease', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('mutations', 'Var', (256, 265))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
25046	27398030	Although its pathophysiology remains unclear, chemoirradiation is believed to induce a transient local inflammatory reaction, edema, and increased vessel permeability, which manifests as increased signal on contrast-enhanced images.	('edema', 'Disease', (126, 131))	('increased vessel permeability', 'Phenotype', 'HP:0030005', (137, 166))	('edema', 'Disease', 'MESH:D004487', (126, 131))	('chemoirradiation', 'Var', (46, 62))	('vessel permeability', 'CPA', (147, 166))	('increased', 'PosReg', (137, 146))	('increased', 'PosReg', (187, 196))	('edema', 'Phenotype', 'HP:0000969', (126, 131))
25061	27398030	Using DCE-CT imaging, a combination of high BV and PS was associated with poor overall survival for Grade III and IV gliomas and for Grade IV gliomas alone.	('Grade III', 'Disease', (100, 109))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('DCE', 'Gene', (6, 9))	('gliomas', 'Disease', (117, 124))	('gliomas', 'Disease', (142, 149))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('poor', 'NegReg', (74, 78))	('high BV', 'Var', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('PS', 'Chemical', '-', (51, 53))	('DCE', 'Gene', '1718', (6, 9))
25076	27398030	Batchelor et al showed that patients treated with cediranib demonstrated decreased MR signal enhancement as early as one day after the initiation of treatment, despite considerable variability in tumor response.	('MR signal enhancement', 'MPA', (83, 104))	('tumor', 'Disease', (196, 201))	('decreased', 'NegReg', (73, 82))	('cediranib', 'Chemical', 'MESH:C500926', (50, 59))	('cediranib', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
25078	27398030	For recurrent GBMs, high nBV and Ktrans prior to anti-VEGF monotherapy or in combination with temozolomide were associated with poor survival.	('poor', 'NegReg', (128, 132))	('nBV', 'Chemical', '-', (25, 28))	('Ktrans', 'Chemical', '-', (33, 39))	('VEGF', 'Gene', (54, 58))	('Ktrans', 'Var', (33, 39))	('high', 'Var', (20, 24))	('GBM', 'Phenotype', 'HP:0012174', (14, 17))	('nBV', 'Gene', (25, 28))	('temozolomide', 'Chemical', 'MESH:D000077204', (94, 106))	('VEGF', 'Gene', '7422', (54, 58))
25105	25494501	Finally, a large variety of imaging modalities can be used for mapping tumor-induced tissue changes, including T2 and FLAIR MRI (highlighting differences in tissue water relaxational properties), post-Gadolinium T1 MRI (showing pathological intratumoral take-up of contrast agents), perfusion and diffusion MRI (local water diffusion and blood flow), and MRSI (relative concentrations of selected metabolites), among others.	('water', 'Chemical', 'MESH:D014867', (318, 323))	('Gadolinium', 'Chemical', 'MESH:D005682', (201, 211))	('post-Gadolinium', 'Var', (196, 211))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('water', 'Chemical', 'MESH:D014867', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('diffusion MRI', 'CPA', (297, 310))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('MRSI', 'Disease', (355, 359))	('perfusion', 'CPA', (283, 292))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (71, 76))	('MRSI', 'Disease', 'None', (355, 359))
25313	25494501	We label voxels that show tumor specific changes in the T2 channel as edema, and voxels that show hyper-intense tumor specific changes as tumor core.	('edema', 'Phenotype', 'HP:0000969', (70, 75))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('edema', 'Disease', (70, 75))	('changes', 'Var', (41, 48))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (26, 31))	('edema', 'Disease', 'MESH:D004487', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
25323	25494501	The first set includes non-local features such as pixel intensities (IT1, IT2, IFL, IT1c) and differences of intensities (d1 = IT1 - IT2, d2 = IT2 - IFL, d3 = IFL - IT1c) that represents global characteristics of brain tissues.	('IT1', 'Gene', (69, 72))	('d3 =', 'Var', (154, 158))	('IT1', 'Gene', (84, 87))	('d1', 'Var', (122, 124))	('IT1', 'Gene', '79441', (84, 87))	('IT1', 'Gene', (127, 130))	('IT1', 'Gene', '79441', (127, 130))	('d2 = IT2 -', 'Var', (138, 148))	('IT1', 'Gene', (165, 168))	('IT1', 'Gene', '79441', (165, 168))	('IT1', 'Gene', '79441', (69, 72))
25386	20524825	Factors independently associated with prolonged functional independence were: preoperative KPS score >= 90 (p = 0.004), preoperative seizures (p = 0.002), primary glioblastoma (p < 0.0001), gross-total resection (p < 0.0001), and temozolomide chemotherapy (p < 0.0001).	('seizures', 'Disease', 'MESH:D012640', (133, 141))	('seizures', 'Phenotype', 'HP:0001250', (133, 141))	('primary glioblastoma', 'Disease', 'MESH:D005909', (155, 175))	('gross-total resection', 'Var', (190, 211))	('seizures', 'Disease', (133, 141))	('temozolomide', 'Chemical', 'MESH:D000077204', (230, 242))	('primary glioblastoma', 'Disease', (155, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))
25459	20524825	Among the patients in this study, improved preoperative functional status was associated with prolonged survival (RR 0.987, 95% CI 0.975-0.998; p = 0.02); patients with KPS scores >= 90 had the greatest statistical association with survival (RR 0.796.	('improved', 'PosReg', (34, 42))	('patients', 'Species', '9606', (10, 18))	('KPS scores >= 90', 'Var', (169, 185))	('patients', 'Species', '9606', (155, 163))
25515	20524825	In fact, some studies have shown that GTR leads to an approximate 40% increase in median survival as compared with STR.	('GTR', 'Var', (38, 41))	('increase', 'PosReg', (70, 78))	('STR', 'Gene', (115, 118))	('GTR', 'Chemical', '-', (38, 41))	('median survival', 'MPA', (82, 97))	('STR', 'Gene', '6779', (115, 118))
25516	20524825	Likewise, we found that GTR results in an approximate 45% increase in prolonged functional independence.	('GTR', 'Chemical', '-', (24, 27))	('GTR', 'Var', (24, 27))	('increase', 'PosReg', (58, 66))	('prolonged functional independence', 'CPA', (70, 103))
25518	20524825	Temozolomide in this study was associated with an approximate 40% increase (or approximately 6 months) in prolonged functional independence duration.	('increase', 'PosReg', (66, 74))	('prolonged functional independence duration', 'CPA', (106, 148))	('Temozolomide', 'Var', (0, 12))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
25550	20524825	Second, this study follows patients who presented with a KPS score >= 80 and follows these patients until they lose their functional independence (KPS score < 60).	('lose', 'NegReg', (111, 115))	('functional', 'MPA', (122, 132))	('patients', 'Species', '9606', (91, 99))	('KPS', 'Var', (57, 60))	('patients', 'Species', '9606', (27, 35))
25595	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('TGCACGA', 'Gene', (65, 72))	('MIR-184', 'Gene', (55, 62))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
25610	32731376	Thus far, the results provided by prospective and retrospective studies show that the utilization of this fluorophore may be associated with better visualization and improvement of resection for several tumors of the central nervous system.	('utilization', 'Var', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (203, 239))	('men', 'Species', '9606', (173, 176))	('improvement', 'PosReg', (166, 177))	('tumors of the central nervous system', 'Disease', (203, 239))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (203, 239))	('resection', 'CPA', (181, 190))	('visualization', 'CPA', (148, 161))
25620	32731376	(4) Conclusions: The use of FL and YE560 is a readily available method for safe fluorescence-guided tumor resection, possibly visualizing tumor margins intraoperatively similar to contrast enhancement in T1-weighted MRI.	('men', 'Species', '9606', (196, 199))	('visualizing tumor', 'Disease', (126, 143))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FL', 'Gene', '2323', (28, 30))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (100, 105))	('visualizing tumor', 'Disease', 'MESH:D014786', (126, 143))	('YE560', 'Var', (35, 40))	('YE560', 'Chemical', '-', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
25776	32334471	Ki-67 Labeling Index and Glioma Grading  The lowest Ki-67 labeling index was 0.15% and the highest was 73.55%.	('Ki-67', 'Var', (0, 5))	('Ki-67', 'Chemical', '-', (0, 5))	('Glioma', 'Disease', 'MESH:D005910', (25, 31))	('Glioma', 'Phenotype', 'HP:0009733', (25, 31))	('lowest', 'NegReg', (45, 51))	('Ki-67', 'Chemical', '-', (52, 57))	('Glioma', 'Disease', (25, 31))
25780	32334471	By using this cut off value a significant association was found between Ki67 labelling index and grade of glioma (p<0.001) (Table 3).	('Ki67', 'Var', (72, 76))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Disease', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))
25802	32334471	To differentiate between reactive lesion and true neoplasm, analyses for isocitrate dehydrogenase and p53 mutation combined with clinical and radiological assessment can be helpful (Kurtkaya-Yapicier et al., 2002; Capper et al., 2010).	('neoplasm', 'Disease', 'MESH:D009369', (50, 58))	('mutation', 'Var', (106, 114))	('neoplasm', 'Disease', (50, 58))	('p53', 'Gene', (102, 105))	('p53', 'Gene', '7157', (102, 105))	('neoplasm', 'Phenotype', 'HP:0002664', (50, 58))
25861	32467745	Selection of 1.06 and 1.36 x 10-3 mm2/s as cut-off values of ADC of the tumoural and peritumoural regions to differentiate between grade II and III gliomas revealed AUC of 0.701 and 0.748, accuracy of 80.6% and 80.6%, sensitivity of 70.6%, 82.6%, and specificity of 89.5% and 78.9%, respectively (Figure 3).	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumoural', 'Disease', (89, 97))	('III gliomas', 'Disease', 'MESH:D005910', (144, 155))	('tumoural', 'Disease', 'MESH:D009369', (72, 80))	('tumoural', 'Disease', (72, 80))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('ADC', 'Chemical', '-', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('III gliomas', 'Disease', (144, 155))	('tumoural', 'Disease', 'MESH:D009369', (89, 97))	('0.748', 'Var', (182, 187))
25887	26904387	Herein we propose a model of tumor growth inhibition integrating a tumor's genetic characteristics (p53 mutation and 1p/19q codeletion) that successfully describes the time course of tumor size in patients with low-grade gliomas treated with first-line temozolomide chemotherapy.	('temozolomide', 'Chemical', 'MESH:D000077204', (253, 265))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('gliomas', 'Disease', (221, 228))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('patients', 'Species', '9606', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('gliomas', 'Disease', 'MESH:D005910', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('gliomas', 'Phenotype', 'HP:0009733', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p53', 'Gene', '7157', (100, 103))	('tumor', 'Disease', (29, 34))	('mutation', 'Var', (104, 112))	('tumor', 'Disease', (183, 188))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('tumor', 'Disease', (67, 72))	('p53', 'Gene', (100, 103))
25892	26904387	The duration of response depends on genetic characteristics such as 1p/19q chromosomal codeletion, p53 mutation, and IDH mutations.	('1p/19q', 'Var', (68, 74))	('p53', 'Gene', (99, 102))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (117, 120))	('p53', 'Gene', '7157', (99, 102))	('mutation', 'Var', (103, 111))
25905	26904387	We analyzed data from 120 LGG patients treated between 1999 and 2007.12 Data included information on tumor size in all patients and on up to three molecular (genetic) characteristics in 77 patients: 1p/19q chromosomal codeletion, p53 overexpression (a surrogate marker for TP53 missense mutations17), and IDH mutation status.	('1p/19q', 'Var', (199, 205))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('p53', 'Gene', '7157', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('patients', 'Species', '9606', (30, 38))	('IDH', 'Gene', (305, 308))	('TP53', 'Gene', '7157', (273, 277))	('patients', 'Species', '9606', (189, 197))	('IDH', 'Gene', '3417', (305, 308))	('overexpression', 'PosReg', (234, 248))	('p53', 'Gene', (230, 233))	('TP53', 'Gene', (273, 277))
25915	26904387	To allow for MTD increase during TMZ treatment, we extended the previously proposed model16 by taking into account the possibility that proliferative cells can repair their DNA lesions during the division process, instead of immediately dying, and thus acquire resistance to TMZ.	('resistance', 'MPA', (261, 271))	('TMZ', 'Chemical', 'MESH:D000077204', (275, 278))	('repair', 'Var', (160, 166))	('acquire', 'PosReg', (253, 260))	('DNA lesions', 'MPA', (173, 184))	('TMZ', 'Chemical', 'MESH:D000077204', (33, 36))
25921	26904387	The data from the 42 patients with complete molecular status (codeletion 1p/19q, p53, and IDH mutations) was used as a training dataset to obtain statistics on this genetic information.	('IDH', 'Gene', (90, 93))	('IDH', 'Gene', '3417', (90, 93))	('patients', 'Species', '9606', (21, 29))	('1p/19q', 'Var', (73, 79))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))
25928	26904387	(1) could be simplified: where   denotes the population value of the parameter for the reference group of patients (with non-codeleted 1p/19q or wild p53), and   is the population value for the group of patients with mutated covariate.	('1p/19q', 'Var', (135, 141))	('patients', 'Species', '9606', (203, 211))	('p53', 'Gene', (150, 153))	('patients', 'Species', '9606', (106, 114))	('p53', 'Gene', '7157', (150, 153))
25952	26904387	The covariate analysis performed with the three molecular status characteristics showed that p53 mutation could be included as a covariate of the TMZ efficacy parameter .	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (93, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (146, 149))	('mutation', 'Var', (97, 105))
25954	26904387	In the stepwise analysis procedure, IDH mutation status identified as having an effect on model parameters when tested independently from the two other covariates was not identified as a significant covariate in the presence of p53 and 1p/19q information.	('effect', 'Reg', (80, 86))	('p53', 'Gene', '7157', (228, 231))	('p53', 'Gene', (228, 231))	('IDH', 'Gene', (36, 39))	('IDH', 'Gene', '3417', (36, 39))	('1p/19q information', 'Var', (236, 254))
25979	26904387	Using p53 mutation and 1p/19q codeletion as covariates significantly improved the model accuracy.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('improved', 'PosReg', (69, 77))	('mutation', 'Var', (10, 18))
25980	26904387	In agreement with the literature, p53 and 1p/19q molecular statuses significantly impacted the dynamics of LGG response to treatment: p53 mutation impaired TMZ efficacy and 1p/19q codeleted tumors had less ability to repair TMZ-induced DNA lesions in quiescent tissue, thus increasing the overall efficacy of treatment.	('impacted', 'Reg', (82, 90))	('less', 'NegReg', (201, 205))	('p53', 'Gene', (34, 37))	('TMZ', 'Chemical', 'MESH:D000077204', (224, 227))	('p53', 'Gene', '7157', (134, 137))	('p53', 'Gene', '7157', (34, 37))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('impaired', 'NegReg', (147, 155))	('increasing', 'PosReg', (274, 284))	('efficacy', 'MPA', (297, 305))	('TMZ', 'Chemical', 'MESH:D000077204', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('1p/19q', 'Var', (173, 179))	('mutation', 'Var', (138, 146))	('TMZ efficacy', 'MPA', (156, 168))	('tumors', 'Disease', (190, 196))	('p53', 'Gene', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
26001	26904387	The duration of response depends on genetic characteristic such as 1p/19q chromosomal codeletion, p53 mutation, and IDH mutations.	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (116, 119))	('mutation', 'Var', (102, 110))	('1p/19q', 'Var', (67, 73))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))
26006	25219808	The three core aHGG pathways, the receptor tyrosine kinase(RTK)/Ras/Phosphatidylinositide 3-kinase (PI3K), p53, and retinoblastoma (RB) networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation.	('retinoblastoma (RB', 'Gene', (116, 134))	('aHGG pathways', 'Pathway', (15, 28))	('retinoblastoma', 'Phenotype', 'HP:0009919', (116, 130))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('pHGG', 'Var', (168, 172))	('receptor tyrosine kinase(RTK)', 'Gene', '5979', (34, 63))	('RB', 'Phenotype', 'HP:0009919', (132, 134))	('retinoblastoma (RB)', 'Gene', '5925', (116, 135))	('receptor tyrosine kinase(RTK', 'Gene', (34, 62))	('disrupted', 'NegReg', (155, 164))
26008	25219808	In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ~35% of pNBS-HGG.	('NBS-HGG', 'Disease', (82, 89))	('H3', 'Gene', '126961', (17, 19))	('identified', 'Reg', (35, 45))	('pNBS', 'Chemical', 'MESH:C081297', (81, 85))	('DIPGs', 'Disease', (63, 68))	('DIPGs', 'Chemical', 'MESH:C060938', (63, 68))	('NBS-HGG', 'Disease', 'MESH:D049932', (82, 89))	('mutations', 'Var', (20, 29))
26009	25219808	These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis.	('histone', 'Protein', (32, 39))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (40, 49))	('human', 'Species', '9606', (53, 58))	('glioma', 'Disease', (106, 112))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
26014	25219808	Given the clear importance of histone mutations in pHGG, it will be interesting to see how aberrant epigenetic regulation contributes to tumorigenesis in the pediatric context.	('tumor', 'Disease', (137, 142))	('contributes', 'Reg', (122, 133))	('aberrant', 'Var', (91, 99))	('pHGG', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('epigenetic regulation', 'MPA', (100, 121))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
26027	25219808	For example, epidermal growth factor receptor (EGFR) is the most commonly altered receptor tyrosine kinase (RTK) in aHGG; with the corresponding gene locus undergoing amplification, intragenic deletion, or both in ~50% of cases.	('deletion', 'Var', (193, 201))	('epidermal growth factor receptor', 'Gene', (13, 45))	('aHGG', 'Gene', (116, 120))	('RTK', 'Gene', (108, 111))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('RTK', 'Gene', '5979', (108, 111))	('EGFR', 'Gene', '1956', (47, 51))	('altered', 'Reg', (74, 81))	('receptor tyrosine kinase', 'Gene', (82, 106))	('EGFR', 'Gene', (47, 51))	('receptor tyrosine kinase', 'Gene', '5979', (82, 106))
26028	25219808	First identified in adult glioblastoma, EGFRvIII is the most common EGFR variant in aHGG and is formed by deletion of exons 2-7 resulting in a constitutively active kinase.	('aHGG', 'Gene', (84, 88))	('constitutively active kinase', 'MPA', (143, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('EGFR', 'Gene', '1956', (68, 72))	('deletion', 'Var', (106, 114))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (40, 44))	('adult glioblastoma', 'Disease', (20, 38))	('EGFR', 'Gene', (68, 72))	('variant', 'Var', (73, 80))	('adult glioblastoma', 'Disease', 'MESH:D005909', (20, 38))
26032	25219808	Experimentally, overexpression of wild type (WT) or mutant PDGFRalpha conferred a growth advantage to astrocytes, an effect that was diminished by introduction of the ATP-competitive inhibitors crenolanib or dasatinib.	('ATP', 'Chemical', 'MESH:D000255', (167, 170))	('crenolanib', 'Chemical', 'MESH:C577197', (194, 204))	('overexpression', 'PosReg', (16, 30))	('mutant', 'Var', (52, 58))	('growth', 'MPA', (82, 88))	('PDGFRalpha', 'Gene', (59, 69))	('dasatinib', 'Chemical', 'MESH:D000069439', (208, 217))
26033	25219808	PDGFRalpha mutants drive glioma formation in vivo, with murine-derived HGGs recapitulating critical features of the human disease such as histopathologic characteristics and expression profiles.	('mutants', 'Var', (11, 18))	('PDGFRalpha', 'Gene', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('human', 'Species', '9606', (116, 121))	('drive', 'Reg', (19, 24))	('glioma', 'Disease', (25, 31))	('murine', 'Species', '10090', (56, 62))
26040	25219808	Activation of PI3K signaling caused by mutations of PIK3CA, encoding the catalytic p110alpha subunit of PI3K, or PIK3R1, encoding the regulatory subunit of PI3K, are usually present in mutually exclusive patterns, occurring in approximately 20% of aHGGs and a similar frequency of pHGG, including DIPG .	('PIK3R1', 'Gene', '5295', (113, 119))	('p110alpha', 'Gene', (83, 92))	('PIK3R1', 'Gene', (113, 119))	('PIK3CA', 'Gene', (52, 58))	('mutations', 'Var', (39, 48))	('PI3K signaling', 'MPA', (14, 28))	('DIPG', 'Chemical', '-', (297, 301))	('Activation', 'PosReg', (0, 10))	('PIK3CA', 'Gene', '5290', (52, 58))	('p110alpha', 'Gene', '5290', (83, 92))
26042	25219808	It remains unclear whether all tumors with loss of chromosome 10q are targeting PTEN loss of function when a wild-type PTEN allele is still retained.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('tumors', 'Disease', (31, 37))	('loss of function', 'NegReg', (85, 101))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('loss', 'Var', (43, 47))
26044	25219808	Loss of heterozygosity of chromosome 10q, with or without concurrent PTEN mutation is very frequent in adult glioblastoma, with 10q LOH in approximately 80% and PTEN mutation in 25-40%, while the frequency is significantly lower in pHGGs, with 10q LOH in approximately 30% and PTEN mutation in less than 5-15% .	('mutation', 'Var', (74, 82))	('PTEN', 'Gene', '5728', (69, 73))	('adult glioblastoma', 'Disease', 'MESH:D005909', (103, 121))	('PTEN', 'Gene', '5728', (161, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('PTEN', 'Gene', (277, 281))	('Loss', 'NegReg', (0, 4))	('adult glioblastoma', 'Disease', (103, 121))	('PTEN', 'Gene', '5728', (277, 281))	('PTEN', 'Gene', (161, 165))	('mutation', 'Var', (166, 174))	('10q', 'Var', (128, 131))	('PTEN', 'Gene', (69, 73))
26047	25219808	Notably, homozygous deletion of CDKN2A/B appears to be almost exclusive to pNBS tumors and largely absent in DIPG.	('CDKN2A/B', 'Gene', '1029;1030', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pNBS tumors', 'Disease', (75, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('pNBS tumors', 'Disease', 'MESH:D009369', (75, 86))	('DIPG', 'Chemical', '-', (109, 113))	('deletion', 'Var', (20, 28))	('CDKN2A/B', 'Gene', (32, 40))
26051	25219808	Therapeutic inhibition of this cyclin/CDK complex, using PD-0332991, a highly-selective non-ATP competitive CDK4/6 inhibitor, significantly increased survival in a murine model of DIPG, both as a single agent or following irradiation.	('CDK', 'Gene', (108, 111))	('DIPG', 'Chemical', '-', (180, 184))	('ATP', 'Chemical', 'MESH:D000255', (92, 95))	('CDK', 'Gene', '1019;12567;1021;12571', (108, 111))	('PD-0332991', 'Chemical', 'MESH:C500026', (57, 67))	('survival', 'CPA', (150, 158))	('DIPG', 'Disease', (180, 184))	('murine', 'Species', '10090', (164, 170))	('CDK', 'Gene', (38, 41))	('PD-0332991', 'Var', (57, 67))	('increased', 'PosReg', (140, 149))	('CDK', 'Gene', '1019;12567;1021;12571', (38, 41))
26052	25219808	TP53 mutations occur in up to 35% of pNBS-HGGs (range, 18-35%) and appear to be more common in DIPGs (40-50% of cases).	('TP53', 'Gene', '7157', (0, 4))	('NBS-HGGs', 'Disease', 'MESH:D049932', (38, 46))	('TP53', 'Gene', (0, 4))	('pNBS', 'Chemical', 'MESH:C081297', (37, 41))	('mutations', 'Var', (5, 14))	('DIPGs', 'Chemical', 'MESH:C060938', (95, 100))	('NBS-HGGs', 'Disease', (38, 46))
26055	25219808	Despite some common copy number imbalances such as 13q and 14q loss in approximately one third of HGG regardless of age or location, adult and pHGGs also exhibit a unique constellation of gains and losses that distinguish one from the other, and the same can be said for DIPGs and pNBS-HGGs.	('NBS-HGGs', 'Disease', 'MESH:D049932', (282, 290))	('losses', 'NegReg', (198, 204))	('NBS-HGGs', 'Disease', (282, 290))	('HGG', 'Gene', (98, 101))	('pNBS', 'Chemical', 'MESH:C081297', (281, 285))	('13q', 'Var', (51, 54))	('gains', 'PosReg', (188, 193))	('imbalances', 'Phenotype', 'HP:0002172', (32, 42))	('loss', 'NegReg', (63, 67))	('DIPGs', 'Chemical', 'MESH:C060938', (271, 276))
26065	25219808	As the first reports of histone mutations in human cancer, these mutations implicated novel mechanisms in pHGG tumor biology that are not found to play a significant role in the adult disease.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('implicated', 'Reg', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (45, 50))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (65, 74))
26066	25219808	Whole-genome sequencing of 7 DIPGs and matched germline DNA, as part of the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, identified somatic mutations in H3F3A leading to a p.K27M substitution in histone H3.3 in 4 of 7 cases.	('p.K27M', 'Var', (220, 226))	('H3F3A', 'Gene', (201, 206))	('p.K27M', 'Mutation', 'p.K27M', (220, 226))	('DIPGs', 'Chemical', 'MESH:C060938', (29, 34))	('H3F3A', 'Gene', '3020', (201, 206))	('histone H3.3', 'Gene', (243, 255))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutations', 'Var', (188, 197))	('histone H3.3', 'Gene', '3020', (243, 255))	('Children', 'Species', '9606', (85, 93))
26067	25219808	A fifth case contained an analogous mutation in HIST1H3B yielding a p.K27M alteration in histone H3.1.	('p.K27M', 'Mutation', 'p.K27M', (68, 74))	('histone H3.1', 'Gene', (89, 101))	('HIST1H3B', 'Gene', (48, 56))	('HIST1H3B', 'Gene', '8358', (48, 56))	('histone H3.1', 'Gene', '8358', (89, 101))	('p.K27M', 'Var', (68, 74))
26068	25219808	Subsequent targeted sequencing of all 16 genes encoding histone H3 in a larger cohort of pHGG found p.K27M somatic mutations in 78% of DIPGs; 60% were mutations in H3F3A and 18% in HIST1H3B.	('H3F3A', 'Gene', '3020', (164, 169))	('DIPGs', 'Chemical', 'MESH:C060938', (135, 140))	('H3', 'Gene', '126961', (164, 166))	('H3', 'Gene', '126961', (64, 66))	('p.K27M', 'Var', (100, 106))	('HIST1H3B', 'Gene', (181, 189))	('HIST1H3B', 'Gene', '8358', (181, 189))	('p.K27M', 'Mutation', 'p.K27M', (100, 106))	('H3F3A', 'Gene', (164, 169))	('H3', 'Gene', '126961', (186, 188))
26069	25219808	Similar frequency of histone H3 mutation was found in an independent cohort; however, the proportion of H3F3A and HIST1H3B mutations varied between the groups, likely due to patient age, with HIST1H3B mutations arising in younger children.	('HIST1H3B', 'Gene', (192, 200))	('HIST1H3B', 'Gene', '8358', (192, 200))	('H3', 'Gene', '126961', (119, 121))	('patient', 'Species', '9606', (174, 181))	('HIST1H3B', 'Gene', (114, 122))	('HIST1H3B', 'Gene', '8358', (114, 122))	('H3F3A', 'Gene', '3020', (104, 109))	('H3', 'Gene', '126961', (104, 106))	('H3', 'Gene', '126961', (29, 31))	('H3F3A', 'Gene', (104, 109))	('mutations', 'Var', (123, 132))	('children', 'Species', '9606', (230, 238))	('H3', 'Gene', '126961', (197, 199))
26070	25219808	In pNBS-HGG, H3F3A and HIST1H3B p.K27M substitutions were found in 19% and 3% of cases, respectively.	('H3F3A', 'Gene', '3020', (13, 18))	('NBS-HGG', 'Disease', 'MESH:D049932', (4, 11))	('NBS-HGG', 'Disease', (4, 11))	('H3F3A', 'Gene', (13, 18))	('p.K27M', 'Var', (32, 38))	('p.K27M', 'Mutation', 'p.K27M', (32, 38))	('pNBS', 'Chemical', 'MESH:C081297', (3, 7))	('found', 'Reg', (58, 63))	('HIST1H3B', 'Gene', (23, 31))	('HIST1H3B', 'Gene', '8358', (23, 31))
26071	25219808	Additionally, 14% of pNBS-HGGs harbored somatic mutations in H3F3A leading to p.G34R substitution, whereas no such alteration was identified in any DIPG.	('DIPG', 'Chemical', '-', (148, 152))	('H3F3A', 'Gene', (61, 66))	('pNBS', 'Chemical', 'MESH:C081297', (21, 25))	('p.G34R', 'Mutation', 'rs1057519902', (78, 84))	('NBS-HGGs', 'Disease', (22, 30))	('substitution', 'Var', (85, 97))	('NBS-HGGs', 'Disease', 'MESH:D049932', (22, 30))	('p.G34R substitution', 'Var', (78, 97))	('H3F3A', 'Gene', '3020', (61, 66))
26073	25219808	However, of 8 DIPG samples collected from patients who had not received adjuvant therapy, 7 contained p.K27M substitutions.	('p.K27M', 'Var', (102, 108))	('contained', 'Reg', (92, 101))	('patients', 'Species', '9606', (42, 50))	('DIPG', 'Chemical', '-', (14, 18))	('p.K27M', 'Mutation', 'p.K27M', (102, 108))
26075	25219808	Collaborating groups in Canada and Germany performed whole-exome sequencing of 48 pNBS-HGGs and identified p.K27M, p.G34R, and p.G34V alterations in 19%, 10%, and 2% of cases, respectively, with all changes affecting H3F3A encoding the histone H3.3 variant.	('NBS-HGGs', 'Disease', (83, 91))	('p.G34R', 'Var', (115, 121))	('histone H3.3', 'Gene', '3020', (236, 248))	('p.G34R', 'Mutation', 'rs1057519902', (115, 121))	('NBS-HGGs', 'Disease', 'MESH:D049932', (83, 91))	('p.K27M', 'Var', (107, 113))	('p.K27M', 'Mutation', 'p.K27M', (107, 113))	('H3F3A', 'Gene', '3020', (217, 222))	('pNBS', 'Chemical', 'MESH:C081297', (82, 86))	('H3F3A', 'Gene', (217, 222))	('histone H3.3', 'Gene', (236, 248))	('p.G34V', 'Mutation', 'p.G34V', (127, 133))	('p.G34V', 'Var', (127, 133))	('affecting', 'Reg', (207, 216))
26076	25219808	Additional targeted sequencing of the H3F3A locus in over 700 gliomas of various grades and patient ages revealed these mutations to be exclusive to high-grade tumors and significantly enriched in pediatric cases.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('patient', 'Species', '9606', (92, 99))	('H3F3A', 'Gene', '3020', (38, 43))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('H3F3A', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (160, 166))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
26077	25219808	Of the 11 adult cases harboring H3F3A mutation, all were missense substitutions of G34, and the majority was identified in young adults aged 20-30 years old.	('missense substitutions', 'Var', (57, 79))	('H3F3A', 'Gene', (32, 37))	('G34', 'Gene', (83, 86))	('mutation', 'Var', (38, 46))	('H3F3A', 'Gene', '3020', (32, 37))
26078	25219808	p.K27M mutations occured in tumors involving midline structures (such as the brainstem, cerebellum, and thalamus); while p.G34R/V mutations occurred in non-midline supratentorial lesions (Figure 3).	('p.K27M', 'Mutation', 'p.K27M', (0, 6))	('non-midline supratentorial lesions', 'Disease', 'MESH:D015173', (152, 186))	('p.K27M mutations', 'Var', (0, 16))	('tumors', 'Disease', (28, 34))	('non-midline supratentorial lesions', 'Disease', (152, 186))	('p.G34R', 'Var', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('p.G34R', 'SUBSTITUTION', 'None', (121, 127))	('occured', 'Reg', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
26084	25219808	Notably, recurrent ATRX loss of function mutations were found in approximately one quarter of pHGG, which were also associated with alternative lengthening of telomeres (ALT).	('mutations', 'Var', (41, 50))	('ATRX', 'Gene', '546', (19, 23))	('loss of function', 'NegReg', (24, 40))	('pHGG', 'Gene', (94, 98))	('ATRX', 'Gene', (19, 23))
26085	25219808	All tumors with H3F3A p.G34R/V mutation carried concomitant ATRX mutations, suggesting synergy between the two mutations.	('H3F3A', 'Gene', (16, 21))	('ATRX', 'Gene', (60, 64))	('p.G34R', 'SUBSTITUTION', 'None', (22, 28))	('p.G34R', 'Var', (22, 28))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('ATRX', 'Gene', '546', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('carried', 'Reg', (40, 47))	('H3F3A', 'Gene', '3020', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (65, 74))
26086	25219808	All histone H3 mutations in pHGG were heterozygous, and in any individual tumor, only one of 16 genes encoding histone H3 was mutated.	('H3', 'Gene', '126961', (119, 121))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('pHGG', 'Gene', (28, 32))	('tumor', 'Disease', (74, 79))	('H3', 'Gene', '126961', (12, 14))
26087	25219808	Lysine 27 on histone H3 (H3K27) is a residue that can be acetylated or mono-, di-, or trimethylated (H3K27me3).	('H3K27', 'Gene', (25, 30))	('H3K27', 'Gene', (101, 106))	('H3K27', 'Gene', '126961', (25, 30))	('H3K27', 'Gene', '126961', (101, 106))	('H3', 'Gene', '126961', (21, 23))	('H3', 'Gene', '126961', (25, 27))	('trimethylated', 'Var', (86, 99))	('di-', 'Var', (78, 81))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('H3', 'Gene', '126961', (101, 103))
26088	25219808	Although mutant histone H3.1/3.3 make up a minority of the total cellular histone H3 pool, p.K27M mutations led to loss of total H3K27me2/3 of the entire cellular H3 pool, most of which is wild-type.	('p.K27M mutations', 'Var', (91, 107))	('H3', 'Gene', '126961', (129, 131))	('H3', 'Gene', '126961', (82, 84))	('loss', 'NegReg', (115, 119))	('histone H3.1', 'Gene', '8358', (16, 28))	('histone H3.1', 'Gene', (16, 28))	('H3', 'Gene', '126961', (24, 26))	('H3K27', 'Gene', (129, 134))	('p.K27M', 'Mutation', 'p.K27M', (91, 97))	('H3K27', 'Gene', '126961', (129, 134))	('H3', 'Gene', '126961', (163, 165))
26089	25219808	This dominant negative effect appears to be caused by inhibition of the H3K27 methylase EZH2 due to interaction with p.K27M mutant histone H3.	('EZH2', 'Gene', (88, 92))	('p.K27M', 'Var', (117, 123))	('H3K27', 'Gene', (72, 77))	('p.K27M', 'Mutation', 'p.K27M', (117, 123))	('H3K27', 'Gene', '126961', (72, 77))	('interaction', 'Interaction', (100, 111))	('H3', 'Gene', '126961', (72, 74))	('inhibition', 'NegReg', (54, 64))	('negative', 'NegReg', (14, 22))	('H3', 'Gene', '126961', (139, 141))	('EZH2', 'Gene', '2146', (88, 92))
26090	25219808	Globally, both p.K27M and p.G34R/V tumors exhibit DNA hypomethylation.	('DNA hypomethylation', 'MPA', (50, 69))	('p.G34R', 'SUBSTITUTION', 'None', (26, 32))	('p.G34R', 'Var', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('V tumors', 'Disease', 'MESH:D009369', (33, 41))	('p.K27M', 'Mutation', 'p.K27M', (15, 21))	('p.K27M', 'Var', (15, 21))	('V tumors', 'Disease', (33, 41))
26091	25219808	In an unsupervised comparison of genome-wide DNA methylation signatures, tumors with p.K27M and tumors with p.G34R/V form independent clusters based on histone mutation status.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('p.K27M', 'Var', (85, 91))	('p.K27M', 'Mutation', 'p.K27M', (85, 91))	('p.G34R', 'SUBSTITUTION', 'None', (108, 114))	('p.G34R', 'Var', (108, 114))
26095	25219808	Genome-wide sequencing approaches revealed that 20-32% of DIPGs harbored somatic missense mutations in ACVR1, also known as ALK2 which encodes a receptor serine/threonine kinase mediating bone morphogenetic protein (BMP)-induced signal transduction.	('missense mutations', 'Var', (81, 99))	('ALK2', 'Gene', (124, 128))	('bone morphogenetic protein', 'Gene', (188, 214))	('bone morphogenetic protein', 'Gene', '649', (188, 214))	('ALK2', 'Gene', '90', (124, 128))	('BMP', 'Gene', '649', (216, 219))	('ACVR1', 'Gene', (103, 108))	('ACVR1', 'Gene', '90', (103, 108))	('DIPGs', 'Chemical', 'MESH:C060938', (58, 63))	('BMP', 'Gene', (216, 219))
26096	25219808	These mutations frequently co-occur with histone H3.1 p.K27M substitutions.	('histone H3.1', 'Gene', '8358', (41, 53))	('histone H3.1', 'Gene', (41, 53))	('co-occur', 'Reg', (27, 35))	('p.K27M', 'Var', (54, 60))	('p.K27M', 'Mutation', 'p.K27M', (54, 60))
26098	25219808	Thus, these mutations further clarify molecular subgroups within DIPG.	('clarify', 'Reg', (30, 37))	('mutations', 'Var', (12, 21))	('DIPG', 'Chemical', '-', (65, 69))
26099	25219808	Surprisingly, some of the somatic mutations found in DIPG were the same as previously reported ACVR1 germline mutations in fibrodysplasia ossificans progressiva (FOP), a disease characterized by heterotopic bone formation exacerbated by inflammation that is not associated with cancer predisposition.	('inflammation', 'Disease', (237, 249))	('heterotopic bone formation', 'Phenotype', 'HP:0011986', (195, 221))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', (278, 284))	('mutations', 'Var', (110, 119))	('fibrodysplasia', 'Disease', 'MESH:D009221', (123, 137))	('ACVR1', 'Gene', (95, 100))	('DIPG', 'Chemical', '-', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('ACVR1', 'Gene', '90', (95, 100))	('fibrodysplasia', 'Disease', (123, 137))	('inflammation', 'Disease', 'MESH:D007249', (237, 249))	('mutations', 'Var', (34, 43))
26100	25219808	Expression of fusion genes was common in pHGG, including DIPG, although most of the fusion genes were not recurrent.	('common', 'Reg', (31, 37))	('pHGG', 'Disease', (41, 45))	('DIPG', 'Chemical', '-', (57, 61))	('fusion', 'Var', (14, 20))	('DIPG', 'Disease', (57, 61))
26101	25219808	Strikingly, chimeric genes fusing N-terminal sequences from a number of different genes to the kinase domain of the neurotrophic tyrosine receptor kinase (NTRK) family members were recurrent gene fusions, found in 40% of infant NBS-HGGs, and at much lower frequency in pHGG overall.	('NBS-HGGs', 'Disease', 'MESH:D049932', (228, 236))	('chimeric genes', 'Var', (12, 26))	('infant', 'Species', '9606', (221, 227))	('NBS-HGGs', 'Disease', (228, 236))
26104	25219808	NTRK fusions were also identified in adult glioblastoma as well as pLGG, but do not appear to be as enriched as in infant NBS-HGG.	('NBS-HGG', 'Disease', 'MESH:D049932', (122, 129))	('NBS-HGG', 'Disease', (122, 129))	('infant', 'Species', '9606', (115, 121))	('fusions', 'Var', (5, 12))	('adult glioblastoma', 'Disease', (37, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('adult glioblastoma', 'Disease', 'MESH:D005909', (37, 55))	('NTRK', 'Gene', (0, 4))	('identified', 'Reg', (23, 33))	('pLGG', 'Disease', (67, 71))
26107	25219808	The high frequency of histone mutations in pHGG strongly suggests that epigenetic dysregulation plays a major role in tumors arising within the pediatric setting.	('pHGG', 'Gene', (43, 47))	('histone', 'Protein', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
26124	30498429	As for glioma, deep learning has shown promising capabilities in predicting key molecular markers such as 1p19q codeletion and MGMT promoter methylation by using MRI images.	('glioma', 'Disease', 'MESH:D005910', (7, 13))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('1p19q codeletion', 'Var', (106, 122))	('MGMT', 'Gene', (127, 131))	('MGMT', 'Gene', '4255', (127, 131))	('glioma', 'Disease', (7, 13))
26194	24825818	The two most widely used amino acid PET radiotracers in human brain tumor imaging include l-[methyl-11C] methionine (MET) and 18F-fluoroethyl-tyrosine (FET).	('l-[methyl-11C', 'Var', (90, 103))	('brain tumor', 'Disease', (62, 73))	('human', 'Species', '9606', (56, 61))	('MET', 'Chemical', 'MESH:D008715', (117, 120))	('brain tumor', 'Disease', 'MESH:D001932', (62, 73))	('18F-fluoroethyl-tyrosine', 'Var', (126, 150))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('brain tumor', 'Phenotype', 'HP:0030692', (62, 73))	('18F-fluoroethyl-tyrosine', 'Chemical', 'MESH:C545932', (126, 150))	('FET', 'Chemical', 'MESH:C545932', (152, 155))	('l-[methyl-11C] methionine', 'Chemical', 'MESH:C038344', (90, 115))
26205	24825818	For brain tumor imaging, amino acid PET has a remarkable advantage over FDG-PET due to its high uptake in tumor cells compared to low uptake in normal brain cells.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('advantage', 'PosReg', (57, 66))	('tumor', 'Disease', (10, 15))	('FDG', 'Chemical', '-', (72, 75))	('brain tumor', 'Disease', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('brain tumor', 'Disease', 'MESH:D001932', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('amino acid PET', 'Var', (25, 39))	('brain tumor', 'Phenotype', 'HP:0030692', (4, 15))	('uptake', 'MPA', (96, 102))	('tumor', 'Disease', (106, 111))
26208	24825818	However, such tracers, especially standard methionine and tryptophan analogues, also produce a number of non-protein-bound metabolites; thus, only 11C-leucine appears to be suitable for measuring protein synthesis, and accurate estimation of protein synthesis rates can be difficult and cumbersome.	('methionine', 'Chemical', 'MESH:D008715', (43, 53))	('tryptophan', 'Chemical', 'MESH:D014364', (58, 68))	('11C-leucine', 'Chemical', '-', (147, 158))	('non-protein-bound metabolites', 'MPA', (105, 134))	('protein synthesis', 'MPA', (196, 213))	('11C-leucine', 'Var', (147, 158))
26231	24825818	A study of 22 non-contrast-enhancing gliomas (where the confounding effect of blood-brain barrier leakage was eliminated) found that high FET SUV in the tumor mass highly correlated with vascular and cellular density.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('high FET', 'Var', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('correlated', 'Reg', (171, 181))	('FET', 'Chemical', 'MESH:C545932', (138, 141))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
26245	24825818	Among the four radiotracers, MET-PET is the most widely studied in brain tumor imaging.	('MET', 'Chemical', 'MESH:D008715', (29, 32))	('brain tumor', 'Phenotype', 'HP:0030692', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('brain tumor', 'Disease', 'MESH:D001932', (67, 78))	('brain tumor', 'Disease', (67, 78))	('MET-PET', 'Var', (29, 36))
26258	24825818	The same group also reported that MET-PET improved tumor volume definition over MRI in the majority (88%) of low-grade tumors during radiotherapy planning, whereas FDG-PET would not be helpful in such cases.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (119, 125))	('MET-PET', 'Var', (34, 41))	('improved', 'PosReg', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('MET', 'Chemical', 'MESH:D008715', (34, 37))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('FDG', 'Chemical', '-', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
26315	24825818	However, most studies focused on measuring abnormalities in brain serotonin synthesis or detecting epileptic foci.	('serotonin', 'Chemical', 'MESH:D012701', (66, 75))	('abnormalities in brain serotonin', 'Phenotype', 'HP:0003144', (43, 75))	('epileptic', 'Disease', (99, 108))	('brain serotonin synthesis', 'MPA', (60, 85))	('abnormalities', 'Var', (43, 56))	('abnormalities in brain', 'Phenotype', 'HP:0012443', (43, 65))	('epileptic', 'Disease', 'MESH:D004827', (99, 108))
26356	24825818	Amino acid PET offers powerful molecular imaging probes for noninvasive evaluation of brain tumors.	('Amino acid', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('brain tumors', 'Disease', 'MESH:D001932', (86, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('brain tumors', 'Phenotype', 'HP:0030692', (86, 98))	('brain tumor', 'Phenotype', 'HP:0030692', (86, 97))	('brain tumors', 'Disease', (86, 98))
26361	23650591	BRAF, GNAQ, and GNA11 mutations and copy number in pediatric low-grade glioma We investigated the occurrence of BRAF, GNAQ, and GNA11 mutations in pediatric low-grade glioma.	('GNA11', 'Gene', (16, 21))	('GNA11', 'Gene', (128, 133))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('RAF', 'Gene', '22882', (1, 4))	('BRAF', 'Gene', '673', (0, 4))	('GNAQ', 'Gene', (6, 10))	('BRAF', 'Gene', (0, 4))	('RAF', 'Gene', (113, 116))	('glioma', 'Disease', (167, 173))	('RAF', 'Gene', (1, 4))	('glioma', 'Disease', 'MESH:D005910', (167, 173))	('GNA11', 'Gene', '2767', (128, 133))	('GNA11', 'Gene', '2767', (16, 21))	('glioma', 'Disease', (71, 77))	('mutations', 'Var', (22, 31))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('GNAQ', 'Chemical', '-', (6, 10))	('GNAQ', 'Chemical', '-', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('RAF', 'Gene', '22882', (113, 116))
26362	23650591	Fifty-two samples of pediatric low-grade glioma (48 primary, 4 recurrent) were analyzed for BRAF copy number variation (digital PCR analysis, CopyCaller) and point mutations of BRAF V600E, and exon 5 Q209 in GNAQ, and GNA11, using the MALDI-TOF mass spectrometer with validation by direct sequencing.	('V600E', 'Mutation', 'rs113488022', (182, 187))	('V600E', 'Var', (182, 187))	('BRAF', 'Gene', (177, 181))	('point mutations', 'Var', (158, 173))	('GNA11', 'Gene', (218, 223))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('low-grade glioma', 'Disease', (31, 47))	('copy number variation', 'Var', (97, 118))	('Q209', 'Var', (200, 204))
26363	23650591	An increased BRAF copy number was found in 18/47 primary samples tested; 15 of them (83.3%) were pilocytic astrocytomas.	('increased', 'PosReg', (3, 12))	('pilocytic astrocytomas', 'Disease', (97, 119))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (97, 118))	('astrocytoma', 'Disease', 'MESH:D001254', (107, 118))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (97, 119))	('astrocytoma', 'Disease', (107, 118))	('BRAF', 'Gene', (13, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('copy number', 'Var', (18, 29))
26364	23650591	A BRAF mutation was found in 3/48 primary tumors, all with a normal BRAF copy number and no GNAQ mutation.	('tumor', 'Disease', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', (2, 6))	('mutation', 'Var', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
26365	23650591	One sample had a GNAQ209 mutation (Q209P626) with a normal BRAF gene; none of the tumors had a GNA11Q209 mutation.	('GNA11Q209', 'Gene', (95, 104))	('GNA11Q209', 'Gene', '2767', (95, 104))	('Q209P626', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('BRAF', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
26367	23650591	Increased BRAF copy number and activating BRAF mutations may be involved in the development of low-grade glioma via overactivation of the Ras/Raf pathway.	('overactivation', 'PosReg', (116, 130))	('involved', 'Reg', (64, 72))	('low-grade glioma', 'Disease', (95, 111))	('Raf', 'Gene', '22882', (142, 145))	('mutations', 'Var', (47, 56))	('activating', 'PosReg', (31, 41))	('BRAF', 'Gene', (10, 14))	('Raf', 'Gene', (142, 145))	('BRAF', 'Gene', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
26375	23650591	The Ras/Raf pathway may also be activated by oncogenic mutations of the RAF gene itself, such as the substitution of glutamic acid for valine at amino acid 600 (V600E).	('Ras/Raf pathway', 'Pathway', (4, 19))	('activated', 'PosReg', (32, 41))	('RAF', 'Gene', (72, 75))	('glutamic acid for valine at amino acid 600', 'Mutation', 'rs113488022', (117, 159))	('V600E', 'Var', (161, 166))	('V600E', 'SUBSTITUTION', 'None', (161, 166))
26378	23650591	BRAF and GNAQ mutations are mutually exclusive in several tumors, such as uveal melanoma.	('GNAQ', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('BRAF', 'Gene', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('mutations', 'Var', (14, 23))
26385	23650591	The V600E point mutation was identified in the BRAF gene in 3 of the 48 primary samples (6.3%) (Table 3), derived from one patient each with pilocytic astrocytoma, ganglioglioma, and pleomorphic xanthoastrocytoma.	('V600E', 'Var', (4, 9))	('V600E', 'SUBSTITUTION', 'None', (4, 9))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('pleomorphic xanthoastrocytoma', 'Disease', (183, 212))	('astrocytoma', 'Phenotype', 'HP:0009592', (151, 162))	('ganglioglioma', 'Disease', (164, 177))	('BRAF', 'Gene', (47, 51))	('astrocytoma', 'Phenotype', 'HP:0009592', (201, 212))
26386	23650591	1 demonstrates the mutation in exon 15 of the BRAF gene, in which the nucleotide thymine (T) is replaced with adenine (A), leading to the translation of glutamic acid instead of valine and, thereby, to overactivation of the Ras/Raf cascade.	('Ras/Raf cascade', 'Pathway', (224, 239))	('BRAF', 'Gene', (46, 50))	('mutation', 'Var', (19, 27))	('adenine', 'Chemical', 'MESH:D000225', (110, 117))	('overactivation', 'PosReg', (202, 216))	('glutamic', 'Protein', (153, 161))	('valine', 'MPA', (178, 184))	('nucleotide thymine', 'Chemical', 'MESH:D013942', (70, 88))	('translation', 'MPA', (138, 149))
26387	23650591	15, Table 3) with a mutation in codon 209, in which the nucleotide adenine (A) is replaced with cytosine (C), causing loss of GTPase activity and constitutive activation of the Ras cascade.	('activation', 'PosReg', (159, 169))	('loss', 'NegReg', (118, 122))	('GTPase', 'Protein', (126, 132))	('Ras cascade', 'Pathway', (177, 188))	('nucleotide adenine', 'Chemical', 'MESH:D000227', (56, 74))	('cytosine', 'Chemical', 'MESH:D003596', (96, 104))	('activity', 'MPA', (133, 141))	('mutation in', 'Var', (20, 31))
26390	23650591	found that 7q34 duplication was the mechanism of BRAF activation in 53% of pilocytic astrocytomas, but was negative in gangliogliomas and pleomorphic xanthoastrocytomas.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('gangliogliomas and pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D018303', (119, 168))	('activation', 'PosReg', (54, 64))	('pilocytic astrocytomas', 'Disease', (75, 97))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('7q34 duplication', 'Var', (11, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (85, 96))
26392	23650591	Mutations in the BRAF gene and changes in its copy number have also been described in lung and colon carcinoma, thyroid cancer, and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('melanoma', 'Disease', (132, 140))	('described', 'Reg', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('thyroid cancer', 'Disease', (112, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('lung', 'Disease', (86, 90))	('thyroid cancer', 'Phenotype', 'HP:0002890', (112, 126))	('BRAF', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('thyroid cancer', 'Disease', 'MESH:D013964', (112, 126))	('colon carcinoma', 'Disease', 'MESH:D015179', (95, 110))	('colon carcinoma', 'Disease', (95, 110))
26393	23650591	Interestingly, administration of a drug that inhibits the mutated activated BRAF gene reportedly led to complete or partial regression of metastatic melanoma in humans.	('activated BRAF', 'Gene', (66, 80))	('inhibits', 'NegReg', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('metastatic melanoma', 'Disease', (138, 157))	('humans', 'Species', '9606', (161, 167))	('mutated', 'Var', (58, 65))
26397	23650591	Inhibitors of the MAPK pathway, such as AZD6244 and sorafenib, have been approved for the treatment of several types of cancer and may be suitable for children with aggressive, recurrent, or unresectable tumors.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('sorafenib', 'Chemical', 'MESH:D000077157', (52, 61))	('MAPK pathway', 'Pathway', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('AZD6244', 'Var', (40, 47))	('sorafenib', 'Gene', (52, 61))	('AZD6244', 'Chemical', 'MESH:C517975', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
26405	23650591	Oncogenic mutations in GNAQ (GNAQQ209, exon 5), GNA11 (GNA11Q209, exon 5) and BRAF (BRAFV600E, exon 15) were analyzed with the chip-based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometer (Sequenom, San Diego, CA).	('GNAQ', 'Gene', (23, 27))	('GNA11Q209', 'Var', (55, 64))	('BRAFV600E', 'Gene', '673', (84, 93))	('GNA11', 'Gene', (48, 53))	('GNAQQ209', 'Var', (29, 37))	('BRAFV600E', 'Gene', (84, 93))
26414	32977537	Recently, the world of non-coding RNAs (ncRNAs) has become a field of intensive research since the discovery of their essential impact on carcinogenesis.	('ncRNA', 'Gene', (40, 45))	('ncRNA', 'Gene', '220202', (40, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))	('non-coding', 'Var', (23, 33))	('carcinogenesis', 'Disease', (138, 152))
26429	32977537	The diverse roles of ncRNAs include regulating gene transcription, post-transcription, translation, and epigenetic modification.	('translation', 'MPA', (87, 98))	('regulating', 'Reg', (36, 46))	('epigenetic modification', 'Var', (104, 127))	('ncRNA', 'Gene', (21, 26))	('post-transcription', 'MPA', (67, 85))	('ncRNA', 'Gene', '220202', (21, 26))	('gene transcription', 'MPA', (47, 65))
26455	32977537	Notably, within gliomas, we can divide these molecular biomarkers into those with a point mutation in the IDH1 or IDH2 gene (IDH-mutant), which occurs predominantly in lower-grade gliomas (WHO grade II/III), or else into secondary GBM with no mutation (IDH-wildtype).	('gliomas', 'Disease', (180, 187))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('IDH', 'Gene', '3417', (114, 117))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('IDH1', 'Gene', '3417', (106, 110))	('IDH', 'Gene', '3417', (106, 109))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('point mutation', 'Var', (84, 98))	('IDH', 'Gene', (253, 256))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (16, 23))	('IDH', 'Gene', (125, 128))	('IDH', 'Gene', '3417', (253, 256))	('GBM', 'Phenotype', 'HP:0012174', (231, 234))	('IDH2', 'Gene', (114, 118))	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('IDH', 'Gene', (114, 117))	('IDH2', 'Gene', '3418', (114, 118))	('IDH1', 'Gene', (106, 110))	('IDH', 'Gene', '3417', (125, 128))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('IDH', 'Gene', (106, 109))
26457	32977537	The presence of the IDH1 mutation is associated with comparatively prolonged patient survival; the median overall survival in these patients is 3.8 years, and in patients without IDH mutation, survival is 1.1 years.	('IDH1', 'Gene', '3417', (20, 24))	('patients', 'Species', '9606', (162, 170))	('IDH1', 'Gene', (20, 24))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (20, 23))	('IDH', 'Gene', '3417', (179, 182))	('mutation', 'Var', (25, 33))	('patient', 'Species', '9606', (162, 169))	('presence', 'Var', (4, 12))	('patient', 'Species', '9606', (132, 139))	('patient', 'Species', '9606', (77, 84))	('patients', 'Species', '9606', (132, 140))
26459	32977537	In GBM, mutations within the gene encoding the tumor suppressor protein TP53 and a protein belonging to the family of chromatin remodeling proteins, ATRX, are most often observed, probably affecting the regulation of gene expression.	('observed', 'Reg', (170, 178))	('TP53', 'Gene', '7157', (72, 76))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('affecting', 'Reg', (189, 198))	('TP53', 'Gene', (72, 76))	('GBM', 'Gene', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('expression', 'Species', '29278', (222, 232))	('ATRX', 'Gene', (149, 153))	('regulation of gene expression', 'MPA', (203, 232))	('tumor', 'Disease', (47, 52))
26462	32977537	Moreover, in 40% of cases of GBM, a deletion is observed in the CDKN2A gene, which encodes the p16INK4a protein:an inhibitor in the cell cycle.	('GBM', 'Phenotype', 'HP:0012174', (29, 32))	('deletion', 'Var', (36, 44))	('p16INK4a', 'Gene', (95, 103))	('CDKN2A', 'Gene', (64, 70))	('p16INK4a', 'Gene', '1029', (95, 103))	('CDKN2A', 'Gene', '1029', (64, 70))
26463	32977537	Epigenetic mechanisms are considered to have a possible prognostic significance in GBM, the most essential of which is incorrect methylation of the CpG islands observed within the suppressor genes, which, consequently, may lead to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (231, 245))	('methylation', 'Var', (129, 140))	('GBM', 'Disease', (83, 86))	('carcinogenesis', 'Disease', (231, 245))	('lead to', 'Reg', (223, 230))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('incorrect methylation', 'Var', (119, 140))
26464	32977537	Likewise, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has prognostic significance in patients, which occurs in approximately 50% of gliomas, and definitely more often in GBM recurrence.	('often', 'Reg', (191, 196))	('MGMT', 'Gene', '4255', (69, 73))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (29, 67))	('patients', 'Species', '9606', (115, 123))	('MGMT', 'Gene', (69, 73))	('gliomas', 'Disease', (162, 169))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('O6-methylguanine-DNA methyltransferase', 'Gene', (29, 67))	('methylation', 'Var', (10, 21))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('GBM recurrence', 'Disease', (200, 214))	('GBM', 'Phenotype', 'HP:0012174', (200, 203))
26465	32977537	Methylation of the MGMT promoter results in its reduced expression, making chemotherapy with alkylating agents more effective in these patients.	('patients', 'Species', '9606', (135, 143))	('Methylation', 'Var', (0, 11))	('reduced', 'NegReg', (48, 55))	('expression', 'Species', '29278', (56, 66))	('MGMT', 'Gene', '4255', (19, 23))	('expression', 'MPA', (56, 66))	('MGMT', 'Gene', (19, 23))
26473	32977537	Somatic histone 3 mutations are observed in more than 50% of pGBMs, namely H3.3 K27M, characteristic of diffuse midline high-grade gliomas, and H3.3 G34R/V, seen in hemispheric high-grade gliomas.	('K27M', 'Var', (80, 84))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('pGBMs', 'Gene', (61, 66))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('H3.3 K27M', 'Var', (75, 84))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('histone 3', 'Gene', (8, 17))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('G34R', 'SUBSTITUTION', 'None', (149, 153))	('G34R', 'Var', (149, 153))	('gliomas', 'Disease', (188, 195))	('K27M', 'Mutation', 'p.K27M', (80, 84))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))
26474	32977537	Mutations in IDH1 and IDH2 are observed in less than 5% of pediatric high-grade gliomas.	('IDH2', 'Gene', '3418', (22, 26))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('IDH2', 'Gene', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('IDH1', 'Gene', '3417', (13, 17))	('observed', 'Reg', (31, 39))
26475	32977537	Further, histone 3 and IDH1/2 wild-type pGBM can be subdivided into three subgroups: (1) receptor tyrosine kinase, characterized by the deletion of CDKN2A/B, the mutation of TP53, and the amplification of EGFR and PDGFRA; (2) mesenchymal, characterized by mutations in NF1; and (3) pleomorphic xanthoastrocytoma (PXA)-like, characterized by the deletion of CKDN2A and BRAF V600E mutations.	('subgroup', 'Species', '167160', (74, 82))	('CDKN2A/B', 'Gene', '1029;1030', (148, 156))	('TP53', 'Gene', (174, 178))	('EGFR', 'Gene', '1956', (205, 209))	('deletion', 'Var', (136, 144))	('mutations', 'Var', (256, 265))	('NF1', 'Gene', (269, 272))	('IDH1/2', 'Gene', '3417;3418', (23, 29))	('V600E', 'Var', (373, 378))	('IDH1/2', 'Gene', (23, 29))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (282, 311))	('TP53', 'Gene', '7157', (174, 178))	('GBM', 'Phenotype', 'HP:0012174', (41, 44))	('EGFR', 'Gene', (205, 209))	('CDKN2A/B', 'Gene', (148, 156))	('BRAF', 'Gene', '673', (368, 372))	('mesenchymal', 'CPA', (226, 237))	('BRAF', 'Gene', (368, 372))	('pleomorphic xanthoastrocytoma', 'Disease', (282, 311))	('deletion', 'Var', (345, 353))	('PDGFRA', 'Gene', (214, 220))	('PDGFRA', 'Gene', '5156', (214, 220))	('CKDN2A', 'Gene', (357, 363))	('V600E', 'Mutation', 'rs113488022', (373, 378))	('NF1', 'Gene', '4763', (269, 272))
26476	32977537	Additionally, in 80% of pediatric high-grade gliomas, activation of the PI3-kinase/Akt/mTOR signaling pathway is observed, and the majority have mutations in the tumor suppressor gene TP53.	('mTOR', 'Gene', '2475', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Akt', 'Gene', (83, 86))	('mutations', 'Var', (145, 154))	('tumor', 'Disease', (162, 167))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('TP53', 'Gene', '7157', (184, 188))	('activation', 'PosReg', (54, 64))	('TP53', 'Gene', (184, 188))	('Akt', 'Gene', '207', (83, 86))	('gliomas', 'Disease', (45, 52))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('mTOR', 'Gene', (87, 91))
26477	32977537	Overexpression of p53 in these gliomas is correlated with a poorer five-year progression-free survival.	('poorer', 'NegReg', (60, 66))	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('expression', 'Species', '29278', (4, 14))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('Overexpression', 'Var', (0, 14))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
26478	32977537	Many pediatric low-grade gliomas are characterized by genetic alterations associated with the RAS-MAPK pathway, the majority of which contain the BRAF oncogene.	('BRAF', 'Gene', (146, 150))	('BRAF', 'Gene', '673', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('genetic alterations', 'Var', (54, 73))	('RAS-MAPK pathway', 'Pathway', (94, 110))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
26479	32977537	Tandem duplication on chromosome 7q34 occurs in 70-80% of pediatric pilocytic astrocytomas.	('Tandem duplication', 'Var', (0, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (78, 90))	('occurs', 'Reg', (38, 44))	('astrocytomas', 'Disease', (78, 90))
26480	32977537	These duplications result in a fusion of BRAF with KIAA1549.	('result in', 'Reg', (19, 28))	('duplications', 'Var', (6, 18))	('BRAF', 'Gene', '673', (41, 45))	('KIAA1549', 'Gene', (51, 59))	('KIAA1549', 'Gene', '57670', (51, 59))	('BRAF', 'Gene', (41, 45))
26483	32977537	It was discovered that another MAPK pathway had mutations in low-grade gliomas, for instance, FGFR1 alterations and NTRK family fusions, and changes in MYB and MYBL1 oncogenes in angiocentric glioma and diffuse astrocytomas (WHO grade II).	('FGFR1', 'Gene', '2260', (94, 99))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('changes', 'Reg', (141, 148))	('mutations', 'Var', (48, 57))	('MYB', 'Gene', '4602', (160, 163))	('MYB', 'Gene', '4602', (152, 155))	('MYB', 'Gene', (152, 155))	('MYB', 'Gene', (160, 163))	('FGFR1', 'Gene', (94, 99))	('astrocytomas', 'Disease', (211, 223))	('MAPK pathway', 'Pathway', (31, 43))	('gliomas', 'Disease', (71, 78))	('MYBL1', 'Gene', (160, 165))	('angiocentric glioma', 'Disease', (179, 198))	('MYBL1', 'Gene', '4603', (160, 165))	('angiocentric glioma', 'Disease', 'MESH:D005910', (179, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('NTRK', 'Gene', (116, 120))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('astrocytomas', 'Disease', 'MESH:D001254', (211, 223))	('alterations', 'Var', (100, 111))
26484	32977537	In diffuse astrocytomas and PXA, CDKN2A/B mutations are sometimes observed.	('observed', 'Reg', (66, 74))	('CDKN2A/B', 'Gene', '1029;1030', (33, 41))	('astrocytomas', 'Disease', 'MESH:D001254', (11, 23))	('CDKN2A/B', 'Gene', (33, 41))	('astrocytomas', 'Disease', (11, 23))	('PXA', 'Disease', (28, 31))	('mutations', 'Var', (42, 51))
26491	32977537	These tumors are associated with the activation of the WNT pathway, and are characterized by frequent mutations in exon 3 of CTNNB1 encoding b-catenin and monosomy 6.	('mutations in exon', 'Var', (102, 119))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('WNT pathway', 'Pathway', (55, 66))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('b-catenin', 'Gene', '1499', (141, 150))	('CTNNB1', 'Gene', (125, 131))	('b-catenin', 'Gene', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('CTNNB1', 'Gene', '1499', (125, 131))
26493	32977537	They harbor mutations in Patched 1, SUFU, and Smoothened, correlating with the activation of the SHH pathway.	('Patched 1', 'Gene', '5727', (25, 34))	('Patched 1', 'Gene', (25, 34))	('SHH', 'Gene', '6469', (97, 100))	('SHH', 'Gene', (97, 100))	('mutations', 'Var', (12, 21))	('activation', 'PosReg', (79, 89))	('SUFU', 'Gene', (36, 40))	('SUFU', 'Gene', '51684', (36, 40))
26494	32977537	This subgroup is also characterized by amplifications of GLI2 and MYCN and mutations in the TERT promoter.	('TERT', 'Gene', (92, 96))	('subgroup', 'Species', '167160', (5, 13))	('TERT', 'Gene', '7015', (92, 96))	('MYC', 'Gene', (66, 69))	('GLI2', 'Protein', (57, 61))	('MYC', 'Gene', '4609', (66, 69))	('mutations', 'Var', (75, 84))	('amplifications', 'Var', (39, 53))
26496	32977537	It is also associated with amplifications of the MYC oncogene.	('MYC', 'Gene', '4609', (49, 52))	('MYC', 'Gene', (49, 52))	('amplifications', 'Var', (27, 41))	('associated', 'Reg', (11, 21))
26497	32977537	However, the most frequent subgroup, which contains 40% of cases, is group D medulloblastoma, which is characterized by amplification of MYCN, tandem duplications of SNCAIP, and mutations in chromosome 17 in 80% of cases.	('medulloblastoma', 'Phenotype', 'HP:0002885', (77, 92))	('tandem duplications', 'Var', (143, 162))	('medulloblastoma', 'Disease', (77, 92))	('subgroup', 'Species', '167160', (27, 35))	('MYC', 'Gene', '4609', (137, 140))	('mutations', 'Var', (178, 187))	('MYC', 'Gene', (137, 140))	('SNCAIP', 'Gene', (166, 172))	('medulloblastoma', 'Disease', 'MESH:D008527', (77, 92))
26512	32977537	LncRNAs have been shown to perform diverse functions, including chromatin structure remodeling and histone modifications, to activate or repress genes in the nucleus or modulate signal transduction in cytosol.	('repress', 'NegReg', (137, 144))	('ncRNA', 'Gene', '220202', (1, 6))	('modifications', 'Var', (107, 120))	('modulate', 'Reg', (169, 177))	('activate', 'PosReg', (125, 133))	('genes', 'Gene', (145, 150))	('ncRNA', 'Gene', (1, 6))	('signal transduction', 'MPA', (178, 197))
26518	32977537	For instance, a notable amount of data suggest that aberrant HOTAIR expression is associated with various types of cancer:for example, breast, hepatocellular, gastric, colorectal, and pancreatic cancers.	('pancreatic cancers', 'Disease', 'MESH:D010190', (184, 202))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('colorectal', 'Disease', (168, 178))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('gastric', 'Disease', (159, 166))	('expression', 'Species', '29278', (68, 78))	('colorectal', 'Disease', 'MESH:D015179', (168, 178))	('cancer', 'Disease', (195, 201))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (184, 202))	('HOTAIR', 'Gene', '100124700', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('pancreatic cancers', 'Disease', (184, 202))	('cancer', 'Disease', (115, 121))	('hepatocellular', 'Disease', (143, 157))	('HOTAIR', 'Gene', (61, 67))	('breast', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('aberrant', 'Var', (52, 60))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))
26522	32977537	Some of the circular transcripts might also appear via direct RNA ligation, circularization of introns that have escaped from debranching, or splicing of intermediates.	('splicing', 'Var', (142, 150))	('debranching', 'Disease', 'MESH:D006010', (126, 137))	('circularization', 'Var', (76, 91))	('debranching', 'Disease', (126, 137))	('appear', 'Reg', (44, 50))
26529	32977537	Less understood functions of circular transcripts have also been reported, such as regulation of expression of the parental genes, serving as a scaffolds in the protein complexes, or alternative splicing control (Figure 2).	('alternative splicing control', 'Var', (183, 211))	('expression', 'MPA', (97, 107))	('expression', 'Species', '29278', (97, 107))
26530	32977537	Circular transcripts are considered to be more often downregulated in tumor tissue compared to healthy tissue, which is explained by back-splicing machinery errors, circRNA degradation by deregulated miRNAs, or reduction of the number of circRNAs by increased cell proliferation.	('errors', 'Var', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miRNAs', 'MPA', (200, 206))	('deregulated', 'Var', (188, 199))	('tumor', 'Disease', (70, 75))	('reduction', 'NegReg', (211, 220))	('circRNA degradation', 'MPA', (165, 184))	('Cir', 'Gene', '9541', (0, 3))	('Cir', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('downregulated', 'NegReg', (53, 66))
26549	32977537	There have also been reports of snoRNAs acting as cancer oncogenes, such as SNORA42, which is overexpressed in non-small cell lung carcinoma (NSCLC) and SNORD112-114 in a subgroup of patients with acute promyelocytic leukemia (APML).	('snoRNA', 'Gene', (32, 38))	('cancer', 'Disease', (50, 56))	('APML', 'Phenotype', 'HP:0004836', (227, 231))	('NSCLC', 'Disease', (142, 147))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (197, 225))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('SNORD112-114', 'Var', (153, 165))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (111, 140))	('SNORA42', 'Gene', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (197, 225))	('patients', 'Species', '9606', (183, 191))	('acute promyelocytic leukemia', 'Disease', (197, 225))	('snoRNA', 'Gene', '6079', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('leukemia', 'Phenotype', 'HP:0001909', (217, 225))	('subgroup', 'Species', '167160', (171, 179))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (111, 140))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('overexpressed', 'PosReg', (94, 107))	('non-small cell lung carcinoma', 'Disease', (111, 140))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (115, 140))
26554	32977537	Once lncRNAs were discovered to perform regulatory functions, their deregulation was the expected cause of switching from the normal to the pathological phenotype, therefore contributing to the onset of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('ncRNA', 'Gene', (6, 11))	('switching', 'MPA', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('ncRNA', 'Gene', '220202', (6, 11))	('deregulation', 'Var', (68, 80))	('contributing', 'Reg', (174, 186))
26562	32977537	In turn, the predominant expression in the brain of snoRNAs HBII-436, HBII-438A, and HBII-438B has been found.	('expression', 'Species', '29278', (25, 35))	('expression', 'MPA', (25, 35))	('snoRNA', 'Gene', (52, 58))	('snoRNA', 'Gene', '6079', (52, 58))	('HBII-438B', 'Var', (85, 94))
26595	32977537	In orthotopic mouse models, SNORD47 limits tumor growth and prolongs mouse survival.	('prolongs', 'NegReg', (60, 68))	('mouse', 'Species', '10090', (14, 19))	('SNORD47', 'Var', (28, 35))	('mouse', 'Species', '10090', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('limits', 'NegReg', (36, 42))	('mouse survival', 'CPA', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
26596	32977537	It has been observed that in forced cell cycle arrest in the G2 phase (by observing the lower expression of G2 phase-specific proteins), the expression of SNORD47 significantly inhibits the proliferation of glioma cells and induces CyclinB1, CDK1, and CDC25C.	('arrest', 'Disease', (47, 53))	('CDK1', 'Gene', (242, 246))	('CyclinB1', 'Protein', (232, 240))	('CDK1', 'Gene', '983', (242, 246))	('induces', 'PosReg', (224, 231))	('glioma', 'Disease', (207, 213))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('expression', 'Species', '29278', (141, 151))	('expression', 'Species', '29278', (94, 104))	('SNORD47', 'Gene', (155, 162))	('arrest', 'Disease', 'MESH:D006323', (47, 53))	('CDC25C', 'MPA', (252, 258))	('proliferation', 'CPA', (190, 203))	('inhibits', 'NegReg', (177, 185))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('expression', 'Var', (141, 151))
26619	32977537	Another lncRNA, MIR22HG, which undergoes high overexpression either in GBM or glioma stem-like cells and represents the host gene of miR-22-3p and miR-22-5p, promotes GBM progression by activating Wnt/beta-catenin signaling via the downregulation of the SFRP2 and PCDH15 genes.	('promotes', 'PosReg', (158, 166))	('PCDH15', 'Gene', (264, 270))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('PCDH15', 'Gene', '65217', (264, 270))	('miR-22-3p', 'Gene', '407008', (133, 142))	('ncRNA', 'Gene', (9, 14))	('GBM', 'Disease', (167, 170))	('SFRP2', 'Gene', '6423', (254, 259))	('ncRNA', 'Gene', '220202', (9, 14))	('miR-22-3p', 'Gene', (133, 142))	('activating', 'PosReg', (186, 196))	('expression', 'Species', '29278', (50, 60))	('miR-22-5p', 'Var', (147, 156))	('downregulation', 'NegReg', (232, 246))	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('beta-catenin', 'Gene', (201, 213))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('SFRP2', 'Gene', (254, 259))	('MIR22HG', 'Gene', (16, 23))	('glioma', 'Disease', (78, 84))	('beta-catenin', 'Gene', '1499', (201, 213))	('MIR22HG', 'Gene', '84981', (16, 23))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
26628	32977537	It has been shown that artificial SNORD47 causes a significantly suppressed migration ability in U87-MG and U251 cells in wound healing assays in contrast to control cells.	('SNORD47', 'Var', (34, 41))	('U251', 'CellLine', 'CVCL:0021', (108, 112))	('suppressed', 'NegReg', (65, 75))	('migration ability', 'CPA', (76, 93))	('U87-MG', 'CellLine', 'CVCL:0022', (97, 103))	('wound healing assays', 'CPA', (122, 142))
26629	32977537	Furthermore, treatment with SNORD47 glioma cells leads to decreased levels of expression of N-cadherin, which is an EMT-related marker.	('N-cadherin', 'Protein', (92, 102))	('SNORD47', 'Var', (28, 35))	('decreased', 'NegReg', (58, 67))	('glioma', 'Disease', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('levels of expression of', 'MPA', (68, 91))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('expression', 'Species', '29278', (78, 88))
26642	32977537	Moreover, a therapeutic effect after the manipulation of the level of this lncRNA has been shown to be obtained upon MALAT1 knockdown, resulting in loss of the chemoresistance feature.	('knockdown', 'Var', (124, 133))	('MALAT1', 'Gene', '378938', (117, 123))	('loss', 'NegReg', (148, 152))	('ncRNA', 'Gene', '220202', (76, 81))	('MALAT1', 'Gene', (117, 123))	('ncRNA', 'Gene', (76, 81))	('chemoresistance feature', 'CPA', (160, 183))
26643	32977537	This lncRNA has been discovered to sponge miRNA-101 in GBM cells and, consequently, to upregulate TMZ resistance via the MGMT and GSK3beta pathways (Figure 3).	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('miRNA-101', 'Var', (42, 51))	('MGMT', 'Gene', '4255', (121, 125))	('MGMT', 'Gene', (121, 125))	('ncRNA', 'Gene', (6, 11))	('GSK3beta', 'Gene', '2931', (130, 138))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('GSK3beta', 'Gene', (130, 138))	('ncRNA', 'Gene', '220202', (6, 11))	('TMZ resistance', 'MPA', (98, 112))	('upregulate', 'PosReg', (87, 97))
26659	32977537	This type of interaction is well-studied for circ_002136:a circRNA able to sponge miR-138, and a potential immunomodulator in glioma.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('miR-138', 'Chemical', '-', (82, 89))	('circ_002136', 'Var', (45, 56))	('glioma', 'Disease', (126, 132))
26680	32977537	The current WHO tumor classification of the CNS already takes advantage of molecular profiling, including in the diagnosis of the IDH1/2 mutation, 1p/19q co-deletion, or histone H3K27 mutation.	('mutation', 'Var', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('histone H3K27', 'Protein', (170, 183))	('IDH1/2', 'Gene', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('1p/19q co-deletion', 'Var', (147, 165))	('tumor', 'Disease', (16, 21))	('IDH1/2', 'Gene', '3417;3418', (130, 136))
26690	32977537	Overexpression of CRNDE in tumor tissues was associated with a higher WHO grade, recurrence, and expansion in tumor volume, thus high expression of this lncRNA can be considered a new prognostic marker for glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (213, 221))	('CRNDE', 'Gene', '643911', (18, 23))	('CRNDE', 'Gene', (18, 23))	('expression', 'Species', '29278', (134, 144))	('tumor', 'Disease', (27, 32))	('WHO grade', 'CPA', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ncRNA', 'Gene', (154, 159))	('ncRNA', 'Gene', '220202', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('expression', 'Species', '29278', (4, 14))	('recurrence', 'CPA', (81, 91))	('associated', 'Reg', (45, 55))	('glioma', 'Disease', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
26694	32977537	This analysis has identified a prognostic signature of three lncRNAs, namely LOC441179, PON2, and USP46-AS1, which could separate GBM samples with longer overall survival from those with shorter survival.	('ncRNA', 'Gene', '220202', (62, 67))	('AS1', 'Gene', '5729', (104, 107))	('PON2', 'Gene', '5445', (88, 92))	('USP46', 'Gene', (98, 103))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('longer', 'PosReg', (147, 153))	('LOC441179', 'Var', (77, 86))	('ncRNA', 'Gene', (62, 67))	('PON2', 'Gene', (88, 92))	('USP46', 'Gene', '64854', (98, 103))	('AS1', 'Gene', (104, 107))
26705	32977537	It was reported that some lncRNAs, such as ARHGEF7-AS2, lnc-HLX-1, lnc-EXPH5-2, lnc-CH25H-2, and lnc-TDRP-3, demonstrate differential expression in these two groups, and that other lncRNAs were subgroup-specific: lnc-CCL2-2 in the WNT subgroup, lnc-ABCE1-5 in the SHH subgroup, USP2-AS1 in group 3, and lnc-TBC1D16-3 in group 4.	('ncRNA', 'Gene', '220202', (182, 187))	('subgroup', 'Species', '167160', (194, 202))	('expression', 'MPA', (134, 144))	('subgroup', 'Species', '167160', (235, 243))	('lnc-ABCE1-5', 'Var', (245, 256))	('AS1', 'Gene', (283, 286))	('SHH', 'Gene', (264, 267))	('ARHGEF7-AS2', 'CellLine', 'CVCL:T366', (43, 54))	('ncRNA', 'Gene', '220202', (27, 32))	('lnc-CCL2-2', 'Var', (213, 223))	('AS1', 'Gene', '5729', (283, 286))	('lnc-TBC1D16-3', 'Var', (303, 316))	('ncRNA', 'Gene', (182, 187))	('ncRNA', 'Gene', (27, 32))	('subgroup', 'Species', '167160', (268, 276))	('SHH', 'Gene', '6469', (264, 267))	('expression', 'Species', '29278', (134, 144))
26711	32977537	Cir-ITCH, circHIPK3, circCPA4, circ_0034642, and circ_0074362 were shown to be related to clinical severity and poor prognosis in patients with glioma.	('circ_0034642', 'Var', (31, 43))	('ITCH', 'Gene', '83737', (4, 8))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('circCPA4', 'Var', (21, 29))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('-ITCH', 'Phenotype', 'HP:0000989', (3, 8))	('Cir', 'Gene', '9541', (0, 3))	('ITCH', 'Gene', (4, 8))	('circHIPK3', 'Var', (10, 19))	('circ_0074362', 'Var', (49, 61))	('glioma', 'Disease', (144, 150))	('patients', 'Species', '9606', (130, 138))	('Cir', 'Gene', (0, 3))	('related', 'Reg', (79, 86))
26712	32977537	The reduction of circ_0001649 was shown to be greatly associated to the larger tumor size, higher malignancy, and WHO grade.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('circ_0001649', 'Var', (17, 29))	('WHO grade', 'CPA', (114, 123))	('reduction', 'NegReg', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('malignancy', 'Disease', (98, 108))
26713	32977537	Moreover, upregulation of circ_0001649 leads to apoptosis by regulating Bcl-2/caspase-3 pathway.	('caspase-3', 'Gene', '836', (78, 87))	('Bcl-2', 'Gene', (72, 77))	('Bcl-2', 'Gene', '596', (72, 77))	('caspase-3', 'Gene', (78, 87))	('circ_0001649', 'Var', (26, 38))	('apoptosis', 'CPA', (48, 57))	('upregulation', 'PosReg', (10, 22))
26715	32977537	The promising biomarkers for predicting the prognosis of cancer patients could be also the peptides and/or proteins encoded by non-coding RNA as shown recently.	('non-coding', 'Var', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('RNA', 'Gene', (138, 141))
26725	32977537	For instance, the locked nucleic acid (LNA) strategy constitutes a potent method of lncRNA activity modulation.	('ncRNA', 'Gene', (85, 90))	('ncRNA', 'Gene', '220202', (85, 90))	('locked nucleic acid', 'Var', (18, 37))
26729	32977537	The knockdown of XIST inhibits the expression of the transcription factor forkhead box C1 (FOXC1) and zonula occludens 2 (ZO-2) with simultaneous upregulation of miR-137.	('FOXC1', 'Gene', '2296', (91, 96))	('ZO-2', 'Gene', (122, 126))	('upregulation', 'PosReg', (146, 158))	('expression', 'Species', '29278', (35, 45))	('XIST', 'Gene', '7503', (17, 21))	('expression', 'MPA', (35, 45))	('XIST', 'Gene', (17, 21))	('miR-137', 'Gene', (162, 169))	('miR-137', 'Gene', '406928', (162, 169))	('inhibits', 'NegReg', (22, 30))	('knockdown', 'Var', (4, 13))	('FOXC1', 'Gene', (91, 96))
26732	32977537	In MB, it was also observed that lncRNA Nkx2-2as depress tumor suppressing targets BTG2 and LATS1 in the SHH subgroup of MB by competing with miR-103 and miR-107 and impeding cell proliferation and migration.	('cell proliferation', 'CPA', (175, 193))	('LATS1', 'Gene', (92, 97))	('subgroup', 'Species', '167160', (109, 117))	('SHH', 'Gene', '6469', (105, 108))	('MB', 'Phenotype', 'HP:0002885', (3, 5))	('depress tumor', 'Disease', (49, 62))	('miR-103', 'Var', (142, 149))	('MB', 'Phenotype', 'HP:0002885', (121, 123))	('impeding', 'NegReg', (166, 174))	('ncRNA', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('depress tumor', 'Disease', 'MESH:D000275', (49, 62))	('SHH', 'Gene', (105, 108))	('BTG2', 'Gene', (83, 87))	('ncRNA', 'Gene', '220202', (34, 39))
26735	32977537	These data indicate that SNORD47 plays a key role in GBM by inhibiting the tumorigenesis process.	('inhibiting', 'NegReg', (60, 70))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('SNORD47', 'Var', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
26773	29034211	In this regard, the four molecular parameters utilized for diffuse gliomas are absence/presence of IDH mutations, 1p/19q chromosomes codeletion, TP53 mutation, and ATRX loss.	('IDH', 'Gene', '3417', (99, 102))	('mutations', 'Var', (103, 112))	('1p/19q chromosomes codeletion', 'Var', (114, 143))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('loss', 'NegReg', (169, 173))	('mutation', 'Var', (150, 158))	('gliomas', 'Disease', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('TP53', 'Gene', '7157', (145, 149))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('TP53', 'Gene', (145, 149))	('IDH', 'Gene', (99, 102))
26775	29034211	As shown in Figure 1, astrocytomas are either IDH mutants with ATRX loss and TP53 mutations or are IDH wild-type, whereas oligodendrogliomas are IDH mutants with 1p/19q codeletion.	('astrocytomas', 'Disease', 'MESH:D001254', (22, 34))	('IDH', 'Gene', '3417', (99, 102))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (122, 140))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('IDH', 'Gene', (145, 148))	('ATRX', 'Gene', (63, 67))	('astrocytomas', 'Disease', (22, 34))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (145, 148))	('oligodendrogliomas', 'Disease', (122, 140))	('mutations', 'Var', (82, 91))	('IDH', 'Gene', '3417', (46, 49))	('loss', 'NegReg', (68, 72))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('TP53', 'Gene', '7157', (77, 81))	('IDH', 'Gene', (99, 102))	('TP53', 'Gene', (77, 81))
26784	29034211	Further support of ATRX's role in mediating chromatin remodeling and potential link with DNA methylation and gene expression has been elucidated by Gibbons and colleagues who have found varied DNA methylation patterns on ATRX syndrome patients on repetitive sequences including rDNA arrays, Y-specific repeat DYZ2, and in a family of subtelomeric repeats (TelBam3.4).	('ATRX syndrome', 'Disease', (221, 234))	('patients', 'Species', '9606', (235, 243))	('Gibbons', 'Species', '9581', (148, 155))	('ATRX syndrome', 'Disease', 'MESH:C538258', (221, 234))	('methylation', 'Var', (197, 208))
26787	29034211	Although DAXX has no effect on the ATPase activity of ATRX, DAXX does attenuate its transcription repression activity and plays a role in recruiting ATRX to PML nuclear bodies.	('transcription repression activity', 'MPA', (84, 117))	('PML', 'Phenotype', 'HP:0004836', (157, 160))	('ATP', 'Chemical', 'MESH:D000255', (35, 38))	('attenuate', 'NegReg', (70, 79))	('DAXX', 'Var', (60, 64))	('ATRX', 'Gene', (149, 153))	('recruiting', 'PosReg', (138, 148))
26791	29034211	One binding pocket is sensitive to unmodified Lys4 (H3K4me0) and the other is responsive to di-/tri-methylated Lys 9 (H3K9me3); this readout of histone H3 modifications and interactions with heterochromatin protein 1 and MeCP2 protein allows ATRX to be recruited to heterochromatin for H3.3 deposition.	('modifications', 'Var', (155, 168))	('Lys', 'Chemical', 'MESH:D008239', (111, 114))	('MeCP2', 'Gene', '4204', (221, 226))	('Lys', 'Chemical', 'MESH:D008239', (46, 49))	('histone', 'Protein', (144, 151))	('interactions', 'Interaction', (173, 185))	('Lys4', 'Chemical', '-', (46, 50))	('MeCP2', 'Gene', (221, 226))
26792	29034211	Within mouse embryonic stem (mES) cells, the ATRX/DAXX complex protects repetitive sequences during DNA hypomethylation and imprinted loci from aberrant transcription and recombination through silencing achieved by H3K9 trimethylation; this serves to conserve genomic integrity.	('mES', 'Chemical', '-', (29, 32))	('trimethylation', 'Var', (220, 234))	('H3K9 trimethylation', 'Var', (215, 234))	('mouse', 'Species', '10090', (7, 12))	('silencing', 'NegReg', (193, 202))
26795	29034211	This cohesion is a favorable factor in tumors presenting ALT that overcome the gradual loss of telomeric DNA after each cell division; the cohesion promotes recombination between sister telomeres, which is crucial for DNA repair and telomere maintenance, and restricts recombination between non-sisters that would affect cell growth.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('recombination', 'MPA', (157, 170))	('restricts', 'NegReg', (259, 268))	('promotes', 'PosReg', (148, 156))	('tumors', 'Disease', (39, 45))	('cohesion', 'Var', (139, 147))	('recombination', 'MPA', (269, 282))
26796	29034211	ATRX depletion within HeLa cells has been shown to induce lobulated nuclei and intranuclear bridges during interphase, poor cell proliferation and viability, lengthened transition between pro-metaphase and metaphase, abnormal chromosome congression, and reduced sister chromatid cohesion.	('depletion', 'Var', (5, 14))	('reduced', 'NegReg', (254, 261))	('abnormal chromosome congression', 'Disease', (217, 248))	('ATRX', 'Gene', (0, 4))	('sister chromatid cohesion', 'CPA', (262, 287))	('viability', 'CPA', (147, 156))	('poor', 'NegReg', (119, 123))	('lengthened', 'PosReg', (158, 168))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (217, 236))	('transition', 'CPA', (169, 179))	('induce', 'PosReg', (51, 57))	('HeLa', 'CellLine', 'CVCL:0030', (22, 26))	('cell proliferation', 'CPA', (124, 142))	('lobulated nuclei', 'Phenotype', 'HP:0003687', (58, 74))	('abnormal chromosome congression', 'Disease', 'MESH:D002869', (217, 248))
26799	29034211	Watson and authors observed that ATRX depletion within mouse neuroprogenitor cells (NPCs) had augmented replicative stress-induced DNA damage that was amplified by p53 loss at PCH and telomeres, as well as enhanced telomeric defects including telomeric fusions.	('loss', 'NegReg', (168, 172))	('telomeric defects', 'CPA', (215, 232))	('telomeric fusions', 'CPA', (243, 260))	('enhanced', 'PosReg', (206, 214))	('p53', 'Gene', (164, 167))	('depletion', 'Var', (38, 47))	('augmented', 'PosReg', (94, 103))	('mouse', 'Species', '10090', (55, 60))	('replicative stress-induced DNA damage', 'MPA', (104, 141))	('ATRX', 'Gene', (33, 37))
26803	29034211	Mutations linked to the ATRX syndrome mostly cluster within the helicase and PHD domains of ATRX.	('linked', 'Reg', (10, 16))	('helicase', 'Gene', '164045', (64, 72))	('ATRX syndrome mostly cluster', 'Disease', (24, 52))	('Mutations', 'Var', (0, 9))	('helicase', 'Gene', (64, 72))	('ATRX syndrome mostly cluster', 'Disease', 'MESH:C538258', (24, 52))
26804	29034211	Although mutations within both domains present similar clinical phenotypes and although there seems to exist a clinical spectrum and severity of symptoms, including MR, gross motor ability, genital abnormality, and alpha-thalassemia, studies have correlated high psychomotor impairments to mutations within the PHD domain.	('MR', 'Phenotype', 'HP:0001249', (165, 167))	('psychomotor impairments', 'Disease', (263, 286))	('psychomotor impairments', 'Disease', 'MESH:D011596', (263, 286))	('mutations', 'Var', (9, 18))	('genital abnormality', 'Disease', 'MESH:D014564', (190, 209))	('gross motor ability', 'Disease', (169, 188))	('genital abnormality', 'Phenotype', 'HP:0000078', (190, 209))	('thalassemia', 'Disease', (221, 232))	('mutations', 'Var', (290, 299))	('psychomotor impairments', 'Phenotype', 'HP:0025356', (263, 286))	('genital abnormality', 'Disease', (190, 209))	('thalassemia', 'Disease', 'MESH:D013789', (221, 232))
26805	29034211	However, there still remains uncertainty in regard to whether mutations in specific domains define symptoms as one study has associated severity of urogenital abnormality with mutations within the PHD domain, whereas another, based on a larger cohort of patients, has linked it to mutations within the C-terminus.	('urogenital abnormality', 'Disease', (148, 170))	('genital abnormality', 'Phenotype', 'HP:0000078', (151, 170))	('mutations', 'Var', (176, 185))	('associated', 'Reg', (125, 135))	('urogenital abnormality', 'Phenotype', 'HP:0000119', (148, 170))	('urogenital abnormality', 'Disease', 'MESH:D014564', (148, 170))	('patients', 'Species', '9606', (254, 262))
26810	29034211	So far, studies have found a strong association of IDH canonical mutations and ATRX mutation, whereas cooccurrence of 1p/19q codeletion and ATRX loss have been nearly non-existent; enabling neuropathologists to be able to make determine whether a tumor is of astrocytic or oligodendrocytic lineage without requiring both studies.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('IDH', 'Gene', (51, 54))	('tumor', 'Disease', (247, 252))	('IDH', 'Gene', '3417', (51, 54))	('ATRX', 'Gene', (79, 83))	('association', 'Interaction', (36, 47))	('astrocytic or oligodendrocytic', 'Disease', 'MESH:D001254', (259, 289))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('astrocytic or oligodendrocytic', 'Disease', (259, 289))	('mutations', 'Var', (65, 74))	('mutation', 'Var', (84, 92))
26811	29034211	ATRX inactivation within gliomas can be due to mutations, deletions, gene fusions, or an amalgam of these causes.	('ATRX', 'Gene', (0, 4))	('gene fusions', 'Var', (69, 81))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('mutations', 'Var', (47, 56))	('deletions', 'Var', (58, 67))	('inactivation', 'NegReg', (5, 17))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
26812	29034211	Furthermore, ATRX mutations correlate with other prominent features including the ALT phenotype, TP53 mutations, and occur most often in astrocytic tumors.	('astrocytic tumors', 'Disease', 'MESH:D001254', (137, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ATRX', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (97, 101))	('occur', 'Reg', (117, 122))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('astrocytic tumors', 'Disease', (137, 154))	('ALT', 'Disease', (82, 85))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (18, 27))
26813	29034211	Platelet-derived growth factor receptor alpha gene (PDGFRA) amplification has also been shown to be significantly associated with ATRX loss and the ALT phenotype; future studies should look in whether possible inhibition of the PDGFRA signaling cascade may serve as a specialized therapeutic intervention within these subset of glioma patients.	('PDGFRA', 'Gene', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (328, 334))	('ALT', 'Disease', (148, 151))	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('Platelet-derived growth factor receptor alpha', 'Gene', (0, 45))	('amplification', 'Var', (60, 73))	('loss', 'NegReg', (135, 139))	('PDGFRA', 'Gene', '5156', (52, 58))	('Platelet-derived growth factor receptor alpha', 'Gene', '5156', (0, 45))	('PDGFRA', 'Gene', (228, 234))	('glioma', 'Disease', (328, 334))	('associated', 'Reg', (114, 124))	('patients', 'Species', '9606', (335, 343))	('PDGFRA', 'Gene', '5156', (228, 234))	('ATRX', 'MPA', (130, 134))
26814	29034211	Interestingly, Kannan and colleagues reported that within their cohort, mutations related to ATRX cofactor DAXX were not found in LGGs and therefore in these tumors, interactions with histone is not as important perhaps.	('tumors', 'Disease', (158, 164))	('mutations', 'Var', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('interactions', 'Interaction', (166, 178))	('LGGs', 'Disease', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
26815	29034211	In terms of prognostication, low-grade glioma patients with ATRX retention and IDH mutations have lower progression-free survival and overall survival (OS) than tumors with 1p/19q codeletion and IDH mutations and longer time to treatment failure than those patients with IDH mutation and wild-type ATRX (55.6 vs. 31.8 months, respectively).	('patients', 'Species', '9606', (46, 54))	('tumors', 'Disease', (161, 167))	('IDH', 'Gene', '3417', (195, 198))	('lower', 'NegReg', (98, 103))	('ATRX', 'Gene', (60, 64))	('overall survival', 'CPA', (134, 150))	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', '3417', (271, 274))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (257, 265))	('glioma', 'Disease', (39, 45))	('progression-free survival', 'CPA', (104, 129))	('IDH', 'Gene', '3417', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('mutations', 'Var', (83, 92))	('IDH', 'Gene', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH', 'Gene', (271, 274))
26818	29034211	Ebrahimi and colleagues found these patients to have H3F3A G34 or K27 mutations, which is concordant with Ikemura and colleagues' finding of ATRX-loss glioblastomas in younger patients being most commonly non-hemispheric in location.	('patients', 'Species', '9606', (176, 184))	('H3F3A', 'Gene', (53, 58))	('mutations', 'Var', (70, 79))	('ATRX-loss glioblastomas', 'Disease', 'MESH:C538258', (141, 164))	('patients', 'Species', '9606', (36, 44))	('glioblastomas', 'Phenotype', 'HP:0012174', (151, 164))	('H3F3A', 'Gene', '3020', (53, 58))	('G34', 'Var', (59, 62))	('K27', 'Gene', '342574', (66, 69))	('K27', 'Gene', (66, 69))	('ATRX-loss glioblastomas', 'Disease', (141, 164))
26821	29034211	Together, these findings culminated in the authors recommending assessment of both IDH and ATRX status and sequencing for both IDH1/2 and H3F3A for any age group when a tumor is found to have ATRX loss and lacking IDH1/2 mutations by immunohistochemistry.	('IDH1/2', 'Gene', '3417;3418', (127, 133))	('IDH1/2', 'Gene', (214, 220))	('IDH', 'Gene', '3417', (83, 86))	('loss', 'NegReg', (197, 201))	('IDH1/2', 'Gene', (127, 133))	('IDH', 'Gene', (127, 130))	('mutations', 'Var', (221, 230))	('tumor', 'Disease', (169, 174))	('IDH', 'Gene', (214, 217))	('IDH', 'Gene', '3417', (127, 130))	('ATRX', 'Gene', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('H3F3A', 'Gene', '3020', (138, 143))	('IDH', 'Gene', '3417', (214, 217))	('IDH', 'Gene', (83, 86))	('lacking', 'NegReg', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('IDH1/2', 'Gene', '3417;3418', (214, 220))	('H3F3A', 'Gene', (138, 143))
26824	29034211	Furthermore, DNA methylation and genetic expression profiles have been found to differ among tumors with high- and low-ATRX mRNA expression; the low-ATRX subgroup had augmented methylation levels at chromatin ends.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('low-ATRX', 'Var', (145, 153))	('tumors', 'Disease', (93, 99))	('augmented', 'PosReg', (167, 176))	('methylation levels at', 'MPA', (177, 198))
26825	29034211	Cai and colleagues also found that tumors with low-ATRX expression levels overexpressed genes involved in the transport, modification, and ubiquitination of proteins, in addition to (signal transduction, including GTP-related signal transduction and positive regulation of GTPase).	('genes', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('GTPase', 'Protein', (273, 279))	('low-ATRX', 'Var', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('modification', 'MPA', (121, 133))	('tumors', 'Disease', (35, 41))	('ubiquitination', 'MPA', (139, 153))	('transport', 'MPA', (110, 119))	('overexpressed', 'PosReg', (74, 87))	('positive regulation', 'PosReg', (250, 269))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('GTP-related signal transduction', 'MPA', (214, 245))	('GTP', 'Chemical', 'MESH:D006160', (214, 217))	('GTP', 'Chemical', 'MESH:D006160', (273, 276))
26827	29034211	In addition, in vitro analysis of ATRX knockdown in glioma cells inhibited cell migration, increased cell death, and reduced cell viability.	('cell death', 'CPA', (101, 111))	('ATRX', 'Gene', (34, 38))	('reduced', 'NegReg', (117, 124))	('cell viability', 'CPA', (125, 139))	('knockdown', 'Var', (39, 48))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('lys', 'Chemical', 'MESH:D008239', (25, 28))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('inhibited', 'NegReg', (65, 74))	('cell migration', 'CPA', (75, 89))	('increased', 'PosReg', (91, 100))	('glioma', 'Disease', (52, 58))
26828	29034211	Overall, these studies highlight some important characteristics of ATRX mutations within gliomas that will aid in their detection.	('ATRX', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))
26835	29034211	Another study found that ectopic ATRX expression within telomerase-deficient, ALT-positive osteosarcoma epithelial (U-2 OS) cells led to DAXX-dependent reduction of several features of the ALT phenotype, signifying that ATRX loss is imperative for the maintenance of the ALT phenotype.	('DAXX-dependent', 'MPA', (137, 151))	('U-2 OS', 'CellLine', 'CVCL:0042', (116, 122))	('osteosarcoma epithelial', 'Disease', 'MESH:D012516', (91, 114))	('ectopic', 'Var', (25, 32))	('osteosarcoma epithelial', 'Disease', (91, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('ATRX', 'Gene', (33, 37))	('ALT', 'Disease', (189, 192))	('reduction', 'NegReg', (152, 161))
26841	29034211	This potency of reduced cell survival was increased in most cancer cell lines when the ATR inhibitor VE-821 was paired with genotoxic agents, especially cisplatin; a significant synergy between VE-821 and cisplatin was also seen within ATM-/p53-deficient cells.	('increased', 'PosReg', (42, 51))	('VE-821', 'Chemical', 'MESH:C560580', (194, 200))	('ATM', 'Gene', (236, 239))	('VE-821', 'Chemical', 'MESH:C560580', (101, 107))	('cell survival', 'CPA', (24, 37))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('reduced', 'NegReg', (16, 23))	('cancer', 'Disease', (60, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (205, 214))	('ATM', 'Gene', '472', (236, 239))	('ATR', 'Gene', '545', (87, 90))	('ATR', 'Gene', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('VE-821', 'Var', (194, 200))
26846	29034211	Formalin-fixed paraffin-embedded tissue (FFPE) remains as a popular method of tissue processing; however, biosample processing also needs to be updated to adhere for future applications of molecular diagnostics as currently FFPE degrades proteins for standard analysis.	('standard analysis', 'MPA', (251, 268))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('degrades', 'NegReg', (229, 237))	('proteins', 'Protein', (238, 246))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('lys', 'Chemical', 'MESH:D008239', (263, 266))	('FFPE', 'Var', (224, 228))
26871	25883906	Behaviors such as social disinhibition, physical and verbal aggression, limited insight, and loss of social judgment may be associated with lesions to the orbitofrontal and ventromedial prefrontal cortex.	('loss of social judgment', 'Disease', (93, 116))	('limited', 'NegReg', (72, 79))	('loss of social judgment', 'Disease', 'OMIM:300082', (93, 116))	('social disinhibition', 'CPA', (18, 38))	('aggression', 'Phenotype', 'HP:0000718', (60, 70))	('lesions', 'Var', (140, 147))	('verbal aggression', 'Disease', 'MESH:D013064', (53, 70))	('verbal aggression', 'Disease', (53, 70))	('disinhibition', 'Phenotype', 'HP:0000734', (25, 38))	('insight', 'CPA', (80, 87))
26872	25883906	Behaviors including apathy, adynamia, and perseveration can be associated with damage to the medial prefrontal cortex and its connections.	('damage', 'Var', (79, 85))	('perseveration', 'Phenotype', 'HP:0030223', (42, 55))	('apathy', 'Phenotype', 'HP:0000741', (20, 26))	('perseveration', 'Disease', (42, 55))	('apathy, adynamia', 'Disease', 'MESH:D020513', (20, 36))
27021	31133717	Kaplan-Meier survival plots indicated that glioma patients with high NLRC4 expression had a significantly lower overall survival than those with low NLRC4 expression, whereas the expression of NLRP3 did not have a significant association with overall survival.	('lower', 'NegReg', (106, 111))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('NLRC4', 'Gene', '58484', (69, 74))	('glioma', 'Disease', (43, 49))	('NLRC4', 'Gene', (69, 74))	('NLRC4', 'Gene', '58484', (149, 154))	('NLRC4', 'Gene', (149, 154))	('overall survival', 'MPA', (112, 128))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
27024	31133717	Figure 2b showed that the median survival time of glioma patients with highly expression NLRC4 was significantly decreased compared to patients with low NLRC4 expression.	('NLRC4', 'Gene', (89, 94))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (57, 65))	('glioma', 'Disease', (50, 56))	('NLRC4', 'Gene', '58484', (153, 158))	('NLRC4', 'Gene', (153, 158))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('highly expression', 'Var', (71, 88))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('decreased', 'NegReg', (113, 122))	('NLRC4', 'Gene', '58484', (89, 94))
27053	31133717	In addition, a Kaplan-Meier survival analysis based on NLRP3 and NLRC4 expression demonstrated that patients with high expression of both had a significantly poorer prognosis (p < 0.023; Fig.	('NLRC4', 'Gene', '58484', (65, 70))	('poorer', 'NegReg', (158, 164))	('NLRC4', 'Gene', (65, 70))	('patients', 'Species', '9606', (100, 108))	('NLRP3', 'Gene', (55, 60))	('high expression', 'Var', (114, 129))
27062	31133717	The results of this study reveal that NLRP3 and NLRC4 inflammasomes are expressed and activated in gliomas and that high expression of NLRC4 in particular is associated with poor overall survival.	('NLRC4', 'Gene', '58484', (48, 53))	('NLRC4', 'Gene', (48, 53))	('high expression', 'Var', (116, 131))	('gliomas', 'Disease', (99, 106))	('NLRP3', 'Gene', (38, 43))	('NLRC4', 'Gene', '58484', (135, 140))	('NLRC4', 'Gene', (135, 140))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('activated', 'PosReg', (86, 95))
27077	31133717	Moreover, high expression of NLRC4 was associated with poor patient survival.	('patient', 'Species', '9606', (60, 67))	('poor', 'NegReg', (55, 59))	('NLRC4', 'Gene', '58484', (29, 34))	('high', 'Var', (10, 14))	('NLRC4', 'Gene', (29, 34))	('patient survival', 'CPA', (60, 76))
27092	31133717	J.J. Lim, M.J. Kim and Y.	('M.J. Kim', 'Var', (10, 18))	('Lim', 'Gene', '10611', (5, 8))	('Lim', 'Gene', (5, 8))
27095	31133717	J.J. Lim, M.J. Kim, Y.	('M.J. Kim', 'Var', (10, 18))	('Lim', 'Gene', '10611', (5, 8))	('Lim', 'Gene', (5, 8))
27105	30127875	Depending on mutation of the isocitrate dehydrogenase (IDH) gene, three main GM subsets can be identified: IDH-wild type, that represent ~90% of the cases, IDH-mutated, generally observed in younger patients with prior lower grade gliomas and NOS (no otherwise specified), where evaluation of the IDH gene cannot be performed.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('isocitrate dehydrogenase', 'Gene', (29, 53))	('IDH', 'Gene', (55, 58))	('mutation', 'Var', (13, 21))	('gliomas', 'Disease', (231, 238))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', (297, 300))	('gliomas', 'Disease', 'MESH:D005910', (231, 238))	('IDH', 'Gene', '3417', (55, 58))	('IDH', 'Gene', (156, 159))	('isocitrate dehydrogenase', 'Gene', '3417', (29, 53))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('IDH', 'Gene', '3417', (107, 110))	('IDH', 'Gene', '3417', (297, 300))	('patients', 'Species', '9606', (199, 207))	('IDH', 'Gene', '3417', (156, 159))	('GM', 'Chemical', '-', (77, 79))
27130	30127875	In agreement with these data, a study in primary GBM cells has shown that inhibition of MIF with ISO-1, an inhibitor of its D-dopachrome tautomerase site, reduced the growth rate of primary GBM cells in a dose-dependent manner.	('growth rate', 'CPA', (167, 178))	('D-dopachrome tautomerase', 'Gene', (124, 148))	('D-dopachrome tautomerase', 'Gene', '1652', (124, 148))	('inhibition', 'Var', (74, 84))	('reduced', 'NegReg', (155, 162))	('ISO-1', 'Gene', '10209', (97, 102))	('MIF', 'Gene', (88, 91))	('ISO-1', 'Gene', (97, 102))	('MIF', 'Gene', '4282', (88, 91))
27153	30127875	These aberrations included: 2 cases (over 283 samples) among lower grade gliomas of MIF and D-DT gene amplification; 1 amplification and 2 deletions for CD74 in lower grade glioma samples; 2 cases of CD44 deletion among glioma samples and 2 missense mutations in glioma samples, as well as, 1 missense and 2 nonsense mutations among GBM samples (over 273 samples); 1 case of amplification and 1 missense mutation of the CXCR2 gene in GBM samples, as well as 3 missense mutations among glioma samples; 1 missense mutation of CXCR4 and 1 gene amplification among glioma and GBM samples, respectively; 1 case of missense mutation of JAB1 and 13 cases of deletions among gliomas and 2 deletions among GBM patient (Fig.	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('glioma', 'Disease', (561, 567))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('JAB1', 'Gene', '10987', (630, 634))	('D-DT', 'Gene', (92, 96))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (561, 567))	('CXCR4 and 1', 'Gene', '7852;3577', (524, 535))	('CD44', 'Gene', '960', (200, 204))	('CD44', 'Gene', (200, 204))	('gliomas', 'Phenotype', 'HP:0009733', (667, 674))	('MIF', 'Gene', '4282', (84, 87))	('glioma', 'Disease', (263, 269))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('CD74', 'Gene', (153, 157))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('glioma', 'Disease', (485, 491))	('gliomas', 'Disease', (73, 80))	('glioma', 'Disease', (667, 673))	('glioma', 'Disease', (73, 79))	('glioma', 'Disease', 'MESH:D005910', (667, 673))	('glioma', 'Disease', 'MESH:D005910', (485, 491))	('MIF', 'Gene', (84, 87))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('CXCR2', 'Gene', (420, 425))	('gliomas', 'Disease', (667, 674))	('deletions', 'Var', (651, 660))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('glioma', 'Phenotype', 'HP:0009733', (485, 491))	('glioma', 'Disease', (173, 179))	('patient', 'Species', '9606', (701, 708))	('missense mutation', 'Var', (609, 626))	('CXCR2', 'Gene', '3579', (420, 425))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('JAB1', 'Gene', (630, 634))	('D-DT', 'Gene', '1652', (92, 96))	('CD74', 'Gene', '972', (153, 157))	('glioma', 'Disease', (220, 226))	('gliomas', 'Disease', 'MESH:D005910', (667, 674))
27164	30127875	Also, Wang and collaborators have shown that in patients with WHO grade III and IV gliomas the survival time was significantly shorter in patients with high expression of MIF or IL-8 in high-grade tumors than those with protein low expression in their tumors.	('survival time', 'CPA', (95, 108))	('IL-8', 'Gene', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('gliomas', 'Disease', (83, 90))	('MIF', 'Gene', '4282', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('patients', 'Species', '9606', (138, 146))	('tumors', 'Disease', (252, 258))	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('high expression', 'Var', (152, 167))	('IL-8', 'Gene', '3576', (178, 182))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('MIF', 'Gene', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('shorter', 'NegReg', (127, 134))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('patients', 'Species', '9606', (48, 56))
27174	30127875	Also, it should be pointed out that MIF undergoes post-translational modifications, including carbamylation of the Pro-2; cysteinylation at Cys-60; S-nitrosilation and phosphorylation of Cys-81 and Ser-91, that may alter MIF activity at specific sites, especially where oxidative events occur.	('alter', 'Reg', (215, 220))	('Cys', 'Chemical', 'MESH:D003545', (187, 190))	('S-nitrosilation', 'MPA', (148, 163))	('cysteinylation', 'MPA', (122, 136))	('MIF', 'Gene', (36, 39))	('phosphorylation', 'MPA', (168, 183))	('MIF', 'Gene', (221, 224))	('Cys-60', 'Var', (140, 146))	('activity', 'MPA', (225, 233))	('Cys', 'Chemical', 'MESH:D003545', (140, 143))	('MIF', 'Gene', '4282', (36, 39))	('Ser', 'Chemical', 'MESH:D012694', (198, 201))	('carbamylation', 'MPA', (94, 107))	('MIF', 'Gene', '4282', (221, 224))
27181	31440245	T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('destroy', 'NegReg', (85, 92))	('tumor', 'Disease', (57, 62))
27182	31440245	Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens.	('virulence of the immune system', 'MPA', (59, 89))	('increase', 'PosReg', (46, 54))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('cytotoxicity', 'Disease', (111, 123))	('increasing', 'PosReg', (93, 103))	('immunotherapy antibodies', 'Var', (17, 41))
27183	31440245	Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations.	('mutations', 'Var', (153, 162))	('activate', 'PosReg', (86, 94))	('patient', 'Species', '9606', (95, 102))
27184	31440245	Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells.	('increases', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutation-targeting', 'Var', (12, 30))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
27185	31440245	At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
27186	31440245	For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('TP53', 'Gene', (91, 95))	('HER2', 'Gene', '2064', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('breast tumors', 'Phenotype', 'HP:0100013', (123, 136))	('HER2', 'Gene', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('breast tumors', 'Disease', 'MESH:D001943', (123, 136))	('TP53', 'Gene', '7157', (91, 95))	('breast tumors', 'Disease', (123, 136))	('mutations', 'Var', (96, 105))	('mutated proteins', 'MPA', (65, 81))
27187	31440245	HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors.	('proteins', 'Protein', (38, 46))	('mutations', 'Var', (200, 209))	('neck tumors', 'Disease', 'MESH:D006258', (74, 85))	('TP53', 'Gene', '7157', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (79, 85))	('head and neck tumors', 'Phenotype', 'HP:0012288', (65, 85))	('HPV', 'Gene', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('p53', 'Gene', '7157', (157, 160))	('mutations', 'Var', (220, 229))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('neck tumors', 'Disease', (74, 85))	('TP53', 'Gene', (215, 219))	('p53', 'Gene', (157, 160))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('mutated', 'MPA', (30, 37))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
27190	31440245	Mutation neoantigens are critical for tumor control: T cells recognize mutant peptides bound to MHC alleles on tumor cells both in mice and humans and tumor mutational burden (TMB) predicts tumor response to anti-CTLA4 and anti-PD1 treatment.	('CTLA4', 'Gene', '1493', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PD1', 'Gene', (228, 231))	('PD1', 'Gene', '9825', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CTLA4', 'Gene', (213, 218))	('humans', 'Species', '9606', (140, 146))	('mutant', 'Var', (71, 77))	('mice', 'Species', '10090', (131, 135))	('TMB', 'Chemical', '-', (176, 179))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('MHC', 'Gene', (96, 99))
27191	31440245	Tumors that become resistant to pembrolizumab, an anti-PD1-therapy immunotherapy, often contain mutations in immune-related genes, including in interferon-receptor-associated Janus kinases and the antigen-presenting protein beta-2-microglobulin, suggesting that anti-PD1 therapeutic activity is mediated through neoantigen presentation and recognition.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PD1', 'Gene', (55, 58))	('PD1', 'Gene', '9825', (55, 58))	('PD1', 'Gene', '9825', (267, 270))	('pembrolizumab', 'Chemical', 'MESH:C582435', (32, 45))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('beta-2-microglobulin', 'Gene', '567', (224, 244))	('PD1', 'Gene', (267, 270))	('beta-2-microglobulin', 'Gene', (224, 244))	('mutations', 'Var', (96, 105))
27194	31440245	Together, these demonstrate that neoantigens encoding mutations can mediate the tumor-focused immune response and can be exploited as an exquisitely tumor-specific therapeutic target.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mediate', 'Reg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (149, 154))
27197	31440245	In addition to analysis of individual tumors, intra- and inter-indication analyses pinpoint re-occurring mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (105, 114))
27201	31440245	Missense mutations were mapped to human reference genome GRCh37 and filtered for those mutations present in at least two tumor samples.	('human', 'Species', '9606', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Missense mutations', 'Var', (0, 18))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
27203	31440245	Tumor mutational burden by indication: rather than examine mutation rates, Figure 1 shows the TMB as the number of proteins with non-synonymous point mutations in a tumor, grouped by cancer indication, along with the indication-specific median.	('non-synonymous point mutations', 'Var', (129, 159))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (183, 189))	('TMB', 'Chemical', '-', (94, 97))	('proteins', 'Protein', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Disease', (165, 170))
27210	31440245	Other indications with high median mutational burden show long tails (populations of tumors with many mutations), in particular melanoma and lung adenocarcinoma, but also lung squamous, bladder, and head and neck tumors.	('tumors', 'Disease', (213, 219))	('lung squamous', 'Disease', (171, 184))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('bladder', 'Disease', (186, 193))	('neck tumors', 'Disease', 'MESH:D006258', (208, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (102, 111))	('head and neck tumors', 'Phenotype', 'HP:0012288', (199, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('particular melanoma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 160))	('neck tumors', 'Disease', (208, 219))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('long tail', 'Phenotype', 'HP:0002831', (58, 67))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('tumors', 'Disease', (85, 91))
27211	31440245	While MSI tumors are uncommon in breast cancer, there is curiously a clear population of breast tumors with significantly more mutations.	('MSI tumors', 'Disease', 'MESH:D009369', (6, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MSI tumors', 'Disease', (6, 16))	('breast tumors', 'Phenotype', 'HP:0100013', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('breast tumors', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('mutations', 'Var', (127, 136))	('breast tumors', 'Disease', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
27215	31440245	Normal breast tumors have the lowest median, 19 mutations, while luminal A tumors show a tight symmetrical distribution around the median, 25 mutations.	('A tumors', 'Disease', (73, 81))	('A tumors', 'Disease', 'MESH:D009369', (73, 81))	('breast tumors', 'Phenotype', 'HP:0100013', (7, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('breast tumors', 'Disease', 'MESH:D001943', (7, 20))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (48, 57))	('breast tumors', 'Disease', (7, 20))
27216	31440245	Interestingly, the percentage of tumors containing p53 mutations roughly tracks the median number of mutations in each class, highest in basal and HER2 positive tumors and lowest in luminal A tumors.	('p53', 'Gene', (51, 54))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', (192, 198))	('HER2', 'Gene', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('lowest', 'NegReg', (172, 178))	('A tumors', 'Disease', (190, 198))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HER2', 'Gene', '2064', (147, 151))	('p53', 'Gene', '7157', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('A tumors', 'Disease', 'MESH:D009369', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
27222	31440245	In agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have p53 mutations, vs. 86% of the HPV negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (129, 138))	('tumors', 'Disease', (168, 174))	('p53', 'Gene', (125, 128))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (125, 128))	('p53', 'Gene', '7157', (67, 70))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('HPV', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
27223	31440245	This suggests that the presence of HPV removes the need to mutate p53.	('mutate', 'Var', (59, 65))	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (66, 69))
27227	31440245	In colon tumors, the MSI-H tumors contain a median of 944 mutations vs. 93 and 86 in the MSI-L and MSS tumors, respectively.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (58, 67))	('MSS tumors', 'Disease', 'MESH:D013132', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('colon tumors', 'Disease', 'MESH:D015179', (3, 15))	('MSS tumors', 'Disease', (99, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('colon tumors', 'Disease', (3, 15))	('colon tumors', 'Phenotype', 'HP:0100273', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('MSI-H tumors', 'Disease', 'MESH:D009369', (21, 33))	('MSI-H tumors', 'Disease', (21, 33))
27228	31440245	The number of tumors with PIK3CA mutations is similar across the three sub-groups.	('PIK3CA', 'Gene', '5290', (26, 32))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PIK3CA', 'Gene', (26, 32))
27229	31440245	However, similar to the HPV positive tumors, the percentage of MSI-H tumors with p53 mutations is much lower, here suggesting that the MSI-H status lessens the need of p53 mutations for oncogenesis.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MSI-H tumors', 'Disease', (63, 75))	('MSI-H tumors', 'Disease', 'MESH:D009369', (63, 75))	('MSI-H', 'Disease', 'MESH:D000848', (135, 140))	('p53', 'Gene', '7157', (168, 171))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('HPV positive tumors', 'Disease', (24, 43))	('HPV positive tumors', 'Disease', 'MESH:D030361', (24, 43))	('mutations', 'Var', (85, 94))	('MSI-H', 'Disease', (63, 68))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('MSI-H', 'Disease', (135, 140))	('p53', 'Gene', (168, 171))	('MSI-H', 'Disease', 'MESH:D000848', (63, 68))
27234	31440245	Recent clinical trials have shown increased benefit of anti-PD1 and anti-CTLA4 antibodies for the treatment of non-small-cell lung cancer (NSCLC) tumors with high TMB, defined as tumors with >10 mutations per megabase or as tumors with great than a median of 158 mutations.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('TMB', 'Chemical', '-', (163, 166))	('CTLA4', 'Gene', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('non-small-cell lung cancer (NSCLC) tumors', 'Disease', 'MESH:D002289', (111, 152))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('PD1', 'Gene', '9825', (60, 63))	('PD1', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('high TMB', 'Var', (158, 166))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CTLA4', 'Gene', '1493', (73, 78))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumors', 'Disease', (146, 152))
27235	31440245	The percentage of tumors with TP53 protein mutations is almost three-fold higher in current smokers than in never-smokers, 61% vs. 23%, respectively.	('TP53', 'Gene', (30, 34))	('higher', 'PosReg', (74, 80))	('mutations', 'Var', (43, 52))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('TP53', 'Gene', '7157', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
27236	31440245	Further examining the association of TP53 mutations, Figure 3, right, shows the relationship between TP53 mutations and TMB.	('TMB', 'Chemical', '-', (120, 123))	('TP53', 'Gene', '7157', (101, 105))	('relationship', 'Interaction', (80, 92))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('TMB', 'Disease', (120, 123))
27237	31440245	The tumors with TP53 mutations have over twice the number of mutated proteins compared to tumors with non-mutated TP53, 285 vs. 121 mutated proteins, respectively.	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (114, 118))	('mutated proteins', 'MPA', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('TP53', 'Gene', '7157', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('TP53', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
27238	31440245	Conversely, the rate of mutated KRAS is almost twice as large in the TP53 non-mutated tumors, 41% vs. 21%, respectively.	('mutated', 'Var', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('KRAS', 'Gene', (32, 36))	('tumors', 'Disease', (86, 92))	('KRAS', 'Gene', '3845', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))
27243	31440245	HLA allele B08, for example, is predicted to strongly bind (<10 nM) the peptide containing mutation NBPF10 p.E3455K, a mutation found in uterine carcinosarcoma and prostate tumors.	('p.E3455K', 'Var', (107, 115))	('NBPF10', 'Gene', '100132406', (100, 106))	('p.E3455K', 'Mutation', 'p.E3455K', (107, 115))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (137, 159))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('bind', 'Interaction', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('carcinosarcoma and prostate tumors', 'Disease', 'MESH:D002296', (145, 179))	('NBPF10', 'Gene', (100, 106))
27245	31440245	Most of the re-occurring mutations are predicted to bind one or more common HLA allele with binding affinity 500 nM or stronger, suggesting candidate patient subsets for investigation of each re-occurring mutation.	('binding', 'Interaction', (92, 99))	('mutations', 'Var', (25, 34))	('patient', 'Species', '9606', (150, 157))
27246	31440245	The IDH1 p.R132H mutation is found primarily in lower grade glioma, and found in 42% of these tumors.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Disease', (60, 66))	('p.R132H', 'Var', (9, 16))	('IDH1', 'Gene', (4, 8))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('p.R132H', 'Mutation', 'rs121913500', (9, 16))
27247	31440245	Other mutations, such as PIK3CA p.E545K, KRAS p.G12D, and KRAS p.G12V, occur in many indications.	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (41, 45))	('KRAS', 'Gene', '3845', (58, 62))	('PIK3CA', 'Gene', (25, 31))	('p.G12V', 'Mutation', 'rs121913529', (63, 69))	('PIK3CA', 'Gene', '5290', (25, 31))	('p.E545K', 'Var', (32, 39))	('p.G12D', 'Mutation', 'rs121913529', (46, 52))	('p.E545K', 'Mutation', 'rs104886003', (32, 39))	('KRAS', 'Gene', (41, 45))
27249	31440245	When ranked from most to less frequent, the most common mutations in an indication occur in 50% (thyroid) to <1% (renal clear cell) of the tumors.	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
27250	31440245	Of the indications considered here, only thyroid, melanoma, pancreatic, and lower grade glioma tumors have a mutation found in more than 20% of the tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('pancreatic', 'Disease', 'MESH:D010195', (60, 70))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('glioma tumors', 'Disease', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('pancreatic', 'Disease', (60, 70))	('glioma tumors', 'Disease', 'MESH:D005910', (88, 101))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('mutation', 'Var', (109, 117))
27251	31440245	When examining the cumulative sum of the first five mutations, one finds that contributions of mutations two through five are large for the profiled pancreatic and uterine cancers: over 80 and 40% of the profiled pancreatic and uterine tumors, respectively, have one of the five most frequent mutations.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('uterine cancers', 'Phenotype', 'HP:0010784', (164, 179))	('pancreatic', 'Disease', (149, 159))	('mutations', 'Var', (293, 302))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('pancreatic', 'Disease', 'MESH:D010195', (213, 223))	('uterine tumors', 'Phenotype', 'HP:0010784', (228, 242))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cancers', 'Disease', (172, 179))	('pancreatic', 'Disease', (213, 223))	('tumors', 'Disease', (236, 242))	('uterine tumor', 'Phenotype', 'HP:0010784', (228, 241))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))
27252	31440245	The three most frequent mutations in pancreatic tumors are KRAS p.G12D, G12V, and G12R, demonstrating the importance of this aberration for pancreatic tumor oncogenicity.	('KRAS', 'Gene', '3845', (59, 63))	('G12V', 'Var', (72, 76))	('G12R', 'Mutation', 'rs121913530', (82, 86))	('KRAS', 'Gene', (59, 63))	('p.G12D', 'Mutation', 'rs121913529', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (37, 53))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (140, 156))	('G12R', 'Var', (82, 86))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (37, 54))	('p.G12D', 'Var', (64, 70))	('pancreatic tumor', 'Disease', (140, 156))	('pancreatic tumor', 'Disease', 'MESH:D010190', (37, 53))	('pancreatic tumor', 'Disease', 'MESH:D010190', (140, 156))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic tumors', 'Disease', 'MESH:D010190', (37, 54))	('pancreatic tumors', 'Disease', (37, 54))	('G12V', 'SUBSTITUTION', 'None', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
27253	31440245	Conversely, the most frequent uterine tumor mutations are found in different genes, including TP53, PIK3CA, ZNF814, and KRAS, suggesting engagement of alternative pathways.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ZNF814', 'Gene', (108, 114))	('uterine tumor', 'Phenotype', 'HP:0010784', (30, 43))	('TP53', 'Gene', '7157', (94, 98))	('PIK3CA', 'Gene', (100, 106))	('TP53', 'Gene', (94, 98))	('PIK3CA', 'Gene', '5290', (100, 106))	('frequent uterine tumor', 'Phenotype', 'HP:0000130', (21, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (120, 124))	('KRAS', 'Gene', '3845', (120, 124))	('ZNF814', 'Gene', '730051', (108, 114))
27254	31440245	While not reviewed here, there are re-occurring mutations in other indications, such as uveal melanoma and diffuse intrinsic pontine glioma (DIPG) tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('intrinsic pontine glioma (DIPG) tumors', 'Disease', 'MESH:D000080443', (115, 153))	('uveal melanoma', 'Disease', (88, 102))	('mutations', 'Var', (48, 57))
27255	31440245	Cancer mutations are found in tumor cells and absent in non-tumorous cells.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (30, 35))	('mutations', 'Var', (7, 16))
27256	31440245	Thus, as targets, mutations are, by definition, uniquely found in the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutations', 'Var', (18, 27))
27257	31440245	Some of the mutations are expressed, processed, and presented on tumor HLA molecules to T cells; those mutation-containing peptides that are recognized by T cells are neoantigens.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
27259	31440245	The number of mutations, and particularly the number of clonal immunogenic mutations, predicts tumor response to immune-strengthening therapeutics, such as anti-CLTA4 and anti-PD(L)1 mAbs.	('predicts', 'Reg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD(L)1', 'Gene', (176, 182))	('PD(L)1', 'Gene', '29126', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (95, 100))
27260	31440245	Tumors with exceptionally high mutational burden respond favorably to immune-strengthening: pembrolizumab, an anti-PD-1 mAb, has been approved to treat MSI-H or mismatch repair deficient solid tumors, regardless of tumor site or histology.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mismatch', 'Var', (161, 169))	('deficient solid tumors', 'Disease', 'MESH:D009369', (177, 199))	('MSI-H', 'Disease', 'MESH:D000848', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('pembrolizumab', 'Chemical', 'MESH:C582435', (92, 105))	('deficient solid tumors', 'Disease', (177, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (193, 198))	('MSI-H', 'Disease', (152, 157))
27261	31440245	Thus, Figure 1, and the subclasses in Figures 2, 3, identifies the tumors and indications:those with higher mutation burden:potentially more likely to respond to general immune strengthening agents (those agents not targeting specific mutations).	('more', 'PosReg', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutation', 'Var', (108, 116))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('respond', 'MPA', (151, 158))
27263	31440245	Mutations are identified in a patient's tumor using next-generation sequencing and bioinformatics, prioritized for vaccine inclusion using criteria including mutation clonality and peptide HLA binding affinity, manufactured, and administered with an adjuvant, potentially as part of combination therapy.	('patient', 'Species', '9606', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
27267	31440245	However, there are mutations found frequently in specific indications, such as IDH1 p.R132H in lower grade glioma.	('p.R132H', 'Mutation', 'rs121913500', (84, 91))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1', 'Gene', (79, 83))	('p.R132H', 'Var', (84, 91))	('glioma', 'Disease', (107, 113))
27268	31440245	BRAF p.V600E, KRAS p.G12D, and KRAS p.G12V are frequent in multiple indications.	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', '3845', (14, 18))	('p.V600E', 'Var', (5, 12))	('KRAS', 'Gene', '3845', (31, 35))	('BRAF', 'Gene', '673', (0, 4))	('p.G12D', 'Mutation', 'rs121913529', (19, 25))	('BRAF', 'Gene', (0, 4))	('p.G12V', 'Mutation', 'rs121913529', (36, 42))	('KRAS', 'Gene', (14, 18))
27269	31440245	Other mutations, such as PIK3CA p.E545K, are less frequently found in a single indication but are found in the tumors of many indications.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('PIK3CA', 'Gene', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('PIK3CA', 'Gene', '5290', (25, 31))	('p.E545K', 'Var', (32, 39))	('p.E545K', 'Mutation', 'rs104886003', (32, 39))
27271	31440245	The five most frequent mutations in each indication typically account for more than 30% of the tumors in pancreatic, thyroid, lower grade glioma, melanoma, and uterine cancers.	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('account', 'Reg', (62, 69))	('cancers', 'Disease', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioma', 'Disease', (138, 144))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('pancreatic', 'Disease', 'MESH:D010195', (105, 115))	('mutations', 'Var', (23, 32))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('uterine cancers', 'Phenotype', 'HP:0010784', (160, 175))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('thyroid', 'Disease', (117, 124))	('pancreatic', 'Disease', (105, 115))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
27275	31440245	Using the impressive public domain TCGA dataset, this work shows the presence of non-synonymous single-nucleotide mutations across a broad panel of tumor indications and potential immunotherapy application.	('tumor', 'Disease', (148, 153))	('non-synonymous single-nucleotide mutations', 'Var', (81, 123))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))
27276	31440245	As previously described, melanoma and lung cancers have higher numbers of mutations relative to other tumors.	('melanoma and lung cancers', 'Disease', 'MESH:D008175', (25, 50))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('mutations', 'Var', (74, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
27279	31440245	Mutation rates vary among molecularly-defined tumor sub-groups: breast basal tumors have, on average, more mutations than luminal A tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('A tumors', 'Disease', 'MESH:D009369', (130, 138))	('mutations', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('A tumors', 'Disease', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('basal tumors', 'Phenotype', 'HP:0002671', (71, 83))	('breast basal tumors', 'Disease', 'MESH:D001943', (64, 83))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('breast basal tumors', 'Disease', (64, 83))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
27280	31440245	Smoking and TP53 mutations are associated with high tumor mutation burden in lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', (12, 16))	('lung cancers', 'Disease', 'MESH:D008175', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('TP53', 'Gene', '7157', (12, 16))	('high tumor', 'Disease', (47, 57))	('lung cancers', 'Disease', (77, 89))	('high tumor', 'Disease', 'MESH:D009369', (47, 57))	('mutations', 'Var', (17, 26))
27281	31440245	Finally, re-occurring mutations can be found in the profiled tumors: BRAF p.V600E is found in many thyroid tumors and melanomas and mutations such as PIK3CA p.E454K can be found at appreciable levels across multiple indications.	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('PIK3CA', 'Gene', '5290', (150, 156))	('p.E454K', 'Var', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))	('tumors', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('thyroid tumors and melanomas', 'Disease', 'MESH:D013959', (99, 127))	('p.V600E', 'Mutation', 'rs113488022', (74, 81))	('tumors', 'Disease', (107, 113))	('p.V600E', 'Var', (74, 81))	('p.E454K', 'Mutation', 'p.E454K', (157, 164))	('PIK3CA', 'Gene', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('found', 'Reg', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
27296	29946897	The present paper serves several aims: (1) to describe the new features introduced in ITK-SNAP software since the original 2006 publication; (2) to demonstrate that the new semi-automatic functionality in ITK-SNAP can be applied to problems where threshold and edge-based active contour tools are ineffective; (3) to quantitatively compare ITK-SNAP semi-automatic segmentation to state-of-the-art specialized automatic segmentation algorithms in a widely studied problem; (4) to show that semi-automatic segmentation in ITK-SNAP can reduce segmentation time over manual segmentation; and (5) to demonstrate that ITK-SNAP segmentation capabilities can be applied in multiple application domains and imaging modalities.	('semi-automatic', 'Var', (489, 503))	('ITK', 'Gene', '3702', (86, 89))	('SNAP', 'Gene', (616, 620))	('SNAP', 'Gene', '40233', (616, 620))	('ITK', 'Gene', '3702', (205, 208))	('ITK', 'Gene', (520, 523))	('ITK', 'Gene', '3702', (340, 343))	('SNAP', 'Gene', (209, 213))	('SNAP', 'Gene', '40233', (209, 213))	('ITK', 'Gene', (612, 615))	('SNAP', 'Gene', (90, 94))	('SNAP', 'Gene', '40233', (90, 94))	('SNAP', 'Gene', (344, 348))	('SNAP', 'Gene', '40233', (344, 348))	('ITK', 'Gene', '3702', (520, 523))	('SNAP', 'Gene', (524, 528))	('SNAP', 'Gene', '40233', (524, 528))	('ITK', 'Gene', (86, 89))	('ITK', 'Gene', (205, 208))	('segmentation time', 'MPA', (540, 557))	('ITK', 'Gene', '3702', (612, 615))	('ITK', 'Gene', (340, 343))	('reduce', 'NegReg', (533, 539))
27299	29946897	ITK-SNAP was used by three neuroradiologists as well as one novice user to label a set of 20 glioma cases from multi-modality MRI (pre-contrast T1, post-contrast T1, T2, and FLAIR).	('glioma', 'Disease', (93, 99))	('SNAP', 'Gene', '40233', (4, 8))	('SNAP', 'Gene', (4, 8))	('pre-contrast T1', 'Var', (131, 146))	('ITK', 'Gene', '3702', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('ITK', 'Gene', (0, 3))
27338	29946897	Most high-grade gliomas have four distinct tissue classes: edema, which appears bright on T2 and FLAIR; enhancing tumor core (EC), which appears bright on T1CE; non-enhancing tumor core (NEC), which is abnormal in T2 but appears as normal gray/white matter in T1CE; and necrosis, which appears dark in T1.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (175, 180))	('edema', 'Disease', (59, 64))	('necrosis', 'Disease', 'MESH:D009336', (270, 278))	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gliomas', 'Disease', (16, 23))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('tumor', 'Disease', (114, 119))	('necrosis', 'Disease', (270, 278))	('enhancing', 'PosReg', (104, 113))	('edema', 'Disease', 'MESH:D004487', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('edema', 'Phenotype', 'HP:0000969', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('non-enhancing', 'Var', (161, 174))
27414	23881924	While surgery, chemotherapy and radiation remain the mainstay of upfront treatment, recent advances in molecular interrogation of pLGG have shown a small number of recurring genetic mutations in these tumors that might be exploited therapeutically.	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('genetic mutations', 'Var', (174, 191))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('pLGG', 'Gene', (130, 134))
27433	23881924	Most patients with TSC harbor a mutation in either the TSC1 (hamartin) or TSC2 (tuberin) gene; either mutation leads to overactivation of mTOR.	('mTOR', 'Gene', (138, 142))	('hamartin', 'Gene', '7248', (61, 69))	('mTOR', 'Gene', '2475', (138, 142))	('TSC', 'Gene', '7248', (74, 77))	('TSC', 'Gene', '7248', (19, 22))	('hamartin', 'Gene', (61, 69))	('patients', 'Species', '9606', (5, 13))	('leads to', 'Reg', (111, 119))	('TSC2', 'Gene', '7249', (74, 78))	('mutation', 'Var', (32, 40))	('tuberin', 'Gene', '7249', (80, 87))	('TSC', 'Gene', (74, 77))	('TSC', 'Gene', (19, 22))	('overactivation', 'MPA', (120, 134))	('tuberin', 'Gene', (80, 87))	('TSC', 'Gene', '7248', (55, 58))	('TSC2', 'Gene', (74, 78))	('TSC1', 'Gene', (55, 59))	('TSC1', 'Gene', '7248', (55, 59))	('TSC', 'Gene', (55, 58))
27436	23881924	In non-NF-1-associated LGG, the most common alteration is a fusion and tandem duplication of BRAF with KIAA1549, a protein of unknown function.	('fusion', 'Var', (60, 66))	('BRAF', 'Gene', (93, 97))	('NF-1', 'Gene', '4763', (7, 11))	('tandem duplication', 'Var', (71, 89))	('common', 'Reg', (37, 43))	('NF-1', 'Gene', (7, 11))	('KIAA1549', 'Gene', (103, 111))	('KIAA1549', 'Gene', '57670', (103, 111))	('LGG', 'Disease', (23, 26))	('BRAF', 'Gene', '673', (93, 97))
27438	23881924	A smaller percentage of LGG harbor the BRAFV600E mutation that is a hallmark of cutaneous melanoma.	('cutaneous melanoma', 'Disease', (80, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('BRAFV600E', 'Var', (39, 48))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
27439	23881924	Another subset harbors fibroblast growth factor receptor (FGFR) alterations leading to constitutive activation of the mitogen-activated protein (MAP) kinase and mTOR pathways.	('FGFR', 'Gene', (58, 62))	('alterations', 'Var', (64, 75))	('mTOR', 'Gene', '2475', (161, 165))	('activation', 'PosReg', (100, 110))	('mTOR', 'Gene', (161, 165))
27442	23881924	High-level activation of the MAP kinase pathway is associated with oncogene-induced senescence in many neoplasms, and the most aggressive pLGGs have deletion or silencing of the p16INK4a locus, allowing them to bypass this antitumor mechanism.	('deletion', 'Var', (149, 157))	('neoplasms', 'Disease', 'MESH:D009369', (103, 112))	('neoplasms', 'Disease', (103, 112))	('tumor', 'Disease', (227, 232))	('p16INK4a', 'Gene', (178, 186))	('p16INK4a', 'Gene', '1029', (178, 186))	('MAP kinase pathway', 'Pathway', (29, 47))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('neoplasms', 'Phenotype', 'HP:0002664', (103, 112))	('silencing', 'Var', (161, 170))	('activation', 'PosReg', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
27443	23881924	For example, the finding of BRAFV600E in a subset of pLGGs led to the hypothesis that some of the pharmaceuticals designed to inhibit this mutation in melanoma might be active against these tumors.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('BRAFV600E', 'Var', (28, 37))	('BRAFV600E', 'Mutation', 'rs113488022', (28, 37))
27447	23881924	Adding further complexity, there are several different BRAF/KIAA1549 fusions, and several BRAF translocations identified that do not involve KIAA1549.	('BRAF', 'Gene', (90, 94))	('BRAF', 'Gene', '673', (90, 94))	('KIAA1549', 'Gene', '57670', (60, 68))	('BRAF', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (55, 59))	('KIAA1549', 'Gene', (141, 149))	('KIAA1549', 'Gene', '57670', (141, 149))	('KIAA1549', 'Gene', (60, 68))	('fusions', 'Var', (69, 76))
27459	23881924	In low-grade fibrillary astrocytomas (WHO grade II) and a percentage of pilocytic astrocytomas, genomic rearrangements remove the regulatory domain of c-MYB and the closely related MYBL1 transcription factors.	('regulatory domain', 'MPA', (130, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('fibrillary astrocytomas', 'Disease', (13, 36))	('pilocytic astrocytomas', 'Disease', (72, 94))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (72, 94))	('remove', 'NegReg', (119, 125))	('rearrangements', 'Var', (104, 118))	('MYBL1', 'Gene', (181, 186))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('MYBL1', 'Gene', '4603', (181, 186))	('low-grade', 'Disease', (3, 12))	('c-MYB', 'Gene', (151, 156))	('fibrillary astrocytomas', 'Disease', 'MESH:D001254', (13, 36))	('c-MYB', 'Gene', '4602', (151, 156))
27474	23881924	The predominance of mutations along the single RAS/RAF/MEK pathway in the absence of other concurrent oncogenic lesions may account for the activity of low-dose treatment regimens in pLGGs.	('RAF', 'Gene', '22882', (51, 54))	('RAF', 'Gene', (51, 54))	('pLGGs', 'Disease', (183, 188))	('activity', 'MPA', (140, 148))	('mutations', 'Var', (20, 29))
27488	23881924	Although it has been suggested that the presence of KIAA/BRAF fusions may correlate with improved event-free survival, another study has not associated BRAF molecular alteration with outcome or identified a mutational signature in all members of a specific tumor subtype.	('improved', 'PosReg', (89, 97))	('BRAF', 'Gene', (152, 156))	('event-free survival', 'CPA', (98, 117))	('tumor', 'Disease', (257, 262))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('fusions', 'Var', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('BRAF', 'Gene', '673', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
27496	23881924	For example, while 60% of ganglioglioma and PXAs have the BRAFV600E mutation, we do not yet know what drives the remaining 40%.	('ganglioglioma', 'Disease', (26, 39))	('BRAFV600E', 'Var', (58, 67))	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('PXAs', 'Disease', (44, 48))	('ganglioglioma', 'Disease', 'MESH:D018303', (26, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
27511	24179752	Patients also showed higher PLI in the right FPN after resection in the upper alpha band (z = - 2.803; p = 0.003; Fig.	('Patients', 'Species', '9606', (0, 8))	('PLI', 'CPA', (28, 31))	('resection', 'Var', (55, 64))	('higher', 'PosReg', (21, 27))
27516	24179752	On the other hand, a central role or high connectivity in the presurgical network can also predict seizure freedom after resection, depending on the frequency of the analyzed oscillations.	('seizure', 'Disease', (99, 106))	('seizure', 'Disease', 'MESH:D012640', (99, 106))	('seizure', 'Phenotype', 'HP:0001250', (99, 106))	('predict', 'Reg', (91, 98))	('high connectivity', 'Var', (37, 54))
27525	21829728	Here, we demonstrated that (1) IDH1/2 mutation is closely correlated with MGMT promoter methylation and 1p/19q codeletion in LGGs, (2) LINE-1 methylation levels in primary and secondary GBMs are lower than those in LGGs and normal brain tissues, (3) LINE-1 methylation is proportional to MGMT promoter methylation in gliomas, and (4) higher LINE-1 methylation is a favorable prognostic factor in primary GBMs, even compared to MGMT promoter methylation.	('gliomas', 'Disease', 'MESH:D005910', (317, 324))	('gliomas', 'Phenotype', 'HP:0009733', (317, 324))	('gliomas', 'Disease', (317, 324))	('MGMT', 'Gene', (288, 292))	('MGMT', 'Gene', (74, 78))	('MGMT', 'Gene', '4255', (427, 431))	('MGMT', 'Gene', '4255', (288, 292))	('MGMT', 'Gene', '4255', (74, 78))	('MGMT', 'Gene', (427, 431))	('mutation', 'Var', (38, 46))	('glioma', 'Phenotype', 'HP:0009733', (317, 323))	('IDH1/2', 'Gene', (31, 37))	('primary GBMs', 'Disease', (396, 408))
27531	21829728	A subanalysis in an international randomized trial by the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) compared the results of radiotherapy alone with those of concomitant radiotherapy and TMZ and showed that epigenetic silencing of the MGMT gene by promoter methylation increased the survival time of patients with primary GBM.	('patients', 'Species', '9606', (365, 373))	('increased', 'PosReg', (334, 343))	('MGMT', 'Gene', '4255', (300, 304))	('MGMT', 'Gene', (300, 304))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('epigenetic silencing', 'Var', (272, 292))	('TMZ', 'Chemical', 'MESH:D000077204', (252, 255))	('primary GBM', 'Disease', (379, 390))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('survival time', 'CPA', (348, 361))	('promoter methylation', 'Var', (313, 333))
27534	21829728	Although the predictive value of MGMT methylation has largely been confirmed in numerous prospective and retrospective clinical investigations, it is unclear if this is directly due to reduced MGMT expression.	('MGMT', 'Gene', (193, 197))	('methylation', 'Var', (38, 49))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (193, 197))	('MGMT', 'Gene', '4255', (33, 37))	('expression', 'MPA', (198, 208))	('reduced', 'NegReg', (185, 192))
27536	21829728	In addition, Van den Vent et al reported that a methylated MGMT promoter was of prognostic significance among patients with anaplastic gliomas treated with radiation alone.	('anaplastic gliomas', 'Disease', 'MESH:D005910', (124, 142))	('methylated', 'Var', (48, 58))	('anaplastic gliomas', 'Disease', (124, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('MGMT', 'Gene', (59, 63))	('patients', 'Species', '9606', (110, 118))	('MGMT', 'Gene', '4255', (59, 63))
27537	21829728	These results suggest that a methylated MGMT promoter is prognostic as well as predictive for the outcome of adjuvant therapy in high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('methylated', 'Var', (29, 39))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))
27538	21829728	Cancer-specific DNA methylation changes are hallmarks of human cancers, with global DNA hypomethylation often seen concomitantly with hypermethylation of CpG islands.	('human cancers', 'Disease', 'MESH:D009369', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('human cancers', 'Disease', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('changes', 'Var', (32, 39))
27540	21829728	Colorectal CIMP is associated with microsatellite instability and transcriptional silencing.	('microsatellite instability', 'Var', (35, 61))	('transcriptional silencing', 'Var', (66, 91))	('Colorectal CIMP', 'Disease', (0, 15))	('Colorectal CIMP', 'Phenotype', 'HP:0200063', (0, 15))	('CIMP', 'Chemical', '-', (11, 15))
27545	21829728	In various cancers such as colon and ovarian cancer, it is thought that hypomethylation of LINE-1 is correlated with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('hypomethylation', 'Var', (72, 87))	('colon and ovarian cancer', 'Disease', 'MESH:D010051', (27, 51))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
27547	21829728	Recently, many studies have suggested that low-grade gliomas (LGGs, WHO grade 2) including astrocytoma (As), oligodendroglioma (OG) and oligoastrocytoma (OA) display a highly methylated profile, in particular LGGs with mutated IDH1 .	('astrocytoma', 'Disease', 'MESH:D001254', (141, 152))	('astrocytoma', 'Disease', (141, 152))	('oligoastrocytoma', 'Disease', (136, 152))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('IDH1', 'Gene', '3417', (227, 231))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('mutated', 'Var', (219, 226))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('astrocytoma', 'Disease', 'MESH:D001254', (91, 102))	('highly methylated profile', 'MPA', (168, 193))	('LGGs', 'Disease', (209, 213))	('astrocytoma', 'Disease', (91, 102))	('oligodendroglioma', 'Disease', 'MESH:D009837', (109, 126))	('astrocytoma', 'Phenotype', 'HP:0009592', (141, 152))	('oligodendroglioma', 'Disease', (109, 126))	('IDH1', 'Gene', (227, 231))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (136, 152))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('As', 'Phenotype', 'HP:0009592', (104, 106))	('gliomas', 'Disease', (53, 60))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
27556	21829728	The analysis was performed using the SALSA MLPA KIT P088-B1 and P105-C1 in accordance with the manufacturer's protocol (MRC Holland, Amsterdam, Netherland).	('P088-B1', 'Var', (52, 59))	('P105-C1', 'Var', (64, 71))	('MRC', 'CellLine', 'CVCL:0440', (120, 123))
27570	21829728	For IDH1/2 mutations, we applied conventional PCR at 35 cycles with denaturation at 95 C for 30 s, annealing at 56 C for 40 s, and extension at 72 C for 50 s, ending at 72 C for 7 min to complete extension.	('mutations', 'Var', (11, 20))	('50 s', 'Species', '1214577', (153, 157))	('IDH1/2', 'Gene', (4, 10))
27573	21829728	The effect of each single factor on OS and PFS was investigated using the Cox proportional hazards model, adjusting for the major clinical prognostic factors, including age at diagnosis (<40 vs. >=40), Sex (male vs. female), Eastern Cooperative Oncology Group (ECOG) performance status score (ECOG PS; <=1 vs. >1), extent of resection (macroscopic [gross] total resection [GTR] or subtotal resection [STR] vs. partial resection or biopsy), MGMT promoter methylation status, chromosome 1p loss of heterozygosity (LOH), 19q LOH, PTEN loss, CDKN2A loss, TP53 loss and mutation, ERBB2 amplification, EGFR amplification, IDH1 and IDH2 mutation, and adjuvant therapy immediately following the surgery (with radiotherapy or chemotherapy vs. none).	('IDH2', 'Gene', (625, 629))	('CDKN2A', 'Gene', '1029', (538, 544))	('loss', 'NegReg', (545, 549))	('IDH2', 'Gene', '3418', (625, 629))	('loss', 'NegReg', (488, 492))	('MGMT', 'Gene', (440, 444))	('mutation', 'Var', (630, 638))	('Oncology', 'Phenotype', 'HP:0002664', (245, 253))	('TP53', 'Gene', (551, 555))	('EGFR', 'Gene', (596, 600))	('PTEN', 'Gene', (527, 531))	('mutation', 'Var', (565, 573))	('amplification', 'Var', (581, 594))	('IDH1', 'Gene', (616, 620))	('loss', 'NegReg', (556, 560))	('PTEN', 'Gene', '5728', (527, 531))	('loss', 'NegReg', (532, 536))	('ERBB2', 'Gene', (575, 580))	('MGMT', 'Gene', '4255', (440, 444))	('TP53', 'Gene', '7157', (551, 555))	('EGFR', 'Gene', '1956', (596, 600))	('IDH1', 'Gene', '3417', (616, 620))	('amplification', 'Var', (601, 614))	('CDKN2A', 'Gene', (538, 544))	('ERBB2', 'Gene', '2064', (575, 580))
27575	21829728	We used direct sequencing for TP53 and IDH1/2 and employed MLPA for the analysis of 1p/19q loss, PTEN and CDKN2A loss, and amplification of ERBB2 and EGFR.	('TP53', 'Gene', (30, 34))	('EGFR', 'Gene', (150, 154))	('PTEN', 'Gene', (97, 101))	('CDKN2A', 'Gene', '1029', (106, 112))	('PTEN', 'Gene', '5728', (97, 101))	('ERBB2', 'Gene', '2064', (140, 145))	('1p/19q', 'Protein', (84, 90))	('ERBB2', 'Gene', (140, 145))	('loss', 'NegReg', (113, 117))	('CDKN2A', 'Gene', (106, 112))	('loss', 'NegReg', (91, 95))	('amplification', 'Var', (123, 136))	('TP53', 'Gene', '7157', (30, 34))	('EGFR', 'Gene', '1956', (150, 154))
27578	21829728	In LGGs, IDH1/2 mutation and methylation of the MGMT promoter were frequently observed (~80%).	('MGMT', 'Gene', (48, 52))	('IDH1/2', 'Gene', (9, 15))	('mutation', 'Var', (16, 24))	('MGMT', 'Gene', '4255', (48, 52))	('observed', 'Reg', (78, 86))	('methylation', 'MPA', (29, 40))
27579	21829728	Of the 46 tumors with IDH1 mutations, 44 exhibited R132H, one R132G, and one R132S.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('R132S', 'Mutation', 'rs121913499', (77, 82))	('exhibited', 'Reg', (41, 50))	('R132G', 'Var', (62, 67))	('R132H', 'Var', (51, 56))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('R132H', 'Mutation', 'rs121913500', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('R132G', 'Mutation', 'rs121913499', (62, 67))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('R132S', 'Var', (77, 82))
27580	21829728	In contrast, TP53 mutation was more frequently observed in As (41%) and OA (45%) than in OG (10%).	('As', 'Phenotype', 'HP:0009592', (59, 61))	('TP53', 'Gene', (13, 17))	('observed', 'Reg', (47, 55))	('mutation', 'Var', (18, 26))	('TP53', 'Gene', '7157', (13, 17))
27582	21829728	In comparison with primary GBM, secondary GBM had more IDH1/2 and TP53 mutations and CDKN2A loss, a higher frequency of methylated MGMT promoter, and less EGFR amplification, although the number of secondary GBM (n = 3) was limited (Table 3, Figure 1B).	('TP53', 'Gene', '7157', (66, 70))	('EGFR', 'Gene', '1956', (155, 159))	('TP53', 'Gene', (66, 70))	('MGMT', 'Gene', '4255', (131, 135))	('methylated', 'MPA', (120, 130))	('MGMT', 'Gene', (131, 135))	('CDKN2A', 'Gene', (85, 91))	('EGFR', 'Gene', (155, 159))	('CDKN2A', 'Gene', '1029', (85, 91))	('less', 'NegReg', (150, 154))	('mutations', 'Var', (71, 80))	('loss', 'NegReg', (92, 96))	('higher', 'PosReg', (100, 106))	('IDH1/2', 'Gene', (55, 61))
27583	21829728	Recently, emerging evidence revealed correlations between the methylation status of the MGMT promoter, IDH1 mutations, and 1p/19q codeletions.	('methylation', 'MPA', (62, 73))	('IDH1', 'Gene', '3417', (103, 107))	('mutations', 'Var', (108, 117))	('MGMT', 'Gene', (88, 92))	('MGMT', 'Gene', '4255', (88, 92))	('IDH1', 'Gene', (103, 107))
27584	21829728	Using the chi2 test in LGGs, IDH1/2 mutation was correlated significantly with a methylated MGMT promoter (p = 0.038) and 1p/19q codeletion (p = 0.024).	('MGMT', 'Gene', (92, 96))	('MGMT', 'Gene', '4255', (92, 96))	('IDH1/2', 'Gene', (29, 35))	('mutation', 'Var', (36, 44))
27585	21829728	Further, the presence of a methylated MGMT promoter was correlated significantly with 1p/19q codeletion (p = 0.026).	('MGMT', 'Gene', '4255', (38, 42))	('methylated', 'Var', (27, 37))	('presence', 'Var', (13, 21))	('MGMT', 'Gene', (38, 42))	('1p/19q codeletion', 'Disease', (86, 103))
27586	21829728	Additionally, of the 24 cases with 1p/19q codeletion, 23 and 22 cases exhibited IDH1/2 mutations and methylated MGMT promoters, respectively, but none showed TP53 mutations.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('exhibited', 'Reg', (70, 79))	('MGMT', 'Gene', (112, 116))	('MGMT', 'Gene', '4255', (112, 116))	('mutations', 'Var', (87, 96))	('IDH1/2', 'Gene', (80, 86))
27587	21829728	Of the 44 cases with methylated MGMT promoters, 39 cases exhibited IDH1/2 mutations.	('IDH1/2', 'Gene', (67, 73))	('methylated', 'Var', (21, 31))	('mutations', 'Var', (74, 83))	('MGMT', 'Gene', '4255', (32, 36))	('MGMT', 'Gene', (32, 36))	('exhibited', 'Reg', (57, 66))
27588	21829728	These results suggest that almost all patients having tumors with 1p/19q codeletions exhibited methylated MGMT promoters and that almost all tumors with methylated MGMT promoters exhibited IDH1/2 mutations (Figure 1A).	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('MGMT', 'Gene', (164, 168))	('methylated', 'Var', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IDH1/2', 'Gene', (189, 195))	('MGMT', 'Gene', (106, 110))	('tumors', 'Disease', (54, 60))	('1p/19q', 'Var', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('MGMT', 'Gene', '4255', (164, 168))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (196, 205))	('MGMT', 'Gene', '4255', (106, 110))	('exhibited', 'Reg', (85, 94))	('exhibited', 'Reg', (179, 188))
27597	21829728	Previously, it was reported that G-CIMP tumors are more prevalent among LGGs, and are tightly associated with IDH1 mutation.	('IDH1', 'Gene', '3417', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('G-CIMP', 'Chemical', '-', (33, 39))	('LGGs', 'Disease', (72, 76))	('associated', 'Reg', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mutation', 'Var', (115, 123))	('IDH1', 'Gene', (110, 114))	('tumors', 'Disease', (40, 46))
27598	21829728	Thus, it may be interesting to know whether LINE-1 methylation is correlated with IDH1 mutation in our sample sets.	('IDH1', 'Gene', '3417', (82, 86))	('correlated', 'Reg', (66, 76))	('mutation', 'Var', (87, 95))	('IDH1', 'Gene', (82, 86))
27602	21829728	Of particular note, high LINE-1 methylation (68% <=) was significantly correlated with prolonged OS of patients aged over 40 (p = 0.039), whereas statistical significant association was not obtained between high LINE-1 methylation and PFS (Figure 5).	('methylation', 'Var', (32, 43))	('prolonged OS', 'Disease', (87, 99))	('correlated', 'Reg', (71, 81))	('patients', 'Species', '9606', (103, 111))	('high LINE-1', 'Gene', (20, 31))
27603	21829728	To our surprise, in the Kaplan-Meier survival curve of patients with primary GBM, univariate analysis indicated a lower p value in the comparison of <68% and >=68% of LINE-1 methylation than in the comparison of <14% and >=14% of MGMT promoter methylation (p = 0.010 and 0.015, Figure 6AB).	('MGMT', 'Gene', '4255', (230, 234))	('methylation', 'Var', (174, 185))	('lower', 'NegReg', (114, 119))	('patients', 'Species', '9606', (55, 63))	('MGMT', 'Gene', (230, 234))	('p value', 'MPA', (120, 127))
27604	21829728	Prolonged overall survival time was significantly correlated with a high LINE-1 methylation status but not with a methylated MGMT promoter (p = 0.031, Figure 6C).	('MGMT', 'Gene', (125, 129))	('methylation status', 'Var', (80, 98))	('high', 'Var', (68, 72))	('MGMT', 'Gene', '4255', (125, 129))	('Prolonged', 'PosReg', (0, 9))	('overall survival time', 'CPA', (10, 31))
27606	21829728	The secondary GBM tumors already had TP53 mutation and IDH1 mutation at the time of the low-grade tumors but displayed a 2-fold increase in methylation of the MGMT promoter and an 8% decrease in methylation of LINE-1 during malignant transformation.	('mutation', 'Var', (60, 68))	('tumors', 'Disease', (98, 104))	('tumors', 'Disease', (18, 24))	('TP53', 'Gene', (37, 41))	('IDH1', 'Gene', (55, 59))	('methylation', 'MPA', (195, 206))	('MGMT', 'Gene', '4255', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('mutation', 'Var', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('IDH1', 'Gene', '3417', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('TP53', 'Gene', '7157', (37, 41))	('decrease', 'NegReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('increase', 'PosReg', (128, 136))	('MGMT', 'Gene', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('methylation', 'MPA', (140, 151))
27608	21829728	In this study, 57 LGG samples exhibited IDH1/2 mutations most frequently (82%), followed by methylated MGMT promoters (77%), 1p/19q codeletion (42%), and TP53 mutations (26%).	('MGMT', 'Gene', '4255', (103, 107))	('TP53', 'Gene', (154, 158))	('IDH1/2', 'Gene', (40, 46))	('mutations', 'Var', (47, 56))	('TP53', 'Gene', '7157', (154, 158))	('MGMT', 'Gene', (103, 107))
27609	21829728	We demonstrated that higher methylation levels of LINE-1 and the MGMT promoter and 1p/19q codeletion were associated with oligodendroglial tumors.	('MGMT', 'Gene', (65, 69))	('1p/19q codeletion', 'Var', (83, 100))	('MGMT', 'Gene', '4255', (65, 69))	('associated', 'Reg', (106, 116))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (122, 145))	('oligodendroglial tumors', 'Disease', (122, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('methylation levels', 'MPA', (28, 46))	('higher', 'PosReg', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
27610	21829728	Additionally, the presence of 1p/19q codeletion was significantly correlated with higher MGMT promoter methylation.	('MGMT', 'Gene', (89, 93))	('MGMT', 'Gene', '4255', (89, 93))	('higher', 'PosReg', (82, 88))	('codeletion', 'Var', (37, 47))
27611	21829728	In our study, IDH1/2 mutation was not correlated with prolonged PFS and OS in LGG patients.	('patients', 'Species', '9606', (82, 90))	('mutation', 'Var', (21, 29))	('PFS', 'Disease', (64, 67))	('IDH1/2', 'Gene', (14, 20))	('LGG', 'Disease', (78, 81))
27612	21829728	The finding was consistent with previous reports demonstrating that IDH1/2 mutations are not a prognostic factor for LGGs, but there was opposed evidence showing significant and independent associations between IDH mutation and improved survival in LGGs.	('mutation', 'Var', (215, 223))	('IDH', 'Gene', '3417', (68, 71))	('LGGs', 'Disease', (117, 121))	('IDH', 'Gene', (211, 214))	('improved', 'PosReg', (228, 236))	('IDH', 'Gene', '3417', (211, 214))	('IDH', 'Gene', (68, 71))
27614	21829728	In various cancers, such as colorectal cancer, global DNA hypomethylation was correlated with poor prognosis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('colorectal cancer', 'Disease', (28, 45))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('global DNA hypomethylation', 'Var', (47, 73))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
27620	21829728	Notably, only low LINE-1 methylation indicated poor prognosis in primary GBM patients, as analyzed by both univariate and multivariate analyses.	('LINE-1', 'Gene', (18, 24))	('primary GBM', 'Disease', (65, 76))	('patients', 'Species', '9606', (77, 85))	('methylation', 'Var', (25, 36))	('low', 'Var', (14, 17))
27621	21829728	Prolonged overall survival time was significantly correlated with high LINE-1 methylation status but not with a methylated MGMT promoter.	('overall survival time', 'CPA', (10, 31))	('MGMT', 'Gene', (123, 127))	('Prolonged', 'PosReg', (0, 9))	('MGMT', 'Gene', '4255', (123, 127))	('methylation status', 'Var', (78, 96))	('high LINE-1', 'Gene', (66, 77))
27623	21829728	This is consistent with other cancers such as colorectal cancer and ovarian cancer, in which hypomethylation of LINE-1 is correlated with shortened survival.	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('cancers', 'Disease', (30, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('LINE-1', 'Gene', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('shortened', 'NegReg', (138, 147))	('ovarian cancer', 'Disease', (68, 82))	('hypomethylation', 'Var', (93, 108))	('colorectal cancer', 'Disease', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
27626	21829728	Previously, it was reported that G-CIMP tumors are tightly associated with IDH1 mutation.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('G-CIMP', 'Chemical', '-', (33, 39))	('associated', 'Reg', (59, 69))	('IDH1', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (75, 79))	('mutation', 'Var', (80, 88))	('tumors', 'Disease', (40, 46))
27627	21829728	More recently, IDH mutations and resultant 2-hydroxyglutarate (2HG) production in leukemia cells were reported to induce global DNA hypermethylation through impaired TET2 catalytic function.	('global DNA hypermethylation', 'MPA', (121, 148))	('leukemia', 'Disease', (82, 90))	('TET2', 'Gene', '54790', (166, 170))	('TET2', 'Gene', (166, 170))	('mutations', 'Var', (19, 28))	('IDH', 'Gene', (15, 18))	('induce', 'Reg', (114, 120))	('impaired', 'NegReg', (157, 165))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (43, 61))	('IDH', 'Gene', '3417', (15, 18))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('leukemia', 'Disease', 'MESH:D007938', (82, 90))
27628	21829728	The higher levels of LINE-1 methylation in low grade gliomas may be attributable to the differential prevalence of IDH mutation in low versus high-grade glioma, and the methylator phenotype associated with IDH mutation.	('IDH', 'Gene', (206, 209))	('mutation', 'Var', (119, 127))	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', (153, 159))	('methylation', 'MPA', (28, 39))	('gliomas', 'Disease', (53, 60))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('IDH', 'Gene', '3417', (206, 209))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('IDH', 'Gene', (115, 118))	('higher', 'PosReg', (4, 10))	('IDH', 'Gene', '3417', (115, 118))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('levels', 'MPA', (11, 17))
27635	31568700	Meanwhile, the high level of MIR155HG was associated with poorer OS in glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM).	('glioblastoma multiforme', 'Disease', (71, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (71, 94))	('GBM', 'Disease', (96, 99))	('GBM', 'Disease', 'MESH:D005909', (96, 99))	('glioma', 'Disease', (162, 168))	('KIRC', 'Disease', (137, 141))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (102, 135))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('UVM', 'Disease', 'MESH:C536494', (196, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('KIRC', 'Disease', 'MESH:D002292', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('UVM', 'Disease', (196, 199))	('kidney renal clear cell carcinoma', 'Disease', (102, 135))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('MIR155HG', 'Var', (29, 37))
27636	31568700	(b) The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells and immune molecules, especially with immune checkpoint molecules such as programmed cell death protein 1 (PD-1), PD-1 ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) in most kinds of cancers.	('CTLA4', 'Gene', (287, 292))	('MIR155HG', 'Var', (22, 30))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (242, 285))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (242, 285))	('PD-L1', 'Gene', (230, 235))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('PD-L1', 'Gene', '29126', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('PD-1', 'Gene', (215, 219))	('PD-1', 'Gene', '5133', (215, 219))	('PD-1', 'Gene', (208, 212))	('correlated', 'Reg', (49, 59))	('PD-1', 'Gene', '5133', (208, 212))	('PD-1 ligand 1', 'Gene', (215, 228))	('programmed cell death protein 1', 'Gene', (175, 206))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('infiltrating levels of immune cells', 'MPA', (65, 100))	('CTLA4', 'Gene', '1493', (287, 292))	('PD-1 ligand 1', 'Gene', '29126', (215, 228))	('programmed cell death protein 1', 'Gene', '5133', (175, 206))
27637	31568700	(c) Detection of clinical CHOL and liver hepatocellular carcinoma tissues confirmed that there was a strong positive correlation between MIR155HG expression and the levels of CTLA4 and PD-L1.	('CTLA4', 'Gene', '1493', (175, 180))	('MIR155HG', 'Var', (137, 145))	('CHOL', 'Disease', (26, 30))	('CTLA4', 'Gene', (175, 180))	('CHOL', 'Disease', 'MESH:D018281', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('PD-L1', 'Gene', '29126', (185, 190))	('liver hepatocellular carcinoma', 'Disease', (35, 65))	('PD-L1', 'Gene', (185, 190))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (41, 65))	('clinical', 'Species', '191496', (17, 25))
27647	31568700	At the same time, MIR155HG is also thought to be involved in the human immune response.	('human', 'Species', '9606', (65, 70))	('involved', 'Reg', (49, 57))	('MIR155HG', 'Var', (18, 26))
27649	31568700	We also analyzed the association of MIR155HG with tumor-infiltrating immune cells and immune molecules in tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (50, 55))	('MIR155HG', 'Var', (36, 44))	('tumor', 'Disease', (106, 111))
27650	31568700	The results indicated that the expression of MIR155HG in these tumors is closely related to the immunological checkpoint molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('CTLA4', 'Gene', (144, 149))	('PD-L1', 'Gene', (137, 142))	('MIR155HG', 'Var', (45, 53))	('LAG3', 'Gene', (151, 155))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('LAG3', 'Gene', '3902', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TIM3', 'Gene', (161, 165))	('PD-1', 'Gene', (131, 135))	('PD-L1', 'Gene', '29126', (137, 142))	('TIM3', 'Gene', '84868', (161, 165))	('PD-1', 'Gene', '5133', (131, 135))	('CTLA4', 'Gene', '1493', (144, 149))
27652	31568700	Therefore, we believe that MIR155HG can be used as a predictor for assessing the prognosis of cancer patients and the effectiveness of immunotherapy with checkpoint blockade.	('patients', 'Species', '9606', (101, 109))	('MIR155HG', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
27654	31568700	The gene pattern was used to analyze the correlation of MIR155HG with immune cell infiltration in various tumors, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells (DCs).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MIR155HG', 'Var', (56, 64))
27656	31568700	The gene expression profiling interactive analysis (GEPIA) database integrates tens of thousands of tumor and non-tumor samples from TCGA and GTEx gene expression data to analyze gene expression, differential gene expression, survival, correlation, and co-expression of genes online.21 We analyzed the expression of MIR155HG in various tumors and corresponding normal tissues by GEPIA quick start tab.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (336, 342))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Disease', (114, 119))	('MIR155HG', 'Var', (316, 324))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))
27661	31568700	The TIMER online database was used to analyze the differential expression of MIR155HG in 17 types of tumors and adjacent tissues in TCGA, and the differential expression was evaluated by Wilcoxon test.	('MIR155HG', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
27662	31568700	The results showed that, compared to the paracancerous control, MIR155HG was highly expressed in breast invasive carcinoma, HNSC, KIRC, kidney renal papillary cell carcinoma, LUAD, stomach adenocarcinoma and uterine corpus endometrial carcinoma, lower expression in kidney chromophobe (KICH), rectum adenocarcinoma (P < .05) (Figure 1A).	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (97, 122))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('stomach adenocarcinoma', 'Disease', (181, 203))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (136, 173))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (143, 173))	('KIRC', 'Disease', (130, 134))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (97, 122))	('kidney chromophobe', 'Disease', (266, 284))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (293, 314))	('LUAD', 'Disease', (175, 179))	('MIR155HG', 'Var', (64, 72))	('KIRC', 'Disease', 'MESH:D002292', (130, 134))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (181, 203))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('kidney renal papillary cell carcinoma', 'Disease', (136, 173))	('cancer', 'Disease', (45, 51))	('expression', 'MPA', (252, 262))	('lower', 'NegReg', (246, 251))	('LUAD', 'Disease', 'MESH:C538231', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('breast invasive carcinoma', 'Disease', (97, 122))	('rectum adenocarcinoma', 'Disease', (293, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))
27663	31568700	The GEPIA database analyzes the expression of MIR155HG in various tumors and matched normal tissues (match TCGA normal and GTEx data), and the results showed that MIR155HG was higher than the matched normal tissue in the lymphoid neoplasm DLBC lymphoma, GBM, KIRC, acute myeloid leukemia, thymoma (cutoff criteria:  log2fold change  > 1.0 and P < .05) (Figure 1B).	('KIRC', 'Disease', (259, 263))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (265, 287))	('lymphoma', 'Disease', (244, 252))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('lymphoma', 'Disease', 'MESH:D008223', (244, 252))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (265, 287))	('thymoma', 'Disease', (289, 296))	('MIR155HG', 'Var', (163, 171))	('thymoma', 'Phenotype', 'HP:0100522', (289, 296))	('KIRC', 'Disease', 'MESH:D002292', (259, 263))	('GBM', 'Disease', (254, 257))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (221, 238))	('GBM', 'Disease', 'MESH:D005909', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (244, 252))	('higher', 'PosReg', (176, 182))	('MIR155HG', 'Var', (46, 54))	('acute myeloid leukemia', 'Disease', (265, 287))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (230, 238))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('tumors', 'Disease', (66, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (271, 287))	('thymoma', 'Disease', 'MESH:D013945', (289, 296))
27664	31568700	We used GEPIA to analyze the relation of MIR155HG and clinical features in 33 kinds of tumors and found that MIR155HG was correlated with OS, DFS, and staging in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('multiple tumors', 'Disease', (162, 177))	('DFS', 'Disease', (142, 145))	('clinical', 'Species', '191496', (54, 62))	('correlated', 'Reg', (122, 132))	('tumors', 'Disease', (87, 93))	('multiple tumors', 'Disease', 'MESH:D009369', (162, 177))	('tumors', 'Disease', (171, 177))	('MIR155HG', 'Var', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
27665	31568700	The MIR155HG higher expression has better OS and DFS in CHOL and prophase SKCM.	('SKCM', 'Disease', 'MESH:C562393', (74, 78))	('SKCM', 'Disease', (74, 78))	('DFS', 'MPA', (49, 52))	('MIR155HG higher expression', 'Var', (4, 30))	('better', 'PosReg', (35, 41))	('CHOL', 'Disease', (56, 60))	('CHOL', 'Disease', 'MESH:D018281', (56, 60))
27666	31568700	In LUAD and early stage of HNSC, patients with high levels of MIR155HG have better OS than patients with low expression of MIR155HG.	('LUAD', 'Disease', (3, 7))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (33, 41))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('MIR155HG', 'Var', (62, 70))	('better', 'PosReg', (76, 82))
27667	31568700	While high levels of MIR155HG was associated with poor OS in GBM, KIRC, LGG, and UVM, and poor DFS in LGG early stage and UVM MIR155HG was closely related to tumor stage in KICH, KIRC, LUAD, SKCM, Thyroid carcinoma (THCA) (Figure 2; Table S2).	('SKCM', 'Disease', (191, 195))	('GBM', 'Disease', 'MESH:D005909', (61, 64))	('KIRC', 'Disease', (179, 183))	('UVM', 'Disease', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('THCA', 'Disease', 'MESH:D013964', (216, 220))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (197, 214))	('UVM', 'Disease', (122, 125))	('LUAD', 'Disease', (185, 189))	('KIRC', 'Disease', 'MESH:D002292', (179, 183))	('related', 'Reg', (147, 154))	('THCA', 'Disease', (216, 220))	('SKCM', 'Disease', 'MESH:C562393', (191, 195))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', 'MESH:C538231', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Disease', (158, 163))	('MIR155HG', 'Var', (21, 29))	('UVM', 'Disease', 'MESH:C536494', (81, 84))	('MIR155HG', 'Var', (126, 134))	('Thyroid carcinoma', 'Disease', (197, 214))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('UVM', 'Disease', 'MESH:C536494', (122, 125))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (197, 214))	('GBM', 'Disease', (61, 64))
27668	31568700	According to the correlation between MIR155HG and OS or DFS in eight types of tumors (CHOL, HNSC, GBM, KIRC, LGG, LUAD, SKCM, UVM), the gene pathway enrichment and functional enrichment were further analyzed.	('CHOL', 'Disease', 'MESH:D018281', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SKCM', 'Disease', (120, 124))	('GBM', 'Disease', (98, 101))	('GBM', 'Disease', 'MESH:D005909', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('LUAD', 'Disease', (114, 118))	('LGG', 'Disease', (109, 112))	('UVM', 'Disease', 'MESH:C536494', (126, 129))	('tumors', 'Disease', (78, 84))	('SKCM', 'Disease', 'MESH:C562393', (120, 124))	('KIRC', 'Disease', (103, 107))	('CHOL', 'Disease', (86, 90))	('LUAD', 'Disease', 'MESH:C538231', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('UVM', 'Disease', (126, 129))	('HNSC', 'Disease', (92, 96))	('KIRC', 'Disease', 'MESH:D002292', (103, 107))	('MIR155HG', 'Var', (37, 45))
27669	31568700	The top 80 mRNAs co-expressed with MIR155HG in various tumors were obtained by GEPIA's similar genes model.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MIR155HG', 'Var', (35, 43))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
27673	31568700	To investigate the correlation between MIR155HG and tumor immune cells, we used the TIMER to analyze the correlation of MIR155HG with tumor purity, lymphocytes, macrophages, neutrophils, DCs, NK cells, Treg cells, mast cells, Th1, Th2, Th17, Tfh cells, MDSC in the above eight tumors.	('Th1', 'Gene', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Th1', 'Gene', '51497', (236, 239))	('tumor', 'Disease', (52, 57))	('MIR155HG', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Th1', 'Gene', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Th1', 'Gene', '51497', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (134, 139))	('tumors', 'Disease', (277, 283))
27674	31568700	The results showed that the expression of MIR155HG in CHOL, HNSC, KIRC, LGG, LUAD, and SKCM was significantly correlated with tumor purity and the infiltration level of immune cells such as B lymphocytes, CD8+ T cells, CD4+ T cells and DCs.	('CHOL', 'Disease', (54, 58))	('SKCM', 'Disease', (87, 91))	('CHOL', 'Disease', 'MESH:D018281', (54, 58))	('correlated', 'Reg', (110, 120))	('infiltration level', 'MPA', (147, 165))	('MIR155HG', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('SKCM', 'Disease', 'MESH:C562393', (87, 91))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', (77, 81))	('LUAD', 'Disease', 'MESH:C538231', (77, 81))	('tumor', 'Disease', (126, 131))
27676	31568700	MIR155 host gene was highly correlated with NK cells, Treg cells, macrophages, Th1, Tfh cells and M-MDSC in CHOL, HNSC, KIRC, LUAD, and SKCM, and have a certain correlation with MDSC in GBM MIR155HG was related to the infiltration of macrophages, Th1 and DMSC in a certain degree in LGG, and has moderate correlated with Treg cells, Th1 and Tfh cells in UVM (Table S3).	('LUAD', 'Disease', 'MESH:C538231', (126, 130))	('Th1', 'Gene', (79, 82))	('Th1', 'Gene', '51497', (333, 336))	('SKCM', 'Disease', (136, 140))	('GBM', 'Disease', (186, 189))	('Th1', 'Gene', '51497', (79, 82))	('GBM', 'Disease', 'MESH:D005909', (186, 189))	('MIR155', 'Gene', (0, 6))	('UVM', 'Disease', 'MESH:C536494', (354, 357))	('SKCM', 'Disease', 'MESH:C562393', (136, 140))	('KIRC', 'Disease', (120, 124))	('CHOL', 'Disease', (108, 112))	('MIR155HG', 'Var', (190, 198))	('Th1', 'Gene', (247, 250))	('LUAD', 'Disease', (126, 130))	('KIRC', 'Disease', 'MESH:D002292', (120, 124))	('UVM', 'Disease', (354, 357))	('Th1', 'Gene', '51497', (247, 250))	('CHOL', 'Disease', 'MESH:D018281', (108, 112))	('Th1', 'Gene', (333, 336))
27678	31568700	To evaluate the efficacy of MIR155HG in predicting cancer patient response to checkpoint inhibitor, we used the TIMER database to analyze the relevance of MIR155HG and the currently available blocking molecules with superior therapeutic effects PD-1, PD-L1, CTLA4, LAG3, TIM3.	('LAG3', 'Gene', '3902', (265, 269))	('TIM3', 'Gene', '84868', (271, 275))	('PD-L1', 'Gene', '29126', (251, 256))	('CTLA4', 'Gene', '1493', (258, 263))	('PD-1', 'Gene', '5133', (245, 249))	('patient', 'Species', '9606', (58, 65))	('CTLA4', 'Gene', (258, 263))	('MIR155HG', 'Var', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', (251, 256))	('PD-1', 'Gene', (245, 249))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('LAG3', 'Gene', (265, 269))	('TIM3', 'Gene', (271, 275))
27679	31568700	A significant strong positive correlation (cor > 0.5) was found between MIR155HG with PD-1 (PDCD1), PD-L1 (CD274), CTLA4, LAG3, and TIM3 (HAVCR2) molecules in LUAD and SKCM, and with a median or higher correlation in CHOL and UVM patients (cor > 0.3), a significant correlation in HNSC, LGG (P < .0001).	('TIM3', 'Gene', (132, 136))	('UVM', 'Disease', (226, 229))	('HAVCR2', 'Gene', '84868', (138, 144))	('TIM3', 'Gene', '84868', (132, 136))	('CD274', 'Gene', '29126', (107, 112))	('CHOL', 'Disease', (217, 221))	('SKCM', 'Disease', (168, 172))	('HNSC', 'Disease', (281, 285))	('LGG', 'Disease', (287, 290))	('PDCD1', 'Gene', '5133', (92, 97))	('PDCD1', 'Gene', (92, 97))	('CTLA4', 'Gene', '1493', (115, 120))	('LAG3', 'Gene', '3902', (122, 126))	('CHOL', 'Disease', 'MESH:D018281', (217, 221))	('CD274', 'Gene', (107, 112))	('HAVCR2', 'Gene', (138, 144))	('SKCM', 'Disease', 'MESH:C562393', (168, 172))	('LAG3', 'Gene', (122, 126))	('LUAD', 'Disease', (159, 163))	('MIR155HG', 'Var', (72, 80))	('CTLA4', 'Gene', (115, 120))	('UVM', 'Disease', 'MESH:C536494', (226, 229))	('PD-L1', 'Gene', (100, 105))	('PD-L1', 'Gene', '29126', (100, 105))	('patients', 'Species', '9606', (230, 238))	('LUAD', 'Disease', 'MESH:C538231', (159, 163))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))
27681	31568700	The relationship between MIR155HG and immunity was relatively close in the eight types of prognostic-related tumor mentioned above, and what is the relationship with other types of tumors that unrelated to prognosis?	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('MIR155HG', 'Var', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (109, 114))
27683	31568700	The results showed that MIR155HG was significantly negative associated with tumor purity, positive correlated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('negative', 'NegReg', (51, 59))	('tumor', 'Disease', (76, 81))	('MIR155HG', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
27684	31568700	In LIHC, MIR155HG has a high correlation with immunological checkpoint molecules PD-1, CTLA4, LAG3, and TIM3 (cor > 0.5), and also has a significant correlation with PD-L1.	('LAG3', 'Gene', (94, 98))	('LIHC', 'Disease', 'MESH:D006528', (3, 7))	('PD-L1', 'Gene', '29126', (166, 171))	('TIM3', 'Gene', '84868', (104, 108))	('PD-1', 'Gene', (81, 85))	('LIHC', 'Disease', (3, 7))	('CTLA4', 'Gene', '1493', (87, 92))	('PD-1', 'Gene', '5133', (81, 85))	('CTLA4', 'Gene', (87, 92))	('correlation', 'Interaction', (149, 160))	('LAG3', 'Gene', '3902', (94, 98))	('MIR155HG', 'Var', (9, 17))	('PD-L1', 'Gene', (166, 171))	('correlation', 'Interaction', (29, 40))	('TIM3', 'Gene', (104, 108))
27686	31568700	We also analyzed the relationship between MIR155HG and immune in other tumors, and found that MIR155HG is closely related to immune cells and molecules in most kind of tumors (Figures S2 and S3).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('MIR155HG', 'Var', (94, 102))	('related', 'Reg', (114, 121))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
27687	31568700	Since the great value of MIR155HG predicting the immune checkpoint molecular expression level in tumor, we selected the prognostic-related tumor type CHOL and the prognostic-unrelated tumor type LIHC to detect the correlation.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CHOL', 'Disease', (150, 154))	('MIR155HG', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('immune checkpoint molecular expression level', 'MPA', (49, 93))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (184, 189))	('CHOL', 'Disease', 'MESH:D018281', (150, 154))	('LIHC', 'Disease', (195, 199))	('LIHC', 'Disease', 'MESH:D006528', (195, 199))
27688	31568700	The relationship of MIR155HG and the immunological checkpoint molecules PD-L1 and CTLA4 were verified by qRT-PCR.	('PD-L1', 'Gene', '29126', (72, 77))	('MIR155HG', 'Var', (20, 28))	('CTLA4', 'Gene', '1493', (82, 87))	('PD-L1', 'Gene', (72, 77))	('CTLA4', 'Gene', (82, 87))
27689	31568700	The results showed that MIR155HG showed a striking positive correlation with both PD-L1 and CTLA4 in CHOL and LIHC (Figure 7).	('CTLA4', 'Gene', (92, 97))	('LIHC', 'Disease', 'MESH:D006528', (110, 114))	('PD-L1', 'Gene', (82, 87))	('MIR155HG', 'Var', (24, 32))	('PD-L1', 'Gene', '29126', (82, 87))	('positive', 'PosReg', (51, 59))	('LIHC', 'Disease', (110, 114))	('CHOL', 'Disease', (101, 105))	('CTLA4', 'Gene', '1493', (92, 97))	('CHOL', 'Disease', 'MESH:D018281', (101, 105))	('correlation', 'Interaction', (60, 71))
27690	31568700	In this report, we analyzed the expression of MIR155HG in various cancers and paracancer or normal tissues, and analyzed the relationship between MIR155HG expression and OS, DFS and staging, consistent with Wu's finding that MIR155HG was associated with poor tumor prognosis in glioma.10 As reported, the expression of MIR155HG was significantly higher in cancer than paracancer in KIRC,26 and MIR155HG was associated with poor OS.27 GO and KEGG analysis in these types of tumors showed that mRNAs co-expressed with MIR155HG were mostly enriched in immune-related functions and immune-related pathways, which indicated that MIR155HG may be related to immunity.	('tumors', 'Disease', 'MESH:D009369', (473, 479))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (473, 478))	('tumor', 'Disease', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('immune-related functions', 'CPA', (549, 573))	('cancer', 'Disease', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (473, 478))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('glioma', 'Disease', (278, 284))	('enriched', 'Reg', (537, 545))	('KIRC', 'Disease', (382, 386))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('tumors', 'Phenotype', 'HP:0002664', (473, 479))	('cancer', 'Disease', (372, 378))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('immune-related pathways', 'Pathway', (578, 601))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MIR155HG', 'Var', (516, 524))	('tumor', 'Phenotype', 'HP:0002664', (473, 478))	('KIRC', 'Disease', 'MESH:D002292', (382, 386))	('tumors', 'Disease', (473, 479))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('cancer', 'Disease', (66, 72))
27693	31568700	In this study, we examined the association of MIR155HG with immune cells attempting to reveal the immune status in cancer patients by understanding the expression of MIR155HG.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('MIR155HG', 'Var', (166, 174))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
27694	31568700	The results showed that MIR155HG was significantly negatively correlated with tumor purity and significantly positively correlated with B cells, CD8+ T cells, CD4+ T cells, and DCs in most kinds of cancers.	('positively correlated', 'Reg', (109, 130))	('negatively', 'NegReg', (51, 61))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Disease', (198, 205))	('MIR155HG', 'Var', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (78, 83))
27695	31568700	Moreover, to fully demonstrate the relationship between MIR155HG and immunity, we also analyzed the association of MIR155HG with immunosuppressive molecules and immunostimulatory molecules in the above described cancer types.	('association', 'Interaction', (100, 111))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('MIR155HG', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
27699	31568700	We found that MIR155HG was significantly associated with immunological checkpoint blocking molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3 in many tumors, and some of those types of tumor have better reactivity against immunological checkpoint blockade.	('tumors', 'Disease', (144, 150))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('reactivity', 'MPA', (197, 207))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TIM3', 'Gene', (131, 135))	('TIM3', 'Gene', '84868', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LAG3', 'Gene', '3902', (121, 125))	('tumor', 'Disease', (144, 149))	('CTLA4', 'Gene', '1493', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('LAG3', 'Gene', (121, 125))	('PD-L1', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Gene', '29126', (107, 112))	('MIR155HG', 'Var', (14, 22))	('PD-1', 'Gene', (101, 105))	('PD-1', 'Gene', '5133', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CTLA4', 'Gene', (114, 119))	('tumor', 'Disease', (179, 184))
27703	31568700	They found that the expression of LAYN was associated with increased levels of immune permeation of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in colon and gastric cancer.41 Compared with the results of Pan et al, MIR155HG has a wider range of tumor applicability and was more closely related to immune cells and immune molecules.	('LAYN', 'Gene', '143903', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('MIR155HG', 'Var', (233, 241))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (263, 268))	('LAYN', 'Gene', (34, 38))	('colon and gastric cancer', 'Disease', 'MESH:D013274', (165, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))
27704	31568700	The previous research reported that MIR155HG participate the regulator of innate immunity17 and macrophage polarization,16 and associated with acute rejection, T-cell-mediated acute rejection and graft loss.42 MIR-155 regulates the expression of many immune-specific transcripts, such as regulate polarization of macrophages, DCs maturation, T-cell differentiation, controls B cell proliferation and antibody production.43, 44 Consider that MIR155 is derived from MIR155HG and that MIR155HG play a critical role by interaction with MIR155,9, 10 we speculated that MIR155HG may affect the immune process through its interaction with MIR155 or other mechanisms.	('affect', 'Reg', (577, 583))	('graft loss', 'Disease', 'MESH:D055589', (196, 206))	('interaction', 'Interaction', (615, 626))	('graft loss', 'Disease', (196, 206))	('MIR-155', 'Gene', '406947', (210, 217))	('MIR155HG', 'Var', (564, 572))	('MIR-155', 'Gene', (210, 217))	('immune process', 'CPA', (588, 602))
27705	31568700	To preliminarily verify the relationship between MIR155HG and immune infiltration in an individual patient, we verified the correlation between MIR155HG and immune checkpoint molecules PD-L1 and CTLA4 by realtime quantitative reverse transcription polymerase chain reaction (qRT-PCR) in frozen tissue specimens of patients with CHOL and LIHC.	('CTLA4', 'Gene', '1493', (195, 200))	('patient', 'Species', '9606', (99, 106))	('LIHC', 'Disease', (337, 341))	('patients', 'Species', '9606', (314, 322))	('LIHC', 'Disease', 'MESH:D006528', (337, 341))	('CTLA4', 'Gene', (195, 200))	('CHOL', 'Disease', (328, 332))	('MIR155HG', 'Var', (144, 152))	('CHOL', 'Disease', 'MESH:D018281', (328, 332))	('PD-L1', 'Gene', (185, 190))	('patient', 'Species', '9606', (314, 321))	('PD-L1', 'Gene', '29126', (185, 190))
27706	31568700	There was a significant positive correlation between the expression of MIR155HG and PD-L1, CTLA4 in clinical specimens.	('expression', 'MPA', (57, 67))	('clinical', 'Species', '191496', (100, 108))	('PD-L1', 'Gene', (84, 89))	('MIR155HG', 'Var', (71, 79))	('PD-L1', 'Gene', '29126', (84, 89))	('CTLA4', 'Gene', '1493', (91, 96))	('CTLA4', 'Gene', (91, 96))
27708	31568700	In conclusion, the above results indicate that MIR155HG expression might help to predict the prognosis and understanding immune status in cancer.	('MIR155HG', 'Var', (47, 55))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('help', 'Reg', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
27709	31568700	In this study, we found that MIR155HG can be used as a biomarker of prognosis in CHOL, GBM, HNSC, KIRC, LGG, LUAD, SKCM, and UVM through bioinformatics analysis.	('UVM', 'Disease', 'MESH:C536494', (125, 128))	('SKCM', 'Disease', (115, 119))	('GBM', 'Disease', (87, 90))	('KIRC', 'Disease', (98, 102))	('CHOL', 'Disease', (81, 85))	('KIRC', 'Disease', 'MESH:D002292', (98, 102))	('CHOL', 'Disease', 'MESH:D018281', (81, 85))	('UVM', 'Disease', (125, 128))	('LUAD', 'Disease', 'MESH:C538231', (109, 113))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('HNSC', 'Disease', (92, 96))	('SKCM', 'Disease', 'MESH:C562393', (115, 119))	('LUAD', 'Disease', (109, 113))	('MIR155HG', 'Var', (29, 37))
27710	31568700	And the expression level of MIR155HG has a certain correlation with immune molecules in various types of tumors, especially in HNSC, LUAD, KIRC, SKCM, and LIHC, which are suitable for predicting the curative effect of immune checkpoint blockade therapy.	('tumors', 'Disease', (105, 111))	('LIHC', 'Disease', (155, 159))	('KIRC', 'Disease', (139, 143))	('correlation', 'Reg', (51, 62))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('SKCM', 'Disease', (145, 149))	('LUAD', 'Disease', 'MESH:C538231', (133, 137))	('LIHC', 'Disease', 'MESH:D006528', (155, 159))	('MIR155HG', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('expression', 'MPA', (8, 18))	('SKCM', 'Disease', 'MESH:C562393', (145, 149))	('HNSC', 'Disease', (127, 131))	('LUAD', 'Disease', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('KIRC', 'Disease', 'MESH:D002292', (139, 143))
27769	29359162	Clinical trial studies in patients with colorectal cancer have shown that RSV hinders tumor cell proliferation and increases caspase-3 in the malignant hepatic tissue compared to the placebo patients.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('caspase-3', 'Gene', (125, 134))	('patients', 'Species', '9606', (191, 199))	('colorectal cancer', 'Disease', (40, 57))	('tumor', 'Disease', (86, 91))	('hinders', 'NegReg', (78, 85))	('increases', 'PosReg', (115, 124))	('patients', 'Species', '9606', (26, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('caspase-3', 'Gene', '836', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('RSV', 'Var', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
27771	29359162	In earlier studies by Gangemi et al., RSV was found to induce apoptosis by activating caspase-3 in a human glioma cell line U251.	('caspase-3', 'Gene', (86, 95))	('U251', 'CellLine', 'CVCL:0021', (124, 128))	('RSV', 'Var', (38, 41))	('caspase-3', 'Gene', '836', (86, 95))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('human', 'Species', '9606', (101, 106))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('apoptosis', 'CPA', (62, 71))	('induce', 'PosReg', (55, 61))	('activating', 'PosReg', (75, 85))	('glioma', 'Disease', (107, 113))
27776	29359162	This G2/M arrest was p53 independent, as it was observed in all glioma cells tested, including p53 mutant cells U251 and U138.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('M arrest', 'Disease', (8, 16))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', (95, 98))	('glioma', 'Disease', (64, 70))	('p53', 'Gene', '7157', (95, 98))	('mutant', 'Var', (99, 105))	('U251', 'CellLine', 'CVCL:0021', (112, 116))	('p53', 'Gene', (21, 24))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('M arrest', 'Disease', 'MESH:D006323', (8, 16))
27789	29359162	EGCG also sensitized GSLCs to temozolomide, a phenomenon associated with downregulation of P-gp in vitro.	('P-gp', 'Gene', '283871', (91, 95))	('temozolomide', 'Chemical', 'MESH:D000077204', (30, 42))	('P-gp', 'Gene', (91, 95))	('GSLCs', 'Chemical', '-', (21, 26))	('sensitized', 'Reg', (10, 20))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))
27790	29359162	EGCG was observed to induce apoptosis in U87 GSLCs by reducing Akt phosphorylation, inactivating antiapoptotic protein Bcl-2, upregulating the apoptosis-promoting protein Bax, and cleaving PARP.	('Bax', 'Gene', '581', (171, 174))	('inactivating', 'NegReg', (84, 96))	('PARP', 'Gene', '1302', (189, 193))	('upregulating', 'PosReg', (126, 138))	('U87', 'CellLine', 'CVCL:0022', (41, 44))	('cleaving', 'Reg', (180, 188))	('PARP', 'Gene', (189, 193))	('Bax', 'Gene', (171, 174))	('apoptosis-promoting', 'CPA', (143, 162))	('GSLCs', 'Chemical', '-', (45, 50))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('Akt', 'Gene', '207', (63, 66))	('EGCG', 'Var', (0, 4))	('Bcl-2', 'Gene', '596', (119, 124))	('Bcl-2', 'Gene', (119, 124))	('reducing', 'NegReg', (54, 62))	('Akt', 'Gene', (63, 66))
27809	29359162	Delta9-THC in combination with temozolomide (TMZ) has shown a robust anticancer activity in TMZ-sensitive as well as TMZ-resistant tumors in glioma xenografts.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('temozolomide', 'Chemical', 'MESH:D000077204', (31, 43))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Delta9-THC', 'Var', (0, 10))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('Delta9-THC', 'Chemical', '-', (0, 10))	('TMZ', 'Chemical', 'MESH:D000077204', (45, 48))	('glioma', 'Disease', (141, 147))
27812	29359162	In recognition of the promising anticancer potential of Delta9-THC in the preclinical studies with a fair safety profile, it has become an important therapeutic target for the treatment of GBM and has also prompted a human clinical trial.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('GBM', 'Disease', (189, 192))	('human', 'Species', '9606', (217, 222))	('cancer', 'Disease', (36, 42))	('GBM', 'Phenotype', 'HP:0012174', (189, 192))	('Delta9-THC', 'Var', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Delta9-THC', 'Chemical', '-', (56, 66))
27819	29359162	The promitogenic pathways of MAPK and PI3K were also reportedly blocked through the inhibition of EGFR signaling.	('EGFR', 'Gene', (98, 102))	('inhibition', 'NegReg', (84, 94))	('PI3K', 'Var', (38, 42))	('promitogenic pathways', 'Pathway', (4, 25))	('blocked', 'NegReg', (64, 71))	('EGFR', 'Gene', '1956', (98, 102))	('MAPK', 'Gene', (29, 33))
27826	29359162	The reported studies indicate that the OP-A causes mitochondrial dysfunction and ER stress, impairs cell cycle progression, and inhibits multiple oncogenic signaling pathways in glioblastoma cells.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (51, 76))	('causes', 'Reg', (44, 50))	('OP-A', 'Var', (39, 43))	('impairs', 'NegReg', (92, 99))	('oncogenic signaling pathways', 'Pathway', (146, 174))	('glioblastoma', 'Disease', (178, 190))	('mitochondrial dysfunction', 'Disease', (51, 76))	('cell cycle progression', 'CPA', (100, 122))	('inhibits', 'NegReg', (128, 136))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (51, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('ER stress', 'MPA', (81, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))
27857	28571582	Question 34: Why is epidermal growth factor receptor (EGFR) 19 Del-positive tumor more sensitive to targeted therapy than EGFR 21 L858R-positive tumor in patients with non-small cell lung cancer?	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('L858R', 'Mutation', 'rs121434568', (130, 135))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', (145, 150))	('Del-positive', 'Var', (63, 75))	('sensitive', 'MPA', (87, 96))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
27889	28571582	chenmy@sysucc.org.cn Among the patients with advanced NSCLC who underwent EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment, the patients with EGFR exon 19 deletion (19 Del)-positive tumor had a higher objective response rate, longer progression-free survival duration, and longer overall survival duration than those with exon 21 L858R mutation (21 L858R)-positive tumor.	('tumor', 'Disease', (368, 373))	('objective response rate', 'CPA', (204, 227))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('rat', 'Species', '10116', (223, 226))	('progression-free survival', 'CPA', (236, 261))	('rat', 'Species', '10116', (302, 305))	('tumor', 'Disease', (185, 190))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('exon', 'Var', (150, 154))	('higher', 'PosReg', (197, 203))	('EGFR', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('overall survival', 'CPA', (283, 299))	('NSCLC', 'Disease', (54, 59))	('L858R', 'Mutation', 'rs121434568', (352, 357))	('patients', 'Species', '9606', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('deletion (19 Del)-positive', 'Var', (158, 184))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('L858R', 'Mutation', 'rs121434568', (333, 338))	('patients', 'Species', '9606', (31, 39))	('rat', 'Species', '10116', (264, 267))	('longer', 'PosReg', (276, 282))	('longer', 'PosReg', (229, 235))
27899	28571582	buw@niaid.nih.gov; jcohen@niaid.nih.gov Carcinomas commonly metastasize via the lymphatic system followed by the involvement of the blood vessel system, whereas sarcomas commonly spread via the blood vessel system in the first place.	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Disease', (161, 169))	('niaid.nih.gov', 'Var', (26, 39))	('metastasize', 'CPA', (60, 71))	('Carcinomas', 'Disease', (40, 50))	('Carcinomas', 'Disease', 'MESH:D002277', (40, 50))	('Carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))
27920	28571582	Diffuse LGGs are characterized by mutually exclusive telomerase reverse transcriptase (TERT) and ATRX mutations, one of the best defined characteristic gene mutations such as isocitrate dehydrogenase 1,2 (IDH1/2) and tumor protein p53 (TP53) mutations and the combined deletion of 1p/19q regions.	('p53', 'Gene', '7157', (231, 234))	('IDH1/2', 'Gene', '3417;3418', (205, 211))	('TP53', 'Gene', (236, 240))	('tumor', 'Disease', (217, 222))	('IDH1/2', 'Gene', (205, 211))	('p53', 'Gene', (231, 234))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('rat', 'Species', '10116', (181, 184))	('telomerase reverse transcriptase', 'Gene', (53, 85))	('ATRX', 'Gene', (97, 101))	('TP53', 'Gene', '7157', (236, 240))	('ATRX', 'Gene', '546', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('mutations', 'Var', (242, 251))	('TERT', 'Gene', (87, 91))	('LGGs', 'Disease', (8, 12))	('telomerase reverse transcriptase', 'Gene', '7015', (53, 85))	('TERT', 'Gene', '7015', (87, 91))
27921	28571582	The IDH mutations are very early genetic events and are frequent in diffuse gliomas.	('gliomas', 'Disease', (76, 83))	('IDH', 'Gene', '3417', (4, 7))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('mutations', 'Var', (8, 17))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('frequent', 'Reg', (56, 64))	('IDH', 'Gene', (4, 7))
27924	28571582	Followed by the mutations in characteristic genes, the acquisition of epigenetic modifications may reinforce the classification criteria of LGG subtypes with astrocytic and oligodendroglial origins which otherwise are less likely to be established by histological features alone.	('astrocytic', 'Disease', (158, 168))	('reinforce', 'PosReg', (99, 108))	('epigenetic modifications', 'Var', (70, 94))	('astrocytic', 'Disease', 'MESH:D001254', (158, 168))	('LGG subtypes', 'Disease', (140, 152))
27926	28571582	This standardized and rigorously validated classifier by integrating genetic, epigenetic, and histological features of LGG should be superior to histological classification alone.	('epigenetic', 'Var', (78, 88))	('rat', 'Species', '10116', (62, 65))	('LGG', 'Disease', (119, 122))
27940	24202321	Here, we review the techniques used to study 5-hmC and evidence that alterations to 5-hmC physiology play a functional role in the molecular pathogenesis of human cancers.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('5-hmC', 'Chemical', 'MESH:C011865', (84, 89))	('alterations', 'Var', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('human', 'Species', '9606', (157, 162))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('5-hmC', 'Chemical', 'MESH:C011865', (45, 50))
28044	24202321	We will review the role of 5-hmC briefly in normal physiology, since its role in normal cellular processes sheds light on how alterations to 5-hmC regulation may aid tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('5-hmC', 'Chemical', 'MESH:C011865', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('aid', 'Gene', '57379', (162, 165))	('tumor', 'Disease', (166, 171))	('aid', 'Gene', (162, 165))	('alterations', 'Var', (126, 137))	('5-hmC', 'Chemical', 'MESH:C011865', (27, 32))
28049	24202321	Tet3 depletion inhibits paternal genome demethylation, leads to incomplete activation of paternal copies of genes such as Oct4, and reduces fetal survival, confirming its function in paternal genome demethylation.	('activation', 'MPA', (75, 85))	('Oct4', 'Gene', (122, 126))	('depletion', 'Var', (5, 14))	('Oct4', 'Gene', '5460', (122, 126))	('Tet3', 'Gene', (0, 4))	('reduces', 'NegReg', (132, 139))	('paternal genome', 'CPA', (24, 39))	('inhibits', 'NegReg', (15, 23))	('fetal survival', 'CPA', (140, 154))
28060	24202321	Although Tet-mediated gene repression via the polycomb complex has not yet been studied in cancer, this observation suggests that interfering with Tet activity has the potential to have bidirectional effects on tumor cell gene expression.	('Tet', 'Chemical', 'MESH:C010349', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('effects', 'Reg', (200, 207))	('Tet', 'Chemical', 'MESH:C010349', (9, 12))	('tumor', 'Disease', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Tet', 'MPA', (147, 150))	('interfering', 'Var', (130, 141))
28075	24202321	Disruption of either enzyme family may be responsible for loss of 5-hmC in glioma.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('loss', 'NegReg', (58, 62))	('glioma', 'Disease', (75, 81))	('5-hmC', 'MPA', (66, 71))	('5-hmC', 'Chemical', 'MESH:C011865', (66, 71))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('Disruption', 'Var', (0, 10))
28076	24202321	IDH1/2 mutations are common in several cancers, including gliomas.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('IDH1/2', 'Gene', (0, 6))	('common', 'Reg', (21, 27))	('mutations', 'Var', (7, 16))
28077	24202321	IDH1/2 mutations produce the oncometabolite 2-hydroxyglutarate (2-HG), which acts as a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases, including the TET enzymes.	('oxygen', 'Chemical', 'MESH:D010100', (144, 150))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (112, 131))	('TET', 'Chemical', 'MESH:C010349', (170, 173))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (44, 62))	('IDH1/2', 'Gene', (0, 6))	('2-HG', 'Chemical', 'MESH:C019417', (64, 68))	('mutations', 'Var', (7, 16))
28080	24202321	A significant proportion of low grade gliomas (>85%) and a smaller proportion of glioblastomas contain mutations in IDH1 or IDH2, which have been shown to associate with a specific hypermethylated phenotype and predict better overall survival for those patients.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('mutations', 'Var', (103, 112))	('glioblastomas', 'Phenotype', 'HP:0012174', (81, 94))	('associate', 'Reg', (155, 164))	('better', 'PosReg', (219, 225))	('glioblastomas', 'Disease', 'MESH:D005909', (81, 94))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('patients', 'Species', '9606', (253, 261))	('IDH1', 'Gene', (116, 120))	('hypermethylated phenotype', 'MPA', (181, 206))	('glioblastomas', 'Disease', (81, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('IDH1', 'Gene', '3417', (116, 120))	('IDH2', 'Gene', (124, 128))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
28081	24202321	Mutations in IDH1/2 are thought to occur early in the progression of gliomas, and some studies of other human cancers, such as leukemia (see below), have suggested a link between IDH mutations and loss of 5-hmC.	('gliomas', 'Disease', (69, 76))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('IDH', 'Gene', '3417', (179, 182))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('leukemia', 'Disease', (127, 135))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('mutations', 'Var', (183, 192))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('human', 'Species', '9606', (104, 109))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('IDH', 'Gene', (13, 16))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('cancers', 'Disease', (110, 117))	('5-hmC', 'Chemical', 'MESH:C011865', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', (179, 182))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
28082	24202321	As a result, several groups searched for associations between IDH mutations and loss of 5-hmC in gliomas.	('mutations', 'Var', (66, 75))	('associations', 'Interaction', (41, 53))	('IDH', 'Gene', '3417', (62, 65))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('loss', 'NegReg', (80, 84))	('5-hmC', 'Chemical', 'MESH:C011865', (88, 93))	('5-hmC', 'Protein', (88, 93))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH', 'Gene', (62, 65))
28084	24202321	demonstrated that expression of mutant IDH in astrocytes reduces 5-hmC levels.	('mutant', 'Var', (32, 38))	('IDH', 'Gene', (39, 42))	('5-hmC levels', 'MPA', (65, 77))	('5-hmC', 'Chemical', 'MESH:C011865', (65, 70))	('IDH', 'Gene', '3417', (39, 42))	('reduces', 'NegReg', (57, 64))
28088	24202321	Kim and colleagues examined low-grade gliomas with wild-type IDH1/2 for mutations in or hypermethylation of TET2.	('mutations in', 'Var', (72, 84))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('TET2', 'Gene', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH1/2', 'Gene', (61, 67))	('hypermethylation', 'Var', (88, 104))	('amine', 'Chemical', 'MESH:D000588', (21, 26))	('IDH1/2', 'Gene', '3417;3418', (61, 67))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
28105	24202321	Mutations in TET2 or IDH1/IDH2 disrupt 5-hmC homeostasis, resulting in inadequate maintenance of 5-hmC in hematopoietic progenitor and stem cells.	('5-hmC', 'Chemical', 'MESH:C011865', (97, 102))	('inadequate', 'NegReg', (71, 81))	('5-hmC', 'Chemical', 'MESH:C011865', (39, 44))	('5-hmC homeostasis', 'MPA', (39, 56))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (21, 25))	('TET2', 'Gene', (13, 17))	('maintenance of 5-hmC', 'MPA', (82, 102))	('disrupt', 'Reg', (31, 38))
28106	24202321	As discussed above, TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in adult and pediatric leukemias with the translocation t(10:11)(q22;q23).	('leukemia', 'Disease', (130, 138))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('leukemia', 'Disease', 'MESH:D007938', (130, 138))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('leukemia', 'Disease', 'MESH:D007938', (87, 95))	('leukemias', 'Phenotype', 'HP:0001909', (130, 139))	('t(10:11)(q22;q23', 'Var', (163, 179))	('leukemias', 'Disease', (130, 139))	('MLL', 'Gene', (97, 100))	('leukemia', 'Disease', (87, 95))	('MLL', 'Gene', '4297', (97, 100))	('t(10:11)(q22;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (163, 180))	('leukemias', 'Disease', 'MESH:D007938', (130, 139))
28107	24202321	Six years later, TET2 somatic mutations were identified in myeloproliferative neoplasms (MPN) and myelo-dysplastic syndrome (MDS).	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('MPN', 'Phenotype', 'HP:0005547', (89, 92))	('MDS', 'Disease', (125, 128))	('MDS', 'Disease', 'MESH:D009190', (125, 128))	('myelo-dysplastic syndrome', 'Disease', (98, 123))	('MDS', 'Phenotype', 'HP:0002863', (125, 128))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (59, 87))	('myelo-dysplastic syndrome', 'Disease', 'MESH:D004416', (98, 123))	('myelo-dysplastic syndrome', 'Phenotype', 'HP:0002863', (98, 123))	('mutations', 'Var', (30, 39))	('TET2', 'Gene', (17, 21))	('myeloproliferative neoplasms', 'Disease', (59, 87))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (59, 87))
28108	24202321	Among hematological malignancies, TET2 is mutated most frequently in AML, secondary AML (sAML), myelodysplastic syndrome (MDS), systemic mastocytosis, chronic myelomonocytic leukemia (CMML), and other MPNs.	('CMML', 'Disease', 'MESH:D054429', (184, 188))	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('myelodysplastic syndrome', 'Disease', (96, 120))	('AML', 'Phenotype', 'HP:0004808', (90, 93))	('AML', 'Disease', (90, 93))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (151, 182))	('CMML', 'Disease', (184, 188))	('CMML', 'Phenotype', 'HP:0012325', (184, 188))	('MDS', 'Disease', 'MESH:D009190', (122, 125))	('hematological malignancies', 'Disease', (6, 32))	('MDS', 'Phenotype', 'HP:0002863', (122, 125))	('chronic myelomonocytic leukemia', 'Disease', (151, 182))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (96, 120))	('MDS', 'Disease', (122, 125))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (128, 149))	('TET2', 'Gene', (34, 38))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (96, 120))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('systemic mastocytosis', 'Disease', (128, 149))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (151, 182))	('AML', 'Phenotype', 'HP:0004808', (69, 72))	('AML', 'Disease', (69, 72))	('mutated', 'Var', (42, 49))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('hematological malignancies', 'Disease', 'MESH:D019337', (6, 32))	('AML', 'Phenotype', 'HP:0004808', (84, 87))	('AML', 'Disease', (84, 87))	('mastocytosis', 'Phenotype', 'HP:0100495', (137, 149))	('hematological malignancies', 'Phenotype', 'HP:0004377', (6, 32))	('AML', 'Disease', 'MESH:D015470', (90, 93))	('MPN', 'Phenotype', 'HP:0005547', (201, 204))
28109	24202321	Although frameshift and nonsense mutations of TET2 occur throughout the entire gene, point mutations are found within exons encoding the TET/JBP component of the catalytic domain (Figure 5).	('nonsense mutations', 'Var', (24, 42))	('frameshift', 'Var', (9, 19))	('TET', 'Chemical', 'MESH:C010349', (137, 140))	('TET2', 'Gene', (46, 50))	('TET', 'Chemical', 'MESH:C010349', (46, 49))
28111	24202321	The observation of heterozygous TET2 mutations suggests that TET2 is haploinsufficient or the mutations have dominant-negative effects.	('TET2', 'Gene', (32, 36))	('mutations', 'Var', (37, 46))	('haploinsufficient', 'Disease', (69, 86))	('haploinsufficient', 'Disease', 'MESH:D058495', (69, 86))
28112	24202321	Although a global decrease in 5-hmC levels might suggest there would be a corresponding increase in global levels of 5-mC, the reported effects of TET2 mutations on 5-mC level in patients have been unclear.	('mutations', 'Var', (152, 161))	('5-mC', 'Chemical', 'MESH:D044503', (165, 169))	('increase', 'PosReg', (88, 96))	('5-hmC', 'Chemical', 'MESH:C011865', (30, 35))	('5-hmC levels', 'MPA', (30, 42))	('patients', 'Species', '9606', (179, 187))	('decrease', 'NegReg', (18, 26))	('C,', 'Chemical', 'MESH:D002244', (120, 122))	('5-mC', 'Chemical', 'MESH:D044503', (117, 121))	('global levels of 5-mC', 'MPA', (100, 121))	('TET2', 'Gene', (147, 151))
28113	24202321	These differences may be the result of these groups using different techniques (the Illumina Infinium 27K methylation array versus HPLC-MS and the HELP assay, respectively), or because they studied different diseases (MDS/MPN, primary and secondary AML versus AML, respectively).	('MPN', 'Phenotype', 'HP:0005547', (222, 225))	('AML versus AML', 'Disease', 'MESH:D015470', (249, 263))	('methylation', 'Var', (106, 117))	('MDS', 'Disease', (218, 221))	('AML versus AML', 'Disease', (249, 263))	('MDS', 'Disease', 'MESH:D009190', (218, 221))	('AML', 'Phenotype', 'HP:0004808', (249, 252))	('AML', 'Phenotype', 'HP:0004808', (260, 263))	('MDS', 'Phenotype', 'HP:0002863', (218, 221))	('primary', 'Disease', (227, 234))
28114	24202321	In agreement with the results from Figueroa et al., samples from CMML patients with TET2 mutations have also demonstrated significant global hypermethylation.	('patients', 'Species', '9606', (70, 78))	('global hypermethylation', 'MPA', (134, 157))	('CMML', 'Disease', (65, 69))	('CMML', 'Phenotype', 'HP:0012325', (65, 69))	('TET2', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))	('CMML', 'Disease', 'MESH:D054429', (65, 69))
28117	24202321	One of these models, published by Moran-Crusio, carried a conditional knockout of the Tet2 allele and showed progressive hematopoietic stem cell (HSC) expansion and myeloproliferation (neutrophilia, monocytosis, and splenomegaly).	('splenomegaly', 'Disease', 'MESH:D013163', (216, 228))	('neutrophilia', 'Phenotype', 'HP:0011897', (185, 197))	('neutrophilia', 'Disease', (185, 197))	('splenomegaly', 'Phenotype', 'HP:0001744', (216, 228))	('myeloproliferation', 'CPA', (165, 183))	('monocytosis', 'CPA', (199, 210))	('monocytosis', 'Phenotype', 'HP:0012311', (199, 210))	('splenomegaly', 'Disease', (216, 228))	('neutrophilia', 'Disease', 'MESH:C563010', (185, 197))	('knockout', 'Var', (70, 78))	('Tet2', 'Gene', (86, 90))
28119	24202321	showed with two mouse models, a gene-trap and a conditional knockout, that alteration of Tet2 function resulted in pleiotropic hematopoietic abnormalities.	('resulted in', 'Reg', (103, 114))	('alteration', 'Var', (75, 85))	('hematopoietic abnormalities', 'Disease', (127, 154))	('hematopoietic abnormalities', 'Disease', 'MESH:D019337', (127, 154))	('mouse', 'Species', '10090', (16, 21))	('Tet2', 'Gene', (89, 93))	('hematopoietic abnormalities', 'Phenotype', 'HP:0001871', (127, 154))
28121	24202321	Other Tet2 knockout mouse models have also been characterized as having a similar, CMML-like phenotype of increased HSC and myeloid proliferation that corresponds to CMML.	('CMML', 'Disease', 'MESH:D054429', (166, 170))	('Tet2', 'Gene', (6, 10))	('CMML', 'Disease', (83, 87))	('CMML', 'Disease', 'MESH:D054429', (83, 87))	('increased HSC', 'Phenotype', 'HP:0001899', (106, 119))	('CMML', 'Phenotype', 'HP:0012325', (83, 87))	('CMML', 'Disease', (166, 170))	('CMML', 'Phenotype', 'HP:0012325', (166, 170))	('increased', 'PosReg', (106, 115))	('knockout', 'Var', (11, 19))	('mouse', 'Species', '10090', (20, 25))
28122	24202321	Moreover, depletion of TET2 by RNA interference in cord blood CD34+ cells skews progenitor differentiation toward the granulo-monocytic lineage at the expense of lymphoid and erythroid lineages.	('progenitor differentiation', 'CPA', (80, 106))	('CD34', 'Gene', '947', (62, 66))	('depletion', 'Var', (10, 19))	('TET2', 'Gene', (23, 27))	('CD34', 'Gene', (62, 66))	('RNA interference', 'MPA', (31, 47))	('skews', 'Reg', (74, 79))
28123	24202321	Taken together, these mouse studies suggest that loss of Tet2 promotes myelomonocytic expansion and illustrates that the TET2 enzyme plays a significant role in stem cell development and differentiation.	('loss', 'Var', (49, 53))	('myelomonocytic expansion', 'CPA', (71, 95))	('Tet2', 'Gene', (57, 61))	('promotes', 'PosReg', (62, 70))	('mouse', 'Species', '10090', (22, 27))
28124	24202321	Acquisition of TET2 mutations is an early clonal event in MPN with mutations in Janus kinase 2 (JAK2) and myeloproliferative leukemia oncogene (MPL), implying that loss of 5-hmC levels may have a functional role in the onset and/or progression of hematological malignancies.	('hematological malignancies', 'Phenotype', 'HP:0004377', (247, 273))	('myeloproliferative leukemia oncogene', 'Gene', '4352', (106, 142))	('MPL', 'Gene', '4352', (144, 147))	('hematological malignancies', 'Disease', (247, 273))	('Janus kinase 2', 'Gene', (80, 94))	('hematological malignancies', 'Disease', 'MESH:D019337', (247, 273))	('JAK2', 'Gene', '3717', (96, 100))	('MPN', 'Phenotype', 'HP:0005547', (58, 61))	('TET2', 'Gene', (15, 19))	('mutations', 'Var', (67, 76))	('myeloproliferative leukemia oncogene', 'Gene', (106, 142))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('myeloproliferative leukemia', 'Phenotype', 'HP:0005547', (106, 133))	('MPL', 'Gene', (144, 147))	('Janus kinase 2', 'Gene', '3717', (80, 94))	('JAK2', 'Gene', (96, 100))	('5-hmC', 'Chemical', 'MESH:C011865', (172, 177))	('mutations', 'Var', (20, 29))
28125	24202321	To date, results from published studies have not demonstrated any significance of TET2 mutations in the outcome for patients with MPN or MDS.	('MDS', 'Phenotype', 'HP:0002863', (137, 140))	('MPN', 'Disease', (130, 133))	('patients', 'Species', '9606', (116, 124))	('MPN', 'Phenotype', 'HP:0005547', (130, 133))	('TET2', 'Gene', (82, 86))	('MDS', 'Disease', (137, 140))	('MDS', 'Disease', 'MESH:D009190', (137, 140))	('mutations', 'Var', (87, 96))
28128	24202321	Mutations in IDH1 were first identified in colorectal adenocarcinomas.	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (43, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('IDH1', 'Gene', (13, 17))	('identified', 'Reg', (29, 39))	('colorectal adenocarcinomas', 'Disease', (43, 69))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
28129	24202321	Subsequently, mutations in both IDH1 and IDH2 were found in more than 70% of gliomas and secondary glioblastomas (discussed above), as well as in AML, with a frequency of approximately 15%.	('AML', 'Disease', (146, 149))	('gliomas', 'Disease', (77, 84))	('IDH1', 'Gene', (32, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('AML', 'Phenotype', 'HP:0004808', (146, 149))	('glioblastomas', 'Disease', 'MESH:D005909', (99, 112))	('AML', 'Disease', 'MESH:D015470', (146, 149))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('IDH1', 'Gene', '3417', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioblastomas', 'Phenotype', 'HP:0012174', (99, 112))	('IDH2', 'Gene', (41, 45))	('glioblastomas', 'Disease', (99, 112))	('mutations', 'Var', (14, 23))	('found', 'Reg', (51, 56))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
28132	24202321	Mutations in IDH1 and IDH2 lead to an aberrant gain-of-function phenotype that enables these enzymes to convert isocitrate to 2-hydroxyglutarate (2-HG) instead of its normal product, alpha-KG.	('alpha-KG', 'Chemical', 'MESH:D007656', (183, 191))	('gain-of-function', 'PosReg', (47, 63))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('2-HG', 'Chemical', 'MESH:C019417', (146, 150))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (126, 144))	('isocitrate', 'Chemical', 'MESH:C034219', (112, 122))
28138	24202321	Loss of EGLN1 activity blocks transformation driven by mutant IDH or TET2, accounting for the inability of (S)-2-HG to transform these cells.	('EGLN1', 'Gene', (8, 13))	('TET2', 'Gene', (69, 73))	('IDH', 'Gene', '3417', (62, 65))	('blocks', 'NegReg', (23, 29))	('mutant', 'Var', (55, 61))	('(S)-2-HG', 'Chemical', 'MESH:C019417', (107, 115))	('Loss', 'NegReg', (0, 4))	('EGLN1', 'Gene', '54583', (8, 13))	('transformation', 'CPA', (30, 44))	('IDH', 'Gene', (62, 65))
28140	24202321	This is supported by work showing that in IDH mutant AML, 2-HG levels decrease and increase with disease remission and relapse, respectively.	('IDH', 'Gene', (42, 45))	('increase', 'PosReg', (83, 91))	('AML', 'Disease', 'MESH:D015470', (53, 56))	('IDH', 'Gene', '3417', (42, 45))	('2-HG', 'Chemical', 'MESH:C019417', (58, 62))	('AML', 'Disease', (53, 56))	('mutant', 'Var', (46, 52))	('AML', 'Phenotype', 'HP:0004808', (53, 56))	('decrease', 'NegReg', (70, 78))	('2-HG levels', 'MPA', (58, 69))
28142	24202321	The reduced frequency of recurrent chromosomal aberrations and other AML-associated mutations in IDH1/2-mutant leukemias implies that mutations in IDH1/2 may represent a distinct mechanism for AML pathogenesis.	('AML', 'Phenotype', 'HP:0004808', (69, 72))	('leukemias', 'Disease', (111, 120))	('recurrent chromosomal aberrations', 'Phenotype', 'HP:0040012', (25, 58))	('AML', 'Disease', (69, 72))	('IDH1/2', 'Gene', '3417;3418', (147, 153))	('AML', 'Phenotype', 'HP:0004808', (193, 196))	('AML', 'Disease', (193, 196))	('leukemias', 'Disease', 'MESH:D007938', (111, 120))	('mutations', 'Var', (84, 93))	('IDH1/2', 'Gene', (147, 153))	('IDH1/2', 'Gene', '3417;3418', (97, 103))	('leukemia', 'Phenotype', 'HP:0001909', (111, 119))	('mutations', 'Var', (134, 143))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('AML', 'Disease', 'MESH:D015470', (193, 196))	('leukemias', 'Phenotype', 'HP:0001909', (111, 120))	('IDH1/2', 'Gene', (97, 103))
28143	24202321	A common feature of CN-AML with IDH1/2 mutations is a 10 to 100-times higher level of 2-HG compared with IDH wild-type AMLs.	('AML', 'Disease', 'MESH:D015470', (23, 26))	('IDH1/2', 'Gene', (32, 38))	('CN-AML', 'Disease', 'MESH:D015470', (20, 26))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('CN-AML', 'Disease', (20, 26))	('mutations', 'Var', (39, 48))	('AML', 'Phenotype', 'HP:0004808', (23, 26))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', (105, 108))	('AML', 'Disease', (23, 26))	('AML', 'Disease', (119, 122))	('2-HG', 'Chemical', 'MESH:C019417', (86, 90))	('higher', 'PosReg', (70, 76))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('IDH', 'Gene', '3417', (32, 35))	('IDH', 'Gene', '3417', (105, 108))	('AML', 'Phenotype', 'HP:0004808', (119, 122))
28144	24202321	Data collected as a part of the ECOG E1900 clinical trial, which includes 385 primary leukemia samples, demonstrates that 2-HG reduces 5-hmC levels and promotes global DNA hypermethylation.	('reduces', 'NegReg', (127, 134))	('2-HG', 'Chemical', 'MESH:C019417', (122, 126))	('5-hmC', 'Chemical', 'MESH:C011865', (135, 140))	('5-hmC levels', 'MPA', (135, 147))	('2-HG', 'Var', (122, 126))	('leukemia', 'Disease', (86, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (86, 94))	('promotes', 'PosReg', (152, 160))	('global DNA hypermethylation', 'MPA', (161, 188))
28147	24202321	Mutations of the IDH1 and IDH2 genes have certain prognostic value.	('IDH2', 'Gene', (26, 30))	('IDH1', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (17, 21))
28148	24202321	Although the IDH1-R132H and IDH2-R172K mutations have not been demonstrated to influence prognosis, the IDH2-R140Q mutation is associated with a favorable clinical outcome, as shown in a large dataset with over 1000 patients enrolled in the UK MRC AML 10 and AML 12 clinical trials.	('IDH2-R140Q', 'Var', (104, 114))	('MRC', 'CellLine', 'CVCL:0440', (244, 247))	('AML', 'Phenotype', 'HP:0004808', (248, 251))	('AML', 'Disease', (248, 251))	('R132H', 'Mutation', 'rs121913500', (18, 23))	('AML', 'Disease', 'MESH:D015470', (259, 262))	('AML', 'Phenotype', 'HP:0004808', (259, 262))	('IDH1', 'Gene', (13, 17))	('patients', 'Species', '9606', (216, 224))	('AML', 'Disease', (259, 262))	('R140Q', 'Mutation', 'rs121913502', (109, 114))	('IDH1', 'Gene', '3417', (13, 17))	('AML', 'Disease', 'MESH:D015470', (248, 251))	('R172K', 'Mutation', 'rs121913503', (33, 38))
28149	24202321	Moreover, IDH1/2 mutations often co-occur with mutations in NPM1, which is, in itself, favorable.	('NPM1', 'Gene', (60, 64))	('IDH1/2', 'Gene', '3417;3418', (10, 16))	('mutations', 'Var', (47, 56))	('NPM1', 'Gene', '4869', (60, 64))	('IDH1/2', 'Gene', (10, 16))	('mutations', 'Var', (17, 26))
28150	24202321	Concurrent IDH1 and IDH2 mutations in AML are absent or very rare, and TET2 and IDH mutations are mutually exclusive.	('AML', 'Disease', (38, 41))	('mutations', 'Var', (25, 34))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (11, 14))	('IDH', 'Gene', '3417', (20, 23))	('IDH1', 'Gene', '3417', (11, 15))	('IDH', 'Gene', (80, 83))	('IDH', 'Gene', '3417', (80, 83))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('IDH1', 'Gene', (11, 15))	('AML', 'Phenotype', 'HP:0004808', (38, 41))
28151	24202321	In primary myelofibrosis, IDH mutations may identify patients at risk for premature death and/or leukemic transformation.	('myelofibrosis', 'Disease', 'MESH:D055728', (11, 24))	('patients', 'Species', '9606', (53, 61))	('leukemic', 'Disease', 'MESH:D007938', (97, 105))	('myelofibrosis', 'Phenotype', 'HP:0011974', (11, 24))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('leukemic', 'Disease', (97, 105))	('IDH', 'Gene', '3417', (26, 29))	('myelofibrosis', 'Disease', (11, 24))
28158	24202321	found a 5-fold decrease of 5-hmC by LC-MS/MS in stage I squamous cell carcinomas of the lung with respect to matched normal tissue samples.	('decrease', 'NegReg', (15, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('I squamous cell carcinomas of the lung', 'Disease', (54, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('I squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (54, 92))	('5-hmC', 'MPA', (27, 32))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (70, 92))	('LC-MS/MS', 'Var', (36, 44))	('5-hmC', 'Chemical', 'MESH:C011865', (27, 32))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (56, 80))
28167	24202321	Although IDH1 mutations have been identified in 10% of melanomas in one patient cohort, TET and/or IDH gene repression seems to be a more common mechanism for blocking 5-mC to 5-hmC conversion in non-glioma solid tumors rather than TET or IDH mutations, which are found more commonly in gliomas and hematological malignancies.	('IDH', 'Gene', '3417', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('IDH1', 'Gene', (9, 13))	('patient', 'Species', '9606', (72, 79))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', (239, 242))	('hematological malignancies', 'Disease', 'MESH:D019337', (299, 325))	('TET', 'Chemical', 'MESH:C010349', (232, 235))	('gliomas', 'Phenotype', 'HP:0009733', (287, 294))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('hematological malignancies', 'Phenotype', 'HP:0004377', (299, 325))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('blocking', 'NegReg', (159, 167))	('IDH1', 'Gene', '3417', (9, 13))	('non-glioma solid tumors', 'Disease', 'MESH:D005910', (196, 219))	('IDH', 'Gene', '3417', (9, 12))	('non-glioma solid tumors', 'Disease', (196, 219))	('TET', 'Chemical', 'MESH:C010349', (88, 91))	('mutations', 'Var', (14, 23))	('IDH', 'Gene', '3417', (239, 242))	('5-mC to 5-hmC conversion', 'MPA', (168, 192))	('gliomas', 'Disease', (287, 294))	('5-mC', 'Chemical', 'MESH:D044503', (168, 172))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('hematological malignancies', 'Disease', (299, 325))	('IDH', 'Gene', (99, 102))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('melanomas', 'Disease', 'MESH:D008545', (55, 64))	('gliomas', 'Disease', 'MESH:D005910', (287, 294))	('melanomas', 'Disease', (55, 64))	('5-hmC', 'Chemical', 'MESH:C011865', (176, 181))
28177	24202321	Studies addressing the role of 5-hmC in cancer have revealed loss of 5-hmC to be associated commonly with tumorigenesis in both hematological diseases and solid tumors.	('solid tumors', 'Disease', (155, 167))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (106, 111))	('5-hmC', 'Protein', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('solid tumors', 'Disease', 'MESH:D009369', (155, 167))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('loss', 'Var', (61, 65))	('5-hmC', 'Chemical', 'MESH:C011865', (69, 74))	('5-hmC', 'Chemical', 'MESH:C011865', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('hematological disease', 'Phenotype', 'HP:0001871', (128, 149))	('hematological diseases', 'Disease', 'MESH:D006402', (128, 150))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('hematological diseases', 'Disease', (128, 150))	('associated', 'Reg', (81, 91))
28180	24202321	Moreover, to gain a full understanding of how gene specific changes in 5-hmC facilitate tumor evolution, it will be critical to determine how changes in 5-hmC levels alter transcription.	('5-hmC', 'Chemical', 'MESH:C011865', (153, 158))	('changes', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('transcription', 'MPA', (172, 185))	('facilitate', 'PosReg', (77, 87))	('5-hmC', 'Chemical', 'MESH:C011865', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('alter', 'Reg', (166, 171))	('tumor', 'Disease', (88, 93))
28183	24202321	Hydroxymethylation is decreased in some hematological diseases and gliomas when the genes encoding for TET and IDH enzymes are mutated, whereas in solid tumors the same end result is achieved by down-regulation of TET and IDH transcription.	('hematological diseases', 'Disease', (40, 62))	('gliomas', 'Disease', (67, 74))	('hematological disease', 'Phenotype', 'HP:0001871', (40, 61))	('solid tumors', 'Disease', (147, 159))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('Hydroxymethylation', 'MPA', (0, 18))	('IDH', 'Gene', (111, 114))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH', 'Gene', (222, 225))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('TET', 'Chemical', 'MESH:C010349', (103, 106))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('IDH', 'Gene', '3417', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('down-regulation', 'NegReg', (195, 210))	('TET', 'Chemical', 'MESH:C010349', (214, 217))	('decreased', 'NegReg', (22, 31))	('IDH', 'Gene', '3417', (222, 225))	('hematological diseases', 'Disease', 'MESH:D006402', (40, 62))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mutated', 'Var', (127, 134))
28186	32038986	The Clinical Significance of Soluble Programmed Cell Death-Ligand 1 (sPD-L1) in Patients With Gliomas Background: Soluble PD-L1 (sPD-L1) in the circulation has been documented to activate global immunosuppression and is considered a predictor of negative clinical outcomes in several malignances.	('Gliomas', 'Disease', (94, 101))	('global immunosuppression', 'MPA', (188, 212))	('activate', 'PosReg', (179, 187))	('Soluble PD-L1', 'Var', (114, 127))	('Gliomas', 'Disease', 'MESH:D005910', (94, 101))	('Gliomas', 'Phenotype', 'HP:0009733', (94, 101))
28200	32038986	However, molecular information such as the mutational status of isocitrate dehydrogenase (IDH) genes and the combined deletion of chromosome arms 1p and 19q (1p/19q codeletion) is integral to the 2016 World Health Organization (WHO) criteria for gliomas.	('IDH', 'Gene', (90, 93))	('isocitrate', 'Chemical', 'MESH:D007523', (64, 74))	('gliomas', 'Disease', 'MESH:D005910', (246, 253))	('gliomas', 'Phenotype', 'HP:0009733', (246, 253))	('gliomas', 'Disease', (246, 253))	('deletion', 'Var', (118, 126))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
28205	32038986	Considering the lack of effective treatments for gliomas, immunotherapy, especially anti-PD-1/PD-L1 antibodies, has brought hope for brain malignances.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('brain malignances', 'Phenotype', 'HP:0030692', (133, 150))	('brain malignances', 'Disease', 'MESH:D001932', (133, 150))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('anti-PD-1/PD-L1', 'Var', (84, 99))	('brain malignances', 'Disease', (133, 150))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
28211	32038986	It is worth mentioning that our previous study showed that sPD-L1 in the peripheral blood was a potential predictor for the diagnosis and prognosis of preoperative patients with glioma.	('glioma', 'Disease', (178, 184))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('sPD-L1', 'Var', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))
28220	32038986	Molecular markers of glioma, such as the IDH1 genotype (IDH1 mutant or wild type), Ki-67 expression status and 1p/19q status (1p/19q codeleted or maintained), were recorded when possible.	('Ki-67', 'Gene', (83, 88))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('mutant', 'Var', (61, 67))	('glioma', 'Disease', (21, 27))
28260	32038986	The glioma patients with mutated IDH-1 (p = 0.042) or 1p/19q codeletion (p = 0.017) were found to have relatively low levels of CSF sPD-L1.	('CSF sPD-L1', 'MPA', (128, 138))	('low levels of CSF', 'Phenotype', 'HP:0025457', (114, 131))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('1p/19q codeletion', 'Var', (54, 71))	('IDH-1', 'Gene', (33, 38))	('mutated', 'Var', (25, 32))	('glioma', 'Disease', (4, 10))
28264	32038986	When blood-based biomarkers in glioma patients were compared with the corresponding markers in healthy volunteers and meningioma patients, we observed that serum sPD-L1 had the best value for the diagnosis of glioma [0.906 (0.850-0.962), Figure 4A].	('meningioma', 'Disease', (118, 128))	('sPD-L1', 'Gene', (162, 168))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('meningioma', 'Disease', 'MESH:D008579', (118, 128))	('meningioma', 'Phenotype', 'HP:0002858', (118, 128))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Disease', (209, 215))	('serum', 'Var', (156, 161))	('glioma', 'Disease', (31, 37))
28279	32038986	The multivariate analysis revealed that sPD-L1 is independently associated with glioma after adjusting for age and the mentioned hematological markers (Table S2).	('glioma', 'Disease', (80, 86))	('associated', 'Reg', (64, 74))	('sPD-L1', 'Var', (40, 46))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
28292	32038986	Although the mechanistic link remains unclear, we suggest that sPD-L1 represents the PD-L1 expression in tumor tissue, which is accompanied by suppression of the immune response.	('immune response', 'CPA', (162, 177))	('PD-L1', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sPD-L1', 'Var', (63, 69))	('tumor', 'Disease', (105, 110))	('suppression', 'NegReg', (143, 154))
28294	32038986	Therefore, abnormal expression of sPD-L1 may be an indicator of the occurrence and development of brain malignances.	('expression', 'MPA', (20, 30))	('brain malignances', 'Phenotype', 'HP:0030692', (98, 115))	('abnormal', 'Var', (11, 19))	('sPD-L1', 'Gene', (34, 40))	('brain malignances', 'Disease', 'MESH:D001932', (98, 115))	('brain malignances', 'Disease', (98, 115))
28300	32038986	An explanation for the results may be that the CSF is in direct contact with the CNS, which indicates that CSF sPD-L1 may be more suitable for CNS malignancies than serum sPD-L1 in clinical practice.	('CSF', 'Var', (107, 110))	('CNS malignancies', 'Disease', (143, 159))	('CNS malignancies', 'Disease', 'MESH:D016543', (143, 159))
28301	32038986	Numerous published reports have declared that an IDH mutation or 1p/19q codeletion can affect the pathological behaviors of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('1p/19q codeletion', 'Var', (65, 82))	('affect', 'Reg', (87, 93))	('IDH', 'Gene', (49, 52))	('pathological behaviors', 'CPA', (98, 120))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
28303	32038986	Several lines of evidence have demonstrated that mutation of IDH1 indicates enhanced chemosensitivity and is associated with an improved prognosis in glioma patients.	('chemosensitivity', 'CPA', (85, 101))	('improved', 'PosReg', (128, 136))	('mutation', 'Var', (49, 57))	('IDH1', 'Gene', (61, 65))	('enhanced', 'PosReg', (76, 84))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
28304	32038986	Additionally, it has been reported that glioma with 1p/19q codeletion is sensitive to alkylating agents and tends to have prolonged survival.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('prolonged', 'PosReg', (122, 131))	('1p/19q codeletion', 'Var', (52, 69))	('glioma', 'Disease', (40, 46))	('survival', 'CPA', (132, 140))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
28305	32038986	In this study, the upregulated CSF sPD-L1 levels tended to occur in the glioma patients with wild-type IDH-1 or maintained 1p/19q.	('glioma', 'Disease', (72, 78))	('upregulated', 'PosReg', (19, 30))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('maintained 1p/19q', 'Var', (112, 129))	('CSF sPD-L1 levels', 'MPA', (31, 48))	('1p/19q', 'Var', (123, 129))
28323	31555204	With a long course of slowly progressing, this was a rare case of secondary glioblastoma with the absence of isocitrate dehydrogenase 1 (IDH1) gene mutation.	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('isocitrate dehydrogenase 1', 'Gene', (109, 135))	('IDH1', 'Gene', (137, 141))	('isocitrate dehydrogenase 1', 'Gene', '3417', (109, 135))	('glioblastoma', 'Disease', (76, 88))	('mutation', 'Var', (148, 156))	('IDH1', 'Gene', '3417', (137, 141))
28335	31555204	In October 2017, however, his headache returned, and the pain was more severe.	('headache', 'Disease', (30, 38))	('headache', 'Phenotype', 'HP:0002315', (30, 38))	('pain', 'Phenotype', 'HP:0012531', (57, 61))	('October 2017', 'Var', (3, 15))	('pain', 'Disease', 'MESH:D010146', (57, 61))	('headache', 'Disease', 'MESH:D006261', (30, 38))	('pain', 'Disease', (57, 61))
28359	31555204	Although the patient underwent DWI (Figure 2) in 2017, MRS (Figure 5A) in 2018, and DTI (Figure 5B) in 2018, all of which indicated glioblastoma, the opportunity for a timely and appropriate treatment has gone.	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('patient', 'Species', '9606', (13, 20))	('indicated', 'Reg', (122, 131))	('DTI', 'Var', (84, 87))	('glioblastoma', 'Disease', (132, 144))	('Al', 'Chemical', 'MESH:D000535', (0, 2))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))
28582	26707628	Based on ROC analysis, the cut-off for value Vpmean (AUC=0.757 with standard deviation=0.1) that provided the best combination of high sensitivity (70%) and specificity (70%) to distinguish between grade II and III oligodendrogliomas was 2.35 (p<0.03) (Figure 3).	('II oligodendrogliomas', 'Disease', (212, 233))	('grade II', 'Disease', (198, 206))	('II oligodendrogliomas', 'Disease', 'MESH:D009837', (212, 233))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('Vpmean', 'Var', (45, 51))
28615	26707628	Finally, we were not able to correlate pharmacokinetic parameters with molecular differences between oligodendrogliomas because of (1) unavailable data and (2) the overwhelming majority of the remaining lesions demonstrated 1p/19q chromosomal co-deletions which did not allow for meaningful subgroup comparison.	('oligodendrogliomas', 'Disease', (101, 119))	('1p/19q chromosomal co-deletions', 'Var', (224, 255))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (101, 119))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
28767	24219161	In people, low-grade gliomas (World Health Organization Grade 1 and II) will have 2-deoxy-2[18 F] fluoro-D-glucose uptake similar to white matter where as Grade III gliomas will uptake equal to gray matter.	('2-deoxy-2[18 F] fluoro-D-glucose uptake', 'MPA', (82, 121))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('low-grade', 'Var', (11, 20))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('2-deoxy-2', 'Chemical', '-', (82, 91))	('fluoro-D-glucose', 'Chemical', '-', (98, 114))	('gliomas', 'Disease', (21, 28))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Disease', (165, 172))	('people', 'Species', '9606', (3, 9))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
28779	24219161	Although 18F-O-(2) fluoroethyl-L-tyrosine (FET) has a high-sensitivity for the detection of high-grade brain tumors, its specificity is somewhat limited by the passive leakage of tracer into non-neoplastic lesions that disrupt the blood-brain-barrier, such as encephalitis.	('brain tumors', 'Disease', (103, 115))	('brain tumor', 'Phenotype', 'HP:0030692', (103, 114))	('18F-O-(2) fluoroethyl-L-tyrosine', 'Chemical', '-', (9, 41))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('encephalitis', 'Phenotype', 'HP:0002383', (260, 272))	('FET', 'Chemical', '-', (43, 46))	('18F-O-(2', 'Var', (9, 17))	('brain tumors', 'Phenotype', 'HP:0030692', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (195, 213))	('encephalitis', 'Disease', 'MESH:D004660', (260, 272))	('encephalitis', 'Disease', (260, 272))	('brain tumors', 'Disease', 'MESH:D001932', (103, 115))
28817	23688241	A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFalpha or VEGF expression.	('Cygb', 'Protein', (51, 55))	('TNFalpha', 'Gene', (90, 98))	('negative', 'NegReg', (14, 22))	('expression', 'MPA', (56, 66))	('Akt', 'Gene', '207', (79, 82))	('PI3K', 'Var', (71, 75))	('Akt', 'Gene', (79, 82))
28826	23688241	Although the function of Cygb in vivo remains largely unknown, decreased expression of Cygb and the hypermethylation of the Cygb promoter has been reported in patients with tylosis, non-small-cell lung carcinomas, head and neck cancers, ovarian cancers, and breast cancers.	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('breast cancers', 'Disease', 'MESH:D001943', (258, 272))	('breast cancers', 'Disease', (258, 272))	('Cygb', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tylosis', 'Disease', (173, 180))	('ovarian cancers', 'Disease', (237, 252))	('ovarian cancers', 'Disease', 'MESH:D010051', (237, 252))	('breast cancers', 'Phenotype', 'HP:0003002', (258, 272))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (186, 212))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (182, 212))	('decreased', 'NegReg', (63, 72))	('Cygb', 'Gene', (124, 128))	('expression', 'MPA', (73, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('lung carcinomas', 'Disease', 'MESH:D008175', (197, 212))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('hypermethylation', 'Var', (100, 116))	('head and neck cancers', 'Phenotype', 'HP:0012288', (214, 235))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('ovarian cancers', 'Phenotype', 'HP:0100615', (237, 252))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('lung carcinomas', 'Disease', (197, 212))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('patients', 'Species', '9606', (159, 167))	('neck cancers', 'Disease', (223, 235))	('neck cancers', 'Disease', 'MESH:D006258', (223, 235))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('tylosis', 'Disease', 'MESH:D053546', (173, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
28829	23688241	Deregulated signaling through phosphatidylinositol-3 kinase (PI-3K)/Akt pathways has been implicated in the malignant transformation of glial cells.	('implicated', 'Reg', (90, 100))	('Deregulated', 'Var', (0, 11))	('phosphatidylinositol-3 kinase', 'Gene', (30, 59))	('malignant transformation', 'CPA', (108, 132))	('Akt', 'Gene', '207', (68, 71))	('Akt', 'Gene', (68, 71))	('phosphatidylinositol-3 kinase', 'Gene', '5295', (30, 59))	('signaling', 'MPA', (12, 21))
28830	23688241	Akt is known to regulate actin cytoskeleton reorganization that plays role in tumor cell migration and invasion, and inhibition of Akt prevents glioma cell growth.	('prevents', 'NegReg', (135, 143))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('Akt', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Akt', 'Gene', '207', (0, 3))	('glioma', 'Disease', (144, 150))	('inhibition', 'Var', (117, 127))	('tumor', 'Disease', (78, 83))	('Akt', 'Gene', (0, 3))	('invasion', 'CPA', (103, 111))	('Akt', 'Gene', '207', (131, 134))
28855	23688241	The following antibodies were used: anti-Cygb diluted 1:300(bs-0590R, Bioss), anti-PI3K diluted 1:200(bs-0128R, Bioss), anti-Akt diluted 1:200(bs-0115R, Bioss), anti-IL-6 diluted 1:300(bs-0781R, Bioss), anti-TNFalpha diluted 1:300(bs-0078R, Bioss), and anti-VEGF diluted 1:200(RAB-0157, Maixin_Bio).	('bs-0115R', 'Var', (143, 151))	('Akt', 'Gene', '207', (125, 128))	('Akt', 'Gene', (125, 128))
28861	23688241	In each section, the percentage of tumor cells with Cygb, PI3K, p-Akt, IL-6, TNFalpha and VEGF immunoreactivity was calculated in at least 500 cells counted in several randomly chosen high power fields.	('Akt', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('PI3K', 'Var', (58, 62))	('tumor', 'Disease', (35, 40))	('Akt', 'Gene', '207', (66, 69))
28862	23688241	In each case, the percentage of tumor cells with Cygb, PI3K, p-Akt, IL-6, TNFalpha and VEGF immunoreactivity was the mean value of the 3 continual sections.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Cygb', 'Var', (49, 53))	('PI3K', 'Var', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Akt', 'Gene', '207', (63, 66))	('tumor', 'Disease', (32, 37))	('Akt', 'Gene', (63, 66))
28878	23688241	Positive staining for Cygb, PI3K, p-Akt, IL-6, TNFalpha and VEGF were observed in 10%-86% (median value: 39%), 3%-62% (median value: 20%), 5%-67% (median value: 21%), 4%-70% (median value: 35%), 3%-67% (median value: 30%) and 10%-89% (median value: 56%), respectively.	('TNFalpha', 'Gene', (47, 55))	('Cygb', 'Gene', (22, 26))	('PI3K', 'Var', (28, 32))	('Akt', 'Gene', (36, 39))	('IL-6', 'Gene', (41, 45))	('Akt', 'Gene', '207', (36, 39))
28879	23688241	High expression of PI3K, p-Akt, IL-6, TNFalpha and VEGF were significantly associated with the higher histological grade, and high expression of PI3K, p-Akt and IL-6 were significantly associated with tumor recurrence.	('IL-6', 'Gene', (32, 36))	('PI3K', 'Gene', (19, 23))	('Akt', 'Gene', '207', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('TNFalpha', 'Gene', (38, 46))	('Akt', 'Gene', (153, 156))	('Akt', 'Gene', '207', (27, 30))	('associated with', 'Reg', (185, 200))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('PI3K', 'Var', (145, 149))	('tumor', 'Disease', (201, 206))	('Akt', 'Gene', (27, 30))	('associated', 'Reg', (75, 85))	('VEGF', 'Gene', (51, 55))
28883	23688241	High PI3K and p-Akt expression was correlated with high IL-6 (r = 0.302, p = 0.004 and r = 0.328, p = 0.002, respectively) and TNFalpha expression (r = 0.278, p = 0.009 and r = 0.308, p = 0.004, respectively).	('expression', 'MPA', (136, 146))	('expression', 'MPA', (20, 30))	('TNFalpha', 'Protein', (127, 135))	('Akt', 'Gene', (16, 19))	('high', 'Var', (51, 55))	('Akt', 'Gene', '207', (16, 19))
28888	23688241	The IMD was significantly higher in tumors with high expression of PI3K, p-Akt, IL-6, TNFalpha or VEGF than in tumors with lower protein expression (Table 2).	('IL-6', 'Gene', (80, 84))	('Akt', 'Gene', '207', (75, 78))	('higher', 'PosReg', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TNFalpha', 'Gene', (86, 94))	('tumors', 'Disease', (111, 117))	('Akt', 'Gene', (75, 78))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('IMD', 'MPA', (4, 7))	('VEGF', 'Gene', (98, 102))	('tumors', 'Disease', (36, 42))	('PI3K', 'Var', (67, 71))
28895	23688241	The median survival time for patients whose tumors displayed overexpression of PI3K and p-Akt were 29.2 +- 4.2 months and 29.6 +- 4.3 months respectively.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('patients', 'Species', '9606', (29, 37))	('Akt', 'Gene', (90, 93))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('overexpression', 'PosReg', (61, 75))	('PI3K', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Akt', 'Gene', '207', (90, 93))
28905	23688241	We postulated that Cygb was likely to influence the prognosis of glioma patients by effect on production of immunosuppressive cytokines and angiogenesis in gliomas.	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', (156, 162))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('influence', 'Reg', (38, 47))	('effect', 'Reg', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('angiogenesis', 'CPA', (140, 152))	('production of immunosuppressive cytokines', 'MPA', (94, 135))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('Cygb', 'Var', (19, 23))	('patients', 'Species', '9606', (72, 80))
28916	23688241	The increased levels of Akt and PI3K correlated with a marked elevation of IL-6 and TNFalpha.	('IL-6 and TNFalpha', 'Gene', '3569;7124', (75, 92))	('elevation of IL-6', 'Phenotype', 'HP:0030783', (62, 79))	('PI3K', 'Var', (32, 36))	('Akt', 'Gene', '207', (24, 27))	('elevation', 'PosReg', (62, 71))	('increased', 'PosReg', (4, 13))	('Akt', 'Gene', (24, 27))
28954	32456359	There are only a few ligand-receptor pairs that are clearly defined as highly specific, such as CCL20 and receptor CCR6 or CXCL13 with receptor CXCR5.	('CCR6', 'Gene', (115, 119))	('CCR6', 'Gene', '1235', (115, 119))	('CXCR5', 'Gene', (144, 149))	('CXCR5', 'Gene', '643', (144, 149))	('CXCL13', 'Var', (123, 129))	('CCL20', 'Gene', (96, 101))	('CCL20', 'Gene', '6364', (96, 101))
28986	32456359	The angiogenic potential and chemotactic properties of these subfamily members depend on the presence of conserved sequence of the three AAs, Glu-Leu-Arg, termed as "ELR motif", in the N-terminal domain of chemokine molecule.	('angiogenic potential', 'CPA', (4, 24))	('Glu', 'Chemical', 'MESH:D018698', (142, 145))	('Leu', 'Chemical', 'MESH:D007930', (146, 149))	('Arg', 'Chemical', 'MESH:D001120', (150, 153))	('Glu-Leu-Arg', 'Var', (142, 153))
29006	32456359	It was also demonstrated that chemokine CXCL10 may induce the dissociation of newly formed vessels and their regression during wound healing, as well as endothelial cell death, whereas antibodies neutralizing both CXCR3 and CXCL10 could inhibit cord dissociation mediated by this chemokine.	('cord dissociation', 'CPA', (245, 262))	('death', 'Disease', 'MESH:D003643', (170, 175))	('CXCL10', 'Gene', '3627', (40, 46))	('CXCL10', 'Gene', (40, 46))	('chemokine', 'Var', (30, 39))	('rat', 'Species', '10116', (19, 22))	('dissociation of newly formed vessels', 'CPA', (62, 98))	('CXCL10', 'Gene', '3627', (224, 230))	('CXCL10', 'Gene', (224, 230))	('death', 'Disease', (170, 175))	('regression', 'CPA', (109, 119))
29024	32456359	It was demonstrated that endothelial cells express CCR2, the receptor for CCL2, and in response to CCL2 they exhibit chemotaxis and endothelial tube formation in vitro.	('CCL2', 'Var', (99, 103))	('chemotaxis', 'CPA', (117, 127))	('endothelial tube formation', 'CPA', (132, 158))	('CCR2', 'Gene', '729230', (51, 55))	('CCR2', 'Gene', (51, 55))	('exhibit', 'Reg', (109, 116))	('rat', 'Species', '10116', (14, 17))
29031	32456359	It was demonstrated in a rodent model of angiogenesis that CCL11 directly caused microvessel sprouting, what occurred earlier and with greater effects than after stimulation with VEGF.	('VEGF', 'Gene', '7422', (179, 183))	('microvessel sprouting', 'CPA', (81, 102))	('VEGF', 'Gene', (179, 183))	('caused', 'Reg', (74, 80))	('rat', 'Species', '10116', (14, 17))	('CCL11', 'Var', (59, 64))
29043	32456359	After the treatment with murine 6C-kine the vessel density was significantly reduced in the mice model when compared with control animals.	('murine', 'Var', (25, 31))	('vessel density', 'CPA', (44, 58))	('reduced', 'NegReg', (77, 84))	('murine', 'Species', '10090', (25, 31))	('mice', 'Species', '10090', (92, 96))
29109	32456359	Whereas isocitrate dehydrogenase 1/2 (IDH)1/2 mutations are frequent (>80%) in ScGBMs that have progressed from low-grade or anaplastic astrocytomas, PrGBM bearing this mutations account for less than <5%.	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('GBM', 'Phenotype', 'HP:0012174', (81, 84))	('anaplastic astrocytomas', 'Disease', (125, 148))	('mutations', 'Var', (46, 55))	('IDH', 'Gene', (38, 41))	('ScGBMs', 'Disease', (79, 85))	('IDH', 'Gene', '3417', (38, 41))	('low-grade', 'Disease', (112, 121))	('GBM', 'Phenotype', 'HP:0012174', (152, 155))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (125, 148))	('rat', 'Species', '10116', (14, 17))
29110	32456359	Other alterations significantly more frequent in ScGBM include TP53 mutations, loss of heterozygosity (LOH) 19q, and LOH 22q.	('LOH 22q', 'Var', (117, 124))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('ScGBM', 'Disease', (49, 54))	('loss of heterozygosity', 'Var', (79, 101))	('frequent', 'Reg', (37, 45))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('mutations', 'Var', (68, 77))	('rat', 'Species', '10116', (10, 13))
29111	32456359	On the contrary, genetic alterations more characteristic for PrGBM than ScGBM are LOH 10p, amplification of epidermal growth factor (EGFR), and PTEN mutations.	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('mutations', 'Var', (149, 158))	('PTEN', 'Gene', '5728', (144, 148))	('LOH 10p', 'Var', (82, 89))	('epidermal growth factor', 'Gene', (108, 131))	('rat', 'Species', '10116', (29, 32))	('amplification', 'Var', (91, 104))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('EGFR', 'Gene', '1956', (133, 137))	('epidermal growth factor', 'Gene', '1950', (108, 131))	('PTEN', 'Gene', (144, 148))	('PrGBM', 'Disease', (61, 66))	('EGFR', 'Gene', (133, 137))
29117	32456359	Although several genetic alterations, including mutations, activation of oncogenes, loss of telomerase and induction of aneuploidy, as well as some molecular changes and epigenetic alterations have been reported as the factors affecting the development of CNS tumors, together with gliomas, the precise etiology of these malignancies is still unclear.	('aneuploidy', 'Disease', 'MESH:D000782', (120, 130))	('loss', 'NegReg', (84, 88))	('CNS tumors', 'Disease', (256, 266))	('activation', 'PosReg', (59, 69))	('mutations', 'Var', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('epigenetic alterations', 'Var', (170, 192))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('aneuploidy', 'Disease', (120, 130))	('affecting', 'Reg', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('CNS tumors', 'Disease', 'MESH:D016543', (256, 266))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('rat', 'Species', '10116', (29, 32))	('malignancies', 'Disease', 'MESH:D009369', (321, 333))	('telomerase', 'Protein', (92, 102))	('malignancies', 'Disease', (321, 333))	('CNS tumor', 'Phenotype', 'HP:0100006', (256, 265))	('oncogenes', 'Protein', (73, 82))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('rat', 'Species', '10116', (185, 188))
29146	32456359	GBM patients with high levels of CXCL8 displayed shorter disease-free and overall survival, showing that this chemokine may be a prognostic factor of survival in glioblastoma patients.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('shorter', 'NegReg', (49, 56))	('patients', 'Species', '9606', (175, 183))	('high', 'Var', (18, 22))	('overall survival', 'CPA', (74, 90))	('patients', 'Species', '9606', (4, 12))	('glioblastoma', 'Disease', (162, 174))	('CXCL8', 'Gene', (33, 38))	('CXCL8', 'Gene', '3576', (33, 38))
29176	32456359	In addition, human glioblastoma cell lines induced by Bcl-xl protein showed increased in vitro endothelial cell functions, such as morphogenesis and proliferation, as well as enhanced in vivo formation of vessels in angiogenesis models.	('glioblastoma', 'Disease', (19, 31))	('rat', 'Species', '10116', (156, 159))	('enhanced', 'PosReg', (175, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('human', 'Species', '9606', (13, 18))	('protein', 'Var', (61, 68))	('increased', 'PosReg', (76, 85))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('Bcl-xl', 'Gene', (54, 60))	('proliferation', 'CPA', (149, 162))	('morphogenesis', 'CPA', (131, 144))	('formation of vessels in angiogenesis models', 'CPA', (192, 235))	('vitro endothelial cell functions', 'CPA', (89, 121))	('Bcl-xl', 'Gene', '598', (54, 60))
29225	32456359	These initial-recurrence expression alterations include VEGF-A, its receptors VEGFR2 and VEGFR1, HIF1alpha, and urokinase plasminogen activator (uPA) as well as CXCL12 and CXCR4, the changes were largely consistent between RNA and protein expression.	('VEGFR1', 'Gene', (89, 95))	('alterations', 'Var', (36, 47))	('rat', 'Species', '10116', (40, 43))	('urokinase plasminogen activator', 'Gene', '5328', (112, 143))	('HIF1alpha', 'Gene', '3091', (97, 106))	('expression', 'MPA', (25, 35))	('CXCR4', 'Gene', '7852', (172, 177))	('urokinase plasminogen activator', 'Gene', (112, 143))	('VEGF-A', 'Gene', (56, 62))	('HIF1alpha', 'Gene', (97, 106))	('CXCR4', 'Gene', (172, 177))	('CXCL12', 'Gene', '6387', (161, 167))	('uPA', 'Gene', (145, 148))	('uPA', 'Gene', '5328', (145, 148))	('CXCL12', 'Gene', (161, 167))	('VEGFR2', 'Gene', (78, 84))	('VEGF-A', 'Gene', '7422', (56, 62))	('VEGFR2', 'Gene', '3791', (78, 84))	('VEGFR1', 'Gene', '2321', (89, 95))
29235	32456359	The presence of CXCR6 in GBM is associated with glioma-stem cells.	('CXCR6', 'Gene', (16, 21))	('CXCR6', 'Gene', '10663', (16, 21))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('GBM', 'Gene', (25, 28))	('associated', 'Reg', (32, 42))	('presence', 'Var', (4, 12))	('glioma', 'Disease', (48, 54))
29244	32456359	Inhibition of endogenous CX3CL1 using a neutralizing monoclonal antibody resulted in marked latency of tumor cell aggregation and increased glioma invasiveness.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('glioma invasiveness', 'Disease', 'MESH:D005910', (140, 159))	('CX3CL1', 'Gene', (25, 31))	('CX3CL1', 'Gene', '6376', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('glioma invasiveness', 'Disease', (140, 159))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
29271	32456359	It was shown that increased expression of CCR2, a receptor for CCL2, also stimulates the recruitment of TAMs and fibroblasts at the primary tumors, where they enhance invasion, angiogenesis, and metastasis of glioma and other cancers (Figure 5).	('metastasis of glioma', 'Disease', (195, 215))	('expression', 'Var', (28, 38))	('metastasis of glioma', 'Disease', 'MESH:D009362', (195, 215))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('stimulates', 'PosReg', (74, 84))	('angiogenesis', 'CPA', (177, 189))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('CCR2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('increased', 'PosReg', (18, 27))	('tumors', 'Disease', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('invasion', 'CPA', (167, 175))	('CCR2', 'Gene', '729230', (42, 46))	('recruitment', 'MPA', (89, 100))	('TAMs', 'Chemical', 'MESH:D013629', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('CCL2', 'Gene', (63, 67))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('enhance', 'PosReg', (159, 166))	('cancers', 'Disease', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
29278	32456359	Moreover, it was shown that blocking of CCR5 could prevent polarization of macrophages into M2 microglia phenotype, what was associated with a significant reduction in microglia migration, an effect mediated through the inhibition of the AKT pathway.	('AKT', 'Gene', (238, 241))	('prevent', 'NegReg', (51, 58))	('blocking', 'Var', (28, 36))	('CCR5', 'Gene', (40, 44))	('rat', 'Species', '10116', (181, 184))	('microglia migration', 'CPA', (168, 187))	('AKT', 'Gene', '207', (238, 241))	('reduction', 'NegReg', (155, 164))
29289	32456359	However, it was demonstrated that expression of ACKR2 can regulate the micro-environment in some malignant tumors, suggesting a possible role of these receptors in carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rat', 'Species', '10116', (23, 26))	('ACKR2', 'Gene', (48, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('expression', 'Var', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('role', 'Reg', (137, 141))	('carcinogenesis', 'Disease', (164, 178))	('ACKR2', 'Gene', '1238', (48, 53))	('regulate', 'Reg', (58, 66))	('micro-environment', 'MPA', (71, 88))	('malignant tumors', 'Disease', (97, 113))	('malignant tumors', 'Disease', 'MESH:D009369', (97, 113))
29307	32456359	Moreover, ACKR1 overexpression in different tumor mouse models of non-small cell lung cancer (NSCLC) led to a decrease in tumor cellularity and vascularity, as well as significantly increased necrosis, what inhibited tumorigenesis and reduced the metastatic capacity of tumor.	('increased', 'PosReg', (182, 191))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (122, 127))	('non-small cell lung cancer', 'Disease', (66, 92))	('tumor', 'Disease', (217, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('increased necrosis', 'Phenotype', 'HP:0010885', (182, 200))	('NSCLC', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('overexpression', 'Var', (16, 30))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (270, 275))	('inhibited', 'NegReg', (207, 216))	('vascularity', 'CPA', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('necrosis', 'Disease', 'MESH:D009336', (192, 200))	('ACKR1', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('reduced', 'NegReg', (235, 242))	('decrease', 'NegReg', (110, 118))	('mouse', 'Species', '10090', (50, 55))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (66, 92))	('necrosis', 'Disease', (192, 200))
29322	32456359	On the contrary, the lack of ACKR2 resulted in accumulation of CC chemokines and infiltration of leukocytes at tumor sites.	('ACKR2', 'Gene', '1238', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('lack', 'Var', (21, 25))	('tumor', 'Disease', (111, 116))	('ACKR2', 'Gene', (29, 34))	('rat', 'Species', '10116', (87, 90))	('accumulation', 'PosReg', (47, 59))	('CC chemokines', 'MPA', (63, 76))
29326	32456359	Overexpression of ACKR2 inhibited proliferation and invasion of breast cancer cells in vitro as well as reduced lung metastasis in vivo.	('proliferation', 'CPA', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('reduced', 'NegReg', (104, 111))	('ACKR2', 'Gene', '1238', (18, 23))	('ACKR2', 'Gene', (18, 23))	('lung metastasis', 'CPA', (112, 127))	('inhibited', 'NegReg', (24, 33))	('rat', 'Species', '10116', (41, 44))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('invasion', 'CPA', (52, 60))	('breast cancer', 'Disease', (64, 77))
29345	32456359	Deficiency of this receptor in mice resulted in disturbed cardiac development, cardiovascular defects, and early postnatal lethality in those animals.	('early postnatal lethality', 'CPA', (107, 132))	('disturbed', 'Reg', (48, 57))	('cardiovascular defects', 'Disease', (79, 101))	('cardiovascular defects', 'Phenotype', 'HP:0001626', (79, 101))	('mice', 'Species', '10090', (31, 35))	('cardiac development', 'CPA', (58, 77))	('cardiovascular defects', 'Disease', 'MESH:D002318', (79, 101))	('Deficiency', 'Var', (0, 10))
29348	32456359	By controlling chemokine response, ACKR3 influences also neuronal migration, especially facial motor neurons, together with the classical CXCR4 receptor, although it seems that their functions in the regulation of interneuron relocation may differ.	('ACKR3', 'Var', (35, 40))	('influences', 'Reg', (41, 51))	('CXCR4', 'Gene', '7852', (138, 143))	('facial motor neurons', 'CPA', (88, 108))	('CXCR4', 'Gene', (138, 143))	('neuronal migration', 'CPA', (57, 75))	('rat', 'Species', '10116', (69, 72))
29354	32456359	It was also shown that ACKR3 may enhance tumor cell proliferation and inhibit their apoptosis, thus promoting tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('apoptosis', 'CPA', (84, 93))	('tumor', 'Disease', (41, 46))	('promoting', 'PosReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ACKR3', 'Var', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('rat', 'Species', '10116', (59, 62))	('inhibit', 'NegReg', (70, 77))	('enhance', 'PosReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
29357	32456359	ACKR3 expression at the protein level was elevated in aggressive prostate tumors, where ACKR3 can increase the expression of pro-angiogenic factors such as CXCL8 and VEGF and support the transendothelial migration of cancer cells.	('rat', 'Species', '10116', (207, 210))	('aggressive prostate tumors', 'Disease', 'MESH:D011471', (54, 80))	('expression', 'MPA', (111, 121))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('support', 'PosReg', (175, 182))	('elevated', 'PosReg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('increase', 'PosReg', (98, 106))	('VEGF', 'Gene', '7422', (166, 170))	('CXCL8', 'Gene', '3576', (156, 161))	('CXCL8', 'Gene', (156, 161))	('aggressive prostate tumors', 'Disease', (54, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('VEGF', 'Gene', (166, 170))	('expression', 'MPA', (6, 16))	('cancer', 'Disease', (217, 223))	('ACKR3', 'Var', (88, 93))	('ACKR3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
29360	32456359	After ACKR3-mediated internalization, CXCL12 was transported to intracellular compartments, namely lysosomes, where the ligand was degraded, although levels of ACKR3 remained unchanged.	('CXCL12', 'Gene', (38, 44))	('ACKR3-mediated', 'Var', (6, 20))	('transported', 'MPA', (49, 60))	('CXCL12', 'Gene', '6387', (38, 44))	('degraded', 'NegReg', (131, 139))	('internalization', 'Var', (21, 36))
29378	32456359	In addition, a pro-tumoral function of ACKR3 was confirmed in a murine model of glioblastoma ACKR3, where anti-ACKR3 monoclonal antibodies used in combination with temozolomide, a chemotherapy agent, activated immune responses, induced the phagocytic activity of macrophages and the cytotoxic activity of NK cells and complement, what resulted in extended survival of mice.	('phagocytic activity', 'CPA', (240, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('cytotoxic activity', 'CPA', (283, 301))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('immune responses', 'CPA', (210, 226))	('temozolomide', 'Chemical', 'MESH:D000077204', (164, 176))	('murine', 'Species', '10090', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (368, 372))	('induced', 'PosReg', (228, 235))	('anti-ACKR3', 'Var', (106, 116))	('tumor', 'Disease', (19, 24))	('activated', 'PosReg', (200, 209))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('complement', 'CPA', (318, 328))
29381	32456359	It was revealed that ACKR3 and CXCL12 were associated with high-proliferative tumors.	('tumors', 'Disease', (78, 84))	('CXCL12', 'Gene', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('rat', 'Species', '10116', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CXCL12', 'Gene', '6387', (31, 37))	('associated', 'Reg', (43, 53))	('ACKR3', 'Var', (21, 26))
29385	32456359	This promiscuous atypical receptor may bind ligands from different chemokine subfamilies: CCL2, CCL8, CCL13, CCL19, CCL21, and CCL25 with high affinity, whereas CXCL13 with low affinity.	('CCL19', 'Gene', '6363', (109, 114))	('CCL8', 'Gene', '6355', (96, 100))	('CCL13', 'Gene', '6357', (102, 107))	('CCL25', 'Gene', '6370', (127, 132))	('CCL19', 'Gene', (109, 114))	('CCL25', 'Gene', (127, 132))	('bind', 'Interaction', (39, 43))	('CCL21', 'Gene', '6366', (116, 121))	('CCL2', 'Var', (90, 94))	('CCL8', 'Gene', (96, 100))	('CCL21', 'Gene', (116, 121))	('CCL13', 'Gene', (102, 107))
29442	32456359	Physiologically, PITPNM3 and its Drosophila homologous rdgB are involved in the visual transduction pathway, whereas mutation in human Pyk2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy.	('PITPNM3', 'Gene', '83394', (17, 24))	('involved', 'Reg', (64, 72))	('Drosophila', 'Species', '7227', (33, 43))	('PITPNM3', 'Gene', (158, 165))	('autosomal dominant cone dystrophy', 'Disease', (173, 206))	('PITPNM3', 'Gene', (17, 24))	('cone dystrophy', 'Phenotype', 'HP:0008020', (192, 206))	('visual transduction pathway', 'Pathway', (80, 107))	('rdgB', 'Gene', (55, 59))	('autosomal dominant cone dystrophy', 'Disease', 'MESH:C566719', (173, 206))	('rdgB', 'Gene', '32340', (55, 59))	('human', 'Species', '9606', (129, 134))	('mutation in', 'Var', (117, 128))	('PITPNM3', 'Gene', '83394', (158, 165))	('Pyk2', 'Gene', '2185', (135, 139))	('causes', 'Reg', (166, 172))	('Pyk2', 'Gene', (135, 139))
29491	32456359	However, the biomarker occurrence in CSF might result not only from the secretion or leaking by tumor tissues, but also from dysfunction of BBB and their increased filtration from peripheral blood.	('CSF', 'Disease', (37, 40))	('filtration', 'MPA', (164, 174))	('BBB', 'Protein', (140, 143))	('result', 'Reg', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('rat', 'Species', '10116', (168, 171))	('dysfunction', 'Var', (125, 136))	('secretion', 'MPA', (72, 81))	('leaking', 'MPA', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('increased', 'PosReg', (154, 163))
29506	32093414	MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear.	('deletion', 'Var', (5, 13))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('MTAP', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('MTAP', 'Gene', '4507', (0, 4))
29516	32093414	Analysis of cell proliferation, migration, and invasion did not show any significant differences between MTAP gene-edited and control cells.	('MTAP', 'Gene', '4507', (105, 109))	('gene-edited', 'Var', (110, 121))	('MTAP', 'Gene', (105, 109))
29523	32093414	GBM accounts for 70% of gliomas and can be subdivided in GBM IDH-wild type (the most frequent, >90%), previously known as primary (de novo) GBM and exhibiting a short clinical history, and GBM IDH-mutant, also called secondary GBM, which results from the malignant progression from lower-grade gliomas of diffuse (WHO grade II) or anaplastic (WHO grade III) astrocytomas and is related to point mutations in IDH1/2 genes.	('IDH', 'Gene', '3417', (408, 411))	('IDH', 'Gene', '3417', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (294, 300))	('diffuse', 'Disease', (305, 312))	('IDH', 'Gene', '3417', (193, 196))	('gliomas', 'Phenotype', 'HP:0009733', (294, 301))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('IDH1', 'Gene', '3417', (408, 412))	('astrocytomas', 'Disease', 'MESH:D001254', (358, 370))	('astrocytoma', 'Phenotype', 'HP:0009592', (358, 369))	('gliomas', 'Disease', (294, 301))	('point mutations', 'Var', (389, 404))	('IDH', 'Gene', (408, 411))	('gliomas', 'Disease', (24, 31))	('IDH', 'Gene', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH', 'Gene', (193, 196))	('gliomas', 'Disease', 'MESH:D005910', (294, 301))	('anaplastic', 'Disease', (331, 341))	('IDH1', 'Gene', (408, 412))	('astrocytomas', 'Disease', (358, 370))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
29530	32093414	We previously described the most frequent chromosomal alterations in a series of Brazilian astrocytomas.	('astrocytomas', 'Disease', (91, 103))	('frequent', 'Reg', (33, 41))	('chromosomal alterations', 'Var', (42, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (91, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
29531	32093414	We identified chromosome 7 gain, EGFR amplification, and losses in chromosomes 9p, 10, and 13, in accordance with other populations.	('gain', 'PosReg', (27, 31))	('losses', 'NegReg', (57, 63))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))	('amplification', 'Var', (38, 51))
29532	32093414	We also found 9p- deletion in approximately 50% of GBMs, affecting primarily the 9p21 locus where several tumor suppressor genes are located, including CDKN2A/B and MTAP.	('affecting', 'Reg', (57, 66))	('CDKN2A', 'Gene', (152, 158))	('CDKN2A', 'Gene', '1029', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('MTAP', 'Gene', (165, 169))	('9p- deletion', 'Var', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('MTAP', 'Gene', '4507', (165, 169))
29538	32093414	showed that knockdown of MTAP blocks prostate cancer growth in vitro and in vivo.	('knockdown', 'Var', (12, 21))	('MTAP blocks prostate cancer', 'Disease', 'MESH:D011471', (25, 52))	('MTAP blocks prostate cancer', 'Disease', (25, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))
29539	32093414	In addition, methionine deprivation acts by inhibiting cell migration, invasion, and metastasis in breast cancer.	('inhibiting', 'NegReg', (44, 54))	('methionine deprivation', 'Var', (13, 35))	('metastasis in breast cancer', 'Disease', (85, 112))	('methionine', 'Chemical', 'MESH:D008715', (13, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('invasion', 'CPA', (71, 79))	('cell migration', 'CPA', (55, 69))	('metastasis in breast cancer', 'Disease', 'MESH:D009362', (85, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
29570	32093414	The analysis of hotspot mutations of isocitrate dehydrogenase 1 (IDH1-exon 4) was performed by PCR followed by direct sequencing.	('P', 'Chemical', 'MESH:D010758', (95, 96))	('mutations', 'Var', (24, 33))	('IDH1', 'Gene', (65, 69))	('IDH1', 'Gene', '3417', (65, 69))
29575	32093414	The analysis of hotspot mutations in the promoter region of the telomerase reverse transcriptase gene (TERT) was performed by PCR followed by direct Sanger sequencing.	('telomerase reverse transcriptase gene', 'Gene', (64, 101))	('S', 'Chemical', 'MESH:D013455', (149, 150))	('P', 'Chemical', 'MESH:D010758', (126, 127))	('telomerase reverse transcriptase gene', 'Gene', '7015', (64, 101))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))	('mutations', 'Var', (24, 33))
29576	32093414	Briefly, the TERT promoter region was amplified by PCR using the following primers: 59-AGTGGATTCGCGGGCACAGA-39 (forward) and 59-CAGCGCTGCCTGAAACTC-39 (reverse), leading to a 235 bp PCR product containing C228T and C250T mutations.	('C250T', 'Var', (214, 219))	('P', 'Chemical', 'MESH:D010758', (181, 182))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('C228T', 'Var', (204, 209))	('P', 'Chemical', 'MESH:D010758', (51, 52))	('C250T', 'Mutation', 'c.250C>T', (214, 219))	('C228T', 'Mutation', 'c.228C>T', (204, 209))
29593	32093414	Based on normalized MTAP values, patients were stratified in normal (n = 150) (>-0.1) and MTAP homozygous deletion carriers (n = 200) (<=-1.5).	('MTAP', 'Gene', (90, 94))	('patients', 'Species', '9606', (33, 41))	('MTAP', 'Gene', '4507', (90, 94))	('deletion carriers', 'Var', (106, 123))	('MTAP', 'Gene', (20, 24))	('MTAP', 'Gene', '4507', (20, 24))
29608	32093414	U251 MTAP-/-; U251 EV; U251 WT and SW1088 MTAP+/+; SW1088 LB; SW1088 WT were split, and 5-10 x 103 cells in 100 microL of media supplemented with fetal bovine serum (FBS; 10%) were added to each well.	('MTAP', 'Gene', '4507', (42, 46))	('MTAP', 'Gene', (5, 9))	('FBS', 'Disease', (166, 169))	('FBS', 'Disease', 'MESH:D005198', (166, 169))	('MTAP', 'Gene', '4507', (5, 9))	('U251', 'Var', (14, 18))	('bovine', 'Species', '9913', (152, 158))	('MTAP', 'Gene', (42, 46))
29664	32093414	To address the functional impact on cell proliferation, U251MTAP-/-, U251EV, and U251WT (1x105 cells) as well as SW1088MTAP+/+, SW1088LB, and SW1088WT (5 x 103 cells) were seeded in E-plates, and then the cell index and the doubling time were evaluated (Figure 6).	('MTAP', 'Gene', (60, 64))	('MTAP', 'Gene', (119, 123))	('SW1088LB', 'Var', (128, 136))	('MTAP', 'Gene', '4507', (60, 64))	('MTAP', 'Gene', '4507', (119, 123))
29669	32093414	To investigate whether the loss of MTAP could affect glioma cell motility and invasiveness, we used the transwell cell migration assay (Figure 7A,B).	('glioma cell motility', 'Disease', 'MESH:D005910', (53, 73))	('loss', 'Var', (27, 31))	('MTAP', 'Gene', (35, 39))	('MTAP', 'Gene', '4507', (35, 39))	('affect', 'Reg', (46, 52))	('invasiveness', 'CPA', (78, 90))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma cell motility', 'Disease', (53, 73))
29671	32093414	Regarding the invasive properties of edited cells, as shown in Figure 7C, U251EV cells (601.7 +- 201.6) exhibited an 8% greater invasion compared to U251MTAP-/- (553.5 +- 92.1), yet it was not statistically significant (p = 0.857).	('greater', 'PosReg', (120, 127))	('MTAP', 'Gene', (153, 157))	('U251EV', 'Var', (74, 80))	('MTAP', 'Gene', '4507', (153, 157))	('invasion', 'CPA', (128, 136))
29681	32093414	In fact, Zhao and Zhao in a tumor suppressor pan-cancer study reported the association between copy number loss (9p21) and reduced MTAP mRNA expression.	('tumor', 'Disease', (28, 33))	('MTAP', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('9p21', 'Var', (113, 117))	('MTAP', 'Gene', '4507', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('copy number loss (9p21', 'Var', (95, 117))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Disease', (49, 55))	('reduced', 'NegReg', (123, 130))
29684	32093414	The deletion of this region usually causes co-deletion of MTAP and some classic and well-known tumor suppressor genes such as CDKN2A/B.	('MTAP', 'Gene', '4507', (58, 62))	('CDKN2A', 'Gene', (126, 132))	('co-deletion', 'MPA', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CDKN2A', 'Gene', '1029', (126, 132))	('deletion', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('MTAP', 'Gene', (58, 62))	('tumor', 'Disease', (95, 100))	('causes', 'Reg', (36, 42))
29688	32093414	By analyzing the TCGA-GBM dataset, we also observed that deletion, rather than MTAP promoter methylation, is associated with MTAP mRNA expression.	('MTAP', 'Gene', (125, 129))	('associated', 'Reg', (109, 119))	('MTAP', 'Gene', '4507', (79, 83))	('deletion', 'Var', (57, 65))	('MTAP', 'Gene', '4507', (125, 129))	('MTAP', 'Gene', (79, 83))
29689	32093414	Our results contrast with a recent study that found a significant association of MTAP methylation with gene expression.	('methylation', 'Var', (86, 97))	('MTAP', 'Gene', '4507', (81, 85))	('MTAP', 'Gene', (81, 85))	('gene expression', 'MPA', (103, 118))
29692	32093414	When using the TCGA-GBM dataset, we observed that MTAP loss of expression was more pronounced within the classical subtype (65.2%), corroborating previous reports that patients with classical subtype are characterized by CDKN2A gene deletion that is contiguous with the MTAP gene.	('CDKN2A', 'Gene', '1029', (221, 227))	('MTAP', 'Gene', (270, 274))	('MTAP', 'Gene', (50, 54))	('loss of', 'NegReg', (55, 62))	('expression', 'MPA', (63, 73))	('MTAP', 'Gene', '4507', (270, 274))	('MTAP', 'Gene', '4507', (50, 54))	('patients', 'Species', '9606', (168, 176))	('deletion', 'Var', (233, 241))	('CDKN2A', 'Gene', (221, 227))
29693	32093414	On the other hand, only 7.4% of the G-CIMP glioblastomas showed loss of MTAP, which is associated with secondary glioblastoma, tumor-harboring mutation of the IDH1 gene, and lesions that progressed from LGG.	('glioblastomas', 'Phenotype', 'HP:0012174', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH1', 'Gene', (159, 163))	('glioblastoma', 'Disease', 'MESH:D005909', (43, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('associated', 'Reg', (87, 97))	('secondary', 'Disease', (103, 112))	('glioblastoma', 'Disease', (113, 125))	('MTAP', 'Gene', (72, 76))	('glioblastoma', 'Disease', (43, 55))	('MTAP', 'Gene', '4507', (72, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('IDH1', 'Gene', '3417', (159, 163))	('glioblastomas', 'Disease', (43, 56))	('mutation', 'Var', (143, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('loss', 'NegReg', (64, 68))	('G-CIMP', 'Chemical', '-', (36, 42))	('glioblastomas', 'Disease', 'MESH:D005909', (43, 56))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
29698	32093414	Herein, we extended the immunohistochemistry analysis to a large set of diffuse infiltrative astrocytomas and observed association between loss of MTAP expression and malignancy grade of gliomas.	('gliomas', 'Disease', (187, 194))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('malignancy', 'Disease', (167, 177))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('loss', 'Var', (139, 143))	('astrocytomas', 'Disease', 'MESH:D001254', (93, 105))	('MTAP', 'Gene', '4507', (147, 151))	('MTAP', 'Gene', (147, 151))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('malignancy', 'Disease', 'MESH:D009369', (167, 177))	('astrocytomas', 'Disease', (93, 105))
29700	32093414	that identified the high frequency of MTAP deletion (60%) in glioblastoma series but rare presence in low-grade glioma.	('MTAP', 'Gene', '4507', (38, 42))	('deletion', 'Var', (43, 51))	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('glioma', 'Disease', (112, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('MTAP', 'Gene', (38, 42))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
29703	32093414	identified, in a series of pediatric gliomas, rare episodes of deletion in grade I glioma (12.2%) but frequent 9p21 deletion in high-grade glioma (62.5%).	('glioma', 'Disease', (83, 89))	('I glioma', 'Disease', 'MESH:D005910', (81, 89))	('9p21', 'Gene', (111, 115))	('glioma', 'Disease', (139, 145))	('pediatric gliomas', 'Disease', 'MESH:D005910', (27, 44))	('glioma', 'Disease', (37, 43))	('I glioma', 'Disease', (81, 89))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('deletion', 'Var', (63, 71))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('pediatric gliomas', 'Disease', (27, 44))
29705	32093414	Despite the frequent loss of expression associated with higher-grade lesions, when evaluating its clinical impact in our HGG and adult GBM cases, the loss of MTAP was surprisingly correlated with a better prognosis.	('MTAP', 'Gene', '4507', (158, 162))	('MTAP', 'Gene', (158, 162))	('expression', 'MPA', (29, 39))	('loss', 'Var', (150, 154))	('loss', 'NegReg', (21, 25))
29708	32093414	In addition, through the bioinformatics approach, we did not observe any association of MTAP expression/deletion with overall survival (p = 0.942) and disease-free survival (p = 0.230) from the TCGA-GBM dataset.	('MTAP', 'Gene', (88, 92))	('MTAP', 'Gene', '4507', (88, 92))	('expression/deletion', 'Var', (93, 112))
29713	32093414	The results also showed a lack of association between MTAP deletion and GBM patients' prognosis.	('patients', 'Species', '9606', (76, 84))	('MTAP', 'Gene', (54, 58))	('GBM', 'Disease', (72, 75))	('MTAP', 'Gene', '4507', (54, 58))	('deletion', 'Var', (59, 67))
29724	32093414	For these genes, significant differences were observed only for FN1 and MAPK10 between U251MTAP-/- and U251EV without difference for other genes evaluated.	('FN1', 'Gene', '2335', (64, 67))	('differences', 'Reg', (29, 40))	('MAPK10', 'Gene', (72, 78))	('MAPK10', 'Gene', '5602', (72, 78))	('FN1', 'Gene', (64, 67))	('MTAP', 'Gene', (91, 95))	('MTAP', 'Gene', '4507', (91, 95))	('U251EV', 'Var', (103, 109))
29737	32093414	In summary, the present work showed that loss of MTAP expression is a frequent event in high-grade gliomas.	('loss', 'Var', (41, 45))	('MTAP', 'Gene', '4507', (49, 53))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('MTAP', 'Gene', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
29756	32093414	Spina MLC was a recipient of Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) fellowships (100707/2014-9, 116477/2014-8, 1282245/2014-0).	('100707/2014-9', 'Var', (111, 124))	('P', 'Chemical', 'MESH:D010758', (94, 95))	('MLC', 'Gene', (6, 9))	('MLC', 'Gene', '23209', (6, 9))	('S', 'Chemical', 'MESH:D013455', (0, 1))
29763	32093414	), A172, U87MG, SW1088, SW1783, and T98G (obtained from ATCC, American Type Culture Collection), NHA (obtained from The European Collection of Authenticated Cell Cultures (ECACC).	('SW1088', 'Var', (16, 22))	('SW1783', 'Var', (24, 30))	('U87MG', 'Var', (9, 14))	('T98G', 'Var', (36, 40))	('A172', 'Var', (3, 7))	('S', 'Chemical', 'MESH:D013455', (16, 17))	('S', 'Chemical', 'MESH:D013455', (24, 25))
29764	32093414	NHA, pediatric, and adult glioma cell lines (RES259, SF188, UW479, KNS42, U251, GAMG, A172, U87MG, SW1088, SW1783, and T98G) were grown in Dulbecco's modified Eagle's medium (DMEM) (GIBCO  , Paisley, Scotland, UK).	('DMEM', 'Chemical', '-', (175, 179))	('S', 'Chemical', 'MESH:D013455', (107, 108))	('SW1088', 'Var', (99, 105))	('S', 'Chemical', 'MESH:D013455', (200, 201))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('U87MG', 'Var', (92, 97))	('glioma', 'Disease', (26, 32))	('UW479', 'Var', (60, 65))	('S', 'Chemical', 'MESH:D013455', (53, 54))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (139, 173))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('S', 'Chemical', 'MESH:D013455', (99, 100))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('P', 'Chemical', 'MESH:D010758', (191, 192))
29777	32093414	The stably deleted cell line was designated as U251 MTAP-/- and U251 EV for empty vector control as well as the wild type parental control (U251 WT).	('MTAP', 'Gene', '4507', (52, 56))	('U251', 'Var', (64, 68))	('MTAP', 'Gene', (52, 56))
29780	32093414	Stable cell lines were generated by transducing the MTAP or the Blank control (without insert) and were selected with 25 microg/mL puromycin according to the supplier's protocol.	('transducing', 'Var', (36, 47))	('MTAP', 'Gene', '4507', (52, 56))	('puromycin', 'Chemical', 'MESH:D011691', (131, 140))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('MTAP', 'Gene', (52, 56))
29781	32093414	First, to select the multiplicity of infection (MOI), the green fluorescent protein (GFP) control (LV006) was transfected into the SW1088 cell line cultured in a 96-well tissue culture plate (TPP , Lausanne, Vaud, Switzerland) at a MOI of 2, 4, 6, 8, or 10.	('S', 'Chemical', 'MESH:D013455', (131, 132))	('transfected', 'Var', (110, 121))	('P', 'Chemical', 'MESH:D010758', (87, 88))	('S', 'Chemical', 'MESH:D013455', (214, 215))	('P', 'Chemical', 'MESH:D010758', (194, 195))	('infection', 'Disease', (37, 46))	('P', 'Chemical', 'MESH:D010758', (193, 194))	('infection', 'Disease', 'MESH:D007239', (37, 46))
29787	32093414	The stably expressing cell lines were designated as SW1088 MTAP+/+ and SW1088 LB for lentivirus blank control, beyond the wild type cell line (SW1088 WT).	('MTAP', 'Gene', (59, 63))	('MTAP', 'Gene', '4507', (59, 63))	('SW1088 LB', 'Var', (71, 80))
29799	30279327	One of the main difficulties of prognosis prediction is the heterogeneity of cancer resulting from genetic instability.	('genetic instability', 'Var', (99, 118))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
29805	30279327	We applied the proposed method to copy number alteration data (CNA), gene expression data (mRNA), DNA methylation data, and somatic mutation data (SNP) for five cancer types: pancreatic adenocarcinoma (PAAD), breast invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and stomach adenocarcinoma (STAD).	('kidney renal clear cell carcinoma', 'Disease', (243, 276))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (321, 343))	('BRCA', 'Gene', '672', (236, 240))	('cancer', 'Disease', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (175, 200))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreatic adenocarcinoma', 'Disease', (175, 200))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (209, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (209, 234))	('BRCA', 'Gene', (236, 240))	('glioma', 'Disease', (303, 309))	('stomach adenocarcinoma', 'Disease', (321, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('copy', 'Var', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (303, 309))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (243, 276))	('breast invasive carcinoma', 'Disease', (209, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('PAAD', 'Phenotype', 'HP:0006725', (202, 206))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (175, 200))	('glioma', 'Phenotype', 'HP:0009733', (303, 309))	('BRCA', 'Phenotype', 'HP:0003002', (236, 240))
29820	30279327	Pancreatic cancer frequently involves mutations in KRAS, which contribute to the activation of MAPK, and active MAPK influences downstream genes that may play roles in malignant pancreatic cancer.	('KRAS', 'Gene', '3845', (51, 55))	('MAPK', 'Gene', (95, 99))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('influences', 'Reg', (117, 127))	('malignant pancreatic cancer', 'Disease', 'MESH:D010190', (168, 195))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('activation', 'PosReg', (81, 91))	('malignant pancreatic cancer', 'Disease', (168, 195))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('mutations', 'Var', (38, 47))	('KRAS', 'Gene', (51, 55))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
29832	30279327	We identified JunD by means of DNA methylation data (Table 2), and Figure 7 shows, using the KEGG pathway, that JunD, through DNA methylation, may affect apoptosis of cancer cells.	('methylation', 'Var', (130, 141))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('JunD', 'Gene', (112, 116))	('cancer', 'Disease', (167, 173))	('JunD', 'Gene', '3727', (112, 116))	('JunD', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('JunD', 'Gene', '3727', (14, 18))	('affect', 'Reg', (147, 153))
29850	21324923	COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells Epidemiological studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and reduced glioma risks in humans.	('inhibiting', 'NegReg', (43, 53))	('suppresses', 'NegReg', (15, 25))	('humans', 'Species', '9606', (242, 248))	('glioma', 'Disease', 'MESH:D005910', (226, 232))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('associations', 'Interaction', (128, 140))	('reduced', 'NegReg', (218, 225))	('myeloid-derived suppressor cells', 'CPA', (54, 86))	('glioma', 'Disease', (26, 32))	('blockade', 'Var', (6, 14))	('COX-2', 'Gene', '19225', (0, 5))	('glioma', 'Disease', (226, 232))	('COX-2', 'Gene', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
29852	21324923	Since PGE2 induces expansion of myeloid-derived suppressor cells (MDSCs), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME).	('blockade', 'Var', (101, 109))	('glioma', 'Disease', (125, 131))	('accumulation', 'PosReg', (174, 186))	('MDSC development', 'CPA', (153, 169))	('PGE2', 'Chemical', 'MESH:D015232', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('PGE2', 'Gene', (6, 10))	('COX-2', 'Gene', (95, 100))	('COX-2', 'Gene', '19225', (95, 100))	('tumor', 'Disease', (194, 199))	('suppress', 'NegReg', (116, 124))	('inhibiting', 'NegReg', (142, 152))
29857	21324923	Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development.	('CXCL10', 'Gene', (94, 100))	('delayed', 'NegReg', (37, 44))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('depletion', 'Var', (18, 27))	('increase', 'PosReg', (82, 90))	('CXCL10', 'Gene', '15945', (94, 100))	('CTLs', 'MPA', (105, 109))	('MDSCs', 'Gene', (31, 36))	('glioma', 'Disease', (164, 170))	('glioma', 'Disease', (45, 51))
29866	21324923	Thus, MDSCs facilitate tumor progression by dampening immunosurveillance and are considered to be an important target for tumor immunotherapy.	('MDSCs', 'Var', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('dampening', 'NegReg', (44, 53))	('facilitate', 'PosReg', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (23, 28))	('immunosurveillance', 'MPA', (54, 72))	('tumor', 'Disease', (122, 127))
29883	21324923	The following primers and probes were obtained from Applied Biosystems: Ccl2 (Mm00441242_m1), Cxcl10 (Mm99999072_m1), a n d Nos2 (Mm01290688_m1).	('Ccl2', 'Gene', '20296', (72, 76))	('Mm01290688_m1', 'Var', (130, 143))	('Cxcl10', 'Gene', (94, 100))	('Nos2', 'Gene', (124, 128))	('Mm00441242_m1', 'Var', (78, 91))	('Mm99999072_m1', 'Var', (102, 115))	('Nos2', 'Gene', '18126', (124, 128))	('Ccl2', 'Gene', (72, 76))	('Cxcl10', 'Gene', '15945', (94, 100))
29886	21324923	Fluorescent dye-conjugated antibodies for flow cytometry were obtained as follows: anti-CD4 (VH129.19), anti-CD8 (53-6.7), and anti-Ly6C (AL-21) from BD Biosciences; anti-CD11b (M1/70), anti-CD107a (1D4B), anti-FoxP3 (NRRF-30), and anti-Gr-1 (RB6-8C5) from eBioScience; anti-Ly6G (1A8) from BioLegend; anti-COX-2 (SP21) from AbCam.	('CD4', 'Gene', '12504', (88, 91))	('FoxP3', 'Gene', '20371', (211, 216))	('CD8', 'Gene', (109, 112))	('anti-CD11b', 'Var', (166, 176))	('COX-2', 'Gene', (307, 312))	('Ly6G', 'Gene', '546644', (275, 279))	('Ly6C', 'Gene', (132, 136))	('COX-2', 'Gene', '19225', (307, 312))	('M1/70', 'Gene', '22238', (178, 183))	('CD107a', 'Gene', '16783', (191, 197))	('CD8', 'Gene', '925', (109, 112))	('FoxP3', 'Gene', (211, 216))	('Ly6C', 'Gene', '17067', (132, 136))	('Ly6G', 'Gene', (275, 279))	('CD4', 'Gene', (88, 91))	('M1/70', 'Gene', (178, 183))	('CD107a', 'Gene', (191, 197))
29973	21324923	In the current study, we demonstrated for the first time that COX-2 blockade by NSAIDs as well as genetic deletion of Cox-2 suppress glioma development in mice primarily by inhibiting MDSC accumulation in the TME (Figs.	('COX-2', 'Gene', (62, 67))	('genetic deletion', 'Var', (98, 114))	('COX-2', 'Gene', '19225', (62, 67))	('suppress', 'NegReg', (124, 132))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('Cox-2', 'Gene', '19225', (118, 123))	('MDSC accumulation', 'MPA', (184, 201))	('Cox-2', 'Gene', (118, 123))	('glioma', 'Disease', (133, 139))	('mice', 'Species', '10090', (155, 159))	('inhibiting', 'NegReg', (173, 183))
29975	21324923	4C and 5C), suggesting that MDSCs suppress the effector function of CD8+ T-cells in the TME and thereby facilitate glioma progression.	('glioma', 'Disease', (115, 121))	('effector function', 'MPA', (47, 64))	('MDSCs', 'Var', (28, 33))	('CD8', 'Gene', (68, 71))	('CD8', 'Gene', '925', (68, 71))	('facilitate', 'PosReg', (104, 114))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('suppress', 'NegReg', (34, 42))
29989	21324923	CCL2 is known to be one of the primary chemokines attracting MDSCs towards TME, which is consistent with our observation that genetic depletion of Ccl2 induced a significant decrease in MDSC accumulation in the TME (Fig.	('genetic depletion', 'Var', (126, 143))	('CCL2', 'Gene', (0, 4))	('CCL2', 'Gene', '20296', (0, 4))	('MDSC accumulation', 'MPA', (186, 203))	('Ccl2', 'Gene', (147, 151))	('decrease', 'NegReg', (174, 182))	('depletion', 'Var', (134, 143))	('Ccl2', 'Gene', '20296', (147, 151))
29991	21324923	Simultaneously, our data showed that CCL2 blockade (and resulting inhibition of MDSCs) led to increases of Cxcl10 expression and CD8+ T-cell infiltration in the TME (Figs.	('CD8', 'Gene', (129, 132))	('CD8', 'Gene', '925', (129, 132))	('Cxcl10', 'Gene', (107, 113))	('increases', 'PosReg', (94, 103))	('blockade', 'Var', (42, 50))	('Cxcl10', 'Gene', '15945', (107, 113))	('CCL2', 'Gene', '20296', (37, 41))	('MDSCs', 'Gene', (80, 85))	('inhibition', 'NegReg', (66, 76))	('CCL2', 'Gene', (37, 41))
30011	21324923	With regard to novel risk factors for glioma, we recently reported that single-nucleotide polymorphisms (SNPs) in IFNAR1 and IFNA8 correlate with altered overall survival of patients with WHO grade 2-3 gliomas.	('IFNAR1', 'Gene', (114, 120))	('gliomas', 'Disease', 'MESH:D005910', (202, 209))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('altered', 'Reg', (146, 153))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('IFNAR1', 'Gene', '3454', (114, 120))	('IFNA8', 'Gene', '3445', (125, 130))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('patients', 'Species', '9606', (174, 182))	('IFNA8', 'Gene', (125, 130))	('glioma', 'Disease', (202, 208))	('glioma', 'Disease', (38, 44))	('gliomas', 'Phenotype', 'HP:0009733', (202, 209))	('gliomas', 'Disease', (202, 209))	('overall', 'MPA', (154, 161))	('single-nucleotide polymorphisms', 'Var', (72, 103))
30012	21324923	Others have reported that SNPs in IL-4R and CX3CR1 correlate with survival of glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('SNPs', 'Var', (26, 30))	('correlate with', 'Reg', (51, 65))	('patients', 'Species', '9606', (85, 93))	('IL-4R', 'Gene', '3566', (34, 39))	('survival', 'CPA', (66, 74))	('glioma', 'Disease', (78, 84))	('IL-4R', 'Gene', (34, 39))	('CX3CR1', 'Gene', '1524', (44, 50))	('CX3CR1', 'Gene', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
30014	21324923	Based on the current study, future studies evaluating SNPs in Cox-2, Ccl2 as well as Cxcl10 in relation to glioma risks and prognosis are warranted.	('Cxcl10', 'Gene', '15945', (85, 91))	('Cox-2', 'Gene', '19225', (62, 67))	('Cox-2', 'Gene', (62, 67))	('SNPs', 'Var', (54, 58))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('Ccl2', 'Gene', (69, 73))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('Ccl2', 'Gene', '20296', (69, 73))	('Cxcl10', 'Gene', (85, 91))	('glioma', 'Disease', (107, 113))
30015	33130890	Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033 EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('22033-26033', 'Var', (141, 152))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('glioma', 'Disease', (231, 237))	('temozolomide', 'Chemical', 'MESH:D000077204', (65, 77))	('patients', 'Species', '9606', (27, 35))	('TMZ', 'Chemical', 'MESH:D000077204', (290, 293))	('glioma', 'Disease', (20, 26))	('temozolomide', 'Chemical', 'MESH:D000077204', (276, 288))	('glioma', 'Disease', 'MESH:D005910', (231, 237))
30027	33130890	Mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene are commonly seen in LGGs.	('IDH1', 'Gene', '3417', (45, 49))	('IDH2', 'Gene', (54, 58))	('IDH2', 'Gene', '3418', (54, 58))	('isocitrate dehydrogenase 1', 'Gene', (17, 43))	('Mutations', 'Var', (0, 9))	('isocitrate dehydrogenase 1', 'Gene', '3417', (17, 43))	('seen', 'Reg', (77, 81))	('IDH1', 'Gene', (45, 49))	('LGGs', 'Disease', (85, 89))
30037	33130890	Since most patients in both arms experienced a gain in MMSE scores over time, with no difference between arms, the authors conclude that the addition of PCV to RT improves progression-free survival without excessive neurocognitive decline over RT alone.	('cognitive decline', 'Disease', (221, 238))	('MMSE scores', 'MPA', (55, 66))	('progression-free survival', 'CPA', (172, 197))	('PCV', 'Var', (153, 156))	('cognitive decline', 'Disease', 'MESH:D003072', (221, 238))	('cognitive decline', 'Phenotype', 'HP:0001268', (221, 238))	('gain', 'PosReg', (47, 51))	('patients', 'Species', '9606', (11, 19))	('neurocognitive decline', 'Phenotype', 'HP:0001268', (216, 238))	('improves', 'PosReg', (163, 171))
30039	33130890	Considering the low sensitivity of the MMSE to detect changes in specific neurocognitive domains and the finding of a multicenter study where neurocognitive disability in the memory domain was a prominent feature of irradiated LGG patients, EORTC 22033-26033 incorporated comprehensive neurocognitive testing with a special focus on memory functioning in dedicated centers.	('patients', 'Species', '9606', (231, 239))	('neurocognitive disability', 'Phenotype', 'HP:0100543', (142, 167))	('LGG', 'Disease', (227, 230))	('EORTC', 'Var', (241, 246))	('neurocognitive disability', 'Disease', (142, 167))	('neurocognitive disability', 'Disease', 'MESH:D019965', (142, 167))
30099	30943868	Qualitative and Quantitative Analysis of IDH1 Mutation in Progressive Gliomas by Allele-Specific qPCR and Western Blot Analysis To date, diagnosis of IDH1 mutation is based on DNA sequencing and immunohistochemistry, methods limited in terms of sensitivity and ease of use.	('IDH1', 'Gene', (150, 154))	('Gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('mutation', 'Var', (155, 163))	('IDH1', 'Gene', (41, 45))	('Gliomas', 'Disease', (70, 77))	('Gliomas', 'Disease', 'MESH:D005910', (70, 77))	('Mutation', 'Var', (46, 54))	('IDH1', 'Gene', '3417', (41, 45))	('IDH1', 'Gene', '3417', (150, 154))
30100	30943868	Recently, the diagnosis of IDH1 mutation by real-time polymerase chain reaction was introduced as an alternative method.	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))	('IDH1', 'Gene', (27, 31))
30101	30943868	In this study, real-time polymerase chain reaction was validated as a tool for detection of IDH1 mutation, and expression levels were analyzed for correlation with course of the disease.	('IDH1', 'Gene', '3417', (92, 96))	('IDH1', 'Gene', (92, 96))	('mutation', 'Var', (97, 105))
30104	30943868	Hereafter, quantitative expression of IDH1 messenger RNA was assessed using real-time polymerase chain reaction with specific primers for IDH1 mutation and -wt; protein expression was verified by Western Blot analysis and immunohistochemistry.	('IDH1', 'Gene', '3417', (38, 42))	('IDH1', 'Gene', '3417', (138, 142))	('mutation', 'Var', (143, 151))	('IDH1', 'Gene', (38, 42))	('IDH1', 'Gene', (138, 142))
30106	30943868	IDH1 mutation was identified in 63% of samples by DNA sequencing.	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
30107	30943868	Above this threshold, sensitivity and specificity of real-time polymerase chain reaction in detecting IDH1 mutation were 98% and 94%, respectively.	('mutation', 'Var', (107, 115))	('IDH1', 'Gene', (102, 106))	('IDH1', 'Gene', '3417', (102, 106))	('detecting', 'Reg', (92, 101))
30108	30943868	Quantitative analysis revealed that IDH1 mutation expression is upregulated in secondary glioblastoma (mean +- standard error of mean: 3.52 +- 0.55) compared to lower grade glioma (II = 1.54 +- 0.22; III = 1.67 +- 0.23).	('IDH1', 'Gene', (36, 40))	('glioma', 'Disease', (173, 179))	('glioblastoma', 'Disease', (89, 101))	('upregulated', 'PosReg', (64, 75))	('mutation', 'Var', (41, 49))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('IDH1', 'Gene', '3417', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('expression', 'MPA', (50, 60))
30110	30943868	Western Blot analysis showed a high concordance to both sequencing and real-time polymerase chain reaction results in qualitative analysis of IDH1 mutation status (specificity 100% and sensitivity 100%).	('mutation', 'Var', (147, 155))	('IDH1', 'Gene', '3417', (142, 146))	('IDH1', 'Gene', (142, 146))
30111	30943868	Moreover, semiquantitative protein expression analysis also showed higher expression levels of mutated IDH1 in secondary glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('higher', 'PosReg', (67, 73))	('IDH1', 'Gene', '3417', (103, 107))	('mutated', 'Var', (95, 102))	('expression levels', 'MPA', (74, 91))	('glioblastoma', 'Disease', (121, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('IDH1', 'Gene', (103, 107))
30112	30943868	In our study, real-time polymerase chain reaction and Western Blot analysis were found to be highly efficient methods in detecting IDH1 mutation in glioma samples.	('IDH1', 'Gene', (131, 135))	('glioma', 'Disease', (148, 154))	('mutation', 'Var', (136, 144))	('IDH1', 'Gene', '3417', (131, 135))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))
30113	30943868	As cost-effective and time-saving methods, real-time polymerase chain reaction and Western Blot analysis may therefore play an important role in IDH1 mutation analysis in the future.	('mutation', 'Var', (150, 158))	('IDH1', 'Gene', '3417', (145, 149))	('IDH1', 'Gene', (145, 149))
30117	30943868	IDH1 mutations (IDH1mut) occur in more than 70% of these tumors.	('IDH1', 'Gene', '3417', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IDH1', 'Gene', '3417', (16, 20))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
30119	30943868	Identification of IDH mutations help in the delineation of gliomas from other tumor types.	('IDH', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('IDH', 'Gene', '3417', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', (78, 83))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
30120	30943868	IDH1 mutations are heterozygous point mutations leading to a substitution of arginine in codon 132.	('arginine', 'Chemical', 'MESH:D001120', (77, 85))	('substitution', 'Var', (61, 73))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
30121	30943868	More than 90% of these IDH1mut are based on a basepair exchange of guanine to adenine (G395A) resulting in a specific amino acid replacement of arginine by histidine (R132H).	('histidine', 'Chemical', 'MESH:D006639', (156, 165))	('IDH1', 'Gene', (23, 27))	('arginine', 'Chemical', 'MESH:D001120', (144, 152))	('guanine', 'Chemical', 'MESH:D006147', (67, 74))	('IDH1', 'Gene', '3417', (23, 27))	('G395A', 'Var', (87, 92))	('basepair', 'MPA', (46, 54))	('G395A', 'Mutation', 'rs121913500', (87, 92))	('adenine', 'Chemical', 'MESH:D000225', (78, 85))	('R132H', 'Chemical', '-', (167, 172))
30123	30943868	IDH1 mutations not only inactivate the normal enzymatic activity of IDH1 but, additionally, also lead to a gain of function.	('IDH1', 'Gene', (68, 72))	('mutations', 'Var', (5, 14))	('inactivate', 'NegReg', (24, 34))	('IDH1', 'Gene', '3417', (68, 72))	('enzymatic activity', 'MPA', (46, 64))	('IDH1', 'Gene', (0, 4))	('gain of function', 'PosReg', (107, 123))	('IDH1', 'Gene', '3417', (0, 4))
30124	30943868	Thus, mutated IDH1 catalyzes the reduction of alpha-ketoglutarate to 2-hydroxyglutarate.	('alpha-ketoglutarate to 2-hydroxyglutarate', 'MPA', (46, 87))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (46, 65))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (69, 87))	('reduction', 'MPA', (33, 42))	('IDH1', 'Gene', (14, 18))	('mutated', 'Var', (6, 13))	('IDH1', 'Gene', '3417', (14, 18))
30127	30943868	On a clinical level, the presence of IDH1mut is associated with a better prognosis in patients with glioma of all grades.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('IDH1', 'Gene', (37, 41))	('clinical', 'Species', '191496', (5, 13))	('IDH1', 'Gene', '3417', (37, 41))	('presence', 'Var', (25, 33))	('patients', 'Species', '9606', (86, 94))
30128	30943868	Moreover, in conjunction with O-6-Methylguanine-DNA methyltransferase (MGMT) promotor methylation status, IDH1 mut seems to be prognostic and maybe even predictive value for the efficacy of chemotherapeutic treatment.	('mut', 'Var', (111, 114))	('O-6-Methylguanine-DNA methyltransferase', 'Gene', '4255', (30, 69))	('O-6-Methylguanine-DNA methyltransferase', 'Gene', (30, 69))	('IDH1', 'Gene', (106, 110))	('MGMT', 'Gene', '4255', (71, 75))	('MGMT', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (106, 110))	('predictive', 'Reg', (153, 163))
30129	30943868	Thus, clinical treatment decisions may increasingly become based on IDH1 mutational status.	('IDH1', 'Gene', '3417', (68, 72))	('clinical', 'Species', '191496', (6, 14))	('mutational status', 'Var', (73, 90))	('IDH1', 'Gene', (68, 72))
30134	30943868	While DNA sequencing is regarded as "gold standard" for diagnosing IDH1 mutational status, and pyrosequencing and melting curve analysis actually have higher sensitivity than Sanger sequencing, all of these methods are limited in terms of sensitivity and ease of use.	('mutational', 'Var', (72, 82))	('IDH1', 'Gene', (67, 71))	('higher', 'PosReg', (151, 157))	('IDH1', 'Gene', '3417', (67, 71))	('sensitivity', 'MPA', (158, 169))
30137	30943868	In regard to the potential role of downstream products of mutated IDH1 in gliomagenesis and glioma progression, in this study, we aimed at (1) establishing qPCR as a tool in analysis of IDH1mut status and (2) analyzing the correlation between level of IDH1mut expression and course of the disease.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('IDH1', 'Gene', (186, 190))	('IDH1', 'Gene', '3417', (66, 70))	('IDH1', 'Gene', '3417', (186, 190))	('IDH1', 'Gene', (252, 256))	('glioma', 'Disease', (92, 98))	('glioma', 'Disease', (74, 80))	('IDH1', 'Gene', '3417', (252, 256))	('mutated', 'Var', (58, 65))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('IDH1', 'Gene', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
30143	30943868	IDH1 mutations were detected by PCR and direct sequencing of amplified complementary DNA (cDNA).	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
30156	30943868	IDH1 mutation was found in 71 (62.8%) of 113 patient samples.	('IDH1', 'Gene', (0, 4))	('patient', 'Species', '9606', (45, 52))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
30158	30943868	Among those, C394T, C394A, and C394G mutations were found in 2, 4, and 4 samples, respectively.	('found', 'Reg', (52, 57))	('C394T', 'Mutation', 'rs121913499', (13, 18))	('C394A', 'Mutation', 'rs121913499', (20, 25))	('C394T', 'Var', (13, 18))	('C394G', 'Mutation', 'rs121913499', (31, 36))	('C394G', 'Var', (31, 36))	('C394A', 'Var', (20, 25))
30159	30943868	Diffuse glioma (n = 21) were positive for G395A mutation in 18 (86%) patients, anaplastic gliomas (n = 22) in 19 (86%) patients, and secondary glioblastomas (n = 22) in 17 (77%) patients.	('glioblastomas', 'Disease', 'MESH:D005909', (143, 156))	('G395A', 'Mutation', 'rs121913500', (42, 47))	('patients', 'Species', '9606', (69, 77))	('glioma', 'Disease', (90, 96))	('patients', 'Species', '9606', (178, 186))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioblastomas', 'Phenotype', 'HP:0012174', (143, 156))	('glioma', 'Disease', (8, 14))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (8, 14))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (79, 97))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('anaplastic gliomas', 'Disease', (79, 97))	('patients', 'Species', '9606', (119, 127))	('G395A mutation', 'Var', (42, 56))	('glioblastomas', 'Disease', (143, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('positive', 'Reg', (29, 37))
30160	30943868	No G395A IDH1mut was found in primary glioblastoma samples (see Figure 1 and Table 2).	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('G395A', 'Mutation', 'rs121913500', (3, 8))	('G395A', 'Var', (3, 8))	('primary glioblastoma', 'Disease', 'MESH:D005909', (30, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('primary glioblastoma', 'Disease', (30, 50))
30167	30943868	Based on qPCR results, 76% of patients with diffuse glioma, 86% of patients with anaplastic glioma, and 59% of patients with secondary glioblastoma were positive for the G395A IDH1mut.	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('diffuse', 'Disease', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('anaplastic glioma', 'Disease', 'MESH:D005910', (81, 98))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH1', 'Gene', '3417', (176, 180))	('patients', 'Species', '9606', (30, 38))	('IDH1', 'Gene', (176, 180))	('positive', 'Reg', (153, 161))	('anaplastic glioma', 'Disease', (81, 98))	('patients', 'Species', '9606', (67, 75))	('glioma', 'Disease', (52, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('G395A', 'Var', (170, 175))	('glioma', 'Disease', (92, 98))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioblastoma', 'Disease', (135, 147))	('G395A', 'Mutation', 'rs121913500', (170, 175))	('patients', 'Species', '9606', (111, 119))
30169	30943868	As the IDH1mut primer only allows amplification of the G395A mutation, no other mutations of IDH1 were detected.	('IDH1', 'Gene', (93, 97))	('IDH1', 'Gene', '3417', (7, 11))	('IDH1', 'Gene', '3417', (93, 97))	('G395A', 'Var', (55, 60))	('IDH1', 'Gene', (7, 11))	('G395A', 'Mutation', 'rs121913500', (55, 60))
30175	30943868	However, in 1 particular patient, DNA sequencing revealed a change in IDH1mut status from an IDH1 mutated low-grade glioma (LGG) to a consecutive higher grade glioma (IDH1-wt) and in a later sample back to IDH1mut again.	('IDH1', 'Gene', (93, 97))	('glioma', 'Disease', (159, 165))	('change', 'Reg', (60, 66))	('IDH1', 'Gene', '3417', (93, 97))	('glioma', 'Disease', (116, 122))	('IDH1', 'Gene', '3417', (70, 74))	('IDH1', 'Gene', (167, 171))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('IDH1', 'Gene', '3417', (167, 171))	('patient', 'Species', '9606', (25, 32))	('IDH1', 'Gene', '3417', (206, 210))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('mutated', 'Var', (98, 105))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('IDH1', 'Gene', (206, 210))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('IDH1', 'Gene', (70, 74))
30208	30943868	While qPCR might be even more sensitive in detecting IDH1mut than DNA sequencing in some cases, a drawback of this technique is that it only detects the most common point mutation (G395A).	('G395A', 'Mutation', 'rs121913500', (181, 186))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))	('G395A', 'Var', (181, 186))
30219	30943868	As the primer used in our study specifically amplifies the most common G395A IDH1mut, only the IDH1mut expression levels of those samples that were characterized as IDH1mut by DNA sequencing were further analyzed.	('G395A', 'Mutation', 'rs121913500', (71, 76))	('G395A', 'Var', (71, 76))	('IDH1', 'Gene', (77, 81))	('IDH1', 'Gene', (95, 99))	('IDH1', 'Gene', (165, 169))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', '3417', (95, 99))	('IDH1', 'Gene', '3417', (165, 169))
30225	30943868	However, in a recent publication, mutant IDH1 was found to sensitize glioma cells to oxidative stress as induced by chemotherapy.	('glioma', 'Disease', (69, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (85, 101))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH1', 'Gene', (41, 45))	('oxidative stress', 'MPA', (85, 101))	('sensitize', 'Reg', (59, 68))	('IDH1', 'Gene', '3417', (41, 45))	('mutant', 'Var', (34, 40))
30226	30943868	Hence, the reduced expression of IDH1mut in previously treated secondary glioblastomas may be caused by a loss of cells bearing high levels of mutated IDH1 due to Cx treatment.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('reduced', 'NegReg', (11, 18))	('expression', 'MPA', (19, 29))	('IDH1', 'Gene', (33, 37))	('glioblastomas', 'Phenotype', 'HP:0012174', (73, 86))	('IDH1', 'Gene', '3417', (33, 37))	('IDH1', 'Gene', (151, 155))	('glioblastomas', 'Disease', 'MESH:D005909', (73, 86))	('mutated', 'Var', (143, 150))	('IDH1', 'Gene', '3417', (151, 155))	('glioblastomas', 'Disease', (73, 86))
30227	30943868	The potential influence of prior Cx on IDH1 expression levels could suggest that IDH1 mutant cells may be more sensitive to DNA damage, as suggested in the published literature.	('mutant', 'Var', (86, 92))	('IDH1', 'Gene', (39, 43))	('more', 'PosReg', (106, 110))	('sensitive to DNA damage', 'MPA', (111, 134))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', '3417', (81, 85))
30228	30943868	Mutant IDH1 drives a unique set of transformative events that indirectly enhance homologous recombination and facilitate repair of temozolomide-induced DNA damage and temozolomide resistance.	('IDH1', 'Gene', '3417', (7, 11))	('temozolomide', 'Chemical', 'MESH:D000077204', (167, 179))	('temozolomide resistance', 'MPA', (167, 190))	('facilitate', 'PosReg', (110, 120))	('enhance', 'PosReg', (73, 80))	('repair of temozolomide-induced DNA damage', 'MPA', (121, 162))	('temozolomide', 'Chemical', 'MESH:D000077204', (131, 143))	('homologous recombination', 'MPA', (81, 105))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))
30233	30943868	Moreover, our study did not include an analysis of 2-hydroxyglutarate levels as a downstream product of mutated IDH1.	('IDH1', 'Gene', '3417', (112, 116))	('IDH1', 'Gene', (112, 116))	('mutated', 'Var', (104, 111))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (51, 69))
30235	30943868	Therefore, it is possible that, due to a yet unknown mechanism, the translation from IDH1mut messenger RNA to mutated IDH1 is inhibited, leading to a mismatch between IDH1mut expression level and 2-hydroxyglutarate levels during progression of glioma.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (196, 214))	('glioma', 'Disease', (244, 250))	('2-hydroxyglutarate levels', 'MPA', (196, 221))	('mutated', 'Var', (110, 117))	('IDH1', 'Gene', (118, 122))	('mismatch', 'MPA', (150, 158))	('inhibited', 'NegReg', (126, 135))	('IDH1', 'Gene', '3417', (118, 122))	('translation', 'MPA', (68, 79))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('IDH1', 'Gene', (167, 171))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('IDH1', 'Gene', (85, 89))	('leading to', 'Reg', (137, 147))	('IDH1', 'Gene', '3417', (167, 171))	('IDH1', 'Gene', '3417', (85, 89))
30236	30943868	The clinical uses in establishing qPCR for the detection of IDH1 mutational status could be cases with small amounts of tumors cells or longitudinal cases, where the mutational status seems to change.	('clinical', 'Species', '191496', (4, 12))	('mutational', 'Var', (65, 75))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('IDH1', 'Gene', (60, 64))	('IDH1', 'Gene', '3417', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
30251	26000059	The maximum standardized uptake values (SUVmax) and the maximum target to non-target ratios (T/NTmax) of 68Ga-NOTA-NFB PET/CT in glioma tissues were 4.11 +- 2.90 (range, 0.45-8.21) and 9.21 +- 8.75 (range, 3.66-24.88), respectively, while those of 18F-FDG PET/CT were 7.34 +- 2.90 (range, 3.50-12.27) and 0.86 +- 0.41 (range, 0.35-1.59).	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('NOTA-NFB', 'Chemical', '-', (110, 118))	('rat', 'Species', '10116', (85, 88))	('18F-FDG', 'Chemical', 'MESH:D019788', (248, 255))	('standardized uptake values', 'MPA', (12, 38))	('glioma', 'Disease', (129, 135))	('68Ga-NOTA-NFB', 'Var', (105, 118))
30263	26000059	T140, a 14-residue peptide possessing disulfide bond, was initially identified as an anti-HIV agent due to its strong binding with CXCR4.	('disulfide', 'Chemical', 'MESH:D004220', (38, 47))	('T140', 'Var', (0, 4))	('T140', 'Chemical', 'MESH:C116977', (0, 4))	('binding', 'Interaction', (118, 125))	('CXCR4', 'MPA', (131, 136))
30265	26000059	In the precilinical imaging studies, NOTA-NFB displayed highly specific accumulation in CXCR4-positive tumors and high tumor-to-background ratios, suggesting the feasibility of NOTA-NFB for clinical translation for cancer detection.	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('NOTA-NFB', 'Var', (37, 45))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('rat', 'Species', '10116', (139, 142))	('tumor', 'Disease', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('accumulation', 'PosReg', (72, 84))	('NOTA-NFB', 'Chemical', '-', (177, 185))	('NOTA-NFB', 'Chemical', '-', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
30304	26000059	The decay-corrected radio chemical yield (RCY) of 68Ga-NOTA-NFB was 74 +- 3 % (n = 5) and the radiochemical purity (RCP) tested by HPLC was nearly 100%.	('NOTA-NFB', 'Chemical', '-', (55, 63))	('68Ga-NOTA-NFB', 'Var', (50, 63))	('radio chemical yield', 'MPA', (20, 40))
30316	26000059	As a result, the T/NTmax of 68Ga-NOTA-NFB (9.21+- 8.75, range: 3.7-24.9) was significantly higher than that of 18F-FDG (0.86 +- 0.41, range: 0.35-1.59) (p < 0.05), indicating that 68Ga-NOTA-NFB is superior to 18F-FDG in determining the boundary of glioma.	('glioma', 'Disease', (248, 254))	('18F-FDG', 'Chemical', 'MESH:D019788', (209, 216))	('68Ga-NOTA-NFB', 'Var', (28, 41))	('higher', 'PosReg', (91, 97))	('NOTA-NFB', 'Chemical', '-', (33, 41))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('18F-FDG', 'Chemical', 'MESH:D019788', (111, 118))	('T/NTmax', 'MPA', (17, 24))	('NOTA-NFB', 'Chemical', '-', (185, 193))
30325	26000059	In this investigation, we first assessed the biodistrubtion and dosimetric properties of 68Ga-NOTA-NFB and then evaluated its potential for glioma diagnosis.	('68Ga-NOTA-NFB', 'Var', (89, 102))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('NOTA-NFB', 'Chemical', '-', (94, 102))	('glioma', 'Disease', (140, 146))
30326	26000059	68Ga-NOTA-NFB had prominent uptake in the liver and spleen.	('68Ga-NOTA-NFB', 'Var', (0, 13))	('NOTA-NFB', 'Chemical', '-', (5, 13))	('uptake', 'MPA', (28, 34))
30340	26000059	68Ga-NOTA-NFB specifically accumulated in glioma and was vacant in normal brain tissues.	('68Ga-NOTA-NFB', 'Var', (0, 13))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('NOTA-NFB', 'Chemical', '-', (5, 13))	('accumulated', 'PosReg', (27, 38))	('glioma', 'Disease', (42, 48))
30342	26000059	Compared to 18F-FDG PET/CT, the favorable SUVmax and high T/NTmax of 68Ga-NOTA-NFB PET/CT could improve the sensitivity of glioma diagnosis.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('T/NTmax', 'MPA', (58, 65))	('68Ga-NOTA-NFB', 'Var', (69, 82))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('improve', 'PosReg', (96, 103))	('NOTA-NFB', 'Chemical', '-', (74, 82))	('glioma', 'Disease', (123, 129))	('18F-FDG', 'Chemical', 'MESH:D019788', (12, 19))	('SUVmax', 'MPA', (42, 48))
30344	26000059	68Ga-NOTA-PRGD2 was found to have high accumulation in the glioma, and low uptakes in the normal brain except for the choroid plexus.	('NOTA', 'Chemical', 'MESH:C048993', (5, 9))	('accumulation', 'MPA', (39, 51))	('glioma', 'Disease', (59, 65))	('uptakes', 'MPA', (75, 82))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('68Ga-NOTA-PRGD2', 'Var', (0, 15))
30385	24947265	There is likely a physiologic and temporal relationship between white matter changes and frank radionecrosis, and white matter changes and radionecrosis are not mutually exclusive.	('changes', 'Var', (77, 84))	('white matter changes', 'Phenotype', 'HP:0002500', (64, 84))	('necrosis', 'Disease', 'MESH:D009336', (144, 152))	('necrosis', 'Disease', 'MESH:D009336', (100, 108))	('frank', 'Disease', (89, 94))	('white matter changes', 'Phenotype', 'HP:0002500', (114, 134))	('necrosis', 'Disease', (144, 152))	('necrosis', 'Disease', (100, 108))
30461	24947265	There are provocative data to suggest that pseudoprogression is more frequent in patients who harbor a methylated MGMT promoter.	('MGMT', 'Gene', (114, 118))	('patients', 'Species', '9606', (81, 89))	('pseudoprogression', 'Disease', (43, 60))	('methylated', 'Var', (103, 113))	('MGMT', 'Gene', '4255', (114, 118))
30553	24947265	The sensitivity of the T1/T2 mismatch in identifying necrosis was 83.3% and the specificity was 91.2%.	('mismatch', 'Var', (29, 37))	('necrosis', 'Disease', (53, 61))	('necrosis', 'Disease', 'MESH:D009336', (53, 61))	('T1/T2', 'Var', (23, 28))
30554	24947265	In terms of identifying tumor recurrence, the sensitivity of T1/T2 match was 93.9%, and the specificity was 76.9%.	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('T1/T2 match', 'Var', (61, 72))
30600	24947265	For example, in the case of 18-flurodeoxyglucose PET (FDG-PET) imaging, the presence of glucose transporters leads to uptake and entrapment of FDG in the cell.	('uptake', 'MPA', (118, 124))	('entrapment', 'CPA', (129, 139))	('presence', 'Var', (76, 84))	('glucose transporters', 'Protein', (88, 108))	('FDG', 'Chemical', 'MESH:D019788', (54, 57))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('18-flurodeoxyglucose', 'Chemical', '-', (28, 48))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('leads to', 'Reg', (109, 117))	('FDG', 'Chemical', 'MESH:D019788', (143, 146))
30603	24947265	Using the same principle, high FDG uptake in a previously low-grade glioma may indicate anaplastic transformation.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('FDG', 'Chemical', 'MESH:D019788', (31, 34))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('high', 'Var', (26, 30))	('anaplastic transformation', 'CPA', (88, 113))	('indicate', 'Reg', (79, 87))	('glioma', 'Disease', (68, 74))
30614	24947265	Amino acid radiotracers generally have a higher specificity compared with other radiotracers for distinguishing radionecrosis from tumor recurrence with reported specificity of 100% for 11C-Met, 93.5% for 18F-FET, and 86% for 18F-FDOPA.	('11C-Met', 'Var', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('necrosis', 'Disease', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('18F-FET', 'Var', (205, 212))	('tumor', 'Disease', (131, 136))	('necrosis', 'Disease', 'MESH:D009336', (117, 125))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (226, 235))	('11C-Met', 'Chemical', '-', (186, 193))
30774	32376723	To explore the contextual prognostic value of cancer immune phenotypes, we applied a multimodal pan-cancer analysis among 31 different histologies (9282 patients), encompassing immune and oncogenic transcriptomic analysis, mutational and neoantigen load and copy number variations.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (100, 106))	('copy number variations', 'Var', (258, 280))
30776	32376723	WNT-beta catenin, barrier molecules, Notch, hedgehog, mismatch repair, telomerase activity and AMPK signaling were the pathways most coherently associated with an immune silent phenotype together with mutations of driver genes including IDH1/2, FOXA2, HDAC3, PSIP1, MAP3K1, KRAS, NRAS, EGFR, FGFR3, WNT5A and IRF7.	('NRAS', 'Gene', (280, 284))	('associated', 'Reg', (144, 154))	('EGFR', 'Gene', '1956', (286, 290))	('IDH1/2', 'Gene', '3417;3418', (237, 243))	('FOXA2', 'Gene', '3170', (245, 250))	('beta catenin', 'Gene', '1499', (4, 16))	('FGFR3', 'Gene', (292, 297))	('KRAS', 'Gene', (274, 278))	('beta catenin', 'Gene', (4, 16))	('IDH1/2', 'Gene', (237, 243))	('HDAC3', 'Gene', (252, 257))	('FGFR3', 'Gene', '2261', (292, 297))	('WNT5A', 'Gene', (299, 304))	('NRAS', 'Gene', '4893', (280, 284))	('EGFR', 'Gene', (286, 290))	('HDAC3', 'Gene', '8841', (252, 257))	('MAP3K1', 'Gene', (266, 272))	('IRF7', 'Gene', '3665', (309, 313))	('mutations', 'Var', (201, 210))	('MAP3K1', 'Gene', '4214', (266, 272))	('AMPK', 'Gene', '5564', (95, 99))	('FOXA2', 'Gene', (245, 250))	('WNT5A', 'Gene', '7474', (299, 304))	('PSIP1', 'Gene', (259, 264))	('AMPK', 'Gene', (95, 99))	('KRAS', 'Gene', '3845', (274, 278))	('IRF7', 'Gene', (309, 313))	('PSIP1', 'Gene', '11168', (259, 264))
30785	32376723	In breast cancer, a positive association between survival and density of tumor infiltrating lymphocytes, as estimated by transcriptomic data, was restricted to tumors displaying a high mutational load or an aggressive/high proliferative phenotype.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('high mutational load', 'Var', (180, 200))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
30791	32376723	In particular, we reported that transcriptional dysregulation of the MAPK pathways sustained by genetic alterations (ie, MAP3K1 and MAP2K4 mutations) are enriched in immune silent tumors.	('genetic alterations', 'Var', (96, 115))	('alterations', 'Var', (104, 115))	('MAP2K4', 'Gene', '6416', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (139, 148))	('silent tumors', 'Disease', 'MESH:C566065', (173, 186))	('MAPK pathways', 'Pathway', (69, 82))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('MAP2K4', 'Gene', (132, 138))	('MAP3K1', 'Gene', (121, 127))	('silent tumors', 'Disease', (173, 186))	('transcriptional dysregulation', 'MPA', (32, 61))	('MAP3K1', 'Gene', '4214', (121, 127))
30803	32376723	Raw fastq files of datasets GSE78220 and GSE78220 were downloaded from National Center for Biotechnology Information (NCBI) storage replication adapter (SRA) servers, quality control and adapter trimming was performed using Trim_Galore (https://github.com/FelixKrueger/TrimGalore).	('FelixKrueger', 'Disease', 'None', (256, 268))	('FelixKrueger', 'Disease', (256, 268))	('GSE78220', 'Var', (41, 49))	('GSE78220', 'Var', (28, 36))
30819	32376723	Factors added in the multivariate analyzes (overall and stratified according to the ICR-enabling categories) include representative oncogenic pathways (proliferation and transforming growth factor beta (TGF-ss) signaling), mutation rate, aneuploidy, stage or histological grade.	('transforming growth factor beta', 'Gene', '7124', (170, 201))	('transforming growth factor beta', 'Gene', (170, 201))	('aneuploidy', 'Disease', (238, 248))	('mutation', 'Var', (223, 231))	('oncogenic pathways', 'Pathway', (132, 150))	('aneuploidy', 'Disease', 'MESH:D000782', (238, 248))
30824	32376723	Finally, several pathways were added that have previously been hypothesized to associate with cancer immune phenotypes, including Hypoxia/Adenosine Immune Cell Suppression, immunogenic cell death, NOS1 Signature, PI3Kgamma signature and SHC1/pSTAT3 signatures as described by Lu et al, barrier genes as described by Salerno et al, the proliferation metagene as described by Miller et al  and genes upregulated in MAPK mutated breast cancer.	('SHC1', 'Gene', '6464', (237, 241))	('cancer', 'Disease', 'MESH:D009369', (433, 439))	('mutated', 'Var', (418, 425))	('death', 'Disease', (190, 195))	('PI3Kgamma', 'Gene', (213, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (426, 439))	('MAPK', 'Gene', (413, 417))	('STAT3', 'Gene', '20848', (243, 248))	('cancer', 'Disease', (94, 100))	('NOS1', 'Gene', '4842', (197, 201))	('Hypoxia', 'Disease', (130, 137))	('Adenosine', 'Chemical', 'MESH:D000241', (138, 147))	('breast cancer', 'Disease', 'MESH:D001943', (426, 439))	('upregulated', 'PosReg', (398, 409))	('breast cancer', 'Disease', (426, 439))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('NOS1', 'Gene', (197, 201))	('cancer', 'Disease', (433, 439))	('death', 'Disease', 'MESH:D003643', (190, 195))	('STAT3', 'Gene', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('SHC1', 'Gene', (237, 241))	('PI3Kgamma', 'Gene', '5294', (213, 222))	('Hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
30827	32376723	An elastic net regularized model was built to predict the ICR score as function of mutations in each sample and using the tumor-type as a covariate.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
30829	32376723	A ratio >1 implies that the ICR score is higher in the mutated group compared with WT, while a ratio <1 implies that the ICR score is higher in subset of tumors without mutation.	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('mutated', 'Var', (55, 62))	('ICR score', 'MPA', (28, 37))	('higher', 'PosReg', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
30831	32376723	For PTEN deletion, CNV-low versus CNV-high categories were also defined using a Log R ratio cut-off of -0.4, previously optimized in melanoma.	('PTEN', 'Gene', '5728', (4, 8))	('deletion', 'Var', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('PTEN', 'Gene', (4, 8))
30912	32376723	To define the association of specific oncogenic mutations with ICR immune phenotypes, we first selected a set of 470 frequently mutated genes in cancer, then trained an elastic net model to predict the ICR score as function of mutations in each sample and using the tumor type as covariate.	('cancer', 'Disease', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', (266, 271))	('mutations', 'Var', (227, 236))
30913	32376723	The use of tumor type as covariate tends to limit the effect of the enrichment of mutations in specific cancer types and their correlation with ICR score.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (11, 16))	('mutations', 'Var', (82, 91))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
30916	32376723	Interestingly MAP3K1 mutations, whose effect on ICR low has been described in breast cancer, were also associated to ICR low tumors pan-cancer.	('low tumors pan-cancer', 'Disease', (121, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('low tumors pan-cancer', 'Disease', 'MESH:D009369', (121, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('associated', 'Reg', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('MAP3K1', 'Gene', '4214', (14, 20))	('MAP3K1', 'Gene', (14, 20))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('mutations', 'Var', (21, 30))
30917	32376723	The top genes of which mutations positively correlate with ICR reflect immune-evasion mechanisms that follow immunological pressure such as mutations of antigen-presenting machinery transcripts previously described (ie, B2M, HLA-A, HLA-B and CASP8).	('ICR', 'Disease', (59, 62))	('B2M', 'Gene', (220, 223))	('B2M', 'Gene', '567', (220, 223))	('HLA-B', 'Gene', (232, 237))	('mutations', 'Var', (23, 32))	('HLA-A', 'Gene', '3105', (225, 230))	('HLA-B', 'Gene', '3106', (232, 237))	('mutations', 'Var', (140, 149))	('CASP8', 'Gene', (242, 247))	('HLA-A', 'Gene', (225, 230))	('CASP8', 'Gene', '841', (242, 247))
30918	32376723	To better compare the association between specific mutations and ICR groups within individual cancer types, we calculated, for each of the identified genes, the mean ICR score in the mutated group divided by the mean ICR score in the WT within each individual cancer type.	('mutated', 'Var', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
30921	32376723	While for most cancer types, ICR score is indeed lower in the mutated group, results for cancer types COAD, UCEC and STAD show the reverse (figure 4A-B, right panels).	('COAD', 'Disease', (102, 106))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('COAD', 'Disease', 'MESH:D029424', (102, 106))	('cancer', 'Disease', (89, 95))	('lower', 'NegReg', (49, 54))	('mutated', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ICR score', 'MPA', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('UCEC', 'Disease', (108, 112))
30924	32376723	Mutated genes were frequently part of multiple pathways, suggesting impact on various tumor biological systems (online supplementary figure 11).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('part', 'Reg', (30, 34))	('Mutated genes', 'Var', (0, 13))	('tumor', 'Disease', (86, 91))	('impact', 'Reg', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
30925	32376723	PTEN and CTNNB1 somatic alterations (either mutations or CNVs) have been associated with differential response to immunotherapy (PTEN) and intratumoral immune response (PTEN  and CTNNB1).	('tumor', 'Disease', (144, 149))	('CTNNB1', 'Gene', '1499', (179, 185))	('CTNNB1', 'Gene', '1499', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PTEN', 'Gene', (169, 173))	('PTEN', 'Gene', '5728', (169, 173))	('associated', 'Reg', (73, 83))	('CTNNB1', 'Gene', (179, 185))	('PTEN', 'Gene', (129, 133))	('PTEN', 'Gene', '5728', (129, 133))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CTNNB1', 'Gene', (9, 15))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
30927	32376723	PTEN mutations, however, were associated with higher ICR score in four individual cancer types (LGG, BRCA, COAD and Lung Adenocarcinoma (LUAD)) and in the pan-cancer analysis (online supplementary figure 12).	('LGG', 'Disease', (96, 99))	('cancer', 'Disease', (82, 88))	('Lung Adenocarcinoma', 'Disease', (116, 135))	('BRCA', 'Disease', (101, 105))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('higher', 'PosReg', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('COAD', 'Disease', 'MESH:D029424', (107, 111))	('ICR score', 'MPA', (53, 62))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('PTEN', 'Gene', (0, 4))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('COAD', 'Disease', (107, 111))	('PTEN', 'Gene', '5728', (0, 4))
30928	32376723	As for CTNNB1, a significant association between higher copy number and lower ICR was found in five cancer types (KIRP, Ovarian Cancer (OV), BLCA STAD and TGCT).	('higher copy number', 'Var', (49, 67))	('BLCA STAD', 'Disease', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lower', 'NegReg', (72, 77))	('CTNNB1', 'Gene', (7, 13))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (120, 134))	('Cancer', 'Disease', (128, 134))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ICR', 'MPA', (78, 81))	('Cancer', 'Disease', 'MESH:D009369', (128, 134))	('CTNNB1', 'Gene', '1499', (7, 13))
30930	32376723	CTNNB1 mutations (either in all positions or in exon 3) were associated with lower ICR in ACC, with a non-significant trend in SKCM, PRAD and LGG (online supplementary figure 13).	('lower', 'NegReg', (77, 82))	('CTNNB1', 'Gene', '1499', (0, 6))	('ICR', 'MPA', (83, 86))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
30939	32376723	As anticipated, pan-cancer survival analysis of all samples that formed a cluster along with samples of the ICR-disabled cancer types, named the ICR non-beneficial cluster, revealed no survival benefit of a high ICR expression.	('high', 'Var', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
30969	32376723	In tumor types with medium/high mutational burden, the mutational or neoantigenic load tended to be higher in hot (ICR high) versus cold (ICR low) tumors while this association was not observed within cancer types with overall low mutational burden.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (147, 152))	('mutational burden', 'Var', (32, 49))	('tumor', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('cancer', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('neoantigenic load', 'MPA', (69, 86))	('mutational', 'MPA', (55, 65))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
30970	32376723	By adding granularity to previous observations that described an overall weak correlation between immunologic correlates of antitumor immune response and mutational load, we demonstrated here that the differences in term of mutational load was especially evident in tumors types known to be constituted by a significant proportion of microsatellite instable cases, such as COAD, STAD and UCEC.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutational', 'Var', (224, 234))	('COAD', 'Disease', (373, 377))	('microsatellite', 'Var', (334, 348))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('COAD', 'Disease', 'MESH:D029424', (373, 377))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('STAD', 'Disease', (379, 383))	('UCEC', 'Disease', (388, 392))	('tumor', 'Disease', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Disease', (266, 271))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
30973	32376723	The top pathways associated with the absence of the Th-1/hot immune phenotype included, barriers genes, WNT-ss catenin, mismatch repair, telomerase extension by telomerase, Notch, Hedgehog and AMPK signaling pathways.	('AMPK', 'Gene', '5564', (193, 197))	('mismatch', 'Var', (120, 128))	('WNT-ss', 'Gene', (104, 110))	('Notch', 'Pathway', (173, 178))	('barriers genes', 'Gene', (88, 102))	('AMPK', 'Gene', (193, 197))
30977	32376723	CTNNB1 somatic alterations leading to WNT-ss catenin activation (ie, amplifications and somatic mutations preventing proteolytic ss-catenin degradations) have been associated with a non-T cell inflamed immune phenotype in melanoma and across different tumor types.	('CTNNB1', 'Gene', '1499', (0, 6))	('associated with', 'Reg', (164, 179))	('activation', 'PosReg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('CTNNB1', 'Gene', (0, 6))	('alterations', 'Var', (15, 26))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('WNT-ss catenin', 'MPA', (38, 52))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('tumor', 'Disease', (252, 257))
30978	32376723	Interestingly, neither the elastic model nor the single-gene level analysis selected CTNNB1 mutations in relationship to ICR expression, while associations between CTNNB1 amplifications and low ICR score were observed across several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('CTNNB1', 'Gene', (85, 91))	('ICR expression', 'MPA', (121, 135))	('mutations', 'Var', (92, 101))	('cancer', 'Disease', (233, 239))	('CTNNB1', 'Gene', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('CTNNB1', 'Gene', '1499', (85, 91))	('CTNNB1', 'Gene', '1499', (164, 170))	('associations', 'Interaction', (143, 155))
30979	32376723	Similarly, no associations between CTNNB1 mutations and intratumoral immune response were detected by two pan-cancer studies assessing an immune signature closely related to ICR and the level of cytolytic activity (PRF1 and GZMA).	('ICR', 'Disease', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('CTNNB1', 'Gene', '1499', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CTNNB1', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PRF1', 'Gene', (215, 219))	('PRF1', 'Gene', '5551', (215, 219))	('GZMA', 'Gene', (224, 228))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (61, 66))	('GZMA', 'Gene', '3001', (224, 228))
30980	32376723	Interestingly, in addition to a negative (although modest) correlation between ICR score and mutations of APC (an inhibitor of the WNT-ss catenin pathway), we detected a stronger correlation between WNT5A mutations and decreased ICR score.	('mutations', 'Var', (93, 102))	('ICR', 'Disease', (79, 82))	('decreased', 'NegReg', (219, 228))	('APC', 'Disease', 'MESH:D011125', (106, 109))	('mutations', 'Var', (205, 214))	('APC', 'Disease', (106, 109))	('WNT5A', 'Gene', '7474', (199, 204))	('ICR', 'Disease', (229, 232))	('WNT5A', 'Gene', (199, 204))
30982	32376723	However, associations between the WNT5A mutations and decreased intratumoral immune response were not previously checked in WNT-ss catenin-focused analyzes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('WNT5A', 'Gene', '7474', (34, 39))	('tumor', 'Disease', (69, 74))	('mutations', 'Var', (40, 49))	('decreased', 'NegReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('WNT5A', 'Gene', (34, 39))
30983	32376723	The correlation between WNT5A mutations and immune suppression might deserve mechanistic investigation considering the complexity of this pathway.	('WNT5A', 'Gene', (24, 29))	('WNT5A', 'Gene', '7474', (24, 29))	('mutations', 'Var', (30, 39))
30985	32376723	Loss of PTEN (a negative regulator of the PI3K-AKT pathway), due to somatic mutations or deletions has been associated with decreased response to checkpoint blockade in melanoma, glioblastoma, lung cancer and uterine sarcoma.	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (209, 224))	('melanoma', 'Disease', (169, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('PTEN', 'Gene', '5728', (8, 12))	('response to checkpoint blockade', 'MPA', (134, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('AKT', 'Gene', (47, 50))	('glioblastoma', 'Disease', (179, 191))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('Loss', 'NegReg', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('sarcoma', 'Disease', (217, 224))	('deletions', 'Var', (89, 98))	('AKT', 'Gene', '207', (47, 50))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('lung cancer', 'Disease', (193, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('mutations', 'Var', (76, 85))	('PTEN', 'Gene', (8, 12))	('decreased', 'NegReg', (124, 133))
30986	32376723	In melanoma, PTEN deletions have been associated with reduced T-cell infiltration.	('reduced', 'NegReg', (54, 61))	('T-cell infiltration', 'CPA', (62, 81))	('reduced T-cell', 'Phenotype', 'HP:0005403', (54, 68))	('deletions', 'Var', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('PTEN', 'Gene', (13, 17))	('melanoma', 'Disease', (3, 11))	('PTEN', 'Gene', '5728', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
30988	32376723	Paradoxically, PTEN mutations have not been associated with decreased intratumoral immune infiltration but rather with an increased leukocyte fraction across tumors, and an increased expression of immune-suppressive signature in glioblastoma.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (229, 241))	('PTEN', 'Gene', '5728', (15, 19))	('increased', 'PosReg', (173, 182))	('leukocyte fraction', 'MPA', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (75, 80))	('tumors', 'Disease', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('expression', 'MPA', (183, 193))	('increased leukocyte', 'Phenotype', 'HP:0001974', (122, 141))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutations', 'Var', (20, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (229, 241))	('tumor', 'Disease', (158, 163))	('PTEN', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('glioblastoma', 'Disease', (229, 241))
30989	32376723	Consistently, PTEN mutations were found to be associated with higher ICR score across cancers when PTEN mutational status was evaluated as a single variable.	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (19, 28))	('ICR score', 'MPA', (69, 78))	('higher', 'PosReg', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('PTEN', 'Gene', (99, 103))	('cancers', 'Disease', (86, 93))	('PTEN', 'Gene', '5728', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
30990	32376723	The lack of selection of PTEN mutations by the elastic model might be explained by the co-occurrence with mutations in other genes with higher coefficient selected by the model.	('PTEN', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('PTEN', 'Gene', '5728', (25, 29))
30991	32376723	Overall, these findings suggest a differential immune-regulatory role of PTEN mutations and deletions.	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (73, 77))	('deletions', 'Var', (92, 101))	('mutations', 'Var', (78, 87))
30996	32376723	As for the Hedgehog pathway, in breast cancer models, inhibition of this signaling induces a marked reduction in immune-suppressive innate and adaptive cells paralleled with an enrichment of cytotoxic immune cells.	('reduction', 'NegReg', (100, 109))	('breast cancer', 'Disease', (32, 45))	('inhibition', 'Var', (54, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
30998	32376723	In lung cancer mouse models, the deletion of Lkb1, an upstream modulator of AMPK pathway, was associated with decrease T-cell tumor infiltration, and impaired production of pro-inflammatory cytokines, which was mediated by induction of STAT3 and IL-6 secretion.	('Lkb1', 'Gene', '20869', (45, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('deletion', 'Var', (33, 41))	('STAT3', 'Gene', '20848', (236, 241))	('IL-6', 'Gene', (246, 250))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('production of pro-inflammatory cytokines', 'MPA', (159, 199))	('AMPK', 'Gene', (76, 80))	('AMPK', 'Gene', '5564', (76, 80))	('decrease T-cell tumor', 'Disease', (110, 131))	('decrease T-cell', 'Phenotype', 'HP:0005403', (110, 125))	('IL-6', 'Gene', '16193', (246, 250))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('STAT3', 'Gene', (236, 241))	('impaired', 'NegReg', (150, 158))	('lung cancer', 'Disease', (3, 14))	('Lkb1', 'Gene', (45, 49))	('decrease T-cell tumor', 'Disease', 'MESH:D016399', (110, 131))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
31004	32376723	Interestingly, MAP3K1 mutations were previously associated with low ICR in breast cancer in our previous work.	('ICR', 'MPA', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('MAP3K1', 'Gene', (15, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('MAP3K1', 'Gene', '4214', (15, 21))	('mutations', 'Var', (22, 31))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
31005	32376723	Remarkably, mutations of other genes of the RAS/MAPK pathways such as FGFR3 (previously associated with T-cell exclusion in bladder cancer and diminished leukocyte infiltration pan-cancer), EGFR, NRAS and KRAS were associated with a low ICR score, substantiating their potential role in mediating immune exclusion.	('EGFR', 'Gene', '1956', (190, 194))	('diminished leukocyte', 'Phenotype', 'HP:0001882', (143, 163))	('FGFR3', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('NRAS', 'Gene', '4893', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('FGFR3', 'Gene', '2261', (70, 75))	('KRAS', 'Gene', '3845', (205, 209))	('NRAS', 'Gene', (196, 200))	('EGFR', 'Gene', (190, 194))	('cancer', 'Disease', (181, 187))	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('cancer', 'Disease', (132, 138))	('KRAS', 'Gene', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('associated', 'Reg', (88, 98))	('ICR', 'Disease', (237, 240))
31008	32376723	Other mutations associated with the immune silent phenotype include WNT5A, corroborating the immune-suppressive role of the WNT ss catenin pathway  and GATA3, which was also previously associated with low leukocyte infiltration.	('GATA3', 'Gene', (152, 157))	('GATA3', 'Gene', '2625', (152, 157))	('WNT5A', 'Gene', '7474', (68, 73))	('low leukocyte', 'Phenotype', 'HP:0001882', (201, 214))	('associated', 'Reg', (16, 26))	('mutations', 'Var', (6, 15))	('WNT5A', 'Gene', (68, 73))
31009	32376723	Mutations of FKBP5, MAT2A, PPP2R5A, MECOM, SMAD2, MED17, ADAM10, PRKAR1A, DIS3, PRRX1, MFNG, TNPO1, KDM6A, IRF7, SUZ12, RPSAP58 and SF3B1 represent additional novel findings.	('ADAM10', 'Gene', (57, 63))	('PRRX1', 'Gene', '5396', (80, 85))	('RPSAP58', 'Gene', '388524', (120, 127))	('DIS3', 'Gene', (74, 78))	('MAT2A', 'Gene', (20, 25))	('MFNG', 'Gene', '4242', (87, 91))	('FKBP5', 'Gene', '2289', (13, 18))	('PRKAR1A', 'Gene', (65, 72))	('FKBP5', 'Gene', (13, 18))	('ADAM10', 'Gene', '102', (57, 63))	('SMAD2', 'Gene', (43, 48))	('PPP2R5A', 'Gene', (27, 34))	('SF3B1', 'Gene', '23451', (132, 137))	('IRF7', 'Gene', '3665', (107, 111))	('MFNG', 'Gene', (87, 91))	('Mutations', 'Var', (0, 9))	('TNPO1', 'Gene', (93, 98))	('KDM6A', 'Gene', '7403', (100, 105))	('MED17', 'Gene', (50, 55))	('PRKAR1A', 'Gene', '5573', (65, 72))	('PRRX1', 'Gene', (80, 85))	('DIS3', 'Gene', '22894', (74, 78))	('IRF7', 'Gene', (107, 111))	('MED17', 'Gene', '9440', (50, 55))	('PPP2R5A', 'Gene', '5525', (27, 34))	('MAT2A', 'Gene', '4144', (20, 25))	('TNPO1', 'Gene', '3842', (93, 98))	('SUZ12', 'Gene', (113, 118))	('RPSAP58', 'Gene', (120, 127))	('MECOM', 'Gene', (36, 41))	('KDM6A', 'Gene', (100, 105))	('MECOM', 'Gene', '2122', (36, 41))	('SF3B1', 'Gene', (132, 137))	('SMAD2', 'Gene', '4087', (43, 48))	('SUZ12', 'Gene', '23512', (113, 118))
31011	32376723	B2M mutations have been associated with disease progression following immune checkpoint therapy.	('B2M', 'Gene', (0, 3))	('disease', 'Disease', (40, 47))	('B2M', 'Gene', '567', (0, 3))	('associated with', 'Reg', (24, 39))	('mutations', 'Var', (4, 13))
31013	32376723	The occurrence of B2M mutations might indicate an early phase of immune editing, which however did not completely compromise the protective effect of the immunological pressure at this early phase of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('B2M', 'Gene', '567', (18, 21))	('mutations', 'Var', (22, 31))	('B2M', 'Gene', (18, 21))
31014	32376723	This is consistent with recent observations in colon cancer, in which immune-edited metastases have a decrease risk of relapse as compared with the non-immune edited ones.	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('metastases', 'Disease', (84, 94))	('decrease', 'NegReg', (102, 110))	('immune-edited', 'Var', (70, 83))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('relapse', 'CPA', (119, 126))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colon cancer', 'Disease', (47, 59))
31019	32376723	To compare cancer types based on the prognostic value of ICR, we categorized them into two groups: one for which ICR high was associated with increased OS and one for which ICR was associated with worse OS.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('increased', 'PosReg', (142, 151))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('ICR high', 'Var', (113, 121))	('cancer', 'Disease', (11, 17))
31034	32376723	The pan-cancer survival analysis of samples of ICR-neutral cancer types showed that for samples that coclustered with samples of ICR-enabled cancer types (the ICR beneficial cluster), ICR high was associated with significant prolonged survival.	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ICR high', 'Var', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('prolonged', 'PosReg', (225, 234))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
31035	32376723	In fact, the positive prognostic role of ICR was present also in a subset of samples with low proliferation and high mutational load but absent only in tumors with both low proliferation and low mutational load.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('high mutational load', 'Var', (112, 132))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
31037	32376723	We hypothesize that, in tumor with high mutational burden and/or high proliferative capacity, the high level of ICR captures a true protective antitumoral immune response, while in the other cases, such as in tumors dominated by cancer signaling, the high ICR captures a bystander, or heavily suppressed, lymphocyte infiltration with no protective effect.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (209, 215))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (229, 235))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutational', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
31091	30813777	Occasional tumor cells showed positivity for epithelial membrane antigen.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('positivity', 'Var', (30, 40))	('tumor', 'Disease', (11, 16))	('epithelial membrane antigen', 'Protein', (45, 72))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
31117	30813777	The typical radiological appearance of astroblastoma represent FLAIR images, heterogeneous hyperintense signal on T2-weighted sequences (T2WS), and hypointense to isointense on T1-weighted sequences (T1WS), as observed in our case.	('heterogeneous hyperintense signal', 'MPA', (77, 110))	('astroblastoma', 'Disease', (39, 52))	('hypointense', 'Var', (148, 159))	('astroblastoma', 'Disease', 'MESH:D018302', (39, 52))	('T2-weighted sequences', 'MPA', (114, 135))
31160	24202337	Epigenetic abnormalities can occur both as a cause and as a consequence of cancer.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('occur', 'Reg', (29, 34))	('Epigenetic abnormalities', 'Var', (0, 24))
31161	24202337	In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('epigenetic dysfunctions', 'Var', (29, 52))	('oncogenic transformation', 'CPA', (63, 87))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('drive', 'Reg', (57, 62))
31162	24202337	Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development.	('mutations', 'Var', (111, 120))	('FH', 'Gene', '2271', (151, 153))	('IDH', 'Gene', (159, 162))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('IDH', 'Gene', '3417', (159, 162))	('contribute', 'Reg', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('SDH', 'Gene', (146, 149))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
31165	24202337	Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas.	('epigenetic events', 'Var', (41, 58))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
31166	24202337	In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas.	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('mutations', 'Var', (80, 89))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))
31169	24202337	Notably, acetylation occurs on numerous histone tail lysines, including H3K9, H3K14, H3K18, H4K5, H4K8 and H4K12.	('H4K8', 'Var', (98, 102))	('acetylation', 'MPA', (9, 20))	('histone tail lysines', 'Protein', (40, 60))	('H3K9', 'Var', (72, 76))	('H3K14', 'Var', (78, 83))	('occurs', 'Reg', (21, 27))	('lysines', 'Chemical', 'MESH:D008239', (53, 60))	('H4K12', 'Var', (107, 112))	('H4K5', 'Var', (92, 96))	('H3K18', 'Var', (85, 90))
31179	24202337	Lysines may be mono-, di- or tri-methylated.	('tri-methylated', 'Var', (29, 43))	('di-', 'Var', (22, 25))	('Lysines', 'Chemical', 'MESH:D008239', (0, 7))	('mono-', 'Var', (15, 20))
31180	24202337	Although many lysine residues on the various histones are methylated, the best studied are H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20.	('H3K4', 'Var', (91, 95))	('lysine', 'Chemical', 'MESH:D008239', (14, 20))	('H3K9', 'Var', (97, 101))	('H3K36', 'Var', (110, 115))	('H3K27', 'Var', (103, 108))	('H3K79', 'Var', (117, 122))	('H4K20', 'Var', (128, 133))
31182	24202337	Numerous HKMTs have since been identified, the vast majority of which methylate lysines within the N-terminal tails.	('lysines', 'Chemical', 'MESH:D008239', (80, 87))	('methylate', 'Var', (70, 79))	('lysines', 'Protein', (80, 87))
31183	24202337	HKMTs tend to be relatively specific enzymes (for example SUV39H targets H3K9 and MLL targets H3K4).	('SUV39H', 'Gene', '6839', (58, 64))	('MLL', 'Gene', (82, 85))	('MLL', 'Gene', '4297', (82, 85))	('SUV39H', 'Gene', (58, 64))	('H3K9', 'Protein', (73, 77))	('H3K4', 'Var', (94, 98))
31190	24202337	Two years later another lysine demethylase JMJD2 that demethylates H3K9me3 and H3K36me3 was discovered.	('JMJD2', 'Gene', '9682', (43, 48))	('H3K36me3', 'Var', (79, 87))	('lysine', 'Chemical', 'MESH:D008239', (24, 30))	('JMJD2', 'Gene', (43, 48))	('H3K9me3', 'Protein', (67, 74))
31195	24202337	Methylation of DNA at cytosine residues within CpG dinucleotides occurs in genomes of most higher eukaryotes and is strongly correlated with transcriptional repression of imprinted genes as well as silencing of certain tissue-specific genes in mammals (Figure 1).	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (47, 64))	('tissue-specific genes', 'Gene', (219, 240))	('Methylation', 'Var', (0, 11))	('cytosine', 'Chemical', 'MESH:D003596', (22, 30))	('correlated with', 'Reg', (125, 140))	('silencing', 'MPA', (198, 207))	('imprinted genes', 'Gene', (171, 186))	('transcriptional repression', 'MPA', (141, 167))
31205	24202337	It has been suggested that the R882 DNMT3A mutations may alter functions of DNMT3A such as its ability to bind other proteins involved in transcriptional regulation and localization to chromatin regions containing methylated DNA.	('DNMT3A', 'Gene', (36, 42))	('DNMT3A', 'Gene', '1788', (36, 42))	('functions', 'MPA', (63, 72))	('alter', 'Reg', (57, 62))	('ability', 'MPA', (95, 102))	('R882', 'Var', (31, 35))	('mutations', 'Var', (43, 52))	('localization', 'MPA', (169, 181))	('bind', 'Interaction', (106, 110))	('DNMT3A', 'Gene', (76, 82))	('DNMT3A', 'Gene', '1788', (76, 82))
31207	24202337	Loss-of-function TET2 mutations were also identified in 20%-30% myeloid neoplasms.	('Loss-of-function', 'NegReg', (0, 16))	('TET2', 'Gene', '54790', (17, 21))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (64, 81))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (64, 81))	('myeloid neoplasms', 'Disease', (64, 81))	('mutations', 'Var', (22, 31))	('TET2', 'Gene', (17, 21))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))
31208	24202337	Cytogenetic studies, as well as next generation sequencing of various cancer genomes, have demonstrated recurrent translocations and/or coding mutations in a large number of lysine methyltransferases, including MMSET, EZH2, and MLL family members.	('lysine methyltransferases', 'Enzyme', (174, 199))	('MMSET', 'Gene', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('coding mutations', 'Var', (136, 152))	('translocations', 'Var', (114, 128))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('MMSET', 'Gene', '7468', (211, 216))	('lysine', 'Chemical', 'MESH:D008239', (174, 180))	('MLL', 'Gene', '4297', (228, 231))	('EZH2', 'Gene', '2146', (218, 222))	('cancer', 'Disease', (70, 76))	('MLL', 'Gene', (228, 231))	('EZH2', 'Gene', (218, 222))
31209	24202337	Follicular lymphomas contain recurrent mutations of the histone methyltransferase MLL2 in close to 90% of cases.	('Follicular lymphomas', 'Disease', (0, 20))	('histone methyltransferase', 'Gene', '56979', (56, 81))	('histone methyltransferase', 'Gene', (56, 81))	('mutations', 'Var', (39, 48))	('MLL2', 'Gene', (82, 86))	('lymphomas', 'Phenotype', 'HP:0002665', (11, 20))	('Follicular lymphomas', 'Disease', 'MESH:D008224', (0, 20))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('MLL2', 'Gene', '8085', (82, 86))
31211	24202337	Mutations affecting the Polycomb repressive complex (PRC) components, such as EZH2, can also affect histone modifications and have recently been reported.	('histone modifications', 'MPA', (100, 121))	('affect', 'Reg', (93, 99))	('PRC', 'Gene', (53, 56))	('Mutations', 'Var', (0, 9))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))
31216	24202337	Mutations in UTX, in particular, are prevalent in a large number of solid and hematological cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('prevalent', 'Reg', (37, 46))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('UTX', 'Gene', (13, 16))	('hematological cancers', 'Disease', 'MESH:D009369', (78, 99))	('hematological cancers', 'Disease', (78, 99))	('UTX', 'Gene', '7403', (13, 16))
31222	24202337	Interestingly, mutations in the genes coding for metabolic enzymes such as succinate dehydrogenase (SDH), fumarate hydratase (FH), isocitrate dehydrogenases 1/2 (IDH1/2) and phosphoglycerate dehydrogenase (PHGDH) have been reported in various tumors: paraganglioma, renal cancer and glioblastoma multiforme.	('succinate dehydrogenase', 'Gene', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('PHGDH', 'Gene', '26227', (206, 211))	('renal cancer', 'Disease', (266, 278))	('paraganglioma', 'Disease', (251, 264))	('PHGDH', 'Gene', (206, 211))	('paraganglioma', 'Disease', 'MESH:D010235', (251, 264))	('renal cancer', 'Phenotype', 'HP:0009726', (266, 278))	('glioblastoma multiforme', 'Disease', (283, 306))	('glioblastoma', 'Phenotype', 'HP:0012174', (283, 295))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (283, 306))	('mutations', 'Var', (15, 24))	('fumarate hydratase', 'Gene', (106, 124))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('succinate dehydrogenase', 'Gene', '6390', (75, 98))	('renal cancer', 'Disease', 'MESH:D007680', (266, 278))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('reported', 'Reg', (223, 231))	('paraganglioma', 'Phenotype', 'HP:0002668', (251, 264))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('fumarate hydratase', 'Gene', '2271', (106, 124))	('tumors', 'Disease', (243, 249))	('IDH1/2) and phosphoglycerate dehydrogenase', 'Gene', '26227;3417;3418', (162, 204))	('SDH', 'Gene', (100, 103))	('isocitrate', 'Chemical', 'MESH:C034219', (131, 141))	('FH', 'Gene', '2271', (126, 128))
31223	24202337	Mutations in IDH1 and IDH2 are also noted as recurrent mutations in a range of myeloid malignancies, most notably AML.	('AML', 'Disease', (114, 117))	('myeloid malignancies', 'Disease', (79, 99))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('AML', 'Disease', 'MESH:D015470', (114, 117))	('myeloid malignancies', 'Disease', 'MESH:D009369', (79, 99))
31224	24202337	Mutations in RET, NF1 (neurofibromatosis 1), VHL (the von Hippel-Lindau) and SDH genes are frequent in paragangliomas which are neuroendocrine tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('paragangliomas', 'Disease', 'MESH:D010235', (103, 117))	('paragangliomas', 'Phenotype', 'HP:0002668', (103, 117))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (23, 40))	('neurofibromatosis 1', 'Gene', '4763', (23, 42))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (103, 116))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('von Hippel-Lindau', 'Gene', '7428', (54, 71))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (128, 149))	('VHL', 'Disease', 'MESH:D006623', (45, 48))	('Mutations', 'Var', (0, 9))	('neurofibromatosis 1', 'Gene', (23, 42))	('RET', 'Gene', '5979', (13, 16))	('paragangliomas', 'Disease', (103, 117))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (128, 149))	('NF1', 'Gene', '4763', (18, 21))	('SDH', 'Gene', (77, 80))	('RET', 'Gene', (13, 16))	('frequent', 'Reg', (91, 99))	('VHL', 'Disease', (45, 48))	('von Hippel-Lindau', 'Gene', (54, 71))	('NF1', 'Gene', (18, 21))	('neuroendocrine tumors', 'Disease', (128, 149))
31235	24202337	Recent studies characterizing different GBM subgroups with regard to gene expression, DNA methylation or miRNA expression profiles indicate that besides genetic alterations, epigenetic modifications could be involved in the development and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('epigenetic modifications', 'Var', (174, 198))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('involved', 'Reg', (208, 216))
31237	24202337	Candidate gene approaches have demonstrated the hypermethylation of notable genes in GBM, including tumor suppressors, apoptosis machinery, suppressor of cytokine signaling family, members of Wnt-signaling pathway and hypomethylation of normally silenced genes such as CD133, MMP9 or IL8 (reviewed in) (Table 1).	('Wnt', 'Gene', '7471', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('Wnt', 'Gene', (192, 195))	('hypermethylation', 'Var', (48, 64))	('IL8', 'Gene', (284, 287))	('CD133', 'Gene', (269, 274))	('IL8', 'Gene', '3576', (284, 287))	('MMP9', 'Gene', (276, 280))	('CD133', 'Gene', '8842', (269, 274))	('GBM', 'Gene', (85, 88))	('MMP9', 'Gene', '4318', (276, 280))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('hypomethylation', 'Var', (218, 233))
31238	24202337	To date, the strongest evidence that epigenetic alterations are associated with patient survival is provided by the methylation-associated silencing of the MGMT gene in gliomas.	('methylation-associated', 'Var', (116, 138))	('associated', 'Reg', (64, 74))	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('silencing', 'NegReg', (139, 148))	('epigenetic alterations', 'Var', (37, 59))	('MGMT', 'Gene', '4255', (156, 160))	('MGMT', 'Gene', (156, 160))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('patient', 'Species', '9606', (80, 87))
31241	24202337	Recent findings related to recurrent mutations in the genes encoding the metabolic enzymes IDH1 and IDH2 have broad implications for the Jumonji class of demethylases, which use a-ketoglutarate (a-KG).	('a-ketoglutarate', 'Chemical', '-', (178, 193))	('IDH1', 'Gene', (91, 95))	('mutations', 'Var', (37, 46))	('IDH2', 'Gene', (100, 104))	('IDH1', 'Gene', '3417', (91, 95))	('IDH2', 'Gene', '3418', (100, 104))
31243	24202337	These mutations manifest in a neomorphic enzymatic activity which results in the NADPH-dependent reduction of a-KG to 2-hydroxyglutarate (2-HG).	('reduction', 'NegReg', (97, 106))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (118, 136))	('mutations', 'Var', (6, 15))	('NADPH', 'Chemical', 'MESH:D009249', (81, 86))
31244	24202337	Alternative mechanisms include: increased angiogenesis due to accumulation of hypoxia inducible factor (HIF)-1alpha; a glioma CpG island methylator phenotype induced by inhibition of TET2, and increased vulnerability to oxidative stress due to depletion of antioxidants.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('TET2', 'Gene', (183, 187))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('accumulation', 'PosReg', (62, 74))	('oxidative stress', 'Phenotype', 'HP:0025464', (220, 236))	('glioma', 'Disease', (119, 125))	('increased', 'PosReg', (32, 41))	('angiogenesis', 'CPA', (42, 54))	('hypoxia inducible factor (HIF)-1alpha', 'Gene', '3091', (78, 115))	('TET2', 'Gene', '54790', (183, 187))	('inhibition', 'Var', (169, 179))
31246	24202337	Loss-of-function mutations and deletions of NSD1 gene have been found in Sotos syndrome, which is an autosomal dominant condition characterized by overgrowth (tall stature and macrocephaly) and an increased risk of tumorigenesis.	('Sotos syndrome', 'Disease', 'MESH:D058495', (73, 87))	('Loss-of-function', 'NegReg', (0, 16))	('Sotos syndrome', 'Disease', (73, 87))	('macrocephaly', 'Phenotype', 'HP:0000256', (176, 188))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('NSD1', 'Gene', '64324', (44, 48))	('overgrowth', 'Phenotype', 'HP:0001548', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('deletions', 'Var', (31, 40))	('tall stature', 'Phenotype', 'HP:0000098', (159, 171))	('macrocephaly', 'Disease', 'MESH:D058627', (176, 188))	('tumor', 'Disease', (215, 220))	('NSD1', 'Gene', (44, 48))	('mutations', 'Var', (17, 26))	('macrocephaly', 'Disease', (176, 188))
31248	24202337	The epigenetic inactivation of NSD1 in transformed cells resulted in diminished methylation of the histone lysine residues H4-K20 and H3-K36.	('lysine', 'Chemical', 'MESH:D008239', (107, 113))	('NSD1', 'Gene', '64324', (31, 35))	('methylation', 'MPA', (80, 91))	('histone', 'Protein', (99, 106))	('epigenetic inactivation', 'Var', (4, 27))	('NSD1', 'Gene', (31, 35))	('H3-K36', 'Protein', (134, 140))	('diminished', 'NegReg', (69, 79))	('H4-K20', 'Protein', (123, 129))
31249	24202337	The IDH1 or IDH2 genes are mutated in 50%-80% of astrocytomas, oligodendrogliomas or oligoastrocytomas of grades II and III, and secondary glioblastomas.	('astrocytomas', 'Disease', (90, 102))	('IDH1', 'Gene', '3417', (4, 8))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('glioblastomas', 'Phenotype', 'HP:0012174', (139, 152))	('astrocytomas', 'Disease', 'MESH:D001254', (49, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (49, 60))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (63, 81))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('IDH2', 'Gene', (12, 16))	('oligoastrocytomas', 'Disease', (85, 102))	('mutated', 'Var', (27, 34))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('glioblastomas', 'Disease', (139, 152))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (85, 102))	('IDH2', 'Gene', '3418', (12, 16))	('IDH1', 'Gene', (4, 8))	('oligodendrogliomas', 'Disease', (63, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (139, 152))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('astrocytomas', 'Disease', (49, 61))
31250	24202337	IDH1 and IDH2 mutations are heterozygous, affect only a single codon: the 132 amino acid in the IDH1 and the analogous amino acid (172) of the IDH2 gene, and rarely occur together.	('affect', 'Reg', (42, 48))	('IDH2', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (96, 100))	('IDH2', 'Gene', (143, 147))	('IDH2', 'Gene', '3418', (9, 13))	('IDH2', 'Gene', '3418', (143, 147))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', (96, 100))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
31251	24202337	Higher IDH1 mutation rates are seen in grade II and III astrocytomas and oligodendrogliomas.	('IDH1', 'Gene', '3417', (7, 11))	('grade II', 'Disease', (39, 47))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (56, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('Higher', 'PosReg', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('astrocytoma', 'Phenotype', 'HP:0009592', (56, 67))	('II astrocytomas', 'Disease', 'MESH:D001254', (53, 68))	('mutation', 'Var', (12, 20))	('IDH1', 'Gene', (7, 11))	('II astrocytomas', 'Disease', (53, 68))
31253	24202337	Similar results were reported by Hartmann et al., who detected 716 IDH1 mutations and 31 IDH2 mutations (Table 2).	('mutations', 'Var', (72, 81))	('IDH1', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (67, 71))	('IDH2', 'Gene', (89, 93))	('IDH2', 'Gene', '3418', (89, 93))
31255	24202337	Gliomas with IDH1/2 mutations always harbor either TP53 mutations or total 1p/19q loss.	('TP53', 'Gene', '7157', (51, 55))	('mutations', 'Var', (56, 65))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('TP53', 'Gene', (51, 55))	('harbor', 'Reg', (37, 43))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('IDH1/2', 'Gene', (13, 19))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('loss', 'NegReg', (82, 86))	('Gliomas', 'Disease', (0, 7))	('mutations', 'Var', (20, 29))	('1p/19q', 'CPA', (75, 81))
31257	24202337	Glioblastomas with the CpG island methylator phenotype constitute a subset of tumors with extensive epigenomic aberrations and distinct biology.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('CpG island methylator', 'Var', (23, 44))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('Glioblastomas', 'Disease', (0, 13))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))
31258	24202337	Assessment of the epigenome of a large set of intermediate-grade gliomas demonstrates a CpG island methylator phenotype which is highly dependent on the presence of IDH mutation (IDH1-R132).	('gliomas', 'Disease', (65, 72))	('mutation', 'Var', (169, 177))	('IDH', 'Gene', (165, 168))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (165, 168))	('IDH', 'Gene', '3417', (179, 182))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH1', 'Gene', (179, 183))	('IDH1', 'Gene', '3417', (179, 183))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
31259	24202337	Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that resembles the CpG island methylator phenotype in low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('induces', 'Reg', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('methylome', 'MPA', (146, 155))	('histone', 'Protein', (74, 81))	('alters', 'Reg', (58, 64))	('IDH1', 'Gene', (23, 27))	('human', 'Species', '9606', (41, 46))	('reshapes', 'Reg', (133, 141))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('mutant', 'Var', (16, 22))	('gliomas', 'Disease', (233, 240))	('IDH1', 'Gene', '3417', (23, 27))	('DNA hypermethylation', 'MPA', (107, 127))	('specific', 'MPA', (65, 73))
31260	24202337	The epigenomic alterations produced by a mutant IDH1 activate gene expression programs resembling proneural glioblastomas but not other glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (108, 121))	('glioblastomas', 'Phenotype', 'HP:0012174', (136, 149))	('mutant', 'Var', (41, 47))	('IDH1', 'Gene', '3417', (48, 52))	('glioblastomas', 'Disease', (108, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('glioblastomas', 'Disease', 'MESH:D005909', (136, 149))	('glioblastomas', 'Phenotype', 'HP:0012174', (108, 121))	('epigenomic', 'MPA', (4, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('IDH1', 'Gene', (48, 52))	('glioblastomas', 'Disease', (136, 149))	('gene expression programs', 'MPA', (62, 86))	('activate', 'PosReg', (53, 61))
31261	24202337	As IDH1/2 mutations are frequent (>80%) in secondary glioblastomas that have progressed from low-grade or anaplastic astrocytomas, it suggests that these tumors share a common progenitor cell population.	('glioblastomas', 'Phenotype', 'HP:0012174', (53, 66))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('IDH1/2', 'Gene', '3417;3418', (3, 9))	('glioblastomas', 'Disease', 'MESH:D005909', (53, 66))	('glioblastomas', 'Disease', (53, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (117, 129))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('IDH1/2', 'Gene', (3, 9))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('astrocytomas', 'Disease', (117, 129))	('frequent', 'Reg', (24, 32))
31262	24202337	Primary glioblastomas with IDH1/2 mutations are very rare (<5%); show age distribution and genetic profiles similar to secondary glioblastomas, therefore could be misclassified.	('glioblastomas', 'Disease', 'MESH:D005909', (8, 21))	('glioblastomas', 'Phenotype', 'HP:0012174', (129, 142))	('glioblastomas', 'Disease', 'MESH:D005909', (129, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('glioblastomas', 'Disease', (8, 21))	('IDH1/2', 'Gene', '3417;3418', (27, 33))	('glioblastomas', 'Disease', (129, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('Primary glioblastomas', 'Disease', (0, 21))	('IDH1/2', 'Gene', (27, 33))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('Primary glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('mutations', 'Var', (34, 43))
31265	24202337	Methylation profiling revealed that GBM samples with low grade glioma-like hypermethylated profiles had a high rate of IDH1 mutations and a better outcome.	('mutations', 'Var', (124, 133))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('IDH1', 'Gene', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', '3417', (119, 123))	('glioma', 'Disease', (63, 69))
31267	24202337	The concept of sequential molecular evolution of the IDH1 mutant glioblastoma has been conceived.	('mutant', 'Var', (58, 64))	('IDH1', 'Gene', (53, 57))	('glioblastoma', 'Disease', (65, 77))	('IDH1', 'Gene', '3417', (53, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
31268	24202337	The observed patterns of DNA changes, DNA methylation, and copy number alterations suggest an ordered molecular evolution of IDH1(R132MUT) GBM in which the appearance of mutant IDH1 protein in spatially and temporally restricted neural precursors is an initial event, followed by production of TP53 mutant protein, and finally by copy number alterations of PTEN and EGFR.	('PTEN', 'Gene', '5728', (357, 361))	('EGFR', 'Gene', (366, 370))	('protein', 'Protein', (182, 189))	('IDH1', 'Gene', (177, 181))	('IDH1', 'Gene', '3417', (125, 129))	('TP53', 'Gene', '7157', (294, 298))	('protein', 'Protein', (306, 313))	('PTEN', 'Gene', (357, 361))	('mutant', 'Var', (170, 176))	('IDH1', 'Gene', '3417', (177, 181))	('EGFR', 'Gene', '1956', (366, 370))	('TP53', 'Gene', (294, 298))	('IDH1', 'Gene', (125, 129))
31269	24202337	However, immunohistochemical analysis of the global pattern of H3K4me2, H4K20me3, H3K9Ac and H3K18Ac in resected 230 glioma samples showed that histone modifications may have prognostic relevance in gliomas, as some correlations with progression free- and overall survival of glioma patients were reported.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('glioma', 'Disease', (276, 282))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('patients', 'Species', '9606', (283, 291))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (276, 282))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('H3K18Ac', 'Var', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))	('H3K9Ac', 'Var', (82, 88))	('glioma', 'Disease', (199, 205))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (199, 206))	('glioma', 'Disease', (117, 123))	('H3K4me2', 'Var', (63, 70))	('H4K20me3', 'Var', (72, 80))
31274	24202337	In a recent immunohistochemical study, H3K9me3 positivity was found in all grades of astrocytic tumors and showed significant relationship with the IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (232, 245))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('relationship', 'Reg', (126, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (216, 227))	('II astrocytomas', 'Disease', 'MESH:D001254', (179, 194))	('II astrocytomas', 'Disease', (179, 194))	('glioblastomas', 'Phenotype', 'HP:0012174', (232, 245))	('IDH', 'Gene', (148, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (182, 193))	('astrocytic tumors', 'Disease', (85, 102))	('found', 'Reg', (62, 67))	('II astrocytomas', 'Disease', 'MESH:D001254', (213, 228))	('astrocytic tumors', 'Disease', 'MESH:D001254', (85, 102))	('II astrocytomas', 'Disease', (213, 228))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('glioblastomas', 'Disease', (232, 245))	('glioblastoma', 'Phenotype', 'HP:0012174', (232, 244))	('IDH', 'Gene', '3417', (148, 151))	('H3K9me3 positivity', 'Var', (39, 57))
31285	24202337	Pharmacologic and shRNA-mediated depletion of EZH2 in glioblastoma cancer stem cells reduced their ability to form new spheres in vitro and new tumors in vivo.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('ability', 'CPA', (99, 106))	('depletion', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('glioblastoma cancer', 'Disease', 'MESH:D005909', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('EZH2', 'Gene', (46, 50))	('glioblastoma cancer', 'Disease', (54, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('EZH2', 'Gene', '2146', (46, 50))	('reduced', 'NegReg', (85, 92))
31287	24202337	Two recent studies have demonstrated recurrent somatic mutations in genes encoding the replication-independent histone H3 variant H3.3 (H3F3A) and the canonical histone H3.1 (HIST1H3B) in 30% of pediatric glioblastomas and only 3.4% of adult GBM.	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('mutations', 'Var', (55, 64))	('H3F3A', 'Gene', (136, 141))	('HIST1H3B', 'Gene', (175, 183))	('H3 variant H3.3', 'CellLine', 'CVCL:F498', (119, 134))	('HIST1H3B', 'Gene', '8358', (175, 183))	('glioblastomas', 'Phenotype', 'HP:0012174', (205, 218))	('pediatric glioblastomas', 'Disease', (195, 218))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (195, 218))	('H3F3A', 'Gene', '3020', (136, 141))	('histone H3.1', 'Gene', '8358', (161, 173))	('histone H3.1', 'Gene', (161, 173))
31288	24202337	These heterozygous mutations are clustered and result in amino acid substitutions at two critical residues in the tail of histone H3 (K27M, G34R/G34V).	('G34R', 'Var', (140, 144))	('K27M', 'Mutation', 'p.K27M', (134, 138))	('G34R', 'SUBSTITUTION', 'None', (140, 144))	('result in', 'Reg', (47, 56))	('G34V', 'Mutation', 'p.G34V', (145, 149))	('amino acid substitutions', 'Var', (57, 81))	('K27M', 'Var', (134, 138))	('substitutions', 'Var', (68, 81))
31289	24202337	The H3 K27M mutation alters the ability of this critical residue to be both methylated and acetylated.	('methylated', 'MPA', (76, 86))	('acetylated', 'MPA', (91, 101))	('K27M', 'Mutation', 'p.K27M', (7, 11))	('alters', 'Reg', (21, 27))	('H3 K27M', 'Var', (4, 11))	('ability', 'MPA', (32, 39))
31290	24202337	Tumors carrying the H3 K27M and G34R/G34V mutations had globally diminished trimethylation at histone H3 K27, distinct gene expression profiles.	('trimethylation at', 'MPA', (76, 93))	('K27M', 'Mutation', 'p.K27M', (23, 27))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('G34R', 'Var', (32, 36))	('G34R', 'SUBSTITUTION', 'None', (32, 36))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('diminished', 'NegReg', (65, 75))	('G34V', 'Mutation', 'p.G34V', (37, 41))	('H3 K27M', 'Var', (20, 27))
31292	24202337	H3.3K27M mutations alone are not transforming and H3.3K27M is unable to promote glioma even in a p53 null background, suggesting that other genetic events are needed.	('glioma', 'Disease', (80, 86))	('H3.3K27M', 'Var', (0, 8))	('p53', 'Gene', (97, 100))	('p53', 'Gene', '7157', (97, 100))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('promote', 'PosReg', (72, 79))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('H3.3K27M', 'Var', (50, 58))
31293	24202337	The mutant histone H3 may act as a selective inhibitor of the PRC2 chromatin-modifying complex by binding and presumably sequestering it contributes to the etiology of pediatric glioblastomas.	('binding', 'Interaction', (98, 105))	('pediatric glioblastomas', 'Disease', (168, 191))	('mutant', 'Var', (4, 10))	('contributes', 'Reg', (137, 148))	('glioblastomas', 'Phenotype', 'HP:0012174', (178, 191))	('histone H3', 'Protein', (11, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (168, 191))	('sequestering', 'NegReg', (121, 133))
31294	24202337	Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein) genes that encode two subunits of a chromatin remodeling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of pediatric GBMs.	('mental retardation', 'Phenotype', 'HP:0001249', (38, 56))	('ATRX', 'Gene', (13, 17))	('thalassaemia/mental retardation syndrome X-linked', 'Disease', (25, 74))	('DAXX', 'Gene', '1616', (80, 84))	('H3.3', 'Gene', (197, 201))	('Mutations', 'Var', (0, 9))	('thalassaemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (25, 74))	('DAXX', 'Gene', (80, 84))	('H3.3', 'Gene', '3020', (197, 201))
31295	24202337	Tumors with mutations in the ATRX/DAXX genes harbored a G34R or G34V H3.3 mutation in a majority of cases.	('G34V', 'Var', (64, 68))	('DAXX', 'Gene', (34, 38))	('H3.3', 'Gene', '3020', (69, 73))	('mutations', 'Var', (12, 21))	('G34R', 'Mutation', 'rs1057519902', (56, 60))	('G34R', 'Var', (56, 60))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DAXX', 'Gene', '1616', (34, 38))	('H3.3', 'Gene', (69, 73))	('G34V', 'Mutation', 'p.G34V', (64, 68))
31296	24202337	Tumors with mutations in H3F3A/ATRX/DAXX genes were associated with the increased length of telomeres and genomic instability.	('genomic instability', 'CPA', (106, 125))	('increased', 'PosReg', (72, 81))	('mutations', 'Var', (12, 21))	('DAXX', 'Gene', '1616', (36, 40))	('H3F3A', 'Gene', '3020', (25, 30))	('Tumors', 'Disease', (0, 6))	('length', 'MPA', (82, 88))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('H3F3A', 'Gene', (25, 30))	('DAXX', 'Gene', (36, 40))
31297	24202337	Another study using whole exome sequencing in four low grade astrocytomas, followed by focused resequencing in an additional 28 samples found a high incidence of mutations in the ATRX gene.	('astrocytomas', 'Disease', 'MESH:D001254', (61, 73))	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('mutations', 'Var', (162, 171))	('ATRX', 'Gene', (179, 183))	('astrocytomas', 'Disease', (61, 73))
31298	24202337	ATRX mutations were entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q co-deletion, the molecular hallmark of oligodendroglioma.	('IDH', 'Gene', '3417', (43, 46))	('mutation', 'Var', (91, 99))	('astrocytic differentiation', 'CPA', (104, 130))	('oligodendroglioma', 'Disease', (206, 223))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('ATRX', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (86, 90))	('oligodendroglioma', 'Disease', 'MESH:D009837', (206, 223))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('IDH', 'Gene', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('correlated', 'Reg', (70, 80))
31300	24202337	FUBP1 mutations may lead to activation of a MYC oncogene.	('MYC oncogene', 'Gene', (44, 56))	('FUBP1', 'Gene', (0, 5))	('FUBP1', 'Gene', '8880', (0, 5))	('lead to', 'Reg', (20, 27))	('activation', 'PosReg', (28, 38))	('mutations', 'Var', (6, 15))
31303	24202337	The mutational analysis of 363 brain tumors reported the distribution of ATRX, CIC (homolog of the Drosophila capicua gene), and FUBP1 mutations in gliomas.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('FUBP1', 'Gene', (129, 134))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('CIC', 'Gene', (79, 82))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('mutations', 'Var', (135, 144))	('Drosophila', 'Species', '7227', (99, 109))	('ATRX', 'Gene', (73, 77))	('brain tumors', 'Phenotype', 'HP:0030692', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('FUBP1', 'Gene', '8880', (129, 134))	('capicua gene', 'Gene', '53560', (110, 122))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('brain tumors', 'Disease', 'MESH:D001932', (31, 43))	('capicua gene', 'Gene', (110, 122))	('brain tumors', 'Disease', (31, 43))
31304	24202337	ATRX was frequently mutated in grade II-III adult astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%).	('glioblastomas', 'Phenotype', 'HP:0012174', (109, 122))	('II-III adult astrocytomas', 'Disease', (37, 62))	('II-III adult astrocytomas', 'Disease', 'MESH:C535354', (37, 62))	('ATRX', 'Gene', (0, 4))	('glioblastomas', 'Disease', 'MESH:D005909', (109, 122))	('oligoastrocytomas', 'Disease', (70, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('glioblastomas', 'Disease', (109, 122))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (70, 87))	('adult astrocytomas', 'Phenotype', 'HP:0009592', (44, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('mutated', 'Var', (20, 27))
31305	24202337	ATRX mutations were found to be associated with IDH1 mutations and with an alternative lengthening of telomeres.	('ATRX', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (48, 52))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (53, 62))	('associated', 'Reg', (32, 42))	('IDH1', 'Gene', (48, 52))
31306	24202337	CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas (10%).	('FUBP1', 'Gene', (8, 13))	('mutations', 'Var', (14, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (129, 140))	('oligodendrogliomas', 'Disease', (47, 65))	('astrocytomas or oligoastrocytomas', 'Disease', (108, 141))	('astrocytomas or oligoastrocytomas', 'Disease', 'MESH:D001254', (108, 141))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('FUBP1', 'Gene', '8880', (8, 13))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (47, 65))	('CIC', 'Gene', (0, 3))
31311	24202337	Decreased RRP22 expression was in part explained by 5'-CpG island hypermethylation and acetylated histone H3 and H4.	('acetylated', 'MPA', (87, 97))	('hypermethylation', 'Var', (66, 82))	('RRP22', 'Gene', '10633', (10, 15))	('Decreased', 'NegReg', (0, 9))	('RRP22', 'Gene', (10, 15))	('expression', 'MPA', (16, 26))
31312	24202337	In primary human glioblastomas, the increased levels of H3K9me3-bound and the decreased levels of pan-Ac-H3-bound RRP22 were observed as compared to non-neoplastic brain tissue.	('neoplastic brain', 'Phenotype', 'HP:0030692', (153, 169))	('RRP22', 'Gene', (114, 119))	('human', 'Species', '9606', (11, 16))	('levels', 'MPA', (88, 94))	('glioblastomas', 'Phenotype', 'HP:0012174', (17, 30))	('levels', 'MPA', (46, 52))	('glioblastomas', 'Disease', 'MESH:D005909', (17, 30))	('increased', 'PosReg', (36, 45))	('RRP22', 'Gene', '10633', (114, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (17, 29))	('H3K9me3-bound', 'Var', (56, 69))	('glioblastomas', 'Disease', (17, 30))	('decreased', 'NegReg', (78, 87))
31313	24202337	It shows that 5'-CpG island hypermethylation and histone modifications may contribute to the frequent and prognostically unfavorable transcriptional down-regulation of RRP22 in malignant gliomas.	('down-regulation', 'NegReg', (149, 164))	('hypermethylation', 'Var', (28, 44))	('RRP22', 'Gene', '10633', (168, 173))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('modifications', 'Var', (57, 70))	('RRP22', 'Gene', (168, 173))	('malignant gliomas', 'Disease', (177, 194))	('malignant gliomas', 'Disease', 'MESH:D005910', (177, 194))
31314	24202337	As epigenetic modifications by its nature are reversible, therefore changes in the epigenome associated with cancer are potentially reversible.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('epigenetic modifications', 'Var', (3, 27))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
31317	24202337	Indeed, HDAC inhibitors have been found to be particularly effective in inhibiting tumor growth, promoting apoptosis and inducing differentiation, at least in part via the reactivation of certain tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (83, 88))	('inhibitors', 'Var', (13, 23))	('promoting', 'PosReg', (97, 106))	('inducing', 'Reg', (121, 129))	('inhibiting', 'NegReg', (72, 82))	('HDAC', 'Gene', (8, 12))	('HDAC', 'Gene', '9734', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('differentiation', 'CPA', (130, 145))	('apoptosis', 'CPA', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
31320	24202337	For example the histone deacetylation inhibitor, suberoylanilide hydroxamic acid crossed the blood-brain barrier, inhibited the proliferation of intracranial gliomas and increased mice survival.	('suberoylanilide hydroxamic acid', 'Var', (49, 80))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('intracranial gliomas', 'Disease', (145, 165))	('mice survival', 'CPA', (180, 193))	('increased', 'PosReg', (170, 179))	('intracranial gliomas', 'Disease', 'MESH:D005910', (145, 165))	('mice', 'Species', '10090', (180, 184))	('suberoylanilide hydroxamic acid', 'Chemical', 'MESH:D000077337', (49, 80))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('inhibited', 'NegReg', (114, 123))
31322	24202337	Blockade of a mutant IDH1 impaired the growth of IDH1-mutant, but not IDH1-wild-type, glioma cells.	('glioma', 'Disease', (86, 92))	('IDH1', 'Gene', '3417', (49, 53))	('growth', 'MPA', (39, 45))	('mutant', 'Var', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('IDH1', 'Gene', '3417', (70, 74))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('impaired', 'NegReg', (26, 34))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (21, 25))	('IDH1', 'Gene', (49, 53))	('IDH1', 'Gene', (70, 74))
31323	24202337	Interestingly, inhibition of a mutant IDH1 did not induce detectable changes in genome-wide DNA methylation that suggests additional growth supporting mechanisms beyond well-characterized epigenetic effects of a mutant IDH1.	('IDH1', 'Gene', '3417', (219, 223))	('mutant', 'Var', (31, 37))	('IDH1', 'Gene', '3417', (38, 42))	('IDH1', 'Gene', (38, 42))	('IDH1', 'Gene', (219, 223))
31324	24202337	The study provided a proof-of-concept that mutant IDHs are therapeutically targetable, and that their effects are reversible.	('mutant', 'Var', (43, 49))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))
31326	24202337	Occurrence of somatic mutations in genes encoding the replication-independent histone H3 variant H3.3 and the canonical histone H3.1, the presence of mutant IDH1 protein in spatially and temporally restricted neural precursors, deregulated expression/activity of epigenetic enzymes may lead to aberrant histone modification and DNA methylation profiles which are intimately linked to glioma pathology.	('histone H3.1', 'Gene', (120, 132))	('glioma', 'Phenotype', 'HP:0009733', (384, 390))	('H3 variant H3.3', 'CellLine', 'CVCL:F498', (86, 101))	('aberrant histone modification', 'MPA', (294, 323))	('expression/activity', 'MPA', (240, 259))	('protein', 'Protein', (162, 169))	('lead to', 'Reg', (286, 293))	('IDH1', 'Gene', (157, 161))	('mutations', 'Var', (22, 31))	('glioma pathology', 'Disease', (384, 400))	('IDH1', 'Gene', '3417', (157, 161))	('histone H3.1', 'Gene', '8358', (120, 132))	('glioma pathology', 'Disease', 'MESH:D005910', (384, 400))	('epigenetic', 'Enzyme', (263, 273))	('mutant', 'Var', (150, 156))	('deregulated', 'Var', (228, 239))	('DNA methylation profiles', 'MPA', (328, 352))
31328	24202337	The high frequency (>80%) of IDH1/2 mutations in secondary glioblastomas which have progressed from low-grade gliomas, suggests that these tumors share a common progenitor cell population which through sequential molecular evolution gives rise to the IDH1 mutant glioblastoma.	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('gives rise', 'Reg', (233, 243))	('IDH1/2', 'Gene', '3417;3418', (29, 35))	('glioblastomas', 'Phenotype', 'HP:0012174', (59, 72))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('mutant', 'Var', (256, 262))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('IDH1/2', 'Gene', (29, 35))	('glioblastoma', 'Disease', (59, 71))	('IDH1', 'Gene', (251, 255))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioblastomas', 'Disease', (59, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (263, 275))	('IDH1', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('glioblastomas', 'Disease', 'MESH:D005909', (59, 72))	('tumors', 'Disease', (139, 145))	('glioblastoma', 'Disease', (263, 275))	('IDH1', 'Gene', '3417', (251, 255))	('gliomas', 'Disease', (110, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (263, 275))	('mutations', 'Var', (36, 45))	('IDH1', 'Gene', '3417', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (139, 145))
31329	24202337	The observed patterns of DNA changes, DNA methylation and copy number alterations suggest molecular evolution in which the appearance of mutant IDH1 protein in spatially and temporally restricted neural precursors is an initial event, followed by production of TP53 mutant protein, and finally by copy number alterations of PTEN and EGFR.	('EGFR', 'Gene', '1956', (333, 337))	('EGFR', 'Gene', (333, 337))	('TP53', 'Gene', '7157', (261, 265))	('PTEN', 'Gene', (324, 328))	('protein', 'Protein', (149, 156))	('PTEN', 'Gene', '5728', (324, 328))	('TP53', 'Gene', (261, 265))	('IDH1', 'Gene', (144, 148))	('protein', 'Protein', (273, 280))	('mutant', 'Var', (137, 143))	('IDH1', 'Gene', '3417', (144, 148))
31330	24202337	It suggests a causative role of epigenetic deregulation in pathobiology of glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (75, 88))	('epigenetic deregulation', 'Var', (32, 55))	('glioblastomas', 'Disease', 'MESH:D005909', (75, 88))	('glioblastomas', 'Disease', (75, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))
31332	24202337	Though, there are a few studies testing the impact of epigenetic inhibitors on glioblastomas, some of them show promising results and undoubtedly will lead to further preclinical and clinical studies of those compounds in glioblastoma therapy.	('glioblastoma', 'Disease', (222, 234))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (222, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (222, 234))	('lead', 'Reg', (151, 155))	('glioblastoma', 'Disease', (79, 91))	('glioblastomas', 'Disease', 'MESH:D005909', (79, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('epigenetic inhibitors', 'Var', (54, 75))	('glioblastomas', 'Disease', (79, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))
31342	26366972	The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted.	('II tumors', 'Disease', 'MESH:D009369', (145, 154))	('II gliomas', 'Disease', (44, 54))	('tumors', 'Disease', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('MIB-1', 'Gene', (10, 15))	('II gliomas', 'Disease', 'MESH:D005910', (44, 54))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('higher', 'PosReg', (59, 65))	('MIB-1', 'Gene', '57534', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('fluorescing', 'Var', (25, 36))	('II tumors', 'Disease', (145, 154))
31396	26366972	Of 61 patients with grade III gliomas, 37 (60.7%) showed MGMT promoter methylation.	('methylation', 'Var', (71, 82))	('II gliomas', 'Disease', (27, 37))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('MGMT', 'Gene', '4255', (57, 61))	('patients', 'Species', '9606', (6, 14))	('MGMT', 'Gene', (57, 61))	('II gliomas', 'Disease', 'MESH:D005910', (27, 37))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
31397	26366972	A total of 65% of grade II tumors showed IDH1 (R132H) mutations compared with only 49% of grade III tumors and none of the GBMs.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('III tumors', 'Disease', 'MESH:D009369', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('II tumors', 'Disease', 'MESH:D009369', (24, 33))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('III tumors', 'Disease', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('II tumors', 'Disease', (24, 33))	('IDH1', 'Gene', (41, 45))	('R132H', 'Mutation', 'rs121913500', (47, 52))	('IDH1', 'Gene', '3417', (41, 45))	('II tumors', 'Disease', 'MESH:D009369', (97, 106))
31416	26366972	No relationship was noted between fluorescence and IDH mutations, 1p19q co-deletions, or MGMT promotor methylation.	('MGMT', 'Gene', (89, 93))	('fluoresce', 'Chemical', '-', (34, 43))	('IDH', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))	('IDH', 'Gene', '3417', (51, 54))	('1p19q', 'Var', (66, 71))	('MGMT', 'Gene', '4255', (89, 93))
31465	26366972	Their series also included patients with patchy, weak, or focal fluorescence termed tumors with "nonsignificant" enhancement.	('focal', 'Var', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patients', 'Species', '9606', (27, 35))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('fluoresce', 'Chemical', '-', (64, 73))
31472	26366972	Although a correlation between fluorescence and 1p19q co-deletion or MGMT promoter methylation would appear unexpected, a correlation between fluorescence and IDH mutations could be hypothetically be possible.	('MGMT', 'Gene', '4255', (69, 73))	('IDH', 'Gene', (159, 162))	('MGMT', 'Gene', (69, 73))	('fluoresce', 'Chemical', '-', (142, 151))	('fluoresce', 'Chemical', '-', (31, 40))	('IDH', 'Gene', '3417', (159, 162))	('1p19q co-deletion', 'Var', (48, 65))
31475	26366972	Thus, tumors with IDH mutations might have demonstrated differences regarding protoporphyrin IX synthesis, possibly upregulation of this important pathway in response to a lower physiological availability of 5-ALA.	('IDH', 'Gene', (18, 21))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('IDH', 'Gene', '3417', (18, 21))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('upregulation', 'PosReg', (116, 128))	('mutations', 'Var', (22, 31))	('protoporphyrin IX synthesis', 'MPA', (78, 105))	('protoporphyrin IX', 'Chemical', 'MESH:C028025', (78, 95))	('differences', 'Reg', (56, 67))	('5-ALA', 'Chemical', 'MESH:C000614854', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
31572	25756397	Finally, high levels of expression were associated with poor prognosis in glioma patients.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('patients', 'Species', '9606', (81, 89))	('glioma', 'Disease', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('high', 'Var', (9, 13))
31575	25756397	Other circulating miRNAs, miR-128 and miR-342-3p, have also been found to be dysregulated in human gliomas.	('miR-128', 'Var', (26, 33))	('human', 'Species', '9606', (93, 98))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('miR-342-3p', 'Var', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
31608	30341300	Genes strongly associated with a cancer type or pancancer subgroups provide insights into the molecular mechanisms, which are key for pinpointing novel therapeutic opportunities and improving current treatment strategies.	('cancer', 'Disease', (33, 39))	('Genes', 'Var', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('associated', 'Reg', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
31609	30341300	For example, analysis of endometrial carcinoma showed genetic similarities to certain types of breast and ovarian cancer while olaparib, approved for BRCA-mutated ovarian cancer, provided a good response in metastatic prostate cancer patients with DNA repair mutations.	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (25, 46))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (218, 233))	('prostate cancer', 'Phenotype', 'HP:0012125', (218, 233))	('ovarian cancer', 'Disease', (163, 177))	('olaparib', 'Chemical', 'MESH:C531550', (127, 135))	('prostate cancer', 'Disease', (218, 233))	('ovarian cancer', 'Disease', (106, 120))	('patients', 'Species', '9606', (234, 242))	('ovarian cancer', 'Phenotype', 'HP:0100615', (163, 177))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (95, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('mutations', 'Var', (259, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('DNA repair', 'Gene', (248, 258))	('endometrial carcinoma', 'Disease', (25, 46))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (25, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (163, 177))
31618	30341300	Stratifying the TCGA mutation data by tissue of origin, we built Bayesian networks (Methods) separately for each cancer type.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('TCGA', 'Gene', (16, 20))	('cancer', 'Disease', (113, 119))	('mutation', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
31626	30341300	TP53 mutations in lower-grade glioma have previously been associated with the disease, along with IDH1, FUBP1, ATRX, CIC, NOTCH1, EGFR, and PIK3CA among which we see some interactions.	('ATRX', 'Gene', '546', (111, 115))	('PIK3CA', 'Gene', (140, 146))	('IDH1', 'Gene', '3417', (98, 102))	('EGFR', 'Gene', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('TP53', 'Gene', '7157', (0, 4))	('CIC', 'Gene', (117, 120))	('FUBP1', 'Gene', (104, 109))	('NOTCH1', 'Gene', (122, 128))	('mutations', 'Var', (5, 14))	('PIK3CA', 'Gene', '5290', (140, 146))	('EGFR', 'Gene', '1956', (130, 134))	('CIC', 'Gene', '23152', (117, 120))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (58, 68))	('NOTCH1', 'Gene', '4851', (122, 128))	('FUBP1', 'Gene', '8880', (104, 109))	('IDH1', 'Gene', (98, 102))	('glioma', 'Disease', (30, 36))	('ATRX', 'Gene', (111, 115))	('glioma', 'Disease', 'MESH:D005910', (30, 36))
31629	30341300	Mutations in these genes have previously been associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('associated', 'Reg', (46, 56))
31632	30341300	For the example of FAT1, our study finds relevant interacting mutations in breast, colorectal, endometrial, kidney, lung, liver, stomach and head and neck cancer, with mutation rates between 2 and 24%.	('colorectal', 'Disease', (83, 93))	('FAT1', 'Gene', '2195', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('liver', 'Disease', (122, 127))	('FAT1', 'Gene', (19, 23))	('neck cancer', 'Disease', 'MESH:D006258', (150, 161))	('endometrial', 'Disease', (95, 106))	('neck cancer', 'Disease', (150, 161))	('stomach', 'Disease', (129, 136))	('head and neck cancer', 'Phenotype', 'HP:0012288', (141, 161))	('kidney', 'Disease', (108, 114))	('lung', 'Disease', (116, 120))	('breast', 'Disease', (75, 81))	('mutations', 'Var', (62, 71))
31633	30341300	Although FAT1 was reported to be recurrently mutated in several cancer types, our results suggest that the gene correlates with a large number of mutations in different cancer types, including FAT1 in breast cancer, ATM in colorectal cancer, and APC, MTOR and MLL3 in endometrial cancer.	('APC', 'Disease', (246, 249))	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', (169, 175))	('FAT1', 'Gene', '2195', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('endometrial cancer', 'Phenotype', 'HP:0012114', (268, 286))	('cancer', 'Disease', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ATM', 'Gene', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('MLL3', 'Gene', '58508', (260, 264))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('endometrial cancer', 'Disease', (268, 286))	('FAT1', 'Gene', (193, 197))	('cancer', 'Disease', (64, 70))	('endometrial cancer', 'Disease', 'MESH:D016889', (268, 286))	('colorectal cancer', 'Disease', (223, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('APC', 'Disease', 'MESH:D011125', (246, 249))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('FAT1', 'Gene', (9, 13))	('MLL3', 'Gene', (260, 264))	('MTOR', 'Gene', (251, 255))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Disease', (201, 214))	('MTOR', 'Gene', '2475', (251, 255))	('FAT1', 'Gene', '2195', (193, 197))	('ATM', 'Gene', '472', (216, 219))	('mutations', 'Var', (146, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (234, 240))
31637	30341300	Although the drugs are only targeting the mutation itself, we see for example several interactions of KRAS in lung adenocarcinoma (with TP53, EGRF and STK11) and there are currently several clinical trials investigating the effectiveness and safety of targeted therapies against KRAS for this cancer type (NCT02642042, NCT01912625 or NCT02079740).	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('TP53', 'Gene', '7157', (136, 140))	('STK11', 'Gene', '6794', (151, 156))	('NCT02642042', 'Var', (306, 317))	('KRAS', 'Gene', '3845', (279, 283))	('cancer', 'Disease', (293, 299))	('KRAS', 'Gene', (279, 283))	('NCT02079740', 'Var', (334, 345))	('EGRF', 'Disease', 'None', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('EGRF', 'Disease', (142, 146))	('TP53', 'Gene', (136, 140))	('KRAS', 'Gene', '3845', (102, 106))	('lung adenocarcinoma', 'Disease', (110, 129))	('NCT01912625', 'Var', (319, 330))	('interactions', 'Interaction', (86, 98))	('STK11', 'Gene', (151, 156))	('KRAS', 'Gene', (102, 106))
31643	30341300	This model-based de novo clustering of the binary mutation data (Methods and Supplementary Section F) identified 22 groups, coincidentally the same number as the original cancer types (which was not imposed), but distinct in their composition.	('original cancer', 'Disease', 'MESH:D009369', (162, 177))	('original cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutation', 'Var', (50, 58))
31648	30341300	Almost all thyroid cancer samples belong to cluster V, along with samples from other cancer types, and this cluster exhibits a strong enrichment in BRAF mutations (17% compared to an overall rate of 7%, Supplementary Table 9).	('thyroid cancer', 'Phenotype', 'HP:0002890', (11, 25))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (153, 162))	('thyroid cancer', 'Disease', 'MESH:D013964', (11, 25))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('BRAF', 'Gene', '673', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('thyroid cancer', 'Disease', (11, 25))	('BRAF', 'Gene', (148, 152))
31650	30341300	The ovarian cancer samples belong almost entirely to cluster U (where all samples exhibit a TP53 mutation).	('mutation', 'Var', (97, 105))	('exhibit', 'Reg', (82, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (4, 18))	('TP53', 'Gene', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('TP53', 'Gene', '7157', (92, 96))	('ovarian cancer', 'Disease', 'MESH:D010051', (4, 18))	('ovarian cancer', 'Disease', (4, 18))
31651	30341300	Samples with no mutations among the 201 genes are assigned to cluster V. The de novo clustering also split patient samples from the same cancer type, like the glioma samples into clusters G and N: cluster N has elevated mutation rates in TP53 and ATRX which are largely absent from cluster G which instead has elevated rates of CIC as well as even higher rates of IDH1 than N (98% compared to 86%).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('glioma', 'Disease', (159, 165))	('ATRX', 'Gene', (247, 251))	('elevated', 'PosReg', (211, 219))	('ATRX', 'Gene', '546', (247, 251))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CIC', 'Gene', '23152', (328, 331))	('TP53', 'Gene', '7157', (238, 242))	('mutation', 'Var', (220, 228))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('CIC', 'Gene', (328, 331))	('cancer', 'Disease', (137, 143))	('IDH1', 'Gene', (364, 368))	('patient', 'Species', '9606', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('TP53', 'Gene', (238, 242))	('IDH1', 'Gene', '3417', (364, 368))
31655	30341300	For example, the microsatellite stable subtype of uterine cancer has a rather different cluster composition than the other uterine patient samples (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (58, 64))	('uterine cancer', 'Phenotype', 'HP:0010784', (50, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patient', 'Species', '9606', (131, 138))	('different', 'Reg', (78, 87))	('microsatellite', 'Var', (17, 31))
31670	30341300	For example all members of cluster U possess a TP53 mutations while none of cluster V do.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
31676	30341300	For example, BRAF inhibitors are being currently tested or have already been approved for multiple cancer types, including lung cancer, ovarian cancer, and thyroid cancer.	('thyroid cancer', 'Disease', (156, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('inhibitors', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('BRAF', 'Gene', '673', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('BRAF', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('thyroid cancer', 'Disease', 'MESH:D013964', (156, 170))	('lung cancer', 'Disease', (123, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('ovarian cancer', 'Disease', (136, 150))	('thyroid cancer', 'Phenotype', 'HP:0002890', (156, 170))	('cancer', 'Disease', (164, 170))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (99, 105))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
31682	30341300	Larger networks than those analysed may not lead to any further benefit, since many cancer mutations are quite rare and therefore unlikely to show strong interactions detectable in network modelling.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
31724	30341300	To evaluate the prognostic power of the clusters derived from the mutational data for survival prediction, we employed the Cox proportional hazards model, with and without adjustment for age, stage and tissue type which are all significant predictors.	('Cox', 'Gene', '1351', (123, 126))	('Cox', 'Gene', (123, 126))	('mutational', 'Var', (66, 76))
31754	27739438	BRAF-KIAA1549 fusions, as well as other genetic rearrangements and mutations lead to downstream activation of signaling pathways, particularly the mitogen-activated protein kinase pathway .	('mitogen-activated protein kinase pathway', 'Pathway', (147, 187))	('BRAF-KIAA1549', 'Disease', (0, 13))	('BRAF-KIAA1549', 'Disease', 'None', (0, 13))	('signaling pathways', 'Pathway', (110, 128))	('fusions', 'Var', (14, 21))	('activation', 'PosReg', (96, 106))
31755	27739438	More recently, comprehensive sequencing studies have documented genetic hits in mitogen-activated protein kinase pathway components in essentially 100% of pilocytic astrocytomas .	('pilocytic astrocytomas', 'Disease', (155, 177))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('mitogen-activated protein kinase pathway', 'Pathway', (80, 120))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (155, 177))	('genetic hits', 'Var', (64, 76))
31756	27739438	In patients with neurofibromatosis type 1, pilocytic astrocytomas develop homozygous mutations in the NF1 gene, also leading to MAPK pathway activation.	('neurofibromatosis type 1', 'Gene', '4763', (17, 41))	('MAPK pathway', 'Pathway', (128, 140))	('neurofibromatosis type 1', 'Gene', (17, 41))	('NF1', 'Gene', (102, 105))	('mutations', 'Var', (85, 94))	('NF1', 'Gene', '4763', (102, 105))	('patients', 'Species', '9606', (3, 11))	('pilocytic astrocytomas', 'Disease', (43, 65))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (17, 34))	('astrocytoma', 'Phenotype', 'HP:0009592', (53, 64))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (43, 65))	('activation', 'PosReg', (141, 151))
31758	27739438	Other pediatric low grade glioma subsets have different alterations, for example, partial duplication of the transcription factor MYBL1 with truncated transcript, intragenic duplications of the tyrosine kinase domain in the FGFR1 gene, and MYB rearrangements in diffuse pediatric low grade gliomas .	('MYBL1', 'Gene', (130, 135))	('glioma', 'Disease', (290, 296))	('gliomas', 'Disease', (290, 297))	('MYBL1', 'Gene', '4603', (130, 135))	('FGFR1', 'Gene', (224, 229))	('MYB', 'Gene', '4602', (130, 133))	('MYB', 'Gene', (130, 133))	('glioma', 'Disease', 'MESH:D005910', (290, 296))	('MYB', 'Gene', '4602', (240, 243))	('MYB', 'Gene', (240, 243))	('gliomas', 'Disease', 'MESH:D005910', (290, 297))	('glioma', 'Disease', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (290, 296))	('truncated transcript', 'MPA', (141, 161))	('rearrangements', 'Var', (244, 258))	('gliomas', 'Phenotype', 'HP:0009733', (290, 297))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('FGFR1', 'Gene', '2260', (224, 229))	('duplications', 'Var', (174, 186))	('partial duplication', 'Var', (82, 101))
31830	27739438	Effective miR-1246 knockdown was reliably achieved in KNS42 cells, which were subjected to further functional experiments.	('knockdown', 'Var', (19, 28))	('miR-1246', 'Gene', '100302142', (10, 18))	('miR-1246', 'Gene', (10, 18))
31832	27739438	miR-487b overexpression led to a decrease in colony formation in soft agar (30%)(p<0.05) (Figure 5C) and decreased expression of the neural stem cell markers, known to be predicted targets of miR-487b, PROM1 and Nestin (but not WNT5A) (Figure 5D).	('WNT5A', 'Gene', '7474', (228, 233))	('Nestin', 'Gene', (212, 218))	('decrease', 'NegReg', (33, 41))	('PROM1', 'Gene', '8842', (202, 207))	('miR-487b', 'Gene', '664616', (192, 200))	('overexpression', 'Var', (9, 23))	('miR-487b', 'Gene', '664616', (0, 8))	('expression', 'MPA', (115, 125))	('Nestin', 'Gene', '10763', (212, 218))	('WNT5A', 'Gene', (228, 233))	('agar', 'Chemical', 'MESH:D000362', (70, 74))	('PROM1', 'Gene', (202, 207))	('miR-487b', 'Gene', (192, 200))	('decreased', 'NegReg', (105, 114))	('miR-487b', 'Gene', (0, 8))
31836	27739438	Alterations in microRNA levels have emerged as an important mechanism in cancer, including glial tumors .	('glial tumors', 'Disease', (91, 103))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('microRNA levels', 'MPA', (15, 30))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('glial tumors', 'Disease', 'MESH:D005910', (91, 103))
31843	27739438	In our study, the directionality of altered microRNA expression of these low grade gliomas was similar to each other and to microRNAs identified in previously published high grade gliomas studies that were summarized in a recent meta-analysis (Figure 6)  Many of these alterations are consistent in directionality with malignancies from other sites, such as miR-21a-5p, which is upregulated in many tumor types .	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('alterations', 'Var', (269, 280))	('tumor', 'Disease', 'MESH:D009369', (399, 404))	('miR-21', 'Gene', '406991', (358, 364))	('malignancies', 'Disease', 'MESH:D009369', (319, 331))	('gliomas', 'Disease', (180, 187))	('man', 'Species', '9606', (394, 397))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('miR-21', 'Gene', (358, 364))	('malignancies', 'Disease', (319, 331))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('tumor', 'Disease', (399, 404))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))
31853	27739438	Subependymal giant cell astrocytoma is frequently associated with tuberous sclerosis, characterized at the genetic level by germline inactivation of the TSC1 or TSC2 tumor suppressor genes, while rosette forming glioneuronal tumor has frequent mutations in PIK3CA.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (225, 230))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (212, 230))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('rosette', 'Phenotype', 'HP:0031925', (196, 203))	('PIK3CA', 'Gene', (257, 263))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (66, 84))	('mutations', 'Var', (244, 253))	('Subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (0, 35))	('tuberous sclerosis', 'Disease', (66, 84))	('TSC2 tumor', 'Disease', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('TSC1', 'Gene', (153, 157))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('tumor', 'Disease', (166, 171))	('TSC2 tumor', 'Disease', 'MESH:C566021', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('rosette forming glioneuronal tumor', 'Phenotype', 'HP:0025171', (196, 230))	('Subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (0, 35))	('Subependymal giant cell astrocytoma', 'Disease', (0, 35))	('PIK3CA', 'Gene', '5290', (257, 263))	('associated', 'Reg', (50, 60))	('inactivation', 'Var', (133, 145))
31854	27739438	Activation of this pathway through TSC1 deletion in mouse and human cell lines has been shown to cause a global inhibition of microRNA biogenesis through the degradation of Drosha .	('TSC1', 'Gene', (35, 39))	('microRNA biogenesis', 'MPA', (126, 145))	('Drosha', 'Gene', (173, 179))	('deletion', 'Var', (40, 48))	('mouse', 'Species', '10090', (52, 57))	('human', 'Species', '9606', (62, 67))	('inhibition', 'NegReg', (112, 122))	('Drosha', 'Gene', '29102', (173, 179))	('Activation', 'PosReg', (0, 10))	('degradation', 'MPA', (158, 169))
31859	27739438	In the current study miR-487b overexpression led to decreased colony formation in soft agar and decreased levels of the neural stem cell markers nestin and PROM1 in a pediatric glioma cell line.	('nestin', 'Gene', (145, 151))	('PROM1', 'Gene', (156, 161))	('pediatric glioma', 'Disease', (167, 183))	('decreased', 'NegReg', (96, 105))	('decreased', 'NegReg', (52, 61))	('agar', 'Chemical', 'MESH:D000362', (87, 91))	('miR-487b', 'Gene', '664616', (21, 29))	('nestin', 'Gene', '10763', (145, 151))	('levels of the', 'MPA', (106, 119))	('overexpression', 'Var', (30, 44))	('PROM1', 'Gene', '8842', (156, 161))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('pediatric glioma', 'Disease', 'MESH:D005910', (167, 183))	('colony formation in', 'CPA', (62, 81))	('miR-487b', 'Gene', (21, 29))
31866	27739438	Interestingly, miR-487b may also be regulated by DNA methylation in tumorigenesis, as a response to cigarette smoke, a proposed mechanism for its involvement in lung tumors.	('tumor', 'Disease', (68, 73))	('miR-487b', 'Gene', '664616', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('lung tumors', 'Disease', 'MESH:D008175', (161, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('regulated', 'Reg', (36, 45))	('miR-487b', 'Gene', (15, 23))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('lung tumors', 'Phenotype', 'HP:0100526', (161, 172))	('lung tumors', 'Disease', (161, 172))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('DNA methylation', 'Var', (49, 64))
31960	25586623	The SelMQC-CSI spectra were fitted in QUEST, showing significantly higher lactate in GBM (7.3 +- 1.9 mM, mean +- standard deviation) compared with LGG (1.9 +- 1.5 mM, p = 0.049).	('lactate', 'MPA', (74, 81))	('GBM', 'Var', (85, 88))	('higher', 'PosReg', (67, 73))	('lactate', 'Chemical', 'MESH:D019344', (74, 81))
32035	24099560	Survival analysis showed that patients with high BMP4 expression had significantly poorer postoperative disease-specific survival than those with low/no BMP4 expression (P = 0.001) (Figure 4).	('high', 'Var', (44, 48))	('expression', 'Var', (54, 64))	('poorer', 'NegReg', (83, 89))	('patients', 'Species', '9606', (30, 38))	('BMP4', 'Gene', (49, 53))	('postoperative disease-specific survival', 'CPA', (90, 129))
32038	24099560	reported that the biological behavior of osteosarcoma cells with high BMP4 expression was obviously different from that of cells with low or no BMP4 expression.	('osteosarcoma', 'Disease', (41, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('expression', 'Var', (75, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (41, 53))	('different', 'Reg', (100, 109))	('high', 'Var', (65, 69))	('BMP4', 'Gene', (70, 74))
32051	24099560	Interestingly, we found that high BMP4 expression can increase bone metastasis from brain glioma.	('high', 'Var', (29, 33))	('brain glioma', 'Disease', 'MESH:C564230', (84, 96))	('increase', 'PosReg', (54, 62))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('bone metastasis', 'CPA', (63, 78))	('BMP4', 'Protein', (34, 38))	('expression', 'MPA', (39, 49))	('brain glioma', 'Disease', (84, 96))
32055	30558563	BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - Markers in the clinical stratification of pediatric gliomas Genetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity.	('CDKN2A/B', 'Gene', (30, 38))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('gliomas', 'Disease', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('brain tumors', 'Disease', 'MESH:D001932', (164, 176))	('CDKN2A/B', 'Gene', '1029;1030', (30, 38))	('brain tumors', 'Phenotype', 'HP:0030692', (164, 176))	('BRAF', 'Gene', (0, 4))	('brain tumors', 'Disease', (164, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))
32056	30558563	This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance.	('patients', 'Species', '9606', (323, 331))	('V600E', 'Mutation', 'rs113488022', (73, 78))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('deletions', 'Var', (109, 118))	('pediatric gliomas', 'Disease', 'MESH:D005910', (138, 155))	('BRAF', 'Gene', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('p21', 'Gene', (105, 108))	('p21', 'Gene', '644914', (105, 108))	('pediatric gliomas', 'Disease', (138, 155))
32057	30558563	Sanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 for the detection of 9p21 alterations.	('mutations', 'Var', (54, 63))	('p21', 'Gene', (163, 166))	('p21', 'Gene', '644914', (163, 166))	('RP11', 'Gene', (130, 134))	('RP11', 'Gene', '26121', (130, 134))
32060	30558563	BRAF V600E mutations were detected in 15 cases.	('BRAF', 'Gene', (0, 4))	('V600E', 'Var', (5, 10))	('V600E', 'Mutation', 'rs113488022', (5, 10))
32062	30558563	Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p = 0.0178) but frequent in grade IV gliomas (62.5%, p = 0.0087).	('MTAP', 'Gene', (46, 50))	('gliomas', 'Disease', (77, 84))	('I gliomas', 'Disease', (75, 84))	('CDKN2A/B', 'Gene', '1029;1030', (33, 41))	('p21', 'Gene', (14, 17))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('grade IV', 'Disease', (121, 129))	('gliomas', 'Disease', (130, 137))	('p21', 'Gene', '644914', (14, 17))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('CDKN2A/B', 'Gene', (33, 41))	('I gliomas', 'Disease', 'MESH:D005910', (75, 84))	('abrogating', 'NegReg', (18, 28))	('Deletions', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
32076	30558563	This occurs at high frequency by activation of the BRAF oncogene; and in lower frequencies: by MYB and MYBL1 amplifications and rearrangements, and FGFR1 rearrangements and mutations.	('rearrangements', 'Var', (154, 168))	('MYBL1', 'Gene', '4603', (103, 108))	('amplifications', 'Var', (109, 123))	('MYB', 'Gene', '4602', (103, 106))	('MYB', 'Gene', (103, 106))	('activation', 'PosReg', (33, 43))	('MYB', 'Gene', '4602', (95, 98))	('mutations', 'Var', (173, 182))	('rearrangements', 'Var', (128, 142))	('BRAF oncogene', 'Gene', (51, 64))	('MYB', 'Gene', (95, 98))	('FGFR1', 'Gene', (148, 153))	('MYBL1', 'Gene', (103, 108))	('FGFR1', 'Gene', '2260', (148, 153))
32077	30558563	Two different mechanisms may lead to BRAF activation in pediatric brain gliomas: chromosomal rearrangements and point mutations.	('pediatric brain gliomas', 'Disease', (56, 79))	('point mutations', 'Var', (112, 127))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('BRAF', 'Gene', (37, 41))	('activation', 'PosReg', (42, 52))	('chromosomal rearrangements', 'Var', (81, 107))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('pediatric brain gliomas', 'Disease', 'MESH:C564230', (56, 79))
32078	30558563	The most common BRAF rearrangement is the one resulting in BRAF/KIAA1549 fusion protein in which the N-terminus of the protein encoded by KIAA1549 gene is fused with the C-terminus of the protein encoded by BRAF gene, preserving the BRAF kinase domain.	('KIAA1549', 'Gene', (64, 72))	('KIAA1549', 'Gene', '57670', (64, 72))	('BRAF', 'MPA', (233, 237))	('rearrangement', 'Var', (21, 34))	('KIAA1549', 'Gene', (138, 146))	('KIAA1549', 'Gene', '57670', (138, 146))	('resulting in', 'Reg', (46, 58))
32079	30558563	BRAF activating rearrangements were reported to be present in 70% of the pilocytic astrocytomas, in 15% of other low-grade gliomas, and have only been punctually observed in high-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('activating', 'PosReg', (5, 15))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('pilocytic astrocytomas', 'Disease', (73, 95))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('gliomas', 'Disease', (123, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (73, 95))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('rearrangements', 'Var', (16, 30))	('BRAF', 'Gene', (0, 4))	('gliomas', 'Disease', (185, 192))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))
32080	30558563	(2008), showed that BRAF rearrangements were an independent favorable prognostic factor in both supra-tentorial and posterior fossa low-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('rearrangements', 'Var', (25, 39))	('supra-tentorial', 'Disease', (96, 111))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('BRAF', 'Gene', (20, 24))
32081	30558563	The vast majority (> 90%) of BRAF mutations in pediatric gliomas are BRAF V600E mutations, a somatic mutation causing the substitution of the amino acid valine by glutamic acid at residue 600 of exon 15.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('BRAF', 'Gene', (29, 33))	('pediatric gliomas', 'Disease', (47, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('V600E', 'Var', (74, 79))	('mutations', 'Var', (34, 43))	('valine by glutamic acid at residue 600', 'Mutation', 'rs113488022', (153, 191))	('BRAF', 'Gene', (69, 73))	('pediatric gliomas', 'Disease', 'MESH:D005910', (47, 64))
32082	30558563	BRAF V600E mutations have been described in a wide variety of lesions: 80% of pleomorphic xanthoastrocytomas 33% of the gangliogliomas, 23% of the diffuse astrocytomas, 10% of the glioblastomas being more frequent in tumors located in the cerebral cortex.	('V600E mutations', 'Var', (5, 20))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('BRAF', 'Gene', (0, 4))	('glioblastomas', 'Disease', (180, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (180, 192))	('astrocytomas', 'Disease', 'MESH:D001254', (96, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('astrocytomas', 'Disease', (155, 167))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (78, 108))	('glioblastomas', 'Disease', 'MESH:D005909', (180, 193))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('gliomas', 'Disease', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('pleomorphic xanthoastrocytomas', 'Disease', (78, 108))	('tumors', 'Disease', (217, 223))	('astrocytomas', 'Disease', 'MESH:D001254', (155, 167))	('astrocytoma', 'Phenotype', 'HP:0009592', (155, 166))	('astrocytomas', 'Disease', (96, 108))	('glioblastomas', 'Phenotype', 'HP:0012174', (180, 193))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
32084	30558563	At variance with BRAF rearrangements, the role of BRAF V600E mutation in the glioma's evolution and patient's follow-up is far from being fully understood and some contradictory results are found in literature.	('BRAF', 'Gene', (50, 54))	('V600E', 'Var', (55, 60))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('patient', 'Species', '9606', (100, 107))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('V600E', 'Mutation', 'rs113488022', (55, 60))
32087	30558563	(2015) described a subgroup of glioblastomas, exclusive to the pediatric population, that was characterized by the BRAF V600E mutation and CDKN2A deletion.	('deletion', 'Var', (146, 154))	('BRAF', 'Gene', (115, 119))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('glioblastomas', 'Phenotype', 'HP:0012174', (31, 44))	('glioblastomas', 'Disease', 'MESH:D005909', (31, 44))	('V600E', 'Var', (120, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('CDKN2A', 'Gene', (139, 145))	('glioblastomas', 'Disease', (31, 44))
32103	30558563	FISH technique was used to identify heterozygous and homozygous deletions of the 9p21 chromosomal region.	('p21', 'Gene', (82, 85))	('deletions', 'Var', (64, 73))	('p21', 'Gene', '644914', (82, 85))
32108	30558563	In the context of this work, sequencing using Sanger methodology was used to identify a single point mutation (V600E) in the exon 15 of the BRAF gene.	('V600E', 'Var', (111, 116))	('BRAF', 'Gene', (140, 144))	('V600E', 'Mutation', 'rs113488022', (111, 116))
32110	30558563	In cases with 9p21 deletions (detected by FISH) expression analysis was performed by real-time qPCR, using commercial TaqMan probes for the CDKN2A (Hs00233365_m1) and MTAP (Hs00559618_m1) genes (ThermoFisher Scientific, USA).	('p21', 'Gene', '644914', (15, 18))	('CDKN2A', 'Gene', (140, 146))	('MTAP', 'Gene', (167, 171))	('p21', 'Gene', (15, 18))	('Hs00233365_m1', 'Var', (148, 161))	('Hs00559618_m1', 'Var', (173, 186))
32114	30558563	Total RNA extraction and single-strand cDNA synthesis could only be performed for 3 LGG presenting 9p21 heterozygous loss: LGG64, LGG73 and LGG74 and for 3 HGG (grade IV) with 9p21 homozygous loss: HGG3, HGG18 and HGG23.	('HGG23', 'Gene', (214, 219))	('HGG18', 'Gene', (204, 209))	('p21', 'Gene', (100, 103))	('LGG73', 'Gene', (130, 135))	('loss', 'NegReg', (117, 121))	('p21', 'Gene', (177, 180))	('p21', 'Gene', '644914', (100, 103))	('LGG74', 'Var', (140, 145))	('p21', 'Gene', '644914', (177, 180))	('LGG64', 'Var', (123, 128))
32120	30558563	In total, 94 pediatric gliomas were analyzed for the BRAF V600E mutation and 15 were found to harbor this mutation (Fig.	('pediatric gliomas', 'Disease', 'MESH:D005910', (13, 30))	('V600E', 'Var', (58, 63))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('BRAF', 'Gene', (53, 57))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('pediatric gliomas', 'Disease', (13, 30))	('V600E', 'Mutation', 'rs113488022', (58, 63))
32122	30558563	The presence of BRAFV600E mutation did not show any correlation with tumor's WHO grade, histologic subtype, patients' age (p = 0.9299) and patients' gender (p = 0.1539).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patients', 'Species', '9606', (139, 147))	('tumor', 'Disease', (69, 74))	('BRAFV600E', 'Var', (16, 25))	('BRAFV600E', 'Mutation', 'rs113488022', (16, 25))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
32128	30558563	6/17 (35,3%) HGG (HGG: 3, 9, 18, 19, 21 and 23) presented 9p21 deletions, four of which had a homozygous 9p21 chromosomal region deletion.	('p21', 'Gene', (59, 62))	('HGG', 'Gene', (13, 16))	('p21', 'Gene', '644914', (59, 62))	('p21', 'Gene', '644914', (106, 109))	('deletions', 'Var', (63, 72))	('p21', 'Gene', (106, 109))
32136	30558563	This patient (ruled out as having Neurofibromatosis type 1) was diagnosed at the age of 4 with a diffuse astrocytoma of the optical nerve, which was positive for the BRAF V600E mutation and presented a recurrence, 3 years later, that also was positive for BRAF V600E.	('astrocytoma of the optical nerve', 'Disease', (105, 137))	('patient', 'Species', '9606', (5, 12))	('V600E', 'Mutation', 'rs113488022', (261, 266))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (34, 51))	('V600E', 'Mutation', 'rs113488022', (171, 176))	('astrocytoma of the optical nerve', 'Disease', 'MESH:D020339', (105, 137))	('BRAF V600E', 'Var', (166, 176))	('BRAF V600E', 'Var', (256, 266))	('positive', 'Reg', (149, 157))	('Neurofibromatosis type 1', 'Gene', (34, 58))	('Neurofibromatosis type 1', 'Gene', '4763', (34, 58))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
32146	30558563	One, HGG15 had a BRAF V600E mutation.	('HGG15', 'Gene', (5, 10))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('V600E', 'Var', (22, 27))
32147	30558563	However, none of them presented a deletion of 9p21 region.	('p21', 'Gene', '644914', (47, 50))	('deletion', 'Var', (34, 42))	('p21', 'Gene', (47, 50))
32151	30558563	As to the incidence rate of BRAF V600E mutation results corroborated previous data, showing that this mutation occurred in all spectra of glioma types, although being more frequent in gangliogliomas and diffuse astrocytomas.	('glioma', 'Disease', (138, 144))	('occurred', 'Reg', (111, 119))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('gliomas', 'Disease', (191, 198))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('astrocytoma', 'Phenotype', 'HP:0009592', (211, 222))	('glioma', 'Disease', (191, 197))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('V600E', 'Var', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('BRAF', 'Gene', (28, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (211, 223))	('frequent', 'Reg', (172, 180))	('astrocytomas', 'Disease', (211, 223))
32154	30558563	(2015) by analysis of a cohort of 886 patients reported a similar incidence rate of pediatric LGG transformation to sHGG - 2,9%, but at variance with our data they showed BRAF V600E mutation to be associated with prolonged latency periods in pediatric low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (262, 269))	('gliomas', 'Phenotype', 'HP:0009733', (262, 269))	('gliomas', 'Disease', (262, 269))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('patients', 'Species', '9606', (38, 46))	('BRAF V600E', 'Var', (171, 181))	('V600E', 'Mutation', 'rs113488022', (176, 181))
32161	30558563	LGG82 did not present ab initio a BRAF V600E mutation and had a much longer latency period until the development of the HGG (13 years).	('BRAF', 'Gene', (34, 38))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('V600E', 'Var', (39, 44))
32162	30558563	Although the number of cases is recognizably small, these findings suggest that in LGG81, a cooperative interplay might have occurred between BRAF mutation and 9p21 homozygous loss, which enhanced malignant transformation.	('LGG81', 'Gene', (83, 88))	('enhanced', 'PosReg', (188, 196))	('p21', 'Gene', (161, 164))	('p21', 'Gene', '644914', (161, 164))	('mutation', 'Var', (147, 155))	('malignant transformation', 'CPA', (197, 221))	('BRAF', 'Gene', (142, 146))
32165	30558563	(2012) by performing functional studies in neural progenitor cell and mouse models evidenced that homozygous CDKN2A/INK4a-Arf deletion in BRAF V600E expressing cells was sufficient for the formation of tumors with histologic features similar to the malignant astrocytomas in humans.	('V600E', 'Var', (143, 148))	('malignant astrocytomas', 'Disease', 'MESH:D020339', (249, 271))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('mouse', 'Species', '10090', (70, 75))	('INK4a-Arf', 'Gene', (116, 125))	('INK4a-Arf', 'Gene', '12578', (116, 125))	('deletion', 'Var', (126, 134))	('V600E', 'Mutation', 'rs113488022', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('astrocytoma', 'Phenotype', 'HP:0009592', (259, 270))	('BRAF', 'Gene', (138, 142))	('humans', 'Species', '9606', (275, 281))	('malignant astrocytomas', 'Disease', (249, 271))
32166	30558563	(2015) in an array of comparative genomic hybridization analysis of 886 pediatric gliomas alsodefined that CDKN2A deletions had a central role in low-grade glioma malignant transformation.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('low-grade', 'Disease', (146, 155))	('glioma', 'Disease', (156, 162))	('pediatric gliomas', 'Disease', 'MESH:D005910', (72, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Disease', (82, 88))	('deletions', 'Var', (114, 123))	('CDKN2A', 'Gene', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('pediatric gliomas', 'Disease', (72, 89))
32171	30558563	(2016) deletions at 9p abrogating the MTAP gene lead to the accumulation of its substrate 5' methilthioadenosine (MTA) and a metabolic "rewiring" of the tumor cells, which rendered them specifically sensible to drugs that inhibit the methyltransferase axis composed by: Methionine Adenosyltransferase II alpha (MAT2A), Protein Arginine Methyltransferase 5 (PMRT5) and Rio domain containing protein 1 (RIOK1).	('MAT2A', 'Gene', '4144', (311, 316))	('RIOK1', 'Gene', '83732', (401, 406))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Protein Arginine Methyltransferase 5', 'Gene', (319, 355))	('Methionine Adenosyltransferase II alpha', 'Gene', '4144', (270, 309))	('MAT2A', 'Gene', (311, 316))	('abrogating', 'NegReg', (23, 33))	('deletions', 'Var', (7, 16))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('MTAP gene', 'Gene', (38, 47))	('RIOK1', 'Gene', (401, 406))	('Methionine Adenosyltransferase II alpha', 'Gene', (270, 309))	('Protein Arginine Methyltransferase 5', 'Gene', '10419', (319, 355))	('accumulation', 'PosReg', (60, 72))
32174	30558563	HGG18 was negative for the presence of BRAF V600E mutation but positive for 9p21 deletion (Table 1).	('positive', 'Reg', (63, 71))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('p21', 'Gene', (77, 80))	('p21', 'Gene', '644914', (77, 80))	('V600E', 'Var', (44, 49))
32191	23590708	BMP4 also showed a Proneural subtype, G1 subtype and Isocitrate Dehydrogenase 1 (IDH1) mutation preference and cell development association.	('Isocitrate Dehydrogenase 1', 'Gene', (53, 79))	('cell development', 'CPA', (111, 127))	('BMP4', 'Gene', (0, 4))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (53, 79))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (81, 85))	('mutation', 'Var', (87, 95))	('BMP4', 'Gene', '652', (0, 4))
32214	23590708	The survival curve of patients with high or low expressed BMP4 was calculated with the Kaplan-Meier method and the difference was analyzed using the two-sided log-rank test.	('low', 'NegReg', (44, 47))	('BMP4', 'Gene', '652', (58, 62))	('expressed', 'Var', (48, 57))	('patients', 'Species', '9606', (22, 30))	('BMP4', 'Gene', (58, 62))	('high', 'Var', (36, 40))
32223	23590708	As is shown in Figure 3, both anaplastic glioma (Figure 3B) and GBM (Figure 3C) patients with high or low expression of BMP4 had considerable different prognosis.	('patients', 'Species', '9606', (80, 88))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('BMP4', 'Gene', (120, 124))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('expression', 'MPA', (106, 116))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('low', 'NegReg', (102, 105))	('BMP4', 'Gene', '652', (120, 124))	('glioma', 'Disease', (41, 47))	('high', 'Var', (94, 98))
32227	23590708	Patients with IDH1 gene mutation also showed higher expression of BMP4 than those with wild-type IDH1 gene (Figure 4).	('BMP4', 'Gene', '652', (66, 70))	('IDH1', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (97, 101))	('expression', 'MPA', (52, 62))	('Patients', 'Species', '9606', (0, 8))	('BMP4', 'Gene', (66, 70))	('mutation', 'Var', (24, 32))	('IDH1', 'Gene', (14, 18))	('higher', 'PosReg', (45, 51))	('IDH1', 'Gene', '3417', (14, 18))
32238	23590708	Firstly, BMP4 gene variants have been shown to predispose to colorectal cancer.	('colorectal cancer', 'Disease', (61, 78))	('BMP4', 'Gene', '652', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('predispose', 'Reg', (47, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('variants', 'Var', (19, 27))	('BMP4', 'Gene', (9, 13))
32247	23590708	Patients with higher expression of BMP4 showed a significantly better prognosis in anaplastic gliomas and GBMs.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('BMP4', 'Gene', (35, 39))	('BMP4', 'Gene', '652', (35, 39))	('GBMs', 'Disease', (106, 110))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('expression', 'MPA', (21, 31))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('better', 'PosReg', (63, 69))	('higher', 'Var', (14, 20))
32250	23590708	We also found the preference expression of BMP4 in IDH1 mutation patients, Proneural subtype or G1 subtype, which was in concordance with the better prognosis of BMP4 overexpressed patients.	('IDH1', 'Gene', '3417', (51, 55))	('BMP4', 'Gene', '652', (162, 166))	('BMP4', 'Gene', (43, 47))	('patients', 'Species', '9606', (181, 189))	('BMP4', 'Gene', '652', (43, 47))	('patients', 'Species', '9606', (65, 73))	('BMP4', 'Gene', (162, 166))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))
32251	23590708	BMP4 was preferentially expressed in LGGs, IDH1 mutation patients, Proneural subtype and G1 subtype.	('preferentially', 'PosReg', (9, 23))	('patients', 'Species', '9606', (57, 65))	('IDH1', 'Gene', (43, 47))	('BMP4', 'Gene', (0, 4))	('mutation', 'Var', (48, 56))	('LGGs', 'Disease', (37, 41))	('IDH1', 'Gene', '3417', (43, 47))	('BMP4', 'Gene', '652', (0, 4))
32254	17948060	Somatic cell type specific gene transfer reveals a tumor-promoting function for p21Waf1/Cip1 How proteins participate in tumorigenesis can be obscured by their multifunctional nature.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (121, 126))	('p21Waf1/Cip1', 'Var', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
32255	17948060	For example, depending on the cellular context, the cdk inhibitors can affect cell proliferation, cell motility, apoptosis, receptor tyrosine kinase signaling, and transcription.	('cell motility', 'CPA', (98, 111))	('apoptosis', 'CPA', (113, 122))	('cdk', 'Gene', (52, 55))	('receptor tyrosine kinase signaling', 'MPA', (124, 158))	('cdk', 'Gene', '12566;12567;12571', (52, 55))	('affect', 'Reg', (71, 77))	('inhibitors', 'Var', (56, 66))	('transcription', 'CPA', (164, 177))	('cell proliferation', 'CPA', (78, 96))
32262	17948060	Alterations that disrupt stem/progenitor cell dynamics and cell cycle arrest may affect the progression of ODG.	('cell cycle arrest', 'CPA', (59, 76))	('progression', 'CPA', (92, 103))	('Alterations', 'Var', (0, 11))	('ODG', 'Disease', (107, 110))	('cy', 'Chemical', 'MESH:D003545', (64, 66))	('affect', 'Reg', (81, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (59, 76))	('stem/progenitor cell dynamics', 'CPA', (25, 54))
32267	17948060	Cki are classified into two subfamilies: the Ink4 subfamily (p15, p16, p18, and p19), which specifically target cdk4 and cdk6 and disrupt the cyclin D-cdk complex; and the Cip/Kip subfamily (p21, p27 and p57), which inhibit cyclin-cdk2 complexes.	('cdk2', 'Gene', (231, 235))	('p16', 'Gene', (66, 69))	('p18', 'Gene', (71, 74))	('disrupt', 'NegReg', (130, 137))	('cdk6', 'Gene', (121, 125))	('Kip', 'Gene', (176, 179))	('p21', 'Var', (191, 194))	('p18', 'Gene', '12580', (71, 74))	('cdk', 'Gene', '12566;12567;12571', (121, 124))	('cdk2', 'Gene', '12566', (231, 235))	('p19', 'Gene', (80, 83))	('cdk', 'Gene', '12566;12567;12571', (231, 234))	('cdk', 'Gene', '12566;12567;12571', (112, 115))	('cdk', 'Gene', '12566;12567;12571', (151, 154))	('p57', 'Gene', '12721', (204, 207))	('cdk6', 'Gene', '12571', (121, 125))	('Cip', 'Gene', '69642', (172, 175))	('Cip', 'Gene', (172, 175))	('Kip', 'Gene', '23991', (176, 179))	('p19', 'Gene', '12581', (80, 83))	('cdk4', 'Gene', (112, 116))	('p57', 'Gene', (204, 207))	('p15', 'Gene', (61, 64))	('cdk4', 'Gene', '12567', (112, 116))	('target', 'Reg', (105, 111))	('p15', 'Gene', '12579', (61, 64))	('cdk', 'Gene', (121, 124))	('p16', 'Gene', '12578', (66, 69))	('cdk', 'Gene', (231, 234))	('inhibit', 'NegReg', (216, 223))	('cdk', 'Gene', (112, 115))	('cdk', 'Gene', (151, 154))
32268	17948060	Cki are considered tumor suppressors because their binding to cdks generally inhibits cell proliferation; however, cki can also increase cell motility, reduce apoptosis, modulate receptor tyrosine kinase signaling, and alter the activity of a host of transcription factors and chromatin remodeling enzymes.	('reduce', 'NegReg', (152, 158))	('chromatin remodeling enzymes', 'Enzyme', (277, 305))	('tumor', 'Disease', (19, 24))	('receptor tyrosine kinase signaling', 'MPA', (179, 213))	('binding', 'Var', (51, 58))	('modulate', 'Reg', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('activity', 'MPA', (229, 237))	('cki', 'Var', (115, 118))	('inhibits', 'NegReg', (77, 85))	('cell motility', 'CPA', (137, 150))	('cdks', 'Gene', '12566;12567;12571', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cell proliferation', 'CPA', (86, 104))	('increase', 'PosReg', (128, 136))	('alter', 'Reg', (219, 224))	('cdks', 'Gene', (62, 66))	('transcription factors', 'Enzyme', (251, 272))	('apoptosis', 'CPA', (159, 168))
32269	17948060	For example, cytosolic p27 can modulate rho activity and affect cell migration.	('rho', 'Protein', (40, 43))	('affect', 'Reg', (57, 63))	('cy', 'Chemical', 'MESH:D003545', (13, 15))	('modulate', 'Reg', (31, 39))	('p27', 'Protein', (23, 26))	('cell migration', 'CPA', (64, 78))	('cytosolic', 'Var', (13, 22))
32270	17948060	p21 and p27 can also bind nuclear cyclin D-cdk4 complexes, preventing their crm1-dependent export into the cytoplasm, where cyclin D1 would be degraded in a ubiquitin-dependent process.	('preventing', 'NegReg', (59, 69))	('cyclin D1', 'Gene', (124, 133))	('cy', 'Chemical', 'MESH:D003545', (34, 36))	('crm1', 'Gene', (76, 80))	('p27', 'Var', (8, 11))	('cdk4', 'Gene', (43, 47))	('p21', 'Var', (0, 3))	('cyclin D1', 'Gene', '12443', (124, 133))	('cy', 'Chemical', 'MESH:D003545', (107, 109))	('crm1', 'Gene', '103573', (76, 80))	('cy', 'Chemical', 'MESH:D003545', (124, 126))	('cdk4', 'Gene', '12567', (43, 47))
32275	17948060	Our studies of introducing PDGF into nestin-positive progenitors and driving the development of growth-factor-induced ODG highlighted a critical role for the cyclin-binding domains of p21, and we showed that a mutant of cyclin D1 which accumulates in the nucleus and binds cdk4 in p21-deficient cells could bypass the requirement for p21 during tumor development.	('cdk4', 'Gene', '12567', (273, 277))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('mutant', 'Var', (210, 216))	('accumulates', 'PosReg', (236, 247))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('cyclin D1', 'Gene', '12443', (220, 229))	('tumor', 'Disease', (345, 350))	('binds', 'Interaction', (267, 272))	('cyclin D1', 'Gene', (220, 229))	('cdk4', 'Gene', (273, 277))
32276	17948060	Mutants that did not bind cdk4 or did not accumulate in the nucleus did not bypass the requirement.	('cdk4', 'Gene', '12567', (26, 30))	('cdk4', 'Gene', (26, 30))	('Mutants', 'Var', (0, 7))
32279	17948060	Consequently to understand if these cki contributed in a causal manner to the pathogenesis of ODG, we crossed mice with targeted deletion of p21 or a mutation of p27, p27D51/D51, which removes the N-terminal 51 amino acids of the protein preventing cyclin-cdk interaction, onto an Ntv-a background and infected newborn wild-type, heterozygous, and deficient mice with a single intracranial injection of 104 DF-1 cells producing RCAS-PDGF-HA.	('p27D51/D51', 'Var', (167, 177))	('p21', 'Gene', (141, 144))	('mice', 'Species', '10090', (358, 362))	('deletion', 'Var', (129, 137))	('mice', 'Species', '10090', (110, 114))	('cdk', 'Gene', (256, 259))	('cdk', 'Gene', '12566;12567;12571', (256, 259))	('p27', 'Gene', (162, 165))	('RCAS', 'Chemical', '-', (428, 432))
32281	17948060	Whereas p27 loss was associated with enhanced progression of tumors, as expected of a tumor suppressor (Wendy See, EH, Marilyn Resh, and AK, manuscript in preparation), the loss of p21 unexpectedly reduced the development of tumors (Table I).	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('loss', 'NegReg', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('loss', 'Var', (173, 177))	('progression', 'CPA', (46, 57))	('tumors', 'Disease', (61, 67))	('p21', 'Gene', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('reduced', 'NegReg', (198, 205))	('enhanced', 'PosReg', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (86, 91))	('p27', 'Gene', (8, 11))	('tumors', 'Disease', (225, 231))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (61, 66))
32283	17948060	All mice were killed at the end of the 12 weeks, and two p21-/- had a tumor visible by gross histology.	('p21-/-', 'Var', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (4, 8))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
32286	17948060	Similar to gliomas in wild-type animals, tumors in the p21+/- and p21-/- animals were composed of small cells with round nuclei and scant cytoplasm.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('p21-/-', 'Var', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('cy', 'Chemical', 'MESH:D003545', (138, 140))	('gliomas', 'Disease', (11, 18))
32291	17948060	We noted that the Ki67 index, a marker for proliferating cells, was approximately two-fold lower in the two tumors arising in the p21-/- mice (per x 400 field: tumor A, 36+-25, P<0.001; tumor B, 59+-35, P<0.05) compared to the average level seen in five randomly chosen wild-type mice (per x 400 field: 86+-53).	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('Ki67', 'Gene', '17345', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p21-/-', 'Var', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mice', 'Species', '10090', (280, 284))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', (160, 165))	('Ki67', 'Gene', (18, 22))	('mice', 'Species', '10090', (137, 141))
32292	17948060	Furthermore, apoptotic indices, measured by the percentage of cells staining positively for cleaved caspase 3, were approximately 3-4-fold higher in the two tumors that arose in the p21-/- mice (per x 400 field: tumor A, 6+-2; tumor B, 8+-4) compared to wild-type mice (per x 400 field: 1+-1).	('tumor', 'Disease', (227, 232))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('caspase 3', 'Gene', '12367', (100, 109))	('apoptotic indices', 'CPA', (13, 30))	('higher', 'PosReg', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumors', 'Disease', (157, 163))	('mice', 'Species', '10090', (264, 268))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', (157, 162))	('caspase 3', 'Gene', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('p21-/-', 'Var', (182, 188))
32296	17948060	As shown in the accompanying Supplementary Figure 7, we confirmed that p21 deficiency did not affect the appearance of nestin-positive cells in the brains of neonatal mice or the expression of PDGF from the retroviral vector.	('PDGF', 'Gene', (193, 197))	('p21', 'Gene', (71, 74))	('cy', 'Chemical', 'MESH:D003545', (83, 85))	('mice', 'Species', '10090', (167, 171))	('deficiency', 'Var', (75, 85))
32298	17948060	To determine whether restoring p21 function in glial progenitors was sufficient to support tumor formation, we coinfected animals with an equal number of DF-1 cells expressing RCAS-PDGF-HA and RCAS-3xFp21 and scored for gliomagenesis.	('tumor', 'Disease', (91, 96))	('RCAS-3xFp21', 'Var', (193, 204))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('RCAS-PDGF-HA', 'Var', (176, 188))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RCAS', 'Chemical', '-', (176, 180))	('RCAS', 'Chemical', '-', (193, 197))	('glioma', 'Disease', (220, 226))
32302	17948060	p21-/- animals coinfected with both RCAS-PDGF-HA and RCAS-3xFp21 developed tumors (Figure 2).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('RCAS-3xFp21', 'Var', (53, 64))	('developed', 'PosReg', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RCAS', 'Chemical', '-', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('RCAS-PDGF-HA', 'Var', (36, 48))	('tumors', 'Disease', (75, 81))	('RCAS', 'Chemical', '-', (53, 57))
32316	17948060	Tumor latency, incidence and grade were similar to those seen in p21-deficient mice infected with RCAS-3xFp21 and RCAS-PDGF-HA (Figure 2B and C).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RCAS', 'Chemical', '-', (98, 102))	('Tumor latency', 'CPA', (0, 13))	('mice', 'Species', '10090', (79, 83))	('cy', 'Chemical', 'MESH:D003545', (11, 13))	('RCAS-3xFp21', 'Var', (98, 109))	('RCAS', 'Chemical', '-', (114, 118))
32319	17948060	Mutation of the cyclin binding or Cy element, in either fragment, reduced complementation activity (Figure 2B).	('reduced', 'NegReg', (66, 73))	('complementation activity', 'MPA', (74, 98))	('Mutation', 'Var', (0, 8))	('cyclin binding', 'Protein', (16, 30))	('Cy', 'Chemical', 'MESH:D003545', (34, 36))
32320	17948060	Tumors that arose in animals infected with constructs containing mutated Cy elements were of lower grade (Figure 2C).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Cy', 'Chemical', 'MESH:D003545', (73, 75))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutated', 'Var', (65, 72))
32322	17948060	Our analysis of these single base alanine substitutions and another multisite mutation in Cy1 (HRSK-to-AASA) revealed a role for this element in tumor initiation or progression.	('Cy', 'Chemical', 'MESH:D003545', (90, 92))	('alanine', 'Chemical', 'MESH:D000409', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor initiation', 'Disease', 'MESH:D009369', (145, 161))	('Cy1', 'Gene', (90, 93))	('tumor initiation', 'Disease', (145, 161))	('single', 'Var', (22, 28))
32324	17948060	Mutation of D6 slowed tumor development, and mutation of S2 abrogated complementation activity.	('slowed', 'NegReg', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (45, 53))	('tumor', 'Disease', (22, 27))	('abrogated', 'NegReg', (60, 69))	('complementation activity', 'MPA', (70, 94))
32325	17948060	An in silico analysis of protein folding suggests that neither the S2A and D6A mutation converted the flexible linker of the Cy element region, bordered by S14 and D25, to a more rigid helical fold as observed in the other noncomplementing mutants (Figure 3B).	('D6A', 'Var', (75, 78))	('flexible linker', 'MPA', (102, 117))	('converted', 'Reg', (88, 97))	('S2A', 'Var', (67, 70))	('Cy', 'Chemical', 'MESH:D003545', (125, 127))
32327	17948060	The p21Cy2 and p21Cy1Cy2 mutants were expressed at levels similar to full-length p21 (Figure 3C).	('Cy', 'Chemical', 'MESH:D003545', (18, 20))	('Cy', 'Chemical', 'MESH:D003545', (21, 23))	('p21Cy1Cy2', 'Var', (15, 24))	('p21Cy2', 'Var', (4, 10))	('Cy', 'Chemical', 'MESH:D003545', (7, 9))
32335	17948060	No mouse, regardless of p21 status, developed tumors when injected with an RCAS vector encoding p21 or any of the p21 mutants used in this study alone.	('RCAS', 'Chemical', '-', (75, 79))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('p21', 'Var', (96, 99))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
32336	17948060	PDGF was required to drive tumor development and p21, through its Cy domains, appears to affect progression.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('progression', 'CPA', (96, 107))	('affect', 'Reg', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('p21', 'Var', (49, 52))	('Cy', 'Chemical', 'MESH:D003545', (66, 68))
32339	17948060	Evidence from our lab and others has suggested that binding of p21 and p27 to cyclin D-cdk4 complexes does not inhibit their kinase activity in proliferating cells, but rather can interfere with nuclear export and cytosolic ubiquitin-dependent protein turnover.	('cy', 'Chemical', 'MESH:D003545', (214, 216))	('p21', 'Var', (63, 66))	('inhibit', 'NegReg', (111, 118))	('cdk4', 'Gene', (87, 91))	('cy', 'Chemical', 'MESH:D003545', (78, 80))	('cdk4', 'Gene', '12567', (87, 91))	('binding', 'Interaction', (52, 59))	('interfere', 'NegReg', (180, 189))	('nuclear export', 'MPA', (195, 209))	('cytosolic ubiquitin-dependent protein turnover', 'MPA', (214, 260))	('kinase activity', 'MPA', (125, 140))	('p27', 'Var', (71, 74))
32343	17948060	In p21-deficient cells, the amount of cyclin D-cdk4 complex and cyclin D-associated kinase activity were reduced (Supplementary Figure 9C and D), even though p27, a related cdk inhibitor, was present (Supplementary Figure 9E), suggesting that there might be a division of function between Kip-family members in this cell type.	('cdk4', 'Gene', '12567', (47, 51))	('p21-deficient', 'Var', (3, 16))	('Kip', 'Gene', (289, 292))	('cdk', 'Gene', (173, 176))	('cdk', 'Gene', '12566;12567;12571', (173, 176))	('reduced', 'NegReg', (105, 112))	('cyclin D-associated kinase activity', 'MPA', (64, 99))	('Kip', 'Gene', '23991', (289, 292))	('cdk4', 'Gene', (47, 51))	('cdk', 'Gene', '12566;12567;12571', (47, 50))	('cdk', 'Gene', (47, 50))	('amount', 'MPA', (28, 34))
32344	17948060	Furthermore, the amount of the D-type cyclins and cdk6 were reduced in p21-/- PDGF-transformed progenitor cells (Supplementary Figure 9E).	('p21-/- PDGF-transformed', 'Var', (71, 94))	('cdk6', 'Gene', (50, 54))	('cdk6', 'Gene', '12571', (50, 54))	('D-type', 'Protein', (31, 37))	('reduced', 'NegReg', (60, 67))	('amount', 'MPA', (17, 23))
32346	17948060	While the amount of cyclin E, cyclin A and cdk2 were only modestly affected by p21 deficiency (Supplementary Figure 9E), cdk2- and cyclin A-associated kinase activity was increased approximately 60% in p21-deficient cells (Supplementary Figure 9F).	('cdk2', 'Gene', (121, 125))	('activity', 'MPA', (158, 166))	('cdk2', 'Gene', '12566', (121, 125))	('p21', 'Gene', (79, 82))	('cyclin A', 'Gene', (30, 38))	('cy', 'Chemical', 'MESH:D003545', (91, 93))	('cy', 'Chemical', 'MESH:D003545', (30, 32))	('cyclin A', 'Gene', '12428', (131, 139))	('cy', 'Chemical', 'MESH:D003545', (20, 22))	('cdk2', 'Gene', (43, 47))	('deficiency', 'Var', (83, 93))	('cdk2', 'Gene', '12566', (43, 47))	('cy', 'Chemical', 'MESH:D003545', (131, 133))	('cyclin A', 'Gene', (131, 139))	('increased', 'PosReg', (171, 180))	('cyclin A', 'Gene', '12428', (30, 38))
32347	17948060	This reduces the likelihood that p21 deficiency is affecting PDGF receptor accumulation at the cell surface by acting in the receptor trafficking or endosome-sorting pathway.	('deficiency', 'Var', (37, 47))	('endosome-sorting pathway', 'Pathway', (149, 173))	('PDGF receptor', 'Protein', (61, 74))	('acting in', 'Reg', (111, 120))	('receptor trafficking', 'MPA', (125, 145))	('accumulation at the', 'MPA', (75, 94))	('affecting', 'Reg', (51, 60))	('cy', 'Chemical', 'MESH:D003545', (45, 47))	('p21', 'Gene', (33, 36))	('reduces', 'NegReg', (5, 12))
32350	17948060	Simply overexpressing wild-type cyclin D1 did not suffice to drive nuclear accumulation in p21-deficient glial cells; however, two cyclin D1 mutants were previously shown to accumulate in cki-deficient cells, and we confirmed this in our p21-deficient glial cells as well.	('accumulate', 'PosReg', (174, 184))	('cyclin D1', 'Gene', '12443', (32, 41))	('cyclin D1', 'Gene', (131, 140))	('mutants', 'Var', (141, 148))	('deficient glial cells', 'Phenotype', 'HP:0100705', (242, 263))	('cyclin D1', 'Gene', (32, 41))	('deficient glial cells', 'Phenotype', 'HP:0100705', (95, 116))	('cyclin D1', 'Gene', '12443', (131, 140))
32351	17948060	Mutation of Thr286 to Ala (cycD1T286A) blocks phosphorylation at this residue and prevents nuclear export.	('Mutation', 'Var', (0, 8))	('prevents', 'NegReg', (82, 90))	('nuclear export', 'MPA', (91, 105))	('phosphorylation at this residue', 'MPA', (46, 77))	('cy', 'Chemical', 'MESH:D003545', (27, 29))	('Thr286 to Ala', 'Mutation', 'p.T286A', (12, 25))	('blocks', 'NegReg', (39, 45))
32352	17948060	Mutation of Thr156 to Ala (cycD1T156A) largely, although not completely, accumulates in the cytosol where it binds cdk4 but fails to activate it.	('Thr156', 'Gene', (12, 18))	('Mutation', 'Var', (0, 8))	('cy', 'Chemical', 'MESH:D003545', (92, 94))	('cdk4', 'Gene', (115, 119))	('Thr156 to Ala', 'Mutation', 'p.T156A', (12, 25))	('cdk4', 'Gene', '12567', (115, 119))	('cy', 'Chemical', 'MESH:D003545', (27, 29))	('binds', 'Interaction', (109, 114))	('accumulates', 'PosReg', (73, 84))
32356	17948060	Approximately 15% of the cycD1T156A-expressing cells also had some nuclear staining, consistent with previously published work.	('cy', 'Chemical', 'MESH:D003545', (25, 27))	('nuclear staining', 'CPA', (67, 83))	('cycD1T156A-expressing', 'Var', (25, 46))
32357	17948060	Although cycD1T286A is a weak oncogene in a lymphoma model, we did not observe this in our model probably because of the short time frame in which animals were maintained post-infection.	('lymphoma', 'Disease', 'MESH:D008223', (44, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('cy', 'Chemical', 'MESH:D003545', (9, 11))	('cycD1T286A', 'Var', (9, 19))	('lymphoma', 'Disease', (44, 52))
32358	17948060	Similarly, expression of cycD1T156A alone did not induce tumors in mice.	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cy', 'Chemical', 'MESH:D003545', (25, 27))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('cycD1T156A', 'Var', (25, 35))	('mice', 'Species', '10090', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
32360	17948060	p21-deficient mice infected with cycD1T286A had reduced survival compared to those infected with cycD1T156A (Figure 4B).	('survival', 'CPA', (56, 64))	('mice', 'Species', '10090', (14, 18))	('reduced', 'NegReg', (48, 55))	('cy', 'Chemical', 'MESH:D003545', (33, 35))	('cycD1T286A', 'Var', (33, 43))	('cy', 'Chemical', 'MESH:D003545', (97, 99))
32361	17948060	Survival of cycD1T286A animals was slightly better, although not statistically significant, than those reconstituted with full-length p21.	('Survival', 'CPA', (0, 8))	('better', 'PosReg', (44, 50))	('cycD1T286A', 'Var', (12, 22))	('cy', 'Chemical', 'MESH:D003545', (12, 14))
32362	17948060	Greater than 50% of the p21-deficient mice infected with cycD1T286A developed moderate grade ODGs within 5 weeks and most of the mice were dead by 10 weeks with moderate- to high-grade glioma.	('cy', 'Chemical', 'MESH:D003545', (57, 59))	('mice', 'Species', '10090', (38, 42))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('moderate grade ODGs', 'CPA', (78, 97))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('mice', 'Species', '10090', (129, 133))	('cycD1T286A', 'Var', (57, 67))	('glioma', 'Disease', (185, 191))
32363	17948060	Consistent with the reduced nuclear accumulation of cycD1T156A, the rate of tumor progression was significantly slower in p21-/- mice infected with the RCAS-cycD1T156A mutant.	('slower', 'NegReg', (112, 118))	('reduced', 'NegReg', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('rate', 'CPA', (68, 72))	('cy', 'Chemical', 'MESH:D003545', (157, 159))	('cy', 'Chemical', 'MESH:D003545', (52, 54))	('RCAS', 'Chemical', '-', (152, 156))	('mice', 'Species', '10090', (129, 133))	('cycD1T156A', 'Var', (52, 62))	('RCAS-cycD1T156A', 'Var', (152, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('nuclear accumulation', 'MPA', (28, 48))
32364	17948060	Of the 10 p21-deficient mice infected with cycD1T156A, only two died within the first 6 weeks and these had low-grade tumors.	('cy', 'Chemical', 'MESH:D003545', (43, 45))	('mice', 'Species', '10090', (24, 28))	('cycD1T156A', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
32366	17948060	The tumors that arose in both cycD1T286A- and cycD1T156A-expressing animals were ODGs as judged by histological appearance of the cells, positive staining for olig2 and negative staining for NeuN.	('cy', 'Chemical', 'MESH:D003545', (46, 48))	('NeuN', 'Gene', '52897', (191, 195))	('cy', 'Chemical', 'MESH:D003545', (30, 32))	('olig2', 'Gene', (159, 164))	('olig2', 'Gene', '50913', (159, 164))	('cycD1T156A-expressing', 'Var', (46, 67))	('tumors', 'Disease', (4, 10))	('NeuN', 'Gene', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cycD1T286A-', 'Var', (30, 41))
32367	17948060	cycD1T286A was able to bind to cdk4, and did not bind cdk2 or cdk6 (Figure 4C).	('cycD1T286A', 'Var', (0, 10))	('cdk4', 'Gene', (31, 35))	('cdk2', 'Gene', (54, 58))	('cdk4', 'Gene', '12567', (31, 35))	('bind', 'Interaction', (23, 27))	('cdk2', 'Gene', '12566', (54, 58))	('cy', 'Chemical', 'MESH:D003545', (0, 2))	('cdk6', 'Gene', (62, 66))	('cdk6', 'Gene', '12571', (62, 66))
32371	17948060	Thus, we wanted to determine whether the ability of cycD1T286A to complement the p21 deficiency was also dependent on its ability to bind to cdk4.	('cy', 'Chemical', 'MESH:D003545', (93, 95))	('complement the p21 deficiency', 'Disease', 'MESH:C535365', (66, 95))	('cycD1T286A', 'Var', (52, 62))	('cdk4', 'Gene', (141, 145))	('cdk4', 'Gene', '12567', (141, 145))	('bind', 'Interaction', (133, 137))	('cy', 'Chemical', 'MESH:D003545', (52, 54))	('complement the p21 deficiency', 'Disease', (66, 95))
32372	17948060	To accomplish this, we generated an RCAS vector expressing another cyclin D1 mutant, cycD1T286A/K114E, which did not bind to cdk2, 4, or 6 (Figure 5A), but accumulated in the nucleus of all cells (Figure 5B).	('cyclin D1', 'Gene', '12443', (67, 76))	('cdk2', 'Gene', (125, 129))	('cy', 'Chemical', 'MESH:D003545', (67, 69))	('cdk2', 'Gene', '12566', (125, 129))	('cy', 'Chemical', 'MESH:D003545', (85, 87))	('accumulated', 'PosReg', (156, 167))	('K114E', 'Mutation', 'rs1280426773', (96, 101))	('cycD1T286A/K114E', 'Var', (85, 101))	('cyclin D1', 'Gene', (67, 76))	('RCAS', 'Chemical', '-', (36, 40))
32373	17948060	This cycD1K114E mutant was originally characterized as a non-cdk-binding protein.	('K114E', 'Mutation', 'rs1280426773', (10, 15))	('cy', 'Chemical', 'MESH:D003545', (5, 7))	('cycD1K114E', 'Var', (5, 15))	('cdk', 'Gene', (61, 64))	('cdk', 'Gene', '12566;12567;12571', (61, 64))
32376	17948060	However, unlike cycD1T286A, cycD1T286A/K114E did not support the development of ODG induced by RCAS-PDGF (Figure 5C).	('RCAS', 'Chemical', '-', (95, 99))	('cy', 'Chemical', 'MESH:D003545', (16, 18))	('not', 'NegReg', (49, 52))	('cycD1T286A/K114E', 'Var', (28, 44))	('K114E', 'Mutation', 'rs1280426773', (39, 44))	('cy', 'Chemical', 'MESH:D003545', (28, 30))
32383	17948060	In our studies we found that p21 facilitates the development of PDGF-induced ODG in mice.	('p21', 'Var', (29, 32))	('PDGF-induced', 'Gene', (64, 76))	('development', 'CPA', (49, 60))	('facilitates', 'PosReg', (33, 44))	('mice', 'Species', '10090', (84, 88))
32384	17948060	Thus, p21 makes a contribution to tumor progression.	('p21', 'Var', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
32388	17948060	A more recent study in a p27ck(-) knock-in animal model suggested a cdk-independent function promoting stem cell expansion and tumor development, and p27ck(-) protein was both nuclear and cytoplasmic.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('stem cell expansion', 'CPA', (103, 122))	('tumor', 'Disease', (127, 132))	('promoting', 'PosReg', (93, 102))	('cy', 'Chemical', 'MESH:D003545', (188, 190))	('p27ck(-', 'Var', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cdk', 'Gene', '12566;12567;12571', (68, 71))	('cdk', 'Gene', (68, 71))
32389	17948060	In addition to ODG, there are suggestions for p21 'oncogenicity' in other human cancers as well, including prostate, cervical, breast, squamous cell carcinoma, and tall-cell and well-differentiated papillary thyroid cancer (RG, BS and AK, unpublished data).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('breast', 'Disease', (127, 133))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (198, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('papillary thyroid cancer', 'Disease', (198, 222))	('p21', 'Var', (46, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cancers', 'Disease', (80, 87))	('squamous cell carcinoma', 'Disease', (135, 158))	('tall-cell', 'Disease', (164, 173))	('prostate', 'Disease', (107, 115))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (198, 222))	('thyroid cancer', 'Phenotype', 'HP:0002890', (208, 222))	('cervical', 'Disease', (117, 125))	('human', 'Species', '9606', (74, 79))
32400	17948060	In the studies presented here we have shown that p21 accumulates in the nucleus of ODG tumor cells and in glial cells stimulated by PDGF signaling.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('accumulates', 'PosReg', (53, 64))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('p21', 'Var', (49, 52))
32402	17948060	Most importantly, by using somatic cell engineering, we established that p21 acts cell autonomously to promote tumor development, and this depends on the Cy element.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('Cy', 'Chemical', 'MESH:D003545', (154, 156))	('promote', 'PosReg', (103, 110))	('p21', 'Var', (73, 76))
32404	17948060	Nevertheless, the status of p21 had no effect on the accumulation of PDGF receptors at the cell surface, and we were able to bypass the effect of p21 deficiency by enforcing accumulation of functional cyclin D1.	('cy', 'Chemical', 'MESH:D003545', (201, 203))	('accumulation', 'PosReg', (174, 186))	('PDGF', 'Protein', (69, 73))	('deficiency', 'Var', (150, 160))	('cyclin D1', 'Gene', (201, 210))	('cy', 'Chemical', 'MESH:D003545', (158, 160))	('p21', 'Gene', (146, 149))	('cyclin D1', 'Gene', '12443', (201, 210))
32405	17948060	Mutants of cyclin D1 that fail to accumulate in the nucleus but bind cdk4, or that accumulate in the nucleus but fail to bind cdk4 were both unable to support tumor development.	('cdk4', 'Gene', (126, 130))	('cyclin D1', 'Gene', (11, 20))	('cdk4', 'Gene', (69, 73))	('cdk4', 'Gene', '12567', (126, 130))	('unable', 'NegReg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cdk4', 'Gene', '12567', (69, 73))	('tumor', 'Disease', (159, 164))	('cyclin D1', 'Gene', '12443', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('Mutants', 'Var', (0, 7))
32406	17948060	All together, this suggests that p21 promotes ODG by stabilizing cyclin D1-cdk4 in the nucleus.	('stabilizing', 'MPA', (53, 64))	('p21', 'Var', (33, 36))	('ODG', 'Disease', (46, 49))	('cyclin D1-cdk4', 'Gene', (65, 79))	('cyclin D1-cdk4', 'Gene', '12443;12567', (65, 79))	('promotes', 'PosReg', (37, 45))
32407	17948060	Although this mechanism has been suggested before, specifically for p27 in the Pten/Nkx3.1 and MMTV-erbB2 models, and for p21 in the MMTV-Wnt1 model, this is the first time that a genetic proof has been used to assess the veracity of this model.	('p27', 'Var', (68, 71))	('erbB2', 'Gene', '13866', (100, 105))	('erbB2', 'Gene', (100, 105))	('MMTV', 'Species', '11757', (133, 137))	('MMTV', 'Species', '11757', (95, 99))
32408	17948060	For example, it was surprising that the ability of the p21Cy2 and p21Cy1Cy2 mutants were comparable, albeit there was a 'cy-dose' dependency to the onset of morbidity.	('Cy', 'Chemical', 'MESH:D003545', (69, 71))	('p21Cy1Cy2', 'Var', (66, 75))	('cy', 'Chemical', 'MESH:D003545', (138, 140))	('Cy', 'Chemical', 'MESH:D003545', (58, 60))	('cy', 'Chemical', 'MESH:D003545', (121, 123))	('p21Cy2', 'Var', (55, 61))	('Cy', 'Chemical', 'MESH:D003545', (72, 74))
32409	17948060	We expected that the p21Cy2 mutant, with an intact Cy1 element, would support tumor development, just like Np21.	('Cy', 'Chemical', 'MESH:D003545', (51, 53))	('Cy', 'Chemical', 'MESH:D003545', (24, 26))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('p21Cy2', 'Var', (21, 27))	('tumor', 'Disease', (78, 83))	('support', 'PosReg', (70, 77))
32414	17948060	PDGF-transformed glial progenitors were generated by infecting whole brain cultures of either p21+/+Ntv-a or p21-/-Ntv-a mice with RCAS-PDGF-HA viral supernatants obtained from infected DF-1 cells, and maintained in DMEM supplemented with 10% fetal bovine serum.	('p21-/-Ntv-a', 'Var', (109, 120))	('mice', 'Species', '10090', (121, 125))	('RCAS', 'Chemical', '-', (131, 135))	('p21+/+Ntv-a', 'Var', (94, 105))	('DMEM', 'Chemical', '-', (216, 220))	('bovine', 'Species', '9913', (249, 255))
32427	30397180	Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists.	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('mutant', 'Var', (83, 89))	('Isocitrate dehydrogenase', 'Gene', (97, 121))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('isocitrate dehydrogenase', 'Gene', '3417', (58, 82))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('mutant', 'Var', (128, 134))	('DLL3', 'Gene', (26, 30))	('glioma', 'Disease', (135, 141))	('isocitrate dehydrogenase', 'Gene', (58, 82))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Disease', (158, 164))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('IDH', 'Gene', (123, 126))	('DLL3', 'Gene', '10683', (26, 30))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('Isocitrate dehydrogenase', 'Gene', '3417', (97, 121))	('gliomas', 'Disease', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('IDH', 'Gene', '3417', (123, 126))
32430	30397180	We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody.	('tumor brain', 'Phenotype', 'HP:0030692', (124, 135))	('gliomas', 'Disease', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('IDH', 'Gene', (177, 180))	('tumor', 'Disease', (124, 129))	('mutant', 'Var', (194, 200))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('IDH', 'Gene', '3417', (177, 180))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
32431	30397180	The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('IDH', 'Gene', (51, 54))	('glioma tumorspheres', 'Disease', (62, 81))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH', 'Gene', '3417', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutant', 'Var', (55, 61))	('patient', 'Species', '9606', (24, 31))	('Rova-T', 'Chemical', 'MESH:C000620223', (14, 20))	('glioma tumorspheres', 'Disease', 'MESH:D005910', (62, 81))
32434	30397180	Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T. DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres.	('glioma tumorspheres', 'Disease', (27, 46))	('IDH', 'Gene', '3417', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('IDH', 'Gene', (16, 19))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('glioma tumorspheres', 'Disease', 'MESH:D005910', (237, 256))	('Rova-T', 'Chemical', 'MESH:C000620223', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('mutant', 'Var', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('IDH', 'Gene', '3417', (16, 19))	('DLL3', 'Protein', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('glioma tumorspheres', 'Disease', (237, 256))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('IDH', 'Gene', (156, 159))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('IDH', 'Gene', (226, 229))	('glioma tumorspheres', 'Disease', 'MESH:D005910', (27, 46))	('overexpressed', 'PosReg', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Rova-T', 'Chemical', 'MESH:C000620223', (200, 206))	('patient', 'Species', '9606', (210, 217))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('IDH', 'Gene', '3417', (156, 159))	('Patient', 'Species', '9606', (0, 7))
32436	30397180	Mutations in the isocitrate dehydrogenase (IDH) 1 and IDH2 genes identify a subtype of glioma with distinct biological, clinical and radiographic features.	('glioma', 'Disease', (87, 93))	('IDH2', 'Gene', (54, 58))	('IDH2', 'Gene', '3418', (54, 58))	('Mutations', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (17, 49))
32437	30397180	These gliomas develop through early mutation of IDH, which results in accumulation of 2-hydroxyglutarate and a genome-wide DNA hypermethylation phenotype, followed by acquisition of one of two sets of co-occurring genetic alterations: TP53 and ATRX mutations, or 1p/19q codeletion and mutations in TERT, CIC and FUBP1.	('FUBP1', 'Gene', (312, 317))	('CIC', 'Gene', '23152', (304, 307))	('ATRX', 'Gene', (244, 248))	('ATRX', 'Gene', '546', (244, 248))	('TP53', 'Gene', (235, 239))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('IDH', 'Gene', (48, 51))	('TERT', 'Gene', (298, 302))	('DNA hypermethylation', 'MPA', (123, 143))	('TERT', 'Gene', '7015', (298, 302))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('1p/19q codeletion', 'Var', (263, 280))	('FUBP1', 'Gene', '8880', (312, 317))	('2-hydroxyglutarate', 'MPA', (86, 104))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))	('mutations', 'Var', (285, 294))	('IDH', 'Gene', '3417', (48, 51))	('CIC', 'Gene', (304, 307))	('TP53', 'Gene', '7157', (235, 239))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (86, 104))	('accumulation', 'PosReg', (70, 82))	('gliomas', 'Disease', (6, 13))	('mutation', 'Var', (36, 44))
32438	30397180	More recent studies have identified a small subset of more aggressive IDH mutant gliomas associated with lower global DNA methylation and homozygous CDKN2A/B deletion, and alterations that are frequently acquired at recurrence, including temozolomide-induced hypermutation phenotype, Myc pathway alterations, and driver oncogenes and tumor suppressors.	('aggressive', 'PosReg', (59, 69))	('CDKN2A/B', 'Gene', '1029;1030', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('temozolomide', 'Chemical', 'MESH:D000077204', (238, 250))	('mutant', 'Var', (74, 80))	('Myc', 'Gene', (284, 287))	('gliomas', 'Disease', (81, 88))	('deletion', 'Var', (158, 166))	('lower', 'NegReg', (105, 110))	('IDH', 'Gene', (70, 73))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('tumor', 'Disease', (334, 339))	('CDKN2A/B', 'Gene', (149, 157))	('global DNA methylation', 'MPA', (111, 133))	('Myc', 'Gene', '4609', (284, 287))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('IDH', 'Gene', '3417', (70, 73))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('alterations', 'Var', (172, 183))
32440	30397180	Standard adjuvant treatment consisting of radiation and the procarbazine, CCNU, vincristine (PCV) chemotherapy regimen improves survival of IDH mutant glioma patients; however, most tumors eventually recur and are lethal.	('survival', 'MPA', (128, 136))	('CCNU', 'Gene', (74, 78))	('CCNU', 'Gene', '10309', (74, 78))	('procarbazine', 'Chemical', 'MESH:D011344', (60, 72))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('IDH', 'Gene', '3417', (140, 143))	('improves', 'PosReg', (119, 127))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('vincristine', 'Chemical', 'MESH:D014750', (80, 91))	('patients', 'Species', '9606', (158, 166))	('mutant', 'Var', (144, 150))	('glioma', 'Disease', (151, 157))	('IDH', 'Gene', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
32447	30397180	Because 80-90% of low-grade gliomas are IDH mutant, we therefore hypothesized that DLL3 would be highly overexpressed in IDH mutant glioma and that expression would be tightly associated with IDH mutant gliomas compared to IDH wildtype glioma.	('glioma', 'Disease', (132, 138))	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('IDH', 'Gene', (121, 124))	('IDH', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('gliomas', 'Disease', (203, 210))	('gliomas', 'Disease', (28, 35))	('IDH', 'Gene', '3417', (192, 195))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH', 'Gene', (223, 226))	('IDH', 'Gene', '3417', (121, 124))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('IDH', 'Gene', '3417', (40, 43))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('mutant', 'Var', (125, 131))	('overexpressed', 'PosReg', (104, 117))	('IDH', 'Gene', '3417', (223, 226))	('IDH', 'Gene', (192, 195))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Disease', (236, 242))	('associated', 'Reg', (176, 186))	('expression', 'MPA', (148, 158))	('DLL3', 'Gene', (83, 87))	('glioma', 'Disease', (203, 209))	('glioma', 'Disease', (28, 34))	('glioma', 'Disease', 'MESH:D005910', (236, 242))
32449	30397180	We then tested the therapeutic potential of the anti-DLL3 ADC Rova-T using patient-derived glioma tumorsphere cultures.	('tested', 'Reg', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('glioma tumorsphere', 'Disease', (91, 109))	('Rova-T', 'Chemical', 'MESH:C000620223', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('anti-DLL3', 'Var', (48, 57))	('patient', 'Species', '9606', (75, 82))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('glioma tumorsphere', 'Disease', 'MESH:D005910', (91, 109))
32452	30397180	For the validation set, 62 gliomas with known IDH1/2 mutation status were obtained from the NYU pathology database to compare DLL3 expression in IDH mutant glioma and IDH wildtype glioblastoma.	('glioma', 'Disease', (156, 162))	('IDH', 'Gene', '3417', (145, 148))	('IDH1/2', 'Gene', '3417;3418', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('gliomas', 'Disease', (27, 34))	('IDH', 'Gene', (167, 170))	('glioma', 'Disease', (27, 33))	('IDH1/2', 'Gene', (46, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (180, 192))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('IDH', 'Gene', (46, 49))	('IDH wildtype glioblastoma', 'Disease', (167, 192))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('IDH wildtype glioblastoma', 'Disease', 'MESH:D005909', (167, 192))	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('IDH', 'Gene', '3417', (167, 170))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('mutant', 'Var', (149, 155))	('IDH', 'Gene', '3417', (46, 49))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('IDH', 'Gene', (145, 148))
32454	30397180	Within IDH mutant gliomas, there were 14 recurrent tumors, 11 of which had paired original tumors from the same patient.	('IDH', 'Gene', (7, 10))	('tumors', 'Disease', (91, 97))	('mutant', 'Var', (11, 17))	('gliomas', 'Disease', (18, 25))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('patient', 'Species', '9606', (112, 119))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('IDH', 'Gene', '3417', (7, 10))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
32474	30397180	Specifically, the methylation class family "Glioma, IDH mutant" comprises the methylation classes "astrocytoma, IDH mutant", "astrocytoma, IDH mutant, subtype high grade" and "oligodendroglioma, IDH mutant and 1p/19q codeleted".	('Glioma', 'Disease', 'MESH:D005910', (44, 50))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', '3417', (52, 55))	('oligodendroglioma', 'Disease', 'MESH:D009837', (176, 193))	('IDH', 'Gene', (112, 115))	('IDH', 'Gene', '3417', (139, 142))	('astrocytoma', 'Disease', 'MESH:D001254', (126, 137))	('oligodendroglioma', 'Disease', (176, 193))	('astrocytoma', 'Disease', (126, 137))	('Glioma', 'Phenotype', 'HP:0009733', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('astrocytoma', 'Disease', 'MESH:D001254', (99, 110))	('astrocytoma', 'Disease', (99, 110))	('IDH', 'Gene', '3417', (112, 115))	('Glioma', 'Disease', (44, 50))	('mutant', 'Var', (116, 122))	('IDH', 'Gene', (195, 198))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', (139, 142))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
32479	30397180	For the IDH mutant glioma cohort in the validation set, IDH mutation status was determined by immunohistochemistry for IDH1 R132H or by the clinical targeted NGS panel.	('IDH', 'Gene', '3417', (119, 122))	('IDH', 'Gene', (8, 11))	('IDH', 'Gene', (56, 59))	('R132H', 'Var', (124, 129))	('glioma', 'Disease', (19, 25))	('IDH', 'Gene', '3417', (8, 11))	('IDH1', 'Gene', (119, 123))	('IDH', 'Gene', '3417', (56, 59))	('R132H', 'Mutation', 'rs121913500', (124, 129))	('IDH1', 'Gene', '3417', (119, 123))	('IDH', 'Gene', (119, 122))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
32481	30397180	1p/19q codeletion status for IDH mutant gliomas in the validation set was previously determined utilizing a loss of heterozygosity (LOH) PCR CLIA laboratory developed assay.	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('IDH', 'Gene', (29, 32))	('mutant', 'Var', (33, 39))	('IDH', 'Gene', '3417', (29, 32))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
32483	30397180	The polymorphic chromosomal markers of 1p (7 loci, D1S1612, D1S430, D1S199, D1S224, DIS162, DIS171 and D1S1161) and 19q (4 loci, D19S601, D19S412, D19S112 and D19S559) were used to evaluate 1p/19q LOH in the tumor by PCR.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('D1S199', 'Var', (68, 74))	('D1S224', 'Var', (76, 82))	('D1S1161', 'Var', (103, 110))	('DIS162', 'Var', (84, 90))	('D19S412', 'Var', (138, 145))	('D1S1612', 'Var', (51, 58))	('D19S112', 'Var', (147, 154))	('DIS171', 'Var', (92, 98))	('D19S559', 'Var', (159, 166))	('D1S430', 'Var', (60, 66))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('D19S601', 'Var', (129, 136))
32485	30397180	To detect 1p/19q LOH, tumor tissue was no less than 75% of the total sample tissue.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('1p/19q LOH', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
32489	30397180	U87 cells constitutively expressing GFP (U87-GFP) or IDH1 R132H (U87-IDH) were engineered previously in our lab.	('U87', 'Gene', '641648', (41, 44))	('U87', 'Gene', '641648', (0, 3))	('U87', 'Gene', '641648', (65, 68))	('IDH', 'Gene', (69, 72))	('R132H', 'Mutation', 'rs121913500', (58, 63))	('IDH1', 'Gene', (53, 57))	('IDH', 'Gene', '3417', (69, 72))	('IDH1', 'Gene', '3417', (53, 57))	('U87', 'Gene', (41, 44))	('IDH', 'Gene', (53, 56))	('U87', 'Gene', (0, 3))	('GFP', 'Var', (36, 39))	('U87', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (53, 56))
32492	30397180	To induce mutant IDH1 expression, MGG18-IDH1 cells were cultured with doxycycline (Sigma-Aldrich, 1 mug/ml) for 72 hours.	('doxycycline', 'Chemical', 'MESH:D004318', (70, 81))	('mutant', 'Var', (10, 16))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (40, 44))	('IDH1', 'Gene', (17, 21))	('IDH1', 'Gene', '3417', (17, 21))	('expression', 'MPA', (22, 32))
32504	30397180	Among all glial and neuronal tumors in the TCGA dataset with available sequence data, including diffuse gliomas, pilocytic astrocytomas, and medulloblastomas, only 4 tumors had DLL3 gene amplification (all glioblastomas), 3 DLL3 missense mutations were detected (two diffuse gliomas, one medulloblastoma), and 1 DLL3 fusion was detected in an oligodendroglioma (Supplementary Table S2).	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (113, 135))	('neuronal tumors', 'Disease', 'MESH:D009410', (20, 35))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('medulloblastoma', 'Disease', 'MESH:D008527', (141, 156))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('oligodendroglioma', 'Disease', (343, 360))	('medulloblastoma', 'Phenotype', 'HP:0002885', (141, 156))	('DLL3', 'Gene', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('glioblastomas', 'Disease', (206, 219))	('gliomas', 'Disease', 'MESH:D005910', (275, 282))	('medulloblastoma', 'Disease', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('medulloblastomas', 'Disease', 'MESH:D008527', (141, 157))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('glioma', 'Phenotype', 'HP:0009733', (354, 360))	('amplification', 'PosReg', (187, 200))	('tumors', 'Disease', (29, 35))	('tumors', 'Disease', (166, 172))	('gliomas', 'Phenotype', 'HP:0009733', (275, 282))	('glioblastomas', 'Disease', 'MESH:D005909', (206, 219))	('DLL3 gene', 'Gene', (177, 186))	('gliomas', 'Disease', (104, 111))	('missense mutations', 'Var', (229, 247))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('pilocytic astrocytomas', 'Disease', (113, 135))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('neuronal tumors', 'Phenotype', 'HP:0025170', (20, 35))	('medulloblastoma', 'Phenotype', 'HP:0002885', (288, 303))	('medulloblastoma', 'Disease', 'MESH:D008527', (288, 303))	('medulloblastoma', 'Disease', (288, 303))	('neuronal tumors', 'Disease', (20, 35))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('glioblastomas', 'Phenotype', 'HP:0012174', (206, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('medulloblastomas', 'Disease', (141, 157))	('gliomas', 'Disease', (275, 282))	('oligodendroglioma', 'Disease', 'MESH:D009837', (343, 360))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
32509	30397180	There were 17 classified as IDH wildtype glioblastoma, 19 as IDH mutant gliomas (including nine IDH mutant, 1p/19q codeleted and 10 IDH mutant, non-codeleted tumors), and 10 tumors of other major designated classes.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('IDH', 'Gene', '3417', (61, 64))	('IDH wildtype glioblastoma', 'Disease', (28, 53))	('IDH wildtype glioblastoma', 'Disease', 'MESH:D005909', (28, 53))	('IDH', 'Gene', '3417', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('tumors', 'Disease', (174, 180))	('IDH', 'Gene', '3417', (96, 99))	('1p/19q', 'Var', (108, 114))	('gliomas', 'Disease', (72, 79))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('IDH', 'Gene', (132, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('IDH', 'Gene', (61, 64))	('IDH', 'Gene', (28, 31))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('IDH', 'Gene', '3417', (132, 135))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('IDH', 'Gene', (96, 99))
32511	30397180	Based on the differences in gene expression, we compared the DLL3 IHC scores by H-score (scored at Abbvie Stemcentrx) and percent of positive tumor cells (scored independently at NYU) between IDH mutant glioma and IDH wildtype glioblastoma and found a marked difference in DLL3 expression (P=0.0014 for H-score, P=0.003 for percent of DLL3 positive tumor cells) (Table 1, Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('DLL3', 'Gene', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('IDH', 'Gene', '3417', (192, 195))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('expression', 'MPA', (278, 288))	('IDH', 'Gene', (214, 217))	('glioblastoma', 'Phenotype', 'HP:0012174', (227, 239))	('tumor', 'Disease', (142, 147))	('IDH wildtype glioblastoma', 'Disease', (214, 239))	('difference', 'Reg', (259, 269))	('IDH wildtype glioblastoma', 'Disease', 'MESH:D005909', (214, 239))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('IDH', 'Gene', '3417', (214, 217))	('mutant', 'Var', (196, 202))	('tumor', 'Disease', (349, 354))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('glioma', 'Disease', (203, 209))	('IDH', 'Gene', (192, 195))
32520	30397180	In the validation set, we confirmed that DLL3 expression in IDH mutant glioma was intense, homogeneous, and significantly higher than in IDH wildtype glioblastoma, with median H-scores of 130 vs. 10 (P=4.3 x 10-6) for IDH mutant glioma and IDH wildtype glioblastoma, respectively, and median proportion of positive tumor cells of 60% vs. 5% (P=1.7 x 10-7), respectively (Table 1).	('IDH', 'Gene', (240, 243))	('glioblastoma', 'Phenotype', 'HP:0012174', (253, 265))	('IDH', 'Gene', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('DLL3', 'Gene', (41, 45))	('IDH wildtype glioblastoma', 'Disease', (137, 162))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('IDH wildtype glioblastoma', 'Disease', 'MESH:D005909', (137, 162))	('IDH', 'Gene', '3417', (218, 221))	('IDH wildtype glioblastoma', 'Disease', (240, 265))	('IDH wildtype glioblastoma', 'Disease', 'MESH:D005909', (240, 265))	('H-scores', 'MPA', (176, 184))	('IDH', 'Gene', '3417', (137, 140))	('IDH', 'Gene', '3417', (240, 243))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('mutant', 'Var', (64, 70))	('higher', 'PosReg', (122, 128))	('glioma', 'Disease', (71, 77))	('IDH', 'Gene', (60, 63))	('expression', 'MPA', (46, 56))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Disease', (229, 235))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH', 'Gene', (218, 221))	('glioma', 'Disease', 'MESH:D005910', (229, 235))	('IDH', 'Gene', '3417', (60, 63))	('tumor', 'Disease', (315, 320))
32527	30397180	All IDH mutant, 1p/19q codeleted gliomas expressed DLL3, with the lowest H-score being 50, while in 8 of 9 (89%) tumors DLL3 was positive in >=50% of tumor cells and in 6 of 9 (67%) DLL3 was positive in at least 90% of tumor cells, including two high-grade (grade III) tumors.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumors', 'Disease', (113, 119))	('IDH', 'Gene', '3417', (4, 7))	('tumor', 'Disease', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('expressed', 'Reg', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('mutant', 'Var', (8, 14))	('tumors', 'Disease', (269, 275))	('DLL3', 'Protein', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (113, 118))	('gliomas', 'Disease', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('tumor', 'Disease', (150, 155))	('IDH', 'Gene', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('tumor', 'Disease', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('1p/19q', 'Var', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
32529	30397180	In the discovery set, there was a significant difference in DLL3 expression between the two subclasses (P=0.012 for H-score, P=0.01 for percent of positive tumor cells), with median H-scores and DLL3 positive tumor cell proportions of 270 and 90%, respectively, for the 1p/19q codeleted subclass and 85 and 55%, respectively, for the astrocytoma subclass.	('tumor', 'Disease', (209, 214))	('astrocytoma', 'Disease', 'MESH:D001254', (334, 345))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('astrocytoma', 'Disease', (334, 345))	('DLL3', 'Gene', (60, 64))	('astrocytoma', 'Phenotype', 'HP:0009592', (334, 345))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('expression', 'MPA', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('1p/19q', 'Var', (270, 276))
32530	30397180	In the validation set, however, there was no statistically significant difference between the astrocytoma and 1p/19q codeleted subset of IDH mutant gliomas (Figure 4, Supplementary Table S6).	('astrocytoma', 'Disease', 'MESH:D001254', (94, 105))	('gliomas', 'Disease', (148, 155))	('mutant', 'Var', (141, 147))	('IDH', 'Gene', '3417', (137, 140))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('astrocytoma', 'Disease', (94, 105))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('IDH', 'Gene', (137, 140))
32531	30397180	In the IDH mutant, astrocytoma subclass half (5 of 10) had at least 50% of tumor cells DLL3 positive, including 4 (40%) with >=80% DLL3 positive tumor cells.	('IDH', 'Gene', (7, 10))	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('mutant', 'Var', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('astrocytoma subclass half', 'Disease', (19, 44))	('IDH', 'Gene', '3417', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('DLL3', 'Var', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (145, 150))	('astrocytoma subclass half', 'Disease', 'MESH:D001254', (19, 44))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
32534	30397180	Notably, there were two glioblastomas in the molecular IDH mutant astrocytoma set, with tumor cells positive in only 5% in one and 80% in the other.	('astrocytoma', 'Disease', (66, 77))	('glioblastomas', 'Disease', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IDH', 'Gene', (55, 58))	('mutant', 'Var', (59, 65))	('glioblastomas', 'Phenotype', 'HP:0012174', (24, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (66, 77))	('IDH', 'Gene', '3417', (55, 58))	('glioblastomas', 'Disease', 'MESH:D005909', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (24, 36))	('tumor', 'Disease', (88, 93))	('astrocytoma', 'Disease', 'MESH:D001254', (66, 77))
32535	30397180	Similar to the discovery set, only 2 of 25 (8%) IDH mutant gliomas in the validation set lacked DLL3 expression, both were astrocytomas (Figure 4, Supplementary Tables S4, S5).	('astrocytomas', 'Disease', 'MESH:D001254', (123, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('IDH', 'Gene', (48, 51))	('DLL3 expression', 'MPA', (96, 111))	('mutant', 'Var', (52, 58))	('lacked', 'NegReg', (89, 95))	('IDH', 'Gene', '3417', (48, 51))	('astrocytomas', 'Disease', (123, 135))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
32546	30397180	We first confirmed by Western blot that our patient-derived, endogenous IDH mutant glioma tumorsphere lines MGG119 and MGG152 expressed DLL3 (Figure 5).	('patient', 'Species', '9606', (44, 51))	('glioma tumorsphere', 'Disease', 'MESH:D005910', (83, 101))	('mutant', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('glioma tumorsphere', 'Disease', (83, 101))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('DLL3', 'Protein', (136, 140))
32549	30397180	We then tested whether patient-derived, endogenous IDH mutant glioma tumorsphere lines could be killed with an agent that targets cell surface DLL3.	('tested', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('IDH', 'Gene', (51, 54))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioma tumorsphere', 'Disease', 'MESH:D005910', (62, 80))	('IDH', 'Gene', '3417', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutant', 'Var', (55, 61))	('glioma tumorsphere', 'Disease', (62, 80))	('DLL3', 'Protein', (143, 147))	('patient', 'Species', '9606', (23, 30))
32551	30397180	In cells expressing DLL3, Rova-T is specifically internalized and trafficked to late endosomes and induces cytotoxicity.	('induces', 'Reg', (99, 106))	('cytotoxicity', 'Disease', 'MESH:D064420', (107, 119))	('DLL3', 'Var', (20, 24))	('Rova-T', 'Var', (26, 32))	('cytotoxicity', 'Disease', (107, 119))	('Rova-T', 'Chemical', 'MESH:C000620223', (26, 32))
32552	30397180	In cell vibility assays we found that the IDH mutant tumorsphere lines MGG119 and MGG152, both of which express high levels of DLL3, were sensitive to SC16LD6.5 and resistant to control ADC at picomolar concentrations (Figure 5).	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutant', 'Var', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
32553	30397180	Therefore, our endogenous IDH mutant patient-derived glioma tumorspheres expressed high levels of DLL3 and were highly sensitive to Rova-T, whereas cells lacking DLL3 were resistant.	('patient', 'Species', '9606', (37, 44))	('DLL3', 'MPA', (98, 102))	('glioma tumorspheres', 'Disease', 'MESH:D005910', (53, 72))	('glioma tumorspheres', 'Disease', (53, 72))	('sensitive', 'MPA', (119, 128))	('IDH', 'Gene', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Rova-T', 'Chemical', 'MESH:C000620223', (132, 138))	('IDH', 'Gene', '3417', (26, 29))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('mutant', 'Var', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
32555	30397180	Additionally, we found that patient-derived endogenous IDH mutant glioma tumorspheres, which overexpress DLL3, were potently and selectively sensitive to the anti-DLL3 ADC Rova-T in vitro.	('IDH', 'Gene', (55, 58))	('glioma tumorspheres', 'Disease', (66, 85))	('mutant', 'Var', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Rova-T', 'Chemical', 'MESH:C000620223', (172, 178))	('IDH', 'Gene', '3417', (55, 58))	('sensitive', 'Reg', (141, 150))	('patient', 'Species', '9606', (28, 35))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('glioma tumorspheres', 'Disease', 'MESH:D005910', (66, 85))
32556	30397180	Therefore, we show that that DLL3 is a newly identified cell surface therapeutic target in IDH mutant glioma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('IDH', 'Gene', (91, 94))	('mutant', 'Var', (95, 101))	('glioma', 'Disease', (102, 108))	('IDH', 'Gene', '3417', (91, 94))
32559	30397180	Rova-T is in clinical development for cancer and therefore our findings could be immediately translated to clinical trials in IDH mutant glioma.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('IDH', 'Gene', '3417', (126, 129))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('Rova-T', 'Chemical', 'MESH:C000620223', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('glioma', 'Disease', (137, 143))	('cancer', 'Disease', (38, 44))	('mutant', 'Var', (130, 136))	('IDH', 'Gene', (126, 129))
32561	30397180	In addition, the cell surface localization of DLL3 and its homogeneous expression in IDH mutant glioma potentially opens the door for development of additional therapeutic strategies that exploit clonal cell surface antigens, such as adoptive cell transfer and other antibody-based targeting strategies.	('IDH', 'Gene', '3417', (85, 88))	('DLL3', 'Gene', (46, 50))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH', 'Gene', (85, 88))	('mutant', 'Var', (89, 95))	('glioma', 'Disease', (96, 102))
32563	30397180	It is intriguing to speculate that the progenitor cell of IDH mutant gliomas is a DLL3-expressing low proliferation rate neuroblast, and that IDH mutation and the subsequent epigenetic reprogramming induced by the mutation prevents terminal differentiation of neuroblasts into neurons.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('IDH', 'Gene', '3417', (58, 61))	('gliomas', 'Disease', (69, 76))	('mutant', 'Var', (62, 68))	('mutation', 'Var', (146, 154))	('mutation', 'Var', (214, 222))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('IDH', 'Gene', (142, 145))	('IDH', 'Gene', '3417', (142, 145))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('epigenetic reprogramming', 'CPA', (174, 198))	('prevents', 'NegReg', (223, 231))	('IDH', 'Gene', (58, 61))
32564	30397180	Evidence for the similarity of IDH mutant gliomas and neuroblasts exists in prior literature.	('IDH', 'Gene', (31, 34))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH', 'Gene', '3417', (31, 34))	('mutant', 'Var', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
32565	30397180	In 2006, prior to the identification of cancer-associated IDH1/2 mutations, Phillips et al.	('IDH1/2', 'Gene', '3417;3418', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('IDH1/2', 'Gene', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (65, 74))
32574	30397180	In addition, although DLL3 was expressed in the majority of tumor cells in IDH mutant gliomas in our validation set, median H scores were lower compared to the discovery set.	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('tumor', 'Disease', (60, 65))	('mutant', 'Var', (79, 85))	('lower', 'NegReg', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('H scores', 'MPA', (124, 132))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
32578	30397180	In conclusion, we have identified DLL3 as tumor associated antigen and a novel cell surface therapeuticl target in IDH mutant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumor', 'Disease', (42, 47))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('DLL3', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('mutant', 'Var', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
32580	30397180	Additionally, the tight association between DLL3 expression and IDH mutant glioma raises interesting questions regarding the cell of origin of IDH mutant glioma given the essential role of DLL3 in cell fate decisions during neurogenesis.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('mutant', 'Var', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH', 'Gene', '3417', (64, 67))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('IDH', 'Gene', '3417', (143, 146))	('DLL3', 'Gene', (44, 48))	('glioma', 'Disease', (75, 81))	('glioma', 'Disease', (154, 160))	('IDH', 'Gene', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('IDH', 'Gene', (143, 146))
32583	30397180	Although IDH mutant gliomas are sensitive to radiation and chemotherapy, most tumors eventually recur and become fatal as no therapy is effective at recurrence.	('mutant', 'Var', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', '3417', (9, 12))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
32584	30397180	Here, we show that the Notch ligand DLL3 is intensely and homogeneously expressed in IDH mutant gliomas and high DLL3 expression is tightly associated with IDH mutant gliomas compared to other glioma subtypes.	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('mutant', 'Var', (89, 95))	('glioma', 'Disease', (193, 199))	('glioma', 'Disease', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('IDH', 'Gene', (85, 88))	('gliomas', 'Disease', (96, 103))	('glioma', 'Disease', 'MESH:D005910', (167, 173))	('glioma', 'Disease', (96, 102))	('associated', 'Reg', (140, 150))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('IDH', 'Gene', (156, 159))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('IDH', 'Gene', '3417', (85, 88))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('IDH', 'Gene', '3417', (156, 159))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))
32643	31552168	On the one hand, it is evident knowledge that gross total resection results in the increased progression-free and overall survival time among patients with LGG.	('gross', 'Var', (46, 51))	('overall survival time', 'CPA', (114, 135))	('increased', 'PosReg', (83, 92))	('LGG', 'Disease', (156, 159))	('patients', 'Species', '9606', (142, 150))	('progression-free', 'CPA', (93, 109))
32701	31462295	Even in the absence of ALT, variations in telomere length are being increasingly recognized as a prognostic factor in cancer.	('cancer', 'Disease', (118, 124))	('variations', 'Var', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('telomere', 'Protein', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
32702	31462295	Prior studies have related alterations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX), death domain-associated protein (DAXX), or SWI/SNF related, matrix associated, actin dependent regulator of chromatin (SMARCAL1) genes with ALT in some cancers.	('SMARCAL1', 'Gene', (228, 236))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('cancers', 'Disease', (261, 268))	('ATRX', 'Gene', (102, 106))	('DAXX', 'Gene', '1616', (142, 146))	('death', 'Disease', 'MESH:D003643', (109, 114))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (52, 100))	('death', 'Disease', (109, 114))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (52, 100))	('ATRX', 'Gene', '546', (102, 106))	('ALT', 'Disease', (249, 252))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('DAXX', 'Gene', (142, 146))	('SMARCAL1', 'Gene', '50485', (228, 236))	('mental retardation', 'Phenotype', 'HP:0001249', (64, 82))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('alterations', 'Var', (27, 38))
32703	31462295	ATRX mutations and ALT are associated with specific molecular subgroups of brain tumors.	('ATRX', 'Gene', (0, 4))	('brain tumors', 'Disease', 'MESH:D001932', (75, 87))	('brain tumors', 'Phenotype', 'HP:0030692', (75, 87))	('associated', 'Reg', (27, 37))	('mutations', 'Var', (5, 14))	('brain tumors', 'Disease', (75, 87))	('ATRX', 'Gene', '546', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
32704	31462295	We reported for the first time a high frequency of ATRX loss and ALT in high-grade and diffuse gliomas developing in NF1 patients, and more recent studies have also documented ATRX mutations in aggressive NF1-associated gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('ALT', 'MPA', (65, 68))	('NF1', 'Gene', '4763', (205, 208))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('NF1', 'Gene', '4763', (117, 120))	('NF1', 'Gene', (205, 208))	('ATRX', 'Gene', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('mutations', 'Var', (181, 190))	('ATRX', 'Gene', '546', (51, 55))	('NF1', 'Gene', (117, 120))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('gliomas', 'Disease', (95, 102))	('ATRX', 'Gene', (176, 180))	('high-grade', 'Disease', (72, 82))	('patients', 'Species', '9606', (121, 129))	('ATRX', 'Gene', '546', (176, 180))	('loss', 'NegReg', (56, 60))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Disease', (220, 227))
32705	31462295	Genomic studies have identified alterations in SUZ12 and EED in the majority of malignant nerve sheath tumors (MPNST).	('EED', 'Gene', '8726', (57, 60))	('malignant nerve', 'Phenotype', 'HP:0030430', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('EED', 'Gene', (57, 60))	('malignant nerve sheath tumors', 'Disease', (80, 109))	('alterations', 'Var', (32, 43))	('malignant nerve sheath tumors', 'Disease', 'MESH:D019574', (80, 109))	('malignant nerve sheath tumors', 'Phenotype', 'HP:0100697', (80, 109))	('SUZ12', 'Gene', '23512', (47, 52))	('malignant nerve sheath tumor', 'Phenotype', 'HP:0100697', (80, 108))	('SUZ12', 'Gene', (47, 52))
32723	31462295	However, in most cases immunohistochemical studies were systematically performed using antibodies recognizing either ATRX, DAXX, or H3K27me3.	('DAXX', 'Gene', (123, 127))	('DAXX', 'Gene', '1616', (123, 127))	('ATRX', 'Gene', (117, 121))	('ATRX', 'Gene', '546', (117, 121))	('H3K27me3', 'Var', (132, 140))
32750	31462295	Thus, ALT was a feature of predominantly high-grade or non-PA NF1-associated gliomas, while abnormally long telomeres (in the absence of ALT) are present in a subset of low-grade astrocytomas.	('gliomas', 'Disease', (77, 84))	('astrocytomas', 'Disease', 'MESH:D001254', (179, 191))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('high-grade', 'Disease', (41, 51))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('NF1', 'Gene', (62, 65))	('astrocytomas', 'Disease', (179, 191))	('NF1', 'Gene', '4763', (62, 65))	('ALT', 'Disease', (6, 9))	('non-PA', 'Var', (55, 61))
32763	31462295	These findings collectively suggest that abnormal telomere lengths are frequent in MPNST, in contrast to their benign neurofibroma counterparts, and are characterized by the presence of ALT or abnormally shortened telomeres.	('abnormal', 'Var', (41, 49))	('shortened telomeres', 'Phenotype', 'HP:0031413', (204, 223))	('neurofibroma', 'Phenotype', 'HP:0001067', (118, 130))	('abnormal telomere lengths', 'Phenotype', 'HP:0031412', (41, 66))	('MPNST', 'Disease', (83, 88))	('benign neurofibroma', 'Disease', (111, 130))	('benign neurofibroma', 'Disease', 'MESH:D009455', (111, 130))
32768	31462295	In the ALT-positive glioma group, all 6 had pathogenic NF1 mutations, with a high VAF suggestive of LOH (n = 4) or a second mutation (n = 1).	('LOH', 'NegReg', (100, 103))	('NF1', 'Gene', '4763', (55, 58))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('pathogenic', 'Reg', (44, 54))	('glioma', 'Disease', (20, 26))	('mutations', 'Var', (59, 68))	('NF1', 'Gene', (55, 58))
32769	31462295	Three (of 6) had ATRX mutations, 2 had homozygous CDKN2A/B deletions, but none had a DAXX mutation.	('ATRX', 'Gene', (17, 21))	('DAXX', 'Gene', (85, 89))	('CDKN2A/B', 'Gene', '1029;1030', (50, 58))	('deletions', 'Var', (59, 68))	('ATRX', 'Gene', '546', (17, 21))	('mutations', 'Var', (22, 31))	('CDKN2A/B', 'Gene', (50, 58))	('DAXX', 'Gene', '1616', (85, 89))
32770	31462295	All 3 ALT-positive MPNST had pathogenic NF1 mutations and lacked EED, SUZ12, or DAXX mutations.	('pathogenic', 'Reg', (29, 39))	('SUZ12', 'Gene', '23512', (70, 75))	('DAXX', 'Gene', '1616', (80, 84))	('NF1', 'Gene', (40, 43))	('SUZ12', 'Gene', (70, 75))	('EED', 'Gene', '8726', (65, 68))	('NF1', 'Gene', '4763', (40, 43))	('mutations', 'Var', (44, 53))	('EED', 'Gene', (65, 68))	('DAXX', 'Gene', (80, 84))
32771	31462295	Case 110 had an ATRX p.E511Kfs*3 mutation with ATRX protein loss (Fig.	('ATRX', 'Gene', (47, 51))	('p.E511Kfs*3', 'Var', (21, 32))	('protein', 'Protein', (52, 59))	('ATRX', 'Gene', '546', (16, 20))	('ATRX', 'Gene', '546', (47, 51))	('loss', 'NegReg', (60, 64))	('p.E511Kfs*3', 'Mutation', 'p.E511KfsX3', (21, 32))	('ATRX', 'Gene', (16, 20))
32772	31462295	Case 78 had an ATRX variant (p.Q929E) with a 67% VAF and partial ATRX protein loss; whereas case 53 lacked an ATRX mutation, but contained two RECQL4 variants (Additional file 1: Table S2).	('RECQL4', 'Gene', (143, 149))	('ATRX', 'Gene', '546', (15, 19))	('ATRX', 'Gene', (110, 114))	('ATRX', 'Gene', (65, 69))	('RECQL4', 'Gene', '9401', (143, 149))	('loss', 'NegReg', (78, 82))	('p.Q929E', 'Mutation', 'rs3088074', (29, 36))	('ATRX', 'Gene', '546', (110, 114))	('ATRX', 'Gene', (15, 19))	('ATRX', 'Gene', '546', (65, 69))	('p.Q929E', 'Var', (29, 36))	('VAF', 'Protein', (49, 52))
32773	31462295	RECQL4 is a DNA helicase and alterations in genes associated with DNA repair could lead to ALT, in the absence of the better known alterations in the chromatin remodelers ATRX and DAXX.	('ATRX', 'Gene', (171, 175))	('RECQL4', 'Gene', (0, 6))	('DAXX', 'Gene', '1616', (180, 184))	('RECQL4', 'Gene', '9401', (0, 6))	('ALT', 'Disease', (91, 94))	('alterations', 'Var', (29, 40))	('ATRX', 'Gene', '546', (171, 175))	('lead to', 'Reg', (83, 90))	('DAXX', 'Gene', (180, 184))
32774	31462295	RECQL4 variants were also present in two ALT-positive, ATRX intact NF1-gliomas.	('NF1', 'Gene', (67, 70))	('RECQL4', 'Gene', (0, 6))	('gliomas', 'Disease', (71, 78))	('NF1', 'Gene', '4763', (67, 70))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('ATRX', 'Gene', (55, 59))	('variants', 'Var', (7, 15))	('RECQL4', 'Gene', '9401', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('present', 'Reg', (26, 33))	('ATRX', 'Gene', '546', (55, 59))
32775	31462295	The ALT-negative MPNST with sequencing data displayed NF1 and SUZ12 mutations.	('SUZ12', 'Gene', '23512', (62, 67))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('SUZ12', 'Gene', (62, 67))	('mutations', 'Var', (68, 77))
32776	31462295	Next, we analyzed publicly available gene sequencing data from cBioPortal and identified missense DAXX mutations in 2 (of 15) MPNSTs, both NF1-associated.	('mutations', 'Var', (103, 112))	('missense', 'Var', (89, 97))	('DAXX', 'Gene', (98, 102))	('NF1', 'Gene', (139, 142))	('NF1', 'Gene', '4763', (139, 142))	('DAXX', 'Gene', '1616', (98, 102))
32777	31462295	These tumors lacked PRC2 (EED, SUZ12) mutations, and no mutations were present in RBL2 or SP100, two altered telomere maintenance genes found to be enriched in ALT-positive leiomyosarcomas.	('SUZ12', 'Gene', (31, 36))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (173, 188))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('EED', 'Gene', (26, 29))	('leiomyosarcomas', 'Disease', (173, 188))	('SUZ12', 'Gene', '23512', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('mutations', 'Var', (38, 47))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (173, 188))	('PRC2', 'Gene', (20, 24))	('SP100', 'Gene', '6672', (90, 95))	('tumors', 'Disease', (6, 12))	('RBL2', 'Gene', (82, 86))	('EED', 'Gene', '8726', (26, 29))	('RBL2', 'Gene', '5934', (82, 86))	('lacked', 'NegReg', (13, 19))	('SP100', 'Gene', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (6, 12))
32780	31462295	When restricting the analysis to cases with evaluable telomere lengths, there was also a trend for intermediate survival for patients with long telomeres and better survival for patients with normal telomeres, although the differences in survival appeared to be driven mostly by the ALT-positive group (p = 0.0021, log rank test) (Fig.	('better', 'PosReg', (158, 164))	('patients', 'Species', '9606', (178, 186))	('long telomeres', 'Var', (139, 153))	('patients', 'Species', '9606', (125, 133))
32789	31462295	identified ATRX mutations in 38% of NF1-associated high grade gliomas, compared to 3.1% of low-grade gliomas.	('NF1', 'Gene', (36, 39))	('gliomas', 'Disease', (101, 108))	('NF1', 'Gene', '4763', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('ATRX', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('gliomas', 'Disease', (62, 69))	('ATRX', 'Gene', '546', (11, 15))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
32790	31462295	In addition, another group of aggressive gliomas characterized by a high frequency of ATRX alterations and ALT activation is PA with anaplasia, approximately one third of which are NF1-associated or demonstrate somatic NF1 gene mutations.	('ATRX', 'Gene', '546', (86, 90))	('ALT', 'CPA', (107, 110))	('aggressive gliomas', 'Disease', 'MESH:D005910', (30, 48))	('anaplasia', 'Disease', 'MESH:D000708', (133, 142))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('alterations', 'Var', (91, 102))	('ATRX', 'Gene', (86, 90))	('NF1', 'Gene', '4763', (181, 184))	('NF1', 'Gene', (181, 184))	('NF1', 'Gene', (219, 222))	('anaplasia', 'Disease', (133, 142))	('aggressive gliomas', 'Disease', (30, 48))	('NF1', 'Gene', '4763', (219, 222))
32798	31462295	In addition, an ATRX variant was found in 1 (of 7) NF1-associated MPNSTs through next generation sequencing in a previous study.	('ATRX', 'Gene', '546', (16, 20))	('variant', 'Var', (21, 28))	('NF1', 'Gene', (51, 54))	('NF1', 'Gene', '4763', (51, 54))	('ATRX', 'Gene', (16, 20))
32799	31462295	reported aberrant ATRX immunoreactivity in 65% of NF1-associated MPNST, a finding associated with shorter overall survival.	('NF1', 'Gene', (50, 53))	('NF1', 'Gene', '4763', (50, 53))	('ATRX', 'Gene', (18, 22))	('MPNST', 'Disease', (65, 70))	('aberrant', 'Var', (9, 17))	('ATRX', 'Gene', '546', (18, 22))
32800	31462295	Of note, in cBioPortal, ATRX mutations were present in 4 (2.5%) of 162 pheochromocytomas/ paragangliomas, another tumor type that develops in NF1 patients.	('pheochromocytomas', 'Disease', 'MESH:D010673', (71, 88))	('NF1', 'Gene', '4763', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('paragangliomas', 'Disease', (90, 104))	('mutations', 'Var', (29, 38))	('ATRX', 'Gene', (24, 28))	('paragangliomas', 'Disease', 'MESH:D010235', (90, 104))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Disease', (114, 119))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (71, 88))	('paragangliomas', 'Phenotype', 'HP:0002668', (90, 104))	('ATRX', 'Gene', '546', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('present', 'Reg', (44, 51))	('NF1', 'Gene', (142, 145))	('pheochromocytomas', 'Disease', (71, 88))
32801	31462295	Others have reported ATRX mutations in 12.6% of pheochromocytomas/paragangliomas, mostly associated with SDH alterations, but also in one tumor with an NF1 mutation.	('NF1', 'Gene', (152, 155))	('SDH', 'Gene', (105, 108))	('associated', 'Reg', (89, 99))	('NF1', 'Gene', '4763', (152, 155))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('tumor', 'Disease', (138, 143))	('ATRX', 'Gene', (21, 25))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (48, 80))	('paragangliomas', 'Phenotype', 'HP:0002668', (66, 80))	('mutations', 'Var', (26, 35))	('pheochromocytomas/paragangliomas', 'Disease', (48, 80))	('ATRX', 'Gene', '546', (21, 25))	('alterations', 'Var', (109, 120))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
32802	31462295	Additionally, telomerase activation and ATRX mutations were found to be independent factors for poor prognosis in pheochromocytomas/paragangliomas in a recent study.	('mutations', 'Var', (45, 54))	('ATRX', 'Gene', '546', (40, 44))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (114, 131))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('telomerase', 'Protein', (14, 24))	('ATRX', 'Gene', (40, 44))	('pheochromocytomas/paragangliomas', 'Disease', (114, 146))	('activation', 'PosReg', (25, 35))	('paragangliomas', 'Phenotype', 'HP:0002668', (132, 146))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (114, 146))
32807	31462295	However, only one of these ALT-positive tumors contained a pathogenic ATRX mutation.	('pathogenic', 'Reg', (59, 69))	('ATRX', 'Gene', '546', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('mutation', 'Var', (75, 83))	('ATRX', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
32809	31462295	Another key finding in our study is that short telomeres were prevalent in ALT-negative MPNST, while long telomeres were present in ALT-negative gliomas, independent of grade.	('prevalent', 'Reg', (62, 71))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('MPNST', 'Disease', (88, 93))	('short telomeres', 'Var', (41, 56))	('ALT-negative MPNST', 'Disease', (75, 93))	('short telomeres', 'Phenotype', 'HP:0031413', (41, 56))	('short telomere', 'Phenotype', 'HP:0031413', (41, 55))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('gliomas', 'Disease', (145, 152))
32812	31462295	Recent studies in MPNST have demonstrated frequent mutations in SUZ12 and EED which encode protein components of the PRC2 complex.	('mutations', 'Var', (51, 60))	('SUZ12', 'Gene', (64, 69))	('EED', 'Gene', (74, 77))	('EED', 'Gene', '8726', (74, 77))	('SUZ12', 'Gene', '23512', (64, 69))
32814	31462295	Prior studies suggest that ATRX mutation alone is not sufficient for tumorigenesis or the development of ALT.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('development of ALT', 'CPA', (90, 108))	('tumor', 'Disease', (69, 74))	('ATRX', 'Gene', (27, 31))	('ATRX', 'Gene', '546', (27, 31))	('mutation', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
32815	31462295	Rather, ATRX mutations in CNS tumors seem to develop in the context of other more basic genetic drivers to facilitate tumorigenesis.	('ATRX', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('CNS tumors', 'Disease', 'MESH:D016543', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('facilitate', 'PosReg', (107, 117))	('ATRX', 'Gene', '546', (8, 12))	('CNS tumor', 'Phenotype', 'HP:0100006', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('CNS tumors', 'Disease', (26, 36))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (30, 35))
32816	31462295	In the context of NF1-associated tumors, this seems to be NF1 loss, while IDH mutations and histone H3 mutations (particularly G34) frequently coexist with ATRX loss in other tumor subsets.	('loss', 'NegReg', (62, 66))	('histone H3', 'Protein', (92, 102))	('ATRX', 'Gene', (156, 160))	('IDH', 'Gene', '3417', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('ATRX', 'Gene', '546', (156, 160))	('mutations', 'Var', (103, 112))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (33, 38))	('NF1', 'Gene', '4763', (58, 61))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('NF1', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('NF1', 'Gene', '4763', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IDH', 'Gene', (74, 77))	('NF1', 'Gene', (18, 21))	('tumors', 'Disease', (33, 39))
32819	31462295	Detecting ATRX alterations may also have management implications for NF1 patients with gliomas, since when present they identify subgroups that are clinically more aggressive.	('NF1', 'Gene', '4763', (69, 72))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('ATRX', 'Gene', (10, 14))	('patients', 'Species', '9606', (73, 81))	('alterations', 'Var', (15, 26))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('ATRX', 'Gene', '546', (10, 14))	('NF1', 'Gene', (69, 72))	('gliomas', 'Disease', (87, 94))
32912	24369857	the expression -kappa T  (T - T*), and (ii) the tumour cell growth due to biological processes, i.e.	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('expression -kappa', 'Var', (4, 21))	('tumour', 'Disease', (48, 54))
32919	24369857	Thereby, we find out the minimization conditions, i.e.,  J/ U M  = 0, and  J/ U L  = 0, whence we get the expressions for the two variables: Temozolomide efficiency term, Cytotoxic T-lymphocyte efficiency term, where, Further, from eq.	('Cytotoxic', 'Disease', 'MESH:D064420', (171, 180))	('Temozolomide', 'Chemical', 'MESH:D000077204', (141, 153))	('Temozolomide efficiency', 'MPA', (141, 164))	('Cytotoxic', 'Disease', (171, 180))	('J/ U', 'Var', (75, 79))
32934	24369857	Interleukin-2 efficiency term, Tumour-infiltrating lymphocyte injection dose-rate, where By transposing U I  = {(p I L I )/(g I  + I)} [i.e., eq.	('Interleukin-2', 'Gene', '3558', (0, 13))	('Tumour', 'Phenotype', 'HP:0002664', (31, 37))	('transposing', 'Var', (92, 103))	('Interleukin-2', 'Gene', (0, 13))
32942	24369857	Thus, if we have the value of rate constant of the tumour cell population, kappa T  and then we obtain the value of the other constants in terms of kappa T  : In the above example, since, kappa T  = 0.067/day, we get kappa L  = 0.201/day, kappa M  = 0.201/day, and kappa I  = 0.603/day.	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('kappa', 'Var', (188, 193))	('tumour', 'Disease', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))
33080	20981146	In this context, it is worth mentioning that genetic alterations that drive glial cell transformation and malignant progression result in tumor-specific changes in protein expression and/or posttranslational modifications.	('posttranslational modifications', 'MPA', (190, 221))	('protein expression', 'MPA', (164, 182))	('tumor', 'Disease', (138, 143))	('glial cell transformation', 'CPA', (76, 101))	('malignant progression', 'CPA', (106, 127))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('changes', 'Reg', (153, 160))	('genetic alterations', 'Var', (45, 64))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
33143	20981146	After a Decision tree analysis, Dpl-positive tumor samples were roughly subdivided into two main branches, according to the molecular mass of Dpl isoforms (Figure 5): for Dpl masses lower than 47.5 kDa, low-grade astrocytoma samples (i.e., WHO grades I and II) were clustered; in this group, a minority of WHO grade IV samples (9/32, 28%) were also identified.	('astrocytoma', 'Disease', (213, 224))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('astrocytoma', 'Disease', 'MESH:D001254', (213, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (213, 224))	('Dpl', 'Gene', (32, 35))	('Dpl', 'Gene', '23627', (171, 174))	('tumor', 'Disease', (45, 50))	('lower', 'Var', (182, 187))	('Dpl', 'Gene', (171, 174))	('Dpl', 'Gene', '23627', (142, 145))	('Dpl', 'Gene', '23627', (32, 35))	('Dpl', 'Gene', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
33149	20981146	Previous studies performed on the aberrant expression of doppel (PRND) gene in astrocytoma bioptic specimens and in derived-astrocytoma cell lines showed that transcripts levels were associated with glial tumor progression.	('glial tumor', 'Disease', (199, 210))	('transcripts levels', 'MPA', (159, 177))	('astrocytoma', 'Disease', 'MESH:D001254', (79, 90))	('aberrant', 'Var', (34, 42))	('PRND', 'Gene', (65, 69))	('astrocytoma', 'Disease', 'MESH:D001254', (124, 135))	('astrocytoma', 'Disease', (79, 90))	('astrocytoma', 'Disease', (124, 135))	('PRND', 'Gene', '23627', (65, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('glial tumor', 'Disease', 'MESH:D005910', (199, 210))	('associated with', 'Reg', (183, 198))
33187	32349342	Immunohistochemical double staining showed that VAP-1 immunoreactivity was present around CD163+ M2 infiltration location, including aggressive lesions and neighboring neovasculature.	('VAP-1', 'Gene', (48, 53))	('aggressive lesions', 'Disease', 'MESH:D001523', (133, 151))	('aggressive lesions', 'Disease', (133, 151))	('CD163+ M2', 'Var', (90, 99))
33188	32349342	We demonstrated that high VAP-1 expression levels positively correlated with CD163+ M2 activation and coexpression of these two proteins was associated with worse survival in gliomas (p < 0.0001).	('activation', 'PosReg', (87, 97))	('VAP-1', 'Gene', (26, 31))	('worse', 'NegReg', (157, 162))	('high', 'Var', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('gliomas', 'Disease', (175, 182))	('expression levels', 'MPA', (32, 49))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('CD163+ M2', 'MPA', (77, 86))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
33222	32349342	The purpose of the current study was to investigate the relationship between altered VAP-1 expression and TAM distribution as well as prognosis in human gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('VAP-1', 'Gene', (85, 90))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('TAM', 'Gene', '8205', (106, 109))	('altered', 'Var', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('TAM', 'Gene', (106, 109))
33234	32349342	This dataset involves twelve methylation probes, namely, cg22530519, cg16048817, cg24662231, cg09040752, cg08834922, cg21602160, cg11744144, cg25512683, cg16066544, cg19055390, cg21308545, and cg08562004, and a bimodal distribution of the beta value was observed.	('cg08562004', 'Var', (193, 203))	('cg22530519', 'Var', (57, 67))	('cg08834922', 'Var', (105, 115))	('cg21308545', 'Var', (177, 187))	('cg11744144', 'Var', (129, 139))	('cg16048817', 'Var', (69, 79))	('cg24662231', 'Chemical', '-', (81, 91))	('cg22530519', 'Chemical', '-', (57, 67))	('cg19055390', 'Var', (165, 175))	('cg21602160', 'Var', (117, 127))	('cg24662231', 'Var', (81, 91))	('cg25512683', 'Var', (141, 151))	('cg16066544', 'Var', (153, 163))	('cg21308545', 'Chemical', '-', (177, 187))	('cg09040752', 'Var', (93, 103))
33265	32349342	The patients were divided into low (-) and high (+) expression groups based on the cut-off of the median of the AOC3 exon expression (0.4471) and methylation status (0.7207).	('0.4471', 'Var', (134, 140))	('patients', 'Species', '9606', (4, 12))	('AOC3', 'Gene', (112, 116))	('0.7207', 'Var', (166, 172))	('AOC3', 'Gene', '8639', (112, 116))
33275	32349342	The populations of overall TAMs, M1, and M2 macrophages in neoplastic lesions were measured with anti-CD68, anti-iNOS, and anti-CD163 antibodies, respectively.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (59, 77))	('TAMs', 'Chemical', '-', (27, 31))	('anti-CD68', 'Var', (97, 106))	('iNOS', 'Gene', '4843', (113, 117))	('iNOS', 'Gene', (113, 117))
33280	32349342	From double-staining, it was found that iNOS+ M1 and CD163+ M2 existed in different glioma areas (Figure 2E,F).	('glioma', 'Disease', (84, 90))	('iNOS', 'Gene', '4843', (40, 44))	('CD163+ M2', 'Var', (53, 62))	('iNOS', 'Gene', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
33285	32349342	Immunoreactivity percentage of VAP-1 co-expressed with CD68, iNOS, and CD163 phenotypes were observed in lesions (Figure 2G-I).	('VAP-1', 'Gene', (31, 36))	('iNOS', 'Gene', (61, 65))	('iNOS', 'Gene', '4843', (61, 65))	('CD163', 'Var', (71, 76))
33289	32349342	High VAP-1 expression was detected in 56 (51.85%) out of 108 patients, and it was strongly correlated with advanced WHO grades (p < 0.0001), poor survival (p < 0.0001) and IDH1 mutant (p = 0.0262, Table 2).	('IDH1', 'Gene', '3417', (172, 176))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('IDH1', 'Gene', (172, 176))	('patients', 'Species', '9606', (61, 69))	('correlated', 'Reg', (91, 101))	('mutant', 'Var', (177, 183))	('poor survival', 'CPA', (141, 154))	('VAP-1', 'Gene', (5, 10))
33291	32349342	VAP-1/CD68+ TAM was significantly increased with WHO grade (p < 0.0001) and poor survival (p < 0.0001, Table 2).	('TAM', 'Gene', '8205', (12, 15))	('WHO grade', 'CPA', (49, 58))	('TAM', 'Gene', (12, 15))	('poor survival', 'CPA', (76, 89))	('VAP-1/CD68+', 'Var', (0, 11))	('increased', 'PosReg', (34, 43))
33293	32349342	A significant increasing trend in the VAP-1+/CD163+ M2 phenotype was observed in cancer specimens for age (p = 0.0164), WHO grade (p < 0.0001), patient survival (p < 0.0001) and IDH mutations (p = 0.0053, Table 2).	('IDH', 'Gene', '3417', (178, 181))	('patient survival', 'CPA', (144, 160))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('patient', 'Species', '9606', (144, 151))	('VAP-1+/CD163+ M2', 'Var', (38, 54))	('increasing', 'PosReg', (14, 24))	('IDH', 'Gene', (178, 181))
33296	32349342	Overall survival was significantly lower in patients with positive VAP-1 and CD163 phenotypes (both p < 0.0001, Figure 3A and Appendix Figure A1C), but not in patients with positive CD68 or iNOS immunoreactivities (p = 0.0509 and p = 0.1174, Appendix Figure A1A,B).	('CD163', 'Gene', (77, 82))	('VAP-1', 'Gene', (67, 72))	('patients', 'Species', '9606', (44, 52))	('iNOS', 'Gene', '4843', (190, 194))	('positive', 'Var', (58, 66))	('iNOS', 'Gene', (190, 194))	('lower', 'NegReg', (35, 40))	('Overall survival', 'CPA', (0, 16))	('A1C', 'Mutation', 'c.1A>C', (142, 145))	('patients', 'Species', '9606', (159, 167))
33297	32349342	Coexpression of VAP-1 and CD68+ total TAMs, iNOS+ M1, CD163+ M2 displayed significant prognostic effects on patient survival (p < 0.0001, p = 0.0101 and p < 0.0001, respectively, log-rank test; Figure 3B-D).	('VAP-1', 'Gene', (16, 21))	('CD68+ total', 'Var', (26, 37))	('TAMs', 'Chemical', '-', (38, 42))	('patient survival', 'CPA', (108, 124))	('CD163+ M2', 'Var', (54, 63))	('iNOS', 'Gene', '4843', (44, 48))	('iNOS', 'Gene', (44, 48))	('patient', 'Species', '9606', (108, 115))
33301	32349342	In multivariate regression analysis, reference parameters, such as gender, age, tumor size, recurrence, and IDH1 mutation were used.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutation', 'Var', (113, 121))	('IDH1', 'Gene', '3417', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('IDH1', 'Gene', (108, 112))
33303	32349342	Multivariate analysis adjusted by gender, age, tumor size, recurrence, and IDH1 mutant status indicated the hazard ratio for VAP-1 co-expressed with CD68 or CD163 enhanced the prognostic capability significantly in gliomas (VAP-1/CD68, HR: 3.226, 95% CI: 1.980-5.256, p < 0.0001; VAP-1/CD163, HR: 6.597, 95% CI: 3.677-11.836, p < 0.0001; Table 4).	('CD163', 'Var', (157, 162))	('mutant', 'Var', (80, 86))	('gliomas', 'Disease', (215, 222))	('prognostic capability', 'CPA', (176, 197))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('gliomas', 'Disease', 'MESH:D005910', (215, 222))	('IDH1', 'Gene', (75, 79))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('enhanced', 'PosReg', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('VAP-1', 'Gene', (125, 130))	('IDH1', 'Gene', '3417', (75, 79))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('tumor', 'Disease', (47, 52))	('CD68', 'Var', (149, 153))
33327	32349342	In a total of 108 glioma patients, VAP-1 expression and VAP-1/CD163 coexpression were both correlated with age, grade, survival, and IDH1 mutations.	('glioma', 'Disease', (18, 24))	('correlated', 'Reg', (91, 101))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('IDH1', 'Gene', (133, 137))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('patients', 'Species', '9606', (25, 33))	('VAP-1', 'Gene', (35, 40))	('IDH1', 'Gene', '3417', (133, 137))	('mutations', 'Var', (138, 147))
33338	32349342	Overall, VAP-1 abundancy is strongly linked to alternative M2 activation that might contribute to tumor immunity during glioma progression.	('contribute', 'Reg', (84, 94))	('abundancy', 'Var', (15, 24))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('alternative M2', 'Protein', (47, 61))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('linked', 'Reg', (37, 43))	('glioma', 'Disease', (120, 126))	('tumor', 'Disease', (98, 103))	('VAP-1', 'Gene', (9, 14))	('activation', 'PosReg', (62, 72))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
33341	32349342	This research and APC were mainly funded by Ministry of Science and Technology, Taiwan, grant number MOST105-2314-B037-004-MY2 and MOST107-2314-B037-036.	('APC', 'Disease', (18, 21))	('APC', 'Disease', 'MESH:D011125', (18, 21))	('MOST107-2314-B037-036', 'Var', (131, 152))	('MOST105-2314-B037-004-MY2', 'Var', (101, 126))
33461	25010867	However, dysfunction in miR-107 expression may contribute to neoplasia, neurodegeneration, cardiovascular dysfunction, and other diseases.	('miR-107', 'Gene', (24, 31))	('contribute', 'Reg', (47, 57))	('neurodegeneration', 'Disease', (72, 89))	('neurodegeneration', 'Disease', 'MESH:D019636', (72, 89))	('neoplasia', 'Disease', 'MESH:D009369', (61, 70))	('neoplasia', 'Disease', (61, 70))	('cardiovascular dysfunction', 'Phenotype', 'HP:0001626', (91, 117))	('cardiovascular dysfunction', 'Disease', 'MESH:D002318', (91, 117))	('dysfunction', 'Var', (9, 20))	('miR-107', 'Gene', '406901', (24, 31))	('cardiovascular dysfunction', 'Disease', (91, 117))	('neurodegeneration', 'Phenotype', 'HP:0002180', (72, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (61, 70))
33480	25010867	HEK-293T, 786-O, ACHN and Caki-2 cells were seeded in 24-well plates and incubated overnight, then transiently transfected with miR-646 precursor, control miR-646 antisense oligonucleotide or siRNA oligos using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions.	('antisense', 'Var', (163, 172))	('ACHN', 'Gene', '55323', (17, 21))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (211, 229))	('miR-646', 'Gene', '693231', (155, 162))	('oligonucleotide', 'Chemical', 'MESH:D009841', (173, 188))	('miR-646', 'Gene', (155, 162))	('Caki-2', 'CellLine', 'CVCL:0235', (26, 32))	('HEK-293T', 'CellLine', 'CVCL:0063', (0, 8))	('ACHN', 'Gene', (17, 21))	('miR-646', 'Gene', (128, 135))	('miR-646', 'Gene', '693231', (128, 135))
33481	25010867	The full-length NOB1 (NM_014062.2) cDNA containing plasmid was ordered from IBSbio (IBS Solutions Co. Ltd, Shanghai, China).	('IBS', 'Disease', 'MESH:D043183', (76, 79))	('NM_014062.2', 'Var', (22, 33))	('NOB1', 'Gene', (16, 20))	('IBS', 'Disease', 'MESH:D043183', (84, 87))	('IBS', 'Disease', (84, 87))	('IBS', 'Disease', (76, 79))
33510	25010867	When the female BALB/cnu mice were ~7-8 weeks old, each mouse was inoculated with 1.5 x 107 ACHN cells transfected with miR-646 or miR-control or NOB1-shRNA in 0.2 ml of PBS subcutaneously in the forelimb with the mice being injected with mock-infected cells as control.	('ACHN', 'Gene', '55323', (92, 96))	('mice', 'Species', '10090', (25, 29))	('PBS', 'Chemical', '-', (170, 173))	('NOB1-shRNA', 'Var', (146, 156))	('miR-646', 'Gene', '693231', (120, 127))	('mouse', 'Species', '10090', (56, 61))	('miR-646', 'Gene', (120, 127))	('ACHN', 'Gene', (92, 96))	('miR-control', 'Var', (131, 142))	('mice', 'Species', '10090', (214, 218))
33524	25010867	The miR-646 target sequences and wild-type NOB1 3'-UTR reduced the relative luciferase activity only when miR-646 was present, but not when the corresponding mutant was introduced with miR-646 (Figure 1B).	('activity', 'MPA', (87, 95))	('reduced', 'NegReg', (55, 62))	('miR-646', 'Gene', '693231', (106, 113))	('miR-646', 'Gene', '693231', (4, 11))	('miR-646', 'Gene', (106, 113))	('miR-646', 'Gene', '693231', (185, 192))	('miR-646', 'Gene', (185, 192))	('miR-646', 'Gene', (4, 11))	('sequences', 'Var', (19, 28))	('luciferase', 'Enzyme', (76, 86))
33529	25010867	786-O and ACHN cell lines were transfected with miR-646, miR-NC, NOB1-shRNA, control shRNA or non-treated controls and were inspected using the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] assay.	('miR-646', 'Gene', '693231', (48, 55))	('miR-NC', 'Var', (57, 63))	('3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide', 'Chemical', 'MESH:C000598529', (149, 213))	('miR-646', 'Gene', (48, 55))	('ACHN', 'Gene', '55323', (10, 14))	('MTT', 'Chemical', 'MESH:C070243', (144, 147))	('ACHN', 'Gene', (10, 14))
33530	25010867	As shown in Figure 3A and C, ectopic expression of miR-646 significantly inhibited the growth of 786-O and ACHN cell lines compared to the negative control 3 days after infection (P<0.05), and no statistically significant differences in growth rate between miR-646 overexpressing cells and NOB1-shRNA-infected cells was observed.	('ectopic expression', 'Var', (29, 47))	('ACHN', 'Gene', (107, 111))	('miR-646', 'Gene', '693231', (257, 264))	('miR-646', 'Gene', '693231', (51, 58))	('miR-646', 'Gene', (257, 264))	('inhibited', 'NegReg', (73, 82))	('miR-646', 'Gene', (51, 58))	('ACHN', 'Gene', '55323', (107, 111))
33549	25010867	The pcDNA3.1-NOB1 and LNA-anti-miR-646 cells had migrated significantly faster than the empty vector and LNA-anti-miR NC cells 48 h after wound creation (Figure 5E).	('migrated', 'CPA', (49, 57))	('faster', 'PosReg', (72, 78))	('miR-646', 'Gene', '693231', (31, 38))	('miR-646', 'Gene', (31, 38))	('pcDNA3.1-NOB1', 'Var', (4, 17))
33560	25010867	Similar to NOB1 silencing, overexpression of miR-646 caused a substantial reduction in colony formation in soft agar compared with the control group (P<0.05; Figure 6A-D).	('agar', 'Chemical', 'MESH:D000362', (112, 116))	('NOB1', 'Gene', (11, 15))	('colony formation in soft agar', 'CPA', (87, 116))	('reduction', 'NegReg', (74, 83))	('miR-646', 'Gene', '693231', (45, 52))	('silencing', 'Var', (16, 25))	('miR-646', 'Gene', (45, 52))	('overexpression', 'PosReg', (27, 41))
33563	25010867	Mean tumour volume in the miR-646 group or the NOB1-shRNA group was 702.2 mm3 or 761.8 mm3, whereas tumour volumes in mice treated with saline or negative control plasmid were 973.0 mm3 or 1163.8 mm3, respectively (P<0.01) after 35 days (Figure 6E-G).	('miR-646', 'Gene', '693231', (26, 33))	('tumour volumes', 'Disease', (100, 114))	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('miR-646', 'Gene', (26, 33))	('saline', 'Chemical', 'MESH:D012965', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', (5, 11))	('NOB1-shRNA', 'Var', (47, 57))	('tumour volumes', 'Disease', 'MESH:D009369', (100, 114))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('mice', 'Species', '10090', (118, 122))	('tumour', 'Disease', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
33565	25010867	In 786-O and ACHN cells, the phosphorylation of p38 (T180/Y182), ERK1/2 (T202/Y204, T185/Y187), and JNK (T183/Y185, T221/Y223) increased significantly after NOB1 suppression compared to the negative control (P<0.05; Figure 7).	('p38', 'Gene', (48, 51))	('JNK', 'Gene', '5599', (100, 103))	('ACHN', 'Gene', '55323', (13, 17))	('suppression', 'NegReg', (162, 173))	('ERK1/2', 'Gene', (65, 71))	('ERK1/2', 'Gene', '5595;5594', (65, 71))	('T183/Y185', 'Var', (105, 114))	('ACHN', 'Gene', (13, 17))	('T221/Y223', 'Var', (116, 125))	('T202/Y204', 'Var', (73, 82))	('T185/Y187', 'Var', (84, 93))	('JNK', 'Gene', (100, 103))	('p38', 'Gene', '5594', (48, 51))	('NOB1', 'Gene', (157, 161))	('T180/Y182', 'Var', (53, 62))	('increased', 'PosReg', (127, 136))	('phosphorylation', 'MPA', (29, 44))
33594	25010867	Our results indicate that silencing of NOB1 expression increased the phosphorylation of these proteins, suggesting that the anti-tumour effect of NOB1 might be mediated by MAPK activation.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('increased', 'PosReg', (55, 64))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('NOB1', 'Gene', (39, 43))	('phosphorylation of these proteins', 'MPA', (69, 102))	('silencing', 'Var', (26, 35))
33600	25010867	The aberrant expression of miR-646 protein linked to poor prognosis of patients has not been investigated in renal cancer before.	('renal cancer', 'Disease', 'MESH:D007680', (109, 121))	('protein', 'Protein', (35, 42))	('patients', 'Species', '9606', (71, 79))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR-646', 'Gene', '693231', (27, 34))	('miR-646', 'Gene', (27, 34))	('linked', 'Reg', (43, 49))	('renal cancer', 'Disease', (109, 121))	('renal cancer', 'Phenotype', 'HP:0009726', (109, 121))
33620	32810311	These include an immune-inflamed phenotype, 15 ,  16  expression of T cell signaling pathway genes such as IFNgamma, 17  microsatellite instability, 18  somatic copy-number alterations, 19  human leukocyte antigen (HLA) class I diversity, 20  T cell repertoire clonality change, 21  WNT-beta-catenin signaling, 22  TGFbeta expression, 23  and even commensal microbiota.	('IFNgamma', 'Gene', '3458', (107, 115))	('beta-catenin', 'Gene', '1499', (287, 299))	('T cell signaling pathway genes', 'Gene', (68, 98))	('TGFbeta', 'Gene', (315, 322))	('alterations', 'Var', (173, 184))	('TGFbeta', 'Gene', '7039', (315, 322))	('beta-catenin', 'Gene', (287, 299))	('human', 'Species', '9606', (190, 195))	('IFNgamma', 'Gene', (107, 115))
33679	32810311	We analyzed RNA-Seq data of 28 pretreatment tumors from melanoma patients who received anti-PD-1 ICI.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('anti-PD-1', 'Var', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))
33685	32810311	35  Axis 6 (Treg) and axis 7 (MDSC) were high in Pt25 and Pt16, respectively, suggesting that the strategies to deplete Treg or MDSC might be recommended to these patients.	('Pt16', 'Var', (58, 62))	('Treg', 'Chemical', '-', (12, 16))	('Pt25', 'Var', (49, 53))	('patients', 'Species', '9606', (163, 171))	('Treg', 'Chemical', '-', (120, 124))
33700	32810311	For example, immunograms for hallmarks of cancer could also be compiled by adopting gene sets for the eight hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.	('death', 'Disease', 'MESH:D003643', (198, 203))	('death', 'Disease', (198, 203))	('hallmarks of cancer', 'Disease', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('replicative immortality', 'CPA', (214, 237))	('evading', 'Var', (155, 162))	('invasion', 'CPA', (273, 281))	('immune destruction', 'CPA', (346, 364))	('activating', 'PosReg', (262, 272))	('enabling', 'PosReg', (205, 213))	('inducing', 'PosReg', (239, 247))	('reprogramming', 'Reg', (298, 311))	('angiogenesis', 'CPA', (248, 260))	('proliferative signaling', 'MPA', (130, 153))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (29, 48))	('sustaining', 'PosReg', (119, 129))
33857	29973405	In glioma patients with tumors that have a methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, high BCL-3 expression was associated with a poor response to TMZ.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('BCL-3', 'Gene', (115, 120))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('MGMT', 'Gene', '4255', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('MGMT', 'Gene', (94, 98))	('expression', 'MPA', (121, 131))	('TMZ', 'Chemical', 'MESH:D000077204', (171, 174))	('BCL-3', 'Gene', '602', (115, 120))	('glioma', 'Disease', (3, 9))	('patients', 'Species', '9606', (10, 18))	('high', 'PosReg', (110, 114))	('O6-methylguanine DNA methyltransferase', 'Gene', (54, 92))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (54, 92))	('methylated', 'Var', (43, 53))
33866	29973405	Glioma cells are distinguished by the presence of recurrent copy number alterations (CNAs) affecting broad chromosomal regions.	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('copy number alterations', 'Var', (60, 83))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', (0, 6))
33867	29973405	However, passenger genes, unlike drivers, have not yet been shown to mediate therapeutic susceptibility in clinical glioma.	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('passenger genes', 'Var', (9, 24))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('glioma', 'Disease', (116, 122))
33878	29973405	Knockdown of BCL3 in GSCs with high basal BCL-3 increased cell death after treatment with TMZ (Fig.	('BCL3', 'Gene', (13, 17))	('increased', 'PosReg', (48, 57))	('TMZ', 'Chemical', 'MESH:D000077204', (90, 93))	('BCL-3', 'Gene', '602', (42, 47))	('BCL3', 'Gene', '602', (13, 17))	('cell death', 'CPA', (58, 68))	('high', 'Var', (31, 35))	('BCL-3', 'Gene', (42, 47))
33880	29973405	Moreover, in U87, U251, and T98 GBM cell lines, knockdown of BCL3 with short interfering RNA (si-RNA) increased the TMZ-induced effect on clonal survival (fig.	('U87', 'CellLine', 'CVCL:0022', (13, 16))	('TMZ', 'Chemical', 'MESH:D000077204', (116, 119))	('U251', 'CellLine', 'CVCL:0021', (18, 22))	('clonal survival', 'CPA', (138, 153))	('TMZ-induced', 'MPA', (116, 127))	('BCL3', 'Gene', '602', (61, 65))	('increased', 'PosReg', (102, 111))	('BCL3', 'Gene', (61, 65))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))	('T98', 'CellLine', 'CVCL:B368', (28, 31))	('knockdown', 'Var', (48, 57))
33901	29973405	Specifically, in GBM with high MGMT promoter methylation, the HR based on BCL3 expression was greater than in the entire GBM population (1.88 versus 1.41, respectively, univariate Cox regression; Fig.	('MGMT', 'Gene', '4255', (31, 35))	('high', 'Var', (26, 30))	('expression', 'MPA', (79, 89))	('MGMT', 'Gene', (31, 35))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('greater', 'PosReg', (94, 101))	('BCL3', 'Gene', '602', (74, 78))	('Cox', 'Gene', '1351', (180, 183))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('BCL3', 'Gene', (74, 78))	('Cox', 'Gene', (180, 183))
33906	29973405	Data analysis showed that GBM patients with low BCL-3 staining survived significantly longer than those with high staining [P < 0.0001; HR, 5.418; 95% confidence interval (CI), 2.747 to 9.647; Fig.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('BCL-3', 'Gene', '602', (48, 53))	('low', 'Var', (44, 47))	('longer', 'PosReg', (86, 92))	('patients', 'Species', '9606', (30, 38))	('BCL-3', 'Gene', (48, 53))	('to 9', 'Species', '1214577', (183, 187))
33910	29973405	Multivariate analysis that included age, isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q co-deletion, and MGMT promoter methylation showed that BCL3 expression remained associated with survival (Table 2); moreover, BCL3 separated LGG patients into different survival groups in tumors with high MGMT promoter methylation (Fig.	('BCL3', 'Gene', (147, 151))	('BCL3', 'Gene', (218, 222))	('patients', 'Species', '9606', (237, 245))	('tumors', 'Disease', 'MESH:D009369', (280, 286))	('mutation', 'Var', (75, 83))	('MGMT', 'Gene', (297, 301))	('MGMT', 'Gene', '4255', (109, 113))	('IDH1', 'Gene', (69, 73))	('associated', 'Reg', (172, 182))	('isocitrate dehydrogenase 1', 'Gene', (41, 67))	('isocitrate dehydrogenase 1', 'Gene', '3417', (41, 67))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('BCL3', 'Gene', '602', (147, 151))	('IDH1', 'Gene', '3417', (69, 73))	('MGMT', 'Gene', (109, 113))	('BCL3', 'Gene', '602', (218, 222))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('MGMT', 'Gene', '4255', (297, 301))	('tumors', 'Disease', (280, 286))
33925	29973405	In this pan-glioma data set, BCL3 was correlated with survival on multivariate analysis, taking IDH1 mutation, MGMT methylation, 1p/19q co-deletion, and age into consideration (Table 3).	('IDH1', 'Gene', '3417', (96, 100))	('MGMT', 'Gene', (111, 115))	('BCL3', 'Gene', '602', (29, 33))	('MGMT', 'Gene', '4255', (111, 115))	('glioma', 'Disease', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('BCL3', 'Gene', (29, 33))	('IDH1', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))	('correlated', 'Reg', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
33927	29973405	In these patients, BCL3 expression remained significant (P = 0.023) on multivariate analysis incorporating IDH1 mutation and MGMT promoter methylation (table S8).	('IDH1', 'Gene', (107, 111))	('patients', 'Species', '9606', (9, 17))	('MGMT', 'Gene', (125, 129))	('mutation', 'Var', (112, 120))	('IDH1', 'Gene', '3417', (107, 111))	('MGMT', 'Gene', '4255', (125, 129))	('BCL3', 'Gene', '602', (19, 23))	('significant', 'Reg', (44, 55))	('BCL3', 'Gene', (19, 23))
33934	29973405	Tumors with hemizygous BCL3 deletion had significantly lower BCL-3 than nondeleted tumors, as assessed by IHC (P = 0.0007; Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BCL-3', 'Gene', '602', (61, 66))	('BCL-3', 'Gene', (61, 66))	('tumors', 'Disease', (83, 89))	('BCL3', 'Gene', '602', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('lower', 'NegReg', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('BCL3', 'Gene', (23, 27))	('deletion', 'Var', (28, 36))
33936	29973405	In both LGG and GBM groups, patients who had tumors with BCL3 deletion survived significantly longer than those with nondeleted tumors (P < 0.05; Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BCL3', 'Gene', '602', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('survived', 'CPA', (71, 79))	('tumors', 'Disease', (128, 134))	('longer', 'PosReg', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('BCL3', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('deletion', 'Var', (62, 70))	('patients', 'Species', '9606', (28, 36))	('GBM', 'Phenotype', 'HP:0012174', (16, 19))
33938	29973405	These results indicate that genetic deletion of BCL3 is associated with reduced BCL-3 expression and improved survival.	('BCL3', 'Gene', '602', (48, 52))	('reduced', 'NegReg', (72, 79))	('BCL-3', 'Gene', (80, 85))	('genetic deletion', 'Var', (28, 44))	('BCL3', 'Gene', (48, 52))	('improved', 'PosReg', (101, 109))	('survival', 'CPA', (110, 118))	('BCL-3', 'Gene', '602', (80, 85))
33940	29973405	The lack of reported BCL3 mutations or translocations in glioma suggested that BCL3 loss is not a driver of these tumors (fig.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BCL3', 'Gene', (79, 83))	('glioma', 'Disease', (57, 63))	('loss', 'NegReg', (84, 88))	('mutations', 'Var', (26, 35))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('BCL3', 'Gene', '602', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('BCL3', 'Gene', '602', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('BCL3', 'Gene', (21, 25))
33944	29973405	S3C), suggesting that BCL3 deletion occurs as a result of modifications targeted to a broad region of 19q13.	('BCL3', 'Gene', '602', (22, 26))	('BCL3', 'Gene', (22, 26))	('modifications', 'Var', (58, 71))
33945	29973405	This finding is consistent not only with the fact that the entire 19q arm is lost in oligodendrogliomas but also with the observation that, in astrocytic tumors and GBM, CNAs within 19q13 involve a broad region.	('lost', 'NegReg', (77, 81))	('astrocytic tumors', 'Disease', 'MESH:D001254', (143, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (85, 103))	('CNAs', 'Var', (170, 174))	('involve', 'Reg', (188, 195))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('oligodendrogliomas', 'Disease', (85, 103))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('astrocytic tumors', 'Disease', (143, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))
33947	29973405	Despite the importance of deletion, some BCL3 nondeleted gliomas also had low mRNA expression.	('BCL3', 'Gene', (41, 45))	('low', 'NegReg', (74, 77))	('mRNA expression', 'MPA', (78, 93))	('deletion', 'Var', (26, 34))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('BCL3', 'Gene', '602', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
33949	29973405	In TCGA pan-glioma data, a significant inverse correlation between BCL3 promoter methylation and expression was seen (P < 0.0001; fig.	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('inverse', 'NegReg', (39, 46))	('methylation', 'Var', (81, 92))	('glioma', 'Disease', (12, 18))	('BCL3', 'Gene', '602', (67, 71))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('BCL3', 'Gene', (67, 71))	('expression', 'MPA', (97, 107))
33951	29973405	Analysis of the pan-glioma data set demonstrated that BCL3 promoter methylation was significantly associated with survival on multivariate analysis incorporating IDH mutation, MGMT promoter methylation, and 1p/19q co-deletion (P = 0.018; table S10).	('survival', 'MPA', (114, 122))	('associated with', 'Reg', (98, 113))	('1p/19q co-deletion', 'Var', (207, 225))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('MGMT', 'Gene', (176, 180))	('IDH', 'Gene', (162, 165))	('MGMT', 'Gene', '4255', (176, 180))	('BCL3', 'Gene', '602', (54, 58))	('IDH', 'Gene', '3417', (162, 165))	('glioma', 'Disease', (20, 26))	('BCL3', 'Gene', (54, 58))	('mutation', 'Var', (166, 174))
33954	29973405	These results indicate that, in glioma, the genetic and epigenetic alterations of BCL3 that regulate expression are significantly associated with survival.	('genetic', 'Var', (44, 51))	('glioma', 'Disease', (32, 38))	('BCL3', 'Gene', '602', (82, 86))	('survival', 'Disease', (146, 154))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('epigenetic alterations', 'Var', (56, 78))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('associated with', 'Reg', (130, 145))	('BCL3', 'Gene', (82, 86))
33964	29973405	Conversely, knockdown of BCL3 in GSCs expressing high basal BCL-3, GBM43S and GBM34, resulted in decreased mesenchymal marker expression (Fig.	('BCL-3', 'Gene', '602', (60, 65))	('BCL3', 'Gene', (25, 29))	('GBM43S', 'Var', (67, 73))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('GBM34', 'Var', (78, 83))	('mesenchymal marker expression', 'CPA', (107, 136))	('knockdown', 'Var', (12, 21))	('BCL-3', 'Gene', (60, 65))	('decreased', 'NegReg', (97, 106))	('BCL3', 'Gene', '602', (25, 29))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
33965	29973405	Loss of BCL3 reduced neurosphere formation ability in GBM34 cells, whereas overexpression of BCL-3 had the opposite effect in GBM44 GSCs, supporting the role of BCL-3 in mesenchymal differentiation (Fig.	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('BCL-3', 'Gene', '602', (161, 166))	('BCL3', 'Gene', '602', (8, 12))	('BCL-3', 'Gene', (93, 98))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('BCL-3', 'Gene', (161, 166))	('BCL3', 'Gene', (8, 12))	('BCL-3', 'Gene', '602', (93, 98))	('Loss', 'Var', (0, 4))	('reduced', 'NegReg', (13, 20))	('neurosphere formation ability', 'CPA', (21, 50))
34006	29973405	CAII was induced by TMZ in GSCs (Fig.	('TMZ', 'Var', (20, 23))	('CAII', 'Disease', (0, 4))	('TMZ', 'Chemical', 'MESH:D000077204', (20, 23))
34008	29973405	Also, in clinical databases, tumors with low BCL3 expression had lower CAII mRNA expression than those with high BCL3 expression, as did tumors with 19q deletion compared to the nondeleted group (Fig.	('CAII mRNA expression', 'MPA', (71, 91))	('BCL3', 'Gene', (45, 49))	('tumors', 'Disease', (137, 143))	('19q deletion', 'Var', (149, 161))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BCL3', 'Gene', '602', (113, 117))	('lower', 'NegReg', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('low BCL3 expression', 'Phenotype', 'HP:0031037', (41, 60))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('BCL3', 'Gene', (113, 117))	('BCL3', 'Gene', '602', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
34013	29973405	These findings suggest that TMZ induces CAII via formation of cytotoxic O6-methylguanine adducts.	('CAII', 'Disease', (40, 44))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (72, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('cytotoxic O6-methylguanine adducts', 'MPA', (62, 96))	('TMZ', 'Var', (28, 31))	('formation', 'MPA', (49, 58))
34015	29973405	Although knockdown of either p50/NFkappaB1 or p65 did not alter basal CAII expression, loss of p52/NFkappaB2 attenuated basal and TMZ-induced CAII expression in GBM34 GSCs (Fig.	('kappaB', 'Gene', '4790', (101, 107))	('basal', 'CPA', (120, 125))	('loss', 'Var', (87, 91))	('kappaB', 'Gene', (101, 107))	('p50', 'Gene', (29, 32))	('p65', 'Gene', '5970', (46, 49))	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('p50', 'Gene', '4790', (29, 32))	('kappaB', 'Gene', '4790', (35, 41))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('kappaB', 'Gene', (35, 41))	('p52', 'Gene', (95, 98))	('p52', 'Gene', '4791', (95, 98))	('p65', 'Gene', (46, 49))	('attenuated', 'NegReg', (109, 119))
34024	29973405	Given that TMZ induces phosphorylation of p50 S329 and that S329 is a residue that potentially interacts with BCL-3, we examined the role of this residue in regulating the BCL-3/p50 interaction in response to TMZ.	('BCL-3', 'Gene', (110, 115))	('phosphorylation', 'MPA', (23, 38))	('S329', 'Chemical', '-', (46, 50))	('TMZ', 'Chemical', 'MESH:D000077204', (209, 212))	('p50', 'Gene', (178, 181))	('p50', 'Gene', '4790', (178, 181))	('S329', 'Chemical', '-', (60, 64))	('BCL-3', 'Gene', '602', (172, 177))	('BCL-3', 'Gene', '602', (110, 115))	('p50', 'Gene', (42, 45))	('p50', 'Gene', '4790', (42, 45))	('TMZ', 'Chemical', 'MESH:D000077204', (11, 14))	('BCL-3', 'Gene', (172, 177))	('S329', 'Var', (60, 64))
34025	29973405	Mutation of S329 to an unphosphorylatable form blocked the dissociation of p50 and BCL-3 after TMZ treatment (Fig.	('p50', 'Gene', (75, 78))	('p50', 'Gene', '4790', (75, 78))	('Mutation', 'Var', (0, 8))	('blocked', 'NegReg', (47, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))	('S329', 'Chemical', '-', (12, 16))	('BCL-3', 'Gene', '602', (83, 88))	('S329', 'Var', (12, 16))	('BCL-3', 'Gene', (83, 88))
34029	29973405	S6, I and J), whereas knockdown of CAII in GBM26 GSCs led to an increase in TMZ-induced cytotoxicity (Fig.	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('cytotoxicity', 'Disease', (88, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (76, 79))	('knockdown', 'Var', (22, 31))	('increase', 'PosReg', (64, 72))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))
34037	29973405	ACZ enhanced cytotoxicity by TMZ in GBM34 GSCs that express high BCL-3, and knockdown of BCL3 blocked the chemosensitizing effect of ACZ (Fig.	('BCL3', 'Gene', (89, 93))	('ACZ', 'Chemical', 'MESH:D000086', (0, 3))	('knockdown', 'Var', (76, 85))	('enhanced', 'PosReg', (4, 12))	('cytotoxicity', 'Disease', (13, 25))	('BCL-3', 'Gene', '602', (65, 70))	('TMZ', 'Chemical', 'MESH:D000077204', (29, 32))	('cytotoxicity', 'Disease', 'MESH:D064420', (13, 25))	('BCL3', 'Gene', '602', (89, 93))	('BCL-3', 'Gene', (65, 70))	('ACZ', 'Chemical', 'MESH:D000086', (133, 136))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
34064	29973405	Whereas expression of a control sh-RNA did not modulate the response in GBM34 tumors, knockdown of BCL3 completely blocked the ability of ACZ to increase the prosurvival effect of TMZ (Fig.	('tumors', 'Disease', (78, 84))	('knockdown', 'Var', (86, 95))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('blocked', 'NegReg', (115, 122))	('ACZ', 'Chemical', 'MESH:D000086', (138, 141))	('TMZ', 'Chemical', 'MESH:D000077204', (180, 183))	('increase', 'PosReg', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('BCL3', 'Gene', '602', (99, 103))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('prosurvival effect', 'CPA', (158, 176))	('BCL3', 'Gene', (99, 103))
34072	29973405	Our results indicate that only tumors with low BCL3 expression will likely benefit from adding TMZ to IR, an important clinical observation given that TMZ induces deleterious hypermutation that can cause malignant progression.	('cause', 'Reg', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('low BCL3 expression', 'Phenotype', 'HP:0031037', (43, 62))	('only tumors', 'Disease', 'MESH:D054331', (26, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('only tumors', 'Disease', (26, 37))	('TMZ', 'Var', (151, 154))	('induces', 'Reg', (155, 162))	('hypermutation', 'MPA', (175, 188))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))	('BCL3', 'Gene', '602', (47, 51))	('TMZ', 'Chemical', 'MESH:D000077204', (151, 154))	('BCL3', 'Gene', (47, 51))
34073	29973405	The data demonstrate that, in glioma, BCL3 expression is regulated by genetic, and epigenetic, modifications and that these alterations are linked to patient outcome.	('patient', 'Species', '9606', (150, 157))	('BCL3', 'Gene', (38, 42))	('regulated', 'Reg', (57, 66))	('expression', 'MPA', (43, 53))	('glioma', 'Disease', (30, 36))	('BCL3', 'Gene', '602', (38, 42))	('linked', 'Reg', (140, 146))	('modifications', 'Var', (95, 108))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
34074	29973405	We see that BCL3 CN loss occurs as a result of modifications targeted to the chromosomal band 19q13.	('modifications', 'Var', (47, 60))	('loss', 'NegReg', (20, 24))	('BCL3', 'Gene', '602', (12, 16))	('BCL3', 'Gene', (12, 16))
34076	29973405	Although the ability of passenger events to promote unintended therapeutic susceptibility has been shown in animal models, the link between loss of BCL3 and TMZ susceptibility demonstrates the importance of passenger modification to chemosensitivity in a clinical setting.	('BCL3', 'Gene', '602', (148, 152))	('BCL3', 'Gene', (148, 152))	('TMZ', 'Disease', (157, 160))	('TMZ', 'Chemical', 'MESH:D000077204', (157, 160))	('loss', 'Var', (140, 144))
34077	29973405	The effect of BCL3 deletion in glioma is particularly relevant given that alterations of 19q play an important role in modulating patient outcome in these tumors.	('patient', 'Species', '9606', (130, 137))	('modulating', 'Reg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('BCL3', 'Gene', (14, 18))	('deletion', 'Var', (19, 27))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('alterations', 'Var', (74, 85))	('BCL3', 'Gene', '602', (14, 18))	('glioma', 'Disease', (31, 37))
34078	29973405	Specifically, 19q, with 1p, co-deletion is predictive of response to alkylating chemotherapy in oligodendroglioma, whereas loss of 19q13 alone is associated with long-term survival in GBM.	('GBM', 'Phenotype', 'HP:0012174', (184, 187))	('response to alkylating chemotherapy', 'MPA', (57, 92))	('oligodendroglioma', 'Disease', (96, 113))	('co-deletion', 'Var', (28, 39))	('oligodendroglioma', 'Disease', 'MESH:D009837', (96, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('associated', 'Reg', (146, 156))
34083	29973405	From a mechanistic standpoint, high BCL-3 led to a change in the composition of the NF-kappaB dimer at MES gene promoters involving replacement of p50 by p52.	('BCL-3', 'Gene', '602', (36, 41))	('NF-kappaB', 'Gene', (84, 93))	('MES', 'Chemical', '-', (103, 106))	('p50', 'Gene', (147, 150))	('change', 'Reg', (51, 57))	('replacement', 'Var', (132, 143))	('composition of', 'MPA', (65, 79))	('BCL-3', 'Gene', (36, 41))	('p50', 'Gene', '4790', (147, 150))	('NF-kappaB', 'Gene', '4790', (84, 93))	('p52', 'Gene', (154, 157))	('p52', 'Gene', '4791', (154, 157))
34085	29973405	Whereas previous work demonstrates a cell-extrinsic pathway for activation of p65 in GBM cells by cytokines released from infiltrating macrophages and microglia, genetic and epigenetic regulation of BCL3 represents mechanisms by which cell-intrinsic pathways also contribute to promoting NF-kappaB-dependent mesenchymal differentiation.	('NF-kappaB', 'Gene', '4790', (288, 297))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('promoting', 'PosReg', (278, 287))	('BCL3', 'Gene', (199, 203))	('p65', 'Gene', (78, 81))	('NF-kappaB', 'Gene', (288, 297))	('activation', 'PosReg', (64, 74))	('genetic', 'Var', (162, 169))	('p65', 'Gene', '5970', (78, 81))	('epigenetic regulation', 'Var', (174, 195))	('BCL3', 'Gene', '602', (199, 203))
34087	29973405	MGMT promoter methylation is one such predictor; however, inhibiting MGMT has not proven to be an effective chemosensitizing strategy clinically.	('MGMT', 'Gene', (0, 4))	('MGMT', 'Gene', '4255', (69, 73))	('inhibiting', 'Var', (58, 68))	('MGMT', 'Gene', (69, 73))	('MGMT', 'Gene', '4255', (0, 4))
34101	29973405	Given the increase in molecular analysis of gliomas, factors such as BCL-3 might assume an important role in individualizing patient treatment, a strategy occurring with increasing frequency in cancer therapy.	('cancer', 'Disease', (194, 200))	('molecular', 'Var', (22, 31))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('BCL-3', 'Gene', '602', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('patient', 'Species', '9606', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('BCL-3', 'Gene', (69, 74))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
34106	29973405	This gave n = 74 and 32 patients per group, respectively, to have 80% power to detect a significant difference between low and high BCL-3 expression at a two-sided P < 0.05.	('high', 'Var', (127, 131))	('BCL-3', 'Gene', (132, 137))	('low', 'Var', (119, 122))	('patients', 'Species', '9606', (24, 32))	('BCL-3', 'Gene', '602', (132, 137))
34114	30931252	Recently, recurrent Fibroblast growth factor receptor 1 (FGFR1) mutations in pediatric gliomas have been reported.	('FGFR1', 'Gene', (57, 62))	('Fibroblast growth factor receptor 1', 'Gene', (20, 55))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (20, 55))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('FGFR1', 'Gene', '2260', (57, 62))	('pediatric gliomas', 'Disease', (77, 94))	('mutations', 'Var', (64, 73))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('pediatric gliomas', 'Disease', 'MESH:D005910', (77, 94))
34119	30931252	High FGFR1 expression was associated with age, malignancy, tumor location and tumor grade among astrocytomas.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('High', 'Var', (0, 4))	('FGFR1', 'Gene', '2260', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('expression', 'MPA', (11, 21))	('astrocytomas', 'Disease', 'MESH:D001254', (96, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('astrocytomas', 'Disease', (96, 108))	('tumor', 'Disease', (78, 83))	('malignancy', 'Disease', 'MESH:D009369', (47, 57))	('malignancy', 'Disease', (47, 57))	('associated', 'Reg', (26, 36))	('FGFR1', 'Gene', (5, 10))
34128	30931252	Pediatric LGGs are strikingly characterized by oncogenic mutations in the BRAF gene leading to constitutive BRAF kinase activity.	('LGGs', 'Disease', (10, 14))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutations', 'Var', (57, 66))	('BRAF', 'Gene', '673', (108, 112))	('constitutive', 'MPA', (95, 107))	('BRAF', 'Gene', (108, 112))
34132	30931252	In pediatric gliomas, genomic analyses have reported recurrent FGFR1 mutations.	('mutations', 'Var', (69, 78))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('pediatric gliomas', 'Disease', 'MESH:D005910', (3, 20))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('pediatric gliomas', 'Disease', (3, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
34133	30931252	sequenced blood and tumor tissues from pilocytic astrocytomas and identified FGFR1 mutations with the mutational hotspots located on codons Asn546 and Lys656.	('mutations', 'Var', (83, 92))	('FGFR1', 'Gene', (77, 82))	('Asn546', 'Var', (140, 146))	('FGFR1', 'Gene', '2260', (77, 82))	('Asn546', 'Chemical', '-', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('pilocytic astrocytomas', 'Disease', (39, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (39, 61))	('tumor', 'Disease', (20, 25))	('Lys656', 'Chemical', '-', (151, 157))	('Lys656', 'Var', (151, 157))
34134	30931252	reported that 6.7% of pilocytic tumors had FGFR1 point mutations on Lys656 and subsequently that tumors carrying the mutation had significantly poorer prognoses compared to wild-type variants.	('FGFR1', 'Gene', (43, 48))	('point mutations on Lys656', 'Var', (49, 74))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR1', 'Gene', '2260', (43, 48))	('pilocytic tumors', 'Disease', (22, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (97, 103))	('pilocytic tumors', 'Disease', 'MESH:D001254', (22, 38))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Lys656', 'Chemical', '-', (68, 74))	('tumors', 'Disease', (32, 38))	('Lys656', 'Var', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
34137	30931252	Additionally, studies on FGFR1 and FGFR1 mutations have mainly concentrated on pediatric LGGs and further research is needed in pediatric HGGs.	('mutations', 'Var', (41, 50))	('FGFR1', 'Gene', (25, 30))	('FGFR1', 'Gene', (35, 40))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR1', 'Gene', '2260', (35, 40))
34139	30931252	We screened patient derived and established pLGG and pHGG cell lines for the FGFR1 reported mutational hotspots and determined FGFR1 and pFGFR1 protein expression levels.	('FGFR1', 'Gene', (77, 82))	('FGFR1', 'Gene', '2260', (77, 82))	('mutational', 'Var', (92, 102))	('FGFR1', 'Gene', (138, 143))	('FGFR1', 'Gene', (127, 132))	('FGFR1', 'Gene', '2260', (127, 132))	('FGFR1', 'Gene', '2260', (138, 143))	('patient', 'Species', '9606', (12, 19))
34144	30931252	FGFR1 inhibitors had an anti-migratory effect on the two HGG cell lines whereas we observed an anti-migratory or potentially pro-migratory effect among the LGG cell lines.	('anti-migratory', 'CPA', (24, 38))	('pro-migratory', 'CPA', (125, 138))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('inhibitors', 'Var', (6, 16))	('anti-migratory', 'CPA', (95, 109))
34145	30931252	As all cell lines were FGFR1 wildtype we propose that FGFR1 amplification alone may contribute to disease progression.	('contribute', 'Reg', (84, 94))	('FGFR1', 'Gene', (23, 28))	('amplification', 'Var', (60, 73))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('FGFR1', 'Gene', '2260', (23, 28))
34146	30931252	Five rare pediatric LGG patient-derived cell lines were studied including IN1591, IN2017, IN2356, IN2688, and IN1520.	('IN1520', 'Var', (110, 116))	('IN2356', 'Var', (90, 96))	('patient', 'Species', '9606', (24, 31))	('IN2017', 'Var', (82, 88))	('IN1591', 'Var', (74, 80))	('IN2688', 'Var', (98, 104))
34153	30931252	IN1591, IN2017, IN2356, IN2688, and IN1520 were grown in Ham's F-10 Nutrient mixture (1X) (Gibco) supplemented only with 10% HI-FCS (Labtech).	('HI-FCS', 'Disease', (125, 131))	('IN1591', 'Var', (0, 6))	('IN2017', 'Var', (8, 14))	('HI-FCS', 'Disease', 'MESH:C538424', (125, 131))	('IN1520', 'Var', (36, 42))	('IN2356', 'Var', (16, 22))	('IN2688', 'Var', (24, 30))
34156	30931252	The inhibitors used were Ponatinib (Selleckchem), SSR128129E (Selleckchem), and BGJ398 (Selleckchem).	('Ponatinib', 'Chemical', 'MESH:C545373', (25, 34))	('SSR128129E', 'Var', (50, 60))	('BGJ398', 'Chemical', 'MESH:C568950', (80, 86))	('BGJ398', 'Gene', (80, 86))
34172	30931252	Q-PCR was performed using 2.5 mul of cDNA from each culture, primers and TaqMan probes specific for the KIAA1549-BRAF fusions 16-9, 15-9, and 16-11 (Assays-on-Demand Gene Expression products Hs04396516_ft, Hs04421337_ft and Hs04396507_ft) and TaqMan Gene Expression Mastermix on an ABI 7500 HT Sequence Detection System (Applied Biosystems, Warrington, UK).	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('Hs04396507_ft', 'Var', (224, 237))	('KIAA1549', 'Gene', (104, 112))	('KIAA1549', 'Gene', '57670', (104, 112))	('Hs04421337_ft', 'Var', (206, 219))	('Hs04396516_ft', 'Var', (191, 204))
34198	30931252	There was a significant correlation between high FGFR1 expression in the cerebrum compared to the cerebellum.	('FGFR1', 'Gene', '2260', (49, 54))	('high', 'Var', (44, 48))	('expression', 'MPA', (55, 65))	('FGFR1', 'Gene', (49, 54))
34204	30931252	The BRAF fusion was present in 4 of 5 (80%) patient-derived cell cultures of pLGG (IN1520, IN1591, IN2017, and IN2688), all of which expressed the KIAA1549-BRAF 15-9 fusion supporting a true representation of high BRAF frequency common to pLGGs in our in vitro models.	('patient', 'Species', '9606', (44, 51))	('BRAF', 'Gene', '673', (214, 218))	('KIAA1549', 'Gene', (147, 155))	('BRAF', 'Gene', (156, 160))	('KIAA1549', 'Gene', '57670', (147, 155))	('BRAF', 'Gene', (214, 218))	('IN2017', 'Var', (99, 105))	('BRAF', 'Gene', (4, 8))	('IN1591', 'Var', (91, 97))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', '673', (156, 160))
34207	30931252	None of the cell lines had FGFR1 mutations in the investigated mutational hotspots.	('FGFR1', 'Gene', (27, 32))	('FGFR1', 'Gene', '2260', (27, 32))	('mutations', 'Var', (33, 42))
34210	30931252	Among the pLGGs IN2356 exhibited the greatest migratory activity, which was the cell line that did not have the BRAF mutation.	('migratory activity', 'CPA', (46, 64))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('IN2356', 'Var', (16, 22))
34211	30931252	We went on to investigate the relationship of migratory activity and FGFR1 expression and activity, given that FGFR1 mutations have been recently identified in pediatric gliomas and we had also determined associations of FGFR1 levels and pFGFR1 localization and various clinicopathologic parameters in our TMAs.	('FGFR1', 'Gene', '2260', (111, 116))	('mutations', 'Var', (117, 126))	('FGFR1', 'Gene', '2260', (239, 244))	('pediatric gliomas', 'Disease', (160, 177))	('TMAs', 'Chemical', 'MESH:C071868', (306, 310))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('associations', 'Interaction', (205, 217))	('identified', 'Reg', (146, 156))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('FGFR1', 'Gene', (69, 74))	('pediatric gliomas', 'Disease', 'MESH:D005910', (160, 177))	('FGFR1', 'Gene', (111, 116))	('FGFR1', 'Gene', '2260', (69, 74))	('FGFR1', 'Gene', (221, 226))	('FGFR1', 'Gene', '2260', (221, 226))	('FGFR1', 'Gene', (239, 244))
34216	30931252	We demonstrated the highest FGFR1 levels in IN2356, followed by IN2688, IN1591, IN2017, and IN1520.	('IN2017', 'Var', (80, 86))	('IN1591', 'Var', (72, 78))	('FGFR1', 'Gene', (28, 33))	('IN1520', 'Var', (92, 98))	('FGFR1', 'Gene', '2260', (28, 33))	('IN2688', 'Var', (64, 70))	('levels', 'MPA', (34, 40))	('IN2356', 'Var', (44, 50))
34229	30931252	We observed anti-migratory effects with the inhibitors Ponatinib (Pona), BGJ398 (BGJ), and SSR128129E (SSR) at pre-determined anti-migratory concentrations.	('SSR128129E', 'Var', (91, 101))	('anti-migratory effects', 'CPA', (12, 34))	('Ponatinib', 'Gene', (55, 64))	('BGJ398', 'Chemical', 'MESH:C568950', (73, 79))	('BGJ398', 'Gene', (73, 79))	('Ponatinib', 'Chemical', 'MESH:C545373', (55, 64))
34230	30931252	In 2D random cell migration, SF188 velocity was affected by Ponatinib and SSR128129E and all three inhibitors reduced cell velocity in KNS42.	('velocity', 'MPA', (35, 43))	('reduced', 'NegReg', (110, 117))	('SF188', 'Gene', (29, 34))	('SSR128129E', 'Var', (74, 84))	('Ponatinib', 'Chemical', 'MESH:C545373', (60, 69))	('affected', 'Reg', (48, 56))	('cell', 'CPA', (118, 122))
34231	30931252	IN1591 was affected by treatment with SSR128129E and BGJ398.	('BGJ398', 'Gene', (53, 59))	('BGJ398', 'Chemical', 'MESH:C568950', (53, 59))	('SSR128129E', 'Var', (38, 48))
34236	30931252	For the migration edge, decreased migration was observed in SF188 with BGJ398 and in KNS42 with Ponatinib, as well as in IN1591 and IN1520 with Ponatinib.	('decreased', 'NegReg', (24, 33))	('Ponatinib', 'Chemical', 'MESH:C545373', (96, 105))	('BGJ398', 'Gene', (71, 77))	('Ponatinib', 'Chemical', 'MESH:C545373', (144, 153))	('BGJ398', 'Chemical', 'MESH:C568950', (71, 77))	('SF188', 'Var', (60, 65))	('migration', 'CPA', (34, 43))
34237	30931252	Markers for apoptosis (cleaved caspase 3) remained unchanged in the spheroids tested, confirming that the observed inhibitor effect resulted from anti-migratory activity and not cytotoxicity; proliferation (Ki67) was affected after treatment with SSR128129E in IN1520, KNS42, and SF188 and in KNS42 after treatment with BGJ398 (Tables 6, 7).	('proliferation', 'CPA', (192, 205))	('BGJ398', 'Chemical', 'MESH:C568950', (320, 326))	('cytotoxicity', 'Disease', (178, 190))	('SSR128129E', 'Var', (247, 257))	('affected', 'Reg', (217, 225))	('anti-migratory activity', 'CPA', (146, 169))	('cytotoxicity', 'Disease', 'MESH:D064420', (178, 190))
34240	30931252	Following recent reports of recurrent FGFR1 mutations in pediatric gliomas and known roles for FGFR1 in invasion in other cancer types, we firstly wanted to determine clinical relevance of FGFR1 expression.	('FGFR1', 'Gene', (95, 100))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('cancer', 'Disease', (122, 128))	('FGFR1', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('pediatric gliomas', 'Disease', (57, 74))	('FGFR1', 'Gene', '2260', (95, 100))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('mutations', 'Var', (44, 53))	('FGFR1', 'Gene', '2260', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('pediatric gliomas', 'Disease', 'MESH:D005910', (57, 74))
34255	30931252	Reduced directionality in the cell lines may indicate a loss of cell polarity following FGFR1 stimulation.	('stimulation', 'Var', (94, 105))	('FGFR1', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (88, 93))	('loss', 'NegReg', (56, 60))	('Reduced', 'NegReg', (0, 7))	('directionality', 'MPA', (8, 22))	('cell polarity', 'CPA', (64, 77))
34259	30931252	Treatment with Ponatinib, a multi-targeted tyrosine kinase inhibitor, BGJ398, a pan-FGFR inhibitor with VEGFR activity, and SSR128129E, a highly specific FGFR1 inhibitor induced different responses in the cell lines.	('VEGFR', 'Gene', (104, 109))	('Ponatinib', 'Chemical', 'MESH:C545373', (15, 24))	('FGFR1', 'Gene', (154, 159))	('BGJ398', 'Chemical', 'MESH:C568950', (70, 76))	('FGFR1', 'Gene', '2260', (154, 159))	('VEGFR', 'Gene', '3791', (104, 109))	('BGJ398', 'Gene', (70, 76))	('SSR128129E', 'Var', (124, 134))
34261	30931252	We propose to include BGJ398 in future in vitro treatment combination studies targeting BRAF in patients with BRAF mutations to investigate potential new therapeutic avenues.	('mutations', 'Var', (115, 124))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('BRAF', 'Gene', '673', (110, 114))	('BGJ398', 'Chemical', 'MESH:C568950', (22, 28))	('patients', 'Species', '9606', (96, 104))	('BRAF', 'Gene', (110, 114))	('BGJ398', 'Gene', (22, 28))
34262	30931252	We also suggest further testing of BGJ398 in combination and as stand-alone in BRAF wildtype/FGFR1 mutation patients.	('BGJ398', 'Chemical', 'MESH:C568950', (35, 41))	('BGJ398', 'Gene', (35, 41))	('mutation', 'Var', (99, 107))	('BRAF', 'Gene', '673', (79, 83))	('FGFR1', 'Gene', (93, 98))	('patients', 'Species', '9606', (108, 116))	('BRAF', 'Gene', (79, 83))	('FGFR1', 'Gene', '2260', (93, 98))
34267	30931252	Reports from other cancer types targeted with FGFR1 inhibitors support the notion that inhibitors do not have equivalent efficiency varying from one tumor type and drug family to another suggesting the FGFR alterations have different biological meanings.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('FGFR1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('inhibitors', 'Var', (52, 62))	('FGFR1', 'Gene', '2260', (46, 51))
34372	30659022	Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis.	('NODAL expression', 'MPA', (23, 39))	('decreased tumor', 'Disease', (79, 94))	('MNK1', 'Gene', (8, 12))	('decreased tumor', 'Disease', 'MESH:D009369', (79, 94))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('IDC', 'Gene', '4000', (59, 62))	('IDC', 'Gene', (59, 62))	('inhibited', 'NegReg', (41, 50))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
34376	30659022	In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('IDC', 'Gene', '4000', (21, 24))	('microinvasion', 'Var', (39, 52))	('IDC', 'Gene', (21, 24))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('clinical samples', 'Species', '191496', (3, 19))	('higher', 'PosReg', (63, 69))	('levels of phospho-MNK1', 'MPA', (70, 92))
34377	30659022	Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease.	('invasive disease', 'Disease', (101, 117))	('invasive disease', 'Disease', 'MESH:D009362', (101, 117))	('inhibitors', 'Var', (59, 69))	('MNK1', 'Gene', (54, 58))
34378	30659022	These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.	('clinical', 'Species', '191496', (96, 104))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (67, 83))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (169, 193))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (169, 185))	('MNK1', 'Gene', (120, 124))	('ductal carcinoma', 'Disease', 'MESH:D044584', (206, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ductal carcinoma', 'Disease', 'MESH:D044584', (169, 185))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (197, 222))	('ductal carcinoma', 'Disease', (169, 185))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (206, 222))	('invasive ductal carcinoma', 'Disease', (197, 222))	('ductal carcinoma', 'Disease', 'MESH:D044584', (67, 83))	('delay', 'NegReg', (139, 144))	('ductal carcinoma', 'Disease', (67, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('inhibitors', 'Var', (125, 135))
34384	30659022	The best characterized function of MNK1/2 is to phosphorylate eukaryotic initiation factor 4E (eIF4E) at Ser209.	('Ser209', 'Var', (105, 111))	('eukaryotic initiation factor 4E', 'Gene', (62, 93))	('Ser209', 'Chemical', '-', (105, 111))	('eIF4E', 'Gene', (95, 100))	('eIF4E', 'Gene', '13684', (95, 100))	('eukaryotic initiation factor 4E', 'Gene', '13684', (62, 93))	('MNK1/2', 'Gene', (35, 41))
34389	30659022	Finally, lack of MNK1 decreases the oncogenic potential of leukemia, gliomas, melanoma, ovarian cancer, and malignant peripheral nerve sheath tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gliomas', 'Disease', (69, 76))	('MNK1', 'Gene', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('decreases', 'NegReg', (22, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (108, 148))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('ovarian cancer', 'Disease', (88, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('oncogenic potential', 'CPA', (36, 55))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (108, 148))	('leukemia', 'Disease', 'MESH:D007938', (59, 67))	('leukemia', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('malignant peripheral nerve sheath tumors', 'Disease', (108, 148))	('lack', 'Var', (9, 13))
34424	30659022	Briefly, human and mouse tumor sections were stained for p63, MNK1, p-MNK1, NODAL, VIMEN-TIN, p-histone H3, Ki67, and cleaved caspase-3 and counter-stained with 20% Harris-modified hematoxylin (Thermo Fisher Scientific).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('VIMEN-TIN', 'Gene', (83, 92))	('tumor', 'Disease', (25, 30))	('Ki67', 'Gene', '17345', (108, 112))	('hematoxylin', 'Chemical', 'MESH:D006416', (181, 192))	('human', 'Species', '9606', (9, 14))	('VIMEN-TIN', 'Gene', '22352', (83, 92))	('p-MNK1', 'Var', (68, 74))	('mouse', 'Species', '10090', (19, 24))	('p63', 'Gene', '22061', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('p63', 'Gene', (57, 60))	('Ki67', 'Gene', (108, 112))	('p-histone', 'Chemical', '-', (94, 103))
34443	30659022	Thus, our results show that increased expression of phospho-MNK1 and MNK1 occurs in a larger percentage of high-grade DCIS/IDC samples, compared with low-grade DCIS specimens.	('increased', 'PosReg', (28, 37))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('IDC', 'Gene', '4000', (123, 126))	('expression', 'MPA', (38, 48))	('IDC', 'Gene', (123, 126))	('phospho-MNK1', 'Var', (52, 64))	('MNK1', 'Gene', (69, 73))	('DCIS', 'Phenotype', 'HP:0030075', (160, 164))
34458	30659022	Although not statistically significant, mice that had received MNK1-KO cells showed a trend toward better overall survival, than those animals that were implanted with CTL cells (Fig.	('better', 'PosReg', (99, 105))	('mice', 'Species', '10090', (40, 44))	('MNK1-KO cells', 'Var', (63, 76))
34459	30659022	Furthermore, 80% of mice that received CTL cells had relapsed metastatic disease, while no mice that received MNK1- KO cells had metastasis (Fig.	('mice', 'Species', '10090', (91, 95))	('CTL cells', 'Var', (39, 48))	('mice', 'Species', '10090', (20, 24))	('relapsed metastatic disease', 'CPA', (53, 80))
34469	30659022	Unlike the lack of proliferative advantage observed in 2D culture, caMNK1-expressing tumors were larger compared with pBABE control expressing tumors (Fig.	('caMNK1-expressing', 'Var', (67, 84))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
34474	30659022	In addition, 6 of the 10 mice injected with caMNK1 cells have tumors with central necrosis, while only 2 of 10 mice injected with pBABE cells present with tumors with central necrosis (Fig.	('caMNK1', 'Var', (44, 50))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('necrosis', 'Disease', 'MESH:D009336', (175, 183))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mice', 'Species', '10090', (111, 115))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('necrosis', 'Disease', (82, 90))	('necrosis', 'Disease', (175, 183))
34477	30659022	Tumor formation in the orthotopic mammary fat pad was significantly increased in mice injected with caMNK1 cells compared with those injected with the control pBABE cells (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (81, 85))	('Tumor formation in the orthotopic mammary fat pad', 'CPA', (0, 49))	('caMNK1 cells', 'Var', (100, 112))	('increased', 'PosReg', (68, 77))
34478	30659022	We further interrogated whether the increase in tumor formation associated with caMNK1 expression was due to an increase in proliferation or a decrease in apoptosis.	('expression', 'Var', (87, 97))	('tumor', 'Disease', (48, 53))	('decrease', 'NegReg', (143, 151))	('increase', 'PosReg', (36, 44))	('increase', 'PosReg', (112, 120))	('caMNK1', 'Gene', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('apoptosis', 'CPA', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
34482	30659022	These data suggest that caMNK1-derived tumors are larger than their pBABE counterparts, due to an evasion of apoptotic cell death.	('apoptotic', 'CPA', (109, 118))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('caMNK1-derived', 'Var', (24, 38))	('evasion', 'MPA', (98, 105))	('tumors', 'Disease', (39, 45))
34483	30659022	Cumulatively, the data presented here demonstrate that modulation of MNK1 influences the DCIS to IDC transition in vivo.	('influences', 'Reg', (74, 84))	('MNK1', 'Gene', (69, 73))	('modulation', 'Var', (55, 65))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('IDC', 'Gene', '4000', (97, 100))	('IDC', 'Gene', (97, 100))
34494	30659022	Moreover, we determined whether depletion of MNK1 could reduce the tumor-initiating cell subpopulation by performing FACS analysis for CD44hi/ CD24lo populations in the MCFDCIS.com cells knocked out for MNK1.	('FACS', 'Gene', (117, 121))	('depletion', 'Var', (32, 41))	('FACS', 'Gene', '14081', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('CD24', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MNK1', 'Gene', (45, 49))	('reduce', 'NegReg', (56, 62))	('CD24', 'Gene', '12484', (143, 147))	('tumor', 'Disease', (67, 72))	('MNK1', 'Gene', (203, 207))	('MCFDCIS.com', 'CellLine', 'CVCL:5552', (169, 180))
34498	30659022	Similar to our results in DCIS cells, depleting MNK1 in 66cl4 cells using CRISPR-Cas9 technology, and by siRNA in MB-MDA-468 cells, caused these cells to express less NODAL (Supplementary Fig.	('less', 'NegReg', (162, 166))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('depleting', 'Var', (38, 47))	('MNK1', 'Gene', (48, 52))	('NODAL', 'MPA', (167, 172))	('MB-MDA-468', 'CellLine', 'CVCL:0419', (114, 124))
34499	30659022	Similarly, concomitant with the reduced NODAL levels observed when we silence MNK1 in MDA-MB-468 cells, their invasion is also impaired (Supplementary Fig.	('silence', 'Var', (70, 77))	('MNK1', 'Gene', (78, 82))	('NODAL levels', 'MPA', (40, 52))	('impaired', 'NegReg', (127, 135))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (86, 96))	('invasion', 'MPA', (110, 118))
34503	30659022	S3I, the caMNK1-expressing cells have an increased tumor-initiating capability, compared with their pBABE control counterparts.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('increased', 'PosReg', (41, 50))	('tumor', 'Disease', (51, 56))	('caMNK1-expressing', 'Var', (9, 26))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
34523	30659022	Furthermore, xenografts from the SEL201 group showed a reduced percentage of IDC (10% of tumors) compared with the vehicle group (87.5% of tumors; Fig.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('IDC', 'Gene', (77, 80))	('reduced', 'NegReg', (55, 62))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('IDC', 'Gene', '4000', (77, 80))	('SEL201', 'Var', (33, 39))
34524	30659022	Consistent with our previous work, SEL201 showed no overt systemic toxicity, as evidenced by body weight (Supplementary Fig.	('body weight', 'CPA', (93, 104))	('SEL201', 'Var', (35, 41))	('toxicity', 'Disease', (67, 75))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))
34527	30659022	SEL201 also inhibits colony formation of SUM225 cells in vitro, and slows down the transition from DCIS to IDC in the SUM225 intraductal model of DCIS (Supplementary Fig.	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('transition', 'MPA', (83, 93))	('SEL201', 'Var', (0, 6))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('slows down', 'NegReg', (68, 78))	('colony formation', 'CPA', (21, 37))	('inhibits', 'NegReg', (12, 20))	('IDC', 'Gene', '4000', (107, 110))	('IDC', 'Gene', (107, 110))
34528	30659022	In summary, our results provide evidence to show the feasibility of inhibiting MNK1 to slow the conversion of DCIS to IDC.	('conversion', 'MPA', (96, 106))	('inhibiting', 'Var', (68, 78))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('MNK1', 'Gene', (79, 83))	('slow', 'NegReg', (87, 91))	('IDC', 'Gene', '4000', (118, 121))	('IDC', 'Gene', (118, 121))
34536	30659022	Similar results were previously shown in response to Twist1 expression, which induces a partial EMT and dedifferentiation toward "sternness".	('dedifferentiation', 'CPA', (104, 121))	('EMT', 'Gene', (96, 99))	('Twist1', 'Gene', '22160', (53, 59))	('induces', 'Reg', (78, 85))	('expression', 'Var', (60, 70))	('Twist1', 'Gene', (53, 59))	('EMT', 'Gene', '16428', (96, 99))
34717	31447670	The eight functional modules include anti-cancer action associated with sustaining proliferative signaling, resisting cell death, deregulating cellular energetics, enabling replicative immortality, avoiding immune destruction, genome instability and mutation, angiogenesis, and activating invasion and metastasis.	('cellular energetics', 'MPA', (143, 162))	('mutation', 'Var', (250, 258))	('immune destruction', 'CPA', (207, 225))	('enabling', 'PosReg', (164, 172))	('avoiding', 'NegReg', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('deregulating', 'Reg', (130, 142))	('replicative immortality', 'CPA', (173, 196))	('sustaining', 'PosReg', (72, 82))	('proliferative signaling', 'MPA', (83, 106))	('activating', 'PosReg', (278, 288))	('angiogenesis', 'CPA', (260, 272))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('genome instability', 'CPA', (227, 245))	('cell death', 'CPA', (118, 128))
34725	31447670	Among 56 pathways, PI3K-Akt (hsa04151; q = 2.0 x 10-12), p53 (hsa04115; q = 2.7 x 10-9), HIF-1 (hsa04066; q = 3.9 x 10-9), FoxO (hsa04068; q = 4.9 x 10-9), VEGF (hsa04370; q = 5.7 x 10-7), MAPK (hsa04010; q = 2.5 x 10-6), Ras (hsa04014; q = 6.4 x 10-6), Jak-STAT (hsa04630; q = 9.9 x 10-4), mTOR (hsa04150; q= 1.5 x 10-2), AMPK (hsa04152; q = 1.9 x 10-2), and NF-kappa B (hsa04064; q = 4.0 x 10-2) signaling pathways have been confirmed to be associated with berberine in previous literatures ( Table 1 ).	('VEGF', 'Gene', (156, 160))	('HIF-1', 'Gene', '3091', (89, 94))	('hsa04630;', 'Var', (264, 273))	('Akt', 'Gene', '207', (24, 27))	('NF-kappa B', 'Gene', '4790', (360, 370))	('mTOR', 'Gene', '2475', (291, 295))	('p53', 'Gene', '7157', (57, 60))	('hsa04010', 'Var', (195, 203))	('HIF-1', 'Gene', (89, 94))	('p53', 'Gene', (57, 60))	('AMPK', 'Gene', '5562', (323, 327))	('hsa04370;', 'Var', (162, 171))	('berberine', 'Chemical', 'MESH:D001599', (459, 468))	('NF-kappa B', 'Gene', (360, 370))	('mTOR', 'Gene', (291, 295))	('VEGF', 'Gene', '7422', (156, 160))	('hsa04064;', 'Var', (372, 381))	('AMPK', 'Gene', (323, 327))	('Akt', 'Gene', (24, 27))
34766	31447670	According to previous study, the oncogenic ras genes GTPase HRas (HRAS) mutations, endogenously expressed in T24 bladder cancer cell line, were associated with grades and stages of BLCA detected in more than 35% of patients.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (215, 223))	('GTPase HRas', 'Gene', (53, 64))	('BLCA', 'Chemical', '-', (181, 185))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('associated', 'Reg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('GTPase HRas', 'Gene', '3265', (53, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('HRAS', 'Gene', (66, 70))	('grades', 'Disease', (160, 166))	('bladder cancer', 'Disease', (113, 127))	('HRAS', 'Gene', '3265', (66, 70))
34782	29046514	A recent study reported that a mutation in the PPM1D gene is associated with poor prognosis in brainstem gliomas.	('PPM1D', 'Gene', (47, 52))	('brainstem glioma', 'Phenotype', 'HP:0010796', (95, 111))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('mutation', 'Var', (31, 39))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('PPM1D', 'Gene', '8493', (47, 52))	('associated', 'Reg', (61, 71))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (95, 112))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
34789	29046514	Multivariate analysis demonstrated that PPM1D expression (hazard ratio [HR], 2.58; p=.032), age over 60 years (HR, 2.55; p=.018), and IDH1 mutation (HR, 0.18; p=.002) were significantly independent prognostic factors; p53 expression had no prognostic significance (p=.986).	('mutation', 'Var', (139, 147))	('PPM1D', 'Gene', (40, 45))	('IDH1', 'Gene', (134, 138))	('p53', 'Gene', '7157', (218, 221))	('p53', 'Gene', (218, 221))	('PPM1D', 'Gene', '8493', (40, 45))	('IDH1', 'Gene', '3417', (134, 138))
34796	29046514	Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes occur in 70%-80% of grade II/III gliomas and most secondary glioblastomas.	('IDH1', 'Gene', '3417', (45, 49))	('IDH2', 'Gene', '3418', (55, 59))	('glioblastomas', 'Disease', (126, 139))	('IDH2', 'Gene', (55, 59))	('glioblastomas', 'Phenotype', 'HP:0012174', (126, 139))	('occur', 'Reg', (66, 71))	('gliomas', 'Disease', (99, 106))	('isocitrate dehydrogenase 1', 'Gene', (17, 43))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (126, 139))	('isocitrate dehydrogenase 1', 'Gene', '3417', (17, 43))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('IDH1', 'Gene', (45, 49))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
34797	29046514	Co-deletion of 1p/19q is typically related with tumors of the oligodendroglial lineage and is closely associated with IDH mutations.	('tumors of the oligodendroglial', 'Disease', (48, 78))	('1p/19q', 'Gene', (15, 21))	('associated', 'Reg', (102, 112))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Co-deletion', 'Var', (0, 11))	('IDH', 'Gene', (118, 121))	('tumors of the oligodendroglial', 'Disease', 'MESH:D009369', (48, 78))	('IDH', 'Gene', '3417', (118, 121))	('related', 'Reg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
34798	29046514	Alterations in the p53 and its pathway genes occur in 78% of glioblastomas, and are thought to promote progression to high-grade malignancy.	('glioblastomas', 'Phenotype', 'HP:0012174', (61, 74))	('promote', 'Reg', (95, 102))	('malignancy', 'Disease', (129, 139))	('glioblastomas', 'Disease', 'MESH:D005909', (61, 74))	('Alterations', 'Var', (0, 11))	('glioblastomas', 'Disease', (61, 74))	('occur', 'Reg', (45, 50))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))
34802	29046514	Recent studies have reported C-terminal truncating alterations in the PPM1D gene, which enhance the functional ability of PPM1D.	('PPM1D', 'Gene', '8493', (70, 75))	('PPM1D', 'Gene', (122, 127))	('functional', 'MPA', (100, 110))	('C-terminal', 'Var', (29, 39))	('PPM1D', 'Gene', '8493', (122, 127))	('PPM1D', 'Gene', (70, 75))	('enhance', 'PosReg', (88, 95))
34814	29046514	The slides were incubated with primary antibodies against PPM1D (1:100, 2804D1a, Abcam, Cambridge, UK) and p53 (1:1,500, DO.7, DAKO, Glostrup, Denmark).	('PPM1D', 'Gene', '8493', (58, 63))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('PPM1D', 'Gene', (58, 63))	('1:100', 'Var', (65, 70))
34822	29046514	The signals per cell were divided into four groups according to the manufacturer's semi-quantitative scoring guideline: score 0, no staining or less than 1 dot in 10 cells; score 1, 1-3 dots in a cell; score 2, 4-9 dots in a cell; and score 3, >=10 dots in a cell or the presence of gene clusters in >= 10% of the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('presence', 'Reg', (271, 279))	('score 2', 'Var', (202, 209))	('tumor', 'Disease', (314, 319))	('gene clusters', 'CPA', (283, 296))
34831	29046514	The 84 cases consisted of 26 glioblastomas, IDH-wildtype (31.0%), 16 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q-codeleted (19.0%), 12 oligodendrogliomas, IDH-mutant and 1p/19q-codeleted (14.3%), and 10 diffuse astrocytomas, IDH-mutant (11.9%).	('oligodendrogliomas', 'Disease', 'MESH:D009837', (144, 162))	('IDH', 'Gene', '3417', (234, 237))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (80, 98))	('glioblastomas', 'Disease', (29, 42))	('1p/19q-codeleted', 'Var', (115, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('oligodendrogliomas', 'Disease', (144, 162))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('astrocytomas', 'Disease', (220, 232))	('IDH', 'Gene', (164, 167))	('oligodendrogliomas', 'Disease', (80, 98))	('glioblastomas', 'Disease', 'MESH:D005909', (29, 42))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('IDH', 'Gene', (100, 103))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (234, 237))	('IDH', 'Gene', '3417', (164, 167))	('astrocytomas', 'Disease', 'MESH:D001254', (220, 232))	('IDH', 'Gene', '3417', (100, 103))	('glioblastomas', 'Phenotype', 'HP:0012174', (29, 42))	('IDH', 'Gene', '3417', (44, 47))
34833	29046514	Those with oligodendrogliomas, IDH-mutant and 1p/19q-codeleted were treated with surgery without any additional therapy (100%, 12/12).	('IDH', 'Gene', (31, 34))	('1p/19q-codeleted', 'Var', (46, 62))	('IDH', 'Gene', '3417', (31, 34))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (11, 29))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('oligodendrogliomas', 'Disease', (11, 29))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))
34835	29046514	Among the 36 patients (42.9%) with IDH1 mutations, 35 had R132H mutation and 1 had R132S mutation.	('R132H', 'Var', (58, 63))	('IDH1', 'Gene', (35, 39))	('R132H', 'Mutation', 'rs121913500', (58, 63))	('IDH1', 'Gene', '3417', (35, 39))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (40, 49))	('R132S', 'Mutation', 'rs121913499', (83, 88))
34841	29046514	There was a marginally negative relationship between PPM1D expression and IDH1 mutation (p = .062).	('IDH1', 'Gene', (74, 78))	('negative', 'NegReg', (23, 31))	('PPM1D', 'Gene', '8493', (53, 58))	('mutation', 'Var', (79, 87))	('IDH1', 'Gene', '3417', (74, 78))	('PPM1D', 'Gene', (53, 58))
34846	29046514	A large number of cases involving PPM1D positivity (90.2%, 37/41) showed mRNA expression (low or high expression), and over half of the cases (58.5%, 24/41) presented high PPM1D mRNA levels.	('PPM1D', 'Gene', '8493', (172, 177))	('PPM1D', 'Gene', (34, 39))	('PPM1D', 'Gene', (172, 177))	('PPM1D', 'Gene', '8493', (34, 39))	('positivity', 'Var', (40, 50))
34852	29046514	Age, diagnosis, IDH1 mutation, and PPM1D expression were significant predictors of survival in univariate Cox proportional hazard regression analyses (Table 3).	('Cox', 'Gene', '1351', (106, 109))	('PPM1D', 'Gene', '8493', (35, 40))	('Cox', 'Gene', (106, 109))	('mutation', 'Var', (21, 29))	('IDH1', 'Gene', (16, 20))	('PPM1D', 'Gene', (35, 40))	('IDH1', 'Gene', '3417', (16, 20))
34856	29046514	Mutant IDH1 was a significant protective factor when compared with wild-type IDH1 (HR, 0.14; 95% CI, 0.05 to 0.38; p < .001), and the patients with mutant IDH1 showed significantly longer OS from the initial diagnosis (median OS, 102 months [95% CI, 102 to not reached] vs 19 months [95% CI, 14 to not reached]; p < .001) (Fig.	('IDH1', 'Gene', (155, 159))	('IDH1', 'Gene', '3417', (7, 11))	('IDH1', 'Gene', '3417', (155, 159))	('patients', 'Species', '9606', (134, 142))	('IDH1', 'Gene', (77, 81))	('mutant', 'Var', (148, 154))	('longer', 'PosReg', (181, 187))	('IDH1', 'Gene', '3417', (77, 81))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))
34857	29046514	In multivariate analyses, age (> 60 years) (HR, 2.55; 95% CI, 1.17 to 5.55; p = .018), PPM1D positivity (HR, 2.58; 95% CI, 1.08 to 6.17; p = .032), and IDH1 mutation (HR, 0.18; 95% CI, 0.06 to 0.53; p = .002) were independent prognostic factors (Table 3).	('IDH1', 'Gene', (152, 156))	('PPM1D', 'Gene', '8493', (87, 92))	('IDH1', 'Gene', '3417', (152, 156))	('mutation', 'Var', (157, 165))	('positivity', 'Var', (93, 103))	('PPM1D', 'Gene', (87, 92))
34859	29046514	Patients with mutant IDH1 and PPM1D-negative (IDH1mut/PPM1D-negative) tumors had the best OS, whereas patients with wild-type IDH1 and PPM1D expression (IDH1wt/PPM1D-positive) showed the worst OS (p < .001) (Fig.	('IDH1', 'Gene', (153, 157))	('PPM1D', 'Gene', '8493', (135, 140))	('patients', 'Species', '9606', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('PPM1D', 'Gene', '8493', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (153, 157))	('tumors', 'Disease', (70, 76))	('Patients', 'Species', '9606', (0, 8))	('PPM1D', 'Gene', '8493', (54, 59))	('IDH1', 'Gene', (126, 130))	('PPM1D', 'Gene', '8493', (30, 35))	('IDH1', 'Gene', (21, 25))	('PPM1D', 'Gene', (135, 140))	('PPM1D', 'Gene', (160, 165))	('IDH1', 'Gene', '3417', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('IDH1', 'Gene', '3417', (21, 25))	('IDH1', 'Gene', '3417', (126, 130))	('PPM1D', 'Gene', (54, 59))	('mutant', 'Var', (14, 20))	('PPM1D', 'Gene', (30, 35))
34866	29046514	Genetic alterations of PPM1D are observed in various tumors, and are significantly associated with poor prognosis.	('PPM1D', 'Gene', (23, 28))	('Genetic alterations', 'Var', (0, 19))	('observed', 'Reg', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PPM1D', 'Gene', '8493', (23, 28))	('associated', 'Reg', (83, 93))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))
34869	29046514	p53 mutation status rather than p53 protein expression is clearly associated with poor prognosis in malignant gliomas.	('mutation status', 'Var', (4, 19))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('malignant gliomas', 'Disease', (100, 117))	('associated', 'Reg', (66, 76))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('malignant gliomas', 'Disease', 'MESH:D005910', (100, 117))
34870	29046514	In our study, PPM1D positivity was significantly correlated with its mRNA transcript levels (p = .035) and marginally associated with PPM1D gene amplification (p = .079).	('positivity', 'Var', (20, 30))	('PPM1D', 'Gene', '8493', (14, 19))	('PPM1D', 'Gene', (134, 139))	('PPM1D', 'Gene', (14, 19))	('PPM1D', 'Gene', '8493', (134, 139))	('associated', 'Reg', (118, 128))	('mRNA transcript levels', 'MPA', (69, 91))
34875	29046514	PPM1D mutation is very rare in gliomas arising outside the brainstem.	('PPM1D', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('PPM1D', 'Gene', '8493', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
34876	29046514	Our data suggest that PPM1D expression in supratentorial diffuse astrocytic and oligodendroglial tumors may have similar effects as PPM1D mutations in brainstem gliomas, resulting in stabilized and extended phosphatase activities of PPM1D.	('oligodendroglial tumors', 'Disease', (80, 103))	('PPM1D', 'Gene', (132, 137))	('brainstem glioma', 'Phenotype', 'HP:0010796', (151, 167))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (151, 168))	('PPM1D', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PPM1D', 'Gene', '8493', (132, 137))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('PPM1D', 'Gene', '8493', (22, 27))	('PPM1D', 'Gene', '8493', (233, 238))	('PPM1D', 'Gene', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('phosphatase activities', 'MPA', (207, 229))	('gliomas', 'Disease', (161, 168))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (80, 103))	('mutations', 'Var', (138, 147))
34883	29046514	We further characterized two prognostic factors: IDH1 mutation and PPM1D expression (Fig.	('mutation', 'Var', (54, 62))	('IDH1', 'Gene', '3417', (49, 53))	('PPM1D', 'Gene', (67, 72))	('PPM1D', 'Gene', '8493', (67, 72))	('IDH1', 'Gene', (49, 53))
34908	28829841	The exclusion criteria were the followings: 1) evidence of tumor located in the primary motor cortex or centered in this region demonstrated on contrast-enhanced MR images or abnormal T2-hyperintensity; 2) CST regions affected by other diseases such as leukodystrophy, vascular diseases, etc; 3) lesions in the motor cortex may lead to limb motor dysfunction such as cerebral infarction, infection,etc; 4) obvious motion artifacts; 5) muscle motor dysfunction caused by other diseases such as limb disuse, arthrogenous, osteoporotic or joint soft tissue injury.	('tumor', 'Disease', (59, 64))	('osteoporotic or joint soft tissue injury', 'Disease', (520, 560))	('lesions', 'Var', (296, 303))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('leukodystrophy', 'Disease', (253, 267))	('vascular diseases', 'Disease', (269, 286))	('cerebral infarction', 'Disease', 'MESH:D002544', (367, 386))	('motor dysfunction', 'Disease', 'MESH:D000068079', (341, 358))	('osteoporotic or joint soft tissue injury', 'Disease', 'MESH:D017695', (520, 560))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cerebral infarction', 'Disease', (367, 386))	('caused', 'Reg', (460, 466))	('infection', 'Disease', (388, 397))	('lead to', 'Reg', (328, 335))	('infection', 'Disease', 'MESH:D007239', (388, 397))	('vascular diseases', 'Disease', 'MESH:D000783', (269, 286))	('motor dysfunction', 'Disease', (341, 358))	('leukodystrophy', 'Disease', 'MESH:D007966', (253, 267))	('arthrogenous', 'Disease', (506, 518))	('motor dysfunction', 'Disease', 'MESH:D000068079', (442, 459))	('limb disuse', 'Disease', (493, 504))	('leukodystrophy', 'Phenotype', 'HP:0002415', (253, 267))	('motor dysfunction', 'Disease', (442, 459))
34928	28829841	Nerve fiber tract damage results in the inability of nerve impulses to spread sequentially, thus resulting in reduce of limb resistive exercise.	('resistive exercise', 'Phenotype', 'HP:0003546', (125, 143))	('limb resistive exercise', 'CPA', (120, 143))	('damage', 'Var', (18, 24))	('inability of nerve impulses', 'Disease', (40, 67))	('inability of nerve impulses', 'Disease', 'MESH:D016388', (40, 67))	('reduce', 'NegReg', (110, 116))
34930	28829841	Fiber disruption and tumor infiltration may lead to decreasing units within the fiber voxel with consequent reduction of FDi and rFDi.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('units within the fiber', 'MPA', (63, 85))	('FDi', 'MPA', (121, 124))	('disruption', 'Var', (6, 16))	('decreasing', 'NegReg', (52, 62))	('reduction', 'NegReg', (108, 117))
34982	25364437	The activation of oncogenes and inactivation or mutation of tumor suppressor genes is associated with tumorigenesis.	('oncogenes', 'Protein', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('associated', 'Reg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutation', 'Var', (48, 56))	('inactivation', 'Var', (32, 44))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (102, 107))	('activation', 'PosReg', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
35033	25364437	The prognosis was significantly different in the patients with high ADAM17 expression compared with the patients with low ADAM17 expression.	('ADAM17', 'Gene', '6868', (122, 128))	('ADAM17', 'Gene', '6868', (68, 74))	('ADAM17', 'Gene', (122, 128))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('ADAM17', 'Gene', (68, 74))	('different', 'Reg', (32, 41))	('patients', 'Species', '9606', (104, 112))
35034	25364437	Survival analysis showed that the patients with low ADAM17 expression longer survival times compared with the patients with high ADAM17 expression (P<0.005) (Fig.	('ADAM17', 'Gene', '6868', (129, 135))	('ADAM17', 'Gene', '6868', (52, 58))	('ADAM17', 'Gene', (129, 135))	('longer', 'PosReg', (70, 76))	('patients', 'Species', '9606', (34, 42))	('survival times', 'CPA', (77, 91))	('ADAM17', 'Gene', (52, 58))	('low', 'Var', (48, 51))	('patients', 'Species', '9606', (110, 118))
35044	25364437	EGFR has functions in the proliferation, migration, invasion and DNA damage repair processes of glioma cells, and aberrant signal transduction pathways are able to promote the growth, migration, angiogenesis and apoptosis of the tumor cells.	('migration', 'CPA', (41, 50))	('EGFR', 'Gene', (0, 4))	('migration', 'CPA', (184, 193))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('growth', 'CPA', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('apoptosis', 'CPA', (212, 221))	('promote', 'PosReg', (164, 171))	('aberrant', 'Var', (114, 122))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('tumor', 'Disease', (229, 234))	('angiogenesis', 'CPA', (195, 207))	('invasion', 'CPA', (52, 60))	('EGFR', 'Gene', '1956', (0, 4))	('glioma', 'Disease', (96, 102))
35048	25364437	iii) Survival analysis confirmed that ADAM17 expression was correlated with patient survival time, such that patients with a high expression of ADAM17 had a worse prognosis.	('patient', 'Species', '9606', (109, 116))	('ADAM17', 'Gene', '6868', (144, 150))	('patients', 'Species', '9606', (109, 117))	('ADAM17', 'Gene', '6868', (38, 44))	('ADAM17', 'Gene', (144, 150))	('high expression', 'Var', (125, 140))	('patient', 'Species', '9606', (76, 83))	('ADAM17', 'Gene', (38, 44))
35052	31891366	report that the lncRNA MIR22HG promotes glioma progression by generating miR-22-3p and miR-22-5p, and show that targeting MIR22HG/miR-22 with a novel small molecule inhibitor leads to inhibition of tumour growth in vivo.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('tumour', 'Disease', (198, 204))	('inhibition', 'NegReg', (184, 194))	('MIR22HG/miR-22', 'Var', (122, 136))	('promotes', 'PosReg', (31, 39))	('rat', 'Species', '10116', (66, 69))	('miR-22-5p', 'MPA', (87, 96))	('glioma', 'Disease', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('MIR22HG', 'Gene', (23, 30))	('miR-22-3p', 'Gene', '407008', (73, 82))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('miR-22-3p', 'Gene', (73, 82))
35054	31891366	Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long non-coding RNAs in glioblastoma.	('miR-22-3p', 'Gene', (107, 116))	('miR-22-5p', 'Var', (121, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (194, 206))	('miR-22-3p', 'Gene', '407008', (107, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (194, 206))	('MIR22HG', 'Gene', (71, 78))	('glioblastoma', 'Disease', (194, 206))
35057	31891366	In glioblastoma, increased expression of MIR22HG is associated with poor prognosis.	('increased', 'PosReg', (17, 26))	('MIR22HG', 'Var', (41, 48))	('expression', 'MPA', (27, 37))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))
35058	31891366	Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/beta-catenin signalling pathway through loss of miR-22-3p and -5p.	('loss', 'NegReg', (128, 132))	('miR-22-3p', 'Gene', (136, 145))	('MIR22HG', 'Gene', (53, 60))	('silencing', 'Var', (61, 70))	('beta-catenin', 'Gene', (88, 100))	('miR-22-3p', 'Gene', '407008', (136, 145))	('inhibits', 'NegReg', (71, 79))	('beta-catenin', 'Gene', '1499', (88, 100))
35061	31891366	AC1L6JTK treatment caused an inhibition of tumour growth in vivo.	('inhibition', 'NegReg', (29, 39))	('tumour', 'Disease', (43, 49))	('AC1L6JTK', 'Var', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
35062	31891366	Our findings show that MIR22HG is a critical inducer of the Wnt/beta-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.	('inducer', 'PosReg', (45, 52))	('rat', 'Species', '10116', (156, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('patients', 'Species', '9606', (179, 187))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (64, 76))	('glioblastoma', 'Disease', (166, 178))	('MIR22HG', 'Var', (23, 30))	('glioblastoma', 'Disease', 'MESH:D005909', (166, 178))
35114	31891366	These results were further corroborated using the Chinese Glioma Genome Atlas (CGGA), where MIR22HG appeared among the top two highly expressed lncRNAs (log2 fold-change = 1.88, adjusted P = 1.01 x 10-13) when overlapped with the top 50 candidates from TCGA data (Fig.	('MIR22HG', 'Var', (92, 99))	('ncRNAs', 'Disease', 'MESH:C565633', (145, 151))	('Glioma', 'Disease', 'MESH:D005910', (58, 64))	('Glioma', 'Phenotype', 'HP:0009733', (58, 64))	('Glioma', 'Disease', (58, 64))	('ncRNAs', 'Disease', (145, 151))	('rat', 'Species', '10116', (34, 37))
35116	31891366	MIR22HG was lower in LGG-Oligo (IDHmut, 1p/19q co-deletion), LGG-Astro (IDHmut, 1p/19q non-co-deletion) while higher in LGG-IDHwt subtype in TCGA (Fig.	('1p/19q co-deletion', 'Var', (40, 58))	('MIR22HG', 'Gene', (0, 7))	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', '3417', (124, 127))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('higher', 'PosReg', (110, 116))	('lower', 'NegReg', (12, 17))
35118	31891366	In addition, data from the Cancer Cell Line Encyclopedia demonstrated that glioma cell lines exhibited higher expression of MIR22HG than most other cancer cell lines (Supplementary Fig.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('glioma', 'Disease', (75, 81))	('MIR22HG', 'Var', (124, 131))	('rat', 'Species', '10116', (64, 67))	('expression', 'MPA', (110, 120))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
35120	31891366	However, to confirm the increased expression of MIR22HG compared to normal brain, we performed in situ hybridization on an independent cohort of gliomas (n = 18) and normal brain tissue (n = 5) from Qilu Hospital.	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('expression', 'MPA', (34, 44))	('MIR22HG', 'Var', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('increased', 'PosReg', (24, 33))	('gliomas', 'Disease', (145, 152))
35124	31891366	Patient age and genetic features, including O-6-methylguanine-DNA methyltransferase (MGMT) promotor methylation, codeletion of 1p/19q, telomerase reverse transcriptase (TERT) loss, and IDH and ATRX chromatin remodeler (ATRX) mutations, have been reported to be associated with a favourable prognosis.	('TERT', 'Gene', '7015', (169, 173))	('ATRX', 'Gene', '546', (193, 197))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (44, 83))	('IDH', 'Gene', (185, 188))	('mutations', 'Var', (225, 234))	('IDH', 'Gene', '3417', (185, 188))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (44, 83))	('ATRX', 'Gene', (219, 223))	('telomerase reverse transcriptase', 'Gene', (135, 167))	('ATRX', 'Gene', (193, 197))	('MGMT', 'Gene', (85, 89))	('telomerase reverse transcriptase', 'Gene', '7015', (135, 167))	('TERT', 'Gene', (169, 173))	('MGMT', 'Gene', '4255', (85, 89))	('ATRX', 'Gene', '546', (219, 223))	('Patient', 'Species', '9606', (0, 7))
35126	31891366	Low MIR22HG was found to be associated with methylated MGMT, 1p/19q codeletion, loss of TERT and mutated ATRX in tumours (P < 0.001; Supplementary Table 4).	('methylated', 'Var', (44, 54))	('MGMT', 'Gene', '4255', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('MGMT', 'Gene', (55, 59))	('ATRX', 'Gene', '546', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('MIR22HG', 'Gene', (4, 11))	('mutated', 'Var', (97, 104))	('loss', 'NegReg', (80, 84))	('Low', 'Var', (0, 3))	('TERT', 'Gene', '7015', (88, 92))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('tumours', 'Disease', (113, 120))	('ATRX', 'Gene', (105, 109))	('1p/19q codeletion', 'Var', (61, 78))	('TERT', 'Gene', (88, 92))
35128	31891366	The MIR22HGhigh group patients exhibited significantly shorter overall survival as well as progression-free survival compared to the MIR22HGlow group in all cohorts (Fig.	('overall', 'MPA', (63, 70))	('patients', 'Species', '9606', (22, 30))	('shorter', 'NegReg', (55, 62))	('MIR22HGhigh', 'Var', (4, 15))	('progression-free survival', 'CPA', (91, 116))
35129	31891366	In addition, MIR22HG levels significantly associated with poor survival in cases with wild-type IDH (Supplementary Fig.	('IDH', 'Gene', '3417', (96, 99))	('associated', 'Reg', (42, 52))	('MIR22HG levels', 'Var', (13, 27))	('poor', 'NegReg', (58, 62))	('IDH', 'Gene', (96, 99))
35130	31891366	Finally, MIR22HG was validated as an independent prognostic indicator in univariate and multivariate Cox regression analysis of overall survival [hazard ratio (HR) = 1.177, 95% confidence interval (CI) = 1.034 to 1.339, P = 0.009; Supplementary Table 5] and progression-free survival (HR = 1.617, 95% CI = 1.617 to 2.499, P = 0.030; Supplementary Table 6) in glioma patients.	('glioma', 'Disease', (359, 365))	('rat', 'Species', '10116', (153, 156))	('patients', 'Species', '9606', (366, 374))	('glioma', 'Disease', 'MESH:D005910', (359, 365))	('glioma', 'Phenotype', 'HP:0009733', (359, 365))	('MIR22HG', 'Var', (9, 16))
35132	31891366	Biological processes, including proliferation, apoptosis, stem cell function, and tumour invasion exhibited the strongest association with high MIR22HG levels (Fig.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('high MIR22HG levels', 'Var', (139, 158))	('apoptosis', 'CPA', (47, 56))	('stem cell function', 'CPA', (58, 76))	('rat', 'Species', '10116', (39, 42))	('tumour invasion', 'Disease', (82, 97))	('tumour invasion', 'Disease', 'MESH:D009361', (82, 97))	('proliferation', 'CPA', (32, 45))
35133	31891366	We first detected the expression levels of MIR22HG in a panel of GBM cell lines including three GBM cell lines (U87MG, LN229, LN18) and four patient-derived primary GSCs (GBM#P3, GBM#BG7, GBM#BG5 and GBM#06).	('MIR22HG', 'Var', (43, 50))	('GSC', 'Gene', '145258', (165, 168))	('LN18', 'CellLine', 'CVCL:0392', (126, 130))	('GSC', 'Gene', (165, 168))	('BG7', 'CellLine', 'CVCL:6570', (183, 186))	('U87MG', 'CellLine', 'CVCL:0022', (112, 117))	('GBM', 'Phenotype', 'HP:0012174', (188, 191))	('GBM', 'Phenotype', 'HP:0012174', (171, 174))	('patient', 'Species', '9606', (141, 148))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('LN229', 'CellLine', 'CVCL:0393', (119, 124))
35141	31891366	Flow cytometry apoptosis assays showed that inhibition of cell growth was mediated both by an increased apoptotic cell death (~2-fold compared to controls in U87MG, GBM#P3 and GBM#BG7) (Fig.	('BG7', 'CellLine', 'CVCL:6570', (180, 183))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('inhibition', 'NegReg', (44, 54))	('U87MG', 'CellLine', 'CVCL:0022', (158, 163))	('U87MG', 'Var', (158, 163))	('cell growth', 'CPA', (58, 69))	('GBM', 'Phenotype', 'HP:0012174', (176, 179))
35144	31891366	In tumoursphere formation and extreme limiting dilution assays (ELDA), MIR22HG knockdown resulted in a remarkable decrease in sphere formation in GBM#P3, GBM#BG7, GBM#BG5 and GBM#06 cells (Fig.	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('decrease', 'NegReg', (114, 122))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('GBM', 'Phenotype', 'HP:0012174', (175, 178))	('sphere formation', 'CPA', (126, 142))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('MIR22HG', 'Gene', (71, 78))	('tumours', 'Disease', (3, 10))	('BG7', 'CellLine', 'CVCL:6570', (158, 161))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('knockdown', 'Var', (79, 88))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))
35149	31891366	After 72 h, the number of cells invading the brain organoids as well as the area invaded by tumour cells was significantly decreased in the si-MIR22HG group compared to the si-Ctrl group in both GBM#BG7 (P < 0.05; Fig.	('BG7', 'CellLine', 'CVCL:6570', (199, 202))	('si-MIR22HG', 'Var', (140, 150))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('decreased', 'NegReg', (123, 132))	('tumour', 'Disease', (92, 98))	('GBM', 'Phenotype', 'HP:0012174', (195, 198))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
35152	31891366	The proliferation index marker Ki-67 was decreased in sh-MIR22HG xenografts (Fig.	('rat', 'Species', '10116', (11, 14))	('decreased', 'NegReg', (41, 50))	('proliferation index marker Ki-67', 'MPA', (4, 36))	('sh-MIR22HG', 'Var', (54, 64))
35155	31891366	Finally, several classical invasive markers, including ZEB1, MMP2 and MMP7, were found to be dramatically decreased in U87MG-sh-MIR22HG xenografts (Supplementary Fig.	('decreased', 'NegReg', (106, 115))	('MMP7', 'Gene', '4316', (70, 74))	('MMP2', 'Gene', (61, 65))	('MMP2', 'Gene', '4313', (61, 65))	('U87MG-sh-MIR22HG', 'Var', (119, 135))	('U87MG', 'CellLine', 'CVCL:0022', (119, 124))	('MMP7', 'Gene', (70, 74))	('ZEB1', 'Gene', (55, 59))	('ZEB1', 'Gene', '6935', (55, 59))
35157	31891366	In summary, these results support a key role of MIR22HG in promoting tumour invasive growth in vivo.	('promoting', 'PosReg', (59, 68))	('MIR22HG', 'Var', (48, 55))	('tumour invasive', 'Disease', 'MESH:D009361', (69, 84))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour invasive', 'Disease', (69, 84))
35158	31891366	Knockdown studies were performed in U87MG and GBM#P3 cells in vitro to determine whether MIR22HG was involved in the regulation of the canonical Wnt/beta-catenin pathway.	('MIR22HG', 'Var', (89, 96))	('beta-catenin', 'Gene', (149, 161))	('U87MG', 'CellLine', 'CVCL:0022', (36, 41))	('involved', 'Reg', (101, 109))	('beta-catenin', 'Gene', '1499', (149, 161))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))
35159	31891366	MIR22HG silencing led to a downregulation of beta-catenin, a key transcriptional regulator of Wnt, along with the suppression of several Wnt downstream targets, including c-Myc, cyclin D1, and LEF1 (Fig.	('MIR22HG', 'Gene', (0, 7))	('beta-catenin', 'Gene', '1499', (45, 57))	('silencing', 'Var', (8, 17))	('suppression', 'NegReg', (114, 125))	('cyclin D1', 'Gene', '595', (178, 187))	('c-Myc', 'Gene', '4609', (171, 176))	('downregulation', 'NegReg', (27, 41))	('cyclin D1', 'Gene', (178, 187))	('c-Myc', 'Gene', (171, 176))	('LEF1', 'Gene', '51176', (193, 197))	('beta-catenin', 'Gene', (45, 57))	('LEF1', 'Gene', (193, 197))
35163	31891366	After MIR22HG knockdown, levels of both cytoplasmic and nuclear beta-catenin were reduced (Fig.	('MIR22HG', 'Gene', (6, 13))	('levels of', 'MPA', (25, 34))	('beta-catenin', 'Gene', (64, 76))	('knockdown', 'Var', (14, 23))	('reduced', 'NegReg', (82, 89))	('beta-catenin', 'Gene', '1499', (64, 76))
35164	31891366	In summary, these data show that alterations in MIR22HG levels substantially affects beta-catenin protein levels and Wnt signalling activity.	('affects', 'Reg', (77, 84))	('Wnt signalling activity', 'CPA', (117, 140))	('beta-catenin', 'Gene', '1499', (85, 97))	('rat', 'Species', '10116', (37, 40))	('MIR22HG', 'Gene', (48, 55))	('alterations', 'Var', (33, 44))	('beta-catenin', 'Gene', (85, 97))
35166	31891366	Given the fact that a major function of certain lncRNAs is the production of embedded miRNAs, we asked if MIR22HG-induced glioma progression was mediated by miR-22-3p and miR-22-5p.	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('miR', 'Gene', '220972', (171, 174))	('miR', 'Gene', '220972', (157, 160))	('miR', 'Gene', (171, 174))	('miR', 'Gene', (157, 160))	('glioma', 'Disease', (122, 128))	('miR', 'Gene', (86, 89))	('miR', 'Gene', '220972', (86, 89))	('miR-22-3p', 'Gene', (157, 166))	('ncRNAs', 'Disease', (49, 55))	('miR-22-3p', 'Gene', '407008', (157, 166))	('mediated', 'Reg', (145, 153))	('MIR22HG-induced', 'Var', (106, 121))	('ncRNAs', 'Disease', 'MESH:C565633', (49, 55))
35167	31891366	In culture, we observed, by qRT-PCR, a corresponding decrease of miR-22-3p and miR-22-5p, in U87MG and GBM#P3 MIR22HG depleted cells (>80%; P < 0.01; Fig.	('miR-22-3p', 'Gene', '407008', (65, 74))	('U87MG', 'Var', (93, 98))	('decrease', 'NegReg', (53, 61))	('MIR22HG depleted', 'Var', (110, 126))	('miR-22-5p', 'MPA', (79, 88))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('miR-22-3p', 'Gene', (65, 74))	('U87MG', 'CellLine', 'CVCL:0022', (93, 98))
35172	31891366	U87MG and GBM#P3 cells were then transfected with miR-22 mimics or anti-miR-22, and overexpression as well as knockdown were confirmed by qRT-PCR (Supplementary Fig.	('anti-miR-22', 'Var', (67, 78))	('miR-22', 'Gene', (50, 56))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('GBM', 'Phenotype', 'HP:0012174', (10, 13))
35173	31891366	In functional studies, knockdown of miR-22-3p or -5p resulted in an inhibition of tumoursphere formation (P < 0.01 and P < 0.05; Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('knockdown', 'Var', (23, 32))	('miR-22-3p', 'Gene', (36, 45))	('miR-22-3p', 'Gene', '407008', (36, 45))	('tumours', 'Disease', (82, 89))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('inhibition', 'NegReg', (68, 78))
35180	31891366	5F) were correspondingly restored in si-MIR22HG cells transfected with miR-22-3p or miR-22-5p (less rescue effect of -5p was observed in GBM#BG7 possibly caused by interpatient cellular heterogeneity).	('BG7', 'CellLine', 'CVCL:6570', (141, 144))	('GBM', 'Phenotype', 'HP:0012174', (137, 140))	('miR-22-5p', 'Var', (84, 93))	('miR-22-3p', 'Gene', '407008', (71, 80))	('miR-22-3p', 'Gene', (71, 80))	('patient', 'Species', '9606', (169, 176))
35182	31891366	Immunofluorescence confirmed the restoration of beta-catenin expression in U87MG-si-MIR22HG (Supplementary Fig.	('U87MG-si-MIR22HG', 'Var', (75, 91))	('beta-catenin', 'Gene', (48, 60))	('U87MG', 'CellLine', 'CVCL:0022', (75, 80))	('beta-catenin', 'Gene', '1499', (48, 60))	('restoration', 'PosReg', (33, 44))	('rat', 'Species', '10116', (38, 41))
35184	31891366	Finally, to confirm that MIR22HG functions as the host gene of miR-22s in GBM progression and to exclude the effect of the other regions of the full-length 2.6 kb MIR22HG transcript, we performed ectopic expression experiments with a MIR22HG full-length construct (wild-type, WT), as well as a MIR22HG mutant construct, MIR22HG-Deltaexon2 (deletion of miR-22 region in exon 2) (Supplementary Fig.	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('deletion', 'Var', (340, 348))	('MIR22HG-Deltaexon2', 'Gene', '84981', (320, 338))	('MIR22HG-Deltaexon2', 'Gene', (320, 338))	('miR-22', 'Gene', (352, 358))
35185	31891366	In a functional assay, we found that overexpression (OE) of MIR22HG-WT significantly promoted U87MG cell growth in vitro compared to the control group and MIR22HG-Deltaexon2-OE group (P < 0.001); while MIR22HG-Deltaexon2-OE minimally promoted cell proliferation in GBM.	('U87MG', 'CellLine', 'CVCL:0022', (94, 99))	('overexpression', 'PosReg', (37, 51))	('promoted', 'PosReg', (85, 93))	('cell proliferation in GBM', 'CPA', (243, 268))	('MIR22HG-Deltaexon2', 'Gene', '84981', (202, 220))	('rat', 'Species', '10116', (255, 258))	('GBM', 'Phenotype', 'HP:0012174', (265, 268))	('MIR22HG-Deltaexon2', 'Gene', '84981', (155, 173))	('U87MG cell growth', 'CPA', (94, 111))	('MIR22HG-Deltaexon2', 'Gene', (202, 220))	('MIR22HG-WT', 'Var', (60, 70))	('MIR22HG-Deltaexon2', 'Gene', (155, 173))
35188	31891366	Using computational target prediction based algorithms (TargetScan v7.1 and miRanda), several genes were found to have 3' UTR putative binding sites for miR-22-3p and miR-22-5p (Fig.	('miR-22-3p', 'Gene', (153, 162))	('miR-22-3p', 'Gene', '407008', (153, 162))	('miR-22-5p', 'Var', (167, 176))	('binding', 'Interaction', (135, 142))	('miRanda', 'Disease', (76, 83))	('miRanda', 'Disease', 'MESH:C537402', (76, 83))
35190	31891366	6B); a similar relationship was revealed between miR-22-5p and PCDH15 (PearsonmiR-22-5p = -0.351, P < 0.001; Fig.	('miR-22-5p', 'Var', (49, 58))	('PCDH15', 'Gene', '65217', (63, 69))	('PCDH15', 'Gene', (63, 69))
35191	31891366	However, other candidates such as TET2 (PearsonmiR-22-3p = -0.201), CLIC4 (PearsonmiR-22-3p = 0.163), DUSP1 (PearsonmiR-22-5p = -0.096) or TXN2 (PearsonmiR-22-5p = -0.101), showed no significant association with the miR-22s in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('gliomas', 'Disease', (227, 234))	('TET2', 'Gene', (34, 38))	('CLIC4', 'Gene', '25932', (68, 73))	('DUSP1', 'Gene', '1843', (102, 107))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('miR-22-3p', 'Gene', (82, 91))	('miR-22-3p', 'Gene', '407008', (82, 91))	('CLIC4', 'Gene', (68, 73))	('miR-22-3p', 'Gene', (47, 56))	('TET2', 'Gene', '54790', (34, 38))	('miR-22-3p', 'Gene', '407008', (47, 56))	('TXN2', 'Gene', '25828', (139, 143))	('TXN2', 'Gene', (139, 143))	('DUSP1', 'Gene', (102, 107))	('miR-22s', 'Gene', (216, 223))	('PearsonmiR-22-5p', 'Var', (109, 125))
35194	31891366	In addition, the combined expression levels of the miR-22-3phigh and SFRP2low, or miR-22-5phigh and PCDH15low, in glioma patients, more accurately predicted a shorter overall survival and progression-free survival (Supplementary Fig.	('expression', 'MPA', (26, 36))	('patients', 'Species', '9606', (121, 129))	('miR-22-3p', 'Gene', '407008', (51, 60))	('glioma', 'Disease', (114, 120))	('SFRP2', 'Gene', '6423', (69, 74))	('PCDH15', 'Gene', '65217', (100, 106))	('shorter', 'NegReg', (159, 166))	('PCDH15', 'Gene', (100, 106))	('SFRP2', 'Gene', (69, 74))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('miR-22-5phigh', 'Var', (82, 95))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('overall survival', 'CPA', (167, 183))	('rat', 'Species', '10116', (140, 143))	('progression-free survival', 'CPA', (188, 213))	('miR-22-3p', 'Gene', (51, 60))
35201	31891366	Overexpression of miR-22-3p or miR-22-5p mimics in GBM cells resulted in a decrease in SFRP2 or PCDH15 protein and mRNA levels, respectively (Fig.	('miR-22-3p', 'Gene', '407008', (18, 27))	('decrease', 'NegReg', (75, 83))	('SFRP2', 'Gene', '6423', (87, 92))	('PCDH15', 'Gene', '65217', (96, 102))	('SFRP2', 'Gene', (87, 92))	('mRNA levels', 'MPA', (115, 126))	('PCDH15', 'Gene', (96, 102))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('miR-22-3p', 'Gene', (18, 27))	('miR-22-5p', 'Var', (31, 40))
35204	31891366	However, mutations in the corresponding miR binding sites rendered the miR mimics ineffective in targeting the luciferase mRNA construct (Fig.	('miR', 'Gene', (71, 74))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('mutations', 'Var', (9, 18))	('ineffective', 'NegReg', (82, 93))	('miR', 'Gene', '220972', (71, 74))
35206	31891366	We next assessed whether miR-22-3p and miR-22-5p interfered with the activity of Wnt signalling via SFRP2 or PCDH15 in GBM cells.	('activity', 'MPA', (69, 77))	('miR-22-3p', 'Gene', '407008', (25, 34))	('PCDH15', 'Gene', (109, 115))	('interfered', 'NegReg', (49, 59))	('SFRP2', 'Gene', '6423', (100, 105))	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('Wnt', 'MPA', (81, 84))	('SFRP2', 'Gene', (100, 105))	('miR-22-5p', 'Var', (39, 48))	('miR-22-3p', 'Gene', (25, 34))	('PCDH15', 'Gene', '65217', (109, 115))
35216	31891366	qRT-PCR indicated that after treatment of U87MG and GBM#P3 cells with AC1L6JTK (50 and 100 muM) for 24 h, the expression levels of both miR-22-3p and -5p were significantly decreased (P < 0.001, Fig.	('expression levels', 'MPA', (110, 127))	('miR-22-3p', 'Gene', (136, 145))	('decreased', 'NegReg', (173, 182))	('miR-22-3p', 'Gene', '407008', (136, 145))	('muM', 'Gene', '56925', (91, 94))	('U87MG', 'CellLine', 'CVCL:0022', (42, 47))	('U87MG', 'Var', (42, 47))	('muM', 'Gene', (91, 94))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))
35217	31891366	AC1L6JTK treatment also attenuated transcriptional activity of beta-catenin in GBM#P3 cells, similar to MIR22HG knockdown, implicating the Wnt signalling pathway as a potential target (Fig.	('beta-catenin', 'Gene', (63, 75))	('attenuated', 'NegReg', (24, 34))	('beta-catenin', 'Gene', '1499', (63, 75))	('transcriptional activity', 'MPA', (35, 59))	('AC1L6JTK', 'Var', (0, 8))	('GBM', 'Phenotype', 'HP:0012174', (79, 82))
35220	31891366	In a rescue study, AC1L6JTK treatment (100 microM) for 48 h led to an inhibition of cell growth, while this effect was restored when U87MG cells were transfected with miR-22-3p (P < 0.01) or miR-22-5p mimics (P < 0.05; Supplementary Fig.	('inhibition', 'NegReg', (70, 80))	('AC1L6JTK', 'Var', (19, 27))	('U87MG', 'CellLine', 'CVCL:0022', (133, 138))	('cell growth', 'CPA', (84, 95))	('miR-22-3p', 'Gene', (167, 176))	('miR-22-3p', 'Gene', '407008', (167, 176))
35222	31891366	12A and B), we observed three ribonucleotides in the binding pocket, C47, A48 and A52, which could form hydrogen bonds with the AC1KL6JTK molecular structure, thus competing with Dicer to inhibit MIR22HG processing.	('A52', 'Var', (82, 85))	('C47', 'Chemical', 'MESH:C010808', (69, 72))	('inhibit', 'NegReg', (188, 195))	('A48', 'Var', (74, 77))	('ribonucleotides', 'Chemical', 'MESH:D012265', (30, 45))	('MIR22HG processing', 'MPA', (196, 214))	('C47', 'Var', (69, 72))	('hydrogen', 'Chemical', 'MESH:D006859', (104, 112))
35223	31891366	Consequently, to verify the specificity of AC1KL6JTK to the hairpin loop region of pre-miR-22 RNA sequence, we constructed new 3D structures of pre-miR-22 hairpin loop with point mutations at these binding sites, including MUT-1 (A52G), MUT-2 (C47T), MUT-3 (A48C) and MUT-4 (A52G, C47T, A48C) (Supplementary Fig.	('A52G', 'Mutation', 'c.52A>G', (230, 234))	('A52G', 'Mutation', 'c.52A>G', (275, 279))	('C47T', 'SUBSTITUTION', 'None', (244, 248))	('C47T', 'Var', (244, 248))	('A48C', 'Mutation', 'c.48A>C', (287, 291))	('MUT-2', 'Chemical', 'MESH:C096895', (237, 242))	('A52G', 'Var', (275, 279))	('MUT-4', 'Chemical', 'MESH:C033127', (268, 273))	('MUT-3', 'Chemical', 'MESH:C096895', (251, 256))	('A48C', 'Mutation', 'c.48A>C', (258, 262))	('A48C', 'Var', (287, 291))	('point mutations', 'Var', (173, 188))	('C47T', 'SUBSTITUTION', 'None', (281, 285))	('C47T', 'Var', (281, 285))
35226	31891366	Treatment with AC1L6JTK led to a significant reduction in tumour size and tumour weight at the treatment endpoint (Fig.	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('reduction', 'NegReg', (45, 54))	('AC1L6JTK', 'Var', (15, 23))
35232	31891366	Intriguingly, we found that MIR22HG triggers GBM progression by producing miR-22-3p and -5p, which are encoded in exon 2 of the gene.	('MIR22HG', 'Var', (28, 35))	('miR-22-3p', 'Gene', '407008', (74, 83))	('miR-22-3p', 'Gene', (74, 83))	('GBM progression', 'CPA', (45, 60))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('triggers', 'PosReg', (36, 44))
35233	31891366	Finally, knockdown of MIR22HG in an in vivo orthotopic human xenograft model led to improved survival.	('knockdown', 'Var', (9, 18))	('human', 'Species', '9606', (55, 60))	('survival', 'CPA', (93, 101))	('improved', 'PosReg', (84, 92))	('MIR22HG', 'Gene', (22, 29))
35234	31891366	Our results indicate that MIR22HG is a GBM promoting lncRNA that might serve as a novel prognostic marker in glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('patients', 'Species', '9606', (116, 124))	('lncRNA', 'MPA', (53, 59))	('glioma', 'Disease', (109, 115))	('MIR22HG', 'Var', (26, 33))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
35237	31891366	Functional studies have shown that MIR22HG knockdown represses migration, invasion and proliferation of ovarian cancer cells.	('rat', 'Species', '10116', (94, 97))	('invasion', 'CPA', (74, 82))	('MIR22HG', 'Gene', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('knockdown', 'Var', (43, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('proliferation of ovarian cancer', 'Disease', (87, 118))	('represses', 'NegReg', (53, 62))	('proliferation of ovarian cancer', 'Disease', 'MESH:D010051', (87, 118))	('rat', 'Species', '10116', (66, 69))	('migration', 'CPA', (63, 72))
35238	31891366	Conversely, MIR22HG has recently been described to mediate a tumour-suppressive effect in lung cancer and hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('hepatocellular carcinoma', 'Disease', (106, 130))	('tumour-suppressive effect in lung cancer', 'Disease', (61, 101))	('tumour-suppressive effect in lung cancer', 'Disease', 'MESH:D008175', (61, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('MIR22HG', 'Var', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (106, 130))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (106, 130))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
35239	31891366	It has been reported that MIR22HG can serve as a competing endogenous RNA (ceRNA) to modulate the miRNA-10a-5p level and its downstream target gene, NCOR2, in hepatocellular carcinoma.	('miRNA-10a', 'Gene', (98, 107))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('NCOR2', 'Gene', '9612', (149, 154))	('miRNA-10a', 'Gene', '406902', (98, 107))	('hepatocellular carcinoma', 'Disease', (159, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('modulate', 'Reg', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('NCOR2', 'Gene', (149, 154))	('MIR22HG', 'Var', (26, 33))
35241	31891366	Dysregulation of miRNAs also contributes to malignant progression, including GBM.	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('GBM', 'Disease', (77, 80))	('malignant progression', 'CPA', (44, 65))	('contributes', 'Reg', (29, 40))
35245	31891366	In haematopoietic malignancies, miR-22 enhances the repopulating capacity of haematopoietic stem progenitor cells in vivo, and miR-22 transgenic mice develop primary haematological diseases.	('haematopoietic malignancies', 'Disease', 'MESH:D009369', (3, 30))	('haematological diseases', 'Disease', (166, 189))	('enhances', 'PosReg', (39, 47))	('miR-22 transgenic', 'Var', (127, 144))	('haematopoietic malignancies', 'Disease', (3, 30))	('transgenic', 'Var', (134, 144))	('transgenic mice', 'Species', '10090', (134, 149))	('miR-22', 'Gene', (32, 38))	('develop', 'PosReg', (150, 157))	('haematological diseases', 'Disease', 'MESH:D006402', (166, 189))
35252	31891366	Notably, we found that overexpression of wild-type MIR22HG promoted cell proliferation, while mutant MIR22HG (deletion of miR-22 region in exon 2) lost the growth promoting effect.	('lost', 'NegReg', (147, 151))	('cell proliferation', 'CPA', (68, 86))	('rat', 'Species', '10116', (80, 83))	('mutant', 'Var', (94, 100))	('promoted', 'PosReg', (59, 67))	('MIR22HG', 'Gene', (101, 108))	('miR-22', 'Gene', (122, 128))
35253	31891366	Collectively, our findings indicate that miR-22-3p and -5p mediate the pro-oncogenic functions of MIR22HG in GBM.	('MIR22HG', 'Var', (98, 105))	('miR-22-3p', 'Gene', '407008', (41, 50))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('miR-22-3p', 'Gene', (41, 50))	('GBM', 'Disease', (109, 112))
35263	31891366	In addition to the inhibition of SFRP2 by miR22 described here, SFRP2 is also downregulated in GBM via promoter hypermethylation.	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('SFRP2', 'Gene', '6423', (64, 69))	('SFRP2', 'Gene', (64, 69))	('miR22', 'Gene', '407004', (42, 47))	('miR22', 'Gene', (42, 47))	('SFRP2', 'Gene', '6423', (33, 38))	('SFRP2', 'Gene', (33, 38))	('promoter hypermethylation', 'Var', (103, 128))	('downregulated', 'NegReg', (78, 91))
35267	31891366	In functional assays, ectopic expression of SFRP2 suppressed GBM malignant behaviours and Wnt signalling activity, thus demonstrating its tumour-suppressive role in GBM.	('suppressed', 'NegReg', (50, 60))	('SFRP2', 'Gene', (44, 49))	('Wnt signalling activity', 'CPA', (90, 113))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('ectopic expression', 'Var', (22, 40))	('GBM malignant behaviours', 'CPA', (61, 85))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('rat', 'Species', '10116', (127, 130))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('SFRP2', 'Gene', '6423', (44, 49))	('tumour', 'Disease', (138, 144))
35270	31891366	The inhibitory effect was partially restored by co-transfection of miR-22-5p (or miR-22-3p in the case of SFRP2) mimics.	('SFRP2', 'Gene', (106, 111))	('miR-22-5p', 'Var', (67, 76))	('miR-22-3p', 'Gene', (81, 90))	('inhibitory effect', 'MPA', (4, 21))	('miR-22-3p', 'Gene', '407008', (81, 90))	('SFRP2', 'Gene', '6423', (106, 111))
35271	31891366	Although we found that miR-22-3p and miR-22-5p work together to target negative regulators of Wnt signalling, providing a previously unknown regulatory mechanism of this pathway, we cannot exclude the possibility that these microRNAs contribute to glioma progression through other mechanisms than Wnt signalling.	('glioma', 'Disease', (248, 254))	('miR-22-3p', 'Gene', (23, 32))	('miR-22-5p', 'Var', (37, 46))	('contribute', 'Reg', (234, 244))	('miR-22-3p', 'Gene', '407008', (23, 32))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))
35274	31891366	Interestingly, AC1L6JTK has previously been tested for therapeutic efficacy in inflammatory bowel disease.	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (79, 105))	('inflammatory bowel disease', 'Disease', (79, 105))	('AC1L6JTK', 'Var', (15, 23))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (79, 105))
35275	31891366	In the present study, we found that AC1L6JTK treatment inhibited GBM proliferation and induced apoptosis, indicating that AC1L6JTK could be used as an anticancer agent in GBM (see schematic representation Supplementary Fig.	('GBM proliferation', 'CPA', (65, 82))	('inhibited', 'NegReg', (55, 64))	('rat', 'Species', '10116', (76, 79))	('GBM', 'Phenotype', 'HP:0012174', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('apoptosis', 'CPA', (95, 104))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('induced', 'Reg', (87, 94))	('AC1L6JTK', 'Var', (36, 44))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
35277	31891366	In conclusion, our work not only uncovers an oncogenic role for MIR22HG in promoting GBM aggressiveness and GSC self-renewal, but also implicates MIR22HG/miR-22 as a potential target for treating gliomas through pharmacological blockade.	('aggressiveness', 'Disease', 'MESH:D001523', (89, 103))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('aggressiveness', 'Disease', (89, 103))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('GSC', 'Gene', (108, 111))	('GSC', 'Gene', '145258', (108, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('promoting', 'PosReg', (75, 84))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))	('MIR22HG/miR-22', 'Var', (146, 160))	('MIR22HG', 'Gene', (64, 71))
35286	32010368	Hematoxylin and eosin-stained sections were used to characterise the tumours histologically based on cellularity, nuclear hyperchromasia, polymorphism, mitotic activity, vascular proliferation and necrosis with or without pseudopallisading of tumour cells.	('hyperchromasia', 'Disease', (122, 136))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('eosin', 'Chemical', 'MESH:D004801', (16, 21))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('necrosis', 'Disease', 'MESH:D009336', (197, 205))	('tumour', 'Disease', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('polymorphism', 'Var', (138, 150))	('tumour', 'Disease', 'MESH:D009369', (243, 249))	('tumour', 'Disease', (243, 249))	('necrosis', 'Disease', (197, 205))	('pseudopallisading', 'CPA', (222, 239))	('Hematoxylin', 'Chemical', 'MESH:D006416', (0, 11))	('hyperchromasia', 'Disease', 'None', (122, 136))	('tumours', 'Disease', (69, 76))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('vascular proliferation', 'CPA', (170, 192))	('mitotic activity', 'CPA', (152, 168))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
35308	32010368	Many molecular markers used as prognostic markers in glioma these include IDH mutations, 1p/19q codeletion, MGMT promoter methylation, TERT promoter mutations and EGFR amplification.	('TERT', 'Gene', '7015', (135, 139))	('MGMT', 'Gene', (108, 112))	('glioma', 'Disease', (53, 59))	('MGMT', 'Gene', '4255', (108, 112))	('EGFR', 'Gene', '1956', (163, 167))	('mutations', 'Var', (78, 87))	('IDH', 'Gene', (74, 77))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('EGFR', 'Gene', (163, 167))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('IDH', 'Gene', '3417', (74, 77))	('TERT', 'Gene', (135, 139))
35309	32010368	Isocitrate dehydrogenase (IDH1, IDH2) and TP53 gene mutations are considered to be early events in neoplastic progression.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (42, 46))	('IDH2', 'Gene', (32, 36))	('Isocitrate', 'Chemical', 'MESH:D007523', (0, 10))	('TP53', 'Gene', (42, 46))	('IDH1', 'Gene', (26, 30))	('IDH2', 'Gene', '3418', (32, 36))	('IDH1', 'Gene', '3417', (26, 30))
35310	32010368	In contrast, allelic loss of chromosome 10 occurs predominantly in glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (67, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (67, 80))	('allelic loss', 'Var', (13, 25))	('glioblastomas', 'Disease', (67, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))
35312	32010368	In particular, Epidermal growth factor receptor (EGFR) overexpression is common in primary glioblastoma, while IDH1 mutations are common in secondary glioblastoma.	('overexpression', 'PosReg', (55, 69))	('EGFR', 'Gene', '1956', (49, 53))	('Epidermal growth factor receptor', 'Gene', (15, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('Epidermal growth factor receptor', 'Gene', '1956', (15, 47))	('glioblastoma', 'Disease', (150, 162))	('EGFR', 'Gene', (49, 53))	('glioblastoma', 'Disease', 'MESH:D005909', (150, 162))	('IDH1', 'Gene', '3417', (111, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('common', 'Reg', (130, 136))	('mutations', 'Var', (116, 125))	('glioblastoma', 'Disease', (91, 103))	('IDH1', 'Gene', (111, 115))
35317	32010368	In astrocytoma, overexpression of EGFR or ErbB1 (chromosome 7p11-p12) is a late event promoting malignant progression to a glioblastoma, with amplification and often accompanying activating mutations.	('glioblastoma', 'Disease', (123, 135))	('astrocytoma', 'Disease', (3, 14))	('EGFR', 'Gene', (34, 38))	('overexpression', 'PosReg', (16, 30))	('astrocytoma', 'Phenotype', 'HP:0009592', (3, 14))	('promoting', 'PosReg', (86, 95))	('p12', 'Gene', (65, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('EGFR', 'Gene', '1956', (34, 38))	('malignant progression', 'CPA', (96, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('ErbB1', 'Gene', '1956', (42, 47))	('ErbB1', 'Gene', (42, 47))	('astrocytoma', 'Disease', 'MESH:D001254', (3, 14))	('p12', 'Gene', '56655', (65, 68))	('amplification', 'Var', (142, 155))
35320	32010368	It has been shown that EGFR amplification promotes invasion, proliferation and resistance to radiotherapy and chemotherapy,,,.	('promotes', 'PosReg', (42, 50))	('EGFR', 'Gene', '1956', (23, 27))	('invasion', 'CPA', (51, 59))	('proliferation', 'CPA', (61, 74))	('EGFR', 'Gene', (23, 27))	('amplification', 'Var', (28, 41))
35342	32010368	Over-expression of the EGFR due to gene amplification has been reported in primary brain tumours of glial origin.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('Over-expression', 'PosReg', (0, 15))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('primary brain tumours', 'Disease', 'MESH:D001932', (75, 96))	('gene amplification', 'Var', (35, 53))	('EGFR', 'Gene', '1956', (23, 27))	('primary brain tumours', 'Disease', (75, 96))	('EGFR', 'Gene', (23, 27))	('brain tumours', 'Phenotype', 'HP:0030692', (83, 96))
35365	32010368	Smith et al., showed that EGFR amplification was present in 17% of anaplastic astrocytoma and 41% of glioblastomas.	('EGFR', 'Gene', (26, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (78, 89))	('glioblastomas', 'Disease', (101, 114))	('anaplastic astrocytoma', 'Disease', (67, 89))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (67, 89))	('present', 'Reg', (49, 56))	('glioblastomas', 'Phenotype', 'HP:0012174', (101, 114))	('EGFR', 'Gene', '1956', (26, 30))	('glioblastomas', 'Disease', 'MESH:D005909', (101, 114))	('amplification', 'Var', (31, 44))
35369	32010368	found that overexpression of EGFR and gene amplification frequently occurs in gliomas and is restricted to high-grade tumours, especially anaplastic astrocytoma and glioblastoma multiforme.	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (138, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (165, 177))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('gene amplification', 'Var', (38, 56))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('EGFR', 'Gene', '1956', (29, 33))	('glioblastoma multiforme', 'Disease', (165, 188))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (165, 188))	('overexpression', 'PosReg', (11, 25))	('tumours', 'Disease', (118, 125))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('anaplastic astrocytoma', 'Disease', (138, 160))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('occurs', 'Reg', (68, 74))	('gliomas', 'Disease', (78, 85))	('EGFR', 'Gene', (29, 33))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))
35377	31263678	Isocitrate Dehydrogenase Mutations in Glioma: From Basic Discovery to Therapeutics Development Isocitrate dehydrogenase (IDH) is a key rate-limiting enzyme in the Krebs cycle that plays an important role in energy metabolism.	('Glioma', 'Disease', 'MESH:D005910', (38, 44))	('Glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH', 'Gene', (121, 124))	('Glioma', 'Disease', (38, 44))	('IDH', 'Gene', '3418', (121, 124))	('Mutations', 'Var', (25, 34))	('Krebs', 'Chemical', '-', (163, 168))
35378	31263678	In recent years, it has been found that IDH mutations are closely related to the occurrence and development of glioma, and it is a notable potential therapeutic target.	('glioma', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('IDH', 'Gene', (40, 43))	('IDH', 'Gene', '3418', (40, 43))	('mutations', 'Var', (44, 53))	('related', 'Reg', (66, 73))
35379	31263678	First, IDH mutations can produce high levels of 2-hydroxyglutaric acid (2-HG), thereby inhibiting glioma stem cell differentiation.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3418', (7, 10))	('mutations', 'Var', (11, 20))	('2-hydroxyglutaric acid', 'Chemical', 'MESH:C019417', (48, 70))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('2-HG', 'Chemical', 'MESH:C019417', (72, 76))	('glioma', 'Disease', (98, 104))	('inhibiting', 'NegReg', (87, 97))
35380	31263678	At the same time, IDH mutations can upregulate vascular endothelial growth factor (VEGF) to promote the formation of the tumor microenvironment.	('VEGF', 'Gene', (83, 87))	('vascular endothelial growth factor', 'Gene', (47, 81))	('promote', 'PosReg', (92, 99))	('IDH', 'Gene', (18, 21))	('IDH', 'Gene', '3418', (18, 21))	('upregulate', 'PosReg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('vascular endothelial growth factor', 'Gene', '7422', (47, 81))	('tumor', 'Disease', (121, 126))	('VEGF', 'Gene', '7422', (83, 87))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
35381	31263678	In addition, IDH mutations can also induce high levels of hypoxia-inducible factor-1alpha (HIF-1alpha) to promote glioma invasion.	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (58, 89))	('HIF-1alpha', 'Gene', '3091', (91, 101))	('glioma', 'Disease', (114, 120))	('hypoxia-inducible factor-1alpha', 'Gene', (58, 89))	('promote', 'PosReg', (106, 113))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('HIF-1alpha', 'Gene', (91, 101))	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', '3418', (13, 16))	('mutations', 'Var', (17, 26))
35382	31263678	Ultimately, these changes will lead to the development of glioma.	('changes', 'Var', (18, 25))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('lead to', 'Reg', (31, 38))	('glioma', 'Disease', (58, 64))
35390	31263678	Gliomas are reclassified by molecular similarity beyond histological boundaries: diffuse astrocytoma [isocitrate dehydrogenase (IDH) mutant, wild-type, or not otherwise specified (NOS)], gemistocytic astrocytoma (IDH mutant), anaplastic astrocytoma (IDH mutant, wild-type, or NOS), glioblastoma (IDH mutant, wild-type, or NOS), diffuse midline glioma (H3K27M mutant), oligodendroglioma (IDH mutant and 1p/19q codeleted or NOS), anaplastic oligodendroglioma (IDH mutant and 1p/19q codeleted or NOS), oligoastrocytoma (NOS), and anaplastic oligoastrocytoma (NOS).	('astrocytoma', 'Disease', 'MESH:D001254', (237, 248))	('astrocytoma', 'Phenotype', 'HP:0009592', (504, 515))	('astrocytoma', 'Disease', (237, 248))	('oligodendroglioma', 'Disease', (368, 385))	('oligodendroglioma', 'Disease', 'MESH:D009837', (439, 456))	('mutant', 'Var', (359, 365))	('IDH', 'Gene', (128, 131))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (226, 248))	('midline glioma', 'Disease', 'MESH:D005910', (336, 350))	('astrocytoma', 'Phenotype', 'HP:0009592', (543, 554))	('oligoastrocytoma', 'Disease', (499, 515))	('astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('glioma', 'Phenotype', 'HP:0009733', (379, 385))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (428, 456))	('IDH', 'Gene', '3418', (250, 253))	('Gliomas', 'Disease', (0, 7))	('IDH', 'Gene', (213, 216))	('glioblastoma', 'Disease', 'MESH:D005909', (282, 294))	('oligodendroglioma', 'Disease', (439, 456))	('oligoastrocytoma', 'Disease', (538, 554))	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('IDH', 'Gene', '3418', (296, 299))	('glioma', 'Phenotype', 'HP:0009733', (450, 456))	('anaplastic oligodendroglioma', 'Disease', (428, 456))	('IDH', 'Gene', (458, 461))	('astrocytoma', 'Disease', 'MESH:D001254', (504, 515))	('glioblastoma', 'Disease', (282, 294))	('gemistocytic astrocytoma', 'Disease', 'MESH:D001254', (187, 211))	('IDH', 'Gene', (387, 390))	('astrocytoma', 'Disease', (504, 515))	('glioblastoma', 'Phenotype', 'HP:0012174', (282, 294))	('gemistocytic astrocytoma', 'Disease', (187, 211))	('astrocytoma', 'Disease', 'MESH:D001254', (543, 554))	('astrocytoma', 'Disease', 'MESH:D001254', (200, 211))	('astrocytoma', 'Phenotype', 'HP:0009592', (237, 248))	('astrocytoma', 'Disease', (200, 211))	('astrocytoma', 'Disease', (543, 554))	('IDH', 'Gene', '3418', (128, 131))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('IDH', 'Gene', (250, 253))	('midline glioma', 'Disease', (336, 350))	('anaplastic astrocytoma', 'Disease', (226, 248))	('glioma', 'Phenotype', 'HP:0009733', (344, 350))	('astrocytoma', 'Disease', 'MESH:D001254', (89, 100))	('mutant', 'Var', (133, 139))	('IDH', 'Gene', '3418', (213, 216))	('astrocytoma', 'Disease', (89, 100))	('IDH', 'Gene', (296, 299))	('isocitrate', 'Chemical', 'MESH:C034219', (102, 112))	('anaplastic oligoastrocytoma', 'Disease', 'MESH:D001254', (527, 554))	('oligodendroglioma', 'Disease', 'MESH:D009837', (368, 385))	('IDH', 'Gene', '3418', (458, 461))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (499, 515))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('anaplastic oligoastrocytoma', 'Disease', (527, 554))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (538, 554))	('IDH', 'Gene', '3418', (387, 390))
35392	31263678	The mutant-IDH1/2 enzyme inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy.	('mutations', 'Var', (90, 99))	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('IDH1/2', 'Gene', '3417;3418', (83, 89))	('patients', 'Species', '9606', (69, 77))	('IDH1/2', 'Gene', (11, 17))	('IDH1/2', 'Gene', (83, 89))
35400	31263678	Currently, IDH1 and IDH2 mutations have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma.	('glioblastoma', 'Disease', (119, 131))	('mutations', 'Var', (25, 34))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (65, 85))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (59, 85))	('identified', 'Reg', (45, 55))	('glioma', 'Disease', (97, 103))	('acute myelogenous leukemia', 'Disease', (59, 85))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (59, 85))	('IDH2', 'Gene', (20, 24))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH1', 'Gene', (11, 15))	('IDH2', 'Gene', '3418', (20, 24))
35401	31263678	While IDH3 mutations do not occur at an appreciable frequency in glioblastoma.	('mutations', 'Var', (11, 20))	('IDH3', 'Gene', (6, 10))	('IDH3', 'Gene', '3418', (6, 10))	('glioblastoma', 'Disease', (65, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
35403	31263678	As early as 2008, Parsons et al found a link between glioma and IDH mutation in the exon sequencing of glioblastoma.	('link', 'Reg', (40, 44))	('mutation', 'Var', (68, 76))	('glioma', 'Disease', (53, 59))	('glioblastoma', 'Disease', (103, 115))	('IDH', 'Gene', '3418', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('IDH', 'Gene', (64, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
35406	31263678	Further studies have found that the IDH1 R132H mutation is the most common mutation in gliomas, while the IDH2 gene also undergoes similar mutations at R172, but the frequency of such mutations are relatively low.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('IDH1', 'Gene', (36, 40))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('R132H', 'Var', (41, 46))	('IDH2', 'Gene', (106, 110))	('R132H', 'Mutation', 'rs121913500', (41, 46))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('IDH2', 'Gene', '3418', (106, 110))	('gliomas', 'Disease', (87, 94))
35408	31263678	The study also found that IDH1/2 mutations are relatively independent and mutually exclusive with few mutations at the same time.	('IDH1/2', 'Gene', (26, 32))	('IDH1/2', 'Gene', '3417;3418', (26, 32))	('mutations', 'Var', (33, 42))
35409	31263678	Mutations in genes encoding enzymes of the TCA cycle often contribute to cancer development and progression by disrupting cell metabolism and altering the epigenetic landscape.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('epigenetic landscape', 'MPA', (155, 175))	('altering', 'Reg', (142, 150))	('progression', 'CPA', (96, 107))	('Mutations', 'Var', (0, 9))	('disrupting', 'NegReg', (111, 121))	('contribute', 'Reg', (59, 69))	('cell metabolism', 'CPA', (122, 137))	('TCA', 'Chemical', 'MESH:D014233', (43, 46))
35410	31263678	IDH catalyses the production of alpha-KG from isocitrate, and when the IDH1/2 gene is mutated, its corresponding function and product will change.	('function', 'MPA', (113, 121))	('IDH1/2', 'Gene', (71, 77))	('mutated', 'Var', (86, 93))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3418', (0, 3))	('alpha-KG', 'Chemical', 'MESH:D007656', (32, 40))	('IDH', 'Gene', (71, 74))	('change', 'Reg', (139, 145))	('isocitrate', 'MPA', (46, 56))	('IDH1/2', 'Gene', '3417;3418', (71, 77))	('isocitrate', 'Chemical', 'MESH:C034219', (46, 56))	('IDH', 'Gene', '3418', (71, 74))
35417	31263678	IDH1/2 mutations confer a gain of function in glioma cells, resulting in the accumulation and secretion of a vast excess of an oncometabolite, D-2-HG, which ultimately inhibits the catalytic activity of alpha-KG-dependent dioxygenase, damaging the key steps in histone modification and DNA demethylation.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('damaging', 'NegReg', (235, 243))	('inhibits', 'NegReg', (168, 176))	('accumulation', 'MPA', (77, 89))	('alpha-KG', 'Chemical', 'MESH:D007656', (203, 211))	('IDH1/2', 'Gene', (0, 6))	('histone modification', 'MPA', (261, 281))	('catalytic activity', 'MPA', (181, 199))	('glioma', 'Disease', (46, 52))	('oxygen', 'Chemical', 'MESH:D010100', (224, 230))	('secretion', 'MPA', (94, 103))	('2-HG', 'Chemical', 'MESH:C019417', (145, 149))	('alpha-KG-dependent dioxygenase', 'Enzyme', (203, 233))	('DNA demethylation', 'MPA', (286, 303))	('gain', 'PosReg', (26, 30))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('mutations', 'Var', (7, 16))
35418	31263678	This hypermethylation state caused by IDH1/2 mutations are widely present in the CpG island of the human malignant tumor genome.	('mutations', 'Var', (45, 54))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('IDH1/2', 'Gene', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('human', 'Species', '9606', (99, 104))
35419	31263678	It is noteworthy that such changes are more likely to occur in cancer stem cells of IDH1/2 mutant tumors.	('IDH1/2', 'Gene', (84, 90))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH1/2', 'Gene', '3417;3418', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('mutant', 'Var', (91, 97))	('cancer', 'Disease', (63, 69))
35420	31263678	Studies have shown that the hypermethylation status of CpG islands leads to the inactivation of tumor suppressor genes and this epigenetic modification.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('epigenetic modification', 'MPA', (128, 151))	('tumor', 'Disease', (96, 101))	('inactivation', 'NegReg', (80, 92))	('hypermethylation status', 'Var', (28, 51))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
35421	31263678	Therefore, IDH1/2 mutations block glioma stem cell differentiation.	('block glioma', 'Disease', (28, 40))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('block glioma', 'Disease', 'MESH:D005910', (28, 40))	('IDH1/2', 'Gene', (11, 17))	('mutations', 'Var', (18, 27))
35427	31263678	It was found that the mutations of IDH1/2 could promote the formation of the tumor microenvironment by increasing the expression of VEGF and make it suitable for glioblastoma stem cell development.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('VEGF', 'Gene', (132, 136))	('make', 'Reg', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('increasing', 'PosReg', (103, 113))	('VEGF', 'Gene', '7422', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (22, 31))	('glioblastoma', 'Disease', (162, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('promote', 'PosReg', (48, 55))	('tumor', 'Disease', (77, 82))	('expression', 'MPA', (118, 128))	('IDH1/2', 'Gene', (35, 41))
35430	31263678	The IDH1/2 mutations can upregulate VEGF to promote tumor microvessel formation by inhibiting the breakdown of HIF-1alpha.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (11, 20))	('promote', 'PosReg', (44, 51))	('HIF-1alpha', 'Gene', (111, 121))	('tumor', 'Disease', (52, 57))	('VEGF', 'Gene', (36, 40))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('inhibiting', 'NegReg', (83, 93))	('IDH1/2', 'Gene', (4, 10))	('upregulate', 'PosReg', (25, 35))	('HIF-1alpha', 'Gene', '3091', (111, 121))	('VEGF', 'Gene', '7422', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
35432	31263678	The IDH1/2 mutations make the tumor microenvironment easier to form.	('mutations', 'Var', (11, 20))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IDH1/2', 'Gene', (4, 10))	('tumor', 'Disease', (30, 35))
35436	31263678	Continuous seeding of tumor seeds will further promote the development of tumors, and IDH1/2 mutations play an important role in this process.	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('promote', 'PosReg', (47, 54))	('IDH1/2', 'Gene', '3417;3418', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (22, 27))	('IDH1/2', 'Gene', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
35439	31263678	van Lith et al found that IDH2 mutation can induce nuclear accumulation of beta-catenin and upregulated HIF-1alpha, which is closely related to tumor invasion and chemoresistance, manifested as a search for glutamate.	('nuclear accumulation', 'MPA', (51, 71))	('upregulated', 'PosReg', (92, 103))	('tumor', 'Disease', (144, 149))	('van Lith', 'Disease', (0, 8))	('beta-catenin', 'Gene', '1499', (75, 87))	('HIF-1alpha', 'Gene', (104, 114))	('IDH2', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('IDH2', 'Gene', '3418', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('beta-catenin', 'Gene', (75, 87))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('van Lith', 'Disease', 'MESH:C536530', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('glutamate', 'Chemical', 'MESH:D018698', (207, 216))	('induce', 'Reg', (44, 50))
35440	31263678	In addition, the IDH1/2 mutations can cause abnormal expression of platelet-derived growth factor (PDGF).	('PD', 'Disease', 'MESH:D010300', (99, 101))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('cause', 'Reg', (38, 43))	('IDH1/2', 'Gene', (17, 23))	('expression', 'MPA', (53, 63))	('mutations', 'Var', (24, 33))
35444	31263678	We can further explain the relationship between IDH1/2 mutations and HIF-1alpha.	('HIF-1alpha', 'Gene', (69, 79))	('mutations', 'Var', (55, 64))	('IDH1/2', 'Gene', '3417;3418', (48, 54))	('HIF-1alpha', 'Gene', '3091', (69, 79))	('IDH1/2', 'Gene', (48, 54))
35447	31263678	The IDH1/2 mutations cause alpha-KG-dependent dioxygenase activity to be inhibited.	('mutations', 'Var', (11, 20))	('activity', 'MPA', (58, 66))	('oxygen', 'Chemical', 'MESH:D010100', (48, 54))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('inhibited', 'NegReg', (73, 82))	('alpha-KG', 'Chemical', 'MESH:D007656', (27, 35))	('IDH1/2', 'Gene', (4, 10))	('alpha-KG-dependent dioxygenase', 'Enzyme', (27, 57))
35449	31263678	This finding indicates that glioma cells are more likely to escape from the hypoxic environment and necrotic areas in the case of IDH1/2 mutations, therefore the glioma cells have stronger invasiveness.	('invasiveness', 'CPA', (189, 201))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glioma', 'Disease', (162, 168))	('necrotic', 'Disease', 'MESH:D009336', (100, 108))	('IDH1/2', 'Gene', (130, 136))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('mutations', 'Var', (137, 146))	('stronger', 'PosReg', (180, 188))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('glioma', 'Disease', (28, 34))	('IDH1/2', 'Gene', '3417;3418', (130, 136))	('necrotic', 'Disease', (100, 108))
35451	31263678	Therefore, these changes caused by the IDH1/2 mutations will eventually lead to the development of glioma.	('mutations', 'Var', (46, 55))	('IDH1/2', 'Gene', (39, 45))	('glioma', 'Disease', (99, 105))	('lead to', 'Reg', (72, 79))	('IDH1/2', 'Gene', '3417;3418', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
35452	31263678	In view of the important role of IDH1/2 mutations in the occurrence and development of glioma, studies of these proteins may enable researchers to identify appropriate inhibitors and intervene in the treatment of glioma patients with IDH1/2 mutations.	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioma', 'Disease', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('IDH1/2', 'Gene', (33, 39))	('IDH1/2', 'Gene', '3417;3418', (234, 240))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (220, 228))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Disease', (213, 219))	('IDH1/2', 'Gene', '3417;3418', (33, 39))	('IDH1/2', 'Gene', (234, 240))
35454	31263678	In addition, vaccines against IDH1/2 mutants have also been studied (Table 1).	('mutants', 'Var', (37, 44))	('IDH1/2', 'Gene', (30, 36))	('IDH1/2', 'Gene', '3417;3418', (30, 36))
35456	31263678	The inhibitors can both quantitatively inhibit IDH1/2 mutants and reduce 2-HG dose-dependently to normal levels and partially reverse histone modification and DNA hypermethylation, thereby playing a protective role.	('IDH1/2', 'Gene', '3417;3418', (47, 53))	('reverse', 'NegReg', (126, 133))	('2-HG', 'MPA', (73, 77))	('histone modification', 'MPA', (134, 154))	('2-HG', 'Chemical', 'MESH:C019417', (73, 77))	('inhibit', 'NegReg', (39, 46))	('IDH1/2', 'Gene', (47, 53))	('mutants', 'Var', (54, 61))	('DNA hypermethylation', 'MPA', (159, 179))	('reduce', 'NegReg', (66, 72))
35457	31263678	The AGI-5198 (the first selective IDH1 R132H/R132C mutant inhibitor) reduced 2-HG in a dose-dependent manner and inhibited the growth of tumors both in vitro and in vivo.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('reduced', 'NegReg', (69, 76))	('inhibited', 'NegReg', (113, 122))	('R132H', 'Var', (39, 44))	('R132C', 'Var', (45, 50))	('R132C', 'SUBSTITUTION', 'None', (45, 50))	('2-HG', 'MPA', (77, 81))	('AGI-5198', 'Chemical', 'MESH:C581156', (4, 12))	('R132H', 'SUBSTITUTION', 'None', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('2-HG', 'Chemical', 'MESH:C019417', (77, 81))
35458	31263678	In the IDH1-mutant glioma model, AGI-5198 induces the expression of genes related to the differentiation of astrocytes and oligodendrocytes and reduces the inhibitory histones at the promoters of these genes, thereby promoting the differentiation of glioma cells.	('AGI-5198', 'Gene', (33, 41))	('induces', 'PosReg', (42, 49))	('reduces', 'NegReg', (144, 151))	('inhibitory histones', 'MPA', (156, 175))	('AGI-5198', 'Chemical', 'MESH:C581156', (33, 41))	('glioma', 'Disease', (250, 256))	('glioma', 'Disease', (19, 25))	('IDH1-mutant', 'Var', (7, 18))	('glioma', 'Disease', 'MESH:D005910', (250, 256))	('differentiation', 'CPA', (231, 246))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('expression of genes', 'MPA', (54, 73))	('promoting', 'PosReg', (217, 226))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
35459	31263678	In addition to preclinical studies, IDH1/2 mutants enzyme inhibitors also show great potential in clinical trials.	('mutants', 'Var', (43, 50))	('IDH1/2', 'Gene', '3417;3418', (36, 42))	('IDH1/2', 'Gene', (36, 42))
35460	31263678	Ivosidenib (AG-120) and enasidenib (AG-221) are the preferred reversible selective inhibitors of IDH1 and IDH2 mutant enzymes, respectively.	('IDH1', 'Gene', (97, 101))	('enasidenib', 'Chemical', 'MESH:C000605269', (24, 34))	('mutant', 'Var', (111, 117))	('IDH2', 'Gene', (106, 110))	('AG-221', 'Chemical', 'MESH:C000605269', (36, 42))	('AG-120', 'Chemical', 'MESH:C000627630', (12, 18))	('IDH2', 'Gene', '3418', (106, 110))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))
35462	31263678	Interestingly, as early as 2014, a clinical study of oral AG-221 was carried out in patients with advanced solid tumors, including gliomas with IDH2 mutation and angioimmunoblastic T-cell lymphoma.	('gliomas', 'Disease', (131, 138))	('patients', 'Species', '9606', (84, 92))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('angioimmunoblastic T-cell lymphoma', 'Disease', (162, 196))	('solid tumors', 'Disease', (107, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (188, 196))	('IDH2', 'Gene', (144, 148))	('angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (162, 196))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (181, 196))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('cell lymphoma', 'Phenotype', 'HP:0012191', (183, 196))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutation', 'Var', (149, 157))	('IDH2', 'Gene', '3418', (144, 148))	('AG-221', 'Chemical', 'MESH:C000605269', (58, 64))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))
35464	31263678	Since the IDH1 R132H mutation is more common in gliomas, more clinical trials have been conducted for IDH1.	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('R132H', 'Var', (15, 20))	('IDH1', 'Gene', (10, 14))	('R132H', 'Mutation', 'rs121913500', (15, 20))	('common', 'Reg', (38, 44))	('gliomas', 'Disease', (48, 55))
35465	31263678	In 2014, a phase I/II clinical trial (NCT02073994), named "Study on IDH1 mutation of AG-120 in patients with advanced solid tumors including gliomas," was conducted, which mainly verified the safety and tolerance of AG-120 and preliminarily explored the clinical therapeutic effect of AG-120.	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (118, 130))	('patients', 'Species', '9606', (95, 103))	('AG-120', 'Chemical', 'MESH:C000627630', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('AG-120', 'Chemical', 'MESH:C000627630', (285, 291))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('solid tumors', 'Disease', (118, 130))	('mutation', 'Var', (73, 81))	('gliomas', 'Disease', (141, 148))	('AG-120', 'Chemical', 'MESH:C000627630', (85, 91))	('AG-120', 'Gene', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
35468	31263678	Patients requiring surgery have mutation in IDH1 R132H.	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (44, 48))	('R132H', 'Mutation', 'rs121913500', (49, 54))	('R132H', 'Var', (49, 54))
35469	31263678	The aim of this study was to evaluate the inhibition of 2-HG by comparing 2-HG concentrations in excised and untreated control tumors of IDH1 mutant glioma subjects treated with AG-120 or AG-881 (non-specific IDH inhibitors).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('glioma', 'Disease', (149, 155))	('tumors', 'Disease', (127, 133))	('AG-120', 'Chemical', 'MESH:C000627630', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mutant', 'Var', (142, 148))	('2-HG', 'Chemical', 'MESH:C019417', (56, 60))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('IDH', 'Gene', '3418', (209, 212))	('2-HG', 'Chemical', 'MESH:C019417', (74, 78))	('IDH', 'Gene', (209, 212))	('IDH', 'Gene', (137, 140))	('IDH', 'Gene', '3418', (137, 140))
35470	31263678	Data on clinical safety, tolerance, pharmacokinetics/pharmacodynamics (PK/PD), and antineoplastic activity of subjects with IDH1 R132H mutation in recurrent non-enhanced low-grade glioma will be studied.	('PD', 'Disease', 'MESH:D010300', (74, 76))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('R132H', 'Var', (129, 134))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('R132H', 'Mutation', 'rs121913500', (129, 134))	('IDH1', 'Gene', (124, 128))	('glioma', 'Disease', (180, 186))
35471	31263678	This study will provide recommended doses of AG-120 and AG-881 for future glioma research.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('AG-120', 'Chemical', 'MESH:C000627630', (45, 51))	('AG-120', 'Var', (45, 51))	('glioma', 'Disease', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('AG-881', 'Var', (56, 62))
35473	31263678	Since IDH1/2 mutants enzyme inhibitors have good application prospects in pre-clinical research and clinical trials of glioma, we believe that IDH1/IDH2 mutant enzyme inhibitors will bring new hope to glioma patients.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('patients', 'Species', '9606', (208, 216))	('IDH2', 'Gene', '3418', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glioma', 'Disease', (201, 207))	('IDH2', 'Gene', (148, 152))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('mutant', 'Var', (153, 159))	('glioma', 'Disease', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('mutants', 'Var', (13, 20))	('IDH1/2', 'Gene', (6, 12))
35476	31263678	In some low-grade glioma patients, the spontaneous immune response to IDH1 mutation has been found.	('glioma', 'Disease', (18, 24))	('mutation', 'Var', (75, 83))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('patients', 'Species', '9606', (25, 33))	('IDH1', 'Gene', (70, 74))
35479	31263678	The IDH1 R132H mutation occurs in 70% of low-grade gliomas.	('gliomas', 'Disease', (51, 58))	('R132H', 'Var', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('IDH1', 'Gene', (4, 8))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
35481	31263678	In animal experiments, it was found that IDH1 mutant cancer cells could be prevented from growing in the brain, and the vaccine did not destroy the normal physiological function of the IDH1 enzyme.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutant', 'Var', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IDH1', 'Gene', (41, 45))
35482	31263678	In addition, by site-directed mutagenesis, the R132H mutation was introduced into the mouse glioma cell line GL261 to produce the mIDH1-GL261 cell line.	('mIDH1', 'Gene', (130, 135))	('GL261', 'Chemical', '-', (109, 114))	('mouse', 'Species', '10090', (86, 91))	('glioma', 'Disease', (92, 98))	('mIDH1', 'Gene', '15926', (130, 135))	('R132H', 'Var', (47, 52))	('GL261', 'Chemical', '-', (136, 141))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('R132H', 'Mutation', 'rs121913500', (47, 52))
35485	31263678	These results indicate the potential of the vaccine in the treatment of glioma patients with IDH1 mutation.	('IDH1', 'Gene', (93, 97))	('glioma', 'Disease', (72, 78))	('mutation', 'Var', (98, 106))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('patients', 'Species', '9606', (79, 87))
35486	31263678	Subsequently, the German National Cancer Center launched a Phase I trial, IDH1 Peptide Vaccine in IDH1 R132H Mutant III-IV Glioma (NOA-16) (NCT02454634), and Duke University also launched a clinical trial, called "IDH1 Peptide Vaccine for Recurrent Grade II Glioma (RESIST)" (NCT02193347).	('III-IV Glioma', 'Disease', 'MESH:D005910', (116, 129))	('Glioma', 'Phenotype', 'HP:0009733', (123, 129))	('R132H', 'Mutation', 'rs121913500', (103, 108))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Glioma', 'Phenotype', 'HP:0009733', (258, 264))	('Mutant', 'Var', (109, 115))	('II Glioma', 'Disease', 'MESH:D005910', (255, 264))	('R132H Mutant', 'Var', (103, 115))	('III-IV Glioma', 'Disease', (116, 129))	('IDH1', 'Gene', (98, 102))	('II Glioma', 'Disease', (255, 264))
35491	31263678	It is generally known that trials of IDH mutations inhibitors and vaccines in IDH mutant gliomas and recurrent gliomas have been conducted.	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', '3418', (78, 81))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3418', (37, 40))	('mutant', 'Var', (82, 88))
35492	31263678	Meanwhile, old drugs for other tumors have also been developed to treat glioma with IDH1/2 mutations (Table 1), such as azacitidine, nivolumab, and temozolomide.	('IDH1/2', 'Gene', (84, 90))	('glioma', 'Disease', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('nivolumab', 'Chemical', 'MESH:D000077594', (133, 142))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('mutations', 'Var', (91, 100))	('IDH1/2', 'Gene', '3417;3418', (84, 90))	('temozolomide', 'Chemical', 'MESH:D000077204', (148, 160))	('azacitidine', 'Chemical', 'MESH:D001374', (120, 131))
35495	31263678	A clinical trial treating recurrent gliomas with IDH1/2 mutations with azacitidine was conducted.	('mutations', 'Var', (56, 65))	('gliomas', 'Disease', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('azacitidine', 'Chemical', 'MESH:D001374', (71, 82))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('IDH1/2', 'Gene', (49, 55))
35499	31263678	Jinsong Wu's study provides a higher level (IIb) of evidence for the correlation between IDH mutations and the responsiveness to up-front adjuvant metronomic temozolomide chemotherapy in young patients with low grade gliomas located in eloquent brain areas.	('patients', 'Species', '9606', (193, 201))	('mutations', 'Var', (93, 102))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('temozolomide', 'Chemical', 'MESH:D000077204', (158, 170))	('IDH', 'Gene', '3418', (89, 92))	('IDH', 'Gene', (89, 92))	('gliomas', 'Disease', (217, 224))	('gliomas', 'Phenotype', 'HP:0009733', (217, 224))	('gliomas', 'Disease', 'MESH:D005910', (217, 224))
35503	31263678	The IDH1/2 mutations can produce a high level of 2-HG to inhibit the differentiation of glioma stem cells, upregulate the formation of the tumor microenvironment, and produce a high level of HIF-1alpha to promote the invasion of glioma.	('mutations', 'Var', (11, 20))	('inhibit', 'NegReg', (57, 64))	('formation of the', 'MPA', (122, 138))	('tumor', 'Disease', (139, 144))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('glioma', 'Disease', (88, 94))	('invasion', 'CPA', (217, 225))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('upregulate', 'PosReg', (107, 117))	('promote', 'PosReg', (205, 212))	('HIF-1alpha', 'Gene', '3091', (191, 201))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('IDH1/2', 'Gene', (4, 10))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (229, 235))	('HIF-1alpha', 'Gene', (191, 201))	('glioma', 'Disease', 'MESH:D005910', (229, 235))
35504	31263678	Ultimately, these changes will lead to the occurrence and development of glioma (Figure 1).	('changes', 'Var', (18, 25))	('glioma', 'Disease', (73, 79))	('lead to', 'Reg', (31, 38))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))
35582	20725730	IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group Recent studies have demonstrated a high frequency of IDH mutations in adult "secondary" malignant gliomas arising from preexisting lower grade lesions, often in young adults, but not in "primary" gliomas.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (168, 171))	('gliomas', 'Disease', (311, 318))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('Oncology', 'Phenotype', 'HP:0002664', (100, 108))	('malignant gliomas', 'Disease', 'MESH:D005910', (29, 46))	('IDH1', 'Gene', '3417', (0, 4))	('Children', 'Species', '9606', (89, 97))	('IDH', 'Gene', '3417', (0, 3))	('malignant gliomas', 'Disease', 'MESH:D005910', (203, 220))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (311, 318))	('malignant gliomas', 'Disease', (29, 46))	('gliomas', 'Disease', (213, 220))	('glioma', 'Phenotype', 'HP:0009733', (311, 317))	('mutations', 'Var', (172, 181))	('malignant gliomas', 'Disease', (203, 220))	('gliomas', 'Phenotype', 'HP:0009733', (311, 318))	('gliomas', 'Disease', (39, 46))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH', 'Gene', (168, 171))
35584	20725730	We examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant gliomas treated on the Children's Oncology Group ACNS0423 study.	('Oncology', 'Phenotype', 'HP:0002664', (191, 199))	('malignant gliomas', 'Disease', 'MESH:D005910', (147, 164))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('Children', 'Species', '9606', (180, 188))	('mutations', 'Var', (33, 42))	('IDH', 'Gene', (29, 32))	('IDH', 'Gene', '3417', (29, 32))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('malignant gliomas', 'Disease', (147, 164))
35585	20725730	The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated.	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('mutations', 'Var', (29, 38))
35586	20725730	IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed.	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('IDH2', 'Gene', '3418', (59, 63))	('mutations', 'Var', (5, 14))	('IDH2', 'Gene', (59, 63))	('observed', 'Reg', (20, 28))	('IDH1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('IDH1', 'Gene', '3417', (0, 4))
35587	20725730	A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from children >=14 years, but in 0 of 23 (0%) younger children (p=0.0024).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('children', 'Species', '9606', (98, 106))	('tumors', 'Disease', (80, 86))	('children', 'Species', '9606', (147, 155))	('mutations', 'Var', (48, 57))
35590	20725730	IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis.	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('children', 'Species', '9606', (56, 64))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('malignant gliomas', 'Disease', (139, 156))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('malignant gliomas', 'Disease', (29, 46))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH1', 'Gene', (0, 4))	('malignant gliomas', 'Disease', 'MESH:D005910', (139, 156))	('malignant gliomas', 'Disease', 'MESH:D005910', (29, 46))	('IDH1', 'Gene', '3417', (0, 4))
35593	20725730	For example, childhood primary malignant gliomas usually lack EGFR amplification or PTEN deletion, which are characteristic features of adult primary glioblastoma, but often exhibit TP53 mutations, particularly in tumors that arise in older children.	('amplification', 'MPA', (67, 80))	('TP53', 'Gene', (182, 186))	('glioblastoma', 'Disease', (150, 162))	('PTEN', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('deletion', 'Var', (89, 97))	('tumors', 'Disease', (214, 220))	('children', 'Species', '9606', (241, 249))	('EGFR', 'Gene', '1956', (62, 66))	('PTEN', 'Gene', '5728', (84, 88))	('malignant gliomas', 'Disease', 'MESH:D005910', (31, 48))	('lack', 'NegReg', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('TP53', 'Gene', '7157', (182, 186))	('malignant gliomas', 'Disease', (31, 48))	('exhibit', 'Reg', (174, 181))	('glioblastoma', 'Disease', 'MESH:D005909', (150, 162))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (187, 196))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))
35595	20725730	Recent studies have demonstrated a high frequency of mutations of the IDH1 and IDH2 genes, which encode the isocitrate dehydrogenase (IDH) enzymes, in adult secondary malignant gliomas.	('IDH2', 'Gene', '3418', (79, 83))	('malignant gliomas', 'Disease', 'MESH:D005910', (167, 184))	('isocitrate dehydrogenase', 'Gene', '3417', (108, 132))	('IDH', 'Gene', '3417', (134, 137))	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (79, 82))	('IDH1', 'Gene', '3417', (70, 74))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('mutations', 'Var', (53, 62))	('IDH', 'Gene', '3417', (70, 73))	('IDH2', 'Gene', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('isocitrate dehydrogenase', 'Gene', (108, 132))	('IDH', 'Gene', (134, 137))	('malignant gliomas', 'Disease', (167, 184))	('IDH1', 'Gene', (70, 74))
35596	20725730	These alterations inhibit the normal function of the IDH enzyme in converting isocitrate to alpha-ketoglutarate, and instead drive the conversion of alpha-ketoglutarate to R(-)-s-hydroxyglutarate, a metabolite that may contribute to tumor development.	('function', 'MPA', (37, 45))	('alterations', 'Var', (6, 17))	('conversion', 'MPA', (135, 145))	('inhibit', 'NegReg', (18, 25))	('isocitrate', 'Chemical', 'MESH:C034219', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('converting isocitrate to alpha-ketoglutarate', 'MPA', (67, 111))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (92, 111))	('R(-)-s-hydroxyglutarate', 'Chemical', '-', (172, 195))	('drive', 'Reg', (125, 130))	('IDH', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('IDH', 'Gene', '3417', (53, 56))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (149, 168))
35597	20725730	IDH mutations likely represent an early step in tumorigenesis because such alterations are also observed commonly in grade II (diffuse) astrocytomas, oligodendrogliomas, and oligoastrocytomas, in some instances preceding the acquisition of other characteristic molecular features, such as TP53 mutations in astrocytomas and 1p/19q deletions in oligodendroglial neoplasms.	('astrocytomas', 'Disease', 'MESH:D001254', (179, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (179, 190))	('astrocytomas', 'Disease', (136, 148))	('neoplasms', 'Phenotype', 'HP:0002664', (361, 370))	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (150, 168))	('IDH', 'Gene', (0, 3))	('oligoastrocytomas', 'Disease', (174, 191))	('TP53', 'Gene', (289, 293))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (174, 191))	('mutations', 'Var', (294, 303))	('grade II', 'Disease', (117, 125))	('astrocytomas', 'Disease', (307, 319))	('tumor', 'Disease', (48, 53))	('astrocytomas', 'Disease', 'MESH:D001254', (136, 148))	('IDH', 'Gene', '3417', (0, 3))	('oligodendrogliomas', 'Disease', (150, 168))	('1p/19q deletions', 'Var', (324, 340))	('astrocytomas', 'Disease', (179, 191))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TP53', 'Gene', '7157', (289, 293))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('astrocytomas', 'Disease', 'MESH:D001254', (307, 319))	('oligodendroglial neoplasms', 'Disease', 'MESH:D009369', (344, 370))	('astrocytoma', 'Phenotype', 'HP:0009592', (307, 318))	('oligodendroglial neoplasms', 'Disease', (344, 370))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
35598	20725730	In contrast, IDH mutations are uncommon in primary adult malignant gliomas, supporting the existence of mechanistically distinct pathways of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('IDH', 'Gene', '3417', (13, 16))	('malignant gliomas', 'Disease', 'MESH:D005910', (57, 74))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('tumor', 'Disease', (141, 146))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH', 'Gene', (13, 16))	('malignant gliomas', 'Disease', (57, 74))	('mutations', 'Var', (17, 26))
35599	20725730	Although several large surveys of IDH mutations that have included childhood brain tumors have reported that such alterations are uncommon, many of these studies have predominantly incorporated pilocytic astrocytomas and medulloblastomas, which are distinct histologically from gliomas that arise in adults.	('incorporated', 'Reg', (181, 193))	('medulloblastomas', 'Disease', (221, 237))	('gliomas', 'Disease', 'MESH:D005910', (278, 285))	('gliomas', 'Disease', (278, 285))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('gliomas', 'Phenotype', 'HP:0009733', (278, 285))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('pilocytic astrocytomas', 'Disease', (194, 216))	('brain tumors', 'Disease', (77, 89))	('medulloblastomas', 'Disease', 'MESH:D008527', (221, 237))	('astrocytoma', 'Phenotype', 'HP:0009592', (204, 215))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (194, 216))	('mutations', 'Var', (38, 47))
35601	20725730	Our results indicate the IDH mutations are common in malignant gliomas that occur in older children, suggesting that a subset of such lesions may be comparable on a molecular basis to lesions that arise in young adults.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('mutations', 'Var', (29, 38))	('children', 'Species', '9606', (91, 99))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('malignant gliomas', 'Disease', (53, 70))	('malignant gliomas', 'Disease', 'MESH:D005910', (53, 70))
35613	20725730	Detection of IDH1 and IDH2 mutations was performed using real-time polymerase chain reaction (PCR) and post-PCR fluorescence melting curve analysis (FMCA) on the LightCycler (Roche Applied Science, Indianapolis, IN).	('mutations', 'Var', (27, 36))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))
35622	20725730	Sections were then incubated with primary antibodies against Ki-67 (Immunotech, Westbrook, ME; USA 1:100), p53 (DO-7, Dako Corporation, Carpinteria, CA, 1:300), and pAkt (Se473) [Cell Signaling Technology, Inc., Danvers, MA; 1:100], in Common Antibody Diluent (BioGenex, San Ramon, CA, USA) at room temperature for 2 h. The p53 antibody recognizes a denaturation-stable determinant of wild-type and mutant p53.	('p53', 'Gene', (324, 327))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (324, 327))	('p53', 'Gene', '7157', (107, 110))	('denaturation-stable determinant', 'MPA', (350, 381))	('mutant', 'Var', (399, 405))	('p53', 'Gene', (406, 409))	('p53', 'Gene', '7157', (406, 409))
35630	20725730	For outcome analysis, tumors were classified according to the presence or absence of IDH mutations.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('IDH', 'Gene', '3417', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (89, 98))	('IDH', 'Gene', (85, 88))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
35634	20725730	Comparisons of the distribution of IDH mutations between different patient subgroups defined by age, gender, histology, p53 expression, extent of resection, and MIB1 labeling were based on two-sided Fisher exact test.	('MIB1', 'Gene', '57534', (161, 165))	('IDH', 'Gene', (35, 38))	('p53', 'Gene', '7157', (120, 123))	('IDH', 'Gene', '3417', (35, 38))	('mutations', 'Var', (39, 48))	('MIB1', 'Gene', (161, 165))	('p53', 'Gene', (120, 123))	('patient', 'Species', '9606', (67, 74))
35636	20725730	Seven of these tumors (16.3%) had mutations of IDH1; none had mutations of IDH2.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('IDH1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('IDH2', 'Gene', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('IDH2', 'Gene', '3418', (75, 79))	('IDH1', 'Gene', '3417', (47, 51))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', (15, 21))
35639	20725730	Figure 1 shows an illustrative example of a tumor with an IDH1 mutation as contrasted against another case lacking this feature.	('IDH1', 'Gene', '3417', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutation', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('IDH1', 'Gene', (58, 62))
35640	20725730	Four tumors were positive for R132H mutations, two for R132S, and one R132C.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('positive', 'Reg', (17, 25))	('R132S', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('R132H mutations', 'Var', (30, 45))	('R132C', 'Mutation', 'rs121913499', (70, 75))	('R132S', 'Mutation', 'rs121913499', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('R132H', 'Mutation', 'rs121913500', (30, 35))
35641	20725730	The distribution of IDH mutations as a function of clinical and other molecular factors is shown in Table 2.	('mutations', 'Var', (24, 33))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))
35642	20725730	When the cohort was subdivided as a function of age, it was determined that IDH1 mutations were seen in 7 of 20 (35%) children older than 14 years versus 0 of 23 (0%) children younger than 14 years (p=0.0024).	('IDH1', 'Gene', (76, 80))	('children', 'Species', '9606', (118, 126))	('IDH1', 'Gene', '3417', (76, 80))	('mutations', 'Var', (81, 90))	('children', 'Species', '9606', (167, 175))
35643	20725730	No association between IDH mutations and pAkt immunoreactivity or MIB1 labeling was apparent.	('mutations', 'Var', (27, 36))	('MIB1', 'Gene', '57534', (66, 70))	('IDH', 'Gene', (23, 26))	('MIB1', 'Gene', (66, 70))	('IDH', 'Gene', '3417', (23, 26))
35644	20725730	Among the seven tumors with IDH mutations, p53 overexpression was seen in 1 (14.3%) versus 20 of the 36 tumors lacking mutations (55.6%; p=0.09).	('IDH', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('overexpression', 'PosReg', (47, 61))	('IDH', 'Gene', '3417', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (104, 110))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('tumors', 'Disease', (16, 22))
35645	20725730	Average MIB labeling in the IDH1 mutated subset was 34.6+-11.4 versus 32.0+-3.18 in those without IDH mutations (p=0.83).	('IDH', 'Gene', (28, 31))	('labeling', 'MPA', (12, 20))	('IDH1', 'Gene', '3417', (28, 32))	('IDH', 'Gene', '3417', (28, 31))	('mutated', 'Var', (33, 40))	('MIB', 'Gene', (8, 11))	('IDH', 'Gene', (98, 101))	('MIB', 'Gene', '57534', (8, 11))	('IDH', 'Gene', '3417', (98, 101))	('IDH1', 'Gene', (28, 32))
35649	20725730	To assess the prognostic significance of IDH mutations in pediatric malignant gliomas, overall survival and event-free survival were compared between the subgroup of tumors showing IDH mutations and those lacking this feature.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH', 'Gene', (41, 44))	('IDH', 'Gene', (181, 184))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('malignant gliomas', 'Disease', 'MESH:D005910', (68, 85))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('IDH', 'Gene', '3417', (41, 44))	('IDH', 'Gene', '3417', (181, 184))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('mutations', 'Var', (185, 194))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('malignant gliomas', 'Disease', (68, 85))
35652	20725730	These results show that there is a significant difference in early outcome as a function of IDH mutation status.	('mutation status', 'Var', (96, 111))	('IDH', 'Gene', '3417', (92, 95))	('IDH', 'Gene', (92, 95))
35655	20725730	Recent studies have demonstrated frequent mutations of the IDH1 and IDH2 genes in adult secondary malignant gliomas that arise from preexisting lower grade lesions.	('IDH1', 'Gene', '3417', (59, 63))	('malignant gliomas', 'Disease', 'MESH:D005910', (98, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('IDH2', 'Gene', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH2', 'Gene', '3418', (68, 72))	('malignant gliomas', 'Disease', (98, 115))	('IDH1', 'Gene', (59, 63))	('mutations', 'Var', (42, 51))
35656	20725730	Alteration in a single IDH1 allele significantly inhibits the normal function of IDH in promoting the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, with resultant conversion of NADP+ to NADPH.	('NADP+', 'Chemical', 'MESH:D009249', (195, 200))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (81, 84))	('Alteration', 'Var', (0, 10))	('inhibits', 'NegReg', (49, 57))	('IDH1', 'Gene', (23, 27))	('isocitrate', 'Chemical', 'MESH:C034219', (131, 141))	('NADPH', 'Chemical', 'MESH:D009249', (204, 209))	('IDH1', 'Gene', '3417', (23, 27))	('promoting', 'PosReg', (88, 97))	('conversion', 'MPA', (181, 191))	('NADP+', 'MPA', (195, 200))	('IDH', 'Gene', (81, 84))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (145, 164))	('IDH', 'Gene', '3417', (23, 26))
35657	20725730	Because alpha-ketoglutarate enhances the degradation of hypoxia-inducible factor subunit HIF-1alpha, inhibition of alpha-ketoglutarate formation increases the levels of HIF-1alpha, which favors tumor growth under hypoxic conditions.	('HIF-1alpha', 'Gene', '3091', (169, 179))	('inhibition', 'Var', (101, 111))	('hypoxic conditions', 'Disease', (213, 231))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (115, 134))	('levels', 'MPA', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (8, 27))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('HIF-1alpha', 'Gene', (169, 179))	('hypoxic conditions', 'Disease', 'MESH:D009135', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('increases', 'PosReg', (145, 154))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('tumor', 'Disease', (194, 199))	('enhances', 'PosReg', (28, 36))	('HIF-1alpha', 'Gene', (89, 99))	('hypoxia', 'Disease', (56, 63))	('degradation', 'MPA', (41, 52))
35658	20725730	IDH1 mutations also drive the conversion of alpha-ketoglutarate to R(-)-s-hydroxyglutarate, a metabolite that may contribute to tumor development.	('R(-)-s-hydroxyglutarate', 'Chemical', '-', (67, 90))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('IDH1', 'Gene', '3417', (0, 4))	('drive', 'Reg', (20, 25))	('mutations', 'Var', (5, 14))	('conversion', 'MPA', (30, 40))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (44, 63))	('alpha-ketoglutarate', 'MPA', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('IDH1', 'Gene', (0, 4))	('contribute', 'Reg', (114, 124))
35659	20725730	The potentially contributory role of this alteration to tumor development is highlighted by the fact that IDH mutations are observed not only in secondary glioblastomas, but also in diffuse gliomas of lower histological grades, in some instances preceding the acquisition of other molecular alterations.	('observed', 'Reg', (124, 132))	('glioblastomas', 'Disease', 'MESH:D005909', (155, 168))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('IDH', 'Gene', '3417', (106, 109))	('mutations', 'Var', (110, 119))	('glioblastomas', 'Disease', (155, 168))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('gliomas', 'Disease', (190, 197))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('diffuse', 'Disease', (182, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('glioblastomas', 'Phenotype', 'HP:0012174', (155, 168))	('IDH', 'Gene', (106, 109))
35660	20725730	However, IDH mutations are uncommon in primary adult malignant gliomas, suggesting that these lesions arise by a mechanistically distinct pathway of tumorigenesis.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('IDH', 'Gene', (9, 12))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('tumor', 'Disease', (149, 154))	('IDH', 'Gene', '3417', (9, 12))	('malignant gliomas', 'Disease', (53, 70))	('mutations', 'Var', (13, 22))	('malignant gliomas', 'Disease', 'MESH:D005910', (53, 70))
35661	20725730	Although several large surveys of IDH mutations that have included pediatric brain tumors have reported that such alterations are uncommon, many of these studies have predominantly incorporated pilocytic astrocytomas and medulloblastomas, which are distinct histologically from gliomas that arise in adults, and a comparatively small number of diffuse low-grade gliomas and malignant gliomas of childhood have been reported.	('gliomas', 'Disease', 'MESH:D005910', (278, 285))	('IDH', 'Gene', (34, 37))	('gliomas', 'Disease', (362, 369))	('malignant gliomas', 'Disease', 'MESH:D005910', (374, 391))	('gliomas', 'Disease', (384, 391))	('brain tumors', 'Disease', (77, 89))	('medulloblastomas', 'Disease', 'MESH:D008527', (221, 237))	('incorporated', 'Reg', (181, 193))	('gliomas', 'Phenotype', 'HP:0009733', (278, 285))	('IDH', 'Gene', '3417', (34, 37))	('malignant gliomas', 'Disease', (374, 391))	('gliomas', 'Disease', 'MESH:D005910', (362, 369))	('pilocytic astrocytomas', 'Disease', (194, 216))	('gliomas', 'Disease', 'MESH:D005910', (384, 391))	('mutations', 'Var', (38, 47))	('glioma', 'Phenotype', 'HP:0009733', (362, 368))	('glioma', 'Phenotype', 'HP:0009733', (384, 390))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('gliomas', 'Phenotype', 'HP:0009733', (362, 369))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('astrocytoma', 'Phenotype', 'HP:0009592', (204, 215))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (194, 216))	('gliomas', 'Phenotype', 'HP:0009733', (384, 391))	('medulloblastomas', 'Disease', (221, 237))	('gliomas', 'Disease', (278, 285))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))
35662	20725730	included only 14 pediatric GBMs, one of which had an IDH1 mutation.	('mutation', 'Var', (58, 66))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))
35663	20725730	reported IDH mutations in only 4 of 73 children with non-pilocytic gliomas, with an average age of 16 years in the affected subset, but the histological composition of the analyzed tumors was not specified.	('non-pilocytic gliomas', 'Disease', (53, 74))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('non-pilocytic gliomas', 'Disease', 'MESH:D005910', (53, 74))	('IDH', 'Gene', (9, 12))	('children', 'Species', '9606', (39, 47))	('not specified', 'Species', '32644', (192, 205))	('IDH', 'Gene', '3417', (9, 12))	('mutations', 'Var', (13, 22))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
35664	20725730	noted mutations in 0 of 15 primary pediatric glioblastomas (median age 5).	('glioblastomas', 'Phenotype', 'HP:0012174', (45, 58))	('glioblastomas', 'Disease', 'MESH:D005909', (45, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('mutations', 'Var', (6, 15))	('glioblastomas', 'Disease', (45, 58))
35667	20725730	noted no IDH1 mutations in a series of 27 pediatric high-grade gliomas, although the age range extended only to 17 years, and the mean age of their overall cohort was 9.4 years, whereas 20 of our 46 patients were 14 to 18 years of age, suggesting that the composition of our analyzed patient groups may have differed somewhat.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('patient', 'Species', '9606', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('patients', 'Species', '9606', (199, 207))	('mutations', 'Var', (14, 23))	('patient', 'Species', '9606', (284, 291))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
35668	20725730	In this regard, the incidence of TP53 mutations observed in their patients (18.5%) is also somewhat lower than the frequencies we have previously observed in older children (~40%), suggesting that there may well be several age-related patterns of tumorigenesis within the broad group of childhood malignant gliomas.	('children', 'Species', '9606', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('gliomas', 'Phenotype', 'HP:0009733', (307, 314))	('tumor', 'Disease', (247, 252))	('TP53', 'Gene', '7157', (33, 37))	('malignant gliomas', 'Disease', 'MESH:D005910', (297, 314))	('TP53', 'Gene', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('malignant gliomas', 'Disease', (297, 314))	('patients', 'Species', '9606', (66, 74))
35669	20725730	Given the molecular similarities that have been noted between primary pediatric malignant gliomas that arise in older children and secondary malignant gliomas that occur in adults, in terms of their high frequency of TP53 mutations and infrequency of EGFR amplification and PTEN deletions, we questioned whether a more focused analysis of childhood high-grade gliomas, including samples from both older and younger children, might identify an association between IDH mutations and age in these tumors.	('TP53', 'Gene', '7157', (217, 221))	('IDH', 'Gene', '3417', (463, 466))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('PTEN', 'Gene', (274, 278))	('malignant gliomas', 'Disease', 'MESH:D005910', (80, 97))	('EGFR', 'Gene', '1956', (251, 255))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('gliomas', 'Disease', (90, 97))	('children', 'Species', '9606', (415, 423))	('tumors', 'Disease', 'MESH:D009369', (494, 500))	('malignant gliomas', 'Disease', (80, 97))	('malignant gliomas', 'Disease', 'MESH:D005910', (141, 158))	('PTEN', 'Gene', '5728', (274, 278))	('mutations', 'Var', (222, 231))	('gliomas', 'Disease', (360, 367))	('glioma', 'Phenotype', 'HP:0009733', (360, 366))	('children', 'Species', '9606', (118, 126))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('TP53', 'Gene', (217, 221))	('malignant gliomas', 'Disease', (141, 158))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('gliomas', 'Disease', (151, 158))	('deletions', 'Var', (279, 288))	('gliomas', 'Disease', 'MESH:D005910', (360, 367))	('IDH', 'Gene', (463, 466))	('tumors', 'Phenotype', 'HP:0002664', (494, 500))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('EGFR', 'Gene', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (494, 499))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('tumors', 'Disease', (494, 500))	('gliomas', 'Phenotype', 'HP:0009733', (360, 367))
35670	20725730	Our results indicate that IDH mutations are relatively common in malignant gliomas that occur in older children, although are less frequent than the reported incidence in secondary adult malignant gliomas, which exceeds 80% in some studies.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('common', 'Reg', (55, 61))	('malignant gliomas', 'Disease', (65, 82))	('children', 'Species', '9606', (103, 111))	('malignant gliomas', 'Disease', 'MESH:D005910', (65, 82))	('gliomas', 'Phenotype', 'HP:0009733', (197, 204))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('malignant gliomas', 'Disease', (187, 204))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('IDH', 'Gene', '3417', (26, 29))	('malignant gliomas', 'Disease', 'MESH:D005910', (187, 204))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
35673	20725730	In contrast, IDH mutations are rare in tumors arising in younger children, supporting the existence of age-related pathways of tumorigenesis in childhood.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH', 'Gene', '3417', (13, 16))	('children', 'Species', '9606', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (39, 44))	('IDH', 'Gene', (13, 16))	('tumors', 'Disease', (39, 45))
35674	20725730	The potential for multiple pathways of tumor development in childhood fits with our previous observations that TP53 mutations are common in malignant gliomas that occur in older children, but are rare in lesions that arise in younger children.	('malignant gliomas', 'Disease', (140, 157))	('malignant gliomas', 'Disease', 'MESH:D005910', (140, 157))	('TP53', 'Gene', '7157', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('fits', 'Disease', 'MESH:D012640', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TP53', 'Gene', (111, 115))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('common', 'Reg', (130, 136))	('mutations', 'Var', (116, 125))	('children', 'Species', '9606', (234, 242))	('tumor', 'Disease', (39, 44))	('children', 'Species', '9606', (178, 186))	('fits', 'Disease', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
35675	20725730	The current results indicate that primary malignant gliomas in young children lack not only EGFR amplification, and PTEN and TP53 mutations, but also IDH mutations, implying that these lesions incorporate distinct, but so far, uncharacterized pathways of tumorigenesis.	('malignant gliomas', 'Disease', (42, 59))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('incorporate', 'Reg', (193, 204))	('TP53', 'Gene', (125, 129))	('IDH', 'Gene', (150, 153))	('PTEN', 'Gene', (116, 120))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('EGFR', 'Gene', '1956', (92, 96))	('PTEN', 'Gene', '5728', (116, 120))	('IDH', 'Gene', '3417', (150, 153))	('tumor', 'Disease', (255, 260))	('TP53', 'Gene', '7157', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('lack', 'NegReg', (78, 82))	('children', 'Species', '9606', (69, 77))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('malignant gliomas', 'Disease', 'MESH:D005910', (42, 59))	('mutations', 'Var', (130, 139))	('mutations', 'Var', (154, 163))	('EGFR', 'Gene', (92, 96))
35719	30620400	BRAF duplication (a surrogate for BRAF-KIAA1549 fusion) was present in 6 of 9 patients in whom the test was performed, and BRAF V600E mutation, in 2 of 6.	('KIAA1549', 'Gene', (39, 47))	('V600E mutation', 'Var', (128, 142))	('duplication', 'Var', (5, 16))	('KIAA1549', 'Gene', '57670', (39, 47))	('V600E', 'Mutation', 'rs113488022', (128, 133))	('BRAF', 'Gene', (123, 127))	('patients', 'Species', '9606', (78, 86))	('BRAF', 'Gene', '673', (123, 127))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (34, 38))
35737	30620400	Patients receiving GTR upfront (vs all other patients, log rank P=0.025, Cox regression P=0.085) and those not experiencing diencephalic syndrome had better PFS on univariate analysis, with the latter also being significant in multivariate analysis (log rank P=0.007, Cox regression P=0.036).	('diencephalic syndrome', 'Disease', (124, 145))	('better', 'PosReg', (150, 156))	('PFS', 'MPA', (157, 160))	('diencephalic syndrome', 'Disease', 'MESH:D007027', (124, 145))	('GTR', 'Var', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (45, 53))
35775	30620400	NF-1 status predicted fewer surgeries, consistent with the more benign course of glioma in these patients, but tumors not completely resectable at diagnosis and those in the HT/OP:commonly found in infants:resulted in increased chemotherapy/systemic therapy.	('NF-1', 'Gene', '4763', (0, 4))	('infants', 'Species', '9606', (198, 205))	('HT', 'Disease', 'MESH:D006973', (174, 176))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('NF-1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('status', 'Var', (5, 11))	('increased', 'PosReg', (218, 227))	('glioma', 'Disease', (81, 87))	('tumors', 'Disease', (111, 117))	('chemotherapy/systemic therapy', 'CPA', (228, 257))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('surgeries', 'CPA', (28, 37))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
35804	30620400	Molecular alterations that have recently been shown to be of prognostic significance, such as BRAF V600E mutation and CDKN2A deletion, were not tested for in most patients and could not be factored into the current analysis.	('CDKN2A', 'Gene', (118, 124))	('BRAF', 'Gene', (94, 98))	('patients', 'Species', '9606', (163, 171))	('CDKN2A', 'Gene', '1029', (118, 124))	('V600E mutation', 'Var', (99, 113))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', '673', (94, 98))	('deletion', 'Var', (125, 133))
35832	25748242	Several transcription factors including SNAI1, SNAI2, TWIST1, ZEB-1 play important role in the MES differentiation and aberrant activation of transcriptional factors such as STAT3, ZEB-1and NFkappaB is shown to be responsible for MES shift in the GBM.	('NFkappaB', 'Gene', (190, 198))	('STAT3', 'Gene', (174, 179))	('aberrant', 'Var', (119, 127))	('SNAI2', 'Gene', (47, 52))	('STAT3', 'Gene', '6774', (174, 179))	('TWIST1', 'Gene', (54, 60))	('activation', 'PosReg', (128, 138))	('SNAI2', 'Gene', '6591', (47, 52))	('SNAI1', 'Gene', '6615', (40, 45))	('ZEB-1', 'Gene', (181, 186))	('ZEB-1', 'Gene', '6935', (181, 186))	('SNAI1', 'Gene', (40, 45))	('ZEB-1', 'Gene', (62, 67))	('MES', 'Chemical', '-', (95, 98))	('ZEB-1', 'Gene', '6935', (62, 67))	('TWIST1', 'Gene', '7291', (54, 60))	('MES', 'Chemical', '-', (230, 233))	('NFkappaB', 'Gene', '4790', (190, 198))	('MES differentiation', 'CPA', (95, 114))	('MES shift', 'Disease', (230, 239))
35833	25748242	STAT3 is activated through phosphorylation of tyrosine 705 in response to cytokines and growth factors that results in transcription of diverse genes involved in cell cycle progression, apoptosis, cell survival, angiogenesis, migration, and invasion.	('results in', 'Reg', (108, 118))	('STAT3', 'Gene', (0, 5))	('cell survival', 'CPA', (197, 210))	('cell cycle progression', 'CPA', (162, 184))	('tyrosine', 'Chemical', 'MESH:D014443', (46, 54))	('transcription', 'MPA', (119, 132))	('angiogenesis', 'CPA', (212, 224))	('STAT3', 'Gene', '6774', (0, 5))	('phosphorylation', 'Var', (27, 42))	('invasion', 'CPA', (241, 249))	('migration', 'CPA', (226, 235))	('apoptosis', 'CPA', (186, 195))
35853	25748242	After 60 hours of incubation, cells were trypsinized and 1000 cells were seeded into the low attachment 6 well plate in serum-free media containing DMEM/F12 with 1X B27supplement (GIBCO), 20 ng/ml of bFGF and EGF (Peprotech).	('bFGF', 'Gene', '2247', (200, 204))	('bFGF', 'Gene', (200, 204))	('DMEM/F12', 'Var', (148, 156))	('DMEM', 'Chemical', '-', (148, 152))
35881	25748242	Kaplan-Meier analysis of all GBM patients revealed that patients with high OSMR expression correlated with poor survival compared to cases with intermediate expression (Figure 1D).	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (33, 41))	('OSMR', 'Gene', (75, 79))	('survival', 'MPA', (112, 120))	('high', 'Var', (70, 74))	('poor', 'NegReg', (107, 111))
35882	25748242	LIFR expression was associated with poor survival in LGG (P = 0.048) but not in GBM (Figure S4, A and B).	('poor', 'NegReg', (36, 40))	('expression', 'Var', (5, 15))	('LIFR', 'Gene', '3977', (0, 4))	('LGG', 'Disease', (53, 56))	('LIFR', 'Gene', (0, 4))
35885	25748242	Recently, based on The Cancer Genome Atlas (TCGA) data GBM has been classified into four genetic subtypes -mesenchymal, classical, neural and pro-neural characterized by aberrations in genes including PDGFRA/IDH1, EGFR, and NF1.	('IDH1', 'Gene', (208, 212))	('Cancer Genome Atlas', 'Disease', (23, 42))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('neural', 'Gene', '4901', (131, 137))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (23, 42))	('aberrations', 'Var', (170, 181))	('EGFR', 'Gene', '1956', (214, 218))	('IDH1', 'Gene', '3417', (208, 212))	('neural', 'Gene', '4901', (146, 152))	('PDGFRA', 'Gene', (201, 207))	('PDGFRA', 'Gene', '5156', (201, 207))	('EGFR', 'Gene', (214, 218))	('NF1', 'Gene', (224, 227))	('neural', 'Gene', (131, 137))	('neural', 'Gene', (146, 152))	('NF1', 'Gene', '4763', (224, 227))
35903	25748242	OSM enhanced MMP-9 activity by > 2 fold as measured by gelatine zymography in the GBM cells, the effect was significantly greater in LN18 and primary culture- G1 compared to LN229 (Figure 6, C and D).	('greater', 'PosReg', (122, 129))	('MMP-9', 'Gene', (13, 18))	('LN229', 'CellLine', 'CVCL:0393', (174, 179))	('enhanced', 'PosReg', (4, 12))	('LN18', 'Var', (133, 137))	('activity', 'MPA', (19, 27))	('MMP-9', 'Gene', '4318', (13, 18))
35909	25748242	We observed that silencing of STAT3 abrogated the expression of mesenchymal signature genes- fibronectin and YKL-40 induced by OSM in LN18 and LN229 (Figure 7, A and B).	('LN229', 'CellLine', 'CVCL:0393', (143, 148))	('LN229', 'Var', (143, 148))	('YKL-40', 'Gene', (109, 115))	('fibronectin', 'Gene', (93, 104))	('STAT3', 'Gene', '6774', (30, 35))	('abrogated', 'NegReg', (36, 45))	('STAT3', 'Gene', (30, 35))	('silencing', 'Var', (17, 26))	('fibronectin', 'Gene', '2335', (93, 104))	('expression', 'MPA', (50, 60))	('YKL-40', 'Gene', '1116', (109, 115))
35912	25748242	The OSM induced invasion in LN18 and G1 was decreased 2 and 3 fold respectively, in STAT3 knockdown cells compared to untransfected OSM treated cells (Figure 9, A and B).	('STAT3', 'Gene', '6774', (84, 89))	('knockdown', 'Var', (90, 99))	('invasion', 'CPA', (16, 24))	('STAT3', 'Gene', (84, 89))	('decreased', 'NegReg', (44, 53))
35913	25748242	MMP-9 activity also abrogated with the knockdown of STAT3 compared to the OSM induced untransfected cells (2.5 and 1.5 fold in LN18 and G1 cells respectively) (Figure 9, C and D).	('activity', 'MPA', (6, 14))	('STAT3', 'Gene', (52, 57))	('knockdown', 'Var', (39, 48))	('MMP-9', 'Gene', '4318', (0, 5))	('STAT3', 'Gene', '6774', (52, 57))	('abrogated', 'NegReg', (20, 29))	('MMP-9', 'Gene', (0, 5))
35916	25748242	Silencing of STAT3 using siRNA inhibited the neurosphere formation induced by OSM (Figure 9, E and F).	('neurosphere formation', 'CPA', (45, 66))	('STAT3', 'Gene', '6774', (13, 18))	('inhibited', 'NegReg', (31, 40))	('Silencing', 'Var', (0, 9))	('STAT3', 'Gene', (13, 18))
35929	25748242	Our results with Kaplan-Meier analysis of GBM patients from REMBRANDT and TCGA data revealed that samples with high expression of OSMR showed poor survival compared to cases with intermediate expression.	('poor', 'NegReg', (142, 146))	('high expression', 'Var', (111, 126))	('patients', 'Species', '9606', (46, 54))	('survival', 'CPA', (147, 155))	('OSMR', 'Gene', (130, 134))
35951	25748242	Furthermore, silencing of STAT3 abrogated the effect of OSM suggesting the role of STAT3 signaling in regulating the expression of mesenchymal markers.	('STAT3', 'Gene', (83, 88))	('STAT3', 'Gene', '6774', (26, 31))	('abrogated', 'NegReg', (32, 41))	('STAT3', 'Gene', (26, 31))	('STAT3', 'Gene', '6774', (83, 88))	('silencing', 'Var', (13, 22))
35959	25748242	The findings underscore the role of OSMR in GBM and suggest that OSMR can be explored as potential target for therapeutic intervention and inhibitors to OSMR may be active against malignant gliomas.	('inhibitors', 'Var', (139, 149))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('OSMR', 'Gene', (153, 157))	('malignant gliomas', 'Disease', (180, 197))	('malignant gliomas', 'Disease', 'MESH:D005910', (180, 197))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))
35973	22869051	miRNAs are able to regulate the expression of more than 30% of human genes via specific base pairing to the 3'-UTRs of messenger RNAs, which either blocks translation or promotes the degradation of the mRNA target.	('regulate', 'Reg', (19, 27))	('human', 'Species', '9606', (63, 68))	('base pairing', 'Var', (88, 100))	('degradation', 'MPA', (183, 194))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('translation', 'MPA', (155, 166))	('promotes', 'PosReg', (170, 178))	('blocks', 'NegReg', (148, 154))	('expression', 'MPA', (32, 42))	('mRNA target', 'MPA', (202, 213))
35981	22869051	Moreover, miR-145 is able to down-regulate several genes implicated in cell invasion, such as JAM-A, MUC1 and FSCN1, in breast, bladder and prostate cancer.	('MUC1', 'Gene', (101, 105))	('MUC1', 'Gene', '4582', (101, 105))	('JAM-A', 'Gene', (94, 99))	('bladder and prostate cancer', 'Disease', 'MESH:D001749', (128, 155))	('prostate cancer', 'Phenotype', 'HP:0012125', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('FSCN1', 'Gene', (110, 115))	('FSCN1', 'Gene', '6624', (110, 115))	('down-regulate', 'NegReg', (29, 42))	('JAM-A', 'Gene', '50848', (94, 99))	('genes', 'Gene', (51, 56))	('miR-145', 'Var', (10, 17))	('breast', 'Disease', (120, 126))
35987	22869051	We evaluated the expression levels of different microRNAs previously known to be down-regulated in both tumors and stem cells: miR128a, let7a, miR181a, miR101, and miR-145.	('down-regulated', 'NegReg', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('miR', 'Gene', '220972', (164, 167))	('miR', 'Gene', (164, 167))	('miR128a', 'Gene', (127, 134))	('expression', 'MPA', (17, 27))	('miR', 'Gene', (143, 146))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('miR', 'Gene', '220972', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('miR128a', 'Gene', '406915', (127, 134))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', (152, 155))	('let7a', 'Var', (136, 141))
35992	22869051	H3K27 methylation causes gene silencing and is important for stem cell maintenance and proliferation, and miR101 was found to be moderately down-regulated in GB-NS.	('GB', 'Phenotype', 'HP:0012174', (158, 160))	('down-regulated', 'NegReg', (140, 154))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (106, 109))	('methylation', 'Var', (6, 17))	('H3K27', 'Protein', (0, 5))	('gene', 'MPA', (25, 29))	('GB-NS', 'Disease', (158, 163))	('GB-NS', 'Chemical', '-', (158, 163))
36054	22869051	Fang et al proposed a bistable system involving reciprocal interactions of SOX2 and miR-145 and suggested the involvement of miR-145 in GB stemness.	('miR-145', 'Var', (125, 132))	('GB stemness', 'CPA', (136, 147))	('miR-145', 'Gene', (84, 91))	('interactions', 'Interaction', (59, 71))	('SOX2', 'Gene', (75, 79))	('SOX2', 'Gene', '6657', (75, 79))	('GB', 'Phenotype', 'HP:0012174', (136, 138))	('involvement', 'Reg', (110, 121))
36060	22869051	Because the invasive ability is one of the most important features of GB and one of the causes of poor prognosis, miR-145 appears to be an important factor for GB aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (163, 177))	('miR-145', 'Var', (114, 121))	('GB', 'Phenotype', 'HP:0012174', (70, 72))	('aggressiveness', 'Disease', 'MESH:D001523', (163, 177))	('aggressiveness', 'Disease', (163, 177))	('GB', 'Phenotype', 'HP:0012174', (160, 162))
36098	22869051	A total of 45 immune-deficient CD1-nude mice received brain injections of 105 miRover-NS or Empty-NS cells (n = 10/group for survival, n = 5/group for histological studies) from four GB-NS cell lines (BT165NS, BT168NS, BT273NS, BT275NS) infected with retroviral vectors (pCLNSX-miR-145 and pCLNSX-Empty).	('BT275NS', 'Var', (228, 235))	('nude mice', 'Species', '10090', (35, 44))	('CD1', 'Gene', '111334', (31, 34))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('GB-NS', 'Chemical', '-', (183, 188))	('miR', 'Gene', '220972', (278, 281))	('GB', 'Phenotype', 'HP:0012174', (183, 185))	('miR', 'Gene', (278, 281))	('CD1', 'Gene', (31, 34))
36118	22276196	KLF8 protein and mRNA expression was not only significantly higher in renal cell carcinoma (RCC) than in non-neoplastic renal tissue, inhibition of KLF8 via siRNA could also induce cell apoptosis in vitro and reduced tumor growth in vivo.	('renal cell carcinoma', 'Disease', (70, 90))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('induce', 'PosReg', (174, 180))	('higher', 'PosReg', (60, 66))	('inhibition', 'Var', (134, 144))	('cell apoptosis', 'CPA', (181, 195))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('RCC', 'Disease', (92, 95))	('mRNA expression', 'MPA', (17, 32))	('KLF8', 'Gene', (148, 152))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('reduced', 'NegReg', (209, 216))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('neoplastic renal tissue', 'Phenotype', 'HP:0009726', (109, 132))
36171	22276196	The median Ki67 index was 9% (range: 0-39%) in the LGG, 6% (0-12%) in the AA and 16% (1-46%) in the highly proliferative GBM (Table S2).	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('Ki67', 'Var', (11, 15))	('LGG', 'Chemical', '-', (51, 54))	('highly proliferative', 'CPA', (100, 120))
36175	22276196	Since KLF8 has been demonstrated to be essential in proliferation of non-glial tumors, we selectively inhibited KLF8 by shRNA transfection in U87-MG glioma cell line (detected positive for KLF8, Figure S1 B).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('U87-MG glioma', 'Disease', 'MESH:D005910', (142, 155))	('U87-MG glioma', 'Disease', (142, 155))	('inhibited', 'NegReg', (102, 111))	('transfection', 'Var', (126, 138))	('non-glial tumors', 'Disease', 'MESH:D005910', (69, 85))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('KLF8', 'Gene', (112, 116))	('non-glial tumors', 'Disease', (69, 85))	('shRNA', 'Gene', (120, 125))
36191	22276196	Hence, we subjected U87-MG cells to shRNA-knockdown of KLF8, which led to a significant time dependent impairment in their proliferation, providing first evidence for the potency of this transcription factor in human gliomas.	('proliferation', 'CPA', (123, 136))	('impairment', 'NegReg', (103, 113))	('shRNA-knockdown', 'Var', (36, 51))	('U87-MG', 'CellLine', 'CVCL:0022', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('KLF8', 'Gene', (55, 59))	('gliomas', 'Phenotype', 'HP:0009733', (217, 224))	('gliomas', 'Disease', (217, 224))	('human', 'Species', '9606', (211, 216))	('gliomas', 'Disease', 'MESH:D005910', (217, 224))
36195	22276196	Inhibition of this potent transcription factor led to an almost complete loss of glioma cell proliferation in vitro, but its ubiquitous expression might counteract KLF8-targeting in malignant gliomas as a future antiproliferative strategy.	('loss of glioma', 'Disease', 'MESH:D005910', (73, 87))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('malignant gliomas', 'Disease', (182, 199))	('malignant gliomas', 'Disease', 'MESH:D005910', (182, 199))	('loss of glioma', 'Disease', (73, 87))	('Inhibition', 'Var', (0, 10))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))
36201	32493985	CD274 and PDCD1LG2 cis-regulatory regions were cloned from genomic DNA and assessed in full or by mutating and/or deleting regulatory elements by luciferase assays.	('PDCD1LG2', 'Gene', '80380', (10, 18))	('PDCD1LG2', 'Gene', (10, 18))	('CD274', 'Gene', (0, 5))	('deleting', 'Var', (114, 122))	('mutating', 'Var', (98, 106))
36210	32493985	Several mechanisms can drive cell-intrinsic PD-L1 induction including PTEN loss, aberrant signaling, genomic amplification, and post-translational modifications.	('aberrant signaling', 'Var', (81, 99))	('PTEN loss', 'Disease', (70, 79))	('PTEN loss', 'Disease', 'MESH:D006223', (70, 79))	('PD-L1', 'Gene', (44, 49))
36224	32493985	and have been sequenced; KNS60, LN464, LN340, YKG1, KALS-1, AM38, and GMS10 were obtained from the Broad Institute (Cambridge, MA).	('LN340', 'Var', (39, 44))	('LN464', 'Var', (32, 37))	('LN464', 'CellLine', 'CVCL:3962', (32, 37))
36230	32493985	CD274 constructs: promoter region PD-L1.Pr1 (-4167 to +538), enhancer regions Pr2 (+4564 to +5691) and Pr3 (+8572 to +10276), and Pr3 minimal (+8572 to +9297).	('+8572 to +10276', 'Var', (108, 123))	('Pr3', 'Gene', '5657', (130, 133))	('Pr1', 'Gene', (40, 43))	('-4167 to +538', 'Var', (45, 58))	('Pr3', 'Gene', (130, 133))	('+8572 to +9297', 'Var', (143, 157))	('+4564 to +5691', 'Var', (83, 97))	('Pr1', 'Gene', '140738', (40, 43))	('Pr3', 'Gene', '5657', (103, 106))	('Pr3', 'Gene', (103, 106))
36231	32493985	PDCD1LG2 constructs: PD-L2.Pr1 + 2 (-1145 to +780), PD-L2.Pr1 (-1145 to -495), and PD-L2.Pr2 (-525 to +780).	('-1145', 'Var', (36, 41))	('Pr1', 'Gene', '140738', (27, 30))	('Pr1', 'Gene', '140738', (58, 61))	('PDCD1LG2', 'Gene', '80380', (0, 8))	('PDCD1LG2', 'Gene', (0, 8))	('Pr1', 'Gene', (27, 30))	('Pr1', 'Gene', (58, 61))	('-1145 to -495', 'Var', (63, 76))
36232	32493985	Mutated/truncated PD-L2.Pr1 constructs: PD-L2.Pr1(DeltaSTAT1) (-1145 to -694) and PD-L2.Pr1(DeltaGATA2/3) (-709 to -495).	('-1145', 'Var', (63, 68))	('Pr1', 'Gene', (46, 49))	('Pr1', 'Gene', '140738', (24, 27))	('STAT1', 'Gene', (55, 60))	('Pr1', 'Gene', '140738', (88, 91))	('Pr1', 'Gene', (88, 91))	('STAT1', 'Gene', '6772', (55, 60))	('Pr1', 'Gene', '140738', (46, 49))	('Pr1', 'Gene', (24, 27))
36235	32493985	Quantitative PCR was performed using a CFX96 Real-Time system (Bio-Rad, Hercules, CA) and Taqman gene expression assays for Cd274, Pdcd1lg2, Gata2 and Gata3 (Hs00204257_m1, Hs00228839_m1, Hs00231069_m1, Hs00231119_m1, Hs00231122_m1, respectively Thermo Fisher Scientific).	('Gata2', 'Gene', (141, 146))	('Gata3', 'Gene', '2625', (151, 156))	('Hs00231119_m1', 'Var', (203, 216))	('Rad', 'Gene', '6236', (67, 70))	('Rad', 'Gene', (67, 70))	('Hs00228839_m1', 'Var', (173, 186))	('Gata2', 'Gene', '2624', (141, 146))	('Pdcd1lg2', 'Gene', '80380', (131, 139))	('Hs00231122_m1', 'Var', (218, 231))	('Cd274', 'Gene', (124, 129))	('Pdcd1lg2', 'Gene', (131, 139))	('Hs00231069_m1', 'Var', (188, 201))	('Hs00204257_m1', 'Var', (158, 171))	('Gata3', 'Gene', (151, 156))	('Cd274', 'Gene', '29126', (124, 129))
36236	32493985	GAPDH was the endogenous control (Hs02786624_g1, Thermo Fisher Scientific).	('Hs02786624_g1', 'Var', (34, 47))	('GAPDH', 'Gene', '2597', (0, 5))	('GAPDH', 'Gene', (0, 5))
36241	32493985	Lymphocytes were purified using the Dead Cell Removal kit (#130090101 Miltenyi Biotec, CA) and CD8 positive selection (StemCell Technologies, MA).	('#130090101', 'Var', (59, 69))	('CD8', 'Gene', (95, 98))	('CD8', 'Gene', '925', (95, 98))
36246	32493985	LN464 and LN340 were transduced with pBabe-GATA2 (Addgene plasmid#1285) and pBabe-GATA3 (cloned from Addgene plasmid#83814) retrovirus.	('GATA2', 'Gene', '2624', (43, 48))	('GATA3', 'Gene', (82, 87))	('LN340', 'Var', (10, 15))	('GATA3', 'Gene', '2625', (82, 87))	('GATA2', 'Gene', (43, 48))	('LN464', 'CellLine', 'CVCL:3962', (0, 5))
36248	32493985	Isotype controls are mouse IgG2a, kappa (Cat#400213, Biolegend) and mouse IgG2b, kappa (Cat#400322, Biolegend), respectively.	('mouse', 'Species', '10090', (68, 73))	('IgG2b', 'Gene', (74, 79))	('IgG2a', 'Gene', (27, 32))	('mouse', 'Species', '10090', (21, 26))	('Cat#400213', 'Var', (41, 51))	('IgG2b', 'Gene', '16016', (74, 79))	('Cat#400322', 'Var', (88, 98))	('IgG2a', 'Gene', '668478', (27, 32))
36250	32493985	Isotype controls were Rat IgG2a, kappa (Cat#400508, Biolegend) and Rat IgG2b, kappa (Cat#400612, Biolegend), respectively.	('Cat#400508', 'Var', (40, 50))	('IgG2b', 'Gene', (71, 76))	('IgG2a', 'Gene', '668478', (26, 31))	('IgG2b', 'Gene', '16016', (71, 76))	('Cat#400612', 'Var', (85, 95))	('IgG2a', 'Gene', (26, 31))
36260	32493985	High PD-L1 and PD-L2 expression correlated with worse outcomes in GBM and low-grade glioma, while high PD-L2 independently correlated with shorter disease-free survival in low-grade glioma.	('GBM', 'Disease', (66, 69))	('PD-L2', 'Gene', (15, 20))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('PD-L1', 'Gene', (5, 10))	('glioma', 'Disease', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('high', 'Var', (98, 102))	('expression', 'MPA', (21, 31))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', (182, 188))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('shorter', 'NegReg', (139, 146))
36263	32493985	Analyzing 967 cell lines, we identified cancer lines that expressed PD-L1 and PD-L2; 350 cell lines expressed PD-L1 mRNA above the mean expression level, and 193 cell lines expressed PD-L1 mRNA more than 1 standard deviation above all CCLE lines (Fig.	('PD-L1', 'Var', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('PD-L2', 'Gene', (78, 83))	('cancer', 'Disease', (40, 46))	('PD-L1', 'Var', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
36264	32493985	Cell lines expressing high levels of PD-L1 and/or PD-L2 were derived from all cancers (Supplementary Fig.	('PD-L2', 'Var', (50, 55))	('PD-L1', 'Var', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
36270	32493985	High PD-L1 and PD-L2 mRNA in the representative B36 BTIC line was concordant with cell surface expression compared to the lower-expressing B49 cell line (Fig.	('PD-L2 mRNA', 'Var', (15, 25))	('PD-L1', 'Var', (5, 10))	('B49', 'CellLine', 'CVCL:S156', (139, 142))
36275	32493985	We tested the effects of PD-L1 and/or PD-L2 overexpression in the GL261 brain tumor model in which the GL261-derived mutant Imp3-D81N 8-mer is an immunogenic neoantigen.	('Imp3-D81N', 'Var', (124, 133))	('tested', 'Reg', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('brain tumor', 'Disease', (72, 83))	('brain tumor', 'Disease', 'MESH:D001932', (72, 83))	('brain tumor', 'Phenotype', 'HP:0030692', (72, 83))	('D81N', 'Mutation', 'p.D81N', (129, 133))
36282	32493985	When we integrated these datasets for CD274, we identified 3 candidate regulatory elements relative to the TSS using the Genome Reference Consortium Human Build 37: PD-L1.Pr1 (-4167 to +538), PD-L1.Pr2 (+4564 to +5691), and PD-L1.Pr3 (+8572 to +10276) (Fig.	('Pr1', 'Gene', '140738', (171, 174))	('Human', 'Species', '9606', (149, 154))	('+8572 to +10276', 'Var', (235, 250))	('Pr3', 'Gene', '5657', (230, 233))	('Pr1', 'Gene', (171, 174))	('Pr3', 'Gene', (230, 233))	('-4167 to +538', 'Var', (176, 189))	('+4564 to +5691', 'Var', (203, 217))
36287	32493985	We cloned 3 elements from IOMM-Lee cell line genomic DNA relative to the transcription start site: PD-L2.Pr1 (-1145 to -495), PD-L2.Pr2 (-525 to +780), and the PD-L2.Pr1 + 2 region encompassing both sites (-1145 to +780)(Fig.	('-1145 to +780', 'Var', (206, 219))	('Pr1', 'Gene', (166, 169))	('Pr1', 'Gene', (105, 108))	('Pr1', 'Gene', '140738', (105, 108))	('Pr1', 'Gene', '140738', (166, 169))
36290	32493985	Moreover, the PD-L2.Pr1 construct drove identical levels of luciferase activity in the high PD-L2 IOMM-Lee and AM38 cell lines compared to the low PD-L2 LN340 and LN464 cell lines.	('Pr1', 'Gene', '140738', (20, 23))	('luciferase', 'Enzyme', (60, 70))	('LN464', 'CellLine', 'CVCL:3962', (163, 168))	('activity', 'MPA', (71, 79))	('Pr1', 'Gene', (20, 23))	('high PD-L2', 'Var', (87, 97))
36292	32493985	To test the hypothesis that regulatory elements harbored within the PD-L2.Pr1 region were necessary for activity in PD-L2 high-expressing cell lines, we generated mutant constructs of the PD-L2.Pr1 element based on predictions from both the UCSCGB and the PROMO TF prediction resource.	('Pr1', 'Gene', (194, 197))	('mutant', 'Var', (163, 169))	('Pr1', 'Gene', (74, 77))	('Pr1', 'Gene', '140738', (194, 197))	('Pr1', 'Gene', '140738', (74, 77))
36296	32493985	The PD-L2.Pr1 construct drove robust luciferase activity in high-expressing cell lines that increased when the STAT1 TF binding site was truncated (Fig.	('activity', 'MPA', (48, 56))	('luciferase', 'Enzyme', (37, 47))	('Pr1', 'Gene', '140738', (10, 13))	('STAT1', 'Gene', (111, 116))	('Pr1', 'Gene', (10, 13))	('increased', 'PosReg', (92, 101))	('STAT1', 'Gene', '6772', (111, 116))	('truncated', 'Var', (137, 146))
36310	32493985	However, GATA2 knockdown using 2 distinct shRNA constructs led to decreased gene expression (Supplementary Fig.	('knockdown', 'Var', (15, 24))	('decreased', 'NegReg', (66, 75))	('GATA2', 'Gene', (9, 14))	('gene expression', 'MPA', (76, 91))	('GATA2', 'Gene', '2624', (9, 14))
36311	32493985	4D), PD-L2 high-expressing cell lines concordant with the level of GATA2 protein knockdown observed by western blot.	('knockdown', 'Var', (81, 90))	('GATA2', 'Gene', '2624', (67, 72))	('GATA2', 'Gene', (67, 72))
36314	32493985	Although individual PD-L1 ligand expression status did not significantly influence disease-free survival (DFS) in GBM (data not shown), GBM patients with high PD-L2 expression showed a trend of shorter DFS than patients with low expression (Fig.	('PD-L2', 'Gene', (159, 164))	('patients', 'Species', '9606', (211, 219))	('high', 'Var', (154, 158))	('DFS', 'MPA', (202, 205))	('patients', 'Species', '9606', (140, 148))	('shorter', 'NegReg', (194, 201))
36316	32493985	GBM patients with high PD-L1/PD-L2 harbored a statistically significant decreased DFS compared to patients who harbored both low expression levels (both high vs. both low: HR, 95% CI = 1.95, 1.21~3.15, log rank test P = 0.0072).	('high PD-L1/PD-L2', 'Var', (18, 34))	('decreased DFS', 'Disease', 'MESH:D002303', (72, 85))	('decreased DFS', 'Disease', (72, 85))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (4, 12))	('PD-L1/PD-L2', 'Var', (23, 34))
36318	32493985	Patients with high PD-L2 levels exhibited statistically significant shorter overall survival (OS) and DFS compared to patients with low expression levels of PD-L2 (Fig.	('high PD-L2 levels', 'Var', (14, 31))	('overall survival', 'CPA', (76, 92))	('Patients', 'Species', '9606', (0, 8))	('DFS', 'CPA', (102, 105))	('patients', 'Species', '9606', (118, 126))	('shorter', 'NegReg', (68, 75))
36319	32493985	LGG patients with both high PD-L1 and PD-L2 expression levels harbored statistically significant shorter OS and DFS compared to patients with either low expression of one or both ligands (Fig.	('LGG', 'Disease', (0, 3))	('high', 'Var', (23, 27))	('PD-L2', 'Gene', (38, 43))	('shorter', 'NegReg', (97, 104))	('DFS', 'CPA', (112, 115))	('PD-L1', 'Gene', (28, 33))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (128, 136))
36320	32493985	In multivariate analsyis, high PD-L2 levels alone were independently associated with worse DFS even after adjusting for age, gender, and IDH1 status (HR, 95% CI = 2.98, 1.36~6.50, p = 0.0062, Fig.	('high', 'Var', (26, 30))	('PD-L2', 'MPA', (31, 36))	('IDH1', 'Gene', (137, 141))	('IDH1', 'Gene', '3417', (137, 141))	('DFS', 'Disease', (91, 94))
36345	32493985	PD-L2 expression has been previously recognized as a biomarker of host immune responses in melanoma, and PD-L2 expression was also predictor of positive clinical responses to anti-PD-1/Keytruda in the Keynote-12 trial for head and neck cancer patients with recurrent or metastatic disease.	('expression', 'Var', (111, 121))	('patients', 'Species', '9606', (243, 251))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('PD-L2', 'Gene', (105, 110))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('PD-L2', 'Gene', (0, 5))	('head and neck cancer', 'Disease', 'MESH:D006258', (222, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('head and neck cancer', 'Phenotype', 'HP:0012288', (222, 242))
36351	31906036	Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines.	('TMZ resistance', 'MPA', (81, 95))	('H2AFJ', 'Gene', '55766', (51, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('H2AFJ', 'Gene', (51, 56))	('H2AFJ', 'Gene', '55766', (8, 13))	('diminished', 'NegReg', (24, 34))	('H2AFJ', 'Gene', (8, 13))	('TMZ resistance', 'MPA', (35, 49))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('knockdown', 'Var', (14, 23))	('promoted', 'PosReg', (72, 80))
36353	31906036	Luciferase-based promoter activity assay further validated that the activities of NF-kappaB and STAT3 are causally affected by H2AFJ expression in GBM cells.	('STAT3', 'Gene', (96, 101))	('H2AFJ', 'Gene', '55766', (127, 132))	('NF-kappaB', 'Gene', (82, 91))	('STAT3', 'Gene', '6774', (96, 101))	('expression', 'Var', (133, 143))	('H2AFJ', 'Gene', (127, 132))	('affected', 'Reg', (115, 123))	('NF-kappaB', 'Gene', '4790', (82, 91))	('activities', 'MPA', (68, 78))
36361	31906036	Recent studies have demonstrated that 12% of GBM patients, especially young patients and patients with secondary GBM, acquire mutations in the active site of isocitrate dehydrogenase 1 (IDH1).	('patients', 'Species', '9606', (76, 84))	('IDH1', 'Gene', (186, 190))	('GBM', 'Disease', (45, 48))	('IDH1', 'Gene', '3417', (186, 190))	('isocitrate dehydrogenase 1', 'Gene', (158, 184))	('isocitrate dehydrogenase 1', 'Gene', '3417', (158, 184))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (49, 57))	('mutations', 'Var', (126, 135))
36363	31906036	Prognostic estimations have revealed that an IDH1 mutation is associated with an increased survival probability in glioma patients who receive TMZ treatment.	('IDH1', 'Gene', '3417', (45, 49))	('survival', 'CPA', (91, 99))	('glioma', 'Disease', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('patients', 'Species', '9606', (122, 130))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (143, 146))	('IDH1', 'Gene', (45, 49))	('increased', 'PosReg', (81, 90))	('mutation', 'Var', (50, 58))
36365	31906036	As a result, the hypermethylation of the GC island in the MGMT promoter has been used as a predictive marker for a prolonged survival time in GBM patients undergoing TMZ therapy.	('MGMT', 'Gene', '4255', (58, 62))	('MGMT', 'Gene', (58, 62))	('TMZ', 'Chemical', 'MESH:D000077204', (166, 169))	('GC island', 'Protein', (41, 50))	('patients', 'Species', '9606', (146, 154))	('hypermethylation', 'Var', (17, 33))
36370	31906036	Accordingly, the genetic variation of the H2AFX promoter has been associated with the risk of glioma, particularly adult glioma.	('genetic variation', 'Var', (17, 34))	('H2AFX', 'Gene', '3014', (42, 47))	('glioma', 'Disease', (94, 100))	('H2AFX', 'Gene', (42, 47))	('associated', 'Reg', (66, 76))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Disease', (121, 127))
36371	31906036	On the other hand, the fusion of H2AFY with MDS1 and EVI1 Complex (MECOM) and the downregulation of H2AFZ have been associated with cancer progression in leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (154, 162))	('cancer', 'Disease', (132, 138))	('leukemia', 'Disease', 'MESH:D007938', (154, 162))	('associated with', 'Reg', (116, 131))	('fusion', 'Var', (23, 29))	('EVI1', 'Gene', (53, 57))	('leukemia', 'Disease', (154, 162))	('MDS1', 'Gene', '2122', (44, 48))	('downregulation', 'NegReg', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('H2AFY', 'Gene', (33, 38))	('H2AFY', 'Gene', '9555', (33, 38))	('MDS1', 'Gene', (44, 48))	('H2AFZ', 'Gene', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('EVI1', 'Gene', '2122', (53, 57))	('H2AFZ', 'Gene', '3015', (100, 105))
36375	31906036	Artificially silencing H2AFJ enhanced TMZ cytotoxicity against GBM cells, whereas overexpressing exogenous H2AFJ rendered GBM cells more resistant to TMZ treatment.	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('H2AFJ', 'Gene', '55766', (107, 112))	('TMZ cytotoxicity', 'Disease', (38, 54))	('H2AFJ', 'Gene', (23, 28))	('silencing', 'Var', (13, 22))	('H2AFJ', 'Gene', '55766', (23, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (150, 153))	('TMZ cytotoxicity', 'Disease', 'MESH:D064420', (38, 54))	('enhanced', 'PosReg', (29, 37))	('H2AFJ', 'Gene', (107, 112))
36383	31906036	Similar to the transcriptional levels, H2AFJ protein expression examined by immunohistochemistry staining was dramatically upregulated in GBM compared to normal brain tissues (Figure 1D) even though the sample size was not sufficient.	('protein', 'Protein', (45, 52))	('upregulated', 'PosReg', (123, 134))	('H2AFJ', 'Gene', '55766', (39, 44))	('H2AFJ', 'Gene', (39, 44))	('GBM', 'Var', (138, 141))	('expression', 'MPA', (53, 63))
36384	31906036	Since IDH1 mutation, MGMT promoter methylation, and CpG island methylation phenotype (CIMP) have been widely used to estimate the effectiveness of radiation and TMZ therapies on GBM patients, we next analyzed the transcription profiling of H2AFJ in these molecular classifications.	('IDH1', 'Gene', '3417', (6, 10))	('CIMP', 'Chemical', '-', (86, 90))	('MGMT', 'Gene', '4255', (21, 25))	('H2AFJ', 'Gene', (240, 245))	('patients', 'Species', '9606', (182, 190))	('mutation', 'Var', (11, 19))	('IDH1', 'Gene', (6, 10))	('H2AFJ', 'Gene', '55766', (240, 245))	('TMZ', 'Chemical', 'MESH:D000077204', (161, 164))	('MGMT', 'Gene', (21, 25))
36385	31906036	Whereas the mRNA levels of other H2As were not robustly different (Figure S2A-C), the mRNA levels of H2AFJ were significantly (p < 0.001) higher in GBM with wild-type IDH1, MGMT promoter unmethylation or non-CIMP, respectively, than in GBM with IDH1 mutations, MGMT promoter methylation or CIMP (Figure 1E).	('H2As', 'Gene', '85235', (33, 37))	('unmethylation', 'Var', (187, 200))	('H2AFJ', 'Gene', '55766', (101, 106))	('H2As', 'Gene', (33, 37))	('MGMT', 'Gene', (261, 265))	('IDH1', 'Gene', (245, 249))	('H2AFJ', 'Gene', (101, 106))	('CIMP', 'Chemical', '-', (208, 212))	('MGMT', 'Gene', '4255', (261, 265))	('CIMP', 'Chemical', '-', (290, 294))	('IDH1', 'Gene', (167, 171))	('IDH1', 'Gene', '3417', (245, 249))	('MGMT', 'Gene', '4255', (173, 177))	('MGMT', 'Gene', (173, 177))	('IDH1', 'Gene', '3417', (167, 171))	('higher', 'PosReg', (138, 144))	('non-CIMP', 'Var', (204, 212))	('mRNA levels', 'MPA', (86, 97))
36399	31906036	Since the methylation of the MGMT promoter has been correlated with a favorable TMZ response, we next examined the prognostic significance of H2AFJ in patients receiving radiation therapy combined with or without TMZ treatment and in GBM with or without MGMT methylation using the GSE7696 dataset.	('MGMT', 'Gene', (254, 258))	('H2AFJ', 'Gene', (142, 147))	('examined', 'Reg', (102, 110))	('MGMT', 'Gene', '4255', (29, 33))	('patients', 'Species', '9606', (151, 159))	('MGMT', 'Gene', (29, 33))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('TMZ response', 'MPA', (80, 92))	('TMZ', 'Chemical', 'MESH:D000077204', (213, 216))	('methylation', 'Var', (10, 21))	('GSE7696', 'Chemical', '-', (281, 288))	('MGMT', 'Gene', '4255', (254, 258))	('H2AFJ', 'Gene', '55766', (142, 147))
36414	31906036	Moreover, a luciferase-based reporter assay demonstrated that H2AFJ knockdown reduced but overexpression elevated the transcription factor activities of NF-kappaB (Figure 4J) and STAT3 (Figure 4K) in the tested D54MG and T98G cells, respectively.	('H2AFJ', 'Gene', '55766', (62, 67))	('D54MG', 'CellLine', 'CVCL:5735', (211, 216))	('knockdown', 'Var', (68, 77))	('T98G', 'CellLine', 'CVCL:0556', (221, 225))	('STAT3', 'Gene', '6774', (179, 184))	('reduced', 'NegReg', (78, 85))	('overexpression elevated', 'PosReg', (90, 113))	('NF-kappaB', 'Gene', '4790', (153, 162))	('STAT3', 'Gene', (179, 184))	('H2AFJ', 'Gene', (62, 67))	('NF-kappaB', 'Gene', (153, 162))	('transcription factor activities', 'MPA', (118, 149))
36421	31906036	The Pearson's correlation test against H2AFJ mRNA levels and the IC50 AUC values of deposited compounds showed that the IC50 concentrations of tacedinaline, a selective inhibitor for class I histone deacetylase (HDAC) 1, 2, 3, and 8, and ML029, an inhibitor for NF-kappaB negatively correlates with H2AFJ mRNA levels in a panel of glioma cell lines (Figure 6A,B and Figure S4).	('histone deacetylase', 'Gene', (191, 210))	('negatively', 'NegReg', (272, 282))	('glioma', 'Phenotype', 'HP:0009733', (331, 337))	('H2AFJ', 'Gene', '55766', (39, 44))	('NF-kappaB', 'Gene', '4790', (262, 271))	('glioma', 'Disease', (331, 337))	('H2AFJ', 'Gene', (39, 44))	('HDAC', 'Gene', '9734', (212, 216))	('tacedinaline', 'Chemical', 'MESH:C081895', (143, 155))	('histone deacetylase', 'Gene', '9734', (191, 210))	('ML029', 'Var', (238, 243))	('glioma', 'Disease', 'MESH:D005910', (331, 337))	('NF-kappaB', 'Gene', (262, 271))	('HDAC', 'Gene', (212, 216))	('H2AFJ', 'Gene', '55766', (299, 304))	('correlates', 'Reg', (283, 293))	('ML029', 'Chemical', '-', (238, 243))	('H2AFJ', 'Gene', (299, 304))
36433	31906036	Moreover, artificially silencing H2AFJ sensitized but overexpressing H2AFJ desensitized GBM cells to the cancericidal effect of TMZ.	('H2AFJ', 'Gene', (69, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (128, 131))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('H2AFJ', 'Gene', '55766', (33, 38))	('H2AFJ', 'Gene', (33, 38))	('silencing', 'Var', (23, 32))	('overexpressing', 'PosReg', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('H2AFJ', 'Gene', '55766', (69, 74))	('desensitized', 'NegReg', (75, 87))
36442	31906036	Moreover, we found that H2AFJ knockdown dramatically suppressed IL-6 expression and NF-kappaB activity in GBM cells.	('NF-kappaB', 'Gene', (84, 93))	('IL-6', 'Gene', (64, 68))	('expression', 'MPA', (69, 79))	('IL-6', 'Gene', '3569', (64, 68))	('activity', 'MPA', (94, 102))	('knockdown', 'Var', (30, 39))	('H2AFJ', 'Gene', (24, 29))	('NF-kappaB', 'Gene', '4790', (84, 93))	('suppressed', 'NegReg', (53, 63))	('H2AFJ', 'Gene', '55766', (24, 29))
36446	31906036	In contrast, the inhibition of NF-kappaB by the small molecule inhibitor BAY 11-7082 or by siRNA-mediated gene silencing reduced MGMT levels and thereby sensitized glioma stem-like cells to TMZ treatment.	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('NF-kappaB', 'Gene', (31, 40))	('gene silencing', 'Var', (106, 120))	('TMZ', 'Chemical', 'MESH:D000077204', (190, 193))	('reduced', 'NegReg', (121, 128))	('NF-kappaB', 'Gene', '4790', (31, 40))	('MGMT', 'Gene', (129, 133))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (73, 84))	('MGMT', 'Gene', '4255', (129, 133))	('sensitized', 'Reg', (153, 163))	('inhibition', 'NegReg', (17, 27))	('glioma', 'Disease', (164, 170))
36449	31906036	Moreover, an in silico simulation using Pathway Commons Network Visualizer program demonstrated that the interaction of HDAC3 with H2AFJ may epigenetically regulate the elevation of the IL-6 transcription, thereby enhancing the activity of IL-6/STAT3 signaling axis which subsequently triggers the activation of TNF-alpha/NF-kappaB pathway via elevating the gene expression of TNF-alpha.	('STAT3', 'Gene', (245, 250))	('activation', 'PosReg', (298, 308))	('HDAC3', 'Gene', '8841', (120, 125))	('regulate', 'Reg', (156, 164))	('enhancing', 'PosReg', (214, 223))	('STAT3', 'Gene', '6774', (245, 250))	('IL-6', 'Gene', '3569', (186, 190))	('TNF-alpha', 'Gene', '7124', (312, 321))	('epigenetically', 'Var', (141, 155))	('TNF-alpha', 'Gene', (312, 321))	('IL-6', 'Gene', '3569', (240, 244))	('IL-6', 'Gene', (186, 190))	('TNF-alpha', 'Gene', '7124', (377, 386))	('H2AFJ', 'Gene', '55766', (131, 136))	('NF-kappaB', 'Gene', (322, 331))	('H2AFJ', 'Gene', (131, 136))	('TNF-alpha', 'Gene', (377, 386))	('elevating', 'PosReg', (344, 353))	('IL-6', 'Gene', (240, 244))	('activity', 'MPA', (228, 236))	('interaction', 'Interaction', (105, 116))	('NF-kappaB', 'Gene', '4790', (322, 331))	('HDAC3', 'Gene', (120, 125))	('elevation', 'MPA', (169, 178))	('gene expression', 'MPA', (358, 373))
36456	31906036	Nevertheless, the use of additional genetic brain tumor profiling resources (e.g., longitudinal tumor trajectories) and further experimental validation in diverse genotypic context (IDH1 mutant cell models, etc.)	('IDH1', 'Gene', '3417', (182, 186))	('longitudinal tumor', 'Disease', 'MESH:D017887', (83, 101))	('brain tumor', 'Disease', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('brain tumor', 'Disease', 'MESH:D001932', (44, 55))	('brain tumor', 'Phenotype', 'HP:0030692', (44, 55))	('mutant', 'Var', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('IDH1', 'Gene', (182, 186))	('longitudinal tumor', 'Disease', (83, 101))
36472	31906036	Cells (50% confluence) grown on six-well plates were incubated in fresh media containing 5 mug/mL polybrene (Santa Cruz Biotechnology, Santa Cruz, CA, USA) before infection overnight with a lentiviral viral particle-driven control or candidate gene shRNA at 2-10 multiplicity of infection (MOI).	('polybrene', 'Chemical', 'MESH:D006583', (98, 107))	('polybrene', 'Var', (98, 107))	('shRNA', 'Gene', (249, 254))	('multiplicity of infection', 'Disease', (263, 288))	('multiplicity of infection', 'Disease', 'MESH:D007239', (263, 288))
36501	31205522	TCGA (The Cancer Genome Atlas, https://cancergenome.nih.gov/) data was reviewed to analyze the expression of PTPRZ1 gene and PTPRZ1 gene mutations.	('PTPRZ1', 'Gene', (125, 131))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PTPRZ1', 'Gene', (109, 115))
36505	31205522	The rates of PTPRZ1 gene mutations were different across tumors, and uterine corpus endometrial carcinoma (UCEC) (16.79%) has the highest rate of PTPRZ1 gene mutation, followed by lung adenocarcinoma (LUAD) (12.87%) and skin cutaneous melanoma (SKCM) (12.15%) (Figure 2).	('lung adenocarcinoma', 'Disease', (180, 199))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (84, 105))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('corpus endometrial carcinoma', 'Disease', (77, 105))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (77, 105))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (180, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (220, 243))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('skin cutaneous melanoma', 'Disease', (220, 243))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (138, 141))	('LUAD', 'Phenotype', 'HP:0030078', (201, 205))	('PTPRZ1', 'Gene', (146, 152))	('mutation', 'Var', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (225, 243))
36506	31205522	Fusion genes combine parts of two or more original genes, generating from chromosomal rearrangement or abnormal transcription.	('rat', 'Species', '10116', (62, 65))	('abnormal transcription', 'Var', (103, 125))	('chromosomal rearrangement', 'Var', (74, 99))
36509	31205522	PTPRZ1-MET induces gliomas through elevated expression levels of MET mRNA, preserve fundamental properties of wild-type MET, and enhance phosphorylation.	('MET mRNA', 'MPA', (65, 73))	('fundamental properties', 'MPA', (84, 106))	('induces', 'Reg', (11, 18))	('phosphorylation', 'MPA', (137, 152))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('PTPRZ1-MET', 'Var', (0, 10))	('elevated', 'PosReg', (35, 43))	('expression levels', 'MPA', (44, 61))	('enhance', 'PosReg', (129, 136))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
36512	31205522	Several splice variants of PTPRZ1 have been discovered, including PTPRZ1-A (9.4 kb), a full-length transmembrane receptor form; PTPRZ1-B (6.4 kb), a short transmembrane receptor form with a deletion in the extracellular region; the other two are soluble secreted forms that lack both a transmembrane region and tyrosine phosphatase activity (phosphacan, short (4 kb) and long (8.4 kb; also known as phosphacan, PTPRZ-S)).	('phosphacan', 'Gene', '5803', (342, 352))	('PTPRZ', 'Gene', (27, 32))	('phosphacan', 'Gene', (399, 409))	('PTPRZ', 'Gene', (66, 71))	('PTPRZ', 'Gene', '5803', (66, 71))	('PTPRZ', 'Gene', '5803', (128, 133))	('deletion', 'Var', (190, 198))	('PTPRZ', 'Gene', (128, 133))	('phosphacan', 'Gene', '5803', (399, 409))	('PTPRZ', 'Gene', '5803', (411, 416))	('tyrosine', 'Chemical', 'MESH:D014443', (311, 319))	('PTPRZ', 'Gene', '5803', (27, 32))	('PTPRZ', 'Gene', (411, 416))	('phosphacan', 'Gene', (342, 352))
36519	31205522	PTPRZ1-PTN interaction results in accumulation of tyrosine phosphorylation of multiple downstream proteins including SRC kinase, calmodulin, anaplastic lymphoma kinase (ALK), GIT1/Cat1, beta-catenin, beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP, which in turn have been related to activation of multiple pro-tumorigenic signaling cascades.	('beta-adducin', 'Gene', (200, 212))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	('Fyn', 'Gene', '2534', (214, 217))	('GIT1', 'Gene', (175, 179))	('GIT1', 'Gene', '850462', (219, 223))	('Cat-1', 'Species', '717647', (224, 229))	('ALK', 'Gene', '238', (169, 172))	('accumulation', 'PosReg', (34, 46))	('P190RhoGAP', 'Gene', '2909', (235, 245))	('tyrosine phosphorylation', 'MPA', (50, 74))	('ALK', 'Gene', (169, 172))	('SRC', 'Gene', '6714', (117, 120))	('calmodulin', 'MPA', (129, 139))	('beta-adducin', 'Gene', '119', (200, 212))	('tumor', 'Disease', (309, 314))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (141, 160))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (141, 160))	('SRC', 'Gene', (117, 120))	('interaction', 'Var', (11, 22))	('GIT1', 'Gene', '850462', (175, 179))	('Cat1', 'Species', '717647', (180, 184))	('Fyn', 'Gene', (214, 217))	('GIT1', 'Gene', (219, 223))	('PTPRZ1-PTN', 'Gene', (0, 10))	('beta-catenin', 'Gene', (186, 198))	('P190RhoGAP', 'Gene', (235, 245))	('beta-catenin', 'Gene', '1499', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('anaplastic lymphoma', 'Disease', (141, 160))
36525	31205522	PTN has been shown to activate both the mitogen- activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)-Akt signaling axes, and inhibitors of Erk1/2 or PI3K inhibit DNA synthesis stimulated by PTN.	('phosphatidylinositol 3-kinase', 'Gene', '5295', (89, 118))	('Erk1/2', 'Gene', '5595;5594', (164, 170))	('DNA synthesis', 'MPA', (187, 200))	('Erk1/2', 'Gene', (164, 170))	('inhibitors', 'Var', (150, 160))	('Akt', 'Gene', '207', (126, 129))	('activate', 'PosReg', (22, 30))	('phosphatidylinositol 3-kinase', 'Gene', (89, 118))	('inhibit', 'NegReg', (179, 186))	('Akt', 'Gene', (126, 129))
36541	31205522	found PTPRZ1 inhibition also potentiated GSK3beta-regulated beta-catenin translocation and two pools of beta-catenin, which are regulated by PTPRZ1 and GSK3beta are partially but incompletely overlapping, with GSK3beta appearing to regulate beta-catenin availability beyond that influenced by PTPRZ1.	('PTPRZ1', 'Gene', (6, 12))	('GSK3beta', 'Gene', '2932', (210, 218))	('GSK3beta', 'Gene', '2932', (41, 49))	('GSK3beta', 'Gene', (152, 160))	('beta-catenin', 'Gene', (104, 116))	('beta-catenin', 'Gene', (241, 253))	('beta-catenin', 'Gene', '1499', (104, 116))	('inhibition', 'Var', (13, 23))	('potentiated', 'PosReg', (29, 40))	('GSK3beta', 'Gene', '2932', (152, 160))	('beta-catenin', 'Gene', '1499', (241, 253))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('GSK3beta', 'Gene', (41, 49))	('GSK3beta', 'Gene', (210, 218))
36565	31205522	PTPRZ1 gene knockdown increased the ability of human prostate cancer cells to migrate and invade in vitro and to metastasize in vivo .	('PTPRZ1', 'Gene', (0, 6))	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('rat', 'Species', '10116', (81, 84))	('knockdown', 'Var', (12, 21))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('increased', 'PosReg', (22, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('metastasize', 'CPA', (113, 124))	('human', 'Species', '9606', (47, 52))
36566	31205522	PTPRZ1 gene knockdown interrupts hydrogen peroxide-induced cell migration and PTPRZ1 gene knockdown in human umbilical vein endothelial cells (HUVEC) inhibited PTN-induced migration and tube formation on matrigel.	('PTPRZ1', 'Gene', (0, 6))	('tube formation on matrigel', 'CPA', (186, 212))	('interrupts', 'NegReg', (22, 32))	('rat', 'Species', '10116', (67, 70))	('hydrogen peroxide-induced', 'MPA', (33, 58))	('knockdown', 'Var', (90, 99))	('human', 'Species', '9606', (103, 108))	('inhibited', 'NegReg', (150, 159))	('cell migration', 'CPA', (59, 73))	('PTPRZ1', 'Gene', (78, 84))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (33, 50))	('rat', 'Species', '10116', (175, 178))
36571	31205522	In prostate cancer, the loss of PTPRZ1 gene expression initiated EMT and increased the ability of the cells to migrate and invade.	('loss', 'Var', (24, 28))	('increased', 'PosReg', (73, 82))	('EMT', 'CPA', (65, 68))	('rat', 'Species', '10116', (114, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('PTPRZ1', 'Gene', (32, 38))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('initiated', 'PosReg', (55, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
36573	31205522	Tumor-associated macrophages (TAMs) secrete abundant PTN to stimulate glioma stem cells (GSCs) through PTPRZ1 thus promoting GBM malignant growth, and disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential.	('PTPRZ1', 'Gene', (103, 109))	('tumor', 'Disease', (199, 204))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioma', 'Disease', (70, 76))	('promoting', 'PosReg', (115, 124))	('disrupting', 'Var', (151, 161))	('stimulate', 'PosReg', (60, 69))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('abrogated', 'NegReg', (169, 178))	('PTPRZ1', 'Gene', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('GBM malignant growth', 'CPA', (125, 145))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('GSC maintenance', 'CPA', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
36574	31205522	Knocking down PTPRZ1 gene altered the expression levels of SOX2, OLIG2, and POU3F2 and decreased the sphere- forming abilities in glioblastoma cells.	('expression levels', 'MPA', (38, 55))	('glioblastoma', 'Disease', (130, 142))	('PTPRZ1', 'Gene', (14, 20))	('decreased', 'NegReg', (87, 96))	('POU3F2', 'Gene', '5454', (76, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('POU3F2', 'Gene', (76, 82))	('OLIG2', 'Gene', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('SOX2', 'Gene', '6657', (59, 63))	('altered', 'Reg', (26, 33))	('OLIG2', 'Gene', '10215', (65, 70))	('SOX2', 'Gene', (59, 63))	('Knocking', 'Var', (0, 8))
36575	31205522	Another study found the knockdown of PTPRZ1 gene led to reduction of OCT4 and SOX2 transcripts by approximately 40%.	('OCT4', 'Gene', (69, 73))	('PTPRZ1', 'Gene', (37, 43))	('SOX2', 'Gene', '6657', (78, 82))	('SOX2', 'Gene', (78, 82))	('reduction', 'NegReg', (56, 65))	('knockdown', 'Var', (24, 33))	('OCT4', 'Gene', '5460', (69, 73))
36576	31205522	OCT4 knockdown also resulted in 90% decrease of PTPRZ1 gene transcripts, consistent with the marked decrease of PTPRZ1 in differentiating embryonic stem cells.	('PTPRZ1 gene', 'Gene', (48, 59))	('knockdown', 'Var', (5, 14))	('transcripts', 'MPA', (60, 71))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))	('decrease', 'NegReg', (36, 44))
36583	31205522	Ectopic menin expression significantly repressed PTN transcription, and indirectly inhibited PTPRZ1 expression through repressing PTN expression, and further inhibits FAK and ERK1/2 phosphorylation.	('expression', 'Var', (14, 24))	('PTN expression', 'MPA', (130, 144))	('menin', 'Gene', '4221', (8, 13))	('inhibits', 'NegReg', (158, 166))	('PTN transcription', 'MPA', (49, 66))	('PTPRZ1', 'Gene', (93, 99))	('FAK', 'Gene', '5747', (167, 170))	('menin', 'Gene', (8, 13))	('inhibited', 'NegReg', (83, 92))	('repressed', 'NegReg', (39, 48))	('expression', 'MPA', (100, 110))	('FAK', 'Gene', (167, 170))	('repressing', 'NegReg', (119, 129))	('Ectopic', 'Var', (0, 7))	('ERK1/2', 'Gene', (175, 181))	('ERK1/2', 'Gene', '5595;5594', (175, 181))
36586	31205522	identified several other substrates: Git1, p190, PIST, MAGI-3, Veli-3, Synj2bp, Syntrophin acidic1, Syntrophin basic1, MUPP1, Cardiac troponin T, hDKFZp434G232, KIAA0167, SPOP by a genetic method named the ''yeast substrate-trapping system''.	('Synj2bp', 'Var', (71, 78))	('MAGI-3', 'Gene', (55, 61))	('PIST', 'Gene', '57120', (49, 53))	('p190', 'Var', (43, 47))	('rat', 'Species', '10116', (30, 33))	('PIST', 'Gene', (49, 53))	('MAGI-3', 'Gene', '260425', (55, 61))	('rat', 'Species', '10116', (219, 222))	('Cardiac troponin', 'MPA', (126, 142))	('yeast', 'Species', '4932', (208, 213))
36589	31205522	High PTPRZ1 gene expression might be associated with better OS in BRCA, CESC, LUAD, PAAD, and SKCM, and low PTPRZ1 expression might be associated with better OS in BLCA, COAD, GBM, LGG, LIHC.	('LIHC', 'Disease', (186, 190))	('associated', 'Reg', (135, 145))	('low', 'NegReg', (104, 107))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('High', 'Var', (0, 4))	('LIHC', 'Disease', 'None', (186, 190))	('expression', 'MPA', (17, 27))	('GBM', 'Disease', (176, 179))	('better OS', 'Disease', (151, 160))	('associated', 'Reg', (37, 47))	('BLCA', 'Disease', (164, 168))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('CESC', 'Disease', (72, 76))	('COAD', 'Disease', 'MESH:D029424', (170, 174))	('LGG', 'Disease', (181, 184))	('PTPRZ1', 'Gene', (108, 114))	('BRCA', 'Gene', '672', (66, 70))	('PTPRZ1', 'Gene', (5, 11))	('LUAD', 'Disease', (78, 82))	('PAAD', 'Phenotype', 'HP:0006725', (84, 88))	('BRCA', 'Gene', (66, 70))	('expression', 'MPA', (115, 125))	('COAD', 'Disease', (170, 174))
36591	31205522	In human breast cancer, high expression of PTPRZ1 may be an independent risk indicator for triple- negative breast cancer (TNBC) recurrence and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TNBC', 'Disease', 'None', (123, 127))	('PTPRZ1', 'Gene', (43, 49))	('high expression', 'Var', (24, 39))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Disease', (9, 22))	('TNBC', 'Disease', (123, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
36592	31205522	PTPRZ1 has a significant impact on survival of patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1.	('positive', 'Var', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('death', 'Disease', 'MESH:D003643', (167, 172))	('patients', 'Species', '9606', (95, 103))	('death', 'Disease', (167, 172))	('PTPRZ1', 'Gene', (118, 124))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (47, 55))	('impact', 'Reg', (25, 31))	('lower', 'NegReg', (153, 158))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
36595	31205522	identified NAZ2329, a cell-permeable small molecule that allosterically inhibits PTPRZ1, which reduced the expression of SOX2 and abrogated the sphere-forming abilities in glioblastoma cells.	('SOX2', 'Gene', (121, 125))	('SOX2', 'Gene', '6657', (121, 125))	('NAZ2329', 'Chemical', '-', (11, 18))	('expression', 'MPA', (107, 117))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('inhibits', 'NegReg', (72, 80))	('abrogated', 'NegReg', (130, 139))	('PTPRZ1', 'Gene', (81, 87))	('glioblastoma', 'Disease', (172, 184))	('reduced', 'NegReg', (95, 102))	('NAZ2329', 'Var', (11, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
36599	31205522	showed the intracellular delivery of SCB4380, the first potent inhibitor for PTPRZ1, by liposome carriers inhibited PTPRZ1 activity in glioblastoma cells, and thereby suppressed cell migration and proliferation in vitro and tumor growth in a rat allograft model.	('suppressed', 'NegReg', (167, 177))	('cell migration', 'CPA', (178, 192))	('SCB4380', 'Var', (37, 44))	('rat', 'Species', '10116', (242, 245))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('rat', 'Species', '10116', (186, 189))	('rat', 'Species', '10116', (204, 207))	('inhibited', 'NegReg', (106, 115))	('tumor', 'Disease', (224, 229))	('SCB4380', 'Chemical', '-', (37, 44))	('PTPRZ1', 'Gene', (77, 83))	('PTPRZ1', 'Gene', (116, 122))	('glioblastoma', 'Disease', (135, 147))	('activity', 'MPA', (123, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
36603	31205522	Given the strong up-regulation of PTPRZ1, antagonization of PTPRZ1 expression and/or signaling may be a promising strategy to inhibit the tumor growth.	('tumor', 'Disease', (138, 143))	('PTPRZ1', 'Gene', (34, 40))	('inhibit', 'NegReg', (126, 133))	('rat', 'Species', '10116', (116, 119))	('PTPRZ1', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('antagonization', 'Var', (42, 56))	('up-regulation', 'PosReg', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
36609	31205522	PTPRZ1 gene mutation accounts for a high proportion of cancer patients, especially in UCEC, the proportion could be up to 16.79%.	('PTPRZ1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutation', 'Var', (12, 20))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Disease', (55, 61))	('UCEC', 'Disease', (86, 90))
36610	31205522	Such a high proportion of cancer patients have PTPRZ1 mutations, so whether PTPRZ1 mutations could predict therapy efficacy or not deserved further research.	('patients', 'Species', '9606', (33, 41))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (54, 63))	('PTPRZ1', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
36613	31205522	In the future, the value of PTPRZ1 gene mutation in cancer therapy deserved to be researched and drugs that target patients with PTPRZ1 mutations were studied in literature.	('mutation', 'Var', (40, 48))	('PTPRZ1', 'Gene', (28, 34))	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rat', 'Species', '10116', (166, 169))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
36614	31205522	Tumors from patients harboring PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy and have significantly compromised overall survival rates.	('temozolomide', 'Chemical', 'MESH:D000077204', (78, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('patients', 'Species', '9606', (12, 20))	('PTPRZ1-MET-fused', 'Var', (31, 47))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('compromised', 'NegReg', (122, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('overall', 'MPA', (134, 141))	('rat', 'Species', '10116', (151, 154))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('resistant to temozolomide therapy', 'MPA', (65, 98))
36624	31205522	Our previous study showed high expression of PTPRZ1 may be an independent risk indicator for triple negative breast cancer recurrence and metastasis.	('PTPRZ1', 'Gene', (45, 51))	('metastasis', 'CPA', (138, 148))	('high expression', 'Var', (26, 41))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
36625	31205522	PTPRZ1 has a significant impact on survival in patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1.	('positive', 'Var', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('death', 'Disease', 'MESH:D003643', (167, 172))	('patients', 'Species', '9606', (95, 103))	('death', 'Disease', (167, 172))	('PTPRZ1', 'Gene', (118, 124))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (47, 55))	('impact', 'Reg', (25, 31))	('lower', 'NegReg', (153, 158))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
36628	31205522	Future studies should screen drugs for patients with PTPRZ1 gene mutations, PTPRZ1 fusion genes, and PTPRZ1 protein positivity.	('PTPRZ1', 'Gene', (76, 82))	('patients', 'Species', '9606', (39, 47))	('PTPRZ1', 'Gene', (53, 59))	('mutations', 'Var', (65, 74))
36629	31205522	Second, pharmacological inhibition or activation of PTPRZ1 is a promising strategy for the treatment of several tumors.	('activation', 'Var', (38, 48))	('rat', 'Species', '10116', (76, 79))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('PTPRZ1', 'Gene', (52, 58))
36647	30936423	In addition, our data also showed that NAF1 depletion could trigger ribosome stress, not only impairing ribosomal biosynthesis but also reactivating p53 signaling via blocking MDM2.	('ribosomal biosynthesis', 'MPA', (104, 126))	('p53', 'Gene', (149, 152))	('reactivating', 'Reg', (136, 148))	('impairing', 'NegReg', (94, 103))	('depletion', 'Var', (44, 53))	('p53', 'Gene', '7157', (149, 152))	('MDM2', 'Gene', (176, 180))	('blocking', 'NegReg', (167, 175))	('MDM2', 'Gene', '4193', (176, 180))	('NAF1', 'Gene', (39, 43))
36655	30936423	Mutations in ribosome biogenesis are connected to several human ribosomal genetic diseases, including inherited bone marrow failure syndromes.	('human', 'Species', '9606', (58, 63))	('connected', 'Reg', (37, 46))	('bone marrow failure syndromes', 'Disease', (112, 141))	('bone marrow failure', 'Phenotype', 'HP:0005528', (112, 131))	('bone marrow failure syndromes', 'Disease', 'MESH:D000080983', (112, 141))	('Mutations', 'Var', (0, 9))	('genetic diseases', 'Disease', 'MESH:D030342', (74, 90))	('genetic diseases', 'Disease', (74, 90))	('ribosome biogenesis', 'Gene', (13, 32))
36656	30936423	In addition, the dysregulation of ribosomal may also be linked to muscle wasting.	('muscle wasting', 'Disease', 'MESH:D009133', (66, 80))	('linked', 'Reg', (56, 62))	('muscle wasting', 'Disease', (66, 80))	('dysregulation', 'Var', (17, 30))	('muscle wasting', 'Phenotype', 'HP:0003202', (66, 80))	('ribosomal', 'Protein', (34, 43))
36663	30936423	Moreover, there is also evidence showing that single nucleotide polymorphisms (SNPs) in NAF1 are associated with cancer risk probably through affecting telomere length; however, to our knowledge, no studies are available to define its role in human cancers, especially in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (272, 279))	('human', 'Species', '9606', (243, 248))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancers', 'Disease', (249, 256))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (249, 255))	('NAF1', 'Gene', (88, 92))	('associated', 'Reg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gliomas', 'Disease', (272, 279))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('telomere length', 'MPA', (152, 167))	('gliomas', 'Disease', 'MESH:D005910', (272, 279))	('single nucleotide polymorphisms', 'Var', (46, 77))	('affecting', 'Reg', (142, 151))
36670	30936423	As shown in Supplementary Table S1, NAF1 expression was significantly downregulated in the patients with LGGs (P = 0.005) and ATRX mutations (P = 0.001) compared to those with GBMs and wild-type ATRX, while was obviously associated with poor patient survival (P = 0.006).	('mutations', 'Var', (131, 140))	('GBMs', 'Phenotype', 'HP:0012174', (176, 180))	('LGGs', 'Gene', (105, 109))	('patients', 'Species', '9606', (91, 99))	('ATRX', 'Gene', (195, 199))	('expression', 'MPA', (41, 51))	('ATRX', 'Gene', (126, 130))	('downregulated', 'NegReg', (70, 83))	('ATRX', 'Gene', '546', (195, 199))	('NAF1', 'Gene', (36, 40))	('patient', 'Species', '9606', (242, 249))	('ATRX', 'Gene', '546', (126, 130))	('patient', 'Species', '9606', (91, 98))
36671	30936423	This was supported by the previous studies that glioma patients with LGGs and ATRX mutations generally had better prognosis than those with GBMs and wild-type ATRX.	('mutations', 'Var', (83, 92))	('ATRX', 'Gene', (78, 82))	('ATRX', 'Gene', '546', (159, 163))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('ATRX', 'Gene', '546', (78, 82))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('better', 'PosReg', (107, 113))	('patients', 'Species', '9606', (55, 63))	('ATRX', 'Gene', (159, 163))	('GBMs', 'Phenotype', 'HP:0012174', (140, 144))	('LGGs', 'Gene', (69, 73))	('glioma', 'Disease', (48, 54))
36675	30936423	In addition, the results showed that knocking down c-Myc and NRF2 in SF295 and U87 cells dramatically decreased mRNA and protein expression of NAF1 compared to the controls (Fig.	('c-Myc', 'Gene', '4609', (51, 56))	('SF295', 'CellLine', 'CVCL:1690', (69, 74))	('c-Myc', 'Gene', (51, 56))	('NRF2', 'Gene', '4780', (61, 65))	('knocking down', 'Var', (37, 50))	('NRF2', 'Gene', (61, 65))	('decreased', 'NegReg', (102, 111))	('NAF1', 'Gene', (143, 147))
36680	30936423	The results indicated that ectopic expression of c-Myc and NRF2 were able to dramatically increase promoter activity of NAF1 compared to the controls (Fig.	('c-Myc', 'Gene', '4609', (49, 54))	('NAF1', 'Gene', (120, 124))	('NRF2', 'Gene', (59, 63))	('increase', 'PosReg', (90, 98))	('c-Myc', 'Gene', (49, 54))	('promoter activity', 'MPA', (99, 116))	('ectopic expression', 'Var', (27, 45))	('NRF2', 'Gene', '4780', (59, 63))
36683	30936423	As expected, compared to control cells, all four fragments within NAF1 promoter (P1: -100/-26; P2: -519/-410; P3: -981/-543; P4: -1648/-1551) were strongly enriched in cells expressing c-Myc (Fig.	('c-Myc', 'Gene', (185, 190))	('c-Myc', 'Gene', '4609', (185, 190))	('enriched', 'Reg', (156, 164))	('P4: -1648/-1551', 'Var', (125, 140))
36686	30936423	In recent years, TERT promoter mutations have been frequently discovered in human cancers particularly in GBMs.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (31, 40))	('GBMs', 'Disease', (106, 110))	('TERT', 'Gene', (17, 21))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('TERT', 'Gene', '7015', (17, 21))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('GBMs', 'Phenotype', 'HP:0012174', (106, 110))	('discovered', 'Reg', (62, 72))
36690	30936423	The results showed that knocking down TERT in SF295 and U87 cells significantly downregulated NAF1 expression, while ectopic expression of TERT in these two cell lines dramatically upregulated NAF1 expression at both protein and mRNA levels (Supplementary Fig.	('expression', 'MPA', (99, 109))	('knocking down', 'Var', (24, 37))	('TERT', 'Gene', '7015', (139, 143))	('TERT', 'Gene', (38, 42))	('SF295', 'CellLine', 'CVCL:1690', (46, 51))	('upregulated', 'PosReg', (181, 192))	('NAF1', 'Gene', (193, 197))	('NAF1', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (38, 42))	('downregulated', 'NegReg', (80, 93))	('expression', 'MPA', (198, 208))	('TERT', 'Gene', (139, 143))
36694	30936423	First, we validated inhibition efficiency of two different siRNAs targeting NAF1 (si-NAF1-654 and si-NAF1-927) in SF295 and U87 cells by qRT-PCR and western blot assays (Supplementary Fig.	('siRNAs', 'Enzyme', (59, 65))	('SF295', 'CellLine', 'CVCL:1690', (114, 119))	('si-NAF1-654', 'Var', (82, 93))	('inhibition', 'NegReg', (20, 30))	('si-NAF1-927', 'Var', (98, 109))
36695	30936423	Next, we assessed the effect of NAF1 knockdown on glioma cell growth in vitro, and found that the proliferation of SF295 and U87 cells was significantly inhibited upon siRNA-mediated NAF1 knockdown compared to the controls (Fig.	('SF295', 'CellLine', 'CVCL:1690', (115, 120))	('NAF1', 'Gene', (183, 187))	('glioma', 'Disease', (50, 56))	('knockdown', 'Var', (188, 197))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('proliferation', 'CPA', (98, 111))	('inhibited', 'NegReg', (153, 162))
36699	30936423	The results showed that NAF1 knockdown dramatically inhibited migration and invasion potential of glioma cells relative to control cells (Fig.	('knockdown', 'Var', (29, 38))	('NAF1', 'Gene', (24, 28))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('inhibited', 'NegReg', (52, 61))	('glioma', 'Disease', (98, 104))
36703	30936423	Moreover, alterations in ribosome biogenesis have been demonstrated to contribute to tumor initiation and progression.	('tumor initiation', 'Disease', (85, 101))	('alterations', 'Var', (10, 21))	('contribute', 'Reg', (71, 81))	('progression', 'CPA', (106, 117))	('tumor initiation', 'Disease', 'MESH:D009369', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ribosome biogenesis', 'MPA', (25, 44))
36714	30936423	Conversely, ectopic expression of NAF1 in SF295 and U87 cells dramatically increased U17 levels and decreased the levels of unprocessed 18S rRNA (Fig.	('NAF1', 'Gene', (34, 38))	('SF295', 'CellLine', 'CVCL:1690', (42, 47))	('levels of unprocessed 18S rRNA', 'MPA', (114, 144))	('ectopic expression', 'Var', (12, 30))	('U17 levels', 'MPA', (85, 95))	('decreased', 'NegReg', (100, 109))	('increased', 'PosReg', (75, 84))
36716	30936423	To determine whether aberrant expression of NAF1 in glioma cells can perturb the accumulation of ribosomal 40S subunits, we performed the sucrose gradient centrifugation.	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('aberrant expression', 'Var', (21, 40))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('sucrose', 'Chemical', 'MESH:D013395', (138, 145))	('perturb', 'Reg', (69, 76))	('glioma', 'Disease', (52, 58))	('NAF1', 'Gene', (44, 48))	('accumulation of ribosomal 40S subunits', 'MPA', (81, 119))
36718	30936423	4f, relative to the control, we discovered that overexpression of NAF1 obviously increased global protein concentration, while NAF1 knockdown decreased global protein levels when total proteins of the same numbers of SF295 cells were extracted and run the PAGE-silver staining assay.	('NAF1', 'Gene', (127, 131))	('silver', 'Chemical', 'MESH:D012834', (261, 267))	('SF295', 'CellLine', 'CVCL:1690', (217, 222))	('knockdown', 'Var', (132, 141))	('decreased', 'NegReg', (142, 151))	('global protein levels', 'MPA', (152, 173))	('NAF1', 'Gene', (66, 70))	('overexpression', 'PosReg', (48, 62))	('global protein concentration', 'MPA', (91, 119))	('increased', 'PosReg', (81, 90))
36720	30936423	The result showed that the NAF1 knockdown in SF295 cells evidently inhibited protein synthesis of exogenous GFP, while ectopic expression of NAF1 increased the levels of exogenous GFP compared to the controls (Fig.	('inhibited', 'NegReg', (67, 76))	('NAF1', 'Gene', (27, 31))	('increased', 'PosReg', (146, 155))	('SF295', 'CellLine', 'CVCL:1690', (45, 50))	('knockdown', 'Var', (32, 41))	('levels', 'MPA', (160, 166))	('protein synthesis of exogenous GFP', 'MPA', (77, 111))	('NAF1', 'Gene', (141, 145))
36722	30936423	4i, NAF1 knockdown in SF295 cells exhibited weaker fluorescence intensity, indicating a decreased ability of protein synthesis, while NAF1 re-expression exhibited brighter fluorescence intensity, indicating an enhanced ability of protein synthesis.	('NAF1', 'Gene', (134, 138))	('knockdown', 'Var', (9, 18))	('NAF1', 'Gene', (4, 8))	('enhanced', 'PosReg', (210, 218))	('protein synthesis', 'MPA', (109, 126))	('weaker', 'NegReg', (44, 50))	('fluorescence intensity', 'MPA', (172, 194))	('fluorescence intensity', 'MPA', (51, 73))	('decreased', 'NegReg', (88, 97))	('brighter', 'PosReg', (163, 171))	('protein synthesis', 'MPA', (230, 247))	('SF295', 'CellLine', 'CVCL:1690', (22, 27))
36724	30936423	Thus, we suppose that aberrant expression of NAF1 will impact the translation of key molecules in malignant progression of gliomas such as c-Myc, NRF2, and TERT, which have been demonstrated to regulated NAF1 transcription as mentioned above.	('aberrant expression', 'Var', (22, 41))	('NRF2', 'Gene', '4780', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('NAF1', 'Gene', (45, 49))	('malignant progression', 'CPA', (98, 119))	('translation of key molecules', 'MPA', (66, 94))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('c-Myc', 'Gene', '4609', (139, 144))	('NRF2', 'Gene', (146, 150))	('gliomas', 'Disease', (123, 130))	('c-Myc', 'Gene', (139, 144))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('NAF1', 'Gene', (204, 208))	('impact', 'Reg', (55, 61))	('TERT', 'Gene', (156, 160))	('TERT', 'Gene', '7015', (156, 160))
36725	30936423	Indeed, we found that NAF1 depletion in SF295 and U87 cells dramatically decreased protein levels of c-Myc, NRF2, and TERT (Fig.	('TERT', 'Gene', '7015', (118, 122))	('decreased', 'NegReg', (73, 82))	('NRF2', 'Gene', (108, 112))	('c-Myc', 'Gene', '4609', (101, 106))	('c-Myc', 'Gene', (101, 106))	('depletion', 'Var', (27, 36))	('SF295', 'CellLine', 'CVCL:1690', (40, 45))	('NAF1', 'Gene', (22, 26))	('NRF2', 'Gene', '4780', (108, 112))	('TERT', 'Gene', (118, 122))	('protein levels', 'MPA', (83, 97))
36726	30936423	However, we surprisingly found that knockdown or ectopic expression of NAF1 in glioma cells also impacted mRNA levels of c-Myc, NRF2, and TERT (Fig.	('c-Myc', 'Gene', '4609', (121, 126))	('glioma', 'Disease', (79, 85))	('NRF2', 'Gene', (128, 132))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('impacted', 'Reg', (97, 105))	('knockdown', 'Var', (36, 45))	('c-Myc', 'Gene', (121, 126))	('TERT', 'Gene', (138, 142))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('NRF2', 'Gene', '4780', (128, 132))	('TERT', 'Gene', '7015', (138, 142))	('ectopic expression', 'Var', (49, 67))	('NAF1', 'Gene', (71, 75))
36728	30936423	5e, NAF1 knockdown dramatically decreased protein levels of the core subunit of RNA pol I, POLR1A, and the key subunit of RNA pol II, POLR2A, in SF295 and U87 cells.	('POLR1A', 'Gene', (91, 97))	('POLR2A', 'Gene', '5430', (134, 140))	('NAF1', 'Gene', (4, 8))	('knockdown', 'Var', (9, 18))	('SF295', 'CellLine', 'CVCL:1690', (145, 150))	('POLR2A', 'Gene', (134, 140))	('protein levels', 'MPA', (42, 56))	('POLR1A', 'Gene', '25885', (91, 97))	('decreased', 'NegReg', (32, 41))
36733	30936423	Aberrant telomere length has been considered as one of the hallmarks for cell proliferation and human cancers, including glioma.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (96, 101))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('glioma', 'Disease', (121, 127))
36738	30936423	S8a, b), while ectopic expression of NAF1 elevated the levels of TERC and lengthened telomere length (Supplementary Fig.	('ectopic expression', 'Var', (15, 33))	('lengthened', 'PosReg', (74, 84))	('telomere length', 'MPA', (85, 100))	('TERC', 'Gene', (65, 69))	('elevated', 'PosReg', (42, 50))	('TERC', 'Gene', '7012', (65, 69))	('NAF1', 'Gene', (37, 41))
36742	30936423	Thus, we speculate that NAF1 depletion in glioma cells may result in nucleolar/ribosomal stress.	('depletion', 'Var', (29, 38))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('NAF1', 'Gene', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('nucleolar/ribosomal stress', 'MPA', (69, 95))	('result in', 'Reg', (59, 68))	('glioma', 'Disease', (42, 48))
36743	30936423	Given that SF295 and U251 cells harbor mutant p53 (https://cancer.sanger.ac.uk/cosmic), thus we chose U87 and SHG44 cells carrying wild-type p53 for the following studies.	('SF295', 'CellLine', 'CVCL:1690', (11, 16))	('p53', 'Gene', '7157', (141, 144))	('p53', 'Gene', (141, 144))	('p53', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('p53', 'Gene', '7157', (46, 49))	('mutant', 'Var', (39, 45))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
36744	30936423	Expectedly, NAF1 knockdown in U87 and SHG44 cells clearly decreased MDM2 expression, and subsequently elevated p53 expression (Fig.	('MDM2', 'Gene', '4193', (68, 72))	('knockdown', 'Var', (17, 26))	('MDM2', 'Gene', (68, 72))	('elevated', 'PosReg', (102, 110))	('p53', 'Gene', (111, 114))	('decreased', 'NegReg', (58, 67))	('p53', 'Gene', '7157', (111, 114))	('expression', 'MPA', (73, 83))	('NAF1', 'Gene', (12, 16))
36745	30936423	Meanwhile, NAF1 depletion also decreased the expression of ribosome small subunit RPS14 and nucleophosmin NPM1 in these two cell lines (Fig.	('RPS14', 'Gene', (82, 87))	('RPS14', 'Gene', '6208', (82, 87))	('depletion', 'Var', (16, 25))	('decreased', 'NegReg', (31, 40))	('NPM1', 'Gene', (106, 110))	('expression', 'MPA', (45, 55))	('NPM1', 'Gene', '4869', (106, 110))
36747	30936423	By western blot and immunofluorescence assays, we found that NAF1 knockdown caused RPS14 and NPM1 translocating from nucleolus to nucleoplasm (Fig.	('NAF1', 'Gene', (61, 65))	('NPM1', 'Gene', '4869', (93, 97))	('translocating', 'MPA', (98, 111))	('RPS14', 'Gene', (83, 88))	('RPS14', 'Gene', '6208', (83, 88))	('knockdown', 'Var', (66, 75))	('NPM1', 'Gene', (93, 97))
36750	30936423	The results showed that xenograft tumors induced by U87 cells stably knocking down NAF1 grew slowly and exhibited a dramatic reduction of tumor volume and weight relative to control tumors (Fig.	('reduction', 'NegReg', (125, 134))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('slowly', 'NegReg', (93, 99))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('knocking down', 'Var', (69, 82))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('xenograft tumors', 'Disease', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (34, 40))	('xenograft tumors', 'Disease', 'MESH:D009369', (24, 40))	('tumor', 'Disease', (182, 187))	('NAF1', 'Gene', (83, 87))	('grew', 'CPA', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
36753	30936423	S9, we found a lower percentage of Ki-67-positive cells in the tumors stably knocking down NAF1, while an increased number of Ki-67 cells in the tumors stably expressing NAF1 compared to control tumors.	('NAF1', 'Gene', (91, 95))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('knocking down', 'Var', (77, 90))
36755	30936423	Using western blot analysis, we found that the protein level of NAF1 was dramatically decreased in the tumors stably knocking down NAF1 relative to control tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('knocking down', 'Var', (117, 130))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('decreased', 'NegReg', (86, 95))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('NAF1', 'Gene', (131, 135))	('tumors', 'Disease', (156, 162))	('protein level', 'MPA', (47, 60))
36759	30936423	During ribosome biogenesis, high expression of NAF1 enhances the assembly of 40S subunits and protein synthesis ability through increasing the levels of U17 snoRNA and accelerating 18S rRNA maturation in gliomas cells.	('protein synthesis', 'CPA', (94, 111))	('levels', 'MPA', (143, 149))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('assembly', 'MPA', (65, 73))	('accelerating', 'PosReg', (168, 180))	('snoRNA', 'Gene', (157, 163))	('high expression', 'Var', (28, 43))	('snoRNA', 'Gene', '85388', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('increasing', 'PosReg', (128, 138))	('18S rRNA maturation', 'MPA', (181, 200))	('enhances', 'PosReg', (52, 60))	('NAF1', 'Gene', (47, 51))
36769	30936423	Second, we discovered that NAF1 depletion in glioma cells significantly inhibited cell proliferation, colony formation, migration, invasion, and tumorigenic ability in nude mice, and induced cell apoptosis.	('cell apoptosis', 'CPA', (191, 205))	('invasion', 'CPA', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('NAF1', 'Gene', (27, 31))	('depletion', 'Var', (32, 41))	('cell proliferation', 'CPA', (82, 100))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('colony formation', 'CPA', (102, 118))	('tumor', 'Disease', (145, 150))	('migration', 'CPA', (120, 129))	('inhibited', 'NegReg', (72, 81))	('nude mice', 'Species', '10090', (168, 177))	('induced', 'Reg', (183, 190))	('glioma', 'Disease', (45, 51))
36770	30936423	Conversely, ectopic expression of NAF1 obviously enhanced malignant phenotypes of glioma cells, indicating that NAF1 is a functional oncogene in gliomas.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Disease', (145, 151))	('NAF1', 'Gene', (34, 38))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('ectopic expression', 'Var', (12, 30))	('enhanced', 'PosReg', (49, 57))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('glioma', 'Disease', (82, 88))	('gliomas', 'Disease', (145, 152))
36772	30936423	Our data showed that NAF1 expressions were decreased upon c-Myc or NRF2 knockdown in glioma cells, while the mRNA and protein levels of NAF1 were increased upon overexpression of c-Myc or NRF2, suggesting that NAF1 may be a potential target of c-Myc and NRF2.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('c-Myc', 'Gene', (58, 63))	('NRF2', 'Gene', '4780', (67, 71))	('c-Myc', 'Gene', '4609', (58, 63))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('increased', 'PosReg', (146, 155))	('NRF2', 'Gene', (67, 71))	('NRF2', 'Gene', '4780', (254, 258))	('c-Myc', 'Gene', (244, 249))	('NAF1', 'Gene', (21, 25))	('NRF2', 'Gene', '4780', (188, 192))	('c-Myc', 'Gene', '4609', (244, 249))	('knockdown', 'Var', (72, 81))	('expressions', 'MPA', (26, 37))	('c-Myc', 'Gene', (179, 184))	('NRF2', 'Gene', (254, 258))	('glioma', 'Disease', (85, 91))	('NRF2', 'Gene', (188, 192))	('c-Myc', 'Gene', '4609', (179, 184))	('decreased', 'NegReg', (43, 52))
36774	30936423	Thus, we speculate that TERT may also be involved in regulating NAF1 transcription, as indicated by our data that TERT knockdown downregulated NAF1 expression, while ectopic expression of TERT upregulated its expression.	('downregulated', 'NegReg', (129, 142))	('expression', 'MPA', (209, 219))	('TERT', 'Gene', (188, 192))	('TERT', 'Gene', '7015', (114, 118))	('TERT', 'Gene', '7015', (188, 192))	('TERT', 'Gene', (24, 28))	('knockdown', 'Var', (119, 128))	('TERT', 'Gene', '7015', (24, 28))	('expression', 'MPA', (148, 158))	('TERT', 'Gene', (114, 118))	('NAF1', 'Gene', (143, 147))
36778	30936423	Expectedly, our data presented that NAF1 ectopic expression in glioma cells dramatically accelerated 18S rRNA processing and 40S ribosome synthesis through increasing the levels of the scissor U17 H/ACA snoRNA, while NAF1 depletion in glioma cells obviously impaired the removal of 5'ETS of pre-rRNA, the maturation of 18S rRNA and the formation of 40S ribosomal subunit.	('ACA snoRNA', 'Phenotype', 'HP:0025267', (199, 209))	('glioma', 'Disease', (235, 241))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Disease', 'MESH:D005910', (235, 241))	('impaired', 'NegReg', (258, 266))	('18S rRNA processing', 'MPA', (101, 120))	('snoRNA', 'Gene', (203, 209))	('40S ribosome synthesis', 'MPA', (125, 147))	('levels', 'MPA', (171, 177))	('snoRNA', 'Gene', '85388', (203, 209))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))	('increasing', 'PosReg', (156, 166))	('formation of 40S ribosomal subunit', 'MPA', (336, 370))	('maturation', 'MPA', (305, 315))	('NAF1', 'Gene', (36, 40))	('ectopic expression', 'Var', (41, 59))	('glioma', 'Disease', (63, 69))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('accelerated', 'PosReg', (89, 100))	("removal of 5'ETS of pre-rRNA", 'MPA', (271, 299))
36783	30936423	Given the above, our findings indicate that NAF1 depletion in wild-type p53 glioma cells not only can attenuate ribosomal biosynthesis but also reactivate p53 signaling by blocking MDM2-p53 loop, thereby inhibiting malignant phenotypes of glioma cells.	('attenuate', 'NegReg', (102, 111))	('blocking', 'NegReg', (172, 180))	('glioma', 'Disease', (76, 82))	('MDM2', 'Gene', '4193', (181, 185))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('ribosomal biosynthesis', 'MPA', (112, 134))	('p53', 'Gene', (186, 189))	('p53', 'Gene', '7157', (72, 75))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('p53', 'Gene', '7157', (155, 158))	('p53', 'Gene', (72, 75))	('glioma', 'Disease', (239, 245))	('depletion', 'Var', (49, 58))	('p53', 'Gene', (155, 158))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('MDM2', 'Gene', (181, 185))	('p53', 'Gene', '7157', (186, 189))	('inhibiting', 'NegReg', (204, 214))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
36785	30936423	In recent years, inactivation or polymorphisms of NAF1 gene have been reported to be implicated in telomere length maintenance in human diseases including cancer.	('inactivation', 'Var', (17, 29))	('polymorphisms', 'Var', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('telomere length maintenance', 'MPA', (99, 126))	('implicated', 'Reg', (85, 95))	('NAF1', 'Gene', (50, 54))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('human', 'Species', '9606', (130, 135))
36786	30936423	To be consistent with this, our data demonstrated that knocking down NAF1 in glioma cells obviously shortened telomere length, while ectopic expression of NAF1 significantly lengthened telomere length.	('knocking down', 'Var', (55, 68))	('lengthened', 'PosReg', (174, 184))	('shortened telomere', 'Phenotype', 'HP:0031413', (100, 118))	('NAF1', 'Gene', (69, 73))	('shortened', 'NegReg', (100, 109))	('glioma', 'Disease', (77, 83))	('telomere', 'MPA', (185, 193))	('telomere', 'MPA', (110, 118))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
36790	30936423	In addition, we find that NAF1 depletion can trigger ribosome stress, not only impairing ribosomal biosynthesis but also reactivating p53 signaling via blocking MDM2.	('NAF1', 'Gene', (26, 30))	('p53', 'Gene', '7157', (134, 137))	('reactivating', 'PosReg', (121, 133))	('MDM2', 'Gene', '4193', (161, 165))	('MDM2', 'Gene', (161, 165))	('blocking', 'NegReg', (152, 160))	('ribosome', 'Disease', (53, 61))	('depletion', 'Var', (31, 40))	('p53', 'Gene', (134, 137))	('ribosomal biosynthesis', 'MPA', (89, 111))	('impairing', 'NegReg', (79, 88))
36833	30936423	The right armpit region of nude mice was subcutaneously inoculated of 8 x 106 U87 cells stably knocking down NAF1 or 6 x 106 U87 cells stably expressing NAF1 and the same number of control cells to establish tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('NAF1', 'Gene', (109, 113))	('knocking down', 'Var', (95, 108))	('nude mice', 'Species', '10090', (27, 36))
36840	30876455	Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7).	('MN1', 'Gene', '4330', (43, 46))	('mutations', 'Reg', (84, 93))	('BRAFV600E', 'Mutation', 'rs113488022', (74, 83))	('rearrangements', 'Var', (47, 61))	('MN1', 'Gene', (43, 46))	('BRAFV600E', 'Gene', (74, 83))
36842	30876455	By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively.	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (94, 115))	('neuroepithelial tumor', 'Disease', (94, 115))	('ependymoma', 'Disease', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('HGNET-MN1', 'CellLine', 'CVCL:U508', (137, 146))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (94, 115))	('MN1', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MN1', 'Gene', (121, 124))	('ependymoma', 'Phenotype', 'HP:0002888', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MN1', 'Gene', (143, 146))	('tumors', 'Disease', (30, 36))	('RELA', 'Gene', (49, 53))	('RELA', 'Gene', '5970', (49, 53))	('MN1', 'Gene', '4330', (42, 45))	('MN1', 'Gene', '4330', (121, 124))	('ependymoma', 'Disease', 'MESH:D004806', (164, 174))	('rearrangement', 'Var', (54, 67))	('RELA', 'Gene', (152, 156))	('RELA', 'Gene', '5970', (152, 156))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('MN1', 'Gene', '4330', (143, 146))	('alteration', 'Var', (125, 135))
36843	30876455	In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA).	('BRAFV600E-mutant', 'Var', (13, 29))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (50, 79))	('pleomorphic xanthoastrocytoma', 'Disease', (50, 79))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
36846	30876455	They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('MN1', 'Gene', '4330', (102, 105))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (74, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('ependymoma', 'Phenotype', 'HP:0002888', (143, 153))	('rearrangement', 'Var', (106, 119))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('ependymomas', 'Disease', 'MESH:D004806', (143, 154))	('glial tumors', 'Disease', 'MESH:D005910', (51, 63))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (74, 95))	('RELA', 'Gene', (138, 142))	('RELA', 'Gene', '5970', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('neuroepithelial tumors', 'Disease', (74, 96))	('ependymomas', 'Disease', (143, 154))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('glial tumors', 'Disease', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (130, 136))	('MN1', 'Gene', (102, 105))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (74, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))
36852	30876455	We recently provided evidence that ABs may be related to pleomorphic xanthoastrocytomas (PXAs), based on overlapping clinicopathologic features and detection of the V600E mutation of the B-Raf serine-threonine kinase (BRAFV600E) in a subset of lesions.	('B-Raf', 'Gene', (187, 192))	('BRAFV600E', 'Gene', (218, 227))	('V600E', 'Var', (165, 170))	('B-Raf', 'Gene', '673', (187, 192))	('pleomorphic xanthoastrocytomas', 'Disease', (57, 87))	('V600E', 'Mutation', 'rs113488022', (222, 227))	('ABs', 'Disease', (35, 38))	('BRAFV600E', 'Mutation', 'rs113488022', (218, 227))	('V600E', 'Mutation', 'rs113488022', (165, 170))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (57, 87))
36855	30876455	One group, termed high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1), showed recurrent rearrangements of the MN1 gene, located at 22q12.3-qter.	('MN1', 'Gene', (123, 126))	('neuroepithelial tumor', 'Disease', (29, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('alteration', 'Var', (60, 70))	('MN1', 'Gene', '4330', (78, 81))	('MN1', 'Gene', '4330', (123, 126))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (29, 50))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (29, 50))	('MN1', 'Gene', (56, 59))	('rearrangements', 'Var', (101, 115))	('HGNET-MN1', 'CellLine', 'CVCL:U508', (72, 81))	('MN1', 'Gene', '4330', (56, 59))	('MN1', 'Gene', (78, 81))
36857	30876455	Subsequent evaluation of limited cohorts confirmed that MN1 rearrangements occur in a subset of ABs.	('rearrangements', 'Var', (60, 74))	('ABs', 'Disease', (96, 99))	('MN1', 'Gene', (56, 59))	('MN1', 'Gene', '4330', (56, 59))	('occur', 'Reg', (75, 80))
36858	30876455	The presence of BRAFV600E mutations in some ABs and MN1 rearrangements in others raises questions as to whether AB represents a distinct entity, or a histologic pattern exhibited by multiple glial tumor types.	('glial tumor', 'Disease', (191, 202))	('MN1', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('MN1', 'Gene', '4330', (52, 55))	('BRAFV600E', 'Var', (16, 25))	('BRAFV600E', 'Mutation', 'rs113488022', (16, 25))	('glial tumor', 'Disease', 'MESH:D005910', (191, 202))
36862	30876455	Cases from our original cohort were designated with the corresponding case numbers from that study and included cases C1, C3, C5-C14, C16, C17, C19-C24, and C26.	('C5-C14', 'Var', (126, 132))	('C17', 'Gene', (139, 142))	('C17', 'Gene', '54360', (139, 142))	('C19-C24', 'Var', (144, 151))	('C26', 'Var', (157, 160))	('C16', 'Var', (134, 137))
36868	30876455	Break-apart probes for MN1 were derived from BAC clones RP11-432I9 and RP11-736H16 (BACPAC Resources, Oakland, CA).	('RP11-432I9', 'Var', (56, 66))	('RP11-736H16', 'Var', (71, 82))	('H16', 'CellLine', 'CVCL:0H99', (79, 82))	('MN1', 'Gene', (23, 26))	('MN1', 'Gene', '4330', (23, 26))
36890	30876455	Five tumors yielded a probability score below the reporting threshold of 0.90; however, in two of these (C22, and C30), the highest probability was consistent with the unsupervised hierarchical clustering analyses (LGG-PA/GG-ST 0.55 and EPEND RELA 0.89, respectively).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('RELA', 'Gene', (243, 247))	('RELA', 'Gene', '5970', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('C30', 'Var', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
36894	30876455	The BRAFV600E mutation was identified in seven of nine tumors clustering in the PXA methylation group by t-SNE (Table 1).	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
36895	30876455	BRAFV600E mutations were not detected in the two tumors in which t-SNE and hierarchical clustering were discordant (C14 and C20) (Figs.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('C20', 'Var', (124, 127))	('BRAFV600E', 'Var', (0, 9))
36899	30876455	These findings were consistent with those of the reference cohort of HGNET-MN1 tumors, with the exception of a slightly increased proportion of chromosome 14 loss in ABs.	('HGNET-MN1', 'CellLine', 'CVCL:U508', (69, 78))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('chromosome', 'Var', (144, 154))	('loss', 'NegReg', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
36900	30876455	BRAFV600E-positive ABs that grouped with PXA showed more extensive chromosomal instability compared to other ABs (Fig.	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('chromosomal instability', 'Phenotype', 'HP:0040012', (67, 90))	('chromosomal instability', 'CPA', (67, 90))	('BRAFV600E-positive', 'Var', (0, 18))
36902	30876455	Unlike commonly observed in glioblastoma and in the approximately 20% of PXAs (especially anaplastic PXAs) with chromosome 7 and 10 aberrations, gain of chromosome 7 and loss of chromosome 10 were mutually exclusive in ABs (Additional file 5: Figure S4A).	('gain', 'Disease', (145, 149))	('gain', 'Disease', 'MESH:D015430', (145, 149))	('ABs', 'Disease', (219, 222))	('glioblastoma', 'Disease', (28, 40))	('loss', 'Var', (170, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))
36906	30876455	Three of seven tumors that both grouped with PXA and contained BRAFV600E mutations showed focal copy number loss at CDKN2A/B (Additional file 5: Figure S4B).	('BRAFV600E', 'Var', (63, 72))	('BRAFV600E', 'Mutation', 'rs113488022', (63, 72))	('loss', 'NegReg', (108, 112))	('copy', 'MPA', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('CDKN2A/B', 'Gene', '1029;1030', (116, 124))	('CDKN2A/B', 'Gene', (116, 124))	('tumors', 'Disease', (15, 21))
36909	30876455	MN1-rearranged, BRAFV600E-mutant, RELA-rearranged, and tumors without identified driver mutations all occasionally demonstrated nuclear pseudoinclusions (Fig.	('nuclear pseudoinclusions', 'Disease', (128, 152))	('MN1', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('demonstrated', 'Reg', (115, 127))	('MN1', 'Gene', '4330', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('RELA', 'Gene', (34, 38))	('RELA', 'Gene', '5970', (34, 38))	('tumors', 'Disease', (55, 61))	('BRAFV600E-mutant', 'Var', (16, 32))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('BRAFV600E', 'Mutation', 'rs113488022', (16, 25))
36913	30876455	BRAFV600E-mutant ABs tended to have stouter cells (Fig.	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E-mutant', 'Var', (0, 16))	('stouter cells', 'CPA', (36, 49))
36927	30876455	RELA rearrangements were detected in tumors from one female and one male (C1 and C30), aged 10 and 19 years, respectively.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('RELA', 'Gene', (0, 4))	('RELA', 'Gene', '5970', (0, 4))	('rearrangements', 'Var', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('C1 and C30', 'Gene', '393', (74, 84))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('detected', 'Reg', (25, 33))
36930	30876455	Six other tumors negative for BRAFV600E mutations and MN1 or RELA rearrangements consisted of lesions from three females and three male patients ranging in age from 4 to 71 years.	('MN1', 'Gene', '4330', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (10, 16))	('RELA', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('RELA', 'Gene', '5970', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('patients', 'Species', '9606', (136, 144))	('MN1', 'Gene', (54, 57))	('BRAFV600E', 'Var', (30, 39))	('BRAFV600E', 'Mutation', 'rs113488022', (30, 39))
36934	30876455	In pairwise analysis, there was no appreciable difference in overall survival between ABs with BRAFV600E mutations and tumors without specific driver mutations (P = 0.398).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('BRAFV600E', 'Gene', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('mutations', 'Var', (105, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
36939	30876455	The overall survival of the MN1-rearranged tumor patients' ranged from 68 to 221 months (mean, 138 months; n = 7) compared to 2 to 141 months (mean, 61 months; n = 7) for patients whose tumors had BRAFV600E mutation, and 18 to 279 months (mean, 127 months; n = 8) for patients with neither genetic alteration.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('MN1', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (186, 191))	('patients', 'Species', '9606', (171, 179))	('MN1', 'Gene', '4330', (28, 31))	('BRAFV600E', 'Mutation', 'rs113488022', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('BRAFV600E', 'Var', (197, 206))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Disease', (43, 48))	('patients', 'Species', '9606', (268, 276))
36943	30876455	ABs with MN1 rearrangement presented herein were notable for favorable overall survival.	('rearrangement', 'Var', (13, 26))	('MN1', 'Gene', (9, 12))	('MN1', 'Gene', '4330', (9, 12))
36947	30876455	While especially BRAFV600E-mutant ABs showed genomic methylation patterns and other genetic changes common to PXA (e.g., CDKN2A/B deletion in three cases), several findings suggest they may not be entirely equivalent entities.	('CDKN2A/B', 'Gene', '1029;1030', (121, 129))	('BRAFV600E-mutant', 'Var', (17, 33))	('CDKN2A/B', 'Gene', (121, 129))	('BRAFV600E', 'Mutation', 'rs113488022', (17, 26))
36953	30876455	RELA ependymomas can be further differentiated from other AB pseudorosette-predominant lesions by BRAF mutational analysis, FISH for MN1 rearrangement, or genomic DNA methylation analysis.	('MN1', 'Gene', '4330', (133, 136))	('ependymomas', 'Disease', (5, 16))	('BRAF', 'Gene', (98, 102))	('RELA', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (98, 102))	('RELA', 'Gene', '5970', (0, 4))	('ependymoma', 'Phenotype', 'HP:0002888', (5, 15))	('mutational analysis', 'Var', (103, 122))	('MN1', 'Gene', (133, 136))	('ependymomas', 'Disease', 'MESH:D004806', (5, 16))	('rearrangement', 'Var', (137, 150))
36960	30876455	These findings suggest that additional drivers, other than MN1 rearrangements, BRAFV600E mutations, and RELA fusions, may exist for tumors with AB histology.	('BRAFV600E', 'Mutation', 'rs113488022', (79, 88))	('MN1', 'Gene', (59, 62))	('MN1', 'Gene', '4330', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BRAFV600E', 'Gene', (79, 88))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (89, 98))	('RELA', 'Gene', (104, 108))	('RELA', 'Gene', '5970', (104, 108))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
36972	22741575	Both high HGF expression in tumor cells (59.2%, 45/76) and high PI were significantly associated with high-grade glioma and increased microvessels in tumors (P < 0.05).	('tumors', 'Disease', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('high', 'Var', (5, 9))	('tumor', 'Disease', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('increased', 'PosReg', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('HGF', 'Gene', (10, 13))	('associated', 'Reg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('glioma', 'Disease', (113, 119))	('HGF', 'Gene', '3082', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('high PI', 'Var', (59, 66))	('tumor', 'Disease', (150, 155))
36973	22741575	However, only histological grading (P = 0.004) and high-expression of HGF (P = 0.008) emerged as independent prognostic factors for the overall survival of glioma patients.	('patients', 'Species', '9606', (163, 171))	('glioma', 'Disease', (156, 162))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('HGF', 'Gene', (70, 73))	('high-expression', 'Var', (51, 66))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('HGF', 'Gene', '3082', (70, 73))
36974	22741575	The tumor-derived HGF mRNA and protein expressions were significantly decreased in vitro after transfection of HGF siRNA.	('tumor', 'Disease', (4, 9))	('HGF', 'Gene', '3082', (111, 114))	('transfection', 'Var', (95, 107))	('decreased', 'NegReg', (70, 79))	('HGF siRNA', 'Gene', '3082', (111, 120))	('HGF', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('HGF', 'Gene', '3082', (18, 21))	('HGF', 'Gene', (111, 114))	('HGF siRNA', 'Gene', (111, 120))
36976	22741575	Moreover, HGF siRNA transfection enhanced the chemosensitivity of U87MG glioma cells to cisplatin.	('glioma', 'Disease', (72, 78))	('chemosensitivity', 'MPA', (46, 62))	('HGF siRNA', 'Gene', '3082', (10, 19))	('transfection', 'Var', (20, 32))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('HGF siRNA', 'Gene', (10, 19))	('U87MG', 'CellLine', 'CVCL:0022', (66, 71))	('enhanced', 'PosReg', (33, 41))
36997	22741575	Recently, a study has also exhibited that inhibition of c-Met enhanced the chemosensitivity of glioma cell lines to cisplatin, but no clear molecular mechanism involvement has emerged.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('c-Met', 'Gene', (56, 61))	('c-Met', 'Gene', '4233', (56, 61))	('chemosensitivity', 'MPA', (75, 91))	('enhanced', 'PosReg', (62, 70))	('inhibition', 'Var', (42, 52))	('glioma', 'Disease', (95, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
37056	22741575	The mean proliferation index (PI) values were significantly higher in cases with high HGF expression than those in cases with low expression of HGF (P = 0.001).	('higher', 'PosReg', (60, 66))	('high', 'Var', (81, 85))	('HGF', 'Gene', (144, 147))	('HGF', 'Gene', (86, 89))	('expression', 'MPA', (90, 100))	('HGF', 'Gene', '3082', (144, 147))	('HGF', 'Gene', '3082', (86, 89))	('proliferation index', 'CPA', (9, 28))
37059	22741575	The IMD was significantly higher in tumors with high expression of HGF or with high-grade gliomas.	('gliomas', 'Disease', (90, 97))	('HGF', 'Gene', '3082', (67, 70))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('higher', 'PosReg', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('HGF', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('IMD', 'MPA', (4, 7))	('high', 'Var', (48, 52))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
37062	22741575	In univariate analysis, high-grade tumor, high-expression of HGF and higher PI were significantly associated with a short survival time of patients with gliomas.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('patients', 'Species', '9606', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('HGF', 'Gene', (61, 64))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('tumor', 'Disease', (35, 40))	('HGF', 'Gene', '3082', (61, 64))	('high-expression', 'Var', (42, 57))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('high-grade', 'Var', (24, 34))
37064	22741575	However, in multivariate analysis, only histological grade and high expression of HGF in gliomas were independently associated with survival.	('associated with', 'Reg', (116, 131))	('HGF', 'Gene', (82, 85))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('HGF', 'Gene', '3082', (82, 85))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('high', 'Var', (63, 67))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))
37070	22741575	By RT-PCR assay, we found the HGF mRNA level was also dramatically decreased in the cell after 48 h of siHGF transfection (Figure 3c).	('HGF', 'Gene', (105, 108))	('HGF', 'Gene', (30, 33))	('transfection', 'Var', (109, 121))	('HGF', 'Gene', '3082', (105, 108))	('HGF', 'Gene', '3082', (30, 33))	('decreased', 'NegReg', (67, 76))
37072	22741575	As shown in Figure 4a, siHGF transfection resulted in inhibition of glioma cell viability.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('HGF', 'Gene', (25, 28))	('inhibition', 'NegReg', (54, 64))	('HGF', 'Gene', '3082', (25, 28))	('glioma', 'Disease', (68, 74))	('transfection', 'Var', (29, 41))
37079	22741575	Meanwhile, the IC50 concentration of cisplatin for U87MG cells decreased significantly from 7.06 ug/ml in control cells and 2.01 ug/ml in siHGF-transfected cells, respectively, which indicated that siHGF might be one of the factors that enhanced the chemosensitivity of glioma cells to cisplatin.	('glioma', 'Phenotype', 'HP:0009733', (270, 276))	('HGF', 'Gene', '3082', (200, 203))	('U87MG', 'Var', (51, 56))	('decreased', 'NegReg', (63, 72))	('HGF', 'Gene', (140, 143))	('enhanced', 'PosReg', (237, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (286, 295))	('glioma', 'Disease', (270, 276))	('HGF', 'Gene', '3082', (140, 143))	('chemosensitivity', 'CPA', (250, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('IC50 concentration', 'MPA', (15, 33))	('HGF', 'Gene', (200, 203))	('U87MG', 'CellLine', 'CVCL:0022', (51, 56))	('glioma', 'Disease', 'MESH:D005910', (270, 276))
37093	22741575	Although the number of grade I gliomas examined in this study was not sufficient to allow us to draw a definite conclusion, these findings indicated that high expression of HGF could be used as a predictor for the recurrence of gliomas and could help determine whether aggressive therapy is necessary, particularly for those gliomas with lower WHO grades.	('gliomas', 'Disease', 'MESH:D005910', (228, 235))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('gliomas', 'Disease', (228, 235))	('high', 'Var', (154, 158))	('gliomas', 'Phenotype', 'HP:0009733', (325, 332))	('gliomas', 'Disease', (325, 332))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (325, 331))	('gliomas', 'Disease', 'MESH:D005910', (325, 332))	('HGF', 'Gene', (173, 176))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('HGF', 'Gene', '3082', (173, 176))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
37099	22741575	However, multivariate analysis for overall survival in patients indicated that cell proliferation in tumors was not an independent predictive factor for the prognosis of gliomas, although high PI was significantly correlated with a high histological grade and a decreased survival rate in patients.	('survival rate', 'CPA', (272, 285))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('gliomas', 'Disease', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('decreased', 'NegReg', (262, 271))	('high PI', 'Var', (188, 195))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (55, 63))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('tumors', 'Disease', (101, 107))	('patients', 'Species', '9606', (289, 297))
37236	33235233	that isocitrate dehydrogenase (IDH) mutation, which is mainly found in LGG, leads to an increased accumulation of TCA cycle metabolites and enhanced production of mitochondrial NADH.	('IDH', 'Gene', (31, 34))	('enhanced', 'PosReg', (140, 148))	('isocitrate dehydrogenase', 'Gene', (5, 29))	('increased accumulation', 'PosReg', (88, 110))	('IDH', 'Gene', '3417', (31, 34))	('isocitrate dehydrogenase', 'Gene', '3417', (5, 29))	('TCA', 'Chemical', '-', (114, 117))	('NADH', 'Chemical', 'MESH:D009243', (177, 181))	('TCA cycle metabolites', 'MPA', (114, 135))	('production of mitochondrial NADH', 'MPA', (149, 181))	('LGG', 'Chemical', '-', (71, 74))	('mutation', 'Var', (36, 44))
37314	30547008	Advances in molecular genetics have allowed for the identification of additional prognostic and/or predictive mutations and epigenetic changes such as isocitrate dehydrogenase (IDH) mutation, chromosome 1p/19q co-deletion, and O -methylguanine-DNA methyltransferase (MGMT) hypermethylation.	('co-deletion', 'Var', (210, 221))	('mutations', 'Var', (110, 119))	('IDH', 'Gene', (177, 180))	('MGMT', 'Gene', (267, 271))	('mutation', 'Var', (182, 190))	('IDH', 'Gene', '3417', (177, 180))	('hypermethylation', 'Var', (273, 289))	('MGMT', 'Gene', '4255', (267, 271))
37342	30547008	), laterality, focality (unifocal vs. multifocal), tumor size, WHO Grade, histology (e.g., astrocytoma, oligodendroglioma, glioblastoma), loss of heterozygosity (LOH) of chromosome 1p/19q.	('glioblastoma', 'Disease', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('loss of heterozygosity', 'Var', (138, 160))	('tumor', 'Disease', (51, 56))	('oligodendroglioma', 'Disease', (104, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('astrocytoma', 'Disease', 'MESH:D001254', (91, 102))	('oligodendroglioma', 'Disease', 'MESH:D009837', (104, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('astrocytoma', 'Disease', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
37412	30547008	With limited information available for important prognostic variables such as performance status, MGMT methylation, and 1p19q co-deletion, the results of our study will require validation in a randomized clinical trial setting where such variables are adequately recorded.	('MGMT', 'Gene', '4255', (98, 102))	('1p19q', 'Var', (120, 125))	('MGMT', 'Gene', (98, 102))
37452	29731795	A statistically significant association was observed between PSMA expression and tumor grade (P value=0.009), meaning that high grade gliomas more commonly had positive results for PSMA; although most of them had negative findings.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('PSMA', 'Gene', '2346', (181, 185))	('high grade', 'Var', (123, 133))	('gliomas', 'Disease', (134, 141))	('PSMA', 'Gene', (181, 185))	('PSMA', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PSMA', 'Gene', '2346', (61, 65))	('positive', 'Reg', (160, 168))	('tumor', 'Disease', (81, 86))
37490	29731795	Chang et al.,, evaluated 5 different Anti PSMA Antibodies (7E11, J591, J415, HybritechPEQ226.5 and PM2Joo4.5), each bounded a distinct epitope of PSMA.	('PSMA', 'Gene', (146, 150))	('bounded', 'Reg', (116, 123))	('PSMA', 'Gene', '2346', (42, 46))	('PSMA', 'Gene', '2346', (146, 150))	('J415', 'Var', (71, 75))	('PSMA', 'Gene', (42, 46))	('J591', 'Var', (65, 69))
37507	32244981	Recently, RNA modifications, especially m6A, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs).	('malignancy', 'Disease', (278, 288))	('m6A', 'Var', (40, 43))	('R', 'Chemical', 'MESH:D001120', (55, 56))	('alpha-ketoglutarate-dependent dioxygenase alkB homolog 5', 'Gene', '54890', (131, 187))	('pluripotency of glioma', 'Disease', 'MESH:D005910', (312, 334))	('R', 'Chemical', 'MESH:D001120', (10, 11))	('GSC', 'Chemical', '-', (352, 355))	('aggressiveness', 'Disease', (259, 273))	('ALKBH5', 'Gene', (189, 195))	('pluripotency of glioma', 'Disease', (312, 334))	('aggressiveness', 'Phenotype', 'HP:0000718', (259, 273))	('malignancy', 'Disease', 'MESH:D009369', (278, 288))	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('methyltransferase like 3', 'Gene', (93, 117))	('methyltransferase like 3', 'Gene', '56339', (93, 117))	('GBM', 'Phenotype', 'HP:0012174', (292, 295))	('aggressiveness', 'Disease', 'MESH:D001523', (259, 273))	('R', 'Chemical', 'MESH:D001120', (79, 80))	('ALKBH5', 'Gene', '54890', (189, 195))
37516	32244981	Covalent modifications in RNA and their connections with cancers are also an area of concentrated activity in cancer biology research.	('RNA', 'Protein', (26, 29))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Covalent modifications', 'Var', (0, 22))	('cancer', 'Disease', (57, 63))	('R', 'Chemical', 'MESH:D001120', (26, 27))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
37528	32244981	Moreover, eukaryotic tRNAs also contain many modifications (13 modifications per molecule on average) to maintain their chemical diversity, thereby contributing to decoding fidelity, folding efficiency, cellular stability and localization.	('localization', 'MPA', (226, 238))	('R', 'Chemical', 'MESH:D001120', (22, 23))	('modifications', 'Var', (45, 58))	('decoding fidelity', 'MPA', (164, 181))	('contributing', 'Reg', (148, 160))	('chemical diversity', 'MPA', (120, 138))	('cellular stability', 'MPA', (203, 221))	('folding efficiency', 'MPA', (183, 201))
37533	32244981	These modifications are not only needed for normal function but also play essential roles in pathological processes, such as tumorigenesis.	('modifications', 'Var', (6, 19))	('roles', 'Reg', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('play', 'Reg', (69, 73))
37536	32244981	Since m6A is the best-known RNA mark, it is highly connected with GBM progression and aggressiveness and some regulators may be potential drug targets.	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('GBM', 'Disease', (66, 69))	('aggressiveness', 'Disease', 'MESH:D001523', (86, 100))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('aggressiveness', 'Disease', (86, 100))	('R', 'Chemical', 'MESH:D001120', (28, 29))	('connected', 'Reg', (51, 60))	('m6A', 'Var', (6, 9))
37537	32244981	Recently, other kinds of RNA marks, including m6Am, m1A, m5C, hm5C, I and psi, as well as their modulators are also emerging to be correlated with GBM progression (Table 1).	('correlated', 'Reg', (131, 141))	('GBM progression', 'CPA', (147, 162))	('GBM', 'Phenotype', 'HP:0012174', (147, 150))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('m6Am', 'Var', (46, 50))	('R', 'Chemical', 'MESH:D001120', (25, 26))	('m1A', 'Chemical', '-', (52, 55))	('m5C', 'Chemical', '-', (57, 60))	('m5C', 'Chemical', '-', (63, 66))
37538	32244981	RNA m6A modification is the most prevalent and abundant modifications that occur in the mRNAs, rRNAs and small nuclear RNAs (snRNAs).	('R', 'Chemical', 'MESH:D001120', (89, 90))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('R', 'Chemical', 'MESH:D001120', (127, 128))	('R', 'Chemical', 'MESH:D001120', (119, 120))	('R', 'Chemical', 'MESH:D001120', (96, 97))	('RNA m6A', 'Gene', (0, 7))	('modification', 'Var', (8, 20))
37539	32244981	m6A modification of mRNA usually occurs in nuclear speckles where the methyltransferases and demethylases are concentrated and are enriched in single nucleotide polymorphisms (SNPs).	('occurs', 'Reg', (33, 39))	('mRNA', 'Gene', (20, 24))	('methyltransferases', 'Enzyme', (70, 88))	('modification', 'Var', (4, 16))	('demethylases', 'Enzyme', (93, 105))	('R', 'Chemical', 'MESH:D001120', (21, 22))	('m6A', 'Var', (0, 3))
37543	32244981	Other factors, such as insulin-like growth factor 2 mRNA-binding protein 1/2/3 (IGF2BP1/2/3, also known as IMP1/2/3), eukaryotic translation initiation factor 3a/b/h (eIF3a/b/h), heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) and heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) were recently shown to be able to read the m6A marks, too.	('eukaryotic translation initiation factor 3a/b/h', 'Gene', '3692', (118, 165))	('heterogeneous nuclear ribonucleoprotein A2/B1', 'Gene', (179, 224))	('eIF3', 'Gene', (167, 171))	('hnRNPA2B1', 'Gene', '3181', (226, 235))	('R', 'Chemical', 'MESH:D001120', (228, 229))	('R', 'Chemical', 'MESH:D001120', (53, 54))	('m6A', 'Var', (339, 342))	('heterogeneous nuclear ribonucleoprotein A2/B1', 'Gene', '3181', (179, 224))	('IMP1/2/3', 'Gene', '10642;10644;55272', (107, 115))	('heterogeneous nuclear ribonucleoprotein C1/C2', 'Gene', (241, 286))	('insulin-like growth factor 2', 'Gene', (23, 51))	('IGF2BP1/2/3', 'Gene', (80, 91))	('eIF3', 'Gene', '8661', (167, 171))	('R', 'Chemical', 'MESH:D001120', (290, 291))	('hnRNPC', 'Gene', '3183', (288, 294))	('heterogeneous nuclear ribonucleoprotein C1/C2', 'Gene', '3183', (241, 286))	('IGF2BP1/2/3', 'Gene', '10642;3481', (80, 91))	('hnRNPC', 'Gene', (288, 294))	('eukaryotic translation initiation factor 3a/b/h', 'Gene', (118, 165))	('IMP1/2/3', 'Gene', (107, 115))	('hnRNPA2B1', 'Gene', (226, 235))	('insulin-like growth factor 2', 'Gene', '3481', (23, 51))
37553	32244981	Additionally, expression levels of ALKBH5, YTHDF2, RBM15, METTL3, METTL14, FTO and YTHDC1 in LGGs with or without mutant isocitrate dehydrogenase (IDH) are significantly different.	('isocitrate dehydrogenase', 'Gene', (121, 145))	('RBM15', 'Gene', (51, 56))	('IDH', 'Gene', '3417', (147, 150))	('ALKBH5', 'Gene', (35, 41))	('FTO', 'Gene', (75, 78))	('METTL14', 'Gene', (66, 73))	('YTHDC1', 'Gene', '91746', (83, 89))	('mutant', 'Var', (114, 120))	('ALKBH5', 'Gene', '54890', (35, 41))	('expression levels', 'MPA', (14, 31))	('YTHDF2', 'Gene', (43, 49))	('YTHDC1', 'Gene', (83, 89))	('RBM15', 'Gene', '64783', (51, 56))	('different', 'Reg', (170, 179))	('isocitrate dehydrogenase', 'Gene', '3417', (121, 145))	('METTL3', 'Gene', (58, 64))	('IDH', 'Gene', (147, 150))	('YTHDF2', 'Gene', '51441', (43, 49))	('METTL14', 'Gene', '57721', (66, 73))
37554	32244981	Moreover, FTO, YTHDC1 and METTL3 are also differentially expressed between GBM with and without IDH mutation.	('METTL3', 'Gene', (26, 32))	('IDH', 'Gene', '3417', (96, 99))	('differentially', 'Reg', (42, 56))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))	('mutation', 'Var', (100, 108))	('YTHDC1', 'Gene', (15, 21))	('FTO', 'Gene', (10, 13))	('YTHDC1', 'Gene', '91746', (15, 21))	('IDH', 'Gene', (96, 99))
37560	32244981	Moreover, METTL3 silencing also reverses RasV12-mediated malignant transformation of mouse immortalized astrocytes and suppresses GBM tumor growth in vitro and in vivo.	('R', 'Chemical', 'MESH:D001120', (41, 42))	('mouse', 'Species', '10090', (85, 90))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('METTL3', 'Gene', (10, 16))	('suppresses', 'NegReg', (119, 129))	('reverses', 'NegReg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('malignant transformation', 'CPA', (57, 81))	('RasV12-mediated', 'Gene', (41, 56))	('silencing', 'Var', (17, 26))	('GBM tumor', 'Disease', 'MESH:D005910', (130, 139))	('GBM tumor', 'Disease', (130, 139))
37561	32244981	Furthermore, METTL3 silencing in GSCs enhances their sensitivity to gamma-irradiation and reduces DNA repair.	('DNA repair', 'MPA', (98, 108))	('sensitivity to gamma-irradiation', 'MPA', (53, 85))	('METTL3', 'Gene', (13, 19))	('silencing', 'Var', (20, 29))	('reduces', 'NegReg', (90, 97))	('GSC', 'Chemical', '-', (33, 36))	('enhances', 'PosReg', (38, 46))
37562	32244981	Mechanically, METTL3 seems to be responsible for the m6A modification in some GSCs-specifically-expressed genes.	('responsible', 'Reg', (33, 44))	('m6A', 'Var', (53, 56))	('METTL3', 'Gene', (14, 20))	('GSCs-specifically-expressed genes', 'Gene', (78, 111))	('GSC', 'Chemical', '-', (78, 81))
37563	32244981	Particularly, METTL3 mediates m6A modification of mRNA of SRY-box transcription factor 2 (SOX2), a pluripotent gene, at three METTL3/m6A sites present in its 3' untranslated region (UTR), leading to the recruitment of human antigen R (HuR) to SOX2 mRNA to enhance its stability, thereby resulting in GSC maintenance and dedifferentiation.	('R', 'Chemical', 'MESH:D001120', (237, 238))	('HuR', 'Gene', '1994', (235, 238))	('resulting in', 'Reg', (287, 299))	('SOX2', 'Gene', '6657', (90, 94))	('SOX2', 'Gene', (90, 94))	('GSC', 'Chemical', '-', (300, 303))	('m6A', 'Var', (30, 33))	('R', 'Chemical', 'MESH:D001120', (59, 60))	('recruitment', 'MPA', (203, 214))	('R', 'Chemical', 'MESH:D001120', (249, 250))	('enhance', 'PosReg', (256, 263))	('R', 'Chemical', 'MESH:D001120', (51, 52))	('R', 'Chemical', 'MESH:D001120', (184, 185))	('R', 'Chemical', 'MESH:D001120', (232, 233))	('stability', 'MPA', (268, 277))	('SOX2', 'Gene', (243, 247))	('SOX2', 'Gene', '6657', (243, 247))	('human', 'Species', '9606', (218, 223))	('GSC maintenance', 'CPA', (300, 315))	('HuR', 'Gene', (235, 238))	('dedifferentiation', 'CPA', (320, 337))
37564	32244981	In addition to directly affecting the pluripotent genes, an m6A-specific methylated RNA immunoprecipitation with NGS (MeRIP-Seq or m6A-Seq) analysis also shows that m6A modification peaks seem to be enriched at transcripts responsible for metabolic pathways in GSCs, compared with neural progenitor cells.	('R', 'Chemical', 'MESH:D001120', (84, 85))	('GSC', 'Chemical', '-', (261, 264))	('R', 'Chemical', 'MESH:D001120', (120, 121))	('GSCs', 'Disease', (261, 265))	('m6A', 'Var', (165, 168))
37567	32244981	Additionally, in GSCs, METTL3-dependent m6A modification also affects the levels of serine- and arginine-rich splicing factors (SRSFs) through upregulating BCL-X (Bcl-2-like protein 1, BCL2L1) or nuclear receptor corepressor 2 (NCOR2) isoforms, which are important to prevent YTHDC1-dependent nonsense-mediated mRNA decay (NMD).	('nuclear receptor corepressor 2', 'Gene', (196, 226))	('modification', 'Var', (44, 56))	('m6A', 'Gene', (40, 43))	('Bcl-2-like protein 1', 'Gene', (163, 183))	('BCL2L1', 'Gene', (185, 191))	('NCOR2', 'Gene', (228, 233))	('arginine', 'Chemical', 'MESH:D001120', (96, 104))	('NCOR2', 'Gene', '9612', (228, 233))	('Bcl-2-like protein 1', 'Gene', '598', (163, 183))	('METTL3-dependent', 'Gene', (23, 39))	('R', 'Chemical', 'MESH:D001120', (312, 313))	('upregulating', 'PosReg', (143, 155))	('BCL-X', 'Gene', '598', (156, 161))	('YTHDC1', 'Gene', '91746', (276, 282))	('nuclear receptor corepressor 2', 'Gene', '9612', (196, 226))	('GSC', 'Chemical', '-', (17, 20))	('R', 'Chemical', 'MESH:D001120', (231, 232))	('BCL-X', 'Gene', (156, 161))	('BCL2L1', 'Gene', '598', (185, 191))	('R', 'Chemical', 'MESH:D001120', (129, 130))	('affects', 'Reg', (62, 69))	('YTHDC1', 'Gene', (276, 282))	('serine', 'Chemical', 'MESH:D012694', (84, 90))
37568	32244981	lncRNAs with METTL3-dependent m6A marks is also highly expressed in GSCs, compared with that of protein-coding genes.	('m6A marks', 'Var', (30, 39))	('METTL3-dependent', 'Gene', (13, 29))	('GSCs', 'Disease', (68, 72))	('R', 'Chemical', 'MESH:D001120', (3, 4))	('GSC', 'Chemical', '-', (68, 71))	('highly', 'PosReg', (48, 54))
37569	32244981	m6A marks within 3'UTRs seem to hinder the miRNA binding in GSCs.	('GSC', 'Chemical', '-', (60, 63))	('m6A marks', 'Var', (0, 9))	('GSCs', 'Disease', (60, 64))	('miRNA binding', 'MPA', (43, 56))	('R', 'Chemical', 'MESH:D001120', (21, 22))	('hinder', 'NegReg', (32, 38))	('R', 'Chemical', 'MESH:D001120', (45, 46))
37571	32244981	Their results show that deficiency of METTL3 or METTL14 significantly enhances the growth, self-renewal, and tumorigenesis of GBM stem cells.	('self-renewal', 'CPA', (91, 103))	('tumor', 'Disease', (109, 114))	('METTL3', 'Gene', (38, 44))	('deficiency', 'Var', (24, 34))	('growth', 'CPA', (83, 89))	('METTL14', 'Gene', (48, 55))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('METTL14', 'Gene', '57721', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('enhances', 'PosReg', (70, 78))
37572	32244981	Subsequently, m6A sequencing and molecular experiments implies that METTL3 or METTL14 knockdown induced alterations in mRNA m6A enrichment and the mRNA expression of critical factors, such as a disintegrin and metallopeptidase domain 19 (ADAM19), that participate in modulation of GBM stem cells.	('METTL14', 'Gene', (78, 85))	('R', 'Chemical', 'MESH:D001120', (148, 149))	('alterations', 'Reg', (104, 115))	('knockdown', 'Var', (86, 95))	('ADAM19', 'Gene', '8728', (238, 244))	('METTL3', 'Gene', (68, 74))	('a disintegrin and metallopeptidase domain 19', 'Gene', '8728', (192, 236))	('GBM', 'Phenotype', 'HP:0012174', (281, 284))	('R', 'Chemical', 'MESH:D001120', (120, 121))	('mRNA m6A enrichment', 'MPA', (119, 138))	('mRNA', 'MPA', (147, 151))	('ADAM19', 'Gene', (238, 244))	('METTL14', 'Gene', '57721', (78, 85))
37579	32244981	A recent study shows that ZC3H13 mutation combined with retinoblastoma 1 (RB1) mutation can recapture human GBM in a mouse model.	('mutation', 'Var', (33, 41))	('retinoblastoma 1', 'Gene', (56, 72))	('mouse', 'Species', '10090', (117, 122))	('ZC3H13', 'Gene', (26, 32))	('RB1', 'Gene', (74, 77))	('retinoblastoma 1', 'Gene', '5925', (56, 72))	('retinoblastoma', 'Phenotype', 'HP:0009919', (56, 70))	('mutation', 'Var', (79, 87))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('human', 'Species', '9606', (102, 107))
37580	32244981	Moreover, ZC3H13 mutation also alters the gene expression profiles of RB1 mutants, rendering GBM tumors more resistant to TMZ.	('RB1', 'Gene', (70, 73))	('GBM tumors', 'Disease', (93, 103))	('GBM tumors', 'Disease', 'MESH:D005910', (93, 103))	('resistant', 'CPA', (109, 118))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('more', 'PosReg', (104, 108))	('alters', 'Reg', (31, 37))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gene expression profiles', 'MPA', (42, 66))	('mutants', 'Var', (74, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (122, 125))
37581	32244981	These evidences connote that ZC3H13 may be an anti-cancer factor.	('ZC3H13', 'Var', (29, 35))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
37583	32244981	Inhibition of FTO, an m6A eraser, also impedes the self-renewal ability and tumorigenecity of GBM stem cells both in vitro and in mice models.	('self-renewal ability', 'CPA', (51, 71))	('mice', 'Species', '10090', (130, 134))	('impedes', 'NegReg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Inhibition', 'Var', (0, 10))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('FTO', 'Gene', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
37587	32244981	Silencing ALKBH5 inhibits cell proliferation of GSCs.	('inhibits', 'NegReg', (17, 25))	('GSC', 'Chemical', '-', (48, 51))	('ALKBH5', 'Gene', (10, 16))	('ALKBH5', 'Gene', '54890', (10, 16))	('Silencing', 'Var', (0, 9))	('cell proliferation of GSCs', 'CPA', (26, 52))
37589	32244981	ALKBH5 demethylates FOXM1 nascent transcripts, thereby enhancing its expression.	('ALKBH5', 'Gene', (0, 6))	('expression', 'MPA', (69, 79))	('FOXM1', 'Gene', (20, 25))	('demethylates', 'Var', (7, 19))	('FOXM1', 'Gene', '2305', (20, 25))	('enhancing', 'PosReg', (55, 64))	('ALKBH5', 'Gene', '54890', (0, 6))
37593	32244981	Importantly, the aberrant expression of m6A readers may contribute to GBM tumorigenesis independently of m6A alterations to some extent.	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('GBM tumor', 'Disease', 'MESH:D005910', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('aberrant expression', 'Var', (17, 36))	('m6A readers', 'Gene', (40, 51))	('GBM tumor', 'Disease', (70, 79))	('contribute', 'Reg', (56, 66))
37594	32244981	Based on current study, several families that exert as m6A readers are tightly related to the tumorigenesis of GBM.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('m6A', 'Var', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GBM', 'Disease', (111, 114))	('tumor', 'Disease', (94, 99))	('related', 'Reg', (79, 86))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
37597	32244981	YTHDC1 reads the m6A marks dependent on its tryptophan 377 (W377) or W428 sites.	('tryptophan', 'Chemical', 'MESH:D014364', (44, 54))	('YTHDC1', 'Gene', (0, 6))	('YTHDC1', 'Gene', '91746', (0, 6))	('W428 sites', 'Var', (69, 79))
37599	32244981	For instance, YTHDC1 deficiency reduces sphere number substantially in METTL3 overexpressed U87 cells but not in control cells.	('YTHDC1', 'Gene', (14, 20))	('YTHDC1', 'Gene', '91746', (14, 20))	('sphere number', 'CPA', (40, 53))	('deficiency', 'Var', (21, 31))	('reduces', 'NegReg', (32, 39))	('U87', 'CellLine', 'CVCL:0022', (92, 95))
37600	32244981	Overexpressing W377A/W428A mutant YTHDC1 cannot promotes the sphere formation capacity of U87 cells, suggesting that YTHDC1 promotes GBM phenotype dependently on its m6A binding activity.	('m6A', 'Protein', (166, 169))	('YTHDC1', 'Gene', (34, 40))	('YTHDC1', 'Gene', '91746', (34, 40))	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('YTHDC1', 'Gene', (117, 123))	('W377A', 'SUBSTITUTION', 'None', (15, 20))	('GBM phenotype', 'CPA', (133, 146))	('W428A', 'SUBSTITUTION', 'None', (21, 26))	('U87', 'CellLine', 'CVCL:0022', (90, 93))	('YTHDC1', 'Gene', '91746', (117, 123))	('promotes', 'PosReg', (124, 132))	('W377A', 'Var', (15, 20))	('binding', 'Interaction', (170, 177))	('W428A', 'Var', (21, 26))
37601	32244981	Another m6A reader protein family, the IGF2BP family, including IGF2BP1/2/3, inhibits the degradation of m6A-modified transcripts and facilitates their translation.	('degradation', 'MPA', (90, 101))	('translation', 'MPA', (152, 163))	('IGF2', 'Gene', '3481', (64, 68))	('IGF2', 'Gene', '3481', (39, 43))	('IGF2BP1/2/3', 'Gene', '10642;3481', (64, 75))	('IGF2', 'Gene', (64, 68))	('IGF2', 'Gene', (39, 43))	('IGF2BP1/2/3', 'Gene', (64, 75))	('m6A-modified', 'Var', (105, 117))	('inhibits', 'NegReg', (77, 85))	('facilitates', 'PosReg', (134, 145))
37605	32244981	Additionally, inhibition of IGF2BP2 sensitizes GBM to TMZ treatment.	('sensitizes', 'Reg', (36, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('IGF2BP2', 'Gene', '10644', (28, 35))	('inhibition', 'Var', (14, 24))	('IGF2BP2', 'Gene', (28, 35))
37618	32244981	eIF3a/b/h, also function as m6A readers, and can directly, physically and functionally interact with METTL3, thereby enhancing translation, and the formation of densely packed polyribosomes through recognizing m6A modification at the 5' UTR of mRNA.	('METTL3', 'Gene', (101, 107))	('eIF3', 'Gene', (0, 4))	('R', 'Chemical', 'MESH:D001120', (245, 246))	('m6A modification', 'Var', (210, 226))	('interact', 'Interaction', (87, 95))	('R', 'Chemical', 'MESH:D001120', (239, 240))	('eIF3', 'Gene', '8661', (0, 4))	('translation', 'MPA', (127, 138))	('enhancing', 'PosReg', (117, 126))
37620	32244981	eIF3b silencing significantly inhibits cell proliferation of U87 cells via inducing G0/G1-phase arrest and apoptosis.	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('U87', 'CellLine', 'CVCL:0022', (61, 64))	('arrest', 'Disease', (96, 102))	('eIF3b', 'Gene', (0, 5))	('eIF3b', 'Gene', '8668', (0, 5))	('cell proliferation', 'CPA', (39, 57))	('apoptosis', 'CPA', (107, 116))	('silencing', 'Var', (6, 15))	('inducing', 'Reg', (75, 83))	('inhibits', 'NegReg', (30, 38))
37622	32244981	During nuclear RNA processing period, hnRNPC and hnRNPA2B1 are other types of m6A readers that can bind to unfolded RNA through an m6A structural switch mechanism, since the m6A marked RNA cannot efficiently form secondary structures because the base pairing of m6A-U is weaker of than that of A-U.	('R', 'Chemical', 'MESH:D001120', (15, 16))	('base pairing', 'MPA', (246, 258))	('R', 'Chemical', 'MESH:D001120', (40, 41))	('R', 'Chemical', 'MESH:D001120', (116, 117))	('hnRNPA2B1', 'Gene', (49, 58))	('R', 'Chemical', 'MESH:D001120', (185, 186))	('hnRNPC', 'Gene', (38, 44))	('hnRNPA2B1', 'Gene', '3181', (49, 58))	('m6A-U', 'Var', (262, 267))	('hnRNPC', 'Gene', '3183', (38, 44))	('R', 'Chemical', 'MESH:D001120', (51, 52))
37633	32244981	However, most of their functions are dependent on their RNA binding capacity, implying that m6A in RNAs may be involved in their binding and their functions in GBM.	('RNAs', 'Gene', (99, 103))	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('R', 'Chemical', 'MESH:D001120', (56, 57))	('R', 'Chemical', 'MESH:D001120', (99, 100))	('involved', 'Reg', (111, 119))	('m6A', 'Var', (92, 95))	('binding', 'Interaction', (129, 136))
37634	32244981	These readers are like messengers of m6A marks but beyond that, because they not only deliver message of m6A modified mRNA, but also determine their fate.	('R', 'Chemical', 'MESH:D001120', (119, 120))	('m6A', 'Var', (105, 108))	('determine', 'Reg', (133, 142))	('mRNA', 'MPA', (118, 122))
37636	32244981	m6Am plays essential roles in RNA splicing, snRNA biogenesis, mRNA stability and cap-dependent translation.	('m6Am', 'Var', (0, 4))	('R', 'Chemical', 'MESH:D001120', (46, 47))	('mRNA stability', 'MPA', (62, 76))	('R', 'Chemical', 'MESH:D001120', (30, 31))	('R', 'Chemical', 'MESH:D001120', (63, 64))	('cap-dependent translation', 'MPA', (81, 106))	('RNA splicing', 'MPA', (30, 42))	('snRNA biogenesis', 'MPA', (44, 60))
37638	32244981	Recent evidence shows that FTO-mediated m6Am demethylation is an important regulatory mechanism in adjusting the stem-like properties of colorectal cancer cells, and many clues also imply that m6Am also emerges as an essential regulator in GBM (Figure 2, m6Am part).	('colorectal cancer', 'Disease', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('stem-like properties', 'CPA', (113, 133))	('GBM', 'Phenotype', 'HP:0012174', (240, 243))	('m6Am', 'Var', (40, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))
37640	32244981	DCP2 is upregulated in miR-338-5p overexpressed GBM cells and may participate in radiosensitivity and DNA damage response induced by miR-338-5p overexpression in GBM cells.	('DCP2', 'Gene', (0, 4))	('miR-338-5p overexpressed', 'Var', (23, 47))	('-5p', 'Chemical', '-', (140, 143))	('GBM', 'Phenotype', 'HP:0012174', (162, 165))	('DCP2', 'Gene', '167227', (0, 4))	('R', 'Chemical', 'MESH:D001120', (25, 26))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('DNA damage', 'MPA', (102, 112))	('miR-338-5p', 'Var', (133, 143))	('participate', 'Reg', (66, 77))	('-5p', 'Chemical', '-', (30, 33))	('upregulated', 'PosReg', (8, 19))	('R', 'Chemical', 'MESH:D001120', (135, 136))	('radiosensitivity', 'CPA', (81, 97))
37649	32244981	NSUN5, another RNA methyltransferase that is responsible for m5C in the C3782 position of human 28S rRNA, undergoes epigenetic loss in gliomas, which drives an overall depletion of protein synthesis, resulting in an adaptive translational program for survival under cellular stress and renders gliomas sensitive to bio-activatable substrates of the stress-related enzyme NAD(P)H quinone dehydrogenase 1 (NQO1).	('R', 'Chemical', 'MESH:D001120', (15, 16))	('glioma', 'Phenotype', 'HP:0009733', (294, 300))	('NQO1', 'Gene', (404, 408))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('human', 'Species', '9606', (90, 95))	('protein synthesis', 'MPA', (181, 198))	('gliomas', 'Phenotype', 'HP:0009733', (294, 301))	('R', 'Chemical', 'MESH:D001120', (101, 102))	('survival', 'CPA', (251, 259))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('depletion', 'MPA', (168, 177))	('NAD(P)H quinone dehydrogenase 1', 'Gene', '1728', (371, 402))	('gliomas', 'Disease', (294, 301))	('loss', 'NegReg', (127, 131))	('translational program', 'MPA', (225, 246))	('NQO1', 'Gene', '1728', (404, 408))	('gliomas', 'Disease', (135, 142))	('epigenetic', 'Var', (116, 126))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('gliomas', 'Disease', 'MESH:D005910', (294, 301))	('m5C', 'Chemical', '-', (61, 64))	('NSUN5', 'Gene', '55695', (0, 5))	('NSUN5', 'Gene', (0, 5))
37654	32244981	For example, hm5C is distributed at lncRNA loci, involved in long-range chromatin interactions and positively correlated with lncRNA transcription.	('m5C', 'Chemical', '-', (14, 17))	('R', 'Chemical', 'MESH:D001120', (39, 40))	('correlated', 'Reg', (110, 120))	('R', 'Chemical', 'MESH:D001120', (129, 130))	('lncRNA transcription', 'MPA', (126, 146))	('hm5C', 'Var', (13, 17))	('involved in', 'Reg', (49, 60))
37658	32244981	In nucleus, m1A modifications in pre-tRNA and pre-mRNA are catalyzed by tRNA methyltransferase 6/61A (TRMT6-TRMT61A) catalytic complex and are erased by ALKBH1 and ALKBH3, respectively.	('TRMT6', 'Gene', (108, 113))	('R', 'Chemical', 'MESH:D001120', (73, 74))	('TRMT61A', 'Gene', (108, 115))	('R', 'Chemical', 'MESH:D001120', (38, 39))	('TRMT61A', 'Gene', '115708', (108, 115))	('m1A', 'Var', (12, 15))	('ALKBH3', 'Gene', '221120', (164, 170))	('R', 'Chemical', 'MESH:D001120', (109, 110))	('tRNA methyltransferase 6/61A', 'Gene', '51605;115708', (72, 100))	('modifications', 'Var', (16, 29))	('TRMT6', 'Gene', '51605', (102, 107))	('m1A', 'Chemical', '-', (12, 15))	('ALKBH3', 'Gene', (164, 170))	('TRMT6', 'Gene', (102, 107))	('R', 'Chemical', 'MESH:D001120', (51, 52))	('pre-mRNA', 'MPA', (46, 54))	('TRMT6', 'Gene', '51605', (108, 113))	('tRNA methyltransferase 6/61A', 'Gene', (72, 100))	('R', 'Chemical', 'MESH:D001120', (103, 104))
37663	32244981	The eraser ALKBH1 also seems to be an important regulator in GBM, since targeting ALKBH1 in patient-derived GBM models induces cell proliferation inhibition and extends the survival of tumor-bearing mice.	('tumor', 'Disease', (185, 190))	('extends', 'PosReg', (161, 168))	('patient', 'Species', '9606', (92, 99))	('mice', 'Species', '10090', (199, 203))	('inhibition', 'NegReg', (146, 156))	('cell proliferation', 'CPA', (127, 145))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('ALKBH1', 'Gene', (82, 88))	('targeting', 'Var', (72, 81))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
37664	32244981	However, this effect may be caused by ALKBH1-induced DNA demethylation on hypoxia response genes, while not ALKBH1-controlled tRNA stability.	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('hypoxia', 'Disease', (74, 81))	('DNA', 'Reg', (53, 56))	('R', 'Chemical', 'MESH:D001120', (127, 128))	('caused by', 'Reg', (28, 37))	('ALKBH1-induced', 'Var', (38, 52))
37665	32244981	A-to-I RNA editing is abundant in the human transcriptome and plays essential roles in RNA processing, such as post-transcriptionally altering codons, introducing or removing splice sites, and affecting the base pairing of the RNA molecule with itself or with other RNAs.	('removing', 'NegReg', (166, 174))	('altering', 'Reg', (134, 142))	('human', 'Species', '9606', (38, 43))	('codons', 'MPA', (143, 149))	('introducing', 'Reg', (151, 162))	('base pairing', 'MPA', (207, 219))	('R', 'Chemical', 'MESH:D001120', (266, 267))	('splice sites', 'MPA', (175, 187))	('R', 'Chemical', 'MESH:D001120', (87, 88))	('R', 'Chemical', 'MESH:D001120', (7, 8))	('editing', 'Var', (11, 18))	('R', 'Chemical', 'MESH:D001120', (227, 228))	('affecting', 'Reg', (193, 202))
37668	32244981	In addition, abnormal expression of an ADAR2 alternative splicing variant also downregulates A-to-I RNA editing in glioma, because ADAR2 can prevent GBM tumor growth via modulating an important cell cycle pathway involving S-phase kinase associated protein 2 (Skp2), p21 and p27 proteins by introducing an A-to-I editing in the pre-mRNA of a phosphatase cell division cycle 14B (CDC14B).	('glioma', 'Disease', (115, 121))	('S-phase kinase associated protein 2', 'Gene', '6502', (223, 258))	('R', 'Chemical', 'MESH:D001120', (134, 135))	('R', 'Chemical', 'MESH:D001120', (333, 334))	('prevent', 'NegReg', (141, 148))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('modulating', 'Reg', (170, 180))	('S-phase kinase associated protein 2', 'Gene', (223, 258))	('p27', 'Gene', '3429', (275, 278))	('p27', 'Gene', (275, 278))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('phosphatase', 'Gene', (342, 353))	('ADAR2', 'Gene', '104', (131, 136))	('R', 'Chemical', 'MESH:D001120', (100, 101))	('ADAR2', 'Gene', (39, 44))	('Skp2', 'Gene', (260, 264))	('proteins', 'Protein', (279, 287))	('phosphatase', 'Gene', '5728', (342, 353))	('downregulates', 'NegReg', (79, 92))	('R', 'Chemical', 'MESH:D001120', (42, 43))	('p21', 'Gene', (267, 270))	('Skp2', 'Gene', '6502', (260, 264))	('CDC14B', 'Gene', (379, 385))	('editing', 'Var', (313, 320))	('p21', 'Gene', '644914', (267, 270))	('GBM tumor', 'Disease', 'MESH:D005910', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('CDC14B', 'Gene', '8555', (379, 385))	('GBM tumor', 'Disease', (149, 158))	('ADAR2', 'Gene', (131, 136))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('ADAR2', 'Gene', '104', (39, 44))	('cell cycle pathway', 'Pathway', (194, 212))
37669	32244981	Additionally, A-to-I editing in miR-376a-3p is attenuated in GBM, thus promoting invasiveness of this disease.	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('R', 'Chemical', 'MESH:D001120', (34, 35))	('miR-376a-3p', 'Var', (32, 43))	('invasiveness', 'MPA', (81, 93))	('promoting', 'PosReg', (71, 80))	('attenuated', 'NegReg', (47, 57))	('GBM', 'Disease', (61, 64))
37678	32244981	These emerging evidences provide us the importance of pseudouridine modification in RNAs during the pathogenesis of GBM (Figure 2, psi part).	('R', 'Chemical', 'MESH:D001120', (84, 85))	('pseudouridine', 'Chemical', 'MESH:D011560', (54, 67))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('RNAs', 'Gene', (84, 88))	('pseudouridine modification', 'Var', (54, 80))	('GBM', 'Disease', (116, 119))
37679	32244981	Although most of the other RNA modifications are not well described, there are also some studies regarding the effect of these RNA modifications on GBM progression.	('R', 'Chemical', 'MESH:D001120', (27, 28))	('modifications', 'Var', (31, 44))	('modifications', 'Var', (131, 144))	('R', 'Chemical', 'MESH:D001120', (127, 128))	('GBM progression', 'CPA', (148, 163))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))
37680	32244981	For instance, ADAR2 and ADAR3 binds to the pre-mRNA of glutamate receptor subunit B, glutamate receptor ionotropic AMPA (GRIA2), contributing to a RNA editing at the Q/R site by modifying a codon replacing the glutamine (Q) with arginine (R).	('ADAR3', 'Gene', '105', (24, 29))	('GRIA2', 'Gene', (121, 126))	('R', 'Chemical', 'MESH:D001120', (27, 28))	('glutamine', 'Chemical', 'MESH:D005973', (210, 219))	('modifying', 'Var', (178, 187))	('R', 'Chemical', 'MESH:D001120', (122, 123))	('R', 'Chemical', 'MESH:D001120', (239, 240))	('ADAR2', 'Gene', '104', (14, 19))	('ADAR2', 'Gene', (14, 19))	('GRIA2', 'Gene', '2891', (121, 126))	('R', 'Chemical', 'MESH:D001120', (147, 148))	('ADAR3', 'Gene', (24, 29))	('RNA editing', 'MPA', (147, 158))	('R', 'Chemical', 'MESH:D001120', (17, 18))	('R', 'Chemical', 'MESH:D001120', (48, 49))	('R', 'Chemical', 'MESH:D001120', (168, 169))	('arginine', 'Chemical', 'MESH:D001120', (229, 237))
37681	32244981	ADAR2/3 deficiency in GBM leads to increased unedited GRIA2 subunits, thereby leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion.	('calcium-permeable', 'MPA', (89, 106))	('leads to', 'Reg', (78, 86))	('tumor', 'Disease', (164, 169))	('increased', 'PosReg', (35, 44))	('unedited', 'MPA', (45, 53))	('cell migration', 'CPA', (145, 159))	('promote', 'PosReg', (137, 144))	('calcium', 'Chemical', 'MESH:D002118', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('GRIA2', 'Gene', (54, 59))	('GBM', 'Phenotype', 'HP:0012174', (22, 25))	('deficiency', 'Var', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ADAR2/3', 'Gene', '104;105', (0, 7))	('GRIA2', 'Gene', '2891', (54, 59))	('ADAR2/3', 'Gene', (0, 7))
37683	32244981	CFIm25 knockdown leads to at least 1,450 genes with shortened 3'UTRs and marked increases in the expression of several oncogenes in GBM, including cyclin D1 (CCND1), glutaminase (GLS) and methyl-CpG-binding protein 2 (MECP2), thereby enhancing their tumorigenesis.	('glutaminase', 'Gene', '2744', (166, 177))	('cyclin D1', 'Gene', '595', (147, 156))	('tumor', 'Disease', (250, 255))	('GBM', 'Phenotype', 'HP:0012174', (132, 135))	('methyl-CpG-binding protein 2', 'Gene', (188, 216))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('GLS', 'Gene', '2744', (179, 182))	('expression', 'MPA', (97, 107))	('methyl-CpG-binding protein 2', 'Gene', '4204', (188, 216))	('glutaminase', 'Gene', (166, 177))	('CCND1', 'Gene', '595', (158, 163))	('CFIm25', 'Gene', '11051', (0, 6))	('enhancing', 'PosReg', (234, 243))	('increases', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('R', 'Chemical', 'MESH:D001120', (66, 67))	('CCND1', 'Gene', (158, 163))	('GLS', 'Gene', (179, 182))	('CFIm25', 'Gene', (0, 6))	('MECP2', 'Gene', '4204', (218, 223))	('MECP2', 'Gene', (218, 223))	('knockdown', 'Var', (7, 16))	('cyclin D1', 'Gene', (147, 156))
37688	32244981	Chemical modifications in both DNA and proteins have been well studied in cancer biology, and many chemical modifications such as DNA methylation, histone modification and EGFR post-translational modifications, as well as some of their modification enzymes have been shown to have clinical significance in both the diagnosis and therapy.	('EGFR', 'Gene', '1956', (172, 176))	('DNA', 'Gene', (130, 133))	('histone modification', 'MPA', (147, 167))	('methylation', 'Var', (134, 145))	('EGFR', 'Gene', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
37689	32244981	Actually, as kinds of chemical modifications, RNA modifications and their RMPs also give promise to both the diagnosis and therapeutics of GBM in the future.	('R', 'Chemical', 'MESH:D001120', (46, 47))	('R', 'Chemical', 'MESH:D001120', (74, 75))	('modifications', 'Var', (50, 63))	('GBM', 'Disease', (139, 142))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
37690	32244981	For example, the epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) significantly affects the TMZ treatment of GBM.	('O6-methylguanine-DNA methyltransferase', 'Gene', (45, 83))	('MGMT', 'Gene', '4255', (85, 89))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('affects', 'Reg', (105, 112))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (45, 83))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('MGMT', 'Gene', (85, 89))	('TMZ treatment', 'MPA', (117, 130))	('epigenetic silencing', 'Var', (17, 37))
37692	32244981	As a kind of chemical modifications in RNA, the alterations of their regulations may also predict the prognosis or be used for diagnosis of GBM.	('predict', 'Reg', (90, 97))	('R', 'Chemical', 'MESH:D001120', (39, 40))	('alterations', 'Var', (48, 59))	('regulations', 'MPA', (69, 80))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))
37693	32244981	Actually, m6A in in peripheral blood RNA has shown to be a predictive biomarker for gastric cancer.	('m6A', 'Var', (10, 13))	('R', 'Chemical', 'MESH:D001120', (37, 38))	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
37699	32244981	Covalent modifications in both DNA, histones and other proteins have shown promising probability for cancer treatment.	('DNA', 'Protein', (31, 34))	('proteins', 'Protein', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('Covalent modifications', 'Var', (0, 22))	('cancer', 'Disease', (101, 107))	('histones', 'Protein', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
37707	32244981	Recently, a small molecule inhibitor of METTL3 is also shown to curb the development of acute myeloid leukemia (AML) in vivo.	('METTL3', 'Gene', (40, 46))	('acute myeloid leukemia', 'Disease', (88, 110))	('AML', 'Disease', 'MESH:D015470', (112, 115))	('inhibitor', 'Var', (27, 36))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (88, 110))	('curb', 'NegReg', (64, 68))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (88, 110))	('AML', 'Phenotype', 'HP:0004808', (112, 115))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (94, 110))	('AML', 'Disease', (112, 115))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))
37752	32111152	The basic assumption of our simulation studies is that cancer progression operates through dysregulation of key pathways and that all the genes in specific pathways contribute to prognosis and survival.	('dysregulation', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('contribute', 'Reg', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('key pathways', 'Pathway', (108, 120))	('cancer', 'Disease', (55, 61))
37773	32111152	The authors are grateful for the financial support from research grants 1K01LM012426 NIH/NLM, P20GM130454 NIH/NIGMS, U01CA196386 NIH/NCI and CA023108 NIH/NCI.	('NIH/NCI', 'CellLine', 'CVCL:0601', (129, 136))	('NIH/NCI', 'CellLine', 'CVCL:0601', (150, 157))	('P20GM130454', 'Var', (94, 105))	('CA023108 NIH/NCI', 'Var', (141, 157))	('U01CA196386', 'Var', (117, 128))
37779	24287492	GBM tumors harbor a series of mutations that provide cells with selective growth advantages that promote survival and proliferation in a hostile and hypoxic environment.	('GBM tumors', 'Disease', (0, 10))	('GBM tumors', 'Disease', 'MESH:D005910', (0, 10))	('rat', 'Species', '10116', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('proliferation', 'CPA', (118, 131))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('survival', 'CPA', (105, 113))	('promote', 'PosReg', (97, 104))
37780	24287492	For example, 30%-40% of GBM tumors have amplification of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor that activates MAPK and PI3K signaling.	('epidermal growth factor receptor', 'Gene', (61, 93))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('epidermal growth factor receptor', 'Gene', '1956', (61, 93))	('EGFR', 'Gene', (95, 99))	('amplification', 'Var', (40, 53))	('EGFR', 'Gene', '1956', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('GBM tumors', 'Disease', (24, 34))	('GBM tumors', 'Disease', 'MESH:D005910', (24, 34))
37781	24287492	In addition, a subset of GBM tumors expresses an EGFRVIII variant in which the extracellular domain of the receptor is lacking, resulting in constitutive activation.	('GBM tumors', 'Disease', (25, 35))	('EGFR', 'Gene', '1956', (49, 53))	('GBM tumors', 'Disease', 'MESH:D005910', (25, 35))	('EGFR', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('constitutive activation', 'MPA', (141, 164))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('variant', 'Var', (58, 65))
37782	24287492	Tumor suppressor genes, such as p53, p21, p16, and PTEN are commonly mutated in GBMs, pointing to the highly unstable nature of the cells.	('p16', 'Gene', '1029', (42, 45))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutated', 'Var', (69, 76))	('p53', 'Gene', (32, 35))	('p16', 'Gene', (42, 45))	('p21', 'Gene', (37, 40))	('PTEN', 'Gene', (51, 55))	('p21', 'Gene', '644914', (37, 40))	('PTEN', 'Gene', '5728', (51, 55))
37823	24287492	Methylation of the MGMT promoter occurs in approximately 45% of newly diagnosed glioblastoma patients and is prognostic for response to TMZ treatment.	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('MGMT promoter', 'Gene', (19, 32))	('Methylation', 'Var', (0, 11))	('TMZ', 'Chemical', 'MESH:D000077204', (136, 139))	('glioblastoma', 'Disease', (80, 92))	('patients', 'Species', '9606', (93, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))
37830	24287492	This study provides an explanation for tumors with unmethylated MGMT promoter and low MGMT expression and provides further insight into molecular mechanisms that regulate MGMT expression.	('expression', 'MPA', (91, 101))	('unmethylated', 'Var', (51, 63))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('MGMT', 'Gene', (86, 90))	('MGMT promoter', 'Gene', (64, 77))	('low', 'NegReg', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))
37832	24287492	Inhibition of MGMT in combination with TMZ has been studied as an approach to improve treatment of GBMs in the clinic.	('MGMT', 'Gene', (14, 18))	('GBMs', 'Disease', (99, 103))	('Inhibition', 'Var', (0, 10))	('TMZ', 'Chemical', 'MESH:D000077204', (39, 42))
37834	24287492	Initial phase I clinical trials showed that O6-BG effectively inhibits MGMT in GBM tumors, but TMZ therapy in combination with O6-BG was limited by myelosuppression.	('MGMT', 'MPA', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('O6-BG', 'Chemical', 'MESH:C064976', (44, 49))	('myelosuppression', 'Disease', (148, 164))	('inhibits', 'NegReg', (62, 70))	('O6-BG', 'Chemical', 'MESH:C064976', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))	('O6-BG', 'Var', (44, 49))	('myelosuppression', 'Disease', 'MESH:D001855', (148, 164))	('GBM tumors', 'Disease', (79, 89))	('GBM tumors', 'Disease', 'MESH:D005910', (79, 89))
37846	24287492	Both in vitro and in vivo, MGMT siRNA enhanced sensitivity to TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (62, 65))	('enhanced', 'PosReg', (38, 46))	('MGMT siRNA', 'Var', (27, 37))	('sensitivity to TMZ', 'MPA', (47, 65))
37864	24287492	Direct sequencing of MSH6 identified mutations, many of which did not hinder generation of wild-type protein.	('mutations', 'Var', (37, 46))	('rat', 'Species', '10116', (81, 84))	('MSH6', 'Gene', '2956', (21, 25))	('MSH6', 'Gene', (21, 25))
37871	24287492	Single nucleotide polymorphism (SNPs) analysis of patient samples treated with radiation alone or with TMZ showed that 50% harbored MSH6 G268A polymorphisms.	('TMZ', 'Chemical', 'MESH:D000077204', (103, 106))	('MSH6', 'Gene', (132, 136))	('G268A', 'Mutation', 'rs142649575', (137, 142))	('G268A', 'Var', (137, 142))	('MSH6', 'Gene', '2956', (132, 136))	('patient', 'Species', '9606', (50, 57))
37872	24287492	However, no OS benefit was noted between samples harboring or lacking MSH6 G268A.	('G268A', 'Var', (75, 80))	('MSH6', 'Gene', (70, 74))	('MSH6', 'Gene', '2956', (70, 74))	('G268A', 'Mutation', 'rs142649575', (75, 80))
37876	24287492	focused their studies on a cohort of The Cancer Genome Atlas (TCGA) recurrent tumors, which had been previously found to have MSH6 mutations.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('MSH6', 'Gene', '2956', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Cancer Genome Atlas', 'Disease', (41, 60))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (41, 60))	('MSH6', 'Gene', (126, 130))
37877	24287492	Analysis of samples pre and post exposure to alkylating agents showed the MSH6 mutations were not present in pre-treatment samples indicative that these mutations arose as a result of therapy.	('MSH6', 'Gene', (74, 78))	('MSH6', 'Gene', '2956', (74, 78))	('mutations', 'Var', (79, 88))
37880	24287492	Similarly, knockdown of MSH6 in the glioma U251 line reduced sensitivity to TMZ.	('MSH6', 'Gene', (24, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (76, 79))	('MSH6', 'Gene', '2956', (24, 28))	('glioma', 'Disease', (36, 42))	('sensitivity to TMZ', 'MPA', (61, 79))	('reduced', 'NegReg', (53, 60))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('knockdown', 'Var', (11, 20))
37882	24287492	Some of the contradictory reports may be attributed to the fact that high levels of MSI have been correlated to deficient MMR and thus used as a readout for MMR deficiency, despite reports indicating no correlation between the two.	('MMR', 'Protein', (122, 125))	('deficient', 'Var', (112, 121))	('MMR deficiency', 'Disease', (157, 171))	('MMR deficiency', 'Disease', 'MESH:C536143', (157, 171))	('MSI', 'MPA', (84, 87))
37885	24287492	Surviving tumor cells are likely to have acquired MMR mutations, resulting in acquired tolerance to further TMZ therapy: a situation typical of GBMs in the clinic.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('tumor', 'Disease', (10, 15))	('mutations', 'Var', (54, 63))	('MMR', 'Gene', (50, 53))	('tolerance to further TMZ therapy', 'MPA', (87, 119))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
37899	24287492	isolated a population of cells from human GBM tumors that co-expressed the stem cell marker, CD133+, and the endothelial progenitor marker, CD144+.	('GBM tumors', 'Disease', (42, 52))	('GBM tumors', 'Disease', 'MESH:D005910', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD133+', 'Var', (93, 99))	('CD144', 'Gene', '1003', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (36, 41))	('CD144', 'Gene', (140, 145))
37919	24287492	The existence of GECs in GBMs may provide a novel therapeutic target in which the inhibition of differentiation may reduce tumor burden via decreased tumor angiogenesis.	('decreased', 'NegReg', (140, 149))	('reduce', 'NegReg', (116, 122))	('tumor', 'Disease', (123, 128))	('inhibition', 'Var', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
37934	24287492	Tumors initiated by C6 CSCs had increased microvessel density, increased proliferation, and more circulating endothelial progenitor cells than non-CSCs, suggesting these cells significantly contribute to the development of tumor vasculature.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('more', 'PosReg', (92, 96))	('microvessel density', 'CPA', (42, 61))	('increased', 'PosReg', (63, 72))	('proliferation', 'CPA', (73, 86))	('rat', 'Species', '10116', (80, 83))	('C6 CSCs', 'Var', (20, 27))	('circulating endothelial progenitor cells', 'CPA', (97, 137))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('increased', 'PosReg', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (223, 228))
37938	24287492	found that human GBM CSCs (nestin+/CD133+) preferentially associate with endothelial cells in vivo.	('preferentially', 'PosReg', (43, 57))	('nestin+/CD133+', 'Var', (27, 41))	('associate', 'Interaction', (58, 67))	('human', 'Species', '9606', (11, 16))
37945	24287492	When co-cultured cells (CD133+ with tMVECs) were treated with both IR and TMZ, CD133+ cells showed increased proliferation, indicating resistance to the standard of care.	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('rat', 'Species', '10116', (116, 119))	('increased', 'PosReg', (99, 108))	('CD133+', 'Var', (79, 85))	('proliferation', 'CPA', (109, 122))
37955	24287492	It was found that BMI1, a member of the polycomb group that represses gene expression, is enriched in CD133+ GBM CSCs, possibly increasing recognition and repair of IR induced DSBs.	('DSBs', 'Chemical', '-', (176, 180))	('increasing', 'PosReg', (128, 138))	('CD133+', 'Var', (102, 108))	('BMI1', 'Gene', '648', (18, 22))	('BMI1', 'Gene', (18, 22))
37965	24287492	CSCs promote vasculogenesis as well as angiogenesis, can become resistant to chemotherapy by up-regulating cell cycle checkpoints and survival pathways, and may mediate tumor recurrence.	('survival pathways', 'Pathway', (134, 151))	('CSCs', 'Var', (0, 4))	('promote', 'PosReg', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cell cycle', 'CPA', (107, 117))	('angiogenesis', 'CPA', (39, 51))	('mediate', 'Reg', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('vasculogenesis', 'CPA', (13, 27))	('tumor', 'Disease', (169, 174))	('up-regulating', 'PosReg', (93, 106))
37968	24287492	Over-expression of VEGFA activates the VEGFR pathway, promoting the proliferation, migration, and survival of endothelial cells, resulting in the formation of tumor blood vessels.	('proliferation', 'CPA', (68, 81))	('survival', 'CPA', (98, 106))	('VEGFR', 'Gene', (39, 44))	('rat', 'Species', '10116', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('promoting', 'PosReg', (54, 63))	('VEGFA', 'Gene', (19, 24))	('VEGFR', 'Gene', '3791', (39, 44))	('tumor', 'Disease', (159, 164))	('Over-expression', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('rat', 'Species', '10116', (86, 89))	('migration', 'CPA', (83, 92))
37983	24287492	First, the combination of bevacizumab with irinotecan is efficacious in other aggressive solid tumors; for example, bevacizumab plus irinotecan increased the OS of metastatic colorectal cancer patients versus single agent or placebo.	('irinotecan', 'Chemical', 'MESH:D000077146', (43, 53))	('bevacizumab', 'Var', (116, 127))	('patients', 'Species', '9606', (193, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('aggressive solid tumors', 'Disease', (78, 101))	('irinotecan', 'Chemical', 'MESH:D000077146', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (175, 192))	('bevacizumab', 'Chemical', 'MESH:D000068258', (26, 37))	('bevacizumab', 'Chemical', 'MESH:D000068258', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('aggressive solid tumors', 'Disease', 'MESH:D009369', (78, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('increased', 'PosReg', (144, 153))
38017	24287492	TMZ induces autophagy in glioma cells as demonstrated by the increase in LC3-GFP-positive vacuoles and levels of LC3B-II, as well as an accumulation of auto-fluorescent monodansylcadaverine in autophagic vacuoles.	('LC3', 'Gene', (113, 116))	('autophagic vacuoles', 'Phenotype', 'HP:0003736', (193, 212))	('accumulation', 'PosReg', (136, 148))	('glioma', 'Disease', (25, 31))	('LC3', 'Gene', '84557', (113, 116))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('monodansylcadaverine', 'Chemical', 'MESH:C008542', (169, 189))	('autophagy', 'CPA', (12, 21))	('LC3', 'Gene', '84557', (73, 76))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('TMZ', 'Var', (0, 3))	('LC3', 'Gene', (73, 76))	('increase', 'PosReg', (61, 69))	('auto-fluorescent monodansylcadaverine', 'MPA', (152, 189))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('rat', 'Species', '10116', (48, 51))
38022	24287492	Disruption of the MSH2-MSH6 complex or ATM kinase, via siRNA knockdown, abrogated autophagy, demonstrating that an intact MMR and ATM kinase is required for autophagy induction.	('abrogated', 'NegReg', (72, 81))	('MSH6', 'Gene', '2956', (23, 27))	('ATM', 'Gene', (39, 42))	('ATM', 'Gene', (130, 133))	('MSH6', 'Gene', (23, 27))	('MSH2', 'Gene', (18, 22))	('MSH2', 'Gene', '4436', (18, 22))	('autophagy', 'CPA', (82, 91))	('ATM', 'Gene', '472', (39, 42))	('ATM', 'Gene', '472', (130, 133))	('rat', 'Species', '10116', (100, 103))	('Disruption', 'Var', (0, 10))
38035	24287492	Initial in vivo studies evaluating the therapeutic efficacy of NVP-BEZ235 alone showed an increase in survival of mice in an U87 intracranial model over vehicle-treated mice.	('NVP-BEZ235', 'Var', (63, 73))	('increase', 'PosReg', (90, 98))	('survival', 'CPA', (102, 110))	('mice', 'Species', '10090', (169, 173))	('U87', 'CellLine', 'CVCL:0022', (125, 128))	('mice', 'Species', '10090', (114, 118))	('BEZ235', 'Chemical', 'MESH:C531198', (67, 73))
38038	24287492	Inhibiting autophagy in combination with other therapies is a promising approach to reduce tumor cell survival following chemotherapy and is now being tested in the clinic.	('reduce', 'NegReg', (84, 90))	('Inhibiting', 'Var', (0, 10))	('autophagy', 'CPA', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
38051	24287492	CD133+ neurospheres showed increased autophagy when exposed to rapamycin and radiation.	('increased', 'PosReg', (27, 36))	('autophagy', 'CPA', (37, 46))	('CD133+', 'Var', (0, 6))	('rapamycin', 'Chemical', 'MESH:D020123', (63, 72))
38056	24287492	One explanation proposed to explain the conflicting studies is that NVP-BEZ235 simultaneously induces autophagy (decreasing radiosensitivity) and impairs DNA damage repair (increasing radiosensitivity).	('impairs', 'NegReg', (146, 153))	('decreasing', 'NegReg', (113, 123))	('induces', 'PosReg', (94, 101))	('BEZ235', 'Chemical', 'MESH:C531198', (72, 78))	('DNA damage', 'MPA', (154, 164))	('decreasing radiosensitivity', 'Phenotype', 'HP:0010997', (113, 140))	('autophagy', 'CPA', (102, 111))	('increasing radiosensitivity', 'Phenotype', 'HP:0010997', (173, 200))	('NVP-BEZ235', 'Var', (68, 78))
38057	24287492	It is important to note that radiosensitization by NVP-BEZ235 is dependent on the drug-irradiation schedule.	('NVP-BEZ235', 'Var', (51, 61))	('radiosensitization', 'MPA', (29, 47))	('BEZ235', 'Chemical', 'MESH:C531198', (55, 61))
38058	24287492	Cells treated with NVP-BEZ235 prior to IR arrested in G1 and showed less DNA damage as assessed by histone gammaH2AX expression.	('NVP-BEZ235', 'Var', (19, 29))	('arrested', 'NegReg', (42, 50))	('BEZ235', 'Chemical', 'MESH:C531198', (23, 29))
38059	24287492	In contrast, NVP-BEZ235 administration before, during, and after radiation sensitized glioma cultures which was characterized by an increase in apoptosis, DNA damage, a prolonged G2/M arrest.	('glioma', 'Disease', (86, 92))	('G2/M arrest', 'CPA', (179, 190))	('rat', 'Species', '10116', (32, 35))	('increase', 'PosReg', (132, 140))	('BEZ235', 'Chemical', 'MESH:C531198', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('apoptosis', 'CPA', (144, 153))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('DNA', 'CPA', (155, 158))	('NVP-BEZ235', 'Var', (13, 23))
38068	24287492	Other than the free carboxylic acid (2, R = H), these compounds have all been shown active against GBM and colorectal cells lines that are resistant to TMZ, whether because of proficient MGMT or having deficiency or mutation in the MMR components hMLH1 or hMSH6.	('deficiency', 'Disease', (202, 212))	('hMLH1', 'Gene', (247, 252))	('TMZ', 'Chemical', 'MESH:D000077204', (152, 155))	('deficiency', 'Disease', 'MESH:D007153', (202, 212))	('carboxylic acid', 'Chemical', 'MESH:D002264', (20, 35))	('MGMT', 'CPA', (187, 191))	('mutation', 'Var', (216, 224))	('hMSH6', 'Gene', (256, 261))	('hMSH6', 'Gene', '2956', (256, 261))	('hMLH1', 'Gene', '4292', (247, 252))
38082	24287492	In screening against A2780 (MMR+, MGMT+) and A278-cp70 (MMR-, MGMT+) cells in the presence and absence of PaTrin2, monofunctional compounds such as DP86 were as potent as mitozolomide (the more potent but myelosuppressive 3-chloroethyl analogue of TMZ).	('mitozolomide', 'Chemical', 'MESH:C040369', (171, 183))	('TMZ', 'Chemical', 'MESH:D000077204', (248, 251))	('mitozolomide', 'MPA', (171, 183))	('A278-cp70', 'Var', (45, 54))	('DP86', 'Chemical', '-', (148, 152))
38083	24287492	The bifunctional agents were significantly more active than TMZ.	('more', 'PosReg', (43, 47))	('bifunctional', 'Var', (4, 16))	('TMZ', 'Chemical', 'MESH:D000077204', (60, 63))	('active', 'MPA', (48, 54))
38085	24287492	Moreover, matrix COMPARE analysis showed that the new agents are pharmacologically distinct from standard agents that generate aziridinium or diazonium ions, that react at G-N7 or G-O6, or crosslink DNA such as nitrogen mustards, nitrosoureas and cisplatin.	('nitrosourea', 'Chemical', 'MESH:D009607', (230, 241))	('crosslink', 'Reg', (189, 198))	('G-N7', 'Var', (172, 176))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('G-O6', 'Chemical', '-', (180, 184))	('G-O6', 'Var', (180, 184))	('rat', 'Species', '10116', (122, 125))	('diazonium', 'Chemical', '-', (142, 151))	('aziridinium', 'Chemical', '-', (127, 138))	('nitrogen', 'Chemical', 'MESH:D009584', (211, 219))
38086	24287492	DP68 has further been shown to effectively crosslink DNA in cells [R.M.	('DP68', 'Var', (0, 4))	('DP68', 'Chemical', '-', (0, 4))	('crosslink', 'Interaction', (43, 52))
38088	24287492	This finding is doubly significant as it shows that there is an escape pathway for healthy cells to survive damage by DP68, and also that a tumor with deficiency or mutation in the ATR/FANCD2 pathway (which includes BRCA1 and BRCA2) would be hypersensitive to this agent.	('FANCD2', 'Gene', '2177', (185, 191))	('BRCA2', 'Gene', '675', (226, 231))	('FANCD2', 'Gene', (185, 191))	('BRCA1', 'Gene', (216, 221))	('deficiency', 'Disease', (151, 161))	('hypersensitive', 'Disease', 'MESH:D004342', (242, 256))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutation', 'Var', (165, 173))	('hypersensitive', 'Disease', (242, 256))	('DP68', 'Chemical', '-', (118, 122))	('ATR', 'Gene', '545', (181, 184))	('deficiency', 'Disease', 'MESH:D007153', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('ATR', 'Gene', (181, 184))	('BRCA2', 'Gene', (226, 231))	('DP68', 'Var', (118, 122))	('BRCA1', 'Gene', '672', (216, 221))	('tumor', 'Disease', (140, 145))
38089	24287492	Using large-scale sequencing, several novel and exciting glioblastoma-associated mutations were identified.	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('mutations', 'Var', (81, 90))	('glioblastoma', 'Disease', (57, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))
38090	24287492	They found that 50%-80% of low-grade gliomas carried mutations of isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2).	('IDH2', 'Gene', (131, 135))	('IDH1', 'Gene', (94, 98))	('isocitrate', 'Chemical', 'MESH:C034219', (103, 113))	('IDH1', 'Gene', '3417', (94, 98))	('IDH2', 'Gene', '3418', (131, 135))	('isocitrate', 'Chemical', 'MESH:C034219', (66, 76))	('mutations', 'Var', (53, 62))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
38091	24287492	Later studies showed that 5% of primary glioblastomas and 60-90% of secondary glioblastomas express mutant IDH proteins.	('glioblastomas', 'Disease', 'MESH:D005909', (78, 91))	('glioblastomas', 'Phenotype', 'HP:0012174', (40, 53))	('mutant', 'Var', (100, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('glioblastomas', 'Disease', (78, 91))	('glioblastomas', 'Disease', 'MESH:D005909', (40, 53))	('IDH', 'Gene', (107, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('IDH', 'Gene', '3417', (107, 110))	('glioblastomas', 'Disease', (40, 53))	('glioblastomas', 'Phenotype', 'HP:0012174', (78, 91))
38097	24287492	For both enzymes, arginines in the catalytic pocket (IDH1 R132 and IDH2 R140 or R172) were mutated.	('IDH2', 'Gene', (67, 71))	('IDH1', 'Gene', (53, 57))	('R140', 'Var', (72, 76))	('IDH2', 'Gene', '3418', (67, 71))	('IDH1', 'Gene', '3417', (53, 57))	('arginines', 'Chemical', 'MESH:D001120', (18, 27))	('R172', 'Var', (80, 84))
38098	24287492	The uniqueness of these mutations suggested a gain-of-function mutation, and a subsequent study demonstrated that these mutated IDH enzymes reduced alpha-KG to an oncometabolite, 2-hydroxyglutarate (2-HG).	('rat', 'Species', '10116', (103, 106))	('rat', 'Species', '10116', (193, 196))	('IDH', 'Gene', (128, 131))	('alpha-KG', 'Chemical', '-', (148, 156))	('IDH', 'Gene', '3417', (128, 131))	('mutations', 'Var', (24, 33))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (179, 197))	('alpha-KG to an oncometabolite', 'MPA', (148, 177))	('reduced', 'NegReg', (140, 147))	('mutated', 'Var', (120, 127))
38099	24287492	Overexpression of these mutated IDH enzymes induces histone and DNA hypermethylation and blocks cellular differentiation.	('mutated', 'Var', (24, 31))	('DNA hypermethylation', 'MPA', (64, 84))	('blocks', 'NegReg', (89, 95))	('cellular differentiation', 'CPA', (96, 120))	('histone', 'MPA', (52, 59))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('induces', 'PosReg', (44, 51))
38101	24287492	One appealing model is that 2-HG, which accumulates to high levels in cells with IDH mutations, competitively inhibits alpha-KG-dependent enzymes.	('inhibits', 'NegReg', (110, 118))	('mutations', 'Var', (85, 94))	('alpha-KG', 'Chemical', '-', (119, 127))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', '3417', (81, 84))	('alpha-KG-dependent enzymes', 'Enzyme', (119, 145))
38110	24287492	Although IDH is universally expressed, the unique IDH mutations could be specifically targeted, lowering levels of 2-HG and hopefully retarding tumor growth.	('levels of 2-HG', 'MPA', (105, 119))	('retarding tumor', 'Disease', (134, 149))	('mutations', 'Var', (54, 63))	('lowering', 'NegReg', (96, 104))	('IDH', 'Gene', (9, 12))	('retarding tumor', 'Disease', 'MESH:D009369', (134, 149))	('IDH', 'Gene', (50, 53))	('IDH', 'Gene', '3417', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('IDH', 'Gene', '3417', (50, 53))
38116	24287492	For example, a mutated IDH inhibitor with low toxicity might delay progression of low-grade to high-grade tumors.	('progression', 'CPA', (67, 78))	('delay', 'NegReg', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutated', 'Var', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('IDH', 'Gene', (23, 26))	('toxicity', 'Disease', 'MESH:D064420', (46, 54))	('toxicity', 'Disease', (46, 54))	('IDH', 'Gene', '3417', (23, 26))
38125	24287492	Furthermore, inhibitors that specifically target mutated IDH may provide physicians with a drug to slow or prevent the progression of low-grade tumors to GBMs with few side effects.	('tumors', 'Disease', (144, 150))	('mutated', 'Var', (49, 56))	('IDH', 'Gene', '3417', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('IDH', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
38130	28547590	Sixty-five patients with 2007 histological designations (astrocytomas and oligodendrogliomas), 1p/19q status (+ = intact/- = co-deleted), and IDH1 mutation status (MUT/WT) were included in this study.	('IDH1', 'Gene', '3417', (142, 146))	('1p/19q status', 'Var', (95, 108))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (57, 68))	('patients', 'Species', '9606', (11, 19))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (57, 92))	('IDH1', 'Gene', (142, 146))
38133	28547590	A multivariable logistic regression model was also used to differentiate between 1p19q+ and 1p19q- WHO II-III gliomas.	('II-III gliomas', 'Disease', 'MESH:D005910', (103, 117))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('1p19q- WHO', 'Var', (92, 102))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('II-III gliomas', 'Disease', (103, 117))	('1p19q+', 'Var', (81, 87))
38138	28547590	Within IDHMUT WHO II-III gliomas, a separate multivariable logistic regression model was able to differentiate between 1p19q+ and 1p19q- WHO II-III gliomas with an AUC of 0.80 (p = 0.0015, 64% sensitivity, 82% specificity).	('II-III gliomas', 'Disease', 'MESH:D005910', (141, 155))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('IDHMUT WHO II-III gliomas', 'Disease', (7, 32))	('II-III gliomas', 'Disease', 'MESH:D005910', (18, 32))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('1p19q- WHO', 'Var', (130, 140))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('II-III gliomas', 'Disease', (141, 155))	('1p19q+', 'Var', (119, 125))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('IDHMUT WHO II-III gliomas', 'Disease', 'MESH:D005910', (7, 32))
38152	28547590	As more molecular and genetic information about these types of tumors have become mature in the literature it has became clear that sub-stratification of tumor types should likely be performed using genetic tests for common deletions and mutations.	('tumor', 'Disease', (63, 68))	('mutations', 'Var', (238, 247))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('deletions', 'Var', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumors', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (154, 159))
38154	28547590	Co-deletion of 1p and 19q is most commonly associated with oligodendroglial tumors and is both predictive of therapeutic response and prognostic for survival.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Co-deletion', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (59, 82))	('associated', 'Reg', (43, 53))	('oligodendroglial tumors', 'Disease', (59, 82))
38161	28547590	Several studies have illustrated differences in diffusion and perfusion MR measurements between oligodendrogliomas from astrocytomas, 1p/19q co-deleted tumors (1p19q-) from non-1p/19q co-deleted tumors (1p19q+), and IDH mutant (IDHMUT) from IDH wild-type (IDHWT) diffuse gliomas.	('IDH', 'Gene', (216, 219))	('IDH', 'Gene', '3417', (241, 244))	('astrocytomas', 'Disease', (120, 132))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (96, 114))	('tumors', 'Disease', (152, 158))	('men', 'Species', '9606', (82, 85))	('IDH', 'Gene', '3417', (256, 259))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('differences', 'Reg', (33, 44))	('gliomas', 'Disease', (107, 114))	('IDH', 'Gene', '3417', (216, 219))	('IDH', 'Gene', (228, 231))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('gliomas', 'Disease', (271, 278))	('oligodendrogliomas', 'Disease', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('1p/19q co-deleted', 'Var', (134, 151))	('astrocytomas', 'Disease', 'MESH:D001254', (120, 132))	('tumors', 'Disease', (195, 201))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('IDH', 'Gene', '3417', (228, 231))	('gliomas', 'Disease', 'MESH:D005910', (271, 278))	('IDH', 'Gene', (241, 244))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('1p19q-', 'Var', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('IDH', 'Gene', (256, 259))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('gliomas', 'Phenotype', 'HP:0009733', (271, 278))
38164	28547590	We hypothesize a combination of diffusion and perfusion MR measurements will better separate tumors based on their genetic characteristics (1p19q co-deletion and IDH1 mutation status) than the more subjective histologic criteria.	('men', 'Species', '9606', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1', 'Gene', '3417', (162, 166))	('1p19q co-deletion', 'Var', (140, 157))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('IDH1', 'Gene', (162, 166))
38168	28547590	Patients were only included if they met all of the following inclusion criteria: 1) histologic diagnosis of WHO grade II or grade III gliomas; 2) dynamic susceptibility contrast (DSC) perfusion-weighted MRI, diffusion-weighted MRI, T2-weighted, and post-contrast T1-weighted anatomical scan performed at initial diagnosis and prior to any surgery; 3) diagnosis of astrocytoma, mixed glioma, or oligodendroglioma via histology; and 4) known IDH1 mutation and 1p/19q co-deletion status.	('oligodendroglioma', 'Disease', (394, 411))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('III gliomas', 'Disease', 'MESH:D005910', (130, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('astrocytoma', 'Disease', 'MESH:D001254', (364, 375))	('glioma', 'Disease', (383, 389))	('astrocytoma', 'Disease', (364, 375))	('glioma', 'Disease', (405, 411))	('Patients', 'Species', '9606', (0, 8))	('III gliomas', 'Disease', (130, 141))	('glioma', 'Disease', 'MESH:D005910', (383, 389))	('mutation', 'Var', (445, 453))	('glioma', 'Disease', 'MESH:D005910', (405, 411))	('glioma', 'Disease', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (383, 389))	('IDH1', 'Gene', (440, 444))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (405, 411))	('oligodendroglioma', 'Disease', 'MESH:D009837', (394, 411))	('astrocytoma', 'Phenotype', 'HP:0009592', (364, 375))	('IDH1', 'Gene', '3417', (440, 444))
38169	28547590	Patients with the rare combination of 1p/19q co-deletion positive and IDH1 wild-type were excluded from statistical analysis due to their small sample size (Grade II: n = 1; Grade III: n = 1).	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', '3417', (70, 74))	('1p/19q co-deletion positive', 'Var', (38, 65))	('IDH1', 'Gene', (70, 74))
38183	28547590	IDH1 mutation status was determined by sequencing for codon 132 in the catalytic domain of IDH1 via standard genomic sequencing practices (Sanger sequencing method), as previously described.	('codon 132', 'Var', (54, 63))	('IDH1', 'Gene', (91, 95))	('IDH1', 'Gene', '3417', (91, 95))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
38186	28547590	The gliomas were separated according to grade and one of the following categories (Fig 1): IDH1 wild-type (IDHWT); IDH1 mutant with intact 1p or 19q (IDHMUT/1p19q+); or IDH1 mutant with 1p/19q co-deleted (IDHMUT/1p19q-).	('IDH1', 'Gene', (169, 173))	('IDH1', 'Gene', '3417', (115, 119))	('IDH', 'Gene', '3417', (115, 118))	('IDH', 'Gene', '3417', (107, 110))	('IDH', 'Gene', (150, 153))	('IDH1', 'Gene', '3417', (91, 95))	('IDH', 'Gene', '3417', (169, 172))	('gliomas', 'Disease', (4, 11))	('mutant', 'Var', (120, 126))	('IDH', 'Gene', (205, 208))	('IDH1', 'Gene', '3417', (169, 173))	('IDH', 'Gene', '3417', (150, 153))	('gliomas', 'Disease', 'MESH:D005910', (4, 11))	('mutant', 'Var', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('IDH', 'Gene', (91, 94))	('IDH', 'Gene', '3417', (205, 208))	('gliomas', 'Phenotype', 'HP:0009733', (4, 11))	('IDH1', 'Gene', (115, 119))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', (169, 172))	('IDH1', 'Gene', (91, 95))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (91, 94))
38209	28547590	We then evaluated performance of a similar model to further differentiate 1p19q+ from 1p19q- gliomas within the IDHMUT subtype.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('1p19q+', 'Var', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH', 'Gene', (112, 115))	('1p19q-', 'Var', (86, 92))	('IDH', 'Gene', '3417', (112, 115))
38221	28547590	However, using rCBV and ADC along with the more traditional biomarkers of contrast enhancement and volume of T2-enhancement allows us to better identify the IDH1 mutation as well as 1p19q co-deletion within IDHMUT tumors.	('IDHMUT tumors', 'Disease', 'MESH:D009369', (207, 220))	('men', 'Species', '9606', (90, 93))	('1p19q co-deletion', 'Var', (182, 199))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('IDH1', 'Gene', (157, 161))	('IDHMUT tumors', 'Disease', (207, 220))	('men', 'Species', '9606', (119, 122))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('mutation', 'Var', (162, 170))	('IDH1', 'Gene', '3417', (157, 161))
38236	28547590	Consistent with previous studies, we observed significant differences in diffusion MR measurements between 1p/19q co-deleted tumors from non-1p/19q co-deleted tumors and IDH1 mutant from IDH1 wild-type diffuse gliomas.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('IDH1', 'Gene', '3417', (170, 174))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (159, 165))	('1p/19q', 'Gene', (107, 113))	('mutant', 'Var', (175, 181))	('gliomas', 'Disease', (210, 217))	('diffusion MR measurements', 'MPA', (73, 98))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))	('IDH1', 'Gene', (187, 191))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('IDH1', 'Gene', (170, 174))	('men', 'Species', '9606', (93, 96))	('IDH1', 'Gene', '3417', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('differences', 'Reg', (58, 69))
38240	28547590	There have been a few studies that have tried to identify IDH1 mutations using MR spectroscopy.	('mutations', 'Var', (63, 72))	('IDH1', 'Gene', '3417', (58, 62))	('IDH1', 'Gene', (58, 62))
38241	28547590	There have been other, more complex MRS techniques that have been more successful, such as Choi et al., who identified all patients with IDH mutations without false-positive results.	('patients', 'Species', '9606', (123, 131))	('mutations', 'Var', (141, 150))	('IDH', 'Gene', (137, 140))	('IDH', 'Gene', '3417', (137, 140))
38243	28547590	Although not specifically tested, the current data in both WHO II and III gliomas may suggest tumors with different genetic subtypes evolve with either changes in rCBV or ADC, depending on the genotype.	('changes', 'Var', (152, 159))	('III gliomas', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('rCBV', 'Gene', (163, 167))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('ADC', 'Gene', (171, 174))	('III gliomas', 'Disease', 'MESH:D005910', (70, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
38245	28547590	Future studies aimed at testing these specific hypotheses through serial imaging in tumors are warranted to further test how shifts in rCBV and ADC may reflect increasing tumor malignancy within a certain genotype at a time in which biopsy has not yet been performed.	('ADC', 'Gene', (144, 147))	('increasing', 'PosReg', (160, 170))	('tumor malignancy', 'Disease', 'MESH:D009369', (171, 187))	('rCBV', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor malignancy', 'Disease', (171, 187))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('shifts', 'Var', (125, 131))
38258	28380454	Recently, accumulating evidence has found microRNAs (miRNAs) play pivotal modulators in pathogenesis and potential treatment for epilepsy.	('microRNAs', 'Var', (42, 51))	('epilepsy', 'Disease', (129, 137))	('epilepsy', 'Disease', 'MESH:D004827', (129, 137))	('epilepsy', 'Phenotype', 'HP:0001250', (129, 137))
38264	28380454	Although their role in neuronal functions is the most studied, more evidences point towards an involvement of these miRNAs in human cancer have been found such as miR-212 may improve the current prognostic risk stratification of mixed acute myeloid leukemia, epigenetic regulation of miR-212 expression in lung cancer and down-regulation of microRNA-132 is associated with poor prognosis of colorectal cancer.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (235, 257))	('colorectal cancer', 'Disease', (391, 408))	('cancer', 'Disease', (311, 317))	('improve', 'PosReg', (175, 182))	('cancer', 'Disease', 'MESH:D009369', (402, 408))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('epigenetic regulation', 'Var', (259, 280))	('lung cancer', 'Disease', (306, 317))	('colorectal cancer', 'Phenotype', 'HP:0003003', (391, 408))	('human', 'Species', '9606', (126, 131))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (241, 257))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('myeloid leukemia', 'Disease', (241, 257))	('down-regulation', 'NegReg', (322, 337))	('cancer', 'Disease', (402, 408))	('leukemia', 'Phenotype', 'HP:0001909', (249, 257))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('microRNA-132', 'Gene', (341, 353))	('miR-212', 'Gene', (284, 291))	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (391, 408))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('myeloid leukemia', 'Disease', 'MESH:D007951', (241, 257))
38266	28380454	So, studying all genes directly target by miR-212/132 is important for us to understand thoroughly how they are involve in pathological mechanism of neurological disorders like epilepsy.	('epilepsy', 'Disease', (177, 185))	('neurological disorders', 'Disease', (149, 171))	('miR-212/132', 'Var', (42, 53))	('epilepsy', 'Disease', 'MESH:D004827', (177, 185))	('neurological disorders', 'Disease', 'MESH:D009422', (149, 171))	('epilepsy', 'Phenotype', 'HP:0001250', (177, 185))	('neurological disorder', 'Phenotype', 'HP:0000707', (149, 170))
38269	28380454	Furthermore, miR-132-3p and miR-212-3p share similar mature sequences and common target gene, which is important for further analysis.	('miR-132-3p', 'Gene', '100302255', (13, 23))	('miR-212-3p', 'Var', (28, 38))	('miR-132-3p', 'Gene', (13, 23))
38280	28380454	MiR-132 is important regulators of seizure-induced neuronal death and whose silencing inhibit the spontaneous seizures through the MFs-CA3 pathway.	('neuronal death', 'Disease', 'MESH:D009410', (51, 65))	('silencing', 'Var', (76, 85))	('MFs-CA3 pathway', 'Pathway', (131, 146))	('seizure', 'Disease', (110, 117))	('seizure', 'Disease', (35, 42))	('neuronal death', 'Disease', (51, 65))	('seizures', 'Disease', 'MESH:D012640', (110, 118))	('seizure', 'Disease', 'MESH:D012640', (110, 117))	('seizure', 'Disease', 'MESH:D012640', (35, 42))	('seizure', 'Phenotype', 'HP:0001250', (110, 117))	('seizure', 'Phenotype', 'HP:0001250', (35, 42))	('inhibit', 'NegReg', (86, 93))	('seizures', 'Phenotype', 'HP:0001250', (110, 118))	('seizures', 'Disease', (110, 118))	('MiR-132', 'Gene', (0, 7))
38281	28380454	miR-212-3p and miR-132-3p work synergistically to control Sox11 expression in the setting of epilepsy.	('control', 'PosReg', (50, 57))	('expression', 'MPA', (64, 74))	('epilepsy', 'Disease', 'MESH:D004827', (93, 101))	('Sox11', 'Gene', (58, 63))	('miR-132-3p', 'Gene', '100302255', (15, 25))	('epilepsy', 'Phenotype', 'HP:0001250', (93, 101))	('Sox11', 'Gene', '6664', (58, 63))	('miR-212-3p', 'Var', (0, 10))	('epilepsy', 'Disease', (93, 101))	('miR-132-3p', 'Gene', (15, 25))
38285	28380454	In this article, we want to assure whether these genes significantly associated with epilepsy can be directly and indirectly affected by miR-132-3p and miR-212-3p.	('epilepsy', 'Phenotype', 'HP:0001250', (85, 93))	('miR-132-3p', 'Gene', (137, 147))	('epilepsy', 'Disease', (85, 93))	('associated', 'Reg', (69, 79))	('miR-212-3p', 'Var', (152, 162))	('miR-132-3p', 'Gene', '100302255', (137, 147))	('epilepsy', 'Disease', 'MESH:D004827', (85, 93))	('affected', 'Reg', (125, 133))
38289	28380454	Gene ontology and pathway enrichment analysis about validated and remaining target genes indicated miR-132-3p and miR-212-3p may play a critical role in human cancer.	('cancer', 'Disease', (159, 165))	('miR-132-3p', 'Gene', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (153, 158))	('miR-212-3p', 'Var', (114, 124))	('miR-132-3p', 'Gene', '100302255', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
38291	28380454	Literature search (pubmed) show that 26.1 % (95/364) ("miR-132"/"miR-132" and"cancer") and 37.2 %(45/145) ("miR-212"/"miR-212" and"cancer") studies are related to cancer for miR-132 and miR-212, respectively.	('miR-212', 'Var', (186, 193))	('cancer', 'Disease', (131, 137))	('related', 'Reg', (152, 159))	('miR-132', 'Gene', '406921', (174, 181))	('miR-132', 'Gene', (65, 72))	('miR-132', 'Gene', (55, 62))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miR-132', 'Gene', '406921', (65, 72))	('miR-132', 'Gene', '406921', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('miR-132', 'Gene', (174, 181))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
38292	28380454	Given all that, survival analysis sourced from TCGA data was performed and the result showed that miR-132-3p and miR-212-3p were presented to be up-regulated or down-regulated in different cancer types, and Kaplan-Meier analysis curves demonstrated that aberrantly expression of both miRs was conspicuously associated with poor overall survival (Figure 4A).	('poor', 'NegReg', (323, 327))	('miR-212-3p', 'Var', (113, 123))	('up-regulated', 'PosReg', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('down-regulated', 'NegReg', (161, 175))	('miR-132-3p', 'Gene', '100302255', (98, 108))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('aberrantly', 'Var', (254, 264))	('associated', 'Reg', (307, 317))	('overall', 'MPA', (328, 335))	('miR-132-3p', 'Gene', (98, 108))	('cancer', 'Disease', (189, 195))
38293	28380454	Previous research have found that miR-212/132 have bilateral function depending on cancer types, which is in line with the our analytic result, such as high miR-132-3p and low miR-132-3p expression are significantly associated with poor survival in bladder urothelial carcinoma (BLCA) and pancreatic adenocarcinoma (PAAD), respectively.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (216, 226))	('AD', 'Phenotype', 'HP:0002511', (318, 320))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (249, 277))	('AD', 'Disease', (318, 320))	('miR-132-3p', 'Gene', '100302255', (176, 186))	('AD', 'Disease', 'MESH:D000544', (318, 320))	('miR-132-3p', 'Gene', (157, 167))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (289, 314))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('poor', 'NegReg', (232, 236))	('miR-132-3p', 'Gene', (176, 186))	('PAAD', 'Phenotype', 'HP:0006725', (316, 320))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (289, 314))	('pancreatic adenocarcinoma', 'Disease', (289, 314))	('low', 'Var', (172, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('bladder urothelial carcinoma', 'Disease', (249, 277))	('expression', 'MPA', (187, 197))	('miR-132-3p', 'Gene', '100302255', (157, 167))	('cancer', 'Disease', (83, 89))
38297	28380454	Based on the fact that a large amount of biomolecular networks are associated with caner, we wonder whether there are common gene or pathway related to both miRs cause the epilepsy and cancer.IRAK4 clearly relevant to epilepsy assigned to further study, Figure 4B and Figure 4D show IRAK4 is negatively with the miR-132/212 in kidney chromophobe and aberrantly expression of IRAK4 are significantly related to poor survival of several cancers, certainly, somatic mutations of IRAK4 itself in cancer is another main reason in cancer (Figure 4C), but on the whole all of which suggest that miR-132/212 may be involved differently disease though single gene.	('miR-132', 'Gene', '406921', (312, 319))	('IRAK4', 'Gene', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (435, 441))	('cancer', 'Disease', (525, 531))	('cancers', 'Disease', 'MESH:D009369', (435, 442))	('IRAK4', 'Gene', '51135', (192, 197))	('epilepsy', 'Disease', 'MESH:D004827', (218, 226))	('miR-132', 'Gene', '406921', (588, 595))	('IRAK4', 'Gene', (476, 481))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (525, 531))	('IRAK4', 'Gene', '51135', (476, 481))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('epilepsy', 'Phenotype', 'HP:0001250', (172, 180))	('cancer', 'Disease', 'MESH:D009369', (492, 498))	('epilepsy', 'Disease', (172, 180))	('IRAK4', 'Gene', (283, 288))	('epilepsy', 'Phenotype', 'HP:0001250', (218, 226))	('cancer', 'Disease', (492, 498))	('IRAK4', 'Gene', '51135', (283, 288))	('related', 'Reg', (399, 406))	('epilepsy', 'Disease', (218, 226))	('cancers', 'Phenotype', 'HP:0002664', (435, 442))	('cancer', 'Disease', 'MESH:D009369', (525, 531))	('cancer', 'Phenotype', 'HP:0002664', (492, 498))	('cancer', 'Disease', (435, 441))	('cancers', 'Disease', (435, 442))	('aberrantly', 'Var', (350, 360))	('kidney chromophobe', 'Disease', 'MESH:D000238', (327, 345))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('miR-132', 'Gene', (312, 319))	('cancer', 'Phenotype', 'HP:0002664', (435, 441))	('miR-132', 'Gene', (588, 595))	('kidney chromophobe', 'Disease', (327, 345))	('IRAK4', 'Gene', (375, 380))	('IRAK4', 'Gene', '51135', (375, 380))	('epilepsy', 'Disease', 'MESH:D004827', (172, 180))
38307	28380454	Certainly, two things are worth mentioning when considering further discussion, firstly, miR-132 and miR-212 also presented different expression and miR-132 may be play a major role, each of these miRNAs respectively repress specific targets(diverging nucleotides between miR-132 and miR-212 sequences (see Figure 1A) and have a nonsynchronous status.	('diverging nucleotides', 'Var', (242, 263))	('miR-212', 'Gene', (284, 291))	('miR-132', 'Gene', '406921', (89, 96))	('miR-132', 'Gene', (149, 156))	('miR-132', 'Gene', (272, 279))	('specific targets', 'MPA', (225, 241))	('miR-132', 'Gene', '406921', (272, 279))	('miR-132', 'Gene', (89, 96))	('miR-132', 'Gene', '406921', (149, 156))	('repress', 'NegReg', (217, 224))
38308	28380454	The second one is that miR-132-3p/5p and miR-212-3p/5p, originating from opposite arms of the same pre-miRNA and with different seed sequence, may be involve in another unique role in CNS (figure 1C have showed 5p also have a high concordance of brain tissue-specific expression in human).	('miR-132-3p', 'Gene', (23, 33))	('involve', 'Reg', (150, 157))	('human', 'Species', '9606', (282, 287))	('miR-132-3p', 'Gene', '100302255', (23, 33))	('miR-212-3p/5p', 'Var', (41, 54))
38311	28380454	To achieve a more comprehensive analysis of target gene, the same analysis was carried on remaining predicted targets, Axon guidance ranked first in these genes, previous study have found hippocampal axon guidance can be regulated by nor-1 and involve in seizure susceptibility, and mTOR signaling pathway can sever as a new therapeutic strategy in epilepsy and epileptogenesis, all which absented in validated target genes may be provide a valuable reference and guide for future study on miR-212/132in epilepsy.	('miR-212/132in', 'Var', (490, 503))	('epilepsy', 'Disease', (504, 512))	('epilepsy', 'Disease', (349, 357))	('seizure', 'Disease', (255, 262))	('seizure', 'Disease', 'MESH:D012640', (255, 262))	('nor-1', 'Gene', '8013', (234, 239))	('mTOR', 'Gene', '2475', (283, 287))	('epilepsy', 'Disease', 'MESH:D004827', (504, 512))	('mTOR', 'Gene', (283, 287))	('epilepsy', 'Disease', 'MESH:D004827', (349, 357))	('epilepsy', 'Phenotype', 'HP:0001250', (504, 512))	('epilepsy', 'Phenotype', 'HP:0001250', (349, 357))	('seizure', 'Phenotype', 'HP:0001250', (255, 262))	('nor-1', 'Gene', (234, 239))
38314	28380454	Certainly, epilepsy is also belong to CNS disorder and results from a variety of CNS insults, theoretically, all disease caused by dysregulated expression of miR-132/212 can become the trigger factors for epileptic seizures.	('seizures', 'Disease', (215, 223))	('epileptic', 'Disease', (205, 214))	('seizures', 'Phenotype', 'HP:0001250', (215, 223))	('CNS disorder', 'Disease', 'MESH:D002493', (38, 50))	('epilepsy', 'Disease', 'MESH:D004827', (11, 19))	('seizure', 'Phenotype', 'HP:0001250', (215, 222))	('miR-132', 'Gene', '406921', (158, 165))	('epilepsy', 'Phenotype', 'HP:0001250', (11, 19))	('dysregulated', 'Var', (131, 143))	('CNS disorder', 'Disease', (38, 50))	('epilepsy', 'Disease', (11, 19))	('seizures', 'Disease', 'MESH:D012640', (215, 223))	('epileptic', 'Disease', 'MESH:D004827', (205, 214))	('miR-132', 'Gene', (158, 165))
38315	28380454	In addition to Pubmed search, the MalaCards disease database with high credibility and having been used widely was also used for further analysis of research potential that miR-132/212 can cause epilepsy, the MalaCards provides 43 affiliated genes found to be associated with the epilepsy, what has specific value in this article is that 32.6% of genes related to epilepsy may be directly targeted by miR-132-3p and miR-212-3p.	('epilepsy', 'Disease', 'MESH:D004827', (195, 203))	('epilepsy', 'Phenotype', 'HP:0001250', (364, 372))	('miR-132', 'Gene', (173, 180))	('epilepsy', 'Disease', 'MESH:D004827', (280, 288))	('MalaCards disease', 'Disease', 'MESH:D004194', (34, 51))	('epilepsy', 'Disease', (364, 372))	('MalaCards disease', 'Disease', (34, 51))	('miR-132-3p', 'Gene', (401, 411))	('epilepsy', 'Phenotype', 'HP:0001250', (195, 203))	('targeted', 'Reg', (389, 397))	('epilepsy', 'Disease', (195, 203))	('epilepsy', 'Phenotype', 'HP:0001250', (280, 288))	('miR-132', 'Gene', '406921', (173, 180))	('epilepsy', 'Disease', (280, 288))	('miR-132', 'Gene', (401, 408))	('miR-212-3p', 'Var', (416, 426))	('epilepsy', 'Disease', 'MESH:D004827', (364, 372))	('miR-132', 'Gene', '406921', (401, 408))	('miR-132-3p', 'Gene', '100302255', (401, 411))
38316	28380454	Although in the beginning we did not take cancer as the main research object, as data are accumulated and analysis continues, the result demonstrated miR-132-3p and miR-212-3p may participates extensively in human cancer, For experimental validated genes and predicted genes with conservative sites, 34.9 % (15/43) and 38.2% (13/34) pathway are statistically enriched in cancer directly, respectively.	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('miR-132-3p', 'Gene', (150, 160))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('miR-212-3p', 'Var', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (371, 377))	('miR-132-3p', 'Gene', '100302255', (150, 160))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (371, 377))	('human', 'Species', '9606', (208, 213))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
38317	28380454	Such as pathways in cancer, MicroRNAs in cancer and Proteoglycans in cancer, which is consistent with previous literatures about the emerging role of miR-132/212 involved in cancer.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('miR-132', 'Gene', '406921', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('MicroRNAs', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (41, 47))	('pathways', 'Pathway', (8, 16))	('miR-132', 'Gene', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Proteoglycans', 'Protein', (52, 65))	('cancer', 'Disease', (69, 75))
38318	28380454	Survival analysis reveals that dysregulation of miR-132-3p and miR-212-3p is conspicuously related with poor survival in several human cancer including BLCA, PAAD, KICH and LGG.	('BLCA', 'Disease', (152, 156))	('cancer', 'Disease', (135, 141))	('AD', 'Disease', 'MESH:D000544', (160, 162))	('KICH', 'Disease', (164, 168))	('AD', 'Phenotype', 'HP:0002511', (160, 162))	('PAAD', 'Phenotype', 'HP:0006725', (158, 162))	('miR-132-3p', 'Gene', (48, 58))	('AD', 'Disease', (160, 162))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('LGG', 'Disease', (173, 176))	('miR-212-3p', 'Var', (63, 73))	('poor', 'NegReg', (104, 108))	('dysregulation', 'Var', (31, 44))	('KICH', 'Disease', 'None', (164, 168))	('human', 'Species', '9606', (129, 134))	('miR-132-3p', 'Gene', '100302255', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
38324	28380454	Apart from the somatic mutations of IRAK4 itself, all indicated miRs may target single gene to interfere the process of cancer and epilepsy.	('IRAK4', 'Gene', '51135', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('target', 'Reg', (73, 79))	('cancer', 'Disease', (120, 126))	('interfere', 'NegReg', (95, 104))	('epilepsy', 'Disease', 'MESH:D004827', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('epilepsy', 'Phenotype', 'HP:0001250', (131, 139))	('miRs', 'Var', (64, 68))	('IRAK4', 'Gene', (36, 41))	('epilepsy', 'Disease', (131, 139))
38328	28380454	Fascinating thing is 31.1% DEGs may be directly target by both miRs, and further mechanism study indicated miR-132-3p and miR-212-3p may be participated in brain tumor-induced epilepsy through direct intervention, ceRNA network and indirect adjustment.	('miR-212-3p', 'Var', (122, 132))	('participated', 'Reg', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('epilepsy', 'Disease', 'MESH:D004827', (176, 184))	('brain tumor', 'Phenotype', 'HP:0030692', (156, 167))	('miR-132-3p', 'Gene', (107, 117))	('brain tumor', 'Disease', 'MESH:D001932', (156, 167))	('epilepsy', 'Phenotype', 'HP:0001250', (176, 184))	('epilepsy', 'Disease', (176, 184))	('miR-132-3p', 'Gene', '100302255', (107, 117))	('brain tumor', 'Disease', (156, 167))
38332	28380454	We would like to acknowledge that the number (3801) of possible target genes occupied a high percentage in genome, by comparison (data no shown), the proportion of genes related to miR-212/132 and have function in epilepsy at the same time is relatively high.	('epilepsy', 'Disease', (214, 222))	('miR-212/132', 'Var', (181, 192))	('epilepsy', 'Disease', 'MESH:D004827', (214, 222))	('epilepsy', 'Phenotype', 'HP:0001250', (214, 222))
38340	28380454	Several Web based tools for "The Cancer Genome Atlas" (TCGA) have been used to visualize, analyze and interpret all the data types whether miR-132-3p and miR-212-3p may be involve in human cancer.	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('miR-212-3p', 'Var', (154, 164))	('Cancer Genome Atlas', 'Disease', (33, 52))	('miR-132-3p', 'Gene', '100302255', (139, 149))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (33, 52))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('human', 'Species', '9606', (183, 188))	('involve', 'Reg', (172, 179))	('miR-132-3p', 'Gene', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
38396	27741525	In the evolution of malignization (Fig 4), the same growth pattern in the DTI-derived maps was observed in all patients: (i) Resection of the glioma leads to a cavity filled with cerebrospinal fluid (ii) adjacent to the resection cavity, a T2w-hyperintense zone evolves or may be present already directly after the surgery, potentially harboring residual tumor cells in both controls and transformers (iii) in patients with transformation within this T2w-hyperintense zone, the recurrence evolves with increasing diffusion restriction over time.	('diffusion restriction', 'MPA', (513, 534))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('glioma', 'Disease', (142, 148))	('patients', 'Species', '9606', (410, 418))	('tumor', 'Disease', (355, 360))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('Resection', 'Var', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (355, 360))	('DTI', 'Chemical', '-', (74, 77))	('patients', 'Species', '9606', (111, 119))
38406	27741525	In the inter-group comparison, mean and minimum values of AD, RD and MD were significantly lower in transformers compared to non-transformers at the date of CE (p<0.0001, respectively) (Fig 8, Table 3).	('lower', 'NegReg', (91, 96))	('AD', 'Chemical', '-', (58, 60))	('AD', 'CPA', (58, 60))	('transformers', 'Var', (100, 112))
38414	27741525	The gradual mutations evolving in WHO II glioma lead to two mainstays of MT: an increase in cellularity followed by neo-angiogenesis.	('neo-angiogenesis', 'CPA', (116, 132))	('increase', 'PosReg', (80, 88))	('mutations', 'Var', (12, 21))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('II glioma', 'Disease', (38, 47))	('cellularity', 'CPA', (92, 103))	('II glioma', 'Disease', 'MESH:D005910', (38, 47))
38517	23646258	In this study, we have focused our statistical analysis on individual items within each of the QOL measures (EORTC QLQ-C30, EORTC QLQ-BN20, and HADS) and not scale scores.	('EORTC', 'Chemical', '-', (109, 114))	('EORTC QLQ-BN20', 'Var', (124, 138))	('EORTC QLQ-C30', 'Var', (109, 122))	('EORTC', 'Chemical', '-', (124, 129))
38595	32181818	WNT2 knockdown in glioma cells significantly suppressed growth and associated with the decrease of PI3K/p-AKT expression in vitro and in vivo.	('AKT', 'Gene', (106, 109))	('glioma', 'Disease', (18, 24))	('knockdown', 'Var', (5, 14))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('suppressed', 'NegReg', (45, 55))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('decrease', 'NegReg', (87, 95))	('expression', 'MPA', (110, 120))	('AKT', 'Gene', '207', (106, 109))	('growth', 'MPA', (56, 62))	('WNT2', 'Gene', (0, 4))	('WNT2', 'Gene', '7472', (0, 4))
38602	32181818	Abnormality of WNT signaling cascade has been found in many cancers.	('Abnormality', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('WNT signaling cascade', 'Pathway', (15, 36))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('found', 'Reg', (46, 51))
38658	32181818	Up to now, increasing evidences suggested that defective WNT signaling is a causative factor in various cancers including breast cancer, lung cancer, pancreas cancer, colorectal cancer, hepatocellular carcinoma and as well as glioma.	('defective', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('glioma', 'Disease', (226, 232))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal cancer', 'Disease', (167, 184))	('glioma', 'Disease', 'MESH:D005910', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (186, 210))	('causative', 'Reg', (76, 85))	('pancreas cancer', 'Disease', 'MESH:D010190', (150, 165))	('pancreas cancer', 'Phenotype', 'HP:0002894', (150, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('pancreas cancer', 'Disease', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (186, 210))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('breast cancer', 'Disease', (122, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('lung cancer', 'Disease', (137, 148))	('hepatocellular carcinoma', 'Disease', (186, 210))
38670	32181818	revealed higher WNT5A expression in recurrent GBM compared with primary GBMs, and pointed out that epigenetic activation of WNT5A triggered stem-cell like GBM invasive growth and differentiation.	('differentiation', 'CPA', (179, 194))	('epigenetic activation', 'Var', (99, 120))	('WNT5A', 'Gene', '7474', (16, 21))	('WNT5A', 'Gene', (124, 129))	('triggered', 'PosReg', (130, 139))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('stem-cell like GBM invasive growth', 'CPA', (140, 174))	('WNT5A', 'Gene', (16, 21))	('WNT5A', 'Gene', '7474', (124, 129))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('expression', 'MPA', (22, 32))	('higher', 'PosReg', (9, 15))
38743	25872487	Results indicate that only DAC microscopy is able to consistently detect PpIX across all glioma tissue samples (n = 7 patients).	('PpIX', 'Var', (73, 77))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('PpIX', 'Chemical', 'MESH:C028025', (73, 77))	('DAC', 'Chemical', '-', (27, 30))	('glioma', 'Disease', (89, 95))	('patients', 'Species', '9606', (118, 126))
38770	32112907	T2-Weighted and Fluid Attenuated Inversion Recovery (T2W/FLAIR) imaging: In the context of tumor imaging, T2W/FLAIR imaging provides information that generally relates to tissue water content.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('water', 'Chemical', 'MESH:D014867', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('T2W/FLAIR', 'Var', (106, 115))	('tumor', 'Disease', (91, 96))
38819	32112907	For instance, recent advances in MRS have enabled non-invasive detection of molecular signatures, specifically mutations in Isocitrate dehydrogenase (IDH), which are presumably homogeneously expressed across the entire tumor.	('Isocitrate dehydrogenase', 'Gene', '3417', (124, 148))	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('IDH', 'Gene', (150, 153))	('Isocitrate dehydrogenase', 'Gene', (124, 148))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('IDH', 'Gene', '3417', (150, 153))
38830	32112907	The use of ML algorithms has enabled the emerging field of radiogenomics, which utilizes inputs from image features (often from texture analysis) and genetic profiles (e.g., EGFR amplification status, PTEN deletion status), to train predictive models that inform of genetic status using the image features alone.	('EGFR', 'Gene', (174, 178))	('PTEN', 'Gene', (201, 205))	('PTEN', 'Gene', '5728', (201, 205))	('amplification', 'Var', (179, 192))	('deletion status', 'Var', (206, 221))	('EGFR', 'Gene', '1956', (174, 178))
38835	32112907	By working in spherical symmetry and assuming the T1+C abnormality represents regions exhibiting 80% of the tumor cell carrying capacity and above and the T2/FLAIR regions correspond to 16% and above, one can parameterize this model in a patient-specific way given just the standard imaging.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('patient', 'Species', '9606', (238, 245))	('T1+C abnormality', 'Var', (50, 66))
38840	32112907	All of these factors can contribute to a reported 30% incidence of sampling error and misdiagnosis (i.e., undergrading) of non-enhancing high-grade gliomas.	('misdiagnosis', 'Var', (86, 98))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))
38852	32112907	Because surgical resection favors T1+C enhancing volume, and because T2W imaging lacks the capability to distinguish infiltrating tumor from vasogenic edema, the non-enhancing tumor component is often left unresected after surgery and submaximally dosed by radiation therapy.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('T1+C', 'Var', (34, 38))	('vasogenic edema', 'Disease', (141, 156))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('vasogenic edema', 'Disease', 'MESH:D001929', (141, 156))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('edema', 'Phenotype', 'HP:0000969', (151, 156))
38920	31857632	Gliomas are primary brain tumors caused by glial cell mutations.	('caused by', 'Reg', (33, 42))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('brain tumor', 'Disease', 'MESH:D001932', (20, 31))	('brain tumors', 'Phenotype', 'HP:0030692', (20, 32))	('brain tumor', 'Disease', (20, 31))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('Gliomas', 'Disease', (0, 7))	('brain tumor', 'Phenotype', 'HP:0030692', (20, 31))	('tumors', 'Disease', (26, 32))
38977	31857632	The LASSO-LR can construct a classification model with sparse explanatory variables by solving an L1-norm regularized objective function expressed as follows:wherewhere  is an optimal coefficient vector, n is the number of patients, y is a label for the glioma grades, and lambda is a hyper-parameter of the regularization.	('wherewhere', 'Var', (158, 168))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('glioma', 'Disease', (254, 260))	('patients', 'Species', '9606', (223, 231))
39160	28478462	Finally, a total of 66 patients (33 males; 22-73 years of age; mean age 51.5 years) with T2-FLAIR and T1WI-CE sequences, and 63 patients with DWI sequences were included.	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (128, 136))	('T1WI-CE sequences', 'Var', (102, 119))	('T2-FLAIR', 'Var', (89, 97))
39327	28279210	GSE10611 included 8 normal, 8 Grade 1, 24 Grade 2, 85 Grade 3, and 159 Grade 4 glioma samples, as detailed in Additional file 1: Table S1.	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('GSE10611', 'Var', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))
39345	28279210	Using a chemoattractant (1% FBS), we observed that inhibition of CD44 expression abrogated the tumor cell ability to invade through a matrigel coated membrane (Fig.	('FBS', 'Disease', (28, 31))	('CD44', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('FBS', 'Disease', 'MESH:D005198', (28, 31))	('CD44', 'Gene', '960', (65, 69))	('inhibition', 'Var', (51, 61))	('abrogated', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
39352	28279210	However, U251 cells with downregulated CD44 expression attracted significantly less stem cells across the matrigel coated membrane (Fig.	('stem cells across the matrigel coated membrane', 'CPA', (84, 130))	('CD44', 'Gene', '960', (39, 43))	('expression', 'Var', (44, 54))	('CD44', 'Gene', (39, 43))	('downregulated', 'NegReg', (25, 38))	('U251', 'CellLine', 'CVCL:0021', (9, 13))	('less', 'NegReg', (79, 83))
39405	26158673	Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) previously associated with metabolic disorders are also associated with prostate volume (PV).	('single nucleotide polymorphisms', 'Var', (38, 69))	('metabolic disorders', 'Disease', 'MESH:D008659', (104, 123))	('prostate volume', 'Disease', (149, 164))	('metabolic disorders', 'Disease', (104, 123))	('associated', 'Reg', (133, 143))
39409	26158673	Other noteworthy SNPs that were nominally associated (p-value < 1x10-4) with log-PV included rs9583484 (intronic SNP in COL4A2), rs10146527 (intronic SNP in NRXN3), rs9909466 (SNP near RPL32P31), and rs2241606 (synonymous SNP in SLC12A7).	('rs9909466', 'Mutation', 'rs9909466', (165, 174))	('SLC12A7', 'Gene', '10723', (229, 236))	('rs9583484', 'Mutation', 'rs9583484', (93, 102))	('COL4A2', 'Gene', '1284', (120, 126))	('RPL32P31', 'Gene', (185, 193))	('rs2241606', 'Mutation', 'rs2241606', (200, 209))	('rs9583484', 'Var', (93, 102))	('rs10146527', 'Var', (129, 139))	('NRXN3', 'Gene', (157, 162))	('NRXN3', 'Gene', '9369', (157, 162))	('RPL32P31', 'Gene', '201259', (185, 193))	('rs9909466', 'Var', (165, 174))	('rs10146527', 'Mutation', 'rs10146527', (129, 139))	('rs2241606', 'Var', (200, 209))	('SLC12A7', 'Gene', (229, 236))	('COL4A2', 'Gene', (120, 126))
39420	26158673	However, results from these studies are not conclusive, and, much like prostate cancer (PC), it is unclear that genetic variability in androgen activity contributes to PV or BPH progression.	('genetic variability', 'Var', (112, 131))	('prostate cancer', 'Disease', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))
39421	26158673	In contrast, there do appear to be shared associations between BPH and PC susceptibility, as a recent study evaluating 14 SNPs previously associated with PC found SNPs near IRX4, ITGA6, and RFX6 genes were also associated with increased BPH risk or increased BPH aggressiveness.	('SNPs', 'Var', (163, 167))	('increased BPH aggressiveness', 'Disease', (249, 277))	('increased', 'PosReg', (227, 236))	('aggressiveness', 'Phenotype', 'HP:0000718', (263, 277))	('ITGA6', 'Gene', '3655', (179, 184))	('ITGA6', 'Gene', (179, 184))	('IRX4', 'Gene', (173, 177))	('IRX4', 'Gene', '50805', (173, 177))	('RFX6', 'Gene', '222546', (190, 194))	('RFX6', 'Gene', (190, 194))	('BPH', 'Disease', (237, 240))	('increased BPH aggressiveness', 'Disease', 'MESH:D001523', (249, 277))
39435	26158673	We intentionally did not include high-grade PC cases from the validation sample because genetic factors leading to advanced PC are likely to be distinct from those involved in prostate enlargement, and men with high-grade PC had significantly smaller prostate volume and higher PSA levels than men with either low-grade PC or men without PC at biopsy.	('smaller', 'NegReg', (243, 250))	('men', 'Species', '9606', (202, 205))	('PSA', 'Gene', (278, 281))	('prostate enlargement', 'Disease', (176, 196))	('PSA', 'Gene', '354', (278, 281))	('prostate enlargement', 'Disease', 'MESH:D011472', (176, 196))	('high-grade', 'Var', (211, 221))	('higher', 'PosReg', (271, 277))	('men', 'Species', '9606', (294, 297))	('men', 'Species', '9606', (192, 195))	('men', 'Species', '9606', (326, 329))	('smaller prostate', 'Phenotype', 'HP:0008687', (243, 259))	('prostate volume', 'MPA', (251, 266))
39451	26158673	Although median prostate volume was approximately 8 ml lower in men with low-grade PC compared with men without PC (p-value <0.001), a substantial number of men in both groups as a PV > 40 ml (44.3%), and PSA levels were not significantly different across groups.	('low-grade', 'Var', (73, 82))	('men', 'Species', '9606', (100, 103))	('prostate', 'CPA', (16, 24))	('PSA', 'Gene', '354', (205, 208))	('PSA', 'Gene', (205, 208))	('lower', 'NegReg', (55, 60))	('men', 'Species', '9606', (64, 67))	('men', 'Species', '9606', (157, 160))
39454	26158673	SNP rs11736129, near the LOC100131429 gene, was the only statistically significant SNP after accounting for multiple testing (Beta 0.16, p-value 1.16x10-8), and heterogeneity in the rs11736129 and PV association was low between the two clinical groups.	('LOC100131429', 'Gene', '100131429', (25, 37))	('rs11736129', 'Mutation', 'rs11736129', (4, 14))	('rs11736129', 'Mutation', 'rs11736129', (182, 192))	('rs11736129', 'Var', (4, 14))	('LOC100131429', 'Gene', (25, 37))
39455	26158673	SNP rs9583484, located in the intronic region of the COL4A2 gene was nominally associated with PV (Beta -0.11, p-value 1.01x10-05), with a stronger association among biopsy-negative men (I2 = 51%).	('COL4A2', 'Gene', '1284', (53, 59))	('rs9583484', 'Mutation', 'rs9583484', (4, 13))	('associated', 'Reg', (79, 89))	('COL4A2', 'Gene', (53, 59))	('men', 'Species', '9606', (182, 185))	('SNP rs9583484', 'Var', (0, 13))
39456	26158673	Additionally, two SNPs near NRXN3 (rs10146527, Beta = -0.08, p-value = 3.49x10-05; rs2202167, Beta = 0.08, p-value = 3.49x10-05), a SNP near RPL32P31 (rs9909466, Beta = 0.09, p-value = 5.88x10-05) and a synonymous polymorphism in the SLC12A7 exon (rs2241606, Beta = 0.07, p-value = 8.51x10-05) were nominally associated with log-PV at the p-value threshold of < 1x10-04.	('RPL32P31', 'Gene', '201259', (141, 149))	('rs2202167', 'Mutation', 'rs2202167', (83, 92))	('associated', 'Reg', (309, 319))	('rs10146527', 'Var', (35, 45))	('rs2241606', 'Mutation', 'rs2241606', (248, 257))	('rs10146527', 'Mutation', 'rs10146527', (35, 45))	('SLC12A7', 'Gene', (234, 241))	('rs2241606', 'Var', (248, 257))	('RPL32P31', 'Gene', (141, 149))	('SLC12A7', 'Gene', '10723', (234, 241))	('NRXN3', 'Gene', (28, 33))	('rs9909466', 'Mutation', 'rs9909466', (151, 160))	('rs9909466', 'Var', (151, 160))	('NRXN3', 'Gene', '9369', (28, 33))	('log-PV', 'Disease', (325, 331))
39457	26158673	Among men with a negative prostate biopsy, SNPs meeting the nominal significance level included rs10400014 (Beta = 0.12, p-value = 2.05x10-5) near ZEB1 and ARHGAP12, and rs12662869 (Beta = -0.10, p-value = 8.64x10-5) in and intron of SLC17A1/A4.	('rs10400014', 'Var', (96, 106))	('rs12662869', 'Var', (170, 180))	('SLC17A1', 'Gene', '6568', (234, 241))	('ARHGAP12', 'Gene', (156, 164))	('rs12662869', 'Mutation', 'rs12662869', (170, 180))	('ZEB1', 'Gene', (147, 151))	('SLC17A1', 'Gene', (234, 241))	('intron', 'MPA', (224, 230))	('ZEB1', 'Gene', '6935', (147, 151))	('ARHGAP12', 'Gene', '94134', (156, 164))	('rs10400014', 'Mutation', 'rs10400014', (96, 106))	('men', 'Species', '9606', (6, 9))
39458	26158673	In men with low-grade PC, PV was associated with SNPs in the intronic regions of PKP2, AKAP13, and SNPs near LOC100131429, AGTR1, and ANAPC1.	('AKAP13', 'Gene', '11214', (87, 93))	('AGTR1', 'Gene', (123, 128))	('PKP2', 'Gene', '5318', (81, 85))	('AGTR1', 'Gene', '185', (123, 128))	('SNPs', 'Var', (99, 103))	('LOC100131429', 'Gene', (109, 121))	('PKP2', 'Gene', (81, 85))	('ANAPC1', 'Gene', '64682', (134, 140))	('AKAP13', 'Gene', (87, 93))	('associated', 'Reg', (33, 43))	('SNPs', 'Var', (49, 53))	('LOC100131429', 'Gene', '100131429', (109, 121))	('ANAPC1', 'Gene', (134, 140))	('men', 'Species', '9606', (3, 6))
39462	26158673	Hypothesizing that genetic variants related to the metabolic syndrome may also be positively associated with BPH, we evaluated SNPs throughout the genome that have been implicated with several metabolic disorders in relation to prostate volume in men without PC and men with low-grade PC.	('variants', 'Var', (27, 35))	('metabolic syndrome', 'Disease', 'MESH:D008659', (51, 69))	('metabolic syndrome', 'Disease', (51, 69))	('metabolic disorders', 'Disease', (193, 212))	('associated', 'Reg', (93, 103))	('BPH', 'Disease', (109, 112))	('men', 'Species', '9606', (266, 269))	('men', 'Species', '9606', (247, 250))	('metabolic disorders', 'Disease', 'MESH:D008659', (193, 212))
39463	26158673	rs11736129, the most statistically significant result in our analysis, lies approximately 13 kilo-bases downstream of the pseudo-gene LOC100131429, which bears sequence similarity to the armadillo repeat containing 1 gene (ARMC1) which encodes a metal ion binding protein.	('rs11736129', 'Mutation', 'rs11736129', (0, 10))	('ARMC1', 'Gene', '55156', (223, 228))	('LOC100131429', 'Gene', (134, 146))	('armadillo repeat containing 1', 'Gene', '55156', (187, 216))	('rs11736129', 'Var', (0, 10))	('ARMC1', 'Gene', (223, 228))	('metal', 'Chemical', 'MESH:D008670', (246, 251))	('LOC100131429', 'Gene', '100131429', (134, 146))	('armadillo repeat containing 1', 'Gene', (187, 216))
39464	26158673	While pseudo-genes lack coding potential due to the presence of various mutations such as premature stop codons and frame shifts, unprocessed pseudo-genes like the LOC100131429 may be transcribed.	('LOC100131429', 'Gene', '100131429', (164, 176))	('coding potential', 'MPA', (24, 40))	('frame shifts', 'Var', (116, 128))	('lack', 'NegReg', (19, 23))	('LOC100131429', 'Gene', (164, 176))	('premature stop codons', 'MPA', (90, 111))
39467	26158673	RNA expression analysis reports from Genecards show that the LOC100121429 pseudo-gene and the ARMC1 gene are expressed in normal human prostate tissues.	('LOC100121429', 'Var', (61, 73))	('ARMC1', 'Gene', (94, 99))	('ARMC1', 'Gene', '55156', (94, 99))	('human', 'Species', '9606', (129, 134))
39469	26158673	SLC7A11 is the closest protein-coding gene near rs11736129, which is approximately 250KB from the SNP.	('rs11736129', 'Var', (48, 58))	('SLC7A11', 'Gene', (0, 7))	('rs11736129', 'Mutation', 'rs11736129', (48, 58))	('SLC7A11', 'Gene', '23657', (0, 7))
39472	26158673	Among loci for which evidence was suggestive, we found two polymorphisms in the NRXN3 associated with PV.	('NRXN3', 'Gene', (80, 85))	('NRXN3', 'Gene', '9369', (80, 85))	('polymorphisms', 'Var', (59, 72))	('associated', 'Reg', (86, 96))
39475	26158673	Similar evidence was observed at the SNP rs9583484 in the intronic region of the Type IV collagen COL4A2 gene, a gene providing the major structural component of basement membranes.	('rs9583484', 'Mutation', 'rs9583484', (41, 50))	('rs9583484', 'Var', (41, 50))	('COL4A2', 'Gene', '1284', (98, 104))	('men', 'Species', '9606', (166, 169))	('COL4A2', 'Gene', (98, 104))
39479	26158673	Other loci of interest included a polymorphism in the RPL32P31 pseudogene and polymorphisms in the solute carrier family of genes (SLC12A7, SLC12A1) involved in the transport of sodium and other inorganic compounds across the cell membrane and the sodium/potassium channel (SLC17A1).	('polymorphism', 'Var', (34, 46))	('SLC17A1', 'Gene', '6568', (274, 281))	('SLC12A1', 'Gene', '6557', (140, 147))	('RPL32P31', 'Gene', '201259', (54, 62))	('SLC17A1', 'Gene', (274, 281))	('SLC12A1', 'Gene', (140, 147))	('sodium', 'Chemical', 'MESH:D012964', (178, 184))	('SLC12A7', 'Gene', '10723', (131, 138))	('RPL32P31', 'Gene', (54, 62))	('sodium', 'Chemical', 'MESH:D012964', (248, 254))	('SLC12A7', 'Gene', (131, 138))	('polymorphisms', 'Var', (78, 91))
39490	26158673	Obesity may have a separate association with advanced PC, and we therefore excluded men with high-grade PC hypothesizing that any association between genetic variability in men with high-grade PC would likely be a consequence of effects on PC rather than prostate size.	('genetic variability', 'Var', (150, 169))	('advanced PC', 'Disease', (45, 56))	('men', 'Species', '9606', (173, 176))	('Obesity', 'Disease', (0, 7))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('men', 'Species', '9606', (84, 87))
39581	19959032	In a recent report, the amplification of MYC/MYCN and gains or losses in 6q or 17q was prognostic for overall survival in pediatric patients.	('MYCN', 'Gene', (45, 49))	('MYC', 'Gene', (45, 48))	('MYCN', 'Gene', '4613', (45, 49))	('gains', 'PosReg', (54, 59))	('amplification', 'Var', (24, 37))	('MYC', 'Gene', '4609', (41, 44))	('MYC', 'Gene', '4609', (45, 48))	('MYC', 'Gene', (41, 44))	('patients', 'Species', '9606', (132, 140))	('17q', 'Protein', (79, 82))	('losses', 'NegReg', (63, 69))
39598	19959032	Genetic differences in ependymoma are considered to be the key to successful risk classification for future clinical trials and highlight many of the differences between pediatric and adult ependymoma.	('ependymoma', 'Phenotype', 'HP:0002888', (190, 200))	('ependymoma', 'Disease', 'MESH:D004806', (190, 200))	('adult ependymoma', 'Disease', (184, 200))	('ependymoma', 'Disease', (190, 200))	('adult ependymoma', 'Disease', 'MESH:C531673', (184, 200))	('ependymoma', 'Phenotype', 'HP:0002888', (23, 33))	('ependymoma', 'Disease', (23, 33))	('ependymoma', 'Disease', 'MESH:D004806', (23, 33))	('Genetic differences', 'Var', (0, 19))
39599	19959032	Chromosomal gains of 1q are commonly associated with ependymoma in children, particularly the intracranial and anaplastic tumor types.	('associated with', 'Reg', (37, 52))	('ependymoma', 'Phenotype', 'HP:0002888', (53, 63))	('ependymoma', 'Disease', (53, 63))	('ependymoma', 'Disease', 'MESH:D004806', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('children', 'Species', '9606', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Chromosomal gains of', 'Var', (0, 20))	('tumor', 'Disease', (122, 127))
39600	19959032	Others have shown that genetic imbalances are predictive of tumor site, histologic subtype, and the age of the patient, suggesting further differences between adult and pediatric ependymoma.	('pediatric ependymoma', 'Disease', 'MESH:D004806', (169, 189))	('genetic imbalances', 'Var', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ependymoma', 'Phenotype', 'HP:0002888', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('imbalances', 'Phenotype', 'HP:0002172', (31, 41))	('patient', 'Species', '9606', (111, 118))	('tumor', 'Disease', (60, 65))	('pediatric ependymoma', 'Disease', (169, 189))	('differences', 'Reg', (139, 150))
39651	29371945	First, high BICD1 expression was correlated with poor prognosis in the TCGA GBM cohort (n=523) and in the CGGA glioma cohort (n=220).	('glioma', 'Disease', (111, 117))	('BICD1', 'Gene', '636', (12, 17))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('BICD1', 'Gene', (12, 17))	('expression', 'MPA', (18, 28))	('high', 'Var', (7, 11))
39652	29371945	Second, high BICD1 expression predicted poor outcome in patients with TMZ treatment (n=301) and radiation therapy (n=405).	('patients', 'Species', '9606', (56, 64))	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('TMZ', 'Chemical', 'MESH:D000077204', (70, 73))	('BICD1', 'Gene', '636', (13, 18))	('BICD1', 'Gene', (13, 18))
39656	29371945	In conclusion, our study suggests that high BICD1 expression may result in worse prognosis and could be a predictor of poor response to TMZ and radiation therapies in GBM patients.	('GBM', 'Disease', (167, 170))	('high', 'Var', (39, 43))	('patients', 'Species', '9606', (171, 179))	('BICD1', 'Gene', '636', (44, 49))	('BICD1', 'Gene', (44, 49))	('result', 'Reg', (65, 71))	('TMZ', 'Chemical', 'MESH:D000077204', (136, 139))	('expression', 'MPA', (50, 60))
39664	29371945	Its active form can methylate DNA at the sites of O6-guanine, N7-guanine, or N3-adenine.	('N7-guanine', 'Var', (62, 72))	('methylate', 'MPA', (20, 29))	('N3-adenine', 'Chemical', '-', (77, 87))	('O6-guanine', 'Chemical', '-', (50, 60))	('N3-adenine', 'Var', (77, 87))	('O6-guanine', 'Var', (50, 60))	('N7-guanine', 'Chemical', '-', (62, 72))
39665	29371945	The DNA damage is primarily mediated by the O6-methylguanine (O6-MeG), which induces double-strand breaks and base mispairing, and thereby causes apoptosis and cell death.	('cell death', 'CPA', (160, 170))	('O6-methylguanine', 'Var', (44, 60))	('base mispairing', 'MPA', (110, 125))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (44, 60))	('apoptosis', 'CPA', (146, 155))	('O6-MeG', 'Chemical', 'MESH:C008449', (62, 68))	('causes', 'Reg', (139, 145))	('double-strand breaks', 'MPA', (85, 105))	('induces', 'Reg', (77, 84))
39676	29371945	MGMT promoter methylation in high-grade astrocytomas and co-deletion of 1p/19q in oligodendrogliomas are proven prognostic and predictive markers that play a role in standard practice, and mutations of IDH1 or IDH2 are of strong prognostic value in lower grade gliomas (LGG), which are the most widely validated biomarkers in neuro-oncology currently.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (261, 268))	('astrocytomas', 'Disease', (40, 52))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (82, 100))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('prognostic', 'Reg', (229, 239))	('co-deletion', 'Var', (57, 68))	('gliomas', 'Phenotype', 'HP:0009733', (261, 268))	('MGMT', 'Gene', '4255', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('oligodendrogliomas', 'Disease', (82, 100))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH2', 'Gene', (210, 214))	('mutations', 'Var', (189, 198))	('astrocytomas', 'Disease', 'MESH:D001254', (40, 52))	('IDH2', 'Gene', '3418', (210, 214))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH1', 'Gene', (202, 206))	('gliomas', 'Disease', (261, 268))	('MGMT', 'Gene', (0, 4))	('oncology', 'Phenotype', 'HP:0002664', (332, 340))	('IDH1', 'Gene', '3417', (202, 206))
39692	29371945	According to our result of MTT assay, the EC50 of TMZ was 400muM in T98G, and 20muM in U87 (Figure 1A), which were compatible with other study groups' data.	('muM', 'Gene', (61, 64))	('MTT', 'Chemical', 'MESH:C070243', (27, 30))	('T98G', 'Var', (68, 72))	('TMZ', 'Chemical', 'MESH:D000077204', (50, 53))	('muM', 'Gene', '56925', (80, 83))	('muM', 'Gene', (80, 83))	('muM', 'Gene', '56925', (61, 64))
39694	29371945	A total of 13 probes, which were up-regulated in T98G and down-regulated in U87 after TMZ treatment, were identified by the method of hierarchical clustering analysis (Figure 1B).	('down-regulated', 'NegReg', (58, 72))	('T98G', 'Var', (49, 53))	('up-regulated', 'PosReg', (33, 45))	('TMZ', 'Chemical', 'MESH:D000077204', (86, 89))
39696	29371945	A heat map was constructed by ranking these probes according to the extent of expression change in T98G and U87 (with or without TMZ treatment), and there were 8 genes represented by these 13 probes (Figure 1C).	('TMZ', 'Chemical', 'MESH:D000077204', (129, 132))	('T98G', 'Var', (99, 103))	('expression', 'MPA', (78, 88))
39697	29371945	Notably, FUBP1 expression was highly increased in T98G after TMZ treatment and was the top-ranked marker out of the 13 identified probes (Figure 1C).	('T98G', 'Var', (50, 54))	('FUBP1', 'Gene', '8880', (9, 14))	('expression', 'MPA', (15, 25))	('increased', 'PosReg', (37, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (61, 64))	('FUBP1', 'Gene', (9, 14))
39700	29371945	Therefore, we chose BICD1, the top-ranked gene in impacting the overall survival of GBM patients (HR=1.577; 95% CI=1.299-1.914; P=0.000004) (Figure 1D), as a candidate marker because of its high potential in developing a biomarker of GBMs, and its novelty in the study of GBMs.	('gene', 'Var', (42, 46))	('patients', 'Species', '9606', (88, 96))	('BICD1', 'Gene', (20, 25))	('overall survival', 'MPA', (64, 80))	('BICD1', 'Gene', '636', (20, 25))	('GBM', 'Disease', (84, 87))	('GBMs', 'Phenotype', 'HP:0012174', (234, 238))	('GBMs', 'Phenotype', 'HP:0012174', (272, 276))	('impacting', 'Reg', (50, 59))
39701	29371945	The differential expression of BICD1 mRNA in U87 and T98G (with or without TMZ treatment) was further confirmed by RT-PCR (Figure 1E).	('U87', 'Var', (45, 48))	('BICD1', 'Gene', (31, 36))	('T98G', 'Var', (53, 57))	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))	('BICD1', 'Gene', '636', (31, 36))
39702	29371945	Additionally, the gene expression status of MGMT in U87 and T98G (with or without TMZ treatment) and its prognostic value were analyzed and presented as reference (Figure 1C, 1D).	('U87', 'Var', (52, 55))	('T98G', 'Var', (60, 64))	('MGMT', 'Gene', (44, 48))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('MGMT', 'Gene', '4255', (44, 48))
39705	29371945	The expression levels of BICD1 were significantly higher in GBMs than in LGGs (***) (Figure 2C).	('expression levels', 'MPA', (4, 21))	('higher', 'PosReg', (50, 56))	('GBMs', 'Var', (60, 64))	('GBMs', 'Phenotype', 'HP:0012174', (60, 64))	('BICD1', 'Gene', '636', (25, 30))	('BICD1', 'Gene', (25, 30))
39706	29371945	GBMs had a significantly higher percentage of high BICD1 expression than LGGs (GBMs: 134/165 vs. LGGs: 210/524, P<0.00001) (Figure 2D) (Table 2).	('BICD1', 'Gene', (51, 56))	('high', 'Var', (46, 50))	('expression', 'MPA', (57, 67))	('GBMs', 'Phenotype', 'HP:0012174', (0, 4))	('GBMs', 'Phenotype', 'HP:0012174', (79, 83))	('BICD1', 'Gene', '636', (51, 56))
39715	29371945	The percentage of high BICD1 expression was significantly correlated with poor prognosis in glioma patients when they are grouped according to the WHO grade and patient age in the TCGA GBMLGG cohort (P<0.00001) (Figure 2G).	('patient', 'Species', '9606', (99, 106))	('BICD1', 'Gene', '636', (23, 28))	('patient', 'Species', '9606', (161, 168))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('BICD1', 'Gene', (23, 28))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('high', 'Var', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('expression', 'MPA', (29, 39))
39722	29371945	In comparison of BICD1 with MGMT expression in predicting the overall survival of glioma patients by the Kaplan-Meier survival analysis, high BICD1 expression showed more significant impact (P<0.000001) than high MGMT expression (P=0.00003) on worse overall survival in the TCGA GBMLGG cohort (Figure 4A).	('MGMT', 'Gene', (28, 32))	('MGMT', 'Gene', '4255', (213, 217))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('expression', 'MPA', (148, 158))	('MGMT', 'Gene', '4255', (28, 32))	('overall survival', 'MPA', (250, 266))	('high', 'Var', (137, 141))	('patients', 'Species', '9606', (89, 97))	('BICD1', 'Gene', '636', (17, 22))	('glioma', 'Disease', (82, 88))	('BICD1', 'Gene', (17, 22))	('MGMT', 'Gene', (213, 217))	('BICD1', 'Gene', '636', (142, 147))	('BICD1', 'Gene', (142, 147))
39724	29371945	High BICD1 expression also showed more significant impact (P=0.009932) than high MGMT expression (P=0.028420) on worse overall survival in the CGGA (Chinese Glioma Genome Atlas) cohort (Figure 4C).	('High', 'Var', (0, 4))	('BICD1', 'Gene', '636', (5, 10))	('BICD1', 'Gene', (5, 10))	('Glioma', 'Phenotype', 'HP:0009733', (157, 163))	('MGMT', 'Gene', '4255', (81, 85))	('Glioma Genome Atlas', 'Disease', 'MESH:D005910', (157, 176))	('Glioma Genome Atlas', 'Disease', (157, 176))	('MGMT', 'Gene', (81, 85))
39726	29371945	The time to experience a new tumor event was significantly shorter in patients with high BICD1 expression (P=0.000127) than in those with high MGMT expression (P=0.008955) (Figure 5A).	('patients', 'Species', '9606', (70, 78))	('high', 'Var', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('shorter', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BICD1', 'Gene', '636', (89, 94))	('tumor', 'Disease', (29, 34))	('MGMT', 'Gene', (143, 147))	('MGMT', 'Gene', '4255', (143, 147))	('BICD1', 'Gene', (89, 94))
39727	29371945	The time to experience tumor progression was also significantly shorter in patients with high BICD1 expression (P=0.000321), while it was not significantly shorter in patients with high MGMT expression (P=0.469433) (Figure 5B).	('BICD1', 'Gene', '636', (94, 99))	('BICD1', 'Gene', (94, 99))	('MGMT', 'Gene', (186, 190))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('patients', 'Species', '9606', (167, 175))	('MGMT', 'Gene', '4255', (186, 190))	('high', 'Var', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('shorter', 'NegReg', (64, 71))
39728	29371945	And the time to experience tumor recurrence was significantly shorter in patients with high BICD1 expression (P=0.000117) than in those with high MGMT expression (P=0.005083) (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('shorter', 'NegReg', (62, 69))	('MGMT', 'Gene', '4255', (146, 150))	('tumor', 'Disease', (27, 32))	('MGMT', 'Gene', (146, 150))	('expression', 'Var', (98, 108))	('BICD1', 'Gene', '636', (92, 97))	('BICD1', 'Gene', (92, 97))	('high', 'Var', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (73, 81))
39731	29371945	In patients without TMZ treatment, high BICD1 expression still showed significant impact (P=0.009929) on poor overall survival, while high MGMT expression did not show significance (P=0.341587) (Figure 6B), which was compatible with the current knowledge that MGMT is a specific biomarker for predicting the response to TMZ treatment in glioma patients.	('TMZ', 'Chemical', 'MESH:D000077204', (320, 323))	('glioma', 'Disease', 'MESH:D005910', (337, 343))	('MGMT', 'Gene', (139, 143))	('BICD1', 'Gene', '636', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (337, 343))	('glioma', 'Disease', (337, 343))	('MGMT', 'Gene', '4255', (139, 143))	('patients', 'Species', '9606', (3, 11))	('BICD1', 'Gene', (40, 45))	('MGMT', 'Gene', '4255', (260, 264))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('MGMT', 'Gene', (260, 264))	('patients', 'Species', '9606', (344, 352))	('TMZ', 'Chemical', 'MESH:D000077204', (20, 23))
39733	29371945	In patients who received radiation therapy, high BICD1 expression showed more significant impact (P=0.000068) on poor overall survival than high MGMT expression (P=0.015122) (Figure 6C).	('high', 'Var', (44, 48))	('BICD1', 'Gene', (49, 54))	('poor', 'NegReg', (113, 117))	('MGMT', 'Gene', '4255', (145, 149))	('MGMT', 'Gene', (145, 149))	('patients', 'Species', '9606', (3, 11))	('BICD1', 'Gene', '636', (49, 54))
39752	29371945	The patient group with age>=65 and high BICD1 expression had the highest HR and the poorest prognosis (adjusted HR=3.210, median survival: 0.636 years, and 2-year survival rate: 9.0%).	('BICD1', 'Gene', '636', (40, 45))	('patient', 'Species', '9606', (4, 11))	('BICD1', 'Gene', (40, 45))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))
39764	29371945	And the patient group with age<65 and low MGMT expression had the best prognosis (median survival: 1.756 years, and 2-year survival rate: 43.8%).	('MGMT', 'Gene', (42, 46))	('MGMT', 'Gene', '4255', (42, 46))	('low', 'Var', (38, 41))	('patient', 'Species', '9606', (8, 15))
39766	29371945	The patient group with age>=65, high MGMT and high BICD1 expression had the highest HR and the poorest prognosis (adjusted HR=4.420, median survival: 1.047 years, and 2-year survival rate: 7.8%).	('expression', 'MPA', (57, 67))	('high', 'Var', (46, 50))	('BICD1', 'Gene', (51, 56))	('patient', 'Species', '9606', (4, 11))	('MGMT', 'Gene', '4255', (37, 41))	('MGMT', 'Gene', (37, 41))	('BICD1', 'Gene', '636', (51, 56))
39767	29371945	The patient group with age<65, low MGMT and low BICD1 expression had the best prognosis (median survival: 2.140 years, and 2-year survival rate: 53.8%).	('expression', 'MPA', (54, 64))	('low', 'NegReg', (44, 47))	('MGMT', 'Gene', (35, 39))	('patient', 'Species', '9606', (4, 11))	('MGMT', 'Gene', '4255', (35, 39))	('BICD1', 'Gene', '636', (48, 53))	('BICD1', 'Gene', (48, 53))	('low', 'Var', (31, 34))
39778	29371945	The patient group with age>=65 and high BICD1 expression had the highest HR and the poorest prognosis (adjusted HR=2.572, median survival: 0.904 years, and 2-year survival rate: 15.3%).	('BICD1', 'Gene', '636', (40, 45))	('patient', 'Species', '9606', (4, 11))	('BICD1', 'Gene', (40, 45))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))
39785	29371945	Patients with high BICD1 expression had a significantly higher percentage of high EMT spectrum than those with low BICD1 expression (High BICD1 expression: 168/261 vs. Low BICD1 expression: 94/262) (P<0.00001) (Figure 11B).	('BICD1', 'Gene', (115, 120))	('BICD1', 'Gene', '636', (19, 24))	('BICD1', 'Gene', (19, 24))	('high EMT spectrum', 'CPA', (77, 94))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('BICD1', 'Gene', '636', (172, 177))	('high EMT', 'Phenotype', 'HP:0008151', (77, 85))	('BICD1', 'Gene', '636', (138, 143))	('BICD1', 'Gene', (138, 143))	('BICD1', 'Gene', (172, 177))	('BICD1', 'Gene', '636', (115, 120))
39801	29371945	In our results, high BICD1 expression was significantly correlated with poor overall survival in GBM patients.	('patients', 'Species', '9606', (101, 109))	('high', 'Var', (16, 20))	('GBM', 'Disease', (97, 100))	('expression', 'MPA', (27, 37))	('BICD1', 'Gene', '636', (21, 26))	('overall survival', 'MPA', (77, 93))	('BICD1', 'Gene', (21, 26))	('poor', 'NegReg', (72, 76))
39802	29371945	Patients with high BICD1 expression spent a significantly shorter time to experience a new tumor event, tumor progress, and tumor recurrence than those with low BICD1 expression.	('shorter', 'NegReg', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BICD1', 'Gene', '636', (19, 24))	('BICD1', 'Gene', (19, 24))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('BICD1', 'Gene', '636', (161, 166))	('high', 'Var', (14, 18))	('BICD1', 'Gene', (161, 166))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('expression', 'Var', (25, 35))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
39806	29371945	Notably, in our microarray result, the most differentially expressed gene in T98G after TMZ treatment was the Far Upstream Element-Binding Protein 1 (FUBP1), which suggested that FUBP1 may play a certain role in response to TMZ treatment in GBM cells.	('TMZ', 'Chemical', 'MESH:D000077204', (224, 227))	('FUBP1', 'Gene', (150, 155))	('FUBP1', 'Gene', (179, 184))	('T98G', 'Var', (77, 81))	('differentially', 'PosReg', (44, 58))	('TMZ', 'Chemical', 'MESH:D000077204', (88, 91))	('Far Upstream Element-Binding Protein 1', 'Gene', '8880', (110, 148))	('Far Upstream Element-Binding Protein 1', 'Gene', (110, 148))	('FUBP1', 'Gene', '8880', (150, 155))	('FUBP1', 'Gene', '8880', (179, 184))
39808	29371945	In addition, FUBP1 has been shown to be associated with poor prognosis in glioma patients, and mutations in CIC and FUBP1 have been reported to contribute to human oligodendroglioma.	('FUBP1', 'Gene', '8880', (116, 121))	('associated', 'Reg', (40, 50))	('FUBP1', 'Gene', '8880', (13, 18))	('CIC', 'Gene', (108, 111))	('glioma', 'Disease', (74, 80))	('glioma', 'Disease', (175, 181))	('mutations', 'Var', (95, 104))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('human', 'Species', '9606', (158, 163))	('contribute', 'Reg', (144, 154))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('CIC', 'Gene', '23152', (108, 111))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('FUBP1', 'Gene', (116, 121))	('oligodendroglioma', 'Disease', 'MESH:D009837', (164, 181))	('FUBP1', 'Gene', (13, 18))	('patients', 'Species', '9606', (81, 89))	('oligodendroglioma', 'Disease', (164, 181))
39811	29371945	IDH1 mutation is a key molecular marker in WHO grades II and III gliomas.	('gliomas', 'Disease', (65, 72))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutation', 'Var', (5, 13))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('IDH1', 'Gene', '3417', (0, 4))
39813	29371945	IDH1 mutations were present commonly in 70% of lower grade gliomas and secondary GBMs.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('GBMs', 'Phenotype', 'HP:0012174', (81, 85))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Disease', (59, 66))	('secondary GBMs', 'Disease', (71, 85))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('IDH1', 'Gene', '3417', (0, 4))
39815	29371945	This finding was similar to our observation that there was only a small percentage of IDH1 mutant in proneural subtype (13/60), neural subtype (1/43), and in all GBMs (14/248) (Supplementary Figure 1B).	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('mutant', 'Var', (91, 97))	('Supplementary Figure 1B', 'Disease', (177, 200))	('GBMs', 'Phenotype', 'HP:0012174', (162, 166))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (177, 200))
39829	29371945	Many cellular responses have been proposed to cause chemotherapeutic resistance in cancer cells, including apoptosis inhibition, DNA damage repair, drug target alteration, the epithelial-mesenchymal transition (EMT), drug efflux, and drug inactivation.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('alteration', 'Var', (160, 170))	('drug', 'MPA', (234, 238))	('DNA', 'MPA', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('epithelial-mesenchymal transition', 'CPA', (176, 209))	('cause', 'Reg', (46, 51))	('inhibition', 'NegReg', (117, 127))	('apoptosis', 'CPA', (107, 116))	('drug efflux', 'MPA', (217, 228))	('cancer', 'Disease', (83, 89))
39841	29371945	Our analysis also showed a high correlation between the expression levels of BICD1 and cytoplasmic dyneins (Supplementary Figure 2), which suggested another possible mechanism by which high BICD1 expression may result in TMZ resistance in GBM cells through the dynein-mediated pathway.	('BICD1', 'Gene', '636', (190, 195))	('BICD1', 'Gene', (190, 195))	('result in', 'Reg', (211, 220))	('dynein', 'Gene', '79659', (99, 105))	('dynein', 'Gene', (99, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (221, 224))	('BICD1', 'Gene', '636', (77, 82))	('BICD1', 'Gene', (77, 82))	('high', 'Var', (185, 189))	('dynein', 'Gene', '79659', (261, 267))	('dynein', 'Gene', (261, 267))	('TMZ resistance', 'MPA', (221, 235))
39842	29371945	In summary, our study indicated that high BICD1 expression is associated with poor prognosis and therapeutic response in GBMs.	('high', 'Var', (37, 41))	('expression', 'MPA', (48, 58))	('GBMs', 'Disease', (121, 125))	('BICD1', 'Gene', '636', (42, 47))	('BICD1', 'Gene', (42, 47))	('GBMs', 'Phenotype', 'HP:0012174', (121, 125))
39861	29371945	Patients were also grouped according to the molecular subclassification of GBMs defined by TCGA and the IDH1 mutation status.	('IDH1', 'Gene', '3417', (104, 108))	('GBMs', 'Phenotype', 'HP:0012174', (75, 79))	('Patients', 'Species', '9606', (0, 8))	('TCGA', 'Gene', (91, 95))	('IDH1', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
39869	31681595	Methods: Differentially expressed pseudogenes between low grade glioma (LGG) and glioblastoma multiforme (GBM) were identified in the training cohort.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('pseudogenes', 'Var', (34, 45))	('GBM', 'Disease', (106, 109))	('glioblastoma multiforme', 'Disease', (81, 104))	('GBM', 'Disease', 'MESH:D005909', (106, 109))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (81, 104))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
39870	31681595	Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox proportional hazards regression analyses were used to select pseudogenes associated with prognosis of glioma.	('associated', 'Reg', (161, 171))	('glioma', 'Disease', (190, 196))	('pseudogenes', 'Var', (149, 160))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('Cox', 'Gene', '1351', (84, 87))	('Cox', 'Gene', (84, 87))
39876	31681595	Conclusions: In this study, a risk signature with five pseudogenes was constructed and shown to accurately predict 1-, 3-, and 5-year survival for glioma patient.	('patient', 'Species', '9606', (154, 161))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('predict', 'Reg', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('pseudogenes', 'Var', (55, 66))	('glioma', 'Disease', (147, 153))
39884	31681595	With the development of high-throughput sequencing technologies, non-coding RNAs have been discovered and proven to be involved in multiple cellular programs as well as many pathological processes, such as cancer.	('involved', 'Reg', (119, 127))	('non-coding', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('RNAs', 'Gene', (76, 80))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
39885	31681595	Increasing evidence suggests that non-coding RNAs can serve as biomarkers and therapeutic targets in cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('non-coding', 'Var', (34, 44))
39886	31681595	Some pseudogene RNAs, belonging to long non-coding RNA (lncRNA) with more than 200 nucleotides in length, act as RNA sponges for miRNAs and regulate gene expression via competing endogenous RNA (ceRNA) networks.	('N', 'Chemical', 'MESH:D009584', (114, 115))	('N', 'Chemical', 'MESH:D009584', (198, 199))	('N', 'Chemical', 'MESH:D009584', (132, 133))	('N', 'Chemical', 'MESH:D009584', (191, 192))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('regulate', 'Reg', (140, 148))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('gene expression', 'MPA', (149, 164))	('pseudogene', 'Var', (5, 15))
39889	31681595	Several studies have also demonstrated that pseudogene transcripts have histological specificity and contribute to tumorigenesis.	('pseudogene transcripts', 'Var', (44, 66))	('contribute', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
39890	31681595	It has been reported that 440 pseudogenes are transcribed in breast cancer, and 309 of them are differentially expressed in different breast cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pseudogenes', 'Var', (30, 41))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
39891	31681595	The functions of pseudogenes in glioma have also been reported.	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Disease', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('pseudogenes', 'Var', (17, 28))
39902	31681595	The training cohort was used to select pseudogenes and establish a prognostic risk signature in glioma, and the validation cohort was used for internal validation.	('pseudogenes', 'Var', (39, 50))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Disease', (96, 102))
39905	31681595	Univariate Cox models were used to assess the association between pseudogenes and glioma patient's overall survival (OS) from data in the training cohort.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('patient', 'Species', '9606', (89, 96))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('pseudogenes', 'Var', (66, 77))	('association', 'Interaction', (46, 57))	('glioma', 'Disease', (82, 88))
39923	31681595	The 15 pseudogenes were all correlated with glioma prognosis according to univariate Cox analysis (Supplementary Table 1, P < 0.0001).	('Cox', 'Gene', (85, 88))	('pseudogenes', 'Var', (7, 18))	('correlated with', 'Reg', (28, 43))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('Cox', 'Gene', '1351', (85, 88))
39931	31681595	The risk scores were calculated using the formula mentioned in the methods, as follows: risk score = (0.2279 x expression level of ANXA2P2) + (-0.2170 x expression level of EEF1A1P9) + (0.1056 x expression level of FER1L4) + (0.1232 x expression level of HILS1) + (0.1448 x expression level of RAET1K).	('ANXA2P2', 'Gene', '304', (131, 138))	('-0.2170 x', 'Var', (143, 152))	('EEF1A1P9', 'Gene', (173, 181))	('EEF1A1P9', 'Gene', '441032', (173, 181))	('ANXA2P2', 'Gene', (131, 138))	('RAET1K', 'Gene', '646024', (294, 300))	('RAET1K', 'Gene', (294, 300))	('FER1L4', 'Gene', (215, 221))	('0.2279', 'Var', (102, 108))	('HILS1', 'Gene', (255, 260))	('FER1L4', 'Gene', '80307', (215, 221))	('HILS1', 'Gene', '373861', (255, 260))
39939	31681595	To confirm the prognostic value of the risk signature, univariate and multivariate Cox regression analysis were conducted in the training cohort, and showed that the risk signature with five pseudogenes was independently associated with overall survival of glioma (Table 3).	('overall', 'MPA', (237, 244))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('Cox', 'Gene', '1351', (83, 86))	('Cox', 'Gene', (83, 86))	('pseudogenes', 'Var', (191, 202))	('associated with', 'Reg', (221, 236))	('glioma', 'Disease', (257, 263))
39947	31681595	For IDH status, risk scores decreased in patients with an IDH mutant compared with patients with wildtype IDH (Figure 6C, P < 0.0001).	('risk scores', 'MPA', (16, 27))	('IDH', 'Gene', '3417', (58, 61))	('mutant', 'Var', (62, 68))	('IDH', 'Gene', '3417', (106, 109))	('decreased', 'NegReg', (28, 37))	('IDH', 'Gene', '3417', (4, 7))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (83, 91))	('IDH', 'Gene', (58, 61))	('IDH', 'Gene', (106, 109))	('IDH', 'Gene', (4, 7))
39948	31681595	The risk scores of patients with a methylated MGMT promoter were lower than patients without MGMT promoter methylation (Figure 6D, P < 0.0001).	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (19, 27))	('MGMT', 'Gene', '4255', (93, 97))	('MGMT', 'Gene', (46, 50))	('MGMT', 'Gene', (93, 97))	('lower', 'NegReg', (65, 70))	('MGMT', 'Gene', '4255', (46, 50))	('risk scores', 'MPA', (4, 15))	('methylated', 'Var', (35, 45))
39953	31681595	Pseudogenes can positively or negatively regulate gene expression by functioning as miRNA decoys.	('gene expression', 'MPA', (50, 65))	('Pseudogenes', 'Var', (0, 11))	('regulate', 'Reg', (41, 49))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('negatively', 'NegReg', (30, 40))
39969	31681595	As a special group of lncRNAs, pseudogenes are remnants of their parental genes that lost their ability to encode proteins.	('ability to encode proteins', 'MPA', (96, 122))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('pseudogenes', 'Var', (31, 42))
39970	31681595	It has been reported, based on supervised analysis, that 71 pseudogenes were found differentially expressed among GBM subtypes (classical, mesenchymal, neural, and proneural), indicating their potential roles in glioma.	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('GBM', 'Disease', (114, 117))	('GBM', 'Disease', 'MESH:D005909', (114, 117))	('roles', 'Reg', (203, 208))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('glioma', 'Disease', (212, 218))	('pseudogenes', 'Var', (60, 71))
39984	31681595	Accumulating evidence suggests vital roles for pseudogenes in multiple cellular processes and various cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('pseudogenes', 'Var', (47, 58))
39985	31681595	Mechanistically, some pseudogenes with specific miRNA target sites are capable of regulating gene expression via acting as ceRNAs.	('pseudogenes', 'Var', (22, 33))	('regulating gene expression', 'MPA', (82, 108))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('N', 'Chemical', 'MESH:D009584', (126, 127))
39997	31681595	In conclusion, we identified five pseudogenes associated with glioma patient survival.	('pseudogenes', 'Var', (34, 45))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('patient', 'Species', '9606', (69, 76))	('associated with', 'Reg', (46, 61))	('glioma', 'Disease', (62, 68))
40023	25345514	Recent observations have demonstrated that mutations within CLDN genes are responsible for various diseases, which include neonatal sclerosis cholangitis (CLDN1), nonsyndromic recessive deafness (CLDN14) and familial hypomagnesemia (CLDN16).	('CLDN16', 'Gene', (233, 239))	('rat', 'Species', '10116', (32, 35))	('CLDN1', 'Gene', (233, 238))	('deafness', 'Phenotype', 'HP:0000365', (186, 194))	('CLDN14', 'Gene', (196, 202))	('sclerosis cholangitis', 'Phenotype', 'HP:0030991', (132, 153))	('nonsyndromic recessive deafness', 'Disease', (163, 194))	('CLDN1', 'Gene', '9076', (196, 201))	('responsible', 'Reg', (75, 86))	('CLDN14', 'Gene', '23562', (196, 202))	('CLDN1', 'Gene', '9076', (155, 160))	('familial hypomagnesemia', 'Disease', 'MESH:C537153', (208, 231))	('various diseases', 'Disease', (91, 107))	('neonatal sclerosis cholangitis', 'Disease', 'MESH:D002761', (123, 153))	('nonsyndromic recessive deafness', 'Disease', 'MESH:C580334', (163, 194))	('CLDN1', 'Gene', '9076', (233, 238))	('neonatal sclerosis cholangitis', 'Disease', (123, 153))	('cholangitis', 'Phenotype', 'HP:0030151', (142, 153))	('familial hypomagnesemia', 'Disease', (208, 231))	('various diseases', 'Disease', 'MESH:C566351', (91, 107))	('mutations', 'Var', (43, 52))	('CLDN1', 'Gene', (155, 160))	('CLDN1', 'Gene', (196, 201))	('CLDN', 'Gene', (60, 64))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (217, 231))	('CLDN16', 'Gene', '10686', (233, 239))
40028	25345514	Earlier reports suggested that the particle association with the P-/E face in endothelial cells is believed to be a combination of CLDN1 and CLDN5.	('CLDN1', 'Gene', (131, 136))	('CLDN1', 'Gene', '9076', (131, 136))	('P-/E face', 'Var', (65, 74))
40033	25345514	Disruption of TJs causes the loss of cohesion, invasiveness and lack of differentiation which ultimately leads to the tumorigenesis in epithelial cells.	('leads to', 'Reg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('invasiveness', 'Disease', (47, 59))	('TJs', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Disruption', 'Var', (0, 10))	('invasiveness', 'Disease', 'MESH:D009362', (47, 59))	('loss', 'NegReg', (29, 33))	('tumor', 'Disease', (118, 123))	('lack', 'CPA', (64, 68))	('cohesion', 'MPA', (37, 45))
40039	25345514	Immunohistochemical analysis revealed a significant association between high CLDN1 expression and basal-like breast cancer.	('CLDN1', 'Gene', (77, 82))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('CLDN1', 'Gene', '9076', (77, 82))	('expression', 'MPA', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('high', 'Var', (72, 76))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
40040	25345514	Disruption of TJs is not only a hallmark of epithelial cancer development and malignant expression but also associated with a number of pathological conditions such as kidney disorders, inflammatory bowel disease, pulmonary edema, diarrhea and jaundice [- ].	('TJs', 'Gene', (14, 17))	('jaundice', 'Disease', (244, 252))	('pulmonary edema', 'Disease', 'MESH:D011654', (214, 229))	('Disruption', 'Var', (0, 10))	('pulmonary edema', 'Phenotype', 'HP:0100598', (214, 229))	('epithelial cancer', 'Phenotype', 'HP:0031492', (44, 61))	('jaundice', 'Disease', 'MESH:D007565', (244, 252))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (186, 212))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (186, 212))	('diarrhea', 'Phenotype', 'HP:0002014', (231, 239))	('pulmonary edema', 'Disease', (214, 229))	('inflammatory bowel disease', 'Disease', (186, 212))	('kidney disorders', 'Phenotype', 'HP:0000112', (168, 184))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('hallmark of epithelial cancer', 'Disease', 'MESH:D000077216', (32, 61))	('associated', 'Reg', (108, 118))	('diarrhea', 'Disease', (231, 239))	('kidney disorders', 'Disease', (168, 184))	('edema', 'Phenotype', 'HP:0000969', (224, 229))	('kidney disorders', 'Disease', 'MESH:D007674', (168, 184))	('hallmark of epithelial cancer', 'Disease', (32, 61))	('jaundice', 'Phenotype', 'HP:0000952', (244, 252))	('diarrhea', 'Disease', 'MESH:D003967', (231, 239))
40056	25345514	The malignant glioma cell lines comprising C6 (low-grade), U373, U118, T98MG, U87MG (high-grade) and the control non-CNS cell line ECV304 were used in the current study, and were obtained from the cell line repository of the National Centre for Cell Science (NCCS), India, and from American Type Culture Collection (ATCC).	('T98MG', 'CellLine', 'CVCL:B368', (71, 76))	('U87MG', 'CellLine', 'CVCL:0022', (78, 83))	('U87MG', 'Var', (78, 83))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('ECV304', 'CellLine', 'CVCL:2029', (131, 137))	('malignant glioma', 'Disease', 'MESH:D005910', (4, 20))	('malignant glioma', 'Disease', (4, 20))
40092	25345514	A significant down regulation of CLDN1 expression was also evident in glioma cell lines of higher grade, of more than three-fold in U373, U87MG, U118 and T98, as compared to their lower grade counterpart and the ECV 304 control cell line [Figure 5 and Table 2b].	('glioma', 'Disease', (70, 76))	('down regulation', 'NegReg', (14, 29))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('CLDN1', 'Gene', '9076', (33, 38))	('expression', 'MPA', (39, 49))	('U87MG', 'CellLine', 'CVCL:0022', (138, 143))	('CLDN1', 'Gene', (33, 38))	('U87MG', 'Var', (138, 143))
40102	25345514	U373, U118, T98 and U87MG), as compared to lower grade C6 glioma cell line and the control cell line ECV 304 [Figure 6 and Table 2e].	('U373', 'Var', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('U87MG', 'CellLine', 'CVCL:0022', (20, 25))	('U87MG', 'Var', (20, 25))	('U118', 'Var', (6, 10))	('glioma', 'Disease', (58, 64))
40124	25345514	It may additionally relate to local proinflammatory cytokine levels as reductions in CLDN1 have also been reported in hepatitis C. Interestingly, the ectopic expression of CLDN-1 in mice prevents blood-brain barrier loss of permeability in the EAE model of multiple sclerosis, compared to control littermates.	('CLDN-1', 'Gene', '12737', (172, 178))	('CLDN1', 'Gene', (85, 90))	('hepatitis C.', 'Disease', (118, 130))	('CLDN-1', 'Gene', (172, 178))	('mice', 'Species', '10090', (182, 186))	('hepatitis', 'Phenotype', 'HP:0012115', (118, 127))	('reductions', 'NegReg', (71, 81))	('blood-brain barrier loss of permeability', 'CPA', (196, 236))	('ectopic expression', 'Var', (150, 168))	('multiple sclerosis', 'Disease', (257, 275))	('multiple sclerosis', 'Disease', 'MESH:D009103', (257, 275))	('CLDN1', 'Gene', '9076', (85, 90))	('prevents', 'NegReg', (187, 195))
40127	25345514	Regardless of the cellular origin, it is now widely accepted that an alteration in CLDN expression can lead to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CLDN', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('lead to', 'Reg', (103, 110))	('alteration', 'Var', (69, 79))	('expression', 'MPA', (88, 98))	('rat', 'Species', '10116', (73, 76))
40132	25345514	The occurrence of epithelial-mesenchymal transition, an early step during cancer progression due to the alteration of TJ proteins, is already well supported.	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('epithelial-mesenchymal transition', 'CPA', (18, 51))	('cancer', 'Disease', (74, 80))	('TJ proteins', 'Protein', (118, 129))	('alteration', 'Var', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
40140	25345514	Our present study suggests that glioma progression associates with dysregulation of CLDN1 and CLDN5 genes.	('dysregulation', 'Var', (67, 80))	('CLDN5', 'Gene', (94, 99))	('glioma', 'Disease', (32, 38))	('CLDN1', 'Gene', '9076', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('CLDN1', 'Gene', (84, 89))
40141	25345514	The discovery of CLDN alterations in GBM provides a pathophysiologic link between TJ proteins and glioma progression; whether or not one can take advantage of this to find novel therapeutics is an avenue worth pursuing.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('rat', 'Species', '10116', (26, 29))	('alterations', 'Var', (22, 33))	('glioma', 'Disease', (98, 104))	('CLDN', 'Gene', (17, 21))
40145	25345514	Further studies are required to assess the molecular mechanisms underpinning these changes in expression, and whether normalization of CLDN1, CLDN5 and beta-catenin protein levels in gliomas might improve their responsiveness to radio- and chemotherapy.	('gliomas', 'Disease', (183, 190))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('normalization', 'Var', (118, 131))	('beta-catenin', 'Gene', (152, 164))	('CLDN1', 'Gene', '9076', (135, 140))	('beta-catenin', 'Gene', '1499', (152, 164))	('responsiveness', 'MPA', (211, 225))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('CLDN1', 'Gene', (135, 140))	('improve', 'PosReg', (197, 204))	('CLDN5', 'MPA', (142, 147))
40152	33568653	High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes.	('mutations', 'Var', (45, 54))	('SSV', 'Chemical', '-', (13, 16))	('SSV', 'Disease', (13, 16))	('histone H3.3', 'Gene', (56, 68))	('H3F3C', 'Gene', (74, 79))	('transcription', 'MPA', (99, 112))	('mutations', 'Var', (80, 89))	('histone H3.3', 'Gene', '3020', (56, 68))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('H3F3C', 'Gene', '440093', (74, 79))
40158	33568653	All classes of somatic structural variants (SSVs):including tandem duplications, insertions, deletions, inversions, and translocations:can potentially alter the regulation of specific genes through several possible mechanisms, including gene fusion, promoter element disruption, enhancer hijacking, disruption of topologically associated domains (TADs), and altered DNA methylation.	('variants', 'Var', (34, 42))	('DNA methylation', 'MPA', (366, 381))	('disruption', 'Reg', (299, 309))	('tandem duplications', 'Var', (60, 79))	('altered', 'Reg', (358, 365))	('disruption', 'Reg', (267, 277))	('TADs', 'Disease', (347, 351))	('gene', 'CPA', (237, 241))	('enhancer hijacking', 'PosReg', (279, 297))	('deletions', 'Var', (93, 102))	('promoter', 'MPA', (250, 258))	('TADs', 'Disease', 'None', (347, 351))	('alter', 'Reg', (151, 156))	('regulation', 'MPA', (161, 171))	('specific genes', 'Gene', (175, 189))	('SSV', 'Chemical', '-', (44, 47))	('insertions', 'Var', (81, 91))
40159	33568653	Also, cancers harboring a high overall structural variation burden may exhibit an altered molecular profile reflective of extensive DNA damage.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('molecular profile', 'MPA', (90, 107))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('altered', 'Reg', (82, 89))	('structural variation', 'Var', (39, 59))
40177	33568653	Here, a high SSV burden is associated with TP53 mutations, histone H3.3 gene H3F3C mutations, and increased expression of DNA damage response genes.	('mutations', 'Var', (83, 92))	('DNA damage response genes', 'Gene', (122, 147))	('SSV', 'Chemical', '-', (13, 16))	('histone H3.3', 'Gene', '3020', (59, 71))	('H3F3C', 'Gene', (77, 82))	('increased', 'PosReg', (98, 107))	('expression', 'MPA', (108, 118))	('TP53', 'Gene', '7157', (43, 47))	('histone H3.3', 'Gene', (59, 71))	('SSV burden', 'Disease', (13, 23))	('H3F3C', 'Gene', '440093', (77, 82))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
40187	33568653	In line with previous observations in adult cancers, here, genomic rearrangements could be associated with widespread CNA patterns in pediatric brain tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('widespread CNA patterns', 'Disease', (107, 130))	('adult cancers', 'Disease', (38, 51))	('brain tumors', 'Disease', 'MESH:D001932', (144, 156))	('brain tumors', 'Phenotype', 'HP:0030692', (144, 156))	('genomic rearrangements', 'Var', (59, 81))	('brain tumors', 'Disease', (144, 156))	('brain tumor', 'Phenotype', 'HP:0030692', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('adult cancers', 'Disease', 'MESH:D009369', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associated', 'Reg', (91, 101))
40188	33568653	When we considered the set of all SSV-gene associations involving an SSV breakpoint falling within 1 Mb of gene start site for a given tumor, we found these associations to be highly enriched for gene-level amplification or deletion, though more so for the former.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SSV', 'Chemical', '-', (34, 37))	('SSV', 'Chemical', '-', (69, 72))	('tumor', 'Disease', (135, 140))	('falling', 'Phenotype', 'HP:0002527', (84, 91))	('deletion', 'Var', (224, 232))	('fall', 'Phenotype', 'HP:0002527', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
40189	33568653	While a significant proportion of SSVs associated with gene amplification involved tandem duplication SSVs as might be expected, all classes of SSV were involved with altered CNA patterns (Supplementary Fig.	('SSV', 'Chemical', '-', (102, 105))	('SSV', 'Chemical', '-', (34, 37))	('SSV', 'Chemical', '-', (144, 147))	('CNA patterns', 'MPA', (175, 187))	('gene amplification', 'Var', (55, 73))	('involved with altered', 'Reg', (153, 174))	('SSVs', 'Disease', (34, 38))	('tandem duplication', 'Var', (83, 101))	('involved', 'Reg', (74, 82))
40190	33568653	The intra-chromosomal, non-translocation SSVs associated with CNA showed enrichment for SSVs of larger DNA sizes (>100 kb, Supplementary Fig.	('CNA', 'Disease', (62, 65))	('non-translocation', 'Var', (23, 40))	('SSV', 'Chemical', '-', (41, 44))	('SSV', 'Chemical', '-', (88, 91))
40196	33568653	SSV patterns:together with patterns of CNA, insertion/deletion of nucleotide bases (indels), and Single Nucleotide Variants (SNVs):revealed both concordant and discordant patterns among tumors from the same patient.	('SSV', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('insertion/deletion', 'Var', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('patient', 'Species', '9606', (207, 214))
40202	33568653	In principle, SSVs with breakpoints nearby a gene could lead to altered cis-regulation, e.g., by enhancer hijacking or altered DNA methylation, and SSV breakpoints within a gene could result in gene disruption or a gene fusion (Fig.	('lead to altered', 'Reg', (56, 71))	('result in', 'Reg', (184, 193))	('SSV', 'Var', (148, 151))	('SSV', 'Chemical', '-', (14, 17))	('DNA methylation', 'MPA', (127, 142))	('enhancer', 'PosReg', (97, 105))	('breakpoints', 'Var', (24, 35))	('SSV', 'Chemical', '-', (148, 151))	('cis-regulation', 'MPA', (72, 86))	('altered', 'Reg', (119, 126))	('gene', 'CPA', (194, 198))	('gene fusion', 'CPA', (215, 226))
40231	33568653	For particular genes of interest, including oncogenes TERT and MYB and tumor suppressor gene NF1, the relative expression changes in tumors harboring an SSV breakpoint were more dramatic as compared to tumors with CNA (Fig.	('TERT', 'Gene', '7015', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SSV', 'Chemical', '-', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('NF1', 'Gene', '4763', (93, 96))	('tumor', 'Disease', (202, 207))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('MYB', 'Gene', '4602', (63, 66))	('NF1', 'Gene', (93, 96))	('MYB', 'Gene', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (133, 139))	('breakpoint', 'Var', (157, 167))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TERT', 'Gene', (54, 58))
40236	33568653	Similarly, SSV breakpoints involving gene overexpression were enriched (p < 1E-15, chi-squared test) for putative enhancer translocation events, with the rearrangement bringing an enhancer within 500 kb of the gene (Fig.	('enhancer', 'PosReg', (180, 188))	('SSV', 'Chemical', '-', (11, 14))	('rearrangement', 'Var', (154, 167))
40253	33568653	We found a highly significant degree of overlapping gene-to-tumor associations involving predicted fusions using RNA-seq chimeric reads, gene overexpression, and SSVs breakpoint falling within the boundary of a gene (Supplementary Fig.	('SSVs breakpoint falling', 'Disease', 'MESH:D002303', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SSVs breakpoint falling', 'Disease', (162, 185))	('fall', 'Phenotype', 'HP:0002527', (178, 182))	('fusions', 'Var', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('falling', 'Phenotype', 'HP:0002527', (178, 185))	('tumor', 'Disease', (60, 65))
40256	33568653	This set of 1208 fusion calls with the highest level of support involved 974 distinct gene fusions, 368 tumors, and 331 patients (Supplementary Data 4), as well as the majority of gene body-associated SSV breakpoints with overexpression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('overexpression', 'PosReg', (222, 236))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (91, 98))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('SSV', 'Chemical', '-', (201, 204))	('patients', 'Species', '9606', (120, 128))
40257	33568653	Of the 368 tumors, 182 had fusions both detectable in two or more tumors and including a known cancer-associated gene by COSMIC (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (66, 72))	('cancer', 'Disease', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('fusions', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
40264	33568653	Alterations considered were gene fusion, SSV-mediated altered cis-regulation or gene disruption (taking from the genes significant for 1 Mb region), SNV or indel, and deep deletion or high-level amplification (Supplementary Data 5).	('high-level amplification', 'Var', (184, 208))	('SSV', 'Chemical', '-', (41, 44))	('deep deletion', 'Var', (167, 180))	('gene fusion', 'Var', (28, 39))	('cis-regulation', 'MPA', (62, 76))	('gene', 'CPA', (80, 84))	('SNV', 'Var', (149, 152))	('altered', 'Reg', (54, 61))	('indel', 'Var', (156, 161))
40269	33568653	Some tumor types showed particularly high enrichment for alterations affecting a specific pathway (Fig.	('alterations', 'Var', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (5, 10))
40270	33568653	RTK-related alterations showed enrichment within PLGG; p53/Rb-related alterations, within PHGG; alterations involving chromatin modifiers, TERT, and MYC family, within MBL; SWI/SNF alterations, within ATRT; Wnt/beta-catenin alterations, within CRANIO; and HIPPO pathway alterations, within MNG.	('alterations', 'Var', (70, 81))	('MBL', 'Disease', (168, 171))	('MBL', 'Disease', 'MESH:C563602', (168, 171))	('p53', 'Gene', (55, 58))	('TERT', 'Gene', '7015', (139, 143))	('p53', 'Gene', '7157', (55, 58))	('RTK', 'Gene', '5979', (0, 3))	('MYC', 'Gene', (149, 152))	('beta-catenin', 'Gene', (211, 223))	('SWI/SNF', 'Gene', (173, 180))	('HIPPO pathway', 'Pathway', (256, 269))	('beta-catenin', 'Gene', '1499', (211, 223))	('MYC', 'Gene', '4609', (149, 152))	('RTK', 'Gene', (0, 3))	('TERT', 'Gene', (139, 143))
40291	33568653	We searched for genes with inactivating SNVs or indels correlated with high SSV burden, with 17 genes being significant (Fig.	('SNVs', 'Var', (40, 44))	('high SSV burden', 'Disease', (71, 86))	('indels', 'Var', (48, 54))	('SSV', 'Chemical', '-', (76, 79))
40294	33568653	TP53 hotspot SNVs and inactivating SNVs and indels, along with single-copy loss, were associated with higher SSV burden, in both the CBTTC pediatric brain and TCGA adult pan-cancer cohorts (Fig.	('SSV', 'Chemical', '-', (109, 112))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('higher', 'PosReg', (102, 108))	('cancer', 'Disease', (174, 180))	('pan', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('SNVs', 'Var', (13, 17))	('inactivating', 'Var', (22, 34))	('pan', 'Gene', '51816', (170, 173))	('SSV', 'Disease', (109, 112))
40296	33568653	TP53 mutation also corresponded to increases in detected SNVs and indels, in addition to SSV burden (Supplementary Figs.	('SNVs', 'MPA', (57, 61))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('increases', 'PosReg', (35, 44))	('indels', 'MPA', (66, 72))	('SSV burden', 'MPA', (89, 99))	('mutation', 'Var', (5, 13))	('SSV', 'Chemical', '-', (89, 92))
40297	33568653	6b), with mutation and copy loss events mostly occurring in PHGG and MBL tumors.	('occurring', 'Reg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('MBL tumors', 'Disease', 'MESH:C563602', (69, 79))	('MBL tumors', 'Disease', (69, 79))	('PHGG', 'Disease', (60, 64))	('copy loss', 'Var', (23, 32))
40307	33568653	A survey of Histone H3 genes showed frequent mutations in H3F3A and H3F3C across CBTTC tumors (Supplementary Fig.	('H3F3C', 'Gene', '440093', (68, 73))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('H3F3A', 'Gene', '3020', (58, 63))	('H3F3A', 'Gene', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('H3F3C', 'Gene', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
40308	33568653	While H3F3A mutations are commonly associated with pediatric brain tumors, particularly with PHGG and DIPG, H3F3C, which also encodes for an H3.3 histone component, appears to be much less studied in the context of cancer, including pediatric brain cancer.	('H3F3C', 'Gene', (108, 113))	('brain cancer', 'Phenotype', 'HP:0030692', (243, 255))	('cancer', 'Disease', (249, 255))	('brain tumors', 'Disease', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('brain cancer', 'Disease', 'MESH:D001932', (243, 255))	('H3F3A', 'Gene', '3020', (6, 11))	('cancer', 'Disease', (215, 221))	('H3F3C', 'Gene', '440093', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('H3F3A', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (61, 72))	('brain cancer', 'Disease', (243, 255))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('brain tumors', 'Disease', 'MESH:D001932', (61, 73))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (35, 45))	('brain tumors', 'Phenotype', 'HP:0030692', (61, 73))
40310	33568653	7b), with no hypermutated tumors having H3F3C mutations.	('mutations', 'Var', (46, 55))	('H3F3C', 'Gene', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('H3F3C', 'Gene', '440093', (40, 45))	('tumors', 'Disease', (26, 32))
40311	33568653	While H3F3A mutations in CBTTC tumors primarily involved the known K28M/K27M hotspot (n = 30 tumors), followed by the G35R/G34R hotspot (n = 4), H3F3C mutations followed another distinctive pattern.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('H3F3C', 'Gene', (145, 150))	('K27M', 'Var', (72, 76))	('G35R', 'SUBSTITUTION', 'None', (118, 122))	('H3F3A', 'Gene', '3020', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('K28M', 'SUBSTITUTION', 'None', (67, 71))	('involved', 'Reg', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('G34R', 'SUBSTITUTION', 'None', (123, 127))	('G34R', 'Var', (123, 127))	('H3F3A', 'Gene', (6, 11))	('H3F3C', 'Gene', '440093', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', (93, 99))	('K28M', 'Var', (67, 71))	('CBTTC', 'Disease', (25, 30))	('mutations', 'Var', (12, 21))	('G35R', 'Var', (118, 122))	('K27M', 'SUBSTITUTION', 'None', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (93, 99))
40312	33568653	All nine impacted tumors (three PLGG, two EPMT, and one each for ATRT, MNG, PHGG, and SARCNOS; two progressive, two recurrent, and one second malignancy) had nucleotide changes involving both K37 duplication and N79K amino acid change (Fig.	('K37', 'Gene', '8688', (192, 195))	('N79K amino acid change', 'Var', (212, 234))	('N79K', 'Mutation', 'rs768711923', (212, 216))	('malignancy', 'Disease', 'MESH:D009369', (142, 152))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('malignancy', 'Disease', (142, 152))	('K37', 'Gene', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
40313	33568653	Two of the nine tumors also harbored amino acid changes L104F and V89I.	('L104F', 'Mutation', 'rs765335762', (56, 61))	('L104F', 'Var', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('V89I', 'Mutation', 'rs148314204', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('V89I', 'Var', (66, 70))
40314	33568653	H3F3C mutations were mutually exclusive with TP53 alterations (Fig.	('TP53', 'Gene', (45, 49))	('H3F3C', 'Gene', (0, 5))	('TP53', 'Gene', '7157', (45, 49))	('H3F3C', 'Gene', '440093', (0, 5))	('mutations', 'Var', (6, 15))
40318	33568653	We went on to survey whole-exome sequencing data from 10,224 TCGA adult cancers for H3F3C mutations.	('adult cancers', 'Disease', 'MESH:D009369', (66, 79))	('H3F3C', 'Gene', (84, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('H3F3C', 'Gene', '440093', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('adult cancers', 'Disease', (66, 79))
40319	33568653	Of all TCGA tumors, 49:representing many different tissues of origin:harbored a mutation in H3F3C (Fig.	('H3F3C', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('H3F3C', 'Gene', '440093', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mutation', 'Var', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
40322	33568653	The TCGA H3F3C mutations did not show the same tight hotspot pattern found in CBTTC tumors, although TCGA mutations did include G35R (two patients), N79K (one patient), and V89I (four patients).	('V89I', 'Mutation', 'rs148314204', (173, 177))	('G35R', 'Var', (128, 132))	('N79K', 'Mutation', 'rs768711923', (149, 153))	('V89I', 'Var', (173, 177))	('TCGA', 'Gene', (101, 105))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patient', 'Species', '9606', (184, 191))	('G35R', 'Mutation', 'rs748979871', (128, 132))	('H3F3C', 'Gene', '440093', (9, 14))	('patient', 'Species', '9606', (138, 145))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('patient', 'Species', '9606', (159, 166))	('N79K', 'Var', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (138, 146))	('H3F3C', 'Gene', (9, 14))
40325	33568653	Aspects of this phenomenon, as observed in both PCAWG and CBTTC cohorts, include: hundreds of genes recurrently impacted, SSV breakpoints as far as 1 Mb from the gene contributing to deregulation, rearrangements involving widespread CNA patterns, many more genes with increased over decreased expression associated with SSV breakpoints, and overexpressed and under-expressed genes respectively representing known oncogenes and tumor suppressor genes.	('increased over', 'PosReg', (268, 282))	('SSV', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (427, 432))	('SSV', 'Chemical', '-', (320, 323))	('tumor', 'Phenotype', 'HP:0002664', (427, 432))	('tumor', 'Disease', (427, 432))	('rearrangements', 'Var', (197, 211))	('expression', 'MPA', (293, 303))	('impacted', 'Reg', (112, 120))
40340	33568653	For a given patient, the overall numbers of SSVs and other somatic mutations tend to increase in a recurrent or progressive tumor as compared to the primary tumor.	('tumor', 'Disease', (157, 162))	('recurrent', 'CPA', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SSVs', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('patient', 'Species', '9606', (12, 19))	('increase', 'PosReg', (85, 93))	('SSV', 'Chemical', '-', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
40345	33568653	DNA mutation correlates of high SSV burden included mutations in TP53 and histone H3.3 genes.	('mutations', 'Var', (52, 61))	('histone H3.3', 'Gene', '3020', (74, 86))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('histone H3.3', 'Gene', (74, 86))	('SSV', 'Chemical', '-', (32, 35))
40346	33568653	Our TP53-related findings would be consistent with those of an adult pan-cancer study of TCGA data, in which TP53 mutational status was associated with global increases in DNA copy number instability and somatic SNV/indel frequency.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('pan', 'Gene', '51816', (69, 72))	('TP53', 'Gene', (4, 8))	('pan', 'Gene', (69, 72))	('increases', 'PosReg', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (109, 113))	('DNA copy number instability', 'MPA', (172, 199))	('mutational status', 'Var', (114, 131))	('TP53', 'Gene', (109, 113))	('TP53', 'Gene', '7157', (4, 8))
40347	33568653	Other studies have also linked TP53 mutation with increased numbers of chromosome rearrangements in pediatric cancers.	('cancers', 'Disease', (110, 117))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('chromosome rearrangements', 'MPA', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('mutation', 'Var', (36, 44))
40348	33568653	While H3F3A mutations are commonly associated with pediatric brain cancers, H3F3C appears to be much less studied in cancer, including pediatric brain cancer.	('brain cancer', 'Disease', (145, 157))	('brain cancer', 'Phenotype', 'HP:0030692', (61, 73))	('brain cancer', 'Disease', 'MESH:D001932', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('H3F3A', 'Gene', '3020', (6, 11))	('H3F3C', 'Gene', '440093', (76, 81))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (117, 123))	('brain cancer', 'Phenotype', 'HP:0030692', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('H3F3A', 'Gene', (6, 11))	('brain cancer', 'Disease', 'MESH:D001932', (145, 157))	('brain cancers', 'Disease', (61, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('brain cancers', 'Disease', 'MESH:D001932', (61, 74))	('H3F3C', 'Gene', (76, 81))
40349	33568653	Interestingly, a search of the PeCan (https://pecan.stjude.cloud/) and PedCBioportal (https://pedcbioportal.kidsfirstdrc.org/) databases:representing more than 1000 additional pediatric brain tumors:did not uncover additional cases of H3F3C hotspot mutation.	('mutation', 'Var', (249, 257))	('brain tumors', 'Disease', 'MESH:D001932', (186, 198))	('brain tumors', 'Phenotype', 'HP:0030692', (186, 198))	('H3F3C', 'Gene', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('brain tumor', 'Phenotype', 'HP:0030692', (186, 197))	('brain tumors', 'Disease', (186, 198))	('PeCan', 'Species', '32201', (31, 36))	('H3F3C', 'Gene', '440093', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('pecan', 'Species', '32201', (46, 51))
40350	33568653	This may be because mutations in CBTTC cohort were few and spread among multiple histologic types and involving progressive or recurrent or second malignancy cases.	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('CBTTC', 'Gene', (33, 38))	('malignancy', 'Disease', (147, 157))	('spread', 'Reg', (59, 65))	('mutations', 'Var', (20, 29))	('involving', 'Reg', (102, 111))
40351	33568653	At the same time, the observations in adult tumors would suggest that alteration of histone H3.3 genes (including H3F3C) may cumulatively involve many patients, with the functional impact not being limited to hotspot mutations.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('H3F3C', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('histone H3.3', 'Gene', (84, 96))	('patients', 'Species', '9606', (151, 159))	('H3F3C', 'Gene', '440093', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('alteration', 'Var', (70, 80))	('histone H3.3', 'Gene', '3020', (84, 96))	('involve', 'Reg', (138, 145))
40368	33568653	Manta algorithm classified each SSV call as one of the following: tandem duplications, insertions, deletions, inversions, and translocations.	('deletions', 'Var', (99, 108))	('insertions', 'Var', (87, 97))	('SSV', 'Chemical', '-', (32, 35))
40377	33568653	This aspect would include treating SSV breakpoints representing different classes (tandem duplications, insertions, deletions, inversions, and translocations) and insert sizes the same in the integration with gene expression.	('deletions', 'Var', (116, 125))	('insertions', 'Var', (104, 114))	('SSV', 'Chemical', '-', (35, 38))
40400	33568653	We considered all inactivating SNVs (nonstop/nonsense) and indels in putative tumor suppressor genes (e.g., TP53) in the analyses.	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('nonstop/nonsense', 'Var', (37, 53))	('tumor', 'Disease', (78, 83))
40402	33568653	At both the gene and pathway levels, we tabulated somatic alterations in the following order: SNV or indel, gene fusion, deep deletion (approximating homozygous loss), high-level amplification (approximating five or more copies), and SSV (for oncogenes, breakpoint falling with 1 Mb of gene and associated with expression >0.4 SD from median for the given tumor; for tumor suppressors, breakpoint falling within the gene body and expression < -0.4 SD).	('fall', 'Phenotype', 'HP:0002527', (397, 401))	('expression', 'MPA', (311, 321))	('SSV', 'Var', (234, 237))	('deep deletion', 'Var', (121, 134))	('tumor', 'Disease', (367, 372))	('SSV', 'Chemical', '-', (234, 237))	('falling', 'Phenotype', 'HP:0002527', (265, 272))	('falling', 'Phenotype', 'HP:0002527', (397, 404))	('high-level amplification', 'Var', (168, 192))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('gene fusion', 'Var', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('SNV', 'Var', (94, 97))	('fall', 'Phenotype', 'HP:0002527', (265, 269))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumor', 'Disease', (356, 361))
40410	33568653	For CBTTC datasets, we constructed a [gene x tumor] matrix, involving 567 genes with nonsense/nonstop/indel mutations in at least three tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('nonsense/nonstop/indel mutations', 'Var', (85, 117))	('x tumor', 'Disease', 'MESH:C562844', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('x tumor', 'Disease', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
40460	32545571	We show that MSC enhances glioblastoma and stem cell matrix invasion via CCR5.	('CCR5', 'Gene', '1234', (73, 77))	('glioblastoma', 'Disease', (26, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('CCR5', 'Gene', (73, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('enhances', 'PosReg', (17, 25))	('MSC', 'Var', (13, 16))
40555	32545571	Here, we focused on MSCs, proven as glioblastoma-infiltrating cells, recruited from bone marrow or brain tissues, and also present in GSC niches, where MSCs may also affect glioblastoma cell differentiation and proliferation as well as invasion, as proven by us and others.	('MSCs', 'Var', (152, 156))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (173, 185))	('invasion', 'CPA', (236, 244))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('affect', 'Reg', (166, 172))	('proliferation', 'CPA', (211, 224))	('glioblastoma', 'Disease', (36, 48))	('glioblastoma', 'Disease', (173, 185))
40588	32545571	Immunohistochemistry (IHC) analyses were performed using antibodies against CCR5 (ab65850, Abcam, Cambridge, UK), CCR5 peptide (ab192862, Abcam, Cambridge, UK), and CCL5-RANTES (ab189841, Abcam, Cambridge, UK).	('RANTES', 'Gene', '6352', (170, 176))	('CCR5', 'Gene', '1234', (76, 80))	('CCL5', 'Gene', '6352', (165, 169))	('ab192862', 'Var', (128, 136))	('CCR5', 'Gene', '1234', (114, 118))	('ab65850', 'Var', (82, 89))	('CCR5', 'Gene', (76, 80))	('RANTES', 'Gene', (170, 176))	('CCR5', 'Gene', (114, 118))	('CCL5', 'Gene', (165, 169))
40598	32545571	The spheroids were stained for 30 min at room temperature with the following antibodies: CCR5 (ab65850, Abcam, Cambridge, UK ) and CCL5-RANTES (ab189841, Abcam, Cambridge, UK).	('CCR5', 'Gene', '1234', (89, 93))	('RANTES', 'Gene', (136, 142))	('RANTES', 'Gene', '6352', (136, 142))	('CCR5', 'Gene', (89, 93))	('CCL5', 'Gene', '6352', (131, 135))	('CCL5', 'Gene', (131, 135))	('ab65850', 'Var', (95, 102))	('ab189841', 'Var', (144, 152))
40604	32545571	Sections were incubated overnight at 4  C with primary antibodies, diluted in PBS containing 1% BSA (Sigma-Aldrich, St. Louis, MO, USA); CCR5 (ab65850, Abcam, Cambridge, UK), CCL5-RANTES (ab189841, Abcam, Cambridge, UK), CD68 (Dako, clone EBM11), CD105 (ab27422, Abcam, Cambridge, UK), CD133 (ab19898, Abcam, Cambridge, UK) and GFAP (ab10062, Abcam, Cambridge, UK).	('GFAP', 'Gene', '2670', (328, 332))	('CCR5', 'Gene', (137, 141))	('CD133', 'Gene', (286, 291))	('CD133', 'Gene', '8842', (286, 291))	('PBS', 'Chemical', 'MESH:D007854', (78, 81))	('CCL5', 'Gene', '6352', (175, 179))	('CD68', 'Gene', (221, 225))	('ab189841', 'Var', (188, 196))	('CD68', 'Gene', '968', (221, 225))	('GFAP', 'Gene', (328, 332))	('RANTES', 'Gene', (180, 186))	('CCR5', 'Gene', '1234', (137, 141))	('ab65850', 'Var', (143, 150))	('RANTES', 'Gene', '6352', (180, 186))	('CCL5', 'Gene', (175, 179))
40610	32545571	The lower compartment was seeded with MSC (20,000/insert) in MSC media containing 10% FBS or with recombinant CCL5/RANTES peptide (R&D, 278-RN-050, Minneapolis, MN, USA) (300 ng/mL).	('MN', 'CellLine', 'CVCL:U508', (161, 163))	('CCL5', 'Gene', (110, 114))	('R&', 'Var', (131, 133))	('RANTES', 'Gene', (115, 121))	('CCL5', 'Gene', '6352', (110, 114))	('RANTES', 'Gene', '6352', (115, 121))
40630	32289278	Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS/MAPK pathway yet show unexplained variability in their clinical outcome.	('driven by', 'Reg', (130, 139))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('gliomas', 'Disease', (72, 79))	('genetic alterations', 'Var', (140, 159))	('RAS/MAPK pathway', 'Pathway', (167, 183))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (100, 107))
40631	32289278	Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared to SNV-driven tumors.	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('Rearrangement-driven', 'Var', (0, 20))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('death', 'Disease', 'MESH:D003643', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('death', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
40638	32289278	Most commonly, these are somatic events involving BRAF or germline NF1 alterations.	('NF1', 'Gene', (67, 70))	('BRAF', 'Gene', (50, 54))	('NF1', 'Gene', '4763', (67, 70))	('alterations', 'Var', (71, 82))	('BRAF', 'Gene', '673', (50, 54))
40639	32289278	In addition to these common pLGG alterations, rarer alterations affecting RAS/MAPK signalling, including those involving FGFR1/2/3, NTRK2, RAF1, ALK, and ROS1, as well as non-RAS/MAPK alterations such as MYB, MYBL1, IDH1, and H3F3A have been identified in small numbers of cases.	('NTRK2', 'Gene', '4915', (132, 137))	('RAS/MAPK signalling', 'MPA', (74, 93))	('MYBL1', 'Gene', (209, 214))	('MYBL1', 'Gene', '4603', (209, 214))	('IDH1', 'Gene', '3417', (216, 220))	('RAF1', 'Gene', '5894', (139, 143))	('ALK', 'Gene', '238', (145, 148))	('ROS1', 'Gene', '6098', (154, 158))	('ALK', 'Gene', (145, 148))	('H3F3A', 'Gene', '3020', (226, 231))	('NTRK2', 'Gene', (132, 137))	('FGFR1/2/3', 'Gene', '2260;2263;2261', (121, 130))	('RAF1', 'Gene', (139, 143))	('alterations', 'Var', (33, 44))	('ROS1', 'Gene', (154, 158))	('H3F3A', 'Gene', (226, 231))	('MYB', 'Gene', '4602', (204, 207))	('MYB', 'Gene', (204, 207))	('MYB', 'Gene', '4602', (209, 212))	('IDH1', 'Gene', (216, 220))	('FGFR1/2/3', 'Gene', (121, 130))	('MYB', 'Gene', (209, 212))
40640	32289278	Are all NF1, BRAF fused and BRAF mutant tumors the same?	('NF1', 'Gene', (8, 11))	('BRAF', 'Gene', '673', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('NF1', 'Gene', '4763', (8, 11))	('BRAF', 'Gene', '673', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('BRAF', 'Gene', (13, 17))	('mutant', 'Var', (33, 39))	('BRAF', 'Gene', (28, 32))	('tumors', 'Disease', (40, 46))
40649	32289278	Patients diagnosed with the genetic pre-disposition disorder NF1 are done so by a series of clinical observations and tests indicative of a germline NF1 mutation.	('germline', 'Var', (140, 148))	('NF1', 'Gene', (61, 64))	('Patients', 'Species', '9606', (0, 8))	('NF1', 'Gene', '4763', (61, 64))	('mutation', 'Var', (153, 161))	('NF1', 'Gene', (149, 152))	('NF1', 'Gene', '4763', (149, 152))
40656	32289278	Furthermore, of the high risk, recurrent and biopsied NF1 pLGG, 20% were found to harbor mutations in other molecular drivers including BRAF p.V600E, FGFR1, and/or H3F3A (H3.3) p.K27M.	('H3.3', 'Gene', '3020', (171, 175))	('H3F3A', 'Gene', '3020', (164, 169))	('FGFR1', 'Gene', (150, 155))	('BRAF', 'Gene', '673', (136, 140))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('FGFR1', 'Gene', '2260', (150, 155))	('p.K27M', 'Mutation', 'p.K27M', (177, 183))	('H3F3A', 'Gene', (164, 169))	('BRAF', 'Gene', (136, 140))	('H3.3', 'Gene', (171, 175))	('p.K27M', 'Var', (177, 183))	('p.V600E', 'Mutation', 'rs113488022', (141, 148))	('p.V600E', 'Var', (141, 148))
40660	32289278	Together, KIAA1549-BRAF (n= 1 66), BRAF p.V600E (n=79), and germline NF1 mutations (n=79) accounted for 68% (n=324) of tumors (Figure 2A-C).	('NF1', 'Gene', '4763', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('BRAF', 'Gene', (35, 39))	('BRAF', 'Gene', '673', (19, 23))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('p.V600E', 'Var', (40, 47))	('KIAA1549', 'Gene', (10, 18))	('BRAF', 'Gene', (19, 23))	('KIAA1549', 'Gene', '57670', (10, 18))	('BRAF', 'Gene', '673', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('NF1', 'Gene', (69, 72))	('mutations', 'Var', (73, 82))	('p.V600E', 'Mutation', 'rs113488022', (40, 47))
40661	32289278	These included non-canonical BRAF alterations, such as fusions partnered with genes others than KIAA1549 (n=4), 2 insertion events at position 600 (p.V600ins) and 1 SNV at position 594 (p.D594N) (Figure 2A-C,E).	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('KIAA1549', 'Gene', (96, 104))	('KIAA1549', 'Gene', '57670', (96, 104))	('p.D594N', 'Mutation', 'rs397516896', (186, 193))	('p.V600ins', 'Var', (148, 157))	('p.V600ins', 'Mutation', 'p.600insV', (148, 157))	('fusions', 'Var', (55, 62))
40662	32289278	A further 1.3% (n=6) of cases contained alterations in other direct members of the RAS/MAPK pathway, including 3 RAF1 fusions, 2 KRAS mutations and one patient with a short deletion in MAP2K1 (Figure 2A-C,E).	('fusions', 'Var', (118, 125))	('MAP2K1', 'Gene', (185, 191))	('RAF1', 'Gene', (113, 117))	('RAF1', 'Gene', '5894', (113, 117))	('KRAS', 'Gene', (129, 133))	('alterations', 'Reg', (40, 51))	('patient', 'Species', '9606', (152, 159))	('KRAS', 'Gene', '3845', (129, 133))	('MAP2K1', 'Gene', '5604', (185, 191))	('RAS/MAPK pathway', 'Pathway', (83, 99))
40663	32289278	Alterations in FGFR most frequently involved FGFR1/2 (n=29, 6.1%) and included FGFR1-TACC1 fusions (n=7, 1.5%), FGFR1 tyrosine kinase domain duplications (TKD, n=10, 2.1%), FGFR2 fusions (n=5, 1.0%), and hotspot mutations in FGFR1 (n=7, 1.5%) (Figure 2A-C).	('FGFR1', 'Gene', (112, 117))	('Alterations', 'Var', (0, 11))	('TACC1', 'Gene', (85, 90))	('FGFR2', 'Gene', '2263', (173, 178))	('FGFR1', 'Gene', (79, 84))	('FGFR1/2', 'Gene', '2260;2263', (45, 52))	('FGFR1', 'Gene', '2260', (45, 50))	('FGFR', 'Gene', (15, 19))	('FGFR1', 'Gene', '2260', (225, 230))	('fusions', 'Var', (91, 98))	('fusions', 'Var', (179, 186))	('mutations', 'Var', (212, 221))	('TACC1', 'Gene', '6867', (85, 90))	('FGFR1', 'Gene', '2260', (112, 117))	('FGFR1', 'Gene', (45, 50))	('FGFR1', 'Gene', '2260', (79, 84))	('FGFR1', 'Gene', (225, 230))	('involved', 'Reg', (36, 44))	('FGFR2', 'Gene', (173, 178))	('FGFR1/2', 'Gene', (45, 52))
40664	32289278	Alterations in other RTK (n=16, 3.4%) included mutations in MET (n=5, 1.0%) or PDGFRA (n=l, 0.2%), as well as fusions involving ALK (n=2, 0.4%), ROS1 (n=2, 0.4%), and NTRK2 (n=2, 0.4%) (Figure 2A-C,E).	('ROS1', 'Gene', '6098', (145, 149))	('ALK', 'Gene', '238', (128, 131))	('NTRK2', 'Gene', (167, 172))	('MET', 'Gene', '79811', (60, 63))	('PDGFRA', 'Gene', '5156', (79, 85))	('PDGFRA', 'Gene', (79, 85))	('mutations', 'Var', (47, 56))	('NTRK2', 'Gene', '4915', (167, 172))	('ALK', 'Gene', (128, 131))	('ROS1', 'Gene', (145, 149))	('MET', 'Gene', (60, 63))	('fusions', 'Var', (110, 117))
40665	32289278	These included mutations in H3F3A (n=4, 0.8%), IDH1 (n=4, 0.8%) and rearrangements involving MYB (n=6, 1.3%) or MYBL1 (n=5, 1.0%) (Figure 2A-C).	('MYB', 'Gene', '4602', (93, 96))	('rearrangements', 'Var', (68, 82))	('H3F3A', 'Gene', '3020', (28, 33))	('MYB', 'Gene', (93, 96))	('MYBL1', 'Gene', (112, 117))	('IDH1', 'Gene', (47, 51))	('mutations', 'Var', (15, 24))	('MYBL1', 'Gene', '4603', (112, 117))	('H3F3A', 'Gene', (28, 33))	('MYB', 'Gene', '4602', (112, 115))	('IDH1', 'Gene', '3417', (47, 51))	('MYB', 'Gene', (112, 115))
40666	32289278	Incidences of molecular alterations excluding NF1 patients (n=398) are seen in Figures 2B,D and enrichment across tumor location and pathology in Figure S3B,C.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patients', 'Species', '9606', (50, 58))	('NF1', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('NF1', 'Gene', '4763', (46, 49))	('tumor', 'Disease', (114, 119))	('molecular alterations', 'Var', (14, 35))
40667	32289278	The predilection of NF1 patients for developing pLGG together with the identification of KIAA1549-BRAF and BRAF p.V600E as molecular drivers in pLGG led to the hypothesis that up-regulation of the RAS/MAPK pathway may be the primary driver for tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('BRAF', 'Gene', (107, 111))	('up-regulation', 'PosReg', (176, 189))	('p.V600E', 'Mutation', 'rs113488022', (112, 119))	('tumor', 'Disease', (244, 249))	('KIAA1549', 'Gene', '57670', (89, 97))	('BRAF', 'Gene', (98, 102))	('KIAA1549', 'Gene', (89, 97))	('RAS/MAPK pathway', 'Pathway', (197, 213))	('p.V600E', 'Var', (112, 119))	('patients', 'Species', '9606', (24, 32))	('BRAF', 'Gene', '673', (98, 102))	('pLGG', 'Disease', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('NF1', 'Gene', (20, 23))	('BRAF', 'Gene', '673', (107, 111))	('NF1', 'Gene', '4763', (20, 23))
40668	32289278	To test this hypothesis, we first analyzed a series of pLGG with non-BRAF alterations including FGFR alterations, rare RTK, RAF1 fusions, KRAS mutations and MYB or MYBL1 rearrangements and compared their phosphorylated ERK (ppERK) levels to KIAA1549-BRAF and BRAF p.V600E tumors.	('alterations', 'Var', (101, 112))	('KRAS', 'Gene', '3845', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('RAF1', 'Gene', (124, 128))	('ERK', 'Gene', (226, 229))	('ERK', 'Gene', (219, 222))	('KRAS', 'Gene', (138, 142))	('BRAF', 'Gene', '673', (69, 73))	('alterations', 'Var', (74, 85))	('BRAF', 'Gene', (69, 73))	('mutations', 'Var', (143, 152))	('BRAF', 'Gene', (259, 263))	('BRAF', 'Gene', '673', (259, 263))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('fusions', 'Var', (129, 136))	('KIAA1549', 'Gene', '57670', (241, 249))	('rearrangements', 'Var', (170, 184))	('MYB', 'Gene', '4602', (157, 160))	('MYB', 'Gene', '4602', (164, 167))	('MYB', 'Gene', (164, 167))	('MYB', 'Gene', (157, 160))	('p.V600E', 'Mutation', 'rs113488022', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('BRAF', 'Gene', '673', (250, 254))	('FGFR', 'Gene', (96, 100))	('BRAF', 'Gene', (250, 254))	('KIAA1549', 'Gene', (241, 249))	('ERK', 'Gene', '5594', (226, 229))	('ERK', 'Gene', '5594', (219, 222))	('MYBL1', 'Gene', (164, 169))	('RAF1', 'Gene', '5894', (124, 128))	('MYBL1', 'Gene', '4603', (164, 169))
40674	32289278	Patients with rearrangement-driven pLGG had good long-term outcome with very few deaths (n=7, 2.6%) and fewer progressions (n=67, 27%) (Figure 4B-D, Table 1).	('rearrangement-driven', 'Var', (14, 34))	('Patients', 'Species', '9606', (0, 8))	('deaths', 'Disease', (81, 87))	('pLGG', 'Disease', (35, 39))	('deaths', 'Disease', 'MESH:D003643', (81, 87))
40675	32289278	In contrast, patients with SNV-driven pLGG were significantly more likely to succumb to their disease (n=24, 13%, p<0.0001, Fisher's exact test versus rearrangement-driven) and/or progress (n=80, 44%, p<0.0001, Fisher's exact test versus fusion-driven) (Table 1, Figure 4B-D).	('SNV-driven', 'Var', (27, 37))	('patients', 'Species', '9606', (13, 21))	('progress', 'PosReg', (180, 188))
40677	32289278	When investigating BRAF in grade I tumors alone, the pattern remained (5-year PFS of 72% and 56% for KIAA1549-BRAF and BRAF p.V600E, respectively, p=0.0176).	('BRAF', 'Gene', '673', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('BRAF', 'Gene', (119, 123))	('tumors', 'Disease', (35, 41))	('BRAF', 'Gene', '673', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('p.V600E', 'Mutation', 'rs113488022', (124, 131))	('KIAA1549', 'Gene', '57670', (101, 109))	('BRAF', 'Gene', (110, 114))	('KIAA1549', 'Gene', (101, 109))	('p.V600E', 'Var', (124, 131))
40679	32289278	Patients with FGFR1 SNVs, on the other hand, were more similar to BRAF p.V600E (5-year PFS of 53% and 52% for FGFR1 SNV and BRAF p.V600E, respectively.	('p.V600E', 'Mutation', 'rs113488022', (71, 78))	('p.V600E', 'Mutation', 'rs113488022', (129, 136))	('p.V600E', 'Var', (71, 78))	('FGFR1', 'Gene', (14, 19))	('BRAF', 'Gene', '673', (124, 128))	('p.V600E', 'Var', (129, 136))	('Patients', 'Species', '9606', (0, 8))	('BRAF', 'Gene', '673', (66, 70))	('FGFR1', 'Gene', '2260', (14, 19))	('BRAF', 'Gene', (124, 128))	('BRAF', 'Gene', (66, 70))	('FGFR1', 'Gene', (110, 115))	('FGFR1', 'Gene', '2260', (110, 115))
40684	32289278	The most common KIAA1549-BRAF fusion involved exon 16 in KIAA1549 and 9 in BRAF (16:09).	('KIAA1549', 'Gene', '57670', (16, 24))	('KIAA1549', 'Gene', '57670', (57, 65))	('fusion', 'Var', (30, 36))	('KIAA1549', 'Gene', (57, 65))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('KIAA1549', 'Gene', (16, 24))
40685	32289278	Like all KIAA1549-BRAF fusions, 16:09 was significantly enriched in pilocytic astrocytoma (n=73/83, 88%, p<0.0001, Fisher's exact test) and in cerebellar tumors (n=60/83, 72%, p<0.0001, Fisher's exact test) (Figure S4B,C).	('astrocytoma', 'Phenotype', 'HP:0009592', (78, 89))	('pilocytic astrocytoma', 'Disease', (68, 89))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cerebellar tumors', 'Disease', (143, 160))	('16:09', 'Var', (32, 37))	('KIAA1549', 'Gene', (9, 17))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (68, 89))	('BRAF', 'Gene', '673', (18, 22))	('KIAA1549', 'Gene', '57670', (9, 17))	('cerebellar tumors', 'Disease', 'MESH:D002528', (143, 160))	('BRAF', 'Gene', (18, 22))
40687	32289278	15:09 was also the primary fusion seen in tumors with extensive dissemination (n=5, 83%, p<0.0001, Fisher's exact test).	('15:09', 'Var', (0, 5))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
40690	32289278	FGFR1-TACC1 pLGG were often cystic lesions, most commonly pilocytic astrocytoma (n=7/14, 50%) and occurred throughout the CNS, most commonly in the cerebral hemispheres (n=6/14, 43%) (Figure 5B).	('cystic lesions', 'Disease', (28, 42))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('pilocytic astrocytoma', 'Disease', (58, 79))	('FGFR1', 'Gene', (0, 5))	('cystic lesions', 'Disease', 'MESH:D052177', (28, 42))	('FGFR1', 'Gene', '2260', (0, 5))	('TACC1', 'Gene', (6, 11))	('pLGG', 'Var', (12, 16))	('TACC1', 'Gene', '6867', (6, 11))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (58, 79))
40691	32289278	FGFR1 TKD and FGFR2 fused pLGG were primarily glioneuronal or oligodendroglial in origin, respectively and were restricted to the cerebral hemispheres (Figure 5C-D).	('FGFR2', 'Gene', (14, 19))	('FGFR2', 'Gene', '2263', (14, 19))	('glioneuronal', 'CPA', (46, 58))	('oligodendroglial', 'CPA', (62, 78))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('TKD', 'Var', (6, 9))
40694	32289278	These included CCDC88A-ALK, PPP1CB-ALK, GOPC-ROS1 and NTRK2-MID1 in addition to novel NTRK2-SF3B1 and PDGFB-LRP1 fusions (Figure 2E).	('CCDC88A', 'Gene', (15, 22))	('ALK', 'Gene', (23, 26))	('SF3B1', 'Gene', '23451', (92, 97))	('PDGFB', 'Gene', '5155', (102, 107))	('PPP1CB', 'Gene', '5500', (28, 34))	('NTRK2', 'Gene', (86, 91))	('PPP1CB', 'Gene', (28, 34))	('ALK', 'Gene', '238', (35, 38))	('CCDC88A', 'Gene', '55704', (15, 22))	('ROS1', 'Gene', (45, 49))	('NTRK2', 'Gene', (54, 59))	('ALK', 'Gene', (35, 38))	('PDGFB', 'Gene', (102, 107))	('GOPC', 'Gene', '57120', (40, 44))	('fusions', 'Var', (113, 120))	('GOPC', 'Gene', (40, 44))	('SF3B1', 'Gene', (92, 97))	('NTRK2', 'Gene', '4915', (86, 91))	('LRP1', 'Gene', (108, 112))	('ROS1', 'Gene', '6098', (45, 49))	('NTRK2', 'Gene', '4915', (54, 59))	('ALK', 'Gene', '238', (23, 26))	('LRP1', 'Gene', '4035', (108, 112))
40697	32289278	No patients harboring these alterations succumbed to their disease after a median follow-up of 4.9 years and only a single ALK and ROSl fused patient progressed.	('ALK', 'Gene', (123, 126))	('alterations', 'Var', (28, 39))	('patient', 'Species', '9606', (3, 10))	('patients', 'Species', '9606', (3, 11))	('patient', 'Species', '9606', (142, 149))	('ALK', 'Gene', '238', (123, 126))
40698	32289278	MYB and MYBL1 alterations were histologically enriched for angiocentric glioma (n=14, 100%, p<0.0001, Fisher's exact test) and diffuse astrocytoma (n=5, 83%, p<0.0001, Fisher's exact test), respectively, with both primarily arising in the cerebral hemispheres (n=13/14, 92% and n=5/6, 83%, respectively, p<0.0001, Fisher's exact test) (Figure 5E,F).	('alterations', 'Var', (14, 25))	('MYB', 'Gene', (0, 3))	('MYBL1', 'Gene', (8, 13))	('MYB', 'Gene', '4602', (8, 11))	('MYB', 'Gene', (8, 11))	('MYBL1', 'Gene', '4603', (8, 13))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('astrocytoma', 'Disease', 'MESH:D001254', (135, 146))	('angiocentric glioma', 'Disease', (59, 78))	('astrocytoma', 'Disease', (135, 146))	('angiocentric glioma', 'Disease', 'MESH:D005910', (59, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (135, 146))	('MYB', 'Gene', '4602', (0, 3))
40699	32289278	All patients harboring either MYB or MYBL1 rearrangements are alive with median follow-up of 8.1 and 5.3 years, respectively.	('MYBL1', 'Gene', (37, 42))	('MYBL1', 'Gene', '4603', (37, 42))	('MYB', 'Gene', '4602', (37, 40))	('MYB', 'Gene', '4602', (30, 33))	('MYB', 'Gene', (30, 33))	('MYB', 'Gene', (37, 40))	('patients', 'Species', '9606', (4, 12))	('rearrangements', 'Var', (43, 57))
40702	32289278	BRAF p.V600E was the second most common alteration in pLGG (17%) and was frequently associated with additional alterations, most commonly deletion of CDKN2A (n=13, 9.6%) (Figure 2A).	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('CDKN2A', 'Gene', (150, 156))	('p.V600E', 'Var', (5, 12))	('CDKN2A', 'Gene', '1029', (150, 156))	('BRAF', 'Gene', '673', (0, 4))	('associated', 'Reg', (84, 94))	('BRAF', 'Gene', (0, 4))	('deletion', 'Var', (138, 146))
40703	32289278	BRAF p.V600E also co-occurred with several other SNVs including those in NF1, FGFR1, KRAS and H3F3A, but never with a fusion event (Figure 2A).	('FGFR1', 'Gene', (78, 83))	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('NF1', 'Gene', '4763', (73, 76))	('FGFR1', 'Gene', '2260', (78, 83))	('p.V600E', 'Var', (5, 12))	('H3F3A', 'Gene', '3020', (94, 99))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('KRAS', 'Gene', (85, 89))	('co-occurred', 'Reg', (18, 29))	('H3F3A', 'Gene', (94, 99))	('KRAS', 'Gene', '3845', (85, 89))	('NF1', 'Gene', (73, 76))
40704	32289278	Unlike KLAA1549-BRAF, tumors with BRAF p.V600E were histologically diverse and included ganglioglioma (n=36, 31%), diffuse astrocytoma (n=16, 14%), and pleomorphic xanthoastrocytoma (n=12, 10%) (Figure 6A).	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('ganglioglioma', 'Disease', 'MESH:D018303', (88, 101))	('p.V600E', 'Mutation', 'rs113488022', (39, 46))	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('pleomorphic xanthoastrocytoma', 'Disease', (152, 181))	('p.V600E', 'Var', (39, 46))	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('astrocytoma', 'Disease', 'MESH:D001254', (123, 134))	('ganglioglioma', 'Disease', (88, 101))	('tumors', 'Disease', (22, 28))	('astrocytoma', 'Disease', (123, 134))	('astrocytoma', 'Disease', 'MESH:D001254', (170, 181))	('astrocytoma', 'Disease', (170, 181))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (152, 181))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
40705	32289278	Both ganglioglioma and pleomorphic xanthoastrocytoma were more likely to harbor BRAF p.V600E than other tumor types (p=0.0028, p=0.0048, respectively, Fisher's exact test, Figure S3C).	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('BRAF', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p.V600E', 'Mutation', 'rs113488022', (85, 92))	('tumor', 'Disease', (104, 109))	('ganglioglioma and pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D018303', (5, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('p.V600E', 'Var', (85, 92))	('BRAF', 'Gene', '673', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
40706	32289278	BRAF p.V600E cases occurred most frequently in the cerebral hemispheres (n=64, 56%) but were also common in the diencephalon (n=33, 29%) and in contrast to KLAA1549-BRAF, were rare in the cerebellum (n=6, 5.2%) (Figure 6A).	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('BRAF', 'Gene', '673', (165, 169))	('p.V600E', 'Var', (5, 12))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (165, 169))	('BRAF', 'Gene', (0, 4))	('common', 'Reg', (98, 104))
40707	32289278	BRAF p.V600E pLGG had worse OS and PFS than those with KIAA1549-BRAF(10-year OS 97% versus 89%, p=0.0416 and 10-year PFS of 64% versus 30%, p=0.0058, respectively, log-rank test, Figure S6A-B).	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('p.V600E', 'Var', (5, 12))	('KIAA1549', 'Gene', '57670', (55, 63))	('BRAF', 'Gene', '673', (0, 4))	('KIAA1549', 'Gene', (55, 63))	('PFS', 'CPA', (35, 38))	('BRAF', 'Gene', (0, 4))
40708	32289278	BRAF p.V600E tumors with pleomorphic xanthoastrocytoma histology had a worse outcome than those without (5-year PFS of 14% versus 58%, respectively, p=0.0328, log-rank test Figure S6C), although OS was not significantly different (p=0.1892, Figure S6D).	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('p.V600E', 'Var', (5, 12))	('BRAF', 'Gene', '673', (0, 4))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (25, 54))	('BRAF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('pleomorphic xanthoastrocytoma', 'Disease', (25, 54))
40709	32289278	The same was not the case for BRAF p.V600E tumors with co-occurring CDKN2A deletions (5-year PFS of 34% versus 55%, respectively, p=0.1157, log-rank test, Figure S6E), although OS was significantly different (p=0.0100, log-rank test, Figure S6F).	('deletions', 'Var', (75, 84))	('CDKN2A', 'Gene', (68, 74))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CDKN2A', 'Gene', '1029', (68, 74))	('p.V600E', 'Mutation', 'rs113488022', (35, 42))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('p.V600E', 'Var', (35, 42))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
40710	32289278	However, both non-pleomorphic xanthoastrocytoma (5-year PFS of 55%) and CDKN2A balanced (5-year PFS of 55%) BRAF p.V600E tumors had inferior PFS to KIAA1549-BRAF (5-year PFS of 69%) fused tumors (p=0.0139 and p=0.0356, respectively, log-rank test, Figure S7A,B), despite their OS not being significantly different (p=0.1169 and 0.1888, respectively, log-rank test) (Figure S7C,D).	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('KIAA1549', 'Gene', '57670', (148, 156))	('non-pleomorphic xanthoastrocytoma', 'Disease', (14, 47))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('BRAF', 'Gene', '673', (157, 161))	('BRAF', 'Gene', (157, 161))	('KIAA1549', 'Gene', (148, 156))	('BRAF', 'Gene', '673', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('CDKN2A', 'Gene', (72, 78))	('BRAF', 'Gene', (108, 112))	('tumors', 'Disease', (188, 194))	('p.V600E', 'Mutation', 'rs113488022', (113, 120))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('p.V600E', 'Var', (113, 120))	('CDKN2A', 'Gene', '1029', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('PFS', 'MPA', (141, 144))	('non-pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (14, 47))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))
40711	32289278	FGFR1 point mutations were observed in 1.5% of pLGG and primarily consisted of p.N546K and p.K656E.	('pLGG', 'Disease', (47, 51))	('p.N546K', 'Var', (79, 86))	('consisted', 'Reg', (66, 75))	('p.N546K', 'Mutation', 'rs779707422', (79, 86))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('p.K656E', 'Var', (91, 98))	('p.K656E', 'Mutation', 'rs869320694', (91, 98))
40712	32289278	Histologically, these tumors were most frequently dysembryoplastic neuroepithelial tumors (n=13, 41%) or pilocytic astrocytoma (n=9, 28%), diagnosed in older children (p=0.032, Fisher's exact test), and often (n=16, 50%) co-occurred with other genetic alterations including NF1 (n=7, 22%) or additional RAS/MAPK pathway mutations (n=11, 34%) (Figure 2A, 6B).	('RAS/MAPK pathway', 'Pathway', (303, 319))	('mutations', 'Var', (320, 329))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('astrocytoma', 'Phenotype', 'HP:0009592', (115, 126))	('co-occurred', 'Reg', (221, 232))	('dysembryoplastic neuroepithelial tumors', 'Disease', (50, 89))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('NF1', 'Gene', '4763', (274, 277))	('tumors', 'Disease', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (105, 126))	('NF1', 'Gene', (274, 277))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (50, 89))	('pilocytic astrocytoma', 'Disease', (105, 126))	('children', 'Species', '9606', (158, 166))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (67, 89))	('tumors', 'Disease', (83, 89))
40715	32289278	IDH1 mutations are common in adult lower grade gliomas, arising in approximately 70% of grade II and III gliomas.	('III gliomas', 'Disease', 'MESH:D005910', (101, 112))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('III gliomas', 'Disease', (101, 112))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('common', 'Reg', (19, 25))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('IDH1', 'Gene', '3417', (0, 4))
40716	32289278	In pLGG, IDH1 p.R132H mutations were extremely rare, accounting for only 0.8% of cases (Figure 2B).	('p.R132H', 'Mutation', 'rs121913500', (14, 21))	('p.R132H', 'Var', (14, 21))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))
40717	32289278	Most IDH1 p.R132H patients presented with a prolonged history of seizures, sometimes years before the biopsy was performed.	('IDH1', 'Gene', (5, 9))	('p.R132H', 'Var', (10, 17))	('seizures', 'Disease', 'MESH:D012640', (65, 73))	('IDH1', 'Gene', '3417', (5, 9))	('seizures', 'Disease', (65, 73))	('p.R132H', 'Mutation', 'rs121913500', (10, 17))	('presented', 'Reg', (27, 36))	('patients', 'Species', '9606', (18, 26))	('seizures', 'Phenotype', 'HP:0001250', (65, 73))
40719	32289278	Patients harboring IDH1 p.R132H were diagnosed in late childhood (median: 15.7 years), with the youngest patient being diagnosed at 8.9 years (Figure 6C).	('patient', 'Species', '9606', (105, 112))	('IDH1', 'Gene', (19, 23))	('p.R132H', 'Var', (24, 31))	('IDH1', 'Gene', '3417', (19, 23))	('Patients', 'Species', '9606', (0, 8))	('p.R132H', 'Mutation', 'rs121913500', (24, 31))
40720	32289278	50% of IDH1 p.R132H pLGG progressed within a median of 5.1 years (5-year PFS of 56%) despite only one succumbing to their disease (Figure 6C).	('p.R132H', 'Mutation', 'rs121913500', (12, 19))	('IDH1', 'Gene', '3417', (7, 11))	('progressed', 'PosReg', (25, 35))	('p.R132H', 'Var', (12, 19))	('IDH1', 'Gene', (7, 11))
40721	32289278	H3F3A mutations are common in childhood high grade gliomas and DIPG and confer a dismal outcome.	('gliomas', 'Disease', (51, 58))	('H3F3A', 'Gene', '3020', (0, 5))	('DIPG', 'Disease', (63, 67))	('H3F3A', 'Gene', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('common', 'Reg', (20, 26))	('mutations', 'Var', (6, 15))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
40722	32289278	In our pLGG series, all H3F3A mutations were p.K27M, with no p.G34R/V alterations identified (Table S1).	('p.K27M', 'Var', (45, 51))	('p.K27M', 'Mutation', 'p.K27M', (45, 51))	('H3F3A', 'Gene', '3020', (24, 29))	('p.G34R', 'SUBSTITUTION', 'None', (61, 67))	('p.G34R', 'Var', (61, 67))	('mutations', 'Var', (30, 39))	('H3F3A', 'Gene', (24, 29))
40723	32289278	These cases were restricted to the midline (diencephalon [n=8] and brainstem [n=4]), enriched for diffuse astrocytomas (n=8, 67%, p=0.0011, Fischer Exact), and like other SNVs, often co-occurred with other alterations (25%), most often with BRAF p.V600E (Figure 2A, 6D).	('astrocytomas', 'Disease', 'MESH:D001254', (106, 118))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('p.V600E', 'Var', (246, 253))	('astrocytomas', 'Disease', (106, 118))	('BRAF', 'Gene', '673', (241, 245))	('co-occurred', 'Reg', (183, 194))	('BRAF', 'Gene', (241, 245))	('p.V600E', 'Mutation', 'rs113488022', (246, 253))
40724	32289278	Although morphologically and clinically different than midline HGG, H3.3 p.K27M patients progressed early (median time to progression=0.8 years), with all patients eventually succumbing to their disease (Figure 6D).	('H3.3', 'Gene', '3020', (68, 72))	('patients', 'Species', '9606', (80, 88))	('p.K27M', 'Var', (73, 79))	('H3.3', 'Gene', (68, 72))	('p.K27M', 'Mutation', 'p.K27M', (73, 79))	('patients', 'Species', '9606', (155, 163))	('succumbing', 'Reg', (175, 185))
40725	32289278	These data support the role of H3.3 p.K27M as a marker of aggressive behavior regardless of the initial morphology and presentation.	('H3.3', 'Gene', (31, 35))	('aggressive behavior', 'CPA', (58, 77))	('H3.3', 'Gene', '3020', (31, 35))	('p.K27M', 'Var', (36, 42))	('p.K27M', 'Mutation', 'p.K27M', (36, 42))	('aggressive behavior', 'Phenotype', 'HP:0000718', (58, 77))
40727	32289278	pLGG harboring gene fusions or germline NF1 mutations comprise the low risk group.	('NF1', 'Gene', (40, 43))	('germline', 'Var', (31, 39))	('NF1', 'Gene', '4763', (40, 43))	('mutations', 'Var', (44, 53))	('gene fusions', 'Var', (15, 27))
40730	32289278	The intermediate risk group of pLGG includes tumors with BRAF p.V600E without CDKN2A deletion, FGFR1 SNV, IDH1 p.R132H or MET mutations.	('MET', 'Gene', '79811', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('FGFR1', 'Gene', (95, 100))	('BRAF', 'Gene', '673', (57, 61))	('tumors', 'Disease', (45, 51))	('CDKN2A', 'Gene', (78, 84))	('MET', 'Gene', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BRAF', 'Gene', (57, 61))	('FGFR1', 'Gene', '2260', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('CDKN2A', 'Gene', '1029', (78, 84))	('IDH1', 'Gene', (106, 110))	('p.R132H', 'Var', (111, 118))	('p.V600E', 'Mutation', 'rs113488022', (62, 69))	('IDH1', 'Gene', '3417', (106, 110))	('p.V600E', 'Var', (62, 69))	('p.R132H', 'Mutation', 'rs121913500', (111, 118))
40734	32289278	High risk pLGG include those with H3.3 p.K27M, or BRAF p.V600E with CDKN2A deletion.	('BRAF', 'Gene', (50, 54))	('H3.3', 'Gene', '3020', (34, 38))	('deletion', 'Var', (75, 83))	('CDKN2A', 'Gene', (68, 74))	('p.K27M', 'Var', (39, 45))	('p.K27M', 'Mutation', 'p.K27M', (39, 45))	('CDKN2A', 'Gene', '1029', (68, 74))	('p.V600E', 'Mutation', 'rs113488022', (55, 62))	('H3.3', 'Gene', (34, 38))	('BRAF', 'Gene', '673', (50, 54))	('p.V600E', 'Var', (55, 62))
40736	32289278	Patients with H3.3 p.K27M do worse than those with BRAF p.V600E and CDKN2A deletion (10-year PFS and OS was 0% and 35% and 0% and 60%, respectively), but both do far worse than low and intermediate risk patients.	('p.V600E', 'Var', (56, 63))	('H3.3', 'Gene', '3020', (14, 18))	('CDKN2A', 'Gene', (68, 74))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (203, 211))	('BRAF', 'Gene', '673', (51, 55))	('p.K27M', 'Var', (19, 25))	('CDKN2A', 'Gene', '1029', (68, 74))	('p.K27M', 'Mutation', 'p.K27M', (19, 25))	('p.V600E', 'Mutation', 'rs113488022', (56, 63))	('BRAF', 'Gene', (51, 55))	('H3.3', 'Gene', (14, 18))
40737	32289278	Although H3.3 p.K27M tumors are more likely to result in patient death, both H3.3 p.K27M and BRAF p.V600E and CDKN2A deletions result in rapid progression, indicating a need for immediate, aggressive treatment and the introduction of novel, targeted agents.	('CDKN2A', 'Gene', '1029', (110, 116))	('p.K27M', 'Mutation', 'p.K27M', (14, 20))	('H3.3', 'Gene', (77, 81))	('patient', 'Species', '9606', (57, 64))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('death', 'Disease', 'MESH:D003643', (65, 70))	('BRAF', 'Gene', '673', (93, 97))	('H3.3', 'Gene', '3020', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('BRAF', 'Gene', (93, 97))	('p.K27M', 'Mutation', 'p.K27M', (82, 88))	('p.K27M', 'Var', (14, 20))	('p.V600E', 'Mutation', 'rs113488022', (98, 105))	('H3.3', 'Gene', (9, 13))	('tumors', 'Disease', (21, 27))	('p.V600E', 'Var', (98, 105))	('CDKN2A', 'Gene', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('result in', 'Reg', (47, 56))	('death', 'Disease', (65, 70))	('H3.3', 'Gene', '3020', (9, 13))	('result in', 'Reg', (127, 136))	('deletions', 'Var', (117, 126))	('p.K27M', 'Var', (82, 88))
40740	32289278	RAS/MAPK activation and pLGG were first linked due to the appearance of OPGs in patients with NF1 and was further supported upon the discovery of KIAA1549-BRAF and BRAF p.V600E in these tumors.	('NF1', 'Gene', '4763', (94, 97))	('p.V600E', 'Mutation', 'rs113488022', (169, 176))	('BRAF', 'Gene', (155, 159))	('p.V600E', 'Var', (169, 176))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('BRAF', 'Gene', '673', (164, 168))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('KIAA1549', 'Gene', (146, 154))	('BRAF', 'Gene', (164, 168))	('KIAA1549', 'Gene', '57670', (146, 154))	('BRAF', 'Gene', '673', (155, 159))	('NF1', 'Gene', (94, 97))	('OPGs', 'Disease', (72, 76))
40741	32289278	Here 378 tumors from 2000-2017 had an identifiable alteration impacting the RAS/MAPK pathway with an additional 10 showing up-regulation via ssGSEA analysis of RNA sequencing data.	('RAS/MAPK pathway', 'Pathway', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('impacting', 'Reg', (62, 71))	('alteration', 'Var', (51, 61))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('up-regulation', 'PosReg', (123, 136))
40747	32289278	This suggests that these oncogenic alterations may occur early in development, promoting tumor initiation in a developmental context permissive for one-hit tumorigenesis.	('promoting', 'PosReg', (79, 88))	('alterations', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
40748	32289278	Previous work identified that BRAF fusions promoted gliogenesis in region specific neural stem cell populations, while having little effect in differentiated astrocytes.	('promoted', 'PosReg', (43, 51))	('gliogenesis', 'CPA', (52, 63))	('BRAF', 'Gene', '673', (30, 34))	('BRAF', 'Gene', (30, 34))	('fusions', 'Var', (35, 42))
40752	32289278	Genetic rearrangements, including all fusions and duplications, as well as germline NF1 inactivation are considered low-risk.	('duplications', 'Var', (50, 62))	('NF1', 'Gene', (84, 87))	('NF1', 'Gene', '4763', (84, 87))	('fusions', 'Var', (38, 45))	('inactivation', 'Var', (88, 100))
40760	32289278	Finally, high risk tumors harboring H3.3 p.K27M or BRAF p.V600E and CDKN2A deletion may require new approaches to improve survival including the development of novel agents as well as combination therapies to promote synthetic lethality in these difficult tumor entities.	('p.K27M', 'Var', (41, 47))	('p.V600E', 'Var', (56, 63))	('tumors', 'Disease', (19, 25))	('H3.3', 'Gene', (36, 40))	('CDKN2A', 'Gene', (68, 74))	('tumor', 'Disease', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CDKN2A', 'Gene', '1029', (68, 74))	('H3.3', 'Gene', '3020', (36, 40))	('tumor', 'Disease', (256, 261))	('p.K27M', 'Mutation', 'p.K27M', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('BRAF', 'Gene', '673', (51, 55))	('improve', 'PosReg', (114, 121))	('BRAF', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('deletion', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('p.V600E', 'Mutation', 'rs113488022', (56, 63))
40777	32289278	95 C for 10min 39 cycles of 94 C for 30 s followed by 55 C for 60 s (with a 2 C s-1 ramp rate) 98 C for 10min Held at 4 C Reactions consisted of IX ddPCR Supermix for probes (no dUTP) (Bio-Rad, Hercules, CA), 900 nM of HPLC-purified forward and reverse primers, 250 nM of target-specific mutant and wild-type probes, and 10-20 ng of genomic DNA in 20 mul of total volume.	('mutant', 'Var', (288, 294))	('dUTP', 'Chemical', 'MESH:C027078', (178, 182))	('Rad', 'Gene', (189, 192))	('Rad', 'Gene', '6236', (189, 192))
40782	32289278	BRAF p.V600E: BRAF p.V600E detection was completed as previously described.	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('p.V600E', 'Mutation', 'rs113488022', (19, 26))	('p.V600E', 'Var', (19, 26))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (14, 18))
40783	32289278	PrimePCR ddPCR mutation assay BRAF wild-type/p.V600E for p.V600E, Human (unique assay ID: dHsaCP2000027/28) was used (Bio-Rad, Hercules, CA).	('p.V600E', 'Mutation', 'rs113488022', (57, 64))	('Human', 'Species', '9606', (66, 71))	('p.V600E', 'Var', (57, 64))	('BRAF', 'Gene', (30, 34))	('p.V600E', 'Mutation', 'rs113488022', (45, 52))	('BRAF', 'Gene', '673', (30, 34))	('Rad', 'Gene', '6236', (122, 125))	('Rad', 'Gene', (122, 125))
40784	32289278	H3F3A p.K27M: H3F3A p.K27M detection was completed as previously described.	('H3F3A', 'Gene', '3020', (0, 5))	('H3F3A', 'Gene', '3020', (14, 19))	('p.K27M', 'Mutation', 'p.K27M', (6, 12))	('H3F3A', 'Gene', (0, 5))	('H3F3A', 'Gene', (14, 19))	('p.K27M', 'Var', (20, 26))	('p.K27M', 'Mutation', 'p.K27M', (20, 26))
40785	32289278	PrimePCR ddPCR mutation assay H3F3A wild-type/K28M for p.K28M, Human (unique assay ID: dHsaCP2500510/l 1) was used (Bio-Rad, Hercules, CA).	('K28M', 'Mutation', 'rs1057519903', (46, 50))	('Human', 'Species', '9606', (63, 68))	('H3F3A', 'Gene', (30, 35))	('K28M', 'Mutation', 'rs1057519903', (57, 61))	('p.K28M', 'SUBSTITUTION', 'None', (55, 61))	('Rad', 'Gene', '6236', (120, 123))	('H3F3A', 'Gene', '3020', (30, 35))	('p.K28M', 'Var', (55, 61))	('Rad', 'Gene', (120, 123))
40786	32289278	H3F3A p.G34R: H3F3A p.G34R detection was completed as previously described.	('p.G34R', 'Mutation', 'rs1057519902', (6, 12))	('H3F3A', 'Gene', '3020', (0, 5))	('H3F3A', 'Gene', '3020', (14, 19))	('H3F3A', 'Gene', (0, 5))	('H3F3A', 'Gene', (14, 19))	('p.G34R', 'Var', (20, 26))	('p.G34R', 'Mutation', 'rs1057519902', (20, 26))
40787	32289278	PrimePCR ddPCR mutation assay H3F3A wild-type/G35R for p.G35R, Human (unique assay ID: dHsaMDS720957813) was used (Bio-Rad, Hercules, CA).	('G35R', 'Mutation', 'p.G35R', (57, 61))	('p.G35R', 'SUBSTITUTION', 'None', (55, 61))	('Human', 'Species', '9606', (63, 68))	('H3F3A', 'Gene', (30, 35))	('p.G35R', 'Var', (55, 61))	('Rad', 'Gene', '6236', (119, 122))	('Rad', 'Gene', (119, 122))	('G35R', 'Mutation', 'p.G35R', (46, 50))	('H3F3A', 'Gene', '3020', (30, 35))
40789	32289278	CDKN2A Deletion: CDKN2A deletion detection was completed as previously described (Lassaletta et al, 2016).	('CDKN2A', 'Gene', (17, 23))	('deletion', 'Var', (24, 32))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (17, 23))	('CDKN2A', 'Gene', '1029', (0, 6))
40791	32289278	IDH1 p.R132H: IDH1 p.R132H detection was completed as described above.	('IDH1', 'Gene', '3417', (14, 18))	('IDH1', 'Gene', (14, 18))	('p.R132H', 'Mutation', 'rs121913500', (19, 26))	('p.R132H', 'Mutation', 'rs121913500', (5, 12))	('p.R132H', 'Var', (19, 26))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
40792	32289278	PrimePCR ddPCR mutation assay BRAF wild-type/p.R132H for p.R132H, Human (unique assay ID: dHsaCP2000055/56) was used (Bio-Rad, Hercules, CA).	('p.R132H', 'Var', (57, 64))	('Human', 'Species', '9606', (66, 71))	('p.R132H', 'Mutation', 'rs121913500', (57, 64))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('Rad', 'Gene', '6236', (122, 125))	('p.R132H', 'Mutation', 'rs121913500', (45, 52))	('Rad', 'Gene', (122, 125))
40793	32289278	FGFR1 p.N546K, p. K656E: FGFR1 p. N546K, p. K656E detection was completed as described above.	('N546K', 'Var', (34, 39))	('FGFR1', 'Gene', '2260', (25, 30))	('N546K', 'SUBSTITUTION', 'None', (34, 39))	('p.N546K', 'Mutation', 'rs779707422', (6, 13))	('FGFR1', 'Gene', (0, 5))	('K656E', 'Var', (44, 49))	('FGFR1', 'Gene', '2260', (0, 5))	('K656E', 'SUBSTITUTION', 'None', (44, 49))	('FGFR1', 'Gene', (25, 30))	('N546K', 'Var', (8, 13))	('K656E', 'Var', (18, 23))	('K656E', 'SUBSTITUTION', 'None', (18, 23))	('N546K', 'SUBSTITUTION', 'None', (8, 13))
40794	32289278	Custom primer and probe sequences used for this target are as follows: N546KFP: 5'-TGATGAAGATGATCGGGAAGC-3' N546KRP: 5'-CACCCACCATCCTGCGT-3' N546K wild-type Probe: AATATCATCAACCTGCTGG N546K Probe: AATATCATCAAACTGCTGG K656E FP: 5'-CACGGGACATTCACCACATC-3' K656ERP: 5'-CACAGGGCGGCCTTGTC-3' K656E wild-type Probe: CTACTATAAAAAGACAACCAA K656E Probe: TACTATAAAGAGACAACCAA Probes that targeted KIAA1549-BRAF fusion variants were designed in collaboration with NanoString (Seattle, WA) and samples tested as previously described.	('variants', 'Var', (408, 416))	('K656E', 'Mutation', 'rs869320694', (287, 292))	('KIAA1549', 'Gene', (387, 395))	('KIAA1549', 'Gene', '57670', (387, 395))	('BRAF', 'Gene', '673', (396, 400))	('N546K', 'Mutation', 'rs779707422', (141, 146))	('N546K', 'Mutation', 'rs779707422', (108, 113))	('K656E', 'Mutation', 'rs869320694', (332, 337))	('K656E', 'Mutation', 'rs869320694', (217, 222))	('N546K', 'Mutation', 'rs779707422', (184, 189))	('K656E', 'Mutation', 'rs869320694', (254, 259))	('N546K', 'Mutation', 'rs779707422', (71, 76))	('BRAF', 'Gene', (396, 400))
40804	32289278	Mouse Anti-Human BRAF p.V600E Monoclonal Antibody from Spring Bioscience (El9290, Pleasanton, CA).	('p.V600E', 'Mutation', 'rs113488022', (22, 29))	('BRAF', 'Gene', '673', (17, 21))	('p.V600E', 'Var', (22, 29))	('Human', 'Species', '9606', (11, 16))	('BRAF', 'Gene', (17, 21))
40805	32289278	Rabbit Anti-Histone H3F3A p.K27M Polyclonal Antibody from Millipore (ABE419, Burlington, MA) Detection of BRAF p.V600E and H3.3 p.K27M by immunohistochemistry was performed on a Benchmark Ventana Machine (Tucson, AZ) using the Optiview detection kit (Tucson, AZ).	('H3F3A', 'Gene', '3020', (20, 25))	('p.V600E', 'Var', (111, 118))	('H3F3A', 'Gene', (20, 25))	('p.K27M', 'Mutation', 'p.K27M', (128, 134))	('BRAF', 'Gene', '673', (106, 110))	('kit', 'Gene', (246, 249))	('p.K27M', 'Var', (128, 134))	('H3.3', 'Gene', (123, 127))	('BRAF', 'Gene', (106, 110))	('p.K27M', 'Mutation', 'p.K27M', (26, 32))	('kit', 'Gene', '3815', (246, 249))	('p.V600E', 'Mutation', 'rs113488022', (111, 118))	('H3.3', 'Gene', '3020', (123, 127))
40816	32289278	KIAA1549-BRAF, BRAF p.V600E, and NF1 mutations account for 2/3 of pLGG.	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', (15, 19))	('NF1', 'Gene', (33, 36))	('KIAA1549', 'Gene', '57670', (0, 8))	('KIAA1549', 'Gene', (0, 8))	('pLGG', 'Disease', (66, 70))	('NF1', 'Gene', '4763', (33, 36))	('mutations', 'Var', (37, 46))	('p.V600E', 'Mutation', 'rs113488022', (20, 27))	('p.V600E', 'Var', (20, 27))	('BRAF', 'Gene', '673', (9, 13))
40821	31551755	Within these genes, high Tau/MAPT expression shows the strongest correlation with several indicators of prolonged survival on glioma patients.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('Tau/MAPT', 'Protein', (25, 33))	('expression', 'MPA', (34, 44))	('patients', 'Species', '9606', (133, 141))	('high', 'Var', (20, 24))	('glioma', 'Disease', (126, 132))
40860	31551755	The following primary antibodies (anti-Tau, Dako A0024; anti-Ki67, Dako M7240 and anti-GFAP, M 0761) were incubated O/N at 4 C. The second day, section was washed with PBS three times prior to incubation with the appropriate fluorescent secondary antibody (anti-mouse and anti rabbit Jackson immunoresearch) for 2 h at room temperature.	('GFAP', 'Gene', '2670', (87, 91))	('anti-Ki67', 'Var', (56, 65))	('mouse', 'Species', '10090', (262, 267))	('rabbit', 'Species', '9986', (277, 283))	('GFAP', 'Gene', (87, 91))
40866	31551755	To begin to address if there is a molecular correlation between gliomas and neurodegenerative diseases we analyzed the TCGA merge dataset for LGG and GBM looking for the presence of mutations and copy number alterations in genes associated with AD, PD, and ALS.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (76, 101))	('PD', 'Disease', 'MESH:D010300', (249, 251))	('ALS', 'Phenotype', 'HP:0007354', (257, 260))	('neurodegenerative diseases', 'Disease', (76, 102))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('AD', 'Disease', (245, 247))	('ALS', 'Disease', (257, 260))	('AD', 'Phenotype', 'HP:0002511', (245, 247))	('ALS', 'Disease', 'MESH:D000690', (257, 260))	('GBM', 'Disease', (150, 153))	('GBM', 'Disease', 'MESH:D005909', (150, 153))	('AD', 'Disease', 'MESH:D000544', (245, 247))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (76, 102))	('gliomas', 'Disease', (64, 71))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (76, 102))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('copy number alterations', 'Var', (196, 219))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))
40870	31551755	Figure 1A shows that there is a very low frequency of somatic mutations or copy number variations (CNV) in glioma samples for all the genes included in the study.	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('copy number variations', 'Var', (75, 97))	('glioma', 'Disease', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (107, 113))
40871	31551755	The higher percentage of genetic alterations was found in the C9orf7 gene (3%), mainly associated with deep deletions that, in any case, are not frequently found in ALS patients.	('C9orf7', 'Gene', '11094', (62, 68))	('C9orf7', 'Gene', (62, 68))	('patients', 'Species', '9606', (169, 177))	('ALS', 'Phenotype', 'HP:0007354', (165, 168))	('ALS', 'Disease', (165, 168))	('associated', 'Reg', (87, 97))	('ALS', 'Disease', 'MESH:D000690', (165, 168))	('deep deletions', 'Var', (103, 117))	('genetic alterations', 'Var', (25, 44))
40872	31551755	Overall, these results suggest that genetic alterations in genes associated with neurodegeneration are not common drivers of gliomas.	('gliomas', 'Disease', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('neurodegeneration', 'Phenotype', 'HP:0002180', (81, 98))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('genetic alterations', 'Var', (36, 55))
40890	31551755	To gain further insight into the relevance of Tau in cancer we analyzed the TCGA cohorts for different cancers and we used the median of Tau/MAPT expression to classify tumors into High or Low-Tau.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (53, 59))	('High', 'Var', (181, 185))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Disease', (103, 109))	('tumors', 'Disease', (169, 175))	('cancers', 'Disease', (103, 110))
40891	31551755	In accordance with our previous data (Table 1), gliomas with high levels of Tau/MAPT have a much better prognosis (Table 2).	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('Tau/MAPT', 'Protein', (76, 84))	('high levels', 'Var', (61, 72))	('gliomas', 'Disease', (48, 55))
40892	31551755	However, the expression of this gene also correlates with an increase in the overall survival of patients with breast cancer, kidney clear cell carcinoma, lung adenocarcinoma and pheochromocytoma/paraganglioma (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (179, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Var', (13, 23))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('kidney clear cell carcinoma, lung adenocarcinoma and pheochromocytoma/paraganglioma', 'Disease', 'MESH:D018262', (126, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('increase', 'PosReg', (61, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('breast cancer', 'Disease', (111, 124))	('patients', 'Species', '9606', (97, 105))
40923	31551755	It is worth mentioning that there have been previous reports of deregulations (mutations and copy number losses) observed in PARK2 in GBM, which argue in favor of a possible tumor suppressor function of this gene in such tumors.	('tumor', 'Disease', (174, 179))	('GBM', 'Disease', (134, 137))	('tumors', 'Disease', (221, 227))	('GBM', 'Disease', 'MESH:D005909', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('PARK2', 'Gene', '5071', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('PARK2', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('deregulations', 'MPA', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutations', 'Var', (79, 88))	('copy number losses', 'Var', (93, 111))
40924	31551755	Still, our meta-analysis indicates a lower frequency of PARK2 deletions in the joint cohort of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('PARK2', 'Gene', '5071', (56, 61))	('PARK2', 'Gene', (56, 61))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('deletions', 'Var', (62, 71))
40925	31551755	However, we only accounted for those CNV that appear in homozygosity, which could explain why we found a reduced percentage of gliomas with these deletions.	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('deletions', 'Var', (146, 155))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
40928	31551755	However, our analysis has found a very small percentage of gliomas (0.3%) with Tau alterations (amplifications and deletions).	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('Tau', 'Protein', (79, 82))	('gliomas', 'Disease', (59, 66))	('deletions', 'Var', (115, 124))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('alterations', 'Reg', (83, 94))
40932	31551755	In AD and other tauopathies, it has been postulated that changes in the expression of the different Tau/MAPT splicing isoforms might facilitate the neurodegeneration.	('tauopathies', 'Disease', 'MESH:D024801', (16, 27))	('neurodegeneration', 'CPA', (148, 165))	('tauopathies', 'Disease', (16, 27))	('changes', 'Var', (57, 64))	('expression', 'MPA', (72, 82))	('AD', 'Phenotype', 'HP:0002511', (3, 5))	('AD', 'Disease', 'MESH:D000544', (3, 5))	('AD', 'Disease', (3, 5))	('facilitate', 'PosReg', (133, 143))	('neurodegeneration', 'Phenotype', 'HP:0002180', (148, 165))
40943	31551755	Therefore, we could speculate that changes in Tau expression could affect at the same time the EMT and the invasion capacity of the glioma cells.	('glioma', 'Disease', (132, 138))	('affect', 'Reg', (67, 73))	('EMT', 'CPA', (95, 98))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('Tau', 'Protein', (46, 49))	('changes', 'Var', (35, 42))	('expression', 'MPA', (50, 60))
40949	31551755	More recently, Tau deletion has been linked to defects in the insulin signaling pathway in the brain.	('deletion', 'Var', (19, 27))	('defects', 'NegReg', (47, 54))	('insulin', 'Gene', (62, 69))	('Tau', 'Gene', (15, 18))	('insulin', 'Gene', '3630', (62, 69))
40959	31551755	Cabazitaxel has been evaluated with a limited success in a phase II study for temozolomide refractory gliomas (NCT01740570 and NCT01866449) and now is being investigated clinically in combination with cisplatin.	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('Cabazitaxel', 'Chemical', 'MESH:C552428', (0, 11))	('NCT01866449', 'Var', (127, 138))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('temozolomide refractory gliomas', 'Phenotype', 'HP:0012174', (78, 109))	('temozolomide refractory gliomas', 'Disease', (78, 109))	('NCT01740570', 'Var', (111, 122))	('temozolomide refractory gliomas', 'Disease', 'MESH:D005910', (78, 109))
40964	31551755	By contrast, low Tau expression identifies a subset of ER-positive breast cancers that have poor prognosis when treated with tamoxifen alone, although they may benefit from chemotherapy with taxanes.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('Tau', 'Protein', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('ER', 'Gene', '2099', (55, 57))	('low', 'Var', (13, 16))	('taxanes', 'Chemical', 'MESH:C080625', (191, 198))	('breast cancers', 'Phenotype', 'HP:0003002', (67, 81))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancers', 'Disease', 'MESH:D001943', (67, 81))	('breast cancers', 'Disease', (67, 81))
40976	29742423	CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal.	('promote', 'PosReg', (115, 122))	('PKA', 'Gene', '34284', (25, 28))	('Inhibition', 'Var', (5, 15))	('neoplastic growth', 'CPA', (123, 140))	('deregulating', 'NegReg', (153, 165))	('Glioma', 'Disease', (79, 85))	('CREB1', 'Gene', '12912', (60, 65))	('PKA', 'Gene', (25, 28))	('asymmetric cell division', 'Phenotype', 'HP:0100555', (166, 190))	('CDK5', 'Gene', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('asymmetric cell division', 'CPA', (166, 190))	('enhancing', 'PosReg', (195, 204))	('Glioma', 'Disease', 'MESH:D005910', (79, 85))	('CREB1', 'Gene', (60, 65))	('CDK5', 'Gene', '36727', (0, 4))	('cAMP', 'Chemical', 'MESH:D000242', (29, 33))	('Activation', 'PosReg', (46, 56))	('Glioma', 'Phenotype', 'HP:0009733', (79, 85))	('self-renewal', 'CPA', (205, 217))
40979	29742423	Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('inhibition', 'Var', (47, 57))	('suppressing', 'NegReg', (150, 161))	('CREB1', 'Protein', (162, 167))	('CDK5', 'Gene', (61, 65))	('activation', 'MPA', (168, 178))	('PKA', 'Gene', '34284', (196, 199))	('PKA', 'Gene', (196, 199))	('GSC self-renewal', 'CPA', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('prevents', 'NegReg', (66, 74))	('cAMP', 'Chemical', 'MESH:D000242', (200, 204))
40994	29742423	We also show that antagonizing this CDK5-CREB1 pathway suppresses both self-renewal of GSCs and glioma growth.	('glioma growth', 'Disease', 'MESH:D005910', (96, 109))	('glioma growth', 'Disease', (96, 109))	('antagonizing', 'Var', (18, 30))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('CDK5-CREB1', 'Gene', (36, 46))	('suppresses', 'NegReg', (55, 65))	('self-renewal of GSCs', 'CPA', (71, 91))
41000	29742423	To search for kinases that antagonize the tumor stem cell phenotype and that could represent potential therapeutic targets, we performed a genetic screen where we crossed RNAi lines for specific kinase genes with ey-GAL4 > brat-RNAi stock and determined the extent of reduction in the brat-RNAi eye tumor in the progeny.	('reduction', 'NegReg', (268, 277))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (299, 304))	('brat', 'Gene', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('brat', 'Gene', (285, 289))	('eye tumor', 'Phenotype', 'HP:0100012', (295, 304))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('ey-GAL4 >', 'Var', (213, 222))	('eye tumor', 'Disease', 'MESH:D005134', (295, 304))	('eye tumor', 'Disease', (295, 304))	('brat', 'Gene', '35197', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('brat', 'Gene', '35197', (285, 289))
41002	29742423	It is noteworthy that dCdk5 and dP35 knockdown in normal eye, in the absence of brat-RNAi, does not result in a phenotype (not shown).	('brat', 'Gene', '35197', (80, 84))	('dP35', 'Gene', (32, 36))	('dP35', 'Gene', '34385', (32, 36))	('knockdown', 'Var', (37, 46))	('dCdk5', 'Gene', '36727', (22, 27))	('dCdk5', 'Gene', (22, 27))	('brat', 'Gene', (80, 84))
41011	29742423	Because suppression of dCdk5 had the capacity to suppress brat-RNAi tumor stem cell proliferation (Figure 1C, v), we hypothesized that the CDK5 signaling pathway might also regulate asymmetric cell division.	('tumor', 'Disease', (68, 73))	('suppression', 'Var', (8, 19))	('regulate', 'Reg', (173, 181))	('brat', 'Gene', (58, 62))	('dCdk5', 'Gene', (23, 28))	('dCdk5', 'Gene', '36727', (23, 28))	('asymmetric cell division', 'CPA', (182, 206))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('brat', 'Gene', '35197', (58, 62))	('suppress', 'NegReg', (49, 57))	('asymmetric cell division', 'Phenotype', 'HP:0100555', (182, 206))
41022	29742423	We observed that CP681301 reduced active phospho-dCdk5 (Y15) (white) in tumor cells (Figures 1E, iii and iv, and S1E) after 10 days of feeding and reduced the self-renewal properties of stem cells as shown by the absence of Mira (green) (Figures 1E, i and ii, and S1D).	('dCdk5', 'Gene', '36727', (49, 54))	('dCdk5', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Mira', 'Gene', '42379', (224, 228))	('tumor', 'Disease', (72, 77))	('Mira', 'Gene', (224, 228))	('reduced', 'NegReg', (26, 33))	('self-renewal properties of stem cells', 'CPA', (159, 196))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('CP681301', 'Var', (17, 25))	('CP681301', 'Chemical', '-', (17, 25))	('reduced', 'NegReg', (147, 154))
41023	29742423	CP681301 also increased the expression of neuronal marker ElaV in these cells, showing that in flies, dCdk5 inhibition causes differentiation (Figure S1F).	('increased', 'PosReg', (14, 23))	('differentiation', 'CPA', (126, 141))	('inhibition', 'NegReg', (108, 118))	('expression', 'MPA', (28, 38))	('dCdk5', 'Gene', '36727', (102, 107))	('dCdk5', 'Gene', (102, 107))	('ElaV', 'Gene', '31000', (58, 62))	('CP681301', 'Var', (0, 8))	('CP681301', 'Chemical', '-', (0, 8))	('ElaV', 'Gene', (58, 62))
41024	29742423	Finally, we measured the lifespan of flies with tumors and found that CP681301 increased the median survival by 2.8-fold, although the tumors remained fatal (Figure 1F).	('increased', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CP681301', 'Var', (70, 78))	('median survival', 'CPA', (93, 108))	('CP681301', 'Chemical', '-', (70, 78))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
41028	29742423	Our analysis of the complete lower grade glioma (LGG) and GBM data from The Cancer Genomic Atlas (TCGA) revealed that CDK5 is frequently amplified in GBM (83%) and to a greater degree than in LGGs (15%) (Figure 2A).	('Cancer Genomic Atlas', 'Disease', 'MESH:D009369', (76, 96))	('CDK5', 'Gene', (118, 122))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('amplified', 'Var', (137, 146))	('glioma', 'Disease', (41, 47))	('Cancer Genomic Atlas', 'Disease', (76, 96))
41032	29742423	Some of these differences in CDK5 expression are likely due to frequent copy number gains of chromosome 7 in IDH wild-type GBMs, but not in IDH mutant GBMs, in agreement with previous findings that CDK5 is one of the few amplified genes on chromosome 7 that correlates with high mRNA expression.	('CDK5', 'Gene', (29, 33))	('expression', 'MPA', (34, 44))	('IDH', 'Gene', '44291', (109, 112))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('gains', 'PosReg', (84, 89))	('GBM', 'Phenotype', 'HP:0012174', (151, 154))	('differences', 'Reg', (14, 25))	('IDH', 'Gene', '44291', (140, 143))	('IDH', 'Gene', (109, 112))	('copy number', 'Var', (72, 83))	('IDH', 'Gene', (140, 143))
41048	29742423	To determine if the CDK5 inhibitor CP681301 can suppress the kinase activity of both of these complexes, we tested the drug in a range of concentrations starting from 0.1 nM to 1 muM.	('tested', 'Reg', (108, 114))	('suppress', 'NegReg', (48, 56))	('ran', 'Gene', (129, 132))	('CP681301', 'Chemical', '-', (35, 43))	('ran', 'Gene', '44072', (129, 132))	('kinase activity', 'MPA', (61, 76))	('muM', 'Gene', (179, 182))	('CP681301', 'Var', (35, 43))	('muM', 'Gene', '33903', (179, 182))
41049	29742423	Our results showed that CP681301 completely abolished activities of both CDK5-P35 and CDK5-P25 at a concentration of 1 muM (Figure 3A).	('muM', 'Gene', (119, 122))	('CP681301', 'Chemical', '-', (24, 32))	('muM', 'Gene', '33903', (119, 122))	('CDK5-P35', 'Protein', (73, 81))	('activities', 'MPA', (54, 64))	('P25', 'Gene', (91, 94))	('P25', 'Gene', '5657633', (91, 94))	('CP681301', 'Var', (24, 32))	('abolished', 'NegReg', (44, 53))
41050	29742423	Next, we tested the cytotoxic effect of CP681301 on GBM neurosphere cultures and NHNPs (normal human neuro-progenitors) in order to determine if there was differential toxicity among neoplastic and non-neoplastic cells.	('human', 'Species', '9606', (95, 100))	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('toxicity', 'Disease', (168, 176))	('CP681301', 'Var', (40, 48))	('CP681301', 'Chemical', '-', (40, 48))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('tested', 'Reg', (9, 15))
41052	29742423	We also found that treatment of GSCs with CP681301 for 48 hr moderately suppressed the expression of CDK5 total protein but had a more marked suppressive effect on the tyrosine-15 (Y15) phosphorylation status, which is associated with CDK5 kinase activation (Figure 3C).	('CP681301', 'Chemical', '-', (42, 50))	('tyrosine', 'Chemical', 'MESH:D014443', (168, 176))	('suppressive', 'NegReg', (142, 153))	('expression', 'MPA', (87, 97))	('CDK5 total protein', 'Protein', (101, 119))	('suppressed', 'NegReg', (72, 82))	('CP681301', 'Var', (42, 50))
41053	29742423	As mentioned, CP681301 is more specific to CDK5 than its closest relative CDK2, whose phosphorylation and activation is not affected in these cells upon 1 muM CP681301 treatment (Figure S4A).	('CP681301', 'Chemical', '-', (159, 167))	('CP681301', 'Chemical', '-', (14, 22))	('muM', 'Gene', '33903', (155, 158))	('CP681301', 'Var', (14, 22))	('CDK2', 'Gene', '42453', (74, 78))	('muM', 'Gene', (155, 158))	('CDK2', 'Gene', (74, 78))	('CP681301', 'Var', (159, 167))
41054	29742423	Interestingly, the inactivation of CDK5 by CP681301 was also associated with a reduction of the stem cell markers CD133, OLIG2, and SOX2 (Figure 3C) and the cell proliferation marker Ki67 (Figure 3C), but did not change GFAP and TUJ1 expression upon differentiation conditions (Figures 3C, S4B, and S4C).	('CDK5', 'Gene', (35, 39))	('S4C', 'Mutation', 'p.S4C', (299, 302))	('cell', 'CPA', (157, 161))	('stem cell markers', 'CPA', (96, 113))	('CD133', 'Gene', (114, 119))	('CD133', 'Gene', '8842', (114, 119))	('CP681301', 'Var', (43, 51))	('CP681301', 'Chemical', '-', (43, 51))	('inactivation', 'Var', (19, 31))	('reduction', 'NegReg', (79, 88))
41055	29742423	To examine the effects of CDK5 inactivation by CP681301 on GSC self-renewal function, we tested the neurosphere formation using the extreme limiting dilution assay (ELDA) (http://bioinf.wehi.edu.au/software/elda/) and found that sphere formation rate is dramatically suppressed within 72 hr (Figure 3D).	('tested', 'Reg', (89, 95))	('sphere formation rate', 'CPA', (229, 250))	('CP681301', 'Var', (47, 55))	('CP681301', 'Chemical', '-', (47, 55))	('suppressed', 'NegReg', (267, 277))
41056	29742423	We also performed a visual primary sphere formation experiment in the absence and presence of CP681301 for 96 hr and found that even at early time points, the rate of sphere formation drops down from 77.87% to 52.31% in GBM121 GSCs and from 77.93% to 53.88% in GBM39 GSCs (Figure 3E).	('CP681301', 'Var', (94, 102))	('CP681301', 'Chemical', '-', (94, 102))	('GBM', 'Phenotype', 'HP:0012174', (220, 223))	('sphere formation', 'CPA', (167, 183))	('GBM', 'Phenotype', 'HP:0012174', (261, 264))	('drops down', 'NegReg', (184, 194))	('GBM121', 'Var', (220, 226))
41058	29742423	After observing the effect of CP681301 on GBM121 and GBM39 GSCs in vitro, we generated xenograft orthotopic tumors in NSG mice.	('mice', 'Species', '10090', (122, 126))	('GBM121', 'Gene', (42, 48))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GBM39', 'Gene', (53, 58))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('CP681301', 'Var', (30, 38))	('CP681301', 'Chemical', '-', (30, 38))
41060	29742423	We then removed the brains and established ex vivo or-ganotypic explant slice cultures (300-mum) to directly observe glioma growth dynamics and the expression of stem cell markers in the presence of 0, 10, or 50 muM CP681301.	('mum', 'Gene', '33903', (92, 95))	('glioma growth', 'Disease', (117, 130))	('muM', 'Gene', (212, 215))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mum', 'Gene', (92, 95))	('glioma growth', 'Disease', 'MESH:D005910', (117, 130))	('muM', 'Gene', '33903', (212, 215))	('expression', 'MPA', (148, 158))	('CP681301', 'Var', (216, 224))	('CP681301', 'Chemical', '-', (216, 224))
41061	29742423	After 48 hr, CP681301 reduced the phosphorylation of CDK5 as well as the expression of the proliferation marker Ki67 (Figure 4B).	('phosphorylation', 'MPA', (34, 49))	('CP681301', 'Chemical', '-', (13, 21))	('CDK5', 'Protein', (53, 57))	('expression', 'MPA', (73, 83))	('CP681301', 'Var', (13, 21))	('reduced', 'NegReg', (22, 29))
41063	29742423	We also tested the contralateral brain hemispheres (without neoplastic cells) and found that CP681301 did not affect the viability of normal tissue or affect cell self-renewal markers or active CDK5 status (Figure S5G).	('CP681301', 'Var', (93, 101))	('affect', 'Reg', (151, 157))	('CP681301', 'Chemical', '-', (93, 101))	('active', 'MPA', (187, 193))	('cell self-renewal markers', 'CPA', (158, 183))
41065	29742423	Together, these data indicate that CP681301 reduces CDK5 activation, stem cell marker expression, and cell proliferation in mouse xenografts ex vivo.	('stem cell marker', 'CPA', (69, 85))	('activation', 'MPA', (57, 67))	('CP681301', 'Chemical', '-', (35, 43))	('mouse', 'Species', '10090', (124, 129))	('expression', 'MPA', (86, 96))	('reduces', 'NegReg', (44, 51))	('CP681301', 'Var', (35, 43))	('cell proliferation', 'CPA', (102, 120))	('CDK5', 'Protein', (52, 56))
41067	29742423	We found that the phosphorylation of RB (Ser807/811) and CREB1 (Ser133) (Figures S6A and S6B) were reduced following CDK inhibition (Figure 4D).	('CDK', 'Gene', (117, 120))	('S6B', 'Gene', (89, 92))	('RB', 'Phenotype', 'HP:0009919', (37, 39))	('CDK', 'Gene', '36854', (117, 120))	('RB', 'Gene', '31027', (37, 39))	('Ser133', 'Chemical', '-', (64, 70))	('phosphorylation', 'MPA', (18, 33))	('Ser807', 'Chemical', '-', (41, 47))	('S6B', 'Gene', '32047', (89, 92))	('Ser807/811', 'Var', (41, 51))	('reduced', 'NegReg', (99, 106))
41068	29742423	Activation of CREB occurs by Serine 133 phosphorylation and our western blot and immunocytochemistry data (Figures 4H and S5D) indicates CDK5 activates CREB1 in this manner.	('activates', 'PosReg', (142, 151))	('Serine', 'Chemical', 'MESH:D012694', (29, 35))	('CREB1', 'Gene', (152, 157))	('CDK5', 'Var', (137, 141))	('Serine 133 phosphorylation', 'MPA', (29, 55))
41076	29742423	We next tested CP681301 for its effects on CREB1 in ex vivo xenograft organotypic cultures by immunohistochemistry and western blotting and found that CREB1 phosphorylation was substantially suppressed after treatment (Figures 5A and 5B).	('suppressed', 'NegReg', (191, 201))	('CREB1', 'Gene', (151, 156))	('phosphorylation', 'MPA', (157, 172))	('CP681301', 'Var', (15, 23))	('CP681301', 'Chemical', '-', (15, 23))
41077	29742423	Finally, in order to find the specific effect of CREB1 on GSCs self-renewal programs, we knocked down CREB1 using siRNA, which resulted in the reduction of self-renewal behavior measured by ELDA (Figure S5F) and expression of critical self-renewal transcription factors, including OLIG2, POU3F2, and SALL2, indicating that CREB1 indeed regulates stem cell programs in GSCs (Figure S6C).	('stem cell programs', 'CPA', (346, 364))	('self-renewal behavior', 'CPA', (156, 177))	('regulates', 'Reg', (336, 345))	('knocked', 'Var', (89, 96))	('reduction', 'NegReg', (143, 152))	('ran', 'Gene', (249, 252))	('CREB1', 'Gene', (102, 107))	('ran', 'Gene', '44072', (249, 252))
41080	29742423	The results clearly show that both CDK5-P35 and CDK5-P25 phosphorylated CREB1 (Figure 5D).	('P25', 'Gene', (53, 56))	('P25', 'Gene', '5657633', (53, 56))	('CDK5-P35', 'Var', (35, 43))
41082	29742423	We also established that CP681301 (0.5 muM and 1 muM) was capable of suppressing CREB Ser133 phosphorylation by CDK5 (Figure 5D), similar to in situ GSC data.	('muM', 'Gene', (39, 42))	('CREB Ser133 phosphorylation', 'MPA', (81, 108))	('muM', 'Gene', (49, 52))	('muM', 'Gene', '33903', (39, 42))	('Ser133', 'Chemical', '-', (86, 92))	('suppressing', 'NegReg', (69, 80))	('CP681301', 'Var', (25, 33))	('CP681301', 'Chemical', '-', (25, 33))	('muM', 'Gene', '33903', (49, 52))
41111	29742423	p35 and cdk5 RNAi stocks were used to knockdown these gene's expressions in brat-RNAi brain tumor to see the rescue.	('stocks', 'Species', '3724', (18, 24))	('brat', 'Gene', '35197', (76, 80))	('brat', 'Gene', (76, 80))	('brain tumor', 'Disease', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('brain tumor', 'Disease', 'MESH:D001932', (86, 97))	('p35', 'Gene', '34385', (0, 3))	('knockdown', 'Var', (38, 47))	('brain tumor', 'Phenotype', 'HP:0030692', (86, 97))	('p35', 'Gene', (0, 3))
41118	29742423	Primary antibodies are: Mira (Miranda) (1:200) (gift from Dr. Chengyu Lee) and phospho-Cdk5 (1:200) (sc-12918-R) (Santa Cruz).	('sc-12918-R', 'Var', (101, 111))	('Miranda', 'Gene', (30, 37))	('Mira', 'Gene', '42379', (30, 34))	('Mira', 'Gene', '42379', (24, 28))	('Mira', 'Gene', (30, 34))	('Miranda', 'Gene', '42379', (30, 37))	('Mira', 'Gene', (24, 28))	('Cdk5', 'Gene', (87, 91))	('Cdk5', 'Gene', '36727', (87, 91))
41132	29742423	Thermo Fisher Scientific tested the inhibitory efficiency of CP681301 on active CDK5/P25 and CDK5/P35 in vitro.	('P25', 'Gene', '5657633', (85, 88))	('inhibitory efficiency', 'MPA', (36, 57))	('CP681301', 'Var', (61, 69))	('CP681301', 'Chemical', '-', (61, 69))	('P25', 'Gene', (85, 88))
41147	29742423	Active Tau protein (Anaspec: 55556-50) and active CREB1 (Life Tech: 10074-H10E-5) proteins were used as substrates.	('Tau', 'Gene', '326116', (7, 10))	('H10E', 'Var', (74, 78))	('H10E', 'SUBSTITUTION', 'None', (74, 78))	('Tau', 'Gene', (7, 10))
41148	29742423	The in vitro kinase assay buffer, ATP (Cell Signaling Tech), and 0, 0.5 muM, and 1 muM of CP681301 were added and mixed well.	('muM', 'Gene', '33903', (83, 86))	('CP681301', 'Var', (90, 98))	('CP681301', 'Chemical', '-', (90, 98))	('muM', 'Gene', '33903', (72, 75))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('muM', 'Gene', (83, 86))	('muM', 'Gene', (72, 75))
41149	29742423	3 siRNAs and one scrambled siRNA were transfected using Lipofectamine 3000 in GBM121 and GBM39 GSCs.	('Lipofectamine', 'Chemical', 'MESH:C086724', (56, 69))	('ran', 'Gene', '44072', (39, 42))	('GBM', 'Phenotype', 'HP:0012174', (89, 92))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('GBM39', 'Var', (89, 94))	('ran', 'Gene', (39, 42))
41156	29742423	Drosophila Cdk5 promotes stemness by altering asymmetric division of brain tumor stem cells CDK5 regulates self-renewal by directly activating CREB1 independently of PKA/cAMP CDK5 inhibitor CP681301 reduces self-renewal in mouse glioma xenografts CDK5 and asymmetric stem cell division markers segregate in non-mesenchymal tumors	('mouse', 'Species', '10090', (223, 228))	('non-mesenchymal tumors', 'Disease', 'MESH:C535700', (307, 329))	('Cdk5', 'Gene', '36727', (11, 15))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('CREB1', 'Gene', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('CP681301', 'Var', (190, 198))	('PKA', 'Gene', '34284', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (323, 329))	('reduces', 'NegReg', (199, 206))	('CP681301', 'Chemical', '-', (190, 198))	('activating', 'Reg', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PKA', 'Gene', (166, 169))	('self-renewal', 'CPA', (207, 219))	('brain tumor', 'Phenotype', 'HP:0030692', (69, 80))	('non-mesenchymal tumors', 'Disease', (307, 329))	('glioma', 'Disease', (229, 235))	('brain tumor', 'Disease', 'MESH:D001932', (69, 80))	('brain tumor', 'Disease', (69, 80))	('Drosophila', 'Species', '7227', (0, 10))	('Cdk5', 'Gene', (11, 15))	('glioma', 'Disease', 'MESH:D005910', (229, 235))	('cAMP', 'Chemical', 'MESH:D000242', (170, 174))
41190	25722937	One example is the use of BCNU wafers (Gliadel) in recurrent glioma where a double-blinded, randomized prospective trial showing a 6-month OS of 64% in BCNU wafer implanted patients compared with 44% in placebo treated patients.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('BCNU', 'Chemical', 'MESH:D002330', (26, 30))	('patients', 'Species', '9606', (173, 181))	('implanted', 'Var', (163, 172))	('glioma', 'Disease', (61, 67))	('BCNU', 'Chemical', 'MESH:D002330', (152, 156))	('patients', 'Species', '9606', (219, 227))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
41219	25722937	The study did, however, demonstrate that tumors lacking the 1p/19q deletion were less aggressive and more responsive to either therapy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('aggressive', 'CPA', (86, 96))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('less', 'NegReg', (81, 85))	('1p/19q deletion', 'Var', (60, 75))	('more', 'PosReg', (101, 105))	('responsive', 'Reg', (106, 116))
41229	25722937	With our knowledge of the genetic variability across histologically similar tumors in patients, we are now designing clinical trials and performing surgeries on patients not based on tissue diagnosis but on molecular information such as 1p19q deletion or MGMT hyper-methylation.	('1p19q deletion', 'Var', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('patients', 'Species', '9606', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('MGMT', 'Gene', '4255', (255, 259))	('MGMT', 'Gene', (255, 259))	('patients', 'Species', '9606', (86, 94))
41234	24767714	Eighty-seven percent of the tumors had at least one pathogenic copy number alteration.	('copy number alteration', 'Var', (63, 85))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
41235	24767714	Nineteen of 56 low grade gliomas (LGGs) demonstrated a duplication in 7q34, which resulted in a KIAA1549-BRAF fusion.	('KIAA1549-BRAF', 'Disease', 'None', (96, 109))	('7q34', 'Gene', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('resulted in', 'Reg', (82, 93))	('KIAA1549-BRAF', 'Disease', (96, 109))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))	('duplication in', 'Var', (55, 69))
41236	24767714	Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma and one dysembryoplastic neuroepithelial tumor (DNT).	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('resulted in', 'Reg', (38, 49))	('pilocytic astrocytoma', 'Disease', (96, 117))	('dysembryoplastic neuroepithelial tumor', 'Disease', 'MESH:D018302', (126, 164))	('deletions', 'Var', (21, 30))	('FAM131B', 'Gene', (52, 59))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (143, 164))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (96, 117))	('dysembryoplastic neuroepithelial tumor', 'Disease', (126, 164))	('FAM131B', 'Gene', '9715', (52, 59))
41238	24767714	Monosomy 6, deletion of 9q and 10q, and an i(17)(q10) were each detected in the medulloblastomas (MBs).	('deletion', 'Var', (12, 20))	('MB', 'Phenotype', 'HP:0002885', (98, 100))	('detected', 'Reg', (64, 72))	('medulloblastomas', 'Disease', 'MESH:D008527', (80, 96))	('medulloblastoma', 'Phenotype', 'HP:0002885', (80, 95))	('Monosomy 6', 'Var', (0, 10))	('medulloblastomas', 'Disease', (80, 96))
41239	24767714	Deletions and regions of loss of heterozygosity that encompassed TP53, RB1, CDKN2A/B, CHEK2, NF1, and NF2 were identified in a variety of tumors, which led to a recommendation for germline testing.	('TP53', 'Gene', '7157', (65, 69))	('NF1', 'Gene', '4763', (93, 96))	('TP53', 'Gene', (65, 69))	('CHEK2', 'Gene', '11200', (86, 91))	('NF2', 'Gene', '4771', (102, 105))	('identified', 'Reg', (111, 121))	('CHEK2', 'Gene', (86, 91))	('RB1', 'Gene', (71, 74))	('CDKN2A/B', 'Gene', (76, 84))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('RB1', 'Gene', '5925', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CDKN2A/B', 'Gene', '1029;1030', (76, 84))	('NF2', 'Gene', (102, 105))	('Deletions', 'Var', (0, 9))	('NF1', 'Gene', (93, 96))
41240	24767714	A BRAF p.Thr599dup or p.V600E mutation was identified by Sanger sequencing in one and five LGGs, respectively, and a somatic TP53 mutation was identified in a fibrillary astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('p.Thr599dup', 'Mutation', 'p.599dup', (7, 18))	('p.V600E', 'Mutation', 'rs113488022', (22, 29))	('TP53', 'Gene', '7157', (125, 129))	('fibrillary astrocytoma', 'Disease', 'MESH:D001254', (159, 181))	('p.V600E', 'Var', (22, 29))	('TP53', 'Gene', (125, 129))	('p.Thr599dup', 'Var', (7, 18))	('fibrillary astrocytoma', 'Disease', (159, 181))
41250	24767714	Although the vast majority of pediatric brain tumors are thought to be sporadic, certain cancers, such as rhabdoid tumor (RT), demonstrate a higher incidence of patients (35%) with germline mutations.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('brain tumors', 'Phenotype', 'HP:0030692', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (106, 120))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('brain tumor', 'Phenotype', 'HP:0030692', (40, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('germline mutations', 'Var', (181, 199))	('rhabdoid tumor', 'Disease', (106, 120))	('patients', 'Species', '9606', (161, 169))	('cancers', 'Disease', (89, 96))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (30, 52))	('pediatric brain tumors', 'Disease', (30, 52))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
41253	24767714	Notably, a variety of different platforms have been used to identify copy number alterations (CNAs) in pediatric brain tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('brain tumors', 'Phenotype', 'HP:0030692', (113, 125))	('pediatric brain tumors', 'Disease', (103, 125))	('copy number alterations', 'Var', (69, 92))	('brain tumor', 'Phenotype', 'HP:0030692', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (103, 125))
41254	24767714	The most commonly identified CNA in pediatric low grade gliomas (LGGs) is a duplication in 7q34 that results in a fusion protein (KIAA1549-BRAF) and constitutively active MAPK signaling.	('KIAA1549-BRAF', 'Disease', (130, 143))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('results in', 'Reg', (101, 111))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('KIAA1549-BRAF', 'Disease', 'None', (130, 143))	('duplication', 'Var', (76, 87))	('7q34', 'Gene', (91, 95))
41255	24767714	Other frequent CNAs include an i(17)(q10) in MB and frequent loss of 22q in pediatric meningiomas and ependymomas.	('meningiomas', 'Disease', (86, 97))	('MB', 'Phenotype', 'HP:0002885', (45, 47))	('meningioma', 'Phenotype', 'HP:0002858', (86, 96))	('ependymomas', 'Disease', (102, 113))	('meningiomas', 'Phenotype', 'HP:0002858', (86, 97))	('ependymoma', 'Phenotype', 'HP:0002888', (102, 112))	('i(17)(q10', 'Var', (31, 40))	('loss', 'NegReg', (61, 65))	('ependymomas', 'Disease', 'MESH:D004806', (102, 113))	('meningiomas', 'Disease', 'MESH:D008577', (86, 97))
41257	24767714	In contrast, the presence of an i(17)(q10), with or without MYC amplification, places the tumor into either a poor (Group 3) or intermediate (Group 4) risk category.	('i(17)(q10', 'Var', (32, 41))	('MYC', 'Gene', '4609', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('MYC', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
41259	24767714	Similarly, amplification of a miRNA cluster (miR371-373), which is located in 19q13.41 in supratentorial primitive neuroectodermal tumors (sPNETs), is reportedly associated with a poor prognosis.	('miR371', 'Gene', '442916', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (115, 137))	('neuroectodermal tumors', 'Disease', (115, 137))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (115, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (105, 137))	('miR371', 'Gene', (45, 51))	('amplification', 'Var', (11, 24))
41265	24767714	Herein, we report our findings from the analysis of brain tumor specimens from 100 patients who were analyzed with the Human610-Quad or the HumanOmni1-Quad geno-typing bead SNP array.	('brain tumor', 'Phenotype', 'HP:0030692', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Human', 'Species', '9606', (140, 145))	('Human', 'Species', '9606', (119, 124))	('Human610-Quad', 'Var', (119, 132))	('brain tumor', 'Disease', (52, 63))	('patients', 'Species', '9606', (83, 91))	('brain tumor', 'Disease', 'MESH:D001932', (52, 63))
41288	24767714	TP53 sequence variants were determined to be polymorphic or likely pathogenic based on the IARC database and the Catalogue of Somatic Mutations in Cancer (COSMIC).	('TP53', 'Gene', '7157', (0, 4))	('variants', 'Var', (14, 22))	('TP53', 'Gene', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))
41291	24767714	All KIAA1549-BRAF fusions were detected with either primers located in exon 4 of KIAA1549 and exon 16 of BRAF as described in Sievert et al.	('detected', 'Reg', (31, 39))	('KIAA1549', 'Gene', '57670', (81, 89))	('fusions', 'Var', (18, 25))	('KIAA1549-BRAF', 'Disease', (4, 17))	('KIAA1549', 'Gene', (81, 89))	('KIAA1549', 'Gene', (4, 12))	('KIAA1549', 'Gene', '57670', (4, 12))	('KIAA1549-BRAF', 'Disease', 'None', (4, 17))
41294	24767714	Probes used for FISH analysis were all purchased from Abbott Molecular (Des Plaines, IL), except for LUC7L2 (RP11-236O18), which was purchased from the BACPAC Resources at the Children's Hospital Oakland Research Institute (Oakland, CA), and D9S2020 (WI-7383) and PTCH (provided by Robert Jenkins).	('Children', 'Species', '9606', (176, 184))	('PTCH', 'Gene', (264, 268))	('D9S2020', 'Var', (242, 249))	('PTCH', 'Gene', '5727', (264, 268))
41315	24767714	In 5 of the 13 tumors, the gain of chromosome 7 occurred in conjunction with the 7q34 duplication (Figures 2 and 3A; Supplementary Table 2).	('tumors', 'Disease', (15, 21))	('gain', 'PosReg', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('7q34 duplication', 'Var', (81, 97))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
41316	24767714	A gain of chromosome 7 was also accompanied by a BRAF mutation (see BRAF mutation and fusion screening) in 3 of the 13 tumors (Figure 2).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutation', 'Var', (54, 62))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('BRAF', 'Gene', (49, 53))	('gain', 'PosReg', (2, 6))
41321	24767714	This tumor also showed mosaic gains for a number of chromosomes as well as the 7q34 duplication (Supplementary Table 2).	('7q34', 'Gene', (79, 83))	('mosaic gains', 'Var', (23, 35))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
41324	24767714	Case 12-234 was also found to harbor an IDH1 mutation.	('mutation', 'Var', (45, 53))	('IDH1', 'Gene', '3417', (40, 44))	('IDH1', 'Gene', (40, 44))
41325	24767714	Tumor 10-210, a ganglioglioma (GG), displayed a mosaic 30 Mb deletion in 6q23.3q26 in ~75% of cells, with a proximal breakpoint in the last intron of the MYB gene.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('ganglioglioma', 'Disease', 'MESH:D018303', (16, 29))	('deletion', 'Var', (61, 69))	('MYB', 'Gene', '4602', (154, 157))	('MYB', 'Gene', (154, 157))	('ganglioglioma', 'Disease', (16, 29))
41326	24767714	The distal end of this deletion occurred within the QKI gene and likely resulted in a fusion similar to the MYB-QKI fusion reported by Zhang et al.	('fusion', 'Disease', (86, 92))	('MYB', 'Gene', '4602', (108, 111))	('MYB', 'Gene', (108, 111))	('deletion', 'Var', (23, 31))	('QKI', 'Gene', (112, 115))	('occurred', 'Reg', (32, 40))	('QKI', 'Gene', '9444', (112, 115))	('QKI', 'Gene', (52, 55))	('resulted in', 'Reg', (72, 83))	('QKI', 'Gene', '9444', (52, 55))
41328	24767714	Additionally, tumor 12-175 displayed CN-LOH for the short arm of chromosome 17 in ~35% of cells (Figure 3E; Supplementary Table 2).	('tumor', 'Disease', (14, 19))	('CN-LOH', 'Var', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('short arm', 'Phenotype', 'HP:0009824', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
41329	24767714	TP53 sequencing of tumor 12-175 yielded a heterozygous 2 bp deletion in exon 5 (c.547_548delTC), which is predicted to result in a truncated protein product (p.Ser183Argfs*2) (data not shown).	('c.547_548delTC', 'Var', (80, 94))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('p.Ser183Argfs*2', 'Mutation', 'p.S183RfsX2', (158, 173))	('c.547_548delTC', 'Mutation', 'c.547_548delTC', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('p.Ser183Argfs*2', 'Var', (158, 173))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('result in', 'Reg', (119, 128))	('tumor', 'Disease', (19, 24))
41334	24767714	A homozygous deletion of CDKN2A was observed in two LGGs: 10-286 and 12-229 (Figure 3F).	('deletion', 'Var', (13, 21))	('CDKN2A', 'Gene', '1029', (25, 31))	('CDKN2A', 'Gene', (25, 31))
41335	24767714	In tumor 10-286, the deletion was located within a region of mosaic CN-LOH, which was present in ~50% of cells.	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('deletion', 'Var', (21, 29))
41336	24767714	In addition, tumor 10-286 was from a patient with NF1 (see SNP array findings in LGGs in the setting of cancer predisposition syndromes) and displayed heterozygous deletions that included RB1 and TP53 (Figure 2; Supplementary Table 2).	('TP53', 'Gene', (196, 200))	('tumor', 'Disease', (13, 18))	('RB1', 'Gene', '5925', (188, 191))	('patient', 'Species', '9606', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NF1', 'Gene', (50, 53))	('deletions', 'Var', (164, 173))	('NF1', 'Gene', '4763', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('RB1', 'Gene', (188, 191))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('TP53', 'Gene', '7157', (196, 200))
41338	24767714	The risk of LGG, especially optic pathway glioma, is increased in patients with RASopathies, which is a group of genetic disorders associated with mutations in the RASMAPK signaling pathway genes.	('mutations', 'Var', (147, 156))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('RASopathies', 'Disease', (80, 91))	('genetic disorders', 'Disease', (113, 130))	('associated', 'Reg', (131, 141))	('optic pathway glioma', 'Phenotype', 'HP:0009734', (28, 48))	('LGG', 'Disease', (12, 15))	('RASopathies', 'Disease', 'None', (80, 91))	('genetic disorders', 'Disease', 'MESH:D030342', (113, 130))	('glioma', 'Disease', (42, 48))	('patients', 'Species', '9606', (66, 74))
41341	24767714	A germline mutation in NF1 was documented in the fourth patient (12-379) with clinical features of NF1 (data from an outside laboratory and not shown).	('germline mutation', 'Var', (2, 19))	('NF1', 'Gene', (23, 26))	('NF1', 'Gene', (99, 102))	('NF1', 'Gene', '4763', (23, 26))	('NF1', 'Gene', '4763', (99, 102))	('clinical', 'Species', '191496', (78, 86))	('patient', 'Species', '9606', (56, 63))
41343	24767714	We did not identify any additional BRAF alterations in the tumors from these patients, although BRAF fusions and mutations have been reported in gliomas from NF1 patients.	('patients', 'Species', '9606', (162, 170))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('NF1', 'Gene', (158, 161))	('tumors', 'Disease', (59, 65))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (113, 122))	('NF1', 'Gene', '4763', (158, 161))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('gliomas', 'Disease', (145, 152))
41350	24767714	In addition, RT-PCR to detect the presence of a BRAF fusion was performed on three tumors, 11-274, 11-326, and 12-058, which demonstrated variant deletions in 7q34.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('7q34', 'Gene', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (83, 89))	('variant deletions', 'Var', (138, 155))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
41354	24767714	Four of the mutations, which were identified in a PA (case 12-318), fibrillary astrocytoma (FA) (case 12-264), pleomorphic xanthoastrocytoma (PXA) (case 12-093), and an indeterminate subtype LGG (case 11-018), were missense substitutions that resulted in a BRAF V600E alteration.	('astrocytoma', 'Phenotype', 'HP:0009592', (129, 140))	('pleomorphic xanthoastrocytoma', 'Disease', (111, 140))	('resulted in', 'Reg', (243, 254))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('fibrillary astrocytoma', 'Disease', (68, 90))	('BRAF', 'Gene', (257, 261))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (111, 140))	('V600E', 'Mutation', 'rs113488022', (262, 267))	('V600E alteration', 'Var', (262, 278))	('fibrillary astrocytoma', 'Disease', 'MESH:D001254', (68, 90))
41355	24767714	The remaining BRAF mutation in our cohort was identified in a recurrent PA (case 12-222) and consisted of a three base pair insertion (c.1794_1796dupTAC), which is predicted to result in duplication of a threonine at position 599 (p.Thr599dup).	('c.1794_1796dupTAC', 'Var', (135, 152))	('threonine', 'Chemical', 'MESH:D013912', (204, 213))	('c.1794_1796dupTAC', 'Mutation', 'rs727502902', (135, 152))	('BRAF', 'Gene', (14, 18))	('p.Thr599dup', 'Mutation', 'p.599dup', (231, 242))	('duplication', 'MPA', (187, 198))
41357	24767714	The primary tumor, which corresponded to 12-222 (data not shown), demonstrated the same alteration, c.1794_1796dupTAC in BRAF exon 15.	('c.1794_1796dupTAC', 'Var', (100, 117))	('primary tumor', 'Disease', 'MESH:D009369', (4, 17))	('c.1794_1796dupTAC', 'Mutation', 'rs727502902', (100, 117))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('BRAF exon 15', 'Gene', (121, 133))	('primary tumor', 'Disease', (4, 17))
41360	24767714	Three of the four grade III gliomas (10-399B, 11-116, and 11-430) were characterized by whole chromosome gains (Supplementary Table 2).	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('10-399B', 'Var', (37, 44))	('II gliomas', 'Disease', (25, 35))	('II gliomas', 'Disease', 'MESH:D005910', (25, 35))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))
41365	24767714	In contrast, tumor 11-447, a GBM, displayed a homozygous deletion of CDKN2A in conjunction with a BRAF V600E mutation, but was otherwise relatively simple, suggesting that it arose from a lower grade tumor.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('CDKN2A', 'Gene', '1029', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('deletion', 'Var', (57, 65))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('CDKN2A', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
41366	24767714	Homozygous deletions of PTEN and RB1 were seen in tumor 13-023, as well as varying copy number gains of 1q, a finding noted previously in pediatric HGG.	('PTEN', 'Gene', '5728', (24, 28))	('copy number gains', 'Var', (83, 100))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('RB1', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('PTEN', 'Gene', (24, 28))	('RB1', 'Gene', '5925', (33, 36))
41367	24767714	The complexity of CNAs displayed by the recurrent HGGs (11-116, 11-238, and 12-320) was likely due to the radiation treatment for previous tumors.	('11-116', 'Var', (56, 62))	('CNAs', 'Disease', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
41369	24767714	No IDH1 mutations were found in exon 4, which was consistent with a previous report showing the lack of IDH1 mutations in pediatric HGG.	('IDH1', 'Gene', '3417', (104, 108))	('mutations', 'Var', (8, 17))	('IDH1', 'Gene', (3, 7))	('IDH1', 'Gene', (104, 108))	('IDH1', 'Gene', '3417', (3, 7))
41370	24767714	BRAF V600E mutations have been detected in 10% of pediatric HGGs, compared with 50% of non-PA grade I and grade II gliomas.	('detected', 'Reg', (31, 39))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('II gliomas', 'Disease', 'MESH:D005910', (112, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('V600E', 'Var', (5, 10))	('HGGs', 'Disease', (60, 64))	('BRAF', 'Gene', (0, 4))	('II gliomas', 'Disease', (112, 122))
41371	24767714	BRAF exon 15 screening yielded one of nine HGGs (case 11-447) that was positive for a BRAF V600E mutation (Supplementary Table 2).	('V600E', 'Var', (91, 96))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('BRAF', 'Gene', (86, 90))
41375	24767714	The two myxopapillary ependymomas, 12-015 and 12-217, displayed a variety of whole chromosome gains, including gains of 7, 9, 16, and 18, which is a pattern that is reportedly associated with myxopapillary ependymomas.	('myxopapillary ependymomas', 'Disease', 'MESH:D004806', (8, 33))	('ependymoma', 'Phenotype', 'HP:0002888', (22, 32))	('myxopapillary ependymomas', 'Disease', 'MESH:D004806', (192, 217))	('gains', 'Var', (111, 116))	('ependymoma', 'Phenotype', 'HP:0002888', (206, 216))	('myxopapillary ependymomas', 'Disease', (8, 33))	('myxopapillary ependymomas', 'Disease', (192, 217))
41377	24767714	SNP array analysis revealed approximately 118 Mb of the genome to be homozygous, as well as amplification of MYCN.	('amplification', 'Var', (92, 105))	('MYCN', 'Gene', '4613', (109, 113))	('MYCN', 'Gene', (109, 113))
41383	24767714	We observed two tumors (12-097 and 10-367) that demonstrated monosomy 6 on a background of relatively few other CNAs, which clearly placed these tumors into the WNT subgroup (Figure 5).	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('monosomy 6', 'Var', (61, 71))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
41384	24767714	Two additional tumors (12-381 and 12-310) also demonstrated monosomy 6 along with a variety of additional CNAs, which included whole chromosome gains for almost the entire genome in tumor 12-310 and gain of chromosome 19 in 12-381.	('additional tumors', 'Disease', 'MESH:D009369', (4, 21))	('monosomy', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (182, 187))	('gain', 'PosReg', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('additional tumors', 'Disease', (4, 21))	('gains', 'PosReg', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
41387	24767714	Thus, although these tumors had monosomy 6, we did not categorize them as WNT pathway tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('monosomy 6', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
41390	24767714	The extended ROH in this tumor could unmask a mutation on the remaining allele in the APC gene, which maps to 5q21q22.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('APC', 'Gene', (86, 89))	('APC', 'Gene', '324', (86, 89))	('mutation', 'Var', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
41391	24767714	APC mutations predispose individuals to both colon and brain tumors, especially in families with Turcot syndrome.	('brain tumor', 'Phenotype', 'HP:0030692', (55, 66))	('predispose', 'Reg', (14, 24))	('Turcot syndrome', 'Disease', 'MESH:C536928', (97, 112))	('APC', 'Gene', (0, 3))	('colon and brain tumors', 'Disease', 'MESH:D015179', (45, 67))	('APC', 'Gene', '324', (0, 3))	('brain tumors', 'Phenotype', 'HP:0030692', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Turcot syndrome', 'Disease', (97, 112))	('mutations', 'Var', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
41392	24767714	Specific APC mutations result in the protein being unable to sequester CTNNB1 in the cytoplasm, which may explain the nuclear localization that was observed in this tumor.	('APC', 'Gene', '324', (9, 12))	('unable', 'NegReg', (51, 57))	('sequester', 'MPA', (61, 70))	('CTNNB1', 'Gene', '1499', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('APC', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutations', 'Var', (13, 22))	('CTNNB1', 'Gene', (71, 77))	('tumor', 'Disease', (165, 170))
41396	24767714	Three tumors, 10-337, 10-375, and 12-225, demonstrated a heterozygous deletion of 9q (Supplementary Table 2; Figure 5), each of which included the PTCH gene.	('deletion', 'Var', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('PTCH', 'Gene', '5727', (147, 151))	('PTCH', 'Gene', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
41407	24767714	Tumor 13-060 also demonstrated numerous CNAs that are common in Group 3 and 4 tumors, including gain of 7, monosomy 8, deletion 11p, and gain of 18q; however, the presence of monosomy X and MYCN amplification distinguish this tumor as belonging to Group 4.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('gain', 'PosReg', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('monosomy 8', 'Var', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('gain', 'Var', (137, 141))	('MYCN', 'Gene', (190, 194))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('MYCN', 'Gene', '4613', (190, 194))	('deletion 11p', 'Var', (119, 131))	('tumor', 'Disease', (226, 231))
41416	24767714	Tumor 12-135 displayed a variety of CNAs that included heterozygous deletions of NF2 and CDKN2A, as well as a gain involving MYCN and ALK.	('NF2', 'Gene', '4771', (81, 84))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('deletions', 'Var', (68, 77))	('gain', 'PosReg', (110, 114))	('ALK', 'Gene', (134, 137))	('MYCN', 'Gene', (125, 129))	('CDKN2A', 'Gene', (89, 95))	('CNAs', 'Disease', (36, 40))	('MYCN', 'Gene', '4613', (125, 129))	('NF2', 'Gene', (81, 84))	('CDKN2A', 'Gene', '1029', (89, 95))	('ALK', 'Gene', '238', (134, 137))
41419	24767714	The remaining two meningiomas, 12-114 and 12-360, had numerous CNAs, including loss of chromosome 22q and NF2.	('meningiomas', 'Disease', 'MESH:D008577', (18, 29))	('meningioma', 'Phenotype', 'HP:0002858', (18, 28))	('meningiomas', 'Disease', (18, 29))	('loss', 'Var', (79, 83))	('NF2', 'Gene', '4771', (106, 109))	('meningiomas', 'Phenotype', 'HP:0002858', (18, 29))	('NF2', 'Gene', (106, 109))
41425	24767714	Although SNP array analysis did not detect any abnormalities, FISH analysis on touch imprints of this tumor demonstrated separation of the EWSR1 gene due to a translocation that is characteristic of Ewing sarcoma (Supplementary Tables 1 and 2).	('Ewing sarcoma', 'Disease', (199, 212))	('EWSR1', 'Gene', (139, 144))	('translocation', 'Var', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (199, 212))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (199, 212))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
41426	24767714	Overall, 62 of 101 tumors demonstrated alterations that helped to confirm the diagnosis, allowed for subclassification of tumor type, enabled prognostic assessment, and/or led to a recommendation to the treating physician for further genetic testing to rule out a germline mutation in a cancer predisposition gene.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('alterations', 'Var', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('germline mutation', 'Var', (264, 281))	('tumor', 'Disease', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('led to', 'Reg', (172, 178))	('tumor', 'Disease', (122, 127))
41429	24767714	Finally, recommendations for germline testing based on SNP array findings were made in nine cases to rule out a germline NF2, TP53, RB1, or PTEN alteration.	('TP53', 'Gene', (126, 130))	('RB1', 'Gene', (132, 135))	('NF2', 'Gene', (121, 124))	('RB1', 'Gene', '5925', (132, 135))	('NF2', 'Gene', '4771', (121, 124))	('alteration', 'Var', (145, 155))	('PTEN', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (126, 130))	('PTEN', 'Gene', '5728', (140, 144))
41441	24767714	In contrast, although we and others have identified a tandem duplication in 7q34 in the majority of PAs, it is now evident that this alteration is not specific for this subtype of LGG.	('PAs', 'Chemical', 'MESH:D011478', (100, 103))	('tandem duplication', 'Var', (54, 72))	('7q34', 'Gene', (76, 80))	('PAs', 'Disease', (100, 103))
41442	24767714	We identified a FAM131B-BRAF fusion in a DNT, whereas all prior FAM131B-BRAF fusions have been identified in PA and diffuse astrocytoma.	('FAM131B', 'Gene', '9715', (16, 23))	('FAM131B', 'Gene', '9715', (64, 71))	('astrocytoma', 'Disease', 'MESH:D001254', (124, 135))	('astrocytoma', 'Disease', (124, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('FAM131B', 'Gene', (16, 23))	('fusion', 'Var', (29, 35))	('FAM131B', 'Gene', (64, 71))
41445	24767714	TP53 mutations, which have been identified in both WNT and SHH MBs, have proven to be a poor prognostic indicator in the SHH MBs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('SHH', 'Gene', (59, 62))	('SHH', 'Gene', (121, 124))	('mutations', 'Var', (5, 14))	('MB', 'Phenotype', 'HP:0002885', (125, 127))	('MB', 'Phenotype', 'HP:0002885', (63, 65))	('SHH', 'Gene', '6469', (59, 62))	('SHH', 'Gene', '6469', (121, 124))
41447	24767714	MB patients with WNT pathway tumors, which are characterized by monosomy 6 and nuclear CTNNB1 staining, have the best prognosis, whereas tumors in the current MB consensus group 3 have the worst prognosis.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('WNT', 'Pathway', (17, 20))	('CTNNB1', 'Gene', '1499', (87, 93))	('MB', 'Phenotype', 'HP:0002885', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('MB', 'Phenotype', 'HP:0002885', (159, 161))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('patients', 'Species', '9606', (3, 11))	('CTNNB1', 'Gene', (87, 93))	('tumors', 'Disease', (29, 35))	('monosomy 6', 'Var', (64, 74))
41454	24767714	BRAF inhibitors targeted to the mutant V600E protein have shown efficacy in inhibition of mutant cells in vitro and in murine xenografts.	('inhibition', 'NegReg', (76, 86))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('V600E', 'Var', (39, 44))	('murine', 'Species', '10090', (119, 125))
41464	24767714	First, these tumors may arise as a result of sequential genetic alterations in different clones of cells.	('genetic alterations', 'Var', (56, 75))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', (13, 19))	('arise', 'Reg', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
41465	24767714	Second, although we do not yet know the clinical significance of the extra chromosomal gains, especially in tumors with the 7q34 duplication, it was interesting to note that similar chromosomes are often gained in grade III gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('II gliomas', 'Disease', 'MESH:D005910', (221, 231))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('clinical', 'Species', '191496', (40, 48))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('7q34 duplication', 'Var', (124, 140))	('II gliomas', 'Disease', (221, 231))
41467	24767714	One LGG in our study, case 12-175, demonstrated mosaic CN-LOH of 17p in approximately 35% of the tumor cells.	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mosaic CN-LOH of', 'Var', (48, 64))
41468	24767714	Sequencing of TP53 (located in 17p13.1) revealed a frameshift mutation in exon 5 in w38% of cells.	('frameshift mutation in', 'Var', (51, 73))	('TP53', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (14, 18))
41472	24767714	Similarly, several cases in our study demonstrated heterozygous or homozygous deletions of tumor suppressor genes that may predispose to cancer when inactivated in the germline, including TP53, PTEN, RB1, CDKN2A, NF1, and NF2.	('NF1', 'Gene', (213, 216))	('CDKN2A', 'Gene', '1029', (205, 211))	('cancer', 'Disease', (137, 143))	('RB1', 'Gene', '5925', (200, 203))	('predispose', 'Reg', (123, 133))	('tumor', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('NF2', 'Gene', '4771', (222, 225))	('PTEN', 'Gene', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP53', 'Gene', '7157', (188, 192))	('NF2', 'Gene', (222, 225))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('PTEN', 'Gene', '5728', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('deletions', 'Var', (78, 87))	('CDKN2A', 'Gene', (205, 211))	('RB1', 'Gene', (200, 203))	('NF1', 'Gene', '4763', (213, 216))	('TP53', 'Gene', (188, 192))
41477	24767714	Previous studies of CNAs in LGG suggest the mutual exclusivity of NF1 and BRAF MAPK pathway mutations, demonstrating that one hit in the pathway is sufficient for tumorigenesis; however, patients with NF1 have also reportedly demonstrated the presence of the KIAA1549-BRAF fusion, BRAF V600E mutation, or both the fusion and mutation.	('patients', 'Species', '9606', (187, 195))	('NF1', 'Gene', '4763', (201, 204))	('KIAA1549-BRAF', 'Disease', 'None', (259, 272))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (281, 285))	('NF1', 'Gene', (66, 69))	('tumor', 'Disease', (163, 168))	('KIAA1549-BRAF', 'Disease', (259, 272))	('NF1', 'Gene', '4763', (66, 69))	('V600E mutation', 'Var', (286, 300))	('NF1', 'Gene', (201, 204))	('V600E', 'Mutation', 'rs113488022', (286, 291))
41484	22473874	This phenotype is strikingly similar in Cnp heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106.	('mice', 'Species', '10090', (57, 61))	('rs2070106', 'Var', (131, 140))	('mental disease', 'Disease', 'MESH:D008607', (80, 94))	('SNP rs2070106', 'Var', (127, 140))	('rs2070106', 'Mutation', 'rs2070106', (131, 140))	('mental disease', 'Disease', (80, 94))	('patients', 'Species', '9606', (66, 74))
41485	22473874	The characteristic features in both species with their partial CNP 'loss-of-function' genotype are best described as 'catatonia-depression' syndrome.	('depression', 'Phenotype', 'HP:0000716', (128, 138))	("'catatonia-depression' syndrome", 'Disease', 'MESH:D000275', (117, 148))	("partial CNP 'loss-of-function", 'Var', (55, 84))	("'catatonia-depression' syndrome", 'Disease', (117, 148))
41496	22473874	Several genetic association studies have explored a potential impact of genetic variability in the CNP gene (chr17q21.2, 11Kb) on the overall risk for schizophrenia, with inconclusive results so far (Che et al,; Peirce et al,).	('schizophrenia', 'Phenotype', 'HP:0100753', (151, 164))	('genetic variability', 'Var', (72, 91))	('schizophrenia', 'Disease', 'MESH:D012559', (151, 164))	('schizophrenia', 'Disease', (151, 164))	('CNP gene', 'Gene', (99, 107))
41497	22473874	Interestingly, however, a synonymous (Gly/Gly) single nucleotide polymorphism (SNP), localized in the fourth exon of the gene (rs2070106), influences CNP expression in the human cortex, especially in frontal areas, with the rarer A-allele showing lower expression in comparison to the G-allele (Iwamoto et al,; Mitkus et al,; Peirce et al,).	('expression', 'MPA', (253, 263))	('CNP expression', 'MPA', (150, 164))	('rs2070106', 'Mutation', 'rs2070106', (127, 136))	('lower', 'NegReg', (247, 252))	('human', 'Species', '9606', (172, 177))	('Gly', 'Chemical', 'MESH:D005998', (38, 41))	('Gly', 'Chemical', 'MESH:D005998', (42, 45))	('influences', 'Reg', (139, 149))	('rs2070106', 'Var', (127, 136))
41501	22473874	We examined old Cnp+/- mice and schizophrenic patients with the AA versus GG genotype in the CNP SNP rs2070106.	('patients', 'Species', '9606', (46, 54))	('rs2070106', 'Var', (101, 110))	('schizophrenic', 'Disease', (32, 45))	('schizophrenic', 'Disease', 'MESH:D012559', (32, 45))	('rs2070106', 'Mutation', 'rs2070106', (101, 110))	('mice', 'Species', '10090', (23, 27))
41502	22473874	We report here the surprising association of CNP partial loss-of-function with a catatonia-depression syndrome both in mouse and man upon aging.	('mouse', 'Species', '10090', (119, 124))	('CNP', 'Gene', (45, 48))	('man', 'Species', '9606', (129, 132))	('catatonia-depression syndrome', 'Disease', 'MESH:D000275', (81, 110))	('partial', 'Var', (49, 56))	('depression', 'Phenotype', 'HP:0000716', (91, 101))	('catatonia-depression syndrome', 'Disease', (81, 110))
41504	22473874	In patients carrying the low-expression genotype (AA), a comparable process might be reflected by axonal loss in the frontal corpus callosum as detectable by neuroimaging.	('axonal loss', 'Disease', (98, 109))	('axonal loss', 'Disease', 'MESH:D012183', (98, 109))	('axonal loss', 'Phenotype', 'HP:0003447', (98, 109))	('low-expression', 'Var', (25, 39))	('patients', 'Species', '9606', (3, 11))
41507	22473874	Axonal swellings (spheroids) as readout of neurodegeneration were determined in corpus callosum, striatum and anterior commissure using amyloid precursor protein (APP) immunoreactivity (Fig 1I/J).	('1I/J', 'Var', (190, 194))	('amyloid precursor protein', 'Gene', '11820', (136, 161))	('amyloid precursor protein', 'Gene', (136, 161))	('neurodegeneration', 'Phenotype', 'HP:0002180', (43, 60))	('1I/J', 'SUBSTITUTION', 'None', (190, 194))	('neurodegeneration', 'Disease', (43, 60))	('neurodegeneration', 'Disease', 'MESH:D019636', (43, 60))
41508	22473874	Thereafter, an age-dependent increase in axonal swellings became evident, again more prominent in Cnp+/- mice (Fig 1I/J).	('axonal swellings', 'CPA', (41, 57))	('1I/J', 'Var', (115, 119))	('Cnp+/-', 'Var', (98, 104))	('increase', 'PosReg', (29, 37))	('1I/J', 'SUBSTITUTION', 'None', (115, 119))	('mice', 'Species', '10090', (105, 109))
41512	22473874	Taken together, old Cnp+/- mice show a more pronounced low-grade inflammatory phenotype with axonal degeneration compared to Wt mice.	('axonal degeneration', 'Disease', (93, 112))	('axonal degeneration', 'Disease', 'MESH:D009410', (93, 112))	('mice', 'Species', '10090', (27, 31))	('Cnp+/-', 'Var', (20, 26))	('mice', 'Species', '10090', (128, 132))	('low-grade inflammatory phenotype', 'MPA', (55, 87))	('axonal degeneration', 'Phenotype', 'HP:0040078', (93, 112))
41514	22473874	In the open field test, a measure for general locomotor activity and anxiety, Cnp+/- mice tended to spend less time in the centre than Wt (p = 0.096; Fig 2A).	('mice', 'Species', '10090', (85, 89))	('anxiety', 'Disease', (69, 76))	('Cnp+/-', 'Var', (78, 84))	('anxiety', 'Phenotype', 'HP:0000739', (69, 76))	('less', 'NegReg', (106, 110))	('anxiety', 'Disease', 'MESH:D001008', (69, 76))
41515	22473874	In the elevated plus maze, a classical anxiety test, open arm visits were reduced in Cnp+/- mice (p = 0.036; Fig 2D), whereas, the light/dark-box did not yield differences in the time spent in light (Fig 2E).	('elevated plus maze', 'CPA', (7, 25))	('anxiety', 'Disease', 'MESH:D001008', (39, 46))	('anxiety', 'Phenotype', 'HP:0000739', (39, 46))	('anxiety', 'Disease', (39, 46))	('reduced', 'NegReg', (74, 81))	('Cnp+/- mice', 'Var', (85, 96))	('open arm visits', 'CPA', (53, 68))	('mice', 'Species', '10090', (92, 96))
41517	22473874	Cnp+/- mice showed higher percentage of freezing in the fear conditioning chamber already at baseline, that is before measurement of conditioned or cued memory (p = 0.007; Fig 2F), precluding the use of fear conditioning for memory assessment in these mice.	('mice', 'Species', '10090', (252, 256))	('men', 'Species', '9606', (238, 241))	('men', 'Species', '9606', (125, 128))	('mice', 'Species', '10090', (7, 11))	('Cnp+/-', 'Var', (0, 6))	('freezing', 'MPA', (40, 48))
41520	22473874	To summarize, 24 months old Cnp+/- mice show normal overall motor performance and a mildly elevated anxiety profile in different anxiety-relevant tests compared to Wt mice.	('elevated', 'PosReg', (91, 99))	('anxiety', 'Disease', (100, 107))	('anxiety', 'Disease', 'MESH:D001008', (129, 136))	('anxiety', 'Phenotype', 'HP:0000739', (100, 107))	('man', 'Species', '9606', (72, 75))	('Cnp+/-', 'Var', (28, 34))	('mice', 'Species', '10090', (35, 39))	('anxiety', 'Disease', (129, 136))	('anxiety', 'Phenotype', 'HP:0000739', (129, 136))	('anxiety', 'Disease', 'MESH:D001008', (100, 107))	('mice', 'Species', '10090', (167, 171))	('motor performance', 'CPA', (60, 77))
41525	22473874	In the hole board test, measuring exploratory behaviour of mice, old Cnp+/- mice had significantly less head dips (p = 0.011; Fig 2L), indicating loss of interest (in the absence of any signs of altered basic motor activity).	('mice', 'Species', '10090', (59, 63))	('less', 'NegReg', (99, 103))	('head dips', 'CPA', (104, 113))	('mice', 'Species', '10090', (76, 80))	('Cnp+/-', 'Var', (69, 75))
41527	22473874	In the Morris water maze task, Cnp+/- mice displayed prominent floating behaviour, precluding analysis of this test for learning and memory.	('mice', 'Species', '10090', (38, 42))	('Morris water maze task', 'CPA', (7, 29))	('floating behaviour', 'CPA', (63, 81))	('Cnp+/-', 'Var', (31, 37))
41528	22473874	Analysis of the time mice spent floating within a swim trial of 90 s yielded threefold higher floating rates of Cnp+/- mice in comparison to Wt, which we interpret as a potential sign of depression (p = 0.016; Fig 2M).	('mice', 'Species', '10090', (119, 123))	('mice', 'Species', '10090', (21, 25))	('depression', 'Disease', 'MESH:D000275', (187, 197))	('depression', 'Phenotype', 'HP:0000716', (187, 197))	('floating rates', 'MPA', (94, 108))	('higher', 'PosReg', (87, 93))	('depression', 'Disease', (187, 197))	('Cnp+/- mice', 'Var', (112, 123))
41530	22473874	Fractionated analysis revealed that Cnp+/- mice had a higher duration of immobility in the second and last third of the test period compared to Wt (p = 0.025; Fig 2N), consistent with the typical 'give up' behaviour of depressed individuals.	('mice', 'Species', '10090', (43, 47))	('Cnp+/-', 'Var', (36, 42))	('higher', 'PosReg', (54, 60))	("'give up'", 'Disease', (196, 205))	('depressed', 'Disease', (219, 228))	('duration', 'MPA', (61, 69))	('depressed', 'Disease', 'MESH:D000275', (219, 228))
41537	22473874	Expectedly, the score was significantly higher in Cnp+/- (0.32 +- 0.44) than in Wt mice (-0.43 +- 0.41; p = 0.0001).	('Cnp+/-', 'Var', (50, 56))	('higher', 'PosReg', (40, 46))	('mice', 'Species', '10090', (83, 87))
41539	22473874	To search for potential behavioural consequences of a previously described CNP loss-of-function genotype in humans (Iwamoto et al,; Mitkus et al,; Peirce et al,), we conducted a phenotype-based genetic association study (PGAS) targeting the CNP SNP rs2070106 (A/G; Fig 3A) in >1000 schizophrenic patients of the Gottingen Research Association for Schizophrenia (GRAS) data collection (Begemann et al,; Ribbe et al,).	('schizophrenic', 'Disease', (282, 295))	('schizophrenic', 'Disease', 'MESH:D012559', (282, 295))	('rs2070106', 'Var', (249, 258))	('SNP', 'Gene', (245, 248))	('PGAS', 'Chemical', '-', (221, 225))	('Schizophrenia', 'Disease', (347, 360))	('Schizophrenia', 'Disease', 'MESH:D012559', (347, 360))	('man', 'Species', '9606', (110, 113))	('man', 'Species', '9606', (389, 392))	('Schizophrenia', 'Phenotype', 'HP:0100753', (347, 360))	('patients', 'Species', '9606', (296, 304))	('rs2070106', 'Mutation', 'rs2070106', (249, 258))	('humans', 'Species', '9606', (108, 114))
41552	22473874	We report here the unexpected finding that CNP loss-of-function genotypes are causative of a mental syndrome, consisting of catatonia, depression, mild anxiety/social withdrawal, impaired social interaction and reduced interest in the outside world, which is remarkably similar in mouse and man.	('impaired social interaction', 'Disease', (179, 206))	('depression', 'Disease', 'MESH:D000275', (135, 145))	('anxiety', 'Phenotype', 'HP:0000739', (152, 159))	('CNP', 'Gene', (43, 46))	('depression', 'Phenotype', 'HP:0000716', (135, 145))	('mental syndrome', 'Disease', (93, 108))	('anxiety', 'Disease', (152, 159))	('depression', 'Disease', (135, 145))	('impaired social interaction', 'Phenotype', 'HP:0000735', (179, 206))	('mouse', 'Species', '10090', (281, 286))	('genotypes', 'Var', (64, 73))	('catatonia', 'Disease', 'MESH:D002389', (124, 133))	('anxiety', 'Disease', 'MESH:D001008', (152, 159))	('loss-of-function', 'NegReg', (47, 63))	('catatonia', 'Disease', (124, 133))	('impaired social interaction', 'Disease', 'MESH:D000067404', (179, 206))	('man', 'Species', '9606', (291, 294))	('mental syndrome', 'Disease', 'MESH:D008607', (93, 108))	('reduced', 'NegReg', (211, 218))
41557	22473874	We expect that in individuals suffering from other mental disorders and even to some (perhaps mild) degree in healthy subjects, the phenotypical consequence of the CNP rs2070106 AA genotype will be comparable.	('rs2070106 AA', 'Var', (168, 180))	('mental disorders', 'Disease', 'MESH:D001523', (51, 67))	('mental disorders', 'Disease', (51, 67))	('rs2070106', 'Mutation', 'rs2070106', (168, 177))
41564	22473874	It will be interesting to determine whether depressed individuals that exhibit catatonic signs are also preferentially carriers of the CNP rs2070106 AA genotype.	('depressed', 'Disease', (44, 53))	('rs2070106 AA', 'Var', (139, 151))	('depressed', 'Disease', 'MESH:D000275', (44, 53))	('CNP', 'Gene', (135, 138))	('rs2070106', 'Mutation', 'rs2070106', (139, 148))
41566	22473874	The here observed Cnp+/- associated catalepsy/catatonia represents, therefore, the first clearly defined genetic catatonia model.	('catatonia', 'Disease', 'MESH:D002389', (46, 55))	('catatonia', 'Disease', (46, 55))	('catatonia', 'Disease', 'MESH:D002389', (113, 122))	('catalepsy/catatonia', 'Disease', 'MESH:D002375', (36, 55))	('catatonia', 'Disease', (113, 122))	('catalepsy/catatonia', 'Disease', (36, 55))	('Cnp+/-', 'Var', (18, 24))
41572	22473874	The CNP rs2070106 AA genotype leads to reduced expression of CNP (Mitkus et al,; Peirce et al,), constituting 'partial loss-of-function'.	('CNP', 'Gene', (4, 7))	('rs2070106 AA', 'Var', (8, 20))	('reduced', 'NegReg', (39, 46))	('rs2070106', 'Mutation', 'rs2070106', (8, 17))	('expression', 'MPA', (47, 57))
41578	22473874	Interestingly, low-grade inflammation has been found to be associated with behavioural consequences in mouse studies (Bercik et al,) and hypothesized to play a role in mental diseases (Gardner & Boles,; Monji et al,; Muller & Schwarz,; Schnieder & Dwork,).	('inflammation', 'Disease', (25, 37))	('mental diseases', 'Disease', (168, 183))	('role', 'Reg', (160, 164))	('play', 'Reg', (153, 157))	('mouse', 'Species', '10090', (103, 108))	('mental diseases', 'Disease', 'MESH:D008607', (168, 183))	('associated', 'Reg', (59, 69))	('low-grade', 'Var', (15, 24))	('inflammation', 'Disease', 'MESH:D007249', (25, 37))	('; Muller', 'Disease', (215, 223))
41580	22473874	To conclude, the major finding of the present study is the proof-of-principle that subtle changes of subcortical white matter can be the cause, rather than merely the consequence, of a complex neuropsychiatric syndrome.	('neuropsychiatric syndrome', 'Disease', 'MESH:D001523', (193, 218))	('psychiatric syndrome', 'Phenotype', 'HP:0000708', (198, 218))	('subcortical white matter', 'Disease', 'MESH:D056784', (101, 125))	('cause', 'Reg', (137, 142))	('neuropsychiatric syndrome', 'Disease', (193, 218))	('subcortical white matter', 'Disease', (101, 125))	('changes', 'Var', (90, 97))
41582	22473874	Our analysis was possible by building on genetic variants of the cell type-specific CNP gene that lead to a partial loss-of-function genotype in both mouse and man.	('man', 'Species', '9606', (160, 163))	('loss-of-function', 'NegReg', (116, 132))	('variants', 'Var', (49, 57))	('CNP', 'Gene', (84, 87))	('mouse', 'Species', '10090', (150, 155))
41583	22473874	Importantly, Cnp heterozygosity (in mice) and moderately reduced CNP expression levels (in humans) are well tolerated until an advanced age.	('CNP expression levels', 'MPA', (65, 86))	('humans', 'Species', '9606', (91, 97))	('Cnp heterozygosity', 'Var', (13, 31))	('mice', 'Species', '10090', (36, 40))	('reduced', 'NegReg', (57, 64))
41610	22473874	Primary antibodies were directed against APP (1:750, Chemicon (Millipore) Billerica, MA, USA), CD3 (1:150, Serotec, Oxford, UK), GFAP (1:200, Novocastra (Leica) Newcastle Upon Tyne, UK), IBA-1 (1:1000, Wako, Neuss, Germany) and Mac-3 (1:400, BD Pharmingen, Franklin Lakes, NJ, USA).	('Mac-3', 'Gene', '16784', (228, 233))	('Mac-3', 'Gene', (228, 233))	('GFAP', 'Gene', '14580', (129, 133))	('CD3', 'Gene', '12501', (95, 98))	('GFAP', 'Gene', (129, 133))	('IBA-1', 'Gene', (187, 192))	('1:400', 'Var', (235, 240))	('man', 'Species', '9606', (218, 221))	('1:1000', 'Var', (194, 200))	('IBA-1', 'Gene', '11629', (187, 192))	('CD3', 'Gene', (95, 98))	('1:200', 'Var', (135, 140))
41620	22473874	In the present translational approach, we report for the first time phenotypical consequences of moderate CNP 'loss-of-function' genotypes, that is genetic variants leading to decreased CNP expression, both in man (single nucleotide polymorphism rs2070106) and mouse (heterozygous Cnp null mutant mice).	("'loss-of-function'", 'NegReg', (110, 128))	('single nucleotide polymorphism rs2070106', 'Var', (215, 255))	('rs2070106', 'Mutation', 'rs2070106', (246, 255))	('mouse', 'Species', '10090', (261, 266))	('decreased', 'NegReg', (176, 185))	('man', 'Species', '9606', (210, 213))	('variants', 'Var', (156, 164))	('CNP', 'Gene', (186, 189))	('expression', 'MPA', (190, 200))	('mice', 'Species', '10090', (297, 301))	('CNP', 'Gene', (106, 109))
41621	22473874	This phenotype is strikingly similar between Cnp heterozygous mice and patients with mental disease, carrying the AA genotype at CNP SNP rs2070106.	('rs2070106', 'Mutation', 'rs2070106', (137, 146))	('patients', 'Species', '9606', (71, 79))	('mice', 'Species', '10090', (62, 66))	('mental disease', 'Disease', (85, 99))	('rs2070106', 'Var', (137, 146))	('mental disease', 'Disease', 'MESH:D008607', (85, 99))
41632	32906592	Therapeutically Significant MicroRNAs in Primary and Metastatic Brain Malignancies The overall survival of brain cancer patients remains grim, with conventional therapies such as chemotherapy and radiotherapy only providing marginal benefits to patient survival.	('brain cancer', 'Disease', (107, 119))	('MicroRNAs', 'Var', (28, 37))	('Brain Malignancies', 'Phenotype', 'HP:0030692', (64, 82))	('patient', 'Species', '9606', (120, 127))	('brain cancer', 'Disease', 'MESH:D001932', (107, 119))	('Primary and Metastatic Brain Malignancies', 'Disease', 'MESH:D001932', (41, 82))	('patients', 'Species', '9606', (120, 128))	('brain cancer', 'Phenotype', 'HP:0030692', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('patient', 'Species', '9606', (245, 252))
41646	32906592	This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis.	('miR-125b', 'Chemical', '-', (110, 118))	('miR-31', 'Gene', '407035', (75, 81))	('miR-143', 'Var', (101, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('miR-125b', 'Var', (110, 118))	('miR-19a', 'Gene', (92, 99))	('miR-328', 'Gene', '442901', (120, 127))	('miR-19a', 'Gene', '406979', (92, 99))	('glioblastoma', 'Disease', (164, 176))	('miR-210', 'Gene', '406992', (129, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('miR-451', 'Gene', '574411', (83, 90))	('miR-145', 'Gene', '406937', (66, 73))	('miR-210', 'Gene', (129, 136))	('miR-145', 'Gene', (66, 73))	('miR-31', 'Gene', (75, 81))	('miR-451', 'Gene', (83, 90))	('miR-146a', 'Var', (138, 146))	('miR-328', 'Gene', (120, 127))
41690	32906592	Deadenylation promotes subsequent mRNA decapping by the enzymes DCP1 and DCP2, which facilitates 5' to 3' degradation by the exoribonuclease Xrn1p.	('Xrn1p', 'Gene', (141, 146))	('DCP1', 'Gene', (64, 68))	('Deadenylation', 'Var', (0, 13))	('DCP2', 'Gene', (73, 77))	('DCP2', 'Gene', '167227', (73, 77))	('Xrn1p', 'Gene', '54464', (141, 146))	("5' to 3' degradation", 'MPA', (97, 117))	('facilitates', 'PosReg', (85, 96))	('DCP1', 'Gene', '196513', (64, 68))	('mRNA decapping', 'MPA', (34, 48))
41691	32906592	In slicer-independent silencing, multiple complementary sites with imperfect base-pairing create bulges in the RNA duplex, inhibiting the slicer activity of Ago2.	('Ago2', 'Gene', (157, 161))	('inhibiting', 'NegReg', (123, 133))	('imperfect', 'Var', (67, 76))	('slicer activity', 'MPA', (138, 153))	('silencing', 'Var', (22, 31))	('Ago2', 'Gene', '27161', (157, 161))
41699	32906592	Dysregulation of miRNA expression profiles has been associated in most, if not all tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (52, 62))	('tumors', 'Disease', (83, 89))	('miRNA expression profiles', 'MPA', (17, 42))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
41703	32906592	Generally, upregulated miRNAs in tumor cells are considered oncogenic miRNAs (oncomiRs), which can silence tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('silence tumor', 'Disease', 'MESH:D009369', (99, 112))	('miRNAs', 'Var', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('upregulated', 'PosReg', (11, 22))	('silence tumor', 'Disease', (99, 112))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
41704	32906592	Conversely, miRNAs which are often downregulated in cancers, can inhibit tumor progression and are termed tumor suppressor miRs.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miRNAs', 'Var', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('inhibit', 'NegReg', (65, 72))	('tumor', 'Disease', (106, 111))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
41706	32906592	miRNA signatures have not only been shown to be dysregulated in cancers; interestingly, restoration of these dysregulated miRNAs have also been shown to abrogate and even reverse the malignant phenotype of cancers.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('abrogate', 'NegReg', (153, 161))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('restoration', 'Var', (88, 99))	('cancers', 'Disease', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('malignant phenotype', 'CPA', (183, 202))	('reverse', 'NegReg', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('rat', 'Species', '10116', (93, 96))
41709	32906592	In line with recently published reports, the most important miRNAs implicated in the pathology of GBM and BrM are found to be miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126.	('miR-19a', 'Gene', '406979', (152, 159))	('miR-145', 'Gene', '406937', (126, 133))	('miR-328', 'Gene', (180, 187))	('miR-125b', 'Chemical', '-', (170, 178))	('miR-451', 'Gene', '574411', (143, 150))	('miR-210', 'Gene', '406992', (189, 196))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('miR-31', 'Gene', (135, 141))	('miR-126', 'Var', (212, 219))	('miR-19a', 'Gene', (152, 159))	('miR-145', 'Gene', (126, 133))	('miR-146a', 'Var', (198, 206))	('miR-125b', 'Var', (170, 178))	('miR-143', 'Var', (161, 168))	('miR-210', 'Gene', (189, 196))	('miR-451', 'Gene', (143, 150))	('miR-31', 'Gene', '407035', (135, 141))	('miR-328', 'Gene', '442901', (180, 187))
41712	32906592	Both increased and decreased expression of miRNAs such as miR-145, miR-31, miR-125b, and miR-146a were reported to contribute to poor survival of GBM patients.	('miR-31', 'Gene', '407035', (67, 73))	('miR-146a', 'Var', (89, 97))	('miR-125b', 'Var', (75, 83))	('poor', 'NegReg', (129, 133))	('survival', 'CPA', (134, 142))	('GBM', 'Disease', (146, 149))	('miR-125b', 'Chemical', '-', (75, 83))	('miR-31', 'Gene', (67, 73))	('patients', 'Species', '9606', (150, 158))	('miR-145', 'Gene', (58, 65))	('decreased', 'NegReg', (19, 28))	('miR-145', 'Gene', '406937', (58, 65))	('expression', 'MPA', (29, 39))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))
41713	32906592	In addition, low levels of miR-31, miR-126, and high levels of miR-328 shortened survival of BrM patients.	('miR-328', 'Gene', (63, 70))	('survival', 'CPA', (81, 89))	('miR-31', 'Gene', (27, 33))	('miR-328', 'Gene', '442901', (63, 70))	('miR-126', 'Var', (35, 42))	('BrM', 'Disease', (93, 96))	('miR-31', 'Gene', '407035', (27, 33))	('shortened', 'NegReg', (71, 80))	('patients', 'Species', '9606', (97, 105))
41775	32906592	By silencing FOXD2-AS1, cell cycle arrest and CDK1 downregulation were achieved in glioma cells.	('CDK1', 'Gene', (46, 50))	('glioma', 'Disease', (83, 89))	('silencing', 'Var', (3, 12))	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('CDK1', 'Gene', '983', (46, 50))	('AS1', 'Gene', '5729', (19, 22))	('AS1', 'Gene', (19, 22))	('FOXD2', 'Gene', (13, 18))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('arrest', 'Disease', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (24, 41))	('downregulation', 'NegReg', (51, 65))	('FOXD2', 'Gene', '2306', (13, 18))
41779	32906592	Silencing of LINC01116 reduced VEGFA expression and inhibited invasion, migration, angiogenesis, and induced cell cycle arrest of glioma cells both in vitro and in vivo.	('LINC01116', 'Gene', (13, 22))	('arrest of glioma', 'Disease', (120, 136))	('VEGFA', 'Gene', (31, 36))	('migration', 'CPA', (72, 81))	('rat', 'Species', '10116', (75, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('arrest of glioma', 'Disease', 'MESH:D006323', (120, 136))	('LINC01116', 'Gene', '375295', (13, 22))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('inhibited', 'NegReg', (52, 61))	('invasion', 'CPA', (62, 70))	('reduced', 'NegReg', (23, 30))	('expression', 'MPA', (37, 47))	('Silencing', 'Var', (0, 9))	('angiogenesis', 'CPA', (83, 95))	('induced', 'Reg', (101, 108))	('VEGFA', 'Gene', '7422', (31, 36))
41796	32906592	Another study revealed that increasing the expression of miR-451 using 2 -O-methyl (2 -OMe)-modified miR-451 mimics led to apoptosis, reduced viability, and invasion of GBM cells.	('GBM', 'Phenotype', 'HP:0012174', (169, 172))	('mimics', 'Var', (109, 115))	('miR-451', 'Gene', (101, 108))	('miR-451', 'Gene', '574411', (57, 64))	('viability', 'CPA', (142, 151))	('apoptosis', 'CPA', (123, 132))	('increasing', 'PosReg', (28, 38))	('miR-451', 'Gene', (57, 64))	('reduced', 'NegReg', (134, 141))	('expression', 'MPA', (43, 53))	('miR-451', 'Gene', '574411', (101, 108))	('invasion of GBM cells', 'CPA', (157, 178))	('2 -O-methyl (2 -OMe', 'Chemical', '-', (71, 90))
41812	32906592	This revealed that miR-19a is upregulated in glioma progression and inhibition of miR-19a reduced glioma cell proliferation.	('rat', 'Species', '10116', (117, 120))	('reduced', 'NegReg', (90, 97))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('upregulated', 'PosReg', (30, 41))	('miR-19a', 'Gene', '406979', (19, 26))	('inhibition', 'Var', (68, 78))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('miR-19a', 'Gene', '406979', (82, 89))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', (98, 104))	('miR-19a', 'Gene', (19, 26))	('glioma', 'Disease', (45, 51))	('miR-19a', 'Gene', (82, 89))
41816	32906592	Additionally, miR-19a/b inhibition leads to reduced expression of cyclin-D1, c-MYC, AKT1, and VEGF.	('c-MYC', 'Gene', '4609', (77, 82))	('VEGF', 'Gene', (94, 98))	('miR-19a/b', 'Gene', (14, 23))	('expression', 'MPA', (52, 62))	('cyclin-D1', 'Gene', '595', (66, 75))	('inhibition', 'Var', (24, 34))	('VEGF', 'Gene', '7422', (94, 98))	('reduced', 'NegReg', (44, 51))	('miR-19a/b', 'Gene', '406979', (14, 23))	('c-MYC', 'Gene', (77, 82))	('cyclin-D1', 'Gene', (66, 75))	('AKT1', 'Gene', '207', (84, 88))	('AKT1', 'Gene', (84, 88))
41839	32906592	Another study showed that overexpression of miR-143 reduced N-RAS expression, leading to inhibition of PI3K/AKT, extracellular signal-regulated kinase (ERK1/2) phosphorylation, and P65 accumulation in the nucleus.	('AKT', 'Gene', '207', (108, 111))	('reduced', 'NegReg', (52, 59))	('accumulation', 'PosReg', (185, 197))	('miR-143', 'Var', (44, 51))	('AKT', 'Gene', (108, 111))	('P65', 'Gene', '5970', (181, 184))	('expression', 'MPA', (66, 76))	('ERK1/2', 'Gene', (152, 158))	('N-RAS', 'Gene', (60, 65))	('inhibition', 'NegReg', (89, 99))	('P65', 'Gene', (181, 184))	('N-RAS', 'Gene', '4893', (60, 65))	('ERK1/2', 'Gene', '5595;5594', (152, 158))
41857	32906592	miR-125b directly binds and negatively regulates the Bcl-2 modifying factor (Bmf), thereby sensitizing these cells to apoptosis.	('apoptosis', 'CPA', (118, 127))	('regulates', 'Reg', (39, 48))	('Bcl-2 modifying factor', 'Gene', (53, 75))	('Bcl-2 modifying factor', 'Gene', '90427', (53, 75))	('binds', 'Interaction', (18, 23))	('miR-125b', 'Var', (0, 8))	('Bmf', 'Gene', '90427', (77, 80))	('Bmf', 'Gene', (77, 80))	('sensitizing', 'Reg', (91, 102))	('miR-125b', 'Chemical', '-', (0, 8))	('negatively', 'NegReg', (28, 38))
41861	32906592	In addition, combinatorial use of inhibitors for both miR-125b and PI3K resulted in inactivation of Wnt/beta-catenin signaling, by downregulation of Connexin43 (CX43).	('miR-125b', 'Var', (54, 62))	('CX43', 'Gene', (161, 165))	('beta-catenin', 'Gene', (104, 116))	('beta-catenin', 'Gene', '1499', (104, 116))	('Connexin43', 'Gene', '2697', (149, 159))	('miR-125b', 'Chemical', '-', (54, 62))	('Connexin43', 'Gene', (149, 159))	('CX43', 'Gene', '2697', (161, 165))	('inactivation', 'NegReg', (84, 96))	('downregulation', 'NegReg', (131, 145))	('PI3K', 'Var', (67, 71))
41865	32906592	reported that miR-125b mediated NF-kappaB activity by downregulating tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and NF-kappaB inhibitor interacting RAS-like 2 (NKIRAS2), resulting in TMZ resistance in GBM cells.	('GBM', 'Phenotype', 'HP:0012174', (214, 217))	('NKIRAS2', 'Gene', (173, 180))	('TMZ resistance', 'MPA', (196, 210))	('NF-kappaB inhibitor interacting RAS-like 2', 'Gene', '28511', (129, 171))	('resulting in', 'Reg', (183, 195))	('downregulating', 'NegReg', (54, 68))	('tumor necrosis factor alpha-induced protein 3', 'Gene', (69, 114))	('NKIRAS2', 'Gene', '28511', (173, 180))	('miR-125b', 'Chemical', '-', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('NF-kappaB', 'Gene', (32, 41))	('miR-125b', 'Var', (14, 22))	('NF-kappaB inhibitor interacting RAS-like 2', 'Gene', (129, 171))	('TMZ', 'Chemical', 'MESH:D000077204', (196, 199))	('NF-kappaB', 'Gene', '4790', (32, 41))	('tumor necrosis factor alpha-induced protein 3', 'Gene', '7128', (69, 114))	('NF-kappaB', 'Gene', (129, 138))	('TNFAIP3', 'Gene', '7128', (116, 123))	('NF-kappaB', 'Gene', '4790', (129, 138))	('TNFAIP3', 'Gene', (116, 123))
41867	32906592	reported that miR-125b correlates positively with the migration of CD133+ve GSCs, and miR-125b regulates the expression of matrix metalloproteins (MMP-2, MMP-9) and its inhibitors (RECK and TIMP3), modulating the invasiveness of CD133+ve GSCs.	('migration of CD133+ve GSCs', 'CPA', (54, 80))	('rat', 'Species', '10116', (57, 60))	('RECK', 'Gene', '8434', (181, 185))	('miR-125b', 'Chemical', '-', (14, 22))	('miR-125b', 'Chemical', '-', (86, 94))	('GSCs', 'Chemical', '-', (76, 80))	('invasiveness of CD133+ve GSCs', 'CPA', (213, 242))	('miR-125b', 'Var', (86, 94))	('MMP-9', 'Gene', '4318', (154, 159))	('MMP-2', 'Gene', '4313', (147, 152))	('modulating', 'Reg', (198, 208))	('MMP-9', 'Gene', (154, 159))	('TIMP3', 'Gene', '7078', (190, 195))	('TIMP3', 'Gene', (190, 195))	('expression', 'MPA', (109, 119))	('regulates', 'Reg', (95, 104))	('MMP-2', 'Gene', (147, 152))	('RECK', 'Gene', (181, 185))	('GSCs', 'Chemical', '-', (238, 242))
41868	32906592	stated that increased levels of MMP2, MMP9, and Ki-67 accompanied by increased expression of miR-125b in SU3 cells increased its invasiveness both in vitro and in vivo.	('miR-125b', 'Chemical', '-', (93, 101))	('MMP2', 'Gene', '4313', (32, 36))	('MMP9', 'Gene', '4318', (38, 42))	('increased', 'PosReg', (69, 78))	('expression', 'MPA', (79, 89))	('increased', 'PosReg', (115, 124))	('Ki-67', 'Var', (48, 53))	('invasiveness', 'CPA', (129, 141))	('miR-125b', 'Gene', (93, 101))	('MMP2', 'Gene', (32, 36))	('MMP9', 'Gene', (38, 42))
41880	32906592	In MGMT unmethylated GBM, miR-125b is reported to be associated with poor prognosis.	('MGMT', 'Gene', (3, 7))	('MGMT', 'Gene', '4255', (3, 7))	('miR-125b', 'Var', (26, 34))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('miR-125b', 'Chemical', '-', (26, 34))
41893	32906592	Microarray analysis of BrM and non-BrM NSCLCpatient samples revealed that miR-328 and miR-330-3p could potentially discriminate BrM and non-BrM NSCLC.	('NSCLC', 'Disease', (144, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('miR-328', 'Gene', '442901', (74, 81))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('miR-330-3p', 'Chemical', '-', (86, 96))	('miR-328', 'Gene', (74, 81))	('discriminate', 'Reg', (115, 127))	('BrM', 'Disease', (128, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('NSCLC', 'Disease', (39, 44))	('miR-330-3p', 'Var', (86, 96))
41905	32906592	In GBM, inhibition of miR-210 led to decreased proliferation, invasion, and increased apoptosis, possibly through targeting ROD1 and SIN3A.	('ROD1', 'Gene', (124, 128))	('proliferation', 'CPA', (47, 60))	('increased', 'PosReg', (76, 85))	('miR-210', 'Gene', (22, 29))	('rat', 'Species', '10116', (54, 57))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('ROD1', 'Gene', '9991', (124, 128))	('miR-210', 'Gene', '406992', (22, 29))	('SIN3A', 'Gene', '25942', (133, 138))	('invasion', 'CPA', (62, 70))	('inhibition', 'Var', (8, 18))	('SIN3A', 'Gene', (133, 138))	('decreased', 'NegReg', (37, 46))	('apoptosis', 'CPA', (86, 95))
41907	32906592	Inhibitors of miR-210 substantially increased ROD1 expression, resulting in apoptosis and cell proliferation inhibition.	('ROD1', 'Gene', (46, 50))	('ROD1', 'Gene', '9991', (46, 50))	('Inhibitors', 'Var', (0, 10))	('cell proliferation', 'CPA', (90, 108))	('increased', 'PosReg', (36, 45))	('expression', 'MPA', (51, 61))	('rat', 'Species', '10116', (102, 105))	('apoptosis', 'CPA', (76, 85))	('miR-210', 'Gene', (14, 21))	('miR-210', 'Gene', '406992', (14, 21))
41925	32906592	showed that rs2910164 polymorphism in precursor miR-146a resulted in reduced levels of mature miR-146a.	('levels of mature miR-146a', 'MPA', (77, 102))	('rs2910164', 'Var', (12, 21))	('reduced', 'NegReg', (69, 76))	('miR-146a', 'Gene', (48, 56))	('rs2910164', 'DBSNP_MENTION', 'None', (12, 21))
41927	32906592	Specifically, rs2910164 CC/GC genotypes were reported to be associated with increased risk of glioma in elderly people and the C allele with decreased survival of GBM patients.	('glioma', 'Disease', (94, 100))	('rs2910164', 'DBSNP_MENTION', 'None', (14, 23))	('patients', 'Species', '9606', (167, 175))	('decreased', 'NegReg', (141, 150))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('people', 'Species', '9606', (112, 118))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('rs2910164', 'Var', (14, 23))
41928	32906592	reported that rs2910164 CC genotype is linked to decreased survival of high-grade glioma patients with a gradual decrease in mature miR-146a expression.	('mature miR-146a expression', 'MPA', (125, 151))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('decrease', 'NegReg', (113, 121))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('rs2910164', 'DBSNP_MENTION', 'None', (14, 23))	('decreased', 'NegReg', (49, 58))	('patients', 'Species', '9606', (89, 97))	('glioma', 'Disease', (82, 88))	('rs2910164', 'Var', (14, 23))	('survival', 'MPA', (59, 67))
41931	32906592	Loss of miR-146a due to the rs2910164 polymorphism altered the Notch1/Notch2 ratio, leading to malignant transformation of GBM cells.	('altered', 'Reg', (51, 58))	('rat', 'Species', '10116', (77, 80))	('leading to', 'Reg', (84, 94))	('rs2910164', 'DBSNP_MENTION', 'None', (28, 37))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('Notch1', 'Gene', (63, 69))	('malignant transformation of GBM cells', 'CPA', (95, 132))	('Notch1', 'Gene', '4851', (63, 69))	('Loss', 'NegReg', (0, 4))	('miR-146a', 'Gene', (8, 16))	('Notch2', 'Gene', (70, 76))	('rs2910164', 'Var', (28, 37))	('Notch2', 'Gene', '4853', (70, 76))
41940	32906592	Additionally, miR-146a inhibits metastatic activity of BrM melanoma cells by upregulating beta-catenin and downregulating hnRNPC.	('BrM melanoma', 'Disease', (55, 67))	('upregulating', 'PosReg', (77, 89))	('miR-146a', 'Var', (14, 22))	('beta-catenin', 'Gene', (90, 102))	('hnRNPC', 'Gene', (122, 128))	('downregulating', 'NegReg', (107, 121))	('metastatic activity', 'CPA', (32, 51))	('hnRNPC', 'Gene', '3183', (122, 128))	('beta-catenin', 'Gene', '1499', (90, 102))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('BrM melanoma', 'Disease', 'MESH:D008545', (55, 67))	('inhibits', 'NegReg', (23, 31))
41949	32906592	IRS-1 is regulated by miR-126 through the PI3K/AKT signaling pathway.	('AKT', 'Gene', (47, 50))	('miR-126', 'Var', (22, 29))	('regulated', 'Reg', (9, 18))	('IRS-1', 'Gene', '25467', (0, 5))	('AKT', 'Gene', '207', (47, 50))	('IRS-1', 'Gene', (0, 5))
41957	32906592	revealed that miR-126 could potentially induce TMZ sensitivity and overcome resistance in GBM cells, by downregulating the expression of SOX2 (oncoprotein and associated with drug resistance in cancer) and Wnt/beta catenin signaling.	('cancer', 'Disease', (194, 200))	('expression', 'MPA', (123, 133))	('drug resistance', 'Phenotype', 'HP:0020174', (175, 190))	('TMZ sensitivity', 'MPA', (47, 62))	('overcome', 'MPA', (67, 75))	('downregulating', 'NegReg', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('beta catenin', 'Gene', (210, 222))	('SOX2', 'Gene', '6657', (137, 141))	('beta catenin', 'Gene', '1499', (210, 222))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('miR-126', 'Var', (14, 21))	('SOX2', 'Gene', (137, 141))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('induce', 'PosReg', (40, 46))
41960	32906592	This revealed that loss of miR-126 is associated with breast cancer relapse and metastasis.	('breast cancer', 'Disease', (54, 67))	('metastasis', 'CPA', (80, 90))	('associated', 'Reg', (38, 48))	('miR-126', 'Gene', (27, 34))	('loss', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
41973	32906592	Among the ten miRNAs discussed here, some of them are predominantly reported to be tumor suppressors (miR-145, miR-31, miR-451, miR-143, miR-146a, miR-126) and oncomiRs (miR-19a, miR-125b, miR-210).	('miR-145', 'Gene', '406937', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-19a', 'Gene', '406979', (170, 177))	('miR-210', 'Gene', '406992', (189, 196))	('miR-451', 'Gene', '574411', (119, 126))	('tumor', 'Disease', (83, 88))	('miR-31', 'Gene', (111, 117))	('miR-125b', 'Var', (179, 187))	('miR-126', 'Var', (147, 154))	('miR-19a', 'Gene', (170, 177))	('miR-145', 'Gene', (102, 109))	('miR-146a', 'Var', (137, 145))	('miR-451', 'Gene', (119, 126))	('miR-31', 'Gene', '407035', (111, 117))	('miR-125b', 'Chemical', '-', (179, 187))	('miR-210', 'Gene', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('miR-143', 'Var', (128, 135))
41974	32906592	Mimics of tumor suppressor miRNAs including miR-145, miR-31, miR-451, miR-143, miR-146a, and miR-126 could serve as potential therapeutic molecules for tackling primary and metastatic brain cancers.	('brain cancers', 'Disease', (184, 197))	('miR-146a', 'Var', (79, 87))	('miR-451', 'Gene', '574411', (61, 68))	('tumor', 'Disease', (10, 15))	('miR-145', 'Gene', '406937', (44, 51))	('brain cancers', 'Disease', 'MESH:D001932', (184, 197))	('miR-31', 'Gene', (53, 59))	('tackling', 'NegReg', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('brain cancer', 'Phenotype', 'HP:0030692', (184, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('miR-145', 'Gene', (44, 51))	('miR-451', 'Gene', (61, 68))	('miR-143', 'Var', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('miR-31', 'Gene', '407035', (53, 59))	('primary', 'Disease', (161, 168))	('miR-126', 'Var', (93, 100))
41975	32906592	In addition, antimiRs (or antagomiRs) of miR-19a, miR-125b, and miR-210 could be used to suppress glioblastoma progression and metastasis.	('glioblastoma', 'Disease', (98, 110))	('antimiRs', 'Var', (13, 21))	('miR-19a', 'Gene', (41, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('miR-125b', 'Chemical', '-', (50, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('miR-210', 'Gene', (64, 71))	('miR-210', 'Gene', '406992', (64, 71))	('miR-19a', 'Gene', '406979', (41, 48))	('suppress', 'NegReg', (89, 97))	('miR-125b', 'Var', (50, 58))	('metastasis', 'CPA', (127, 137))
41977	32906592	miRNAs such as miR-145, miR-31, miR-125b, and miR-126 could be considered as prognostic markers in GBM progression.	('miR-126', 'Var', (46, 53))	('miR-31', 'Gene', (24, 30))	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('miR-125b', 'Chemical', '-', (32, 40))	('miR-145', 'Gene', (15, 22))	('miR-145', 'Gene', '406937', (15, 22))	('miR-31', 'Gene', '407035', (24, 30))	('GBM', 'Disease', (99, 102))	('miR-125b', 'Var', (32, 40))
41981	32906592	Due to the complexity and number of miRNA interactions, and dysregulation of multiple pathways within cancers, it is unlikely that modulating the expression of a single miRNA will have a sustained effect on the overall phenotype.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('interactions', 'Interaction', (42, 54))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('dysregulation', 'Var', (60, 73))
41982	32906592	; writing:original draft preparation, A.A.B., L.M.L., S.C.; writing:review and editing, A.A.B., L.M.L., S.C., R.N.V.	('L.M.L.', 'Var', (96, 102))	('S.C.', 'Var', (104, 108))	('A.A.B.', 'Var', (88, 94))	('rat', 'Species', '10116', (30, 33))
41991	31386080	Median overall survival (OS) ranges from 5 to more than 15 years depending on tumor phenotype, isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion, tumor size, and spontaneous imaging growth rate.	('1p19q codeletion', 'Var', (139, 155))	('tumor', 'Disease', (157, 162))	('OS', 'Chemical', '-', (25, 27))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('isocitrate dehydrogenase', 'Gene', (95, 119))	('IDH', 'Gene', (121, 124))	('mutation', 'Var', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('isocitrate dehydrogenase', 'Gene', '3417', (95, 119))	('IDH', 'Gene', '3417', (121, 124))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
42007	31386080	Chemotherapy (TMZ or PCV) is started (after obtaining a histopathological diagnosis by biopsy) based on the following criteria in unresectable tumors: clinical parameters in 16/20 centers (80.0%), tumor volume in 10/20 (50.0%), growth kinetics in 12/20 (60.0%), contrast enhancement in 12/20 (60.0%), MRI multimodality parameters in 8/20 (40.0%), nuclear imaging parameters in 1/20 (5.0%), and 1p19q status in 5/20 (25.0%).	('TMZ', 'Chemical', 'MESH:D000077204', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('nuclear imaging', 'MPA', (347, 362))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('1p19q status', 'Var', (394, 406))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (197, 202))	('contrast enhancement', 'MPA', (262, 282))
42011	31386080	Molecular tumor markers influence the choice of starting an adjuvant treatment in a minority of centers, especially the IDH mutation in 2/20 (10.0%), the 1p19q codeletion in 2/20 (10.0%), and/or the MGMT promoter methylation in 2/20 (10.0%).	('MGMT', 'Gene', '4255', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('IDH', 'Gene', '3417', (120, 123))	('tumor', 'Disease', (10, 15))	('1p19q codeletion', 'Var', (154, 170))	('influence', 'Reg', (24, 33))	('mutation', 'Var', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('MGMT', 'Gene', (199, 203))	('IDH', 'Gene', (120, 123))
42013	31386080	In that case, the decision is influenced by the IDH mutation in 4/19 centers (21.1%), the 1p19q codeletion in 4/19 (21.1%), and/or the MGMT promoter methylation in 2/19 (10.5%).	('IDH', 'Gene', (48, 51))	('MGMT', 'Gene', (135, 139))	('IDH', 'Gene', '3417', (48, 51))	('MGMT', 'Gene', '4255', (135, 139))	('influenced', 'Reg', (30, 40))	('1p19q codeletion', 'Var', (90, 106))	('mutation', 'Var', (52, 60))
42014	31386080	The choice of the type of adjuvant treatment is influenced by the IDH mutation in 8/20 centers (40.0%), the 1p19q codeletion in 10/20 (50.0%), the MGMT promoter methylation in 3/20 (15.0%), and by none of these parameters in 8/20 centers (40.0%).	('IDH', 'Gene', (66, 69))	('influenced', 'Reg', (48, 58))	('IDH', 'Gene', '3417', (66, 69))	('MGMT', 'Gene', (147, 151))	('1p19q codeletion', 'Var', (108, 124))	('MGMT', 'Gene', '4255', (147, 151))
42018	31386080	PCV is preferentially used in case of 1p19q codeletion in 8/21 centers (38.1%), clinical progression (headache, neurological deficit, intractable epilepsy) in 5 (23.8%), contrast enhancement in 4 (19.0%), large tumor volume in 3 (14.3%), growth kinetics >6 mm per year in 3 (14.3%), young patients in 2 (9.5%), and/or based on nuclear imaging in 1 (4.8%).	('headache', 'Disease', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('epilepsy', 'Disease', 'MESH:D004827', (146, 154))	('headache', 'Phenotype', 'HP:0002315', (102, 110))	('epilepsy', 'Phenotype', 'HP:0001250', (146, 154))	('1p19q codeletion', 'Var', (38, 54))	('headache', 'Disease', 'MESH:D006261', (102, 110))	('neurological deficit', 'Disease', (112, 132))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('epilepsy', 'Disease', (146, 154))	('neurological deficit', 'Phenotype', 'HP:0000707', (112, 132))	('neurological deficit', 'Disease', 'MESH:D009461', (112, 132))	('patients', 'Species', '9606', (289, 297))
42046	31386080	The planned European Organization for Research and Treatment of Cancer (EORTC) I-WOT study comparing immediate adjuvant treatment ("treat") to follow-up ("wait") following resection in IDH-mutant, 1p19q-intact lower-grade glioma patients will provide new data regarding this question.	('patients', 'Species', '9606', (229, 237))	('Cancer', 'Disease', (64, 70))	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', '3417', (185, 188))	('1p19q-intact', 'Var', (197, 209))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('glioma', 'Disease', (222, 228))	('glioma', 'Disease', 'MESH:D005910', (222, 228))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
42061	31386080	Finally, the lack of comparative QOL data is a main issue, as well as the insufficiency of the neurocognitive assessment, which included only a MMSE with no prolonged follow-up.36 Of note, the interim results from the CATNON trial (EORTC 26053-22054) of RT with concurrent and adjuvant TMZ for 1p19q-intact anaplastic gliomas suggest an increased survival for patients receiving adjuvant TMZ.	('insufficiency', 'Disease', 'MESH:D000309', (74, 87))	('survival', 'MPA', (347, 355))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (307, 325))	('insufficiency', 'Disease', (74, 87))	('increased', 'PosReg', (337, 346))	('TMZ', 'Chemical', 'MESH:D000077204', (286, 289))	('anaplastic gliomas', 'Disease', (307, 325))	('1p19q-intact', 'Var', (294, 306))	('gliomas', 'Phenotype', 'HP:0009733', (318, 325))	('glioma', 'Phenotype', 'HP:0009733', (318, 324))	('patients', 'Species', '9606', (360, 368))	('TMZ', 'Chemical', 'MESH:D000077204', (388, 391))
42068	31386080	Secondly, the chemotherapy group is favored with 22.8% of patients having a 1p19q-codeleted tumor compared with 7.5% in the radiochemotherapy group (P < .001).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('patients', 'Species', '9606', (58, 66))	('1p19q-codeleted', 'Var', (76, 91))
42072	31386080	This limitation is all the more important given that, among patients with a known 1p19q status, 66.8% in the chemotherapy group had a codeleted tumor compared with 33.82% in the RT group.	('tumor', 'Disease', (144, 149))	('1p19q status', 'Var', (82, 94))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
42073	31386080	In our survey, the choice of the adjuvant treatment (chemotherapy vs RT vs combined treatment) is influenced by the IDH status in 40.0% of centers, the 1p19q status in 50.0%, and none of these parameters in 40%.	('IDH', 'Gene', '3417', (116, 119))	('IDH', 'Gene', (116, 119))	('influenced', 'Reg', (98, 108))	('1p19q status', 'Var', (152, 164))
42075	31386080	In the study by Ricard et al, 50% of 38 patients with a 1p19q-non-codeleted DLGG had a minor or partial response under TMZ, and 39.5% showed a stable disease.	('patients', 'Species', '9606', (40, 48))	('partial', 'NegReg', (96, 103))	('TMZ', 'Chemical', 'MESH:D000077204', (119, 122))	('1p19q-non-codeleted', 'Var', (56, 75))
42076	31386080	In another study of patients treated with TMZ in a "neoadjuvant" setting, the IDH and 1p19q status had no significant impact on the velocity of the MTD decrease.	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))	('1p19q', 'Var', (86, 91))	('patients', 'Species', '9606', (20, 28))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', '3417', (78, 81))
42079	31386080	In a series of 39 DLGG patients receiving TMZ, 92% experienced an initial decrease of the MTD, with a longer duration of response for patients with a 1p19q-codeleted tumor, confirming previous data.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('decrease', 'NegReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', (166, 171))	('1p19q-codeleted', 'Var', (150, 165))	('MTD', 'MPA', (90, 93))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))
42080	31386080	Of note, in a recent study of 120 IDH-mutant DLGGs included in the EORTC 22033 trial, a high MGMT methylation score was predictive of a benefit from TMZ treatment, regardless of 1p19q status.	('TMZ', 'Chemical', 'MESH:D000077204', (149, 152))	('high', 'Var', (88, 92))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('MGMT', 'Gene', '4255', (93, 97))	('MGMT', 'Gene', (93, 97))	('benefit', 'PosReg', (136, 143))
42082	31386080	The time to maximum tumor volume reduction is shorter with TMZ: median time to maximum response 12 months (range, 3-30 months) with TMZ, median time to maximal MTD decrease 40.8 months with PCV.	('tumor', 'Disease', (20, 25))	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TMZ', 'Var', (132, 135))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
42243	26098902	In other words, with the knowledge that the deaths were mostly due to tumor progression, the risk of treatment failure appeared to be higher for children less than 1 year old than for older children and did not improve over time.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('children', 'Species', '9606', (145, 153))	('tumor', 'Disease', (70, 75))	('treatment failure', 'Disease', (101, 118))	('children', 'Species', '9606', (190, 198))	('treatment failure', 'Disease', 'MESH:D016609', (101, 118))	('deaths', 'Disease', (44, 50))	('deaths', 'Disease', 'MESH:D003643', (44, 50))	('less than 1', 'Var', (154, 165))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
42287	24755548	Additionally, nearly all classical gliomas harbored EGFR amplifications.	('amplifications', 'Var', (57, 71))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('gliomas', 'Disease', (35, 42))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))
42311	24755548	Through analyzing, the percentage of IDH1 mutation is 73.9%, 43.1%, 22.0% and 22.6% for Proneural, Neural, Classical and Mesenchymal samples of all histological gliomas, respectively.	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('gliomas', 'Disease', (161, 168))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))
42313	24755548	In the present study, we first report that EGFR amplification is also enriched in Classical anaplastic glioma samples.	('Classical anaplastic glioma', 'Disease', 'MESH:D005910', (82, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('EGFR', 'Gene', '1956', (43, 47))	('Classical anaplastic glioma', 'Disease', (82, 109))	('EGFR', 'Gene', (43, 47))	('amplification', 'Var', (48, 61))
42314	24755548	As shown in Figure 5A, nearly all Classical gliomas harbored EGFR amplifications.	('amplifications', 'Var', (66, 80))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('Classical gliomas', 'Disease', (34, 51))	('EGFR', 'Gene', '1956', (61, 65))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('EGFR', 'Gene', (61, 65))	('Classical gliomas', 'Disease', 'MESH:D005910', (34, 51))
42315	24755548	The ROC curve showed that EGFR amplification is a potential diagnostic marker of Classical gliomas (ROC: AUC = 0.897, P<0.001;Figure 5B).	('EGFR', 'Gene', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('EGFR', 'Gene', '1956', (26, 30))	('Classical gliomas', 'Disease', (81, 98))	('amplification', 'Var', (31, 44))	('Classical gliomas', 'Disease', 'MESH:D005910', (81, 98))
42337	24755548	Additionally, EGFR amplification was enriched in Classical glioblastomas.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('amplification', 'Var', (19, 32))	('glioblastomas', 'Phenotype', 'HP:0012174', (59, 72))	('Classical glioblastomas', 'Disease', (49, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('Classical glioblastomas', 'Disease', 'MESH:D005909', (49, 72))
42338	24755548	In the present study, we found that nearly all Classical samples, including glioblastomas and anaplastic gliomas, harbored EGFR amplifications; also, Classical anaplastic gliomas had similar clinical outcomes to their glioblastoma counterparts and therefore should be treated more aggressively.	('EGFR', 'Gene', (123, 127))	('gliomas', 'Disease', (171, 178))	('amplifications', 'Var', (128, 142))	('glioblastomas', 'Phenotype', 'HP:0012174', (76, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('Classical anaplastic gliomas', 'Disease', 'MESH:D005910', (150, 178))	('Classical anaplastic gliomas', 'Disease', (150, 178))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('EGFR', 'Gene', '1956', (123, 127))	('glioblastoma', 'Disease', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma', 'Disease', (218, 230))	('glioblastomas', 'Disease', (76, 89))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('glioblastomas', 'Disease', 'MESH:D005909', (76, 89))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))
42347	24555482	On multivariate analysis the relative risk to die increased with a KPS <= 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age >= 40 by the factor 1.7.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('IV gliomas', 'Disease', (107, 117))	('IV gliomas', 'Disease', 'MESH:D005910', (107, 117))	('increased', 'PosReg', (50, 59))	('KPS <= 70', 'Var', (67, 76))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))
42349	24555482	Low KPS, age >= 40 and higher tumor grade have a negative impact on overall survival.	('Low KPS', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
42400	24555482	No tumor-specific therapy was initiated in 54.2% of patients with a KPS <= 70 compared to 8.1% of patients with a KPS > 70 (p<0.001).	('tumor', 'Disease', (3, 8))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('KPS <= 70', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('patients', 'Species', '9606', (52, 60))
42405	24555482	Karnofsky performance score at diagnosis was associated with prognosis: patients with a KPS > 70 had a median overall survival of 56.3 months whereas patients with a KPS <= 70 had a median overall survival of 4.8 months (p<0.001, Figure 1c), with an increased risk of death by factor 7.1.	('patients', 'Species', '9606', (150, 158))	('death', 'Disease', 'MESH:D003643', (268, 273))	('death', 'Disease', (268, 273))	('KPS > 70', 'Var', (88, 96))	('patients', 'Species', '9606', (72, 80))
42408	24555482	Karnofsky performance score <= 70 showed the strongest effect and increased the relative risk to die by factor 6.7, followed by therapy (radio-chemotherapy reduced the relative risc to die by factor 0.3 and external beam radiation by factor 0.4).	('risc', 'Gene', '59342', (177, 181))	('risc', 'Gene', (177, 181))	('<= 70', 'Var', (28, 33))
42412	24555482	In multivariate analysis KPS <= 70, higher tumor grade and age >= 40 were negative prognostic factors, whereas radiation therapy or radio-chemotherapy improved prognosis.	('negative', 'NegReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('KPS <= 70', 'Var', (25, 34))
42459	24555482	Cornerstone of therapy remains radiation and alternative strategies like interstitial radiosurgery, chemotherapy or antiangiogenic drugs need to be further explored, ideally in the context of molecular profiling for common alterations such as 1p/19q codeletion, MGMT promoter methylation and IDH mutation.	('MGMT', 'Gene', (262, 266))	('IDH', 'Gene', (292, 295))	('MGMT', 'Gene', '4255', (262, 266))	('IDH', 'Gene', '3417', (292, 295))	('1p/19q codeletion', 'Var', (243, 260))
42484	22621614	The hypothesis of the study was that the contrast between tumour and normal tissue is higher in the ultrasound strain images than in the ultrasound B-mode images.	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('higher', 'PosReg', (86, 92))	('contrast', 'MPA', (41, 49))	('ultrasound strain', 'Var', (100, 117))
42506	22621614	For the subgroup of patients with high-grade gliomas the contrast in the strain images were significantly higher than the contrast in the B-mode images (P < 0.0001), and the same was observed for the subgroup with low-grade gliomas (P < 0.0001).	('gliomas', 'Disease', (224, 231))	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('strain', 'MPA', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('higher', 'PosReg', (106, 112))	('contrast', 'MPA', (57, 65))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('patients', 'Species', '9606', (20, 28))	('high-grade', 'Var', (34, 44))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Disease', 'MESH:D005910', (224, 231))	('gliomas', 'Disease', (45, 52))
42534	33195415	However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated.	('malignant tumors', 'Disease', (61, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (61, 77))	('ACE2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant', 'Var', (33, 41))	('ACE2', 'Gene', '59272', (42, 46))
42547	33195415	GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors.	('hyperactivated', 'PosReg', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('expression', 'MPA', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('GSEA', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ACE2', 'Gene', '59272', (63, 67))	('tumors', 'Disease', (218, 224))	('cancer', 'Disease', (101, 107))	('ACE2', 'Gene', '59272', (188, 192))	('ACE2', 'Gene', (63, 67))	('immune-related pathways', 'Pathway', (132, 155))	('ACE2', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
42582	33195415	Neoantigen is a neonatal antigen that is encoded by a mutant gene of a tumor cell.	('mutant', 'Var', (54, 60))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
42584	33195415	Neoantigen vaccines can be developed using the immune activity of tumor neoantigens, according to a specific mutation in the tumor cells, then administered to patients to achieve the required therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (159, 167))	('mutation', 'Var', (109, 117))
42587	33195415	The Tumor Mutational Burden (TMB) is usually measured by the number of somatic mutations that occur within an average of 1 Mb in the coding region (exon region) of the tumor cell genome (non-synonymous mutations).	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('TMB', 'Chemical', '-', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mutations', 'Var', (79, 88))
42591	33195415	Microsatellite Instability (MSI) refers to any change in the length of a microsatellite due to the insertion or deletion of a repeating unit in a tumor compared to normal tissue.	('change', 'Reg', (47, 53))	('S', 'Gene', '43740568', (29, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('length', 'MPA', (61, 67))	('insertion', 'Var', (99, 108))	('deletion', 'Var', (112, 120))	('tumor', 'Disease', (146, 151))	('Microsatellite Instability', 'Disease', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
42597	33195415	We visualized the tumor with the most ACE2 mutations using an R data package, maftools.	('tumor', 'Disease', (18, 23))	('ACE2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('ACE2', 'Gene', '59272', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
42598	33195415	Therefore, TCGA expression profiling was used to evaluate the relationship between ACE2 and five MMRs genes: MLH1, MSH2, MSH6, PMS2, and EPCAM mutations.	('PMS2', 'Gene', (127, 131))	('MLH1', 'Gene', '4292', (109, 113))	('MLH1', 'Gene', (109, 113))	('MSH6', 'Gene', (121, 125))	('PMS2', 'Gene', '5395', (127, 131))	('MMRs genes', 'Gene', (97, 107))	('ACE2', 'Gene', (83, 87))	('EPCAM', 'Gene', (137, 142))	('MSH6', 'Gene', '2956', (121, 125))	('MSH2', 'Gene', (115, 119))	('ACE2', 'Gene', '59272', (83, 87))	('MSH2', 'Gene', '4436', (115, 119))	('EPCAM', 'Gene', '4072', (137, 142))	('mutations', 'Var', (143, 152))
42657	33195415	A schematic diagram of the tumor with the highest number of mutations is shown in Figure 12.	('tumor', 'Disease', (27, 32))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
42658	33195415	Notably, ACE2 mutations were only observed in BLCA, BRCA, COAD, HNSC, LAML, LGG, LUAD, LUSC, OV, SKCM, STAD, and UCEC.	('S', 'Gene', '43740568', (66, 67))	('S', 'Gene', '43740568', (97, 98))	('S', 'Gene', '43740568', (103, 104))	('ACE2', 'Gene', '59272', (9, 13))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('COAD', 'Disease', (58, 62))	('S', 'Gene', '43740568', (89, 90))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (14, 23))	('ACE2', 'Gene', (9, 13))
42659	33195415	These findings indicate that ACE2 mutations seldom occur in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ACE2', 'Gene', '59272', (29, 33))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (34, 43))	('ACE2', 'Gene', (29, 33))
42664	33195415	DNA hypermethylation in the promoter region of a tumor suppressor gene leads to gene silencing, which in turn leads to dysregulation of multiple signaling pathways associated with human malignancy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('multiple signaling pathways', 'Pathway', (136, 163))	('gene', 'MPA', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('leads to', 'Reg', (110, 118))	('human', 'Species', '9606', (180, 185))	('tumor', 'Disease', (49, 54))	('dysregulation', 'MPA', (119, 132))	('malignancy', 'Disease', (186, 196))	('hypermethylation', 'Var', (4, 20))
42704	33195415	It has been demonstrated that overexpressed ACE2 may inhibit cell growth and vascular endothelial growth factor production in lung cancer, breast cancer, colon cancer, and pancreatic cancer.	('ACE2', 'Gene', '59272', (44, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ACE2', 'Gene', (44, 48))	('inhibit', 'NegReg', (53, 60))	('vascular endothelial growth factor', 'Gene', '7422', (77, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('lung cancer', 'Disease', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('vascular endothelial growth factor', 'Gene', (77, 111))	('pancreatic cancer', 'Disease', (172, 189))	('cell growth', 'CPA', (61, 72))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('overexpressed', 'Var', (30, 43))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
42705	33195415	On the other hand, overexpressed ACE2 may promote the migration and invasion of human renal carcinoma cells.	('ACE2', 'Gene', '59272', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('migration', 'CPA', (54, 63))	('overexpressed', 'Var', (19, 32))	('promote', 'PosReg', (42, 49))	('human', 'Species', '9606', (80, 85))	('renal carcinoma', 'Disease', (86, 101))	('ACE2', 'Gene', (33, 37))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))
42714	33195415	ACE2 expression also has a significantly positive correlation with the infiltrating levels of dendritic cells, macrophages M0, mast cells resting, and neutrophils in multiple cancers.	('ACE2', 'Gene', (0, 4))	('multiple cancers', 'Disease', (166, 182))	('expression', 'Var', (5, 15))	('infiltrating levels of dendritic cells', 'MPA', (71, 109))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ACE2', 'Gene', '59272', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (166, 182))	('positive correlation', 'Reg', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
42718	33195415	We found that increased ACE2 expression correlates with immune infiltration levels in most tumors and that higher ACE2 expression was related to immune neoantigen, TMB, and microsatellite instability.	('tumors', 'Disease', (91, 97))	('increased', 'PosReg', (14, 23))	('expression', 'MPA', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('TMB', 'Chemical', '-', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('ACE2', 'Gene', '59272', (114, 118))	('related', 'Reg', (134, 141))	('ACE2', 'Gene', (24, 28))	('microsatellite instability', 'Var', (173, 199))	('expression', 'MPA', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ACE2', 'Gene', '59272', (24, 28))	('higher', 'PosReg', (107, 113))	('ACE2', 'Gene', (114, 118))	('immune infiltration levels', 'MPA', (56, 82))
42815	33889755	Integrating TEAD4 CNV increase, IDH mutations, TP53 mutation, ATRX mutation and 1p19q co-deletion would separate patients with LGG into four groups with significant differences in prognosis.	('LGG', 'Disease', (127, 130))	('mutation', 'Var', (67, 75))	('patients', 'Species', '9606', (113, 121))	('TEAD4', 'Gene', '7004', (12, 17))	('ATRX', 'Gene', (62, 66))	('TEAD4', 'Gene', (12, 17))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('TP53', 'Gene', '7157', (47, 51))	('mutation', 'Var', (52, 60))	('1p19q co-deletion', 'Var', (80, 97))	('ATRX', 'Gene', '546', (62, 66))	('TP53', 'Gene', (47, 51))
42816	33889755	These study results suggested that TEAD4 variations were independent predictive biomarkers for the prognosis in patients with LGG with IDH mutation.	('TEAD4', 'Gene', '7004', (35, 40))	('LGG', 'Disease', (126, 129))	('mutation', 'Var', (139, 147))	('TEAD4', 'Gene', (35, 40))	('variations', 'Var', (41, 51))	('patients', 'Species', '9606', (112, 120))	('IDH', 'Gene', (135, 138))	('IDH', 'Gene', '3417', (135, 138))
42820	33889755	Majority of the patients with LGGs are sensitive to therapy and experience extended survival depending on the molecular subtype, such as IDH mutant and 1p19q co-deletion.	('IDH', 'Gene', '3417', (137, 140))	('patients', 'Species', '9606', (16, 24))	('1p19q co-deletion', 'Var', (152, 169))	('IDH', 'Gene', (137, 140))	('LGGs', 'Disease', (30, 34))
42838	33889755	Data of isocitrate dehydrogenase (IDH) mutations, 1p19q co-deletion status, gene expression and clinical phenotypes in CGGA-mRNAseq_693 were derived from the CGGA database (http://www.cgga.org.cn/).	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))	('mutations', 'Var', (39, 48))
42840	33889755	In this study, Kaplan-Meier (KM) analysis was used to perform univariate survival analysis to determine the effects of TEAD mutations, CNV and gene expression on the overall survival (OS) or disease-free survival (DFS) in patients with LGG.	('disease-free', 'MPA', (191, 203))	('mutations', 'Var', (124, 133))	('CNV', 'Gene', (135, 138))	('patients', 'Species', '9606', (222, 230))	('LGG', 'Disease', (236, 239))
42841	33889755	The candidate covariates contained IDH mutation, TP53 mutation, ATRX mutation, 1p19q co-deletion, tumor grade and age.	('ATRX', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (49, 53))	('IDH', 'Gene', (35, 38))	('TP53', 'Gene', (49, 53))	('ATRX', 'Gene', '546', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('1p19q co-deletion', 'Var', (79, 96))	('IDH', 'Gene', '3417', (35, 38))	('mutation', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
42844	33889755	We conducted coexpression analysis in carriers of IDH mutation and wild-type patients in both TCGA-LGG and CGGA-mRNAseq_693 LGG data sets.	('mutation', 'Var', (54, 62))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))	('patients', 'Species', '9606', (77, 85))
42857	33889755	TCGA data set showed that the incidence of somatic mutations in TEADs in gliomas was extremely low, as only 0.3% (3/812) of the patients was carrying the mutations.	('TEADs', 'Gene', (64, 69))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('mutations', 'Var', (51, 60))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('patients', 'Species', '9606', (128, 136))	('gliomas', 'Disease', (73, 80))
42869	33889755	Backward stepwise cox regression analysis selected 1p19q co-deletion, TP53 mutation, tumor grade and age as the covariates for OS; and IDH mutation, 1p19q co-deletion and age as the covariates for DFS.	('tumor', 'Disease', (85, 90))	('TP53', 'Gene', '7157', (70, 74))	('OS', 'Disease', (127, 129))	('TP53', 'Gene', (70, 74))	('IDH', 'Gene', (135, 138))	('1p19q co-deletion', 'Var', (51, 68))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('IDH', 'Gene', '3417', (135, 138))	('1p19q', 'Var', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
42872	33889755	Integrated analysis of TEAD4 CNV increase, IDH mutations, TP53 mutation, ATRX mutation and 1p19q co-deletion showed that the patients with LGG would divide into four groups with different prognosis.	('IDH', 'Gene', '3417', (43, 46))	('mutation', 'Var', (78, 86))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('TEAD4', 'Gene', '7004', (23, 28))	('mutations', 'Var', (47, 56))	('mutation', 'Var', (63, 71))	('TEAD4', 'Gene', (23, 28))	('ATRX', 'Gene', (73, 77))	('IDH', 'Gene', (43, 46))	('ATRX', 'Gene', '546', (73, 77))	('patients', 'Species', '9606', (125, 133))
42873	33889755	Group 1 (n = 167) included the patients with both IDH mutation and 1p19q co-deletion, and they had the best outcomes.	('patients', 'Species', '9606', (31, 39))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))	('1p19q co-deletion', 'Var', (67, 84))
42874	33889755	Group 2 (n = 203) included the patients with IDH mutation but without either TEAD4 CNV increase or 1p19q co-deletion, and their outcomes were only second to group 1.	('1p19q', 'Var', (99, 104))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', '3417', (45, 48))	('TEAD4', 'Gene', '7004', (77, 82))	('mutation', 'Var', (49, 57))	('patients', 'Species', '9606', (31, 39))	('TEAD4', 'Gene', (77, 82))
42875	33889755	Most of the group 2 patients carried TP53 mutation and/or ATRX mutation, and only two patients had neither TP53 mutation nor ATRX mutation.	('ATRX', 'Gene', '546', (125, 129))	('TP53', 'Gene', '7157', (107, 111))	('ATRX', 'Gene', (58, 62))	('TP53', 'Gene', (107, 111))	('mutation', 'Var', (63, 71))	('ATRX', 'Gene', (125, 129))	('patients', 'Species', '9606', (20, 28))	('TP53', 'Gene', '7157', (37, 41))	('ATRX', 'Gene', '546', (58, 62))	('TP53', 'Gene', (37, 41))	('patients', 'Species', '9606', (86, 94))
42879	33889755	To find the reasons for the diverse clinical effects of TEAD4 CNV increase on LGG and GBM, we conducted a series of explorations, including mutation co-occurrence analysis.	('TEAD4', 'Gene', '7004', (56, 61))	('increase', 'PosReg', (66, 74))	('TEAD4', 'Gene', (56, 61))	('CNV', 'Var', (62, 65))	('LGG', 'Disease', (78, 81))
42880	33889755	Results showed that TEAD4 CNV increase and TP53 mutations were significantly mutually exclusive in GBM, while it was opposite in LGG (Figure 3).	('TEAD4', 'Gene', '7004', (20, 25))	('GBM', 'Disease', (99, 102))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('TEAD4', 'Gene', (20, 25))	('mutations', 'Var', (48, 57))
42881	33889755	In addition, TEAD4 CNV increase and 1p19q co-deletion were significantly mutually exclusive in LGG, while this phenomenon did not occur in GBM.	('1p19q co-deletion', 'Var', (36, 53))	('TEAD4', 'Gene', '7004', (13, 18))	('increase', 'PosReg', (23, 31))	('LGG', 'Disease', (95, 98))	('TEAD4', 'Gene', (13, 18))
42882	33889755	Moreover, 28/29 TEAD4 CNV increase carriers simultaneously had IDH mutation in LGG, while only 1/9 TEAD4 CNV increase carriers had IDH mutation in GBM.	('mutation', 'Var', (67, 75))	('IDH', 'Gene', (63, 66))	('TEAD4', 'Gene', '7004', (16, 21))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (131, 134))	('TEAD4', 'Gene', (16, 21))	('TEAD4', 'Gene', '7004', (99, 104))	('IDH', 'Gene', '3417', (131, 134))	('TEAD4', 'Gene', (99, 104))	('increase', 'PosReg', (26, 34))	('LGG', 'Gene', (79, 82))
42883	33889755	Differential expression analysis showed that carriers with TEAD4 CNV increase had a higher TEAD4 expression level than the normal TEAD4 copy number carriers (LGG p = 8.27 x 10-7; GBM p = 0.004) (Figure 4a and b; FPKM means the expression data were normalized by FPKM method; and RMA means the expression data were normalized by RMA method).	('increase', 'PosReg', (69, 77))	('higher', 'PosReg', (84, 90))	('expression level', 'MPA', (97, 113))	('TEAD4', 'Gene', '7004', (91, 96))	('CNV', 'Var', (65, 68))	('TEAD4', 'Gene', '7004', (130, 135))	('TEAD4', 'Gene', '7004', (59, 64))	('TEAD4', 'Gene', (130, 135))	('TEAD4', 'Gene', (59, 64))	('TEAD4', 'Gene', (91, 96))
42886	33889755	We found that the expression of TEAD4 was significantly downregulated in both TCGA-LGG and CGGA-mRNAseq_693 LGG cohorts when 1p19q co-deletion occurred (Figure 4c and d).	('TEAD4', 'Gene', '7004', (32, 37))	('TEAD4', 'Gene', (32, 37))	('downregulated', 'NegReg', (56, 69))	('expression', 'MPA', (18, 28))	('1p19q co-deletion', 'Var', (125, 142))
42888	33889755	In addition, the expression of TEAD4 was also found to be significantly upregulated in TP53 mutation or ATRX mutation carriers in TCGA-LGG (Figure A2).	('TP53', 'Gene', '7157', (87, 91))	('TEAD4', 'Gene', '7004', (31, 36))	('mutation', 'Var', (92, 100))	('TEAD4', 'Gene', (31, 36))	('ATRX', 'Gene', (104, 108))	('expression', 'MPA', (17, 27))	('TP53', 'Gene', (87, 91))	('upregulated', 'PosReg', (72, 83))	('ATRX', 'Gene', '546', (104, 108))	('mutation', 'Var', (109, 117))
42892	33889755	Similarly, the median DFS time was markedly shorter in patients with high TEAD4 expression than the low TEAD4 expression group (41.060 months vs 72.170 months; p = 0.022, HR = 1.431, 95% CI: 1.050-1.949).	('TEAD4', 'Gene', '7004', (104, 109))	('TEAD4', 'Gene', '7004', (74, 79))	('TEAD4', 'Gene', (104, 109))	('DFS time', 'MPA', (22, 30))	('TEAD4', 'Gene', (74, 79))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (55, 63))	('shorter', 'NegReg', (44, 51))
42896	33889755	Based on stratified survival analysis of TEAD4 expression according to IDH mutation status, we found that TEAD4 expression significantly affected the OS in patients with LGG carrying IDH mutants after adjusting for covariates.	('patients', 'Species', '9606', (156, 164))	('TEAD4', 'Gene', '7004', (41, 46))	('affected', 'Reg', (137, 145))	('TEAD4', 'Gene', (41, 46))	('IDH', 'Gene', (183, 186))	('TEAD4', 'Gene', '7004', (106, 111))	('mutants', 'Var', (187, 194))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (183, 186))	('IDH', 'Gene', '3417', (71, 74))	('TEAD4', 'Gene', (106, 111))
42898	33889755	The results suggested that TEAD4 expression might be an independent predictor of prognosis for patients with LGG carrying IDH mutation, and the TEAD4 gene function might have a synergistic effect with the IDH mutation.	('TEAD4', 'Gene', (144, 149))	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('TEAD4', 'Gene', (27, 32))	('patients', 'Species', '9606', (95, 103))	('mutation', 'Var', (126, 134))	('IDH', 'Gene', (205, 208))	('IDH', 'Gene', '3417', (205, 208))	('TEAD4', 'Gene', '7004', (27, 32))	('TEAD4', 'Gene', '7004', (144, 149))
42904	33889755	The same results were found in patients with TCGA-LGG carrying IDH mutation.	('patients', 'Species', '9606', (31, 39))	('mutation', 'Var', (67, 75))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (63, 66))
42905	33889755	In patients with TCGA-LGG carrying wild-type IDH mutation, except for macrophage, the immune infiltration scores of myeloid dendritic cell, T-cell CD4+ and neutrophil significantly positively correlated with TEAD4 expression (Figure 5).	('IDH', 'Gene', (45, 48))	('TEAD4', 'Gene', '7004', (208, 213))	('CD4', 'Gene', '920', (147, 150))	('IDH', 'Gene', '3417', (45, 48))	('mutation', 'Var', (49, 57))	('TEAD4', 'Gene', (208, 213))	('positively', 'PosReg', (181, 191))	('patients', 'Species', '9606', (3, 11))	('correlated', 'Reg', (192, 202))	('expression', 'MPA', (214, 224))	('CD4', 'Gene', (147, 150))
42910	33889755	Meanwhile, we also found that TEAD4 CNV increase and IDH mutations might be mutually exclusive in GBM; while in LGG, these two mutations occur synergistically.	('mutations', 'Var', (57, 66))	('TEAD4', 'Gene', '7004', (30, 35))	('IDH', 'Gene', (53, 56))	('TEAD4', 'Gene', (30, 35))	('GBM', 'Disease', (98, 101))	('IDH', 'Gene', '3417', (53, 56))
42911	33889755	Moreover, integrating TEAD4 CNV, TP53 mutation, ATRX mutation, IDH mutations and 1p19q co-deletion would separate patients with LGG into four groups with different prognosis, which might provide a new biomarker for developing new therapeutic regimens to improve the outcomes in patients with LGG carrying IDH mutations but suffering poor prognosis.	('IDH', 'Gene', (63, 66))	('TP53', 'Gene', '7157', (33, 37))	('IDH', 'Gene', '3417', (63, 66))	('ATRX', 'Gene', (48, 52))	('improve', 'PosReg', (254, 261))	('TEAD4', 'Gene', '7004', (22, 27))	('IDH', 'Gene', (305, 308))	('TEAD4', 'Gene', (22, 27))	('TP53', 'Gene', (33, 37))	('patients', 'Species', '9606', (278, 286))	('patients', 'Species', '9606', (114, 122))	('IDH', 'Gene', '3417', (305, 308))	('mutations', 'Var', (309, 318))	('ATRX', 'Gene', '546', (48, 52))
42912	33889755	In our study, we discovered that TEAD4 CNV increase might lead to poor prognosis in patients with LGG carrying IDH mutations, but not in patients with LGG not carrying IDH mutation or the patients with GBM.	('mutations', 'Var', (115, 124))	('IDH', 'Gene', '3417', (168, 171))	('patients', 'Species', '9606', (84, 92))	('TEAD4', 'Gene', '7004', (33, 38))	('patients', 'Species', '9606', (137, 145))	('IDH', 'Gene', (111, 114))	('patients', 'Species', '9606', (188, 196))	('increase', 'PosReg', (43, 51))	('TEAD4', 'Gene', (33, 38))	('IDH', 'Gene', '3417', (111, 114))	('IDH', 'Gene', (168, 171))
42913	33889755	This compelling phenomenon might most probably be due to the IDH mutation that could promote the synthesis of 2-hydroxyglutarate and then lead to hypermethylation phenotype in cells which would regulate lots of gene expression levels in various pathways.	('regulate', 'Reg', (194, 202))	('hypermethylation phenotype', 'MPA', (146, 172))	('IDH', 'Gene', '3417', (61, 64))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (110, 128))	('promote', 'PosReg', (85, 92))	('mutation', 'Var', (65, 73))	('synthesis of 2-hydroxyglutarate', 'MPA', (97, 128))	('lead to', 'Reg', (138, 145))	('IDH', 'Gene', (61, 64))
42914	33889755	So there might be significant differences in the activity of many signaling pathways including Hippo and Wnt between IDH mutation and wild-type individuals.	('activity', 'MPA', (49, 57))	('differences', 'Reg', (30, 41))	('IDH', 'Gene', (117, 120))	('signaling pathways', 'Pathway', (66, 84))	('IDH', 'Gene', '3417', (117, 120))	('mutation', 'Var', (121, 129))	('Wnt', 'Pathway', (105, 108))	('Hippo', 'Disease', (95, 100))
42915	33889755	Meanwhile, we conducted TEAD4 coexpression analysis in IDH mutant and IDH wild-type patients, and pathway analysis was performed for the relating genes.	('patients', 'Species', '9606', (84, 92))	('IDH', 'Gene', (55, 58))	('mutant', 'Var', (59, 65))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (55, 58))	('IDH', 'Gene', '3417', (70, 73))	('TEAD4', 'Gene', '7004', (24, 29))	('TEAD4', 'Gene', (24, 29))
42916	33889755	The results suggested enormous difference in TEAD4 coexpression genes between IDH mutation and wild-type patients.	('IDH', 'Gene', '3417', (78, 81))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (82, 90))	('TEAD4', 'Gene', (45, 50))	('IDH', 'Gene', (78, 81))	('TEAD4', 'Gene', '7004', (45, 50))
42917	33889755	In IDH mutation carriers, the TEAD4 correlating genes mainly enriched in immune response-related pathways; while in IDH wild-type patients, the genes concentrated in other biological pathways.	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (116, 119))	('IDH', 'Gene', '3417', (3, 6))	('immune response-related pathways', 'Pathway', (73, 105))	('enriched', 'Reg', (61, 69))	('patients', 'Species', '9606', (130, 138))	('mutation', 'Var', (7, 15))	('TEAD4', 'Gene', '7004', (30, 35))	('TEAD4', 'Gene', (30, 35))	('IDH', 'Gene', (3, 6))
42918	33889755	The reported IDH mutant could alter the tumor immunological microenvironment in LGGs, and the immune system gene signature could predict the prognosis of glioma.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('IDH', 'Gene', '3417', (13, 16))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('alter', 'Reg', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('glioma', 'Disease', (154, 160))	('predict', 'Reg', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('IDH', 'Gene', (13, 16))	('mutant', 'Var', (17, 23))
42925	33889755	Our results suggested that TEAD4 CNV increases and the high expression level would dramatically aggravate outcomes in patients with LGG carrying IDH mutations, which might partly explain why these patients are experiencing poorer prognosis.	('mutations', 'Var', (149, 158))	('TEAD4', 'Gene', (27, 32))	('patients', 'Species', '9606', (197, 205))	('aggravate', 'PosReg', (96, 105))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('outcomes', 'MPA', (106, 114))	('increases', 'PosReg', (37, 46))	('TEAD4', 'Gene', '7004', (27, 32))	('patients', 'Species', '9606', (118, 126))
42926	33889755	In the meantime, our study discovered that 1p19q co-deletion would downregulate TEAD4 expression in glioma.	('glioma', 'Disease', (100, 106))	('1p19q co-deletion', 'Var', (43, 60))	('TEAD4', 'Gene', '7004', (80, 85))	('downregulate', 'NegReg', (67, 79))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('TEAD4', 'Gene', (80, 85))	('expression', 'MPA', (86, 96))
42929	33889755	The specific reason for the correlation of 1p19q co-deletion with TEAD4 expression is not clear at present, and further functional studies are needed to determine it.	('expression', 'MPA', (72, 82))	('TEAD4', 'Gene', '7004', (66, 71))	('1p19q co-deletion', 'Var', (43, 60))	('TEAD4', 'Gene', (66, 71))
42930	33889755	Our study found that CNV and overexpression of TEAD4 only affected the prognosis in patients with LGG carrying IDH mutation.	('patients', 'Species', '9606', (84, 92))	('IDH', 'Gene', (111, 114))	('affected', 'Reg', (58, 66))	('TEAD4', 'Gene', '7004', (47, 52))	('TEAD4', 'Gene', (47, 52))	('IDH', 'Gene', '3417', (111, 114))	('mutation', 'Var', (115, 123))	('LGG', 'Disease', (98, 101))
42931	33889755	did not distinguish the discrepancy of prognosis and genes expression between LGG and GBM, and they had not considered the effects of IDH mutation, TP53 mutation, ATRX mutation and 1p19q on the prognosis of glioma.	('ATRX', 'Gene', '546', (163, 167))	('IDH', 'Gene', '3417', (134, 137))	('TP53', 'Gene', '7157', (148, 152))	('glioma', 'Disease', (207, 213))	('TP53', 'Gene', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('ATRX', 'Gene', (163, 167))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('IDH', 'Gene', (134, 137))	('mutation', 'Var', (153, 161))
42933	33889755	This might because they did not take into account that the frequency of IDH mutation was extremely low in GBM and the relatively higher level of TEAD4 expression in GBM.	('TEAD4', 'Gene', '7004', (145, 150))	('low', 'NegReg', (99, 102))	('TEAD4', 'Gene', (145, 150))	('expression', 'MPA', (151, 161))	('higher', 'PosReg', (129, 135))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('mutation', 'Var', (76, 84))
42934	33889755	So it appeared that IDH1 mutation was significantly negatively related with TEAD4 expression.	('IDH1', 'Gene', '3417', (20, 24))	('negatively', 'NegReg', (52, 62))	('TEAD4', 'Gene', '7004', (76, 81))	('expression', 'MPA', (82, 92))	('TEAD4', 'Gene', (76, 81))	('mutation', 'Var', (25, 33))	('IDH1', 'Gene', (20, 24))
42937	33889755	This study discovered that CNV and gene expression status of TEAD4 were closely related to the prognosis of patients with LGG carrying IDH mutation.	('related', 'Reg', (80, 87))	('mutation', 'Var', (139, 147))	('TEAD4', 'Gene', '7004', (61, 66))	('IDH', 'Gene', (135, 138))	('TEAD4', 'Gene', (61, 66))	('IDH', 'Gene', '3417', (135, 138))	('patients', 'Species', '9606', (108, 116))
43030	27806344	Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development.	('glioblastoma', 'Disease', 'MESH:D005909', (194, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (194, 206))	('amplification', 'Var', (120, 133))	('PTN', 'Gene', (81, 84))	('increased', 'PosReg', (71, 80))	('increased PTN', 'Phenotype', 'HP:0008151', (71, 84))	('glioblastoma', 'Disease', (194, 206))
43032	27806344	Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF)B-induced gliomagenesis.	('RCAS', 'Chemical', '-', (120, 124))	('PDGF)B', 'Gene', '18591', (157, 163))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('RCAS-platelet', 'Var', (120, 133))	('glioma', 'Disease', (50, 56))	('enhanced', 'PosReg', (111, 119))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('glioma', 'Disease', (172, 178))	('RCAS', 'Chemical', '-', (26, 30))
43034	27806344	Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('stimulating', 'PosReg', (130, 141))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('proliferation', 'CPA', (142, 155))	('glioma', 'Disease', (113, 119))	('gain', 'PosReg', (71, 75))	('PDGFB-induced', 'Gene', (99, 112))	('PTN', 'Var', (86, 89))	('enhances', 'PosReg', (90, 98))
43038	27806344	Studies of the somatic genomic alterations reveal that classical tumors harbor high level of EGFR amplification, mesenchymal samples are associated with NF1 mutations, proneural with PDGFRA alterations or IDH1/2 mutations while the neural subtype lacks specific genetic abnormalities.	('associated', 'Reg', (137, 147))	('amplification', 'MPA', (98, 111))	('NF1', 'Gene', (153, 156))	('genetic abnormalities', 'Disease', 'MESH:D030342', (262, 283))	('tumors', 'Disease', (65, 71))	('genetic abnormalities', 'Disease', (262, 283))	('IDH1/2', 'Gene', '15926;269951', (205, 211))	('IDH1/2', 'Gene', (205, 211))	('mutations', 'Var', (157, 166))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (212, 221))	('mesenchymal samples', 'CPA', (113, 132))	('PDGFRA', 'Gene', '18595', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('EGFR', 'Gene', (93, 97))	('PDGFRA', 'Gene', (183, 189))	('alterations', 'Var', (190, 201))	('EGFR', 'Gene', '13649', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('NF1', 'Gene', '18015', (153, 156))
43039	27806344	Proneural tumors that have IDH1/2 mutations are of the glioma-CpG island methylator phenotype (G-CIMP).	('glioma', 'Disease', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('neural tumors', 'Disease', (3, 16))	('neural tumors', 'Disease', 'MESH:C536149', (3, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('IDH1/2', 'Gene', '15926;269951', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('G-CIMP', 'Chemical', '-', (95, 101))	('IDH1/2', 'Gene', (27, 33))	('mutations', 'Var', (34, 43))
43040	27806344	Mathematical modeling and in vivo experiments have suggested that most human G-CIMP- tumors may evolve from a common proneural-like glioma and indicated that gain of chromosome 7 and loss of chromosome 10 are common early events of gliomagenesis PDGFA amplification was found to be the most likely initial driver of glioma formation, and sufficient for gliomagenesis in mice, but the potential contribution of other chromosome 7 genes to the initial oncogenic events are still unclear.	('glioma', 'Disease', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (316, 322))	('glioma', 'Disease', (353, 359))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (353, 359))	('mice', 'Species', '10090', (370, 374))	('glioma', 'Disease', (232, 238))	('PDGFA', 'Gene', '5154', (246, 251))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('G-CIMP', 'Chemical', '-', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('human', 'Species', '9606', (71, 76))	('tumors', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (353, 359))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('glioma', 'Disease', (316, 322))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('PDGFA', 'Gene', (246, 251))	('loss', 'Var', (183, 187))	('glioma', 'Disease', 'MESH:D005910', (316, 322))
43045	27806344	PTN can stimulate glioma cell migration and proliferation, and blocking PTN or its receptors reduces tumor growth.	('stimulate', 'PosReg', (8, 17))	('glioma', 'Disease', (18, 24))	('PTN', 'Gene', (72, 75))	('reduces', 'NegReg', (93, 100))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('blocking', 'Var', (63, 71))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('proliferation', 'CPA', (44, 57))
43055	27806344	Thus, increased PTN expression in glioma is associated with amplification of chromosome 7.	('increased', 'PosReg', (6, 15))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('amplification', 'Var', (60, 73))	('increased PTN', 'Phenotype', 'HP:0008151', (6, 19))	('PTN', 'Protein', (16, 19))	('glioma', 'Disease', (34, 40))
43060	27806344	Neonatal G/tv-a;Arf-/- mice, expressing the tv-a receptor under control of a GFAP-promoter, were intracranially injected with equal numbers of DF1 RCAS-ev, DF1 RCAS-PTN or DF1 RCAS-PDGFB.	('tv-a', 'Chemical', 'MESH:C050413', (11, 15))	('GFAP', 'Gene', '14580', (77, 81))	('RCAS-ev', 'Chemical', '-', (147, 154))	('GFAP', 'Gene', (77, 81))	('RCAS', 'Chemical', '-', (147, 151))	('DF1 RCAS-ev', 'Var', (143, 154))	('DF1 RCAS-PDGFB', 'Var', (172, 186))	('tv-a', 'Chemical', 'MESH:C050413', (44, 48))	('RCAS', 'Chemical', '-', (176, 180))	('RCAS', 'Chemical', '-', (160, 164))	('mice', 'Species', '10090', (23, 27))
43065	27806344	Tumor incidence, as determined by the presence of Ki-67+ cells, was strikingly increased in mice injected with RCAS-PDGFB+RCAS-PTN (66.7%) as compared to mice injected with RCAS-PDGFB+RCAS-ev (38.7%) (Fisher's exact test, P = 0.0467) (Figure 2C).	('increased', 'PosReg', (79, 88))	('RCAS', 'Chemical', '-', (122, 126))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (154, 158))	('mice', 'Species', '10090', (92, 96))	('Tumor incidence', 'CPA', (0, 15))	('RCAS', 'Chemical', '-', (111, 115))	('RCAS', 'Chemical', '-', (184, 188))	('RCAS-ev', 'Chemical', '-', (184, 191))	('RCAS-PDGFB+RCAS-PTN', 'Var', (111, 130))	('RCAS', 'Chemical', '-', (173, 177))
43073	27806344	The histopathology of gliomas induced by RCAS-PDGFB+RCAS-PTN was similar to gliomas induced by RCAS-PDGFB+RCAS-ev.	('RCAS', 'Chemical', '-', (106, 110))	('RCAS-ev', 'Chemical', '-', (106, 113))	('gliomas', 'Disease', (76, 83))	('RCAS', 'Chemical', '-', (95, 99))	('RCAS', 'Chemical', '-', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Disease', (22, 29))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('RCAS', 'Chemical', '-', (52, 56))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('RCAS-PDGFB+RCAS-PTN', 'Var', (41, 60))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))
43075	27806344	Grade II tumors grew diffusely in the brain, a proportion of the cells were Ki-67+, and apoptotic cells were present (Figure S2B-C).	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Ki-67+', 'Var', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('II tumors', 'Disease', (6, 15))	('II tumors', 'Disease', 'MESH:D009369', (6, 15))
43077	27806344	A similar proportion of grade III and grade II tumors formed in mice induced by RCAS-PDGFB+RCAS-PTN as in mice induced by RCAS-PDGFB+RCAS-ev (Figure 3B).	('RCAS', 'Chemical', '-', (91, 95))	('RCAS', 'Chemical', '-', (122, 126))	('RCAS-ev', 'Chemical', '-', (133, 140))	('RCAS', 'Chemical', '-', (133, 137))	('mice', 'Species', '10090', (106, 110))	('II tumors', 'Disease', (44, 53))	('II tumors', 'Disease', 'MESH:D009369', (44, 53))	('RCAS', 'Chemical', '-', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mice', 'Species', '10090', (64, 68))	('RCAS-PDGFB+RCAS-PTN', 'Var', (80, 99))
43082	27806344	No differences in vascular diameter or area were observed when comparing grade II tumors induced by RCAS-PDGFB+RCAS-PTN to grade II tumors induced by RCAS-PDGFB+RCAS-ev (Figure 3C).	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('II tumors', 'Disease', (129, 138))	('II tumors', 'Disease', 'MESH:D009369', (129, 138))	('RCAS', 'Chemical', '-', (150, 154))	('RCAS-ev', 'Chemical', '-', (161, 168))	('RCAS', 'Chemical', '-', (161, 165))	('RCAS', 'Chemical', '-', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('II tumors', 'Disease', (79, 88))	('II tumors', 'Disease', 'MESH:D009369', (79, 88))	('RCAS', 'Chemical', '-', (111, 115))	('RCAS-PDGFB+RCAS-PTN', 'Var', (100, 119))
43083	27806344	In contrast, grade III tumors induced by RCAS-PDGFB+RCAS-PTN frequently displayed disorganized, thick-walled vessels not observed in grade III gliomas induced by RCAS-PDGFB+RCAS-ev (Figure 3C).	('disorganized', 'CPA', (82, 94))	('RCAS', 'Chemical', '-', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('RCAS', 'Chemical', '-', (52, 56))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('RCAS', 'Chemical', '-', (162, 166))	('RCAS-ev', 'Chemical', '-', (173, 180))	('gliomas', 'Disease', (143, 150))	('II tumors', 'Disease', (20, 29))	('II tumors', 'Disease', 'MESH:D009369', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('RCAS-PDGFB+RCAS-PTN', 'Var', (41, 60))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('RCAS', 'Chemical', '-', (173, 177))
43084	27806344	Grade III tumors induced by RCAS-PDGFB+RCAS-PTN also had a significantly higher vascular area and vessel diameter (Figure 3D-3E).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('RCAS', 'Chemical', '-', (28, 32))	('II tumors', 'Disease', (7, 16))	('II tumors', 'Disease', 'MESH:D009369', (7, 16))	('RCAS-PDGFB+RCAS-PTN', 'Var', (28, 47))	('RCAS', 'Chemical', '-', (39, 43))	('higher', 'PosReg', (73, 79))
43085	27806344	This indicates that PTN enhances vascular abnormalization in high-grade tumors, but not low-grade tumors, and that PTN-induced increase in tumor incidence was not generally associated with increased angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (98, 104))	('tumors', 'Disease', (72, 78))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (98, 103))	('PTN', 'Var', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('vascular abnormalization', 'CPA', (33, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('enhances', 'PosReg', (24, 32))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('vascular abnormalization', 'Phenotype', 'HP:0002597', (33, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
43097	27806344	However, using G/tv-a wild type mice in which gliomas are induced by PDGFB in only roughly a third of the injected mice, we found that PTN markedly enhanced PDGFB-induced tumor formation.	('mice', 'Species', '10090', (115, 119))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('PTN', 'Var', (135, 138))	('enhanced', 'PosReg', (148, 156))	('mice', 'Species', '10090', (32, 36))	('tv-a', 'Chemical', 'MESH:C050413', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('PDGFB', 'Gene', (69, 74))
43102	27806344	This indicates that PTN enhances vascular abnormalization in high-grade tumors in combination with other factors in the tumor microenvironment, but that PTN-stimulation is not sufficient to induce vascular abnormalization in low-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumors', 'Disease', (72, 78))	('PTN', 'Var', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('enhances', 'PosReg', (24, 32))	('tumor', 'Disease', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('vascular abnormalization', 'Phenotype', 'HP:0002597', (33, 57))	('vascular abnormalization', 'MPA', (33, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumors', 'Disease', (235, 241))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (235, 240))	('vascular abnormalization', 'Phenotype', 'HP:0002597', (197, 221))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
43133	27806344	Cells were grown in neural stem cell medium containing DMEM-F12 GlutaMAX (31331093, ThermoFisher), 10mM HEPES (15630049, ThermoFisher ), B27 (12587010, ThermoFisher), penicillin G/streptomycin (P4093,Sigma), 20mug/ml insulin (I-6634, Sigma), 20ng/ml FGF2 (100-18B, Peprotech) and 20ng/ml EGF (AF-100-15, Peprotech).	('FGF2', 'Gene', (250, 254))	('AF-100-15', 'Disease', 'OMIM:613980', (293, 302))	('FGF2', 'Gene', '14173', (250, 254))	('15630049', 'Var', (111, 119))	('P4093', 'Var', (194, 199))	('31331093', 'Var', (74, 82))	('AF-100-15', 'Disease', (293, 302))
43138	23583981	We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs).	('H3F3A', 'Gene', '3020', (175, 180))	('FGFR1', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('LGGs', 'Disease', (197, 201))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('RAF1', 'Gene', '5894', (99, 103))	('H3F3A', 'Gene', (175, 180))	('MYB', 'Gene', '4602', (112, 115))	('BRAF', 'Gene', '673', (93, 97))	('MYB', 'Gene', (112, 115))	('tumors', 'Disease', (229, 235))	('BRAF', 'Gene', (93, 97))	('ATRX', 'Gene', (185, 189))	('RAF1', 'Gene', (99, 103))	('alterations', 'Var', (71, 82))	('MYBL1', 'Gene', (117, 122))	('ATRX', 'Gene', '546', (185, 189))	('MYBL1', 'Gene', '4603', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (216, 235))	('MYB', 'Gene', '4602', (117, 120))	('MYB', 'Gene', (117, 120))
43140	23583981	Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs.	('grade II diffuse LGGs', 'Disease', (140, 161))	('MYB', 'Gene', '4602', (88, 91))	('MYB', 'Gene', (88, 91))	('duplications', 'Var', (11, 23))	('FGFR1', 'Gene', (31, 36))
43141	23583981	Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance.	('astrocytomas', 'Disease', (128, 140))	('Trp53', 'Gene', '22059', (19, 24))	('nude mice', 'Species', '10090', (97, 106))	('TKD-duplicated', 'Var', (61, 75))	('Trp53', 'Gene', (19, 24))	('astrocytomas', 'Disease', 'MESH:D001254', (128, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))	('FGFR1', 'Gene', (76, 81))
43142	23583981	TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors.	('ERK', 'Gene', '5594', (84, 87))	('ERK', 'Gene', (84, 87))	('TKD-duplicated', 'Var', (0, 14))	('upregulation', 'PosReg', (59, 71))	('autophosphorylation', 'MPA', (35, 54))	('FGFR1', 'Gene', (29, 34))	('FGFR1', 'Gene', (15, 20))
43147	23583981	Studies of pediatric LGGs and related low-grade glioneuronal tumors (LGGNTs) have implicated abnormalities of the MAPK/ERK pathway in their oncogenesis , but detailed knowledge of driver mutations in these diverse tumors is lacking.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('abnormalities', 'Var', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('ERK', 'Gene', '5594', (119, 122))	('ERK', 'Gene', (119, 122))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('LGGs', 'Disease', (21, 25))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (48, 67))
43151	23583981	Other mechanisms activating the MAPK/ERK pathway in LGGs are comparatively rare and include RAF1 fusion genes and BRAF:p.V600E or KRAS mutations, though the BRAF:p.V600E mutation is present in a proportion of LGGNTs .	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (114, 126))	('BRAF:p.V600E', 'Var', (157, 169))	('RAF1', 'Gene', (92, 96))	('RAF1', 'Gene', '5894', (92, 96))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (37, 40))	('KRAS', 'Gene', (130, 134))	('BRAF:p.V600E', 'Var', (114, 126))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (157, 169))	('KRAS', 'Gene', '3845', (130, 134))
43152	23583981	While nearly all World Health Organization (WHO) grade I LGGs from the intracranial posterior fossa will harbor one of the above mutations, they occur less frequently in supratentorial grade I LGGs and rarely in diffuse grade II tumors .	('mutations', 'Var', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('II tumors', 'Disease', (226, 235))	('II tumors', 'Disease', 'MESH:D009369', (226, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))
43155	23583981	The principal novel findings, duplication of the tyrosine kinase domain (TKD) of fibroblast growth factor receptor-1 (FGFR1) and rearrangements of MYB or MYBL1, occur most frequently in diffuse cerebral LGGs.	('occur', 'Reg', (161, 166))	('rearrangements', 'Var', (129, 143))	('diffuse cerebral LGGs', 'Disease', (186, 207))	('duplication', 'Var', (30, 41))	('MYBL1', 'Gene', (154, 159))	('MYB', 'Gene', '4602', (154, 157))	('frequently', 'Reg', (172, 182))	('fibroblast growth factor receptor-1', 'Gene', (81, 116))	('MYB', 'Gene', (154, 157))	('MYBL1', 'Gene', '4603', (154, 159))	('MYB', 'Gene', '4602', (147, 150))	('fibroblast growth factor receptor-1', 'Gene', '2260', (81, 116))	('FGFR1', 'Gene', (118, 123))	('MYB', 'Gene', (147, 150))
43157	23583981	Tumor series 1 included a 'discovery set' of 39 paired tumor / germline samples analyzed by WGS at an average of 45x haploid coverage (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('haploid', 'Var', (117, 124))
43160	23583981	Seven tumors from the WGS series were also analyzed by high-coverage exome sequencing (245x average coverage), which showed that WGS was able to detect >85% of somatic coding variants, including subclonal mutations in these tumors (Supplementary Note; Supplementary Table 3).	('variants', 'Var', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumors', 'Disease', (6, 12))	('subclonal mutations', 'Var', (195, 214))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
43162	23583981	Despite this low lesion burden, we found multiple recurrent abnormalities among different histopathological subtypes, including KIAA1549-BRAF fusions in PAs, frequent BRAF:p.V600E mutations in pleomorphic xanthoastrocytomas (PXAs), rearrangements and amplification of MYB in diffuse gliomas, and intragenic TKD duplications of FGFR1, all of which recurred at a frequency of more than 6% when sought across the cohort of 151 tumors (Figs.	('gliomas', 'Disease', 'MESH:D005910', (283, 290))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (167, 179))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (193, 223))	('amplification', 'Var', (251, 264))	('gliomas', 'Phenotype', 'HP:0009733', (283, 290))	('KIAA1549-BRAF fusions in PAs', 'Disease', (128, 156))	('tumors', 'Phenotype', 'HP:0002664', (424, 430))	('pleomorphic xanthoastrocytomas', 'Disease', (193, 223))	('BRAF:p.V600E', 'Var', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (424, 429))	('tumors', 'Disease', (424, 430))	('MYB', 'Gene', '4602', (268, 271))	('MYB', 'Gene', (268, 271))	('gliomas', 'Disease', (283, 290))	('KIAA1549-BRAF fusions in PAs', 'Disease', 'MESH:D000069337', (128, 156))	('rearrangements', 'Var', (232, 246))	('FGFR1', 'Gene', (327, 332))	('tumors', 'Disease', 'MESH:D009369', (424, 430))	('astrocytoma', 'Phenotype', 'HP:0009592', (211, 222))
43163	23583981	However, among these were NF1 and FGFR1 sequence mutations, episome-associated FGFR1-TACC1 and FGFR3-TACC3 gene fusions, a rearrangement of MYBL1, an H3F3A:p.K27M mutation in three supratentorial diffuse astrocytomas, and three novel gene fusions involving BRAF or RAF1;FXR1-BRAF, BRAF-MACF1, and QKI-RAF1.	('RAF1', 'Gene', (301, 305))	('FXR1', 'Gene', '8087', (270, 274))	('FGFR3', 'Gene', (95, 100))	('TACC1', 'Gene', (85, 90))	('FGFR3', 'Gene', '2261', (95, 100))	('FXR1', 'Gene', (270, 274))	('MACF1', 'Gene', (286, 291))	('H3F3A:p.K27M', 'Var', (150, 162))	('rearrangement', 'Var', (123, 136))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', '673', (275, 279))	('BRAF', 'Gene', (275, 279))	('RAF1', 'Gene', '5894', (265, 269))	('TACC1', 'Gene', '6867', (85, 90))	('astrocytomas', 'Disease', (204, 216))	('NF1', 'Gene', '4763', (26, 29))	('BRAF', 'Gene', (257, 261))	('BRAF', 'Gene', '673', (257, 261))	('astrocytoma', 'Phenotype', 'HP:0009592', (204, 215))	('RAF1', 'Gene', (265, 269))	('MACF1', 'Gene', '23499', (286, 291))	('H3F3A:p.K27M', 'SUBSTITUTION', 'None', (150, 162))	('QKI', 'Gene', '9444', (297, 300))	('RAF1', 'Gene', '5894', (301, 305))	('TACC3', 'Gene', '10460', (101, 106))	('MYBL1', 'Gene', (140, 145))	('BRAF', 'Gene', '673', (281, 285))	('NF1', 'Gene', (26, 29))	('FGFR1', 'Gene', (34, 39))	('fusions', 'Var', (112, 119))	('BRAF', 'Gene', (281, 285))	('astrocytomas', 'Disease', 'MESH:D001254', (204, 216))	('TACC3', 'Gene', (101, 106))	('MYBL1', 'Gene', '4603', (140, 145))	('QKI', 'Gene', (297, 300))
43164	23583981	When considering sequence mutations alone, the only genes with a mutation rate significantly higher than the background rate were BRAF, NF1, H3F3A and FGFR1 (Supplementary Table 9).	('higher', 'PosReg', (93, 99))	('NF1', 'Gene', '4763', (136, 139))	('BRAF', 'Gene', '673', (130, 134))	('H3F3A', 'Gene', '3020', (141, 146))	('BRAF', 'Gene', (130, 134))	('mutation', 'Var', (65, 73))	('NF1', 'Gene', (136, 139))	('FGFR1', 'Gene', (151, 156))	('H3F3A', 'Gene', (141, 146))
43165	23583981	Only four of 39 tumors (10%) in the WGS series lacked a MYB/MYBL1 rearrangement, FGFR1 alteration, or aberration of a gene in the NF1/RAS/RAF pathway.	('FGFR1', 'Gene', (81, 86))	('RAF', 'Gene', (138, 141))	('MYBL1', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MYBL1', 'Gene', '4603', (60, 65))	('tumors', 'Disease', (16, 22))	('rearrangement', 'Var', (66, 79))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('lacked', 'NegReg', (47, 53))	('aberration', 'Var', (102, 112))	('MYB', 'Gene', '4602', (56, 59))	('MYB', 'Gene', (56, 59))	('NF1', 'Gene', '4763', (130, 133))	('RAF', 'Gene', '22882', (138, 141))	('MYB', 'Gene', '4602', (60, 63))	('NF1', 'Gene', (130, 133))	('MYB', 'Gene', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('alteration', 'Var', (87, 97))
43166	23583981	One of these, SJLGG034, was an oligodendroglioma from a patient aged 15 years that demonstrated genetic aberrations characteristic of adult-type disease; an IDH1 mutation and co-deletion of chromosomes 1p and 19q (Fig.	('oligodendroglioma', 'Disease', (31, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('oligodendroglioma', 'Disease', 'MESH:D009837', (31, 48))	('adult-type disease', 'Disease', (134, 152))	('IDH1', 'Gene', (157, 161))	('patient', 'Species', '9606', (56, 63))	('mutation', 'Var', (162, 170))	('adult-type disease', 'Disease', 'MESH:C538052', (134, 152))	('IDH1', 'Gene', '3417', (157, 161))
43167	23583981	This tumor also had the highest number of sequence mutations in the WGS series, with six non-silent mutations in five genes: IDH1:p.R132H, CIC:p.V676fs and p.S726R, CHD2:p.D1722V, STYK1:p.P101L, BAI3:p.I869 splice site.	('CHD2:p.D1722V', 'Var', (165, 178))	('p.S726R', 'Var', (156, 163))	('BAI3', 'Gene', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('IDH1:p.R132H', 'SUBSTITUTION', 'None', (125, 137))	('p.I869 splice site', 'Var', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('STYK1:p.P101L', 'SUBSTITUTION', 'None', (180, 193))	('CHD2:p.D1722V', 'SUBSTITUTION', 'None', (165, 178))	('CIC:p.V676fs', 'FRAMESHIFT', 'None', (139, 151))	('STYK1:p.P101L', 'Var', (180, 193))	('tumor', 'Disease', (5, 10))	('CIC:p.V676fs', 'Var', (139, 151))	('IDH1:p.R132H', 'Var', (125, 137))	('BAI3', 'Gene', '577', (195, 199))	('p.S726R', 'Mutation', 'rs1239763774', (156, 163))
43168	23583981	No other tumor in the entire study cohort harbored an IDH1/2 mutation.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('IDH1/2', 'Gene', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutation', 'Var', (61, 69))	('tumor', 'Disease', (9, 14))	('IDH1/2', 'Gene', '3417;3418', (54, 60))
43169	23583981	Key abnormalities in the other three tumors from the WGS series were an ETV6-NTRK3 fusion associated with CDKN2A deletion, an H3F3A mutation, and a rearrangement of WHSC1 (Supplementary Table 4).	('WHSC1', 'Gene', (165, 170))	('ETV6', 'Gene', (72, 76))	('Key abnormalities', 'Disease', (0, 17))	('Key abnormalities', 'Disease', 'MESH:D000014', (0, 17))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('H3F3A', 'Gene', '3020', (126, 131))	('NTRK3', 'Gene', '4916', (77, 82))	('CDKN2A', 'Gene', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('NTRK3', 'Gene', (77, 82))	('H3F3A', 'Gene', (126, 131))	('ETV6', 'Gene', '2120', (72, 76))	('CDKN2A', 'Gene', '1029', (106, 112))	('WHSC1', 'Gene', '7468', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('deletion', 'Var', (113, 121))	('associated', 'Reg', (90, 100))	('rearrangement', 'Var', (148, 161))	('mutation', 'Var', (132, 140))
43170	23583981	H3F3A, WHSC1 and three other genes found to have mutations in 'discovery series' tumors, ATRX, EP300, and CHD2, have histone-related functions.	('EP300', 'Gene', '2033', (95, 100))	('tumors', 'Disease', (81, 87))	('H3F3A', 'Gene', '3020', (0, 5))	('CHD2', 'Gene', (106, 110))	('mutations', 'Var', (49, 58))	('ATRX', 'Gene', (89, 93))	('EP300', 'Gene', (95, 100))	('H3F3A', 'Gene', (0, 5))	('WHSC1', 'Gene', (7, 12))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('ATRX', 'Gene', '546', (89, 93))	('CHD2', 'Gene', '1106', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('histone-related functions', 'MPA', (117, 142))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('WHSC1', 'Gene', '7468', (7, 12))
43171	23583981	Despite the paucity of somatic lesions in most tumors, multiple SVs probably resulting from a single complex rearrangement event were detected in five cerebral tumors: SJLGG039, SJLGG038, SJLGG033, SJLGG035 and SJLGG005, with 19, 13, 5, 4 and 3 SVs respectively.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', (47, 53))	('SJLGG035', 'Var', (198, 206))	('SJLGG033', 'Var', (188, 196))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('cerebral tumors', 'Phenotype', 'HP:0030692', (151, 166))	('cerebral tumors', 'Disease', (151, 166))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('SJLGG039', 'Var', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', (160, 166))	('SJLGG005', 'Var', (211, 219))	('cerebral tumors', 'Disease', 'MESH:D001932', (151, 166))	('SJLGG038', 'Var', (178, 186))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
43172	23583981	WGS identified fusion of ST6GAL1 (exon 2) to the first coding exon (exon 4) of WHSC1, and this was validated by mRNA-seq, Sanger sequencing and iFISH (Supplementary Fig.	('fusion', 'Var', (15, 21))	('WHSC1', 'Gene', (79, 84))	('ST6GAL1', 'Gene', (25, 32))	('ST6GAL1', 'Gene', '6480', (25, 32))	('WHSC1', 'Gene', '7468', (79, 84))
43173	23583981	Across the tumor cohort, we identified two tumors with a germline NF1 mutation (Supplementary Table 8).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('NF1', 'Gene', (66, 69))	('NF1', 'Gene', '4763', (66, 69))	('tumors', 'Disease', (43, 49))	('mutation', 'Var', (70, 78))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
43174	23583981	The first, a series 1 tumor (SJLGG022), had a germline splice mutation affecting R2214 at exon 43, as well as a somatic 4-bp frameshift mutation at T2263.	('T2263', 'Var', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('R2214 at', 'Var', (81, 89))	('tumor', 'Disease', (22, 27))
43176	23583981	Loss of wild-type NF1 was due to somatically acquired LOH at this locus.	('Loss', 'NegReg', (0, 4))	('NF1', 'Gene', (18, 21))	('LOH', 'Var', (54, 57))	('NF1', 'Gene', '4763', (18, 21))
43177	23583981	This was first suggested in the sequence chromatogram by an increase in the mutant allele fraction from 50% in germline to 80% in tumor (Supplementary Fig.	('mutant', 'Var', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('increase', 'PosReg', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
43180	23583981	Paired copy number analysis using WGS identified subclonal gain or deletion across multiple chromosomes in three tumors: SJLGG008, SJLGG039, and SJLGG042 (Supplementary Fig.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('gain', 'PosReg', (59, 63))	('deletion', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
43183	23583981	BRAF:p.V600E mutations were detected in a high proportion of pleomorphic xanthoastrocytomas (70%) and at lower frequencies in diffuse astrocytomas (23%), gangliogliomas (33%) and PAs (6%).	('astrocytomas', 'Disease', 'MESH:D001254', (134, 146))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('detected', 'Reg', (28, 36))	('gangliogliomas', 'Disease', (154, 168))	('BRAF:p.V600E', 'Var', (0, 12))	('astrocytomas', 'Disease', 'MESH:D001254', (79, 91))	('gangliogliomas', 'Disease', 'MESH:D018303', (154, 168))	('pleomorphic xanthoastrocytomas', 'Disease', (61, 91))	('astrocytomas', 'Disease', (134, 146))	('PAs', 'Disease', (179, 182))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('astrocytomas', 'Disease', (79, 91))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (0, 12))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (61, 91))
43184	23583981	Abnormalities of genes encoding proteins influencing the MAPK/ERK pathway were detected in almost all (95%) PAs/PMAs and 82% of all LGGs/LGGNTs in the study.	('detected', 'Reg', (79, 87))	('PAs/PMAs', 'Disease', (108, 116))	('Abnormalities', 'Var', (0, 13))	('ERK', 'Gene', '5594', (62, 65))	('ERK', 'Gene', (62, 65))
43185	23583981	Among LGGs characterized by diffuse infiltration of adjacent brain, grade II gliomas and angiocentric gliomas, aberrations of MYB, MYBL1, or FGFR1/3 (TKD duplication, missense mutation, or TACC1/3 fusion) were detected in 68%.	('MYBL1', 'Gene', '4603', (131, 136))	('MYB', 'Gene', '4602', (131, 134))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (89, 109))	('MYB', 'Gene', (131, 134))	('II gliomas', 'Disease', 'MESH:D005910', (74, 84))	('angiocentric gliomas', 'Disease', (89, 109))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('TACC1', 'Gene', '6867', (189, 194))	('detected', 'Reg', (210, 218))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('FGFR1/3', 'Gene', (141, 148))	('aberrations', 'Var', (111, 122))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('missense mutation', 'Var', (167, 184))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('TKD duplication', 'Var', (150, 165))	('MYB', 'Gene', '4602', (126, 129))	('II gliomas', 'Disease', (74, 84))	('MYB', 'Gene', (126, 129))	('TACC1', 'Gene', (189, 194))	('MYBL1', 'Gene', (131, 136))
43186	23583981	Of the rest, one oligodendroglioma was characterized by alterations typical of adult-type disease (SJLGG034), three contained an H3F3A:p.K27M mutation, four others harbored a BRAF:p.V600E mutation, and one had a FAM131B-BRAF fusion gene.	('adult-type disease', 'Disease', 'MESH:C538052', (79, 97))	('oligodendroglioma', 'Disease', (17, 34))	('FAM131B', 'Gene', (212, 219))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('BRAF:p.V600E', 'Var', (175, 187))	('oligodendroglioma', 'Disease', 'MESH:D009837', (17, 34))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (220, 224))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (175, 187))	('BRAF', 'Gene', '673', (175, 179))	('FAM131B', 'Gene', '9715', (212, 219))	('BRAF', 'Gene', (220, 224))	('H3F3A:p.K27M', 'SUBSTITUTION', 'None', (129, 141))	('adult-type disease', 'Disease', (79, 97))	('H3F3A:p.K27M', 'Var', (129, 141))
43188	23583981	WGS identified an intragenic duplication of the entire TKD of FGFR1 in two of 39 tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('duplication', 'Var', (29, 40))	('FGFR1', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
43191	23583981	Genomic profiles of the paired primary and relapsed tumor samples analyzed by WGS (SJLGG006_D/R) were identical; alongside the FGFR1 duplication, there were no tier 1 SNVs, one tier 2 SNV, and 6 tier 3 SNVs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('duplication', 'Var', (133, 144))	('tumor', 'Disease', (52, 57))	('FGFR1', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
43192	23583981	All but three of the 11 primary tumors with FGFR1 TKD duplication were diffuse (grade II) gliomas, and all but one were located in the cerebral cortex (Figs.	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('FGFR1', 'Gene', (44, 49))	('diffuse', 'Disease', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('TKD duplication', 'Var', (50, 65))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
43193	23583981	Although relatively infrequent across the entire cohort of LGGs/LGGNTs (7.4%), FGFR1 TKD duplication was present in 24% of grade II diffuse cerebral gliomas.	('TKD duplication', 'Var', (85, 100))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('FGFR1', 'Gene', (79, 84))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('cerebral gliomas', 'Disease', 'MESH:C564230', (140, 156))	('cerebral gliomas', 'Disease', (140, 156))
43194	23583981	The entire tumor cohort was screened by iFISH for FGFR1 amplification or rearrangement, and none was found.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FGFR1', 'Gene', (50, 55))	('tumor', 'Disease', (11, 16))	('rearrangement', 'Var', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('amplification', 'Var', (56, 69))
43197	23583981	Using copy number data from SNP array analysis or mRNA-seq, we were able to identify and then to validate by RT-PCR two additional tumors (SJLGG01212, SJLGG01264) with amplification segments on FGFR1 and TACC1 and fusion of these genes.	('FGFR1', 'Gene', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('TACC1', 'Gene', '6867', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('amplification segments', 'Var', (168, 190))	('TACC1', 'Gene', (204, 209))
43200	23583981	Pediatric high-grade gliomas (n=33) were screened for FGFR1 TKD duplication, and only one example was detected, in an anaplastic oligoastrocytoma (grade III) that had progressed from a grade II tumor.	('TKD duplication', 'Var', (60, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('FGFR1', 'Gene', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('II tumor', 'Disease', (191, 199))	('gliomas', 'Disease', (21, 28))	('II tumor', 'Disease', 'MESH:D009369', (191, 199))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (129, 145))	('oligoastrocytoma', 'Disease', (129, 145))
43201	23583981	No FGFR1 TKD duplication was detected in 11 adult-type oligodendrogliomas, all having IDH1 mutation and 1p/19q co-deletion.	('mutation', 'Var', (91, 99))	('oligodendrogliomas', 'Disease', (55, 73))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('FGFR1', 'Gene', (3, 8))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (55, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))
43202	23583981	Four tumors analyzed by WGS harbored a novel rearrangement of MYB or MYBL1, all of which were cerebral grade II diffuse astrocytomas.	('MYBL1', 'Gene', '4603', (69, 74))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('astrocytomas', 'Disease', 'MESH:D001254', (120, 132))	('MYB', 'Gene', (69, 72))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('rearrangement', 'Var', (45, 58))	('astrocytomas', 'Disease', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('MYBL1', 'Gene', (69, 74))	('MYB', 'Gene', '4602', (62, 65))	('MYB', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('MYB', 'Gene', '4602', (69, 72))
43203	23583981	Subsequent analysis of the entire study cohort using iFISH with MYB, MYBL1, and MYBL2 probes revealed a potential MYB rearrangement or copy number abnormality in a further five tumors: two diffuse astrocytomas, two angiocentric gliomas, and one oligodendroglioma (Figs.2, 6; SupplementaryFigs.	('MYB', 'Gene', '4602', (114, 117))	('MYB', 'Gene', (114, 117))	('number abnormality', 'Disease', 'MESH:D007674', (140, 158))	('number abnormality', 'Disease', (140, 158))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('astrocytomas', 'Disease', (197, 209))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('MYBL2', 'Gene', (80, 85))	('MYB', 'Gene', '4602', (64, 67))	('MYB', 'Gene', (64, 67))	('oligodendroglioma', 'Disease', 'MESH:D009837', (245, 262))	('MYBL2', 'Gene', '4605', (80, 85))	('MYB', 'Gene', '4602', (80, 83))	('oligodendroglioma', 'Disease', (245, 262))	('MYB', 'Gene', (80, 83))	('MYBL1', 'Gene', (69, 74))	('astrocytomas', 'Disease', 'MESH:D001254', (197, 209))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('astrocytoma', 'Phenotype', 'HP:0009592', (197, 208))	('MYB', 'Gene', '4602', (69, 72))	('MYBL1', 'Gene', '4603', (69, 74))	('MYB', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (215, 235))	('tumors', 'Disease', (177, 183))	('rearrangement', 'Var', (118, 131))	('angiocentric gliomas', 'Disease', (215, 235))
43207	23583981	All SVs were associated with deletion of the MYB 3' regulatory region.	('MYB', 'Gene', '4602', (45, 48))	('MYB', 'Gene', (45, 48))	('deletion', 'Var', (29, 37))	('associated', 'Reg', (13, 23))	('SVs', 'Disease', (4, 7))
43208	23583981	Of two tumors with MYB amplification, one also showed a 3' deletion, but the amplicon in the other (SJLGG035) extended beyond the 3'UTR and miRNA binding sites.	('amplification', 'Var', (23, 36))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('MYB', 'Gene', '4602', (19, 22))	('MYB', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
43209	23583981	In all tumors with MYB rearrangement or amplification, MYB expression was elevated at the protein level (Fig.	('MYB', 'Gene', (55, 58))	('elevated', 'PosReg', (74, 82))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('MYB', 'Gene', '4602', (19, 22))	('MYB', 'Gene', (19, 22))	('amplification', 'Var', (40, 53))	('expression', 'MPA', (59, 69))	('rearrangement', 'Var', (23, 36))	('MYB', 'Gene', '4602', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
43215	23583981	Multiplex immunoassays and western blotting demonstrated activation of the MAPK/ERK and PI3K pathways in groups of LGGs/LGGNTs characterized by KIAA1549-BRAF fusion, FGFR1 TKD duplication, or MYB alteration (Fig.	('ERK', 'Gene', '5594', (80, 83))	('KIAA1549-BRAF', 'Disease', (144, 157))	('activation', 'PosReg', (57, 67))	('TKD duplication', 'Var', (172, 187))	('ERK', 'Gene', (80, 83))	('MYB', 'Gene', '4602', (192, 195))	('KIAA1549-BRAF', 'Disease', 'None', (144, 157))	('FGFR1', 'Gene', (166, 171))	('MYB', 'Gene', (192, 195))
43217	23583981	Transplanted cells containing empty vector or wild-type FGFR1 constructs have failed to generate tumors in mice imaged at 60 days post-transplant.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mice', 'Species', '10090', (107, 111))	('FGFR1', 'Gene', (56, 61))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('constructs', 'Var', (62, 72))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
43218	23583981	Tumors generated with both Dp006 and Dp008 were characterized by activation of the MAPK/ERK and PI3K pathways (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Dp006', 'Var', (27, 32))	('ERK', 'Gene', '5594', (88, 91))	('Dp008', 'Var', (37, 42))	('ERK', 'Gene', (88, 91))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('activation', 'PosReg', (65, 75))
43220	23583981	FGFR1 inhibitors blocked autophosphorylation and downstream activation of the MAPK/ERK pathway, and MEK1 inhibitors abrogated MAPK/ERK activity (Fig.	('inhibitors', 'Var', (105, 115))	('ERK', 'Gene', (83, 86))	('ERK', 'Gene', '5594', (131, 134))	('ERK', 'Gene', (131, 134))	('FGFR1', 'Gene', (0, 5))	('activity', 'MPA', (135, 143))	('MEK1', 'Gene', '5604', (100, 104))	('activation', 'PosReg', (60, 70))	('blocked', 'NegReg', (17, 24))	('abrogated', 'NegReg', (116, 125))	('inhibitors', 'Var', (6, 16))	('autophosphorylation', 'MPA', (25, 44))	('MEK1', 'Gene', (100, 104))	('ERK', 'Gene', '5594', (83, 86))
43221	23583981	When transfected into MCF7 cells, TKD-duplicated FGFR1 constructs produced receptor autophosphorylation and activation of the PI3K pathway, which were both blocked by a specific FGFR1 inhibitor.	('PI3K pathway', 'Pathway', (126, 138))	('TKD-duplicated', 'Var', (34, 48))	('MCF7', 'CellLine', 'CVCL:0031', (22, 26))	('FGFR1', 'Gene', (49, 54))	('receptor autophosphorylation', 'MPA', (75, 103))	('constructs', 'Var', (55, 65))	('activation', 'PosReg', (108, 118))
43229	23583981	Furthermore, only one of 151 tumors (SJLGG001259_D1), with an NF1 frameshift mutation, an activating FGFR1 mutation, and a KRAS mutation, harbored genetic abnormalities with potentially overlapping effects on the MAPK/ERK pathway.	('genetic abnormalities', 'Disease', 'MESH:D030342', (147, 168))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ERK', 'Gene', '5594', (218, 221))	('genetic abnormalities', 'Disease', (147, 168))	('NF1', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('activating', 'PosReg', (90, 100))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('effects', 'Reg', (198, 205))	('KRAS', 'Gene', (123, 127))	('ERK', 'Gene', (218, 221))	('tumors', 'Disease', (29, 35))	('NF1', 'Gene', '4763', (62, 65))	('KRAS', 'Gene', '3845', (123, 127))	('mutation', 'Var', (107, 115))	('FGFR1', 'Gene', (101, 106))	('frameshift mutation', 'Var', (66, 85))
43232	23583981	In the present study, 24% of diffuse WHO grade II cerebral gliomas showed a previously unreported duplication of the FGFR1 TKD, which produces FGFR1 autophosphorylation and activation of both MAPK/ERK and PI3K pathways.	('produces', 'Reg', (134, 142))	('ERK', 'Gene', '5594', (197, 200))	('II cerebral gliomas', 'Disease', 'MESH:C564230', (47, 66))	('activation', 'PosReg', (173, 183))	('duplication', 'Var', (98, 109))	('ERK', 'Gene', (197, 200))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('FGFR1', 'Gene', (143, 148))	('FGFR1', 'Gene', (117, 122))	('II cerebral gliomas', 'Disease', (47, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('autophosphorylation', 'MPA', (149, 168))
43234	23583981	Duplication of the EGFR TKD domain has been reported in a single glioblastoma , but FGFR1 TKD duplication has not been previously described in other CNS tumors.	('CNS tumors', 'Disease', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('glioblastoma', 'Disease', (65, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('reported', 'Reg', (44, 52))	('EGFR', 'Gene', (19, 23))	('Duplication', 'Var', (0, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('CNS tumors', 'Disease', 'MESH:D009369', (149, 159))
43235	23583981	Our dataset includes other infrequent FGFR aberrations in LGGs/LGGNTs; missense FGFR1 mutations and FGFR1-TACC1 and FGFR3-TACC3 fusions that are all predicted to result in constitutive FGFR signaling.	('fusions', 'Var', (128, 135))	('mutations', 'Var', (86, 95))	('TACC3', 'Gene', (122, 127))	('FGFR3', 'Gene', (116, 121))	('TACC1', 'Gene', (106, 111))	('FGFR1', 'Gene', (80, 85))	('TACC3', 'Gene', '10460', (122, 127))	('TACC1', 'Gene', '6867', (106, 111))	('FGFR3', 'Gene', '2261', (116, 121))
43236	23583981	Missense FGFR1 mutations have been reported as a rare event in glioblastoma and malignant melanoma , and fusions with TACC genes have recently been reported at low frequency (3%) in glioblastomas .	('glioblastomas', 'Phenotype', 'HP:0012174', (182, 195))	('mutations', 'Var', (15, 24))	('glioblastoma', 'Disease', (182, 194))	('glioblastoma', 'Disease', (63, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (182, 194))	('malignant melanoma', 'Phenotype', 'HP:0002861', (80, 98))	('glioblastomas', 'Disease', 'MESH:D005909', (182, 195))	('malignant melanoma', 'Disease', (80, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('malignant melanoma', 'Disease', 'MESH:D008545', (80, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('glioblastomas', 'Disease', (182, 195))	('FGFR1', 'Gene', (9, 14))	('Missense', 'Var', (0, 8))
43237	23583981	This study also reported micro-amplification at the FGFR3-TACC3 locus suggesting that the FGFR3-TACC3 fusion is likely to arise from tandem duplication, because both FGFR3 and TACC3 are transcribed in the same orientation on the reference genome and are less than 50kb apart.	('arise from', 'Reg', (122, 132))	('TACC3', 'Gene', '10460', (58, 63))	('fusion', 'Var', (102, 108))	('TACC3', 'Gene', '10460', (176, 181))	('TACC3', 'Gene', '10460', (96, 101))	('FGFR3', 'Gene', '2261', (166, 171))	('TACC3', 'Gene', (58, 63))	('FGFR3', 'Gene', '2261', (52, 57))	('TACC3', 'Gene', (176, 181))	('FGFR3', 'Gene', '2261', (90, 95))	('TACC3', 'Gene', (96, 101))	('FGFR3', 'Gene', (166, 171))	('FGFR3', 'Gene', (52, 57))	('FGFR3', 'Gene', (90, 95))
43240	23583981	FGFR1 amplifications and other FGFR1 fusions, which are important oncogenetic mechanisms in several neoplasms , were not detected in our series of LGGs/LGGNTs.	('amplifications', 'Var', (6, 20))	('neoplasms', 'Disease', 'MESH:D009369', (100, 109))	('neoplasms', 'Disease', (100, 109))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', (31, 36))	('neoplasms', 'Phenotype', 'HP:0002664', (100, 109))
43243	23583981	Aside from these fusions, recurrent somatic mutations and SVs in FGFR1, LETM1 (S580R) and WHSC1 (ST6GAL1-WHSC1 fusion) were found in tumors from our study cohort, suggesting in the setting of minimal somatic lesions that disruption of this highly conserved multi-gene group may be important in gliomagenesis.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('gliomagenesis', 'Disease', (294, 307))	('S580R', 'Var', (79, 84))	('glioma', 'Phenotype', 'HP:0009733', (294, 300))	('S580R', 'Mutation', 'p.S580R', (79, 84))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('WHSC1', 'Gene', '7468', (90, 95))	('ST6GAL1', 'Gene', '6480', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('FGFR1', 'Gene', (65, 70))	('ST6GAL1', 'Gene', (97, 104))	('LETM1', 'Gene', '3954', (72, 77))	('WHSC1', 'Gene', '7468', (105, 110))	('WHSC1', 'Gene', (90, 95))	('LETM1', 'Gene', (72, 77))	('WHSC1', 'Gene', (105, 110))
43247	23583981	In the present study, WGS and mRNA-seq revealed novel MYB and MYBL1 rearrangements that involved fusion with several different genes.	('fusion', 'Interaction', (97, 103))	('rearrangements', 'Var', (68, 82))	('MYB', 'Gene', '4602', (54, 57))	('MYB', 'Gene', (54, 57))	('MYBL1', 'Gene', (62, 67))	('MYB', 'Gene', '4602', (62, 65))	('MYB', 'Gene', (62, 65))	('MYBL1', 'Gene', '4603', (62, 67))
43248	23583981	While some MYB fusion partners have reported roles in oncogenesis, all detected aberrations can produce MYB overexpression by one of the two mechanisms described above.	('MYB', 'Gene', (11, 14))	('MYB', 'Gene', '4602', (104, 107))	('aberrations', 'Var', (80, 91))	('MYB', 'Gene', (104, 107))	('MYB', 'Gene', '4602', (11, 14))	('overexpression', 'PosReg', (108, 122))	('produce', 'Reg', (96, 103))
43249	23583981	Overall, mutually exclusive FGFR1 or MYB/MYBL1 aberrations were present in 56% of diffuse gliomas.	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('FGFR1', 'Gene', (28, 33))	('MYB', 'Gene', '4602', (37, 40))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('MYB', 'Gene', (37, 40))	('MYB', 'Gene', '4602', (41, 44))	('aberrations', 'Var', (47, 58))	('present', 'Reg', (64, 71))	('MYBL1', 'Gene', (41, 46))	('MYB', 'Gene', (41, 44))	('MYBL1', 'Gene', '4603', (41, 46))
43250	23583981	Our comprehensive analysis of NF1/RAF/RAS, FGFR1, and MYB abnormalities across a series of LGG/LGGNTs representative of the disease demonstrated that nearly all LGGs/LGGNTs in the spinal and posterior fossa compartments, which are dominated by PAs, are characterized by KIAA1549-BRAF fusion genes, while cerebral tumors, including most diffuse gliomas, are more heterogeneous.	('RAF', 'Gene', '22882', (34, 37))	('cerebral tumors', 'Disease', (304, 319))	('NF1', 'Gene', '4763', (30, 33))	('RAF', 'Gene', (280, 283))	('RAF', 'Gene', (34, 37))	('KIAA1549-BRAF', 'Disease', (270, 283))	('LGGs/LGGNTs', 'Disease', (161, 172))	('gliomas', 'Disease', (344, 351))	('NF1', 'Gene', (30, 33))	('MYB abnormalities', 'Disease', 'MESH:D000014', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('gliomas', 'Disease', 'MESH:D005910', (344, 351))	('MYB abnormalities', 'Disease', (54, 71))	('KIAA1549-BRAF', 'Disease', 'None', (270, 283))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('glioma', 'Phenotype', 'HP:0009733', (344, 350))	('cerebral tumors', 'Phenotype', 'HP:0030692', (304, 319))	('gliomas', 'Phenotype', 'HP:0009733', (344, 351))	('cerebral tumors', 'Disease', 'MESH:D001932', (304, 319))	('RAF', 'Gene', '22882', (280, 283))	('fusion genes', 'Var', (284, 296))
43251	23583981	A subset of 7 LGGs (4.7%), most with a concurrent BRAF abnormality, demonstrated H3F3A mutations or abnormalities in other genes linked to histone function; ATRX, EP300, WHSC1, and CHD2.	('BRAF abnormality', 'Disease', 'MESH:D000014', (50, 66))	('ATRX', 'Gene', (157, 161))	('abnormalities', 'Var', (100, 113))	('BRAF abnormality', 'Disease', (50, 66))	('WHSC1', 'Gene', '7468', (170, 175))	('H3F3A', 'Gene', (81, 86))	('CHD2', 'Gene', (181, 185))	('ATRX', 'Gene', '546', (157, 161))	('WHSC1', 'Gene', (170, 175))	('CHD2', 'Gene', '1106', (181, 185))	('EP300', 'Gene', (163, 168))	('EP300', 'Gene', '2033', (163, 168))	('mutations', 'Var', (87, 96))	('H3F3A', 'Gene', '3020', (81, 86))
43252	23583981	H3F3A mutations have recently been demonstrated in up to one third of pediatric glioblastomas, the most aggressive of high-grade gliomas (HGGs).	('glioblastomas', 'Disease', (80, 93))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('H3F3A', 'Gene', '3020', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('H3F3A', 'Gene', (0, 5))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('glioblastomas', 'Phenotype', 'HP:0012174', (80, 93))	('glioblastomas', 'Disease', 'MESH:D005909', (80, 93))	('mutations', 'Var', (6, 15))
43253	23583981	Midline tumors are associated with an H3F3A:p.K27M mutation and are particularly prevalent in diffuse pontine gliomas .	('associated', 'Reg', (19, 29))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('Midline tumors', 'Disease', (0, 14))	('H3F3A:p.K27M', 'Var', (38, 50))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('H3F3A:p.K27M', 'SUBSTITUTION', 'None', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Midline tumors', 'Disease', 'MESH:D009369', (0, 14))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('prevalent', 'Reg', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
43254	23583981	Although we detected an H3F3A:p.K27M mutation in only three (1.9%) of tumors in our series, this finding does indicate some overlap between the genetics of pediatric LGGs and HGGs, and it is notable that two of three diffuse grade II astrocytomas in which we found this mutation were thalamic; the other was from the cerebral cortex.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('H3F3A:p.K27M', 'Var', (24, 36))	('astrocytomas', 'Disease', 'MESH:D001254', (234, 246))	('H3F3A:p.K27M', 'SUBSTITUTION', 'None', (24, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (234, 245))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('diffuse', 'Disease', (217, 224))	('astrocytomas', 'Disease', (234, 246))
43256	23583981	None of these three tumors also contained a TP53 or ATRX mutation; instead one contained a KRAS:p.Q61H mutation and another a BRAF:p.V600E mutation.	('ATRX', 'Gene', '546', (52, 56))	('tumors', 'Disease', (20, 26))	('KRAS:p.Q61H', 'SUBSTITUTION', 'None', (91, 102))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('BRAF:p.V600E', 'Var', (126, 138))	('ATRX', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (126, 138))	('TP53', 'Gene', (44, 48))	('KRAS:p.Q61H', 'Var', (91, 102))
43257	23583981	Only one of 33 tested HGGs (3%), an anaplastic oligoastrocytoma that had progressed from a grade II tumor, contained an FGFR1 TKD duplication, and no MYB abnormalities were found.	('oligoastrocytoma', 'Disease', 'MESH:D001254', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('oligoastrocytoma', 'Disease', (47, 63))	('FGFR1', 'Gene', (120, 125))	('II tumor', 'Disease', (97, 105))	('TKD duplication', 'Var', (126, 141))	('II tumor', 'Disease', 'MESH:D009369', (97, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('MYB abnormalities', 'Disease', 'MESH:D000014', (150, 167))	('contained', 'Reg', (107, 116))	('MYB abnormalities', 'Disease', (150, 167))
43258	23583981	Any overlap between the genetics of adult high-grade gliomas (HGGs) and pediatric LGGs seems to be confined to rare FGFR1 missense mutations and FGFR-TACC fusions.	('missense mutations', 'Var', (122, 140))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('FGFR1', 'Gene', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
43262	23583981	Most adult grade II gliomas (>80%) display an IDH1 or IDH2 mutation, usually IDH1:p.R132H, which is considered to be an early transforming event.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('IDH2', 'Gene', (54, 58))	('IDH1:p.R132H', 'Var', (77, 89))	('IDH1', 'Gene', (46, 50))	('II gliomas', 'Disease', (17, 27))	('IDH2', 'Gene', '3418', (54, 58))	('IDH1', 'Gene', (77, 81))	('IDH1', 'Gene', '3417', (46, 50))	('IDH1', 'Gene', '3417', (77, 81))	('II gliomas', 'Disease', 'MESH:D005910', (17, 27))	('IDH1:p.R132H', 'SUBSTITUTION', 'None', (77, 89))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))
43263	23583981	About two thirds of adult diffuse gliomas with an astrocytic phenotype have a concurrent TP53 mutation, and >80% of grade II oligodendrogliomas show co-deletion of chromosomes 1p and 19q .	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('II oligodendrogliomas', 'Disease', 'MESH:D009837', (122, 143))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('gliomas', 'Disease', (136, 143))	('II oligodendrogliomas', 'Disease', (122, 143))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('mutation', 'Var', (94, 102))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
43265	23583981	Rarely, adult-type grade II disease can present in childhood , and our series contained one such example, an oligodendroglioma with an IDH1:p.R132H mutation, 1p/19q co-deletion, and CIC mutations.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('oligodendroglioma', 'Disease', 'MESH:D009837', (109, 126))	('1p/19q co-deletion', 'Var', (158, 176))	('CIC', 'Gene', '23152', (182, 185))	('IDH1:p.R132H', 'SUBSTITUTION', 'None', (135, 147))	('oligodendroglioma', 'Disease', (109, 126))	('IDH1:p.R132H', 'Var', (135, 147))	('CIC', 'Gene', (182, 185))	('child', 'Species', '9606', (51, 56))
43266	23583981	There is a high concordance between IDH1 and CIC mutations in adult oligodendrogliomas, suggesting cooperation between these genes .	('IDH1', 'Gene', (36, 40))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (68, 86))	('CIC', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', '3417', (36, 40))	('oligodendrogliomas', 'Disease', (68, 86))	('CIC', 'Gene', '23152', (45, 48))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
43268	23583981	LGGs with duplication of the FGFR1 TKD or MYB overexpression show activation of the MAPK/ERK and PI3K pathways, demonstrating immunoassay profiles that are similar to PAs with KIAA1549-BRAF fusions and suggesting potential targets for therapeutic intervention.	('KIAA1549-BRAF fusions', 'Disease', 'MESH:D000069337', (176, 197))	('MYB', 'Gene', (42, 45))	('ERK', 'Gene', '5594', (89, 92))	('MYB', 'Gene', '4602', (42, 45))	('ERK', 'Gene', (89, 92))	('duplication', 'Var', (10, 21))	('KIAA1549-BRAF fusions', 'Disease', (176, 197))	('FGFR1', 'Gene', (29, 34))	('activation', 'PosReg', (66, 76))
43269	23583981	Against a facilitative Tp53-null background in transplanted neonatal astrocytes, TKD-duplicated FGFR1 was transforming, rapidly generating high-grade astrocytic tumors that demonstrated combined activation of these signaling pathways.	('astrocytic tumors', 'Disease', 'MESH:D001254', (150, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('TKD-duplicated', 'Var', (81, 95))	('generating', 'Reg', (128, 138))	('activation', 'PosReg', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('FGFR1', 'Gene', (96, 101))	('astrocytic tumors', 'Disease', (150, 167))
43270	23583981	In vitro studies utilizing two cell lines transfected with TKD-duplicated FGFR1 constructs showed that the specific FGFR1 inhibitors PD173074 and BGJ398 and MEK1 inhibitor PD0325901 could block FGFR1 autophosphorylation and constitutive activation of the MAPK/ERK pathway respectively and that upregulation of the PI3K pathway could be blocked by the specific inhibitor BEZ235.	('PD173074', 'Var', (133, 141))	('BEZ235', 'Chemical', 'MESH:C531198', (370, 376))	('PD173074', 'Chemical', 'MESH:C115711', (133, 141))	('ERK', 'Gene', '5594', (260, 263))	('PI3K pathway', 'Pathway', (314, 326))	('FGFR1', 'Gene', (116, 121))	('BGJ398', 'Var', (146, 152))	('MEK1', 'Gene', '5604', (157, 161))	('ERK', 'Gene', (260, 263))	('FGFR1', 'Pathway', (194, 199))	('PD0325901', 'Var', (172, 181))	('MEK1', 'Gene', (157, 161))	('BGJ398', 'Chemical', 'MESH:C568950', (146, 152))	('PD0325901', 'Chemical', 'MESH:C506614', (172, 181))	('autophosphorylation', 'MPA', (200, 219))	('activation', 'PosReg', (237, 247))	('block', 'NegReg', (188, 193))
43275	23583981	Tissue was available at the time of diagnosis and relapse for 2 tumors (SJLGG006_D / R, SJLGG049_D / R).	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('SJLGG006_D / R', 'Var', (72, 86))	('SJLGG049_D / R', 'Var', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
43286	23583981	Non-silent coding variations present in tumor, but absent in normal tissue, were considered somatic mutations after manual review using the program consed.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Non-silent coding variations', 'Var', (0, 28))
43290	23583981	Full-length open reading frame cDNA for human wild-type FGFR1 and three FGFR1 duplication variants were amplified by reverse transcription-PCR from human brain RNA pools or LGG RNA from SJLGG006_D, SJLGG008_D, and SJLGG044_D, with forward primer FGFR1ex2-for (aactgggatgtggagctgga) and reverse primer FGFR1ex18-rev (cagtcagcggcgtttgagtc).	('SJLGG044_D', 'Var', (214, 224))	('human', 'Species', '9606', (148, 153))	('SJLGG008_D', 'Var', (198, 208))	('SJLGG006_D', 'Var', (186, 196))	('variants', 'Var', (90, 98))	('FGFR1', 'Gene', (72, 77))	('human', 'Species', '9606', (40, 45))
43291	23583981	After introducing 5' BamHI and 3' XhoI restriction sties by PCR, fragments encoding wt and duplication variants were sub-cloned into BamHI-XhoI digested retroviral vector MSCV-ires-GFP (MIG) to generate MIG-FGFR1-wt, MIG-FGFR1-Dp006, MIG-FGFR1-Dp008 and MIG-FGFR1-Dp044 constructs .	('MIG-FGFR1-Dp006', 'Var', (217, 232))	('MIG-FGFR1-Dp008', 'Var', (234, 249))	('MIG-FGFR1-Dp044', 'Var', (254, 269))	('MIG-FGFR1-wt', 'Var', (203, 215))	('MSCV', 'Species', '258023', (171, 175))
43295	23583981	The FGFR1 inhibitors BGJ398 and PD173074, MEK inhibitor PD0325901, and PI3K/mTOR inhibitor BEZ235 were dissolved in DMSO and added to cell cultures at a concentration of 100nM when used as single agents.	('BEZ235', 'Chemical', 'MESH:C531198', (91, 97))	('BGJ398', 'Chemical', 'MESH:C568950', (21, 27))	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('FGFR1', 'Gene', (4, 9))	('BGJ398', 'Gene', (21, 27))	('MEK', 'Gene', (42, 45))	('DMSO', 'Chemical', 'MESH:D004121', (116, 120))	('MEK', 'Gene', '5609', (42, 45))	('PD173074', 'Var', (32, 40))	('PD0325901', 'Chemical', 'MESH:C506614', (56, 65))	('PD173074', 'Chemical', 'MESH:C115711', (32, 40))
43297	23583981	FGFR1 retroviral constructs (MIG-FGFR1-wt, MIG-FGFR1-Dp006, MIG-FGFR1-Dp008) or control GFP retrovirus (MIG) were used to transduce p53-null early passage primary mouse astrocytes (PMAs) established from 2-day old GFAPcre;Trp53 mice, as previously described .	('MIG-FGFR1-Dp008', 'Var', (60, 75))	('p53', 'Gene', (224, 227))	('p53', 'Gene', '22059', (224, 227))	('Trp53', 'Gene', '22059', (222, 227))	('GFAP', 'Gene', (214, 218))	('p53', 'Gene', (132, 135))	('transduce', 'Reg', (122, 131))	('p53', 'Gene', '22059', (132, 135))	('GFAP', 'Gene', '2670', (214, 218))	('mouse', 'Species', '10090', (163, 168))	('Trp53', 'Gene', (222, 227))	('mice', 'Species', '10090', (228, 232))	('MIG-FGFR1-Dp006', 'Var', (43, 58))
43300	23583981	Immunohistochemistry using heat-mediated antigen retrieval in citrate buffer employed antibodies to GFAP (Z0334 at 1:1500) from Dako, Carpinteria, CA and phospho-Akt Ser473 (#9271 at 1:50), phospho-MAPK (#4370 at 1:400), and FGFR1 (#9740 at 1:500) from Cell Signaling, Beverly, MA.	('Z0334', 'Var', (106, 111))	('#4370', 'Var', (204, 209))	('GFAP', 'Gene', '2670', (100, 104))	('Akt', 'Gene', (162, 165))	('Ser473', 'Chemical', '-', (166, 172))	('#9740', 'Var', (232, 237))	('GFAP', 'Gene', (100, 104))	('FGFR1', 'Gene', (225, 230))	('#9271', 'Var', (174, 179))	('citrate', 'Chemical', 'MESH:D019343', (62, 69))	('Akt', 'Gene', '207', (162, 165))
43305	23583981	The immunoassay utilized antibodies to the following phosphoproteins: p-ERK1/2, p-MEK1, p-AKT, p-GSK3alpha/beta, p-c-JUN, p-P70 S6 kinase, and p-NF-kappaB p65.	('p-P70', 'Var', (122, 127))	('ERK1/2', 'Gene', (72, 78))	('MEK1', 'Gene', '5604', (82, 86))	('AKT', 'Gene', (90, 93))	('p-GSK3alpha/beta', 'Var', (95, 111))	('MEK1', 'Gene', (82, 86))	('ERK1/2', 'Gene', '5595;5594', (72, 78))	('c-JUN', 'Gene', '3725', (115, 120))	('p65', 'Gene', (155, 158))	('c-JUN', 'Gene', (115, 120))	('AKT', 'Gene', '207', (90, 93))	('p65', 'Gene', '5970', (155, 158))
43318	32987955	Primary glioblastoma primarily occurs in older patients (mean age, 62-64 years) and typically shows epidermal growth factor receptor (EGFR) overexpression, PTEN mutations, cyclin-dependent kinase inhibitor (CDKN2A) (p16) deletion, and, sometimes, mouse double minute 2 homolog (MDM2) amplification.	('PTEN', 'Gene', (156, 160))	('Primary glioblastoma', 'Disease', 'MESH:D005909', (0, 20))	('MDM2', 'Gene', '17246', (278, 282))	('patients', 'Species', '9606', (47, 55))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (172, 205))	('overexpression', 'PosReg', (140, 154))	('EGFR', 'Gene', '1956', (134, 138))	('deletion', 'Var', (221, 229))	('mouse double minute 2 homolog', 'Gene', '17246', (247, 276))	('PTEN', 'Gene', '5728', (156, 160))	('epidermal growth factor receptor', 'Gene', (100, 132))	('p16', 'Gene', (216, 219))	('epidermal growth factor receptor', 'Gene', '1956', (100, 132))	('p16', 'Gene', '1029', (216, 219))	('CDKN2A', 'Gene', (207, 213))	('mouse double minute 2 homolog', 'Gene', (247, 276))	('MDM2', 'Gene', (278, 282))	('cyclin-dependent kinase inhibitor', 'Gene', (172, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('EGFR', 'Gene', (134, 138))	('CDKN2A', 'Gene', '1029', (207, 213))	('mutations', 'Var', (161, 170))	('Primary glioblastoma', 'Disease', (0, 20))
43319	32987955	Secondary glioblastoma patients are generally younger (mean age, 45-48 years), and their tumors are characterized by TP53 mutations, 1p19q loss and isocitrate dehydrogenase (IDH) mutations, the latter suggested to be present in 70-80% of cases.	('IDH', 'Gene', '3417', (174, 177))	('tumors', 'Disease', (89, 95))	('1p19q loss', 'Var', (133, 143))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('isocitrate dehydrogenase', 'Gene', '3417', (148, 172))	('TP53', 'Gene', '7157', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('TP53', 'Gene', (117, 121))	('patients', 'Species', '9606', (23, 31))	('glioblastoma', 'Disease', (10, 22))	('mutations', 'Var', (122, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (10, 22))	('mutations', 'Var', (179, 188))	('IDH', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))	('isocitrate dehydrogenase', 'Gene', (148, 172))
43320	32987955	Patients with IDH mutations are considered to have a better prognosis, demonstrating an about twice-as-long median OS as patients with primary glioblastoma.	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('primary glioblastoma', 'Disease', 'MESH:D005909', (135, 155))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('primary glioblastoma', 'Disease', (135, 155))	('patients', 'Species', '9606', (121, 129))	('mutations', 'Var', (18, 27))
43321	32987955	Among 14 patients with IDH1 or IDH2 mutations, the median OS was reported to be 31 months, as compared to 15 months in 115 patients with IDH1 wild-type primary glioblastoma tumors.	('patients', 'Species', '9606', (9, 17))	('IDH2', 'Gene', '3418', (31, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('IDH1', 'Gene', (137, 141))	('IDH1', 'Gene', (23, 27))	('mutations', 'Var', (36, 45))	('primary glioblastoma', 'Disease', 'MESH:D005909', (152, 172))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('primary glioblastoma', 'Disease', (152, 172))	('IDH1', 'Gene', '3417', (23, 27))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (160, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('IDH1', 'Gene', '3417', (137, 141))	('IDH2', 'Gene', (31, 35))	('glioblastoma tumors', 'Disease', (160, 179))
43329	32987955	Patients with glioblastoma who have lower loads of CMV in their tumor at diagnosis appear to survive longer, and anti-CMV therapy in mouse models decreased tumor growth and improved survival.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('decreased', 'NegReg', (146, 155))	('glioblastoma', 'Disease', (14, 26))	('Patients', 'Species', '9606', (0, 8))	('survival', 'CPA', (182, 190))	('glioblastoma', 'Disease', 'MESH:D005909', (14, 26))	('improved', 'PosReg', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (156, 161))	('mouse', 'Species', '10090', (133, 138))	('anti-CMV', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
43343	32987955	O6-methylguanine-DNA methyltransferase (MGMT) promoter status and p53 and IDH mutations were tested in the pathology department at our hospital and reported when available.	('O6-methylguanine-DNA methyltransferase', 'Gene', (0, 38))	('p53', 'Gene', '7157', (66, 69))	('MGMT', 'Gene', '4255', (40, 44))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 38))	('mutations', 'Var', (78, 87))	('MGMT', 'Gene', (40, 44))	('IDH', 'Gene', (74, 77))	('men', 'Species', '9606', (123, 126))	('IDH', 'Gene', '3417', (74, 77))	('p53', 'Gene', (66, 69))
43366	32987955	The TP53 mutation status had been investigated in five cases in the primary tumors, and four of them had tumors with mutated TP53.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('primary tumors', 'Disease', (68, 82))	('mutated', 'Var', (117, 124))	('TP53', 'Gene', (4, 8))	('TP53', 'Gene', '7157', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('primary tumors', 'Disease', 'MESH:D001932', (68, 82))	('TP53', 'Gene', (125, 129))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', '7157', (4, 8))
43376	32987955	The MGMT promoter status was known for eight patients, of which three had secondary GBM with a methylated MGMT promoter.	('MGMT', 'Gene', '4255', (4, 8))	('methylated', 'Var', (95, 105))	('patients', 'Species', '9606', (45, 53))	('MGMT', 'Gene', '4255', (106, 110))	('MGMT', 'Gene', (106, 110))	('MGMT', 'Gene', (4, 8))
43377	32987955	The TP53 mutational status was investigated in the primary tumors of 19 patients, of which 15 had mutated TP53.	('TP53', 'Gene', (4, 8))	('primary tumors', 'Disease', (51, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('TP53', 'Gene', '7157', (4, 8))	('mutated', 'Var', (98, 105))	('primary tumors', 'Disease', 'MESH:D001932', (51, 65))	('TP53', 'Gene', '7157', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('TP53', 'Gene', (106, 110))	('patients', 'Species', '9606', (72, 80))
43393	32987955	Thus, targeting CMV in glioblastoma continues to show potential treatment benefits, representing a promising new therapy option, in need of further evaluation in randomized trials.	('men', 'Species', '9606', (69, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('targeting', 'Var', (6, 15))	('CMV', 'Gene', (16, 19))	('glioblastoma', 'Disease', (23, 35))
43394	32987955	Can CMV promote tumor progression and thereby explain the potential positive effect of anti-viral therapy in glioblastoma patients?	('glioblastoma', 'Disease', (109, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('CMV', 'Var', (4, 7))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Disease', (16, 21))	('promote', 'PosReg', (8, 15))
43397	32987955	CMV may, therefore, promote progression from low-grade to high-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('CMV', 'Var', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('promote', 'PosReg', (20, 27))	('low-grade', 'Disease', (45, 54))
43398	32987955	In experimental models, CMV proteins can cause all the ten hallmarks of cancer, and certain viral strains have been shown to induce oncogenic transformation.	('CMV', 'Var', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('induce', 'Reg', (125, 131))	('men', 'Species', '9606', (9, 12))	('cause', 'Reg', (41, 46))	('oncogenic transformation', 'CPA', (132, 156))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
43406	32987955	Thus, the presence of this virus in glioblastoma may confer higher aggressive potential to virus-positive tumor cells.	('aggressive potential', 'CPA', (67, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('higher', 'PosReg', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('presence', 'Var', (10, 18))	('glioblastoma', 'Disease', (36, 48))	('tumor', 'Disease', (106, 111))
43413	32987955	In another mouse model, CMV promoted glioblastoma development, which was prevented with anti-viral therapy.	('mouse', 'Species', '10090', (11, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (37, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('CMV', 'Var', (24, 27))	('promoted', 'PosReg', (28, 36))	('men', 'Species', '9606', (57, 60))	('glioblastoma', 'Disease', (37, 49))
43425	32987955	Both patients with methylated MGMT and those with an unmethylated MGMT promoter showed potential benefit from valganciclovir treatment.	('methylated', 'Var', (19, 29))	('men', 'Species', '9606', (130, 133))	('MGMT', 'Gene', (66, 70))	('patients', 'Species', '9606', (5, 13))	('MGMT', 'Gene', '4255', (66, 70))	('valganciclovir', 'Chemical', 'MESH:D000077562', (110, 124))	('benefit', 'PosReg', (97, 104))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))
43427	32987955	Mitchell and Sampsons' teams have also shown promising effects from dendritic cell therapy using CMV-pp65-mRNA-pulsed dendritic cells in patients with glioblastoma, which provides further support for the hypothesis that CMV can represent a target for therapy in patients with glioblastoma.	('effects', 'Reg', (55, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (276, 288))	('CMV-pp65-mRNA-pulsed', 'Var', (97, 117))	('glioblastoma', 'Disease', (151, 163))	('patients', 'Species', '9606', (137, 145))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('patients', 'Species', '9606', (262, 270))	('glioblastoma', 'Disease', (276, 288))	('glioblastoma', 'Disease', 'MESH:D005909', (276, 288))
43436	32987955	However, in an animal model, we observed that the tumor growth of human xenografted tumors was only prevented in CMV-positive tumors but was not evident in a CMV-negative tumor.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('human', 'Species', '9606', (66, 71))	('CMV-positive', 'Var', (113, 125))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('prevented', 'NegReg', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (171, 176))
43451	32987955	holds an unlicensed patent on diagnostics and treatment of a variant CMV strain highly associated with cancer titled "Genetic variant of cytomegalovirus (CMV)."	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('men', 'Species', '9606', (51, 54))	('variant', 'Var', (61, 68))	('associated', 'Reg', (87, 97))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
43456	32300588	In particular, SLK was more likely to be cancer-related due to its high missense mutation rate and associated with cell adhesion.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('missense mutation', 'Var', (72, 89))	('SLK', 'Gene', '9748', (15, 18))	('SLK', 'Gene', (15, 18))	('cell adhesion', 'CPA', (115, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('associated', 'Reg', (99, 109))
43467	32300588	developed a prognostic 3-miRNA classifier (miR-106b-5p, miR-148a-3p, and miR-338-3p) in early-stage mycosis fungoides.	('miR-338-3p', 'Var', (73, 83))	('miR-148a-3p', 'Var', (56, 67))	('miR-106b', 'Gene', '406900', (43, 51))	('early-stage mycosis fungoides', 'Disease', (88, 117))	('miR-106b', 'Gene', (43, 51))
43499	32300588	Univariate Cox proportional hazards regression model was used to identify candidate survival-related genes from each omics data through the formula: where the explanatory variable X was the omics data (DM, GE, copy number variation, or miRNA expression) of a gene, and the response variable t was the survival time.	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('DM', 'Disease', 'MESH:D009223', (202, 204))	('copy number variation', 'Var', (210, 231))	('survival-related', 'Gene', (84, 100))	('survival-related', 'Gene', '54897', (84, 100))
43557	32300588	We found that SLK had an unconservative exon region, which containing four missense variants (Figure 7A).	('missense', 'Var', (75, 83))	('SLK', 'Gene', '9748', (14, 17))	('SLK', 'Gene', (14, 17))
43558	32300588	In order to further verify the close relationship of SLK and cancer, we checked the mutation of SLK in the COSMIC database, and found that missense substitution occurred in 36.93% of the samples (Figure 7B).	('missense substitution', 'Var', (139, 160))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('SLK', 'Gene', '9748', (53, 56))	('SLK', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('SLK', 'Gene', '9748', (96, 99))	('occurred', 'Reg', (161, 169))	('SLK', 'Gene', (96, 99))
43568	32300588	Based on the COSMIC database, we found extensive mutations occurred in EPRS, and 70% of them were missense mutation.	('EPRS', 'Gene', (71, 75))	('missense mutation', 'Var', (98, 115))	('EPRS', 'Gene', '2058', (71, 75))	('mutations', 'Var', (49, 58))
43575	32300588	These locations were the peak regions of copy number alternation, suggesting a relationship between these genes and cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('relationship', 'Reg', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('copy number', 'Var', (41, 52))
43600	32300588	Cell adhesion plays an important role in the maintenance of tissue structure, whose abnormality results in tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('metastasis', 'CPA', (126, 136))	('results in', 'Reg', (96, 106))	('abnormality', 'Var', (84, 95))
43621	30143669	Functional assays demonstrated that PR-LncRNA silencing increased glioma cell proliferation and oncosphere formation.	('glioma', 'Disease', (66, 72))	('PR-LncRNA', 'Protein', (36, 45))	('increased', 'PosReg', (56, 65))	('silencing', 'Var', (46, 55))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('oncosphere formation', 'CPA', (96, 116))
43623	30143669	Moreover, knock-down of SOX activity abolished the effect of PR-LncRNA silencing in glioma cell activity.	('PR-LncRNA', 'Protein', (61, 70))	('glioma', 'Disease', (84, 90))	('silencing', 'NegReg', (71, 80))	('knock-down', 'Var', (10, 20))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('abolished', 'NegReg', (37, 46))
43635	30143669	Increasing evidence is demonstrating that frequent major genomic mutations in cancer reside inside this vast majority of regions that do not encode proteins.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (65, 74))
43636	30143669	Thus, mutations and dysregulations of lncRNAs contribute to the development of several human complex diseases, including cancer.	('contribute', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (87, 92))	('dysregulations', 'Var', (20, 34))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('lncRNAs', 'Gene', (38, 45))	('cancer', 'Disease', (121, 127))	('mutations', 'Var', (6, 15))
43641	30143669	Moreover, abnormal LncRNA function plays critical roles in the development and progression of gliomas, controlling processes such as proliferation, apoptosis, self-renewal and migration.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('LncRNA', 'Protein', (19, 25))	('gliomas', 'Disease', (94, 101))	('abnormal', 'Var', (10, 18))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
43647	30143669	Since mutations on p53 are common and p53 pathway is frequently deregulated in gliomas, in this work, we characterized the expression and function of the PR-LncRNA signature, by studying the expression and clinical relevance of four members of this signature in human glioma samples of different grades and assessing the effect of loss of function in glioma cells.	('glioma', 'Disease', (268, 274))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('p53', 'Gene', (19, 22))	('glioma', 'Disease', 'MESH:D005910', (268, 274))	('glioma', 'Disease', (351, 357))	('clinical', 'Species', '191496', (206, 214))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('human', 'Species', '9606', (262, 267))	('glioma', 'Disease', 'MESH:D005910', (351, 357))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('mutations', 'Var', (6, 15))	('p53', 'Gene', '7157', (38, 41))	('glioma', 'Phenotype', 'HP:0009733', (351, 357))	('deregulated', 'Reg', (64, 75))	('gliomas', 'Disease', (79, 86))	('p53', 'Gene', (38, 41))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('p53', 'Gene', '7157', (19, 22))
43655	30143669	Glioma cell lines U87-MG (U87), U373MG (U373), U251MG (U251) and A172 purchased from the ATCC, were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco), 100 U/ml penicillin and 100 microg/ml streptomycin for traditional monolayer cultures.	('DMEM', 'Chemical', '-', (112, 116))	('U251MG', 'CellLine', 'CVCL:0021', (47, 53))	('U251MG', 'Var', (47, 53))	('U373MG', 'CellLine', 'CVCL:2219', (32, 38))	('FBS', 'Disease', (147, 150))	('FBS', 'Disease', 'MESH:D005198', (147, 150))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('U87-MG', 'CellLine', 'CVCL:0022', (18, 24))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('streptomycin', 'Chemical', 'MESH:D013307', (198, 210))	('Glioma', 'Disease', (0, 6))	('U373MG', 'Var', (32, 38))	('penicillin', 'Chemical', 'MESH:D010406', (169, 179))
43690	30143669	We observed that majority of samples with high levels of PR-LncRNAs had wild type p53, while over 50% of cases with low expression of PR-LncRNAs had mutated p53 genes, although this difference was not statistically significant (Fig.	('mutated', 'Var', (149, 156))	('p53', 'Gene', (157, 160))	('p53', 'Gene', '7157', (82, 85))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (157, 160))
43698	30143669	Moreover, the expression of p53 downstream targets such as p21cip, BAX and SerpinB5 was lower in cells transfected with ASOs for PR-LncRNA1 and 10 (Fig.	('p53', 'Gene', (28, 31))	('p21cip', 'Var', (59, 65))	('p53', 'Gene', '7157', (28, 31))	('ASO', 'Chemical', 'MESH:D016376', (120, 123))	('expression', 'MPA', (14, 24))	('BAX', 'Gene', (67, 70))	('SerpinB5', 'Gene', '5268', (75, 83))	('BAX', 'Gene', '581', (67, 70))	('lower', 'NegReg', (88, 93))	('SerpinB5', 'Gene', (75, 83))	('PR-LncRNA1 and 10', 'Gene', '105371267', (129, 146))
43702	30143669	Moreover, the ability to form oncospheres was significantly elevated in cells with silencing of PR-LncRNA1 and 10 expression (Fig.	('elevated', 'PosReg', (60, 68))	('PR-LncRNA1 and 10', 'Gene', '105371267', (96, 113))	('silencing', 'Var', (83, 92))
43712	30143669	On the contrary, cells with overexpression and silencing of SOX1, SOX2 and SOX9 do not present a clear pattern of decreased and increased levels of PR-LncRNAs respectively (Fig.	('SOX9', 'Gene', (75, 79))	('SOX2', 'Gene', '6657', (66, 70))	('SOX2', 'Gene', (66, 70))	('levels', 'MPA', (138, 144))	('SOX9', 'Gene', '6662', (75, 79))	('increased', 'PosReg', (128, 137))	('SOX1', 'Gene', '6656', (60, 64))	('silencing', 'Var', (47, 56))	('SOX1', 'Gene', (60, 64))	('PR-LncRNAs', 'MPA', (148, 158))
43715	30143669	Interestingly, silencing of SOX1 or SOX9 abolished the increase in proliferation and oncosphere formation promoted by PR-LncRNA1 and 10 inhibition (Fig.	('SOX1', 'Gene', '6656', (28, 32))	('increase', 'PosReg', (55, 63))	('SOX1', 'Gene', (28, 32))	('abolished', 'NegReg', (41, 50))	('silencing', 'Var', (15, 24))	('inhibition', 'NegReg', (136, 146))	('proliferation', 'CPA', (67, 80))	('oncosphere formation', 'CPA', (85, 105))	('SOX9', 'Gene', (36, 40))	('PR-LncRNA1 and 10', 'Gene', '105371267', (118, 135))	('SOX9', 'Gene', '6662', (36, 40))
43730	30143669	Deregulation of the p53 pathway is well known to occur and play a major role in the development and progression of several types of cancer including glioblastoma.	('glioblastoma', 'Disease', (149, 161))	('p53', 'Gene', (20, 23))	('cancer', 'Disease', (132, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('p53', 'Gene', '7157', (20, 23))	('Deregulation', 'Var', (0, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('role', 'Reg', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
43741	30143669	Indeed, silencing of the PR-LncRNAs1 and 10 significantly increased the oncosphere formation ability of glioma cells and their self-renewal potential.	('increased', 'PosReg', (58, 67))	('silencing', 'Var', (8, 17))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('PR-LncRNAs1', 'Gene', (25, 36))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('self-renewal potential', 'CPA', (127, 149))	('glioma', 'Disease', (104, 110))
43747	30143669	Moreover, experiments in vitro revealed that their levels, especially of SOX1 and SOX2, were significantly elevated in PR-LncRNA silencing cells and that knock-down of SOX1 and SOX9 expression dramatically reduced the pro-oncogenic activities promoted by PR-LncRNA silencing in glioma cells.	('levels', 'MPA', (51, 57))	('knock-down', 'Var', (154, 164))	('reduced', 'NegReg', (206, 213))	('SOX1', 'Gene', '6656', (73, 77))	('pro-oncogenic activities', 'CPA', (218, 242))	('SOX1', 'Gene', (73, 77))	('SOX1', 'Gene', (168, 172))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('SOX2', 'Gene', '6657', (82, 86))	('SOX9', 'Gene', (177, 181))	('glioma', 'Disease', (278, 284))	('SOX2', 'Gene', (82, 86))	('SOX1', 'Gene', '6656', (168, 172))	('elevated', 'PosReg', (107, 115))	('SOX9', 'Gene', '6662', (177, 181))
43766	18445660	Glioblastoma shows the greatest range of genetic abnormalities, with common changes in the de novo tumours including homozygous deletion of CDKN2A, CDKN2B, and p14ARF (9p21), loss of one allele and mutation of the retained allele of PTEN (10q23) and amplification of the EGFR gene (7p12).	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('eta', 'Gene', '1909', (215, 218))	('CDKN2A', 'Gene', '1029', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('Glioblastoma', 'Disease', (0, 12))	('EGFR', 'Gene', (271, 275))	('amplification', 'Var', (250, 263))	('eta', 'Gene', (215, 218))	('PTEN', 'Gene', (233, 237))	('CDKN2B', 'Gene', (148, 154))	('p14ARF', 'Gene', '1029', (160, 166))	('loss', 'NegReg', (175, 179))	('EGFR', 'Gene', '1956', (271, 275))	('mutation', 'Var', (198, 206))	('PTEN', 'Gene', '5728', (233, 237))	('genetic abnormalities', 'Disease', 'MESH:D030342', (41, 62))	('CDKN2A', 'Gene', (140, 146))	('CDKN2B', 'Gene', '1030', (148, 154))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('p21', 'Gene', (169, 172))	('tumours', 'Disease', (99, 106))	('genetic abnormalities', 'Disease', (41, 62))	('p21', 'Gene', '644914', (169, 172))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('p14ARF', 'Gene', (160, 166))	('deletion', 'Var', (128, 136))
43833	18445660	The 4 ambiguous AA tumours classified by our ANN as ANGIO comprised 100% (2/2) of the EGFR amplifications, 100% (2/2) PTEN mutations and 66% (2/3) of the CDKNA/B nullizygosity found across all the AA samples assessed.	('amplifications', 'Var', (91, 105))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('EGFR', 'Gene', '1956', (86, 90))	('PTEN', 'Gene', '5728', (118, 122))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('PTEN', 'Gene', (118, 122))	('EGFR', 'Gene', (86, 90))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('A tumour', 'Disease', (17, 25))	('A tumour', 'Disease', 'MESH:D009369', (17, 25))	('mutations', 'Var', (123, 132))
43836	18445660	Although GB154 had some non-classic GB characteristics, the presence of amplification of CDK4, necrosis and microvascular proliferation, the latter being major histological criteria for glioblastoma, support the original histopathological diagnosis.	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('amplification', 'Var', (72, 85))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('GB', 'Chemical', '-', (36, 38))	('GB', 'Chemical', '-', (9, 11))	('necrosis', 'Disease', (95, 103))	('CDK4', 'Gene', (89, 93))	('CDK4', 'Gene', '1019', (89, 93))	('necrosis', 'Disease', 'MESH:D009336', (95, 103))	('glioblastoma', 'Disease', (186, 198))	('microvascular proliferation', 'CPA', (108, 135))
43850	18445660	TP53 mutations are observed in over 65% of secondary GB and are considered a major hallmark that defines the separate molecular pathways, responsible for the development of the secondary GB and the primary (de novo) GB.	('TP53', 'Gene', '7157', (0, 4))	('GB', 'Chemical', '-', (216, 218))	('TP53', 'Gene', (0, 4))	('GB', 'Chemical', '-', (187, 189))	('mutations', 'Var', (5, 14))	('GB', 'Chemical', '-', (53, 55))	('secondary GB', 'Disease', (43, 55))
43851	18445660	In order to identify genes with distinct signatures for these two separate pathways, we performed a leave-one-out cross-validation using only the GB - separated into TP53 mutated and wild-type- and identified an optimum set of 11 probes (see supplementary information Table F).	('mutated', 'Var', (171, 178))	('TP53', 'Gene', '7157', (166, 170))	('TP53', 'Gene', (166, 170))	('GB', 'Chemical', '-', (146, 148))
43858	18445660	Finally, ANN analysis of TP53 mutated and wild-type samples identified a gene signature that appears to further separate the ANGIO subtype into two groups reflecting primary and secondary GB.	('TP53', 'Gene', (25, 29))	('ANGIO', 'Disease', (125, 130))	('mutated', 'Var', (30, 37))	('GB', 'Chemical', '-', (188, 190))	('TP53', 'Gene', '7157', (25, 29))
43884	32197031	Based on messenger RNA (mRNA) data from the Cancer Genome Atlas (TCGA) and CCGA dataset, combined with related clinical information, we detected the expression of CTGF mRNA in glioma and assessed its effect on the prognosis of glioma patients.	('Cancer', 'Disease', (44, 50))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('Cancer', 'Disease', 'MESH:D009369', (44, 50))	('CTGF', 'Gene', '1490', (163, 167))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('CTGF', 'Gene', (163, 167))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('Cancer', 'Phenotype', 'HP:0002664', (44, 50))	('patients', 'Species', '9606', (234, 242))	('mRNA', 'Var', (168, 172))	('glioma', 'Disease', (227, 233))
43892	32197031	Inhibiting CTGF expression could significantly suppress the proliferation, migration, and invasion of gliomas.	('Inhibiting', 'Var', (0, 10))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('CTGF', 'Gene', '1490', (11, 15))	('CTGF', 'Gene', (11, 15))	('suppress', 'NegReg', (47, 55))	('gliomas', 'Disease', (102, 109))	('proliferation', 'CPA', (60, 73))	('migration', 'CPA', (75, 84))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('invasion', 'CPA', (90, 98))
43904	32197031	According to previous reports, the role of deregulated CTGF is complicated with a tissue-dependent manner, related to angiogenesis and modulated signal pathways including Wnt.	('related', 'Reg', (107, 114))	('deregulated', 'Var', (43, 54))	('CTGF', 'Gene', (55, 59))	('angiogenesis', 'CPA', (118, 130))	('CTGF', 'Gene', '1490', (55, 59))
43948	32197031	The median OS among patients with higher CTGF expression was 35.4 months compared to 63.3 months among those with lower expression in TCGA databases (P < 0.01).	('CTGF', 'Gene', (41, 45))	('expression', 'Var', (46, 56))	('patients', 'Species', '9606', (20, 28))	('CTGF', 'Gene', '1490', (41, 45))
43949	32197031	The median OS among patients with higher CTGF expression was 26.97 months compared to 55.1 months among those with lower expression in CGGA databases (P < 0.01).	('CTGF', 'Gene', (41, 45))	('expression', 'Var', (46, 56))	('patients', 'Species', '9606', (20, 28))	('CTGF', 'Gene', '1490', (41, 45))
43951	32197031	Glioma patients with low CTGF expression levels had better survival than those with high expression.	('expression', 'MPA', (30, 40))	('CTGF', 'Gene', (25, 29))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('better', 'PosReg', (52, 58))	('survival', 'CPA', (59, 67))	('low', 'Var', (21, 24))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('CTGF', 'Gene', '1490', (25, 29))	('patients', 'Species', '9606', (7, 15))
43953	32197031	After being assessed by RT-PCR, transcriptional levels of CTGF decreased up to 75.0% and 99.8% in siCTGF-seg1 transfected, 23.0% and 62.0% in siCTGF-seg2 transfected, 86.0% and 87.0% in siCTGF-seg3 transfected U251 cells and U87 cells respectively, compared to the negative control (NC) groups.	('CTGF', 'Gene', '1490', (100, 104))	('CTGF', 'Gene', (144, 148))	('CTGF', 'Gene', (100, 104))	('transcriptional levels', 'MPA', (32, 54))	('CTGF', 'Gene', '1490', (58, 62))	('CTGF', 'Gene', (58, 62))	('decreased', 'NegReg', (63, 72))	('U87', 'Gene', (225, 228))	('transfected', 'Var', (110, 121))	('U87', 'Gene', '641648', (225, 228))	('CTGF', 'Gene', '1490', (144, 148))	('CTGF', 'Gene', '1490', (188, 192))	('CTGF', 'Gene', (188, 192))	('transfected', 'Var', (154, 165))
43960	32197031	After 48 h transfection, cells exhibited an increase in the cell fraction in G1 phase (U251-NC 34.68%, U251-siCTGF 44.87%, U87-NC 67.66%, U87-siCTGF 72.05%, P < 0.0001) with a corresponding reduction in the fraction of cells in S and G2/M phase.	('U87', 'Gene', (138, 141))	('reduction', 'NegReg', (190, 199))	('CTGF', 'Gene', (144, 148))	('G1 phase', 'CPA', (77, 85))	('U87', 'Gene', '641648', (138, 141))	('CTGF', 'Gene', '1490', (110, 114))	('CTGF', 'Gene', (110, 114))	('increase', 'PosReg', (44, 52))	('U87', 'Gene', (123, 126))	('transfection', 'Var', (11, 23))	('U87', 'Gene', '641648', (123, 126))	('CTGF', 'Gene', '1490', (144, 148))
43973	32197031	Interestingly, we found that knockdown of CTGF expression downregulated cell proliferation, migration, and invasion of glioma cells in vitro.	('CTGF', 'Gene', '1490', (42, 46))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('CTGF', 'Gene', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('knockdown', 'Var', (29, 38))	('downregulated', 'NegReg', (58, 71))	('cell proliferation', 'CPA', (72, 90))	('glioma', 'Disease', (119, 125))	('migration', 'CPA', (92, 101))
44047	31967990	NICK with STRING Text Mining) do improve the performance of within-dataset cross-validation (using only GDSC samples) compared to LASSO (see Supplementary Methods in S1 Text).	('improve', 'PosReg', (33, 40))	('cross-validation', 'Var', (75, 91))	('LASSO', 'Chemical', 'MESH:C000188', (130, 135))
44050	31967990	For our analysis, we focused on variations of LASSO (without including gene interactions), which previously yielded the best performance among all the tested algorithms (Table 1).	('variations', 'Var', (32, 42))	('LASSO', 'Gene', (46, 51))	('LASSO', 'Chemical', 'MESH:C000188', (46, 51))
44081	31967990	More importantly, the knockdown or overexpression of many of the identified genes has been shown to influence the sensitivity of cancer cells to these drugs.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('knockdown', 'Var', (22, 31))	('overexpression', 'PosReg', (35, 49))	('influence', 'Reg', (100, 109))
44082	31967990	For example, the shRNA knockdown of CHI3L1, a gene identified for etoposide and cisplatin response in every tissue (but was not identified using LASSO for any of these drugs), has been shown to sensitize glioma cells to these two drugs, while its overexpression reduced their sensitivity.	('CHI3L1', 'Gene', '1116', (36, 42))	('sensitize', 'Reg', (194, 203))	('reduced', 'NegReg', (262, 269))	('glioma', 'Disease', (204, 210))	('knockdown', 'Var', (23, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('overexpression', 'PosReg', (247, 261))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('CHI3L1', 'Gene', (36, 42))	('sensitivity', 'MPA', (276, 287))	('LASSO', 'Chemical', 'MESH:C000188', (145, 150))	('etoposide', 'Chemical', 'MESH:D005047', (66, 75))
44083	31967990	As another example, the knockdown of SALL4 (identified in all tissues) in cancer cell lines has been shown to increase the sensitivity of lung cancer cells and esophageal squamous cell carcinoma cells to cisplatin.	('increase', 'PosReg', (110, 118))	('sensitivity', 'MPA', (123, 134))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Disease', (74, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('esophageal squamous cell carcinoma', 'Disease', (160, 194))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('SALL4', 'Gene', (37, 42))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (204, 213))	('lung cancer', 'Disease', (138, 149))	('knockdown', 'Var', (24, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (160, 194))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('SALL4', 'Gene', '57167', (37, 42))
44103	31967990	In addition, its knockdown has been shown to inhibit glioma cell proliferation and invasion and has been suggested as a therapeutic target for glioma.	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Disease', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Disease', (143, 149))	('invasion', 'CPA', (83, 91))	('knockdown', 'Var', (17, 26))	('inhibit', 'NegReg', (45, 52))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
44150	31967990	Then, given the predicted log(IC50) values of the tumors and their annotation as 'sensitive' or 'resistant' (based on their known CDR), we defined  where R100-K is the number of resistant tumors whose predicted log(IC50) is larger than t100-K, SK is the number of sensitive tumors whose predicted log(IC50) is smaller than tK, N100-K is the total number of tumors whose predicted log(IC50) is larger than t100-K, and NK is the total number of tumors whose predicted log(IC50) is smaller than tK.	('R100-K', 'Var', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (443, 449))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('sensitive tumors', 'Disease', 'MESH:D009369', (264, 280))	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (443, 448))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('tumors', 'Disease', (443, 449))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Disease', (357, 363))	('sensitive tumors', 'Disease', (264, 280))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (443, 449))	('tumors', 'Disease', 'MESH:D009369', (357, 363))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
44151	31967990	Intuitively, this measure shows the precision of predicting the tumors with predicted log(IC50) values larger than t100-K as resistant and those with predicted log(IC50) values smaller than tK as sensitive.	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('t100-K', 'Var', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
44164	26268363	In addition, assessment of tumor type and genetic biomarkers (e.g., 1p19q status) may provide valuable information on the response of a given therapy for LGG.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('1p19q status', 'Var', (68, 80))	('tumor', 'Disease', (27, 32))	('LGG', 'Disease', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
44180	26268363	proposed a content-based active contour for segmentation of brain tumors in different types of MR images (i.e., pre-contrast T1W, post-contrast T1W, and T2W).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('brain tumors', 'Disease', 'MESH:D001932', (60, 72))	('T1W', 'Var', (144, 147))	('brain tumors', 'Phenotype', 'HP:0030692', (60, 72))	('brain tumors', 'Disease', (60, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (60, 71))	('T1W', 'Var', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('T2W', 'Var', (153, 156))
44191	26268363	It provides anatomical images (T1W, T2W, and proton density) and probabilistic tissue images (CSF probability, white matter (WM) probability, gray matter (GM) probability, and tissue labels).	('T1W', 'Var', (31, 34))	('white matter', 'Disease', (111, 123))	('white matter', 'Disease', 'MESH:D056784', (111, 123))
44262	18952580	Children with low-grade gliomatypically present with an insidious onset of symptoms suggestive of intracranial hypertension or a protracted history of seizures.	('Children', 'Species', '9606', (0, 8))	('low-grade', 'Var', (14, 23))	('seizures', 'Disease', 'MESH:D012640', (151, 159))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('hypertension', 'Phenotype', 'HP:0000822', (111, 123))	('intracranial hypertension', 'Disease', (98, 123))	('seizures', 'Disease', (151, 159))	('seizures', 'Phenotype', 'HP:0001250', (151, 159))	('intracranial hypertension', 'Phenotype', 'HP:0002516', (98, 123))	('glioma', 'Disease', (24, 30))	('intracranial hypertension', 'Disease', 'MESH:D019586', (98, 123))
44268	18952580	The treatment of choice for low-grade gliomas that are in favorable locations is gross total resection (Figure 3).	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('gliomas', 'Disease', (38, 45))	('gross total', 'Var', (81, 92))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
44279	18952580	Childhood high-grade gliomas consistently display more frequent chromosomal aberrations and imbalance with multiple regions of abnormality.	('chromosomal aberrations', 'Var', (64, 87))	('frequent chromosomal aberrations', 'Phenotype', 'HP:0040012', (55, 87))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('imbalance', 'Phenotype', 'HP:0002172', (92, 101))	('gliomas', 'Disease', (21, 28))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
44294	18952580	A significant association between overexpression of p53 and outcome in high-grade glioma has been described; 5-year progression free survival was 44 +- 6% in the group with low-level expression of p53 and 17 +- 6% in the group with overexpression of p53.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('low-level expression', 'Var', (173, 193))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('p53', 'Gene', (197, 200))	('p53', 'Gene', (250, 253))	('p53', 'Gene', '7157', (197, 200))	('p53', 'Gene', '7157', (250, 253))	('glioma', 'Disease', (82, 88))
44404	21029453	The highly-regulated Wnt signal transduction pathway is essential for normal developmental processes, and defects in the pathway are closely linked to oncogenesis.	('linked', 'Reg', (141, 147))	('Wnt', 'Gene', (21, 24))	('Wnt', 'Gene', '32838', (21, 24))	('oncogenesis', 'Disease', (151, 162))	('defects', 'Var', (106, 113))
44421	21029453	early activation by mutation in APC or beta-catenin occurs in a proportion of carcinomas.	('carcinomas', 'Disease', (78, 88))	('APC', 'Disease', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutation', 'Var', (20, 28))	('beta-catenin', 'Protein', (39, 51))	('APC', 'Phenotype', 'HP:0005227', (32, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('APC', 'Disease', 'MESH:D011125', (32, 35))	('activation', 'PosReg', (6, 16))	('carcinomas', 'Disease', 'MESH:D002277', (78, 88))
44431	21029453	However, one recent report has demonstrated that restoration of DKK-1 expression suppresses cell growth and induces apoptotic cell death in beta-catenin-deficient mesothelioma cell lines H28 and MS-1.	('restoration', 'Var', (49, 60))	('suppresses', 'NegReg', (81, 91))	('cell growth', 'CPA', (92, 103))	('deficient mesothelioma', 'Disease', 'MESH:D008654', (153, 175))	('DKK-1', 'Gene', (64, 69))	('induces', 'Reg', (108, 115))	('deficient mesothelioma', 'Disease', (153, 175))	('death', 'Disease', (131, 136))	('death', 'Disease', 'MESH:D003643', (131, 136))
44432	21029453	Similarly, DKK-1 sensitized HeLa cervical carcinoma cells to apoptosis, acting as a suppressor of cell transformation.	('apoptosis', 'CPA', (61, 70))	('sensitized', 'Reg', (17, 27))	('DKK-1', 'Var', (11, 16))	('HeLa cervical carcinoma', 'Disease', 'MESH:D002575', (28, 51))	('HeLa cervical carcinoma', 'Disease', (28, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
44433	21029453	This effect of DKK-1 was not due to inhibition of beta-catenin/TCF4-regulated transcription, as the cellular localization of beta-catenin and activities of targets in the Wnt/beta-catenin pathway remained unchanged.	('TCF4', 'Gene', '6925', (63, 67))	('TCF4', 'Gene', (63, 67))	('Wnt', 'Gene', (171, 174))	('activities', 'MPA', (142, 152))	('Wnt', 'Gene', '32838', (171, 174))	('DKK-1', 'Var', (15, 20))
44434	21029453	These data suggest that DKK-1 may be able to antagonize Wnt signaling and have additional tumor suppressive effects through beta-catenin-independent non-canonical pathways (i.e., the Wnt/JNK pathway).	('Wnt', 'Gene', '32838', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('DKK-1', 'Var', (24, 29))	('Wnt', 'Gene', '32838', (56, 59))	('antagonize', 'NegReg', (45, 55))	('Wnt', 'Gene', (183, 186))	('beta-catenin-independent non-canonical pathways', 'Pathway', (124, 171))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Wnt', 'Gene', (56, 59))
44439	21029453	It has been demonstrated that the progression and development of glioma is closely-related with the overexpression of several oncogenes and inactivation of tumor suppressor genes, however, the specific molecular mechanism remains largely unknown.	('inactivation', 'Var', (140, 152))	('glioma', 'Disease', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('overexpression', 'PosReg', (100, 114))
44443	21029453	The 14 cancer cell lines used in this study included twelve glioblastomas (U251, SF767, SF295, T98G, MGR1, MGR2, MGR3, SKMG-1, SKMG-4, UWR7, UW-28, and SKI-N2), one medulloblastoma (D341), and one low-grade glioma (SHG-44).	('SKI', 'Gene', (152, 155))	('SHG-44', 'CellLine', 'CVCL:6728', (215, 221))	('SF295', 'Var', (88, 93))	('SKMG-1', 'CellLine', 'CVCL:1698', (119, 125))	('MGR1', 'Gene', '192115', (101, 105))	('MGR1', 'Gene', (101, 105))	('MGR2', 'Gene', '8249', (107, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('glioblastomas', 'Disease', (60, 73))	('medulloblastoma', 'Disease', 'MESH:D008527', (165, 180))	('medulloblastoma', 'Phenotype', 'HP:0002885', (165, 180))	('SF295', 'CellLine', 'CVCL:1690', (88, 93))	('cancer', 'Disease', (7, 13))	('MGR2', 'Gene', (107, 111))	('medulloblastoma', 'Disease', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('SKMG-4', 'CellLine', 'CVCL:8577', (127, 133))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('SKI', 'Gene', '6497', (152, 155))	('glioma', 'Disease', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('MGR3', 'Gene', '337892', (113, 117))	('MGR3', 'Gene', (113, 117))	('T98G', 'Var', (95, 99))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))
44497	21029453	Furthermore, DKK-1 seems to induce the proliferation of human adult bone marrow stem cells and contribute to the control of osteoporosis, as mutations in LRP5 that impede binding of DKK-1 are responsible for high bone density.	('binding', 'Interaction', (171, 178))	('mutations', 'Var', (141, 150))	('high', 'PosReg', (208, 212))	('induce', 'PosReg', (28, 34))	('osteoporosis', 'Disease', 'MESH:D010024', (124, 136))	('osteoporosis', 'Disease', (124, 136))	('human', 'Species', '9606', (56, 61))	('responsible', 'Reg', (192, 203))	('high bone density', 'Phenotype', 'HP:0011001', (208, 225))	('proliferation', 'CPA', (39, 52))	('LRP5', 'Gene', '4041', (154, 158))	('osteoporosis', 'Phenotype', 'HP:0000939', (124, 136))	('LRP5', 'Gene', (154, 158))	('control', 'MPA', (113, 120))
44518	33178960	Proton magnetic resonance spectroscopic imaging (MRSI) is a non-invasive diagnostic technique for investigating brain metabolism to establish cancer diagnosis and IDH gene mutation diagnosis as well as facilitate pre-operative planning and treatment response monitoring.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('IDH', 'Gene', (163, 166))	('mutation', 'Var', (172, 180))	('IDH', 'Gene', '3417', (163, 166))	('cancer', 'Disease', (142, 148))
44520	33178960	In addition to these common metabolites, 2-hydroxygluterate (2HG) has also been quantified using MRSI following the recent discovery of IDH mutations in gliomas.	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('gliomas', 'Disease', (153, 160))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('2HG', 'Chemical', '-', (61, 64))	('2-hydroxygluterate', 'Chemical', '-', (41, 59))	('mutations', 'Var', (140, 149))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))
44521	33178960	This has opened up targeted drug development to inhibit the mutant IDH pathway.	('IDH', 'Gene', (67, 70))	('mutant', 'Var', (60, 66))	('IDH', 'Gene', '3417', (67, 70))	('inhibit', 'NegReg', (48, 55))
44530	33178960	Among GBM lesions, 90% have no missense of IDH mutations.	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', (43, 46))	('missense', 'Var', (31, 39))
44531	33178960	IDH mutant tumors have better prognosis compared with wild-type IDH have poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (64, 67))	('mutant', 'Var', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('IDH', 'Gene', '3417', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('IDH', 'Gene', (64, 67))
44540	33178960	Hence, by simply considering the area of contrast enhancement on CE-T1W as the macroscopic tumor and the surrounding hyperintensity on T2W/FLAIR images as the related edema, MRI represents an oversimplified approach that does not reflect the biologic and histologic characteristics of the lesion, and in the case of treated lesions, does not distinguish viable tumor from treatment-related changes.	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('edema', 'Disease', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('CE-T1W', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (361, 366))	('edema', 'Disease', 'MESH:D004487', (167, 172))	('edema', 'Phenotype', 'HP:0000969', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
44547	33178960	Very recently, IDH mutations have also been discovered in gliomas, resulting in the MRS-detectable oncometabolite 2-hydroxygluterate (2HG).	('2HG', 'Chemical', '-', (134, 137))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('mutations', 'Var', (19, 28))	('IDH', 'Gene', '3417', (15, 18))	('IDH', 'Gene', (15, 18))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('MRS-detectable oncometabolite 2-hydroxygluterate', 'MPA', (84, 132))	('2-hydroxygluterate', 'Chemical', '-', (114, 132))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
44575	33178960	Nearly 80% of World Health Organization Grades II and III gliomas show the presence of mutation in the IDH1 and IDH2 genes that regulate the omonimous enzymes.	('IDH1', 'Gene', '3417', (103, 107))	('III gliomas', 'Disease', 'MESH:D005910', (54, 65))	('IDH2', 'Gene', (112, 116))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('III gliomas', 'Disease', (54, 65))	('IDH2', 'Gene', '3418', (112, 116))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('regulate', 'Reg', (128, 136))	('omonimous enzymes', 'MPA', (141, 158))	('mutation', 'Var', (87, 95))	('IDH1', 'Gene', (103, 107))
44577	33178960	Oncologic patients with IDH1 and IDH2 mutant enzymes have a gain-of-function to further convert the alpha-ketoglutarate to 2HG, an oncometabolite which has been described as a useful oncomarker in the diagnosis and follow-up in glioma patients.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (24, 28))	('gain-of-function', 'PosReg', (60, 76))	('alpha-ketoglutarate', 'MPA', (100, 119))	('IDH2', 'Gene', (33, 37))	('glioma', 'Disease', (228, 234))	('2HG', 'Chemical', '-', (123, 126))	('patients', 'Species', '9606', (235, 243))	('IDH2', 'Gene', '3418', (33, 37))	('convert', 'MPA', (88, 95))	('IDH1', 'Gene', (24, 28))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (100, 119))	('enzymes', 'Gene', (45, 52))	('patients', 'Species', '9606', (10, 18))
44580	33178960	As patients with IDH1 mutation have a greater 5 year survival rate than patients with wild-type IDH1 gliomas (93% vs 51%) when correcting for age, 2HG is also an important prognostic marker.	('IDH1 gliomas', 'Disease', 'MESH:D005910', (96, 108))	('IDH1', 'Gene', '3417', (96, 100))	('mutation', 'Var', (22, 30))	('IDH1 gliomas', 'Disease', (96, 108))	('greater', 'PosReg', (38, 45))	('2HG', 'Chemical', '-', (147, 150))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('IDH1', 'Gene', (17, 21))	('patients', 'Species', '9606', (3, 11))	('IDH1', 'Gene', '3417', (17, 21))	('IDH1', 'Gene', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('patients', 'Species', '9606', (72, 80))
44583	33178960	In previous studies, the accumulation of 2HG in brain gliomas as detected on MRSI has been correlated with mutations in IDH1 and IDH2.	('IDH2', 'Gene', (129, 133))	('mutations', 'Var', (107, 116))	('accumulation', 'PosReg', (25, 37))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('2HG', 'Chemical', '-', (41, 44))	('IDH1', 'Gene', (120, 124))	('IDH2', 'Gene', '3418', (129, 133))	('brain gliomas', 'Disease', 'MESH:C564230', (48, 61))	('IDH1', 'Gene', '3417', (120, 124))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('brain gliomas', 'Disease', (48, 61))
44584	33178960	A representative example of a patient with mutant IDH tumor showing the positive 2HG peak is shown in Figure 1.	('patient', 'Species', '9606', (30, 37))	('IDH tumor', 'Disease', 'MESH:D009369', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutant', 'Var', (43, 49))	('IDH tumor', 'Disease', (50, 59))	('2HG', 'Chemical', '-', (81, 84))
44653	32025722	Stratifying by molecular subtype, the Kaplan-Meier curves showed that the isocitrate dehydrogenase mutant/codeletion (IDHmut/codel) subtype had the best survival (median survival has not been reached), followed by the IDHmut/noncodel subtype (median survival = 79.4 mo), while IDH wildtype (wt) had the worst prognosis (median survival = 52.0 mo) (Figure 1A).	('IDH', 'Gene', '3417', (277, 280))	('mutant/codeletion', 'Var', (99, 116))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (118, 121))	('IDH', 'Gene', (218, 221))	('IDH', 'Gene', (277, 280))	('IDH', 'Gene', '3417', (218, 221))
44733	31915981	Minimizing the dense tumor, as defined by hyperintensity in T2w images, may prolong time to transformation.	('Minimizing', 'Var', (0, 10))	('tumor', 'Disease', (21, 26))	('prolong', 'PosReg', (76, 83))	('time', 'MPA', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
44778	31734532	Moreover, A Pearson's correlation analysis between change in disconnectivity score and change in picture naming scores highlighted that the disconnectivity of the left superior temporal gyrus (STG, r = =-0.385, auditory network), left middle frontal gyrus (MFG, r = =-0.428, post-salience network), right superior parietal lobule (SPL, r = =-0.378, post-salience network) and right inferior parietal lobule (IPL, r = =-0.369, visuospatial network) were significantly (p < 0.05) related to task performance, whereby increased disconnectivity scores were linked to decreased picture naming scores, i.e.	('left middle frontal gyrus', 'Disease', (230, 255))	('eta', 'Gene', '1909', (395, 398))	('left middle frontal gyrus', 'Disease', 'MESH:D020244', (230, 255))	('decreased', 'NegReg', (563, 572))	('task performance', 'MPA', (489, 505))	('eta', 'Gene', (395, 398))	('picture naming scores', 'MPA', (573, 594))	('eta', 'Gene', '1909', (318, 321))	('disconnectivity', 'Var', (525, 540))	('related', 'Reg', (478, 485))	('eta', 'Gene', (318, 321))
44839	30952620	We demonstrated that qGBM cells exhibit higher therapy resistance than their proliferative counterparts.	('higher', 'PosReg', (40, 46))	('rat', 'Species', '10116', (84, 87))	('therapy resistance', 'CPA', (47, 65))	('qGBM', 'Var', (21, 25))	('rat', 'Species', '10116', (10, 13))
44861	30952620	Correct knock-in of the iH2B-GFP cassette at the AAVS1 locus destroys the AAVS1 sgRNA target site (Fig.	('knock-in', 'Var', (8, 16))	('AAVS1', 'Gene', '17', (49, 54))	('iH2B-GFP', 'Gene', (24, 32))	('AAVS1', 'Gene', '17', (74, 79))	('AAVS1', 'Gene', (49, 54))	('AAVS1', 'Gene', (74, 79))	('destroys', 'NegReg', (61, 69))
44903	30952620	SD3-iH2B-GFP (parental line SD3 classified as IDH1/2 wild-type GBM cell line, proneural molecular subtype, with elevated PDGFRalpha expression), and SD2-iH2B-GFP (parental line SD2 characterized as IDH1/2 wild-type, mesenchymal subtype, with elevated EGFR and MET expression) (Fig.	('elevated', 'PosReg', (242, 250))	('IDH1/2', 'Gene', (198, 204))	('IDH1/2', 'Gene', (46, 52))	('EGFR', 'Gene', (251, 255))	('SD2-iH2B-GFP', 'Var', (149, 161))	('MET', 'CPA', (260, 263))	('IDH1/2', 'Gene', '3417;3418', (198, 204))	('IDH1/2', 'Gene', '3417;3418', (46, 52))	('EGFR', 'Gene', '1956', (251, 255))
44918	30952620	Sphere sizes were also measured as an indicator of proliferative rate, which revealed that the spheres derived from qGBM cells were on average smaller than those from pGBM (Fig.	('smaller', 'NegReg', (143, 150))	('pGBM', 'Chemical', '-', (167, 171))	('qGBM', 'Var', (116, 120))	('rat', 'Species', '10116', (58, 61))	('rat', 'Species', '10116', (65, 68))
44952	30952620	Among the category Transcriptional regulators, inactivation of MYCN and MYC were detected as top ranked candidates (Fig.	('inactivation', 'Var', (47, 59))	('MYC', 'Gene', (63, 66))	('MYCN', 'Gene', (63, 67))	('MYC', 'Gene', (72, 75))	('MYCN', 'Gene', '4613', (63, 67))	('MYC', 'Gene', '4609', (63, 66))	('MYC', 'Gene', '4609', (72, 75))
44961	30952620	Conversely, the fraction of qGBM cells in organoids expanded in the presence of a TGFbeta inhibitor was significantly reduced as compared to vehicle-treated controls (Fig.	('inhibitor', 'Var', (90, 99))	('TGFbeta', 'Gene', (82, 89))	('reduced', 'NegReg', (118, 125))	('TGFbeta', 'Gene', '7040', (82, 89))
44967	30952620	NanoString Pathway Score analysis was carried out for functional annotation of gene expression changes in both SD2 and SD3 qGBM relative to pGBM cells (Fig.	('SD2', 'Gene', (111, 114))	('pGBM', 'Chemical', '-', (140, 144))	('changes', 'Reg', (95, 102))	('SD3', 'Var', (119, 122))
44968	30952620	In general, pathway score values were higher for SD2 cells (both qGBM and pGBM populations) than for SD3 cells, reflecting the underlying differences between mesenchymal and proneural GBM subtypes.	('pGBM', 'Chemical', '-', (74, 78))	('SD2 cells', 'Var', (49, 58))	('higher', 'PosReg', (38, 44))	('pathway', 'Pathway', (12, 19))
44979	30952620	To further examine the clinical significance of qGBM DEGs that are associated with ECM, we analyzed patient data and tissue microarrays, focusing on SPP1, FN1, and TNC.	('qGBM', 'Gene', (48, 52))	('ECM', 'Disease', (83, 86))	('DEGs', 'Var', (53, 57))	('patient', 'Species', '9606', (100, 107))	('associated', 'Reg', (67, 77))
44984	30952620	Transcriptional changes in qGBM cells not only align with reduced proliferation and lower energy need, but also facilitate physiological adaptions to enhance stress-coping capabilities and engage a shift towards mesenchymal features, including expression of ECM-associated proteins of the microenvironment.	('stress-coping capabilities', 'CPA', (158, 184))	('qGBM', 'Gene', (27, 31))	('shift', 'Reg', (198, 203))	('changes', 'Var', (16, 23))	('energy need', 'MPA', (90, 101))	('facilitate', 'PosReg', (112, 122))	('expression', 'MPA', (244, 254))	('lower', 'NegReg', (84, 89))	('mesenchymal features', 'CPA', (212, 232))	('physiological adaptions', 'CPA', (123, 146))	('enhance', 'PosReg', (150, 157))	('reduced', 'NegReg', (58, 65))	('rat', 'Species', '10116', (73, 76))
45038	29687214	Gross total resection was strongly associated with reduced seizure frequency (p < 0.009).	('Gross total', 'Var', (0, 11))	('reduced', 'NegReg', (51, 58))	('seizure', 'Disease', (59, 66))	('seizure', 'Disease', 'MESH:D012640', (59, 66))	('seizure', 'Phenotype', 'HP:0001250', (59, 66))
45041	29687214	Gross total resection was associated with lower seizure frequency.	('seizure', 'Phenotype', 'HP:0001250', (48, 55))	('lower', 'NegReg', (42, 47))	('seizure', 'Disease', (48, 55))	('Gross', 'Var', (0, 5))	('seizure', 'Disease', 'MESH:D012640', (48, 55))
45052	29687214	Supratentorial and infratentorial gliomas were classified according to the 2007 WHO classification of brain tumors as follows: fibrillary astrocytoma (9420/3), protoplasmic astrocytoma (9410/3), gemistocytic astrocytoma (9411/3), oligodendroglioma (9450/3), oligoastrocytoma (9382/3), anaplastic astrocytoma (9401/3), anaplastic oligodendroglioma (9451/3), anaplastic oligoastrocytoma (9382/3), gliosarcoma (9442/3), or glioblastoma (9440/3).	('oligodendroglioma', 'Disease', 'MESH:D009837', (329, 346))	('glioblastoma', 'Phenotype', 'HP:0012174', (420, 432))	('anaplastic oligodendroglioma', 'Disease', (318, 346))	('astrocytoma', 'Disease', 'MESH:D001254', (173, 184))	('gliosarcoma', 'Disease', (395, 406))	('astrocytoma', 'Phenotype', 'HP:0009592', (296, 307))	('astrocytoma', 'Phenotype', 'HP:0009592', (138, 149))	('astrocytoma', 'Disease', (173, 184))	('9442/3', 'Var', (408, 414))	('9382/3', 'Var', (386, 392))	('oligodendroglioma', 'Disease', (329, 346))	('9411/3', 'Var', (221, 227))	('oligodendroglioma', 'Disease', 'MESH:D009837', (230, 247))	('glioma', 'Phenotype', 'HP:0009733', (340, 346))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (258, 274))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (368, 384))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('oligodendroglioma', 'Disease', (230, 247))	('astrocytoma', 'Phenotype', 'HP:0009592', (263, 274))	('gliomas', 'Disease', (34, 41))	('astrocytoma', 'Phenotype', 'HP:0009592', (208, 219))	('gliosarcoma', 'Disease', 'MESH:D018316', (395, 406))	('astrocytoma', 'Disease', 'MESH:D001254', (296, 307))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('anaplastic astrocytoma', 'Disease', (285, 307))	('astrocytoma', 'Disease', (296, 307))	('9450/3', 'Var', (249, 255))	('astrocytoma', 'Disease', 'MESH:D001254', (373, 384))	('astrocytoma', 'Disease', 'MESH:D001254', (138, 149))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('glioblastoma', 'Disease', (420, 432))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('brain tumors', 'Disease', 'MESH:D001932', (102, 114))	('astrocytoma', 'Disease', (138, 149))	('oligoastrocytoma', 'Disease', (258, 274))	('brain tumors', 'Phenotype', 'HP:0030692', (102, 114))	('oligoastrocytoma', 'Disease', (368, 384))	('brain tumor', 'Phenotype', 'HP:0030692', (102, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('9401/3', 'Var', (309, 315))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('glioblastoma', 'Disease', 'MESH:D005909', (420, 432))	('protoplasmic astrocytoma', 'Disease', (160, 184))	('9451/3', 'Var', (348, 354))	('protoplasmic astrocytoma', 'Disease', 'MESH:D001254', (160, 184))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (318, 346))	('astrocytoma', 'Disease', 'MESH:D001254', (208, 219))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (285, 307))	('astrocytoma', 'Disease', 'MESH:D001254', (263, 274))	('brain tumors', 'Disease', (102, 114))	('astrocytoma', 'Disease', (263, 274))	('9382/3', 'Var', (276, 282))	('astrocytoma', 'Disease', (208, 219))	('astrocytoma', 'Disease', (373, 384))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
45090	29687214	Chronic deafferentation and disconnection of functionally isolated regions of cortex, causing a denervation hypersensitivity is connected to seizure risk in LGGs, whereas the direct effects of tissue damage in fast-growing high-grade gliomas by disturbed microvascularization and peritumoral ischemia are thought to be causative factors.	('causing', 'Reg', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('ischemia', 'Disease', (292, 300))	('gliomas', 'Disease', (234, 241))	('disconnection', 'Var', (28, 41))	('seizure', 'Disease', 'MESH:D012640', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('seizure', 'Phenotype', 'HP:0001250', (141, 148))	('ischemia', 'Disease', 'MESH:D007511', (292, 300))	('peritumoral ischemia', 'Phenotype', 'HP:0002637', (280, 300))	('hypersensitivity', 'Disease', (108, 124))	('seizure', 'Disease', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('connected', 'Reg', (128, 137))	('hypersensitivity', 'Disease', 'MESH:D004342', (108, 124))	('deafferentation', 'Var', (8, 23))	('tumor', 'Disease', (284, 289))
45091	29687214	We also found that patients with low-grade astrocytoma patients had significantly more recurrent seizures in spite of combined antiepileptic treatments.	('astrocytoma', 'Disease', (43, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('patients', 'Species', '9606', (19, 27))	('seizure', 'Phenotype', 'HP:0001250', (97, 104))	('seizures', 'Disease', 'MESH:D012640', (97, 105))	('epileptic', 'Disease', 'MESH:D004827', (131, 140))	('low-grade', 'Var', (33, 42))	('astrocytoma', 'Disease', 'MESH:D001254', (43, 54))	('epileptic', 'Disease', (131, 140))	('patients', 'Species', '9606', (55, 63))	('seizures', 'Phenotype', 'HP:0001250', (97, 105))	('recurrent', 'MPA', (87, 96))	('seizures', 'Disease', (97, 105))
45109	29687214	Somatic isocitrate-dehydrogenase 1 (IDH1) mutations are common in LGGs, leading to the production of D-2 hydroxyglutarate, a metabolite that bears structural similarities to glutamate.	('leading to', 'Reg', (72, 82))	('glutamate', 'Chemical', 'MESH:D018698', (174, 183))	('LGGs', 'Disease', (66, 70))	('IDH1', 'Gene', (36, 40))	('D-2 hydroxyglutarate', 'MPA', (101, 121))	('IDH1', 'Gene', '3417', (36, 40))	('D-2 hydroxyglutarate', 'Chemical', 'MESH:C019417', (101, 121))	('production', 'MPA', (87, 97))	('mutations', 'Var', (42, 51))
45110	29687214	Thus, the IDH1 mutation in the tumor cells renders the tumor in a higher excitatory state and may be directly involved in the pathogenesis of tumor-related seizures in LGGs.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('seizures', 'Phenotype', 'HP:0001250', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('IDH1', 'Gene', '3417', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('involved', 'Reg', (110, 118))	('tumor', 'Disease', (142, 147))	('higher', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('seizures', 'Disease', (156, 164))	('mutation', 'Var', (15, 23))	('LGGs', 'Disease', (168, 172))	('seizure', 'Phenotype', 'HP:0001250', (156, 163))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (55, 60))	('IDH1', 'Gene', (10, 14))	('seizures', 'Disease', 'MESH:D012640', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
45112	29687214	However, given that the frequency of IDH mutation in LGG approaches 80% and its possible role in epileptogenesis, a partial explanation for the observed higher frequency of epileptic seizures in LGGs could be due to IDH1 mutation status.	('IDH', 'Gene', (216, 219))	('seizures', 'Phenotype', 'HP:0001250', (183, 191))	('IDH', 'Gene', '3417', (216, 219))	('mutation', 'Var', (41, 49))	('IDH1', 'Gene', (216, 220))	('epileptic seizures', 'Disease', (173, 191))	('IDH', 'Gene', (37, 40))	('seizure', 'Phenotype', 'HP:0001250', (183, 190))	('IDH1', 'Gene', '3417', (216, 220))	('epileptic seizures', 'Disease', 'MESH:D004827', (173, 191))	('IDH', 'Gene', '3417', (37, 40))
45121	29687214	Although we only had data from a subset of the population, which may not be representative of the population as a whole, we observed a significant correlation between reduced seizure frequency and gross total resection, which is also consistent with previous studies where the extent of surgical resection is recognized as an independent predictor of controlled epileptic seizures after oncological treatment.	('seizures', 'Phenotype', 'HP:0001250', (372, 380))	('seizure', 'Phenotype', 'HP:0001250', (372, 379))	('seizure', 'Disease', (175, 182))	('seizure', 'Disease', 'MESH:D012640', (175, 182))	('seizure', 'Disease', (372, 379))	('epileptic seizures', 'Disease', (362, 380))	('epileptic seizures', 'Disease', 'MESH:D004827', (362, 380))	('seizure', 'Disease', 'MESH:D012640', (372, 379))	('seizure', 'Phenotype', 'HP:0001250', (175, 182))	('gross total', 'Var', (197, 208))	('reduced', 'NegReg', (167, 174))
45138	21804599	PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma The PI3K-Akt pathway is activated in cancer by genetic or epigenetic events and efforts are under way to develop targeted therapies.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('genetic', 'Var', (135, 142))	('PHLPP', 'Gene', '23239', (17, 22))	('PHLPP', 'Gene', (17, 22))	('PI3K-Akt pathway', 'Pathway', (92, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Disease', (125, 131))	('glioblastoma', 'Disease', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('activated', 'PosReg', (112, 121))	('NHERF1', 'Gene', (6, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('PTEN', 'Gene', (0, 4))	('NHERF1', 'Gene', '9368', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('epigenetic events', 'Var', (146, 163))	('tumor', 'Disease', (30, 35))	('PTEN', 'Gene', '5728', (0, 4))
45149	21804599	The oncogenic activation of the pathway can take place at different levels in tumor cells, either by mutation or amplification of the activators of the pathway or by inactivation of the inhibitors of the pathway.	('activators', 'MPA', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('amplification', 'MPA', (113, 126))	('inactivation', 'NegReg', (166, 178))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('mutation', 'Var', (101, 109))
45150	21804599	The enzymatic product of the PI3K, phosphatidylinositol 3,4,5-trisphosphate (PIP3), acts as second messenger and recruits the serine-threonine kinase Akt through binding to its pleckstrin-homology (PH)-domain.	('PIP3', 'Chemical', '-', (77, 81))	('phosphatidylinositol 3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (35, 75))	('recruits', 'PosReg', (113, 121))	('binding', 'Interaction', (162, 169))	('serine-threonine kinase Akt', 'Pathway', (126, 153))	('PI3K', 'Var', (29, 33))
45151	21804599	This binding releases the PH domain from masking the kinase domain, and allows the phosphorylation of Akt on Thr308 in the activation loop and on Ser473 in the carboxyl-terminal (CT) hydrophobic motif.	('Ser473', 'Var', (146, 152))	('Ser473', 'Chemical', '-', (146, 152))	('Thr308', 'Var', (109, 115))	('phosphorylation', 'MPA', (83, 98))	('kinase domain', 'MPA', (53, 66))	('masking', 'MPA', (41, 48))	('allows', 'Reg', (72, 78))	('Thr308', 'Chemical', '-', (109, 115))	('Akt', 'Pathway', (102, 105))
45155	21804599	PTEN mutation with loss of heterozygosity (LOH) is one of the major genetic alterations in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('rat', 'Species', '10116', (80, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('loss of', 'NegReg', (19, 26))	('PTEN', 'Gene', (0, 4))	('glioblastoma', 'Disease', (91, 103))	('mutation', 'Var', (5, 13))
45166	21804599	We confirmed this synergistic Akt activation by double PTEN-NHERF1 depletion in DU145 prostate cancer cells in which single depletion of PTEN or NHERF1 had no significant effect on Akt phosphorylation (Fig.	('NHERF1', 'Gene', (60, 66))	('DU145', 'CellLine', 'CVCL:0105', (80, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('depletion', 'Var', (67, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('Akt phosphorylation', 'MPA', (181, 200))	('NHERF1', 'Gene', '9368', (145, 151))	('activation', 'PosReg', (34, 44))	('NHERF1', 'Gene', (145, 151))	('Akt', 'Pathway', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('NHERF1', 'Gene', '9368', (60, 66))	('prostate cancer', 'Disease', (86, 101))
45168	21804599	Overall, these results demonstrated synergistic activation of the PI3K/Akt pathway by double PTEN-NHERF1 depletion and suggested independent PI3K/Akt inhibitory activities for NHERF1.	('NHERF1', 'Gene', '9368', (98, 104))	('depletion', 'Var', (105, 114))	('NHERF1', 'Gene', (98, 104))	('NHERF1', 'Gene', '9368', (176, 182))	('rat', 'Species', '10116', (30, 33))	('NHERF1', 'Gene', (176, 182))	('activation', 'PosReg', (48, 58))	('PI3K/Akt pathway', 'Pathway', (66, 82))
45185	21804599	We expressed FLAG-tagged NHERF1 with either PHLPP1alpha-FL (full-length) or PHLPP1alpha-DeltaPDZ in 293T cells.	('NHERF1', 'Gene', '9368', (25, 31))	('293T', 'CellLine', 'CVCL:0063', (100, 104))	('PHLPP1alpha-FL', 'Var', (44, 58))	('NHERF1', 'Gene', (25, 31))	('PHLPP1alpha-DeltaPDZ', 'Var', (76, 96))
45200	21804599	Co-expression of Myr-NHERF1 with either PHLPP1alpha-FL or PHLPP1alpha-DeltaPDZ in LN18 cells resulted in recruitment to the plasma membrane of PHLPP1alpha-FL but not PHLPP1alpha-DeltaPDZ by Myr-NHERF1 (Fig.	('expression', 'Species', '29278', (3, 13))	('NHERF1', 'Gene', '9368', (21, 27))	('PHLPP1alpha-FL', 'Var', (143, 157))	('NHERF1', 'Gene', (21, 27))	('NHERF1', 'Gene', '9368', (194, 200))	('recruitment to the plasma membrane', 'MPA', (105, 139))	('NHERF1', 'Gene', (194, 200))
45207	21804599	PHLPP1 overexpression has been shown to suppress growth or promote apoptosis in a variety of cancer cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('apoptosis', 'CPA', (67, 76))	('overexpression', 'Var', (7, 21))	('expression', 'Species', '29278', (11, 21))	('growth', 'CPA', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('suppress', 'NegReg', (40, 48))	('promote', 'PosReg', (59, 66))	('PHLPP1', 'Gene', (0, 6))
45210	21804599	Virtually complete NHERF1 depletion increased cell proliferation, consistent with a tumor suppressor role of NHERF1 at the plasma membrane, in this case independent of PTEN (Fig.	('NHERF1', 'Gene', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('NHERF1', 'Gene', (109, 115))	('depletion', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('increased', 'PosReg', (36, 45))	('rat', 'Species', '10116', (58, 61))	('NHERF1', 'Gene', '9368', (19, 25))	('NHERF1', 'Gene', '9368', (109, 115))	('cell proliferation', 'CPA', (46, 64))
45214	21804599	Remarkably, knockdown of PHLPP1 in the LN229 PTEN-depleted cells robustly activated Akt by increasing phosphorylation on both Thr308 and Ser473 activation sites (Fig.	('Thr308', 'Chemical', '-', (126, 132))	('increasing', 'PosReg', (91, 101))	('Ser473 activation', 'MPA', (137, 154))	('phosphorylation on', 'MPA', (102, 120))	('activated', 'PosReg', (74, 83))	('knockdown', 'Var', (12, 21))	('Akt', 'Pathway', (84, 87))	('LN229', 'CellLine', 'CVCL:0393', (39, 44))	('Ser473', 'Chemical', '-', (137, 143))	('PHLPP1', 'Gene', (25, 31))
45215	21804599	Similarly, PTEN-PHLPP1 double depletion in DU145 cells elevated Akt phosphorylation levels similarly to the double PTEN-NHERF1 depletion (Figs.	('NHERF1', 'Gene', '9368', (120, 126))	('Akt phosphorylation levels', 'MPA', (64, 90))	('NHERF1', 'Gene', (120, 126))	('PTEN-PHLPP1', 'Gene', (11, 22))	('DU145', 'CellLine', 'CVCL:0105', (43, 48))	('elevated', 'PosReg', (55, 63))	('double depletion', 'Var', (23, 39))
45217	21804599	Loss of both PTEN and PHLPP1 substantially increased the anchorage-independent growth of LN229 cells, whereas depletion of PTEN alone had no effect (Fig.	('LN229', 'CellLine', 'CVCL:0393', (89, 94))	('anchorage-independent growth', 'CPA', (57, 85))	('PHLPP1', 'Gene', (22, 28))	('increased', 'PosReg', (43, 52))	('PTEN', 'Gene', (13, 17))	('Loss', 'Var', (0, 4))
45224	21804599	Examination of the tumors for cell dispersal, the main cause of glioblastoma relapse in patients, revealed that both PTEN single-depleted and PTEN-PHLPP1 double-depleted cells markedly infiltrated the meninges and the brain parenchyma either as isolated cells or surrounding the vessels, as compared to control or PHLPP1 single-depleted cells (Fig.4D, arrowheads and Figs.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('PTEN', 'Gene', (117, 121))	('rat', 'Species', '10116', (191, 194))	('patients', 'Species', '9606', (88, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PTEN-PHLPP1', 'Gene', (142, 153))	('infiltrated', 'PosReg', (185, 196))	('single-depleted', 'Var', (122, 137))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
45225	21804599	This indicated that within the PTEN-PHLPP1 network, PTEN is the main brake of glioblastoma cell dispersal, most likely through suppressing the PI3K-Akt pathway.	('glioblastoma', 'Disease', (78, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('PTEN', 'Var', (52, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('suppressing', 'NegReg', (127, 138))	('PI3K-Akt pathway', 'Pathway', (143, 159))
45240	21804599	In this study, we attempted to characterize the multimodal mechanism of PI3K-Akt activation in cancer cells by the inactivation of the upstream tumor suppressors of the pathway.	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('activation', 'PosReg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('inactivation', 'Var', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PI3K-Akt', 'Pathway', (72, 80))
45241	21804599	PTEN is the pathway's most frequently altered tumor suppressor in cancers, in many instances by mutation with LOH, leading to complete absence of the protein.	('absence', 'NegReg', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (46, 51))	('mutation', 'Var', (96, 104))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('PTEN', 'Gene', (0, 4))	('LOH', 'Gene', (110, 113))	('protein', 'Protein', (150, 157))
45249	21804599	Importantly, complex formation with NHERF1 appeared essential for regulating the growth suppressive effects of PHLPP1, as the absence of NHERF1 prevented PHLPP1 from inhibiting cell growth.	('NHERF1', 'Gene', '9368', (137, 143))	('prevented', 'NegReg', (144, 153))	('NHERF1', 'Gene', (137, 143))	('growth', 'MPA', (81, 87))	('cell growth', 'CPA', (177, 188))	('absence', 'Var', (126, 133))	('PHLPP1', 'Gene', (154, 160))	('NHERF1', 'Gene', '9368', (36, 42))	('inhibiting', 'NegReg', (166, 176))	('NHERF1', 'Gene', (36, 42))
45250	21804599	Previous reports have described unchanged Akt phosphorylation following PHLPP silencing or overexpression in a multitude of cancer cells.	('cancer', 'Disease', (124, 130))	('Akt', 'Pathway', (42, 45))	('PHLPP', 'Gene', (72, 77))	('PHLPP', 'Gene', '23239', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('silencing', 'Var', (78, 87))	('expression', 'Species', '29278', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
45251	21804599	In our hands, PHLPP1 silencing in a series of PTEN-positive cells of different origins had no effect on Akt phosphorylation, suggesting that PHLPP loss cannot efficiently activate Akt in the presence of PTEN.	('activate', 'PosReg', (171, 179))	('PHLPP', 'Gene', (14, 19))	('PHLPP', 'Gene', '23239', (14, 19))	('PHLPP', 'Gene', '23239', (141, 146))	('PHLPP', 'Gene', (141, 146))	('Akt', 'Pathway', (180, 183))	('Akt phosphorylation', 'MPA', (104, 123))	('loss', 'NegReg', (147, 151))	('silencing', 'Var', (21, 30))
45252	21804599	Notably, PHLPP1 silencing following PTEN silencing significantly and massively activated Akt by phosphorylation on both Ser473 and Thr308.	('PHLPP1', 'Gene', (9, 15))	('phosphorylation', 'MPA', (96, 111))	('Ser473', 'Var', (120, 126))	('silencing', 'NegReg', (16, 25))	('Thr308', 'Chemical', '-', (131, 137))	('activated', 'PosReg', (79, 88))	('Ser473', 'Chemical', '-', (120, 126))	('Akt', 'Pathway', (89, 92))	('Thr308', 'Var', (131, 137))
45256	21804599	Even more apparent, PHLPP1 depletion that had no detectable effect on Akt activation in these cells significantly increased their growth and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('increased', 'PosReg', (114, 123))	('tumor', 'Disease', (141, 146))	('PHLPP1', 'Gene', (20, 26))	('depletion', 'Var', (27, 36))
45257	21804599	It results that single NHERF1 or PHLPP1 losses activate PI3K-Akt-independent signaling pathways that lead to cancer cell growth.	('NHERF1', 'Gene', '9368', (23, 29))	('PI3K-Akt-independent signaling pathways', 'Pathway', (56, 95))	('activate', 'PosReg', (47, 55))	('NHERF1', 'Gene', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('PHLPP1', 'Gene', (33, 39))	('cancer', 'Disease', (109, 115))	('losses', 'NegReg', (40, 46))	('single', 'Var', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lead to', 'Reg', (101, 108))
45261	21804599	These observations suggest that the loss of PHLPP1 and NHERF1 in glioblastoma that we report here for the first time, most likely induce both PI3K-Akt-dependent effects on cell growth in cooperation with PTEN loss, and PI3K-Akt-independent effects, explaining thus the pronounced aggressiveness of these tumors and the dismal patient survival (Table 2).	('tumors', 'Disease', (304, 310))	('aggressiveness', 'Disease', (280, 294))	('patient', 'Species', '9606', (326, 333))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('aggressiveness', 'Phenotype', 'HP:0000718', (280, 294))	('loss', 'Var', (36, 40))	('PHLPP1', 'Gene', (44, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('NHERF1', 'Gene', (55, 61))	('aggressiveness', 'Disease', 'MESH:D001523', (280, 294))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('PI3K-Akt-dependent', 'Var', (142, 160))	('glioblastoma', 'Disease', (65, 77))	('NHERF1', 'Gene', '9368', (55, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('rat', 'Species', '10116', (192, 195))	('cell growth', 'MPA', (172, 183))	('induce', 'Reg', (130, 136))
45262	21804599	In conclusion, our results show that silencing of PTEN separately does not potently activate Akt.	('rat', 'Species', '10116', (59, 62))	('PTEN', 'Gene', (50, 54))	('Akt', 'Pathway', (93, 96))	('silencing', 'Var', (37, 46))
45263	21804599	Remarkably, simultaneous knockdown of PTEN and NHERF1, or of PTEN and PHLPP1 that is recruited by NHERF1 at the plasma membrane, significantly activates Akt and increases cell tumorigenicity.	('NHERF1', 'Gene', '9368', (98, 104))	('NHERF1', 'Gene', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('NHERF1', 'Gene', (98, 104))	('activates', 'PosReg', (143, 152))	('Akt', 'Pathway', (153, 156))	('NHERF1', 'Gene', '9368', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('knockdown', 'Var', (25, 34))	('increases', 'PosReg', (161, 170))	('PHLPP1', 'Gene', (70, 76))
45269	21804599	These and LN382T (Dr. Erwin Van Meir, Emory University, Atlanta, GA; 2004) and SNB19 (ATCC; 1998), as well as the prostate cancer cell line DU145 (Dr. David Nanus, Weiss Medical College, New York, NY; 2000), were authenticated in October 2009, as described.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SNB19', 'Var', (79, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('DU145', 'CellLine', 'CVCL:0105', (140, 145))	('LN382T', 'Var', (10, 16))	('prostate cancer', 'Disease', (114, 129))
45275	21804599	Full-length PHLPP1alpha and DeltaPDZ mutant lacking the last 3 residues that form the PDZ-binding motif were inserted in pcDNA3 and pCXb (blasticidin resistance) mammalian expression vectors.	('mammalian', 'Species', '9606', (162, 171))	('mutant', 'Var', (37, 43))	('PHLPP1alpha', 'Gene', (12, 23))	('blasticidin', 'Chemical', 'MESH:C004500', (138, 149))	('DeltaPDZ', 'Gene', (28, 36))	('expression vectors', 'Species', '29278', (172, 190))	('lacking', 'NegReg', (44, 51))
45277	21804599	CT fragments encoding 130 residues for PHLPP1 and 141 residues for PHLPP2, and their corresponding DeltaPDZ mutants, were cloned in pGEX-6P-1 vector with or without an NT Myc tag for recombinant protein expression.	('Myc', 'Gene', '4609', (171, 174))	('expression', 'Species', '29278', (203, 213))	('Myc', 'Gene', (171, 174))	('mutants', 'Var', (108, 115))	('PHLPP2', 'Gene', '23035', (67, 73))	('PHLPP1', 'Gene', (39, 45))	('PHLPP2', 'Gene', (67, 73))
45318	33926541	devised a 'suitability score' as a metric of the molecular similarity of CCLs to high-grade serous ovarian carcinoma based on a heuristic weighting of copy number alterations, mutation status of several genes that distinguish ovarian cancer subtypes, and hypermutation status.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('serous ovarian carcinoma', 'Disease', (92, 116))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('copy number alterations', 'Var', (151, 174))	('ovarian cancer', 'Disease', 'MESH:D010051', (226, 240))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (92, 116))	('CCLs', 'Chemical', '-', (73, 77))	('ovarian cancer', 'Disease', (226, 240))	('CCLs', 'Disease', (73, 77))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (99, 116))	('mutation', 'Var', (176, 184))	('ovarian cancer', 'Phenotype', 'HP:0100615', (226, 240))
45319	33926541	transcriptomic and copy number alterations) to quantify the similarity of cell lines to tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('copy number alterations', 'Var', (19, 42))
45322	33926541	have developed methods to assess CCLs using molecular traits such as copy number alterations (CNA), somatic mutations, DNA methylation, and transcriptomics.	('copy number alterations', 'Var', (69, 92))	('CCLs', 'Chemical', '-', (33, 37))	('CCLs', 'Disease', (33, 37))
45393	33926541	SK-OV-3, Vcap, and RT4 were cultured in Dulbecco's modified Eagle medium (DMEM, high glucose, 11960069, Gibco) with 1% penicillin-streptomycin-glutamine (10378016, Life Technologies); Caov-4, PC-3, NCCIT, and A2780 were cultured using RPMI-1640 medium (11875093, Gibco) while HEC-59 was in Iscove's modified Dulbecco's medium (IMDM, 12440053, Gibco).	('11875093', 'Var', (253, 261))	('penicillin', 'Chemical', 'MESH:D010406', (119, 129))	('PC-3', 'Gene', (192, 196))	('PC-3', 'Gene', '57332', (192, 196))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('SK-OV-3', 'Chemical', '-', (0, 7))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('HEC-59', 'CellLine', 'CVCL:2930', (276, 282))	('streptomycin', 'Chemical', 'MESH:D013307', (130, 142))	('Vcap', 'Chemical', '-', (9, 13))
45475	33926541	We reasoned that if SK-OV-3, A2780, and PC-3 were classified most strongly as UCEC, TGCT, and BLCA, respectively, then they would express proteins that are indicative of these cancer types.	('PC-3', 'Gene', (40, 44))	('PC-3', 'Gene', '57332', (40, 44))	('proteins', 'Protein', (138, 146))	('UCEC', 'Disease', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('A2780', 'Var', (29, 34))	('SK-OV-3', 'Chemical', '-', (20, 27))	('BLCA', 'Phenotype', 'HP:0009725', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('TGCT', 'Disease', (84, 88))	('express', 'Reg', (130, 137))
45480	33926541	From our computational analysis and experimental validation, SK-OV-3 is most likely an endometrioid subtype of ovarian cancer.	('ovarian cancer', 'Disease', (111, 125))	('SK-OV-3', 'Var', (61, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('SK-OV-3', 'Chemical', '-', (61, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
45481	33926541	This result is also consistent with prior classification of SK-OV-3, and the fact that SK-OV-3 lacks p53 mutations, which is prevalent in high-grade serous ovarian cancer, and it harbors an endometrioid-associated mutation in ARID1A.	('SK-OV-3', 'Chemical', '-', (87, 94))	('lacks', 'NegReg', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ARID1A', 'Gene', '8289', (226, 232))	('SK-OV-3', 'Chemical', '-', (60, 67))	('serous ovarian cancer', 'Disease', (149, 170))	('ARID1A', 'Gene', (226, 232))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (149, 170))	('mutations', 'Var', (105, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('high-grade', 'Disease', (138, 148))
45483	33926541	The OV marker WT1 was also expressed in fewer A2780 cells as compared to Caov-4 (48% vs 85%), which suggests that A2780 could be a germ cell-derived ovarian tumor.	('ovarian tumor', 'Phenotype', 'HP:0100615', (149, 162))	('ovarian tumor', 'Disease', 'MESH:D010051', (149, 162))	('A2780', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ovarian tumor', 'Disease', (149, 162))
45484	33926541	Taken together, our results suggest that SK-OV-3 and A2780 could represent OV subtypes that are not well represented in TCGA training data, which resulted in a low OV score and higher CCN score in other categories.	('low', 'NegReg', (160, 163))	('higher', 'PosReg', (177, 183))	('OV score', 'MPA', (164, 172))	('CCN', 'Chemical', '-', (184, 187))	('CCN score', 'MPA', (184, 193))	('SK-OV-3', 'Var', (41, 48))	('SK-OV-3', 'Chemical', '-', (41, 48))	('A2780', 'Var', (53, 58))
45495	33926541	For example, HEC-1A, HEC-1B, and KLE were previously characterized as type II endometrial cancer, which includes a serous histological subtype.	('type II endometrial cancer', 'Disease', 'MESH:D016889', (70, 96))	('HEC-1A', 'Disease', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('KLE', 'Disease', (33, 36))	('HEC-1B', 'Var', (21, 27))	('endometrial cancer', 'Phenotype', 'HP:0012114', (78, 96))	('type II endometrial cancer', 'Disease', (70, 96))
45502	33926541	Similarly, LUDLU-1 and EPLC-272H, previously reported as classical and basal respectively, had maximal tumor subtype CCN scores for these subtypes (0.323 and 0.256) (Fig.	('CCN', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EPLC-272H', 'Var', (23, 32))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
45525	33926541	In contrast to LGG CCLs, LGG GEMMs, generated by Nf1 mutations expressed in different neural progenitors in combination with Pten deletion, consistently were classified as LGG (Fig.	('LGG', 'Disease', (172, 175))	('Nf1', 'Gene', '4763', (49, 52))	('Nf1', 'Gene', (49, 52))	('mutations', 'Var', (53, 62))	('CCLs', 'Chemical', '-', (19, 23))	('Pten', 'Gene', '5728', (125, 129))	('Pten', 'Gene', (125, 129))
45528	33926541	GEMMs sharing genotypes across studies, such as LUAD GEMMs driven by Kras mutation and loss of p53, also received similar general and subtype classification scores (Fig.	('mutation', 'Var', (74, 82))	('loss', 'Var', (87, 91))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('Kras', 'Gene', (69, 73))	('Kras', 'Gene', '3845', (69, 73))
45542	33926541	Most of the LUAD GEMMs, which were generated using various combinations of activating Kras mutation, loss of Trp53, and loss of Smarca4L, were correctly classified (Fig.	('mutation', 'Var', (91, 99))	('Kras', 'Gene', '3845', (86, 90))	('loss', 'NegReg', (101, 105))	('Trp53', 'Gene', '7157', (109, 114))	('Smarca4L', 'Gene', (128, 136))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('activating', 'PosReg', (75, 85))	('Trp53', 'Gene', (109, 114))	('loss', 'Var', (120, 124))	('Kras', 'Gene', (86, 90))
45630	33926541	Microarray tumor validation data: Microarray tumor datasets used for validation are available in the GEO database: GSE36771, GSE21653, GSE20685, GSE50948, GSE23177, GSE26639, GSE12276, GSE31448, GSE32646, GSE65194, GSE42568, GSE26682, GSE17536, GSE41328, GSE33114, GSE26906, GSE39582, GSE62080, GSE20916, GSE18088, GSE17537, GSE23878, GSE60697, GSE37892, GSE30540, GSE50161, GSE4290, GSE60184, GSE36245, GSE53733, GSE32374, GSE34824, GSE41137, GSE53757, GSE46699, GSE36895, GSE2109, GSE45436, GSE9843, GSE6222, GSE19665, GSE41804, GSE10245, GSE12667, GSE37745, GSE19188, GSE40595, GSE12172, GSE20565, GSE18520, GSE10971, GSE51373, GSE14001, GSE26193, GSE55512, GSE42404, GSE16515, GSE17891, GSE15471, GSE22780, GSE32688, GSE17951, GSE32448, GSE7307, GSE32982, GSE3325, GSE26910, GSE55945, GSE7553, GSE10282, GSE19293, GSE19234, GSE35640, GSE22968, GSE34599, and GSE23376.	('GSE23376', 'Var', (862, 870))	('GSE35640', 'Var', (828, 836))	('GSE22968', 'Var', (838, 846))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('GSE10282', 'Var', (798, 806))	('tumor', 'Disease', (11, 16))	('GSE7307', 'Var', (741, 748))	('GSE32982', 'Var', (750, 758))	('GSE19234', 'Var', (818, 826))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GSE55945', 'Var', (779, 787))	('GSE34599', 'Var', (848, 856))	('GSE7553', 'Var', (789, 796))	('GSE32448', 'Var', (731, 739))	('GSE3325', 'Var', (760, 767))	('GSE19293', 'Var', (808, 816))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('GSE26910', 'Var', (769, 777))
45633	33926541	The other tumoroid datasets are available in the GEO database: GSE84073, GSE103990, and GSE109982.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('GSE84073', 'Var', (63, 71))	('GSE103990', 'Var', (73, 82))	('tumor', 'Disease', (10, 15))	('GSE109982', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
45656	32486389	Despite the abundant body of literature on OPGs in NF1, very few studies have focused on other CNS tumors.	('OPGs', 'Chemical', '-', (43, 47))	('CNS tumors', 'Disease', 'MESH:D016543', (95, 105))	('CNS tumor', 'Phenotype', 'HP:0100006', (95, 104))	('CNS tumors', 'Disease', (95, 105))	('OPGs', 'Var', (43, 47))	('NF1', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NF1', 'Gene', '4763', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
45705	32486389	NF1 mutations were identified in 18 patients, of which 17 carried truncating mutations.	('patients', 'Species', '9606', (36, 44))	('truncating mutations', 'MPA', (66, 86))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))
45744	32486389	The following variants are associated with specific phenotypes: missense variants at the NF1 codons p.Arg1809, p.Met1149, p.Arg1276, and p.Lys1423 and the in-frame deletion c.2970-2972 delAAT.	('p.Met1', 'SUBSTITUTION', 'None', (111, 117))	('Arg1276', 'Chemical', '-', (124, 131))	('Lys1423', 'Chemical', '-', (139, 146))	('NF1', 'Gene', (89, 92))	('p.Arg1809', 'Var', (100, 109))	('c.2970-2972 delAAT', 'Mutation', 'rs267606606', (173, 191))	('p.Lys1423', 'Var', (137, 146))	('NF1', 'Gene', '4763', (89, 92))	('p.Met1', 'Var', (111, 117))	('Arg1809', 'Chemical', '-', (102, 109))	('p.Arg1276', 'Var', (122, 131))	('c.2970-2972 delAAT', 'Var', (173, 191))
45745	32486389	In our series, 19 out of 35 patients underwent molecular testing for NF1 and an NF1 mutation was identified in 18 cases (Table 4).	('NF1', 'Gene', '4763', (69, 72))	('NF1', 'Gene', (80, 83))	('NF1', 'Gene', '4763', (80, 83))	('patients', 'Species', '9606', (28, 36))	('NF1', 'Gene', (69, 72))	('mutation', 'Var', (84, 92))
45746	32486389	Seventeen of these mutations were predicted to produce a truncated neurofibromin.	('neurofibromin', 'Gene', '4763', (67, 80))	('neurofibromin', 'Gene', (67, 80))	('mutations', 'Var', (19, 28))
45747	32486389	NF1 germline mutations were shown to result in different levels of neurofibromin expression in NF1 patient fibroblasts, ranging from 25% to 75%.	('patient', 'Species', '9606', (99, 106))	('germline', 'Var', (4, 12))	('NF1', 'Gene', (95, 98))	('neurofibromin', 'Gene', '4763', (67, 80))	('NF1', 'Gene', '4763', (95, 98))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))	('neurofibromin', 'Gene', (67, 80))
45748	32486389	This finding supports the hypothesis that not all NF1 mutations are equivalent and that residual amounts of functionally active neurofibromin might be linked to the phenotype.	('NF1', 'Gene', (50, 53))	('mutations', 'Var', (54, 63))	('neurofibromin', 'Gene', '4763', (128, 141))	('NF1', 'Gene', '4763', (50, 53))	('neurofibromin', 'Gene', (128, 141))
45772	32486389	NF1 mutations were recorded in terms of the genomic and protein location and type of mutation.	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (0, 3))
45781	30833594	In vivo investigation of hyperpolarized [1,3-13C2]acetoacetate as a metabolic probe in normal brain and in glioma Dysregulation in NAD+/NADH levels is associated with increased cell division and elevated levels of reactive oxygen species in rapidly proliferating cancer cells.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (214, 237))	('cell division', 'CPA', (177, 190))	('NAD+/NADH', 'MPA', (131, 140))	('cancer', 'Disease', (263, 269))	('rat', 'Species', '10116', (256, 259))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('increased', 'PosReg', (167, 176))	('Dysregulation', 'Var', (114, 127))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (195, 237))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('levels of reactive oxygen species', 'MPA', (204, 237))	('[1,3-13C2]acetoacetate', 'Chemical', '-', (40, 62))	('NAD+', 'Chemical', 'MESH:D009243', (131, 135))	('glioma', 'Disease', (107, 113))	('NADH', 'Chemical', 'MESH:D009243', (136, 140))
45806	30833594	Specifically, up to 70% of LGG and 90% of secondary upgraded GBM harbor a heterozygous missense mutation in one copy of the gene encoding for the isocitrate dehydrogenase 1 (IDH1) enzyme, and this mutation is now recognized as an essential driver of LGG development.	('isocitrate dehydrogenase 1', 'Gene', (146, 172))	('IDH1', 'Gene', (174, 178))	('isocitrate dehydrogenase 1', 'Gene', '15926', (146, 172))	('missense mutation', 'Var', (87, 104))
45807	30833594	Mutant IDH1 catalyzes the conversion of alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG) and NADPH serves as a co-factor for this reaction leading to changes in redox.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (40, 59))	('IDH1', 'Gene', (7, 11))	('alpha-KG', 'Chemical', 'MESH:D007656', (61, 69))	('changes', 'Reg', (161, 168))	('NADPH', 'Gene', (104, 109))	('2-HG', 'Chemical', 'MESH:C019417', (94, 98))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (74, 92))	('Mutant', 'Var', (0, 6))	('redox', 'MPA', (172, 177))	('NADPH', 'Gene', '67460', (104, 109))
45817	30833594	The most common probe, hyperpolarized [1-13C]pyruvate, is currently in clinical trials for patients with prostate cancer, brain tumors, liver metastases and heart disease.	('hyperpolarized', 'Var', (23, 37))	('patients', 'Species', '9606', (91, 99))	('liver metastases', 'Disease', 'MESH:D009362', (136, 152))	('heart disease', 'Disease', (157, 170))	('prostate cancer', 'Disease', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('brain tumors', 'Disease', 'MESH:D001932', (122, 134))	('brain tumors', 'Phenotype', 'HP:0030692', (122, 134))	('heart disease', 'Disease', 'MESH:D006331', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('brain tumors', 'Disease', (122, 134))	('[1-13C]pyruvate', 'Chemical', '-', (38, 53))	('liver metastases', 'Disease', (136, 152))
45832	30833594	Following polarization, resonances of [1-13C]AcAc and [3-13C]AcAc were detected with an enhancement of 18 +- 5% (n = 3) and 22 +- 4% (n = 3), respectively, when compared to the thermal spectrum (Fig.	('[1-13C]AcAc', 'Chemical', '-', (38, 49))	('enhancement', 'PosReg', (88, 99))	('[1-13C]', 'Var', (38, 45))	('[3-13C]AcAc', 'Var', (54, 65))	('[3-13C]AcAc', 'Chemical', '-', (54, 65))
45838	30833594	Signals from hyperpolarized [1-13C]AcAc, [3-13C]AcAc and [1-13C]beta-HB could be detected in tumor-bearing and tumor-free animals in hyperpolarized 13C dynamic and 90  acquisitions (Fig.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('beta-HB', 'Chemical', 'MESH:D020155', (64, 71))	('[1-13C]AcAc', 'Chemical', '-', (28, 39))	('[1-13C', 'Chemical', '-', (57, 63))	('13C', 'Chemical', 'MESH:C000615229', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('13C', 'Chemical', 'MESH:C000615229', (60, 63))	('13C', 'Chemical', 'MESH:C000615229', (44, 47))	('[3-13C]AcAc', 'Chemical', '-', (41, 52))	('[1-13C]', 'Var', (28, 35))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('[1-13C', 'Chemical', '-', (28, 34))	('C]beta', 'Species', '10703', (62, 68))	('[3-13C]AcAc', 'Var', (41, 52))	('tumor', 'Disease', (93, 98))	('[1-13C]', 'Var', (57, 64))	('13C', 'Chemical', 'MESH:C000615229', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
45841	30833594	3D, summed dynamic data showed a significantly higher SNR for [1-13C]AcAc in U87wt-bearing mice (n = 8) compared to controls (n = 11) and U87mut-bearing mice (n = 10), but no significant differences in the SNR of [1-13C]-beta-HB between any of the groups (p value  > 0.35).	('mice', 'Species', '10090', (91, 95))	('[1-13C', 'Chemical', '-', (62, 68))	('SNR', 'MPA', (54, 57))	('higher', 'PosReg', (47, 53))	('C]-beta', 'Species', '10703', (218, 225))	('beta-HB', 'Chemical', 'MESH:D020155', (221, 228))	('[1-13C]AcAc', 'Chemical', '-', (62, 73))	('[1-13C]', 'Var', (62, 69))	('mice', 'Species', '10090', (153, 157))	('U87wt-bearing', 'Var', (77, 90))	('[1-13C', 'Chemical', '-', (213, 219))
45842	30833594	The ratio of [1-13C]beta-HB-to-[1-13C]AcAc was significantly lower in U87wt- and U87mut-bearing mice compared to controls.	('lower', 'NegReg', (61, 66))	('beta-HB', 'Chemical', 'MESH:D020155', (20, 27))	('mice', 'Species', '10090', (96, 100))	('[1-13C', 'Chemical', '-', (31, 37))	('U87wt-', 'Var', (70, 76))	('C]beta', 'Species', '10703', (18, 24))	('[1-13C]AcAc', 'Chemical', '-', (31, 42))	('rat', 'Species', '10116', (4, 7))	('[1-13C', 'Chemical', '-', (13, 19))
45849	30833594	The NAD+/NADH ratios in U87wt tumor samples (n = 7), U87mut (n = 10) tumor samples, normal-appearing brain tissue from both tumor groups, and tissue from control tumor-free mice (n = 8) were, respectively, 7.8 +- 2.8, 5.1 +- 3.1, 2.9 +- 1.2, 2.3 +- 1.3 and 2.1 +- 0.6 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (162, 167))	('NAD+', 'Chemical', 'MESH:D009243', (4, 8))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('rat', 'Species', '10116', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NADH', 'Chemical', 'MESH:D009243', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (30, 35))	('U87mut', 'Var', (53, 59))	('mice', 'Species', '10090', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
45852	30833594	BDH enzyme activities in U87wt tumor samples (n = 7), U87mut (n = 8) tumor samples, normal-appearing brain tissue samples and tissue from controls (n = 7) were 0.05 +- 0.03, 0.37 +- 0.30, 0.04 +- 0.03, 0.27 +- 0.16 and 0.36 +- 0.15 mumol/min/mug of protein respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('U87mut', 'Var', (54, 60))	('activities', 'MPA', (11, 21))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (31, 36))	('BDH enzyme', 'Enzyme', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
45858	30833594	As such, we could readily detect the delivery of hyperpolarized AcAc into the brain of a normal mouse.	('hyperpolarized', 'Var', (49, 63))	('AcAc', 'Chemical', 'MESH:C016635', (64, 68))	('detect', 'Reg', (26, 32))	('mouse', 'Species', '10090', (96, 101))
45867	30833594	But it should be noted that in the case of [3-13C]beta-HB, the directly bonded proton leads to a very short T1 that precluded detection of this second signal in vivo in our study at high field.	('C]beta', 'Species', '10703', (48, 54))	('[3-13C', 'Chemical', '-', (43, 49))	('beta-HB', 'Chemical', 'MESH:D020155', (50, 57))	('beta-HB', 'Protein', (50, 57))	('[3-13C]', 'Var', (43, 50))
45873	30833594	As previously mentioned, the IDH1 mutation is the most prevalent driver mutation in low-grade glioma and upgraded secondary glioblastoma.	('IDH1', 'Gene', (29, 33))	('glioma', 'Disease', (94, 100))	('mutation', 'Var', (34, 42))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
45874	30833594	It is responsible for the conversion of alpha-KG to 2-HG using NADPH as a cofactor, and previous studies have shown that the mutation results in increased reactive oxygen species, and changes in NADPH.	('NADPH', 'Gene', (195, 200))	('changes', 'Reg', (184, 191))	('NADPH', 'Gene', (63, 68))	('alpha-KG', 'Chemical', 'MESH:D007656', (40, 48))	('2-HG', 'Chemical', 'MESH:C019417', (52, 56))	('increased', 'PosReg', (145, 154))	('reactive oxygen species', 'MPA', (155, 178))	('NADPH', 'Gene', '67460', (195, 200))	('NADPH', 'Gene', '67460', (63, 68))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (155, 178))	('mutation', 'Var', (125, 133))
45875	30833594	Nonetheless, and although NADP+/NADPH and NAD+/NADH are interconnected, we did not observe any difference in the NAD+/NADH ratio between the U87 IDH1 wild type and U87 IDH1 mutant tumor extracts (p value = 0.09).	('NADH', 'Chemical', 'MESH:D009243', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('NADPH', 'Gene', '67460', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('NADP+', 'Chemical', 'MESH:D009249', (26, 31))	('tumor', 'Disease', (180, 185))	('NADPH', 'Gene', (32, 37))	('mutant', 'Var', (173, 179))	('rat', 'Species', '10116', (123, 126))	('NAD+', 'Chemical', 'MESH:D009243', (42, 46))	('NADH', 'Chemical', 'MESH:D009243', (118, 122))	('U87', 'Var', (164, 167))	('U87', 'Var', (141, 144))	('NAD+', 'Chemical', 'MESH:D009243', (113, 117))
45877	30833594	A possible reason is that our model was generated by genetically engineering glioblastoma cells to express mutant or wild type IDH1.	('mutant', 'Var', (107, 113))	('glioblastoma', 'Disease', (77, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('rat', 'Species', '10116', (44, 47))	('IDH1', 'Gene', (127, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))
45878	30833594	As such, our cells might not fully recapitulate the complete metabolic signature associated with IDH1 mutant glioma.	('mutant', 'Var', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH1', 'Gene', (97, 101))	('glioma', 'Disease', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
45885	30833594	As a result, there was a significantly lower (~38%, average for U87wt and U87mut tumors) [1-13C]beta-HB-to-[1-13C]AcAc ratio in the brain of tumor-bearing mice compared to tumor-free healthy controls.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Disease', (81, 87))	('tumor', 'Disease', (172, 177))	('rat', 'Species', '10116', (119, 122))	('[1-13C]AcAc', 'Chemical', '-', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('[1-13C', 'Chemical', '-', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('[1-13C]beta-HB-to-[1-13C]AcAc ratio', 'MPA', (89, 124))	('mice', 'Species', '10090', (155, 159))	('tumor', 'Disease', (81, 86))	('brain of tumor', 'Phenotype', 'HP:0030692', (132, 146))	('U87wt', 'Var', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('lower', 'NegReg', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('U87mut', 'Var', (74, 80))	('[1-13C', 'Chemical', '-', (107, 113))	('tumor', 'Disease', (141, 146))	('C]beta', 'Species', '10703', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('beta-HB', 'Chemical', 'MESH:D020155', (96, 103))
45888	30833594	The increase observed in our tumors was consistent with one previous study but most previous reports suggest that the ratio of NAD+/NADH should decrease in cancer cells.	('NAD+/NADH', 'Var', (127, 136))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Disease', (156, 162))	('NAD+', 'Chemical', 'MESH:D009243', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('decrease', 'NegReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NADH', 'Chemical', 'MESH:D009243', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))
45890	30833594	Our studies showed a significant increase (~60-70%) in NAD+/NADH in the tumor tissues compared to normal brain, which is consistent with the hyperpolarized observations.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('increase', 'PosReg', (33, 41))	('NAD+/NADH', 'Var', (55, 64))	('NAD+', 'Chemical', 'MESH:D009243', (55, 59))	('NADH', 'Chemical', 'MESH:D009243', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
45926	30833594	8 mice were implanted with IDH1 wild-type (U87wt) U87 cells and 12 with U87 cells genetically-engineered to express mutant IDH1 (U87mut).	('mutant', 'Var', (116, 122))	('IDH1', 'Gene', (123, 127))	('mice', 'Species', '10090', (2, 6))
45927	30833594	4 U87mut and 1 U87wt mice underwent the hyperpolarized study prior to tumor implantation and served as additional tumor-free controls.	('U87mut', 'Var', (2, 8))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
45943	30833594	Resonances of [1-13C]AcAc, [3-13C]AcAc and [1-13C]beta-HB were fitted with a Lorentzian-Gaussian line shape.	('[3-13C]', 'Var', (27, 34))	('C]beta', 'Species', '10703', (48, 54))	('[3-13C]AcAc', 'Chemical', '-', (27, 38))	('[1-13C', 'Chemical', '-', (14, 20))	('[1-13C]', 'Var', (43, 50))	('beta-HB', 'Chemical', 'MESH:D020155', (50, 57))	('[1-13C]AcAc', 'Chemical', '-', (14, 25))	('[1-13C', 'Chemical', '-', (43, 49))	('[1-13C]AcAc', 'Var', (14, 25))
45962	30833594	An unpaired t-test was used to determine statistical significance of tumor size measured by T2-weighted MRI between U87wt and U87mut mice (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (133, 137))	('U87mut', 'Var', (126, 132))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
45966	28881745	Using this approach, we demonstrate that optic gliomas generated by altering the germline Nf1 gene mutation, the glioma cell of origin, or the presence of co-existing genetic alterations represent molecularly-distinct tumors.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('optic glioma', 'Phenotype', 'HP:0009734', (41, 53))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('optic gliomas', 'Phenotype', 'HP:0009734', (41, 54))	('glioma', 'Disease', (47, 53))	('Nf1', 'Gene', (90, 93))	('mutation', 'Var', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('glioma', 'Disease', (113, 119))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('optic gliomas', 'Disease', 'MESH:D020339', (41, 54))	('optic gliomas', 'Disease', (41, 54))	('tumors', 'Disease', (218, 224))	('altering', 'Reg', (68, 76))
45989	28881745	In an effort to accurately represent the heterogeneity inherent in human NF1-associated optic pathway glioma (NF1-OPG), we have previously engineered mice that differ with respect to the germline Nf1 gene mutation (null allele (FMC) versus NF1 patient germline NF1 gene mutation; R681* (F18C)), the cell of origin (GFAP+ neuroglial progenitors (FMC) versus Olig2+ progenitor cells (FMOC) (Solga A, manuscript in preparation)), and the presence of a co-existing heterozygous Pten deletion in the tumor cells (FMPC).	('tumor', 'Disease', 'MESH:D009369', (495, 500))	('mice', 'Species', '10090', (150, 154))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('Pten', 'Gene', (474, 478))	('deletion', 'Var', (479, 487))	('patient', 'Species', '9606', (244, 251))	('tumor', 'Disease', (495, 500))	('F18C', 'Mutation', 'p.F18C', (287, 291))	('optic pathway glioma', 'Phenotype', 'HP:0009734', (88, 108))	('R681*', 'Var', (280, 285))	('glioma', 'Disease', (102, 108))	('human', 'Species', '9606', (67, 72))	('R681*', 'SUBSTITUTION', 'None', (280, 285))
46020	28881745	In this regard, tumor shrinkage is observed in the minority of children with NF1-OPG, and, when observed, is often relatively modest or not longstanding (durable response).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('NF1-OPG', 'Var', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('children', 'Species', '9606', (63, 71))
46026	28881745	As noted above, Pten deletion altered both the lineage resemblance and core signature expression of the FMC optic glioma model.	('core signature expression', 'MPA', (71, 96))	('optic glioma', 'Phenotype', 'HP:0009734', (108, 120))	('Pten', 'Gene', (16, 20))	('deletion', 'Var', (21, 29))	('lineage resemblance', 'CPA', (47, 66))	('optic glioma', 'Disease', 'MESH:D020339', (108, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('altered', 'Reg', (30, 37))	('optic glioma', 'Disease', (108, 120))
46031	28881745	Since the heterozygous Pten deletion was restricted to the neoplastic cells by virtue of the fact that Cre-mediated Pten reduction was targeted to GFAP transgene-expressing cells containing somatic Nf1 loss, we sought to determine whether this signature was maintained in optic glioma stem cells (o-GSCs) that derived from FMC and FMPC mouse tumors.	('tumors', 'Disease', 'MESH:D009369', (342, 348))	('Pten', 'Gene', (23, 27))	('optic glioma', 'Phenotype', 'HP:0009734', (272, 284))	('Pten', 'Gene', (116, 120))	('optic glioma', 'Disease', 'MESH:D020339', (272, 284))	('tumors', 'Phenotype', 'HP:0002664', (342, 348))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('mouse', 'Species', '10090', (336, 341))	('deletion', 'Var', (28, 36))	('tumors', 'Disease', (342, 348))	('optic glioma', 'Disease', (272, 284))	('loss', 'NegReg', (202, 206))	('reduction', 'NegReg', (121, 130))
46032	28881745	Previously, we showed that o-GSCs from FMC mice are true cancer stem cells, with the ability to self-renew, undergo multi-lineage differentiation, (Supplementary Figure 2) and form glioma-like lesions when transplanted into naive mice.	('mice', 'Species', '10090', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('mice', 'Species', '10090', (230, 234))	('cancer', 'Disease', (57, 63))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('multi-lineage differentiation', 'CPA', (116, 145))	('form', 'Reg', (176, 180))	('undergo', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('FMC', 'Var', (39, 42))	('glioma', 'Disease', (181, 187))
46034	28881745	Similar to that observed in the whole tumors, there was a relative depletion of the BKM120 normalized signature in FMC versus FMPC o-GSCs (Figure 4D), supporting a primary effect of heterozygous Pten deletion on the neoplastic cells in these gliomas.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('deletion', 'Var', (200, 208))	('tumors', 'Disease', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (242, 249))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('gliomas', 'Phenotype', 'HP:0009733', (242, 249))	('gliomas', 'Disease', (242, 249))	('depletion', 'MPA', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('Pten', 'Gene', (195, 199))	('BKM120', 'Gene', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('BKM120', 'Chemical', 'MESH:C571178', (84, 90))
46035	28881745	In addition, to determine whether BKM120 treatment normalizes this gene signature in purified o-GSCs, we treated separate pools of o-GSCs derived from FMPC mice with BKM120 in vitro and observed decreased PI3K/AKT activity (Supplementary Figure 3).	('AKT', 'Gene', (210, 213))	('BKM120', 'Chemical', 'MESH:C571178', (166, 172))	('BKM120', 'Chemical', 'MESH:C571178', (34, 40))	('BKM120', 'Var', (166, 172))	('mice', 'Species', '10090', (156, 160))	('AKT', 'Gene', '11651', (210, 213))	('decreased', 'NegReg', (195, 204))
46036	28881745	As observed following BKM120 treatment of FMPC mice, we found the same signature to be significantly depleted in BKM120 treated o-GSCs relative to vehicle-treated controls (Figure 4E).	('BKM120', 'Chemical', 'MESH:C571178', (22, 28))	('BKM120', 'Chemical', 'MESH:C571178', (113, 119))	('mice', 'Species', '10090', (47, 51))	('BKM120', 'Var', (113, 119))	('depleted', 'NegReg', (101, 109))
46040	28881745	However, in striking contrast, differences in patient survival were observed using an expression signature comprised of the top 50 FMPC-associated genes that were most significantly normalized by BKM120 treatment (BKM120 normalized signature).	('BKM120', 'Var', (196, 202))	('patient', 'Species', '9606', (46, 53))	('FMPC-associated genes', 'Gene', (131, 152))	('BKM120', 'Chemical', 'MESH:C571178', (196, 202))	('expression', 'MPA', (86, 96))	('normalized', 'Reg', (182, 192))	('BKM120', 'Chemical', 'MESH:C571178', (214, 220))
46047	28881745	In addition, co-existing genetic mutations targeted to the neoplastic cell compartment (Pten and Nf1 inactivation) can create differential core signatures that reflect the individual contributions of these molecular events to the cancer cells, which can be used to identify prognostic signatures relevant to patient survival and the potential interpretation of successful inhibition of the regulated growth control pathways.	('patient', 'Species', '9606', (308, 315))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('Pten', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('mutations', 'Var', (33, 42))	('Nf1', 'Gene', (97, 100))	('inactivation', 'NegReg', (101, 113))	('cancer', 'Disease', (230, 236))	('genetic mutations', 'Var', (25, 42))
46049	28881745	FF (Nf1flox/flox), FMC (Nf1flox/mut; GFAP-Cre) FMPC (Nf1flox/mut; Ptenflox/wt; GFAP-Cre), F18C (Nf1 gene mutation c.2041C>T; p.R681X; Nf1flox/R681*; GFAP-Cre) mice were generated as previously described.	('F18C', 'Mutation', 'p.F18C', (90, 94))	('R681*', 'Var', (142, 147))	('c.2041C>T', 'Mutation', 'rs768638173', (114, 123))	('p.R681X', 'Var', (125, 132))	('R681*', 'SUBSTITUTION', 'None', (142, 147))	('c.2041C>T; p.R681X', 'Var', (114, 132))	('mice', 'Species', '10090', (159, 163))	('p.R681X', 'Mutation', 'rs768638173', (125, 132))
46093	31877126	Compared to siRNAs, oligonucleotides have higher specificity and fewer off-target effects due to the direct targeting of lncRNAs.	('lncRNAs', 'Protein', (121, 128))	('higher', 'PosReg', (42, 48))	('specificity', 'MPA', (49, 60))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('oligonucleotides', 'Var', (20, 36))	('N', 'Chemical', 'MESH:D009584', (15, 16))
46149	31877126	The cross-validation results showed that 7.2% to 68.3% of lncRNA-gene pairs with PCCs larger than 0.5 and smaller than 0.7 (larger than 0.3 and smaller than 0.5 for those PCCs larger than 0.5 as positives) had a predicted score larger than 0.9 (Fig 2C and S1 Table), while there were more than ten thousand lncRNA-gene pairs with PCC larger than 0.5 and smaller than 0.7 (larger than 0.3 and smaller than 0.5 for those PCCs larger than 0.5 as positives).	('PCC', 'Gene', (81, 84))	('PCC', 'Gene', '1421', (330, 333))	('PCC', 'Gene', '1421', (419, 422))	('PCC', 'Gene', (171, 174))	('N', 'Chemical', 'MESH:D009584', (311, 312))	('PCC', 'Gene', (419, 422))	('PCC', 'Gene', (330, 333))	('PCC', 'Gene', '1421', (81, 84))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('PCC', 'Gene', '1421', (171, 174))	('larger', 'Var', (86, 92))
46178	31877126	LY294002, which was reported to be related to breast cancer cell apoptosis, was associated with BRCAT64.1 through the ALACD model (Fig 4B).	('LY294002', 'Var', (0, 8))	('BRCA', 'Gene', '672', (96, 100))	('BRCA', 'Gene', (96, 100))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
46179	31877126	Three out of the five genes that were associated with LY294002 and BRCAT64.1 were linked to breast cancer, as supported by the literature.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('breast cancer', 'Disease', (92, 105))	('LY294002', 'Var', (54, 62))	('BRCA', 'Gene', (67, 71))	('linked', 'Reg', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BRCA', 'Gene', '672', (67, 71))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
46202	31877126	For instance, the drug fluphenazine was linked to myeloma according to the literature reports, but had not been previously used for the treatment of patients with HNSC.	('patients', 'Species', '9606', (149, 157))	('myeloma', 'Disease', (50, 57))	('fluphenazine', 'Var', (23, 35))	('linked to', 'Reg', (40, 49))	('fluphenazine', 'Chemical', 'MESH:D005476', (23, 35))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('myeloma', 'Disease', 'MESH:D009101', (50, 57))
46207	31877126	Thus, targeting LGAT93.1 provides a novel therapeutic choice for the treatment of LGG, which has the potential to improve patient survival.	('LGG', 'Disease', (82, 85))	('patient', 'Species', '9606', (122, 129))	('targeting', 'Var', (6, 15))	('improve', 'PosReg', (114, 121))	('LGAT93.1', 'Gene', (16, 24))
46208	31877126	In the future, further validations could test cancer cell activity after silencing LGAT93.1 to assess the variations in the expression levels of the associated gene PJA2, which could help to reveal the underlying role of LGAT93.1 in LGG.	('LGG', 'Disease', (233, 236))	('test', 'Reg', (41, 45))	('silencing', 'Var', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('PJA2', 'Gene', '9867', (165, 169))	('cancer', 'Disease', (46, 52))	('LGAT93.1', 'Gene', (83, 91))	('expression', 'MPA', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PJA2', 'Gene', (165, 169))
46251	24328868	Multiple genes with specific types of alterations have now been identified that are associated with improved response to chemotherapy and radiotherapy, such as o6-methylguanine methyltranferase (MGMT) or loss of chromosomes 1p and/or 19q.	('o6-methylguanine methyltranferase', 'Gene', (160, 193))	('response', 'CPA', (109, 117))	('improved', 'PosReg', (100, 108))	('o6-methylguanine methyltranferase', 'Gene', '4255', (160, 193))	('loss', 'Var', (204, 208))	('alterations', 'Var', (38, 49))	('MGMT', 'Gene', (195, 199))	('MGMT', 'Gene', '4255', (195, 199))
46252	24328868	Other alterations have been identified that are associated with improved overall survival, such as mutations in isocitrate dehydrogenase 1 (IDH1) and/or isocitrate dehydrogenase 2 (IDH2) or having the glioma CpG island DNA methylator phenotype (G-CIMP).	('IDH1', 'Gene', '3417', (140, 144))	('overall', 'MPA', (73, 80))	('glioma', 'Disease', (201, 207))	('IDH2', 'Gene', (181, 185))	('mutations', 'Var', (99, 108))	('IDH1', 'Gene', (140, 144))	('G-CIMP', 'Chemical', '-', (245, 251))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('improved', 'PosReg', (64, 72))	('IDH2', 'Gene', '3418', (181, 185))
46257	24328868	IDH1 mutations are common in infiltrating lower grade (WHO II and III) and secondary high grade (WHO IV) glioblastomas, where the most common mutation in this gene is R132H.	('glioblastomas', 'Disease', 'MESH:D005909', (105, 118))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('glioblastomas', 'Disease', (105, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('mutations', 'Var', (5, 14))	('infiltrating lower grade', 'Disease', (29, 53))	('secondary high grade', 'Disease', (75, 95))	('common', 'Reg', (19, 25))	('R132H', 'Var', (167, 172))	('IDH1', 'Gene', (0, 4))	('R132H', 'Mutation', 'rs121913500', (167, 172))	('IDH1', 'Gene', '3417', (0, 4))
46262	24328868	In a PCR based analyses of pediatric malignant gliomas, IDH1 mutations were found in 16.3% of tumors and IDH2 mutations were found in none.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('found', 'Reg', (76, 81))	('IDH2', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IDH1', 'Gene', '3417', (56, 60))	('mutations', 'Var', (61, 70))	('IDH2', 'Gene', '3418', (105, 109))	('gliomas', 'Disease', (47, 54))	('tumors', 'Disease', (94, 100))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('IDH1', 'Gene', (56, 60))
46263	24328868	These mutations are useful for diagnosis of low grade malignant adult gliomas, but are of little utility in other adult tumors or pediatric gliomas.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('pediatric gliomas', 'Disease', 'MESH:D005910', (130, 147))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('adult tumors', 'Disease', 'MESH:C538052', (114, 126))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('pediatric gliomas', 'Disease', (130, 147))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('adult tumors', 'Disease', (114, 126))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('mutations', 'Var', (6, 15))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
46264	24328868	Mutations in IDH1 and IDH2 have been associated with improved overall survival.	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('improved', 'PosReg', (53, 61))	('overall survival', 'MPA', (62, 78))
46265	24328868	In adolescents that had ID1H mutation, one year overall and recurrence-free survival was significantly improved (p=0.035, and p=0.03 respectively)  The Cancer Genome Atlas (TCGA) is a National Cancer Institute funded effort to fully molecularly characterize multiple different cancer types including glioblastoma (WHO grade IV; GBM) and lower grade gliomas (WHO grade II and III).	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('mutation', 'Var', (29, 37))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (152, 171))	('glioma', 'Phenotype', 'HP:0009733', (349, 355))	('gliomas', 'Phenotype', 'HP:0009733', (349, 356))	('glioblastoma', 'Disease', (300, 312))	('glioblastoma', 'Phenotype', 'HP:0012174', (300, 312))	('Cancer Genome Atlas', 'Disease', (152, 171))	('Cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (277, 283))	('improved', 'PosReg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Cancer', 'Disease', (193, 199))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('GBM', 'Phenotype', 'HP:0012174', (328, 331))	('gliomas', 'Disease', (349, 356))	('Cancer', 'Disease', (152, 158))	('Cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('gliomas', 'Disease', 'MESH:D005910', (349, 356))	('ID1H', 'Gene', (24, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (300, 312))
46268	24328868	Positive G-CIMP status is tightly associated with IDH1 mutation in low grade glioma.	('associated', 'Reg', (34, 44))	('IDH1', 'Gene', (50, 54))	('G-CIMP', 'Chemical', '-', (9, 15))	('IDH1', 'Gene', '3417', (50, 54))	('glioma', 'Disease', (77, 83))	('mutation', 'Var', (55, 63))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
46269	24328868	G-CIMP was also a significant independent predictor of survival in low grade glioma, after adjusting for age and tumor grade.	('G-CIMP', 'Var', (0, 6))	('tumor', 'Disease', (113, 118))	('glioma', 'Disease', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('G-CIMP', 'Chemical', '-', (0, 6))
46270	24328868	However, the most recently updated analysis of the TCGA data does not show a survival advantage by gene expression subtype class, but does continue to show an overall survival advantage for those that are G-CIMP positive and have IDH1 mutations (who are also more likely to be proneural), although this is a small proportion of all GBM patients (~10%).	('GBM', 'Phenotype', 'HP:0012174', (332, 335))	('mutations', 'Var', (235, 244))	('G-CIMP', 'Chemical', '-', (205, 211))	('patients', 'Species', '9606', (336, 344))	('IDH1', 'Gene', (230, 234))	('IDH1', 'Gene', '3417', (230, 234))
46273	24328868	Hypermethylation has been found in a significant number of glioblastoma (GBM) patients (20-40%).	('Hypermethylation', 'Var', (0, 16))	('patients', 'Species', '9606', (78, 86))	('glioblastoma', 'Disease', (59, 71))	('found', 'Reg', (26, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))
46274	24328868	Patients with MGMT methylation had a significant survival benefit from concurrent temozolomide (TMZ) chemotherapy and radiotherapy as compared to radiotherapy alone, while those who did not have methylation of the MGMT promoter had a statistically insignificant gain in survival from the addition of chemotherapy.	('MGMT', 'Gene', (14, 18))	('TMZ', 'Chemical', 'MESH:D000077204', (96, 99))	('temozolomide', 'Chemical', 'MESH:D000077204', (82, 94))	('methylation', 'Var', (19, 30))	('gain', 'PosReg', (262, 266))	('survival', 'CPA', (49, 57))	('MGMT', 'Gene', '4255', (214, 218))	('Patients', 'Species', '9606', (0, 8))	('MGMT', 'Gene', (214, 218))	('MGMT', 'Gene', '4255', (14, 18))	('benefit', 'PosReg', (58, 65))
46277	24328868	Loss of 1p has been significantly associated with response to TMZ chemotherapy, with all tumors expressing this phenotype responding positively to chemotherapy in one analysis (p < 0.001).	('associated', 'Reg', (34, 44))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (62, 65))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
46282	24328868	Presenting with seizure as first symptom is significantly associated with IDH1 or IDH2 mutation in lower grade glioma.	('glioma', 'Disease', (111, 117))	('seizure', 'Phenotype', 'HP:0001250', (16, 23))	('associated', 'Reg', (58, 68))	('IDH1', 'Gene', (74, 78))	('IDH2', 'Gene', (82, 86))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('seizure', 'Disease', (16, 23))	('IDH2', 'Gene', '3418', (82, 86))	('IDH1', 'Gene', '3417', (74, 78))	('seizure', 'Disease', 'MESH:D012640', (16, 23))	('mutation', 'Var', (87, 95))
46286	24328868	Studies of glioneuronal tumors have suggested that high neuronal density may be associated with epileptiform discharge patterns.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('epileptiform discharge', 'Phenotype', 'HP:0011182', (96, 118))	('epileptiform', 'Disease', (96, 108))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('glioneuronal tumors', 'Disease', (11, 30))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (11, 30))	('associated', 'Reg', (80, 90))	('high', 'Var', (51, 55))	('epileptiform', 'Disease', 'MESH:D004827', (96, 108))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (11, 30))
46296	28801186	Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear.	('1p/19q non-co-deleted', 'Var', (272, 293))	('anaplastic glioma', 'Disease', 'MESH:D005910', (294, 311))	('tumours', 'Disease', 'MESH:D009369', (417, 424))	('tumours', 'Disease', (417, 424))	('gliomas', 'Disease', (305, 312))	('temozolomide', 'Chemical', 'MESH:D000077204', (106, 118))	('gliomas', 'Disease', 'MESH:D005910', (305, 312))	('gliomas', 'Phenotype', 'HP:0009733', (305, 312))	('anaplastic glioma', 'Disease', (145, 162))	('temozolomide', 'Chemical', 'MESH:D000077204', (227, 239))	('tumour', 'Phenotype', 'HP:0002664', (417, 423))	('anaplastic glioma', 'Disease', (294, 311))	('tumours', 'Phenotype', 'HP:0002664', (417, 424))	('anaplastic glioma', 'Disease', 'MESH:D005910', (145, 162))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))
46312	28801186	No survival benefit was found at the time of the first analyses, but the deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q co-deletion, was found to be an important prognostic factor.	('as 1p', 'Gene', (172, 177))	('deletion', 'Var', (73, 81))	('as 1p', 'Gene', '5729', (172, 177))	('short arm', 'Phenotype', 'HP:0009824', (94, 103))
46313	28801186	This co-deletion had previously been associated with increased sensitivity to chemotherapy compared with 1p/19q non-co-deleted tumours.	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('sensitivity to chemotherapy', 'MPA', (63, 90))	('tumours', 'Disease', 'MESH:D009369', (127, 134))	('tumours', 'Disease', (127, 134))	('increased', 'PosReg', (53, 62))	('co-deletion', 'Var', (5, 16))
46366	28801186	In the univariate analysis, adjuvant temozolomide was associated with improved overall survival (HR 0 67, 95% CI 0 51-0 88), as was progression-free survival (HR 0 62, 95% CI 0 50-0 76; figure 2).	('adjuvant', 'Var', (28, 36))	('temozolomide', 'Chemical', 'MESH:D000077204', (37, 49))	('improved', 'PosReg', (70, 78))	('overall survival', 'MPA', (79, 95))
46372	28801186	The planned interim analysis of the CATNON trial showed significant and clinically meaningful benefits for overall and progression-free survival with adjuvant temozolomide in patients with non-co-deleted anaplastic glioma.	('overall', 'CPA', (107, 114))	('benefits', 'PosReg', (94, 102))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('temozolomide', 'Chemical', 'MESH:D000077204', (159, 171))	('anaplastic glioma', 'Disease', (204, 221))	('non-co-deleted', 'Var', (189, 203))	('patients', 'Species', '9606', (175, 183))	('anaplastic glioma', 'Disease', 'MESH:D005910', (204, 221))	('CATNON', 'Chemical', '-', (36, 42))	('progression-free survival', 'CPA', (119, 144))
46379	28801186	We decided to take this approach because patients with 1p/19q non-co-deleted tumours had worse outcomes than patients with 1p/19q co-deletion tumours in the trials of PCV chemotherapy to treat anaplastic oligodendroglioma.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', (142, 149))	('anaplastic oligodendroglioma', 'Disease', (193, 221))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('1p/19q non-co-deleted', 'Var', (55, 76))	('patients', 'Species', '9606', (109, 117))	('tumours', 'Disease', (77, 84))	('patients', 'Species', '9606', (41, 49))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (193, 221))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
46384	28801186	Although the patients in the CATNON trial had 1p/19q non-co-deleted anaplastic glioma, which are less chemotherapy sensitive than 1p/19q co-deleted tumours, temozolomide was clearly beneficial.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('temozolomide', 'Chemical', 'MESH:D000077204', (157, 169))	('tumours', 'Disease', (148, 155))	('anaplastic glioma', 'Disease', 'MESH:D005910', (68, 85))	('patients', 'Species', '9606', (13, 21))	('1p/19q non-co-deleted', 'Var', (46, 67))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('CATNON', 'Chemical', '-', (29, 35))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('anaplastic glioma', 'Disease', (68, 85))
46388	28801186	In 2009, mutations in IDH1 and IDH2 were reported to occur in 70-80% of all grade II and III diffuse glioma.	('IDH2', 'Gene', '3418', (31, 35))	('glioma', 'Disease', (101, 107))	('mutations', 'Var', (9, 18))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('IDH2', 'Gene', (31, 35))	('occur', 'Reg', (53, 58))
46389	28801186	These mutations are associated with improved outcomes and are now the cornerstone of the WHO 2016 classification of glioma.	('glioma', 'Disease', (116, 122))	('improved', 'PosReg', (36, 44))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('mutations', 'Var', (6, 15))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
46390	28801186	In 2011, we amended our study protocol to incorporate analyses of mutations in IDH1 and IDH2 to investigate their predictive value for temozolomide efficacy, for which the analyses are pending.	('mutations', 'Var', (66, 75))	('IDH1', 'Gene', '3417', (79, 83))	('IDH2', 'Gene', (88, 92))	('IDH2', 'Gene', '3418', (88, 92))	('temozolomide', 'Chemical', 'MESH:D000077204', (135, 147))	('IDH1', 'Gene', (79, 83))
46391	28801186	As there are substantial metabolic differences between tumours with and without these mutations, we suggest that future trials should involve only patients with either mutated or wild-type IDH1 and IDH2 grade II and III gliomas.	('mutated', 'Var', (168, 175))	('tumours', 'Disease', (55, 62))	('metabolic', 'MPA', (25, 34))	('IDH1', 'Gene', '3417', (189, 193))	('IDH2', 'Gene', (198, 202))	('III glioma', 'Disease', 'MESH:D005910', (216, 226))	('III glioma', 'Disease', (216, 226))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (147, 155))	('IDH2', 'Gene', '3418', (198, 202))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('IDH1', 'Gene', (189, 193))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('gliomas', 'Disease', (220, 227))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
46392	28801186	Results from MGMT promoter methylation testing were not available for 63% of patients at the time of randomisation, mainly because testing of 1p/19q co-deletion and MGMT methylation status could not always be completed in the limited time beforehand.	('1p/19q', 'Var', (142, 148))	('patients', 'Species', '9606', (77, 85))	('MGMT', 'Gene', (13, 17))	('MGMT', 'Gene', '4255', (13, 17))	('MGMT', 'Gene', (165, 169))	('MGMT', 'Gene', '4255', (165, 169))
46397	28801186	The presence of IDH1 and IDH2 mutations and MGMT promoter methylation have both been proposed as predictive factors for benefit from chemotherapy.	('benefit', 'PosReg', (120, 127))	('IDH1', 'Gene', (16, 20))	('MGMT', 'Gene', (44, 48))	('mutations', 'Var', (30, 39))	('IDH2', 'Gene', (25, 29))	('MGMT', 'Gene', '4255', (44, 48))	('IDH1', 'Gene', '3417', (16, 20))	('IDH2', 'Gene', '3418', (25, 29))
46398	28801186	The results of this study, in which we enrolled patients with IDH1 and IDH2 mutant and wild-type gliomas, could show differences in prognosis and sensitivity to chemotherapy and will help to identify the best discriminating molecular factor for benefit.	('IDH1', 'Gene', '3417', (62, 66))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('IDH2', 'Gene', (71, 75))	('mutant', 'Var', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('differences', 'Reg', (117, 128))	('IDH2', 'Gene', '3418', (71, 75))	('IDH1', 'Gene', (62, 66))	('patients', 'Species', '9606', (48, 56))
46408	28801186	In the CATNON trial, 12 cycles of adjuvant temozolomide after radiotherapy significantly improved overall survival in patients with 1p/19q non-co-deleted anaplastic glioma, and should now constitute the standard care for this group of patients.	('improved', 'PosReg', (89, 97))	('temozolomide', 'Chemical', 'MESH:D000077204', (43, 55))	('1p/19q non-co-deleted', 'Var', (132, 153))	('anaplastic glioma', 'Disease', 'MESH:D005910', (154, 171))	('patients', 'Species', '9606', (235, 243))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('CATNON', 'Chemical', '-', (7, 13))	('overall survival', 'MPA', (98, 114))	('patients', 'Species', '9606', (118, 126))	('anaplastic glioma', 'Disease', (154, 171))
46411	28801186	Additionally, prognosis was much worse in patients with 1p/19q non-co-deleted tumours than in those with 1p/19q co-deleted tumours.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('1p/19q non-co-deleted', 'Var', (56, 77))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('tumours', 'Disease', (78, 85))	('worse', 'NegReg', (33, 38))	('tumours', 'Disease', (123, 130))	('patients', 'Species', '9606', (42, 50))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
46416	28801186	The standard of care for 1p/19q non-co-deleted anaplastic glioma should be surgery followed by radiotherapy and 12 4-week cycles of temozolomide given on days 1-5.	('1p/19q non-co-deleted', 'Var', (25, 46))	('anaplastic glioma', 'Disease', 'MESH:D005910', (47, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('temozolomide', 'Chemical', 'MESH:D000077204', (132, 144))	('anaplastic glioma', 'Disease', (47, 64))
46482	25742877	In this subset of patients, the median PSI was significantly longer in those who had PD (3.7 mo vs. 1.3 mo, p=0.03), and we observed a longer median PSI in patients with less than gross total resection and in patients with seizures, although these differences were not statistically significant (Table 6).	('patients', 'Species', '9606', (156, 164))	('longer', 'PosReg', (61, 67))	('less', 'Var', (170, 174))	('PD', 'Disease', 'MESH:D010300', (85, 87))	('seizure', 'Phenotype', 'HP:0001250', (223, 230))	('PSI', 'MPA', (39, 42))	('seizures', 'Phenotype', 'HP:0001250', (223, 231))	('seizures', 'Disease', 'MESH:D012640', (223, 231))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (18, 26))	('PSI', 'MPA', (149, 152))	('seizures', 'Disease', (223, 231))	('longer', 'PosReg', (135, 141))
46549	25407389	PTC299 suppresses tumor overproduction of all four VEGF isoforms and inhibits production of other angiogenic cytokines.	('tumor', 'Disease', (18, 23))	('inhibits', 'NegReg', (69, 77))	('PTC299', 'Var', (0, 6))	('VEGF', 'Gene', '7422', (51, 55))	('PTC299', 'Chemical', 'MESH:C052026', (0, 6))	('production of other angiogenic cytokines', 'MPA', (78, 118))	('suppresses', 'NegReg', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('VEGF', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
46551	25407389	In vitro studies have demonstrated that PTC299 preferentially inhibits VEGF production in cells stimulated by stressors such as hypoxia.	('PTC299', 'Var', (40, 46))	('inhibits', 'NegReg', (62, 70))	('VEGF', 'Gene', (71, 75))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('hypoxia', 'Disease', (128, 135))	('PTC299', 'Chemical', 'MESH:C052026', (40, 46))	('VEGF', 'Gene', '7422', (71, 75))
46588	25407389	Tumor response was defined as follows: complete response (CR), disappearance of all measurable lesions on magnetic resonance imaging (MRI); partial response (PR), >=50% reduction in tumor size by bidimensional measurement on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurological exam; progressive disease (PD), worsening neurologic status or >25% increase in the bidimensional measurement, or appearance of new lesions, or increasing corticosteroids doses; and stable disease (SD).	('steroids', 'Chemical', 'MESH:D013256', (485, 493))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('decreasing dose of corticosteroids', 'Phenotype', 'HP:0032363', (237, 271))	('reduction', 'NegReg', (169, 178))	('tumor', 'Disease', (182, 187))	('partial', 'Var', (140, 147))	('PD', 'Disease', 'MESH:D010300', (350, 352))	('bidimensional measurement', 'MPA', (407, 432))	('SD', 'Disease', 'MESH:D029461', (521, 523))	('stable disease', 'Disease', (505, 519))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('worsening neurologic status', 'Phenotype', 'HP:0002344', (355, 382))	('increase', 'PosReg', (391, 399))	('progressive disease', 'Disease', (329, 348))	('steroids', 'Chemical', 'MESH:D013256', (263, 271))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
46638	25407389	Pre-clinical data had demonstrated potential synergy between PTC299 and bevacizumab and between PTC299 and mTOR-inhibitors.	('PTC299', 'Chemical', 'MESH:C052026', (61, 67))	('mTOR', 'Gene', (107, 111))	('mTOR', 'Gene', '2475', (107, 111))	('PTC299', 'Chemical', 'MESH:C052026', (96, 102))	('synergy', 'Interaction', (45, 52))	('bevacizumab', 'Chemical', 'MESH:D000068258', (72, 83))	('PTC299', 'Var', (61, 67))
46641	31324855	PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival 70-90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase 1 (IDHmut).	('reduced', 'NegReg', (52, 59))	('glioma', 'Disease', (36, 42))	('mTOR', 'Gene', '2475', (5, 9))	('IDH1', 'Gene', (24, 28))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('gliomas', 'Disease', (138, 145))	('glioma', 'Disease', (138, 144))	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', (236, 239))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('increased', 'PosReg', (99, 108))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('glioblastomas', 'Phenotype', 'HP:0012174', (160, 173))	('isocitrate dehydrogenase 1', 'Gene', (208, 234))	('IDH1', 'Gene', '3417', (24, 28))	('isocitrate dehydrogenase 1', 'Gene', '3417', (208, 234))	('mutant', 'Var', (29, 35))	('IDH', 'Gene', '3417', (24, 27))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('mutations', 'Var', (195, 204))	('IDH', 'Gene', '3417', (236, 239))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('glioblastomas', 'Disease', (160, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('2HG production', 'MPA', (60, 74))	('mTOR', 'Gene', (5, 9))	('glioblastomas', 'Disease', 'MESH:D005909', (160, 173))
46645	31324855	1H-MRS of two cell lines genetically modified to express IDHmut showed that XL765 induced a significant reduction in several intracellular metabolites including 2HG.	('IDH', 'Gene', '3417', (57, 60))	('XL765', 'Var', (76, 81))	('reduction', 'NegReg', (104, 113))	('2HG', 'MPA', (161, 164))	('1H', 'Chemical', '-', (0, 2))	('MRS', 'Gene', '148398', (3, 6))	('MRS', 'Gene', (3, 6))	('several intracellular metabolites', 'MPA', (117, 150))	('IDH', 'Gene', (57, 60))
46654	31324855	In this context, the main characteristic of ~70-90% LGGs and secondary GBM is the presence of a mutation in the cytosolic form of isocitrate dehydrogenase 1 (IDHmut).	('IDH', 'Gene', '3417', (158, 161))	('presence', 'Reg', (82, 90))	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('isocitrate dehydrogenase 1', 'Gene', (130, 156))	('isocitrate dehydrogenase 1', 'Gene', '3417', (130, 156))	('IDH', 'Gene', (158, 161))	('mutation in', 'Var', (96, 107))
46657	31324855	Mutation occurs as a single amino acid substitution in the active site of IDH, and the IDHmut enzyme catalyzes the reduction of alpha-KG to 2-hydroxyglutarate (2HG).	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (140, 158))	('IDH', 'Gene', (87, 90))	('Mutation', 'Var', (0, 8))	('IDH', 'Gene', '3417', (87, 90))	('IDH', 'Gene', (74, 77))	('IDH', 'Gene', '3417', (74, 77))	('alpha-KG', 'Chemical', 'MESH:D007656', (128, 136))	('alpha-KG to 2-hydroxyglutarate', 'MPA', (128, 158))
46658	31324855	2HG has been shown to inhibit the activity of alpha-KG-dependent dioxygenases such as histone demethylases, prolyl hydroxylases and TET family of 5-methylcytosine hydroxylases.	('activity', 'MPA', (34, 42))	('prolyl hydroxylases', 'Enzyme', (108, 127))	('alpha-KG', 'Chemical', 'MESH:D007656', (46, 54))	('histone demethylases', 'Enzyme', (86, 106))	('inhibit', 'NegReg', (22, 29))	('alpha-KG-dependent dioxygenases', 'Enzyme', (46, 77))	('2HG', 'Var', (0, 3))	('TET family of 5-methylcytosine hydroxylases', 'Enzyme', (132, 175))
46677	31324855	Activation of the pathway is frequently detected in LGG and secondary glioblastoma, either as a result of enhanced platelet-derived growth factor (PDGF) signaling (via receptor amplification/mutation or ligand overexpression) or due to inactivation of the regulatory inhibitor PTEN (via PTEN promoter methylation and silencing).	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('enhanced', 'PosReg', (106, 114))	('PTEN', 'Gene', '5728', (287, 291))	('amplification/mutation', 'Var', (177, 199))	('LGG', 'Disease', (52, 55))	('silencing', 'Var', (317, 326))	('PTEN', 'Gene', (277, 281))	('PTEN', 'Gene', '5728', (277, 281))	('PTEN', 'Gene', (287, 291))	('glioblastoma', 'Disease', (70, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('inactivation', 'Var', (236, 248))
46680	31324855	At the same time, inhibitors of the PI3K/mTOR pathway investigated in preclinical studies as well as in clinical trials in GBM and other tumor types, show improved median survival, reduced local and metastatic growth, and tumor growth inhibition.	('reduced', 'NegReg', (181, 188))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('improved', 'PosReg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mTOR', 'Gene', '2475', (41, 45))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mTOR', 'Gene', (41, 45))	('inhibitors', 'Var', (18, 28))	('median survival', 'CPA', (164, 179))
46681	31324855	Based on these earlier findings, inhibitors of the PI3K/mTOR pathway have entered clinical trials for LGG (NCT02023905, NCT01316809).	('mTOR', 'Gene', '2475', (56, 60))	('mTOR', 'Gene', (56, 60))	('NCT02023905', 'Var', (107, 118))
46682	31324855	However, PI3K inhibitors often induce tumor stasis rather than shrinkage.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('induce', 'Reg', (31, 37))	('PI3K inhibitors', 'Var', (9, 24))	('tumor stasis', 'Disease', 'MESH:D014647', (38, 50))	('tumor stasis', 'Disease', (38, 50))
46690	31324855	Our findings indicate that MRS could help assess the efficacy of PI3K inhibitors in IDHmut tumors and possibly predict treatment outcome.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MRS', 'Gene', (27, 30))	('PI3K', 'Var', (65, 69))	('MRS', 'Gene', '148398', (27, 30))	('IDHmut tumors', 'Disease', 'MESH:D009369', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('IDHmut tumors', 'Disease', (84, 97))
46697	31324855	Taken together, these results confirmed that XL765 inhibited PI3K/mTOR signaling in our low-grade glioma models.	('XL765', 'Var', (45, 50))	('mTOR', 'Gene', (66, 70))	('mTOR', 'Gene', '2475', (66, 70))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Disease', (98, 104))	('inhibited', 'NegReg', (51, 60))
46699	31324855	2B: NHAIDHmut, R2X (fraction of variation of X variables explained by model) = 0.407, Q2 (goodness of prediction) = 0.0484; N = 6 for control and N = 7 for XL765; Fig.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('goodness', 'Disease', 'None', (90, 98))	('R2X', 'Var', (15, 18))	('goodness', 'Disease', (90, 98))
46704	31324855	Consistent with our findings in our cell models, XL765 reduced levels of p4E-BP1 without affecting total 4E-BP1 levels (Fig.	('4E-BP1', 'Gene', '1978', (74, 80))	('4E-BP1', 'Gene', '1978', (105, 111))	('levels', 'MPA', (63, 69))	('reduced', 'NegReg', (55, 62))	('4E-BP1', 'Gene', (74, 80))	('4E-BP1', 'Gene', (105, 111))	('XL765', 'Var', (49, 54))
46708	31324855	Taken together, these results indicated that XL765 inhibited PI3K/mTOR signaling in vivo and pointed to a cytostatic effect of XL765 on tumor proliferation, consistent with previous studies indicating that PI3K/mTOR inhibition leads to tumor stasis.	('XL765', 'Var', (45, 50))	('mTOR', 'Gene', (66, 70))	('cytostatic effect', 'MPA', (106, 123))	('mTOR', 'Gene', '2475', (66, 70))	('mTOR', 'Gene', '2475', (211, 215))	('tumor stasis', 'Disease', 'MESH:D014647', (236, 248))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('mTOR', 'Gene', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor stasis', 'Disease', (236, 248))	('tumor', 'Disease', (136, 141))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Disease', (236, 241))
46722	31324855	Our results indicate that, following XL765 treatment, flux from both glucose and glutamine towards 2HG was significantly reduced in both NHAIDHmut and U87IDHmut models, thus explaining the drop in 2HG steady state levels observed by 1H MRS.	('IDH', 'Gene', (140, 143))	('1H', 'Chemical', '-', (233, 235))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('IDH', 'Gene', '3417', (140, 143))	('XL765', 'Var', (37, 42))	('reduced', 'NegReg', (121, 128))	('flux from', 'MPA', (54, 63))	('glutamine', 'Chemical', 'MESH:D005973', (81, 90))	('IDH', 'Gene', (154, 157))	('MRS', 'Gene', '148398', (236, 239))	('MRS', 'Gene', (236, 239))	('IDH', 'Gene', '3417', (154, 157))
46739	31324855	This choice was driven by research in other tumor types that has shown that inhibition of mTOR only results in a feedback loop, activation of compensatory pathways, and tumor resistance.	('activation', 'PosReg', (128, 138))	('feedback loop', 'MPA', (113, 126))	('mTOR', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mTOR', 'Gene', '2475', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('compensatory pathways', 'Pathway', (142, 163))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (169, 174))	('inhibition', 'Var', (76, 86))	('results in', 'Reg', (100, 110))	('tumor', 'Disease', (44, 49))
46740	31324855	More effective inhibition of tumor growth was achieved by simultaneously targeting both PI3K and mTOR.	('inhibition', 'NegReg', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('targeting', 'Reg', (73, 82))	('tumor', 'Disease', (29, 34))	('PI3K', 'Var', (88, 92))
46742	31324855	Collectively such studies have led to the use of dual inhibitors in clinical phase I and II trials in a range of tumor types including GBM and, importantly, several such studies have resulted in clinically-relevant disease stability (NCT03522298, NCT01547546).	('tumor', 'Disease', (113, 118))	('NCT03522298', 'Var', (234, 245))	('GBM', 'Disease', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('GBM', 'Phenotype', 'HP:0012174', (135, 138))	('NCT01547546', 'Var', (247, 258))	('resulted', 'Reg', (183, 191))
46747	31324855	who showed reduce 2HG production in IDHmut fibrosarcoma cells following mTOR inhibition.	('2HG production', 'MPA', (18, 32))	('inhibition', 'Var', (77, 87))	('fibrosarcoma', 'Disease', (43, 55))	('mTOR', 'Gene', '2475', (72, 76))	('mTOR', 'Gene', (72, 76))	('IDH', 'Gene', (36, 39))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (43, 55))	('fibrosarcoma', 'Disease', 'MESH:D005354', (43, 55))	('reduce', 'NegReg', (11, 17))	('IDH', 'Gene', '3417', (36, 39))
46748	31324855	Our observation that 2HG drops in vivo was independent of tumor size, but was associated with enhanced animal survival, pointing to the value of this biomarker as an indicator of PI3K inhibition and likely response to treatment.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('animal survival', 'CPA', (103, 118))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('2HG drops', 'Var', (21, 30))	('enhanced', 'PosReg', (94, 102))
46753	31324855	However, this model has lost 2HG production due to loss of the wild-type IDH allele, a phenomenon that has been shown to occur in IDH mutant gliomas.	('2HG production', 'MPA', (29, 43))	('IDH', 'Gene', '3417', (130, 133))	('loss', 'NegReg', (51, 55))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('IDH', 'Gene', (73, 76))	('lost', 'NegReg', (24, 28))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', (130, 133))	('gliomas', 'Disease', (141, 148))	('mutant', 'Var', (134, 140))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
46754	31324855	Importantly, we have previously demonstrated that 2HG levels in our U87IDHmut tumor tissue extracts (9.8 +- 1.6 mumol/g of tissue) were comparable to 2HG levels reported in patients (5-35 mumol/g).	('patients', 'Species', '9606', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('U87IDHmut', 'Var', (68, 77))	('tumor', 'Disease', (78, 83))
46756	31324855	Based on these observations, we believe that the use of the U87IDHmut glioma model in vivo is justified for the purposes of the current study.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('U87IDHmut', 'Var', (60, 69))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))
46760	31324855	Inhibition of PI3K/mTOR would thus inhibit glucose and glutamine metabolism providing a possible explanation for our observations.	('glutamine', 'Chemical', 'MESH:D005973', (55, 64))	('mTOR', 'Gene', '2475', (19, 23))	('mTOR', 'Gene', (19, 23))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))	('Inhibition', 'Var', (0, 10))	('inhibit', 'NegReg', (35, 42))
46769	31324855	Briefly cells were created by introduction of lentiviral constructs encoding for R132H IDH1 cDNA into U87 GBM cells or immortalized normal human astrocytes (NHA) respectively.	('IDH1', 'Gene', '3417', (87, 91))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('U87', 'Gene', '641648', (102, 105))	('human', 'Species', '9606', (139, 144))	('U87', 'Gene', (102, 105))	('R132H', 'Var', (81, 86))	('IDH1', 'Gene', (87, 91))	('R132H', 'Mutation', 'rs121913500', (81, 86))
46778	31324855	Membranes were blocked in blocking buffer containing 5% BSA in Tris-Buffered Saline Tween-20 (TBST) and incubated with the primary antibodies anti-p4E-BP1 (Thr37/46, Cell Signaling #2855), anti-4E-BP1 (Cell Signaling #9452), anti-pS6 kinase (Thr389, Cell Signaling #9234), anti-S6 kinase (Cell Signaling #9202) and anti-beta-actin (Cell Signaling #4970) overnight at 4  C. HRP-conjugated secondary antibodies (Cell Signaling #7074) were incubated for 60 min in TBST at room temperature.	('beta-actin', 'Gene', '728378', (320, 330))	('S6 kinase', 'Gene', (278, 287))	('4E-BP1', 'Gene', (148, 154))	('S6 kinase', 'Gene', '6198', (231, 240))	('4E-BP1', 'Gene', (194, 200))	('S6 kinase', 'Gene', (231, 240))	('Thr389', 'Var', (242, 248))	('4E-BP1', 'Gene', '1978', (148, 154))	('S6 kinase', 'Gene', '6198', (278, 287))	('4E-BP1', 'Gene', '1978', (194, 200))	('beta-actin', 'Gene', (320, 330))
46821	31173217	The results revealed that CDCA7L was highly expressed in human GBM tissues, and a high expression of CDCA7L was associated with a poor prognosis of glioma patients through the TCGA database.	('associated with', 'Reg', (112, 127))	('high', 'Var', (82, 86))	('glioma', 'Disease', (148, 154))	('CDCA7L', 'Gene', (26, 32))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('patients', 'Species', '9606', (155, 163))	('CDCA7L', 'Gene', (101, 107))	('human', 'Species', '9606', (57, 62))
46823	31173217	In addition, we found that the mRNA and protein levels of CCND1 were markedly decreased following transfection with CDCA7L siRNA compared with NC siRNA in vitro.	('CCND1', 'Gene', (58, 63))	('CCND1', 'Gene', '595', (58, 63))	('CDCA7L', 'Var', (116, 122))	('decreased', 'NegReg', (78, 87))
46825	31173217	On the whole, the results of the current study indicate that CDCA7L is highly expressed in human glioma tissues and that a high CDCA7L expression predicts a poor prognosis of glioma patients.	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (97, 103))	('high', 'Var', (123, 127))	('CDCA7L', 'Gene', (128, 134))	('expression', 'MPA', (135, 145))	('glioma tissues', 'Disease', (97, 111))	('glioma', 'Disease', (175, 181))	('patients', 'Species', '9606', (182, 190))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma tissues', 'Disease', 'MESH:D005910', (97, 111))	('CDCA7L', 'Gene', (61, 67))	('human', 'Species', '9606', (91, 96))
46870	31173217	Following transfection with NC siRNA or CDCA7L siRNA, the glioma U87 cells were counted by cell counting instrument (Countess, Invitrogen; Thermo Fisher Scientific, Inc.) and then seeded into 24-well plates at a density of 1x104 cells/well.	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Disease', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('CDCA7L siRNA', 'Var', (40, 52))
46873	31173217	The U87 cells were infected with CDCA7L siRNA or NC siRNA and incubated at 37 C. The transfected glioma cells were then harvested, washed twice with phosphate-buffered saline (PBS), and fixed with 75% ice-cold ethanol.	('ethanol', 'Chemical', 'MESH:D000431', (210, 217))	('PBS', 'Chemical', '-', (176, 179))	('glioma', 'Disease', (97, 103))	('CDCA7L', 'Var', (33, 39))	('phosphate-buffered saline', 'Chemical', '-', (149, 174))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
46893	31173217	To examine the effects of CDCA7L on the growth of glioma cells, CCK-8 and colony formation assays were performed after the glioma U87 cells were transfected with CDCA7L siRNA or NC siRNA.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('CDCA7L', 'Var', (162, 168))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
46894	31173217	Furthermore, the effects of CDCA7L on cell proliferation following the downregulation of CDCA7L were evaluated through an EdU cell-image assay, and the results were consistent with those of the CCK-8 and colony formation assays, indicating that the EdU-positive rates of U87 cells were lower in the CDCA7L siRNA group compared with those in the NC siRNA group and that the number of EdU-positive cells was decreased by approximately 16.6% (Fig.	('EdU', 'Chemical', 'MESH:C031086', (383, 386))	('CDCA7L', 'Var', (299, 305))	('EdU', 'Chemical', 'MESH:C031086', (249, 252))	('lower', 'NegReg', (286, 291))	('EdU-positive rates', 'CPA', (249, 267))	('EdU', 'Chemical', 'MESH:C031086', (122, 125))
46895	31173217	Thus, on the whole, these data indicate that the knockdown of CDCA7L effectively prevents the development of U87 glioma cells.	('knockdown', 'Var', (49, 58))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('prevents', 'NegReg', (81, 89))	('CDCA7L', 'Gene', (62, 68))	('glioma', 'Disease', (113, 119))
46898	31173217	The results revealed that the CCND1 mRNA expression level was markedly reduced following transfection with CDCA7L siRNA compared with NC siRNA (Fig.	('CDCA7L', 'Var', (107, 113))	('reduced', 'NegReg', (71, 78))	('CCND1', 'Gene', (30, 35))	('CCND1', 'Gene', '595', (30, 35))
46900	31173217	To assess whether CDCA7L downregulation can could suppress glioma growth in vivo, U87 human glioma cells transfected with CDCA7L siRNA or NC siRNA were injected into the brains of nude mice to form intracranial xenografts.	('nude mice', 'Species', '10090', (180, 189))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('suppress', 'NegReg', (50, 58))	('human', 'Species', '9606', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Disease', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('CDCA7L', 'Gene', (18, 24))	('CDCA7L', 'Var', (122, 128))	('downregulation', 'NegReg', (25, 39))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
46901	31173217	Bioluminescence imaging revealed that tumor growth in the CDCA7L siRNA group (maximum diameter, 0.5 cm) was inhibited compared with that in NC siRNA group (maximum diameter, 1.0 cm) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('inhibited', 'NegReg', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CDCA7L', 'Var', (58, 64))
46905	31173217	Furthermore, to analyze survival in the different treatment groups, a Kaplan-Meier survival curve was plotted, which revealed that the survival of the mice in the CDCA7L siRNA groups was evidently prolonged compared with that of mice in the NC siRNA groups (Fig.	('mice', 'Species', '10090', (151, 155))	('CDCA7L', 'Var', (163, 169))	('mice', 'Species', '10090', (229, 233))	('survival', 'CPA', (135, 143))	('prolonged', 'PosReg', (197, 206))
46906	31173217	Thus, these data suggested that the knockdown of CDCA7L expression suppresses glioma growth by downregulating CCND1 expression in vivo.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('expression', 'MPA', (116, 126))	('CCND1', 'Gene', (110, 115))	('suppresses', 'NegReg', (67, 77))	('CCND1', 'Gene', '595', (110, 115))	('CDCA7L', 'Gene', (49, 55))	('knockdown', 'Var', (36, 45))	('glioma', 'Disease', (78, 84))	('downregulating', 'NegReg', (95, 109))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
46909	31173217	Additionally, CDCA7L can also complement the c-Myc transformation-defective mutant W135E and potentiate the Myc-mediated transformation.	('Myc', 'Gene', '4609', (47, 50))	('Myc', 'Gene', (47, 50))	('W135E', 'SUBSTITUTION', 'None', (83, 88))	('Myc', 'Gene', '4609', (108, 111))	('c-Myc', 'Gene', (45, 50))	('potentiate', 'PosReg', (93, 103))	('Myc', 'Gene', (108, 111))	('W135E', 'Var', (83, 88))	('c-Myc', 'Gene', '4609', (45, 50))
46912	31173217	Tian et al reported that CDCA7L activated the extracellular signal-regulated kinase 1/2 signaling pathway and controlled the cell cycle, thereby promoting the progression of hepatic carcinoma.	('extracellular signal-regulated kinase 1', 'Gene', (46, 85))	('activated', 'PosReg', (32, 41))	('cell cycle', 'CPA', (125, 135))	('promoting', 'PosReg', (145, 154))	('hepatic carcinoma', 'Disease', (174, 191))	('progression', 'CPA', (159, 170))	('extracellular signal-regulated kinase 1', 'Gene', '5594', (46, 85))	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (174, 191))	('controlled', 'Reg', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('hepatic carcinoma', 'Disease', 'MESH:D056486', (174, 191))	('CDCA7L', 'Var', (25, 31))
46914	31173217	The analysis of the databases suggested that the CDCA7L expression level was markedly upregulated in GBM compared with that in LGG tissues, and a high CDCA7L expression was associated with a poor prognosis of glioma patients.	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('CDCA7L expression level', 'MPA', (49, 72))	('GBM', 'Disease', (101, 104))	('patients', 'Species', '9606', (216, 224))	('glioma', 'Disease', (209, 215))	('upregulated', 'PosReg', (86, 97))	('high', 'Var', (146, 150))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))
46921	31173217	It was found in the current study that the mRNA and protein expression levels of CCND1 were markedly downregulated following transfection with CDCA7L siRNA compared with NC siRNA in vitro.	('CCND1', 'Gene', '595', (81, 86))	('CDCA7L', 'Var', (143, 149))	('downregulated', 'NegReg', (101, 114))	('CCND1', 'Gene', (81, 86))
46929	31173217	Moreover, CDCA7L is highly expressed in human glioma tissues, and a high CDCA7L expression predicts a poor prognosis for glioma patients.	('glioma tissues', 'Disease', 'MESH:D005910', (46, 60))	('high', 'Var', (68, 72))	('glioma', 'Disease', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('CDCA7L', 'Gene', (10, 16))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('CDCA7L', 'Gene', (73, 79))	('expression', 'MPA', (80, 90))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('glioma tissues', 'Disease', (46, 60))	('patients', 'Species', '9606', (128, 136))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('human', 'Species', '9606', (40, 45))	('glioma', 'Disease', (121, 127))
46940	27705947	Ectopic miR203 expression in glioblastoma cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon or temozolomide in vitro, and inhibited tumorigenesis in vivo.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('temozolomide', 'Chemical', 'MESH:D000077204', (157, 169))	('increased', 'PosReg', (97, 106))	('inhibited', 'NegReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('glioblastoma', 'Disease', (29, 41))	('cell proliferation', 'CPA', (63, 81))	('interferon', 'Gene', '3439', (143, 153))	('Ectopic', 'Var', (0, 7))	('tumor', 'Disease', (194, 199))	('inhibited', 'NegReg', (184, 193))	('sensitivity to apoptosis', 'MPA', (107, 131))	('interferon', 'Gene', (143, 153))	('miR203', 'Gene', (8, 14))
46941	27705947	We further show that STAT1 is a direct functional target of miR203, and miR203 level is negatively correlated with STAT1 expression in brain cancer patients.	('patients', 'Species', '9606', (148, 156))	('miR203', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('brain cancer', 'Disease', (135, 147))	('negatively', 'NegReg', (88, 98))	('brain cancer', 'Disease', 'MESH:D001932', (135, 147))	('brain cancer', 'Phenotype', 'HP:0030692', (135, 147))	('STAT1 expression', 'MPA', (115, 131))
46943	27705947	High STAT1 expression significantly correlated with poor survival in brain cancer patients.	('brain cancer', 'Disease', (69, 81))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (82, 90))	('expression', 'MPA', (11, 21))	('brain cancer', 'Disease', 'MESH:D001932', (69, 81))	('STAT1', 'Gene', (5, 10))	('brain cancer', 'Phenotype', 'HP:0030692', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('poor', 'NegReg', (52, 56))
46944	27705947	Mechanistically, we found that enforced miR203 expression in glioblastoma suppressed STAT1 expression directly, as well as that of a number of STAT1 regulated genes.	('miR203', 'Var', (40, 46))	('suppressed', 'NegReg', (74, 84))	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('STAT1 expression', 'MPA', (85, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))
46945	27705947	Taken together, our data suggest that miR203 acts as a tumor suppressor in glioblastoma by suppressing the pro-tumorigenic action of STAT1.	('suppressing', 'NegReg', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('glioblastoma', 'Disease', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('miR203', 'Var', (38, 44))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (111, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))
46956	27705947	Defects in the IFN system can lead to increased susceptibility to cancer through mechanisms that are incompletely understood.	('cancer', 'Disease', (66, 72))	('IFN', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Defects', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('IFN', 'Gene', '3439', (15, 18))
46959	27705947	MicroRNAs (miRNAs) are abundant, endogenous, small (20 to 24 nucleotide) single-stranded RNAs that suppress the expression of genes implicated in such fundamental biological processes as differentiation, proliferation and apoptosis.	('apoptosis', 'CPA', (222, 231))	('proliferation', 'CPA', (204, 217))	('differentiation', 'CPA', (187, 202))	('miR', 'Gene', (11, 14))	('miR', 'Gene', '220972', (11, 14))	('single-stranded', 'Var', (73, 88))	('suppress', 'NegReg', (99, 107))	('expression', 'MPA', (112, 122))
46968	27705947	Overexpression of miR203 or STAT1 knockdown inhibited the growth of GBM tumors in immunocompromised mice.	('miR203', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('STAT1', 'Gene', (28, 33))	('mice', 'Species', '10090', (100, 104))	('inhibited', 'NegReg', (44, 53))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('knockdown', 'Var', (34, 43))	('GBM tumors', 'Disease', (68, 78))	('GBM tumors', 'Disease', 'MESH:D005910', (68, 78))	('growth', 'CPA', (58, 64))
46969	27705947	Furthermore, miR203 expression is inversely related to STAT1 levels in patient samples from glioma, and high STAT1 expression closely correlates with poor patient survival and prognosis.	('miR203', 'Var', (13, 19))	('related', 'Reg', (44, 51))	('STAT1 levels', 'MPA', (55, 67))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('patient', 'Species', '9606', (155, 162))	('glioma', 'Disease', (92, 98))	('poor', 'NegReg', (150, 154))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('patient', 'Species', '9606', (71, 78))
46974	27705947	When the LGG patient samples with accompanying survival data in the TCGA database were grouped according to miR203 expression (Figure 1B), high miR203 LGG patients had significantly longer survival (~4-fold) as compared to patients with low miR203 expression (mean of 1370 and 349 days, respectively).	('survival', 'MPA', (189, 197))	('high miR203', 'Var', (139, 150))	('patient', 'Species', '9606', (13, 20))	('longer', 'PosReg', (182, 188))	('patient', 'Species', '9606', (155, 162))	('patient', 'Species', '9606', (223, 230))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (223, 231))
46979	27705947	Both MT330 and SJG2 transduced GBM cells have significantly higher miR203 expression than empty vector (EV)-transduced cells, and IFN induced an increase in miR203 expression in both EV and miR203 expressing cells (Figure 2A).	('miR203', 'MPA', (157, 163))	('expression', 'MPA', (74, 84))	('higher', 'PosReg', (60, 66))	('miR203', 'Gene', (67, 73))	('IFN', 'Gene', '3439', (130, 133))	('expression', 'MPA', (164, 174))	('MT330', 'Chemical', '-', (5, 10))	('IFN', 'Gene', (130, 133))	('MT330', 'Var', (5, 10))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))
46983	27705947	Cells were treated with IFN or temozolomide (TMZ), the frontline chemotherapy for GBM that induces apoptosis through DNA strand breaks.	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('IFN', 'Gene', '3439', (24, 27))	('apoptosis', 'CPA', (99, 108))	('temozolomide', 'Chemical', 'MESH:D000077204', (31, 43))	('IFN', 'Gene', (24, 27))	('DNA strand breaks', 'Var', (117, 134))	('TMZ', 'Chemical', 'MESH:D000077204', (45, 48))
46984	27705947	While basal apoptosis was slightly increased by enforced miR203 expression, apoptosis induced by IFN and TMZ was markedly increased in both MT330 and SJG2 cells with enforced miR203 expression (Figure 3D).	('enforced miR203', 'Var', (166, 181))	('TMZ', 'Chemical', 'MESH:D000077204', (105, 108))	('MT330', 'Chemical', '-', (140, 145))	('IFN', 'Gene', '3439', (97, 100))	('increased', 'PosReg', (122, 131))	('apoptosis', 'CPA', (76, 85))	('enforced miR203', 'Var', (48, 63))	('miR203', 'Var', (57, 63))	('IFN', 'Gene', (97, 100))	('miR203', 'Var', (175, 181))
46985	27705947	To identify potential miR203 targets, we isolated RNA from MT330 and SJG2 cells with enforced miR203 expression, performed microarray analysis, and found that, although the expression of several hundred genes were down-regulated by enforced miR203 expression, the expression of STAT1, IVNS1ABP and PI3KCA were consistently downregulated in both GBM cell lines.	('STAT1', 'Gene', (278, 283))	('PI3KCA', 'Gene', (298, 304))	('expression', 'MPA', (264, 274))	('enforced', 'Var', (232, 240))	('downregulated', 'NegReg', (323, 336))	('miR203', 'Gene', (241, 247))	('expression', 'MPA', (173, 183))	('MT330', 'Chemical', '-', (59, 64))	('down-regulated', 'NegReg', (214, 228))	('GBM', 'Phenotype', 'HP:0012174', (345, 348))
46988	27705947	To determine whether expression of STAT proteins was globally suppressed by miR203 expression, whole cell lysates were also immunoblotted for different STATs.	('expression', 'MPA', (21, 31))	('suppressed', 'NegReg', (62, 72))	('STATs', 'Gene', '6772;20846;6773;6774;20848', (152, 157))	('miR203 expression', 'Var', (76, 93))	('STATs', 'Gene', (152, 157))
46989	27705947	While STAT1 expression is markedly lower in cells with enforced miR203 expression, both STAT2 and STAT3 are unaffected by miR203 expression (Figure 4A).	('expression', 'Var', (71, 81))	('STAT2', 'Gene', (88, 93))	('miR203', 'Gene', (64, 70))	('lower', 'NegReg', (35, 40))	('enforced', 'Var', (55, 63))	('STAT1 expression', 'MPA', (6, 22))	('STAT2', 'Gene', '6773', (88, 93))
47000	27705947	We then examined the effect of STAT1KD on the proliferation of MT330 and SJG2 glioma cells, and found that similar to the results with enforced miR203 expression STAT1KD resulted in a decrease in cell proliferation (Figure 5B) and cell migration (Figure 5C).	('decrease', 'NegReg', (184, 192))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('cell proliferation', 'CPA', (196, 214))	('MT330', 'Chemical', '-', (63, 68))	('glioma', 'Disease', (78, 84))	('STAT1KD', 'Var', (162, 169))	('cell migration', 'CPA', (231, 245))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
47003	27705947	We then sought to determine the roles of miR203 and STAT1 in the tumorigenicity of GBM cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('STAT1', 'Gene', (52, 57))	('miR203', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))
47005	27705947	Enforced miR203 expression or STAT1KD markedly suppressed tumor formation by both GBM cell lines (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('suppressed', 'NegReg', (47, 57))	('STAT1KD', 'Var', (30, 37))	('tumor', 'Disease', (58, 63))	('miR203', 'Gene', (9, 15))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
47007	27705947	To validate that the inhibition of tumor formation reflected enforced miR203 expression, RNA and protein was extracted from three individual tumors of mice injected with EV and miR203 expressing SJG2 cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('miR203', 'Var', (177, 183))	('miR203', 'Gene', (70, 76))	('inhibition', 'NegReg', (21, 31))
47010	27705947	Furthermore, the effect of enforced miR203 expression or STAT1KD was also determined in the orthotopic (brain) microenvironment for GBM by intracranial injections of luciferase-expressing cells, and tumorigenesis followed by live animal imaging after D-luciferin injection.	('tumor', 'Disease', (199, 204))	('KD', 'Disease', 'MESH:C537017', (62, 64))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('miR203', 'Var', (36, 42))	('D-luciferin', 'Chemical', 'MESH:C532924', (251, 262))	('GBM', 'Phenotype', 'HP:0012174', (132, 135))
47011	27705947	Although EV transduced MT330 exhibited significant bioluminescent signal throughout the brain of injected mice demonstrating tumor invasion, enforced miR203 expression or STAT1KD resulted in a marked reduction in bioluminescent signal which is localized around the injection site after intracranial injection of luciferase labeled cells (Figure 6D).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('bioluminescent signal', 'MPA', (51, 72))	('mice', 'Species', '10090', (106, 110))	('reduction', 'NegReg', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('miR203 expression', 'Var', (150, 167))	('STAT1KD', 'Var', (171, 178))	('MT330', 'Chemical', '-', (23, 28))	('tumor', 'Disease', (125, 130))	('MT330', 'Var', (23, 28))	('bioluminescent signal', 'MPA', (213, 234))
47013	27705947	In GBM samples in the TCGA database we found a statistically significant inverse relationship between STAT1 expression and patient survival using the Pearson correlation (Figure 7A), showing that high STAT1 expression is associated with poor patient survival (p < 0.001).	('patient', 'Species', '9606', (123, 130))	('patient survival', 'CPA', (242, 258))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('expression', 'MPA', (207, 217))	('patient', 'Species', '9606', (242, 249))	('high STAT1', 'Var', (196, 206))	('poor', 'NegReg', (237, 241))	('inverse', 'NegReg', (73, 80))
47017	27705947	Moreover, patients bearing STAT1-intermediate glioma have longer disease-specific survival when compared with STAT1-high glioma (p = 0.0023), and shorter disease-specific survival when compared with STAT-low glioma (p = 0.0279) (Figure 7C).	('disease-specific', 'MPA', (154, 170))	('STAT1-high glioma', 'Disease', (110, 127))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('glioma', 'Disease', (121, 127))	('glioma', 'Disease', (208, 214))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('longer', 'PosReg', (58, 64))	('shorter', 'NegReg', (146, 153))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('disease-specific survival', 'CPA', (65, 90))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('STAT-low glioma', 'Disease', (199, 214))	('patients', 'Species', '9606', (10, 18))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('STAT1-intermediate', 'Var', (27, 45))	('STAT1-high glioma', 'Disease', 'MESH:D005910', (110, 127))	('glioma', 'Disease', (46, 52))	('STAT-low glioma', 'Disease', 'MESH:D005910', (199, 214))	('glioma', 'Disease', 'MESH:D005910', (46, 52))
47022	27705947	In the present study, we found that miR203 was nearly universally expressed at extremely low levels in GBM patient samples in the TCGA database However, in the more benign form of brain cancer LGG, which overall has a better patient prognosis, there is a significant variation in miR203 expression, and we found that high miR203-expressing patients had significantly 4-fold longer survival than low miR203-expressing patients.	('high miR203-expressing', 'Var', (317, 339))	('longer', 'PosReg', (374, 380))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('patient', 'Species', '9606', (340, 347))	('brain cancer', 'Disease', (180, 192))	('brain cancer', 'Phenotype', 'HP:0030692', (180, 192))	('patient', 'Species', '9606', (417, 424))	('patients', 'Species', '9606', (340, 348))	('brain cancer', 'Disease', 'MESH:D001932', (180, 192))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('patient', 'Species', '9606', (107, 114))	('patient', 'Species', '9606', (225, 232))	('patients', 'Species', '9606', (417, 425))
47025	27705947	In addition, the tumorigenicity in vivo of GBM cells with enforced miR203 expression was markedly impaired when injected subcutaneously or intracranially into immunocompromised mice.	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('tumor', 'Disease', (17, 22))	('miR203', 'Gene', (67, 73))	('expression', 'Var', (74, 84))	('impaired', 'NegReg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('mice', 'Species', '10090', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
47031	27705947	STAT1KD GBM cell lines showed inhibited proliferation and migration when compared to cells transduced with empty vector, as well as increased sensitivity to apoptosis induced by IFN and TMZ.	('IFN', 'Gene', '3439', (178, 181))	('STAT1KD', 'Var', (0, 7))	('inhibited', 'NegReg', (30, 39))	('increased', 'PosReg', (132, 141))	('TMZ', 'Chemical', 'MESH:D000077204', (186, 189))	('IFN', 'Gene', (178, 181))	('GBM', 'Phenotype', 'HP:0012174', (8, 11))	('proliferation', 'CPA', (40, 53))	('migration', 'CPA', (58, 67))	('sensitivity to apoptosis', 'MPA', (142, 166))
47036	27705947	For example, high NMI expression has been found to predict poor prognosis and promotes tumor growth in human GBM.	('poor prognosis', 'CPA', (59, 73))	('promotes', 'PosReg', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('human', 'Species', '9606', (103, 108))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('tumor', 'Disease', (87, 92))	('high NMI', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
47038	27705947	Dysregulation of the epidermal growth factor receptor (EFGR) is found in ~50% of GBM patient samples analyzed.	('GBM', 'Phenotype', 'HP:0012174', (81, 84))	('patient', 'Species', '9606', (85, 92))	('Dysregulation', 'Var', (0, 13))	('epidermal growth factor receptor', 'Gene', (21, 53))	('EFGR', 'Gene', (55, 59))	('epidermal growth factor receptor', 'Gene', '1956', (21, 53))	('GBM', 'Disease', (81, 84))
47047	27705947	Moreover, in liver cancer both high miR203-expressing and low STAT1-expressing patients had a significantly longer survival than low miR203 expressing patients and high STAT1-expressing patients (Figure S2).	('liver cancer', 'Disease', 'MESH:D006528', (13, 25))	('liver cancer', 'Disease', (13, 25))	('high miR203-expressing', 'Var', (31, 53))	('survival', 'MPA', (115, 123))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (79, 87))	('longer', 'PosReg', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('patients', 'Species', '9606', (186, 194))	('liver cancer', 'Phenotype', 'HP:0002896', (13, 25))
47049	27705947	Thus, there are subsets of cancer patients with low miR203 expression for whom miR203 targeted therapies may have therapeutic benefit.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Disease', (27, 33))	('miR203', 'Gene', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('low', 'Var', (48, 51))
47051	27705947	In summary, we identified STAT1 as a novel miR203 target gene in GBM, and characterized the role of the opposing actions of miR203 and STAT1 in GBM as well as in biopsy specimens from cancer patients, which suggests that miR203 inhibits GBM tumorigenesis through suppressing the expression of the tumor promoting activity of STAT1.	('cancer', 'Disease', (184, 190))	('GBM', 'Disease', (237, 240))	('patients', 'Species', '9606', (191, 199))	('suppressing', 'NegReg', (263, 274))	('tumor', 'Disease', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('GBM', 'Phenotype', 'HP:0012174', (237, 240))	('GBM', 'Phenotype', 'HP:0012174', (144, 147))	('expression', 'MPA', (279, 289))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('miR203', 'Var', (221, 227))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('inhibits', 'NegReg', (228, 236))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
47067	27705947	Xenografts were established in five-week-old male NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJmice (Jackson Laboratory) by injection of MT330 and SJG2 cells (1x106) directly into the flanks.	('mice', 'Species', '10090', (82, 86))	('NOD', 'Gene', '1822', (50, 53))	('MT330', 'Chemical', '-', (124, 129))	('MT330', 'Var', (124, 129))	('NOD', 'Gene', (50, 53))
47072	27705947	The data set was filtered for samples having expression data for miR203, STAT1 and clinical data, yielding a final set of 420 GBM, and 438 LGG cancer patient samples.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patient', 'Species', '9606', (150, 157))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('miR203', 'Var', (65, 71))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
47104	24872922	However, resection of these cells within otherwise normal surrounding brain may also raise the risk of neurological deficit.	('raise', 'Reg', (85, 90))	('neurological deficit', 'Disease', (103, 123))	('neurological deficit', 'Phenotype', 'HP:0000707', (103, 123))	('neurological deficit', 'Disease', 'MESH:D009461', (103, 123))	('resection', 'Var', (9, 18))
47107	24872922	These results were reproduced in a prospective study; however, it should be noted that both studies failed to show a significant survival benefit despite higher rates of GTR in patients who received fluorescein.	('GTR', 'MPA', (170, 173))	('fluorescein', 'Chemical', 'MESH:D019793', (199, 210))	('patients', 'Species', '9606', (177, 185))	('higher', 'PosReg', (154, 160))	('GTR', 'Chemical', '-', (170, 173))	('fluorescein', 'Var', (199, 210))	('rat', 'Species', '10116', (161, 164))
47108	24872922	In a separate study of low-grade gliomas, use of fluorescein was shown to significantly increase the achievement of GTR, as well as to increase 6-month progression-free survival.	('GTR', 'Chemical', '-', (116, 119))	('rat', 'Species', '10116', (9, 12))	('increase', 'PosReg', (135, 143))	('fluorescein', 'Chemical', 'MESH:D019793', (49, 60))	('GTR', 'MPA', (116, 119))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('increase', 'PosReg', (88, 96))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('fluorescein', 'Var', (49, 60))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
47222	24872922	The first use of FLIM for brain tumor image-guided surgery in humans showed that GBM had a significantly more irregular excitation lifetime distribution as compared to normal cortex.	('brain tumor', 'Disease', (26, 37))	('GBM', 'Var', (81, 84))	('GBM', 'Phenotype', 'HP:0012174', (81, 84))	('irregular excitation lifetime distribution', 'MPA', (110, 152))	('brain tumor', 'Disease', 'MESH:D001932', (26, 37))	('brain tumor', 'Phenotype', 'HP:0030692', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('irregular excitation', 'Phenotype', 'HP:0004309', (110, 130))	('humans', 'Species', '9606', (62, 68))
47246	32301283	These findings not only demonstrated that a poorer prognosis, higher WHO grade, lower frequency of isocitrate dehydrogenase mutation and higher 1p/19q non-codeletion status were significantly correlated with cluster 4 compared with the other clusters, but also indicated that the malignant progression of glioma was closely correlated with the expression of PDI family members.	('higher', 'PosReg', (137, 143))	('isocitrate dehydrogenase', 'Gene', (99, 123))	('isocitrate dehydrogenase', 'Gene', '3417', (99, 123))	('glioma', 'Disease', (305, 311))	('1p/19q non-codeletion status', 'MPA', (144, 172))	('lower', 'NegReg', (80, 85))	('mutation', 'Var', (124, 132))	('glioma', 'Disease', 'MESH:D005910', (305, 311))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))
47259	32301283	15  Additionally, knockdown of PDIA4 was indicated to contribute to a reduction in hepatic tumorigenesis and increase the survival of mice with spontaneous hepatoma, 16  while PDI was also reported to be closely correlated with the resistance of HeLa cells to the chemotherapeutic agent plitidepsin.	('knockdown', 'Var', (18, 27))	('reduction', 'NegReg', (70, 79))	('mice', 'Species', '10090', (134, 138))	('hepatoma', 'Disease', (156, 164))	('survival', 'CPA', (122, 130))	('hepatic', 'MPA', (83, 90))	('increase', 'PosReg', (109, 117))	('PDIA4', 'Gene', (31, 36))	('HeLa', 'CellLine', 'CVCL:0030', (246, 250))	('hepatoma', 'Disease', 'MESH:D006528', (156, 164))
47275	32301283	Tumour mutation burden (TMB) was calculated using Perl scripts (https://www.perl.org/), and the algorithm to calculate the TMB was the total number of somatic mutations (including non-synonymous point mutations, insertions and deletions in the coding region)/size of the target region, in units of mutations/Mb.	('TMB', 'Chemical', '-', (24, 27))	('insertions', 'Var', (212, 222))	('deletions', 'Var', (227, 236))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('TMB', 'Chemical', '-', (123, 126))
47281	32301283	To clarify the biological function of PDI members in glioma occurrence and development, we comprehensively analysed the relationship between 17 PDI family members and glioma based on different clinicopathological features, such as WHO grade, IDH status and 1p/19q codeletion status.	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', (167, 173))	('1p/19q codeletion status', 'Var', (257, 281))	('IDH', 'Gene', (242, 245))	('IDH', 'Gene', '3417', (242, 245))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('analysed', 'Reg', (107, 115))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
47290	32301283	In contrast, the levels of TMX2 and CASQ1 were significantly up-regulated in the mutant IDH state compared with that in the wild-type state (Figure 1F).	('CASQ1', 'Gene', '844', (36, 41))	('TMX2', 'Gene', (27, 31))	('IDH', 'Gene', (88, 91))	('mutant', 'Var', (81, 87))	('TMX2', 'Gene', '51075', (27, 31))	('IDH', 'Gene', '3417', (88, 91))	('up-regulated', 'PosReg', (61, 73))	('CASQ1', 'Gene', (36, 41))
47303	32301283	We found that IDH-mutant status, 1p/19q codeletion status and lower WHO grade of gliomas presented higher level in the cluster 2 compared with the other clusters (Table S2).	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH', 'Gene', (14, 17))	('1p/19q codeletion status', 'Var', (33, 57))	('IDH', 'Gene', '3417', (14, 17))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))
47304	32301283	In contrast, the cluster 4 was significantly correlated with wild-type IDH status (P < .0001), 1p/19q non-codeletion status (P < .0001) and higher WHO grade of gliomas (P < .0001) compared with the other clusters.	('1p/19q non-codeletion status', 'Var', (95, 123))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('higher', 'PosReg', (140, 146))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('gliomas', 'Disease', (160, 167))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (71, 74))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('correlated', 'Reg', (45, 55))
47316	32301283	The result suggested that significant differences existed between clusters (P < .001), 1p/19q status (P < .001), IDH status (P < .001), age (P < .001) and WHO grade (P < .001; Table S3).	('1p/19q status', 'Var', (87, 100))	('differences', 'Reg', (38, 49))	('IDH', 'Gene', (113, 116))	('IDH', 'Gene', '3417', (113, 116))
47318	32301283	Univariate analysis showed that WHO grade, age, IDH status, 1p/19q status and risk score were closely correlated with OS (Figure 6F,G), while WHO grade (P < .001), age (P < .001), IDH (P = .001) and risk score (P = .012) remained a significant relationship with OS in the multivariate Cox regression analysis.	('1p/19q status', 'Var', (60, 73))	('IDH', 'Gene', (48, 51))	('IDH', 'Gene', '3417', (48, 51))	('IDH', 'Gene', (180, 183))	('correlated', 'Reg', (102, 112))	('IDH', 'Gene', '3417', (180, 183))
47319	32301283	Multivariate regression analysis showed that WHO grade (P < .001), IDH status (P = .004), 1p/19q status (P = .004) and risk score (P = .016) were significantly associated with OS.	('IDH', 'Gene', (67, 70))	('1p/19q status', 'Var', (90, 103))	('associated', 'Reg', (160, 170))	('IDH', 'Gene', '3417', (67, 70))
47323	32301283	The result suggested that SNPs in IDH1 and ATRX exerted a higher somatic mutation burden in the low-risk group than in the high-risk group (Figure 7A).	('IDH1', 'Gene', '3417', (34, 38))	('ATRX', 'Gene', '546', (43, 47))	('SNPs', 'Var', (26, 30))	('higher', 'PosReg', (58, 64))	('somatic mutation burden', 'CPA', (65, 88))	('IDH1', 'Gene', (34, 38))	('ATRX', 'Gene', (43, 47))
47327	32301283	Subsequently, Kaplan-Meier survival analysis suggested that OS with a high TMB was significantly shorter than that with a low TMB (Figure 7D).	('high', 'Var', (70, 74))	('TMB', 'Chemical', '-', (126, 129))	('TMB', 'Chemical', '-', (75, 78))	('shorter', 'NegReg', (97, 104))
47340	32301283	Interestingly, CASQ1, a gene related to myopathy, 30  vacuolar myopathy 31  and tubular aggregate myopathy, 32  showed increased expression in samples of LGGs, as well as in those with mutated IDH and 1p/19q codeletion.	('mutated', 'Var', (185, 192))	('IDH and 1p/19q', 'Gene', '3417', (193, 207))	('expression', 'MPA', (129, 139))	('myopathy', 'Disease', (98, 106))	('myopathy', 'Phenotype', 'HP:0003198', (40, 48))	('myopathy', 'Phenotype', 'HP:0003198', (63, 71))	('CASQ1', 'Gene', '844', (15, 20))	('vacuolar myopathy', 'Disease', (54, 71))	('myopathy', 'Disease', (63, 71))	('myopathy', 'Disease', 'MESH:D009135', (40, 48))	('myopathy', 'Phenotype', 'HP:0003198', (98, 106))	('myopathy', 'Disease', 'MESH:D009135', (98, 106))	('vacuolar myopathy', 'Disease', 'MESH:C536522', (54, 71))	('CASQ1', 'Gene', (15, 20))	('myopathy', 'Disease', (40, 48))	('increased', 'PosReg', (119, 128))	('myopathy', 'Disease', 'MESH:D009135', (63, 71))
47345	32301283	We found that cluster 4 was significantly correlated with poor prognosis as well as with wild-type IDH status, 1p/19q non-codeletion and higher WHO grade of gliomas.	('IDH', 'Gene', '3417', (99, 102))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('gliomas', 'Disease', (157, 164))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('correlated', 'Reg', (42, 52))	('1p/19q non-codeletion', 'Var', (111, 132))	('IDH', 'Gene', (99, 102))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))
47353	32301283	Mutational analysis of TCGA data set revealed that SNPs in IDH1, ATRX, PTEN and EGFR were significantly associated with risk status in glioma.	('IDH1', 'Gene', '3417', (59, 63))	('glioma', 'Disease', (135, 141))	('EGFR', 'Gene', '1956', (80, 84))	('associated with', 'Reg', (104, 119))	('PTEN', 'Gene', (71, 75))	('ATRX', 'Gene', (65, 69))	('SNPs', 'Var', (51, 55))	('EGFR', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (71, 75))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('ATRX', 'Gene', '546', (65, 69))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('IDH1', 'Gene', (59, 63))
47354	32301283	Consistent with the fact that the mutation of IDH1 and ATRX is associated with prolonged survival in glioma, 36 ,  37  our result showed that the SNPs in IDH1 and ATRX exerted a higher somatic mutation burden in the low-risk group than in the high-risk group.	('ATRX', 'Gene', '546', (163, 167))	('ATRX', 'Gene', '546', (55, 59))	('IDH1', 'Gene', (46, 50))	('glioma', 'Disease', (101, 107))	('mutation', 'Var', (34, 42))	('ATRX', 'Gene', (55, 59))	('IDH1', 'Gene', '3417', (46, 50))	('somatic mutation burden', 'MPA', (185, 208))	('higher', 'PosReg', (178, 184))	('IDH1', 'Gene', '3417', (154, 158))	('IDH1', 'Gene', (154, 158))	('ATRX', 'Gene', (163, 167))	('SNPs', 'Var', (146, 150))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
47355	32301283	The loss of PTEN function was reported to promote tumour insensitivity to multiple therapeutic approaches, and the polymorphisms of EGFR were reported to increase the risk of gliomas 38 ,  39 ,  40 ; similar results were found in our result that the SNPs with PTEN and EGFR were higher in the high-risk group than in the low-risk group.	('promote', 'PosReg', (42, 49))	('PTEN', 'Gene', (260, 264))	('loss', 'NegReg', (4, 8))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('SNPs', 'MPA', (250, 254))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', '1956', (269, 273))	('PTEN', 'Gene', (12, 16))	('polymorphisms', 'Var', (115, 128))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('PTEN', 'Gene', '5728', (260, 264))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('PTEN', 'Gene', '5728', (12, 16))	('gliomas', 'Disease', (175, 182))	('increase', 'PosReg', (154, 162))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('higher', 'Reg', (279, 285))	('EGFR', 'Gene', (132, 136))	('EGFR', 'Gene', (269, 273))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))
47358	32301283	Kaplan-Meier curve analysis further revealed that a high TMB was associated with a lower OS compared with that with a low TMB.	('high', 'Var', (52, 56))	('lower OS', 'Disease', (83, 91))	('TMB', 'Chemical', '-', (57, 60))	('TMB', 'Chemical', '-', (122, 125))
47369	30737083	Finally, impairment of V-ATPase reduces LOs activity.	('LOs activity', 'MPA', (40, 52))	('V-ATPase', 'Protein', (23, 31))	('impairment', 'Var', (9, 19))	('reduces', 'NegReg', (32, 39))	('LO', 'Chemical', '-', (40, 42))
47372	30737083	The V-ATPase proton pump has been involved in cancer stem cells maintenance and V-ATPase-high glioblastomas express higher levels of homeobox genes.	('homeobox genes', 'Gene', (133, 147))	('glioblastomas', 'Disease', 'MESH:D005909', (94, 107))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('glioblastomas', 'Disease', (94, 107))	('cancer', 'Disease', (46, 52))	('higher levels', 'PosReg', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('V-ATPase-high', 'Var', (80, 93))	('glioblastomas', 'Phenotype', 'HP:0012174', (94, 107))
47387	30737083	Indeed EVs might contribute to glioma cell plasticity and to influence functional integration of glioma stem cells (GSC) with other cancer cell populations.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('glioma', 'Disease', (97, 103))	('influence', 'Reg', (61, 70))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('contribute', 'Reg', (17, 27))	('EVs', 'Var', (7, 10))	('glioma cell plasticity', 'Disease', 'MESH:D005910', (31, 53))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma cell plasticity', 'Disease', (31, 53))	('glioma', 'Disease', (31, 37))	('functional integration', 'CPA', (71, 93))
47389	30737083	However, whether such genes are also able to influence the tumor surrounding milieu possibly through EVs is not known.	('tumor', 'Disease', (59, 64))	('genes', 'Var', (22, 27))	('influence', 'Reg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
47403	30737083	IHC for V-ATPase G1 (16143-1-AP, Proteintech), Nestin (MAB1259, R&D Systems), HOXA10, or POU3F2 was performed using a Ventana Benchmark instrument and the Ultraview DAB or Red Detection kits as described.	('POU3F2', 'Gene', (89, 95))	('16143-1-AP', 'Var', (21, 31))	('HOXA10', 'Gene', (78, 84))	('Nestin', 'Gene', '10763', (47, 53))	('DAB', 'Chemical', 'MESH:C000469', (165, 168))	('Nestin', 'Gene', (47, 53))	('POU3F2', 'Gene', '5454', (89, 95))	('HOXA10', 'Gene', '3206', (78, 84))
47406	30737083	LO were isolated from supernatant of NS (n = 12) at basal condition (after 24 h of NS culture with fresh media), after 10 nM BafA1 treatment of NS for 24 h, or after siRNA-mediated knockdown of V-ATPase G1 in NS as described.	('NS', 'Chemical', '-', (83, 85))	('LO', 'Chemical', '-', (0, 2))	('V-ATPase G1', 'Protein', (194, 205))	('NS', 'Chemical', '-', (37, 39))	('NS', 'Chemical', '-', (144, 146))	('NS', 'Chemical', '-', (209, 211))	('knockdown', 'Var', (181, 190))
47465	30737083	In particular, experiments involving patients' derived NS were performed with five V1G1High- and five V1G1Low- NS in triplicate.	('NS', 'Chemical', '-', (111, 113))	('NS', 'Chemical', '-', (55, 57))	('patients', 'Species', '9606', (37, 45))	('V1G1High-', 'Var', (83, 92))	('V1G1Low- NS', 'Var', (102, 113))
47468	30737083	Therefore we analyzed these homeobox proteins in GBM patients-derived orthotopic xenografts generated by V1G1Low or V1G1HighNSand in human GBM tissues characterized for V1G1 expression.	('patients', 'Species', '9606', (53, 61))	('NS', 'Chemical', '-', (124, 126))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('V1G1HighNSand', 'Var', (116, 129))	('human', 'Species', '9606', (133, 138))	('V1G1Low', 'Var', (105, 112))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
47469	30737083	Overexpression of homeobox genes in V1G1HIGH NS was also preserved in vivo (Fig.	('V1G1HIGH', 'Var', (36, 44))	('homeobox genes', 'Gene', (18, 32))	('NS', 'Chemical', '-', (45, 47))
47470	30737083	In fact, orthotopic brain tumors generated from V1G1HIGHNS contained more HOXA10- or POU3F2-positive cells (p = 0.006 and p = 0.0012, respectively; Fig.	('HOXA10', 'Gene', '3206', (74, 80))	('HOXA10', 'Gene', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('V1G1HIGHNS', 'Var', (48, 58))	('NS', 'Chemical', '-', (56, 58))	('brain tumors', 'Disease', 'MESH:D001932', (20, 32))	('brain tumors', 'Phenotype', 'HP:0030692', (20, 32))	('POU3F2', 'Gene', '5454', (85, 91))	('more', 'PosReg', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('brain tumors', 'Disease', (20, 32))	('POU3F2', 'Gene', (85, 91))	('brain tumor', 'Phenotype', 'HP:0030692', (20, 31))
47482	30737083	Next, we verified that purified LO from either NS V1G1Low or V1G1High were similarly internalized by recipient cells (Fig.	('NS V1G1Low', 'Var', (47, 57))	('LO', 'Chemical', '-', (32, 34))	('NS', 'Chemical', '-', (47, 49))	('V1G1High', 'Var', (61, 69))
47484	30737083	LO from V1G1High NS (LOHigh) contained more homeobox transcripts than LO generated by V1G1Low NS (LOLow; Fig.	('NS', 'Chemical', '-', (94, 96))	('LO', 'Chemical', '-', (0, 2))	('more', 'PosReg', (39, 43))	('LO', 'Chemical', '-', (21, 23))	('homeobox', 'Protein', (44, 52))	('LO', 'Chemical', '-', (70, 72))	('V1G1High NS', 'Var', (8, 19))	('NS', 'Chemical', '-', (17, 19))	('LO', 'Chemical', '-', (98, 100))
47491	30737083	From a functional point-of-view, supplementation of the culture medium with LOHigh increased the survival and proliferative activity of cultured non-neoplastic cells (derived from margin tissues; Fig.	('LOHigh', 'Var', (76, 82))	('increased', 'PosReg', (83, 92))	('LO', 'Chemical', '-', (76, 78))	('survival', 'CPA', (97, 105))	('proliferative activity', 'CPA', (110, 132))
47514	30737083	These data, though preliminary, show that aggressive gliomas actively secrete LO loaded with V1G1 and POU3F2 oncogenic cargoes into the circulation, suggesting the possibility of using these markers for staging or follow-up purposes.	('POU3F2', 'Gene', (102, 108))	('aggressive gliomas', 'Disease', (42, 60))	('V1G1', 'Var', (93, 97))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('aggressive gliomas', 'Disease', 'MESH:D005910', (42, 60))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('secrete', 'MPA', (70, 77))	('LO', 'Chemical', '-', (78, 80))	('POU3F2', 'Gene', '5454', (102, 108))
47518	30737083	LO production by NS was not affected by either BafA1 treatment or V1G1 knockdown (Fig.	('V1G1', 'Gene', (66, 70))	('LO', 'Chemical', '-', (0, 2))	('knockdown', 'Var', (71, 80))	('NS', 'Chemical', '-', (17, 19))
47519	30737083	Besides reducing transcript levels in NS, silencing of V1G1 decreased its messenger RNA together with POU3F2 and HOXA10 mRNAs in NS and LO (Fig.	('transcript levels', 'MPA', (17, 34))	('silencing', 'Var', (42, 51))	('decreased', 'NegReg', (60, 69))	('POU3F2', 'Gene', (102, 108))	('messenger RNA', 'MPA', (74, 87))	('HOXA10', 'Gene', (113, 119))	('V1G1', 'Gene', (55, 59))	('NS', 'Chemical', '-', (129, 131))	('reducing', 'NegReg', (8, 16))	('LO', 'Chemical', '-', (136, 138))	('NS', 'Chemical', '-', (38, 40))	('POU3F2', 'Gene', '5454', (102, 108))	('HOXA10', 'Gene', '3206', (113, 119))
47525	30737083	Interestingly, NH4Cl partially reduced the clonogenicity of primary GBM cultures and NS invasiveness (Fig.	('reduced', 'NegReg', (31, 38))	('clonogenicity of primary GBM cultures', 'CPA', (43, 80))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('NH4Cl', 'Var', (15, 20))	('NH4Cl', 'Chemical', 'MESH:D000643', (15, 20))	('NS invasiveness', 'Disease', (85, 100))	('NS invasiveness', 'Disease', 'MESH:D009404', (85, 100))
47530	30737083	Remarkably, LOs loaded with V1G1 and POU3F2 were present in the circulation of glioma patients, and their levels increased with tumor grade or in patients with a poorer outcome.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('glioma', 'Disease', (79, 85))	('V1G1', 'Var', (28, 32))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('POU3F2', 'Gene', '5454', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('LO', 'Chemical', '-', (12, 14))	('POU3F2', 'Gene', (37, 43))	('increased', 'PosReg', (113, 122))	('tumor', 'Disease', (128, 133))	('levels', 'MPA', (106, 112))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (86, 94))
47540	30737083	Furthermore, EVs are proposed to be partly responsible for the molecular plasticity exhibited by glioma stem cells, as well as to participate in the switching from a transcriptomic subtype to another.	('glioma', 'Disease', (97, 103))	('participate', 'Reg', (130, 141))	('responsible', 'Reg', (43, 54))	('EVs', 'Var', (13, 16))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
47560	30460631	Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis IDH1 mutation has been identified as a early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('gliomagenesis', 'Disease', (115, 128))	('IDH1', 'Gene', (129, 133))	('mutation', 'Var', (134, 142))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('gliomagenesis', 'Disease', 'None', (115, 128))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('gliomas', 'Disease', 'MESH:D005910', (206, 213))	('IDH1', 'Gene', '3417', (129, 133))	('gliomas', 'Disease', (206, 213))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
47561	30460631	Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis.	('mutation', 'Var', (22, 30))	('gliomagenesis', 'Disease', (222, 235))	('IDH1', 'Gene', (17, 21))	('gliomagenesis', 'Disease', 'None', (222, 235))	('IDH1', 'Gene', '3417', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
47562	30460631	We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors.	('mutant', 'Var', (58, 64))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))
47564	30460631	We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('IDH1', 'Gene', (238, 242))	('genetic lesions', 'Disease', (191, 206))	('mutation', 'Var', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (146, 151))	('IDH1', 'Gene', '3417', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (60, 65))	('genetic lesions', 'Disease', 'MESH:D020022', (191, 206))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
47565	30460631	Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e.	('IDH1', 'Gene', (145, 149))	('mutation', 'Var', (150, 158))	('IDH1', 'Gene', '3417', (145, 149))	('IDH1', 'Gene', (25, 29))	('IDH1', 'Gene', '3417', (25, 29))
47566	30460631	cells prior to acquisition of IDH1 mutation.	('IDH1', 'Gene', (30, 34))	('IDH1', 'Gene', '3417', (30, 34))	('mutation', 'Var', (35, 43))
47567	30460631	As expected, we found that none of the iPSC clones contains IDH1 mutation.	('IDH1', 'Gene', (60, 64))	('mutation', 'Var', (65, 73))	('IDH1', 'Gene', '3417', (60, 64))
47568	30460631	These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool.	('IDH1', 'Gene', '3417', (107, 111))	('IDH1', 'Gene', (107, 111))	('gene amplification', 'Var', (76, 94))
47570	30460631	Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.	('LGGs', 'Disease', (151, 155))	('mutations', 'Var', (115, 124))	('IDH', 'Gene', '3417', (111, 114))	('IDH', 'Gene', (111, 114))
47572	30460631	Monoallelic R132 (Arginine 132) mutations of IDH1 or R172 (Arginine 172) mutations of IDH2, which encode isocitrate dehydrogenases (IDH) that convert isocitrate into alpha-ketoglutarate (alphaKG), have been detected in nearly all secondary glioblastoma multiforme (GBM) and 80% of low grade gliomas (LGGs).	('GBM', 'Disease', (265, 268))	('isocitrate dehydrogenases', 'Gene', (105, 130))	('GBM', 'Disease', 'MESH:D005909', (265, 268))	('gliomas', 'Disease', (291, 298))	('glioma', 'Phenotype', 'HP:0009733', (291, 297))	('IDH2', 'Gene', (86, 90))	('IDH', 'Gene', (86, 89))	('isocitrate', 'Chemical', 'MESH:D007523', (150, 160))	('Arginine', 'Chemical', 'MESH:D001127', (59, 67))	('IDH2', 'Gene', '3418', (86, 90))	('gliomas', 'Disease', 'MESH:D005910', (291, 298))	('mutations', 'Var', (32, 41))	('glioblastoma', 'Disease', 'MESH:D005909', (240, 252))	('GBM', 'Phenotype', 'HP:0012174', (265, 268))	('IDH1', 'Gene', (45, 49))	('IDH', 'Gene', (45, 48))	('detected', 'Reg', (207, 215))	('IDH', 'Gene', '3417', (86, 89))	('alpha-ketoglutarate', 'Chemical', 'MESH:C029743', (166, 185))	('Arginine', 'Chemical', 'MESH:D001127', (18, 26))	('IDH', 'Gene', (132, 135))	('glioblastoma', 'Disease', (240, 252))	('gliomas', 'Phenotype', 'HP:0009733', (291, 298))	('glioblastoma', 'Phenotype', 'HP:0012174', (240, 252))	('isocitrate dehydrogenases', 'Gene', '3417', (105, 130))	('IDH1', 'Gene', '3417', (45, 49))	('IDH', 'Gene', '3417', (45, 48))	('IDH', 'Gene', '3417', (132, 135))	('alphaKG', 'Chemical', 'MESH:C029743', (187, 194))	('isocitrate', 'Chemical', 'MESH:D007523', (105, 115))	('mutations', 'Var', (73, 82))
47573	30460631	The mutant IDH, which forms a heterodimer with the wild-type enzyme, acquires neomorphic activity to catalyze alphaKG into D-2-Hydroxyglutarate (D2HG).	('IDH', 'Gene', '3417', (11, 14))	('IDH', 'Gene', (11, 14))	('mutant', 'Var', (4, 10))	('D-2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (123, 143))	('D2HG', 'Chemical', 'MESH:C019417', (145, 149))	('alphaKG', 'Chemical', 'MESH:C029743', (110, 117))	('alphaKG into D-2-Hydroxyglutarate', 'MPA', (110, 143))
47574	30460631	Because of the structural similarity, D2HG effectively inhibits alphaKG-dependent enzymes including the TET-family DNA methyl hydroxylases, Jumonji-family histone demethylases, and the hydroxylases that regulate HIF1alpha stability.	('HIF1alpha', 'Gene', (212, 221))	('Jumonji-family histone demethylases', 'Enzyme', (140, 175))	('D2HG', 'Var', (38, 42))	('alphaKG', 'Chemical', 'MESH:C029743', (64, 71))	('inhibits', 'NegReg', (55, 63))	('HIF1alpha', 'Gene', '3091', (212, 221))	('TET-family DNA methyl hydroxylases', 'Enzyme', (104, 138))	('methyl', 'Chemical', 'MESH:C031105', (119, 125))	('hydroxylases', 'Enzyme', (185, 197))	('methyl', 'Chemical', 'MESH:C031105', (165, 171))	('alphaKG-dependent enzymes', 'Enzyme', (64, 89))	('D2HG', 'Chemical', 'MESH:C019417', (38, 42))
47575	30460631	The IDH mutations are therefore considered as drivers for gliomagenesis because of the acquired capacities to alter the epigenome and respond to hypoxia.	('epigenome', 'MPA', (120, 129))	('gliomagenesis', 'Disease', 'None', (58, 71))	('IDH', 'Gene', '3417', (4, 7))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('mutations', 'Var', (8, 17))	('gliomagenesis', 'Disease', (58, 71))	('hypoxia', 'Disease', (145, 152))	('hypoxia', 'Disease', 'MESH:D000860', (145, 152))	('alter', 'Reg', (110, 115))	('IDH', 'Gene', (4, 7))
47577	30460631	Besides the IDH mutations, progression of LGGs involves gradual accumulation of additional genetic alterations including mutations in TP53, ATRX, TERT and chromosome 1p/19q co-deletion.	('mutations', 'Var', (121, 130))	('TP53', 'Gene', (134, 138))	('LGGs', 'Disease', (42, 46))	('ATRX', 'Gene', (140, 144))	('chromosome 1p/19q co-deletion', 'Var', (155, 184))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('ATRX', 'Gene', '546', (140, 144))	('TERT', 'Gene', (146, 150))	('TERT', 'Gene', '7015', (146, 150))	('TP53', 'Gene', '7157', (134, 138))
47578	30460631	Analyses of multiple LGG biopsies collected from the same patients indicated sequential acquisition of genetic alterations, in which IDH mutations occur invariably prior to the other aforementioned mutations/chromosomal deletions.	('mutations', 'Var', (137, 146))	('IDH', 'Gene', '3417', (133, 136))	('IDH', 'Gene', (133, 136))	('patients', 'Species', '9606', (58, 66))
47579	30460631	However, whether there are LGG-associated genetic lesions that occur even prior to the IDH mutations remains unknown.	('genetic lesions', 'Disease', 'MESH:D020022', (42, 57))	('IDH', 'Gene', (87, 90))	('genetic lesions', 'Disease', (42, 57))	('IDH', 'Gene', '3417', (87, 90))	('mutations', 'Var', (91, 100))	('LGG-associated', 'Disease', (27, 41))
47580	30460631	One approach to gain insight is to make induced pluripotent stem cell (iPSC) clones from pooled primary tumor cells and then examine their genetic composition including amplifications or deletions by aCGH.	('aCGH', 'Gene', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('amplifications', 'Var', (169, 183))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('deletions', 'Var', (187, 196))
47582	30460631	Interestingly, we observed that cells containing IDH1 mutation are refractory to reprogramming by forced expression of Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc.	('mutation', 'Var', (54, 62))	('Oct4', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (49, 53))	('Sox2', 'Gene', '6657', (156, 160))	('c-Myc', 'Gene', (172, 177))	('Klf4', 'Gene', (162, 166))	('Sox2', 'Gene', (156, 160))	('Oct4', 'Gene', '5460', (150, 154))	('Klf4', 'Gene', '9314', (162, 166))	('IDH1', 'Gene', (49, 53))	('c-Myc', 'Gene', '4609', (172, 177))
47583	30460631	Therefore, iPSC clones originated from primary cell pool of IDH1 mutant glioma should exclude all the cells harboring IDH mutations and thus amplify cells containing early genetic lesions.	('glioma', 'Disease', (72, 78))	('IDH1', 'Gene', (60, 64))	('genetic lesions', 'Disease', 'MESH:D020022', (172, 187))	('mutant', 'Var', (65, 71))	('IDH', 'Gene', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('IDH', 'Gene', (60, 63))	('IDH', 'Gene', '3417', (118, 121))	('genetic lesions', 'Disease', (172, 187))	('IDH1', 'Gene', '3417', (60, 64))	('IDH', 'Gene', '3417', (60, 63))
47584	30460631	In this study, we generated iPSC (LGG-iPSC) clones from primary cells from freshly surgically resected IDH1 mutant LGGs.	('IDH1', 'Gene', '3417', (103, 107))	('mutant', 'Var', (108, 114))	('IDH1', 'Gene', (103, 107))
47587	30460631	As expected, we found that none of the iPSC clones carried the IDH1 mutations suggesting that tumor cells cannot be reprogrammed as long as they contain IDH1 mutation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IDH1', 'Gene', '3417', (153, 157))	('tumor', 'Disease', (94, 99))	('mutation', 'Var', (158, 166))	('mutations', 'Var', (68, 77))	('IDH1', 'Gene', (63, 67))
47588	30460631	These data suggest that the LGG-iPSCs are originated from tumor cells not yet acquiring the IDH1 mutations.	('mutations', 'Var', (97, 106))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('LGG-iPSCs', 'Disease', (28, 37))
47589	30460631	Furthermore, the observed chromosomal alterations were detected in a fraction of LGGs in the Cancer Genome Atlas (TCGA) database.	('detected', 'Reg', (55, 63))	('CGA', 'Gene', (115, 118))	('chromosomal alterations', 'Var', (26, 49))	('CGA', 'Gene', '1113', (115, 118))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))
47590	30460631	Taken together, by reprogramming freshly resected LGG cells, we demonstrated that IDH1 mutation-bearing LGG cells are resistant to become iPSCs and that certain regional chromosomal alterations exist prior to the acquisition of IDH mutations at least in a fraction of LGGs.	('IDH', 'Gene', '3417', (82, 85))	('mutation-bearing', 'Var', (87, 103))	('IDH1', 'Gene', (82, 86))	('IDH', 'Gene', (228, 231))	('IDH1', 'Gene', '3417', (82, 86))	('IDH', 'Gene', '3417', (228, 231))	('IDH', 'Gene', (82, 85))
47596	30460631	Slides were blocked by with horse serum, incubated with the IDH1 R132H antibody (DIA-H09, Dianova) at 4 C overnight, and secondary antibody at RT for 30 min.	('IDH1', 'Gene', (60, 64))	('R132H', 'SUBSTITUTION', 'None', (65, 70))	('4 C', 'Chemical', 'MESH:C060809', (102, 105))	('IDH1', 'Gene', '3417', (60, 64))	('R132H', 'Var', (65, 70))
47598	30460631	DNA fragments containing the R132 mutation of IDH1 and R172 mutation of IDH2 were PCR amplified.	('IDH2', 'Gene', (72, 76))	('R172 mutation', 'Var', (55, 68))	('R132', 'Var', (29, 33))	('IDH1', 'Gene', (46, 50))	('IDH2', 'Gene', '3418', (72, 76))	('IDH1', 'Gene', '3417', (46, 50))
47611	30460631	Genetic regions of interest were analyzed for copy number variation in low-grade gliomas with and without IDH1 mutations.	('mutations', 'Var', (111, 120))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('IDH1', 'Gene', (106, 110))	('gliomas', 'Disease', (81, 88))	('IDH1', 'Gene', '3417', (106, 110))
47614	30460631	Histochemical analysis indicated that BT01 is an astrocytoma that is not reactive to the antibody specifically recognizing the IDH1 R132H mutation (Fig.	('astrocytoma', 'Disease', 'MESH:D001254', (49, 60))	('astrocytoma', 'Disease', (49, 60))	('IDH1', 'Gene', (127, 131))	('R132H', 'Var', (132, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (49, 60))	('IDH1', 'Gene', '3417', (127, 131))	('R132H', 'SUBSTITUTION', 'None', (132, 137))
47615	30460631	1E and 1F), while BT03 is an oligodendroglioma strongly expressing the IDH1 R132H mutation (Fig.	('R132H', 'Var', (76, 81))	('oligodendroglioma', 'Disease', (29, 46))	('IDH1', 'Gene', (71, 75))	('R132H', 'SUBSTITUTION', 'None', (76, 81))	('IDH1', 'Gene', '3417', (71, 75))	('oligodendroglioma', 'Disease', 'MESH:D009837', (29, 46))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
47616	30460631	1I-K) but not in BT01 cells (data not shown), which demonstrated 1p/19q co-deletion in BT03 and is consistent with the molecular feature that 1p/19q co-deletion occurs in oligodendrogliomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (171, 189))	('co-deletion', 'Var', (72, 83))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('oligodendrogliomas', 'Disease', (171, 189))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))
47617	30460631	Sequencing of the IDH1 gene demonstrated that BT01 carries an IDH1 R132C mutation while BT03 carries an IDH1 R132H mutation (Fig.	('R132C', 'SUBSTITUTION', 'None', (67, 72))	('IDH1', 'Gene', '3417', (104, 108))	('R132H', 'SUBSTITUTION', 'None', (109, 114))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', '3417', (18, 22))	('R132H', 'Var', (109, 114))	('IDH1', 'Gene', (62, 66))	('IDH1', 'Gene', (104, 108))	('IDH1', 'Gene', (18, 22))	('R132C', 'Var', (67, 72))
47618	30460631	Sequencing of IDH2 gene confirmed that both BT01 and BT03 have the wild type IDH2, which is consistent with the notion that mutations of IDH1 and IDH2 are mutually exclusive in LGGs.	('BT01', 'Var', (44, 48))	('mutations', 'Var', (124, 133))	('IDH2', 'Gene', '3418', (146, 150))	('IDH2', 'Gene', (77, 81))	('IDH1', 'Gene', (137, 141))	('IDH2', 'Gene', '3418', (14, 18))	('IDH2', 'Gene', (14, 18))	('IDH2', 'Gene', '3418', (77, 81))	('IDH1', 'Gene', '3417', (137, 141))	('IDH2', 'Gene', (146, 150))	('BT03', 'Var', (53, 57))
47621	30460631	Sequencing analysis of the genomic DNA of at least 15 LGG-iPSC clones from each tumor revealed that none of the clones contained the IDH1 or IDH2 mutations (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutations', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH2', 'Gene', '3418', (141, 145))	('tumor', 'Disease', (80, 85))	('IDH1', 'Gene', (133, 137))	('IDH1', 'Gene', '3417', (133, 137))	('IDH2', 'Gene', (141, 145))
47622	30460631	These data indicate that the IDH1 mutations inhibit somatic cell reprogramming.	('IDH1', 'Gene', (29, 33))	('inhibit', 'NegReg', (44, 51))	('IDH1', 'Gene', '3417', (29, 33))	('somatic cell reprogramming', 'CPA', (52, 78))	('mutations', 'Var', (34, 43))
47623	30460631	To further test whether IDH1 mutation inhibits somatic cell reprogramming, we attempted to generate iPSCs from the brain tumor cell line BT142 (ATCC #ACS-1018), which was originally established from a grade III oligoastrocytoma carrying the monoallelic IDH1 R132H mutation but subsequently became homozygous of the IDH1 mutation because of loss of heterozygosity.	('brain tumor', 'Disease', (115, 126))	('mutation', 'Var', (29, 37))	('R132H', 'Var', (258, 263))	('IDH1', 'Gene', '3417', (24, 28))	('astrocytoma', 'Phenotype', 'HP:0009592', (216, 227))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('somatic cell reprogramming', 'CPA', (47, 73))	('IDH1', 'Gene', (253, 257))	('inhibits', 'NegReg', (38, 46))	('R132H', 'SUBSTITUTION', 'None', (258, 263))	('brain tumor', 'Phenotype', 'HP:0030692', (115, 126))	('IDH1', 'Gene', (315, 319))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (211, 227))	('IDH1', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (253, 257))	('IDH1', 'Gene', '3417', (315, 319))	('oligoastrocytoma', 'Disease', (211, 227))	('brain tumor', 'Disease', 'MESH:D001932', (115, 126))
47624	30460631	Although we can propagate BT142 cells in culture, we were unable to make iPSCs (data not shown), suggesting that the IDH1 mutation and/or other genetic aberrations in BT142 cells are incompatible with iPSCs.	('mutation', 'Var', (122, 130))	('IDH1', 'Gene', '3417', (117, 121))	('IDH1', 'Gene', (117, 121))
47625	30460631	Because the IDH1 mutations acquire the neomorphic activity to produce D2HG, which inhibits all alphaKG-dependent epigenetic modifying enzymes, we then tested whether human PSCs could tolerate D2HG.	('IDH1', 'Gene', (12, 16))	('alphaKG', 'Chemical', 'MESH:C029743', (95, 102))	('D2HG', 'Chemical', 'MESH:C019417', (70, 74))	('human', 'Species', '9606', (166, 171))	('inhibits', 'NegReg', (82, 90))	('D2HG', 'Chemical', 'MESH:C019417', (192, 196))	('IDH1', 'Gene', '3417', (12, 16))	('tested', 'Reg', (151, 157))	('mutations', 'Var', (17, 26))
47626	30460631	Our data discovered a deterioration of colonies of human H9 ESCs or BJ-iPSCs after a 24-hour treatment of D2HG (Fig.	('D2HG', 'Var', (106, 110))	('BJ-iPSCs', 'CPA', (68, 76))	('deterioration', 'NegReg', (22, 35))	('ESCs', 'CellLine', 'CVCL:9108', (60, 64))	('human', 'Species', '9606', (51, 56))	('H9', 'CellLine', 'CVCL:1240', (57, 59))	('D2HG', 'Chemical', 'MESH:C019417', (106, 110))	('colonies', 'CPA', (39, 47))
47627	30460631	S2), which further supports the notion that iPSCs cannot tolerate D2HG and the IDH mutations.	('mutations', 'Var', (83, 92))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (79, 82))	('D2HG', 'Chemical', 'MESH:C019417', (66, 70))
47628	30460631	To rule out the possibility that we may selectively eliminate LGG cells carrying the IDH1 mutations during tumor dissociation or cell culture, we compared IDH1 mutation status in freshly dissociated primary LGG cells and the same cells that have been cultured.	('IDH1', 'Gene', (155, 159))	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('IDH1', 'Gene', '3417', (155, 159))	('IDH1', 'Gene', (85, 89))	('tumor dissociation', 'Disease', 'MESH:D004213', (107, 125))	('tumor dissociation', 'Disease', (107, 125))	('IDH1', 'Gene', '3417', (85, 89))
47629	30460631	However, we found that the proportion of IDH1 mutation-carrying cells, as judged by the relative peak heights on the DNA sequencing chromatograms, remained relatively stable over a 4-month period for the BT01 cells or a 14-day period for the BT03 cells (Fig.	('IDH1', 'Gene', '3417', (41, 45))	('mutation-carrying', 'Var', (46, 63))	('IDH1', 'Gene', (41, 45))
47630	30460631	Therefore, our observation of none of the LGG-iPSCs carrying the IDH1 mutations is unlikely explained by selective loss of mutation-bearing cells during sample processing and the subsequent culture.	('IDH1', 'Gene', '3417', (65, 69))	('IDH1', 'Gene', (65, 69))	('mutations', 'Var', (70, 79))
47634	30460631	Because primary tumors likely consist of normal brain cells and a mixture of tumor cells at various stages of tumor progression, the LGG-iPSCs could originate from normal cells or tumor cells prior to acquiring the IDH1 mutations.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('IDH1', 'Gene', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (180, 185))	('IDH1', 'Gene', '3417', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', (16, 22))	('tumor', 'Disease', (77, 82))	('mutations', 'Var', (220, 229))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
47635	30460631	An 8q gain is a common chromosomal abnormality reported in IDH1 mutated gliomas.	('IDH1', 'Gene', '3417', (59, 63))	('gain', 'PosReg', (6, 10))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (23, 46))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('mutated', 'Var', (64, 71))	('IDH1', 'Gene', (59, 63))	('chromosomal abnormality', 'Disease', (23, 46))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
47636	30460631	One of the BT01-iPSC clones, BT01-iPS16, contains no chromosomal abnormality (data not shown), suggesting that the BT01-iPS16 cells originated from a normal cell in the tumor mass.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BT01-iPS16', 'Var', (115, 125))	('chromosomal abnormality', 'Disease', (53, 76))	('tumor', 'Disease', (169, 174))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (53, 76))
47640	30460631	Furthermore, among the subset LGGs carrying the Xq23 amplification, most (6 of 7) also have the IDH1 mutation (Fig.	('IDH1', 'Gene', '3417', (96, 100))	('Xq23 amplification', 'Var', (48, 66))	('mutation', 'Var', (101, 109))	('IDH1', 'Gene', (96, 100))
47642	30460631	Because tumor cells gradually accumulate multiple genetic lesions during tumorigenesis, these data suggest that the Xq23 amplification occurred before the IDH1 mutation in BT01.	('amplification', 'Var', (121, 134))	('IDH1', 'Gene', (155, 159))	('mutation', 'Var', (160, 168))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Xq23', 'Gene', (116, 120))	('genetic lesions', 'Disease', (50, 65))	('IDH1', 'Gene', '3417', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (8, 13))	('genetic lesions', 'Disease', 'MESH:D020022', (50, 65))
47645	30460631	Among the nine LGGs carrying the 7q31 amplification, all carried mutations in IDH1 (8 of 9) or IDH2 (1 of 9) (Fig.	('IDH1', 'Gene', (78, 82))	('IDH2', 'Gene', '3418', (95, 99))	('IDH2', 'Gene', (95, 99))	('IDH1', 'Gene', '3417', (78, 82))	('carried', 'Reg', (57, 64))	('mutations', 'Var', (65, 74))
47648	30460631	Because these cells do not carry the IDH1 mutations, the 7q31 amplification in BT03 is mostly likely an early genetic amplification exist before the IDH1 mutations.	('7q31', 'Var', (57, 61))	('BT03', 'Gene', (79, 83))	('IDH1', 'Gene', (149, 153))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (149, 153))	('IDH1', 'Gene', '3417', (37, 41))
47650	30460631	These lesions could represent predisposing conditions for IDH1 mutations and/or be cooperating with the IDH1 mutations in gliomagenesis.	('mutations', 'Var', (63, 72))	('IDH1', 'Gene', '3417', (104, 108))	('IDH1', 'Gene', '3417', (58, 62))	('gliomagenesis', 'Disease', (122, 135))	('gliomagenesis', 'Disease', 'None', (122, 135))	('IDH1', 'Gene', (104, 108))	('IDH1', 'Gene', (58, 62))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
47653	30460631	Although IDH1 mutations can be clearly detected in primary BT01 and BT03 cells (Fig.	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (9, 13))	('IDH1', 'Gene', (9, 13))
47654	30460631	Because reprogramming of iPSCs involves global erasure of epigenetic marks of the differentiated cells and establishment of the marks of pluripotent cells, it is likely that the IDH mutations, which produce high levels of D2HG and inhibit epigenetic remodeling enzymes such as the TET-family DNA demethylases and Jumonji-family histone demethylases, completely block the transition of brain tumor cells into iPSCs.	('epigenetic remodeling enzymes', 'Enzyme', (239, 268))	('IDH', 'Gene', '3417', (178, 181))	('methyl', 'Chemical', 'MESH:C031105', (338, 344))	('inhibit', 'NegReg', (231, 238))	('block', 'NegReg', (361, 366))	('Jumonji-family histone demethylases', 'Enzyme', (313, 348))	('brain tumor', 'Disease', 'MESH:D001932', (385, 396))	('D2HG', 'Chemical', 'MESH:C019417', (222, 226))	('brain tumor', 'Disease', (385, 396))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('methyl', 'Chemical', 'MESH:C031105', (298, 304))	('IDH', 'Gene', (178, 181))	('mutations', 'Var', (182, 191))	('brain tumor', 'Phenotype', 'HP:0030692', (385, 396))
47655	30460631	Furthermore, it is likely that pluripotent cells rely on the activities of these alphaKG-dependent enzymes to maintain its status because treatment with D2HG caused rapid death of PSCs (Figure S2).	('D2HG', 'Chemical', 'MESH:C019417', (153, 157))	('D2HG', 'Var', (153, 157))	('PSCs', 'Disease', (180, 184))	('alphaKG', 'Chemical', 'MESH:C029743', (81, 88))
47656	30460631	Consistent with this notion, human patients carrying the neomorphic IDH1 R132 germline mutations have never been reported, suggesting that the IDH1 mutations are detrimental to early embryonic cells.	('mutations', 'Var', (148, 157))	('IDH1', 'Gene', (143, 147))	('IDH1', 'Gene', (68, 72))	('IDH1', 'Gene', '3417', (68, 72))	('human', 'Species', '9606', (29, 34))	('patients', 'Species', '9606', (35, 43))	('IDH1', 'Gene', '3417', (143, 147))
47657	30460631	The monoallelic mutations of IDH1 or IDH2 have been identified in most LGGs and secondary GBMs.	('identified', 'Reg', (52, 62))	('IDH1', 'Gene', (29, 33))	('IDH2', 'Gene', (37, 41))	('GBM', 'Disease', (90, 93))	('IDH1', 'Gene', '3417', (29, 33))	('GBM', 'Disease', 'MESH:D005909', (90, 93))	('IDH2', 'Gene', '3418', (37, 41))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('monoallelic mutations', 'Var', (4, 25))
47658	30460631	Comparing to the IDH2 mutations, the IDH1 mutations (e.g., R132H and R132C) are more prevalent and have been identified in over 90% of all patients carrying IDH mutations.	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', '3417', (17, 20))	('IDH', 'Gene', '3417', (157, 160))	('patients', 'Species', '9606', (139, 147))	('R132H', 'SUBSTITUTION', 'None', (59, 64))	('IDH2', 'Gene', '3418', (17, 21))	('IDH1', 'Gene', (37, 41))	('IDH2', 'Gene', (17, 21))	('R132C', 'Var', (69, 74))	('R132C', 'SUBSTITUTION', 'None', (69, 74))	('IDH1', 'Gene', '3417', (37, 41))	('IDH', 'Gene', (37, 40))	('identified', 'Reg', (109, 119))	('IDH', 'Gene', '3417', (37, 40))	('R132H', 'Var', (59, 64))	('IDH', 'Gene', (157, 160))
47659	30460631	Furthermore, mutations in IDH1 or IDH2 are mutually exclusive in patients, suggesting that they play similar roles in driving gliomagenesis.	('gliomagenesis', 'Disease', 'None', (126, 139))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('IDH1', 'Gene', (26, 30))	('gliomagenesis', 'Disease', (126, 139))	('patients', 'Species', '9606', (65, 73))	('IDH2', 'Gene', (34, 38))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', '3417', (26, 30))	('IDH2', 'Gene', '3418', (34, 38))
47660	30460631	Our data agree with the previous findings because BT01 and BT03 carry the IDH1 mutations but they have wild type IDH2 (Fig.	('IDH2', 'Gene', (113, 117))	('IDH1', 'Gene', (74, 78))	('IDH2', 'Gene', '3418', (113, 117))	('IDH1', 'Gene', '3417', (74, 78))	('mutations', 'Var', (79, 88))
47661	30460631	Besides the IDH mutations, additional genetic alterations have been identified to be closely associated with subtypes of LGGs.	('LGGs', 'Disease', (121, 125))	('mutations', 'Var', (16, 25))	('associated', 'Reg', (93, 103))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))
47662	30460631	The recurrent genetic changes include mutations in TP53 and ATRX in over 80% of IDH mutation-bearing astrocytomas, and TERT promoter mutation and chromosome 1p/19q co-deletion in over 80% of oligodendrogliomas.	('astrocytomas', 'Disease', (101, 113))	('TP53', 'Gene', (51, 55))	('TERT', 'Gene', (119, 123))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (191, 209))	('oligodendrogliomas', 'Disease', (191, 209))	('TERT', 'Gene', '7015', (119, 123))	('ATRX', 'Gene', '546', (60, 64))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('IDH', 'Gene', (80, 83))	('IDH', 'Gene', '3417', (80, 83))	('astrocytomas', 'Disease', 'MESH:D001254', (101, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('mutations', 'Var', (38, 47))	('gliomas', 'Phenotype', 'HP:0009733', (202, 209))	('TP53', 'Gene', '7157', (51, 55))	('ATRX', 'Gene', (60, 64))
47663	30460631	The IDH1 mutations are considered as an early event acquired prior to these other major genetic changes.	('mutations', 'Var', (9, 18))	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', (4, 8))
47664	30460631	Our data agree with this conclusion because the LGG-iPSCs contained neither the IDH1 mutations nor the major chromosomal gains/losses detected in primary LGG cells (Fig.	('mutations', 'Var', (85, 94))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))
47665	30460631	It has been reported that the IDH1 mutations could be deleted in later stage of gliomagenesis, which raises the possibility that the LGG-iPSCs may originate from these cells.	('gliomagenesis', 'Disease', 'None', (80, 93))	('IDH1', 'Gene', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('gliomagenesis', 'Disease', (80, 93))	('IDH1', 'Gene', '3417', (30, 34))	('mutations', 'Var', (35, 44))
47667	30460631	Third, amplifications in the same chromosomal regions were also identified in a fraction of TCGA LGG samples (Fig.	('CGA', 'Gene', (93, 96))	('amplifications', 'Var', (7, 21))	('CGA', 'Gene', '1113', (93, 96))
47670	30460631	Previous genome-wide association studies (GWAS) have identified rare inherited variants on chromosome 8q24 and 11q23 that may increase the risk of IDH-mutant gliomas.	('IDH', 'Gene', '3417', (147, 150))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('variants', 'Var', (79, 87))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('gliomas', 'Disease', (158, 165))	('increase', 'PosReg', (126, 134))	('IDH', 'Gene', (147, 150))
47672	30460631	It is also possible that these regional chromosomal changes represent early genetic events in gliomagenesis that can cooperate with IDH1 mutations.	('IDH1', 'Gene', (132, 136))	('IDH1', 'Gene', '3417', (132, 136))	('mutations', 'Var', (137, 146))	('gliomagenesis', 'Disease', 'None', (94, 107))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('gliomagenesis', 'Disease', (94, 107))
47673	30460631	In primary glioblastoma (GBM), it has been reported that the earliest genetic alterations are polysomy of chromosome 7 and monosomy of chromosome 10, which occur in 86% and 90% of GBM, respectively.	('GBM', 'Disease', (25, 28))	('GBM', 'Disease', 'MESH:D005909', (25, 28))	('monosomy of chromosome', 'Var', (123, 145))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('glioblastoma', 'Disease', (11, 23))	('GBM', 'Disease', (180, 183))	('GBM', 'Disease', 'MESH:D005909', (180, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (11, 23))	('GBM', 'Phenotype', 'HP:0012174', (180, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (11, 23))
47674	30460631	3D and 5B), it is possible that many different genetic lesions may exist to facilitate the acquisition of IDH1 mutations and/or cooperate with the IDH mutations to initiate LGGs.	('mutations', 'Var', (111, 120))	('IDH', 'Gene', '3417', (147, 150))	('genetic lesions', 'Disease', 'MESH:D020022', (47, 62))	('IDH', 'Gene', '3417', (106, 109))	('facilitate', 'PosReg', (76, 86))	('genetic lesions', 'Disease', (47, 62))	('IDH1', 'Gene', (106, 110))	('LGGs', 'Disease', (173, 177))	('IDH1', 'Gene', '3417', (106, 110))	('IDH', 'Gene', (147, 150))	('IDH', 'Gene', (106, 109))
47675	30460631	The method established in current study enables identification of genetic lesions that occur prior to acquisition of the IDH mutations in gliomagenesis, which would provide novel insights into conditions leading to the initiation of LGGs.	('mutations', 'Var', (125, 134))	('genetic lesions', 'Disease', 'MESH:D020022', (66, 81))	('gliomagenesis', 'Disease', 'None', (138, 151))	('IDH', 'Gene', (121, 124))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('IDH', 'Gene', '3417', (121, 124))	('gliomagenesis', 'Disease', (138, 151))	('genetic lesions', 'Disease', (66, 81))
47689	20676727	In our previous studies of heterogeneous groups of brain tumors, increased AMT uptake was found in both low- and high-grade tumors, and tryptophan metabolic rates measured on PET were lower in tumor samples with no or minimal IDO expression as compared to those with widespread IDO staining.	('tryptophan metabolic rates', 'MPA', (136, 162))	('tumor', 'Disease', (124, 129))	('brain tumors', 'Disease', (51, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tryptophan', 'Chemical', 'MESH:D014364', (136, 146))	('IDO', 'Gene', '3620', (226, 229))	('minimal', 'Var', (218, 225))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('lower', 'NegReg', (184, 189))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (57, 62))	('IDO', 'Gene', (278, 281))	('increased AMT', 'Phenotype', 'HP:0008151', (65, 78))	('increased', 'PosReg', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('AMT uptake', 'MPA', (75, 85))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('IDO', 'Gene', (226, 229))	('brain tumors', 'Phenotype', 'HP:0030692', (51, 63))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IDO', 'Gene', '3620', (278, 281))	('tumors', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('brain tumors', 'Disease', 'MESH:D001932', (51, 63))	('AMT', 'Chemical', 'MESH:C020774', (75, 78))	('brain tumor', 'Phenotype', 'HP:0030692', (51, 62))
47749	20676727	Increased amino acid tumor tissue uptake, as compared to normal brain tissue, has been reported in low-grade gliomas by 11C-methionine PET, with relatively higher concentration values in oligodendrogliomas.	('oligodendrogliomas', 'Disease', (187, 205))	('tumor', 'Disease', (21, 26))	('11C-methionine', 'Var', (120, 134))	('11C-methionine', 'Chemical', '-', (120, 134))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('gliomas', 'Disease', (198, 205))	('Increased', 'PosReg', (0, 9))	('gliomas', 'Disease', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (187, 205))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
47810	33673104	The current WHO 2016 classification still uses the histopathological grading system, but now molecular markers such as isocitrate dehydrogenase (IDH) 1/2 mutations and co-deletions in chromosomes 1p and 19q complete the integrated diagnosis of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('mutations', 'Var', (154, 163))	('gliomas', 'Disease', (244, 251))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))
47811	33673104	This resulted in three main glioma classes: IDH mutant, 1p19q codeleted (oligodendrogliomas), IDH mutant, 1p19q intact (astrocytomas), and IDH wild-type gliomas.	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('gliomas', 'Disease', (84, 91))	('astrocytomas', 'Disease', (120, 132))	('1p19q', 'Var', (56, 61))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (73, 91))	('IDH', 'Gene', '3417', (139, 142))	('gliomas', 'Disease', (153, 160))	('resulted in', 'Reg', (5, 16))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glioma', 'Disease', (153, 159))	('IDH', 'Gene', (94, 97))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('oligodendrogliomas', 'Disease', (73, 91))	('astrocytomas', 'Disease', 'MESH:D001254', (120, 132))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('IDH', 'Gene', '3417', (94, 97))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('1p19q', 'Var', (106, 111))	('glioma', 'Disease', (84, 90))	('IDH', 'Gene', (139, 142))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('glioma', 'Disease', (28, 34))
47812	33673104	Specific alterations are associated with each group, such as mutations on CIC, FUBP1, and TERT promoter; on ATRX and TP53; and on EGFR, PDGFRA, and TERT promoter, respectively.	('TERT', 'Gene', '7015', (90, 94))	('CIC', 'Gene', '23152', (74, 77))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('mutations', 'Var', (61, 70))	('FUBP1', 'Gene', (79, 84))	('ATRX', 'Gene', (108, 112))	('CIC', 'Gene', (74, 77))	('TERT', 'Gene', (148, 152))	('TERT', 'Gene', (90, 94))	('TERT', 'Gene', '7015', (148, 152))	('ATRX', 'Gene', '546', (108, 112))	('PDGFRA', 'Gene', '5156', (136, 142))	('PDGFRA', 'Gene', (136, 142))	('FUBP1', 'Gene', '8880', (79, 84))
47814	33673104	For IDH mutant astrocytomas, any combination of microvascular proliferation, necrosis (characteristics of anaplastic astrocytomas) or CDKN2A/B homozygous deletion now allows for the diagnosis of Astrocytoma, IDH-mutant, WHO grade 4:note the use of Arabic is now suggested, rather than Roman, numbers.	('IDH', 'Gene', '3417', (4, 7))	('Astrocytoma', 'Disease', 'MESH:D001254', (195, 206))	('IDH', 'Gene', (208, 211))	('Astrocytoma', 'Disease', (195, 206))	('allows', 'Reg', (167, 173))	('astrocytomas', 'Disease', (15, 27))	('mutant', 'Var', (8, 14))	('astrocytomas', 'Disease', (117, 129))	('IDH', 'Gene', '3417', (208, 211))	('necrosis', 'Disease', 'MESH:D009336', (77, 85))	('Astrocytoma', 'Phenotype', 'HP:0009592', (195, 206))	('CDKN2A', 'Gene', (134, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (15, 26))	('astrocytomas', 'Disease', 'MESH:D001254', (15, 27))	('necrosis', 'Disease', (77, 85))	('IDH', 'Gene', (4, 7))	('astrocytomas', 'Disease', 'MESH:D001254', (117, 129))	('CDKN2A', 'Gene', '1029', (134, 140))
47815	33673104	The diagnosis of GBM is now exclusive for IDH wild-type tumors with specific molecular features (gains in chromosome 7 and losses in chromosome 10, EGFR amplifications, and TERT promoter mutations), independent of the histopathological grade.	('GBM', 'Disease', (17, 20))	('TERT', 'Gene', (173, 177))	('IDH', 'Gene', (42, 45))	('gains', 'PosReg', (97, 102))	('TERT', 'Gene', '7015', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('IDH', 'Gene', '3417', (42, 45))	('EGFR', 'Gene', (148, 152))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('amplifications', 'Var', (153, 167))	('losses', 'NegReg', (123, 129))
47817	33673104	DNA methylation pattern identified a group of GBMs and LGGs with hypermethylation at a large number of loci, called CpG Island Methylator Phenotype (G-CIMP), and favorable outcomes, which are virtually always related to the presence of IDH mutations.	('hypermethylation', 'Var', (65, 81))	('GBMs', 'Phenotype', 'HP:0012174', (46, 50))	('G-CIMP', 'Chemical', '-', (149, 155))	('IDH', 'Gene', (236, 239))	('IDH', 'Gene', '3417', (236, 239))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))
47818	33673104	Finally, a comprehensive analysis of these classifications defined three subgroups of IDH mutant gliomas (G-CIMP high:LGm1, G-CIMP low:LGm 2, and 1p19q codeleted:LGm 3) and four subgroups of IDH wild-type gliomas (classical-like:LGm4, mesenchymal-like:LGm5, and two rare subtypes:LGm6-GBM and PA-like), closely associated with transcriptional subtypes.	('IDH', 'Gene', (86, 89))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Disease', (205, 212))	('IDH', 'Gene', '3417', (86, 89))	('gliomas', 'Disease', (97, 104))	('mutant', 'Var', (90, 96))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('IDH', 'Gene', (191, 194))	('G-CIMP', 'Chemical', '-', (124, 130))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH', 'Gene', '3417', (191, 194))	('GBM', 'Phenotype', 'HP:0012174', (285, 288))	('G-CIMP', 'Chemical', '-', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
47819	33673104	Not surprisingly, the molecular subtypes are closely associated with the main prognostic factors in GBM, IDH mutations and methylation of the promoter region of O6-methylguanine-DNA methyltransferase (MGMT).	('GBM', 'Disease', (100, 103))	('MGMT', 'Gene', (201, 205))	('MGMT', 'Gene', '4255', (201, 205))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (161, 199))	('methylation', 'Var', (123, 134))	('GBM', 'Phenotype', 'HP:0012174', (100, 103))	('associated', 'Reg', (53, 63))	('IDH', 'Gene', (105, 108))	('mutations', 'Var', (109, 118))	('IDH', 'Gene', '3417', (105, 108))	('O6-methylguanine-DNA methyltransferase', 'Gene', (161, 199))
47820	33673104	Virtually all proneural GBMs harbor IDH mutations and usually present G-CIMP, therefore reducing the prognostic/predictive power of MGMT promoter methylation in this group of tumors.	('prognostic/predictive power', 'MPA', (101, 128))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('GBMs harbor IDH', 'Disease', (24, 39))	('MGMT', 'Gene', '4255', (132, 136))	('G-CIMP', 'Chemical', '-', (70, 76))	('MGMT', 'Gene', (132, 136))	('G-CIMP', 'MPA', (70, 76))	('GBM', 'Phenotype', 'HP:0012174', (24, 27))	('mutations', 'Var', (40, 49))	('GBMs harbor IDH', 'Disease', 'MESH:C537062', (24, 39))	('GBMs', 'Phenotype', 'HP:0012174', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('reducing', 'NegReg', (88, 96))
47842	33673104	With systematic evaluation of IHC stains, several authors showed that while endothelial cells do not express EGFR, regional differences in EGFR staining in GBM tumor cells may be explained by different levels of EGFR amplification, with higher EGFR amplification being associated with high proliferative activity, higher mutational burden, and shorter OS.	('mutational burden', 'MPA', (321, 338))	('EGFR', 'Gene', (244, 248))	('amplification', 'Var', (249, 262))	('GBM tumor', 'Disease', 'MESH:D005910', (156, 165))	('GBM tumor', 'Disease', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('high proliferative activity', 'CPA', (285, 312))
47846	33673104	On the other hand, because TP53, ATRX and IDH mutations are early events in gliomas, protein expression assessed by IHC is either diffusely lost (ATRX) or diffusely present (protein IDH1 R132H, p53) in tumor cells (Figure 5).	('IDH', 'Gene', (42, 45))	('p53', 'Gene', (194, 197))	('IDH', 'Gene', (182, 185))	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (46, 55))	('gliomas', 'Disease', (76, 83))	('tumor', 'Disease', (202, 207))	('IDH', 'Gene', '3417', (42, 45))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('ATRX', 'Gene', (146, 150))	('protein', 'Protein', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('ATRX', 'Gene', '546', (146, 150))	('IDH', 'Gene', '3417', (182, 185))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('lost', 'NegReg', (140, 144))	('R132H', 'Mutation', 'p.R132H', (187, 192))	('ATRX', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('TP53', 'Gene', '7157', (27, 31))	('ATRX', 'Gene', '546', (33, 37))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('p53', 'Gene', '7157', (194, 197))
47847	33673104	ATRX has shown heterogeneous expression in only about 20% of GBMs, associated with higher frequency of EGFR amplifications.	('ATRX', 'Gene', (0, 4))	('EGFR', 'Gene', (103, 107))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('GBMs', 'Phenotype', 'HP:0012174', (61, 65))	('ATRX', 'Gene', '546', (0, 4))	('amplifications', 'Var', (108, 122))
47848	33673104	Whereas p53 IHC staining is not sensitive nor specific for TP53 mutations, the diffuse staining reflects its early occurrence in gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('TP53', 'Gene', (59, 63))	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('mutations', 'Var', (64, 73))	('glioma', 'Disease', (129, 135))	('TP53', 'Gene', '7157', (59, 63))
47856	33673104	These findings suggested that in polygenomic GBMs the tumorigenic potential depends on DNA ploidy of CSCs.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ploidy of CSCs', 'Disease', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('ploidy of CSCs', 'Disease', 'None', (91, 105))	('GBMs', 'Phenotype', 'HP:0012174', (45, 49))	('tumor', 'Disease', (54, 59))	('polygenomic', 'Var', (33, 44))
47857	33673104	At chromosomal level, early cytogenetic analyses of multiple samples obtained from one tumor diagnosed as "low grade oligoastrocytoma" demonstrated a ubiquitous tumor cell clone with gains in chromosome 7 (47XY, +7), while cells with concurrent chromosome 7 gains and chromosome 9 losses (47,XY,+7/47,idem,+del(9)(q21.2)/47,idem -9,+ 16) were deemed a subclonal population.	('47', 'Var', (289, 291))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (122, 133))	('gains', 'PosReg', (183, 188))	('tumor', 'Disease', (87, 92))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (117, 133))	('losses', 'NegReg', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('oligoastrocytoma', 'Disease', (117, 133))	('47,XY,+7', 'STRUCTURAL_ABNORMALITY', 'None', (289, 297))	('gains', 'PosReg', (258, 263))	('tumor', 'Disease', (161, 166))
47865	33673104	Given that alterations in receptor tyrosine kinase (RTKs) are a hallmark of 50% of GBMs, multiple groups have investigated the frequency and distribution of RTK amplifications with array comparative genomic hybridization (aCGH) with single-nucleotide polymorphism (SNP) analysis of specific gene loci in chromosomal regions.	('alterations', 'Var', (11, 22))	('RTKs', 'Gene', '5979', (52, 56))	('RTKs', 'Gene', (52, 56))	('receptor tyrosine kinase', 'Gene', (26, 50))	('receptor tyrosine kinase', 'Gene', '5979', (26, 50))	('GBMs', 'Phenotype', 'HP:0012174', (83, 87))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))
47866	33673104	EGFR amplifications were more frequent in GBMs than in LGGs, while PDGFRA amplifications were more homogenous among different tumor grades.	('amplifications', 'Var', (5, 19))	('EGFR', 'Gene', (0, 4))	('frequent', 'Reg', (30, 38))	('GBMs', 'Disease', (42, 46))	('PDGFRA', 'Gene', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('PDGFRA', 'Gene', '5156', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('GBMs', 'Phenotype', 'HP:0012174', (42, 46))	('tumor', 'Disease', (126, 131))
47870	33673104	Post-mortem analysis of one GBM with a mosaic pattern of RTK amplifications showed that tumor cells with PDGFRA amplifications were limited to the bulk of the tumor, while EGFR amplifications were observed in the cell population present at areas of infiltration.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('PDGFRA', 'Gene', (105, 111))	('RTK', 'Gene', (57, 60))	('PDGFRA', 'Gene', '5156', (105, 111))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('amplifications', 'Var', (112, 126))
47871	33673104	Single-cell RNA sequencing has also confirmed the possibility of mosaic expression of multiple RTK amplifications in EGFR, PDGFRA, PDGFA, FGFR1, FGF1, NOTCH2, and JAG1 in GBMs.	('amplifications', 'Var', (99, 113))	('FGF1', 'Gene', '2246', (145, 149))	('PDGFA', 'Gene', '5154', (131, 136))	('NOTCH2', 'Gene', (151, 157))	('GBM', 'Phenotype', 'HP:0012174', (171, 174))	('EGFR', 'Gene', (117, 121))	('RTK', 'Gene', (95, 98))	('FGF1', 'Gene', (145, 149))	('FGFR1', 'Gene', (138, 143))	('NOTCH2', 'Gene', '4853', (151, 157))	('JAG1', 'Gene', '182', (163, 167))	('GBMs', 'Phenotype', 'HP:0012174', (171, 175))	('JAG1', 'Gene', (163, 167))	('FGFR1', 'Gene', '2260', (138, 143))	('PDGFA', 'Gene', (131, 136))	('PDGFRA', 'Gene', '5156', (123, 129))	('PDGFRA', 'Gene', (123, 129))
47878	33673104	Based on these findings, this group was one of the first to describe the putative order of molecular alterations in gliomas incorporated in the WHO 2016 classification with IDH point mutations, TERT promoter mutations, and 1p19q co-deletion as early events.	('TERT', 'Gene', (194, 198))	('TERT', 'Gene', '7015', (194, 198))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', '3417', (173, 176))	('1p19q co-deletion', 'Var', (223, 240))	('gliomas', 'Disease', (116, 123))	('point mutations', 'Var', (177, 192))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
47879	33673104	These events are followed by frequent mutations in ATRX/TP53 (in 1p19q intact tumors) or FUBP1/CIC (in 1p19q co-deleted tumors), which affect different tumor cell sub-clones, reflecting on the concept that clonal evolution of tumors occurs in both space and time.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('CIC', 'Gene', '23152', (95, 98))	('ATRX', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (56, 60))	('FUBP1', 'Gene', (89, 94))	('tumor', 'Disease', (152, 157))	('ATRX', 'Gene', '546', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (78, 83))	('FUBP1', 'Gene', '8880', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('affect', 'Reg', (135, 141))	('tumors', 'Disease', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('CIC', 'Gene', (95, 98))	('TP53', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (226, 231))
47880	33673104	Even before the genomic landscape of LGGs was described, GBM spatial-longitudinal evolution was inferred based on the frequency of the alterations between the samples by assessing DNA somatic copy number alterations (CNAs), single-nucleotide variants (SNVs), and gene expression profiles in multiple tumor areas.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Disease', (300, 305))	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('single-nucleotide variants', 'Var', (224, 250))
47883	33673104	Subsequent alterations affected genomic regions containing PDGFRA (chromosome 4), PTEN (chromosome 10), and TP53 (chromosome 17), and were observed in limited/unique areas.	('alterations', 'Var', (11, 22))	('affected', 'Reg', (23, 31))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('PDGFRA', 'Gene', '5156', (59, 65))	('PDGFRA', 'Gene', (59, 65))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))
47886	33673104	described spatial heterogeneity of midline HGGs (mHGG), which included tumors with and without K27M mutations in H3F3A or HIST1H3B (collectively called H3K27M).	('mutations', 'Var', (100, 109))	('K27M mutations', 'Var', (95, 109))	('K27M', 'Mutation', 'p.K27M', (95, 99))	('H3F3A', 'Gene', '3020', (113, 118))	('HIST1H3B', 'Gene', (122, 130))	('HIST1H3B', 'Gene', '8358', (122, 130))	('K27M', 'Mutation', 'p.K27M', (154, 158))	('H3F3A', 'Gene', (113, 118))	('midline HGGs', 'Disease', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('midline HGGs', 'Disease', 'MESH:D009436', (35, 47))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
47887	33673104	In diffuse intrinsic pontine glioma (DIPG:also called diffuse midline gliomas), H3K27M mutations, as well as ACVR1, FGFR1, MET, and PIK3CA mutations, were clonal.	('K27M', 'Mutation', 'p.K27M', (82, 86))	('FGFR1', 'Gene', '2260', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('PIK3CA', 'Gene', (132, 138))	('MET', 'Gene', '79811', (123, 126))	('mutations', 'Var', (87, 96))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('ACVR1', 'Gene', (109, 114))	('midline gliomas', 'Disease', 'MESH:D005910', (62, 77))	('FGFR1', 'Gene', (116, 121))	('ACVR1', 'Gene', '90', (109, 114))	('DIPG', 'Chemical', 'MESH:C060938', (37, 41))	('H3K27M', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (132, 138))	('MET', 'Gene', (123, 126))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', (29, 35))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('midline gliomas', 'Disease', (62, 77))	('glioma', 'Disease', 'MESH:D005910', (29, 35))
47889	33673104	On the other hand, one pediatric case of mHGG H3- wild-type showed diffuse (probably clonal) ATRX and TP53 mutations and PDGFRA amplification.	('TP53', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))	('PDGFRA', 'Gene', (121, 127))	('PDGFRA', 'Gene', '5156', (121, 127))	('ATRX', 'Gene', (93, 97))	('TP53', 'Gene', '7157', (102, 106))	('ATRX', 'Gene', '546', (93, 97))
47890	33673104	Although these changes are frequent in adult gliomas following an initiating IDH mutation, in pediatric patients they are probably initiating events, since IDH mutations are rare in DIPG and pediatric HGG.	('adult gliomas', 'Disease', 'MESH:D005910', (39, 52))	('DIPG', 'Chemical', 'MESH:C060938', (182, 186))	('mutation', 'Var', (81, 89))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH', 'Gene', (156, 159))	('IDH', 'Gene', (77, 80))	('adult gliomas', 'Disease', (39, 52))	('IDH', 'Gene', '3417', (156, 159))	('IDH', 'Gene', '3417', (77, 80))	('patients', 'Species', '9606', (104, 112))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))
47891	33673104	further confirmed the clonal nature of H3K27M, ATRX, and NF1 mutations, as well as the subclonal expansion of cells bearing mutations in TP53, BRAF, PDGFRA, among others, in pediatric GBM (pGBM) and DIPG.	('ATRX', 'Gene', (47, 51))	('GBM', 'Phenotype', 'HP:0012174', (190, 193))	('GBM', 'Phenotype', 'HP:0012174', (184, 187))	('H3K27M', 'Gene', (39, 45))	('DIPG', 'Chemical', 'MESH:C060938', (199, 203))	('mutations', 'Var', (124, 133))	('K27M', 'Mutation', 'p.K27M', (41, 45))	('NF1', 'Gene', (57, 60))	('BRAF', 'Gene', (143, 147))	('mutations', 'Var', (61, 70))	('PDGFRA', 'Gene', (149, 155))	('pediatric GBM', 'Disease', (174, 187))	('NF1', 'Gene', '4763', (57, 60))	('ATRX', 'Gene', '546', (47, 51))	('BRAF', 'Gene', '673', (143, 147))	('PDGFRA', 'Gene', '5156', (149, 155))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))
47893	33673104	For example, rare mutations in the histone H4 methyltransferase KMT5B, enhanced invasiveness, and sensitivity of tumor cells to PARP inhibitors in vitro and in vivo.	('KMT5B', 'Gene', (64, 69))	('tumor', 'Disease', (113, 118))	('sensitivity', 'MPA', (98, 109))	('enhanced', 'PosReg', (71, 79))	('KMT5B', 'Gene', '51111', (64, 69))	('PARP', 'Gene', '1302', (128, 132))	('invasiveness', 'CPA', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('PARP', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (18, 27))
47894	33673104	Co-culture of KMT5B mutant and KMT5B wild-type cells and monoculture using conditioned medium from the parental cells (bulk cells) showed significant enhancement of migration and invasion compared with single clone culture, both in vitro and in vivo, and suggested the importance of cell-cell interaction and paracrine signaling as mechanisms in tumor development.	('KMT5B', 'Gene', (14, 19))	('KMT5B', 'Gene', (31, 36))	('KMT5B', 'Gene', '51111', (14, 19))	('KMT5B', 'Gene', '51111', (31, 36))	('enhancement', 'PosReg', (150, 161))	('invasion', 'CPA', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('migration', 'CPA', (165, 174))	('mutant', 'Var', (20, 26))	('tumor', 'Disease', (346, 351))
47909	33673104	On the other hand, specific gene mutations unique to different foci point toward a parallel genetic evolution from a common tumor precursor clone (early separation of cell clones).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
47910	33673104	described different IDH1 point mutations (R132H and R132C) in different tumor areas of one M-LGG.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('R132H', 'Var', (42, 47))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('tumor', 'Disease', (72, 77))	('R132C', 'Var', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('R132H', 'Mutation', 'p.R132H', (42, 47))	('R132C', 'Mutation', 'p.R132C', (52, 57))
47911	33673104	The patient had a germline mutation on TP53 present in only in the tumor foci with the non-canonical IDH1 mutation.	('germline mutation on', 'Var', (18, 38))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IDH', 'Gene', (101, 104))	('TP53', 'Gene', '7157', (39, 43))	('tumor', 'Disease', (67, 72))	('IDH', 'Gene', '3417', (101, 104))	('TP53', 'Gene', (39, 43))
47914	33673104	Finally, two patients in this series presented M-LGG with divergent ATRX/1p19q status between the tumor foci, challenging the discouragement of the diagnosis of "oligoastrocytoma" in tumors with mixed histopathological aspects.	('astrocytoma', 'Phenotype', 'HP:0009592', (167, 178))	('M-LGG', 'Var', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('patients', 'Species', '9606', (13, 21))	('ATRX', 'Gene', '546', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (162, 178))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('oligoastrocytoma', 'Disease', (162, 178))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (98, 103))	('tumors', 'Disease', (183, 189))	('ATRX', 'Gene', (68, 72))
47916	33673104	Epigenetic characterization of GBMs has provided great insight into inter-tumoral heterogeneity and glioma classification and prognosis.	('glioma', 'Disease', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('GBMs', 'Gene', (31, 35))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Epigenetic', 'Var', (0, 10))	('tumor', 'Disease', (74, 79))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('GBMs', 'Phenotype', 'HP:0012174', (31, 35))
47917	33673104	These bear a close relationship with hypermethylated status conferred by IDH mutations in gliomas.	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('hypermethylated status', 'MPA', (37, 59))	('IDH', 'Gene', (73, 76))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH', 'Gene', '3417', (73, 76))	('mutations', 'Var', (77, 86))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
47919	33673104	DNA methylation has also advanced the knowledge in intra-tumor spatial heterogeneity, especially in the characterization of CSCs and inflammatory cells.	('intra-tumor', 'Disease', (51, 62))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('intra-tumor', 'Disease', 'MESH:D009369', (51, 62))	('CSCs', 'Disease', (124, 128))
47924	33673104	The changes in the DNA methylation profile reflected the phylogenetic tree of gene mutations among tumor areas from a single tumor and between matched primary and recurrent tumors.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (99, 104))	('DNA', 'MPA', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('changes', 'Reg', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
47925	33673104	However, in one patient with three LGG recurrences, the genomic changes occurred prior to (but in co-dependency with) epigenomic alteration in the glioma recurrences with grade progression.	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('epigenomic alteration', 'Var', (118, 139))	('glioma', 'Disease', (147, 153))	('patient', 'Species', '9606', (16, 23))
47930	33673104	characterized the DNA methylation profile of GSCs, and observed higher frequencies of methylated CpGs than GBM bulk tumor cells, especially in mesenchymal GBMs.	('higher', 'PosReg', (64, 70))	('methylated', 'Var', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))	('tumor', 'Disease', (116, 121))	('GBMs', 'Phenotype', 'HP:0012174', (155, 159))
47934	33673104	More specifically, because GSCs are pluripotent cells with self-renewal and proliferation properties, the expression of EZH2, a protein related to maintenance of stemness is of high importance, especially in H3K27- mutant tumors.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('H3K27- mutant', 'Var', (208, 221))	('EZH2', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('EZH2', 'Gene', '2146', (120, 124))
47935	33673104	Overexpression of EZH2 in HGGs is associated with worse OS.	('worse OS', 'Disease', (50, 58))	('EZH2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('EZH2', 'Gene', '2146', (18, 22))
47948	33673104	The expression of TGF-beta by TAMs is also associated with increased GSC invasiveness, whereas GSC recruit TAMs more efficiently than differentiated tumor cells.	('TAMs', 'Chemical', '-', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('TGF-beta', 'Gene', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('TGF-beta', 'Gene', '7039', (18, 26))	('GSC invasiveness', 'CPA', (69, 85))	('TAMs', 'Chemical', '-', (107, 111))	('tumor', 'Disease', (149, 154))	('expression', 'Var', (4, 14))	('increased', 'PosReg', (59, 68))
47953	33673104	For example, the metabolic product of mutant IDH1/2, 2-hydroxiglutarate (2-HG), suppresses antitumor activity of tumor-infiltrated cytotoxic T-cells in vivo, and therefore, IDH mutations are, per se, targets for new vaccines.	('mutant', 'Var', (38, 44))	('tumor', 'Disease', (113, 118))	('2-HG', 'Chemical', '-', (73, 77))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', '3417', (45, 48))	('2-hydroxiglutarate', 'Chemical', '-', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('IDH', 'Gene', '3417', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('suppresses', 'NegReg', (80, 90))	('tumor', 'Disease', (95, 100))
47975	33673104	Hypermutational state was associated with treatment with alkylating agent, and significantly more frequent in IDH mutant-noncodel gliomas (47%), than in IDH mutant-codels (25%) and IDH wild-type gliomas (16%).	('IDH', 'Gene', '3417', (153, 156))	('mutant-noncodel', 'Var', (114, 129))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('IDH', 'Gene', (181, 184))	('IDH', 'Gene', (110, 113))	('gliomas', 'Disease', 'MESH:D005910', (195, 202))	('frequent', 'Reg', (98, 106))	('IDH', 'Gene', '3417', (181, 184))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('IDH', 'Gene', '3417', (110, 113))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('IDH', 'Gene', (153, 156))	('gliomas', 'Disease', (195, 202))	('more', 'PosReg', (93, 97))	('alkylating agent', 'MPA', (57, 73))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
47978	33673104	The order of IDH1, ATRX, and TP53 mutations followed previous reports.	('IDH', 'Gene', '3417', (13, 16))	('ATRX', 'Gene', '546', (19, 23))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('ATRX', 'Gene', (19, 23))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (34, 43))
47979	33673104	On the other hand, in IDH wild-type tumors, their findings indicated chromosome 10 deletions as earlier events than chromosome 7 amplifications.	('chromosome 10', 'Gene', (69, 82))	('IDH', 'Gene', (22, 25))	('deletions', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('IDH', 'Gene', '3417', (22, 25))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
47980	33673104	A gross comparison of all shared mutations revealed that cancer cell fractions (CCF) increased in recurrent IDH-mutant-noncodel gliomas and decreased in recurrent IDH wild-type glioma, which suggests, respectively, reductions and increases in intra-tumor heterogeneity in recurrent tumors.	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('cancer', 'Disease', (57, 63))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('increased', 'PosReg', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('glioma', 'Disease', (177, 183))	('intra-tumor', 'Disease', 'MESH:D009369', (243, 254))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('increases', 'PosReg', (230, 239))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('gliomas', 'Disease', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('glioma', 'Disease', (128, 134))	('IDH', 'Gene', (108, 111))	('tumors', 'Disease', (282, 288))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('IDH', 'Gene', (163, 166))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('IDH', 'Gene', '3417', (108, 111))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('IDH', 'Gene', '3417', (163, 166))	('intra-tumor', 'Disease', (243, 254))
47981	33673104	Concerning specific drivers of glioma progression, recurrent IDH mutant-noncodel gliomas presented an enrichment in CDKN2A homozygous deletions, with subsequent DNA aneuploidy and genetic instability that were associated with shorter OS.	('aneuploidy', 'Disease', (165, 175))	('IDH', 'Gene', '3417', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('CDKN2A', 'Gene', '1029', (116, 122))	('DNA', 'MPA', (161, 164))	('glioma', 'Disease', (81, 87))	('gliomas', 'Disease', (81, 88))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('aneuploidy', 'Disease', 'MESH:D000782', (165, 175))	('IDH', 'Gene', (61, 64))	('mutant-noncodel', 'Var', (65, 80))	('glioma', 'Disease', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('deletions', 'Var', (134, 143))	('CDKN2A', 'Gene', (116, 122))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('genetic', 'MPA', (180, 187))
47984	33673104	Additionally, although the heterogeneity in recurrent tumors was inherited from the primary lesion, most sub-clones in recurrent tumors showed additional driver mutations not found in the primary lesion, indicating ongoing genetic evolution.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (161, 170))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
47985	33673104	Among the SNVs, TERT promoter, TP53, PTEN and EGFR mutations were the most frequent clonal alterations.	('TERT', 'Gene', (16, 20))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (31, 35))	('TERT', 'Gene', '7015', (16, 20))	('TP53', 'Gene', (31, 35))	('frequent', 'Reg', (75, 83))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('EGFR', 'Gene', (46, 50))
47993	33673104	We have demonstrated quality improvement in MS analysis of FFPE samples, which enabled the identification of differential proteomic profiles between IDH wild-type and IDH mutant gliomas, as well as among multiple areas of LGGs and GBMs, reflecting different molecular pathways.	('IDH', 'Gene', '3417', (167, 170))	('IDH', 'Gene', (149, 152))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('GBMs', 'Phenotype', 'HP:0012174', (231, 235))	('IDH', 'Gene', '3417', (149, 152))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('gliomas', 'Disease', (178, 185))	('mutant', 'Var', (171, 177))	('IDH', 'Gene', (167, 170))	('GBM', 'Phenotype', 'HP:0012174', (231, 234))
47998	33673104	Given the phenotypic differences given by IDH mutations in gliomas and its product 2-HG, which interferes in the Kreb's Cycle, there is opportunity for exploration of the metabolic consequences of these mutations for GBMs.	('IDH', 'Gene', (42, 45))	('mutations', 'Var', (46, 55))	("Kreb's Cycle", 'MPA', (113, 125))	('IDH', 'Gene', '3417', (42, 45))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('GBM', 'Phenotype', 'HP:0012174', (217, 220))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('GBMs', 'Phenotype', 'HP:0012174', (217, 221))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('2-HG', 'Chemical', '-', (83, 87))
48001	31085957	Patients with low-grade brain tumors often experience chronic drug-resistant epilepsy starting in childhood, which led to the concept of long-term epilepsy-associated tumors (LEATs).	('epilepsy-associated tumors', 'Disease', 'MESH:D004827', (147, 173))	('low-grade', 'Var', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('epilepsy', 'Phenotype', 'HP:0001250', (77, 85))	('epilepsy', 'Disease', (77, 85))	('epilepsy', 'Phenotype', 'HP:0001250', (147, 155))	('epilepsy', 'Disease', (147, 155))	('Patients', 'Species', '9606', (0, 8))	('brain tumors', 'Disease', 'MESH:D001932', (24, 36))	('brain tumors', 'Phenotype', 'HP:0030692', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('epilepsy', 'Disease', 'MESH:D004827', (77, 85))	('epilepsy', 'Disease', 'MESH:D004827', (147, 155))	('brain tumor', 'Phenotype', 'HP:0030692', (24, 35))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('epilepsy-associated tumors', 'Disease', (147, 173))	('brain tumors', 'Disease', (24, 36))
48005	31085957	LEATs and pediatric-type DLGG are characterized by mutations in BRAF, FGFR1, and MYB/MYBL1, which converge on the RAS-RAF-MAPK pathway.	('LEATs', 'Disease', (0, 5))	('pediatric-type DLGG', 'Disease', (10, 29))	('RAF', 'Gene', '22882', (65, 68))	('mutations', 'Var', (51, 60))	('RAF', 'Gene', (65, 68))	('RAF', 'Gene', '22882', (118, 121))	('MYBL1', 'Gene', (85, 90))	('MYB', 'Gene', '4602', (81, 84))	('RAF', 'Gene', (118, 121))	('MYB', 'Gene', '4602', (85, 88))	('FGFR1', 'Gene', (70, 75))	('MYB', 'Gene', (81, 84))	('MYB', 'Gene', (85, 88))	('MYBL1', 'Gene', '4603', (85, 90))	('FGFR1', 'Gene', '2260', (70, 75))
48043	31085957	The frequent temporal lobe involvement, cortical location, low-grade pathology, and association with FCD all appear to contribute to the high propensity of LEATs to cause chronic drug-resistant epilepsy.	('association', 'Interaction', (84, 95))	('FCD', 'Disease', (101, 104))	('cause', 'Reg', (165, 170))	('FCD', 'Phenotype', 'HP:0032046', (101, 104))	('epilepsy', 'Disease', 'MESH:D004827', (194, 202))	('FCD', 'Disease', 'MESH:C563256', (101, 104))	('epilepsy', 'Phenotype', 'HP:0001250', (194, 202))	('low-grade pathology', 'Var', (59, 78))	('epilepsy', 'Disease', (194, 202))
48066	31085957	However, many patients with DLGG attain long-term survival and subsequently face the same problem of long-standing epilepsy as patients with LEATs.	('DLGG', 'Var', (28, 32))	('epilepsy', 'Disease', 'MESH:D004827', (115, 123))	('patients', 'Species', '9606', (127, 135))	('problem of long-standing', 'Phenotype', 'HP:0003698', (90, 114))	('epilepsy', 'Phenotype', 'HP:0001250', (115, 123))	('patients', 'Species', '9606', (14, 22))	('epilepsy', 'Disease', (115, 123))
48069	31085957	For example, pediatric-type astrocytomas lack IDH1/2 mutations and rarely undergo malignant transformation.	('lack', 'NegReg', (41, 45))	('IDH1/2', 'Gene', (46, 52))	('astrocytomas', 'Disease', 'MESH:D001254', (28, 40))	('mutations', 'Var', (53, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (28, 39))	('astrocytomas', 'Disease', (28, 40))	('IDH1/2', 'Gene', '3417;3418', (46, 52))
48070	31085957	So-called pediatric-type oligodendrogliomas are frequently devoid of IDH1/2 mutation and 1p/19q codeletion, the hallmarks of oligodendroglioma.	('1p/19q codeletion', 'Var', (89, 106))	('devoid', 'NegReg', (59, 65))	('oligodendroglioma', 'Disease', (25, 42))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('oligodendroglioma', 'Disease', 'MESH:D009837', (25, 42))	('oligodendroglioma', 'Disease', (125, 142))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (25, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('oligodendroglioma', 'Disease', 'MESH:D009837', (125, 142))	('oligodendrogliomas', 'Disease', (25, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('mutation', 'Var', (76, 84))	('IDH1/2', 'Gene', (69, 75))
48073	31085957	In the 50 cases of oligodendrogliomas, IDH1 mutation and 1p/19q codeletion were found in only 18% and 25% of cases, respectively.	('oligodendrogliomas', 'Disease', (19, 37))	('mutation', 'Var', (44, 52))	('IDH1', 'Gene', (39, 43))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('IDH1', 'Gene', '3417', (39, 43))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (19, 37))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
48081	31085957	In particular, pediatric DLGG showed either duplication of the tyrosine kinase domain of the FGFR1 gene or rearrangement of the MYB/MYBL1 genes.	('MYBL1', 'Gene', (132, 137))	('MYB', 'Gene', (128, 131))	('FGFR1', 'Gene', '2260', (93, 98))	('MYB', 'Gene', '4602', (132, 135))	('MYB', 'Gene', (132, 135))	('duplication', 'Var', (44, 55))	('MYBL1', 'Gene', '4603', (132, 137))	('rearrangement', 'Var', (107, 120))	('tyrosine kinase domain', 'MPA', (63, 85))	('FGFR1', 'Gene', (93, 98))	('MYB', 'Gene', '4602', (128, 131))
48082	31085957	Mutations of IDH1/2, the hallmark of adult-type DLGG were rarely found in pediatric DLGG, supporting the distinction of pediatrictype DLGG from its adult counterpart.	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('IDH1/2', 'Gene', '3417;3418', (13, 19))
48083	31085957	Mutations of TP53 and ATRX, the other common variations in adult-type diffuse astrocytomas were also rarely found in pediatric-type DLGG.	('ATRX', 'Gene', (22, 26))	('astrocytomas', 'Disease', 'MESH:D001254', (78, 90))	('TP53', 'Gene', (13, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (78, 89))	('adult-type', 'Disease', (59, 69))	('astrocytomas', 'Disease', (78, 90))	('ATRX', 'Gene', '546', (22, 26))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))
48084	31085957	In LEAT group, alterations of the BRAF gene, notably the BRAF V600E mutation is highly represented in gangliogliomas.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('V600E', 'Var', (62, 67))	('BRAF', 'Gene', (57, 61))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('BRAF gene', 'Gene', (34, 43))	('V600E', 'Mutation', 'rs113488022', (62, 67))
48085	31085957	In 36 gangliogliomas that were sequenced, 27 tumors (75%) had a BRAF V600E mutation, variant BRAF mutation, or BRAF fusion.	('V600E', 'Var', (69, 74))	('variant BRAF mutation', 'Var', (85, 106))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('mutation', 'Var', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BRAF', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('gliomas', 'Disease', (13, 20))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
48086	31085957	The other tumors had mutations in KRAS, RAF, NF1, or an FGFR1/2 alteration, confirming that ganglioglioma develops through alterations in the RAS-RAF-MAPK pathway.	('tumors', 'Disease', (10, 16))	('RAF', 'Gene', (146, 149))	('glioma', 'Disease', (99, 105))	('FGFR1', 'Gene', (56, 61))	('RAF', 'Gene', '22882', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('NF1', 'Gene', '4763', (45, 48))	('KRAS', 'Gene', '3845', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('RAF', 'Gene', (40, 43))	('alterations', 'Reg', (123, 134))	('NF1', 'Gene', (45, 48))	('KRAS', 'Gene', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('FGFR1', 'Gene', '2260', (56, 61))	('mutations', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('RAF', 'Gene', '22882', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('alteration', 'Reg', (64, 74))
48087	31085957	A study showed that mutated BRAF V600E protein was predominantly expressed in neuronal lineage cells, although BRAF was expressed in both the neuronal and glial compartments.	('BRAF', 'Gene', (28, 32))	('V600E', 'Var', (33, 38))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('mutated', 'Var', (20, 27))
48088	31085957	Interestingly, when the BRAF V600E pathogenic mutation was introduced into mouse embryos, the embryos postnatally developed an increased neuronal size and epileptic phenotype, whereas the same mutation transfected into postnatal mouse brains led to glial proliferation only, indicating that BRAF V600E induced epileptogenesis in the neuronal lineage and tumorigenesis in the glial lineage.	('V600E', 'Mutation', 'rs113488022', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('V600E', 'Mutation', 'rs113488022', (296, 301))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Disease', (354, 359))	('induced', 'Reg', (302, 309))	('epileptogenesis', 'CPA', (310, 325))	('epileptic', 'Disease', (155, 164))	('mouse', 'Species', '10090', (229, 234))	('epileptic', 'Disease', 'MESH:D004827', (155, 164))	('mouse', 'Species', '10090', (75, 80))	('BRAF V600E', 'Var', (291, 301))	('mutation', 'Var', (46, 54))	('increased', 'PosReg', (127, 136))	('BRAF V600E', 'Gene', (24, 34))
48089	31085957	A large-scale study on DNET revealed that alterations of FGFR1 (duplication or point mutation) were predominant (58%) with no observed cases of BRAF alterations.	('FGFR1', 'Gene', (57, 62))	('point mutation', 'Var', (79, 93))	('alterations', 'Var', (42, 53))	('FGFR1', 'Gene', '2260', (57, 62))	('DNET', 'Chemical', '-', (23, 27))
48090	31085957	Previous small-scale studies reported the presence of BRAF alterations in up to 30% of DNET.	('alterations', 'Var', (59, 70))	('DNET', 'Disease', (87, 91))	('DNET', 'Chemical', '-', (87, 91))	('BRAF', 'Gene', (54, 58))
48091	31085957	The discrepancy in BRAF alterations can be explained by the fact that examining 'non-DNET' (DNET tissues that do not meet the strict WHO criteria in a central pathology review) revealed a lower frequency (19%) of FGFR1 mutations and a higher proportion (13%) of BRAF V600E mutations.	('lower', 'NegReg', (188, 193))	('V600E', 'Mutation', 'rs113488022', (267, 272))	('FGFR1', 'Gene', (213, 218))	('DNET', 'Chemical', '-', (92, 96))	('DNET', 'Chemical', '-', (85, 89))	('V600E', 'Var', (267, 272))	('FGFR1', 'Gene', '2260', (213, 218))	('BRAF', 'Gene', (262, 266))	('mutations', 'Var', (219, 228))
48098	31085957	As expected, group 1 was enriched for the BRAF V600E mutation, and group 2 was enriched for FGFR1 alterations.	('FGFR1', 'Gene', (92, 97))	('FGFR1', 'Gene', '2260', (92, 97))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('V600E', 'Var', (47, 52))	('BRAF', 'Gene', (42, 46))
48137	31085957	As we have seen, epilepsy-associated tumors, including many LEATs and pediatric-type DLGG, have a key driver mutation in BRAF, FGFR1, or MYB/MYBL1.	('BRAF', 'Gene', (121, 125))	('epilepsy-associated tumors', 'Disease', 'MESH:D004827', (17, 43))	('MYB', 'Gene', (141, 144))	('MYBL1', 'Gene', '4603', (141, 146))	('epilepsy', 'Phenotype', 'HP:0001250', (17, 25))	('mutation', 'Var', (109, 117))	('FGFR1', 'Gene', (127, 132))	('FGFR1', 'Gene', '2260', (127, 132))	('MYB', 'Gene', '4602', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('MYBL1', 'Gene', (141, 146))	('MYB', 'Gene', (137, 140))	('MYB', 'Gene', '4602', (141, 144))	('LEATs', 'Disease', (60, 65))	('epilepsy-associated tumors', 'Disease', (17, 43))	('pediatric-type DLGG', 'Disease', (70, 89))
48141	31085957	It is also interesting that the highly epileptogenic FCD is largely driven by somatic mutations of the PI3K-AKT-mTOR pathway, with which FGFR1 and MYB/MYBL1 are also involved.	('mutations', 'Var', (86, 95))	('driven by', 'Reg', (68, 77))	('FCD', 'Disease', (53, 56))	('FGFR1', 'Gene', (137, 142))	('MYB', 'Gene', '4602', (147, 150))	('FCD', 'Phenotype', 'HP:0032046', (53, 56))	('mTOR', 'Gene', '2475', (112, 116))	('FGFR1', 'Gene', '2260', (137, 142))	('MYBL1', 'Gene', (151, 156))	('mTOR', 'Gene', (112, 116))	('MYB', 'Gene', '4602', (151, 154))	('MYB', 'Gene', (151, 154))	('MYBL1', 'Gene', '4603', (151, 156))	('FCD', 'Disease', 'MESH:C563256', (53, 56))	('MYB', 'Gene', (147, 150))
48148	31085957	LEATs and pediatric type DLGG are characterized by major mutations in BRAF, FGFR1, and MYB/MYBL1.	('LEATs', 'Disease', (0, 5))	('MYB', 'Gene', '4602', (87, 90))	('MYBL1', 'Gene', (91, 96))	('MYB', 'Gene', (87, 90))	('MYB', 'Gene', '4602', (91, 94))	('MYB', 'Gene', (91, 94))	('mutations', 'Var', (57, 66))	('MYBL1', 'Gene', '4603', (91, 96))	('FGFR1', 'Gene', (76, 81))	('FGFR1', 'Gene', '2260', (76, 81))	('BRAF', 'Gene', (70, 74))
48173	21610707	Consequently, the biological behaviour of the glioma (e.g., whether it is stable or progressive) appears to be affected by the TMZ treatment (even at short delays).	('biological behaviour', 'CPA', (18, 38))	('glioma', 'Disease', (46, 52))	('TMZ', 'Var', (127, 130))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('affected', 'Reg', (111, 119))	('TMZ', 'Chemical', 'MESH:D000077204', (127, 130))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
48273	31609499	Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features "Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I).	('p.K385L', 'SUBSTITUTION', 'None', (398, 405))	('isoleucine', 'Chemical', 'MESH:D007532', (386, 396))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Myxoid glioneuronal tumor', 'Disease', (0, 25))	('PDGFRA', 'Gene', (330, 336))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (108, 126))	('Myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (0, 25))	('PDGFRA', 'Gene', '5156', (330, 336))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('p.K385-mutant', 'Var', (135, 148))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('PDGFRA', 'Gene', '5156', (27, 33))	('PDGFRA', 'Gene', (27, 33))	('leucine', 'Chemical', 'MESH:D007930', (375, 382))	('Myxoid glioneuronal tumor', 'Disease', (101, 126))	('Myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (101, 126))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('leucine', 'Chemical', 'MESH:D007930', (389, 396))	('p.K385L', 'Var', (398, 405))	('PDGFRA', 'Gene', '5156', (128, 134))	('PDGFRA', 'Gene', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor entity of the central nervous system', 'Phenotype', 'HP:0100006', (174, 216))	('lysine', 'Chemical', 'MESH:D008239', (356, 362))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (7, 25))	('tumor', 'Disease', (20, 25))
48278	31609499	Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.	('CNS tumor', 'Disease', 'MESH:D016543', (91, 100))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (35, 53))	('CNS tumor', 'Phenotype', 'HP:0100006', (91, 100))	('PDGFRA', 'Gene', (55, 61))	('CNS tumor', 'Disease', (91, 100))	('p.K385-mutant', 'Var', (62, 75))	('neoplasm', 'Disease', (186, 194))	('PDGFRA', 'Gene', '5156', (55, 61))	('neoplasm', 'Phenotype', 'HP:0002664', (186, 194))	('myxoid glioneuronal tumor', 'Disease', (28, 53))	('neoplasm', 'Disease', 'MESH:D009369', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (28, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
48279	31609499	"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system (CNS) that has a stereotypic location in the septum pellucidum and a characteristic dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I) in the encoded platelet-derived growth factor receptor alpha protein.	('lysine', 'Chemical', 'MESH:D008239', (269, 275))	('tumor', 'Disease', (21, 26))	('isoleucine', 'Chemical', 'MESH:D007532', (299, 309))	('stereotypic location', 'Phenotype', 'HP:0000733', (134, 154))	('platelet-derived growth factor receptor alpha', 'Gene', (337, 382))	('Myxoid glioneuronal tumor', 'Disease', (1, 26))	('tumor', 'Disease', (74, 79))	('p.K385-mutant', 'Var', (35, 48))	('Myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (1, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('PDGFRA', 'Gene', '5156', (28, 34))	('PDGFRA', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor entity of the central nervous system', 'Phenotype', 'HP:0100006', (74, 116))	('PDGFRA', 'Gene', '5156', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('PDGFRA', 'Gene', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('leucine', 'Chemical', 'MESH:D007930', (288, 295))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (337, 382))	('p.K385L', 'Var', (311, 318))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (8, 26))	('leucine', 'Chemical', 'MESH:D007930', (302, 309))	('p.K385L', 'SUBSTITUTION', 'None', (311, 318))
48281	31609499	However, they uniformly lack the well-defined mucin-patterned nodules of cortically-based DNT and also lack the BRAF and FGFR1 mutations or rearrangements that genetically characterize DNT, RGNT, and other low-grade neuroepithelial tumor entities.	('RGNT', 'Disease', (190, 194))	('DNT', 'Chemical', '-', (90, 93))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('RGNT', 'Phenotype', 'HP:0025171', (190, 194))	('DNT', 'Chemical', '-', (185, 188))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (216, 237))	('mucin', 'Gene', (46, 51))	('mutations', 'Var', (127, 136))	('FGFR1', 'Gene', '2260', (121, 126))	('rearrangements', 'Var', (140, 154))	('DNT', 'Disease', (185, 188))	('lack', 'NegReg', (24, 28))	('lack', 'NegReg', (103, 107))	('mucin', 'Gene', '100508689', (46, 51))	('neuroepithelial tumor', 'Disease', (216, 237))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (216, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('FGFR1', 'Gene', (121, 126))
48283	31609499	A recent study that combined genome-wide methylation profiling and sequencing analysis on a series of 11 cases of "septal dysembryoplastic neuroepithelial tumor" found that all 8 cases harboring PDGFRA p.K385L/I mutation formed a distinct methylation cluster separate from all other known CNS tumor entities, while the remaining few cases harboring NF1 or FGFR1 alterations instead clustered with other low-grade neuroepithelial tumors (e.g.	('NF1', 'Gene', (349, 352))	('CNS tumor', 'Disease', 'MESH:D016543', (289, 298))	('PDGFRA', 'Gene', '5156', (195, 201))	('PDGFRA', 'Gene', (195, 201))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (413, 435))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (139, 160))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('FGFR1', 'Gene', (356, 361))	('septal dysembryoplastic neuroepithelial tumor', 'Disease', (115, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (413, 435))	('p.K385L', 'Var', (202, 209))	('septal dysembryoplastic neuroepithelial tumor', 'Disease', 'MESH:D018302', (115, 160))	('CNS tumor', 'Phenotype', 'HP:0100006', (289, 298))	('CNS tumor', 'Disease', (289, 298))	('tumors', 'Phenotype', 'HP:0002664', (429, 435))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (413, 434))	('p.K385L', 'SUBSTITUTION', 'None', (202, 209))	('FGFR1', 'Gene', '2260', (356, 361))	('NF1', 'Gene', '4763', (349, 352))	('neuroepithelial tumors', 'Disease', (413, 435))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))
48286	31609499	Here, we report our experience with the clinical, radiologic, histopathologic, and molecular characteristics of eight cases of myxoid glioneuronal tumor, PDGFRA p.K385-mutant.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (127, 152))	('myxoid glioneuronal tumor', 'Disease', (127, 152))	('p.K385-mutant', 'Var', (161, 174))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (134, 152))	('PDGFRA', 'Gene', (154, 160))	('PDGFRA', 'Gene', '5156', (154, 160))
48287	31609499	Eight patients with low-grade glioneuronal tumors harboring the defining PDGFRA p.K385I or p.K385L dinucleotide substitution by targeted next-generation sequencing analysis were included in this study.	('p.K385L', 'Var', (91, 98))	('p.K385I', 'Mutation', 'p.K385I', (80, 87))	('p.K385L', 'Mutation', 'p.K385L', (91, 98))	('PDGFRA', 'Gene', (73, 79))	('PDGFRA', 'Gene', '5156', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('patients', 'Species', '9606', (6, 14))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (30, 48))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (30, 49))	('p.K385I', 'Var', (80, 87))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('glioneuronal tumors', 'Disease', (30, 49))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (30, 49))
48297	31609499	Capture-based next-generation DNA sequencing was performed using an assay that targets all coding exons of 479 cancer-related genes, select introns and upstream regulatory regions of 47 genes to enable detection of structural variants including gene fusions, and DNA segments at regular intervals along each chromosome to enable genome-wide copy number and zygosity analysis, with a total sequencing footprint of 2.8 Mb (Supplementary Table 1).	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('variants', 'Var', (226, 234))
48332	31609499	All eight cases harbored a dinucleotide substitution at codon 385 of the PDGFRA oncogene, resulting in either a lysine to leucine change (p.K385L, n=6) or a lysine to isoleucine change (p.K385I, n=2) (Figure 5 and Supplementary Table 2).	('p.K385I', 'Mutation', 'p.K385I', (186, 193))	('dinucleotide substitution at', 'Var', (27, 55))	('p.K385L', 'Mutation', 'p.K385L', (138, 145))	('leucine', 'Chemical', 'MESH:D007930', (122, 129))	('lysine', 'MPA', (157, 163))	('lysine to leucine change', 'MPA', (112, 136))	('PDGFRA', 'Gene', (73, 79))	('lysine', 'Chemical', 'MESH:D008239', (112, 118))	('PDGFRA', 'Gene', '5156', (73, 79))	('isoleucine', 'Chemical', 'MESH:D007532', (167, 177))	('leucine', 'Chemical', 'MESH:D007930', (170, 177))	('lysine', 'Chemical', 'MESH:D008239', (157, 163))
48333	31609499	The 20-44% allele frequencies of these PDGFRA p.K385L/I mutations are consistent with being clonal heterozygous somatic variants in each case.	('PDGFRA', 'Gene', (39, 45))	('p.K385L', 'SUBSTITUTION', 'None', (46, 53))	('PDGFRA', 'Gene', '5156', (39, 45))	('p.K385L', 'Var', (46, 53))
48334	31609499	This p.K385L/I mutation localizes within exon 8 that encodes one of the immunoglobulin-like C2 domains in the extracellular ligand-binding domain portion of the receptor tyrosine kinase (Figure 5B).	('p.K385L', 'Var', (5, 12))	('p.K385L', 'SUBSTITUTION', 'None', (5, 12))	('receptor tyrosine kinase', 'Gene', (161, 185))	('receptor tyrosine kinase', 'Gene', '5979', (161, 185))
48335	31609499	The PDGFRA mutation was the solitary somatic pathogenic alteration identified in all cases.	('mutation', 'Var', (11, 19))	('PDGFRA', 'Gene', '5156', (4, 10))	('PDGFRA', 'Gene', (4, 10))
48336	31609499	One tumor (MGNT #5) harbored trisomy 12q as the solitary copy number alteration observed.	('tumor', 'Disease', (4, 9))	('trisomy 12q', 'Var', (29, 40))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
48344	31609499	The myxoid glioneuronal tumor from the left periventricular region lacked the MYCN amplification and TP53 deletion observed in the medulloblastoma, but instead harbored PDGFRA p.K385I mutation which was not present in the medulloblastoma.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('myxoid glioneuronal tumor', 'Disease', (4, 29))	('TP53', 'Gene', (101, 105))	('harbored', 'Reg', (160, 168))	('medulloblastoma', 'Disease', 'MESH:D008527', (222, 237))	('medulloblastoma', 'Phenotype', 'HP:0002885', (222, 237))	('medulloblastoma', 'Disease', (222, 237))	('medulloblastoma', 'Disease', 'MESH:D008527', (131, 146))	('medulloblastoma', 'Phenotype', 'HP:0002885', (131, 146))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (11, 29))	('MYCN', 'Gene', '4613', (78, 82))	('medulloblastoma', 'Disease', (131, 146))	('TP53', 'Gene', '7157', (101, 105))	('PDGFRA', 'Gene', (169, 175))	('p.K385I', 'Var', (176, 183))	('PDGFRA', 'Gene', '5156', (169, 175))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (4, 29))	('MYCN', 'Gene', (78, 82))	('lacked', 'NegReg', (67, 73))	('p.K385I', 'Mutation', 'p.K385I', (176, 183))
48346	31609499	Thus, the contribution of the germline BRCA2 inactivating mutation to the development of the myxoid glioneuronal tumor, PDGFRA p.K385-mutant, in this child is uncertain.	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (100, 118))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (93, 118))	('BRCA2', 'Gene', (39, 44))	('child', 'Species', '9606', (150, 155))	('p.K385-mutant', 'Var', (127, 140))	('BRCA2', 'Gene', '675', (39, 44))	('myxoid glioneuronal tumor', 'Disease', (93, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PDGFRA', 'Gene', '5156', (120, 126))	('PDGFRA', 'Gene', (120, 126))
48359	31609499	PDGFRA activation via amplification, mutation, or intragenic deletion/rearrangement is known to be a frequent genetic driver amongst a select group of human tumor types including gastrointestinal stromal tumors, both pediatric and adult glioblastomas, and myxoid glioneuronal tumor.	('PDGFRA', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mutation', 'Var', (37, 45))	('PDGFRA', 'Gene', '5156', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('amplification', 'Var', (22, 35))	('deletion/rearrangement', 'Var', (61, 83))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (256, 281))	('myxoid glioneuronal tumor', 'Disease', (256, 281))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (179, 210))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (179, 210))	('human', 'Species', '9606', (151, 156))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (263, 281))	('tumor', 'Disease', (276, 281))	('activation', 'PosReg', (7, 17))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('glioblastomas', 'Phenotype', 'HP:0012174', (237, 250))	('tumor', 'Disease', (204, 209))	('adult glioblastomas', 'Disease', (231, 250))	('adult glioblastomas', 'Disease', 'MESH:D005909', (231, 250))	('gastrointestinal stromal tumors', 'Disease', (179, 210))
48360	31609499	In gastrointestinal stromal tumors lacking KIT mutations, there are frequent PDGFRA activating missense mutations that localize at a couple different mutational hotspots within the intracellular kinase domain (p.D842V and p.V561D).	('missense mutations', 'Var', (95, 113))	('p.D842V', 'Mutation', 'rs121908585', (210, 217))	('KIT', 'Gene', '3815', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (3, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (3, 34))	('KIT', 'Gene', (43, 46))	('p.V561D', 'Var', (222, 229))	('p.V561D', 'Mutation', 'rs121908586', (222, 229))	('activating', 'PosReg', (84, 94))	('p.D842V', 'Var', (210, 217))	('PDGFRA', 'Gene', '5156', (77, 83))	('PDGFRA', 'Gene', (77, 83))	('gastrointestinal stromal tumors', 'Disease', (3, 34))
48361	31609499	In both pediatric and adult glioblastomas, there is frequent amplification and overexpression of PDGFRA, which is commonly accompanied by intragenic deletions or various missense mutations on the amplified alleles.	('missense mutations', 'Var', (170, 188))	('amplification', 'MPA', (61, 74))	('glioblastomas', 'Phenotype', 'HP:0012174', (28, 41))	('PDGFRA', 'Gene', (97, 103))	('PDGFRA', 'Gene', '5156', (97, 103))	('overexpression', 'PosReg', (79, 93))	('accompanied', 'Reg', (123, 134))	('adult glioblastomas', 'Disease', 'MESH:D005909', (22, 41))	('deletions', 'Var', (149, 158))	('adult glioblastomas', 'Disease', (22, 41))
48362	31609499	A number of different recurrent missense mutations in PDGFRA have been identified in pediatric and adult glioblastomas (including p.C235Y, p.E229K, and p.Y288C), which also perturb the coding sequence of the extracellular ligand-binding domain.	('p.E229K', 'Var', (139, 146))	('missense mutations', 'Var', (32, 50))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('p.E229K', 'Mutation', 'p.E229K', (139, 146))	('p.Y288C', 'Var', (152, 159))	('p.Y288C', 'Mutation', 'p.Y288C', (152, 159))	('p.C235Y', 'Var', (130, 137))	('adult glioblastomas', 'Disease', (99, 118))	('identified', 'Reg', (71, 81))	('perturb', 'Reg', (173, 180))	('PDGFRA', 'Gene', '5156', (54, 60))	('PDGFRA', 'Gene', (54, 60))	('p.C235Y', 'Mutation', 'p.C235Y', (130, 137))	('adult glioblastomas', 'Disease', 'MESH:D005909', (99, 118))
48363	31609499	However, mutations at codon p.K385 of PDGFRA appear to be highly specific to "myxoid glioneuronal tumor, PDGFRA p.K385-mutant", as only 5 tumors among the greater than 83,000 tumors with sequencing data for the PDGFRA gene in the version 89 release of the Catalog of Somatic Mutations In Cancer (COSMIC) database harbor somatic variants at this codon.	('tumors', 'Disease', (175, 181))	('PDGFRA', 'Gene', (38, 44))	('PDGFRA', 'Gene', '5156', (38, 44))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (85, 103))	('variants', 'Var', (328, 336))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (288, 294))	('PDGFRA', 'Gene', (211, 217))	('PDGFRA', 'Gene', '5156', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('Cancer', 'Disease', (288, 294))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (78, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('PDGFRA', 'Gene', (105, 111))	('PDGFRA', 'Gene', '5156', (105, 111))	('myxoid glioneuronal tumor', 'Disease', (78, 103))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('Cancer', 'Disease', 'MESH:D009369', (288, 294))	('tumors', 'Disease', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('p.K385', 'Var', (28, 34))
48364	31609499	These five tumors in the current version of the COSMIC database with PDGFRA p.K385I (n=1) or p.K385M (n=4) mutations are all reportedly pediatric gliomas, with precise anatomic location and histologic diagnosis not clearly specified.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('p.K385I', 'Mutation', 'p.K385I', (76, 83))	('PDGFRA', 'Gene', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('p.K385M', 'Var', (93, 100))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('PDGFRA', 'Gene', '5156', (69, 75))	('p.K385I', 'Var', (76, 83))	('p.K385M', 'Mutation', 'p.K385M', (93, 100))
48365	31609499	While PDGFRA amplification and mutation/rearrangement are common in high-grade diffuse gliomas in both children and adults, these PDGFRA alterations invariably co-occur with other pathogenic alterations such as p.K27M mutation of H3F3A or HIST1H3B genes in diffuse midline gliomas, IDH1 p.R132H mutation in IDH-mutant glioblastomas, or TERT promoter mutation and CDKN2A deletion in IDH-wildtype glioblastomas.	('p.R132H', 'Var', (287, 294))	('H3F3A', 'Gene', '3020', (230, 235))	('midline gliomas', 'Disease', 'MESH:D005910', (265, 280))	('HIST1H3B', 'Gene', '8358', (239, 247))	('glioblastomas', 'Disease', 'MESH:D005909', (318, 331))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('IDH1', 'Gene', '3417', (282, 286))	('IDH', 'Gene', (382, 385))	('IDH', 'Gene', '3417', (282, 285))	('CDKN2A', 'Gene', '1029', (363, 369))	('glioblastomas', 'Disease', (395, 408))	('p.K27M', 'Mutation', 'p.K27M', (211, 217))	('PDGFRA', 'Gene', (6, 12))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('PDGFRA', 'Gene', '5156', (6, 12))	('H3F3A', 'Gene', (230, 235))	('glioblastomas', 'Disease', 'MESH:D005909', (395, 408))	('gliomas', 'Disease', (273, 280))	('IDH', 'Gene', '3417', (382, 385))	('PDGFRA', 'Gene', (130, 136))	('midline gliomas', 'Disease', (265, 280))	('PDGFRA', 'Gene', '5156', (130, 136))	('glioblastomas', 'Phenotype', 'HP:0012174', (318, 331))	('TERT', 'Gene', (336, 340))	('children', 'Species', '9606', (103, 111))	('IDH', 'Gene', (307, 310))	('TERT', 'Gene', '7015', (336, 340))	('deletion', 'Var', (370, 378))	('p.K27M', 'Var', (211, 217))	('gliomas', 'Disease', 'MESH:D005910', (273, 280))	('gliomas', 'Disease', (87, 94))	('IDH1', 'Gene', (282, 286))	('glioblastomas', 'Disease', (318, 331))	('IDH', 'Gene', (282, 285))	('CDKN2A', 'Gene', (363, 369))	('p.R132H', 'Mutation', 'rs121913500', (287, 294))	('glioblastomas', 'Phenotype', 'HP:0012174', (395, 408))	('IDH', 'Gene', '3417', (307, 310))	('gliomas', 'Phenotype', 'HP:0009733', (273, 280))	('HIST1H3B', 'Gene', (239, 247))
48366	31609499	PDGFRA mutation has not been identified as the solitary genetic driver in any CNS tumor entity to date other than "myxoid glioneuronal tumor, PDGFRA p.K385-mutant".	('CNS tumor', 'Phenotype', 'HP:0100006', (78, 87))	('PDGFRA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CNS tumor', 'Disease', (78, 87))	('PDGFRA', 'Gene', '5156', (0, 6))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (115, 140))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (122, 140))	('PDGFRA', 'Gene', '5156', (142, 148))	('PDGFRA', 'Gene', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('myxoid glioneuronal tumor', 'Disease', (115, 140))	('p.K385-mutant', 'Var', (149, 162))	('CNS tumor', 'Disease', 'MESH:D016543', (78, 87))
48367	31609499	This p.K385L/I mutation in PDGFRA localizes within exon 8 that encodes one of the immunoglobulin-like C2 domains in the extracellular ligand-binding domain portion of the receptor tyrosine kinase.	('p.K385L', 'Var', (5, 12))	('receptor tyrosine kinase', 'Gene', '5979', (171, 195))	('PDGFRA', 'Gene', '5156', (27, 33))	('PDGFRA', 'Gene', (27, 33))	('receptor tyrosine kinase', 'Gene', (171, 195))	('p.K385L', 'SUBSTITUTION', 'None', (5, 12))
48368	31609499	These mutations all result in substitution from a basic amino acid (lysine) to a hydrophobic amino acid (leucine or isoleucine).	('leucine', 'Chemical', 'MESH:D007930', (119, 126))	('result in', 'Reg', (20, 29))	('substitution', 'Var', (30, 42))	('isoleucine', 'Chemical', 'MESH:D007532', (116, 126))	('leucine', 'Chemical', 'MESH:D007930', (105, 112))	('lysine', 'Chemical', 'MESH:D008239', (68, 74))
48369	31609499	While the precise functional consequence of this recurrent p.K385L/I mutation in PDGFRA has yet to be elucidated, it is predicted to be an oncogenic, gain-of-function mutation that causes constitutive activation of the intracellular kinase domain in the absence of ligand.	('activation', 'PosReg', (201, 211))	('gain-of-function', 'PosReg', (150, 166))	('p.K385L', 'SUBSTITUTION', 'None', (59, 66))	('p.K385L', 'Var', (59, 66))	('PDGFRA', 'Gene', (81, 87))	('PDGFRA', 'Gene', '5156', (81, 87))
48370	31609499	It remains to be determined if these myxoid glioneuronal tumors with PDGFRA p.K385 mutation might perhaps be sensitive to small molecule tyrosine kinase inhibitors such as imatinib or dasatinib.	('myxoid glioneuronal tumor', 'Disease', (37, 62))	('p.K385', 'Var', (76, 82))	('imatinib', 'Chemical', 'MESH:D000068877', (172, 180))	('PDGFRA', 'Gene', (69, 75))	('PDGFRA', 'Gene', '5156', (69, 75))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (37, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('dasatinib', 'Chemical', 'MESH:D000069439', (184, 193))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (44, 62))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (44, 63))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('glioneuronal tumors', 'Disease', (44, 63))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (44, 63))	('sensitive', 'Reg', (109, 118))
48371	31609499	Together with the two prior reports, this study provides further support for "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" representing a distinct CNS tumor entity.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CNS tumor', 'Disease', 'MESH:D016543', (151, 160))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (78, 103))	('CNS tumor', 'Phenotype', 'HP:0100006', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (85, 103))	('PDGFRA', 'Gene', (105, 111))	('CNS tumor', 'Disease', (151, 160))	('PDGFRA', 'Gene', '5156', (105, 111))	('myxoid glioneuronal tumor', 'Disease', (78, 103))	('p.K385-mutant', 'Var', (112, 125))
48377	31609499	Unfortunately, many of the cases previously described as "dysembryoplastic neuroepithelial tumor-like neoplasm of the septum pellucidum" and intraventricular DNT have not been molecularly characterized, though it is likely that the majority represent "myxoid glioneuronal tumor, PDGFRA p.K385-mutant".	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('dysembryoplastic neuroepithelial tumor', 'Disease', (58, 96))	('myxoid glioneuronal tumor', 'Disease', (252, 277))	('neoplasm', 'Disease', 'MESH:D009369', (102, 110))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (259, 277))	('PDGFRA', 'Gene', '5156', (279, 285))	('PDGFRA', 'Gene', (279, 285))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (75, 96))	('myxoid glioneuronal tumor', 'Disease', 'MESH:D045888', (252, 277))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('dysembryoplastic neuroepithelial tumor', 'Disease', 'MESH:D018302', (58, 96))	('p.K385-mutant', 'Var', (286, 299))	('neoplasm', 'Disease', (102, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (102, 110))	('DNT', 'Chemical', '-', (158, 161))
48379	31286678	GATAD1 gene amplification promotes glioma malignancy by directly regulating CCND1 transcription The GATAD1 gene overexpression induced by GATAD1 amplification upregulation is detected in different human tumors.	('CCND1', 'Gene', (76, 81))	('glioma malignancy', 'Disease', (35, 52))	('glioma malignancy', 'Disease', 'MESH:D005910', (35, 52))	('GATAD1', 'Gene', (138, 144))	('GATAD1', 'Gene', '57798', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('amplification', 'Var', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('amplification', 'Var', (145, 158))	('tumors', 'Disease', (203, 209))	('overexpression', 'PosReg', (112, 126))	('GATAD1', 'Gene', '57798', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('human', 'Species', '9606', (197, 202))	('GATAD1', 'Gene', (0, 6))	('transcription', 'MPA', (82, 95))	('promotes', 'PosReg', (26, 34))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('CCND1', 'Gene', '595', (76, 81))	('GATAD1', 'Gene', '57798', (138, 144))	('regulating', 'Reg', (65, 75))	('GATAD1', 'Gene', (100, 106))	('upregulation', 'PosReg', (159, 171))
48380	31286678	To date, the relationship between GATAD1 amplification and glioma oncogenesis and malignancy is still unknown.	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('GATAD1', 'Gene', (34, 40))	('amplification', 'Var', (41, 54))	('glioma oncogenesis and malignancy', 'Disease', 'MESH:D005910', (59, 92))
48391	31286678	Furthermore, unraveling the oncogenic molecular mechanisms of the identified novel gene targets with copy number variation could also contribute to understand the glioma oncogenesis process and to develop better therapeutic methods to reduce mortality of patients.	('glioma oncogenesis', 'Disease', (163, 181))	('contribute', 'Reg', (134, 144))	('patients', 'Species', '9606', (255, 263))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('copy number variation', 'Var', (101, 122))	('glioma oncogenesis', 'Disease', 'MESH:D063646', (163, 181))
48392	31286678	CCND1, also named as cyclin D1, belongs to D cyclin family and drives the cell cycle progression of G1 to S phase.14, 15 The CCND1 overexpression or CCND1 downstream pathway  aberrant activation could directly promote neoplastic growth.	('CCND1', 'Gene', (125, 130))	('activation', 'PosReg', (184, 194))	('CCND1', 'Gene', (149, 154))	('aberrant', 'Var', (175, 183))	('neoplastic growth', 'CPA', (218, 235))	('CCND1', 'Gene', '595', (125, 130))	('overexpression', 'PosReg', (131, 145))	('CCND1', 'Gene', (0, 5))	('promote', 'PosReg', (210, 217))	('CCND1', 'Gene', '595', (149, 154))	('cyclin D1', 'Gene', '595', (21, 30))	('cyclin D1', 'Gene', (21, 30))	('CCND1', 'Gene', '595', (0, 5))
48393	31286678	Therefore CCND1 overexpression could be detected in different human tumors such as hepatocellular carcinoma, breast cancer and glioma.16, 17, 18  In this manuscript, we identified copy number amplification of GATA zinc finger domain containg 1 (GATAD1) in glioma tissues.	('CCND1', 'Gene', '595', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('copy number amplification', 'Var', (180, 205))	('CCND1', 'Gene', (10, 15))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('glioma', 'Disease', (256, 262))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('breast cancer', 'Disease', (109, 122))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('human', 'Species', '9606', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('glioma', 'Disease', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('tumors', 'Disease', (68, 74))	('GATAD1', 'Gene', (245, 251))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hepatocellular carcinoma', 'Disease', (83, 107))
48395	31286678	In this study, we characterized that, by targeting CCND1, GATAD1 gene amplification is associated with GATAD1 overexpression and glioma progression.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('CCND1', 'Gene', (51, 56))	('amplification', 'Var', (70, 83))	('CCND1', 'Gene', '595', (51, 56))	('associated', 'Reg', (87, 97))	('glioma', 'Disease', (129, 135))	('GATAD1', 'Gene', (58, 64))	('GATAD1', 'Gene', (103, 109))	('overexpression', 'PosReg', (110, 124))
48422	31286678	More importantly, we found that the incidences of GATAD1 amplification were correlated with the glioma grade.	('GATAD1', 'Gene', (50, 56))	('amplification', 'Var', (57, 70))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma', 'Disease', (96, 102))	('correlated', 'Reg', (76, 86))
48425	31286678	The above data suggested that the GATAD1 copy number amplification contributed to hyper-expression of GATAD1 and indicated higher WHO grade in glioma.	('hyper-expression', 'PosReg', (82, 98))	('copy number amplification', 'Var', (41, 66))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('higher', 'PosReg', (123, 129))	('GATAD1', 'Gene', (34, 40))	('GATAD1', 'Gene', (102, 108))	('glioma', 'Disease', (143, 149))	('WHO grade', 'CPA', (130, 139))
48429	31286678	We found that GATAD1 amplification conditions also indicated shorter DFS and OS in wild-type IDH1/2 or IDH mutation groups (Figure S1).	('shorter', 'NegReg', (61, 68))	('IDH1/2', 'Gene', (93, 99))	('IDH', 'Gene', (103, 106))	('IDH', 'Gene', (93, 96))	('IDH', 'Gene', '3417', (103, 106))	('DFS', 'MPA', (69, 72))	('IDH', 'Gene', '3417', (93, 96))	('IDH1/2', 'Gene', '3417;3418', (93, 99))	('mutation', 'Var', (107, 115))
48430	31286678	Univariate and multivariate Cox regression of the survival data was also performed; the statistics results showed that both GATAD1 gene amplification and GATAD1 hyper-expression were independent predictors of poorer survival of glioma patients (Tables S5-S8).	('GATAD1', 'Gene', (124, 130))	('poorer', 'NegReg', (209, 215))	('hyper-expression', 'Var', (161, 177))	('glioma', 'Disease', (228, 234))	('patients', 'Species', '9606', (235, 243))	('gene amplification', 'Var', (131, 149))	('GATAD1', 'Gene', (154, 160))	('amplification', 'Var', (136, 149))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('survival', 'MPA', (216, 224))
48432	31286678	The results indicated that knocking down of GATAD1 in GBM cells (GATAD1-sh1/2) could significantly repress the proliferation of U87MG and U251 cells (Figure 3A,B).	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('U87MG', 'CellLine', 'CVCL:0022', (128, 133))	('knocking down', 'Var', (27, 40))	('U251', 'CellLine', 'CVCL:0021', (138, 142))	('sh1', 'Gene', '100125848', (72, 75))	('proliferation', 'CPA', (111, 124))	('GATAD1', 'Gene', (44, 50))	('sh1', 'Gene', (72, 75))	('repress', 'NegReg', (99, 106))
48436	31286678	The results showed that knocking down of GATAD1 could inhibit GBM tumor growth in vivo (Figure 3C, upper panel).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('knocking down', 'Var', (24, 37))	('inhibit', 'NegReg', (54, 61))	('tumor', 'Disease', (66, 71))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('GATAD1', 'Gene', (41, 47))
48438	31286678	The KM results indicated that GATAD1 knockdown could prolong the survival time of xenografted mice (Figure 3D).	('survival time of xenografted mice', 'CPA', (65, 98))	('knockdown', 'Var', (37, 46))	('prolong', 'PosReg', (53, 60))	('GATAD1', 'Gene', (30, 36))	('mice', 'Species', '10090', (94, 98))
48444	31286678	The results confirmed that knocking down of GATAD1 would dramatically repress the expression of CCND1 in both U87MG and U251 cells (Figure 4D-E).	('U251', 'CellLine', 'CVCL:0021', (120, 124))	('expression', 'MPA', (82, 92))	('repress', 'NegReg', (70, 77))	('knocking down', 'Var', (27, 40))	('CCND1', 'Gene', '595', (96, 101))	('GATAD1', 'Gene', (44, 50))	('CCND1', 'Gene', (96, 101))	('U87MG', 'CellLine', 'CVCL:0022', (110, 115))
48449	31286678	However, knocking down GATAD1 in U87MG cells repressed CCND1 transcription activity to basal levels (Figure 5A).	('U87MG', 'CellLine', 'CVCL:0022', (33, 38))	('CCND1', 'Gene', '595', (55, 60))	('transcription activity', 'MPA', (61, 83))	('knocking down', 'Var', (9, 22))	('GATAD1', 'Gene', (23, 29))	('CCND1', 'Gene', (55, 60))
48455	31286678	The ChIP result of GATAD1 showed that knocking down of GATAD1 would specifically inhibit the binding of GATAD1 to CCND1 promoter (Figure 6A).	('knocking down', 'Var', (38, 51))	('GATAD1', 'Gene', (55, 61))	('CCND1', 'Gene', (114, 119))	('inhibit', 'NegReg', (81, 88))	('binding', 'Interaction', (93, 100))	('CCND1', 'Gene', '595', (114, 119))
48456	31286678	Then we used ChIP-qPCR to detect the histone modification condition after GATAD1 knockdown, the result showed that, in both GBM cells, GATAD1 shRNA transfection would inhibit the histone H3K9Ac and H3K27Ac modification of GATAD1 binding sites on CCND1 promoter (Figure 6B,C).	('H3K27Ac', 'Protein', (198, 205))	('CCND1', 'Gene', (246, 251))	('histone H3K9Ac', 'Protein', (179, 193))	('inhibit', 'NegReg', (167, 174))	('CCND1', 'Gene', '595', (246, 251))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))	('transfection', 'Var', (148, 160))	('GATAD1', 'Var', (135, 141))
48463	31286678	We then rehabilitated CCND1 expression in GATAD1 knocking down cells to confirm the importance of CCND1 to GATAD1-promoted GBM proliferation.	('knocking', 'Var', (49, 57))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', (98, 103))	('CCND1', 'Gene', '595', (22, 27))	('CCND1', 'Gene', '595', (98, 103))	('GBM proliferation', 'CPA', (123, 140))
48470	31286678	These results suggested that GATAD1 overexpression in glioma is mostly induced by GATAD1 gene amplification.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('gene amplification', 'Var', (89, 107))	('induced', 'Reg', (71, 78))	('GATAD1', 'Gene', (29, 35))	('overexpression', 'PosReg', (36, 50))	('glioma', 'Disease', (54, 60))	('GATAD1', 'Gene', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
48472	31286678	These results suggested that, compared to other genetic and epigenetic regulation mechanisms, gene amplification is the main reason for GATAD1 overexpression in glioma samples.	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('gene amplification', 'Var', (94, 112))	('overexpression', 'PosReg', (143, 157))	('GATAD1', 'Gene', (136, 142))	('glioma', 'Disease', (161, 167))
48475	31286678	GATAD1 gene amplification and overexpression could be a promising prognosis factor for all grades of glioma patients.	('glioma', 'Disease', (101, 107))	('amplification', 'Var', (12, 25))	('overexpression', 'PosReg', (30, 44))	('patients', 'Species', '9606', (108, 116))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('GATAD1', 'Gene', (0, 6))
48481	31286678	The GATAD1 shRNA transfection significantly inhibited the proliferation of glioma cell.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('shRNA', 'Gene', (11, 16))	('inhibited', 'NegReg', (44, 53))	('transfection', 'Var', (17, 29))	('glioma', 'Disease', (75, 81))	('GATAD1 shRNA', 'Gene', (4, 16))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
48488	31286678	The mechanism of GATAD1 amplification promoting glioma cell proliferation was mediated by CCND1.	('CCND1', 'Gene', (90, 95))	('promoting', 'PosReg', (38, 47))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('CCND1', 'Gene', '595', (90, 95))	('amplification', 'Var', (24, 37))	('GATAD1', 'Gene', (17, 23))	('glioma', 'Disease', (48, 54))
48489	31286678	In summary, we identified that GATAD1 gene copy amplification induced GATAD1 overexpression and played an oncogenetic role in patients with glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('overexpression', 'PosReg', (77, 91))	('gene copy amplification', 'Var', (38, 61))	('GATAD1', 'Gene', (31, 37))	('induced', 'Reg', (62, 69))	('patients', 'Species', '9606', (126, 134))	('glioma', 'Disease', (140, 146))	('GATAD1', 'Gene', (70, 76))
48491	31286678	Univariate and multivariate survival analysis showed that amplification and expression level of GATAD1 were independent predictors of poorer survival of glioma patients, which provided a strong rationale for focusing on GATAD1 in malignant glioma diagnosis and therapy.	('GATAD1', 'Gene', (96, 102))	('glioma', 'Disease', (240, 246))	('patients', 'Species', '9606', (160, 168))	('glioma', 'Disease', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('expression level', 'MPA', (76, 92))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('malignant glioma', 'Disease', (230, 246))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('malignant glioma', 'Disease', 'MESH:D005910', (230, 246))	('amplification', 'Var', (58, 71))	('poorer', 'NegReg', (134, 140))
48493	30877769	Molecular classification of IDH-mutant glioblastomas based on gene expression profiles Isocitrate dehydrogenase (IDH) mutant glioblastoma (GBM), accounts for ~10% GBMs, arises from lower grade diffuse glioma and preferentially appears in younger patients.	('glioblastoma', 'Disease', (39, 51))	('patients', 'Species', '9606', (246, 254))	('IDH', 'Gene', '3417', (28, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('glioblastomas', 'Disease', (39, 52))	('glioblastoma', 'Disease', (125, 137))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('IDH', 'Gene', '3417', (113, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('glioma', 'Disease', (201, 207))	('glioblastomas', 'Disease', 'MESH:D005909', (39, 52))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))	('mutant', 'Var', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('glioblastomas', 'Phenotype', 'HP:0012174', (39, 52))	('IDH', 'Gene', (28, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('IDH', 'Gene', (113, 116))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
48504	30877769	The Cancer Genome Atlas (TCGA) reported an integrative analysis of DNA copy number, expression and DNA methylation aberrations in 206 GBMs, confirming biologically relevant abnormalities in three core pathways, namely TP53, RB and receptor tyrosine kinase (RTK)/Ras/phosphoinositide 3-kinase (PI3K) signaling.	('RB', 'Disease', 'MESH:D012175', (224, 226))	('copy', 'Var', (71, 75))	('RTK', 'Gene', '5979', (257, 260))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('abnormalities', 'Reg', (173, 186))	('aberrations', 'Var', (115, 126))	('receptor tyrosine kinase', 'Gene', (231, 255))	('TP53', 'Gene', '7157', (218, 222))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('receptor tyrosine kinase', 'Gene', '5979', (231, 255))	('Cancer Genome Atlas', 'Disease', (4, 23))	('TP53', 'Gene', (218, 222))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('RTK', 'Gene', (257, 260))
48548	30877769	Kaplan-Meier analysis found that high-risk score conferred reduced OS in this cohort (Figure 5A).	('OS', 'Chemical', '-', (67, 69))	('reduced', 'NegReg', (59, 66))	('high-risk score', 'Var', (33, 48))
48569	30877769	Most of these genes had been studied widely in various tumors except LOC100506474.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('LOC100506474', 'Var', (69, 81))
48571	30877769	High expression of these genes was associated with poor outcome except DEDD (Supplementary Figure 9B, available at Carcinogenesis Online).	('DEDD', 'Gene', '9191', (71, 75))	('DEDD', 'Gene', (71, 75))	('High', 'Var', (0, 4))
48577	30738431	Widely metastatic IDH1-mutant glioblastoma with oligodendroglial features and atypical molecular findings: a case report and review of current challenges in molecular diagnostics Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy.	('mutation', 'Var', (221, 229))	('glioblastoma', 'Disease', (30, 42))	('oligodendrogliomas', 'Disease', (297, 315))	('glioblastoma', 'Disease', 'MESH:D005909', (30, 42))	('IDH1', 'Gene', '3417', (18, 22))	('Gliomas', 'Disease', 'MESH:D005910', (179, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (233, 265))	('1p/19q-codeletion', 'Var', (192, 209))	('gliomas', 'Phenotype', 'HP:0009733', (308, 315))	('oligodendroglial features', 'Phenotype', 'HP:0100709', (48, 73))	('Gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (297, 315))	('Gliomas', 'Disease', (179, 186))	('IDH1', 'Gene', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (308, 314))
48578	30738431	We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH1', 'Gene', '3417', (49, 53))	('abnormalities', 'Var', (93, 106))	('mutant', 'Var', (63, 69))	('man', 'Species', '9606', (37, 40))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('widespread metastatic disease', 'Disease', (201, 230))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (145, 173))	('glioma', 'Disease', (167, 173))	('glioma', 'Disease', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('anaplastic oligodendroglioma', 'Disease', (145, 173))	('IDH1', 'Gene', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
48583	30738431	Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('alterations', 'Var', (39, 50))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
48584	30738431	The understanding of molecular features of diffuse gliomas has been revolutionized by the discovery of two distinct molecular markers: complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) (1p/19q-codeletion) in oligodendroglial tumors, as well as mutations of the isocitrate dehydrogenase (IDH) 1 or 2 genes in oligodendrogliomas and a subset of astrocytic tumors.	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('mutations', 'Var', (295, 304))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('gliomas', 'Disease', (370, 377))	('oligodendrogliomas', 'Disease', (359, 377))	('glioma', 'Phenotype', 'HP:0009733', (370, 376))	('gliomas', 'Disease', (51, 58))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (312, 344))	('gliomas', 'Disease', 'MESH:D005910', (370, 377))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('oligodendroglial tumors', 'Disease', (259, 282))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('astrocytic tumors', 'Disease', (394, 411))	('gliomas', 'Phenotype', 'HP:0009733', (370, 377))	('tumors', 'Phenotype', 'HP:0002664', (405, 411))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (259, 282))	('astrocytic tumors', 'Disease', 'MESH:D001254', (394, 411))	('short arm', 'Phenotype', 'HP:0009824', (165, 174))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (359, 377))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))
48587	30738431	Further analysis of the data illustrated that patients whose tumors harbored an IDH1 mutation in addition to a 1p/19q-codeletion fared better overall compared to patients with co-deletion alone.	('patients', 'Species', '9606', (162, 170))	('tumors', 'Disease', (61, 67))	('IDH1', 'Gene', (80, 84))	('patients', 'Species', '9606', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('a 1p', 'Gene', '28881', (109, 113))	('a 1p', 'Gene', (109, 113))	('IDH1', 'Gene', '3417', (80, 84))	('mutation', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
48589	30738431	Although the biological effect of 1p/19q-codeletion remains unclear, it is considered the diagnostic molecular signature of oligodendrogliomas.	('oligodendrogliomas', 'Disease', (124, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('1p/19q-codeletion', 'Var', (34, 51))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (124, 142))
48590	30738431	There are several different methods that have been used to identify patients whose tumors harbor 1p/19q-codeletion; however, there is no consensus over which test should be used clinically.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('1p/19q-codeletion', 'Var', (97, 114))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (83, 89))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
48591	30738431	Array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array are capable of identifying loss of the whole arm of 1p or 19q with higher reliability but introduce additional interpretative challenges in samples with low tumor purity or high tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('low tumor purity', 'Disease', (247, 263))	('loss', 'NegReg', (121, 125))	('high tumor', 'Disease', (267, 277))	('single', 'Var', (51, 57))	('low tumor purity', 'Disease', 'MESH:D009800', (247, 263))	('high tumor', 'Disease', 'MESH:D009369', (267, 277))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
48592	30738431	Here we present a case of a young man with a high grade IDH1-mutant glioma with abnormalities in chromosomes 1 and 19 who experienced an unusually aggressive disease progression following standard therapy for anaplastic oligodendrogliomas.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (209, 238))	('anaplastic oligodendrogliomas', 'Disease', (209, 238))	('man', 'Species', '9606', (34, 37))	('IDH1', 'Gene', '3417', (56, 60))	('glioma', 'Disease', (231, 237))	('aggressive disease', 'Disease', 'MESH:D001523', (147, 165))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('abnormalities in', 'Var', (80, 96))	('aggressive disease', 'Disease', (147, 165))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (231, 237))	('IDH1', 'Gene', (56, 60))
48593	30738431	This case illustrates the clinical impact that variations of otherwise favorable prognostic markers can have on clinical outcome and it highlights current molecular diagnostic challenges in characterizing glial neoplasms.	('glial neoplasms', 'Disease', 'MESH:D005910', (205, 220))	('neoplasms', 'Phenotype', 'HP:0002664', (211, 220))	('neoplasm', 'Phenotype', 'HP:0002664', (211, 219))	('glial neoplasms', 'Disease', (205, 220))	('variations', 'Var', (47, 57))
48597	30738431	The tumor was found to be IDH1 and TP53 mutant by amplicon-based next generation sequencing (NGS) targeting the hotspot regions of 27 cancer associated genes (not including ATRX), and had monosomy 1 and 19q loss by single nucleotide polymorphism (SNP) array (Figs.	('tumor', 'Disease', (4, 9))	('IDH1', 'Gene', '3417', (26, 30))	('loss', 'NegReg', (207, 211))	('ATRX', 'Gene', '546', (173, 177))	('TP53', 'Gene', '7157', (35, 39))	('IDH1', 'Gene', (26, 30))	('cancer', 'Disease', (134, 140))	('TP53', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutant', 'Var', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ATRX', 'Gene', (173, 177))
48619	30738431	Further analysis of the patient's tumor tissue using a targeted, capture-based next generation sequencing panel covering the full coding regions of 644 cancer associated genes showed the presence of a number of additional genetic alterations (Table 1), including an ATRX missense mutation, and amplification of MYCN, MET, and CDK4.	('missense mutation', 'Var', (271, 288))	('cancer', 'Disease', (152, 158))	('ATRX', 'Gene', '546', (266, 270))	('tumor', 'Disease', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('MYCN', 'Gene', '4613', (311, 315))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('amplification', 'Var', (294, 307))	('CDK4', 'Gene', (326, 330))	('patient', 'Species', '9606', (24, 31))	('MET', 'Gene', (317, 320))	('CDK4', 'Gene', '1019', (326, 330))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ATRX', 'Gene', (266, 270))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('MYCN', 'Gene', (311, 315))
48628	30738431	Temozolomide is also viewed as a reasonable option for 1p/19q-codeleted tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))	('1p/19q-codeleted', 'Var', (55, 71))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
48632	30738431	Foremost, the chromosome 1 and 19 alterations are not typical of those seen in oligodendrogliomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (79, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('oligodendrogliomas', 'Disease', (79, 97))	('alterations', 'Var', (34, 45))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
48633	30738431	1p/19q-codeletion represents an unbalanced centromeric whole-arm chromosomal translocation (with the loss of the derivative chromosome) t (1;19) (q10;p10) in which both the entire 1p and 19q arm are lost.	('p10', 'Gene', (150, 153))	('p10', 'Gene', '6281', (150, 153))	('1p/19q-codeletion', 'Var', (0, 17))
48639	30738431	Furthermore, the presence of concurrent IDH and TP53 mutations are now considered molecular hallmark features of diffuse and anaplastic astrocytomas (WHO grades II and III), as well as clinicopathologically defined secondary glioblastoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('anaplastic astrocytomas', 'Disease', (125, 148))	('TP53', 'Gene', '7157', (48, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (225, 237))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('IDH', 'Gene', (40, 43))	('IDH', 'Gene', '3417', (40, 43))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (125, 148))	('glioblastoma', 'Disease', (225, 237))	('glioblastoma', 'Disease', 'MESH:D005909', (225, 237))
48640	30738431	Also characteristic of diffuse adult IDH-mutant astrocytic tumors are truncating ATRX mutations with loss of nuclear ATRX expression by immunohistochemistry.	('astrocytic tumors', 'Disease', (48, 65))	('ATRX', 'Gene', (81, 85))	('mutations', 'Var', (86, 95))	('loss', 'NegReg', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('astrocytic tumors', 'Disease', 'MESH:D001254', (48, 65))	('ATRX', 'Gene', '546', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('ATRX', 'Gene', (117, 121))	('IDH', 'Gene', (37, 40))	('ATRX', 'Gene', '546', (117, 121))	('truncating', 'MPA', (70, 80))	('IDH', 'Gene', '3417', (37, 40))
48641	30738431	In this case, however, ATRX immunoexpression was retained and the ATRX mutation was not definitively deleterious, despite being located in an evolutionarily highly conserved functional domain of the gene (Snf2 ATPase) and classified as probably damaging/disease causing by three in silico prediction callers (PolyPhen-2, MutationTaster, SIFT/PROVEAN).	('ATPase', 'Gene', '1769', (210, 216))	('mutation', 'Var', (71, 79))	('SIFT', 'Disease', (337, 341))	('ATRX', 'Gene', '546', (23, 27))	('damaging/disease causing', 'Reg', (245, 269))	('ATPase', 'Gene', (210, 216))	('ATRX', 'Gene', (66, 70))	('SIFT', 'Disease', 'None', (337, 341))	('Snf2', 'Gene', '6597', (205, 209))	('ATRX', 'Gene', '546', (66, 70))	('Snf2', 'Gene', (205, 209))	('ATRX', 'Gene', (23, 27))
48642	30738431	A closer a look at the literature reveals that somatic ATRX missense mutations are detected in a subset of adult gliomas.	('detected', 'Reg', (83, 91))	('adult gliomas', 'Disease', (107, 120))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('missense mutations', 'Var', (60, 78))	('ATRX', 'Gene', (55, 59))	('adult gliomas', 'Disease', 'MESH:D005910', (107, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('ATRX', 'Gene', '546', (55, 59))
48643	30738431	Interpretation of ATRX staining is especially problematic in these cases, since tumors with missense mutations that result in loss of protein function will continue to show protein expression and nuclear localization.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('show', 'Reg', (168, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('ATRX', 'Gene', (18, 22))	('protein expression', 'MPA', (173, 191))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('ATRX', 'Gene', '546', (18, 22))	('nuclear localization', 'MPA', (196, 216))	('missense mutations', 'Var', (92, 110))
48644	30738431	Similarly, not all insertions/deletions or nonsense will show loss of nuclear ATRX expression.	('loss', 'NegReg', (62, 66))	('ATRX', 'Gene', (78, 82))	('ATRX', 'Gene', '546', (78, 82))	('nuclear', 'MPA', (70, 77))	('nonsense', 'Var', (43, 51))	('insertions/deletions', 'Var', (19, 39))
48645	30738431	Further complicating diagnostic interpretation are the lack of standard criteria for what constitutes loss of ATRX expression, which is often used as a surrogate marker for ATRX mutations in gliomas, and the presence of intratumoral heterogeneity.	('ATRX', 'Gene', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('gliomas', 'Disease', (191, 198))	('ATRX', 'Gene', '546', (173, 177))	('ATRX', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('tumor', 'Disease', (225, 230))	('expression', 'MPA', (115, 125))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('loss', 'NegReg', (102, 106))	('ATRX', 'Gene', '546', (110, 114))	('mutations', 'Var', (178, 187))
48656	30738431	compared mutation, copy number, gene expression, and DNA methylation data of 41 IDH1-mutant grade II and III gliomas (including oligodendrogliomas and astrocytomas) obtained at their initial diagnosis to their progressed counterparts and found that amplification of the MYC locus (22% of patients) on chromosome 8q was significantly associated with progression as were alterations in the individual MYC signaling components FBXW7 and MAX and the MYC-related FOXM1 locus on 12p.	('FOXM1', 'Gene', (458, 463))	('MYC', 'Gene', (399, 402))	('FBXW7', 'Gene', '55294', (424, 429))	('associated', 'Reg', (333, 343))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('MYC', 'Gene', (446, 449))	('IDH1', 'Gene', (80, 84))	('III gliomas', 'Disease', 'MESH:D005910', (105, 116))	('amplification', 'Var', (249, 262))	('alterations', 'Var', (369, 380))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('MYC', 'Gene', (270, 273))	('MYC', 'Gene', '4609', (399, 402))	('patients', 'Species', '9606', (288, 296))	('IDH1', 'Gene', '3417', (80, 84))	('FOXM1', 'Gene', '2305', (458, 463))	('astrocytoma', 'Phenotype', 'HP:0009592', (151, 162))	('MYC', 'Gene', '4609', (446, 449))	('III gliomas', 'Disease', (105, 116))	('FBXW7', 'Gene', (424, 429))	('MYC', 'Gene', '4609', (270, 273))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('oligodendrogliomas and astrocytomas', 'Disease', 'MESH:D009837', (128, 163))	('progression', 'Disease', (349, 360))
48657	30738431	Of note, deletion of the CDKN2A-CDKN2B tumor suppressor locus was the most frequent copy number alteration detected in the cohort, occurring in 44% of all tumors analyzed.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('CDKN2A', 'Gene', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deletion', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CDKN2B', 'Gene', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('CDKN2B', 'Gene', '1030', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', (39, 44))	('CDKN2A', 'Gene', '1029', (25, 31))
48658	30738431	Neither amplification of MYC nor deletion of CDKN2A-CDKN2B were shown to be enriched in either of the oligodendroglial or astrocytic subtypes.	('MYC', 'Gene', (25, 28))	('deletion', 'Var', (33, 41))	('MYC', 'Gene', '4609', (25, 28))	('CDKN2A', 'Gene', (45, 51))	('CDKN2B', 'Gene', (52, 58))	('CDKN2B', 'Gene', '1030', (52, 58))	('CDKN2A', 'Gene', '1029', (45, 51))
48660	30738431	Cells with IDH1 copy number alterations (deletion or amplification of the mutant or wild-type allele) were also shown to occupy a substantial portion of the recurrent tumor in these cases, suggesting a growth advantage, as well as have hypomethylation of non-CpG island CpG sites.	('IDH1', 'Gene', '3417', (11, 15))	('amplification', 'Var', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('deletion', 'Var', (41, 49))	('growth advantage', 'CPA', (202, 218))	('hypomethylation', 'Var', (236, 251))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutant', 'Var', (74, 80))	('tumor', 'Disease', (167, 172))	('IDH1', 'Gene', (11, 15))
48661	30738431	details malignant progression of an IDH1-mutant glioma through whole-genome doubling, evolution of a double-minute chromosome containing PDGFRA, KIT, CDK4, AVIL, and miR-26a-2 (regulator of PTEN), and loss of the mutated IDH1 allele with retention of the wild-type allele.	('PTEN', 'Gene', '5728', (190, 194))	('CDK4', 'Gene', '1019', (150, 154))	('IDH1', 'Gene', (221, 225))	('miR-26a-2', 'Gene', '407016', (166, 175))	('loss', 'NegReg', (201, 205))	('miR-26a-2', 'Gene', (166, 175))	('glioma', 'Disease', (48, 54))	('IDH1', 'Gene', (36, 40))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('IDH1', 'Gene', '3417', (221, 225))	('PDGFRA', 'Gene', '5156', (137, 143))	('PDGFRA', 'Gene', (137, 143))	('PTEN', 'Gene', (190, 194))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('AVIL', 'Gene', (156, 160))	('AVIL', 'Gene', '10677', (156, 160))	('IDH1', 'Gene', '3417', (36, 40))	('CDK4', 'Gene', (150, 154))	('mutated', 'Var', (213, 220))
48666	30738431	Of particular interest are non-lineage specific alterations implicated as drivers of higher grade and progressive IDH-mutant diffuse gliomas and associated with shorter progression-free survival.	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('shorter', 'NegReg', (161, 168))	('IDH', 'Gene', (114, 117))	('alterations', 'Var', (48, 59))	('IDH', 'Gene', '3417', (114, 117))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))
48668	30738431	Amplification of MYCN, as seen in this case, has been previously reported in a subset of glioblastomas and IDH-mutant gliomas by multiple groups.	('MYCN', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('MYCN', 'Gene', '4613', (17, 21))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('reported', 'Reg', (65, 73))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('glioblastomas', 'Phenotype', 'HP:0012174', (89, 102))	('IDH', 'Gene', (107, 110))	('glioblastomas', 'Disease', 'MESH:D005909', (89, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('IDH', 'Gene', '3417', (107, 110))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioblastomas', 'Disease', (89, 102))
48671	30738431	of malignant gliomas with primitive neuronal components (MG-PNET), which are enriched for MYCN amplifications, showed no difference in overall survival between MG-PNETs and conventional glioblastoma.	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('malignant gliomas', 'Disease', (3, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('malignant gliomas', 'Disease', 'MESH:D005910', (3, 20))	('MYCN', 'Gene', (90, 94))	('MYCN', 'Gene', '4613', (90, 94))	('glioblastoma', 'Disease', (186, 198))	('MG-PNETs', 'Var', (160, 168))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))
48673	30738431	Amplification of MYCN is also associated with poor prognosis in medulloblastomas, and strongly predicts a poorer prognosis in both time to tumor progression and overall survival in all stages of neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (195, 208))	('MYCN', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('medulloblastomas', 'Disease', (64, 80))	('poorer', 'NegReg', (106, 112))	('poor', 'NegReg', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('MYCN', 'Gene', '4613', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('neuroblastoma', 'Disease', 'MESH:D009447', (195, 208))	('neuroblastoma', 'Disease', (195, 208))	('medulloblastomas', 'Disease', 'MESH:D008527', (64, 80))
48674	30738431	High grade diffuse midline gliomas, H3-K27 M mutant, are also particularly enriched for MYCN, MET, and CDK4 amplifications and usually characterized by poor clinical outcome.	('H3-K27 M', 'Var', (36, 44))	('CDK4', 'Gene', '1019', (103, 107))	('MYCN', 'Gene', '4613', (88, 92))	('midline gliomas', 'Disease', (19, 34))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('MET', 'Disease', (94, 97))	('midline gliomas', 'Disease', 'MESH:D005910', (19, 34))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('amplifications', 'Var', (108, 122))	('MYCN', 'Gene', (88, 92))	('CDK4', 'Gene', (103, 107))	('K27 M', 'Mutation', 'p.K27M', (39, 44))
48675	30738431	Our own analysis of the TCGA Merged Cohort of LGG and GBM dataset revealed MYCN amplification in 18 of 794 (2%) sequenced cases/patients with copy number data.	('MYCN', 'Gene', (75, 79))	('amplification', 'Var', (80, 93))	('MYCN', 'Gene', '4613', (75, 79))	('copy', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))
48677	30738431	IDH1 mutations were present in 39% (7 of 18) of MYCN amplified glioma cases and TP53 mutations in 67% (12 of 18).	('IDH1', 'Gene', '3417', (0, 4))	('MYCN', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (80, 84))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (80, 84))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('MYCN', 'Gene', '4613', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', (0, 4))	('glioma', 'Disease', (63, 69))
48681	30738431	IDH1/2 mutations were present in 45% (15 of 33) of cases.	('IDH1/2', 'Gene', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('mutations', 'Var', (7, 16))
48682	30738431	The most frequent co-amplification involved EGFR in 27% of cases (9 of 33, two of which also had concurrent IDH1 mutations), followed by PDGFRA in 24% (8 of 33, two of which also had EGFR amplification).	('IDH1', 'Gene', '3417', (108, 112))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('mutations', 'Var', (113, 122))	('PDGFRA', 'Gene', '5156', (137, 143))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('co-amplification', 'Var', (18, 34))	('IDH1', 'Gene', (108, 112))	('PDGFRA', 'Gene', (137, 143))
48687	30738431	First, although there is growing knowledge regarding the importance of 1p/19q-codeletion and IDH1 mutations in the clinical care of patients with oligodendrogliomas, we still have limited understanding of how to address cases with less common aberrations involving discordant clonal populations with 1p and/or 19q deletion and deletions involving both arms of either chromosome 1 or 19.	('IDH1', 'Gene', (93, 97))	('oligodendrogliomas', 'Disease', (146, 164))	('IDH1', 'Gene', '3417', (93, 97))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('mutations', 'Var', (98, 107))	('deletions', 'Var', (327, 336))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (146, 164))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('patients', 'Species', '9606', (132, 140))
48689	30738431	Lastly, current molecular testing guidelines for gliomas by the National Comprehensive Cancer Network  (NCCN ) are limited to 1p/19q-codeletion or loss of heterozygosity (LOH), IDH1/2 mutations, and MGMT promoter methylation.	('MGMT', 'Gene', '4255', (199, 203))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('IDH1/2', 'Gene', (177, 183))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (184, 193))	('loss of heterozygosity', 'Var', (147, 169))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1/2', 'Gene', '3417;3418', (177, 183))	('Cancer', 'Disease', (87, 93))	('gliomas', 'Disease', (49, 56))	('MGMT', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
48818	30066946	Furthermore, the biological implication of aberrant CKAP2 expression in high-grade glioma (HGG) was investigated using Gene Ontology analysis, gene set enrichment analysis, gene set variation analysis and STRING.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('CKAP2', 'Gene', '26586', (52, 57))	('CKAP2', 'Gene', (52, 57))	('aberrant', 'Var', (43, 51))
48821	30066946	Furthermore, CKAP2 was also positively correlated with known malignant factors, including high Ki67 expression and phosphatase and tensin homolog mutations.	('mutations', 'Var', (146, 155))	('correlated', 'Reg', (39, 49))	('CKAP2', 'Gene', '26586', (13, 18))	('CKAP2', 'Gene', (13, 18))	('Ki67 expression', 'Protein', (95, 110))
48831	30066946	Furthermore, various tumor-specific molecular alterations have been associated with glioma, in particular, isocitrate dehydrogenase 1 (IDH1) mutations, 1p/19q co-deletion, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation and epidermal growth factor receptor variant III amplification have been identified as predictive and prognostic indicators, and/or therapeutic targets for patients with glioma.	('tumor', 'Disease', (21, 26))	('O6-methylguanine DNA methyltransferase', 'Gene', (172, 210))	('patients', 'Species', '9606', (395, 403))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('isocitrate dehydrogenase 1', 'Gene', (107, 133))	('isocitrate dehydrogenase 1', 'Gene', '3417', (107, 133))	('glioma', 'Disease', (409, 415))	('IDH1', 'Gene', (135, 139))	('glioma', 'Disease', 'MESH:D005910', (409, 415))	('MGMT', 'Gene', '4255', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('epidermal growth factor receptor', 'Gene', (243, 275))	('mutations', 'Var', (141, 150))	('epidermal growth factor receptor', 'Gene', '1956', (243, 275))	('glioma', 'Phenotype', 'HP:0009733', (409, 415))	('IDH1', 'Gene', '3417', (135, 139))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (172, 210))	('associated', 'Reg', (68, 78))	('glioma', 'Disease', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('MGMT', 'Gene', (212, 216))
48841	30066946	Furthermore, univariate and multivariate Cox regression analyses demonstrated that high CKAP2 expression appeared to be a predictor for poor clinical outcomes in patients with HGG.	('patients', 'Species', '9606', (162, 170))	('CKAP2', 'Gene', '26586', (88, 93))	('CKAP2', 'Gene', (88, 93))	('HGG', 'Disease', (176, 179))	('Cox', 'Gene', '1351', (41, 44))	('Cox', 'Gene', (41, 44))	('high', 'Var', (83, 87))	('expression', 'MPA', (94, 104))
48853	30066946	1800; ScienCell Research Laboratories, Inc., San Diego, CA, USA) cell line and human glioma cell lines H4, U-87MG ATCC (U87), LN229, U-118MG (U118) and U-251MG (U251) were purchased from the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Beijing, China).	('U-87MG ATCC', 'Gene', '641648', (107, 118))	('human', 'Species', '9606', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('U-251MG', 'CellLine', 'CVCL:0021', (152, 159))	('U-87MG ATCC', 'Gene', (107, 118))	('U-118MG', 'Var', (133, 140))	('glioma', 'Disease', (85, 91))	('H4', 'CellLine', 'CVCL:6C19', (103, 105))	('U87', 'Gene', (120, 123))	('U-251MG', 'Var', (152, 159))	('LN229', 'CellLine', 'CVCL:0393', (126, 131))	('U87', 'Gene', '641648', (120, 123))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
48901	30066946	Patients with HGG and high CKAP2 mRNA expression were observed to have a worse prognosis compared with those with low CKAP2 expression.	('CKAP2', 'Gene', '26586', (118, 123))	('CKAP2', 'Gene', (118, 123))	('mRNA expression', 'MPA', (33, 48))	('high', 'Var', (22, 26))	('Patients', 'Species', '9606', (0, 8))	('CKAP2', 'Gene', '26586', (27, 32))	('CKAP2', 'Gene', (27, 32))	('HGG', 'Disease', (14, 17))
48902	30066946	In TCGA RNA sequencing database, the patients with HGG and high CKAP2 expression also exhibited worse OS compared with those with low CKAP2 expression (P=0.023, log-rank test; Fig.	('patients', 'Species', '9606', (37, 45))	('CKAP2', 'Gene', '26586', (64, 69))	('CKAP2', 'Gene', '26586', (134, 139))	('CKAP2', 'Gene', (64, 69))	('CKAP2', 'Gene', (134, 139))	('high', 'Var', (59, 63))	('expression', 'Var', (70, 80))
48907	30066946	According to these results, the incidence of the biomarkers that indicate a poor prognosis, including high Ki67 expression and phosphatase and tensin homolog mutations, were higher in patients with glioma and higher CKAP2 expression.	('patients', 'Species', '9606', (184, 192))	('glioma', 'Disease', (198, 204))	('high', 'PosReg', (102, 106))	('higher', 'PosReg', (174, 180))	('CKAP2', 'Gene', '26586', (216, 221))	('CKAP2', 'Gene', (216, 221))	('higher', 'PosReg', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('mutations', 'Var', (158, 167))	('Ki67', 'Gene', (107, 111))	('expression', 'MPA', (222, 232))	('expression', 'MPA', (112, 122))
48910	30066946	The results demonstrated that high CKAP2 expression was a risk factor for patients with HGG (P=0.003 for OS and P=0.001 for PFS).	('expression', 'MPA', (41, 51))	('patients', 'Species', '9606', (74, 82))	('HGG', 'Disease', (88, 91))	('high', 'Var', (30, 34))	('CKAP2', 'Gene', '26586', (35, 40))	('CKAP2', 'Gene', (35, 40))
48911	30066946	Furthermore, other factors, including age and IDH1 mutation state, were also significantly associated with the OS and PFS of patients with HGG.	('patients', 'Species', '9606', (125, 133))	('IDH1', 'Gene', (46, 50))	('PFS', 'Disease', (118, 121))	('IDH1', 'Gene', '3417', (46, 50))	('mutation', 'Var', (51, 59))	('associated', 'Reg', (91, 101))
48912	30066946	A multivariate Cox regression analysis was performed incorporating CKAP2 expression, age, WHO grade, Karnofsky Performance Status score, MGMT methylation state, IDH1 mutation state, chemotherapy and radiotherapy (Tables II and III).	('CKAP2', 'Gene', '26586', (67, 72))	('CKAP2', 'Gene', (67, 72))	('IDH1', 'Gene', (161, 165))	('MGMT', 'Gene', (137, 141))	('Cox', 'Gene', '1351', (15, 18))	('MGMT', 'Gene', '4255', (137, 141))	('mutation', 'Var', (166, 174))	('IDH1', 'Gene', '3417', (161, 165))	('Cox', 'Gene', (15, 18))
48914	30066946	In addition, the results of K-M survival curve analysis indicated that high expression levels of CKAP2 were closely associated with poor prognosis in patients with HGG with or without IDH1 mutations (P=0.001 for IDH1 mutation and P=0.045 for IDH1 wild-type, log-rank test; Fig.	('CKAP2', 'Gene', (97, 102))	('IDH1', 'Gene', (184, 188))	('IDH1', 'Gene', (242, 246))	('high', 'PosReg', (71, 75))	('expression levels', 'MPA', (76, 93))	('IDH1', 'Gene', '3417', (184, 188))	('IDH1', 'Gene', '3417', (242, 246))	('IDH1', 'Gene', (212, 216))	('patients', 'Species', '9606', (150, 158))	('HGG', 'Disease', (164, 167))	('IDH1', 'Gene', '3417', (212, 216))	('mutations', 'Var', (189, 198))	('CKAP2', 'Gene', '26586', (97, 102))
48928	30066946	In addition, CKAP2 siRNA was transfected to knockdown CKAP2 expression in U87 and CGGA-N33 cells.	('CKAP2', 'Gene', '26586', (54, 59))	('CKAP2', 'Gene', (54, 59))	('U87', 'Gene', (74, 77))	('CKAP2', 'Gene', '26586', (13, 18))	('CKAP2', 'Gene', (13, 18))	('U87', 'Gene', '641648', (74, 77))	('knockdown', 'Var', (44, 53))
48933	30066946	The results indicated that silencing CKAP2 expression suppressed the proliferative capacity and clonogenicity of glioma cells (Fig.	('CKAP2', 'Gene', '26586', (37, 42))	('CKAP2', 'Gene', (37, 42))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('silencing', 'Var', (27, 36))	('suppressed', 'NegReg', (54, 64))	('glioma', 'Disease', (113, 119))	('proliferative capacity', 'CPA', (69, 91))
48943	30066946	In a previous study of early-stage breast cancer, high CKAP2 expression was revealed to promote the proliferation of tumor cells and significantly shorten relapse-free survival.	('relapse-free survival', 'CPA', (155, 176))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', (117, 122))	('shorten', 'NegReg', (147, 154))	('proliferation', 'CPA', (100, 113))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('CKAP2', 'Gene', '26586', (55, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('high', 'Var', (50, 54))	('CKAP2', 'Gene', (55, 60))
48952	30066946	Furthermore, in both databases, the OS of patients with HGG and high CKAP2 expression was shorter.	('HGG', 'Protein', (56, 59))	('high', 'Var', (64, 68))	('shorter', 'NegReg', (90, 97))	('CKAP2', 'Gene', '26586', (69, 74))	('CKAP2', 'Gene', (69, 74))	('patients', 'Species', '9606', (42, 50))	('expression', 'MPA', (75, 85))
48953	30066946	Additionally, analysis of the CGGA database indicated that high CKAP2 expression shortened the PFS of patients with HGG.	('shortened', 'NegReg', (81, 90))	('patients', 'Species', '9606', (102, 110))	('CKAP2', 'Gene', '26586', (64, 69))	('CKAP2', 'Gene', (64, 69))	('high', 'Var', (59, 63))	('HGG', 'Disease', (116, 119))	('PFS', 'CPA', (95, 98))
48954	30066946	The univariate and multivariate Cox regression analyses revealed that high CKAP2 expression may be an independent predictor for poor clinical outcomes in patients with HGG.	('Cox', 'Gene', '1351', (32, 35))	('CKAP2', 'Gene', '26586', (75, 80))	('CKAP2', 'Gene', (75, 80))	('HGG', 'Disease', (168, 171))	('patients', 'Species', '9606', (154, 162))	('high', 'Var', (70, 74))	('Cox', 'Gene', (32, 35))	('expression', 'MPA', (81, 91))
48959	30066946	However, U-87MG was confirmed to be derived from GBM and is still one of the most commonly used cell lines in glioma research.	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('glioma', 'Disease', (110, 116))	('U-87MG', 'Var', (9, 15))
48960	30066946	The American Type Culture Collection website declares that U-118MG and U-138MG are very similar cell lines, whereas they are not the same .	('U-138MG', 'Var', (71, 78))	('U-118MG', 'Var', (59, 66))	('U-138MG', 'CellLine', 'CVCL:0020', (71, 78))
48961	30066946	Furthermore, since both U-118MG and U-138MG glioma cell lines are derived from malignant gliomas, these misidentifications should not change the interpretation of the present results.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('malignant gliomas', 'Disease', (79, 96))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('malignant gliomas', 'Disease', 'MESH:D005910', (79, 96))	('U-138MG', 'Var', (36, 43))	('U-118MG', 'Var', (24, 31))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('U-138MG', 'CellLine', 'CVCL:0020', (36, 43))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
48971	28649001	Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02-7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site.	('M/F 231', 'Var', (35, 42))	('vincristine carboplatin', 'Chemical', '-', (136, 159))	('etoposide', 'Chemical', 'MESH:D005047', (186, 195))	('VCE', 'Chemical', '-', (197, 200))	('tumour', 'Disease', (252, 258))	('VC', 'Chemical', '-', (197, 199))	('VC', 'Chemical', '-', (178, 180))	('patients', 'Species', '9606', (25, 33))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('VC', 'Chemical', '-', (161, 163))	('M/F 231', 'SUBSTITUTION', 'None', (35, 42))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
49114	28649001	The higher 5-year EFS for TPCV in COG 9952 is of interest, however it did not translate to improved OS.	('OS', 'Chemical', '-', (100, 102))	('COG', 'Chemical', '-', (34, 37))	('COG 9952', 'Var', (34, 42))	('EFS', 'MPA', (18, 21))	('TPCV', 'Chemical', '-', (26, 30))
49165	28649001	Glioneuronal and pilocytic histology had the most favourable OS; the other groups including imaging-diagnosed patients had inferior OS.	('Glioneuronal', 'Var', (0, 12))	('OS', 'Chemical', '-', (132, 134))	('OS', 'Chemical', '-', (61, 63))	('pilocytic histology', 'Var', (17, 36))	('patients', 'Species', '9606', (110, 118))
49177	28649001	Following the identification of mutations within genes for the MAPKinase pathway a major signalling pathways within LGG, tumour biology needs to be assessed by integrating molecular and histological factors, as well as clinical criteria for prognostic impact to be established in prospective clinical trials.	('LGG', 'Disease', (116, 119))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('mutations', 'Var', (32, 41))	('tumour', 'Disease', (121, 127))
49234	26077989	Our study provides evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients.	('transcriptional repression', 'Var', (117, 143))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (97, 103))	('participate', 'Reg', (44, 55))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('patients', 'Species', '9606', (220, 228))	('TRIM8', 'Gene', (34, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('glioma', 'Disease', (213, 219))	('TRIM8', 'Gene', (147, 152))	('carcinogenesis', 'Disease', (63, 77))
49240	26077989	TRIM8 interacts with and negatively regulates PIAS3, a protein inhibitor of IL-6-dependent activation of STAT3, a signaling pathway important for cancer development and progression.	('IL-6', 'Gene', (76, 80))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('negatively', 'NegReg', (25, 35))	('IL-6', 'Gene', '3569', (76, 80))	('TRIM8', 'Var', (0, 5))	('regulates', 'Reg', (36, 45))	('STAT3', 'Gene', '6774', (105, 110))	('PIAS3', 'Gene', '10401', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PIAS3', 'Gene', (46, 51))	('STAT3', 'Gene', (105, 110))
49241	26077989	In agreement with previously data, we recently reported TRIM8 as a new modulator of the p53-mediated tumor suppression mechanism.	('modulator', 'Reg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('p53', 'Gene', '7157', (88, 91))	('p53', 'Gene', (88, 91))	('TRIM8', 'Var', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
49288	26077989	The linear trend of TRIM8 copy numbers across tumor grades was tested using Mantel-Haenszel Chi-Square.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('copy numbers', 'Var', (26, 38))	('TRIM8', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
49291	26077989	Multivariable Cox proportional hazard models included the following covariates: TRIM8 expression (in tertiles), age, the presence of IDH1 mutation and the presence of any treatment therapy (i.e.	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('IDH1', 'Gene', (133, 137))	('mutation', 'Var', (138, 146))	('IDH1', 'Gene', '3417', (133, 137))
49307	26077989	MTT assay confirmed that, in the presence of TRIM8, the rate of cell proliferation is significantly reduced by about 30 % (Fig.	('reduced', 'NegReg', (100, 107))	('TRIM8', 'Var', (45, 50))	('cell proliferation', 'CPA', (64, 82))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))
49315	26077989	We found a linear trend of TRIM8 copy number across tumor grades (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('copy number', 'Var', (33, 44))	('tumor', 'Disease', (52, 57))	('TRIM8', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
49317	26077989	To confirm this evidence, we used the available TRIM8 copy number information from the 526 of TCGA cohort, detecting a heterozygous deletion of TRIM8 gene in 303 out of 526 (57.6 %) analyzed glioma tissues.	('deletion', 'Var', (132, 140))	('glioma', 'Disease', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('TRIM8', 'Gene', (144, 149))
49344	26077989	These results suggest that loss of TRIM8 expression may be necessary for the transition to a more aggressive phenotype typical of WHO grade III gliomas as compared with WHO grade II tumours, but it may have less effect on the clinical behaviour of GBMs, suggesting a likely role of TRIM8 gene in gliomagenesis and disease progression.	('loss', 'Var', (27, 31))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('glioma', 'Disease', (144, 150))	('II tumours', 'Disease', 'MESH:D009369', (179, 189))	('II tumours', 'Disease', (179, 189))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('glioma', 'Disease', (296, 302))	('TRIM8', 'Gene', (35, 40))
49348	26077989	Based on this group of experimental data, we can hypothesize that defects in TRIM8 E3 ligase activity in glioma cells might promote carcinogenesis and cancerous growth by contributing to oncogenes stabilization and/or enhancing tumour suppressors degradation.	('defects', 'Var', (66, 73))	('tumour', 'Disease', (228, 234))	('carcinogenesis', 'Disease', (132, 146))	('glioma', 'Disease', (105, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('activity', 'MPA', (93, 101))	('stabilization', 'MPA', (197, 210))	('cancerous', 'Disease', 'MESH:D009369', (151, 160))	('oncogenes', 'Protein', (187, 196))	('promote', 'PosReg', (124, 131))	('enhancing', 'PosReg', (218, 227))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('TRIM8 E3 ligase', 'Protein', (77, 92))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('contributing', 'Reg', (171, 183))	('cancerous', 'Disease', (151, 160))
49349	26077989	Our data give preliminary evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients.	('participate', 'Reg', (51, 62))	('transcriptional repression', 'Var', (124, 150))	('glioma', 'Disease', (220, 226))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('TRIM8', 'Gene', (154, 159))	('patients', 'Species', '9606', (227, 235))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('carcinogenesis', 'Disease', (70, 84))	('glioma', 'Disease', (104, 110))	('TRIM8', 'Gene', (41, 46))
49356	25012071	Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors.	('associated', 'Reg', (78, 88))	('IDH1', 'Gene', (94, 98))	('GBM', 'Phenotype', 'HP:0012174', (112, 115))	('IDH1', 'Gene', '3417', (94, 98))	('mutation', 'Var', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('GBM tumors', 'Disease', (112, 122))	('GBM tumors', 'Disease', 'MESH:D005910', (112, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
49359	25012071	Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles.	('GBM', 'Phenotype', 'HP:0012174', (283, 286))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('IDH1', 'Gene', '3417', (62, 66))	('methylation', 'MPA', (145, 156))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))	('IDH1', 'Gene', '3417', (201, 205))	('pGBM', 'Chemical', '-', (38, 42))	('mutated', 'Var', (67, 74))	('IDH1', 'Gene', (62, 66))	('IDH1', 'Gene', (201, 205))
49368	25012071	For example, pGBM demonstrate mutation of the PTEN gene and frequent loss of heterozygosity on chromosome 10q (inclusive of the PTEN gene locus), amplification of EGFR, deletions of CDKN2A (p16), while sGBM and their lower grade precursor lesions have frequent mutations of the TP53 gene and the IDH1 gene.	('loss', 'NegReg', (69, 73))	('mutation', 'Var', (30, 38))	('PTEN', 'Gene', '5728', (46, 50))	('GBM', 'Phenotype', 'HP:0012174', (14, 17))	('EGFR', 'Gene', (163, 167))	('amplification', 'Var', (146, 159))	('TP53', 'Gene', '7157', (278, 282))	('IDH1', 'Gene', '3417', (296, 300))	('pGBM', 'Chemical', '-', (13, 17))	('GBM', 'Phenotype', 'HP:0012174', (203, 206))	('deletions', 'Var', (169, 178))	('PTEN', 'Gene', (128, 132))	('EGFR', 'Gene', '1956', (163, 167))	('CDKN2A', 'Gene', (182, 188))	('p16', 'Gene', (190, 193))	('TP53', 'Gene', (278, 282))	('PTEN', 'Gene', (46, 50))	('PTEN', 'Gene', '5728', (128, 132))	('p16', 'Gene', '1029', (190, 193))	('IDH1', 'Gene', (296, 300))	('CDKN2A', 'Gene', '1029', (182, 188))
49370	25012071	A good example is the epigenetic silencing of the MGMT promoter that has provided an exciting and clinically relevant epigenetic marker in gliomas.	('gliomas', 'Disease', (139, 146))	('MGMT', 'Gene', (50, 54))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('MGMT', 'Gene', '4255', (50, 54))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('epigenetic silencing', 'Var', (22, 42))
49374	25012071	The gain of function mutations within the isocitrate dehydrogenase 1 gene (IDH1) are thought to be largely responsible for the glioma hypermethylator phenotype due to the massively increased production of the 2-hydroxyglutarate oncometabolite and have recently been shown to be sufficient to result in a hypermethylator phenotype in glioma cell lines.	('glioma', 'Disease', 'MESH:D005910', (333, 339))	('glioma', 'Phenotype', 'HP:0009733', (333, 339))	('glioma', 'Disease', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('hypermethylator phenotype', 'MPA', (304, 329))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gain of function', 'PosReg', (4, 20))	('IDH1', 'Gene', (75, 79))	('glioma', 'Disease', (333, 339))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (209, 227))	('IDH1', 'Gene', '3417', (75, 79))	('increased', 'PosReg', (181, 190))	('production', 'MPA', (191, 201))	('mutations', 'Var', (21, 30))
49376	25012071	In this report we utilized these comprehensive Infinium HumanMethylation450 BeadChip arrays to define genome-wide methylation in paired samples of early/late astrocytic gliomas and to demonstrate any alterations induced by progression.	('late astrocytic gliomas', 'Disease', (153, 176))	('alterations', 'Reg', (200, 211))	('late astrocytic gliomas', 'Disease', 'MESH:D001254', (153, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('methylation', 'Var', (114, 125))
49391	25012071	Illumina Infinium HumanMethylation450 BeadChip array data was used for the following 19 TCGA primary glioblastomas: TCGA-06-5416, TCGA-06-0171, TCGA-26-5136, TCGA-06-0190, TCGA-06-5418, TCGA-06-0210, TCGA-26-5135, TCGA-26-5134, TCGA-26-5132, TCGA-12-5295, TCGA-06-5414, TCGA-06-0211, TCGA-26-5133, TCGA-06-5417, TCGA-06-0221, TCGA-26-1442, TCGA-06-6389, TCGA-06-6701, TCGA-15-1444.	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('TCGA-26-5133', 'CellLine', 'CVCL:X317', (284, 296))	('glioblastomas', 'Disease', (101, 114))	('TCGA-06-0221', 'Var', (312, 324))	('TCGA-06-0190', 'Var', (158, 170))	('TCGA-06-5417', 'Var', (298, 310))	('TCGA-26-5133', 'Var', (284, 296))	('TCGA-26-1442', 'CellLine', 'CVCL:8806', (326, 338))	('TCGA-26-5134', 'CellLine', 'CVCL:8806', (214, 226))	('glioblastomas', 'Phenotype', 'HP:0012174', (101, 114))	('TCGA-26-5136', 'CellLine', 'CVCL:8806', (144, 156))	('TCGA-06-0210', 'Var', (186, 198))	('TCGA-06-0211', 'Var', (270, 282))	('glioblastomas', 'Disease', 'MESH:D005909', (101, 114))	('TCGA-26-5132', 'CellLine', 'CVCL:8806', (228, 240))	('TCGA-26-5134', 'Var', (214, 226))	('TCGA-06-5414', 'Var', (256, 268))
49395	25012071	In addition, these samples had been assessed for IDH1 and IDH2 mutation status, 14 out of 20 (70%) samples demonstrated mutation in the IDH1 R132 codon.	('R132', 'Var', (141, 145))	('IDH2', 'Gene', '3418', (58, 62))	('IDH1', 'Gene', '3417', (49, 53))	('mutation', 'Var', (120, 128))	('IDH1', 'Gene', (136, 140))	('IDH1', 'Gene', '3417', (136, 140))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', (49, 53))
49396	25012071	No IDH2 mutations were detected (Additional file 2: Table S1).	('IDH2', 'Gene', (3, 7))	('IDH2', 'Gene', '3418', (3, 7))	('mutations', 'Var', (8, 17))
49397	25012071	Samples within major cluster 2 demonstrate a high level of methylation throughout the most variable 2000 loci indicating the CpG island methylator phenotype (CIMP) and these samples were designated CIMP+ve with all but one sample (P19E) demonstrating an IDH1 mutation (Figure 1).	('IDH1', 'Gene', '3417', (254, 258))	('methylation', 'MPA', (59, 70))	('P19E', 'Mutation', 'p.P19E', (231, 235))	('CIMP', 'Chemical', '-', (198, 202))	('CIMP', 'Chemical', '-', (158, 162))	('CIMP+ve', 'Chemical', '-', (198, 205))	('IDH1', 'Gene', (254, 258))	('mutation', 'Var', (259, 267))
49400	25012071	Interestingly, major cluster 1 included several IDH1 mutation positive samples as well as all the IDH1 mutation negative samples except for P19E (Figure 1a).	('mutation', 'Var', (53, 61))	('IDH1', 'Gene', '3417', (48, 52))	('IDH1', 'Gene', (98, 102))	('P19E', 'Mutation', 'p.P19E', (140, 144))	('IDH1', 'Gene', (48, 52))	('IDH1', 'Gene', '3417', (98, 102))
49401	25012071	In general, IDH1 mutation negative samples (P2, P3, P4 and P9) demonstrated very similar methylation patterns between early and late grades (Figure 1a).	('IDH1', 'Gene', (12, 16))	('P2', 'Var', (44, 46))	('IDH1', 'Gene', '3417', (12, 16))	('P4 and P9', 'Gene', '201780', (52, 61))	('methylation', 'MPA', (89, 100))
49404	25012071	In progression to the later grades the IDH1 positive sample split into two categories; those samples that retain a very similar methylation profile after progression (P5, P8, P10, P11, P15, P17) and those that demonstrate a partially remaining CIMP+ve between early and late lesions or greatly reduced (becoming CIMP-ve) degree of methylation after progression (P1, P7, P12, P13, P14, P18, P20) (Figure 1a).	('P18', 'Gene', (385, 388))	('P18', 'Gene', '100689229', (385, 388))	('P12', 'Gene', (370, 373))	('methylation', 'MPA', (331, 342))	('CIMP', 'Chemical', '-', (244, 248))	('P20', 'Gene', '51673', (390, 393))	('P20', 'Gene', (390, 393))	('P14', 'Gene', (380, 383))	('P15', 'Gene', (185, 188))	('CIMP+ve', 'Chemical', '-', (244, 251))	('IDH1', 'Gene', (39, 43))	('P11', 'Gene', (180, 183))	('P13', 'Gene', (375, 378))	('P11', 'Gene', '6281', (180, 183))	('P13', 'Gene', '440926', (375, 378))	('P1', 'Var', (362, 364))	('reduced', 'NegReg', (294, 301))	('P10', 'Gene', '6281', (175, 178))	('P10', 'Gene', (175, 178))	('CIMP', 'Chemical', '-', (312, 316))	('IDH1', 'Gene', '3417', (39, 43))	('P17', 'Gene', (190, 193))	('P17', 'Gene', '54107', (190, 193))	('P15', 'Gene', '1030', (185, 188))	('P12', 'Gene', '56655', (370, 373))	('P14', 'Gene', '1029', (380, 383))
49407	25012071	Although the sample was negative for IDH1 or IDH2 mutation it could possibly have another mutation capable of causing a similar effect, such as a TET2 mutation, that was not assessed for.	('TET2', 'Gene', (146, 150))	('mutation', 'Var', (151, 159))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))	('IDH2', 'Gene', (45, 49))	('TET2', 'Gene', '54790', (146, 150))	('mutation', 'Var', (50, 58))	('IDH2', 'Gene', '3418', (45, 49))
49413	25012071	Of the 2189 loci that are hypermethylated in grade II astrocytomas, approximately 24.9% (n = 544) are specifically hypermethylated within this group, in contrast, grade III and IV samples showed a lower level of specific grade methylation (10.8%, n = 198 and 8.4%, n = 102) respectively (Figure 2).	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))	('II astrocytomas', 'Disease', (51, 66))	('hypermethylated', 'Var', (115, 130))	('II astrocytomas', 'Disease', 'MESH:D001254', (51, 66))
49421	25012071	To further expand this analysis we then downloaded all pGBM IDH1 p.R132H mutated samples that had available Infinium HumanMethylation450 BeadChip methylation data (4 additional samples, there were no IDH2 mutated samples).	('mutated', 'Var', (73, 80))	('IDH1', 'Gene', (60, 64))	('IDH2', 'Gene', '3418', (200, 204))	('GBM', 'Phenotype', 'HP:0012174', (56, 59))	('p.R132H mutated', 'Var', (65, 80))	('IDH1', 'Gene', '3417', (60, 64))	('pGBM', 'Chemical', '-', (55, 59))	('p.R132H', 'Mutation', 'rs121913500', (65, 72))	('IDH2', 'Gene', (200, 204))
49422	25012071	Clustering of the total 19 pGBM samples with our 15 grade IV sGBM samples showed the CIMP phenotype within all five pGBM IDH1 mutated samples, which clustered together with our sGBM CIMP+veIDH1 mutation positive samples, indicating the CIMP+ve phenotype induced by IDH1 mutation in pGBM is similar in sGBM.	('CIMP+ve', 'Chemical', '-', (182, 189))	('IDH1', 'Gene', (121, 125))	('CIMP+ve', 'Chemical', '-', (236, 243))	('CIMP', 'Chemical', '-', (182, 186))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('GBM', 'Phenotype', 'HP:0012174', (283, 286))	('IDH1', 'Gene', '3417', (121, 125))	('GBM', 'Phenotype', 'HP:0012174', (178, 181))	('IDH1', 'Gene', '3417', (265, 269))	('CIMP', 'Chemical', '-', (236, 240))	('CIMP', 'Chemical', '-', (85, 89))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('IDH1', 'Gene', (189, 193))	('mutation', 'Var', (270, 278))	('pGBM', 'Chemical', '-', (116, 120))	('pGBM', 'Chemical', '-', (27, 31))	('pGBM', 'Chemical', '-', (282, 286))	('IDH1', 'Gene', '3417', (189, 193))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('IDH1', 'Gene', (265, 269))
49426	25012071	Three of the four sGBM CIMP-veIDH1 mutation positive samples are the samples that exhibited CIMP in the earlier lesion but not the later lesion, whilst the fourth sGBM and its paired earlier lesion were CIMP-ve.	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('CIMP', 'Chemical', '-', (92, 96))	('CIMP', 'Chemical', '-', (23, 27))	('GBM', 'Phenotype', 'HP:0012174', (164, 167))	('IDH1', 'Gene', (30, 34))	('sGBM', 'Gene', (18, 22))	('mutation', 'Var', (35, 43))	('CIMP', 'Chemical', '-', (203, 207))	('IDH1', 'Gene', '3417', (30, 34))
49434	25012071	Thus, the differing patterns of methylation between these two subtypes of glioma may provide differing advantages to these tumor cells.	('methylation', 'Var', (32, 43))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('glioma', 'Disease', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
49436	25012071	These tumors demonstrate distinct genetic heterogeneity compared to primary GBM, including a considerably greater mutation rate of the IDH1 gene that has been shown to result in a CpG island methylator phenotype (CIMP).	('greater', 'PosReg', (106, 113))	('IDH1', 'Gene', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CpG island methylator phenotype', 'MPA', (180, 211))	('IDH1', 'Gene', '3417', (135, 139))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutation', 'Var', (114, 122))	('CIMP', 'Chemical', '-', (213, 217))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('result in', 'Reg', (168, 177))
49442	25012071	We demonstrated that these samples had the expected high levels of IDH1 mutation and that in the lower grade precursors this nearly uniformly resulted in a CIMP phenotype.	('CIMP', 'Chemical', '-', (156, 160))	('IDH1', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (67, 71))	('mutation', 'Var', (72, 80))	('resulted in', 'Reg', (142, 153))	('CIMP phenotype', 'MPA', (156, 170))
49443	25012071	We saw one case (P16, early and late lesions) where there was evidence of an IDH1 mutation but no CIMP phenotype.	('mutation', 'Var', (82, 90))	('P16', 'Gene', (17, 20))	('P16', 'Gene', '1029', (17, 20))	('IDH1', 'Gene', (77, 81))	('CIMP', 'Chemical', '-', (98, 102))	('IDH1', 'Gene', '3417', (77, 81))
49445	25012071	However, it has previously been suggested that even when negative for the known IDH1 p.R132H mutation, it is possible that other IDH1 mutations could be present in some cases that might therefore potentially affect CIMP status.	('IDH1', 'Gene', (80, 84))	('CIMP status', 'MPA', (215, 226))	('IDH1', 'Gene', (129, 133))	('p.R132H', 'Mutation', 'rs121913500', (85, 92))	('affect', 'Reg', (208, 214))	('CIMP', 'Chemical', '-', (215, 219))	('IDH1', 'Gene', '3417', (80, 84))	('IDH1', 'Gene', '3417', (129, 133))	('p.R132H', 'Var', (85, 92))
49446	25012071	The early presentation of IDH1 mutation and CIMP that we have seen in our study suggests this is an early and important event in gliomagenesis and that if not acquired at an early stage is not gained during progression as no later stage glioblastoma presented with CIMP where the precursor did not.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('CIMP', 'Chemical', '-', (265, 269))	('mutation', 'Var', (31, 39))	('IDH1', 'Gene', (26, 30))	('CIMP', 'Chemical', '-', (44, 48))	('glioblastoma', 'Disease', (237, 249))	('glioblastoma', 'Disease', 'MESH:D005909', (237, 249))	('glioma', 'Disease', (129, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('IDH1', 'Gene', '3417', (26, 30))
49447	25012071	Although the total number of samples is small the large degree of IDH1 mutation and CIMP argues strongly that this is true.	('mutation', 'Var', (71, 79))	('CIMP', 'Chemical', '-', (84, 88))	('IDH1', 'Gene', '3417', (66, 70))	('IDH1', 'Gene', (66, 70))
49448	25012071	In addition to increased overall survival, IDH1 mutation status has been shown to correlate with genetic features including the presence of MGMT methylation and codeletion of 1p and 19q, as well as inversely correlating with EGFR amplification, chromosome 10 loss and chromosome 7 polysomy and therefore if we had been able to analyze a larger sample set, it would have been interesting to look at the relationship between these factors.	('loss', 'NegReg', (259, 263))	('IDH1', 'Gene', (43, 47))	('increased', 'PosReg', (15, 24))	('correlating', 'Reg', (208, 219))	('EGFR', 'Gene', '1956', (225, 229))	('mutation', 'Var', (48, 56))	('IDH1', 'Gene', '3417', (43, 47))	('EGFR', 'Gene', (225, 229))	('MGMT', 'Gene', (140, 144))	('MGMT', 'Gene', '4255', (140, 144))
49451	25012071	While those samples presenting with CIMP in their precursor lesion, largely in association with IDH1 mutation, split approximately in half to follow two paths after progression.	('IDH1', 'Gene', '3417', (96, 100))	('CIMP', 'Chemical', '-', (36, 40))	('mutation', 'Var', (101, 109))	('IDH1', 'Gene', (96, 100))
49455	25012071	If a subset of these cells contained hypermethylation of a particular tumor suppressor that resulted in a considerable growth advantage then these cells could grow out and progress to be the higher grade lesion.	('particular tumor', 'Disease', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('grow out', 'CPA', (159, 167))	('growth advantage', 'CPA', (119, 135))	('hypermethylation', 'Var', (37, 53))	('particular tumor', 'Disease', 'MESH:D009369', (59, 75))
49456	25012071	This lesion would still have the evolutionary pressure to maintain the hypermethylation of this specific tumor suppressor but not necessarily the need to maintain a global methylation phenotype, although in general you would expect some degree of maintenance by the IDH1 mutation, it is plausible that due to changing tumor heterogeneity this would be visualized at a lesser extent.	('IDH1', 'Gene', (266, 270))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('mutation', 'Var', (271, 279))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('IDH1', 'Gene', '3417', (266, 270))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (105, 110))
49462	25012071	Promisingly, 5-azacitidine has recently been shown to be effective in reducing selected promoter methylation, tumor growth, cell proliferation and inducing differentiation in an in vivo primary xenograft IDH1 mutant glioma.	('inducing', 'Reg', (147, 155))	('5-azacitidine', 'Chemical', 'MESH:D001374', (13, 26))	('IDH1', 'Gene', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('differentiation', 'CPA', (156, 171))	('IDH1', 'Gene', '3417', (204, 208))	('promoter methylation', 'MPA', (88, 108))	('reducing', 'NegReg', (70, 78))	('cell proliferation', 'CPA', (124, 142))	('mutant', 'Var', (209, 215))	('glioma', 'Disease', (216, 222))
49470	25012071	This was further observed when comparing the functions of genes commonly hypermethylated in grade IV sGBMs compared to grade IV pGBMs with sGBMs preferentially hypermethylating genes involved in cell death, survival and maintenance pathways and pGBMs preferentially hypermethylating genes that alter or control gene expression.	('pGBMs', 'Chemical', '-', (245, 250))	('pGBMs', 'Chemical', '-', (128, 133))	('preferentially', 'PosReg', (145, 159))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('GBM', 'Phenotype', 'HP:0012174', (246, 249))	('hypermethylating', 'Var', (160, 176))
49471	25012071	Interestingly, a small number of the pGBM tumors demonstrated CIMP that was also largely associated with IDH1 mutation, demonstrating a very similar hypermethylation profile to CIMP positive grade IV sGBM.	('associated', 'Reg', (89, 99))	('pGBM', 'Chemical', '-', (37, 41))	('IDH1', 'Gene', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('CIMP', 'Chemical', '-', (62, 66))	('CIMP', 'Chemical', '-', (177, 181))	('IDH1', 'Gene', '3417', (105, 109))	('GBM', 'Phenotype', 'HP:0012174', (38, 41))	('mutation', 'Var', (110, 118))	('GBM', 'Phenotype', 'HP:0012174', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('GBM tumors', 'Disease', (38, 48))	('GBM tumors', 'Disease', 'MESH:D005910', (38, 48))
49473	25012071	Included in this were two pGBM tumors exhibiting CIMP that lacked mutation in IDH1 or IDH2 that could possibly retain other mutations capable of resulting in CIMP such as could be present in our 19th pair.	('IDH2', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutations', 'Var', (124, 133))	('pGBM', 'Chemical', '-', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('IDH2', 'Gene', '3418', (86, 90))	('IDH1', 'Gene', (78, 82))	('lacked', 'NegReg', (59, 65))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('IDH1', 'Gene', '3417', (78, 82))	('CIMP', 'Chemical', '-', (158, 162))	('CIMP', 'Chemical', '-', (49, 53))	('GBM tumors', 'Disease', (27, 37))	('GBM tumors', 'Disease', 'MESH:D005910', (27, 37))
49577	33558504	The activation of PPARA has been shown to promote proliferation in human breast cancer and its genetic polymorphism has been linked to an increase in the odds of postmenopausal breast cancer.	('breast cancer', 'Disease', (177, 190))	('PPARA', 'Gene', (18, 23))	('genetic polymorphism', 'Var', (95, 115))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('proliferation', 'CPA', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('increase', 'Reg', (138, 146))	('PPARA', 'Gene', '5465', (18, 23))	('promote', 'PosReg', (42, 49))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('human', 'Species', '9606', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('activation', 'PosReg', (4, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
49647	33558504	More precisely, under the Null hypothesis that TF i is not associated with gene j, the distribution of pii,j is not uniform (a characteristic of a true p value), but instead is biased towards small values (see Supplementary Figs.	('TF i', 'Gene', (47, 51))	('pii', 'Var', (103, 106))	('TF i', 'Gene', '7033', (47, 51))
49662	33558504	As a result, we modeled the prior distribution of these unknown parameters according to  and , to ensure that alpha0j > alpha1j and a more significant bias towards small values exists when TF i is a regulator of gene j (see Supplementary Fig.	('TF i', 'Gene', '7033', (189, 193))	('TF i', 'Gene', (189, 193))	('alpha0j', 'Var', (110, 117))
49676	33558504	Simiplified-InPheRNo: to obtain cancer type-relevant networks using simplified-InPheRNo, we used the Pearson's correlation to obtain the p values of TF-gene associations and a two-sided t test to obtain the p values of gene-phenotype associations differentiating one cancer type from other types of cancer.	('associations', 'Var', (157, 169))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TF', 'Gene', '2152', (149, 151))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))
49841	32640719	Furthermore, NRP2, PLXNC1 and PLXNB3 were also positively associated with cell sensitivity to Dabrafenib, which is the treatment for late-stage melanoma and metastatic non-small cell lung cancer with BRAF V600E or V600K mutations (Figure 5C and Table S5).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('BRAF', 'Gene', (200, 204))	('Dabrafenib', 'Chemical', 'MESH:C561627', (94, 104))	('V600E', 'Mutation', 'rs113488022', (205, 210))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('NRP2', 'Gene', (13, 17))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('V600K', 'Var', (214, 219))	('cell sensitivity', 'MPA', (74, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('PLXNB3', 'Gene', '5365', (30, 36))	('PLXNC1', 'Gene', '10154', (19, 25))	('PLXNB3', 'Gene', (30, 36))	('PLXNC1', 'Gene', (19, 25))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('associated', 'Reg', (58, 68))	('NRP2', 'Gene', '8828', (13, 17))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('lung cancer', 'Disease', (183, 194))	('V600K', 'Mutation', 'rs121913227', (214, 219))	('BRAF', 'Gene', '673', (200, 204))	('metastatic', 'CPA', (157, 167))
49853	32640719	Various cell types in the TME of breast cancer tumors might contribute to the dysregulated expression of SEMA3 and their receptors.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('expression', 'MPA', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer tumors', 'Disease', 'MESH:D001943', (33, 53))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (33, 52))	('SEMA', 'Gene', '7869', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancer tumors', 'Disease', (33, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('dysregulated', 'Var', (78, 90))	('SEMA', 'Gene', (105, 109))
49868	32640719	The semaphorin/neuropilin/plexin complexes control a wide range of biological processes and deregulation of these complexes is associated with multiple pathological statuses.	('sema', 'Gene', '7869', (4, 8))	('associated', 'Reg', (127, 137))	('control', 'Reg', (43, 50))	('sema', 'Gene', (4, 8))	('neuropilin', 'Gene', '8829', (15, 25))	('deregulation', 'Var', (92, 104))	('neuropilin', 'Gene', (15, 25))
49885	32640719	The dysregulated expression of NRPs and PLXNs in cancer tumors was generally associated with patient overall survival and progression free interval in 33 cancer types, while the direction of association is dependent on the cancer type tested and the genes queried.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer tumors', 'Disease', (49, 62))	('PLXNs', 'Gene', (40, 45))	('cancer', 'Disease', (223, 229))	('dysregulated', 'Var', (4, 16))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('associated', 'Reg', (77, 87))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer tumors', 'Disease', 'MESH:D009369', (49, 62))	('NRP', 'Gene', '8829', (31, 34))	('NRP', 'Gene', (31, 34))	('cancer', 'Disease', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
49959	32431729	Recently, the 2016 WHO brain tumor classification established the molecular markers for subclassification, including the chromosomal 1p and 19q (chr1p/19q) co-deletion, the isocitrate dehydrogenase (IDH) mutation, and the histone 3 mutational status.	('mutation', 'Var', (204, 212))	('brain tumor', 'Disease', 'MESH:D001932', (23, 34))	('isocitrate dehydrogenase', 'Gene', '3417', (173, 197))	('brain tumor', 'Disease', (23, 34))	('IDH', 'Gene', '3417', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('co-deletion', 'Var', (156, 167))	('brain tumor', 'Phenotype', 'HP:0030692', (23, 34))	('chr1p/19q', 'Gene', (145, 154))	('isocitrate dehydrogenase', 'Gene', (173, 197))	('IDH', 'Gene', (199, 202))
50020	32431729	Finally, a risk score formula was developed based on the seven key genes along with their individual coefficients and expression level, which was defined as follows: (-0.88603 x expression level of ADAP2) + (0.416964 x expression level of ALOX- 5AP) + (0.914674 x expression level of APOBE- C3C) + (-0.73585 x expression level of FCGRT) + (0.631697 x expression level of GNG5) + (-0.64501 x expression level of LRRC25) + (0.745358 x expression level of SP100).	('ALOX- 5AP', 'Gene', (239, 248))	('FCGRT', 'Gene', (330, 335))	('APOBE- C3C', 'Gene', '27350', (284, 294))	('ALOX- 5AP', 'Gene', '241', (239, 248))	('-0.88603', 'Var', (167, 175))	('GNG5', 'Gene', '2787', (371, 375))	('ADAP2', 'Gene', '55803', (198, 203))	('LRRC25', 'Gene', '126364', (411, 417))	('ADAP2', 'Gene', (198, 203))	('SP100', 'Gene', '6672', (453, 458))	('APOBE- C3C', 'Gene', (284, 294))	('GNG5', 'Gene', (371, 375))	('SP100', 'Gene', (453, 458))	('FCGRT', 'Gene', '2217', (330, 335))	('LRRC25', 'Gene', (411, 417))
50033	32431729	As for the CGGA database, the risk scores of patients with IDH1 mutant type, and grade II were lower than IDH1 wild type, and grade III, respectively (Supplementary Figure S6B).	('IDH1', 'Gene', '3417', (59, 63))	('lower', 'NegReg', (95, 100))	('risk scores', 'MPA', (30, 41))	('mutant type', 'Var', (64, 75))	('IDH1', 'Gene', '3417', (106, 110))	('IDH1', 'Gene', (106, 110))	('patients', 'Species', '9606', (45, 53))	('IDH1', 'Gene', (59, 63))
50039	32431729	In the current study, significant differences were found in survival between low- and high mRNAsi (mRNAsi/purity) score groups in the Kaplan Meier curve.	('mRNAsi', 'Disease', 'None', (91, 97))	('differences', 'Reg', (34, 45))	('mRNAsi', 'Disease', (99, 105))	('mRNAsi', 'Disease', (91, 97))	('low-', 'Var', (77, 81))	('mRNAsi', 'Disease', 'None', (99, 105))
50070	32431729	Some investigations have shown that the expression of APOBEC3C played a positive role in the invasiveness and prognosis of breast cancer, hepatocellular carcinoma, and prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('invasiveness', 'CPA', (93, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (138, 162))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('expression', 'Var', (40, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('hepatocellular carcinoma', 'Disease', (138, 162))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('APOBEC3C', 'Gene', '27350', (54, 62))	('prostate cancer', 'Disease', (168, 183))	('APOBEC3C', 'Gene', (54, 62))	('positive', 'PosReg', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
50074	32431729	Consistent with our results, found that high expression of ALOX5AP is associated with poor survival outcome in esophageal carcinoma.	('high expression', 'Var', (40, 55))	('ALOX5AP', 'Gene', (59, 66))	('esophageal carcinoma', 'Disease', (111, 131))	('ALOX5AP', 'Gene', '241', (59, 66))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (111, 131))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (111, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
50077	32431729	It was found that high expression of SP100 was associated with poor cell differentiation in laryngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('SP100', 'Gene', '6672', (37, 42))	('SP100', 'Gene', (37, 42))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('high', 'Var', (18, 22))	('poor cell differentiation', 'CPA', (63, 88))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (92, 108))	('associated', 'Reg', (47, 57))
50078	32431729	Moreover, the expression of SP100 could regulate the transcriptional activity of ETS1 and further influence the cell invasion in breast cancer.	('breast cancer', 'Disease', (129, 142))	('cell invasion', 'CPA', (112, 125))	('expression', 'Var', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('influence', 'Reg', (98, 107))	('ETS1', 'Gene', (81, 85))	('regulate', 'Reg', (40, 48))	('ETS1', 'Gene', '2113', (81, 85))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('SP100', 'Gene', '6672', (28, 33))	('transcriptional activity', 'MPA', (53, 77))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('SP100', 'Gene', (28, 33))
50088	32431729	found that the expression of LRRC25 was significantly associated with the risk of breast cancer.	('breast cancer', 'Disease', (82, 95))	('expression', 'Var', (15, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('LRRC25', 'Gene', '126364', (29, 35))	('LRRC25', 'Gene', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('associated with', 'Reg', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
50096	31768950	Novel IDH1 Targeted Glioma Therapies Mutations in the isocitrate dehydrogenase (IDH) 1 gene are commonly found in human glioma, with the majority of low-grade gliomas harboring a recurrent point mutation (IDH1 R132H).	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('Glioma', 'Phenotype', 'HP:0009733', (20, 26))	('R132H', 'Mutation', 'rs121913500', (210, 215))	('human', 'Species', '9606', (114, 119))	('Glioma', 'Disease', (20, 26))	('found', 'Reg', (105, 110))	('IDH', 'Gene', (205, 208))	('IDH', 'Gene', (80, 83))	('glioma', 'Disease', (120, 126))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('glioma', 'Disease', (159, 165))	('IDH', 'Gene', (6, 9))	('gliomas', 'Disease', (159, 166))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('IDH', 'Gene', '3417', (205, 208))	('IDH', 'Gene', '3417', (80, 83))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('Glioma', 'Disease', 'MESH:D005910', (20, 26))	('Mutations', 'Var', (37, 46))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (54, 86))	('IDH', 'Gene', '3417', (6, 9))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))
50097	31768950	Mutant IDH reveals an altered enzymatic activity leading to the synthesis of 2-hydroxyglutarate, which has been implicated in epigenetic mechanisms of oncogenesis.	('IDH', 'Gene', (7, 10))	('synthesis of 2-hydroxyglutarate', 'MPA', (64, 95))	('IDH', 'Gene', '3417', (7, 10))	('altered', 'Reg', (22, 29))	('Mutant', 'Var', (0, 6))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (77, 95))	('enzymatic activity', 'MPA', (30, 48))
50098	31768950	Nevertheless, it is unclear exactly how IDH mutations drive glioma initiation and progression, and it is also not clear why tumors with this mutation generally have a better prognosis than IDH wild type tumors.	('IDH', 'Gene', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('glioma initiation', 'Disease', 'MESH:D005910', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('IDH', 'Gene', '3417', (189, 192))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('IDH', 'Gene', (40, 43))	('tumors', 'Disease', (124, 130))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('type tumors', 'Disease', 'MESH:D009369', (198, 209))	('IDH', 'Gene', '3417', (40, 43))	('type tumors', 'Disease', (198, 209))	('glioma initiation', 'Disease', (60, 77))
50099	31768950	The recognition of the high frequency of IDH mutations in glioma (and also in other malignancies, including acute myeloid leukemia (AML) and cholangiocarcinoma) have led to the development of a number of targeted agents that can inhibit these enzymes.	('IDH', 'Gene', (41, 44))	('glioma', 'Disease', (58, 64))	('IDH', 'Gene', '3417', (41, 44))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('acute myeloid leukemia', 'Disease', (108, 130))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (141, 159))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('AML', 'Disease', 'MESH:D015470', (132, 135))	('malignancies', 'Disease', (84, 96))	('mutations', 'Var', (45, 54))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('AML', 'Disease', (132, 135))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('cholangiocarcinoma', 'Disease', (141, 159))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (141, 159))
50101	31768950	Both agents are still in early clinical phases for glioma therapy, as are a number of additional candidates (including AG 881, BAY1436032, and DS1001).	('glioma', 'Disease', (51, 57))	('BAY1436032', 'Chemical', 'MESH:C000622445', (127, 137))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('AG 881', 'Chemical', '-', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('DS1001', 'Chemical', '-', (143, 149))	('BAY1436032', 'Var', (127, 137))
50102	31768950	An alternative approach to target the IDH1 mutation is by the induction of synthetic lethality with compounds that target PARP, glutamine metabolism, and the Bcl-2 family of proteins.	('Bcl-2', 'Gene', '596', (158, 163))	('PARP', 'Gene', (122, 126))	('mutation', 'Var', (43, 51))	('IDH', 'Gene', (38, 41))	('glutamine', 'Chemical', 'MESH:D005973', (128, 137))	('IDH', 'Gene', '3417', (38, 41))	('synthetic', 'MPA', (75, 84))	('PARP', 'Gene', '142', (122, 126))	('Bcl-2', 'Gene', (158, 163))
50103	31768950	We conclude that within the last decade several approaches have been devised to therapeutically target the IDH1 mutation and that potentially both IDH1 inhibitors as well as synthetic lethal approaches might be relevant for future therapies.	('IDH', 'Gene', '3417', (147, 150))	('mutation', 'Var', (112, 120))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', '3417', (107, 110))	('IDH', 'Gene', (147, 150))
50104	31768950	Preceding the discovery of mutated isocitrate dehydrogenase (IDH) 1 in gliomas was the earlier observation of mutations in this gene in colon carcinoma.	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (35, 67))	('mutated', 'Var', (27, 34))	('colon carcinoma', 'Disease', (136, 151))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('colon carcinoma', 'Disease', 'MESH:D003110', (136, 151))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
50105	31768950	IDH1 was found to be mutated in about 10 % of glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('IDH', 'Gene', (0, 3))	('glioblastomas', 'Disease', (46, 59))	('IDH', 'Gene', '3417', (0, 3))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('mutated', 'Var', (21, 28))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))
50106	31768950	Follow up studies demonstrated that a large proportion of roughly 80-90% of low grade gliomas, including astrocytomas and oligodendrogliomas, displayed mutated IDH1.	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('mutated', 'Var', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('IDH', 'Gene', (160, 163))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('IDH', 'Gene', '3417', (160, 163))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (105, 140))
50107	31768950	In gliomas, the most common IDH1 mutation, which comprises roughly 90% of all mutated cases, is located at codon 132, resulting in a switch from arginine to histidine at this position.	('switch', 'Reg', (133, 139))	('IDH', 'Gene', (28, 31))	('mutation', 'Var', (33, 41))	('arginine', 'Chemical', 'MESH:D001120', (145, 153))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('IDH', 'Gene', '3417', (28, 31))	('histidine', 'Chemical', 'MESH:D006639', (157, 166))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('arginine to histidine', 'MPA', (145, 166))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))
50108	31768950	A relatively small fraction (fewer than 1%) of gliomas harbor IDH2 mutations (leading to IDH2 R172), which is more common in acute myeloid leukemia.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (125, 147))	('IDH', 'Gene', '3417', (62, 65))	('common', 'Reg', (115, 121))	('mutations', 'Var', (67, 76))	('gliomas', 'Disease', (47, 54))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (125, 147))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (131, 147))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('IDH', 'Gene', (89, 92))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('acute myeloid leukemia', 'Disease', (125, 147))	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', (62, 65))
50110	31768950	When no 1p/19q co-deletion is present, the IDH1 mutation is often accompanied by mutations in ATRX and TP53.	('IDH', 'Gene', '3417', (43, 46))	('TP53', 'Gene', (103, 107))	('ATRX', 'Gene', (94, 98))	('pan', 'Gene', (71, 74))	('mutation', 'Var', (48, 56))	('mutations', 'Var', (81, 90))	('pan', 'Gene', '51816', (71, 74))	('IDH', 'Gene', (43, 46))
50111	31768950	In glioma pat8ients, the presence of an IDH1 mutation is linked to an improved survival and this holds true even in the setting of high-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('glioma', 'Disease', (142, 148))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('improved', 'PosReg', (70, 78))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('IDH', 'Gene', (40, 43))	('mutation', 'Var', (45, 53))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('glioma', 'Disease', (3, 9))	('IDH', 'Gene', '3417', (40, 43))	('survival', 'MPA', (79, 87))	('presence', 'Var', (25, 33))
50112	31768950	However, in AML the IDH1 mutation confers worse patient outcomes.	('AML', 'Disease', 'MESH:D015470', (12, 15))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('mutation', 'Var', (25, 33))	('AML', 'Disease', (12, 15))	('patient', 'Species', '9606', (48, 55))
50113	31768950	Although gliomas harboring the IDH1 mutation appear to behave more favorably, they nonetheless require therapy.	('IDH', 'Gene', (31, 34))	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('IDH', 'Gene', '3417', (31, 34))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('mutation', 'Var', (36, 44))
50114	31768950	Therefore, targeting IDH1 may be a therapeutic option for low grade gliomas and maybe secondary glioblastomas that arise from lower grade gliomas.	('IDH', 'Gene', (21, 24))	('gliomas', 'Disease', (138, 145))	('glioblastomas', 'Disease', (96, 109))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH', 'Gene', '3417', (21, 24))	('glioblastomas', 'Phenotype', 'HP:0012174', (96, 109))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('targeting', 'Var', (11, 20))	('glioblastomas', 'Disease', 'MESH:D005909', (96, 109))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))
50115	31768950	A further important notion is the fact that the IDH1 mutation is usually identified in the vast majority of tumor cells, thus when targeted this will affect essentially the entire fraction of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (192, 197))	('IDH', 'Gene', (48, 51))	('mutation', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('IDH', 'Gene', '3417', (48, 51))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('affect', 'Reg', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
50117	31768950	Although not part of this review, this has also resulted in the conceptualization of vaccine strategies for IDH1 mutated gliomas.	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (108, 111))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('mutated', 'Var', (113, 120))
50126	31768950	Consistently, when IDH1 is mutated, glioma cells tend to produce more reactive oxygen species likely related to the impaired "redox buffering" capacity due to a dysregulated GSH/GSSG ratio.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (70, 93))	('GSH/GSSG', 'MPA', (174, 182))	('mutated', 'Var', (27, 34))	('GSSG', 'Chemical', 'MESH:D019803', (178, 182))	('glioma', 'Disease', (36, 42))	('IDH', 'Gene', '3417', (19, 22))	('reactive oxygen species', 'MPA', (70, 93))	('more', 'PosReg', (65, 69))	('IDH', 'Gene', (19, 22))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('GSH', 'Chemical', '-', (174, 177))	('produce', 'MPA', (57, 64))
50128	31768950	A major property of mutant IDH1 is its ability to produce 2-HG in significant amounts.	('IDH', 'Gene', (27, 30))	('produce 2-HG', 'MPA', (50, 62))	('IDH', 'Gene', '3417', (27, 30))	('2-HG', 'Chemical', 'MESH:C019417', (58, 62))	('mutant', 'Var', (20, 26))
50131	31768950	In turn, mutated IDH1 and IDH2 produce alpha-ketoglutarate, which gets further converted to 2-HG through depletion of NADPH2 and fixation of CO2 (reductive carboxylation).	('IDH', 'Gene', '3417', (17, 20))	('fixation', 'MPA', (129, 137))	('mutated', 'Var', (9, 16))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (39, 58))	('CO2', 'Chemical', 'MESH:D002245', (141, 144))	('depletion', 'MPA', (105, 114))	('alpha-ketoglutarate', 'MPA', (39, 58))	('CO2', 'MPA', (141, 144))	('NADPH2', 'MPA', (118, 124))	('IDH', 'Gene', (26, 29))	('NADPH2', 'Chemical', '-', (118, 124))	('IDH', 'Gene', '3417', (26, 29))	('2-HG', 'Chemical', 'MESH:C019417', (92, 96))	('IDH', 'Gene', (17, 20))
50134	31768950	Another pivotal question about the IDH1 mutation and its related oncometabolite, 2-HG, is the question of "driver vs. passenger" metabolic alteration/mutation since the IDH1 R132H mutation confers a better prognosis and in preclinical model systems there is evidence that IDH1 mutated glioma cells and/or 2-HG exposed tumor cells reveal a reduced proliferation rate.	('proliferation rate', 'CPA', (347, 365))	('IDH', 'Gene', (272, 275))	('IDH', 'Gene', '3417', (35, 38))	('glioma', 'Phenotype', 'HP:0009733', (285, 291))	('IDH', 'Gene', '3417', (169, 172))	('mutated', 'Var', (277, 284))	('IDH', 'Gene', '3417', (272, 275))	('tumor', 'Disease', (318, 323))	('2-HG', 'Chemical', 'MESH:C019417', (305, 309))	('mutation', 'Var', (40, 48))	('R132H', 'Mutation', 'rs121913500', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('reduced', 'NegReg', (339, 346))	('2-HG', 'Chemical', 'MESH:C019417', (81, 85))	('glioma', 'Disease', (285, 291))	('IDH', 'Gene', (35, 38))	('glioma', 'Disease', 'MESH:D005910', (285, 291))	('IDH', 'Gene', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('R132H', 'Var', (174, 179))
50135	31768950	Therefore, several hypotheses emerge with regards to the role of the IDH1 mutation in established gliomas and especially high-grade gliomas.	('mutation', 'Var', (74, 82))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('IDH', 'Gene', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('IDH', 'Gene', '3417', (69, 72))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
50136	31768950	In this context, it is conceivable that the IDH1 mutation may start out as a driver and in the course of tumor development/progression reverts into a passenger mutation.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mutation', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IDH', 'Gene', (44, 47))	('tumor', 'Disease', (105, 110))	('IDH', 'Gene', '3417', (44, 47))
50137	31768950	This assumption is coherent with findings that suggest that mutated IDH can block the differentiation of tumor cells although more evidence is necessary in glioma model systems to rigorously validate this point.	('IDH', 'Gene', '3417', (68, 71))	('glioma', 'Disease', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('block', 'NegReg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutated', 'Var', (60, 67))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('IDH', 'Gene', (68, 71))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('tumor', 'Disease', (105, 110))
50138	31768950	Recent evidence from elegant transgenic mouse models confirms the earlier notion that the IDH1 mutation is indeed a driver mutation early in tumor development.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('IDH', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('IDH', 'Gene', '3417', (90, 93))	('tumor', 'Disease', (141, 146))	('mouse', 'Species', '10090', (40, 45))	('mutation', 'Var', (95, 103))
50139	31768950	It is critical to appreciate that IDH1 R132H is insufficient on its own to induce tumor formation.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('R132H', 'Var', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('tumor', 'Disease', (82, 87))
50140	31768950	Studies in subventricular zone nestin expressing cells (inducible nestin-cre background) harboring mutated IDH1 showed enhanced proliferation and invasion, but not distinct tumor formation.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('IDH', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('proliferation', 'CPA', (128, 141))	('mutated', 'Var', (99, 106))	('IDH', 'Gene', '3417', (107, 110))	('enhanced', 'PosReg', (119, 127))	('invasion', 'CPA', (146, 154))
50145	31768950	In the context of glioblastoma and colon carcinoma model systems, in which the IDH1 mutation was ectopically introduced it was demonstrated that 2-HG appears to be capable of binding to complex V of the electron transport chain (ETC).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('IDH', 'Gene', (79, 82))	('binding', 'Interaction', (175, 182))	('IDH', 'Gene', '3417', (79, 82))	('2-HG', 'Chemical', 'MESH:C019417', (145, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (18, 30))	('glioblastoma and colon carcinoma', 'Disease', 'MESH:D003110', (18, 50))	('mutation', 'Var', (84, 92))
50148	31768950	In this regard, 2-HG elicits its inhibitory function at the same complex as the classical ATP-synthase inhibitor, oligomycin.	('2-HG', 'Chemical', 'MESH:C019417', (16, 20))	('inhibitory function', 'MPA', (33, 52))	('oligomycin', 'Chemical', 'MESH:D009840', (114, 124))	('elicits', 'Reg', (21, 28))	('2-HG', 'Var', (16, 20))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))
50151	31768950	The inhibition of the ETC suggests that the ability of aspartate biosynthesis is likely to be impaired in the context of mutated IDH1 and presumably IDH2 as well since recent research has suggested that the pivotal role of the ETC in tumor cells is not primarily the production of ATP, but is the ability of oxygen to serve as an electron acceptor.	('ATP', 'Chemical', 'MESH:D000255', (281, 284))	('tumor', 'Disease', (234, 239))	('IDH', 'Gene', (149, 152))	('oxygen', 'Chemical', 'MESH:D010100', (308, 314))	('mutated', 'Var', (121, 128))	('IDH', 'Gene', '3417', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('IDH', 'Gene', (129, 132))	('aspartate', 'Chemical', 'MESH:D001224', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('IDH', 'Gene', '3417', (129, 132))
50163	31768950	A couple of years ago, an intriguing observation was made in the context of mutated IDH1 and the epigenome.	('IDH', 'Gene', '3417', (84, 87))	('mutated', 'Var', (76, 83))	('IDH', 'Gene', (84, 87))
50164	31768950	Mutated IDH1 was shown to be associated with the development of a glioma CpG island methylated phenotype (G-CIMP) in intermediate grade gliomas.	('glioma', 'Disease', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('IDH', 'Gene', (8, 11))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('IDH', 'Gene', '3417', (8, 11))	('gliomas', 'Disease', (136, 143))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('glioma', 'Disease', (136, 142))	('Mutated', 'Var', (0, 7))	('associated with', 'Reg', (29, 44))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
50165	31768950	Notably, human astrocytes transduced with mutated IDH1 R132H resembled the "methylated phenotype" and gene expression observed in low-grade gliomas, strongly suggesting that mutated IDH1 is the driver of this epigenetic phenotype and low-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('mutated', 'Var', (42, 49))	('IDH', 'Gene', '3417', (182, 185))	('R132H', 'Var', (55, 60))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))	('R132H', 'Mutation', 'rs121913500', (55, 60))	('human', 'Species', '9606', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('IDH', 'Gene', (50, 53))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))	('mutated', 'Var', (174, 181))	('gliomas', 'Disease', (244, 251))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (182, 185))
50166	31768950	One of the underlying mechanisms related to the hypermethylated phenotype involved mutant IDH1 mediated inhibition of the TET2 enzyme.	('inhibition', 'NegReg', (104, 114))	('IDH', 'Gene', (90, 93))	('mutant', 'Var', (83, 89))	('IDH', 'Gene', '3417', (90, 93))	('TET2', 'Gene', '54790', (122, 126))	('TET2', 'Gene', (122, 126))
50168	31768950	When 2-HG is present in abundant amounts (such as in the context of mutated IDH1/2) it competes with the cofactor of these enzymes, alpha-ketoglutarate.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (132, 151))	('IDH1/2', 'Gene', '3417;3418', (76, 82))	('2-HG', 'Chemical', 'MESH:C019417', (5, 9))	('mutated', 'Var', (68, 75))	('IDH1/2', 'Gene', (76, 82))
50169	31768950	One of the challenges to study the impact of the IDH1 mutations on cancer biology and therapy is presented by the fact that at least for gliomas it is difficult to obtain a stable cell line derived from patients.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('cancer', 'Disease', (67, 73))	('IDH', 'Gene', (49, 52))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', '3417', (49, 52))	('patients', 'Species', '9606', (203, 211))	('gliomas', 'Disease', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))
50170	31768950	The IDH mutation is hard to be propagated under in vitro conditions and successfully established IDH1 mutated tumors often end up losing their mutated IDH1 allele.	('IDH', 'Gene', '3417', (151, 154))	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (97, 100))	('losing', 'NegReg', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('IDH', 'Gene', '3417', (97, 100))	('mutated', 'MPA', (143, 150))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mutated', 'Var', (102, 109))	('IDH', 'Gene', (151, 154))	('IDH', 'Gene', (4, 7))
50171	31768950	These challenging culture conditions may be related to the fact that IDH1 mutated gliomas have an impaired metabolism with regards to the electron transport chain and oxidative phosphorylation since as mentioned earlier both processes have been shown to be suppressed by 2-HG.	('metabolism', 'MPA', (107, 117))	('2-HG', 'Chemical', 'MESH:C019417', (271, 275))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (69, 72))	('oxidative phosphorylation', 'MPA', (167, 192))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('impaired', 'NegReg', (98, 106))	('gliomas', 'Disease', (82, 89))	('mutated', 'Var', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))
50172	31768950	Given this implication it may be beneficial to adjust culture conditions in a way that pyruvate and aspartate levels are elevated and possibly also glutamate levels need adjustment since it was shown by another study that IDH1 mutated gliomas have lower glutamate and glutathione levels.	('IDH', 'Gene', '3417', (222, 225))	('mutated', 'Var', (227, 234))	('glutamate', 'Chemical', 'MESH:D018698', (254, 263))	('lower', 'NegReg', (248, 253))	('lower glutamate and glutathione levels', 'Phenotype', 'HP:0500150', (248, 286))	('gliomas', 'Disease', (235, 242))	('glutathione', 'Chemical', 'MESH:D005978', (268, 279))	('glutamate', 'Chemical', 'MESH:D018698', (148, 157))	('gliomas', 'Disease', 'MESH:D005910', (235, 242))	('gliomas', 'Phenotype', 'HP:0009733', (235, 242))	('pyruvate', 'Chemical', 'MESH:D019289', (87, 95))	('aspartate', 'Chemical', 'MESH:D001224', (100, 109))	('IDH', 'Gene', (222, 225))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))	('elevated', 'PosReg', (121, 129))
50173	31768950	To remedy this situation, scientists have started to over-express mutated IDH1 by diverse non-viral and viral constructs in various established glioblastoma cell lines.	('mutated', 'Var', (66, 73))	('glioblastoma', 'Disease', (144, 156))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('IDH', 'Gene', (74, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('IDH', 'Gene', '3417', (74, 77))	('over-express', 'PosReg', (53, 65))
50174	31768950	The situation becomes even more challenging when the IDH1 mutation is introduced into a genetic background that does not exist in patients.	('mutation', 'Var', (58, 66))	('patients', 'Species', '9606', (130, 138))	('IDH', 'Gene', '3417', (53, 56))	('IDH', 'Gene', (53, 56))
50175	31768950	For instance, it is well accepted that a loss of PTEN or alterations in the EGFR gene are mutually exclusive with the IDH1 mutation.	('PTEN', 'Gene', '5728', (49, 53))	('EGFR', 'Gene', '1956', (76, 80))	('IDH', 'Gene', (118, 121))	('alterations', 'Var', (57, 68))	('IDH', 'Gene', '3417', (118, 121))	('EGFR', 'Gene', (76, 80))	('loss', 'NegReg', (41, 45))	('PTEN', 'Gene', (49, 53))
50176	31768950	Yet, many experiments in the literature are based on cell culture systems where the IDH1 mutation was introduced in cells that harbor for instance a PTEN loss.	('PTEN', 'Gene', (149, 153))	('mutation', 'Var', (89, 97))	('PTEN', 'Gene', '5728', (149, 153))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', (84, 87))	('loss', 'NegReg', (154, 158))
50177	31768950	Nevertheless, having a knock-in mutation should be the more suitable approach after all since over-expression of the mutation may cause other features that will not be representative of the human disease.	('mutation', 'Var', (117, 125))	('over-expression', 'PosReg', (94, 109))	('cause', 'Reg', (130, 135))	('human', 'Species', '9606', (190, 195))
50179	31768950	For instance, using IDH1-R132H knock-in mice in the background of a TP53 mutation would be a system to be considered to be more representative of the actual scenario in a patient's tumor.	('TP53', 'Gene', (68, 72))	('IDH', 'Gene', (20, 23))	('tumor', 'Disease', (181, 186))	('IDH', 'Gene', '3417', (20, 23))	('patient', 'Species', '9606', (171, 178))	('R132H', 'Mutation', 'rs121913500', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('mice', 'Species', '10090', (40, 44))	('mutation', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
50180	31768950	Indeed, there are recent other mouse model systems that might gain traction in the scientific community, such as a mouse model in the context of dual TP53 and ATRX loss.	('TP53', 'Gene', (150, 154))	('dual', 'Var', (145, 149))	('mouse', 'Species', '10090', (31, 36))	('mouse', 'Species', '10090', (115, 120))	('ATRX', 'Gene', (159, 163))	('loss', 'NegReg', (164, 168))
50181	31768950	IDH1 mutated tumors have been shown to be susceptible to the inhibition of several targets.	('IDH', 'Gene', (0, 3))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('IDH', 'Gene', '3417', (0, 3))	('mutated', 'Var', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
50182	31768950	In this regard, a couple of years ago using model systems of transduced IDH1 R132H mutated established glioblastoma cells it was demonstrated that these cells are more prone to the cytotoxic actions of radiation.	('cytotoxic actions', 'CPA', (181, 198))	('R132H mutated', 'Var', (77, 90))	('IDH', 'Gene', (72, 75))	('prone', 'PosReg', (168, 173))	('IDH', 'Gene', '3417', (72, 75))	('glioblastoma', 'Disease', (103, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('R132H', 'Mutation', 'rs121913500', (77, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
50183	31768950	Similar effects were seen in the context when the IDH2 R172K mutation was introduced.	('R172K', 'Var', (55, 60))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))	('R172K', 'Mutation', 'rs121913503', (55, 60))
50184	31768950	Mechanistically, it appears that ROS played a crucial role in this process since application of the ROS scavenger, N-acetylcystein, reversed the sensitization effect of the IDH1/IDH2 mutations on radiation.	('IDH', 'Gene', '3417', (178, 181))	('mutations', 'Var', (183, 192))	('sensitization', 'MPA', (145, 158))	('IDH', 'Gene', (173, 176))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('N-acetylcystein', 'Chemical', '-', (115, 130))	('IDH', 'Gene', '3417', (173, 176))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('IDH', 'Gene', (178, 181))
50185	31768950	The other issue that has arisen over the years is the fact that many studies have used the U87 or other established glioblastoma cell lines that in fact harbor genetic alterations, such as the loss of PTEN that in patients would not co-exist with the IDH1 mutation.	('IDH', 'Gene', '3417', (251, 254))	('patients', 'Species', '9606', (214, 222))	('glioblastoma', 'Disease', (116, 128))	('PTEN', 'Gene', (201, 205))	('U87', 'Gene', (91, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('loss', 'Var', (193, 197))	('PTEN', 'Gene', '5728', (201, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('U87', 'Gene', '641648', (91, 94))	('IDH', 'Gene', (251, 254))
50186	31768950	Therefore, concerns were generally raised about how representative these established cell line models would be in the context of studying the impact of mutated IDH1.	('IDH', 'Gene', '3417', (160, 163))	('IDH', 'Gene', (160, 163))	('mutated', 'Var', (152, 159))
50187	31768950	Given the central role of temozolomide for the treatment of brain tumors other groups have interrogated the susceptibility of IDH1 mutated glioma model systems to chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('temozolomide', 'Chemical', 'MESH:D000077204', (26, 38))	('IDH', 'Gene', '3417', (126, 129))	('brain tumors', 'Disease', 'MESH:D001932', (60, 72))	('brain tumors', 'Phenotype', 'HP:0030692', (60, 72))	('glioma', 'Disease', (139, 145))	('mutated', 'Var', (131, 138))	('brain tumors', 'Disease', (60, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IDH', 'Gene', (126, 129))
50188	31768950	They found that the IDH1 mutation appears to enhance the efficacy of temozolomide and a platinum derived chemotherapeutic.	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('efficacy', 'MPA', (57, 65))	('enhance', 'PosReg', (45, 52))	('mutation', 'Var', (25, 33))	('platinum', 'Chemical', 'MESH:D010984', (88, 96))	('temozolomide', 'Chemical', 'MESH:D000077204', (69, 81))
50190	31768950	Several reports have indicated a link between the presence of the IDH1 mutation and impaired repair of the DNA.	('mutation', 'Var', (71, 79))	('IDH', 'Gene', (66, 69))	('IDH', 'Gene', '3417', (66, 69))	('impaired', 'NegReg', (84, 92))
50193	31768950	Since ALKBH requires alpha-ketoglutarate for its functionality, the high abundance of 2-HG produced by the IDH1 mutation interferes with its enzymatic activity.	('interferes', 'NegReg', (121, 131))	('mutation', 'Var', (112, 120))	('enzymatic activity', 'MPA', (141, 159))	('2-HG', 'MPA', (86, 90))	('IDH', 'Gene', (107, 110))	('ALKBH', 'Gene', (6, 11))	('IDH', 'Gene', '3417', (107, 110))	('2-HG', 'Chemical', 'MESH:C019417', (86, 90))	('ALKBH', 'Gene', '8846', (6, 11))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (21, 40))
50194	31768950	Elegant rescue experiments have provided a strong foundation for this relationship because elimination of the mutated IDH1 allele, which lowers 2-HG, reactivates the enzymatic activity of ALKBH (as noted above, 2-HG will be produced at high levels in the presence of a wild-type and mutated allele of IDH1).	('2-HG', 'Chemical', 'MESH:C019417', (144, 148))	('mutated', 'Var', (110, 117))	('IDH', 'Gene', '3417', (301, 304))	('enzymatic activity', 'MPA', (166, 184))	('ALKBH', 'Gene', (188, 193))	('IDH', 'Gene', (118, 121))	('elimination', 'Var', (91, 102))	('IDH', 'Gene', (301, 304))	('IDH', 'Gene', '3417', (118, 121))	('ALKBH', 'Gene', '8846', (188, 193))	('reactivates', 'MPA', (150, 161))	('2-HG', 'Chemical', 'MESH:C019417', (211, 215))	('2-HG', 'MPA', (144, 148))	('lowers', 'NegReg', (137, 143))
50197	31768950	As noted above, the IDH1 mutation impacts tumor cell metabolism.	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('mutation', 'Var', (25, 33))	('impacts tumor', 'Disease', 'MESH:D014095', (34, 47))	('impacts tumor', 'Disease', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
50198	31768950	While energy metabolism is directly impacted at the level of the electron transport chain by the IDH1 mutation, it was also shown that the electron acceptor NAD+ and its reduced counterpart, NADH2, are affected by the IDH1 mutation.	('NADH2', 'Chemical', '-', (191, 196))	('IDH', 'Gene', (97, 100))	('mutation', 'Var', (102, 110))	('NAD+', 'Chemical', 'MESH:D009243', (157, 161))	('affected', 'Reg', (202, 210))	('IDH', 'Gene', '3417', (97, 100))	('mutation', 'Var', (223, 231))	('energy metabolism', 'MPA', (6, 23))	('impacted', 'Reg', (36, 44))	('IDH', 'Gene', (218, 221))	('electron acceptor NAD+', 'MPA', (139, 161))	('IDH', 'Gene', '3417', (218, 221))
50201	31768950	A couple of years ago it was found that IDH1 mutated gliomas harbor lower levels in the NAPRT1 enzyme.	('lower', 'NegReg', (68, 73))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('IDH', 'Gene', (40, 43))	('NAPRT1', 'Gene', '93100', (88, 94))	('IDH', 'Gene', '3417', (40, 43))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('NAPRT1', 'Gene', (88, 94))	('mutated', 'Var', (45, 52))
50202	31768950	Therefore, it was tempting to speculate whether or not interference with the NAD+ salvage pathway through NAMPT1 inhibitors is synthetically lethal in IDH1 mutated gliomas.	('IDH', 'Gene', '3417', (151, 154))	('NAD+', 'Chemical', 'MESH:D009243', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('mutated', 'Var', (156, 163))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))	('IDH', 'Gene', (151, 154))
50203	31768950	Indeed, two inhibitors, FK866 and GMX1778, showed selective reduction of cellular viability in several IDH1 mutated glioma cell lines such as MGG152 and MGG119.	('FK866', 'Chemical', 'MESH:C480543', (24, 29))	('mutated', 'Var', (108, 115))	('GMX1778', 'Var', (34, 41))	('IDH', 'Gene', (103, 106))	('GMX1778', 'Chemical', 'MESH:C401312', (34, 41))	('glioma', 'Disease', (116, 122))	('IDH', 'Gene', '3417', (103, 106))	('reduction', 'NegReg', (60, 69))	('cellular viability', 'CPA', (73, 91))	('FK866', 'Var', (24, 29))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
50205	31768950	glycolysis, TCA-cycle, and ETC, it appears conceivable that loss of NAD+ may elicit a state of energy deprivation.	('elicit', 'Reg', (77, 83))	('NAD+', 'Chemical', 'MESH:D009243', (68, 72))	('TCA', 'Chemical', 'MESH:D014238', (12, 15))	('loss', 'Var', (60, 64))	('TCA-cycle', 'MPA', (12, 21))	('energy deprivation', 'Disease', 'MESH:D012892', (95, 113))	('glycolysis', 'MPA', (0, 10))	('energy deprivation', 'Disease', (95, 113))	('NAD+', 'Gene', (68, 72))
50208	31768950	The NAMPT1 inhibitors were shown to activate cell death with features of autophagy, which was rescued by 3-methyladenine.	('autophagy', 'CPA', (73, 82))	('3-methyladenine', 'Chemical', 'MESH:C025946', (105, 120))	('NAMPT1', 'Gene', (4, 10))	('inhibitors', 'Var', (11, 21))	('cell death', 'CPA', (45, 55))	('activate', 'PosReg', (36, 44))
50209	31768950	Regarding translational implications, GMX1778 extended animal survival in a murine orthotopic IDH1 mutated glioblastoma model, suggesting a potential novel treatment option for IDH1 mutated gliomas.	('extended', 'PosReg', (46, 54))	('GMX1778', 'Chemical', 'MESH:C401312', (38, 45))	('IDH', 'Gene', (94, 97))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('animal survival', 'CPA', (55, 70))	('GMX1778', 'Var', (38, 45))	('gliomas', 'Disease', (190, 197))	('IDH', 'Gene', (177, 180))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('IDH', 'Gene', '3417', (94, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('glioblastoma', 'Disease', (107, 119))	('mutated', 'Var', (99, 106))	('IDH', 'Gene', '3417', (177, 180))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('murine', 'Species', '10090', (76, 82))
50210	31768950	In model systems of chondrosarcoma, which harbor IDH1 mutations as well, NAMPT inhibition did not correlate with the IDH1 or IDH2 mutation status.	('chondrosarcoma', 'Disease', 'MESH:D002813', (20, 34))	('IDH', 'Gene', (49, 52))	('IDH', 'Gene', (117, 120))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', '3417', (49, 52))	('IDH', 'Gene', (125, 128))	('IDH', 'Gene', '3417', (117, 120))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (20, 34))	('IDH', 'Gene', '3417', (125, 128))	('chondrosarcoma', 'Disease', (20, 34))
50211	31768950	More recently, it was found that IDH1 mutated tumors are susceptible to a combination treatment involving temozolomide and NAMPT inhibitors in vitro and in subcutaneous xenograft models.	('susceptible', 'Reg', (57, 68))	('mutated', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('temozolomide', 'Chemical', 'MESH:D000077204', (106, 118))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('IDH', 'Gene', (33, 36))	('tumors', 'Disease', (46, 52))	('IDH', 'Gene', '3417', (33, 36))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
50213	31768950	Since IDH1 mutated cells are already prone to NAD+ depletion, temozolomide might render these cells particularly sensitive to inhibition of NAMPT.	('NAD+ depletion', 'MPA', (46, 60))	('IDH', 'Gene', (6, 9))	('prone', 'Reg', (37, 42))	('IDH', 'Gene', '3417', (6, 9))	('temozolomide', 'Chemical', 'MESH:D000077204', (62, 74))	('NAD+', 'Chemical', 'MESH:D009243', (46, 50))	('mutated', 'Var', (11, 18))
50214	31768950	An interesting recent observation was made that IDH1 mutated glioma cells display an impaired ability to synthesize glutamate since 2-HG inhibits the activity of two branched chain amino acid transaminases, BCAT1 and BCAT2, which physiologically require the presence of alpha-ketoglutarate.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('IDH', 'Gene', (48, 51))	('BCAT1', 'Gene', (207, 212))	('BCAT2', 'Gene', (217, 222))	('branched chain amino acid transaminases', 'Enzyme', (166, 205))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (270, 289))	('IDH', 'Gene', '3417', (48, 51))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('mutated', 'Var', (53, 60))	('2-HG', 'Chemical', 'MESH:C019417', (132, 136))	('BCAT1', 'Gene', '586', (207, 212))	('inhibits', 'NegReg', (137, 145))	('BCAT2', 'Gene', '587', (217, 222))	('glutamate', 'Chemical', 'MESH:D018698', (116, 125))	('activity', 'MPA', (150, 158))
50215	31768950	Consequently, IDH1 mutated gliomas show suppressed levels of glutamate and in turn are more reliant on glutaminase, which catalyzes the production of glutamate from glutamine.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('IDH', 'Gene', (14, 17))	('suppressed', 'NegReg', (40, 50))	('levels of glutamate', 'MPA', (51, 70))	('glutaminase', 'Gene', '2744', (103, 114))	('IDH', 'Gene', '3417', (14, 17))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('mutated', 'Var', (19, 26))	('gliomas', 'Disease', (27, 34))	('more', 'PosReg', (87, 91))	('suppressed levels of glutamate', 'Phenotype', 'HP:0500150', (40, 70))	('glutamine', 'Chemical', 'MESH:D005973', (165, 174))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('glutaminase', 'Gene', (103, 114))	('glutamate', 'Chemical', 'MESH:D018698', (150, 159))	('glutamate', 'Chemical', 'MESH:D018698', (61, 70))
50216	31768950	A major compound to be synthesized from glutamate is glutathione, which was reduced in the presence of the IDH1 mutation as well.	('glutamate', 'Chemical', 'MESH:D018698', (40, 49))	('mutation', 'Var', (112, 120))	('IDH', 'Gene', (107, 110))	('reduced', 'NegReg', (76, 83))	('IDH', 'Gene', '3417', (107, 110))	('glutathione', 'Chemical', 'MESH:D005978', (53, 64))
50217	31768950	Another report suggested an increase in enzymes related to glutathione synthesis in IDH1 mutated glioma models, which may serve to support glutathione levels.	('glutathione synthesis', 'MPA', (59, 80))	('glutathione levels', 'MPA', (139, 157))	('support', 'PosReg', (131, 138))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glutathione', 'Chemical', 'MESH:D005978', (59, 70))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH', 'Gene', (84, 87))	('IDH', 'Gene', '3417', (84, 87))	('mutated', 'Var', (89, 96))	('glutathione', 'Chemical', 'MESH:D005978', (139, 150))	('enzymes related', 'MPA', (40, 55))	('increase', 'PosReg', (28, 36))
50218	31768950	Therefore, under conditions of oxidative stress IDH1 mutated glioma cells were more sensitive to cell death induction by the clinically validated glutaminase inhibitor, CB-839, which was rescued by exogenous glutathione.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('sensitive', 'MPA', (84, 93))	('IDH', 'Gene', (48, 51))	('IDH', 'Gene', '3417', (48, 51))	('glutathione', 'Chemical', 'MESH:D005978', (208, 219))	('CB-839', 'Chemical', 'MESH:C000593334', (169, 175))	('glioma', 'Disease', (61, 67))	('glutaminase', 'Gene', '2744', (146, 157))	('oxidative stress', 'Phenotype', 'HP:0025464', (31, 47))	('mutated', 'Var', (53, 60))	('more', 'PosReg', (79, 83))	('glutaminase', 'Gene', (146, 157))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('cell death', 'CPA', (97, 107))
50219	31768950	Interestingly, when CB-839 was combined with radiation a significant increase in overall survival of animals harboring mutated IDH1 (orthotopic model) was seen.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('CB-839', 'Chemical', 'MESH:C000593334', (20, 26))	('increase', 'PosReg', (69, 77))	('survival', 'CPA', (89, 97))	('mutated', 'Var', (119, 126))
50220	31768950	Another report showed that DNA double strand break repair is inhibited by 2-HG produced by the IDH1 mutation.	('inhibited', 'NegReg', (61, 70))	('DNA double strand break repair', 'MPA', (27, 57))	('mutation', 'Var', (100, 108))	('IDH', 'Gene', (95, 98))	('2-HG', 'Chemical', 'MESH:C019417', (74, 78))	('IDH', 'Gene', '3417', (95, 98))
50221	31768950	In turn, IDH1 mutated solid tumor model systems were shown to be more susceptible to PARP inhibitors in vitro and subcutaneous model systems in vivo.	('mutated', 'Var', (14, 21))	('tumor', 'Disease', (28, 33))	('PARP', 'Gene', (85, 89))	('susceptible', 'MPA', (70, 81))	('IDH', 'Gene', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('IDH', 'Gene', '3417', (9, 12))	('PARP', 'Gene', '142', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
50222	31768950	Interestingly, when IDH1 mutated tumors were treated with IDH1 inhibitors, the enhanced sensitivity to these drug compounds was reversed.	('IDH', 'Gene', '3417', (58, 61))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('tumors', 'Disease', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('IDH', 'Gene', (58, 61))	('mutated', 'Var', (25, 32))
50223	31768950	As anticipated, exogenous 2-HG recapitulates the effect of the IDH1 mutation.	('mutation', 'Var', (68, 76))	('2-HG', 'Chemical', 'MESH:C019417', (26, 30))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (63, 66))
50224	31768950	Similarly, leukemia cells with mutated IDH1/IDH2 showed higher amounts of DNA damage and were more sensitive to radiation and PARP inhibitors.	('PARP', 'Gene', (126, 130))	('leukemia', 'Phenotype', 'HP:0001909', (11, 19))	('DNA damage', 'MPA', (74, 84))	('leukemia', 'Disease', 'MESH:D007938', (11, 19))	('leukemia', 'Disease', (11, 19))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (39, 42))	('PARP', 'Gene', '142', (126, 130))	('higher', 'PosReg', (56, 62))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', '3417', (39, 42))	('mutated', 'Var', (31, 38))
50235	31768950	By performing a high throughput shRNA lentiviral library screen it was demonstrated that IDH mutated myeloid leukemia cells are highly dependent on the expression of Bcl-2 for their survival.	('Bcl-2', 'Gene', (166, 171))	('Bcl-2', 'Gene', '596', (166, 171))	('mutated', 'Var', (93, 100))	('myeloid leukemia', 'Disease', (101, 117))	('IDH', 'Gene', (89, 92))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (101, 117))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('myeloid leukemia', 'Disease', 'MESH:D007951', (101, 117))	('IDH', 'Gene', '3417', (89, 92))
50236	31768950	In light of the fact that ABT199 was available it was enticing to test the hypothesis that IDH mutated AML cells may be more prone to cell death induction by this BH3-mimetc.	('prone', 'Reg', (125, 130))	('AML', 'Disease', (103, 106))	('cell death', 'CPA', (134, 144))	('BH3-mimetc', 'Chemical', '-', (163, 173))	('mutated', 'Var', (95, 102))	('IDH', 'Gene', (91, 94))	('ABT199', 'Chemical', 'MESH:C579720', (26, 32))	('AML', 'Disease', 'MESH:D015470', (103, 106))	('IDH', 'Gene', '3417', (91, 94))
50241	31768950	This observation is especially relevant in light of the fact that in leukemia cells 2-HG and/or the IDH1 mutation did not modulate the levels of anti- or pro-apopotic Bcl-2 family of proteins in a significant manner, suggesting that ETC inhibition is sufficient to enhance the apoptotic effects of ABT199.	('IDH', 'Gene', (100, 103))	('mutation', 'Var', (105, 113))	('ABT199', 'Chemical', 'MESH:C579720', (298, 304))	('enhance', 'PosReg', (265, 272))	('IDH', 'Gene', '3417', (100, 103))	('leukemia', 'Disease', (69, 77))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('leukemia', 'Disease', 'MESH:D007938', (69, 77))	('Bcl-2', 'Gene', (167, 172))	('Bcl-2', 'Gene', '596', (167, 172))	('2-HG', 'Chemical', 'MESH:C019417', (84, 88))	('inhibition', 'NegReg', (237, 247))	('apoptotic effects', 'CPA', (277, 294))
50242	31768950	Although ABT199 was efficient to induce apoptosis in IDH mutated leukemia cells, it was not in solid malignancies.	('malignancies', 'Disease', (101, 113))	('apoptosis', 'CPA', (40, 49))	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('leukemia', 'Disease', 'MESH:D007938', (65, 73))	('leukemia', 'Disease', (65, 73))	('ABT199', 'Var', (9, 15))	('ABT199', 'Chemical', 'MESH:C579720', (9, 15))	('IDH', 'Gene', (53, 56))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('IDH', 'Gene', '3417', (53, 56))
50244	31768950	In line with this observation, it was demonstrated that IDH1 (R132H) mutated glioblastoma cell cultures and xenografts are more susceptible to apoptosis induction by Bcl-xL inhibition.	('susceptible', 'Reg', (128, 139))	('more', 'PosReg', (123, 127))	('glioblastoma', 'Disease', (77, 89))	('mutated', 'Var', (69, 76))	('IDH', 'Gene', (56, 59))	('R132H', 'Mutation', 'rs121913500', (62, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('IDH', 'Gene', '3417', (56, 59))	('apoptosis', 'CPA', (143, 152))	('Bcl-xL', 'Gene', '598', (166, 172))	('R132H) mutated', 'Var', (62, 76))	('Bcl-xL', 'Gene', (166, 172))
50245	31768950	Given that there is a clinically validated Bcl-xL inhibitor available (ABT263) it was obvious to assess its potency in the diverse IDH1 mutated model systems and ABT263 resembled the killing effects observed with genetic silencing of Bcl-xL.	('Bcl-xL', 'Gene', (43, 49))	('Bcl-xL', 'Gene', '598', (234, 240))	('ABT263', 'Chemical', 'MESH:C528561', (162, 168))	('ABT263', 'Chemical', 'MESH:C528561', (71, 77))	('IDH', 'Gene', (131, 134))	('ABT263', 'Var', (162, 168))	('Bcl-xL', 'Gene', (234, 240))	('potency', 'MPA', (108, 115))	('genetic silencing', 'Var', (213, 230))	('IDH', 'Gene', '3417', (131, 134))	('Bcl-xL', 'Gene', '598', (43, 49))
50246	31768950	This synthetic lethal interaction was not limited to glioblastoma and was validated in a model system of colonic carcinoma, harboring a genetically engineered heterozygous IDH1 mutation.	('IDH', 'Gene', (172, 175))	('glioblastoma', 'Disease', (53, 65))	('mutation', 'Var', (177, 185))	('colonic carcinoma', 'Disease', (105, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (53, 65))	('colonic carcinoma', 'Disease', 'MESH:D003110', (105, 122))	('IDH', 'Gene', '3417', (172, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))
50247	31768950	Contrasting the findings in leukemia, the IDH1 mutation was associated with lower Mcl-1 protein levels in IDH1 mutated anaplastic astrocytomas.	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (106, 109))	('astrocytomas', 'Disease', 'MESH:D001254', (130, 142))	('mutated', 'Var', (111, 118))	('IDH', 'Gene', '3417', (42, 45))	('mutation', 'Var', (47, 55))	('lower Mcl', 'Phenotype', 'HP:0025066', (76, 85))	('leukemia', 'Disease', (28, 36))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('Mcl-1 protein levels', 'MPA', (82, 102))	('leukemia', 'Disease', 'MESH:D007938', (28, 36))	('astrocytomas', 'Disease', (130, 142))	('lower', 'NegReg', (76, 81))	('IDH', 'Gene', (106, 109))
50248	31768950	Similarly, 2HG and mutated IDH1 suppressed Mcl-1 levels in cell cultures.	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', '3417', (27, 30))	('Mcl-1 levels', 'MPA', (43, 55))	('mutated', 'Var', (19, 26))	('suppressed', 'NegReg', (32, 42))
50251	31768950	It is noteworthy that the vulnerability to Bcl-xL inhibition appeared to be selective since IDH1 mutated glioma cells were not sensitive to cell death induction by generic chemotherapeutic drugs or the cytotoxic ligand TRAIL.	('TRAIL', 'Gene', '8743', (219, 224))	('Bcl-xL', 'Gene', (43, 49))	('mutated', 'Var', (97, 104))	('TRAIL', 'Gene', (219, 224))	('glioma', 'Disease', (105, 111))	('IDH', 'Gene', (92, 95))	('Bcl-xL', 'Gene', '598', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('IDH', 'Gene', '3417', (92, 95))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
50252	31768950	IDH1 mutated cholangiocarcinomas have been reported to be more sensitive to SRC kinase inhibition by the drug compound, dasatinib, which was rescued through overexpression of a SRC mutant.	('SRC', 'Gene', '6714', (76, 79))	('dasatinib', 'Chemical', 'MESH:D000069439', (120, 129))	('SRC', 'Gene', '6714', (177, 180))	('IDH', 'Gene', (0, 3))	('SRC', 'Gene', (76, 79))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (13, 32))	('IDH', 'Gene', '3417', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('mutated', 'Var', (5, 12))	('more', 'PosReg', (58, 62))	('sensitive', 'MPA', (63, 72))	('cholangiocarcinomas', 'Disease', (13, 32))	('SRC', 'Gene', (177, 180))
50256	31768950	The wide preponderance of IDH mutations in certain types of cancer and a strong biological evidence for these genetic alterations to cause tumor-driving epigenetic changes lead to a rapid success in identifying and developing inhibitors of mutant IDH.	('IDH', 'Gene', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('IDH', 'Gene', '3417', (247, 250))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', (139, 144))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('IDH', 'Gene', '3417', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
50257	31768950	While the rationale for targeting mutant IDH in diseases such as AML has been proven to be well founded and clinical proof-of-concept was established, the data in glioma are less consistent and substantial clinical benefits following IDH inhibitor treatment remain to be proven.	('AML', 'Disease', (65, 68))	('IDH', 'Gene', (41, 44))	('IDH', 'Gene', (234, 237))	('glioma', 'Disease', (163, 169))	('IDH', 'Gene', '3417', (41, 44))	('IDH', 'Gene', '3417', (234, 237))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('mutant', 'Var', (34, 40))
50258	31768950	In the following, we will focus on mutant IDH inhibitors AG-120, AG-221, AG-881, BAY1436032, and DS-1001b (Table 2), which are currently evaluated in clinical trials involving patients with gliomas.	('patients', 'Species', '9606', (176, 184))	('DS-1001b', 'Chemical', '-', (97, 105))	('IDH', 'Gene', (42, 45))	('DS-1001b', 'Var', (97, 105))	('BAY1436032', 'Chemical', 'MESH:C000622445', (81, 91))	('AG-881', 'Var', (73, 79))	('AG-221', 'Chemical', 'MESH:C000605269', (65, 71))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('IDH', 'Gene', '3417', (42, 45))	('AG-221', 'Var', (65, 71))	('gliomas', 'Disease', (190, 197))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('BAY1436032', 'Var', (81, 91))	('AG-120', 'Chemical', 'MESH:C000627630', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('AG-120', 'Var', (57, 63))	('AG-881', 'Chemical', '-', (73, 79))
50261	31768950	AG-120 was shown to have a strong selectivity for mutant IDH1 with an EC50-value of 40nM (R132H) to 50nM (R132C) and an 85-106 fold separation in potency, relative to wild-type IDH1, when tested against purified recombinant protein.	('IDH', 'Gene', '3417', (57, 60))	('R132C', 'Mutation', 'rs121913499', (106, 111))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('IDH', 'Gene', (177, 180))	('IDH', 'Gene', (57, 60))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('IDH', 'Gene', '3417', (177, 180))	('mutant', 'Var', (50, 56))	('potency', 'MPA', (146, 153))
50273	31768950	AG-221 (Celgene/Agios) is an orally bioavailable allosteric inhibitor of mutant IDH2.	('Agios', 'Chemical', '-', (16, 21))	('IDH', 'Gene', (80, 83))	('mutant', 'Var', (73, 79))	('IDH', 'Gene', '3417', (80, 83))	('AG-221', 'Chemical', 'MESH:C000605269', (0, 6))
50275	31768950	AG-221 has a strong selectivity for mutant IDH2 with an EC50-value of 44 nM (R172Q) when compared to wild-type IDH2 (EC50 > 30 muM) or mutant IDH1 R132H/R132C (EC50 = 15.556 muM) and tested against purified recombinant protein.	('IDH', 'Gene', '3417', (43, 46))	('R132H', 'Var', (147, 152))	('R132H', 'SUBSTITUTION', 'None', (147, 152))	('IDH', 'Gene', (142, 145))	('IDH', 'Gene', (111, 114))	('R172Q', 'Mutation', 'rs375031910', (77, 82))	('IDH', 'Gene', '3417', (142, 145))	('mutant', 'Var', (36, 42))	('IDH', 'Gene', '3417', (111, 114))	('R132C', 'Mutation', 'rs121913499', (153, 158))	('IDH', 'Gene', (43, 46))	('AG-221', 'Chemical', 'MESH:C000605269', (0, 6))
50278	31768950	However, considering the facts that in gliomas, IDH2 mutations are much less frequent than IDH1 mutations and a blood-brain barrier crossing pan-mutant IDH inhibitor is in clinical trial it seems currently rather unlikely that selective IDH2 inhibitors will play a predominant role for the treatment of IDH-mutated gliomas.	('IDH', 'Gene', (303, 306))	('IDH', 'Gene', (152, 155))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Disease', 'MESH:D005910', (315, 322))	('IDH', 'Gene', (237, 240))	('glioma', 'Phenotype', 'HP:0009733', (315, 321))	('IDH', 'Gene', (48, 51))	('pan', 'Gene', '51816', (141, 144))	('IDH', 'Gene', '3417', (303, 306))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (315, 322))	('IDH', 'Gene', '3417', (152, 155))	('IDH', 'Gene', '3417', (237, 240))	('pan', 'Gene', (141, 144))	('IDH', 'Gene', '3417', (48, 51))	('mutations', 'Var', (53, 62))	('IDH', 'Gene', (91, 94))	('gliomas', 'Disease', (39, 46))	('gliomas', 'Disease', (315, 322))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH', 'Gene', '3417', (91, 94))
50282	31768950	AG-881 was reported to inhibit tumor growth in an orthotopic mutant IDH1-R132H grade III oligodendroglioma model with a greater than 98% inhibition of intra-tumoral 2-HG levels.	('tumor', 'Disease', (157, 162))	('IDH', 'Gene', '3417', (68, 71))	('oligodendroglioma', 'Disease', 'MESH:D009837', (89, 106))	('2-HG', 'Chemical', 'MESH:C019417', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('inhibit', 'NegReg', (23, 30))	('AG-881', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('inhibition', 'NegReg', (137, 147))	('mutant', 'Var', (61, 67))	('AG-881', 'Chemical', '-', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('IDH', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('oligodendroglioma', 'Disease', (89, 106))
50294	31768950	BAY1436032 (Bayer) was identified based on a drug screen searching for compounds with an IC50 lower than 1muM for IDH1-R132H and an IC50 10 fold higher for wild-type IDH1.	('R132H', 'Mutation', 'rs121913500', (119, 124))	('IDH', 'Gene', (114, 117))	('BAY1436032', 'Chemical', 'MESH:C000622445', (0, 10))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', '3417', (114, 117))	('IDH', 'Gene', '3417', (166, 169))	('BAY1436032', 'Var', (0, 10))
50297	31768950	Pre-clinical studies showed that treatment with BAY1436032 lead to reduced 2-HG levels in multiple cell lines bearing different IDH1 mutations and reduced the cellular viability as well as promoted the differentiation of IDH1-R132H mutant NCH551b secondary glioblastoma cells.	('IDH', 'Gene', (128, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (257, 269))	('BAY1436032', 'Chemical', 'MESH:C000622445', (48, 58))	('cellular viability', 'CPA', (159, 177))	('2-HG levels', 'MPA', (75, 86))	('differentiation', 'CPA', (202, 217))	('glioblastoma', 'Disease', (257, 269))	('promoted', 'PosReg', (189, 197))	('IDH', 'Gene', '3417', (128, 131))	('IDH', 'Gene', (221, 224))	('mutations', 'Var', (133, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (257, 269))	('NCH551b', 'Gene', (239, 246))	('2-HG', 'Chemical', 'MESH:C019417', (75, 79))	('IDH', 'Gene', '3417', (221, 224))	('R132H', 'Mutation', 'rs121913500', (226, 231))	('reduced', 'NegReg', (67, 74))	('BAY1436032', 'Var', (48, 58))	('reduced', 'NegReg', (147, 154))
50298	31768950	In a murine orthotopic NCH551b xenograft model, treatment with BAY1436032 resulted in significantly lower intra-tumoral 2-HG levels.	('2-HG', 'Chemical', 'MESH:C019417', (120, 124))	('BAY1436032', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('murine', 'Species', '10090', (5, 11))	('lower', 'NegReg', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('BAY1436032', 'Chemical', 'MESH:C000622445', (63, 73))	('tumor', 'Disease', (112, 117))
50299	31768950	In addition, mice subjected to treatment with BAY1436032 at a daily dose of 150 mg/kg showed a slight but statistically significant prolonged survival.	('mice', 'Species', '10090', (13, 17))	('prolonged', 'PosReg', (132, 141))	('BAY1436032', 'Chemical', 'MESH:C000622445', (46, 56))	('BAY1436032', 'Var', (46, 56))
50300	31768950	A phase I clinical trial studying the safety profile and maximum tolerated dose of BAY1436032 in patients with IDH1-mutated advanced solid cancers is ongoing (www.clinicaltrials.gov, ).	('BAY1436032', 'Var', (83, 93))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('IDH', 'Gene', (111, 114))	('IDH', 'Gene', '3417', (111, 114))	('BAY1436032', 'Chemical', 'MESH:C000622445', (83, 93))	('patients', 'Species', '9606', (97, 105))
50301	31768950	DS-1001b (Daiichi Sankyo Co) represents another inhibitor of mutant IDH1 which is orally bioavailable.	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', (68, 71))	('DS-1001b', 'Chemical', '-', (0, 8))	('mutant', 'Var', (61, 67))
50302	31768950	In IDH1 mutant chondrosarcoma cells, treatment with DS-1001b resulted in a GI50-value of 289.6 nM (JJ012 IDH1 R132G, after 7 days of treatment) and 160.9 nM (L835 IDH1 R132C, after 21 days of treatment) 1.	('DS-1001b', 'Chemical', '-', (52, 60))	('DS-1001b', 'Var', (52, 60))	('IDH', 'Gene', '3417', (3, 6))	('R132C', 'Mutation', 'rs121913499', (168, 173))	('IDH', 'Gene', (163, 166))	('mutant', 'Var', (8, 14))	('chondrosarcoma', 'Disease', 'MESH:D002813', (15, 29))	('IDH', 'Gene', (105, 108))	('chondrosarcoma', 'Disease', (15, 29))	('IDH', 'Gene', '3417', (163, 166))	('R132G', 'Mutation', 'rs121913499', (110, 115))	('IDH', 'Gene', '3417', (105, 108))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (15, 29))	('IDH', 'Gene', (3, 6))
50303	31768950	In contrast, IDH1 wild-type cells displayed GI50-values exceeding 10 muM after 10 days of treatment with DS-1001b.	('IDH', 'Gene', '3417', (13, 16))	('DS-1001b', 'Chemical', '-', (105, 113))	('DS-1001b', 'Var', (105, 113))	('GI50-values', 'Var', (44, 55))	('IDH', 'Gene', (13, 16))
50304	31768950	The anti-proliferative effects of DS-1001b in IDH1 mutant chondrosarcoma cells were accompanied by a significant reduction of D-2HG levels, induction of differentiation through up-regulation of SOX9 and a decrease in H3K4me3 and H3K9me3 levels.	('H3K9me3 levels', 'MPA', (229, 243))	('mutant', 'Var', (51, 57))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (58, 72))	('up-regulation', 'PosReg', (177, 190))	('pan', 'Gene', (89, 92))	('anti-proliferative effects', 'CPA', (4, 30))	('IDH', 'Gene', (46, 49))	('differentiation', 'CPA', (153, 168))	('SOX9', 'Gene', (194, 198))	('DS-1001b', 'Var', (34, 42))	('D-2HG levels', 'MPA', (126, 138))	('reduction', 'NegReg', (113, 122))	('IDH', 'Gene', '3417', (46, 49))	('chondrosarcoma', 'Disease', 'MESH:D002813', (58, 72))	('SOX9', 'Gene', '6662', (194, 198))	('chondrosarcoma', 'Disease', (58, 72))	('D-2HG', 'Chemical', '-', (126, 131))	('DS-1001b', 'Chemical', '-', (34, 42))	('pan', 'Gene', '51816', (89, 92))	('decrease', 'NegReg', (205, 213))
50306	31768950	In this study, 45 patients with IDH1 mutant gliomas were included and received between 125 and 1400 mg DS-1001b twice a day.	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('mutant', 'Var', (37, 43))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('patients', 'Species', '9606', (18, 26))	('DS-1001b', 'Chemical', '-', (103, 111))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
50310	31768950	The subsequent observation that mutated IDH1 leads to the production of 2-HG and that this metabolite elicits a significant impact on tumors by regulation of cell death, the epigenome and metabolism, is part of the foundation for targeting the mutated enzyme for therapy.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('production', 'MPA', (58, 68))	('2-HG', 'MPA', (72, 76))	('mutated', 'Var', (32, 39))	('IDH', 'Gene', (40, 43))	('2-HG', 'Chemical', 'MESH:C019417', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('IDH', 'Gene', '3417', (40, 43))	('impact', 'Reg', (124, 130))
50312	31768950	At the moment, the evaluation of efficacy of these molecules (e.g., AG-120, AG-221, AG-881, BAY1436032, and DS-1001b) is still in early clinical development and the results of ongoing and subsequent clinical trials will provide pivotal insight about the efficacy and toxicity of these compounds in patients.	('BAY1436032', 'Chemical', 'MESH:C000622445', (92, 102))	('AG-120', 'Chemical', 'MESH:C000627630', (68, 74))	('AG-881', 'Chemical', '-', (84, 90))	('AG-120', 'Var', (68, 74))	('AG-221', 'Chemical', 'MESH:C000605269', (76, 82))	('AG-221', 'Var', (76, 82))	('BAY1436032', 'Var', (92, 102))	('AG-881', 'Var', (84, 90))	('patients', 'Species', '9606', (298, 306))	('DS-1001b', 'Var', (108, 116))	('DS-1001b', 'Chemical', '-', (108, 116))	('toxicity', 'Disease', 'MESH:D064420', (267, 275))	('toxicity', 'Disease', (267, 275))
50313	31768950	An additional concept from preclinical studies is the induction of synthetic lethality since IDH mutations confer unique vulnerabilities that render tumor cells sensitive to inhibition of oncogenic pathways.	('mutations', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('oncogenic pathways', 'Pathway', (188, 206))	('IDH', 'Gene', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('vulnerabilities', 'MPA', (121, 136))	('IDH', 'Gene', '3417', (93, 96))	('tumor', 'Disease', (149, 154))
50314	31768950	However, thus far, this concept has not received much attention for clinical trials in the context of IDH1 mutated gliomas.	('IDH', 'Gene', '3417', (102, 105))	('gliomas', 'Disease', (115, 122))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('mutated', 'Var', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('IDH', 'Gene', (102, 105))
50315	31768950	Given the recent emergence of Idh1 R132H mouse models it may be possible to more efficiently identify synthetic lethal interaction in the context of mutated IDH1 in gliomas.	('IDH', 'Gene', '3417', (157, 160))	('mutated', 'Var', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('mouse', 'Species', '10090', (41, 46))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('R132H', 'Mutation', 'rs121913500', (35, 40))	('gliomas', 'Disease', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('IDH', 'Gene', (157, 160))
50316	31768950	IDH1 mutations are common in low grade gliomas and secondary glioblastomas, and IDH1 R132H is the most common IDH1 mutation found in gliomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (61, 74))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('R132H', 'Var', (85, 90))	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', (80, 83))	('glioblastomas', 'Disease', (61, 74))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('glioblastomas', 'Disease', 'MESH:D005909', (61, 74))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (110, 113))	('mutations', 'Var', (5, 14))	('common', 'Reg', (19, 25))	('IDH', 'Gene', '3417', (80, 83))	('R132H', 'Mutation', 'rs121913500', (85, 90))	('gliomas', 'Disease', (39, 46))	('gliomas', 'Disease', (133, 140))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
50317	31768950	Mutated IDH1 causes a neomorphic enzymatic activity that leads to the production of an oncometabolite, 2-hydroxyglutarate.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (103, 121))	('IDH', 'Gene', (8, 11))	('causes', 'Reg', (13, 19))	('IDH', 'Gene', '3417', (8, 11))	('production of', 'MPA', (70, 83))	('2-hydroxyglutarate', 'MPA', (103, 121))	('neomorphic enzymatic activity', 'MPA', (22, 51))	('Mutated', 'Var', (0, 7))	('leads to', 'Reg', (57, 65))
50318	31768950	Several small molecules have been designed that target mutated IDH enzymes, but the clinical benefit of IDH1 inhibitors in gliomas appears to be limited at the current stage.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('IDH', 'Gene', (104, 107))	('IDH', 'Gene', (63, 66))	('mutated', 'Var', (55, 62))	('IDH', 'Gene', '3417', (104, 107))	('IDH', 'Gene', '3417', (63, 66))	('gliomas', 'Disease', (123, 130))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))
50319	31768950	A compelling complementary approach to IDH1 inhibitors may be the concept of synthetic lethality whereby mutated IDH1 renders cancer cell dependent on certain pathways that in turn may be targeted therapeutically.	('IDH', 'Gene', '3417', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mutated', 'Var', (105, 112))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', (113, 116))	('IDH', 'Gene', '3417', (39, 42))
50337	33435412	The following trials defined initial experiences: The Phase I dose escalation trial included patients with metastatic solid tumours, regardless of NTRK gene fusion status, including patients with NTRK variants/substitutions and amplifications.	('TRK', 'Gene', (197, 200))	('solid tumours', 'Disease', 'MESH:D009369', (118, 131))	('patients', 'Species', '9606', (93, 101))	('solid tumours', 'Disease', (118, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('patients', 'Species', '9606', (182, 190))	('TRK', 'Gene', '7294', (148, 151))	('variants/substitutions', 'Var', (201, 223))	('TRK', 'Gene', '7294', (197, 200))	('amplifications', 'Var', (228, 242))	('TRK', 'Gene', (148, 151))
50348	33435412	ALKA-372-001 (adult Phase I basket trial) (NCT02097810), STARTRK-1 (adult Phase I basket trial) (NCT02097810), STARTRK-2 (adult Phase II basket trial) (NCT02568267), STARTRK-NG (adolescent/pediatric [<=20 years of age] Phase I/II basket trial) (NCT02650401).	('STARTRK-NG', 'Chemical', '-', (166, 176))	('TRK', 'Gene', (170, 173))	('TRK', 'Gene', '7294', (61, 64))	('ALK', 'Gene', '238', (0, 3))	('NCT02097810', 'Var', (97, 108))	('TRK', 'Gene', (61, 64))	('ALK', 'Gene', (0, 3))	('TRK', 'Gene', '7294', (115, 118))	('TRK', 'Gene', '7294', (170, 173))	('TRK', 'Gene', (115, 118))
50355	33435412	Acquired mutations in NTRK that lead to mutations in the kinase domain of TRK interfere with the binding of first-generation TRK inhibitors and cause resistance.	('TRK', 'Gene', '7294', (74, 77))	('TRK', 'Gene', (23, 26))	('kinase', 'MPA', (57, 63))	('interfere', 'NegReg', (78, 87))	('TRK', 'Gene', (74, 77))	('mutations in', 'Var', (40, 52))	('mutations', 'Var', (9, 18))	('cause', 'Reg', (144, 149))	('resistance', 'MPA', (150, 160))	('binding', 'Interaction', (97, 104))	('TRK', 'Gene', '7294', (125, 128))	('TRK', 'Gene', (125, 128))	('TRK', 'Gene', '7294', (23, 26))
50356	33435412	Acquired mutations have been demonstrated to lead to resistance to both entrectinib and larotrectinib.	('resistance', 'MPA', (53, 63))	('mutations', 'Var', (9, 18))	('lead to', 'Reg', (45, 52))	('entrectinib', 'Chemical', 'MESH:C000607349', (72, 83))	('larotrectinib', 'Chemical', 'MESH:C000609083', (88, 101))
50358	33435412	Larotrectinib was approved by Health Canada in July 2019 for adult and pediatric patients with solid tumours with NTRK gene fusions without a known acquired resistance mutation, whose disease is metastatic, or where surgery would result in severe morbidity, and who have no satisfactory alternate treatment options.	('TRK', 'Gene', '7294', (115, 118))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (0, 13))	('patients', 'Species', '9606', (81, 89))	('solid tumours', 'Disease', 'MESH:D009369', (95, 108))	('gene fusions', 'Var', (119, 131))	('solid tumours', 'Disease', (95, 108))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('TRK', 'Gene', (115, 118))
50364	33435412	It was designed to assist laboratories across the country to validate laboratory-developed IHC assays for pan-TRK screening as well as comprehensive molecular testing by NGS to detect NTRK gene fusions, relying on existing diagnostic laboratory infrastructure.	('fusions', 'Var', (194, 201))	('TRK', 'Gene', '7294', (185, 188))	('TRK', 'Gene', '7294', (110, 113))	('TRK', 'Gene', (185, 188))	('TRK', 'Gene', (110, 113))
50377	33435412	Undifferentiated sarcomas with YWHAE and BCOR alterations can over-express TRKC, resulting in positive pan-TRK IHC.	('BCOR', 'Gene', '54880', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('TRK', 'Gene', (75, 78))	('TRKC', 'Gene', (75, 79))	('Undifferentiated sarcomas', 'Disease', (0, 25))	('TRK', 'Gene', '7294', (75, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))	('alterations', 'Var', (46, 57))	('over-express', 'PosReg', (62, 74))	('YWHAE', 'Gene', (31, 36))	('Undifferentiated sarcomas', 'Disease', 'MESH:D002277', (0, 25))	('TRK', 'Gene', '7294', (107, 110))	('TRK', 'Gene', (107, 110))	('BCOR', 'Gene', (41, 45))	('positive', 'PosReg', (94, 102))	('YWHAE', 'Gene', '7531', (31, 36))	('TRKC', 'Gene', '4916', (75, 79))
50380	33435412	These must be tested with a molecular method to confirm/exclude NTRK gene fusions due to the suboptimal sensitivity and specificity of currently available pan-TRK assays.	('TRK', 'Gene', '7294', (159, 162))	('fusions', 'Var', (74, 81))	('TRK', 'Gene', '7294', (65, 68))	('TRK', 'Gene', (159, 162))	('TRK', 'Gene', (65, 68))
50386	33435412	Similarly, canonical fusions in ETV6-NTRK3 are also seen in cellular and mixed congenital mesoblastic nephroma, and FISH testing would routinely be sought to confirm this diagnosis.	('NTRK3', 'Gene', '4916', (37, 42))	('seen', 'Reg', (52, 56))	('congenital mesoblastic nephroma', 'Disease', (79, 110))	('congenital mesoblastic nephroma', 'Phenotype', 'HP:0100881', (79, 110))	('congenital mesoblastic nephroma', 'Disease', 'MESH:D018201', (79, 110))	('ETV6', 'Gene', (32, 36))	('cellular', 'Disease', (60, 68))	('NTRK3', 'Gene', (37, 42))	('fusions', 'Var', (21, 28))	('ETV6', 'Gene', '2120', (32, 36))
50388	33435412	If the 5' partner is unknown, three separate break apart FISH tests are required to detect NTRK1, NTRK2, and NTRK3 fusions and intrachromosomal fusions are difficult to identify.	('fusions', 'Var', (115, 122))	('NTRK2', 'Gene', (98, 103))	('NTRK3', 'Gene', (109, 114))	('break apart', 'Phenotype', 'HP:0001061', (45, 56))	('NTRK3', 'Gene', '4916', (109, 114))	('NTRK2', 'Gene', '4915', (98, 103))	('NTRK1', 'Gene', (91, 96))
50397	33435412	While this publication focuses on three pediatric tumour types (non-rhabdomyosarcoma [RMS] STS/unspecified spindle cell tumours, including IFS; differentiated thyroid carcinoma (DTC); and glioma), investigators have identified NTRK gene fusions in multiple additional pediatric tumour types in the larotrectinib trials.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (159, 176))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (68, 84))	('DTC', 'Chemical', '-', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (68, 84))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('TRK', 'Gene', '7294', (228, 231))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('larotrectinib', 'Chemical', 'MESH:C000609083', (298, 311))	('tumour', 'Disease', 'MESH:D009369', (278, 284))	('tumour', 'Disease', (120, 126))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (159, 176))	('tumour', 'Disease', (278, 284))	('unspecified', 'Species', '32644', (95, 106))	('TRK', 'Gene', (228, 231))	('thyroid carcinoma', 'Disease', (159, 176))	('IFS', 'Chemical', '-', (139, 142))	('rhabdomyosarcoma', 'Disease', (68, 84))	('gene fusions', 'Var', (232, 244))	('glioma', 'Disease', (188, 194))
50407	33435412	Histological/immunohistochemical features suggestive of a high probability of an NTRK gene fusion include: IFS-like, lipofibromatosis-like neural tumour, malignant peripheral nerve sheath-like tumour with stromal and perivascular hyalinization, S100 and CD34 co-immunoreactivity, SOX10 immunonegative, and adult-type fibrosarcoma.	('TRK', 'Gene', '7294', (82, 85))	('CD34', 'Protein', (254, 258))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (317, 329))	('fusion', 'Var', (91, 97))	('SOX10', 'Gene', '6663', (280, 285))	('TRK', 'Gene', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('IFS-like', 'Disease', (107, 115))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('fibrosarcoma', 'Disease', 'MESH:D005354', (317, 329))	('tumour', 'Disease', (193, 199))	('tumour', 'Disease', (146, 152))	('lipofibromatosis-like neural tumour', 'Disease', (117, 152))	('SOX10', 'Gene', (280, 285))	('fibrosarcoma', 'Disease', (317, 329))	('malignant peripheral nerve sheath-like tumour', 'Phenotype', 'HP:0100697', (154, 199))	('S100', 'Gene', (245, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (322, 329))	('IFS', 'Chemical', '-', (107, 110))	('S100', 'Gene', '6271', (245, 249))	('malignant', 'Disease', (154, 163))	('lipofibromatosis-like neural tumour', 'Disease', 'MESH:D009369', (117, 152))
50434	33435412	We believe upfront testing for NTRK gene fusions in non-RMS STS is worthwhile because TRK inhibition may represent a reasonable first-line therapy.	('TRK', 'Gene', (32, 35))	('non-RMS STS', 'Disease', (52, 63))	('TRK', 'Gene', '7294', (86, 89))	('TRK', 'Gene', (86, 89))	('fusions', 'Var', (41, 48))	('TRK', 'Gene', '7294', (32, 35))
50445	33435412	Although the prevalence of NTRK gene fusions in pediatric tumours varies among studies, it appears to exceed that in adults and may be as high as 26%.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('gene fusions', 'Var', (32, 44))	('TRK', 'Gene', '7294', (28, 31))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))	('TRK', 'Gene', (28, 31))
50456	33435412	This testing should include targetable oncogenic drivers including: NTRK1-3 gene fusions, BRAF mutations, RET gene fusions, ALK gene fusions, and MET overexpression/fusion (Figure 2).	('BRAF', 'Gene', (90, 94))	('NTRK1-3', 'Gene', (68, 75))	('ALK', 'Gene', '238', (124, 127))	('RET', 'Gene', (106, 109))	('MET', 'Gene', '79811', (146, 149))	('ALK', 'Gene', (124, 127))	('MET', 'Gene', (146, 149))	('mutations', 'Var', (95, 104))	('BRAF', 'Gene', '673', (90, 94))	('RET', 'Gene', '5979', (106, 109))
50462	33435412	In whole genome sequencing analyses of patients with LGGs, NTRK gene fusions have been found in 0.4-3.1% of tumours and were mutually exclusive with BRAF mutations and fusions as well as NF1, MYB, FGFR1, and MYBL1 mutations.	('patients', 'Species', '9606', (39, 47))	('TRK', 'Gene', (60, 63))	('FGFR1', 'Gene', '2260', (197, 202))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('MYB', 'Gene', '4602', (192, 195))	('MYB', 'Gene', (192, 195))	('fusions', 'Var', (69, 76))	('NF1', 'Gene', '4763', (187, 190))	('MYBL1', 'Gene', (208, 213))	('MYB', 'Gene', '4602', (208, 211))	('MYBL1', 'Gene', '4603', (208, 213))	('LGGs', 'Gene', (53, 57))	('mutations', 'Var', (214, 223))	('MYB', 'Gene', (208, 211))	('found', 'Reg', (87, 92))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('NF1', 'Gene', (187, 190))	('FGFR1', 'Gene', (197, 202))	('fusions', 'Var', (168, 175))	('TRK', 'Gene', '7294', (60, 63))	('tumours', 'Disease', (108, 115))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('mutations', 'Var', (154, 163))	('tumours', 'Disease', 'MESH:D009369', (108, 115))
50463	33435412	Rearrangement driven LGGs are more likely in younger patients.	('Rearrangement', 'Var', (0, 13))	('LGGs', 'Disease', (21, 25))	('patients', 'Species', '9606', (53, 61))
50467	33435412	Pediatric HGGs are usually not the result of transformation from LGG and, in contrast to adult HGG, most commonly harbour recurrent mutations in the genes encoding histone H3.3 and H3.1.	('H3.1', 'Gene', (181, 185))	('mutations', 'Var', (132, 141))	('H3.1', 'Gene', '8352', (181, 185))	('histone H3.3', 'Gene', '3021', (164, 176))	('histone H3.3', 'Gene', (164, 176))
50470	33435412	NTRK1-3 gene fusions are mostly found in hemispheric tumours, typically involve NTRK2, and have an intermediate prognosis.	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('NTRK2', 'Gene', '4915', (80, 85))	('NTRK1-3', 'Gene', (0, 7))	('found', 'Reg', (32, 37))	('fusions', 'Var', (13, 20))	('involve', 'Reg', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('NTRK2', 'Gene', (80, 85))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
50477	33435412	We recommend testing for common oncogenic drivers based on patient age, tumour location, and histology: BRAF V600E and KIAA1549-BRAF fusion for LGG and BRAF V600E, H3K27M, and G34R/V for HGG.	('KIAA1549', 'Gene', '57670', (119, 127))	('BRAF', 'Gene', (104, 108))	('BRAF', 'Gene', (152, 156))	('KIAA1549', 'Gene', (119, 127))	('LGG', 'Disease', (144, 147))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('patient', 'Species', '9606', (59, 66))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('G34R', 'SUBSTITUTION', 'None', (176, 180))	('V600E', 'Mutation', 'rs113488022', (157, 162))	('G34R', 'Var', (176, 180))	('H3K27M', 'Var', (164, 170))	('BRAF', 'Gene', '673', (104, 108))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('BRAF', 'Gene', '673', (128, 132))	('tumour', 'Disease', (72, 78))	('BRAF', 'Gene', '673', (152, 156))	('BRAF', 'Gene', (128, 132))
50479	33435412	NTRK1-3 fusions are particularly important to rule out in infants with hemispheric HGG.	('hemispheric HGG', 'Disease', (71, 86))	('NTRK1-3', 'Gene', (0, 7))	('infants', 'Species', '9606', (58, 65))	('fusions', 'Var', (8, 15))
50484	33435412	Given the poor outcome and morbidities associated with non-targeted systemic therapy, we recommend considering a selective TRK inhibitor as the first-line systemic treatment in HGG with NTRK gene fusions that are unresectable, metastatic, progressive, or in some cases of localized HGG.	('TRK', 'Gene', '7294', (123, 126))	('HGG', 'Disease', (177, 180))	('TRK', 'Gene', (123, 126))	('gene fusions', 'Var', (191, 203))	('TRK', 'Gene', '7294', (187, 190))	('TRK', 'Gene', (187, 190))
50489	33435412	Rosen and colleagues used a database of ~26,000 prospectively sequenced patients to identify those with NTRK gene fusions and assess their outcomes.	('TRK', 'Gene', (105, 108))	('gene fusions', 'Var', (109, 121))	('TRK', 'Gene', '7294', (105, 108))	('patients', 'Species', '9606', (72, 80))
50493	33435412	Positive results would confirm the ETV6-NTRK3 gene fusion and patients with negative results should be offered an RNA-based NGS panel for alternative oncogenic drivers, including NTRK1-3 gene fusions, BRAF, and MET.	('BRAF', 'Gene', '673', (201, 205))	('gene fusions', 'Var', (187, 199))	('NTRK1-3', 'Gene', (179, 186))	('ETV6', 'Gene', (35, 39))	('NTRK3', 'Gene', '4916', (40, 45))	('ETV6', 'Gene', '2120', (35, 39))	('MET', 'Gene', '79811', (211, 214))	('patients', 'Species', '9606', (62, 70))	('NTRK3', 'Gene', (40, 45))	('MET', 'Gene', (211, 214))	('BRAF', 'Gene', (201, 205))
50495	33435412	If there are standard of care treatment options considered satisfactory, we recommend exhausting these before treating a patient known to harbour an NTRK gene fusion with a TRK inhibitor, in accordance with the Health Canada-approved label.	('TRK', 'Gene', '7294', (150, 153))	('TRK', 'Gene', (150, 153))	('TRK', 'Gene', '7294', (173, 176))	('patient', 'Species', '9606', (121, 128))	('TRK', 'Gene', (173, 176))	('gene fusion', 'Var', (154, 165))
50496	33435412	In areas of high unmet need, where none of the available options are considered satisfactory (e.g., surgery with high morbidity, significant toxicity, or low response rates), it is reasonable to consider a TRK inhibitor as the first systemic treatment in patients with TRK fusion cancer, ideally on study if available (e.g., NCT02637687 or NCT03213704) (Figure 4).	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', (280, 286))	('TRK', 'Gene', '7294', (206, 209))	('TRK', 'Gene', '7294', (269, 272))	('TRK', 'Gene', (206, 209))	('patients', 'Species', '9606', (255, 263))	('NCT02637687', 'Var', (325, 336))	('toxicity', 'Disease', 'MESH:D064420', (141, 149))	('TRK', 'Gene', (269, 272))	('toxicity', 'Disease', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('NCT03213704', 'Var', (340, 351))
50517	32473077	Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells.	('N', 'Chemical', 'MESH:D009584', (73, 74))	('reduced', 'NegReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('transfection', 'Var', (49, 61))	('CD73 siRNA', 'Gene', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('MMP-2 production', 'MPA', (13, 29))
50522	32473077	Emmprin and CD73 form a complex, and MMP-2 production from fibroblasts is reduced by knockdown of CD73 in fibroblasts cocultured with squamous cell carcinoma cells.	('CD73', 'Gene', (98, 102))	('Emmprin', 'Gene', '682', (0, 7))	('knockdown', 'Var', (85, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('squamous cell carcinoma', 'Disease', (134, 157))	('reduced', 'NegReg', (74, 81))	('Emmprin', 'Gene', (0, 7))	('MMP-2 production', 'MPA', (37, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
50576	32473077	27  A431, CRL-2095, and ST353i were cultured in a growth medium consisting of DMEM supplemented with 10% FBS, streptomycin (50 mug/mL), and penicillin G (50 U/mL).	('penicillin G', 'Chemical', 'MESH:D010400', (140, 152))	('streptomycin', 'Chemical', 'MESH:D013307', (110, 122))	('CRL', 'Gene', (10, 13))	('ST353i', 'Var', (24, 30))	('A431', 'CellLine', 'CVCL:0037', (4, 8))	('CRL', 'Gene', '133396', (10, 13))	('men', 'Species', '9606', (89, 92))	('DMEM', 'Chemical', '-', (78, 82))
50581	32473077	Small interference RNA sequences were used for knockdown of CD73 or emmprin mRNA.	('knockdown', 'Var', (47, 56))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('CD73', 'Gene', (60, 64))	('N', 'Chemical', 'MESH:D009584', (20, 21))
50582	32473077	Three different CD73 siRNAs (Invitrogen):NT5EHSS107326, NT5EHSS107328, and NT5EHSS181585:were tested by immunoblotting (data not shown).	('NT5EHSS107326', 'Var', (41, 54))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('NT5EHSS107328', 'Var', (56, 69))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('N', 'Chemical', 'MESH:D009584', (56, 57))
50585	32473077	The siRNAs targeting CD73 were transfected into A431, CRL-2095, and ST353i using Oligofectamine transfection reagent in Opti-MEM (Thermo Fisher Scientific) in the absence of serum and antibiotics according to the manufacturer's instructions.	('Opti-MEM', 'Chemical', '-', (120, 128))	('Oligofectamine', 'Chemical', 'MESH:C484027', (81, 95))	('CRL', 'Gene', '133396', (54, 57))	('A431', 'CellLine', 'CVCL:0037', (48, 52))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('CRL', 'Gene', (54, 57))	('CD73', 'Var', (21, 25))
50621	32473077	CD73 or emmprin expression was inhibited by the transfection of CD73 or emmprin siRNA, respectively.	('CD73', 'Gene', (64, 68))	('CD73', 'Protein', (0, 4))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('emmprin', 'Gene', (8, 15))	('transfection', 'Var', (48, 60))	('inhibited', 'NegReg', (31, 40))
50624	32473077	The MMP-2 production from ST353i cells was increased in conditions of coculture with A431 or CRL-2095 cells and was inhibited by transfection of CD73 siRNA (Figure 4E,F) or emmprin siRNA (data not shown).	('N', 'Chemical', 'MESH:D009584', (153, 154))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('A431', 'CellLine', 'CVCL:0037', (85, 89))	('inhibited', 'NegReg', (116, 125))	('MMP-2 production', 'MPA', (4, 20))	('CD73', 'Var', (145, 149))	('CRL', 'Gene', (93, 96))	('increased', 'PosReg', (43, 52))	('CRL', 'Gene', '133396', (93, 96))
50631	32473077	In vitro, CD73 forms a complex with emmprin and is associated with increased production of MMP-2 from fibroblasts cocultured with SCC cells.	('SCC', 'Gene', (130, 133))	('production', 'MPA', (77, 87))	('complex', 'Interaction', (23, 30))	('CD73', 'Var', (10, 14))	('SCC', 'Gene', '6317', (130, 133))	('increased', 'PosReg', (67, 76))	('emmprin', 'Protein', (36, 43))
50632	32473077	High emmprin expression in the tumor cells is associated with poor prognosis in SCC of the oral cavity, skin, and hypopharynx.	('SCC', 'Gene', '6317', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('High', 'Var', (0, 4))	('tumor', 'Disease', (31, 36))	('SCC', 'Gene', (80, 83))	('emmprin', 'Gene', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
50635	32473077	33  In high-grade serous ovarian cancer, high CD73 intensity of fibroblasts is associated with poor prognosis.	('serous ovarian cancer', 'Disease', (18, 39))	('high CD73', 'Var', (41, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (18, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
50658	32473077	46  CD73 is also known to promote invasion and metastasis through the PI3K/Akt pathway.	('promote', 'PosReg', (26, 33))	('Akt', 'Gene', '207', (75, 78))	('Akt', 'Gene', (75, 78))	('46  CD73', 'Var', (0, 8))
50700	32080132	According to evidence from a comprehensive meta-analysis, the diagnostic accuracy of DWI in grading glioma is lower than MR spectroscopy, DSC and DCE MRI.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('DCE', 'Chemical', '-', (146, 149))	('lower', 'NegReg', (110, 115))	('DWI', 'Var', (85, 88))
50709	30442178	The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('predict', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('response to therapy', 'MPA', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('genetic alterations', 'Var', (62, 81))
50710	30442178	The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
50712	30442178	To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis.	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mutation', 'Var', (181, 189))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
50718	30442178	Next-generation sequencing has facilitated comprehensive mutational profiling of all major cancers and has led to the discovery of oncogenic driver mutations, many of which can be targeted therapeutically.	('mutations', 'Var', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
50720	30442178	However, sequencing data has shown that actionable mutations, albeit with different frequencies, occur across cancers, which has raised the question about histotype-independent therapies and novel ways of tumor classifications no longer relying on histology but on genetic profiles.	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
50723	30442178	That targeted therapies against the same single molecular alteration can be effective across cancers, as shown, for instance, by the efficacy of anti-Her2 therapy in both gastric and breast cancers or the clinical benefit from inhibition of mutated cKIT in gastrointestinal stromal tumors (GIST) and melanoma or mastocytosis.	('gastric and breast cancers', 'Disease', 'MESH:D013274', (171, 197))	('melanoma or mastocytosis', 'Disease', (300, 324))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Her2', 'Gene', '2064', (150, 154))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('gastrointestinal stromal tumors', 'Disease', (257, 288))	('GIST', 'Phenotype', 'HP:0100723', (290, 294))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('Her2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutated', 'Var', (241, 248))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cKIT', 'Gene', '3815', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancers', 'Disease', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('melanoma or mastocytosis', 'Disease', 'MESH:D008415', (300, 324))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (257, 288))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (257, 288))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('inhibition', 'Var', (227, 237))	('mastocytosis', 'Phenotype', 'HP:0100495', (312, 324))	('cKIT', 'Gene', (249, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
50724	30442178	However, the fact that inhibition of BRAF mutated at V600 is effective in melanoma but not in colorectal cancer is a prominent example against the general transferability of knowledge on a single actionable mutation from one histological tumor type to another.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('BRAF', 'Gene', '673', (37, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('BRAF', 'Gene', (37, 41))	('mutated at V600', 'Var', (42, 57))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('ran', 'Gene', (156, 159))	('ran', 'Gene', '5901', (156, 159))
50726	30442178	Using mutational profiles or just single genetic aberrations, as is the case in the current basket trials, is unlikely to cover the full scope of (tissue-specific) molecular effects including epigenetic mechanisms and downstream regulation such as post-translational modifications.	('mutational', 'Var', (6, 16))	('ran', 'Gene', (254, 257))	('ran', 'Gene', '5901', (254, 257))
50741	30442178	To address the question of how mutational differences between two classes affect protein expressions in more than one histotype in the same way, we performed a cross-cancer effect analysis.	('mutational differences', 'Var', (31, 53))	('affect', 'Reg', (74, 80))	('protein expressions', 'MPA', (81, 100))	('cross-cancer', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cross-cancer', 'Disease', 'MESH:C537866', (160, 172))
50756	30442178	At this point, it is unclear whether the reason for this inconsistency between genetic and protein profiles is the differential translation of genetic profiles into protein levels in different cancer types, or organ- and tissue-specific protein base levels that are modulated by mutations:or a combination of both.	('ran', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('ran', 'Gene', '5901', (129, 132))	('mutations', 'Var', (279, 288))	('cancer', 'Disease', (193, 199))	('modulated', 'Reg', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
50770	30442178	In the proposal by Ciriello et al., tumors are classified by the presence of somatic mutations and copy number alterations in cancer-related pathways.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('copy number alterations', 'Var', (99, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
50782	30442178	The least pronounced but still significant class discriminability is achieved for classes C12 and C5 in breast cancer (sdis = - 0.31, p = 4.4e-3; srand = - 8.0e-5).	('sdis', 'Chemical', '-', (119, 123))	('ran', 'Gene', (147, 150))	('ran', 'Gene', '5901', (147, 150))	('C12', 'Var', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
50801	30442178	With CES = 2%, the overall classification effectivity score of this classification is the lowest among all tested classifications indicating that global comparisons based on somatic mutations only are not effective in classifying tumors in a meaningful way if the available protein profiles are considered relevant.	('CES', 'Chemical', '-', (5, 8))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Disease', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('CES', 'Var', (5, 8))	('lowest', 'NegReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
50804	30442178	For this classification, class discriminability sdis is highest between class toLGG (cases that are most similar to low-grade glioma cases by their mutation profile) and class toPRAD for low-grade glioma (LGG) (sdis = - 3.26; p = 0.0; srand = - 6.1e-5; characteristic protein profiles increased in toLGG: p70S6K_pT389; increased in ToPRAD: YAP_pS127, HER2_pY1248, HER2, EGFR_pY1068, EGFR_pY1173, Src_pY416, and Cyclin_D1).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('EGFR', 'Gene', (370, 374))	('HER2', 'Gene', '2064', (351, 355))	('increased', 'PosReg', (285, 294))	('sdis', 'Chemical', '-', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('p70S6K', 'Gene', '6198', (305, 311))	('Cyclin_D1', 'Gene', (411, 420))	('EGFR', 'Gene', (383, 387))	('sdis', 'Chemical', '-', (211, 215))	('EGFR', 'Gene', '1956', (370, 374))	('HER2', 'Gene', '2064', (364, 368))	('HER2', 'Gene', (351, 355))	('glioma', 'Disease', (126, 132))	('ran', 'Gene', (236, 239))	('ran', 'Gene', '5901', (236, 239))	('increased', 'PosReg', (319, 328))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('p70S6K', 'Gene', (305, 311))	('EGFR', 'Gene', '1956', (383, 387))	('glioma', 'Disease', (197, 203))	('Src_pY416', 'Var', (396, 405))	('HER2', 'Gene', (364, 368))	('Cyclin_D1', 'Gene', '595', (411, 420))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
50827	30442178	Using the same approach as above, we are systematically evaluating all major actionable somatic mutations and copy number alterations against which drugs are approved for clinical use or which are currently tested in clinical trials with respect to their effects on proteins across cancers.	('cancers', 'Disease', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('copy number alterations', 'Var', (110, 133))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('mutations', 'Var', (96, 105))
50832	30442178	Overall, our analysis showed for all analyzed 12 actionable genes (OncoKB evidence levels 1-3) that the mutational status is associated with significant differences in protein profiles in histotypes for which the respective targeted drugs are approved or currently being clinically tested and showed additional mutation-associated protein profiles in 9 histological tumor types.	('tumor', 'Disease', (366, 371))	('mutational', 'Var', (104, 114))	('associated', 'Reg', (125, 135))	('protein profiles', 'MPA', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('differences', 'Reg', (153, 164))
50834	30442178	Only KRAS/NRAS mutations in colorectal cancer do not result in discriminable protein profiles comparing wild-type and mutated cases, whereas an effect can be observed for thyroid cancer and melanoma.	('result', 'Reg', (53, 59))	('NRAS', 'Gene', '4893', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (15, 24))	('colorectal cancer', 'Disease', (28, 45))	('KRAS', 'Gene', (5, 9))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('KRAS', 'Gene', '3845', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('thyroid cancer', 'Disease', (171, 185))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('NRAS', 'Gene', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))
50837	30442178	Our results demonstrate that in addition to confirming known druggable genes in the available cell line data, protein profile discriminability in between presence or absence of oncogenic mutations is predictive of drug response in cell line data across cancers (p = 0.048, Table 2).	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('mutations', 'Var', (187, 196))	('protein profile', 'MPA', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
50838	30442178	BRAF mutations are actionable in melanomas (OncoKB level 1).	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (33, 42))
50839	30442178	Mutations of BRAF are frequent enough in our data for melanoma (46% cases with mutation) and thyroid carcinoma (not yet reported by OncoKB, 56% cases with mutation) for further analysis.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('thyroid carcinoma', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAF', 'Gene', (13, 17))	('melanoma', 'Disease', (54, 62))	('Mutations', 'Var', (0, 9))	('mutation', 'Var', (79, 87))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (93, 110))
50840	30442178	The actionable mutations create discriminable groups of cases for thyroid carcinoma (sdis = - 2.07; p = 0.0; srand = - 1.0e-4) and melanoma (sdis = - 0.10; p = 4.7e-3; srand = - 1.1e-4).	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (66, 83))	('melanoma', 'Disease', (131, 139))	('thyroid carcinoma', 'Disease', (66, 83))	('sdis', 'Chemical', '-', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('sdis', 'Chemical', '-', (141, 145))	('ran', 'Gene', (169, 172))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (66, 83))	('ran', 'Gene', '5901', (169, 172))
50844	30442178	CDK4 amplification is actionable for differentiated sarcomas (OncoKB level 2).	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('amplification', 'Var', (5, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcomas', 'Disease', (52, 60))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
50846	30442178	For sarcoma, 36% of the cases show CDK4 amplification and protein profiles are discriminable (sdis = - 0.34; p = 0.0; srand = - 6.0e-5) with E-Cadherin, Caveolin-1, Akt_pS473, Cyclin_B1, ER-alpha, Akt_pT308, YAP_pS127, S6_pS240_S244, and Cyclin_E1 decreased and HSP70, Syk, Lck, Src_pY416, and Src_pY527 increased in CDK4 amplified cases.	('CDK4', 'Gene', '1019', (317, 321))	('Cyclin_B1', 'Gene', (176, 185))	('decreased', 'NegReg', (248, 257))	('Lck', 'Gene', (274, 277))	('ER-alpha', 'Gene', (187, 195))	('E-Cadherin', 'Gene', '999', (141, 151))	('ER-alpha', 'Gene', '2099', (187, 195))	('increased', 'PosReg', (304, 313))	('sdis', 'Chemical', '-', (94, 98))	('Syk', 'Gene', '6850', (269, 272))	('Cyclin_B1', 'Gene', '891', (176, 185))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('CDK4', 'Gene', (35, 39))	('HSP70', 'Gene', (262, 267))	('ran', 'Gene', (119, 122))	('sarcoma', 'Disease', (4, 11))	('ran', 'Gene', '5901', (119, 122))	('Syk', 'Gene', (269, 272))	('Cyclin_E1', 'Gene', '898', (238, 247))	('E-Cadherin', 'Gene', (141, 151))	('Caveolin-1', 'Gene', (153, 163))	('CDK4', 'Gene', (317, 321))	('CDK4', 'Gene', '1019', (35, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Src_pY416', 'Var', (279, 288))	('Caveolin-1', 'Gene', '857', (153, 163))	('Src_pY527', 'Var', (294, 303))	('Cyclin_E1', 'Gene', (238, 247))	('HSP70', 'Gene', '3308', (262, 267))	('Lck', 'Gene', '3932', (274, 277))
50848	30442178	EGFR mutations are actionable in non-small cell lung cancer (OncoKB level 1).	('EGFR', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', (33, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('EGFR', 'Gene', '1956', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
50850	30442178	Lung adenocarcinoma (LUAD) cases with actionable mutation of EGFR are discriminable from those without by protein profile (sdis = - 0.44; p = 5.9e-4; srand = 3.1e-5).	('sdis', 'Chemical', '-', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('ran', 'Gene', (151, 154))	('ran', 'Gene', '5901', (151, 154))	('mutation', 'Var', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
50851	30442178	EGFR_pY1068 levels are increased for cases with the respective mutations, and Claudin-7 levels are decreased among those cases.	('mutations', 'Var', (63, 72))	('decreased', 'NegReg', (99, 108))	('EGFR', 'Gene', (0, 4))	('Claudin-7', 'Gene', '1366', (78, 87))	('increased', 'PosReg', (23, 32))	('EGFR', 'Gene', '1956', (0, 4))	('Claudin-7', 'Gene', (78, 87))
50852	30442178	ERBB2/HER2 amplification is actionable in breast cancer and gastric cancer (level 1 evidence, FDA-approved).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ERBB2', 'Gene', (0, 5))	('gastric cancer', 'Disease', (60, 74))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('breast cancer', 'Disease', (42, 55))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (6, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('amplification', 'Var', (11, 24))
50862	30442178	Two histological tumor types in which ERBB2 amplification has a similar impact on proteins are breast (BRCA) and gastric (STAD) cancers (p = 2.3e-3).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (17, 22))	('BRCA', 'Gene', '672', (103, 107))	('BRCA', 'Gene', (103, 107))	('gastric (STAD) cancers', 'Disease', 'MESH:D013274', (113, 135))	('amplification', 'Var', (44, 57))	('ERBB2', 'Gene', (38, 43))	('proteins', 'MPA', (82, 90))	('ERBB2', 'Gene', '2064', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('impact', 'Reg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
50867	30442178	For FGFR1 amplification, clinical evidence (OncoKB level 3) exists on its actionability in lung squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('FGFR1', 'Gene', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('lung squamous cell carcinomas', 'Disease', (91, 120))	('FGFR1', 'Gene', '2260', (4, 9))	('amplification', 'Var', (10, 23))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (96, 120))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
50868	30442178	Our analysis shows that besides lung squamous cell carcinoma, protein expression of amplified cases is discriminable from non-amplified cases in renal clear cell carcinoma, testicular germ cell tumors, lung adenocarcinoma, endometrial carcinoma, breast cancer, and thymoma (all currently not reported by OncoKB).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (145, 171))	('renal clear cell carcinoma', 'Disease', (145, 171))	('thymoma', 'Disease', (265, 272))	('thymoma', 'Phenotype', 'HP:0100522', (265, 272))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('lung adenocarcinoma', 'Disease', (202, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 60))	('lung squamous cell carcinoma', 'Disease', (32, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumors', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('protein expression', 'MPA', (62, 80))	('thymoma', 'Disease', 'MESH:D013945', (265, 272))	('testicular', 'Disease', (173, 183))	('amplified', 'Var', (84, 93))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
50871	30442178	A cross-cancer effect is found between breast cancer and lung adenocarcinoma with HER2, HER2_pY1248, and EGFR_pY1068 levels decrease and 4E-BP1 levels increase associated with FGFR1 amplification for both histological tumor types.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('A cross-cancer', 'Disease', 'MESH:C537866', (0, 14))	('increase', 'PosReg', (151, 159))	('HER2', 'Gene', '2064', (88, 92))	('4E-BP1', 'Gene', (137, 143))	('decrease', 'NegReg', (124, 132))	('EGFR', 'Gene', (105, 109))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Disease', (218, 223))	('breast cancer', 'Disease', (39, 52))	('levels', 'MPA', (117, 123))	('A cross-cancer', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('lung adenocarcinoma', 'Disease', (57, 76))	('HER2', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR1', 'Gene', '2260', (176, 181))	('HER2', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('4E-BP1', 'Gene', '1978', (137, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FGFR1', 'Gene', (176, 181))	('HER2', 'Gene', '2064', (82, 86))	('levels', 'MPA', (144, 150))	('amplification', 'Var', (182, 195))
50872	30442178	Certain FGFR3 mutations are actionable in bladder cancer (OncoKB level 3).	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('FGFR3', 'Gene', '2261', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('actionable', 'Reg', (28, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
50873	30442178	Targetable FGFR3 mutations are only frequent enough in urothelial and bladder carcinoma for our analysis.	('frequent', 'Reg', (36, 44))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (70, 87))	('FGFR3', 'Gene', '2261', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('bladder carcinoma', 'Disease', 'MESH:D001749', (70, 87))	('FGFR3', 'Gene', (11, 16))	('bladder carcinoma', 'Disease', (70, 87))	('urothelial', 'Disease', (55, 65))	('mutations', 'Var', (17, 26))
50874	30442178	The protein profiles of cases with at least one of these mutations are discriminable from the profiles of those without (sdis = - 0.76; p = 2.7e-3; srand = - 1.3e-5).	('ran', 'Gene', '5901', (149, 152))	('mutations', 'Var', (57, 66))	('sdis', 'Chemical', '-', (121, 125))	('ran', 'Gene', (149, 152))
50875	30442178	E-Cadherin, beta-Catenin, HER2, Ku80, PTEN, IRS1, and 53BP1 are increased among cases having one or more specific FGF3 mutation.	('53BP1', 'Gene', (54, 59))	('beta-Catenin', 'Gene', '1499', (12, 24))	('FGF3', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('Ku80', 'Gene', '7520', (32, 36))	('53BP1', 'Gene', '7158', (54, 59))	('PTEN', 'Gene', '5728', (38, 42))	('Ku80', 'Gene', (32, 36))	('HER2', 'Gene', (26, 30))	('E-Cadherin', 'Gene', (0, 10))	('HER2', 'Gene', '2064', (26, 30))	('FGF3', 'Gene', '2248', (114, 118))	('IRS1', 'Gene', (44, 48))	('IRS1', 'Gene', '3667', (44, 48))	('increased', 'PosReg', (64, 73))	('E-Cadherin', 'Gene', '999', (0, 10))	('PTEN', 'Gene', (38, 42))	('beta-Catenin', 'Gene', (12, 24))
50876	30442178	IDH1 mutations are actionable in acute myeloid leukemia, cholangiocarcinoma, and glioma (OncoKB level 3).	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('acute myeloid leukemia', 'Disease', (33, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('mutations', 'Var', (5, 14))	('glioma', 'Disease', (81, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('IDH1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (57, 75))	('IDH1', 'Gene', '3417', (0, 4))
50877	30442178	Specific IDH1 mutations lead to discriminable protein profiles for low-grade glioma (sdis = - 0.47; p = 0.0; srand = - 3.1e-6) and glioblastoma (sdis = - 1.59; p = 5.0e-4; srand = - 1.0e-5).	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH1', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('sdis', 'Chemical', '-', (85, 89))	('IDH1', 'Gene', '3417', (9, 13))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('ran', 'Gene', (173, 176))	('glioma', 'Disease', (77, 83))	('protein profiles', 'MPA', (46, 62))	('ran', 'Gene', '5901', (173, 176))	('sdis', 'Chemical', '-', (145, 149))	('mutations', 'Var', (14, 23))	('glioblastoma', 'Disease', (131, 143))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
50879	30442178	For glioblastoma IGFBP2, EGFR_pY1068, HER2_pY1248, Caveolin-1, Akt_pT308, Fibronectin, Collagen_VI, and EGFR_pY1173 are decreased in the group of mutated cases.	('decreased', 'NegReg', (120, 129))	('Fibronectin', 'Gene', (74, 85))	('HER2', 'Gene', (38, 42))	('EGFR', 'Gene', (25, 29))	('mutated', 'Var', (146, 153))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (104, 108))	('Caveolin-1', 'Gene', '857', (51, 61))	('glioblastoma', 'Disease', (4, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('Caveolin-1', 'Gene', (51, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('IGFBP2', 'Gene', '3485', (17, 23))	('IGFBP2', 'Gene', (17, 23))	('EGFR', 'Gene', '1956', (25, 29))	('HER2', 'Gene', '2064', (38, 42))	('Fibronectin', 'Gene', '2335', (74, 85))
50880	30442178	Therefore, IGFBP2, EGFR_pY1068, HER2_pY1248, and EGFR_pY1173 are affected in the same way by IDH1 mutations in low-grade glioma and glioblastoma, and we report a cross-cancer effect for those groups.	('HER2', 'Gene', '2064', (32, 36))	('EGFR', 'Gene', (19, 23))	('glioblastoma', 'Disease', (132, 144))	('glioma', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('EGFR', 'Gene', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('cross-cancer', 'Disease', 'MESH:C537866', (162, 174))	('IDH1', 'Gene', (93, 97))	('HER2', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cross-cancer', 'Disease', (162, 174))	('IGFBP2', 'Gene', '3485', (11, 17))	('EGFR', 'Gene', '1956', (49, 53))	('IDH1', 'Gene', '3417', (93, 97))	('mutations', 'Var', (98, 107))	('affected', 'Reg', (65, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('IGFBP2', 'Gene', (11, 17))
50881	30442178	KIT mutations are actionable in gastrointestinal stromal tumors (OncoKB level 1).	('gastrointestinal stromal tumors', 'Disease', (32, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (4, 13))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (32, 63))	('KIT', 'Gene', (0, 3))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (32, 63))
50882	30442178	For the tested KIT mutations, only testicular germ cell tumors (TGCT) had enough mutated cases sufficient for our analysis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('KIT', 'Gene', (15, 18))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
50883	30442178	The protein profiles of the mutated and wild-type cases are discriminable (sdis = - 0.90; p = 4.5e-3; srand = - 2.6e-4) with decreased E-Cadherin and Fibronectin expression in wildtype cases and increased c-Kit, STAT5-alpha, and Syk expression levels.	('Fibronectin', 'Gene', '2335', (150, 161))	('mutated', 'Var', (28, 35))	('c-Kit', 'Gene', (205, 210))	('Fibronectin', 'Gene', (150, 161))	('E-Cadherin', 'Gene', '999', (135, 145))	('expression levels', 'MPA', (233, 250))	('c-Kit', 'Gene', '3815', (205, 210))	('Syk', 'Gene', '6850', (229, 232))	('decreased', 'NegReg', (125, 134))	('sdis', 'Chemical', '-', (75, 79))	('STAT5-alpha', 'Gene', '6776', (212, 223))	('ran', 'Gene', (103, 106))	('expression', 'MPA', (162, 172))	('ran', 'Gene', '5901', (103, 106))	('Syk', 'Gene', (229, 232))	('STAT5-alpha', 'Gene', (212, 223))	('increased', 'PosReg', (195, 204))	('E-Cadherin', 'Gene', (135, 145))
50885	30442178	KRAS/NRAS mutations are therapeutically relevant for melanomas, colorectal cancer, and thyroid cancer (OncoKB level 3).	('melanomas', 'Disease', (53, 62))	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', (64, 81))	('NRAS', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('NRAS', 'Gene', '4893', (5, 9))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
50886	30442178	Specific KRAS/NRAS mutations are correlated with differences in protein profiles for melanomas and thyroid cancer and also for testicular germ cell tumors, endometrial carcinoma, and lung adenocarcinoma (in conformity with OncoKB level 4 data).	('melanomas', 'Disease', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('thyroid cancer', 'Disease', (99, 113))	('differences', 'Reg', (49, 60))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('NRAS', 'Gene', '4893', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (156, 177))	('KRAS', 'Gene', '3845', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))	('protein profiles', 'MPA', (64, 80))	('lung adenocarcinoma', 'Disease', (183, 202))	('KRAS', 'Gene', (9, 13))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumors', 'Disease', (148, 154))	('NRAS', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('mutations', 'Var', (19, 28))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('endometrial carcinoma', 'Disease', (156, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
50889	30442178	For melanoma (sdis = - 0.16; p = 1.0e-3; and = 5.2e-6) E-Cadherin, Caveolin-1, and c-Kit expression levels are decreased for mutated cases, and MAPK_pT202_Y204 is increased.	('E-Cadherin', 'Gene', '999', (55, 65))	('Caveolin-1', 'Gene', (67, 77))	('mutated', 'Var', (125, 132))	('MAPK_pT202_Y204', 'Var', (144, 159))	('decreased', 'NegReg', (111, 120))	('sdis', 'Chemical', '-', (14, 18))	('Caveolin-1', 'Gene', '857', (67, 77))	('c-Kit', 'Gene', (83, 88))	('c-Kit', 'Gene', '3815', (83, 88))	('E-Cadherin', 'Gene', (55, 65))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('expression levels', 'MPA', (89, 106))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
50890	30442178	For thyroid carcinoma (sdis = - 1.53; p = 0.0; srand = - 3.0e-4), the level of Fibronectin is decreased in mutated cases.	('sdis', 'Chemical', '-', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('ran', 'Gene', (48, 51))	('mutated', 'Var', (107, 114))	('ran', 'Gene', '5901', (48, 51))	('Fibronectin', 'Gene', '2335', (79, 90))	('decreased', 'NegReg', (94, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (4, 21))	('Fibronectin', 'Gene', (79, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (4, 21))	('thyroid carcinoma', 'Disease', (4, 21))
50891	30442178	For lung adenocarcinoma and endometrial carcinoma, we observed a cross-cancer effect for KRAS/NRAS-mutated cases as ATM levels are decreased, and MAPK_pT202_Y204, Claudin-7, S6_pS235_S236, and MEK1_pS217_S221 are increased in both histological tumor types consistently.	('S6_pS235_S236', 'Var', (174, 187))	('endometrial carcinoma', 'Disease', (28, 49))	('Claudin-7', 'Gene', '1366', (163, 172))	('lung adenocarcinoma', 'Disease', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (28, 49))	('NRAS', 'Gene', '4893', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MEK', 'Gene', '5609', (193, 196))	('ATM', 'Gene', '472', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('KRAS', 'Gene', '3845', (89, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (28, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('cross-cancer', 'Disease', 'MESH:C537866', (65, 77))	('MEK', 'Gene', (193, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('MAPK_pT202_Y204', 'Var', (146, 161))	('KRAS', 'Gene', (89, 93))	('NRAS', 'Gene', (94, 98))	('tumor', 'Disease', (244, 249))	('cross-cancer', 'Disease', (65, 77))	('decreased', 'NegReg', (131, 140))	('ATM', 'Gene', (116, 119))	('Claudin-7', 'Gene', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('increased', 'PosReg', (213, 222))
50892	30442178	MDM2 amplification is actionable in liposarcoma (OncoKB level 3).	('liposarcoma', 'Disease', (36, 47))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
50893	30442178	Besides sarcoma, the protein profiles of cases with MDM2 amplification are discriminable from those with normal copy numbers for renal clear cell carcinoma, lung adenocarcinoma, thyroid carcinoma, breast cancer, ovarian carcinoma, and low-grade glioma (all currently not reported by OncoKB).	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('MDM2', 'Gene', (52, 56))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (129, 155))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('renal clear cell carcinoma', 'Disease', (129, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (178, 195))	('MDM2', 'Gene', '4193', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('thyroid carcinoma', 'Disease', (178, 195))	('breast cancer', 'Disease', (197, 210))	('amplification', 'Var', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (212, 229))	('ovarian carcinoma', 'Disease', (212, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (178, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma', 'Disease', (8, 15))	('glioma', 'Disease', (245, 251))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('lung adenocarcinoma', 'Disease', (157, 176))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
50894	30442178	Protein levels of sarcoma cases with MDM2 amplifications are discriminable from those without, with a dissimilarity score of sdis = - 0.41 (p = 0.0; srand = - 8.9e-5).	('ran', 'Gene', '5901', (150, 153))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('sarcoma', 'Disease', (18, 25))	('Protein levels', 'MPA', (0, 14))	('MDM2', 'Gene', '4193', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('amplifications', 'Var', (42, 56))	('MDM2', 'Gene', (37, 41))	('sdis', 'Chemical', '-', (125, 129))	('ran', 'Gene', (150, 153))
50895	30442178	Amplified cases show decreased levels of E-Cadherin, Akt_pS473, Akt_pT308, ER-alpha, Caveolin-1, S6_pS240_S244, S6_pS235_S236, and Cyclin_B1 and increased levels of HSP70, Syk, and Lck.	('Lck', 'Gene', (181, 184))	('Akt_pT308', 'Gene', (64, 73))	('HSP70', 'Gene', '3308', (165, 170))	('Cyclin_B1', 'Gene', '891', (131, 140))	('Caveolin-1', 'Gene', (85, 95))	('E-Cadherin', 'Gene', (41, 51))	('Caveolin-1', 'Gene', '857', (85, 95))	('S6_pS240_S244', 'Var', (97, 110))	('levels', 'MPA', (155, 161))	('ER-alpha', 'Gene', (75, 83))	('increased', 'PosReg', (145, 154))	('ER-alpha', 'Gene', '2099', (75, 83))	('Syk', 'Gene', '6850', (172, 175))	('HSP70', 'Gene', (165, 170))	('S6_pS235_S236', 'Var', (112, 125))	('Syk', 'Gene', (172, 175))	('decreased', 'NegReg', (21, 30))	('Cyclin_B1', 'Gene', (131, 140))	('Lck', 'Gene', '3932', (181, 184))	('Akt_pS473', 'Protein', (53, 62))	('E-Cadherin', 'Gene', '999', (41, 51))
50898	30442178	In addition to these histotypes, we found 11 other histological tumor types (renal clear cell carcinoma, low-grade glioma, renal papillary cell carcinoma, colon carcinoma, thyroid carcinoma, thymoma, sarcoma, lung adenocarcinoma, testicular germ cell tumors, prostate adenocarcinoma, glioblastoma, breast and ovarian carcinoma) where MET amplification is associated with a significant change in protein expression.	('glioma', 'Disease', (115, 121))	('tumor', 'Disease', (251, 256))	('breast and ovarian carcinoma', 'Disease', 'MESH:D001943', (298, 326))	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('protein expression', 'MPA', (395, 413))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MET amplification', 'Var', (334, 351))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lung adenocarcinoma', 'Disease', (209, 228))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (172, 189))	('thymoma', 'Disease', 'MESH:D013945', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('thyroid carcinoma', 'Disease', (172, 189))	('renal papillary cell carcinoma', 'Disease', (123, 153))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (209, 228))	('thymoma', 'Disease', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (172, 189))	('thymoma', 'Phenotype', 'HP:0100522', (191, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('tumors', 'Disease', (251, 257))	('prostate adenocarcinoma', 'Disease', (259, 282))	('colon carcinoma', 'Disease', (155, 170))	('change', 'Reg', (385, 391))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (77, 103))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (309, 326))	('renal clear cell carcinoma', 'Disease', (77, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Disease', (64, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('colon carcinoma', 'Disease', 'MESH:D015179', (155, 170))	('sarcoma', 'Disease', (200, 207))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (259, 282))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('glioblastoma', 'Disease', (284, 296))
50901	30442178	MET amplification is present in renal clear cell carcinoma cases, and protein profiles of amplified and non-amplified cases can be discriminated (sdis = - 0.18; p = 0.0; srand = - 2.0e-5; Src_pY527, Bcl-2, beta-Catenin, PTEN, MAPK_pT202_Y204 are decreased in amplified cases and ACC1, Cyclin_B1, ASNS, ACC_pS79, and Transglutaminase are increased).	('Cyclin_B1', 'Gene', '891', (285, 294))	('ran', 'Gene', (171, 174))	('ran', 'Gene', '5901', (171, 174))	('beta-Catenin', 'Gene', '1499', (206, 218))	('ASNS', 'Gene', (296, 300))	('Src_pY527', 'Var', (188, 197))	('PTEN', 'Gene', '5728', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('increased', 'PosReg', (337, 346))	('ACC_pS79', 'MPA', (302, 310))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (32, 58))	('ACC1', 'Gene', (279, 283))	('beta-Catenin', 'Gene', (206, 218))	('MAPK_pT202_Y204', 'Gene', (226, 241))	('renal clear cell carcinoma', 'Disease', (32, 58))	('decreased', 'NegReg', (246, 255))	('ACC1', 'Gene', '597', (279, 283))	('Cyclin_B1', 'Gene', (285, 294))	('ran', 'Gene', (317, 320))	('ran', 'Gene', '5901', (317, 320))	('sdis', 'Chemical', '-', (146, 150))	('Bcl-2', 'Gene', (199, 204))	('ASNS', 'Gene', '440', (296, 300))	('PTEN', 'Gene', (220, 224))	('Bcl-2', 'Gene', '596', (199, 204))
50903	30442178	PIK3CA activating mutations are actionable for breast cancer (OncoKB evidence level 3).	('breast cancer', 'Disease', (47, 60))	('activating', 'PosReg', (7, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('mutations', 'Var', (18, 27))
50905	30442178	OncoKB level 4 data lists all available histological tumor types as possibly actionable for PIK3CA activating mutations.	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', '5290', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('PIK3CA', 'Gene', (92, 98))
50907	30442178	Breast cancer cases with PIK3CA-activating mutations are discriminable from those without (sdis = - 0.52; p = 0.0; srand = 6.2e-6) with specific proteins (increased levels) PR, ER-alpha, MAPK_pT202_Y204, Fibronectin, AR, and GATA3 in mutated cases and Cyclin_B1, Cyclin_E1, ASNS, and HER2 being decreased.	('ran', 'Gene', (116, 119))	('ran', 'Gene', '5901', (116, 119))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cyclin_B1', 'Gene', '891', (252, 261))	('PIK3CA', 'Gene', '5290', (25, 31))	('increased', 'PosReg', (155, 164))	('HER2', 'Gene', '2064', (284, 288))	('Cyclin_E1', 'Gene', '898', (263, 272))	('ASNS', 'Gene', '440', (274, 278))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutated', 'Var', (234, 241))	('GATA3', 'Gene', '2625', (225, 230))	('PIK3CA', 'Gene', (25, 31))	('Cyclin_E1', 'Gene', (263, 272))	('Fibronectin', 'Gene', '2335', (204, 215))	('Cyclin_B1', 'Gene', (252, 261))	('sdis', 'Chemical', '-', (91, 95))	('ASNS', 'Gene', (274, 278))	('ER-alpha', 'Gene', (177, 185))	('GATA3', 'Gene', (225, 230))	('HER2', 'Gene', (284, 288))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (43, 52))	('ER-alpha', 'Gene', '2099', (177, 185))	('Breast cancer', 'Disease', (0, 13))	('Fibronectin', 'Gene', (204, 215))
50911	30442178	However, many open questions remain because apart from mutations with unknown functional effects, it is often not possible even for oncogenic mutations with established clinical relevance in one cancer type to transfer knowledge of actionability to another cancer type.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('ran', 'Gene', (211, 214))	('ran', 'Gene', '5901', (211, 214))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
50917	30442178	This indicates that identical genetic alterations are not translated into protein profiles in the same way in different histotypes.	('ran', 'Gene', '5901', (59, 62))	('ran', 'Gene', (59, 62))	('genetic alterations', 'Var', (30, 49))
50921	30442178	In addition to showing that our analysis identifies protein-level effects for known actionable genes and corresponding cancer types, our approach also identified protein-level alterations indicative of potential novel actionable gene:cancer combinations that are so far unknown according to OncoKB including level 4 evidence (biological information).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('combinations', 'Var', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
50922	30442178	This includes ERBB2/HER2 amplification in endometrial carcinoma, renal papillary carcinoma, testicular germ cell tumors, urothelial carcinoma, renal clear cell carcinoma, colon carcinoma, ovarian carcinoma, thymoma, thyroid carcinoma, cervical carcinoma, and head and neck squamous cell carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (171, 186))	('tumors', 'Disease', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('HER2', 'Gene', (20, 24))	('thymoma', 'Disease', 'MESH:D013945', (207, 214))	('renal papillary carcinoma', 'Disease', (65, 90))	('cervical carcinoma', 'Disease', (235, 253))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinoma', 'Disease', (42, 63))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (216, 233))	('ERBB2', 'Gene', (14, 19))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (121, 141))	('thyroid carcinoma', 'Disease', (216, 233))	('thymoma', 'Disease', (207, 214))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 169))	('cervical carcinoma', 'Disease', 'MESH:D002575', (235, 253))	('renal clear cell carcinoma', 'Disease', (143, 169))	('thymoma', 'Phenotype', 'HP:0100522', (207, 214))	('neck squamous cell carcinoma', 'Disease', (268, 296))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (188, 205))	('ERBB2', 'Gene', '2064', (14, 19))	('ovarian carcinoma', 'Disease', (188, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (42, 63))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (268, 296))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (216, 233))	('HER2', 'Gene', '2064', (20, 24))	('amplification', 'Var', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (65, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (42, 63))	('colon carcinoma', 'Disease', (171, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (188, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('urothelial carcinoma', 'Disease', (121, 141))
50926	30442178	Interestingly, actionable genes with copy number alterations showed effects on protein expression for more histotypes than those with simple somatic mutations (10.2 affected tumor types on average for amplifications vs. 2.14 for simple somatic mutations).	('tumor', 'Disease', (174, 179))	('protein expression', 'MPA', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('effects', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('copy number alterations', 'Var', (37, 60))
50930	30442178	With respect to the actionable gene analysis, our approach may underestimate the number of potentially druggable genes, but the fact that it readily identifies many well-established actionable gene, cancer combinations, such as, for instance, HER2 amplification in breast and gastric cancer, indicates its validity.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('HER2', 'Gene', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HER2', 'Gene', '2064', (243, 247))	('cancer', 'Disease', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (265, 290))	('amplification', 'Var', (248, 261))
50937	30442178	By evaluating protein-level effects of genetic aberrations, our approach facilitates the identification of functionally relevant mutations and may therefore contribute to predicting actionable mutations across cancers and to guide basket trial design.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (129, 138))	('facilitates', 'PosReg', (73, 84))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))
50963	28842674	Each panel within the figure presents a different method for evaluating PpIX emissions, and the series highlights how PpIX quantification is influenced not only by PpIX concentration, but also by attenuation caused by tissue optical properties.	('influenced', 'Reg', (141, 151))	('PpIX', 'Var', (164, 168))	('PpIX', 'Disease', (118, 122))	('PpIX', 'Chemical', 'MESH:C028025', (164, 168))	('quantification', 'MPA', (123, 137))	('PpIX', 'Chemical', 'MESH:C028025', (72, 76))	('PpIX', 'Chemical', 'MESH:C028025', (118, 122))
50987	28842674	These results clearly demonstrate that accounting for optical property distortions specific to each individual phantom yields a highly linear relationship between probe and HIS C PpIX estimates (r = 0.98) with reduced variation in the data (mRPE = 35 +- 35%) relative to integrated fluorescence intensity (r = 0.82; mRPE = 281%), or spectral fitting without phantom-specific optical property correction (r = 0.91; mRPE = 45%).	('PpIX', 'Chemical', 'MESH:C028025', (179, 183))	('reduced', 'NegReg', (210, 217))	('mRPE', 'Gene', (316, 320))	('mRPE', 'Gene', (241, 245))	('distortions', 'Var', (71, 82))	('mRPE', 'Gene', (414, 418))	('mRPE', 'Gene', '66646', (316, 320))	('mRPE', 'Gene', '66646', (241, 245))	('variation', 'MPA', (218, 227))	('mRPE', 'Gene', '66646', (414, 418))	('HIS', 'Chemical', '-', (173, 176))	('C PpIX', 'Gene', (177, 183))
51003	28842674	6 to illustrate the value of C PpIX images filtered by PpIX CR in terms of localization and contrast relative to visual fluorescence (IF PpIX) over the course of surgery.	('PpIX', 'Var', (55, 59))	('PpIX CR', 'Chemical', '-', (55, 62))	('PpIX', 'Chemical', 'MESH:C028025', (55, 59))	('PpIX', 'Chemical', 'MESH:C028025', (31, 35))	('PpIX', 'Gene', (55, 59))	('PpIX', 'Chemical', 'MESH:C028025', (137, 141))
51024	28842674	The limiting factor in detecting PpIX using spectral fitting is signal; detection of even lower concentrations is possible if a longer exposure or spatial filtering is used to reduce noise, as the contrast of CR filtered pixels remains elevated (CNR > 3) even at the lowest limit of detectable concentrations.	('CNR > 3', 'Gene', '26307', (246, 253))	('CNR > 3', 'Gene', (246, 253))	('elevated', 'PosReg', (236, 244))	('contrast', 'MPA', (197, 205))	('CR', 'Chemical', '-', (209, 211))	('PpIX', 'Var', (33, 37))	('PpIX', 'Chemical', 'MESH:C028025', (33, 37))
51036	28842674	Second, the HIS samples a tissue surface that is not flat and will include height- and orientation-based variations in collected fluorescence intensity, while the probe is placed in gentle contact with the tissue surface and (as long as good contact is achieved) is unaffected by topographic variations.	('variations', 'Var', (105, 115))	('collected fluorescence intensity', 'MPA', (119, 151))	('HIS', 'Chemical', '-', (12, 15))
51051	28842674	Additionally, phantoms with a fixed BVF of 2% were made with variations in LVF of (0.5, 1, 2)% for a total of 81 combinations, including baseline phantoms with no PpIX for each combination.	('variations', 'Var', (61, 71))	('PpIX', 'Chemical', 'MESH:C028025', (163, 167))	('combinations', 'Var', (113, 125))
51080	28842674	CNR was defined aswhere mu target is the average fluorescence metric (IF PpIX, SF PpIX, or C PpIX) over a 40,000 pixel ROI in the phantom of interest, mu bkg is the average fluorescence metric in a optical property matched phantom with no PpIX, and sigma bkg is the standard deviation of the fluorescence metric in a optical property matched phantom with no PpIX.	('PpIX', 'Chemical', 'MESH:C028025', (73, 77))	('PpIX', 'Chemical', 'MESH:C028025', (358, 362))	('PpIX', 'Chemical', 'MESH:C028025', (93, 97))	('mu bkg', 'Var', (151, 157))	('C PpIX', 'Var', (91, 97))	('PpIX', 'Chemical', 'MESH:C028025', (239, 243))	('PpIX', 'Chemical', 'MESH:C028025', (82, 86))
51121	25867683	Inaccurate grading represents a risk for the patient, since it could lead to an inappropriate therapy .	('patient', 'Species', '9606', (45, 52))	('lead to', 'Reg', (69, 76))	('Inaccurate', 'Var', (0, 10))
51207	23630597	However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression.	('EGFR', 'Gene', (179, 183))	('EGFR', 'Gene', '1956', (179, 183))	('gliomas', 'Disease', (9, 16))	('IDH1', 'Gene', '3417', (142, 146))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('mutation', 'Var', (147, 155))	('gliomas', 'Disease', 'MESH:D005910', (266, 273))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (266, 273))	('gliomas', 'Disease', (266, 273))	('contained', 'Reg', (62, 71))	('PDGFRA', 'Gene', (37, 43))	('less', 'NegReg', (174, 178))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (266, 272))	('IDH1', 'Gene', (142, 146))	('better', 'PosReg', (232, 238))
51227	23630597	Inhibition of PDGFRA signaling resulted in a reversion of transformed phenotype in glioma cell lines, or a reversion from high-grade to lower grade tumor histology in mouse model.	('glioma', 'Disease', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('PDGFRA signaling', 'Gene', (14, 30))	('reversion', 'NegReg', (107, 116))	('tumor', 'Disease', (148, 153))	('transformed phenotype', 'CPA', (58, 79))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mouse', 'Species', '10090', (167, 172))
51268	23630597	The frequency of IDH1 mutation was significantly higher in PDGFRA-high gliomas compared to PDGFRA-low gliomas.	('mutation', 'Var', (22, 30))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('IDH1', 'Gene', (17, 21))	('gliomas', 'Disease', (102, 109))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('IDH1', 'Gene', '3417', (17, 21))	('higher', 'Reg', (49, 55))
51269	23630597	Furthermore, compared to PDGFRA-low and PDGFRA-intermediate gliomas, PDGFRA-high gliomas were associated with significantly higher frequency of loss of heterozygosity (LOH) at 1p and 19q.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('loss of heterozygosity', 'Var', (144, 166))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('PDGFRA-high', 'Disease', (69, 80))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
51270	23630597	Conversely, PDGFRA-low and PDGFRA-intermediate gliomas were associated with significantly higher frequency of EGFR amplification compared to PDGFRA-high gliomas ( Table 1 ).	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('gliomas', 'Disease', (47, 54))	('PDGFRA-low', 'Var', (12, 22))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))
51271	23630597	Interestingly, in both the GSE16011 and the Rembrandt data sets, PDGFRA-high gliomas were associated with younger age at disease onset compared to PDGFRA-low gliomas (p<0.01, t test,  Table 1 ).	('PDGFRA-high', 'Var', (65, 76))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('gliomas', 'Disease', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('gliomas', 'Disease', (158, 165))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
51274	23630597	In the Rembrandt data set, patients with PDGFRA-high GBMs or PDGFRA-high low-grade gliomas showed significant better survival and younger age at disease onset compared to patients with PDGFRA-low GBMs or PDGFRA-low low-grade gliomas, respectively (Figure S2).	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('PDGFRA-high', 'Var', (41, 52))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (225, 232))	('gliomas', 'Disease', (225, 232))	('gliomas', 'Disease', 'MESH:D005910', (225, 232))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (27, 35))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('better', 'PosReg', (110, 116))	('PDGFRA-high', 'Var', (61, 72))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))
51284	23630597	A decline in PDGFRA expression following withdrawal of FGF2 was concordant with diminished cell proliferation, as assessed by cell counting and BrdU incorporation assays ( Figure 4 ).	('expression', 'MPA', (20, 30))	('BrdU', 'Chemical', 'MESH:D001973', (144, 148))	('withdrawal', 'Var', (41, 51))	('decline', 'NegReg', (2, 9))	('FGF2', 'Gene', (55, 59))	('diminished', 'NegReg', (80, 90))	('PDGFRA', 'Protein', (13, 19))	('cell proliferation', 'CPA', (91, 109))
51300	23630597	These gliomas were significantly associated with frequent IDH1 mutation, younger age at disease onset and better survival outcome compared to the gliomas with lower levels of PDGFRA expression.	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('IDH1', 'Gene', '3417', (58, 62))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('mutation', 'Var', (63, 71))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('gliomas', 'Disease', (6, 13))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('IDH1', 'Gene', (58, 62))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))
51302	23630597	Our findings extend previous reports that irrespective of morphological diagnosis, gliomas with high level PDGFRA expression are associated with concomitant IDH1 mutation, higher frequency of deletions at 1p and 19q, lower frequency of EGFR amplification, younger age at diagnosis and better patient's survival.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('PDGFRA', 'Gene', (107, 113))	('lower', 'NegReg', (217, 222))	('deletions at 1p and', 'Var', (192, 211))	('patient', 'Species', '9606', (292, 299))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH1', 'Gene', (157, 161))	('EGFR', 'Gene', '1956', (236, 240))	('mutation', 'Var', (162, 170))	('IDH1', 'Gene', '3417', (157, 161))	('EGFR', 'Gene', (236, 240))
51305	23630597	PDGFRA gene amplification and mutation in gliomas with high expression levels was also reported previously.	('PDGFRA', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('mutation', 'Var', (30, 38))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
51306	23630597	Our findings showed that in adulthood gliomas as analyzed in this report, amplification of PDGFRA gene was unlikely the main cause of PDGFRA overexpression in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('amplification', 'Var', (74, 87))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('PDGFRA', 'Gene', (91, 97))	('overexpression', 'PosReg', (141, 155))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
51309	23630597	Our analyses on hallmark alterations in glioma genome show that LOH of 1p and 19q is more frequent in PDGFRA-high gliomas, and that EGFR amplification is more frequent in PDGFRA-low and PDGFRA-intermediate gliomas.	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('PDGFRA-low', 'Disease', (171, 181))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('LOH', 'Var', (64, 67))	('gliomas', 'Disease', (114, 121))	('EGFR', 'Gene', '1956', (132, 136))	('glioma', 'Disease', (114, 120))	('amplification', 'Var', (137, 150))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('glioma', 'Disease', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('gliomas', 'Disease', (206, 213))	('glioma', 'Disease', (206, 212))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('EGFR', 'Gene', (132, 136))	('gliomas', 'Disease', 'MESH:D005910', (206, 213))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
51310	23630597	Previous studies demonstrate that gliomas with deletion at both 1p and 19q and gliomas with EGFR amplifications are mutually exclusive regarding their cell(s) of origin, profiles of transcriptomic and genomic alterations, and clinical characteristics.	('gliomas', 'Disease', (79, 86))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('deletion at', 'Var', (47, 58))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
51322	33769711	Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NRF2', 'Gene', '4780', (130, 134))	('NFE2L2', 'Gene', '4780', (35, 41))	('NRF2', 'Gene', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('NFE2L2', 'Gene', (35, 41))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (42, 51))
51328	33769711	For example, activating mutations in KRAS/NRAS are frequently accompanied by loss of function of CDKN2A/B in melanoma, lung, pancreatic, and other cancers.	('pancreatic', 'Disease', (125, 135))	('loss of function', 'NegReg', (77, 93))	('CDKN2A/B', 'Gene', '1029;1030', (97, 105))	('NRAS', 'Gene', '4893', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('KRAS', 'Gene', '3845', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('CDKN2A/B', 'Gene', (97, 105))	('KRAS', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('activating mutations', 'Var', (13, 33))	('cancers', 'Disease', (147, 154))	('pancreatic', 'Disease', 'MESH:D010195', (125, 135))	('lung', 'Disease', (119, 123))	('NRAS', 'Gene', (42, 46))
51331	33769711	From a biological perspective, co-occurrence of driver alterations clearly does occur (Ulz et al, 2016; Wang et al, 2017; VanderLaan et al, 2017; Kim et al, 2019), and appears to be a requirement for most carcinogenesis events, as evidenced by the insufficiency of BRAF and RAS hotspot mutations to transform benign colon polyps and nevi into invasive carcinoma (Pollock et al, 2003; Juarez et al, 2017).	('benign colon polyps', 'Disease', 'MESH:D003111', (309, 328))	('carcinogenesis', 'Disease', (205, 219))	('insufficiency of BRAF', 'Disease', (248, 269))	('mutations', 'Var', (286, 295))	('nevi', 'Phenotype', 'HP:0003764', (333, 337))	('Pollock', 'Species', '8060', (363, 370))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('nevi', 'Disease', (333, 337))	('benign colon polyps', 'Disease', (309, 328))	('invasive carcinoma', 'Disease', 'MESH:D009361', (343, 361))	('insufficiency of BRAF', 'Disease', 'MESH:D000309', (248, 269))	('RAS', 'Gene', (274, 277))	('invasive carcinoma', 'Disease', (343, 361))	('carcinogenesis', 'Disease', 'MESH:D063646', (205, 219))
51338	33769711	CRSO seeks to find a collection of rules called a rule set that represents all of the unique minimal combinations that can explain all of the given tumors in the study population, i.e., every sample is required to harbor all of the alterations in at least one of the rules.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('alterations', 'Var', (232, 243))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', (148, 154))
51340	33769711	We show that CRSO can identify known and novel combinations of driver alterations in 19 tissue types from The Cancer Genome Atlas (TCGA) (Cancer Genome Atlas Network, 2013; Tomczak et al, 2015) and that some of these combinations correlate with clinical outcomes.	('Cancer', 'Disease', 'MESH:D009369', (110, 116))	('alterations', 'Var', (70, 81))	('Cancer', 'Disease', 'MESH:D009369', (138, 144))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Disease', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Cancer', 'Disease', (138, 144))	('correlate with', 'Reg', (230, 244))
51341	33769711	CRSO finds combinations of genomic alterations (referred to as events) that are predicted to cooperate to drive cancer in individual patients.	('genomic alterations', 'Var', (27, 46))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (133, 141))	('drive', 'PosReg', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
51342	33769711	Three primary event types were considered: coding mutations identified as candidate drivers by dNdScv (Martincorena et al, 2017), as well as copy number amplifications and deletions identified as candidate drivers by GISTIC2 (Mermel et al, 2011).	('deletions', 'Var', (172, 181))	('dNdScv', 'Gene', (95, 101))	('copy number', 'Var', (141, 152))	('dNdScv', 'Chemical', '-', (95, 101))
51343	33769711	However, CRSO models can include additional alteration types, such as gene fusions and aneuploidies.	('aneuploidies', 'Disease', 'MESH:D000782', (87, 99))	('gene fusions', 'Var', (70, 82))	('aneuploidies', 'Disease', (87, 99))
51344	33769711	Similarly, deletion events take values in {Z, WD, SD}, corresponding to wild type, weak deletion (hemizygous), and strong deletion (homozygous), respectively.	('deletion', 'Var', (11, 19))	('deletion', 'Var', (122, 130))	('WD', 'Disease', 'MESH:D006527', (46, 48))
51385	33769711	The union of the melanoma core RS and con-GCRs comprise 11 distinct rules and are dominated by rules that contain either BRAF or NRAS mutations (Table 2).	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', '673', (121, 125))	('melanoma core RS', 'Disease', 'MESH:D041441', (17, 33))	('NRAS', 'Gene', (129, 133))	('GCR', 'Gene', (42, 45))	('NRAS', 'Gene', '4893', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('GCR', 'Gene', '2908', (42, 45))	('mutations', 'Var', (134, 143))	('melanoma core RS', 'Disease', (17, 33))
51387	33769711	Hotspot mutations in BRAF and NRAS define the two major subtypes of melanoma that are mutually exclusive, with 50% of patients harboring BRAFV600E mutations and 30% of patients harboring NRAS hotspot mutations (Cancer Genome Atlas Network, 2015a).	('mutations', 'Var', (147, 156))	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('Cancer', 'Disease', (211, 217))	('NRAS', 'Gene', '4893', (187, 191))	('mutations', 'Var', (8, 17))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('NRAS', 'Gene', '4893', (30, 34))	('Cancer', 'Disease', 'MESH:D009369', (211, 217))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('BRAFV600E', 'Mutation', 'rs113488022', (137, 146))	('NRAS', 'Gene', (187, 191))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('NRAS', 'Gene', (30, 34))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (118, 126))
51389	33769711	The first 4 of these rules are instances of co-occurring MAPK3 pathway activation with P53 inactivation:a synergy that is known to promote carcinogenesis (Gen, 2004; Stramucci et al, 2018).	('carcinogenesis', 'Disease', (139, 153))	('activation', 'PosReg', (71, 81))	('MAPK3', 'Gene', (57, 62))	('MAPK3', 'Gene', '5595', (57, 62))	('inactivation', 'Var', (91, 103))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('P53', 'Gene', (87, 90))	('P53', 'Gene', '7157', (87, 90))	('promote', 'PosReg', (131, 138))
51406	33769711	Mazur et al (2014) showed that SMYD3 methylation of MAP3K2 leads to upregulation of MAP kinase signaling and promotes carcinogenesis in RAS mutated lung and pancreatic cancers.	('RAS mutated lung', 'Disease', (136, 152))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinogenesis', 'Disease', (118, 132))	('methylation', 'Var', (37, 48))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (157, 175))	('MAP3K2', 'Gene', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('upregulation', 'PosReg', (68, 80))	('MAP kinase signaling', 'MPA', (84, 104))	('pancreatic cancers', 'Disease', (157, 175))	('pancreatic cancers', 'Disease', 'MESH:D010190', (157, 175))	('MAP3K2', 'Gene', '10746', (52, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('promotes', 'PosReg', (109, 117))
51407	33769711	The authors further showed that preventing SMYD3 catalytic activity in mouse models with oncogenic RAS mutations inhibited tumor development (Mazur et al, 2014).	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (123, 128))	('inhibited', 'NegReg', (113, 122))	('preventing', 'NegReg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mouse', 'Species', '10090', (71, 76))	('SMYD3', 'Gene', (43, 48))	('RAS', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('catalytic activity', 'MPA', (49, 67))
51408	33769711	This presents a direct biological link between SMYD3 expression and RAS mutations, and nominates SMYD3 as a drug target for RAS-driven cancers.	('RAS', 'Gene', (68, 71))	('mutations', 'Var', (72, 81))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('SMYD3', 'Gene', (47, 52))
51415	33769711	Because TCGA tumors are primary and treatment-naive, this observation suggests that BRAF amplification and BRAFV600E may be a sufficient combination for tumor formation, and a cause of intrinsic resistance to BRAF inhibition.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('ntr', 'Gene', (186, 189))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('BRAF', 'Gene', '673', (84, 88))	('tumors', 'Disease', (13, 19))	('BRAFV600E', 'Mutation', 'rs113488022', (107, 116))	('BRAF', 'Gene', (84, 88))	('ntr', 'Gene', '4923', (186, 189))	('amplification', 'Var', (89, 102))	('BRAF', 'Gene', '673', (107, 111))	('BRAF', 'Gene', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))
51423	33769711	NFE2L2 mutations were identified as part of a con-GCR in 4 cancer types: LUSC, HNSC, ESCA, and BLCA.	('GCR', 'Gene', '2908', (50, 53))	('HNSC', 'Disease', (79, 83))	('GCR', 'Gene', (50, 53))	('LUSC', 'Disease', (73, 77))	('ESCA', 'Disease', (85, 89))	('NFE2L2', 'Gene', '4780', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('BLCA', 'Disease', (95, 99))	('NFE2L2', 'Gene', (0, 6))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (7, 16))
51427	33769711	However, we now have evidence that constitutive NRF2 activation via mutations in KEAP1 or recurrent NFE2L2 exon 2 deletions can drive tumor proliferation and metastasis (Goldstein et al, 2016; Rojo de la Vega et al, 2018).	('NRF2', 'Gene', '4780', (48, 52))	('KEAP1', 'Gene', (81, 86))	('activation', 'PosReg', (53, 63))	('deletions', 'Var', (114, 123))	('NRF2', 'Gene', (48, 52))	('NFE2L2', 'Gene', '4780', (100, 106))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('NFE2L2', 'Gene', (100, 106))	('KEAP1', 'Gene', '9817', (81, 86))	('metastasis', 'CPA', (158, 168))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('drive', 'PosReg', (128, 133))
51428	33769711	NFE2L2 mutations have recently been shown to define subtypes with differential prognosis in lung and head and neck cancers (Frank et al, 2018; Namani et al, 2018; Xu et al, 2020; Liu et al, 2020b).	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('NFE2L2', 'Gene', '4780', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('head and neck cancers', 'Disease', 'MESH:D006258', (101, 122))	('NFE2L2', 'Gene', (0, 6))	('lung', 'Disease', (92, 96))	('head and neck cancers', 'Phenotype', 'HP:0012288', (101, 122))	('mutations', 'Var', (7, 16))
51429	33769711	Several upcoming clinical trials are designed to explore the therapeutic benefit of compounds that inhibit NRF2 in advanced cancer patients harboring mutations in NFE2L2 or KEAP1 (ClinicalTrials.gov, NCT02417701; ClinicalTrials.gov, NCT04267913; ClinicalTrials.gov, NCT03872427).	('patients', 'Species', '9606', (131, 139))	('NRF2', 'Gene', '4780', (107, 111))	('cancer', 'Disease', (124, 130))	('NRF2', 'Gene', (107, 111))	('inhibit', 'NegReg', (99, 106))	('NFE2L2', 'Gene', '4780', (163, 169))	('KEAP1', 'Gene', '9817', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (150, 159))	('NFE2L2', 'Gene', (163, 169))	('KEAP1', 'Gene', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
51432	33769711	Patients that have these two mutations and are also wild type for TP53 have been shown to define a biologically distinct subtype characterized by low SCNV burden (Cancer Genome Atlas Network, 2015c).	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('mutations', 'Var', (29, 38))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Patients', 'Species', '9606', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (163, 169))	('Cancer', 'Disease', (163, 169))
51434	33769711	Two high confidence GCRs were identified in LIHC involving ALB mutations: ALB-M + CTNNB1-M (conf.	('mutations', 'Var', (63, 72))	('ALB', 'Gene', (59, 62))	('CTNNB1', 'Gene', (82, 88))	('GCR', 'Gene', '2908', (20, 23))	('ALB', 'Gene', '213', (74, 77))	('GCR', 'Gene', (20, 23))	('CTNNB1', 'Gene', '1499', (82, 88))	('ALB', 'Gene', (74, 77))	('ALB', 'Gene', '213', (59, 62))
51437	33769711	Cooperations involving ALB have not been systematically reported, and the two combinations we identified may help inform context-dependent treatments of ALB mutant patients.	('mutant', 'Var', (157, 163))	('ALB', 'Gene', '213', (153, 156))	('ALB', 'Gene', '213', (23, 26))	('ALB', 'Gene', (153, 156))	('ALB', 'Gene', (23, 26))	('patients', 'Species', '9606', (164, 172))
51449	33769711	IDH1 mutations occur in 78% of LGGs and are a biomarker for improved outcome in LGG patients (Cancer Genome Atlas Network, 2015d) (Fig 6A).	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('LGGs', 'Disease', (31, 35))	('patients', 'Species', '9606', (84, 92))	('mutations', 'Var', (5, 14))	('Cancer', 'Disease', (94, 100))	('LGG', 'Disease', (80, 83))	('IDH1', 'Gene', (0, 4))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('IDH1', 'Gene', '3417', (0, 4))
51450	33769711	Differential outcomes were detected between the event/rule pairings IDH1-M versus IDH1-M + IC-M and IDH1-M versus IDH1-M + PIK3CA-M that could further stratify IDH1 mutant samples (Fig 6).	('mutant', 'Var', (165, 171))	('IDH1', 'Gene', (114, 118))	('IDH1', 'Gene', '3417', (100, 104))	('IDH1', 'Gene', (160, 164))	('PIK3CA', 'Gene', (123, 129))	('IDH1', 'Gene', (68, 72))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (160, 164))	('PIK3CA', 'Gene', '5290', (123, 129))	('IDH1', 'Gene', '3417', (114, 118))	('IDH1', 'Gene', '3417', (82, 86))	('IDH1', 'Gene', '3417', (68, 72))	('IDH1', 'Gene', (100, 104))
51453	33769711	Collectively, these results suggest that LGG patients could be stratified into 4 groups: IDH1 wild type, IDH1 mutant + CIC mutant, IDH1 mutant + PIK3CA mutant, and IDH1 mutant + CIC/PIK3CA wild type.	('LGG', 'Disease', (41, 44))	('IDH1', 'Gene', '3417', (131, 135))	('IDH1', 'Gene', '3417', (105, 109))	('patients', 'Species', '9606', (45, 53))	('IDH1', 'Gene', (89, 93))	('CIC', 'Gene', '23152', (119, 122))	('PIK3CA', 'Gene', '5290', (182, 188))	('PIK3CA', 'Gene', (145, 151))	('CIC', 'Gene', (178, 181))	('IDH1', 'Gene', '3417', (89, 93))	('mutant +', 'Var', (136, 144))	('IDH1', 'Gene', (164, 168))	('mutant +', 'Var', (110, 118))	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', (105, 109))	('PIK3CA', 'Gene', (182, 188))	('CIC', 'Gene', '23152', (178, 181))	('CIC', 'Gene', (119, 122))	('PIK3CA', 'Gene', '5290', (145, 151))	('mutant', 'Var', (123, 129))	('IDH1', 'Gene', '3417', (164, 168))
51455	33769711	The improved prognosis of IDH1-M + CIC-M relative to other IDH1 mutant LGGs has been previously reported and has been independently characterized by p1/q19 co-deletions, which overlap highly with CIC mutations (Jiao et al, 2012; Brat et al, 2015; Cancer Genome Atlas Network, 2015d).	('CIC', 'Gene', (35, 38))	('IDH1', 'Gene', '3417', (59, 63))	('improved', 'PosReg', (4, 12))	('prognosis', 'MPA', (13, 22))	('Cancer', 'Disease', (247, 253))	('IDH1', 'Gene', (26, 30))	('Cancer', 'Disease', 'MESH:D009369', (247, 253))	('Cancer', 'Phenotype', 'HP:0002664', (247, 253))	('CIC', 'Gene', '23152', (196, 199))	('CIC', 'Gene', '23152', (35, 38))	('IDH1', 'Gene', (59, 63))	('IDH1', 'Gene', '3417', (26, 30))	('mutant', 'Var', (64, 70))	('CIC', 'Gene', (196, 199))
51456	33769711	We did not find literature evidence of the poor prognosis of IDH1 tumors harboring PIK3CA mutations in LGGs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('IDH1 tumors', 'Disease', 'MESH:D009369', (61, 72))	('mutations', 'Var', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('IDH1 tumors', 'Disease', (61, 72))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))
51464	33769711	In our study, CDKN2A deletion and CDKN2A mutations were combined into a single hybrid event, resulting in a simple association between CDKN2A-MD status and poor PFI (Fig 9A).	('mutations', 'Var', (41, 50))	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('CDKN2A', 'Gene', '1029', (14, 20))	('deletion', 'Var', (21, 29))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('CDKN2A', 'Gene', (14, 20))
51468	33769711	For each tissue, we compared the total coverage of all statistically co-occurrent pairs identified by SELECT within a curated set of 505 pan-cancer mutations and CNVs (Mina et al, 2017), versus the coverages of the core rule sets identified by CRSO (Table 5).	('mutations', 'Var', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('CNVs', 'Gene', (162, 166))
51478	33769711	Many driver alterations are recurrently identified by GISTIC2 and dNdScv in multiple different cancer types.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('alterations', 'Var', (12, 23))	('dNdScv', 'Chemical', '-', (66, 72))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
51499	33769711	We developed CRSO as a stochastic optimization procedure for predicting combinations of alterations that are minimally sufficient to drive cancer in individual patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('alterations', 'Var', (88, 99))	('cancer', 'Disease', (139, 145))
51516	33769711	However, many other types of alterations were omitted that may contribute to cancer formation, including germline alterations, arm level CNVs, gene fusions, chromosomal translocations, and epigenetic alterations.	('ntr', 'Gene', '4923', (65, 68))	('ntr', 'Gene', (65, 68))	('cancer', 'Disease', (77, 83))	('chromosomal', 'Disease', (157, 168))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('epigenetic alterations', 'Var', (189, 211))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gene fusions', 'Var', (143, 155))
51517	33769711	For example, TMPRSS2-ERG fusions are observed in 40% of prostate cancers (Cancer Genome Atlas Network, 2015b), and p1/q19 chromosomal co-deletions are observed in 30% of lower-grade gliomas (Brat et al, 2015).	('ERG', 'Gene', (21, 24))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('p1/q19', 'Var', (115, 121))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('TMPRSS2', 'Gene', '7113', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('ERG', 'Gene', '2078', (21, 24))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TMPRSS2', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancers', 'Disease', 'MESH:D011471', (56, 72))	('Cancer', 'Disease', (74, 80))	('observed', 'Reg', (37, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate cancers', 'Phenotype', 'HP:0012125', (56, 72))	('gliomas', 'Disease', (182, 189))	('prostate cancers', 'Disease', (56, 72))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))
51538	33769711	Similarly, deletion events take values in {Z, WD, SD}, corresponding to wild type, weak deletion (hemizygous), and strong deletion (homozygous).	('deletion', 'Var', (11, 19))	('deletion', 'Var', (122, 130))	('WD', 'Disease', 'MESH:D006527', (46, 48))
51542	33769711	Some tumors may contain one of many nonsense point mutations within TP53, whereas other tumors may contain a highly recurrent missense mutation, or a splice site mutation that produces an alternative isoform of the TP53 protein.	('missense mutation', 'Var', (126, 143))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', '7157', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('nonsense point mutations', 'Var', (36, 60))	('tumors', 'Disease', (88, 94))	('contain', 'Reg', (16, 23))	('TP53', 'Gene', (215, 219))	('TP53', 'Gene', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('contain', 'Reg', (99, 106))
51543	33769711	Although all of these alterations are TP53 mutations, they occur with very different passenger probabilities, sometimes spanning multiple orders of magnitude.	('TP53', 'Gene', (38, 42))	('alterations', 'Var', (22, 33))	('TP53', 'Gene', '7157', (38, 42))
51544	33769711	Silent mutations and intronic mutations do not lead to amino acid changes and by definition cannot be hotspots.	('ntr', 'Gene', (22, 25))	('Silent mutations', 'Var', (0, 16))	('ntr', 'Gene', '4923', (22, 25))
51550	33769711	Mutation rates for every possible amino acid substitution in each SMG were calculated as described in Cannataro et al (2018).	('SMG', 'Gene', (66, 69))	('SMG', 'Gene', '23034', (66, 69))	('amino acid substitution', 'Var', (34, 57))
51565	33769711	The entries of MG take values in {SD, WD, Z, WA, SA}, corresponding, respectively, to strong deletions (SD), weak deletions (WD), wild type (Z), weak amplifications (WA), and strong amplifications (SA).	('WD', 'Disease', 'MESH:D006527', (38, 40))	('weak deletions', 'Var', (109, 123))	('ntr', 'Gene', '4923', (5, 8))	('WD', 'Disease', 'MESH:D006527', (125, 127))	('ntr', 'Gene', (5, 8))
51639	33769711	For each cancer type, a set of common mutations was identified as the intersection of the SELECT pan-cancer mutations with the cancer-specific mutation events identified by dNdScv that were used in the CRSO analysis.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (108, 117))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('dNdScv', 'Chemical', '-', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
51641	33769711	In these cancers, large coverage discrepancies were observed in duos involving CDKN2A because SELECT encoded CDKN2A mutations as separate events from CDKN2A copy number loss.	('CDKN2A', 'Gene', '1029', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('CDKN2A', 'Gene', (150, 156))	('CDKN2A', 'Gene', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CDKN2A', 'Gene', '1029', (150, 156))	('CDKN2A', 'Gene', '1029', (109, 115))	('mutations', 'Var', (116, 125))	('CDKN2A', 'Gene', (79, 85))
51664	33397920	Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies.	('ALT', 'Var', (27, 30))	('patient', 'Species', '9606', (161, 168))	('1H', 'Chemical', '-', (58, 60))	('patient', 'Species', '9606', (195, 202))	('glioma', 'Disease', (177, 183))	('TERT', 'Var', (18, 22))	('metabolic', 'MPA', (110, 119))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))
51672	33397920	Mutations in the TERT promoter rank among the most common noncoding mutations in cancer and lead to the creation of a novel binding site for the transcription factor GABP, which reactivates TERT expression.	('reactivates TERT expression', 'MPA', (178, 205))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('TERT', 'Gene', (17, 21))	('cancer', 'Disease', (81, 87))	('binding', 'Interaction', (124, 131))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
51674	33397920	Loss-of-function mutations in the chromatin remodeling protein, alpha-thalassemia/mental retardation syndrome X-linked (ATRX), which occur in the majority of LGAs, are associated with induction of the ALT pathway, and ATRX re-expression has been shown to repress the ALT pathway.	('ATRX', 'Gene', (120, 124))	('Loss-of-function', 'NegReg', (0, 16))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (70, 118))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (70, 118))	('ALT pathway', 'Pathway', (267, 278))	('ATRX', 'Gene', '546', (218, 222))	('repress', 'NegReg', (255, 262))	('ATRX', 'Gene', '546', (120, 124))	('mutations', 'Var', (17, 26))	('mental retardation', 'Phenotype', 'HP:0001249', (82, 100))	('ATRX', 'Gene', (218, 222))	('ALT pathway', 'Pathway', (201, 212))
51676	33397920	TERT promoter mutations occur exclusively in tumor cells and not in normal somatic cells or stem cells.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TERT promoter', 'Gene', (0, 13))	('tumor', 'Disease', (45, 50))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
51677	33397920	Although directly targeting TERT activity results in toxicity due to stem cell inhibition, inhibiting TERT expression from the mutant TERT promoter by disrupting GABP function is a viable therapeutic strategy.	('mutant', 'Var', (127, 133))	('inhibiting', 'NegReg', (91, 101))	('rat', 'Species', '10116', (202, 205))	('TERT', 'Gene', (134, 138))	('TERT expression', 'Gene', (102, 117))	('disrupting', 'NegReg', (151, 161))	('stem cell', 'CPA', (69, 78))	('GABP function', 'MPA', (162, 175))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('toxicity', 'Disease', (53, 61))
51679	33397920	Pharmacological or genetic inhibition of TERT abrogates glucose flux through the pentose phosphate pathway and de novo fatty acid synthesis in gliomas.	('abrogates', 'NegReg', (46, 55))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('TERT', 'Gene', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('inhibition', 'Var', (27, 37))	('gliomas', 'Disease', (143, 150))	('fatty acid', 'Chemical', 'MESH:D005227', (119, 129))	('glucose flux', 'MPA', (56, 68))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('pentose phosphate', 'Chemical', 'MESH:D010428', (81, 98))	('de novo fatty acid synthesis', 'MPA', (111, 139))
51680	33397920	TERT has also been linked to altered redox status and, specifically, to higher levels of reduced glutathione (GSH) and reduced oxidative stress in cancer cells.	('levels of reduced glutathione', 'MPA', (79, 108))	('TERT', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('GSH', 'Chemical', 'MESH:D005978', (110, 113))	('oxidative stress', 'Phenotype', 'HP:0025464', (127, 143))	('redox status', 'MPA', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('glutathione', 'Chemical', 'MESH:D005978', (97, 108))	('altered', 'Reg', (29, 36))	('higher', 'PosReg', (72, 78))	('cancer', 'Disease', (147, 153))	('oxidative stress', 'MPA', (127, 143))	('reduced', 'NegReg', (119, 126))
51689	33397920	However, the recent development of hyperpolarized 13C-MRS has enhanced the signal-to-noise ratio (SNR) by >10,000-fold and provides a translational method of imaging metabolic fluxes.	('signal-to-noise ratio', 'MPA', (75, 96))	('rat', 'Species', '10116', (91, 94))	('13C', 'Chemical', 'MESH:C000615229', (50, 53))	('enhanced', 'PosReg', (62, 70))	('hyperpolarized', 'Var', (35, 49))
51697	33397920	We examined cells that were engineered to endogenously reactivate TERT expression (NHATERT) or activate the ALT pathway following ATRX loss (NHAALT).	('ATRX', 'Gene', (130, 134))	('loss', 'NegReg', (135, 139))	('ATRX', 'Gene', '546', (130, 134))	('reactivate', 'Var', (55, 65))	('TERT expression', 'MPA', (66, 81))	('activate', 'PosReg', (95, 103))	('ALT pathway', 'Pathway', (108, 119))
51725	33397920	Similarly, in contrast to NHATERT cells, levels of GSH, NAD(P)/H, aspartate, and AXP were not altered in NHATERT+IDHmut- cells relative to NHACONTROL cells (see Supplementary Fig.	('GSH', 'Chemical', 'MESH:D005978', (51, 54))	('TR', 'Gene', '2149', (145, 147))	('aspartate', 'MPA', (66, 75))	('NAD(P)', 'Chemical', 'MESH:D009249', (56, 62))	('NHATERT+IDHmut-', 'Var', (105, 120))	('aspartate', 'Chemical', 'MESH:D001224', (66, 75))	('AXP', 'Chemical', '-', (81, 84))
51738	33397920	Quantification indicated a significantly higher pyruvate/alanine ratio in NHAALT cells relative to NHATERT and NHACONTROL (Fig.	('rat', 'Species', '10116', (65, 68))	('pyruvate/alanine ratio', 'MPA', (48, 70))	('pyruvate', 'Chemical', 'MESH:D019289', (48, 56))	('higher', 'PosReg', (41, 47))	('NHAALT', 'Var', (74, 80))	('alanine', 'Chemical', 'MESH:D000409', (57, 64))	('TR', 'Gene', '2149', (117, 119))
51741	33397920	Next, we examined whether modulation of TERT expression and the ALT pathway in clinically relevant, patient-derived LGOG and LGA models resulted in modulation of their corresponding 1H-MRS-detectable metabolic alterations and hyperpolarized [1-13C]-alanine metabolism.	('modulation', 'Reg', (148, 158))	('1H', 'Chemical', '-', (182, 184))	('[1-13C]-alanine', 'Chemical', '-', (241, 256))	('rat', 'Species', '10116', (214, 217))	('1H-MRS-detectable metabolic alterations', 'MPA', (182, 221))	('patient', 'Species', '9606', (100, 107))	('modulation', 'Var', (26, 36))	('LGOG', 'Chemical', '-', (116, 120))	('hyperpolarized [1-13C]-alanine metabolism', 'MPA', (226, 267))
51742	33397920	To this end, for TERT status, we investigated BT54 neurospheres which were originally derived from a patient carrying an IDHmut LGOG tumor, and examined the effect of silencing TERT using two nonoverlapping siRNA oligonucleotides directed against TERT.	('LGOG tumor', 'Disease', (128, 138))	('LGOG tumor', 'Disease', 'MESH:D009369', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('silencing', 'Var', (167, 176))	('oligonucleotides', 'Chemical', 'MESH:D009841', (213, 229))	('patient', 'Species', '9606', (101, 108))
51745	33397920	NAD(P)/H, GSH, aspartate, and AXP were significantly reduced in BT54 TERT- neurospheres relative to BT54 TERT+.	('AXP', 'Chemical', '-', (30, 33))	('NAD(P)', 'Chemical', 'MESH:D009249', (0, 6))	('AXP', 'MPA', (30, 33))	('GSH', 'MPA', (10, 13))	('aspartate', 'Chemical', 'MESH:D001224', (15, 24))	('reduced', 'NegReg', (53, 60))	('aspartate', 'MPA', (15, 24))	('BT54 TERT- neurospheres', 'Var', (64, 87))	('GSH', 'Chemical', 'MESH:D005978', (10, 13))
51746	33397920	Spectrophotometric assays confirmed that both NADH and NAD+ were reduced in BT54 TERT- neurospheres relative to BT54 TERT+, leading to a higher NAD+/NADH ratio (Supplementary Fig.	('NADH', 'Chemical', 'MESH:D009243', (149, 153))	('reduced', 'NegReg', (65, 72))	('NAD+/NADH ratio', 'MPA', (144, 159))	('BT54', 'Var', (76, 80))	('rat', 'Species', '10116', (154, 157))	('higher', 'PosReg', (137, 143))	('NAD+', 'Chemical', 'MESH:D009243', (144, 148))	('NAD+', 'Chemical', 'MESH:D009243', (55, 59))	('NADH', 'Chemical', 'MESH:D009243', (46, 50))
51756	33397920	Consistent with our results in the NHA models, assessment of steady-state metabolite levels by 1H-MRS revealed significant reductions in alpha-KG, glutamate, alanine, and AXP in BT142 ALT- neurospheres relative to BT142 ALT+ (Fig.	('alpha-KG', 'MPA', (137, 145))	('AXP', 'Chemical', '-', (171, 174))	('BT142', 'Var', (178, 183))	('BT142', 'Chemical', '-', (214, 219))	('AXP', 'MPA', (171, 174))	('glutamate', 'Chemical', 'MESH:D018698', (147, 156))	('alpha-KG', 'Chemical', 'MESH:D007656', (137, 145))	('alanine', 'MPA', (158, 165))	('reductions', 'NegReg', (123, 133))	('glutamate', 'MPA', (147, 156))	('BT142', 'Chemical', '-', (178, 183))	('alanine', 'Chemical', 'MESH:D000409', (158, 165))	('1H', 'Chemical', '-', (95, 97))
51758	33397920	Importantly, consistent with reduced alpha-KG in BT142 ALT- neurospheres, hyperpolarized [1-13C]-alanine metabolism to pyruvate was significantly reduced (Fig.	('BT142', 'Chemical', '-', (49, 54))	('pyruvate', 'Chemical', 'MESH:D019289', (119, 127))	('alpha-KG', 'Chemical', 'MESH:D007656', (37, 45))	('BT142', 'Var', (49, 54))	('reduced', 'NegReg', (146, 153))	('reduced', 'NegReg', (29, 36))	('[1-13C]-alanine', 'Chemical', '-', (89, 104))
51759	33397920	Quantification of the data showed significant reductions in the hyperpolarized pyruvate/alanine and lactate/alanine ratios in BT142 ALT- neurospheres relative to BT142 ALT+ (Fig.	('BT142', 'Var', (126, 131))	('reductions', 'NegReg', (46, 56))	('alanine', 'Chemical', 'MESH:D000409', (108, 115))	('pyruvate', 'Chemical', 'MESH:D019289', (79, 87))	('lactate/alanine ratios', 'MPA', (100, 122))	('BT142', 'Chemical', '-', (126, 131))	('rat', 'Species', '10116', (116, 119))	('alanine', 'Chemical', 'MESH:D000409', (88, 95))	('BT142', 'Chemical', '-', (162, 167))	('lactate', 'Chemical', 'MESH:D019344', (100, 107))	('hyperpolarized pyruvate/alanine', 'MPA', (64, 95))
51760	33397920	In addition to assessing the effect of silencing TERT expression or the ALT pathway as described above, we also interrogated the validity of our metabolic imaging biomarkers in isogenic patient-derived models that were engineered to be either ALT+ or TERT+.	('patient', 'Species', '9606', (186, 193))	('TERT expression', 'Gene', (49, 64))	('silencing', 'Var', (39, 48))	('ALT pathway', 'Pathway', (72, 83))
51761	33397920	Previous studies suggest that exogenous TERT expression in ALT+ cells can potentially lead to a TERT+ phenotype, thereby providing an isogenic platform to interrogate TMM status.	('TERT+ phenotype', 'MPA', (96, 111))	('TMM', 'Chemical', '-', (167, 170))	('lead to', 'Reg', (86, 93))	('exogenous', 'Var', (30, 39))
51769	33397920	4a, b, 1H-MRS-detectable levels of TERT-linked metabolites (GSH, NAD(P)/H and aspartate) were significantly higher and levels of ALT-linked metabolites (alpha-KG, glutamate, and alanine) were significantly lower in MGG119 TERT+ and BT142 TERT+ neurospheres relative to MGG119 ALT+ and BT142 ALT+ neurospheres, respectively.	('aspartate', 'Chemical', 'MESH:D001224', (78, 87))	('BT142 TERT+', 'Var', (232, 243))	('NAD(P)', 'Chemical', 'MESH:D009249', (65, 71))	('higher', 'PosReg', (108, 114))	('BT142', 'Chemical', '-', (232, 237))	('MGG119 TERT+', 'Var', (215, 227))	('alpha-KG', 'Chemical', 'MESH:D007656', (153, 161))	('1H', 'Chemical', '-', (7, 9))	('lower', 'NegReg', (206, 211))	('GSH', 'Chemical', 'MESH:D005978', (60, 63))	('TERT-linked metabolites', 'MPA', (35, 58))	('alanine', 'Chemical', 'MESH:D000409', (178, 185))	('glutamate', 'Chemical', 'MESH:D018698', (163, 172))	('levels of ALT-linked metabolites', 'MPA', (119, 151))	('BT142', 'Chemical', '-', (285, 290))	('levels', 'MPA', (25, 31))
51771	33397920	2c), there was no difference in AXP levels between MGG119 TERT+ and BT142 TERT+ neurospheres relative to their corresponding ALT+ counterparts (Fig.	('AXP levels', 'MPA', (32, 42))	('BT142', 'Var', (68, 73))	('MGG119', 'Var', (51, 57))	('BT142', 'Chemical', '-', (68, 73))	('AXP', 'Chemical', '-', (32, 35))
51773	33397920	Importantly, consistent with elevated NADH, MGG119 TERT+ and BT142 TERT+ neurospheres showed significantly higher production of hyperpolarized [1-13C]-lactate from hyperpolarized [1-13C]-alanine relative to MGG119 ALT+ and BT142 ALT+ neurospheres, respectively (Fig.	('MGG119', 'Var', (44, 50))	('elevated', 'PosReg', (29, 37))	('production of hyperpolarized [1-13C]-lactate', 'MPA', (114, 158))	('NADH', 'Chemical', 'MESH:D009243', (38, 42))	('[1-13C]-alanine', 'Chemical', '-', (179, 194))	('hyperpolarized [1-13C]-alanine', 'MPA', (164, 194))	('[1-13C]-lactate', 'Chemical', '-', (143, 158))	('BT142', 'Chemical', '-', (61, 66))	('NADH', 'MPA', (38, 42))	('higher', 'PosReg', (107, 113))	('BT142', 'Chemical', '-', (223, 228))
51778	33397920	5a, consistent with our cell studies, NAD(P)/H, GSH, aspartate, and AXP were significantly higher in NHATERT tumors relative to normal brain and NHAALT tumors.	('aspartate', 'Chemical', 'MESH:D001224', (53, 62))	('GSH', 'Chemical', 'MESH:D005978', (48, 51))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('NAD(P)', 'Chemical', 'MESH:D009249', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('AXP', 'Chemical', '-', (68, 71))	('higher', 'PosReg', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('AXP', 'MPA', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('GSH', 'MPA', (48, 51))	('NHATERT', 'Var', (101, 108))	('aspartate', 'MPA', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (152, 158))	('tumors', 'Disease', (109, 115))	('NAD', 'MPA', (38, 41))
51786	33397920	Following intravenous injection of hyperpolarized [1-13C]-alanine, we observed a build-up of [1-13C]-pyruvate and [1-13C]-lactate in NHATERT tumor-bearing rats with lactate being the predominant product peak (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('[1-13C]-pyruvate', 'MPA', (93, 109))	('lactate', 'MPA', (165, 172))	('lactate', 'Chemical', 'MESH:D019344', (165, 172))	('[1-13C]-pyruvate', 'Chemical', '-', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('rats', 'Species', '10116', (155, 159))	('[1-13C]-lactate', 'MPA', (114, 129))	('build-up', 'PosReg', (81, 89))	('lactate', 'Chemical', 'MESH:D019344', (122, 129))	('hyperpolarized', 'Var', (35, 49))	('[1-13C]-alanine', 'Chemical', '-', (50, 65))	('[1-13C]-lactate', 'Chemical', '-', (114, 129))
51787	33397920	Injection of hyperpolarized [1-13C]-alanine into NHAALT tumor-bearing rats showed considerable production of hyperpolarized [1-13C]-pyruvate and limited further conversion to hyperpolarized [1-13C]-lactate (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('[1-13C]-lactate', 'Chemical', '-', (190, 205))	('tumor', 'Disease', (56, 61))	('[1-13C]-alanine', 'Chemical', '-', (28, 43))	('[1-13C]-pyruvate', 'Chemical', '-', (124, 140))	('rats', 'Species', '10116', (70, 74))	('hyperpolarized [1-13C]-pyruvate', 'MPA', (109, 140))	('conversion', 'MPA', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('hyperpolarized [', 'Var', (13, 29))
51826	33397920	Importantly, GLS activity was significantly reduced in BT142 ALT- neurospheres relative to BT142 ALT+ (Fig.	('BT142', 'Chemical', '-', (55, 60))	('GLS activity', 'MPA', (13, 25))	('BT142', 'Chemical', '-', (91, 96))	('BT142 ALT-', 'Var', (55, 65))	('reduced', 'NegReg', (44, 51))
51829	33397920	1H-MRS-detectable glutamate and alpha-KG were significantly reduced in BT142 GLS- neurospheres relative to BT142 GLS+ (Fig.	('1H', 'Chemical', '-', (0, 2))	('alpha-KG', 'Chemical', 'MESH:D007656', (32, 40))	('alpha-KG', 'Protein', (32, 40))	('glutamate', 'Protein', (18, 27))	('BT142', 'Chemical', '-', (71, 76))	('glutamate', 'Chemical', 'MESH:D018698', (18, 27))	('reduced', 'NegReg', (60, 67))	('BT142 GLS-', 'Var', (71, 81))	('BT142', 'Chemical', '-', (107, 112))
51831	33397920	8c), thereby leading to significantly reduced pyruvate/alanine and lactate/alanine ratios in BT142 GLS- neurospheres relative to BT142 GLS+ (Supplementary Fig.	('rat', 'Species', '10116', (83, 86))	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('reduced', 'NegReg', (38, 45))	('BT142', 'Var', (93, 98))	('BT142', 'Chemical', '-', (129, 134))	('alanine', 'Chemical', 'MESH:D000409', (55, 62))	('alanine', 'Chemical', 'MESH:D000409', (75, 82))	('pyruvate', 'Chemical', 'MESH:D019289', (46, 54))	('lactate/alanine ratios', 'MPA', (67, 89))	('BT142', 'Chemical', '-', (93, 98))	('pyruvate/alanine', 'MPA', (46, 62))
51837	33397920	Importantly, TERT silencing significantly reduced NAMPT activity in BT54 neurospheres (Fig.	('TERT silencing', 'Var', (13, 27))	('NAMPT', 'Gene', (50, 55))	('reduced', 'NegReg', (42, 49))	('NAMPT', 'Gene', '10135', (50, 55))
51842	33397920	These results point to a mechanistic role for NAMPT in linking TERT to NADH and to hyperpolarized [1-13C]-alanine metabolism to lactate.	('[1-13C]-alanine', 'Chemical', '-', (98, 113))	('NAMPT', 'Gene', '10135', (46, 51))	('NADH', 'Disease', (71, 75))	('TERT', 'Var', (63, 67))	('NAMPT', 'Gene', (46, 51))	('hyperpolarized', 'PosReg', (83, 97))	('lactate', 'Chemical', 'MESH:D019344', (128, 135))	('NADH', 'Chemical', 'MESH:D009243', (71, 75))
51845	33397920	ASCT2 and LAT2 expression were higher in both NHATERT and NHAALT cells relative to NHACONTROL (Supplementary Fig.	('LAT2', 'Gene', '7462', (10, 14))	('NHAALT', 'Var', (58, 64))	('LAT2', 'Gene', (10, 14))	('expression', 'MPA', (15, 25))	('ASCT2', 'Gene', '6510', (0, 5))	('ASCT2', 'Gene', (0, 5))	('TR', 'Gene', '2149', (89, 91))	('higher', 'PosReg', (31, 37))
51846	33397920	In line with higher transporter expression, intracellular import of [1-13C]-alanine from the medium was significantly higher in NHATERT and NHAALT cells relative to NHACONTROL (Supplementary Fig.	('higher', 'PosReg', (118, 124))	('[1-13C]-alanine', 'Chemical', '-', (68, 83))	('NHATERT', 'Var', (128, 135))	('TR', 'Gene', '2149', (171, 173))	('NHAALT', 'Var', (140, 146))	('intracellular import of [1-13C]-alanine from the', 'MPA', (44, 92))
51847	33397920	Importantly, silencing TERT expression significantly reduced ASCT2 and LAT2 expression and [1-13C]-alanine import in the BT54 LGOG model (Fig.	('TERT expression', 'Gene', (23, 38))	('ASCT2', 'Gene', '6510', (61, 66))	('reduced', 'NegReg', (53, 60))	('ASCT2', 'Gene', (61, 66))	('[1-13C]-alanine import', 'MPA', (91, 113))	('LAT2', 'Gene', '7462', (71, 75))	('[1-13C]-alanine', 'Chemical', '-', (91, 106))	('LAT2', 'Gene', (71, 75))	('silencing', 'Var', (13, 22))	('LGOG', 'Chemical', '-', (126, 130))
51848	33397920	Similarly, expression of ASCT2 and LAT2 as well as [1-13C]-alanine import were significantly reduced in BT142 ALT- neurospheres relative to BT142 ALT+ (Fig.	('ASCT2', 'Gene', '6510', (25, 30))	('[1-13C]-alanine import', 'MPA', (51, 73))	('BT142', 'Chemical', '-', (104, 109))	('expression', 'MPA', (11, 21))	('LAT2', 'Gene', '7462', (35, 39))	('reduced', 'NegReg', (93, 100))	('[1-13C]-alanine', 'Chemical', '-', (51, 66))	('BT142', 'Var', (104, 109))	('BT142', 'Chemical', '-', (140, 145))	('LAT2', 'Gene', (35, 39))	('ASCT2', 'Gene', (25, 30))
51849	33397920	These results suggest that both TERT expression and the ALT pathway are mechanistically associated with elevated alanine import in LGOG and LGAs, respectively.	('ALT pathway', 'Pathway', (56, 67))	('TERT expression', 'Var', (32, 47))	('LGOG', 'Chemical', '-', (131, 135))	('alanine import', 'MPA', (113, 127))	('alanine', 'Chemical', 'MESH:D000409', (113, 120))	('elevated alanine', 'Phenotype', 'HP:0003348', (104, 120))	('elevated', 'PosReg', (104, 112))
51880	33397920	However, histopathologically similar gliomas carry different oncogenic mutations driving tumor initiation and maintenance.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('mutations', 'Var', (71, 80))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('tumor', 'Disease', (89, 94))
51881	33397920	Among the molecular features that define low-grade gliomas, mutually exclusive mutations in the TERT promoter and ATRX, which define LGOGs and LGAs, respectively, are notable because they both lead to TMMs.	('gliomas', 'Disease', (51, 58))	('ATRX', 'Gene', '546', (114, 118))	('TMM', 'Chemical', '-', (201, 204))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('TMMs', 'Disease', (201, 205))	('ATRX', 'Gene', (114, 118))	('LGOG', 'Chemical', '-', (133, 137))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('TERT promoter', 'Gene', (96, 109))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('mutations', 'Var', (79, 88))	('lead to', 'Reg', (193, 200))
51892	33397920	Second, silencing TERT expression or the ALT pathway normalizes their associated 1H-MRS-detectable biomarkers as well as hyperpolarized [1-13C]-alanine metabolism, pointing to a causal link between TMMs and these biomarkers.	('hyperpolarized [1-13C]-alanine metabolism', 'MPA', (121, 162))	('TMM', 'Chemical', '-', (198, 201))	('silencing', 'Var', (8, 17))	('1H-MRS-detectable biomarkers', 'MPA', (81, 109))	('ALT pathway', 'Pathway', (41, 52))	('normalizes', 'NegReg', (53, 63))	('TERT expression', 'Gene', (18, 33))	('[1-13C]-alanine', 'Chemical', '-', (136, 151))	('1H', 'Chemical', '-', (81, 83))
51893	33397920	Similarly, exogenous TERT expression in isogenic ALT+ models modulates 1H-MRS-detectable levels of TERT- and ALT-linked metabolites as well as hyperpolarized [1-13C]-alanine metabolism.	('[1-13C]-alanine', 'Chemical', '-', (158, 173))	('exogenous', 'Var', (11, 20))	('1H', 'Chemical', '-', (71, 73))	('modulates', 'Reg', (61, 70))	('hyperpolarized [1-13C]-alanine metabolism', 'MPA', (143, 184))
51904	33397920	Nevertheless, lactate dehydrogenase activity and pyruvate flux to lactate are detectable in our patient-derived LGOG and LGA models, possibly due to residual lactate dehydrogenase A expression that is below immunoblotting detection limits, variations in lactate dehydrogenase A promoter methylation or lactate dehydrogenase B expression.	('lactate dehydrogenase A', 'Gene', (254, 277))	('lactate', 'Chemical', 'MESH:D019344', (302, 309))	('lactate dehydrogenase A', 'Gene', '3939', (254, 277))	('patient', 'Species', '9606', (96, 103))	('lactate', 'Chemical', 'MESH:D019344', (158, 165))	('variations', 'Var', (240, 250))	('LGOG', 'Chemical', '-', (112, 116))	('pyruvate', 'Chemical', 'MESH:D019289', (49, 57))	('lactate', 'Chemical', 'MESH:D019344', (66, 73))	('lactate dehydrogenase activity', 'MPA', (14, 44))	('lactate', 'Chemical', 'MESH:D019344', (14, 21))	('lactate dehydrogenase A', 'Gene', (158, 181))	('pyruvate flux to lactate', 'MPA', (49, 73))	('lactate dehydrogenase B', 'Gene', (302, 325))	('lactate dehydrogenase A', 'Gene', '3939', (158, 181))	('lactate', 'Chemical', 'MESH:D019344', (254, 261))	('lactate dehydrogenase B', 'Gene', '3945', (302, 325))
51905	33397920	Importantly, when comparing LGOG and LGA models, the difference in lactate production from hyperpolarized [1-13C]-alanine results from elevated NADH in LGOGs since reducing NADH production via NAMPT silencing abrogates lactate production and leads to accumulation of pyruvate.	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('LGOG', 'Chemical', '-', (28, 32))	('NADH', 'Chemical', 'MESH:D009243', (144, 148))	('[1-13C]-alanine', 'Chemical', '-', (106, 121))	('accumulation', 'MPA', (251, 263))	('lactate production', 'MPA', (67, 85))	('NAMPT', 'Gene', (193, 198))	('reducing', 'NegReg', (164, 172))	('NAMPT', 'Gene', '10135', (193, 198))	('LGOG', 'Chemical', '-', (152, 156))	('abrogates', 'NegReg', (209, 218))	('lactate', 'Chemical', 'MESH:D019344', (219, 226))	('pyruvate', 'Chemical', 'MESH:D019289', (267, 275))	('NADH', 'Chemical', 'MESH:D009243', (173, 177))	('silencing', 'Var', (199, 208))	('lactate production', 'MPA', (219, 237))
51923	33397920	Our studies with hyperpolarized [1-13C]-alanine in TERT- neurospheres indicate that silencing TERT expression abrogates hyperpolarized lactate production and leads to an accumulation of hyperpolarized pyruvate.	('abrogates', 'NegReg', (110, 119))	('lactate', 'Chemical', 'MESH:D019344', (135, 142))	('silencing', 'Var', (84, 93))	('pyruvate', 'Chemical', 'MESH:D019289', (201, 209))	('hyperpolarized lactate production', 'MPA', (120, 153))	('hyperpolarized pyruvate', 'MPA', (186, 209))	('[1-13C]-alanine', 'Chemical', '-', (32, 47))	('accumulation', 'PosReg', (170, 182))	('TERT expression', 'Gene', (94, 109))
51924	33397920	Conversely, TERT expression in ALT+ models leads to elevated lactate production from hyperpolarized alanine and a corresponding drop in hyperpolarized pyruvate.	('lactate production from hyperpolarized alanine', 'MPA', (61, 107))	('hyperpolarized pyruvate', 'MPA', (136, 159))	('TERT expression', 'Var', (12, 27))	('alanine', 'Chemical', 'MESH:D000409', (100, 107))	('pyruvate', 'Chemical', 'MESH:D019289', (151, 159))	('drop', 'NegReg', (128, 132))	('lactate', 'Chemical', 'MESH:D019344', (61, 68))	('elevated', 'PosReg', (52, 60))
51927	33397920	Our results indicate that silencing TMMs normalizes 1H-MRS-detectable biomarkers and hyperpolarized [1-13C]-alanine metabolism.	('1H-MRS-detectable biomarkers', 'MPA', (52, 80))	('[1-13C]-alanine metabolism', 'MPA', (100, 126))	('1H', 'Chemical', '-', (52, 54))	('[1-13C]-alanine', 'Chemical', '-', (100, 115))	('TMM', 'Chemical', '-', (36, 39))	('hyperpolarized', 'PosReg', (85, 99))	('normalizes', 'PosReg', (41, 51))	('silencing', 'Var', (26, 35))	('TMMs', 'Gene', (36, 40))
51951	33397920	Briefly, NHAs immortalized via loss of p53 and pRb were engineered to express IDHmut to generate the NHACONTROL cell line.	('TR', 'Gene', '2149', (107, 109))	('IDHmut', 'Gene', (78, 84))	('loss', 'Var', (31, 35))	('rat', 'Species', '10116', (92, 95))	('p53', 'Gene', (39, 42))	('pRb', 'Gene', '5925', (47, 50))	('p53', 'Gene', '7157', (39, 42))	('pRb', 'Gene', (47, 50))
51953	33397920	NHAALT cells were generated by silencing ATRX expression in NHACONTROL cells.	('TR', 'Gene', '2149', (42, 44))	('silencing', 'Var', (31, 40))	('ATRX', 'Gene', (41, 45))	('rat', 'Species', '10116', (22, 25))	('ATRX', 'Gene', '546', (41, 45))	('TR', 'Gene', '2149', (66, 68))
51970	33397920	Briefly, for every sample, 16 ng of genomic DNA was mixed with 0.2 microg/microl bovine serum albumin, 0.1% Tween, 4 microM dithiothreitol, 1 mM of each dNTP, 3.75U of phi29 DNA polymerase, and 1x phi29 buffer and incubated at 30  C for 8 h followed by 20 min at 65  C. The telomeric content of samples with and without phi29 polymerase was calculated by qPCR and normalized to the respective single-copy gene reference (36B4).	('phi29', 'Var', (320, 325))	('albumin', 'Gene', (94, 101))	('albumin', 'Gene', '213', (94, 101))
51991	33397920	NHATERT, NHAALT, SF10417, or BT142 cells (3 x 105cells/10 mul) were intracranially injected into athymic nude rats (male, rnu/rnu homozygous, 5-6-weeks old, Envigo Laboratories).	('rat', 'Species', '10116', (110, 113))	('BT142', 'Chemical', '-', (29, 34))	('SF10417', 'Var', (17, 24))	('rats', 'Species', '10116', (110, 114))	('rat', 'Species', '10116', (168, 171))	('SF10417', 'Chemical', '-', (17, 24))	('BT142', 'Gene', (29, 34))
51992	33397920	Twenty-three rats were used (n = 3 each for NHATERT for slab dynamic and EPSI studies; n = 3 each for NHAALT for slab dynamic and EPSI studies; n = 3 for tumor-free controls for slab studies; n = 3 for SF10417 and n = 5 for BT142 for EPSI).	('rats', 'Species', '10116', (13, 17))	('tumor', 'Disease', (154, 159))	('SF10417', 'Var', (202, 209))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('SF10417', 'Chemical', '-', (202, 209))	('BT142', 'Chemical', '-', (224, 229))
51994	33397920	For slab studies, following injection of 2.2 ml of hyperpolarized [1-13C]-alanine (final concentration of 96 mM) via a tail-vein catheter over 12 s, dynamic 13C spectra were acquired from a 15 mm slab through the brain every 3 s using a flyback spectral-spatial RF pulse with a 30  flip angle on pyruvate and lactate and 3  flip angle on alanine.	('pyruvate', 'MPA', (296, 304))	('lactate', 'MPA', (309, 316))	('alanine', 'Chemical', 'MESH:D000409', (338, 345))	('[1-13C]-alanine', 'Chemical', '-', (66, 81))	('13C', 'Chemical', 'MESH:C000615229', (157, 160))	('pyruvate', 'Chemical', 'MESH:D019289', (296, 304))	('lactate', 'Chemical', 'MESH:D019344', (309, 316))	('hyperpolarized', 'Var', (51, 65))	('rat', 'Species', '10116', (96, 99))	('13C', 'Chemical', 'MESH:C000615229', (69, 72))	('alanine', 'Chemical', 'MESH:D000409', (74, 81))
52000	33397920	Samples were diagnosed as LGOG with IDHmut and 1p19q codeletion, diffuse LGA, IDHmut, or gliosis from epilepsy patients by a board-certified neuropathologist (J.J.P.).	('diffuse LGA', 'Disease', (65, 76))	('IDHmut', 'Disease', (36, 42))	('epilepsy', 'Disease', (102, 110))	('IDHmut', 'Disease', (78, 84))	('gliosis', 'Disease', (89, 96))	('1p19q codeletion', 'Var', (47, 63))	('epilepsy', 'Phenotype', 'HP:0001250', (102, 110))	('gliosis', 'Phenotype', 'HP:0002171', (89, 96))	('epilepsy', 'Disease', 'MESH:D004827', (102, 110))	('LGOG', 'Chemical', '-', (26, 30))	('gliosis', 'Disease', 'MESH:D005911', (89, 96))	('patients', 'Species', '9606', (111, 119))
52008	31225516	Also, excessive resection of peri-tumoral tissue often carries risks of damaging the nearby functioning cortical and subcortical structures with an unacceptable decrease in patient's quality of life and postoperative functional status, and the risk of making patients not eligible to adjuvant treatments.	('damaging', 'Reg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('patients', 'Species', '9606', (259, 267))	('decrease', 'NegReg', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('patient', 'Species', '9606', (173, 180))	('excessive', 'Var', (6, 15))	('patient', 'Species', '9606', (259, 266))
52021	31225516	These are the portions of brain we can currently monitor during surgery because their dysfunction will cause significant changes in patient's functions and behavior.	('changes', 'Reg', (121, 128))	('patient', 'Species', '9606', (132, 139))	('functions', 'MPA', (142, 151))	('dysfunction', 'Var', (86, 97))
52058	31225516	The major part of psychological contraindication to the awake surgery can be partly spotted in the preoperative psychological assessment: distress, agitation, anxiety, terror, and lack of compliance are also detrimental to the assessment, as they compromise the quality of the mapping or can lead to a wrong interpretation of changes in patient's performances.	('agitation', 'Phenotype', 'HP:0000713', (148, 157))	('agitation', 'Disease', 'MESH:D011595', (148, 157))	('agitation', 'Disease', (148, 157))	('anxiety', 'Disease', (159, 166))	('anxiety', 'Phenotype', 'HP:0000739', (159, 166))	('quality', 'MPA', (262, 269))	('lead to', 'Reg', (292, 299))	('mapping', 'MPA', (277, 284))	('compromise', 'NegReg', (247, 257))	('patient', 'Species', '9606', (337, 344))	('anxiety', 'Disease', 'MESH:D001008', (159, 166))	('lack', 'Var', (180, 184))
52156	30675185	Comparing information on prominent mutations within glioma discloses well-known, unknown, possible, as well as inapplicable biomarkers.	('glioma', 'Disease', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('mutations', 'Var', (35, 44))
52161	30675185	The spectrum of mutations which occur in pediatric cancers is different from adult cancers involving a lower mutation rate and frequently single cancer-driving mutations.	('cancer', 'Disease', (145, 151))	('pediatric cancers', 'Disease', 'MESH:D009369', (41, 58))	('pediatric cancers', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (16, 25))	('adult cancers', 'Disease', (77, 90))	('adult cancers', 'Disease', 'MESH:C535836', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (83, 89))
52185	30675185	The tools and databases are further described below:    St Jude/Washington University Pediatric Cancer Genomic Data Portal (PeCan) aims to provide interactive visualizations of pediatric cancer mutations across various collaborative projects, freely for nonclinical academic research.	('pediatric cancer', 'Disease', (177, 193))	('mutations', 'Var', (194, 203))	('PeCan', 'Species', '32201', (124, 129))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pediatric cancer', 'Disease', 'MESH:D009369', (177, 193))
52202	30675185	TARGET lists genetic changes that drive the initiation and progression of hard-to-treat childhood cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('child', 'Species', '9606', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('genetic changes', 'Var', (13, 28))
52224	30675185	A high frequency of mutations in the region of the IDH1 gene has been observed in most of low grade gliomas (LGG) and secondary high grade gliomas (HGG).	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('gliomas', 'Disease', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IDH1', 'Gene', (51, 55))	('mutations', 'Var', (20, 29))	('gliomas', 'Disease', (100, 107))	('observed', 'Reg', (70, 78))
52225	30675185	However, such mutations are less frequently found in pediatric gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('pediatric gliomas', 'Disease', (53, 70))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('pediatric gliomas', 'Disease', 'MESH:D005910', (53, 70))	('mutations', 'Var', (14, 23))
52229	30675185	The availability of processed data is not exclusively limited to cancer gene census (CGC), which lists cancer-implicated mutations by comparison of sequenced data to the reference genome GRCh38.	('mutations', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
52233	30675185	The query for information on mutations regarding glioma using pedican lists several entries which have to be manually opened in order to extract further mutation information.	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('mutations', 'Var', (29, 38))	('glioma', 'Disease', (49, 55))
52239	30675185	Several study cohorts are found from querying the disease "brain tumor": While it is difficult to scan through a total of 3045 samples from 2900 patients, a summary of genes with mutations the most found is displayed as bubble chart, sorted by known pathway relations.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('brain tumor', 'Disease', (59, 70))	('brain tumor', 'Disease', 'MESH:D001932', (59, 70))	('mutations', 'Var', (179, 188))	('brain tumor', 'Phenotype', 'HP:0030692', (59, 70))
52241	30675185	The query on IDH1 reveals 10 mutations for pediatric brain tumor samples (from DKTK, PCGP and BROAD).	('brain tumor', 'Phenotype', 'HP:0030692', (53, 64))	('mutations', 'Var', (29, 38))	('PCGP', 'Chemical', '-', (85, 89))	('brain tumor', 'Disease', 'MESH:D001932', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('brain tumor', 'Disease', (53, 64))
52245	30675185	HGG results in 3239 mutations with mutated H3F3A and TP53 as the most prominent ones, followed by ACVR1.	('mutated', 'Var', (35, 42))	('ACVR1', 'Gene', (98, 103))	('H3F3A', 'Gene', (43, 48))	('ACVR1', 'Gene', '90', (98, 103))	('TP53', 'Gene', '7157', (53, 57))	('H3F3A', 'Gene', '3020', (43, 48))	('mutations', 'Var', (20, 29))	('TP53', 'Gene', (53, 57))
52257	30675185	The project's overview page shows the top 20 mutated cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutated', 'Var', (45, 52))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))
52262	30675185	The project's related publications include information on IDH1 mutations to be rare for childhood glioblastoma.	('mutations', 'Var', (63, 72))	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('child', 'Species', '9606', (88, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('IDH1', 'Gene', (58, 62))
52264	30675185	Cancer distribution shows that mutated IDH1 is mainly found in brain cancer, in particular within LGG and only to a low extent in medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (130, 145))	('brain cancer', 'Disease', 'MESH:D001932', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IDH1', 'Gene', (39, 43))	('medulloblastoma', 'Disease', (130, 145))	('brain cancer', 'Phenotype', 'HP:0030692', (63, 75))	('found', 'Reg', (54, 59))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('medulloblastoma', 'Disease', 'MESH:D008527', (130, 145))	('mutated', 'Var', (31, 38))	('brain cancer', 'Disease', (63, 75))
52265	30675185	Filtering of gene IDH1 results in only 13 mutations in 20 donors out of 554 donors.	('donor', 'Species', '9606', (58, 63))	('IDH1', 'Gene', (18, 22))	('mutations', 'Var', (42, 51))	('donor', 'Species', '9606', (76, 81))
52269	30675185	Selecting all available entries for pediatric brain tumors highlights IDH1 as the most prominent example of genes affected by mutations within the young cancer patients, followed by CDR2 and ATRX.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('CDR2', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patients', 'Species', '9606', (160, 168))	('cancer', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('brain tumors', 'Phenotype', 'HP:0030692', (46, 58))	('CDR2', 'Gene', '1039', (182, 186))	('brain tumor', 'Phenotype', 'HP:0030692', (46, 57))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (36, 58))	('pediatric brain tumors', 'Disease', (36, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (126, 135))	('ATRX', 'Gene', (191, 195))	('ATRX', 'Gene', '546', (191, 195))	('IDH1', 'Gene', (70, 74))
52277	30675185	For example, searching for IDH1 in UCSC visgene results in a brain image of a mouse.	('brain image', 'CPA', (61, 72))	('searching', 'Var', (13, 22))	('mouse', 'Species', '10090', (78, 83))	('results in', 'Reg', (48, 58))
52280	30675185	Moreover, the analysis of another Treehouse dataset on neuroblastoma showed that copy number variations are higher in undifferentiated or poorly differentiated cells.	('neuroblastoma', 'Disease', (55, 68))	('higher', 'Reg', (108, 114))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))	('copy number variations', 'Var', (81, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (55, 68))
52285	30675185	Those resources offering mainly pediatric data-sets do hardly include higher numbers on mutations within IDH1 while in adult samples the mutated gene is known to be connected to glioma.	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('IDH1', 'Gene', (105, 109))	('mutations', 'Var', (88, 97))	('connected', 'Reg', (165, 174))	('glioma', 'Disease', (178, 184))
52377	30381916	Although methionine PET has been shown to have high sensitivity for gliomas, false-positive results may be seen under benign conditions, such as cases of demyelination, leukoencephalitis, or abscess.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('abscess', 'Disease', (191, 198))	('abscess', 'Phenotype', 'HP:0025615', (191, 198))	('leukoencephalitis', 'Disease', (169, 186))	('demyelination', 'Disease', (154, 167))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('demyelination', 'Disease', 'MESH:D003711', (154, 167))	('leukoencephalitis', 'Disease', 'MESH:D004684', (169, 186))	('methionine PET', 'Var', (9, 23))	('methionine', 'Chemical', 'MESH:D008715', (9, 19))	('demyelination', 'Phenotype', 'HP:0011096', (154, 167))
52378	30381916	Several studies diagnosing untreated brain tumors with methionine PET have reported relatively high sensitivities, ranging from 76% to 91%, and specificities ranging from 75% to 100%.	('brain tumors', 'Disease', 'MESH:D001932', (37, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (37, 49))	('brain tumors', 'Disease', (37, 49))	('brain tumor', 'Phenotype', 'HP:0030692', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('methionine PET', 'Var', (55, 69))	('methionine', 'Chemical', 'MESH:D008715', (55, 65))	('sensitivities', 'MPA', (100, 113))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))
52379	30381916	Methionine PET is more suitable than FDG PET alone for diagnosing and managing patients, particularly those with low-grade tumors.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('patients', 'Species', '9606', (79, 87))	('FDG', 'Chemical', 'MESH:D019788', (37, 40))	('Methionine', 'Var', (0, 10))
52383	30381916	Methionine PET can also detect recurrent tumors with high sensitivity and specificity, allowing differentiation between tumor recurrence and radionecrosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Methionine', 'Var', (0, 10))	('tumor', 'Disease', (120, 125))
52499	23807424	Notice (intensity, PTPSA, and multi-FD) feature combination captures more tumor regions for three astrocytoma (P030, P040, and P090) and three medulloblastoma (M020, M040, and M100) patients, respectively.	('astrocytoma', 'Phenotype', 'HP:0009592', (98, 109))	('M040', 'Var', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('medulloblastoma', 'Disease', 'MESH:D008527', (143, 158))	('P030', 'Var', (111, 115))	('astrocytoma', 'Disease', 'MESH:D001254', (98, 109))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('medulloblastoma', 'Phenotype', 'HP:0002885', (143, 158))	('tumor', 'Disease', (74, 79))	('M020', 'Var', (160, 164))	('P040', 'Var', (117, 121))	('M100', 'Var', (176, 180))	('P090', 'Var', (127, 131))	('patients', 'Species', '9606', (182, 190))	('medulloblastoma', 'Disease', (143, 158))	('astrocytoma', 'Disease', (98, 109))
52500	23807424	Furthermore, the same feature combination also shows superiority in correctly classifying nontumor regions for two astrocytoma (P040 and P060) and three medulloblastoma (P090, M040, and M060) patients, respectively.	('M040', 'Var', (176, 180))	('P060', 'Var', (137, 141))	('medulloblastoma', 'Disease', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('patients', 'Species', '9606', (192, 200))	('tumor', 'Disease', (93, 98))	('P090', 'Var', (170, 174))	('astrocytoma', 'Disease', 'MESH:D001254', (115, 126))	('astrocytoma', 'Disease', (115, 126))	('P040', 'Var', (128, 132))	('medulloblastoma', 'Phenotype', 'HP:0002885', (153, 168))	('medulloblastoma', 'Disease', 'MESH:D008527', (153, 168))	('M060', 'Var', (186, 190))	('astrocytoma', 'Phenotype', 'HP:0009592', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
52512	23807424	In summary, it is worth noting that intensity and fractal feature combinations outperform Gabor-like features for brain tumor segmentation performance.	('brain tumor', 'Phenotype', 'HP:0030692', (114, 125))	('outperform', 'NegReg', (79, 89))	('combinations', 'Var', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('brain tumor', 'Disease', (114, 125))	('brain tumor', 'Disease', 'MESH:D001932', (114, 125))
52620	22268087	Multivariable prediction rules were applied for ADC < 925 10-6 mm2/s, the presence of enhancement, and the presence of calcification.	('calcification', 'Disease', (119, 132))	('mm2', 'Gene', '10687', (63, 66))	('ADC < 925 10-6', 'Var', (48, 62))	('mm2', 'Gene', (63, 66))	('enhancement', 'MPA', (86, 97))	('calcification', 'Disease', 'MESH:D002114', (119, 132))
52622	22268087	The most accurate (82.2%) predictive rule was seen when either ADC < 925 10-6 mm2/s or enhancement and calcification were present.	('calcification', 'Disease', 'MESH:D002114', (103, 116))	('mm2', 'Gene', (78, 81))	('calcification', 'Disease', (103, 116))	('ADC < 925 10-6', 'Var', (63, 77))	('mm2', 'Gene', '10687', (78, 81))
52729	33807423	Deletions on Chromosome Y and Downregulation of the SRY Gene in Tumor Tissue Are Associated with Worse Survival of Glioblastoma Patients Glioblastoma (GBM) is one of the most common and most aggressive brain tumors with higher prevalence among men than women.	('SRY', 'Gene', '6736', (52, 55))	('men', 'Species', '9606', (255, 258))	('aggressive brain', 'Phenotype', 'HP:0000718', (191, 207))	('Tumor', 'Phenotype', 'HP:0002664', (64, 69))	('women', 'Species', '9606', (253, 258))	('SRY', 'Gene', (52, 55))	('aggressive brain tumors', 'Disease', 'MESH:D001932', (191, 214))	('Glioblastoma', 'Disease', 'MESH:D005909', (115, 127))	('Downregulation', 'NegReg', (30, 44))	('Glioblastoma', 'Disease', 'MESH:D005909', (137, 149))	('Glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('aggressive brain tumors', 'Disease', (191, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('Glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('men', 'Species', '9606', (244, 247))	('brain tumors', 'Phenotype', 'HP:0030692', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Glioblastoma', 'Disease', (115, 127))	('Deletions', 'Var', (0, 9))	('Glioblastoma', 'Disease', (137, 149))
52730	33807423	Loss of chromosome Y (LOY) in the peripheral blood cells has been associated with increased risk of developing cancer.	('chromosome', 'Gene', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Loss', 'Var', (0, 4))
52732	33807423	Through droplet digital PCR (ddPCR) analysis of 10 markers spread throughout chromosome Y in 105 male GBM patients, we were able to identify deletion of SRY gene as a factor strongly correlating with reduced overall survival.	('deletion', 'Var', (141, 149))	('reduced', 'NegReg', (200, 207))	('patients', 'Species', '9606', (106, 114))	('overall', 'MPA', (208, 215))	('SRY', 'Gene', (153, 156))
52734	33807423	One of the considered aspects is the involvement of the sex chromosomes, especially loss of chromosome Y (LOY).	('men', 'Species', '9606', (44, 47))	('involvement', 'Reg', (37, 48))	('loss', 'Var', (84, 88))
52735	33807423	Methods: Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y.	('IDH', 'Gene', (51, 54))	('patients', 'Species', '9606', (75, 83))	('IDH', 'Gene', '3417', (51, 54))	('Tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Tumors', 'Disease', (9, 15))	('Tumors', 'Disease', 'MESH:D009369', (9, 15))	('Tumors', 'Phenotype', 'HP:0002664', (9, 15))	('copy number changes', 'Var', (125, 144))
52737	33807423	Results: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, p = 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months, p = 0.0031).	('overall survival', 'MPA', (55, 71))	('shorter', 'NegReg', (47, 54))	('SRY', 'Gene', (230, 233))	('sex-determining region Y', 'Gene', '6736', (199, 223))	('loss', 'NegReg', (187, 191))	('LOY', 'Var', (9, 12))	('sex-determining region Y', 'Gene', (199, 223))
52739	33807423	Conclusion: Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.	('chromosome Y', 'Gene', (72, 84))	('reduced', 'NegReg', (45, 52))	('gliomagenesis', 'Disease', 'None', (216, 229))	('survival', 'CPA', (136, 144))	('reduced', 'NegReg', (128, 135))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('SRY', 'Gene', (103, 106))	('patients', 'Species', '9606', (157, 165))	('gliomagenesis', 'Disease', (216, 229))	('deletions', 'Var', (31, 40))	('reduced survival of male GBM', 'Phenotype', 'HP:0000026', (128, 156))	('gene expression', 'MPA', (53, 68))	('connected', 'Reg', (170, 179))
52748	33807423	Despite the first reports about aneuploidy of sex chromosomes in brain tumors already decades ago, loss of chromosome Y (LOY) was commonly considered a physiological process in aging men, accelerated by smoking and associated with increased risk of Alzheimer disease.	('Alzheimer disease', 'Phenotype', 'HP:0002511', (249, 266))	('Alzheimer disease', 'Disease', 'MESH:D000544', (249, 266))	('men', 'Species', '9606', (183, 186))	('accelerated', 'PosReg', (188, 199))	('aneuploidy', 'Disease', (32, 42))	('brain tumors', 'Disease', 'MESH:D001932', (65, 77))	('brain tumors', 'Phenotype', 'HP:0030692', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('associated', 'Reg', (215, 225))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('loss', 'Var', (99, 103))	('brain tumors', 'Disease', (65, 77))	('Alzheimer disease', 'Disease', (249, 266))	('aneuploidy', 'Disease', 'MESH:D000782', (32, 42))
52749	33807423	Renewed interest in the "genetic wasteland" of chromosome Y came with LOY associations to cancer, even though not all studies could confirm the relationship.	('cancer', 'Disease', (90, 96))	('LOY', 'Var', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
52751	33807423	We hypothesized that LOY influences the OS of male GBM patients, thus contributing to the observed sex bias.	('LOY', 'Var', (21, 24))	('patients', 'Species', '9606', (55, 63))	('influences', 'Reg', (25, 35))	('contributing', 'Reg', (70, 82))
52758	33807423	In accordance with the WHO classification, tumor samples were tested for isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations with Sanger sequencing (described below) and all were negative.	('mutations', 'Var', (115, 124))	('IDH1/2', 'Gene', '3417;3418', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IDH1/2', 'Gene', (107, 113))	('tumor', 'Disease', (43, 48))
52779	33807423	Only six samples harbored deletion of all markers, indicating complete LOY in the fraction of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('deletion', 'Var', (26, 34))	('tumor', 'Disease', (94, 99))	('LOY', 'NegReg', (71, 74))
52784	33807423	Median survival of males with SRY deletion in at least 60% of the DNA was 4 months shorter than the OS of the remaining patients (10.8 vs. 14.8 months).	('SRY', 'Gene', (30, 33))	('deletion', 'Var', (34, 42))	('patients', 'Species', '9606', (120, 128))	('shorter', 'NegReg', (83, 90))
52787	33807423	With this cut-off, deletions of AMELY and NLGN4Y correlated with a shorter OS (11.5 vs. 15.2 months, p = 0.01; 10.8 vs. 14.5 months, p = 0.031, respectively) (Figure 2).	('AMELY', 'Gene', (32, 37))	('NLGN4Y', 'Gene', (42, 48))	('NLGN4Y', 'Gene', '22829', (42, 48))	('AMELY', 'Gene', '266', (32, 37))	('deletions', 'Var', (19, 28))
52788	33807423	In five cases (ZFY, USP9Y, ARSEP1, TMSB4Y, and KDM5D), no significant correlation with survival was detected (p > 0.05) (Supplementary Materials, Figure S1f-j).	('ARSEP1', 'Var', (27, 33))	('KDM5D', 'Gene', (47, 52))	('USP9Y', 'Gene', (20, 25))	('TMSB4Y', 'Gene', '9087', (35, 41))	('ZFY', 'Gene', (15, 18))	('USP9Y', 'Gene', '8287', (20, 25))	('ZFY', 'Gene', '7544', (15, 18))	('men', 'Species', '9606', (127, 130))	('KDM5D', 'Gene', '8284', (47, 52))	('TMSB4Y', 'Gene', (35, 41))
52790	33807423	No significant influence of deletion of the reported 3-gene cluster (ARSEP1, TMSB4Y, and UTY) on OS was observed (p > 0.05).	('UTY', 'Gene', '7404', (89, 92))	('ARSEP1', 'Gene', (69, 75))	('UTY', 'Gene', (89, 92))	('TMSB4Y', 'Gene', (77, 83))	('TMSB4Y', 'Gene', '9087', (77, 83))	('deletion', 'Var', (28, 36))
52795	33807423	Known chromosomal aberrations in tumors, as well as published research about Y chromosome loss in aging men, led to our finding regarding the impact of loss of SRY.	('men', 'Species', '9606', (104, 107))	('loss', 'NegReg', (90, 94))	('loss', 'Var', (152, 156))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (6, 29))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('SRY', 'Gene', (160, 163))	('tumors', 'Disease', (33, 39))
52796	33807423	Interestingly, the Mann-Whitney U tests did not show any significant age difference between males with the SRY deletion (mean age 56.8 years) and normal or elevated SRY CN (mean age 57.4 years), nor in TCGA group of patients with low (mean age 61.9 years) or high SRY expression (mean age 61.6 years).	('SRY', 'Gene', (107, 110))	('SRY', 'MPA', (165, 168))	('deletion', 'Var', (111, 119))	('patients', 'Species', '9606', (216, 224))
52797	33807423	Additional CN analysis of SRY in the 61 tumor matched blood samples (Figure 5) revealed that only three tumor-blood pairs had deletions (CN <=0.8) in both, indicating that SRY deletions are mainly tumor private.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SRY', 'Gene', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (104, 109))	('deletions', 'Var', (126, 135))	('deletions', 'Var', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
52800	33807423	The Cox proportional hazard model created for the cohort showed an impact on OS for age (p = 0.017), MGMT status (p = 0.002), and to the greatest extent for deletion of SRY (p = 0.001) (Table 2).	('impact', 'Reg', (67, 73))	('MGMT', 'Gene', (101, 105))	('MGMT', 'Gene', '4255', (101, 105))	('deletion', 'Var', (157, 165))	('SRY', 'Gene', (169, 172))
52806	33807423	In this study, we have shown that deletion of SRY, loss of genes located on chromosome Y, and complete LOY significantly influence survival of male GBM patients.	('deletion', 'Var', (34, 42))	('patients', 'Species', '9606', (152, 160))	('SRY', 'Gene', (46, 49))	('influence', 'Reg', (121, 130))	('loss', 'NegReg', (51, 55))	('survival', 'CPA', (131, 139))
52807	33807423	Different mutational burden, sex-dependent effects of IDH mutations together with glycolytic dependency, and overrepresentation of Frizzled-7 receptor in the tumor cells are only some of the proposed contributors.	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (158, 163))	('overrepresentation', 'PosReg', (109, 127))	('IDH', 'Gene', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('IDH', 'Gene', '3417', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
52808	33807423	Mosaic LOY has previously been linked with increased risk of non-hematological cancers, poor prognosis in head and neck squamous cell carcinoma, and/or all-cause mortality.	('mortality', 'Disease', (162, 171))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Mosaic LOY', 'Var', (0, 10))	('hematological cancer', 'Phenotype', 'HP:0004377', (65, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('neck squamous cell carcinoma', 'Disease', (115, 143))	('mortality', 'Disease', 'MESH:D003643', (162, 171))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (106, 143))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (115, 143))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
52810	33807423	Counterintuitively to the aforementioned studies, LOY also provides reduced risk of leukemic transformation in patients with myelodysplastic syndromes, but without this influencing survival.	('leukemic transformation', 'Disease', 'MESH:D002472', (84, 107))	('men', 'Species', '9606', (31, 34))	('LOY', 'Var', (50, 53))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (125, 150))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (125, 150))	('reduced', 'NegReg', (68, 75))	('myelodysplastic syndromes', 'Disease', (125, 150))	('leukemic transformation', 'Disease', (84, 107))	('patients', 'Species', '9606', (111, 119))
52812	33807423	Similar to the methods applied by Mitchell et al., we used probes across chromosome Y and an autosomal reference probe located on chromosome 5, which is seldom lost in brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (168, 180))	('brain tumors', 'Phenotype', 'HP:0030692', (168, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('brain tumors', 'Disease', (168, 180))	('probes', 'Var', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
52815	33807423	presented a model based on TCGA data, in which cancer development is most likely an outcome of the extreme downregulation of chromosome Y, which in turn is a result of age dependent LOY.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('downregulation', 'NegReg', (107, 121))	('men', 'Species', '9606', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('LOY', 'Var', (182, 185))	('chromosome', 'Gene', (125, 135))
52816	33807423	Interestingly, deletions of SRY had an even greater impact on survival than MGMT promoter methylation, a biomarker proven to be indispensable for the successful treatment with temozolomide.	('survival', 'MPA', (62, 70))	('MGMT', 'Gene', (76, 80))	('MGMT', 'Gene', '4255', (76, 80))	('SRY', 'Gene', (28, 31))	('men', 'Species', '9606', (166, 169))	('impact', 'Reg', (52, 58))	('temozolomide', 'Chemical', 'MESH:D000077204', (176, 188))	('deletions', 'Var', (15, 24))
52818	33807423	Ectopic expression of SRY in a transgenic mice model promoted hepatocarcinogenesis via activation of the SRY-box transcription factor 9 (Sox9), PDGFRalpha/PI3K/Akt, and c-Myc/CyclinD1 pathways.	('activation', 'PosReg', (87, 97))	('Sox9', 'Gene', (137, 141))	('promoted', 'PosReg', (53, 61))	('PDGFRalpha', 'Gene', (144, 154))	('PDGFRalpha', 'Gene', '18595', (144, 154))	('c-Myc', 'Gene', '4609', (169, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('Ectopic expression', 'Var', (0, 18))	('CyclinD1', 'Gene', (175, 183))	('carcinogenesis', 'Disease', (68, 82))	('c-Myc', 'Gene', (169, 174))	('CyclinD1', 'Gene', '12443', (175, 183))	('Sox9', 'Gene', '20682', (137, 141))	('SRY', 'Gene', (22, 25))	('transgenic mice', 'Species', '10090', (31, 46))
52821	33807423	Surprisingly, these pathways were enriched in the low SRY expression group, contradicting findings from the hepatocellular carcinoma studies.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (108, 132))	('hepatocellular carcinoma', 'Disease', (108, 132))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (108, 132))	('low SRY expression', 'Var', (50, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
52824	33807423	Furthermore, GSEA revealed several of the GBM associated signaling pathways to be enriched in the low SRY expressing tumors, for example, EGFR, one of the key tumor regulators, aberrant especially in the classical subtype of GBM.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('EGFR', 'Gene', '1956', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (117, 122))	('EGFR', 'Gene', (138, 142))	('tumors', 'Disease', (117, 123))	('tumor', 'Disease', (159, 164))	('GBM', 'Disease', (225, 228))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('GSEA', 'Chemical', '-', (13, 17))	('aberrant', 'Var', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
52829	33807423	This then being in line with our results from the tumor-matched blood samples showing that SRY deletions are more common in tumor tissue than in the blood of the GBM patients.	('deletions', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('common', 'Reg', (114, 120))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('patients', 'Species', '9606', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SRY', 'Gene', (91, 94))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
52841	33050528	Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma The presence of the IDH mutation in glioma raises the possibility that these CNS malignancies could be targeted with metabolic-based therapeutics, however, the exploration of the role that regulatory lipids, such as sphingolipids serve within the IDH1mut gliomas remains limited.	('Glioma', 'Phenotype', 'HP:0009733', (61, 67))	('gliomas', 'Disease', (323, 330))	('mutation', 'Var', (92, 100))	('glioma', 'Disease', (323, 329))	('glioma', 'Disease', 'MESH:D005910', (323, 329))	('IDH', 'Gene', (88, 91))	('lipids', 'Chemical', 'MESH:D008055', (291, 297))	('gliomas', 'Disease', 'MESH:D005910', (323, 330))	('lipids', 'Chemical', 'MESH:D008055', (268, 274))	('Glioma', 'Disease', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (323, 329))	('Sphingolipid', 'Chemical', 'MESH:D013107', (0, 12))	('IDH', 'Gene', (315, 318))	('IDH', 'Gene', '3417', (88, 91))	('glioma', 'Disease', (104, 110))	('sphingolipids', 'Chemical', 'MESH:D013107', (284, 297))	('gliomas', 'Phenotype', 'HP:0009733', (323, 330))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('IDH', 'Gene', (53, 56))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))	('IDH', 'Gene', '3417', (315, 318))	('malignancies', 'Disease', (149, 161))	('Glioma', 'Disease', 'MESH:D005910', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('IDH', 'Gene', '3417', (53, 56))
52843	33050528	We revealed elevation in certain lipids produced along the sphingolipid pathway for IDH1 mutated glioma cells and upregulation of the corresponding enzymes.	('upregulation', 'PosReg', (114, 126))	('elevation', 'PosReg', (12, 21))	('glioma', 'Disease', (97, 103))	('sphingolipid', 'Chemical', 'MESH:D013107', (59, 71))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('lipids produced', 'MPA', (33, 48))	('IDH', 'Gene', (84, 87))	('IDH', 'Gene', '3417', (84, 87))	('enzymes', 'Enzyme', (148, 155))	('lipids', 'Chemical', 'MESH:D008055', (33, 39))	('mutated', 'Var', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
52844	33050528	We demonstrated that inhibiting sphingosine kinase which exacerbating the imbalance between sphingosine and sphingosine 1-phosphate leads to cell death, specifically for IDH1mut gliomas.	('inhibiting', 'Var', (21, 31))	('sphingosine 1-phosphate', 'Chemical', 'MESH:C060506', (108, 131))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('IDH', 'Gene', '3417', (170, 173))	('sphingosine', 'Chemical', 'MESH:D013110', (108, 119))	('IDH', 'Gene', (170, 173))	('sphingosine kinase', 'Enzyme', (32, 50))	('imbalance', 'Phenotype', 'HP:0002172', (74, 83))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('cell death', 'CPA', (141, 151))	('gliomas', 'Disease', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('exacerbating', 'PosReg', (57, 69))	('sphingosine', 'Chemical', 'MESH:D013110', (32, 43))	('sphingosine', 'Chemical', 'MESH:D013110', (92, 103))
52853	33050528	To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1mut gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.	('altering', 'Var', (57, 65))	('sphingolipid pathway', 'Pathway', (70, 90))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('IDH', 'Gene', (94, 97))	('sphingolipid', 'Chemical', 'MESH:D013107', (70, 82))	('arrest', 'Disease', (145, 151))	('IDH', 'Gene', '3417', (94, 97))	('gliomas', 'Disease', (102, 109))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('cellular death', 'CPA', (190, 204))
52856	33050528	Gain-of-function mutations in isocitrate dehydrogenase I (IDHmut) are very common events in lower grade gliomas and secondary glioblastomas, causing overproduction of D-2-hydroxyglutarate at millimolar concentrations.	('gliomas', 'Disease', (104, 111))	('IDH', 'Gene', '3417', (58, 61))	('glioblastomas', 'Phenotype', 'HP:0012174', (126, 139))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('overproduction', 'MPA', (149, 163))	('Gain-of-function', 'PosReg', (0, 16))	('glioblastomas', 'Disease', 'MESH:D005909', (126, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('glioblastomas', 'Disease', (126, 139))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (167, 187))	('IDH', 'Gene', (58, 61))	('mutations', 'Var', (17, 26))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
52869	33050528	While certain sphingolipids (e.g., analogs of ceramide, sphingosine and sphinganine) can serve as bioeffectors that disrupt pro-survival cellular signaling pathways, S1P has been classified as an oncopotent biomolecule which mediates cell signaling as an intracellular second messenger and a ligand of G protein-coupled receptors (GPCR).	('G protein-coupled', 'Protein', (302, 319))	('sphinganine', 'Chemical', 'MESH:C005682', (72, 83))	('S1P', 'Chemical', 'MESH:C060506', (166, 169))	('S1P', 'Var', (166, 169))	('ceramide', 'Chemical', 'MESH:D002518', (46, 54))	('sphingolipids', 'Chemical', 'MESH:D013107', (14, 27))	('sphingosine', 'Chemical', 'MESH:D013110', (56, 67))	('pro-survival', 'Pathway', (124, 136))	('disrupt', 'NegReg', (116, 123))
52870	33050528	S1P utilizes multiple targets to stimulate complex cellular processes involving chemotactic motility, migration, differentiation, proliferation, apoptotic survival response, capillary permeability, differentiation and angiogenesis, which are key hallmarks of cancers.	('apoptotic survival response', 'CPA', (145, 172))	('capillary permeability', 'CPA', (174, 196))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('chemotactic motility', 'CPA', (80, 100))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('angiogenesis', 'CPA', (218, 230))	('cancers', 'Disease', (259, 266))	('proliferation', 'CPA', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('migration', 'CPA', (102, 111))	('differentiation', 'CPA', (113, 128))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))	('S1P', 'Var', (0, 3))	('differentiation', 'CPA', (198, 213))	('stimulate', 'PosReg', (33, 42))
52873	33050528	Given their historical, vital roles in cell signaling and regulation, we hypothesized that manipulating the dynamic relationship between ceramide, sphingosine and S1P would reveal vulnerabilities and potentially translate into therapeutic targets to combat proliferation in IDH1mut gliomas.	('manipulating', 'Var', (91, 103))	('ceramide', 'Chemical', 'MESH:D002518', (137, 145))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('sphingosine', 'Chemical', 'MESH:D013110', (147, 158))	('S1P', 'Chemical', 'MESH:C060506', (163, 166))	('translate', 'Reg', (212, 221))	('IDH', 'Gene', (274, 277))	('reveal', 'Reg', (173, 179))	('vulnerabilities', 'MPA', (180, 195))	('IDH', 'Gene', '3417', (274, 277))
52880	33050528	We then designed a rational drug screen targeting this pathway and identified that combining NDMS with sphingosine-C17 increased the efficiency of arresting cellular proliferation and triggering cell death.	('arrest', 'Disease', (147, 153))	('cell death', 'CPA', (195, 205))	('C17', 'Gene', '54360', (115, 118))	('NDMS', 'Chemical', 'MESH:C061800', (93, 97))	('sphingosine', 'Chemical', 'MESH:D013110', (103, 114))	('cellular proliferation', 'CPA', (157, 179))	('NDMS', 'Var', (93, 97))	('triggering', 'Reg', (184, 194))	('arrest', 'Disease', 'MESH:D006323', (147, 153))	('increased', 'PosReg', (119, 128))	('C17', 'Gene', (115, 118))
52882	33050528	To probe the alterations in the sphingolipid pathway, in this study, we utilized patient-derived cell lines which endogenously express the R132H variant of IDH1.	('patient', 'Species', '9606', (81, 88))	('R132H', 'Var', (139, 144))	('IDH', 'Gene', (156, 159))	('R132H', 'SUBSTITUTION', 'None', (139, 144))	('sphingolipid', 'Chemical', 'MESH:D013107', (32, 44))	('IDH', 'Gene', '3417', (156, 159))
52883	33050528	To overcome this limitation, we conducted a 72 h treatment for mutant IDH1-R132H BT142 (astrocytoma) and TS603 (oligodendroglioma) cell lines with AGI5198, which specifically inhibits IDH1R132H enzyme activity disrupting D-2HG formation (Figure 1a).	('IDH', 'Gene', (184, 187))	('oligodendroglioma', 'Disease', 'MESH:D009837', (112, 129))	('R132H', 'Var', (188, 193))	('AGI5198', 'Chemical', 'MESH:C581156', (147, 154))	('oligodendroglioma', 'Disease', (112, 129))	('R132H', 'Var', (75, 80))	('IDH', 'Gene', '3417', (184, 187))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('R132H', 'SUBSTITUTION', 'None', (188, 193))	('mutant', 'Var', (63, 69))	('BT142', 'Gene', (81, 86))	('IDH', 'Gene', (70, 73))	('D-2HG', 'Chemical', '-', (221, 226))	('R132H', 'SUBSTITUTION', 'None', (75, 80))	('activity', 'MPA', (201, 209))	('IDH', 'Gene', '3417', (70, 73))	('disrupting', 'NegReg', (210, 220))	('astrocytoma', 'Disease', 'MESH:D001254', (88, 99))	('D-2HG formation', 'MPA', (221, 236))	('astrocytoma', 'Disease', (88, 99))	('inhibits', 'NegReg', (175, 183))
52887	33050528	The relative abundance analysis in the heat maps provides evidence of a functional relationship between the D-2HG-driven metabolic reprogramming and sphingolipid pathway.	('D-2HG', 'Chemical', '-', (108, 113))	('D-2HG-driven', 'Var', (108, 120))	('sphingolipid', 'Chemical', 'MESH:D013107', (149, 161))	('sphingolipid pathway', 'Pathway', (149, 169))
52892	33050528	To validate out lipidomic findings in the patient-derived cell lines, we used a model system in which U251 glioblastoma cells were genetically engineered to overexpress the IDH1-R132H, the most glioma-prevalent variant of IDH.	('R132H', 'Var', (178, 183))	('IDH', 'Gene', '3417', (222, 225))	('glioma', 'Disease', (194, 200))	('R132H', 'SUBSTITUTION', 'None', (178, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('overexpress', 'PosReg', (157, 168))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', '3417', (173, 176))	('glioblastoma', 'Disease', (107, 119))	('patient', 'Species', '9606', (42, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('IDH', 'Gene', (222, 225))	('lipid', 'Chemical', 'MESH:D008055', (16, 21))
52894	33050528	In order to measure the alterations in the de-novo sphingolipid synthesis, we extracted the endoplasmic reticulum from cells containing U251WT, U251R132H and U251R132H + AGI5198, and then extracted the lipids from these organelles (Figure 2a).	('lipids', 'Chemical', 'MESH:D008055', (202, 208))	('sphingolipid', 'Chemical', 'MESH:D013107', (51, 63))	('U251R132H', 'Chemical', '-', (144, 153))	('U251R132H', 'Chemical', '-', (158, 167))	('U251WT', 'Var', (136, 142))	('U251R132H + AGI5198', 'Var', (158, 177))	('AGI5198', 'Chemical', 'MESH:C581156', (170, 177))	('U251R132H', 'Var', (144, 153))
52895	33050528	Lipidomic analysis revealed that there was well-defined separation between each cohort, presenting a progression from U251WT, U251R132H treated with IDHR132H protein inhibitor, to U251R132H (Figure 2b).	('U251R132H', 'Var', (180, 189))	('IDHR132H', 'Mutation', 'rs121913500', (149, 157))	('U251R132H', 'Chemical', '-', (126, 135))	('U251R132H', 'Var', (126, 135))	('U251R132H', 'Chemical', '-', (180, 189))
52896	33050528	Moreover, the introduction of the R132H variant to IDH1 protein resulted in elevated ceramides (especially containing C18:1-fatty acid chains), N-palmitoylserine, sphingomyelin, in addition to glycoceramides (glucosylceramides and gangliosides) which are downstream products of ceramide (Figure 2c,d, Table S3).	('ceramide', 'Chemical', 'MESH:D002518', (85, 93))	('1-fatty acid', 'Chemical', '-', (122, 134))	('N-palmitoylserine', 'Chemical', '-', (144, 161))	('IDH', 'Gene', '3417', (51, 54))	('ceramides', 'Chemical', 'MESH:D002518', (217, 226))	('ceramides', 'MPA', (85, 94))	('elevated', 'PosReg', (76, 84))	('ceramide', 'Chemical', 'MESH:D002518', (217, 225))	('R132H', 'Var', (34, 39))	('glycoceramides', 'MPA', (193, 207))	('ceramides', 'Chemical', 'MESH:D002518', (198, 207))	('glycoceramides', 'Chemical', '-', (193, 207))	('ceramide', 'Chemical', 'MESH:D002518', (278, 286))	('glucosylceramides', 'Chemical', 'MESH:D005963', (209, 226))	('C18', 'Gene', '27241', (118, 121))	('ceramide', 'Chemical', 'MESH:D002518', (198, 206))	('sphingomyelin', 'MPA', (163, 176))	('gangliosides', 'Chemical', 'MESH:D005732', (231, 243))	('IDH', 'Gene', (51, 54))	('R132H', 'SUBSTITUTION', 'None', (34, 39))	('C18', 'Gene', (118, 121))	('ceramides', 'Chemical', 'MESH:D002518', (85, 94))	('N-palmitoylserine', 'MPA', (144, 161))
52897	33050528	Their global levels were specifically decreased upon addition of 12.5 microM AGI-5198 inhibitor over 72 h, suggesting a correlation between the levels of D-2HG and increased de-novo sphingolipid synthesis (Figure 2c,d).	('sphingolipid', 'Chemical', 'MESH:D013107', (182, 194))	('decreased', 'NegReg', (38, 47))	('D-2HG', 'Var', (154, 159))	('D-2HG', 'Chemical', '-', (154, 159))	('AGI-5198', 'Gene', (77, 85))	('AGI-5198', 'Chemical', 'MESH:C581156', (77, 85))	('global levels', 'MPA', (6, 19))	('de-novo sphingolipid synthesis', 'MPA', (174, 204))	('increased', 'PosReg', (164, 173))
52905	33050528	Overexpression of these enzymes has been reported to potentiate stress-induced ceramide accumulation and subsequent caspase-3-directed apoptosis in certain cancers.	('ceramide accumulation', 'MPA', (79, 100))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('ceramide', 'Chemical', 'MESH:D002518', (79, 87))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('caspase-3', 'Gene', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Overexpression', 'Var', (0, 14))	('potentiate', 'PosReg', (53, 63))	('caspase-3', 'Gene', '836', (116, 125))
52931	33050528	Interestingly, NDMS, which is an endogenous bioeffector that inhibits SphK, elicited a potent biostatic effect that exceeded most of the synthetic SphK inhibitors present in our rational panel, particularly PF543 used in the pilot experiment.	('NDMS', 'Var', (15, 19))	('SphK', 'Gene', '8877', (70, 74))	('SphK', 'Gene', (70, 74))	('biostatic effect', 'MPA', (94, 110))	('NDMS', 'Chemical', 'MESH:C061800', (15, 19))	('SphK', 'Gene', (147, 151))	('SphK', 'Gene', '8877', (147, 151))	('inhibits', 'NegReg', (61, 69))
52934	33050528	In particular, the oligodendroglioma cell lines (TS603 and NCH612) displayed an increased effect by combining both NDMS and Sph C17 while the astrocytoma cell line (BT142) was equally sensitive to independent versus combined treatment (Figure 4c-e, Table S5).	('increased', 'PosReg', (80, 89))	('astrocytoma', 'Disease', 'MESH:D001254', (142, 153))	('C17', 'Gene', '54360', (128, 131))	('oligodendroglioma', 'Disease', (19, 36))	('astrocytoma', 'Disease', (142, 153))	('Sph', 'Var', (124, 127))	('NDMS', 'Chemical', 'MESH:C061800', (115, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (142, 153))	('C17', 'Gene', (128, 131))	('NDMS', 'Var', (115, 119))	('oligodendroglioma', 'Disease', 'MESH:D009837', (19, 36))	('combining', 'Interaction', (100, 109))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
52940	33050528	The discovery of prevalent mutations in IDH1 has revealed a unique metabolic phenotype in these tumors and motivated us to explore metabolic-based drug targets via lipidomic-based workflows.	('mutations', 'Var', (27, 36))	('lipid', 'Chemical', 'MESH:D008055', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('IDH', 'Gene', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('revealed', 'Reg', (49, 57))	('IDH', 'Gene', '3417', (40, 43))
52943	33050528	Our laboratory has begun to unravel unique perturbations along lipid pathways that are associated with IDH1 mutations and offer potential avenues for translation to therapeutic targets.	('mutations', 'Var', (108, 117))	('IDH', 'Gene', (103, 106))	('lipid', 'Chemical', 'MESH:D008055', (63, 68))	('IDH', 'Gene', '3417', (103, 106))	('lipid pathways', 'Pathway', (63, 77))
52944	33050528	Herein, we reported for the first-time, to our knowledge, dysregulations in sphingolipid metabolism as they relate to IDHmut gliomas.	('gliomas', 'Disease', (125, 132))	('sphingolipid metabolism', 'Disease', 'MESH:D013106', (76, 99))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('IDH', 'Gene', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('sphingolipid metabolism', 'Disease', (76, 99))	('IDH', 'Gene', '3417', (118, 121))	('dysregulations', 'Var', (58, 72))
52945	33050528	In particular, we identified decreased levels of S1P and increased levels of ceramide, sphingosine and sphinganine that correlate with the presence of IDH1 mutation.	('S1P', 'Chemical', 'MESH:C060506', (49, 52))	('sphinganine', 'Chemical', 'MESH:C005682', (103, 114))	('IDH', 'Gene', '3417', (151, 154))	('levels', 'MPA', (39, 45))	('sphingosine', 'MPA', (87, 98))	('sphingosine', 'Chemical', 'MESH:D013110', (87, 98))	('levels of ceramide', 'MPA', (67, 85))	('S1P', 'MPA', (49, 52))	('increased', 'PosReg', (57, 66))	('decreased', 'NegReg', (29, 38))	('ceramide', 'Chemical', 'MESH:D002518', (77, 85))	('IDH', 'Gene', (151, 154))	('mutation', 'Var', (156, 164))
52948	33050528	To exploit this funding therapeutically, we employed a rational drug panel screen, which revealed that modulating the sphingolipid rheostat towards accumulation of sphingosine and blocking the synthesis of S1P, we could induce cellular death in a dose-dependent manner IDHmut gliomas subtypes.	('sphingosine', 'Chemical', 'MESH:D013110', (164, 175))	('induce', 'Reg', (220, 226))	('IDH', 'Gene', (269, 272))	('blocking', 'NegReg', (180, 188))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('gliomas', 'Disease', (276, 283))	('sphingolipid rheostat', 'Disease', 'MESH:D013106', (118, 139))	('IDH', 'Gene', '3417', (269, 272))	('gliomas', 'Disease', 'MESH:D005910', (276, 283))	('S1P', 'MPA', (206, 209))	('accumulation', 'PosReg', (148, 160))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('synthesis', 'MPA', (193, 202))	('cellular death', 'CPA', (227, 241))	('modulating', 'Var', (103, 113))	('sphingolipid rheostat', 'Disease', (118, 139))	('S1P', 'Chemical', 'MESH:C060506', (206, 209))
52951	33050528	To the best of our knowledge, this is the first study that shows alteration in sphingolipid metabolism specific to lower grade gliomas with an IDH mutation and ways to exploit this intrinsic vulnerability.	('IDH', 'Gene', '3417', (143, 146))	('IDH', 'Gene', (143, 146))	('mutation', 'Var', (147, 155))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('sphingolipid metabolism', 'Disease', (79, 102))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('sphingolipid metabolism', 'Disease', 'MESH:D013106', (79, 102))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('alteration', 'Reg', (65, 75))
52952	33050528	Unraveling this unique vulnerability in lower grade gliomas with IDH mutation provides avenues for future therapeutic strategies.	('gliomas', 'Disease', (52, 59))	('IDH', 'Gene', (65, 68))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH', 'Gene', '3417', (65, 68))	('mutation', 'Var', (69, 77))
52956	33050528	Cells phenotype was validated based upon DNA methylation (1p/19q co-deletion) as previously described, DNA sequencing (IDH1 mutation) and D-2HG measurements (IDH1 mutation).	('IDH', 'Gene', '3417', (158, 161))	('IDH', 'Gene', '3417', (119, 122))	('IDH', 'Gene', (158, 161))	('D-2HG', 'Chemical', '-', (138, 143))	('mutation', 'Var', (124, 132))	('IDH', 'Gene', (119, 122))
52958	33050528	About 20 flasks were used per variant (U251WT, U251R132H, U251R132H + 12.5 muM AGI5198).	('U251R132H', 'Chemical', '-', (47, 56))	('AGI5198', 'Chemical', 'MESH:C581156', (79, 86))	('U251WT', 'Var', (39, 45))	('U251R132H', 'Var', (47, 56))	('U251R132H', 'Chemical', '-', (58, 67))	('U251R132H +', 'Var', (58, 69))
53001	33050528	Ultimately, the response of IDH1mut gliomas to the targeting of SphK1 in order to obstruct S1P production and subsequent S1P signaling suggests that the sphingolipid metabolism plays a vital role in glioma's growth and survival.	('gliomas', 'Disease', (36, 43))	('IDH', 'Gene', '3417', (28, 31))	('glioma', 'Disease', (36, 42))	('obstruct', 'NegReg', (82, 90))	('S1P signaling', 'MPA', (121, 134))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('targeting', 'Var', (51, 60))	('S1P', 'Chemical', 'MESH:C060506', (121, 124))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('sphingolipid metabolism', 'Disease', (153, 176))	('glioma', 'Disease', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('SphK1', 'Gene', '8877', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('S1P production', 'MPA', (91, 105))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('IDH', 'Gene', (28, 31))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('SphK1', 'Gene', (64, 69))	('S1P', 'Chemical', 'MESH:C060506', (91, 94))	('sphingolipid metabolism', 'Disease', 'MESH:D013106', (153, 176))
53004	33050528	The following are available online at , Figure S1: Western Blots for ASAH2, SMPD3, SPHK1, SPHK2 and a-Tubulin; Figure S2: The effect of SPHK1 inhibitor PF-543 on BT142 and TS603 cell morphology, Figure S3: Full WB blot images from Figure 3f,g, Table S1: Sphingolipids and polar lipid analysis for BT142 untreated and treated with AGI5198, Table S2: Sphingolipids and polar lipid analysis for TS603 untreated and treated with AGI5198, Table S3: ER sphingolipids analysis for U251WT, U251R132H and U251R132H + AGI5198, Table S4: Histological and Methylation Types of Tissue Present in Clusters EC1-EC6, Table S5: EC50 for SphC17, NDMS and combination treatments.	('U251R132H', 'Chemical', '-', (482, 491))	('lipids', 'Chemical', 'MESH:D008055', (261, 267))	('NDMS', 'Chemical', 'MESH:C061800', (628, 632))	('AGI5198', 'Chemical', 'MESH:C581156', (330, 337))	('SPHK1', 'Gene', (83, 88))	('sphingolipids', 'Chemical', 'MESH:D013107', (447, 460))	('SMPD3', 'Gene', '55512', (76, 81))	('SPHK1', 'Gene', '8877', (83, 88))	('PF-543', 'Chemical', 'MESH:C573330', (152, 158))	('EC1-EC6', 'CellLine', 'CVCL:5V05', (592, 599))	('ER', 'Gene', '2069', (444, 446))	('U251R132H', 'Chemical', '-', (496, 505))	('AGI5198', 'Chemical', 'MESH:C581156', (425, 432))	('C17', 'Gene', '54360', (623, 626))	('SMPD3', 'Gene', (76, 81))	('SPHK1', 'Gene', (136, 141))	('C17', 'Gene', (623, 626))	('lipid', 'Chemical', 'MESH:D008055', (278, 283))	('SPHK1', 'Gene', '8877', (136, 141))	('U251R132H', 'Var', (482, 491))	('SPHK2', 'Gene', (90, 95))	('U251R132H +', 'Var', (496, 507))	('lipid', 'Chemical', 'MESH:D008055', (454, 459))	('SPHK2', 'Gene', '56848', (90, 95))	('lipid', 'Chemical', 'MESH:D008055', (356, 361))	('lipid', 'Chemical', 'MESH:D008055', (373, 378))	('lipids', 'Chemical', 'MESH:D008055', (454, 460))	('lipid', 'Chemical', 'MESH:D008055', (261, 266))	('AGI5198', 'Chemical', 'MESH:C581156', (508, 515))	('ASAH2', 'Gene', (69, 74))	('lipids', 'Chemical', 'MESH:D008055', (356, 362))	('ASAH2', 'Gene', '56624', (69, 74))
53028	33174046	Mitochondrial dysfunction in glioma involves abnormalities in energy metabolism, changes in mitochondrial membrane potential (DeltaPsim) regulation, disruption of apoptotic signaling pathways and mutations in the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase.	('citrate', 'Chemical', 'MESH:D019343', (254, 261))	('TCA', 'Chemical', 'MESH:D014233', (233, 236))	('disruption', 'Reg', (149, 159))	('DeltaPsim', 'Disease', 'None', (126, 135))	('changes', 'Reg', (81, 88))	('Mitochondrial dysfunction', 'Disease', (0, 25))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (213, 231))	('glioma involves abnormalities', 'Disease', (29, 58))	('DeltaPsim', 'Disease', (126, 135))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('apoptotic signaling pathways', 'Pathway', (163, 191))	('glioma involves abnormalities', 'Disease', 'MESH:D005910', (29, 58))	('energy metabolism', 'MPA', (62, 79))	('mutations', 'Var', (196, 205))
53078	33174046	U87-MG and U118-MG glioma cells were grown on glass coverslips in 6-well plates.	('U87-MG', 'CellLine', 'CVCL:0022', (0, 6))	('U118-MG', 'CellLine', 'CVCL:0633', (11, 18))	('glioma', 'Disease', (19, 25))	('U118-MG', 'Var', (11, 18))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
53127	33174046	The results revealed that the expression levels of the proinflammatory cytokines IL-6, IL-8, HIF-1alpha, STAT3, NF-kappaB1 and NF-kappaB2 were significantly upregulated in GBM compared with in LGG samples (Fig.	('HIF-1alpha', 'Gene', (93, 103))	('NF-kappaB2', 'Gene', (127, 137))	('NF-kappaB1', 'Gene', (112, 122))	('upregulated', 'PosReg', (157, 168))	('GBM', 'Var', (172, 175))	('STAT3', 'Gene', '6774', (105, 110))	('IL-8', 'Gene', '3576', (87, 91))	('GBM', 'Phenotype', 'HP:0012174', (172, 175))	('IL-6', 'Gene', (81, 85))	('IL-8', 'Gene', (87, 91))	('STAT3', 'Gene', (105, 110))	('IL-6', 'Gene', '3569', (81, 85))	('expression levels', 'MPA', (30, 47))	('HIF-1alpha', 'Gene', '3091', (93, 103))
53132	33174046	The gene expression data in the CGGA revealed that the expression levels of the glycolysis enzymes HK1, LDHA and GAPDH were significantly upregulated in GBM compared with in LGG samples (Fig.	('GBM', 'Var', (153, 156))	('GAPDH', 'Gene', (113, 118))	('glycolysis enzymes', 'MPA', (80, 98))	('LDHA', 'Gene', (104, 108))	('HK1', 'Gene', '3098', (99, 102))	('HK1', 'Gene', (99, 102))	('LDHA', 'Gene', '3939', (104, 108))	('GAPDH', 'Gene', '2597', (113, 118))	('expression levels', 'MPA', (55, 72))	('upregulated', 'PosReg', (138, 149))	('GBM', 'Phenotype', 'HP:0012174', (153, 156))
53139	33174046	Compared with the 0 h group, the ratio of cells with fragmented mitochondria in U87-MG was decreased at 24 h after the proinflammatory stimulation, while it was still high at 24 h in U118-MG cells (Figs.	('U118-MG', 'CellLine', 'CVCL:0633', (183, 190))	('U87-MG', 'CellLine', 'CVCL:0022', (80, 86))	('decreased', 'NegReg', (91, 100))	('U87-MG', 'Var', (80, 86))
53145	33174046	After 4 h of treatment with LPS and IFN-gamma, the levels of ceROS and mtROS production were significantly increased compared with those in non-stimulated glioma cells, and the high ROS levels persisted until 8 h after treatment; notably, mtROS production decreased at 24 h, but ceROS production was unchanged (Fig.	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('mtROS', 'Chemical', '-', (239, 244))	('decreased', 'NegReg', (256, 265))	('mtROS production', 'MPA', (71, 87))	('ROS', 'Chemical', 'MESH:D017382', (182, 185))	('increased', 'PosReg', (107, 116))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('mtROS', 'Chemical', '-', (71, 76))	('ROS', 'Chemical', 'MESH:D017382', (281, 284))	('LPS', 'Chemical', 'MESH:D008070', (28, 31))	('LPS', 'Var', (28, 31))	('IFN-gamma', 'Gene', '3458', (36, 45))	('IFN-gamma', 'Gene', (36, 45))	('levels', 'MPA', (51, 57))	('ROS', 'Chemical', 'MESH:D017382', (241, 244))	('ceROS', 'MPA', (61, 66))	('mtROS production', 'MPA', (239, 255))	('glioma', 'Disease', (155, 161))
53171	33174046	Mitochondrial dysfunction in tumors has been associated with abnormalities in mitochondrial energy metabolism, marked by a metabolic shift from oxidative phosphorylation to glycolysis (known as the 'Warburg effect'), disturbances in DeltaPsim regulation and apoptotic signaling.	('mitochondrial energy metabolism', 'Disease', (78, 109))	('mitochondrial energy metabolism', 'Disease', 'MESH:D028361', (78, 109))	('DeltaPsim', 'Disease', 'None', (233, 242))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Mitochondrial dysfunction', 'Disease', (0, 25))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('disturbances', 'Reg', (217, 229))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('abnormalities', 'Var', (61, 74))	('apoptotic signaling', 'CPA', (258, 277))	('metabolic shift', 'MPA', (123, 138))	('DeltaPsim', 'Disease', (233, 242))	('tumors', 'Disease', (29, 35))
53206	33174046	It has been reported that reduction or ablation of the DeltaPsim can induce nuclear translocation of activating transcription factor associated with stress-1, where it initiates the mitochondrial unfolded protein response, which is a mitochondria self-help mechanism.	('ablation', 'Var', (39, 47))	('induce', 'Reg', (69, 75))	('nuclear translocation', 'MPA', (76, 97))	('reduction', 'NegReg', (26, 35))	('mitochondrial unfolded protein response', 'MPA', (182, 221))	('DeltaPsim', 'Disease', 'None', (55, 64))	('DeltaPsim', 'Disease', (55, 64))	('initiates', 'Reg', (168, 177))
53210	33174046	Additionally, isocitrate dehydrogenase mutation status may dramatically affect the function of mitochondria.	('affect', 'Reg', (72, 78))	('citrate', 'Chemical', 'MESH:D019343', (17, 24))	('mutation', 'Var', (39, 47))	('function of mitochondria', 'MPA', (83, 107))
53214	33174046	Although the recovery or biogenesis of the mitochondria, and the role of the TCA cycle in glioma after proinflammatory stimuli should be further investigated, the present results demonstrated that the dysfunction of these organelles did not affect the viability but decreased the apoptosis of glioma cells (Fig.	('TCA', 'Chemical', 'MESH:D014233', (77, 80))	('apoptosis', 'CPA', (280, 289))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', (293, 299))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('dysfunction', 'Var', (201, 212))	('glioma', 'Disease', 'MESH:D005910', (293, 299))	('glioma', 'Phenotype', 'HP:0009733', (293, 299))	('decreased', 'NegReg', (266, 275))
53223	28710382	Netrin-1 knockdown reduced cell proliferation and attenuated tumor growth in a xenograft mouse model.	('knockdown', 'Var', (9, 18))	('cell proliferation', 'CPA', (27, 45))	('Netrin-1', 'Gene', (0, 8))	('attenuated tumor', 'Disease', (50, 66))	('attenuated tumor', 'Disease', 'MESH:C538265', (50, 66))	('reduced', 'NegReg', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mouse', 'Species', '10090', (89, 94))
53225	28710382	Interestingly, activation of NF-kappaB by netrin-1 was dependent on UNC5A receptor, because suppression of UNC5A significantly inhibited NF-kappaB p65ser536 phosphorylation, c-Myc up-regulation and reduced cell proliferation.	('NF-kappaB', 'Gene', (29, 38))	('c-Myc', 'Gene', (174, 179))	('UNC5A', 'Gene', (68, 73))	('NF-kappaB', 'Gene', '4790', (137, 146))	('up-regulation', 'PosReg', (180, 193))	('UNC5A', 'Gene', (107, 112))	('UNC5A', 'Gene', '90249', (68, 73))	('cell proliferation', 'CPA', (206, 224))	('NF-kappaB', 'Gene', (137, 146))	('p65', 'Gene', (147, 150))	('suppression', 'Var', (92, 103))	('inhibited', 'NegReg', (127, 136))	('phosphorylation', 'MPA', (157, 172))	('reduced', 'NegReg', (198, 205))	('p65', 'Gene', '5970', (147, 150))	('c-Myc', 'Gene', '4609', (174, 179))	('NF-kappaB', 'Gene', '4790', (29, 38))	('UNC5A', 'Gene', '90249', (107, 112))
53231	28710382	In the last two decades, a variety of genetic abnormalities and aberrant cell signaling pathways have been implicated in glioma tumorigenesis, including amplification of VEGF , loss of PTEN , dysfunction of p53 , and mutations of NF1 .	('p53', 'Gene', '7157', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NF1', 'Gene', (230, 233))	('VEGF', 'Gene', '7422', (170, 174))	('glioma', 'Disease', (121, 127))	('genetic abnormalities', 'Disease', 'MESH:D030342', (38, 59))	('VEGF', 'Gene', (170, 174))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('p53', 'Gene', (207, 210))	('genetic abnormalities', 'Disease', (38, 59))	('PTEN', 'Gene', (185, 189))	('dysfunction', 'Var', (192, 203))	('amplification', 'Var', (153, 166))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumor', 'Disease', (128, 133))	('PTEN', 'Gene', '5728', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('loss', 'Var', (177, 181))	('NF1', 'Gene', '4763', (230, 233))	('mutations', 'Var', (217, 226))	('implicated', 'Reg', (107, 117))
53241	28710382	The addition of netrin-1 effectively enhanced cell proliferation, whereas knockdown of netrin-1 expression greatly reduced tumorigenesis in vitro and in vivo.	('tumor', 'Disease', (123, 128))	('netrin-1', 'Gene', (87, 95))	('reduced', 'NegReg', (115, 122))	('knockdown', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('enhanced', 'PosReg', (37, 45))	('cell proliferation', 'CPA', (46, 64))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
53286	28710382	On the 22nd day after tumor implantation, glioma formation in shCtrl-injected mice was visible, whereas mice injected with either shNetrin-1 exhibited weaker luciferase signals (Fig.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('shCtrl-injected', 'Var', (62, 77))	('glioma', 'Disease', (42, 48))	('mice', 'Species', '10090', (78, 82))
53291	28710382	In contrast, mice injected with shNetrin-1 cells exhibited relatively smaller tumor foci in the forehead, and no tumor formation was observed in the ventral brain or any other part of the brain (middle and right panels, Fig.	('tumor', 'Disease', (113, 118))	('mice', 'Species', '10090', (13, 17))	('shNetrin-1', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('smaller', 'NegReg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
53299	28710382	5c), and knockdown of netrin-1 decreased c-Myc expression (Fig.	('c-Myc', 'Gene', '4609', (41, 46))	('knockdown', 'Var', (9, 18))	('c-Myc', 'Gene', (41, 46))	('decreased', 'NegReg', (31, 40))	('netrin-1', 'Gene', (22, 30))
53304	28710382	Previous studies have shown that NF-kappaB regulates c-Myc expression levels via phosphorylation of Ser536 in the p65 subunit of NF-kappaB.	('NF-kappaB', 'Gene', (33, 42))	('regulates', 'Reg', (43, 52))	('phosphorylation', 'MPA', (81, 96))	('p65 subunit of NF-kappaB', 'Gene', (114, 138))	('NF-kappaB', 'Gene', (129, 138))	('p65 subunit of NF-kappaB', 'Gene', '5970', (114, 138))	('c-Myc', 'Gene', '4609', (53, 58))	('Ser536', 'Chemical', '-', (100, 106))	('NF-kappaB', 'Gene', '4790', (33, 42))	('c-Myc', 'Gene', (53, 58))	('Ser536', 'Var', (100, 106))	('NF-kappaB', 'Gene', '4790', (129, 138))
53308	28710382	Phosphorylation of Ser536 in the p65 subunit is known to be a marker of NF-kappaB signaling pathway activation.	('Ser536', 'Chemical', '-', (19, 25))	('p65', 'Gene', (33, 36))	('Phosphorylation', 'Var', (0, 15))	('Ser536', 'Var', (19, 25))	('NF-kappaB', 'Gene', '4790', (72, 81))	('p65', 'Gene', '5970', (33, 36))	('NF-kappaB', 'Gene', (72, 81))	('activation', 'PosReg', (100, 110))
53316	28710382	The incubation of Bay117085 in cultured cells completely blocked NF-kappaB p65ser536 phosphorylation with or without netrin-1 stimulation.	('p65', 'Gene', (75, 78))	('Bay117085', 'Chemical', 'MESH:C416282', (18, 27))	('p65', 'Gene', '5970', (75, 78))	('blocked', 'NegReg', (57, 64))	('NF-kappaB', 'Gene', '4790', (65, 74))	('NF-kappaB', 'Gene', (65, 74))	('Bay117085', 'Var', (18, 27))
53318	28710382	It was worth noting that Bay117085 also inhibited endogenous netrin-1 expression, as previously reported.	('Bay117085', 'Chemical', 'MESH:C416282', (25, 34))	('inhibited', 'NegReg', (40, 49))	('expression', 'MPA', (70, 80))	('netrin-1', 'Gene', (61, 69))	('Bay117085', 'Var', (25, 34))	('endogenous', 'MPA', (50, 60))
53322	28710382	6f, Bay117085 not only reversed the growth advantage stimulated by netrin-1, but also significantly reduced the cell proliferation well below the basal level in both U251 and SHG44 cells.	('cell proliferation', 'CPA', (112, 130))	('Bay117085', 'Chemical', 'MESH:C416282', (4, 13))	('reduced', 'NegReg', (100, 107))	('growth advantage', 'CPA', (36, 52))	('Bay117085', 'Var', (4, 13))	('U251', 'CellLine', 'CVCL:0021', (166, 170))	('netrin-1', 'Gene', (67, 75))
53333	28710382	We found silencing of the UNC5A receptor did not alter NF-kappaB p65ser536 phosphorylation or c-Myc expression without netrin-1 stimulation (left panel of Fig.	('c-Myc', 'Gene', '4609', (94, 99))	('p65', 'Gene', '5970', (65, 68))	('silencing', 'Var', (9, 18))	('c-Myc', 'Gene', (94, 99))	('UNC5A', 'Gene', '90249', (26, 31))	('p65', 'Gene', (65, 68))	('NF-kappaB', 'Gene', '4790', (55, 64))	('UNC5A', 'Gene', (26, 31))	('phosphorylation', 'MPA', (75, 90))	('NF-kappaB', 'Gene', (55, 64))
53334	28710382	However, UNC5A silencing strongly abolished exogenous netrin-1-induced NF-kappaB p65ser536 phosphorylation and decreased c-Myc expression in the presence of netrin-1 (right panel of Fig.	('phosphorylation', 'MPA', (91, 106))	('p65', 'Gene', (81, 84))	('c-Myc', 'Gene', '4609', (121, 126))	('UNC5A', 'Gene', '90249', (9, 14))	('abolished', 'NegReg', (34, 43))	('NF-kappaB', 'Gene', (71, 80))	('decreased', 'NegReg', (111, 120))	('UNC5A', 'Gene', (9, 14))	('p65', 'Gene', '5970', (81, 84))	('c-Myc', 'Gene', (121, 126))	('silencing', 'Var', (15, 24))	('NF-kappaB', 'Gene', '4790', (71, 80))
53335	28710382	Netrin-1-induced cell proliferation was partially abolished by silencing of UNC5A (Fig.	('UNC5A', 'Gene', '90249', (76, 81))	('cell proliferation', 'CPA', (17, 35))	('UNC5A', 'Gene', (76, 81))	('abolished', 'NegReg', (50, 59))	('silencing', 'Var', (63, 72))
53354	28710382	This finding was validated in the glioma xenograft mouse models, in which silencing of netrin-1 not only inhibited tumor cells proliferation, but also decreased cellular migration and invasion.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('invasion', 'CPA', (184, 192))	('cellular migration', 'CPA', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('netrin-1', 'Gene', (87, 95))	('inhibited', 'NegReg', (105, 114))	('tumor', 'Disease', (115, 120))	('mouse', 'Species', '10090', (51, 56))	('decreased', 'NegReg', (151, 160))	('silencing', 'Var', (74, 83))	('glioma', 'Disease', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
53356	28710382	Another recent study also discovered that netrin-1 knockdown inhibited glioblastoma stem-like cells proliferation, invasion and angiogenesis.	('netrin-1', 'Gene', (42, 50))	('inhibited', 'NegReg', (61, 70))	('glioblastoma', 'Disease', (71, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('angiogenesis', 'CPA', (128, 140))	('knockdown', 'Var', (51, 60))
53365	28710382	This possibility was further supported by the results that knockdown of UNC5A effectively blocked NF-kappaB activation and inhibited c-Myc expression.	('NF-kappaB', 'Gene', '4790', (98, 107))	('UNC5A', 'Gene', '90249', (72, 77))	('NF-kappaB', 'Gene', (98, 107))	('UNC5A', 'Gene', (72, 77))	('c-Myc', 'Gene', '4609', (133, 138))	('activation', 'MPA', (108, 118))	('inhibited', 'NegReg', (123, 132))	('c-Myc', 'Gene', (133, 138))	('knockdown', 'Var', (59, 68))	('blocked', 'NegReg', (90, 97))
53381	28710382	Elevated netrin-1 alters the glioma into more invasive phenotype.	('glioma', 'Disease', (29, 35))	('netrin-1', 'Gene', (9, 17))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('Elevated', 'Var', (0, 8))
53491	25325361	The p53 protein is a transcription factor that plays a vital role in regulating cell growth, DNA repair and apoptosis, and p53 mutations are involved in disease progression.	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (123, 126))	('cell', 'CPA', (80, 84))	('involved', 'Reg', (141, 149))	('p53', 'Gene', '7157', (123, 126))	('mutations', 'Var', (127, 136))	('p53', 'Gene', (4, 7))
53492	25325361	In a recent study it was found that use of mobile phones for >=3 h a day was associated with increased risk for the mutant type of p53 gene expression in the peripheral zone of astrocytoma grade IV, and that this increase was statistically significant correlated with shorter overall survival time.	('expression', 'MPA', (140, 150))	('p53', 'Gene', (131, 134))	('mutant type', 'Var', (116, 127))	('p53', 'Gene', '7157', (131, 134))	('astrocytoma', 'Disease', 'MESH:D001254', (177, 188))	('shorter', 'NegReg', (268, 275))	('astrocytoma', 'Disease', (177, 188))	('astrocytoma', 'Phenotype', 'HP:0009592', (177, 188))
53546	26095141	Radial expansion rates and tumor growth kinetics predict malignant transformation in contrast-enhancing low-grade diffuse astrocytoma Contrast-enhancing low-grade diffuse astrocytomas are an understudied, aggressive subtype at increased risk because of few radiographic indications of malignant transformation.	('astrocytoma', 'Disease', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('astrocytoma', 'Disease', (122, 133))	('astrocytomas', 'Disease', 'MESH:D001254', (171, 183))	('astrocytoma', 'Phenotype', 'HP:0009592', (122, 133))	('tumor', 'Disease', (27, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (171, 182))	('low-grade', 'Var', (153, 162))	('astrocytomas', 'Disease', (171, 183))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('astrocytoma', 'Disease', 'MESH:D001254', (171, 182))	('astrocytoma', 'Disease', 'MESH:D001254', (122, 133))
53595	26095141	Multiple comparisons testing confirmed that nontransforming diffuse astrocytomas had significantly lower rates of T2/FLAIR radial expansion compared with both tumors that recurred as anaplastic astrocytomas (WHO II-III; Dunn's test, adjusted p = 0.0174) as well as those that transformed to GBM (WHO II-IV; Dunn's test, adjusted p = 0.0050).	('astrocytomas', 'Disease', (194, 206))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('lower', 'NegReg', (99, 104))	('anaplastic astrocytomas', 'Disease', (183, 206))	('astrocytomas', 'Disease', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('astrocytoma', 'Phenotype', 'HP:0009592', (194, 205))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('astrocytomas', 'Disease', 'MESH:D001254', (194, 206))	('T2/FLAIR', 'Var', (114, 122))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (183, 206))
53598	26095141	Estimates of proliferation rate, rho, varied significantly by patient group (Figure 3D) (Kruskal-Wallis, p = 0.0324), for which proliferation rate during tumor progression was higher in low-grade astrocytomas that transformed to GBM (WHO II-IV; Dunn's test, adjusted p = 0.027) but no difference was observed between nontransformers and tumors that recurred as anaplastic astrocytomas.	('anaplastic astrocytomas', 'Disease', (361, 384))	('tumor', 'Disease', (337, 342))	('low-grade', 'Var', (186, 195))	('proliferation', 'CPA', (128, 141))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('astrocytomas', 'Disease', (372, 384))	('tumor', 'Disease', (154, 159))	('patient', 'Species', '9606', (62, 69))	('astrocytomas', 'Disease', (196, 208))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumors', 'Disease', (337, 343))	('astrocytomas', 'Disease', 'MESH:D001254', (372, 384))	('astrocytoma', 'Phenotype', 'HP:0009592', (372, 383))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('higher', 'PosReg', (176, 182))	('astrocytomas', 'Disease', 'MESH:D001254', (196, 208))	('astrocytoma', 'Phenotype', 'HP:0009592', (196, 207))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (361, 384))
53642	33381564	Higher E2F3-6 and E2F1-8 expressions correlated with poor prognosis and increased immune infiltration levels in CD8+ T cells, macrophages, neutrophils, and DCs in GBM and CD8+ T cells, B cells, CD4+ T cells, neutrophils, macrophages, and DCs in LGG, respectively.	('CD8', 'Gene', (112, 115))	('increased', 'PosReg', (72, 81))	('E2F3', 'Gene', '1871', (7, 11))	('E2F3-6', 'Gene', '1871;1874;1875;1876', (7, 13))	('expressions', 'MPA', (25, 36))	('CD8', 'Gene', (171, 174))	('immune infiltration levels', 'MPA', (82, 108))	('CD8', 'Gene', '925', (112, 115))	('CD8', 'Gene', '925', (171, 174))	('E2F1-8', 'Var', (18, 24))	('poor prognosis', 'CPA', (53, 67))	('CD4', 'Gene', (194, 197))	('CD4', 'Gene', '920', (194, 197))	('E2F3-6', 'Gene', (7, 13))	('E2F3', 'Gene', (7, 11))
53643	33381564	E2F1-8 and E2F2-8 could be hopeful prognostic biomarkers of GBM and LGG, respectively.	('LGG', 'Disease', (68, 71))	('E2F1-8', 'Var', (0, 6))	('E2F2-8', 'Gene', (11, 17))	('E2F2-8', 'Gene', '1870;1871;1874;1875;1876;144455;79733', (11, 17))	('E2F2', 'Gene', '1870', (11, 15))	('GBM', 'Disease', (60, 63))	('E2F2', 'Gene', (11, 15))
53644	33381564	E2F3-6 and E2F1-8 could be likely therapeutic targets in patients with immune cell infiltration of GBM and LGG, respectively.	('patients', 'Species', '9606', (57, 65))	('E2F1-8', 'Var', (11, 17))	('E2F3-6', 'Var', (0, 6))
53654	33381564	Overexpression of E2F1 blocked the proliferation repression caused by miR-342-3p or miR-377 in glioma cells, and E2F1 overexpression conferred resistance to cisplatin in glioma cells.	('miR-377', 'Gene', '494326', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('miR-342-3p', 'Chemical', '-', (70, 80))	('E2F1', 'Gene', (18, 22))	('overexpression', 'PosReg', (118, 132))	('miR-377', 'Gene', (84, 91))	('conferred', 'Reg', (133, 142))	('E2F1', 'Gene', (113, 117))	('proliferation repression', 'CPA', (35, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('resistance', 'MPA', (143, 153))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('miR-342-3p', 'Var', (70, 80))
53656	33381564	The silencing of E2F5 inhibited the proliferative ability of GBM cells.	('E2F5', 'Gene', '1875', (17, 21))	('inhibited', 'NegReg', (22, 31))	('E2F5', 'Gene', (17, 21))	('proliferative ability of GBM cells', 'CPA', (36, 70))	('silencing', 'Var', (4, 13))
53664	33381564	In the Sun Brain Statistics (Table 1), E2F5 was also overexpressed in anaplastic astrocytoma with a fold change of 2.545, in oligodendroglioma with a fold change of 2.580, and in glioblastoma with a fold change of 2.877.	('astrocytoma', 'Phenotype', 'HP:0009592', (81, 92))	('anaplastic astrocytoma', 'Disease', (70, 92))	('oligodendroglioma', 'Disease', (125, 142))	('glioblastoma', 'Disease', (179, 191))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (70, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('overexpressed', 'PosReg', (53, 66))	('E2F5', 'Var', (39, 43))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
53665	33381564	Kaplan-Meier overall survival curves showed that gene alterations of E2F1, E2F2, E2F4, and E2F6-8 were remarkably related to overall survival (OS) (P < 0.05) among LGG (Figure 4(d)).	('overall survival', 'MPA', (125, 141))	('related to', 'Reg', (114, 124))	('E2F6-8', 'Gene', '1876;144455;79733', (91, 97))	('E2F2', 'Gene', (75, 79))	('E2F6-8', 'Gene', (91, 97))	('E2F4', 'Var', (81, 85))	('E2F1', 'Gene', (69, 73))
53666	33381564	In particular, TIMER analysis revealed that E2F1 was significantly correlated with monocyte markers (CD86), TAM markers (CCL2, IL10), and M2 macrophage markers (VSIG4, MS4A4A) in GBM (P < 0.0001; Table 2).	('CCL2', 'Gene', '6347', (121, 125))	('TAM', 'Chemical', 'MESH:D013629', (108, 111))	('E2F1', 'Var', (44, 48))	('MS4A4A', 'Gene', (168, 174))	('correlated', 'Reg', (67, 77))	('MS4A4A', 'Gene', '51338', (168, 174))	('CCL2', 'Gene', (121, 125))	('VSIG4', 'Gene', '11326', (161, 166))	('CD86', 'Gene', '942', (101, 105))	('IL10', 'Gene', (127, 131))	('IL10', 'Gene', '3586', (127, 131))	('CD86', 'Gene', (101, 105))	('VSIG4', 'Gene', (161, 166))
53667	33381564	E2F5 was significantly correlated with monocyte markers (CD115) and M1 macrophage markers (IRF5) in GBM (P < 0.0001; Table 2).	('IRF5', 'Gene', (91, 95))	('CD115', 'Gene', (57, 62))	('correlated', 'Reg', (23, 33))	('CD115', 'Gene', '1436', (57, 62))	('IRF5', 'Gene', '3663', (91, 95))	('E2F5', 'Var', (0, 4))
53668	33381564	E2F6 was significantly correlated with monocyte markers (CD86, CD115), TAM markers (CD68, IL10), M1 macrophage markers (IRF5), and M2 macrophage markers (VSIG4, MS4A4A) in GBM (P < 0.0001; Table 2).	('CD68', 'Gene', (84, 88))	('CD68', 'Gene', '968', (84, 88))	('correlated', 'Reg', (23, 33))	('E2F6', 'Var', (0, 4))
53669	33381564	Meanwhile, E2F1 was significantly correlated with monocyte markers (CD86, CD115), TAM markers (CCL2), M1 macrophage markers (INOS), and M2 macrophage markers (VSIG4) in LGG (P < 0.0001; Table 2).	('CD115', 'Gene', (74, 79))	('INOS', 'Gene', (125, 129))	('correlated', 'Reg', (34, 44))	('E2F1', 'Var', (11, 15))	('INOS', 'Gene', '4843', (125, 129))
53670	33381564	E2F2 was significantly correlated with monocyte markers (CD86, CD115), TAM markers (CD68, IL10), M1 macrophage markers (IRF5), and M2 macrophage markers (CD163, VSIG4, MS4A4A) in LGG (P < 0.0001; Table 2).	('CD163', 'Gene', (154, 159))	('correlated', 'Reg', (23, 33))	('CD163', 'Gene', '9332', (154, 159))	('E2F2', 'Var', (0, 4))
53679	33381564	Chromosome, replication, transcription factor complex, and protein serine/threonine kinase activity were also significantly controlled by these E2F alterations (Figures 10(b) and 10(c)).	('alterations', 'Var', (148, 159))	('E2F', 'Gene', (144, 147))	('protein serine/threonine kinase activity', 'MPA', (59, 99))	('transcription factor complex', 'MPA', (25, 53))	('controlled', 'Reg', (124, 134))	('replication', 'CPA', (12, 23))	('serine', 'Chemical', 'MESH:D012694', (67, 73))
53680	33381564	Among these pathways, cfa04110: cell cycle, cfa04350: TGF-beta signaling pathway, ptr05200: pathways in cancer, and cfa04115: p53 signaling pathway were involved in the tumorigenesis and pathogenesis about brain and CNS cancer (Figures 11(a) and 11(b)).	('p53', 'Gene', '7157', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('p53', 'Gene', (126, 129))	('CNS cancer', 'Phenotype', 'HP:0100006', (216, 226))	('cfa04110', 'Var', (22, 30))	('TGF-beta', 'Gene', (54, 62))	('cfa04115', 'Var', (116, 124))	('cfa04110', 'Chemical', '-', (22, 30))	('cfa04115', 'Chemical', '-', (116, 124))	('involved', 'Reg', (153, 161))	('TGF-beta', 'Gene', '7039', (54, 62))	('cfa04350', 'Var', (44, 52))
53684	33381564	miRNA-320 and miRNA-329 inhibited glioma proliferation by targeting E2F1.	('miRNA-329', 'Chemical', '-', (14, 23))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('miRNA-320', 'Chemical', '-', (0, 9))	('miRNA-329', 'Var', (14, 23))	('miRNA-320', 'Var', (0, 9))	('inhibited', 'NegReg', (24, 33))	('E2F1', 'Gene', (68, 72))	('targeting', 'Reg', (58, 67))	('glioma', 'Disease', (34, 40))
53686	33381564	Downregulation of E2F2 was shown to inhibit glioma cell growth in vitro and in vivo by inducing cell cycle arrest in G0/G1.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('arrest', 'Disease', (107, 113))	('inhibit', 'NegReg', (36, 43))	('inducing', 'Reg', (87, 95))	('Downregulation', 'Var', (0, 14))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('E2F2', 'Gene', (18, 22))	('glioma cell growth', 'CPA', (44, 62))
53689	33381564	The primary factor of miR-195-mediated cell arrest was E2F3.	('miR-195', 'Gene', '406971', (22, 29))	('E2F3', 'Var', (55, 59))	('cell arrest', 'CPA', (39, 50))	('miR-195', 'Gene', (22, 29))
53704	31998650	Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients.	('FUNDC1', 'Gene', (9, 15))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('high', 'Var', (60, 64))	('FUNDC1', 'Gene', (85, 91))	('FUNDC1', 'Gene', '139341', (9, 15))	('LIHC', 'Disease', (127, 131))	('detrimental', 'NegReg', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('LIHC', 'Disease', 'MESH:D006528', (127, 131))	('FUNDC1', 'Gene', '139341', (85, 91))	('patients', 'Species', '9606', (132, 140))
53722	31998650	For example, cytotoxic T lymphocyte associated antigen 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) inhibitors were found to have promising antitumor effects on malignant melanoma and non-small-cell lung carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('programmed death ligand-1', 'Gene', (97, 122))	('malignant melanoma', 'Phenotype', 'HP:0002861', (192, 210))	('non-small-cell lung carcinoma', 'Disease', (215, 244))	('programmed death-1', 'Gene', '5133', (66, 84))	('programmed death-1', 'Gene', (66, 84))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (215, 244))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', (13, 56))	('programmed death ligand-1', 'Gene', '29126', (97, 122))	('tumor', 'Disease', (175, 180))	('CTLA4', 'Gene', '1493', (58, 63))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', '1493', (13, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('melanoma', 'Disease', (202, 210))	('inhibitors', 'Var', (131, 141))	('PD-L1', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (124, 129))	('CTLA4', 'Gene', (58, 63))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (219, 244))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (215, 244))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
53763	31998650	The findings for lung cancer were partly different from those using PrognoScan, as a high expression of FUNDC1 only benefited LUSC (OS: HR = 0.64, 95 % CI from 0.48 to 0.85 logrank P = 0.0017; RFS: HR = 0.55, 95% CI from 0.33 to 0.91, logrank P = 0.019) (Figures 2C,D) and not LUAD (OS: HR = 0.8, 95% CI from 0.6 to 1.08, logrank P = 0.15; RFS: HR = 1.41, 95% CI from 0.91 to 2.19, logrank P = 0.13) (Figures 3M,N).	('LUSC', 'Disease', (126, 130))	('FUNDC1', 'Gene', (104, 110))	('lung cancer', 'Disease', (17, 28))	('benefited', 'PosReg', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('FUNDC1', 'Gene', '139341', (104, 110))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('high', 'Var', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('LUAD', 'Disease', (277, 281))	('LUAD', 'Disease', 'MESH:C538231', (277, 281))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('LUSC', 'Disease', 'MESH:D002294', (126, 130))
53779	31998650	For progression-free survival (PFS), FUNDC1 expression was significantly hazardous to LIHC patients without hepatitis virus infection (n = 167, HR = 2.1, 95% CI from 1.3 to 3.38, P = 0.0019) but became protective to LIHC patients at stage 2 (n = 84, HR = 0.52, 95% CI from 0.28 to 0.98, P = 0.039) and grade 3 (n = 119, HR = 0.6, 95% CI from 0.36 to 0.98, P = 0.041) (Figure 4).	('LIHC', 'Disease', (86, 90))	('patients', 'Species', '9606', (221, 229))	('hepatitis virus infection', 'Disease', (108, 133))	('patients', 'Species', '9606', (91, 99))	('LIHC', 'Disease', 'MESH:D006528', (86, 90))	('hepatitis', 'Phenotype', 'HP:0012115', (108, 117))	('FUNDC1', 'Gene', (37, 43))	('expression', 'Var', (44, 54))	('FUNDC1', 'Gene', '139341', (37, 43))	('LIHC', 'Disease', (216, 220))	('LIHC', 'Disease', 'MESH:D006528', (216, 220))	('hepatitis virus infection', 'Disease', 'MESH:D006525', (108, 133))
53803	31998650	Mitochondria are essential for human immunity, and aberrant mitochondrial activity affects immune responses.	('aberrant', 'Var', (51, 59))	('mitochondrial activity', 'MPA', (60, 82))	('human', 'Species', '9606', (31, 36))	('immune responses', 'CPA', (91, 107))	('affects', 'Reg', (83, 90))
53804	31998650	For example, some studies have demonstrated that viruses (e.g., HBV in LIHC) can manipulate mitophagy, which enables viruses to promote persistent infection and attenuate the innate immune responses.	('attenuate', 'NegReg', (161, 170))	('mitophagy', 'CPA', (92, 101))	('innate immune responses', 'CPA', (175, 198))	('manipulate', 'Reg', (81, 91))	('infection', 'Disease', (147, 156))	('LIHC', 'Disease', (71, 75))	('infection', 'Disease', 'MESH:D007239', (147, 156))	('persistent infection', 'Phenotype', 'HP:0031035', (136, 156))	('viruses', 'Var', (117, 124))	('LIHC', 'Disease', 'MESH:D006528', (71, 75))	('promote', 'PosReg', (128, 135))
53807	31998650	FUNDC1-mediated mitophagy is negatively regulated by the phosphorylation of FUNDC1, as the phosphorylation of Tyr 18 in the FUNDC1 LC3-interacting region motif can weaken the binding affinity of FUNDC1 to LC3.	('FUNDC1', 'Gene', (76, 82))	('Tyr 18', 'Var', (110, 116))	('mitophagy', 'CPA', (16, 25))	('FUNDC1', 'Gene', (124, 130))	('phosphorylation', 'Var', (91, 106))	('FUNDC1', 'Gene', '139341', (0, 6))	('FUNDC1', 'Gene', '139341', (76, 82))	('FUNDC1', 'Gene', '139341', (124, 130))	('weaken', 'NegReg', (164, 170))	('Tyr', 'Chemical', 'MESH:C042696', (110, 113))	('binding affinity', 'Interaction', (175, 191))	('FUNDC1', 'Gene', (195, 201))	('FUNDC1', 'Gene', '139341', (195, 201))	('FUNDC1', 'Gene', (0, 6))	('LC3', 'Protein', (205, 208))
53815	31998650	Thus, it is reasonable to surmise that FUNDC1 expression may influence patient survival through tumor cell proliferation.	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('influence', 'Reg', (61, 70))	('tumor', 'Disease', (96, 101))	('FUNDC1', 'Gene', (39, 45))	('FUNDC1', 'Gene', '139341', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patient', 'Species', '9606', (71, 78))	('patient survival', 'CPA', (71, 87))
53819	31998650	One previous study has demonstrated that FUNDC1-mediated mitophagy can suppress hepatocarcinogenesis.	('FUNDC1', 'Gene', (41, 47))	('FUNDC1', 'Gene', '139341', (41, 47))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (80, 100))	('mitophagy', 'Var', (57, 66))	('suppress', 'NegReg', (71, 79))	('hepatocarcinogenesis', 'Disease', (80, 100))
53820	31998650	This study found that the specific knockout of FUNDC1 in hepatocytes promotes the initiation and progression of chemical carcinogen diethylnitrosamine-induced HCC.	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (132, 150))	('FUNDC1', 'Gene', (47, 53))	('progression', 'CPA', (97, 108))	('promotes', 'PosReg', (69, 77))	('knockout', 'Var', (35, 43))	('FUNDC1', 'Gene', '139341', (47, 53))
53821	31998650	The study also found that FUNDC1 transgenic hepatocytes protect against the development of HCC.	('FUNDC1', 'Gene', (26, 32))	('HCC', 'Disease', (91, 94))	('transgenic', 'Var', (33, 43))	('FUNDC1', 'Gene', '139341', (26, 32))
53844	31998650	In 8 datasets in PrognoScan, high FUNDC1 expression levels could be used as an independent risk factor for a poor prognosis in brain, breast, colorectal, and skin cancers (Figure 2).	('high', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colorectal', 'Disease', (142, 152))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('skin cancers', 'Disease', (158, 170))	('skin cancers', 'Phenotype', 'HP:0008069', (158, 170))	('brain', 'Disease', (127, 132))	('FUNDC1', 'Gene', (34, 40))	('skin cancers', 'Disease', 'MESH:D012878', (158, 170))	('breast', 'Disease', (134, 140))	('FUNDC1', 'Gene', '139341', (34, 40))
53845	31998650	In addition, a high level of FUNDC1 expression was shown to be related to a poor prognosis in LIHC with micro-vascular invasion but a favorable prognosis in LIHC with AJCC T2 (Figure 4).	('high', 'Var', (15, 19))	('LIHC', 'Disease', (94, 98))	('FUNDC1', 'Gene', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (94, 98))	('LIHC', 'Disease', (157, 161))	('FUNDC1', 'Gene', '139341', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('expression', 'MPA', (36, 46))
53847	31998650	Another major finding from this study is that FUNDC1 expression correlates with diverse immune infiltration levels in cancers, especially in LIHC and LUSC.	('LIHC', 'Disease', (141, 145))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('correlates with', 'Reg', (64, 79))	('immune infiltration levels', 'MPA', (88, 114))	('expression', 'Var', (53, 63))	('FUNDC1', 'Gene', (46, 52))	('LIHC', 'Disease', 'MESH:D006528', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FUNDC1', 'Gene', '139341', (46, 52))	('LUSC', 'Disease', 'MESH:D002294', (150, 154))	('LUSC', 'Disease', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (150, 154))
53871	31998650	These interactions between tumor cells and infiltrating immune cells help explain the findings from this study indicating that TAMs have a positive correlation with FUNDC1 expression in LIHC and that the high expression of FUNDC1 is associated with a worse LIHC patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('high expression', 'Var', (204, 219))	('FUNDC1', 'Gene', '139341', (223, 229))	('FUNDC1', 'Gene', '139341', (165, 171))	('tumor', 'Disease', (27, 32))	('LIHC', 'Disease', (186, 190))	('associated with', 'Reg', (233, 248))	('LIHC', 'Disease', 'MESH:D006528', (186, 190))	('TAM', 'Gene', '8205', (127, 130))	('expression', 'MPA', (172, 182))	('TAM', 'Gene', (127, 130))	('patient', 'Species', '9606', (262, 269))	('LIHC', 'Disease', (257, 261))	('LIHC', 'Disease', 'MESH:D006528', (257, 261))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('FUNDC1', 'Gene', (223, 229))	('FUNDC1', 'Gene', (165, 171))
53891	30588509	Through the identification of tumor-specific changes, it is now possible to diagnose, assign a prognostic subgroup, and develop targeted chemotherapeutic treatment plans for many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('changes', 'Var', (45, 52))	('cancer', 'Disease', (179, 185))	('tumor', 'Disease', (30, 35))
53921	30588509	ctDNA can be distinguished from background cfDNA based on the presence of tumor-specific mutations not found in the DNA of healthy cells, which provides a highly specific biomarker.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ctDNA', 'Disease', (0, 5))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (89, 98))
53926	30588509	Indeed, highly sensitive assays have enabled detection of ctDNA harboring disease-specific mutations in the blood of patients diagnosed with colorectal, lung, and breast cancers, and in the CSF of adult and pediatric brain tumor patients.	('colorectal', 'Disease', (141, 151))	('patients', 'Species', '9606', (229, 237))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('brain tumor', 'Disease', 'MESH:D001932', (217, 228))	('brain tumor', 'Disease', (217, 228))	('breast cancers', 'Phenotype', 'HP:0003002', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (91, 100))	('colorectal', 'Disease', 'MESH:D015179', (141, 151))	('breast cancers', 'Disease', (163, 177))	('lung', 'Disease', (153, 157))	('breast cancers', 'Disease', 'MESH:D001943', (163, 177))	('ctDNA', 'Gene', (58, 63))	('patients', 'Species', '9606', (117, 125))	('brain tumor', 'Phenotype', 'HP:0030692', (217, 228))
53930	30588509	This would be ideal for pediatric CNS tumors that are molecularly characterized by fusions, including KIAA1549-BRAF fusion positive low-grade gliomas, and by elevated transcript levels due to changes in gene expression or copy number alterations (CNAs), such as those occurring in medulloblastoma.	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('pediatric CNS tumors', 'Disease', 'MESH:D063766', (24, 44))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('KIAA1549-BRAF', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('copy number alterations', 'Var', (222, 245))	('pediatric CNS tumors', 'Disease', (24, 44))	('CNS tumor', 'Phenotype', 'HP:0100006', (34, 43))	('gene expression', 'MPA', (203, 218))	('KIAA1549-BRAF', 'Disease', 'None', (102, 115))	('transcript levels', 'MPA', (167, 184))	('gliomas', 'Disease', (142, 149))	('medulloblastoma', 'Disease', 'MESH:D008527', (281, 296))	('changes', 'Reg', (192, 199))	('medulloblastoma', 'Phenotype', 'HP:0002885', (281, 296))	('medulloblastoma', 'Disease', (281, 296))	('elevated', 'PosReg', (158, 166))
53960	30588509	Therefore, while CSF may serve as a better upfront medium for preliminary diagnosis and to detect commonly occurring mutations (using targeted sequencing and/or digital droplet PCR (ddPCR)), blood or urine may be a preferable source for long-term monitoring of variants associated with tumor response and progression.	('variants', 'Var', (261, 269))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Disease', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))
53963	30588509	For example, in some cases ctRNA is needed for detection of fusion variants that characterize a certain tumor type.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('fusion variants', 'Var', (60, 75))
53964	30588509	In other instances, single gene mutations in ctDNA can be used to diagnose tumor subclass.	('ctDNA', 'Gene', (45, 50))	('diagnose', 'Reg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('single gene mutations', 'Var', (20, 41))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
53968	30588509	Due to its ability to detect and quantify rare mutant alleles using very low levels of ctDNA, ddPCR has increasingly become the platform of choice in preclinical studies of colorectal, breast, melanoma, lymphoma, brain, and other cancer types (Table 1).	('colorectal', 'Disease', (173, 183))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('breast', 'Disease', (185, 191))	('melanoma, lymphoma', 'Disease', 'MESH:D008545', (193, 211))	('brain', 'Disease', (213, 218))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('lymphoma', 'Phenotype', 'HP:0002665', (203, 211))	('mutant', 'Var', (47, 53))	('colorectal', 'Disease', 'MESH:D015179', (173, 183))
53969	30588509	In a recent publication, our group showed that ddPCR monitoring of single nucleotide variants associated with histone H3 (H3K27M mutation), both in blood and CSF, can be effective for tumor subtyping and following tumor response in DIPG and other midline tumors.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('H3K27M', 'Gene', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('midline tumors', 'Disease', (247, 261))	('single nucleotide variants', 'Var', (67, 93))	('tumor', 'Disease', (184, 189))	('midline tumors', 'Disease', 'MESH:D009369', (247, 261))	('tumor', 'Disease', (214, 219))	('DIPG', 'Chemical', 'MESH:C060938', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('DIPG', 'Disease', (232, 236))
53972	30588509	In addition to single nucleotide variants, ddPCR can detect differentially methylated cfDNA, which has been particularly useful for colorectal cancer in adults.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('cfDNA', 'Gene', (86, 91))	('differentially', 'Var', (60, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('detect', 'Reg', (53, 59))	('colorectal cancer', 'Disease', (132, 149))
53975	30588509	Another highly sensitive platform for detecting tumor mutations in cfDNA is beads, emulsification, amplification and magnetics PCR (BEAMing PCR).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
53976	30588509	These PCR-based approaches are highly sensitive and detect tumor-specific variants at a frequency as low as 0.001%, provide a measurement of mutation load, and enable identification of residual disease post-treatment.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('variants', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutation load', 'MPA', (141, 154))
53977	30588509	BEAMing PCR has shown promise in detecting mutations in preclinical studies of adult colorectal, lung, breast, and glioma (Table 1).	('glioma', 'Disease', (115, 121))	('colorectal', 'Disease', 'MESH:D015179', (85, 95))	('breast', 'Disease', (103, 109))	('lung', 'Disease', (97, 101))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('mutations', 'Var', (43, 52))	('colorectal', 'Disease', (85, 95))	('glioma', 'Disease', 'MESH:D005910', (115, 121))
53981	30588509	NGS would be ideal for the discovery of mutations acquired at the time of progression, or the detection of mutations in ctDNA from patients where the molecular profile of the tumor is unknown.	('patients', 'Species', '9606', (131, 139))	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (107, 116))	('ctDNA', 'Gene', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
53985	30588509	This has been used to detect hypomethylation in cfDNA in plasma of cancer patients with high sensitivity and specificity.	('cfDNA', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('detect', 'Reg', (22, 28))	('hypomethylation', 'Var', (29, 44))
53988	30588509	This has been useful for the detection of EGFR(v)III amplification in high-grade gliomas, and IDH1 G395A mutant transcripts in adult glioma (Table 1).	('adult glioma', 'Disease', 'MESH:D005910', (127, 139))	('G395A mutant', 'Var', (99, 111))	('IDH1', 'Gene', (94, 98))	('EGFR', 'Gene', '1956', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('amplification', 'Var', (53, 66))	('IDH1', 'Gene', '3417', (94, 98))	('EGFR', 'Gene', (42, 46))	('adult glioma', 'Disease', (127, 139))	('G395A', 'Mutation', 'rs121913500', (99, 104))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))
53991	30588509	Liquid chromatography-mass spectrometry (LC-MS) is a commonly used method for protein biomarker discovery and quantification (including quantification of tumor-specific missense mutant proteins) in specimens including plasma, serum, urine and tissue.	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('missense mutant', 'Var', (169, 184))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
53995	30588509	This approach was used to analyze intact proteins in the CSF of pediatric patients with posterior cranial fossa brain tumors, leading to identification of LVV- and VV-hemorphin-7 as potential biomarkers for this tumor type.	('posterior cranial fossa brain tumors', 'Disease', 'MESH:D015192', (88, 124))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (74, 82))	('posterior cranial fossa brain tumors', 'Disease', (88, 124))	('brain tumors', 'Phenotype', 'HP:0030692', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('brain tumor', 'Phenotype', 'HP:0030692', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (118, 123))	('LVV-', 'Var', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))
54005	30588509	cfDNA requires extremely sensitive, high-throughput sequencing platforms that reduce background noise, detect low frequency variants, and encompass the diversity of tumor molecular alterations.	('reduce', 'NegReg', (78, 84))	('variants', 'Var', (124, 132))	('background noise', 'MPA', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
54010	30588509	Although not currently being used in the context of liquid biopsy, these novel approaches could potentially allow for rapid detection of epigenetic biomarkers in CTCs, and should be considered in pediatric CNS tumor biomarker research.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('CNS tumor', 'Phenotype', 'HP:0100006', (206, 215))	('CNS tumor', 'Disease', 'MESH:D009369', (206, 215))	('epigenetic', 'Var', (137, 147))	('CNS tumor', 'Disease', (206, 215))
54013	30588509	Finally, in order to capture the variety of alterations in pediatric CNS tumors (Table 3), distinct and specialized methods will need to be developed for accurate analysis of different types of alterations, including single nucleotide variants, fusions, copy number alterations, differential methylation patterns and miRNA profiles.	('pediatric CNS tumors', 'Disease', (59, 79))	('differential methylation patterns', 'Var', (279, 312))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('copy number alterations', 'Var', (254, 277))	('fusions', 'Var', (245, 252))	('CNS tumor', 'Phenotype', 'HP:0100006', (69, 78))	('miRNA', 'MPA', (317, 322))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('pediatric CNS tumors', 'Disease', 'MESH:D063766', (59, 79))	('single nucleotide variants', 'Var', (217, 243))
54020	30588509	At progression, molecular profiling of ctDNA can detect new mutations, possibly before changes in the tumor are seen on MRI, allowing for earlier intervention and overall improved outcomes.	('ctDNA', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('improved', 'PosReg', (171, 179))
54027	29844863	In cultured glioma cells, we show that PAM-OBG is converted to O6BG, inhibiting MGMT and sensitizing cells to DNA alkylating agents such as BCNU, CCNU, and Temozolomide (TMZ).	('O6BG', 'Chemical', 'MESH:C064976', (63, 67))	('BCNU', 'MPA', (140, 144))	('BCNU', 'Chemical', 'MESH:D002330', (140, 144))	('MGMT', 'Gene', '4255', (80, 84))	('glioma', 'Disease', (12, 18))	('MGMT', 'Gene', (80, 84))	('TMZ', 'Chemical', 'MESH:D000077204', (170, 173))	('Temozolomide', 'Chemical', 'MESH:D000077204', (156, 168))	('sensitizing', 'Reg', (89, 100))	('inhibiting', 'NegReg', (69, 79))	('PAM-OBG', 'Var', (39, 46))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
54029	29844863	In mouse intracranial models of primary human glioma, we show that PAM-OBG increases survival of mice treated with either BCNU or CCNU by a factor of six and that in a chemoradiation model utilizing six rounds of TMZ/2Gy radiation, pre-treatment with PAM-OBG more than doubled survival time.	('BCNU', 'Chemical', 'MESH:D002330', (122, 126))	('survival time', 'CPA', (277, 290))	('mouse', 'Species', '10090', (3, 8))	('glioma', 'Disease', (46, 52))	('survival', 'CPA', (85, 93))	('mice', 'Species', '10090', (97, 101))	('PAM-OBG', 'Var', (67, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (213, 216))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('human', 'Species', '9606', (40, 45))	('increases', 'PosReg', (75, 84))
54054	29844863	High-grade tumors are heterogeneous, an indicator of rapid evolution, and tumor cells are characterized by high mutation loads, amplifications, deletions and structural rearrangements of swathes of DNA.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mutation', 'Var', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('deletions', 'Var', (144, 153))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Disease', (74, 79))	('amplifications', 'Var', (128, 142))	('structural rearrangements', 'Var', (158, 183))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
54055	29844863	We postulated that aberrations in DNA repair pathways would be selected for in GBM, allowing these cancer cells to undergo rapid evolution and niche exploitation, but could be its 'Achilles heel' for a highly targeted chemotherapeutic drug strategy.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('aberrations', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
54059	29844863	Each MGMT can only repair a single lesion, as after adduct transfer and formation of alkyl thioether, MGMT is inactivated.	('alkyl thioether', 'Chemical', '-', (85, 100))	('adduct', 'Var', (52, 58))	('MGMT', 'Gene', '4255', (5, 9))	('MGMT', 'Gene', (5, 9))	('MGMT', 'Gene', (102, 106))	('MGMT', 'Gene', '4255', (102, 106))
54071	29844863	Agarwal noted that after TMZ therapeutic failure there was generally an upregulation of MGMT or there was a downregulation of canonical MMR (or mutations in MutSa/MutLa) in second resection tumor samples.	('upregulation', 'PosReg', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('MGMT', 'Gene', (88, 92))	('tumor', 'Disease', (190, 195))	('MGMT', 'Gene', '4255', (88, 92))	('downregulation', 'NegReg', (108, 122))	('canonical MMR', 'Protein', (126, 139))	('mutations', 'Var', (144, 153))	('MutSa/MutLa', 'Gene', (157, 168))	('TMZ', 'Chemical', 'MESH:D000077204', (25, 28))
54074	29844863	O6BG, a potent inhibitor of MGMT, is nontoxic when administered to animals or humans as a single agent.	('MGMT', 'Gene', (28, 32))	('MGMT', 'Gene', '4255', (28, 32))	('O6BG', 'Var', (0, 4))	('humans', 'Species', '9606', (78, 84))	('O6BG', 'Chemical', 'MESH:C064976', (0, 4))
54075	29844863	A phase III trial utilizing O6BG to ablate MGMT activity throughout a patient's tissues, prior to radiotherapy/BCNU + BCNU, was highly disappointing as O6BG did not provide an added benefit, but instead caused additional toxicity.	('caused', 'Reg', (203, 209))	('ablate', 'NegReg', (36, 42))	('patient', 'Species', '9606', (70, 77))	('MGMT', 'Gene', '4255', (43, 47))	('O6BG', 'Var', (152, 156))	('O6BG', 'Chemical', 'MESH:C064976', (28, 32))	('MGMT', 'Gene', (43, 47))	('toxicity', 'Disease', 'MESH:D064420', (221, 229))	('toxicity', 'Disease', (221, 229))	('BCNU', 'Chemical', 'MESH:D002330', (118, 122))	('BCNU', 'Chemical', 'MESH:D002330', (111, 115))	('O6BG', 'Chemical', 'MESH:C064976', (152, 156))
54076	29844863	Hematologic Grade 4 or higher toxicities quadrupled in patients receiving O6BG & BCNU vs. the BCNU arm.	('toxicities', 'Disease', 'MESH:D064420', (30, 40))	('BCNU', 'Chemical', 'MESH:D002330', (81, 85))	('O6BG', 'Chemical', 'MESH:C064976', (74, 78))	('BCNU', 'Chemical', 'MESH:D002330', (94, 98))	('toxicities', 'Disease', (30, 40))	('O6BG &', 'Var', (74, 80))	('patients', 'Species', '9606', (55, 63))
54083	29844863	We envisioned a prodrug that would become active after oxidation by MAOB and that after maturation would generate O6BG to inhibit MGMT would sensitize cells to TMZ chemoradiation.	('O6BG', 'Chemical', 'MESH:C064976', (114, 118))	('TMZ', 'Chemical', 'MESH:D000077204', (160, 163))	('MGMT', 'Gene', '4255', (130, 134))	('MAOB', 'Gene', (68, 72))	('O6BG', 'Var', (114, 118))	('MGMT', 'Gene', (130, 134))	('inhibit', 'NegReg', (122, 129))	('MAOB', 'Gene', '4129', (68, 72))	('sensitize', 'Reg', (141, 150))
54091	29844863	We have used the latter for the design of PAM-OBG, which allows an inactive 'masked' adduct of O6BG to be converted in O6BG only inside cells with MAOB activity.	('MAOB', 'Gene', '4129', (147, 151))	('O6BG', 'Var', (95, 99))	('O6BG', 'Chemical', 'MESH:C064976', (119, 123))	('O6BG', 'Chemical', 'MESH:C064976', (95, 99))	('MAOB', 'Gene', (147, 151))
54097	29844863	indicated that the addition to the 2-amino of O6-alkylguanine position would result in a sterically hindered molecule that could no longer fit the MGMT substrate pocket.	('O6-alkylguanine', 'Var', (46, 61))	('result in', 'Reg', (77, 86))	('sterically hindered molecule', 'MPA', (89, 117))	('O6-alkylguanine', 'Chemical', '-', (46, 61))	('MGMT', 'Gene', (147, 151))	('MGMT', 'Gene', '4255', (147, 151))
54103	29844863	It has been shown that overexpression of ALKBH2 in glioma cell lines enhances resistance to TMZ, and conversely, siRNA-knockdown of ALKBH2 increases TMZ sensitivity.	('TMZ', 'Chemical', 'MESH:D000077204', (149, 152))	('glioma', 'Disease', (51, 57))	('ALKBH2', 'Gene', (41, 47))	('ALKBH2', 'Gene', '121642', (41, 47))	('resistance to TMZ', 'MPA', (78, 95))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('ALKBH2', 'Gene', (132, 138))	('siRNA-knockdown', 'Var', (113, 128))	('TMZ sensitivity', 'MPA', (149, 164))	('increases', 'PosReg', (139, 148))	('overexpression', 'Var', (23, 37))	('ALKBH2', 'Gene', '121642', (132, 138))	('enhances', 'PosReg', (69, 77))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))
54120	29844863	Agnihotri and co-workers found MPG to be a glioma risk factor, mainly examining pediatric tumors, and suggested that it could directly repair TMZ generated O6MeG lesions.	('O6MeG', 'Var', (156, 161))	('TMZ', 'Chemical', 'MESH:D000077204', (142, 145))	('pediatric tumors', 'Disease', (80, 96))	('MPG', 'Gene', '4350', (31, 34))	('glioma', 'Disease', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MPG', 'Gene', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('pediatric tumors', 'Disease', 'MESH:D063766', (80, 96))	('O6MeG', 'Chemical', 'MESH:C008449', (156, 161))
54129	29844863	It has been shown by others that the pairing of ALKBH3 with a helicase (ASCC3) allows efficient removal of many dsDNA lesions, which are generated by TMZ, especially N1-MeA and N3-MeC.	('removal', 'NegReg', (96, 103))	('dsDNA', 'Disease', (112, 117))	('ASCC3', 'Gene', '10973', (72, 77))	('ALKBH3', 'Gene', (48, 54))	('MeC', 'Gene', (180, 183))	('ALKBH3', 'Gene', '221120', (48, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (150, 153))	('MeC', 'Gene', '56477', (180, 183))	('ASCC3', 'Gene', (72, 77))	('N1-MeA', 'Var', (166, 172))
54132	29844863	ALKBH1, but not ALKBH3, also demethylates histones, altering epigenetic gene expression.	('epigenetic gene expression', 'MPA', (61, 87))	('ALKBH1', 'Gene', '8846', (0, 6))	('altering', 'Reg', (52, 60))	('ALKBH3', 'Gene', '221120', (16, 22))	('demethylates', 'Var', (29, 41))	('ALKBH3', 'Gene', (16, 22))	('histones', 'Protein', (42, 50))	('ALKBH1', 'Gene', (0, 6))
54140	29844863	The pattern of DNA repair pathways indicates poorly functional BER and MMR pathways and that PAM-OBG derived HOPdG lesions will slow ALKBH3 removal of TMZ generated DNA-methyl lesions.	('ALKBH3', 'Gene', (133, 139))	('ALKBH3', 'Gene', '221120', (133, 139))	('MMR pathways', 'Pathway', (71, 83))	('BER', 'Pathway', (63, 66))	('TMZ', 'Chemical', 'MESH:D000077204', (151, 154))	('slow', 'NegReg', (128, 132))	('lesions', 'Var', (115, 122))
54148	29844863	TMZ causes activation of the ATM and ATR kinases, phosphorylation of CHK1, CHK2, and p53, and triggering of the G(2)/M arrest via ATR/ATR MutSalpha/MutLalpha phosphorylation.	('phosphorylation', 'MPA', (50, 65))	('ATR', 'Gene', (37, 40))	('ATR', 'Gene', '545', (37, 40))	('ATM', 'Gene', (29, 32))	('CHK2', 'Gene', (75, 79))	('ATR', 'Gene', '545', (130, 133))	('ATR', 'Gene', (130, 133))	('ATR', 'Gene', '545', (134, 137))	('ATR', 'Gene', (134, 137))	('CHK1', 'Gene', (69, 73))	('TMZ', 'Var', (0, 3))	('ATM', 'Gene', '472', (29, 32))	('CHK2', 'Gene', '11200', (75, 79))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('activation', 'PosReg', (11, 21))	('CHK1', 'Gene', '1111', (69, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
54151	29844863	In the Q1 cohort, NER appeared to be the major dsDNA break/ICL repair pathway, whereas in Q3 the GBM were biased toward NHEJ/MMEJ, and to HR, with FA core complex functionality.	('ICL', 'Disease', 'MESH:D018344', (59, 62))	('NHEJ/MMEJ', 'Var', (120, 129))	('ICL', 'Disease', (59, 62))
54154	29844863	The generation of O6BG, from PAM-OBG, in these tumors will cause sensitization via MGMT inhibition.	('tumors', 'Disease', (47, 53))	('MGMT', 'Gene', '4255', (83, 87))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('MGMT', 'Gene', (83, 87))	('O6BG', 'Var', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('O6BG', 'Chemical', 'MESH:C064976', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('sensitization', 'MPA', (65, 78))
54163	29844863	We stratified the patient population with respect to expression of XRCC1 (BER-SP), with one sub-population (n = 33) with high XRCC1 and the second sub-population (n = 77) with low XRCC1.	('XRCC1', 'Gene', (67, 72))	('XRCC1', 'Gene', '7515', (180, 185))	('XRCC1', 'Gene', (126, 131))	('high', 'Var', (121, 125))	('BER-SP', 'Chemical', '-', (74, 80))	('XRCC1', 'Gene', '7515', (67, 72))	('patient', 'Species', '9606', (18, 25))	('XRCC1', 'Gene', (180, 185))	('XRCC1', 'Gene', '7515', (126, 131))
54166	29844863	In the subpopulation with high XRCC1 levels, MPG aided survival with patients with high MPG levels having a median survival of 14.1 months, but those with low MPG levels having a median survival of only 7.7 months, p = 0.015, Supplementary Figure 5C.	('high', 'Var', (26, 30))	('XRCC1', 'Gene', '7515', (31, 36))	('MPG', 'Gene', '4350', (45, 48))	('MPG', 'Gene', (159, 162))	('MPG', 'Gene', (45, 48))	('survival', 'CPA', (55, 63))	('MPG', 'Gene', '4350', (159, 162))	('MPG', 'Gene', '4350', (88, 91))	('XRCC1', 'Gene', (31, 36))	('patients', 'Species', '9606', (69, 77))	('MPG', 'Gene', (88, 91))
54169	29844863	It was shown that MPG repair of methyl lesions in mtDNA initiates mitochondrial driven apoptosis, in cases when the MPG glycosylase activity is higher than the downstream repair processes in BER-SP, causing an overload in AP-sites and DNA breaks.	('initiates', 'Reg', (56, 65))	('MPG', 'Gene', '4350', (116, 119))	('DNA breaks', 'MPA', (235, 245))	('activity', 'MPA', (132, 140))	('MPG', 'Gene', (116, 119))	('overload', 'PosReg', (210, 218))	('MPG', 'Gene', '4350', (18, 21))	('BER-SP', 'Chemical', '-', (191, 197))	('MPG', 'Gene', (18, 21))	('repair', 'Var', (22, 28))	('methyl lesions', 'Var', (32, 46))	('AP-sites', 'MPA', (222, 230))	('mitochondrial driven apoptosis', 'CPA', (66, 96))
54172	29844863	In these cells, the generation of O6BG- and acrolein adducts, from PAM-OBG, will sensitize the tumor cells to chemoradiation.	('acrolein', 'Chemical', 'MESH:D000171', (44, 52))	('sensitize', 'Reg', (81, 90))	('O6BG-', 'Var', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('acrolein', 'Protein', (44, 52))	('O6BG', 'Chemical', 'MESH:C064976', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
54175	29844863	In cells incubated with 10 microM O6BG, there was sensitization toward TMZ and BCNU, with IC50 values dropping to   280 microM and   130 microM, respectively.	('O6BG', 'Var', (34, 38))	('sensitization', 'MPA', (50, 63))	('BCNU', 'MPA', (79, 83))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('BCNU', 'Chemical', 'MESH:D002330', (79, 83))	('O6BG', 'Chemical', 'MESH:C064976', (34, 38))
54181	29844863	It has been demonstrated that ubiquitination, and subsequent proteolysis, of alkylated MGMT is more rapid than that of the native, active enzyme.	('MGMT', 'Gene', (87, 91))	('MGMT', 'Gene', '4255', (87, 91))	('proteolysis', 'MPA', (61, 72))	('alkylated', 'Var', (77, 86))	('ubiquitination', 'MPA', (30, 44))
54182	29844863	In initial experiments, we incubated primary GBM157 cells in BCNU, O6BG, and PAM-OBG +- Seg and observed that PAM-OBG resulted in higher than canonical MGMT molecular weight bands, which we interpret as evidence for ubiquitination.	('BCNU', 'Chemical', 'MESH:D002330', (61, 65))	('higher', 'PosReg', (130, 136))	('PAM-OBG', 'Var', (110, 117))	('MGMT', 'Gene', (152, 156))	('O6BG', 'Chemical', 'MESH:C064976', (67, 71))	('MGMT', 'Gene', '4255', (152, 156))
54186	29844863	Primary glioma cells were incubated with an MGMT substrate, either O6BG or PAM-OBG, for a defined time period and then 100 microM O6PGG was added, and 10 minutes later the cells were fixed with paraformaldehyde (PFA).	('Primary glioma', 'Disease', 'MESH:D005910', (0, 14))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('O6PGG', 'Chemical', '-', (130, 135))	('O6BG', 'Chemical', 'MESH:C064976', (67, 71))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (194, 210))	('MGMT', 'Gene', (44, 48))	('MGMT', 'Gene', '4255', (44, 48))	('Primary glioma', 'Disease', (0, 14))	('PFA', 'Chemical', 'MESH:C003043', (212, 215))	('O6BG', 'Var', (67, 71))
54189	29844863	Pre-incubation of cells with 10 microM O6BG before application of O6PGG causes (almost) complete loss of active MGMT signal, Figure 3C (ii).	('loss', 'NegReg', (97, 101))	('O6BG', 'Chemical', 'MESH:C064976', (39, 43))	('O6PGG', 'Var', (66, 71))	('MGMT', 'Gene', (112, 116))	('O6PGG', 'Chemical', '-', (66, 71))	('MGMT', 'Gene', '4255', (112, 116))	('O6BG', 'Var', (39, 43))
54197	29844863	The data indicate that the Km of MAOB for PAM-OBG is   200 microM and its Vmax   13% of that observed with control MAOB substrate, benzylamine.	('PAM-OBG', 'Var', (42, 49))	('Vmax', 'MPA', (74, 78))	('MAOB', 'Gene', (115, 119))	('MAOB', 'Gene', (33, 37))	('MAOB', 'Gene', '4129', (115, 119))	('MAOB', 'Gene', '4129', (33, 37))	('benzylamine', 'Chemical', 'MESH:C030796', (131, 142))
54200	29844863	In addition to inhibiting CDK7, SNS-032 also inhibits the cyclin-dependent kinases CDK2, CDK5 and CDK9, however, even though SNS-032 can alter glioma response to hypoxia, it is not toxic toward U87 cells even at very high drug concentrations (500 nM).	('CDK2', 'Gene', (83, 87))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('CDK7', 'Gene', (26, 30))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('SNS-032', 'Chemical', 'MESH:C484864', (32, 39))	('CDK7', 'Gene', '1022', (26, 30))	('inhibits', 'NegReg', (45, 53))	('CDK9', 'Gene', (98, 102))	('alter', 'Reg', (137, 142))	('CDK5', 'Gene', (89, 93))	('CDK5', 'Gene', '1020', (89, 93))	('glioma', 'Disease', (143, 149))	('inhibiting', 'NegReg', (15, 25))	('CDK9', 'Gene', '1025', (98, 102))	('SNS-032', 'Var', (125, 132))	('SNS-032', 'Chemical', 'MESH:C484864', (125, 132))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('CDK2', 'Gene', '1017', (83, 87))	('U87', 'CellLine', 'CVCL:0022', (194, 197))	('hypoxia', 'Disease', (162, 169))
54201	29844863	In primary acute myeloid leukemia (ALM) SNS-032 acts in a synergistic fashion toward the deoxycytidine memetic drug Cytarabine, and it is also known that AML sensitivity, and patient outcome with cytarabine therapy, is linked to polymorphisms in nucleotide excision repair genes.	('linked', 'Reg', (219, 225))	('deoxycytidine', 'Chemical', 'MESH:D003841', (89, 102))	('SNS-032', 'Chemical', 'MESH:C484864', (40, 47))	('leukemia', 'Phenotype', 'HP:0001909', (25, 33))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (17, 33))	('AML', 'Disease', 'MESH:D015470', (154, 157))	('Cytarabine', 'Chemical', 'MESH:D003561', (116, 126))	('patient', 'Species', '9606', (175, 182))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (11, 33))	('SNS-032', 'Gene', (40, 47))	('cytarabine', 'Chemical', 'MESH:D003561', (196, 206))	('AML', 'Disease', (154, 157))	('acute myeloid leukemia', 'Disease', (11, 33))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (11, 33))	('polymorphisms', 'Var', (229, 242))	('synergistic fashion', 'MPA', (58, 77))	('deoxycytidine memetic drug Cytarabine', 'MPA', (89, 126))
54207	29844863	In Figure 4B and 4C, we show the viable cells numbers and levels of dead/dying observed in cells treated with SNS-032 and titrated with PAM-OBG.	('SNS-032', 'Chemical', 'MESH:C484864', (110, 117))	('levels of dead/dying', 'MPA', (58, 78))	('SNS-032', 'Var', (110, 117))
54236	29844863	PAM-OBG is a MAOB specific prodrug that generates O6BG and acrolein after enzymatic oxidation.	('O6BG', 'Chemical', 'MESH:C064976', (50, 54))	('acrolein', 'Chemical', 'MESH:D000171', (59, 67))	('MAOB', 'Gene', (13, 17))	('O6BG', 'Var', (50, 54))	('MAOB', 'Gene', '4129', (13, 17))
54242	29844863	Acrolein generated by PAM-OBG potentiates the toxicities of alkylating agents BCNU and TMZ and we demonstrate that the acrolein generated ICLs are normally repaired by the glioma translational NER pathway.	('TMZ', 'Chemical', 'MESH:D000077204', (87, 90))	('ICL', 'Disease', (138, 141))	('acrolein', 'Chemical', 'MESH:D000171', (119, 127))	('Acrolein', 'Chemical', 'MESH:D000171', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('toxicities', 'Disease', (46, 56))	('potentiates', 'PosReg', (30, 41))	('ICL', 'Disease', 'MESH:D018344', (138, 141))	('PAM-OBG', 'Var', (22, 29))	('glioma', 'Disease', (172, 178))	('toxicities', 'Disease', 'MESH:D064420', (46, 56))	('BCNU', 'Chemical', 'MESH:D002330', (78, 82))
54244	29844863	The increased survival of animals treated with PAM-OBG and TMZ/radiation is due to the generation of O6BG, inhibiting MGMT, increasing the steady state level of TMZ-induced O6MeG in DNA and also to the formation of acrolein adducts.	('acrolein', 'MPA', (215, 223))	('increased', 'PosReg', (4, 13))	('TMZ', 'Chemical', 'MESH:D000077204', (161, 164))	('acrolein', 'Chemical', 'MESH:D000171', (215, 223))	('TMZ-induced O6MeG', 'MPA', (161, 178))	('MGMT', 'Gene', '4255', (118, 122))	('MGMT', 'Gene', (118, 122))	('survival', 'CPA', (14, 22))	('adducts', 'Interaction', (224, 231))	('O6BG', 'Var', (101, 105))	('inhibiting', 'NegReg', (107, 117))	('O6MeG', 'Chemical', 'MESH:C008449', (173, 178))	('increasing', 'PosReg', (124, 134))	('O6BG', 'Chemical', 'MESH:C064976', (101, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
54272	29844863	The emission of FITC-labeled MGMT was collected using ex 450-490 nm, em 500-550 nm and Hoechst 33342 using ex 325-375 nm, em 435-485 nm.	('MGMT', 'Gene', '4255', (29, 33))	('FITC', 'Chemical', 'MESH:D016650', (16, 20))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (87, 100))	('MGMT', 'Gene', (29, 33))	('ex 450-490 nm', 'Var', (54, 67))
54274	29844863	Active MGMT was labeled by incubating cells with 100 microM O6PGG for 10 minutes, prior to fixation.	('MGMT', 'Gene', '4255', (7, 11))	('MGMT', 'Gene', (7, 11))	('O6PGG', 'Var', (60, 65))	('O6PGG', 'Chemical', '-', (60, 65))
54367	22914772	Using a dual-labeled cyclic RGD motif for NIR fluorescence (NIRF) imaging (IRDye 800CW) and gamma scintigraphy (111In), the NIRF from IRDye 800CW provided greater signal to noise than the radiotracer 111In.	('greater', 'PosReg', (155, 162))	('signal to noise', 'MPA', (163, 178))	('IRDye 800CW', 'Var', (134, 145))	('800CW', 'Chemical', '-', (81, 86))	('800CW', 'Chemical', '-', (140, 145))
54388	22914772	The TS543 glioblastoma model was developed from a human patient with the PDGFRA gene amplification, and has been used to investigate the function of glioblastoma-associated oncogenes/tumor suppressor genes and microRNA, as well as response to receptor tyrosine kinase inhibitors.	('glioblastoma', 'Disease', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('PDGFRA', 'Gene', (73, 79))	('glioblastoma', 'Disease', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('PDGFRA', 'Gene', '5156', (73, 79))	('amplification', 'Var', (85, 98))	('tumor', 'Disease', (183, 188))	('glioblastoma', 'Disease', 'MESH:D005909', (10, 22))	('patient', 'Species', '9606', (56, 63))	('human', 'Species', '9606', (50, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
54405	22914772	NIRF-800 images from ventral view showed that IRDye 800CW-RGD probe accumulated in the bladder, indicating renal clearance of the agent.	('renal', 'MPA', (107, 112))	('IRDye 800CW-RGD', 'Var', (46, 61))	('800CW', 'Chemical', '-', (52, 57))
54427	22914772	4C), even the Fluorescence-800 from the IRDye 800CW-RGD peptide in the tumor area was very low.	('low', 'NegReg', (91, 94))	('IRDye 800CW-RGD', 'Var', (40, 55))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Fluorescence-800', 'MPA', (14, 30))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('800CW', 'Chemical', '-', (46, 51))	('tumor', 'Disease', (71, 76))	('peptide', 'Chemical', 'MESH:D010455', (56, 63))
54431	22914772	The images from this high-resolution laser scanner confirmed that the IRDye 800CW-RGD probe had accumulated in the integrin beta3-high glioblastoma tissue (Fig.	('accumulated', 'PosReg', (96, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('800CW', 'Chemical', '-', (76, 81))	('glioblastoma', 'Disease', (135, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('IRDye 800CW-RGD', 'Var', (70, 85))
54448	22914772	The NIR fluorophores include cyanine analogs (such as Cy5, Cy5.5, and Cy7) and fluorescent nanoparticles (such as semiconductor nanocrystals, i.e.	('Cy5', 'Var', (54, 57))	('Cy7', 'Chemical', '-', (70, 73))	('Cy5', 'Chemical', 'MESH:C085321', (54, 57))	('Cy5.5', 'Var', (59, 64))	('cyanine', 'Chemical', 'MESH:C009469', (29, 36))	('Cy5', 'Chemical', 'MESH:C085321', (59, 62))	('semiconductor nanocrystals', 'Disease', 'None', (114, 140))	('semiconductor nanocrystals', 'Disease', (114, 140))	('Cy7', 'Var', (70, 73))
54453	22914772	In addition, the uptake and retention of quantum dots in other organs (e.g., spleen, liver and lung), and the potential toxicity may provide obstacles to further clinical applications.	('uptake', 'MPA', (17, 23))	('toxicity', 'Disease', 'MESH:D064420', (120, 128))	('toxicity', 'Disease', (120, 128))	('quantum dots', 'Var', (41, 53))
54454	22914772	IRDye 800CW (Ex/Em=774/805 nm) is a good candidate because the RGD peptides coupled with IRDye 800CW showed deeper tissue penetration, less scattering, and lower background fluorescence compared to Cy5.5 (Ex/Em=675/694 nm) and Cy7 (Ex/Em=743/767 nm) in a U-87 MG subcutaneous tumor model, as well as a M21 melanoma model.	('less', 'NegReg', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('800CW', 'Chemical', '-', (95, 100))	('scattering', 'MPA', (140, 150))	('melanoma', 'Disease', (306, 314))	('800CW', 'Chemical', '-', (6, 11))	('Cy7', 'Chemical', '-', (227, 230))	('melanoma', 'Disease', 'MESH:D008545', (306, 314))	('peptide', 'Chemical', 'MESH:D010455', (67, 74))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (263, 281))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('background fluorescence', 'MPA', (162, 185))	('tumor', 'Disease', (276, 281))	('Cy5', 'Chemical', 'MESH:C085321', (198, 201))	('IRDye 800CW', 'Var', (89, 100))	('deeper', 'PosReg', (108, 114))	('lower', 'NegReg', (156, 161))
54461	22914772	This would also allow for fluorescence multiplexing, by combining the IRDye 800CW with other NIR fluorophores with different emission wavelengths.	('allow', 'Reg', (16, 21))	('800CW', 'Chemical', '-', (76, 81))	('IRDye 800CW', 'Var', (70, 81))	('fluorescence', 'MPA', (26, 38))
54462	22914772	Ex vivo binding assays also showed that the IRDye 800CW-RGD peptide had significantly higher affinity to integrin receptors than the nonspecific peptide (IRDye 800CW-RAD), and ex vivo blocking assays confirmed that the receptor binding of IRDye 800CW-RGD peptide was saturable.	('800CW', 'Chemical', '-', (160, 165))	('affinity', 'Interaction', (93, 101))	('peptide', 'Chemical', 'MESH:D010455', (60, 67))	('IRDye 800CW-RGD', 'Var', (239, 254))	('IRDye 800CW-RGD', 'Var', (44, 59))	('peptide', 'Chemical', 'MESH:D010455', (255, 262))	('higher', 'PosReg', (86, 92))	('integrin receptors', 'Protein', (105, 123))	('peptide', 'Chemical', 'MESH:D010455', (145, 152))	('800CW', 'Chemical', '-', (245, 250))	('800CW', 'Chemical', '-', (50, 55))
54463	22914772	We have also demonstrated the selective retention and long-lasting tumor accumulation of the IRDye 800CW-RGD peptide in the integrin beta3-high glioblastomas, both in vivo and ex vivo.	('800CW', 'Chemical', '-', (99, 104))	('glioblastomas', 'Phenotype', 'HP:0012174', (144, 157))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('peptide', 'Chemical', 'MESH:D010455', (109, 116))	('glioblastomas', 'Disease', 'MESH:D005909', (144, 157))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('glioblastomas', 'Disease', (144, 157))	('tumor', 'Disease', (67, 72))	('IRDye 800CW-RGD', 'Var', (93, 108))
54464	22914772	Noninvasive dynamic NIRF imaging showed rapid clearance of the IRDye 800CW-RGD peptide in the brains of normal mice and high tumor-targeting of the IRDye 800CW-RGD peptide in the glioblastoma-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('IRDye 800CW-RGD', 'Var', (148, 163))	('800CW', 'Chemical', '-', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('glioblastoma', 'Disease', (179, 191))	('clearance', 'CPA', (46, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', (125, 130))	('peptide', 'Chemical', 'MESH:D010455', (164, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('mice', 'Species', '10090', (200, 204))	('IRDye 800CW-RGD', 'Var', (63, 78))	('peptide', 'Chemical', 'MESH:D010455', (79, 86))	('800CW', 'Chemical', '-', (154, 159))
54474	22914772	demonstrated in a Phase III trial that 5-ALA/PpIX fluorescence-assisted neurosurgical resection of gliomas led to a significantly higher frequency of compete resections (MRI contrast-enhancing tumor area) as compared to the conventionally operated white light resection group (65% versus 36%, respectively).	('PpIX', 'Chemical', 'MESH:C028025', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('5-ALA/PpIX', 'Var', (39, 49))	('gliomas', 'Disease', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('5-ALA', 'Chemical', 'MESH:D000622', (39, 44))	('tumor', 'Disease', (193, 198))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
54477	22914772	For example, we were able to detect IRDye 800CW-RGD fluorescence from intracranial glioblastomas in intact animals, with photons having to penetrate the skull and skin.	('intracranial glioblastomas', 'Disease', (70, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('IRDye 800CW-RGD', 'Var', (36, 51))	('800CW', 'Chemical', '-', (42, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (83, 96))	('intracranial glioblastomas', 'Disease', 'MESH:D005909', (70, 96))
54501	33194713	We established a ROS-based drug efficacy evaluation network and experimentally validated the predicted effects, suggesting that modulating ROS metabolism improves treatment sensitivity and expands drug application scopes.	('ROS', 'Gene', (139, 142))	('ROS', 'Chemical', 'MESH:D017382', (17, 20))	('modulating', 'Var', (128, 138))	('improves', 'PosReg', (154, 162))	('treatment sensitivity', 'CPA', (163, 184))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))
54513	33194713	Considerable evidence has shown that ROS dysregulation activates oncogenic pathways and promotes phenotypic transformation to a malignant state.	('promotes', 'PosReg', (88, 96))	('ROS', 'Gene', (37, 40))	('activates', 'PosReg', (55, 64))	('dysregulation', 'Var', (41, 54))	('oncogenic pathways', 'Pathway', (65, 83))	('ROS', 'Chemical', 'MESH:D017382', (37, 40))	('phenotypic transformation', 'CPA', (97, 122))
54520	33194713	Therefore, ROS modulation is a promising strategy to improve the therapeutic efficacy of established treatments.	('ROS', 'Protein', (11, 14))	('modulation', 'Var', (15, 25))	('ROS', 'Chemical', 'MESH:D017382', (11, 14))
54596	33194713	Considering the lower ROS accumulation in LN229 than in U87, LN229 displayed a higher mitochondria/cytoplasmic ratio (index V) (Figure 1D).	('LN229', 'CellLine', 'CVCL:0393', (42, 47))	('LN229', 'Var', (61, 66))	('U87', 'Gene', (56, 59))	('U87', 'Gene', '641648', (56, 59))	('LN229', 'Var', (42, 47))	('mitochondria/cytoplasmic ratio', 'MPA', (86, 116))	('ROS accumulation', 'MPA', (22, 38))	('LN229', 'CellLine', 'CVCL:0393', (61, 66))	('higher', 'PosReg', (79, 85))	('lower', 'NegReg', (16, 21))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))
54637	33194713	Cluster I was characterized by enrichment of mutations in IDH1 (52%, FDR = 1.42 x 10-8) and ATRX (27%, FDR = 0.0232), consistent with their predominance in glioma samples.	('Cluster', 'Species', '68295', (0, 7))	('ATRX', 'Gene', (92, 96))	('mutations', 'Var', (45, 54))	('IDH1', 'Gene', '3417', (58, 62))	('glioma', 'Disease', (156, 162))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('IDH1', 'Gene', (58, 62))
54642	33194713	Featured up-regulated miRNA varied from 144 in cluster I to 0 in cluster III, while down-regulated RNA varied from 106 in cluster IV to 0 in cluster III and cluster V. Interestingly, we observed that featured miRNAs activating (miR-128, FDR = 2.78 x 10-3) or suppressing (miR-146, FDR = 2.95 x 10-3 and miR-27, FDR = 1.33 x 10-11) NF-kappaB were, respectively, up- or down-regulated in cluster I.	('miR-128', 'Var', (228, 235))	('cluster', 'Species', '68295', (122, 129))	('suppressing', 'NegReg', (259, 270))	('cluster V', 'Species', '68295', (157, 166))	('cluster', 'Species', '68295', (65, 72))	('FDR =', 'Var', (237, 242))	('cluster', 'Species', '68295', (141, 148))	('activating', 'PosReg', (216, 226))	('cluster', 'Species', '68295', (157, 164))	('NF-kappaB', 'Gene', '4790', (331, 340))	('cluster', 'Species', '68295', (386, 393))	('miR-27', 'Var', (303, 309))	('down-regulated', 'NegReg', (368, 382))	('up-', 'PosReg', (361, 364))	('miR-146', 'Var', (272, 279))	('cluster', 'Species', '68295', (47, 54))	('NF-kappaB', 'Gene', (331, 340))
54647	33194713	The multi-omics alterations would lead to functional changes of tumor samples and functional enrichment analysis, indicating that homogenous clusters tended to have more characteristic GO alterations than heterogeneous clusters.	('cluster', 'Species', '68295', (219, 226))	('tumor', 'Disease', (64, 69))	('cluster', 'Species', '68295', (141, 148))	('alterations', 'Var', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
54675	33194713	If an index II correlated drug's IC50 was greater than the safety concentration, anti-oxidant inhibitors could be combined to abolish normal ROS responses and force cells into oxidative stress (Figure 5E).	('ROS', 'Chemical', 'MESH:D017382', (141, 144))	('normal ROS responses', 'MPA', (134, 154))	('force', 'Reg', (159, 164))	('IC50', 'Var', (33, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (176, 192))	('abolish', 'NegReg', (126, 133))
54682	33194713	Similar to the U87 cell line, low concentrations of H2O2 could diminish the anti-tumor effect in U251 and LN229 cell lines (Supplementary Figures 4A,C).	('U87', 'Gene', (15, 18))	('H2O2', 'Var', (52, 56))	('H2O2', 'Chemical', 'MESH:D006861', (52, 56))	('U251', 'CellLine', 'CVCL:0021', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('U87', 'Gene', '641648', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('LN229', 'CellLine', 'CVCL:0393', (106, 111))	('tumor', 'Disease', (81, 86))	('diminish', 'NegReg', (63, 71))
54687	33194713	We found that although bortezomib inhibited tumor growth, the administration of H2O2 fully abolished the established antitumor effects (Figures 6C,D).	('bortezomib', 'Chemical', 'MESH:D000069286', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('H2O2', 'Chemical', 'MESH:D006861', (80, 84))	('H2O2', 'Var', (80, 84))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('abolished', 'NegReg', (91, 100))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
54699	33194713	Aberrant ROS production and scavenging are key tumor characteristics for maintaining optimal redox homeostasis.	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ROS production', 'MPA', (9, 23))	('tumor', 'Disease', (47, 52))
54733	33194713	Multi-omics analyses suggested that recurrent oncogenic molecular events in cluster I, e. g., IDH1 mutation and EGFR amplification, reprogrammed tumors to a ROS promoting status.	('EGFR', 'Gene', (112, 116))	('ROS', 'Chemical', 'MESH:D017382', (157, 160))	('IDH1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('IDH1', 'Gene', '3417', (94, 98))	('tumors', 'Disease', (145, 151))	('mutation', 'Var', (99, 107))	('cluster', 'Species', '68295', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('EGFR', 'Gene', '1956', (112, 116))	('amplification', 'Var', (117, 130))
54735	33194713	For cancers like ESCA and KIRC, patients with high ROS accumulation have also shown reduced survival time compared to their counterparts (Figure 3G).	('high', 'Var', (46, 50))	('survival time', 'CPA', (92, 105))	('ESCA', 'Disease', (17, 21))	('patients', 'Species', '9606', (32, 40))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('ROS', 'Protein', (51, 54))	('KIRC', 'Disease', (26, 30))	('reduced', 'NegReg', (84, 91))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
54784	32383980	Users are provided with all results in the form of hypertext markup language (HTML) reports that are generated in an automated manner for individual cohorts using Imaging-AMARETTO and multiple cohorts using Imaging-Community-AMARETTO.	('Imaging-AMARETTO', 'Var', (163, 179))	('hypertext markup language', 'Disease', (51, 76))	('hypertext markup language', 'Disease', 'MESH:D007806', (51, 76))
54819	31969485	Here we describe that the expression of Tau, a gene classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wild-type and mutant IDH1/2 in gliomas.	('expression', 'MPA', (26, 36))	('IDH1/2', 'Gene', '3417;3418', (181, 187))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('gliomas', 'Disease', (191, 198))	('neurodegenerative diseases', 'Disease', (80, 106))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (80, 106))	('Tau', 'Gene', '4137', (40, 43))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('IDH1/2', 'Gene', (181, 187))	('Tau', 'Gene', (40, 43))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (80, 106))	('mutant', 'Var', (174, 180))
54820	31969485	Moreover, Tau is almost absent from tumors with EGFR mutations, whereas its expression is inversely correlated with overall survival in gliomas carrying wild-type or amplified EGFR.	('amp', 'Chemical', 'MESH:D000249', (166, 169))	('Tau', 'Gene', (10, 13))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('EGFR', 'Gene', (48, 52))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('mutations', 'Var', (53, 62))	('gliomas', 'Disease', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('Tau', 'Gene', '4137', (10, 13))	('expression', 'MPA', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
54822	31969485	However, mutant EGFR induces a constitutive activation of this pathway, which is no longer sensitive to Tau.	('Tau', 'Gene', (104, 107))	('mutant', 'Var', (9, 15))	('activation', 'PosReg', (44, 54))	('EGFR', 'Gene', (16, 20))	('Tau', 'Gene', '4137', (104, 107))
54830	31969485	Particularly, the identification of mutations in the IDH1/2 (Isocitrate dehydrogenase 1/2) genes, which are associated with a more favorable prognosis in gliomas, is common now in the routine clinical practice.	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH1/2', 'Gene', (53, 59))	('mutations', 'Var', (36, 45))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('associated', 'Reg', (108, 118))	('gliomas', 'Disease', (154, 161))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('IDH1/2', 'Gene', '3417;3418', (53, 59))
54831	31969485	IDH1/2 mutated proteins induce the accumulation of the oncometabolite, 2-D-hydroxyglutarate (2-HG), which competes with the alpha-ketoglutarate (alpha-KG) produced by the wild-type IDH enzymes and blocks TET (Ten Eleven Translocation)-mediated DNA demethylation.	('2-HG', 'Chemical', '-', (93, 97))	('alpha-KG', 'Chemical', 'MESH:D007656', (145, 153))	('blocks', 'NegReg', (197, 203))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('accumulation', 'PosReg', (35, 47))	('proteins', 'Protein', (15, 23))	('2-D-hydroxyglutarate', 'Chemical', '-', (71, 91))	('IDH1/2', 'Gene', (0, 6))	('TET', 'Chemical', '-', (204, 207))	('mutated', 'Var', (7, 14))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (124, 143))
54833	31969485	Therefore, it has been proposed that the balance between the wild-type and the mutant IDH1/2 function determines the clinical outcome of gliomas, including their sensitivity to radiation and chemotherapy.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (162, 186))	('mutant', 'Var', (79, 85))	('IDH1/2', 'Gene', '3417;3418', (86, 92))	('determines', 'Reg', (102, 112))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('IDH1/2', 'Gene', (86, 92))
54834	31969485	Within the new subclasses of high grade gliomas (proneural (PN), classic (CL) or mesenchymal (MES)), IDH1/2 mutations are accumulated in the first group, which is enriched in secondary GB and includes tumors with a better clinical prognosis.	('MES', 'Chemical', '-', (94, 97))	('mutations', 'Var', (108, 117))	('IDH1/2', 'Gene', (101, 107))	('GB', 'Phenotype', 'HP:0012174', (185, 187))	('PN', 'Gene', '79650', (60, 62))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('CL', 'Disease', 'None', (74, 76))	('IDH1/2', 'Gene', '3417;3418', (101, 107))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
54835	31969485	Mutations in EGFR (Epidermal growth factor receptor), by contrast, accumulate in the CL and MES subtypes.	('Epidermal growth factor receptor', 'Gene', '1956', (19, 51))	('Mutations', 'Var', (0, 9))	('CL', 'Disease', 'None', (85, 87))	('MES', 'Chemical', '-', (92, 95))	('EGFR', 'Gene', (13, 17))	('Epidermal growth factor receptor', 'Gene', (19, 51))
54846	31969485	Therefore, we propose a novel role for Tau, acting downstream of IDH mutations in gliomas, to orchestrate the vascular phenotype and the aggressiviness of these tumors.	('mutations', 'Var', (69, 78))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH', 'Gene', (65, 68))	('tumors', 'Disease', (161, 167))	('Tau', 'Gene', '4137', (39, 42))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('aggressiviness', 'Disease', 'None', (137, 151))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('aggressiviness', 'Disease', (137, 151))	('Tau', 'Gene', (39, 42))
54855	31969485	Collectively, these results support the idea that Tau expression is associated with a less aggressive behavior of gliomas, independently of the tumor grade.	('tumor', 'Disease', (144, 149))	('associated with', 'Reg', (68, 83))	('Tau', 'Gene', '4137', (50, 53))	('expression', 'Var', (54, 64))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('aggressive behavior', 'Phenotype', 'HP:0000718', (91, 110))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('aggressive behavior of gliomas', 'Disease', 'MESH:D001523', (91, 121))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('aggressive behavior of gliomas', 'Disease', (91, 121))	('Tau', 'Gene', (50, 53))
54867	31969485	We analyzed the genetic background of gliomas in relation to the levels of Tau (MAPT) and we found that IDH1 mutations accumulate in high-Tau gliomas (Fig.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('MAPT', 'Gene', '4137', (80, 84))	('gliomas', 'Disease', (142, 149))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('MAPT', 'Gene', (80, 84))	('Tau', 'Gene', (138, 141))	('Tau', 'Gene', '4137', (75, 78))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('Tau', 'Gene', (75, 78))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('mutations', 'Var', (109, 118))	('Tau', 'Gene', '4137', (138, 141))	('IDH1', 'Gene', (104, 108))	('gliomas', 'Disease', (38, 45))	('accumulate', 'PosReg', (119, 129))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
54868	31969485	Furthermore, Tau protein was detected in the majority of tumor cells that express the most common IDH1 mutation (R132H) (Supplementary Fig.	('R132H', 'Mutation', 'rs121913500', (113, 118))	('Tau', 'Gene', '4137', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IDH1', 'Gene', (98, 102))	('R132H', 'Var', (113, 118))	('tumor', 'Disease', (57, 62))	('Tau', 'Gene', (13, 16))
54870	31969485	We then quantified the amount of Tau IHC staining in wild-type and mutant IDH gliomas and we found a clear enrichment of high and medium stained sections in the second group (Fig.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('Tau', 'Gene', '4137', (33, 36))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('IDH gliomas', 'Disease', 'MESH:D005910', (74, 85))	('mutant', 'Var', (67, 73))	('Tau', 'Gene', (33, 36))	('IDH gliomas', 'Disease', (74, 85))
54871	31969485	These results suggest that there is a strong correlation between the presence of IDH mutations and the expression of Tau.	('expression', 'MPA', (103, 113))	('Tau', 'Gene', (117, 120))	('mutations', 'Var', (85, 94))	('IDH', 'Gene', (81, 84))	('Tau', 'Gene', '4137', (117, 120))
54874	31969485	In order to confirm the relationship between Tau and IDH mut, we analyzed a recently published glioma model, in which IDH1 wt or IDH R132H had been expressed in an ATRX mutant background.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('ATRX', 'Gene', (164, 168))	('Tau', 'Gene', (45, 48))	('glioma', 'Disease', (95, 101))	('ATRX', 'Gene', '546', (164, 168))	('R132H', 'Var', (133, 138))	('Tau', 'Gene', '4137', (45, 48))	('R132H', 'Mutation', 'rs121913500', (133, 138))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
54875	31969485	As expected, there was a clear delay in the tumor growth after the expression of mutant IDH1 (Fig.	('IDH1', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('delay', 'NegReg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutant', 'Var', (81, 87))	('tumor', 'Disease', (44, 49))
54876	31969485	Moreover, when we dissected out the intracranial tumors we measured a clear increase in Tau protein levels in the mutant compared to the wild-type allografts (Fig.	('intracranial tumors', 'Disease', 'MESH:D001932', (36, 55))	('Tau', 'Gene', '4137', (88, 91))	('increase', 'PosReg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('mutant', 'Var', (114, 120))	('intracranial tumors', 'Disease', (36, 55))	('Tau', 'Gene', (88, 91))
54877	31969485	These results suggest that the expression of Tau in gliomas is induced by mutant IDH proteins.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('Tau', 'Gene', (45, 48))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('expression', 'MPA', (31, 41))	('Tau', 'Gene', '4137', (45, 48))	('IDH', 'Gene', (81, 84))	('mutant', 'Var', (74, 80))	('induced', 'Reg', (63, 70))
54881	31969485	These results support a model in which Tau promoter might be controlled by the epigenetic changes induced by IDH mutations.	('controlled', 'Reg', (61, 71))	('Tau', 'Gene', '4137', (39, 42))	('mutations', 'Var', (113, 122))	('IDH', 'Gene', (109, 112))	('Tau', 'Gene', (39, 42))
54883	31969485	Using epigenetic data from the TCGA (LGG cohort) we compared the methylation of the whole promoter region in mutant vs wild-type IDH tumors.	('IDH tumors', 'Disease', (129, 139))	('LGG', 'Chemical', '-', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('compared', 'Reg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('IDH tumors', 'Disease', 'MESH:D009369', (129, 139))	('mutant', 'Var', (109, 115))
54885	31969485	In order to obtain an independent confirmation of the epigenetic upregulation of Tau (MAPT) in response to mutant IDH, we treated primary GB cells with 2-HG and we observed a dose-dependent accumulation of its mRNA (Supplementary Fig.	('2-HG', 'Chemical', '-', (152, 156))	('MAPT', 'Gene', '4137', (86, 90))	('mutant', 'Var', (107, 113))	('IDH', 'Gene', (114, 117))	('MAPT', 'Gene', (86, 90))	('Tau', 'Gene', '4137', (81, 84))	('GB', 'Phenotype', 'HP:0012174', (138, 140))	('accumulation', 'PosReg', (190, 202))	('Tau', 'Gene', (81, 84))
54887	31969485	In summary, these results strongly suggest that the increase in the methylation of the CpG:26 region, induced by IDH mutant proteins, changes the chromosomal insulator topology and the binding of CTCF to the Tau promoter, activating its transcription.	('CTCF', 'Gene', (196, 200))	('changes', 'Reg', (134, 141))	('Tau', 'Gene', '4137', (208, 211))	('proteins', 'Protein', (124, 132))	('increase', 'PosReg', (52, 60))	('binding', 'Interaction', (185, 192))	('transcription', 'MPA', (237, 250))	('mutant', 'Var', (117, 123))	('CTCF', 'Gene', '10664', (196, 200))	('methylation', 'MPA', (68, 79))	('chromosomal insulator topology', 'MPA', (146, 176))	('IDH', 'Gene', (113, 116))	('activating', 'PosReg', (222, 232))	('CpG:26', 'Gene', (87, 93))	('Tau', 'Gene', (208, 211))
54888	31969485	IDH1/2 mutations define a distinct subset of gliomas with a better outcome.	('mutations', 'Var', (7, 16))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH1/2', 'Gene', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
54891	31969485	These results allow us to propose that the epigenetic induction of Tau transcription might depend on the equilibrium between wild-type and mutant IDH expression.	('depend', 'Reg', (91, 97))	('Tau', 'Gene', '4137', (67, 70))	('IDH', 'Gene', (146, 149))	('epigenetic induction', 'MPA', (43, 63))	('mutant', 'Var', (139, 145))	('Tau', 'Gene', (67, 70))
54895	31969485	In addition, our in silico analysis indicated that IDH mutations, as well as higher levels of Tau are mutually exclusive with EGFR and PTEN mutations (Fig.	('mutations', 'Var', (55, 64))	('EGFR', 'Gene', (126, 130))	('PTEN', 'Gene', (135, 139))	('Tau', 'Gene', (94, 97))	('PTEN', 'Gene', '5728', (135, 139))	('IDH', 'Disease', (51, 54))	('mutations', 'Var', (140, 149))	('Tau', 'Gene', '4137', (94, 97))
54896	31969485	To interrogate if Tau could be modulating this signaling pathway, we expressed IDH wt or IDH R132H in a EGFR amplified cell line (RG1).	('Tau', 'Gene', (18, 21))	('amp', 'Chemical', 'MESH:D000249', (109, 112))	('R132H', 'Mutation', 'rs121913500', (93, 98))	('Tau', 'Gene', '4137', (18, 21))	('IDH R132H', 'Var', (89, 98))
54898	31969485	3d), IDH mut impaired tumor burden (Fig.	('IDH mut', 'Var', (5, 12))	('impaired tumor', 'Disease', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('impaired tumor', 'Disease', 'MESH:D060825', (13, 27))
54906	31969485	These models were generated by transforming subventricular zone (SVZ) progenitors from p16/p19 ko mice with retrovirus expressing either the wild-type or the variant III (vIII) isoform or the receptor.	('variant', 'Var', (158, 165))	('p19', 'Gene', '83430', (91, 94))	('p16', 'Gene', (87, 90))	('p19', 'Gene', (91, 94))	('p16', 'Gene', '13088', (87, 90))	('mice', 'Species', '10090', (98, 102))
54910	31969485	Similar results were obtained when we overexpressed Tau in two human primary cell lines, RG1 (EGFRamp) and 12o150 (EGFR amplified and mutated, EGFRmut).	('Tau', 'Gene', '4137', (52, 55))	('human', 'Species', '9606', (63, 68))	('amp', 'Chemical', 'MESH:D000249', (98, 101))	('amp', 'Chemical', 'MESH:D000249', (120, 123))	('mutated', 'Var', (134, 141))	('Tau', 'Gene', (52, 55))
54911	31969485	Tau expression impaired the growth of the EGFRamp cell line (Fig.	('Tau', 'Gene', (0, 3))	('impaired', 'NegReg', (15, 23))	('Tau', 'Gene', '4137', (0, 3))	('expression', 'Var', (4, 14))	('growth of the EGFRamp cell line', 'CPA', (28, 59))	('amp', 'Chemical', 'MESH:D000249', (46, 49))
54918	31969485	These data reinforce the notion that Tau opposes wild-type but not mutant EGFR signaling.	('EGFR', 'Gene', (74, 78))	('Tau', 'Gene', '4137', (37, 40))	('Tau', 'Gene', (37, 40))	('mutant', 'Var', (67, 73))
54946	31969485	Previous results from our group and others have show that, in comparison with PN cancer stem cells (CSCs), MES CSCs are more capable of glioma initiation, probably associated with their increased angiogenic capacity.	('glioma initiation', 'Disease', (136, 153))	('PN cancer', 'Disease', (78, 87))	('MES CSCs', 'Var', (107, 115))	('MES', 'Chemical', '-', (107, 110))	('more', 'PosReg', (120, 124))	('glioma initiation', 'Disease', 'MESH:D005910', (136, 153))	('PN cancer', 'Disease', 'MESH:C565820', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
54992	31969485	IDH1/2 mutations identify a genetically and clinically distinct glioma entity.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioma', 'Disease', (64, 70))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('mutations', 'Var', (7, 16))
54994	31969485	Indeed, the re-expression of IDH1 R132H in GB can reduce tumor growth (Fig.	('R132H', 'Mutation', 'rs121913500', (34, 39))	('reduce', 'NegReg', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IDH1 R132H', 'Var', (29, 39))	('GB', 'Phenotype', 'HP:0012174', (43, 45))	('tumor', 'Disease', (57, 62))
54995	31969485	However, the molecular basis for the tumor-suppressor functions of IDH mutations are unclear.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
54997	31969485	Based on our results we can propose that these mutant enzymes, acting through the increase in Tau expression, favor the normalization of the vasculature and impede the progression of the disease (Supplementary Fig.	('normalization of the vasculature', 'MPA', (120, 152))	('favor', 'PosReg', (110, 115))	('Tau', 'Gene', (94, 97))	('Tau', 'Gene', '4137', (94, 97))	('progression', 'CPA', (168, 179))	('increase', 'PosReg', (82, 90))	('impede', 'NegReg', (157, 163))	('mutant', 'Var', (47, 53))	('expression', 'MPA', (98, 108))
55002	31969485	Indeed, it has been recently shown that the non-mutated IDH1 is upregulated in primary GB in comparison with secondary GB or LGG, where it promotes aggressive growth and therapy resistance.	('primary GB', 'Disease', (79, 89))	('GB', 'Phenotype', 'HP:0012174', (119, 121))	('non-mutated', 'Var', (44, 55))	('upregulated', 'PosReg', (64, 75))	('therapy resistance', 'CPA', (170, 188))	('aggressive growth', 'CPA', (148, 165))	('GB', 'Phenotype', 'HP:0012174', (87, 89))	('LGG', 'Chemical', '-', (125, 128))	('promotes', 'PosReg', (139, 147))	('IDH1', 'Gene', (56, 60))
55003	31969485	From the moment that IDH1/2 mutations were identified in gliomas, it seemed clear that they represent early events in the process of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('IDH1/2', 'Gene', '3417;3418', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('tumor', 'Disease', (133, 138))	('IDH1/2', 'Gene', (21, 27))	('mutations', 'Var', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
55013	31969485	We propose that a similar mechanism could be operating in gliomas, but only in the absence of EGFR mutations.	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
55015	31969485	The data presented here further supports that EGFR mutations induce a constitutive activation of NF-kappaB, which would be unsensitive to microtubule modulators.	('mutations', 'Var', (51, 60))	('NF-kappaB', 'Gene', '4790', (97, 106))	('EGFR', 'Gene', (46, 50))	('NF-kappaB', 'Gene', (97, 106))	('activation', 'PosReg', (83, 93))
55021	31969485	It is well known that IDH mutant gliomas are characterized by a lesser extent of contrast enhancement than wild-type tumors, even if we only consider GB.	('IDH mutant', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('gliomas', 'Disease', (33, 40))	('tumors', 'Disease', (117, 123))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('contrast', 'MPA', (81, 89))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('GB', 'Phenotype', 'HP:0012174', (150, 152))
55028	31969485	However, this aggregation of Tau compromises its microtubule-stabilising functions (loss of physiological function), favoring the evolution of the pathology.	('evolution', 'MPA', (130, 139))	('favoring', 'PosReg', (117, 125))	('Tau', 'Gene', '4137', (29, 32))	('compromises', 'NegReg', (33, 44))	('Tau', 'Gene', (29, 32))	('microtubule-stabilising functions', 'MPA', (49, 82))	('aggregation', 'Var', (14, 25))
55048	31969485	Lentiviral vector to express shRNAs were: shCD248 (Sigma #SHCLNG-NM_020404: TRCN0000053455, TRCN0000053457, TRCN00000443679, TRCN00000429396, TRCN0000043782) and shTAZ (TRCN0000370006, TRCN0000370007).	('TRCN0000043782', 'Var', (142, 156))	('TRCN00000443679', 'Var', (108, 123))	('CD248', 'Gene', (44, 49))	('TAZ', 'Gene', '6901', (164, 167))	('TRCN0000053455', 'Var', (76, 90))	('TAZ', 'Gene', (164, 167))	('CD248', 'Gene', '57124', (44, 49))	('TRCN0000053457', 'Var', (92, 106))	('CL', 'Disease', 'None', (60, 62))	('TRCN0000370007', 'Var', (185, 199))	('TRCN0000370006', 'Var', (169, 183))
55049	31969485	Retroviral vectors used were pBabe-EGFR wt (#11011), MSCV-XZ066-GFP-EGFR vIII (#20737), pBabe-puro-Flag-IDH1 (#62923), pBabe-puro-Flag-IDH1-R132H (#62924) (Addgene) and pBabePuroTAZ-WT was a generous gift from Kun-Liang Guan.	('#62923', 'Var', (110, 116))	('pBabePuroTAZ-WT', 'Disease', (169, 184))	('#62924', 'Var', (147, 153))	('pBabePuroTAZ-WT', 'Disease', 'MESH:C536751', (169, 184))	('#20737', 'Var', (79, 85))	('R132H', 'Mutation', 'rs121913500', (140, 145))	('#11011', 'Var', (44, 50))
55084	31969485	Correlation values were independently calculated for IDH1 mutant or wild-type samples in the TCGA LGG cohort.	('amp', 'Chemical', 'MESH:D000249', (79, 82))	('mutant', 'Var', (58, 64))	('IDH1', 'Gene', (53, 57))	('LGG', 'Chemical', '-', (98, 101))
55085	31969485	ChIP-seq analysis using anti-CTCF antibody was performed from profiling in IDH1 mutant and wild-type glioma patient specimens and culture models (GSE70991).	('mutant', 'Var', (80, 86))	('glioma', 'Disease', (101, 107))	('IDH1', 'Gene', (75, 79))	('CTCF', 'Gene', (29, 33))	('patient', 'Species', '9606', (108, 115))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('CTCF', 'Gene', '10664', (29, 33))
55086	31969485	Briefly tdf files from GEO repository from both IDH1 mutant and wild-type samples were downloaded and visualized using IGV browser.	('IDH1', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (75, 78))	('mutant', 'Var', (53, 59))
55089	29487691	In this study, we first found that the expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was significantly higher in Grade III or Grade IV than that in Grade II in glioma (P = 0.007 and P < 0.001, respectively).	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('Grade IV', 'Var', (162, 170))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('TOPK', 'Gene', '55872', (115, 119))	('glioma', 'Disease', (196, 202))	('expression', 'MPA', (39, 49))	('higher', 'PosReg', (139, 145))	('TOPK', 'Gene', (115, 119))
55106	29487691	Temozolomide (TMZ), a first line chemotherapeutic drug for glioma patients, can induce DNA lesions including N7-MeG, N3-MeA and O6-MeG by DNA methylation, leading to DNA double strand breaks, thereby exerting its anti-cancer cytotoxicity.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('glioma', 'Disease', (59, 65))	('TMZ', 'Chemical', 'MESH:D000077204', (14, 17))	('MeG', 'Gene', '5775', (131, 134))	('cancer', 'Disease', (218, 224))	('MeG', 'Gene', (131, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (225, 237))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('MeG', 'Gene', '5775', (112, 115))	('DNA double strand breaks', 'MPA', (166, 190))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('MeG', 'Gene', (112, 115))	('patients', 'Species', '9606', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('N3-MeA', 'Var', (117, 123))	('cytotoxicity', 'Disease', (225, 237))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
55109	29487691	In addition to MGMT repair mechanism, mismatch repair and base excision repair are involved in TMZ resistance as well.	('mismatch', 'Var', (38, 46))	('MGMT', 'Gene', '4255', (15, 19))	('involved', 'Reg', (83, 91))	('MGMT', 'Gene', (15, 19))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))
55111	29487691	TOPK expression was closely associated with glioma grading, poor survival of glioma patients, cell proliferation and tumorigenesis of glioma, and more importantly, with chemotherapeutic resistance to TMZ.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('TMZ', 'Chemical', 'MESH:D000077204', (200, 203))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patients', 'Species', '9606', (84, 92))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('poor survival', 'CPA', (60, 73))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('associated', 'Reg', (28, 38))	('TOPK', 'Gene', (0, 4))	('glioma', 'Disease', (134, 140))	('cell proliferation', 'CPA', (94, 112))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('TOPK', 'Gene', '55872', (0, 4))	('tumor', 'Disease', (117, 122))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))
55118	29487691	Meanwhile, we examine the expression of Ki67, P53 and EGFR, common molecules associated with histological grade or prognosis in human glioma.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('P53', 'Gene', '7157', (46, 49))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', '1956', (54, 58))	('P53', 'Gene', (46, 49))	('human', 'Species', '9606', (128, 133))	('glioma', 'Disease', (134, 140))	('Ki67', 'Var', (40, 44))	('Ki67', 'Chemical', '-', (40, 44))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
55120	29487691	Our results also showed that Ki67 was significantly increased in Grade III or Grade IV glioma compared to Grade II glioma (P = 0.0003 and P < 0.0001, respectively) (Figure 1B).	('glioma', 'Disease', (87, 93))	('glioma', 'Disease', (115, 121))	('increased', 'PosReg', (52, 61))	('II glioma', 'Disease', (112, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('II glioma', 'Disease', 'MESH:D005910', (112, 121))	('Grade III', 'Disease', (65, 74))	('Ki67', 'Var', (29, 33))	('Ki67', 'Chemical', '-', (29, 33))
55121	29487691	EGFR gene amplification is one of the most frequent genetic alterations observed in glioma, and EGFR expression generally correlates with WHO grade in gliomas.	('EGFR', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('EGFR', 'Gene', (96, 100))	('glioma', 'Disease', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('correlates with', 'Reg', (122, 137))	('amplification', 'Var', (10, 23))	('expression', 'MPA', (101, 111))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('gliomas', 'Disease', (151, 158))	('EGFR', 'Gene', '1956', (0, 4))	('glioma', 'Disease', (151, 157))	('EGFR', 'Gene', '1956', (96, 100))
55122	29487691	P53 mutations were found in glioblastomas, astrocytomas and anaplastic astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (71, 83))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('found', 'Reg', (19, 24))	('astrocytomas', 'Disease', (71, 83))	('astrocytomas', 'Disease', (43, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('glioblastomas', 'Phenotype', 'HP:0012174', (28, 41))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('glioblastomas', 'Disease', 'MESH:D005909', (28, 41))	('mutations', 'Var', (4, 13))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))	('glioblastomas', 'Disease', (28, 41))
55123	29487691	Studies reported that mutant P53 was positively correlated with TOPK expression in cancer cell.	('P53', 'Gene', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('TOPK', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('P53', 'Gene', '7157', (29, 32))	('mutant', 'Var', (22, 28))	('TOPK', 'Gene', '55872', (64, 68))	('correlated', 'Reg', (48, 58))	('cancer', 'Disease', (83, 89))
55129	29487691	Results showed that levels of TOPK in U-87 MG or U-251 cells were higher than those in A-172, Hs 683 or U373 cells (Figure 2A).	('U-251', 'CellLine', 'CVCL:0021', (49, 54))	('TOPK', 'Gene', '55872', (30, 34))	('TOPK', 'Gene', (30, 34))	('U-87 MG', 'Var', (38, 45))	('U-251', 'Var', (49, 54))	('U373', 'CellLine', 'CVCL:2219', (104, 108))	('higher', 'PosReg', (66, 72))	('levels', 'MPA', (20, 26))
55130	29487691	Therefore, we used shRNAs to knock down TOPK in U-87 MG or U-251 cells (U-87 MG/shTOPK or U-251/shTOPK) and U-87 MG/shMock or U-251/shMock is control.	('U-251', 'CellLine', 'CVCL:0021', (90, 95))	('knock', 'Var', (29, 34))	('TOPK', 'Gene', (82, 86))	('TOPK', 'Gene', (98, 102))	('TOPK', 'Gene', '55872', (40, 44))	('U-251', 'CellLine', 'CVCL:0021', (126, 131))	('TOPK', 'Gene', '55872', (98, 102))	('TOPK', 'Gene', '55872', (82, 86))	('U-251', 'CellLine', 'CVCL:0021', (59, 64))	('TOPK', 'Gene', (40, 44))
55154	29487691	TMZ can induce DNA double strand breaks (DSBs).	('TMZ', 'Var', (0, 3))	('induce', 'Reg', (8, 14))	('DNA double strand breaks', 'MPA', (15, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
55158	29487691	H2AX+/+ MEF and H2AX-/- MEF cells were treated with TMZ, and we observed that knockout of H2AX promoted cell apoptosis (Figure 4F).	('H2AX', 'Gene', '3014', (90, 94))	('H2AX', 'Gene', (0, 4))	('promoted', 'PosReg', (95, 103))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('H2AX', 'Gene', (90, 94))	('knockout', 'Var', (78, 86))	('H2AX', 'Gene', '3014', (16, 20))	('MEF', 'Gene', '2000', (24, 27))	('H2AX', 'Gene', (16, 20))	('MEF', 'Gene', (24, 27))	('H2AX', 'Gene', '3014', (0, 4))	('cell apoptosis', 'CPA', (104, 118))	('MEF', 'Gene', '2000', (8, 11))	('MEF', 'Gene', (8, 11))
55162	29487691	Patients with high TOPK expression had a shorter median survival time (MST) and overall survival (OS) than patients with low TOPK expression.	('TOPK', 'Gene', (19, 23))	('median survival time', 'MPA', (49, 69))	('shorter', 'NegReg', (41, 48))	('overall survival', 'MPA', (80, 96))	('TOPK', 'Gene', '55872', (125, 129))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('TOPK', 'Gene', '55872', (19, 23))	('TOPK', 'Gene', (125, 129))	('patients', 'Species', '9606', (107, 115))
55166	29487691	We also compared the correlation between Ki67 expression and survival in the same patient samples, and the results indicated that patients with high Ki67 expression have poor survival outcome as well.	('Ki67', 'Gene', (149, 153))	('patient', 'Species', '9606', (130, 137))	('Ki67', 'Chemical', '-', (41, 45))	('patient', 'Species', '9606', (82, 89))	('high', 'Var', (144, 148))	('patients', 'Species', '9606', (130, 138))	('Ki67', 'Chemical', '-', (149, 153))
55172	29487691	The results indicated that patients with high levels of TOPK or Ki67 have at least two months' shorter survival time than those with low level of TOPK or Ki67 in TMZ-resistant patients (Figure 5C).	('Ki67', 'Chemical', '-', (64, 68))	('patients', 'Species', '9606', (176, 184))	('TOPK', 'Gene', '55872', (56, 60))	('Ki67', 'Chemical', '-', (154, 158))	('TMZ', 'Chemical', 'MESH:D000077204', (162, 165))	('TOPK', 'Gene', '55872', (146, 150))	('patients', 'Species', '9606', (27, 35))	('survival time', 'CPA', (103, 116))	('TOPK', 'Gene', (56, 60))	('TOPK', 'Gene', (146, 150))	('shorter', 'NegReg', (95, 102))	('Ki67', 'Var', (64, 68))
55176	29487691	The most frequent genetic alterations associated with glioma initiation and progression include mutation of isocitrate dehydrogenase 1/2 (IDH1/2), co-deletion of chromosomes 1p and 19q (1p/19q co-deletion), p53 mutation and EGFR amplification or mutation.	('co-deletion', 'Var', (147, 158))	('glioma initiation', 'Disease', 'MESH:D005910', (54, 71))	('mutation', 'Var', (246, 254))	('EGFR', 'Gene', (224, 228))	('mutation', 'Var', (211, 219))	('mutation', 'Var', (96, 104))	('p53', 'Gene', (207, 210))	('citrate', 'Chemical', 'MESH:D019343', (111, 118))	('IDH1/2', 'Gene', '3417;3418', (138, 144))	('p53', 'Gene', '7157', (207, 210))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('amplification', 'PosReg', (229, 242))	('glioma initiation', 'Disease', (54, 71))	('IDH1/2', 'Gene', (138, 144))	('EGFR', 'Gene', '1956', (224, 228))
55188	29487691	High TOPK expression is associated with poor outcome, and TOPK has been identified as prognostic marker in various cancer.	('cancer', 'Disease', (115, 121))	('TOPK', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('TOPK', 'Gene', '55872', (58, 62))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TOPK', 'Gene', '55872', (5, 9))	('TOPK', 'Gene', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
55189	29487691	Lung adenocarcinoma patients with high level of TOPK expression had shorter OS and time to recurrence when compared to patients with lower level of TOPK expression.	('TOPK', 'Gene', '55872', (48, 52))	('expression', 'Var', (53, 63))	('TOPK', 'Gene', '55872', (148, 152))	('patients', 'Species', '9606', (119, 127))	('Lung adenocarcinoma', 'Disease', (0, 19))	('TOPK', 'Gene', (48, 52))	('patients', 'Species', '9606', (20, 28))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('TOPK', 'Gene', (148, 152))	('high level', 'Var', (34, 44))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('shorter', 'NegReg', (68, 75))
55190	29487691	High level of TOPK expression was associated with poor progression-free survival (PFS) and OS in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('TOPK', 'Gene', '55872', (14, 18))	('poor', 'NegReg', (50, 54))	('ovarian cancer', 'Disease', (97, 111))	('progression-free survival', 'CPA', (55, 80))	('TOPK', 'Gene', (14, 18))	('High level', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))
55202	29487691	In the current study, we found that blocking TOPK expression promoted glioma cell apoptosis when treatment with TMZ in U-87 MG and U-251 cells.	('glioma', 'Disease', (70, 76))	('TOPK', 'Gene', '55872', (45, 49))	('U-251', 'CellLine', 'CVCL:0021', (131, 136))	('promoted', 'PosReg', (61, 69))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('TOPK', 'Gene', (45, 49))	('TMZ', 'Chemical', 'MESH:D000077204', (112, 115))	('blocking', 'Var', (36, 44))
55209	29487691	gamma-H2AX is required for the accumulation of DNA damage response (DDR) proteins and the defects of DNA damage repair response associated with downregulation of TOPK expression sensitized cells to TMZ treatment.	('defects', 'Var', (90, 97))	('TOPK', 'Gene', '55872', (162, 166))	('downregulation', 'NegReg', (144, 158))	('TMZ', 'Chemical', 'MESH:D000077204', (198, 201))	('TOPK', 'Gene', (162, 166))	('gamma-H2AX', 'Gene', (0, 10))	('gamma-H2AX', 'Gene', '3014', (0, 10))
55213	29487691	In this study, we demonstrated that TOPK was highly expressed in HGG, and high level of TOPK was significantly associated with TMZ resistance and poor survival in glioma patients.	('TOPK', 'Gene', (88, 92))	('patients', 'Species', '9606', (170, 178))	('glioma', 'Disease', (163, 169))	('TMZ resistance', 'MPA', (127, 141))	('associated', 'Reg', (111, 121))	('TOPK', 'Gene', '55872', (36, 40))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('TOPK', 'Gene', '55872', (88, 92))	('high level', 'Var', (74, 84))	('poor', 'NegReg', (146, 150))	('TMZ', 'Chemical', 'MESH:D000077204', (127, 130))	('TOPK', 'Gene', (36, 40))
55215	29487691	Either HI-032 treatment or TOPK knockdown can promote cell apoptosis to TMZ treatment.	('TOPK', 'Gene', '55872', (27, 31))	('promote', 'PosReg', (46, 53))	('cell apoptosis', 'CPA', (54, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (72, 75))	('knockdown', 'Var', (32, 41))	('TOPK', 'Gene', (27, 31))	('HI-032', 'Chemical', '-', (7, 13))
55236	29487691	Five shRNA sequences were designed to knock down TOPK.	('knock', 'Var', (38, 43))	('TOPK', 'Gene', (49, 53))	('TOPK', 'Gene', '55872', (49, 53))
55243	29487691	G418, puromycin, TMZ and HI-032 (an agonist binding to the active site of TOPK) were from Sigma (St. Louis, USA).	('TOPK', 'Gene', (74, 78))	('G418', 'Chemical', 'MESH:C010680', (0, 4))	('TOPK', 'Gene', '55872', (74, 78))	('G418', 'Var', (0, 4))	('TMZ', 'Chemical', 'MESH:D000077204', (17, 20))	('HI-032', 'Chemical', '-', (25, 31))	('puromycin', 'Chemical', 'MESH:D011691', (6, 15))
55273	22895403	The resection of brain tumors in peri-eloquent and eloquent brain regions is associated with increased risk of neurological impairment.	('brain tumors', 'Phenotype', 'HP:0030692', (17, 29))	('brain tumors', 'Disease', 'MESH:D001932', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('brain tumors', 'Disease', (17, 29))	('neurological impairment', 'Disease', 'MESH:D009422', (111, 134))	('neurological impairment', 'Phenotype', 'HP:0000707', (111, 134))	('brain tumor', 'Phenotype', 'HP:0030692', (17, 28))	('neurological impairment', 'Disease', (111, 134))	('resection', 'Var', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
55275	22895403	Moreover, studies of stroke patients suggest that damage to the white matter tracts may induce more severe deficits than would a cortical injury.	('stroke', 'Phenotype', 'HP:0001297', (21, 27))	('cortical injury', 'Disease', 'MESH:D001927', (129, 144))	('stroke', 'Disease', (21, 27))	('induce', 'Reg', (88, 94))	('stroke', 'Disease', 'MESH:D020521', (21, 27))	('damage', 'Var', (50, 56))	('patients', 'Species', '9606', (28, 36))	('cortical injury', 'Disease', (129, 144))
55288	22895403	It is our hypothesis that, since levels of functional connectivity correlate with IES mapping, one would also expect resection of highly connected regions to be associated with post-operative deficit.	('IES', 'Chemical', '-', (82, 85))	('functional connectivity', 'MPA', (43, 66))	('associated', 'Reg', (161, 171))	('resection', 'Var', (117, 126))
55376	22895403	IES of the temporal lobe posterior to the tumor elicited anomia.	('tumor', 'Disease', (42, 47))	('IES', 'Var', (0, 3))	('anomia', 'Disease', 'MESH:D000849', (57, 63))	('anomia', 'Phenotype', 'HP:0030784', (57, 63))	('IES', 'Chemical', '-', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('anomia', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
55382	22895403	We observed that in patients with decreased connectivity in the entire tumor volume, the probability of developing early neurological morbidity is 28.6%, while the probability of a long-term deficit is 0%.	('decreased', 'NegReg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('patients', 'Species', '9606', (20, 28))	('connectivity', 'Var', (44, 56))	('tumor', 'Disease', (71, 76))
55405	22895403	Our MEG results support this finding: the resection of an area of increased connectivity, even if located within a lesion, predicts a postoperative neurological deficit.	('neurological deficit', 'Phenotype', 'HP:0000707', (148, 168))	('increased', 'PosReg', (66, 75))	('resection', 'Var', (42, 51))	('postoperative neurological deficit', 'Disease', (134, 168))	('connectivity', 'MPA', (76, 88))	('predicts', 'Reg', (123, 131))	('postoperative neurological deficit', 'Disease', 'MESH:D009461', (134, 168))
55445	23577290	Results on extracted tumor tissues clearly demonstrate that ratio620/634 tends towards 0 in the solid component of glioblastomas (GBM), whereas it is higher than 1 in LGG and in the infiltrative component of GBM.	('glioblastomas', 'Disease', (115, 128))	('tumor', 'Disease', (21, 26))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('ratio620/634', 'Var', (60, 72))	('glioblastomas', 'Phenotype', 'HP:0012174', (115, 128))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('GBM', 'Phenotype', 'HP:0012174', (208, 211))	('glioblastomas', 'Disease', 'MESH:D005909', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
55455	23577290	Three experimental parameters are obtained: [PpIX620]eta620, [PpIX634]eta634, and also ratio620/634 which enables identification of non-uniqueness cases.	('PpIX', 'Chemical', 'MESH:C028025', (45, 49))	('eta', 'Gene', '1909', (70, 73))	('PpIX', 'Chemical', 'MESH:C028025', (62, 66))	('eta', 'Gene', (70, 73))	('eta', 'Gene', '1909', (53, 56))	('eta', 'Gene', (53, 56))	('ratio620/634', 'Var', (87, 99))
55496	23577290	2(b)) that at a constant [PpIX] and in the case of a decreasing ratio620/634, [PpIX634]eta634 increases very steeply while [PpIX620]eta620 is rather stable.	('PpIX', 'Chemical', 'MESH:C028025', (79, 83))	('PpIX', 'Chemical', 'MESH:C028025', (124, 128))	('eta', 'Gene', '1909', (132, 135))	('eta', 'Gene', '1909', (87, 90))	('ratio620/634', 'Var', (64, 76))	('increases', 'PosReg', (94, 103))	('eta', 'Gene', (87, 90))	('eta', 'Gene', (132, 135))	('PpIX', 'Chemical', 'MESH:C028025', (26, 30))
55514	23577290	The ratio620/634 could be useful not only as an indicator of non-uniqueness; the pH of tumor tissues strongly influences its value.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('influences', 'Reg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ratio620/634', 'Var', (4, 16))
55519	23577290	The ratio620/634 and [PpIX620]eta620 can significantly distinguish the solid component of GBM from the infiltrative component of GBM and LGG.	('PpIX', 'Chemical', 'MESH:C028025', (22, 26))	('solid component', 'Disease', (71, 86))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('GBM', 'Disease', (90, 93))	('eta', 'Gene', '1909', (30, 33))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('ratio620/634', 'Var', (4, 16))	('eta', 'Gene', (30, 33))	('distinguish', 'Reg', (55, 66))
55521	23577290	Fluorescent dyes are promising for intracellular pH measurement, and since the ratio620/634 is correlated to the pH, this method could give a new in vivo pH-sensitive indicator for tumor tissues.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('ratio620/634', 'Var', (79, 91))
55537	31927310	By correlating TP63 isoform expression with clinical outcomes, we find that while the DNp63 isoforms correlated with improved patient prognosis, the TAp63 isoforms correlated with worse patient prognosis in bladder, breast and lung cancers.	('TP63', 'Gene', '8626', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('bladder', 'Disease', (207, 214))	('breast and lung cancers', 'Disease', 'MESH:D001943', (216, 239))	('TAp63', 'Var', (149, 154))	('TP63', 'Gene', (15, 19))	('worse', 'NegReg', (180, 185))	('improved', 'PosReg', (117, 125))	('patient', 'Species', '9606', (126, 133))	('DNp63', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patient', 'Species', '9606', (186, 193))	('lung cancers', 'Phenotype', 'HP:0100526', (227, 239))
55557	31927310	In MIBC, TP63 expression has been shown to be correlated with induction of EMT and worse patient outcomes and expression of DNp63 was shown to identify basal-subtype bladder cancers with aggressive clinical courses and poor prognosis.	('TP63', 'Gene', '8626', (9, 13))	('bladder cancers', 'Disease', (166, 181))	('MIBC', 'Disease', (3, 7))	('patient', 'Species', '9606', (89, 96))	('TP63', 'Gene', (9, 13))	('bladder cancers', 'Disease', 'MESH:D001749', (166, 181))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('correlated', 'Reg', (46, 56))	('MIBC', 'Disease', 'MESH:D001749', (3, 7))	('bladder cancers', 'Phenotype', 'HP:0009725', (166, 181))	('bladder cancer', 'Phenotype', 'HP:0009725', (166, 180))	('DNp63', 'Gene', (124, 129))	('EMT', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('EMT', 'Gene', '3702', (75, 78))	('expression', 'Var', (110, 120))
55561	31927310	Using previously annotated, as well as, un-annotated TP63 isoforms, we show that DNp63 is the most commonly expressed isoform type in bladder cancer and most other cancer types in the TCGA and find that high expression is generally associated with improved patient outcomes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('improved', 'PosReg', (248, 256))	('TP63', 'Gene', '8626', (53, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patient', 'Species', '9606', (257, 264))	('TP63', 'Gene', (53, 57))	('cancer', 'Disease', (164, 170))	('DNp63', 'Var', (81, 86))	('bladder cancer', 'Disease', (134, 148))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))	('C', 'Chemical', 'MESH:D002244', (185, 186))	('cancer', 'Disease', (142, 148))
55562	31927310	Conversely, although less commonly expressed, TAp63 is associated with worse patient outcomes in bladder and other tumor types.	('TAp63', 'Var', (46, 51))	('bladder', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
55563	31927310	In bladder cancers, the favorable association of DNp63 was selectively observed in luminal tumors, whereas, the negative association of TAp63 was observed specifically in basal squamous tumor subtypes.	('squamous tumor', 'Disease', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('DNp63', 'Var', (49, 54))	('luminal tumors', 'Disease', 'MESH:D009369', (83, 97))	('bladder cancers', 'Disease', 'MESH:D001749', (3, 18))	('basal squamous tumor', 'Phenotype', 'HP:0002671', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('squamous tumor', 'Phenotype', 'HP:0002860', (177, 191))	('bladder cancers', 'Disease', (3, 18))	('luminal tumors', 'Disease', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('squamous tumor', 'Disease', 'MESH:D002294', (177, 191))	('bladder cancers', 'Phenotype', 'HP:0009725', (3, 18))
55582	31927310	For example, TAp63 isoform expression was calculated by adding together all TPM values for all TP63 isoforms with a 5p trans-activation domain (TAp63alpha, TAp63alphaP, TAp63beta, TAp63gamma, TAp63delta).	('TAp63gamma', 'Var', (180, 190))	('p63alpha', 'Gene', '8626', (158, 166))	('p63alpha', 'Gene', (158, 166))	('p63alpha', 'Gene', '8626', (146, 154))	('TP63', 'Gene', '8626', (95, 99))	('TAp63delta', 'Var', (192, 202))	('p63alpha', 'Gene', (146, 154))	('TAp63beta', 'Var', (169, 178))	('TP63', 'Gene', (95, 99))
55584	31927310	Initial investigation using Cox regression showed evidence of an association with survival in BLCA, BRCA, and LUSC patient cohorts with expression of TP63, DNp63, and TAp63 isoforms.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('BLCA', 'Disease', (94, 98))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('BRCA', 'Gene', '672', (100, 104))	('BRCA', 'Gene', (100, 104))	('association', 'Interaction', (65, 76))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('TAp63', 'Var', (167, 172))	('DNp63', 'Var', (156, 161))	('TP63', 'Gene', (150, 154))	('TP63', 'Gene', '8626', (150, 154))	('BLCA', 'Disease', 'MESH:D001749', (94, 98))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('patient', 'Species', '9606', (115, 122))
55586	31927310	Genes were rank-ordered by negative log10 p-value from a Wilcoxon test to quantify differences in patient gene expression for patients with high or low TP63 isoform expression with negative fold changes represented as a negative score for ranking.	('TP63', 'Gene', (152, 156))	('TP63', 'Gene', '8626', (152, 156))	('patient', 'Species', '9606', (98, 105))	('high', 'Var', (140, 144))	('patient', 'Species', '9606', (126, 133))	('patients', 'Species', '9606', (126, 134))	('low', 'NegReg', (148, 151))
55594	31927310	Pairing of the nonprime or prime forward primer with the alpha, beta or gamma reverse primer allowed amplification of nonprime or prime alpha, beta or gamma PCR product of (567, 572 and 427 base pairs) respectively if these transcripts were present in the cDNA pools used as template.	('C', 'Chemical', 'MESH:D002244', (158, 159))	('amplification', 'MPA', (101, 114))	('567', 'Var', (173, 176))
55628	31927310	These un-annotated isoform variants are closely related to DNp63alpha and DNp63beta but harbor a 4 amino acid alternative splice junction acceptor site at the 3' end of exon 8 resulting in an alternative exon 8-9 junction (Fig.	('variants', 'Var', (27, 35))	('amino', 'Chemical', 'MESH:D000596', (99, 104))	('alternative exon 8-9 junction', 'MPA', (192, 221))	('p63alpha', 'Gene', '8626', (61, 69))	('p63alpha', 'Gene', (61, 69))
55629	31927310	This alternative exon 8-9 junction is present in TAp63alpha and DNp63delta (NM_001329148 and NM_001329149) forms, but is not present in Refgene or Encode gene definitions as a variant of DNp63alpha or DNp63beta isoforms.	('p63alpha', 'Gene', '8626', (189, 197))	('p63alpha', 'Gene', (189, 197))	('NM_001329148', 'Var', (76, 88))	('p63alpha', 'Gene', '8626', (51, 59))	('p63alpha', 'Gene', (51, 59))	('NM_001329149', 'Var', (93, 105))
55630	31927310	Here we will refer to these isoforms as DNp63alphaP (DNp63alpha prime) and DNp63betaP (DNp63beta prime).	('p63alpha', 'Gene', '8626', (42, 50))	('p63alpha', 'Gene', (42, 50))	('p63alpha', 'Gene', '8626', (55, 63))	('p63alpha', 'Gene', (55, 63))	('DNp63betaP', 'Var', (75, 85))
55631	31927310	To confirm that the DNp63alphaP and DNp63betaP isoforms were truly expressed in human bladder cancer, we designed PCR primers specific to their unique 8a-9 or 8b-9 exon junctions and the exon 12-13 junction (unique to alpha isoforms), exon 12-14 junction (beta isoforms) and for the exon 11b-14 junction (delta isoforms) (Fig.	('bladder cancer', 'Disease', (86, 100))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('exon 11b-14', 'Var', (283, 294))	('human', 'Species', '9606', (80, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('p63alpha', 'Gene', '8626', (22, 30))	('p63alpha', 'Gene', (22, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))
55633	31927310	PCR products for both p63alpha, p63beta and p63delta non-prime and prime isoforms were detectable in UM-UC14 and UM-UC5 but not 253J or UM-UC10 control bladder cancer cells (Fig.	('C', 'Chemical', 'MESH:D002244', (117, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (152, 166))	('bladder cancer', 'Disease', (152, 166))	('p63beta', 'Var', (32, 39))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('p63delta', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('p63alpha', 'Gene', (22, 30))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('p63alpha', 'Gene', '8626', (22, 30))
55639	31927310	In bladder cancer, TP63 expression was dominated by DNp63 group isoforms (DNp63alpha, DNp63alphaP, DNp63beta, and DNp63betaP, DNp63gamma, DNp63delta, DNp63 deltaP) whereas TAp63 group isoforms (TAp63alpha, TAp63alphaP, TAp63beta, TAp63gamma and TAp63delta) were expressed in only a minority of patients (Fig.	('DNp63betaP', 'Var', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TP63', 'Gene', '8626', (19, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('p63alpha', 'Gene', '8626', (88, 96))	('p63alpha', 'Gene', '8626', (208, 216))	('DNp63beta', 'Var', (99, 108))	('p63alpha', 'Gene', (76, 84))	('DNp63delta', 'Var', (138, 148))	('p63alpha', 'Gene', '8626', (196, 204))	('p63alpha', 'Gene', (88, 96))	('p63alpha', 'Gene', (208, 216))	('DNp63gamma', 'Var', (126, 136))	('patients', 'Species', '9606', (294, 302))	('p63alpha', 'Gene', '8626', (76, 84))	('TP63', 'Gene', (19, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('p63alpha', 'Gene', (196, 204))
55641	31927310	In all three data sets, prime versions of DNp63alpha and DNp63beta demonstrated slightly less expression than non-prime analogs, although they were among the most highly expressed transcripts.	('DNp63beta', 'Var', (57, 66))	('p63alpha', 'Gene', '8626', (44, 52))	('expression', 'MPA', (94, 104))	('p63alpha', 'Gene', (44, 52))	('less', 'NegReg', (89, 93))
55653	31927310	Diseases with the highest TP63 gene level expression had, on average, the highest amounts of DNp63alpha, DNp63alphaP, DNp63beta and DNp63betaP with lower to moderate expression of TAp63 isoforms (Fig.	('expression', 'MPA', (42, 52))	('p63alpha', 'Gene', '8626', (107, 115))	('DNp63betaP', 'Var', (132, 142))	('TP63', 'Gene', (26, 30))	('p63alpha', 'Gene', (107, 115))	('TP63', 'Gene', '8626', (26, 30))	('p63alpha', 'Gene', (95, 103))	('p63alpha', 'Gene', '8626', (95, 103))	('expression', 'MPA', (166, 176))	('DNp63beta', 'Var', (118, 127))
55667	31927310	Stratification of BLCA patients into those with TAp63 isoform expression (5%) and those without (95%) demonstrated that patients with high TAp63 or TAp63beta expressing tumors had significantly worse OS than those with low/no expression (median OS 13.4 mos.	('TAp63beta expressing', 'Var', (148, 168))	('high TAp63', 'Var', (134, 144))	('patients', 'Species', '9606', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BLCA', 'Disease', 'MESH:D001749', (18, 22))	('worse', 'NegReg', (194, 199))	('patients', 'Species', '9606', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BLCA', 'Disease', (18, 22))	('tumors', 'Disease', (169, 175))
55670	31927310	Similarly, DNp63 expression was significantly associated with reduced hazard in luminal patients (HR = 0.89, CI 0.80-0.99, Cox p = 0.034), but did not show a significant association in patients with a basal squamous subtype (HR = 1.00, CI 0.91-1.10, Cox p = 0.95) (Fig.	('Cox', 'Gene', (250, 253))	('Cox', 'Gene', '1351', (123, 126))	('Cox', 'Gene', (123, 126))	('patients', 'Species', '9606', (88, 96))	('C', 'Chemical', 'MESH:D002244', (236, 237))	('C', 'Chemical', 'MESH:D002244', (250, 251))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('DNp63 expression', 'Var', (11, 27))	('patients', 'Species', '9606', (185, 193))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('Cox', 'Gene', '1351', (250, 253))	('reduced', 'NegReg', (62, 69))
55671	31927310	TAp63 was significantly associated with increased hazard in basal squamous subtype patients (HR = 2.35, CI 1.64-3.37, Cox p < 0.0001), but not in patients with luminal tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('luminal tumors', 'Disease', (160, 174))	('basal squamous subtype', 'Disease', (60, 82))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('Cox', 'Gene', '1351', (118, 121))	('luminal tumors', 'Disease', 'MESH:D009369', (160, 174))	('TAp63', 'Var', (0, 5))	('patients', 'Species', '9606', (83, 91))	('Cox', 'Gene', (118, 121))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
55672	31927310	Taken together, these results suggest that DNp63 plays a protective role in luminal bladder cancer patients whereas TAp63 is associated with poor risk in basal bladder cancers (Fig.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('luminal bladder cancer', 'Disease', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('basal bladder cancers', 'Disease', (154, 175))	('luminal bladder cancer', 'Disease', 'MESH:D001749', (76, 98))	('patients', 'Species', '9606', (99, 107))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('bladder cancers', 'Phenotype', 'HP:0009725', (160, 175))	('TAp63', 'Var', (116, 121))	('DNp63', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('basal bladder cancers', 'Disease', 'MESH:D001749', (154, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))
55673	31927310	To determine if the prognostic importance of TAp63 or DNp63 was independent of other known factors associated with bladder cancer patient prognosis, we performed multivariable Cox regression to adjust for potentially relevant clinical attributes (age, gender, grade, pathologic stage).	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patient', 'Species', '9606', (130, 137))	('DNp63', 'Var', (54, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('Cox', 'Gene', '1351', (176, 179))	('Cox', 'Gene', (176, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
55675	31927310	Multivariable Cox regression analysis confirmed that high DNp63 expression continued to trend with increased survival when controlling for age and pathologic stage (HR 0.68, CI 0.45-1.0, Cox p = 0.062) (Fig.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('expression', 'MPA', (64, 74))	('high', 'Var', (53, 57))	('DNp63', 'Gene', (58, 63))	('survival', 'MPA', (109, 117))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('Cox', 'Gene', (14, 17))	('Cox', 'Gene', '1351', (14, 17))	('increased', 'PosReg', (99, 108))	('Cox', 'Gene', (187, 190))	('Cox', 'Gene', '1351', (187, 190))	('C', 'Chemical', 'MESH:D002244', (174, 175))
55676	31927310	Likewise, high TAp63 expression was significantly associated with an increased risk of death when controlling for age and pathologic stage (HR 2.7, CI 1.6-4.6, Cox p = 0.0002).	('Cox', 'Gene', (160, 163))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('expression', 'MPA', (21, 31))	('death', 'Disease', 'MESH:D003643', (87, 92))	('TAp63', 'Gene', (15, 20))	('high', 'Var', (10, 14))	('C', 'Chemical', 'MESH:D002244', (160, 161))	('death', 'Disease', (87, 92))	('Cox', 'Gene', '1351', (160, 163))	('associated', 'Reg', (50, 60))
55681	31927310	Likewise, these analyses confirmed that TAp63 was associated with reduced survival for BLCA (HR 1.8, CI 1.4-2.4, Cox p = 0.0002).	('Cox', 'Gene', (113, 116))	('reduced', 'NegReg', (66, 73))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('BLCA', 'Disease', 'MESH:D001749', (87, 91))	('survival', 'MPA', (74, 82))	('TAp63', 'Var', (40, 45))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('BLCA', 'Disease', (87, 91))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('Cox', 'Gene', '1351', (113, 116))
55683	31927310	1(b)), the isoform level DNp63 expression was associated with worse survival (HR 1.2, CI 1.1-1.4, Cox p = 0.0003) and TAp63 associated with improved survival (HR 0.70, CI 0.51-0.96, Cox p = 0.020) which was also in the opposite direction of BLCA, BRCA and LUSC.	('Cox', 'Gene', (182, 185))	('worse', 'NegReg', (62, 67))	('C', 'Chemical', 'MESH:D002244', (249, 250))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('C', 'Chemical', 'MESH:D002244', (243, 244))	('BRCA', 'Gene', '672', (247, 251))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('Cox', 'Gene', '1351', (98, 101))	('TAp63', 'Var', (118, 123))	('DNp63', 'Gene', (25, 30))	('BLCA', 'Disease', (241, 245))	('C', 'Chemical', 'MESH:D002244', (182, 183))	('improved', 'PosReg', (140, 148))	('BRCA', 'Gene', (247, 251))	('Cox', 'Gene', (98, 101))	('Cox', 'Gene', '1351', (182, 185))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('survival', 'MPA', (149, 157))	('C', 'Chemical', 'MESH:D002244', (259, 260))	('BLCA', 'Disease', 'MESH:D001749', (241, 245))	('survival', 'MPA', (68, 76))
55686	31927310	To investigate this hypothesis, we grouped entire TCGA tumor cohorts together and plotted the average proportion of TAp63 or DNp63 over total TP63 for each population vs. TP63 HR for the entire cohort (Fig.	('TP63', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('DNp63', 'Var', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('tumor', 'Disease', (55, 60))	('TP63', 'Gene', '8626', (171, 175))	('TP63', 'Gene', (171, 175))	('TP63', 'Gene', '8626', (142, 146))
55690	31927310	These results suggest that the relative proportion of TAp63 or DNp63 vs. total TP63 associates with clinical outcome regardless of tumor type.	('DNp63', 'Var', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('TAp63', 'Var', (54, 59))	('TP63', 'Gene', '8626', (79, 83))	('TP63', 'Gene', (79, 83))	('clinical outcome', 'MPA', (100, 116))
55692	31927310	had previously shown that DNp63 and TAp63 promoted transcriptional programs of prognostic significance in various tumor types including bladder cancer.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('tumor', 'Disease', (114, 119))	('bladder cancer', 'Disease', (136, 150))	('transcriptional programs', 'MPA', (51, 75))	('DNp63', 'Var', (26, 31))	('promoted', 'PosReg', (42, 50))	('TAp63', 'Gene', (36, 41))
55693	31927310	Contrasting isoform-specific associations with patient survival observed across multiple diseases lead us to investigate transcriptional signaling programs that distinguish patient populations with high levels of DNp63 or TAp63.	('patient', 'Species', '9606', (47, 54))	('TAp63', 'Gene', (222, 227))	('patient', 'Species', '9606', (173, 180))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('DNp63', 'Var', (213, 218))
55695	31927310	Patients with tumors with high levels of DNp63 enriched for gene sets related to epidermal cell differentiation, keratinization, and skin development (Fig.	('DNp63', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('skin development', 'CPA', (133, 149))
55710	31927310	In this context, DNp63 isoforms appear to be the predominate cancer-associated isoform.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('DNp63', 'Var', (17, 22))
55716	31927310	Genome-wide association studies (GWAS) have found that bladder cancer risk is associated with a sequence variant of an enhancer specifically controlling DNp63 expression.	('associated', 'Reg', (78, 88))	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('sequence variant', 'Var', (96, 112))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('expression', 'MPA', (159, 169))	('DNp63', 'Gene', (153, 158))
55717	31927310	In contrast, DNp63 in NMIBC did not correlate with tumor risk of relapse and was associated with reduced risk of invasive progression in T1 bladder tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('bladder tumor', 'Phenotype', 'HP:0009725', (140, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (51, 56))	('reduced', 'NegReg', (97, 104))	('bladder tumors', 'Disease', 'MESH:D001749', (140, 154))	('bladder tumors', 'Phenotype', 'HP:0009725', (140, 154))	('MIBC', 'Disease', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('MIBC', 'Disease', 'MESH:D001749', (23, 27))	('bladder tumors', 'Disease', (140, 154))	('DNp63', 'Var', (13, 18))	('invasive progression', 'CPA', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
55724	31927310	Finally, we hypothesize that patient prognosis may be determined by the proportion of TP63 that is expressed as DNp63 vs. TAp63.	('TP63', 'Gene', '8626', (86, 90))	('DNp63', 'Var', (112, 117))	('patient', 'Species', '9606', (29, 36))	('TP63', 'Gene', (86, 90))
55732	31927310	Although prime variant isoforms have previously been described, here we characterize two commonly expressed variants, DNp63alphaP and DNp63betaP, which are not currently part of the TP63 isoform definitions present in Refgene and Gencode.	('p63alpha', 'Gene', (120, 128))	('DNp63betaP', 'Var', (134, 144))	('TP63', 'Gene', '8626', (182, 186))	('TP63', 'Gene', (182, 186))	('p63alpha', 'Gene', '8626', (120, 128))
55798	26557503	Literature review on pediatric brainstem gliomas suggests the following criteria for a typical DIPG: a combination of clinical symptoms and signs with short latency <3-6 months - triad of: (1) cerebellar signs, e.g., ataxia, dysmetria and dysarthria; (2) long tract signs: hypertonia, hyper-reflexia, motor deficits; and (3) cranial nerve palsies-isolated or multiple sixth, seventh) and radiological findings on MRI: an intrinsic, centrally located tumor involving greater than 50-66% of the axial diameter of the pons with hypointensity on T1 images, hyperintensity on T2 images with indistinct tumor margins with engulfment of basilar artery and no cystic or exophytic components.	('hypertonia', 'Disease', 'MESH:D009122', (273, 283))	('cranial nerve palsies', 'Phenotype', 'HP:0006824', (325, 346))	('tumor', 'Disease', (450, 455))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (31, 48))	('cerebellar signs', 'Phenotype', 'HP:0001317', (193, 209))	('tumor', 'Disease', 'MESH:D009369', (450, 455))	('hyper-reflexia', 'Phenotype', 'HP:0001347', (285, 299))	('hyper-reflexia', 'Disease', (285, 299))	('ataxia', 'Phenotype', 'HP:0001251', (217, 223))	('long tract signs', 'Phenotype', 'HP:0002423', (255, 271))	('dysarthria', 'Phenotype', 'HP:0001260', (239, 249))	('cranial nerve palsies', 'Disease', 'MESH:D003389', (325, 346))	('hyperintensity', 'Var', (553, 567))	('palsies-isolated', 'Disease', (339, 355))	('gliomas', 'Disease', (41, 48))	('dysmetria and dysarthria', 'Disease', 'MESH:D002524', (225, 249))	('dysmetria', 'Phenotype', 'HP:0001310', (225, 234))	('tumor', 'Phenotype', 'HP:0002664', (450, 455))	('tumor', 'Disease', (597, 602))	('ataxia', 'Disease', (217, 223))	('brainstem glioma', 'Phenotype', 'HP:0010796', (31, 47))	('ataxia', 'Disease', 'MESH:D001259', (217, 223))	('hyper-reflexia', 'Disease', 'MESH:D053307', (285, 299))	('tumor', 'Disease', 'MESH:D009369', (597, 602))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('cranial nerve', 'Phenotype', 'HP:0001291', (325, 338))	('hypertonia', 'Phenotype', 'HP:0001276', (273, 283))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('DIPG', 'Chemical', '-', (95, 99))	('palsies-isolated', 'Disease', 'MESH:D010243', (339, 355))	('hypertonia', 'Disease', (273, 283))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('cranial nerve palsies', 'Disease', (325, 346))	('tumor', 'Phenotype', 'HP:0002664', (597, 602))
55804	26557503	The ability to identify the whole mutational landscape of DIPG using tissue obtained by small-needle pretreatment biopsies coupled with availability of antibodies to detect (a) K27M mutations in both Histone 3 (H3) variants (H3.3 and H3.1) and (b) loss of tri-methylation (anti-HEK27me3) due to these mutations provides opportunities to improve diagnosis, assignment of prognosis, and identification of potentially druggable targets (PDGFRA, ACVR1, and FGFR1).	('K27M', 'Mutation', 'p.K27M', (177, 181))	('ACVR1', 'Gene', (442, 447))	('DIPG', 'Chemical', '-', (58, 62))	('HEK27', 'CellLine', 'CVCL:8807', (278, 283))	('ACVR1', 'Gene', '90', (442, 447))	('PDGFRA', 'Gene', '5156', (434, 440))	('mutations', 'Var', (301, 310))	('PDGFRA', 'Gene', (434, 440))	('tri-methylation', 'MPA', (256, 271))	('FGFR1', 'Gene', (453, 458))	('FGFR1', 'Gene', '2260', (453, 458))	('loss', 'NegReg', (248, 252))	('K27M mutations', 'Var', (177, 191))
55805	26557503	There is sufficient evidence in the literature to suggest that as the field moves forward, testing for H3K27M mutations will help in diagnosis, stratification into subgroups and prognosis and will be included in the design of prospective clinical trials testing new agents and treatment approaches.	('K27M', 'Mutation', 'p.K27M', (105, 109))	('help', 'Reg', (125, 129))	('mutations', 'Var', (110, 119))	('H3K27M', 'Gene', (103, 109))
55833	26557503	However, there were TP53 mutations in 6 of the 11 patients tested and none of the patients with LMD were found to have the ALT (alternate lengthening of telomeres) phenotype.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (82, 90))	('LMD', 'Disease', (96, 99))	('LMD', 'Disease', 'MESH:C537267', (96, 99))	('TP53', 'Gene', '7157', (20, 24))
55835	26557503	Histone H3 mutations were observed in all histology grades of DIPG (II-IV): 88% in GBM, 60% of AA, and 71% of low grade astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (120, 132))	('mutations', 'Var', (11, 20))	('DIPG', 'Chemical', '-', (62, 66))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('DIPG', 'Disease', (62, 66))	('GBM', 'Disease', (83, 86))	('astrocytomas', 'Disease', (120, 132))	('Histone H3', 'Protein', (0, 10))	('observed', 'Reg', (26, 34))
55836	26557503	K27M-H3.3 mutations were higher in GBM patients (78%) when compared to AA histology (33%) (P = 0.0016).	('GBM', 'Disease', (35, 38))	('K27M-H3.3 mutations', 'Var', (0, 19))	('patients', 'Species', '9606', (39, 47))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('mutations', 'Var', (10, 19))	('higher', 'Reg', (25, 31))
55837	26557503	Importantly, low grade tumors carrying H3.3 mutations had OS similar to that of GBM tumors and patients with high grade tumors with wild-type H3.3 had OS comparable to wild-type low grade astrocytomas.	('OS', 'Chemical', '-', (58, 60))	('tumors', 'Disease', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('astrocytomas', 'Disease', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('GBM tumors', 'Disease', (80, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', (23, 29))	('OS', 'Chemical', '-', (151, 153))	('GBM tumors', 'Disease', 'MESH:D005910', (80, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('astrocytomas', 'Disease', 'MESH:D001254', (188, 200))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (188, 199))	('patients', 'Species', '9606', (95, 103))	('H3.3', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
55838	26557503	At the time of diagnosis, whenever available, biopsy specimens of DIPG are suggested to be tested for Histone K27M mutations (H3.3 and 3.1) along with routine WHO histological grading and other markers (TP53, PDGFRA, ACVR1, and FGFR1).	('TP53', 'Gene', '7157', (203, 207))	('PDGFRA', 'Gene', '5156', (209, 215))	('mutations', 'Var', (115, 124))	('DIPG', 'Chemical', '-', (66, 70))	('Histone K27M', 'Protein', (102, 114))	('FGFR1', 'Gene', '2260', (228, 233))	('TP53', 'Gene', (203, 207))	('K27M', 'Mutation', 'p.K27M', (110, 114))	('ACVR1', 'Gene', (217, 222))	('ACVR1', 'Gene', '90', (217, 222))	('PDGFRA', 'Gene', (209, 215))	('FGFR1', 'Gene', (228, 233))
55843	26557503	proposed that tumor cells stimulated to invade by sub-lethal doses of irradiation may escape the target volume of post-operative RT, thereby evading delivery of a cumulative lethal dose and forming the basis for loco-regional relapse a few months after RT.	('tumor', 'Disease', (14, 19))	('sub-lethal', 'Var', (50, 60))	('delivery of a cumulative lethal dose', 'MPA', (149, 185))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('loco-regional relapse', 'CPA', (212, 233))	('evading', 'NegReg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
55855	26557503	The current standard of care for newly diagnosed DIPG patients is fractionated focal intensity modulated radiation therapy (IMRT) to the tumor along with 1-2 cm margins (54-60 Gy, 1.8-2 Gy fractions, given once daily for 5 days per week over a period of 6 weeks).	('DIPG', 'Disease', (49, 53))	('tumor', 'Disease', (137, 142))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('54-60 Gy', 'Var', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('DIPG', 'Chemical', '-', (49, 53))
55890	26557503	Patients receiving RT + TMZ + chemotherapy (other than TMZ) showed prolonged survival when compared to patients receiving only RT (P = 0.005).	('TMZ', 'Chemical', 'MESH:D000077204', (24, 27))	('RT + TMZ', 'Var', (19, 27))	('TMZ', 'Chemical', 'MESH:D000077204', (55, 58))	('RT + TMZ', 'Chemical', '-', (19, 27))	('survival', 'CPA', (77, 85))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (103, 111))	('prolonged', 'PosReg', (67, 76))
55928	26557503	Diffuse intrinsic pontine glioma patients who have histone mutations (H3.3 and H3.1, K27M) identified by IHC and other methods have a worse OS when compared to wild-type tumors, and this association is independent of patient age and histological diagnosis.	('patient', 'Species', '9606', (33, 40))	('patients', 'Species', '9606', (33, 41))	('K27M', 'Mutation', 'p.K27M', (85, 89))	('H3.1', 'Gene', (79, 83))	('patient', 'Species', '9606', (217, 224))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('H3.3', 'Var', (70, 74))	('K27M', 'Var', (85, 89))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('intrinsic pontine glioma', 'Disease', 'MESH:D000080443', (8, 32))	('OS', 'Chemical', '-', (140, 142))	('intrinsic pontine glioma', 'Disease', (8, 32))	('tumors', 'Disease', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
55937	26557503	(5) Pre-clinical testing and validation of appropriately chosen targets [e.g., JMJD3, H3K27 demethylase, Menin, ACVR1 ] in available tumor models will help to identify novel effective therapies and provide options to personalize treatment and limit side effects and long-term toxicities.	('toxicities', 'Disease', 'MESH:D064420', (276, 286))	('Menin', 'Gene', (105, 110))	('ACVR1', 'Gene', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ACVR1', 'Gene', '90', (112, 117))	('Menin', 'Gene', '4221', (105, 110))	('toxicities', 'Disease', (276, 286))	('JMJD3', 'Gene', (79, 84))	('tumor', 'Disease', (133, 138))	('JMJD3', 'Gene', '23135', (79, 84))	('H3K27', 'Var', (86, 91))
55945	32872331	Chimeric proteins derived from the fusion of several genes with neurotrophic tyrosine receptor kinase mutations have been described in high-grade gliomas in infants as well as in neonatal age and the recent discovery of targeted drugs may change the long-term prognosis of these tumors, along with other target-driven therapies.	('change', 'Reg', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('infants', 'Species', '9606', (157, 164))	('tumors', 'Disease', (279, 285))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('mutations', 'Var', (102, 111))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('described', 'Reg', (122, 131))
56002	32872331	These alterations have been described in pediatric HGG and in particular in 40% of non-brainstem HGGs in infants.	('alterations', 'Var', (6, 17))	('non-brainstem HGGs', 'Disease', (83, 101))	('infants', 'Species', '9606', (105, 112))
56003	32872331	All fusions include the C-terminal kinase domain from NTRK1, NTRK2 or NTRK3 with the N-terminal sequences of different genes, leading to the transcription of chimeric Trk proteins with constitutively activated or overexpressed kinase function and subsequent oncogenic potential.	('overexpressed', 'PosReg', (213, 226))	('Trk', 'Gene', (167, 170))	('NTRK2', 'Gene', (61, 66))	('NTRK1', 'Gene', '4914', (54, 59))	('NTRK3', 'Gene', (70, 75))	('oncogenic potential', 'CPA', (258, 277))	('NTRK2', 'Gene', '4915', (61, 66))	('transcription', 'MPA', (141, 154))	('Trk', 'Gene', '4914', (167, 170))	('chimeric', 'Var', (158, 166))	('NTRK1', 'Gene', (54, 59))	('NTRK3', 'Gene', '4916', (70, 75))
56010	32872331	As for molecular alterations, in adults the most frequent alterations involve the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatase and tensin homolog (PTEN), INK4a/ARF and TP53 or, more rarely, Isocitrate dehydrogenase1 (IDH1) and ATRX.	('INK4a/ARF', 'Gene', '1029', (211, 220))	('ATRX', 'Gene', '546', (284, 288))	('PTEN', 'Gene', (204, 208))	('alterations', 'Var', (58, 69))	('INK4a/ARF', 'Gene', (211, 220))	('Isocitrate dehydrogenase1', 'Gene', (247, 272))	('PTEN', 'Gene', '5728', (204, 208))	('TP53', 'Gene', (225, 229))	('EGFR', 'Gene', '1956', (116, 120))	('IDH1', 'Gene', (274, 278))	('PDGFR', 'Gene', (164, 169))	('PDGFR', 'Gene', '5159', (164, 169))	('epidermal growth factor receptor', 'Gene', (82, 114))	('platelet-derived growth factor receptor', 'Gene', '5159', (123, 162))	('platelet-derived growth factor receptor', 'Gene', (123, 162))	('phosphatase and tensin homolog', 'Gene', '5728', (172, 202))	('TP53', 'Gene', '7157', (225, 229))	('Isocitrate dehydrogenase1', 'Gene', '3417', (247, 272))	('epidermal growth factor receptor', 'Gene', '1956', (82, 114))	('IDH1', 'Gene', '3417', (274, 278))	('ATRX', 'Gene', (284, 288))	('EGFR', 'Gene', (116, 120))
56012	32872331	In addition, while mutations in TP53 and PTEN and CDKN2A/B deletions are often seen in older children they are typically not found infant HGG.	('children', 'Species', '9606', (93, 101))	('CDKN2A/B', 'Gene', '1029;1030', (50, 58))	('TP53', 'Gene', '7157', (32, 36))	('deletions', 'Var', (59, 68))	('mutations', 'Var', (19, 28))	('TP53', 'Gene', (32, 36))	('CDKN2A/B', 'Gene', (50, 58))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))
56013	32872331	Even IDH1 mutations are rare while occasional BRAF (B-Raf proto-oncogene, serine/threonine kinase) V600E mutations can be found.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('V600E', 'Var', (99, 104))	('IDH1', 'Gene', (5, 9))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('IDH1', 'Gene', '3417', (5, 9))	('B-Raf proto-oncogene', 'Gene', '673', (52, 72))	('mutations', 'Var', (10, 19))	('B-Raf proto-oncogene', 'Gene', (52, 72))	('serine', 'Chemical', 'MESH:D012694', (74, 80))
56018	32872331	On the contrary, EGFR and PDGFRa alterations, including amplification or mutations, have been reported in 57% and 13% of aGBMs, respectively, as well as frequent PTEN mutations/deletions and gains of MYCN.	('PTEN', 'Gene', (162, 166))	('PTEN', 'Gene', '5728', (162, 166))	('aGBMs', 'Gene', (121, 126))	('PDGFRa', 'Gene', '5156', (26, 32))	('gains', 'PosReg', (191, 196))	('PDGFRa', 'Gene', (26, 32))	('mutations/deletions', 'Var', (167, 186))	('alterations', 'Var', (33, 44))	('MYCN', 'Gene', (200, 204))	('MYCN', 'Gene', '4613', (200, 204))	('EGFR', 'Gene', '1956', (17, 21))	('mutations', 'Var', (73, 82))	('EGFR', 'Gene', (17, 21))
56019	32872331	None of the patients with cGBMs had the recently described histone H3.3 mutations found in pGBMs, which are instead extremely rare in aGBMs.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (12, 20))	('pGBMs', 'Gene', (91, 96))	('histone H3.3', 'Gene', '3021', (59, 71))	('histone H3.3', 'Gene', (59, 71))
56021	32872331	Notably, derangements in another metabolic pathway involved in energy production have been described including glutamate homeostasis through the aberrant expression of the mitochondrial enzyme GLUD2 in glioblastoma tumor cells.	('GLUD2', 'Gene', '2747', (193, 198))	('glioblastoma tumor', 'Disease', (202, 220))	('derangements', 'Reg', (9, 21))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (202, 220))	('glutamate homeostasis', 'MPA', (111, 132))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('glutamate', 'Chemical', 'MESH:D018698', (111, 120))	('aberrant', 'Var', (145, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('GLUD2', 'Gene', (193, 198))
56023	32872331	In a recent report, DNA methylation and transcriptomic analysis showed a lower incidence in cGBMs compared with pGBMs and aGBMs of typical GBM-related copy number aberrations (CNAs) but identified cyclin dependent kinase 6 (CDK6) and cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) deletions and MET proto-oncogene, a receptor tyrosine kinase (MET) fusion gene.	('MET', 'Gene', '79811', (346, 349))	('MET', 'Gene', (298, 301))	('MET', 'Gene', (346, 349))	('receptor tyrosine kinase', 'Gene', (320, 344))	('cyclin dependent kinase 6', 'Gene', '1021', (197, 222))	('CDKN2A/B', 'Gene', '1029;1030', (274, 282))	('receptor tyrosine kinase', 'Gene', '5979', (320, 344))	('CDK6', 'Gene', (224, 228))	('cyclin dependent kinase 6', 'Gene', (197, 222))	('CDK6', 'Gene', '1021', (224, 228))	('2A/B', 'SUBSTITUTION', 'None', (278, 282))	('2A/B', 'Var', (278, 282))	('2A/B', 'SUBSTITUTION', 'None', (268, 272))	('2A/B', 'Var', (268, 272))	('CDKN2A/B', 'Gene', (274, 282))	('MET', 'Gene', '79811', (298, 301))	('deletions', 'Var', (284, 293))
56030	32872331	These alterations are targetable lesions with evidence of efficacy in the clinic, thus supporting the concept that infant gliomas require a change in diagnostic practice and management.	('alterations', 'Var', (6, 17))	('gliomas', 'Disease', (122, 129))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
56031	32872331	BRAF V600E mutation has been recently detected in 17% of patients with pediatric low-grade gliomas (including infants) and in HGGs.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('gliomas', 'Disease', (91, 98))	('patients', 'Species', '9606', (57, 65))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('V600E', 'Var', (5, 10))	('infants', 'Species', '9606', (110, 117))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
56032	32872331	BRAF V600E confers worse outcomes when patients are treated with chemotherapy and radiation compared with BRAF wild-type patients, especially when CDKN2A deletion occurs.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('patients', 'Species', '9606', (39, 47))	('BRAF', 'Gene', '673', (106, 110))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (106, 110))	('deletion', 'Var', (154, 162))	('CDKN2A', 'Gene', (147, 153))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (121, 129))	('CDKN2A', 'Gene', '1029', (147, 153))
56033	32872331	The same group published a case report on a two month old patient with a V600E mutant hypothalamic/chiasmatic glioma who was successfully treated with the BRAF inhibitor dabrafenib, which resulted in a rapid and sustained disappearance of clinical symptoms and cytoreduction.	('V600E', 'Mutation', 'rs113488022', (73, 78))	('BRAF', 'Gene', (155, 159))	('disappearance', 'NegReg', (222, 235))	('glioma', 'Disease', (110, 116))	('dabrafenib', 'Chemical', 'MESH:C561627', (170, 180))	('patient', 'Species', '9606', (58, 65))	('hypothalamic', 'Disease', (86, 98))	('V600E', 'Var', (73, 78))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('hypothalamic', 'Disease', 'MESH:D007027', (86, 98))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('BRAF', 'Gene', '673', (155, 159))
56034	32872331	In addition, several reports have been published of pediatric LGGs harboring the BRAF V600E mutation that was successfully treated with Vemurafenib.	('Vemurafenib', 'Chemical', 'MESH:D000077484', (136, 147))	('LGGs', 'Disease', (62, 66))	('V600E', 'Var', (86, 91))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('V600E', 'Mutation', 'rs113488022', (86, 91))
56048	32872331	This highly selective small molecule has shown activity in preclinical models and in adults with tumors harboring TRK fusions.	('fusions', 'Var', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('activity', 'MPA', (47, 55))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('TRK', 'Gene', (114, 117))	('TRK', 'Gene', '4914', (114, 117))
56052	32872331	The ongoing NCT02576431 and NCT02637687 trials will further increase the number of patients studied in disease-specific settings and may help to monitor its safety and efficacy data.	('NCT02637687', 'Var', (28, 39))	('patients', 'Species', '9606', (83, 91))	('NCT02576431', 'Gene', (12, 23))	('increase', 'PosReg', (60, 68))
56098	29195506	Therein, 5-year LC was 100% in patients with disease <=20 cm3 versus 95% with tumors over 20 cm3.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('<=20 cm3', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (31, 39))
56112	29195506	Because PBT affords lower integral brain doses, its dosimetric improvements as compared to IMRT may be notable in an otherwise largely healthy population of patients with low-grade gliomas that are expected to achieve long-term cure with RT-based therapy.	('lower', 'NegReg', (20, 25))	('integral brain doses', 'MPA', (26, 46))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('PBT', 'Var', (8, 11))	('patients', 'Species', '9606', (157, 165))	('gliomas', 'Disease', (181, 188))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
56114	29195506	It has also been postulated, similar to the aforementioned analogous data in meningiomas, that PBT roughly halves the risk of developing RT-induced neoplasms as compared with photon-based therapies, owing to the decreased dose to the whole brain, even though this is of comparatively less importance in HGGs.	('decreased', 'NegReg', (212, 221))	('meningiomas', 'Phenotype', 'HP:0002858', (77, 88))	('halves', 'NegReg', (107, 113))	('neoplasms', 'Disease', (148, 157))	('meningioma', 'Phenotype', 'HP:0002858', (77, 87))	('neoplasms', 'Disease', 'MESH:D009369', (148, 157))	('PBT', 'Var', (95, 98))	('meningiomas', 'Disease', 'MESH:D008577', (77, 88))	('dose', 'MPA', (222, 226))	('meningiomas', 'Disease', (77, 88))	('neoplasm', 'Phenotype', 'HP:0002664', (148, 156))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))
56115	29195506	Late effects were also studied by Karunamuni et al., who found a temporal lobe-pronounced dose-dependent cortical thinning of 0.0033 mm per Gy, which could relate to the higher likelihood of dementia observed after long-term follow up after radiotherapy.	('Gy', 'Chemical', 'MESH:C022013', (140, 142))	('dementia', 'Disease', 'MESH:D003704', (191, 199))	('0.0033 mm', 'Var', (126, 135))	('cortical', 'CPA', (105, 113))	('dementia', 'Phenotype', 'HP:0000726', (191, 199))	('dementia', 'Disease', (191, 199))
56141	29195506	Next, the same working group described a more uniform population of 14 diffuse grade II astrocytoma cases treated with CIRT (46.2-50.4 Gy(RBE) or 55.2 Gy(RBE)).	('II astrocytoma', 'Disease', 'MESH:D001254', (85, 99))	('46.2-50.4', 'Var', (125, 134))	('diffuse', 'Disease', (71, 78))	('II astrocytoma', 'Disease', (85, 99))	('Gy', 'Chemical', 'MESH:C022013', (151, 153))	('Gy', 'Chemical', 'MESH:C022013', (135, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))
56157	28528867	A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations Molecular alterations involving PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11219 human cancers representing 32 major types.	('Pan-Cancer', 'Disease', (2, 12))	('PI3K/AKT', 'Gene', (102, 110))	('human', 'Species', '9606', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('AKT', 'Gene', '207', (41, 44))	('PI3K/AKT', 'Gene', '5295;207', (102, 110))	('PI3K/AKT', 'Gene', (36, 44))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('PI3K/AKT', 'Gene', '5295;207', (36, 44))	('AKT', 'Gene', (107, 110))	('mTOR', 'Gene', (111, 115))	('Pan-Cancer', 'Disease', 'MESH:C537931', (2, 12))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', (45, 49))	('mTOR', 'Gene', '2475', (111, 115))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('copy number', 'Var', (145, 156))	('mTOR', 'Gene', '2475', (45, 49))	('AKT', 'Gene', '207', (107, 110))
56159	28528867	In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance.	('structural variations', 'Var', (25, 46))	('STK11', 'Gene', (90, 95))	('PTEN', 'Gene', (81, 85))	('partial copy losses', 'Var', (51, 70))	('STK11', 'Gene', '6794', (90, 95))
56160	28528867	A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.	('activity', 'MPA', (59, 67))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('IDH1', 'Gene', (159, 163))	('VHL', 'Disease', (167, 170))	('VHL', 'Disease', 'MESH:D006623', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('IDH1', 'Gene', '3417', (159, 163))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('mTOR pathway', 'Pathway', (46, 58))	('mutations', 'Var', (171, 180))	('cancers', 'Disease', (141, 148))
56168	28528867	AKT is phosphorylated at Thr308 by PDK1 and at Ser473 by mTOR complex 2 (mTORC2), which increases its kinase activity.	('mTORC2', 'Gene', '74343', (73, 79))	('mTORC2', 'Gene', (73, 79))	('Thr308', 'Chemical', '-', (25, 31))	('Ser473', 'Chemical', '-', (47, 53))	('AKT', 'Pathway', (0, 3))	('increases', 'PosReg', (88, 97))	('kinase activity', 'MPA', (102, 117))	('PDK1', 'Gene', '5163', (35, 39))	('Thr308', 'Var', (25, 31))	('PDK1', 'Gene', (35, 39))
56176	28528867	PIK3R1 and less commonly PIK3R2, which encode the p85alpha and p85beta regulatory subunits of PI3K, are commonly mutated, resulting in reduced ability to inhibit PI3K p110a.	('p85beta', 'Gene', (63, 70))	('PI3', 'Gene', (94, 97))	('PI3', 'Gene', (162, 165))	('PIK3R2', 'Gene', (25, 31))	('PIK3R2', 'Gene', '5296', (25, 31))	('p110a', 'Gene', (167, 172))	('ability', 'MPA', (143, 150))	('inhibit', 'NegReg', (154, 161))	('PIK3R1', 'Gene', (0, 6))	('p85alpha', 'Gene', '5295', (50, 58))	('p85beta', 'Gene', '5296', (63, 70))	('p110a', 'Gene', '5290', (167, 172))	('PI3', 'Gene', '5266', (94, 97))	('reduced', 'NegReg', (135, 142))	('mutated', 'Var', (113, 120))	('PI3', 'Gene', '5266', (162, 165))	('p85alpha', 'Gene', (50, 58))
56177	28528867	PTEN is subject to both genomic deletion and small point mutations that inactivate its function, and is one of the most commonly mutated cancer genes overall.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('deletion', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('function', 'MPA', (87, 95))	('cancer', 'Disease', (137, 143))	('inactivate', 'NegReg', (72, 82))	('PTEN', 'Gene', (0, 4))
56178	28528867	AKT1 is occasionally activated by mutation at a single site, E17K.	('E17K', 'Var', (61, 65))	('AKT1', 'Gene', '207', (0, 4))	('AKT1', 'Gene', (0, 4))	('activated', 'PosReg', (21, 30))	('E17K', 'Mutation', 'rs121434592', (61, 65))
56179	28528867	Inactivating mutations in both TSC1 and TSC2 have been identified in cancer at low frequency, as well as activating mutations in MTOR .	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('MTOR', 'Gene', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Inactivating mutations', 'Var', (0, 22))	('TSC2', 'Gene', '7249', (40, 44))	('MTOR', 'Gene', '2475', (129, 133))	('TSC1', 'Gene', '7248', (31, 35))	('TSC2', 'Gene', (40, 44))	('TSC1', 'Gene', (31, 35))	('cancer', 'Disease', (69, 75))
56180	28528867	RHEB mutations are rare but focal at Y35, suggesting a driver effect.	('RHEB', 'Gene', '6009', (0, 4))	('Y35', 'Var', (37, 40))	('RHEB', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
56200	28528867	With the notable exception of AKT3, copy number alterations of PI3K/AKT/mTOR pathway member genes were highly correlated with their mRNA expression (Figure S2A).	('mRNA expression', 'MPA', (132, 147))	('AKT3', 'Gene', '10000', (30, 34))	('correlated', 'Reg', (110, 120))	('AKT3', 'Gene', (30, 34))	('PI3K/AKT', 'Gene', (63, 71))	('copy number alterations', 'Var', (36, 59))	('PI3K/AKT', 'Gene', '5295;207', (63, 71))
56203	28528867	Out of 1363 cases with WGS data available (1218 by low-pass sequencing), 63 cases (~5%) harbored a rearrangement within pathway suppressor genes PTEN (39 cases), INPP4B (14), STK11 (5), TSC1 (2), TSC2 (2), PIK3R1 (2), or PPP2R1A (2)(Figure 2C).	('PTEN', 'Gene', (145, 149))	('TSC1', 'Gene', (186, 190))	('rearrangement', 'Var', (99, 112))	('STK11', 'Gene', (175, 180))	('PIK3R1', 'Gene', (206, 212))	('PPP2R1A', 'Gene', (221, 228))	('INPP4B', 'Gene', '8821', (162, 168))	('STK11', 'Gene', '6794', (175, 180))	('PPP2R1A', 'Gene', '5518', (221, 228))	('INPP4B', 'Gene', (162, 168))	('TSC1', 'Gene', '7248', (186, 190))	('TSC2', 'Gene', '7249', (196, 200))	('TSC2', 'Gene', (196, 200))
56204	28528867	By structural variation (SV), copy loss (partial or total), or mutation, PTEN was found altered in 40% of cancers with both RPPA and WGS data, with PTEN protein expression most impacted in tumors with SV, homozygous loss, or nonsense/indel/frameshift mutations (Figure 2D).	('PTEN', 'Gene', (148, 152))	('copy loss', 'Var', (30, 39))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('altered', 'Reg', (88, 95))	('impacted', 'Reg', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('expression', 'MPA', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('SV', 'Disease', 'None', (201, 203))	('PTEN', 'Gene', (73, 77))	('SV', 'Disease', 'None', (25, 27))	('tumors', 'Disease', (189, 195))	('mutation', 'Var', (63, 71))	('homozygous loss', 'Var', (205, 220))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('nonsense/indel/frameshift mutations', 'Var', (225, 260))	('protein', 'Protein', (153, 160))	('tumors', 'Disease', 'MESH:D009369', (189, 195))
56206	28528867	Furthermore, high-level and low-level copy number loss for several pathway genes were strongly correlated with reduced mRNA levels (Figure S2B), and 20 cases harbored candidate gene fusions involving PIK3CA, AKT1, AKT2, AKT3, or MTOR (Figure S2C and Table S3).	('AKT3', 'Gene', '10000', (220, 224))	('MTOR', 'Gene', (229, 233))	('harbored', 'Reg', (158, 166))	('loss', 'NegReg', (50, 54))	('fusions', 'Reg', (182, 189))	('AKT2', 'Gene', (214, 218))	('copy number', 'Var', (38, 49))	('reduced', 'NegReg', (111, 118))	('AKT1', 'Gene', '207', (208, 212))	('PIK3CA', 'Gene', (200, 206))	('AKT2', 'Gene', '208', (214, 218))	('MTOR', 'Gene', '2475', (229, 233))	('mRNA levels', 'MPA', (119, 130))	('AKT1', 'Gene', (208, 212))	('AKT3', 'Gene', (220, 224))
56207	28528867	A large proportion of mutations identified in driver genes that activate PI3K/AKT/mTOR are of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers .	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('PI3K/AKT', 'Gene', '5295;207', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('mutations', 'Var', (22, 31))	('long tail', 'Phenotype', 'HP:0002831', (161, 170))	('cancers', 'Disease', (220, 227))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('PI3K/AKT', 'Gene', (73, 81))
56208	28528867	For example, PIK3CA is the gene most commonly activated by mutation in the cancer genome, with mutations being most frequent at positions E542, E545, and H1047 (Figure 3A); on the other hand, 13% of PIK3CA mutations observed occurred in a single case and showed no significant pattern of occurrence.	('mutations', 'Var', (206, 215))	('E545', 'Var', (144, 148))	('PIK3CA', 'Gene', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('H1047', 'Var', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('E542', 'Var', (138, 142))
56209	28528867	Somatic copy alteration represents another potential mechanism for altering gene function, where for example, amplification of PIK3CA impacts p110alpha protein expression (Figure 3B).	('p110alpha', 'Gene', (142, 151))	('impacts', 'Reg', (134, 141))	('amplification', 'Var', (110, 123))	('PIK3CA', 'Gene', (127, 133))	('p110alpha', 'Gene', '5290', (142, 151))
56210	28528867	Previous pan-cancer sequence analyses  have identified recurrent mutational hotspots, where such hotspots would presumably have greater impact on protein function.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mutational', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
56211	28528867	In the case of PIK3CA, 73% of somatic, nonsilent mutation variants identified in TCGA pan-cancer cohort involved a hotspot residue as identified by Chang et al., while 13% of PIK3R1 mutations and 7% of MTOR mutations involved a hotspot residue (Figure 3C).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('variants', 'Var', (58, 66))	('involved', 'Reg', (217, 225))	('mutations', 'Var', (207, 216))	('involved', 'Reg', (104, 112))	('MTOR', 'Gene', (202, 206))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('MTOR', 'Gene', '2475', (202, 206))	('mutations', 'Var', (182, 191))	('PIK3R1', 'Gene', (175, 181))
56213	28528867	For each of the genes considered (AKT1, MTOR, PIK3CA, PIK3R1, PTEN), tumors harboring mutations that were predicted to have functional effects had elevated phospho-AKT levels on average, as compared to tumors that did not harbor an alteration; in addition, tumors with mutations not predicted to be functional showed either a lesser effect or no significant effect on phospho-AKT.	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('elevated', 'PosReg', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MTOR', 'Gene', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('MTOR', 'Gene', '2475', (40, 44))	('mutations', 'Var', (86, 95))	('AKT1', 'Gene', '207', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('phospho-AKT levels', 'MPA', (156, 174))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumors', 'Disease', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('AKT1', 'Gene', (34, 38))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
56215	28528867	Using MCF10A and Ba/F3 cells, 69 different nonsilent PIK3CA mutation variants were functionally assessed in vitro for their activating potential (Figures 4A and S4 and Table S5).	('MCF10A', 'CellLine', 'CVCL:0598', (6, 12))	('variants', 'Var', (69, 77))	('activating potential', 'MPA', (124, 144))	('mutation variants', 'Var', (60, 77))	('PIK3CA', 'Gene', (53, 59))
56216	28528867	When the results of the functional studies were aligned with data from TCGA, a significant trend was observed for both PIK3CA and PIK3R1, whereby variants that were associated with functionality in vitro had a higher frequency of occurrence in human tumors (Figure 4C), suggesting that natural selection favored tumor development for those variants with greater functional effects.	('human', 'Species', '9606', (244, 249))	('PIK3CA', 'Gene', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('variants', 'Var', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('favored', 'PosReg', (304, 311))	('tumor', 'Disease', (312, 317))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('tumor', 'Disease', (250, 255))	('PIK3R1', 'Gene', (130, 136))
56217	28528867	Most variants showing some functionality also had higher phospho-AKT on average, as compared to tumors with the corresponding wild-type gene (Figures 4A and 4B), though variants associated with higher phospho-AKT were not necessarily associated with higher phospho-TSC2 (downstream in the pathway from AKT).	('higher', 'PosReg', (194, 200))	('higher', 'PosReg', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('phospho-AKT', 'MPA', (201, 212))	('tumors', 'Disease', (96, 102))	('phospho-AKT', 'MPA', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('TSC2', 'Gene', '7249', (265, 269))	('TSC2', 'Gene', (265, 269))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('variants', 'Var', (5, 13))	('variants', 'Var', (169, 177))
56220	28528867	MTOR, RPTOR) resulted in gene signature patterns inversely correlated to those of our PI3K/AKT/mTOR signature, while knockdown of pathway suppressors (e.g.	('PI3K/AKT', 'Gene', (86, 94))	('PI3K/AKT', 'Gene', '5295;207', (86, 94))	('RPTOR', 'Gene', (6, 11))	('RPTOR', 'Gene', '57521', (6, 11))	('MTOR', 'Gene', (0, 4))	('knockdown', 'Var', (117, 126))	('MTOR', 'Gene', '2475', (0, 4))
56222	28528867	Notably, knockdown of MYC and KRAS also suppressed the PI3K/AKT/mTOR signature; furthermore, when scoring TCGA pan-cancer mRNA profiles for pre-defined signatures of PI3K/AKT/mTOR, MYC, and k-ras, cancers scoring high for PI3K/AKT/mTOR also tended to score high for MYC and k-ras (Figures 5C, S5A, and S5B), suggesting that multiple oncogenic signaling pathways may converge on similar sets of transcriptional targets.	('MYC', 'Gene', '4609', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('PI3K/AKT', 'Gene', '5295;207', (55, 63))	('PI3K/AKT', 'Gene', (222, 230))	('PI3K/AKT', 'Gene', '5295;207', (166, 174))	('k-ras', 'Gene', (190, 195))	('MYC', 'Gene', '4609', (181, 184))	('KRAS', 'Gene', (30, 34))	('PI3K/AKT', 'Gene', '5295;207', (222, 230))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('suppressed', 'NegReg', (40, 50))	('MYC', 'Gene', '4609', (266, 269))	('S5B', 'Gene', (302, 305))	('k-ras', 'Gene', '3845', (274, 279))	('KRAS', 'Gene', '3845', (30, 34))	('knockdown', 'Var', (9, 18))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('cancer', 'Disease', (197, 203))	('MYC', 'Gene', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('k-ras', 'Gene', (274, 279))	('high', 'Reg', (257, 261))	('MYC', 'Gene', (181, 184))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('k-ras', 'Gene', '3845', (190, 195))	('S5B', 'Gene', '5711', (302, 305))	('MYC', 'Gene', (266, 269))	('PI3K/AKT', 'Gene', (55, 63))	('PI3K/AKT', 'Gene', (166, 174))
56236	28528867	Features significantly associated with worse patient outcome, independent of cancer type, included STK11 mutation, STK11 copy loss, PTEN copy loss, PIK3CA amplification, and higher phospho-4EBP1 expression.	('4EBP1', 'Gene', (189, 194))	('amplification', 'Var', (155, 168))	('mutation', 'Var', (105, 113))	('STK11', 'Gene', (99, 104))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PTEN copy loss', 'Disease', (132, 146))	('higher', 'PosReg', (174, 180))	('STK11', 'Gene', '6794', (99, 104))	('STK11', 'Gene', (115, 120))	('PTEN copy loss', 'Disease', 'MESH:D006223', (132, 146))	('patient', 'Species', '9606', (45, 52))	('PIK3CA', 'Gene', (148, 154))	('4EBP1', 'Gene', '1978', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('copy', 'Var', (121, 125))	('STK11', 'Gene', '6794', (115, 120))
56237	28528867	Focusing on PTEN and STK11 copy alterations, these features were found significant within several individual cancer types, with the aggregated patterns across cancer types denoting pan-cancer significance (Figure 6B).	('cancer', 'Disease', (159, 165))	('significant', 'Reg', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (109, 115))	('STK11', 'Gene', (21, 26))	('PTEN', 'Gene', (12, 16))	('copy alterations', 'Var', (27, 43))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('STK11', 'Gene', '6794', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (185, 191))
56238	28528867	Interestingly, for both PTEN and STK11, low level deletion (approximating partial copy loss) but not high level deletion (approximating total loss) was associated with significantly worse outcome compared to wild-type (Figures 6C and 6D); loss of one copy combined with somatic mutation of the other copy was associated with the poorest outcome.	('loss', 'Var', (239, 243))	('STK11', 'Gene', (33, 38))	('PTEN', 'Gene', (24, 28))	('STK11', 'Gene', '6794', (33, 38))
56239	28528867	For both PTEN and STK11, neither high-level deletion nor mutation without copy loss could be associated with worse outcome, where in this instance, survival differences by tumor type were a likely confounder (e.g.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PTEN', 'Gene', (9, 13))	('tumor', 'Disease', (172, 177))	('deletion', 'Var', (44, 52))	('STK11', 'Gene', (18, 23))	('STK11', 'Gene', '6794', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
56240	28528867	65% of the PTEN mutation with no copy alteration group were UCEC:or uterine corpus endometrial carcinoma:cases).	('PTEN', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (83, 104))	('endometrial carcinoma', 'Disease', (83, 104))	('UCEC', 'Disease', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (83, 104))
56242	28528867	We then sought to examine the effects on pathway activation of some key genomic events in the tumors in which they occurred (including mutations represented in Figure 2A and copy alterations involving PIK3CA, PTEN, and STK11).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (135, 144))	('copy alterations', 'Var', (174, 190))	('STK11', 'Gene', (219, 224))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('PIK3CA', 'Gene', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('STK11', 'Gene', '6794', (219, 224))	('PTEN', 'Gene', (209, 213))
56243	28528867	Of the 7099 tumor cases examined (with both mutation and protein data), 4468 (63%) harbored at least one nonsilent somatic mutation or copy alteration involving PI3K/AKT/mTOR pathway (Figures 7A and S6A).	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('PI3K/AKT', 'Gene', (161, 169))	('tumor', 'Disease', (12, 17))	('PI3K/AKT', 'Gene', '5295;207', (161, 169))	('copy alteration', 'Var', (135, 150))
56245	28528867	In comparison to a set of tumors that did not show pathway alteration at the DNA or protein level (an "unaligned" set, n=1058), mutation or copy alteration of individual PI3K/AKT/mTOR pathway members in general could be associated with higher PI3K/AKT or mTOR signaling as measured by protein arrays (Figures 7B and S6B).	('PI3K/AKT', 'Gene', (170, 178))	('higher', 'PosReg', (236, 242))	('copy alteration', 'Var', (140, 155))	('PI3K/AKT', 'Gene', (243, 251))	('mTOR signaling', 'Pathway', (255, 269))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('PI3K/AKT', 'Gene', '5295;207', (170, 178))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('PI3K/AKT', 'Gene', '5295;207', (243, 251))	('mutation', 'Var', (128, 136))	('tumors', 'Disease', (26, 32))
56246	28528867	Notably, STK11 alteration or low phospho-AMPK was strongly associated with high mTOR signaling but not with high PI3K/AKT signaling, consistent with the LKB1/AMPK pathway acting on mTOR independently of PI3K/AKT (Figure 2A).	('PI3K/AKT', 'Gene', '5295;207', (113, 121))	('PI3K/AKT', 'Gene', '5295;207', (203, 211))	('STK11', 'Gene', '6794', (9, 14))	('low', 'Var', (29, 32))	('PI3K/AKT', 'Gene', (113, 121))	('AMPK', 'Gene', '5562', (158, 162))	('associated', 'Reg', (59, 69))	('PI3K/AKT', 'Gene', (203, 211))	('AMPK', 'Gene', '5562', (41, 45))	('high mTOR signaling', 'MPA', (75, 94))	('AMPK', 'Gene', (41, 45))	('LKB1', 'Gene', (153, 157))	('AMPK', 'Gene', (158, 162))	('STK11', 'Gene', (9, 14))	('LKB1', 'Gene', '6794', (153, 157))	('alteration', 'Var', (15, 25))
56247	28528867	Mutations associated with Receptor Tyrosine Kinase (RTK) signaling were not strongly associated with PI3K/AKT/mTOR activation (Figures 7A and 7B), indicative of decoupling between PI3K/AKT/mTOR and RTK.	('PI3K/AKT', 'Gene', (101, 109))	('RTK', 'Gene', '5979', (198, 201))	('RTK', 'Gene', (52, 55))	('Receptor Tyrosine Kinase', 'Gene', (26, 50))	('PI3K/AKT', 'Gene', '5295;207', (180, 188))	('PI3K/AKT', 'Gene', '5295;207', (101, 109))	('Mutations', 'Var', (0, 9))	('RTK', 'Gene', '5979', (52, 55))	('RTK', 'Gene', (198, 201))	('Receptor Tyrosine Kinase', 'Gene', '5979', (26, 50))	('PI3K/AKT', 'Gene', (180, 188))
56248	28528867	Low-level as well as high-level copy losses of PTEN and STK11 could be associated with greater mTOR signaling.	('greater', 'PosReg', (87, 94))	('STK11', 'Gene', (56, 61))	('PTEN', 'Gene', (47, 51))	('mTOR signaling', 'MPA', (95, 109))	('STK11', 'Gene', '6794', (56, 61))	('copy losses', 'Var', (32, 43))
56249	28528867	PI3K/AKT/mTOR pathway activity, when measured at the protein level, was explained by known mutations or copy alteration in most but not all of the cases examined, suggesting additional, unexplained or underappreciated mechanisms of pathway activation.	('PI3K/AKT', 'Gene', '5295;207', (0, 8))	('copy alteration', 'Var', (104, 119))	('mutations', 'Var', (91, 100))	('PI3K/AKT', 'Gene', (0, 8))	('activity', 'MPA', (22, 30))
56250	28528867	Focusing on the "High P-AKT" tumor group (n=764), with high phospho-AKT but lacking a DNA alteration classically associated with PI3K/AKT activation, these tumors were highly enriched for specific cancer types including LGG, PRAD, KIRC, and PCPG (Figure 7C), as well as for IDH1 mutations (associated primarily with LGG, i.e.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('PRAD', 'Disease', (225, 229))	('P-AKT" tumor', 'Disease', (22, 34))	('mutations', 'Var', (279, 288))	('P-AKT" tumor', 'Disease', 'MESH:C000656865', (22, 34))	('LGG', 'Disease', (316, 319))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('KIRC', 'Disease', (231, 235))	('LGG', 'Disease', (220, 223))	('PI3K/AKT', 'Gene', (129, 137))	('cancer', 'Disease', (197, 203))	('IDH1', 'Gene', (274, 278))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('PI3K/AKT', 'Gene', '5295;207', (129, 137))	('tumors', 'Disease', (156, 162))	('PCPG', 'Disease', (241, 245))	('IDH1', 'Gene', '3417', (274, 278))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
56251	28528867	gliomas) and VHL mutations (associated with renal cancers).	('renal cancers', 'Disease', (44, 57))	('VHL', 'Disease', (13, 16))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('associated', 'Reg', (28, 38))	('glioma', 'Phenotype', 'HP:0009733', (0, 6))	('renal cancers', 'Disease', 'MESH:D007680', (44, 57))	('gliomas', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (0, 7))	('mutations', 'Var', (17, 26))	('gliomas', 'Phenotype', 'HP:0009733', (0, 7))
56253	28528867	These mutations and proteins would suggest a model (Figure 7E), whereby mutant IDH1 may lead to high phospho-ERK, and SRC can activate PI3K  and where activated mTOR signaling may activate transcription targets of hypoxia via HIF-1alpha (particularly in the absence of VHL), including NDRG1 and growth factors that may lead to a further increase ERK and PI3K signaling.	('PI3', 'Gene', (354, 357))	('NDRG1', 'Gene', (285, 290))	('activate', 'PosReg', (126, 134))	('hypoxia via HIF-1alpha', 'Disease', (214, 236))	('VHL', 'Disease', 'MESH:D006623', (269, 272))	('activate', 'PosReg', (180, 188))	('IDH1', 'Gene', (79, 83))	('ERK', 'Gene', (346, 349))	('SRC', 'Gene', '6714', (118, 121))	('mutant', 'Var', (72, 78))	('PI3', 'Gene', '5266', (135, 138))	('IDH1', 'Gene', '3417', (79, 83))	('increase', 'PosReg', (337, 345))	('SRC', 'Gene', (118, 121))	('ERK', 'Gene', '5594', (109, 112))	('VHL', 'Disease', (269, 272))	('PI3', 'Gene', '5266', (354, 357))	('NDRG1', 'Gene', '10397', (285, 290))	('hypoxia via HIF-1alpha', 'Disease', 'MESH:D000860', (214, 236))	('PI3', 'Gene', (135, 138))	('ERK', 'Gene', '5594', (346, 349))	('ERK', 'Gene', (109, 112))
56254	28528867	Notably, VHL was recently found to directly suppress AKT activity, and generation of 2-hydroxyglutarate (2HG) by mutated IDH1/2 was also recently found to lead to the activation of mTOR; our data here would highlight the importance of both of the above relationships in the setting of human cancer.	('mTOR', 'Pathway', (181, 185))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('AKT', 'Pathway', (53, 56))	('IDH1/2', 'Gene', '3417;3418', (121, 127))	('activation', 'PosReg', (167, 177))	('human', 'Species', '9606', (285, 290))	('suppress', 'NegReg', (44, 52))	('mutated', 'Var', (113, 120))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (85, 103))	('IDH1/2', 'Gene', (121, 127))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('VHL', 'Disease', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
56259	28528867	Most of the correlations observed in our study fit well with our understanding of PI3K/AKT/mTOR signaling, in particular the genetic or genomic alteration of specific genes having an impact on phospho-protein expression of key downstream intermediates.	('PI3K/AKT', 'Gene', (82, 90))	('alteration', 'Var', (144, 154))	('PI3K/AKT', 'Gene', '5295;207', (82, 90))	('phospho-protein expression', 'MPA', (193, 219))	('impact', 'Reg', (183, 189))
56261	28528867	Where gene mutation often inactivates one allele, loss of one allele by copy alteration, which is common across multiple cancer types for both PTEN and STK11, would presumably have the same impact on loss of gene function.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('loss', 'NegReg', (50, 54))	('copy alteration', 'Var', (72, 87))	('inactivates', 'NegReg', (26, 37))	('STK11', 'Gene', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('mutation', 'Var', (11, 19))	('cancer', 'Disease', (121, 127))	('STK11', 'Gene', '6794', (152, 157))
56262	28528867	IDH1 and VHL mutations would also be implicated here with PI3K/AKT/mTOR, where such alterations were associated with particularly high AKT/mTOR signaling, and which genes might be put forth for consideration as part of the "canon" of what would be recognized to constitute the core standard model of PI3K/AKT/mTOR pathway.	('IDH1', 'Gene', '3417', (0, 4))	('PI3K/AKT', 'Gene', '5295;207', (300, 308))	('PI3K/AKT', 'Gene', (58, 66))	('implicated', 'Reg', (37, 47))	('PI3K/AKT', 'Gene', '5295;207', (58, 66))	('high', 'PosReg', (130, 134))	('associated', 'Reg', (101, 111))	('AKT/mTOR signaling', 'MPA', (135, 153))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('VHL', 'Disease', (9, 12))	('PI3K/AKT', 'Gene', (300, 308))
56271	28528867	Results of this study include a comprehensive and annotated catalog of PI3K/AKT/mTOR-associated variants across over 10,000 tumors, which may serve as an additional resource for assessing variants in the clinical setting.	('000 tumors', 'Disease', 'MESH:D009369', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('variants', 'Var', (96, 104))	('PI3K/AKT', 'Gene', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('000 tumors', 'Disease', (120, 130))	('PI3K/AKT', 'Gene', '5295;207', (71, 79))
56274	28528867	PIK3CA mutation, has been shown to increase response rates in clinical trials testing inhibitors to PI3K/AKT/mTOR pathway, though non-responders are still common.	('PI3K/AKT', 'Gene', '5295;207', (100, 108))	('increase', 'PosReg', (35, 43))	('response', 'MPA', (44, 52))	('PIK3CA', 'Gene', (0, 6))	('PI3K/AKT', 'Gene', (100, 108))	('mutation', 'Var', (7, 15))
56290	28528867	Pan-cancer RPPA profiles were scored for a PI3K/AKT pathway signature, defined as the sum of normalized phosphoprotein levels of AKT (both S473 and T308 RPPA features), GSK3 (S9 and S21/S9 features), PRAS40, and phospho-TSC2.	('TSC2', 'Gene', '7249', (220, 224))	('S9', 'Var', (175, 177))	('PRAS40', 'Gene', '84335', (200, 206))	('Pan-cancer', 'Disease', (0, 10))	('TSC2', 'Gene', (220, 224))	('PI3K/AKT', 'Gene', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('AKT', 'Pathway', (129, 132))	('T308 RPPA', 'Var', (148, 157))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('PI3K/AKT', 'Gene', '5295;207', (43, 51))	('PRAS40', 'Gene', (200, 206))	('S21/S9 features', 'Var', (182, 197))
56291	28528867	RPPA profiles were also scored for an mTOR pathway signature, defined as the sum of phosphoprotein levels of mTOR, 4EBP1 (S65, T37/T46, and T70 RPPA features), P70S6K, and S6 (S235/S236 and S240/S244 features).	('4EBP1', 'Gene', '1978', (115, 120))	('S240/S244 features', 'Var', (190, 208))	('P70S6K', 'Gene', (160, 166))	('4EBP1', 'Gene', (115, 120))	('mTOR', 'Gene', (109, 113))	('S65', 'Var', (122, 125))	('T70 RPPA', 'Var', (140, 148))	('S235/S236', 'Var', (176, 185))	('T37/T46', 'Var', (127, 134))	('P70S6K', 'Gene', '6198', (160, 166))
56299	28528867	Manual review of variants involving AKT1/2/3, MTOR, PIK3CA, PTEN, RHEB, TSC1/2 was also carried out by domain experts in the analysis group.	('MTOR', 'Gene', (46, 50))	('TSC1/2', 'Gene', (72, 78))	('variants', 'Var', (17, 25))	('AKT1/2/3', 'Gene', (36, 44))	('PIK3CA', 'Gene', (52, 58))	('MTOR', 'Gene', '2475', (46, 50))	('RHEB', 'Gene', (66, 70))	('PTEN', 'Gene', (60, 64))	('RHEB', 'Gene', '6009', (66, 70))	('AKT1/2/3', 'Gene', '207;208;10000', (36, 44))	('TSC1/2', 'Gene', '7248;7249', (72, 78))
56300	28528867	Mutations that were predicted as potentially functional by any of the above:as well as mutations in tumor suppressor genes (e.g.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
56301	28528867	The effects of mutations on the function of PIK3CA and PIK3R1 were assessed in Ba/F3 and MCF10A by survival assay as previously described  with lentiviral vector pHAGE used in the cloning.	('PIK3CA', 'Gene', (44, 50))	('PIK3R1', 'Gene', (55, 61))	('mutations', 'Var', (15, 24))	('MCF10A', 'CellLine', 'CVCL:0598', (89, 95))
56302	28528867	In Ba/F3, the PIK3CA mutations were assigned as "Strong activating (SA)" if the mutations have an activity higher than M1043I (known moderate driver); as "Moderate activating (MA)" if the mutations have a similar or lower activity than M1043I; as "No difference from WT (NDFW)" if the mutations have a similar activity with WT; or as "Inactivating (INA)" if the mutations have an activity similar to negative controls (GFP/mCherry/Luciferase).	('M1043I', 'Mutation', 'rs121913283', (236, 242))	('lower', 'NegReg', (216, 221))	('mutations', 'Var', (80, 89))	('M1043I', 'Mutation', 'rs121913283', (119, 125))	('higher', 'PosReg', (107, 113))	('PIK3CA', 'Gene', (14, 20))	('activity', 'MPA', (222, 230))	('activity', 'MPA', (98, 106))	('mutations', 'Var', (21, 30))
56303	28528867	The PIK3R1 mutations were assigned as "SA" if the mutations have a relative level of activation higher than that of PIK3CA M1043I comparing to negative controls; as "MA" if the mutations have a relative level of activation between PIK3CA M1043I and WT; as "Weak activating (WA)" if the mutations have a relative level of activation between PIK3CA WT and negative controls; or as "NDFW" if the mutations have a similar activity with WT.	('mutations', 'Var', (11, 20))	('activating', 'MPA', (262, 272))	('PIK3R1', 'Gene', (4, 10))	('M1043I', 'Mutation', 'rs121913283', (123, 129))	('activation higher', 'PosReg', (85, 102))	('M1043I', 'Mutation', 'rs121913283', (238, 244))	('PIK3CA M1043I', 'Var', (231, 244))
56304	28528867	In MCF10A, the PIK3CA mutations were assigned as "SA" and "NDFW" by the same mean as in Ba/F3 model.	('MCF10A', 'CellLine', 'CVCL:0598', (3, 9))	('mutations', 'Var', (22, 31))	('PIK3CA', 'Gene', (15, 21))
56305	28528867	The mutations were assigned as "MA" and "WA" if the mutations have an activity above and lower than 50% of that of M1043I, respectively.	('mutations', 'Var', (52, 61))	('M1043I', 'Mutation', 'rs121913283', (115, 121))	('lower', 'NegReg', (89, 94))	('activity', 'MPA', (70, 78))
56308	28528867	An "other gene mutation" class of Figures 7A and 7B involved nonsilent mutations for other genes represented in Figure 2A (AKTS1, DEPDC5, DEPTOR, MAPKAP1, MLST8, NPRL2, NPRL3, PDK1, PRR5, RHEB, RICTOR, RPTOR, PIK3C2B).	('RICTOR', 'Gene', (194, 200))	('MAPKAP1', 'Gene', '79109', (146, 153))	('DEPTOR', 'Gene', '64798', (138, 144))	('RPTOR', 'Gene', (202, 207))	('MLST8', 'Gene', '64223', (155, 160))	('PDK1', 'Gene', '5163', (176, 180))	('MLST8', 'Gene', (155, 160))	('NPRL3', 'Gene', (169, 174))	('RHEB', 'Gene', '6009', (188, 192))	('PIK3C2B', 'Gene', (209, 216))	('DEPDC5', 'Gene', '9681', (130, 136))	('PRR5', 'Gene', (182, 186))	('mutations', 'Var', (71, 80))	('DEPDC5', 'Gene', (130, 136))	('MAPKAP1', 'Gene', (146, 153))	('DEPTOR', 'Gene', (138, 144))	('PRR5', 'Gene', '55615', (182, 186))	('NPRL2', 'Gene', '10641', (162, 167))	('PIK3C2B', 'Gene', '5287', (209, 216))	('RPTOR', 'Gene', '57521', (202, 207))	('PDK1', 'Gene', (176, 180))	('RICTOR', 'Gene', '253260', (194, 200))	('NPRL3', 'Gene', '8131', (169, 174))	('NPRL2', 'Gene', (162, 167))	('RHEB', 'Gene', (188, 192))
56309	28528867	The RTK group represented cases with hotspot mutations in KRAS, BRAF, EGFR, or ERBB2, that were not also included in the other PI3K/AKT/mTOR-related groups.	('KRAS', 'Gene', (58, 62))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', '673', (64, 68))	('KRAS', 'Gene', '3845', (58, 62))	('EGFR', 'Gene', '1956', (70, 74))	('BRAF', 'Gene', (64, 68))	('RTK', 'Gene', '5979', (4, 7))	('ERBB2', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (79, 84))	('PI3K/AKT', 'Gene', (127, 135))	('EGFR', 'Gene', (70, 74))	('PI3K/AKT', 'Gene', '5295;207', (127, 135))	('RTK', 'Gene', (4, 7))
56311	28528867	When defining proteins that were highly expressed specifically within the High P-AKT group (Figure 7D), RPPA features were selected that were over- or under-expressed in the High P-AKT compared to unaligned cases (p<0.05, t-test on log-transformed data) for at least four of the seven cancer types, and differentially expressed in High P-AKT compared to unaligned and to PI3K/AKT/mTOR or RTK-altered cases across all cancer cases (p<0.01 for each).	('over-', 'PosReg', (142, 147))	('cancer', 'Disease', (417, 423))	('RTK', 'Gene', '5979', (388, 391))	('High', 'Var', (174, 178))	('under-expressed', 'NegReg', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('PI3K/AKT', 'Gene', (371, 379))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('High P-AKT', 'Var', (331, 341))	('RTK', 'Gene', (388, 391))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('PI3K/AKT', 'Gene', '5295;207', (371, 379))	('cancer', 'Disease', 'MESH:D009369', (417, 423))
56321	28528867	Multiplatform-based survey of PI3K/AKT/mTOR across over 10,000 human cancers Distinct classes of somatic alteration associated with greater pathway activation Functional interrogation of specific mutations in PIK3CA and PIK3R1 Support for inclusion of IDH1 and VHL mutations within the canonical pathway model	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Disease', (69, 76))	('human', 'Species', '9606', (63, 68))	('PIK3CA', 'Gene', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PIK3R1', 'Gene', (220, 226))	('IDH1', 'Gene', (252, 256))	('VHL', 'Disease', 'MESH:D006623', (261, 264))	('VHL', 'Disease', (261, 264))	('PI3K/AKT', 'Gene', (30, 38))	('IDH1', 'Gene', '3417', (252, 256))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('PI3K/AKT', 'Gene', '5295;207', (30, 38))	('mutations', 'Var', (196, 205))
56425	22490764	A key hallmark of tumor formation involves a loss of normal cell homeostasis because of the deregulated and dysfunctional cell signaling mediated by one or more of four principal mechanisms: (1) autocrine activation, (2) chromosomal translocation, (3) the overexpression of receptor tyrosine kinases, and (4) gain of function mutations.	('tumor', 'Disease', (18, 23))	('overexpression', 'PosReg', (256, 270))	('chromosomal', 'CPA', (221, 232))	('deregulated', 'MPA', (92, 103))	('mutations', 'Var', (326, 335))	('cell homeostasis', 'MPA', (60, 76))	('gain of function', 'PosReg', (309, 325))	('dysfunctional', 'Disease', (108, 121))	('dysfunctional', 'Disease', 'MESH:D006331', (108, 121))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('autocrine activation', 'MPA', (195, 215))	('loss', 'NegReg', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
56430	22490764	Truncations, amplifications, and the overexpression of the epidermal growth factor receptor family of receptors were reported in pediatric high grade gliomas and brainstem gliomas, ependymomas, and medulloblastomas, making the epidermal growth factor receptor a rational therapeutic target.	('overexpression', 'PosReg', (37, 51))	('brainstem glioma', 'Phenotype', 'HP:0010796', (162, 178))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('Truncations', 'Var', (0, 11))	('ependymoma', 'Phenotype', 'HP:0002888', (181, 191))	('medulloblastomas', 'Disease', 'MESH:D008527', (198, 214))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('medulloblastoma', 'Phenotype', 'HP:0002885', (198, 213))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (162, 179))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))	('ependymomas', 'Disease', 'MESH:D004806', (181, 192))	('amplifications', 'Var', (13, 27))	('gliomas', 'Disease', (150, 157))	('medulloblastomas', 'Disease', (198, 214))	('ependymomas', 'Disease', (181, 192))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Disease', (172, 179))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
56454	22490764	Amplifications of platelet-derived growth factor receptor-alpha were demonstrated in pediatric high-grade gliomas and diffuse, intrinsic brainstem gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (18, 63))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('Amplifications', 'Var', (0, 14))	('brainstem glioma', 'Phenotype', 'HP:0010796', (137, 153))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Disease', (147, 154))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Disease', (106, 113))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('platelet-derived growth factor receptor-alpha', 'Gene', (18, 63))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (137, 154))
56455	22490764	Another study revealed that the high expression of platelet-derived growth factor receptor had a significant association with malignant histology in pediatric gliomas.	('high', 'Var', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('pediatric gliomas', 'Disease', (149, 166))	('association', 'Reg', (109, 120))	('malignant', 'Disease', (126, 135))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('pediatric gliomas', 'Disease', 'MESH:D005910', (149, 166))	('platelet-derived', 'Protein', (51, 67))
56467	22490764	Inhibiting the vascular endothelial growth factor receptor pathways constitutes a promising method to prevent further tumor expansion.	('vascular endothelial growth factor', 'Gene', '7422', (15, 49))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('vascular endothelial growth factor', 'Gene', (15, 49))
56479	22490764	The activation of Ras because of the overexpression or amplification of growth factor receptors such as epidermal growth factor receptor, as well as Ras mutations, have both been implicated in Ras-induced gliomagenesis because of the resultant activation of downstream effector pathways such as the Raf-mitogen-activated protein kinase-extracellular regulated mitogen-activated protein kinase-extracellular regulated mitogen-activated protein kinase pathway.	('overexpression', 'PosReg', (37, 51))	('Raf', 'Gene', '22882', (299, 302))	('Ras', 'Gene', (149, 152))	('Ras', 'Gene', (18, 21))	('mutations', 'Var', (153, 162))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('glioma', 'Disease', (205, 211))	('implicated', 'Reg', (179, 189))	('Raf', 'Gene', (299, 302))	('Ras-induced', 'Disease', (193, 204))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('activation', 'PosReg', (4, 14))	('activation', 'PosReg', (244, 254))
56480	22490764	v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations have been implicated in pediatric low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('mutations', 'Var', (54, 63))	('implicated', 'Reg', (74, 84))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (0, 46))	('BRAF', 'Gene', (48, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (0, 46))
56486	22490764	Sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals, Inc., Wayne, NJ, and Onyx Pharmaceuticals, Inc., Emeryville, CA) is a multikinase inhibitor with activity against v-raf-1 murine leukemia viral oncogene homolog 1 (CRAF) and wild-type and mutant (V600E) BRAF kinases, and also demonstrates activity against kinases involved in angiogenesis (vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, platelet-derived growth factor receptor-beta, c-kit, and fibroblast growth factor receptor-1).	('activity', 'MPA', (151, 159))	('v-raf-1 murine leukemia viral oncogene homolog 1', 'Gene', '5894', (168, 216))	('activity', 'MPA', (293, 301))	('V600E', 'Mutation', 'rs113488022', (250, 255))	('v-raf-1 murine leukemia viral oncogene homolog 1', 'Gene', (168, 216))	('CRAF', 'Gene', (218, 222))	('fibroblast growth factor receptor-1', 'Gene', (495, 530))	('c-kit', 'Gene', (484, 489))	('platelet-derived growth factor receptor-beta', 'Gene', '5159', (438, 482))	('vascular endothelial growth factor receptor-3', 'Gene', (391, 436))	('V600E', 'Var', (250, 255))	('mutant (V600E', 'Var', (242, 255))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('platelet-derived growth factor receptor-beta', 'Gene', (438, 482))	('vascular endothelial growth factor receptor-3', 'Gene', '2324', (391, 436))	('c-kit', 'Gene', '16590', (484, 489))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('CRAF', 'Gene', '110157', (218, 222))	('fibroblast growth factor receptor-1', 'Gene', '14182', (495, 530))
56487	22490764	Sorafenib is also under study for children with recurrent low-grade gliomas, based primarily on data demonstrating BRAF mutations in the majority of pediatric pilocytic astrocytomas.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('BRAF', 'Gene', (115, 119))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('mutations', 'Var', (120, 129))	('pediatric pilocytic astrocytomas', 'Disease', (149, 181))	('pediatric pilocytic astrocytomas', 'Disease', 'MESH:D001254', (149, 181))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('children', 'Species', '9606', (34, 42))
56492	22490764	Tumors with BRAF mutations were demonstrated to be very sensitive to mitogen-activated protein kinase-extracellular regulated mitogen-activated protein kinase inhibitors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRAF', 'Gene', (12, 16))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (17, 26))
56493	22490764	A mitogen-activated protein kinase-extracellular regulated mitogen-activated protein kinase inhibitor, AZD6244, was demonstrated to be active against BRAF mutant juvenile pilocytic astrocytoma xenografts in preclinical testing.	('pilocytic astrocytoma', 'Disease', (171, 192))	('AZD6244', 'Chemical', 'MESH:C517975', (103, 110))	('astrocytoma', 'Phenotype', 'HP:0009592', (181, 192))	('mutant', 'Var', (155, 161))	('BRAF', 'Gene', (150, 154))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (171, 192))
56496	22490764	Mutations resulting in the loss of the phosphatase and tensin homologue, as observed in gliomas, result in activation of the phosphatidylinositol 3-kinase/protein kinase B pathway and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('protein kinase B', 'Gene', '2185', (155, 171))	('gliomas', 'Disease', (88, 95))	('tumor', 'Disease', (184, 189))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('activation', 'PosReg', (107, 117))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('loss', 'NegReg', (27, 31))	('protein kinase B', 'Gene', (155, 171))
56501	22490764	This idea is based on the premise that the inhibition of phosphatidylinositol 3-kinase may activate other prosurvival pathways, which may be inhibited by the addition of mammalian target of rapamycin inhibitors.	('mammalian target of rapamycin', 'Gene', '2475', (170, 199))	('mammalian target of rapamycin', 'Gene', (170, 199))	('inhibition', 'Var', (43, 53))	('prosurvival pathways', 'Pathway', (106, 126))	('phosphatidylinositol', 'Var', (57, 77))	('activate', 'PosReg', (91, 99))
56503	22490764	A recent study revealed that phosphatidylinositol 3-kinase/protein kinase B pathway inhibitors can inhibit Wingless-type murine mammary virus type integration site family/beta-catenin pathways via crosstalk, thus suggesting a potential role for phosphatidylinositol 3-kinase/protein kinase B inhibitors in medulloblastoma.	('inhibitors', 'Var', (84, 94))	('protein kinase B', 'Gene', '2185', (275, 291))	('protein kinase B', 'Gene', '2185', (59, 75))	('inhibit', 'NegReg', (99, 106))	('medulloblastoma', 'Phenotype', 'HP:0002885', (306, 321))	('medulloblastoma', 'Disease', 'MESH:D008527', (306, 321))	('protein kinase B', 'Gene', (275, 291))	('murine', 'Species', '10090', (121, 127))	('crosstalk', 'Interaction', (197, 206))	('protein kinase B', 'Gene', (59, 75))	('medulloblastoma', 'Disease', (306, 321))
56529	22490764	Sonic Hedgehog pathway mutations have been implicated in the pathogenesis of medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (77, 92))	('implicated', 'Reg', (43, 53))	('medulloblastoma', 'Disease', (77, 92))	('mutations', 'Var', (23, 32))	('Sonic', 'Gene', (0, 5))	('medulloblastoma', 'Disease', 'MESH:D008527', (77, 92))
56530	22490764	Gorlin syndrome, which is characterized by multiple basal cell carcinomas with a predisposition for medulloblastomas, was associated with PTCH1 mutations.	('basal cell carcinomas', 'Disease', (52, 73))	('associated', 'Reg', (122, 132))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (52, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('medulloblastomas', 'Disease', 'MESH:D008527', (100, 116))	('medulloblastoma', 'Phenotype', 'HP:0002885', (100, 115))	('PTCH1', 'Gene', (138, 143))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (52, 73))	('medulloblastomas', 'Disease', (100, 116))	('Gorlin syndrome', 'Disease', (0, 15))	('mutations', 'Var', (144, 153))
56531	22490764	Since then, multiple studies indicate that PTCH1, SMO, and suppressor of fused homolog mutations are associated with medulloblastoma.	('PTCH1', 'Gene', (43, 48))	('medulloblastoma', 'Disease', 'MESH:D008527', (117, 132))	('medulloblastoma', 'Phenotype', 'HP:0002885', (117, 132))	('SMO', 'Gene', (50, 53))	('associated', 'Reg', (101, 111))	('medulloblastoma', 'Disease', (117, 132))	('mutations', 'Var', (87, 96))
56534	22490764	GDC0449 is a SMO inhibitor currently undergoing medulloblastoma clinical trials.	('medulloblastoma', 'Phenotype', 'HP:0002885', (48, 63))	('medulloblastoma', 'Disease', 'MESH:D008527', (48, 63))	('GDC0449', 'Chemical', 'MESH:C538724', (0, 7))	('GDC0449', 'Var', (0, 7))	('medulloblastoma', 'Disease', (48, 63))
56572	20718706	Although somatic oncogenic mutations of Ras genes are frequent in several cancer types, early investigations on gliomas revealed disappointing facts that the Ras mutations are nearly absent in malignant gliomas and that the BRAF mutations are present in a very small percentage of gliomas.	('cancer', 'Disease', (74, 80))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('malignant gliomas', 'Disease', (193, 210))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gliomas', 'Disease', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('gliomas', 'Disease', (281, 288))	('Ras', 'Gene', (158, 161))	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('gliomas', 'Disease', (112, 119))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('gliomas', 'Disease', 'MESH:D005910', (281, 288))	('mutations', 'Var', (162, 171))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('absent', 'NegReg', (183, 189))	('gliomas', 'Phenotype', 'HP:0009733', (281, 288))	('malignant gliomas', 'Disease', 'MESH:D005910', (193, 210))
56574	20718706	In contrast to the initial negative results on the somatic mutations of H-Ras, K-Ras and BRAF, recent breakthrough studies on pediatric low-grade astrocytomas uncovered genetic alterations of the BRAF gene involving copy number gains and rearrangements.	('copy number gains', 'Var', (216, 233))	('K-Ras', 'Gene', '3845', (79, 84))	('astrocytomas', 'Disease', 'MESH:D001254', (146, 158))	('K-Ras', 'Gene', (79, 84))	('astrocytoma', 'Phenotype', 'HP:0009592', (146, 157))	('BRAF', 'Gene', (196, 200))	('rearrangements', 'Var', (238, 252))	('astrocytomas', 'Disease', (146, 158))
56575	20718706	The 7q34 rearrangements result in a novel in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E).	('BRAF', 'MPA', (105, 109))	('V600E', 'Mutation', 'rs113488022', (153, 158))	('KIAA1549', 'Gene', (51, 59))	('KIAA1549', 'Gene', '57670', (51, 59))	('result in', 'Reg', (24, 33))	('rearrangements', 'Var', (9, 23))
56604	20718706	Most recent discoveries of the BRAF and RAF-1 gene copy number gains, rearrangements and the resulted constitutive active fusion proteins in pediatric pilocytic astrocytomas have drawn significant attention and provided novel genetic mechanisms by which the Ras-RAF signaling can be permanently activated.	('RAF', 'Gene', (262, 265))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('RAF', 'Gene', '22882', (262, 265))	('rearrangements', 'Var', (70, 84))	('RAF', 'Gene', (32, 35))	('pediatric pilocytic astrocytomas', 'Disease', (141, 173))	('pediatric pilocytic astrocytomas', 'Disease', 'MESH:D001254', (141, 173))	('RAF', 'Gene', '22882', (32, 35))	('RAF', 'Gene', (40, 43))	('RAF', 'Gene', '22882', (40, 43))	('copy number', 'Var', (51, 62))	('gains', 'PosReg', (63, 68))
56610	20718706	Discoveries of H-Ras mutations in 1980's have led to the accepted notion that the Ras genes are the most common targets for somatic gain-of-function mutations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (149, 158))	('H-Ras', 'Gene', (15, 20))	('human', 'Species', '9606', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('gain-of-function', 'PosReg', (132, 148))	('mutations', 'Var', (21, 30))
56612	20718706	Specifically, mutations in codon 12, 13, or 61 of one of the three Ras proto-oncogenes (H-Ras, K-Ras and N-Ras) transform them into oncogenes.	('K-Ras', 'Gene', '3845', (95, 100))	('transform', 'Reg', (112, 121))	('oncogenes', 'CPA', (132, 141))	('K-Ras', 'Gene', (95, 100))	('mutations in', 'Var', (14, 26))
56616	20718706	evaluated 30 primary GBM tumors for Ras mutations and did not find any specimen to carry the mutant genes.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (40, 49))	('Ras', 'Protein', (36, 39))	('GBM tumors', 'Disease', (21, 31))	('GBM tumors', 'Disease', 'MESH:D005910', (21, 31))
56617	20718706	screened 94 primary GBMs for mutations in the three Ras genes and failed to find any of the tumors to carry H-Ras and K-Ras mutations and only two GBMs (2.1%) to express mutated N-Ras (G12D).	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (124, 133))	('K-Ras', 'Gene', (118, 123))	('mutations', 'Var', (29, 38))	('H-Ras', 'Protein', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('G12D', 'Mutation', 'rs121913529', (185, 189))	('K-Ras', 'Gene', '3845', (118, 123))	('tumors', 'Disease', (92, 98))
56618	20718706	In line with these observations, The Cancer Genome Atlas (TCGA) pilot project reported a 2% mutation rate in the Ras genes in 206 GBM samples.	('Cancer Genome Atlas', 'Disease', (37, 56))	('mutation', 'Var', (92, 100))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (37, 56))	('Ras genes', 'Gene', (113, 122))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))
56619	20718706	identified one of 21 pilocytic astrocytomas to carry the K-Ras (G13R) mutation but did not detect any H-Ras or N-Ras mutations in the tumor cohort.	('pilocytic astrocytomas', 'Disease', (21, 43))	('H-Ras or N-Ras', 'Disease', (102, 116))	('K-Ras', 'Gene', '3845', (57, 62))	('G13R', 'Mutation', 'rs121913535', (64, 68))	('H-Ras or N-Ras', 'Disease', 'MESH:D000848', (102, 116))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (21, 43))	('astrocytoma', 'Phenotype', 'HP:0009592', (31, 42))	('K-Ras', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutation', 'Var', (70, 78))	('tumor', 'Disease', (134, 139))
56620	20718706	identified one pilocytic astrocytoma out of 25 low-grade astrocytomas to contain the somatic G12A K-Ras mutation and did not find any mutations in the H-Ras and N-Ras genes.	('K-Ras', 'Gene', '3845', (98, 103))	('astrocytomas', 'Disease', 'MESH:D001254', (57, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('astrocytomas', 'Disease', (57, 69))	('K-Ras', 'Gene', (98, 103))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (15, 36))	('G12A', 'Mutation', 'rs121913529', (93, 97))	('G12A', 'Var', (93, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (57, 68))	('pilocytic astrocytoma', 'Disease', (15, 36))
56621	20718706	Despite a low incidence of Ras mutations in GBM, TCGA pilot project found that at least 23% harbored somatic neurofibromatosis 1 (NF1) gene inactivating mutations or deletions albeit earlier studies reported a lower frequency of NF1 mutations.	('NF1', 'Gene', (229, 232))	('NF1', 'Gene', '4763', (229, 232))	('neurofibromatosis 1', 'Gene', '4763', (109, 128))	('inactivating', 'NegReg', (140, 152))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (109, 126))	('NF1', 'Gene', (130, 133))	('neurofibromatosis 1', 'Gene', (109, 128))	('NF1', 'Gene', '4763', (130, 133))	('deletions', 'Var', (166, 175))
56625	20718706	The BRAF somatic missense mutations are present within the kinase domain in which a single substitution (V599E; also named as V600E) accounts for 80% of all BRAF mutations and transforms NIH3T3 cells.	('V600E', 'Var', (126, 131))	('mutations', 'Var', (162, 171))	('transforms', 'Reg', (176, 186))	('V600E', 'Mutation', 'rs113488022', (126, 131))	('NIH3T3', 'CellLine', 'CVCL:0594', (187, 193))	('BRAF', 'Gene', (157, 161))	('V599E;', 'Var', (105, 111))	('V599E', 'Mutation', 'p.V599E', (105, 110))
56626	20718706	BRAF mutations are frequent in several types of human cancers including the majority of malignant melanomas and melanoma metastases.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('melanoma metastases', 'Disease', 'MESH:D009362', (112, 131))	('cancers', 'Disease', (54, 61))	('frequent', 'Reg', (19, 27))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('human', 'Species', '9606', (48, 53))	('mutations', 'Var', (5, 14))	('malignant melanomas', 'Phenotype', 'HP:0002861', (88, 107))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('malignant melanomas', 'Disease', 'MESH:D008545', (88, 107))	('BRAF', 'Gene', (0, 4))	('melanoma metastases', 'Disease', (112, 131))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('malignant melanomas', 'Disease', (88, 107))
56627	20718706	Analyses of glioma cell lines and primary specimens, however, revealed a lower frequency of BRAF mutation.	('glioma', 'Disease', (12, 18))	('BRAF', 'Gene', (92, 96))	('mutation', 'Var', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
56631	20718706	recently reported the identification of a novel BRAF mutation from a pilocytic astrocytoma that is the result of a three nucleotide insertion at codon 598 of the BRAF gene.	('mutation', 'Var', (53, 61))	('BRAF', 'Gene', (162, 166))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('pilocytic astrocytoma', 'Disease', (69, 90))	('BRAF', 'Disease', (48, 52))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (69, 90))
56632	20718706	Despite its low frequency (1/44), this novel BRAF mutant mimics the hotspot V600E mutation and is constitutively active and transforming.	('V600E', 'Var', (76, 81))	('V600E', 'Mutation', 'rs113488022', (76, 81))	('mutant', 'Var', (50, 56))
56633	20718706	Together, these findings indicate that BRAF activation mutations are not a frequent event in gliomas.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('mutations', 'Var', (55, 64))	('BRAF', 'Gene', (39, 43))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
56647	20718706	reported that BRAF rearrangements are present in 42 of the 70 sporadic pilocytic astrocytomas analyzed and that they are frequent in pilocytic astrocytomas located in the cerebellum (74%), brainstem (63%) and the 4th ventricle (50%), but is absent in optic nerve and midbrain.	('astrocytoma', 'Phenotype', 'HP:0009592', (81, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (133, 155))	('pilocytic astrocytomas', 'Disease', (71, 93))	('rearrangements', 'Var', (19, 33))	('BRAF', 'Gene', (14, 18))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (71, 93))	('pilocytic astrocytomas', 'Disease', (133, 155))
56648	20718706	Taken, together, these interesting observations warrant future investigations that determine whether BRAF gene duplication and rearrangements are the cause of pilocytic astrocytomas and whether these genetic alterations are also present in other cancer types with increased BRAF activity.	('BRAF', 'Gene', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('rearrangements', 'Var', (127, 141))	('cause', 'Reg', (150, 155))	('cancer', 'Disease', (246, 252))	('pilocytic astrocytomas', 'Disease', (159, 181))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (159, 181))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('gene duplication', 'Var', (106, 122))
56650	20718706	Both studies identified tandem duplication at chromosome 3p25 which produces an inframe fusion between SRGAP3 and RAF-1.	('produces', 'Reg', (68, 76))	('SRGAP3', 'Gene', '9901', (103, 109))	('RAF-1', 'Gene', (114, 119))	('tandem duplication', 'Var', (24, 42))	('SRGAP3', 'Gene', (103, 109))	('inframe fusion', 'MPA', (80, 94))
56653	20718706	The incidence of this novel fusion, however, is very low in low-grade astrocytomas with reported 1/44 and 1/32 of the low-grade astrocytomas carrying the rearranged gene product.	('astrocytomas', 'Disease', (128, 140))	('rearranged', 'Var', (154, 164))	('astrocytomas', 'Disease', 'MESH:D001254', (70, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('astrocytomas', 'Disease', 'MESH:D001254', (128, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))	('astrocytomas', 'Disease', (70, 82))
56654	20718706	Taken together, recent discoveries of BRAF and RAF-1 genetic alterations point to a new avenue of research that will shed new light onto the mechanisms by which the Ras signaling is activated in low-grade astrocytomas.	('RAF-1', 'Gene', (47, 52))	('genetic alterations', 'Var', (53, 72))	('BRAF', 'Gene', (38, 42))	('activated', 'PosReg', (182, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (205, 216))	('astrocytomas', 'Disease', 'MESH:D001254', (205, 217))	('Ras', 'MPA', (165, 168))	('astrocytomas', 'Disease', (205, 217))
56656	20718706	Given the consistent high incidences of the rearranged KIAA1549:BRAF fusion gene in pilocytic astrocytomas, it is of importance to conduct in vivo animal studies in order to determine whether the rearrangement event is a cause for the formation of these tumors.	('tumors', 'Disease', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('rearranged', 'Var', (44, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('KIAA1549', 'Gene', '57670', (55, 63))	('KIAA1549', 'Gene', (55, 63))	('pilocytic astrocytomas', 'Disease', (84, 106))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (84, 106))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
56657	20718706	This investigation is essential given the facts that low-grade astrocytomas are the most frequent CNS tumors in children and its recurrence is common following surgical removal and that in adults, low-grade gliomas can undergo malignant transformation into malignant highgrade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('gliomas', 'Disease', 'MESH:D005910', (277, 284))	('astrocytomas', 'Disease', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('malignant transformation', 'CPA', (227, 251))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('gliomas', 'Phenotype', 'HP:0009733', (277, 284))	('children', 'Species', '9606', (112, 120))	('tumors', 'Disease', (102, 108))	('gliomas', 'Disease', (207, 214))	('low-grade', 'Disease', (53, 62))	('astrocytomas', 'Disease', 'MESH:D001254', (63, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('gliomas', 'Disease', 'MESH:D005910', (207, 214))	('low-grade', 'Var', (197, 206))	('gliomas', 'Disease', (277, 284))	('CNS tumors in children', 'Phenotype', 'HP:0100006', (98, 120))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))
56658	20718706	Furthermore, in light of the fact that BRAF oncogenic mutation predicts sensitivity to MEK inhibition, it is worth investigating whether MEK inhibition can be used to treat pilocytic astrocytomas with the BRAF fusion protein that resembles the activity of oncogenic BRAF protein.	('mutation', 'Var', (54, 62))	('MEK', 'Gene', (137, 140))	('MEK', 'Gene', '5609', (137, 140))	('MEK', 'Gene', (87, 90))	('MEK', 'Gene', '5609', (87, 90))	('pilocytic astrocytomas', 'Disease', (173, 195))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (173, 195))	('astrocytoma', 'Phenotype', 'HP:0009592', (183, 194))
56663	20718706	Albeit neither K-Ras (G12D) nor Akt alone was sufficient to induce GBM formation, their combination induced the formation of high-grade gliomas with the histological features of human GBMs.	('K-Ras', 'Gene', (15, 20))	('human', 'Species', '9606', (178, 183))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('gliomas', 'Disease', (136, 143))	('G12D', 'Mutation', 'rs121913529', (22, 26))	('induced', 'Reg', (100, 107))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('K-Ras', 'Gene', '3845', (15, 20))	('combination', 'Var', (88, 99))
56664	20718706	These investigators further demonstrated that K-Ras (G12D) expression cooperated with loss of INK4a-Arf locus to induce malignant transformation of astrocytes and neural progenitors into GBMs in mice.	('INK4a-Arf', 'Gene', (94, 103))	('mice', 'Species', '10090', (195, 199))	('induce', 'PosReg', (113, 119))	('loss', 'Var', (86, 90))	('expression', 'Species', '29278', (59, 69))	('G12D', 'Mutation', 'rs121913529', (53, 57))	('K-Ras', 'Gene', '3845', (46, 51))	('malignant transformation', 'CPA', (120, 144))	('INK4a-Arf', 'Gene', '12578', (94, 103))	('K-Ras', 'Gene', (46, 51))
56665	20718706	These results were in part supported by a more recent study by de Vries et al.. More recently in 2008, these researchers subsequently found that constitutive activation of RAF-1 cooperates with Akt activation or loss of INK4a-Arf to induce glioma oncogenesis in mice.	('induce', 'PosReg', (233, 239))	('activation', 'PosReg', (198, 208))	('mice', 'Species', '10090', (262, 266))	('glioma oncogenesis', 'Disease', 'MESH:D063646', (240, 258))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('glioma oncogenesis', 'Disease', (240, 258))	('INK4a-Arf', 'Gene', (220, 229))	('activation', 'PosReg', (158, 168))	('INK4a-Arf', 'Gene', '12578', (220, 229))	('Akt', 'Pathway', (194, 197))	('RAF-1', 'Gene', (172, 177))	('loss', 'Var', (212, 216))
56666	20718706	recently reported that combined expression of oncogenic BRAF (V600E) and activated Akt or loss of INK4a-Arf in neuronal progenitors induced GBM formation in nude mice.	('GBM formation', 'CPA', (140, 153))	('V600E', 'Var', (62, 67))	('loss', 'NegReg', (90, 94))	('INK4a-Arf', 'Gene', '12578', (98, 107))	('Akt', 'Pathway', (83, 86))	('nude mice', 'Species', '10090', (157, 166))	('INK4a-Arf', 'Gene', (98, 107))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('expression', 'Species', '29278', (32, 42))	('activated', 'PosReg', (73, 82))	('induced', 'Reg', (132, 139))
56670	20718706	demonstrated that H-Ras (G12V) cooperated with expression of human telomerase catalytic component (hTERT) and inactivation of tumor suppressors Rb/p53, thereby transforming normal astrocytes into AAs.	('transforming', 'Reg', (160, 172))	('p53', 'Gene', (147, 150))	('tumor', 'Disease', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('inactivation', 'Var', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('expression', 'Species', '29278', (47, 57))	('human', 'Species', '9606', (61, 66))	('G12V', 'Mutation', 'rs104894230', (25, 29))	('p53', 'Gene', '7157', (147, 150))
56671	20718706	When H-Ras (G12V) was replaced by myristoylated Akt or activated EGFR, the genetically modified astrocytes surprisingly did not undergo malignant transformation.	('myristoylated', 'Var', (34, 47))	('G12V', 'Mutation', 'rs104894230', (12, 16))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))
56684	20718706	Additional evidence further supports the notion that deregulated Ras-RAF pathway, independent of somatic mutations, plays an important role in the biology of malignant gliomas.	('malignant gliomas', 'Disease', (158, 175))	('RAF', 'Gene', '22882', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('RAF', 'Gene', (69, 72))	('malignant gliomas', 'Disease', 'MESH:D005910', (158, 175))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('deregulated', 'Var', (53, 64))
56687	20718706	Increased expression of BRAF due to copy number gains is a frequent event in low-grade pediatric astrocytomas.	('pediatric astrocytomas', 'Phenotype', 'HP:0009592', (87, 109))	('expression', 'MPA', (10, 20))	('expression', 'Species', '29278', (10, 20))	('Increased', 'PosReg', (0, 9))	('astrocytomas', 'Disease', 'MESH:D001254', (97, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('BRAF', 'Gene', (24, 28))	('copy number gains', 'Var', (36, 53))	('astrocytomas', 'Disease', (97, 109))
56695	20718706	An orally active, non-peptidic, small molecule FTI SCH 66336 (lonafarnib; Sarasar; Schering-Plough) competes with the CAAX substrate to inhibit Ras processing in tumor cells both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('inhibit', 'NegReg', (136, 143))	('tumor', 'Disease', (162, 167))	('Ras', 'Protein', (144, 147))	('lonafarnib', 'Chemical', 'MESH:C115354', (62, 72))	('FTI', 'Var', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
56705	20718706	Results of in vitro studies showed that POH resulted in a transient arrest in the G2/M phase of the cell cycle and induced apoptosis in human GBM cells.	('human', 'Species', '9606', (136, 141))	('POH', 'Chemical', 'MESH:C032208', (40, 43))	('apoptosis', 'CPA', (123, 132))	('arrest', 'CPA', (68, 74))	('induced', 'Reg', (115, 122))	('POH', 'Var', (40, 43))
56712	20718706	generated mice with a conditional RCE1 allele that is subjected to Cre-mediated excision and found that the loss of RCE1 reduced Ras-induced transformation in vitro.	('mice', 'Species', '10090', (10, 14))	('loss', 'Var', (108, 112))	('reduced', 'NegReg', (121, 128))	('RCE1', 'Gene', (116, 120))	('Ras-induced transformation', 'CPA', (129, 155))
56713	20718706	Using the same strategy, inactivation of ICMT1 has been shown to inhibit oncogenic K-Ras and BRAF-mediated transformation of normal fibroblasts.	('oncogenic', 'Protein', (73, 82))	('ICMT1', 'Gene', (41, 46))	('inactivation', 'Var', (25, 37))	('K-Ras', 'Gene', '3845', (83, 88))	('BRAF-mediated transformation', 'CPA', (93, 121))	('K-Ras', 'Gene', (83, 88))	('inhibit', 'NegReg', (65, 72))
56721	20718706	In GBM cells, an orally active RAF-1/VEGFR kinase inhibitor AAL881 has been shown to block the growth of malignant gliomas in vitro and in vivo.	('VEGFR', 'Gene', (37, 42))	('AAL881', 'Var', (60, 66))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('malignant gliomas', 'Disease', (105, 122))	('VEGFR', 'Gene', '3791', (37, 42))	('malignant gliomas', 'Disease', 'MESH:D005910', (105, 122))	('growth', 'CPA', (95, 101))	('AAL881', 'Chemical', 'MESH:C514876', (60, 66))	('block', 'NegReg', (85, 90))
56722	20718706	AAL881 inhibited proliferation and induced apoptosis of cultured GBM cells.	('proliferation', 'CPA', (17, 30))	('AAL881', 'Chemical', 'MESH:C514876', (0, 6))	('apoptosis', 'CPA', (43, 52))	('AAL881', 'Var', (0, 6))	('induced', 'Reg', (35, 42))	('inhibited', 'NegReg', (7, 16))
56724	20718706	AAL881 treatment also extended the survival of orthotopic glioma xenografts-bearing nude mice.	('AAL881', 'Chemical', 'MESH:C514876', (0, 6))	('extended', 'PosReg', (22, 30))	('nude mice', 'Species', '10090', (84, 93))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('survival', 'CPA', (35, 43))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('AAL881', 'Var', (0, 6))	('glioma', 'Disease', (58, 64))
56725	20718706	Another RAF-1 inhibitor GW5074 has been shown to synergize with MEK inhibitor U0126 and other anti-cancer drugs to target GBM cells.	('MEK', 'Gene', (64, 67))	('RAF-1', 'Gene', (8, 13))	('MEK', 'Gene', '5609', (64, 67))	('GW5074', 'Var', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('GW5074', 'Chemical', 'MESH:C489251', (24, 30))	('cancer', 'Disease', (99, 105))	('U0126', 'Chemical', 'MESH:C113580', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
56775	20718706	Complementary to translational and clinical studies, genetic analyses have yielded breakthrough discoveries on BRAF gene duplication and rearrangements that are drawing additional enthusiasm to this already exciting field and pointing to a new direction of Ras-RAF-ERK research in brain tumors and potentially in other malignancies and developmental disorders.	('ERK', 'Gene', (265, 268))	('developmental disorders', 'Disease', 'MESH:D002658', (336, 359))	('RAF', 'Gene', (261, 264))	('malignancies', 'Disease', 'MESH:D009369', (319, 331))	('RAF', 'Gene', '22882', (261, 264))	('brain tumors', 'Disease', 'MESH:D001932', (281, 293))	('brain tumors', 'Phenotype', 'HP:0030692', (281, 293))	('malignancies', 'Disease', (319, 331))	('duplication', 'Var', (121, 132))	('brain tumors', 'Disease', (281, 293))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('brain tumor', 'Phenotype', 'HP:0030692', (281, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('ERK', 'Gene', '5594', (265, 268))	('RAF', 'Gene', (112, 115))	('RAF', 'Gene', '22882', (112, 115))	('developmental disorders', 'Disease', (336, 359))
56805	32033160	Of these, alpha-emitting radionuclides have significantly higher relative biological effectiveness compared to beta-emitting radionuclides.	('alpha-emitting radionuclides', 'Var', (10, 38))	('radionuclides', 'Chemical', 'MESH:D011868', (125, 138))	('higher', 'PosReg', (58, 64))	('radionuclides', 'Chemical', 'MESH:D011868', (25, 38))
56825	32033160	Increased cellular metabolism (i.e., glucose uptake and phosphorylation) is the underlying mechanism of higher SUVs of [18F]FDG in cancer cells compared to healthy tissue (i.e., Warburg effect).	('cancer', 'Disease', (131, 137))	('[18F]FDG', 'Var', (119, 127))	('glucose uptake', 'MPA', (37, 51))	('cellular metabolism', 'MPA', (10, 29))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Increased', 'PosReg', (0, 9))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('phosphorylation', 'MPA', (56, 71))	('higher', 'PosReg', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('SUVs', 'MPA', (111, 115))
56838	32033160	To avoid the practical challenges related to the short half-life of carbon-11, next-generation amino acid tracers were labeled with fluorine-18, namely [18F]DOPA, [18F]FET, and [18F]FGln.	('fluorine-18', 'Chemical', 'MESH:C000615276', (132, 143))	('[18F]FET', 'Var', (163, 171))	('DOPA', 'Chemical', 'MESH:D004295', (157, 161))	('[18F]FGln', 'Var', (177, 186))	('carbon-11', 'Chemical', 'MESH:C000615233', (68, 77))
56839	32033160	[18F]DOPA and [18F]FET are also taken up by the tumor via amino acid transporters located on the cell surface (i.e., LAT1 and LAT1 and LAT2, respectively) but unlike [11C]Met, they are not subsequently incorporated into proteins.	('LAT1', 'Gene', '8140', (117, 121))	('[18F]FET', 'Var', (14, 22))	('tumor', 'Disease', (48, 53))	('LAT1', 'Gene', (117, 121))	('DOPA', 'Chemical', 'MESH:D004295', (5, 9))	('LAT2', 'Gene', '7462', (135, 139))	('LAT2', 'Gene', (135, 139))	('LAT1', 'Gene', '8140', (126, 130))	('11C', 'Chemical', 'MESH:C000615233', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('LAT1', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
56840	32033160	Both [18F]DOPA and [18F]FET show specific uptake in tumor cells, resulting in good contrast with similar predictive values as [11C]MET for diagnosing CNS tumors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('DOPA', 'Chemical', 'MESH:D004295', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CNS tumor', 'Phenotype', 'HP:0100006', (150, 159))	('tumor', 'Disease', (52, 57))	('[18F]', 'Var', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('[18F]FET', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('11C', 'Chemical', 'MESH:C000615233', (127, 130))	('tumor', 'Disease', (154, 159))
56843	32033160	In glioma patients, [18F]FGln has shown to be useful for differentiation between progressive and stable disease and enables the non-invasive delineation of tumors.	('[18F]FGln', 'Var', (20, 29))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('glioma', 'Disease', (3, 9))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (10, 18))
56844	32033160	A study including three patients with brain metastases showed a high detection rate with the use of [18F]FGln compared to [18F]FDG (81.6% versus 36.8%, respectively).	('brain metastases', 'Disease', 'MESH:D009362', (38, 54))	('brain metastases', 'Disease', (38, 54))	('[18F]FGln', 'Var', (100, 109))	('patients', 'Species', '9606', (24, 32))
56859	32033160	One study by Jacobs et al., on the other hand, showed an uptake of [18F]FLT also in non-enhancing tumor areas and in LGG.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('[18F]FLT', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('uptake', 'PosReg', (57, 63))	('tumor', 'Disease', (98, 103))
56866	32033160	The use of [11C]acetate for the detection of HGG showed a sensitivity of 90% compared to sensitivities of 100% and 40% for [11C]Met and [18F]FDG, respectively.	('[11C]acetate', 'Chemical', 'MESH:C438206', (11, 23))	('11C', 'Chemical', 'MESH:C000615233', (124, 127))	('11C', 'Chemical', 'MESH:C000615233', (12, 15))	('[11C', 'Var', (11, 15))	('HGG', 'Disease', (45, 48))
56884	32033160	Its expression has shown to be upregulated in astrocytic tumors, and the targeting of TSPO with a radioactively labeled ligand, R-[11C]PK11195, showed potential for the detection of early anaplastic transformation in glioma.	('TSPO', 'Gene', (86, 90))	('glioma', 'Disease', 'MESH:D005910', (217, 223))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('astrocytic tumors', 'Disease', (46, 63))	('expression', 'MPA', (4, 14))	('11C', 'Chemical', 'MESH:C000615233', (131, 134))	('upregulated', 'PosReg', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('glioma', 'Disease', (217, 223))	('astrocytic tumors', 'Disease', 'MESH:D001254', (46, 63))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('TSPO', 'Gene', '706', (86, 90))	('R-[', 'Var', (128, 131))
56886	32033160	Due to the short half-life of carbon-11 and the relatively low TBR provided by R-[11C]PK11195, a novel third generation 18F-labeled TSPO targeting ligand named [18F]GE-180 has been developed, which showed improved contrast in HGG patients.	('TSPO', 'Gene', (132, 136))	('patients', 'Species', '9606', (230, 238))	('improved', 'PosReg', (205, 213))	('TSPO', 'Gene', '706', (132, 136))	('HGG', 'Disease', (226, 229))	('carbon-11', 'Chemical', 'MESH:C000615233', (30, 39))	('R-[11C]PK11195', 'Var', (79, 93))	('11C', 'Chemical', 'MESH:C000615233', (82, 85))	('TBR', 'Chemical', '-', (63, 66))
56891	32033160	As a first step, the expression and accessibility of a target peptide receptor, here the somatostatin receptor 2 (SSTR2), was studied by using an analog of somatostatin, octreotide, labeled with the positron-emitting radionuclide gallium-68 via a so-called DOTA chelator (i.e., [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-TOC, or [68Ga]Ga-DOTA-NOC).	('Ga', 'Chemical', 'MESH:D005708', (281, 283))	('radionuclide', 'Chemical', 'MESH:D011868', (217, 229))	('DOTA', 'Chemical', 'MESH:C071349', (307, 311))	('SSTR2', 'Gene', (114, 119))	('Ga', 'Chemical', 'MESH:D005708', (301, 303))	('SSTR2', 'Gene', '6752', (114, 119))	('Ga', 'Chemical', 'MESH:D005708', (326, 328))	('[68Ga]Ga-DOTA-TATE', 'Var', (278, 296))	('Ga-DOTA', 'Chemical', '-', (304, 311))	('Ga-DOTA-TATE', 'Chemical', '-', (284, 296))	('DOTA', 'Chemical', 'MESH:C071349', (257, 261))	('[68Ga]Ga-DOTA-NOC', 'Var', (320, 337))	('somatostatin receptor 2', 'Gene', '6752', (89, 112))	('Ga', 'Chemical', 'MESH:D005708', (284, 286))	('DOTA', 'Chemical', 'MESH:C071349', (329, 333))	('Ga-DOTA', 'Chemical', '-', (326, 333))	('[68Ga]Ga-DOTA-TOC', 'Var', (298, 315))	('octreotide', 'Chemical', 'MESH:D015282', (170, 180))	('Ga', 'Chemical', 'MESH:D005708', (323, 325))	('gallium-68', 'Chemical', 'MESH:C000615430', (230, 240))	('DOTA', 'Chemical', 'MESH:C071349', (287, 291))	('Ga-DOTA', 'Chemical', '-', (284, 291))	('Ga', 'Chemical', 'MESH:D005708', (304, 306))	('somatostatin receptor 2', 'Gene', (89, 112))
56893	32033160	The positron-emitting radionuclide can hereafter be used again for the assessment of therapeutic efficacy as shown in the first study using [90Y]Y-DOTA-TOC in patients with GBM, where post-therapeutic follow-up PET images showed a decreased uptake of [68Ga]Ga-DOTA-TOC, which is suggestive of therapeutic efficacy (Figure 2).	('Ga', 'Chemical', 'MESH:D005708', (254, 256))	('Ga', 'Chemical', 'MESH:D005708', (257, 259))	('Y-DOTA-TOC', 'Chemical', '-', (145, 155))	('Ga-DOTA', 'Chemical', '-', (257, 264))	('GBM', 'Disease', (173, 176))	('GBM', 'Disease', 'MESH:D005909', (173, 176))	('[68Ga]Ga-DOTA-TOC', 'Var', (251, 268))	('radionuclide', 'Chemical', 'MESH:D011868', (22, 34))	('decreased', 'NegReg', (231, 240))	('patients', 'Species', '9606', (159, 167))	('uptake', 'MPA', (241, 247))
56900	32033160	For theranostic purposes, neurokinin type-1 receptor can be targeted by [213Bi]Bi-DOTA-[Thi8, Met(O2)11]-substance P ([213Bi]Bi-DOTA-SP), an alpha-particle emitting radionuclide.	('Thi8', 'Chemical', '-', (88, 92))	('substance P', 'Gene', (105, 116))	('Met(O2)11', 'Chemical', '-', (94, 103))	('DOTA', 'Chemical', 'MESH:C071349', (128, 132))	('neurokinin type-1 receptor', 'Protein', (26, 52))	('DOTA', 'Chemical', 'MESH:C071349', (82, 86))	('Bi-DOTA-SP', 'Chemical', '-', (125, 135))	('[213Bi]Bi-DOTA-', 'Var', (72, 87))	('targeted', 'Reg', (60, 68))	('substance P', 'Gene', '6863', (105, 116))	('radionuclide', 'Chemical', 'MESH:D011868', (165, 177))
56901	32033160	Today's literature comprises two studies investigating the therapeutic use of [213Bi]Bi-DOTA-SP in CNS tumors: one study including nine patients and a second study including 20 patients with recurrent GBM.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('[213Bi]', 'Var', (78, 85))	('CNS tumor', 'Phenotype', 'HP:0100006', (99, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('patients', 'Species', '9606', (177, 185))	('GBM', 'Disease', (201, 204))	('patients', 'Species', '9606', (136, 144))	('GBM', 'Disease', 'MESH:D005909', (201, 204))	('Bi-DOTA-SP', 'Chemical', '-', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
56907	32033160	Eligible patients first received the human small immune protein L19SIP labeled with iodine-124, followed by PET imaging at 1, 4, 24, 48, and 96 h after administration to assess and predict the optimal protein dose for achieving potentially effective radiation at the target site(s) and to study unwanted accumulation of tracer at other sites (i.e., bone red marrow and healthy organs) to anticipate toxicity.	('toxicity', 'Disease', (399, 407))	('patients', 'Species', '9606', (9, 17))	('iodine-124', 'Chemical', 'MESH:C000614959', (84, 94))	('L19SIP', 'Var', (64, 70))	('human', 'Species', '9606', (37, 42))	('toxicity', 'Disease', 'MESH:D064420', (399, 407))
56911	32033160	The first PET studies investigating PSMA expression in CNS tumors made use of [68Ga]Ga-HBED-CC-PSMA ([68Ga]Ga-PSMA-11) and confirmed selective target expression and target accessibility in LGG, HGG, and gliosarcoma, with higher expression in HGG compared to LGG.	('PSMA', 'Gene', (36, 40))	('Ga', 'Chemical', 'MESH:D005708', (104, 106))	('tumor', 'Disease', (59, 64))	('HGG', 'Disease', (194, 197))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('CNS tumor', 'Phenotype', 'HP:0100006', (55, 64))	('Ga', 'Chemical', 'MESH:D005708', (84, 86))	('gliosarcoma', 'Disease', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('PSMA', 'Gene', '2346', (110, 114))	('Ga', 'Chemical', 'MESH:D005708', (107, 109))	('LGG', 'Disease', (189, 192))	('[68Ga]', 'Var', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('PSMA', 'Gene', '2346', (95, 99))	('PSMA', 'Gene', (110, 114))	('gliosarcoma', 'Disease', 'MESH:D018316', (203, 214))	('PSMA', 'Gene', '2346', (36, 40))	('PSMA', 'Gene', (95, 99))	('Ga', 'Chemical', 'MESH:D005708', (81, 83))
56914	32033160	Finally, PSMA target expression has been studied using the anti-PSMA minibody, IAB2M, labeled with zirconium-89, [89Zr]Zr-IAB2M, in patients with HGG and metastatic brain tumors.	('[89Zr', 'Var', (113, 118))	('patients', 'Species', '9606', (132, 140))	('PSMA', 'Gene', (9, 13))	('HGG', 'Disease', (146, 149))	('PSMA', 'Gene', (64, 68))	('PSMA', 'Gene', '2346', (9, 13))	('zirconium-89', 'Chemical', 'MESH:C000615502', (99, 111))	('brain tumors', 'Disease', 'MESH:D001932', (165, 177))	('PSMA', 'Gene', '2346', (64, 68))	('brain tumors', 'Phenotype', 'HP:0030692', (165, 177))	('metastatic', 'CPA', (154, 164))	('Zr', 'Chemical', 'MESH:D015040', (116, 118))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('brain tumors', 'Disease', (165, 177))	('Zr', 'Chemical', 'MESH:D015040', (119, 121))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
56968	30312684	Proliferation of GBM cell lines is reduced by lowering YAP1 expression and increased with YAP1 over-expression, which overcomes the anti-proliferative effect of Myt1/Myt1l expression.	('expression', 'MPA', (60, 70))	('GBM', 'Disease', (17, 20))	('GBM', 'Disease', 'MESH:D005909', (17, 20))	('reduced', 'NegReg', (35, 42))	('over-expression', 'Var', (95, 110))	('YAP1', 'Gene', (55, 59))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('YAP1', 'Gene', (90, 94))	('increased', 'PosReg', (75, 84))	('Proliferation', 'CPA', (0, 13))	('lowering', 'NegReg', (46, 54))
56989	30312684	The NF2 gene, which is an upstream activator of the Hippo pathway, has been identified as a tumor suppressor gene that is mutated in Type 2 neurofibromatosis, an autosomal dominant syndrome that results in meningioma and schwannoma.	('meningioma and schwannoma', 'Disease', 'MESH:D009442', (206, 231))	('results', 'Reg', (195, 202))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (140, 157))	('schwannoma', 'Phenotype', 'HP:0100008', (221, 231))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (162, 189))	('autosomal dominant syndrome', 'Disease', (162, 189))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('meningioma', 'Phenotype', 'HP:0002858', (206, 216))	('NF2', 'Gene', '4771', (4, 7))	('tumor', 'Disease', (92, 97))	('Type 2 neurofibromatosis', 'Disease', 'MESH:D016518', (133, 157))	('mutated', 'Var', (122, 129))	('Type 2 neurofibromatosis', 'Disease', (133, 157))	('NF2', 'Gene', (4, 7))
56991	30312684	In contrast, YAP1 expression is higher in GBM than in normal tissue, and inhibition of YAP1 activity has been suggested as a potential therapeutic approach in glioma.	('glioma', 'Disease', (159, 165))	('higher', 'PosReg', (32, 38))	('GBM', 'Disease', (42, 45))	('GBM', 'Disease', 'MESH:D005909', (42, 45))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('expression', 'MPA', (18, 28))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('activity', 'MPA', (92, 100))	('inhibition', 'Var', (73, 83))	('YAP1', 'Gene', (13, 17))
56996	30312684	Finally, we show that reducing YAP1 expression in GBM cells decreases tumor growth in a xenograft model, and we propose a model in which Myt1/Myt1l directly repress YAP1 expression to limit proliferation and tumor growth.	('YAP1', 'Gene', (165, 169))	('repress', 'NegReg', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reducing', 'Var', (22, 30))	('GBM', 'Phenotype', 'HP:0012174', (50, 53))	('decreases tumor', 'Disease', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (70, 75))	('YAP1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('GBM', 'Disease', (50, 53))	('tumor', 'Disease', (208, 213))	('limit', 'NegReg', (184, 189))	('decreases tumor', 'Disease', 'None', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('expression', 'MPA', (170, 180))	('GBM', 'Disease', 'MESH:D005909', (50, 53))
57007	30312684	The YAP1-luc reporter was a kind gift from Dr. R. Janknecht (University of Oklahoma), and mutant versions were generated within this plasmid by PCR.	('Oklahoma', 'Disease', (75, 83))	('mutant', 'Var', (90, 96))	('Oklahoma', 'Disease', 'MESH:C537147', (75, 83))
57011	30312684	For comparison of gene expression data to expression correlations in GBM and LGG, we overlapped genes that were significantly increased or decreased (p-adj < 0.0001, log2 fc +/-0.5) in both Myt1 and Myt1l expressing U87 compared to control, with the top ~1000 negatively and positively correlated genes (using the minimum Spearman cut-off that yielded >1000 genes) from TCGA data.	('GBM', 'Disease', (69, 72))	('Myt1', 'Gene', (190, 194))	('GBM', 'Disease', 'MESH:D005909', (69, 72))	('negatively', 'NegReg', (260, 270))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('decreased', 'NegReg', (139, 148))	('Myt1l', 'Gene', (199, 204))	('increased', 'PosReg', (126, 135))	('U87', 'Var', (216, 219))
57020	30312684	Introduction of Myt1 or Myt1l into a second GBM cell line, A172, similarly reduced proliferation when assayed in a serial re-plating assay (Fig 1E, F).	('Myt1', 'Var', (16, 20))	('proliferation', 'CPA', (83, 96))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('reduced', 'NegReg', (75, 82))	('GBM', 'Disease', (44, 47))	('Myt1l', 'Var', (24, 29))	('GBM', 'Disease', 'MESH:D005909', (44, 47))
57024	30312684	This analysis suggests that reintroduction of either Myt1 or Myt1l can limit proliferation of glioblastoma cells in vitro and is consistent with a previous report that MYT1L inhibits GBM.	('limit', 'NegReg', (71, 76))	('reintroduction', 'Var', (28, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('Myt1', 'Gene', (53, 57))	('GBM', 'Disease', (183, 186))	('Myt1l', 'Gene', (61, 66))	('GBM', 'Disease', 'MESH:D005909', (183, 186))	('GBM', 'Phenotype', 'HP:0012174', (183, 186))	('MYT1L', 'Gene', (168, 173))	('glioblastoma', 'Disease', (94, 106))	('inhibits', 'NegReg', (174, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))	('proliferation', 'CPA', (77, 90))	('MYT1L', 'Gene', '23040', (168, 173))
57033	30312684	LGG has generally been classified by grade (II or III) and by histological type (oligodendroglioma and astrocytoma), but recent analysis suggests that three sub-types defined by mutations in IDH1/2 and deletion of 1p/19q may be more valuable.	('IDH1/2', 'Gene', (191, 197))	('oligodendroglioma and astrocytoma', 'Disease', 'MESH:D009837', (81, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('IDH1/2', 'Gene', '3417;3418', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('mutations', 'Var', (178, 187))	('deletion of', 'Var', (202, 213))
57034	30312684	Analysis of TCGA data from LGG revealed higher expression of both MYT1 and MYT1L in the less aggressive subtype, characterized by the presence of IDH mutations and co-deletion of 1p and 19q chromosome arms (Fig 2C).	('less aggressive', 'Disease', (88, 103))	('MYT1', 'Gene', '4661', (66, 70))	('MYT1', 'Gene', (75, 79))	('higher', 'PosReg', (40, 46))	('IDH', 'Gene', (146, 149))	('MYT1L', 'Gene', (75, 80))	('MYT1L', 'Gene', '23040', (75, 80))	('IDH', 'Gene', '3417', (146, 149))	('mutations', 'Var', (150, 159))	('MYT1', 'Gene', (66, 70))	('MYT1', 'Gene', '4661', (75, 79))	('expression', 'MPA', (47, 57))
57036	30312684	Similarly, expression of either MYT1 or MYT1L was predictive of overall or diseasefree survival in the TCGA LGG dataset (Supplementary Fig 3A).	('diseasefree survival', 'CPA', (75, 95))	('MYT1', 'Gene', '4661', (40, 44))	('MYT1', 'Gene', '4661', (32, 36))	('MYT1L', 'Gene', (40, 45))	('MYT1L', 'Gene', '23040', (40, 45))	('MYT1', 'Gene', (40, 44))	('expression', 'Var', (11, 21))	('MYT1', 'Gene', (32, 36))
57040	30312684	Expression of CTGF, a known YAP1 target gene, was not decreased by Myt expression in either U87 or A172 cells, and increased significantly in Myt1l expressing U87 cells (Fig 3D), perhaps suggesting an independent mechanism of regulation.	('Myt', 'Gene', (67, 70))	('CTGF', 'Gene', '1490', (14, 18))	('Myt1l', 'Gene', (142, 147))	('CTGF', 'Gene', (14, 18))	('increased', 'PosReg', (115, 124))	('Expression', 'MPA', (0, 10))	('expression', 'Var', (71, 81))
57041	30312684	This analysis suggests that expression of either Myt1 or Myt1l in GBM cells modulates the activity of the Hippo pathway by repressing expression of YAP1, and this reduces expression of at least some YAP1 target genes.	('expression', 'MPA', (171, 181))	('GBM', 'Disease', (66, 69))	('expression', 'MPA', (134, 144))	('activity', 'MPA', (90, 98))	('GBM', 'Disease', 'MESH:D005909', (66, 69))	('reduces', 'NegReg', (163, 170))	('Hippo pathway', 'Pathway', (106, 119))	('Myt1', 'Var', (49, 53))	('YAP1', 'Gene', (148, 152))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('modulates', 'Reg', (76, 85))	('Myt1l', 'Var', (57, 62))	('repressing', 'NegReg', (123, 133))
57043	30312684	Similarly, relative YAP1 expression was lower in the less aggressive IDH mutant, 1p/19q co-deleted LGG subtype (Fig 4C).	('1p/19q co-deleted', 'Var', (81, 98))	('YAP1', 'Gene', (20, 24))	('IDH', 'Gene', (69, 72))	('expression', 'MPA', (25, 35))	('IDH', 'Gene', '3417', (69, 72))	('lower', 'NegReg', (40, 45))
57044	30312684	In contrast to MYT1 and MTY1L, high YAP1 expression was associated with poor survival in human glioma (Fig 4D).	('human', 'Species', '9606', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('expression', 'MPA', (41, 51))	('MYT1', 'Gene', '4661', (15, 19))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('YAP1', 'Gene', (36, 40))	('high', 'Var', (31, 35))	('MYT1', 'Gene', (15, 19))	('poor', 'NegReg', (72, 76))
57055	30312684	As shown in Figure 5A, increasing Verteporfin decreased activation of this reporter in parental U87 cells, and also reduced total cell number when U87 cells were incubated with increasing concentrations of Verteporfin for four days (Fig 5B).	('Verteporfin', 'Chemical', 'MESH:C098350', (206, 217))	('activation', 'MPA', (56, 66))	('Verteporfin', 'Var', (34, 45))	('decreased', 'NegReg', (46, 55))	('reduced', 'NegReg', (116, 123))	('Verteporfin', 'Chemical', 'MESH:C098350', (34, 45))	('total cell', 'MPA', (124, 134))
57064	30312684	This is clearly consistent with the model that YAP1 expression promotes glioma progression, and together with previous analyses, suggests that repression of YAP1 expression by Myt1 or Myt1l mediates at least part of their antitumorigenic effect.	('glioma', 'Disease', (72, 78))	('YAP1', 'Gene', (157, 161))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('promotes', 'PosReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('expression', 'Var', (52, 62))	('tumor', 'Disease', (226, 231))
57065	30312684	Here we demonstrate that re-expression of Myt1 or Myt1l in GBM cell lines slows proliferation, that expression of both is lower in more aggressive sub-types of glioma, and that reduced expression correlates with poor prognosis in both GBM and LGG.	('GBM', 'Disease', (59, 62))	('expression', 'MPA', (185, 195))	('proliferation', 'CPA', (80, 93))	('reduced', 'NegReg', (177, 184))	('GBM', 'Disease', 'MESH:D005909', (59, 62))	('lower', 'NegReg', (122, 127))	('GBM', 'Phenotype', 'HP:0012174', (235, 238))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('re-expression', 'Var', (25, 38))	('glioma', 'Disease', (160, 166))	('LGG', 'Disease', (243, 246))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('Myt1l', 'Gene', (50, 55))	('expression', 'MPA', (100, 110))	('slows', 'NegReg', (74, 79))	('GBM', 'Disease', (235, 238))	('Myt1', 'Gene', (42, 46))	('GBM', 'Disease', 'MESH:D005909', (235, 238))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
57066	30312684	We show that compared to YAP1, Myt proteins have an opposing effect on proliferation of GBM cells, and that YAP1 promotes tumor growth in vivo.	('promotes', 'PosReg', (113, 121))	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('GBM', 'Disease', 'MESH:D005909', (88, 91))	('YAP1', 'Var', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('proliferation', 'CPA', (71, 84))	('GBM', 'Disease', (88, 91))	('tumor', 'Disease', (122, 127))
57073	30312684	However, a role for MYT1L in GBM has been examined, with knock-down of MYT1L in neural stem cells resulting in increased tumorigenesis in an orthotopic tumor model.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('GBM', 'Phenotype', 'HP:0012174', (29, 32))	('increased', 'PosReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (152, 157))	('MYT1L', 'Gene', (71, 76))	('GBM', 'Disease', (29, 32))	('MYT1L', 'Gene', '23040', (71, 76))	('MYT1L', 'Gene', (20, 25))	('MYT1L', 'Gene', '23040', (20, 25))	('GBM', 'Disease', 'MESH:D005909', (29, 32))	('knock-down', 'Var', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
57074	30312684	Surprisingly, knock-down of Myt1 in the Neuro2a neuroblastoma cell line resulted in reduced proliferation, an effect that was also seen with knock-down of the Myt1-interacting LSD1 lysine demethylase.	('neuroblastoma', 'Phenotype', 'HP:0003006', (48, 61))	('reduced', 'NegReg', (84, 91))	('knock-down', 'Var', (14, 24))	('Myt1', 'Gene', (28, 32))	('neuroblastoma', 'Disease', 'MESH:D009447', (48, 61))	('lysine', 'Chemical', 'MESH:C114808', (181, 187))	('proliferation', 'CPA', (92, 105))	('neuroblastoma', 'Disease', (48, 61))
57085	30312684	Analysis of human brain cancer data-sets suggests an inverse expression pattern comparing YAP1 with MYT1 and MYT1L, and survival data suggest that high YAP1 expression predicts poor survival in both GBM and LGG.	('GBM', 'Disease', (199, 202))	('MYT1', 'Gene', '4661', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('GBM', 'Disease', 'MESH:D005909', (199, 202))	('poor', 'NegReg', (177, 181))	('brain cancer', 'Disease', 'MESH:D001932', (18, 30))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('MYT1', 'Gene', (100, 104))	('high', 'Var', (147, 151))	('YAP1', 'Gene', (152, 156))	('MYT1', 'Gene', '4661', (109, 113))	('brain cancer', 'Phenotype', 'HP:0030692', (18, 30))	('brain cancer', 'Disease', (18, 30))	('human', 'Species', '9606', (12, 17))	('MYT1L', 'Gene', (109, 114))	('MYT1L', 'Gene', '23040', (109, 114))	('MYT1', 'Gene', (109, 113))
57175	26050593	For example, valproic acid has been associated with improved survival in some studies; however, it is associated with many toxicities (Table 2).	('valproic acid', 'Var', (13, 26))	('toxicities', 'Disease', 'MESH:D064420', (123, 133))	('improved', 'PosReg', (52, 60))	('valproic acid', 'Chemical', 'MESH:D014635', (13, 26))	('survival', 'MPA', (61, 69))	('toxicities', 'Disease', (123, 133))
57332	32761097	Based on the hypothesis that there is a trade-off between reconstruction quality and desired latent space property regulated by , it can be expected that removing the regularization term (= 0) may even improve the vanilla VAE's (= 1) imputation performance.	('regularization', 'MPA', (167, 181))	('removing', 'Var', (154, 162))	('improve', 'PosReg', (202, 209))	('VAE', 'Chemical', '-', (222, 225))
57338	32761097	Research reported in this publication was supported by the Fund for Innovation in Cancer Informatics (www.the-ici-fund.org); the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (https://www.nibib.nih.gov/) grant numbers R01 EB020527 and R56 EB020527; and the National Cancer Institute (https://www.cancer.gov/) grant numbers U01 CA217851 and U01 CA199241, all to O.G.	('U01 CA199241', 'Var', (391, 403))	('U01', 'CellLine', 'CVCL:2220', (374, 377))	('Cancer', 'Disease', 'MESH:D009369', (317, 323))	('U01 CA217851', 'Var', (374, 386))	('C', 'Chemical', 'MESH:D003596', (317, 318))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('R56 EB020527', 'Var', (286, 298))	('cancer', 'Disease', (347, 353))	('C', 'Chemical', 'MESH:D003596', (395, 396))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('R01 EB020527', 'Var', (269, 281))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (317, 323))	('C', 'Chemical', 'MESH:D003596', (378, 379))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('U01', 'CellLine', 'CVCL:2220', (391, 394))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('C', 'Chemical', 'MESH:D003596', (82, 83))	('Cancer', 'Disease', (317, 323))
57346	31701682	At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high-risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non-1p/19q codeleted.	('PCV', 'Species', '28355', (237, 240))	('IDH', 'Gene', '3417', (207, 210))	('patients', 'Species', '9606', (245, 253))	('IDH mutant tumors', 'Disease', (263, 280))	('PCV', 'Species', '28355', (94, 97))	('IDH', 'Gene', (207, 210))	('IDH', 'Gene', (263, 266))	('patients', 'Species', '9606', (106, 114))	('IDH mutant tumors', 'Disease', 'MESH:D016115', (263, 280))	('1p/19q codeletion', 'Var', (305, 322))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('IDH', 'Gene', '3417', (263, 266))	('TMZ', 'Chemical', 'MESH:C047246', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))
57351	31701682	However, in 2016, the WHO issued an updated classification for primary CNS tumors utilizing molecular parameters in addition to histology.2, 3, 4 The distinction of grade II vs grade III has given way to IDH mutation status foremost and then 1p/19q codeletion.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('IDH', 'Gene', (204, 207))	('1p/19q codeletion', 'Var', (242, 259))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('IDH', 'Gene', '3417', (204, 207))	('tumors', 'Disease', (75, 81))
57352	31701682	Notably, IDH status does not play a role in grading and 1p/19q codeletion automatically renders a tumor an oligodendroglioma.	('renders', 'Reg', (88, 95))	('oligodendroglioma', 'Disease', (107, 124))	('1p/19q codeletion', 'Var', (56, 73))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('oligodendroglioma', 'Disease', 'MESH:D009837', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', '3417', (9, 12))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('tumor', 'Disease', (98, 103))
57358	31701682	Post hoc molecular subtyping of 113 cases revealed that IDH1-R132H mutations were present in 61% of the group that received radiotherapy alone (35 of 57 patients) and 64% of the group that received radiotherapy with PCV (36 of 36 patients).5 1p/19q codeletion status was assessable in 63 cases: 29 patients in the radiotherapy alone arm and 34 patients in the radiotherapy with PCV arm.5 At a median follow-up of 11.9 years, patients randomized to receive PCV after radiotherapy had improved progression free survival (PFS) compared to those randomized to receive radiotherapy alone (median PFS 10.4 vs 4.0 years, respectively, HR 0.50, P < .001).	('PCV', 'Species', '28355', (216, 219))	('PCV', 'Species', '28355', (378, 381))	('PCV', 'Species', '28355', (456, 459))	('patients', 'Species', '9606', (153, 161))	('IDH1', 'Gene', '3417', (56, 60))	('patients', 'Species', '9606', (298, 306))	('patients', 'Species', '9606', (230, 238))	('progression free survival', 'CPA', (492, 517))	('improved', 'PosReg', (483, 491))	('patients', 'Species', '9606', (425, 433))	('PCV', 'Var', (456, 459))	('R132H', 'Mutation', 'rs121913500', (61, 66))	('patients', 'Species', '9606', (344, 352))	('IDH1', 'Gene', (56, 60))
57359	31701682	Additionally, patients in the PCV arm exhibited improved OS compared to those in the radiotherapy alone arm (median OS 13.3 years vs 7.8 years, respectively, HR 0.59, P = .003).	('improved', 'PosReg', (48, 56))	('patients', 'Species', '9606', (14, 22))	('PCV', 'Species', '28355', (30, 33))	('PCV', 'Var', (30, 33))
57363	31701682	Patients who received PCV and radiotherapy experienced superior PFS compared to those receiving radiotherapy alone (2.6 years vs 1.7 years, P = .004).19 On a longer follow-up post hoc analysis, patients with 1p/19q codeleted tumors experienced significantly longer OS following treatment with PCV and radiotherapy compared to radiation therapy alone (14.7 vs 7.3 years, P = .03), whereas this benefit was not seen among patients without 1p/19q codeleted tumors.11 A subsequent analysis demonstrated that patients in this study with IDH-mutant gliomas experienced significantly prolonged survival after treatment with PCV and radiotherapy compared to radiotherapy alone.20 The benefit provided by the addition of PCV was seen for both patients with IDH-mutant codeleted tumors (14.7 vs 6.8 years, P = .01) and IDH-mutant noncodeleted tumors (5.5 vs 3.3 years, P < .05).20  Taken together, these three randomized trials provide strong evidence supporting the use of adjuvant PCV chemotherapy in conjunction with radiotherapy for patients with high-risk LGG, particularly those harboring 1p/19q codeletion.	('tumor', 'Phenotype', 'HP:0002664', (454, 459))	('patients', 'Species', '9606', (420, 428))	('tumor', 'Phenotype', 'HP:0002664', (833, 838))	('tumors', 'Disease', (454, 460))	('tumors', 'Disease', (833, 839))	('tumor', 'Phenotype', 'HP:0002664', (769, 774))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumors', 'Disease', (769, 775))	('IDH', 'Gene', (532, 535))	('IDH', 'Gene', '3417', (748, 751))	('patients', 'Species', '9606', (504, 512))	('patients', 'Species', '9606', (734, 742))	('tumors', 'Disease', 'MESH:D009369', (454, 460))	('Patients', 'Species', '9606', (0, 8))	('PCV', 'Species', '28355', (293, 296))	('IDH', 'Gene', (809, 812))	('PCV', 'Species', '28355', (22, 25))	('tumors', 'Disease', 'MESH:D009369', (833, 839))	('tumors', 'Disease', 'MESH:D009369', (769, 775))	('patients', 'Species', '9606', (194, 202))	('IDH', 'Gene', '3417', (532, 535))	('PCV', 'Species', '28355', (617, 620))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('PCV', 'Species', '28355', (973, 976))	('glioma', 'Phenotype', 'HP:0009733', (543, 549))	('IDH-mutant gliomas', 'Disease', 'MESH:D005910', (532, 550))	('PCV', 'Species', '28355', (712, 715))	('IDH', 'Gene', (748, 751))	('patients', 'Species', '9606', (1027, 1035))	('IDH', 'Gene', '3417', (809, 812))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('1p/19q codeletion', 'Var', (1085, 1102))	('LGG', 'Disease', (1051, 1054))	('gliomas', 'Phenotype', 'HP:0009733', (543, 550))	('tumors', 'Phenotype', 'HP:0002664', (454, 460))	('tumors', 'Phenotype', 'HP:0002664', (833, 839))	('IDH-mutant gliomas', 'Disease', (532, 550))	('tumors', 'Disease', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (769, 775))
57384	31701682	Overall, there was no difference in PFS among patients with LGG treated with either radiotherapy or TMZ chemotherapy alone, however the data are not yet mature for survival analysis.45 Exploratory analysis revealed that patients with IDH-mutant, non-1p/19q codeleted tumors had a longer PFS when treated with radiotherapy alone compared to TMZ alone (HR 1.86, P = .0043).45 While the study was designed prior to the mature reporting of RTOG 9802, the authors conclude that these findings may support the option of initial TMZ alone for some patients with IDH-mutant 1p/19q codeleted tumors.45  A retrospective study of 1013 patients with anaplastic oligodendroglial tumors treated between 1981 and 2007 compared outcomes following treatment with chemoradiotherapy, radiotherapy alone, or chemotherapy alone.46 For patients with 1p/19q codeleted tumors, time to progression (TTP) was longer following treatment with combined chemoradiotherapy (median TTP 7.2 years) compared to either chemotherapy alone (median TTP 3.9 years, P = .003) or radiotherapy alone (median TTP 2.5 years, P < .001).46 In addition, the median TTP was longer following PCV alone (7.6 years) compared to TMZ alone (median TTP 3.3 years, P = .019) in patients with 1p/19q codeleted tumors.46 Although retrospective and encompassing a large timeframe of treatment years, this data set is large with relatively long follow-up (median follow-up 5.2 years) and suggests that PCV chemotherapy may be more effective than TMZ.46  Finally, another relevant but smaller retrospective series reporting on outcomes of 109 patients with anaplastic astrocytoma who received surgery, radiotherapy, and chemotherapy suggested comparable findings between chemotherapy regimen.47 Of 49 patients who received PCV and 60 patients who received TMZ, the 3-year overall survival rates were 74% and 59%, respectively, and 49% of patients in both groups were progression-free at 3 years.	('patients', 'Species', '9606', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (583, 589))	('TMZ', 'Chemical', 'MESH:C047246', (1796, 1799))	('tumors', 'Phenotype', 'HP:0002664', (666, 672))	('IDH', 'Gene', '3417', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (1254, 1259))	('tumors', 'Disease', 'MESH:D009369', (845, 851))	('patients', 'Species', '9606', (220, 228))	('tumors', 'Disease', (1254, 1260))	('IDH', 'Gene', (555, 558))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('PCV', 'Species', '28355', (1763, 1766))	('TMZ', 'Chemical', 'MESH:C047246', (1177, 1180))	('PCV', 'Species', '28355', (1143, 1146))	('tumor', 'Phenotype', 'HP:0002664', (666, 671))	('patients', 'Species', '9606', (1774, 1782))	('patients', 'Species', '9606', (814, 822))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumors', 'Disease', (666, 672))	('PCV', 'Species', '28355', (1443, 1446))	('patients', 'Species', '9606', (624, 632))	('patients', 'Species', '9606', (1741, 1749))	('patients', 'Species', '9606', (1878, 1886))	('patients', 'Species', '9606', (1583, 1591))	('tumors', 'Disease', 'MESH:D009369', (1254, 1260))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (1597, 1619))	('tumors', 'Disease', (267, 273))	('IDH', 'Gene', '3417', (555, 558))	('tumors', 'Phenotype', 'HP:0002664', (583, 589))	('TMZ', 'Chemical', 'MESH:C047246', (522, 525))	('tumors', 'Phenotype', 'HP:0002664', (845, 851))	('tumors', 'Disease', 'MESH:D009369', (666, 672))	('anaplastic oligodendroglial tumors', 'Disease', (638, 672))	('patients', 'Species', '9606', (1223, 1231))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (583, 588))	('IDH', 'Gene', (234, 237))	('tumors', 'Disease', (583, 589))	('TMZ', 'Chemical', 'MESH:C047246', (100, 103))	('TMZ', 'Chemical', 'MESH:C047246', (340, 343))	('tumor', 'Phenotype', 'HP:0002664', (845, 850))	('tumors', 'Disease', (845, 851))	('PCV', 'Var', (1763, 1766))	('patients', 'Species', '9606', (541, 549))	('astrocytoma', 'Phenotype', 'HP:0009592', (1608, 1619))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (638, 672))	('tumors', 'Phenotype', 'HP:0002664', (1254, 1260))	('TMZ', 'Chemical', 'MESH:C047246', (1487, 1490))	('anaplastic astrocytoma', 'Disease', (1597, 1619))
57395	31701682	First, further prospective studies are needed to establish the minimum amount of PCV required to achieve the survival benefit shown in RTOG 9802, EORTC 26 951, and RTOG 9402.	('PCV', 'Species', '28355', (81, 84))	('RTOG', 'Var', (164, 168))	('RTOG', 'Var', (135, 139))
57401	31701682	This study, while not expected to mature for another 7-10 years from now, will provide the highest-level data needed to address the optimal chemotherapy regimen for use in high-risk lower grade gliomas (WHO grade II and III) harboring 1p/19q codeletion.	('harboring 1p/19q codeletion', 'Var', (225, 252))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('gliomas', 'Disease', (194, 201))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))
57432	30072063	In the 1990s, the discovery that gliomas with a combined deletion of chromosome arms 1p and 19q (1p/19q codeletion) were associated with significantly improved survival and increased sensitivity to procarbazine, lomustine and vincristine (PCV) chemotherapy paved the way for molecular neuropathology of CNS tumors.	('survival', 'CPA', (160, 168))	('improved', 'PosReg', (151, 159))	('molecular neuropathology of CNS tumors', 'Disease', (275, 313))	('procarbazine', 'Chemical', 'MESH:D011344', (198, 210))	('deletion', 'Var', (57, 65))	('lomustine', 'Chemical', 'MESH:D008130', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('vincristine', 'Chemical', 'MESH:D014750', (226, 237))	('CNS tumor', 'Phenotype', 'HP:0100006', (303, 312))	('gliomas', 'Disease', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('sensitivity', 'MPA', (183, 194))	('increased', 'PosReg', (173, 182))	('molecular neuropathology of CNS tumors', 'Disease', 'MESH:D030342', (275, 313))	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
57436	30072063	Another finding with a major impact on the molecular neuropathology of diffuse gliomas is mutations of the isocitrate dehydrogenase 1 (IDH1) gene and the related IDH2 gene.	('gliomas', 'Disease', (79, 86))	('mutations', 'Var', (90, 99))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('IDH2', 'Gene', '3418', (162, 166))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', '3417', (135, 139))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('isocitrate dehydrogenase 1', 'Gene', (107, 133))	('IDH2', 'Gene', (162, 166))	('isocitrate dehydrogenase 1', 'Gene', '3417', (107, 133))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
57438	30072063	IDH mutations were first reported in glioblastomas (GBM) and later on discovered to be much more prevalent among lower grade (WHO grade II and III) gliomas.	('IDH', 'Gene', (0, 3))	('reported', 'Reg', (25, 33))	('gliomas', 'Disease', (148, 155))	('prevalent', 'Reg', (97, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (37, 50))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('IDH', 'Gene', '3417', (0, 3))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('glioblastomas', 'Disease', (37, 50))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('mutations', 'Var', (4, 13))	('glioblastomas', 'Phenotype', 'HP:0012174', (37, 50))
57439	30072063	IDH mutations contribute to gliomagenesis by activating alternative transcriptional programs via the genome-wide disruption of DNA methylation.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('alternative transcriptional programs', 'Pathway', (56, 92))	('IDH', 'Gene', '3417', (0, 3))	('DNA methylation', 'MPA', (127, 142))	('activating', 'PosReg', (45, 55))	('mutations', 'Var', (4, 13))	('contribute', 'Reg', (14, 24))	('glioma', 'Disease', (28, 34))
57441	30072063	Using modern genomic sequencing technologies, several groups independently reported that histologically similar gliomas could be subdivided into distinct tumor entities based on mutations in IDH and the 1p/19q codeletion, providing further fuel to the notion that a reclassification of these tumors is needed.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('tumors', 'Disease', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('tumor', 'Disease', (292, 297))	('IDH', 'Gene', (191, 194))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('gliomas', 'Disease', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('IDH', 'Gene', '3417', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', (154, 159))
57443	30072063	As was first reported in 2000, epigenetic silencing of the MGMT gene by methylation of the promoter appears to compromise conventional DNA repair mechanisms and thereby increases sensitivity to conventional chemotherapy using alkylating agents such as temozolomide.	('conventional DNA repair mechanisms', 'MPA', (122, 156))	('epigenetic silencing', 'Var', (31, 51))	('temozolomide', 'Chemical', 'MESH:D000077204', (252, 264))	('sensitivity', 'MPA', (179, 190))	('increases', 'PosReg', (169, 178))	('methylation', 'Var', (72, 83))	('compromise', 'NegReg', (111, 121))	('MGMT', 'Gene', (59, 63))	('MGMT', 'Gene', '4255', (59, 63))
57448	30072063	Indeed, state-of-the-art diagnosis of diffuse gliomas now requires assessment of presence or absence of IDH mutation and 1p/19q codeletion.	('IDH', 'Gene', (104, 107))	('1p/19q codeletion', 'Var', (121, 138))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('IDH', 'Gene', '3417', (104, 107))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
57449	30072063	With the addition of molecular features to the 2016 WHO classification scheme, IDH mutation and 1p/19q codeletion status have become glioma subtype-defining features.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('IDH', 'Gene', (79, 82))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('1p/19q codeletion', 'Var', (96, 113))	('IDH', 'Gene', '3417', (79, 82))	('glioma', 'Disease', (133, 139))
57450	30072063	Diffuse gliomas that are both IDH-mutant and 1p/19q-codeleted are classified as oligodendroglioma, whereas tumors lacking codeletion of these chromosome arms are classified as astrocytoma and can be further separated based on IDH-status (Figure 2).	('IDH', 'Gene', '3417', (226, 229))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('IDH', 'Gene', (30, 33))	('oligodendroglioma', 'Disease', 'MESH:D009837', (80, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (176, 187))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('gliomas', 'Disease', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oligodendroglioma', 'Disease', (80, 97))	('tumors', 'Disease', (107, 113))	('Diffuse', 'Disease', (0, 7))	('IDH', 'Gene', '3417', (30, 33))	('IDH', 'Gene', (226, 229))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('astrocytoma', 'Disease', 'MESH:D001254', (176, 187))	('astrocytoma', 'Disease', (176, 187))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('1p/19q-codeleted', 'Var', (45, 61))
57452	30072063	In addition to subtype defining molecular changes, gliomas are characterized by somatic mutations or copy number changes in a number of genes from various pathways, substantiating the hypothesis that the subtypes follow different gliomagenic trajectories and represent different biologies.	('gliomas', 'Disease', (51, 58))	('glioma', 'Disease', (51, 57))	('copy number changes', 'Var', (101, 120))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('glioma', 'Disease', (230, 236))
57454	30072063	IDH-mutant astrocytomas show frequent loss-of-function mutations or deletions in Tumor Protein 53 (TP53) and Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX).	('Tumor Protein 53', 'Gene', (81, 97))	('TP53', 'Gene', (99, 103))	('Alpha Thalassemia/Mental Retardation Syndrome X-Linked', 'Gene', '546', (109, 163))	('IDH', 'Gene', (0, 3))	('mutations', 'Var', (55, 64))	('deletions', 'Var', (68, 77))	('ATRX', 'Gene', (165, 169))	('loss-of-function', 'NegReg', (38, 54))	('IDH', 'Gene', '3417', (0, 3))	('astrocytomas', 'Disease', 'MESH:D001254', (11, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('ATRX', 'Gene', '546', (165, 169))	('Mental Retardation', 'Phenotype', 'HP:0001249', (127, 145))	('TP53', 'Gene', '7157', (99, 103))	('astrocytomas', 'Disease', (11, 23))	('Tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Tumor Protein 53', 'Gene', '7157', (81, 97))
57456	30072063	Inactivation of the ATP-dependent helicase ATRX has been linked to recombination-driven alternative telomere maintenance mechanisms and may provide glioma cells with unlimited proliferative capacity.	('glioma', 'Disease', (148, 154))	('ATP-dependent helicase ATRX', 'Gene', (20, 47))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('provide', 'Reg', (140, 147))	('linked', 'Reg', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('ATP-dependent helicase ATRX', 'Gene', '546', (20, 47))	('Inactivation', 'Var', (0, 12))
57458	30072063	For instance, a diffuse glioma that on immunohistochemical analysis lacks staining of tumor cell nuclei for ATRX and shows extensive and strong p53 staining of these nuclei (most likely representing the presence of respectively deactivating ATRX and TP53 mutation) is highly indicative for an IDH-mutant, 1p/19q-non-codeleted astrocytoma.	('deactivating', 'NegReg', (228, 240))	('ATRX', 'Gene', (108, 112))	('ATRX', 'Gene', '546', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('p53', 'Gene', '7157', (144, 147))	('IDH', 'Gene', (293, 296))	('mutation', 'Var', (255, 263))	('glioma', 'Disease', (24, 30))	('TP53', 'Gene', (250, 254))	('p53', 'Gene', (144, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (326, 337))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('diffuse', 'Disease', (16, 23))	('ATRX', 'Gene', (241, 245))	('IDH', 'Gene', '3417', (293, 296))	('ATRX', 'Gene', '546', (241, 245))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('lacks', 'NegReg', (68, 73))	('tumor', 'Disease', (86, 91))	('TP53', 'Gene', '7157', (250, 254))	('astrocytoma', 'Disease', 'MESH:D001254', (326, 337))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('astrocytoma', 'Disease', (326, 337))
57459	30072063	Obviously, acknowledging that about 90% of IDH-mutant diffuse gliomas carry the IDH1 R132H mutation, immunohistochemistry for the IDH1 R132 mutant protein is a more direct way to test the IDH status of these tumors.	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH1', 'Gene', '3417', (130, 134))	('R132H', 'Var', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', '3417', (130, 133))	('IDH1', 'Gene', (80, 84))	('IDH', 'Gene', (80, 83))	('IDH', 'Gene', (188, 191))	('IDH1', 'Gene', '3417', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('IDH', 'Gene', '3417', (80, 83))	('gliomas', 'Disease', (62, 69))	('IDH', 'Gene', '3417', (188, 191))	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('IDH1', 'Gene', (130, 134))	('tumors', 'Disease', (208, 214))	('IDH', 'Gene', (43, 46))	('IDH', 'Gene', (130, 133))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))
57460	30072063	With a median survival time of 116 months, IDH-mutant and 1p/19q-codeleted oligodendrogliomas demonstrate the highest survival rate amongst diffuse gliomas.	('IDH', 'Gene', '3417', (43, 46))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (75, 93))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('oligodendrogliomas', 'Disease', (75, 93))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('IDH', 'Gene', (43, 46))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))	('1p/19q-codeleted', 'Var', (58, 74))
57462	30072063	IDH-mutant, 1p/19q-codeleted oligodendrogliomas commonly contain point mutations in 1p gene Capicua Transcriptional Repressor (CIC) and 19q gene Far Upstream Element Binding Protein 1 (FUBP1).	('FUBP1', 'Gene', '8880', (185, 190))	('oligodendrogliomas', 'Disease', (29, 47))	('contain', 'Reg', (57, 64))	('IDH', 'Gene', (0, 3))	('FUBP1', 'Gene', (185, 190))	('Far Upstream Element Binding Protein 1', 'Gene', '8880', (145, 183))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('CIC', 'Gene', '23152', (127, 130))	('point mutations', 'Var', (65, 80))	('Far Upstream Element Binding Protein 1', 'Gene', (145, 183))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (29, 47))	('Capicua Transcriptional Repressor', 'Gene', (92, 125))	('CIC', 'Gene', (127, 130))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('Capicua Transcriptional Repressor', 'Gene', '23152', (92, 125))
57463	30072063	Nearly 100% of gliomas in this category harbor mutations in the Telomerase Reverse Transcriptase (TERT) promoter.	('TERT', 'Gene', (98, 102))	('Telomerase Reverse Transcriptase', 'Gene', '7015', (64, 96))	('TERT', 'Gene', '7015', (98, 102))	('gliomas', 'Disease', (15, 22))	('mutations', 'Var', (47, 56))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('Telomerase Reverse Transcriptase', 'Gene', (64, 96))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
57464	30072063	The mechanism for CIC and FUBP1 mutations remains unknown, although FUBP1 mutant tumors are associated with poorer outcomes.	('FUBP1', 'Gene', '8880', (26, 31))	('FUBP1', 'Gene', '8880', (68, 73))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('CIC', 'Gene', (18, 21))	('FUBP1', 'Gene', (68, 73))	('FUBP1', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutant', 'Var', (74, 80))	('CIC', 'Gene', '23152', (18, 21))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
57465	30072063	TERT promoter mutations result in telomere maintenance and replicative immortality by constitutively activating the transcription of the enzymatic component of telomerase.	('transcription', 'MPA', (116, 129))	('replicative immortality', 'CPA', (59, 82))	('telomere maintenance', 'CPA', (34, 54))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('result in', 'Reg', (24, 33))	('activating', 'PosReg', (101, 111))	('mutations', 'Var', (14, 23))
57468	30072063	Common events include TERT promoter mutations, loss-of-function mutations or deletions in phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog (PTEN), and cell cycle regulator cyclin dependent kinase Inhibitor 2A (CDKN2A), as well as gain-of-function mutations and/or amplifications in receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor alpha (PDGFRA).	('amplifications', 'Var', (280, 294))	('deletions', 'Var', (77, 86))	('PTEN', 'Gene', (156, 160))	('mutations', 'Var', (263, 272))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (375, 420))	('EGFR', 'Gene', '1956', (365, 369))	('CDKN2A', 'Gene', (226, 232))	('cyclin dependent kinase Inhibitor 2A', 'Gene', '1029', (188, 224))	('TERT', 'Gene', (22, 26))	('TERT', 'Gene', '7015', (22, 26))	('RTK', 'Gene', (325, 328))	('PTEN', 'Gene', '5728', (156, 160))	('mutations', 'Var', (64, 73))	('epidermal growth factor receptor', 'Gene', (331, 363))	('RTK', 'Gene', '5979', (325, 328))	('CDKN2A', 'Gene', '1029', (226, 232))	('epidermal growth factor receptor', 'Gene', '1956', (331, 363))	('EGFR', 'Gene', (365, 369))	('PI3K', 'Gene', (117, 121))	('PDGFRA', 'Gene', '5156', (422, 428))	('PDGFRA', 'Gene', (422, 428))	('gain-of-function', 'PosReg', (246, 262))	('loss-of-function', 'NegReg', (47, 63))	('cyclin dependent kinase Inhibitor 2A', 'Gene', (188, 224))	('mutations', 'Var', (36, 45))	('platelet derived growth factor receptor alpha', 'Gene', (375, 420))
57469	30072063	Deletions or loss-of-function mutations of the tumor suppressor PTEN are thought to promote tumorigenesis by antagonizing the suppression of RTKs es including EGFR and PDGFRA.	('EGFR', 'Gene', '1956', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('antagonizing', 'NegReg', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RTK', 'Gene', (141, 144))	('RTK', 'Gene', '5979', (141, 144))	('suppression', 'MPA', (126, 137))	('EGFR', 'Gene', (159, 163))	('PTEN', 'Gene', (64, 68))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (47, 52))	('PDGFRA', 'Gene', (168, 174))	('loss-of-function', 'NegReg', (13, 29))	('PDGFRA', 'Gene', '5156', (168, 174))	('promote', 'PosReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PTEN', 'Gene', '5728', (64, 68))	('Deletions', 'Var', (0, 9))
57470	30072063	Amplifications or gain-of-function mutations of the latter genes promote tumorigenesis by stimulating cellular proliferation through increased growth factor signaling.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cellular proliferation', 'CPA', (102, 124))	('growth factor signaling', 'MPA', (143, 166))	('tumor', 'Disease', (73, 78))	('Amplifications', 'Var', (0, 14))	('stimulating', 'PosReg', (90, 101))	('promote', 'PosReg', (65, 72))	('gain-of-function', 'PosReg', (18, 34))	('increased', 'PosReg', (133, 142))	('mutations', 'Var', (35, 44))
57471	30072063	Deletions of CDKN2A make tumor cells insensitive to growth-inhibitory signals and allow cells to bypass cellular senescence.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('CDKN2A', 'Gene', (13, 19))	('CDKN2A', 'Gene', '1029', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Deletions', 'Var', (0, 9))
57496	30072063	Importantly, altered DNA methylation is a frequent event across cancers, including glioma.	('glioma', 'Disease', (83, 89))	('DNA methylation', 'MPA', (21, 36))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('cancers', 'Disease', (64, 71))	('altered', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
57502	30072063	The authors also discovered that the occurrence of G-CIMP was tightly associated with IDH1 mutations and the proneural expression subtype, and that those patients with G-CIMP positive tumors without IDH1 mutations had a younger age at diagnosis.	('IDH1', 'Gene', '3417', (199, 203))	('IDH1', 'Gene', (86, 90))	('G-CIMP', 'Chemical', '-', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('IDH1', 'Gene', '3417', (86, 90))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Disease', (184, 190))	('associated', 'Reg', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (91, 100))	('IDH1', 'Gene', (199, 203))	('G-CIMP', 'Chemical', '-', (168, 174))
57505	30072063	These seminal contributions led to mechanistic follow-up studies, eventually establishing that IDH1 mutations directly lead to genome-wide hypermethylation via the production of the oncometabolite 2-hydroxyglutarate and its inhibitory effect on the DNA demethylating enzyme ten-eleven translocation methylcytosine dioxygenase 1 (TET1).	('IDH1', 'Gene', '3417', (95, 99))	('mutations', 'Var', (100, 109))	('TET1', 'Gene', '80312', (329, 333))	('hypermethylation', 'MPA', (139, 155))	('lead to', 'Reg', (119, 126))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (197, 215))	('inhibitory effect', 'NegReg', (224, 241))	('IDH1', 'Gene', (95, 99))	('translocation methylcytosine dioxygenase 1', 'Gene', (285, 327))	('translocation methylcytosine dioxygenase 1', 'Gene', '80312', (285, 327))	('TET1', 'Gene', (329, 333))
57508	30072063	Diffuse gliomas in children clustered in different categories that are enriched in mutations in the H3 Histone Family Member 3A (H3F3A) gene.	('mutations', 'Var', (83, 92))	('gliomas', 'Disease', (8, 15))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('H3 Histone Family Member 3A (H3F3A', 'Gene', '3020', (100, 134))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('children', 'Species', '9606', (19, 27))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))
57509	30072063	For example, tumors in the "IDH" cluster carried IDH1 mutations, displayed G-CIMP, and had a more favorable prognosis; "RTK I" tumors significantly more often harbored PDGFRA amplification; "Mesenchymal" tumors had methylation profiles most similar to normal brain tissue despite substantial copy number changes and were enriched for the mesenchymal gene expression cluster; and "RTK II" tumors were characterized by high frequency of chromosome 7 gain and chromosome 10 loss.	('tumors', 'Phenotype', 'HP:0002664', (388, 394))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('IDH', 'Gene', (49, 52))	('IDH', 'Gene', '3417', (28, 31))	('harbored', 'Reg', (159, 167))	('gain', 'PosReg', (448, 452))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('chromosome', 'Var', (457, 467))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH1', 'Gene', '3417', (49, 53))	('tumors', 'Disease', (388, 394))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('II" tumors', 'Disease', 'MESH:D009369', (384, 394))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', '3417', (49, 52))	('RTK', 'Gene', (380, 383))	('tumors', 'Disease', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('RTK', 'Gene', (120, 123))	('RTK', 'Gene', '5979', (380, 383))	('loss', 'NegReg', (471, 475))	('tumors', 'Disease', (13, 19))	('RTK', 'Gene', '5979', (120, 123))	('tumors', 'Disease', 'MESH:D009369', (388, 394))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('G-CIMP', 'Chemical', '-', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('II" tumors', 'Disease', (384, 394))	('PDGFRA', 'Gene', (168, 174))	('IDH', 'Gene', (28, 31))	('PDGFRA', 'Gene', '5156', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('IDH1', 'Gene', (49, 53))
57512	30072063	LGm1-3 tumors were primarily IDH1 or IDH2 mutant tumors (99% of the tumors in these clusters combined) and were heavily enriched for low-grade gliomas (93% of tumors in these clusters).	('mutant', 'Var', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', (49, 55))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('IDH2', 'Gene', (37, 41))	('tumors', 'Disease', (7, 13))	('IDH2', 'Gene', '3418', (37, 41))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('IDH1', 'Gene', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('gliomas', 'Disease', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (68, 74))	('LGm1-3', 'Gene', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('IDH1', 'Gene', '3417', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))
57515	30072063	Notably, the G-CIMP-low tumors demonstrated poorer overall survival when compared with the other IDH-mutant subgroups.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('IDH', 'Gene', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('IDH', 'Gene', '3417', (97, 100))	('G-CIMP-low', 'Var', (13, 23))	('poorer', 'NegReg', (44, 50))	('G-CIMP', 'Chemical', '-', (13, 19))	('overall survival', 'MPA', (51, 67))
57517	30072063	For example, LGm4 was described as "Classic-like" similar to the Sturm RTK II classification, LGm5 was "Mesenchymal-like" similar to the Sturm RTK I classification, and LGm6 was a subtype sharing epigenomic and genomic features with pilocytic astrocytoma (PA) despite a histological diagnosis of diffuse glioma.	('glioma', 'Phenotype', 'HP:0009733', (304, 310))	('astrocytoma', 'Phenotype', 'HP:0009592', (243, 254))	('RTK', 'Gene', '5979', (143, 146))	('RTK', 'Gene', (71, 74))	('LGm6', 'Var', (169, 173))	('glioma', 'Disease', (304, 310))	('LGm5', 'Var', (94, 98))	('pilocytic astrocytoma', 'Disease', (233, 254))	('RTK', 'Gene', (143, 146))	('RTK', 'Gene', '5979', (71, 74))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (233, 254))	('glioma', 'Disease', 'MESH:D005910', (304, 310))
57519	30072063	Thus, the low-grade gliomas in LGm6 were referred to as PA-like, while the glioblastomas in this group were best described as LGm6-GBM.	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('glioblastomas', 'Phenotype', 'HP:0012174', (75, 88))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('LGm6', 'Var', (31, 35))	('glioblastomas', 'Disease', 'MESH:D005909', (75, 88))	('glioblastomas', 'Disease', (75, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
57521	30072063	DNA methylation profiles of longitudinally collected samples support epigenetic reprogramming as a driver of glioma recurrence.	('glioma', 'Disease', 'MESH:D005910', (109, 115))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('epigenetic', 'Var', (69, 79))	('glioma', 'Disease', (109, 115))
57524	30072063	It was recently estimated that between 10-40% of G-CIMP-high tumors recur with a G-CIMP-low phenotype, indicating that the G-CIMP-high to -low transition may be a marker of progression.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('G-CIMP', 'Chemical', '-', (49, 55))	('G-CIMP', 'Chemical', '-', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('G-CIMP', 'Chemical', '-', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('G-CIMP-high', 'Var', (49, 60))
57526	30072063	Similar to previous studies of primary-recurrent glioma samples, the authors discovered that relative hypomethylation was a striking feature at recurrence, and specifically that demethylation of Wnt signaling gene promoters was associated with worse prognosis.	('Wnt signaling gene', 'Gene', (195, 213))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('demethylation', 'Var', (178, 191))	('relative hypomethylation', 'MPA', (93, 117))	('associated', 'Reg', (228, 238))	('glioma', 'Disease', (49, 55))
57530	30072063	Past studies have helped to identify glioma-initiating events, revealed potentially targetable oncogenic proteins, defined co-occurrences of molecular alterations in specific tumor subgroups, demonstrated that epigenetic inactivation of genes is predictive of therapeutic response, and that there exists a dynamic molecular landscape in glioma progression.	('tumor', 'Disease', (175, 180))	('glioma', 'Disease', (37, 43))	('glioma', 'Disease', 'MESH:D005910', (337, 343))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (337, 343))	('therapeutic', 'Disease', (260, 271))	('epigenetic inactivation', 'Var', (210, 233))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Disease', (337, 343))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
57534	30072063	For example, combining multiple molecular data, such as mutations and DNA methylation, further parsed IDH-mutant tumors into subgroups with unique clinical and molecular characteristics.	('IDH', 'Gene', '3417', (102, 105))	('mutations', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IDH', 'Gene', (102, 105))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
57544	30072063	Diffuse gliomas that are both IDH-mutant and 1p/19q-codeleted are classified as oligodendroglioma, whereas tumors lacking codeletion of these chromosome arms are classified as astrocytoma and can be further separated based on IDH-status.	('IDH', 'Gene', '3417', (226, 229))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('IDH', 'Gene', (30, 33))	('oligodendroglioma', 'Disease', 'MESH:D009837', (80, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (176, 187))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('gliomas', 'Disease', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oligodendroglioma', 'Disease', (80, 97))	('tumors', 'Disease', (107, 113))	('Diffuse', 'Disease', (0, 7))	('IDH', 'Gene', '3417', (30, 33))	('IDH', 'Gene', (226, 229))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('astrocytoma', 'Disease', 'MESH:D001254', (176, 187))	('astrocytoma', 'Disease', (176, 187))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('1p/19q-codeleted', 'Var', (45, 61))
57545	30072063	Diffuse midline glioma, H3 K27M-mutant, was added in the WHO 2016 classification as a separate entity.	('K27M', 'Mutation', 'p.K27M', (27, 31))	('midline glioma', 'Disease', 'MESH:D005910', (8, 22))	('midline glioma', 'Disease', (8, 22))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('H3 K27M-mutant', 'Var', (24, 38))
57548	30072063	GBMs can also be classified by methylation subtypes: IDH (which carry IDH1 mutations, display G-CIMP, and have a more favorable prognosis), RTK I (which frequently harbor PDGFRA amplification), Mesenchymal (methylation profiles most similar to normal brain tissue despite substantial copy number changes and were enriched for the mesenchymal gene expression cluster), and RTK II (characterized by high frequency of chromosome 7 gain and chromosome 10 loss).	('loss', 'NegReg', (451, 455))	('RTK', 'Gene', (372, 375))	('IDH', 'Gene', (70, 73))	('G-CIMP', 'Chemical', '-', (94, 100))	('RTK', 'Gene', '5979', (140, 143))	('IDH1', 'Gene', '3417', (70, 74))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('IDH', 'Gene', '3417', (70, 73))	('PDGFRA', 'Gene', '5156', (171, 177))	('RTK', 'Gene', '5979', (372, 375))	('mutations', 'Var', (75, 84))	('IDH', 'Gene', (53, 56))	('gain', 'PosReg', (428, 432))	('PDGFRA', 'Gene', (171, 177))	('RTK', 'Gene', (140, 143))	('IDH', 'Gene', '3417', (53, 56))	('IDH1', 'Gene', (70, 74))
57549	29396294	PD-1 (PDCD1) Promoter Methylation Is a Prognostic Factor in Patients With Diffuse Lower-Grade Gliomas Harboring Isocitrate Dehydrogenase (IDH) Mutations Immune checkpoints are important targets for immunotherapies.	('Gliomas', 'Disease', (94, 101))	('PDCD1', 'Gene', '5133', (6, 11))	('IDH', 'Gene', (138, 141))	('PDCD1', 'Gene', (6, 11))	('PD-1', 'Gene', (0, 4))	('Patients', 'Species', '9606', (60, 68))	('PD-1', 'Gene', '5133', (0, 4))	('IDH', 'Gene', '3417', (138, 141))	('Isocitrate Dehydrogenase', 'Gene', '3417', (112, 136))	('Mutations', 'Var', (143, 152))	('Isocitrate Dehydrogenase', 'Gene', (112, 136))	('Gliomas', 'Disease', 'MESH:D005910', (94, 101))	('Gliomas', 'Phenotype', 'HP:0009733', (94, 101))
57550	29396294	In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas.	('PD-L2', 'Gene', '80380', (76, 81))	('CTLA4', 'Gene', '1493', (62, 67))	('Cancer', 'Phenotype', 'HP:0002664', (399, 405))	('IDH', 'Gene', '3417', (367, 370))	('gliomas', 'Disease', (115, 122))	('PD-L2', 'Gene', (76, 81))	('isocitrate dehydrogenase', 'Gene', '3417', (139, 163))	('patients', 'Species', '9606', (353, 361))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('CTLA4', 'Gene', (62, 67))	('PD-L1', 'Gene', (69, 74))	('IDH', 'Gene', (165, 168))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('PD-1', 'Gene', (87, 91))	('PD-1', 'Gene', '5133', (87, 91))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (399, 418))	('IDH', 'Gene', '3417', (165, 168))	('mutations', 'Var', (170, 179))	('isocitrate dehydrogenase', 'Gene', (139, 163))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH', 'Gene', (367, 370))	('Cancer Genome Atlas', 'Disease', (399, 418))
57553	29396294	MGMT methylation (PD-L1: p < 0.001; PD-L2: p < 0.001), ATRX mutations (PD-L2: p < 0.001, PD-1: p = 0.001), and TERT mutations (PD-L1: p = 0.035, PD-L2: p < 0.001, PD-1: p < 0.001, CTLA4: p < 0.001) as well as methylation subgroups and immune cell infiltrates.	('CTLA4', 'Gene', '1493', (180, 185))	('PD-L2', 'Gene', '80380', (36, 41))	('PD-1', 'Gene', (163, 167))	('PD-1', 'Gene', '5133', (163, 167))	('MGMT', 'Gene', '4255', (0, 4))	('PD-L2', 'Gene', '80380', (145, 150))	('mutations', 'Var', (60, 69))	('PD-L2', 'Gene', (36, 41))	('CTLA4', 'Gene', (180, 185))	('PD-L2', 'Gene', (145, 150))	('PD-1', 'Gene', (89, 93))	('PD-1', 'Gene', '5133', (89, 93))	('PD-L2', 'Gene', '80380', (71, 76))	('MGMT', 'Gene', (0, 4))	('ATRX', 'Gene', (55, 59))	('PD-L2', 'Gene', (71, 76))	('TERT', 'Gene', (111, 115))	('ATRX', 'Gene', '546', (55, 59))	('TERT', 'Gene', '7015', (111, 115))
57554	29396294	In multivariate Cox proportional hazard analysis, PD-1 methylation qualified as strong prognostic factor (HR = 0.51 [0.34-0.76], p = 0.001).	('PD-1', 'Gene', (50, 54))	('PD-1', 'Gene', '5133', (50, 54))	('methylation', 'Var', (55, 66))
57555	29396294	PD-1 methylation may assist the identification of patients that might benefit from an alternative treatment, particularly in the context of emerging immunotherapies.	('PD-1', 'Gene', '5133', (0, 4))	('methylation', 'Var', (5, 16))	('patients', 'Species', '9606', (50, 58))	('PD-1', 'Gene', (0, 4))
57556	29396294	PD-L1, PD-L2, and CTLA4 DNA methylation in lower-grade gliomas is inversely correlated with mRNA expression levels.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('CTLA4', 'Gene', '1493', (18, 23))	('mRNA expression levels', 'MPA', (92, 114))	('CTLA4', 'Gene', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('inversely', 'NegReg', (66, 75))	('methylation', 'Var', (28, 39))	('PD-L2', 'Gene', (7, 12))	('PD-L2', 'Gene', '80380', (7, 12))
57557	29396294	PD-1, PD-L1, PD-L2, and CTLA4 DNA methylation in lower-grade gliomas is associated with age and mutation status.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('CTLA4', 'Gene', '1493', (24, 29))	('methylation', 'Var', (34, 45))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (0, 4))	('CTLA4', 'Gene', (24, 29))	('associated', 'Reg', (72, 82))	('mutation', 'Var', (96, 104))	('gliomas', 'Disease', (61, 68))	('PD-L2', 'Gene', (13, 18))	('PD-L2', 'Gene', '80380', (13, 18))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))
57558	29396294	PD-1 methylation in lower-grade gliomas is correlated with infiltrating immune cells (B, CD8+ T, and dendritic cells).	('CD8', 'Gene', (89, 92))	('methylation', 'Var', (5, 16))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('CD8', 'Gene', '925', (89, 92))	('correlated', 'Reg', (43, 53))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
57559	29396294	PD-1 methylation is an independent prognostic biomarker for overall survival in lower-grade glioma patients.	('methylation', 'Var', (5, 16))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (0, 4))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
57562	29396294	Furthermore, PD-1 methylation was prognostic for survival in lower-grade gliomas harboring isocitrate dehydrogenase (IDH) mutations supporting the pivotal role of DNA methylation in the regulation of immune checkpoint genes in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('gliomas', 'Disease', (227, 234))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('PD-1', 'Gene', (13, 17))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('isocitrate dehydrogenase', 'Gene', (91, 115))	('IDH', 'Gene', (117, 120))	('PD-1', 'Gene', '5133', (13, 17))	('isocitrate dehydrogenase', 'Gene', '3417', (91, 115))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('prognostic', 'Reg', (34, 44))	('IDH', 'Gene', '3417', (117, 120))	('mutations', 'Var', (122, 131))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('gliomas', 'Disease', (73, 80))
57568	29396294	isocitrate dehydrogenase (IDH) mutations and codeletions of chromosome arms 1p and 19q (1p/19q co-deletion)) (summarized by).	('mutations', 'Var', (31, 40))	('isocitrate dehydrogenase', 'Gene', (0, 24))	('IDH', 'Gene', (26, 29))	('isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('IDH', 'Gene', '3417', (26, 29))
57571	29396294	Mutations in the IDH1 and IDH2 genes have previously been identified to lead to a downstream neomorphic enzymatic activity and an accumulation of the onco-metabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutant cells.	('accumulation', 'PosReg', (130, 142))	('neomorphic', 'MPA', (93, 103))	('IDH', 'Gene', '3417', (17, 20))	('IDH2', 'Gene', (26, 30))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (166, 186))	('IDH', 'Gene', '3417', (26, 29))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (26, 29))	('IDH1', 'Gene', (17, 21))	('IDH2', 'Gene', '3418', (26, 30))	('IDH', 'Gene', (198, 201))	('IDH1', 'Gene', '3417', (17, 21))	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', '3417', (198, 201))
57572	29396294	Gliomas harboring IDH mutations consequently display a CpG island methylator phenotype (G-CIMP), which is characterized by DNA hypermethylation in CpG-rich domains and has been shown to constitute a subset of tumors with a distinct biology and clinical behavior.	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('CpG island methylator', 'Disease', (55, 76))	('IDH', 'Gene', (18, 21))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('IDH', 'Gene', '3417', (18, 21))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('mutations', 'Var', (22, 31))	('Gliomas', 'Disease', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
57573	29396294	These findings emphasize the relevance of epigenetic alterations as an underlying and therapeutically relevant mechanism in glioma.	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('epigenetic alterations', 'Var', (42, 64))	('glioma', 'Disease', (124, 130))
57583	29396294	In the present study, we investigated DNA promoter methylation of the immune checkpoints genes PD-1 (Human Genome Organisation (HUGO) gene symbol: PDCD1), PD-L1 (CD274), PD-L2 (PDCD1LG2), and CTLA-4 (CTLA4) in patients with LGG harboring IDH mutations with regard to mRNA expression, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival.	('PD-L2', 'Gene', '80380', (170, 175))	('IDH', 'Gene', (238, 241))	('CD274', 'Gene', '29126', (162, 167))	('PD-L2', 'Gene', (170, 175))	('CTLA-4', 'Gene', '1493', (192, 198))	('IDH', 'Gene', '3417', (238, 241))	('PDCD1LG2', 'Gene', '80380', (177, 185))	('patients', 'Species', '9606', (210, 218))	('Human', 'Species', '9606', (101, 106))	('CTLA-4', 'Gene', (192, 198))	('CD274', 'Gene', (162, 167))	('PDCD1', 'Gene', '5133', (147, 152))	('PDCD1', 'Gene', (147, 152))	('CTLA4', 'Gene', '1493', (200, 205))	('PDCD1', 'Gene', '5133', (177, 182))	('PDCD1', 'Gene', (177, 182))	('PDCD1LG2', 'Gene', (177, 185))	('PD-1', 'Gene', '5133', (95, 99))	('PD-1', 'Gene', (95, 99))	('mutations', 'Var', (242, 251))	('CTLA4', 'Gene', (200, 205))
57588	29396294	In brief, HumanMethylation450 data of level 2 including background-corrected methylated (Intensity_M) and unmethylated (Intensity_U) summary intensities (beads cg15837913, cg02823866, cg14305799, cg13474877, cg19724470 [PD-L1]; cg07211259 [PD-L2]; cg20805133, cg00795812, cg27051683, cg17322655, cg03889044 [PD-1]; cg05074138 and cg08460026 [CTLA4]) were downloaded and extracted by the R package 'methylumi'.	('CTLA4', 'Gene', (342, 347))	('cg05074138', 'Var', (315, 325))	('cg17322655', 'Var', (284, 294))	('PD-1', 'Gene', '5133', (308, 312))	('PD-1', 'Gene', (308, 312))	('PD-L2', 'Gene', '80380', (240, 245))	('Human', 'Species', '9606', (10, 15))	('cg02823866', 'Var', (172, 182))	('cg19724470', 'Var', (208, 218))	('cg08460026', 'Var', (330, 340))	('PD-L2', 'Gene', (240, 245))	('cg27051683', 'Var', (272, 282))	('CTLA4', 'Gene', '1493', (342, 347))	('cg13474877', 'Var', (196, 206))
57591	29396294	In brief, immune checkpoint promoter methylation was significantly associated with patients' age (PD-L2: p = 0.003; PD-1: p = 0.015), O6-methylguanine DNA methyltransferase(MGMT) methylation (PD-L1: p < 0.001; PD-L2: p < 0.001), ATRX mutations (PD-L2: p < 0.001, PD-1: p = 0.001), telomerase reverse transcriptase (TERT) mutations (PD-L1: p = 0.035, PD-L2: p < 0.001, PD-1: p < 0.001, CTLA4: p < 0.001), and methylation subgroups (LGm1, LGm2 and LGm3; PD-L1: p < 0.001, PD-L2: p < 0.001, PD-1: p = 0.001, CTLA4: p < 0.001).	('ATRX', 'Gene', '546', (229, 233))	('PD-1', 'Gene', (116, 120))	('PD-1', 'Gene', '5133', (116, 120))	('PD-L2', 'Gene', '80380', (98, 103))	('PD-1', 'Gene', (368, 372))	('PD-1', 'Gene', (488, 492))	('PD-1', 'Gene', '5133', (368, 372))	('PD-1', 'Gene', '5133', (488, 492))	('MGMT', 'Gene', (173, 177))	('PD-L2', 'Gene', '80380', (470, 475))	('telomerase reverse transcriptase', 'Gene', (281, 313))	('PD-L2', 'Gene', '80380', (210, 215))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (134, 172))	('TERT', 'Gene', (315, 319))	('CTLA4', 'Gene', '1493', (505, 510))	('PD-L2', 'Gene', (98, 103))	('TERT', 'Gene', '7015', (315, 319))	('PD-L2', 'Gene', '80380', (350, 355))	('PD-L2', 'Gene', (470, 475))	('patients', 'Species', '9606', (83, 91))	('PD-1', 'Gene', (263, 267))	('PD-L2', 'Gene', (210, 215))	('PD-1', 'Gene', '5133', (263, 267))	('telomerase reverse transcriptase', 'Gene', '7015', (281, 313))	('CTLA4', 'Gene', '1493', (385, 390))	('PD-L2', 'Gene', '80380', (245, 250))	('PD-L2', 'Gene', (350, 355))	('CTLA4', 'Gene', (505, 510))	('MGMT', 'Gene', '4255', (173, 177))	('associated', 'Reg', (67, 77))	('immune checkpoint promoter', 'Gene', (10, 36))	('mutations', 'Var', (234, 243))	('O6-methylguanine DNA methyltransferase', 'Gene', (134, 172))	('PD-L2', 'Gene', (245, 250))	('mutations', 'Var', (321, 330))	('CTLA4', 'Gene', (385, 390))	('ATRX', 'Gene', (229, 233))
57592	29396294	In a pan-glioma unsupervised cluster analysis, previously identified specific methylation subtypes LGm1/LGm2/LGm3, which carried IDH1 or IDH2 mutations, were enriched for lower-grade gliomas, and presented with a genome-wide hypermethylation compared to other methylation clusters.	('LGm1/LGm2/LGm3', 'Gene', (99, 113))	('mutations', 'Var', (142, 151))	('glioma', 'Disease', (9, 15))	('gliomas', 'Disease', (183, 190))	('hypermethylation', 'MPA', (225, 241))	('glioma', 'Disease', (183, 189))	('IDH1', 'Gene', (129, 133))	('IDH2', 'Gene', (137, 141))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('IDH2', 'Gene', '3418', (137, 141))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('IDH1', 'Gene', '3417', (129, 133))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))
57595	29396294	Additionally, PD-L2 levels were shown to be lower in LGm2 compared to LGm3 (p < 0.001).	('PD-L2', 'Gene', '80380', (14, 19))	('lower', 'NegReg', (44, 49))	('LGm2', 'Var', (53, 57))	('PD-L2', 'Gene', (14, 19))
57596	29396294	Mean PD-1 promoter methylation was significantly lower in LGm1 (40.5% +- 16.7%) compared to LGm2 (50.1% +- 16.4%, p = 0.002; Fig.	('LGm1', 'Var', (58, 62))	('lower', 'NegReg', (49, 54))	('methylation', 'MPA', (19, 30))	('PD-1', 'Gene', (5, 9))	('PD-1', 'Gene', '5133', (5, 9))
57599	29396294	Since PD-1 and CTLA-4 expression has been mainly observed in immune cells, differential PD-1 and CTLA4 promoter methylation may reflect changes in the lymphocyte and antigen presenting cell compartment.	('PD-1', 'Gene', '5133', (88, 92))	('PD-1', 'Gene', (6, 10))	('changes', 'Reg', (136, 143))	('CTLA-4', 'Gene', '1493', (15, 21))	('PD-1', 'Gene', '5133', (6, 10))	('methylation', 'Var', (112, 123))	('CTLA4', 'Gene', '1493', (97, 102))	('CTLA-4', 'Gene', (15, 21))	('CTLA4', 'Gene', (97, 102))	('PD-1', 'Gene', (88, 92))
57600	29396294	Subtypes of tumor infiltrating lymphocytes in the TCGA cohort as assessed by were correlated with PD-1 and CTLA4 promoter methylation.	('PD-1', 'Gene', (98, 102))	('PD-1', 'Gene', '5133', (98, 102))	('methylation', 'Var', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CTLA4', 'Gene', '1493', (107, 112))	('CTLA4', 'Gene', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
57602	29396294	For CTLA4 methylation, no significant association with immune cells was observed.	('CTLA4', 'Gene', (4, 9))	('CTLA4', 'Gene', '1493', (4, 9))	('methylation', 'Var', (10, 21))
57604	29396294	Further, PD-L1 methylation significantly and inversely correlated with infiltrating CD4 positive (CD4+) T lymphocytes (r = - 0.109; p = 0.026; n = 419) and dendritic cells (r = - 0.099; p = 0.043; n = 419).	('methylation', 'Var', (15, 26))	('correlated', 'Reg', (55, 65))	('CD4', 'Gene', '920', (98, 101))	('CD4', 'Gene', (84, 87))	('inversely', 'NegReg', (45, 54))	('CD4', 'Gene', (98, 101))	('CD4', 'Gene', '920', (84, 87))	('PD-L1', 'Gene', (9, 14))
57607	29396294	In univariate and multivariate Cox proportional hazard analysis, PD-1 methylation qualified as a strong prognostic factor together with age (univariate Cox proportional hazard analysis: HR = 0.44 [0.30-0.66], p < 0.001; multivariate Cox proportional hazard analysis: HR = 0.51 [0.34-0.76], p = 0.001; Table 2).	('PD-1', 'Gene', (65, 69))	('PD-1', 'Gene', '5133', (65, 69))	('methylation', 'Var', (70, 81))
57608	29396294	The prognostic value of dichotomized PD-1 methylation was further confirmed by Kaplan-Meier analysis (Chi2 = 13.04, p < 0.001 for hypomethylated PD-1 and hypermethylated PD-1, respectively; Fig.	('PD-1 and hypermethylated PD-1', 'Gene', '5133', (145, 174))	('hypomethylated', 'Var', (130, 144))	('PD-1', 'Gene', (170, 174))	('PD-1', 'Gene', '5133', (170, 174))	('PD-1', 'Gene', (145, 149))	('PD-1', 'Gene', (37, 41))	('PD-1', 'Gene', '5133', (145, 149))	('PD-1', 'Gene', '5133', (37, 41))
57609	29396294	No prognostic impact was observed for PD-L1, PD-L2, and CTLA4 methylation.	('CTLA4', 'Gene', '1493', (56, 61))	('methylation', 'Var', (62, 73))	('CTLA4', 'Gene', (56, 61))	('PD-L1', 'Gene', (38, 43))	('PD-L2', 'Gene', (45, 50))	('PD-L2', 'Gene', '80380', (45, 50))
57615	29396294	Recent publications have further provided evidence for an epigenetic promoter control of PD-1 expression in human T lymphocytes.	('PD-1', 'Gene', (89, 93))	('PD-1', 'Gene', '5133', (89, 93))	('human', 'Species', '9606', (108, 113))	('expression', 'MPA', (94, 104))	('epigenetic', 'Var', (58, 68))
57616	29396294	As gliomas have long been recognized as immunosuppressive neoplasms that are characterized by the activation of various immune escape mechanisms (reviewed by), our findings indicate that high levels of PD-1 promoter methylation might result in functional tumor-specific T cells effectively driving antitumor immune responses, therefore leading to a favorable course of disease.	('PD-1', 'Gene', (202, 206))	('immunosuppressive neoplasms', 'Disease', (40, 67))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', (255, 260))	('PD-1', 'Gene', '5133', (202, 206))	('immunosuppressive neoplasms', 'Disease', 'MESH:D009369', (40, 67))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', (302, 307))	('methylation', 'Var', (216, 227))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('result in', 'Reg', (234, 243))	('neoplasms', 'Phenotype', 'HP:0002664', (58, 67))	('leading to', 'Reg', (336, 346))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
57617	29396294	In addition, promoter methylation of PD-L1 also significantly correlated with PD-1 methylation, suggesting that epigenetic regulation of the PD-1 receptor may be paralleled by PD-L1 induction in tumor tissue.	('PD-1', 'Gene', (78, 82))	('tumor', 'Disease', (195, 200))	('PD-1', 'Gene', '5133', (78, 82))	('epigenetic', 'Var', (112, 122))	('PD-1', 'Gene', (141, 145))	('PD-1', 'Gene', '5133', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('promoter methylation', 'MPA', (13, 33))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('correlated', 'Reg', (62, 72))
57618	29396294	PD-1 methylation further inversely correlated with tumor infiltrating B lymphocytes, CD8+ T lymphocytes, and antigen presenting dendritic cells in our study, suggesting a role of PD-1 methylation as surrogate marker for immune cell infiltration.	('correlated', 'Reg', (35, 45))	('methylation', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CD8', 'Gene', (85, 88))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', (179, 183))	('CD8', 'Gene', '925', (85, 88))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Disease', (51, 56))	('PD-1', 'Gene', '5133', (179, 183))	('inversely', 'NegReg', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
57619	29396294	In addition, PD-L1 methylation inversely correlated with infiltrating CD4+ T lymphocytes and dendritic cells, adding to the seemingly reciprocal relationship of infiltrating immune cells and immune checkpoint methylation in LGG.	('PD-L1', 'Gene', (13, 18))	('methylation', 'Var', (19, 30))	('CD4', 'Gene', (70, 73))	('CD4', 'Gene', '920', (70, 73))
57627	29396294	In this study, the LGm1/LGm2/LGm3 subgroups harbored IDH1 or IDH2 mutations (449 of 450, 99%), were enriched for LGG (421/454, 93%), and showed genome-wide hypermethylation compared to LGm4-6 clusters, corroborating the association between IDH mutation and increased DNA methylation.	('mutations', 'Var', (66, 75))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (240, 243))	('IDH', 'Gene', '3417', (53, 56))	('IDH1', 'Gene', (53, 57))	('IDH', 'Gene', '3417', (240, 243))	('IDH2', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (53, 57))	('hypermethylation', 'PosReg', (156, 172))	('IDH', 'Gene', (53, 56))	('LGm1/LGm2/LGm3', 'Gene', (19, 33))	('IDH2', 'Gene', '3418', (61, 65))	('IDH', 'Gene', (61, 64))	('harbored', 'Reg', (44, 52))
57630	29396294	In line with previous results, also reported the G-CIMP-low subgroup to be associated with a worse survival compared to hypermethylated tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('G-CIMP-low', 'Var', (49, 59))
57631	29396294	In our study, methylation of PD-L2 additionally distinguished between LGm2 and LGm3, thus suggesting differential methylation between these two subgroups independent from cluster-related hypermethylation.	('PD-L2', 'Gene', (29, 34))	('PD-L2', 'Gene', '80380', (29, 34))	('methylation', 'MPA', (114, 125))	('methylation', 'Var', (14, 25))	('distinguished', 'Reg', (48, 61))
57635	29396294	LGG patients harboring an IDH mutation and 1p/19q codeletion for example, representing 40.3% of the cohort under investigation, have a relatively good prognosis with a median overall survival of 8 years (Cancer Genome Atlas Research).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (204, 223))	('LGG', 'Disease', (0, 3))	('IDH', 'Gene', (26, 29))	('1p/19q codeletion', 'Var', (43, 60))	('patients', 'Species', '9606', (4, 12))	('IDH', 'Gene', '3417', (26, 29))	('Cancer Genome Atlas', 'Disease', (204, 223))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))
57636	29396294	The high prognostic power of PD-1 promoter methylation presented in our study, even in the absence of long follow-up, however, indicates the high relevance of this gene in LGG.	('methylation', 'Var', (43, 54))	('PD-1', 'Gene', '5133', (29, 33))	('LGG', 'Disease', (172, 175))	('PD-1', 'Gene', (29, 33))
57637	29396294	The lack of prognostic power of PD-L1, PD-L2, and CTLA4 methylation, on the other hand, might be due to the limited follow-up, and the prognostic potential of these markers might need to be investigated in a study with sufficient clinical follow-up.	('CTLA4', 'Gene', (50, 55))	('PD-L1', 'Gene', (32, 37))	('lack', 'NegReg', (4, 8))	('PD-L2', 'Gene', (39, 44))	('PD-L2', 'Gene', '80380', (39, 44))	('methylation', 'Var', (56, 67))	('CTLA4', 'Gene', '1493', (50, 55))
57638	29396294	Inhibition of the PD-1/PD-L1 and CTLA-4 immune checkpoints is a promising therapeutic approach for the treatment of primary brain tumors.	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('CTLA-4', 'Gene', '1493', (33, 39))	('PD-1', 'Gene', (18, 22))	('CTLA-4', 'Gene', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PD-1', 'Gene', '5133', (18, 22))	('Inhibition', 'Var', (0, 10))	('brain tumors', 'Phenotype', 'HP:0030692', (124, 136))	('primary brain tumors', 'Disease', 'MESH:D001932', (116, 136))	('primary brain tumors', 'Disease', (116, 136))
57701	20307276	When the malignancy grades were divided into two groups (grades II and III vs. grade IV) and analyzed separately, the proliferation index differed significantly in Prx III+ and Prx VI+ lower grade (II and III) astrocytomas compared to their Prx III- and Prx VI- counterparts.	('Prx III', 'Gene', (164, 171))	('Prx VI+', 'Var', (177, 184))	('Prx III', 'Gene', '10935', (164, 171))	('astrocytomas', 'Disease', 'MESH:D001254', (210, 222))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('Prx III', 'Gene', (241, 248))	('lower grade', 'NegReg', (185, 196))	('Prx III', 'Gene', '10935', (241, 248))	('malignancy', 'Disease', 'MESH:D009369', (9, 19))	('malignancy', 'Disease', (9, 19))	('astrocytomas', 'Disease', (210, 222))
57734	20307276	The beneficial connection between Prx I positivity and prognosis was significant mainly in grade II and III astrocytomas, whereas no such statistically significant association was seen in GBMs.	('Prx I', 'Gene', '5052', (34, 39))	('Prx I', 'Gene', (34, 39))	('positivity', 'Var', (40, 50))	('astrocytomas', 'Disease', 'MESH:D001254', (108, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('astrocytomas', 'Disease', (108, 120))	('grade II', 'Disease', (91, 99))	('beneficial', 'PosReg', (4, 14))
57735	20307276	At the same time the decreasing effect of Prx I positivity on the apoptotic rate was significant only in glioblastomas when the histopathology of the tumor was taken into account.	('glioblastomas', 'Disease', 'MESH:D005909', (105, 118))	('Prx I', 'Gene', (42, 47))	('glioblastomas', 'Disease', (105, 118))	('apoptotic rate', 'CPA', (66, 80))	('positivity', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('tumor', 'Disease', (150, 155))	('Prx I', 'Gene', '5052', (42, 47))
57748	20307276	Prx II positivity was found in the vast majority of tumors (in 84%), and Prx II seemed to be expressed to a greater extent that has been reported previously in normal brain tissue, for example in the study of Sarafian.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('positivity', 'Var', (7, 17))	('Prx II', 'Gene', '7001', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('Prx II', 'Gene', (73, 79))	('Prx II', 'Gene', '7001', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('Prx II', 'Gene', (0, 6))
57777	33195240	Hypermethylation of LATS2 Promoter and Its Prognostic Value in IDH-Mutated Low-Grade Gliomas Mutations in the enzyme isocitrate dehydrogenase 1/2 (IDH1/2) are the most common somatic mutations in low-grade glioma (LGG).	('IDH', 'Gene', '3417', (147, 150))	('Glioma', 'Phenotype', 'HP:0009733', (85, 91))	('IDH', 'Gene', (63, 66))	('isocitrate', 'Chemical', 'MESH:C034219', (117, 127))	('Gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('LATS2', 'Gene', (20, 25))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('LATS2', 'Gene', '26524', (20, 25))	('Gliomas', 'Disease', 'MESH:D005910', (85, 92))	('Mutations', 'Var', (93, 102))	('glioma', 'Disease', (206, 212))	('Gliomas', 'Disease', (85, 92))	('IDH', 'Gene', '3417', (63, 66))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('IDH1', 'Gene', (147, 151))	('IDH', 'Gene', (147, 150))	('IDH1', 'Gene', '3417', (147, 151))
57778	33195240	The Hippo signaling pathway is known to play a key role in organ size control, and its dysregulation is involved in the development of diverse cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('involved', 'Reg', (104, 112))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('dysregulation', 'Var', (87, 100))	('Hippo signaling pathway', 'Pathway', (4, 27))
57781	33195240	However, it is unclear if LATS2 hypermethylation is associated with YAP activation and prognosis of LGG patients.	('LATS2', 'Gene', (26, 31))	('LATS2', 'Gene', '26524', (26, 31))	('LGG', 'Disease', (100, 103))	('associated', 'Reg', (52, 62))	('YAP', 'Gene', '10413', (68, 71))	('hypermethylation', 'Var', (32, 48))	('YAP', 'Gene', (68, 71))	('patients', 'Species', '9606', (104, 112))
57784	33195240	LATS2 hypermethylation, however, did not translate into YAP activation but highly correlated with IDH mutation.	('YAP', 'Gene', '10413', (56, 59))	('hypermethylation', 'Var', (6, 22))	('LATS2', 'Gene', (0, 5))	('LATS2', 'Gene', '26524', (0, 5))	('YAP', 'Gene', (56, 59))	('correlated', 'Reg', (82, 92))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', '3417', (98, 101))
57785	33195240	LATS2 hypermethylation may thus serve as an alternative for IDH mutation in diagnosis and a favorable prognostic factor for LGG patients.	('hypermethylation', 'Var', (6, 22))	('LATS2', 'Gene', (0, 5))	('LATS2', 'Gene', '26524', (0, 5))	('LGG', 'Disease', (124, 127))	('IDH', 'Gene', (60, 63))	('patients', 'Species', '9606', (128, 136))	('IDH', 'Gene', '3417', (60, 63))
57786	33195240	Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), mainly Arg132 for IDH1 and Arg140 and Arg172 for IDH2, occur in over 80% of low-grade glioma (LGG).	('IDH2', 'Gene', (105, 109))	('glioma', 'Disease', (142, 148))	('IDH1', 'Gene', (74, 78))	('IDH1', 'Gene', (47, 51))	('Arg140', 'Var', (83, 89))	('occur', 'Reg', (111, 116))	('IDH2', 'Gene', '3418', (105, 109))	('Arg140', 'Chemical', '-', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('Arg172', 'Chemical', '-', (94, 100))	('Arg172', 'Var', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('IDH1', 'Gene', '3417', (74, 78))	('Arg132', 'Chemical', '-', (63, 69))	('IDH1', 'Gene', '3417', (47, 51))	('isocitrate', 'Chemical', 'MESH:C034219', (13, 23))	('Arg132', 'Var', (63, 69))
57787	33195240	While wild type IDH1/2 converts isocitrate to alpha-ketoglutarate (alphaKG), gain-of-function mutations of IDH1/2 lead to the production and accumulation of oncometabolite R-2-hydroxyglutarate (R-2HG).	('IDH1', 'Gene', (107, 111))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (46, 65))	('mutations', 'Var', (94, 103))	('IDH1', 'Gene', '3417', (107, 111))	('gain-of-function', 'PosReg', (77, 93))	('IDH1', 'Gene', (16, 20))	('accumulation', 'PosReg', (141, 153))	('isocitrate', 'Chemical', 'MESH:C034219', (32, 42))	('R-2-hydroxyglutarate', 'Chemical', '-', (172, 192))	('IDH1', 'Gene', '3417', (16, 20))	('R-2-hydroxyglutarate', 'MPA', (172, 192))
57788	33195240	R-2HG drives tumorigenesis by inhibiting alphaKG-dependent enzymes involved in epigenetic modifications, response to hypoxia, and other biological processes.	('alphaKG-dependent enzymes', 'Enzyme', (41, 66))	('inhibiting', 'NegReg', (30, 40))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('epigenetic modifications', 'MPA', (79, 103))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hypoxia', 'Disease', (117, 124))	('R-2HG', 'Var', (0, 5))
57793	33195240	Dysregulation of Hippo pathway has been associated with various cancers.	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('Hippo pathway', 'Pathway', (17, 30))	('cancers', 'Disease', (64, 71))	('associated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
57794	33195240	LATS2 deficiency, for instance, has been studied in several cancers including glioma.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('LATS2', 'Gene', (0, 5))	('cancers', 'Disease', (60, 67))	('LATS2', 'Gene', '26524', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('deficiency', 'Var', (6, 16))	('glioma', 'Disease', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
57795	33195240	A recent report from The Cancer Genome Atlas (TCGA) Research Network revealed that the promoter of LATS2 is hypermethylated in almost all IDH-mutated LGG clinical samples but not in IDH-wild type samples.	('IDH', 'Gene', (138, 141))	('IDH', 'Gene', '3417', (182, 185))	('LATS2', 'Gene', (99, 104))	('IDH', 'Gene', '3417', (138, 141))	('LATS2', 'Gene', '26524', (99, 104))	('Cancer', 'Disease', (25, 31))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Disease', 'MESH:D009369', (25, 31))	('hypermethylated', 'Var', (108, 123))	('LGG', 'Disease', (150, 153))	('IDH', 'Gene', (182, 185))
57800	33195240	The differences in LATS2 gene methylation were mainly located within the promoter region instead of gene body (Figure 1D).	('LATS2', 'Gene', (19, 24))	('LATS2', 'Gene', '26524', (19, 24))	('methylation', 'Var', (30, 41))
57801	33195240	We also collected LGG specimens with or without IDH1/2 mutations, and measured LATS2 promoter methylation using a methylation-specific PCR assay.	('measured', 'Reg', (70, 78))	('mutations', 'Var', (55, 64))	('IDH1', 'Gene', '3417', (48, 52))	('LATS2', 'Gene', (79, 84))	('IDH1', 'Gene', (48, 52))	('LATS2', 'Gene', '26524', (79, 84))	('P', 'Chemical', 'MESH:D010758', (135, 136))	('promoter methylation', 'MPA', (85, 105))
57803	33195240	It is worth noting that while LATS2 promoter hypermethylation had been reported in another cancer with frequent IDH mutations, namely IDH-mutant acute myeloid leukemia (AML), it did not downregulate LATS2 expression as it did in LGG (Supplementary Figure 1A), suggesting a different mechanism or role.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (145, 167))	('AML', 'Phenotype', 'HP:0004808', (169, 172))	('AML', 'Disease', (169, 172))	('LATS2', 'Gene', (199, 204))	('LATS2', 'Gene', '26524', (199, 204))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (151, 167))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (145, 167))	('IDH', 'Gene', (112, 115))	('S', 'Chemical', 'MESH:D013455', (234, 235))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('IDH', 'Gene', (134, 137))	('IDH', 'Gene', '3417', (112, 115))	('S', 'Chemical', 'MESH:D013455', (202, 203))	('downregulate', 'NegReg', (186, 198))	('LATS2', 'Gene', (30, 35))	('LATS2', 'Gene', '26524', (30, 35))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('mutations', 'Var', (116, 125))	('expression', 'MPA', (205, 215))	('acute myeloid leukemia', 'Disease', (145, 167))	('IDH', 'Gene', '3417', (134, 137))	('cancer', 'Disease', (91, 97))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AML', 'Disease', 'MESH:D015470', (169, 172))
57804	33195240	Meanwhile, while LATS1 was also hypermethylated, it was not downregulated as LATS2 (Supplementary Figure 2A).	('hypermethylated', 'Var', (32, 47))	('LATS2', 'Gene', (77, 82))	('LATS2', 'Gene', '26524', (77, 82))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('S', 'Chemical', 'MESH:D013455', (84, 85))	('LATS1', 'Gene', (17, 22))	('LATS1', 'Gene', '9113', (17, 22))	('S', 'Chemical', 'MESH:D013455', (20, 21))
57807	33195240	Using two independent siRNAs to target LATS2 in HEK293 cells, we observed that LATS2 knockdown significantly reduced YAP phosphorylation and increased target gene CYR61 expression (Figure 2A).	('YAP', 'Gene', '10413', (117, 120))	('LATS2', 'Gene', (39, 44))	('CYR61', 'Gene', (163, 168))	('LATS2', 'Gene', '26524', (39, 44))	('YAP', 'Gene', (117, 120))	('increased', 'PosReg', (141, 150))	('HEK293', 'CellLine', 'CVCL:0045', (48, 54))	('CYR61', 'Gene', '3491', (163, 168))	('LATS2', 'Gene', (79, 84))	('LATS2', 'Gene', '26524', (79, 84))	('knockdown', 'Var', (85, 94))	('expression', 'MPA', (169, 179))	('reduced', 'NegReg', (109, 116))
57809	33195240	Hence, silencing LATS2 expression in HEK293 cells led to YAP activation.	('HEK293', 'CellLine', 'CVCL:0045', (37, 43))	('LATS2', 'Gene', (17, 22))	('LATS2', 'Gene', '26524', (17, 22))	('YAP', 'Gene', '10413', (57, 60))	('YAP', 'Gene', (57, 60))	('silencing', 'Var', (7, 16))
57825	33195240	Intriguingly, we found that BTRC, an E3 ligase responsible for YAP degradation, was dramatically upregulated in LGG compared to GBM (Figure 4G).	('LGG', 'Var', (112, 115))	('YAP', 'Gene', (63, 66))	('BTRC', 'Gene', '8945', (28, 32))	('YAP', 'Gene', '10413', (63, 66))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('upregulated', 'PosReg', (97, 108))	('BTRC', 'Gene', (28, 32))
57832	33195240	Low expression of TEAD genes was correlated with LATS2 hypermethylation (Supplementary Figure 5).	('S', 'Chemical', 'MESH:D013455', (52, 53))	('hypermethylation', 'Var', (55, 71))	('LATS2', 'Gene', '26524', (49, 54))	('expression', 'MPA', (4, 14))	('S', 'Chemical', 'MESH:D013455', (73, 74))	('TEAD genes', 'Gene', (18, 28))	('LATS2', 'Gene', (49, 54))	('Low', 'NegReg', (0, 3))
57837	33195240	Our results thus far indicated that the hypermethylation of LATS2 in IDH-mutant LGG failed to activate YAP/TAZ activity.	('YAP', 'Gene', '10413', (103, 106))	('LATS2', 'Gene', (60, 65))	('LATS2', 'Gene', '26524', (60, 65))	('LGG', 'Gene', (80, 83))	('IDH', 'Gene', (69, 72))	('YAP', 'Gene', (103, 106))	('IDH', 'Gene', '3417', (69, 72))	('hypermethylation', 'Var', (40, 56))	('TAZ', 'Gene', (107, 110))	('TAZ', 'Gene', '6901', (107, 110))
57838	33195240	Next, we interrogated whether hypermethylation of LATS2 could serve as a biomarker with clinical significance.	('LATS2', 'Gene', (50, 55))	('LATS2', 'Gene', '26524', (50, 55))	('hypermethylation', 'Var', (30, 46))
57839	33195240	In analyzing survival data of LGG patients, we found that LATS2 hypermethylation is a strong favorable prognostic factor in LGG (Figure 6A).	('LGG', 'Disease', (124, 127))	('LATS2', 'Gene', (58, 63))	('LATS2', 'Gene', '26524', (58, 63))	('patients', 'Species', '9606', (34, 42))	('hypermethylation', 'Var', (64, 80))
57840	33195240	However, when we performed analysis separately in IDH-mutant patients, LATS2 hypermethylation showed no prognostic significance in IDH-mutant subgroups (Figure 6C).	('LATS2', 'Gene', (71, 76))	('LATS2', 'Gene', '26524', (71, 76))	('patients', 'Species', '9606', (61, 69))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', (50, 53))	('IDH', 'Gene', '3417', (131, 134))	('hypermethylation', 'Var', (77, 93))	('IDH', 'Gene', '3417', (50, 53))
57841	33195240	In comparing the clinical features between high and low LATS2 methylation groups, we uncovered several characteristics that varied between these two groups including IDH1/2 status (Supplementary Table 2).	('IDH1', 'Gene', (166, 170))	('IDH1', 'Gene', '3417', (166, 170))	('methylation', 'Var', (62, 73))	('LATS2', 'Gene', (56, 61))	('LATS2', 'Gene', '26524', (56, 61))	('S', 'Chemical', 'MESH:D013455', (181, 182))	('S', 'Chemical', 'MESH:D013455', (59, 60))
57842	33195240	As IDH mutation was a favorable prognostic factor of LGG (; Figure 6B), the prognostic significance of LATS2 hypermethylation was likely due to its enrichment in IDH-mutant samples.	('IDH', 'Gene', '3417', (3, 6))	('IDH', 'Gene', (162, 165))	('IDH', 'Gene', '3417', (162, 165))	('LATS2', 'Gene', '26524', (103, 108))	('mutation', 'Var', (7, 15))	('LGG', 'Disease', (53, 56))	('LATS2', 'Gene', (103, 108))	('IDH', 'Gene', (3, 6))
57844	33195240	We found LATS2 methylation is a prognostic factor in overall LGG after adjusted for a series of covariates, but lost its prognostic value in either IDH-wildtype or mutant LGG subgroups, indicating its prognostic significance comes from correlation with IDH mutation instead of direct impact on Hippo pathway effectors.	('methylation', 'Var', (15, 26))	('mutant', 'Var', (164, 170))	('lost', 'NegReg', (112, 116))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', '3417', (148, 151))	('IDH', 'Gene', (253, 256))	('IDH', 'Gene', '3417', (253, 256))	('LGG', 'Disease', (61, 64))	('LATS2', 'Gene', (9, 14))	('LATS2', 'Gene', '26524', (9, 14))
57848	33195240	Together, these data support that LATS2 hypermethylation is a faithful biomarker of IDH mutations.	('mutations', 'Var', (88, 97))	('IDH', 'Gene', '3417', (84, 87))	('LATS2', 'Gene', (34, 39))	('hypermethylation', 'Var', (40, 56))	('LATS2', 'Gene', '26524', (34, 39))	('IDH', 'Gene', (84, 87))
57850	33195240	The TCGA Network project revealed that LATS2 is commonly hypermethylated in IDH-mutant low-grade gliomas, prompting us to explore its role in LGG.	('LATS2', 'Gene', (39, 44))	('LATS2', 'Gene', '26524', (39, 44))	('hypermethylated', 'Var', (57, 72))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', '3417', (76, 79))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
57854	33195240	Unexpectedly, LATS2 repression failed to activate Hippo pathway target genes, as most of these genes were also hypermethylated in IDH-mutant LGG samples.	('hypermethylated', 'Var', (111, 126))	('IDH', 'Gene', '3417', (130, 133))	('LATS2', 'Gene', (14, 19))	('LATS2', 'Gene', '26524', (14, 19))	('IDH', 'Gene', (130, 133))
57855	33195240	The universal epigenetic changes caused by IDH1/2 mutation could be a key point to understand this phenomenon.	('epigenetic changes', 'MPA', (14, 32))	('IDH1', 'Gene', '3417', (43, 47))	('IDH1', 'Gene', (43, 47))	('mutation', 'Var', (50, 58))
57856	33195240	Oncometabolite R-2HG produced by mutated IDH1/2 inhibits the activity of alphaKG-dependent enzymes including DNA and histone demethylases.	('inhibits', 'NegReg', (48, 56))	('alphaKG-dependent enzymes', 'Enzyme', (73, 98))	('histone demethylases', 'Enzyme', (117, 137))	('mutated', 'Var', (33, 40))	('IDH1', 'Gene', (41, 45))	('activity', 'MPA', (61, 69))	('IDH1', 'Gene', '3417', (41, 45))
57857	33195240	In this way, IDH1/2 mutation may cause genome-wide alterations in DNA methylation, including LATS2, Hippo pathway target genes, and additional Hippo pathway component genes.	('alterations', 'Reg', (51, 62))	('mutation', 'Var', (20, 28))	('IDH1', 'Gene', (13, 17))	('Hippo', 'Gene', (100, 105))	('DNA methylation', 'MPA', (66, 81))	('IDH1', 'Gene', '3417', (13, 17))	('LATS2', 'Gene', (93, 98))	('LATS2', 'Gene', '26524', (93, 98))
57864	33195240	For instance, the dysregulated expression of ZYX and AMOTL2 may inhibit LATS1/2 activity, while reduction of TEAD2-4 expression may limit the transcriptional output of YAP.	('LATS1', 'Gene', '9113', (72, 77))	('dysregulated', 'Var', (18, 30))	('transcriptional output', 'MPA', (142, 164))	('ZYX', 'Gene', '7791', (45, 48))	('ZYX', 'Gene', (45, 48))	('expression', 'MPA', (117, 127))	('AMOTL2', 'Gene', (53, 59))	('TEAD2-4', 'Gene', (109, 116))	('YAP', 'Gene', '10413', (168, 171))	('inhibit', 'NegReg', (64, 71))	('activity', 'MPA', (80, 88))	('expression', 'MPA', (31, 41))	('AMOTL2', 'Gene', '51421', (53, 59))	('LATS1', 'Gene', (72, 77))	('limit', 'NegReg', (132, 137))	('reduction', 'NegReg', (96, 105))	('YAP', 'Gene', (168, 171))
57866	33195240	In addition, LATS2 hypermethylation was a faithful biomarker of IDH mutations, and could potentially be used as an alternative for IDH mutation in diagnosis.	('IDH', 'Gene', '3417', (64, 67))	('LATS2', 'Gene', (13, 18))	('LATS2', 'Gene', '26524', (13, 18))	('IDH', 'Gene', (131, 134))	('hypermethylation', 'Var', (19, 35))	('IDH', 'Gene', '3417', (131, 134))	('mutations', 'Var', (68, 77))	('IDH', 'Gene', (64, 67))
57867	33195240	In conclusion, our study found LATS2 promoter hypermethylation in IDH-mutant LGG samples which, surprisingly, did not translate into YAP activation, raising the role and involvement, if at all, of the Hippo pathway in the development of LGG.	('IDH', 'Gene', (66, 69))	('LGG', 'Disease', (237, 240))	('IDH', 'Gene', '3417', (66, 69))	('YAP', 'Gene', '10413', (133, 136))	('LGG', 'Gene', (77, 80))	('hypermethylation', 'Var', (46, 62))	('LATS2', 'Gene', (31, 36))	('LATS2', 'Gene', '26524', (31, 36))	('YAP', 'Gene', (133, 136))
57868	33195240	Meanwhile, LATS2 hypermethylation showed a strong correlation with IDH mutation.	('LATS2', 'Gene', '26524', (11, 16))	('IDH', 'Gene', (67, 70))	('LATS2', 'Gene', (11, 16))	('IDH', 'Gene', '3417', (67, 70))	('correlation', 'Interaction', (50, 61))	('hypermethylation', 'Var', (17, 33))
57869	33195240	Hence, LATS2 hypermethylation can serve as an alternative for IDH mutation in diagnosis and a favorable prognostic factor for LGG patients.	('LGG', 'Disease', (126, 129))	('IDH', 'Gene', '3417', (62, 65))	('patients', 'Species', '9606', (130, 138))	('LATS2', 'Gene', (7, 12))	('LATS2', 'Gene', '26524', (7, 12))	('hypermethylation', 'Var', (13, 29))	('IDH', 'Gene', (62, 65))
57993	32757451	24  In addition, the frequency of methylation in GATA6 was 68.4%, and hypermethylation in GATA6 was positively related to the prognosis of glioblastoma multiforme (GBM).	('GATA6', 'Gene', (90, 95))	('related', 'Reg', (111, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('methylation', 'Var', (34, 45))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (139, 162))	('hypermethylation', 'Var', (70, 86))	('GATA6', 'Gene', '2627', (49, 54))	('GATA6', 'Gene', (49, 54))	('GATA6', 'Gene', '2627', (90, 95))	('glioblastoma multiforme', 'Disease', (139, 162))
58141	29787563	Since these tumors are not removed or biopsied in children with NF1, we specifically chose this Nf1 genetically-engineered mouse low-grade glioma model system, because it recapitulates many of the features seen in the human condition and has been successfully employed to evaluate promising targeted therapies now in clinical trial for children with the tumors (http://clinicaltrials.org; NCT01089101, NCT01158651 and NCT01734512).	('mouse', 'Species', '10090', (123, 128))	('glioma', 'Disease', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('children', 'Species', '9606', (50, 58))	('tumors', 'Phenotype', 'HP:0002664', (354, 360))	('NCT01734512', 'Var', (418, 429))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('tumors', 'Disease', (354, 360))	('tumors', 'Disease', (12, 18))	('children', 'Species', '9606', (336, 344))	('tumors', 'Disease', 'MESH:D009369', (354, 360))	('human', 'Species', '9606', (218, 223))	('NCT01158651', 'Var', (402, 413))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
58144	29787563	Our proof-of-principle study uses complexity analysis of weighted transcription networks to identify transcription factors that comprise a regulatory network unique to low-grade brain tumors arising in the optic nerves of Nf1 mutant mice (optic gliomas).	('mutant', 'Var', (226, 232))	('optic gliomas', 'Phenotype', 'HP:0009734', (239, 252))	('mice', 'Species', '10090', (233, 237))	('brain tumors', 'Disease', 'MESH:D001932', (178, 190))	('brain tumors', 'Phenotype', 'HP:0030692', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('optic gliomas', 'Disease', 'MESH:D020339', (239, 252))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('gliomas', 'Phenotype', 'HP:0009733', (245, 252))	('optic gliomas', 'Disease', (239, 252))	('brain tumors', 'Disease', (178, 190))	('brain tumor', 'Phenotype', 'HP:0030692', (178, 189))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('Nf1', 'Gene', (222, 225))	('optic glioma', 'Phenotype', 'HP:0009734', (239, 251))
58148	29787563	Nf1flox/flox (N), Nf1flox/null; GFAP-Cre (OPG-1), Nf1flox/R681*; GFAP-Cre (OPG-2), Nf1flox/null; Ptenflox/wt; GFAP-Cre (OPG-3), and Nf1flox/null; Olig2-Cre (OPG-4) mice were maintained on a C57Bl/6 background.	('R681*', 'SUBSTITUTION', 'None', (58, 63))	('R681*', 'Var', (58, 63))	('mice', 'Species', '10090', (164, 168))	('GFAP', 'Gene', '14580', (65, 69))	('GFAP', 'Gene', '14580', (110, 114))	('GFAP', 'Gene', (65, 69))	('GFAP', 'Gene', (110, 114))	('Pten', 'Gene', '5728', (97, 101))	('Pten', 'Gene', (97, 101))	('GFAP', 'Gene', '14580', (32, 36))	('GFAP', 'Gene', (32, 36))
58161	29787563	RNA expression data from optic nerves of Nf1flox/flox (N, normal control group, n = 4) and Nf1flox/mut; GFAP-Cre (OPG-1, tumor group, n = 11) were generated previously and used to create separate weighted networks.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('GFAP', 'Gene', '14580', (104, 108))	('Nf1flox/mut', 'Var', (91, 102))	('GFAP', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
58166	29787563	The non-neoplastic samples are also denoted as FF (Nf1flox/flox); OPG-1 model is also denoted as FMC (Nf1flox/null; GFAP-Cre); the OPG-2 model is also denoted as F18C (Nf1flox/R681*; GFAP-Cre); the OPG-3 is also denoted as FMPC (Nf1flox/null; Ptenflox/wt; GFAP-Cre); and the OPG-4 model is denoted as FMOC (Nf1flox/null; Olig2-Cre).	('F18C', 'Mutation', 'p.F18C', (162, 166))	('GFAP', 'Gene', '14580', (116, 120))	('GFAP', 'Gene', '14580', (256, 260))	('GFAP', 'Gene', (256, 260))	('R681*', 'Var', (176, 181))	('Pten', 'Gene', '5728', (243, 247))	('Pten', 'Gene', (243, 247))	('GFAP', 'Gene', (116, 120))	('GFAP', 'Gene', '14580', (183, 187))	('R681*', 'SUBSTITUTION', 'None', (176, 181))	('GFAP', 'Gene', (183, 187))
58176	29787563	The edges of the transcription network are given weights based on expression data such that expression data from a normal control group (N, optic nerves from Nf1flox/flox mice, which are equivalent to wild-type mice), result in a "normal" network, while data from a group of optic glioma tumor samples (OPG-1, optic nerves from Nf1flox/null; GFAP-Cre mice,) comprise a "tumor" network.	('tumor', 'Disease', (288, 293))	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('GFAP', 'Gene', '14580', (342, 346))	('optic glioma', 'Phenotype', 'HP:0009734', (275, 287))	('mice', 'Species', '10090', (171, 175))	('GFAP', 'Gene', (342, 346))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (370, 375))	('mice', 'Species', '10090', (351, 355))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('Nf1flox/flox', 'Var', (158, 170))	('mice', 'Species', '10090', (211, 215))	('optic glioma tumor', 'Disease', 'MESH:D020339', (275, 293))	('tumor', 'Disease', (370, 375))	('optic glioma tumor', 'Disease', (275, 293))
58208	29787563	In addition to RNA-Seq experiments, we also used quantitative real-time PCR (qPCR) to analyze Etv5 RNA expression in independently-generated non-neoplastic (Nf1flox/flox; abbreviated N for normal) and tumor-bearing (Nf1flox/null GFAP-Cre; "OPG-1") optic nerves.	('GFAP', 'Gene', (229, 233))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('Etv5', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('GFAP', 'Gene', '14580', (229, 233))	('Nf1flox/null', 'Var', (216, 228))	('Etv5', 'Gene', '104156', (94, 98))
58216	29787563	These observations suggest that differential expression of Etv5 defines a ground state of neoplasia that exists at a time when it is not yet possible to clearly classify the mouse optic nerve as a tumor.	('mouse', 'Species', '10090', (174, 179))	('neoplasia', 'Disease', (90, 99))	('Etv5', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('neoplasia', 'Disease', 'MESH:D009369', (90, 99))	('neoplasia', 'Phenotype', 'HP:0002664', (90, 99))	('Etv5', 'Gene', '104156', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('differential', 'Var', (32, 44))	('tumor', 'Disease', (197, 202))
58231	29787563	To demonstrate that differential Etv5 expression is a hallmark of murine Nf1 optic glioma, we leveraged prior data from our laboratory in which multiple distinct genetically-engineered mouse models of optic glioma were generated.	('mouse', 'Species', '10090', (185, 190))	('optic glioma', 'Disease', (201, 213))	('Etv5', 'Gene', '104156', (33, 37))	('optic glioma', 'Disease', 'MESH:D020339', (77, 89))	('expression', 'MPA', (38, 48))	('differential', 'Var', (20, 32))	('optic glioma', 'Disease', (77, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('Etv5', 'Gene', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('optic glioma', 'Disease', 'MESH:D020339', (201, 213))	('murine', 'Species', '10090', (66, 72))	('optic glioma', 'Phenotype', 'HP:0009734', (201, 213))	('optic glioma', 'Phenotype', 'HP:0009734', (77, 89))
58232	29787563	Each of these models differs in important respects, including the germline Nf1 gene mutation (OPG-2; c.2041C>T; p.R681X as seen in several patients with NF1-OPG), the presence of additional genetic mutations (OPG-3; additionally harboring heterozygous Pten loss), and the tumor cell of origin (OPG-4; Nf1flox/mut; Olig2-Cre in which tumors arise from Olig2+ cells).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (333, 338))	('p.R681X', 'Mutation', 'rs768638173', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('c.2041C>T', 'Mutation', 'rs768638173', (101, 110))	('tumors', 'Disease', (333, 339))	('patients', 'Species', '9606', (139, 147))	('tumor', 'Disease', (272, 277))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('Pten', 'Gene', '5728', (252, 256))	('Pten', 'Gene', (252, 256))	('p.R681X', 'Var', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('Nf1', 'Gene', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
58237	29787563	Finally, to determine whether differential ETV5 expression is also a feature of human pediatric low-grade gliomas (pilocytic astrocytoma; PA), we leveraged the only two human RNA microarray datasets that contained reference non-neoplastic tissue for comparison (GSE42656 and GSE12907).	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (115, 136))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('GSE42656', 'Var', (262, 270))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (228, 245))	('GSE12907', 'Var', (275, 283))	('human', 'Species', '9606', (169, 174))	('human', 'Species', '9606', (80, 85))	('ETV5', 'Gene', (43, 47))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('pilocytic astrocytoma', 'Disease', (115, 136))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('gliomas', 'Disease', (106, 113))
58245	29787563	Moreover, the identification of Etv5 and its network as a tissue-level signature is supported by the lack of differential Etv5 expression in isolated Nf1-deficient astrocytes or Nf1-mutant microglia, which are the major neoplastic and non-neoplastic cells in the optic glioma ecosystem.	('Nf1-mutant', 'Gene', (178, 188))	('Etv5', 'Gene', (122, 126))	('Etv5', 'Gene', '104156', (32, 36))	('optic glioma ecosystem', 'Disease', 'MESH:D020339', (263, 285))	('Nf1-deficient', 'Gene', (150, 163))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('Etv5', 'Gene', '104156', (122, 126))	('Etv5', 'Gene', (32, 36))	('Nf1-mutant', 'Var', (178, 188))	('optic glioma', 'Phenotype', 'HP:0009734', (263, 275))	('optic glioma ecosystem', 'Disease', (263, 285))
58261	23762456	Proliferation of U87 cells was unaffected by CsA, FK506 and NFAT1 shRNA transfection.	('CsA', 'Chemical', '-', (45, 48))	('FK506', 'Var', (50, 55))	('NFAT1', 'Gene', (60, 65))	('FK506', 'Chemical', 'MESH:D016559', (50, 55))	('transfection', 'Var', (72, 84))	('U87', 'Gene', (17, 20))	('NFAT1', 'Gene', '4773', (60, 65))	('U87', 'Gene', '641648', (17, 20))
58272	23762456	Dephosphorylation of NFAT1 results in nuclear translocation, and the subsequent initiation of specific transcriptional programs.	('nuclear translocation', 'MPA', (38, 59))	('NFAT1', 'Gene', '4773', (21, 26))	('initiation', 'Reg', (80, 90))	('NFAT1', 'Gene', (21, 26))	('results in', 'Reg', (27, 37))	('Dephosphorylation', 'Var', (0, 17))	('specific transcriptional programs', 'CPA', (94, 127))
58286	23762456	Specific primers for NFAT1, COX-2, MMP-7, MMP-9 and GAPDH were: NFAT1 forward: 5'-CGG GCC CAC TAT GAG ACA GAA-3' and NFAT1 reverse: 5'-GCT CAT CAG CTG TCC CAA TGA A-3'; COX-2 forward: 5'-CAA AAG CTG GGA AGC CTT CTC TAA-3' and COX-2 reverse: 5'-GCC CAG CCC GTT GGT GAA AG-3'; MMP-7 forward: 5'-AAA CTC CCG CGT CAT AGA AAT-3' and MMP-7 reverse: 5'-TCC CTA GAC TGC TAC CAT CCG-3' ; MMP-9 forward 5'-CAA ACC CTG CGT ATT TCC-3': and MMP-9 reverse 5'-AGA GTA CTG CTT GCC CAG GA-3'.	('MMP-7', 'Gene', (328, 333))	('NFAT1', 'Gene', '4773', (21, 26))	('MMP-9 reverse', 'Var', (428, 441))	('AAT-3', 'Gene', '7048', (317, 322))	('COX-2', 'Gene', '5743', (169, 174))	('MMP-7', 'Gene', (35, 40))	('MMP-7', 'Gene', '4316', (275, 280))	('MMP-7', 'Gene', '4316', (328, 333))	('COX-2', 'Gene', (226, 231))	('MMP-7', 'Gene', '4316', (35, 40))	('COX-2', 'Gene', (28, 33))	('NFAT1', 'Gene', (64, 69))	('NFAT1', 'Gene', (117, 122))	('COX-2', 'Gene', '5743', (226, 231))	('NFAT1', 'Gene', '4773', (64, 69))	('COX-2', 'Gene', '5743', (28, 33))	('NFAT1', 'Gene', '4773', (117, 122))	('COX-2', 'Gene', (169, 174))	('NFAT1', 'Gene', (21, 26))	('MMP-7', 'Gene', (275, 280))	('AAT-3', 'Gene', (317, 322))
58303	23762456	2x103 cells (untreated U87, U87 treated with CsA or FK506, U87-NFAT1-shRNA and U87-control-shRNA) were resuspended in 100 microl serum-free DMEM containing 0.1% bovine serum albumin and added in triplicate to transwell chambers.	('NFAT1', 'Gene', '4773', (63, 68))	('U87', 'Gene', '641648', (28, 31))	('CsA', 'Chemical', '-', (45, 48))	('DMEM', 'Chemical', '-', (140, 144))	('U87', 'Gene', '641648', (59, 62))	('U87', 'Gene', '641648', (79, 82))	('bovine', 'Species', '9913', (161, 167))	('U87', 'Gene', (23, 26))	('NFAT1', 'Gene', (63, 68))	('FK506', 'Var', (52, 57))	('U87', 'Gene', '641648', (23, 26))	('U87', 'Gene', (59, 62))	('U87', 'Gene', (79, 82))	('FK506', 'Chemical', 'MESH:D016559', (52, 57))	('U87', 'Gene', (28, 31))
58329	23762456	Similarly, comparing U87-NFAT1-shRNA cells with U87-control-shRNA cells, knockdown of NFAT1 expression by stable transfection with NFAT1-specific shRNA plasmid had no detectable effect on cell proliferation ( Fig.	('cell proliferation', 'CPA', (188, 206))	('U87', 'Gene', '641648', (48, 51))	('NFAT1', 'Gene', '4773', (86, 91))	('NFAT1', 'Gene', '4773', (131, 136))	('NFAT1', 'Gene', '4773', (25, 30))	('U87', 'Gene', (21, 24))	('U87', 'Gene', '641648', (21, 24))	('NFAT1', 'Gene', (86, 91))	('NFAT1', 'Gene', (25, 30))	('U87', 'Gene', (48, 51))	('NFAT1', 'Gene', (131, 136))	('knockdown', 'Var', (73, 82))
58337	23762456	Using RT-PCR, we next observed that NFAT1 knockdown by specific shRNA caused a significant reduction in the mRNA levels of COX-2, MMP-7 and MMP-9 ( Fig.	('COX-2', 'Gene', '5743', (123, 128))	('NFAT1', 'Gene', (36, 41))	('MMP-7', 'Gene', (130, 135))	('MMP-7', 'Gene', '4316', (130, 135))	('reduction', 'NegReg', (91, 100))	('MMP-9', 'MPA', (140, 145))	('NFAT1', 'Gene', '4773', (36, 41))	('COX-2', 'Gene', (123, 128))	('knockdown', 'Var', (42, 51))
58342	23762456	By extension, manipulation of NFAT1 signaling may potentially affect the extent of the GBM-related immune response.	('affect', 'Reg', (62, 68))	('NFAT1', 'Gene', (30, 35))	('manipulation', 'Var', (14, 26))	('GBM-related immune response', 'CPA', (87, 114))	('NFAT1', 'Gene', '4773', (30, 35))
58348	23762456	Inhibition of calcineurin activity by CsA or FK506 caused rapid inactivation and nuclear export of NFAT1 in U87 cells.	('CsA', 'Var', (38, 41))	('FK506', 'Chemical', 'MESH:D016559', (45, 50))	('CsA', 'Chemical', '-', (38, 41))	('NFAT1', 'Gene', (99, 104))	('U87', 'Gene', '641648', (108, 111))	('calcineurin activity', 'MPA', (14, 34))	('NFAT1', 'Gene', '4773', (99, 104))	('FK506', 'Var', (45, 50))	('nuclear export', 'MPA', (81, 95))	('U87', 'Gene', (108, 111))	('inactivation', 'NegReg', (64, 76))
58354	23762456	Specific inhibitors of NFAT1 pathways or NFAT1 shRNA were used to knockdown the expression of NFAT1 in U87 cells.	('NFAT1', 'Gene', '4773', (41, 46))	('U87', 'Gene', '641648', (103, 106))	('NFAT1', 'Gene', '4773', (94, 99))	('NFAT1', 'Gene', '4773', (23, 28))	('NFAT1', 'Gene', (41, 46))	('knockdown', 'Var', (66, 75))	('NFAT1', 'Gene', (94, 99))	('U87', 'Gene', (103, 106))	('NFAT1', 'Gene', (23, 28))
58356	23762456	Since the inhibitory effect of CsA and FK506 is not specific, we developed clones of U87-NFAT1-shRNA cells in which NFAT1 expression is stably knocked down by NFAT1-specific shRNA and showed that the invasive ability of these cells was markedly reduced.	('CsA', 'Chemical', '-', (31, 34))	('invasive ability', 'CPA', (200, 216))	('FK506', 'Chemical', 'MESH:D016559', (39, 44))	('NFAT1', 'Gene', (116, 121))	('NFAT1', 'Gene', '4773', (159, 164))	('NFAT1', 'Gene', (89, 94))	('U87', 'Gene', (85, 88))	('knocked', 'Var', (143, 150))	('reduced', 'NegReg', (245, 252))	('NFAT1', 'Gene', (159, 164))	('U87', 'Gene', '641648', (85, 88))	('NFAT1', 'Gene', '4773', (116, 121))	('NFAT1', 'Gene', '4773', (89, 94))
58365	23762456	These results were confirmed by our in vitro analysis, which demonstrated that specific knockdown of NFAT1 in U87 cells led to marked reduction of COX-2, MMP-7 and MMP-9 expression.	('U87', 'Gene', (110, 113))	('MMP-9', 'Gene', (164, 169))	('U87', 'Gene', '641648', (110, 113))	('MMP-7', 'Gene', (154, 159))	('NFAT1', 'Gene', '4773', (101, 106))	('knockdown', 'Var', (88, 97))	('reduction', 'NegReg', (134, 143))	('MMP-7', 'Gene', '4316', (154, 159))	('COX-2', 'Gene', '5743', (147, 152))	('NFAT1', 'Gene', (101, 106))	('COX-2', 'Gene', (147, 152))	('expression', 'MPA', (170, 180))
58383	23762456	In this study, we showed that in GBM cells, CsA effectively inhibits cell invasion, but has no effect on cell proliferation.	('CsA', 'Var', (44, 47))	('inhibits', 'NegReg', (60, 68))	('cell invasion', 'CPA', (69, 82))	('CsA', 'Chemical', '-', (44, 47))
58398	20187193	necrosis, variations in cellularity) and adjacent to tumors (e.g.	('necrosis', 'Disease', (0, 8))	('necrosis', 'Disease', 'MESH:D009336', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('variations', 'Var', (10, 20))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
58555	19536875	However, other data from our institution suggest that GTR and rSTR correlate with improved OS and PFS, and only 2 patients in the present analysis underwent such aggressive resection, precluding meaningful statistical analysis.	('PFS', 'CPA', (98, 101))	('GTR', 'Var', (54, 57))	('rSTR', 'Var', (62, 66))	('GTR', 'Chemical', '-', (54, 57))	('OS', 'Chemical', '-', (91, 93))	('patients', 'Species', '9606', (114, 122))	('improved', 'PosReg', (82, 90))
58594	28680873	The classification of gliomas by the World Health Organization (WHO) has been updated recently, combining now molecular parameters, such as IDH mutation and 1p/19q co-deletion with histology.	('IDH', 'Gene', '3417', (140, 143))	('gliomas', 'Disease', (22, 29))	('1p/19q co-deletion', 'Var', (157, 175))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('IDH', 'Gene', (140, 143))
58638	28680873	Nevertheless, false-positive uptake of MET, FET and FDOPA has been reported in infectious lesions (e.g., in brain abscesses), demyelinating lesions, ischemic stroke, in cerebral haemorrhages, and also in patients with status epilepticus or seizure clusters.	('seizure', 'Disease', 'MESH:D012640', (240, 247))	('MET', 'Chemical', 'MESH:C038344', (39, 42))	('FET', 'Chemical', '-', (44, 47))	('FDOPA', 'Chemical', 'MESH:C043437', (52, 57))	('seizure', 'Phenotype', 'HP:0001250', (240, 247))	('status epilepticus', 'Phenotype', 'HP:0002133', (218, 236))	('patients', 'Species', '9606', (204, 212))	('cerebral haemorrhages', 'Disease', (169, 190))	('cerebral haemorrhages', 'Phenotype', 'HP:0001342', (169, 190))	('demyelinating lesions', 'Disease', 'MESH:D003711', (126, 147))	('seizure', 'Disease', (240, 247))	('ischemic stroke', 'Disease', 'MESH:D002544', (149, 164))	('brain abscesses', 'Phenotype', 'HP:0030049', (108, 123))	('stroke', 'Phenotype', 'HP:0001297', (158, 164))	('cerebral haemorrhages', 'Disease', 'MESH:D002543', (169, 190))	('status epilepticus', 'Disease', 'MESH:D013226', (218, 236))	('abscesses', 'Phenotype', 'HP:0025615', (114, 123))	('ischemic stroke', 'Disease', (149, 164))	('uptake', 'MPA', (29, 35))	('demyelinating lesions', 'Disease', (126, 147))	('infectious lesions', 'Disease', (79, 97))	('status epilepticus', 'Disease', (218, 236))	('false-positive', 'Var', (14, 28))	('ischemic stroke', 'Phenotype', 'HP:0002140', (149, 164))
58648	28680873	Nevertheless, amino acid PET is clearly superior to the standard MRI and the property of amino acid PET to detect tumour extent has been used in many studies for treatment planning, especially in tumor resection and radiation therapy.	('amino', 'Var', (14, 19))	('tumour', 'Disease', (114, 120))	('tumor', 'Disease', (196, 201))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
58655	28680873	Furthermore, rCBV mapping exhibited a lower lesion-to-brain contrast and a highly variable background noise as compared with amino acid PET.	('rCBV', 'Var', (13, 17))	('lesion-to-brain contrast', 'MPA', (44, 68))	('rCBV', 'Chemical', '-', (13, 17))	('lower', 'NegReg', (38, 43))
58657	28680873	Thus, amino acid PET appears to be superior to rCBV mapping for the detection of the extent of cerebral gliomas and interpretation of rCBV maps appears to be more challenging than with amino acid PET.	('cerebral gliomas', 'Disease', 'MESH:C564230', (95, 111))	('rCBV', 'Chemical', '-', (47, 51))	('rCBV', 'Chemical', '-', (134, 138))	('cerebral gliomas', 'Disease', (95, 111))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('amino', 'Var', (6, 11))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
58665	28680873	In summary, both amino acid PET and PWI may be helpful for biopsy guidance, but the more reliable method to delineate the glioma extent seems to be amino acid PET.	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Disease', (122, 128))	('amino acid PET', 'Var', (148, 162))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
58675	28680873	In contrast, a recent meta-analysis came to the conclusion that differentiation of low- and high-grade gliomas was improved by PWI compared with the conventional MRI.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('PWI', 'Var', (127, 130))	('gliomas', 'Disease', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('improved', 'PosReg', (115, 123))	('differentiation', 'CPA', (64, 79))
58697	28680873	The same group has recently extended these results to a larger cohort of 64 tumours from various histologies, particularly emphasizing the higher accuracy of MET over FDG PET in low-grade gliomas (sensitivity = 93.3% specificity = 90%).	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('MET', 'Chemical', 'MESH:C038344', (158, 161))	('gliomas', 'Disease', (188, 195))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('MET over FDG', 'Var', (158, 170))
58706	28680873	In addition, this latter paper reports on the only available direct comparison between amino acid PET and PWI in this setting, demonstrating better performances of amino acid PET in classifying indeterminate enlarging brain metastases after radiation treatment (37 lesions available for comparison, 91.9 vs 75.6% overall accuracy for FDOPA and DSC PWI, respectively).	('amino acid', 'Var', (164, 174))	('brain metastases', 'Disease', (218, 234))	('enlarging brain', 'Phenotype', 'HP:0001355', (208, 223))	('FDOPA', 'Chemical', 'MESH:C043437', (334, 339))	('brain metastases', 'Disease', 'MESH:D009362', (218, 234))	('enlarging', 'PosReg', (208, 217))
58726	28680873	Amino acid PET, on the other hand, appears to be more powerful to define the tumor extent (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('Amino acid PET', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
58769	31681562	Although both the tumor itself, as well as the use of anticonvulsant therapy, have a deleterious effect on neurocognitive function, radiotherapy (RT) in particular has been associated with a negative impact on neurocognitive function.	('radiotherapy', 'Var', (132, 144))	('tumor', 'Disease', (18, 23))	('effect', 'Reg', (97, 103))	('neurocognitive function', 'MPA', (107, 130))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
58790	31681562	Their formulation was presented as follows: Where t is a function of TD50, the dose to 40% of hippocampus at which the probability of neurocognitive decline is 50%, and m, is a slope parameter (see below).	('cognitive decline', 'Disease', (139, 156))	('TD50', 'Var', (69, 73))	('neurocognitive decline', 'Phenotype', 'HP:0001268', (134, 156))	('cognitive decline', 'Disease', 'MESH:D003072', (139, 156))	('cognitive decline', 'Phenotype', 'HP:0001268', (139, 156))
58796	31681562	In the paper by Gondi et al., a lower rate of neurocognitive impairment was found in the group of patients with a low dose to bilateral hippocampi, defined as dose to 40% of bilateral hippocampus volume in EQD2 Gy (D40%BH) <=7.3 Gy (11.1 vs. 66.7%).	('EQD2 Gy', 'Var', (206, 213))	('neurocognitive impairment', 'Disease', (46, 71))	('neurocognitive impairment', 'Disease', 'MESH:D002493', (46, 71))	('patients', 'Species', '9606', (98, 106))	('neurocognitive impairment', 'Phenotype', 'HP:0100543', (46, 71))
58817	31681562	The groups were comparable with respect to tumor laterality, tumor lobe, performance status, progression free survival, and presence of an 1p/19q codeletion.	('tumor lobe', 'Disease', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('1p/19q', 'Var', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (43, 48))	('tumor lobe', 'Disease', 'MESH:D001932', (61, 71))	('tumor', 'Disease', (61, 66))
58841	31681562	However, we found no significant differences in clinical variables (save for presence of IDH mutation) and time to progressive disease between our subset of and rest of the study population.	('mutation', 'Var', (93, 101))	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', (89, 92))
58851	31114356	Results: We found that high PLA2G5 gene expression was associated with unfavorable prognosis in both low-grade and high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('high', 'Var', (23, 27))	('PLA2G5', 'Gene', (28, 34))	('associated', 'Reg', (55, 65))	('PLA2G5', 'Gene', '5322', (28, 34))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('low-grade', 'Disease', (101, 110))
58894	31114356	We performed a statistical evaluation of the associations between PLA2G5 gene expression and various clinicopathological features, and found that the expression of this gene was positively associated with the WHO grade of the gliomas in the patients (Figure 1A).	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('associated with', 'Reg', (189, 204))	('expression', 'Var', (150, 160))	('PLA2G5', 'Gene', (66, 72))	('PLA2G5', 'Gene', '5322', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', (226, 233))	('patients', 'Species', '9606', (241, 249))
58913	31114356	However, patients with high PLA2G5 gene expression levels had lower long-term survival times than patients with low expression levels (P=0.002, Figure 3B).	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (23, 27))	('long-term survival times', 'CPA', (68, 92))	('PLA2G5', 'Gene', (28, 34))	('patients', 'Species', '9606', (98, 106))	('PLA2G5', 'Gene', '5322', (28, 34))	('lower', 'NegReg', (62, 67))
58916	31114356	For patients with HGGs, the age, chemotherapy, radiotherapy, IDH1 mutation status, and PLA2G5 gene expression were the independent prognostic factors (Table 5).	('HGGs', 'Disease', (18, 22))	('PLA2G5', 'Gene', (87, 93))	('IDH1', 'Gene', (61, 65))	('patients', 'Species', '9606', (4, 12))	('mutation', 'Var', (66, 74))	('IDH1', 'Gene', '3417', (61, 65))	('PLA2G5', 'Gene', '5322', (87, 93))
58918	31114356	We analyzed the PLA2G5 gene expression levels in gliomas with wild-type IDH1 and in those with mutated IDH1 and found that they were related.	('PLA2G5', 'Gene', '5322', (16, 22))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('IDH1', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (103, 107))	('IDH1', 'Gene', '3417', (72, 76))	('mutated', 'Var', (95, 102))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('PLA2G5', 'Gene', (16, 22))	('gliomas', 'Disease', (49, 56))	('IDH1', 'Gene', (103, 107))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
58939	31114356	These studies indicate that high PLA2G5 gene expression may play a role in the development and progression of gliomas by promoting their proliferation, migration, and angiogenesis.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('proliferation', 'CPA', (137, 150))	('migration', 'CPA', (152, 161))	('PLA2G5', 'Gene', '5322', (33, 39))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('promoting', 'PosReg', (121, 130))	('angiogenesis', 'CPA', (167, 179))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('high', 'Var', (28, 32))	('PLA2G5', 'Gene', (33, 39))
58945	31114356	Studies have shown that arachidonic acid promotes the EMT process by inducing the increased expression of VIM, N-cadherin, and matrix metallopeptidase 9 secretion, and lowering the level of E-cadherin junctions.	('arachidonic acid', 'Chemical', 'MESH:D016718', (24, 40))	('E-cadherin', 'Gene', (190, 200))	('EMT process', 'CPA', (54, 65))	('inducing', 'PosReg', (69, 77))	('E-cadherin', 'Gene', '999', (190, 200))	('VIM', 'Gene', '7431', (106, 109))	('matrix metallopeptidase 9', 'Gene', (127, 152))	('promotes', 'PosReg', (41, 49))	('arachidonic acid', 'Var', (24, 40))	('N-cadherin', 'Gene', (111, 121))	('increased', 'PosReg', (82, 91))	('lowering', 'NegReg', (168, 176))	('N-cadherin', 'Gene', '1000', (111, 121))	('matrix metallopeptidase 9', 'Gene', '4318', (127, 152))	('VIM', 'Gene', (106, 109))	('expression', 'MPA', (92, 102))
58948	31114356	Mutations of this protein were first reported in 2008 by Parsons et al, and were subsequently found to occur in most of the LGGs and secondary adult glioblastomas.	('glioblastomas', 'Disease', (149, 162))	('occur', 'Reg', (103, 108))	('Mutations', 'Var', (0, 9))	('glioblastomas', 'Phenotype', 'HP:0012174', (149, 162))	('glioblastomas', 'Disease', 'MESH:D005909', (149, 162))
58949	31114356	The mutated IDH1 is now one of the most widely known glioma biomarkers.	('mutated', 'Var', (4, 11))	('IDH1', 'Gene', (12, 16))	('glioma', 'Disease', (53, 59))	('IDH1', 'Gene', '3417', (12, 16))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
58950	31114356	The prognosis of patients with gliomas carrying the mutated IDH1 is significantly better those carrying the wild-type IDH1, as was confirmed by our findings (Figure S4).	('better', 'PosReg', (82, 88))	('IDH1', 'Gene', (118, 122))	('IDH1', 'Gene', (60, 64))	('mutated', 'Var', (52, 59))	('IDH1', 'Gene', '3417', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('patients', 'Species', '9606', (17, 25))	('IDH1', 'Gene', '3417', (60, 64))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
59036	19959011	The radiological signatures of WM alterations have been categorized as (1) periventricular changes, (2) focal extension of intense signal into WM; (3) diffuse extension into WM; and (4) diffuse coalescence of white and gray matter into intense signal region, loss of architecture, cortical atrophy, and hydrocephalus.	('intense signal', 'MPA', (123, 137))	('hydrocephalus', 'Phenotype', 'HP:0000238', (303, 316))	('architecture', 'CPA', (267, 279))	('hydrocephalus', 'Disease', 'MESH:D006849', (303, 316))	('cortical atrophy', 'Disease', 'MESH:D001284', (281, 297))	('loss', 'NegReg', (259, 263))	('cortical atrophy', 'Phenotype', 'HP:0002120', (281, 297))	('cortical atrophy', 'Disease', (281, 297))	('hydrocephalus', 'Disease', (303, 316))	('periventricular', 'Disease', (75, 90))	('rat', 'Species', '10116', (38, 41))	('alterations', 'Var', (34, 45))	('periventricular changes', 'Phenotype', 'HP:0007109', (75, 98))
59155	27052952	Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features.	('II-III tumors', 'Disease', (200, 213))	('NFKBIA', 'Gene', (31, 37))	('NFKBIA', 'Gene', '4792', (31, 37))	('expression', 'MPA', (17, 27))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('II-III tumors', 'Disease', 'MESH:D009369', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('gliomas', 'Disease', (116, 123))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('Deletion', 'Var', (0, 8))
59158	27052952	Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs.	('NFKBIA', 'Gene', (31, 37))	('low', 'NegReg', (13, 16))	('NFKBIA', 'Gene', '4792', (31, 37))	('expression', 'MPA', (17, 27))	('LGGs', 'Disease', (111, 115))	('enhanced', 'PosReg', (59, 67))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (68, 88))	('aggressiveness', 'Phenotype', 'HP:0000718', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor aggressiveness', 'Disease', (68, 88))	('Deletion', 'Var', (0, 8))
59167	27052952	Additionally, aberrant activation of NFkappaB is increasingly recognized as a crucial factor in cancer initiation and progression.	('cancer initiation', 'Disease', (96, 113))	('NFkappaB', 'Gene', (37, 45))	('NFkappaB', 'Gene', '4790', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aberrant', 'Var', (14, 22))	('cancer initiation', 'Disease', 'MESH:D009369', (96, 113))
59174	27052952	Additionally, recent studies have revealed that NFKBIA, which encodes IkappaBalpha, is deleted in approximately 25% of grade IV gliomas (glioblastomas), the most aggressive primary brain tumors.	('IkappaBalpha', 'Gene', '4792', (70, 82))	('glioblastomas', 'Phenotype', 'HP:0012174', (137, 150))	('NFKBIA', 'Gene', '4792', (48, 54))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('IkappaBalpha', 'Gene', (70, 82))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('glioblastomas', 'Disease', 'MESH:D005909', (137, 150))	('deleted', 'Var', (87, 94))	('brain tumors', 'Disease', 'MESH:D001932', (181, 193))	('brain tumors', 'Phenotype', 'HP:0030692', (181, 193))	('glioblastomas', 'Disease', (137, 150))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('brain tumors', 'Disease', (181, 193))	('NFKBIA', 'Gene', (48, 54))
59175	27052952	Interestingly, after restoring NFKBIA expression in cells cultured from tumors harboring an NFKBIA deletion, the malignant phenotype was attenuated and an increase in chemotherapy sensitivity was observed.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('increase', 'PosReg', (155, 163))	('NFKBIA', 'Gene', (31, 37))	('malignant phenotype', 'CPA', (113, 132))	('expression', 'MPA', (38, 48))	('NFKBIA', 'Gene', '4792', (31, 37))	('tumors', 'Disease', (72, 78))	('NFKBIA', 'Gene', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('NFKBIA', 'Gene', '4792', (92, 98))	('chemotherapy sensitivity', 'CPA', (167, 191))	('deletion', 'Var', (99, 107))	('restoring', 'PosReg', (21, 30))	('attenuated', 'NegReg', (137, 147))
59176	27052952	More importantly, patients with tumors harboring a deletion or low expression of NFKBIA demonstrated decreased survival.	('deletion', 'Var', (51, 59))	('decreased', 'NegReg', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('survival', 'CPA', (111, 119))	('NFKBIA', 'Gene', (81, 87))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Disease', (32, 38))	('low expression', 'NegReg', (63, 77))	('NFKBIA', 'Gene', '4792', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
59179	27052952	NFKBIA deletion was observed in approximately 7% of LGGs from The Cancer Genome Atlas (TCGA) cohort.	('NFKBIA', 'Gene', (0, 6))	('NFKBIA', 'Gene', '4792', (0, 6))	('Cancer Genome Atlas', 'Disease', (66, 85))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (66, 85))	('observed', 'Reg', (20, 28))	('deletion', 'Var', (7, 15))
59180	27052952	The deletion was more common in grade III than in grade II gliomas (Fig.	('II gliomas', 'Disease', 'MESH:D005910', (56, 66))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('II gliomas', 'Disease', (56, 66))	('common', 'Reg', (22, 28))	('deletion', 'Var', (4, 12))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
59181	27052952	Interestingly, grade III astrocytomas, the most aggressive type of LGG, showed the highest frequency of NFKBIA deletion (16.84%, Fig.	('NFKBIA', 'Gene', (104, 110))	('astrocytomas', 'Disease', 'MESH:D001254', (25, 37))	('NFKBIA', 'Gene', '4792', (104, 110))	('astrocytomas', 'Disease', (25, 37))	('deletion', 'Var', (111, 119))
59182	27052952	Deletions were associated with reduced NFKBIA mRNA expression (Fig.	('NFKBIA', 'Gene', '4792', (39, 45))	('reduced', 'NegReg', (31, 38))	('Deletions', 'Var', (0, 9))	('NFKBIA', 'Gene', (39, 45))
59184	27052952	Patients with LGGs harboring a deletion of NFKBIA were significantly older than those with a normal dosage (Table 1).	('NFKBIA', 'Gene', '4792', (43, 49))	('Patients', 'Species', '9606', (0, 8))	('NFKBIA', 'Gene', (43, 49))	('deletion', 'Var', (31, 39))
59186	27052952	Both deletion and low expression of NFKBIA were associated with poor 5-year survival (dosage: HR = 6.54, P < 0.001; expression: HR = 0.47, P < 0.001, Table 3) and 5-year recurrence-free survival (RFS; dosage: HR = 3.65, P = 0.001; expression: HR = 0.58, P = 0.001; Table 3).	('deletion', 'Var', (5, 13))	('poor', 'NegReg', (64, 68))	('NFKBIA', 'Gene', (36, 42))	('5-year survival', 'CPA', (69, 84))	('low', 'NegReg', (18, 21))	('NFKBIA', 'Gene', '4792', (36, 42))	('expression', 'MPA', (22, 32))
59189	27052952	To evaluate the biological relevance of NFKBIA dosage and expression in LGGs, we performed gene set enrichment analysis (GSEA) using genes ranked according to i) their differential expression in tumors with NFKBIA deletion or ii) their Pearson's correlation with the expression of NFKBIA.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('deletion', 'Var', (214, 222))	('GSEA', 'Chemical', '-', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('NFKBIA', 'Gene', (207, 213))	('NFKBIA', 'Gene', (281, 287))	('NFKBIA', 'Gene', '4792', (207, 213))	('NFKBIA', 'Gene', (40, 46))	('NFKBIA', 'Gene', '4792', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('NFKBIA', 'Gene', '4792', (40, 46))
59190	27052952	Among KEGG pathways overexpressed in tumors harboring a deletion of NFKBIA, 32 were significantly enriched (P < 0.05 corrected by false discovery rate, FDR; Supplementary Table S1).	('deletion', 'Var', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('NFKBIA', 'Gene', '4792', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('NFKBIA', 'Gene', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('KEGG pathways', 'Pathway', (6, 19))
59194	27052952	Interestingly, both deletion and low expression of NFKBIA significantly affected the network's spectral distribution (dosage: P = 0.036; expression: P = 0.004; Fig.	('spectral distribution', 'MPA', (95, 116))	('NFKBIA', 'Gene', (51, 57))	('NFKBIA', 'Gene', '4792', (51, 57))	('deletion', 'Var', (20, 28))	('affected', 'Reg', (72, 80))
59195	27052952	5), showing that pro-proliferation NFkappaB target genes were differentially co-expressed between phenotypes (deleted vs. normal and high vs. low; Fig.	('NFkappaB', 'Gene', (35, 43))	('NFkappaB', 'Gene', '4790', (35, 43))	('deleted', 'Var', (110, 117))
59197	27052952	Thus, the present findings demonstrate that deletion and low expression of NFKBIA are associated with enhanced tumor aggressiveness and poor prognosis in LGGs.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (111, 131))	('enhanced', 'PosReg', (102, 110))	('low expression', 'NegReg', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('deletion', 'Var', (44, 52))	('tumor aggressiveness', 'Disease', (111, 131))	('NFKBIA', 'Gene', (75, 81))	('NFKBIA', 'Gene', '4792', (75, 81))	('aggressiveness', 'Phenotype', 'HP:0000718', (117, 131))	('LGGs', 'Disease', (154, 158))
59201	27052952	The dysregulation of the NFkappaB pathway at different levels, either by mutations, epigenetic mechanisms or pharmacological means, is involved in many human diseases, especially chronic inflammation, immunodeficiency and cancer.	('inflammation', 'Disease', 'MESH:D007249', (187, 199))	('epigenetic', 'Var', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('inflammation', 'Disease', (187, 199))	('immunodeficiency', 'Disease', 'MESH:D007153', (201, 217))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', (222, 228))	('NFkappaB', 'Gene', (25, 33))	('immunodeficiency', 'Phenotype', 'HP:0002721', (201, 217))	('immunodeficiency', 'Disease', (201, 217))	('NFkappaB', 'Gene', '4790', (25, 33))	('human', 'Species', '9606', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('involved', 'Reg', (135, 143))	('mutations', 'Var', (73, 82))
59203	27052952	Given that the modulation of NFkappaB activity has an important role in the prevention and management of cancer, careful evaluation of its complex regulation in different tumors is essential.	('NFkappaB', 'Gene', '4790', (29, 37))	('activity', 'MPA', (38, 46))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('modulation', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('NFkappaB', 'Gene', (29, 37))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
59205	27052952	Additionally, grade III tumors presented a higher frequency of NFKBIA deletion, combined with reduced mRNA expression, suggesting an association between NFKBIA and overall glioma malignancy.	('deletion', 'Var', (70, 78))	('glioma malignancy', 'Disease', (172, 189))	('glioma malignancy', 'Disease', 'MESH:D005910', (172, 189))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('association', 'Interaction', (133, 144))	('NFKBIA', 'Gene', (63, 69))	('III tumors', 'Disease', (20, 30))	('reduced', 'NegReg', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('NFKBIA', 'Gene', '4792', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('mRNA expression', 'MPA', (102, 117))	('NFKBIA', 'Gene', (153, 159))	('NFKBIA', 'Gene', '4792', (153, 159))	('III tumors', 'Disease', 'MESH:D009369', (20, 30))
59207	27052952	In both cases, the deletion and low expression of NFKBIA were associated with poor prognosis, corroborating the idea that IkappaB proteins demonstrate tumor suppressor functions.	('low', 'NegReg', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('associated', 'Reg', (62, 72))	('deletion', 'Var', (19, 27))	('tumor', 'Disease', (151, 156))	('NFKBIA', 'Gene', (50, 56))	('NFKBIA', 'Gene', '4792', (50, 56))	('expression', 'MPA', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
59210	27052952	In this sense, GSEA revealed that the expression of many genes involved in cell cycle progression was increased in tumors with NFKBIA deletion and negatively correlated with the expression of NFKBIA.	('NFKBIA', 'Gene', (127, 133))	('NFKBIA', 'Gene', '4792', (192, 198))	('negatively', 'NegReg', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('NFKBIA', 'Gene', '4792', (127, 133))	('expression', 'MPA', (38, 48))	('GSEA', 'Chemical', '-', (15, 19))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('deletion', 'Var', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('increased', 'PosReg', (102, 111))	('NFKBIA', 'Gene', (192, 198))
59211	27052952	Moreover, co-expression network analyses suggested that deletions and low expression of NFKBIA could promote cell proliferation possibly by interfering with the expression pattern of NFkappaB target genes.	('cell proliferation', 'CPA', (109, 127))	('expression', 'MPA', (74, 84))	('promote', 'PosReg', (101, 108))	('NFKBIA', 'Gene', (88, 94))	('expression pattern', 'MPA', (161, 179))	('deletions', 'Var', (56, 65))	('NFKBIA', 'Gene', '4792', (88, 94))	('NFkappaB', 'Gene', (183, 191))	('interfering', 'NegReg', (140, 151))	('NFkappaB', 'Gene', '4790', (183, 191))	('low', 'NegReg', (70, 73))
59212	27052952	Nevertheless, further studies are needed to better understand the mechanistic implications of deletions and low expression of NFKBIA in the control of NFkappaB signaling in LGGs.	('NFkappaB', 'Gene', '4790', (151, 159))	('NFkappaB', 'Gene', (151, 159))	('low', 'NegReg', (108, 111))	('deletions', 'Var', (94, 103))	('NFKBIA', 'Gene', (126, 132))	('NFKBIA', 'Gene', '4792', (126, 132))
59216	27052952	Thus, therapies that stabilize NFkappaB-IkappaBalpha interactions in the cytoplasm might effectively restrain oncogenic signaling, especially in tumors presenting a deletion or low expression of NFKBIA.	('oncogenic signaling', 'MPA', (110, 129))	('IkappaBalpha', 'Gene', '4792', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('NFkappaB', 'Gene', (31, 39))	('restrain', 'NegReg', (101, 109))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('NFkappaB', 'Gene', '4790', (31, 39))	('deletion', 'Var', (165, 173))	('NFKBIA', 'Gene', (195, 201))	('IkappaBalpha', 'Gene', (40, 52))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('low', 'NegReg', (177, 180))	('NFKBIA', 'Gene', '4792', (195, 201))	('interactions', 'Interaction', (53, 65))
59222	27052952	All genes from TCGA RNAseq dataset were pre-ranked according to: i) their differential expression (fold change) comparing tumors with normal and deleted NFKBIA dosages (mediandeleted/mediannormal), or ii) Pearson's correlation between their expression and the expression of NFKBIA.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('deleted', 'Var', (145, 152))	('NFKBIA', 'Gene', '4792', (274, 280))	('NFKBIA', 'Gene', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('NFKBIA', 'Gene', '4792', (153, 159))	('NFKBIA', 'Gene', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('differential expression', 'MPA', (74, 97))
59225	27052952	We used CoGA software to compare networks built according to NFKBIA dosage (normal vs. deleted) and expression (high vs. low).	('NFKBIA', 'Gene', '4792', (61, 67))	('deleted', 'Var', (87, 94))	('NFKBIA', 'Gene', (61, 67))
59226	27052952	The chi-square test was used to access the association between various categorical clinicopathological characteristics and NFKBIA dosage (normal vs. deleted) and expression (high vs. low).	('NFKBIA', 'Gene', '4792', (123, 129))	('NFKBIA', 'Gene', (123, 129))	('deleted', 'Var', (149, 156))
59228	27052952	Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.	('NFKBIA', 'Gene', (31, 37))	('low', 'NegReg', (13, 16))	('patients', 'Species', '9606', (95, 103))	('NFKBIA', 'Gene', '4792', (31, 37))	('expression', 'MPA', (17, 27))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('Deletion', 'Var', (0, 8))
59233	33266110	The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell.	('estrogen receptor', 'Gene', (93, 110))	('estrogen receptor', 'Gene', '2099', (93, 110))	('splicing', 'Var', (163, 171))
59254	33266110	This new classification now includes isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion.	('IDH', 'Gene', (63, 66))	('mutation', 'Var', (68, 76))	('isocitrate dehydrogenase', 'Gene', '3417', (37, 61))	('isocitrate dehydrogenase', 'Gene', (37, 61))	('IDH', 'Gene', '3417', (63, 66))
59256	33266110	The most common mutation of the IDH1 gene is the R132H, which triggers a tridimensional change of the enzyme structure.	('R132H', 'Var', (49, 54))	('tridimensional change of the enzyme structure', 'MPA', (73, 118))	('R132H', 'Mutation', 'rs121913500', (49, 54))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('men', 'Species', '9606', (78, 81))	('triggers', 'Reg', (62, 70))
59257	33266110	The mutated conformation impacts the enzymatic activity which becomes able to convert alpha-ketoglutarate to D-2-hydroxyglutarate (D2HG).	('mutated', 'Var', (4, 11))	('convert alpha-ketoglutarate', 'MPA', (78, 105))	('D2HG', 'Chemical', 'MESH:C019417', (131, 135))	('D-2-hydroxyglutarate', 'MPA', (109, 129))	('enzymatic activity', 'MPA', (37, 55))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (109, 129))	('impacts', 'Reg', (25, 32))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (86, 105))
59259	33266110	Indeed, D2HG acts as an inhibitor of several alpha-ketoglutarate-dependent dioxygenases, including histone demethylases or TET 5-methylcytosine hydroxylases, leading to an increase in repressive histone methylation marks and a global increase in 5-methylcytosine level.	('increase', 'PosReg', (172, 180))	('repressive histone methylation marks', 'MPA', (184, 220))	('D2HG', 'Chemical', 'MESH:C019417', (8, 12))	('5-methylcytosine level', 'MPA', (246, 268))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (246, 262))	('D2HG', 'Var', (8, 12))	('oxygen', 'Chemical', 'MESH:D010100', (77, 83))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (127, 143))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (45, 64))	('increase', 'PosReg', (234, 242))
59260	33266110	Interestingly, in glioma, IDH mutations are associated with a more favorable prognosis because these tumors are more sensitive to the chemotherapeutic drug, temozolomide (TMZ).	('temozolomide', 'Chemical', 'MESH:D000077204', (157, 169))	('glioma', 'Disease', (18, 24))	('more', 'PosReg', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('sensitive to', 'MPA', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('TMZ', 'Chemical', 'MESH:D000077204', (171, 174))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('IDH', 'Gene', '3417', (26, 29))	('tumors', 'Disease', (101, 107))
59262	33266110	The chromosomal 1p/19q codeletion (hallmark of oligodendroglioma) associated with IDH mutation increases the range of response to alkylating agent chemotherapy and thus leads to an even better prognosis.	('IDH', 'Gene', '3417', (82, 85))	('oligodendroglioma', 'Disease', 'MESH:D009837', (47, 64))	('leads to', 'Reg', (169, 177))	('oligodendroglioma', 'Disease', (47, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('range of response to alkylating agent chemotherapy', 'MPA', (109, 159))	('better', 'PosReg', (186, 192))	('mutation', 'Var', (86, 94))	('IDH', 'Gene', (82, 85))	('increases', 'PosReg', (95, 104))
59263	33266110	Other genetic alterations, not required for diagnosis, are currently investigated in clinics to predict the response to treatment: ATRX (alpha thalassemia/mental retardation syndrome X-linked), TERT (telomerase reverse transcriptase), EGFR (epidermal growth factor receptor), BRAF (V-raf murine sarcoma viral oncogene homolog B1), histone H3K27M mutations and MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation (Table 2).	('rat', 'Species', '10116', (18, 21))	('telomerase reverse transcriptase', 'Gene', (200, 232))	('telomerase reverse transcriptase', 'Gene', '21752', (200, 232))	('ATRX', 'Gene', '22589', (131, 135))	('histone H3K27M', 'Protein', (331, 345))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '17314', (366, 405))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (282, 328))	('mental retardation', 'Phenotype', 'HP:0001249', (155, 173))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (366, 405))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))	('alpha thalassemia/mental retardation syndrome X-linked)', 'Gene', '22589', (137, 192))	('BRAF', 'Gene', (276, 280))	('TERT', 'Gene', '21752', (194, 198))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', (282, 328))	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', (137, 191))	('ATRX', 'Gene', (131, 135))	('MGMT', 'Gene', (360, 364))	('MGMT', 'Gene', '17314', (360, 364))	('TERT', 'Gene', (194, 198))	('mutations', 'Var', (346, 355))	('men', 'Species', '9606', (155, 158))	('men', 'Species', '9606', (125, 128))	('EGFR', 'Gene', (235, 239))	('EGFR', 'Gene', '13649', (235, 239))	('BRAF', 'Gene', '109880', (276, 280))
59266	33266110	The current treatment for gliomas is a combination of surgery, chemotherapy (mainly TMZ) and radiotherapy that results in patient outcome regarding the subtypes of gliomas (from 18 months of median overall survival in GBM to more than 15 years of median overall survival in 1p19q codeleted oligodendroglioma).	('results in', 'Reg', (111, 121))	('1p19q', 'Var', (274, 279))	('oligodendroglioma', 'Disease', 'MESH:D009837', (290, 307))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('patient', 'Species', '9606', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('oligodendroglioma', 'Disease', (290, 307))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))	('glioma', 'Phenotype', 'HP:0009733', (301, 307))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('men', 'Species', '9606', (17, 20))
59282	33266110	The IDH1 mutation conferred a survival benefit among patients from both sexes.	('mutation', 'Var', (9, 17))	('patients', 'Species', '9606', (53, 61))	('IDH', 'Gene', '3417', (4, 7))	('survival', 'CPA', (30, 38))	('benefit', 'PosReg', (39, 46))	('IDH', 'Gene', (4, 7))
59284	33266110	The survival benefit of the female "long survivors" was independent of IDH1 mutations whereas IDH1 status exerted a significant influence among the male "long survivors", suggesting that being a female (IDH1 wt or mutated) provided a better survival advantage than being an IDH1-mutated male.	('IDH', 'Gene', (203, 206))	('survival advantage', 'CPA', (241, 259))	('IDH', 'Gene', (94, 97))	('IDH', 'Gene', '3417', (203, 206))	('IDH', 'Gene', '3417', (94, 97))	('better', 'PosReg', (234, 240))	('IDH', 'Gene', (274, 277))	('IDH', 'Gene', (71, 74))	('mutated', 'Var', (214, 221))	('IDH', 'Gene', '3417', (274, 277))	('IDH', 'Gene', '3417', (71, 74))
59363	33266110	Concentrations ranging from 2 to 20 microM of 2-ME caused a decrease in cell viability in multiple GBM cell lines, U87, U138 (human male GBM cell line), LN405 (human female GBM cell line) and RG-2 (rat GBM cell line) by more than 75%, associated with an increase in apoptosis.	('LN405', 'CellLine', 'CVCL:1378', (153, 158))	('decrease', 'NegReg', (60, 68))	('human', 'Species', '9606', (126, 131))	('cell viability', 'CPA', (72, 86))	('2-ME', 'Chemical', 'MESH:D000077584', (46, 50))	('U138', 'CellLine', 'CVCL:0020', (120, 124))	('rat', 'Species', '10116', (198, 201))	('U87', 'CellLine', 'CVCL:0022', (115, 118))	('LN405', 'Var', (153, 158))	('rat', 'Species', '10116', (7, 10))	('human', 'Species', '9606', (160, 165))
59403	33266110	The Delta5-androstene-3beta, 17alpha-diol (17alpha-AED) inhibited T98G cell proliferation by more than 90% (IC50: 14.28 microM +- 5.25) while the 17beta-epimer had no effect.	('rat', 'Species', '10116', (83, 86))	('Delta5-androstene-3beta', 'Var', (4, 27))	('T98G', 'CellLine', 'CVCL:0556', (66, 70))	('17alpha-diol', 'Chemical', '-', (29, 41))	('17beta-epimer', 'Chemical', '-', (146, 159))	('17alpha-AED', 'Chemical', '-', (43, 54))	('inhibited', 'NegReg', (56, 65))	('Delta5', 'Mutation', 'c.del5', (4, 10))
59436	33266110	ERalpha36 knockdown in these TAM-resistant cells restored TAM sensitivity.	('ERalpha36', 'Gene', (0, 9))	('TAM', 'Chemical', 'MESH:D013629', (29, 32))	('restored', 'PosReg', (49, 57))	('TAM sensitivity', 'MPA', (58, 73))	('TAM', 'Chemical', 'MESH:D013629', (58, 61))	('knockdown', 'Var', (10, 19))
59452	33266110	Another study showed that ERbeta5 could be associated with a decrease in cell proliferation and invasive potential through reduced MMP2 activity.	('MMP2', 'Gene', '4313', (131, 135))	('decrease', 'NegReg', (61, 69))	('ERbeta5', 'Var', (26, 33))	('rat', 'Species', '10116', (85, 88))	('invasive potential', 'CPA', (96, 114))	('cell proliferation', 'CPA', (73, 91))	('MMP2', 'Gene', (131, 135))	('reduced', 'NegReg', (123, 130))
59461	33266110	ERbeta1 overexpression was also shown to potentiate TMZ and other chemotherapeutic agent treatment by promoting apoptosis and the cell cycle arrest in vitro and survival of in vivo.	('ERbeta1', 'Gene', (0, 7))	('arrest', 'Disease', 'MESH:D006323', (141, 147))	('apoptosis', 'CPA', (112, 121))	('survival', 'CPA', (161, 169))	('ERbeta1', 'Gene', '15394', (0, 7))	('arrest', 'Disease', (141, 147))	('men', 'Species', '9606', (94, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('potentiate', 'PosReg', (41, 51))	('expression', 'Species', '29278', (12, 22))	('overexpression', 'Var', (8, 22))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('promoting', 'PosReg', (102, 111))
59500	33266110	In T98G cells, a decrease in ARA54, which is an AR co-activator, was associated with a decrease in proliferation and an accumulation of cells in G1 phase.	('accumulation', 'PosReg', (120, 132))	('AR', 'Gene', '14149', (29, 31))	('ARA54', 'Gene', (29, 34))	('T98G', 'CellLine', 'CVCL:0556', (3, 7))	('decrease', 'NegReg', (17, 25))	('decrease', 'NegReg', (87, 95))	('ARA54', 'Gene', '9604', (29, 34))	('rat', 'Species', '10116', (106, 109))	('AR', 'Gene', '14149', (48, 50))	('T98G', 'Var', (3, 7))	('cells in G1 phase', 'CPA', (136, 153))
59518	33266110	Knock down of GRbeta in U118 glioma cell line resulted in a cell growth inhibition.	('glioma', 'Disease', (29, 35))	('U118', 'CellLine', 'CVCL:0633', (24, 28))	('cell growth', 'CPA', (60, 71))	('GRbeta', 'Gene', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('Knock down', 'Var', (0, 10))
59538	33246490	Immunity-low displayed a better survival than other subtypes, indicating a negative correlation between immune infiltration and survival prognosis in gliomas.	('negative', 'NegReg', (75, 83))	('better', 'PosReg', (25, 31))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('Immunity-low', 'Var', (0, 12))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
59539	33246490	IDH mutations had a negative correlation with glioma immunity.	('IDH', 'Gene', (0, 3))	('negative', 'NegReg', (20, 28))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', (46, 52))	('mutations', 'Var', (4, 13))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
59540	33246490	Immunity-high had higher tumor stemness and epithelial-mesenchymal transition scores and included more high-grade tumors than immunity-low, suggesting that elevated immunity is associated with tumor progression in gliomas.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('tumor', 'Disease', (114, 119))	('tumor stemness', 'Disease', 'MESH:D020295', (25, 39))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (25, 30))	('Immunity-high', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor stemness', 'Disease', (25, 39))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gliomas', 'Disease', (214, 221))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (114, 120))	('associated', 'Reg', (177, 187))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('higher', 'PosReg', (18, 24))	('epithelial-mesenchymal transition scores', 'CPA', (44, 84))
59544	33246490	For example, the TCGA network classified LGG into three subtypes: IDH mutation and 1p/19q codeletion, IDH mutation and no 1p/19q codeletion, and IDH wild-type.	('IDH', 'Gene', (66, 69))	('LGG', 'Disease', (41, 44))	('IDH', 'Gene', '3417', (102, 105))	('1p/19q codeletion', 'Var', (83, 100))	('IDH', 'Gene', '3417', (66, 69))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('IDH', 'Gene', (102, 105))
59569	33246490	We calculated the amplification frequency of a gene in a group of tumor samples as the proportion of the tumor samples with the copy number gain in the gene based on the SCNA profiling dataset for TCGA-glioma.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TCGA-glioma', 'Disease', 'MESH:D005910', (197, 208))	('tumor', 'Disease', (66, 71))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TCGA-glioma', 'Disease', (197, 208))	('tumor', 'Disease', (105, 110))	('copy number', 'Var', (128, 139))
59583	33246490	In contrast, tumor purity showed an opposite trend: immunity-high < immunity-medium < immunity-low, in all five datasets (one-tailed Mann-Whitney U test, P < 0.001) (Additional file 3: Fig.	('tumor', 'Disease', (13, 18))	('immunity-high', 'Var', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
59588	33246490	Another interesting finding was that PD-L1 expression levels were significantly different between the three subtypes in the five datasets: immunity-high > immunity-medium > immunity-low (ANOVA test, P < 0.05) (Fig.	('PD-L1', 'Gene', (37, 42))	('different', 'Reg', (80, 89))	('PD-L1', 'Gene', '29126', (37, 42))	('immunity-high >', 'Var', (139, 154))	('expression levels', 'MPA', (43, 60))
59591	33246490	This is consistent with previous findings that IDH1 mutations are prevalent in LGG, which constituted a majority of immunity-low gliomas (Fig.	('mutations', 'Var', (52, 61))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('LGG', 'Disease', (79, 82))	('low gliomas', 'Disease', (125, 136))	('IDH1', 'Gene', (47, 51))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('low gliomas', 'Disease', 'MESH:D005910', (125, 136))	('IDH1', 'Gene', '3417', (47, 51))	('prevalent', 'Reg', (66, 75))
59601	33246490	Also, in the TCGA-glioma dataset, immunity-low had better DFS than immunity-medium and immunity-high (log-rank test, P < 0.001), and there was no significantly different DFS between immunity-medium and immunity-high (log-rank test, P = 0.242) (Fig.	('immunity-low', 'Var', (34, 46))	('TCGA-glioma', 'Disease', 'MESH:D005910', (13, 24))	('TCGA-glioma', 'Disease', (13, 24))	('DFS', 'MPA', (58, 61))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('better', 'PosReg', (51, 57))
59602	33246490	These results are inconsistent with previous studies showing that high immunity was associated with better survival in some cancers, such as triple-negative breast cancer (TNBC), indicating intertumor heterogeneity.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('survival', 'MPA', (107, 115))	('tumor', 'Disease', (195, 200))	('TNBC', 'Disease', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('better', 'PosReg', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('high immunity', 'Var', (66, 79))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('TNBC', 'Disease', 'None', (172, 176))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
59603	33246490	To demonstrate that the survival difference between these subtypes is associated with their different enrichment levels of immune signatures, we compared the survival between high-immune-score (upper third) and low-immune-score (bottom third) gliomas.	('high-immune-score', 'Var', (175, 192))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('low-immune-score', 'Var', (211, 227))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('gliomas', 'Disease', (243, 250))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))
59604	33246490	We found that high-immune-score gliomas had a worse survival prognosis than low-immune-score gliomas (Fig.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('high-immune-score', 'Var', (14, 31))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
59613	33246490	Furthermore, the cancer-associated pathways enriched in immunity-high displayed a positive association with the immune scores, while the pathways enriched in immunity-low showed a negative correlation (Spearman's correlation test, P < 0.05) (Fig.	('immunity-high', 'Var', (56, 69))	('positive', 'PosReg', (82, 90))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('immune scores', 'Disease', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
59616	33246490	In contrast, the neuron projection was highly enriched in immunity-low relative to the other subtypes (P < 0.01) and was associated with better survival in gliomas (P < 0.01).	('better', 'PosReg', (137, 143))	('immunity-low', 'Var', (58, 70))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
59619	33246490	We found that immunity-high had markedly higher tumor stemness and EMT scores in five and four datasets, respectively (one-tailed Mann-Whitney U test, P < 0.01) (Fig.	('immunity-high', 'Var', (14, 27))	('EMT scores', 'CPA', (67, 77))	('tumor stemness', 'Disease', 'MESH:D020295', (48, 62))	('tumor stemness', 'Disease', (48, 62))	('higher', 'PosReg', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
59624	33246490	Accordingly, the predicted tumor neoantigens were more abundant in immunity-high than in immunity-low gliomas (P = 0.007; median neoantigens, 8 versus 7) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('low gliomas', 'Disease', 'MESH:D005910', (98, 109))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('tumor', 'Disease', (27, 32))	('immunity-high', 'Var', (67, 80))	('low gliomas', 'Disease', (98, 109))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))
59625	33246490	We found that arm-level SCNAs were more frequent in immunity-high than in immunity-low gliomas (P = 2.09 x 10-5, 0.001, 2.44 x 10-5 for amplification, deletion, and total alterations, respectively) (Fig.	('low gliomas', 'Disease', (83, 94))	('frequent', 'Reg', (40, 48))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('deletion', 'Var', (151, 159))	('low gliomas', 'Disease', 'MESH:D005910', (83, 94))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('immunity-high', 'Disease', (52, 65))	('arm-level SCNAs', 'Disease', (14, 29))
59626	33246490	Also, focal SCNA levels were higher in immunity-high than in immunity-low gliomas (P = 4.14 x 10-12, 1.90 x 10-12, 4.61 x 10-14 for amplification, deletion, and total alterations, respectively) (Additional file 7: Fig.	('higher', 'PosReg', (29, 35))	('focal SCNA levels', 'MPA', (6, 23))	('low gliomas', 'Disease', (70, 81))	('low gliomas', 'Disease', 'MESH:D005910', (70, 81))	('immunity-high', 'Var', (39, 52))	('deletion', 'Var', (147, 155))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
59627	33246490	These results indicate that immunity-high gliomas have higher levels of SCNAs than immunity-low gliomas, a finding different from that in most other cancer types.	('levels', 'MPA', (62, 68))	('low gliomas', 'Disease', 'MESH:D005910', (92, 103))	('cancer', 'Disease', (149, 155))	('immunity-high', 'Var', (28, 41))	('SCNAs', 'MPA', (72, 77))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('low gliomas', 'Disease', (92, 103))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('higher', 'PosReg', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('gliomas', 'Disease', (42, 49))
59630	33246490	Interestingly, we found 72 genes more frequently mutated in immunity-high than in immunity-low gliomas (Fisher's exact test, adjusted P < 0.05, odds ratio > 2) (Fig.	('low gliomas', 'Disease', 'MESH:D005910', (91, 102))	('mutated', 'Var', (49, 56))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('immunity-high', 'Disease', (60, 73))	('low gliomas', 'Disease', (91, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))
59632	33246490	The mutation of the three members of DNAH genes (DNAH10, 11&17) has been associated with favorable chemotherapy response.	('DNAH', 'Gene', (37, 41))	('mutation', 'Var', (4, 12))	('been', 'Reg', (68, 72))	('DNAH10', 'Gene', (49, 55))	('DNAH10', 'Gene', '196385', (49, 55))
59633	33246490	In contrast, three genes (IDH1, BAGE2, and CIC) were more frequently mutated in Immunity-low than in Immunity-high gliomas.	('Immunity-low', 'Disease', (80, 92))	('gliomas', 'Disease', (115, 122))	('CIC', 'Disease', 'None', (43, 46))	('mutated', 'Var', (69, 76))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH1', 'Gene', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('BAGE2', 'Gene', (32, 37))	('IDH1', 'Gene', '3417', (26, 30))	('BAGE2', 'Gene', '85319', (32, 37))	('CIC', 'Disease', (43, 46))
59634	33246490	IDH1 mutations are prevalent in LGG and occur early during tumorigenesis.	('tumor', 'Disease', (59, 64))	('prevalent', 'Reg', (19, 28))	('mutations', 'Var', (5, 14))	('LGG', 'Disease', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('IDH1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('IDH1', 'Gene', '3417', (0, 4))
59641	33246490	Likewise, we found numerous immune- and cancer-associated pathways highly enriched in immunity-high versus immunity-medium (Additional file 8: Fig.	('enriched', 'Reg', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('immunity-high', 'Var', (86, 99))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
59646	33246490	Consistent with the immune signatures, the ratios of immune-stimulatory/immunosuppressive (CD8+/CD4+ regulatory T cells and M1/M2 macrophages) were the highest in immunity-high and the lowest in immunity-low, suggesting that immunity-high and immunity-low have the strongest and weakest anti-tumor immune responses, respectively.	('CD8', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('CD4', 'Gene', (96, 99))	('CD8', 'Gene', '925', (91, 94))	('tumor', 'Disease', (292, 297))	('CD4', 'Gene', '920', (96, 99))	('immunity-high', 'Var', (163, 176))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
59649	33246490	This is consistent with previous study showing that IDH mutations were associated with low immune infiltration in gliomas.	('mutations', 'Var', (56, 65))	('gliomas', 'Disease', (114, 121))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))
59655	33246490	Moreover, immunity-high gliomas had significantly higher tumor stemness and EMT scores and a higher percentage of high-grade tumors than immunity-low gliomas.	('low gliomas', 'Disease', (146, 157))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('tumor stemness', 'Disease', 'MESH:D020295', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('EMT scores', 'CPA', (76, 86))	('tumor stemness', 'Disease', (57, 71))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Disease', (24, 31))	('immunity-high', 'Var', (10, 23))	('higher', 'PosReg', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('low gliomas', 'Disease', 'MESH:D005910', (146, 157))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
59656	33246490	These results indicate that immunity-high gliomas are more progressive, aggressive, and poorly prognostic than immunity-low gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('immunity-high', 'Var', (28, 41))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('low gliomas', 'Disease', 'MESH:D005910', (120, 131))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('low gliomas', 'Disease', (120, 131))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
59658	33246490	Since both abundant immune cell infiltration and high PD-L1 expression are determinants of the active response to anti-PD-1/PD-L1 immunotherapy, immunity-high gliomas might have a better outcome in the immunotherapy setting.	('PD-L1', 'Gene', (124, 129))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('immunity-high', 'Var', (145, 158))	('PD-L1', 'Gene', (54, 59))	('PD-L1', 'Gene', '29126', (124, 129))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('PD-L1', 'Gene', '29126', (54, 59))
59666	33246490	Compared to immunity-low gliomas, immunity-high gliomas are more progressive, aggressive, and poorly prognostic, but could be more responsive to anti-PD-1/PD-L1 immunotherapy.	('PD-L1', 'Gene', (155, 160))	('gliomas', 'Disease', (48, 55))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('PD-L1', 'Gene', '29126', (155, 160))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('low gliomas', 'Disease', 'MESH:D005910', (21, 32))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('low gliomas', 'Disease', (21, 32))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))	('immunity-high', 'Var', (34, 47))
59670	32532995	A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas.	('NTRK2', 'Gene', (19, 24))	('glioma', 'Phenotype', 'HP:0009733', (343, 349))	('glioma', 'Disease', (56, 62))	('variant', 'Var', (32, 39))	('NTRKs', 'Gene', '18211;396157;4915;18212;25054;18213', (333, 338))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('gliomas', 'Disease', 'MESH:D005910', (343, 350))	('gliomas', 'Phenotype', 'HP:0009733', (343, 350))	('gliomas', 'Disease', (343, 350))	('glioma', 'Disease', (343, 349))	('NTRKs', 'Gene', (333, 338))	('NTRK2', 'Gene', '18212', (19, 24))	('glioma', 'Disease', 'MESH:D005910', (343, 349))
59677	32532995	While recent work independently highlights the evolving importance of aberrant splicing in cancer, simultaneous discoveries have implicated novel NTRK2 fusions in various glioma subtypes, yet little is known about endogenous NTRK2 splicing in human brain or its potential role in brain tumor biology.	('brain tumor', 'Disease', (280, 291))	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('human', 'Species', '9606', (243, 248))	('fusions', 'Var', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('brain tumor', 'Phenotype', 'HP:0030692', (280, 291))	('aberrant', 'Var', (70, 78))	('glioma', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTRK2', 'Gene', (146, 151))	('brain tumor', 'Disease', 'MESH:D001932', (280, 291))
59683	32532995	Once thought dominant-negative due the absence of a kinase domain, TrkB.T1 shares the same extracellular and transmembrane domains, as well as the first 12 intracellular amino acids, as other variants yet contains a unique C-terminal sequence of 11 amino acids that is conserved across species from rodents to humans.	('humans', 'Species', '9606', (310, 316))	('variants', 'Var', (192, 200))	('TrkB.T1', 'Gene', (67, 74))
59701	32532995	Analysis of 50 human glioblastoma stem cell (GSC) lines isolated from primary tumors show that this TrkB.T1 variant predominates over all other NTRK isoforms, further highlighting its potential role in brain tumor biology (Fig.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('glioblastoma', 'Disease', (21, 33))	('brain tumor', 'Disease', 'MESH:D001932', (202, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('brain tumor', 'Disease', (202, 213))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('brain tumor', 'Phenotype', 'HP:0030692', (202, 213))	('human', 'Species', '9606', (15, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('variant', 'Var', (108, 115))
59716	32532995	We then stained archived samples of several different RCAS/tv-a mouse models of glioma including those driven by PDGF and those driven by loss of combined NF1 and PTEN or EGFRvIII.	('glioma', 'Disease', (80, 86))	('RCAS', 'Chemical', '-', (54, 58))	('EGF', 'Gene', '13645', (171, 174))	('PTEN', 'Gene', '19211', (163, 167))	('loss', 'Var', (138, 142))	('NF1', 'Gene', '18015', (155, 158))	('PTEN', 'Gene', (163, 167))	('EGF', 'Gene', (171, 174))	('driven by', 'Reg', (103, 112))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('tv-a', 'Chemical', '-', (59, 63))	('PDGF', 'Gene', (113, 117))	('NF1', 'Gene', (155, 158))	('mouse', 'Species', '10090', (64, 69))
59717	32532995	All mouse glioma models analyzed, regardless of strain, genetic background, or oncogenic driver showed strong diffuse staining for expression of endogenous TrkB.T1 within the tumor boundaries (Fig.	('mouse', 'Species', '10090', (4, 9))	('tumor', 'Disease', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('TrkB.T1', 'Var', (156, 163))	('glioma', 'Disease', (10, 16))
59728	32532995	7a, b) suggesting that while overexpression TrkB.T1 can enhance PDGF-driven gliomas in vivo, this variant also predominates over TrkB.FL in all rodent gliomas analyzed and may be selected for in an oncogenic context.	('gliomas', 'Disease', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('TrkB.FL', 'Var', (129, 136))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
59732	32532995	Previous work has shown that TrkB.T1 enhances both apoptosis and proliferation of neurospheres leading to larger sphere diameter and RCAS-TrkB.T1 delivery to N/tv-a isolated neurospheres recapitulates this phenomenon as shown by the increased size of neurospheres infected with RCAS-TrkB.T1 compared with control neurospheres (Supplementary Fig.	('RCAS', 'Chemical', '-', (133, 137))	('tv-a', 'Chemical', '-', (160, 164))	('infected', 'Disease', 'MESH:D007239', (264, 272))	('RCAS', 'Chemical', '-', (278, 282))	('infected', 'Disease', (264, 272))	('RCAS-TrkB.T1', 'Var', (278, 290))
59737	32532995	TrkB variants, in general, have been shown to alter default recycling pathways and exhibit cross-talk with other tyrosine kinases in different cancer types, suggesting that interactions with other signaling cascades have yet to be elucidated.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cross-talk', 'Reg', (91, 101))	('variants', 'Var', (5, 13))	('default recycling pathways', 'Pathway', (52, 78))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('alter', 'Reg', (46, 51))	('TrkB', 'Gene', (0, 4))
59747	32532995	Combined with RNASeq data suggesting a role for TrkB.T1 in PI3K signaling and enhancement of downstream PDGFR pathways in vitro (Figs.	('PDGFR', 'Gene', (104, 109))	('PI3K signaling', 'Pathway', (59, 73))	('TrkB.T1', 'Var', (48, 55))	('enhancement', 'PosReg', (78, 89))	('PDGFR', 'Gene', '18596', (104, 109))
59759	32532995	TrkB.T1 is also capable of enhancing downstream targets of PDGF signaling in vitro, including Akt, STAT3, and pS6 (Fig.	('TrkB.T1', 'Var', (0, 7))	('Akt', 'Pathway', (94, 97))	('pS6', 'Gene', (110, 113))	('STAT3', 'Gene', '20848', (99, 104))	('enhancing', 'PosReg', (27, 36))	('STAT3', 'Gene', (99, 104))
59762	32532995	Future work should investigate the role of TrkB.T1 in PI3K/Akt pathways and PI3K/ERBB2/ERBB3/ERBB4 networks across various cancer types, as western blots (corresponding to RNASeq data) show upregulation of ERBB3 receptor in TrkB.T1 transduced NCS, along with increased expression NRG2, a ligand for ERBB3 and ERBB4 (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('NRG2', 'Gene', '100042150', (280, 284))	('TrkB.T1', 'Var', (224, 231))	('increased', 'PosReg', (259, 268))	('expression', 'MPA', (269, 279))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('NCS', 'Disease', (243, 246))	('cancer', 'Disease', (123, 129))	('NRG2', 'Gene', (280, 284))	('transduced', 'Reg', (232, 242))
59767	32532995	While the importance of a constitutively active TRK kinase should not be overlooked clinically, it will become increasingly important to tease apart the role of TrkB.T1's role in tumors with- and without-NTRK2 fusions.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('TrkB.T1', 'Gene', (161, 168))	('fusions', 'Var', (210, 217))
59816	32532995	In order to assess the sensitivity of TrkB.T1 and TrkB.FL overexpressing NSCs to LY294002 and rapamycin, we used biological triplicates of each line and seeded 6 x 4000 cells per triplicate into four laminin coated 96-well plates.	('LY294002', 'Var', (81, 89))	('NSCs', 'Gene', (73, 77))	('rapamycin', 'Chemical', 'MESH:D020123', (94, 103))	('LY294002', 'Chemical', 'MESH:C085911', (81, 89))
59842	32532995	For western blot analyses of human brain, mouse brain, and 3T3-Tv-a cells, commercial antibodies were used according to manufacturer specifications and bands were confirmed by size using Spectra  Multicolor Broad Range Protein Ladder (ThermoScientific  catalog # 26634; lot: 00784968): pSTAT3 (Tyr705, Cell Signaling #9145; lot: 22 at 1:1000), pAkt (Ser473, Cell Signaling #4060; lot: 23 at 1:1000), pERK (Cell Signaling phospho-p44/42 MAPK (ERK1/2) (Thr202/Tyr204) (D13.14.4E) XP  #4370; lot: 12 at 1:2000), beta-actin (Sigma #AB1978 Clone AC-15; lot: 021M4821 at 1:10,000), pS6 ribosomal protein (Ser235/236, Cell Signaling #4858; lot: 16 at 1:1000), TrkB (Millipore #07-225; lot: 2187222 and lot: 3277578 @ 1:3000), TrkB (abcam #ab33655; lot: GR266297-1 at 1:1000), TrkB (Abcam #ab18987; lot: GR3280550-2 at 1:2000), pPDGFR beta (Y1021; Abcam #ab62437; lot: GR38791-13 at 1:200), PDGFR beta (Cell Signaling #3169; lot: 13 at 1:800), ERBB3 (Cell Signaling #12708; lot: 4 at 1:1000), NRG2 (Abcam #ab220615; lot: GR3181158-4 at 1:200), vinculin (Sigma-Aldrich, Cat.	('pERK', 'Gene', (400, 404))	('vinculin', 'Gene', '22330', (1036, 1044))	('NRG2', 'Gene', '100042150', (985, 989))	('PDGFR beta', 'Gene', '18595', (821, 831))	('vinculin', 'Gene', (1036, 1044))	('pERK', 'Gene', '13666', (400, 404))	('STAT3', 'Gene', '20848', (287, 292))	('ERK1/2', 'Gene', (442, 448))	('PDGFR beta', 'Gene', (821, 831))	('human', 'Species', '9606', (29, 34))	('Abcam', 'Var', (991, 996))	('beta-actin', 'Gene', (509, 519))	('PDGFR beta', 'Gene', '18595', (883, 893))	('ERK1/2', 'Gene', '26417;26413', (442, 448))	('mouse', 'Species', '10090', (42, 47))	('beta-actin', 'Gene', '11461', (509, 519))	('STAT3', 'Gene', (287, 292))	('PDGFR beta', 'Gene', (883, 893))	('NRG2', 'Gene', (985, 989))
59861	32210587	In line with this, overexpression of B7-H3 enhanced glioma cell proliferation, induced sustained glioma growth, and promoted glioma cell invasion in vitro and in vivo.	('overexpression', 'PosReg', (19, 33))	('glioma', 'Disease', (125, 131))	('enhanced', 'PosReg', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (97, 103))	('promoted', 'PosReg', (116, 124))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('sustained glioma growth', 'Disease', 'MESH:D005910', (87, 110))	('B7-H3', 'Var', (37, 42))	('glioma', 'Disease', (52, 58))	('sustained glioma growth', 'Disease', (87, 110))
59863	32210587	We also found that B7-H3 induced EMT processes through downregulation of E-cadherin and upregulation of MMP-2/-9 expression, resulting in enhanced invasion of glioma cells.	('expression', 'MPA', (113, 123))	('E-cadherin', 'Gene', (73, 83))	('MMP-2/-9', 'Gene', (104, 112))	('EMT processes', 'CPA', (33, 46))	('upregulation', 'PosReg', (88, 100))	('enhanced', 'PosReg', (138, 146))	('glioma cells', 'Disease', 'MESH:D005910', (159, 171))	('E-cadherin', 'Gene', '12550', (73, 83))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('B7-H3', 'Var', (19, 24))	('downregulation', 'NegReg', (55, 69))	('glioma cells', 'Disease', (159, 171))
59875	32210587	Several studies have indicated that B7-H3 can activate prosurvival signaling pathways in tumor cells, resulting in sustained tumor growth and progression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (125, 130))	('activate', 'PosReg', (46, 54))	('progression', 'CPA', (142, 153))	('B7-H3', 'Var', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('prosurvival signaling pathways', 'Pathway', (55, 85))
59878	32210587	Notably, B7-H3 can upregulate the expression of JAK/STAT3 to facilitate the distant metastasis of myeloma cells, suggesting that JAK/STAT3 signaling may have a role in B7-H7-induced tumor progression.	('JAK/STAT3', 'Gene', (48, 57))	('expression', 'MPA', (34, 44))	('tumor', 'Disease', (182, 187))	('myeloma', 'Disease', (98, 105))	('upregulate', 'PosReg', (19, 29))	('B7-H3', 'Var', (9, 14))	('facilitate', 'PosReg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('myeloma', 'Disease', 'MESH:D009101', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
59881	32210587	Expression of B7-H3 in glioma could activate the JAK2/STAT3 prosurvival signaling pathway, resulting in tumor growth and induction of EMT in cancer cells.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('B7-H3', 'Var', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (104, 109))	('glioma', 'Disease', (23, 29))	('induction', 'PosReg', (121, 130))	('activate', 'PosReg', (36, 44))	('JAK2/STAT3 prosurvival signaling pathway', 'Pathway', (49, 89))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
59882	32210587	Additionally, glioma cells overexpressing B7-H3 showed elevated expression of MMP-2 and MMP-9 and downregulation of the levels of the adhesion molecule E-cadherin, thereby providing a possible explanation for the mechanisms underlying glioma invasion.	('glioma', 'Disease', (14, 20))	('expression', 'MPA', (64, 74))	('E-cadherin', 'Gene', (152, 162))	('downregulation', 'NegReg', (98, 112))	('E-cadherin', 'Gene', '12550', (152, 162))	('B7-H3', 'Var', (42, 47))	('glioma cells', 'Disease', 'MESH:D005910', (14, 26))	('glioma', 'Disease', (235, 241))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('MMP-9', 'Gene', (88, 93))	('elevated', 'PosReg', (55, 63))	('glioma', 'Disease', 'MESH:D005910', (235, 241))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))	('MMP-2', 'Gene', (78, 83))	('glioma cells', 'Disease', (14, 26))
59903	32210587	Cell lysates were separated by SDS-PAGE, transferred onto nitrocellulose membranes, and immunoblotted with the following antibodies: anti-beta-actin (Santa Cruz Biotechnology, CA, USA), anti-CD276, anti-STAT3 (phosphor S727), anti-STAT3, anti-JAK2 (phospho Y1007+Y1008), anti-JAK2, anti-SOCS-3, anti-SHP1, anti-SHP1 (phospho Y536), anti-Src, anti-Src (phospho Y529), anti-E-Cadherin, anti-N-Cadherin, and anti-Slug (all from Abcam).	('SOCS-3', 'Gene', '12702', (287, 293))	('Src', 'Gene', '20779', (337, 340))	('SOCS-3', 'Gene', (287, 293))	('SHP1', 'Gene', '15170', (300, 304))	('N-Cadherin', 'Gene', (389, 399))	('Src', 'Gene', (347, 350))	('N-Cadherin', 'Gene', '12558', (389, 399))	('SHP1', 'Gene', (311, 315))	('beta-actin', 'Gene', (138, 148))	('beta-actin', 'Gene', '11461', (138, 148))	('E-Cadherin', 'Gene', '12550', (372, 382))	('CD276', 'Gene', (191, 196))	('Src', 'Gene', (337, 340))	('CD276', 'Gene', '102657', (191, 196))	('E-Cadherin', 'Gene', (372, 382))	('phospho Y529', 'Var', (352, 364))	('SHP1', 'Gene', (300, 304))	('SHP1', 'Gene', '15170', (311, 315))	('Src', 'Gene', '20779', (347, 350))
59916	32210587	This pattern was observed in multiple patients in the H-M glioma group (Figure 1B, n = 10), indicating that B7-H3 might be involved in glioma progression.	('H-M glioma', 'Disease', (54, 64))	('H-M glioma', 'Disease', 'MESH:D005910', (54, 64))	('involved', 'Reg', (123, 131))	('glioma', 'Disease', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('B7-H3', 'Var', (108, 113))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('patients', 'Species', '9606', (38, 46))	('glioma', 'Disease', (58, 64))
59918	32210587	Notably, overexpression of B7-H3 significantly enhanced the proliferative capacity of glioma cells and sustained tumor growth in vitro and in vivo, whereas B7-H3 knockout suppressed these effects (Figure 1D and E).	('tumor', 'Disease', (113, 118))	('overexpression', 'PosReg', (9, 23))	('glioma cells', 'Disease', (86, 98))	('enhanced', 'PosReg', (47, 55))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('B7-H3', 'Var', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('glioma cells', 'Disease', 'MESH:D005910', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
59919	32210587	B7-H3 expression also increased colony formation and tumorigenesis in LN229 and U87 cells (Figure 1F and G), indicating that B7-H3 could efficiently facilitate proliferation and tumorigenesis in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('tumor', 'Disease', (178, 183))	('glioma cells', 'Disease', 'MESH:D005910', (195, 207))	('colony formation', 'CPA', (32, 48))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('facilitate', 'PosReg', (149, 159))	('B7-H3', 'Gene', (0, 5))	('proliferation', 'CPA', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('increased', 'PosReg', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (53, 58))	('expression', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('glioma cells', 'Disease', (195, 207))
59921	32210587	Overexpression of B7-H3 also enhanced the invasive ability of LN229 and U87 cells, whereas blockade of B7-H3 strongly suppressed this effect (Figure 1H), suggesting that B7-H3 has a crucial role in glioma cell invasion.	('invasive ability', 'CPA', (42, 58))	('glioma', 'Disease', (198, 204))	('B7-H3', 'Var', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('B7-H3', 'Gene', (103, 108))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('enhanced', 'PosReg', (29, 37))	('suppressed', 'NegReg', (118, 128))
59922	32210587	Kaplan-Meier analysis of TCGA glioma dataset revealed that patients with high B7-H3 expression presented with worse overall survival (OS) than those with low B7-H3 expression (n = 514; Figure 1I).	('worse', 'NegReg', (110, 115))	('glioma', 'Disease', (30, 36))	('overall survival', 'MPA', (116, 132))	('patients', 'Species', '9606', (59, 67))	('high B7-H3 expression', 'Var', (73, 94))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
59923	32210587	Together, these data suggested that B7-H3 promotes glioma growth and invasion, resulting in a poor prognosis for glioma patients.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Disease', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('glioma growth', 'Disease', (51, 64))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('promotes', 'PosReg', (42, 50))	('glioma', 'Disease', (113, 119))	('glioma growth', 'Disease', 'MESH:D005910', (51, 64))	('invasion', 'CPA', (69, 77))	('patients', 'Species', '9606', (120, 128))	('B7-H3', 'Var', (36, 41))
59925	32210587	The results showed that the levels of p-JAK2 and p-STAT3 were increased in glioma cells overexpressing B7-H3, indicating that the JAK2/STAT3 signaling pathway had been activated (Figure 2A).	('levels', 'MPA', (28, 34))	('increased', 'PosReg', (62, 71))	('glioma cells', 'Disease', 'MESH:D005910', (75, 87))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('p-JAK2', 'MPA', (38, 44))	('B7-H3', 'Var', (103, 108))	('glioma cells', 'Disease', (75, 87))	('p-STAT3', 'MPA', (49, 56))	('JAK2/STAT3 signaling pathway', 'Pathway', (130, 158))
59928	32210587	We found that Src phosphorylation was enhanced, whereas the levels of p-SHP-1, total SHP-1, and SOCS-3 were reduced in glioma cells overexpressing B7-H3 (Figure 2B).	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('B7-H3', 'Var', (147, 152))	('reduced', 'NegReg', (108, 115))	('enhanced', 'PosReg', (38, 46))	('SHP-1', 'Gene', (85, 90))	('SHP-1', 'Gene', '15170', (72, 77))	('SOCS-3', 'Gene', (96, 102))	('Src', 'Gene', '20779', (14, 17))	('Src', 'Gene', (14, 17))	('levels', 'MPA', (60, 66))	('glioma cells', 'Disease', (119, 131))	('SHP-1', 'Gene', (72, 77))	('SHP-1', 'Gene', '15170', (85, 90))	('SOCS-3', 'Gene', '12702', (96, 102))	('glioma cells', 'Disease', 'MESH:D005910', (119, 131))
59929	32210587	These results suggested that B7-H3 induced Src activation and downregulated the levels of the negative regulators SOCS-3/SHP-1, thereby activating JAK2/STAT3 signaling.	('Src', 'Gene', '20779', (43, 46))	('activating', 'PosReg', (136, 146))	('Src', 'Gene', (43, 46))	('SOCS-3', 'Gene', '12702', (114, 120))	('SHP-1', 'Gene', '15170', (121, 126))	('activation', 'PosReg', (47, 57))	('downregulated', 'NegReg', (62, 75))	('SOCS-3', 'Gene', (114, 120))	('SHP-1', 'Gene', (121, 126))	('JAK2/STAT3 signaling', 'MPA', (147, 167))	('B7-H3', 'Var', (29, 34))	('levels of', 'MPA', (80, 89))
59930	32210587	To further assess the role of JAK2/STAT3 signaling in B7-H3-induced glioma progression, we treated B7-H3-overexpressing glioma cells with FLLL32, a JAK2/STAT3 inhibitor.	('glioma cells', 'Disease', 'MESH:D005910', (120, 132))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('FLLL32', 'Chemical', 'MESH:C548902', (138, 144))	('glioma', 'Disease', (120, 126))	('glioma', 'Disease', (68, 74))	('glioma cells', 'Disease', (120, 132))	('B7-H3-overexpressing', 'Var', (99, 119))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
59931	32210587	Notably, the B7-H3-induced proliferation of glioma cells was delayed following FLLL32 treatment (Figure 2C).	('delayed', 'NegReg', (61, 68))	('FLLL32', 'Gene', (79, 85))	('glioma cells', 'Disease', (44, 56))	('FLLL32', 'Chemical', 'MESH:C548902', (79, 85))	('glioma cells', 'Disease', 'MESH:D005910', (44, 56))	('treatment', 'Var', (86, 95))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
59932	32210587	Additionally, FLLL32 treatment also suppressed the B7-H3-induced increase in colony formation, tumorigenesis, and invasion of glioma cells (Figure 2D-F), further indicating that B7-H3 induces the sustained growth and invasive capacity of glioma cells through the JAK2/STAT3 pathway.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('glioma cells', 'Disease', (238, 250))	('induces', 'PosReg', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('FLLL32', 'Chemical', 'MESH:C548902', (14, 20))	('invasion', 'CPA', (114, 122))	('B7-H3', 'Var', (178, 183))	('colony formation', 'CPA', (77, 93))	('glioma cells', 'Disease', 'MESH:D005910', (238, 250))	('glioma cells', 'Disease', (126, 138))	('FLLL32', 'Gene', (14, 20))	('tumor', 'Disease', (95, 100))	('increase', 'PosReg', (65, 73))	('suppressed', 'NegReg', (36, 46))	('glioma cells', 'Disease', 'MESH:D005910', (126, 138))	('JAK2/STAT3 pathway', 'Pathway', (263, 281))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('sustained growth', 'CPA', (196, 212))	('invasive capacity', 'CPA', (217, 234))
59933	32210587	Consistent with this conclusion, increased levels of p-JAK2 and p-STAT3 were also observed in tissues from patients with malignant gliomas (Figure 2G).	('p-JAK2', 'Var', (53, 59))	('malignant gliomas', 'Disease', (121, 138))	('p-STAT3', 'Var', (64, 71))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('levels', 'MPA', (43, 49))	('malignant gliomas', 'Disease', 'MESH:D005910', (121, 138))	('increased', 'PosReg', (33, 42))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('patients', 'Species', '9606', (107, 115))
59935	32210587	Based on these findings, we assessed the expression of the EMT markers E-cadherin and N-cadherin in glioma cells overexpressing B7-H3.	('E-cadherin', 'Gene', '12550', (71, 81))	('glioma cells', 'Disease', 'MESH:D005910', (100, 112))	('E-cadherin', 'Gene', (71, 81))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('N-cadherin', 'Gene', '12558', (86, 96))	('N-cadherin', 'Gene', (86, 96))	('B7-H3', 'Var', (128, 133))	('glioma cells', 'Disease', (100, 112))
59937	32210587	Slug expression was also upregulated in glioma cells overexpressing B7-H3 (Figure 3B).	('expression', 'MPA', (5, 15))	('B7-H3', 'Var', (68, 73))	('Slug', 'Gene', (0, 4))	('glioma cells', 'Disease', (40, 52))	('upregulated', 'PosReg', (25, 36))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma cells', 'Disease', 'MESH:D005910', (40, 52))
59938	32210587	To further assess the role of Slug in glioma invasion, we knocked down Slug in LN229-B7-H3 OE and U87-B7-H3 OE cells (Figure 3C).	('Slug', 'Gene', (71, 75))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('knocked', 'Var', (58, 65))	('glioma', 'Disease', (38, 44))
59939	32210587	Intriguingly, we found that Slug knockdown suppressed B7-H3-induced EMT (Figure 3D) and glioma cell invasion (Figure 3E).	('knockdown', 'Var', (33, 42))	('glioma', 'Disease', (88, 94))	('B7-H3-induced', 'Protein', (54, 67))	('Slug', 'Gene', (28, 32))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('suppressed', 'NegReg', (43, 53))
59942	32210587	Based on these results, we concluded that B7-H3 could induce glioma invasion through JAK2/STAT3/Slug/MMP-2/-9.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('B7-H3', 'Var', (42, 47))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('induce', 'PosReg', (54, 60))
59944	32210587	Therefore, we hypothesized that blocking the JAK2/STAT3 signal would strengthen the anticancer effects of chemotherapeutic agents and lead to improved clinical prognosis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('improved', 'PosReg', (142, 150))	('strengthen', 'PosReg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('clinical prognosis', 'CPA', (151, 169))	('JAK2/STAT3 signal', 'MPA', (45, 62))	('blocking', 'Var', (32, 40))
59946	32210587	Here, we used LN229-luc or LN229-B7-H3-luc cells to establish an orthotopic mouse glioma model, and used a live-imaging system to evaluate tumor growth.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mouse', 'Species', '10090', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('LN229-B7-H3-luc', 'Var', (27, 42))	('glioma', 'Disease', (82, 88))
59951	32210587	We previously showed that B7-H3 expression can enhance glioma cell invasion.	('glioma', 'Disease', (55, 61))	('enhance', 'PosReg', (47, 54))	('B7-H3 expression', 'Var', (26, 42))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))
59953	32210587	As expected, blockade of the STAT3 signal led to a significant delay in glioma cell invasion (Figure 4F and G).	('glioma', 'Disease', (72, 78))	('blockade', 'Var', (13, 21))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('delay', 'NegReg', (63, 68))	('glioma', 'Disease', 'MESH:D005910', (72, 78))
59958	32210587	We found that B7-H3 induced the activation of JAK2/STAT3 signaling through the upregulation of phosphorylated Src and inhibition of the negative regulators SHP-1 and SOCS-3.	('SHP-1', 'Gene', (156, 161))	('inhibition', 'NegReg', (118, 128))	('JAK2/STAT3 signaling', 'MPA', (46, 66))	('activation', 'PosReg', (32, 42))	('B7-H3', 'Var', (14, 19))	('SOCS-3', 'Gene', '12702', (166, 172))	('Src', 'Gene', (110, 113))	('Src', 'Gene', '20779', (110, 113))	('SOCS-3', 'Gene', (166, 172))	('upregulation', 'PosReg', (79, 91))	('SHP-1', 'Gene', '15170', (156, 161))
59959	32210587	Moreover, JAK2/STAT3 signaling also induced the upregulation of the transcription factor Slug, thereby promoting EMT and MMP-2/-9 secretion in glioma cells.	('glioma cells', 'Disease', 'MESH:D005910', (143, 155))	('promoting', 'PosReg', (103, 112))	('JAK2/STAT3 signaling', 'Var', (10, 30))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('Slug', 'Gene', (89, 93))	('MMP-2/-9 secretion', 'MPA', (121, 139))	('EMT', 'CPA', (113, 116))	('glioma cells', 'Disease', (143, 155))	('upregulation', 'PosReg', (48, 60))
59962	32210587	Overexpression of B7-H3 in lung adenocarcinoma patients is closely associated with lymph node invasion, distant metastasis, and disease stage.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (27, 46))	('distant metastasis', 'CPA', (104, 122))	('patients', 'Species', '9606', (47, 55))	('B7-H3', 'Gene', (18, 23))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (27, 46))	('associated', 'Reg', (67, 77))	('Overexpression', 'Var', (0, 14))	('lung adenocarcinoma', 'Disease', (27, 46))	('lymph node invasion', 'CPA', (83, 102))
59965	32210587	Silencing or overexpression of B7-H3 in cervical cancer cell lines showed that B7-H3 is involved in cell proliferation and apoptosis of various tumor cells.	('tumor', 'Disease', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('B7-H3', 'Gene', (79, 84))	('overexpression', 'PosReg', (13, 27))	('cell proliferation', 'CPA', (100, 118))	('apoptosis', 'CPA', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Silencing', 'Var', (0, 9))	('cancer', 'Disease', (49, 55))	('involved', 'Reg', (88, 96))
59967	32210587	In our study, we found that B7-H3 expression could induce sustained glioma growth and enhance glioma cell invasion.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('enhance', 'PosReg', (86, 93))	('glioma', 'Disease', (94, 100))	('sustained glioma growth', 'Disease', 'MESH:D005910', (58, 81))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('induce', 'PosReg', (51, 57))	('sustained glioma growth', 'Disease', (58, 81))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Disease', (68, 74))	('B7-H3 expression', 'Var', (28, 44))
59970	32210587	We further showed that the JAK2/STAT3 pathway has a role in sustained glioma growth and that JAK2/STAT3 has potential as a novel therapeutic target for the treatment of glioma.	('sustained glioma growth', 'Disease', 'MESH:D005910', (60, 83))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', (169, 175))	('JAK2/STAT3', 'Var', (93, 103))	('sustained glioma growth', 'Disease', (60, 83))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('JAK2/STAT3 pathway', 'Pathway', (27, 45))
59975	32210587	Previous studies have demonstrated that B7-H3 enhances inflammatory responses and promotes MMP-9 expression in a pneumococcal meningitis animal model.	('enhances', 'PosReg', (46, 54))	('pneumococcal meningitis', 'Disease', 'MESH:D008586', (113, 136))	('expression', 'MPA', (97, 107))	('inflammatory responses', 'CPA', (55, 77))	('promotes', 'PosReg', (82, 90))	('meningitis', 'Phenotype', 'HP:0001287', (126, 136))	('pneumococcal meningitis', 'Disease', (113, 136))	('MMP-9', 'Gene', (91, 96))	('B7-H3', 'Var', (40, 45))
59976	32210587	In osteosarcoma, B7-H3 also regulates cell migration and promotes tumor invasion through an MMP-2-associated signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cell migration', 'CPA', (38, 52))	('tumor', 'Disease', (66, 71))	('osteosarcoma', 'Disease', (3, 15))	('B7-H3', 'Var', (17, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('regulates', 'Reg', (28, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('MMP-2-associated signaling pathway', 'Pathway', (92, 126))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('promotes', 'PosReg', (57, 65))
59978	32210587	Here, we further demonstrated that B7-H3 can induce EMT and MMP-2/-9 secretion through Slug, a downstream target of JAK2/STAT3, resulting in glioma cell invasion.	('EMT', 'MPA', (52, 55))	('induce', 'PosReg', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('B7-H3', 'Var', (35, 40))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('Slug', 'Gene', (87, 91))	('glioma', 'Disease', (141, 147))
59980	32210587	Ours is the first report to indicate that a correlation exists between B7-H3 and glioma, demonstrating that the elevated expression of B7-H3 can lead to malignant glioma development.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', (163, 169))	('malignant glioma', 'Disease', (153, 169))	('malignant glioma', 'Disease', 'MESH:D005910', (153, 169))	('expression', 'MPA', (121, 131))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('elevated', 'PosReg', (112, 120))	('glioma', 'Disease', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('B7-H3', 'Var', (135, 140))	('lead to', 'Reg', (145, 152))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
59981	32210587	We also identified the mechanism underlying the B7-H3-induced tumor progression, and showed for the first time that B7-H3 is involved in glioma growth and invasion through activation of JAK/STAT3/Slug signaling and regulation of EMT processes.	('B7-H3', 'Var', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EMT processes', 'CPA', (229, 242))	('glioma growth', 'Disease', (137, 150))	('tumor', 'Disease', (62, 67))	('JAK/STAT3/Slug signaling', 'Pathway', (186, 210))	('invasion', 'CPA', (155, 163))	('regulation', 'Reg', (215, 225))	('involved', 'Reg', (125, 133))	('activation', 'PosReg', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('glioma growth', 'Disease', 'MESH:D005910', (137, 150))
59985	32210587	In summary, we showed that B7-H3 can upregulate JAK2/STAT3 signaling and facilitate EMT in glioma cells, thereby inducing glioma development.	('JAK2/STAT3 signaling', 'MPA', (48, 68))	('upregulate', 'PosReg', (37, 47))	('facilitate', 'PosReg', (73, 83))	('glioma', 'Disease', (91, 97))	('glioma', 'Disease', (122, 128))	('B7-H3', 'Var', (27, 32))	('glioma cells', 'Disease', (91, 103))	('EMT', 'CPA', (84, 87))	('inducing', 'PosReg', (113, 121))	('glioma cells', 'Disease', 'MESH:D005910', (91, 103))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
59986	32210587	Blockade of STAT3 by NAP treatment efficiently inhibited glioma growth and invasion, which might serve as a novel therapeutic strategy for the treatment of glioma.	('inhibited', 'NegReg', (47, 56))	('glioma', 'Disease', (156, 162))	('invasion', 'CPA', (75, 83))	('Blockade', 'Var', (0, 8))	('glioma', 'Disease', (57, 63))	('NAP', 'Chemical', 'MESH:C000621033', (21, 24))	('STAT3', 'Gene', (12, 17))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma growth', 'Disease', 'MESH:D005910', (57, 70))	('glioma growth', 'Disease', (57, 70))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
59990	32034238	Based on the 2016 WHO classification, 80 patients (52.3%) had diffuse astrocytoma, IDH-mutant; 45 (29.4%) had oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG); and 28 (18.3%) had diffuse astrocytoma, IDH-wildtype.	('ODG', 'Chemical', 'MESH:C525901', (162, 165))	('astrocytoma', 'Disease', (195, 206))	('astrocytoma', 'Disease', 'MESH:D001254', (70, 81))	('IDH', 'Gene', (83, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (195, 206))	('astrocytoma', 'Disease', (70, 81))	('oligodendroglioma', 'Disease', (110, 127))	('IDH', 'Gene', '3417', (83, 86))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('patients', 'Species', '9606', (41, 49))	('IDH', 'Gene', '3417', (129, 132))	('oligodendroglioma', 'Disease', 'MESH:D009837', (110, 127))	('IDH', 'Gene', (208, 211))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('1p/19q-codeleted', 'Var', (144, 160))	('IDH', 'Gene', (129, 132))	('IDH', 'Gene', '3417', (208, 211))	('astrocytoma', 'Disease', 'MESH:D001254', (195, 206))
59993	32034238	GTR and IDH-mutant and/or 1p/19q codeletion were favorable prognostic factors for PFS and OS.	('IDH', 'Gene', (8, 11))	('PFS', 'Disease', (82, 85))	('1p/19q codeletion', 'Var', (26, 43))	('IDH', 'Gene', '3417', (8, 11))
60001	32034238	With increasing evidence that molecular markers, such as isocitrate dehydrogenase (IDH) 1/2 gene mutation and chromosome 1p/19q codeletion, are more important than histologic subtype in the prediction of tumor response to treatment and prognosis, phenotypic and genotypic parameters have been integrated in the updated 2016 WHO classification of gliomas.	('isocitrate dehydrogenase (IDH) 1/2', 'Gene', '3417;3418', (57, 91))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('gliomas', 'Disease', (346, 353))	('gliomas', 'Disease', 'MESH:D005910', (346, 353))	('mutation', 'Var', (97, 105))	('gliomas', 'Phenotype', 'HP:0009733', (346, 353))	('glioma', 'Phenotype', 'HP:0009733', (346, 352))
60007	32034238	Molecular parameters, such as the deletion of 1p/19q, mutation of IDH1/2, or O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation, were reviewed, and a pathologist revised the diagnosis using the 2016 WHO classification.	('1p/19q', 'Gene', (46, 52))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (77, 115))	('MGMT', 'Gene', (117, 121))	('MGMT', 'Gene', '4255', (117, 121))	('IDH1/2', 'Gene', '3417;3418', (66, 72))	('deletion', 'Var', (34, 42))	('O6-methylguanine-DNA methyltransferase', 'Gene', (77, 115))	('IDH1/2', 'Gene', (66, 72))
60009	32034238	We examined IDH1 mutations using the Ventana Bench Mark XT autostainer (Ventana Medical System, Inc., Tucson, AZ, USA) according to the protocol as described at our previous report.	('IDH1', 'Gene', '3417', (12, 16))	('mutations', 'Var', (17, 26))	('IDH1', 'Gene', (12, 16))
60012	32034238	If the numbers of "deleted" nuclei exceeded 50%, the tumor was considered to show a "deletion" of the targeted chromosome.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('deletion', 'Var', (85, 93))	('tumor', 'Disease', (53, 58))
60019	32034238	Based on the 2016 WHO classification, 45 (29.4%) patients had oligodendroglioma, IDH-mutant and 1p/19q codeleted (ODG); 80 (52.3%) had diffuse astrocytoma, IDH-mutant (IDHmt); and 28 (18.3%) had diffuse astrocytoma, IDH-wildtype (IDHwt).	('IDH', 'Gene', (216, 219))	('astrocytoma', 'Disease', (143, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (203, 214))	('IDH', 'Gene', (168, 171))	('IDH', 'Gene', '3417', (81, 84))	('IDH', 'Gene', (230, 233))	('IDH', 'Gene', '3417', (168, 171))	('IDH', 'Gene', '3417', (216, 219))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('astrocytoma', 'Disease', 'MESH:D001254', (203, 214))	('IDH', 'Gene', '3417', (230, 233))	('astrocytoma', 'Disease', (203, 214))	('IDH', 'Gene', (156, 159))	('oligodendroglioma', 'Disease', 'MESH:D009837', (62, 79))	('patients', 'Species', '9606', (49, 57))	('IDH', 'Gene', (81, 84))	('oligodendroglioma', 'Disease', (62, 79))	('1p/19q', 'Var', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH', 'Gene', '3417', (156, 159))	('astrocytoma', 'Disease', 'MESH:D001254', (143, 154))	('ODG', 'Chemical', 'MESH:C525901', (114, 117))
60036	32034238	GTR, molecular subtype of IDH-mutant and/or 1p/19q codeletion, and tumor size less than 6 cm were favorable prognostic factors for both PFS and OS.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IDH', 'Gene', (26, 29))	('tumor', 'Disease', (67, 72))	('1p/19q codeletion', 'Var', (44, 61))	('IDH', 'Gene', '3417', (26, 29))	('PFS', 'Disease', (136, 139))
60037	32034238	The molecular markers had significance as an independent prognostic factor, and statistical significance was also shown in separate survival analyses of 1p/19q codeletion, IDH mutation, and MGMT methylation status (Supplementary Fig.	('IDH', 'Gene', (172, 175))	('IDH', 'Gene', '3417', (172, 175))	('MGMT', 'Gene', '4255', (190, 194))	('MGMT', 'Gene', (190, 194))	('1p/19q codeletion', 'Var', (153, 170))	('mutation', 'Var', (176, 184))
60040	32034238	Among 21 patients with ODG who received non-GTR and postoperative RT, 4 showed progression at a range of 40.6-72.4 months after surgery, and only 1 patient died of the disease, 66.9 months after diagnosis.	('patients', 'Species', '9606', (9, 17))	('patient', 'Species', '9606', (148, 155))	('non-GTR', 'Var', (40, 47))	('ODG', 'Chemical', 'MESH:C525901', (23, 26))	('ODG', 'Disease', (23, 26))	('patient', 'Species', '9606', (9, 16))
60065	32034238	In the IDHwt group, the impact of GTR was prominent, but patients with GTR had better prognostic factors, such as younger age, small tumor size (2.2-6.7 cm, median 2.9 cm), and non-eloquent area location.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('patients', 'Species', '9606', (57, 65))	('GTR', 'Var', (71, 74))	('small tumor', 'Disease', 'MESH:D058405', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('small tumor', 'Disease', (127, 138))
60072	32034238	A prospective study administering postoperative temozolomide for 1 year showed that patients with 1p/19q codeletion demonstrated a 0% risk of progression during treatment, and the median PFS and OS rates of patients with 1p/19q-codeleted tumors were 4.2 and 9.7 years, respectively.	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (238, 244))	('1p/19q codeletion', 'Var', (98, 115))	('temozolomide', 'Chemical', 'MESH:C047246', (48, 60))
60086	32034238	Patients with tumors that did not have IDH mutations had a particularly poor outcome, regardless of adjuvant treatment, and ODG patients showed excellent long-term survival.	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (43, 52))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('IDH', 'Gene', (39, 42))	('patients', 'Species', '9606', (128, 136))	('ODG', 'Chemical', 'MESH:C525901', (124, 127))	('IDH', 'Gene', '3417', (39, 42))
60113	29732319	Most gliomas harbor molecular alterations disrupting key signaling pathways involved in regulation of cell growth (e.g., receptor tyrosine kinases, MAPK/ERK PIK3CA/AKT/PTEN signaling pathways), cell cycle/DNA repair/apoptosis (e.g., retinoblastoma/E2F/p53), metabolism [e.g., isocitrate dehydrogenase (IDH1)], chromatin, and telomere length.	('PTEN', 'Gene', '5728', (168, 172))	('PIK3CA', 'Gene', (157, 163))	('gliomas', 'Disease', (5, 12))	('retinoblastoma', 'Disease', 'MESH:D012175', (233, 247))	('AKT', 'Gene', (164, 167))	('IDH1', 'Gene', (302, 306))	('ERK', 'Gene', '5594', (153, 156))	('gliomas', 'Disease', 'MESH:D005910', (5, 12))	('p53', 'Gene', '7157', (252, 255))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))	('IDH1', 'Gene', '3417', (302, 306))	('ERK', 'Gene', (153, 156))	('retinoblastoma', 'Phenotype', 'HP:0009919', (233, 247))	('p53', 'Gene', (252, 255))	('gliomas', 'Phenotype', 'HP:0009733', (5, 12))	('AKT', 'Gene', '207', (164, 167))	('isocitrate', 'Chemical', 'MESH:C034219', (276, 286))	('PIK3CA', 'Gene', '5290', (157, 163))	('retinoblastoma', 'Disease', (233, 247))	('PTEN', 'Gene', (168, 172))	('telomere', 'CPA', (325, 333))	('disrupting', 'NegReg', (42, 52))	('alterations', 'Var', (30, 41))
60114	29732319	Among the most relevant genetic alterations affecting GBM are mutations of the IDH gene that may be linked to survival.	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('IDH', 'Gene', (79, 82))	('linked', 'Reg', (100, 106))	('IDH', 'Gene', '3417', (79, 82))	('mutations', 'Var', (62, 71))
60115	29732319	The enzyme catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate and reduces NAD(P)+ to NAD(P)H. IDH has two isoforms (IDH1 and IDH2) of which mutations in IDH1 are the most common (Figure 1).	('IDH', 'Gene', '3417', (179, 182))	('NAD(P)+', 'Chemical', 'MESH:D009249', (100, 107))	('common', 'Reg', (197, 203))	('IDH', 'Gene', (120, 123))	('IDH1', 'Gene', (142, 146))	('IDH', 'Gene', (151, 154))	('mutations', 'Var', (166, 175))	('IDH', 'Gene', (142, 145))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (68, 87))	('oxidative decarboxylation', 'MPA', (25, 50))	('IDH', 'Gene', '3417', (120, 123))	('IDH', 'Gene', '3417', (151, 154))	('IDH1', 'Gene', '3417', (142, 146))	('NAD(P)H', 'Chemical', '-', (111, 118))	('IDH', 'Gene', '3417', (142, 145))	('IDH1', 'Gene', (179, 183))	('isocitrate to alpha-ketoglutarate', 'MPA', (54, 87))	('isocitrate', 'Chemical', 'MESH:C034219', (54, 64))	('IDH', 'Gene', (179, 182))	('IDH2', 'Gene', (151, 155))	('IDH2', 'Gene', '3418', (151, 155))	('IDH1', 'Gene', '3417', (179, 183))
60116	29732319	IDH gene mutations are present in only 5% primary and approximately 80% of secondary GBMs.	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('mutations', 'Var', (9, 18))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))
60117	29732319	Epidermal growth factor receptor (EGFR) is commonly overexpressed in GBM, most frequently due to EGFR gene amplification and/or the EGFR variant III deletion mutation (EGFRvIII).	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', '1956', (97, 101))	('overexpressed', 'PosReg', (52, 65))	('variant III deletion mutation', 'Var', (137, 166))	('EGFR', 'Gene', '1956', (132, 136))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('amplification', 'PosReg', (107, 120))	('EGFR', 'Gene', (132, 136))	('EGFR', 'Gene', (97, 101))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', '1956', (34, 38))
60122	29732319	Epigenetic silencing of the MGMT DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents including temozolomide (Figure 1).	('MGMT', 'Gene', (28, 32))	('promoter methylation', 'Var', (52, 72))	('associated', 'Reg', (109, 119))	('MGMT', 'Gene', '4255', (28, 32))	('DNA repair', 'MPA', (85, 95))	('glioblastoma', 'Disease', (158, 170))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('longer survival', 'PosReg', (125, 140))	('patients', 'Species', '9606', (144, 152))	('Epigenetic silencing', 'Var', (0, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('temozolomide', 'Chemical', 'MESH:D000077204', (211, 223))	('compromises', 'NegReg', (73, 84))
60124	29732319	Telomerases are usually inactive in the adult normal cells, but can be reactivated (e.g., by mutations) in various cancers to promote oncogenesis.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('mutations', 'Var', (93, 102))	('cancers', 'Disease', (115, 122))	('oncogenesis', 'CPA', (134, 145))	('promote', 'PosReg', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Telomerases', 'Protein', (0, 11))
60125	29732319	TERT gene mutations in GBMs are activating (usually in the TERT promoter region).	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('TERT', 'Gene', (59, 63))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', '7015', (59, 63))	('mutations', 'Var', (10, 19))	('activating', 'PosReg', (32, 42))
60128	29732319	A subset of GBMs may also have genetic alterations of PIK3CA, PIK3R1, NF1, and RB1 genes.	('NF1', 'Gene', '4763', (70, 73))	('RB1', 'Gene', (79, 82))	('PIK3R1', 'Gene', '5295', (62, 68))	('PIK3R1', 'Gene', (62, 68))	('RB1', 'Gene', '5925', (79, 82))	('PIK3CA', 'Gene', '5290', (54, 60))	('genetic alterations', 'Var', (31, 50))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('NF1', 'Gene', (70, 73))	('PIK3CA', 'Gene', (54, 60))
60129	29732319	Along with improved understanding of the role of cells in the tumor microenvironment (e.g., reactive astrocytes, activated macrophage, and glioma stem cells), micro RNAs, and long non-coding RNAs in glioma progression, the above genomic and molecular changes are thought to be of growing importance in the diagnosis, development, classification, and therapy of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('gliomas', 'Disease', 'MESH:D005910', (361, 368))	('glioma', 'Disease', (361, 367))	('gliomas', 'Phenotype', 'HP:0009733', (361, 368))	('glioma', 'Disease', (139, 145))	('gliomas', 'Disease', (361, 368))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('tumor', 'Disease', (62, 67))	('glioma', 'Disease', 'MESH:D005910', (361, 367))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (361, 367))	('long non-coding RNAs', 'Var', (175, 195))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Disease', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
60131	29732319	Although little is known about the etiology of GBM or other gliomas, increased risk has been observed following exposure to ionizing radiation or chemical agents or through genetic predisposition (e.g., germline TP53, NF1, and NF2 mutations) in a small proportion of the patients with GBM (e.g., Li-Fraumeni syndrome, neurofibromatosis type 1 and type 2).	('NF2', 'Gene', (227, 230))	('mutations', 'Var', (231, 240))	('NF1', 'Gene', (218, 221))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('NF1', 'Gene', '4763', (218, 221))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (318, 335))	('patients', 'Species', '9606', (271, 279))	('GBM', 'Phenotype', 'HP:0012174', (285, 288))	('NF2', 'Gene', '4771', (227, 230))	('TP53', 'Gene', '7157', (212, 216))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('TP53', 'Gene', (212, 216))	('Li-Fraumeni syndrome, neurofibromatosis type 1 and type 2', 'Gene', '4763', (296, 353))
60164	29732319	In addition, several signaling pathways may also be upregulated by this interaction, including MAPK/ERK, PIK3CA/AKT, JAK/STAT, and Notch pathways.	('PIK3CA', 'Gene', (105, 111))	('interaction', 'Var', (72, 83))	('Notch pathways', 'Pathway', (131, 145))	('PIK3CA', 'Gene', '5290', (105, 111))	('AKT', 'Gene', '207', (112, 115))	('JAK/STAT', 'Pathway', (117, 125))	('signaling pathways', 'Pathway', (21, 39))	('ERK', 'Gene', '5594', (100, 103))	('upregulated', 'PosReg', (52, 63))	('AKT', 'Gene', (112, 115))	('ERK', 'Gene', (100, 103))
60187	29732319	This was in contrast to an earlier report by Wrensch et al., who used serological IgG antibody binding using ELISA assays to demonstrate that about 90% of their GBM patients, from the USA, San Francisco Bay Area Adult Glioma Study from 1991 to 1995, were seropositive for EBV.	('EBV', 'Species', '10376', (272, 275))	('Glioma', 'Disease', 'MESH:D005910', (218, 224))	('Glioma', 'Phenotype', 'HP:0009733', (218, 224))	('Glioma', 'Disease', (218, 224))	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('IgG antibody', 'Phenotype', 'HP:0003237', (82, 94))	('patients', 'Species', '9606', (165, 173))	('seropositive', 'Var', (255, 267))	('EBV', 'Disease', (272, 275))
60206	29732319	used multiplex droplet digital PCR (ddPCR):a highly precise diagnostic tool that enables the absolute quantification of target DNA in a high throughput setting:to show positivity of EBV lmp1 DNA in 4/19 (21.1%) of formalin-fixed paraffin-embedded (FFPE) GBM samples and not in any controls.	('lmp1', 'Gene', '17494204', (186, 190))	('positivity', 'Var', (168, 178))	('formalin', 'Chemical', 'MESH:D005557', (214, 222))	('paraffin', 'Chemical', 'MESH:D010232', (229, 237))	('GBM', 'Phenotype', 'HP:0012174', (254, 257))	('EBV', 'Species', '10376', (182, 185))	('lmp1', 'Gene', (186, 190))
60253	29732319	suggests that EBV might exert some of its oncogenic effects, such as inducing centrosome amplification and chromosomal instability, without having to establish a chronic infection, thereby conferring a risk for development of tumors that do not necessarily carry the viral genome.	('centrosome', 'MPA', (78, 88))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('EBV', 'Species', '10376', (14, 17))	('EBV', 'Var', (14, 17))	('tumors', 'Disease', (226, 232))	('inducing', 'Reg', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('chronic infection', 'Phenotype', 'HP:0031035', (162, 179))	('chromosomal', 'MPA', (107, 118))	('chromosomal instability', 'Phenotype', 'HP:0040012', (107, 130))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))
60257	29732319	Thus, their paradigm-changing study implies that EBV could be a risk factor for the development of gliomas without being present in the tumor.	('EBV', 'Species', '10376', (49, 52))	('EBV', 'Var', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
60289	26250554	The area of abnormal VR (1103+-659mm2) was significantly greater (p=0.019) than the enhancement (543+-530mm2), but significantly smaller (p=0.0011) than the FLAIR abnormality (2363+-1232mm2).	('smaller', 'NegReg', (129, 136))	('1103+-659mm2', 'Var', (25, 37))	('men', 'Species', '9606', (91, 94))
60311	26250554	Comparing Gd-based contrast enhancement and FLAIR to a VR map may be important because Gd-enhancement images underestimate tumor volume while FLAIR overestimates tumor volume (because it includes both tumor and edema).	('men', 'Species', '9606', (35, 38))	('tumor', 'Disease', (162, 167))	('underestimate', 'NegReg', (109, 122))	('overestimates', 'NegReg', (148, 161))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Gd', 'Chemical', 'MESH:D005682', (10, 12))	('tumor', 'Disease', (123, 128))	('men', 'Species', '9606', (97, 100))	('edema', 'Phenotype', 'HP:0000969', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Gd', 'Chemical', 'MESH:D005682', (87, 89))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('edema', 'Disease', 'MESH:D004487', (211, 216))	('edema', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('FLAIR', 'Var', (142, 147))
60403	33498680	Infiltrating lower-grade gliomas (LGG, grade 2/3), i.e., astrocyte- and oligodendrocyte-derived tumors, currently include isocytrate dehydrogenase (IDH) mutant 1p/19q-codeleted (IDHmut1p19qcod) oligodendroglioma, IDH-mutant 1p/19q-intact (IDHmut1p19qint) astrocytoma, and IDH-wildtype (IDHwt) astrocytoma.	('IDH', 'Gene', '3417', (178, 181))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('IDH', 'Gene', (272, 275))	('tumors', 'Disease', (96, 102))	('astrocytoma', 'Disease', 'MESH:D001254', (293, 304))	('oligodendroglioma', 'Disease', (194, 211))	('astrocytoma', 'Disease', (293, 304))	('IDH', 'Gene', (239, 242))	('IDH', 'Gene', (213, 216))	('q', 'Chemical', 'MESH:D005973', (229, 230))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('q', 'Chemical', 'MESH:D005973', (165, 166))	('astrocytoma', 'Phenotype', 'HP:0009592', (255, 266))	('IDH', 'Gene', (286, 289))	('IDH', 'Gene', '3417', (272, 275))	('p', 'Chemical', 'MESH:D010758', (282, 283))	('p', 'Chemical', 'MESH:D010758', (225, 226))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('IDH', 'Gene', '3417', (239, 242))	('p', 'Chemical', 'MESH:D010758', (161, 162))	('gliomas', 'Disease', (25, 32))	('mutant 1p/19q-codeleted', 'Var', (153, 176))	('IDH', 'Gene', '3417', (213, 216))	('p', 'Chemical', 'MESH:D010758', (185, 186))	('q', 'Chemical', 'MESH:D005973', (188, 189))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', '3417', (286, 289))	('astrocytoma', 'Phenotype', 'HP:0009592', (293, 304))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('IDH', 'Gene', (178, 181))	('q', 'Chemical', 'MESH:D005973', (249, 250))	('astrocytoma', 'Disease', 'MESH:D001254', (255, 266))	('astrocytoma', 'Disease', (255, 266))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('IDH', 'Gene', '3417', (148, 151))	('p', 'Chemical', 'MESH:D010758', (246, 247))	('oligodendroglioma', 'Disease', 'MESH:D009837', (194, 211))	('hydrogen', 'Chemical', 'MESH:D006859', (135, 143))
60419	33498680	For glial tumors, isocytrate dehydrogenase (IDH) status is currently the most important molecular feature to assess in gliomas, as the absence of IDH-mutation dramatically worsens prognosis both in LGG and in GBM.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('absence', 'Var', (135, 142))	('glial tumors', 'Disease', 'MESH:D005910', (4, 16))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glial tumors', 'Disease', (4, 16))	('IDH', 'Gene', (146, 149))	('hydrogen', 'Chemical', 'MESH:D006859', (31, 39))	('worsens', 'PosReg', (172, 179))	('gliomas', 'Disease', (119, 126))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('prognosis', 'MPA', (180, 189))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('IDH', 'Gene', '3417', (44, 47))
60427	33498680	In another study enrolling LGG-patients, an ROI-derived measure (rCBVmax, comparing tumor-CBV to the contralateral white matter) also exhibited a good diagnostic performance (AUC 0.82), and the authors proposed a threshold of <2.35 for high-sensitivity IDH-status prediction (sensitivity/specificity 1.00/0.61 in their cohort), meaning that rCBVmax > 2.35 is highly indicative of IDHwt-status and, therefore, of worse prognosis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('rCBVmax', 'Var', (341, 348))	('p', 'Chemical', 'MESH:D010758', (264, 265))	('p', 'Chemical', 'MESH:D010758', (418, 419))	('p', 'Chemical', 'MESH:D010758', (31, 32))	('p', 'Chemical', 'MESH:D010758', (202, 203))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p', 'Chemical', 'MESH:D010758', (162, 163))	('IDH', 'Gene', '3417', (380, 383))	('tumor', 'Disease', (84, 89))	('p', 'Chemical', 'MESH:D010758', (289, 290))	('patients', 'Species', '9606', (31, 39))	('IDH', 'Gene', (253, 256))	('p', 'Chemical', 'MESH:D010758', (205, 206))	('IDH', 'Gene', (380, 383))	('IDH', 'Gene', '3417', (253, 256))	('p', 'Chemical', 'MESH:D010758', (77, 78))
60431	33498680	In addition, moving from the evidence that IDHmut1p19qint-LGG are the only LGG expected to contain large subvolumes with high ADC-values, other authors proposed an alternative index for their identification: the percentage of tumor volume with ADC > 1.5 x 10-3 mm2/s (VADC>1.5), which also demonstrated good accuracy (~0.8 AUC in both their training and validation cohort).	('p', 'Chemical', 'MESH:D010758', (81, 82))	('IDH', 'Gene', '3417', (43, 46))	('ADC', 'Chemical', '-', (269, 272))	('p', 'Chemical', 'MESH:D010758', (212, 213))	('ADC', 'Chemical', '-', (244, 247))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('p', 'Chemical', 'MESH:D010758', (155, 156))	('p', 'Chemical', 'MESH:D010758', (152, 153))	('ADC', 'Chemical', '-', (126, 129))	('p', 'Chemical', 'MESH:D010758', (50, 51))	('ADC > 1.5', 'Var', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('IDH', 'Gene', (43, 46))	('tumor', 'Disease', (226, 231))	('q', 'Chemical', 'MESH:D005973', (53, 54))
60478	33498680	A recent study applied ADC and rCBV histogram metrics to 71 LGG and confirmed that IDHmut1p19qcod-LGG exhibit aMRI characteristics that are compatible with a higher cellularity (ADCmean), microvascularity (rCBFmean), and vascular heterogeneity (rCBVpeak) than IDHmut1p19qint-LGG, and it reported a good diagnostic performance of the combination of such parameters for the detection of 1p19qcod-status (sensitivity/specificity/AUC 0.92/0.81/0.84).	('p', 'Chemical', 'MESH:D010758', (143, 144))	('higher', 'PosReg', (158, 164))	('IDH', 'Gene', '3417', (83, 86))	('ADC', 'Chemical', '-', (178, 181))	('q', 'Chemical', 'MESH:D005973', (389, 390))	('p', 'Chemical', 'MESH:D010758', (267, 268))	('q', 'Chemical', 'MESH:D005973', (270, 271))	('1p19qcod-status', 'Var', (385, 400))	('q', 'Chemical', 'MESH:D005973', (93, 94))	('p', 'Chemical', 'MESH:D010758', (314, 315))	('IDH', 'Gene', (260, 263))	('p', 'Chemical', 'MESH:D010758', (249, 250))	('p', 'Chemical', 'MESH:D010758', (386, 387))	('p', 'Chemical', 'MESH:D010758', (353, 354))	('p', 'Chemical', 'MESH:D010758', (415, 416))	('p', 'Chemical', 'MESH:D010758', (90, 91))	('p', 'Chemical', 'MESH:D010758', (289, 290))	('IDH', 'Gene', '3417', (260, 263))	('p', 'Chemical', 'MESH:D010758', (17, 18))	('IDH', 'Gene', (83, 86))	('ADC', 'Chemical', '-', (23, 26))	('p', 'Chemical', 'MESH:D010758', (16, 17))
60483	33498680	In addition to IDH-status, other molecular features hold a prognostic significance in GBM, including EGFR modifications (mainly mutations or amplifications) and MGMT methylation.	('amplifications', 'MPA', (141, 155))	('GBM', 'Disease', (86, 89))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('mutations', 'Var', (128, 137))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('IDH', 'Gene', (15, 18))	('MGMT', 'Gene', (161, 165))	('IDH', 'Gene', '3417', (15, 18))	('modifications', 'Var', (106, 119))	('MGMT', 'Gene', '4255', (161, 165))
60484	33498680	Epithelial growth factor receptor (EGFR) is altered in ~60% of de novo GBM and ~10% of secondary GBM; its most common alteration (~33% of GBM) is EGFR variant-III (EGFvIII), presenting a mutation in the extracellular portion.	('p', 'Chemical', 'MESH:D010758', (174, 175))	('p', 'Chemical', 'MESH:D010758', (217, 218))	('EGFR', 'Gene', '1956', (146, 150))	('Epithelial growth factor receptor', 'Gene', '1956', (0, 33))	('EGFR', 'Gene', (146, 150))	('EGFR', 'Gene', (35, 39))	('p', 'Chemical', 'MESH:D010758', (29, 30))	('EGFR', 'Gene', '1956', (35, 39))	('Epithelial growth factor receptor', 'Gene', (0, 33))	('p', 'Chemical', 'MESH:D010758', (1, 2))	('variant-III', 'Var', (151, 162))
60485	33498680	EGFR modifications are believed to have a role in tumor invasiveness (regulating proliferation and motility of tumor cells) and often occur in the infiltrating periphery of GBM, accounting for the fuzzier appearance of tumor margins.	('tumor', 'Disease', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('p', 'Chemical', 'MESH:D010758', (206, 207))	('tumor invasiveness', 'Disease', (50, 68))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('p', 'Chemical', 'MESH:D010758', (160, 161))	('p', 'Chemical', 'MESH:D010758', (164, 165))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (111, 116))	('modifications', 'Var', (5, 18))	('tumor invasiveness', 'Disease', 'MESH:D009361', (50, 68))	('p', 'Chemical', 'MESH:D010758', (81, 82))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('p', 'Chemical', 'MESH:D010758', (207, 208))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('EGFR', 'Gene', '1956', (0, 4))
60487	33498680	EGFR alterations have been associated with lower ADC, higher rCBV, and lower PSR (percentage signal recovery, a DSC-derived metric reflecting contrast leakage), as well as higher rVp and rKtrans.	('Ktrans', 'Chemical', '-', (188, 194))	('rVp', 'MPA', (179, 182))	('EGFR', 'Gene', (0, 4))	('higher', 'PosReg', (54, 60))	('rKtrans', 'CPA', (187, 194))	('ADC', 'Chemical', '-', (49, 52))	('higher', 'PosReg', (172, 178))	('alterations', 'Var', (5, 16))	('rCBV', 'MPA', (61, 65))	('p', 'Chemical', 'MESH:D010758', (181, 182))	('EGFR', 'Gene', '1956', (0, 4))	('ADC', 'MPA', (49, 52))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('lower', 'NegReg', (43, 48))	('lower', 'NegReg', (71, 76))
60496	33498680	The methylation of the O6-methylguanine DNA methyltransferase promoter (MGMT methylation) is an epigenetic modification that reduces the expression of MGMT, a DNA-repair enzyme.	('O6-methylguanine DNA methyltransferase', 'Gene', (23, 61))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (23, 61))	('p', 'Chemical', 'MESH:D010758', (165, 166))	('expression', 'MPA', (137, 147))	('p', 'Chemical', 'MESH:D010758', (62, 63))	('MGMT', 'Gene', '4255', (72, 76))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('MGMT', 'Gene', (72, 76))	('reduces', 'NegReg', (125, 132))	('methylation', 'Var', (4, 15))	('p', 'Chemical', 'MESH:D010758', (139, 140))	('MGMT', 'Gene', (151, 155))	('MGMT', 'Gene', '4255', (151, 155))
60497	33498680	MGMT methylation in GBM is a positive prognostic factor for treatment response (with temozolomide and radiation-therapy), and it is also correlated to a better prognosis regardless of treatment.	('MGMT', 'Gene', (0, 4))	('p', 'Chemical', 'MESH:D010758', (38, 39))	('methylation', 'Var', (5, 16))	('temozolomide', 'Chemical', 'MESH:D000077204', (85, 97))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('p', 'Chemical', 'MESH:D010758', (29, 30))	('GBM', 'Gene', (20, 23))	('p', 'Chemical', 'MESH:D010758', (73, 74))	('p', 'Chemical', 'MESH:D010758', (160, 161))	('MGMT', 'Gene', '4255', (0, 4))
60508	33498680	Conversely, the presence of peculiar molecular features (IDHwt-status associated with EGFR amplification, TERT mutation, or +7/-10 chromosome copy number changes) suffices for the definition of GBM, regardless of microscopical features (that is, even though the microscopical evaluation advocates for LGG).	('IDH', 'Gene', '3417', (57, 60))	('p', 'Chemical', 'MESH:D010758', (28, 29))	('EGFR', 'Gene', '1956', (86, 90))	('TERT', 'Gene', (106, 110))	('p', 'Chemical', 'MESH:D010758', (93, 94))	('TERT', 'Gene', '7015', (106, 110))	('amplification', 'Var', (91, 104))	('p', 'Chemical', 'MESH:D010758', (221, 222))	('EGFR', 'Gene', (86, 90))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('IDH', 'Gene', (57, 60))	('p', 'Chemical', 'MESH:D010758', (144, 145))	('p', 'Chemical', 'MESH:D010758', (270, 271))
60510	33498680	A retrospective qualitative evaluation on 71 LGG reported EGFR amplification being almost exclusively seen in IDHwt-LGG and significantly correlating with mild (not avid) contrast enhancement, with >5% enhancing tumor, and with infiltrative/mixed growth pattern.	('mild', 'MPA', (155, 159))	('correlating', 'Reg', (138, 149))	('EGFR', 'Gene', '1956', (58, 62))	('IDH', 'Gene', (110, 113))	('p', 'Chemical', 'MESH:D010758', (254, 255))	('EGFR', 'Gene', (58, 62))	('IDH', 'Gene', '3417', (110, 113))	('p', 'Chemical', 'MESH:D010758', (65, 66))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('enhancing', 'PosReg', (202, 211))	('p', 'Chemical', 'MESH:D010758', (8, 9))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('amplification', 'Var', (63, 76))	('q', 'Chemical', 'MESH:D005973', (16, 17))	('tumor', 'Disease', (212, 217))
60526	33498680	According to cIMPACT-NOW Update 6, another mutation in H3-histone (H3.3-G34mut) has been proposed as a distinctive molecular marker of a novel tumor type, diffuse glioma H3.3-G34mut, a pediatric cerebral hemispheric glioma bearing a similar prognosis as DMG-H3K27Mmut.	('glioma', 'Disease', (163, 169))	('p', 'Chemical', 'MESH:D010758', (151, 152))	('K27', 'Gene', (260, 263))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('p', 'Chemical', 'MESH:D010758', (209, 210))	('glioma', 'Disease', (216, 222))	('p', 'Chemical', 'MESH:D010758', (185, 186))	('cerebral hemispheric glioma', 'Disease', 'MESH:D005910', (195, 222))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('p', 'Chemical', 'MESH:D010758', (241, 242))	('p', 'Chemical', 'MESH:D010758', (26, 27))	('p', 'Chemical', 'MESH:D010758', (89, 90))	('K27', 'Gene', '342574', (260, 263))	('tumor', 'Disease', (143, 148))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('cerebral hemispheric glioma', 'Disease', (195, 222))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('H3.3-G34mut', 'Var', (170, 181))
60527	33498680	Recent studies provided a description of some H3.3-G34mut cMRI features, including inhomogeneous appearance, scarce/absent contrast enhancement, and sometimes cystic components, but aMRI features of this new tumor type are still to be assessed.	('cystic', 'Disease', 'MESH:D052177', (159, 165))	('p', 'Chemical', 'MESH:D010758', (99, 100))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('p', 'Chemical', 'MESH:D010758', (216, 217))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cystic', 'Disease', (159, 165))	('cMRI', 'Disease', (58, 62))	('contrast enhancement', 'MPA', (123, 143))	('tumor', 'Disease', (208, 213))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('p', 'Chemical', 'MESH:D010758', (169, 170))	('p', 'Chemical', 'MESH:D010758', (32, 33))	('p', 'Chemical', 'MESH:D010758', (98, 99))	('H3.3-G34mut', 'Var', (46, 57))
60586	33498680	Another study further proved that quantitative BOLD is capable of providing useful insights regarding tumor-induced vascular abnormalities, in particular detecting areas of tumor-like BOLD alterations beyond cMRI-defined tumor margins.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('q', 'Chemical', 'MESH:D005973', (34, 35))	('vascular abnormalities', 'Disease', 'MESH:D000783', (116, 138))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('p', 'Chemical', 'MESH:D010758', (66, 67))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (116, 138))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('p', 'Chemical', 'MESH:D010758', (57, 58))	('p', 'Chemical', 'MESH:D010758', (22, 23))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('vascular abnormalities', 'Disease', (116, 138))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('alterations', 'Var', (189, 200))
60588	33498680	In addition, they reported IDHmut-gliomas harboring R132H-mutation (R132H+-IDHmut, a mutation associated with better prognosis) exhibiting a remarkably inferior BOLD alteration extension (measured by means of an index named "BOLD-only fraction" of the tumor:BOF) than R132H--gliomas.	('R132H', 'Var', (268, 273))	('IDH', 'Gene', '3417', (27, 30))	('BOLD', 'MPA', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('inferior', 'NegReg', (152, 160))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('gliomas', 'Disease', 'MESH:D005910', (275, 282))	('R132H', 'Var', (52, 57))	('R132H', 'SUBSTITUTION', 'None', (268, 273))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('gliomas', 'Phenotype', 'HP:0009733', (275, 282))	('gliomas', 'Disease', (34, 41))	('R132H', 'Var', (68, 73))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('R132H', 'SUBSTITUTION', 'None', (52, 57))	('IDH', 'Gene', (75, 78))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('IDHmut-gliomas', 'Disease', (27, 41))	('IDH', 'Gene', (27, 30))	('R132H', 'SUBSTITUTION', 'None', (68, 73))	('IDHmut-gliomas', 'Disease', 'MESH:D005910', (27, 41))	('IDH', 'Gene', '3417', (75, 78))	('tumor', 'Disease', (252, 257))	('gliomas', 'Disease', (275, 282))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
60589	33498680	BOF had an excellent diagnostic accuracy in discriminating R132H-status (AUC 0.98) in this cohort of 39 diffuse gliomas, advocating for a role of BOLD in molecular profiling.	('p', 'Chemical', 'MESH:D010758', (164, 165))	('R132H', 'SUBSTITUTION', 'None', (59, 64))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('diffuse', 'Disease', (104, 111))	('R132H', 'Var', (59, 64))
60621	33498680	employed a CNN model based on cMRI datasets for the molecular profiling of both LGG and HGG, and they reported a very high accuracy for the prediction of IDH-, 1p19q-, and MGMT-status (0.94/0.92/0.83, respectively).	('p', 'Chemical', 'MESH:D010758', (140, 141))	('MGMT', 'Gene', '4255', (172, 176))	('1p19q-', 'Var', (160, 166))	('MGMT', 'Gene', (172, 176))	('p', 'Chemical', 'MESH:D010758', (62, 63))	('q', 'Chemical', 'MESH:D005973', (164, 165))	('p', 'Chemical', 'MESH:D010758', (104, 105))	('p', 'Chemical', 'MESH:D010758', (204, 205))	('p', 'Chemical', 'MESH:D010758', (2, 3))	('IDH', 'Gene', (154, 157))	('p', 'Chemical', 'MESH:D010758', (161, 162))	('IDH', 'Gene', '3417', (154, 157))
60664	32424712	The patients' demographics and pathological diagnoses, based on the 2016 WHO classification, are as follows: the 11 HGGs included 7 glioblastomas (isocitrate dehydrogenase (IDH)-wild type; WHO grade IV; age, 48-71 years; 3 males and 4 females); 1 diffuse midline glioma (H3 K27M-mutant type; WHO grade III; age, 31 years; female); 2 anaplastic astrocytomas (IDH-mutant type; WHO grade III; age, 32 and 71 years; 1 male and 1 female); and 1 anaplastic oligodendroglioma (IDH-mutant type; WHO grade III; age, 47 years; female).	('midline glioma', 'Disease', (255, 269))	('IDH', 'Gene', (358, 361))	('IDH', 'Gene', (470, 473))	('astrocytomas', 'Disease', 'MESH:D001254', (344, 356))	('isocitrate dehydrogenase', 'Gene', '3417', (147, 171))	('glioblastomas', 'Phenotype', 'HP:0012174', (132, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', '3417', (358, 361))	('IDH', 'Gene', '3417', (470, 473))	('patients', 'Species', '9606', (4, 12))	('midline glioma', 'Disease', 'MESH:D005910', (255, 269))	('H3 K27M-mutant type', 'Var', (271, 290))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (440, 468))	('glioblastomas', 'Disease', (132, 145))	('isocitrate dehydrogenase', 'Gene', (147, 171))	('IDH', 'Gene', '3417', (173, 176))	('astrocytomas', 'Disease', (344, 356))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('glioma', 'Phenotype', 'HP:0009733', (462, 468))	('anaplastic oligodendroglioma', 'Disease', (440, 468))	('glioblastomas', 'Disease', 'MESH:D005909', (132, 145))	('K27M', 'Mutation', 'p.K27M', (274, 278))
60667	32424712	The mono-exponential DWI provides the ADC values using the formula:where SI0 corresponds to the signal intensity without diffusion weighting (b = 0 s/mm2) and SI1000 is the signal intensity at b = 1000 s/mm2.	('SI1000', 'Var', (159, 165))	('SI0', 'Var', (73, 76))	('ADC', 'Chemical', '-', (38, 41))
60682	32424712	In the combined-parameters analysis, the combination of the D10 and f90 from the bi-exponential DWI model also showed one of the highest diagnostic performances (AUC = 0.96, cutoff values 0.87 x 10-3 mm2/s and 9.1% for D10 and f90, respectively).	('f90', 'Var', (68, 71))	('D10', 'Gene', (60, 63))	('D10', 'Gene', '89832', (60, 63))	('f90', 'Var', (227, 230))	('D10', 'Gene', (219, 222))	('D10', 'Gene', '89832', (219, 222))
60692	32424712	The fast blood flow of the microcirculation observed at low b-values would yield slightly higher ADC and DDC values relative to the D value, as seen in our results.	('b-values', 'Var', (60, 68))	('DDC', 'Gene', (105, 108))	('low b-values', 'Var', (56, 68))	('ADC', 'Chemical', '-', (97, 100))	('higher', 'PosReg', (90, 96))	('DDC', 'Gene', '1644', (105, 108))	('fast blood flow', 'MPA', (4, 19))
60704	32424712	In the combined-parameters analysis, the combination of the D10 and f90 showed the best diagnostic performance of all the parameters investigated in our study.	('f90', 'Var', (68, 71))	('D10', 'Gene', (60, 63))	('D10', 'Gene', '89832', (60, 63))
60743	30697291	Also, expression of CD105 in low-grade gliomas indicates a potential complementary therapeutic option in lower grade tumors in order to prevent tumor recurrence.	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CD105', 'Gene', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('CD105', 'Gene', '13805', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('gliomas', 'Disease', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('expression', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
60781	30697291	Vascular endothelial growth factor (VEGF), for example, is another potent growth factor mediating tumor angiogenesis and overexpression of VEGFR is associated with poor prognosis in glioblastoma.	('VEGFR', 'Gene', (139, 144))	('VEGF', 'Gene', (36, 40))	('VEGF', 'Gene', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('overexpression', 'Var', (121, 135))	('glioblastoma', 'Disease', (182, 194))	('Vascular endothelial growth factor', 'Gene', '7422', (0, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('VEGFR', 'Gene', '3791', (139, 144))	('VEGF', 'Gene', '7422', (139, 143))	('VEGF', 'Gene', '7422', (36, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('tumor', 'Disease', (98, 103))	('Vascular endothelial growth factor', 'Gene', (0, 34))
60789	30697291	Also, regarding the potential utility of anti CD105 antibody for target therapy, the current study supposed that expression of CD105, especially in low-grade glioma, can serve as a basis for selective treatment option in combination with the current standard care in glioma.	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('glioma', 'Disease', (267, 273))	('CD105', 'Gene', '13805', (127, 132))	('CD105', 'Gene', (127, 132))	('expression', 'Var', (113, 123))	('glioma', 'Disease', (158, 164))	('CD105', 'Gene', (46, 51))	('glioma', 'Disease', 'MESH:D005910', (267, 273))	('CD105', 'Gene', '13805', (46, 51))
60803	30197535	The miRNA-200 family is transcribed from two chromosomal locations: chromosome 1p36, which contains miRNA-200b, miRNA-200a, and miRNA-429, and chromosome 12p13, which contains miRNA-200c and miRNA-141.	('miRNA-141', 'Chemical', '-', (191, 200))	('miRNA-200b', 'Var', (100, 110))	('miRNA-200', 'Gene', (4, 13))	('miRNA-200a', 'Var', (112, 122))
60812	30197535	We also collected glioma samples and normal brain tissue samples to test the levels of miRNA-200b.	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('miRNA-200b', 'Var', (87, 97))	('glioma', 'Disease', (18, 24))	('glioma', 'Disease', 'MESH:D005910', (18, 24))
60839	30197535	In the present study, we identified five studies that investigated the effects of miRNA-200b level on the WHO glioma grade.	('miRNA-200b', 'Var', (82, 92))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('glioma', 'Disease', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))
60841	30197535	However, no correlations were found between the miRNA-200b level and sex, age, tumor size, or extent of surgical resection.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('miRNA-200b', 'Var', (48, 58))	('tumor', 'Disease', (79, 84))
60846	30197535	Additionally, miRNA-200b has been reported to play a suppressive role in the regulation of glioma cell growth by targeting CREB1.	('suppressive', 'NegReg', (53, 64))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('glioma', 'Disease', (91, 97))	('miRNA-200b', 'Var', (14, 24))	('CREB1', 'Gene', '1385', (123, 128))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('regulation of', 'MPA', (77, 90))	('CREB1', 'Gene', (123, 128))
60847	30197535	Liu et al suggested that miRNA-200b has suppressive effects on the proliferation, migration, invasion, and epithelial-mesenchymal transition of glioma cells by targeting Zeb2, a DNA-binding transcriptional repressor that plays a role in the TGF-beta signaling pathways that are essential during early cancer development.	('TGF-beta', 'Gene', '7042', (241, 249))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('Zeb2', 'Gene', (170, 174))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('Zeb2', 'Gene', '9839', (170, 174))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('TGF-beta', 'Gene', (241, 249))	('miRNA-200b', 'Var', (25, 35))	('cancer', 'Disease', (301, 307))	('suppressive', 'NegReg', (40, 51))	('migration', 'CPA', (82, 91))	('glioma', 'Disease', (144, 150))	('epithelial-mesenchymal transition', 'CPA', (107, 140))	('invasion', 'CPA', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('targeting', 'Reg', (160, 169))
60848	30197535	In a luciferase reporter assay, Li et al also found that miRNA-200b inhibits the growth and metastasis of glioma cells by targeting ZEB2.	('metastasis of glioma', 'Disease', (92, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('targeting', 'Reg', (122, 131))	('ZEB2', 'Gene', '9839', (132, 136))	('metastasis of glioma', 'Disease', 'MESH:D009362', (92, 112))	('miRNA-200b', 'Var', (57, 67))	('inhibits', 'NegReg', (68, 76))	('ZEB2', 'Gene', (132, 136))
60850	30197535	As such, whether miRNA-200b can be used as a dependable biomarker for WHO glioma grading remains unclear.	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('glioma', 'Disease', (74, 80))	('miRNA-200b', 'Var', (17, 27))	('glioma', 'Disease', 'MESH:D005910', (74, 80))
60852	30197535	We found that miRNA-200b was negatively correlated with higher WHO grades in patients with gliomas.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('negatively', 'NegReg', (29, 39))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('patients', 'Species', '9606', (77, 85))	('miRNA-200b', 'Var', (14, 24))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
60870	30197535	Fifth, as is known, large quantities of miRNAs have been reported to be involved in gliomagenesis.	('glioma', 'Disease', (84, 90))	('miRNAs', 'Var', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('involved', 'Reg', (72, 80))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
60878	22932667	We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC.	('mutation', 'Var', (67, 75))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('copy number alterations', 'Var', (39, 62))	('tumors', 'Disease', (16, 22))
60881	22932667	FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('mutant', 'Var', (6, 12))	('mutation', 'Var', (137, 145))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('FGFR3', 'Gene', (0, 5))	('more', 'PosReg', (25, 29))	('FGFR3', 'Gene', '2261', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('non-muscle-invasive', 'Disease', (191, 210))	('FGFR3', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', (211, 217))	('FGFR3', 'Gene', '2261', (0, 5))
60882	22932667	In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('muscle-invasive (MI) tumors', 'Disease', 'MESH:D009217', (3, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('regions on 10q', 'Var', (84, 98))	('metastasis', 'CPA', (32, 42))	('gains', 'PosReg', (134, 139))	('losses', 'NegReg', (74, 80))
60883	22932667	Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TP53', 'Gene', '7157', (63, 67))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', (63, 67))	('MI tumors', 'Disease', (80, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('losses', 'NegReg', (95, 101))	('gains', 'PosReg', (156, 161))	('MI tumors', 'Disease', 'MESH:D009369', (80, 89))	('associated', 'Reg', (47, 57))
60893	22932667	Frequent genomic alterations include copy number loss and/or LOH involving chromosome 9 in UC of all stages and grades, FGFR3 and PIK3CA mutation in low-grade Ta tumors and TP53 mutation and inactivation of the retinoblastoma (RB) pathway in MI tumors.	('mutation', 'Var', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('TP53', 'Gene', (173, 177))	('MI tumors', 'Disease', 'MESH:D009369', (242, 251))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('PIK3CA', 'Gene', (130, 136))	('mutation', 'Var', (137, 145))	('RB', 'Gene', '5925', (227, 229))	('retinoblastoma', 'Gene', '5925', (211, 225))	('retinoblastoma', 'Phenotype', 'HP:0009919', (211, 225))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Ta tumors', 'Disease', (159, 168))	('Ta tumors', 'Disease', 'MESH:D009369', (159, 168))	('MI tumors', 'Disease', (242, 251))	('TP53', 'Gene', '7157', (173, 177))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('PIK3CA', 'Gene', '5290', (130, 136))	('FGFR3', 'Gene', (120, 125))	('LOH', 'Var', (61, 64))	('inactivation', 'Reg', (191, 203))	('copy number loss', 'Var', (37, 53))	('RB', 'Phenotype', 'HP:0009919', (227, 229))	('retinoblastoma', 'Gene', (211, 225))	('FGFR3', 'Gene', '2261', (120, 125))
60894	22932667	DNA copy number differences underlie a significant proportion of differences in gene expression detected between cancer subtypes and studies in other tumor types have described prognostic subtypes based on DNA copy number alterations.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('gene expression', 'MPA', (80, 95))	('copy number differences', 'Var', (4, 27))	('tumor', 'Disease', (150, 155))
60895	22932667	In general, fewer copy number alterations are found in low-stage and low-grade tumors, and more complex patterns in MI tumors.	('MI tumors', 'Disease', (116, 125))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('copy number alterations', 'Var', (18, 41))	('fewer', 'NegReg', (12, 17))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('MI tumors', 'Disease', 'MESH:D009369', (116, 125))
60897	22932667	Copy number alterations have been associated with stage, grade, recurrence, carcinoma in situ (CIS), and outcome, but few studies have conducted in-depth correlations of findings with clinico-pathologic information, and where this has been done, mutation status was not assessed, full copy number information was not included in the analysis, or tumors of all stages and grades together were subdivided on the basis of gene expression profiles before copy number analysis.	('associated', 'Reg', (34, 44))	('carcinoma in situ', 'Disease', (76, 93))	('tumors', 'Disease', 'MESH:D009369', (346, 352))	('CIS', 'Phenotype', 'HP:0030075', (95, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (76, 93))	('Copy number alterations', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumors', 'Phenotype', 'HP:0002664', (346, 352))	('carcinoma in situ', 'Disease', 'MESH:D002278', (76, 93))	('tumors', 'Disease', (346, 352))
60899	22932667	Here, we assessed 160 bladder tumors, including the largest panel of T1G3 tumors analyzed to date (n = 49), for both genome-wide copy number alterations and mutation of 8 key genes implicated in UC.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('T1G3', 'Gene', '291', (69, 73))	('bladder tumors', 'Disease', 'MESH:D001749', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutation', 'Var', (157, 165))	('bladder tumors', 'Phenotype', 'HP:0009725', (22, 36))	('bladder tumors', 'Disease', (22, 36))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('T1G3', 'Gene', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
60902	22932667	The sample set consisted of 3 TaG1, 39 TaG2, 16 TaG3, 11 T1G2, 49 T1G3, and 42 >=T2 (all grades) tumors (Supplementary Table S1).	('T1G3', 'Gene', '291', (66, 70))	('TaG2', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('T1', 'Gene', '291', (66, 68))	('TaG1', 'Gene', (30, 34))	('TaG3', 'Var', (48, 52))	('tumors', 'Disease', (97, 103))	('TaG1', 'Gene', '6900', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('T1G3', 'Gene', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('T1', 'Gene', '291', (57, 59))
60906	22932667	High-resolution melting (HRM) curve analysis was used to screen for mutations in FGFR3, PIK3CA, HRAS, KRAS, and NRAS.	('KRAS', 'Gene', (102, 106))	('FGFR3', 'Gene', (81, 86))	('HRAS', 'Gene', (96, 100))	('FGFR3', 'Gene', '2261', (81, 86))	('PIK3CA', 'Gene', '5290', (88, 94))	('NRAS', 'Gene', (112, 116))	('NRAS', 'Gene', '4893', (112, 116))	('mutations', 'Var', (68, 77))	('PIK3CA', 'Gene', (88, 94))	('KRAS', 'Gene', '3845', (102, 106))	('HRAS', 'Gene', '3265', (96, 100))
60908	22932667	AKT1 mutations were detected as described.	('mutations', 'Var', (5, 14))	('AKT1', 'Gene', '207', (0, 4))	('AKT1', 'Gene', (0, 4))
60910	22932667	Potential mutations were confirmed by sequencing tumor and matched blood samples to establish somatic mutation status.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
60912	22932667	Microsatellite markers in the CDKN2A region (D9S1748, D9S1749), TSC1 region (D9S1830, D9S1199, D9S149, D9S66), and the PTEN region (D10S1765, D10S215, D10S541) were used.	('D9S1748', 'Var', (45, 52))	('D9S1749', 'CellLine', 'CVCL:BS91', (54, 61))	('TSC1', 'Gene', '7248', (64, 68))	('D9S1199', 'Var', (86, 93))	('CDKN2A', 'Gene', (30, 36))	('D9S1830', 'Var', (77, 84))	('TSC1', 'Gene', (64, 68))	('CDKN2A', 'Gene', '1029', (30, 36))	('D10S541', 'Var', (151, 158))	('D9S1749', 'Var', (54, 61))	('D10S1765', 'Var', (132, 140))	('D9S66', 'Var', (103, 108))	('D10S215', 'Var', (142, 149))	('D9S149', 'CellLine', 'CVCL:V702', (95, 101))	('D9S149', 'Var', (95, 101))
60916	22932667	Candidate gene expression was assessed by RT-PCR using TaqMan assays (Applied Biosystems) for YWHAZ (Hs01122445_g1), ANKRD46 (Hs01569215_m1), SNX31 (Hs00381645_m1), ZNF706 (Hs00706404_s1), NACAP1 (Hs04233493_sH), GRHL2 (Hs00227745_m1), and GRIN2A (Hs00168219_m1).	('SNX31', 'Gene', (142, 147))	('Hs00706404_s1', 'Var', (173, 186))	('Hs00168219_m1', 'Var', (248, 261))	('SNX31', 'Gene', '169166', (142, 147))	('ZNF706', 'Gene', '51123', (165, 171))	('Hs01569215_m1', 'Var', (126, 139))	('Hs04233493_sH', 'Var', (197, 210))	('Hs01122445_g1', 'Var', (101, 114))	('NACAP1', 'Gene', (189, 195))	('YWHAZ', 'Gene', (94, 99))	('ZNF706', 'Gene', (165, 171))	('GRIN2A', 'Gene', '2903', (240, 246))	('YWHAZ', 'Gene', '7534', (94, 99))	('Hs00381645_m1', 'Var', (149, 162))	('ANKRD46', 'Gene', (117, 124))	('GRHL2', 'Gene', '79977', (213, 218))	('Hs00227745_m1', 'Var', (220, 233))	('ANKRD46', 'Gene', '157567', (117, 124))	('NACAP1', 'Gene', '83955', (189, 195))	('GRHL2', 'Gene', (213, 218))	('GRIN2A', 'Gene', (240, 246))
60917	22932667	Levels of expression were normalized to SDHA (Hs00417200_m1) and measured relative to a pool of uncultured normal human urothelial cells isolated from human ureters obtained at nephrectomy.	('human', 'Species', '9606', (151, 156))	('SDHA', 'Gene', '6389', (40, 44))	('human', 'Species', '9606', (114, 119))	('Hs00417200_m1', 'Var', (46, 59))	('SDHA', 'Gene', (40, 44))
60919	22932667	Deletion of all or part of chromosome 9 is common in UC and critical regions have been identified at 9p21.3 (CDKN2A, CDKN2B), 9q22 (PTCH), 9q33 (DBC1), and 9q34 (TSC1).	('p21', 'Gene', '644914', (102, 105))	('CDKN2A', 'Gene', (109, 115))	('DBC1', 'Gene', '57805', (145, 149))	('PTCH', 'Gene', '5727', (132, 136))	('DBC1', 'Gene', (145, 149))	('CDKN2A', 'Gene', '1029', (109, 115))	('CDKN2B', 'Gene', (117, 123))	('TSC1', 'Gene', '7248', (162, 166))	('PTCH', 'Gene', (132, 136))	('p21', 'Gene', (102, 105))	('TSC1', 'Gene', (162, 166))	('CDKN2B', 'Gene', '1030', (117, 123))	('Deletion', 'Var', (0, 8))
60921	22932667	In 6 samples, deletion did not include CDKN2A.	('deletion', 'Var', (14, 22))	('CDKN2A', 'Gene', '1029', (39, 45))	('CDKN2A', 'Gene', (39, 45))
60922	22932667	Two had deletion of a more distal region containing 15 genes (IFN1alpha cluster, IFNE, KLHL9, miR-31) and 4 had deletion proximal to CDKN2A containing ELAVL2 only.	('IFNE', 'Gene', (81, 85))	('ELAVL2', 'Gene', '1993', (151, 157))	('KLHL9', 'Gene', '55958', (87, 92))	('deletion', 'Var', (112, 120))	('ELAVL2', 'Gene', (151, 157))	('CDKN2A', 'Gene', (133, 139))	('miR-31', 'Gene', (94, 100))	('KLHL9', 'Gene', (87, 92))	('CDKN2A', 'Gene', '1029', (133, 139))	('IFNE', 'Gene', '338376', (81, 85))	('IFN1alpha cluster', 'Gene', (62, 79))	('deletion', 'Var', (8, 16))	('miR-31', 'Gene', '407035', (94, 100))
60923	22932667	Four other HD were detected, each in a single tumor; 9q32-q33 (DBC1, ASTN, and part of TLR2); 9p24.2-p24.3 (DOCK8-SMARCA2), 9p22.2-p22.3 (SNAPC3-BNC2), and 9q21.33 (DAPK1).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BNC2', 'Gene', (145, 149))	('DBC1', 'Gene', (63, 67))	('ASTN', 'Gene', '460', (69, 73))	('DAPK1', 'Gene', (165, 170))	('ASTN', 'Gene', (69, 73))	('p24', 'Gene', '140767', (101, 104))	('HD', 'Disease', 'MESH:D006816', (11, 13))	('p24', 'Gene', (101, 104))	('DOCK8', 'Gene', (108, 113))	('SNAPC3', 'Gene', (138, 144))	('SMARCA2', 'Gene', (114, 121))	('9q32-q33', 'Var', (53, 61))	('SMARCA2', 'Gene', '6595', (114, 121))	('9p22.2-p22.3', 'Var', (124, 136))	('DBC1', 'Gene', '57805', (63, 67))	('9q21.33', 'Var', (156, 163))	('DAPK1', 'Gene', '1612', (165, 170))	('tumor', 'Disease', (46, 51))	('DOCK8', 'Gene', '81704', (108, 113))	('SNAPC3', 'Gene', '6619', (138, 144))	('TLR2', 'Gene', '7097', (87, 91))	('BNC2', 'Gene', '54796', (145, 149))	('TLR2', 'Gene', (87, 91))	('p24', 'Gene', '140767', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('p24', 'Gene', (95, 98))
60924	22932667	9p21.3 deletions were associated with high stage (P = 0.01) and grade (P = 0.02).	('grade', 'CPA', (64, 69))	('deletions', 'Var', (7, 16))	('p21', 'Gene', (1, 4))	('high stage', 'CPA', (38, 48))	('p21', 'Gene', '644914', (1, 4))	('associated', 'Reg', (22, 32))
60925	22932667	In >=T2 tumors, deletions on 6p, 6q, 9p, 9q, 11p, 13q, and 17p, and gains on 1q, 4q, 7p, 7q, 8p, 17q, and 20q were positively associated with copy number loss in the CDKN2A region (Fig.	('CDKN2A', 'Gene', (166, 172))	('copy number loss', 'Var', (142, 158))	('CDKN2A', 'Gene', '1029', (166, 172))	('deletions on 6p', 'Var', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
60926	22932667	In other tumor groups, the same chromosome regions were associated with CDKN2A deletion, but the association did not reach significance.	('CDKN2A', 'Gene', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('deletion', 'Var', (79, 87))	('CDKN2A', 'Gene', '1029', (72, 78))
60927	22932667	TSC1 LOH (9q34) was associated with grade (P = 0.005) but not with stage.	('LOH (9q34', 'Var', (5, 14))	('TSC1', 'Gene', (0, 4))	('TSC1', 'Gene', '7248', (0, 4))
60928	22932667	No associations between TSC1 copy number loss and stage, grade or other copy number alterations were observed.	('TSC1', 'Gene', (24, 28))	('TSC1', 'Gene', '7248', (24, 28))	('copy number loss', 'Var', (29, 45))
60932	22932667	These included 1p34.1 (PTCH2), 2q36.1-q36.3 (CUL3), 11p11.2 (DDB2), 18p11.22-p11.21 (FAM38B), and 19q12 (TSHZ3).	('p11', 'Gene', '6281', (70, 73))	('p11', 'Gene', (54, 57))	('DDB2', 'Gene', '1643', (61, 65))	('1p34.1', 'Var', (15, 21))	('PTCH2', 'Gene', '8643', (23, 28))	('p11', 'Gene', '6281', (77, 80))	('DDB2', 'Gene', (61, 65))	('CUL3', 'Gene', '8452', (45, 49))	('TSHZ3', 'Gene', (105, 110))	('CUL3', 'Gene', (45, 49))	('p11', 'Gene', '6281', (54, 57))	('p11', 'Gene', (70, 73))	('FAM38B', 'Gene', (85, 91))	('PTCH2', 'Gene', (23, 28))	('FAM38B', 'Gene', '63895', (85, 91))	('p11', 'Gene', (77, 80))	('TSHZ3', 'Gene', '57616', (105, 110))
60933	22932667	One hundred and seventy-one high-level amplifications were detected in 54 tumors (3/42 TaG2, 5/16 TaG3, 20/49 T1G3, 1/11 T1G2, 25/42 >=T2; Table 2).	('detected', 'Reg', (59, 67))	('T1G3', 'Gene', '291', (110, 114))	('TaG3', 'Var', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('T1', 'Gene', '291', (110, 112))	('T1', 'Gene', '291', (121, 123))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('TaG2', 'Var', (87, 91))	('T1G3', 'Gene', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
60936	22932667	Concomitant amplification of YWHAZ and a paralogous gene YWHAQ (14-3-3-theta, 2p25), which has been reported in UC, was not observed here, but concomitant gain or amplification was observed for 3p25.3-p25.1 (RAF1) and 8q22.2-q22.3 in 21 tumors.	('p25', 'Gene', (195, 198))	('p25', 'Gene', (79, 82))	('p25', 'Gene', '8851', (79, 82))	('RAF1', 'Gene', (208, 212))	('RAF1', 'Gene', '5894', (208, 212))	('tumors', 'Disease', (237, 243))	('YWHAZ', 'Gene', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('p25', 'Gene', '8851', (201, 204))	('YWHAZ', 'Gene', '7534', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('gain', 'PosReg', (155, 159))	('p25', 'Gene', (201, 204))	('8q22.2-q22.3', 'Var', (218, 230))	('amplification', 'MPA', (163, 176))	('p25', 'Gene', '8851', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('YWHAQ (14-3-3-theta, 2p25', 'Gene', '10971', (57, 82))
60937	22932667	Amplification of both regions was detected in 3 samples (2 T1G3, 1>=T2G3), gain of 8q22.2-q22.3 in 6 samples with 3p25.3-p25.1 amplification (1 TaG2, 1 T1G3, 4 T2G3), gain of 3p25.3-p25.1 in 4 samples with 8q22.2-q22.3 amplification (2 T1G3, 2>=T2G3), and gain of both regions in 8 samples (2 TaG3, 2 T1G3, 4 >=T2G3).	('T1G3', 'Gene', '291', (301, 305))	('gain', 'Var', (167, 171))	('T1G3', 'Gene', (59, 63))	('gain', 'PosReg', (75, 79))	('T1G3', 'Gene', (152, 156))	('T1G3', 'Gene', '291', (236, 240))	('gain', 'PosReg', (256, 260))	('T1G3', 'Gene', '291', (59, 63))	('T1G3', 'Gene', (301, 305))	('p25', 'Gene', '8851', (115, 118))	('p25', 'Gene', (115, 118))	('p25', 'Gene', '8851', (121, 124))	('p25', 'Gene', '8851', (176, 179))	('p25', 'Gene', (121, 124))	('T1G3', 'Gene', '291', (152, 156))	('T1G3', 'Gene', (236, 240))	('p25', 'Gene', (176, 179))	('p25', 'Gene', '8851', (182, 185))	('p25', 'Gene', (182, 185))
60939	22932667	FGFR3 mutation (n = 77) was associated with low stage (P < 0.0001) and grade (P < 0.0001) and TP53 mutation (n = 44) with high stage (P < 0.0001) and grade (P < 0.0001).	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('low stage', 'CPA', (44, 53))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))	('FGFR3', 'Gene', '2261', (0, 5))
60940	22932667	Eleven tumors had both FGFR3 and TP53 mutation.	('FGFR3', 'Gene', (23, 28))	('tumors', 'Disease', (7, 13))	('TP53', 'Gene', '7157', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('FGFR3', 'Gene', '2261', (23, 28))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
60946	22932667	Lower median FGA was found in T1 (P = 0.005), T2 (P = 0.02), and grade 3 (P = 0.00002) tumors with FGFR3 mutation (Fig.	('mutation', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FGA', 'MPA', (13, 16))	('FGFR3', 'Gene', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('T1', 'Gene', '291', (30, 32))	('tumors', 'Disease', (87, 93))	('FGFR3', 'Gene', '2261', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
60948	22932667	This inverse relationship was also found in FGFR3 mutant (n = 22) and wild-type (n = 27) T1G3 tumors (P < 0.0001; Fig.	('T1G3', 'Gene', '291', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FGFR3', 'Gene', (44, 49))	('tumors', 'Disease', (94, 100))	('mutant', 'Var', (50, 56))	('T1G3', 'Gene', (89, 93))	('FGFR3', 'Gene', '2261', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
60951	22932667	A previous study at tiling path resolution identified a core region extending more than 1.8Mb from POLR2K to NCALD and revealed strongest correlation between YWHAZ copy number and expression.	('copy number', 'Var', (164, 175))	('POLR2K', 'Gene', '5440', (99, 105))	('expression', 'MPA', (180, 190))	('NCALD', 'Gene', '83988', (109, 114))	('POLR2K', 'Gene', (99, 105))	('correlation', 'Interaction', (138, 149))	('YWHAZ', 'Gene', '7534', (158, 163))	('YWHAZ', 'Gene', (158, 163))	('NCALD', 'Gene', (109, 114))
60955	22932667	PIK3CA and FGFR3 mutation are commonly found together in UC.	('FGFR3', 'Gene', '2261', (11, 16))	('mutation', 'Var', (17, 25))	('PIK3CA', 'Gene', (0, 6))	('FGFR3', 'Gene', (11, 16))	('PIK3CA', 'Gene', '5290', (0, 6))
60956	22932667	Compatible with this, we found that as for FGFR3 mutation, PIK3CA mutation was associated with a lower FGA in Ta (P = 0.003), T1 (P = 0.02), G2 (P = 0.01), and G3 (P = 0.005) tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('T1', 'Gene', '291', (126, 128))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('FGFR3', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('PIK3CA', 'Gene', (59, 65))	('lower', 'NegReg', (97, 102))	('mutation', 'Var', (66, 74))	('FGA', 'MPA', (103, 106))	('FGFR3', 'Gene', '2261', (43, 48))	('PIK3CA', 'Gene', '5290', (59, 65))
60957	22932667	No relationships between TSC1 or RAS gene mutation, FGA, and/or copy number events were observed.	('TSC1', 'Gene', (25, 29))	('mutation', 'Var', (42, 50))	('RAS gene', 'Gene', (33, 41))	('TSC1', 'Gene', '7248', (25, 29))
60958	22932667	Higher FGA was associated with TP53 mutation in T1, T2, and grade 3 tumors (P = 0.006, 0.02, and 0.0003, respectively; Supplementary Fig.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', (68, 74))	('T1', 'Gene', '291', (48, 50))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutation', 'Var', (36, 44))
60959	22932667	However, some TP53 mutant tumors had low FGA.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('FGA', 'MPA', (41, 44))	('mutant', 'Var', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
60960	22932667	A comparison of specific copy number alterations in TP53 mutant (n = 24) and wild-type (n = 18) >=T2 samples revealed significant differences (Fig.	('mutant', 'Var', (57, 63))	('differences', 'Reg', (130, 141))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
60961	22932667	Deletions on 2q, 4q, 11p, 10q, 13q, 14q, 16p, 16q, and 19p and gains on 1p, 8q, 10q, and 12q were positively associated with TP53 mutation.	('associated', 'Reg', (109, 119))	('TP53', 'Gene', '7157', (125, 129))	('mutation', 'Var', (130, 138))	('TP53', 'Gene', (125, 129))	('Deletions on', 'Var', (0, 12))
60966	22932667	USP7 expression examined by immunohistochemistry (IHC) did not correlate with 16p loss in the TP53 mutant subgroup.	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('USP7', 'Gene', (0, 4))	('loss', 'NegReg', (82, 86))	('mutant', 'Var', (99, 105))	('USP7', 'Gene', '7874', (0, 4))
60967	22932667	Mutation scanning of 27 >=T2 tumors including 9 with TP53 mutation and loss of 16p13.2-p13.3 revealed one missense mutation (p. R181S).	('R181S', 'Var', (128, 133))	('R181S', 'SUBSTITUTION', 'None', (128, 133))	('p13', 'Gene', '440926', (81, 84))	('p13', 'Gene', (87, 90))	('p13', 'Gene', '440926', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutation', 'Var', (58, 66))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('p13', 'Gene', (81, 84))	('TP53', 'Gene', '7157', (53, 57))	('tumors', 'Disease', (29, 35))	('TP53', 'Gene', (53, 57))
60972	22932667	In >=T2 tumors, deletions on 10q, 16q, and 22q, and gains on 10p, 11q, 12p, 19p, and 19q were independently associated with metastasis (Fig.	('gains', 'PosReg', (52, 57))	('metastasis', 'CPA', (124, 134))	('deletions on 10q', 'Var', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('associated with', 'Reg', (108, 123))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
60973	22932667	PTEN is located on 10q23.3 and its inactivation is common in advanced bladder cancer and associated with poor outcome.	('associated', 'Reg', (89, 99))	('common', 'Reg', (51, 57))	('inactivation', 'Var', (35, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PTEN', 'Gene', (0, 4))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))
60974	22932667	Eleven of 14 tumors with copy number loss in the PTEN region were in the metastatic group.	('14 tumors', 'Disease', 'MESH:C567448', (10, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('metastatic', 'CPA', (73, 83))	('14 tumors', 'Disease', (10, 19))	('copy number loss', 'Var', (25, 41))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PTEN', 'Gene', (49, 53))
60975	22932667	S3) showed that time to metastasis was shorter for tumors with PTEN deletion (P = 0.00003; log-rank test).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('time to metastasis', 'CPA', (16, 34))	('deletion', 'Var', (68, 76))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('shorter', 'NegReg', (39, 46))	('PTEN', 'Gene', (63, 67))
60976	22932667	As TP53 mutation and loss of RB1 are frequent events in muscle invasive UC, we conducted similar analyses.	('loss', 'Var', (21, 25))	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('RB1', 'Gene', (29, 32))	('muscle invasive UC', 'Disease', (56, 74))	('mutation', 'Var', (8, 16))	('RB', 'Phenotype', 'HP:0009919', (29, 31))	('RB1', 'Gene', '5925', (29, 32))
60977	22932667	TP53 mutation had no effect either alone or in combination with PTEN copy number loss.	('loss', 'NegReg', (81, 85))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
60978	22932667	RB1 copy number loss had a nonsignificant (P = 0.053; log-rank test) trend for association with shorter time to metastasis when assessed alone, and significant association (P = 0.0002; log-rank test) in combination with PTEN loss (Supplementary Fig.	('shorter', 'NegReg', (96, 103))	('RB1', 'Gene', '5925', (0, 3))	('RB1', 'Gene', (0, 3))	('RB', 'Phenotype', 'HP:0009919', (0, 2))	('copy number loss', 'Var', (4, 20))
60983	22932667	FGFR3 mutation was frequent and evenly distributed.	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('FGFR3', 'Gene', '2261', (0, 5))
60987	22932667	Gain of 8q was a feature of this cluster and was mutually exclusive with FGFR3 mutation.	('FGFR3', 'Gene', (73, 78))	('Gain', 'PosReg', (0, 4))	('FGFR3', 'Gene', '2261', (73, 78))	('mutation', 'Var', (79, 87))
60991	22932667	Cluster 3 samples were all FGA group D and displayed losses of 3p, 5q, and 13q (including the RB1 region), and gains of 4p, 4q, and 5p and frequent TP53 mutation (83.3%).	('gains', 'PosReg', (111, 116))	('RB1', 'Gene', (94, 97))	('losses', 'NegReg', (53, 59))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('RB1', 'Gene', '5925', (94, 97))	('RB', 'Phenotype', 'HP:0009919', (94, 96))	('mutation', 'Var', (153, 161))
60998	22932667	As in Ta tumors, Cluster 1 samples had frequent FGFR3 mutation (with increased FGFR3 protein expression) and low median FGA (12%).	('mutation', 'Var', (54, 62))	('FGFR3', 'Gene', '2261', (79, 84))	('Ta tumors', 'Disease', 'MESH:D009369', (6, 15))	('increased', 'PosReg', (69, 78))	('FGFR3', 'Gene', '2261', (48, 53))	('FGA', 'MPA', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('FGFR3', 'Gene', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('FGFR3', 'Gene', (48, 53))	('Ta tumors', 'Disease', (6, 15))
60999	22932667	Clusters 3 and 4 resembled >=T2 Cluster 3, with frequent TP53 mutation, gain of 8q and high median FGA (Cluster 3, 25%; Cluster 4, 69%).	('FGA', 'MPA', (99, 102))	('gain', 'PosReg', (72, 76))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
61000	22932667	Three tumors in Cluster 3 and 2 in Cluster 4 showed p53 overexpression, associated with TP53 mutation.	('p53', 'Protein', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (93, 101))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('TP53', 'Gene', '7157', (88, 92))	('overexpression', 'PosReg', (56, 70))	('TP53', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
61007	22932667	One or more high-level amplifications were detected in 19%, 54%, 71%, and 100% of tumors from Clusters 1, 2, 3, and 4, respectively, and were detected in 5 of 8 tumors that progressed or metastasized.	('metastasized', 'CPA', (187, 199))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('amplifications', 'Var', (23, 37))
61011	22932667	Three also had loss of 10q and the other had TSC1 mutation.	('loss of 10q', 'Var', (15, 26))	('TSC1', 'Gene', '7248', (45, 49))	('mutation', 'Var', (50, 58))	('TSC1', 'Gene', (45, 49))
61012	22932667	In addition, 3 were TP53 mutant and 1 had MDM2 amplification.	('mutant', 'Var', (25, 31))	('TP53', 'Gene', (20, 24))	('MDM2', 'Gene', '4193', (42, 46))	('MDM2', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (20, 24))
61013	22932667	The Cluster 1 sample that metastasized had HD of PTEN, MDM2 amplification and loss of RB1.	('RB1', 'Gene', (86, 89))	('amplification', 'Var', (60, 73))	('HD', 'Disease', 'MESH:D006816', (43, 45))	('RB1', 'Gene', '5925', (86, 89))	('loss', 'NegReg', (78, 82))	('MDM2', 'Gene', '4193', (55, 59))	('RB', 'Phenotype', 'HP:0009919', (86, 88))	('MDM2', 'Gene', (55, 59))	('PTEN', 'Gene', (49, 53))
61015	22932667	Here, we confirmed the distinction between low-grade Ta tumors, with low complexity of chromosomal changes, frequent FGFR3 mutation and infrequent TP53 mutation, and MI tumors, with more complex chromosomal changes, infrequent FGFR3 mutation, and frequent TP53 mutation.	('FGFR3', 'Gene', '2261', (227, 232))	('TP53', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('FGFR3', 'Gene', '2261', (117, 122))	('mutation', 'Var', (123, 131))	('Ta tumors', 'Disease', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('FGFR3', 'Gene', (117, 122))	('MI tumors', 'Disease', (166, 175))	('TP53', 'Gene', '7157', (256, 260))	('FGFR3', 'Gene', (227, 232))	('Ta tumors', 'Disease', 'MESH:D009369', (53, 62))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('MI tumors', 'Disease', 'MESH:D009369', (166, 175))	('TP53', 'Gene', '7157', (147, 151))	('TP53', 'Gene', (256, 260))
61017	22932667	These were characterized by point mutations, including 74% in FGFR3.	('FGFR3', 'Gene', (62, 67))	('point mutations', 'Var', (28, 43))	('FGFR3', 'Gene', '2261', (62, 67))
61024	22932667	Previously a large series of T1G3 tumors was assessed for FGFR3 and TP53 mutation.	('tumors', 'Disease', (34, 40))	('TP53', 'Gene', (68, 72))	('T1G3', 'Gene', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('FGFR3', 'Gene', '2261', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('FGFR3', 'Gene', (58, 63))	('T1G3', 'Gene', '291', (29, 33))	('TP53', 'Gene', '7157', (68, 72))	('mutation', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
61026	22932667	We confirmed this independent distribution, although here the overall frequency of FGFR3 mutation was higher and TP53 frequency lower.	('FGFR3', 'Gene', '2261', (83, 88))	('mutation', 'Var', (89, 97))	('higher', 'PosReg', (102, 108))	('FGFR3', 'Gene', (83, 88))	('TP53', 'Gene', '7157', (113, 117))	('lower', 'NegReg', (128, 133))	('TP53', 'Gene', (113, 117))
61029	22932667	Cluster 1 had frequent FGFR3 mutation (69.2%), with few alterations apart from losses of 17p and chromosome 9, and gains of 1q, 7, and 15.	('FGFR3', 'Gene', (23, 28))	('mutation', 'Var', (29, 37))	('gains', 'PosReg', (115, 120))	('FGFR3', 'Gene', '2261', (23, 28))	('losses', 'NegReg', (79, 85))
61033	22932667	Similarly, an analysis of lung cancer showed that copy number loss was associated with reduced survival.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('copy number loss', 'Var', (50, 66))	('reduced', 'NegReg', (87, 94))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('survival', 'MPA', (95, 103))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
61034	22932667	Such profiles may reflect inactivation of multiple tumor suppressor genes.	('inactivation', 'Var', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('reflect', 'Reg', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
61046	22932667	HD of ELAVL2 has been reported in other cancers and mutation in glioblastoma.	('glioblastoma', 'Disease', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('ELAVL2', 'Gene', '1993', (6, 12))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('cancers', 'Disease', (40, 47))	('ELAVL2', 'Gene', (6, 12))	('mutation', 'Var', (52, 60))	('HD', 'Disease', 'MESH:D006816', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('reported', 'Reg', (22, 30))
61048	22932667	HD at 9p24 and 9p23 were detected previously in UC.	('HD', 'Disease', 'MESH:D006816', (0, 2))	('p24', 'Gene', (7, 10))	('p24', 'Gene', '140767', (7, 10))	('9p23', 'Var', (15, 19))
61050	22932667	Indeed, exome sequencing of 9 invasive UC, detected mutations in several genes on chromosome 9 including DOCK8, which showed HD here.	('mutations', 'Var', (52, 61))	('HD', 'Disease', 'MESH:D006816', (125, 127))	('DOCK8', 'Gene', (105, 110))	('detected', 'Reg', (43, 51))	('invasive UC', 'Disease', (30, 41))	('DOCK8', 'Gene', '81704', (105, 110))
61053	22932667	Amplification of 9p21.3-pter in seminomas is associated with overexpression of DNMT1.	('Amplification', 'Var', (0, 13))	('p21', 'Gene', (18, 21))	('overexpression', 'MPA', (61, 75))	('associated', 'Reg', (45, 55))	('seminomas', 'Disease', 'MESH:D018239', (32, 41))	('p21', 'Gene', '644914', (18, 21))	('DNMT1', 'Gene', (79, 84))	('seminomas', 'Disease', (32, 41))	('DNMT1', 'Gene', '1786', (79, 84))
61055	22932667	An inverse relationship between FGFR3 mutation status and gains of chromosome 6, 8q, and 11q in Ta tumors was reported and gains of 8q11.23-q24.21 in FGFR3 wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('FGFR3', 'Gene', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('Ta tumors', 'Disease', 'MESH:D009369', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('FGFR3', 'Gene', (150, 155))	('Ta tumors', 'Disease', (96, 105))	('FGFR3', 'Gene', '2261', (32, 37))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('gains', 'PosReg', (58, 63))	('FGFR3', 'Gene', '2261', (150, 155))	('tumors', 'Disease', (99, 105))
61056	22932667	Here, FGFR3 mutation and overrepresentation of 8q were mutually exclusive in all non-MI tumors and in T1G3 tumors.	('FGFR3', 'Gene', '2261', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('FGFR3', 'Gene', (6, 11))	('T1G3', 'Gene', (102, 106))	('non-MI tumors', 'Disease', 'MESH:D009369', (81, 94))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('T1G3', 'Gene', '291', (102, 106))	('tumors', 'Disease', (88, 94))	('mutation', 'Var', (12, 20))	('non-MI tumors', 'Disease', (81, 94))
61057	22932667	Several tumors had high-level amplification at 8q22.2-q22.3, which has been associated with more aggressive UC phenotype (e.g.,).	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('associated with', 'Reg', (76, 91))	('amplification', 'Var', (30, 43))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
61059	22932667	Compatible with this, amplification and overexpression contributes to chemotherapy resistance and recurrence of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('recurrence', 'CPA', (98, 108))	('breast cancer', 'Disease', (112, 125))	('overexpression', 'PosReg', (40, 54))	('chemotherapy resistance', 'CPA', (70, 93))	('amplification', 'Var', (22, 35))	('contributes', 'Reg', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
61062	22932667	We found a subgroup of >=T2 tumors with TP53 mutation and concomitant 16p13.2-p13.3 deletion.	('p13', 'Gene', '440926', (78, 81))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('p13', 'Gene', (72, 75))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))	('p13', 'Gene', (78, 81))	('p13', 'Gene', '440926', (72, 75))
61065	22932667	However, it should be noted that here, copy number losses of 16p that included TSC2 were not mutually exclusive with alterations involving TSC1.	('TSC1', 'Gene', '7248', (139, 143))	('TSC2', 'Gene', '7249', (79, 83))	('copy number losses', 'Var', (39, 57))	('TSC1', 'Gene', (139, 143))	('TSC2', 'Gene', (79, 83))
61068	22932667	We found no association between LKB1 deletion and metastasis and when both PTEN deletion and TP53 mutation were examined, PTEN copy number loss alone best predicted metastasis.	('metastasis', 'CPA', (165, 175))	('deletion', 'Var', (37, 45))	('TP53', 'Gene', '7157', (93, 97))	('predicted', 'Reg', (155, 164))	('TP53', 'Gene', (93, 97))	('LKB1', 'Gene', (32, 36))	('PTEN', 'Gene', (75, 79))	('metastasis', 'CPA', (50, 60))	('LKB1', 'Gene', '6794', (32, 36))
61138	26351233	As for the supracollicular route, an incision deeper than the cerebral aqueduct will damage the nuclei of the third and fourth cranial nerves and the medial longitudinal fasciculus.	('incision', 'Var', (37, 45))	('damage', 'Reg', (85, 91))	('longitudinal fasciculus', 'Disease', 'MESH:D017887', (157, 180))	('longitudinal fasciculus', 'Disease', (157, 180))	('cranial nerve', 'Phenotype', 'HP:0001291', (127, 140))
61184	26351233	In the intraoperative period, severe vegetative alterations may occur, such as hypertension and tachycardia in the case of medullary lesions on the right side and bradycardia for medullary lesions on the left side.	('bradycardia', 'Phenotype', 'HP:0001662', (163, 174))	('hypertension', 'Disease', 'MESH:D006973', (79, 91))	('lesions', 'Var', (133, 140))	('tachycardia', 'Phenotype', 'HP:0001649', (96, 107))	('bradycardia', 'Disease', (163, 174))	('tachycardia', 'Disease', 'MESH:D013610', (96, 107))	('tachycardia', 'Disease', (96, 107))	('vegetative alterations', 'Phenotype', 'HP:0031358', (37, 59))	('hypertension', 'Disease', (79, 91))	('hypertension', 'Phenotype', 'HP:0000822', (79, 91))	('bradycardia', 'Disease', 'MESH:D001919', (163, 174))
61300	22509804	Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors.	('PDGF', 'Gene', (140, 144))	('aberrant activity', 'Var', (115, 132))	('PDGF', 'Gene', '5154;18590;5155;18591;24628;56034;80310', (140, 144))	('associated', 'Reg', (99, 109))
61327	22509804	Once activated, intracellular mediators dock to phosphotyrosine residues in the receptor, which leads to downstream activation of intracellular signaling pathways.	('activation', 'PosReg', (116, 126))	('phosphotyrosine residues', 'Var', (48, 72))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (48, 63))	('intracellular signaling pathways', 'Pathway', (130, 162))
61368	22509804	Only 16% of glioblastomas showed PDGFRA amplification, which suggested that other mechanisms were responsible for PDGFRA overexpression in the majority of tumors.	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('glioblastomas', 'Disease', 'MESH:D005909', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('glioblastomas', 'Disease', (12, 25))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('PDGFRA', 'Gene', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('amplification', 'Var', (40, 53))	('glioblastomas', 'Phenotype', 'HP:0012174', (12, 25))
61386	22509804	A large number of gain- and loss-of-function mutations in Pdgf and Pdgfr genes have been created in mice.	('mutations', 'Var', (45, 54))	('mice', 'Species', '10090', (100, 104))	('gain-', 'PosReg', (18, 23))	('loss-of-function', 'NegReg', (28, 44))	('Pdgfr', 'Gene', '18596', (67, 72))	('Pdgf', 'Gene', (58, 62))	('Pdgfr', 'Gene', (67, 72))
61393	22509804	However, excessive or aberrant expression of PDGFs can lead to pathological responses such as atherosclerosis, fibrosis, and tumorigenesis.	('aberrant', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('atherosclerosis', 'Disease', (94, 109))	('PDGF', 'Gene', (45, 49))	('PDGF', 'Gene', '5154;18590;5155;18591;24628;56034;80310', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('expression', 'MPA', (31, 41))	('fibrosis', 'Disease', 'MESH:D005355', (111, 119))	('fibrosis', 'Disease', (111, 119))	('atherosclerosis', 'Disease', 'MESH:D050197', (94, 109))	('atherosclerosis', 'Phenotype', 'HP:0002621', (94, 109))	('lead to', 'Reg', (55, 62))
61410	22509804	A frequent hallmark of malignant gliomas is activation of RTK signaling pathways, most commonly caused by EGFR mutation/amplification or PDGFR amplification/overexpression.	('caused', 'Reg', (96, 102))	('mutation/amplification', 'Var', (111, 133))	('amplification/overexpression', 'Var', (143, 171))	('activation', 'PosReg', (44, 54))	('RTK signaling pathways', 'Pathway', (58, 80))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('amplification/overexpression', 'PosReg', (143, 171))	('PDGFR', 'Gene', (137, 142))	('EGFR', 'Gene', '1956', (106, 110))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('malignant gliomas', 'Disease', (23, 40))	('malignant gliomas', 'Disease', 'MESH:D005910', (23, 40))	('PDGFR', 'Gene', '5159', (137, 142))	('EGFR', 'Gene', (106, 110))
61412	22509804	Amplification of EGFR is found in about 43% of primary GBs and is associated with EGFR overexpression.	('EGFR', 'Gene', (82, 86))	('Amplification', 'Var', (0, 13))	('primary GBs', 'Disease', (47, 58))	('associated', 'Reg', (66, 76))	('GB', 'Phenotype', 'HP:0012174', (55, 57))	('overexpression', 'PosReg', (87, 101))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', (17, 21))
61414	22509804	Furthermore, 70%-90% of all GBs with EGFR overexpression have rearrangements of the gene.	('GB', 'Phenotype', 'HP:0012174', (28, 30))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('rearrangements', 'Var', (62, 76))
61415	22509804	The most widespread mutated variant of EGFR is EGFRvIII, which contains a 267-bp deletion of exons 2-7 in the extracellular domain, resulting in ligand-independent activation of the receptor.	('deletion', 'Var', (81, 89))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('ligand-independent activation', 'MPA', (145, 174))	('EGFR', 'Gene', (47, 51))
61421	22509804	Alterations in other RTK genes have been reported, including ERBB2/HER2 mutations and MET amplifications in 8 and 4% of GBs analyzed, respectively.	('mutations', 'Var', (72, 81))	('ERBB2', 'Gene', (61, 66))	('ERBB2', 'Gene', '2064', (61, 66))	('MET amplifications', 'Var', (86, 104))	('HER2', 'Gene', (67, 71))	('RTK genes', 'Gene', (21, 30))	('HER2', 'Gene', '2064', (67, 71))	('rat', 'Species', '10116', (4, 7))	('GB', 'Phenotype', 'HP:0012174', (120, 122))
61424	22509804	Mutations of NF1 have been linked to the hereditary condition neurofibromatosis type-1, where patients are predisposed to glioma development.	('linked', 'Reg', (27, 33))	('patients', 'Species', '9606', (94, 102))	('hereditary condition neurofibromatosis', 'Disease', 'MESH:C537392', (41, 79))	('NF1', 'Gene', (13, 16))	('glioma', 'Disease', (122, 128))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (62, 79))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (13, 16))	('hereditary condition neurofibromatosis', 'Disease', (41, 79))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
61425	22509804	NF1 was recently found to be mutated in 18% of glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (47, 60))	('glioblastomas', 'Disease', 'MESH:D005909', (47, 60))	('glioblastomas', 'Disease', (47, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('mutated', 'Var', (29, 36))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
61426	22509804	Activation of PI3K/AKT signaling can be achieved by loss of the tumor suppressor gene PTEN or by mutations in PIK3CA.	('mutations', 'Var', (97, 106))	('loss', 'NegReg', (52, 56))	('tumor', 'Disease', (64, 69))	('PTEN', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (86, 90))	('PIK3CA', 'Gene', '5290', (110, 116))	('AKT', 'Gene', '207', (19, 22))	('Activation', 'PosReg', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('AKT', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PIK3CA', 'Gene', (110, 116))
61428	22509804	PTEN loss is rare in low-grade gliomas, but mutations and deletions are found in 50% of high-grade gliomas and are associated with poor patient survival.	('patient', 'Species', '9606', (136, 143))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('gliomas', 'Disease', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('deletions', 'Var', (58, 67))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('mutations', 'Var', (44, 53))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('PTEN', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('PTEN', 'Gene', '5728', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
61432	22509804	It has been described that somatic TP53 mutations are more common in low-grade astrocytomas and secondary GBs than in primary GBs and that the spectrum of mutations is different.	('common', 'Reg', (59, 65))	('GB', 'Phenotype', 'HP:0012174', (106, 108))	('secondary GBs', 'Disease', (96, 109))	('astrocytomas', 'Disease', 'MESH:D001254', (79, 91))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('mutations', 'Var', (40, 49))	('astrocytomas', 'Disease', (79, 91))	('GB', 'Phenotype', 'HP:0012174', (126, 128))
61433	22509804	However, recent studies have confirmed that TP53 mutations are also prevalent in primary GBs.	('mutations', 'Var', (49, 58))	('primary GBs', 'Disease', (81, 92))	('TP53', 'Gene', '7157', (44, 48))	('prevalent', 'Reg', (68, 77))	('GB', 'Phenotype', 'HP:0012174', (89, 91))	('TP53', 'Gene', (44, 48))
61434	22509804	In addition, chromosome 17p is an early and frequent target for LOH in both low-grade and high-grade gliomas.	('LOH', 'Var', (64, 67))	('low-grade', 'Disease', (76, 85))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
61437	22509804	Genetic alterations involving this pathway are found in 78% of glioblastomas.	('Genetic alterations', 'Var', (0, 19))	('rat', 'Species', '10116', (12, 15))	('glioblastomas', 'Phenotype', 'HP:0012174', (63, 76))	('found', 'Reg', (47, 52))	('glioblastomas', 'Disease', 'MESH:D005909', (63, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('glioblastomas', 'Disease', (63, 76))
61439	22509804	Among these subtypes, the proneural subtype is characterized by PDGFRA amplification and loss or mutation of TP53, CDKN2A, and PTEN.	('CDKN2A', 'Gene', (115, 121))	('CDKN2A', 'Gene', '1029', (115, 121))	('amplification', 'Var', (71, 84))	('TP53', 'Gene', '7157', (109, 113))	('TP53', 'Gene', (109, 113))	('mutation', 'Var', (97, 105))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', '5728', (127, 131))	('proneural subtype', 'Disease', (26, 43))	('PDGFRA', 'Gene', (64, 70))	('loss', 'NegReg', (89, 93))
61440	22509804	Mutation of the isocitrate dehydrogenase 1 gene (IDH-1) (see below) and activation of PI3K and PDGFR-alpha pathways are also frequent characteristics of this subtype.	('activation', 'PosReg', (72, 82))	('rat', 'Species', '10116', (22, 25))	('Mutation', 'Var', (0, 8))	('IDH-1', 'Gene', (49, 54))	('IDH-1', 'Gene', '3417', (49, 54))	('PDGFR-alpha pathways', 'Pathway', (95, 115))
61445	22509804	In patients with secondary GB, mutation of IDH-1 is linked to a median survival of 31 months compared to 15 months for the group of patients with wild-type (WT) IDH-1.	('IDH-1', 'Gene', (161, 166))	('GB', 'Phenotype', 'HP:0012174', (27, 29))	('mutation', 'Var', (31, 39))	('patients', 'Species', '9606', (3, 11))	('IDH-1', 'Gene', '3417', (43, 48))	('IDH-1', 'Gene', (43, 48))	('IDH-1', 'Gene', '3417', (161, 166))	('patients', 'Species', '9606', (132, 140))
61446	22509804	Importantly, these mutations also occur together with TP53 mutations in lower-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (19, 28))	('TP53', 'Gene', '7157', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', (54, 58))
61473	22509804	Since the adult brain has only a limited population of proliferating cells that are able to accumulate the several mutations required for transformation into a cancer cell, the adult NSCs/progenitor cells have been suggested as candidate sources for brain CSCs (Figure 2).	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (160, 166))	('NSC', 'Disease', 'OMIM:617394', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rat', 'Species', '10116', (62, 65))	('NSC', 'Disease', (183, 186))
61487	22509804	Tumor progression can be enhanced in the PDGF-induced glioma models by combination of another genetic aberration such as loss of Ink4a/Arf, Trp53, or Pten.	('Ink4a/Arf', 'Gene', '1029', (129, 138))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PDGF', 'Gene', (41, 45))	('enhanced', 'PosReg', (25, 33))	('PDGF', 'Gene', '5154;18590;5155;18591;24628;56034;80310', (41, 45))	('loss', 'Var', (121, 125))	('Pten', 'Gene', '5728', (150, 154))	('Pten', 'Gene', (150, 154))	('glioma', 'Disease', (54, 60))	('rat', 'Species', '10116', (106, 109))	('Trp53', 'Gene', (140, 145))	('Tumor progression', 'CPA', (0, 17))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('Ink4a/Arf', 'Gene', (129, 138))
61488	22509804	However, a disruption of the homology-directed DNA repair mechanism, by introduction of RAD51, decreases PDGF-B-induced tumor incidence and progression.	('introduction', 'Var', (72, 84))	('PDGF-B-induced', 'Gene', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('RAD51', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('RAD51', 'Gene', '5888', (88, 93))	('decreases', 'NegReg', (95, 104))	('tumor', 'Disease', (120, 125))	('disruption', 'NegReg', (11, 21))
61503	22509804	The majority of glioma cells proper, but not the tumor vasculature, expressed the transgene, and together this indicated the possibility of both autocrine and paracrine stimulatory loops similar to those in human tumors.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('glioma', 'Disease', (16, 22))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('human', 'Species', '9606', (207, 212))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('transgene', 'Var', (82, 91))	('indicated', 'Reg', (111, 120))
61524	22509804	However, the fact that concurrent loss of p53, a known regulator of stem cell self-renewal resulted in heavy amplification of a more undifferentiated Nestin+/mostly Gfap- neural cell type, forming GB-like tumors, suggested a difference in the capacity of progenitors to respond to the PDGF proteins.	('p53', 'Gene', (42, 45))	('amplification', 'MPA', (109, 122))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('Gfap', 'Gene', '2670', (165, 169))	('loss', 'Var', (34, 38))	('Gfap', 'Gene', (165, 169))	('PDGF', 'Gene', (285, 289))	('PDGF', 'Gene', '5154;18590;5155;18591;24628;56034;80310', (285, 289))	('Nestin', 'Gene', '10763', (150, 156))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('Nestin', 'Gene', (150, 156))	('GB', 'Phenotype', 'HP:0012174', (197, 199))
61526	22509804	We speculate that in the human situation, the early and almost ubiquitous TP53 mutations/deletions on chromosome 17p observed in low-grade astrocytic glioma may similarly allow for the emergence of stem cell features during glioma progression.	('stem cell features', 'CPA', (198, 216))	('allow', 'Reg', (171, 176))	('astrocytic glioma', 'Disease', 'MESH:D001254', (139, 156))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('human', 'Species', '9606', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('astrocytic glioma', 'Disease', (139, 156))	('TP53', 'Gene', '7157', (74, 78))	('glioma', 'Disease', (150, 156))	('mutations/deletions', 'Var', (79, 98))	('TP53', 'Gene', (74, 78))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Disease', (224, 230))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
61538	28612247	Moreover, genetic/epigenetic evidence is taken into account for the determination of prognosis and in the therapeutic decision-making, including signaling pathways and molecular markers such as mitotic marker MIB-1, isocitrate dehydrogenase 1 (IDH1) mutations, 1p/19q loss for oligodendrogliomas, epigenetic silencing of methylguaninmethyltransferase (MGMT) gene promoter, epidermal growth factor receptor (EGFR) amplification, and microRNAs.	('loss', 'NegReg', (268, 272))	('IDH1', 'Gene', '3417', (244, 248))	('epidermal growth factor receptor', 'Gene', (373, 405))	('MIB-1', 'Gene', (209, 214))	('MIB-1', 'Gene', '57534', (209, 214))	('oligodendrogliomas', 'Disease', (277, 295))	('EGFR', 'Gene', '1956', (407, 411))	('epigenetic silencing', 'Var', (297, 317))	('mutations', 'Var', (250, 259))	('isocitrate dehydrogenase 1', 'Gene', (216, 242))	('IDH1', 'Gene', (244, 248))	('epidermal growth factor receptor', 'Gene', '1956', (373, 405))	('MGMT) gene', 'Gene', (352, 362))	('EGFR', 'Gene', (407, 411))	('isocitrate dehydrogenase 1', 'Gene', '3417', (216, 242))	('gliomas', 'Phenotype', 'HP:0009733', (288, 295))	('glioma', 'Phenotype', 'HP:0009733', (288, 294))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (277, 295))
61546	28612247	18F-FDG enters cells by active transport through nucleoside transporters (salvage thymidine pathway), as well as by passive diffusion.	('nucleoside transporters', 'MPA', (49, 72))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('nucleoside', 'Chemical', 'MESH:D009705', (49, 59))	('thymidine', 'Chemical', 'MESH:D013936', (82, 91))	('18F-FDG', 'Var', (0, 7))	('active transport', 'MPA', (24, 40))
61567	28612247	In accordance with 11C-methionine (11C-MET) imaging, the use of 18F-FLT leads to larger volume when delineating the tumor, compared to Gd-enhanced MRI method.	('11C-methionine', 'Chemical', '-', (19, 33))	('volume', 'MPA', (88, 94))	('Gd', 'Chemical', 'MESH:D005682', (135, 137))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('18F-FLT', 'Var', (64, 71))	('larger', 'PosReg', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('11C-MET', 'Chemical', '-', (35, 42))	('tumor', 'Disease', (116, 121))	('FLT', 'Chemical', '-', (68, 71))
61660	23299463	Accumulation of alpha-[11C]methyl-l-tryptophan (AMT) on positron emission tomography(PET) has been shown in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('Accumulation', 'PosReg', (0, 12))	('AMT', 'Chemical', 'MESH:C020774', (48, 51))	('alpha-[11C]methyl-l-tryptophan', 'Chemical', 'MESH:C020774', (16, 46))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('alpha-[11C', 'Var', (16, 26))
61765	23299463	Increased tryptophan transport may occur due to overexpression of the LAT1 amino acid transporter; high LAT1 expression was in fact reported to correlate with high methionine uptake on PET in newly-diagnosed gliomas.	('Increased tryptophan', 'Phenotype', 'HP:0500134', (0, 20))	('LAT1', 'Gene', (104, 108))	('high', 'PosReg', (159, 163))	('LAT1', 'Gene', '8140', (70, 74))	('expression', 'MPA', (109, 119))	('tryptophan transport', 'MPA', (10, 30))	('LAT1', 'Gene', (70, 74))	('tryptophan', 'Chemical', 'MESH:D014364', (10, 20))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('methionine', 'Chemical', 'MESH:D008715', (164, 174))	('high', 'Var', (99, 103))	('gliomas', 'Disease', (208, 215))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('high methionine', 'Phenotype', 'HP:0003235', (159, 174))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('methionine uptake on PET', 'MPA', (164, 188))	('LAT1', 'Gene', '8140', (104, 108))
61801	30728054	According to the TCGA database, we identified SNHG1, miRNA-154-5p and miR-376b-3p whose expression were significantly changed in the glioma samples.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('changed', 'Reg', (118, 125))	('miR-376b', 'Gene', (70, 78))	('SNHG1', 'Gene', (46, 51))	('glioma', 'Disease', (133, 139))	('miRNA-154-5p', 'Var', (53, 65))	('expression', 'MPA', (88, 98))	('miR-376b', 'Gene', '574435', (70, 78))
61802	30728054	Furthermore, we investigated SNHG1, miRNA-154-5p and miR-376b-3p expression in clinical samples and glioma cell lines using qRT-PCR analysis and the correlation between them using RNA immunoprecipitation and dual-luciferase reporter.	('glioma', 'Disease', (100, 106))	('clinical samples', 'Species', '191496', (79, 95))	('miR-376b', 'Gene', '574435', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('miRNA-154-5p', 'Var', (36, 48))	('SNHG1', 'Gene', (29, 34))	('miR-376b', 'Gene', (53, 61))
61806	30728054	Collectively, this study demonstrates that the SNHG1- microRNA-154-5p/miR-376b-3p- FOXP2- KDM5B feedback loop plays a pivotal role in regulating the malignant behavior of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('KDM5B', 'Gene', (90, 95))	('regulating', 'Reg', (134, 144))	('microRNA-154', 'Gene', '406946', (54, 66))	('FOXP2', 'Gene', (83, 88))	('miR-376b', 'Gene', (70, 78))	('glioma', 'Disease', (171, 177))	('FOXP2', 'Gene', '93986', (83, 88))	('microRNA-154', 'Gene', (54, 66))	('KDM5B', 'Gene', '10765', (90, 95))	('SNHG1-', 'Var', (47, 53))	('miR-376b', 'Gene', '574435', (70, 78))
61810	30728054	In addition to coding genome, the dysregulation of non-coding RNA -- which accounts for the vast majority of genomic sequences -- is proposed to affect the development of tumors.	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('affect', 'Reg', (145, 151))	('dysregulation', 'Var', (34, 47))	('non-coding', 'Protein', (51, 61))	('RNA', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
61813	30728054	In a recent glioma study, it has also been discovered that the expression of SNHG1 can reduce the proliferation and invasion of glioma cells, resulting in more cell apoptosis.	('glioma', 'Disease', (128, 134))	('cell apoptosis', 'CPA', (160, 174))	('glioma', 'Disease', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('more', 'PosReg', (155, 159))	('SNHG1', 'Gene', (77, 82))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('reduce', 'NegReg', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('expression', 'Var', (63, 73))
61815	30728054	Among those SNHG1-associated miRNAs, miR-154-5p and miR-376b-3p were identified.	('miR-376b', 'Gene', '574435', (52, 60))	('miR-376b', 'Gene', (52, 60))	('SNHG1-associated', 'Disease', (12, 28))	('miR-154-5p', 'Var', (37, 47))
61816	30728054	Many studies have shown that miR-154-5p can act as a tumor suppressor via inhibiting the proliferation and metastasis of glioblastoma cells through PIWIL1 binding, which can be used to predict the prognosis of glioma patients.	('inhibiting', 'NegReg', (74, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('patients', 'Species', '9606', (217, 225))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('binding', 'Interaction', (155, 162))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('PIWIL1', 'Gene', '9271', (148, 154))	('tumor', 'Disease', (53, 58))	('miR-154-5p', 'Var', (29, 39))	('glioblastoma', 'Disease', (121, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('glioma', 'Disease', (210, 216))	('PIWIL1', 'Gene', (148, 154))
61817	30728054	Similar tumor suppression effects by miR-154-5p were also found in other tumor cell lines.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (8, 13))	('miR-154-5p', 'Var', (37, 47))
61819	30728054	Similar to SNHG1, the miRNA-376 family -- including miRNA-376a, miRNA-376b, and miRNA-376c -- can be individually used as a biomarker for the diagnosis and prognosis evaluation in glioma.	('miRNA-376a', 'Var', (52, 62))	('miRNA-376b', 'Var', (64, 74))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('miRNA-376c --', 'Var', (80, 93))	('glioma', 'Disease', (180, 186))
61820	30728054	Moreover, the miRNA-376 family clusters can produce specific A to I editing in brain tissue, changing the originally targeted silencing genes, and thus, leading to a change in the invasive ability of malignant glioma cells.	('malignant glioma', 'Disease', (200, 216))	('leading to', 'Reg', (153, 163))	('silencing genes', 'MPA', (126, 141))	('malignant glioma', 'Disease', 'MESH:D005910', (200, 216))	('miRNA-376', 'Var', (14, 23))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('change', 'Reg', (166, 172))	('changing', 'Reg', (93, 101))
61826	30728054	KDM5B can demethylate H3K4me3 and H3K4me2 at lysine 4 on the histone H3 protein, thereby KDM5B regulates individual epigenetic change.	('regulates', 'Reg', (95, 104))	('KDM5B', 'Gene', '10765', (89, 94))	('KDM5B', 'Gene', '10765', (0, 5))	('demethylate', 'Var', (10, 21))	('KDM5B', 'Gene', (89, 94))	('KDM5B', 'Gene', (0, 5))	('H3K4me3', 'Protein', (22, 29))	('H3K4me2', 'Var', (34, 41))	('epigenetic change', 'MPA', (116, 133))	('lysine', 'Chemical', 'MESH:D008239', (45, 51))
61829	30728054	KDM5B can exert biological effects through downstream signaling pathways such as E2F/RB and PI3K/AKT/mTOR.	('AKT', 'Gene', '207', (97, 100))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (101, 105))	('KDM5B', 'Gene', '10765', (0, 5))	('AKT', 'Gene', (97, 100))	('KDM5B', 'Gene', (0, 5))	('E2F/RB', 'Var', (81, 87))
61831	30728054	In this study, we intially identified the endogenous expression of SNHG1, miR-154-5p, miR-376b-3p, FOXP2, and KDM5B in gliomas.	('miR-376b', 'Gene', '574435', (86, 94))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('KDM5B', 'Gene', (110, 115))	('FOXP2', 'Gene', (99, 104))	('FOXP2', 'Gene', '93986', (99, 104))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('miR-376b', 'Gene', (86, 94))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('SNHG1', 'Gene', (67, 72))	('KDM5B', 'Gene', '10765', (110, 115))	('miR-154-5p', 'Var', (74, 84))
61833	30728054	We further investigated whether SNHG1 can control the expression of FOXP2 and KDM5B by regulating the expression of miR-154-5p and miR-376b-3p to understand their potential mechanism in regulating biological behaviors of glioma cells and lay down a new fundation for targeted therapy aiming to cure human glioma.	('miR-154-5p', 'Var', (116, 126))	('miR-376b', 'Gene', '574435', (131, 139))	('KDM5B', 'Gene', '10765', (78, 83))	('FOXP2', 'Gene', (68, 73))	('KDM5B', 'Gene', (78, 83))	('glioma', 'Disease', (221, 227))	('human', 'Species', '9606', (299, 304))	('glioma', 'Disease', (305, 311))	('FOXP2', 'Gene', '93986', (68, 73))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('miR-376b', 'Gene', (131, 139))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('glioma', 'Disease', 'MESH:D005910', (305, 311))	('regulating', 'Reg', (87, 97))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))
61840	30728054	Starbase (http://starbase.sysu.edu.cn/index.php) and Targetscan (http://www.targetscan.org) are used to predict binding sites of miR-154-5p and miR-376b-3p.	('binding', 'Interaction', (112, 119))	('miR-376b', 'Gene', '574435', (144, 152))	('miR-154-5p', 'Var', (129, 139))	('miR-376b', 'Gene', (144, 152))
61843	30728054	qRT-PCR was conducted using TaqMan Universal Master Mix II with TaqMan microRNA assays of miR-154-5p, miR-376b-3p and U6.	('miR-154-5p', 'Var', (90, 100))	('miR-376b', 'Gene', '574435', (102, 110))	('miR-376b', 'Gene', (102, 110))
61849	30728054	Stable transfected cells were obtained by continuous application of Geneticin (G418, Invitrogen, CA, USA) and evaluated for their over-expression and silence efficiencies by qRT-PCR.	('silence', 'MPA', (150, 157))	('G418', 'Chemical', 'MESH:C010680', (79, 83))	('G418', 'Var', (79, 83))
61855	30728054	The fragment of SNHG1 containing the putative miR-154-5p or miR-376b-3p binding sites was subcloned into a pmirGLO Dual-Luciferase miRNA Target Expression Vector (Promega, Madison, WI, USA) to construct the reporter vector SNHG1-wild-type (SNHG1-Wt) (GenePharma, Shanghai, China).	('miR-376b', 'Gene', (60, 68))	('SNHG1', 'Gene', (16, 21))	('miR-376b', 'Gene', '574435', (60, 68))	('miR-154-5p', 'Var', (46, 56))
61862	30728054	The primary antibodies included anti-FOXP2 (1:1000, ab58599, Abcam), anti-KDM5B (1:2000, ab181089, Abcam) and anti-PI3K, anti-p-PI3K, anti-AKT, anti-p-AKT (1:1000, #4257, #4228, #9272, #9271, Cell Signaling Technology), anti-GAPDH (1:10000, 60,004-1-Ig, Proteintech Group).	('KDM5B', 'Gene', '10765', (74, 79))	('AKT', 'Gene', (151, 154))	('FOXP2', 'Gene', '93986', (37, 42))	('KDM5B', 'Gene', (74, 79))	('AKT', 'Gene', '207', (139, 142))	('GAPDH', 'Gene', '2597', (225, 230))	('anti-PI3K', 'Var', (110, 119))	('GAPDH', 'Gene', (225, 230))	('AKT', 'Gene', (139, 142))	('anti-p-PI3K', 'Var', (121, 132))	('AKT', 'Gene', '207', (151, 154))	('FOXP2', 'Gene', (37, 42))
61871	30728054	The isolated and purified RNA was further used for qRT-PCR analysis of SNHG1, miR-154-5p and miR-376b-3p.	('miR-376b', 'Gene', (93, 101))	('miR-154-5p', 'Var', (78, 88))	('SNHG1', 'Gene', (71, 76))	('miR-376b', 'Gene', '574435', (93, 101))
61872	30728054	Biotin-labelled SNHG1 and antisense SNHG1 transcripts were synthesized (GenePharma, Shanghai, China) and transfected into 293 T cells.	('SNHG1', 'Gene', (36, 41))	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('antisense', 'Var', (26, 35))	('293 T', 'CellLine', 'CVCL:0063', (122, 127))
61877	30728054	Lentivirus encoding miR-154-5p and miR-376b-3p were generated using pLenti6.3/V5eDEST Gateway Vector Kit (Life Technologies Corporation, Carlsbad, CA, USA).	('miR-376b', 'Gene', '574435', (35, 43))	('miR-154-5p', 'Var', (20, 30))	('miR-376b', 'Gene', (35, 43))
61881	30728054	After infection, the stable expressing cells of miR-154-5p (pre-miR-154-5p), miR-376b-3p (pre-miR-376b-3p), sh-SNHG1 were picked.	('miR-376b', 'Gene', '574435', (94, 102))	('miR-154-5p', 'Var', (48, 58))	('miR-376b', 'Gene', '574435', (77, 85))	('miR-376b', 'Gene', (94, 102))	('miR-376b', 'Gene', (77, 85))
61883	30728054	The nude mice were divided into five groups: control group, sh-SNHG1 group, pre-miR-154-5p group, pre-miR-376b-3p group and sh-SNHG1+ pre-miR-154-5p + pre-miR-376b-3p group.	('sh-SNHG1+', 'Var', (124, 133))	('miR-376b', 'Gene', (155, 163))	('miR-376b', 'Gene', '574435', (102, 110))	('nude mice', 'Species', '10090', (4, 13))	('miR-376b', 'Gene', '574435', (155, 163))	('miR-376b', 'Gene', (102, 110))
61894	30728054	Compared with the control group, the proliferation ability of U87 and U251 in sh-SNHG1 group was significantly decreased (P < 0.01), as shown in Fig.	('U251', 'Var', (70, 74))	('sh-SNHG1', 'Gene', (78, 86))	('decreased', 'NegReg', (111, 120))	('U251', 'CellLine', 'CVCL:0021', (70, 74))	('U87', 'Gene', (62, 65))	('proliferation ability', 'CPA', (37, 58))	('U87', 'Gene', '641648', (62, 65))
61895	30728054	The results showed that the apoptosis rate of U87 and U251 cells increased significantly in sh-SNHG1 group (P < 0.01), as shown by 1E.	('increased', 'PosReg', (65, 74))	('U87', 'Gene', (46, 49))	('U87', 'Gene', '641648', (46, 49))	('U251', 'CellLine', 'CVCL:0021', (54, 58))	('apoptosis rate', 'CPA', (28, 42))	('sh-SNHG1', 'Var', (92, 100))
61897	30728054	The TCGA database, via the Pearson's correlation analysis showed that the expression of miR-154-5p and miR-376b-3p were significantly inverse in correlation with SNHG1 (P < 0.01) (Fig.	('expression', 'MPA', (74, 84))	('inverse', 'NegReg', (134, 141))	('miR-376b', 'Gene', (103, 111))	('miR-154-5p', 'Var', (88, 98))	('miR-376b', 'Gene', '574435', (103, 111))
61898	30728054	The qRT-PCR detection showed that the expression of miR-154-5p and miR-376b-3p in sh-SNHG1 group was significantly higher than that in sh-NC SNHG1 group (P < 0.01) (Fig.	('expression', 'MPA', (38, 48))	('miR-376b', 'Gene', '574435', (67, 75))	('sh-SNHG1', 'Var', (82, 90))	('miR-154-5p', 'Var', (52, 62))	('higher', 'PosReg', (115, 121))	('miR-376b', 'Gene', (67, 75))
61899	30728054	1h, l), suggesting that SNHG1 may have potential binding sites and interaction with miR-154-5p and miR-376b-3p, respectively.	('SNHG1', 'Gene', (24, 29))	('miR-376b', 'Gene', (99, 107))	('binding sites', 'Interaction', (49, 62))	('miR-376b', 'Gene', '574435', (99, 107))	('interaction', 'Interaction', (67, 78))	('miR-154-5p', 'Var', (84, 94))
61901	30728054	Further RIP test showed that AGO2 antibody enriched SNHG1, miR-154-5p and miR-376b-3p relative to IgG antibody in U87 and U251 cells, and confirmed that they existed in the RISC complex (Fig.	('AGO2', 'Gene', (29, 33))	('miR-376b', 'Gene', '574435', (74, 82))	('U251', 'CellLine', 'CVCL:0021', (122, 126))	('U87', 'Gene', '641648', (114, 117))	('AGO2', 'Gene', '27161', (29, 33))	('miR-154-5p', 'Var', (59, 69))	('IgG antibody', 'Phenotype', 'HP:0003237', (98, 110))	('miR-376b', 'Gene', (74, 82))	('U87', 'Gene', (114, 117))	('SNHG1', 'Var', (52, 57))
61902	30728054	The binding sites between SNHG1 and miR-154-5p, as well as between SNHG1 and miR-376b-3p were verified, and the expression of miR-154-5p and miR-376b-3p was down regulated by binding.	('miR-376b', 'Gene', '574435', (141, 149))	('miR-154-5p', 'Var', (126, 136))	('binding', 'Interaction', (175, 182))	('down regulated', 'NegReg', (157, 171))	('expression', 'MPA', (112, 122))	('miR-154-5p', 'Gene', (36, 46))	('binding', 'Interaction', (4, 11))	('miR-376b', 'Gene', '574435', (77, 85))	('miR-376b', 'Gene', (141, 149))	('SNHG1', 'Gene', (67, 72))	('SNHG1', 'Gene', (26, 31))	('miR-376b', 'Gene', (77, 85))
61905	30728054	According to the TCGA database, the expression of miR-154-5p and miR-376b-3p was significantly decreased in glioma samples in comparison with the normal brain tissue (P < 0.01) (Fig.	('decreased', 'NegReg', (95, 104))	('miR-154-5p', 'Var', (50, 60))	('glioma', 'Disease', (108, 114))	('miR-376b', 'Gene', (65, 73))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('miR-376b', 'Gene', '574435', (65, 73))	('expression', 'MPA', (36, 46))
61906	30728054	2a, g); the expression of miR-154-5p and miR-376b-3p in glioma tissues was lower than that in normal brain tissues (P < 0.01) by qRT-PCR, and the expression level was negatively correlated with histological grade (Fig.	('lower', 'NegReg', (75, 80))	('glioma', 'Disease', (56, 62))	('miR-376b', 'Gene', (41, 49))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('miR-376b', 'Gene', '574435', (41, 49))	('negatively', 'NegReg', (167, 177))	('expression', 'MPA', (12, 22))	('miR-154-5p', 'Var', (26, 36))
61907	30728054	The expression of miR-154-5p and miR-376b-3p in U87 and U251 cells was lower than that in HA cells (P < 0.01) (Fig.	('U87', 'Gene', '641648', (48, 51))	('miR-376b', 'Gene', '574435', (33, 41))	('expression', 'MPA', (4, 14))	('U251', 'CellLine', 'CVCL:0021', (56, 60))	('miR-154-5p', 'Var', (18, 28))	('U87', 'Gene', (48, 51))	('miR-376b', 'Gene', (33, 41))	('lower', 'NegReg', (71, 76))
61909	30728054	The results show that miR-154-5p and miR-376b-3p play a role in inhibiting malignant biological behavior in U87 and U251 cells.	('U87', 'Gene', '641648', (108, 111))	('inhibiting', 'NegReg', (64, 74))	('miR-376b', 'Gene', '574435', (37, 45))	('U251', 'CellLine', 'CVCL:0021', (116, 120))	('miR-154-5p', 'Var', (22, 32))	('U87', 'Gene', (108, 111))	('miR-376b', 'Gene', (37, 45))
61911	30728054	Similarly, compared with the control group, the cell proliferation, migration ability and invasion ability of sh-SNHG1 + pre-miR-376b-3p group were significantly decreased (P < 0.01), the apoptosis rate was significantly increased (P < 0.01), while the biological behavior of sh-SHNG1 + anti-miR-376b-3p group was not significantly different.	('migration ability', 'CPA', (68, 85))	('miR-376b', 'Gene', '574435', (125, 133))	('increased', 'PosReg', (221, 230))	('sh-SNHG1', 'Var', (110, 118))	('miR-376b', 'Gene', (292, 300))	('cell proliferation', 'CPA', (48, 66))	('decreased', 'NegReg', (162, 171))	('invasion ability', 'CPA', (90, 106))	('apoptosis rate', 'CPA', (188, 202))	('miR-376b', 'Gene', (125, 133))	('miR-376b', 'Gene', '574435', (292, 300))
61924	30728054	Compared with anti-miR-154-5p-NC group, the expression of FOXP2 in anti-miR-154-5p group was significantly increased (P < 0.01) (Fig.	('expression', 'MPA', (44, 54))	('increased', 'PosReg', (107, 116))	('FOXP2', 'Gene', (58, 63))	('FOXP2', 'Gene', '93986', (58, 63))	('anti-miR-154-5p', 'Var', (67, 82))
61925	30728054	3g, h), which proved that miR-154-5p could inhibit the expression of FOXP2 mRNA and protein.	('mRNA and', 'MPA', (75, 83))	('inhibit', 'NegReg', (43, 50))	('FOXP2', 'Gene', (69, 74))	('expression', 'MPA', (55, 65))	('protein', 'Protein', (84, 91))	('FOXP2', 'Gene', '93986', (69, 74))	('miR-154-5p', 'Var', (26, 36))
61926	30728054	The same method proved that the overexpression of miR-376b-3p could inhibit the expression of FOXP2, and silencing miR-376b-3p promoted the expression of FOXP2, indicating that miR-376b-3p could inhibit the expression of FOXP2 mRNA and protein (P < 0.01) (Fig.	('FOXP2', 'Gene', '93986', (94, 99))	('miR-376b', 'Gene', '574435', (115, 123))	('miR-376b', 'Gene', '574435', (50, 58))	('promoted', 'PosReg', (127, 135))	('FOXP2', 'Gene', (154, 159))	('miR-376b', 'Gene', '574435', (177, 185))	('FOXP2', 'Gene', '93986', (154, 159))	('protein', 'Protein', (236, 243))	('expression', 'MPA', (80, 90))	('expression', 'MPA', (207, 217))	('inhibit', 'NegReg', (68, 75))	('mRNA and', 'MPA', (227, 235))	('miR-376b', 'Gene', (115, 123))	('inhibit', 'NegReg', (195, 202))	('FOXP2', 'Gene', (221, 226))	('miR-376b', 'Gene', (50, 58))	('FOXP2', 'Gene', '93986', (221, 226))	('expression', 'MPA', (140, 150))	('miR-376b', 'Gene', (177, 185))	('FOXP2', 'Gene', (94, 99))	('silencing', 'Var', (105, 114))
61927	30728054	The results of dual luciferase assay showed that the luciferase activity of cotransfected wild-type FOXP2-3 'UTR plasmid and pre-miR-154-5p group was significantly decreased, and there was statistical difference (P < 0.01); The luciferase activity of pre-miR-154-5p NC group and mutant FOXP2-3 'UTR group did not change compared with that of the control group, indicating that there was a binding site between miR-154-5p and FOXP2 mRNA (Fig.	('decreased', 'NegReg', (164, 173))	('luciferase', 'Enzyme', (53, 63))	('FOXP2', 'Gene', (425, 430))	('FOXP2', 'Gene', '93986', (100, 105))	('FOXP2', 'Gene', '93986', (425, 430))	('FOXP2', 'Gene', (286, 291))	('FOXP2-3', 'Gene', (100, 107))	('FOXP2', 'Gene', (100, 105))	('binding', 'Interaction', (389, 396))	('activity', 'MPA', (64, 72))	('FOXP2-3', 'Gene', (286, 293))	('FOXP2-3', 'Gene', '93986;50943', (100, 107))	('FOXP2', 'Gene', '93986', (286, 291))	('FOXP2-3', 'Gene', '93986;50943', (286, 293))	('miR-154-5p', 'Var', (410, 420))
61930	30728054	In order to further confirm the mechanism of interaction between miR-154-5p and miR-376b-3p with FOXP2, the miR-154-5p overexpression, miR-376b-3p overexpression, 3 'UTR wild-type and 3' UTR mutant FOXP2 overexpression plasmids were transfected into U87 and U251 cell groups.	('miR-376b', 'Gene', '574435', (80, 88))	('FOXP2', 'Gene', '93986', (198, 203))	('miR-376b', 'Gene', '574435', (135, 143))	('U87', 'Gene', (250, 253))	('U251', 'CellLine', 'CVCL:0021', (258, 262))	('mutant', 'Var', (191, 197))	('miR-154-5p', 'Var', (108, 118))	('U87', 'Gene', '641648', (250, 253))	('FOXP2', 'Gene', (97, 102))	('miR-376b', 'Gene', (135, 143))	('miR-376b', 'Gene', (80, 88))	('FOXP2', 'Gene', '93986', (97, 102))	('FOXP2', 'Gene', (198, 203))
61932	30728054	The overexpression of 3 'UTR wild-type FOXP2 group reversed the overexpression of miR-154-5p in inhibiting proliferation, migration, and invasion of glioma cells, and reduced the apoptosis rate of glioma cells induced by overexpression of miR-154-5p (P < 0.01) (Additional file 2: Figure S2D-F).	('miR-154-5p', 'Var', (239, 249))	('FOXP2', 'Gene', '93986', (39, 44))	('glioma', 'Disease', (149, 155))	('miR-154-5p', 'Var', (82, 92))	('proliferation', 'CPA', (107, 120))	('invasion', 'CPA', (137, 145))	('glioma', 'Disease', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('apoptosis rate', 'CPA', (179, 193))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('inhibiting', 'NegReg', (96, 106))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('migration', 'CPA', (122, 131))	('reduced', 'NegReg', (167, 174))	('FOXP2', 'Gene', (39, 44))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
61934	30728054	These results confirm that miR-154-5p and miR-376b-3p play a role in inhibiting malignant biological behavior of glioma by binding to FOXP2 mRNA 3'UTR.	('binding', 'Interaction', (123, 130))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('FOXP2', 'Gene', (134, 139))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('miR-376b', 'Gene', (42, 50))	('FOXP2', 'Gene', '93986', (134, 139))	('miR-154-5p', 'Var', (27, 37))	('glioma', 'Disease', (113, 119))	('inhibiting', 'NegReg', (69, 79))	('miR-376b', 'Gene', '574435', (42, 50))
61946	30728054	The loss of - 921 site significantly reduced the promoter activity of KDM5B after cotransfection with ex-FOXP2 (P < 0.01).	('FOXP2', 'Gene', (105, 110))	('FOXP2', 'Gene', '93986', (105, 110))	('loss of - 921 site', 'Var', (4, 22))	('reduced', 'NegReg', (37, 44))	('promoter activity', 'MPA', (49, 66))	('KDM5B', 'Gene', '10765', (70, 75))	('KDM5B', 'Gene', (70, 75))
61950	30728054	After silencing SNHG1 in U87 and U251, compared with sh-NC group cells, the protein expression of FOXP2 and KDM5B decreased significantly (P < 0.01) (Fig.	('KDM5B', 'Gene', (108, 113))	('U87', 'Gene', '641648', (25, 28))	('FOXP2', 'Gene', '93986', (98, 103))	('protein expression', 'MPA', (76, 94))	('U251', 'CellLine', 'CVCL:0021', (33, 37))	('decreased', 'NegReg', (114, 123))	('U87', 'Gene', (25, 28))	('SNHG1', 'Gene', (16, 21))	('silencing', 'Var', (6, 15))	('KDM5B', 'Gene', '10765', (108, 113))	('FOXP2', 'Gene', (98, 103))
61951	30728054	It is proved that silencing SNHG1 can inhibit the expression of FOXP2 protein and regulate the expression of KDM5B protein.	('protein', 'Protein', (70, 77))	('silencing', 'Var', (18, 27))	('regulate', 'Reg', (82, 90))	('SNHG1', 'Gene', (28, 33))	('FOXP2', 'Gene', (64, 69))	('KDM5B', 'Gene', '10765', (109, 114))	('KDM5B', 'Gene', (109, 114))	('FOXP2', 'Gene', '93986', (64, 69))	('inhibit', 'NegReg', (38, 45))	('expression', 'MPA', (50, 60))	('expression', 'MPA', (95, 105))
61953	30728054	In the overexpression and silencing of miR-154-5p and miR-376b-3p in U87 and U251 cells, through the Western blot method detecting the protein expression of KDM5B, the results showed that compared with pre-NC group, the expression of KDM5B was significantly decreased in pre-miR-154-5p and pre-miR-376b-3p groups, compared with the anti-NC group, the expression of KDM5B in anti-miR-154-5p group and anti-miR-376b-3p group was significantly higher (P < 0.01) (Fig.	('miR-376b', 'Gene', (405, 413))	('expression', 'MPA', (351, 361))	('KDM5B', 'Gene', (234, 239))	('miR-376b', 'Gene', (54, 62))	('KDM5B', 'Gene', '10765', (365, 370))	('miR-376b', 'Gene', '574435', (294, 302))	('KDM5B', 'Gene', '10765', (157, 162))	('U87', 'Gene', '641648', (69, 72))	('miR-376b', 'Gene', '574435', (405, 413))	('anti-miR-154-5p', 'Var', (374, 389))	('miR-376b', 'Gene', '574435', (54, 62))	('higher', 'PosReg', (441, 447))	('KDM5B', 'Gene', '10765', (234, 239))	('U87', 'Gene', (69, 72))	('KDM5B', 'Gene', (365, 370))	('decreased', 'NegReg', (258, 267))	('expression', 'MPA', (220, 230))	('KDM5B', 'Gene', (157, 162))	('U251', 'CellLine', 'CVCL:0021', (77, 81))	('miR-376b', 'Gene', (294, 302))
61954	30728054	Further in the SNHG1 knockdown U87 and U251 cells cotransfected with miR-154-5p overexpression and silence plasmid, then via the Western blot method detecting the protein expression of FOXP2 and KDM5B, the results showed that the protein expression of FOXP2 and KDM5B in sh-SNHG1 + pre-miR-154-5p group decreased significantly (P < 0.01), while silencing miR-154-5p (sh-SNHG1 + anti-miR-154-5p) could counteract the inhibition of FOXP2 and KDM5B protein expression.	('FOXP2', 'Gene', (252, 257))	('protein expression', 'MPA', (230, 248))	('KDM5B', 'Gene', (440, 445))	('U87', 'Gene', '641648', (31, 34))	('FOXP2', 'Gene', (185, 190))	('KDM5B', 'Gene', '10765', (195, 200))	('decreased', 'NegReg', (303, 312))	('FOXP2', 'Gene', (430, 435))	('silencing', 'Var', (345, 354))	('FOXP2', 'Gene', '93986', (252, 257))	('KDM5B', 'Gene', '10765', (262, 267))	('FOXP2', 'Gene', '93986', (185, 190))	('U251', 'CellLine', 'CVCL:0021', (39, 43))	('KDM5B', 'Gene', (195, 200))	('KDM5B', 'Gene', '10765', (440, 445))	('FOXP2', 'Gene', '93986', (430, 435))	('KDM5B', 'Gene', (262, 267))	('U87', 'Gene', (31, 34))
61955	30728054	The protein expression of FOXP2 and KDM5B decreased significantly when SNHG1 knockdown U87 and U251 cells were cotransfected with both miR-154-5p and miR-376b-3p overexpression plasmids (P < 0.01) (Fig.	('U251', 'CellLine', 'CVCL:0021', (95, 99))	('protein expression', 'MPA', (4, 22))	('KDM5B', 'Gene', '10765', (36, 41))	('decreased', 'NegReg', (42, 51))	('FOXP2', 'Gene', (26, 31))	('miR-376b', 'Gene', (150, 158))	('U87', 'Gene', '641648', (87, 90))	('FOXP2', 'Gene', '93986', (26, 31))	('KDM5B', 'Gene', (36, 41))	('miR-154-5p', 'Var', (135, 145))	('miR-376b', 'Gene', '574435', (150, 158))	('SNHG1', 'Gene', (71, 76))	('U87', 'Gene', (87, 90))
61956	30728054	It is proved that miR-154-5p and miR-376b-3p are involved in the SNHG1 regulating transcription factor FOXP2 and downstream protein KDM5B.	('KDM5B', 'Gene', '10765', (132, 137))	('SNHG1', 'Gene', (65, 70))	('KDM5B', 'Gene', (132, 137))	('miR-376b', 'Gene', '574435', (33, 41))	('involved', 'Reg', (49, 57))	('FOXP2', 'Gene', (103, 108))	('miR-154-5p', 'Var', (18, 28))	('FOXP2', 'Gene', '93986', (103, 108))	('miR-376b', 'Gene', (33, 41))
61957	30728054	The detection of downstream protein KDM5B was applied to the 7 groups of glioma cells transfected with miR-154-5p overexpression, miR-376b-3p overexpression, 3 'UTR wild-type and 3' UTR mutant FOXP2 overexpression plasmid.	('glioma', 'Disease', (73, 79))	('KDM5B', 'Gene', '10765', (36, 41))	('FOXP2', 'Gene', '93986', (193, 198))	('miR-376b', 'Gene', (130, 138))	('mutant', 'Var', (186, 192))	('miR-154-5p', 'Var', (103, 113))	('KDM5B', 'Gene', (36, 41))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('miR-376b', 'Gene', '574435', (130, 138))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('FOXP2', 'Gene', (193, 198))
61958	30728054	The results showed that in the group of over expression of 3 'UTR mutant FOXP2, KDM5B protein expression was significantly increased (P < 0.01) (Fig.	('KDM5B', 'Gene', (80, 85))	('increased', 'PosReg', (123, 132))	('over expression', 'PosReg', (40, 55))	('mutant', 'Var', (66, 72))	('FOXP2', 'Gene', (73, 78))	('KDM5B', 'Gene', '10765', (80, 85))	('FOXP2', 'Gene', '93986', (73, 78))
61960	30728054	This further proved that miR-154-5p and miR-376b-3p regulate the expression of downstream protein KDM5B by binding to the 3 'UTR specific sequence of transcription factor FOXP2.	('miR-376b', 'Gene', '574435', (40, 48))	('FOXP2', 'Gene', (171, 176))	('KDM5B', 'Gene', '10765', (98, 103))	('KDM5B', 'Gene', (98, 103))	('FOXP2', 'Gene', '93986', (171, 176))	('miR-154-5p', 'Var', (25, 35))	('expression', 'MPA', (65, 75))	('binding', 'Interaction', (107, 114))	('miR-376b', 'Gene', (40, 48))	('regulate', 'Reg', (52, 60))
61961	30728054	In addition, the Western blot assay also showed that the levels of p-PI3K/PI3K and p-Akt/Akt changed in stably transfected and silenced KDM5B U87 and U251 cells.	('U87', 'Gene', '641648', (142, 145))	('KDM5B', 'Gene', '10765', (136, 141))	('Akt', 'Gene', '207', (85, 88))	('Akt', 'Gene', '207', (89, 92))	('KDM5B', 'Gene', (136, 141))	('Akt', 'Gene', (85, 88))	('p-PI3K/PI3K', 'Var', (67, 78))	('Akt', 'Gene', (89, 92))	('U87', 'Gene', (142, 145))	('U251', 'CellLine', 'CVCL:0021', (150, 154))
61962	30728054	Compared with group ex-NC, p-PI3K/PI3K and p-Akt/Akt increased significantly in group ex-KDM5B; compared with group sh-NC cells, p-PI3K/PI3K, and p-Akt/Akt decreased significantly in sh-KDM5B group, the differences were statistically significant (P < 0.01) (Fig.	('Akt', 'Gene', (45, 48))	('KDM5B', 'Gene', (186, 191))	('Akt', 'Gene', (148, 151))	('KDM5B', 'Gene', '10765', (89, 94))	('Akt', 'Gene', (152, 155))	('KDM5B', 'Gene', '10765', (186, 191))	('Akt', 'Gene', '207', (45, 48))	('decreased', 'NegReg', (156, 165))	('Akt', 'Gene', '207', (49, 52))	('KDM5B', 'Gene', (89, 94))	('Akt', 'Gene', '207', (148, 151))	('Akt', 'Gene', '207', (152, 155))	('p-PI3K/PI3K', 'Var', (129, 140))	('Akt', 'Gene', (49, 52))
61968	30728054	Thus, proving that silencing KDM5B could also inhibit the expression of SNHG1.	('KDM5B', 'Gene', '10765', (29, 34))	('KDM5B', 'Gene', (29, 34))	('inhibit', 'NegReg', (46, 53))	('expression', 'MPA', (58, 68))	('SNHG1', 'Gene', (72, 77))	('silencing', 'Var', (19, 28))
61971	30728054	6d), continuing the pull-down experiments, the Western blot method showed that KDM5B protein could be identified in lncRNA SNHG1 sense strand group, while in lncRNA SNHG1 antisense strand group, KDM5B protein was not identified, and further verified that there was a specific binding between KDM5B and SNHG1 (Fig.	('sense strand', 'Var', (129, 141))	('KDM5B', 'Gene', '10765', (195, 200))	('KDM5B', 'Gene', '10765', (79, 84))	('KDM5B', 'Gene', (195, 200))	('KDM5B', 'Gene', '10765', (292, 297))	('KDM5B', 'Gene', (79, 84))	('binding', 'Interaction', (276, 283))	('KDM5B', 'Gene', (292, 297))
61973	30728054	The results showed that the half-life of SNHG1 in sh-KDM5B transfected cells was shortened, and the degradation of SNHG1 was accelerated significantly compared with the control group.	('half-life', 'MPA', (28, 37))	('transfected', 'Var', (59, 70))	('shortened', 'NegReg', (81, 90))	('KDM5B', 'Gene', (53, 58))	('SNHG1', 'Gene', (41, 46))	('KDM5B', 'Gene', '10765', (53, 58))	('accelerated', 'PosReg', (125, 136))	('degradation', 'MPA', (100, 111))
61978	30728054	Compared with the control group, the sh-SHNG1, pre-miR-154-5p, and pre-miR-376b-3p groups had longer survival time, whereas the survival time of the sh-SHNG1+ pre-miR-154-5p + pre-miR-376b-3p group was the longest, longer than that of the sh-SHNG1, pre-miR-154-5p, and pre-miR-376b-3p groups (Fig.	('miR-376b', 'Gene', '574435', (180, 188))	('sh-SHNG1+', 'Var', (149, 158))	('miR-376b', 'Gene', '574435', (273, 281))	('miR-376b', 'Gene', '574435', (71, 79))	('miR-376b', 'Gene', (180, 188))	('longer', 'PosReg', (94, 100))	('survival time', 'CPA', (101, 114))	('miR-376b', 'Gene', (273, 281))	('miR-376b', 'Gene', (71, 79))
61980	30728054	This analysis illustrated that SNHG1 acts as a tumor promoting factor in glioma tissues and cells.	('SNHG1', 'Var', (31, 36))	('glioma', 'Disease', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
61983	30728054	The research further demonstrated that miR-154-5p and miR-376b-3p play a role in tumor suppressor in glioma tissues and cells respectively.	('miR-376b', 'Gene', '574435', (54, 62))	('glioma', 'Disease', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('miR-376b', 'Gene', (54, 62))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('miR-154-5p', 'Var', (39, 49))	('tumor', 'Disease', (81, 86))
61986	30728054	In the current study of glioma, miR-154-5p combined with PIWIL1 3 'UTR inhibits malignant progression of glioblastoma, the overexpression of miR-154-5p can inhibit proliferation and metastasis of malignant glioma cells and induce apoptosis; miR-154 can also be used as a potential biomarker for clinical prognosis in patients with glioma.	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('glioma', 'Disease', (331, 337))	('clinical', 'Species', '191496', (295, 303))	('glioma', 'Disease', 'MESH:D005910', (331, 337))	('inhibits', 'NegReg', (71, 79))	('miR-154-5p', 'Var', (32, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('induce', 'PosReg', (223, 229))	('overexpression', 'PosReg', (123, 137))	('malignant glioma', 'Disease', 'MESH:D005910', (196, 212))	('miR-154-5p', 'Var', (141, 151))	('PIWIL1', 'Gene', '9271', (57, 63))	('malignant progression of', 'CPA', (80, 104))	('malignant glioma', 'Disease', (196, 212))	('glioma', 'Disease', (24, 30))	('glioblastoma', 'Disease', (105, 117))	('glioma', 'Phenotype', 'HP:0009733', (331, 337))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('inhibit', 'NegReg', (156, 163))	('PIWIL1', 'Gene', (57, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('glioma', 'Disease', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('apoptosis', 'CPA', (230, 239))	('patients', 'Species', '9606', (317, 325))
61988	30728054	In this study, the expression of miR-154-5p and miR-376b-3p was negatively correlated with the expression of SNHG1 by the TCGA database, and the Starbase database predicted that there was a binding site between miR-154-5p and SNHG1, as well as between miR-376b-3p and SNHG1.	('miR-376b', 'Gene', (252, 260))	('expression', 'MPA', (19, 29))	('SNHG1', 'Gene', (226, 231))	('miR-376b', 'Gene', '574435', (252, 260))	('miR-376b', 'Gene', (48, 56))	('miR-376b', 'Gene', '574435', (48, 56))	('miR-154-5p', 'Var', (211, 221))	('SNHG1', 'Gene', (109, 114))	('binding', 'Interaction', (190, 197))	('expression', 'MPA', (95, 105))	('negatively', 'NegReg', (64, 74))
61989	30728054	The research showed that SNHG1 was combined with miR-154-5p and miR-376b-3p, and the silenced SNHG1 enhanced their expression.	('silenced', 'Var', (85, 93))	('miR-376b', 'Gene', '574435', (64, 72))	('enhanced', 'PosReg', (100, 108))	('SNHG1', 'Gene', (94, 99))	('expression', 'MPA', (115, 125))	('miR-376b', 'Gene', (64, 72))
61990	30728054	These results suggest that silencing the expression of SNHG1 can inhibit the proliferation, migration, and invasion of glioma cells by increasing the expression of miR-154-5p and miR-376b-3p, and promote the apoptosis of glioma cells.	('expression', 'MPA', (150, 160))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('silencing', 'Var', (27, 36))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('miR-154-5p', 'Var', (164, 174))	('miR-376b', 'Gene', (179, 187))	('glioma', 'Disease', (221, 227))	('SNHG1', 'Gene', (55, 60))	('promote', 'PosReg', (196, 203))	('migration', 'CPA', (92, 101))	('glioma', 'Disease', (119, 125))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('miR-376b', 'Gene', '574435', (179, 187))	('inhibit', 'NegReg', (65, 72))	('increasing', 'PosReg', (135, 145))	('proliferation', 'CPA', (77, 90))
61991	30728054	In addition, the RIP experiments confirmed that SNHG1 and miR-154-5p or miR-376b-3p existed in the RISC complex, and the study of SNHG1 as a miRNAs sponge binding to miRNAs and affecting the biological behavior of tumor cells has also been sighted in some reports.	('affecting', 'Reg', (177, 186))	('miR-376b', 'Gene', '574435', (72, 80))	('miR-154-5p', 'Var', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('binding', 'Interaction', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('miR-376b', 'Gene', (72, 80))	('tumor', 'Disease', (214, 219))
61994	30728054	A to I editing directed miRNAs to silence target genes, and existing studies have shown that the weakening of miR-376a* A to I editing in miR-376 family promotes the invasive ability of malignant glioma cells.	('miR-376a* A', 'Var', (110, 121))	('malignant glioma', 'Disease', (186, 202))	('malignant glioma', 'Disease', 'MESH:D005910', (186, 202))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('promotes', 'PosReg', (153, 161))
61996	30728054	This study confirms that SNHG1 interacts with miR-376b-3p, which is edited by A to I, and plays a sponge regulating effect of the miRNAs molecule, suggesting that SNHG1 and miR-376b-3p can produce stable effects in glioma cells.	('SNHG1', 'Var', (163, 168))	('miR-376b', 'Gene', '574435', (46, 54))	('miR-376b', 'Gene', '574435', (173, 181))	('glioma', 'Disease', (215, 221))	('miR-376b', 'Gene', (46, 54))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('miR-376b', 'Gene', (173, 181))
62003	30728054	Silencing the expression of FOXP2 inhibits the proliferation, migration, and invasion of glioma cells and promotes apoptosis; the overexpression of FOXP2 has the opposite effect.	('migration', 'CPA', (62, 71))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('inhibits', 'NegReg', (34, 42))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('FOXP2', 'Gene', (28, 33))	('promotes', 'PosReg', (106, 114))	('FOXP2', 'Gene', (148, 153))	('glioma', 'Disease', (89, 95))	('FOXP2', 'Gene', '93986', (28, 33))	('apoptosis', 'CPA', (115, 124))	('Silencing', 'Var', (0, 9))	('FOXP2', 'Gene', '93986', (148, 153))
62005	30728054	Further experiments showed that miR-154-5p and miR-376b-3p had targeted binding with 3 'UTR region of FOXP2, respectively.	('miR-376b', 'Gene', (47, 55))	('FOXP2', 'Gene', (102, 107))	('binding', 'Interaction', (72, 79))	('FOXP2', 'Gene', '93986', (102, 107))	('miR-376b', 'Gene', '574435', (47, 55))	('miR-154-5p', 'Var', (32, 42))
62006	30728054	The experiment shows that the overexpression of miR-154-5p or miR-376b-3 inhibits proliferation, migration, and invasion of malignant glioma and promotes apoptosis; the overexpression of FOXP2 promotes proliferation, migration, and invasion of malignant glioma and inhibits apoptosis; only the overexpression of 3 'UTR wild type FOXP2 can reverse the inhibition of proliferation, migration, and invasion of glioma cells mediated by overexpressing miR-154-5p or miR-376b-3p, and also promote apoptosis of the glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('miR-376b', 'Gene', (461, 469))	('FOXP2', 'Gene', (187, 192))	('apoptosis', 'CPA', (491, 500))	('migration', 'CPA', (380, 389))	('FOXP2', 'Gene', (329, 334))	('FOXP2', 'Gene', '93986', (187, 192))	('glioma', 'Disease', (407, 413))	('miR-376b', 'Gene', (62, 70))	('FOXP2', 'Gene', '93986', (329, 334))	('glioma', 'Disease', (254, 260))	('glioma', 'Disease', 'MESH:D005910', (407, 413))	('malignant glioma', 'Disease', 'MESH:D005910', (244, 260))	('malignant glioma', 'Disease', (124, 140))	('malignant glioma', 'Disease', (244, 260))	('glioma', 'Disease', (508, 514))	('miR-376b', 'Gene', '574435', (461, 469))	('malignant glioma', 'Disease', 'MESH:D005910', (124, 140))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('glioma', 'Disease', 'MESH:D005910', (508, 514))	('promote', 'PosReg', (483, 490))	('glioma', 'Disease', (134, 140))	('miR-376b', 'Gene', '574435', (62, 70))	('glioma', 'Phenotype', 'HP:0009733', (407, 413))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('glioma', 'Phenotype', 'HP:0009733', (508, 514))	('miR-154-5p', 'Var', (447, 457))	('invasion', 'CPA', (395, 403))
62007	30728054	These results suggest that the overexpression of miR-154-5p and miR-376b-3p may negatively regulate the biological behavior of malignant glioma by increasing the binding-to-target gene FOXP2 3'UTR.	('regulate', 'Reg', (91, 99))	('binding-to-target', 'Interaction', (162, 179))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('FOXP2', 'Gene', (185, 190))	('miR-376b', 'Gene', '574435', (64, 72))	('negatively', 'NegReg', (80, 90))	('increasing', 'PosReg', (147, 157))	('malignant glioma', 'Disease', (127, 143))	('miR-154-5p', 'Var', (49, 59))	('malignant glioma', 'Disease', 'MESH:D005910', (127, 143))	('FOXP2', 'Gene', '93986', (185, 190))	('miR-376b', 'Gene', (64, 72))	('overexpression', 'PosReg', (31, 45))
62009	30728054	KDM5B can produce histone 4 lysine (H3K4me3 and H3K4me2) demethylation of histone H3, thereby regulating the epigenetic changes of individuals.	('H3K4me3', 'Var', (36, 43))	('H3K4me2', 'Var', (48, 55))	('epigenetic changes', 'MPA', (109, 127))	('KDM5B', 'Gene', '10765', (0, 5))	('KDM5B', 'Gene', (0, 5))	('regulating', 'Reg', (94, 104))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))
62013	30728054	Silencing the expression of KDM5B inhibits the proliferation, migration, and invasion of glioma cells and promotes apoptosis; the overexpression of KDM5B has the opposite effect.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('inhibits', 'NegReg', (34, 42))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('promotes', 'PosReg', (106, 114))	('KDM5B', 'Gene', '10765', (28, 33))	('glioma', 'Disease', (89, 95))	('KDM5B', 'Gene', (28, 33))	('KDM5B', 'Gene', '10765', (148, 153))	('apoptosis', 'CPA', (115, 124))	('Silencing', 'Var', (0, 9))	('KDM5B', 'Gene', (148, 153))
62022	30728054	In vivo and in vitro studies have demonstrated that PI3K/Akt pathway inhibitors can inhibit the malignant biological behavior of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('inhibitors', 'Var', (69, 79))	('Akt', 'Gene', '207', (57, 60))	('inhibit', 'NegReg', (84, 91))	('glioma', 'Disease', (129, 135))	('Akt', 'Gene', (57, 60))
62023	30728054	This study illustrated that the overexpression of KDM5B increases p-PI3K/PI3K, p-Akt/Akt, and also increases the activity of PI3K/Akt pathway, promotes the proliferation, migration, and invasion of glioma cells, and inhibits apoptosis; The expression of silent KDM5B inhibits p-PI3K/PI3K, p-Akt/Akt, namely, inhibits the activity of PI3K/Akt pathway, and also inhibits the proliferation, migration, and invasion of glioma cells, and promotes apoptosis.	('proliferation', 'CPA', (373, 386))	('KDM5B', 'Gene', (261, 266))	('KDM5B', 'Gene', '10765', (50, 55))	('p-PI3K/PI3K', 'Pathway', (276, 287))	('Akt', 'Gene', '207', (295, 298))	('Akt', 'Gene', (85, 88))	('migration', 'CPA', (388, 397))	('increases', 'PosReg', (99, 108))	('inhibits', 'NegReg', (308, 316))	('apoptosis', 'CPA', (442, 451))	('Akt', 'Gene', (338, 341))	('Akt', 'Gene', '207', (85, 88))	('promotes', 'PosReg', (433, 441))	('KDM5B', 'Gene', '10765', (261, 266))	('Akt', 'Gene', (291, 294))	('inhibits', 'NegReg', (267, 275))	('Akt', 'Gene', '207', (338, 341))	('glioma', 'Disease', (415, 421))	('apoptosis', 'CPA', (225, 234))	('Akt', 'Gene', '207', (291, 294))	('glioma', 'Disease', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (415, 421))	('activity', 'MPA', (321, 329))	('Akt', 'Gene', (81, 84))	('KDM5B', 'Gene', (50, 55))	('Akt', 'Gene', (130, 133))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('inhibits', 'NegReg', (360, 368))	('Akt', 'Gene', '207', (81, 84))	('glioma', 'Phenotype', 'HP:0009733', (415, 421))	('Akt', 'Gene', '207', (130, 133))	('Akt', 'Gene', (295, 298))	('silent', 'Var', (254, 260))	('activity', 'MPA', (113, 121))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))
62030	30728054	Silencing the expression of KDM5B in cell experiments significantly reduced the expression of SNHG1 in glioma cells.	('SNHG1', 'Gene', (94, 99))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('KDM5B', 'Gene', '10765', (28, 33))	('expression', 'MPA', (80, 90))	('KDM5B', 'Gene', (28, 33))	('reduced', 'NegReg', (68, 75))	('Silencing', 'Var', (0, 9))	('glioma', 'Disease', (103, 109))
62032	30728054	Finally, by studying the nude mice experiments, we have proved that sh-SHNG1, miR-154-5p, miR-376b-3p, and sh-SHNG1 + miR-154-5p + miR-376b-3p could inhibit glioma cell tumor and prolong the survival period respectively, compared with the single application of sh-SHNG1, miR-154-5p, miR-376b-3p, the combination of the three factors had the smallest volume and longest survival time.	('inhibit', 'NegReg', (149, 156))	('miR-154-5p', 'Var', (78, 88))	('miR-376b', 'Gene', '574435', (131, 139))	('sh-SHNG1', 'Var', (68, 76))	('survival period', 'CPA', (191, 206))	('glioma cell tumor', 'Disease', 'MESH:D005910', (157, 174))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('miR-376b', 'Gene', '574435', (283, 291))	('nude mice', 'Species', '10090', (25, 34))	('glioma cell tumor', 'Disease', (157, 174))	('miR-376b', 'Gene', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('miR-376b', 'Gene', (131, 139))	('prolong', 'PosReg', (179, 186))	('miR-376b', 'Gene', '574435', (90, 98))	('miR-376b', 'Gene', (283, 291))
62033	30728054	The results suggest that the combined use of sh-SHNG1, miR-154-5p, and miR-376b-3p has potential clinical value.	('clinical', 'Species', '191496', (97, 105))	('miR-376b', 'Gene', '574435', (71, 79))	('miR-154-5p', 'Var', (55, 65))	('sh-SHNG1', 'Gene', (45, 53))	('miR-376b', 'Gene', (71, 79))
62034	30728054	In summary, this study demonstrates that SNHG1 increases the expression of FOXP2 and KDM5B by regulating the expression of miR-154-5p and miR-376b-3p, and that KDM5B itself and its downstream PI3K/Akt pathway affect the biological behavior of glioma cells.	('Akt', 'Gene', (197, 200))	('KDM5B', 'Gene', (85, 90))	('glioma', 'Disease', (243, 249))	('regulating', 'Reg', (94, 104))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('FOXP2', 'Gene', (75, 80))	('Akt', 'Gene', '207', (197, 200))	('KDM5B', 'Gene', '10765', (160, 165))	('FOXP2', 'Gene', '93986', (75, 80))	('affect', 'Reg', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('KDM5B', 'Gene', '10765', (85, 90))	('miR-376b', 'Gene', (138, 146))	('increases', 'PosReg', (47, 56))	('expression', 'MPA', (61, 71))	('miR-154-5p', 'Var', (123, 133))	('expression', 'MPA', (109, 119))	('KDM5B', 'Gene', (160, 165))	('miR-376b', 'Gene', '574435', (138, 146))
62040	27344556	We therefore evaluated the prognostic impact of extensive, mainly intraoperative (i)MRI-guided surgery in low-grade astrocytomas stratified for IDH1 mutation status.	('astrocytomas', 'Disease', 'MESH:D001254', (116, 128))	('astrocytomas', 'Disease', (116, 128))	('IDH1', 'Gene', (144, 148))	('mutation', 'Var', (149, 157))	('IDH1', 'Gene', '3417', (144, 148))
62045	27344556	In IDH1 mutant patients, smaller residual tumor volumes were associated with increased TTR (HR 1.01, p = 0.03).	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', (42, 47))	('smaller', 'NegReg', (25, 32))	('mutant', 'Var', (8, 14))	('TTR', 'MPA', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('increased', 'PosReg', (77, 86))	('IDH1', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IDH1', 'Gene', '3417', (3, 7))
62046	27344556	IDH1 mutation (38/46 cases) was an independent positive prognosticator for overall survival (OS) in multivariate analysis (HR 0.09, p = 0.002), while extensive surgery had limited impact upon OS.	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('overall survival', 'MPA', (75, 91))	('IDH1', 'Gene', '3417', (0, 4))
62047	27344556	In a subgroup of patients with >=40 % EOR (n = 39), however, initial and residual tumor volumes were prognostic for OS (HR 1.03, p = 0.005 and HR 1.08, p = 0.007, respectively), persistent to adjustment for IDH1.	('IDH1', 'Gene', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('IDH1', 'Gene', '3417', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('patients', 'Species', '9606', (17, 25))	('EOR', 'Var', (38, 41))	('tumor', 'Disease', (82, 87))
62055	27344556	In particular, mutations in the isocitrate dehydrogenase 1 (IDH1) encoding gene which are present in 70-80 % of LGGs confer a favorable outcome in astrocytomas and discriminate lower-grade tumors with a rather benign clinical course from IDH1 wildtype (wt) tumors, that molecularly and clinically behave like glioblastoma.	('astrocytomas', 'Disease', 'MESH:D001254', (147, 159))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('IDH1', 'Gene', (238, 242))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('IDH1', 'Gene', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumors', 'Disease', (189, 195))	('IDH1', 'Gene', '3417', (238, 242))	('glioblastoma', 'Disease', 'MESH:D005909', (309, 321))	('astrocytomas', 'Disease', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('isocitrate dehydrogenase 1', 'Gene', '3417', (32, 58))	('isocitrate dehydrogenase 1', 'Gene', (32, 58))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('glioblastoma', 'Disease', (309, 321))	('IDH1', 'Gene', '3417', (60, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (309, 321))
62073	27344556	Analysis was performed for the full study sample (n = 46), for IDH1 mutant (mt) patients (n = 38), for all patients with >=40 % EOR (n = 39) and for IDH1 mt patients with >=40 % EOR (n = 32).	('patients', 'Species', '9606', (107, 115))	('IDH1', 'Gene', '3417', (63, 67))	('patients', 'Species', '9606', (80, 88))	('IDH1', 'Gene', (149, 153))	('patients', 'Species', '9606', (157, 165))	('IDH1', 'Gene', '3417', (149, 153))	('IDH1', 'Gene', (63, 67))	('mutant', 'Var', (68, 74))
62078	27344556	IDH1 mutations were present in 38/46 cases (83 %).	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
62105	27344556	The anticipated prognostic impact of IDH1 mutation status was affirmed by a prolongation of OS in IDH1 mt patients in multivariate analysis (HR 0.09; 95 % CI 0.02-0.42; p = 0.002, Suppl.	('prolongation', 'PosReg', (76, 88))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', (98, 102))	('patients', 'Species', '9606', (106, 114))	('IDH1', 'Gene', '3417', (37, 41))	('IDH1', 'Gene', '3417', (98, 102))
62106	27344556	In contrast to OS, IDH1 mutation status did not impact on PFS, MPFS and TTR.	('IDH1', 'Gene', (19, 23))	('MPFS', 'Disease', (63, 67))	('IDH1', 'Gene', '3417', (19, 23))	('mutation', 'Var', (24, 32))	('PFS', 'Disease', (58, 61))	('TTR', 'Disease', (72, 75))
62108	27344556	dT2T1 was another prognosticator of PFS (HR 1.03; p = 0.028), a finding that was most pronounced in the subgroup of resectable tumors (>=40 % EOR/IDH1 mt) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH1', 'Gene', (146, 150))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('IDH1', 'Gene', '3417', (146, 150))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('dT2T1', 'Var', (0, 5))	('PFS', 'Disease', (36, 39))
62109	27344556	This study sought to evaluate the prognostic impact of extensive surgery in a histologically well-defined cohort of WHO grade II astrocytomas stratified for IDH1 mutation status.	('II astrocytomas', 'Disease', 'MESH:D001254', (126, 141))	('II astrocytomas', 'Disease', (126, 141))	('IDH1', 'Gene', (157, 161))	('mutation', 'Var', (162, 170))	('IDH1', 'Gene', '3417', (157, 161))
62111	27344556	With respect to OS, the anticipated prognostic impact of IDH1 mutation status was confirmed while a universal beneficial effect of extensive surgery was not observed.	('IDH1', 'Gene', '3417', (57, 61))	('IDH1', 'Gene', (57, 61))	('mutation status', 'Var', (62, 77))
62115	27344556	Our approach to exclusively analyze astrocytomas stratified for IDH1 mutation status from a consecutive LGG database reflects the effort to minimize biological confounders for surgical outcome analysis and clearly distinguishes this series from others published in literature.	('astrocytomas', 'Disease', (36, 48))	('IDH1', 'Gene', (64, 68))	('mutation', 'Var', (69, 77))	('IDH1', 'Gene', '3417', (64, 68))	('astrocytomas', 'Disease', 'MESH:D001254', (36, 48))
62116	27344556	As a proof of concept, IDH1 mutation status was an independent prognosticator for OS in our cohort which is in accordance with current literature and underlines the fact that we analyzed a representative patient sample.	('mutation', 'Var', (28, 36))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', (23, 27))	('patient', 'Species', '9606', (204, 211))
62117	27344556	A recent analysis of 200 consecutive LGG surgical cases demonstrated that IDH1 mutation status, among other molecular markers, is independent of EOR, a finding that was affirmed by our association study as well.	('IDH1', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('IDH1', 'Gene', '3417', (74, 78))
62121	27344556	However, our data provide no evidence for a significant association between dT2T1 and EOR or residual tumor volumes on the one hand and dT2T1 and IDH1 mutation status on the other hand.	('EOR', 'CPA', (86, 89))	('IDH1', 'Gene', (146, 150))	('dT2T1', 'Gene', (136, 141))	('IDH1', 'Gene', '3417', (146, 150))	('mutation', 'Var', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('dT2T1', 'Gene', (76, 81))
62122	27344556	Even though IDH mutations are early events in the formation of LGGs, their role in gliomagenesis is not particularly linked to invasiveness of tumor cells but rather to aberrant cellular metabolism resulting in oncometabolites.	('glioma', 'Disease', (83, 89))	('invasiveness of tumor', 'Disease', 'MESH:D009369', (127, 148))	('mutations', 'Var', (16, 25))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('oncometabolites', 'MPA', (211, 226))	('invasiveness of tumor', 'Disease', (127, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cellular metabolism', 'MPA', (178, 197))
62152	22427879	Co-Deletion of Chromosome 1p/19q and IDH1/2 Mutation in Glioma Subsets of Brain Tumors in Chinese Patients To characterize co-deletion of chromosome 1p/19q and IDH1/2 mutation in Chinese brain tumor patients and to assess their associations with clinical features.	('IDH1', 'Gene', (160, 164))	('Tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Mutation', 'Var', (44, 52))	('IDH1', 'Gene', '3417', (160, 164))	('co-deletion', 'Var', (123, 134))	('mutation', 'Var', (167, 175))	('IDH1', 'Gene', (37, 41))	('Glioma', 'Phenotype', 'HP:0009733', (56, 62))	('Co-Deletion', 'Var', (0, 11))	('Glioma Subsets of Brain Tumors', 'Disease', 'MESH:C564230', (56, 86))	('Glioma Subsets of Brain Tumors', 'Disease', (56, 86))	('brain tumor', 'Phenotype', 'HP:0030692', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('IDH1', 'Gene', '3417', (37, 41))	('patients', 'Species', '9606', (199, 207))	('Tumors', 'Phenotype', 'HP:0002664', (80, 86))	('brain tumor', 'Disease', (187, 198))	('Brain Tumors', 'Phenotype', 'HP:0030692', (74, 86))	('brain tumor', 'Disease', 'MESH:D001932', (187, 198))
62157	22427879	Gliomas of frontal origin had significantly higher incidence of 1p/19q co-deletion (50.4%) and IDH1/2 mutation (73.5%) than those of non-frontal origin (27.0% and 48.5%, respectively) (P<0.001), while gliomas of temporal origin had significantly lower incidence of 1p/19q co-deletion (23.9%) and IDH1/2 mutation (41.7%) than those of non-temporal origin (39.9% and 63.2%, respectively) (P = 0.013 and P = 0.003, respectively).	('gliomas', 'Disease', (201, 208))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('1p/19q co-deletion', 'Var', (64, 82))	('1p/19q', 'Var', (265, 271))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('Gliomas', 'Disease', (0, 7))
62160	22427879	However, gliomas from different sides of the brain did not show significant different pathological constituents, incidences of 1p/19q co-deletion or IDH1/2 mutation.	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('1p/19q', 'Gene', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('IDH1/2', 'Gene', (149, 155))	('mutation', 'Var', (156, 164))
62161	22427879	Preferential distribution of pathological subsets, 1p/19q co-deletion and IDH1/2 mutation were confirmed in some brain regions in Chinese glioma patients, implying their distinctive tumor genesis and predictive value for prognosis.	('patients', 'Species', '9606', (145, 153))	('glioma', 'Disease', (138, 144))	('tumor', 'Disease', (182, 187))	('IDH1/2', 'Gene', (74, 80))	('mutation', 'Var', (81, 89))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('1p/19q co-deletion', 'Var', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
62167	22427879	Co-deletion of 1p and 19q is associated with longer progression-free time and longer median survival time, thus representing an independent prognostic factor in anaplastic oligodendroglial tumors (WHO grade III).	('Co-deletion', 'Var', (0, 11))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (161, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('anaplastic oligodendroglial tumors', 'Disease', (161, 195))	('longer', 'PosReg', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
62168	22427879	Similarly, 1p/19q co-deletion also predicts a longer radiographic response to temozolomide and is associated with both superior overall survival and progression-free survival in low-grade oligodendroglial tumors.	('temozolomide', 'Chemical', 'MESH:D000077204', (78, 90))	('longer', 'PosReg', (46, 52))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (188, 211))	('radiographic response to temozolomide', 'MPA', (53, 90))	('oligodendroglial tumors', 'Disease', (188, 211))	('1p/19q co-deletion', 'Var', (11, 29))	('superior', 'PosReg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))
62169	22427879	The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology.	('IDH', 'Gene', '3417', (68, 71))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('glioblastoma', 'Disease', (126, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (126, 138))	('cancer', 'Disease', (171, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('isocitrate dehydrogenase', 'Gene', (42, 66))	('IDH', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('isocitrate dehydrogenase', 'Gene', '3417', (42, 66))
62170	22427879	Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors (WHO grade II and III) and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas.	('mutations', 'Var', (27, 36))	('oligodendroglial tumors', 'Disease', (55, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('glioblastomas', 'Phenotype', 'HP:0012174', (218, 231))	('IDH1', 'Gene', '3417', (172, 176))	('glioblastomas', 'Phenotype', 'HP:0012174', (119, 132))	('astrocytic', 'Disease', (40, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('glioblastomas', 'Disease', 'MESH:D005909', (218, 231))	('glioblastomas', 'Disease', (218, 231))	('glioblastomas', 'Disease', 'MESH:D005909', (119, 132))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('IDH1', 'Gene', (22, 26))	('glioblastomas', 'Disease', (119, 132))	('IDH1', 'Gene', '3417', (22, 26))	('IDH1', 'Gene', (172, 176))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (55, 78))
62171	22427879	Patients with diffusely infiltrative gliomas carrying an IDH1 mutation have a significantly longer overall survival compared to patients with IDH1 wild type.	('IDH1', 'Gene', '3417', (142, 146))	('diffusely', 'Disease', (14, 23))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', (142, 146))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Disease', (37, 44))	('mutation', 'Var', (62, 70))	('IDH1', 'Gene', '3417', (57, 61))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('patients', 'Species', '9606', (128, 136))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('longer', 'PosReg', (92, 98))
62172	22427879	IDH1 codon 132 mutations were found to be associated with reduced NADP-dependent IDH activity in glioblastoma.	('IDH', 'Gene', (0, 3))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('IDH', 'Gene', '3417', (81, 84))	('NADP', 'Chemical', 'MESH:D009249', (66, 70))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (15, 24))	('IDH1', 'Gene', (0, 4))	('IDH', 'Gene', (81, 84))	('NADP-dependent', 'MPA', (66, 80))	('reduced', 'NegReg', (58, 65))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('IDH1', 'Gene', '3417', (0, 4))
62173	22427879	The low NADPH levels may sensitize glioblastoma to irradiation and chemotherapy, thus explaining the prolonged survival of patients with mutated glioblastoma.	('NADPH levels', 'MPA', (8, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('glioblastoma', 'Disease', (35, 47))	('patients', 'Species', '9606', (123, 131))	('glioblastoma', 'Disease', (145, 157))	('NADPH', 'Chemical', 'MESH:D009249', (8, 13))	('mutated', 'Var', (137, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('sensitize', 'Reg', (25, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
62177	22427879	Besides, some studies identified an association between the incidence of 1p/19q co-deletion, IDH1/2 mutation and tumor locations.	('tumor', 'Disease', (113, 118))	('IDH1/2', 'Gene', (93, 99))	('mutation', 'Var', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('1p/19q co-deletion', 'Var', (73, 91))
62178	22427879	suggested that tumor genotypes were closely associated with tumor locations, because they found that anaplastic oligodendrogliomas located in the frontal, parietal, and occipital lobes were significantly more likely to harbor allelic loss of chromosome 1p and 19q than histologically indistinguishable tumors arising in the temporal lobe, insula, and diencephalon; in addition, loss of heterozygosity (LOH) for 1p and 19q was significantly associated with a bilateral pattern of growth.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('diencephalon', 'Disease', 'None', (351, 363))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('diencephalon', 'Disease', (351, 363))	('tumors', 'Disease', (302, 308))	('insula', 'Disease', (339, 345))	('tumor', 'Disease', (60, 65))	('loss of heterozygosity', 'Var', (378, 400))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('oligodendrogliomas', 'Disease', (112, 130))	('occipital lobes', 'Disease', (169, 184))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('occipital lobes', 'Disease', 'MESH:D004828', (169, 184))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('growth', 'MPA', (479, 485))	('tumor', 'Disease', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (15, 20))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('insula', 'Disease', 'None', (339, 345))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (112, 130))
62179	22427879	reported that allelic loss of 1p and 19q was significantly less frequent in temporal oligodendrogliomas and oligoastrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('allelic loss', 'Var', (14, 26))	('less', 'NegReg', (59, 63))	('temporal oligodendrogliomas and oligoastrocytomas', 'Disease', 'MESH:D001254', (76, 125))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))
62180	22427879	reported that oligodendroglial tumors having LOH of 1p and 19q occurred most frequently in the non-temporal lobes.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('LOH', 'Var', (45, 48))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (14, 37))	('oligodendroglial tumors', 'Disease', (14, 37))
62181	22427879	reported a relatively lower incidence of allelic loss of chromosome 1p and 19q in a consecutive series of 12 Grade II gliomas involving the insula.	('II gliomas', 'Disease', 'MESH:D005910', (115, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('insula', 'Disease', 'None', (140, 146))	('allelic loss', 'Var', (41, 53))	('insula', 'Disease', (140, 146))	('II gliomas', 'Disease', (115, 125))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
62182	22427879	reported a high rate of 1p/19q co-deletion in insular oligodendroglial tumors.	('insular oligodendroglial tumors', 'Disease', (46, 77))	('insular oligodendroglial tumors', 'Disease', 'MESH:D009369', (46, 77))	('1p/19q co-deletion', 'Var', (24, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
62183	22427879	It was also found that IDH1 mutant glioblastomas predominantly involved the frontal lobe.	('glioblastomas', 'Disease', 'MESH:D005909', (35, 48))	('glioblastomas', 'Disease', (35, 48))	('mutant', 'Var', (28, 34))	('involved', 'Reg', (63, 71))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (23, 27))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))
62184	22427879	To investigate whether subsets, 1p/19q co-deletion and IDH1/2 mutation of the tumors are correlated with tumor locations in Chinese glioma patients, we analyzed a series of 528 gliomas for the correlation of their pathological constituents of subsets, the incidence of 1p/19q co-deletion and IDH1/2 mutation with tumor locations.	('glioma', 'Disease', (132, 138))	('tumor', 'Disease', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH1/2', 'Gene', (292, 298))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('gliomas', 'Disease', (177, 184))	('glioma', 'Disease', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('tumors', 'Disease', (78, 84))	('patients', 'Species', '9606', (139, 147))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (78, 83))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutation', 'Var', (299, 307))	('1p/19q co-deletion', 'Var', (269, 287))
62203	22427879	Chi-square (chi2) test was used for the comparison of differences among regional constituents of pathological subsets, regional percentages of tumor subsets and regional incidences of 1p/19q co-deletion and IDH1/2 mutation.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('IDH1/2', 'Gene', (207, 213))	('mutation', 'Var', (214, 222))	('tumor', 'Disease', (143, 148))	('1p/19q co-deletion', 'Var', (184, 202))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
62222	22427879	In 339 gliomas, the mean global incidence of 1p/19q co-deletion was 36.6%.	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('1p/19q co-deletion', 'Var', (45, 63))	('gliomas', 'Disease', (7, 14))	('gliomas', 'Disease', 'MESH:D005910', (7, 14))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))
62223	22427879	Irrespective of pathology, the incidence of 1p/19q co-deletion in gliomas of the frontal origin (50.4%) was significantly higher than that of non-frontal origin (27.0%) (P<0.001).	('higher', 'PosReg', (122, 128))	('1p/19q co-deletion', 'Var', (44, 62))	('gliomas of the frontal', 'Disease', (66, 88))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas of the frontal', 'Disease', 'MESH:D005910', (66, 88))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))
62224	22427879	The incidence of 1p/19q co-deletion in gliomas of the temporal origin (23.9%) was significantly lower than that of non-temporal origin (39.9%) (P = 0.013).	('lower', 'NegReg', (96, 101))	('1p/19q co-deletion', 'Var', (17, 35))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Disease', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
62225	22427879	The incidence of 1p/19q co-deletion in deeply located gliomas (13.3%) showed a trend to be lower than that of non-deeply located gliomas (37.7%), but the difference did not reach statistical significance (P = 0.056).	('lower', 'NegReg', (91, 96))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('1p/19q co-deletion', 'Var', (17, 35))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
62226	22427879	In 280 gliomas, the mean global incidence of IDH1/2 mutation was 58.6%.	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('IDH1/2', 'Gene', (45, 51))	('gliomas', 'Disease', (7, 14))	('mutation', 'Var', (52, 60))	('gliomas', 'Disease', 'MESH:D005910', (7, 14))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))
62227	22427879	Irrespective of pathology, the incidence of IDH1/2 mutation in gliomas of the frontal origin (73.5%) was significantly higher than that of non-frontal origin (48.5%) (P<0.001).	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas of the frontal', 'Disease', (63, 85))	('IDH1/2', 'Gene', (44, 50))	('higher', 'PosReg', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('mutation', 'Var', (51, 59))	('gliomas of the frontal', 'Disease', 'MESH:D005910', (63, 85))
62228	22427879	The incidence of IDH1/2 mutation in gliomas of the temporal origin (41.7%) was significantly lower than that of non-temporal origin (63.2%) (P = 0.003).	('gliomas', 'Disease', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('lower', 'NegReg', (93, 98))	('IDH1/2', 'Gene', (17, 23))	('mutation', 'Var', (24, 32))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
62229	22427879	The incidence of IDH1/2 mutation in gliomas of parietal origin (43.3%) showed a trend to be lower than that of non-parietal origin (60.4%) (P = 0.073).	('gliomas', 'Disease', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('IDH1/2', 'Gene', (17, 23))	('mutation', 'Var', (24, 32))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('lower', 'NegReg', (92, 97))
62230	22427879	Furthermore, the incidence of IDH1/2 mutation in deeply located gliomas (35.7%) showed a trend to be lower than that of non-deeply located gliomas (59.8%) (P = 0.075).	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('mutation', 'Var', (37, 45))	('gliomas', 'Disease', (139, 146))	('IDH1/2', 'Gene', (30, 36))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('gliomas', 'Disease', (64, 71))	('lower', 'NegReg', (101, 106))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))
62231	22427879	In 111 oligoastrocytic tumors (Grade II and III), the mean global incidence of 1p/19q co-deletion was 42.3%.	('oligoastrocytic tumors', 'Disease', (7, 29))	('1p/19q co-deletion', 'Var', (79, 97))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (7, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
62232	22427879	The incidence of 1p/19q co-deletion in oligoastrocytic tumors of the frontal origin (58.0%) was significantly higher than that of non-frontal origin (29.5%) (P = 0.003).	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('1p/19q co-deletion', 'Var', (17, 35))	('oligoastrocytic tumors of the frontal', 'Disease', (39, 76))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('oligoastrocytic tumors of the frontal', 'Disease', 'MESH:D001932', (39, 76))	('higher', 'PosReg', (110, 116))
62233	22427879	The incidence of 1p/19q co-deletion in oligoastrocytic tumors of the temporal origin (18.8%) was significantly lower than that of non-temporal origin (46.3%) (P = 0.039).	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (39, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('1p/19q co-deletion', 'Var', (17, 35))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('lower', 'NegReg', (111, 116))	('oligoastrocytic tumors', 'Disease', (39, 61))
62234	22427879	For oligoastrocytic tumors, however, the incidences of 1p/19q co-deletion between different sides of the brain (47.1%, 36.5% and 50.0%, respectively) were not significantly different.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('oligoastrocytic tumors', 'Disease', (4, 26))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (4, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('1p/19q co-deletion', 'Var', (55, 73))
62235	22427879	In 104 oligoastrocytic tumors (Grade II and III), the mean global incidence of IDH1/2 mutation was 54.8%.	('oligoastrocytic tumors', 'Disease', (7, 29))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (7, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutation', 'Var', (86, 94))	('IDH1/2', 'Gene', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
62236	22427879	The incidence of IDH1/2 mutation in oligoastrocytic tumors of the frontal origin (70.0%) was significantly higher than that of non-frontal origin (45.3%) (P = 0.014).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('oligoastrocytic tumors of the frontal', 'Disease', (36, 73))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('oligoastrocytic tumors of the frontal', 'Disease', 'MESH:D001932', (36, 73))	('IDH1/2', 'Gene', (17, 23))	('mutation', 'Var', (24, 32))	('higher', 'PosReg', (107, 113))
62237	22427879	The incidence of IDH1/2 mutation in oligoastrocytic tumors of the temporal origin (30.4%) was significantly lower than that of non-temporal origin (61.7%) (P = 0.008).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (36, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('IDH1/2', 'Gene', (17, 23))	('lower', 'NegReg', (108, 113))	('mutation', 'Var', (24, 32))	('oligoastrocytic tumors', 'Disease', (36, 58))
62238	22427879	The incidence of IDH1/2 mutation in oligoastrocytic tumors of the insular origin (81.3%) was significantly higher than that of non-insular origin (50.0%) (P = 0.021).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('insula', 'Disease', (131, 137))	('oligoastrocytic tumors of the insular', 'Disease', 'MESH:D009369', (36, 73))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('higher', 'PosReg', (107, 113))	('insula', 'Disease', 'None', (66, 72))	('IDH1/2', 'Gene', (17, 23))	('mutation', 'Var', (24, 32))	('oligoastrocytic tumors of the insular', 'Disease', (36, 73))	('insula', 'Disease', 'None', (131, 137))	('insula', 'Disease', (66, 72))
62239	22427879	For oligoastrocytic tumors, however, the incidences of IDH1/2 mutation between different sides of the brain (57.4%, 50.0% and 100.0%, respectively) were not significantly different.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('oligoastrocytic tumors', 'Disease', (4, 26))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (4, 26))	('mutation', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH1/2', 'Gene', (55, 61))
62240	22427879	In 78 oligodendroglial tumors (Grade II and III), the mean global incidence of 1p/19q co-deletion was 74.4%.	('1p/19q co-deletion', 'Var', (79, 97))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (6, 29))	('oligodendroglial tumors', 'Disease', (6, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
62241	22427879	The incidence of 1p/19q co-deletion in oligodendroglial tumors of the frontal origin (84.6%) was significantly higher than that of non-frontal origin (64.1%) (P = 0.038).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('oligodendroglial tumors of the frontal', 'Disease', 'MESH:D001932', (39, 77))	('oligodendroglial tumors of the frontal', 'Disease', (39, 77))	('1p/19q co-deletion', 'Var', (17, 35))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('higher', 'PosReg', (111, 117))
62242	22427879	The incidence of 1p/19q co-deletion in oligodendroglial tumors of the temporal origin (50.0%) showed a trend to be lower than that of non-temporal origin (78.8%), but the difference did not reach significance (P = 0.082).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (39, 62))	('oligodendroglial tumors', 'Disease', (39, 62))	('1p/19q co-deletion', 'Var', (17, 35))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('lower', 'NegReg', (115, 120))
62243	22427879	For oligodendroglial tumors, however, the incidences of 1p/19q co-deletion between different sides of the brain (76.9%, 68.6% and 100.0%, respectively) were not significantly different.	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (4, 27))	('oligodendroglial tumors', 'Disease', (4, 27))	('1p/19q co-deletion', 'Var', (56, 74))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
62244	22427879	In 71 oligodendroglial tumors (Grade II and III), the mean global incidence of IDH1/2 mutation was 81.7%.	('IDH1/2', 'Gene', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutation', 'Var', (86, 94))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (6, 29))	('oligodendroglial tumors', 'Disease', (6, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
62245	22427879	The incidence of IDH1/2 mutation in oligodendroglial tumors of the frontal origin (92.7%) was significantly higher than that of non-frontal origin (66.7%) (P = 0.005).	('oligodendroglial tumors of the frontal', 'Disease', (36, 74))	('oligodendroglial tumors of the frontal', 'Disease', 'MESH:D001932', (36, 74))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH1/2', 'Gene', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (24, 32))
62246	22427879	The incidence of IDH1/2 mutation in oligodendroglial tumors of the temporal origin (40.0%) was significantly lower than that of non-temporal origin (88.5%) (P = 0.001).	('lower', 'NegReg', (109, 114))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (36, 59))	('oligodendroglial tumors', 'Disease', (36, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH1/2', 'Gene', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (24, 32))
62247	22427879	For oligodendroglial tumors, however, the incidences of IDH1/2 mutation between different sides of the brain (84.8%, 75.8% and 100.0%, respectively) were not significantly different.	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mutation', 'Var', (63, 71))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (4, 27))	('oligodendroglial tumors', 'Disease', (4, 27))	('IDH1/2', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
62248	22427879	In 150 astrocytic tumors (Grade II, III and IV), the mean global incidence of 1p/19q co-deletion was 12.7%.	('astrocytic tumors', 'Disease', (7, 24))	('1p/19q co-deletion', 'Var', (78, 96))	('astrocytic tumors', 'Disease', 'MESH:D001254', (7, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
62249	22427879	Astrocytic tumors did not show different incidences of 1p/19q co-deletion with respect to tumor location.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Astrocytic tumors', 'Disease', 'MESH:D001254', (0, 17))	('Astrocytic tumors', 'Disease', (0, 17))	('1p/19q co-deletion', 'Var', (55, 73))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
62250	22427879	For astrocytic tumors, the incidences of 1p/19q co-deletion between different sides of the brain (15.4%, 10.8% and 9.1%, respectively) were not significantly different either.	('astrocytic tumors', 'Disease', 'MESH:D001254', (4, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('1p/19q co-deletion', 'Var', (41, 59))	('astrocytic tumors', 'Disease', (4, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
62251	22427879	In 105 astrocytic tumors (Grade II and III), the mean global incidence of IDH1/2 mutation was 46.7%.	('astrocytic tumors', 'Disease', (7, 24))	('astrocytic tumors', 'Disease', 'MESH:D001254', (7, 24))	('IDH1/2', 'Gene', (74, 80))	('mutation', 'Var', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
62252	22427879	The incidence of IDH1/2 mutation in astrocytic tumors of parietal origin (0.0%) was significantly lower than that of non-parietal origin (51.0%) (P = 0.003).	('lower', 'NegReg', (98, 103))	('astrocytic tumors', 'Disease', (36, 53))	('IDH1/2', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutation', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('astrocytic tumors', 'Disease', 'MESH:D001254', (36, 53))
62253	22427879	For astrocytic tumors, the incidences of IDH1/2 mutation between different sides of the brain (42.6%, 54.2% and 30.0%, respectively) were not significantly different.	('astrocytic tumors', 'Disease', 'MESH:D001254', (4, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutation', 'Var', (48, 56))	('IDH1/2', 'Gene', (41, 47))	('astrocytic tumors', 'Disease', (4, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
62254	22427879	In the present study, we reviewed a series of 528 cases of gliomas retrospectively and compared regional constituents of pathological subsets, regional incidences of 1p/19q co-deletion and IDH1/2 mutation.	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('1p/19q co-deletion', 'Var', (166, 184))	('gliomas', 'Disease', (59, 66))	('IDH1/2', 'Gene', (189, 195))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
62255	22427879	This study provided a detailed incidence map of glioma subsets (relative), 1p/19q co-deletion and IDH1/2 mutation cross the brain in Chinese patients.	('mutation', 'Var', (105, 113))	('1p/19q', 'Gene', (75, 81))	('glioma', 'Disease', (48, 54))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('IDH1/2', 'Gene', (98, 104))	('patients', 'Species', '9606', (141, 149))
62257	22427879	We also showed that gliomas of the frontal lobe had significantly higher incidence of 1p/19q co-deletion (50.4%) and IDH1/2 mutation (73.5%) than those of non-frontal origin (27.0% and 48.5%, respectively), while gliomas of the temporal origin have significantly lower incidence of 1p/19q co-deletion (23.9%) and IDH1/2 mutation (41.7%) than those of non-temporal origin (39.9% and 63.2%, respectively).	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('gliomas of the frontal lobe', 'Disease', (20, 47))	('gliomas', 'Disease', (213, 220))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('1p/19q co-deletion', 'Var', (86, 104))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas of the frontal lobe', 'Disease', 'MESH:C564230', (20, 47))	('gliomas', 'Disease', (20, 27))
62259	22427879	These findings revealed preferential distribution of pathological subsets, 1p/19q co-deletion, and IDH1/2 mutation and implied the distinctiveness among different brain lobes.	('1p/19q co-deletion', 'Var', (75, 93))	('IDH1/2', 'Gene', (99, 105))	('mutation', 'Var', (106, 114))	('brain lobes', 'Disease', (163, 174))	('brain lobes', 'Disease', 'MESH:D001927', (163, 174))
62260	22427879	Although Lai reported a striking predominance of frontal lobe involvement of primary GBM with IDH1 mutation, we provided a more detailed incidence map of IDH1/2 mutation in diffuse gliomas (WHO grade II and III) cross the brain and revealed the preferential distribution of IDH1/2 mutation.	('IDH1', 'Gene', (94, 98))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('mutation', 'Var', (161, 169))	('IDH1', 'Gene', '3417', (94, 98))	('IDH1', 'Gene', (274, 278))	('mutation', 'Var', (99, 107))	('IDH1', 'Gene', (154, 158))	('IDH1', 'Gene', '3417', (274, 278))	('gliomas', 'Disease', (181, 188))	('IDH1', 'Gene', '3417', (154, 158))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
62261	22427879	The distribution of IDH1/2 mutation resembles that of 1p/19q co-deletion and provided another evidence for the distinctiveness of gliomas from different brain lobes.	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('brain lobes', 'Disease', (153, 164))	('IDH1/2', 'Gene', (20, 26))	('gliomas', 'Disease', (130, 137))	('mutation', 'Var', (27, 35))	('brain lobes', 'Disease', 'MESH:D001927', (153, 164))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
62272	22427879	In our study, subgroup analysis confirmed the finding that the incidence of 1p/19q co-deletion was higher in the frontal lobe and lower in the temporal lobe in both oligodendroglial and oligoastrocytic tumors.	('lower', 'NegReg', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('co-deletion', 'Var', (83, 94))	('1p/19q co-deletion', 'Var', (76, 94))	('oligodendroglial and oligoastrocytic tumors', 'Disease', 'MESH:D009369', (165, 208))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
62274	22427879	In Mueller's report, the frequency of 1p/19q co-deletion in the temporal lobe (23.1%) was less than that in non-temporal lobes (81.7%) in oligodendroglial tumors and the frequency in the temporal lobe (33.3%) was less than that in non-temporal lobes (71,4%) in oligoastrocytic tumors.	('less', 'NegReg', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('1p/19q co-deletion', 'Var', (38, 56))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('oligoastrocytic tumors', 'Disease', (261, 283))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (261, 283))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (138, 161))	('oligodendroglial tumors', 'Disease', (138, 161))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
62278	22427879	It was disputable that gliomas in the insular lobe had a lower incidence of 1p/19q co-deletion.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('gliomas in the insular lobe', 'Disease', (23, 50))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('1p/19q co-deletion', 'Var', (76, 94))	('gliomas in the insular lobe', 'Disease', 'MESH:D005910', (23, 50))
62279	22427879	studied co-deletion of 1p/19q in a series of 12 Grade II gliomas, including 11 oligodendrogliomas and 1 oligoastrocytoma, in which they found no complete deletion of 1p/19q in them.	('oligoastrocytoma', 'Disease', 'MESH:D001254', (104, 120))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (79, 97))	('oligoastrocytoma', 'Disease', (104, 120))	('co-deletion', 'Var', (8, 19))	('II gliomas', 'Disease', 'MESH:D005910', (54, 64))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('oligodendrogliomas', 'Disease', (79, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('II gliomas', 'Disease', (54, 64))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
62280	22427879	analyzed a series of insular oligodendroglial tumors (n = 14) and found that the frequencies of co-deletion of 1p/19q were 50% in oligodendrogliomas (Grade II and III, n = 8) and 67% in oligoastrocytomas (Grade II and III, n = 6).	('oligodendrogliomas', 'Disease', 'MESH:D009837', (130, 148))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('co-deletion', 'Var', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('oligodendrogliomas', 'Disease', (130, 148))	('oligoastrocytomas', 'Disease', (186, 203))	('insular oligodendroglial tumors', 'Disease', (21, 52))	('1p/19q', 'Gene', (111, 117))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (186, 203))	('insular oligodendroglial tumors', 'Disease', 'MESH:D009369', (21, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (191, 202))
62281	22427879	Our study with the largest series of patients demonstrated high frequencies of 1p/19q co-deletion in oligodendroglial (90.0%, n = 10) and oligoastrocytic tumors (45.0%, n = 20) of the insular origin.	('insula', 'Disease', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('oligodendroglial', 'Disease', (101, 117))	('patients', 'Species', '9606', (37, 45))	('oligoastrocytic tumors', 'Disease', (138, 160))	('1p/19q co-deletion', 'Var', (79, 97))	('oligoastrocytic tumors', 'Disease', 'MESH:D009369', (138, 160))	('insula', 'Disease', 'None', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
62282	22427879	Thanks to the preferential distribution of low-grade gliomas in the insular lobe with a common incidence of 1p/19q co-deletion, favorable outcomes can be expected as reported by Sanai et al..	('gliomas in the insular lobe', 'Disease', (53, 80))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas in the insular lobe', 'Disease', 'MESH:D005910', (53, 80))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('1p/19q co-deletion', 'Var', (108, 126))
62289	22427879	In spite of these weaknesses, our results and conclusions about constituents of tumor subsets, incidences of 1p/19q co-deletion and IDH 1/2 mutation are convincing and reliable.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('1p/19q', 'Gene', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('weakness', 'Disease', (18, 26))	('weakness', 'Disease', 'MESH:D018908', (18, 26))	('IDH 1/2', 'Gene', '3417;3418', (132, 139))	('mutation', 'Var', (140, 148))	('tumor', 'Disease', (80, 85))	('IDH 1/2', 'Gene', (132, 139))
62290	22427879	In conclusion, by comparing regional constituents of pathological subsets, incidences of 1p/19q co-deletion and IDH1/2 mutation in Chinese patients with gliomas, preferential distribution of tumor subsets, 1p/19q co-deletion and IDH1/2 mutation was confirmed in certain brain regions, implying their distinctiveness in tumor genesis and predictive value for prognosis in Chinese patient populations.	('tumor', 'Disease', (319, 324))	('mutation', 'Var', (119, 127))	('gliomas', 'Disease', (153, 160))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('patients', 'Species', '9606', (139, 147))	('IDH1/2', 'Gene', (112, 118))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('patient', 'Species', '9606', (379, 386))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('patient', 'Species', '9606', (139, 146))
62298	21171016	Co-expression of PDGFB and Bcl-2 promotes progression to AO with prominent foci of necrosis, a feature of high-grade gliomas.	('PDGFB', 'Gene', (17, 22))	('promotes', 'PosReg', (33, 41))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('Bcl-2', 'Gene', (27, 32))	('gliomas', 'Disease', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('foci of necrosis', 'Disease', 'MESH:D009336', (75, 91))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('foci of necrosis', 'Disease', (75, 91))	('Co-expression', 'Var', (0, 13))	('progression', 'MPA', (42, 53))
62299	21171016	Median tumor latency was shorter in mice injected with PDGFB and Bcl-2 compared to those injected with PDGFB alone.	('tumor', 'Disease', (7, 12))	('shorter', 'NegReg', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('PDGFB', 'Var', (55, 60))
62300	21171016	Although independent expression of Bcl-2 was insufficient to induce tumors, suppression of apoptosis (detected by cleaved caspase-3 expression) was more pronounced in AOs induced by PDGFB and Bcl-2 compared to those induced by PDGFB alone.	('tumors', 'Disease', (68, 74))	('caspase-3', 'Gene', '12367', (122, 131))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('apoptosis', 'CPA', (91, 100))	('suppression', 'NegReg', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('insufficient', 'Disease', (45, 57))	('insufficient', 'Disease', 'MESH:D000309', (45, 57))	('caspase-3', 'Gene', (122, 131))	('AOs', 'Disease', (167, 170))	('PDGFB', 'Var', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
62313	21171016	Genetic alterations in PDGF and PDGFR characterize a significant subset of high-grade gliomas .	('Genetic alterations', 'Var', (0, 19))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('PDGFR', 'Gene', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('PDGF', 'Gene', (23, 27))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))	('PDGFR', 'Gene', '18596', (32, 37))
62323	21171016	Members of the B-cell lymphoma-2 (Bcl-2) family of genes are potent suppressors of apoptosis, and alterations in their expression contribute to tumorigenesis .	('expression', 'MPA', (119, 129))	('tumor', 'Disease', (144, 149))	('B-cell lymphoma-2', 'Gene', '12043', (15, 32))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('lymphoma', 'Phenotype', 'HP:0002665', (22, 30))	('contribute to', 'Reg', (130, 143))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (15, 30))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('B-cell lymphoma-2', 'Gene', (15, 32))	('Bcl-2', 'Gene', (34, 39))	('alterations', 'Var', (98, 109))
62326	21171016	The anti-apoptotic effect of these genes may shift the tumor to the anaplastic phenotype by inducing a different mechanism of cell death - necrosis, a cardinal feature of high-grade gliomas .	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('death - necrosis', 'Disease', 'MESH:D003643', (131, 147))	('death - necrosis', 'Disease', (131, 147))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('cell', 'CPA', (126, 130))	('tumor', 'Disease', (55, 60))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('inducing', 'Reg', (92, 100))	('anti-apoptotic', 'CPA', (4, 18))	('gliomas', 'Disease', (182, 189))	('genes', 'Var', (35, 40))
62379	21171016	Tumors were identified in 27 of 33 (82%) mice coinjected with RCAS-PDGFB + RCAS-Bcl-2, whereas injection of RCAS-PDGFB alone resulted in 11 tumors in 26 mice (42%) (chi-square test, P=0.002).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RCAS', 'Chemical', '-', (75, 79))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('RCAS', 'Chemical', '-', (108, 112))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('RCAS', 'Chemical', '-', (62, 66))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (153, 157))	('RCAS-PDGFB +', 'Var', (62, 74))
62393	21171016	As a comparison group for symptomatic tumor formation, we injected RCAS-PDGFB and RCAS-IGFBP2 into a cohort of Ntv-a mice (N=30).	('RCAS', 'Chemical', '-', (82, 86))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Ntv-a', 'Chemical', '-', (111, 116))	('RCAS-IGFBP2', 'Var', (82, 93))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('RCAS', 'Chemical', '-', (67, 71))
62402	21171016	The median mitotic index in tumors generated by RCAS-PDGFB + RCAS-Bcl-2 was 8.1% (range 1.9% to 22%).	('RCAS', 'Chemical', '-', (61, 65))	('RCAS-PDGFB', 'Var', (48, 58))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('RCAS', 'Chemical', '-', (48, 52))	('mitotic index', 'CPA', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
62404	21171016	For high-grade tumors formed by RCAS-PDGFB + RCAS-IGFBP2, the median mitotic index was 2.1% (range 0% to 8.8%).	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('RCAS', 'Chemical', '-', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mitotic index', 'CPA', (69, 82))	('RCAS-PDGFB', 'Var', (32, 42))	('RCAS', 'Chemical', '-', (32, 36))	('tumors', 'Disease', (15, 21))
62405	21171016	Tumors formed by RCAS-PDGFB + RCAS-Bcl-2 had a significantly higher mitotic index than tumors formed by all other injection sets (P<0.001 for the three pairwise comparisons).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RCAS', 'Chemical', '-', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCAS-PDGFB +', 'Var', (17, 29))	('higher', 'PosReg', (61, 67))	('RCAS', 'Chemical', '-', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('mitotic index', 'CPA', (68, 81))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
62409	21171016	The apoptotic index of high-grade tumors formed by RCAS-PDGFB + RCAS-IGFBP2 was 4.8% (range 0.2% to 25%).	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('apoptotic index', 'CPA', (4, 19))	('RCAS', 'Chemical', '-', (51, 55))	('RCAS-PDGFB', 'Var', (51, 61))	('RCAS', 'Chemical', '-', (64, 68))
62410	21171016	We found that the apoptotic index was significantly lower in the high-grade tumors formed by RCAS-PDGFB + RCAS-Bcl-2 than in those formed by either RCAS-PDGFB alone or the combination of RCAS-PDGFB and RCAS-IGFBP2 (P<0.001 in both cases).	('RCAS', 'Chemical', '-', (106, 110))	('RCAS', 'Chemical', '-', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('apoptotic index', 'CPA', (18, 33))	('lower', 'NegReg', (52, 57))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('RCAS', 'Chemical', '-', (148, 152))	('RCAS', 'Chemical', '-', (93, 97))	('RCAS', 'Chemical', '-', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('RCAS-PDGFB', 'Var', (93, 103))
62425	21171016	Our results support a correlation between Bcl-2 expression and higher tumor grade as reported in clinical studies  and in vitro studies showing that ectopic Bcl-2 expression in glioma cell lines promotes a more malignant phenotype .	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('more malignant phenotype', 'CPA', (206, 230))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('glioma', 'Disease', (177, 183))	('promotes', 'PosReg', (195, 203))	('Bcl-2', 'Gene', (157, 162))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('ectopic', 'Var', (149, 156))
62428	21171016	This is a sensitive method for assessing apoptosis because expression of cleaved caspase-3 is an early and probably universal signaling event in apoptosis .	('caspase-3', 'Gene', (81, 90))	('cleaved', 'Var', (73, 80))	('caspase-3', 'Gene', '12367', (81, 90))
62429	21171016	Cleaved caspase-3 expression was significantly lower in AOs induced by PDGFB and Bcl-2 than in high-grade tumors induced by PDGFB alone or in combination with IGFBP2, confirming the anti-apoptotic effect of Bcl-2 expression.	('lower', 'NegReg', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Cleaved', 'MPA', (0, 7))	('caspase-3', 'Gene', (8, 17))	('PDGFB', 'Var', (71, 76))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Bcl-2', 'Var', (81, 86))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('caspase-3', 'Gene', '12367', (8, 17))	('AOs', 'Disease', (56, 59))
62436	21171016	AOs formed more frequently in our study (61% for RCAS-PDGFB + RCAS-Bcl-2 compared with 38% for RCAS-PDGFB+RCAS-IGFBP2), although the symptom-free survival times for these two groups were similar which may be due to additional effects conferred by IGFBP2 on tumor cells including the promotion of migration and invasion (although more recent evidence suggests that Bcl-2 promote these as well).	('migration', 'CPA', (296, 305))	('RCAS', 'Chemical', '-', (106, 110))	('tumor', 'Disease', (257, 262))	('RCAS', 'Chemical', '-', (95, 99))	('RCAS', 'Chemical', '-', (49, 53))	('RCAS', 'Chemical', '-', (62, 66))	('promotion', 'PosReg', (283, 292))	('invasion', 'CPA', (310, 318))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('IGFBP2', 'Gene', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('RCAS-PDGFB + RCAS-Bcl-2', 'Var', (49, 72))
62442	21171016	In our study, necrosis was more common in tumors formed by coexpression of Bcl-2 and PDGFB than by PDGFB alone, correlating with the increased incidence of anaplastic tumors.	('necrosis', 'Disease', (14, 22))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('coexpression', 'Var', (59, 71))	('necrosis', 'Disease', 'MESH:D009336', (14, 22))	('common', 'Reg', (32, 38))	('Bcl-2', 'Gene', (75, 80))	('anaplastic tumors', 'Disease', 'MESH:D002277', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('PDGFB', 'Gene', (85, 90))	('tumors', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('anaplastic tumors', 'Disease', (156, 173))
62445	21171016	Consistent with their results, we observed necrosis in 3 of 11 (27%) tumor-bearing mice injected with RCAS-PDGFB.	('RCAS', 'Chemical', '-', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('RCAS-PDGFB', 'Var', (102, 112))	('necrosis', 'Disease', 'MESH:D009336', (43, 51))	('tumor', 'Disease', (69, 74))	('mice', 'Species', '10090', (83, 87))	('necrosis', 'Disease', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
62446	21171016	However, foci of necrosis were present in 14 (52%) tumor-bearing mice injected with RCAS-PDGFB + RCAS-Bcl-2, and Bcl-2 staining was more prominent in areas of tumor surrounding necrosis.	('necrosis', 'Disease', 'MESH:D009336', (177, 185))	('necrosis', 'Disease', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('foci of necrosis', 'Disease', (9, 25))	('foci of necrosis', 'Disease', 'MESH:D009336', (9, 25))	('necrosis', 'Disease', 'MESH:D009336', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (51, 56))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Disease', (159, 164))	('RCAS-PDGFB', 'Var', (84, 94))	('RCAS', 'Chemical', '-', (97, 101))	('necrosis', 'Disease', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('RCAS', 'Chemical', '-', (84, 88))
62453	21171016	The inhibition of Bcl-2 using anti-sense constructs results in tumor cell death in vitro .	('tumor', 'Disease', (63, 68))	('Bcl-2', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('anti-sense constructs', 'Var', (30, 51))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('inhibition', 'NegReg', (4, 14))
62454	21171016	Small molecule inhibitors of Bcl-2, known as BH3-mimetics, have also been shown to reactivate tumor necrosis factor-related apoptosis inducing ligand (TRAIL).	('reactivate', 'PosReg', (83, 93))	('tumor necrosis factor-related apoptosis inducing ligand', 'Gene', '22035', (94, 149))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('TRAIL', 'Gene', '22035', (151, 156))	('Bcl-2', 'Gene', (29, 34))	('TRAIL', 'Gene', (151, 156))	('BH3', 'Chemical', 'MESH:C006008', (45, 48))	('inhibitors', 'Var', (15, 25))
62474	32993063	Hence, the diagnosis and stratification of diffuse gliomas was facilitated by the recognition of isocitrate dehydrogenase 1/2 (IDH1/2) mutations and 1p/19q codeletion as principal biomarkers.	('gliomas', 'Disease', (51, 58))	('rat', 'Species', '10116', (103, 106))	('IDH1/2', 'Gene', '3417;3418', (127, 133))	('citrate', 'Chemical', 'MESH:D019343', (100, 107))	('mutations', 'Var', (135, 144))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('IDH1/2', 'Gene', (127, 133))	('rat', 'Species', '10116', (27, 30))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
62475	32993063	Mutations in IDH1/2 occur in the majority of low grade gliomas and secondary GBM, being less frequent in primary GBM.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('occur', 'Reg', (20, 25))	('gliomas', 'Disease', (55, 62))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('secondary GBM', 'Disease', (67, 80))
62477	32993063	Most importantly, 1p/19q-codeleted and IDH-mutant tumors present a better clinical outcome, while GBM IDH-wild type presents the worst prognosis, being the most common (50-60%) and the most lethal brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (197, 209))	('brain tumors', 'Phenotype', 'HP:0030692', (197, 209))	('1p/19q-codeleted', 'Var', (18, 34))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('brain tumors', 'Disease', (197, 209))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('brain tumor', 'Phenotype', 'HP:0030692', (197, 208))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
62514	32993063	LAT2 inhibition disturbs glutamine import and disrupts chemoresistance.	('LAT2', 'Gene', '7462', (0, 4))	('glutamine', 'Chemical', 'MESH:D005973', (25, 34))	('chemoresistance', 'CPA', (55, 70))	('disturbs', 'Reg', (16, 24))	('inhibition', 'Var', (5, 15))	('LAT2', 'Gene', (0, 4))	('glutamine import', 'MPA', (25, 41))	('disrupts', 'NegReg', (46, 54))
62532	32993063	The reliance on glutamine metabolism presented by cancer cells can be altered in the GBM-IDH mutant, since IDH1/2 mutated enzymes use alpha-ketoglutarate as a substrate to produce the oncometabolite 2-hydroxyglutarate (D2-HG), therefore a higher commitment of glutamine-derived glutamate is needed to produce alpha-ketoglutarate that will not be used in the TCA cycle, as will be depicted later on in this review.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (309, 328))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('cancer', 'Disease', (50, 56))	('glutamate', 'Chemical', 'MESH:D018698', (278, 287))	('rat', 'Species', '10116', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('rat', 'Species', '10116', (324, 327))	('rat', 'Species', '10116', (149, 152))	('IDH1/2', 'Gene', '3417;3418', (107, 113))	('TCA', 'Chemical', 'MESH:D014233', (358, 361))	('IDH1/2', 'Gene', (107, 113))	('rat', 'Species', '10116', (164, 167))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (199, 217))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('glutamine', 'Chemical', 'MESH:D005973', (16, 25))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (134, 153))	('mutant', 'Var', (93, 99))	('glutamine', 'Chemical', 'MESH:D005973', (260, 269))	('D2-HG', 'Chemical', '-', (219, 224))
62548	32993063	In order to bypass this problem, amino acid traces such as18F-fluoro-ethyl-tyrosine (18F-FET) or 11C-methionine (MET) are already standard of care in neuro-oncology.	('11C-methionine', 'Var', (97, 111))	('methionine', 'Chemical', 'MESH:D008715', (101, 111))	('MET', 'Gene', (113, 116))	('11C', 'Chemical', 'MESH:C000615233', (97, 100))	('MET', 'Gene', '79811', (113, 116))	('oncology', 'Phenotype', 'HP:0002664', (156, 164))
62552	32993063	Although 5-[11C]l-glutamine has the capacity to be actively transported into glioma cells, it has a very short half-life of approximately 20 min, which makes it a tricky clinical tool.	('glioma', 'Disease', (77, 83))	('5-[11C]l-glutamine', 'Var', (9, 27))	('5-[11C]l-glutamine', 'Chemical', '-', (9, 27))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
62554	32993063	Moreover, animal glioma models and human glioma patients showed high uptake of 18F-FGln compared to normal brain tissue in vivo, with a subsequent distinct tumor delineation.	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('18F-FGln', 'Var', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('human', 'Species', '9606', (35, 40))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('patients', 'Species', '9606', (48, 56))	('glioma', 'Disease', (17, 23))	('tumor', 'Disease', (156, 161))	('glioma', 'Disease', (41, 47))	('18F-FGln', 'Chemical', '-', (79, 87))	('uptake', 'MPA', (69, 75))
62576	32993063	In a randomized clinical trial developed by Stupp et al., TTFields treatment in combination with temozolomide resulted in increased OS and PFS.	('increased', 'PosReg', (122, 131))	('temozolomide', 'Chemical', 'MESH:D000077204', (97, 109))	('TTFields', 'Gene', (58, 66))	('treatment', 'Var', (67, 76))
62583	32993063	Even though these strategies may be promising, it has been difficult to apply clinically, due to the heterogeneity of EGFR mutations and even due to compensatory upregulation of other tyrosine kinase receptors.	('upregulation', 'PosReg', (162, 174))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('rat', 'Species', '10116', (20, 23))	('mutations', 'Var', (123, 132))
62586	32993063	As mentioned, the existence of IDH1/2 mutations is an important marker in brain tumor diagnosis and prognosis.	('brain tumor', 'Disease', (74, 85))	('brain tumor', 'Disease', 'MESH:D001932', (74, 85))	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('brain tumor', 'Phenotype', 'HP:0030692', (74, 85))	('mutations', 'Var', (38, 47))	('IDH1/2', 'Gene', (31, 37))
62588	32993063	IDH1/2 mutated gliomas have a better prognosis due to their slow proliferating rate and aggressiveness, again cancer metabolism seems to play a role.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('rat', 'Species', '10116', (72, 75))	('cancer', 'Disease', (110, 116))	('aggressiveness', 'Phenotype', 'HP:0000718', (88, 102))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('aggressiveness', 'Disease', 'MESH:D001523', (88, 102))	('rat', 'Species', '10116', (79, 82))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('aggressiveness', 'Disease', (88, 102))	('mutated', 'Var', (7, 14))
62589	32993063	Mutated IDH1/2 catalyzes the synthesis of D2-HG from alpha-ketoglutarate, consuming NADPH that will not be available for fatty acid synthesis by fatty-acid synthase (FASN), a marker for poor prognosis in IDH-wild type gliomas.	('IDH-wild type gliomas', 'Disease', (204, 225))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (53, 72))	('NADPH', 'Chemical', 'MESH:D009249', (84, 89))	('FASN', 'Gene', '2194', (166, 170))	('fatty-acid synthase', 'Gene', (145, 164))	('IDH1/2', 'Gene', '3417;3418', (8, 14))	('IDH-wild type gliomas', 'Disease', 'MESH:D005910', (204, 225))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('fatty-acid synthase', 'Gene', '2194', (145, 164))	('FASN', 'Gene', (166, 170))	('fatty acid', 'Chemical', 'MESH:D005227', (121, 131))	('D2-HG', 'Chemical', '-', (42, 47))	('Mutated', 'Var', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('IDH1/2', 'Gene', (8, 14))
62591	32993063	Albeit, this metabolic cooperation is lost in IDH1/2 mutated tumors.	('tumors', 'Disease', (61, 67))	('IDH1/2', 'Gene', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mutated', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('IDH1/2', 'Gene', '3417;3418', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('rat', 'Species', '10116', (28, 31))
62593	32993063	The first study showed that the IDH1 mutation and its inactivation induces hypoxia inducible factor 1 (HIF-1) pathways that are important in tumor growth, inhibition of apoptosis, and cell survival under hypoxic conditions.	('hypoxia inducible factor 1', 'Gene', '3091', (75, 101))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('hypoxia inducible factor 1', 'Gene', (75, 101))	('HIF-1', 'Gene', (103, 108))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('tumor', 'Disease', (141, 146))	('induces', 'Reg', (67, 74))	('HIF-1', 'Gene', '3091', (103, 108))
62594	32993063	Simultaneously, another study showed that D2-HG, produced by glioma cells with the IDH1 mutation, contributes to malignant progression of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('gliomas', 'Disease', (138, 145))	('mutation', 'Var', (88, 96))	('malignant progression', 'CPA', (113, 134))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (138, 144))	('contributes', 'Reg', (98, 109))	('glioma', 'Disease', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('D2-HG', 'Chemical', '-', (42, 47))	('IDH1', 'Gene', (83, 87))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
62597	32993063	Thereby, patients with IDH-mutated GBM may benefit from glutamine metabolism targeting, since it will efficiently disrupt de novo lipids synthesis, crucial to sustaining cancer cell proliferation and tumor growth.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('glutamine', 'Chemical', 'MESH:D005973', (56, 65))	('patients', 'Species', '9606', (9, 17))	('glutamine metabolism', 'MPA', (56, 76))	('cancer', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('benefit', 'Reg', (43, 50))	('de novo lipids synthesis', 'MPA', (122, 146))	('disrupt', 'NegReg', (114, 121))	('tumor', 'Disease', (200, 205))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('IDH-mutated', 'Var', (23, 34))	('lipids', 'Chemical', 'MESH:D008055', (130, 136))	('rat', 'Species', '10116', (189, 192))	('GBM', 'Gene', (35, 38))
62598	32993063	Afterward, another relevant study showed that IDH1 and IDH2 mutations reduced alpha-ketoglutarate and accumulated D2-HG, leading to genome-wide histone and DNA methylation alterations.	('reduced', 'NegReg', (70, 77))	('alpha-ketoglutarate', 'MPA', (78, 97))	('rat', 'Species', '10116', (176, 179))	('D2-HG', 'Chemical', '-', (114, 119))	('histone', 'MPA', (144, 151))	('IDH2', 'Gene', (55, 59))	('IDH1', 'Gene', (46, 50))	('D2-HG', 'MPA', (114, 119))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (78, 97))	('reduced alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (70, 97))	('DNA methylation alterations', 'MPA', (156, 183))	('mutations', 'Var', (60, 69))	('accumulated', 'PosReg', (102, 113))	('rat', 'Species', '10116', (93, 96))
62600	32993063	These alterations, resulting from IDH1 and IDH2 mutations, could contribute to gliomagenesis through modifying epigenetic control and potentially the fates of stem or glioma progenitor cells.	('glioma', 'Disease', (79, 85))	('modifying', 'Reg', (101, 110))	('IDH2', 'Gene', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Disease', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('epigenetic control', 'MPA', (111, 129))	('IDH1', 'Gene', (34, 38))	('rat', 'Species', '10116', (10, 13))	('contribute', 'Reg', (65, 75))	('mutations', 'Var', (48, 57))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
62601	32993063	Then, Lu and colleagues showed that D2-HG-producing IDH mutants could prevent the histone demethylation required for cell differentiation for lineage-specific progenitor cells to differentiate into terminally differentiated cells.	('mutants', 'Var', (56, 63))	('IDH', 'Gene', (52, 55))	('prevent', 'NegReg', (70, 77))	('D2-HG', 'Chemical', '-', (36, 41))	('histone demethylation', 'MPA', (82, 103))
62602	32993063	The IDH1 mutation remodels the methylome of gliomas, determined as Glioma CpG island methylator phenotype (G-CIMP), which is a powerful factor in tumor pathology.	('mutation', 'Var', (9, 17))	('G-CIMP', 'Chemical', '-', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('methylome', 'MPA', (31, 40))	('Glioma CpG', 'Disease', (67, 77))	('tumor', 'Disease', (146, 151))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('IDH1', 'Gene', (4, 8))	('remodels', 'Reg', (18, 26))	('Glioma CpG', 'Disease', 'MESH:D005910', (67, 77))	('Glioma', 'Phenotype', 'HP:0009733', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
62603	32993063	G-CIMP was also found in GBM, and was associated with IDH1 somatic mutations and pro-neural GBM subtype, with these patients having a relatively favorable prognosis.	('associated', 'Reg', (38, 48))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('IDH1', 'Gene', (54, 58))	('patients', 'Species', '9606', (116, 124))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('mutations', 'Var', (67, 76))	('G-CIMP', 'Chemical', '-', (0, 6))
62611	32993063	More recently, an association between the IDH1/2 mutations profile and the macrophagic subsets in GBM has pointed to macrophages and microglia as useful players in new immunotherapeutic approaches.	('mutations', 'Var', (49, 58))	('IDH1/2', 'Gene', '3417;3418', (42, 48))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('association', 'Interaction', (18, 29))	('macrophagic subsets', 'CPA', (75, 94))	('IDH1/2', 'Gene', (42, 48))	('GBM', 'Disease', (98, 101))
62621	32993063	While low GS levels can be beneficial for GBM patients as above-mentioned, an experimental study showed that silencing GS potentiated rat C6 glioma cell motility, whereas in another study, GS silencing decreased GBM cell line proliferation and colony formation both in the presence and absence of glutamine.	('patients', 'Species', '9606', (46, 54))	('C6 glioma cell motility', 'Disease', (138, 161))	('C6 glioma cell motility', 'Disease', 'MESH:C567307', (138, 161))	('GBM cell line proliferation', 'CPA', (212, 239))	('decreased', 'NegReg', (202, 211))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('glutamine', 'Chemical', 'MESH:D005973', (297, 306))	('GBM', 'Phenotype', 'HP:0012174', (212, 215))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('silencing', 'Var', (109, 118))	('rat', 'Species', '10116', (233, 236))	('potentiated', 'PosReg', (122, 133))	('rat', 'Species', '10116', (134, 137))	('colony formation', 'CPA', (244, 260))
62632	32993063	The silencing of GLAST inhibits GBM in vitro cell proliferation and migration, this way potentiating in vivo tumor progression.	('rat', 'Species', '10116', (71, 74))	('GLAST', 'Gene', (17, 22))	('potentiating', 'PosReg', (88, 100))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('rat', 'Species', '10116', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibits', 'NegReg', (23, 31))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))	('silencing', 'Var', (4, 13))	('tumor', 'Disease', (109, 114))
62633	32993063	observed a significant correlation between moderate/high GLAST expression with lower OS in patients that had received standard post-surgical concomitant radio-chemotherapy, which points GLAST as a putative prognostic marker for GBM.	('patients', 'Species', '9606', (91, 99))	('moderate/high', 'Var', (43, 56))	('expression', 'MPA', (63, 73))	('rat', 'Species', '10116', (47, 50))	('lower OS', 'Disease', (79, 87))	('GLAST', 'Protein', (57, 62))	('GBM', 'Phenotype', 'HP:0012174', (228, 231))
62636	32993063	Although xc- silencing reduced glutamate export, the proliferation of glioma cells was not altered.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('rat', 'Species', '10116', (60, 63))	('glutamate', 'Chemical', 'MESH:D018698', (31, 40))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('xc- silencing', 'Var', (9, 22))	('glutamate export', 'MPA', (31, 47))	('reduced', 'NegReg', (23, 30))
62639	32993063	Therefore, the inhibition of xc-, besides impairing glutamate export, also impairs cystine import and consequently cysteine bioavailability, which abrogates GSH synthesis and allows ferroptosis to occur.	('abrogates', 'NegReg', (147, 156))	('impairing', 'NegReg', (42, 51))	('cystine', 'Chemical', 'MESH:D003553', (83, 90))	('allows', 'Reg', (175, 181))	('cysteine', 'Chemical', 'MESH:D003545', (115, 123))	('glutamate', 'Chemical', 'MESH:D018698', (52, 61))	('cystine import', 'MPA', (83, 97))	('GSH synthesis', 'MPA', (157, 170))	('glutamate export', 'MPA', (52, 68))	('cysteine bioavailability', 'MPA', (115, 139))	('xc-', 'Protein', (29, 32))	('ferroptosis', 'CPA', (182, 193))	('inhibition', 'Var', (15, 25))	('GSH', 'Chemical', 'MESH:D005978', (157, 160))	('impairs', 'NegReg', (75, 82))
62643	32993063	Other GLS inhibitors were also tested after manipulation of IDH1 R132H, Compound 2 or CB-839 inhibits proliferation preferentially in IDH mutated cells, but it has a poor BBB penetration, and compound 968 was able to sensitize cancer cells to mTOR-targeted therapies in mouse xenograft models.	('CB-839', 'Gene', (86, 92))	('mutated', 'Var', (138, 145))	('rat', 'Species', '10116', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('mouse', 'Species', '10090', (270, 275))	('CB-839', 'Chemical', 'MESH:C000593334', (86, 92))	('inhibits', 'NegReg', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('rat', 'Species', '10116', (109, 112))	('mTOR', 'Gene', '56717', (243, 247))	('mTOR', 'Gene', (243, 247))	('cancer', 'Disease', (227, 233))	('proliferation', 'CPA', (102, 115))	('R132H', 'Mutation', 'rs201093943', (65, 70))	('sensitize', 'Reg', (217, 226))	('R132H', 'Var', (65, 70))
62653	32993063	As aforementioned, the parallel role of IDH to glutamine metabolism ought to be used in the planning and design of new therapies, since the function of mutated IDH enzymes depends on both alpha-ketoglutarate produced by IDH wild type isoforms or alpha-ketoglutarate generated from glutamine-derived glutamate.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (246, 265))	('mutated', 'Var', (152, 159))	('glutamate', 'Chemical', 'MESH:D018698', (299, 308))	('rat', 'Species', '10116', (270, 273))	('rat', 'Species', '10116', (203, 206))	('glutamine', 'Chemical', 'MESH:D005973', (47, 56))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (188, 207))	('depends', 'Reg', (172, 179))	('IDH', 'Gene', (160, 163))	('glutamine', 'Chemical', 'MESH:D005973', (281, 290))	('rat', 'Species', '10116', (261, 264))	('alpha-ketoglutarate', 'MPA', (188, 207))
62656	32993063	This way, the levels of glutamine in the tumor microenvironment and in blood circulation are determinant for cancer cell survival, and again, targeting glutamine directly by promoting its degradation before reaching the tumor could be an effective therapeutic approach.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('iron', 'Chemical', 'MESH:D007501', (55, 59))	('glutamine', 'Chemical', 'MESH:D005973', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (220, 225))	('cancer', 'Disease', (109, 115))	('targeting', 'Var', (142, 151))	('degradation', 'MPA', (188, 199))	('glutamine', 'Chemical', 'MESH:D005973', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('promoting', 'PosReg', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
62659	32993063	Nuclear magnetic resonance (NMR) spectroscopy is a highly reproducible method that allows for the detection of radiofrequency signals emitted from the nuclear spins of 1H, 31P, 13C, and 19F after exposure to an external magnetic field, enabling the measurement of metabolite concentration.	('13C', 'Chemical', 'MESH:C000615229', (177, 180))	('rat', 'Species', '10116', (282, 285))	('1H', 'Chemical', '-', (168, 170))	('radiofrequency signals', 'MPA', (111, 133))	('measurement', 'MPA', (249, 260))	('31P', 'Var', (172, 175))	('metabolite concentration', 'MPA', (264, 288))
62664	32993063	Some preliminary studies were performed to study tumor with IDH1 mutations resorting to hyperpolarized 13C MRS.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('IDH1', 'Gene', (60, 64))	('tumor', 'Disease', (49, 54))	('13C', 'Chemical', 'MESH:C000615229', (103, 106))	('mutations', 'Var', (65, 74))
62665	32993063	In a rat bearing GBM tumors with different IDH1 status, injection of hyperpolarized [1-13C] alpha-ketoglutarate led to hyperpolarized [1-13C] glutamate production, with these levels significantly lower in mutant IDH1 tumors compared with their IDH1-wild type counterparts.	('IDH1 tumors', 'Disease', (212, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('lower', 'NegReg', (196, 201))	('C] alpha', 'Species', '342041', (89, 97))	('[1-13C] glutamate', 'Chemical', '-', (134, 151))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (92, 111))	('hyperpolarized [1-13C] glutamate production', 'MPA', (119, 162))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('IDH1 tumors', 'Disease', 'MESH:D009369', (212, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumors', 'Disease', (21, 27))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('rat', 'Species', '10116', (5, 8))	('13C', 'Chemical', 'MESH:C000615229', (137, 140))	('mutant', 'Var', (205, 211))	('rat', 'Species', '10116', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('13C', 'Chemical', 'MESH:C000615229', (87, 90))
62667	32993063	In a study from Dang et al., transfected human glioma cell lines with mutant IDH1 were metabolically profiled by LC-MS and showed an accumulation of D2-HG, a product of alpha-ketoglutarate reduction by the IDH1 mutant, both in cellular extracts and in the culture medium, compared to the wild type cells.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (169, 188))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('mutant', 'Var', (70, 76))	('D2-HG', 'Chemical', '-', (149, 154))	('human', 'Species', '9606', (41, 46))	('glioma', 'Disease', (47, 53))	('D2-HG', 'MPA', (149, 154))	('IDH1', 'Gene', (77, 81))	('mutant', 'Var', (211, 217))	('IDH1', 'Gene', (206, 210))	('accumulation', 'PosReg', (133, 145))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
62668	32993063	They also analyzed human glioma samples and observed an increase in D2-HG concentration by 100-fold in tumors containing an R132 IDH1 mutation compared to IDH1 wild type tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('R132', 'Var', (124, 128))	('increase', 'PosReg', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('D2-HG concentration', 'MPA', (68, 87))	('rat', 'Species', '10116', (81, 84))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('D2-HG', 'Chemical', '-', (68, 73))	('human', 'Species', '9606', (19, 24))	('glioma', 'Disease', (25, 31))	('tumors', 'Disease', (170, 176))
62669	32993063	Other studies showed that somatic mutations in IDH2 (R172 and R140) also increased the D2-HG levels in acute myelogenous leukemia (AML).	('R172', 'Var', (53, 57))	('increased', 'PosReg', (73, 82))	('D2-HG', 'Chemical', '-', (87, 92))	('AML', 'Disease', 'MESH:D015470', (131, 134))	('IDH2', 'Gene', (47, 51))	('D2-HG levels', 'MPA', (87, 99))	('R140', 'Var', (62, 66))	('AML', 'Disease', (131, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (103, 129))	('acute myelogenous leukemia', 'Disease', (103, 129))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('AML', 'Phenotype', 'HP:0004808', (131, 134))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (103, 129))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (109, 129))
62670	32993063	Hence, IDH1/2 mutations lead to an enzymatic gain-of-function that increases D2-HG levels.	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('gain-of-function', 'PosReg', (45, 61))	('D2-HG', 'Chemical', '-', (77, 82))	('IDH1/2', 'Gene', (7, 13))	('increases', 'PosReg', (67, 76))	('mutations', 'Var', (14, 23))	('D2-HG levels', 'MPA', (77, 89))
62671	32993063	Therefore, D2-HG has been considered as an oncometabolite and its production could be an efficient strategy to identify the IDH1/2 mutated subset of patients with malignant gliomas, as shown by Choi et al., who used MRS to detect D2-HG in 30 glioma patients and proved that this noninvasive diagnostic tool could be powerful to apply clinically.	('D2-HG', 'Chemical', '-', (11, 16))	('patients', 'Species', '9606', (149, 157))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('rat', 'Species', '10116', (101, 104))	('glioma', 'Disease', (173, 179))	('mutated', 'Var', (131, 138))	('patients', 'Species', '9606', (249, 257))	('glioma', 'Disease', (242, 248))	('IDH1/2', 'Gene', '3417;3418', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('malignant gliomas', 'Disease', (163, 180))	('malignant gliomas', 'Disease', 'MESH:D005910', (163, 180))	('D2-HG', 'Chemical', '-', (230, 235))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('IDH1/2', 'Gene', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))
62672	32993063	Recurrent IDH1/2 mutations were detected in gliomas from grade II to IV, showing that IDH1/2 mutated enzymes are needed in gliomagenesis, hence monitoring D2-HG could be a way of following up the therapy response and early diagnosis of clinical relapse.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('D2-HG', 'Chemical', '-', (155, 160))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('IDH1/2', 'Gene', '3417;3418', (10, 16))	('IDH1/2', 'Gene', '3417;3418', (86, 92))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('detected', 'Reg', (32, 40))	('gliomas', 'Disease', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', (123, 129))	('IDH1/2', 'Gene', (10, 16))	('IDH1/2', 'Gene', (86, 92))	('mutations', 'Var', (17, 26))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
62707	32993063	Presence of the IDH mutation led to higher levels of N-acetylputrescine, trimethylamine-N-oxide, niacin, arginine, glucosamine, and methionine in the plasma.	('higher', 'PosReg', (36, 42))	('methionine', 'MPA', (132, 142))	('levels of N-acetylputrescine', 'MPA', (43, 71))	('niacin', 'Chemical', 'MESH:D009525', (97, 103))	('N-acetylputrescine', 'Chemical', 'MESH:C026212', (53, 71))	('glucosamine', 'Chemical', 'MESH:D005944', (115, 126))	('arginine', 'MPA', (105, 113))	('trimethylamine-N-oxide', 'MPA', (73, 95))	('mutation', 'Var', (20, 28))	('niacin', 'MPA', (97, 103))	('IDH', 'Gene', (16, 19))	('trimethylamine-N-oxide', 'Chemical', 'MESH:C005855', (73, 95))	('glucosamine', 'MPA', (115, 126))	('arginine', 'Chemical', 'MESH:D001120', (105, 113))	('methionine', 'Chemical', 'MESH:D008715', (132, 142))
62712	32993063	Moreover, the in vivo D2-HG production in patients with the IDH mutation was also observed.	('mutation', 'Var', (64, 72))	('D2-HG', 'Chemical', '-', (22, 27))	('IDH', 'Gene', (60, 63))	('D2-HG production', 'MPA', (22, 38))	('patients', 'Species', '9606', (42, 50))
62721	32993063	Taking advantage of the natural features of cancer cells that affect determinant metabolic pathways and profiles such as IDH mutations and glutamine-glutamate metabolism can be a valuable opportunity to find effective new strategies that trigger a bottom-up cancer cell death and tumor impairment by targeting the most basal life-sustaining mechanisms and reflecting their disturbance in tumor regression.	('affect', 'Reg', (62, 68))	('glutamine', 'Chemical', 'MESH:D005973', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('death', 'Disease', (270, 275))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('glutamate', 'Chemical', 'MESH:D018698', (149, 158))	('tumor', 'Disease', (280, 285))	('mutations', 'Var', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor impairment', 'Disease', (280, 296))	('tumor impairment', 'Disease', 'MESH:D060825', (280, 296))	('cancer', 'Disease', (258, 264))	('tumor', 'Disease', (388, 393))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('death', 'Disease', 'MESH:D003643', (270, 275))	('cancer', 'Disease', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (388, 393))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('rat', 'Species', '10116', (224, 227))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
62725	30534602	Indeed, IDH mutations are now recognized as a defining differential factor not only influencing global hypermethylation and patient prognosis but also degree of immune infiltration within individual tumors.	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('IDH', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('global hypermethylation', 'MPA', (96, 119))	('IDH', 'Gene', '3417', (8, 11))	('patient', 'Species', '9606', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('influencing', 'Reg', (84, 95))
62729	30534602	In addition to these active immunotherapies, inhibitors of molecular hubs with wide reaching effects, including STAT3, IDO, and TGF-beta, are now in early-phase clinical trials.	('TGF-beta', 'Gene', '7040', (128, 136))	('TGF-beta', 'Gene', (128, 136))	('IDO', 'Gene', '3620', (119, 122))	('STAT3', 'Gene', '6774', (112, 117))	('IDO', 'Gene', (119, 122))	('STAT3', 'Gene', (112, 117))	('inhibitors', 'Var', (45, 55))
62736	30534602	New pathological diagnostic approaches driven by these advancements include analysis of isocitrate dehydrogenase (IDH) mutation status (either by immunohistochemistry or sequencing) and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, which are now considered the standard of care.	('mutation', 'Var', (119, 127))	('IDH', 'Gene', (114, 117))	('isocitrate dehydrogenase', 'Gene', (88, 112))	('isocitrate dehydrogenase', 'Gene', '3417', (88, 112))	('IDH', 'Gene', '3417', (114, 117))	('O6-methylguanine-DNA methyltransferase', 'Gene', (186, 224))	('MGMT', 'Gene', '4255', (226, 230))	('MGMT', 'Gene', (226, 230))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (186, 224))
62737	30534602	However, quantitative analysis of copy number, mutation status, promoter methylation, and deletions may also be informative for other key genes implicated in the pathophysiology of different GBM subtypes, including epidermal growth factor receptor (EGFR), ATRX, cyclin-dependent kinase 4 (CDK4), CDKN2A/B, and Tert.	('ATRX', 'Gene', (256, 260))	('epidermal growth factor receptor', 'Gene', '1956', (215, 247))	('CDK4', 'Gene', '1019', (289, 293))	('cyclin-dependent kinase 4', 'Gene', '1019', (262, 287))	('cyclin-dependent kinase 4', 'Gene', (262, 287))	('CDK4', 'Gene', (289, 293))	('CDKN2A/B', 'Gene', (296, 304))	('mutation', 'Var', (47, 55))	('ATRX', 'Gene', '546', (256, 260))	('EGFR', 'Gene', '1956', (249, 253))	('Tert', 'Gene', '7015', (310, 314))	('EGFR', 'Gene', (249, 253))	('epidermal growth factor receptor', 'Gene', (215, 247))	('deletions', 'Var', (90, 99))	('Tert', 'Gene', (310, 314))	('GBM', 'Phenotype', 'HP:0012174', (191, 194))	('CDKN2A/B', 'Gene', '1029;1030', (296, 304))
62749	30534602	Each glioma is characterized by a unique set of genetic and epigenetic changes that lead to upregulation or silencing of key biological pathways (Fig.	('silencing', 'NegReg', (108, 117))	('epigenetic changes', 'Var', (60, 78))	('glioma', 'Disease', (5, 11))	('upregulation', 'PosReg', (92, 104))	('key biological pathways', 'Pathway', (121, 144))	('glioma', 'Disease', 'MESH:D005910', (5, 11))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))
62750	30534602	The downstream effects of these changes modulate complex signaling pathways and protein-protein interactions regulating tumorigenesis, proliferation, invasion, and apoptosis.	('modulate', 'Reg', (40, 48))	('invasion', 'CPA', (150, 158))	('proliferation', 'CPA', (135, 148))	('apoptosis', 'CPA', (164, 173))	('protein-protein', 'Protein', (80, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))	('changes', 'Var', (32, 39))
62754	30534602	More recently, work from the The Cancer Genome Atlas (TCGA) Consortium separately described four molecular subtypes of grade IV GBM based on common mutations, deletions, amplifications, and methylation patterns, referred to as proneural (or RTKI), neural, classical (or RTKII), and mesenchymal.	('methylation', 'Var', (190, 201))	('mesenchymal', 'CPA', (282, 293))	('neural', 'Disease', (248, 254))	('mutations', 'Var', (148, 157))	('classical', 'Disease', (256, 265))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Cancer Genome Atlas', 'Disease', (33, 52))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (33, 52))	('amplifications', 'Var', (170, 184))	('deletions', 'Var', (159, 168))	('proneural', 'Disease', (227, 236))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))
62755	30534602	Across these classifications, differences in disease progression and survival are negligible, and only a handful of the identified mutations inform patient prognosis.	('patient', 'Species', '9606', (148, 155))	('mutations', 'Var', (131, 140))	('inform', 'Reg', (141, 147))
62756	30534602	Mutation of IDH1, most frequently at exon 4 codon 132 (R132H), separates low-grade gliomas from high-grade GBM and is considered a strong prognostic marker.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('IDH1', 'Gene', (12, 16))	('R132H', 'Var', (55, 60))	('R132H', 'Mutation', 'rs121913500', (55, 60))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH1', 'Gene', '3417', (12, 16))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))
62758	30534602	IDH1 mutation is most frequently detected in less aggressive low-grade gliomas and is associated with mutation of TP53 and ATRX.	('ATRX', 'Gene', (123, 127))	('less', 'Disease', (45, 49))	('gliomas', 'Disease', (71, 78))	('mutation', 'Var', (102, 110))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('associated', 'Reg', (86, 96))	('TP53', 'Gene', '7157', (114, 118))	('ATRX', 'Gene', '546', (123, 127))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('detected', 'Reg', (33, 41))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('TP53', 'Gene', (114, 118))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
62759	30534602	In combination with the co-deletion of chromosomes 1p and 19q, IDH mutations are used to define oligodendrogliomas, although it is also found in 12% of all WHO grade IV GBMs, including 76% of secondary GBMs that progress from lower-grade tumors, and approximately 6% of primary adult GBMs, though typically in younger patients.	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('IDH', 'Gene', (63, 66))	('patients', 'Species', '9606', (318, 326))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('IDH', 'Gene', '3417', (63, 66))	('mutations', 'Var', (67, 76))	('GBM', 'Phenotype', 'HP:0012174', (202, 205))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (96, 114))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('GBM', 'Phenotype', 'HP:0012174', (169, 172))	('tumors', 'Disease', (238, 244))	('oligodendrogliomas', 'Disease', (96, 114))	('GBM', 'Phenotype', 'HP:0012174', (284, 287))
62760	30534602	As alpha-ketoglutarate is a co-factor for ten-eleven translocation (TET) histone demethylases, this mutation is associated with the CpG island methylator phenotype (g-CIMP).	('associated', 'Reg', (112, 122))	('g-CIMP', 'Chemical', '-', (165, 171))	('mutation', 'Var', (100, 108))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (3, 22))	('CpG island methylator phenotype', 'Disease', (132, 163))
62762	30534602	In general, IDH mutations correlate to improved prognosis and increased overall survival, averaging 7 years in low-grade gliomas.	('increased', 'PosReg', (62, 71))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('overall', 'MPA', (72, 79))	('prognosis', 'MPA', (48, 57))	('mutations', 'Var', (16, 25))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('improved', 'PosReg', (39, 47))
62765	30534602	MGMT is a DNA repair protein that contributes to therapeutic resistance, while silencing of this locus through hypermethylation of the promoter is predictive of an improved response to temozolomide (temodol) treatment.	('MGMT', 'Gene', (0, 4))	('therapeutic resistance', 'MPA', (49, 71))	('improved', 'PosReg', (164, 172))	('hypermethylation', 'Var', (111, 127))	('temozolomide', 'Chemical', 'MESH:D000077204', (185, 197))	('response to temozolomide', 'MPA', (173, 197))	('temodol', 'Chemical', '-', (199, 206))	('silencing', 'NegReg', (79, 88))	('MGMT', 'Gene', '4255', (0, 4))
62766	30534602	Although reports on the association between MGMT promoter methylation and progression-free survival are varied in their conclusions, meta-analysis of clinical data shows improved overall survival in methylated patients regardless of therapeutic intervention.	('methylated', 'Var', (199, 209))	('improved', 'PosReg', (170, 178))	('MGMT', 'Gene', (44, 48))	('patients', 'Species', '9606', (210, 218))	('MGMT', 'Gene', '4255', (44, 48))	('overall survival', 'MPA', (179, 195))
62769	30534602	Another prognostic marker associated with increased survival is mutation and loss of expression of the gene ATRX, which encodes a member of the SWI/SNF2 family of chromatin-remodeling proteins.	('increased', 'PosReg', (42, 51))	('mutation', 'Var', (64, 72))	('ATRX', 'Gene', (108, 112))	('loss of expression', 'NegReg', (77, 95))	('ATRX', 'Gene', '546', (108, 112))
62771	30534602	While many pediatric GBMs harbor ATRX mutations, tumorigenesis in these patients is thought to be driven by missense mutations at K27 and G34 in H3F3A, the gene encoding histone 3.3.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('ATRX', 'Gene', '546', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('ATRX', 'Gene', (33, 37))	('missense mutations at K27', 'Var', (108, 133))	('tumor', 'Disease', (49, 54))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('H3F3A', 'Gene', '3020', (145, 150))	('G34', 'Var', (138, 141))	('driven', 'Reg', (98, 104))	('mutations', 'Var', (38, 47))	('H3F3A', 'Gene', (145, 150))	('patients', 'Species', '9606', (72, 80))
62772	30534602	Mutations at K27 are associated with additional mutations in HIST1H3b, ACVR1, and TP53 as well as ATRX.	('TP53', 'Gene', (82, 86))	('ATRX', 'Gene', (98, 102))	('ACVR1', 'Gene', (71, 76))	('Mutations at K27', 'Var', (0, 16))	('ACVR1', 'Gene', '90', (71, 76))	('associated', 'Reg', (21, 31))	('ATRX', 'Gene', '546', (98, 102))	('HIST1H3b', 'Gene', (61, 69))	('TP53', 'Gene', '7157', (82, 86))	('HIST1H3b', 'Gene', '8358', (61, 69))	('mutations', 'Var', (48, 57))
62773	30534602	Although many of the same mutations are found in G34-mutated tumors, these are also associated with DNA hypomethylation.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('DNA', 'MPA', (100, 103))	('mutations', 'Var', (26, 35))	('G34-mutated', 'Var', (49, 60))	('associated', 'Reg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
62774	30534602	These include amplification (~40% of GBMs) and mutation (~25% of GBMs and 50% of EGFR-amplified GBMs) of the EGFR locus, which defines the "classical" GBM subtype and correlates with invasive and more aggressive disease progression.	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('aggressive disease', 'Disease', (201, 219))	('mutation', 'Var', (47, 55))	('GBM', 'Phenotype', 'HP:0012174', (151, 154))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('EGFR', 'Gene', '1956', (109, 113))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('EGFR', 'Gene', (109, 113))	('EGFR', 'Gene', '1956', (81, 85))	('aggressive disease', 'Disease', 'MESH:D001523', (201, 219))	('EGFR', 'Gene', (81, 85))
62775	30534602	Deletion of the locus encoding CDKN2A and CDNK2B is also identified in classical-type primary GBMs, and this deletion can drive progression of low-grade gliomas to GBM.	('CDKN2A', 'Gene', '1029', (31, 37))	('gliomas', 'Disease', (153, 160))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('drive', 'Reg', (122, 127))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('GBM', 'Phenotype', 'HP:0012174', (164, 167))	('CDKN2A', 'Gene', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('CDNK2B', 'Gene', (42, 48))	('Deletion', 'Var', (0, 8))
62776	30534602	With similar downstream effects on the p53/RB pathway as CDKN2A/B deletion, co-amplification of CDK4 and MDM2 occurs in both IDH mutant and wild-type gliomas and is associated with significantly decreased overall survival.	('co-amplification', 'Var', (76, 92))	('MDM2', 'Gene', '4193', (105, 109))	('MDM2', 'Gene', (105, 109))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('CDKN2A/B', 'Gene', '1029;1030', (57, 65))	('IDH', 'Gene', (125, 128))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('overall', 'MPA', (205, 212))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('IDH', 'Gene', '3417', (125, 128))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('CDK4', 'Gene', (96, 100))	('CDKN2A/B', 'Gene', (57, 65))	('deletion', 'Var', (66, 74))	('CDK4', 'Gene', '1019', (96, 100))	('decreased', 'NegReg', (195, 204))
62777	30534602	Within IDH1 wild-type GBMs, the mean survival for patients with CDK4/MDM2 amplification is reported to be 6.6 months, as compared to 12.7 months in non-amplified patients.	('patients', 'Species', '9606', (162, 170))	('IDH1', 'Gene', '3417', (7, 11))	('patients', 'Species', '9606', (50, 58))	('amplification', 'Var', (74, 87))	('CDK4', 'Gene', (64, 68))	('CDK4', 'Gene', '1019', (64, 68))	('MDM2', 'Gene', '4193', (69, 73))	('MDM2', 'Gene', (69, 73))	('IDH1', 'Gene', (7, 11))	('GBM', 'Phenotype', 'HP:0012174', (22, 25))
62778	30534602	In addition, mutation of the TERT promoter was recently identified as a marker of poor prognosis.	('TERT', 'Gene', '7015', (29, 33))	('mutation', 'Var', (13, 21))	('TERT', 'Gene', (29, 33))
62783	30534602	Recently, a combinatorial approach using aCGH and Onco-map, mass spectrometry-based mutation genotyping, demonstrated success in detecting mutations (IDH1, IDH2, TP53, phosphatase and tensin homolog (PTEN)), amplifications (EGFR, PDGFRA, MET), and deletions (EGFRvIII, PTEN, 1p/19q) at clinically relevant GBM loci.	('PDGFRA', 'Gene', '5156', (230, 236))	('PDGFRA', 'Gene', (230, 236))	('PTEN', 'Gene', (269, 273))	('IDH2', 'Gene', (156, 160))	('EGFR', 'Gene', (224, 228))	('TP53', 'Gene', (162, 166))	('IDH2', 'Gene', '3418', (156, 160))	('PTEN', 'Gene', '5728', (269, 273))	('EGFR', 'Gene', '1956', (259, 263))	('deletions', 'Var', (248, 257))	('IDH1', 'Gene', (150, 154))	('GBM', 'Phenotype', 'HP:0012174', (306, 309))	('PTEN', 'Gene', (200, 204))	('IDH1', 'Gene', '3417', (150, 154))	('EGFR', 'Gene', '1956', (224, 228))	('mutations', 'Var', (139, 148))	('TP53', 'Gene', '7157', (162, 166))	('PTEN', 'Gene', '5728', (200, 204))	('EGFR', 'Gene', (259, 263))	('amplifications', 'Var', (208, 222))
62785	30534602	Analysis of GBM through NGS reveals that the most commonly identified GBM mutations, amplifications, and deletions converge on three key signaling pathways, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin (mTOR), Ras/RAF/mitogen-activated protein kinase, and p53/Rb.	('GBM', 'Gene', (70, 73))	('p53', 'Gene', '7157', (271, 274))	('mammalian target of rapamycin', 'Gene', '2475', (187, 216))	('AKT', 'Gene', (183, 186))	('mutations', 'Var', (74, 83))	('mTOR', 'Gene', '2475', (218, 222))	('RAF', 'Gene', '22882', (229, 232))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('RAF', 'Gene', (229, 232))	('mTOR', 'Gene', (218, 222))	('converge', 'Reg', (115, 123))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('p53', 'Gene', (271, 274))	('mammalian target of rapamycin', 'Gene', (187, 216))	('AKT', 'Gene', '207', (183, 186))
62786	30534602	These include amplifications of genes encoding receptor tyrosine kinases (RTKs), such as PDGFR and EGFR, in proneural and classic-type GBMs, respectively, as well as mutation of TP53, PTEN, and CDK4.	('TP53', 'Gene', '7157', (178, 182))	('EGFR', 'Gene', (99, 103))	('CDK4', 'Gene', (194, 198))	('PTEN', 'Gene', (184, 188))	('TP53', 'Gene', (178, 182))	('PTEN', 'Gene', '5728', (184, 188))	('CDK4', 'Gene', '1019', (194, 198))	('GBM', 'Phenotype', 'HP:0012174', (135, 138))	('PDGFR', 'Gene', (89, 94))	('PDGFR', 'Gene', '5159', (89, 94))	('EGFR', 'Gene', '1956', (99, 103))	('mutation', 'Var', (166, 174))
62789	30534602	Indeed, evidence of clonal subpopulations harboring differential mutation and amplification of RTKs were identified through single-cell RNA-seq and constitutive pathway activation driven by PTEN deletion suggests that multi-pronged approaches and drugs targeting downstream factors may be more effective.	('activation', 'PosReg', (169, 179))	('PTEN', 'Gene', (190, 194))	('constitutive pathway', 'Pathway', (148, 168))	('PTEN', 'Gene', '5728', (190, 194))	('deletion', 'Var', (195, 203))
62795	30534602	Tumors recurring adjacent to the primary lesion are more likely to possess the same genetic alterations, suggestive of intrinsic mechanisms of resistance.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('genetic alterations', 'Var', (84, 103))
62812	30534602	In a detailed fluorescence-activated cell sorter-based study, Amankulor and colleagues demonstrated decreased CD45+ immune cell infiltration in human IDH1 mutant tumors as compared to wild-type tumors.	('CD45', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('type tumors', 'Disease', (189, 200))	('human', 'Species', '9606', (144, 149))	('type tumors', 'Disease', 'MESH:D009369', (189, 200))	('mutant', 'Var', (155, 161))	('CD45', 'Gene', '5788', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('decreased', 'NegReg', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (162, 168))	('IDH1', 'Gene', (150, 154))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (194, 200))	('IDH1', 'Gene', '3417', (150, 154))
62814	30534602	Combined with TCGA data supporting decreased transcription of immune cell chemotaxis pathways, these data suggest that mutant IDH-driven changes in the tumor-associated immune cell component may contribute to the differential survival times observed in mutant and wild-type glioma patients.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('glioma', 'Disease', 'MESH:D005910', (274, 280))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('IDH', 'Gene', '3417', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('changes', 'Reg', (137, 144))	('contribute', 'Reg', (195, 205))	('patients', 'Species', '9606', (281, 289))	('tumor', 'Disease', (152, 157))	('glioma', 'Disease', (274, 280))	('mutant', 'Var', (119, 125))	('mutant', 'Var', (253, 259))	('survival times', 'CPA', (226, 240))	('IDH', 'Gene', (126, 129))
62815	30534602	In similar studies, Kohanbash and co-workers demonstrated that IDH mutations reduced the levels of CXC motif chemokine ligand 10 and STAT1, and suppressed T cell accumulation in GBM tumors.	('GBM tumors', 'Disease', (178, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('IDH', 'Gene', (63, 66))	('GBM', 'Phenotype', 'HP:0012174', (178, 181))	('suppressed', 'NegReg', (144, 154))	('mutations', 'Var', (67, 76))	('IDH', 'Gene', '3417', (63, 66))	('reduced', 'NegReg', (77, 84))	('STAT1', 'Gene', (133, 138))	('STAT1', 'Gene', '6772', (133, 138))	('GBM tumors', 'Disease', 'MESH:D005910', (178, 188))	('T cell accumulation', 'MPA', (155, 174))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
62816	30534602	These effects could be reversed by IDH-C35, an inhibitor of mutant IDH1, which enhanced the effectiveness of vaccine immunotherapy.	('IDH', 'Gene', (35, 38))	('IDH1', 'Gene', (67, 71))	('enhanced', 'PosReg', (79, 87))	('IDH', 'Gene', '3417', (35, 38))	('IDH', 'Gene', (67, 70))	('IDH1', 'Gene', '3417', (67, 71))	('IDH', 'Gene', '3417', (67, 70))	('mutant', 'Var', (60, 66))	('vaccine immunotherapy', 'CPA', (109, 130))
62820	30534602	PD-1 is also found on B cells, NK cells, and macrophages, and as such, constitutive PD-L1 expression on GBM tumor cells can induce widespread immunosuppression and alter the tumor microenvironment.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('widespread immunosuppression', 'CPA', (131, 159))	('PD-L1', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('induce', 'Reg', (124, 130))	('alter', 'Reg', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('GBM', 'Phenotype', 'HP:0012174', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('expression', 'Var', (90, 100))
62821	30534602	Interestingly, data from GBM cell lines suggest that high levels of PD-L1 may correlate with mutations in PTEN.	('correlate', 'Reg', (78, 87))	('mutations', 'Var', (93, 102))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('PTEN', 'Gene', (106, 110))	('PTEN', 'Gene', '5728', (106, 110))
62822	30534602	Unsurprisingly, given its widespread function, meta-analysis of GBM patients with high PD-L1 levels showed a correlation with decreased overall survival lengths, suggesting that this marker may have prognostic value.	('overall survival lengths', 'CPA', (136, 160))	('decreased', 'NegReg', (126, 135))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('high', 'Var', (82, 86))	('patients', 'Species', '9606', (68, 76))	('PD-L1', 'MPA', (87, 92))
62827	30534602	Within GBMs, high levels of FoxP3 are associated with poor prognosis, including decreased progression-free and overall survival.	('high levels', 'Var', (13, 24))	('FoxP3', 'Gene', '50943', (28, 33))	('overall survival', 'CPA', (111, 127))	('FoxP3', 'Gene', (28, 33))	('GBM', 'Phenotype', 'HP:0012174', (7, 10))	('decreased', 'NegReg', (80, 89))	('progression-free', 'CPA', (90, 106))
62838	30534602	In addition, IDO prevents the antitumor effects of T cell-dependent complement deposition, and inhibition of IDO was shown to reactive this process.	('IDO', 'Gene', '3620', (109, 112))	('tumor', 'Disease', (34, 39))	('IDO', 'Gene', '3620', (13, 16))	('inhibition', 'Var', (95, 105))	('IDO', 'Gene', (109, 112))	('IDO', 'Gene', (13, 16))	('prevents', 'NegReg', (17, 25))	('T cell-dependent complement deposition', 'MPA', (51, 89))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
62850	22343889	IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('IDH1', 'Gene', (0, 4))	('cancers', 'Disease', (181, 188))	('glioma', 'Disease', (45, 51))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
62853	22343889	Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome.	('IDH1', 'Gene', '3417', (73, 77))	('remodelling', 'Reg', (102, 113))	('methylome', 'MPA', (118, 127))	('G-CIMP', 'Chemical', '-', (92, 98))	('mutation', 'Var', (18, 26))	('isocitrate dehydrogenase 1', 'Gene', (45, 71))	('IDH1', 'Gene', (73, 77))	('isocitrate dehydrogenase 1', 'Gene', '3417', (45, 71))
62854	22343889	Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation.	('IDH', 'Gene', (159, 162))	('presence', 'Var', (147, 155))	('IDH', 'Gene', '3417', (159, 162))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('G-CIMP', 'Chemical', '-', (98, 104))	('mutation', 'Var', (163, 171))	('gliomas', 'Disease', (66, 73))
62855	22343889	Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('induces', 'Reg', (89, 96))	('CIMP-', 'Chemical', '-', (208, 213))	('methylome', 'MPA', (146, 155))	('histone', 'Protein', (74, 81))	('alters', 'Reg', (58, 64))	('IDH1', 'Gene', (23, 27))	('human', 'Species', '9606', (41, 46))	('reshapes', 'Reg', (133, 141))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('mutant', 'Var', (16, 22))	('IDH1', 'Gene', '3417', (23, 27))	('DNA hypermethylation', 'MPA', (107, 127))	('specific', 'MPA', (65, 73))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('gliomas', 'Disease', (234, 241))	('G-CIMP', 'Chemical', '-', (206, 212))
62856	22343889	Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival.	('improved', 'PosReg', (210, 218))	('glioblastomas', 'Disease', (145, 158))	('glioblastomas', 'Disease', 'MESH:D005909', (173, 186))	('key', 'Pathway', (76, 79))	('IDH1', 'Gene', '3417', (62, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('glioblastomas', 'Disease', (173, 186))	('epigenomic alterations', 'MPA', (17, 39))	('mutant', 'Var', (55, 61))	('glioblastomas', 'Phenotype', 'HP:0012174', (145, 158))	('CIMP-', 'Chemical', '-', (121, 126))	('G-CIMP', 'Chemical', '-', (119, 125))	('IDH1', 'Gene', (62, 66))	('glioblastomas', 'Phenotype', 'HP:0012174', (173, 186))	('glioblastomas', 'Disease', 'MESH:D005909', (145, 158))	('activate', 'PosReg', (67, 75))
62857	22343889	Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('gliomas', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('mutation', 'Var', (34, 42))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('human', 'Species', '9606', (224, 229))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('IDH', 'Gene', (30, 33))	('cancers', 'Disease', (230, 237))	('CIMP', 'Chemical', '-', (69, 73))	('IDH', 'Gene', '3417', (30, 33))	('gliomas', 'Disease', (145, 152))
62858	22343889	The isocitrate dehydrogenase genes IDH1 and IDH2 are mutated in >70%of lower-grade gliomas (grades II and III), in some glioblastomas, and in leukaemias and several other cancers.	('IDH1', 'Gene', (35, 39))	('glioblastomas', 'Disease', 'MESH:D005909', (120, 133))	('mutated', 'Var', (53, 60))	('gliomas', 'Disease', (83, 90))	('leukaemias', 'Disease', 'MESH:D007938', (142, 152))	('IDH2', 'Gene', (44, 48))	('IDH1', 'Gene', '3417', (35, 39))	('IDH2', 'Gene', '3418', (44, 48))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('glioblastomas', 'Phenotype', 'HP:0012174', (120, 133))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('leukaemias', 'Disease', (142, 152))	('cancers', 'Disease', (171, 178))	('glioblastomas', 'Disease', (120, 133))
62859	22343889	The most common IDH1 mutations in glioma (>95%) result in an amino acid substitution at arginine 132 (R132), which resides in the enzyme's active site.	('arginine', 'Chemical', 'MESH:D001120', (88, 96))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('IDH1', 'Gene', (16, 20))	('glioma', 'Disease', (34, 40))	('IDH1', 'Gene', '3417', (16, 20))	('result in', 'Reg', (48, 57))	('mutations', 'Var', (21, 30))
62860	22343889	Mutation of IDH imparts the ability to produce 2-hydroxyglutarate (2-HG), a potential oncometabolite.	('Mutation', 'Var', (0, 8))	('produce 2-hydroxyglutarate', 'MPA', (39, 65))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (47, 65))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('2-HG', 'Chemical', 'MESH:C019417', (67, 71))
62863	22343889	Exactly how mutant IDH promotes tumorigenesis and causes G-CIMP:or CIMP in any type of human cancer:is unknown.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('promotes', 'PosReg', (23, 31))	('CIMP', 'Chemical', '-', (67, 71))	('tumorigenesis', 'CPA', (32, 45))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('G-CIMP', 'Chemical', '-', (57, 63))	('mutant', 'Var', (12, 18))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', (19, 22))	('CIMP', 'Chemical', '-', (59, 63))	('G-CIMP', 'Disease', (57, 63))	('causes', 'Reg', (50, 56))
62864	22343889	To determine whether IDH1 mutation directly causes G-CIMP, we used immortalized primary human astrocytes and constructed isogenic cells expressing either mutant IDH1 (R132H), wild-type IDH1, or neither.	('R132H', 'Mutation', 'rs121913500', (167, 172))	('IDH1', 'Gene', '3417', (185, 189))	('IDH1', 'Gene', '3417', (161, 165))	('causes', 'Reg', (44, 50))	('mutation', 'Var', (26, 34))	('G-CIMP', 'Chemical', '-', (51, 57))	('G-CIMP', 'Disease', (51, 57))	('IDH1', 'Gene', (161, 165))	('IDH1', 'Gene', (21, 25))	('R132H', 'Var', (167, 172))	('human', 'Species', '9606', (88, 93))	('IDH1', 'Gene', (185, 189))	('IDH1', 'Gene', '3417', (21, 25))	('mutant', 'Var', (154, 160))
62865	22343889	Introduction of wild-type IDH1 and the R132H IDH1 mutant resulted in equal expression of protein (modest threefold increase) (Fig.	('IDH1', 'Gene', '3417', (45, 49))	('increase', 'PosReg', (115, 123))	('IDH1', 'Gene', (26, 30))	('R132H', 'Var', (39, 44))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('IDH1', 'Gene', (45, 49))	('IDH1', 'Gene', '3417', (26, 30))	('expression', 'MPA', (75, 85))
62866	22343889	Expression of mutant but not wild-type IDH1 in human astrocytes resulted in the production of 2-HG (Fig.	('mutant', 'Var', (14, 20))	('IDH1', 'Gene', (39, 43))	('IDH1', 'Gene', '3417', (39, 43))	('2-HG', 'Chemical', 'MESH:C019417', (94, 98))	('human', 'Species', '9606', (47, 52))	('production of 2-HG', 'MPA', (80, 98))
62867	22343889	To determine whether mutant IDH1 altered the methylation landscape, we analysed genomic DNA from these cells using the Illumina InfiniumHumanMethylation450 platform.	('Human', 'Species', '9606', (136, 141))	('IDH1', 'Gene', '3417', (28, 32))	('mutant', 'Var', (21, 27))	('methylation landscape', 'MPA', (45, 66))	('altered', 'Reg', (33, 40))	('IDH1', 'Gene', (28, 32))
62868	22343889	We thus analysed the methylomes of astrocytes expressing mutant or wild-type IDH1 over successive passages (up to 50).	('analysed', 'Reg', (8, 16))	('mutant', 'Var', (57, 63))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', (77, 81))
62869	22343889	Analysis using self-organizing maps demonstrated that mutant IDH1 progressively remodelled the glial methylome over time (Fig.	('remodelled', 'Reg', (80, 90))	('IDH1', 'Gene', '3417', (61, 65))	('glial methylome', 'MPA', (95, 110))	('IDH1', 'Gene', (61, 65))	('mutant', 'Var', (54, 60))
62870	22343889	Expression of mutant IDH1 caused a marked increase in hypermethylation at a large number of genes, although there was a small group of hypomethylated genes as well (Fig.	('mutant', 'Var', (14, 20))	('hypermethylation at a large number of genes', 'MPA', (54, 97))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (21, 25))	('increase', 'PosReg', (42, 50))
62873	22343889	Mutant IDH1-induced remodelling of the methylome was progressive and reproducible, and resulted in significant changes in gene expression (Fig.	('IDH1', 'Gene', '3417', (7, 11))	('gene expression', 'MPA', (122, 137))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('changes', 'Reg', (111, 118))
62874	22343889	We sought to define the methylation targets of mutant IDH in astrocytes.	('IDH', 'Gene', '3417', (54, 57))	('IDH', 'Gene', (54, 57))	('mutant', 'Var', (47, 53))
62875	22343889	Of the 44,334 CpG sites that were differentially methylated in mutant IDH-expressing cells, 30,988 sites were hypermethylated (3,141 unique genes with promoter CpG island methylation changes; Supplementary Table 1).	('IDH', 'Gene', '3417', (70, 73))	('IDH', 'Gene', (70, 73))	('mutant', 'Var', (63, 69))
62876	22343889	These observations demonstrate that mutant IDH1 is sufficient to reshape the epigenome by altering the global methylation landscape.	('reshape', 'Reg', (65, 72))	('IDH1', 'Gene', (43, 47))	('global methylation landscape', 'MPA', (103, 131))	('altering', 'Reg', (90, 98))	('mutant', 'Var', (36, 42))	('IDH1', 'Gene', '3417', (43, 47))
62884	22343889	Global expression profiles showed that G-CIMP+ tumours possessed markedly different transcriptional profiles than G-CIMP- tumours (Supplementary Tables 8 and 9).	('transcriptional profiles', 'MPA', (84, 108))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('G-CIMP', 'Chemical', '-', (114, 120))	('CIMP-', 'Chemical', '-', (116, 121))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('G-CIMP', 'Chemical', '-', (39, 45))	('G-CIMP+', 'Chemical', '-', (39, 46))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Disease', (47, 54))	('G-CIMP+', 'Var', (39, 46))	('tumours', 'Disease', (122, 129))	('different', 'Reg', (74, 83))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
62887	22343889	Ninety-eight per cent (49/50) of the G-CIMP+ tumours possessed either an IDH1 mutation or IDH2 mutation.	('mutation', 'Var', (78, 86))	('IDH2', 'Gene', '3418', (90, 94))	('IDH1', 'Gene', '3417', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('IDH1', 'Gene', (73, 77))	('IDH2', 'Gene', (90, 94))	('tumours', 'Disease', (45, 52))	('G-CIMP+', 'Chemical', '-', (37, 44))	('mutation', 'Var', (95, 103))
62888	22343889	Notably, none of the G-CIMP- tumours possessed mutant IDH (Supplementary Fig.	('G-CIMP', 'Chemical', '-', (21, 27))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('CIMP-', 'Chemical', '-', (23, 28))	('tumours', 'Disease', (29, 36))	('IDH', 'Gene', (54, 57))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('IDH', 'Gene', '3417', (54, 57))	('mutant', 'Var', (47, 53))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
62889	22343889	These genomic data show that G-CIMP is highly dependent on the presence of IDH mutation and, in LGGs that are CIMP-, IDH mutations do not occur (0%).	('CIMP-', 'Chemical', '-', (110, 115))	('G-CIMP', 'Chemical', '-', (29, 35))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (117, 120))	('mutation', 'Var', (79, 87))	('G-CIMP', 'Disease', (29, 35))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))
62893	22343889	We next sought to define the nature of the methylome differences between IDH mutant and wild-type tumours and characterize the effects of these differences on the LGG transcriptome.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('IDH', 'Gene', (73, 76))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('IDH', 'Gene', '3417', (73, 76))	('methylome', 'MPA', (43, 52))	('mutant', 'Var', (77, 83))
62895	22343889	PCA shows that G-CIMP+ and G-CIMP- LGGs methylome subgroups correlate with marked transcriptome differences (Fig.	('CIMP-', 'Chemical', '-', (29, 34))	('G-CIMP', 'Chemical', '-', (27, 33))	('transcriptome differences', 'MPA', (82, 107))	('G-CIMP- LGGs', 'Var', (27, 39))	('G-CIMP', 'Chemical', '-', (15, 21))	('G-CIMP+', 'Chemical', '-', (15, 22))	('G-CIMP+', 'Var', (15, 22))
62896	22343889	Of the 140,016 sites that were differentially methylated between IDH mutant and wild-type tumours, 121,660 were hypermethylated (Supplementary Table 6).	('IDH', 'Gene', (65, 68))	('mutant', 'Var', (69, 75))	('IDH', 'Gene', '3417', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('hypermethylated', 'PosReg', (112, 127))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))
62898	22343889	Integration of the normalized gene expression and DNA methylation gene sets identified 429 genes with both significant hypermethylation and downregulation and 176 genes that were hypomethylated and upregulated in G-CIMP+ LGGs (Supplementary Table 12).	('upregulated', 'PosReg', (198, 209))	('downregulation', 'NegReg', (140, 154))	('G-CIMP+ LGGs', 'Var', (213, 225))	('hypermethylation', 'Var', (119, 135))	('G-CIMP+', 'Chemical', '-', (213, 220))
62900	22343889	As a critical experiment to prove causality between IDH1 mutation and G-CIMP, we performed an in-depth comparison of methylation marks and gene expression alterations between human astrocytes expressing mutant IDH1 and the LGGs with endogenous IDH1 mutation.	('human', 'Species', '9606', (175, 180))	('mutant', 'Var', (203, 209))	('IDH1', 'Gene', '3417', (210, 214))	('IDH1', 'Gene', '3417', (244, 248))	('IDH1', 'Gene', '3417', (52, 56))	('G-CIMP', 'Chemical', '-', (70, 76))	('IDH1', 'Gene', (244, 248))	('IDH1', 'Gene', (210, 214))	('IDH1', 'Gene', (52, 56))
62901	22343889	Gene set enrichment analysis (GSEA) of the mutant IDH1-induced methylation changes in the isogenic astrocyte system (Fig.	('IDH1', 'Gene', (50, 54))	('methylation', 'MPA', (63, 74))	('IDH1', 'Gene', '3417', (50, 54))	('mutant', 'Var', (43, 49))	('GSEA', 'Chemical', '-', (30, 34))
62903	22343889	Importantly, the genes that were methylated after mutant IDH1 expression correctly classified LGG tumours into CIMP+ or CIMP- groups with very high accuracy (Fig.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('LGG tumours', 'Disease', 'MESH:D009369', (94, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('LGG tumours', 'Disease', (94, 105))	('CIMP+', 'Chemical', '-', (111, 116))	('IDH1', 'Gene', (57, 61))	('CIMP-', 'Chemical', '-', (120, 125))	('mutant', 'Var', (50, 56))	('IDH1', 'Gene', '3417', (57, 61))
62904	22343889	To confirm the impact of these alterations on glioma pathobiology, we used the transcriptomic footprint of mutant IDH to generate an expression signature (mutant IDH repression signature) composed of the most significantly methylated and downregulated genes in both the isogenic astrocyte system and the G-CIMP gene set (17 genes; Supplementary Table 15).	('mutant', 'Var', (107, 113))	('IDH', 'Gene', (114, 117))	('IDH', 'Gene', (162, 165))	('glioma', 'Disease', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('IDH', 'Gene', '3417', (114, 117))	('IDH', 'Gene', '3417', (162, 165))	('G-CIMP', 'Chemical', '-', (304, 310))	('downregulated', 'NegReg', (238, 251))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
62905	22343889	Together, our findings show that introduction of mutant IDH reprograms the epigenome and generates the foundations of G-CIMP.	('G-CIMP', 'Chemical', '-', (118, 124))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', (56, 59))	('mutant', 'Var', (49, 55))
62906	22343889	IDH mutation is highly enriched in the CIMP+, proneural subgroup of glioblastomas.	('CIMP+', 'Var', (39, 44))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('mutation', 'Var', (4, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (68, 81))	('CIMP+', 'Chemical', '-', (39, 44))	('glioblastomas', 'Disease', (68, 81))
62907	22343889	Using data from The Cancer Genome Atlas (TCGA), we applied the mutant IDH repression signature as a classifier to the transcriptomes of all four subgroups of glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (158, 171))	('mutant', 'Var', (63, 69))	('IDH', 'Gene', (70, 73))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('glioblastomas', 'Disease', 'MESH:D005909', (158, 171))	('IDH', 'Gene', '3417', (70, 73))	('Cancer Genome Atlas', 'Disease', (20, 39))	('glioblastomas', 'Disease', (158, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (20, 39))
62908	22343889	The signature segregated IDH mutant and wild-type proneural glioblastomas into two distinct subgroups associated with very different prognoses, but did not do so in other glioblastoma subgroups (Supplementary Fig.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('glioblastoma', 'Disease', (171, 183))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('mutant', 'Var', (29, 35))	('glioblastomas', 'Disease', (60, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (171, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (171, 183))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))
62909	22343889	These data demonstrate that mutant IDH-induced epigenomic alterations have profound biological implications within the proneural class of glioblastomas that are specific for this subclass.	('glioblastomas', 'Disease', (138, 151))	('mutant', 'Var', (28, 34))	('epigenomic alterations', 'Var', (47, 69))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))	('glioblastomas', 'Phenotype', 'HP:0012174', (138, 151))	('glioblastomas', 'Disease', 'MESH:D005909', (138, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))
62910	22343889	Comparison of gene expression programs that occur in astrocytes expressing mutant IDH1 to those in LGG tumours that harbour the IDH mutation showed remarkable similarity (Fig.	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', (128, 131))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('IDH1', 'Gene', (82, 86))	('LGG tumours', 'Disease', 'MESH:D009369', (99, 110))	('IDH', 'Gene', '3417', (128, 131))	('mutant', 'Var', (75, 81))	('IDH1', 'Gene', '3417', (82, 86))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('IDH', 'Gene', (82, 85))	('LGG tumours', 'Disease', (99, 110))
62911	22343889	Moreover, introduction of mutant but not wild-type IDH1 into astrocytes resulted in the upregulation of nestin (and other genes associated with stem cell identity) at the time of DNA methylation increase and the adoption of a neurosphere/stem-like phenotype (Fig.	('IDH1', 'Gene', '3417', (51, 55))	('nestin', 'Gene', (104, 110))	('adoption of a neurosphere/stem-like phenotype', 'CPA', (212, 257))	('upregulation', 'PosReg', (88, 100))	('mutant', 'Var', (26, 32))	('IDH1', 'Gene', (51, 55))	('increase', 'PosReg', (195, 203))
62912	22343889	These data suggest that mutant IDH1 functions by interfering with differentiation state.	('mutant', 'Var', (24, 30))	('IDH1', 'Gene', '3417', (31, 35))	('interfering', 'NegReg', (49, 60))	('differentiation state', 'CPA', (66, 87))	('IDH1', 'Gene', (31, 35))
62913	22343889	Our data show that IDH1 mutation is the mechanistic cause of G-CIMP.	('IDH1', 'Gene', (19, 23))	('IDH1', 'Gene', '3417', (19, 23))	('cause', 'Reg', (52, 57))	('G-CIMP', 'Chemical', '-', (61, 67))	('mutation', 'Var', (24, 32))	('G-CIMP', 'Disease', (61, 67))
62914	22343889	To gain further insight, we determined the effects of mutant IDH1 on histone alterations in our astrocyte system.	('histone alterations', 'MPA', (69, 88))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', (61, 65))	('effects', 'Reg', (43, 50))	('mutant', 'Var', (54, 60))
62915	22343889	Figure 4c (left) shows that expression of the IDH1 mutant increases levels of H3K9me2, H3K27me3 and H3K36me3, consistent with previous findings.	('H3K9me2', 'Protein', (78, 85))	('increases', 'PosReg', (58, 67))	('H3K27me3', 'MPA', (87, 95))	('H3K36me3', 'MPA', (100, 108))	('IDH1', 'Gene', (46, 50))	('mutant', 'Var', (51, 57))	('IDH1', 'Gene', '3417', (46, 50))	('levels', 'MPA', (68, 74))
62916	22343889	Chromatin immunoprecipitation (ChIP) experiments examining representative genes that undergo hypermethylation show H3K9 and H3K27 methylation are both enriched in cells expressing mutant IDH1 (Fig.	('H3K27', 'Protein', (124, 129))	('IDH1', 'Gene', '3417', (187, 191))	('mutant', 'Var', (180, 186))	('H3K9', 'Protein', (115, 119))	('IDH1', 'Gene', (187, 191))
62917	22343889	Next, we determined the effects the mutation had onTET2-dependent 5-hydroxymethylcytosine (5hmC) levels.	('TET2', 'Gene', (51, 55))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (66, 89))	('5hmC', 'Chemical', 'MESH:C011865', (91, 95))	('TET2', 'Gene', '54790', (51, 55))	('mutation', 'Var', (36, 44))
62919	22343889	We found that expression of the IDH1 mutant in astrocytes resulted in a significant decrease in 5hmC (Fig.	('decrease', 'NegReg', (84, 92))	('5hmC', 'MPA', (96, 100))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('mutant', 'Var', (37, 43))	('5hmC', 'Chemical', 'MESH:C011865', (96, 100))
62920	22343889	Expression of TET2 in the astrocytes produced 5hmC, which was inhibited by mutant but not wild-type IDH1 (Fig.	('TET2', 'Gene', (14, 18))	('5hmC', 'Chemical', 'MESH:C011865', (46, 50))	('IDH1', 'Gene', '3417', (100, 104))	('5hmC', 'MPA', (46, 50))	('inhibited', 'NegReg', (62, 71))	('mutant', 'Var', (75, 81))	('IDH1', 'Gene', (100, 104))	('TET2', 'Gene', '54790', (14, 18))
62922	22343889	IDH mutation and the CIMP phenotype are two very common features in cancer, the underlying mechanisms for which are obscure.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('CIMP', 'Chemical', '-', (21, 25))	('cancer', 'Disease', (68, 74))
62923	22343889	The fundamental questions regarding these features are (1) how the IDH mutation contributes to oncogenesis, and (2) what the root cause of CIMP is.	('oncogenesis', 'CPA', (95, 106))	('mutation', 'Var', (71, 79))	('CIMP', 'Chemical', '-', (139, 143))	('IDH', 'Gene', (67, 70))	('contributes', 'Reg', (80, 91))	('IDH', 'Gene', '3417', (67, 70))
62924	22343889	Our data address these important questions by demonstrating that IDH mutation is the cause of CIMP and leads to the CIMP phenotype by stably reshaping the epigenome.	('CIMP', 'Chemical', '-', (94, 98))	('IDH', 'Gene', (65, 68))	('leads', 'Reg', (103, 108))	('cause', 'Reg', (85, 90))	('IDH', 'Gene', '3417', (65, 68))	('mutation', 'Var', (69, 77))	('CIMP', 'Disease', (94, 98))	('CIMP', 'Chemical', '-', (116, 120))
62926	22343889	In summary, these data provide a mechanistic framework for how IDH mutation leads to oncogenesis and the molecular basis of CIMP in gliomas.	('CIMP', 'Chemical', '-', (124, 128))	('oncogenesis', 'CPA', (85, 96))	('mutation', 'Var', (67, 75))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Disease', (132, 139))	('IDH', 'Gene', (63, 66))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('IDH', 'Gene', '3417', (63, 66))	('leads to', 'Reg', (76, 84))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
62930	22343889	Expression of IDH was accomplished by cloning wild-type or mutant IDH1 (R132H) into the vector pLNCX2.	('IDH', 'Gene', (66, 69))	('IDH', 'Gene', (14, 17))	('IDH1', 'Gene', '3417', (66, 70))	('R132H', 'Var', (72, 77))	('IDH', 'Gene', '3417', (66, 69))	('IDH', 'Gene', '3417', (14, 17))	('R132H', 'Mutation', 'rs121913500', (72, 77))	('IDH1', 'Gene', (66, 70))
62932	22343889	Retroviral particles were collected, filtered through a 0.45-microm syringe filter and polybrene was added (8 microgml-1 final concentration) to infect the human astrocytes for 12 h. Stable transfectants were selected with G418 and pooled populations of G418-resistant cells expressing either wild-type IDH1 or IDH1 R132H were confirmed by western blot analysis with anti-IDH1 antibody (rabbit anti-IDH1; Cell Signaling).	('polybrene', 'Chemical', 'MESH:D006583', (87, 96))	('human', 'Species', '9606', (156, 161))	('R132H', 'Var', (316, 321))	('IDH1', 'Gene', (399, 403))	('IDH1', 'Gene', '3417', (303, 307))	('IDH1', 'Gene', '3417', (372, 376))	('R132H', 'Mutation', 'rs121913500', (316, 321))	('IDH1', 'Gene', '3417', (399, 403))	('IDH1', 'Gene', (311, 315))	('IDH1', 'Gene', '3417', (311, 315))	('rabbit', 'Species', '9986', (387, 393))	('IDH1', 'Gene', (372, 376))	('IDH1', 'Gene', (303, 307))
62944	22343889	Analysis of variance (ANOVA) with false discovery correction (FDR) was used to identify genes that were differentially methylated between the astrocytes expressing wild-type IDH1, mutant IDH1, and control astrocytes.	('IDH1', 'Gene', '3417', (187, 191))	('mutant', 'Var', (180, 186))	('IDH1', 'Gene', (174, 178))	('IDH1', 'Gene', '3417', (174, 178))	('IDH1', 'Gene', (187, 191))
62950	22343889	To derive the 17-gene mutant IDH1 repression signature, we identified 605 unique genes that had either statistically significant hypermethylation at promoter-associated CpG islands and decreased gene expression, or had hypomethylation at promoter-associated CpG Islands and increased gene expression in CIMP+ versus CIMP- tumours.	('hypomethylation', 'Var', (219, 234))	('decreased', 'NegReg', (185, 194))	('gene expression', 'MPA', (284, 299))	('tumours', 'Phenotype', 'HP:0002664', (322, 329))	('IDH1', 'Gene', (29, 33))	('CIMP+', 'Chemical', '-', (303, 308))	('tumours', 'Disease', 'MESH:D009369', (322, 329))	('IDH1', 'Gene', '3417', (29, 33))	('gene expression', 'MPA', (195, 210))	('tumour', 'Phenotype', 'HP:0002664', (322, 328))	('tumours', 'Disease', (322, 329))	('mutant', 'Var', (22, 28))	('hypermethylation', 'Var', (129, 145))	('increased', 'PosReg', (274, 283))	('CIMP-', 'Chemical', '-', (316, 321))
62951	22343889	We identified common genes in a comparison of this gene set with that derived from mutant IDH1-expressing astrocytes versus wild type.	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (90, 94))	('mutant', 'Var', (83, 89))
62955	22343889	The hypermethylation signature identified from our analysis of differentially methylated genes in IDH1 mutants compared to IDH1 wild-type was imported into Oncomine (http://www.oncomine.org) to identify associations with molecular concepts signatures derived from independent cancer profiling studies.	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('associations', 'Interaction', (203, 215))	('mutants', 'Var', (103, 110))	('Oncomine', 'Chemical', '-', (156, 164))	('IDH1', 'Gene', (123, 127))	('oncomine', 'Chemical', '-', (177, 185))	('IDH1', 'Gene', '3417', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('IDH1', 'Gene', (98, 102))	('IDH1', 'Gene', '3417', (98, 102))
62956	22343889	Methylation data of parental, wild-type IDH1-expressing astrocytes, and mutant IDH1-expressing astrocytes were clustered using self-organizing maps and visualized with the Gene Expression Dynamics Inspector (GEDI; v.2.1).	('IDH1', 'Gene', '3417', (79, 83))	('IDH1', 'Gene', (40, 44))	('mutant', 'Var', (72, 78))	('IDH1', 'Gene', '3417', (40, 44))	('IDH1', 'Gene', (79, 83))
62959	22343889	We identified the Illumina 450K methylation probe ID (cg12981137) that corresponded to the MGMT MSP primer sequence as identified previously and the Affymetrix probe ID (204880_at) that corresponds to MGMT expression.	('cg12981137', 'Var', (54, 64))	('MGMT', 'Gene', (201, 205))	('MGMT', 'Gene', '4255', (201, 205))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))
62975	22343889	For single-colour flow cytometry, parental and IDH1 mutant astrocytes were stained using anti-5hmC (1:400) followed by Alexa Fluor 488 secondary antibody.	('5hmC', 'Chemical', 'MESH:C011865', (94, 98))	('mutant', 'Var', (52, 58))	('IDH1', 'Gene', (47, 51))	('Alexa Fluor 488', 'Chemical', '-', (119, 134))	('IDH1', 'Gene', '3417', (47, 51))
62977	22343889	Briefly, immortalized human astrocyte (IHA) cells stably expressing wild-type or R132H mutant IDH1 at passage 15 were seeded in 6-well plates at 200,000 cells per well.	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', '3417', (94, 98))	('R132H mutant', 'Var', (81, 93))	('human', 'Species', '9606', (22, 27))	('R132H', 'Mutation', 'rs121913500', (81, 86))
62998	33821340	The molecular biology of DIPG may have prognostic value for overall survival and tumor response to radiation (e.g., H3.3 K27M mutant may portend a poor response to radiotherapy and average survival of 9 months, while H3.1 K27M mutant may portend a good response to radiotherapy and 15 months average survival).	('K27M', 'Mutation', 'p.K27M', (222, 226))	('H3.1 K27M', 'Var', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('K27M', 'Mutation', 'p.K27M', (121, 125))	('H3.3 K27M', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
63016	33821340	Typical radiological characteristics of BTG on MRI include bilateral lesions of the thalami with a homogenous aspect, a compact epicenter, the absence of contrast enhancement, hypointense on T1-weighted images, hyperintense on T2-weighted images and FLAIR, and mild or absent perifocal brain edema, often showing growth of the lesions on follow-up MRI (Fig.	('edema', 'Phenotype', 'HP:0000969', (292, 297))	('absent', 'NegReg', (269, 275))	('absence', 'NegReg', (143, 150))	('hypointense', 'Var', (176, 187))	('BTG', 'Chemical', '-', (40, 43))	('hyperintense', 'Var', (211, 223))	('brain edema', 'Phenotype', 'HP:0002181', (286, 297))	('brain edema', 'Disease', (286, 297))	('brain edema', 'Disease', 'MESH:D001929', (286, 297))
63025	33821340	Very recently, a small series of patients with BTG showed that 85% harbor a mutation of the EGFR oncogene.	('BTG', 'Chemical', '-', (47, 50))	('patients', 'Species', '9606', (33, 41))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('mutation', 'Var', (76, 84))
63032	33821340	Although the course of OPG in NF1 is usually more indolent compared to other instances, sometimes severe impairment of visual function, hypothalamic abnormalities (including precocious puberty), or potentially life-threatening behavior occurs.	('hypothalamic abnormalities', 'Disease', 'MESH:D007027', (136, 162))	('impairment of visual function', 'Disease', 'MESH:D014786', (105, 134))	('OPG', 'Var', (23, 26))	('NF1', 'Gene', (30, 33))	('hypothalamic abnormalities', 'Disease', (136, 162))	('NF1', 'Gene', '4763', (30, 33))	('hypothalamic abnormalities', 'Phenotype', 'HP:0012286', (136, 162))	('precocious puberty', 'Phenotype', 'HP:0000826', (174, 192))	('impairment of visual function', 'Disease', (105, 134))
63049	33821340	For NF1 patients, a biopsy is generally not indicated, even for the detection of BRAF mutation status, before initiating treatment with a MEK 1/2 inhibitor (e.g., selumetinib) for recurrent or progressive tumor growth, and is reserved for cases with suspected tumor transformation or an unusual location and/or presentation.	('tumor', 'Disease', (260, 265))	('NF1', 'Gene', '4763', (4, 7))	('MEK 1/2', 'Gene', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('selumetinib', 'Chemical', 'MESH:C517975', (163, 174))	('MEK 1/2', 'Gene', '5604;5605', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('BRAF', 'Gene', '673', (81, 85))	('NF1', 'Gene', (4, 7))	('BRAF', 'Gene', (81, 85))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mutation', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('patients', 'Species', '9606', (8, 16))
63075	33821340	showed that the combination of lack of hyperintense foci on T1-weighted imaging, mild or no contrast enhancement, and ADC under the threshold value (1.143 x 10-3 mm2/s) had a 100% sensitivity and 100% negative predictive value for discriminating germinoma from non-germinoma.	('germinoma', 'Disease', 'MESH:D018237', (246, 255))	('germinoma', 'Phenotype', 'HP:0100620', (265, 274))	('germinoma', 'Disease', (246, 255))	('lack', 'NegReg', (31, 35))	('contrast enhancement', 'MPA', (92, 112))	('germinoma', 'Disease', 'MESH:D018237', (265, 274))	('germinoma', 'Phenotype', 'HP:0100620', (246, 255))	('hyperintense foci', 'MPA', (39, 56))	('germinoma', 'Disease', (265, 274))	('ADC', 'Var', (118, 121))
63084	33821340	Retinoblastoma (RB) is initiated by mutations in the RB1 tumor suppressor gene.	('RB1', 'Gene', '5925', (53, 56))	('RB', 'Phenotype', 'HP:0009919', (16, 18))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('RB', 'Disease', 'MESH:D012175', (16, 18))	('RB1', 'Gene', (53, 56))	('Retinoblastoma', 'Disease', 'MESH:D012175', (0, 14))	('RB', 'Disease', 'MESH:D012175', (53, 55))	('tumor', 'Disease', (57, 62))	('Retinoblastoma', 'Disease', (0, 14))	('initiated by', 'Reg', (23, 35))	('RB', 'Phenotype', 'HP:0009919', (53, 55))
63085	33821340	Patients with RB1 mutations also have about a 5% risk of developing intracranial midline primitive neuroectodermal tumors (e.g., pineoblastomas).	('RB1', 'Gene', (14, 17))	('pineoblastomas', 'Disease', 'MESH:D010871', (129, 143))	('pineoblastomas', 'Disease', (129, 143))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (99, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('RB1', 'Gene', '5925', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('intracranial midline primitive neuroectodermal tumors', 'Disease', 'MESH:D008527', (68, 121))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (89, 121))	('RB', 'Phenotype', 'HP:0009919', (14, 16))	('mutations', 'Var', (18, 27))
63116	30220459	Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG.	('gliomas', 'Disease', (148, 155))	('Glutamate', 'Chemical', 'None', (54, 63))	('mutations', 'Var', (114, 123))	('Glutamate Biosynthesis', 'MPA', (54, 76))	('Glioma', 'Phenotype', 'HP:0009733', (102, 108))	('overproduction', 'PosReg', (194, 208))	('glioblastomas', 'Phenotype', 'HP:0012174', (170, 183))	('Impairs', 'NegReg', (46, 53))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (27, 45))	('IDH1', 'Gene', (109, 113))	('Glioma', 'Disease', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioblastomas', 'Disease', (170, 183))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('cause', 'Reg', (188, 193))	('Redox Homeostasis', 'MPA', (81, 98))	('glioblastomas', 'Disease', 'MESH:D005909', (170, 183))	('common', 'Reg', (128, 134))	('Glioma', 'Disease', 'MESH:D005910', (102, 108))
63117	30220459	Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione.	('glutamate', 'Chemical', 'None', (216, 225))	('decreasing', 'NegReg', (205, 215))	('pen', 'Gene', (56, 59))	('BCAT1', 'Gene', (150, 155))	('glutamate', 'Chemical', 'None', (298, 307))	('glutaminase', 'Gene', '2744', (262, 273))	('pen', 'Gene', '27344', (128, 131))	('inhibits', 'NegReg', (109, 117))	('increasing', 'PosReg', (237, 247))	('decreasing glutamate levels', 'Phenotype', 'HP:0500150', (205, 232))	('R)-2HG', 'Var', (93, 99))	('pen', 'Gene', (250, 253))	('pen', 'Gene', '27344', (56, 59))	('glutathione', 'MPA', (333, 344))	('glutaminase', 'Gene', (262, 273))	('BCAT2', 'Gene', (160, 165))	('glutathione', 'Chemical', 'MESH:D005978', (333, 344))	('pen', 'Gene', '27344', (250, 253))	('oxygen', 'Chemical', 'MESH:D010100', (66, 72))	('pen', 'Gene', (128, 131))	('glutamate levels', 'MPA', (216, 232))	('BCAT2', 'Gene', '587', (160, 165))	('biosynthesis of glutamate', 'MPA', (282, 307))	('BCAT1', 'Gene', '586', (150, 155))
63118	30220459	Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo.	('IDH mutant glioma', 'Disease', (47, 64))	('glutaminase', 'Gene', '2744', (11, 22))	('Inhibiting', 'Var', (0, 10))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glutaminase', 'Gene', (11, 22))	('oxidative stress', 'MPA', (74, 90))	('sensitized', 'Reg', (36, 46))	('IDH mutant glioma', 'Disease', 'MESH:D005910', (47, 64))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))
63119	30220459	These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.	('glutamate', 'Chemical', 'None', (78, 87))	('IDH mutant gliomas', 'Disease', 'MESH:D005910', (256, 274))	('glutaminase', 'Gene', '2744', (63, 74))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('IDH mutant gliomas', 'Disease', (256, 274))	('glutaminase', 'Gene', '2744', (149, 160))	('glutaminase', 'Gene', (63, 74))	('glutamate biosynthesis', 'MPA', (78, 100))	('gliomas', 'Phenotype', 'HP:0009733', (267, 274))	('BCATs and glutaminase', 'Gene', '2744', (53, 74))	('glutaminase', 'Gene', (149, 160))	('mutant', 'Var', (133, 139))
63120	30220459	Gliomas with IDH mutations show increased sensitivity to radiation in concert with glutaminase inhibition offering a new approach towards treating these tumors.	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('glutaminase', 'Gene', '2744', (83, 94))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('increased sensitivity to radiation', 'Phenotype', 'HP:0011133', (32, 66))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('glutaminase', 'Gene', (83, 94))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('Gliomas', 'Disease', (0, 7))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
63121	30220459	IDH1 and IDH2 mutations occur in various cancers, including gliomas and leukemias.	('leukemias', 'Disease', (72, 81))	('IDH2', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('occur', 'Reg', (24, 29))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('IDH2', 'Gene', '3418', (9, 13))	('leukemias', 'Disease', 'MESH:D007938', (72, 81))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('leukemias', 'Phenotype', 'HP:0001909', (72, 81))	('IDH1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('mutations', 'Var', (14, 23))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('cancers', 'Disease', (41, 48))
63122	30220459	Tumor-associated IDH mutants convert 2-oxoglutarate (2OG) to the (R) enantiomer of 2-hydroxyglutarate, (R)-2HG, which accumulates to mM levels in tumors.	('mutants', 'Var', (21, 28))	('IDH', 'Gene', (17, 20))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('2-oxoglutarate', 'Chemical', 'MESH:C029743', (37, 51))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (146, 152))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (83, 101))
63125	30220459	In this regard, inhibition of TET2 promotes leukemic transformation and is also suspected of playing a role in IDH mutant gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('IDH mutant gliomas', 'Disease', 'MESH:D005910', (111, 129))	('leukemic transformation', 'Disease', 'MESH:D007938', (44, 67))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('promotes', 'PosReg', (35, 43))	('IDH mutant gliomas', 'Disease', (111, 129))	('TET2', 'Gene', '54790', (30, 34))	('TET2', 'Gene', (30, 34))	('leukemic transformation', 'Disease', (44, 67))	('inhibition', 'Var', (16, 26))
63127	30220459	In this regard, Reitman and colleagues reported that the conditioned media of IDH mutant cells had decreased levels of branched chain alpha-ketoacids (BCKAs) compared to control cells.	('decreased', 'NegReg', (99, 108))	('alpha-ketoacids', 'Chemical', 'MESH:C002934', (134, 149))	('levels of branched chain alpha-ketoacids', 'MPA', (109, 149))	('IDH', 'Gene', (78, 81))	('mutant', 'Var', (82, 88))
63130	30220459	We infected IDH1/2 wild-type HOG human glioma cells with a lentivirus encoding the canonical R132H IDH1 mutant, wild-type IDH1, or with the empty vector (EV) (Figure 1B).	('R132H', 'Var', (93, 98))	('R132H', 'Mutation', 'p.R132H', (93, 98))	('glioma', 'Disease', (39, 45))	('IDH1/2', 'Gene', (12, 18))	('human', 'Species', '9606', (33, 38))	('IDH1', 'Gene', (99, 103))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
63131	30220459	We then did GC-MS-based metabolomic profiling of the resulting stable cell lines, as well as parental HOG cells that were treated with BCAT inhibitors (Compound 2 or gabapentin) or were infected to produce one of two BCAT1 shRNAs or a control shRNA (Figures 1C and 1D).	('BCAT1', 'Gene', '586', (217, 222))	('BCAT', 'Gene', (135, 139))	('inhibitors', 'Var', (140, 150))	('BCAT1', 'Gene', (217, 222))	('gabapentin', 'Chemical', 'MESH:C040029', (166, 176))
63132	30220459	IDH1 R132H increased the abundance of the BCAAs and depleted glutamate and the BCKAs alpha-keto-beta-methylvalerate (KMV) and alpha-ketoisocaproate (KIC), as did pharmacologically or genetically inhibiting BCAT1 (Figure 1D).	('abundance', 'MPA', (25, 34))	('BCAA', 'Gene', (42, 46))	('increased', 'PosReg', (11, 20))	('BCAT1', 'Gene', '586', (206, 211))	('glutamate', 'MPA', (61, 70))	('BCAA', 'Gene', '51742', (42, 46))	('IDH1 R132H', 'Var', (0, 10))	('R132H', 'Var', (5, 10))	('R132H', 'Mutation', 'p.R132H', (5, 10))	('alpha-ketoisocaproate', 'MPA', (126, 147))	('depleted glutamate', 'Phenotype', 'HP:0500150', (52, 70))	('BCAT1', 'Gene', (206, 211))	('alpha-keto-beta-methylvalerate', 'MPA', (85, 115))	('depleted', 'NegReg', (52, 60))	('alpha-ketoisocaproate', 'Chemical', 'MESH:C013082', (126, 147))	('glutamate', 'Chemical', 'None', (61, 70))
63133	30220459	Similarly, glioma stem-like cell (GSC) lines derived from IDH1 mutant gliomas (Figure S1B) had elevated BCAAs and lower levels of KIC and glutamate compared to IDH1 wild-type GSC lines (Figures S1A and S1C).	('BCAA', 'Gene', (104, 108))	('BCAA', 'Gene', '51742', (104, 108))	('glioma', 'Disease', (70, 76))	('mutant', 'Var', (63, 69))	('elevated', 'PosReg', (95, 103))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glutamate', 'Chemical', 'None', (138, 147))	('lower', 'NegReg', (114, 119))	('gliomas', 'Disease', (70, 77))	('glioma', 'Disease', (11, 17))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('IDH1', 'Gene', (58, 62))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
63134	30220459	Therefore, both engineered and patient-derived IDH1 mutant cells exhibit metabolic changes consistent with impaired BCAT activity.	('impaired', 'NegReg', (107, 115))	('metabolic', 'MPA', (73, 82))	('mutant', 'Var', (52, 58))	('BCAT activity', 'MPA', (116, 129))	('IDH1', 'Gene', (47, 51))	('patient', 'Species', '9606', (31, 38))
63139	30220459	To ask if mutant IDH inhibits BCAT in cells, we assayed the conversion of 15N-leucine to 15N-glutamate in immortalized human astrocytes (NHA) and HOG cells infected to produce the IDH1 R132H mutant, wild-type IDH1, or with the EV (Figures 2A and 2C).	('R132H', 'Var', (185, 190))	('IDH1', 'Gene', (180, 184))	('mutant', 'Var', (10, 16))	('R132H', 'Mutation', 'p.R132H', (185, 190))	('15N-glutamate', 'Chemical', 'None', (89, 102))	('15N-leucine', 'Chemical', 'MESH:C015905', (74, 85))	('human', 'Species', '9606', (119, 124))
63140	30220459	BCAT1 protein levels were lowered in late passage IDH1 mutant NHA cells (Figure S2C), consistent with a prior study and with reduced BCAT1 mRNA levels in IDH1 mutant gliomas (Figure S2D), but were not downregulated in late passage HOG cells (Figures S2A and S2B).	('BCAT1', 'Gene', (133, 138))	('lowered', 'NegReg', (26, 33))	('IDH1', 'Gene', (50, 54))	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('BCAT1', 'Gene', (0, 5))	('mutant', 'Var', (159, 165))	('gliomas', 'Disease', (166, 173))	('S2B', 'Chemical', 'MESH:D013455', (258, 261))	('mutant', 'Var', (55, 61))	('reduced', 'NegReg', (125, 132))	('IDH1', 'Gene', (154, 158))	('BCAT1', 'Gene', '586', (133, 138))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('BCAT1', 'Gene', '586', (0, 5))
63142	30220459	Both the IDH1 mutant NHA and HOG cells had tumor-relevant (R)-2HG concentrations (Figure 2B).	('IDH1', 'Gene', (9, 13))	('mutant', 'Var', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
63143	30220459	Leucine transamination was impaired in IDH1 mutant NHA and HOG cells (Figures 2D, 2E, and S2F), mirroring the effects of Compound 2 (Figure S2E).	('Leucine', 'Chemical', 'MESH:C038361', (0, 7))	('IDH1', 'Gene', (39, 43))	('S2F', 'Chemical', 'MESH:D013455', (90, 93))	('Leucine transamination', 'MPA', (0, 22))	('impaired', 'NegReg', (27, 35))	('mutant', 'Var', (44, 50))
63145	30220459	Conversely, leucine transamination in IDH1 mutant cells was rescued by AGI-5198, which blocks (R)-2HG production (Figure 2G).	('leucine', 'Chemical', 'MESH:C038361', (12, 19))	('leucine transamination', 'MPA', (12, 34))	('mutant', 'Var', (43, 49))	('IDH1', 'Gene', (38, 42))	('blocks', 'NegReg', (87, 93))
63146	30220459	Metabolic evidence of suppressed BCAT activity was also observed in HCT116 colorectal cancer cells treated with (R)-2HG or engineered to have heterozygous IDH1 or IDH2 mutations (Figure S2G), while BCAT activity was restored in HT1080 IDH1 +/R132C fibrosarcoma cells treated with AGI-5198 (Figure S2H).	('suppressed', 'NegReg', (22, 32))	('IDH1', 'Gene', (155, 159))	('BCAT activity', 'MPA', (33, 46))	('colorectal cancer', 'Disease', (75, 92))	('R132C', 'Mutation', 'p.R132C', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('IDH2', 'Gene', '3418', (163, 167))	('fibrosarcoma', 'Disease', (248, 260))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (248, 260))	('S2H', 'Chemical', 'MESH:C042345', (297, 300))	('BCAT', 'MPA', (198, 202))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('fibrosarcoma', 'Disease', 'MESH:D005354', (248, 260))	('IDH2', 'Gene', (163, 167))	('mutations', 'Var', (168, 177))
63147	30220459	Mutant IDH2, like mutant IDH1, also potently repressed BCAT activity when introduced into NHA and HOG cells (Figures S2I to S2K).	('IDH2', 'Gene', '3418', (7, 11))	('IDH2', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('BCAT activity', 'MPA', (55, 68))	('repressed', 'PosReg', (45, 54))
63154	30220459	To ask whether glutamate suppression by mutant IDH (Figures 1D and S1C) can be linked to loss of BCAT activity, we quantified steady-state 2HG, glutamate, and KIC levels in IDH1 mutant and wild-type HOG cell lines that were treated with AGI-5198 or DMSO (Figure 2H) while grown in cell culture media that contained glucose, glutamate, pyruvate, and amino acid levels based on physiological concentrations in the brain.	('mutant', 'Var', (178, 184))	('glucose', 'MPA', (315, 322))	('glutamate', 'Chemical', 'None', (144, 153))	('glutamate', 'MPA', (15, 24))	('DMSO', 'Chemical', 'MESH:D004121', (249, 253))	('pyruvate', 'Chemical', 'MESH:D011773', (335, 343))	('IDH1', 'Gene', (173, 177))	('glutamate', 'Chemical', 'None', (15, 24))	('glucose', 'Chemical', 'MESH:D005947', (315, 322))	('glutamate', 'Chemical', 'None', (324, 333))	('mutant', 'Var', (40, 46))	('pyruvate', 'MPA', (335, 343))	('glutamate', 'MPA', (324, 333))
63155	30220459	AGI-5198 lowered (R)-2HG and normalized intracellular glutamate and KIC levels in IDH1 mutant cells, with the latter change indicative of restored BCAT activity (Figure 2H).	('normalized', 'NegReg', (29, 39))	('intracellular glutamate', 'MPA', (40, 63))	('restored', 'PosReg', (138, 146))	('KIC levels', 'MPA', (68, 78))	('IDH1', 'Gene', (82, 86))	('BCAT activity', 'MPA', (147, 160))	('mutant', 'Var', (87, 93))	('glutamate', 'Chemical', 'None', (54, 63))	('lowered', 'NegReg', (9, 16))
63156	30220459	Overexpressing an (R)-2HG-insensitive transaminase, ornithine aminotransferase (OAT), and supplementing media with the OAT substrates 2OG (in a cellpermeable form) and L-ornithine substantially reversed mutant IDH-induced glutamate depletion (Figures 2I to 2K).	('mutant', 'Var', (203, 209))	('ornithine aminotransferase', 'Gene', '4942', (52, 78))	('OAT', 'Gene', (80, 83))	('L-ornithine', 'Chemical', 'MESH:C008973', (168, 179))	('OAT', 'Gene', (119, 122))	('OAT', 'Gene', '4942', (80, 83))	('ornithine aminotransferase', 'Gene', (52, 78))	('IDH-induced', 'Gene', (210, 221))	('OAT', 'Gene', '4942', (119, 122))	('glutamate', 'Chemical', 'None', (222, 231))
63157	30220459	IDH1 mutant GSC lines, like our engineered cell lines, also displayed reduced glutamate levels and BCAA catabolism relative to IDH1 wild-type lines despite comparable BCAT1 and BCAT2 protein levels (Figures 2L to 2N).	('glutamate', 'Chemical', 'None', (78, 87))	('reduced glutamate levels', 'Phenotype', 'HP:0500150', (70, 94))	('reduced', 'NegReg', (70, 77))	('BCAT1', 'Gene', (167, 172))	('glutamate levels', 'MPA', (78, 94))	('2N', 'Chemical', 'MESH:D009584', (213, 215))	('mutant', 'Var', (5, 11))	('BCAT2', 'Gene', '587', (177, 182))	('IDH1', 'Gene', (0, 4))	('BCAT2', 'Gene', (177, 182))	('BCAT1', 'Gene', '586', (167, 172))	('BCAA', 'Gene', (99, 103))	('BCAA', 'Gene', '51742', (99, 103))
63158	30220459	Lowering (R)-2HG in MGG152 and BT054 cell lines with AGI-5198 potently stimulated BCAT activity and restored glutamate levels without affecting BCAT1 or BCAT2 protein levels (Figures 2O, 2P, S2P, and S2Q).	('BCAT1', 'Gene', '586', (144, 149))	('glutamate', 'Chemical', 'None', (109, 118))	('glutamate levels', 'MPA', (109, 125))	('2P', 'Chemical', 'MESH:D010695', (192, 194))	('BCAT activity', 'MPA', (82, 95))	('restored', 'PosReg', (100, 108))	('BCAT2', 'Gene', '587', (153, 158))	('stimulated', 'PosReg', (71, 81))	('BCAT1', 'Gene', (144, 149))	('Lowering', 'Var', (0, 8))	('S2Q', 'Mutation', 'p.S2Q', (200, 203))	('BCAT2', 'Gene', (153, 158))	('2P', 'Chemical', 'MESH:D010695', (187, 189))
63162	30220459	We hypothesized that decreased BCAT function in IDH mutant cells would increase their reliance on GLS activity for glutamate production.	('IDH', 'Gene', (48, 51))	('mutant', 'Var', (52, 58))	('reliance on GLS activity for glutamate production', 'MPA', (86, 135))	('decreased', 'NegReg', (21, 30))	('increase', 'PosReg', (71, 79))	('BCAT function', 'MPA', (31, 44))	('glutamate', 'Chemical', 'None', (115, 124))
63163	30220459	Indeed, the conversion of glutamine to glutamate was increased in IDH1 mutant NHA and HOG cells compared to their wild-type counterparts (Figures 3A to 3C and 3E).	('glutamate', 'Chemical', 'None', (39, 48))	('glutamine', 'Chemical', 'MESH:C578860', (26, 35))	('mutant', 'Var', (71, 77))	('increased', 'PosReg', (53, 62))	('conversion of glutamine to glutamate', 'MPA', (12, 48))	('IDH1', 'Gene', (66, 70))
63165	30220459	Moreover, expression of mutant IDH1 in NHA and HOG cells cooperated with the GLS inhibitor CB-839 to deplete intracellular glutamate levels >75% in vitro (Figure 3F) and the glutamate pools in IDH1 mutant GSC lines were hypersensitive to CB-839 (Figure 3G).	('mutant', 'Var', (24, 30))	('IDH1', 'Gene', (193, 197))	('glutamate pools', 'MPA', (174, 189))	('hypersensitive', 'MPA', (220, 234))	('glutamate', 'Chemical', 'None', (123, 132))	('glutamate', 'Chemical', 'None', (174, 183))	('expression', 'Species', '29278', (10, 20))	('mutant', 'Var', (198, 204))	('deplete intracellular glutamate levels >75%', 'MPA', (101, 144))	('IDH1', 'Gene', (31, 35))
63167	30220459	15N-glutamine tracing confirmed that, similar to IDH mutant cells, glutamine catabolism was induced in BCAT null cells (Figure 3I, right panel).	('15N-glutamine', 'Chemical', 'MESH:D009584', (0, 13))	('3I', 'Chemical', 'MESH:D007455', (127, 129))	('null', 'Var', (108, 112))	('glutamine', 'Chemical', 'MESH:C578860', (67, 76))	('glutamine catabolism', 'MPA', (67, 87))	('glutamine', 'Chemical', 'MESH:C578860', (4, 13))	('BCAT', 'Gene', (103, 107))	('induced', 'PosReg', (92, 99))
63169	30220459	Indeed, BCAT null cells potently increased alanine transamination, an effect that was only observed in IDH1 mutant cells when supplemented with 2OG (Figures S3J to S3N).	('increased alanine', 'Phenotype', 'HP:0003348', (33, 50))	('mutant', 'Var', (108, 114))	('alanine transamination', 'MPA', (43, 65))	('increased', 'PosReg', (33, 42))	('alanine', 'Chemical', 'MESH:D000409', (43, 50))	('S3N', 'Chemical', 'MESH:D013455', (164, 167))	('IDH1', 'Gene', (103, 107))
63170	30220459	Therefore, both loss of BCAT activity and increased 2OG consumption contribute to decreased transamination-dependent glutamate synthesis in IDH mutant cells (Figure S3O), leading to increased reliance on GLS (Figure 3J).	('reliance on GLS', 'MPA', (192, 207))	('increased', 'PosReg', (42, 51))	('increased', 'PosReg', (182, 191))	('2OG consumption', 'MPA', (52, 67))	('BCAT', 'Enzyme', (24, 28))	('pen', 'Gene', (109, 112))	('activity', 'MPA', (29, 37))	('loss', 'NegReg', (16, 20))	('pen', 'Gene', '27344', (109, 112))	('glutamate', 'Chemical', 'None', (117, 126))	('S3O', 'Chemical', 'MESH:D013455', (165, 168))	('mutant', 'Var', (144, 150))	('decreased', 'NegReg', (82, 91))	('IDH', 'Gene', (140, 143))
63174	30220459	Furthermore, expressing a hypermorphic GLS variant rescued glutamate production in IDH mutant cells (Figures 3N, 3O, and S3P to S3R).	('glutamate', 'Chemical', 'None', (59, 68))	('glutamate production', 'MPA', (59, 79))	('mutant', 'Var', (87, 93))	('rescued', 'PosReg', (51, 58))	('GLS', 'Gene', (39, 42))	('variant', 'Var', (43, 50))	('3O', 'Chemical', 'MESH:D013481', (113, 115))
63175	30220459	Therefore, BCATs and GLS reciprocally support glutamate synthesis and GLS can be engaged to overcome the loss of BCAT activity caused by mutant IDH.	('IDH', 'Gene', (144, 147))	('glutamate synthesis', 'MPA', (46, 65))	('BCAT activity', 'MPA', (113, 126))	('glutamate', 'Chemical', 'None', (46, 55))	('mutant', 'Var', (137, 143))
63178	30220459	The GFP reporter enabled us to rapidly isolate high-purity tumor tissue from surrounding normal brain tissue for metabolic analyses, which confirmed clinically-relevant concentrations of 2HG in the IDH1 mutant tumors (Figures 4C and 4D).	('mutant', 'Var', (203, 209))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('IDH1', 'Gene', (198, 202))	('tumor', 'Disease', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
63182	30220459	Inactivation of GLS in the IDH1 mutant and wild-type HOG cells using CRISPR/Cas9 (Figure 4H) did not decrease their ability to form brain tumors (Figure S4C), but did, as expected based on our in vitro findings, cooperate with mutant IDH to lower glutamate and aspartate levels (Figures 4I to 4L and S4D).	('brain tumors', 'Disease', (132, 144))	('IDH', 'Gene', (234, 237))	('mutant', 'Var', (227, 233))	('brain tumor', 'Phenotype', 'HP:0030692', (132, 143))	('GLS', 'Gene', (16, 19))	('glutamate', 'Chemical', 'None', (247, 256))	('lower', 'NegReg', (241, 246))	('lower glutamate and aspartate levels', 'Phenotype', 'HP:0500150', (241, 277))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('mutant', 'Var', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('aspartate', 'Chemical', 'None', (261, 270))	('IDH1', 'Gene', (27, 31))	('brain tumors', 'Phenotype', 'HP:0030692', (132, 144))	('Inactivation', 'Var', (0, 12))	('brain tumors', 'Disease', 'MESH:D001932', (132, 144))
63185	30220459	Consistent with prior cell culture studies, neither genetic nor pharmacologic GLS inhibition compromised (R)-2HG synthesis in IDH1 mutant HOG tumors (Figures 4I and S4G).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutant', 'Var', (131, 137))	('compromised', 'NegReg', (93, 104))	('IDH1', 'Gene', (126, 130))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('S4G', 'Chemical', 'MESH:D013455', (165, 168))
63186	30220459	Moreover, U-13C-glutamine tracing in mice bearing orthotopic IDH1 mutant HOG tumors showed that the tumor 2HG pool was not labeled significantly (Figure S4L) despite substantial enrichment of labeled glutamine in plasma (Figure S4K) and robust labeling of tumor glutamate and 2OG pools.	('mutant', 'Var', (66, 72))	('tumor', 'Disease', (100, 105))	('U-13C-glutamine', 'Chemical', 'MESH:C513342', (10, 25))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('glutamine', 'Chemical', 'MESH:C578860', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mice', 'Species', '10090', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('enrichment', 'MPA', (178, 188))	('glutamate', 'Chemical', 'None', (262, 271))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (256, 261))	('tumors', 'Disease', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('IDH1', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('glutamine', 'Chemical', 'MESH:C578860', (200, 209))	('2OG pools', 'MPA', (276, 285))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (77, 82))
63187	30220459	Therefore, GLS inhibition does not impede (R)-2HG synthesis in our IDH1 mutant glioma model.	('glioma', 'Disease', (79, 85))	('mutant', 'Var', (72, 78))	('IDH1', 'Gene', (67, 71))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))
63189	30220459	We confirmed that glutathione levels are decreased in IDH1 mutant orthotopic xenograft gliomas (Figure 5A) and increased by AGI-5198 in both engineered (HOG) and endogenous (MGG152) IDH1 mutant glioma cell lines (Figure 5B).	('glioma', 'Disease', (87, 93))	('glutathione levels', 'MPA', (18, 36))	('increased', 'PosReg', (111, 120))	('glioma', 'Disease', (194, 200))	('IDH1', 'Gene', (54, 58))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('decreased', 'NegReg', (41, 50))	('mutant', 'Var', (59, 65))	('mutant', 'Var', (187, 193))	('glutathione', 'Chemical', 'MESH:D005978', (18, 29))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('gliomas', 'Disease', (87, 94))
63190	30220459	Decreased levels of reduced glutathione (GSH) in IDH1 mutant gliomas could reflect glutamate depletion caused by BCAT inhibition, consumption of NADPH by mutant IDH1, or both (Figure 5C).	('GSH', 'Chemical', 'MESH:D005978', (41, 44))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('levels', 'MPA', (10, 16))	('inhibition', 'NegReg', (118, 128))	('glutamate depletion', 'MPA', (83, 102))	('Decreased', 'NegReg', (0, 9))	('glutathione', 'Chemical', 'MESH:D005978', (28, 39))	('glutamate', 'Chemical', 'None', (83, 92))	('gliomas', 'Disease', (61, 68))	('NADPH', 'Chemical', 'MESH:D009249', (145, 150))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('mutant', 'Var', (54, 60))	('Decreased levels of reduced glutathione', 'Phenotype', 'HP:0003343', (0, 39))	('IDH1', 'Gene', (49, 53))	('mutant', 'Var', (154, 160))
63191	30220459	Arguing against a prominent role for NADPH consumption, the reduced/oxidized glutathione ratio was not impacted by mutant IDH in vitro or in vivo (Figures 5A and S5A) and, consistent with findings in IDH1 mutant macrophages, NADPH levels were not suppressed in IDH1 mutant HOG tumors (Figure S5B).	('mutant', 'Var', (115, 121))	('NADPH levels', 'MPA', (225, 237))	('NADPH', 'Chemical', 'MESH:D009249', (225, 230))	('NADPH', 'Chemical', 'MESH:D009249', (37, 42))	('reduced/oxidized glutathione ratio', 'MPA', (60, 94))	('mutant', 'Var', (266, 272))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('IDH1', 'Gene', (261, 265))	('glutathione', 'Chemical', 'MESH:D005978', (77, 88))	('tumors', 'Disease', (277, 283))
63194	30220459	We then performed 15N-BCAA tracing in isogenic HOG cell lines and found that mutant IDH expression impedes the flow of nitrogen from BCAAs to glutamate and ultimately to glutathione (Figure 5G).	('glutathione', 'Chemical', 'MESH:D005978', (170, 181))	('impedes', 'NegReg', (99, 106))	('BCAA', 'Gene', (133, 137))	('nitrogen', 'Chemical', 'MESH:D009584', (119, 127))	('glutamate', 'Chemical', 'None', (142, 151))	('expression', 'Species', '29278', (88, 98))	('BCAA', 'Gene', '51742', (133, 137))	('IDH', 'Gene', (84, 87))	('BCAA', 'Gene', (22, 26))	('BCAA', 'Gene', '51742', (22, 26))	('mutant', 'Var', (77, 83))
63196	30220459	The effects of BPTES were on-target because they were reversed by BPTES-resistant GLS mutants (Figures S5E to S5G).	('BPTES', 'Chemical', 'MESH:C523193', (15, 20))	('mutants', 'Var', (86, 93))	('GLS', 'Gene', (82, 85))	('BPTES', 'Chemical', 'MESH:C523193', (66, 71))
63197	30220459	The effects of CB-839 and mutant IDH on glutathione levels, like their effects on glutamate, were additive in NHA and HOG cells (Figures 5J and 3F).	('glutamate', 'Chemical', 'None', (82, 91))	('effects', 'Reg', (4, 11))	('glutamate', 'MPA', (82, 91))	('glutathione levels', 'MPA', (40, 58))	('CB-839', 'Gene', (15, 21))	('IDH', 'Gene', (33, 36))	('mutant', 'Var', (26, 32))	('glutathione', 'Chemical', 'MESH:D005978', (40, 51))
63198	30220459	Conversely, expressing the hypermorphic GLS variant that rescued glutamate levels in IDH mutant HOG cells (Figures 3O and S3Q) also rescued glutathione levels (Figures 5K and S5H).	('glutathione', 'Chemical', 'MESH:D005978', (140, 151))	('S3Q', 'Chemical', 'MESH:C500988', (122, 125))	('rescued', 'PosReg', (57, 64))	('variant', 'Var', (44, 51))	('S5H', 'Chemical', 'MESH:C042345', (175, 178))	('3O', 'Chemical', 'MESH:D013481', (115, 117))	('rescued', 'PosReg', (132, 139))	('glutamate', 'Chemical', 'None', (65, 74))	('glutathione levels', 'MPA', (140, 158))	('glutamate levels', 'MPA', (65, 81))	('IDH', 'Gene', (85, 88))	('mutant', 'Var', (89, 95))
63199	30220459	IDH mutant GSC lines display lower glutathione levels relative to IDH wild-type lines and a trend toward greater susceptibility to CB-839-induced glutathione depletion (Figures 5L and 5M).	('susceptibility', 'Reg', (113, 127))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (4, 10))	('lower glutathione levels', 'Phenotype', 'HP:0003343', (29, 53))	('glutathione depletion', 'MPA', (146, 167))	('glutathione', 'Chemical', 'MESH:D005978', (146, 157))	('glutathione', 'Chemical', 'MESH:D005978', (35, 46))	('lower', 'NegReg', (29, 34))	('glutathione levels', 'MPA', (35, 53))
63202	30220459	Treatment of tumor-bearing mice with CB-839 depleted glutathione in IDH mutant HOG gliomas, but not in isogenic wild-type tumors (Figure 5O), mirroring its effects on glutamate (Figure S4I).	('tumor', 'Disease', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (122, 127))	('glutamate', 'Chemical', 'None', (167, 176))	('depleted', 'NegReg', (44, 52))	('gliomas', 'Disease', (83, 90))	('mutant', 'Var', (72, 78))	('mice', 'Species', '10090', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('5O', 'Chemical', 'MESH:D013481', (137, 139))	('glutathione', 'MPA', (53, 64))	('depleted glutathione', 'Phenotype', 'HP:0003343', (44, 64))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('IDH', 'Gene', (68, 71))	('glutathione', 'Chemical', 'MESH:D005978', (53, 64))	('tumors', 'Disease', (122, 128))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))
63205	30220459	We postulated that the loss of glutathione observed after inhibiting GLS in IDH1 mutant cells would impair resistance to oxidative stress.	('IDH1', 'Gene', (76, 80))	('GLS', 'Protein', (69, 72))	('glutathione', 'Chemical', 'MESH:D005978', (31, 42))	('glutathione', 'Protein', (31, 42))	('inhibiting', 'NegReg', (58, 68))	('impair', 'NegReg', (100, 106))	('loss', 'NegReg', (23, 27))	('mutant', 'Var', (81, 87))	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))	('resistance to oxidative stress', 'MPA', (107, 137))
63206	30220459	In cell culture media with physiological metabolite levels, CB-839 cooperated with mutant IDH to profoundly inhibit HOG cell proliferation, mirroring their effects on glutamate and glutathione (Figures 6A, 3F, and 5J, note log scale in Figure 6A).	('glutamate', 'Chemical', 'None', (167, 176))	('IDH', 'Gene', (90, 93))	('glutathione', 'Chemical', 'MESH:D005978', (181, 192))	('mutant', 'Var', (83, 89))	('CB-839', 'Gene', (60, 66))	('inhibit', 'NegReg', (108, 115))	('HOG cell proliferation', 'CPA', (116, 138))
63208	30220459	Exposure to 21% oxygen can, itself, induce oxidative stress and steady-state ROS levels, as determined by an ROS-sensitive dye, were indeed higher in IDH1 mutant HOG cells under 21% oxygen conditions relative to IDH1 wild-type controls (Figures S6C to S6E).	('oxidative stress', 'Phenotype', 'HP:0025464', (43, 59))	('oxygen', 'Chemical', 'MESH:D010100', (182, 188))	('higher', 'PosReg', (140, 146))	('mutant', 'Var', (155, 161))	('oxidative stress', 'MPA', (43, 59))	('ROS levels', 'MPA', (77, 87))	('IDH1', 'Gene', (150, 154))	('S6E', 'Mutation', 'p.S6E', (252, 255))	('oxygen', 'Chemical', 'MESH:D010100', (16, 22))
63209	30220459	In contrast to the effects of CB-839 under 21% oxygen, we noted that GLS inhibition did not significantly impair the proliferation of IDH1 mutant HOG cells at 3% oxygen ex vivo or in orthotopic tumor assays (Figures S6A, S6B, and S4C).	('oxygen', 'Chemical', 'MESH:D010100', (47, 53))	('impair', 'NegReg', (106, 112))	('GLS', 'Protein', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('mutant', 'Var', (139, 145))	('IDH1', 'Gene', (134, 138))	('S6B', 'Chemical', 'MESH:C012008', (221, 224))	('tumor', 'Disease', (194, 199))	('oxygen', 'Chemical', 'MESH:D010100', (162, 168))
63210	30220459	Nonetheless, we hypothesized that inhibiting GLS, by lowering glutathione levels, would preferentially sensitize IDH1 mutant cells to radiation and ROS-inducing drugs.	('GLS', 'Protein', (45, 48))	('inhibiting', 'NegReg', (34, 44))	('glutathione levels', 'MPA', (62, 80))	('lowering', 'NegReg', (53, 61))	('IDH1', 'Gene', (113, 117))	('glutathione', 'Chemical', 'MESH:D005978', (62, 73))	('lowering glutathione levels', 'Phenotype', 'HP:0003343', (53, 80))	('mutant', 'Var', (118, 124))	('sensitize', 'Reg', (103, 112))
63211	30220459	Indeed, IDH1 mutant NHA and HOG cells were highly sensitive to the combination of CB-839 and the oxidant tert-butyl hydroperoxide (tBH) compared to their IDH wild-type counterparts and their effects were reversed by a cell-permeable form of GSH (Figures 6E to 6G).	('mutant', 'Var', (13, 19))	('oxidant tert-butyl', 'MPA', (97, 115))	('IDH1', 'Gene', (8, 12))	('sensitive', 'Reg', (50, 59))	('tert-butyl hydroperoxide', 'Chemical', 'MESH:D020122', (105, 129))	('GSH', 'Chemical', 'MESH:D005978', (241, 244))
63212	30220459	Synergistic cytotoxicity of tBH and CB-839 in IDH mutant HOG cells was also rescued by stimulating glutamate synthesis via ornithine transamination (Figure 6H, left panel) or glutamine catabolism using the hypermorphic Y394L GLS variant (Figure 6H, right panel).	('Y394L', 'Mutation', 'p.Y394L', (219, 224))	('glutamate', 'Chemical', 'None', (99, 108))	('ornithine', 'Chemical', 'MESH:C008973', (123, 132))	('ornithine transamination', 'MPA', (123, 147))	('cytotoxicity of tBH', 'Disease', (12, 31))	('IDH', 'Gene', (46, 49))	('Y394L', 'Var', (219, 224))	('glutamate synthesis', 'MPA', (99, 118))	('CB-839', 'Gene', (36, 42))	('glutamine', 'Chemical', 'MESH:C578860', (175, 184))	('cytotoxicity of tBH', 'Disease', 'MESH:D064420', (12, 31))	('mutant', 'Var', (50, 56))	('stimulating', 'PosReg', (87, 98))	('glutamine catabolism', 'MPA', (175, 195))
63214	30220459	Despite their substantially lower basal glutathione content and higher ROS levels (Figures 5L, S6F, and S6G), IDH mutant GSC lines did not undergo apoptosis upon CB-839- or BSO-induced glutathione depletion (Figure S6H), nor did they display hypersensitivity to tBH treatment alone (Figures S6I and S6J).	('S6G', 'Mutation', 'p.S6G', (104, 107))	('IDH', 'Gene', (110, 113))	('lower', 'NegReg', (28, 33))	('higher', 'PosReg', (64, 70))	('hypersensitivity', 'Disease', (242, 258))	('glutathione', 'Chemical', 'MESH:D005978', (185, 196))	('hypersensitivity', 'Disease', 'MESH:D004342', (242, 258))	('lower basal glutathione', 'Phenotype', 'HP:0003343', (28, 51))	('mutant', 'Var', (114, 120))	('BSO', 'Chemical', 'MESH:C065566', (173, 176))	('ROS levels', 'MPA', (71, 81))	('glutathione', 'Chemical', 'MESH:D005978', (40, 51))	('basal glutathione content', 'MPA', (34, 59))
63215	30220459	Whereas only 1 of 3 IDH wild-type GSC lines was susceptible to synergistic cell killing by tBH and CB-839 treatments (the c-Mychigh/GLShigh TS516 line), all 3 of the IDH1 mutant lines were sensitized to tBH by CB-839.	('mutant', 'Var', (171, 177))	('IDH1', 'Gene', (166, 170))	('c-Myc', 'Gene', (122, 127))	('c-Myc', 'Gene', '4609', (122, 127))
63217	30220459	This suggests that CB-839's ability to preferentially deplete glutathione in IDH mutant GSC lines underlies its selective potentiation of oxidative stress-induced cytotoxicity in these cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (163, 175))	('glutathione', 'Chemical', 'MESH:D005978', (62, 73))	('potentiation', 'PosReg', (122, 134))	('preferentially', 'PosReg', (39, 53))	('oxidative stress', 'Phenotype', 'HP:0025464', (138, 154))	('IDH', 'Gene', (77, 80))	('deplete glutathione', 'MPA', (54, 73))	('cytotoxicity', 'Disease', (163, 175))	('mutant', 'Var', (81, 87))
63218	30220459	Although mutant IDH increases the sensitivity of hematopoietic cells to oxidative DNA damage by downregulating ATM, ATM levels are not suppressed IDH1 mutant glial cells compared to controls (Figures S6K to S6M).	('IDH1', 'Gene', (146, 150))	('sensitivity', 'MPA', (34, 45))	('downregulating', 'NegReg', (96, 110))	('ATM', 'Gene', (111, 114))	('mutant', 'Var', (151, 157))	('mutant', 'Var', (9, 15))	('ATM', 'Gene', '472', (111, 114))	('IDH', 'Gene', (16, 19))	('ATM', 'Gene', (116, 119))	('S6M', 'Mutation', 'p.S6M', (207, 210))	('ATM', 'Gene', '472', (116, 119))	('increases', 'PosReg', (20, 29))
63219	30220459	CB-839 also enhanced the effectiveness of radiation against IDH1 mutant HOG cells, but not IDH1 wild-type HOG cells, in vitro, unless the cells were cotreated with NAC (Figures 7A and 7B).	('CB-839', 'Gene', (0, 6))	('NAC', 'Chemical', 'MESH:C086501', (164, 167))	('IDH1', 'Gene', (60, 64))	('mutant', 'Var', (65, 71))	('enhanced', 'PosReg', (12, 20))	('radiation', 'CPA', (42, 51))	('effectiveness', 'MPA', (25, 38))
63220	30220459	We next established isogenic orthotopic xenograft gliomas from IDH1 mutant and wildtype HOG cells engineered to co-express luciferase and GFP, as in Figure 4.	('gliomas', 'Disease', (50, 57))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('IDH1', 'Gene', (63, 67))	('mutant', 'Var', (68, 74))
63223	30220459	These selective effects correlated with preferential depletion of glutamate (Figure S4I) and glutathione (Figure 5O) by CB-839 in the IDH1 mutant tumors.	('depletion of glutamate', 'MPA', (53, 75))	('5O', 'Chemical', 'MESH:D013481', (113, 115))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('glutathione', 'MPA', (93, 104))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('mutant', 'Var', (139, 145))	('glutamate', 'Chemical', 'None', (66, 75))	('IDH1', 'Gene', (134, 138))	('preferential', 'PosReg', (40, 52))	('CB-839', 'Gene', (120, 126))	('glutathione', 'Chemical', 'MESH:D005978', (93, 104))	('tumors', 'Disease', (146, 152))
63224	30220459	Similar results were observed when subcutaneous tumors formed by the TS603 IDH1 mutant GSC line were treated with radiation and CB-839 (Figures 7G, S7D, S7E, and S7K to S7M), associated with reduced proliferation, reduced angiogenesis and modestly increased apoptosis (Figures S7F to S7J).	('7F', 'Chemical', 'MESH:D005461', (278, 280))	('proliferation', 'CPA', (199, 212))	('S7K', 'Var', (162, 165))	('CB-839', 'Var', (128, 134))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('reduced', 'NegReg', (191, 198))	('angiogenesis', 'CPA', (222, 234))	('IDH1', 'Gene', (75, 79))	('TS603', 'Var', (69, 74))	('S7D', 'Mutation', 'p.S7D', (148, 151))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (35, 54))	('reduced', 'NegReg', (214, 221))	('apoptosis', 'CPA', (258, 267))	('S7E', 'Mutation', 'p.S7E', (153, 156))	('S7M', 'Mutation', 'p.S7M', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
63225	30220459	Our findings help explain why IDH1 mutant gliomas convert 2OG to glutamate more slowly than IDH1 wild-type tumors and have low glutamate and glutathione content.	('low glutamate and glutathione content', 'Phenotype', 'HP:0500150', (123, 160))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glutathione', 'Chemical', 'MESH:D005978', (141, 152))	('tumors', 'Disease', (107, 113))	('low', 'NegReg', (123, 126))	('mutant', 'Var', (35, 41))	('glutamate', 'Chemical', 'None', (127, 136))	('glutamate', 'Chemical', 'None', (65, 74))	('IDH1', 'Gene', (30, 34))	('convert 2OG to glutamate', 'MPA', (50, 74))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('low glutamate', 'Phenotype', 'HP:0500150', (123, 136))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('slowly', 'NegReg', (80, 86))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
63227	30220459	Consistent with earlier analyses of IDH1 mutant brain tumors, our late-passage IDH1 mutant NHA cells also had low BCAT1 protein levels.	('brain tumors', 'Disease', (48, 60))	('brain tumor', 'Phenotype', 'HP:0030692', (48, 59))	('BCAT1', 'Gene', '586', (114, 119))	('mutant', 'Var', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('brain tumors', 'Disease', 'MESH:D001932', (48, 60))	('brain tumors', 'Phenotype', 'HP:0030692', (48, 60))	('IDH1', 'Gene', (79, 83))	('BCAT1', 'Gene', (114, 119))	('low', 'NegReg', (110, 113))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
63228	30220459	However, IDH1 mutant early passage NHA and HOG cells and IDH1 mutant GSC lines had low BCAT activity despite preserved BCAT1 expression.	('mutant', 'Var', (62, 68))	('IDH1', 'Gene', (9, 13))	('mutant', 'Var', (14, 20))	('expression', 'Species', '29278', (125, 135))	('BCAT1', 'Gene', (119, 124))	('preserved', 'NegReg', (109, 118))	('IDH1', 'Gene', (57, 61))	('expression', 'MPA', (125, 135))	('BCAT1', 'Gene', '586', (119, 124))	('BCAT activity', 'MPA', (87, 100))	('low', 'NegReg', (83, 86))
63229	30220459	Therefore, BCAT1 silencing is not required for the loss of BCAT activity displayed by IDH1 mutant glioma cells.	('BCAT1', 'Gene', '586', (11, 16))	('IDH1', 'Gene', (86, 90))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('BCAT activity', 'MPA', (59, 72))	('BCAT1', 'Gene', (11, 16))	('glioma', 'Disease', (98, 104))	('mutant', 'Var', (91, 97))
63234	30220459	Many lines of evidence suggest that IDH mutational status dictates the relative contributions of glutamine versus BCAAs to glutamate synthesis in brain tumors.	('glutamine', 'Chemical', 'MESH:C578860', (97, 106))	('brain tumors', 'Disease', (146, 158))	('brain tumor', 'Phenotype', 'HP:0030692', (146, 157))	('glutamate', 'Chemical', 'None', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('dictates', 'Reg', (58, 66))	('IDH', 'Gene', (36, 39))	('glutamate synthesis', 'MPA', (123, 142))	('BCAA', 'Gene', (114, 118))	('BCAA', 'Gene', '51742', (114, 118))	('mutational', 'Var', (40, 50))	('brain tumors', 'Phenotype', 'HP:0030692', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('brain tumors', 'Disease', 'MESH:D001932', (146, 158))
63238	30220459	Moreover, we found that the glutamate pool in these tumors is unaffected by GLS inactivation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('GLS', 'Gene', (76, 79))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('glutamate', 'Chemical', 'None', (28, 37))	('glutamate pool', 'MPA', (28, 42))	('inactivation', 'Var', (80, 92))
63239	30220459	In our isogenic, IDH1 mutant HOG tumors, however, we observed lower BCAT activity, as evidenced by reduced flux of leucinederived nitrogen into glutamate, decreased basal glutamate levels, and hyperdependence on GLS for the production of glutamate and its downstream product, glutathione.	('nitrogen', 'Chemical', 'MESH:D009584', (130, 138))	('pen', 'Gene', '27344', (200, 203))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('basal glutamate levels', 'MPA', (165, 187))	('glutamate', 'Chemical', 'None', (144, 153))	('glutamate', 'Chemical', 'None', (238, 247))	('leucine', 'Chemical', 'MESH:C038361', (115, 122))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mutant', 'Var', (22, 28))	('glutathione', 'Chemical', 'MESH:D005978', (276, 287))	('glutamate', 'Chemical', 'None', (171, 180))	('pen', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('decreased', 'NegReg', (155, 164))	('lower', 'NegReg', (62, 67))	('IDH1', 'Gene', (17, 21))	('flux of leucinederived nitrogen into glutamate', 'MPA', (107, 153))	('BCAT activity', 'MPA', (68, 81))	('reduced', 'NegReg', (99, 106))	('tumors', 'Disease', (33, 39))
63241	30220459	Therefore, IDH mutations govern the selection of glutamate synthetic routes in glioma cells.	('IDH', 'Gene', (11, 14))	('glioma', 'Disease', (79, 85))	('mutations', 'Var', (15, 24))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('govern', 'Reg', (25, 31))	('glutamate synthetic routes', 'MPA', (49, 75))	('glutamate', 'Chemical', 'None', (49, 58))
63242	30220459	We observed minimal labeling of the (R)-2HG pool in our U-13C-glutamine in vivo tracing studies of IDH1 mutant orthotopic HOG tumors, consistent with earlier in vitro studies.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mutant', 'Var', (104, 110))	('IDH1', 'Gene', (99, 103))	('U-13C-glutamine', 'Chemical', 'MESH:C513342', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
63243	30220459	In contrast, a recent study found that glutamine contributes to (R)-2HG synthesis in an IDH1 mutant chondrosarcoma model.	('chondrosarcoma', 'Disease', 'MESH:D002813', (100, 114))	('IDH1', 'Gene', (88, 92))	('glutamine', 'Chemical', 'MESH:C578860', (39, 48))	('chondrosarcoma', 'Disease', (100, 114))	('mutant', 'Var', (93, 99))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (100, 114))	('glutamine', 'MPA', (39, 48))
63244	30220459	Although there are many technical differences between our study and their study that could account for this discrepancy, even beyond tumor cell of origin and implantation site, both their and our in vivo tracing studies found that less than 3% of the 2HG pool is labeled in the first 30-45 minutes after U-13C-glutamine administration.	('U-13C-glutamine', 'Chemical', 'MESH:C513342', (304, 319))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('U-13C-glutamine', 'Var', (304, 319))
63245	30220459	We show that genetic ablation of BCAT1 and BCAT2 causes cells to engage GLS to make glutamate, recapitulating the effects of mutant IDH.	('BCAT1', 'Gene', (33, 38))	('genetic ablation', 'Var', (13, 29))	('BCAT2', 'Gene', '587', (43, 48))	('BCAT1', 'Gene', '586', (33, 38))	('causes', 'Reg', (49, 55))	('BCAT2', 'Gene', (43, 48))	('glutamate', 'Chemical', 'None', (84, 93))
63246	30220459	Inhibiting GLS in IDH1 mutant cells, in which BCAT is suppressed by (R)-2HG, blocks this adaptation and dramatically impairs their fitness by lowering glutamate, glutathione, and resistance to oxidative stress.	('adaptation', 'MPA', (89, 99))	('blocks', 'NegReg', (77, 83))	('glutathione', 'MPA', (162, 173))	('fitness', 'MPA', (131, 138))	('Inhibiting', 'NegReg', (0, 10))	('IDH1', 'Gene', (18, 22))	('resistance to oxidative stress', 'MPA', (179, 209))	('glutamate', 'Chemical', 'None', (151, 160))	('glutathione', 'Chemical', 'MESH:D005978', (162, 173))	('BCAT', 'MPA', (46, 50))	('oxidative stress', 'Phenotype', 'HP:0025464', (193, 209))	('glutamate', 'MPA', (151, 160))	('impairs', 'NegReg', (117, 124))	('lowering', 'NegReg', (142, 150))	('GLS', 'Gene', (11, 14))	('mutant', 'Var', (23, 29))
63247	30220459	Glutamate loss is key in this context because we could rescue the effects of mutant IDH1 on redox homeostasis by restoring glutamate levels using a GLS hypermorph or OAT, which is (R)-2HG-insensitive.	('redox homeostasis', 'MPA', (92, 109))	('OAT', 'Gene', (166, 169))	('glutamate', 'Chemical', 'None', (123, 132))	('glutamate levels', 'MPA', (123, 139))	('IDH1', 'Gene', (84, 88))	('Glutamate', 'Chemical', 'None', (0, 9))	('OAT', 'Gene', '4942', (166, 169))	('restoring', 'PosReg', (113, 122))	('mutant', 'Var', (77, 83))
63249	30220459	Our findings bear on the recent observations that mutant IDH confers radiosensitivity in an (R)-2HG-dependent manner in preclinical models and suggest that blocking (R)-2HG production could antagonize radiation and radiomimetic drugs.	('radiosensitivity', 'CPA', (69, 85))	('pen', 'Gene', (102, 105))	('mutant', 'Var', (50, 56))	('IDH', 'Gene', (57, 60))	('pen', 'Gene', '27344', (102, 105))
63250	30220459	There are early indications, however, that this strategy will be less effective against IDH mutant gliomas, possibly because mutant IDH acts through a 'hit-and-run' mechanism in this setting.	('mutant', 'Var', (125, 131))	('IDH mutant gliomas', 'Disease', (88, 106))	('IDH', 'Gene', (132, 135))	('IDH mutant gliomas', 'Disease', 'MESH:D005910', (88, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	("'hit-and-run'", 'PosReg', (151, 164))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
63251	30220459	We showed that mutant IDH and GLS inhibition have a synthetic lethal relationship under conditions of oxidative stress because they both converge on glutamate production and redox homeostasis.	('converge', 'Reg', (137, 145))	('oxidative stress', 'Phenotype', 'HP:0025464', (102, 118))	('IDH', 'Gene', (22, 25))	('redox homeostasis', 'MPA', (174, 191))	('inhibition', 'NegReg', (34, 44))	('GLS', 'Protein', (30, 33))	('glutamate', 'Chemical', 'None', (149, 158))	('mutant', 'Var', (15, 21))	('glutamate production', 'MPA', (149, 169))
63253	30220459	Nonetheless, our work was limited by the dearth of available tumorigenic IDH1 mutant glioma lines (and no low-grade glioma lines) and by CB839's poor BBB penetration.	('glioma lines', 'Disease', (85, 97))	('glioma lines', 'Disease', (116, 128))	('glioma lines', 'Disease', 'MESH:D005910', (116, 128))	('pen', 'Gene', (154, 157))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('glioma lines', 'Disease', 'MESH:D005910', (85, 97))	('pen', 'Gene', '27344', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('IDH1', 'Gene', (73, 77))	('mutant', 'Var', (78, 84))	('tumor', 'Disease', (61, 66))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
63254	30220459	Indeed, it is conceivable that decreased BCAT activity and altered redox homeostasis contributes to the difficulty in growing low-grade IDH1 mutant glioma cells ex vivo and in mice.	('redox homeostasis', 'MPA', (67, 84))	('altered', 'Reg', (59, 66))	('mutant', 'Var', (141, 147))	('glioma', 'Disease', (148, 154))	('decreased', 'NegReg', (31, 40))	('BCAT activity', 'MPA', (41, 54))	('IDH1', 'Gene', (136, 140))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('mice', 'Species', '10090', (176, 180))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))
63257	30220459	Nonetheless, the National Cancer Institute Cancer Therapy Evaluation Program (CTEP) is now testing the combination of CB-839 with radiation and temozolomide for the treatment of IDH1 mutant glioma patients (ClinicalTrials.gov Identifier NCT03528642) based on our findings.	('patients', 'Species', '9606', (197, 205))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('glioma', 'Disease', (190, 196))	('mutant', 'Var', (183, 189))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('temozolomide', 'Chemical', 'MESH:C047246', (144, 156))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('IDH1', 'Gene', (178, 182))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
63293	30220459	Where indicated, cell culture media also contained the following additives: gabapentin (Sigma), AGI-5198 (Xcessbio), CB839 (Calithera), BPTES (Sigma), tert-butyl hydroperoxide (Sigma), ethyl-GSH (Sigma), Lglutamic acid (Sigma), L-ornithine (Sigma), N-acetylcysteine (Sigma), dimethyl 2-oxoglutarate (Sigma), L-S,R-buthionine sulfoximine (BSO, Sigma).	('L-S,R-buthionine sulfoximine', 'Chemical', 'MESH:D019328', (308, 336))	('ethyl-GSH', 'Chemical', 'MESH:C042431', (185, 194))	('BPTES', 'Chemical', 'MESH:C523193', (136, 141))	('dimethyl 2-oxoglutarate', 'Chemical', 'MESH:C550691', (275, 298))	('L-S', 'Var', (308, 311))	('dimethyl 2-oxoglutarate', 'MPA', (275, 298))	('BSO', 'Chemical', 'MESH:C065566', (338, 341))	('tert-butyl hydroperoxide', 'Chemical', 'MESH:D020122', (151, 175))	('gabapentin', 'Chemical', 'MESH:C040029', (76, 86))	('N-acetylcysteine', 'MPA', (249, 265))	('Lglutamic acid', 'Chemical', 'MESH:D000596', (204, 218))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (249, 265))	('L-ornithine', 'Chemical', 'MESH:C008973', (228, 239))
63301	30220459	IDH1 wild-type (NM_001282386.1) and R132H cDNAs were cloned into the lentiviral vectors plenti-Ubc-IRES-hygro (used to generate HOG stable cell lines) and plenti-EF1alpha-IRES-hygro (used to generate NHA and HOG stable cell lines in Figure 1).	('EF1alpha', 'Gene', (162, 170))	('Ubc', 'Gene', (95, 98))	('Ubc', 'Gene', '7316', (95, 98))	('R132H', 'Var', (36, 41))	('R132H', 'Mutation', 'p.R132H', (36, 41))	('EF1alpha', 'Gene', '1917', (162, 170))
63324	30220459	The resulting vector, plenti-EF1alpha-GLSIRES-neo, was mutagenized via In-Fusion cloning (Clontech) to introduce the K320A or Y394L mutations.	('EF1alpha', 'Gene', '1917', (29, 37))	('Y394L', 'Var', (126, 131))	('K320A', 'Var', (117, 122))	('K320A', 'Mutation', 'p.K320A', (117, 122))	('EF1alpha', 'Gene', (29, 37))	('Y394L', 'Mutation', 'p.Y394L', (126, 131))
63325	30220459	Wild-type, K320A, and Y394L GLS expression vectors were also mutagenized via InFusion cloning to introduce silent mutations disrupting the binding site and PAM sequence targeted by the GLS sgRNA listed above (GCACGCATCCGCAGCCCGGGG > GtACaCAcCCaCAaCCaGGaG, changed nucleotides in lower case, PAM site in bold).	('mutagenized', 'Var', (61, 72))	('K320A', 'Mutation', 'p.K320A', (11, 16))	('mutations', 'Var', (114, 123))	('expression vectors', 'Species', '29278', (32, 50))	('Y394L', 'Mutation', 'p.Y394L', (22, 27))	('binding', 'Interaction', (139, 146))	('Y394L', 'Var', (22, 27))	('disrupting', 'NegReg', (124, 134))
63331	30220459	Lentiviral and retroviral particles were made by Lipofectamine 2000-based cotransfection of HEK293T cells with expression vectors and packaging plasmids psPAX2 (Addgene 12260) and pMD2.G (Addgene 12259) or gag/pol (Addgene 14887) and VSV.G (Addgene 14888), respectively, in a ratio of 8:3:1 (lentiCRISPR_v2 plasmids) or 4:3:1 (all others).	('Addgene 14887', 'Var', (215, 228))	('Addgene 14887', 'Chemical', 'None', (215, 228))	('Addgene 14888', 'Chemical', 'None', (241, 254))	('Addgene 12259', 'Chemical', 'None', (188, 201))	('Addgene 12259', 'Var', (188, 201))	('expression vectors', 'Species', '29278', (111, 129))
63349	30220459	The resulting ligand-bound forms of human BCAT2 with 2OG, (R)-2HG, or (S)-2HG were energy-minimized using the UCSF Chimera software program.	('BCAT2', 'Gene', (42, 47))	('2OG', 'Var', (53, 56))	('human', 'Species', '9606', (36, 41))	('BCAT2', 'Gene', '587', (42, 47))
63361	30220459	For tracing assays in DMEM and IMDM media, tracer concentrations were: 0.802 mM 15N-Leu/U-13C-Leu, 0.802 mM 15N-Ile/U-13C-Ile, 0.803 mM 15N-Val, 0.1 mM 1-13C-Glu, and 1 mMalpha- N-Gln/U- C-Gln.	('N-Gln', 'Chemical', 'MESH:C544323', (178, 183))	('13C', 'Chemical', 'MESH:C513342', (90, 93))	('U-13C-Leu', 'Chemical', 'MESH:C513342', (88, 97))	('13C', 'Chemical', 'MESH:C513342', (118, 121))	('U-13C-Ile', 'Chemical', 'MESH:C513342', (116, 125))	('0.803 mM 15N-Val', 'Var', (127, 143))	('13C', 'Chemical', 'MESH:C513342', (154, 157))	('0.802 mM 15N-Ile/U-13C-Ile', 'Var', (99, 125))	('0.802 mM 15N-Leu/U-13C-Leu', 'Var', (71, 97))	('0.1 mM 1-13C-Glu', 'Var', (145, 161))
63364	30220459	In Figure S2Q, cells were cultured in NeuroCult NS-A Basal Medium with Proliferation Supplement (StemCell Technologies) supplemented with EGF (20 ng/ml), bFGF (20 ng/ml), heparin (2 mug/ml), 1% penicillin/streptomycin, Fungizone (250 ng/ml), and Plasmocin (2.5 mug/ml).	('bFGF', 'Gene', '2247', (154, 158))	('S2Q', 'Mutation', 'p.S2Q', (10, 13))	('Fungizone', 'Chemical', 'MESH:D000666', (219, 228))	('streptomycin', 'Chemical', 'MESH:D013307', (205, 217))	('bFGF', 'Gene', (154, 158))	('heparin', 'Chemical', 'MESH:D006493', (171, 178))	('250', 'Var', (230, 233))	('penicillin', 'Chemical', 'MESH:D010406', (194, 204))
63399	30220459	For U-13C-glutamine tracing studies, tracer was administered to mice bearing IDH1 mutant orthotopic HOG tumors 3-5 weeks after tumor cell implantation according to a published protocol.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('U-13C-glutamine', 'Chemical', 'MESH:C513342', (4, 19))	('tumor', 'Disease', (104, 109))	('IDH1', 'Gene', (77, 81))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mice', 'Species', '10090', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mutant', 'Var', (82, 88))
63408	30220459	For the PK study assessing CB-839 accumulation in IDH mutant HOG tumors, 4 doses total were administered and mice were euthanized 4 hours after the final dose.	('CB-839', 'Gene', (27, 33))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mice', 'Species', '10090', (109, 113))	('mutant', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
63422	30220459	Primary antibodies included anti-IDH1 R132H (Dianova DIA-H09, mouse monoclonal, 1:30), anti-Ki67 (DAKO M7240, mouse monoclonal, 1:100), anti-CD31 (DAKO M0823, mouse monoclonal, 1:30), and anti-Cleaved Caspase 3 (Cell Signaling Technology #9664, rabbit monoclonal, 1:500).	('R132H', 'Mutation', 'p.R132H', (38, 43))	('mouse', 'Species', '10090', (62, 67))	('DAKO', 'Var', (98, 102))	('CD31', 'Gene', '5175', (141, 145))	('mouse', 'Species', '10090', (159, 164))	('rabbit', 'Species', '9986', (245, 251))	('mouse', 'Species', '10090', (110, 115))	('anti-IDH1 R132H', 'Var', (28, 43))	('anti-Cleaved', 'Var', (188, 200))	('CD31', 'Gene', (141, 145))
63454	30220459	The TCGA Brain Lower Grade Glioma (LGG) dataset was analyzed to quantify BCAT1 and ATM mRNA abundance in IDH1 mutant and wild-type glioma samples.	('glioma', 'Disease', (131, 137))	('BCAT1', 'Gene', (73, 78))	('IDH1', 'Gene', (105, 109))	('ATM', 'Gene', '472', (83, 86))	('mutant', 'Var', (110, 116))	('BCAT1', 'Gene', '586', (73, 78))	('Glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('Glioma', 'Phenotype', 'HP:0009733', (27, 33))	('Glioma', 'Disease', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('ATM', 'Gene', (83, 86))
63460	30220459	(R)-2-hydroxyglutarate, produced by IDH1/2 mutants, inhibits the BCAT transaminases IDH mutant gliomas display a transamination-dependent glutamate biosynthesis defect BCAT loss increases reliance on glutaminase for glutamate and glutathione synthesis Mutant IDH and glutaminase inhibition are synthetic lethal under oxidative stress	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glutamate', 'Chemical', 'None', (216, 225))	('IDH mutant gliomas', 'Disease', (84, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('loss', 'NegReg', (173, 177))	('oxidative stress', 'Phenotype', 'HP:0025464', (317, 333))	('increases', 'PosReg', (178, 187))	('BCAT transaminases', 'Enzyme', (65, 83))	('defect', 'Disease', (161, 167))	('glutaminase', 'Gene', '2744', (267, 278))	('mutants', 'Var', (43, 50))	('IDH1/2', 'Gene', '3417;3418', (36, 42))	('IDH1/2', 'Gene', (36, 42))	('glutaminase', 'Gene', '2744', (200, 211))	('glutathione', 'Chemical', 'MESH:D005978', (230, 241))	('inhibits', 'NegReg', (52, 60))	('(R)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (0, 22))	('IDH mutant gliomas', 'Disease', 'MESH:D005910', (84, 102))	('pen', 'Gene', (130, 133))	('reliance', 'MPA', (188, 196))	('defect', 'Disease', 'MESH:D030342', (161, 167))	('glutaminase', 'Gene', (267, 278))	('glutamate', 'Chemical', 'None', (138, 147))	('glutaminase', 'Gene', (200, 211))	('pen', 'Gene', '27344', (130, 133))
63475	30221069	For example, blockade of the well-studied checkpoint, programmed cell death protein 1 (PD-1), has been FDA approved for the treatment of multiple advanced cancers, such as melanoma and non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('programmed cell death protein 1', 'Gene', (54, 85))	('programmed cell death protein 1', 'Gene', '18566', (54, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('non-small cell lung cancer', 'Disease', (185, 211))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('NSCLC', 'Disease', (213, 218))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (213, 218))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (185, 211))	('PD-1', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (189, 211))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('cancers', 'Disease', (155, 162))	('melanoma', 'Disease', (172, 180))	('blockade', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (185, 211))
63499	30221069	All combination groups (anti-PD-1 + anti-TIGIT A-D) had significantly longer survival compared to the control group, including 57.1%, 85.7%, 42.9% and 57.1% of mice reaching long-term survival (p = 0.002, 0.0002, 0.0006, and 0.0032, respectively).	('long-term survival', 'CPA', (174, 192))	('anti-PD-1', 'Var', (24, 33))	('survival', 'CPA', (77, 85))	('longer', 'PosReg', (70, 76))	('mice', 'Species', '10090', (160, 164))
63511	30221069	Combination therapy with anti-PD-1 and anti-TIGIT significantly increased IFNgamma producing CD8+ T cells relative to both untreated mice and those treated with anti-PD-1 alone (p = 0.0225 and 0.0068 respectively).	('mice', 'Species', '10090', (133, 137))	('anti-TIGIT', 'Gene', (39, 49))	('anti-PD-1', 'Var', (25, 34))	('IFNgamma producing', 'MPA', (74, 92))	('CD8', 'Gene', (93, 96))	('increased', 'PosReg', (64, 73))	('CD8', 'Gene', '925', (93, 96))
63514	30221069	PD-1 and TIGIT co-blockade was found to significantly increase the population of IFNgamma and TNFalpha producing CD8+ T cells to 44.14% +- 4.10 when compared to control (12.0% +- 1.72) and both anti-PD-1 (10.69% +- 3.20) and anti-TIGIT (25.8% +- 7.30) monotherapy groups (p = 0.0008, 0.0003, and 0.0477 respectively).	('TNFalpha', 'Gene', '21926', (94, 102))	('CD8', 'Gene', (113, 116))	('CD8', 'Gene', '925', (113, 116))	('increase', 'PosReg', (54, 62))	('TNFalpha', 'Gene', (94, 102))	('IFNgamma', 'Gene', (81, 89))	('co-blockade', 'Var', (15, 26))
63517	30221069	We also found that anti-PD-1 and anti-TIGIT monotherapies both reduced the percentage of tumor-infiltrating Tregs (6.4% and 5.4% respectively) when compared to control mice (p = 0.0496 and 0.0209, respectively).	('rat', 'Species', '10116', (101, 104))	('reduced', 'NegReg', (63, 70))	('mice', 'Species', '10090', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('anti-PD-1', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
63518	30221069	In contrast, PD-1 blockade increased the expression of PD-1 on Tregs relative to untreated mice (p = 0.0145; Fig.	('mice', 'Species', '10090', (91, 95))	('increased', 'PosReg', (27, 36))	('PD-1', 'Gene', (13, 17))	('expression', 'MPA', (41, 51))	('PD-1', 'Gene', (55, 59))	('blockade', 'Var', (18, 26))
63521	30221069	A prior study has shown that TIDCs with high MHCII expression (CD11b+CD11 c+MHCIIhi) may inhibit CD8+ T cell function in the setting of murine mammary carcinoma.	('CD11b+CD11 c+MHCIIhi', 'Var', (63, 83))	('CD8', 'Gene', '925', (97, 100))	('carcinoma', 'Disease', (151, 160))	('murine', 'Species', '10090', (136, 142))	('inhibit', 'NegReg', (89, 96))	('CD8', 'Gene', (97, 100))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (143, 160))	('carcinoma', 'Disease', 'MESH:D002277', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
63529	30221069	However, those patients with LGG (n = 513), expressing CD155 demonstrated an overall survival significantly lower than those without (p = 0.0121; Fig.	('patients', 'Species', '9606', (15, 23))	('rat', 'Species', '10116', (68, 71))	('lower', 'NegReg', (108, 113))	('CD155', 'Var', (55, 60))
63540	30221069	Likewise, TIGIT expression on TILs has been shown to be upregulated in other solid cancers such as melanoma, colon cancer, and NSCLC in both mice and humans.	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('humans', 'Species', '9606', (150, 156))	('colon cancer', 'Disease', (109, 121))	('mice', 'Species', '10090', (141, 145))	('TIGIT', 'Gene', (10, 15))	('NSCLC', 'Disease', (127, 132))	('solid cancers', 'Disease', 'MESH:D009369', (77, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('solid cancers', 'Disease', (77, 90))	('expression', 'Var', (16, 26))	('colon cancer', 'Disease', 'MESH:D015179', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('upregulated', 'PosReg', (56, 67))
63547	30221069	Unlike anti-TIGIT monotherapy, we found that anti-PD-1 alone led to a significant increase in survival compared to control mice.	('survival', 'CPA', (94, 102))	('increase', 'PosReg', (82, 90))	('anti-PD-1', 'Var', (45, 54))	('mice', 'Species', '10090', (123, 127))
63548	30221069	The treatment effect of anti-PD-1 has been previously described in multiple murine GBM studies., Combination therapy using anti-TIGIT and anti-PD-1 antibodies further conferred a greater survival benefit in all anti-TIGIT treatment schedules, implying a synergistic mechanism following interruption of the two inhibitory checkpoints.	('benefit', 'PosReg', (196, 203))	('greater', 'PosReg', (179, 186))	('Combination', 'Interaction', (97, 108))	('anti-TIGIT', 'Var', (123, 133))	('anti-PD-1', 'Gene', (138, 147))	('survival', 'CPA', (187, 195))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('murine', 'Species', '10090', (76, 82))
63553	30221069	The presence of TILs has been positively correlated with survival in patients with glioma.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('patients', 'Species', '9606', (69, 77))	('presence', 'Var', (4, 12))	('correlated', 'Reg', (41, 51))
63557	30221069	In a rat glioma model, retroviral delivery of IFNgamma was further shown to improve survival.	('IFNgamma', 'Gene', (46, 54))	('glioma', 'Disease', (9, 15))	('rat', 'Species', '10116', (5, 8))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('survival', 'CPA', (84, 92))	('retroviral delivery', 'Var', (23, 42))	('improve', 'PosReg', (76, 83))
63566	30221069	For instance, Norian et al (2009) showed an accumulation of CD11b+CD11 c+MHCIIhi TIDCs in murine mammillary tumors following tumor progression and further demonstrated a suppressive effect on CD8+ T cell function.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('suppressive', 'NegReg', (170, 181))	('rat', 'Species', '10116', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CD8', 'Gene', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CD8', 'Gene', '925', (192, 195))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (125, 130))	('CD11b+CD11', 'Gene', (60, 70))	('CD11b+CD11 c+MHCIIhi', 'Var', (60, 80))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('murine', 'Species', '10090', (90, 96))	('accumulation', 'PosReg', (44, 56))
63568	30221069	Consistent with the literature, we saw a negative correlation between the frequency of CD11b+CD11 c+MHCIIhi TIDCs and pro-inflammatory cytokine production by CD8+ T cells, suggesting that reduction in suppressive TIDCs may contribute to the restoration of effector T cells function.	('rat', 'Species', '10116', (246, 249))	('negative', 'NegReg', (41, 49))	('CD11b+CD11', 'Var', (87, 97))	('CD8', 'Gene', (158, 161))	('CD8', 'Gene', '925', (158, 161))	('pro-inflammatory cytokine production', 'MPA', (118, 154))	('rat', 'Species', '10116', (24, 27))
63572	30221069	While TIGIT and its ligand, CD155 (PVR), have been shown to be highly expressed in patients with GBM, it is unclear whether this is also correlated with survival outcomes.	('CD155', 'Var', (28, 33))	('GBM', 'Disease', (97, 100))	('TIGIT', 'Gene', (6, 11))	('patients', 'Species', '9606', (83, 91))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))	('highly', 'PosReg', (63, 69))
63574	30221069	Despite our finding of high TIGIT expression on CD8+ and CD4+ TILs in GBM patients, PVR expression did not portend worsened survival outcomes in those with GBM.	('CD4+', 'Var', (57, 61))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('patients', 'Species', '9606', (74, 82))	('high', 'PosReg', (23, 27))	('GBM', 'Disease', (70, 73))	('TIGIT expression', 'MPA', (28, 44))	('CD8', 'Gene', (48, 51))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('CD8', 'Gene', '925', (48, 51))
63575	30221069	Interestingly, we found that the expression of PVR was correlated with poor overall survival in patients with low grade glioma (LGG).	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('overall survival', 'MPA', (76, 92))	('expression', 'Var', (33, 43))	('PVR', 'Gene', (47, 50))	('poor', 'NegReg', (71, 75))	('glioma', 'Disease', (120, 126))	('patients', 'Species', '9606', (96, 104))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
63632	31645905	Biomarkers have been developed to predict patients' responsivity to immunotherapy treatments, such as genome-wide mutational load, PD-L1 protein expression in infiltrating immune cells, the number of cytotoxic T cells in a tumor microenvironment, or MSI status.	('men', 'Species', '9606', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('men', 'Species', '9606', (87, 90))	('PD-L1', 'Gene', '29126', (131, 136))	('MSI', 'Gene', '5928', (250, 253))	('MSI', 'Gene', (250, 253))	('mutational load', 'Var', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('patients', 'Species', '9606', (42, 50))	('protein', 'Protein', (137, 144))	('PD-L1', 'Gene', (131, 136))
63672	31645905	In head and neck squamous cell carcinoma (HNSC, P = 0.0044, adjusted) and skin cutaneous melanoma (SKCM, P = 0.0044, adjusted), patients with T3/4 had significantly lower immune response than those with T1/2, while kidney renal clear cell carcinoma (KIRC, P = 0.0044, adjusted) showed the opposite trend.	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (215, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('KIRC', 'Disease', (250, 254))	('SKCM', 'Disease', 'MESH:C562393', (99, 103))	('kidney renal clear cell carcinoma', 'Disease', (215, 248))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('KIRC', 'Disease', 'MESH:D002292', (250, 254))	('immune response', 'MPA', (171, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (12, 40))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('T3/4', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))	('lower', 'NegReg', (165, 170))	('lower immune response', 'Phenotype', 'HP:0002721', (165, 186))	('SKCM', 'Disease', (99, 103))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
63690	31645905	It appears that the hypermutated (HM) colon adenocarcinoma (COAD) patients had the significantly highest immune response among the three different molecular subtypes (CIN, GS, HM) (P = 1.04 x 10-06, Figure 8C).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('immune response', 'MPA', (105, 120))	('hypermutated', 'Var', (20, 32))	('COAD', 'Disease', 'MESH:D015179', (60, 64))	('HM) colon adenocarcinoma', 'Disease', 'MESH:D015179', (34, 58))	('COAD', 'Disease', (60, 64))	('CIN', 'Phenotype', 'HP:0040012', (167, 170))	('highest', 'PosReg', (97, 104))	('patients', 'Species', '9606', (66, 74))
63707	31645905	Our results further demonstrated that the hypermutated (HM) subtype in colon adenocarcinoma (COAD) had a significantly higher immune response than either the chromosomal instability (CIN) or genome stable (GS) subtypes, making such patients potential candidates for immunotherapeutic treatments.	('COAD', 'Disease', 'MESH:D015179', (93, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (158, 181))	('CIN', 'Phenotype', 'HP:0040012', (183, 186))	('patients', 'Species', '9606', (232, 240))	('immune', 'MPA', (126, 132))	('men', 'Species', '9606', (289, 292))	('colon adenocarcinoma', 'Disease', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('higher', 'PosReg', (119, 125))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (71, 91))	('COAD', 'Disease', (93, 97))	('hypermutated', 'Var', (42, 54))
63734	31645905	For the same reason, the molecular subtypes investigated in detail in this study included: Basal/Her2/LumA/LumB in breast invasive carcinoma (BRCA) patients, CIN/GS/HM-indel/HM-SNV or /EBV in gastrointestinal cancer patients, IDH mutation status in glioma patients, and POLE/MSI/CN_Low/CN_High in uterine corpus endometrial carcinoma (UCEC) patients.	('patients', 'Species', '9606', (341, 349))	('IDH', 'Gene', '3417', (226, 229))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (192, 215))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (115, 140))	('gastrointestinal cancer', 'Disease', (192, 215))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (192, 215))	('CIN', 'Phenotype', 'HP:0040012', (158, 161))	('patients', 'Species', '9606', (148, 156))	('LumA', 'Gene', '79188', (102, 106))	('breast invasive carcinoma (BRCA', 'Gene', (115, 146))	('glioma', 'Disease', (249, 255))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (115, 147))	('MSI', 'Gene', (275, 278))	('MSI', 'Gene', '5928', (275, 278))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('patients', 'Species', '9606', (216, 224))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('LumA', 'Gene', (102, 106))	('IDH', 'Gene', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Her2', 'Gene', '2064', (97, 101))	('patients', 'Species', '9606', (256, 264))	('CIN/GS/HM-indel/HM-SNV', 'Var', (158, 180))	('Her2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
63737	31645905	The Normal subtype in breast invasive carcinoma (BRCA) and IDH mutant group in glioblastoma multiforme (GBM) typically had a small number of patients, and as such were excluded from downstream analyses.	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (22, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (79, 102))	('IDH', 'Gene', (59, 62))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (22, 47))	('mutant', 'Var', (63, 69))	('GBM', 'Disease', (104, 107))	('IDH', 'Gene', '3417', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('GBM', 'Disease', 'MESH:D005909', (104, 107))	('breast invasive carcinoma (BRCA', 'Gene', (22, 53))	('glioblastoma multiforme', 'Disease', (79, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('patients', 'Species', '9606', (141, 149))
63741	31645905	CIN Chromosomal instability GS genome stable HM hypermutated MSI microsatellite instability EBV Epstein-Barr virus SNV single-nucleotide variant HPV human papillomavirus	('single-nucleotide variant', 'Var', (119, 144))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (96, 114))	('HPV', 'Species', '10566', (145, 148))	('MSI', 'Gene', '5928', (61, 64))	('MSI', 'Gene', (61, 64))	('human papillomavirus', 'Species', '10566', (149, 169))	('Epstein-Barr virus', 'Disease', (96, 114))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (4, 27))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))
63742	27260798	Copy number analysis of whole-genome data using BIC-seq2 and its application to detection of cancer susceptibility variants Whole-genome sequencing data allow detection of copy number variation (CNV) at high resolution.	('copy number', 'Var', (172, 183))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
63746	27260798	Analysis of colorectal cancer genomes in particular reveals novel recurrent CNVs including deletions at two chromatin-remodeling genes RERE and NPM2.	('colorectal cancer', 'Disease', (12, 29))	('RERE', 'Gene', '473', (135, 139))	('NPM2', 'Gene', '10361', (144, 148))	('RERE', 'Gene', (135, 139))	('deletions', 'Var', (91, 100))	('NPM2', 'Gene', (144, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
63749	27260798	deletion of tumor suppressors or amplification of oncogenes can drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('oncogenes', 'Gene', (50, 59))	('amplification', 'Var', (33, 46))	('tumor', 'Disease', (70, 75))	('drive', 'PosReg', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('deletion', 'Var', (0, 8))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
63811	27260798	Several known arm level alterations have been identified previously, including gains of 7p/q, 8p/q, 13q, 20p/q, deletions of 1p, 4q, 14q, 15q, 17p (including TP53), 21q.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('deletions', 'Var', (112, 121))	('20p/q', 'Var', (105, 110))	('8p/q', 'Var', (94, 98))	('gains', 'PosReg', (79, 84))
63814	27260798	The genes with concordant transcript up-regulation and chromosomal amplification include known oncogenes MYC, IGF2, ERBB2 and HNF4A (Supplementary Figure S10A).	('HNF4A', 'Gene', (126, 131))	('S10A', 'Var', (154, 158))	('IGF2', 'Gene', (110, 114))	('ERBB2', 'Gene', '2064', (116, 121))	('MYC', 'Gene', '4609', (105, 108))	('ERBB2', 'Gene', (116, 121))	('MYC', 'Gene', (105, 108))	('up-regulation', 'PosReg', (37, 50))	('IGF2', 'Gene', '3481', (110, 114))	('S10A', 'SUBSTITUTION', 'None', (154, 158))	('HNF4A', 'Gene', '3172', (126, 131))
63817	27260798	Overexpression of PIP4K2B can confer proliferation advantage to tumor cells and it may therefore serve as a drug target for preventing and treating cancers with mutations in TP53.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('tumor', 'Disease', (64, 69))	('PIP4K2B', 'Gene', (18, 25))	('proliferation advantage', 'CPA', (37, 60))	('cancers', 'Disease', (148, 155))	('TP53', 'Gene', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PIP4K2B', 'Gene', '8396', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TP53', 'Gene', '7157', (174, 178))
63818	27260798	Genes whose transcripts show down-regulation coupled with chromosomal deletions include cancer-related genes such as ARID1A, SDHB, MAP2K4, FLCN (Supplementary Figure S10B).	('S10B', 'Var', (166, 170))	('SDHB', 'Gene', (125, 129))	('cancer', 'Disease', (88, 94))	('MAP2K4', 'Gene', '6416', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('down-regulation', 'NegReg', (29, 44))	('MAP2K4', 'Gene', (131, 137))	('S10B', 'SUBSTITUTION', 'None', (166, 170))	('FLCN', 'Gene', (139, 143))	('ARID1A', 'Gene', '8289', (117, 123))	('ARID1A', 'Gene', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('FLCN', 'Gene', '201163', (139, 143))	('SDHB', 'Gene', '6390', (125, 129))
63823	27260798	Over-expression of RERE was shown to trigger apoptosis and frequent methylation of NPM2 was observed in melanoma and leukemia.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('RERE', 'Gene', (19, 23))	('RERE', 'Gene', '473', (19, 23))	('NPM2', 'Gene', '10361', (83, 87))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('observed', 'Reg', (92, 100))	('NPM2', 'Gene', (83, 87))	('Over-expression', 'Var', (0, 15))	('methylation', 'MPA', (68, 79))	('melanoma and leukemia', 'Disease', 'MESH:D008545', (104, 125))
63825	27260798	Here, we applied our algorithm to identify germline CNVs that may confer cancer susceptibility.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('germline CNVs', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
63833	27260798	Among the known CNVRs, the most significant is the 7p14.1 deletion CNVR overlapping with the gene TARP (Supplementary Figure S11A).	('TARP', 'Gene', (98, 102))	('TARP', 'Gene', '445347', (98, 102))	('S11A', 'Var', (125, 129))	('deletion', 'Var', (58, 66))	('S11A', 'SUBSTITUTION', 'None', (125, 129))
63835	27260798	The 7q34 deletion CNVR (Supplementary Figure S11B) harboring the gene PIP was previously identified as a potential cancer-predisposing variation by screening of high-risk cancer patients.	('cancer', 'Disease', (115, 121))	('S11B', 'Var', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('CNVR', 'Gene', (18, 22))	('S11B', 'SUBSTITUTION', 'None', (45, 49))	('patients', 'Species', '9606', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PIP', 'Gene', (70, 73))	('cancer', 'Disease', (171, 177))	('PIP', 'Gene', '5304', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
63836	27260798	It was also shown that the expression of PIP is significantly associated with good prognosis factors of breast cancer such as lower tumor grade and lower pN stage.	('PIP', 'Gene', '5304', (41, 44))	('associated', 'Reg', (62, 72))	('lower tumor', 'Disease', 'MESH:D009369', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('lower tumor', 'Disease', (126, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('expression', 'Var', (27, 37))	('PIP', 'Gene', (41, 44))
63837	27260798	The 6q37 amplification CNVR (Supplementary Figure S11C) is also known and is significantly enriched in Li-Fraumeni symdrome.	('Li-Fraumeni', 'Disease', (103, 114))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (103, 114))	('S11C', 'SUBSTITUTION', 'None', (50, 54))	('S11C', 'Var', (50, 54))
63839	27260798	Novel CNVRs include the most significant CNVR located at 7q36.1 overlapping with KMT2C (MLL3) (Supplementary Figure S12A).	('MLL3', 'Gene', (88, 92))	('KMT2C', 'Gene', (81, 86))	('S12A', 'SUBSTITUTION', 'None', (116, 120))	('S12A', 'Var', (116, 120))	('KMT2C', 'Gene', '58508', (81, 86))	('MLL3', 'Gene', '58508', (88, 92))
63841	27260798	Recent studies showed that germline mutations in KMT2C might be associated with ovarian cancer, colorectal cancer and acute myeloid leukemia.	('ovarian cancer', 'Disease', (80, 94))	('KMT2C', 'Gene', (49, 54))	('associated', 'Reg', (64, 74))	('KMT2C', 'Gene', '58508', (49, 54))	('acute myeloid leukemia', 'Disease', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (118, 140))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (124, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('colorectal cancer', 'Disease', (96, 113))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('germline mutations', 'Var', (27, 45))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (118, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
63844	27260798	High frequency of GOLPH3 amplification was observed in several solid tumor types such as lung, ovarian, breast, pancreatic, prostate and skin cancers.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('lung', 'Disease', (89, 93))	('skin cancers', 'Phenotype', 'HP:0008069', (137, 149))	('skin cancers', 'Disease', (137, 149))	('tumor', 'Disease', (69, 74))	('breast', 'Disease', (104, 110))	('observed', 'Reg', (43, 51))	('GOLPH3', 'Gene', (18, 24))	('pancreatic, prostate', 'Disease', 'MESH:D010190', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('GOLPH3', 'Gene', '64083', (18, 24))	('skin cancers', 'Disease', 'MESH:D012878', (137, 149))	('ovarian', 'Disease', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('amplification', 'Var', (25, 38))
63852	27260798	In addition, we also identified less significant but novel CNVRs that overlap with known cancer genes.	('CNVRs', 'Var', (59, 64))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
63861	27260798	Germline mutations of ERBB2 that may confer cancer risk were also identified previously, such as in familial lung adenocarcinomas.	('Germline mutations', 'Var', (0, 18))	('ERBB2', 'Gene', '2064', (22, 27))	('ERBB2', 'Gene', (22, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('familial lung adenocarcinomas', 'Disease', (100, 129))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (109, 129))	('familial lung adenocarcinomas', 'Disease', 'MESH:D000077192', (100, 129))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
63874	27260798	In fact, the germline deletion of APOBEC3A and APOBEC3B is known to be associated with modestly increased cancer risk, but it was filtered because 6 individuals in the 1000 Genome control data have this deletion (Supplementary Figure S12B).	('APOBEC3B', 'Gene', (47, 55))	('APOBEC3A', 'Gene', '200315', (34, 42))	('APOBEC3B', 'Gene', '9582', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('S12B', 'SUBSTITUTION', 'None', (234, 238))	('cancer', 'Disease', (106, 112))	('APOBEC3A', 'Gene', (34, 42))	('S12B', 'Var', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
63875	27260798	The method used in this work has allowed us discover both known and novel cancer predisposing CNVRs, but the highly significant CNVRs might still contain copy number polymorphism.	('copy number polymorphism', 'Var', (154, 178))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('contain', 'Reg', (146, 153))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
63881	27260798	On the other hand, among the 16 patients with the amplification at TFG, 5 of them (2 BLCA patients, 1 LGG patient and 2 STAD patients) had data on family history in their clinical annotations.	('amplification', 'Var', (50, 63))	('patients', 'Species', '9606', (32, 40))	('patient', 'Species', '9606', (106, 113))	('TFG', 'Gene', '10342', (67, 70))	('patient', 'Species', '9606', (90, 97))	('TFG', 'Gene', (67, 70))	('patient', 'Species', '9606', (125, 132))	('patient', 'Species', '9606', (32, 39))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (125, 133))
63911	28039453	The mean ADCuh value was 0.436 x 10-3 mm2/sec in LGG and 0.285 x 10-3 mm2 /sec in HGG with significant differences (P < 0.001) (Figure 1a), while no significant differences were found in peritumoral edema area (ADCuh_edema) and contralateral healthy white matter area (ADCuh_wm) (P > 0.05).	('edema', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mm2', 'Gene', '10687', (38, 41))	('edema', 'Disease', (217, 222))	('mm2', 'Gene', '10687', (70, 73))	('mm2', 'Gene', (38, 41))	('mm2', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('0.285 x 10-3', 'Var', (57, 69))	('edema', 'Disease', 'MESH:D004487', (199, 204))	('edema', 'Phenotype', 'HP:0000969', (199, 204))	('edema', 'Disease', 'MESH:D004487', (217, 222))	('edema', 'Phenotype', 'HP:0000969', (217, 222))
63918	28039453	Briefly, ADC1000 parameter achieved a relatively higher diagnostic efficacy with AUC of 0.905, 82.7% sensitivity and 85.2% specificity for differentiating the LGG at the cutoff value of 1.115 x 10-3 mm2/sec (Figure 3), with a similar diagnostic efficacy for other ADC values from mono-exponential model.	('mm2', 'Gene', '10687', (199, 202))	('LGG', 'Disease', (159, 162))	('mm2', 'Gene', (199, 202))	('ADC1000', 'Var', (9, 16))	('higher', 'PosReg', (49, 55))
63929	28039453	In our study, we confirmed that conventional ADC values from different b-values were valuable in glioma grading, but the ADC1000 achieved the highest differentiating diagnostic efficacy among all the other ADC values.	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('ADC1000', 'Var', (121, 128))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (97, 103))
63948	28039453	ADCuh is the apparent diffusion coefficient calculated by fitting the seven ultra-high b-values (1,500, 2,000, 2500, 3,000, 3,500, 4,000, 4,500 sec/mm2) to the mono-exponential equation.	('mm2', 'Gene', '10687', (148, 151))	('mm2', 'Gene', (148, 151))	('1,500', 'Var', (97, 102))
63963	28460453	CBX7 is a glioma prognostic marker and induces G1/S arrest via the silencing of CCNE1 Chromobox homolog 7 (CBX7) cooperates with other polycomb group (PcG) proteins to maintain target genes in a silenced state.	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('CBX7', 'Gene', (107, 111))	('CBX7', 'Gene', '23492', (107, 111))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('silencing', 'Var', (67, 76))	('CBX7', 'Gene', (0, 4))	('induces', 'Reg', (39, 46))	('CBX7', 'Gene', '23492', (0, 4))	('G1/S arrest', 'Disease', (47, 58))	('glioma', 'Disease', (10, 16))
64003	28460453	After incubation with si-CBX7 for 48 h, the growth rate of U251 cells was increased.	('increased', 'PosReg', (74, 83))	('si-CBX7', 'Var', (22, 29))	('growth rate', 'CPA', (44, 55))	('U251', 'CellLine', 'CVCL:0021', (59, 63))
64006	28460453	We found that si-CBX7 treatment potentiated tumor aggressiveness in U251 cells compared with si-ctrl treatment.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (44, 64))	('potentiated', 'PosReg', (32, 43))	('aggressiveness', 'Phenotype', 'HP:0000718', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('si-CBX7', 'Var', (14, 21))	('tumor aggressiveness', 'Disease', (44, 64))	('U251', 'CellLine', 'CVCL:0021', (68, 72))
64011	28460453	Depleted CBX7 levels triggered an improvement in cyclin E1 and CDK2 levels, while the restoration of CBX7 expression lead to decreased cyclin E1 and CDK2 expression (Figure 4C).	('restoration', 'Var', (86, 97))	('CDK2', 'Gene', '1017', (149, 153))	('cyclin E1', 'Gene', (49, 58))	('expression', 'MPA', (106, 116))	('cyclin E1', 'Gene', (135, 144))	('CDK2', 'Gene', (63, 67))	('decreased', 'NegReg', (125, 134))	('CDK2', 'Gene', (149, 153))	('cyclin E1', 'Gene', '898', (49, 58))	('improvement', 'PosReg', (34, 45))	('CDK2', 'Gene', '1017', (63, 67))	('cyclin E1', 'Gene', '898', (135, 144))	('CBX7', 'Gene', (101, 105))	('expression', 'MPA', (154, 164))
64014	28460453	To verify the interaction between CBX7 and HDAC2, lysates of U251, U87 and LN229 cells were subjected to IP with anti-CBX7 antibodies or nonspecific IgG.	('LN229', 'CellLine', 'CVCL:0393', (75, 80))	('anti-CBX7', 'Gene', (113, 122))	('anti-CBX7', 'Var', (113, 122))	('U251', 'CellLine', 'CVCL:0021', (61, 65))
64015	28460453	We tested the degree of histone acetylation and cyclin E1 levels in three GBM cell lines treated with 1muM HDCA2 inhibitor FK228 for 24 h and found that inhibition of HDAC2 rescued the levels of cyclin E1 (Figure 4I).	('levels', 'MPA', (185, 191))	('cyclin E1', 'Gene', (48, 57))	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('cyclin E1', 'Gene', '898', (195, 204))	('HDAC2', 'Gene', (167, 172))	('tested', 'Reg', (3, 9))	('FK228', 'Chemical', 'MESH:C087123', (123, 128))	('cyclin E1', 'Gene', '898', (48, 57))	('rescued', 'PosReg', (173, 180))	('inhibition', 'Var', (153, 163))	('cyclin E1', 'Gene', (195, 204))
64019	28460453	Concomitant with inhibition of tumor formation, mice treated with Lenti-CBX7 had prolonged survival times (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('prolonged', 'PosReg', (81, 90))	('Lenti-CBX7', 'Var', (66, 76))	('tumor', 'Disease', (31, 36))	('mice', 'Species', '10090', (48, 52))	('survival times', 'CPA', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
64022	28460453	Epigenetic alterations such as histone modifications and DNA methylation broadly participate in biological functions and gene regulation, and are essential mechanisms in cancer development apart from genetic abnormalities.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('genetic abnormalities', 'Disease', (200, 221))	('cancer', 'Disease', (170, 176))	('DNA methylation', 'Var', (57, 72))	('participate', 'Reg', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('histone', 'Protein', (31, 38))	('genetic abnormalities', 'Disease', 'MESH:D030342', (200, 221))	('biological', 'CPA', (96, 106))
64042	28460453	The interaction between cyclin E and CDK2 plays an essential role in the G1/S phase transition via phosphorylation of p27Kip.	('interaction', 'Interaction', (4, 15))	('phosphorylation', 'MPA', (99, 114))	('CDK2', 'Gene', '1017', (37, 41))	('G1/S phase transition', 'CPA', (73, 94))	('p27Kip', 'Var', (118, 124))	('CDK2', 'Gene', (37, 41))
64043	28460453	Misregulation of cyclin E/CDK2 complex occurs in various types of tumors and leads to uncontrolled cell growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('CDK2', 'Gene', '1017', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Misregulation', 'Var', (0, 13))	('uncontrolled cell growth', 'MPA', (86, 110))	('CDK2', 'Gene', (26, 30))	('leads to', 'Reg', (77, 85))
64058	28460453	Immunoblot analysis used the following primary antibodies: CBX7 (ab21873), HDAC2 (ab12169), Cyclin E1 (ab3927), p16 (ab51243), p53 (ab28), Actin (ab8226), Tubulin (ab7291) and GAPDH (ab9485) were obtained from Abcam (Cambridge, UK).	('Cyclin E1', 'Gene', '898', (92, 101))	('p16', 'Gene', (112, 115))	('Cyclin E1', 'Gene', (92, 101))	('GAPDH', 'Gene', '2597', (176, 181))	('GAPDH', 'Gene', (176, 181))	('ab51243', 'Var', (117, 124))	('p16', 'Gene', '1029', (112, 115))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
64059	28460453	P21 (#2946), acetyl-histone H3 (Lys56) (#4243), acetyl-histone H2B (Lys20) (#2571) were purchased from Cell Signaling Technology (Massachusetts, USA).	('#4243', 'Var', (40, 45))	('Lys20', 'Chemical', '-', (68, 73))	('#2946', 'Var', (5, 10))	('acetyl-histone', 'Chemical', '-', (13, 27))	('P21', 'Gene', '644914', (0, 3))	('acetyl-histone', 'Chemical', '-', (48, 62))	('Lys56', 'Chemical', '-', (32, 37))	('Lys20) (#2571', 'Var', (68, 81))	('Lys56) (#4243', 'Var', (32, 45))	('P21', 'Gene', (0, 3))
64077	28460453	To establish intracranial glioma model, each nude mouse was implanted with 1 x 106 U87Luciferase/CBX7 or U87Luciferase/Ctrl cells (day 0).	('U87Luciferase/Ctrl', 'Var', (105, 123))	('U87Luciferase/CBX7', 'Var', (83, 101))	('intracranial glioma', 'Disease', 'MESH:D005910', (13, 32))	('mouse', 'Species', '10090', (50, 55))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('intracranial glioma', 'Disease', (13, 32))
64146	26118544	Late clinical consequences of brain irradiation include leukoencephalopathy, neurocognitive decline, reduced quality of life (QoL), and tissue necrosis that may mimic tumour progression.	('leukoencephalopathy', 'Disease', (56, 75))	('brain irradiation', 'Var', (30, 47))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('tissue necrosis', 'Phenotype', 'HP:0010885', (136, 151))	('quality of life', 'CPA', (109, 124))	('necrosis', 'Disease', 'MESH:D009336', (143, 151))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (56, 75))	('neurocognitive decline', 'Phenotype', 'HP:0001268', (77, 99))	('reduced', 'NegReg', (101, 108))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (56, 75))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('necrosis', 'Disease', (143, 151))	('neurocognitive decline', 'CPA', (77, 99))
64220	26118544	We analysed outcome measures including OS, PFS, SAP, FIS, steroid requirement, seizure frequency, QoL, and adverse effects of radiotherapy after stratifying by the following clinical characteristics (if data was available): age, histologic subtype, tumour size and location, extent of resection, performance score, approach of radiotherapy used (conformal EBRT, IMRT, SRS), types of rescue therapy (repeat resection, repeat radiotherapy, chemotherapy), genetic aberrations (p53 status, 1p/19q status), and date of trial.	('p53', 'Gene', (474, 477))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('tumour', 'Disease', 'MESH:D009369', (249, 255))	('men', 'Species', '9606', (73, 76))	('1p/19q status', 'Var', (486, 499))	('p53', 'Gene', '7157', (474, 477))	('steroid', 'Chemical', 'MESH:D013256', (58, 65))	('seizure', 'Disease', (79, 86))	('SRS', 'Disease', 'MESH:C536678', (368, 371))	('seizure', 'Disease', 'MESH:D012640', (79, 86))	('OS', 'Chemical', '-', (39, 41))	('tumour', 'Disease', (249, 255))	('SAP', 'Chemical', '-', (48, 51))	('SRS', 'Disease', (368, 371))	('seizure', 'Phenotype', 'HP:0001250', (79, 86))
64313	26118544	People who received radiation therapy performed worse in measures of executive functioning, attentional functioning, and information processing speed compared with people who did not receive radiation therapy.	('people', 'Species', '9606', (164, 170))	('information processing speed', 'CPA', (121, 149))	('worse', 'NegReg', (48, 53))	('executive functioning', 'CPA', (69, 90))	('People', 'Species', '9606', (0, 6))	('attentional functioning', 'MPA', (92, 115))	('radiation therapy', 'Var', (20, 37))
64388	33735110	NID1 silencing enhanced in vitro apoptosis and the temozolomide sensitivity of U251 and U87-MG glioma cells.	('vitro apoptosis', 'CPA', (27, 42))	('NID1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('U251', 'CellLine', 'CVCL:0021', (79, 83))	('silencing', 'Var', (5, 14))	('glioma', 'Disease', (95, 101))	('temozolomide', 'Chemical', 'MESH:D000077204', (51, 63))	('NID1', 'Gene', '4811', (0, 4))	('U87-MG', 'CellLine', 'CVCL:0022', (88, 94))	('enhanced', 'PosReg', (15, 23))	('temozolomide sensitivity', 'MPA', (51, 75))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
64391	33735110	Kaplan-Meier survival curve analysis showed that low-grade gliomas patients with high NID1 expression were associated with shorter overall survival.	('NID1', 'Gene', '4811', (86, 90))	('shorter', 'NegReg', (123, 130))	('patients', 'Species', '9606', (67, 75))	('overall survival', 'MPA', (131, 147))	('high', 'Var', (81, 85))	('NID1', 'Gene', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
64428	33735110	Furthermore, IDH mutant GBM tissues showed significantly lower NID1 expression than the IDH wild-type GBM tissues, but NID1 expression in IDH mutant and wild-type LGG tissues was similar (Figure 3C).	('IDH', 'Gene', '3417', (13, 16))	('NID1', 'Gene', (63, 67))	('IDH', 'Gene', (138, 141))	('expression', 'MPA', (68, 78))	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', '3417', (138, 141))	('NID1', 'Gene', '4811', (119, 123))	('IDH', 'Gene', (88, 91))	('NID1', 'Gene', '4811', (63, 67))	('NID1', 'Gene', (119, 123))	('IDH', 'Gene', (13, 16))	('mutant', 'Var', (17, 23))	('lower', 'NegReg', (57, 62))
64449	33735110	Kaplan-Meier survival curve analysis showed that high NID1 expression correlated with worse overall survival of LGG patients (Figure 8A, 8C).	('NID1', 'Gene', '4811', (54, 58))	('patients', 'Species', '9606', (116, 124))	('worse', 'NegReg', (86, 91))	('overall survival', 'MPA', (92, 108))	('expression', 'MPA', (59, 69))	('high', 'Var', (49, 53))	('NID1', 'Gene', (54, 58))	('LGG', 'Disease', (112, 115))
64453	33735110	Kaplan-Meier survival curve analysis showed that overall survival (OS) of LGG patients with low NID1 expression was significantly higher compared to LGG patients with high NID1 expression (P = 0.035; Figure 8E).	('overall survival', 'MPA', (49, 65))	('NID1', 'Gene', (96, 100))	('NID1', 'Gene', (172, 176))	('patients', 'Species', '9606', (153, 161))	('higher', 'PosReg', (130, 136))	('patients', 'Species', '9606', (78, 86))	('low', 'Var', (92, 95))	('NID1', 'Gene', '4811', (96, 100))	('LGG', 'Disease', (74, 77))	('NID1', 'Gene', '4811', (172, 176))
64455	33735110	These results suggested that high NID1 expression was associated with worse OS in LGG patients.	('high', 'Var', (29, 33))	('LGG', 'Disease', (82, 85))	('NID1', 'Gene', (34, 38))	('worse OS', 'Disease', (70, 78))	('NID1', 'Gene', '4811', (34, 38))	('expression', 'MPA', (39, 49))	('patients', 'Species', '9606', (86, 94))
64463	33735110	Agrin plays a significant role in maintaining the blood-brain barrier (BBB), and its deficiency leads to brain edema in GBM patients.	('brain edema', 'Phenotype', 'HP:0002181', (105, 116))	('brain edema', 'Disease', (105, 116))	('deficiency', 'Var', (85, 95))	('Agrin', 'Gene', '375790', (0, 5))	('brain edema', 'Disease', 'MESH:D001929', (105, 116))	('edema', 'Phenotype', 'HP:0000969', (111, 116))	('leads to', 'Reg', (96, 104))	('blood-brain', 'MPA', (50, 61))	('Agrin', 'Gene', (0, 5))	('patients', 'Species', '9606', (124, 132))
64465	33735110	Nonsense mutations in the NID1 gene are associated with autosomal dominant Dandy-Walker malformation and occipital cephaloceles (ADDWOC), a disorder characterized by normal neurological development but variable cerebellar hypoplasia, meningeal anomalies, and occipital skull defects.	('meningeal anomalies', 'Disease', (234, 253))	('autosomal dominant Dandy-Walker malformation', 'Disease', (56, 100))	('autosomal dominant Dandy-Walker malformation', 'Disease', 'MESH:D003616', (56, 100))	('skull defects', 'Phenotype', 'HP:0001362', (269, 282))	('cerebellar hypoplasia', 'Disease', 'MESH:C562568', (211, 232))	('cerebellar hypoplasia', 'Phenotype', 'HP:0001321', (211, 232))	('occipital skull defects', 'Disease', (259, 282))	('NID1', 'Gene', '4811', (26, 30))	('Dandy-Walker malformation', 'Phenotype', 'HP:0001305', (75, 100))	('occipital skull', 'Phenotype', 'HP:0000269', (259, 274))	('meningeal anomalies', 'Phenotype', 'HP:0010651', (234, 253))	('occipital cephaloceles', 'Disease', (105, 127))	('occipital cephaloceles', 'Phenotype', 'HP:0004470', (105, 127))	('NID1', 'Gene', (26, 30))	('cerebellar hypoplasia', 'Disease', (211, 232))	('Nonsense mutations', 'Var', (0, 18))	('associated', 'Reg', (40, 50))	('meningeal anomalies', 'Disease', 'MESH:D008581', (234, 253))
64471	33735110	We also showed that NID1 silencing induced glioma cell apoptosis and increased sensitivity of glioma cells to TMZ.	('silencing', 'Var', (25, 34))	('NID1', 'Gene', (20, 24))	('induced', 'PosReg', (35, 42))	('increased', 'PosReg', (69, 78))	('glioma', 'Disease', (94, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (110, 113))	('glioma', 'Disease', (43, 49))	('sensitivity', 'MPA', (79, 90))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('NID1', 'Gene', '4811', (20, 24))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
64487	33735110	reported that deletion of NID1 binding site in laminin gamma1 chain caused defects in the pial basement membrane and disrupted neuronal migration and proper cortical development.	('laminin gamma1 chain', 'Protein', (47, 67))	('neuronal migration', 'CPA', (127, 145))	('defects', 'NegReg', (75, 82))	('NID1', 'Gene', '4811', (26, 30))	('pial basement membrane', 'CPA', (90, 112))	('proper cortical development', 'CPA', (150, 177))	('NID1', 'Gene', (26, 30))	('disrupted', 'NegReg', (117, 126))	('deletion', 'Var', (14, 22))	('disrupted neuronal migration', 'Phenotype', 'HP:0002269', (117, 145))
64490	33735110	demonstrated that MMP-19 preferentially cleaved out the G3 globular domain of NID1, which contained the binding site for the gamma1 chain of laminin-1 and collagen IV, thereby abolishing its ability to cross-link ECM proteins.	('MMP-19', 'Gene', (18, 24))	('NID1', 'Gene', '4811', (78, 82))	('binding', 'Interaction', (104, 111))	('MMP-19', 'Gene', '4327', (18, 24))	('abolishing', 'NegReg', (176, 186))	('NID1', 'Gene', (78, 82))	('cleaved', 'Var', (40, 47))	('cross-link ECM proteins', 'MPA', (202, 225))	('ability', 'MPA', (191, 198))
64492	33735110	We also demonstrated that LGG patients with low NID1 expression showed significantly higher OS rates.	('higher', 'PosReg', (85, 91))	('NID1', 'Gene', (48, 52))	('low', 'Var', (44, 47))	('patients', 'Species', '9606', (30, 38))	('OS rates', 'CPA', (92, 100))	('NID1', 'Gene', '4811', (48, 52))
64497	33735110	NID1 silencing promotes in vitro apoptosis and TMZ sensitivity of glioma cells.	('glioma', 'Disease', (66, 72))	('NID1', 'Gene', (0, 4))	('TMZ sensitivity', 'CPA', (47, 62))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('silencing', 'Var', (5, 14))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('NID1', 'Gene', '4811', (0, 4))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('promotes', 'PosReg', (15, 23))
64521	33735110	The si-NID1 and si-NC transfected glioma cells were lysed in pre-chilled radioimmunoprecipitation (RIPA) buffer (Servicebio, Wuhan, China) containing protease inhibitor PMSF (1:100) and phosphatase inhibitor cocktail (1:100) at 0  C for 30 min.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('NID1', 'Gene', (7, 11))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('chilled', 'Phenotype', 'HP:0025143', (65, 72))	('glioma', 'Disease', (34, 40))	('NID1', 'Gene', '4811', (7, 11))	('si-NC', 'Var', (16, 21))	('PMSF', 'Chemical', '-', (169, 173))
64524	33735110	The membranes were blocked with 5% bovine serum albumin (BSA) for 1 h at room temperature and incubated overnight at 4  C with primary antibodies against NID1 (1:1000;AF2570-SP; R&D Systems, MN, USA) and GAPDH (1:1000;ab9485;Abcam, UK).	('serum albumin', 'Gene', (42, 55))	('GAPDH', 'Gene', '2597', (204, 209))	('1:1000;AF2570-SP;', 'Var', (160, 177))	('NID1', 'Gene', '4811', (154, 158))	('MN', 'CellLine', 'CVCL:U508', (191, 193))	('GAPDH', 'Gene', (204, 209))	('and', 'Gene', (200, 203))	('serum albumin', 'Gene', '213', (42, 55))	('NID1', 'Gene', (154, 158))
64535	33735110	Kaplan-Meier survival curve analysis was used to evaluate overall survival of glioma patients with high and low NID1 expression.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('expression', 'MPA', (117, 127))	('NID1', 'Gene', '4811', (112, 116))	('high', 'Var', (99, 103))	('patients', 'Species', '9606', (85, 93))	('low', 'NegReg', (108, 111))	('glioma', 'Disease', (78, 84))	('NID1', 'Gene', (112, 116))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
64536	31798343	Silencing expression of PHF14 in glioblastoma promotes apoptosis, mitigates proliferation and invasiveness via Wnt signal pathway The plant homeodomain (PHD) finger protein 14 (PHF14) is a vital member of PHD finger protein families.	('mitigates', 'NegReg', (66, 75))	('glioblastoma', 'Disease', (33, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('PHF14', 'Gene', '9678', (177, 182))	('PHF14', 'Gene', (177, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('invasiveness', 'CPA', (94, 106))	('PHF14', 'Gene', '9678', (24, 29))	('plant homeodomain (PHD) finger protein 14', 'Gene', '9678', (134, 175))	('PHF14', 'Gene', (24, 29))	('promotes', 'PosReg', (46, 54))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (55, 64))
64543	31798343	Overexpression of PHF14 translated to poor prognosis in glioma patients.	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('PHF14', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (63, 71))
64544	31798343	In vitro assays revealed that silencing expression of PHF14 in glioma cells inhibited migration, invasiveness and proliferation and promoted cell apoptosis.	('migration', 'CPA', (86, 95))	('PHF14', 'Gene', (54, 59))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('promoted', 'PosReg', (132, 140))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('silencing', 'Var', (30, 39))	('inhibited', 'NegReg', (76, 85))	('cell apoptosis', 'CPA', (141, 155))	('glioma', 'Disease', (63, 69))
64546	31798343	In addition, the mRNA expression of several key markers of EMT (epithelial-mesenchymal transition) and angiogenesis was found to change upon PHF14 silencing.	('change', 'Reg', (129, 135))	('PHF14', 'Gene', (141, 146))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('mRNA expression', 'MPA', (17, 32))	('angiogenesis', 'CPA', (103, 115))	('silencing', 'Var', (147, 156))
64550	31798343	PHD finger plays a key role in the recognition and translation of histone modification marks primarily by differentially recognizing methylated or unmodified lysine, directly contributing to gene transcription activation and silencing.	('contributing', 'Reg', (175, 187))	('methylated', 'Var', (133, 143))	('silencing', 'NegReg', (225, 234))	('lysine', 'Chemical', 'MESH:C114808', (158, 164))	('gene transcription', 'MPA', (191, 209))	('activation', 'PosReg', (210, 220))
64551	31798343	Notably, the dysregulation of PHD finger family proteins (PHF) (e.g., PHF1, PHF6, PHF3, PHF10 and PHF11) can result in immunodeficiency, cancer or neurological disorder via incorrect gene transcription.	('incorrect', 'Reg', (173, 182))	('dysregulation', 'Var', (13, 26))	('PHF1', 'Gene', (70, 74))	('result in', 'Reg', (109, 118))	('cancer', 'Disease', (137, 143))	('PHF3', 'Gene', '23469', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('neurological disorder', 'Disease', (147, 168))	('PHF1', 'Gene', '5252', (70, 74))	('PHF', 'Gene', (58, 61))	('PHF10', 'Gene', '55274', (88, 93))	('PHF6', 'Gene', (76, 80))	('immunodeficiency', 'Disease', (119, 135))	('PHF11', 'Gene', '51131', (98, 103))	('PHF1', 'Gene', (98, 102))	('PHF6', 'Gene', '84295', (76, 80))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('PHF1', 'Gene', (88, 92))	('immunodeficiency', 'Disease', 'MESH:D007153', (119, 135))	('PHF10', 'Gene', (88, 93))	('PHF1', 'Gene', '5252', (98, 102))	('PHF11', 'Gene', (98, 103))	('neurological disorder', 'Phenotype', 'HP:0000707', (147, 168))	('PHF3', 'Gene', (82, 86))	('immunodeficiency', 'Phenotype', 'HP:0002721', (119, 135))	('neurological disorder', 'Disease', 'MESH:D009422', (147, 168))	('PHF1', 'Gene', '5252', (88, 92))
64558	31798343	While PHF14 depletion has been shown to suppress cell proliferation in lung cancer cells and bladder cancer cells, its overexpression constrained BTC cells growth and improved prognosis in colon cancer.	('constrained', 'NegReg', (134, 145))	('colon cancer', 'Disease', (189, 201))	('depletion', 'Var', (12, 21))	('improved', 'PosReg', (167, 175))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('suppress', 'NegReg', (40, 48))	('cell proliferation', 'CPA', (49, 67))	('PHF14', 'Gene', (6, 11))	('prognosis', 'CPA', (176, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (189, 201))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('bladder cancer', 'Disease', (93, 107))	('overexpression', 'PosReg', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('colon cancer', 'Disease', 'MESH:D015179', (189, 201))	('lung cancer', 'Disease', (71, 82))
64581	31798343	The recombinant lentivirus of small interfering RNA targeting PHF14 (PHF14-siRNA-lentivirus) and control lentivirus (GFP-lentivirus) were commercially prepared.	('small interfering', 'Var', (30, 47))	('PHF14', 'Gene', (62, 67))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('N', 'Chemical', 'MESH:D009584', (49, 50))
64604	31798343	Primary antibodies used were anti-PHF14 (ThermoFisher Scientific, Cat# PA5-72775, 1:1000) and anti-beta-Catenin (CST, Cat# 9587T, 1:1000) and anti-Phospho-beta-Catenin (CST, Cat# 4176T, 1:1000).	('CST', 'Gene', '106478911', (169, 172))	('beta-Catenin', 'Gene', '1499', (99, 111))	('beta-Catenin', 'Gene', (99, 111))	('CST', 'Gene', '106478911', (113, 116))	('CST', 'Gene', (169, 172))	('beta-Catenin', 'Gene', '1499', (155, 167))	('beta-Catenin', 'Gene', (155, 167))	('anti-PHF14', 'Var', (29, 39))	('CST', 'Gene', (113, 116))
64618	31798343	8-week-old nude male mice (bablc/nu, SPF level) (SLAC laboratory animal Center, Shanghai, China) (n = 12) were divided equally into 2 groups (n = 6 to each group): U87-NC and U87-sh-PHF14.	('U87-NC', 'Var', (164, 170))	('mice', 'Species', '10090', (21, 25))	('U87-sh-PHF14', 'Var', (175, 187))	('SPF', 'Gene', (37, 40))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('SPF', 'Gene', '67815', (37, 40))
64633	31798343	Subsequently, EdU assay showed that the growth of U251, U87MG and A172 cells decreased after PHF14 gene silencing (Fig.	('gene silencing', 'Var', (99, 113))	('growth', 'CPA', (40, 46))	('PHF14', 'Gene', (93, 98))	('U87MG', 'CellLine', 'CVCL:0022', (56, 61))	('decreased', 'NegReg', (77, 86))
64637	31798343	The results of the transwell assay revealed that both the migration and invasion potential of U251-sh-PHF14, U87MG-sh-PHF14 and A172-sh-PHF14 cells were decreased relative to control cells both in transwell based experiment (Fig.	('U87MG-sh-PHF14', 'Var', (109, 123))	('invasion potential', 'CPA', (72, 90))	('U87MG', 'CellLine', 'CVCL:0022', (109, 114))	('decreased', 'NegReg', (153, 162))	('U251-sh-PHF14', 'Var', (94, 107))	('migration', 'CPA', (58, 67))
64639	31798343	We implanted U87MG scrambled or PHF14 silenced cells into nude mice (6 mice for each group).	('mice', 'Species', '10090', (71, 75))	('PHF14', 'Gene', (32, 37))	('mice', 'Species', '10090', (63, 67))	('U87MG', 'CellLine', 'CVCL:0022', (13, 18))	('U87MG', 'Var', (13, 18))	('nude mice', 'Species', '10090', (58, 67))
64641	31798343	The median overall survival of tumor bearing mice was prolonged from 32 days (n = 6) to 44.5 days (n = 4) after PHF14 was knocked down (P < 0.05) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('overall survival', 'CPA', (11, 27))	('mice', 'Species', '10090', (45, 49))	('knocked down', 'Var', (122, 134))	('tumor', 'Disease', (31, 36))	('PHF14', 'Gene', (112, 117))	('prolonged', 'PosReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
64647	31798343	beta-catenin, which is a highly specific down-stream factor of Wnt signaling pathway decreased after knockdown of PHF14 both in U251 and U87MG cells.	('decreased', 'NegReg', (85, 94))	('PHF14', 'Gene', (114, 119))	('beta-catenin', 'Gene', '1499', (0, 12))	('Wnt signaling pathway', 'Pathway', (63, 84))	('U87MG', 'CellLine', 'CVCL:0022', (137, 142))	('beta-catenin', 'Gene', (0, 12))	('knockdown', 'Var', (101, 110))
64663	31798343	It is well known that the prognosis of glioma patients with IDH mutation and 1p19q co-deletion is relatively good when compared with those with IDH wide type plus Tert promoter mutation.	('IDH', 'Gene', (144, 147))	('IDH wide type plus Tert', 'Disease', 'MESH:D007625', (144, 167))	('1p19q co-deletion', 'Var', (77, 94))	('patients', 'Species', '9606', (46, 54))	('glioma', 'Disease', (39, 45))	('IDH', 'Gene', '3417', (144, 147))	('IDH', 'Gene', (60, 63))	('IDH wide type plus Tert', 'Disease', (144, 167))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('IDH', 'Gene', '3417', (60, 63))
64675	31798343	Our results showed the Wnt signaling pathway to be inhibited by silencing expression of PHF14, suggesting PHF14 involvement in the pathogenesis of glioma via Wnt/beta-catenin signaling pathway.	('PHF14', 'Gene', (88, 93))	('glioma via Wnt', 'Disease', (147, 161))	('beta-catenin', 'Gene', (162, 174))	('Wnt signaling pathway', 'Pathway', (23, 44))	('glioma via Wnt', 'Disease', 'MESH:D005910', (147, 161))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('beta-catenin', 'Gene', '1499', (162, 174))	('PHF14', 'Gene', (106, 111))	('involvement', 'Reg', (112, 123))	('silencing expression', 'Var', (64, 84))	('inhibited', 'NegReg', (51, 60))
64685	31798343	H3K27M was identified in 78% of diffuse midline gliomas and has been categorized as a separate pathological entity in the 2016 WHO classification.	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('diffuse midline gliomas', 'Disease', 'MESH:D005910', (32, 55))	('diffuse midline gliomas', 'Disease', (32, 55))	('H3K27M', 'Var', (0, 6))
64747	31686439	In a prospective nonrandomized study of childhood low-grade glioma (LGG) performed by The Children's Cancer Group and Pediatric Oncology Group, the 5-year PFS was 90% with GTR and 45-65% with any volume of residual tumor (p<0.001).	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('Children', 'Species', '9606', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('glioma', 'Disease', (60, 66))	('Oncology', 'Phenotype', 'HP:0002664', (128, 136))	('tumor', 'Disease', (215, 220))	('GTR', 'Var', (172, 175))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (101, 107))
64785	30191361	GKRS can safely be used as salvage treatment for recurrent glioma and seems to improve survival rates in (high grade) glioma patients with minimal burden.	('patients', 'Species', '9606', (125, 133))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', (118, 124))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('improve', 'PosReg', (79, 86))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('men', 'Species', '9606', (40, 43))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('GKRS', 'Var', (0, 4))	('survival rates', 'CPA', (87, 101))
64858	30191361	A recent study showed a 53.8% TC for LGGs after GKRS, which is comparable to our study.	('LGGs', 'Gene', (37, 41))	('TC', 'Chemical', '-', (30, 32))	('GKRS', 'Var', (48, 52))
64880	30191361	This shows that GKRS can meaningfully lengthen survival in these patients with a 1 day hospitalization, maintenance of QoL and minimal burden.	('QoL', 'MPA', (119, 122))	('lengthen', 'PosReg', (38, 46))	('survival', 'MPA', (47, 55))	('patients', 'Species', '9606', (65, 73))	('GKRS', 'Var', (16, 20))
64899	25013169	Network analysis of aberrantly methylated lincRNAs in cancers showed that lincRNAs with aberrant methylation patterns might be involved in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('lincRNA', 'Chemical', '-', (42, 49))	('methylation patterns', 'Var', (97, 117))	('involved', 'Reg', (127, 135))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lincRNA', 'Chemical', '-', (74, 81))	('cancer', 'Disease', (139, 145))
64900	25013169	The methylated and demethylated lincRNAs identified in this study provide novel insights for developing cancer biomarkers and potential therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lincRNA', 'Chemical', '-', (32, 39))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('demethylated', 'Var', (19, 31))
64916	25013169	Some lincRNAs with aberrant methylation patterns in cancers might involve in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lincRNA', 'Chemical', '-', (5, 12))	('progression', 'CPA', (100, 111))	('involve', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('aberrant methylation patterns', 'Var', (19, 48))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
64917	25013169	Early detection of hypermethylated or hypomethylated lincRNAs could serve as cancer biomarkers for diagnosis or treatment.	('lincRNAs', 'Gene', (53, 61))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypermethylated', 'Var', (19, 34))	('lincRNA', 'Chemical', '-', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypomethylated', 'Var', (38, 52))
64929	25013169	LincRNAs with methylated promoters in more than 20% of all tumor samples were defined as PM lincRNAs.	('tumor', 'Disease', (59, 64))	('methylated', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('lincRNA', 'Chemical', '-', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
64946	25013169	Tumors were separated according to the median methylation of each lincRNA.	('methylation', 'Var', (46, 57))	('lincRNA', 'Chemical', '-', (66, 73))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
64952	25013169	We identified lincRNAs with prognosis-associated (PA) methylation patterns in cancers with tumor sample size available for both clinical and methylation data >= 200 and a censoring (alive sample) rate <= 0.9; or the tumor sample size < 200 and a censoring rate <= 0.8 for an effective survival analysis (Supplementary Table S1).	('tumor', 'Disease', (216, 221))	('methylation', 'Var', (54, 65))	('lincRNA', 'Chemical', '-', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('cancers', 'Disease', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (91, 96))
64964	25013169	Compared with the other three regions, hypermethylation of promoters was more tightly linked to transcriptional silencing of lincRNAs (Supplementary Figure S4).	('transcriptional', 'MPA', (96, 111))	('linked', 'Reg', (86, 92))	('silencing', 'NegReg', (112, 121))	('lincRNA', 'Chemical', '-', (125, 132))	('hypermethylation', 'Var', (39, 55))	('lincRNAs', 'Gene', (125, 133))
64968	25013169	Since disrupting DNA methyltransferases may promote chromosome instability and tumor progression, cancer cells are usually less methylated at individual CpG dinucleotides than healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('promote', 'PosReg', (44, 51))	('chromosome instability', 'CPA', (52, 74))	('tumor', 'Disease', (79, 84))	('disrupting', 'Var', (6, 16))	('less', 'NegReg', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('chromosome instability', 'Phenotype', 'HP:0040012', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
64970	25013169	In contrast, hypermethylation of lincRNAs might be involved in DNA repair, tumor cell invasion, cell cycle regulation and other events in which silencing might induce metastasis.	('lincRNAs', 'Gene', (33, 41))	('cell cycle', 'CPA', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('involved', 'Reg', (51, 59))	('metastasis', 'CPA', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('induce', 'Reg', (160, 166))	('lincRNA', 'Chemical', '-', (33, 40))	('silencing', 'Var', (144, 153))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Disease', (75, 80))
64971	25013169	Aberrant promoter methylation was frequently observed in cancer samples and might have contributed to tumor progression by silencing tumor suppressor genes or activating oncogenes.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Aberrant', 'Var', (0, 8))	('contributed', 'Reg', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('promoter', 'MPA', (9, 17))	('activating', 'PosReg', (159, 169))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('silencing', 'NegReg', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('oncogenes', 'Gene', (170, 179))
64973	25013169	We obtained three representative cancer type-specific methylation patterns for 20 cancer types, and examples were shown in bladder urothelial cancer (BLCA), head and neck squamous cell cancer (HNSC) and LGG (Supplementary Figure S5).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (82, 88))	('neck squamous cell cancer', 'Disease', (166, 191))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HNSC', 'Phenotype', 'HP:0012288', (193, 197))	('methylation', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (123, 148))	('cancer', 'Disease', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (166, 191))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (157, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (171, 191))	('bladder urothelial cancer', 'Disease', (123, 148))	('LGG', 'Disease', (203, 206))
64994	25013169	RE insertion close to a lincRNA promoter or RE hypermethylation might interrupt the transcription factors or other regulatory elements binding to lincRNA promoters, which could contribute to lincRNAs tissue-specific expression.	('contribute', 'Reg', (177, 187))	('transcription', 'Protein', (84, 97))	('lincRNA', 'Chemical', '-', (24, 31))	('lincRNA', 'Chemical', '-', (146, 153))	('binding', 'Interaction', (135, 142))	('interrupt', 'NegReg', (70, 79))	('lincRNA', 'Chemical', '-', (191, 198))	('hypermethylation', 'Var', (47, 63))
65006	25013169	Since aberrant promoter methylation silences tumor suppressor genes and activates oncogenes, we analyzed the different methylation patterns of lincRNA promoters between tumors and corresponding normal tissue samples.	('activates', 'PosReg', (72, 81))	('lincRNA', 'Chemical', '-', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('oncogenes', 'Gene', (82, 91))	('aberrant', 'Var', (6, 14))	('tumor', 'Disease', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('promoter', 'MPA', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('silences', 'NegReg', (36, 44))	('tumors', 'Disease', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
65009	25013169	The hypomethylated CM lincRNAs in BRCA or LUSC showed a more common methylation pattern in normal samples than in tumors.	('BRCA', 'Gene', '672', (34, 38))	('LUSC', 'Phenotype', 'HP:0030359', (42, 46))	('BRCA', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation pattern', 'MPA', (68, 87))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('lincRNA', 'Chemical', '-', (22, 29))	('hypomethylated', 'Var', (4, 18))
65011	25013169	We identified the lincRNAs with subtype-specific methylation patterns in BRCA and LUSC (Figure 4E and F and Supplementary Table S6).	('methylation patterns', 'Var', (49, 69))	('BRCA', 'Gene', '672', (73, 77))	('BRCA', 'Gene', (73, 77))	('lincRNA', 'Chemical', '-', (18, 25))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))
65013	25013169	Several lincRNAs with subtype-specific methylation patterns have been functionally implicated in physiological or pathological processes through experimental validation.	('lincRNA', 'Chemical', '-', (8, 15))	('methylation', 'Var', (39, 50))	('implicated', 'Reg', (83, 93))
65019	25013169	We combined the lincRNA methylation profiles with clinical annotations and identified a subset of lincRNAs with methylation values showing a trend associated with OS in BRCA, LUSC and UCEC.	('UCEC', 'Disease', (184, 188))	('associated', 'Reg', (147, 157))	('methylation', 'Var', (112, 123))	('BRCA', 'Gene', '672', (169, 173))	('lincRNA', 'Chemical', '-', (16, 23))	('LUSC', 'Phenotype', 'HP:0030359', (175, 179))	('BRCA', 'Gene', (169, 173))	('lincRNA', 'Chemical', '-', (98, 105))	('LUSC', 'Disease', (175, 179))
65023	25013169	For example, BRCA patients with lower methylation level of lincRNA XLOC_009284 had better prognosis (Figure 5A).	('methylation level', 'MPA', (38, 55))	('XLOC_009284', 'Var', (67, 78))	('lincRNA', 'Chemical', '-', (59, 66))	('BRCA', 'Gene', '672', (13, 17))	('patients', 'Species', '9606', (18, 26))	('BRCA', 'Gene', (13, 17))	('lower', 'NegReg', (32, 37))
65024	25013169	LUSC patients with relatively lower methylation level of lincRNA XLOC_009367 showed poorer prognosis (Figure 5B).	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (5, 13))	('XLOC_009367', 'Var', (65, 76))	('methylation level', 'MPA', (36, 53))	('lincRNA', 'Gene', (57, 64))	('lincRNA', 'Chemical', '-', (57, 64))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
65025	25013169	For UCEC, patients with the highest methylation level of lincRNA XLOC_007617 had a better prognosis than patients with lower methylation level (Figure 5C).	('XLOC_007617', 'Var', (65, 76))	('patients', 'Species', '9606', (105, 113))	('methylation', 'MPA', (36, 47))	('UCEC', 'Disease', (4, 8))	('patients', 'Species', '9606', (10, 18))	('lincRNA', 'Gene', (57, 64))	('lincRNA', 'Chemical', '-', (57, 64))
65032	25013169	XLOC_007617 was a lincRNA that showed positive correlation between its methylation and drug-free survival in UCEC (log-rank P = 0.013; Supplementary Figure S8).	('methylation', 'Var', (71, 82))	('lincRNA', 'Chemical', '-', (18, 25))	('positive', 'PosReg', (38, 46))	('drug-free survival', 'CPA', (87, 105))	('XLOC_007617', 'Var', (0, 11))
65041	25013169	Using the AM lincRNAs between tumors and corresponding normal samples identified from 14 types of cancers with at least seven normal samples, we constructed an AM lincRNA-cancer network (AMCN; Supplementary Figure S10A).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('lincRNA', 'Chemical', '-', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('S10A', 'SUBSTITUTION', 'None', (214, 218))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('AMCN', 'Chemical', '-', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (171, 177))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('lincRNA', 'Chemical', '-', (163, 170))	('cancers', 'Disease', (98, 105))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('S10A', 'Var', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
65044	25013169	The AMCN illustrated that most lincRNAs were aberrantly methylated in a single cancer and a few lincRNAs were aberrantly methylated in multiple cancers (Supplementary Figure S10B).	('S10B', 'SUBSTITUTION', 'None', (174, 178))	('AMCN', 'Chemical', '-', (4, 8))	('lincRNA', 'Chemical', '-', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lincRNA', 'Chemical', '-', (96, 103))	('multiple cancers', 'Disease', (135, 151))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('methylated', 'Var', (56, 66))	('cancer', 'Disease', (144, 150))	('S10B', 'Var', (174, 178))	('aberrantly methylated', 'Var', (45, 66))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('multiple cancers', 'Disease', 'MESH:D009369', (135, 151))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
65045	25013169	A total of 196 lincRNAs were aberrantly methylated in more than one cancer out of all 434 AM lincRNAs in the AMCN.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('aberrantly methylated', 'Var', (29, 50))	('lincRNA', 'Chemical', '-', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('AMCN', 'Chemical', '-', (109, 113))	('cancer', 'Disease', (68, 74))	('lincRNA', 'Chemical', '-', (15, 22))
65047	25013169	The lincRNA XLOC_013592, located in chromosome 20, co-occurred with other AM lincRNAs in six types of cancer.	('XLOC_013592', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lincRNA', 'Chemical', '-', (4, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lincRNA', 'Chemical', '-', (77, 84))
65053	25013169	Furthermore, 191 AM lincRNAs showed consistent hypermethylated or hypomethylated status in diverse cancers.	('lincRNA', 'Chemical', '-', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('hypermethylated', 'Var', (47, 62))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('hypomethylated', 'Var', (66, 80))
65059	25013169	In UCEC, XLOC_013045 and XLOC_013050 were found to be adjacent to zinc-finger protein genes (ZNF181, ZNF30, ZNF404, ZNF45).	('ZNF30', 'Gene', '90075', (101, 106))	('ZNF181', 'Gene', (93, 99))	('XLOC_013050', 'Var', (25, 36))	('ZNF30', 'Gene', (101, 106))	('ZNF404', 'Gene', '342908', (108, 114))	('ZNF45', 'Gene', '7596', (116, 121))	('ZNF404', 'Gene', (108, 114))	('ZNF181', 'Gene', '339318', (93, 99))	('ZNF45', 'Gene', (116, 121))	('XLOC_013045', 'Var', (9, 20))
65060	25013169	The expression level of XLOC_013350 was negatively correlated with its methylation level (Pearson's correlation coefficient, PCC = -0.63, P < 0.05) and positively correlated with the expression of ZNF404 (PCC = 0.26, P < 0.05).	('expression level', 'MPA', (4, 20))	('XLOC_013350', 'Var', (24, 35))	('PCC', 'Gene', '1421', (125, 128))	('PCC', 'Gene', '1421', (205, 208))	('correlated', 'Interaction', (163, 173))	('negatively', 'NegReg', (40, 50))	('ZNF404', 'Gene', '342908', (197, 203))	('PCC', 'Gene', (125, 128))	('ZNF404', 'Gene', (197, 203))	('methylation level', 'MPA', (71, 88))	('PCC', 'Gene', (205, 208))
65061	25013169	We also observed a positive correlation between the expression of XLOC_013045 and ZNF181 (PCC = 0.18, P < 0.05), indicating that these two lincRNAs may be involved in cell growth and apoptosis.	('ZNF181', 'Gene', (82, 88))	('ZNF181', 'Gene', '339318', (82, 88))	('PCC', 'Gene', '1421', (90, 93))	('XLOC_013045', 'Var', (66, 77))	('cell growth', 'CPA', (167, 178))	('involved', 'Reg', (155, 163))	('PCC', 'Gene', (90, 93))	('lincRNA', 'Chemical', '-', (139, 146))	('apoptosis', 'CPA', (183, 192))
65062	25013169	In PRAD, lincRNA XLOC_002726 was significantly hypermethylated in tumors and showed a negative correlation between its expression and methylation (PCC = -0.26, P < 0.05), which was a newly found susceptibility locus for prostate cancer in genome-wide association studies.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('expression', 'MPA', (119, 129))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('XLOC_002726', 'Var', (17, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('PCC', 'Gene', (147, 150))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('lincRNA', 'Chemical', '-', (9, 16))	('negative', 'NegReg', (86, 94))	('prostate cancer', 'Disease', (220, 235))	('PRAD', 'Gene', (3, 7))	('methylation', 'MPA', (134, 145))	('PCC', 'Gene', '1421', (147, 150))
65065	25013169	Therefore, lincRNAs with aberrant methylation patterns in cancers might be involved in cancer development and progression.	('aberrant methylation patterns', 'Var', (25, 54))	('cancer', 'Disease', (87, 93))	('involved', 'Reg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lincRNA', 'Chemical', '-', (11, 18))	('cancer', 'Disease', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
65066	25013169	Early detection of hypermethylation or hypomethylation of lincRNAs might serve as biomarkers for cancer diagnosis or treatment.	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hypermethylation', 'Var', (19, 35))	('lincRNAs', 'Gene', (58, 66))	('hypomethylation', 'Var', (39, 54))	('lincRNA', 'Chemical', '-', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
65068	25013169	For example, DNA methylation disrupted a long non-coding RNA activity by affecting expression in a lethal lung developmental disorder.	('disrupted', 'NegReg', (29, 38))	('lung developmental disorder', 'Disease', 'MESH:D008171', (106, 133))	('expression in a lethal', 'MPA', (83, 105))	('methylation', 'Var', (17, 28))	('lung developmental disorder', 'Disease', (106, 133))	('affecting', 'Reg', (73, 82))	('DNA', 'Var', (13, 16))	('developmental disorder', 'Phenotype', 'HP:0001263', (111, 133))
65124	33864445	Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors Ferritin is the most important iron storage form and is known to influence tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ferritin', 'Var', (172, 180))	('iron', 'Chemical', 'MESH:D007501', (203, 207))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('influence', 'Reg', (237, 246))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (165, 170))
65150	33864445	The results suggested that high FTL (Figure 2B, 2C) or high FTH1 (Figure 2E-2J) mRNA levels were each related to poor OS in several cancer types.	('cancer', 'Disease', (132, 138))	('FTH1', 'Gene', (60, 64))	('mRNA levels', 'MPA', (80, 91))	('FTL', 'Gene', (32, 35))	('related', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FTH1', 'Gene', '2495', (60, 64))	('high', 'Var', (55, 59))	('FTL', 'Gene', '2512', (32, 35))	('poor OS', 'Disease', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
65153	33864445	FTL expression was significantly associated with PFI in four cancer types (Figure 3A): LGG (HR 1.5, 95% CI 1.26-1.78, P = 3.8 x 10-6), KIRC (HR 1.31, 95% CI 1.06-1.62, P = 1.4 x 10-2), UCEC (HR 1.21, 95% CI 1.00-1.46, P = 4.4 x 10-2), and GBM (HR 1.26, 95% CI 1.02-1.57, P = 3.3 x 10-2).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('FTL', 'Gene', '2512', (0, 3))	('LGG', 'Disease', (87, 90))	('PFI', 'Disease', (49, 52))	('cancer', 'Disease', (61, 67))	('associated', 'Reg', (33, 43))	('expression', 'Var', (4, 14))	('UCEC', 'Disease', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GBM', 'Disease', (239, 242))	('FTL', 'Gene', (0, 3))	('KIRC', 'Disease', (135, 139))
65155	33864445	As was observed for OS, poor PFI was significantly associated with high FTL (Figure 3B, 3C) or high FTH1 (Figure 3E-3J) mRNA levels in some cancers.	('FTH1', 'Gene', '2495', (100, 104))	('FTL', 'Gene', (72, 75))	('high', 'Var', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('FTH1', 'Gene', (100, 104))	('FTL', 'Gene', '2512', (72, 75))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('mRNA levels', 'MPA', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PFI', 'MPA', (29, 32))
65176	33864445	Iron is an essential element in supporting cell proliferation and often accumulates in cancer cells; however, excessive levels of Fe2+ can promote the Fenton reaction, production of reactive oxygen species, and cell death through apoptosis and ferroptosis.	('cancer', 'Disease', (87, 93))	('cell death', 'CPA', (211, 221))	('promote', 'PosReg', (139, 146))	('ferroptosis', 'CPA', (244, 255))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('apoptosis', 'CPA', (230, 239))	('Fe2+', 'Var', (130, 134))	('Fe2+', 'Chemical', '-', (130, 134))	('production of reactive oxygen species', 'MPA', (168, 205))	('Fenton reaction', 'MPA', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('oxygen', 'Chemical', 'MESH:D010100', (191, 197))
65186	33864445	We found that high FTH1 expression is positively related to poor prognosis in 11 cancers, including HNSC, which is consistent with our previous study.	('HNSC', 'Disease', (100, 104))	('FTH1', 'Gene', (19, 23))	('expression', 'MPA', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('FTH1', 'Gene', '2495', (19, 23))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('high', 'Var', (14, 18))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
65191	33864445	showed that FTH1 is critical for proper functioning of the antioxidant system in ovarian cancer cells, suggesting that inhibition of FTH1 may improve cisplatin-induced cytotoxicity.	('FTH1', 'Gene', (12, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (168, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('FTH1', 'Gene', (133, 137))	('inhibition', 'Var', (119, 129))	('ovarian cancer', 'Disease', (81, 95))	('FTH1', 'Gene', '2495', (12, 16))	('FTH1', 'Gene', '2495', (133, 137))	('cytotoxicity', 'Disease', (168, 180))	('cisplatin-induced', 'MPA', (150, 167))	('improve', 'PosReg', (142, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
65212	33864445	However, whether FTL or FTH1 inhibition can induce M2-to-M1 repolarization will need to be investigated in future studies.	('FTH1', 'Gene', '2495', (24, 28))	('FTL', 'Gene', '2512', (17, 20))	('FTH1', 'Gene', (24, 28))	('FTL', 'Gene', (17, 20))	('M2-to-M1 repolarization', 'MPA', (51, 74))	('inhibition', 'Var', (29, 39))
65238	26585233	As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro.	('Ccl5', 'Gene', (38, 42))	('optic nerve astrocyte growth', 'CPA', (67, 95))	('Nf1-deficient', 'Gene', (53, 66))	('glioma', 'Disease', (15, 21))	('increased', 'PosReg', (43, 52))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('recombinant', 'Var', (26, 37))	('deficient optic nerve', 'Phenotype', 'HP:0000609', (57, 78))
65250	26585233	Importantly, pharmacological or genetic disruption of microglia function in mouse high-grade glioma models results in attenuated tumor growth and progression.	('glioma', 'Disease', (93, 99))	('attenuated tumor', 'Disease', (118, 134))	('attenuated tumor', 'Disease', 'MESH:C538265', (118, 134))	('microglia', 'Protein', (54, 63))	('genetic disruption', 'Var', (32, 50))	('mouse', 'Species', '10090', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
65253	26585233	Children with NF1 are born with one mutated copy of the NF1 gene and develop tumors following somatic inactivation of the remaining normal NF1 gene in astroglial progenitors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('Children', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('inactivation', 'Var', (102, 114))	('NF1', 'Gene', (139, 142))	('develop', 'PosReg', (69, 76))	('mutated', 'Var', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NF1', 'Gene', (56, 59))	('NF1', 'Var', (14, 17))
65254	26585233	Similar to their human counterparts, nearly all Nf1+/- mice with somatic Nf1 gene inactivation in neuroglial progenitors develop low-grade gliomas of the optic nerve and chiasm.	('human', 'Species', '9606', (17, 22))	('gliomas of the optic nerve', 'Disease', (139, 165))	('Nf1', 'Gene', (73, 76))	('inactivation', 'Var', (82, 94))	('mice', 'Species', '10090', (55, 59))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('develop', 'PosReg', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('gliomas of the optic nerve', 'Disease', 'MESH:D020339', (139, 165))
65261	26585233	Importantly, minocycline-mediated microglia inactivation decreased Ccl5 expression in vivo, whereas exogenous Ccl5 treatment increased the proliferation of Nf1-deficient optic nerve astrocytes in vitro.	('increased', 'PosReg', (125, 134))	('proliferation', 'CPA', (139, 152))	('minocycline', 'Chemical', 'MESH:D008911', (13, 24))	('deficient optic nerve', 'Phenotype', 'HP:0000609', (160, 181))	('inactivation', 'Var', (44, 56))	('Ccl5', 'Gene', (67, 71))	('decreased', 'NegReg', (57, 66))
65262	26585233	In addition, neutralizing Ccl5 antibody administration reduced glioma growth and optic glioma-associated retinal defects in vivo.	('optic glioma', 'Phenotype', 'HP:0009734', (81, 93))	('reduced', 'NegReg', (55, 62))	('glioma growth', 'Disease', (63, 76))	('glioma growth', 'Disease', 'MESH:D005910', (63, 76))	('neutralizing', 'Var', (13, 25))	('optic glioma-associated retinal defects', 'Disease', (81, 120))	('optic glioma-associated retinal defects', 'Disease', 'MESH:D012175', (81, 120))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('Ccl5', 'Gene', (26, 30))
65264	26585233	Three independent Nf1 optic glioma GEM models were used based on the timing of Nf1 inactivation or the presence of additional genetic changes.	('optic glioma', 'Phenotype', 'HP:0009734', (22, 34))	('optic glioma', 'Disease', 'MESH:D020339', (22, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('Nf1', 'Gene', (79, 82))	('inactivation', 'Var', (83, 95))	('optic glioma', 'Disease', (22, 34))
65265	26585233	The first model (Nf1flox/mut; GFAP-Cre (FMC)) was generated by successive breeding of Nf1 +/- mice with Nf1flox/flox (WT) mice and GFAP-Cre mice.	('mice', 'Species', '10090', (122, 126))	('GFAP', 'Gene', (131, 135))	('mice', 'Species', '10090', (140, 144))	('GFAP', 'Gene', '14580', (30, 34))	('GFAP', 'Gene', (30, 34))	('mice', 'Species', '10090', (94, 98))	('Nf1flox/flox', 'Var', (104, 116))	('GFAP', 'Gene', '14580', (131, 135))
65321	26585233	Whereas prior studies of murine and human NF1 optic nerve gliomas demonstrated an increased percentage of microglia in these tumors, confocal image analysis of these microglia within the mouse optic gliomas also revealed striking morphological changes: Nonglioma (resident) microglia in the optic nerve from either WT or Nf1 +/- (FM) mice exhibited morphologies typical of ramified microglia, with elongated, fine processes that extended into their surroundings, whereas tumor-associated Nf1 +/- microglia (FMC, FMC*, and FMPC mice) harbored shorter processes that were slightly thickened or lacked processes completely (Figure 1, a and b).	('exhibited', 'Reg', (339, 348))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('Nonglioma', 'Disease', 'None', (253, 262))	('optic gliomas', 'Disease', 'MESH:D020339', (193, 206))	('optic glioma', 'Phenotype', 'HP:0009734', (193, 205))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('optic nerve gliomas', 'Disease', 'MESH:D020339', (46, 65))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (471, 476))	('tumors', 'Disease', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (471, 476))	('Nf1', 'Var', (321, 324))	('optic nerve gliomas', 'Disease', (46, 65))	('mice', 'Species', '10090', (527, 531))	('optic nerve gliomas', 'Phenotype', 'HP:0009734', (46, 65))	('mice', 'Species', '10090', (334, 338))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('optic gliomas', 'Disease', (193, 206))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('mouse', 'Species', '10090', (187, 192))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('human', 'Species', '9606', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('optic gliomas', 'Phenotype', 'HP:0009734', (193, 206))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (471, 476))	('tumor', 'Disease', (125, 130))	('Nonglioma', 'Disease', (253, 262))	('lacked', 'NegReg', (592, 598))	('murine', 'Species', '10090', (25, 31))
65326	26585233	We were specifically interested in transcripts unique to Nf1+/- microglia within optic gliomas relative to those found in Nf1+/- microglia within the normal (non-neoplastic) optic nerve.	('Nf1+/-', 'Var', (57, 63))	('optic glioma', 'Phenotype', 'HP:0009734', (81, 93))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('optic gliomas', 'Phenotype', 'HP:0009734', (81, 94))	('optic gliomas', 'Disease', 'MESH:D020339', (81, 94))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('optic gliomas', 'Disease', (81, 94))
65333	26585233	qRT-PCR analysis demonstrated that tumor-associated Nf1 +/- microglia had a 3.3-fold increase in Cxcl13 RNA expression and a 300-fold increase in Ccl5 RNA expression relative to FM (Nf1 +/-) microglia (Figure 2d).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('increase', 'PosReg', (134, 142))	('Ccl5 RNA expression', 'MPA', (146, 165))	('tumor', 'Disease', (35, 40))	('Cxcl13', 'Gene', (97, 103))	('Nf1 +/-', 'Var', (52, 59))	('increase', 'PosReg', (85, 93))	('Cxcl13', 'Gene', '55985', (97, 103))
65335	26585233	Previous studies have demonstrated that minocycline inactivation of microglia reduced Nf1 optic glioma proliferation in vivo .	('optic glioma proliferation', 'Disease', (90, 116))	('optic glioma proliferation', 'Disease', 'MESH:D020339', (90, 116))	('minocycline', 'Chemical', 'MESH:D008911', (40, 51))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('inactivation', 'Var', (52, 64))	('reduced', 'NegReg', (78, 85))	('optic glioma', 'Phenotype', 'HP:0009734', (90, 102))
65340	26585233	These observations suggest that Ccl5, but not Cxcl13, is particularly worthy of further exploration as a potential tumor-associated microglia gliomagen.	('Cxcl13', 'Gene', '55985', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('glioma', 'Disease', (142, 148))	('tumor', 'Disease', (115, 120))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('Ccl5', 'Var', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('Cxcl13', 'Gene', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
65344	26585233	Second, because symptomatic NF1-associated optic gliomas are commonly treated without a prior tissue diagnosis (biopsy), we leveraged available transcriptomal human PA data sets (GSE42556 and GSE44971).	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('optic gliomas', 'Phenotype', 'HP:0009734', (43, 56))	('NF1-associated', 'Gene', (28, 42))	('GSE42556', 'Var', (179, 187))	('optic glioma', 'Phenotype', 'HP:0009734', (43, 55))	('human', 'Species', '9606', (159, 164))	('optic gliomas', 'Disease', 'MESH:D020339', (43, 56))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('optic gliomas', 'Disease', (43, 56))	('GSE44971', 'Var', (192, 200))
65348	26585233	Because these cultures contain 70% NG2+ cells and 30% GFAP+ cells, in which only the GFAP+ astrocytes hyperproliferate following Nf1 gene inactivation, we analyzed the proliferation of optic nerve astroglial cells using Ki67 labeling in vitro.	('Nf1', 'Gene', (129, 132))	('GFAP', 'Gene', '14580', (54, 58))	('gene inactivation', 'Var', (133, 150))	('GFAP', 'Gene', (54, 58))	('NG2', 'Gene', (35, 38))	('Ki67', 'Chemical', '-', (220, 224))	('GFAP', 'Gene', '14580', (85, 89))	('inactivation', 'Var', (138, 150))	('GFAP', 'Gene', (85, 89))	('NG2', 'Gene', '121021', (35, 38))
65361	26585233	Interestingly, consistent with the known chemoattractant properties of Ccl5, anti-Ccl5 treatment also reduced the number of Iba1+ microglia into these tumors in vivo (Figure 6c).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('anti-Ccl5', 'Var', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('Iba1', 'Gene', '114737', (124, 128))	('Iba1', 'Gene', (124, 128))	('reduced', 'NegReg', (102, 109))
65364	26585233	Collectively, these findings demonstrate that microglia-produced Ccl5 is both necessary and sufficient to increase Nf1-deficient astrocyte proliferation relevant to Nf1 optic glioma maintenance and that inhibiting Ccl5 function reduces retinal pathology in the setting of murine Nf1 optic glioma.	('optic glioma', 'Disease', 'MESH:D020339', (283, 295))	('astrocyte proliferation', 'CPA', (129, 152))	('inhibiting', 'Var', (203, 213))	('optic glioma', 'Phenotype', 'HP:0009734', (169, 181))	('optic glioma', 'Disease', (283, 295))	('function', 'MPA', (219, 227))	('optic glioma', 'Disease', (169, 181))	('retinal pathology', 'CPA', (236, 253))	('murine', 'Species', '10090', (272, 278))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('Ccl5', 'Gene', (214, 218))	('reduces', 'NegReg', (228, 235))	('optic glioma', 'Phenotype', 'HP:0009734', (283, 295))	('increase', 'PosReg', (106, 114))	('optic glioma', 'Disease', 'MESH:D020339', (169, 181))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
65372	26585233	In addition, CCL5-expressing melanoma cells form increasingly aggressive tumors in a concentration-dependent fashion, and Ccl5 increases the growth of breast cancer cells in vitro .	('Ccl5', 'Var', (122, 126))	('increases', 'PosReg', (127, 136))	('aggressive tumors', 'Disease', (62, 79))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', (151, 164))	('growth', 'MPA', (141, 147))	('aggressive tumors', 'Disease', 'MESH:D001523', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
65376	26585233	In addition, Ccl5 inhibition resulted in decreased microglia within the optic glioma, suggesting that Ccl5 may be a key stromal determinant of tumor growth and associated optic nerve damage as well as monocyte recruitment to the glioma.	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('optic glioma', 'Disease', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('decreased', 'NegReg', (41, 50))	('optic glioma', 'Disease', 'MESH:D020339', (72, 84))	('inhibition', 'Var', (18, 28))	('optic nerve damage', 'Phenotype', 'HP:0001138', (171, 189))	('Ccl5', 'Gene', (13, 17))	('optic glioma', 'Phenotype', 'HP:0009734', (72, 84))	('tumor', 'Disease', (143, 148))	('optic nerve damage', 'Disease', (171, 189))	('optic nerve damage', 'Disease', 'MESH:D009901', (171, 189))	('glioma', 'Disease', (229, 235))	('microglia', 'CPA', (51, 60))	('glioma', 'Disease', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('glioma', 'Disease', 'MESH:D005910', (229, 235))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
65384	26585233	Similarly, colony-stimulating factor 1 (CSF-1) produced by mouse glioblastoma cells attracts microglia through the CSF-1 receptor to further increase glioma growth, such that attenuation of this CSF-1/CSF-1 receptor axis reduced murine glioblastoma growth in vivo .	('increase glioma growth', 'Disease', 'MESH:D005910', (141, 163))	('glioblastoma', 'Disease', 'MESH:D005909', (236, 248))	('CSF-1', 'Gene', (195, 200))	('attenuation', 'Var', (175, 186))	('colony-stimulating factor 1', 'Gene', '12977', (11, 38))	('CSF-1', 'Gene', '12977', (195, 200))	('CSF-1', 'Gene', (115, 120))	('CSF-1', 'Gene', '12977', (115, 120))	('glioblastoma', 'Disease', (236, 248))	('murine', 'Species', '10090', (229, 235))	('glioblastoma growth', 'Disease', 'MESH:D005909', (236, 255))	('glioblastoma', 'Phenotype', 'HP:0012174', (236, 248))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('mouse', 'Species', '10090', (59, 64))	('CSF-1', 'Gene', (201, 206))	('increase glioma growth', 'Disease', (141, 163))	('glioblastoma', 'Disease', (65, 77))	('reduced', 'NegReg', (221, 228))	('CSF-1', 'Gene', '12977', (201, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('glioblastoma growth', 'Disease', (236, 255))	('CSF-1', 'Gene', (40, 45))	('colony-stimulating factor 1', 'Gene', (11, 38))	('CSF-1', 'Gene', '12977', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
65388	25605251	In vitro assays revealed that KITENIN knockdown inhibited the invasion and migration of glioma cells, whereas KITENIN overexpression promoted their invasion and migration.	('promoted', 'PosReg', (133, 141))	('glioma', 'Disease', (88, 94))	('inhibited', 'NegReg', (48, 57))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('KITENIN', 'Gene', (30, 37))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('knockdown', 'Var', (38, 47))
65389	25605251	In orthotopic mouse tumor models, mice transplanted with KITENIN-transfected glioma cells had significantly shorter survival than mice transplanted with mock-transfected cells.	('mice', 'Species', '10090', (130, 134))	('mice', 'Species', '10090', (34, 38))	('mouse', 'Species', '10090', (14, 19))	('survival', 'CPA', (116, 124))	('KITENIN-transfected', 'Var', (57, 76))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('shorter', 'NegReg', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('glioma', 'Disease', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('tumor', 'Disease', (20, 25))
65390	25605251	Patients with low KITENIN expression showed a significantly longer progression-free survival than patients with high KITENIN expression.	('expression', 'MPA', (26, 36))	('longer', 'PosReg', (60, 66))	('patients', 'Species', '9606', (98, 106))	('Patients', 'Species', '9606', (0, 8))	('progression-free survival', 'CPA', (67, 92))	('KITENIN', 'Protein', (18, 25))	('low', 'Var', (14, 17))
65392	25605251	Taken together, these findings showed that high levels of KITENIN increased glioma invasiveness and progression, associated with the up-regulation of EMT and stemness markers.	('high levels', 'Var', (43, 54))	('increased', 'PosReg', (66, 75))	('KITENIN', 'Protein', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('progression', 'CPA', (100, 111))	('up-regulation', 'PosReg', (133, 146))	('glioma invasiveness', 'Disease', 'MESH:D005910', (76, 95))	('glioma invasiveness', 'Disease', (76, 95))
65410	25605251	A spliced variant of KAI1 at the COOH-terminal region, however, showed a reduction in metastasis suppressor function, suggesting that this region is important for the effects of KAI1 on cell motility.	('KAI1', 'Gene', '3732', (178, 182))	('KAI1', 'Gene', (21, 25))	('KAI1', 'Gene', (178, 182))	('metastasis suppressor function', 'CPA', (86, 116))	('variant', 'Var', (10, 17))	('reduction', 'NegReg', (73, 82))	('KAI1', 'Gene', '3732', (21, 25))
65417	25605251	In addition, small interfering RNA (siRNA) and microRNA-124 targeting KITENIN inhibited tumor metastasis in a mouse colon cancer model.	('tumor metastasis', 'Disease', (88, 104))	('KITENIN', 'Gene', (70, 77))	('inhibited', 'NegReg', (78, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('mouse', 'Species', '10090', (110, 115))	('tumor metastasis', 'Disease', 'MESH:D009362', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('colon cancer', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('microRNA-124', 'Var', (47, 59))
65428	25605251	The difference between these groups was statistically significant (P=0.004, Table 1), with high KITENIN expression correlating with the increase in tumor grade (P=0.001, Fig.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('high', 'Var', (91, 95))	('tumor', 'Disease', (148, 153))	('KITENIN', 'Protein', (96, 103))	('expression', 'MPA', (104, 114))	('increase', 'PosReg', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
65434	25605251	KITENIN knockdown in U251 cells significantly reduced in vitro cell invasion (Fig.	('knockdown', 'Var', (8, 17))	('in vitro cell invasion', 'CPA', (54, 76))	('reduced', 'NegReg', (46, 53))	('U251', 'CellLine', 'CVCL:0021', (21, 25))
65438	25605251	To search for factors associated with alterations invasiveness and migration caused by modulation of KITENIN expression, the levels of expression of EMT markers and regulators were determined.	('modulation', 'Var', (87, 97))	('alterations invasiveness', 'Disease', 'MESH:D009362', (38, 62))	('alterations invasiveness', 'Disease', (38, 62))	('migration', 'CPA', (67, 76))	('KITENIN', 'Protein', (101, 108))
65439	25605251	Stable KITENIN knockdown in U251 cells reduced the expression of N-cadherin (CDH2), ZEB1, ZEB2, SNAIL (SNAI1), and SLUG (SNAI2) mRNA and protein (Fig.	('knockdown', 'Var', (15, 24))	('mRNA', 'Protein', (128, 132))	('U251', 'CellLine', 'CVCL:0021', (28, 32))	('SNAI1', 'Gene', '6615', (103, 108))	('CDH2', 'Gene', (77, 81))	('SNAI2', 'Gene', '6591', (121, 126))	('SNAI2', 'Gene', (121, 126))	('CDH2', 'Gene', '1000', (77, 81))	('expression', 'MPA', (51, 61))	('N-cadherin', 'Protein', (65, 75))	('reduced', 'NegReg', (39, 46))	('SNAI1', 'Gene', (103, 108))
65442	25605251	The U343, U251 and U87 cell lines, with relatively high expression of endogenous KITENIN, showed a higher proportion of CD133 positivity than the U118 and GL261 cells lines, with low endogenous KITENIN levels (Supplementary Fig.	('CD133', 'Gene', (120, 125))	('U251', 'CellLine', 'CVCL:0021', (10, 14))	('U118', 'CellLine', 'CVCL:0633', (146, 150))	('positivity', 'Var', (126, 136))
65443	25605251	Stable KITENIN knockdown in U251 cells decreased the levels of ALDH1, CD133, and EPH-B1 mRNAs (Fig.	('knockdown', 'Var', (15, 24))	('U251', 'CellLine', 'CVCL:0021', (28, 32))	('EPH-B1', 'Gene', (81, 87))	('levels', 'MPA', (53, 59))	('ALDH1', 'MPA', (63, 68))	('CD133', 'MPA', (70, 75))	('decreased', 'NegReg', (39, 48))
65445	25605251	The number of neurospheres on day 7 was significantly lower in shKITENIN-treated than mock-transfected U251 cells (Fig.	('U251', 'CellLine', 'CVCL:0021', (103, 107))	('shKITENIN', 'Chemical', '-', (63, 72))	('lower', 'NegReg', (54, 59))	('shKITENIN-treated', 'Var', (63, 80))
65448	25605251	Moreover, shKITENIN-treated U251 cells had lower colony-forming ability than mock-transfected U251 cells (Fig.	('U251', 'CellLine', 'CVCL:0021', (28, 32))	('colony-forming ability', 'CPA', (49, 71))	('shKITENIN-treated', 'Var', (10, 27))	('U251', 'CellLine', 'CVCL:0021', (94, 98))	('shKITENIN', 'Chemical', '-', (10, 19))	('lower', 'NegReg', (43, 48))
65449	25605251	In orthotopic intracranial mouse tumor models, modulation of KITENIN expression was associated with altered invasiveness and survival rates.	('invasiveness', 'CPA', (108, 120))	('survival rates', 'CPA', (125, 139))	('altered', 'Reg', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('KITENIN', 'Protein', (61, 68))	('mouse', 'Species', '10090', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('expression', 'MPA', (69, 79))	('tumor', 'Disease', (33, 38))	('modulation', 'Var', (47, 57))
65450	25605251	Median survival was significantly longer in mice transplanted with shKITENIN-treated than mock-treated U251 cells (71.0 vs. 49.0 days, P<0.001, Fig 5A, upper), but was significantly shorter in mice transplanted with KITENIN-transfected than mock-transfected GL261 cells (24 vs. 31.5 days, P=0.03, Fig 5A, lower).	('shorter', 'NegReg', (182, 189))	('U251', 'CellLine', 'CVCL:0021', (103, 107))	('longer', 'PosReg', (34, 40))	('Median survival', 'CPA', (0, 15))	('mice', 'Species', '10090', (193, 197))	('shKITENIN', 'Chemical', '-', (67, 76))	('mice', 'Species', '10090', (44, 48))	('shKITENIN-treated', 'Var', (67, 84))
65453	25605251	Although median overall survival (OS) was shorter in patients with high than low KITENIN expression, the difference was not statistically significant (32.8 vs. 47.5 months, P=0.274, Fig.	('high', 'Var', (67, 71))	('expression', 'MPA', (89, 99))	('KITENIN', 'Protein', (81, 88))	('patients', 'Species', '9606', (53, 61))	('overall survival', 'MPA', (16, 32))	('shorter', 'NegReg', (42, 49))
65456	25605251	By contrast, median progression-free survival (PFS) was significantly longer in patients with low than high KITENIN expression (42.0 vs. 23.8 months, P=0.041, Fig.	('low', 'Var', (94, 97))	('expression', 'MPA', (116, 126))	('patients', 'Species', '9606', (80, 88))	('progression-free survival', 'CPA', (20, 45))	('longer', 'PosReg', (70, 76))	('KITENIN', 'Protein', (108, 115))
65461	25605251	Overall, these findings indicate that high KITENIN expression in glioma is predictive of poor patient prognosis.	('glioma', 'Disease', (65, 71))	('KITENIN', 'Protein', (43, 50))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('high', 'Var', (38, 42))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('expression', 'MPA', (51, 61))	('patient', 'Species', '9606', (94, 101))
65465	25605251	In addition, genetic modulation of KITENIN altered the expression of several factors related to glioma stemness, including CD133, CD44, ALDH1, and EPH-B1.	('CD133', 'Gene', (123, 128))	('KITENIN', 'Gene', (35, 42))	('CD44', 'Gene', (130, 134))	('glioma stemness', 'Disease', 'MESH:D005910', (96, 111))	('expression', 'MPA', (55, 65))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma stemness', 'Disease', (96, 111))	('EPH-B1', 'Gene', (147, 153))	('ALDH1', 'Gene', (136, 141))	('genetic modulation', 'Var', (13, 31))	('altered', 'Reg', (43, 50))
65467	25605251	In orthotopic glioma models, mice showed significantly increased survival following KITENIN knockdown but shorter survival with KITENIN overexpression.	('glioma', 'Disease', (14, 20))	('KITENIN', 'Protein', (84, 91))	('knockdown', 'Var', (92, 101))	('increased', 'PosReg', (55, 64))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('mice', 'Species', '10090', (29, 33))
65548	25605251	Samples were incubated overnight at 4 oC with anti-Nestin (1:500, 611659, BD Transduction Laboratories) and anti-CD133 (1:100, LF-PA50121, AB Frontier, Seoul, South Korea) antibodies, followed by incubation with Alexa Flour 488 goat anti-mouse IgG or Alexa Flour 568 goat anti-rabbit IgG (Molecular Probes, Grand Island, NY, USA) for 1 hour at room temperature.	('BD Transduction Laboratories', 'Disease', (74, 102))	('goat', 'Species', '9925', (267, 271))	('goat', 'Species', '9925', (228, 232))	('Nestin', 'Gene', (51, 57))	('1:100', 'Var', (120, 125))	('rabbit', 'Species', '9986', (277, 283))	('BD Transduction Laboratories', 'Disease', 'MESH:D001528', (74, 102))	('mouse', 'Species', '10090', (238, 243))	('Alexa Flour 488', 'Chemical', '-', (212, 227))	('Alexa Flour 568', 'Chemical', '-', (251, 266))	('Nestin', 'Gene', '10763', (51, 57))
65556	31888244	Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas.	('IDH1', 'Gene', (101, 105))	('IDH1', 'Gene', '3417', (7, 11))	('isocitrate dehydrogenase 1', 'Gene', (112, 138))	('Affects', 'Reg', (24, 31))	('IDH1', 'Gene', '3417', (101, 105))	('isocitrate dehydrogenase 1', 'Gene', '3417', (112, 138))	('Redox State', 'MPA', (32, 43))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('gliomas', 'Disease', (198, 205))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('mutations', 'Var', (140, 149))	('Mutant', 'Var', (0, 6))	('Tumor', 'Phenotype', 'HP:0002664', (88, 93))	('IDH1', 'Gene', (7, 11))	('Metabolism', 'MPA', (48, 58))
65557	31888244	IDH1wt converts isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses alpha-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG).	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (202, 220))	('NADPH', 'Gene', (165, 170))	('nicotinamide adenine dinucleotide phosphate', 'MPA', (65, 108))	('NADPH', 'Gene', '1666', (165, 170))	('IDH1R132H', 'Var', (126, 135))	('alpha-ketoglutarate', 'Chemical', 'MESH:C029743', (30, 49))	('NADP+', 'Chemical', 'MESH:D009249', (110, 115))	('reducing', 'NegReg', (56, 64))	('isocitrate', 'Chemical', 'MESH:D007523', (16, 26))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (65, 108))	('alpha-ketoglutarate', 'Chemical', 'MESH:C029743', (141, 160))
65558	31888244	The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro.	('enhanced sensitivity to irradiation', 'Phenotype', 'HP:0011133', (180, 215))	('IDH1R132H expression', 'Var', (36, 56))	('decreased', 'NegReg', (99, 108))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (109, 127))	('reduced', 'NegReg', (153, 160))	('glioblastoma', 'Disease', (224, 236))	('sensitivity to irradiation', 'MPA', (189, 215))	('glioblastoma', 'Disease', 'MESH:D005909', (224, 236))	('enhanced', 'PosReg', (180, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (224, 236))	('TCA', 'Chemical', 'MESH:C000589078', (129, 132))	('proliferation', 'CPA', (161, 174))
65559	31888244	Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction.	('Glioblastoma', 'Disease', (0, 12))	('decreased', 'NegReg', (47, 56))	('NADPH', 'Gene', '1666', (57, 62))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('NAD', 'Chemical', 'MESH:D009243', (67, 70))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('NAD+ levels', 'MPA', (67, 78))	('NAD', 'Chemical', 'MESH:D009243', (57, 60))	('IDH1R132H transduction', 'Var', (84, 106))	('NADPH', 'Gene', (57, 62))
65560	31888244	However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT).	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (91, 129))	('IDH1R132H', 'Var', (23, 32))	('NAMPT', 'Gene', (131, 136))	('elevated', 'PosReg', (40, 48))	('expression', 'MPA', (49, 59))	('NAD', 'Chemical', 'MESH:D009243', (67, 70))	('nicotinamide phosphoribosyltransferase', 'Gene', (91, 129))	('NAMPT', 'Gene', '10135', (131, 136))
65564	31888244	Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('IDH1-mutant', 'Var', (95, 106))	('gliomas', 'Disease', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1-mutant', 'Gene', (95, 106))
65566	31888244	Low-grade gliomas and secondary glioblastomas are characterized by mutations in IDH1/2 (isocitrate dehydrogenase 1/2), which are associated with a longer overall survival and better response to therapy compared to IDH-wildtype gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('glioblastomas', 'Disease', (32, 45))	('gliomas', 'Disease', (227, 234))	('glioblastomas', 'Disease', 'MESH:D005909', (32, 45))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('longer', 'PosReg', (147, 153))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('isocitrate dehydrogenase 1', 'Gene', '3417', (88, 114))	('isocitrate dehydrogenase 1', 'Gene', (88, 114))	('IDH-wildtype gliomas', 'Disease', 'MESH:D005910', (214, 234))	('glioblastomas', 'Phenotype', 'HP:0012174', (32, 45))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('IDH-wildtype gliomas', 'Disease', (214, 234))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('mutations', 'Var', (67, 76))	('IDH1/2', 'Gene', (80, 86))
65567	31888244	The most frequent mutation observed in more than 90% of cases is the amino acid substitution arginine to histidine at codon 132 of the cytoplasmic enzyme isocitrate dehydrogenase 1 (IDH1 c.395G>A; R132H).	('IDH1 c.395G>A; R132H', 'Var', (182, 202))	('arginine', 'Var', (93, 101))	('isocitrate dehydrogenase 1', 'Gene', (154, 180))	('isocitrate dehydrogenase 1', 'Gene', '3417', (154, 180))	('R132H', 'Mutation', 'rs121913500', (197, 202))	('c.395G>A', 'Mutation', 'rs121913500', (187, 195))	('arginine to histidine at codon 132', 'Mutation', 'rs121913500', (93, 127))
65568	31888244	Other rare IDH1 variants in codon 132 have been described in gliomas, including R132C, R132S, R132G, and R132L, which show similar effects on IDH1 activity.	('R132G', 'Var', (94, 99))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('described', 'Reg', (48, 57))	('R132S', 'Var', (87, 92))	('gliomas', 'Disease', (61, 68))	('R132L', 'Var', (105, 110))	('R132S', 'Mutation', 'rs11542041', (87, 92))	('R132G', 'Mutation', 'rs121913499', (94, 99))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('R132C', 'Var', (80, 85))	('R132C', 'Mutation', 'rs121913499', (80, 85))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('R132L', 'Mutation', 'rs121913500', (105, 110))	('variants', 'Var', (16, 24))	('IDH1', 'Gene', (11, 15))
65569	31888244	IDH1/2 mutations are assumed to be one of the earliest genetic alterations and are considered to play a key role in glioma development.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioma', 'Disease', (116, 122))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('mutations', 'Var', (7, 16))
65570	31888244	However, the mechanisms by which mutant IDH transforms the cell remain insufficiently understood.	('IDH', 'Gene', '3417', (40, 43))	('IDH', 'Gene', (40, 43))	('mutant', 'Var', (33, 39))
65572	31888244	In contrast, mutant IDH1 is unable to efficiently catalyze the oxidative decarboxylation of isocitrate, but acquires a neomorphic catalytic activity that allows the NADPH-dependent reduction of alpha-KG into 2-hydroxyglutarate (2-HG).	('mutant', 'Var', (13, 19))	('alpha-KG', 'Chemical', 'MESH:D020410', (194, 202))	('NADPH', 'Gene', (165, 170))	('acquires', 'PosReg', (108, 116))	('NADPH', 'Gene', '1666', (165, 170))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (208, 226))	('IDH1', 'Gene', (20, 24))	('isocitrate', 'Chemical', 'MESH:D007523', (92, 102))
65574	31888244	It has been shown that 2-HG inhibits alpha-KG-dependent dioxygenases such as methylcytosine dioxygenase (TET2), which leads to the CpG island-methylator phenotype (G-CIMP) prevalent in gliomas with IDH1/2 mutations.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('IDH1/2', 'Gene', (198, 204))	('alpha-KG-dependent dioxygenases', 'Enzyme', (37, 68))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))	('CpG island-methylator phenotype', 'MPA', (131, 162))	('methylcytosine', 'Chemical', 'MESH:C036386', (77, 91))	('leads to', 'Reg', (118, 126))	('TET2', 'Gene', (105, 109))	('gliomas', 'Disease', (185, 192))	('methylcytosine dioxygenase', 'Enzyme', (77, 103))	('inhibits', 'NegReg', (28, 36))	('mutations', 'Var', (205, 214))	('oxygen', 'Chemical', 'MESH:D010100', (58, 64))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('prevalent', 'Reg', (172, 181))	('TET2', 'Gene', '54790', (105, 109))	('alpha-KG', 'Chemical', 'MESH:D020410', (37, 45))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('IDH1/2', 'Gene', '3417;3418', (198, 204))
65576	31888244	This rare neurometabolic disease is related to the germline mutations in D2HGDH but, to the best of our knowledge, these patients show no increased prevalence for brain tumor formation.	('brain tumor', 'Phenotype', 'HP:0030692', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('neurometabolic disease', 'Disease', (10, 32))	('brain tumor', 'Disease', (163, 174))	('D2HGDH', 'Gene', (73, 79))	('neurometabolic disease', 'Disease', 'MESH:D030342', (10, 32))	('brain tumor', 'Disease', 'MESH:D001932', (163, 174))	('patients', 'Species', '9606', (121, 129))	('D2HGDH', 'Gene', '728294', (73, 79))	('germline mutations', 'Var', (51, 69))
65579	31888244	Wildtype IDH1 is reported as the major generator of cytosolic NADPH in glia cells and glioblastoma, while IDH1R132H consumes NADPH.	('NADPH', 'Gene', (62, 67))	('IDH1R132H', 'Var', (106, 115))	('NADPH', 'Gene', (125, 130))	('NADPH', 'Gene', '1666', (62, 67))	('NADPH', 'Gene', '1666', (125, 130))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
65580	31888244	The proposed IDH1R132H-associated drop in intracellular NADPH levels is expected to have drastic effects on the cellular metabolome, the redox state of the cell, and various other physiological phenomena.	('drop', 'NegReg', (34, 38))	('IDH1R132H-associated', 'Var', (13, 33))	('redox state of the cell', 'MPA', (137, 160))	('effects', 'Reg', (97, 104))	('NADPH', 'Gene', (56, 61))	('cellular metabolome', 'MPA', (112, 131))	('NADPH', 'Gene', '1666', (56, 61))
65581	31888244	This study aimed to unravel the 2-HG independent effects of mutant IDH1 on the redox state, metabolism, and energy homeostasis in both tumor and non-neoplastic glial cells.	('redox state', 'MPA', (79, 90))	('effects', 'Reg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH1', 'Gene', (67, 71))	('tumor', 'Disease', (135, 140))	('metabolism', 'MPA', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mutant', 'Var', (60, 66))	('energy homeostasis', 'MPA', (108, 126))
65582	31888244	To this end, we transduced glioblastoma cell lines and immortalized astrocytes with the most frequent IDH1R132H mutation for systematic comparative examinations, and also used empty vector control cell lines supplemented with membrane-permeable 2-HG.	('mutation', 'Var', (112, 120))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('IDH1R132H', 'Gene', (102, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))
65583	31888244	We show that IDH1R132H has differing effects on the redox state between tumor cells and astrocytes, indicating that IDH1R132H could have different effects depending on the stage of malignant transformation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('redox state', 'MPA', (52, 63))	('IDH1R132H', 'Var', (116, 125))	('tumor', 'Disease', (72, 77))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('effects', 'Reg', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('R132H', 'Mutation', 'rs121913500', (120, 125))
65585	31888244	We stably transduced U87-MG, the primary patient-derived glioblastoma cell line HT7606, and immortalized astrocytes SVGp12 with IDH1R132H, IDH1wt, or an empty vector.	('HT7606', 'CellLine', 'CVCL:1290', (80, 86))	('glioblastoma', 'Disease', (57, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('patient', 'Species', '9606', (41, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('IDH1R132H', 'Var', (128, 137))
65589	31888244	The transduction with IDH1R132H caused a general drop in the concentrations of metabolites downstream of isocitrate (alpha-KG, succinate, fumarate, and malate) in glioma cells and astrocytes, while isocitrate levels increased.	('IDH1R132H', 'Var', (22, 31))	('glioma', 'Disease', (163, 169))	('transduction', 'Var', (4, 16))	('concentrations of metabolites downstream of', 'MPA', (61, 104))	('drop', 'NegReg', (49, 53))	('isocitrate', 'Chemical', 'MESH:D007523', (105, 115))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('succinate', 'MPA', (127, 136))	('malate', 'Chemical', 'MESH:D008293', (152, 158))	('R132H', 'Mutation', 'rs121913500', (26, 31))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('fumarate', 'Chemical', 'MESH:D005650', (138, 146))	('isocitrate levels', 'MPA', (198, 215))	('isocitrate', 'Chemical', 'MESH:D007523', (198, 208))	('fumarate', 'MPA', (138, 146))	('alpha-KG', 'Chemical', 'MESH:D020410', (117, 125))	('succinate', 'Chemical', 'MESH:D013386', (127, 136))
65591	31888244	On the other hand, the level of the amino acid aspartate increased in the IDH1R132H mutated cells.	('mutated', 'Var', (84, 91))	('IDH1R132H mutated', 'Var', (74, 91))	('level of the amino acid aspartate', 'MPA', (23, 56))	('amino acid aspartate', 'Chemical', 'None', (36, 56))	('increased', 'PosReg', (57, 66))	('acid aspartate increased', 'Phenotype', 'HP:0500159', (42, 66))
65593	31888244	In contrast, cells transduced with IDH1wt had significantly reduced citrate and isocitrate levels, while the alpha-KG levels were increased compared to the empty vector control cells (Figure 1b).	('IDH1wt', 'Var', (35, 41))	('isocitrate', 'Chemical', 'MESH:D007523', (80, 90))	('alpha-KG levels', 'MPA', (109, 124))	('citrate', 'Chemical', 'MESH:C102006', (68, 75))	('alpha-KG', 'Chemical', 'MESH:D020410', (109, 117))	('reduced', 'NegReg', (60, 67))	('citrate', 'Chemical', 'MESH:C102006', (83, 90))	('isocitrate levels', 'MPA', (80, 97))	('increased', 'PosReg', (130, 139))	('citrate', 'MPA', (68, 75))
65595	31888244	This indicates that IDH1R132H affects cell metabolism due to either the insufficient conversion of isocitrate to alpha-KG or the persistent consumption of alpha-KG for 2-HG production, independent of the 2-HG-level elevation.	('isocitrate', 'Chemical', 'MESH:D007523', (99, 109))	('cell metabolism', 'MPA', (38, 53))	('alpha-KG', 'Chemical', 'MESH:D020410', (113, 121))	('affects', 'Reg', (30, 37))	('insufficient', 'NegReg', (72, 84))	('IDH1R132H', 'Var', (20, 29))	('alpha-KG', 'Chemical', 'MESH:D020410', (155, 163))	('consumption', 'MPA', (140, 151))	('conversion of isocitrate', 'MPA', (85, 109))
65596	31888244	Glioma patients with IDH1 mutations have a longer overall survival and show a better response to treatment; the reasons for this are still unclear.	('longer', 'PosReg', (43, 49))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('mutations', 'Var', (26, 35))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('overall', 'MPA', (50, 57))	('IDH1', 'Gene', (21, 25))	('Glioma', 'Disease', (0, 6))	('patients', 'Species', '9606', (7, 15))
65598	31888244	In contrast to the U87-MG cell line model, the HT7606-IDH1R132H and SVGp12-IDH1R132H cells showed a significant decrease in viability in vitro compared to both their empty-vector and IDH1wt counterparts (Figure 2a).	('HT7606-IDH1R132H', 'Var', (47, 63))	('R132H', 'Mutation', 'rs121913500', (79, 84))	('decrease', 'NegReg', (112, 120))	('R132H', 'Mutation', 'rs121913500', (58, 63))	('HT7606', 'CellLine', 'CVCL:1290', (47, 53))	('SVGp12-IDH1R132H', 'Var', (68, 84))	('viability', 'CPA', (124, 133))
65599	31888244	However, the colony formation capacity was either unaltered (SVGp12 IDH1R132H vs. empty vector: 2.1% +- 0.1 vs. 3.4% +- 1.9, p = 0.31, t-Test) or enhanced in HT7606-IDH1R132H compared to the empty vector cells (14.8% +- 4.2 vs. 6.0% +- 1.4; p < 0.05, t-Test) (Figure 2c), implying that the observed reduction in the cell number and viability in IDH1 mutated cells might indeed be due to reduced proliferation.	('IDH1', 'Gene', (345, 349))	('HT7606-IDH1R132H', 'Var', (158, 174))	('colony formation capacity', 'CPA', (13, 38))	('cell number', 'CPA', (316, 327))	('enhanced', 'PosReg', (146, 154))	('HT7606', 'CellLine', 'CVCL:1290', (158, 164))	('mutated', 'Var', (350, 357))	('reduced', 'NegReg', (387, 394))	('reduction', 'NegReg', (299, 308))	('viability', 'CPA', (332, 341))
65601	31888244	There was no difference in proliferation of U87-MG-IDH1R132H compared to IDH1wt cells in 2-D culture growth; however, the colony forming capacity was also increased in the U87-MG-IDH1R132H compared to the empty-vector control (10.8% +- 0.6 vs. 8.0% +- 0.1; p < 0.05 using t-Test) (Figure 2c).	('colony forming capacity', 'CPA', (122, 145))	('increased', 'PosReg', (155, 164))	('R132H', 'Mutation', 'rs121913500', (55, 60))	('U87-MG-IDH1R132H', 'Var', (172, 188))	('R132H', 'Mutation', 'rs121913500', (183, 188))
65605	31888244	However, monitoring the spheroid volume as function of time revealed critically reduced volume growth kinetics of the U87-MG-IDH1R132H spheroids (Figure 2d), indicating that the IDH1R132H indeed inhibits growth even in the U87-MG cell line model, but this only manifests in a 3-D environment.	('growth', 'MPA', (204, 210))	('inhibits', 'NegReg', (195, 203))	('R132H', 'Mutation', 'rs121913500', (182, 187))	('reduced', 'NegReg', (80, 87))	('IDH1R132H', 'Var', (178, 187))	('volume growth kinetics', 'MPA', (88, 110))	('R132H', 'Mutation', 'rs121913500', (129, 134))
65606	31888244	Clonogenic survival assays showed that the tumor cell lines were intrinsically more radio-resistant than the immortalized astrocytes, with U87-MG exhibiting the lowest radio-sensitivity (Figure 2e).	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('U87-MG', 'Var', (139, 145))
65607	31888244	Transduction with mutant IDH1 led to a reproducible and significant radio-sensitization in the glioblastoma cell line U87-MG and astrocytes SVGp12 (p < 0.001) (Figure 2e), while the survival curves of vector control and IDH-mutated patient derived cell line HT7606 did not systematically differ.	('IDH', 'Gene', (220, 223))	('glioblastoma', 'Disease', (95, 107))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('IDH', 'Gene', '3417', (220, 223))	('mutant', 'Var', (18, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('patient', 'Species', '9606', (232, 239))	('radio-sensitization', 'MPA', (68, 87))	('HT7606', 'CellLine', 'CVCL:1290', (258, 264))
65608	31888244	Nonetheless, a clearly reduced clonogenic survival was also observed in the latter upon IDH1R132H transduction for the high radiation doses of 10 Gy.	('reduced', 'NegReg', (23, 30))	('IDH1R132H transduction', 'Var', (88, 110))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('clonogenic survival', 'CPA', (31, 50))
65609	31888244	In addition to the abolishment of the enzyme's wildtype function of generating alpha-KG and providing NADPH, IDH1R132H consumes NADPH to generate 2-HG.	('NADPH', 'Gene', (102, 107))	('R132H', 'Mutation', 'rs121913500', (113, 118))	('NADPH', 'Gene', '1666', (102, 107))	('IDH1R132H', 'Var', (109, 118))	('alpha-KG', 'Chemical', 'MESH:D020410', (79, 87))	('alpha-KG', 'MPA', (79, 87))	('NADPH', 'Gene', (128, 133))	('NADPH', 'Gene', '1666', (128, 133))
65610	31888244	In our cell line panel, the basal levels of NADPH and total NADP (NADPt = NADP+ + NADPH) were highest in HT7606; U87-MG and SVGp12 exhibited similar amounts of NADPH (Supplementary Figure S2).	('NADPH', 'Gene', (44, 49))	('HT7606; U87-MG', 'Var', (105, 119))	('NADP', 'MPA', (60, 64))	('NADPH', 'Gene', '1666', (160, 165))	('U87-MG', 'Var', (113, 119))	('NADPH', 'Gene', (82, 87))	('NADPH', 'Gene', '1666', (44, 49))	('NADP', 'Chemical', 'MESH:D009249', (66, 70))	('NADPt', 'Chemical', 'None', (66, 71))	('NADPH', 'Gene', '1666', (82, 87))	('NADP', 'Chemical', 'MESH:D009249', (160, 164))	('HT7606', 'CellLine', 'CVCL:1290', (105, 111))	('NADP', 'Chemical', 'MESH:D009249', (74, 78))	('NADP', 'Chemical', 'MESH:D009249', (60, 64))	('NADP', 'Chemical', 'MESH:D009249', (44, 48))	('NADP+', 'Chemical', 'MESH:D009249', (74, 79))	('NADP', 'Chemical', 'MESH:D009249', (82, 86))	('NADPH', 'Gene', (160, 165))
65611	31888244	We found significantly lower NADPH levels in U87-MG-IDH1R132H and HT7606-IDH1R132H compared to the empty vector control cells (Figure 3a).	('HT7606', 'CellLine', 'CVCL:1290', (66, 72))	('U87-MG-IDH1R132H', 'Var', (45, 61))	('R132H', 'Mutation', 'rs121913500', (56, 61))	('HT7606-IDH1R132H', 'Var', (66, 82))	('NADPH', 'Gene', (29, 34))	('R132H', 'Mutation', 'rs121913500', (77, 82))	('lower', 'NegReg', (23, 28))	('NADPH', 'Gene', '1666', (29, 34))
65612	31888244	In contrast, the astrocytes displayed increased intracellular NADPH levels upon IDH1R132H transduction.	('increased intracellular NADPH', 'Phenotype', 'HP:0003575', (38, 67))	('NADPH', 'Gene', (62, 67))	('NADPH', 'Gene', '1666', (62, 67))	('IDH1R132H transduction', 'Var', (80, 102))	('increased', 'PosReg', (38, 47))
65615	31888244	The unexpected increase in NADPH levels in the astrocytes expressing IDH1R132H relates to an overall higher intracellular NADPt pool in these cells (Figure 3a).	('NADPt', 'Chemical', 'None', (122, 127))	('higher', 'PosReg', (101, 107))	('increase', 'PosReg', (15, 23))	('NADPH', 'Gene', (27, 32))	('intracellular NADPt pool', 'MPA', (108, 132))	('NADPH', 'Gene', '1666', (27, 32))	('IDH1R132H', 'Var', (69, 78))
65616	31888244	In contrast, U87-MG and HT7606 showed a decrease in NADPt concentrations upon transduction with IDH1R132H.	('decrease', 'NegReg', (40, 48))	('U87-MG', 'Var', (13, 19))	('HT7606', 'Var', (24, 30))	('NADPt', 'Chemical', 'None', (52, 57))	('NADPt concentrations', 'MPA', (52, 72))	('IDH1R132H', 'Var', (96, 105))	('HT7606', 'CellLine', 'CVCL:1290', (24, 30))
65617	31888244	These findings indicate that IDH1R132H can have different effects on NADPt pools in non-neoplastic and neoplastic cells.	('IDH1R132H', 'Var', (29, 38))	('effects', 'Reg', (58, 65))	('NADPt', 'Chemical', 'None', (69, 74))	('R132H', 'Mutation', 'rs121913500', (33, 38))	('NADPt pools', 'MPA', (69, 80))
65620	31888244	Indeed, a significant drop in NAD+ and NADt concentrations in HT7606-IDH1R132H and U87-MG-IDH1R132H was seen compared to the respective empty vector control cells (Figure 3b).	('NADt concentrations', 'MPA', (39, 58))	('U87-MG-IDH1R132H', 'Var', (83, 99))	('HT7606-IDH1R132H', 'Var', (62, 78))	('NAD', 'Chemical', 'MESH:D009243', (30, 33))	('NAD', 'Chemical', 'MESH:D009243', (39, 42))	('NADt', 'Chemical', 'None', (39, 43))	('HT7606', 'CellLine', 'CVCL:1290', (62, 68))	('NAD+', 'MPA', (30, 34))	('drop', 'NegReg', (22, 26))
65621	31888244	In contrast, astrocytes with and without IDH1R132H retain relatively stable levels of NAD+ and NADt.	('NADt', 'MPA', (95, 99))	('NAD', 'Chemical', 'MESH:D009243', (86, 89))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('NAD+', 'MPA', (86, 90))	('IDH1R132H', 'Var', (41, 50))	('NAD', 'Chemical', 'MESH:D009243', (95, 98))	('NADt', 'Chemical', 'None', (95, 99))
65631	31888244	Besides, the three cell lines neither expressed 3-HAO nor the NAPRT protein, irrespective of their IDH1 mutation status or exposure to 2-HG (Figure 4b and Supplementary Figure S6).	('NAPRT', 'Gene', '93100', (62, 67))	('3-HAO', 'Gene', (48, 53))	('NAPRT', 'Gene', (62, 67))	('3-HAO', 'Gene', '23498', (48, 53))	('mutation', 'Var', (104, 112))	('IDH1', 'Gene', (99, 103))
65634	31888244	While the NAMPT protein levels were strongly reduced in U87-MG-IDH1R132H compared to the empty vector controls, transduction with IDH1R132H led to increased NAMPT protein levels in the astrocytes SVGp12 (Figure 4b,d and Supplementary Figure S6).	('R132H', 'Mutation', 'rs121913500', (67, 72))	('reduced', 'NegReg', (45, 52))	('increased', 'PosReg', (147, 156))	('IDH1R132H', 'Var', (130, 139))	('NAMPT', 'Gene', '10135', (157, 162))	('R132H', 'Mutation', 'rs121913500', (134, 139))	('NAMPT', 'Gene', (157, 162))	('NAMPT', 'Gene', '10135', (10, 15))	('U87-MG-IDH1R132H', 'Var', (56, 72))	('NAMPT', 'Gene', (10, 15))
65635	31888244	However, the NAMPT levels in SVGp12-IDH1R132H were still below the NAMPT levels seen in the glioblastoma cells with and without IDH1 mutation (Supplementary Figures S3 and S4).	('mutation', 'Var', (133, 141))	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('SVGp12-IDH1R132H', 'Var', (29, 45))	('NAMPT', 'Gene', '10135', (67, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('NAMPT', 'Gene', (67, 72))	('NAMPT', 'Gene', '10135', (13, 18))	('NAMPT', 'Gene', (13, 18))	('IDH1', 'Gene', (128, 132))	('R132H', 'Mutation', 'rs121913500', (40, 45))
65637	31888244	In HT7606, the NAMPT levels did not change upon transduction with IDH1R132H.	('HT7606', 'CellLine', 'CVCL:1290', (3, 9))	('NAMPT', 'Gene', (15, 20))	('NAMPT', 'Gene', '10135', (15, 20))	('HT7606', 'Var', (3, 9))
65638	31888244	The NMRK1 protein expression was not influenced by IDH1R132H in any of the cell models (Figure 4b and Supplementary Figures S3 and S6).	('NMRK1', 'Gene', '54981', (4, 9))	('IDH1R132H', 'Var', (51, 60))	('NMRK1', 'Gene', (4, 9))	('protein', 'Protein', (10, 17))
65639	31888244	We further investigated the expression of NAD-synthesis enzymes in a very rare cohort of three patient-derived IDH1-mutant glioma cell models that have native homozygous IDH1R132H and additionally five patient-derived glioblastoma cell lines with IDH1-wildtype status.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('NAD', 'Chemical', 'MESH:D009243', (42, 45))	('glioblastoma', 'Disease', (218, 230))	('patient', 'Species', '9606', (95, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('IDH1-mutant', 'Gene', (111, 122))	('patient', 'Species', '9606', (202, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('glioma', 'Disease', (123, 129))	('IDH1-mutant', 'Var', (111, 122))
65644	31888244	Moreover, the IDH1-mutant cells had overall lower protein levels of NAMPT compared to IDH1-wildtype glioblastoma cells (Figure 4c and Supplementary Figure S6).	('lower', 'NegReg', (44, 49))	('IDH1-wildtype glioblastoma', 'Disease', (86, 112))	('protein levels', 'MPA', (50, 64))	('NAMPT', 'Gene', '10135', (68, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('IDH1-mutant', 'Var', (14, 25))	('IDH1-wildtype glioblastoma', 'Disease', 'MESH:D005909', (86, 112))	('NAMPT', 'Gene', (68, 73))
65649	31888244	NMRK1 was equally expressed in both the IDH1-wildtype as well as in the IDH1R132H PDX tissues, and the QPRT expression was low in these PDX models.	('low', 'NegReg', (123, 126))	('QPRT', 'Gene', (103, 107))	('PDX', 'Chemical', 'MESH:C113421', (82, 85))	('IDH1R132H', 'Var', (72, 81))	('NMRK1', 'Gene', (0, 5))	('NMRK1', 'Gene', '54981', (0, 5))	('PDX', 'Chemical', 'MESH:C113421', (136, 139))	('QPRT', 'Gene', '23475', (103, 107))
65650	31888244	Similarly to what we observed in vitro, the PDX with the IDH1R132H mutation had lower protein levels of NAMPT compared to the IDH1-wildtype glioblastoma (Figure 4c and Supplementary Figure S6).	('NAMPT', 'Gene', '10135', (104, 109))	('protein levels', 'MPA', (86, 100))	('NAMPT', 'Gene', (104, 109))	('IDH1-wildtype glioblastoma', 'Disease', 'MESH:D005909', (126, 152))	('PDX', 'Chemical', 'MESH:C113421', (44, 47))	('lower', 'NegReg', (80, 85))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('IDH1-wildtype glioblastoma', 'Disease', (126, 152))	('IDH1R132H mutation', 'Var', (57, 75))
65651	31888244	We next validated our findings in publicly available The Cancer Genome Atlas (TCGA) datasets from primary glioblastoma and low-grade astrocytoma tissues and confirmed that NAMPT, QPRT, and NMRK1 were significantly higher expressed in IDH1-wildtype primary glioblastomas compared to IDH1-mutant astrocytomas WHO grade II and III (Wilcoxon rank sum tests: p-values ranging from 5.6 x 10-12 for NMRK1 to 1.2 x 10-32 for NAMPT), while NAPRT was equally expressed (Figure 4g and Supplementary Figure S5).	('NAPRT', 'Gene', (431, 436))	('higher', 'PosReg', (214, 220))	('astrocytomas', 'Disease', (294, 306))	('astrocytoma tissues', 'Disease', (133, 152))	('NAMPT', 'Gene', '10135', (172, 177))	('NMRK1', 'Gene', (189, 194))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NMRK1', 'Gene', '54981', (392, 397))	('QPRT', 'Gene', (179, 183))	('NAMPT', 'Gene', '10135', (417, 422))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('astrocytomas', 'Disease', 'MESH:D001254', (294, 306))	('NAMPT', 'Gene', (172, 177))	('primary glioblastomas', 'Disease', (248, 269))	('astrocytoma', 'Phenotype', 'HP:0009592', (294, 305))	('IDH1-wildtype', 'Var', (234, 247))	('NMRK1', 'Gene', (392, 397))	('glioblastomas', 'Phenotype', 'HP:0012174', (256, 269))	('glioblastoma', 'Disease', (106, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (256, 268))	('astrocytoma tissues', 'Disease', 'MESH:D001254', (133, 152))	('NAMPT', 'Gene', (417, 422))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('NAPRT', 'Gene', '93100', (431, 436))	('primary glioblastomas', 'Disease', 'MESH:D005909', (248, 269))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('glioblastoma', 'Disease', (256, 268))	('glioblastoma', 'Phenotype', 'HP:0012174', (256, 268))	('QPRT', 'Gene', '23475', (179, 183))	('NMRK1', 'Gene', '54981', (189, 194))
65652	31888244	Here, we demonstrate that IDH1R132H has 2-HG independent effects on metabolism, redox state and energy homeostasis, as well as on proliferation.	('effects', 'Reg', (57, 64))	('IDH1R132H', 'Var', (26, 35))	('energy homeostasis', 'MPA', (96, 114))	('proliferation', 'CPA', (130, 143))	('metabolism', 'MPA', (68, 78))	('R132H', 'Mutation', 'rs121913500', (30, 35))	('redox state', 'MPA', (80, 91))
65653	31888244	In addition, we show for the first time a different impact of IDH1R132H on NADPH and NAD+ levels in glioma cells and astrocytes, suggesting a cell-type- or cancer-stage-dependent effect of the mutation.	('glioma', 'Disease', (100, 106))	('NADPH', 'Gene', '1666', (75, 80))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('NAD', 'Chemical', 'MESH:D009243', (85, 88))	('IDH1R132H', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('NAD', 'Chemical', 'MESH:D009243', (75, 78))	('NADPH', 'Gene', (75, 80))
65654	31888244	Importantly, the IDH1R132H mutation influenced the expression of the NAD-synthesis-associated enzyme NAMPT differently in the glioma cells and astrocytes, supporting the hypothesis that the IDH1 mutation differentially affects cells during tumorigenesis.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('NAMPT', 'Gene', '10135', (101, 106))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumor', 'Disease', (240, 245))	('NAMPT', 'Gene', (101, 106))	('NAD', 'Chemical', 'MESH:D009243', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('mutation', 'Var', (27, 35))	('influenced', 'Reg', (36, 46))	('expression', 'MPA', (51, 61))	('IDH1R132H', 'Gene', (17, 26))	('glioma', 'Disease', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
65655	31888244	The concentrations of TCA cycle metabolites downstream of isocitrate (alpha-KG, succinate, fumarate, and malate) dropped in glioma cells and immortalized astrocytes upon transduction with IDH1R132H.	('fumarate', 'Chemical', 'MESH:D005650', (91, 99))	('R132H', 'Mutation', 'rs121913500', (192, 197))	('TCA cycle', 'Enzyme', (22, 31))	('concentrations', 'MPA', (4, 18))	('dropped', 'NegReg', (113, 120))	('glioma', 'Disease', (124, 130))	('malate', 'MPA', (105, 111))	('fumarate', 'MPA', (91, 99))	('succinate', 'Chemical', 'MESH:D013386', (80, 89))	('isocitrate', 'Chemical', 'MESH:D007523', (58, 68))	('IDH1R132H', 'Var', (188, 197))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('malate', 'Chemical', 'MESH:D008293', (105, 111))	('TCA', 'Chemical', 'MESH:C000589078', (22, 25))	('succinate', 'MPA', (80, 89))	('alpha-KG', 'Chemical', 'MESH:D020410', (70, 78))
65656	31888244	While there is one in vivo study reporting no change in TCA cycle metabolites in tissues from IDH1-mutant gliomas compared to wildtype tumors, our results are in line with other in vitro data and a recently published in vivo study showing that TCA metabolites were reduced in IDH1-mutant patient-derived xenografts and in human glioma tissues.	('patient', 'Species', '9606', (288, 295))	('reduced', 'NegReg', (265, 272))	('IDH1-mutant', 'Gene', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH1-mutant', 'Gene', (276, 287))	('TCA', 'Chemical', 'MESH:C000589078', (244, 247))	('tumors', 'Disease', (135, 141))	('TCA cycle metabolites', 'MPA', (56, 77))	('IDH1-mutant', 'Var', (94, 105))	('TCA metabolites', 'MPA', (244, 259))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('glioma', 'Disease', (328, 334))	('glioma', 'Disease', (106, 112))	('gliomas', 'Disease', (106, 113))	('glioma', 'Disease', 'MESH:D005910', (328, 334))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('human', 'Species', '9606', (322, 327))	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('TCA', 'Chemical', 'MESH:C000589078', (56, 59))
65657	31888244	In line with the previous studies, all of our cell models showed significantly reduced glutamate levels upon transduction with IDH1R132H.	('reduced', 'NegReg', (79, 86))	('glutamate', 'Chemical', 'None', (87, 96))	('IDH1R132H', 'Var', (127, 136))	('R132H', 'Mutation', 'rs121913500', (131, 136))	('glutamate levels', 'MPA', (87, 103))	('reduced glutamate levels', 'Phenotype', 'HP:0500150', (79, 103))
65663	31888244	Interestingly, in addition to the drop in glutamate levels, we observed enhanced levels of aspartate in all our cell models upon transduction with IDH1R132H, which to the best of our knowledge has not been described before.	('aspartate', 'Chemical', 'None', (91, 100))	('levels of aspartate', 'MPA', (81, 100))	('drop in glutamate levels', 'Phenotype', 'HP:0500150', (34, 58))	('glutamate', 'Chemical', 'None', (42, 51))	('enhanced levels of aspartate', 'Phenotype', 'HP:0500159', (72, 100))	('enhanced', 'PosReg', (72, 80))	('IDH1R132H', 'Var', (147, 156))	('glutamate levels', 'MPA', (42, 58))
65665	31888244	The addition of 2-HG alone did not affect TCA cycle metabolite or glutamate levels, underlining that the alteration of TCA cycle metabolites is a direct effect of the changed enzymatic function of IDH1R132H.	('TCA', 'Chemical', 'MESH:C000589078', (119, 122))	('IDH1R132H', 'Var', (197, 206))	('alteration', 'Reg', (105, 115))	('TCA', 'Chemical', 'MESH:C000589078', (42, 45))	('glutamate', 'Chemical', 'None', (66, 75))	('TCA cycle metabolite', 'MPA', (42, 62))	('changed', 'Reg', (167, 174))	('glutamate levels', 'MPA', (66, 82))
65666	31888244	The TCA cycle has been implicated as a potential therapeutic target in IDH1-mutant gliomas and our observation that the TCA cycle is compromised in IDH1R132H cells supports this possibility.	('compromised', 'NegReg', (133, 144))	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('IDH1-mutant', 'Var', (71, 82))	('gliomas', 'Disease', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('TCA', 'Chemical', 'MESH:C000589078', (120, 123))	('TCA', 'Chemical', 'MESH:C000589078', (4, 7))	('R132H', 'Mutation', 'rs121913500', (152, 157))	('IDH1-mutant', 'Gene', (71, 82))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH1R132H', 'Var', (148, 157))
65667	31888244	Altered metabolism in IDH1-mutant tumors can also be used for diagnostic purposes: high levels of 2-HG or decreased levels of glutamate can be detected using in vivo magnetic resonance spectroscopy (MRS).	('decreased', 'NegReg', (106, 115))	('MRS', 'Disease', 'MESH:D008556', (199, 202))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('IDH1-mutant', 'Var', (22, 33))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('glutamate', 'Chemical', 'None', (126, 135))	('IDH1-mutant', 'Gene', (22, 33))	('MRS', 'Disease', (199, 202))	('levels of glutamate', 'MPA', (116, 135))	('2-HG', 'MPA', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('decreased levels of glutamate', 'Phenotype', 'HP:0500150', (106, 135))
65668	31888244	IDH1 mutation but not 2-HG alone led to decreased cell growth in glioblastoma cells as well as astrocytes in vitro.	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('astrocytes', 'CPA', (95, 105))	('glioblastoma', 'Disease', (65, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('IDH1', 'Gene', (0, 4))	('decreased', 'NegReg', (40, 49))	('mutation', 'Var', (5, 13))
65669	31888244	A reduced proliferation rate upon transduction with mutant IDH1 has been reported in glioblastoma cells before, but our results suggest that this is independent of 2-HG accumulation.	('mutant', 'Var', (52, 58))	('glioblastoma', 'Disease', (85, 97))	('reduced', 'NegReg', (2, 9))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('IDH1', 'Gene', (59, 63))	('proliferation rate', 'CPA', (10, 28))
65670	31888244	Since all cell lines showed decreased TCA cycle metabolite concentrations upon IDH1R132H transduction, one could speculate that the growth inhibition is mechanistically related to the impaired central carbon metabolism.	('decreased', 'NegReg', (28, 37))	('IDH1R132H transduction', 'Var', (79, 101))	('R132H', 'Mutation', 'rs121913500', (83, 88))	('TCA', 'Chemical', 'MESH:C000589078', (38, 41))	('TCA cycle metabolite concentrations', 'MPA', (38, 73))	('carbon', 'Chemical', 'MESH:D002244', (201, 207))
65671	31888244	Interestingly, in spite of the overall growth reduction, the colony forming capacity was enhanced in the IDH1R132H glioblastoma cell lines, indicating that the IDH1 mutation improves clonogenic survival, which might promote tumorigenesis.	('colony forming capacity', 'CPA', (61, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('enhanced', 'PosReg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('IDH1', 'Gene', (160, 164))	('improves', 'PosReg', (174, 182))	('tumor', 'Disease', (224, 229))	('mutation', 'Var', (165, 173))	('clonogenic survival', 'CPA', (183, 202))	('promote', 'PosReg', (216, 223))	('glioblastoma', 'Disease', (115, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
65674	31888244	Also other in vitro studies showed that over-expressing IDH1R132H led to a better response to radiation in glioma cell lines due to increased oxidative stress while IDH1R132H inhibition increased radio-resistance in cancer cell lines.	('radio-resistance', 'CPA', (196, 212))	('better', 'PosReg', (75, 81))	('oxidative stress', 'MPA', (142, 158))	('response to radiation', 'MPA', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('increased', 'PosReg', (186, 195))	('IDH1R132H', 'Var', (165, 174))	('over-expressing', 'PosReg', (40, 55))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('increased', 'PosReg', (132, 141))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('IDH1R132H', 'Var', (56, 65))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (132, 158))	('glioma', 'Disease', (107, 113))
65675	31888244	In addition, silencing IDH1 in glioblastoma cells improved responses to radiotherapy.	('IDH1', 'Gene', (23, 27))	('glioblastoma', 'Disease', (31, 43))	('improved', 'PosReg', (50, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('responses to radiotherapy', 'CPA', (59, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('silencing', 'Var', (13, 22))
65677	31888244	It has been hypothesized that lower NADPH concentrations lead to decreased GSH levels and increased reactive oxygen species (ROS), and therefore more radiation induced DNA double-strand breaks in IDH1-mutant glioma cells.	('oxygen', 'Chemical', 'MESH:D010100', (109, 115))	('NADPH', 'Gene', (36, 41))	('NADPH', 'Gene', '1666', (36, 41))	('glioma', 'Disease', (208, 214))	('increased', 'PosReg', (90, 99))	('decreased', 'NegReg', (65, 74))	('IDH1-mutant', 'Var', (196, 207))	('GSH levels', 'MPA', (75, 85))	('DNA double-strand breaks', 'MPA', (168, 192))	('GSH', 'Chemical', 'MESH:D005978', (75, 78))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('IDH1-mutant', 'Gene', (196, 207))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (90, 123))	('more', 'PosReg', (145, 149))
65678	31888244	A recent study in IDH1-mutant patient-derived xenograft models demonstrated that GSH levels were maintained despite altered NADPH/NADP+ ratios, but other compensatory pathways for GSH synthesis appeared to be induced.	('NADP+', 'Chemical', 'MESH:D009249', (130, 135))	('IDH1-mutant', 'Gene', (18, 29))	('patient', 'Species', '9606', (30, 37))	('GSH', 'Chemical', 'MESH:D005978', (180, 183))	('GSH levels', 'MPA', (81, 91))	('NADPH', 'Gene', (124, 129))	('GSH', 'Chemical', 'MESH:D005978', (81, 84))	('NADPH', 'Gene', '1666', (124, 129))	('IDH1-mutant', 'Var', (18, 29))
65679	31888244	We found that astrocytes also displayed enhanced radio-sensitivity upon IDH1R132H-transduction, although they maintained stable NADPH levels, indicating that there might be additional mechanisms involved in IDH1-associated radio-sensitization, which still need to be elucidated.	('radio-sensitivity', 'MPA', (49, 66))	('IDH1R132H-transduction', 'Var', (72, 94))	('NADPH', 'Gene', (128, 133))	('enhanced', 'PosReg', (40, 48))	('NADPH', 'Gene', '1666', (128, 133))
65681	31888244	The neomorphic enzymatic function of IDH1R132H on the other hand leads to reduction of NADPH to NADP+.	('IDH1R132H', 'Var', (37, 46))	('NADPH', 'Gene', (87, 92))	('reduction', 'NegReg', (74, 83))	('NADP+', 'Chemical', 'MESH:D009249', (96, 101))	('NADPH', 'Gene', '1666', (87, 92))
65682	31888244	Accordingly, we observed a shift in the NADPH/NADPt ratio in IDH1-mutant glial cells and tumor cells towards NADP+.	('NADP+', 'Chemical', 'MESH:D009249', (109, 114))	('IDH1-mutant', 'Var', (61, 72))	('NADPH', 'Gene', '1666', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('shift', 'Reg', (27, 32))	('IDH1-mutant', 'Gene', (61, 72))	('NADPt', 'Chemical', 'None', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('NADPH', 'Gene', (40, 45))
65683	31888244	However, while this was accompanied by a significant drop in absolute NAPDH levels in tumor cells, IDH1R132H transduced astrocytes retained stable NADPH levels due to a compensatory increase in the total NADP pool.	('increase', 'PosReg', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('NADPH', 'Gene', (147, 152))	('IDH1R132H transduced', 'Var', (99, 119))	('tumor', 'Disease', (86, 91))	('NADP', 'Chemical', 'MESH:D009249', (147, 151))	('NADPH', 'Gene', '1666', (147, 152))	('NADP pool', 'MPA', (204, 213))	('NADP', 'Chemical', 'MESH:D009249', (204, 208))	('drop', 'NegReg', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('NAPDH levels', 'MPA', (70, 82))
65685	31888244	We therefore hypothesized that IDH1R132H-mediated NADPH loss leads to increased NADK activity and NAD+ consumption.	('NADPH', 'Gene', '1666', (50, 55))	('NADK', 'Gene', (80, 84))	('loss', 'NegReg', (56, 60))	('increased', 'PosReg', (70, 79))	('NAD+ consumption', 'CPA', (98, 114))	('NADK', 'Gene', '65220', (80, 84))	('NAD', 'Chemical', 'MESH:D009243', (80, 83))	('NAD', 'Chemical', 'MESH:D009243', (50, 53))	('NAD', 'Chemical', 'MESH:D009243', (98, 101))	('IDH1R132H-mediated', 'Var', (31, 49))	('NADPH', 'Gene', (50, 55))
65686	31888244	Indeed, we observed a significant drop in NAD+ levels and in the enzymatic activity of NAD+-dependent sirtuins upon IDH1R132H transduction in glioblastoma cells, supporting this theory.	('NAD', 'Chemical', 'MESH:D009243', (42, 45))	('drop', 'NegReg', (34, 38))	('NAD+-dependent sirtuins', 'Enzyme', (87, 110))	('enzymatic activity', 'MPA', (65, 83))	('NAD', 'Chemical', 'MESH:D009243', (87, 90))	('NAD+ levels', 'MPA', (42, 53))	('glioblastoma', 'Disease', (142, 154))	('glioblastoma', 'Disease', 'MESH:D005909', (142, 154))	('IDH1R132H transduction', 'Var', (116, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
65687	31888244	However, non-neoplastic astrocytes were able to retain stable NAD+ levels upon transduction with IDH1R132H.	('neoplastic astrocytes', 'Phenotype', 'HP:0009592', (13, 34))	('NAD', 'Chemical', 'MESH:D009243', (62, 65))	('IDH1R132H', 'Var', (97, 106))	('NAD+ levels', 'MPA', (62, 73))
65692	31888244	Interestingly, transduction with IDH1R132H led to an increased NAMPT expression in non-neoplastic astrocytes, which had overall low NAMPT levels compared to glioblastoma cells.	('glioblastoma', 'Disease', (157, 169))	('NAMPT', 'Gene', '10135', (132, 137))	('neoplastic astrocytes', 'Phenotype', 'HP:0009592', (87, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('NAMPT', 'Gene', (132, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('increased', 'PosReg', (53, 62))	('NAMPT', 'Gene', '10135', (63, 68))	('R132H', 'Mutation', 'rs121913500', (37, 42))	('IDH1R132H', 'Var', (33, 42))	('NAMPT', 'Gene', (63, 68))
65693	31888244	We therefore conclude that in non-neoplastic cells, NAD+-biosynthesis via NAMPT is induced to compensate for the increased NADPH consumption due to IDH1R132H and is sufficient to maintain NAD+ homeostasis while increasing the total NADP pool (Figure 5).	('NADP pool', 'MPA', (232, 241))	('NAD', 'Chemical', 'MESH:D009243', (188, 191))	('increasing', 'PosReg', (211, 221))	('NAMPT', 'Gene', '10135', (74, 79))	('NADPH', 'Gene', (123, 128))	('NAD+-biosynthesis', 'MPA', (52, 69))	('NAD', 'Chemical', 'MESH:D009243', (52, 55))	('NAMPT', 'Gene', (74, 79))	('NADPH', 'Gene', '1666', (123, 128))	('NAD', 'Chemical', 'MESH:D009243', (232, 235))	('NADP', 'Chemical', 'MESH:D009249', (232, 236))	('increased', 'PosReg', (113, 122))	('IDH1R132H', 'Var', (148, 157))	('NADP', 'Chemical', 'MESH:D009249', (123, 127))	('maintain', 'Reg', (179, 187))	('NAD', 'Chemical', 'MESH:D009243', (123, 126))	('NAD+ homeostasis', 'MPA', (188, 204))
65695	31888244	This might explain why glioblastoma cells were not able to compensate for the IDH1R132H-mediated metabolic changes, leading to the observed drop in NAD+ and NADPH in tumor cells.	('drop', 'NegReg', (140, 144))	('NAD', 'Chemical', 'MESH:D009243', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('NADPH', 'Gene', '1666', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('NAD+', 'MPA', (148, 152))	('tumor', 'Disease', (166, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('NAD', 'Chemical', 'MESH:D009243', (148, 151))	('IDH1R132H-mediated', 'Var', (78, 96))	('glioblastoma', 'Disease', (23, 35))	('R132H', 'Mutation', 'rs121913500', (82, 87))	('NADPH', 'Gene', (157, 162))
65697	31888244	A drop in NAD+ concentrations has recently been described in IDH1R132H xenograft-derived cells.	('NAD', 'Chemical', 'MESH:D009243', (10, 13))	('IDH1R132H', 'Var', (61, 70))	('drop', 'NegReg', (2, 6))	('NAD+ concentrations', 'MPA', (10, 29))
65698	31888244	The authors hypothesized that this is caused by the downregulation of NAPRT due to hypermethylation.	('hypermethylation', 'Var', (83, 99))	('NAPRT', 'Gene', '93100', (70, 75))	('downregulation', 'NegReg', (52, 66))	('NAPRT', 'Gene', (70, 75))
65704	31888244	Although a previous study described how the malignant transformation in gliomas is associated with a switch in NAD-metabolism towards the de novo synthesis via QPRT, we found that QPRT was only expressed in U87-MG, but not in astrocytes or HT7606.	('U87-MG', 'Var', (207, 213))	('QPRT', 'Gene', '23475', (160, 164))	('QPRT', 'Gene', '23475', (180, 184))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('NAD', 'Chemical', 'MESH:D009243', (111, 114))	('associated', 'Reg', (83, 93))	('malignant transformation', 'CPA', (44, 68))	('QPRT', 'Gene', (160, 164))	('QPRT', 'Gene', (180, 184))	('NAD-metabolism', 'MPA', (111, 125))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))	('HT7606', 'CellLine', 'CVCL:1290', (240, 246))
65709	31888244	Therefore, the consumption of NADPH due to IDH1R132H in tumor cells and the drop in NAD+ levels, as well as the activity of sirtuins, might affect various processes and should be explored as a potential leverage point for new treatment strategies.	('NAD+ levels', 'MPA', (84, 95))	('NADPH', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('IDH1R132H', 'Var', (43, 52))	('NADPH', 'Gene', '1666', (30, 35))	('tumor', 'Disease', (56, 61))	('drop', 'NegReg', (76, 80))	('processes', 'MPA', (155, 164))	('affect', 'Reg', (140, 146))	('NAD', 'Chemical', 'MESH:D009243', (30, 33))	('NAD', 'Chemical', 'MESH:D009243', (84, 87))	('activity', 'MPA', (112, 120))	('R132H', 'Mutation', 'rs121913500', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
65710	31888244	Recently, it was shown that NAMPT inhibitors lead to vulnerability in IDH1 mutated brain cancer cells.	('NAMPT', 'Gene', (28, 33))	('vulnerability', 'MPA', (53, 66))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('mutated', 'Var', (75, 82))	('cancer', 'Disease', (89, 95))	('brain cancer', 'Phenotype', 'HP:0030692', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('NAMPT', 'Gene', '10135', (28, 33))	('IDH1', 'Gene', (70, 74))
65714	31888244	It is accepted that the IDH1 mutation occurs very early during gliomagenesis.	('mutation', 'Var', (29, 37))	('gliomagenesis', 'Disease', 'None', (63, 76))	('gliomagenesis', 'Disease', (63, 76))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', (24, 28))
65715	31888244	However, the observation that the IDH1 mutation impairs cell proliferation seems incompatible for a tumor-promoting event.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutation', 'Var', (39, 47))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cell proliferation', 'CPA', (56, 74))	('IDH1', 'Gene', (34, 38))	('impairs', 'NegReg', (48, 55))
65716	31888244	Our results show that IDH1 mutation-mediated effects on redox state and NAD+ homeostasis differ between astrocytes and highly proliferating tumor cells.	('effects', 'Reg', (45, 52))	('redox state', 'MPA', (56, 67))	('mutation-mediated', 'Var', (27, 44))	('NAD', 'Chemical', 'MESH:D009243', (72, 75))	('IDH1', 'Gene', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('NAD+ homeostasis', 'MPA', (72, 88))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
65726	31888244	Furthermore, we used RNA and protein from fresh frozen tumor tissue from patient-derived glioma xenografts (PDX) that were generated in NOD/Scid mice from an IDH1R132H glioma (E478 CR500 '26') and an IDH1wt glioma (P3 NC1293 '70').	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('PDX', 'Chemical', 'MESH:C113421', (108, 111))	('patient', 'Species', '9606', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	("E478 CR500 '26'", 'Var', (176, 191))	('glioma', 'Disease', (89, 95))	('glioma', 'Disease', (168, 174))	('NC1293', 'CellLine', 'CVCL:1874', (218, 224))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('glioma', 'Disease', (207, 213))	('mice', 'Species', '10090', (145, 149))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('R132H', 'Mutation', 'rs121913500', (162, 167))	('tumor', 'Disease', (55, 60))	('IDH1R132H', 'Var', (158, 167))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))
65729	31888244	One established cell line of glioblastoma origin (U87-MG), one primary patient-derived glioblastoma cell line (HT7606), and the immortalized astrocytes (SVGp12) were stably transduced with either IDH1R132H, IDH1wt, or a pHATtrick-puroR empty vector as previously described.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('HT7606', 'CellLine', 'CVCL:1290', (111, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('glioblastoma', 'Disease', (87, 99))	('IDH1R132H', 'Var', (196, 205))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('patient', 'Species', '9606', (71, 78))	('glioblastoma', 'Disease', (29, 41))
65751	31888244	In brief, the 3-D aggregation capacity of U87-MG and U87-MG-IDH1R132H was compared by seeding the defined cell concentrations into non-adherent 96-well plates coated with 1.5% agarose in DMEM.	('aggregation', 'MPA', (18, 29))	('U87-MG', 'Var', (42, 48))	('U87-MG-IDH1R132H', 'Var', (53, 69))	('R132H', 'Mutation', 'rs121913500', (64, 69))
65756	31888244	All of the considered astrocytoma samples were reported to have an IDH1/2 mutation.	('mutation', 'Var', (74, 82))	('IDH1/2', 'Gene', (67, 73))	('astrocytoma', 'Disease', 'MESH:D001254', (22, 33))	('astrocytoma', 'Disease', (22, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (22, 33))	('IDH1/2', 'Gene', '3417;3418', (67, 73))
65757	31888244	The vast majority of the glioblastoma samples were from patients with primary glioblastomas that lack IDH1/2 mutations.	('patients', 'Species', '9606', (56, 64))	('primary glioblastomas', 'Disease', 'MESH:D005909', (70, 91))	('glioblastoma', 'Disease', (78, 90))	('IDH1/2', 'Gene', '3417;3418', (102, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('primary glioblastomas', 'Disease', (70, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('glioblastoma', 'Disease', (25, 37))	('IDH1/2', 'Gene', (102, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (25, 37))	('mutations', 'Var', (109, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('glioblastomas', 'Phenotype', 'HP:0012174', (78, 91))
65760	31888244	Moreover, we found that cells depend on NAD+ to compensate for the IDH1R132H-mediated drop in NADPH and that IDH1R132H influences the expression of the NAD+ synthesizing enzyme NAMPT.	('R132H', 'Mutation', 'rs121913500', (113, 118))	('influences', 'Reg', (119, 129))	('expression', 'MPA', (134, 144))	('NAD', 'Chemical', 'MESH:D009243', (94, 97))	('NAMPT', 'Gene', '10135', (177, 182))	('IDH1R132H', 'Var', (109, 118))	('IDH1R132H-mediated', 'Var', (67, 85))	('NAD', 'Chemical', 'MESH:D009243', (152, 155))	('NAMPT', 'Gene', (177, 182))	('drop', 'NegReg', (86, 90))	('NAD', 'Chemical', 'MESH:D009243', (40, 43))	('NADPH', 'Gene', (94, 99))	('R132H', 'Mutation', 'rs121913500', (71, 76))	('NADPH', 'Gene', '1666', (94, 99))
65761	31888244	The impaired redox state and energy homeostasis evoked by the IDH mutation has the potential to serve as a therapeutic target in the future.	('mutation', 'Var', (66, 74))	('impaired', 'NegReg', (4, 12))	('IDH', 'Gene', '3417', (62, 65))	('IDH', 'Gene', (62, 65))
65770	28654422	ATRX (p=0.006), and TP53 (p=0.015) mutations were associated with increased PARP1 expression and PARP1 protein level correlated with ATRX loss and p53 overexpression.	('loss', 'NegReg', (138, 142))	('PARP1', 'Gene', '142', (97, 102))	('increased', 'PosReg', (66, 75))	('TP53', 'Gene', (20, 24))	('PARP1', 'Gene', '142', (76, 81))	('p53', 'Gene', (147, 150))	('PARP1', 'Gene', (97, 102))	('expression', 'MPA', (82, 92))	('ATRX', 'Gene', (0, 4))	('PARP1', 'Gene', (76, 81))	('protein level', 'MPA', (103, 116))	('ATRX', 'Gene', '546', (133, 137))	('p53', 'Gene', '7157', (147, 150))	('ATRX', 'Gene', (133, 137))	('ATRX', 'Gene', '546', (0, 4))	('overexpression', 'PosReg', (151, 165))	('TP53', 'Gene', '7157', (20, 24))	('mutations', 'Var', (35, 44))
65786	28654422	The identification of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations was a breakthrough in the field of GBM research.	('IDH2', 'Gene', '3418', (65, 69))	('citrate', 'Chemical', 'MESH:D019343', (25, 32))	('IDH1', 'Gene', '3417', (56, 60))	('mutations', 'Var', (71, 80))	('IDH2', 'Gene', (65, 69))	('IDH1', 'Gene', (56, 60))
65795	28654422	We first analysed PARP1 mutations and copy numbers of GBM specimens in the TCGA database via cBioPortal (http://www.cbioportal.org/public-portal/).	('mutations', 'Var', (24, 33))	('PARP1', 'Gene', '142', (18, 23))	('PARP1', 'Gene', (18, 23))
65796	28654422	Only two PARP1 somatic mutations were observed (V948I and A709T) in GBM.	('V948I', 'Var', (48, 53))	('A709T', 'Var', (58, 63))	('PARP1', 'Gene', '142', (9, 14))	('PARP1', 'Gene', (9, 14))	('V948I', 'Mutation', 'p.V948I', (48, 53))	('A709T', 'Mutation', 'rs758506201', (58, 63))
65797	28654422	PARP1 exhibited a low-level gain and heterozygous deletions in more than 14% and 6% of the cases, respectively.	('heterozygous deletions', 'Var', (37, 59))	('PARP1', 'Gene', (0, 5))	('gain', 'PosReg', (28, 32))	('PARP1', 'Gene', '142', (0, 5))
65803	28654422	We found, that grade II tumours have the lowest CNA rate (0.036) followed by grade III astrocytomas (0.167) and grade IV GBM (0.215), and high PARP1 copy numbers correlate with higher histological grades (p<0.001) (Supplementary Figure 1).	('PARP1', 'Gene', '142', (143, 148))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('CNA', 'CPA', (48, 51))	('copy numbers', 'Var', (149, 161))	('II astrocytomas', 'Disease', (84, 99))	('lowest', 'NegReg', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('II tumours', 'Disease', (21, 31))	('II tumours', 'Disease', 'MESH:D009369', (21, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('high', 'Var', (138, 142))	('PARP1', 'Gene', (143, 148))	('II astrocytomas', 'Disease', 'MESH:D001254', (84, 99))
65812	28654422	We discovered that samples carrying mutated ATRX (p=0.006) and TP53 (p=0.015) were associated with higher PARP1 expression levels (Table 1).	('ATRX', 'Gene', (44, 48))	('ATRX', 'Gene', '546', (44, 48))	('higher', 'PosReg', (99, 105))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))	('PARP1', 'Gene', '142', (106, 111))	('mutated', 'Var', (36, 43))	('expression levels', 'MPA', (112, 129))	('PARP1', 'Gene', (106, 111))
65816	28654422	Next, mutant TP53 samples were further divided into missense (n=33) and null (n=10) mutations in order to investigate the mutation effects on PARP1 expressions (Figure 3A, Table 2).	('TP53', 'Gene', (13, 17))	('mutant', 'Var', (6, 12))	('PARP1', 'Gene', '142', (142, 147))	('PARP1', 'Gene', (142, 147))	('TP53', 'Gene', '7157', (13, 17))
65817	28654422	PARP1 mRNA expression was higher in TP53 mutated cases (p=0.015) than in its wildtype counterpart.	('mutated', 'Var', (41, 48))	('higher', 'PosReg', (26, 32))	('TP53', 'Gene', '7157', (36, 40))	('mRNA expression', 'MPA', (6, 21))	('TP53', 'Gene', (36, 40))	('PARP1', 'Gene', (0, 5))	('PARP1', 'Gene', '142', (0, 5))
65818	28654422	Importantly, there was no significant changes between missense and null TP53 mutations (Figure 3B).	('TP53', 'Gene', (72, 76))	('missense', 'Var', (54, 62))	('TP53', 'Gene', '7157', (72, 76))
65828	28654422	PARP1 copy number gains were observed in all subtypes: ME (4.4%), PN (4.4%), CL (2.9%) and NE (2.3%).	('ME', 'Chemical', '-', (55, 57))	('PN', 'Chemical', '-', (66, 68))	('copy number', 'Var', (6, 17))	('PARP1', 'Gene', '142', (0, 5))	('gains', 'PosReg', (18, 23))	('PARP1', 'Gene', (0, 5))
65846	28654422	PARP1 levels showed correlation with copy number alterations of CDKN2A and MDM4 genes (Figure 7B).	('MDM4', 'Gene', (75, 79))	('CDKN2A', 'Gene', (64, 70))	('CDKN2A', 'Gene', '1029', (64, 70))	('MDM4', 'Gene', '4194', (75, 79))	('PARP1', 'Gene', '142', (0, 5))	('correlation', 'Reg', (20, 31))	('copy number alterations', 'Var', (37, 60))	('PARP1', 'Gene', (0, 5))
65847	28654422	More specifically, PARP1 levels were decreased in homozygously deleted CDKN2A (p=0.013) cases, and increased in cases with MDM4 gain (p=0.026) when we compared CNAs to the diploid variants of the genes.	('CDKN2A', 'Gene', (71, 77))	('PARP1', 'Gene', (19, 24))	('deleted', 'Var', (63, 70))	('MDM4 gain', 'Disease', (123, 132))	('CDKN2A', 'Gene', '1029', (71, 77))	('PARP1', 'Gene', '142', (19, 24))	('MDM4 gain', 'Disease', 'MESH:D015430', (123, 132))	('increased', 'PosReg', (99, 108))	('decreased', 'NegReg', (37, 46))
65861	28654422	The importance of ATRX, IDH1, and TP53 mutations in the early development and the progression of astrocytic glioma lineage is well-known.	('IDH1', 'Gene', '3417', (24, 28))	('TP53', 'Gene', (34, 38))	('astrocytic glioma', 'Disease', 'MESH:D001254', (97, 114))	('astrocytic glioma', 'Disease', (97, 114))	('mutations', 'Var', (39, 48))	('ATRX', 'Gene', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1', 'Gene', (24, 28))	('ATRX', 'Gene', '546', (18, 22))	('TP53', 'Gene', '7157', (34, 38))
65862	28654422	These markers also have treatment and prognostic relevance and their mutation status can distinguish astrocytomas from oligodendrogliomas, as well as secondary from primary GBM.	('astrocytomas', 'Disease', (101, 113))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (119, 137))	('secondary', 'Disease', (150, 159))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('mutation', 'Var', (69, 77))	('oligodendrogliomas', 'Disease', (119, 137))	('astrocytomas', 'Disease', 'MESH:D001254', (101, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
65863	28654422	PARP1 expression can occur in both IDH-wild type and mutated GBMs.	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))	('mutated', 'Var', (53, 60))	('PARP1', 'Gene', '142', (0, 5))	('PARP1', 'Gene', (0, 5))
65864	28654422	Although there was no statistically proven association between PARP1 expression and IDH mutation status, a recent study reported that 2-hydroxyglutarate produced by mutated IDH induces PARP inhibitor sensitivity in patient-derived primary glioma cells and genetically matched tumour xenografts, which has therapeutic implications.	('tumour xenografts', 'Disease', (276, 293))	('patient', 'Species', '9606', (215, 222))	('mutated', 'Var', (165, 172))	('2-hydroxyglutarate', 'MPA', (134, 152))	('IDH', 'Gene', (173, 176))	('PARP', 'Gene', '142', (185, 189))	('PARP1', 'Gene', (63, 68))	('tumour xenografts', 'Disease', 'MESH:D009369', (276, 293))	('PARP', 'Gene', (185, 189))	('IDH', 'Gene', '3417', (173, 176))	('glioma', 'Disease', (239, 245))	('IDH', 'Gene', (84, 87))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (134, 152))	('induces', 'Reg', (177, 184))	('PARP', 'Gene', '142', (63, 67))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('PARP', 'Gene', (63, 67))	('IDH', 'Gene', '3417', (84, 87))	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('PARP1', 'Gene', '142', (63, 68))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
65865	28654422	On the other hand, higher PARP1 expression levels were tightly associated with ATRX and TP53 mutations.	('mutations', 'Var', (93, 102))	('higher', 'PosReg', (19, 25))	('associated', 'Reg', (63, 73))	('ATRX', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (88, 92))	('PARP1', 'Gene', '142', (26, 31))	('ATRX', 'Gene', '546', (79, 83))	('PARP1', 'Gene', (26, 31))	('expression levels', 'MPA', (32, 49))	('TP53', 'Gene', (88, 92))
65866	28654422	ATRX alterations occur in the vast majority of lower-grade astrocytomas and IDH1-mutated (secondary) GBMs.	('IDH1', 'Gene', (76, 80))	('ATRX', 'Gene', (0, 4))	('astrocytomas', 'Disease', 'MESH:D001254', (59, 71))	('occur', 'Reg', (17, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('IDH1', 'Gene', '3417', (76, 80))	('alterations', 'Var', (5, 16))	('astrocytomas', 'Disease', (59, 71))	('ATRX', 'Gene', '546', (0, 4))
65868	28654422	Considering that the inhibition of PARP1 enzyme is dose-dependent, our results indicate that PARP inhibitors could be more effective in ATRX and TP53 mutated tumours, where PARP1 levels are usually increased.	('PARP', 'Gene', '142', (93, 97))	('TP53', 'Gene', '7157', (145, 149))	('PARP', 'Gene', '142', (173, 177))	('PARP', 'Gene', (93, 97))	('PARP', 'Gene', (173, 177))	('PARP1', 'Gene', (35, 40))	('PARP1', 'Gene', '142', (173, 178))	('tumours', 'Disease', (158, 165))	('PARP', 'Gene', '142', (35, 39))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('TP53', 'Gene', (145, 149))	('PARP', 'Gene', (35, 39))	('PARP1', 'Gene', '142', (35, 40))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('ATRX', 'Gene', (136, 140))	('ATRX', 'Gene', '546', (136, 140))	('PARP1', 'Gene', (173, 178))	('mutated', 'Var', (150, 157))
65870	28654422	To date, the IHC detection of key molecular markers is possible and highly informative: I) using IDH1R132H mutation specific antibody; II) most ATRX mutations result in undetectable ATRX expression by IHC; and III) mutated p53 protein accumulates in the nucleus of tumour cells.	('IDH1', 'Gene', (97, 101))	('mutations', 'Var', (149, 158))	('ATRX', 'Gene', (144, 148))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('protein', 'Protein', (227, 234))	('accumulates', 'PosReg', (235, 246))	('IDH1', 'Gene', '3417', (97, 101))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('ATRX', 'Gene', (182, 186))	('mutated', 'Var', (215, 222))	('ATRX', 'Gene', '546', (144, 148))	('ATRX', 'Gene', '546', (182, 186))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('expression', 'MPA', (187, 197))	('tumour', 'Disease', (265, 271))	('undetectable', 'NegReg', (169, 181))
65875	28654422	Our data showed that high PARP1 levels were associated with shorter survival in the CL group.	('high', 'Var', (21, 25))	('PARP1', 'Gene', '142', (26, 31))	('survival', 'MPA', (68, 76))	('PARP1', 'Gene', (26, 31))	('shorter', 'NegReg', (60, 67))
65876	28654422	It was previously presented that CL GBM is characterized by EGFR amplification and wild-type TP53, whereas PN is characterized by both IDH1 and TP53 mutations and PDGFRA amplification.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('mutations', 'Var', (149, 158))	('IDH1', 'Gene', (135, 139))	('TP53', 'Gene', '7157', (93, 97))	('PDGFRA', 'Gene', '5156', (163, 169))	('TP53', 'Gene', (93, 97))	('PDGFRA', 'Gene', (163, 169))	('IDH1', 'Gene', '3417', (135, 139))	('PN', 'Chemical', '-', (107, 109))	('EGFR', 'Gene', '1956', (60, 64))	('amplification', 'Var', (65, 78))	('EGFR', 'Gene', (60, 64))
65878	28654422	In our previous study, we demonstrated that p53 immunopositivity correlates with TP53 mutational status, except for certain mutation types.	('mutational status', 'Var', (86, 103))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
65880	28654422	In addition, PAPR1 mRNA levels were higher in samples with TP53 mutations.	('higher', 'PosReg', (36, 42))	('TP53', 'Gene', (59, 63))	('PAPR1 mRNA levels', 'MPA', (13, 30))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (59, 63))
65882	28654422	Beside the increased PARP1 levels in TP53 mutated cases, there was no statistical difference between missense and null mutated samples.	('PARP1', 'Gene', '142', (21, 26))	('mutated', 'Var', (42, 49))	('increased', 'PosReg', (11, 20))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('PARP1', 'Gene', (21, 26))
65886	28654422	Interestingly, we found a significantly shorter survival in PARP-high patients with wildtype TP53 gene (Figure 6) - possibly because not only TP53 mutations but also an impaired p53 pathway can facilitate tumour progression.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('mutations', 'Var', (147, 156))	('survival', 'MPA', (48, 56))	('patients', 'Species', '9606', (70, 78))	('tumour', 'Disease', (205, 211))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('TP53', 'Gene', '7157', (93, 97))	('PARP', 'Gene', '142', (60, 64))	('TP53', 'Gene', (93, 97))	('facilitate', 'PosReg', (194, 204))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('shorter', 'NegReg', (40, 47))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('PARP', 'Gene', (60, 64))
65888	28654422	It is widely accepted, that the progression and recurrence of glioblastoma is related to p53 pathway abnormalities in 87% of primary GBM.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('p53', 'Gene', '7157', (89, 92))	('related', 'Reg', (78, 85))	('abnormalities', 'Var', (101, 114))	('primary GBM', 'Disease', (125, 136))	('glioblastoma', 'Disease', (62, 74))	('p53', 'Gene', (89, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))
65889	28654422	To gain insights into the interaction between p53 and PARP1, we investigated and found that PARP1 showed association with CDKN2A deletions and MDM4 gain (both CDKN2A and MDM4 are components of the p53 pathway) (Figure 7B).	('CDKN2A', 'Gene', (122, 128))	('MDM4', 'Gene', '4194', (143, 147))	('deletions', 'Var', (129, 138))	('MDM4', 'Gene', (143, 147))	('CDKN2A', 'Gene', '1029', (122, 128))	('PARP1', 'Gene', '142', (92, 97))	('p53', 'Gene', '7157', (197, 200))	('PARP1', 'Gene', '142', (54, 59))	('p53', 'Gene', '7157', (46, 49))	('CDKN2A', 'Gene', (159, 165))	('p53', 'Gene', (46, 49))	('MDM4 gain', 'Disease', (143, 152))	('p53', 'Gene', (197, 200))	('association', 'Interaction', (105, 116))	('CDKN2A', 'Gene', '1029', (159, 165))	('MDM4', 'Gene', '4194', (170, 174))	('MDM4 gain', 'Disease', 'MESH:D015430', (143, 152))	('MDM4', 'Gene', (170, 174))	('PARP1', 'Gene', (92, 97))	('PARP1', 'Gene', (54, 59))
65890	28654422	These two genetic alterations are frequent in GBM, and result in abnormal p53 signalling in tumour cells.	('alterations', 'Var', (18, 29))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('p53', 'Gene', (74, 77))	('p53', 'Gene', '7157', (74, 77))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('result in abnormal', 'Reg', (55, 73))
65897	28654422	We have demonstrated that increased PARP1 levels show positive correlation with increasing tumour grades in gliomas Higher PARP1 mRNA expression levels were associated with ATRX and TP53 mutations.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('associated', 'Reg', (157, 167))	('gliomas', 'Disease', (108, 115))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('ATRX', 'Gene', '546', (173, 177))	('tumour', 'Disease', (91, 97))	('mutations', 'Var', (187, 196))	('PARP1', 'Gene', '142', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('PARP1', 'Gene', (36, 41))	('increased', 'PosReg', (26, 35))	('ATRX', 'Gene', (173, 177))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('PARP1', 'Gene', (123, 128))	('PARP1', 'Gene', '142', (123, 128))
65904	28654422	In cBioPortal, copy numbers are computed using the GISTIC (Genomic Identification of Significant Targets in Cancer) algorithm, which identifies the putative copy number level as follows: I) high-level amplification, II) low-level gain, III) diploid, IV) heterozygous deletion, or V) homozygous deletion.	('gain', 'PosReg', (230, 234))	('Cancer', 'Disease', (108, 114))	('heterozygous deletion', 'Var', (254, 275))	('Cancer', 'Disease', 'MESH:D009369', (108, 114))	('diploid', 'Var', (241, 248))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))
65973	27568373	Some other findings include a strong nuclear expression of p53 and 10q deletions.	('p53', 'Gene', (59, 62))	('10q deletions', 'Var', (67, 80))	('nuclear expression', 'MPA', (37, 55))	('p53', 'Gene', '7157', (59, 62))
66026	27568373	However, one exception was a specimen from a stillborn fetus (therapeutic termination) whose tumor was discovered by ultrasound at 31-week gestation; intracranial hemorrhage and vascular proliferation were found along with pleomorphism, hypercellularity, and mitotic activity, suggesting perhaps an early in utero transformation to GBM.	('hypercellularity', 'CPA', (237, 253))	('mitotic activity', 'CPA', (259, 275))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GBM', 'Phenotype', 'HP:0012174', (332, 335))	('vascular proliferation', 'CPA', (178, 200))	('intracranial hemorrhage', 'Disease', (150, 173))	('tumor', 'Disease', (93, 98))	('pleomorphism', 'Var', (223, 235))	('intracranial hemorrhage', 'Disease', 'MESH:D020300', (150, 173))	('intracranial hemorrhage', 'Phenotype', 'HP:0002170', (150, 173))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
66101	32793593	N6-methylandenosine (m6A) modification, the most abundant epigenetic methylated modification of messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), plays a vital role in RNA splicing, export, stability and translation.	('m6A', 'Gene', '56339', (21, 24))	('modification', 'Var', (26, 38))	('N6-methylandenosine', 'Chemical', '-', (0, 19))	('ncRNA', 'Gene', (140, 145))	('ncRNA', 'Gene', '220202', (140, 145))	('m6A', 'Gene', (21, 24))	('N6-methylandenosine', 'Var', (0, 19))
66103	32793593	Recent research had revealed that m6A modification can regulate oncogenesis and tumor progression in several kinds of cancers, including glioma.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('m6A', 'Gene', '56339', (34, 37))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('oncogenesis', 'CPA', (64, 75))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (80, 85))	('modification', 'Var', (38, 50))	('regulate', 'Reg', (55, 63))	('glioma', 'Disease', (137, 143))	('m6A', 'Gene', (34, 37))
66104	32793593	For example, METTL14 could enhances leukemia stem cells self-renewing and acts as a cancer promoter in the development and maintenance of acute myeloid leukemia; knockdown of FTO limits glioblastoma stem cells self-renewing and the proliferation and invasion of lung squamous cell carcinoma (SCC) cells; and YTHDF2 restrains cell proliferation by reducing the mRNA stability of EGFR in liver cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (392, 398))	('YTHDF2', 'Gene', (308, 314))	('EGFR', 'Gene', (378, 382))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (144, 160))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('leukemia', 'Disease', 'MESH:D007938', (152, 160))	('liver cancer', 'Phenotype', 'HP:0002896', (386, 398))	('leukemia', 'Disease', (152, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('knockdown', 'Var', (162, 171))	('liver cancer', 'Disease', (386, 398))	('invasion', 'CPA', (250, 258))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (262, 290))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('restrains', 'NegReg', (315, 324))	('acute myeloid leukemia', 'Disease', (138, 160))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('glioblastoma', 'Disease', (186, 198))	('cell proliferation', 'CPA', (325, 343))	('FTO', 'Gene', '79068', (175, 178))	('EGFR', 'Gene', '1956', (378, 382))	('METTL14', 'Gene', '57721', (13, 20))	('YTHDF2', 'Gene', '51441', (308, 314))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('cancer', 'Disease', 'MESH:D009369', (392, 398))	('cancer', 'Disease', (84, 90))	('reducing', 'NegReg', (347, 355))	('FTO', 'Gene', (175, 178))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (262, 290))	('lung squamous cell carcinoma', 'Disease', (262, 290))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('leukemia', 'Disease', (36, 44))	('leukemia', 'Disease', 'MESH:D007938', (36, 44))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (138, 160))	('limits', 'NegReg', (179, 185))	('METTL14', 'Gene', (13, 20))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (138, 160))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('liver cancer', 'Disease', 'MESH:D006528', (386, 398))	('proliferation', 'CPA', (232, 245))	('enhances', 'PosReg', (27, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))
66105	32793593	Recently, bioinformatic research has revealed that dysregulation of m6A regulators involved in the malignant development of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('m6A', 'Gene', (68, 71))	('dysregulation', 'Var', (51, 64))	('m6A', 'Gene', '56339', (68, 71))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
66106	32793593	Aberrant lncRNA expression is also strongly related to tumor malignancy, and dysregulation of long non-coding RNAs had been confirmed to play a critical role in the pathogenicity of gliomas.	('dysregulation', 'Var', (77, 90))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('related', 'Reg', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('tumor malignancy', 'Disease', 'MESH:D009369', (55, 71))	('ncRNA', 'Gene', (10, 15))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('long non-coding RNAs', 'Protein', (94, 114))	('gliomas', 'Disease', (182, 189))	('ncRNA', 'Gene', '220202', (10, 15))	('tumor malignancy', 'Disease', (55, 71))
66107	32793593	For instance, HOXA11-AS is reported to be a cell cycle-related lncRNA as well as a biomarker of glioma patients; MALAT1 was a suppressor of glioma by downregulating MMP2 and devitalizing ERK/MAPK signaling; and knockdown of DANCR could inhibit glioma cell growth and invasion through downregulating miR-135a-5p/BMI1 axis.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('MALAT1', 'Gene', (113, 119))	('glioma', 'Disease', (244, 250))	('ERK', 'Gene', (187, 190))	('invasion', 'CPA', (267, 275))	('HOXA11-AS', 'Gene', (14, 23))	('BMI1', 'Gene', (311, 315))	('DANCR', 'Gene', '57291', (224, 229))	('MMP2', 'Gene', '4313', (165, 169))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('downregulating', 'NegReg', (284, 298))	('MALAT1', 'Gene', '378938', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('inhibit', 'NegReg', (236, 243))	('HOXA11-AS', 'Gene', '221883', (14, 23))	('knockdown', 'Var', (211, 220))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('glioma', 'Disease', (96, 102))	('BMI1', 'Gene', '648', (311, 315))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('ERK', 'Gene', '5594', (187, 190))	('devitalizing', 'NegReg', (174, 186))	('MMP2', 'Gene', (165, 169))	('DANCR', 'Gene', (224, 229))	('ncRNA', 'Gene', (64, 69))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma', 'Disease', (140, 146))	('ncRNA', 'Gene', '220202', (64, 69))	('patients', 'Species', '9606', (103, 111))	('downregulating', 'NegReg', (150, 164))
66108	32793593	However, the full role of m6A regulators in the dysregulation of lncRNAs in cancers remains unclear, and few studies have been performed to explore the mechanisms underlying how m6A modifications contribute to lncRNA-dependent glioma occurrence and development.	('modifications', 'Var', (182, 195))	('ncRNA', 'Gene', '220202', (66, 71))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('ncRNA', 'Gene', (211, 216))	('development', 'CPA', (249, 260))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ncRNA', 'Gene', '220202', (211, 216))	('m6A', 'Gene', (26, 29))	('contribute to', 'Reg', (196, 209))	('m6A', 'Gene', (178, 181))	('ncRNA', 'Gene', (66, 71))	('m6A', 'Gene', '56339', (26, 29))	('m6A', 'Gene', '56339', (178, 181))	('glioma', 'Disease', (227, 233))
66120	32793593	In this part, lncRNAs defined in our analysis included eight types of transcripts (lincRNA, antisense, processed transcript, sense intronic, 3prime overlapping ncRNA, sense overlapping, and macro lncRNA).	('ncRNA', 'Gene', (15, 20))	('ncRNA', 'Gene', (197, 202))	('3prime', 'Var', (141, 147))	('ncRNA', 'Gene', (85, 90))	('ncRNA', 'Gene', (160, 165))	('ncRNA', 'Gene', '220202', (160, 165))	('antisense', 'MPA', (92, 101))	('ncRNA', 'Gene', '220202', (197, 202))	('ncRNA', 'Gene', '220202', (15, 20))	('ncRNA', 'Gene', '220202', (85, 90))
66138	32793593	Chi-square tests were used to compare the distribution of age, gender, WHO grade, IDH status, and 1p/19q status between low- and high-risk subgroups (partitioned by the median value of risk scores) in LGGs of both datasets (Supplementary Table S2).	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', (82, 85))	('1p/19q status', 'Var', (98, 111))
66161	32793593	The heatmap (Figure 3B) shows that C6orf3, LINC00237, and LINC00925 expression decreased with increasing risk score, whereas the expression of the LIN00152, LINC00265, LINC00665, RP11-443B20.1, RP4-758J18.2, and RP4-773N10.4 increased with increasing risk score.	('RP4', 'Gene', (194, 197))	('expression', 'MPA', (68, 78))	('RP11', 'Gene', (179, 183))	('LIN00152', 'Var', (147, 155))	('expression', 'MPA', (129, 139))	('C6orf3', 'Gene', (35, 41))	('decreased', 'NegReg', (79, 88))	('LINC00665', 'Gene', (168, 177))	('LINC00925', 'Gene', (58, 67))	('RP4', 'Gene', '6010', (212, 215))	('RP4', 'Gene', (212, 215))	('LINC00265', 'Gene', (157, 166))	('LINC00925', 'Gene', '254559', (58, 67))	('LINC00237', 'Gene', '101180898', (43, 52))	('C6orf3', 'Gene', '643749', (35, 41))	('RP11', 'Gene', '26121', (179, 183))	('LINC00665', 'Gene', '100506930', (168, 177))	('LINC00237', 'Gene', (43, 52))	('RP4', 'Gene', '6010', (194, 197))	('LINC00265', 'Gene', '349114', (157, 166))
66162	32793593	Their expression levels were also related to the clinicopathological features of glioma, such as IDH mutation status, 1p/19q co-deletion status, MGMT methylation status and WHO grade (Figure 3B).	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('1p/19q co-deletion status', 'Var', (118, 143))	('IDH', 'Gene', (97, 100))	('MGMT', 'Gene', '4255', (145, 149))	('MGMT', 'Gene', (145, 149))	('glioma', 'Disease', (81, 87))	('IDH', 'Gene', '3417', (97, 100))	('related', 'Reg', (34, 41))	('mutation', 'Var', (101, 109))	('expression levels', 'MPA', (6, 23))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
66163	32793593	The Kaplan-Meier survival curves confirmed that higher expression of C6orf3, LINC00237 and LINC00925 and lower expression of LIN00152, LINC00265, LINC00665, RP11-443B20.1, RP4-758J18.2, and RP4-773N10.4 were associated with better OS in the TCGA dataset (Figures 3C-K).	('LINC00665', 'Gene', (146, 155))	('C6orf3', 'Gene', (69, 75))	('LIN00152', 'Var', (125, 133))	('LINC00665', 'Gene', '100506930', (146, 155))	('LINC00925', 'Gene', (91, 100))	('LINC00237', 'Gene', '101180898', (77, 86))	('RP4', 'Gene', '6010', (190, 193))	('C6orf3', 'Gene', '643749', (69, 75))	('LINC00925', 'Gene', '254559', (91, 100))	('LINC00265', 'Gene', (135, 144))	('RP4', 'Gene', (190, 193))	('lower', 'NegReg', (105, 110))	('RP11', 'Gene', '26121', (157, 161))	('RP4', 'Gene', '6010', (172, 175))	('RP4', 'Gene', (172, 175))	('TCGA', 'Disease', (241, 245))	('LINC00237', 'Gene', (77, 86))	('higher', 'PosReg', (48, 54))	('LINC00265', 'Gene', '349114', (135, 144))	('RP11', 'Gene', (157, 161))
66164	32793593	The results revealed that LGG patients with wildtype IDH, 1p/19q non-co-deletion status, unmethylated MGMT, older age and WHO grade III (Figures 4A-E) had higher risk scores, while the risk score was not associated with gender (Figure 4F).	('MGMT', 'Gene', '4255', (102, 106))	('non-co-deletion status', 'Var', (65, 87))	('patients', 'Species', '9606', (30, 38))	('MGMT', 'Gene', (102, 106))	('IDH, 1p/19q', 'Gene', '3417', (53, 64))	('higher', 'PosReg', (155, 161))
66167	32793593	Likewise, we confirmed that m6A-LPS retained its ability to predict OS for patients aged <= 40 or > 40 years (Figures 4I,J) and patients with mutant or wildtype IDH (Figures 4K,L).	('IDH', 'Gene', '3417', (161, 164))	('m6A', 'Gene', (28, 31))	('m6A', 'Gene', '56339', (28, 31))	('patients', 'Species', '9606', (75, 83))	('mutant', 'Var', (142, 148))	('LPS', 'Chemical', 'MESH:D008070', (32, 35))	('patients', 'Species', '9606', (128, 136))	('IDH', 'Gene', (161, 164))
66221	25230881	Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumourigenesis and chromatin regulation as well as developmental signaling pathways.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('mutations', 'Var', (156, 165))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('children', 'Species', '9606', (99, 107))
66237	25230881	DIPGs represent a distinct entity from true low-grade gliomas of the brainstem (WHO grade I), which often have a pronounced dorsal exophytic component, and frequently harbour BRAF:KIAA1549 gene fusions which are a hallmark of low-grade pilocytic astrocytomas.	('DIPGs', 'Chemical', '-', (0, 5))	('DIPGs', 'Disease', (0, 5))	('gliomas of the brainstem', 'Phenotype', 'HP:0010796', (54, 78))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('fusions', 'Var', (194, 201))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('astrocytoma', 'Phenotype', 'HP:0009592', (246, 257))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (236, 258))	('pilocytic astrocytomas', 'Disease', (236, 258))	('KIAA1549', 'Gene', '57670', (180, 188))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('KIAA1549', 'Gene', (180, 188))
66239	25230881	These progressive lesions are strongly associated with the presence of IDH1 mutations, and likely represent a subset of high-grade gliomas occurring in older adolescents.	('mutations', 'Var', (76, 85))	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('IDH1', 'Gene', (71, 75))	('associated', 'Reg', (39, 49))	('IDH1', 'Gene', '3417', (71, 75))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))
66261	25230881	At least some of these cases are hypermutator tumours that arise in the context of germline mutations in mismatch repair genes.	('hypermutator tumours', 'Disease', (33, 53))	('hypermutator tumours', 'Disease', 'MESH:D009369', (33, 53))	('mutations', 'Var', (92, 101))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
66262	25230881	Germline mutations in the TP53 and NF1 tumour suppressors are known to cause inherited predisposition to high-grade gliomas, and a subset of paediatric HGGs arise in this context of increased genetic risk.	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', (26, 30))	('cause', 'Reg', (71, 76))	('tumour', 'Disease', (39, 45))	('paediatric HGGs', 'Disease', (141, 156))	('gliomas', 'Disease', (116, 123))	('TP53', 'Gene', '7157', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('NF1', 'Gene', (35, 38))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('NF1', 'Gene', '4763', (35, 38))
66271	25230881	Thus, the genomic complexity of paediatric HGG spans a wide range, with infant NBS-HGG and HGGs from patients with inherited mutations in mismatch repair genes at the extreme opposite ends of the spectrum (Figure 2).	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (101, 109))	('infant', 'Species', '9606', (72, 78))	('NBS-HGG', 'Disease', 'MESH:D049932', (79, 86))	('NBS-HGG', 'Disease', (79, 86))	('mismatch repair genes', 'Gene', (138, 159))	('HGGs', 'Disease', (91, 95))
66272	25230881	The paucity of mutations in infant tumours suggests that therapeutic targeting of NTRK fusions may be highly effective in the absence of a large number of other mutations.	('tumours', 'Disease', (35, 42))	('fusions', 'Var', (87, 94))	('infant', 'Species', '9606', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('NTRK', 'Gene', (82, 86))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('NTRK', 'Gene', '4914;4915;4916', (82, 86))
66273	25230881	However, the genomic complexity of the majority of HGGs, including DIPGs, indicates that multiple genetic mechanisms generate numerous mutations providing the tumour with diverse potential pathways to therapeutic resistance.	('tumour', 'Disease', (159, 165))	('mutations', 'Var', (135, 144))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('DIPGs', 'Chemical', '-', (67, 72))	('HGGs', 'Disease', (51, 55))
66274	25230881	Paediatric diffuse HGGs show frequent genetic alterations targeting the same canonical cancer pathways that are deregulated by mutation in almost all adult glioblastomas; the receptor tyrosine kinase (RTK)/RAS/PI3K pathway, the TP53 pathway and the RB pathway, however, the specific effectors most frequently targeted by mutation vary between childhood and adult tumours(Figure 3).	('tumour', 'Phenotype', 'HP:0002664', (363, 369))	('RTK', 'Gene', (201, 204))	('TP53', 'Gene', (228, 232))	('RTK', 'Gene', '5979', (201, 204))	('adult glioblastoma', 'Disease', 'MESH:D005909', (150, 168))	('glioblastomas', 'Disease', (156, 169))	('adult tumours', 'Disease', 'MESH:D006528', (357, 370))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('glioblastomas', 'Disease', 'MESH:D005909', (156, 169))	('RB pathway', 'Pathway', (249, 259))	('cancer', 'Disease', (87, 93))	('RB', 'Chemical', 'MESH:D012413', (249, 251))	('receptor tyrosine kinase', 'Gene', '5979', (175, 199))	('mutation', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('adult tumours', 'Disease', (357, 370))	('TP53', 'Gene', '7157', (228, 232))	('tumours', 'Phenotype', 'HP:0002664', (363, 370))	('receptor tyrosine kinase', 'Gene', (175, 199))	('alterations', 'Var', (46, 57))	('deregulated', 'PosReg', (112, 123))	('glioblastomas', 'Phenotype', 'HP:0012174', (156, 169))	('adult glioblastoma', 'Disease', (150, 168))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
66275	25230881	Mutations of the catalytic and regulatory subunits of PI3K, encoded by PIK3CA and PIK3R1, respectively, are found in both paediatric and adult HGG, while biallelic inactivation of the PTEN tumour suppressor is common in adult, but rare in childhood HGGs.	('found', 'Reg', (108, 113))	('PIK3R1', 'Gene', (82, 88))	('PIK3CA', 'Gene', '5290', (71, 77))	('PI3K', 'Gene', (54, 58))	('PTEN', 'Gene', (184, 188))	('PIK3R1', 'Gene', '5295', (82, 88))	('PTEN', 'Gene', '5728', (184, 188))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('PIK3CA', 'Gene', (71, 77))
66276	25230881	The hotspot BRAF V600E activating mutation is found in approximately 10% of paediatric cortical HGGs, lower frequencies in thalamic HGGs, and not detected in DIPG.	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('DIPG', 'Chemical', '-', (158, 162))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('activating', 'PosReg', (23, 33))
66277	25230881	V600E mutations were also found in more than 70% of pleomorphic xanthoastrocytomas, and approximately 50% of anaplastic ganglioglioma, rare tumours found in both children and adults .	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('rare tumours', 'Disease', 'MESH:D035583', (135, 147))	('ganglioglioma', 'Disease', (120, 133))	('children', 'Species', '9606', (162, 170))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (52, 82))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('ganglioglioma', 'Disease', 'MESH:D018303', (120, 133))	('rare tumours', 'Disease', (135, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('found', 'Reg', (26, 31))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('pleomorphic xanthoastrocytomas', 'Disease', (52, 82))	('V600E', 'Var', (0, 5))
66278	25230881	Thus mutant BRAF may be a useful therapeutic target in a subset of childhood HGGs.	('BRAF', 'Gene', '673', (12, 16))	('childhood HGGs', 'Disease', (67, 81))	('mutant', 'Var', (5, 11))	('BRAF', 'Gene', (12, 16))
66279	25230881	PDGFRA is the most commonly mutated RTK in paediatric HGG, and EGFR mutations, which predominate in adult glioblastoma, are relatively rare .	('EGFR', 'Gene', '1956', (63, 67))	('PDGFRA', 'Gene', (0, 6))	('adult glioblastoma', 'Disease', (100, 118))	('EGFR', 'Gene', (63, 67))	('PDGFRA', 'Gene', '5156', (0, 6))	('adult glioblastoma', 'Disease', 'MESH:D005909', (100, 118))	('HGG', 'Disease', (54, 57))	('RTK', 'Gene', (36, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('mutations', 'Var', (68, 77))	('RTK', 'Gene', '5979', (36, 39))
66280	25230881	Approximately 30% of paediatric HGGs across all brain regions carry focal amplification and/or mutation of PDGFRA, involving a unique spectrum of mutations compared to those found in adult glioblastoma.	('PDGFRA', 'Gene', (107, 113))	('HGGs', 'Disease', (32, 36))	('adult glioblastoma', 'Disease', (183, 201))	('PDGFRA', 'Gene', '5156', (107, 113))	('adult glioblastoma', 'Disease', 'MESH:D005909', (183, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('mutation', 'Var', (95, 103))
66281	25230881	Amplification of MET and IGF1R are also found in paediatric HGG.	('IGF1R', 'Gene', '3480', (25, 30))	('Amplification', 'Var', (0, 13))	('MET', 'Gene', (17, 20))	('found', 'Reg', (40, 45))	('IGF1R', 'Gene', (25, 30))
66285	25230881	TP53 mutations are found in approximately 55% of paediatric HGGs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('paediatric HGGs', 'Disease', (49, 64))	('found', 'Reg', (19, 24))	('mutations', 'Var', (5, 14))
66286	25230881	There are also mutually exclusive mutations in 9-23% of DIPGs and midline HGGs in the TP53 target gene PPM1D, which plays a role downstream of TP53 in DNA damage response.	('TP53', 'Gene', (143, 147))	('PPM1D', 'Gene', '8493', (103, 108))	('TP53', 'Gene', '7157', (86, 90))	('DIPGs', 'Chemical', '-', (56, 61))	('TP53', 'Gene', (86, 90))	('midline HGGs', 'Disease', (66, 78))	('TP53', 'Gene', '7157', (143, 147))	('PPM1D', 'Gene', (103, 108))	('mutations', 'Var', (34, 43))	('midline HGGs', 'Disease', 'MESH:D009436', (66, 78))
66288	25230881	Homozygous deletions of CDKN2A are found in approximately 25% of non-brainstem-HGGs, but are extremely rare in DIPGs.	('non-brainstem-HGGs', 'Disease', (65, 83))	('DIPGs', 'Chemical', '-', (111, 116))	('CDKN2A', 'Gene', (24, 30))	('deletions', 'Var', (11, 20))	('CDKN2A', 'Gene', '1029', (24, 30))
66290	25230881	Although loss of chromosome 13q is found in approximately one third of paediatric HGGs regardless of location, biallelic loss of function mutations in RB are extremely rare.	('RB', 'Chemical', 'MESH:D012413', (151, 153))	('mutations', 'Var', (138, 147))	('loss of function', 'NegReg', (121, 137))	('HGGs', 'Disease', (82, 86))
66294	25230881	Genome-wide sequencing efforts of paediatric glioblastoma and DIPG identified recurrent and hotspot mutations in H3F3A and HIST1H3B, which encode the histone H3.3 variants H3.3 and H3.1 respectively.	('H3.1', 'Gene', (181, 185))	('mutations', 'Var', (100, 109))	('H3F3A', 'Gene', '3020', (113, 118))	('H3.3', 'Gene', '3020', (158, 162))	('HIST1H3B', 'Gene', (123, 131))	('H3.3', 'Gene', (172, 176))	('HIST1H3B', 'Gene', '8358', (123, 131))	('DIPG', 'Chemical', '-', (62, 66))	('H3.3', 'Gene', '3020', (172, 176))	('H3F3A', 'Gene', (113, 118))	('H3.1', 'Gene', '8352', (181, 185))	('glioblastoma', 'Disease', (45, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('H3.3', 'Gene', (158, 162))
66297	25230881	Histone H3.1 is encoded by 10 genes encoding identical proteins, though to date, almost all histone H3.1 mutations are found in HIST1H3B with two rare examples of HIST1H3C K27M in DIPG.	('H3.1', 'Gene', '8352', (8, 12))	('HIST1H3C', 'Gene', (163, 171))	('DIPG', 'Chemical', '-', (180, 184))	('H3.1', 'Gene', (100, 104))	('K27M', 'Mutation', 'p.K27M', (172, 176))	('HIST1H3B', 'Gene', (128, 136))	('HIST1H3B', 'Gene', '8358', (128, 136))	('mutations', 'Var', (105, 114))	('found', 'Reg', (119, 124))	('H3.1', 'Gene', '8352', (100, 104))	('H3.1', 'Gene', (8, 12))	('HIST1H3C', 'Gene', '8352', (163, 171))
66298	25230881	HIST1H3B mutant DIPG furthermore appear to represent a distinct subgroup, with a younger age at diagnosis (4-5 years) and longer survival time (median = 15 months), though with no improvement in eventual clinical outcome(Figure 4).	('HIST1H3B', 'Gene', (0, 8))	('mutant', 'Var', (9, 15))	('DIPG', 'Chemical', '-', (16, 20))	('HIST1H3B', 'Gene', '8358', (0, 8))
66299	25230881	Histone H3 mutations occur at two residues - the lysine at position 27 (lysine-to-methionine, K27M) and the glycine at position 34 (glycine-to-arginine or -valine, G34R/V).	('K27M', 'Var', (94, 98))	('mutations', 'Var', (11, 20))	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('lysine', 'Chemical', 'MESH:D008239', (72, 78))	('H3', 'Chemical', 'MESH:C012616', (8, 10))	('valine', 'Chemical', 'MESH:D014633', (156, 162))	('G34R', 'Var', (164, 168))	('glycine', 'Chemical', 'MESH:D005998', (108, 115))	('34 (glycine-to-arginine', 'SUBSTITUTION', 'None', (128, 151))	('glycine', 'Chemical', 'MESH:D005998', (132, 139))	('K27M', 'Mutation', 'p.K27M', (94, 98))	('Histone H3', 'Gene', (0, 10))	('27 (lysine-to-methionine', 'SUBSTITUTION', 'None', (68, 92))	('G34R', 'SUBSTITUTION', 'None', (164, 168))
66300	25230881	Strikingly, the mutations have a distinct anatomical segregation, illustrating a previously unrecognized highly specific selection pressure evident in different cell types during brain development, and providing strong evidence that the molecular pathogenesis of DIPG was significantly different from tumours arising in the cerebral hemispheres.	('tumours', 'Disease', 'MESH:D009369', (301, 308))	('tumours', 'Disease', (301, 308))	('mutations', 'Var', (16, 25))	('DIPG', 'Chemical', '-', (263, 267))	('DIPG', 'Disease', (263, 267))	('tumour', 'Phenotype', 'HP:0002664', (301, 307))	('tumours', 'Phenotype', 'HP:0002664', (301, 308))
66301	25230881	K27M mutations were observed in 78% of DIPGs, as well as other tumours of midline structures including thalamus (40%), and spinal cord, with the majority of these mutations in H3F3A encoding histone H3.3, and up to 25% in histone H3.1.	('H3.1', 'Gene', (230, 234))	('mutations', 'Var', (163, 172))	('H3.3', 'Gene', '3020', (199, 203))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('H3F3A', 'Gene', '3020', (176, 181))	('H3.1', 'Gene', '8352', (230, 234))	('tumours of midline', 'Disease', 'MESH:D009369', (63, 81))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('H3F3A', 'Gene', (176, 181))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours of midline', 'Disease', (63, 81))	('H3.3', 'Gene', (199, 203))	('DIPGs', 'Chemical', '-', (39, 44))	('K27M', 'Var', (0, 4))
66302	25230881	By contrast, G34R/V mutations are exclusively in H3F3A, and predominantly restricted to tumours of the cerebral hemispheres (15%).	('G34R', 'Var', (13, 17))	('tumours of the cerebral hemispheres', 'Disease', 'MESH:D001932', (88, 123))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('H3F3A', 'Gene', '3020', (49, 54))	('tumours of the cerebral hemispheres', 'Disease', (88, 123))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('G34R', 'SUBSTITUTION', 'None', (13, 17))	('H3F3A', 'Gene', (49, 54))
66303	25230881	The different mutations also have a distinct age of diagnosis (median 6-7 years, K27M; median 13-14 years G34R/V) and survival (median = 12 months, K27M; median = 24 months G34R/V), in part reflecting the onset and survival associated with HGGs from cortical versus brainstem and midline locations.	('K27M', 'Mutation', 'p.K27M', (81, 85))	('G34R', 'Var', (106, 110))	('K27M', 'Var', (81, 85))	('K27M', 'Mutation', 'p.K27M', (148, 152))	('G34R', 'SUBSTITUTION', 'None', (173, 177))	('G34R', 'Var', (173, 177))	('G34R', 'SUBSTITUTION', 'None', (106, 110))	('HGGs', 'Disease', (240, 244))	('K27M', 'Var', (148, 152))
66304	25230881	Importantly, G34R/V mutations are found in HGG patients beyond the paediatric age group, extending through patients diagnosed in early adulthood up to approximately 30-40 years of age, indicating that molecular diagnostics spanning traditional paediatric and adult neuro-oncology services will be vital in the common management of these patients as one disease entity.	('G34R', 'Var', (13, 17))	('patients', 'Species', '9606', (47, 55))	('oncology', 'Phenotype', 'HP:0002664', (271, 279))	('HGG', 'Disease', (43, 46))	('G34R', 'SUBSTITUTION', 'None', (13, 17))	('patients', 'Species', '9606', (337, 345))	('patients', 'Species', '9606', (107, 115))
66305	25230881	Similarly, although rare in the adult population, 88% of thalamic tumours arising in patients between the ages of 21-49 years old have K27M mutations.	('thalamic tumours', 'Disease', (57, 73))	('thalamic tumours', 'Disease', 'MESH:D013786', (57, 73))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('patients', 'Species', '9606', (85, 93))	('K27M mutations', 'Var', (135, 149))	('K27M', 'Mutation', 'p.K27M', (135, 139))
66307	25230881	However, the mutations clearly provide a strong selective advantage, because in most cases next generation sequencing shows that the H3F3A mutation appears to be heterozygous in 100% of cells, indicating clonal selection without significant intratumoral heterogeneity.	('H3F3A', 'Gene', (133, 138))	('mutation', 'Var', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))	('H3F3A', 'Gene', '3020', (133, 138))
66308	25230881	Furthermore, histone H3 K27M mutations have been identified at similar high frequency in both untreated biopsies and autopsy specimens after exposure to radiotherapy and other therapies, as well as histological low-grade and high grade regions of DIPGs .	('DIPGs', 'Chemical', '-', (247, 252))	('histone H3', 'Protein', (13, 23))	('mutations', 'Var', (29, 38))	('K27M', 'Mutation', 'p.K27M', (24, 28))	('H3', 'Chemical', 'MESH:C012616', (21, 23))
66311	25230881	All of these different levels of chromatin regulation are increasingly understood to play critical roles in oncogenesis, with numerous recurrent mutations observed in chromatin writers, erasers, readers and remodelers in a diverse series of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('oncogenesis', 'Disease', (108, 119))	('mutations', 'Var', (145, 154))	('human', 'Species', '9606', (241, 246))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('observed', 'Reg', (155, 163))
66313	25230881	The K27M mutation occurs at a specific lysine methylation/acetylation site, and as such was immediately presumed to have profound consequences on the control of gene expression associated with this key residue.	('control of gene expression', 'MPA', (150, 176))	('lysine', 'Chemical', 'MESH:D008239', (39, 45))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('consequences', 'Reg', (130, 142))	('K27M', 'Var', (4, 8))
66314	25230881	Trimethylated lysine 27 interacts with the polycomb repressive complex (PRC2) to repress transcription of target genes, a process seemingly key in stem cell regulation and development.	('repress transcription', 'MPA', (81, 102))	('Trimethylated', 'Var', (0, 13))	('Trimethylated lysine', 'Chemical', '-', (0, 20))	('interacts', 'Interaction', (24, 33))
66315	25230881	K27M (and to a lesser extent K27I) represents the only amino acid substitution at this residue which can ablate this trimethylation, suggestive of why this specific mutation is selected for in pHGG.	('K27I', 'Mutation', 'p.K27I', (29, 33))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('K27I', 'Var', (29, 33))	('ablate', 'NegReg', (105, 111))	('trimethylation', 'MPA', (117, 131))	('K27M', 'Var', (0, 4))
66316	25230881	What is more extraordinary is that although the mutant histone appears to represent only 3.6-17.6% of the total H3 pool in the cell, loss of H3K27me3 is near-absolute, indicative of a trans-dominant negative effect across all three isoforms of the wild-type H3 protein.	('mutant', 'Var', (48, 54))	('H3', 'Chemical', 'MESH:C012616', (141, 143))	('negative', 'NegReg', (199, 207))	('H3', 'Chemical', 'MESH:C012616', (112, 114))	('loss', 'NegReg', (133, 137))	('H3K27me3', 'Protein', (141, 149))	('H3', 'Chemical', 'MESH:C012616', (258, 260))
66317	25230881	In addition, the predicted de-repression of PRC2 target genes is clearly observed in K27M mutant tumours, likely influencing diverse pro-tumourigenic processes.	('tumour', 'Disease', (97, 103))	('K27M', 'Mutation', 'p.K27M', (85, 89))	('tumours', 'Disease', (97, 104))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('K27M mutant', 'Var', (85, 96))	('tumour', 'Disease', (137, 143))	('de-repression', 'NegReg', (27, 40))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
66318	25230881	This differential binding of mutated H3.3 variants may be even more pronounced in cortical tumours harboring G34R/V mutations.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('variants', 'Var', (42, 50))	('H3.3', 'Gene', (37, 41))	('binding', 'Interaction', (18, 25))	('cortical tumours', 'Disease', (82, 98))	('cortical tumours', 'Disease', 'MESH:D009369', (82, 98))	('G34R', 'SUBSTITUTION', 'None', (109, 113))	('G34R', 'Var', (109, 113))	('H3.3', 'Gene', '3020', (37, 41))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
66319	25230881	The mutated residue is not itself a known target of post-translational modification, however it is adjacent to the lysine at position 36, trimethylation of which is associated with activation of gene transcription as well as effects on alternative splicing and DNA repair.	('trimethylation', 'Var', (138, 152))	('gene transcription', 'MPA', (195, 213))	('lysine', 'Chemical', 'MESH:D008239', (115, 121))	('alternative splicing', 'MPA', (236, 256))	('effects', 'Reg', (225, 232))	('activation', 'PosReg', (181, 191))	('DNA repair', 'MPA', (261, 271))
66320	25230881	The glycine-to-arginine G34 substitution has been shown to diminish trimethylation at the K36 position in vitro, however only on the mutant allele.	('arginine', 'Chemical', 'MESH:D001120', (15, 23))	('K36', 'Gene', (90, 93))	('glycine-to-arginine', 'Var', (4, 23))	('glycine', 'Chemical', 'MESH:D005998', (4, 11))	('K36', 'Gene', '8689', (90, 93))	('diminish', 'NegReg', (59, 67))
66321	25230881	Thus, the G34 mutations do not exert the same dominant effect over the entire cellular pool of histone H3 that is observed with K27M mutations.	('G34 mutations', 'Var', (10, 23))	('H3', 'Chemical', 'MESH:C012616', (103, 105))	('K27M mutations', 'Var', (128, 142))	('K27M', 'Mutation', 'p.K27M', (128, 132))
66322	25230881	In a single cell line model of G34V mutant paediatric glioblastoma, the mutant protein was found to bind at a distinct set of target genes associated with cortical development and stem cell maintenance.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('mutant', 'Var', (72, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('protein', 'Protein', (79, 86))	('cortical development', 'CPA', (155, 175))	('G34V', 'Mutation', 'p.G34V', (31, 35))	('G34V mutant', 'Var', (31, 42))	('bind', 'Interaction', (100, 104))	('glioblastoma', 'Disease', (54, 66))
66324	25230881	This upregulation of MYCN was also seen in primary paediatric tumours with G34R/V mutations compared to H3F3A wild-type, with the exception of MYCN amplified cases, which are mutually exclusive with histone mutations.	('G34R', 'Var', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('upregulation', 'PosReg', (5, 17))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('mutations', 'Var', (82, 91))	('H3F3A', 'Gene', '3020', (104, 109))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('H3F3A', 'Gene', (104, 109))	('G34R', 'SUBSTITUTION', 'None', (75, 79))	('tumours', 'Disease', (62, 69))
66325	25230881	While therapeutic approaches to directly target H3.3 mutations remain elusive, numerous strategies have emerged to destabilise the MYCN protein.	('MYCN protein', 'Protein', (131, 143))	('H3.3', 'Gene', '3020', (48, 52))	('destabilise', 'NegReg', (115, 126))	('mutations', 'Var', (53, 62))	('H3.3', 'Gene', (48, 52))
66329	25230881	Recently, alternate histone H3 mutations were found in two rare childhood bone tumours.	('mutations', 'Var', (31, 40))	('bone tumours', 'Disease', (74, 86))	('histone H3', 'Protein', (20, 30))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('bone tumours', 'Disease', 'MESH:D001859', (74, 86))	('H3', 'Chemical', 'MESH:C012616', (28, 30))	('found', 'Reg', (46, 51))
66330	25230881	Giant cell tumours of bone harbor G34W or G34L mutations in H3F3A in 92% cases, indicating that different amino acid substitutions for G34 may be oncogenic in different tumour types.	('H3F3A', 'Gene', '3020', (60, 65))	('H3F3A', 'Gene', (60, 65))	('tumour', 'Disease', (169, 175))	('G34L', 'Mutation', 'p.G34L', (42, 46))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('G34W', 'Var', (34, 38))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('G34L', 'Var', (42, 46))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('G34W', 'Mutation', 'p.G34W', (34, 38))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Disease', (11, 17))	('tumours', 'Disease', (11, 18))
66331	25230881	In addition, 95% of chondroblastomas have K36M mutations in H3F3B, which encodes the histone variant H3.3.	('H3F3B', 'Gene', (60, 65))	('H3F3B', 'Gene', '3021', (60, 65))	('H3.3', 'Gene', (101, 105))	('H3.3', 'Gene', '3020', (101, 105))	('chondroblastomas', 'Disease', (20, 36))	('K36M', 'Mutation', 'p.K36M', (42, 46))	('chondroblastomas', 'Disease', 'MESH:D002804', (20, 36))	('K36M mutations', 'Var', (42, 56))
66332	25230881	Intriguingly, the substitution of methionine for lysine results in a dominant loss of all trimethylation of lysine 36, thus showing a similar function to the K27M mutation, with both mutations showing specificity for dominantly decreasing trimethylation of the lysine in the same position as the mutation.	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('lysine', 'Chemical', 'MESH:D008239', (108, 114))	('trimethylation', 'MPA', (239, 253))	('decreasing', 'NegReg', (228, 238))	('trimethylation of lysine 36', 'MPA', (90, 117))	('K27M', 'Mutation', 'p.K27M', (158, 162))	('methionine', 'Chemical', 'MESH:D008715', (34, 44))	('loss', 'NegReg', (78, 82))	('K27M', 'Var', (158, 162))	('substitution', 'Var', (18, 30))	('lysine', 'Chemical', 'MESH:D008239', (261, 267))	('methionine', 'Var', (34, 44))
66333	25230881	It remains to be seen whether additional tumour types harbor similar histone mutations, and whether there is a specific commonality yet to be elucidated between bone and brain development.	('tumour', 'Disease', (41, 47))	('mutations', 'Var', (77, 86))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))
66334	25230881	Paediatric HGGs with histone H3 mutations were associated with distinct signatures of genome-wide DNA methylation.	('mutations', 'Var', (32, 41))	('H3', 'Chemical', 'MESH:C012616', (29, 31))	('histone H3', 'Protein', (21, 31))
66335	25230881	These methylation signatures as well as the profound and differential gene expression signatures associated with histone H3 mutations also provide clues to the developmental origins of the tumours in which they are found.	('tumours', 'Disease', (189, 196))	('mutations', 'Var', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('histone H3', 'Gene', (113, 123))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('tumours', 'Disease', 'MESH:D009369', (189, 196))	('H3', 'Chemical', 'MESH:C012616', (121, 123))
66339	25230881	By contrast, K27M signatures overlap with hindbrain developmental structures at later fetal timepoints, and likely point to a different cell of origin.	('K27M signatures', 'Var', (13, 28))	('K27M', 'Mutation', 'p.K27M', (13, 17))	('hindbrain developmental structures', 'CPA', (42, 76))	('overlap', 'Reg', (29, 36))
66340	25230881	Of note, the gene expression signatures of K27M mutant tumours from the pons and thalamus show strong similarities, suggestive that these tumours share a common origin and ought to be considered together clinically - supported by the dismal clinical outcome for a significant proportion of thalamic GBM.	('tumours', 'Disease', (55, 62))	('tumours', 'Disease', (138, 145))	('mutant', 'Var', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('K27M', 'Gene', (43, 47))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', 'MESH:D009369', (55, 62))	('K27M', 'Mutation', 'p.K27M', (43, 47))
66343	25230881	The histone chaperones ATRX or DAXX are mutated in 15-25% of tumours, co-segregating with G34R/V mutations.	('DAXX', 'Gene', '1616', (31, 35))	('G34R', 'SUBSTITUTION', 'None', (90, 94))	('ATRX', 'Gene', '546', (23, 27))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('G34R', 'Var', (90, 94))	('mutated', 'Var', (40, 47))	('DAXX', 'Gene', (31, 35))	('tumours', 'Disease', (61, 68))	('ATRX', 'Gene', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
66344	25230881	These proteins are involved in the loading of histone H3.3 to the heterochromatic regions at the telomeres, and the concurrent H3F3A and ATRX/DAXX mutant tumours are strongly associated with a telomerase-independent alternative lengthening of telomeres (ALT) phenotype in a proportion of paediatric HGG.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('mutant', 'Var', (147, 153))	('ATRX', 'Gene', (137, 141))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('associated with', 'Reg', (175, 190))	('DAXX', 'Gene', '1616', (142, 146))	('H3F3A', 'Gene', '3020', (127, 132))	('H3.3', 'Gene', (54, 58))	('alternative lengthening of telomeres', 'CPA', (216, 252))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('ATRX', 'Gene', '546', (137, 141))	('tumours', 'Disease', (154, 161))	('H3F3A', 'Gene', (127, 132))	('DAXX', 'Gene', (142, 146))	('H3.3', 'Gene', '3020', (54, 58))
66345	25230881	In adults, mutations in ATRX and the telomerase reverse transcriptase (TERT) promoter are mutually exclusive and represent alternative mechanisms to lengthen telomeres.	('telomeres', 'CPA', (158, 167))	('mutations', 'Var', (11, 20))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (71, 75))	('ATRX', 'Gene', (24, 28))	('telomerase reverse transcriptase', 'Gene', (37, 69))	('ATRX', 'Gene', '546', (24, 28))	('lengthen', 'PosReg', (149, 157))	('telomerase reverse transcriptase', 'Gene', '7015', (37, 69))
66347	25230881	In addition, the specific methyltransferase responsible for depositing the methyl marks at the K36 residue, SETD2, is also found mutated in 5-15% of paediatric HGG.	('SETD2', 'Gene', (108, 113))	('K36', 'Gene', (95, 98))	('mutated', 'Var', (129, 136))	('SETD2', 'Gene', '29072', (108, 113))	('K36', 'Gene', '8689', (95, 98))
66350	25230881	Thus, in paediatric HGG, disrupted regulation of K27 modification is mediated directly through mutation of histone H3.	('H3', 'Chemical', 'MESH:C012616', (115, 117))	('K27', 'Gene', '342574', (49, 52))	('mediated', 'Reg', (69, 77))	('histone H3', 'Protein', (107, 117))	('K27', 'Gene', (49, 52))	('mutation', 'Var', (95, 103))
66351	25230881	Further non-recurrent mutations are found in diverse chromatin/reader writers such as members of the myeloid/lymphoid or mixed-lineage leukemia (MLL), lysine (K)-specific demethylase (KDM) and chromodomain helicase DNA (CHD) families, in common with other tumour types including primary adult GBM.	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('tumour', 'Disease', (256, 262))	('CHD', 'Disease', 'None', (220, 223))	('leukemia', 'Disease', 'MESH:D007938', (135, 143))	('CHD', 'Disease', (220, 223))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('MLL', 'Gene', (145, 148))	('MLL', 'Gene', '4297', (145, 148))	('lymphoid', 'Disease', 'MESH:D008223', (109, 117))	('mutations', 'Var', (22, 31))	('leukemia', 'Disease', (135, 143))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('lymphoid', 'Disease', (109, 117))	('lysine', 'Chemical', 'MESH:D008239', (151, 157))
66353	25230881	Targeting the downstream consequences of these mutations may also prove to be useful, such as MYCN in G34R/V tumours, and specific K27M targets such as CDK6 and PDGFRA, also dysregulated by gene amplification, pointing to their potential importance in paediatric gliomagenesis.	('G34R', 'Var', (102, 106))	('CDK6', 'Gene', '1021', (152, 156))	('PDGFRA', 'Gene', (161, 167))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('PDGFRA', 'Gene', '5156', (161, 167))	('glioma', 'Disease', (263, 269))	('V tumours', 'Disease', 'MESH:D009369', (107, 116))	('mutations', 'Var', (47, 56))	('K27M', 'Gene', (131, 135))	('V tumours', 'Disease', (107, 116))	('dysregulated', 'Var', (174, 186))	('K27M', 'Mutation', 'p.K27M', (131, 135))	('G34R', 'SUBSTITUTION', 'None', (102, 106))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('MYCN', 'Disease', (94, 98))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('CDK6', 'Gene', (152, 156))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
66354	25230881	The identification of recurrent mutations in the BMP receptor ACVR1/ALK2 in 46/195 (24%) DIPGs, but not in more than 100 non-brainstem paediatric high-grade gliomas provides another clear example of unique selective pressures driving DIPGs.	('DIPGs', 'Chemical', '-', (89, 94))	('BMP', 'Gene', (49, 52))	('DIPGs', 'Chemical', '-', (234, 239))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('ALK2', 'Gene', '90', (68, 72))	('ALK2', 'Gene', (68, 72))	('mutations', 'Var', (32, 41))	('gliomas', 'Disease', (157, 164))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('BMP', 'Gene', '649', (49, 52))
66355	25230881	ACVR1 mutant DIPGs have an earlier age of diagnosis and longer overall survival time, occur more frequently in females, and frequently also contain histone H3.1 K27M mutations (80%).	('contain', 'Reg', (140, 147))	('mutant', 'Var', (6, 12))	('DIPGs', 'Chemical', '-', (13, 18))	('K27M', 'Mutation', 'p.K27M', (161, 165))	('ACVR1', 'Gene', (0, 5))	('K27M mutations', 'Var', (161, 175))	('longer', 'PosReg', (56, 62))	('H3.1', 'Gene', (156, 160))	('H3.1', 'Gene', '8352', (156, 160))
66356	25230881	Given the apparently equivalent consequence of K27M mutations in H3.1 or H3.3 to decrease total cellular levels of H3K27me3, the significant co-occurrence of ACVR1 and HIST1H3B mutations may reflect a specific developmental setting.	('K27M mutations', 'Var', (47, 61))	('K27M', 'Mutation', 'p.K27M', (47, 51))	('decrease', 'NegReg', (81, 89))	('H3.1', 'Gene', (65, 69))	('HIST1H3B', 'Gene', (168, 176))	('mutations', 'Var', (177, 186))	('HIST1H3B', 'Gene', '8358', (168, 176))	('ACVR1', 'Gene', (158, 163))	('H3.3', 'Gene', '3020', (73, 77))	('H3.1', 'Gene', '8352', (65, 69))	('H3.3', 'Gene', (73, 77))
66357	25230881	Surprisingly, some of the same somatic ACVR1 mutations identified in DIPG are found as heterozygous germline mutations causing the congenital malformation syndrome fibrodysplasia ossificans progressiva (FOP), a disease characterized by the formation of heterotopic ossifications in soft tissues at sites of inflammation.	('inflammation', 'Disease', 'MESH:D007249', (307, 319))	('inflammation', 'Disease', (307, 319))	('mutations', 'Var', (45, 54))	('ACVR1', 'Gene', (39, 44))	('heterotopic ossifications', 'Phenotype', 'HP:0011986', (253, 278))	('DIPG', 'Gene', (69, 73))	('congenital malformation syndrome fibrodysplasia ossificans progressiva', 'Disease', 'MESH:D009221', (131, 201))	('causing', 'Reg', (119, 126))	('DIPG', 'Chemical', '-', (69, 73))
66359	25230881	This strongly suggests that ACVR1 mutations do not have a potent tumour initiating effect in DIPG, but rather provide a selective advantage when they are combined with other mutations.	('DIPG', 'Chemical', '-', (93, 97))	('advantage', 'PosReg', (130, 139))	('tumour', 'Disease', (65, 71))	('DIPG', 'Disease', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('ACVR1', 'Gene', (28, 33))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('combined', 'Interaction', (154, 162))	('mutations', 'Var', (34, 43))
66361	25230881	Mutations in ACVR1 associated with DIPG encode amino acid substitutions in the ATP binding pocket of the kinase domain, or in the adjacent glycine/serine-rich inhibitory domain, and would be predicted to result in a shift of the enzyme to the active conformation.	('associated', 'Reg', (19, 29))	('substitutions', 'Var', (58, 71))	('result in', 'Reg', (204, 213))	('DIPG', 'Chemical', '-', (35, 39))	('active conformation', 'MPA', (243, 262))	('shift', 'Reg', (216, 221))	('serine', 'Chemical', 'MESH:D012694', (147, 153))	('ACVR1', 'Gene', (13, 18))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('DIPG', 'Disease', (35, 39))	('Mutations', 'Var', (0, 9))	('glycine', 'Chemical', 'MESH:D005998', (139, 146))
66362	25230881	Indeed, mutations of these residues induce a weak gain of function, as determined by increased phosphorylation of the downstream substrates SMAD1/5/8.	('SMAD1/5', 'Gene', (140, 147))	('mutations', 'Var', (8, 17))	('function', 'MPA', (58, 66))	('increased', 'PosReg', (85, 94))	('SMAD1/5', 'Gene', '4086;4090', (140, 147))	('phosphorylation', 'MPA', (95, 110))
66363	25230881	As in the wild-type setting, interaction of mutant ACVR1 with type II BMP receptors is still required for active signaling.	('BMP', 'Gene', (70, 73))	('interaction', 'Interaction', (29, 40))	('ACVR1', 'Gene', (51, 56))	('mutant', 'Var', (44, 50))	('BMP', 'Gene', '649', (70, 73))
66365	25230881	Expression of ACVR1 mutations found in DIPG disrupts normal dorsoventral patterning, and causes an increased development of ventral structures at the expense of dorsal structures in zebrafish embryos, phenocopying the effects of activated BMP signaling.	('disrupts', 'NegReg', (44, 52))	('development', 'CPA', (109, 120))	('dorsoventral patterning', 'CPA', (60, 83))	('zebrafish', 'Species', '7955', (182, 191))	('BMP', 'Gene', '649', (239, 242))	('DIPG', 'Chemical', '-', (39, 43))	('ACVR1', 'Gene', (14, 19))	('increased', 'PosReg', (99, 108))	('BMP', 'Gene', (239, 242))	('mutations', 'Var', (20, 29))
66367	25230881	Consistent with overactive BMP signaling decreasing the pool of oligodendrocytes, central nervous sytem (CNS) demyelination was detected in a mouse knock-in model carrying the Acvr1 R206H mutation found in both FOP and DIPG, and white matter lesions perhaps associated with demyelination were found in a small group of FOP patients evaluated for CNS abnormalities.	('Acvr1', 'Gene', '11477', (176, 181))	('mouse', 'Species', '10090', (142, 147))	('BMP', 'Gene', '649', (27, 30))	('pool of oligodendrocytes', 'MPA', (56, 80))	('CNS abnormalities', 'Disease', (346, 363))	('DIPG', 'Chemical', '-', (219, 223))	('patients', 'Species', '9606', (323, 331))	('CNS abnormalities', 'Disease', 'MESH:D002493', (346, 363))	('white matter lesions', 'Disease', (229, 249))	('overactive', 'PosReg', (16, 26))	('demyelination', 'Phenotype', 'HP:0011096', (110, 123))	('demyelination', 'Disease', (110, 123))	('Acvr1', 'Gene', (176, 181))	('BMP', 'Gene', (27, 30))	('R206H', 'Var', (182, 187))	('demyelination', 'Disease', 'MESH:D003711', (110, 123))	('R206H', 'Mutation', 'rs121912678', (182, 187))	('white matter lesions', 'Disease', 'MESH:D056784', (229, 249))	('FOP', 'Disease', (211, 214))	('decreasing', 'NegReg', (41, 51))	('demyelination', 'Phenotype', 'HP:0011096', (274, 287))	('demyelination', 'Disease', (274, 287))	('demyelination', 'Disease', 'MESH:D003711', (274, 287))
66368	25230881	In adult glioblastoma cancer stem cells, BMP signaling induced differentiation in one study, and proliferation in another, depending on epigenetic silencing of BMP receptor 1B.	('BMP', 'Gene', (41, 44))	('epigenetic silencing', 'Var', (136, 156))	('differentiation', 'CPA', (63, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (9, 21))	('BMP', 'Gene', '649', (160, 163))	('adult glioblastoma cancer', 'Disease', 'MESH:D005909', (3, 28))	('proliferation', 'CPA', (97, 110))	('BMP', 'Gene', (160, 163))	('adult glioblastoma cancer', 'Disease', (3, 28))	('BMP', 'Gene', '649', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('induced', 'Reg', (55, 62))
66370	25230881	Somatic activating mutations in ACVR1 presumably function as oncogenes in DIPG, likely conferring different downstream cellular responses in this specific context, consistent with different outcomes of BMP signaling during brain development.	('BMP', 'Gene', (202, 205))	('mutations', 'Var', (19, 28))	('DIPG', 'Chemical', '-', (74, 78))	('BMP', 'Gene', '649', (202, 205))	('activating', 'PosReg', (8, 18))	('DIPG', 'Disease', (74, 78))	('ACVR1', 'Gene', (32, 37))
66371	25230881	Indeed, ACVR1 mutations were significantly associated with tumours from younger children, suggesting a developmental context for this oncogenic signal even within DIPG.	('ACVR1', 'Gene', (8, 13))	('DIPG', 'Chemical', '-', (163, 167))	('children', 'Species', '9606', (80, 88))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('associated', 'Reg', (43, 53))	('mutations', 'Var', (14, 23))	('tumours', 'Disease', (59, 66))
66372	25230881	Overall, paediatric HGGs share histological and clinical features with adult HGGs, as well as mutations in common cancer pathways.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('paediatric', 'Var', (9, 19))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
66376	25230881	The extremely high frequency of histone H3 mutations in DIPG revealed a surprising unifying molecular mechanism driving the disease, and therefore offers hope that if these mutations could be targeted, that effective treatment for this devastating disease could be possible.	('H3', 'Chemical', 'MESH:C012616', (40, 42))	('mutations', 'Var', (43, 52))	('histone H3', 'Protein', (32, 42))	('DIPG', 'Chemical', '-', (56, 60))
66377	25230881	While there have been exciting advances in understanding some functional consequences of histone H3 mutations, how these mutations contribute to oncogenesis, and the basis for their regional selectivity remain unclear.	('mutations', 'Var', (100, 109))	('H3', 'Chemical', 'MESH:C012616', (97, 99))	('histone H3', 'Protein', (89, 99))	('oncogenesis', 'CPA', (145, 156))	('contribute', 'Reg', (131, 141))
66378	25230881	Similarly, understanding the oncogenic output of other context-specific mutations such as aberrant BMP signaling in DIPGs is critical.	('DIPGs', 'Disease', (116, 121))	('BMP', 'Gene', '649', (99, 102))	('aberrant', 'Var', (90, 98))	('BMP', 'Gene', (99, 102))	('DIPGs', 'Chemical', '-', (116, 121))
66379	25230881	It remains to be determined how therapeutic targeting of paediatric HGG-specific mutations may alter activity of other signalling pathways in tumor cells or impact non-tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('other signalling pathways', 'Pathway', (113, 138))	('tumor', 'Disease', (168, 173))	('HGG-specific', 'Gene', (68, 80))	('tumor', 'Disease', (142, 147))	('alter', 'Reg', (95, 100))	('activity', 'MPA', (101, 109))	('impact', 'Reg', (157, 163))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
66380	25230881	Although a paucity of in vitro and in vivo models remains a major limitation in translating these new findings into patient benefit, knowledge of these mutations present an opportunity for new therapeutic development as well as novel insights into connections between chromatin regulation, BMP signaling and tumourigenesis.	('mutations', 'Var', (152, 161))	('tumour', 'Disease', 'MESH:D009369', (308, 314))	('patient', 'Species', '9606', (116, 123))	('tumour', 'Disease', (308, 314))	('BMP', 'Gene', '649', (290, 293))	('connections', 'Interaction', (248, 259))	('BMP', 'Gene', (290, 293))	('insights', 'Reg', (234, 242))	('tumour', 'Phenotype', 'HP:0002664', (308, 314))
66384	25230881	Aberrant epigenetic regulation plays an important role in paediatric high-grade gliomas, with hotspot pK27M histone H3 mutations found in nearly 80% of diffuse intrinsic pontine gliomas (DIPGs), and alternative pG34R/V mutations found in paediatric high-grade gliomas of the cerebral hemispheres.	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('gliomas', 'Disease', 'MESH:D005910', (260, 267))	('gliomas', 'Disease', (178, 185))	('G34R/V', 'Mutation', 'rs1057519902', (212, 218))	('glioma', 'Phenotype', 'HP:0009733', (260, 266))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Phenotype', 'HP:0009733', (260, 267))	('K27M', 'Mutation', 'p.K27M', (103, 107))	('gliomas of the cerebral', 'Disease', (260, 283))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('mutations', 'Var', (119, 128))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('DIPGs', 'Chemical', '-', (187, 192))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('gliomas of the cerebral', 'Disease', 'MESH:C564230', (260, 283))	('pG34R/V', 'Gene', (211, 218))	('gliomas', 'Disease', (80, 87))	('H3', 'Chemical', 'MESH:C012616', (116, 118))	('gliomas', 'Disease', (260, 267))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
66385	25230881	Recurrent mutations of the BMP receptor ACVR1/ALK2 are restricted to the youngest DIPG patients, highlighting critical connections between development and gliomagenesis.	('BMP', 'Gene', (27, 30))	('ALK2', 'Gene', (46, 50))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('DIPG', 'Chemical', '-', (82, 86))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('BMP', 'Gene', '649', (27, 30))	('ALK2', 'Gene', '90', (46, 50))	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (87, 95))	('glioma', 'Disease', (155, 161))
66387	25230881	An improved understanding of the oncogenic mutations driving paediatric diffuse HGG has identified new potential therapeutic targets, and shown that different strategies will be needed to combat this disease in children and adults.	('paediatric diffuse HGG', 'Disease', (61, 83))	('mutations', 'Var', (43, 52))	('children', 'Species', '9606', (211, 219))
66391	26251628	Maximal safe surgical resection followed by radiotherapy (RT) was considered as the standard of care since paramount findings regarding molecular aspects, in particular co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19, revealed that these subsets of AO, benefit in terms of overall survival (OS) and progression-free survival (PFS), from the addition of chemotherapy to RT.	('progression-free survival', 'CPA', (330, 355))	('co-deletion', 'Var', (169, 180))	('overall survival', 'CPA', (304, 320))	('benefit', 'PosReg', (284, 291))	('short arm', 'Phenotype', 'HP:0009824', (188, 197))	('OS', 'Gene', '17451', (322, 324))
66392	26251628	Allelic losses of chromosomes 1p and 19q occur in 50%-70% of both low-grade and anaplastic tumors, representing a strong prognostic factor and a powerful predictor of prolonged survival.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Allelic losses', 'Var', (0, 14))	('anaplastic tumors', 'Disease', 'MESH:D002277', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('anaplastic tumors', 'Disease', (80, 97))
66393	26251628	Several other molecular markers have potential clinical significance as IDH1 mutations, confirming the strong prognostic role for OS.	('OS', 'Gene', '17451', (130, 132))	('IDH1', 'Gene', '3417', (72, 76))	('mutations', 'Var', (77, 86))	('IDH1', 'Gene', (72, 76))
66415	26251628	Allelic losses of chromosomes 1p and 19q represent an important molecular signature of OD and occur in 50%-70% of both low-grade and anaplastic tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('Allelic losses', 'Var', (0, 14))	('anaplastic tumors', 'Disease', (133, 150))	('occur', 'Reg', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('anaplastic tumors', 'Disease', 'MESH:D002277', (133, 150))
66417	26251628	In 2012, the follow-up results of more than 11 years from two distinct studies (RTOG 9402 and EORTC 26951) showed that the addition of CHT to radiotherapy (RT) could benefit patients with AO tumors with 1p/19q co-deletion in terms of OS.	('OS', 'Gene', '17451', (234, 236))	('AO tumors', 'Disease', (188, 197))	('1p/19q co-deletion', 'Var', (203, 221))	('patients', 'Species', '9606', (174, 182))	('benefit', 'PosReg', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('AO tumors', 'Disease', 'MESH:D009369', (188, 197))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
66420	26251628	As in the other study, the presence of a p53 mutation was inversely associated with 1p and 19q loss.	('p53', 'Gene', '7157', (41, 44))	('associated', 'Reg', (68, 78))	('mutation', 'Var', (45, 53))	('presence', 'Var', (27, 35))	('p53', 'Gene', (41, 44))	('1p and', 'Disease', (84, 90))
66421	26251628	In contrast, the loss of all or part of chromosome 10 was less common in OD than in astrocytomas and has been associated with a poor prognosis.	('astrocytomas', 'Disease', 'MESH:D001254', (84, 96))	('astrocytomas', 'Disease', (84, 96))	('astrocytoma', 'Phenotype', 'HP:0009592', (84, 95))	('loss', 'Var', (17, 21))	('less', 'NegReg', (58, 62))
66422	26251628	Moreover the molecular profiling of AO tumors has identified several other markers with potential clinical significance, such as mutations of IDH and CDKN2A, as well as the candidate tumor suppressor genes targeted by losses of 1p and 19q genes, CIC on 19q13.2 and FUBP1 on 1p31.1, that have only recently been discovered; however, these markers require further validation before they can be implemented as clinical decision-making tools.	('losses', 'NegReg', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('FUBP1', 'Gene', (265, 270))	('CIC', 'Gene', '23152', (246, 249))	('AO tumors', 'Disease', (36, 45))	('IDH', 'Gene', (142, 145))	('AO tumors', 'Disease', 'MESH:D009369', (36, 45))	('CDKN2A', 'Gene', (150, 156))	('FUBP1', 'Gene', '8880', (265, 270))	('IDH', 'Gene', '3417', (142, 145))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (129, 138))	('CIC', 'Gene', (246, 249))	('CDKN2A', 'Gene', '1029', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
66424	26251628	ATRX alterations are associated with an alternative lengthening of telomeres.	('alterations', 'Var', (5, 16))	('ATRX', 'Gene', '546', (0, 4))	('ATRX', 'Gene', (0, 4))
66425	26251628	The mutation analysis of ATRX in series of adult gliomas revealed a high incidence of this alteration in diffuse astrocytomas (63%) compared with the lower incidence observed in pure ODs (20%).	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('ATRX', 'Gene', (25, 29))	('astrocytomas', 'Disease', (113, 125))	('mutation', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('adult gliomas', 'Disease', (43, 56))	('ATRX', 'Gene', '546', (25, 29))	('astrocytomas', 'Disease', 'MESH:D001254', (113, 125))	('adult gliomas', 'Disease', 'MESH:D005910', (43, 56))
66427	26251628	CIC and FUBP1 mutations occurred frequently in ODs (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas (<10%).	('FUBP1', 'Gene', (8, 13))	('mutations', 'Var', (14, 23))	('astrocytomas or oligoastrocytomas', 'Disease', (93, 126))	('FUBP1', 'Gene', '8880', (8, 13))	('astrocytomas or oligoastrocytomas', 'Disease', 'MESH:D001254', (93, 126))	('ODs', 'Disease', (47, 50))	('CIC', 'Gene', '23152', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('CIC', 'Gene', (0, 3))
66429	26251628	A strong prognostic role was confirmed for IDH 1 mutations in AO tumors with regard to OS without a predictive role for CHT outcome.	('AO tumors', 'Disease', 'MESH:D009369', (62, 71))	('OS', 'Gene', '17451', (87, 89))	('mutations', 'Var', (49, 58))	('IDH 1', 'Gene', (43, 48))	('AO tumors', 'Disease', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('IDH 1', 'Gene', '3417', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
66430	26251628	In particular, in a study by van den Bent et al, a subgroup of 44/91 patients with AO tumors presented with an IDH1 mutation, and this population exhibited a significantly better survival: the 2-year survival rate for the IDH1-intact tumors was 38.3% (95% confidence interval (CI), 24.6-51.8) versus 88.4% (95% CI, 74.3-95.0) for the IDH1-mutated tumors.	('better', 'PosReg', (172, 178))	('mutation', 'Var', (116, 124))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('AO tumors', 'Disease', (83, 92))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (69, 77))	('IDH1', 'Gene', (111, 115))	('AO tumors', 'Disease', 'MESH:D009369', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('IDH1', 'Gene', '3417', (334, 338))	('tumors', 'Disease', (347, 353))	('tumors', 'Disease', (86, 92))	('IDH1', 'Gene', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('IDH1', 'Gene', '3417', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('IDH1', 'Gene', '3417', (222, 226))	('tumors', 'Disease', (234, 240))	('IDH1', 'Gene', (334, 338))
66431	26251628	IDH1 mutations were strongly associated with 1p/19q co-deletion and MGMT promoter methylation.	('IDH1', 'Gene', '3417', (0, 4))	('mutations', 'Var', (5, 14))	('1p/19q', 'Disease', (45, 51))	('MGMT', 'Gene', '4255', (68, 72))	('MGMT', 'Gene', (68, 72))	('associated', 'Reg', (29, 39))	('IDH1', 'Gene', (0, 4))	('methylation', 'MPA', (82, 93))
66432	26251628	However, the IDH1 mutations showed no relation to the outcome of adjuvant PCV CHT.	('adjuvant PCV CHT', 'Disease', (65, 81))	('IDH1', 'Gene', (13, 17))	('adjuvant PCV CHT', 'Disease', 'MESH:D001169', (65, 81))	('IDH1', 'Gene', '3417', (13, 17))	('mutations', 'Var', (18, 27))
66433	26251628	In a multivariate analysis, wild-type IDH is an independent and poor prognostic factor in anaplastic gliomas.	('gliomas', 'Disease', (101, 108))	('IDH', 'Gene', (38, 41))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('IDH', 'Gene', '3417', (38, 41))	('wild-type', 'Var', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
66434	26251628	PTEN deletion and overexpression of p53 protein are typically less frequent in oligodendroglial tumors than in astrocytic tumors.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('deletion', 'Var', (5, 13))	('astrocytic tumors', 'Disease', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('less', 'NegReg', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('PTEN', 'Gene', '5728', (0, 4))	('astrocytic tumors', 'Disease', 'MESH:D001254', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('protein', 'Protein', (40, 47))	('PTEN', 'Gene', (0, 4))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (79, 102))	('oligodendroglial tumors', 'Disease', (79, 102))	('overexpression', 'PosReg', (18, 32))
66436	26251628	The EGFRvIII mutant is most common in primary GBM and is rare in secondary GBM, and in patients with anaplastic ODs, the variant is very rare.	('primary GBM', 'Disease', (38, 49))	('mutant', 'Var', (13, 19))	('common', 'Reg', (28, 34))	('EGFR', 'Gene', (4, 8))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', '1956', (4, 8))
66441	26251628	Seizures are more closely associated with lesions in the frontal, parietal, and temporal lobes; hemiparesis and sensory neglect may also be present in fronto-parietal lesions.	('Seizures', 'Phenotype', 'HP:0001250', (0, 8))	('Seizures', 'Disease', (0, 8))	('sensory neglect', 'Disease', (112, 127))	('lesions', 'Var', (42, 49))	('hemiparesis', 'Disease', 'MESH:D010291', (96, 107))	('Seizure', 'Phenotype', 'HP:0001250', (0, 7))	('hemiparesis', 'Disease', (96, 107))	('hemiparesis', 'Phenotype', 'HP:0001269', (96, 107))	('associated', 'Reg', (26, 36))	('Seizures', 'Disease', 'MESH:D012640', (0, 8))
66460	26251628	It appears that the integration of regional cerebral blood volume and high-resolution MR spectroscopy indices may aid in the detection of ODs with 1p/19q loss of heterozygosity; in particular, in lesions that grow as compact and hypercellular tumors, spectroscopy shows elevated levels of Cho/Cr, and there is a significantly higher susceptibility effect.	('Cr', 'Chemical', 'MESH:D002857', (293, 295))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('Cho', 'Chemical', 'MESH:C034482', (289, 292))	('compact', 'CPA', (217, 224))	('levels', 'MPA', (279, 285))	('elevated', 'PosReg', (270, 278))	('hypercellular tumors', 'Disease', (229, 249))	('hypercellular tumors', 'Disease', 'MESH:D009369', (229, 249))	('Cho/Cr', 'MPA', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('loss', 'Var', (154, 158))
66462	26251628	In particular, a resection of >90% of the contrast-enhancing volume appears to improve both progression-free survival (PFS) and OS, thereby reducing the incidence of recurrence and the risk of malignant transformation.	('resection', 'Var', (17, 26))	('reducing', 'NegReg', (140, 148))	('OS', 'Gene', '17451', (128, 130))	('improve', 'PosReg', (79, 86))	('progression-free survival', 'CPA', (92, 117))
66487	26251628	Recently, a large retrospective study of >1,000 anaplastic glioma conducted by Lassman et al showed that in patients treated with chemo-RT or CHT alone, temozolomide (TMZ) was used far more often than PCV from 2005 to 2007 (87% vs 2%, respectively), especially in patients with a 1p/19q co-deletion.	('000 anaplastic glioma', 'Disease', (44, 65))	('1p/19q co-deletion', 'Var', (280, 298))	('patients', 'Species', '9606', (108, 116))	('000 anaplastic glioma', 'Disease', 'MESH:D005910', (44, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TMZ', 'Chemical', 'MESH:D000077204', (167, 170))	('patients', 'Species', '9606', (264, 272))	('temozolomide', 'Chemical', 'MESH:D000077204', (153, 165))
66494	26251628	The authors demonstrated that 1p/19q co-deletion status and histology can be used to stratify this heterogeneous population into three risk groups, which suggests that RT vs TMZ may be a promising approach for both co-deleted and non-co-deleted AO/AOA, but not for anaplastic astrocytoma patients.	('anaplastic astrocytoma', 'Disease', (265, 287))	('non-co-deleted', 'Var', (230, 244))	('AOA', 'Disease', (248, 251))	('patients', 'Species', '9606', (288, 296))	('co-deleted', 'Var', (215, 225))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (265, 287))	('TMZ', 'Chemical', 'MESH:D000077204', (174, 177))	('astrocytoma', 'Phenotype', 'HP:0009592', (276, 287))	('AOA', 'Disease', 'MESH:C538013', (248, 251))
66497	26251628	If strong evidence now suggests that 1p/19q co-deleted AO/AOAs should be treated with adjuvant RT+CHT, no standard treatment is yet available for tumors without the 1p/19q co-deletion.	('AOA', 'Disease', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('AOA', 'Disease', 'MESH:C538013', (58, 61))	('1p/19q co-deleted', 'Var', (37, 54))	('tumors', 'Disease', (146, 152))
66515	26251628	It is well known that approximately half of all patients with low-grade gliomas show the highest incidence of seizures as one of the presenting clinical symptoms of a brain lesion, and it is considered as a good prognostic factor for survival.	('low-grade', 'Var', (62, 71))	('brain lesion', 'Disease', 'MESH:D001927', (167, 179))	('seizures', 'Disease', 'MESH:D012640', (110, 118))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('seizure', 'Phenotype', 'HP:0001250', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('seizures', 'Phenotype', 'HP:0001250', (110, 118))	('seizures', 'Disease', (110, 118))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('patients', 'Species', '9606', (48, 56))	('brain lesion', 'Disease', (167, 179))	('gliomas', 'Disease', (72, 79))
66589	25680596	Patients with LGGs with fewer than 3 risk factors for recurrence (age >=40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of >=6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ.	('LGGs', 'Disease', (14, 18))	('astrocytoma', 'Disease', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (141, 146))	('Patients', 'Species', '9606', (0, 8))	('LGG', 'Chemical', '-', (14, 17))	('TMZ', 'Chemical', 'MESH:D000077204', (294, 297))	('bihemispherical', 'Var', (105, 120))	('astrocytoma', 'Disease', 'MESH:D001254', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
66600	25680596	Initial reports described an increase in progression-free survival (PFS), but with median follow-up approaching 12 years, there is a categorical overall survival (OS) benefit for the PCV + RT arm compared to the RT-alone arm (median survival times [MSTs] of 13.3 and 7.8 years, respectively), thereby establishing chemo-radiation as a standard of care for high-risk LGG patients.	('benefit', 'PosReg', (167, 174))	('PCV + RT', 'Var', (183, 191))	('progression-free', 'MPA', (41, 57))	('LGG', 'Chemical', '-', (366, 369))	('patients', 'Species', '9606', (370, 378))	('LGG', 'Disease', (366, 369))
66623	25680596	RTOG 0424 patients were considered to have a high-risk LGG according to the definition described by Pignatti et al.	('LGG', 'Disease', (55, 58))	('LGG', 'Chemical', '-', (55, 58))	('RTOG', 'Var', (0, 4))	('patients', 'Species', '9606', (10, 18))
66628	25680596	With the recognition that additional molecular markers such as 1p19q, isocitrate dehydrogenase (IDH), and PTEN promoter methylation are also prognostically significant in this group of patients, a comprehensive molecular analysis is underway and will be reported separately.	('significant', 'Reg', (156, 167))	('isocitrate dehydrogenase', 'Gene', '3417', (70, 94))	('IDH', 'Gene', '3417', (96, 99))	('1p19q', 'Var', (63, 68))	('PTEN', 'Gene', (106, 110))	('patients', 'Species', '9606', (185, 193))	('PTEN', 'Gene', '5728', (106, 110))	('isocitrate dehydrogenase', 'Gene', (70, 94))	('IDH', 'Gene', (96, 99))
66675	25680596	Patients with methylated glioblastoma and those with codeleted anaplastic oligodendroglioma tend to have prolonged OS with chemoradiation than with radiation alone.	('prolonged', 'PosReg', (105, 114))	('oligodendroglioma', 'Disease', (74, 91))	('glioblastoma', 'Disease', (25, 37))	('Patients', 'Species', '9606', (0, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (25, 37))	('methylated', 'Var', (14, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('oligodendroglioma', 'Disease', 'MESH:D009837', (74, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
66676	25680596	IDH mutations are correlated with a higher rate of response to TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (63, 66))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))	('response', 'MPA', (51, 59))
66694	23717811	Two-thirds of pilocytic astrocytomas, a low-grade pediatric glioma, contain a translocation within the BRAF gene called KIAA1549:BRAF that causes an overactivation of the MEK/MAPK signaling cascade.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('MEK', 'Gene', (171, 174))	('pilocytic astrocytomas', 'Disease', (14, 36))	('KIAA1549', 'Gene', (120, 128))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (14, 36))	('MEK', 'Gene', '5609', (171, 174))	('KIAA1549', 'Gene', '57670', (120, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('glioma', 'Disease', (60, 66))	('overactivation', 'PosReg', (149, 163))	('translocation', 'Var', (78, 91))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('BRAF', 'Gene', (103, 107))
66696	23717811	Additionally, 15-20% of high-grade pediatric gliomas express BRAF V600E, an activating mutation of the BRAF gene.	('pediatric gliomas', 'Disease', (35, 52))	('V600E', 'Var', (66, 71))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('pediatric gliomas', 'Disease', 'MESH:D005910', (35, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('BRAF V600E', 'Var', (61, 71))	('V600E', 'Mutation', 'rs113488022', (66, 71))
66697	23717811	Pre-clinical in vivo and in vitro data in BRAF V600E gliomas demonstrate dramatic cooperation between XRT and small molecule inhibitors of BRAF V600E.	('BRAF V600E', 'Var', (42, 52))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('BRAF V600E', 'Var', (139, 149))	('V600E', 'Mutation', 'rs113488022', (144, 149))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
66701	23717811	An analog of thalidomide, CC-5103 increases the secretion of critical cytokines of the tumor microenvironment, including IL-2, IFN-gamma, TNF-alpha, and IL-10, and is currently being evaluated in clinical trials for the treatment of recurrent or refractory pediatric central nervous system tumors.	('IL-10', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('nervous system tumors', 'Phenotype', 'HP:0004375', (275, 296))	('tumor', 'Disease', (290, 295))	('IFN-gamma', 'Gene', '3458', (127, 136))	('IFN-gamma', 'Gene', (127, 136))	('increases', 'PosReg', (34, 43))	('TNF-alpha', 'Gene', '7124', (138, 147))	('TNF-alpha', 'Gene', (138, 147))	('IL-2', 'Gene', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('pediatric central nervous system tumors', 'Disease', (257, 296))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (267, 296))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('secretion of', 'MPA', (48, 60))	('tumor', 'Disease', (87, 92))	('pediatric central nervous system tumors', 'Disease', 'MESH:D016543', (257, 296))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CC-5103', 'Var', (26, 33))	('thalidomide', 'Chemical', 'MESH:D013792', (13, 24))	('IL-2', 'Gene', '3558', (121, 125))	('IL-10', 'Gene', '3586', (153, 158))
66706	23717811	This article summarizes three of the major pathways targeted by novel inhibitors in the clinic, with a particular focus on low-grade gliomas in children.	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('inhibitors', 'Var', (70, 80))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('children', 'Species', '9606', (144, 152))
66709	23717811	Molecular profiling of tissues from different human cancers has shown that mutations of the BRAF gene at locus 1799 (amino acid 600) are the second most common mutations in human cancers, found in 40% of papillary thyroid carcinomas and 40-60% of melanomas (McCubrey et al.,).	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('papillary thyroid carcinomas', 'Disease', (204, 232))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (204, 232))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (214, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('human', 'Species', '9606', (46, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (204, 232))	('melanomas', 'Disease', 'MESH:D008545', (247, 256))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('melanomas', 'Disease', (247, 256))	('BRAF', 'Gene', (92, 96))	('human', 'Species', '9606', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('melanomas', 'Phenotype', 'HP:0002861', (247, 256))	('cancers', 'Disease', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
66711	23717811	The prevalence of this mutation has led to the development of specific inhibitors against BRAF V600E, including vemurafenib (PLX4032, pre-clinical analog PLX4720) (Chapman et al.,) and dabrafenib, both of which have shown remarkable efficacy in BRAF V600E-mutated metastatic melanoma in Phase III clinical trials (Hauschild et al.,), and are discussed further below.	('BRAF', 'Gene', (90, 94))	('V600E', 'Mutation', 'rs113488022', (250, 255))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('PLX4032', 'Chemical', 'MESH:D000077484', (125, 132))	('dabrafenib', 'Chemical', 'MESH:C561627', (185, 195))	('BRAF V600E-mutated', 'Var', (245, 263))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('vemurafenib', 'Chemical', 'MESH:D000077484', (112, 123))
66712	23717811	The activating BRAF V600E is found in 10-25% of grade 2-4 pediatric gliomas (Schiffman et al.,).	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('pediatric gliomas', 'Disease', 'MESH:D005910', (58, 75))	('activating', 'PosReg', (4, 14))	('BRAF V600E', 'Var', (15, 25))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('pediatric gliomas', 'Disease', (58, 75))	('V600E', 'Var', (20, 25))
66713	23717811	In one study of 27 pediatric grade I and II pediatric brain tumors, the frequency of BRAF V600E mutation was queried using an oligonucleotide microarray, and 14 of 31 tumors (40%) were found to encode the BRAF V600E mutation (Dougherty et al.,).	('II pediatric brain tumors', 'Disease', (41, 66))	('V600E', 'Mutation', 'rs113488022', (90, 95))	('oligonucleotide', 'Chemical', 'MESH:D009841', (126, 141))	('brain tumors', 'Phenotype', 'HP:0030692', (54, 66))	('II pediatric brain tumors', 'Disease', 'MESH:D001932', (41, 66))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('brain tumor', 'Phenotype', 'HP:0030692', (54, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('BRAF V600E', 'Var', (205, 215))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('BRAF V600E', 'Gene', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('V600E', 'Mutation', 'rs113488022', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (60, 66))
66715	23717811	In some cases (five of seven in this series), these oncogenic BRAF mutations were associated with homozygous deletions of CDKN2A (Schiffman et al.,).	('associated', 'Reg', (82, 92))	('deletions', 'Var', (109, 118))	('CDKN2A', 'Gene', (122, 128))	('mutations', 'Var', (67, 76))	('CDKN2A', 'Gene', '1029', (122, 128))	('BRAF', 'Disease', (62, 66))
66717	23717811	In a study of 198 pediatric low-grade gliomas, a BRAF V600E mutation was associated with poorer outcomes and decreased progression-free survival in patients, though the poorest survival was predicted by a midline anatomic location (Horbinski et al.,).	('decreased', 'NegReg', (109, 118))	('patients', 'Species', '9606', (148, 156))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('V600E', 'Var', (54, 59))	('gliomas', 'Disease', (38, 45))	('BRAF', 'Gene', (49, 53))	('progression-free survival', 'CPA', (119, 144))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
66718	23717811	Another genetic aberration in BRAF in addition to BRAF V600E point mutations that leads to increased kinase activity in low- and high-grade pediatric brain tumors is a fusion protein of KIAA1549:BRAF that is found in the majority of pilocytic astrocytomas.	('pilocytic astrocytomas', 'Disease', (233, 255))	('astrocytoma', 'Phenotype', 'HP:0009592', (243, 254))	('kinase activity', 'MPA', (101, 116))	('V600E', 'Var', (55, 60))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (233, 255))	('brain tumors', 'Phenotype', 'HP:0030692', (150, 162))	('brain tumor', 'Phenotype', 'HP:0030692', (150, 161))	('BRAF', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (140, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('increased', 'PosReg', (91, 100))	('KIAA1549', 'Gene', (186, 194))	('KIAA1549', 'Gene', '57670', (186, 194))	('pediatric brain tumors', 'Disease', (140, 162))	('V600E', 'Mutation', 'rs113488022', (55, 60))
66720	23717811	One recent study of 51 pilocytic astrocytomas suggests that the presence of a KIAA1549:BRAF fusion should be associated with a pilocytic classification, while a BRAF V600E mutation is more prevalent in non-pilocytic gliomas (Tian et al.,).	('KIAA1549', 'Gene', (78, 86))	('associated', 'Reg', (109, 119))	('KIAA1549', 'Gene', '57670', (78, 86))	('V600E', 'Var', (166, 171))	('pilocytic classification', 'Disease', (127, 151))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('non-pilocytic gliomas', 'Disease', (202, 223))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('pilocytic astrocytomas', 'Disease', (23, 45))	('non-pilocytic gliomas', 'Disease', 'MESH:D005910', (202, 223))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (23, 45))	('V600E', 'Mutation', 'rs113488022', (166, 171))
66724	23717811	In the BRIM3 trial, vemurafenib has shown remarkable activity against BRAF V600E metastatic melanoma, with 80% of patients showing either partial or complete remission, 74% reduction in disease progression or death, and a survival advantage over patients treated with dacarbazine alone, the standard of care (Chapman et al.,).	('vemurafenib', 'Chemical', 'MESH:D000077484', (20, 31))	('death', 'Disease', 'MESH:D003643', (209, 214))	('reduction', 'NegReg', (173, 182))	('patients', 'Species', '9606', (246, 254))	('BRAF V600E', 'Var', (70, 80))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('death', 'Disease', (209, 214))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('patients', 'Species', '9606', (114, 122))	('dacarbazine', 'Chemical', 'MESH:D003606', (268, 279))	('survival advantage', 'CPA', (222, 240))
66729	23717811	A small proportion of metastatic melanoma patients has developed a secondary skin cancer called keratoacanthoma while receiving BRAF V600E inhibitors, but these are considered to be treatable lesions with local therapy (excision or radiation), and some lesions have even disappeared with discontinuation of therapy (Falchook et al.,).	('inhibitors', 'Var', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('skin cancer', 'Disease', (77, 88))	('skin cancer', 'Disease', 'MESH:D012878', (77, 88))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('keratoacanthoma', 'Disease', (96, 111))	('keratoacanthoma', 'Disease', 'MESH:D007636', (96, 111))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('patients', 'Species', '9606', (42, 50))	('keratoacanthoma', 'Phenotype', 'HP:0031525', (96, 111))	('skin cancer', 'Phenotype', 'HP:0008069', (77, 88))	('BRAF', 'Gene', (128, 132))
66730	23717811	Excitingly, pre-clinical data in intracranial xenografts of pediatric gliomas suggest a role for BRAF V600E inhibitors in the treatment of pediatric gliomas.	('pediatric gliomas', 'Disease', 'MESH:D005910', (139, 156))	('pediatric gliomas', 'Disease', (139, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('pediatric gliomas', 'Disease', (60, 77))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('inhibitors', 'Var', (108, 118))	('pediatric gliomas', 'Disease', 'MESH:D005910', (60, 77))	('BRAF', 'Gene', (97, 101))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
66731	23717811	Recently published in vivo murine data suggest that BRAF inhibitors may be effective in high-grade gliomas expressing the BRAF V600E mutation (Nicolaides et al.,).	('V600E', 'Var', (127, 132))	('gliomas', 'Disease', (99, 106))	('BRAF', 'Gene', (122, 126))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('V600E', 'Mutation', 'rs113488022', (127, 132))	('murine', 'Species', '10090', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
66732	23717811	This efficacy of PLX4720 (the pre-clinical analog of vemurafenib) has also been seen in a xenograft flank tumor mouse model of BRAF V600E-mutated pediatric pilocytic astrocytoma (our unpublished results).	('pediatric pilocytic astrocytoma', 'Disease', (146, 177))	('flank tumor', 'Disease', (100, 111))	('V600E', 'Mutation', 'rs113488022', (132, 137))	('BRAF V600E-mutated', 'Var', (127, 145))	('mouse', 'Species', '10090', (112, 117))	('pediatric pilocytic astrocytoma', 'Disease', 'MESH:D001254', (146, 177))	('flank tumor', 'Disease', 'MESH:D021501', (100, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('vemurafenib', 'Chemical', 'MESH:D000077484', (53, 64))	('PLX4720', 'Gene', (17, 24))
66733	23717811	Furthermore, in an intracranial xenograft model of BRAF V600E-mutated glioma, mice were randomized to receive vector alone, BRAF inhibitor (PLX4720) alone, radiation alone, or a combination of both radiation and BRAF inhibitor.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('BRAF', 'Gene', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('mice', 'Species', '10090', (78, 82))	('V600E-mutated', 'Var', (56, 69))
66735	23717811	Combination treatment with PLX4720 and radiation led to a lower tumor proliferation index (Ki67).	('tumor', 'Disease', (64, 69))	('lower', 'NegReg', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PLX4720', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
66736	23717811	These translational studies will inform the next generation of clinical trials of BRAF V600E inhibitors and radiation in patients with BRAF V600E-mutated brain tumors and metastases.	('BRAF V600E-mutated', 'Var', (135, 153))	('BRAF', 'Gene', (82, 86))	('V600E', 'Mutation', 'rs113488022', (140, 145))	('metastases', 'Disease', (171, 181))	('brain tumors', 'Disease', 'MESH:D001932', (154, 166))	('brain tumors', 'Phenotype', 'HP:0030692', (154, 166))	('brain tumor', 'Phenotype', 'HP:0030692', (154, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('V600E', 'Mutation', 'rs113488022', (87, 92))	('brain tumors', 'Disease', (154, 166))	('metastases', 'Disease', 'MESH:D009362', (171, 181))	('patients', 'Species', '9606', (121, 129))
66741	23717811	If the dose limiting toxicities of vemurafenib in this trial are not prohibitive to its administration in children, then a possible next step will be to provide combination treatment of vemurafenib with concurrent external beam radiation in children with BRAF V600E-mutated high-grade gliomas, or recurrent BRAF V600E-mutated low-grade gliomas.	('gliomas', 'Disease', (285, 292))	('toxicities', 'Disease', (21, 31))	('children', 'Species', '9606', (241, 249))	('gliomas', 'Disease', 'MESH:D005910', (285, 292))	('gliomas', 'Phenotype', 'HP:0009733', (285, 292))	('vemurafenib', 'Chemical', 'MESH:D000077484', (35, 46))	('glioma', 'Phenotype', 'HP:0009733', (336, 342))	('V600E', 'Mutation', 'rs113488022', (312, 317))	('BRAF V600E-mutated', 'Var', (255, 273))	('toxicities', 'Disease', 'MESH:D064420', (21, 31))	('V600E', 'Mutation', 'rs113488022', (260, 265))	('glioma', 'Phenotype', 'HP:0009733', (285, 291))	('gliomas', 'Disease', (336, 343))	('vemurafenib', 'Chemical', 'MESH:D000077484', (186, 197))	('gliomas', 'Phenotype', 'HP:0009733', (336, 343))	('gliomas', 'Disease', 'MESH:D005910', (336, 343))	('BRAF V600E-mutated', 'Var', (307, 325))	('children', 'Species', '9606', (106, 114))
66747	23717811	Whether resistance to BRAF V600E inhibitors also arises in gliomas, where EGFR and PI3K/mTOR pathways are often over-activated, remains to be seen in neuro-oncology patients treated with BRAF V600E inhibitors.	('BRAF V600E inhibitors', 'Var', (22, 43))	('over-activated', 'PosReg', (112, 126))	('PI3K/mTOR pathways', 'Pathway', (83, 101))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('oncology', 'Phenotype', 'HP:0002664', (156, 164))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('EGFR', 'Gene', '1956', (74, 78))	('V600E', 'Mutation', 'rs113488022', (192, 197))	('patients', 'Species', '9606', (165, 173))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('gliomas', 'Disease', (59, 66))	('EGFR', 'Gene', (74, 78))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
66748	23717811	Finally, pediatric oncologists should be cautioned that, with the exception of a single case report (Rush et al.,), there is little experience using dabrafenib or vemurafenib in children, and the efficacy of BRAF V600E inhibitors against tumors with the KIAA1549:BRAF molecular fusion is unknown.	('V600E', 'Var', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('vemurafenib', 'Chemical', 'MESH:D000077484', (163, 174))	('KIAA1549', 'Gene', (254, 262))	('KIAA1549', 'Gene', '57670', (254, 262))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('V600E', 'Mutation', 'rs113488022', (213, 218))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (238, 244))	('children', 'Species', '9606', (178, 186))	('dabrafenib', 'Chemical', 'MESH:C561627', (149, 159))
66749	23717811	Additionally, a recent abstract suggests that in glioma cell lines engineered to express the KIAA1549:BRAF fusion, there is resistance to therapy with BRAF V600E inhibitors, and in fact, the paradoxical growth activation (previously only seen in wild-type BRAF cells treated with BRAF V600E inhibitors) is observed (Lang et al.,).	('BRAF', 'Var', (151, 155))	('fusion', 'Var', (107, 113))	('V600E', 'Mutation', 'rs113488022', (156, 161))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('growth', 'MPA', (203, 209))	('KIAA1549', 'Gene', '57670', (93, 101))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('KIAA1549', 'Gene', (93, 101))	('V600E', 'Mutation', 'rs113488022', (285, 290))	('glioma', 'Disease', (49, 55))
66758	23717811	PRAS40 is a negative regulator of mTORC1, but phosphorylation of PRAS40 by Akt can prevent this inhibition and additionally activate the mTORC1 complex (Manning and Cantley,; Wang et al.,).	('mTORC1', 'Gene', '382056', (34, 40))	('mTORC1', 'Gene', '382056', (137, 143))	('Akt', 'Gene', '207', (75, 78))	('phosphorylation', 'Var', (46, 61))	('Akt', 'Gene', (75, 78))	('activate', 'PosReg', (124, 132))	('PRAS40', 'Gene', '84335', (0, 6))	('mTORC1', 'Gene', (137, 143))	('PRAS40', 'Gene', (0, 6))	('mTORC1', 'Gene', (34, 40))	('PRAS40', 'Gene', (65, 71))	('PRAS40', 'Gene', '84335', (65, 71))
66763	23717811	demonstrate that divergent pathways converge at mTOR to activate growth in gliomas with different driver mutations.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('activate', 'PosReg', (56, 64))	('mutations', 'Var', (105, 114))	('growth', 'MPA', (65, 71))
66768	23717811	In newly diagnosed pediatric gliomas, 80% of high-grade gliomas and 50% of low-grade gliomas showed enhanced expression of phospho-S6 and phospho-4EBP1, the major downstream targets of mTORC1.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('4EBP1', 'Gene', (146, 151))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('phospho-S6', 'Var', (123, 133))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('pediatric gliomas', 'Disease', 'MESH:D005910', (19, 36))	('mTORC1', 'Gene', (185, 191))	('enhanced', 'PosReg', (100, 108))	('mTORC1', 'Gene', '382056', (185, 191))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('4EBP1', 'Gene', '1978', (146, 151))	('gliomas', 'Disease', (56, 63))	('expression', 'MPA', (109, 119))	('pediatric gliomas', 'Disease', (19, 36))	('gliomas', 'Disease', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))
66769	23717811	Expression of phospho-S6 and/or phospho-4EBP1 has also been associated with a statistically significant decrease in progression-free survival (PFS), regardless of tumor grade (Populo et al.,).	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('4EBP1', 'Gene', '1978', (40, 45))	('tumor', 'Disease', (163, 168))	('decrease', 'NegReg', (104, 112))	('4EBP1', 'Gene', (40, 45))	('progression-free survival', 'CPA', (116, 141))	('phospho-S6', 'Var', (14, 24))
66771	23717811	In a study of 45 newly diagnosed pediatric brain tumors, there was a strong correlation between phospho-S6 expression and decreased survival.	('brain tumors', 'Phenotype', 'HP:0030692', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (33, 55))	('phospho-S6 expression', 'Var', (96, 117))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('pediatric brain tumors', 'Disease', (33, 55))	('brain tumor', 'Phenotype', 'HP:0030692', (43, 54))	('survival', 'CPA', (132, 140))	('decreased', 'NegReg', (122, 131))
66774	23717811	Also, in a molecular analysis study of 92 pilocytic astrocytomas including 43 conventional pilocytic astrocytomas, 25 clinically aggressive/recurrent pilocytic astrocytomas, and 25 anaplastic pilocytic astrocytomas, an increase in cytoplasmic phosphorylated-Akt (phospho-Akt) and phospho-S6 was associated with anaplastic histology (a more aggressive phenotype) and poorer outcomes in pilocytic astrocytomas (Rodriguez et al.,).	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (192, 214))	('astrocytoma', 'Phenotype', 'HP:0009592', (202, 213))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (150, 172))	('pilocytic astrocytomas', 'Disease', (91, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (160, 171))	('increase', 'PosReg', (219, 227))	('cytoplasmic', 'MPA', (231, 242))	('pilocytic astrocytomas', 'Disease', (42, 64))	('anaplastic histology', 'Disease', (311, 331))	('Akt', 'Gene', (258, 261))	('pilocytic astrocytomas', 'Disease', (385, 407))	('phospho-S6', 'Var', (280, 290))	('Akt', 'Gene', '207', (258, 261))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (91, 113))	('Akt', 'Gene', (271, 274))	('pilocytic astrocytomas', 'Disease', (192, 214))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (42, 64))	('astrocytoma', 'Phenotype', 'HP:0009592', (395, 406))	('Akt', 'Gene', '207', (271, 274))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (385, 407))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('pilocytic astrocytomas', 'Disease', (150, 172))
66783	23717811	PP242 is an ATP-competitive inhibitor identified by kinome profiling and has shown activity against both mTORC1 and mTORC2 (Hoang et al.,).	('mTORC2', 'Gene', (116, 122))	('activity', 'MPA', (83, 91))	('mTORC1', 'Gene', (105, 111))	('mTORC2', 'Gene', '74343', (116, 122))	('PP242', 'Var', (0, 5))	('ATP', 'Chemical', 'MESH:D000255', (12, 15))	('mTORC1', 'Gene', '382056', (105, 111))	('PP242', 'Chemical', 'MESH:C572919', (0, 5))
66784	23717811	Other active site inhibitors of mTORC kinase are at different stages of development including Torin-1 and WYE-354 (in pre-clinical studies) and AZD8055, AZD2014, OSI-027, and MLN0128 (in clinical trials) (Laplante and Sabatini,).	('Torin-1', 'Chemical', '-', (94, 101))	('WYE-354', 'Chemical', 'MESH:C000614249', (106, 113))	('Sabatini', 'Chemical', '-', (218, 226))	('AZD8055', 'Var', (144, 151))	('AZD8055', 'Chemical', 'MESH:C546624', (144, 151))	('AZD2014', 'Var', (153, 160))	('MLN0128', 'Chemical', 'MESH:C572449', (175, 182))	('AZD2014', 'Chemical', 'MESH:C585537', (153, 160))	('OSI-027', 'Chemical', 'MESH:C568605', (162, 169))	('Laplante', 'Chemical', '-', (205, 213))	('MLN0128', 'Var', (175, 182))
66785	23717811	Many early mTOR inhibitors were found to have activity against both PI3K and mTOR because of the sequence and structural homology shared by PI3K and mTOR in the ATP-binding cleft.	('PI3K', 'Disease', (68, 72))	('mTOR', 'Gene', (11, 15))	('PI3K', 'Var', (140, 144))	('ATP', 'Chemical', 'MESH:D000255', (161, 164))	('activity', 'MPA', (46, 54))	('mTOR', 'Gene', (77, 81))
66786	23717811	It soon became apparent that such dual inhibitors had "classical hinge kinase binders" as their scaffold, as in XL765 (SAR245409) (Prasad et al.,), NVP-BEZ235 (Doghman and Lalli,), GNE-317 (Salphati et al.,), OSI-027 (Bhagwat et al.,), and SF1126 (Mahadevan et al.,).	('SF1126', 'CellLine', 'CVCL:2363', (240, 246))	('GNE', 'Gene', '10020', (181, 184))	('OSI-027', 'Chemical', 'MESH:C568605', (209, 216))	('GNE', 'Gene', (181, 184))	('SF1126', 'Var', (240, 246))	('SAR245409', 'Var', (119, 128))
66792	23717811	Pre-clinical data from our laboratory strongly support a role for PI3K/mTOR inhibitors in adult and pediatric low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))	('PI3K/mTOR', 'Var', (66, 75))
66794	23717811	Furthermore, XL765 also shows synergistic activity with temozolomide in high-grade glioma xenografts (Prasad et al.,) and is currently under evaluation in Phase I clinical trials for adult brain tumors, in combination with temozolomide (Nghiemphu et al.,).	('glioma', 'Disease', (83, 89))	('brain tumors', 'Disease', (189, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('synergistic activity', 'MPA', (30, 50))	('temozolomide', 'Chemical', 'MESH:D000077204', (223, 235))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('temozolomide', 'Chemical', 'MESH:D000077204', (56, 68))	('brain tumors', 'Disease', 'MESH:D001932', (189, 201))	('XL765', 'Var', (13, 18))	('brain tumors', 'Phenotype', 'HP:0030692', (189, 201))	('brain tumor', 'Phenotype', 'HP:0030692', (189, 200))
66811	23717811	Additionally, our laboratory is currently seeking to exploit recent findings that suggest crosstalk between the BRAF and PI3K/mTOR signaling pathways as driving mutations in pediatric gliomas.	('pediatric gliomas', 'Disease', 'MESH:D005910', (174, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('BRAF', 'Pathway', (112, 116))	('PI3K/mTOR signaling pathways', 'Pathway', (121, 149))	('crosstalk', 'Reg', (90, 99))	('mutations', 'Var', (161, 170))	('pediatric gliomas', 'Disease', (174, 191))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))
66813	23717811	The neural stem cell proliferation secondary to the BRAF fusion protein is actually mediated by hyper-activation of the mTOR pathway, suggesting crosstalk between these two critical pathways in pediatric gliomagenesis (Kaul et al.,).	('neural stem cell proliferation', 'CPA', (4, 34))	('mTOR pathway', 'Pathway', (120, 132))	('glioma', 'Disease', (204, 210))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('crosstalk', 'Reg', (145, 154))	('fusion', 'Var', (57, 63))	('hyper-activation', 'PosReg', (96, 112))	('BRAF', 'Gene', (52, 56))
66814	23717811	Given the prevalence of activation of the PI3K/mTOR axis and BRAF V600E mutations in pediatric tumors, we designed a pre-clinical study to determine whether inhibitors of mTOR and of BRAF V600E cooperate to enhance cytotoxicity specifically in pediatric low-grade gliomas.	('mutations', 'Var', (72, 81))	('cytotoxicity', 'Disease', (215, 227))	('gliomas', 'Disease', (264, 271))	('enhance', 'PosReg', (207, 214))	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('cytotoxicity', 'Disease', 'MESH:D064420', (215, 227))	('pediatric tumors', 'Disease', 'MESH:D063766', (85, 101))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('BRAF V600E', 'Var', (183, 193))	('BRAF V600E', 'Gene', (61, 71))	('V600E', 'Mutation', 'rs113488022', (188, 193))	('pediatric tumors', 'Disease', (85, 101))	('activation', 'PosReg', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('V600E', 'Mutation', 'rs113488022', (66, 71))
66815	23717811	In an in vivo flank model of a pediatric pilocytic astrocytoma, subcutaneous xenografts of BT40 (which carries a BRAF V600E mutation) were treated with vehicle, PLX4720, everolimus, or combination of PLX4720 + everolimus, and the outcome measures of tumor size and animal survival were followed.	('everolimus', 'Chemical', 'MESH:D000068338', (210, 220))	('pediatric pilocytic astrocytoma', 'Disease', 'MESH:D001254', (31, 62))	('BRAF', 'Gene', (113, 117))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('BT40', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('astrocytoma', 'Phenotype', 'HP:0009592', (51, 62))	('everolimus', 'Chemical', 'MESH:D000068338', (170, 180))	('V600E', 'Var', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('pediatric pilocytic astrocytoma', 'Disease', (31, 62))	('tumor', 'Disease', (250, 255))
66816	23717811	In murine xenografts of a pilocytic astrocytoma with mutated BRAF V600E, treatment with PLX4720 + everolimus led to a statistically significant survival advantage, when compared to treatment with vehicle alone (p = 0.0002), PLX4720 alone (p = 0.0126), or everolimus alone (p = 0.0031).	('everolimus', 'Chemical', 'MESH:D000068338', (255, 265))	('pilocytic astrocytoma', 'Disease', (26, 47))	('survival', 'CPA', (144, 152))	('mutated', 'Var', (53, 60))	('BRAF', 'Gene', (61, 65))	('everolimus', 'Chemical', 'MESH:D000068338', (98, 108))	('murine', 'Species', '10090', (3, 9))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (26, 47))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))	('advantage', 'PosReg', (153, 162))	('V600E', 'Mutation', 'rs113488022', (66, 71))
66817	23717811	Treatment with PLX4720 + everolimus also led to significantly smaller tumors when compared to treatment with vehicle alone (p < 0.0001), PLX4720 alone (p < 0.0001), or everolimus alone (p = 0.0082).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('smaller', 'NegReg', (62, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('PLX4720 +', 'Var', (15, 24))	('everolimus', 'Chemical', 'MESH:D000068338', (168, 178))	('everolimus', 'Chemical', 'MESH:D000068338', (25, 35))
66822	23717811	In gliomas, there is evidence that p53 mutations significantly increase the mean vessel density of pilocytic astrocytomas, and affect important regulators of angiogenesis including thrombospondin-1, serpin E1, and MMP-9 (Gaiser et al.,).	('increase', 'PosReg', (63, 71))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (99, 121))	('p53', 'Gene', (35, 38))	('thrombospondin-1', 'Gene', (181, 197))	('MMP-9', 'Gene', (214, 219))	('p53', 'Gene', '7157', (35, 38))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('serpin E1', 'Gene', (199, 208))	('mutations', 'Var', (39, 48))	('thrombospondin-1', 'Gene', '7057', (181, 197))	('MMP-9', 'Gene', '4318', (214, 219))	('serpin E1', 'Gene', '5054', (199, 208))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('pilocytic astrocytomas', 'Disease', (99, 121))	('affect', 'Reg', (127, 133))
66828	23717811	More recently, an interesting MRI study performed in 46 adults with low-grade gliomas showed that both microvascular leakage and contrast enhancement in low-grade gliomas were associated with the lowest PFS (Piepmeier,; Dhermain et al.,).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('gliomas', 'Disease', (163, 170))	('microvascular leakage', 'CPA', (103, 124))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('contrast enhancement', 'CPA', (129, 149))	('lowest', 'NegReg', (196, 202))	('PFS', 'MPA', (203, 206))	('low-grade', 'Var', (153, 162))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))
66851	23717811	Another retrospective study of 110 patients with high-grade gliomas treated with bevacizumab suggests that treatment with low-dose bevacizumab is associated with a favorable prognosis (Lorgis et al.,).	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('bevacizumab', 'Chemical', 'MESH:D000068258', (81, 92))	('bevacizumab', 'Chemical', 'MESH:D000068258', (131, 142))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('patients', 'Species', '9606', (35, 43))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('low-dose', 'Var', (122, 130))
66932	27568035	Genetic subtype analysis revealed that ZEB1 expression was relatively increased in IDH1/2-mutant gliomas, and IDH1/2-mutant gliomas expressed significantly lower levels of many ZEB1 transcriptional targets.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('expression', 'MPA', (44, 54))	('IDH1/2-mutant', 'Gene', (83, 96))	('increased', 'PosReg', (70, 79))	('IDH1/2-mutant', 'Var', (83, 96))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Disease', (97, 104))	('ZEB1', 'Gene', '6935', (39, 43))	('ZEB1', 'Gene', (177, 181))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('ZEB1', 'Gene', (39, 43))	('ZEB1', 'Gene', '6935', (177, 181))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('lower', 'NegReg', (156, 161))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
66935	27568035	Our findings demonstrate a novel relationship between IDH1/2 mutations and expression of ZEB1 and its transcriptional targets.	('IDH1/2', 'Gene', (54, 60))	('mutations', 'Var', (61, 70))	('ZEB1', 'Gene', (89, 93))	('ZEB1', 'Gene', '6935', (89, 93))	('expression', 'MPA', (75, 85))
66941	27568035	One genetic subtype is characterized by mutations in Isocitrate Dehydrogenase 1 and 2 (IDH1/2), which are found in 70-80 % of grades II-III gliomas and 80-90 % of secondary glioblastomas (GBMs) but only 5-10 % of primary GBMs.	('IDH1/2', 'Gene', (87, 93))	('glioblastomas', 'Disease', 'MESH:D005909', (173, 186))	('GBMs', 'Phenotype', 'HP:0012174', (221, 225))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('II-III gliomas', 'Disease', (133, 147))	('glioblastomas', 'Disease', (173, 186))	('GBMs', 'Phenotype', 'HP:0012174', (188, 192))	('found', 'Reg', (106, 111))	('Isocitrate Dehydrogenase', 'Gene', '3417', (53, 77))	('mutations', 'Var', (40, 49))	('Isocitrate Dehydrogenase', 'Gene', (53, 77))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('II-III gliomas', 'Disease', 'MESH:D005910', (133, 147))	('glioblastomas', 'Phenotype', 'HP:0012174', (173, 186))
66943	27568035	A second genetic subtype of gliomas is characterized by mutations or amplifications in Epidermal Growth Factor Receptor (EGFR), Telomerase Reverse Transcriptase (TERT) and the p53 regulatorMDM4 and inactivating mutations in Phosphatase And Tensin Homolog (PTEN), Neurofibromin 1 (NF1) and Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A).	('Telomerase Reverse Transcriptase', 'Gene', (128, 160))	('p53 regulatorMDM4', 'Gene', (176, 193))	('Telomerase Reverse Transcriptase', 'Gene', '7015', (128, 160))	('gliomas', 'Disease', (28, 35))	('Neurofibromin 1', 'Gene', '4763', (263, 278))	('mutations', 'Var', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('p53 regulatorMDM4', 'Gene', '7157;4194', (176, 193))	('EGFR', 'Gene', (121, 125))	('TERT', 'Gene', (162, 166))	('TERT', 'Gene', '7015', (162, 166))	('CDKN2A', 'Gene', (327, 333))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('Cyclin-Dependent Kinase Inhibitor 2A', 'Gene', '1029', (289, 325))	('NF1', 'Gene', '4763', (280, 283))	('Epidermal Growth Factor Receptor', 'Gene', (87, 119))	('inactivating mutations', 'Var', (198, 220))	('PTEN', 'Gene', (256, 260))	('amplifications', 'Var', (69, 83))	('Cyclin-Dependent Kinase Inhibitor 2A', 'Gene', (289, 325))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('EGFR', 'Gene', '1956', (121, 125))	('NF1', 'Gene', (280, 283))	('CDKN2A', 'Gene', '1029', (327, 333))	('Neurofibromin 1', 'Gene', (263, 278))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (87, 119))	('PTEN', 'Gene', '5728', (256, 260))
66981	27568035	Surprisingly, ZEB1 expression was independently associated with an increase in overall survival in the REMBRANDT dataset (HR 0.668, 95 % CI 0.496-0.898, p=0.008), but this was not observed in the TCGA dataset (HR 0.814, 95 % CI 0.584-1.135, p = 0.225).	('expression', 'Var', (19, 29))	('increase', 'PosReg', (67, 75))	('ZEB1', 'Gene', '6935', (14, 18))	('ZEB1', 'Gene', (14, 18))	('overall survival', 'MPA', (79, 95))
66989	27568035	As mentioned previously, mutations in IDH1 and IDH2 are present in 70-80 % of grades II and III gliomas and, when present, are believed to be the earliest genetic event in gliomagenesis.	('mutations', 'Var', (25, 34))	('IDH1', 'Gene', '3417', (38, 42))	('IDH2', 'Gene', (47, 51))	('glioma', 'Disease', (172, 178))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH1', 'Gene', (38, 42))	('IDH2', 'Gene', '3418', (47, 51))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('glioma', 'Disease', (96, 102))
66990	27568035	Recent efforts have further defined genetic subtypes of IDH1/2-mutant tumors and their associations with pathologic phenotype.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('IDH1/2-mutant', 'Gene', (56, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('IDH1/2-mutant', 'Var', (56, 69))	('tumors', 'Disease', 'MESH:D009369', (70, 76))
66991	27568035	In gliomas with mutations in IDH1 or IDH2, subsequent alterations in TP53 and ATRX are associated with astrocytic differentiation whereas co-deletion of chromosome arms 1p and 19q (1p19q co-deletion), mutations in FUBP1 (on chromosome 1p), CIC (on chromosome 19q), NOTCH1 and PIK3CA are associated with oligodendroglial differentiation.	('ATRX', 'Gene', (78, 82))	('ATRX', 'Gene', '546', (78, 82))	('TP53', 'Gene', (69, 73))	('gliomas', 'Disease', (3, 10))	('CIC', 'Gene', '23152', (240, 243))	('IDH2', 'Gene', (37, 41))	('mutations', 'Var', (16, 25))	('associated', 'Reg', (87, 97))	('IDH2', 'Gene', '3418', (37, 41))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('astrocytic differentiation', 'Disease', (103, 129))	('FUBP1', 'Gene', (214, 219))	('oligodendroglial', 'Disease', (303, 319))	('oligodendroglial', 'Disease', 'None', (303, 319))	('IDH1', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (69, 73))	('PIK3CA', 'Gene', '5290', (276, 282))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('NOTCH1', 'Gene', (265, 271))	('mutations', 'Var', (201, 210))	('CIC', 'Gene', (240, 243))	('IDH1', 'Gene', '3417', (29, 33))	('alterations', 'Var', (54, 65))	('NOTCH1', 'Gene', '4851', (265, 271))	('FUBP1', 'Gene', '8880', (214, 219))	('associated', 'Reg', (287, 297))	('PIK3CA', 'Gene', (276, 282))
66992	27568035	Interestingly, it has been previously shown that the most common IDH1/2 mutations induce a ZEB1-dependent EMT in the colon and breast adenocarcinoma cell lines, but these cancers typically do not contain mutations in IDH1/2, and increased expression of ZEB1 has never been demonstrated in IDH1/2-mutant tumors.	('mutations', 'Var', (72, 81))	('induce', 'Reg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('ZEB1', 'Gene', '6935', (253, 257))	('ZEB1', 'Gene', (253, 257))	('ZEB1', 'Gene', '6935', (91, 95))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('colon and breast adenocarcinoma cell lines', 'Disease', 'MESH:C538614', (117, 159))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('ZEB1', 'Gene', (91, 95))	('tumors', 'Disease', (303, 309))	('cancers', 'Disease', (171, 178))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (127, 148))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('IDH1/2', 'Gene', (65, 71))
66995	27568035	ZEB1 expression was significantly higher in tumors carrying mutations in IDH1 or IDH2 (p < 0.0001).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('expression', 'MPA', (5, 15))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('IDH1', 'Gene', '3417', (73, 77))	('higher', 'PosReg', (34, 40))	('IDH2', 'Gene', (81, 85))	('IDH2', 'Gene', '3418', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ZEB1', 'Gene', (0, 4))	('IDH1', 'Gene', (73, 77))	('ZEB1', 'Gene', '6935', (0, 4))	('mutations', 'Var', (60, 69))
66996	27568035	However, within IDH1/2-mutant tumors, additional 1p19q co-deletion or mutations in ATRX, TP53, CIC, FUBP, NOTCH or PIK3CA were not associated with a significant change in ZEB1 expression.	('1p19q', 'Var', (49, 54))	('expression', 'MPA', (176, 186))	('PIK3CA', 'Gene', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', '7157', (89, 93))	('CIC', 'Gene', '23152', (95, 98))	('ATRX', 'Gene', (83, 87))	('FUBP', 'Gene', '8880', (100, 104))	('ZEB1', 'Gene', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IDH1/2-mutant', 'Gene', (16, 29))	('ATRX', 'Gene', '546', (83, 87))	('tumors', 'Disease', (30, 36))	('mutations', 'Var', (70, 79))	('PIK3CA', 'Gene', '5290', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('TP53', 'Gene', (89, 93))	('FUBP', 'Gene', (100, 104))	('CIC', 'Gene', (95, 98))	('ZEB1', 'Gene', '6935', (171, 175))
66997	27568035	To determine if IDH1/2 mutations contributed to the observed increase in overall survival in tumors expressing relatively high levels of ZEB1, we performed a multivariate Cox regression analysis with IDH1/2 mutation status as well as age, tumor grade and pre-operative KPS on the TCGA LGG dataset.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('Cox', 'Gene', '1351', (171, 174))	('Cox', 'Gene', (171, 174))	('IDH1/2', 'Gene', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('ZEB1', 'Gene', (137, 141))	('mutations', 'Var', (23, 32))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('ZEB1', 'Gene', '6935', (137, 141))	('tumor', 'Disease', (239, 244))	('increase', 'PosReg', (61, 69))	('tumors', 'Disease', (93, 99))	('overall survival', 'MPA', (73, 89))	('IDH1/2', 'Gene', (200, 206))
66999	27568035	To determine whether increased ZEB1 expression has a meaningful effect on gene expression patterns in IDH1/2-mutant tumors, we determined the relative expression of the MIR200BC family targets using the TCGA LGG dataset (Fig.	('IDH1/2-mutant', 'Var', (102, 115))	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('ZEB1', 'Gene', (31, 35))	('increased', 'PosReg', (21, 30))	('MIR200B', 'Gene', '406984', (169, 176))	('MIR200B', 'Gene', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('IDH1/2-mutant', 'Gene', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('ZEB1', 'Gene', '6935', (31, 35))
67007	27568035	Given our observation that ZEB1 and targets of MIR200C were relatively up-regulated in IDH1/2-mutant grades II/III gliomas, we next asked whether ZEB1 is up-regulated in other tumor types that frequently contain mutations in IDH1 or IDH2.	('ZEB1', 'Gene', '6935', (146, 150))	('MIR200C', 'Gene', '406985', (47, 54))	('IDH1', 'Gene', '3417', (225, 229))	('up-regulated', 'PosReg', (71, 83))	('IDH1', 'Gene', (87, 91))	('MIR200C', 'Gene', (47, 54))	('gliomas', 'Disease', (115, 122))	('tumor', 'Disease', (176, 181))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('mutations', 'Var', (212, 221))	('ZEB1', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('ZEB1', 'Gene', (146, 150))	('IDH1', 'Gene', '3417', (87, 91))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('IDH2', 'Gene', (233, 237))	('IDH2', 'Gene', '3418', (233, 237))	('IDH1', 'Gene', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('ZEB1', 'Gene', '6935', (27, 31))
67008	27568035	To answer this question, we compared ZEB1 expression across IDH1/2-wild type and IDH1/2-mutant WHO grade-IV gliomas and acute myeloid leukemia (AML) samples using the TCGA GBM and Acute Myeloid Leukemia (LAML) datasets (Supplementary Figs.	('gliomas', 'Disease', (108, 115))	('Leukemia', 'Phenotype', 'HP:0001909', (194, 202))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (120, 142))	('IDH1/2-mutant', 'Gene', (81, 94))	('IDH1/2-mutant', 'Var', (81, 94))	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (120, 142))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('ZEB1', 'Gene', (37, 41))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (126, 142))	('AML', 'Disease', 'MESH:D015470', (144, 147))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('AML', 'Disease', 'MESH:D015470', (205, 208))	('AML', 'Phenotype', 'HP:0004808', (144, 147))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('AML', 'Disease', (144, 147))	('AML', 'Phenotype', 'HP:0004808', (205, 208))	('AML', 'Disease', (205, 208))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (180, 202))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (180, 202))	('Acute Myeloid Leukemia', 'Disease', (180, 202))	('ZEB1', 'Gene', '6935', (37, 41))	('acute myeloid leukemia', 'Disease', (120, 142))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (186, 202))
67015	27568035	Mutations in IDH1 were detected in 28 tumors (90 %; 27 R132H, 1 R132L), and no tumors carried a mutation in IDH2.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('R132L', 'Mutation', 'rs121913500', (64, 69))	('IDH2', 'Gene', '3418', (108, 112))	('tumors', 'Disease', (38, 44))	('R132H', 'Var', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('R132H', 'Mutation', 'rs121913500', (55, 60))	('IDH1', 'Gene', (13, 17))	('tumors', 'Disease', (79, 85))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('detected', 'Reg', (23, 31))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', (108, 112))	('R132L', 'Var', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
67019	27568035	We next compared transcript levels of ZEB1 to those of ten selected MIR200C targets or ZEB1 correlates and two ZEB1 targets with relatively high transcript levels in the TCGA LGG dataset (F11R and PMEPA1) using qRT-PCR (Fig.	('PMEPA1', 'Gene', '56937', (197, 203))	('ZEB1', 'Gene', (111, 115))	('ZEB1', 'Gene', '6935', (87, 91))	('ZEB1', 'Gene', '6935', (111, 115))	('MIR200C', 'Gene', (68, 75))	('F11R', 'Var', (188, 192))	('MIR200C', 'Gene', '406985', (68, 75))	('PMEPA1', 'Gene', (197, 203))	('ZEB1', 'Gene', '6935', (38, 42))	('ZEB1', 'Gene', (38, 42))	('F11R', 'SUBSTITUTION', 'None', (188, 192))	('ZEB1', 'Gene', (87, 91))
67022	27568035	Surprisingly, ZEB1 was also associated with expression of two genes associated with epithelial differentiation, F11R (R2 = 0.5329, p < 0.0001) and PMEPA1 (R2 = 0.5778, p < 0.0001).	('F11R', 'SUBSTITUTION', 'None', (112, 116))	('F11R', 'Var', (112, 116))	('PMEPA1', 'Gene', '56937', (147, 153))	('epithelial differentiation', 'CPA', (84, 110))	('ZEB1', 'Gene', '6935', (14, 18))	('ZEB1', 'Gene', (14, 18))	('PMEPA1', 'Gene', (147, 153))
67032	27568035	These results suggest that ZEB1 up-regulation and concomitant up-regulation of MIR200C targets may be important to the biology of IDH1/2-mutant tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('MIR200C', 'Gene', (79, 86))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('up-regulation', 'PosReg', (32, 45))	('ZEB1', 'Gene', '6935', (27, 31))	('IDH1/2-mutant', 'Gene', (130, 143))	('MIR200C', 'Gene', '406985', (79, 86))	('IDH1/2-mutant', 'Var', (130, 143))	('ZEB1', 'Gene', (27, 31))	('up-regulation', 'PosReg', (62, 75))
67037	27568035	The MIR200BC family of miRNAs is the major regulator of ZEB1, and loss of MIR200C disinhibits expression of multiple factors that maintain the stem-cell phenotype including the polycomb protein BMI1 (Fig.	('MIR200B', 'Gene', (4, 11))	('ZEB1', 'Gene', (56, 60))	('BMI1', 'Gene', (194, 198))	('loss', 'Var', (66, 70))	('ZEB1', 'Gene', '6935', (56, 60))	('MIR200C', 'Gene', '406985', (74, 81))	('BMI1', 'Gene', '648', (194, 198))	('expression', 'MPA', (94, 104))	('MIR200C', 'Gene', (74, 81))	('disinhibits', 'NegReg', (82, 93))	('MIR200B', 'Gene', '406984', (4, 11))
67039	27568035	Our findings extend the spectrum of ZEB1-associated pathways to include mutations in IDH1 and IDH2 and suggest that further investigation is warranted regarding the use of ZEBI-targeted therapy for grades II-III gliomas.	('mutations', 'Var', (72, 81))	('ZEB1', 'Gene', '6935', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('ZEB1', 'Gene', (36, 40))	('IDH2', 'Gene', '3418', (94, 98))	('II-III gliomas', 'Disease', 'MESH:D005910', (205, 219))	('IDH1', 'Gene', (85, 89))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('II-III gliomas', 'Disease', (205, 219))	('IDH1', 'Gene', '3417', (85, 89))	('IDH2', 'Gene', (94, 98))
67040	27568035	Knowledge of the molecular characteristics of grades II-III gliomas has increased dramatically in the past several years owing to the discovery of IDH1 and IDH2 mutations in the majority of these tumors.	('IDH2', 'Gene', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('IDH1', 'Gene', '3417', (147, 151))	('tumors', 'Disease', (196, 202))	('IDH2', 'Gene', '3418', (156, 160))	('II-III gliomas', 'Disease', 'MESH:D005910', (53, 67))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('mutations', 'Var', (161, 170))	('IDH1', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('II-III gliomas', 'Disease', (53, 67))
67041	27568035	Mutations in exon 4 of either IDH1 or IDH2 code for a neomorphic enzyme incapable of converting isocitrate to alpha-ketoglutarate (alpha-KG).	('code', 'Reg', (43, 47))	('alpha-KG', 'Chemical', 'MESH:D007656', (131, 139))	('isocitrate', 'Chemical', 'MESH:C034219', (96, 106))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', (38, 42))	('Mutations in', 'Var', (0, 12))	('IDH2', 'Gene', '3418', (38, 42))	('IDH1', 'Gene', '3417', (30, 34))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (110, 129))
67042	27568035	This mutant enzyme forms a heterodimer with its wild-type counterpart and instead reduces alpha-KG to enantiomeric-specific D-2-hydroxyglutarate (D-2-HG).	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (124, 144))	('forms', 'Reg', (19, 24))	('alpha-KG', 'Chemical', 'MESH:D007656', (90, 98))	('mutant', 'Var', (5, 11))	('heterodimer', 'MPA', (27, 38))	('D-2-HG', 'Chemical', 'MESH:C019417', (146, 152))	('reduces', 'NegReg', (82, 89))
67044	27568035	The net effect of mutant IDH is a stem-cell phenotype secondary to a block in progenitor cell differentiation.	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('block', 'NegReg', (69, 74))	('mutant', 'Var', (18, 24))	('progenitor cell differentiation', 'CPA', (78, 109))	('stem-cell phenotype', 'CPA', (34, 53))
67045	27568035	One possible explanation for the role of IDH1/2 mutations in cancer is that stem cells maintained by high levels of D-2-HG subsequently become cancerous following accumulation of alterations to other oncogenes and tumor suppressor genes.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('D-2-HG', 'Chemical', 'MESH:C019417', (116, 122))	('cancerous', 'Disease', 'MESH:D009369', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (143, 149))	('tumor', 'Disease', (214, 219))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('IDH1/2', 'Gene', (41, 47))	('cancerous', 'Disease', (143, 152))	('alterations', 'Var', (179, 190))	('mutations', 'Var', (48, 57))
67049	27568035	Similar to this role, it may be that ZEB1 plays a key role in generating cancer stem cells from IDH1/2-mutant neural stem cells.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('IDH1/2-mutant', 'Gene', (96, 109))	('ZEB1', 'Gene', (37, 41))	('IDH1/2-mutant', 'Var', (96, 109))	('ZEB1', 'Gene', '6935', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
67055	27568035	However, the most recent evidence suggests that transcriptional targets of hypoxia-inducible factors (HIFs) are, in fact, not up-regulated at biologically relevant (low-millimolar) concentrations of D-2-HG, which is consistent with the lack of angiogenesis in these tumors.	('hypoxia', 'Disease', (75, 82))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('D-2-HG', 'Var', (199, 205))	('D-2-HG', 'Chemical', 'MESH:C019417', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
67056	27568035	Intriguingly, ZEB1 expression in primary glioblastoma is associated with a low-proliferating, chemoresistant and invasive phenotype in primary GBM.	('low-proliferating', 'CPA', (75, 92))	('expression', 'Var', (19, 29))	('glioblastoma', 'Disease', (41, 53))	('glioblastoma', 'Disease', 'MESH:D005909', (41, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('ZEB1', 'Gene', '6935', (14, 18))	('primary GBM', 'Disease', (135, 146))	('ZEB1', 'Gene', (14, 18))
67057	27568035	Expression of R132H-mutant IDH1 in a model of glioblastoma has been shown to decrease the proliferation of glioma cells in vitro and vivo.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('proliferation', 'CPA', (90, 103))	('decrease', 'NegReg', (77, 85))	('R132H-mutant', 'Var', (14, 26))	('R132H', 'Mutation', 'rs121913500', (14, 19))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1', 'Gene', (27, 31))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('IDH1', 'Gene', '3417', (27, 31))	('glioma', 'Disease', (107, 113))
67074	29050286	A spectrum of genetic alterations has been characterized for glioma, including germline and somatic mutations, recurrent translocations, and copy number variations, yet these do not account for all the underlying biology.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('translocations', 'Var', (121, 135))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('copy number variations', 'Var', (141, 163))
67104	29050286	A large proportion (i.e., 60-90%) of low-grade gliomas harbor a heterozygous mutation (R132H) in the gene encoding the cytosolic isoform of isocitrate dehydrogenase (IDH1).	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH1', 'Gene', (166, 170))	('R132H', 'Var', (87, 92))	('IDH1', 'Gene', '3417', (166, 170))	('R132H', 'Mutation', 'rs121913500', (87, 92))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('isocitrate', 'Chemical', 'MESH:C034219', (140, 150))
67105	29050286	Data from genome-wide association studies of glioma have identified single nucleotide polymorphisms (SNP) associated with altered risk of IDH-mutated glioma, including rs55705857 in 8q24.21, rs4295627 in CCDC26, and rs498872 in PHLDB1, and in a recent case-control study of 285 gliomas, 316 healthy controls, and 531 other types of cancers, the authors showed that SNP rs55705857 was strongly associated with altered risk of IDH-mutant glioma, but not with other cancers.	('gliomas', 'Disease', 'MESH:D005910', (278, 285))	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('rs55705857', 'Var', (369, 379))	('rs55705857', 'Mutation', 'rs55705857', (168, 178))	('IDH', 'Gene', '3417', (425, 428))	('associated', 'Reg', (106, 116))	('rs4295627', 'Var', (191, 200))	('glioma', 'Phenotype', 'HP:0009733', (436, 442))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('IDH', 'Gene', '3417', (138, 141))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('CCDC26', 'Gene', (204, 210))	('gliomas', 'Phenotype', 'HP:0009733', (278, 285))	('rs498872', 'Var', (216, 224))	('rs498872', 'Mutation', 'rs498872', (216, 224))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('PHLDB1', 'Gene', '23187', (228, 234))	('PHLDB1', 'Gene', (228, 234))	('rs55705857', 'Var', (168, 178))	('cancers', 'Disease', 'MESH:D009369', (463, 470))	('glioma', 'Disease', (278, 284))	('rs4295627', 'Mutation', 'rs4295627', (191, 200))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('cancers', 'Disease', (332, 339))	('associated', 'Reg', (393, 403))	('glioma', 'Disease', (150, 156))	('rs55705857', 'Mutation', 'rs55705857', (369, 379))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Disease', (436, 442))	('IDH', 'Gene', (425, 428))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('single', 'Var', (68, 74))	('gliomas', 'Disease', (278, 285))	('IDH', 'Gene', (138, 141))	('glioma', 'Disease', 'MESH:D005910', (436, 442))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (463, 470))	('cancers', 'Disease', (463, 470))	('CCDC26', 'Gene', '137196', (204, 210))	('glioma', 'Disease', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
67106	29050286	The wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate to generate alpha-ketoglutarate (alpha-KG), whereas the mutant enzyme is able to convert alpha-KG into molecules of 2-HG, which is an "oncometabolite" that may mediate several tumorigenic events.	('alpha-KG', 'Chemical', 'MESH:D007656', (162, 170))	('oxidative decarboxylation', 'MPA', (33, 58))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('isocitrate', 'Chemical', 'MESH:C034219', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (85, 104))	('tumor', 'Disease', (249, 254))	('alpha-ketoglutarate', 'MPA', (85, 104))	('alpha-KG', 'Chemical', 'MESH:D007656', (106, 114))	('IDH1', 'Gene', (14, 18))	('mutant', 'Var', (129, 135))	('IDH1', 'Gene', '3417', (14, 18))
67132	29050286	Our findings suggest that impairment of the glycolysis pathway may be an early event during glioma development, likely to support cell proliferation and tumor anabolic activity.	('glycolysis pathway', 'Pathway', (44, 62))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('men', 'Species', '9606', (32, 35))	('glioma', 'Disease', (92, 98))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('support', 'PosReg', (122, 129))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('impairment', 'Var', (26, 36))	('cell proliferation', 'CPA', (130, 148))	('men', 'Species', '9606', (106, 109))
67133	29050286	Of note, impairment of glycolysis has been shown in earlier studies to be associated with activated oncogenes (such as RAS, or MYC) and mutant tumor suppressors (such as TP53) and such mutations have been reported to occur more frequently in low-grade rather than high-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (275, 282))	('tumor', 'Disease', (143, 148))	('oncogenes', 'Protein', (100, 109))	('low-grade', 'Disease', (242, 251))	('MYC', 'Gene', '4609', (127, 130))	('TP53', 'Gene', '7157', (170, 174))	('RAS', 'Disease', (119, 122))	('TP53', 'Gene', (170, 174))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('impairment of glycolysis', 'Disease', (9, 33))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gliomas', 'Phenotype', 'HP:0009733', (275, 282))	('mutant', 'Var', (136, 142))	('gliomas', 'Disease', (275, 282))	('impairment of glycolysis', 'Disease', 'MESH:D009422', (9, 33))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('MYC', 'Gene', (127, 130))
67160	26715733	MicroRNA-584-3p, a novel tumor suppressor and prognostic marker, reduces the migration and invasion of human glioma cells by targeting hypoxia-induced ROCK1 Here, we report that microRNA-584-3p (miR-584-3p) is up-regulated in hypoxic glioma cells and in high-grade human glioma tumors (WHO grades III-IV) relative to normoxic cells and to low-grade tumors (WHO grades I-II), respectively.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('tumors', 'Disease', (278, 284))	('miR-584', 'Gene', '693169', (195, 202))	('human', 'Species', '9606', (265, 270))	('glioma tumors', 'Disease', (271, 284))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('miR-584', 'Gene', (195, 202))	('glioma', 'Disease', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('tumors', 'Disease', (349, 355))	('human', 'Species', '9606', (103, 108))	('microRNA-584-3p', 'Var', (178, 193))	('reduces', 'NegReg', (65, 72))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('glioma', 'Disease', (271, 277))	('glioma tumors', 'Disease', 'MESH:D005910', (271, 284))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('up-regulated', 'PosReg', (210, 222))	('hypoxia', 'Disease', (135, 142))	('tumor', 'Disease', (278, 283))	('tumor', 'Disease', (25, 30))	('hypoxic glioma', 'Disease', 'MESH:D005910', (226, 240))	('glioma', 'Disease', 'MESH:D005910', (271, 277))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (349, 354))	('hypoxia', 'Disease', 'MESH:D000860', (135, 142))	('hypoxic glioma', 'Disease', (226, 240))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('glioma', 'Disease', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
67219	26715733	The synergetic pro-migratory effects of the miR-584-3p inhibitor under hypoxia had dramatic consequences in vitro (Figure 3E, 3H), suggesting that these effects of miR-584-3p deficiency were most likely related to the poorer prognosis of the patients with high-grade (III-IV) glioma and a low miR-584-3p expression level (Figure 1F, 1G).	('miR-584', 'Gene', (293, 300))	('hypoxia', 'Disease', (71, 78))	('deficiency', 'Var', (175, 185))	('miR-584', 'Gene', '693169', (164, 171))	('glioma', 'Disease', (276, 282))	('miR-584', 'Gene', (44, 51))	('miR-584', 'Gene', (164, 171))	('miR-584', 'Gene', '693169', (293, 300))	('related', 'Reg', (203, 210))	('glioma', 'Disease', 'MESH:D005910', (276, 282))	('3H', 'Chemical', 'MESH:D014316', (126, 128))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('low', 'NegReg', (289, 292))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))	('miR-584', 'Gene', '693169', (44, 51))	('patients', 'Species', '9606', (242, 250))
67220	26715733	Taken together, our results clearly demonstrate that miR-584-3p knockdown markedly promotes the migratory and invasive capacities of human glioma cells and aggravates the hypoxia-induced pro-migratory and pro-invasive effects.	('glioma', 'Disease', (139, 145))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('miR-584', 'Gene', '693169', (53, 60))	('promotes', 'PosReg', (83, 91))	('miR-584', 'Gene', (53, 60))	('hypoxia', 'Disease', (171, 178))	('aggravates', 'PosReg', (156, 166))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('knockdown', 'Var', (64, 73))	('human', 'Species', '9606', (133, 138))
67229	26715733	These results and our preliminary observations that the subgroup of high-grade (III-IV) glioma patients with high miR-584-3p expression had a significantly prolonged postoperative survival time (Figure 1G) suggest that miR-584-3p could be a valuable tool for the development of new anti-invasive therapeutic strategies for glioma.	('nt', 'Chemical', '-', (272, 274))	('nt', 'Chemical', '-', (100, 102))	('high', 'Var', (109, 113))	('miR-584', 'Gene', (114, 121))	('glioma', 'Disease', (323, 329))	('postoperative', 'CPA', (166, 179))	('miR-584', 'Gene', '693169', (114, 121))	('miR-584', 'Gene', '693169', (219, 226))	('glioma', 'Disease', (88, 94))	('patients', 'Species', '9606', (95, 103))	('nt', 'Chemical', '-', (283, 285))	('glioma', 'Disease', 'MESH:D005910', (323, 329))	('glioma', 'Phenotype', 'HP:0009733', (323, 329))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('miR-584', 'Gene', (219, 226))	('prolonged', 'PosReg', (156, 165))	('nt', 'Chemical', '-', (151, 153))
67237	26715733	Our results showed that miR-584-3p knockdown facilitated stress fiber formation (Figure 5A) and that its overexpression impaired hypoxia-induced stress fiber formation (Figure 5B).	('knockdown', 'Var', (35, 44))	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('hypoxia', 'Disease', (129, 136))	('overexpression', 'PosReg', (105, 119))	('stress fiber formation', 'CPA', (57, 79))	('miR-584', 'Gene', '693169', (24, 31))	('impaired', 'NegReg', (120, 128))	('facilitated', 'PosReg', (45, 56))	('miR-584', 'Gene', (24, 31))
67241	26715733	We further examined this finding using quantitative real-time PCR (Figure 6A), and the results supported the notion that miR-584-3p knockdown induces ROCK-1 expression.	('miR-584', 'Gene', (121, 128))	('knockdown', 'Var', (132, 141))	('expression', 'MPA', (157, 167))	('ROCK-1', 'Gene', (150, 156))	('miR-584', 'Gene', '693169', (121, 128))	('induces', 'Reg', (142, 149))	('ROCK-1', 'Gene', '6093', (150, 156))	('nt', 'Chemical', '-', (42, 44))
67244	26715733	U251 and U87 glioma cells were treated with Y-27632 and transfected with ROCK1 siRNA, respectively.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('U251', 'CellLine', 'CVCL:0021', (0, 4))	('Y-27632', 'Var', (44, 51))	('glioma', 'Disease', (13, 19))	('Y-27632', 'Chemical', 'MESH:C108830', (44, 51))
67246	26715733	The anti-migratory effect of miR-584-3p overexpression was slightly enhanced by Y-27632, with no significant difference compared with untreated cells (Figure 6B lower and 6D right).	('enhanced', 'PosReg', (68, 76))	('nt', 'Chemical', '-', (135, 137))	('overexpression', 'PosReg', (40, 54))	('miR-584', 'Gene', (29, 36))	('Y-27632', 'Var', (80, 87))	('nt', 'Chemical', '-', (5, 7))	('anti-migratory effect', 'CPA', (4, 25))	('Y-27632', 'Chemical', 'MESH:C108830', (80, 87))	('miR-584', 'Gene', '693169', (29, 36))	('nt', 'Chemical', '-', (106, 108))
67247	26715733	Further Transwell migration assays also showed that Y27632 treatment resulted in the consistent and significant suppression of the pro-migratory effect of the miR-584-3p inhibitor and that it had an indistinguishable synergistic effect with miR-584-3p mimics (Figure 6C, 6E).	('miR-584', 'Gene', (159, 166))	('nt', 'Chemical', '-', (66, 68))	('Y27632', 'Chemical', 'MESH:C108830', (52, 58))	('nt', 'Chemical', '-', (109, 111))	('nt', 'Chemical', '-', (93, 95))	('miR-584', 'Gene', '693169', (241, 248))	('miR-584', 'Gene', '693169', (159, 166))	('Y27632', 'Var', (52, 58))	('pro-migratory effect', 'CPA', (131, 151))	('suppression', 'NegReg', (112, 123))	('miR-584', 'Gene', (241, 248))
67248	26715733	To verify that the RhoA/ROCK1 pathway is involved in the function of miR-584-3p, we investigated the effect of ROCK1 knockdown on miR-584-3p activity.	('miR-584', 'Gene', '693169', (130, 137))	('miR-584', 'Gene', (130, 137))	('RhoA', 'Gene', (19, 23))	('miR-584', 'Gene', '693169', (69, 76))	('RhoA', 'Gene', '387', (19, 23))	('knockdown', 'Var', (117, 126))	('miR-584', 'Gene', (69, 76))
67250	26715733	Similar to Y-27632, ROCK1 knockdown in U87 cells completely eliminated the pro-migratory effect of the miR-584-3p inhibitor, as shown by wound-healing (Figure 7A upper and 7C left) and Transwell migration assays (Figure 7B, 7D).	('miR-584', 'Gene', (103, 110))	('wound-healing', 'CPA', (137, 150))	('eliminated', 'NegReg', (60, 70))	('Y-27632', 'Chemical', 'MESH:C108830', (11, 18))	('miR-584', 'Gene', '693169', (103, 110))	('knockdown', 'Var', (26, 35))	('pro-migratory effect', 'CPA', (75, 95))	('Transwell migration assays', 'CPA', (185, 211))
67252	26715733	In addition, both the Y-27632 and ROCK1 siRNA treatments resulted in morphologic changes of U251 and U87 cells with threadlike pseudopodia (Figures 6 and 7), as described in other studies, and the pro-migratory effect of ROCK1 inhibition itself was only observed in wound-healing assays (Figures 6B, 6D, and 7A, 7C); however, Transwell migration assays were more representative of the in vivo conditions (Figures 6C, 6E, and 7B, 7D).	('nt', 'Chemical', '-', (53, 55))	('U251', 'CellLine', 'CVCL:0021', (92, 96))	('nt', 'Chemical', '-', (370, 372))	('ROCK1', 'Var', (34, 39))	('Y-27632', 'Var', (22, 29))	('Y-27632', 'Chemical', 'MESH:C108830', (22, 29))
67275	26715733	Therefore, miR-584-3p deficiency undoubtedly promoted the full invasive capacities of the glioma cells from the mouse models.	('glioma', 'Disease', (90, 96))	('miR-584', 'Gene', '693169', (11, 18))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('promoted', 'PosReg', (45, 53))	('mouse', 'Species', '10090', (112, 117))	('miR-584', 'Gene', (11, 18))	('deficiency', 'Var', (22, 32))
67280	26715733	However, an increasing number of tumor-suppressive miRNAs have also been discovered, including miR-637, miR-663, miR-218, miR-128, and miR-34a.	('miR-637', 'Gene', (95, 102))	('miR-663', 'Gene', '724033', (104, 111))	('miR-21', 'Gene', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('miR-34a', 'Gene', '407040', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('miR-21', 'Gene', '406991', (113, 119))	('miR-128', 'Var', (122, 129))	('miR-34a', 'Gene', (135, 142))	('tumor', 'Disease', (33, 38))	('miR-637', 'Gene', '693222', (95, 102))	('miR-663', 'Gene', (104, 111))
67309	26715733	Knockout of miR-584-3p promotes the full migratory capacities of glioma cells and likely enhances tumor progression.	('glioma', 'Disease', (65, 71))	('promotes', 'PosReg', (23, 31))	('miR-584', 'Gene', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Knockout', 'Var', (0, 8))	('enhances', 'PosReg', (89, 97))	('tumor', 'Disease', (98, 103))	('miR-584', 'Gene', '693169', (12, 19))
67333	26715733	However, miR-584-3p deficiency undoubtedly promoted the full invasive capacities of glioma cells in the mouse models.	('deficiency', 'Var', (20, 30))	('miR-584', 'Gene', (9, 16))	('glioma', 'Disease', (84, 90))	('promoted', 'PosReg', (43, 51))	('mouse', 'Species', '10090', (104, 109))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('miR-584', 'Gene', '693169', (9, 16))
67401	31254208	[11C] choline SUV and [18F] FET SUV and TBR at all intervals were higher in tumour than in normal samples.	('TBR', 'MPA', (40, 43))	('choline', 'Chemical', 'MESH:D002794', (6, 13))	('TBR', 'Chemical', '-', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('11C', 'Chemical', 'MESH:C000615233', (1, 4))	('[18F]', 'Var', (22, 27))	('[11C] choline SUV', 'MPA', (0, 17))	('higher', 'PosReg', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))
67402	31254208	For [18F] FET, the diagnostic accuracy of TBR was higher than that of SUV for intervals 40-60 min (area under the curve: 0.88 versus 0.81, p = 0.026) and 60-90 min (0.90 versus 0.81, p = 0.047).	('[18F] FET', 'Var', (4, 13))	('TBR', 'Chemical', '-', (42, 45))	('higher', 'PosReg', (50, 56))
67403	31254208	The diagnostic accuracy of [18F] FET TBR 60-90 min was higher than that of [11C] choline SUV 20-40 min (0.87 versus 0.67, p = 0.005).	('[18F] FET', 'Var', (27, 36))	('diagnostic', 'MPA', (4, 14))	('TBR', 'Chemical', '-', (37, 40))	('11C', 'Chemical', 'MESH:C000615233', (76, 79))	('higher', 'PosReg', (55, 61))	('choline', 'Chemical', 'MESH:D002794', (81, 88))
67404	31254208	[18F] FET was more accurate than [11C] choline for detecting glioma infiltration.	('glioma infiltration', 'Disease', (61, 80))	('11C', 'Chemical', 'MESH:C000615233', (34, 37))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('[18F] FET', 'Var', (0, 9))	('glioma infiltration', 'Disease', 'MESH:D017254', (61, 80))	('choline', 'Chemical', 'MESH:D002794', (39, 46))
67416	31254208	Therefore, we set out to compare the diagnostic accuracy of [11C] choline and [18F] FET PET in quantitative maps to detect glioma infiltration using co-registered multi-region stereotactic biopsies as reference.	('[11C]', 'Var', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma infiltration', 'Disease', 'MESH:D017254', (123, 142))	('glioma infiltration', 'Disease', (123, 142))	('choline', 'Chemical', 'MESH:D002794', (66, 73))	('[18F]', 'Var', (78, 83))	('11C', 'Chemical', 'MESH:C000615233', (61, 64))
67432	31254208	Samples were formalin-fixed paraffin-embedded and stained using haematoxylin and eosin (HE) and Ki-67, p53 and IDH1 R132H mutation immunohistochemistry.	('R132H', 'Mutation', 'rs121913500', (116, 121))	('paraffin', 'Chemical', 'MESH:D010232', (28, 36))	('p53', 'Gene', (103, 106))	('haematoxylin', 'Chemical', 'MESH:D006416', (64, 76))	('p53', 'Gene', '7157', (103, 106))	('IDH1', 'Gene', '3417', (111, 115))	('formalin', 'Chemical', 'MESH:D005557', (13, 21))	('HE', 'Chemical', '-', (88, 90))	('eosin', 'Chemical', 'MESH:D004801', (81, 86))	('R132H', 'Var', (116, 121))	('IDH1', 'Gene', (111, 115))
67449	31254208	Of the 66 samples with [18F] FET data, 49 (74%) were classified as tumour and 17 (26%) as normal.	('tumour', 'Disease', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('[18F] FET data', 'Var', (23, 37))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
67462	31254208	In high-grade gliomas, the diagnostic accuracy was highest in the 40-60 and 60-90 min in TBR, with a significantly higher accuracy of 40-60 min TBR than 20-40 min SUV (Additional file 4B).	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('TBR', 'Var', (144, 147))	('TBR', 'Chemical', '-', (89, 92))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('TBR', 'Chemical', '-', (144, 147))	('higher', 'PosReg', (115, 121))	('40-60 min TBR', 'Var', (134, 147))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('gliomas', 'Disease', (14, 21))
67465	31254208	The diagnostic accuracy to detect tumour of the best quantitative map using [18F] FET is higher than the best quantitative map using [11C] choline (AUC (95% CI): 0.87 (0.75-1.0) and 0.68 (0.51-0.85), p = 0.005), as plotted in Fig.	('11C', 'Chemical', 'MESH:C000615233', (134, 137))	('[18F] FET', 'Var', (76, 85))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('higher', 'PosReg', (89, 95))	('choline', 'Chemical', 'MESH:D002794', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
67466	31254208	This was similar in high-grade gliomas, although not significant, while the diagnostic accuracy in low-grade gliomas was comparable between [18F] FET and [11C] choline (Additional file 6).	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('11C', 'Chemical', 'MESH:C000615233', (155, 158))	('[11C] choline', 'Var', (154, 167))	('high-grade', 'Disease', (20, 30))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('[18F] FET', 'Var', (140, 149))	('choline', 'Chemical', 'MESH:D002794', (160, 167))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
67469	31254208	Our study demonstrates that [18F] FET PET is more accurate than [11C] choline PET to detect glioma infiltration.	('glioma infiltration', 'Disease', (92, 111))	('11C', 'Chemical', 'MESH:C000615233', (65, 68))	('choline', 'Chemical', 'MESH:D002794', (70, 77))	('[18F] FET', 'Var', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma infiltration', 'Disease', 'MESH:D017254', (92, 111))
67470	31254208	Few studies have compared [18F] FET and [11C] choline tracers in glioma.	('glioma', 'Disease', (65, 71))	('[11C] choline', 'MPA', (40, 53))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('[18F', 'Var', (26, 30))	('choline', 'Chemical', 'MESH:D002794', (46, 53))	('11C', 'Chemical', 'MESH:C000615233', (41, 44))
67476	31254208	Combining MRI and FET PET was more accurate than MRI alone, and [18F] FET PET accuracy was higher than intra-operative 5-ALA fluoresence .	('higher', 'PosReg', (91, 97))	('5-ALA', 'Chemical', 'MESH:D000622', (119, 124))	('[18F]', 'Var', (64, 69))
67486	31254208	Other preclinical studies, however, found similar and even higher BBB dependency of [18F] FET compared with choline tracers.	('BBB dependency', 'MPA', (66, 80))	('[18F] FET', 'Var', (84, 93))	('choline', 'Chemical', 'MESH:D002794', (108, 115))	('higher', 'PosReg', (59, 65))
67492	31254208	The [18F] FET tracer is more accurate than [11C] choline to detect glioma infiltration.	('choline', 'Chemical', 'MESH:D002794', (49, 56))	('glioma infiltration', 'Disease', (67, 86))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('11C', 'Chemical', 'MESH:C000615233', (44, 47))	('glioma infiltration', 'Disease', 'MESH:D017254', (67, 86))	('[18F]', 'Var', (4, 9))
67541	29427543	All the antibodies were purchased from Abcam as follows: FBW7 (ab109617), Ki-67 (ab15580), Aurora B (ab45145), Mcl-1 (ab32087), Notch-1 (ab52627), Caspase-3 (ab13586) and beta-actin (ab6276).	('FBW7', 'Gene', '55294', (57, 61))	('Caspase-3', 'Gene', (147, 156))	('beta-actin', 'Gene', '728378', (171, 181))	('Caspase-3', 'Gene', '836', (147, 156))	('beta-actin', 'Gene', (171, 181))	('Mcl-1', 'Gene', '4170', (111, 116))	('ab52627', 'Var', (137, 144))	('FBW7', 'Gene', (57, 61))	('Notch-1', 'Gene', '4851', (128, 135))	('Mcl-1', 'Gene', (111, 116))	('Notch-1', 'Gene', (128, 135))	('ab13586', 'Var', (158, 165))	('Aurora B', 'Gene', '9212', (91, 99))	('Aurora B', 'Gene', (91, 99))
67547	29427543	IC50 was calculated according to the OD450 nm by MTT assay as previously described.18 For in vitro cytoxicity testing, U251 cells were cultured in 6-cm dishes until they had reached nearly half confluence and were then treated with Lv-GFP (control), TMZ (8 mug/mL) + LV-GFP, Lv-FBW7-OE, TMZ (8 mug/mL) + Lv-FBW7-OE, shRNA or shRNA + TMZ (8 mug/mL), respectively.	('FBW7', 'Gene', (278, 282))	('FBW7', 'Gene', (307, 311))	('TMZ', 'Chemical', 'MESH:D000077204', (250, 253))	('MTT', 'Chemical', 'MESH:C070243', (49, 52))	('FBW7', 'Gene', '55294', (278, 282))	('Lv-GFP', 'Var', (232, 238))	('FBW7', 'Gene', '55294', (307, 311))	('TMZ', 'Chemical', 'MESH:D000077204', (333, 336))	('TMZ', 'Chemical', 'MESH:D000077204', (287, 290))	('toxicity', 'Disease', 'MESH:D064420', (101, 109))	('toxicity', 'Disease', (101, 109))	('U251', 'CellLine', 'CVCL:0021', (119, 123))
67569	29427543	By contrast, knockdown of FBW7 by interfering shRNA resulted in a time-dependent increase of the proliferation rate, which was expected, from 72 to 120 hours in U251 line and from 96 to 120 hours in U373 line.	('interfering', 'NegReg', (34, 45))	('FBW7', 'Gene', '55294', (26, 30))	('proliferation rate', 'CPA', (97, 115))	('FBW7', 'Gene', (26, 30))	('U373', 'CellLine', 'CVCL:2219', (199, 203))	('shRNA', 'Protein', (46, 51))	('increase', 'PosReg', (81, 89))	('knockdown', 'Var', (13, 22))	('U251', 'CellLine', 'CVCL:0021', (161, 165))
67572	29427543	Upregulating the expression level of FBW7 in U251 and U373 significantly reduced the number of cells transferred to the lower side of the chamber (P-value <.001 compared with control).	('U251', 'CellLine', 'CVCL:0021', (45, 49))	('U373', 'Var', (54, 58))	('FBW7', 'Gene', '55294', (37, 41))	('U373', 'CellLine', 'CVCL:2219', (54, 58))	('reduced', 'NegReg', (73, 80))	('Upregulating', 'PosReg', (0, 12))	('FBW7', 'Gene', (37, 41))	('U251', 'Var', (45, 49))	('expression level', 'MPA', (17, 33))
67578	29427543	Furthermore, this finding was convinced by the results that re-expression of FBW7 in the variant U251/TMZ line partly reversed its resistance to TMZ (P-value <.01, Figure 3C), while reducing FBW7 expression in U251 cells promoted its resistance to TMZ (P-value <.01, Figure 3D).	('promoted', 'PosReg', (221, 229))	('resistance to TMZ', 'MPA', (131, 148))	('U251', 'CellLine', 'CVCL:0021', (210, 214))	('TMZ', 'Chemical', 'MESH:D000077204', (145, 148))	('TMZ', 'Chemical', 'MESH:D000077204', (248, 251))	('FBW7', 'Gene', (191, 195))	('FBW7', 'Gene', '55294', (77, 81))	('U251', 'CellLine', 'CVCL:0021', (97, 101))	('expression', 'MPA', (196, 206))	('variant', 'Var', (89, 96))	('FBW7', 'Gene', (77, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (102, 105))	('resistance to TMZ', 'MPA', (234, 251))	('reversed', 'NegReg', (118, 126))	('FBW7', 'Gene', '55294', (191, 195))
67582	29427543	As expected, specific shRNA-induced FBW7 knockdown attenuated the cytotoxity of TMZ, as shown in Figure 3D,E, with a reduced inhibition rate in the TMZ + Lv-FBW7-OE-sh group relative to the TMZ alone group at 72 hours.	('FBW7', 'Gene', '55294', (36, 40))	('cytotoxity', 'Disease', 'MESH:D064420', (66, 76))	('reduced inhibition', 'NegReg', (117, 135))	('FBW7', 'Gene', (36, 40))	('FBW7', 'Gene', '55294', (157, 161))	('TMZ', 'Chemical', 'MESH:D000077204', (190, 193))	('TMZ', 'Chemical', 'MESH:D000077204', (148, 151))	('attenuated', 'NegReg', (51, 61))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('cytotoxity', 'Disease', (66, 76))	('FBW7', 'Gene', (157, 161))	('knockdown', 'Var', (41, 50))
67588	29427543	As a result, we found that U251 cells with TMZ treatment or FBW7 transfection alone had obviously greater apoptosis rates compared to Lv-GFP transfected cells (P-value <.001).	('U251', 'CellLine', 'CVCL:0021', (27, 31))	('FBW7', 'Gene', '55294', (60, 64))	('apoptosis rates', 'CPA', (106, 121))	('FBW7', 'Gene', (60, 64))	('transfection', 'Var', (65, 77))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('greater', 'PosReg', (98, 105))
67590	29427543	In addition, combining shRNA transfection with TMZ markedly reduced the apoptotic rate induced by TMZ alone.	('apoptotic rate', 'CPA', (72, 86))	('reduced', 'NegReg', (60, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('transfection', 'Var', (29, 41))
67607	29427543	Prior research has demonstrated that FBW7 is frequently inactivated for its mutation in a multitude of tumors, including gastric, colorectal, breast, pancreatic, liver cancers and leukemia.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('FBW7', 'Gene', '55294', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('colorectal', 'Disease', 'MESH:D015179', (130, 140))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('colorectal', 'Disease', (130, 140))	('breast', 'Disease', (142, 148))	('tumors', 'Disease', (103, 109))	('FBW7', 'Gene', (37, 41))	('gastric', 'Disease', (121, 128))	('leukemia', 'Disease', 'MESH:D007938', (180, 188))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('liver cancers', 'Phenotype', 'HP:0002896', (162, 175))	('pancreatic, liver cancers', 'Disease', 'MESH:D010190', (150, 175))	('leukemia', 'Disease', (180, 188))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('mutation', 'Var', (76, 84))
67609	29427543	This might be the comprehensive result of mutation and upstream deregulation of FBW7 and requires further investigation.	('FBW7', 'Gene', '55294', (80, 84))	('mutation', 'Var', (42, 50))	('FBW7', 'Gene', (80, 84))
67611	29427543	Cell proliferation is tightly associated with the cell cycle, which is rigidly regulated by a series of kinases, among which Cyclin E and Aurora B are 2 important FBW7 substrates involved in the promotion of G1/S and G2/M transition, respectively.5, 8, 21 Previous studies have implicated the role of FBW7 in the regulation of cell proliferation in colon, breast and kidney cancers.7 In our study, we found that forced FBW7 expression inhibited the proliferation of glioma cells.	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('inhibited', 'NegReg', (435, 444))	('FBW7', 'Gene', '55294', (301, 305))	('glioma', 'Disease', (466, 472))	('FBW7', 'Gene', (163, 167))	('FBW7', 'Gene', (301, 305))	('FBW7', 'Gene', '55294', (419, 423))	('Aurora B', 'Gene', '9212', (138, 146))	('Aurora B', 'Gene', (138, 146))	('breast and kidney cancers', 'Disease', 'MESH:D001943', (356, 381))	('cancers', 'Phenotype', 'HP:0002664', (374, 381))	('forced', 'Var', (412, 418))	('glioma', 'Disease', 'MESH:D005910', (466, 472))	('glioma', 'Phenotype', 'HP:0009733', (466, 472))	('FBW7', 'Gene', '55294', (163, 167))	('FBW7', 'Gene', (419, 423))
67613	29427543	We also noticed that there were similar changes in G1 proportion with Lv-FBW7-OE or shRNA transfection, suggesting that cyclin E is perhaps involved in FBW7-induced cycle distribution; however, the trend was much less significant than G2/M.	('FBW7', 'Gene', (152, 156))	('FBW7', 'Gene', '55294', (73, 77))	('transfection', 'Var', (90, 102))	('FBW7', 'Gene', (73, 77))	('FBW7', 'Gene', '55294', (152, 156))
67632	27196377	We found the most frequent aberrations in IDH mutant tumors were the combined whole arm-loss of 1p and 19q (1p/19q codeletion) followed by gain on chromosome arm 7q (+7q).	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('gain', 'PosReg', (139, 143))	('mutant', 'Var', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('arm-loss', 'NegReg', (84, 92))
67634	27196377	Kaplan-Meier estimates for progression-free survival showed that the tumors with mutant IDH, -1p/19q, or +7q (in the absence of +7p) survived longer than tumors with wild-type IDH, +7, or -10q.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('IDH', 'Gene', (176, 179))	('survived', 'CPA', (133, 141))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('IDH', 'Gene', '3417', (176, 179))	('IDH', 'Gene', (88, 91))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('mutant', 'Var', (81, 87))	('longer', 'PosReg', (142, 148))	('IDH', 'Gene', '3417', (88, 91))
67639	27196377	Better understanding of glioma development may help identify groups that are at risk for early progression, and specific genetic aberrations may serve as reliable predictors of the clinical outcome.7, 8, 9 Since Cairncross et al.10 reported that allelic loss of chromosome 1p is a statistically significant marker of prognosis for anaplastic oligodendrogliomas, many studies on DNA copy number aberrations (CNAs) in gliomas have reported the utility of CNAs in tumor classification.11, 12, 13, 14, 15, 16, 17, 18, 19 The results from these studies indicated the following: 1p/19q codeletion (1p/19q codel) marks a subset of oligodendroglial tumors,12, 15 the gain of whole chromosome 7 is the most frequent aberration in high-grade astrocytomas,13 the gliomas with losses on chromosomal arms 9p and 10q and gain on chromosome 7 show trends toward short survival,14 the gain on chromosomal arm 7q appears to be a key early event in a subgroup of astrocytomas,16 and +7q and 1p/19q codel are mutually exclusive in low-grade gliomas.16 Many of the cytogenetic analyses were carried out for glioblastomas, but we have also previously shown that grade II-III adult supratentorial gliomas could be classified into clinically relevant subgroups based on the CNAs.20 The astrocytomas of these grades contained a wide variety of genetic subgroups in contrast to oligodendrogliomas and glioblastomas, which are characterized with 1p/19q codel and +7/-10q, respectively.	('gliomas', 'Disease', 'MESH:D005910', (1364, 1371))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (342, 360))	('gliomas', 'Phenotype', 'HP:0009733', (1175, 1182))	('glioma', 'Disease', 'MESH:D005910', (1022, 1028))	('glioma', 'Phenotype', 'HP:0009733', (752, 758))	('tumor', 'Phenotype', 'HP:0002664', (461, 466))	('tumor', 'Disease', 'MESH:D009369', (641, 646))	('glioblastoma', 'Phenotype', 'HP:0012174', (1087, 1099))	('glioblastomas', 'Disease', (1087, 1100))	('glioma', 'Disease', (353, 359))	('anaplastic oligodendrogliomas', 'Disease', (331, 360))	('gliomas', 'Disease', (353, 360))	('astrocytomas', 'Disease', (1263, 1275))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (331, 360))	('gliomas', 'Disease', 'MESH:D005910', (1022, 1029))	('gliomas', 'Disease', (416, 423))	('tumors', 'Phenotype', 'HP:0002664', (641, 647))	('glioma', 'Disease', (416, 422))	('gliomas', 'Phenotype', 'HP:0009733', (752, 759))	('glioblastomas', 'Phenotype', 'HP:0012174', (1376, 1389))	('astrocytomas', 'Disease', (945, 957))	('glioma', 'Disease', 'MESH:D005910', (353, 359))	('astrocytoma', 'Phenotype', 'HP:0009592', (1263, 1274))	('glioma', 'Phenotype', 'HP:0009733', (1022, 1028))	('oligodendrogliomas', 'Disease', (342, 360))	('glioblastomas', 'Disease', 'MESH:D005909', (1087, 1100))	('glioma', 'Disease', 'MESH:D005910', (416, 422))	('tumor', 'Phenotype', 'HP:0002664', (641, 646))	('astrocytoma', 'Phenotype', 'HP:0009592', (945, 956))	('gliomas', 'Disease', 'MESH:D005910', (353, 360))	('astrocytomas', 'Disease', 'MESH:D001254', (732, 744))	('astrocytoma', 'Phenotype', 'HP:0009592', (732, 743))	('gliomas', 'Phenotype', 'HP:0009733', (1022, 1029))	('gliomas', 'Disease', 'MESH:D005910', (416, 423))	('glioma', 'Disease', (24, 30))	('glioma', 'Disease', (1175, 1181))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('1p/19q codel', 'Var', (1420, 1432))	('gliomas', 'Disease', (1175, 1182))	('glioma', 'Phenotype', 'HP:0009733', (353, 359))	('glioma', 'Phenotype', 'HP:0009733', (416, 422))	('astrocytomas', 'Disease', 'MESH:D001254', (1263, 1275))	('tumor', 'Disease', (461, 466))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (1353, 1371))	('glioblastomas', 'Disease', (1376, 1389))	('glioma', 'Disease', 'MESH:D005910', (1175, 1181))	('oligodendrogliomas', 'Disease', (1353, 1371))	('glioblastoma', 'Phenotype', 'HP:0012174', (1376, 1388))	('oligodendroglial tumors', 'Disease', (624, 647))	('astrocytomas', 'Disease', 'MESH:D001254', (945, 957))	('gliomas', 'Disease', (752, 759))	('gliomas', 'Phenotype', 'HP:0009733', (353, 360))	('gliomas', 'Phenotype', 'HP:0009733', (416, 423))	('glioma', 'Disease', (752, 758))	('glioma', 'Disease', (1364, 1370))	('gliomas', 'Disease', 'MESH:D005910', (1175, 1182))	('tumor', 'Disease', 'MESH:D009369', (461, 466))	('gliomas', 'Disease', (1364, 1371))	('glioblastomas', 'Phenotype', 'HP:0012174', (1087, 1100))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('glioblastomas', 'Disease', 'MESH:D005909', (1376, 1389))	('glioma', 'Disease', 'MESH:D005910', (752, 758))	('glioma', 'Disease', 'MESH:D005910', (1364, 1370))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (624, 647))	('glioma', 'Disease', (1022, 1028))	('gliomas', 'Disease', (1022, 1029))	('tumor', 'Disease', (641, 646))	('gliomas', 'Disease', 'MESH:D005910', (752, 759))	('astrocytomas', 'Disease', (732, 744))
67644	27196377	Recently, many studies focusing on genetic prognostic markers for gliomas have highlighted the clinical significance of the mutational status of the gene coding isocitrate dehydrogenase 1 (IDH1).21 Mutations in IDH1 are associated with improved prognosis in glioblastoma and are considered to develop during the early stages of tumorigenesis of astrocytoma and oligodendroglioma,22, 23, 24 which usually progress to a higher-grade tumor.	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (345, 378))	('glioma', 'Phenotype', 'HP:0009733', (372, 378))	('glioblastoma', 'Disease', 'MESH:D005909', (258, 270))	('astrocytoma', 'Phenotype', 'HP:0009592', (345, 356))	('gliomas', 'Disease', (66, 73))	('tumor', 'Disease', (328, 333))	('glioblastoma', 'Disease', (258, 270))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('isocitrate dehydrogenase 1', 'Gene', (161, 187))	('isocitrate dehydrogenase 1', 'Gene', '3417', (161, 187))	('IDH1', 'Gene', (189, 193))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('tumor', 'Disease', (431, 436))	('glioblastoma', 'Phenotype', 'HP:0012174', (258, 270))	('Mutations', 'Var', (198, 207))	('IDH1', 'Gene', (211, 215))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (431, 436))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('improved', 'PosReg', (236, 244))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('IDH1', 'Gene', '3417', (189, 193))	('IDH1', 'Gene', '3417', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (431, 436))
67645	27196377	Although mutant IDH1 is not a predictive marker for radiation or chemotherapy, this information could help in deciding the adjuvant therapy for gliomas, and thus might serve as a critical factor for genetic subgrouping of the tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('tumors', 'Disease', (226, 232))	('mutant', 'Var', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('help', 'Reg', (102, 106))	('IDH1', 'Gene', (16, 20))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('radiation', 'Disease', 'MESH:D004194', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('IDH1', 'Gene', '3417', (16, 20))	('radiation', 'Disease', (52, 61))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))
67663	27196377	Based on the sequencing results, each case of IDH1 mutation was distributed either positive or negative.	('IDH1', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('IDH1', 'Gene', '3417', (46, 50))
67664	27196377	We analyzed relationships of clinical variables and genetic subgroups based on chromosomal CNAs and IDH1 mutation.	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (100, 104))	('IDH1', 'Gene', (100, 104))
67667	27196377	We analyzed both CNAs and IDH1/2 status in a total of 174 primary adult supratentorial glioma samples and found IDH1/2 mutations in 125 tumors and wild-type IDH1/2 in 49 tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('glioma', 'Disease', (87, 93))	('49 tumors', 'Disease', 'OMIM:617237', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('IDH1/2', 'Gene', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('49 tumors', 'Disease', (167, 176))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (119, 128))	('tumors', 'Disease', (170, 176))
67668	27196377	All mutations at codon 132 in IDH1 were found to belong to the CGT to CAT (R132H) type mutation.	('CAT', 'Gene', (70, 73))	('IDH1', 'Gene', (30, 34))	('mutations', 'Var', (4, 13))	('CAT', 'Gene', '847', (70, 73))	('R132H', 'Mutation', 'rs121913500', (75, 80))	('belong', 'Reg', (49, 55))	('IDH1', 'Gene', '3417', (30, 34))
67671	27196377	As previously reported, mutations of IDH1/2 were frequently detected in oligodendrogliomas and low-grade astrocytomas, although wild-type IDH1/2 was detected in higher-grade astrocytomas.	('IDH1/2', 'Gene', (37, 43))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('astrocytomas', 'Disease', (105, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (174, 185))	('astrocytomas', 'Disease', (174, 186))	('detected', 'Reg', (60, 68))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (72, 90))	('astrocytomas', 'Disease', 'MESH:D001254', (105, 117))	('mutations', 'Var', (24, 33))	('astrocytomas', 'Disease', 'MESH:D001254', (174, 186))	('oligodendrogliomas', 'Disease', (72, 90))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
67672	27196377	Concerning genetic subgrouping, 1p/19q codeletion was closely correlated with IDH1/2 mutation with one exceptional case that had wild-type IDH1 and mutant IDH2.	('IDH1', 'Gene', (139, 143))	('IDH2', 'Gene', '3418', (155, 159))	('IDH1', 'Gene', (78, 82))	('mutation', 'Var', (85, 93))	('mutant', 'Var', (148, 154))	('IDH1', 'Gene', '3417', (139, 143))	('IDH1', 'Gene', '3417', (78, 82))	('1p/19q codeletion', 'Var', (32, 49))	('IDH2', 'Gene', (155, 159))	('correlated', 'Reg', (62, 72))
67673	27196377	In tumors with gain on chromosome 7, the most frequent aberration in IDH1/2 mutant tumors was the gain on 7q, whereas the most frequent aberration in IDH1/2 wild-type tumors was the gain of 7 (gain of both 7q and 7p) and +7/-10q.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('gain', 'PosReg', (15, 19))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('gain', 'PosReg', (98, 102))	('tumors', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('IDH1/2', 'Gene', (69, 75))
67675	27196377	The survival was longer in IDH1/2 mutant cases than in IDH1/2 wild-type cases for both PFS (median: total IDH1/2 mutant tumors, 63 months; total IDH1/2 wild type, 12 months; P < 0.0001) and OS (median: total IDH1/2 mutant tumors, undefined; total IDH1/2 wild type, 28 months; P < 0.0001).	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('survival', 'MPA', (4, 12))	('longer', 'PosReg', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('IDH1/2', 'Gene', (27, 33))	('tumors', 'Disease', (222, 228))	('mutant', 'Var', (34, 40))
67676	27196377	Even without 1p/19q codel tumors, which are known to have better prognosis, IDH1/2 mutant cases showed longer survival than IDH1/2 wild-type cases (PFS, median: IDH1/2 mutant, 51 months; IDH1/2 wild type, 12 months; P < 0.0001; OS, median: IDH1/2 mutant, undefined; IDH1/2 wild type, 28 months; P < 0.0001).	('survival', 'MPA', (110, 118))	('mutant', 'Var', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('longer', 'PosReg', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('IDH1/2', 'Gene', (76, 82))	('tumors', 'Disease', (26, 32))
67677	27196377	Interestingly, the curve for IDH1/2 mutant +Ch7 tumors overlapped well with that for the IDH1/2 mutant and of Ch7 and 1p intact (i.e., tumors without classical astrocytic/oligodendroglial genetic markers), whereas the curve for IDH1/2 wild-type +Ch7 tumors overlapped well with those of IDH1/2 wild type and Ch7/1p intact tumors.	('tumors', 'Disease', 'MESH:D009369', (322, 328))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('mutant', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (322, 328))	('tumors', 'Disease', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
67678	27196377	The survival curves for PFS of all the tumors with 1p/19q codel overlapped well with the curves for IDH1/2-mutant +Ch7 and IDH1/2-mutant Ch7/1p intact tumors, whereas OS of 1p/19q codel tumors was longer than that of the other IDH1/2-mutant tumors, although the difference was not statistically significant (P = 0.07).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('1p/19q codel', 'Var', (51, 63))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
67679	27196377	Taken together, our data suggest that, in agreement with previous studies, IDH1/2 mutation is a critical factor with great impact on survival of patients with WHO grade II-III supratentorial gliomas, and that astrocytic tumors (infiltrative gliomas without 1p/19q codel) should be classified by IDH1/2 status but not by the region of the gain on chromosome 7 because +7q tumors and +7 tumors are clinically distinct, whereas IDH1-mutant tumors without 1p/19q codel showed similar prognosis regardless of gain on chromosome 7.	('astrocytic tumors', 'Disease', 'MESH:D001254', (209, 226))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('impact', 'Reg', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (437, 442))	('IDH1', 'Gene', (295, 299))	('tumors', 'Disease', 'MESH:D009369', (385, 391))	('IDH1', 'Gene', '3417', (75, 79))	('gliomas', 'Disease', (241, 248))	('tumors', 'Disease', (437, 443))	('mutation', 'Var', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('IDH1', 'Gene', '3417', (295, 299))	('tumors', 'Disease', 'MESH:D009369', (437, 443))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('gliomas', 'Disease', 'MESH:D005910', (241, 248))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('gliomas', 'Disease', (191, 198))	('tumors', 'Disease', (371, 377))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (385, 391))	('tumors', 'Disease', (220, 226))	('IDH1', 'Gene', (425, 429))	('gliomas', 'Phenotype', 'HP:0009733', (241, 248))	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('tumors', 'Disease', 'MESH:D009369', (371, 377))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumors', 'Disease', (385, 391))	('IDH1', 'Gene', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (437, 443))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('astrocytic tumors', 'Disease', (209, 226))	('IDH1', 'Gene', '3417', (425, 429))
67681	27196377	In summary, the present study showed that +7q is the change only observed in IDH-mutated gliomas, that IDH status had stronger impact than the manner of DNA copy number gain on chromosome 7, and that 10q loss (hallmark of glioblastoma) was not found in IDH mutant tumor.	('+7q', 'Var', (42, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (222, 234))	('hallmark of glioblastoma', 'Disease', 'MESH:D005909', (210, 234))	('loss', 'NegReg', (204, 208))	('IDH', 'Gene', (103, 106))	('tumor', 'Disease', (264, 269))	('gliomas', 'Disease', (89, 96))	('IDH', 'Gene', (77, 80))	('IDH', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('IDH', 'Gene', '3417', (103, 106))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('IDH', 'Gene', '3417', (77, 80))	('IDH', 'Gene', '3417', (253, 256))	('10q', 'Var', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('hallmark of glioblastoma', 'Disease', (210, 234))	('observed', 'Reg', (65, 73))
67685	27196377	This clinical heterogeneity makes it difficult to establish a treatment strategy for gliomas based on their biological nature, and many studies have recently attempted to develop a clinically relevant genetic subgrouping of these tumors.29, 30 We had previously reported that grade II-III gliomas are classified into clinically relevant subgroups according to their chromosomal DNA CNAs.20 This study reported that non-ependymal supratentorial gliomas are basically classified into three categories: tumors with gain on chromosome 7, tumors with 1p/19q codel, and tumors with intact chromosomes 7 and 1p/19q.	('tumors', 'Disease', (534, 540))	('tumor', 'Phenotype', 'HP:0002664', (564, 569))	('gain', 'PosReg', (512, 516))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('gliomas', 'Disease', 'MESH:D005910', (444, 451))	('tumors', 'Disease', (564, 570))	('II-III gliomas', 'Disease', (282, 296))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (500, 505))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('tumors', 'Disease', (500, 506))	('tumors', 'Disease', 'MESH:D009369', (534, 540))	('gliomas', 'Disease', (289, 296))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (564, 570))	('gliomas', 'Phenotype', 'HP:0009733', (444, 451))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('tumors', 'Disease', 'MESH:D009369', (500, 506))	('gliomas', 'Disease', 'MESH:D005910', (289, 296))	('ependymal supratentorial gliomas', 'Disease', 'MESH:D005910', (419, 451))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('tumors', 'Phenotype', 'HP:0002664', (500, 506))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('tumors', 'Phenotype', 'HP:0002664', (534, 540))	('II-III gliomas', 'Disease', 'MESH:D005910', (282, 296))	('gliomas', 'Phenotype', 'HP:0009733', (289, 296))	('gliomas', 'Disease', (444, 451))	('gliomas', 'Disease', (85, 92))	('ependymal supratentorial gliomas', 'Disease', (419, 451))	('tumors', 'Phenotype', 'HP:0002664', (564, 570))	('glioma', 'Phenotype', 'HP:0009733', (444, 450))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('1p/19q codel', 'Var', (546, 558))
67687	27196377	Of them, tumors with +7q and those with 1p/19q codel, that is, low-grade tumors of two major lineages, showed long survival.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('1p/19q', 'Var', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
67691	27196377	As the gain on 7q, as well as 1p/19q codel, was associated with longer survival, whereas +7 and +7/-10q were associated with shorter survival, it could be presumed that +7q would occur in the early stage of glioma progression, and that the tumor might develop malignancy along with gain on 7p to show gain on whole chromosome 7.	('longer', 'PosReg', (64, 70))	('tumor', 'Disease', (240, 245))	('glioma', 'Disease', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('develop', 'PosReg', (252, 259))	('malignancy', 'Disease', 'MESH:D009369', (260, 270))	('1p/19q', 'Var', (30, 36))	('malignancy', 'Disease', (260, 270))
67692	27196377	However, we found that this hypothesis was not reasonable because IDH1/2 mutation, which is considered to occur at an early stage of tumorigenesis,21, 22, 23, 31 does not coexist with +7 when the tumors are of higher grade.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('IDH1/2', 'Gene', (66, 72))	('mutation', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
67693	27196377	Our data suggested that the tumors with a gain on chromosome 7 were divided into at least two lineages: tumors with gain of 7q (only) and mutant IDH1/2 and those with gain of whole chromosome 7 and wild-type IDH1/2.	('IDH1/2', 'Gene', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutant', 'Var', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('gain', 'PosReg', (116, 120))
67696	27196377	In early stages, IDH1/2 mutation occurs in a subset of glioma progenitor cells, and these cells progress to 1p/19q codel tumors and others (including +7q).	('glioma', 'Disease', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('progress', 'PosReg', (96, 104))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH1/2', 'Gene', (17, 23))	('mutation', 'Var', (24, 32))
67698	27196377	However, IDH1/2 wild-type progenitor cells could progress to tumors with +7, +7/-10q or intact 1p/Ch7.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('progress', 'PosReg', (49, 57))	('+7/-10q', 'Var', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
67700	27196377	In contrast to tumors with gain on chromosome 7, there is a lack of evidence to indicate that tumors with 1p/19q codel are composed of multiple lineages.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('1p/19q codel', 'Var', (106, 118))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
67702	27196377	The +7q tumors belong to the latter group, and +7 tumors, mostly both IDH1/2 and TP53 wild type, are clearly distinct tumors in both clinical and genetic aspects (Fig.	('+7q', 'Var', (4, 7))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
67704	27196377	In summary, different from our previous hypothetical glioma progression pathway, tumors with gain on chromosome 7 are classified into three groups: +7q (IDH1/2 mutant), +7 (IDH1/2 wild type), and +7/-10q (similar to primary glioblastoma, IDH1/2 wild type), whereas tumors with 1p/19q codel develop in a single pathway (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('+7q', 'Var', (148, 151))	('gain', 'PosReg', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('glioblastoma', 'Disease', (224, 236))	('hypothetical glioma', 'Disease', (40, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (224, 236))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (224, 236))	('develop', 'PosReg', (290, 297))	('hypothetical glioma', 'Disease', 'MESH:D005910', (40, 59))
67705	27196377	We noted early tumor progression in four cases with IDH1 mutation.	('mutation', 'Var', (57, 65))	('IDH1', 'Gene', '3417', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('IDH1', 'Gene', (52, 56))
67709	27196377	Still a small proportion of +7 tumors might develop from +7q tumors with IDH1/2 mutation because the status of gain of chromosome 7 and IDH1/2 mutation were not completely matched, however, our data suggested that +7 tumors with mutant IDH1/2 should be managed in a similar manner to +7q tumors (Fig.	('IDH1/2', 'Gene', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('IDH1/2', 'Gene', (236, 242))	('tumors', 'Disease', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('develop', 'Reg', (44, 51))	('tumors', 'Disease', (61, 67))	('to +7', 'Species', '1214577', (281, 286))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutant', 'Var', (229, 235))	('mutation', 'Var', (80, 88))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumors', 'Disease', (288, 294))
67712	26684754	Landscape of gene fusions in epithelial cancers: seq and ye shall find Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('epithelial cancers', 'Disease', (29, 47))	('epithelial cancers', 'Disease', 'MESH:D000077216', (121, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('epithelial cancers', 'Disease', 'MESH:D000077216', (29, 47))	('gene fusions', 'Var', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('epithelial cancers', 'Disease', (121, 139))
67715	26684754	Tumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors; for example, gene fusions involving oncogenes such as ERG, ETV1, TFE3, NUT, POU5F1, NFIB, PLAG1, and PAX8 are diagnostically useful.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NUT', 'Gene', '256646', (179, 182))	('NUT', 'Gene', (179, 182))	('NFIB', 'Gene', (192, 196))	('POU5F1', 'Gene', (184, 190))	('PLAG1', 'Gene', '5324', (198, 203))	('PAX8', 'Gene', (209, 213))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('ERG', 'Gene', (162, 165))	('NFIB', 'Gene', '4781', (192, 196))	('PAX8', 'Gene', '7849', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ETV1', 'Gene', (167, 171))	('PLAG1', 'Gene', (198, 203))	('ERG', 'Gene', '2078', (162, 165))	('tumors', 'Disease', (100, 106))	('POU5F1', 'Gene', '5460', (184, 190))	('ETV1', 'Gene', '2115', (167, 171))	('TFE3', 'Gene', (173, 177))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('gene fusions', 'Var', (121, 133))	('TFE3', 'Gene', '7030', (173, 177))
67716	26684754	Tumors with fusions involving therapeutically targetable genes such as ALK, RET, BRAF, RAF1, FGFR1-4, and NOTCH1-3 have immediate implications for precision medicine across tissue types.	('ALK', 'Gene', (71, 74))	('fusions', 'Var', (12, 19))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FGFR1', 'Gene', '2260', (93, 98))	('BRAF', 'Gene', '673', (81, 85))	('ALK', 'Gene', '238', (71, 74))	('NOTCH1', 'Gene', '4851', (106, 112))	('NOTCH1', 'Gene', (106, 112))	('Tumors', 'Disease', (0, 6))	('BRAF', 'Gene', (81, 85))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('RAF1', 'Gene', (87, 91))	('FGFR1', 'Gene', (93, 98))	('RAF1', 'Gene', '5894', (87, 91))	('RET', 'Gene', (76, 79))
67720	26684754	Numerous gene fusions have since been defined at cytogenetically distinct loci of recurrent chromosomal aberrations in hematological malignancies and sarcomas, as well as in solid cancers, albeit much less frequently, arguably owing to technical limitations in resolving karyotypically complex, heterogeneous sub-clones in solid tumor tissues.	('hematological malignancies', 'Disease', (119, 145))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (92, 115))	('sarcomas', 'Disease', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('solid cancers', 'Disease', (174, 187))	('hematological malignancies', 'Disease', 'MESH:D019337', (119, 145))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('hematological malignancies', 'Phenotype', 'HP:0004377', (119, 145))	('solid cancers', 'Disease', 'MESH:D009369', (174, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('recurrent chromosomal aberrations', 'Phenotype', 'HP:0040012', (82, 115))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('chromosomal aberrations', 'Var', (92, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('tumor', 'Disease', (329, 334))
67722	26684754	Developments in high-throughput sequencing techniques over the past decade have made possible a direct, systematic discovery of gene fusions in solid cancers, rapidly revealing a diverse genomic landscape.	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('gene fusions', 'Var', (128, 140))	('solid cancers', 'Disease', (144, 157))	('solid cancers', 'Disease', 'MESH:D009369', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
67726	26684754	The first gene fusions to be defined in solid cancers, RET/PTC and NTRK1 rearrangements in papillary thyroid carcinoma were identified through a "transformation assay" using cancer genomic DNA transfected into murine NIH3T3 cells, followed by retrieval and analysis of human genomic DNA from transformed cells.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('NIH3T3', 'CellLine', 'CVCL:0594', (217, 223))	('rearrangements', 'Var', (73, 87))	('NTRK1', 'Gene', (67, 72))	('solid cancers', 'Disease', 'MESH:D009369', (40, 53))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (101, 118))	('solid cancers', 'Disease', (40, 53))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Disease', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('human', 'Species', '9606', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PTC', 'Gene', '19713', (59, 62))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (91, 118))	('murine', 'Species', '10090', (210, 216))	('papillary thyroid carcinoma', 'Disease', (91, 118))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (91, 118))	('PTC', 'Gene', (59, 62))
67727	26684754	More typically, karyotyping and cytogenetic analysis of recurrent translocations helped define early gene fusions in solid cancers, such as CTNNB1-PLAG1 and HMGA2 fusions in salivary gland pleomorphic adenomas, PRCC-TFE3 in renal cell carcinomas, and ETV6-NTRK3 fusion in secretory breast carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('CTNNB1', 'Gene', (140, 146))	('salivary gland pleomorphic adenomas', 'Disease', 'MESH:C563250', (174, 209))	('HMGA2', 'Gene', (157, 162))	('TFE3', 'Gene', (216, 220))	('PRCC', 'Gene', (211, 215))	('solid cancers', 'Disease', 'MESH:D009369', (117, 130))	('TFE3', 'Gene', '7030', (216, 220))	('breast carcinoma', 'Phenotype', 'HP:0003002', (282, 298))	('fusions', 'Var', (163, 170))	('breast carcinoma', 'Disease', (282, 298))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (224, 245))	('solid cancers', 'Disease', (117, 130))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (224, 244))	('renal cell carcinomas', 'Disease', (224, 245))	('HMGA2', 'Gene', '8091', (157, 162))	('PLAG1', 'Gene', (147, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (251, 268))	('PRCC', 'Gene', '5546', (211, 215))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (224, 245))	('CTNNB1', 'Gene', '1499', (140, 146))	('ETV6-NTRK3 fusion', 'Gene', (251, 268))	('salivary gland pleomorphic adenomas', 'Disease', (174, 209))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PLAG1', 'Gene', '5324', (147, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))	('breast carcinoma', 'Disease', 'MESH:D001943', (282, 298))
67732	26684754	Around the same time, a transformation assay with a cDNA expression library (not genomic libraries) from a lung adenocarcinoma sample led to the discovery of EML4-ALK fusions, and a high-throughput phosphotyrosine signaling screen of lung cancer cell lines and tumors identified SLC34A2-ROS1 fusions in non-small-cell lung carcinoma (NSCLC).	('ROS1', 'Gene', (287, 291))	('EML4', 'Gene', (158, 162))	('SLC34A2', 'Gene', (279, 286))	('NSCLC', 'Disease', (334, 339))	('ALK', 'Gene', '238', (163, 166))	('lung carcinoma', 'Disease', 'MESH:D008175', (318, 332))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('EML4', 'Gene', '27436', (158, 162))	('NSCLC', 'Phenotype', 'HP:0030358', (334, 339))	('ALK', 'Gene', (163, 166))	('lung adenocarcinoma', 'Disease', (107, 126))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('ROS1', 'Gene', '6098', (287, 291))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 126))	('lung cancer', 'Disease', (234, 245))	('lung carcinoma', 'Disease', (318, 332))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (198, 213))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (307, 332))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (303, 332))	('NSCLC', 'Disease', 'MESH:D002289', (334, 339))	('fusions', 'Var', (292, 299))	('SLC34A2', 'Gene', '10568', (279, 286))	('lung cancer', 'Disease', 'MESH:D008175', (234, 245))
67735	26684754	High-throughput sequencing of tumor samples provides a direct readout of chimeric sequences corresponding to putative gene fusions, and the available depth of coverage helps uncover even relatively minor, sub-clonal events.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('chimeric sequences', 'MPA', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('fusions', 'Var', (123, 130))	('tumor', 'Disease', (30, 35))
67736	26684754	In a proof of principle study, high-throughput genomic sequencing was used to identify several gene fusions in a panel of breast cancer cell lines and tissues.	('fusions', 'Var', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
67738	26684754	Additionally, paired-end tag and chromatin interaction analysis by paired-end-tag sequencing have been employed for gene fusion discovery, as well as phosphoproteome analysis, as in the discovery of a SND1-BRAF fusion in a gastric carcinoma sample.	('SND1-BRAF', 'Gene', '27044;673', (201, 210))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (223, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('gastric carcinoma', 'Disease', 'MESH:D013274', (223, 240))	('gastric carcinoma', 'Disease', (223, 240))	('SND1-BRAF', 'Gene', (201, 210))	('fusion', 'Var', (211, 217))
67740	26684754	Similarly, the VTI1A-TCF7L2 fusion, originally identified through genomic sequencing of colorectal carcinoma (CRC) samples, was found in a follow-up study using RNA analyses to be quite prevalent in other cancers, as well as in benign samples.	('prevalent', 'Reg', (186, 195))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('CRC', 'Phenotype', 'HP:0030731', (110, 113))	('cancers', 'Disease', (205, 212))	('fusion', 'Var', (28, 34))	('VTI1A', 'Gene', (15, 20))	('colorectal carcinoma', 'Disease', (88, 108))	('TCF7L2', 'Gene', (21, 27))	('VTI1A', 'Gene', '143187', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('TCF7L2', 'Gene', '6934', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (88, 108))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
67743	26684754	Some useful generalizations have emerged from multiple analyses: first, driver fusions are typically marked by a continuous open reading frame (ORF) that retains functional domains, such as the kinase domain in gene fusions involving oncogenic kinases, or DNA-binding domains in the case of transcription factors; second, some fusions display loss of auto-inhibitory domains (for example, loss of the N-terminal inhibitory domain in the product of BRAF fusions, or loss of 3' UTR sequences in FGFR or HMGA2 fusions that serve as binding sites for inhibitory microRNAs).	('FGFR', 'Gene', (493, 497))	('auto-inhibitory domains', 'MPA', (351, 374))	('loss', 'NegReg', (389, 393))	('BRAF', 'Gene', (448, 452))	('loss', 'NegReg', (465, 469))	('BRAF', 'Gene', '673', (448, 452))	('HMGA2', 'Gene', (501, 506))	("3' UTR sequences", 'MPA', (473, 489))	('loss', 'NegReg', (343, 347))	('N-terminal inhibitory domain', 'MPA', (401, 429))	('HMGA2', 'Gene', '8091', (501, 506))	('fusions', 'Var', (453, 460))
67744	26684754	Yet other types of fusions juxtapose the promoter of certain tissue-specific, inducible or highly expressed genes; for example, the prostate-specific, androgen-inducible genes TMPRSS2 or SLC45A3 fused in frame with the proto-oncogenes ERG or BRAF, respectively, generate the TMPRSS2-ERG and SLC45A3-BRAF gene fusions in prostate cancer.	('fusions', 'Var', (309, 316))	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('prostate cancer', 'Disease', 'MESH:D011471', (320, 335))	('prostate cancer', 'Phenotype', 'HP:0012125', (320, 335))	('ERG', 'Gene', (235, 238))	('ERG', 'Gene', (283, 286))	('TMPRSS2', 'Gene', '7113', (275, 282))	('prostate cancer', 'Disease', (320, 335))	('TMPRSS2', 'Gene', (275, 282))	('BRAF', 'Gene', '673', (299, 303))	('ERG', 'Gene', '2078', (283, 286))	('ERG', 'Gene', '2078', (235, 238))	('BRAF', 'Gene', (299, 303))	('SLC45A3', 'Gene', (187, 194))	('SLC45A3', 'Gene', (291, 298))	('BRAF', 'Gene', '673', (242, 246))	('TMPRSS2', 'Gene', '7113', (176, 183))	('BRAF', 'Gene', (242, 246))	('SLC45A3', 'Gene', '85414', (187, 194))	('TMPRSS2', 'Gene', (176, 183))	('SLC45A3', 'Gene', '85414', (291, 298))
67752	26684754	A large number of fusions display recurrence of a fusion gene in combination with multiple different partners; for example, BRAF/RAF1 and FGFR1/2/3 are fused to several different 5' partners across different tissue types (Additional file 1).	('FGFR1/2/3', 'Gene', '2260;2263;2261', (138, 147))	('RAF1', 'Gene', (129, 133))	('fusions', 'Var', (18, 25))	('RAF1', 'Gene', '5894', (129, 133))	('BRAF', 'Gene', '673', (124, 128))	('FGFR1/2/3', 'Gene', (138, 147))	('BRAF', 'Gene', (124, 128))
67758	26684754	Analysis of mRNA sequencing data from the TCGA compendium, comprising 4366 primary tumor samples from 13 tissue types, revealed kinase fusions involving ALK, ROS, RET, NTRK, and FGFR gene families, which were detected in several types of cancer: bladder carcinoma (3.3 %), glioblastoma (4.4 %), head and neck cancer (1.0 %), low-grade glioma (1.5 %), lung adenocarcinoma (1.6 %), lung squamous cell carcinoma (2.3 %), and thyroid carcinoma (8.7 %).	('carcinoma', 'Phenotype', 'HP:0030731', (399, 408))	('tumor', 'Disease', (83, 88))	('FGFR gene', 'Gene', (178, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (430, 439))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', (238, 244))	('lung adenocarcinoma', 'Disease', (351, 370))	('ROS', 'Gene', (158, 161))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (422, 439))	('glioblastoma', 'Disease', 'MESH:D005909', (273, 285))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (246, 263))	('glioma', 'Disease', (335, 341))	('NTRK', 'Gene', (168, 172))	('thyroid carcinoma', 'Disease', (422, 439))	('bladder carcinoma', 'Disease', 'MESH:D001749', (246, 263))	('cancer', 'Disease', (309, 315))	('glioma', 'Disease', 'MESH:D005910', (335, 341))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('glioblastoma', 'Disease', (273, 285))	('lung squamous cell carcinoma', 'Disease', (380, 408))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (380, 408))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (351, 370))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('neck cancer', 'Disease', 'MESH:D006258', (304, 315))	('glioblastoma', 'Phenotype', 'HP:0012174', (273, 285))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (422, 439))	('ALK', 'Gene', '238', (153, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (351, 370))	('neck cancer', 'Disease', (304, 315))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (385, 408))	('head and neck cancer', 'Phenotype', 'HP:0012288', (295, 315))	('bladder carcinoma', 'Disease', (246, 263))	('kinase fusions', 'Var', (128, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('glioma', 'Phenotype', 'HP:0009733', (335, 341))	('ALK', 'Gene', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (309, 315))
67759	26684754	Gene fusions involving dysregulated expression of transcription factors include ETS family gene fusions, seen in approximately 50 % of all prostate cancers and probably one of the most prevalent transcription factor gene fusions in common epithelial cancers.	('prostate cancers', 'Disease', (139, 155))	('epithelial cancers', 'Disease', 'MESH:D000077216', (239, 257))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gene fusions', 'Var', (91, 103))	('epithelial cancers', 'Disease', (239, 257))	('prostate cancers', 'Disease', 'MESH:D011471', (139, 155))	('ETS family', 'Gene', (80, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('prostate cancers', 'Phenotype', 'HP:0012125', (139, 155))
67761	26684754	Other gene fusions involving transcription factors include NUT (or NUTM1), POU5F1, MAML2, NFIB, PLAG1, TFE3, NOTCH, and PAX8 fusions, imparting spatially and/or stochastically dysregulated expression in multiple different cancer types.	('POU5F1', 'Gene', (75, 81))	('NUT', 'Gene', '256646', (59, 62))	('PLAG1', 'Gene', '5324', (96, 101))	('NUT', 'Gene', (59, 62))	('NUTM1', 'Gene', '256646', (67, 72))	('NUTM1', 'Gene', (67, 72))	('fusions', 'Var', (125, 132))	('NFIB', 'Gene', (90, 94))	('cancer', 'Disease', (222, 228))	('MAML2', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('TFE3', 'Gene', (103, 107))	('PAX8', 'Gene', (120, 124))	('NFIB', 'Gene', '4781', (90, 94))	('TFE3', 'Gene', '7030', (103, 107))	('POU5F1', 'Gene', '5460', (75, 81))	('MAML2', 'Gene', '84441', (83, 88))	('PAX8', 'Gene', '7849', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('PLAG1', 'Gene', (96, 101))	('NUT', 'Gene', (67, 70))	('NUT', 'Gene', '256646', (67, 70))
67762	26684754	NOTCH1 and NOTCH2 fusions result in dysregulated transcriptional outcomes, because after ligand activation, the NOTCH intracellular domain (NICD) forms a transcriptional activator complex, activating genes involved in differentiation, proliferation and apoptosis, and those associated with carcinogenesis.	('apoptosis', 'CPA', (253, 262))	('NOTCH2', 'Gene', (11, 17))	('fusions', 'Var', (18, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (290, 304))	('differentiation', 'CPA', (218, 233))	('carcinogenesis', 'Disease', (290, 304))	('proliferation', 'CPA', (235, 248))	('activating', 'PosReg', (189, 199))	('NOTCH2', 'Gene', '4853', (11, 17))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('genes', 'Gene', (200, 205))
67769	26684754	CD44-SLC1A2/EAAT2 gene fusions are detected in 1-2 % of gastric cancers involving the glutamate transporter SLC1A2, and cause intracellular accumulation of glutamate, a growth-promoting amino acid associated with oncogenic functions.	('cause', 'Reg', (120, 125))	('fusions', 'Var', (23, 30))	('CD44', 'Gene', '960', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('glutamate', 'Chemical', 'MESH:D018698', (86, 95))	('glutamate', 'Chemical', 'MESH:D018698', (156, 165))	('CD44', 'Gene', (0, 4))	('intracellular accumulation of glutamate', 'MPA', (126, 165))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('SLC1A2', 'Gene', '6506', (108, 114))	('SLC1A2', 'Gene', '6506', (5, 11))	('gastric cancers', 'Disease', 'MESH:D013274', (56, 71))	('gastric cancers', 'Disease', (56, 71))	('gastric cancers', 'Phenotype', 'HP:0012126', (56, 71))	('involving', 'Reg', (72, 81))	('EAAT2', 'Gene', (12, 17))	('SLC1A2', 'Gene', (108, 114))	('SLC1A2', 'Gene', (5, 11))	('EAAT2', 'Gene', '6506', (12, 17))
67770	26684754	Thus, this gene fusion may be establishing a pro-oncogenic metabolic milieu, akin to the increased levels of sarcosine reported in prostate cancer.	('gene fusion', 'Var', (11, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('sarcosine', 'Chemical', 'MESH:D012521', (109, 118))	('prostate cancer', 'Disease', (131, 146))
67771	26684754	RNA sequencing of 68 "microsatellite stable" subtype colorectal cancer samples revealed two recurrent fusions involving R-spondin family genes, EIF3E-RSPO2 in two cases and PTPRK-RSPO3 in five cases.	('EIF3E', 'Gene', (144, 149))	('PTPRK', 'Gene', (173, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('RSPO2', 'Gene', '340419', (150, 155))	('EIF3E', 'Gene', '3646', (144, 149))	('fusions', 'Var', (102, 109))	('R-spondin family genes', 'Gene', (120, 142))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('RSPO3', 'Gene', '84870', (179, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('PTPRK', 'Gene', '5796', (173, 178))	('RSPO2', 'Gene', (150, 155))	('RSPO3', 'Gene', (179, 184))	('colorectal cancer', 'Disease', (53, 70))
67775	26684754	Recently, fusions involving SKIL (which encodes a SMAD inhibitor) 3' to androgen-regulated promoters such as TMPRSS2, SLC45A3, and ACPP, were found in 6 of 540 (1.1 %) prostate cancers and one cell line xenograft, LuCaP-77.	('TMPRSS2', 'Gene', (109, 116))	('SKIL', 'Gene', '6498', (28, 32))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('prostate cancers', 'Disease', 'MESH:D011471', (168, 184))	('ACPP', 'Gene', (131, 135))	('TMPRSS2', 'Gene', '7113', (109, 116))	('SLC45A3', 'Gene', (118, 125))	('SLC45A3', 'Gene', '85414', (118, 125))	('prostate cancers', 'Phenotype', 'HP:0012125', (168, 184))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('SKIL', 'Gene', (28, 32))	('prostate cancers', 'Disease', (168, 184))	('found', 'Reg', (142, 147))	('ACPP', 'Gene', '55', (131, 135))	('fusions', 'Var', (10, 17))
67777	26684754	In an analysis of fusion transcripts observed in TCGA data across multiple tumor types, fusions involving chromatin modifier genes, including histone methyltransferase and histone demethylase genes, were identified in 111 samples (2.5 %).	('histone methyltransferase', 'Gene', '56979', (142, 167))	('histone methyltransferase', 'Gene', (142, 167))	('fusions', 'Var', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('multiple tumor', 'Disease', (66, 80))	('multiple tumor', 'Disease', 'MESH:D009369', (66, 80))
67780	26684754	The LACTB2-NCOA2 fusion in colorectal cancer leads to disruption of NCOA2, which encodes an inhibitor of the Wnt/beta-catenin pathway, thus acting to promote carcinogenesis.	('beta-catenin', 'Gene', '1499', (113, 125))	('promote', 'PosReg', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('LACTB2', 'Gene', (4, 10))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('LACTB2', 'Gene', '51110', (4, 10))	('NCOA2', 'Gene', '10499', (68, 73))	('disruption', 'Var', (54, 64))	('fusion', 'Var', (17, 23))	('NCOA2', 'Gene', (68, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('NCOA2', 'Gene', '10499', (11, 16))	('colorectal cancer', 'Disease', (27, 44))	('carcinogenesis', 'Disease', (158, 172))	('beta-catenin', 'Gene', (113, 125))	('NCOA2', 'Gene', (11, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
67785	26684754	CRTC-MAML2 fusions are the defining molecular aberration of mucoepidermoid carcinoma (MEC); translocation-negative MECs are proposed to be designated as a distinct subgroup of adenosquamous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('MAML2', 'Gene', (5, 10))	('translocation-negative', 'Var', (92, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('MAML2', 'Gene', '84441', (5, 10))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (60, 84))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (176, 199))	('adenosquamous carcinoma', 'Disease', (176, 199))	('mucoepidermoid carcinoma', 'Disease', (60, 84))
67787	26684754	In all cases, MAML2 fusions characterize benign or low-grade tumors, and for reasons not described so far have been associated with a favorable prognosis.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('MAML2', 'Gene', (14, 19))	('MAML2', 'Gene', '84441', (14, 19))	('low-grade', 'CPA', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('fusions', 'Var', (20, 27))	('benign', 'Disease', (41, 47))
67788	26684754	Interestingly, pulmonary MECs have shown clinical response to gefitinib in the absence of sensitizing EGFR mutations, suggesting a potential connection with CRTC-MAML2 and the possibility of therapeutic application in other MECs harboring this fusion.	('mutations', 'Var', (107, 116))	('gefitinib', 'Chemical', 'MESH:D000077156', (62, 71))	('MAML2', 'Gene', '84441', (162, 167))	('MAML2', 'Gene', (162, 167))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
67789	26684754	The diagnostic subclass of adenoid cystic carcinomas, including salivary gland and breast cancer, is characterized by MYB-NFIB gene fusions.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MYB', 'Gene', '4602', (118, 121))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('salivary gland', 'Disease', (64, 78))	('MYB', 'Gene', (118, 121))	('breast cancer', 'Disease', (83, 96))	('adenoid cystic carcinomas', 'Disease', (27, 52))	('adenoid cystic carcinomas', 'Disease', 'MESH:D003528', (27, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('NFIB', 'Gene', '4781', (122, 126))	('NFIB', 'Gene', (122, 126))	('gene fusions', 'Var', (127, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
67792	26684754	The EWSR1-ATF1 fusion found in hyalinizing clear cell carcinoma of the salivary glands, a rare and indolent tumor, can potentially be used as a molecular marker of this subtype that is histologically similar to the more aggressive MEC.	('fusion', 'Var', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('EWSR1', 'Gene', '2130', (4, 9))	('ATF1', 'Gene', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ATF1', 'Gene', '466', (10, 14))	('tumor', 'Disease', (108, 113))	('carcinoma of the salivary glands', 'Disease', (54, 86))	('carcinoma of the salivary glands', 'Disease', 'MESH:D012468', (54, 86))	('EWSR1', 'Gene', (4, 9))
67793	26684754	Gene fusions or fusion partners found across tissue types are common in solid cancers.	('solid cancers', 'Disease', 'MESH:D009369', (72, 85))	('fusion', 'Interaction', (16, 22))	('Gene fusions', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('common', 'Reg', (62, 68))	('solid cancers', 'Disease', (72, 85))
67798	26684754	Curiously, BRAF gene fusions in low-grade astrocytomas have been associated with a tendency to growth arrest, conferring a less aggressive clinical phenotype and a better clinical outcome.	('arrest', 'Disease', (102, 108))	('astrocytomas', 'Disease', 'MESH:D001254', (42, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (42, 53))	('gene fusions', 'Var', (16, 28))	('astrocytomas', 'Disease', (42, 54))	('growth arrest', 'Phenotype', 'HP:0001510', (95, 108))	('BRAF', 'Gene', '673', (11, 15))	('less aggressive clinical phenotype', 'MPA', (123, 157))	('arrest', 'Disease', 'MESH:D006323', (102, 108))	('BRAF', 'Gene', (11, 15))
67800	26684754	A screen for BRAF gene fusions in 20,573 solid tumors, using the FoundationOne  targeted gene panel, identified BRAF fusions involving 29 unique 5' fusion partners in 55 (0.3 %) cases across 12 different tumor types, including 3 % (14/531) of melanomas, 2 % (15/701) of gliomas, 1.0 % (3/294) of thyroid cancers, 0.3 % (3/1,062) of pancreatic carcinomas, 0.2 % (8/4,013) of non-small cell lung cancers and 0.2 % (4/2,154) of colorectal cancers, as well as single cases of head and neck cancer, prostate cancer, rectal adenocarcinoma, ovarian, uterine endometrial, and mesothelioma.	('glioma', 'Phenotype', 'HP:0009733', (270, 276))	('melanomas', 'Disease', (243, 252))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (332, 353))	('cancers', 'Phenotype', 'HP:0002664', (304, 311))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('gliomas', 'Phenotype', 'HP:0009733', (270, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('uterine endometrial', 'Disease', (543, 562))	('head and neck cancer', 'Phenotype', 'HP:0012288', (472, 492))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (378, 401))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('prostate cancer', 'Disease', 'MESH:D011471', (494, 509))	('carcinomas', 'Phenotype', 'HP:0030731', (343, 353))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (374, 401))	('neck cancer', 'Disease', 'MESH:D006258', (481, 492))	('prostate cancer', 'Phenotype', 'HP:0012125', (494, 509))	('cancer', 'Phenotype', 'HP:0002664', (486, 492))	('fusions', 'Var', (117, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (425, 442))	('neck cancer', 'Disease', (481, 492))	('prostate cancer', 'Disease', (494, 509))	('BRAF', 'Gene', '673', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('colorectal cancers', 'Disease', (425, 443))	('melanomas', 'Phenotype', 'HP:0002861', (243, 252))	('BRAF', 'Gene', (13, 17))	('thyroid cancers', 'Disease', 'MESH:D013964', (296, 311))	('cancers', 'Phenotype', 'HP:0002664', (436, 443))	('lung cancer', 'Phenotype', 'HP:0100526', (389, 400))	('ovarian', 'Disease', (534, 541))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (511, 532))	('lung cancers', 'Phenotype', 'HP:0100526', (389, 401))	('pancreatic carcinomas', 'Disease', (332, 353))	('carcinoma', 'Phenotype', 'HP:0030731', (523, 532))	('gliomas', 'Disease', (270, 277))	('solid tumors', 'Disease', (41, 53))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('non-small cell lung cancers', 'Disease', (374, 401))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (374, 401))	('tumor', 'Disease', (47, 52))	('thyroid cancer', 'Phenotype', 'HP:0002890', (296, 310))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('colorectal cancers', 'Disease', 'MESH:D015179', (425, 443))	('mesothelioma', 'Disease', (568, 580))	('thyroid cancers', 'Disease', (296, 311))	('gliomas', 'Disease', 'MESH:D005910', (270, 277))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (204, 209))	('melanomas', 'Disease', 'MESH:D008545', (243, 252))	('mesothelioma', 'Disease', 'MESH:D008654', (568, 580))	('cancer', 'Phenotype', 'HP:0002664', (503, 509))	('rectal adenocarcinoma', 'Disease', (511, 532))	('solid tumors', 'Disease', 'MESH:D009369', (41, 53))
67801	26684754	Fusions involving FGFR tyrosine kinase family genes have also been observed across diverse cancers.	('Fusions', 'Var', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('tyrosine kinase', 'Gene', (23, 38))	('observed', 'Reg', (67, 75))	('cancers', 'Disease', (91, 98))	('FGFR', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tyrosine kinase', 'Gene', '7294', (23, 38))
67805	26684754	Subsequently, diverse FGFR fusions, all retaining the tyrosine kinase domain, have been observed in bladder, lung, breast, thyroid, oral, and prostate cancers, involving FGFR1, 2, or 3 either as the 5' or 3' partners.	('FGFR', 'Gene', (22, 26))	('thyroid', 'Disease', (123, 130))	('prostate cancers', 'Disease', (142, 158))	('FGFR1', 'Gene', '2260', (170, 175))	('observed', 'Reg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancers', 'Phenotype', 'HP:0012125', (142, 158))	('tyrosine kinase', 'Gene', (54, 69))	('breast', 'Disease', (115, 121))	('prostate cancers', 'Disease', 'MESH:D011471', (142, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('tyrosine kinase', 'Gene', '7294', (54, 69))	('lung', 'Disease', (109, 113))	('fusions', 'Var', (27, 34))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('FGFR1', 'Gene', (170, 175))	('bladder', 'Disease', (100, 107))	('oral', 'Disease', (132, 136))
67806	26684754	In Additional file 2 we summarize recent clinical trials involving gene fusions in epithelial cancers.	('epithelial cancers', 'Disease', 'MESH:D000077216', (83, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gene fusions', 'Var', (67, 79))	('epithelial cancers', 'Disease', (83, 101))
67809	26684754	Treatment with Pfizer's kinase inhibitor crizotinib (PF02341066) led to a dramatic clinical response in EML4-ALK-positive NSCLC patients, as well as in one patient with an SLC34A2-ROS1-fusion-positive tumor.	('ALK', 'Gene', (109, 112))	('patient', 'Species', '9606', (128, 135))	('tumor', 'Disease', (201, 206))	('ROS1', 'Gene', (180, 184))	('SLC34A2', 'Gene', '10568', (172, 179))	('PF02341066', 'Var', (53, 63))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('SLC34A2', 'Gene', (172, 179))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('EML4', 'Gene', (104, 108))	('crizotinib', 'Chemical', 'MESH:D000077547', (41, 51))	('EML4', 'Gene', '27436', (104, 108))	('patients', 'Species', '9606', (128, 136))	('NSCLC', 'Disease', (122, 127))	('patient', 'Species', '9606', (156, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('ALK', 'Gene', '238', (109, 112))	('ROS1', 'Gene', '6098', (180, 184))
67810	26684754	Unfortunately, resistance is inevitably observed, owing to mutations in the kinase domain, or ALK gene fusion amplification, KIT amplification or increased auto-phosphorylation of EGFR.	('ALK', 'Gene', '238', (94, 97))	('auto-phosphorylation', 'MPA', (156, 176))	('increased', 'PosReg', (146, 155))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('KIT', 'MPA', (125, 128))	('mutations', 'Var', (59, 68))	('ALK', 'Gene', (94, 97))
67813	26684754	Several FGFR inhibitors currently in clinical trials represent potential therapeutics for cancers harboring FGFR fusions across multiple cancer types, including bladder cancer, prostate cancer, and others.	('cancers', 'Disease', (90, 97))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (177, 192))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('cancer', 'Disease', (137, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('FGFR', 'Gene', (8, 12))	('bladder cancer', 'Disease', (161, 175))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('prostate cancer', 'Disease', (177, 192))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('FGFR', 'Gene', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('fusions', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))
67814	26684754	The rare PIK3C family gene fusions in prostate cancer (for example, TBXLR1-PIK3CA and ACPP-PIK3CB) show overexpression of the PI3KC genes and may be sensitive to PIK3CA inhibitors.	('PIK3CA', 'Gene', '5290', (162, 168))	('PIK3C', 'Gene', '5290;5291', (9, 14))	('PI3KC genes', 'Gene', (126, 137))	('PIK3CA', 'Gene', (75, 81))	('ACPP', 'Gene', (86, 90))	('fusions', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('PIK3CA', 'Gene', (162, 168))	('PIK3CB', 'Gene', (91, 97))	('PIK3CB', 'Gene', '5291', (91, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('PIK3C', 'Gene', (162, 167))	('prostate cancer', 'Disease', (38, 53))	('PIK3C', 'Gene', (91, 96))	('PIK3C', 'Gene', (75, 80))	('overexpression', 'PosReg', (104, 118))	('PIK3C', 'Gene', '5290;5291', (162, 167))	('PIK3CA', 'Gene', '5290', (75, 81))	('PIK3C', 'Gene', (9, 14))	('PIK3C', 'Gene', '5290;5291', (91, 96))	('PIK3C', 'Gene', '5290;5291', (75, 80))	('ACPP', 'Gene', '55', (86, 90))
67818	26684754	In a recent clinical sequencing study of 102 pediatric cancers, among 37 non-sarcoma solid cancers, several functional gene fusions were identified, including TFE3 fusions in a colorectal cancer (SFPQ-TFE3) and renal cell cancer (ASPSCR1-TFE3) : both cases were treated with pazopanib, the latter displaying stable disease for 10 months.	('TFE3', 'Gene', (201, 205))	('TFE3', 'Gene', '7030', (201, 205))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('pazopanib', 'Chemical', 'MESH:C516667', (275, 284))	('pediatric cancers', 'Disease', 'MESH:D009369', (45, 62))	('fusions', 'Var', (164, 171))	('colorectal cancer', 'Disease', (177, 194))	('ASPSCR1', 'Gene', (230, 237))	('SFPQ', 'Gene', '6421', (196, 200))	('SFPQ', 'Gene', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('non-sarcoma solid cancers', 'Disease', (73, 98))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('TFE3', 'Gene', (159, 163))	('TFE3', 'Gene', (238, 242))	('renal cell cancer', 'Disease', 'MESH:C538614', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('renal cell cancer', 'Disease', (211, 228))	('TFE3', 'Gene', '7030', (159, 163))	('TFE3', 'Gene', '7030', (238, 242))	('renal cell cancer', 'Phenotype', 'HP:0005584', (211, 228))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('non-sarcoma solid cancers', 'Disease', 'MESH:D009369', (73, 98))	('pediatric cancers', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ASPSCR1', 'Gene', '79058', (230, 237))
67823	26684754	While therapeutic targeting of transcription factor oncogenes is intrinsically challenging, on the basis of the interaction of ERG with the DNA repair enzyme PARP1 and DNA protein kinase DNA-PKc, use of PARP inhibitors was shown to inhibit growth of TMPRSS2-ERG-positive prostate cancer xenografts.	('ERG', 'Gene', '2078', (127, 130))	('PARP', 'Gene', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('PARP', 'Gene', '142', (203, 207))	('PARP1', 'Gene', '142', (158, 163))	('prostate cancer', 'Disease', 'MESH:D011471', (271, 286))	('prostate cancer', 'Phenotype', 'HP:0012125', (271, 286))	('growth', 'CPA', (240, 246))	('ERG', 'Gene', (258, 261))	('TMPRSS2', 'Gene', '7113', (250, 257))	('PARP', 'Gene', (203, 207))	('prostate cancer', 'Disease', (271, 286))	('TMPRSS2', 'Gene', (250, 257))	('ERG', 'Gene', '2078', (258, 261))	('PARP1', 'Gene', (158, 163))	('ERG', 'Gene', (127, 130))	('inhibit', 'NegReg', (232, 239))	('PARP', 'Gene', '142', (158, 162))	('interaction', 'Interaction', (112, 123))	('inhibitors', 'Var', (208, 218))
67825	26684754	These experimental leads point to possible therapeutic avenues targeting a prevalent gene fusion in a common carcinoma.	('carcinoma', 'Disease', (109, 118))	('gene fusion', 'Var', (85, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinoma', 'Disease', 'MESH:D002277', (109, 118))
67827	26684754	Furthermore, typically recurrent gene fusions characterized in cancers represent gain-of-function events arising from the juxtaposition of cell-type- or lineage-specific regulatory elements and proto-oncogenes, or novel combinations of functional domains derived from two proteins that provide combinatorial or additive functionalities to normal genes.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('gain-of-function', 'PosReg', (81, 97))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('fusions', 'Var', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
67828	26684754	However, NGS data also reveal less frequently described loss-of-function chimeras involving tumor suppressor genes such as TP53, PTEN, and others.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('chimeras', 'Var', (73, 81))	('PTEN', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PTEN', 'Gene', '5728', (129, 133))	('loss-of-function', 'NegReg', (56, 72))	('TP53', 'Gene', '7157', (123, 127))	('tumor', 'Disease', (92, 97))	('TP53', 'Gene', (123, 127))
67829	26684754	A systematic analysis of loss-of-function gene fusions could identify additional cancer samples with loss of tumor suppressors that might be currently going unreported, and could help broaden our understanding of the role of gene fusions in cancer.	('gene fusions', 'Var', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('loss-of-function', 'NegReg', (25, 41))	('cancer', 'Disease', (81, 87))	('loss of tumor', 'Disease', (101, 114))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('loss of tumor', 'Disease', 'MESH:D009369', (101, 114))
67832	26684754	Recurrent gene fusions that characterize distinct subtypes of cancers include BRD4-NUT in NUT midline carcinoma, ETV6-NTRK3 in secretory breast carcinoma, CRTC-MAML2 fusions in mucoepidermoid carcinoma, and RAF family fusions in pilocytic astrocytomas.	('fusions', 'Var', (166, 173))	('breast carcinoma', 'Disease', 'MESH:D001943', (137, 153))	('RAF', 'Gene', '22882', (207, 210))	('pilocytic astrocytomas', 'Disease', (229, 251))	('NUT', 'Gene', '256646', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('NUT', 'Gene', '256646', (83, 86))	('NUT', 'Gene', (90, 93))	('mucoepidermoid carcinoma', 'Disease', (177, 201))	('NUT', 'Gene', (83, 86))	('MAML2', 'Gene', '84441', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('ETV6', 'Gene', '2120', (113, 117))	('NTRK3', 'Gene', '4916', (118, 123))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (177, 201))	('breast carcinoma', 'Phenotype', 'HP:0003002', (137, 153))	('NUT midline carcinoma', 'Disease', (90, 111))	('RAF', 'Gene', (207, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('NTRK3', 'Gene', (118, 123))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (229, 251))	('cancers', 'Disease', (62, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (239, 250))	('breast carcinoma', 'Disease', (137, 153))	('BRD4', 'Gene', (78, 82))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (90, 111))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (218, 225))	('ETV6', 'Gene', (113, 117))	('BRD4', 'Gene', '23476', (78, 82))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('MAML2', 'Gene', (160, 165))
67834	26684754	Importantly, the emerging landscape of gene fusions in solid cancers also reveals many gene fusions involving oncogene families or isoforms that are seen across multiple tumor types or subtypes, for example, fusions involving RAF and FGFR family genes.	('RAF', 'Gene', '22882', (226, 229))	('solid cancers', 'Disease', 'MESH:D009369', (55, 68))	('FGFR family', 'Gene', (234, 245))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('fusions', 'Var', (208, 215))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('multiple tumor', 'Disease', (161, 175))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('solid cancers', 'Disease', (55, 68))	('multiple tumor', 'Disease', 'MESH:D009369', (161, 175))	('RAF', 'Gene', (226, 229))
67837	26684754	This indicates that either fusions or activating mutations can independently provide oncogenic function, and that either of these aberrations may render the tumors sensitive to therapeutic targeting.	('render', 'Reg', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (49, 58))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('oncogenic function', 'CPA', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('fusions', 'Var', (27, 34))
67838	26684754	Thus, for example, MEK inhibitors that have been found to be useful for tumors with a BRAF activating mutation may also benefit tumors with the BRAF fusion.	('benefit', 'PosReg', (120, 127))	('activating mutation', 'Var', (91, 110))	('MEK', 'Gene', '5609', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutation', 'Var', (102, 110))	('tumors', 'Disease', (72, 78))	('BRAF', 'Gene', '673', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('BRAF', 'Gene', '673', (144, 148))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('BRAF', 'Gene', (144, 148))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('MEK', 'Gene', (19, 22))	('BRAF', 'Gene', (86, 90))
67841	26684754	Gene fusions are an integral component of the landscape of somatic aberrations in all cancers.	('Gene fusions', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
67842	26684754	Recurrent 3' fusion genes in epithelial cancers are usually kinases or transcription factors, similar to the situation in hematological and soft tissue cancers.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('epithelial cancers', 'Disease', (29, 47))	("3' fusion genes", 'Var', (10, 25))	('soft tissue cancers', 'Disease', (140, 159))	('epithelial cancers', 'Disease', 'MESH:D000077216', (29, 47))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('soft tissue cancers', 'Disease', 'MESH:D012983', (140, 159))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
67843	26684754	Chimeric RNAs expressed independent of chromosomal rearrangements are frequently observed in cancer (and benign) tissues.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('observed', 'Reg', (81, 89))	('Chimeric', 'Var', (0, 8))	('RNAs', 'Protein', (9, 13))
67844	26684754	Functionally recurrent gene fusions provide clinically relevant molecular subclassifications of existing morphological categories of tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('gene fusions', 'Var', (23, 35))
67846	26684754	In an analysis of RAF family gene fusion breakpoints in low-grade astrocytomas, tandem duplications generated by microhomology-mediated break-induced replication were identified as the mechanism of generation of fusions.	('RAF', 'Gene', '22882', (18, 21))	('RAF', 'Gene', (18, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (66, 77))	('astrocytomas', 'Disease', 'MESH:D001254', (66, 78))	('astrocytomas', 'Disease', (66, 78))	('tandem duplications', 'Var', (80, 99))
67849	26684754	Chromothripsis may be responsible for the generation of numerous, apparently random passenger gene fusions that are retained in the multiclonal cells of epithelial cancers, as well as loss-of-function fusions involving tumor suppressors, likely involving the non-homologous end-joining DNA repair system (Fig.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('epithelial cancers', 'Disease', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('fusions', 'Var', (201, 208))	('tumor', 'Disease', (219, 224))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('epithelial cancers', 'Disease', 'MESH:D000077216', (153, 171))	('fusions', 'Var', (99, 106))	('loss-of-function', 'NegReg', (184, 200))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
67851	26684754	Viral integration events have been associated with chromosomal aberrations, such as MYC amplification in HPV-positive genital carcinoma, and not uncommonly, loss of gene function or gene fusions involving viral-human sequences have been reported.	('HPV-positive genital carcinoma', 'Disease', (105, 135))	('amplification', 'Var', (88, 101))	('genital carcinoma', 'Phenotype', 'HP:0010787', (118, 135))	('associated', 'Reg', (35, 45))	('HPV-positive genital carcinoma', 'Disease', 'MESH:D030361', (105, 135))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (51, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('MYC', 'Gene', (84, 87))	('chromosomal aberrations', 'Disease', (51, 74))	('human', 'Species', '9606', (211, 216))
67852	26684754	The recent report of a recurrent gene fusion of UBR5 on 8q22.3 and ZNF423 on 16q12.1 (UBR5-ZNF423) in 8 % of EBV-associated primary nasopharyngeal carcinomas suggests a driver function of this gene fusion in a subset of nasopharyngeal cancers.	('carcinomas', 'Disease', 'MESH:D002277', (147, 157))	('carcinomas', 'Disease', (147, 157))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (220, 242))	('EBV', 'Species', '10376', (109, 112))	('nasopharyngeal cancers', 'Disease', (220, 242))	('gene', 'Var', (33, 37))	('EBV-associated', 'Gene', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (132, 157))
67886	30392092	Patients without progressive tumor growth at the completion of Induction chemotherapy were eligible to proceed with one cycle of the CONSOLIDATION REGIMEN which consisted of carboplatin (calculated using the Calvert formula for a desired area under the curve of 7mg/ml/min on days -8 through -6 to a maximum of 500 mg/m2/day), thiotepa (300mg/m2/day or 10mg/kg/day on days -5 through -3), and etoposide (250mg/m2/day on days or 8.3mg/kg/day -5 through -3).	('carboplatin', 'Chemical', 'MESH:D016190', (174, 185))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('etoposide', 'Chemical', 'MESH:D005047', (393, 402))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (29, 34))	('thiotepa', 'Chemical', 'MESH:D013852', (327, 335))	('300mg/m2/day', 'Var', (337, 349))
67941	30392092	Gokce-Samar et al compared the BSG-98 strategy with targeted therapy approaches including erlotinib, cilengitide and nimotozumab after stereotactic biopsy and reported an increase in median progression-free survival (3 months versus 8.6 months) for the BSG-98 group and a significant increase in median OS (8.8 months versus 16.1 months, p = 0.0003).	('erlotinib', 'Chemical', 'MESH:D000069347', (90, 99))	('nimotozumab', 'Chemical', '-', (117, 128))	('BSG-98', 'Var', (253, 259))	('progression-free survival', 'CPA', (190, 215))	('increase', 'PosReg', (171, 179))
67987	29794239	Using IB Delta Suite, tumor ROIs were determined from deltaT1 (dT1) maps, which are standardized difference maps that enable clear visualization of enhancing lesion free of bright signal from blood products or proteinaceous material.	('dT1', 'Gene', (63, 66))	('deltaT1', 'DELETION', 'None', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('deltaT1', 'Var', (54, 61))	('dT1', 'Gene', '5657503', (63, 66))	('tumor', 'Disease', (22, 27))
68054	27757720	For long time basic cancer research has mainly focused on mutations in cancer cells that result in either gain or loss some functions of cells.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('loss', 'NegReg', (114, 118))	('gain', 'Disease', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('gain', 'Disease', 'MESH:D015430', (106, 110))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
68100	27757720	In fact, MMP-9 can be associated with a 25-kDa protein (lipocalin) giving a band at ~125 kDa and can form a complex with its endogenous inhibitors TIMP-1 giving a band at ~140 kDa.	('TIMP-1', 'Gene', (147, 153))	('form', 'Interaction', (101, 105))	('band', 'MPA', (76, 80))	('associated', 'Interaction', (22, 32))	('MMP-9', 'Var', (9, 14))	('complex', 'Interaction', (108, 115))	('TIMP-1', 'Gene', '7076', (147, 153))
68127	27757720	The comparative evaluation of MMP-9 activity levels in serum from low-grade and high-grade meningioma patients did not reveal significant differences, despite the positive predictive value of MMP-9 (92 and 240 kDa forms) in determining the presence or absence of brain tumor compared to control subjects.	('brain tumor', 'Disease', 'MESH:D001932', (263, 274))	('92', 'Var', (199, 201))	('brain tumor', 'Disease', (263, 274))	('meningioma', 'Disease', (91, 101))	('meningioma', 'Phenotype', 'HP:0002858', (91, 101))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('meningioma', 'Disease', 'MESH:D008577', (91, 101))	('brain tumor', 'Phenotype', 'HP:0030692', (263, 274))
68138	25093246	Our findings demonstrated that 68Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin alphavbeta3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus.	('brain parenchyma', 'Disease', (175, 191))	('accumulated', 'PosReg', (55, 66))	('brain parenchyma', 'Disease', 'MESH:D010195', (175, 191))	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('brain tumor', 'Phenotype', 'HP:0030692', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('brain tumors', 'Disease', (74, 86))	('68Ga-PRGD2', 'Var', (31, 41))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
68140	25093246	The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas 68Ga-PRGD2 seemed to be more superior to 18F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG).	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('glioma grading', 'Disease', (94, 108))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('high-grade glioma', 'Disease', (186, 203))	('correlated', 'Reg', (78, 88))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('68Ga-PRGD2', 'Var', (118, 128))	('TBR', 'Chemical', '-', (35, 38))	('TBRmax', 'Chemical', '-', (35, 41))
68161	25093246	For anaplastic astrocytoma (grade III), the 68Ga -PRGD2 expression had its own characteristic scattered focal area, resembling snowflakes (Figure 1H), while its uptake in GBM (grade IV) had much greater density, with a large bolus of PRGD2 accumulation (Figure 1I,J).	('68Ga -PRGD2', 'Var', (44, 55))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (4, 26))	('PRGD2', 'MPA', (234, 239))	('anaplastic astrocytoma', 'Disease', (4, 26))	('astrocytoma', 'Phenotype', 'HP:0009592', (15, 26))
68186	33477674	In an attempt to develop new therapeutic strategies, the scientific community has taken steps forward to understand the genetic mutations, demystify the cell of origin of these tumours and identify the role the immune environment plays in the complex interplay of tumour formation and evolution.	('tumour', 'Disease', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('tumour', 'Disease', (177, 183))	('tumours', 'Disease', (177, 184))	('mutations', 'Var', (128, 137))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))
68192	33477674	In the WHO classification of 2016, "diffuse gliomas" (Grades II-IV) are classified in two groups based on a hallmark genetic feature, the mutational status of the isocitrate dehydrogenase genes (IDH1 and 2), wildtype (non-mutant) versus mutant (Table 1).	('IDH1 and 2', 'Gene', '3417;3418', (195, 205))	('mutant', 'Var', (237, 243))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('hydrogen', 'Chemical', 'MESH:D006859', (176, 184))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
68193	33477674	IDH mutations have been found in nearly 80% of the lower-grade gliomas and secondary glioblastomas, and in around 10% of primary glioblastomas.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('IDH', 'Gene', (0, 3))	('glioblastomas', 'Disease', 'MESH:D005909', (129, 142))	('glioblastomas', 'Phenotype', 'HP:0012174', (129, 142))	('glioblastomas', 'Phenotype', 'HP:0012174', (85, 98))	('IDH', 'Gene', '3417', (0, 3))	('glioblastomas', 'Disease', (129, 142))	('glioblastomas', 'Disease', 'MESH:D005909', (85, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioblastomas', 'Disease', (85, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('mutations', 'Var', (4, 13))	('found', 'Reg', (24, 29))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
68194	33477674	IDH mutations are thought to occur early on in the genesis of a glioma with the most common heterozygote mutation being IDH1 Arg 132 (R132H).	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (120, 123))	('IDH', 'Gene', '3417', (0, 3))	('Arg', 'Chemical', 'MESH:D001120', (125, 128))	('R132H', 'Mutation', 'rs121913500', (134, 139))	('glioma', 'Disease', (64, 70))	('R132H', 'Var', (134, 139))	('IDH', 'Gene', (120, 123))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
68195	33477674	The mutated IDH enzyme reduces alpha-ketoglutarate (alpha-KG) to D-2-hydroxyglutarate (D-2HG).	('mutated', 'Var', (4, 11))	('alpha-ketoglutarate', 'MPA', (31, 50))	('alpha-KG', 'Chemical', 'MESH:D007656', (52, 60))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (65, 85))	('D-2HG', 'Chemical', 'MESH:C019417', (87, 92))	('reduces alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (23, 50))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('reduces', 'NegReg', (23, 30))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (31, 50))
68196	33477674	D-2HG is thought to act as an oncometabolite, leading to profound cell modifications including histone and DNA hypermethylation, inhibition of cell differentiation and increased proliferation, possibly by competitive inhibition of alpha-KG-dependent dioxygenases.	('met', 'Gene', (116, 119))	('increased', 'PosReg', (168, 177))	('met', 'Gene', (34, 37))	('proliferation', 'CPA', (178, 191))	('D-2HG', 'Var', (0, 5))	('alpha-KG', 'Chemical', 'MESH:D007656', (231, 239))	('met', 'Gene', '79811', (34, 37))	('inhibition', 'NegReg', (129, 139))	('D-2HG', 'Chemical', 'MESH:C019417', (0, 5))	('histone', 'MPA', (95, 102))	('met', 'Gene', '79811', (116, 119))	('oxygen', 'Chemical', 'MESH:D010100', (252, 258))	('cell differentiation', 'CPA', (143, 163))
68198	33477674	Further, mutations within the core promoter of telomerase reverse transcriptase (TERT) can also be found within this group, resulting in an increased telomerase activity, an important step in the immortalization process.	('telomerase reverse transcriptase', 'Gene', '7015', (47, 79))	('TERT', 'Gene', (81, 85))	('mutations', 'Var', (9, 18))	('TERT', 'Gene', '7015', (81, 85))	('telomerase activity', 'MPA', (150, 169))	('increased', 'PosReg', (140, 149))	('telomerase reverse transcriptase', 'Gene', (47, 79))
68200	33477674	Moreover, these data also indicated the presence of a pro-oncogenic pathway activation in glioblastomas, such as the dysregulation of the receptor tyrosine kinase (RTK), Ras and phosphatidyl inositol 3-kinase (PI3K) pathways, via activation of growth factor receptors (EGFR, PDGFRA) and through neurofibromin 1 (NF1) and phosphatase and tensin homolog (PTEN) deletion.	('phosphatase and tensin homolog', 'Gene', '5728', (321, 351))	('phosphatidyl inositol 3-kinase', 'Gene', '5293', (178, 208))	('receptor tyrosine kinase', 'Gene', '5979', (138, 162))	('phosphatidyl inositol 3-kinase', 'Gene', (178, 208))	('PTEN', 'Gene', (353, 357))	('pro-oncogenic', 'Pathway', (54, 67))	('glioblastomas', 'Disease', 'MESH:D005909', (90, 103))	('receptor tyrosine kinase', 'Gene', (138, 162))	('PDGFRA', 'Gene', (275, 281))	('PDGFRA', 'Gene', '5156', (275, 281))	('PTEN', 'Gene', '5728', (353, 357))	('glioblastomas', 'Phenotype', 'HP:0012174', (90, 103))	('neurofibromin 1', 'Gene', '4763', (295, 310))	('NF1', 'Gene', '4763', (312, 315))	('activation', 'PosReg', (230, 240))	('RTK', 'Gene', (164, 167))	('neurofibromin 1', 'Gene', (295, 310))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('glioblastomas', 'Disease', (90, 103))	('RTK', 'Gene', '5979', (164, 167))	('pro-oncogenic', 'CPA', (54, 67))	('NF1', 'Gene', (312, 315))	('activation', 'PosReg', (76, 86))	('deletion', 'Var', (359, 367))
68205	33477674	Although 1p19q codeletion was discovered nearly two decades ago, very little is known regarding its functional impact in the neurobiology of oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (141, 159))	('1p19q', 'Var', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('oligodendrogliomas', 'Disease', (141, 159))
68206	33477674	To date, evidence exists to suggest that TERT promoter mutation is highly prevalent within mutants, leading to an increased TERT promoter transcriptional activity, and consequent telomerase activity, which ultimately determine a crucial progression to immortalization.	('increased', 'PosReg', (114, 123))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('TERT', 'Gene', (124, 128))	('mutants', 'Var', (91, 98))	('mutation', 'Var', (55, 63))	('TERT', 'Gene', '7015', (124, 128))	('telomerase activity', 'MPA', (179, 198))
68207	33477674	Further, whole exosome studies reported that the capicua transcriptional repressor gene (CIC), is frequently and specifically mutated in 1p19q co-deleted oligodendrogliomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (154, 172))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('CIC', 'Gene', '23152', (89, 92))	('oligodendrogliomas', 'Disease', (154, 172))	('CIC', 'Gene', (89, 92))	('1p19q co-deleted', 'Var', (137, 153))	('mutated', 'Var', (126, 133))
68208	33477674	The second group refers to the majority of grade II-III gliomas that carry mutations in the transcriptional regulators ATRX and TP53 but no 1p19q codeletion, encompassing the diffuse or anaplastic astrocytomas (II-III) and secondary glioblastomas (IV).	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (186, 209))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('TP53', 'Gene', '7157', (128, 132))	('anaplastic astrocytomas', 'Disease', (186, 209))	('TP53', 'Gene', (128, 132))	('glioblastomas', 'Phenotype', 'HP:0012174', (233, 246))	('ATRX', 'Gene', '546', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioblastomas', 'Disease', 'MESH:D005909', (233, 246))	('mutations', 'Var', (75, 84))	('II-III gliomas', 'Disease', (49, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (233, 245))	('astrocytoma', 'Phenotype', 'HP:0009592', (197, 208))	('glioblastomas', 'Disease', (233, 246))	('II-III gliomas', 'Disease', 'MESH:D005910', (49, 63))	('ATRX', 'Gene', (119, 123))
68209	33477674	Deciphering the specific role of ATRX mutations to the tumour neurobiology has not been established to date, although there is some evidence to suggest it has a role in cell cycle regulation, histone regulation, and chromatin remodelling.	('tumour', 'Disease', (55, 61))	('ATRX', 'Gene', '546', (33, 37))	('ATRX', 'Gene', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('histone regulation', 'MPA', (192, 210))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('role', 'Reg', (161, 165))	('mutations', 'Var', (38, 47))	('cell cycle regulation', 'CPA', (169, 190))
68211	33477674	By using both genotype (i.e., IDH mutations and 1p19q codeletion status) and phenotype as diagnostic criteria, most (if not all) tumours of this group fall into the category of oligodendroglioma or astrocytoma.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('oligodendroglioma or astrocytoma', 'Disease', 'MESH:D009837', (177, 209))	('fall', 'Phenotype', 'HP:0002527', (151, 155))	('1p19q', 'Var', (48, 53))	('tumours', 'Disease', (129, 136))	('IDH', 'Gene', (30, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (198, 209))	('IDH', 'Gene', '3417', (30, 33))	('oligodendroglioma or astrocytoma', 'Disease', (177, 209))
68221	33477674	Common cell lines derived from high grade glioblastomas, such as U-87MG, LN-18, and LN-229 have provided a useful tool in studying many different drug approaches, such as how caffeine can sensitize glioblastoma cells to the effects of temozolomide (TMZ), or how tumour cells overcome contact inhibition.	('tumour', 'Disease', (262, 268))	('glioblastoma', 'Disease', (198, 210))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('caffeine', 'Chemical', 'MESH:D002110', (175, 183))	('U-87MG', 'CellLine', 'CVCL:0022', (65, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (42, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('LN-229', 'Var', (84, 90))	('effects of temozolomide', 'MPA', (224, 247))	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('temozolomide', 'Chemical', 'MESH:D000077204', (235, 247))	('glioblastomas', 'Disease', (42, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (198, 210))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('TMZ', 'Chemical', 'MESH:D000077204', (249, 252))	('tumour', 'Disease', 'MESH:D009369', (262, 268))	('glioblastomas', 'Disease', 'MESH:D005909', (42, 55))	('sensitize', 'Reg', (188, 197))	('LN-229', 'CellLine', 'CVCL:0393', (84, 90))
68222	33477674	Over time, this may result in genetic aberrations which cause changes in the gene expression and phenotype of the cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('gene expression', 'MPA', (77, 92))	('result', 'Reg', (20, 26))	('changes', 'Reg', (62, 69))	('genetic aberrations', 'Var', (30, 49))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
68239	33477674	were able to cause simultaneous disruption of TP53 and gain of function of HRas proteins, generating tumour formation.	('HRas', 'Gene', (75, 79))	('HRas', 'Gene', '3265', (75, 79))	('disruption', 'Var', (32, 42))	('tumour', 'Disease', (101, 107))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('gain of function', 'PosReg', (55, 71))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
68256	33477674	They found that genetic alterations to the donor mouse brain such as knockout of cell surface proteins led to a reduction in tumour cell invasion.	('knockout', 'Var', (69, 77))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('mouse', 'Species', '10090', (49, 54))	('reduction', 'NegReg', (112, 121))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))
68261	33477674	The drug screening performed showed that cisplatin was able to significantly reduce tumour size, TMZ inhibited tumour cell proliferation, while paclitaxel was shown to cause mitotic slippage of tumour cells.	('inhibited', 'NegReg', (101, 110))	('tumour', 'Disease', (84, 90))	('reduce', 'NegReg', (77, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('tumour', 'Disease', (194, 200))	('mitotic slippage', 'CPA', (174, 190))	('TMZ', 'Chemical', 'MESH:D000077204', (97, 100))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('cause', 'Reg', (168, 173))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('cisplatin', 'Var', (41, 50))	('tumour', 'Disease', (111, 117))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (194, 200))
68277	33477674	There have been many other models developed of high-grade astrocytoma that rely on genetic alterations to Ras, EGFR, and Akt among others.	('genetic alterations', 'Var', (83, 102))	('astrocytoma', 'Disease', (58, 69))	('Akt', 'Gene', (121, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('EGFR', 'Gene', (111, 115))	('Akt', 'Gene', '207', (121, 124))	('astrocytoma', 'Disease', 'MESH:D001254', (58, 69))	('Ras', 'Gene', (106, 109))
68283	33477674	Some EGFRvIII/Ha-RasV12 double mutant mice also demonstrated histological features of astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (86, 97))	('mice', 'Species', '10090', (38, 42))	('astrocytoma', 'Disease', (86, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('double mutant', 'Var', (24, 37))	('EGFRvIII/Ha-RasV12', 'Gene', (5, 23))
68284	33477674	Although GEMMs are useful tools in understanding how acquisition of mutation(s) cause tumour formation, they also present some limitations: the genetic alterations generated are limited to a number of genes, thus they cannot fully represent the genetic complexity and heterogeneity that is often seen in resected human glioma samples.	('glioma', 'Disease', 'MESH:D005910', (319, 325))	('glioma', 'Phenotype', 'HP:0009733', (319, 325))	('mutation', 'Var', (68, 76))	('human', 'Species', '9606', (313, 318))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('glioma', 'Disease', (319, 325))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('cause', 'Reg', (80, 85))	('tumour', 'Disease', (86, 92))
68325	33477674	Thirty-eight tissue samples from 9 patients were profiled for genome-wide DNA somatic copy number, showing consistent heterogeneous putative driver mutations, such as copy number gain/amplification of the PDGFRA, MDM4, and AKT3 loci, and deletion of the genomic locus containing PTEN.	('PTEN', 'Gene', (279, 283))	('MDM4', 'Gene', '4194', (213, 217))	('AKT3', 'Gene', '10000', (223, 227))	('PTEN', 'Gene', '5728', (279, 283))	('copy number', 'Var', (167, 178))	('MDM4', 'Gene', (213, 217))	('PDGFRA', 'Gene', (205, 211))	('gain/amplification', 'PosReg', (179, 197))	('patients', 'Species', '9606', (35, 43))	('PDGFRA', 'Gene', '5156', (205, 211))	('deletion', 'Var', (238, 246))	('AKT3', 'Gene', (223, 227))
68329	33477674	Therefore, it was implied that taking samples from multiple sites within the tumour, enables both spatial and temporal interrogation of mutations.	('mutations', 'Var', (136, 145))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (77, 83))
68332	33477674	The authors concluded that, the founder clone initially displayed amplification/gain of EGFR, CDK6, and MET, and loss/deletion of CDKN2A/B, PTEN, and PARK2.	('CDKN2A/B', 'Gene', (130, 138))	('loss/deletion', 'NegReg', (113, 126))	('MET', 'Gene', '79811', (104, 107))	('MET', 'Gene', (104, 107))	('amplification/gain', 'Var', (66, 84))	('amplification/gain', 'PosReg', (66, 84))	('CDKN2A/B', 'Gene', '1029;1030', (130, 138))	('PARK2', 'Gene', '5071', (150, 155))	('CDK6', 'Gene', (94, 98))	('PARK2', 'Gene', (150, 155))	('PTEN', 'Gene', (140, 144))	('CDK6', 'Gene', '1021', (94, 98))	('EGFR', 'Gene', (88, 92))	('PTEN', 'Gene', '5728', (140, 144))
68338	33477674	Variability was noted in the expression and/or mutational status of important signalling molecules, such as the splicing patterns of receptor tyrosine kinases (RTKs), EGFR truncations and in frame deletions (EGFRvIII).	('in frame deletions', 'Var', (188, 206))	('RTK', 'Gene', (160, 163))	('receptor tyrosine kinase', 'Gene', (133, 157))	('truncations', 'Var', (172, 183))	('receptor tyrosine kinase', 'Gene', '5979', (133, 157))	('EGFR', 'Gene', (167, 171))	('RTK', 'Gene', '5979', (160, 163))
68356	33477674	TME composition might be partly influenced by tumour cell gene expression, i.e., TP53 mutated in astrocytomas has been shown to influence the nuclear factor kappa beta NF-kbeta immunoregulatory pathway.	('TME', 'Chemical', '-', (0, 3))	('mutated', 'Var', (86, 93))	('influence', 'Reg', (128, 137))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('astrocytomas', 'Disease', 'MESH:D001254', (97, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('tumour', 'Disease', 'MESH:D009369', (46, 52))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('astrocytomas', 'Disease', (97, 109))
68357	33477674	In contrast to the difference in TME composition, both IDH-A and IDH-O showed the same developmental hierarchy, suggesting a common progenitor for all IDH mutant gliomas with NSC/NPC-like program.	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('IDH', 'Gene', (65, 68))	('gliomas', 'Disease', (162, 169))	('IDH', 'Gene', '3417', (151, 154))	('IDH', 'Gene', (55, 58))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('IDH', 'Gene', '3417', (65, 68))	('mutant', 'Var', (155, 161))	('IDH', 'Gene', '3417', (55, 58))	('TME', 'Chemical', '-', (33, 36))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('IDH', 'Gene', (151, 154))
68373	33477674	Interestingly Neurofibromatosis type 1 (NF1) deficient MES glioblastoma cells were shown to have an increase in M2 macrophage gene signature, suggesting that NF1 deactivation may promote macrophage/microglia recruitment.	('deactivation', 'Var', (162, 174))	('M2 macrophage gene signature', 'MPA', (112, 140))	('NF1', 'Gene', (40, 43))	('promote', 'PosReg', (179, 186))	('NF1', 'Gene', (158, 161))	('macrophage/microglia recruitment', 'CPA', (187, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('NF1', 'Gene', '4763', (40, 43))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (14, 31))	('NF1', 'Gene', '4763', (158, 161))	('Neurofibromatosis type 1 (NF1) deficient MES glioblastoma', 'Disease', 'MESH:C537392', (14, 71))	('increase', 'PosReg', (100, 108))
68378	33477674	Hypermutations after TMZ treatment may lead to a more immunological reactive microenvironment, which can be subject to immune checkpoint inhibitors.	('lead to', 'Reg', (39, 46))	('immunological reactive microenvironment', 'MPA', (54, 93))	('Hypermutations', 'Var', (0, 14))	('more', 'PosReg', (49, 53))	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))
68433	33477674	Resistant subclones are likely to be generated in response to therapy in two different ways: (1) drug therapies induce genetic changes in a small number of cells, generating mutant subclones, which are preferentially augmented during subsequent treatment; (2) therapy resistant subclones generated during tumour progression, are present pre-treatment and continue to thrive despite further therapy.	('tumour', 'Disease', (305, 311))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('tumour', 'Disease', 'MESH:D009369', (305, 311))	('mutant', 'Var', (174, 180))
68443	33477674	Oligodendroglioma is characterised by either IDH1 or IDH2 mutations combined with the loss of both 1p/19q chromosomal arms.	('mutations', 'Var', (58, 67))	('IDH', 'Gene', (45, 48))	('Oligodendroglioma', 'Disease', 'MESH:D009837', (0, 17))	('IDH', 'Gene', '3417', (45, 48))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('IDH', 'Gene', (53, 56))	('IDH', 'Gene', '3417', (53, 56))	('Oligodendroglioma', 'Disease', (0, 17))
68455	33477674	The in-silico study found that out of the 10 modified TMZ-derivatives, 6 of them had more favourable absorption, distribution, metabolism and excretion (ADME) scores than TMZ itself.	('met', 'Gene', (127, 130))	('met', 'Gene', '79811', (127, 130))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('absorption', 'MPA', (101, 111))	('modified', 'Var', (45, 53))	('distribution', 'MPA', (113, 125))	('TMZ', 'Chemical', 'MESH:D000077204', (171, 174))	('excretion', 'MPA', (142, 151))
68458	33477674	Methylation at the carbon-5 position of cytosine (5-methylcytosine, 5mC) is a well-documented epigenetic DNA alteration that controls the expression of a wide range of genes as well as playing a role in chromatin structure.	('cytosine', 'Chemical', 'MESH:D003596', (40, 48))	('Methylation', 'Var', (0, 11))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (50, 66))	('expression', 'MPA', (138, 148))	('controls', 'Reg', (125, 133))	('cytosine', 'Chemical', 'MESH:D003596', (58, 66))	('role', 'Reg', (195, 199))	('5mC', 'Chemical', '-', (68, 71))	('carbon', 'Chemical', 'MESH:D002244', (19, 25))
68467	33477674	IDH mutations occurs most commonly at position R132 and the most common mutation in glioma results in a change to R132H.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (84, 90))	('IDH', 'Gene', '3417', (0, 3))	('R132H', 'Var', (114, 119))	('change', 'Reg', (104, 110))	('R132H', 'Mutation', 'rs121913500', (114, 119))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
68468	33477674	The result of this mutation is neomorphic enzyme activity that instead of producing alpha-ketoglutarate produces 2-hydroxyglutarate (2-HG).	('2-HG', 'Chemical', 'MESH:C019417', (133, 137))	('mutation', 'Var', (19, 27))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (84, 103))	('2-hydroxyglutarate', 'MPA', (113, 131))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (113, 131))
68470	33477674	Multiple studies conducted on IDH mutant brain tumours have focused on understanding the pathways and mechanisms involved in IDH-related gliomagenesis, and in particular the role of the epigenetic modifications and effects on IDH mutant gliomas.	('IDH', 'Gene', '3417', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('brain tumour', 'Phenotype', 'HP:0030692', (41, 53))	('IDH', 'Gene', (30, 33))	('glioma', 'Disease', (137, 143))	('brain tumours', 'Disease', (41, 54))	('brain tumours', 'Phenotype', 'HP:0030692', (41, 54))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('IDH', 'Gene', (125, 128))	('gliomas', 'Disease', (237, 244))	('IDH', 'Gene', '3417', (30, 33))	('glioma', 'Disease', (237, 243))	('IDH', 'Gene', (226, 229))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('IDH', 'Gene', '3417', (125, 128))	('brain tumours', 'Disease', 'MESH:D001932', (41, 54))	('mutant', 'Var', (34, 40))
68471	33477674	A review by Park and Turcan, discusses alterations in IDH mutational status, resulting in histone modifications and remodelling of chromatin.	('remodelling', 'MPA', (116, 127))	('histone modifications', 'MPA', (90, 111))	('IDH', 'Gene', (54, 57))	('alterations', 'Var', (39, 50))	('IDH', 'Gene', '3417', (54, 57))
68475	33477674	These tumours also showed the highest level of hypomethylation when compared to other cancers, indicating that IDH mutations cannot be associated with a pre-defined methylation pattern across all cancers, but instead is tissue type dependent.	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('IDH', 'Gene', (111, 114))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('met', 'Gene', '79811', (165, 168))	('met', 'Gene', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('IDH', 'Gene', '3417', (111, 114))	('tumours', 'Disease', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (115, 124))	('met', 'Gene', '79811', (51, 54))	('met', 'Gene', (51, 54))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
68478	33477674	The effect of IDH mutations in glioma methylation changes may be influenced by the differentiation state of the cell that the mutation occurs within.	('met', 'Gene', '79811', (38, 41))	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('met', 'Gene', (38, 41))	('glioma', 'Disease', (31, 37))	('mutations', 'Var', (18, 27))
68480	33477674	Although different cancers may contain the same IDH mutation, this may not result in the same phenotypic effect.	('IDH', 'Gene', (48, 51))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('IDH', 'Gene', '3417', (48, 51))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
68482	33477674	IDH mutations in glioma produces a unique methylation pattern termed Glioma CpG Island Methylator Phenotype (G-CIMP).	('IDH', 'Gene', (0, 3))	('met', 'Gene', '79811', (42, 45))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('Glioma CpG Island Methylator', 'Disease', (69, 97))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('IDH', 'Gene', '3417', (0, 3))	('met', 'Gene', (42, 45))	('Glioma', 'Phenotype', 'HP:0009733', (69, 75))	('G-CIMP', 'Chemical', '-', (109, 115))	('glioma', 'Disease', (17, 23))	('mutations', 'Var', (4, 13))	('Glioma CpG Island Methylator', 'Disease', 'MESH:D005910', (69, 97))
68485	33477674	Patients with G-CIMP high at both presentation and tumour recurrence have a better clinical outcome than patients whose primary tumour recurs having undergone methylation changes towards G-CIMP low.	('tumour', 'Disease', (128, 134))	('patients', 'Species', '9606', (105, 113))	('met', 'Gene', '79811', (159, 162))	('G-CIMP', 'Chemical', '-', (14, 20))	('met', 'Gene', (159, 162))	('G-CIMP', 'Chemical', '-', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', (51, 57))	('G-CIMP high', 'Var', (14, 25))
68496	33477674	Levels of N6-mA were higher in human glioblastoma samples than in normal healthy tissue indicating that it may have a tumourigenic role.	('tumour', 'Disease', (118, 124))	('glioblastoma', 'Disease', 'MESH:D005909', (37, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('human', 'Species', '9606', (31, 36))	('N6-mA', 'Var', (10, 15))	('higher', 'PosReg', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('N6-mA', 'Chemical', '-', (10, 15))	('glioblastoma', 'Disease', (37, 49))
68525	33477674	Failure to identify and preserve eloquent brain regions can significantly compromise the patient's quality of life, performance status and potentially render them ineligible for further adjunctive treatment options with consequent serious prognostic implications.	('patient', 'Species', '9606', (89, 96))	('Failure', 'Var', (0, 7))	('performance status', 'CPA', (116, 134))	('compromise', 'NegReg', (74, 84))	('quality of life', 'CPA', (99, 114))
68549	33477674	The interim analysis of CATNON trial showed that non 1p19q codeleted anaplastic astrocytomas can benefit from 12 cycles of TMZ as well.	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (69, 92))	('anaplastic astrocytomas', 'Disease', (69, 92))	('TMZ', 'Chemical', 'MESH:D000077204', (123, 126))	('non 1p19q', 'Var', (49, 58))	('astrocytoma', 'Phenotype', 'HP:0009592', (80, 91))
68550	33477674	The CODEL trial is currently investigating whether TMZ can replace PCV in the treatment of 1p19q codeleted oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (107, 125))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('oligodendrogliomas', 'Disease', (107, 125))	('1p19q', 'Var', (91, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (51, 54))
68551	33477674	Further, the POLCA trial is currently investigating whether radiotherapy for 1p19q codeleted oligodendrogliomas can be replaced by PCV only.	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (93, 111))	('oligodendrogliomas', 'Disease', (93, 111))	('1p19q', 'Var', (77, 82))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
68553	33477674	Additionally, an interim analysis showed that adding electric field therapy to adjuvant TMZ leading to five-month survival benefit, regardless of subgroup prognostic co-factors, i.e., total resection, MGMTp status.	('MGMTp', 'Gene', (201, 206))	('benefit', 'PosReg', (123, 130))	('MGMTp', 'Gene', '4255', (201, 206))	('TMZ', 'Chemical', 'MESH:D000077204', (88, 91))	('electric field', 'Var', (53, 67))	('survival', 'CPA', (114, 122))
68559	33477674	Brem et al., has showed that usage of BCNU showed improvement in median survival (31 vs. 23 weeks compared to the placebo).	('BCNU', 'Chemical', 'MESH:D002330', (38, 42))	('usage', 'Var', (29, 34))	('BCNU', 'Gene', (38, 42))	('improvement', 'PosReg', (50, 61))	('median survival', 'MPA', (65, 80))
68578	33477674	Depatux-M is an antibody-drug conjugate, that targets cancer cells by linking the toxin monomethyl auristatin F (MMAF) with an antibody directed against the epidermal growth factor receptor (EGFR) or mutant EGFRvIII.	('epidermal growth factor receptor', 'Gene', (157, 189))	('monomethyl auristatin F', 'Chemical', 'MESH:C513576', (88, 111))	('EGFRvIII', 'Gene', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('mutant', 'Var', (200, 206))	('cancer', 'Disease', (54, 60))	('EGFR', 'Gene', (191, 195))	('epidermal growth factor receptor', 'Gene', '1956', (157, 189))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('linking', 'Interaction', (70, 77))
68582	33477674	Since a huge percentage of low grade gliomas and secondary glioblastomas bear mutations in IDHs, huge efforts have been spent pursuing the identification of novel direct inhibitors of the mutant IDH.	('IDH', 'Gene', (195, 198))	('IDH', 'Gene', '3417', (195, 198))	('mutations', 'Var', (78, 87))	('glioblastomas', 'Disease', 'MESH:D005909', (59, 72))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('IDH', 'Gene', (91, 94))	('glioblastomas', 'Phenotype', 'HP:0012174', (59, 72))	('glioblastomas', 'Disease', (59, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('IDH', 'Gene', '3417', (91, 94))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
68584	33477674	This drug was able to block the generation of D-2-HG, which is aberrantly produced in IDH mutant gliomas, impairing xenograft progression in vivo.	('IDH', 'Gene', (86, 89))	('D-2-HG', 'Chemical', 'MESH:C019417', (46, 52))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('IDH', 'Gene', '3417', (86, 89))	('gliomas', 'Disease', (97, 104))	('mutant', 'Var', (90, 96))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('xenograft progression in vivo', 'CPA', (116, 145))	('impairing', 'NegReg', (106, 115))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
68585	33477674	AG-120 (ivosidenib) and AG-881 (vorasidenib) and AG-221 (enasidenib) are the second generations selective, reversible drug inhibitors produced, which are approved by Food and Drug Administration for the treatment of acute myeloid leukaemia .	('AG-221', 'Chemical', 'MESH:C000605269', (49, 55))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (216, 239))	('enasidenib', 'Chemical', 'MESH:C000605269', (57, 67))	('acute myeloid leukaemia', 'Disease', (216, 239))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('AG-221', 'Var', (49, 55))	('AG-881', 'Chemical', '-', (24, 30))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (222, 239))	('ivosidenib', 'Chemical', 'MESH:C000627630', (8, 18))	('AG-881', 'Var', (24, 30))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (216, 239))	('vorasidenib', 'Chemical', '-', (32, 43))
68588	33477674	Since the discovery that IDH1 R132H is the most common mutation in 'diffuse' gliomas, more clinical trials have emerged (NCT02073994; NCT02273739; NCT02454634; NCT02454634; NCT02771301).	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('R132H', 'Mutation', 'rs121913500', (30, 35))	('gliomas', 'Disease', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('NCT02073994; NCT02273739; NCT02454634; NCT02454634; NCT02771301', 'Var', (121, 184))	('R132H', 'Var', (30, 35))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
68589	33477674	Recently, Agios Pharmaceuticals has conducted a multicentre clinical study on recurrent LGG with IDH mutation using an AG-120 and AG-881 (NCT03343197).	('AG-120', 'Chemical', 'MESH:C000627630', (119, 125))	('mutation', 'Var', (101, 109))	('AG-881', 'Chemical', '-', (130, 136))	('IDH', 'Gene', (97, 100))	('IDH', 'Gene', '3417', (97, 100))	('LGG', 'Disease', (88, 91))
68592	33477674	A study showed that despite the fact that AGI-5198 reduces neomorphic activity, it also does not alleviate the DNA and histone hypermethylation phenotype since histone methylation was found to be high.	('met', 'Gene', (168, 171))	('reduces', 'NegReg', (51, 58))	('neomorphic activity', 'CPA', (59, 78))	('met', 'Gene', '79811', (132, 135))	('met', 'Gene', (132, 135))	('AGI-5198', 'Var', (42, 50))	('met', 'Gene', '79811', (168, 171))	('DNA', 'MPA', (111, 114))	('AGI-5198', 'Chemical', 'MESH:C581156', (42, 50))
68594	33477674	This has also been confirmed by another study, showing that IDH1 mutated cells under the action of AGI-5198 gain radioprotective abilities.	('gain', 'PosReg', (108, 112))	('IDH', 'Gene', (60, 63))	('AGI-5198', 'Chemical', 'MESH:C581156', (99, 107))	('radioprotective abilities', 'CPA', (113, 138))	('IDH', 'Gene', '3417', (60, 63))	('mutated', 'Var', (65, 72))
68596	33477674	Further, there are currently three trials under investigation for IDH1 peptide vaccines (NCT02454634; NCT02454634; NCT02771301).	('NCT02454634', 'Var', (102, 113))	('IDH', 'Gene', (66, 69))	('IDH', 'Gene', '3417', (66, 69))	('NCT02454634', 'Var', (89, 100))
68597	33477674	Initially, a spontaneous immune response to the IDH mutation has been documented.	('IDH', 'Gene', '3417', (48, 51))	('IDH', 'Gene', (48, 51))	('mutation', 'Var', (52, 60))
68598	33477674	The researchers used a 15 amino acid-base construct to generate an IDH1 peptide, with the R132H mutation and injected to mice.	('R132H', 'Var', (90, 95))	('IDH', 'Gene', (67, 70))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('mice', 'Species', '10090', (121, 125))	('IDH', 'Gene', '3417', (67, 70))
68599	33477674	In animal models, it was reported that IDH1 mutated cells could be prevented from growing in the CNS and the vaccine preserved the normal physiological function of IDH1 wildtype gene.	('IDH', 'Gene', '3417', (164, 167))	('normal physiological function', 'MPA', (131, 160))	('mutated', 'Var', (44, 51))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', (164, 167))	('IDH', 'Gene', '3417', (39, 42))
68615	31023364	We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('IDH', 'Gene', (146, 149))	('tumors', 'Disease', (159, 165))	('patient', 'Species', '9606', (221, 228))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('IDH', 'Gene', '3417', (146, 149))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('Glioma', 'Disease', 'MESH:D005910', (84, 90))	('Glioma', 'Phenotype', 'HP:0009733', (84, 90))	('Glioma', 'Disease', (84, 90))	('mutated', 'Var', (151, 158))
68626	31023364	Recent work has proposed a classification of glioma based mainly on two genetic markers, namely absence or presence of isocitrate dehydrogenase 1 and 2 (IDH) mutation and of codeletion of chromosome arms 1p and 19q (codel), overriding histology.	('codeletion', 'Var', (174, 184))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('mutation', 'Var', (158, 166))	('IDH', 'Gene', (153, 156))	('glioma', 'Disease', (45, 51))	('IDH', 'Gene', '3417', (153, 156))
68628	31023364	Besides genetic factors (DNA-)methylation has emerged an important regulator of gene transcription, and its role in tumorigenesis has become a topic of considerable interest.	('tumor', 'Disease', (116, 121))	('methylation', 'Var', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))
68630	31023364	IDH mutations occur early in gliomagenesis in the vast majority of WHO grade II and III gliomas.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (29, 35))	('III gliomas', 'Disease', 'MESH:D005910', (84, 95))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('III gliomas', 'Disease', (84, 95))	('mutations', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
68634	31023364	Both, genetic and epigenetic events can drive progression of gliomas leading to nearly identical phylo (epi-)genetic relations.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('drive', 'Reg', (40, 45))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('epigenetic events', 'Var', (18, 35))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))
68637	31023364	In general, deregulation of cell functions in cancer is encoded in both the genome and epigenome which underscores the importance of epigenetic analyses in parallel to the discovery of transcriptomics and genetics.	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('deregulation', 'Var', (12, 24))
68654	31023364	The subtypes E2 - E6 and M2 - M5 nearly exclusively contain IDH mutated tumors predominantly without codeletions on Chr1p and Chr19q as genetic hallmarks of astrocytomas while the subtypes E6 and M5 strongly enrich samples with a codeletion on Chr1p and Chr19q as a genetic hallmark of oligodendrogliomas.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('M2 - M5', 'Var', (25, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (157, 169))	('E2 - E6', 'Var', (13, 20))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('tumors', 'Disease', (72, 78))	('astrocytomas', 'Disease', (157, 169))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (297, 304))	('IDH', 'Gene', (60, 63))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (286, 304))	('glioma', 'Phenotype', 'HP:0009733', (297, 303))	('IDH', 'Gene', '3417', (60, 63))	('oligodendrogliomas', 'Disease', (286, 304))
68662	31023364	We assign specimens with reduced tumor cell content to C4 based on the observations that the mean number of copy number aberrations on Chr7 and Chr10 in E1 and on Chr1p and Chr19q in E6 is reduced for samples in E7, respectively (Additional file 1: Figure S5).	('Chr7', 'Gene', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('reduced', 'NegReg', (189, 196))	('Chr19q', 'Var', (173, 179))	('Chr1p', 'Var', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('Chr10', 'Gene', (144, 149))
68692	31023364	Signatures related to epidermal cell differentiation and keratinization are prone to hypo-methylation also in other cancers.	('hypo-methylation', 'Var', (85, 101))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
68695	31023364	In contrast, hypermethylation in C3 (IDH-O), and to a less degree in C1 (IDH-wt) and C2 (IDH-A), is observed for targets of the polycomb repressive complex 2 (PRC2) in de-differentiated tumor cells, for related compounds such as SUZ12 and EED targets and for bivalently H3K4me3 and H3K27me3 marked genes in poised promoter states that are enriched in tumor suppressors.	('H3K4me3', 'Var', (270, 277))	('IDH', 'Gene', (73, 76))	('tumor', 'Disease', (186, 191))	('SUZ12', 'Gene', '23512', (229, 234))	('H3K27me3 marked', 'Var', (282, 297))	('IDH', 'Gene', '3417', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (351, 356))	('IDH', 'Gene', '3417', (73, 76))	('bivalently', 'Var', (259, 269))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('EED', 'Gene', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('IDH', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('IDH', 'Gene', (89, 92))	('SUZ12', 'Gene', (229, 234))	('EED', 'Gene', '8726', (239, 242))	('IDH', 'Gene', '3417', (37, 40))
68696	31023364	Their suppression via hypermethylation promotes cancer development in gliomas and in other cancer entities.	('suppression', 'NegReg', (6, 17))	('promotes', 'PosReg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('hypermethylation', 'Var', (22, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
68697	31023364	The respective expression and methylation profiles closely resemble those of healthy brain and synaptic transmission thus suggesting their suppression by epigenetics in gliomas.	('gliomas', 'Disease', (169, 176))	('epigenetics', 'Var', (154, 165))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('expression', 'MPA', (15, 25))	('suppression', 'NegReg', (139, 150))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('methylation', 'MPA', (30, 41))
68701	31023364	Hence, degeneration of healthy brain functions in all subtypes, activated proliferation in C3 (IDH-O) and partly inflammation in E3 seem to be affected by anti-correlated DNA-promoter-methylation changes.	('degeneration of healthy brain functions', 'Disease', (7, 46))	('proliferation', 'CPA', (74, 87))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('affected', 'Reg', (143, 151))	('inflammation', 'Disease', (113, 125))	('changes', 'Var', (196, 203))	('activated', 'PosReg', (64, 73))	('degeneration of healthy brain functions', 'Disease', 'MESH:D000067329', (7, 46))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))
68725	31023364	These expression profiles are mostly paralleled by G-CIMP and especially G-CIMP-O methylation profiles which suggest deactivation of immune cell activities in C3 by DNA methylation.	('deactivation', 'NegReg', (117, 129))	('G-CIMP', 'Chemical', '-', (73, 79))	('G-CIMP', 'Chemical', '-', (51, 57))	('methylation', 'Var', (169, 180))	('G-CIMP-O', 'Chemical', '-', (73, 81))
68739	31023364	We, therefore, studied a signature of genes that contribute to senescence bypass mechanisms by promoter-hypermethylation during aging and tumorigenesis and which associate with cancer risk.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', (138, 143))	('associate with', 'Reg', (162, 176))	('senescence', 'Disease', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('promoter-hypermethylation', 'Var', (95, 120))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
68741	31023364	Their senescence profile resembles those of the PRC2-targets, RTKII-characteristics, ageing and healthy brain signatures, while the methylation profiles of the two latter signatures differ from the former ones regarding methylation of Chr1p/19q-codeleted tumors in C3.	('Chr1p/19q-codeleted', 'Var', (235, 254))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('methylation', 'MPA', (220, 231))	('tumors', 'Disease', (255, 261))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('differ', 'Reg', (182, 188))
68743	31023364	It is assumed that Chr1p/19q-codeleted gliomas (C3) bypass senescence by other mechanisms than Chr1p/19q-non-codeleted tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('Chr1p/19q-codeleted', 'Var', (19, 38))	('tumors', 'Disease', (119, 125))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Disease', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
68744	31023364	Overall, the LGG-subtypes group along a therapy-resistance signature suggesting that resistance and recurrence are mediated by epigenetics and an inflammatory TME along the proneural mesenchymal-like axis also in LGG accompanied by graded loss of methylation and increased CNV and IDH-wt resemblance.	('methylation', 'MPA', (247, 258))	('LGG', 'Disease', (213, 216))	('IDH', 'Gene', '3417', (281, 284))	('epigenetics', 'Var', (127, 138))	('increased', 'PosReg', (263, 272))	('loss', 'NegReg', (239, 243))	('ME', 'Chemical', '-', (160, 162))	('IDH', 'Gene', (281, 284))
68749	31023364	These genetic aberrations are assumed to act as early events of tumorigenesis (see left part of Fig.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('genetic aberrations', 'Var', (6, 25))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
68751	31023364	For example, 25-40% of all IDH-mut and 1p/19q-codel tumors were not assigned to the oligodendroglioma-like subtype (C3) but rather resemble the astrocytoma-like (C2) or neuronal (C4) types by a series of features.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('IDH', 'Gene', (27, 30))	('resemble', 'Reg', (131, 139))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('IDH', 'Gene', '3417', (27, 30))	('1p/19q-codel', 'Var', (39, 51))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('oligodendroglioma', 'Disease', (84, 101))	('oligodendroglioma', 'Disease', 'MESH:D009837', (84, 101))	('astrocytoma', 'Disease', 'MESH:D001254', (144, 155))	('astrocytoma', 'Disease', (144, 155))
68755	31023364	A more simplistic interpretation of partly decoupled expression and methylation assumes rarely or non-overlapping sets of 'passenger' genes regulated by TFs and/or epigenetic 'drivers' such as the IDH-mutation.	('TFs', 'Gene', (153, 156))	('IDH', 'Gene', '3417', (197, 200))	('IDH', 'Gene', (197, 200))	('epigenetic', 'Var', (164, 174))
68762	31023364	Moreover, we found concerted methylation patterns of the olfactory subgenome collecting GPCR genes and of cancer-related keratin intermediate filament genes, respectively.	('methylation', 'Var', (29, 40))	('keratin intermediate filament genes', 'Gene', (121, 156))	('GPCR', 'Gene', '441931', (88, 92))	('GPCR', 'Gene', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
68768	31023364	Degeneration of apparent healthy brain functions in all subtypes, activated proliferation in C3 and partly inflammation in E3 seem to be driven by anti-correlated DNA-promoter methylation changes.	('inflammation', 'Disease', (107, 119))	('changes', 'Var', (188, 195))	('methylation changes', 'Var', (176, 195))	('proliferation', 'CPA', (76, 89))	('activated', 'PosReg', (66, 75))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))
68769	31023364	Interestingly, the astrocytoma-like subtypes in C2 sort in the order E4-E2-E3 and M4-M3-M2, respectively, which associates with increasing WHO grade of the tumors, their age at first diagnosis, their hazard ratio, the decrease of the global methylation levels and of neuronal expression characteristics and increased senescence bypass characteristics.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('tumors', 'Disease', (156, 162))	('decrease', 'NegReg', (218, 226))	('increased', 'PosReg', (307, 316))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('astrocytoma', 'Disease', 'MESH:D001254', (19, 30))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('global methylation levels', 'MPA', (234, 259))	('astrocytoma', 'Disease', (19, 30))	('senescence bypass', 'CPA', (317, 334))	('increasing', 'PosReg', (128, 138))	('neuronal expression characteristics', 'CPA', (267, 302))	('M4-M3-M2', 'Var', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('E4-E2-E3', 'Var', (69, 77))
68783	31023364	Epigenetic activation of otherwise suppressed cellular programs seems to be essential for glioma development and diversification into subtypes.	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('Epigenetic activation', 'Var', (0, 21))
68790	31023364	Hereby epigenetics, and particularly, DNA methylation is a shaping and driving factor of glioma heterogeneity and progression.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('epigenetics', 'Var', (7, 18))	('glioma', 'Disease', (89, 95))	('DNA methylation', 'Var', (38, 53))
68814	30333036	By binding to its receptor PD-1 expressed on the surface of activated T cells, PD-L1 leads to T cell dysfunction and apoptosis.	('leads to', 'Reg', (85, 93))	('binding', 'Interaction', (3, 10))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (94, 112))	('T cell dysfunction', 'Disease', (94, 112))	('PD-L1', 'Var', (79, 84))	('apoptosis', 'CPA', (117, 126))	('T cell dysfunction', 'Disease', 'MESH:C536780', (94, 112))
68820	30333036	measured PD-L1 expression in 94 patients and found that PD-L1 was a negative prognostic indicator for glioblastoma (GBM).	('patients', 'Species', '9606', (32, 40))	('glioblastoma', 'Disease', (102, 114))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('PD-L1', 'Gene', (9, 14))	('PD-L1', 'Var', (56, 61))
68849	30333036	Samples were permeabilized with 0.25% Triton X-100 for 15 min and blocked in blocking buffer containing 10% donkey serum for 2 h at room temperature or overnight at 4  C. Then, samples were incubated with indicated primary antibodies (Additional file 1: Table S2) overnight at 4  C. Samples were then washed with PBS and incubated with the appropriate fluorophore-conjugated secondary antibodies, namely Alexafloure-488, 594 (Thermo Fisher, USA) and Cy3 (JacksonImmunoResearch Laboratory, USA), at a dilution of 1:500 in 1% BSA for 1 h at room temperature.	('PBS', 'Disease', 'MESH:D011535', (313, 316))	('donkey', 'Species', '9793', (108, 114))	('Cy3', 'Var', (450, 453))	('PBS', 'Disease', (313, 316))
68868	30333036	Besides, many CD4+ or CD8+ apoptotic bodies can be recognized in the IT area (Figs.	('CD4+', 'Var', (14, 18))	('CD8', 'Gene', (22, 25))	('apoptotic bodies', 'CPA', (27, 43))	('CD8', 'Gene', '925', (22, 25))
68923	30333036	In the GL261 glioma model, we found that the expression of PD-1 was elevated in both CD4+ and CD8+ T cells.	('CD4+', 'Var', (85, 89))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('GL261', 'Chemical', '-', (7, 12))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('PD-1', 'Gene', (59, 63))	('elevated', 'PosReg', (68, 76))	('expression', 'MPA', (45, 55))	('CD8', 'Gene', (94, 97))	('CD8', 'Gene', '925', (94, 97))	('glioma', 'Disease', (13, 19))
68948	18506188	p14ARF, p16INK4A and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only.	('p14ARF', 'Gene', (0, 6))	('hTERT', 'Gene', '7015', (95, 100))	('p16INK4A', 'Gene', (8, 16))	('10q26 LOH', 'Var', (160, 169))	('PTEN', 'Gene', '5728', (21, 25))	('13q', 'Chemical', '-', (64, 67))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (207, 225))	('p16INK4A', 'Gene', '1029', (8, 16))	('tumours', 'Disease', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumours', 'Disease', (127, 134))	('glioblastomas', 'Phenotype', 'HP:0012174', (145, 158))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('EGFR', 'Gene', (136, 140))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('hTERT', 'Gene', (95, 100))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('oligodendrogliomas', 'Disease', (207, 225))	('tumours', 'Disease', 'MESH:D009369', (184, 191))	('tumours', 'Disease', 'MESH:D009369', (127, 134))	('glioblastomas', 'Disease', (145, 158))	('p14ARF', 'Gene', '1029', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('anaplastic', 'Disease', (196, 206))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('III tumours', 'Disease', (180, 191))	('III tumours', 'Disease', 'MESH:D009369', (180, 191))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('PTEN', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (136, 140))	('glioblastomas', 'Disease', 'MESH:D005909', (145, 158))
68967	18506188	In addition, cytogenetic parameters, including loss of heterozygosity (LOH), were also collected: 1p, 2p23, 9p, 10p, 10q23, 10q26, 11q, 13q, 17q, 19q, 22q.	('13q', 'Chemical', '-', (136, 139))	('11q', 'Var', (131, 134))	('10q26', 'Var', (124, 129))	('10q23', 'Var', (117, 122))	('10p', 'Var', (112, 115))	('2p23', 'Var', (102, 106))
68973	18506188	The following clinical and biological features were analysed as potential prognostic factors for survival: age, grade ('high' vs 'low'), treatment (surgery+radiotherapy+TMZ, vs surgery+radiotherapy+-other chemotherapy, vs others), loss of heterozygosities, relative expression of p14ARF, p16INK4A, PTEN, EGFR, PDGF, VEGF, MGMT and expression of hTERT.	('p14ARF', 'Gene', (280, 286))	('hTERT', 'Gene', '7015', (345, 350))	('p16INK4A', 'Gene', (288, 296))	('VEGF', 'Gene', (316, 320))	('TMZ', 'Chemical', 'MESH:D000077204', (169, 172))	('p14ARF', 'Gene', '1029', (280, 286))	('loss', 'Var', (231, 235))	('MGMT', 'Gene', (322, 326))	('hTERT', 'Gene', (345, 350))	('VEGF', 'Gene', '7422', (316, 320))	('EGFR', 'Gene', '1956', (304, 308))	('PTEN', 'Gene', (298, 302))	('PDGF', 'Gene', (310, 314))	('MGMT', 'Gene', '4255', (322, 326))	('PTEN', 'Gene', '5728', (298, 302))	('p16INK4A', 'Gene', '1029', (288, 296))	('EGFR', 'Gene', (304, 308))
68979	18506188	Among other factors, the relative expression of VEGF, the expression of hTERT were considered as potential prognostic factors, underexpression or low expression, respectively, showing a slight advantage, as well as EGFR with a very slight advantage when overexpression.	('hTERT', 'Gene', '7015', (72, 77))	('VEGF', 'Gene', (48, 52))	('underexpression', 'Var', (127, 142))	('hTERT', 'Gene', (72, 77))	('VEGF', 'Gene', '7422', (48, 52))	('EGFR', 'Gene', (215, 219))	('EGFR', 'Gene', '1956', (215, 219))	('low expression', 'Var', (146, 160))
68983	18506188	For the entire cohort, 10p15 (carrying KLF6), 10q23 (PTEN), 10q26 (DMBT1) and 13q (Rb1) LOH were correlated with OS.	('Rb1', 'Gene', (83, 86))	('PTEN', 'Gene', '5728', (53, 57))	('KLF6', 'Gene', '1316', (39, 43))	('p15', 'Gene', (25, 28))	('p15', 'Gene', '1030', (25, 28))	('DMBT1', 'Gene', (67, 72))	('Rb1', 'Gene', '5925', (83, 86))	('DMBT1', 'Gene', '1755', (67, 72))	('KLF6', 'Gene', (39, 43))	('PTEN', 'Gene', (53, 57))	('correlated with', 'Reg', (97, 112))	('10q23', 'Var', (46, 51))	('10q26', 'Var', (60, 65))	('13q', 'Chemical', '-', (78, 81))	('OS', 'Chemical', '-', (113, 115))
68984	18506188	10q26 was correlated with OS of high-grade tumours and also with grade III oligodendrogliomas OS.	('correlated', 'Reg', (10, 20))	('oligodendrogliomas OS', 'Disease', (75, 96))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('OS', 'Chemical', '-', (94, 96))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', (43, 50))	('OS', 'Chemical', '-', (26, 28))	('oligodendrogliomas OS', 'Disease', 'MESH:C567932', (75, 96))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('10q26', 'Var', (0, 5))
68992	18506188	Hypermethylation of p14ARF has been associated with progression of astrocytomas (Watanabe et al, 2007) and has been described as a factor of poor prognosis of grade II diffuse gliomas (Watanabe et al, 2003), although its prognostic value in oligodendroglioma is more controversial (Korshunov and Golanov, 2001; Kamiya and Nakazato, 2002).	('oligodendroglioma', 'Disease', (241, 258))	('gliomas', 'Disease', 'MESH:D005910', (176, 183))	('astrocytomas', 'Disease', 'MESH:D001254', (67, 79))	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('gliomas', 'Disease', (176, 183))	('p14ARF', 'Gene', (20, 26))	('Hypermethylation', 'Var', (0, 16))	('astrocytomas', 'Disease', (67, 79))	('oligodendroglioma', 'Disease', 'MESH:D009837', (241, 258))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('grade', 'Disease', (159, 164))	('p14ARF', 'Gene', '1029', (20, 26))	('associated', 'Reg', (36, 46))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))
68995	18506188	Loss or inactivation of PTEN has been described in solid tumours of various organs, and it is mutant in about 30% of GBM, but not in low-grade gliomas and very rarely in anaplastic gliomas (Duerr et al, 1998; Zhou et al, 1999).	('PTEN', 'Gene', '5728', (24, 28))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('solid tumours', 'Disease', (51, 64))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('GBM', 'Disease', (117, 120))	('mutant', 'Var', (94, 100))	('inactivation', 'NegReg', (8, 20))	('Loss', 'NegReg', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('gliomas', 'Disease', (143, 150))	('gliomas', 'Disease', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('solid tumours', 'Disease', 'MESH:D009369', (51, 64))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('PTEN', 'Gene', (24, 28))
69001	18506188	Methylation of the MGMT promoter, a frequent phenomenon, makes gliomas more sensitive to alkylating agents by reducing gene expression (Esteller et al, 2000).	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('gene expression', 'MPA', (119, 134))	('Methylation', 'Var', (0, 11))	('MGMT', 'Gene', '4255', (19, 23))	('reducing', 'NegReg', (110, 118))	('MGMT', 'Gene', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('sensitive', 'MPA', (76, 85))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
69005	18506188	Patients with low MGMT expression treated with alkylating agents presented a better OS than patients not treated by alkylating agents, but it must be remembered that this was not a clinical trial with randomised treatment.	('MGMT', 'Gene', (18, 22))	('MGMT', 'Gene', '4255', (18, 22))	('patients', 'Species', '9606', (92, 100))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (84, 86))	('low', 'Var', (14, 17))
69012	18506188	LOH10p is more frequent in high-grade than in low-grade tumours and is also more frequent in tumours with a large oligodendroglial component.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('LOH10p', 'Var', (0, 6))	('tumours', 'Disease', (93, 100))	('large oligodendroglial component', 'Phenotype', 'HP:0100709', (108, 140))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('frequent', 'Reg', (81, 89))	('oligodendroglial component', 'Disease', 'MESH:C562869', (114, 140))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('oligodendroglial component', 'Disease', (114, 140))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
69055	33550903	For instance, the 1p-19q deletion is a powerful predictor of chemotherapy response and survival and serves as a diagnostic marker for oligodendrogliomas which account for less than 5% of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (134, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('gliomas', 'Disease', (187, 194))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('oligodendrogliomas', 'Disease', (134, 152))	('1p-19q deletion', 'Var', (18, 33))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('gliomas', 'Disease', (145, 152))
69056	33550903	The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations were associated with prolonged overall survival and higher rate of response to temozolomide in LGG.	('response to temozolomide', 'MPA', (130, 154))	('IDH1', 'Gene', '3417', (38, 42))	('IDH2', 'Gene', (47, 51))	('higher', 'PosReg', (115, 121))	('overall survival', 'CPA', (94, 110))	('mutations', 'Var', (53, 62))	('temozolomide', 'Chemical', 'MESH:D000077204', (142, 154))	('IDH1', 'Gene', (38, 42))	('IDH2', 'Gene', '3418', (47, 51))	('prolonged', 'PosReg', (84, 93))
69078	33550903	Patient's age, tumor weight, histological type, histologic grade, IDH1 mutation and targeted therapy were significantly associated with OS in the TCGA cohort (P < 0.05 for all cases, student's t test or Fisher exact test, Table 1).	('associated', 'Reg', (120, 130))	('IDH1', 'Gene', '3417', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('mutation', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('IDH1', 'Gene', (66, 70))	('Patient', 'Species', '9606', (0, 7))
69079	33550903	Moreover, histologic grade, IDH1 mutation and 1p-19q codeletion exhibited significant associations with OS in the CGGA cohort (P < 0.05, Fisher exact test, supplementary Table 1).	('1p-19q codeletion', 'Var', (46, 63))	('mutation', 'Var', (33, 41))	('IDH1', 'Gene', '3417', (28, 32))	('associations', 'Interaction', (86, 98))	('IDH1', 'Gene', (28, 32))
69081	33550903	With respect to the associations of clinicopathologic factors with RFS, LGG patients with IDH1 mutation showed better RFS than those without IDH1 mutation (P < 0.05, Fisher exact test, Table 1).	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', (141, 145))	('RFS', 'Disease', 'MESH:D005198', (67, 70))	('patients', 'Species', '9606', (76, 84))	('IDH1', 'Gene', '3417', (90, 94))	('IDH1', 'Gene', '3417', (141, 145))	('RFS', 'Disease', 'MESH:D005198', (118, 121))	('better', 'PosReg', (111, 117))	('RFS', 'Disease', (67, 70))	('RFS', 'Disease', (118, 121))	('mutation', 'Var', (95, 103))
69086	33550903	Then multivariate Cox regression analysis was performed between OS and the mortality-associated features, including patients' age, tumor weight, histological type, histologic grade and IDH1 mutation and 7675 gene expression levels.	('mutation', 'Var', (190, 198))	('IDH1', 'Gene', '3417', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mortality', 'Disease', 'MESH:D003643', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (116, 124))	('7675 gene expression levels', 'MPA', (203, 230))	('tumor', 'Disease', (131, 136))	('mortality', 'Disease', (75, 84))	('IDH1', 'Gene', (185, 189))
69090	33550903	Then multivariate Cox regression analysis was performed between OS and the mortality-associated features, including histologic grade, IDH1 mutation and 1p19q codeletion and 2099 gene expression levels.	('mortality', 'Disease', 'MESH:D003643', (75, 84))	('mutation', 'Var', (139, 147))	('mortality', 'Disease', (75, 84))	('IDH1', 'Gene', (134, 138))	('2099 gene expression levels', 'MPA', (173, 200))	('IDH1', 'Gene', '3417', (134, 138))	('1p19q codeletion', 'Var', (152, 168))
69102	33550903	Kaplan-Meier RFS analysis showed that high risk score was associated with an inferior RFS (P < 0.05, log rank test, Figure 3B).	('RFS', 'Disease', (13, 16))	('inferior', 'NegReg', (77, 85))	('RFS', 'Disease', 'MESH:D005198', (13, 16))	('RFS', 'Disease', (86, 89))	('RFS', 'Disease', 'MESH:D005198', (86, 89))	('high risk score', 'Var', (38, 53))
69107	33550903	In the TCGA cohort, risk score was significantly positively correlated with histologic grade, TP53 mutation, radiation therapy, targeted molecular therapy and negatively correlated with IDH1 mutation and histological type (p < 0.05 for all cases, supplementary Figure 2A).	('IDH1', 'Gene', (186, 190))	('IDH1', 'Gene', '3417', (186, 190))	('negatively', 'NegReg', (159, 169))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))	('positively', 'PosReg', (49, 59))	('correlated', 'Interaction', (60, 70))
69108	33550903	Furthermore, the risk score exhibited significantly negative correlation with IDH1 mutation and 1p19q codeletion (p < 0.05 for all cases, supplementary Figure 2B).	('IDH1', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('1p19q codeletion', 'Var', (96, 112))	('IDH1', 'Gene', '3417', (78, 82))	('negative', 'NegReg', (52, 60))
69114	33550903	Then multivariate analysis was carried out between OS and the mortality-associated features, including histologic grade, IDH1 mutation and 1p19q codeletion and 10 gene expression levels.	('1p19q codeletion', 'Var', (139, 155))	('IDH1', 'Gene', (121, 125))	('IDH1', 'Gene', '3417', (121, 125))	('mortality', 'Disease', 'MESH:D003643', (62, 71))	('mutation', 'Var', (126, 134))	('mortality', 'Disease', (62, 71))
69124	33550903	The IDH1 and IDH2 mutations are associated with prolonged overall survival and higher rate of response to temozolomide in low-grade gliomas.	('overall', 'MPA', (58, 65))	('IDH1', 'Gene', '3417', (4, 8))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('temozolomide', 'Chemical', 'MESH:D000077204', (106, 118))	('IDH2', 'Gene', (13, 17))	('prolonged', 'PosReg', (48, 57))	('response to temozolomide', 'MPA', (94, 118))	('IDH1', 'Gene', (4, 8))	('IDH2', 'Gene', '3418', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('higher', 'PosReg', (79, 85))	('mutations', 'Var', (18, 27))
69125	33550903	In recent years, gene-signatures based on aberrant mRNA have drawn much attention and displayed great potential in prognostic prediction of LGG patients.	('patients', 'Species', '9606', (144, 152))	('aberrant mRNA', 'Var', (42, 55))	('LGG', 'Disease', (140, 143))
69135	33550903	Inhibiting Sp1 expression suppresses the proliferation, metastasis and induces apoptosis in colon cancer, glioma.	('metastasis', 'CPA', (56, 66))	('Sp1', 'Gene', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Inhibiting', 'Var', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('suppresses', 'NegReg', (26, 36))	('colon cancer', 'Disease', (92, 104))	('apoptosis', 'CPA', (79, 88))	('glioma', 'Disease', (106, 112))	('induces', 'Reg', (71, 78))	('proliferation', 'CPA', (41, 54))
69137	33550903	E2F suppression and Sp1 overexpression induce the differentiation-specific marker, transglutaminase type 1, in a squamous cell carcinoma cell line KJD-1/SV40.	('Sp1', 'Gene', (20, 23))	('suppression', 'NegReg', (4, 15))	('E2F', 'Var', (0, 3))	('transglutaminase type 1', 'MPA', (83, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('overexpression induce', 'PosReg', (24, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinoma', 'Disease', (113, 136))
69143	33550903	Inhibition of ZNF217 profoundly suppressed cell migration and invasion in ovarian clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('ovarian clear cell carcinoma', 'Disease', (74, 102))	('ZNF217', 'Gene', (14, 20))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (74, 102))	('ZNF217', 'Gene', '7764', (14, 20))	('Inhibition', 'Var', (0, 10))	('invasion', 'CPA', (62, 70))	('cell migration', 'CPA', (43, 57))	('suppressed', 'NegReg', (32, 42))
69151	33550903	Silence of EYA3 increased H2A.XY142 ph and inhibited cell viability, migration and percent cells in S stage in gastric cancer and decreased survival of Ewing sarcoma cells.	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('inhibited', 'NegReg', (43, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('survival', 'CPA', (140, 148))	('EYA3', 'Gene', (11, 15))	('increased', 'PosReg', (16, 25))	('migration', 'CPA', (69, 78))	('Ewing sarcoma', 'Disease', (152, 165))	('cell viability', 'CPA', (53, 67))	('gastric cancer', 'Disease', (111, 125))	('decreased', 'NegReg', (130, 139))	('Silence', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
69156	33550903	For instance, silencing the expression of Sp1 resulted in marked decrease in cell proliferation, metastasis in various cancer types.	('silencing', 'Var', (14, 23))	('Sp1', 'Gene', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('decrease', 'NegReg', (65, 73))	('cell proliferation', 'CPA', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
69182	31245913	Changes in tissue caused by glioma are expected to change the scattering properties of the affected brain tissue and therefore measureable by means of quantitative OCT. Low-grade glioma is expected to show an increase interstitial water content and potentially a minor increase in cell density compared to normal brain tissue 24, 25.	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('increase', 'PosReg', (269, 277))	('interstitial water content', 'MPA', (218, 244))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('Low-grade', 'Var', (169, 178))	('water', 'Chemical', 'MESH:D014867', (231, 236))	('glioma', 'Disease', (28, 34))	('glioma', 'Disease', (179, 185))	('increase', 'PosReg', (209, 217))	('cell density', 'CPA', (281, 293))
69368	31016891	Glioblastomas (GBMs) are the most common and devastating subtypes of primary central nervous system tumors.1 Unfortunately, despite the multimodal treatment of surgical resection, radiotherapy, and chemotherapy, the reported median survivals of GBM patients were only 16-19 months.1, 2, 3  Cancer-specific DNA methylation changes play important roles in cancer development and progression.	('cancer', 'Disease', (354, 360))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (249, 257))	('Cancer', 'Phenotype', 'HP:0002664', (290, 296))	('GBMs', 'Phenotype', 'HP:0012174', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('primary central nervous system tumors', 'Disease', (69, 106))	('Glioblastomas', 'Disease', (0, 13))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('methylation changes', 'Var', (310, 329))	('primary central nervous system tumors', 'Disease', 'MESH:D016543', (69, 106))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (354, 360))
69402	31016891	Among the panel, two CpGs (eg, cg05744073 and cg08244382) were hypermethylated and one CpG (eg, cg13767001) was hypomethylated in GBMs, while the other two were not differentially methylated in GBMs (Table 2).	('cg05744073', 'Chemical', '-', (31, 41))	('cg08244382', 'Chemical', '-', (46, 56))	('GBMs', 'Phenotype', 'HP:0012174', (194, 198))	('cg13767001', 'Chemical', '-', (96, 106))	('cg08244382', 'Var', (46, 56))	('GBMs', 'Phenotype', 'HP:0012174', (130, 134))	('CpGs', 'Chemical', 'MESH:C015772', (21, 25))	('cg13767001', 'Var', (96, 106))	('cg05744073', 'Var', (31, 41))
69403	31016891	Upon the correlation with prognosis, three CpGs (eg, cg05744073, cg08244382, and cg20382675) showed negative correlation with OS, while two CpGs (eg, cg24082174 and cg13767001) with positive correlation (Table 2).	('cg13767001', 'Var', (165, 175))	('cg13767001', 'Chemical', '-', (165, 175))	('negative', 'NegReg', (100, 108))	('cg05744073', 'Var', (53, 63))	('cg08244382', 'Var', (65, 75))	('CpGs', 'Chemical', 'MESH:C015772', (43, 47))	('cg05744073', 'Chemical', '-', (53, 63))	('cg20382675', 'Chemical', '-', (81, 91))	('cg24082174', 'Chemical', '-', (150, 160))	('cg20382675', 'Var', (81, 91))	('OS', 'Chemical', '-', (126, 128))	('cg24082174', 'Var', (150, 160))	('CpGs', 'Chemical', 'MESH:C015772', (140, 144))	('cg08244382', 'Chemical', '-', (65, 75))
69404	31016891	Accordingly, the risk score model was constructed as follows: risk score = (-0.534 x M-value of cg05744073) + (-0.446 x M-value of cg08244382) + (-0.263 x M-value of cg20382675) + (0.254 x M-value of cg24082174) + (0.368 x M-value of cg13767001).	('cg08244382', 'Chemical', '-', (131, 141))	('cg05744073', 'Chemical', '-', (96, 106))	('cg20382675', 'Chemical', '-', (166, 176))	('cg24082174', 'Chemical', '-', (200, 210))	('cg13767001', 'Chemical', '-', (234, 244))	('cg20382675) + (0.254 x M-value', 'Var', (166, 196))	('cg08244382) + (-0.263', 'Var', (131, 152))	('cg05744073) + (-0.446', 'Var', (96, 117))	('-0.534', 'Var', (76, 82))	('cg24082174) + (0.368', 'Var', (200, 220))	('cg13767001', 'Var', (234, 244))
69422	31016891	We found that it could consistently predict OS within the subtypes of unmethylated or methylated MGMT tumors (Figure 4A), and the subgroups of <=60 or>60 years (Figure 4B).	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('MGMT tumors', 'Disease', 'MESH:D009369', (97, 108))	('unmethylated', 'Var', (70, 82))	('methylated', 'Var', (86, 96))	('predict', 'Reg', (36, 43))	('OS', 'Chemical', '-', (44, 46))	('MGMT tumors', 'Disease', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
69428	31016891	Pyrosequencing of cg20382675 showed that the miR-1284-associated CpG was consistently associated with high DNA methylation status in glioma cells, that is, U87MG, U251, T98MG, and SHG44 (Figure 7A).	('SHG44', 'Var', (180, 185))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('U251', 'Var', (163, 167))	('high DNA methylation status', 'MPA', (102, 129))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('miR-1284', 'Gene', (45, 53))	('U87MG', 'CellLine', 'CVCL:0022', (156, 161))	('CpG', 'Disease', (65, 68))	('associated', 'Reg', (86, 96))	('U87MG', 'Var', (156, 161))	('glioma', 'Disease', (133, 139))	('miR-1284', 'Gene', '100302112', (45, 53))	('T98MG', 'CellLine', 'CVCL:B368', (169, 174))	('T98MG', 'Var', (169, 174))	('cg20382675', 'Chemical', '-', (18, 28))
69430	31016891	However, after treated with 5-Aza-dC, we found that the expressions of miR-1284 were significantly decreased in U251 and U87MG, indicating a positive impact of DNA methylation on miRNA expression (Figure 7C).	('miR', 'Gene', (71, 74))	('U87MG', 'Var', (121, 126))	('decreased', 'NegReg', (99, 108))	('miR-1284', 'Gene', '100302112', (71, 79))	('U251', 'Var', (112, 116))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (179, 182))	('U87MG', 'CellLine', 'CVCL:0022', (121, 126))	('expressions', 'MPA', (56, 67))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (28, 36))	('positive', 'PosReg', (141, 149))	('miR-1284', 'Gene', (71, 79))	('miR', 'Gene', '220972', (71, 74))
69441	31016891	In this study, the miRNA methylation-based risk subgroups were associated with differential enrichments of pro-angiogenic gene sets (eg, hypoxia or VEGF pathways), suggesting the possibility of differential responses to bevacizumab within the risk subgroups.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('VEGF', 'Gene', (148, 152))	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('methylation-based', 'Var', (25, 42))	('hypoxia', 'Disease', (137, 144))	('VEGF', 'Gene', '7422', (148, 152))	('pro-angiogenic', 'Pathway', (107, 121))	('bevacizumab', 'Chemical', 'MESH:D000068258', (220, 231))
69458	31016891	In general, hypermethylation of promoter inhibits transcription processes and decreases miRNA expression.	('miR', 'Gene', (88, 91))	('inhibits', 'NegReg', (41, 49))	('hypermethylation', 'Var', (12, 28))	('decreases', 'NegReg', (78, 87))	('transcription', 'MPA', (50, 63))	('miR', 'Gene', '220972', (88, 91))
69462	31016891	In conclusion, by analyzing genome-wide DNA methylation microarray data of miRNAs-associated CpGs, we presented the initial report on the prognostic relevance of aberrant DNA methylation in miRNA regions in GBMs.	('CpGs', 'Chemical', 'MESH:C015772', (93, 97))	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('GBMs', 'Phenotype', 'HP:0012174', (207, 211))	('aberrant', 'Var', (162, 170))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))
69465	30053901	Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('protein/phosphoprotein', 'MPA', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (142, 157))
69469	30053901	Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively.	('alterations', 'Var', (76, 87))	('tumors', 'Disease', (98, 104))	('ESR1', 'Gene', '2099', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', (191, 195))	('AKT', 'Gene', '207', (229, 232))	('mTOR', 'Gene', '2475', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESR1', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('BRAF', 'Gene', (224, 228))	('AKT', 'Gene', (229, 232))	('BRAF', 'Gene', '673', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
69470	30053901	We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool.	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
69472	30053901	Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.	('oncology', 'Phenotype', 'HP:0002664', (167, 175))	('alterations', 'Var', (82, 93))	('patients', 'Species', '9606', (179, 187))	('multi-omics', 'Var', (70, 81))
69479	30053901	The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other large-scale sequencing data sets represent an opportunity to identify "druggable" variants, i.e., variants that render a cancer type susceptible to a drug.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('render', 'Reg', (212, 218))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('variants', 'Var', (182, 190))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('variants', 'Var', (198, 206))	('Cancer Genome Atlas', 'Disease', (4, 23))
69482	30053901	We identified tumors with drug-associated mutations and found considerable opportunity for repurposing of drugs across cancer types.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (119, 125))	('drug-associated', 'Reg', (26, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
69483	30053901	We used a structure-based computational tool to identify putative druggable mutations based on proximity to known druggable mutations and experimentally validated a subset of putative druggable mutations in BRAF.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutations', 'Var', (76, 85))	('mutations', 'Var', (194, 203))
69491	30053901	Tumor type is included for each variant/drug entry because, with infrequent exception, a variant's effect on a tumor's response to a given drug has only been rigorously studied in one or only a few cancer type(s).	('response to a given drug', 'MPA', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
69492	30053901	For a variant/drug entry based on preclinical data, tumor type was either inferred from the xenograft or cell line, or left unspecified.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variant/drug', 'Var', (6, 18))	('tumor', 'Disease', (52, 57))	('unspecified', 'Species', '32644', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
69493	30053901	Copy number amplifications (CNA) and losses (CNL), high expression outliers in oncogenes, low expression outliers in tumor suppressors, and fusions that may lead to druggability are also included.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('druggability', 'MPA', (165, 177))	('tumor', 'Disease', (117, 122))	('losses', 'NegReg', (37, 43))	('lead to', 'Reg', (157, 164))	('Copy number amplifications', 'Var', (0, 26))	('oncogenes', 'Gene', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
69494	30053901	Effect describes whether a variant correlates with increased sensitivity of a tumor to a drug or increased resistance of a tumor to a drug.	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('sensitivity', 'MPA', (61, 72))	('tumor', 'Disease', (78, 83))	('variant', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('resistance', 'MPA', (107, 117))
69495	30053901	A given drug entry in DEPO could be associated with multiple drug families to allow for the possibility of combining therapies (e.g., dabrafenib [B-Raf inhibitor] and trametinib [MEK inhibitor] for BRAF V600E/K-mutant melanoma) and multi-targeted tyrosine kinase inhibitors (e.g., afatinib as a dual HER2 and EGFR inhibitor).	('EGFR', 'Gene', '1956', (309, 313))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('MEK', 'Gene', '5609', (179, 182))	('dabrafenib', 'Chemical', 'MESH:C561627', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('B-Raf', 'Gene', '673', (146, 151))	('V600E', 'Var', (203, 208))	('HER2', 'Gene', '2064', (300, 304))	('MEK', 'Gene', (179, 182))	('EGFR', 'Gene', (309, 313))	('tyrosine kinase', 'Gene', (247, 262))	('tyrosine kinase', 'Gene', '7294', (247, 262))	('afatinib', 'Chemical', 'MESH:D000077716', (281, 289))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('B-Raf', 'Gene', (146, 151))	('HER2', 'Gene', (300, 304))
69499	30053901	Variant calls were obtained from the TCGA Genome Data Analysis Centers (GDAC), Data Coordinating Center (DCC), and previously published TCGA marker papers until the end of 2014 (https://cancergenome.nih.gov/publications).	('GDAC', 'Chemical', '-', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCC', 'Chemical', '-', (105, 108))	('cancer', 'Disease', (186, 192))	('Variant', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
69500	30053901	Variant calls were excluded if metastases or recurrent samples were present for samples that already had a primary tumor in the mutation annotation file (MAF).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('metastases', 'Disease', (31, 41))	('Variant', 'Var', (0, 7))
69503	30053901	We identified tumors in our pan-cancer cohort that harbored one or more drug-associated SNP or indel.	('indel', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SNP', 'Var', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
69504	30053901	Iterating through a mutation annotation format (MAF) file containing all variants in our pan-cancer cohort, we performed two actions for each entry in the MAF.	('cancer', 'Disease', (93, 99))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
69505	30053901	First, we queried a hash table containing all druggable, unambiguous mutations in DEPO (e.g., BRAF V600E) and a separate hash table containing all druggable, ambiguous, single-residue mutations in DEPO (e.g., BRAF V600).	('single-residue', 'Var', (169, 183))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('DEPO', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (94, 98))	('DEPO', 'Gene', (82, 86))
69506	30053901	Second, we queried several classes of mutations that occur in a specific exon or segment of a gene (EGFR exon 19 in-frame deletion).	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))
69508	30053901	In some cases, DEPO contains multiple entries per gene/mutation pair to reflect possible druggability of a gene/mutation pair in more than one tumor type, or that it may confer an effect (e.g., sensitivity or resistance) that depends on tumor type or other therapeutic context.	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (143, 148))	('druggability', 'MPA', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gene/mutation', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sensitivity', 'MPA', (194, 205))
69509	30053901	For example, when visualizing "drug repurposing" across tumor types, a given mutation could be associated with > 1 "cancer-type-specific" tumor type, if a given gene/mutation pair had druggability information in DEPO in multiple tumor types at the same level of evidence.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
69513	30053901	When considering potential druggable events in the cancer-type-non-specific setting, the drug with the highest level of evidence found across all tumor types was used for a specific variant (Additional file 2: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (182, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
69515	30053901	If any sensitive interaction for a variant was found regardless of the tumor type and level, it was considered a "druggable" event for these analyses.	('variant', 'Var', (35, 42))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
69516	30053901	HotSpot3D was used to spatially cluster "known" drug-associated mutations in DEPO with putative druggable mutations in our pan-cancer cohort.	('DEPO', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (127, 133))
69530	30053901	The distribution of LN(IC50) values of cell lines with DEPO mutations (both sensitive and resistant) for both the cancer-type-specific and non-specific settings were compared to a background distribution using the Mann-Whitney U test.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DEPO', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (114, 120))
69537	30053901	Constructions expressing BRAF variants were generated from a plasmid expressing a wild-type BRAF (Addgene, #40775) with an N-terminal Flag tag using Q5 site-directed mutagenesis (New England BioLabs).	('variants', 'Var', (30, 38))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
69538	30053901	Cells were transiently transfected with wild-type or mutant BRAF constructs using Lipofectamine 2000 reagent (Life Technologies) in six-well plates.	('BRAF', 'Gene', (60, 64))	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
69545	30053901	For each tumor, we mapped its "druggable" variants against one or more drugs, which were then mapped to one or more drug classes (Additional file 2: Table S8).	('tumor', 'Disease', (9, 14))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
69546	30053901	For each variant, we used the drug that had the highest level of evidence in DEPO regardless of cancer type (Additional file 2: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('variant', 'Var', (9, 16))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
69547	30053901	For the purposes of visualization, we only considered ten FDA-approved drug classes (Additional file 2: Table S9) mapping to the largest number of variants across our pan-cancer cohort (Additional file 2: Table S10).	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
69553	30053901	Further, a substantial number (~ 25%) of sensitive variant/drug interactions are approved by the FDA for a particular cancer type or are based on late-stage clinical studies.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('particular cancer type', 'Disease', (107, 129))	('particular cancer type', 'Disease', 'MESH:D009369', (107, 129))	('variant/drug', 'Var', (51, 63))
69554	30053901	Several genes account for a large proportion of variant/drug interactions (e.g., EGFR, KIT, ERBB2, BRCA1, PDGFRA), reflecting interest in therapeutically exploiting a relatively limited number of cancer driver genes (Fig.	('ERBB2', 'Gene', '2064', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (106, 112))	('ERBB2', 'Gene', (92, 97))	('BRCA1', 'Gene', (99, 104))	('variant/drug', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('BRCA', 'Phenotype', 'HP:0003002', (99, 103))	('BRCA1', 'Gene', '672', (99, 104))	('EGFR', 'Gene', '1956', (81, 85))	('PDGFRA', 'Gene', (106, 112))	('EGFR', 'Gene', (81, 85))
69556	30053901	Our analysis reveals 2364 mutations across 2114 tumors that are associated with sensitivity to one or more drugs (mean = 1.12/tumor) (Additional file 2: Table S2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('sensitivity', 'MPA', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
69557	30053901	The low fraction of drug-associated mutations likely reflects the large number of passengers in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (36, 45))
69558	30053901	Thirty-two percent of tumors had at least one drug-associated mutation, a percentage that is consistent with the 28% of screened patients that could be matched with a targeted therapy or trial.	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
69560	30053901	2), that is, tumors with mutations associated with a known drug response in the cancer type with the highest level of evidence.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (80, 86))
69561	30053901	Only 3.3% of the samples contain a druggable mutation known to be FDA approved; however, if we consider less mature evidence: clinical trials, preclinical, and case reports, we could potentially increase the percentage of tumors with drug-associated mutations to 8.2, 8.5, and 10.5%, respectively.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('drug-associated', 'Reg', (234, 249))	('mutations', 'Var', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('increase', 'PosReg', (195, 203))
69562	30053901	Here, skin cutaneous melanoma (SKCM) is the cancer type with the largest fraction of drug-associated mutations (78%).	('mutations', 'Var', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('skin cutaneous melanoma', 'Disease', (6, 29))	('CM', 'Disease', 'MESH:D009202', (33, 35))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
69563	30053901	SKCM with a BRAF V600E/K mutation (40% of patients) can be treated with BRAF and MEK inhibitors based on FDA approval.	('BRAF', 'Gene', (72, 76))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', (12, 16))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('BRAF', 'Gene', '673', (12, 16))	('CM', 'Disease', 'MESH:D009202', (2, 4))	('patients', 'Species', '9606', (42, 50))	('MEK', 'Gene', (81, 84))	('BRAF', 'Gene', '673', (72, 76))	('MEK', 'Gene', '5609', (81, 84))
69564	30053901	The NRAS Q61 mutations found in 12% of SKCM patients are more challenging to treat, as is any RAS-mutant cancer due to activation of multiple signaling pathways.	('patients', 'Species', '9606', (44, 52))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CM', 'Disease', 'MESH:D009202', (41, 43))	('activation', 'PosReg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (4, 8))
69566	30053901	In colon and rectal carcinoma (COADREAD), glioblastoma multiforme (GBM), and lung adenocarcinoma (LUAD), 21, 14, and 40% of their respective tumors contain a drug-associated mutation in a cancer-type-specific setting.	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (3, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (13, 29))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('glioblastoma multiforme', 'Disease', (42, 65))	('cancer', 'Disease', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung adenocarcinoma', 'Disease', (77, 96))	('contain', 'Reg', (148, 155))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('drug-associated', 'Reg', (158, 173))
69567	30053901	In COADREAD, drug-associated variants PIK3CA E542K, E545K, and H1047R are present in 2.1, 5.2, and 1.8% of tumors, respectively, and are associated with sensitivity to PI3K/AKT/mTOR pathway inhibitors in early-stage trials and aspirin in observational studies.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('AKT', 'Gene', (173, 176))	('sensitivity', 'MPA', (153, 164))	('associated with', 'Reg', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mTOR', 'Gene', (177, 181))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('PIK3CA', 'Gene', '5290', (38, 44))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('aspirin', 'Chemical', 'MESH:D001241', (227, 234))	('E542K', 'Var', (45, 50))	('AKT', 'Gene', '207', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (177, 181))	('E545K', 'Var', (52, 57))	('PIK3CA', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('H1047R', 'Var', (63, 69))
69569	30053901	In GBM, the EGFR extracellular mutations (A289V, G598V, and R108K) and IDH1 mutation R132H are present in 10 and 4.5% of tumors, respectively, and are associated with drug response based on preclinical data.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('A289V', 'Mutation', 'rs149840192', (42, 47))	('associated', 'Reg', (151, 161))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('IDH1', 'Gene', (71, 75))	('G598V', 'Var', (49, 54))	('R108K', 'Mutation', 'rs1057519828', (60, 65))	('EGFR', 'Gene', '1956', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('IDH1', 'Gene', '3417', (71, 75))	('G598V', 'Mutation', 'rs139236063', (49, 54))	('R132H', 'Var', (85, 90))	('EGFR', 'Gene', (12, 16))	('A289V', 'Var', (42, 47))	('R108K', 'Var', (60, 65))
69570	30053901	In non-small cell lung cancer, EGFR inhibitors (e.g., erlotinib) are FDA approved for tumors with activating EGFR mutations, which are present at 10 and 1% in our LUAD and lung squamous cell carcinoma (LUSC) cohorts, respectively.	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (3, 29))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (31, 35))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('activating', 'PosReg', (98, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('EGFR', 'Gene', (31, 35))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))
69571	30053901	Despite the promise of targeted therapy, only 10.5% of this pan-cancer cohort contains potential drug-associated mutations in a cancer-type-specific setting.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('drug-associated', 'Reg', (97, 112))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (128, 134))
69572	30053901	With drug repurposing across cancer types, in which a drug used primarily in cancer type A with mutation X is repurposed for cancer type B with mutation X, we find that an additional 5.4% of patients may be treated with a FDA-approved drug-variant interaction (Figs.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
69574	30053901	In this cancer-type-non-specific setting, cancer types in which at least 40% of tumors have drug-associated mutations include low-grade glioma (LGG, 76%), thyroid carcinoma (THCA, 70%), and colorectal adenocarcinoma (COADREAD, 42%).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('THCA', 'Phenotype', 'HP:0002890', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('colorectal adenocarcinoma', 'Disease', (190, 215))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('cancer', 'Disease', (8, 14))	('thyroid carcinoma', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (190, 215))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (42, 48))
69575	30053901	A small number of drug-associated mutations occur at high frequency in these cancer types.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
69578	30053901	However, BRAF V600E also occurs at a lower frequency in HNSC, KIRP, LGG, and GBM, indicating significant repurposing potential for BRAF inhibitors (Fig.	('HNSC', 'Phenotype', 'HP:0012288', (56, 60))	('BRAF', 'Gene', (131, 135))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', '673', (9, 13))
69579	30053901	However, COADREAD has been difficult to treat due to a large presence of KRAS and BRAF mutations; EGFR inhibition as monotherapy is used for COADREAD, but only in tumors with wild-type KRAS.	('EGFR', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (185, 189))	('KRAS', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (82, 86))	('KRAS', 'Gene', '3845', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (185, 189))
69583	30053901	COADREAD or other cancer types having RAS mutations, such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (AML), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC), could benefit from further exploration of combinatorial therapies targeting downstream targets of KRAS (Fig.	('corpus endometrial carcinoma', 'Disease', (207, 235))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('acute myeloid leukemia', 'Disease', (134, 156))	('cancer', 'Disease', (18, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (61, 125))	('RAS', 'Gene', (38, 41))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('stomach adenocarcinoma', 'Disease', (164, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('KRAS', 'Gene', '3845', (342, 346))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('mutations', 'Var', (42, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (214, 235))
69586	30053901	Together, cancer-type-specific and non-specific mutational analyses identified potential therapeutic targets in 2114 tumors (32%), some of which will be considered druggable only with further clinical development and FDA approval.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (10, 16))
69587	30053901	We applied a structure-based clustering tool, HotSpot3D, to the pan-cancer dataset to reveal putative functional mutations (Additional file 2: Table S13).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
69588	30053901	HotSpot3D's utility in predicting functional mutations is supported by experimental evidence using cell lines expressing one of several EGFR-mutant proteins.	('EGFR', 'Gene', '1956', (136, 140))	('mutations', 'Var', (45, 54))	('proteins', 'Protein', (148, 156))	('EGFR', 'Gene', (136, 140))
69589	30053901	Among all genes in our analysis, EGFR contains the highest number of putative sensitive mutations, with 36 mutations that clustered with 19 mutations in DEPO from seven different clusters (Fig.	('DEPO', 'Gene', (153, 157))	('mutations', 'Var', (107, 116))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
69591	30053901	This procedure yielded four different clusters with a "resistant" mutation in AKT1, MAP2K1, and RAC1; these four clusters contained 14 putative resistant mutations clustering with four known resistant mutations (Additional file 2: Table S13).	('AKT1', 'Gene', (78, 82))	('contained', 'Reg', (122, 131))	('MAP2K1', 'Gene', (84, 90))	('RAC1', 'Gene', '5879', (96, 100))	('AKT1', 'Gene', '207', (78, 82))	('mutation', 'Var', (66, 74))	('RAC1', 'Gene', (96, 100))	('MAP2K1', 'Gene', '5604', (84, 90))
69592	30053901	RAC1 yielded the largest cluster, with RAC1 P29S mediating resistance to BRAF inhibitors in BRAF-mutant SKCM.	('BRAF', 'Gene', '673', (73, 77))	('P29S', 'Mutation', 'rs1057519874', (44, 48))	('resistance to', 'MPA', (59, 72))	('BRAF', 'Gene', '673', (92, 96))	('CM', 'Disease', 'MESH:D009202', (106, 108))	('RAC1', 'Gene', '5879', (39, 43))	('BRAF', 'Gene', (92, 96))	('RAC1', 'Gene', (39, 43))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (44, 48))	('BRAF', 'Gene', (73, 77))	('RAC1', 'Gene', (0, 4))	('mediating', 'Reg', (49, 58))
69593	30053901	Other mutations in this cluster that may affect binding affinity of BRAF inhibitors (or that may mediate resistance to BRAF inhibitors) are C18Y, E31D, A159V, P29L/T, and P34S.	('P29L', 'SUBSTITUTION', 'None', (159, 163))	('C18Y', 'SUBSTITUTION', 'None', (140, 144))	('BRAF', 'Gene', '673', (68, 72))	('E31D', 'Var', (146, 150))	('A159V', 'Mutation', 'p.A159V', (152, 157))	('BRAF', 'Gene', '673', (119, 123))	('binding', 'Interaction', (48, 55))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', (119, 123))	('P34S', 'Var', (171, 175))	('C18Y', 'Var', (140, 144))	('P34S', 'Mutation', 'p.P34S', (171, 175))	('E31D', 'Mutation', 'p.E31D', (146, 150))	('P29L', 'Var', (159, 163))	('affect', 'Reg', (41, 47))	('A159V', 'Var', (152, 157))
69594	30053901	For example, KIT has multiple clusters with known mutations; one of which has three known mutations (E490D, Y494C, S476G) in the same cluster, which are FDA approved as sensitive to combined therapy of imatinib, sunitinib, and regorafenib (KIT and angiogenesis inhibitor).	('E490D', 'Mutation', 'p.E490D', (101, 106))	('S476G', 'Var', (115, 120))	('regorafenib', 'Chemical', 'MESH:C559147', (227, 238))	('E490D', 'Var', (101, 106))	('Y494C', 'Var', (108, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (212, 221))	('Y494C', 'Mutation', 'p.Y494C', (108, 113))	('S476G', 'Mutation', 'p.S476G', (115, 120))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))
69595	30053901	In addition, this cluster contains two other unique mutations (D439H, I438L) not in DEPO that, based on our analysis using HotSpot3D, could also affect binding affinity and potentially tumor sensitivity to KIT combined with angiogenesis inhibitors (Additional file 2: Table S13).	('tumor', 'Disease', (185, 190))	('I438L', 'Var', (70, 75))	('D439H', 'Mutation', 'p.D439H', (63, 68))	('binding affinity', 'Interaction', (152, 168))	('affect', 'Reg', (145, 151))	('I438L', 'Mutation', 'p.I438L', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('D439H', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
69596	30053901	To do this, we assessed the activity and drug sensitivity of a set of six BRAF mutations (F635I, G596D, K601E, W604L, L613F, G596R) in close spatial proximity to the well-studied V600E pathogenic mutation (Fig.	('L613F', 'Mutation', 'p.L613F', (118, 123))	('G596D', 'Mutation', 'rs397507483', (97, 102))	('K601E', 'Mutation', 'rs121913364', (104, 109))	('W604L', 'Mutation', 'p.W604L', (111, 116))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('F635I', 'Mutation', 'p.F635I', (90, 95))	('L613F', 'Var', (118, 123))	('K601E', 'Var', (104, 109))	('G596R', 'Mutation', 'rs121913361', (125, 130))	('G596R', 'Var', (125, 130))	('G596D', 'Var', (97, 102))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('F635I', 'Var', (90, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('W604L', 'Var', (111, 116))
69598	30053901	Therefore, we transfected BRAF mutations, along with wild-type BRAF and BRAF V600E, into HEK293T cells in the presence or absence of BRAF inhibitor dabrafenib, and used phosphorylation changes in MEK1/2 as an indicator of BRAF activity.	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', (72, 76))	('MEK1/2', 'Gene', (196, 202))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', '673', (222, 226))	('BRAF', 'Gene', '673', (133, 137))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', (26, 30))	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('BRAF', 'Gene', (222, 226))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', '673', (63, 67))	('phosphorylation', 'MPA', (169, 184))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (72, 76))
69599	30053901	The undetectable level of endogenous BRAF in HEK293T cells eliminates potential ambiguity in interpreting the effects of transfected BRAF mutations.	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (133, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('mutations', 'Var', (138, 147))
69600	30053901	As expected, BRAF V600E caused drastically increased phosphorylation in MEK1/2 that is reduced by dabrafenib (Fig.	('V600E', 'Var', (18, 23))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1/2', 'Gene', (72, 78))	('BRAF', 'Gene', '673', (13, 17))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (43, 52))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('phosphorylation', 'MPA', (53, 68))
69601	30053901	Three (G596D, K601E, and W604L) out of six other transfected BRAF mutations also showed higher levels of MEK1/2 phosphorylation and sensitivity to dabrafenib than wild-type BRAF, suggesting that a high percentage of mutations identified by Hotspot3D in close spatial proximity to V600E are activated and similarly sensitive to dabrafenib.	('mutations', 'Var', (66, 75))	('K601E', 'Var', (14, 19))	('dabrafenib', 'Chemical', 'MESH:C561627', (327, 337))	('W604L', 'Var', (25, 30))	('G596D', 'Mutation', 'rs397507483', (7, 12))	('BRAF', 'Gene', '673', (173, 177))	('V600E', 'Mutation', 'rs113488022', (280, 285))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (61, 65))	('MEK1/2', 'Gene', '5604;5605', (105, 111))	('MEK1/2', 'Gene', (105, 111))	('higher', 'PosReg', (88, 94))	('W604L', 'Mutation', 'p.W604L', (25, 30))	('G596D', 'Var', (7, 12))	('sensitivity', 'MPA', (132, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('V600E', 'Var', (280, 285))	('K601E', 'Mutation', 'rs121913364', (14, 19))
69602	30053901	Notably, BRAF G596R-transfected cells appeared to have a much lower level of MEK1/2 phosphorylation when compared to those transfected with wild-type BRAF, supporting prior findings that G596R results in BRAF loss of function.	('loss of function', 'NegReg', (209, 225))	('BRAF', 'Gene', (204, 208))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('G596R', 'Mutation', 'rs121913361', (14, 19))	('BRAF', 'Gene', (150, 154))	('lower', 'NegReg', (62, 67))	('BRAF', 'Gene', '673', (150, 154))	('MEK1/2', 'Gene', '5604;5605', (77, 83))	('G596R', 'Var', (187, 192))	('G596R', 'Mutation', 'rs121913361', (187, 192))	('MEK1/2', 'Gene', (77, 83))	('G596R-transfected', 'Var', (14, 31))	('BRAF', 'Gene', '673', (204, 208))
69604	30053901	For example, in the case of breast cancer, elevated mRNA expression and copy number amplification of ESR1 correlate with elevated protein expression of ER, as well as with sensitivity to hormonal therapy with tamoxifen.	('ESR1', 'Gene', '2099', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('copy number amplification', 'Var', (72, 97))	('elevated', 'PosReg', (43, 51))	('elevated', 'PosReg', (121, 129))	('tamoxifen', 'Chemical', 'MESH:D013629', (209, 218))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('ESR1', 'Gene', (101, 105))	('mRNA expression', 'MPA', (52, 67))	('protein expression', 'MPA', (130, 148))
69610	30053901	Interestingly, tumors with "druggable" gene fusions tend to express elevated levels of the corresponding druggable gene (Additional file 2: Table S15, Additional file 3: Figure S1), suggesting that fusions may be one of several drivers of gene and protein expression.	('levels of', 'MPA', (77, 86))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fusions', 'Var', (44, 51))	('elevated', 'PosReg', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
69622	30053901	Similarly, 26 and 52% of BRCA and UCEC, respectively, show elevated activity at ESR1's p.S118 phosphosite.	('BRCA', 'Gene', (25, 29))	('ESR1', 'Gene', '2099', (80, 84))	('p.S118', 'Var', (87, 93))	('S118 phosphosite', 'Chemical', '-', (89, 105))	('ESR1', 'Gene', (80, 84))	('activity', 'MPA', (68, 76))	('elevated', 'PosReg', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
69625	30053901	EGFR phosphosites p.Y1068 and p.Y1173 are active in GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LUAD, and LUSC.	('p.Y1068', 'Var', (18, 25))	('EGFR', 'Gene', (0, 4))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('GBM', 'Disease', (52, 55))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HNSC', 'Phenotype', 'HP:0012288', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('phosphosite', 'Chemical', '-', (5, 16))	('p.Y1173', 'Var', (30, 37))	('EGFR', 'Gene', '1956', (0, 4))
69635	30053901	RAC1 P29S co-occurs with mutations in BRAF and MEK1 in four SKCM tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('mutations', 'Var', (25, 34))	('MEK1', 'Gene', '5604', (47, 51))	('SKCM tumors', 'Disease', 'MESH:D009369', (60, 71))	('MEK1', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SKCM tumors', 'Disease', (60, 71))	('BRAF', 'Gene', (38, 42))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
69636	30053901	RAC1 P29S renders SKCM resistant to BRAF/MEK inhibition; testing for RAC1 P29S may identify patients with BRAF V600E SKCM unlikely to benefit from BRAF/MEK inhibitor.	('CM', 'Disease', 'MESH:D009202', (20, 22))	('V600E', 'Var', (111, 116))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('patients', 'Species', '9606', (92, 100))	('RAC1', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (36, 40))	('P29S', 'Mutation', 'rs1057519874', (74, 78))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', '5609', (41, 44))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('RAC1', 'Gene', '5879', (0, 4))	('MEK', 'Gene', '5609', (152, 155))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('RAC1', 'Gene', (69, 73))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('MEK', 'Gene', (152, 155))	('RAC1', 'Gene', '5879', (69, 73))
69638	30053901	AKT1 E17K co-occurs with BRAF V600E in five tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('tumors', 'Disease', (44, 50))	('AKT1', 'Gene', '207', (0, 4))	('E17K', 'SUBSTITUTION', 'None', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('AKT1', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', (25, 29))	('E17K', 'Var', (5, 9))
69640	30053901	Transcriptomic and proteomic expression profiling reveals 48 additional tumors with BRAF V600E/K and elevated AKT (AKT1/2/3) expression at the mRNA or protein/phosphoprotein levels; these may also benefit from BRAF/AKT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('elevated', 'PosReg', (101, 109))	('AKT', 'Gene', '207', (115, 118))	('AKT', 'Gene', (110, 113))	('AKT1/2/3', 'Gene', (115, 123))	('tumors', 'Disease', (72, 78))	('V600E', 'SUBSTITUTION', 'None', (89, 94))	('AKT', 'Gene', '207', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (110, 113))	('AKT1/2/3', 'Gene', '207;208;10000', (115, 123))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('AKT', 'Gene', (115, 118))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('AKT', 'Gene', (215, 218))	('V600E', 'Var', (89, 94))
69643	30053901	Additionally, 105 tumors contain activating PIK3CA mutations co-occurring with elevated mRNA or protein expression of ESR1 or PGR.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PGR', 'Gene', '5241', (126, 129))	('ESR1', 'Gene', '2099', (118, 122))	('PIK3CA', 'Gene', '5290', (44, 50))	('mRNA or protein expression', 'MPA', (88, 114))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('activating', 'PosReg', (33, 43))	('elevated', 'PosReg', (79, 87))	('ESR1', 'Gene', (118, 122))	('PGR', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
69649	30053901	Overall, the mean LN(IC50) for cell lines that contain a sensitive mutation from DEPO was significantly lower than background LN(IC50) in both the cancer-type-specific and non-specific setting (Mann-Whitney U test, P = 1.1e-96 and P = 1.3e-109, respectively) (Fig.	('DEPO', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (67, 75))	('lower', 'NegReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
69651	30053901	In both the cancer-type-specific and non-specific settings, 19 variant/drug combinations had significantly lower mean LN(IC50) than background LN(IC50) for the corresponding drug.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('variant/drug', 'Var', (63, 75))	('cancer', 'Disease', (12, 18))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('combinations', 'Var', (76, 88))
69653	30053901	For example, cell lines with BRAF V600E were associated with sensitivity to BRAF inhibitors PLX4720 (1), PLX4720 (2), and dabrafenib in both the cancer-type-specific (SKCM) and non-specific settings (BRCA, COADREAD, GBM, LGG, LIHC, and THCA) (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('LIHC', 'Disease', 'None', (226, 230))	('THCA', 'Phenotype', 'HP:0002890', (236, 240))	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('PLX4720', 'Var', (105, 112))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (200, 204))	('sensitivity', 'MPA', (61, 72))	('V600E', 'Var', (34, 39))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('LIHC', 'Disease', (226, 230))	('BRCA', 'Gene', (200, 204))	('PLX4720', 'Gene', (92, 99))
69654	30053901	Two out of six mutations (PIK3CA H1047R and KRAS G12C) was associated with sensitivity in either the cancer-type-specific or the non-specific setting.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('H1047R', 'Var', (33, 39))	('G12C', 'Mutation', 'rs121913530', (49, 53))	('cancer', 'Disease', (101, 107))	('PIK3CA', 'Gene', '5290', (26, 32))	('sensitivity', 'Disease', (75, 86))	('associated', 'Reg', (59, 69))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (26, 32))
69669	30053901	First, with DEPO, our analysis of druggability in a given tumor is exclusively based on mutation/drug interactions rather than gene/drug interactions, with variants including both predefined mutations (e.g., BRAF V600E) and categories of mutations (e.g., EGFR exon 19 deletions).	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (255, 259))	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('deletions', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('V600E', 'Mutation', 'rs113488022', (213, 218))
69672	30053901	Third, it uses an analytic tool to create a set of putative druggable mutations, of which a subset occurring in BRAF were tested and validated in vitro.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
69676	30053901	Realistically, only a fraction of the 48% of tumors with potential drug-associated omics alterations will be clinically druggable because the mere presence of a shared genetic biomarker (mutation, mRNA/protein expression outlier) does not guarantee clinical efficacy across cancer types, nor does it guarantee acceptable clinical toxicity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('toxicity', 'Disease', (330, 338))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
69677	30053901	Further, we recognize that our computational survey of the landscape of potential drug-associated omics alterations may include some controversial drug/biomarker relationships (e.g., PI3K inhibitors in PIK3CA-mutant cancers), some of which have either failed clinical trials and/or are still being actively developed in clinical trials.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
69680	30053901	Second, our analysis does not account for clonal heterogeneity, which is not unreasonable given that therapies targeting genomic alterations with high variant allele frequencies can induce substantial tumor regression.	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('variant', 'Var', (151, 158))
69690	30053901	ACC Adrenocortical carcinoma AML/LAML Acute myeloid leukemia BLCA Bladder urothelial carcinoma BRCA Breast adenocarcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CNA Copy number amplification CNL Copy number loss CNV Copy number variation COADREAD Colon and rectal carcinoma CPTAC Clinical Proteomic Tumor Analysis Consortium DCC Data Coordinating Center DEPO Database of Evidence for Precision Oncology FBS Fetal bovine serum FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded GBM Glioblastoma multiforme GDAC Genome Data Analysis Centers GDSC Genomics of Drug Sensitivity in Cancer HNSC Head and neck squamous cell carcinoma IQR Interquartile range KICH Kidney chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Low-grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma MAF Mutation annotation file NGS Next-generation sequencing NSCLC Non-small cell lung cancer OV Ovarian serous carcinoma PNNL Pacific Northwest National Laboratory PRAD Prostate adenocarcinoma RBN Replicates-based normalization RPPA Reverse phase protein array SKCM Skin cutaneous melanoma SNP Single nucleotide polymorphism STAD Stomach adenocarcinoma STR Short tandem repeat TCGA The Cancer Genome Atlas TCPA The Cancer Protein Atlas THCA Thyroid carcinoma TKI Tyrosine kinase inhibitor UCEC Uterine corpus endometrial carcinoma UCS Uterine carcinosarcoma VCF Variant call format LD designed and supervised the research.	('adenocarcinoma', 'Disease', (1262, 1276))	('Kidney renal clear cell carcinoma', 'Disease', (731, 764))	('carcinosarcoma', 'Disease', (1467, 1481))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (1310, 1329))	('adenocarcinoma', 'Disease', (1102, 1116))	('RBN', 'Chemical', '-', (1117, 1120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (777, 807))	('cancer', 'Phenotype', 'HP:0002664', (1010, 1016))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('DCC', 'Chemical', '-', (356, 359))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('carcinoma', 'Disease', (1445, 1454))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (38, 60))	('squamous cell carcinoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D002277', (798, 807))	('CM', 'Disease', 'MESH:D009202', (1187, 1189))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1262, 1276))	('Cancer', 'Disease', 'MESH:D009369', (1339, 1345))	('glioma', 'Phenotype', 'HP:0009733', (822, 828))	('bovine', 'Species', '9913', (444, 450))	('Cancer', 'Phenotype', 'HP:0002664', (1310, 1316))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (44, 60))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (1426, 1454))	('VCF', 'Gene', '6899', (1482, 1485))	('PNNL', 'Chemical', '-', (1045, 1049))	('Breast adenocarcinoma', 'Disease', 'MESH:D000230', (100, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1195, 1213))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (1365, 1382))	('adenocarcinoma', 'Disease', (177, 191))	('Kidney renal papillary cell carcinoma', 'Disease', (770, 807))	('Non-small cell lung cancer', 'Disease', (990, 1016))	('carcinoma', 'Disease', (85, 94))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (288, 304))	('Skin cutaneous melanoma', 'Disease', (1190, 1213))	('Ovarian serous carcinoma', 'Disease', (1020, 1044))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (770, 807))	('urothelial carcinoma', 'Disease', (74, 94))	('FBS', 'Disease', (434, 437))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('VCF', 'Gene', (1482, 1485))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (990, 1016))	('Uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (1459, 1481))	('NSCLC', 'Disease', 'MESH:D002289', (984, 989))	('Cancer Protein Atlas', 'Disease', 'MESH:D009369', (1339, 1359))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1433, 1454))	('Cancer', 'Disease', (1339, 1345))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('Cancer Genome Atlas', 'Disease', (1310, 1329))	('Ovarian serous carcinoma', 'Disease', 'MESH:D010051', (1020, 1044))	('THCA', 'Phenotype', 'HP:0002890', (1360, 1364))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (1413, 1432))	('adenocarcinoma', 'Disease', (107, 121))	('squamous cell carcinoma', 'Disease', (136, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1102, 1116))	('paraffin', 'Chemical', 'MESH:D010232', (511, 519))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (990, 1016))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (608, 624))	('corpus endometrial carcinoma', 'Disease', (1426, 1454))	('KICH', 'Chemical', '-', (702, 706))	('Tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Kidney chromophobe', 'Disease', 'MESH:D000238', (707, 725))	('Cancer', 'Disease', (628, 634))	('adenocarcinoma', 'Disease', (875, 889))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (649, 677))	('carcinoma', 'Disease', 'MESH:D002277', (755, 764))	('Kidney chromophobe', 'Disease', (707, 725))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1093, 1116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (900, 923))	('Liver hepatocellular carcinoma', 'Disease', (834, 864))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (834, 864))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('Cancer', 'Disease', 'MESH:D009369', (628, 634))	('adenocarcinoma', 'Disease', 'MESH:D000230', (875, 889))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (654, 677))	('Cancer', 'Phenotype', 'HP:0002664', (1339, 1345))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (164, 191))	('LUSC', 'Phenotype', 'HP:0030359', (890, 894))	('LIHC', 'Disease', (829, 833))	('Formalin', 'Chemical', 'MESH:D005557', (495, 503))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (900, 923))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('carcinosarcoma', 'Disease', 'MESH:D002296', (1467, 1481))	('carcinoma', 'Disease', (19, 28))	('glioma', 'Disease', 'MESH:D005910', (822, 828))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (654, 677))	('carcinoma', 'Disease', 'MESH:D002277', (1267, 1276))	('NSCLC', 'Disease', (984, 989))	('carcinoma', 'Disease', (755, 764))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (994, 1016))	('Cancer', 'Phenotype', 'HP:0002664', (628, 634))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1254, 1276))	('Tyrosine kinase', 'Gene', '7294', (1387, 1402))	('NSCLC', 'Phenotype', 'HP:0030358', (984, 989))	('melanoma', 'Phenotype', 'HP:0002861', (1205, 1213))	('Breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (914, 923))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Disease', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (668, 677))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (731, 764))	('carcinoma', 'Disease', 'MESH:D002277', (295, 304))	('HNSC', 'Phenotype', 'HP:0012288', (635, 639))	('Glioblastoma multiforme', 'Disease', (533, 556))	('Variant', 'Var', (1486, 1493))	('Cancer', 'Disease', (1310, 1316))	('Stomach adenocarcinoma', 'Disease', (1254, 1276))	('GDAC', 'Chemical', '-', (557, 561))	('lung cancer', 'Phenotype', 'HP:0100526', (1005, 1016))	('carcinoma', 'Disease', (1267, 1276))	('carcinoma', 'Disease', (1035, 1044))	('LGG Low', 'Phenotype', 'HP:0004315', (808, 815))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('AML', 'Disease', (29, 32))	('carcinoma', 'Disease', (1107, 1116))	('Breast adenocarcinoma', 'Disease', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1190, 1213))	('FBS', 'Disease', 'MESH:D005198', (434, 437))	('Cancer', 'Disease', 'MESH:D009369', (1310, 1316))	('carcinoma', 'Disease', (914, 923))	('glioma', 'Disease', (822, 828))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (533, 556))	('carcinoma', 'Disease', (668, 677))	('carcinoma', 'Disease', (112, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('LUAD', 'Phenotype', 'HP:0030078', (865, 869))	('Acute myeloid leukemia', 'Disease', (38, 60))	('carcinoma', 'Disease', (295, 304))	('BRCA', 'Gene', (95, 99))	('AML', 'Disease', (34, 37))	('carcinoma', 'Disease', 'MESH:D002277', (1035, 1044))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (38, 60))	('LIHC', 'Disease', 'None', (829, 833))	('carcinoma', 'Disease', 'MESH:D002277', (1107, 1116))	('carcinoma', 'Disease', (880, 889))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('carcinoma', 'Disease', (855, 864))	('endocervical adenocarcinoma', 'Disease', (164, 191))	('Tyrosine kinase', 'Gene', (1387, 1402))	('carcinoma', 'Disease', (182, 191))	('neck squamous cell carcinoma', 'Disease', (649, 677))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (870, 889))	('carcinoma', 'Disease', 'MESH:D002277', (1445, 1454))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('Oncology', 'Phenotype', 'HP:0002664', (425, 433))	('UCS', 'Phenotype', 'HP:0002891', (1455, 1458))	('BLCA', 'Chemical', '-', (61, 65))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('Glioblastoma', 'Phenotype', 'HP:0012174', (533, 545))	('Prostate adenocarcinoma', 'Disease', (1093, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (880, 889))	('TCPA', 'Chemical', '-', (1330, 1334))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (840, 864))	('carcinoma', 'Disease', (798, 807))	('carcinoma', 'Disease', 'MESH:D002277', (855, 864))	('Cancer Protein Atlas', 'Disease', (1339, 1359))	('BRCA', 'Gene', '672', (95, 99))
69722	20694068	Such familial cancer syndromes are due to germline mutations and include Li-Fraumeni syndrome, neurofibromatosis, Turcot syndrome, and multiple enchondromatosis.	('familial cancer syndromes', 'Disease', 'MESH:D009386', (5, 30))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (73, 93))	('Turcot syndrome', 'Disease', 'MESH:C536928', (114, 129))	('neurofibromatosis', 'Disease', (95, 112))	('multiple enchondromatosis', 'Disease', (135, 160))	('Li-Fraumeni syndrome', 'Disease', (73, 93))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('multiple enchondromatosis', 'Phenotype', 'HP:0005701', (135, 160))	('Turcot syndrome', 'Disease', (114, 129))	('multiple enchondromatosis', 'Disease', 'MESH:D004687', (135, 160))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (95, 112))	('familial cancer syndromes', 'Disease', (5, 30))	('neurofibromatosis', 'Disease', 'MESH:C537392', (95, 112))	('germline mutations', 'Var', (42, 60))	('due', 'Reg', (35, 38))
69723	20694068	Interestingly, neurofibromatosis type-1 is due to a mutation on chromosome 17, which also harbors the p53 gene implicated in the genesis of many malignant gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (15, 32))	('neurofibromatosis type-1', 'Gene', '4763', (15, 39))	('p53', 'Gene', '7157', (102, 105))	('due', 'Reg', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('malignant gliomas', 'Disease', (145, 162))	('neurofibromatosis type-1', 'Gene', (15, 39))	('malignant gliomas', 'Disease', 'MESH:D005910', (145, 162))	('mutation', 'Var', (52, 60))	('p53', 'Gene', (102, 105))
69731	20694068	Theoretically, asthenumber of geneticmutationsincreases, tumors may progress from low-grade to higher grade phenotypes and genotypes.	('progress', 'PosReg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('geneticmutationsincreases', 'Var', (30, 55))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
69734	20694068	For example, mutation of the proapoptotic p53 gene located on chromosome 17 is believed to be the primary event involved in the genesis of a low-grade astrocytoma and is found with a higher incidence among secondary GBM tumor samples.	('p53', 'Gene', (42, 45))	('astrocytoma', 'Disease', 'MESH:D001254', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('astrocytoma', 'Disease', (151, 162))	('p53', 'Gene', '7157', (42, 45))	('mutation', 'Var', (13, 21))	('tumor', 'Disease', (220, 225))	('astrocytoma', 'Phenotype', 'HP:0009592', (151, 162))	('GBM', 'Phenotype', 'HP:0012174', (216, 219))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
69735	20694068	Consequently, the mutated p53 gene is found with increasing frequency (>65%) in diffuse [World Health Organization (WHO) grade II] astrocytomas.	('astrocytomas', 'Disease', (131, 143))	('mutated', 'Var', (18, 25))	('diffuse [', 'Disease', (80, 89))	('p53', 'Gene', (26, 29))	('astrocytomas', 'Disease', 'MESH:D001254', (131, 143))	('p53', 'Gene', '7157', (26, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))
69737	20694068	The further sequential accumulation of genetic mutations in the form of loss of heterozygosity for chromosome 10q (LOH 10q), as well as mutation of the tumor suppressor retinoblastoma gene, has been observed in the progression of low-grade diffuse astrocytomas (WHO grade II) to AA (WHO grade III).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('LOH 10q', 'Chemical', '-', (115, 122))	('loss', 'NegReg', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (136, 144))	('retinoblastoma', 'Disease', 'MESH:D012175', (169, 183))	('retinoblastoma', 'Disease', (169, 183))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (47, 56))	('astrocytomas', 'Disease', 'MESH:D001254', (248, 260))	('astrocytoma', 'Phenotype', 'HP:0009592', (248, 259))	('AA', 'Phenotype', 'HP:0009592', (279, 281))	('observed', 'Reg', (199, 207))	('astrocytomas', 'Disease', (248, 260))	('retinoblastoma', 'Phenotype', 'HP:0009919', (169, 183))
69738	20694068	For example, p53 mutation is far less frequent in primary GBM (~25%) when compared with AA (~50%) and secondary GBM (~65%).	('GBM', 'Phenotype', 'HP:0012174', (112, 115))	('p53', 'Gene', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('mutation', 'Var', (17, 25))	('AA', 'Phenotype', 'HP:0009592', (88, 90))	('primary GBM', 'Disease', (50, 61))	('p53', 'Gene', '7157', (13, 16))
69741	20694068	These differences may aid in the diagnosis and prognosis of AA and GBM, and potentially identify targeted therapies to specific tumor subtypes based on genetic features.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('differences', 'Var', (6, 17))	('AA', 'Phenotype', 'HP:0009592', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('aid', 'Reg', (22, 25))	('tumor', 'Disease', (128, 133))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
69793	20694068	Although methylation of the O-6 position of guanine represents only a small fraction of the total DNA lesions induced by TMZ, it remains the major effector of its cytotoxic action.	('TMZ', 'Chemical', 'MESH:D000077204', (121, 124))	('DNA', 'Disease', (98, 101))	('guanine', 'Chemical', 'MESH:D006147', (44, 51))	('methylation', 'MPA', (9, 20))	('TMZ', 'Var', (121, 124))
69796	20694068	Since guanine methylation persists, a series of futile replication and repair cycles ensue, ultimately resulting in apoptotic cell death.	('guanine', 'Chemical', 'MESH:D006147', (6, 13))	('resulting in', 'Reg', (103, 115))	('death', 'Disease', 'MESH:D003643', (131, 136))	('guanine methylation', 'Var', (6, 25))	('death', 'Disease', (131, 136))
69814	20694068	This trial enrolled 16 nGBM, seven nAA, and five low-grade glioma patients.	('nGBM', 'Chemical', '-', (23, 27))	('glioma', 'Disease', (59, 65))	('AA', 'Phenotype', 'HP:0009592', (36, 38))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('GBM', 'Phenotype', 'HP:0012174', (24, 27))	('nGBM', 'Var', (23, 27))	('nAA', 'Chemical', '-', (35, 38))	('patients', 'Species', '9606', (66, 74))
69827	20694068	TMZ has been shown to increase the percentage of progression-free patients with malignant gliomas at the 6-month time point following initiation of treatment.	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('increase', 'PosReg', (22, 30))	('TMZ', 'Var', (0, 3))	('malignant gliomas', 'Disease', (80, 97))	('malignant gliomas', 'Disease', 'MESH:D005910', (80, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('patients', 'Species', '9606', (66, 74))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
69846	20694068	Patients receiving concurrent and adjuvant TMZ had a significantly better PFS6m (53.9%, CI 48.1, 59.6), compared with those receiving RT alone (36.4%, CI 30.8, 41.9).	('TMZ', 'Var', (43, 46))	('Patients', 'Species', '9606', (0, 8))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('PFS6m', 'CPA', (74, 79))	('better', 'PosReg', (67, 73))
69886	20694068	The definitive EORTC/NCIC phase III trial has demonstrated conclusively that TMZ can prolong mOS in nGBM patients by 2.5 months.	('TMZ', 'Var', (77, 80))	('patients', 'Species', '9606', (105, 113))	('nGBM', 'Disease', (100, 104))	('mOS', 'Gene', (93, 96))	('nGBM', 'Chemical', '-', (100, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (77, 80))	('mOS', 'Gene', '17451', (93, 96))	('prolong', 'PosReg', (85, 92))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))
69907	20694068	Three pivotal phase II studies demonstrated radiographic response to TMZ in rGBM and rAA patients but failed to prolong mOS compared with historic databases of patients treated with other chemotherapeutic agents.	('rAA', 'Chemical', '-', (85, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('patients', 'Species', '9606', (160, 168))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('mOS', 'Gene', '17451', (120, 123))	('AA', 'Phenotype', 'HP:0009592', (86, 88))	('rGBM', 'Disease', (76, 80))	('patients', 'Species', '9606', (89, 97))	('TMZ', 'Var', (69, 72))	('mOS', 'Gene', (120, 123))
69911	20694068	Patients receiving TMZ treatment had a mOS of 7.3 months compared with 5.8 months in those treated with PCB.	('TMZ', 'Var', (19, 22))	('TMZ', 'Chemical', 'MESH:D000077204', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('PCB', 'Chemical', 'MESH:D011344', (104, 107))	('mOS', 'Gene', (39, 42))	('mOS', 'Gene', '17451', (39, 42))
69929	20694068	Patients receiving TMZ scored consistently higher on seven HRQoL domains, and this improvement was maintained until disease progression.	('TMZ', 'Chemical', 'MESH:D000077204', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('TMZ', 'Var', (19, 22))	('higher', 'PosReg', (43, 49))
69931	20694068	However, the study also demonstrated that TMZ delayed time to tumor progression compared with PCB, a parameter that closely correlates with maintenance or improvement in HRQoL.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('TMZ', 'Var', (42, 45))	('PCB', 'Chemical', 'MESH:D011344', (94, 97))	('delayed', 'NegReg', (46, 53))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
69932	20694068	Whether or not TMZ directly impacts HRQoL parameters, its favorable toxicity profile compared with other chemotherapeutic agents likely plays a role in maintaining quality of life in a population that has to endure many potential adverse drug events.	('TMZ', 'Var', (15, 18))	('toxicity', 'Disease', (68, 76))	('HRQoL parameters', 'MPA', (36, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (15, 18))	('impacts', 'Reg', (28, 35))	('quality', 'MPA', (164, 171))	('adverse drug events', 'Phenotype', 'HP:0020172', (230, 249))	('toxicity', 'Disease', 'MESH:D064420', (68, 76))
69971	20694068	Among patients in the RPA class III receiving RT + TMZ, there was a gain of 7 months in median survival time and of 24% in the 2-year survival time (P =0.006).	('RT + TMZ', 'Var', (46, 54))	('gain', 'PosReg', (68, 72))	('patients', 'Species', '9606', (6, 14))	('RT + TMZ', 'Chemical', '-', (46, 54))
70025	20694068	For example, patients with tumors harboring methylated MGMT promoter were found to have better outcomes compared with those with tumors that had unmethylated MGMT promoters.	('methylated', 'Var', (44, 54))	('outcomes', 'MPA', (95, 103))	('MGMT', 'Gene', '4255', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (129, 135))	('MGMT', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('better', 'PosReg', (88, 94))	('MGMT', 'Gene', '4255', (158, 162))	('MGMT', 'Gene', (158, 162))
70028	20694068	Patients with silenced MGMT gene expression due to hypermethylation of MGMT promoters were shown to respond more favorably to concurrent TMZ/RT compared with those who had unmethylated MGMT promoters and high MGMT gene expression levels.	('MGMT', 'Gene', '4255', (185, 189))	('MGMT', 'Gene', (185, 189))	('hypermethylation', 'Var', (51, 67))	('favorably', 'PosReg', (113, 122))	('respond', 'MPA', (100, 107))	('Patients', 'Species', '9606', (0, 8))	('MGMT', 'Gene', '4255', (23, 27))	('MGMT', 'Gene', '4255', (71, 75))	('MGMT', 'Gene', (23, 27))	('MGMT', 'Gene', (71, 75))	('TMZ', 'Chemical', 'MESH:D000077204', (137, 140))	('MGMT', 'Gene', (209, 213))	('MGMT', 'Gene', '4255', (209, 213))
70051	20694068	In addition, TMZ achieves excellent blood-brain barrier penetration and the measured cerebrospinal fluid area under the curve (AUC) is typically 20%-40% of the plasma AUC.	('TMZ', 'Var', (13, 16))	('cerebrospinal fluid area under the curve', 'MPA', (85, 125))	('blood-brain barrier penetration', 'CPA', (36, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (13, 16))
70063	20694068	Newly-diagnosed patients with a methylated MGMT promoter as well as those in RPA class III (age <50 years and PS of 0) seem to benefit the most from the addition of TMZ.	('patients', 'Species', '9606', (16, 24))	('MGMT', 'Gene', '4255', (43, 47))	('MGMT', 'Gene', (43, 47))	('methylated', 'Var', (32, 42))	('benefit', 'PosReg', (127, 134))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
70065	33489866	 BRAF AMP Frequently Co-occurs With IDH1/2, TP53, and ATRX Mutations in Adult Patients With Gliomas and Is Associated With Poorer Survival Than That of Patients Harboring BRAF V600E Abnormal RAS/RAF signaling plays a critical role in glioma.	('BRAF', 'Gene', '673', (1, 5))	('Glioma', 'Phenotype', 'HP:0009733', (92, 98))	('BRAF', 'Gene', (1, 5))	('Gliomas', 'Disease', 'MESH:D005910', (92, 99))	('ATRX', 'Gene', '546', (54, 58))	('glioma', 'Disease', (234, 240))	('TP53', 'Gene', (44, 48))	('Poorer', 'NegReg', (123, 129))	('AMP', 'Chemical', 'MESH:D000249', (6, 9))	('Patients', 'Species', '9606', (152, 160))	('Glioma', 'Disease', (92, 98))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('Gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('V600E', 'Mutation', 'rs113488022', (176, 181))	('IDH1', 'Gene', (36, 40))	('Patients', 'Species', '9606', (78, 86))	('BRAF', 'Gene', '673', (171, 175))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('IDH', 'Gene', (36, 39))	('Gliomas', 'Disease', (92, 99))	('BRAF', 'Gene', (171, 175))	('TP53', 'Gene', '7157', (44, 48))	('Glioma', 'Disease', 'MESH:D005910', (92, 98))	('Survival', 'MPA', (130, 138))	('IDH1', 'Gene', '3417', (36, 40))	('Mutations', 'Var', (59, 68))	('IDH', 'Gene', '3417', (36, 39))	('ATRX', 'Gene', (54, 58))
70066	33489866	Although it is known that the V600E mutation of v-raf murine viral oncogene homolog B1 (BRAF V600E) and BRAF amplification (BRAF AMP) both result in constitutive activation of the RAS/RAF pathway, whether BRAF V600E and BRAF AMP have different effects on the survival of glioma patients needs to be clarified.	('V600E', 'Var', (93, 98))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('murine', 'Species', '10090', (54, 60))	('V600E', 'Var', (210, 215))	('v-raf', 'Gene', (48, 53))	('v-raf', 'Gene', '110157', (48, 53))	('V600E', 'SUBSTITUTION', 'None', (210, 215))	('V600E', 'SUBSTITUTION', 'None', (93, 98))	('patient', 'Species', '9606', (278, 285))	('patients', 'Species', '9606', (278, 286))	('V600E', 'SUBSTITUTION', 'None', (30, 35))	('activation', 'PosReg', (162, 172))	('V600E', 'Var', (30, 35))	('RAS/RAF pathway', 'Pathway', (180, 195))
70067	33489866	Using cBioPortal, we retrieved studies of both mutations and copy number variations of the BRAF gene in CNS/brain tumors and investigated data from 69 nonredundant glioma patients.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('brain tumor', 'Phenotype', 'HP:0030692', (108, 119))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (91, 95))	('tumor', 'Disease', (114, 119))	('copy number variations', 'Var', (61, 83))	('brain tumors', 'Disease', 'MESH:D001932', (108, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('brain tumors', 'Phenotype', 'HP:0030692', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('brain tumor', 'Disease', 'MESH:D001932', (108, 119))	('brain tumors', 'Disease', (108, 120))
70068	33489866	The BRAF mutation group had significantly more male patients (64.00% vs. 36.84%; P = 0.046) and a higher occurrence of glioblastoma multiforme (66.00% vs. 31.58%; P = 0.013) compared to those in the other group.	('mutation', 'Var', (9, 17))	('glioblastoma', 'Disease', (119, 131))	('glioblastoma multiforme', 'Disease', (119, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('BRAF', 'Gene', (4, 8))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (119, 142))
70069	33489866	The BRAF AMP group had significantly more patients with the mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) (73.68% vs. 18.00%; P = 0.000), tumor protein p53 (TP53) (73.68% vs. 30.00%; P = 0.002), and alpha thalassemia/mental retardation syndrome X linked (ATRX) (63.16% vs. 18.00%; P = 0.001) than the mutation group.	('isocitrate dehydrogenase', 'Gene', (67, 91))	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('isocitrate dehydrogenase', 'Gene', '3417', (67, 91))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mutant', 'Var', (60, 66))	('alpha thalassemia/mental retardation syndrome X linked', 'Gene', '22589', (202, 256))	('mental retardation', 'Phenotype', 'HP:0001249', (220, 238))
70070	33489866	The BRAF AMP and IDH1/2 WT cohort had lower overall survival compared with the BRAF AMP and IDH1/2 MT groups (P = 0.001) and the BRAF mutation cohort (P = 0.019), including the BRAF V600E (P = 0.033) and BRAF non-V600E (P = 0.029) groups, using Kaplan-Meier survival curves and the log rank (Mantel-Cox) test.	('V600E', 'Var', (213, 218))	('V600E', 'SUBSTITUTION', 'None', (213, 218))	('lower', 'NegReg', (38, 43))	('V600E', 'Var', (182, 187))	('V600E', 'SUBSTITUTION', 'None', (182, 187))	('Cox', 'Gene', '1351', (299, 302))	('overall survival', 'MPA', (44, 60))	('Cox', 'Gene', (299, 302))
70077	33489866	The BRAF V600E mutation in which the thymine at nucleotide 1799 is substituted by adenine results in the substitution of valine with glutamic acid at amino acid 600; this is the most common BRAF mutation in glioma.	('substitution', 'Var', (105, 117))	('V600E', 'Var', (9, 14))	('thymine', 'Chemical', 'MESH:D013941', (37, 44))	('valine with glutamic acid at amino acid 600', 'Mutation', 'rs113488022', (121, 164))	('BRAF', 'Gene', (4, 8))	('V600E', 'SUBSTITUTION', 'None', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('adenine', 'Chemical', 'MESH:D000225', (82, 89))	('valine', 'MPA', (121, 127))
70078	33489866	In addition, BRAF amplification (BRAF AMP) can also cause hyperactivation of MAPK signaling, which plays essential roles in the acquired resistance to MAPK inhibitor therapy in cancers harboring BRAF V600E.	('hyperactivation', 'PosReg', (58, 73))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('BRAF amplification', 'Disease', (13, 31))	('V600E', 'Var', (200, 205))	('V600E', 'SUBSTITUTION', 'None', (200, 205))	('MAPK signaling', 'Pathway', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
70079	33489866	Although both BRAF V600E and BRAF AMP can lead to the hyperactivation of MAPK signaling, the differences between the patterns of BRAF V600E and BRAF AMP signaling in glioma, their influence on the survival of glioma patients, and the involvement of other genes, remains unclear.	('V600E', 'SUBSTITUTION', 'None', (134, 139))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('MAPK signaling', 'Pathway', (73, 87))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('V600E', 'Var', (19, 24))	('glioma', 'Disease', (209, 215))	('V600E', 'SUBSTITUTION', 'None', (19, 24))	('hyperactivation', 'PosReg', (54, 69))	('V600E', 'Var', (134, 139))
70080	33489866	In this study, based on cBioPortal data, we found that patients with glioma harboring BRAF AMP had lower overall survival compared with those harboring BRAF V600E.	('glioma', 'Disease', (69, 75))	('V600E', 'SUBSTITUTION', 'None', (157, 162))	('lower', 'NegReg', (99, 104))	('BRAF AMP', 'Var', (86, 94))	('overall survival', 'MPA', (105, 121))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('V600E', 'Var', (157, 162))
70083	33489866	For greater precision of characteristic evaluation, we created a descriptive table and divided the BRAF AMP group into two groups based on the non- and co-occurrence of the IDH1/2 mutation, and the BRAF mutation group into BRAF V600E and BRAF non-V600E groups.	('IDH1/2', 'Gene', (173, 179))	('V600E', 'Var', (247, 252))	('BRAF', 'Disease', (99, 103))	('V600E', 'SUBSTITUTION', 'None', (247, 252))	('V600E', 'Var', (228, 233))	('V600E', 'SUBSTITUTION', 'None', (228, 233))	('mutation', 'Var', (180, 188))
70084	33489866	The overall survival of the BRAF AMP and IDH1/2 MT, BRAF AMP and IDH1/2 WT, BRAF V600E, and BRAF non-V600E groups was determined by a crossover comparison using Kaplan-Meier survival curves and the log rank (Mantel-Cox) test.	('V600E', 'Var', (81, 86))	('V600E', 'SUBSTITUTION', 'None', (81, 86))	('V600E', 'SUBSTITUTION', 'None', (101, 106))	('V600E', 'Var', (101, 106))
70086	33489866	Twenty-five patients harbored BRAF non-V600E mutations; of these, two patients harbored a D594G mutation; two patients, a G469A mutation; and the remaining patients, an A320T mutation combined with A171E, A404Cfs*9, E375*, G466E, G466V, G469R, G469V, G596D, G69S, L331F, L382V, L597R, M531, P708S, S394P, S614P, T121I, V504_R506dup, V504I, W476*, and X709_splice mutations.	('L331F', 'Mutation', 'rs1181422421', (264, 269))	('V504_R506dup', 'Var', (319, 331))	('G466E', 'Var', (223, 228))	('S614P', 'Mutation', 'p.S614P', (305, 310))	('G596D', 'Var', (251, 256))	('V504_R506dup', 'Mutation', 'p.504,506dupR', (319, 331))	('G469R', 'Mutation', 'rs121913357', (237, 242))	('L597R', 'Mutation', 'rs121913366', (278, 283))	('L597R', 'Var', (278, 283))	('V600E', 'Var', (39, 44))	('A320T', 'Var', (169, 174))	('V504I', 'Mutation', 'p.V504I', (333, 338))	('E375*', 'SUBSTITUTION', 'None', (216, 221))	('L382V', 'Var', (271, 276))	('V504I', 'Var', (333, 338))	('A171E', 'Mutation', 'p.A171E', (198, 203))	('G69S', 'Mutation', 'rs757446039', (258, 262))	('S614P', 'Var', (305, 310))	('G469V', 'Var', (244, 249))	('G469V', 'Mutation', 'rs121913355', (244, 249))	('G466E', 'Mutation', 'rs121913351', (223, 228))	('T121I', 'Var', (312, 317))	('A404Cfs*9', 'Var', (205, 214))	('V600E', 'SUBSTITUTION', 'None', (39, 44))	('A320T', 'Mutation', 'rs1461617552', (169, 174))	('G466V', 'Var', (230, 235))	('L382V', 'Mutation', 'p.L382V', (271, 276))	('L331F', 'Var', (264, 269))	('D594G', 'Mutation', 'rs121913338', (90, 95))	('P708S', 'Var', (291, 296))	('M531', 'Var', (285, 289))	('G469R', 'Var', (237, 242))	('W476*', 'SUBSTITUTION', 'None', (340, 345))	('G466V', 'Mutation', 'rs121913351', (230, 235))	('D594G', 'Var', (90, 95))	('A404Cfs*9', 'Mutation', 'rs777474487', (205, 214))	('G596D', 'Mutation', 'rs397507483', (251, 256))	('W476*', 'Var', (340, 345))	('S394P', 'Mutation', 'rs923739321', (298, 303))	('A171E', 'Var', (198, 203))	('T121I', 'Mutation', 'p.T121I', (312, 317))	('S394P', 'Var', (298, 303))	('E375*', 'Var', (216, 221))	('G469A', 'Mutation', 'rs121913355', (122, 127))	('P708S', 'Mutation', 'p.P708S', (291, 296))	('X709_splice', 'Var', (351, 362))	('G69S', 'Var', (258, 262))
70087	33489866	The estimated mean survival time was 67.026 months for patients harboring BRAF AMP and IDH1/2 MT, 9.750 months for patients harboring BRAF AMP and IDH1/2 WT, 41.573 months for patients harboring BRAF V600E, and 89.958 months for patients harboring BRAF non-V600E.	('V600E', 'Var', (257, 262))	('V600E', 'SUBSTITUTION', 'None', (257, 262))	('AMP', 'Var', (79, 82))	('V600E', 'Var', (200, 205))	('V600E', 'SUBSTITUTION', 'None', (200, 205))
70088	33489866	The estimated survival time of the BRAF AMP and IDH1/2 WT cohort was the shortest and was significantly lower compared with that of the BRAF AMP and IDH1/2 MT (9.750 vs. 67.026, chi-square 10.526, P = 0.001), the BRAF V600E (9.750 vs. 41.573, chi-square 4.536, P = 0.033), and the BRAF non-V600E (9.750 vs. 89.958, chi-square 4.747, P = 0.029) cohorts.	('V600E', 'SUBSTITUTION', 'None', (290, 295))	('survival time', 'CPA', (14, 27))	('lower', 'NegReg', (104, 109))	('V600E', 'Var', (218, 223))	('V600E', 'Var', (290, 295))	('V600E', 'SUBSTITUTION', 'None', (218, 223))	('shortest', 'NegReg', (73, 81))
70089	33489866	When analyzed using Kaplan-Meier survival curves and the log rank (Mantel-Cox) test, there was no significance between the following groups: BRAF AMP cohort vs. BRAF mutation cohort (58.835 vs. 71.698, chi-square 0.020, P = 0.886), BRAF V600E cohort vs. BRAF non-V600E cohort (41.573 vs. 89.958, chi-square 1.999, P = 0.157), BRAF AMP and IDH1/2 MT cohort vs. BRAF V600E cohort (67.026 vs. 41.573, chi-square 1.031, P = 0.310), BRAF AMP and IDH1/2 MT cohort vs. BRAF non-V600E cohort (67.026 vs. 89.958, chi-square 0.025, P = 0.875), BRAF AMP and IDH1/2 MT cohort vs. BRAF mutation cohort (67.026 vs. 71.698, chi-square 0.513, P = 0.474) ( Supplementary Figure S1 ).	('V600E', 'Var', (237, 242))	('V600E', 'Var', (471, 476))	('V600E', 'SUBSTITUTION', 'None', (237, 242))	('V600E', 'SUBSTITUTION', 'None', (471, 476))	('V600E', 'Var', (365, 370))	('V600E', 'SUBSTITUTION', 'None', (365, 370))	('V600E', 'Var', (263, 268))	('V600E', 'SUBSTITUTION', 'None', (263, 268))
70090	33489866	The estimated survival time of the BRAF V600E cohort above 30 years of age was 40.135 months, whereas that of the BRAF AMP and IDH1/2 WT cohort was significantly lower (9.750 vs. 40.135, chi-square 5.575, P = 0.018) ( Supplementary Figure S2 ).	('lower', 'NegReg', (162, 167))	('V600E', 'SUBSTITUTION', 'None', (40, 45))	('V600E', 'Var', (40, 45))
70091	33489866	The IDH1/2 mutation in 13 of the 14 BRAF AMP patients was R132H, and one patient harbored the R132G mutation.	('R132H', 'Mutation', 'rs121913500', (58, 63))	('R132H', 'Var', (58, 63))	('R132G', 'Mutation', 'rs121913499', (94, 99))	('IDH1/2', 'Gene', (4, 10))
70092	33489866	The IDH1/2 mutation in eight BRAF non-V600E patients was R132H with the exception of one sample (R132S).	('V600E', 'Var', (38, 43))	('V600E', 'SUBSTITUTION', 'None', (38, 43))	('R132H', 'Var', (57, 62))	('IDH1/2', 'Gene', (4, 10))	('R132S', 'Mutation', 'rs121913499', (97, 102))	('R132H', 'SUBSTITUTION', 'None', (57, 62))
70095	33489866	BRAF mutations and copy number variation have been widely investigated in melanoma, thyroid carcinoma, and lung and colon cancers.	('thyroid carcinoma', 'Disease', 'MESH:D013964', (84, 101))	('investigated', 'Reg', (58, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('colon cancers', 'Disease', (116, 129))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('thyroid carcinoma', 'Disease', (84, 101))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (84, 101))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colon cancers', 'Phenotype', 'HP:0003003', (116, 129))	('colon cancers', 'Disease', 'MESH:D015179', (116, 129))
70096	33489866	Although BRAF V600E is rarely found in adult gliomas, it occurs predominately in pediatric gliomas, accounting for 68%-80% of pleomorphic xanthoastrocytoma (PXA), 20%-70% of ganglioglioma, 9%-10% of pilocytic astrocytoma (PA), 5%-15% of low-grade glioma (LGG), 20% of pediatric glioblastoma (pGBM), and 3% of adult glioblastoma multiforme (GBM) cases.	('astrocytoma', 'Phenotype', 'HP:0009592', (209, 220))	('pilocytic astrocytoma', 'Disease', (199, 220))	('pediatric gliomas', 'Disease', (81, 98))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (126, 155))	('V600E', 'Var', (14, 19))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('ganglioglioma', 'Disease', 'MESH:D018303', (174, 187))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (315, 327))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('pleomorphic xanthoastrocytoma', 'Disease', (126, 155))	('V600E', 'SUBSTITUTION', 'None', (14, 19))	('low-grade glioma', 'Disease', (237, 253))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('ganglioglioma', 'Disease', (174, 187))	('pediatric glioblastoma', 'Disease', (268, 290))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (199, 220))	('glioblastoma', 'Phenotype', 'HP:0012174', (278, 290))
70097	33489866	Because genetic alterations are important in tumor development and progression and both BRAF V600E and BRAF AMP can activate the MAPK pathway, we investigated the different effects of these two BRAF alterations and the mutations associated on the survival of glioma patients.	('activate', 'PosReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('V600E', 'Var', (93, 98))	('investigated', 'Reg', (146, 158))	('V600E', 'SUBSTITUTION', 'None', (93, 98))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('MAPK pathway', 'Pathway', (129, 141))
70098	33489866	In this study, among the various BRAF mutations that were identified using next-generation sequencing, the most frequent mutation was BRAF V600E.	('BRAF', 'Gene', (134, 138))	('V600E', 'Var', (139, 144))	('frequent', 'Reg', (112, 120))	('V600E', 'SUBSTITUTION', 'None', (139, 144))
70099	33489866	Patients with IDH1 WT glioma have a poor prognosis; however, patients with BRAF V600E and IDH1 WT experience favorable outcomes.	('BRAF', 'Var', (75, 79))	('IDH1 WT glioma', 'Disease', (14, 28))	('V600E', 'Var', (80, 85))	('IDH1 WT glioma', 'Disease', 'MESH:D005910', (14, 28))	('V600E', 'SUBSTITUTION', 'None', (80, 85))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))
70100	33489866	report that five patients with grade II glioma harboring BRAF V600E without IDH1 mutation who had undergone gross total resection without treatment were progression-free for 14-35 months; two patients with glioblastoma harboring BRAF V600E and IDH1WT had a progression-free survival of 36 and 19 months, respectively.	('IDH1', 'Gene', (76, 80))	('V600E', 'Var', (62, 67))	('V600E', 'SUBSTITUTION', 'None', (234, 239))	('V600E', 'SUBSTITUTION', 'None', (62, 67))	('BRAF', 'Var', (229, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('V600E', 'Var', (234, 239))
70101	33489866	In addition, a study reported a glioma patient with BRAF V600E without the IDH1 mutation who experienced 2 years of overall survival.	('glioma', 'Disease', (32, 38))	('IDH1', 'Gene', (75, 79))	('V600E', 'Var', (57, 62))	('V600E', 'SUBSTITUTION', 'None', (57, 62))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
70102	33489866	Hiromichi Suzuki's study shows that IDH WT in grade II and III gliomas (type III) is associated with a poorer overall survival rate compared with that of glioblastoma.	('IDH WT', 'Var', (36, 42))	('overall survival', 'MPA', (110, 126))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('III gliomas', 'Disease', (59, 70))	('poorer', 'NegReg', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('III gliomas', 'Disease', 'MESH:D005910', (59, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('grade II', 'Disease', (46, 54))
70103	33489866	Patients with glioma harboring BRAF V600E might benefit from MAPK pathway inhibitor target therapy, a rescue treatment that includes the use of RAF inhibitors and MEK inhibitors alone or in combination, and the results were encouraging.	('glioma', 'Disease', (14, 20))	('benefit', 'PosReg', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('V600E', 'Var', (36, 41))	('MAPK pathway', 'Pathway', (61, 73))	('V600E', 'SUBSTITUTION', 'None', (36, 41))
70104	33489866	Our data show that the survival of the BRAF non-V600E cohort was comparable to that of the BRAF V600E cohort.	('V600E', 'SUBSTITUTION', 'None', (48, 53))	('V600E', 'SUBSTITUTION', 'None', (96, 101))	('V600E', 'Var', (48, 53))	('V600E', 'Var', (96, 101))
70105	33489866	We also find that the gross survival of the BRAF AMP cohort was comparable to that of both the BRAF V600E and BRAF non-V600E cohorts.	('V600E', 'Var', (100, 105))	('V600E', 'SUBSTITUTION', 'None', (100, 105))	('V600E', 'Var', (119, 124))	('V600E', 'SUBSTITUTION', 'None', (119, 124))
70106	33489866	We found that the BRAF AMP and IDH1/2 WT cohort had reduced overall survival compared with that of the BRAF mutation cohort (BRAF V600E and BRAF non-V600E) and the BRAF AMP and IDH1/2 MT groups.	('reduced', 'NegReg', (52, 59))	('V600E', 'Var', (149, 154))	('overall survival', 'MPA', (60, 76))	('V600E', 'SUBSTITUTION', 'None', (149, 154))	('V600E', 'Var', (130, 135))	('V600E', 'SUBSTITUTION', 'None', (130, 135))
70107	33489866	First, the mRNA and protein expression levels of BRAF AMP may be higher than those of BRAF V600E, resulting in higher activation of the MAPK/ERK pathway and subsequent proliferation of cancer cells.	('BRAF AMP', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('MAPK/ERK pathway', 'Pathway', (136, 152))	('V600E', 'Var', (91, 96))	('higher', 'PosReg', (65, 71))	('higher activation', 'PosReg', (111, 128))	('V600E', 'SUBSTITUTION', 'None', (91, 96))
70108	33489866	Young adult patients are enriched with BRAF V600E mutations and have better survival than older patients; we reveal that the survival of patients above 30 years of age in the BRAF AMP and IDH1/2 WT cohort was also significantly reduced compared with that of the BRAF V600E cohort above 30 years (P = 0.018).	('BRAF', 'Var', (175, 179))	('mutations', 'Var', (50, 59))	('reduced', 'NegReg', (228, 235))	('V600E', 'Var', (267, 272))	('survival', 'CPA', (125, 133))	('V600E', 'SUBSTITUTION', 'None', (267, 272))	('V600E', 'Var', (44, 49))	('V600E', 'SUBSTITUTION', 'None', (44, 49))
70109	33489866	IDH1/2 mutations exist in greater than 70% of lower-grade gliomas (grades II and III) and in some glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (98, 111))	('glioblastomas', 'Disease', 'MESH:D005909', (98, 111))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('glioblastomas', 'Disease', (98, 111))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('lower-grade gliomas', 'Disease', (46, 65))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
70110	33489866	We found that BRAF AMP cohorts have lower survival compared with BRAF mutation cohorts, including BRAF V600E and BRAF non-V600E.	('survival', 'MPA', (42, 50))	('lower', 'NegReg', (36, 41))	('V600E', 'Var', (103, 108))	('V600E', 'SUBSTITUTION', 'None', (103, 108))	('V600E', 'Var', (122, 127))	('V600E', 'SUBSTITUTION', 'None', (122, 127))
70111	33489866	However, the survival of patients with BRAF AMP and IDH1/2 MT was better than that of patients with BRAF AMP and IDH1/2 WT and comparable to that of the BRAF non-V600E cohort.	('IDH1/2', 'Var', (52, 58))	('V600E', 'Var', (162, 167))	('V600E', 'SUBSTITUTION', 'None', (162, 167))	('better', 'PosReg', (66, 72))
70112	33489866	Most of the studies of BRAF V600E in gliomas focus on pediatric neoplasms, especially in gangliogliomas and PXA.	('PXA', 'Disease', (108, 111))	('V600E', 'Var', (28, 33))	('V600E', 'SUBSTITUTION', 'None', (28, 33))	('gangliogliomas', 'Disease', (89, 103))	('gangliogliomas', 'Disease', 'MESH:D018303', (89, 103))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
70113	33489866	Although IDH1/2 mutations are scarce in primary GBM, they are common in diffuse/anaplastic gliomas and secondary GBM.	('IDH1/2', 'Gene', (9, 15))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (80, 98))	('anaplastic gliomas', 'Disease', (80, 98))	('secondary GBM', 'Disease', (103, 116))	('mutations', 'Var', (16, 25))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('common', 'Reg', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
70114	33489866	ATRX mutations are detected in adult diffuse gliomas and astrocytomas harboring both TP53 and IDH1/2.	('adult diffuse gliomas', 'Disease', (31, 52))	('ATRX', 'Gene', (0, 4))	('astrocytomas', 'Disease', (57, 69))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('detected', 'Reg', (19, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (57, 68))	('astrocytomas', 'Disease', 'MESH:D001254', (57, 69))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))
70117	33489866	find that the rate of Arg-to-Cys substitutions at position 273 in TP53 is higher than that of Arg-to-His substitutions at position 132 in IDH1.	('Arg', 'Chemical', 'MESH:D001120', (94, 97))	('TP53', 'Gene', (66, 70))	('Cys', 'Chemical', 'MESH:D003545', (29, 32))	('Arg', 'Chemical', 'MESH:D001120', (22, 25))	('substitutions', 'Var', (33, 46))	('Arg-to-Cys substitutions', 'Var', (22, 46))	('His', 'Chemical', 'MESH:D006639', (101, 104))
70118	33489866	In conclusion, our study shows that BRAF AMP and IDH1/2 WT is related to the reduced survival in adult patients with glioma compared with BRAF V600E and that BRAF AMP is associated with mutations in IDH1, TP53, and ATRX.	('V600E', 'Var', (143, 148))	('glioma', 'Disease', (117, 123))	('mutations', 'Var', (186, 195))	('V600E', 'SUBSTITUTION', 'None', (143, 148))	('survival', 'CPA', (85, 93))	('TP53', 'Gene', (205, 209))	('AMP', 'Var', (163, 166))	('ATRX', 'Disease', (215, 219))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('reduced', 'NegReg', (77, 84))	('associated', 'Reg', (170, 180))	('IDH1', 'Gene', (199, 203))
70120	33260892	BRAF: A Two-Faced Janus Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme.	('lung carcinomas', 'Disease', (226, 241))	('thyroid papillary carcinoma', 'Disease', 'MESH:D000077273', (176, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('BRAF', 'Gene', '673', (0, 4))	('Sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('BRAF', 'Gene', (0, 4))	('Gain-of-function', 'PosReg', (24, 40))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('mutations', 'Var', (135, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('thyroid papillary carcinoma', 'Disease', (176, 203))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B', 'Gene', (44, 89))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('ovarian and glioblastoma multiforme', 'Disease', 'MESH:D005909', (267, 302))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('colon', 'Disease', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('BRAF', 'Gene', '673', (91, 95))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B', 'Gene', '673', (44, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('thyroid papillary carcinoma', 'Phenotype', 'HP:0002895', (176, 203))	('BRAF', 'Gene', (91, 95))	('lung carcinomas', 'Disease', 'MESH:D008175', (226, 241))
70121	33260892	This mutation aberrantly activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, thereby eliciting metastatic processes.	('activates', 'PosReg', (25, 34))	('MEK', 'Gene', (117, 120))	('metastatic processes', 'CPA', (203, 223))	('MEK', 'Gene', '5609', (117, 120))	('eliciting', 'Reg', (193, 202))	('mutation', 'Var', (5, 13))
70122	33260892	The relevance of BRAF mutations stems from its prognostic value and, equally important, from its relevant therapeutic utility as an actionable target for personalized treatment.	('men', 'Species', '9606', (172, 175))	('BRAF', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))
70127	33260892	The first evidence of an association between BRAF gene mutations and human cancers dates back to 2002.	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('mutations', 'Var', (55, 64))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('BRAF gene', 'Gene', (45, 54))
70128	33260892	Generally, BRAF mutations are more frequently associated with human cancer than ARAF and CRAF alterations.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('human', 'Species', '9606', (62, 67))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('associated', 'Reg', (46, 56))	('BRAF', 'Gene', (11, 15))
70129	33260892	As some studies suggest, this phenomenon may be due to the fact that whereas BRAF oncogenic activation is triggered by a substitution of a single amino acid, ARAF and CRAF oncogenic alterations require a double mutational event.	('substitution', 'Var', (121, 133))	('men', 'Species', '9606', (35, 38))	('BRAF', 'Disease', (77, 81))	('activation', 'PosReg', (92, 102))	('triggered by', 'Reg', (106, 118))	('oncogenic', 'CPA', (82, 91))
70130	33260892	To date, BRAF mutations account for about 7% of all human solid tumors, with a high prevalence in papillary thyroid carcinomas (PTC), melanomas, colorectal cancers (CRC), and lung cancers.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('BRAF', 'Gene', (9, 13))	('colorectal cancers', 'Disease', 'MESH:D015179', (145, 163))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PTC', 'Phenotype', 'HP:0002895', (128, 131))	('CRC', 'Disease', 'MESH:D015179', (165, 168))	('lung cancers', 'Disease', 'MESH:D008175', (175, 187))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('papillary thyroid carcinomas', 'Disease', (98, 126))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (98, 126))	('mutations', 'Var', (14, 23))	('lung cancers', 'Disease', (175, 187))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('solid tumors', 'Disease', (58, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('lung cancers', 'Phenotype', 'HP:0100526', (175, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('colorectal cancers', 'Disease', (145, 163))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (108, 126))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (98, 126))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('melanomas', 'Disease', (134, 143))	('human', 'Species', '9606', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CRC', 'Disease', (165, 168))	('solid tumors', 'Disease', 'MESH:D009369', (58, 70))
70131	33260892	The most common type of BRAF mutation is exon 15 p.V600E.	('p.V600E', 'Mutation', 'rs113488022', (49, 56))	('BRAF', 'Gene', (24, 28))	('p.V600E', 'Var', (49, 56))
70132	33260892	So far, about 200 BRAF mutant alleles have been described in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('human', 'Species', '9606', (61, 66))	('BRAF', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutant', 'Var', (23, 29))
70133	33260892	These mutations induce elevated levels of kinase activity, thereby promoting the activation of MEK/ERK pathways independently of Ras activation and protein dimerization.	('activation', 'PosReg', (81, 91))	('levels', 'MPA', (32, 38))	('promoting', 'PosReg', (67, 76))	('kinase activity', 'MPA', (42, 57))	('MEK', 'Gene', (95, 98))	('mutations', 'Var', (6, 15))	('MEK', 'Gene', '5609', (95, 98))
70134	33260892	Class II alterations are, instead, less common and involve several point mutations, in particular exon 11 p.G464E/V, exon 11 p. G469A/R/V, exon 15 p. L597Q/V, and exon 15 p.K601E/N/T, as well as gene fusions.	('p.K601E', 'Var', (171, 178))	('L597Q', 'Var', (150, 155))	('G469A', 'Var', (128, 133))	('p.G464E', 'Var', (106, 113))	('p.G464E', 'SUBSTITUTION', 'None', (106, 113))	('p.K601E', 'SUBSTITUTION', 'None', (171, 178))	('L597Q', 'SUBSTITUTION', 'None', (150, 155))	('G469A', 'SUBSTITUTION', 'None', (128, 133))
70136	33260892	Finally, Class III alterations are associated with low or no kinase activity and require both Ras upstream activation and dimerization with CRAF to induce MER/ERK pathway activation; in addition, they commonly co-occur with upstream activating alterations such as Neuroblastoma RAS Viral Oncogene Homolog (NRAS) mutations, Neurofibromin 1 (NF1) loss, or receptor tyrosine kinase mutations.	('NRAS', 'Gene', (306, 310))	('receptor tyrosine kinase', 'Gene', (354, 378))	('NRAS', 'Gene', '4893', (306, 310))	('loss', 'NegReg', (345, 349))	('receptor tyrosine kinase', 'Gene', '5979', (354, 378))	('alterations', 'Var', (19, 30))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (264, 277))	('Neuroblastoma', 'Disease', 'MESH:D009447', (264, 277))	('NF1', 'Gene', '4763', (340, 343))	('mutations', 'Var', (312, 321))	('NF1', 'Gene', (340, 343))	('MER/ERK pathway', 'Pathway', (155, 170))	('Neurofibromin 1', 'Gene', '4763', (323, 338))	('Neurofibromin 1', 'Gene', (323, 338))	('Neuroblastoma', 'Disease', (264, 277))
70137	33260892	Unlike Class II and Class III RAF-mutations, which may have less aggressive behavior, Class I mutations, namely, BRAF exon 15 p. V600, are associated with a higher degree of tumor aggressiveness and poor prognosis.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (174, 194))	('p. V600', 'Var', (126, 133))	('aggressive behavior', 'Phenotype', 'HP:0000718', (65, 84))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor aggressiveness', 'Disease', (174, 194))	('aggressiveness', 'Phenotype', 'HP:0000718', (180, 194))	('BRAF exon 15', 'Gene', (113, 125))
70138	33260892	Indeed, patients carrying this type of mutation have shorter disease-free survival (DFS) and bleaker overall survival (OS) rates than wild-type patients.	('disease-free survival', 'CPA', (61, 82))	('mutation', 'Var', (39, 47))	('overall', 'MPA', (101, 108))	('patients', 'Species', '9606', (144, 152))	('shorter', 'NegReg', (53, 60))	('patients', 'Species', '9606', (8, 16))
70139	33260892	However, besides its prognostic role, accruing evidence has recently highlighted the role of BRAF exon p.V600 mutations, in particular BRAF exon 15 p. V600E, as predictive biomarkers of response to tyrosine kinase inhibitors (TKIs).	('p.V600 mutations', 'Var', (103, 119))	('BRAF exon', 'Gene', (93, 102))	('V600E', 'Var', (151, 156))	('V600E', 'SUBSTITUTION', 'None', (151, 156))	('BRAF exon 15', 'Gene', (135, 147))
70140	33260892	In this review, we will examine the double facets of BRAF gene alterations in different tumor types to highlight the clinical relevance of this biomarker not only in improving the pathological assessment of human solid neoplasms but also in facilitating treatment decision-making and outcomes.	('men', 'Species', '9606', (199, 202))	('neoplasms', 'Disease', 'MESH:D009369', (219, 228))	('alterations', 'Var', (63, 74))	('neoplasms', 'Disease', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('BRAF gene', 'Gene', (53, 62))	('men', 'Species', '9606', (259, 262))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('neoplasms', 'Phenotype', 'HP:0002664', (219, 228))	('human', 'Species', '9606', (207, 212))	('tumor', 'Disease', (88, 93))
70141	33260892	The presence of BRAF mutations in non-small cell lung cancer (NSCLC) patients was first reported in 2011.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('NSCLC', 'Disease', (62, 67))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (34, 60))	('BRAF', 'Gene', (16, 20))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('patients', 'Species', '9606', (69, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (21, 30))
70143	33260892	For instance, whereas some authors highlight a higher prevalence of BRAF exon 15 p.V600E than BRAF non-p.V600E, others state opposite results.	('exon', 'Var', (73, 77))	('p.V600E', 'Mutation', 'rs113488022', (81, 88))	('p.V600E', 'Var', (81, 88))	('p.V600E', 'Mutation', 'rs113488022', (103, 110))
70145	33260892	Although BRAF mutations are strongly associated with glandular morphology, occasional reports have also described this alteration in small cell carcinoma and in different NSCLC subtypes, such as squamous cell carcinoma, large cell neuroendocrine carcinomas, and pulmonary sarcomatoid carcinomas.	('BRAF', 'Gene', (9, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('pulmonary sarcomatoid carcinomas', 'Disease', 'MESH:C538614', (262, 294))	('glandular morphology', 'Disease', (53, 73))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (133, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('neuroendocrine carcinomas', 'Disease', (231, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (246, 256))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (231, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('associated', 'Reg', (37, 47))	('NSCLC', 'Disease', (171, 176))	('mutations', 'Var', (14, 23))	('large cell neuroendocrine carcinomas', 'Phenotype', 'HP:0030360', (220, 256))	('pulmonary sarcomatoid carcinomas', 'Disease', (262, 294))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (284, 294))	('small cell carcinoma', 'Disease', (133, 153))	('small cell carcinoma', 'Disease', 'MESH:D018288', (133, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (195, 218))	('sarcomatoid carcinomas', 'Phenotype', 'HP:0100242', (272, 294))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (231, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('squamous cell carcinoma', 'Disease', (195, 218))
70146	33260892	Thus, it is conceivable that patients carrying BRAF mutations could be eligible to receive TKI treatments, even in the absence of an adenocarcinoma component.	('mutations', 'Var', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('patients', 'Species', '9606', (29, 37))	('men', 'Species', '9606', (100, 103))	('BRAF', 'Gene', (47, 51))	('adenocarcinoma', 'Disease', (133, 147))	('adenocarcinoma', 'Disease', 'MESH:D000230', (133, 147))
70147	33260892	From an epidemiological point of view, whereas some studies have indicated the higher frequency of BRAF mutations among females and current or former smokers, others have found no specific association between BRAF mutations and sex or tobacco smoking.	('tobacco', 'Species', '4097', (235, 242))	('mutations', 'Var', (104, 113))	('BRAF', 'Gene', (99, 103))
70150	33260892	showed a shorter disease-free survival (DFS) in BRAF exon 15 mutant patients than in wild-type patients.	('patients', 'Species', '9606', (95, 103))	('disease-free survival', 'CPA', (17, 38))	('patients', 'Species', '9606', (68, 76))	('mutant', 'Var', (61, 67))	('shorter', 'NegReg', (9, 16))	('BRAF exon 15', 'Gene', (48, 60))
70151	33260892	Indeed, in their large-scale study aimed at identifying the prevalence of BRAF mutations among Chinese patients with lung adenocarcinoma, they found that the median relapse-free survival (RFS) of patients harboring either BRAF exon 11 or BRAF exon 15 was significantly longer than the RFS of NSCLC patients harboring other types of mutations, including Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Anaplastic Lymphoma Kinase (ALK), Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), or wild-type (47.8 vs. 21.5 months).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('Anaplastic Lymphoma', 'Phenotype', 'HP:0012193', (445, 464))	('RFS', 'Disease', (285, 288))	('NSCLC', 'Disease', 'MESH:D002289', (292, 297))	('patients', 'Species', '9606', (196, 204))	('Sarcoma', 'Phenotype', 'HP:0100242', (406, 413))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (353, 385))	('EGFR', 'Gene', '1956', (387, 391))	('mutations', 'Var', (79, 88))	('ERBB2', 'Gene', '24337', (514, 519))	('Erb-B2 Receptor Tyrosine Kinase 2', 'Gene', (479, 512))	('NSCLC', 'Disease', (292, 297))	('RFS', 'Disease', (188, 191))	('patients', 'Species', '9606', (298, 306))	('relapse-free survival', 'CPA', (165, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (292, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('Anaplastic Lymphoma Kinase', 'Gene', '266802', (445, 471))	('Erb-B2 Receptor Tyrosine Kinase 2', 'Gene', '24337', (479, 512))	('ERBB2', 'Gene', (514, 519))	('Kirsten Rat Sarcoma Viral Oncogene Homolog', 'Gene', '3845', (394, 436))	('Anaplastic Lymphoma Kinase', 'Gene', (445, 471))	('RFS', 'Disease', 'MESH:D005198', (285, 288))	('Kirsten Rat Sarcoma Viral Oncogene Homolog', 'Gene', (394, 436))	('lung adenocarcinoma', 'Disease', (117, 136))	('EGFR', 'Gene', (387, 391))	('RFS', 'Disease', 'MESH:D005198', (188, 191))	('longer', 'PosReg', (269, 275))	('patients', 'Species', '9606', (103, 111))	('Epidermal Growth Factor Receptor', 'Gene', (353, 385))	('Lymphoma', 'Phenotype', 'HP:0002665', (456, 464))	('BRAF exon 11', 'Var', (222, 234))
70152	33260892	observed that the 2-year OS in patients harboring BRAF mutations was lower (57%) than that in patients harboring EGFR mutations (69%) and ALK rearrangements (91%).	('men', 'Species', '9606', (151, 154))	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (55, 64))	('lower', 'NegReg', (69, 74))	('EGFR', 'Gene', '1956', (113, 117))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', (113, 117))
70153	33260892	By contrast, it was higher in KRAS-mutated patients (40%).	('KRAS-mutated', 'Var', (30, 42))	('patients', 'Species', '9606', (43, 51))	('higher', 'PosReg', (20, 26))
70154	33260892	reported that the overall survival rate for patients with BRAF mutations was intermediate between those with KRAS (lower) and those with EGFR (higher) mutations.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', (137, 141))	('patients', 'Species', '9606', (44, 52))	('KRAS', 'Gene', (109, 113))	('EGFR', 'Gene', '1956', (137, 141))
70155	33260892	described an insignificant difference between the OS rates of patients with BRAF exon 15 p.V600E and BRAF non-p.V600E mutations and wild-type patients.	('p.V600E', 'Mutation', 'rs113488022', (89, 96))	('p.V600E', 'Var', (89, 96))	('p.V600E', 'Mutation', 'rs113488022', (110, 117))	('BRAF exon 15', 'Gene', (76, 88))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (62, 70))
70158	33260892	Regarding the types of BRAF mutations influencing OS, the median OS was higher in BRAF exon 15 p.V600E mutants than in BRAF non-p.V600E mutants (25 vs. 13 months, respectively), even in stage IV patients (16 vs. 7 months, respectively).	('p.V600E', 'Mutation', 'rs113488022', (95, 102))	('BRAF exon 15', 'Gene', (82, 94))	('p.V600E', 'Var', (95, 102))	('patients', 'Species', '9606', (195, 203))	('higher', 'PosReg', (72, 78))	('p.V600E', 'Mutation', 'rs113488022', (128, 135))
70159	33260892	Clearly, the prognostic significance of BRAF mutations in lung cancer patients needs further elucidation.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
70160	33260892	BRAF mutations occur in about 40-60% of melanomas.	('melanomas', 'Disease', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('BRAF', 'Gene', (0, 4))
70161	33260892	It involves a T-to-A transversion in nucleotide 1799 (c.1799T>A), which, in turn, determines valine to glutamic acid substitution (p.V600E).	('c.1799T>A', 'Mutation', 'rs113488022', (54, 63))	('valine', 'MPA', (93, 99))	('glutamic acid', 'Chemical', 'MESH:D018698', (103, 116))	('valine', 'Chemical', 'MESH:D014633', (93, 99))	('T-to-A transversion in nucleotide 1799', 'Mutation', 'rs113488022', (14, 52))	('determines', 'Reg', (82, 92))	('c.1799T>A', 'Var', (54, 63))	('p.V600E', 'Mutation', 'rs113488022', (131, 138))
70162	33260892	Less frequently, a substitution from valine to lysine (p.V600K, 10-20%), arginine (p.V600R, 1%), methionine (p.V600M, 0.3%), or aspartic acid (p.V600D, 0.1%) may be observed within codon 600.	('p.V600D', 'Mutation', 'rs121913377', (143, 150))	('aspartic acid', 'Chemical', 'MESH:D001224', (128, 141))	('valine', 'Chemical', 'MESH:D014633', (37, 43))	('p.V600D', 'Var', (143, 150))	('p.V600K', 'Var', (55, 62))	('p.V600M', 'Mutation', 'rs121913378', (109, 116))	('p.V600R', 'Mutation', 'rs121913227', (83, 90))	('p.V600K', 'Mutation', 'rs121913227', (55, 62))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('p.V600R', 'Var', (83, 90))	('arginine', 'Chemical', 'MESH:D001120', (73, 81))	('p.V600M', 'Var', (109, 116))	('methionine', 'Chemical', 'MESH:D008715', (97, 107))
70169	33260892	reported that BRAF-driven cases had a much worse prognosis than stage IV wild-types or NRAS-mutant melanoma patients.	('NRAS', 'Gene', '4893', (87, 91))	('BRAF-driven', 'Var', (14, 25))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('patients', 'Species', '9606', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('NRAS', 'Gene', (87, 91))
70170	33260892	demonstrated a negative prognostic role for BRAF mutations in stage III melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', (44, 48))	('patients', 'Species', '9606', (81, 89))	('negative', 'NegReg', (15, 23))
70171	33260892	confirmed the negative prognostic role of BRAF mutations in melanoma patients.	('patients', 'Species', '9606', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('mutations', 'Var', (47, 56))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('BRAF', 'Gene', (42, 46))
70172	33260892	found an association between BRAF mutations and poor prognosis in stage I and stage II melanoma patients.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('BRAF', 'Gene', (29, 33))	('poor', 'Disease', (48, 52))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (34, 43))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
70174	33260892	The occurrence of BRAF mutation in thyroid cancer is even more complex to analyze.	('thyroid cancer', 'Phenotype', 'HP:0002890', (35, 49))	('thyroid cancer', 'Disease', (35, 49))	('mutation', 'Var', (23, 31))	('thyroid cancer', 'Disease', 'MESH:D013964', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRAF', 'Gene', (18, 22))
70175	33260892	A large body of evidence indicates that the frequency of BRAF mutations (almost exclusively occurring as exon 15 p.V600E; from 18% to 87%) varies among thyroid cancers.	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('p.V600E', 'Mutation', 'rs113488022', (113, 120))	('thyroid cancer', 'Phenotype', 'HP:0002890', (152, 166))	('p.V600E', 'Var', (113, 120))	('thyroid cancers', 'Disease', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('thyroid cancers', 'Disease', 'MESH:D013964', (152, 167))	('mutations', 'Var', (62, 71))
70178	33260892	In addition, our research group has demonstrated that BRAF exon 15 p.V600E point mutations play a diagnostic role in refining the risk of malignancy and treatment options in patients with cytological "indeterminate" nodules.	('p.V600E', 'Var', (67, 74))	('malignancy', 'Disease', 'MESH:D009369', (138, 148))	('patients', 'Species', '9606', (174, 182))	('p.V600E', 'Mutation', 'rs113488022', (67, 74))	('malignancy', 'Disease', (138, 148))	('men', 'Species', '9606', (158, 161))	('BRAF exon 15', 'Gene', (54, 66))
70179	33260892	From a prognostic perspective, BRAF-mutated thyroid carcinomas feature more aggressive behavior and poorer outcomes than wild-types.	('thyroid carcinomas', 'Disease', 'MESH:D013964', (44, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('aggressive behavior', 'Phenotype', 'HP:0000718', (76, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('more', 'PosReg', (71, 75))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (44, 62))	('thyroid carcinomas', 'Disease', (44, 62))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (44, 61))	('BRAF-mutated', 'Var', (31, 43))	('aggressive behavior', 'CPA', (76, 95))
70180	33260892	's 15-year follow-up study demonstrated the poorer prognostic outcome of BRAF exon 15 p.V600E-mutated patients compared to wild-types.	('BRAF exon 15', 'Gene', (73, 85))	('patients', 'Species', '9606', (102, 110))	('p.V600E-mutated', 'Var', (86, 101))	('p.V600E', 'Mutation', 'rs113488022', (86, 93))
70181	33260892	carried out a retrospective multicenter study at 16 centers located in eight countries to investigate the role of the BRAF exon 15 p.V600E variant in PTC recurrence.	('p.V600E', 'Mutation', 'rs113488022', (131, 138))	('PTC', 'Phenotype', 'HP:0002895', (150, 153))	('PTC', 'Disease', (150, 153))	('p.V600E', 'Var', (131, 138))
70182	33260892	Interestingly, their findings indicate that BRAF exon 15 p.V600E point mutation is a prognostic factor independent of the other conventional clinicopathological risk factors generally associated with PTC.	('p.V600E', 'Mutation', 'rs113488022', (57, 64))	('PTC', 'Phenotype', 'HP:0002895', (200, 203))	('PTC', 'Disease', (200, 203))	('p.V600E', 'Var', (57, 64))	('associated', 'Reg', (184, 194))
70183	33260892	In addition, the authors emphasized that even in the early stages (stage I or II) of the disease and in micro-PTC, detection of BRAF exon 15 p.V600E is strongly associated with disease recurrence.	('PTC', 'Phenotype', 'HP:0002895', (110, 113))	('associated with', 'Reg', (161, 176))	('disease', 'Disease', (177, 184))	('p.V600E', 'Mutation', 'rs113488022', (141, 148))	('BRAF exon 15', 'Gene', (128, 140))	('p.V600E', 'Var', (141, 148))
70184	33260892	Likewise, a significant negative correlation between BRAF exon 15 p.V600E point mutations and shorter OS rates was also emphasized in Liu et al.	('BRAF exon 15', 'Gene', (53, 65))	('shorter OS rates', 'MPA', (94, 110))	('negative', 'NegReg', (24, 32))	('p.V600E', 'Mutation', 'rs113488022', (66, 73))	('p.V600E', 'Var', (66, 73))
70185	33260892	Different lines of research have also investigated the epigenetic mechanisms whereby BRAF mutation impairs iodine metabolism.	('impairs', 'NegReg', (99, 106))	('iodine', 'Chemical', 'MESH:D007455', (107, 113))	('BRAF', 'Gene', (85, 89))	('iodine metabolism', 'MPA', (107, 124))	('mutation', 'Var', (90, 98))
70186	33260892	Indeed, BRAF exon 15 p.V600E point mutation promotes the downregulation and silencing of sodium-iodide symporter (NIS), a gene involved in iodine metabolism, by inducing histone deacetylation.	('downregulation', 'NegReg', (57, 71))	('inducing', 'Reg', (161, 169))	('sodium-iodide', 'Chemical', 'MESH:D012974', (89, 102))	('p.V600E', 'Mutation', 'rs113488022', (21, 28))	('NIS', 'Gene', '6528', (114, 117))	('iodine', 'Chemical', 'MESH:D007455', (139, 145))	('silencing', 'MPA', (76, 85))	('histone deacetylation', 'MPA', (170, 191))	('NIS', 'Gene', (114, 117))	('p.V600E point', 'Var', (21, 34))
70187	33260892	This phenomenon explains why BRAF exon 15 p.V600E thyroid carcinomas are resistant to radioiodine treatment.	('men', 'Species', '9606', (10, 13))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (50, 68))	('thyroid carcinomas', 'Disease', (50, 68))	('men', 'Species', '9606', (103, 106))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (50, 67))	('p.V600E', 'Mutation', 'rs113488022', (42, 49))	('p.V600E', 'Var', (42, 49))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (50, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('radioiodine', 'Chemical', 'MESH:C000614965', (86, 97))
70191	33260892	BRAF mutations are much less frequent in CRC, accounting for only 10% of reported cases.	('mutations', 'Var', (5, 14))	('CRC', 'Disease', 'MESH:D015179', (41, 44))	('CRC', 'Disease', (41, 44))
70192	33260892	As for the other cancer types, the vast majority of BRAF mutations occur in codon 600 (exon 15 p.V600E).	('p.V600E', 'Mutation', 'rs113488022', (95, 102))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('p.V600E', 'Var', (95, 102))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (17, 23))	('BRAF', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
70193	33260892	Epidemiologically, BRAF-mutated CRCs are detected more frequently in women and older patients (>70 years).	('BRAF-mutated', 'Var', (19, 31))	('CRC', 'Disease', (32, 35))	('patients', 'Species', '9606', (85, 93))	('women', 'Species', '9606', (69, 74))	('CRC', 'Disease', 'MESH:D015179', (32, 35))
70194	33260892	Morphologically, BRAF-mutated CRCs are primarily located in the proximal colon (right side) and show mucinous, serrated, and poorly differentiated histology.	('CRC', 'Disease', (30, 33))	('CRC', 'Disease', 'MESH:D015179', (30, 33))	('BRAF-mutated', 'Var', (17, 29))
70195	33260892	Concerning the subtypes of BRAF mutations, non-p.V600E mutations seem to occur more frequently in men and younger patients, have low-grade histology, and are localized on the distal colon site, in contrast to BRAF exon 15 p.V600E mutations.	('p.V600E', 'Mutation', 'rs113488022', (222, 229))	('p.V600E', 'Mutation', 'rs113488022', (47, 54))	('non-p.V600E mutations', 'Var', (43, 64))	('BRAF', 'Gene', (27, 31))	('men', 'Species', '9606', (98, 101))	('patients', 'Species', '9606', (114, 122))
70197	33260892	Epigenetically, BRAF-mutated CRCs feature a high CpG island methylator phenotype (CIMP-H) and high microsatellite instability (MSI-H).	('BRAF-mutated', 'Var', (16, 28))	('high', 'PosReg', (44, 48))	('CRC', 'Disease', (29, 32))	('MSI', 'Gene', (127, 130))	('microsatellite instability', 'MPA', (99, 125))	('MSI', 'Gene', '5928', (127, 130))	('CRC', 'Disease', 'MESH:D015179', (29, 32))
70198	33260892	Regarding its impact on prognosis, CRC patients with BRAF exon 15 p.V600E mutations show lower OS, DFS, and cancer-specific survival (CSS) rates than wild-type patients, despite the stage of the disease (II or III) or the adoption of chemotherapeutic regimens after surgery.	('BRAF exon 15', 'Gene', (53, 65))	('DFS', 'MPA', (99, 102))	('p.V600E mutations', 'Var', (66, 83))	('lower', 'NegReg', (89, 94))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (160, 168))	('p.V600E', 'Mutation', 'rs113488022', (66, 73))	('CRC', 'Disease', 'MESH:D015179', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('men', 'Species', '9606', (255, 258))	('CRC', 'Disease', (35, 38))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
70200	33260892	highlighted that BRAF exon 15 p.V600E mutant CRC patients have a worse prognosis in terms of OS regardless of age, stage (II to IV), and tumor site compared to BRAF wild-type patients.	('p.V600E', 'Mutation', 'rs113488022', (30, 37))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('p.V600E', 'Var', (30, 37))	('CRC', 'Disease', 'MESH:D015179', (45, 48))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (49, 57))	('CRC', 'Disease', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
70201	33260892	Notably, the authors also observed that BRAF exon 15 p.V600E mutant CRC patients featuring microsatellite-stable (MSS) tumor patterns had significantly lower OS rates than MSI tumors, regardless of the stage of the disease (II to IV).	('CRC', 'Disease', 'MESH:D015179', (68, 71))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('p.V600E', 'Var', (53, 60))	('tumor', 'Disease', (176, 181))	('CRC', 'Disease', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('OS rates', 'MPA', (158, 166))	('lower', 'NegReg', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('MSI', 'Gene', '5928', (172, 175))	('MSI', 'Gene', (172, 175))	('p.V600E', 'Mutation', 'rs113488022', (53, 60))	('patients', 'Species', '9606', (72, 80))
70202	33260892	Conversely, BRAF mutations did not influence the better prognosis of MSI CRCs.	('CRC', 'Disease', (73, 76))	('MSI', 'Gene', '5928', (69, 72))	('CRC', 'Disease', 'MESH:D015179', (73, 76))	('MSI', 'Gene', (69, 72))	('mutations', 'Var', (17, 26))
70203	33260892	In their experience, the authors observed that BRAF-mutated CRC patients were characterized by worse outcomes than BRAF wild-type cases.	('patients', 'Species', '9606', (64, 72))	('CRC', 'Disease', 'MESH:D015179', (60, 63))	('BRAF-mutated', 'Var', (47, 59))	('CRC', 'Disease', (60, 63))
70205	33260892	Interestingly, BRAF mutations only slightly affected the outcome of MSI-H tumors.	('BRAF', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MSI-H tumors', 'Disease', 'MESH:D009369', (68, 80))	('MSI-H tumors', 'Disease', (68, 80))	('mutations', 'Var', (20, 29))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
70206	33260892	Back in 2009, findings from FOCUS, a large, multicenter clinical trial, indicated that although BRAF mutation did not significantly affect progression-free survival (PFS), it did have a worse impact on the OS of patients, compared with wild-types.	('mutation', 'Var', (101, 109))	('BRAF', 'Gene', (96, 100))	('patients', 'Species', '9606', (212, 220))
70208	33260892	In addition, the authors further observed that proficient mismatch repair (pMMR) of CRC tumors harboring BRAF mutations had a lower median PFS and OS than BRAF wild-types.	('lower', 'NegReg', (126, 131))	('mutations', 'Var', (110, 119))	('CRC tumors', 'Disease', (84, 94))	('CRC tumors', 'Disease', 'MESH:D015179', (84, 94))	('BRAF', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('PFS', 'MPA', (139, 142))
70209	33260892	Another broad pooled analysis, assessing the independent negative prognostic role of BRAF mutations in OS, revealed that BRAF-mutant patients had a worse prognosis even after metastasectomy.	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (90, 99))	('BRAF-mutant', 'Gene', (121, 132))	('BRAF', 'Gene', (85, 89))
70211	33260892	Besides the high incidence of BRAF mutants in the neoplasms mentioned above, other less common entities may also feature BRAF mutations.	('neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('mutants', 'Var', (35, 42))	('BRAF', 'Gene', (30, 34))	('neoplasms', 'Disease', 'MESH:D009369', (50, 59))	('neoplasms', 'Disease', (50, 59))	('men', 'Species', '9606', (60, 63))	('mutations', 'Var', (126, 135))
70213	33260892	These lesions are highly frequent among pediatric patients harboring BRAF p.V600E point mutations and have poorer outcomes than wild-type patients.	('patients', 'Species', '9606', (50, 58))	('p.V600E', 'Mutation', 'rs113488022', (74, 81))	('BRAF', 'Gene', (69, 73))	('p.V600E', 'Var', (74, 81))	('patients', 'Species', '9606', (138, 146))
70214	33260892	Conversely, glioblastoma patients harboring BRAF exon 15 p.V600E have the same prognosis as wild-type patients, despite the prevalence of epithelioid morphology without isocitrate dehydrogenase (IDH) alterations.	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('isocitrate dehydrogenase', 'Gene', (169, 193))	('IDH', 'Gene', (195, 198))	('isocitrate dehydrogenase', 'Gene', '3417', (169, 193))	('epithelioid', 'Disease', (138, 149))	('p.V600E', 'Mutation', 'rs113488022', (57, 64))	('patients', 'Species', '9606', (102, 110))	('IDH', 'Gene', '3417', (195, 198))	('p.V600E', 'Var', (57, 64))	('patients', 'Species', '9606', (25, 33))	('glioblastoma', 'Disease', (12, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (12, 24))
70217	33260892	In addition, BRAF gene alterations may be a rare cause of anti-human epidermal growth factor receptor 2 (HER2) therapy resistance.	('HER2', 'Gene', (105, 109))	('epidermal growth factor receptor 2', 'Gene', '2064', (69, 103))	('human', 'Species', '9606', (63, 68))	('HER2', 'Gene', '2064', (105, 109))	('epidermal growth factor receptor 2', 'Gene', (69, 103))	('BRAF gene', 'Gene', (13, 22))	('alterations', 'Var', (23, 34))	('cause', 'Reg', (49, 54))
70218	33260892	Finally, BRAF mutations have also been detected in ovarian cancer.	('BRAF', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('detected', 'Reg', (39, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('mutations', 'Var', (14, 23))	('ovarian cancer', 'Disease', (51, 65))
70219	33260892	rather recently observed that BRAF mutations had better prognostic outcomes in early-stage low-grade serous ovarian cancer.	('serous ovarian cancer', 'Disease', (101, 122))	('BRAF', 'Gene', (30, 34))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (101, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (35, 44))
70220	33260892	The authors hypothesized that the better OS rates in these patients were due to the possibility that BRAF mutations in patients with serous borderline disease prevent progression to more aggressive stages.	('BRAF', 'Gene', (101, 105))	('serous', 'Disease', 'MESH:D018284', (133, 139))	('progression', 'CPA', (167, 178))	('patients', 'Species', '9606', (119, 127))	('serous', 'Disease', (133, 139))	('patients', 'Species', '9606', (59, 67))	('mutations', 'Var', (106, 115))	('prevent', 'NegReg', (159, 166))
70221	33260892	Besides having a prognostic role, BRAF mutations have also emerged as positive predictive markers for identifying NSCLC patients who might benefit from the administration of targeted therapy.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (114, 119))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (120, 128))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('BRAF', 'Gene', (34, 38))
70222	33260892	Considerable evidence has demonstrated that BRAF inhibitors, namely, vemurafenib and dabrafenib, effectively work against BRAF exon 15 p. V600-positive tumor cells.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('work', 'Reg', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('BRAF exon 15', 'Gene', (122, 134))	('vemurafenib', 'Chemical', 'MESH:D000077484', (69, 80))	('tumor', 'Disease', (152, 157))	('p. V600-positive', 'Var', (135, 151))	('dabrafenib', 'Chemical', 'MESH:C561627', (85, 95))
70223	33260892	In a large study in which vemurafenib was administered to pretreated nonmelanoma BRAF exon 15 p.V600E-mutated patients, an objective response was observed in 42% of NSCLC patients, with a median PFS of 7.3 months and a 12-month PFS rate of 23%.	('p.V600E-mutated', 'Var', (94, 109))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('nonmelanoma BRAF', 'Disease', 'None', (69, 85))	('nonmelanoma BRAF', 'Disease', (69, 85))	('patients', 'Species', '9606', (171, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('p.V600E', 'Mutation', 'rs113488022', (94, 101))	('vemurafenib', 'Chemical', 'MESH:D000077484', (26, 37))	('patients', 'Species', '9606', (110, 118))	('NSCLC', 'Disease', (165, 170))
70227	33260892	In a phase I dose-escalation trial, dabrafenib showed safety and efficacy in different solid tumors harboring BRAF exon 15 p.V600 point mutations, including NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('solid tumors', 'Disease', (87, 99))	('dabrafenib', 'Chemical', 'MESH:C561627', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('BRAF exon 15', 'Gene', (110, 122))	('NSCLC', 'Disease', (157, 162))	('p.V600 point mutations', 'Var', (123, 145))
70228	33260892	Noteworthy, in one study, dabrafenib was successfully adopted when a BRAF exon 15 p.V600E-mutated lung adenocarcinoma patient became resistant to vemurafenib.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('p.V600E', 'Mutation', 'rs113488022', (82, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('dabrafenib', 'Chemical', 'MESH:C561627', (26, 36))	('vemurafenib', 'Chemical', 'MESH:D000077484', (146, 157))	('p.V600E-mutated', 'Var', (82, 97))	('lung adenocarcinoma', 'Disease', (98, 117))	('resistant', 'MPA', (133, 142))	('patient', 'Species', '9606', (118, 125))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))
70229	33260892	demonstrated the efficacy of different targeted therapies (vemurafenib, dabrafenib, sorafenib) in advanced-stage NSCLC patients harboring BRAF mutations.	('vemurafenib', 'Chemical', 'MESH:D000077484', (59, 70))	('BRAF', 'Gene', (138, 142))	('patients', 'Species', '9606', (119, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('sorafenib', 'Chemical', 'MESH:D000077157', (84, 93))	('NSCLC', 'Disease', (113, 118))	('dabrafenib', 'Chemical', 'MESH:C561627', (72, 82))	('mutations', 'Var', (143, 152))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
70230	33260892	They observed that the OS of patients receiving targeted therapies was longer in patients harboring a BRAF exon 15 p.V600E mutation than in those harboring non-p.V600E mutations (25.3 vs. 11.8 months).	('p.V600E', 'Mutation', 'rs113488022', (160, 167))	('patients', 'Species', '9606', (29, 37))	('BRAF exon 15', 'Gene', (102, 114))	('p.V600E', 'Var', (115, 122))	('patients', 'Species', '9606', (81, 89))	('p.V600E', 'Mutation', 'rs113488022', (115, 122))
70231	33260892	The efficacy of dabrafenib as monotherapy, or in combination with other drugs, has also been investigated in a phase-II clinical trial involving 84 BRAF (exon 15 p.V600E)-positive NSCLC patients.	('p.V600E', 'Var', (162, 169))	('p.V600E', 'Mutation', 'rs113488022', (162, 169))	('NSCLC', 'Disease', (180, 185))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))	('patients', 'Species', '9606', (186, 194))	('BRAF', 'Gene', (148, 152))
70233	33260892	In Cohorts B and C, dabrafenib, together with trametinib, was administered to previously treated and untreated advanced-stage NSCLC patients harboring the BRAF exon 15 p.V600E point mutation.	('trametinib', 'Chemical', 'MESH:C560077', (46, 56))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('p.V600E', 'Mutation', 'rs113488022', (168, 175))	('dabrafenib', 'Chemical', 'MESH:C561627', (20, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('p.V600E point', 'Var', (168, 181))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))
70235	33260892	After these promising results, the combination of dabrafenib and trametinib was approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for advanced-stage NSCLC patients harboring a BRAF exon 15 p.V600E point mutation, irrespective of previous treatments.	('patients', 'Species', '9606', (194, 202))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('p.V600E point', 'Var', (228, 241))	('men', 'Species', '9606', (282, 285))	('dabrafenib', 'Chemical', 'MESH:C561627', (50, 60))	('trametinib', 'Chemical', 'MESH:C560077', (65, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('p.V600E', 'Mutation', 'rs113488022', (228, 235))	('BRAF exon 15', 'Gene', (215, 227))	('NSCLC', 'Disease', (188, 193))
70237	33260892	Indeed, this inhibitor has a broad spectrum efficacy by acting on several types of kinases in BRAF non-p.V600-mutated patients (exon 11 p.G469R and exon 11 p.G469V).	('acting', 'Reg', (56, 62))	('p.G469V', 'Var', (156, 163))	('p.G469V', 'Mutation', 'rs121913355', (156, 163))	('exon 11 p.G469V', 'Var', (148, 163))	('p.G469R', 'Var', (136, 143))	('p.G469R', 'Mutation', 'rs121913357', (136, 143))	('exon 11 p.G469R', 'Var', (128, 143))	('patients', 'Species', '9606', (118, 126))
70238	33260892	Among these are BRAF, CRAF, KIT Proto-Oncogene, Receptor Tyrosine Kinase (c-KIT), Fms Related Receptor Tyrosine Kinase 3 (FLT-3), Rearranged During Transfection (RET), Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2), VEGFR-3 and Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) in BRAF non-p.V600-mutated patients (exon 11 p.G469R and exon 11 p.G469V).	('FLT-3', 'Gene', '2322', (122, 127))	('Platelet-Derived Growth Factor Receptor Alpha', 'Gene', '5156', (237, 282))	('Rearranged During Transfection', 'Gene', '5979', (130, 160))	('Fms Related Receptor Tyrosine Kinase 3', 'Gene', (82, 120))	('PDGFRA', 'Gene', (284, 290))	('PDGFRA', 'Gene', '5156', (284, 290))	('RET', 'Gene', (162, 165))	('p.G469R', 'Var', (337, 344))	('c-KIT', 'Gene', (74, 79))	('Vascular Endothelial Growth Factor Receptor 2', 'Gene', '3791', (168, 213))	('Platelet-Derived Growth Factor Receptor Alpha', 'Gene', (237, 282))	('c-KIT', 'Gene', '3815', (74, 79))	('FLT-3', 'Gene', (122, 127))	('Vascular Endothelial Growth Factor Receptor 2', 'Gene', (168, 213))	('VEGFR-3', 'Gene', '2324', (225, 232))	('VEGFR-2', 'Gene', '3791', (215, 222))	('p.G469V', 'Mutation', 'rs121913355', (357, 364))	('p.G469R', 'Mutation', 'rs121913357', (337, 344))	('Rearranged During Transfection', 'Gene', (130, 160))	('patients', 'Species', '9606', (319, 327))	('Fms Related Receptor Tyrosine Kinase 3', 'Gene', '2322', (82, 120))	('RET', 'Gene', '5979', (162, 165))	('p.G469V', 'Var', (357, 364))	('KIT Proto-Oncogene, Receptor Tyrosine Kinase', 'Gene', '3815;5979', (28, 72))	('VEGFR-3', 'Gene', (225, 232))	('VEGFR-2', 'Gene', (215, 222))
70239	33260892	Finally, two phase-I clinical trials demonstrated the efficacy and safety of ERK inhibitors (e.g., ulixertinib, an ERK1/2 kinase inhibitor) and pan-RAF inhibitors (e.g., LY3009120) in BRAF-mutant patients.	('BRAF-mutant', 'Disease', (184, 195))	('ERK1/2', 'Gene', (115, 121))	('LY3009120', 'Chemical', 'MESH:C000600963', (170, 179))	('ulixertinib', 'Chemical', 'MESH:C000618314', (99, 110))	('patients', 'Species', '9606', (196, 204))	('ERK1/2', 'Gene', '5595;5594', (115, 121))	('ERK', 'Protein', (77, 80))	('LY3009120', 'Var', (170, 179))
70240	33260892	Like in lung cancer, BRAF mutations, in particular, exon 15 p. V600 point mutations, feature a positive predictive role in melanoma patients for the administration of TKIs.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('p. V600 point mutations', 'Var', (60, 83))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('lung cancer', 'Disease', (8, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))	('patients', 'Species', '9606', (132, 140))
70241	33260892	In the BRIM-3 randomized, phase III clinical trial, the effect of vemurafenib on PFS and OS rates was compared with standard chemotherapy treatment (dacarbazine) in advanced-stage previously untreated melanoma patients harboring a BRAF exon 15 p.V600E point mutation.	('melanoma', 'Disease', (201, 209))	('vemurafenib', 'Chemical', 'MESH:D000077484', (66, 77))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('p.V600E', 'Mutation', 'rs113488022', (244, 251))	('patients', 'Species', '9606', (210, 218))	('men', 'Species', '9606', (143, 146))	('BRAF exon 15', 'Gene', (231, 243))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('dacarbazine', 'Chemical', 'MESH:D003606', (149, 160))	('p.V600E point', 'Var', (244, 257))
70243	33260892	Likewise, in an extended follow-up analysis on the overall population of the BRIM-3 clinical trial, the authors confirmed the efficacy of vemurafenib on OS rates in advanced-stage previously untreated melanoma patients harboring BRAF exon 15 p.V600E or other less common exon 15 p.V600 point mutations compared with dacarbazine.	('OS rates', 'MPA', (153, 161))	('melanoma', 'Disease', (201, 209))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('p.V600E', 'Var', (242, 249))	('p.V600 point', 'Var', (279, 291))	('vemurafenib', 'Chemical', 'MESH:D000077484', (138, 149))	('BRAF exon', 'Gene', (229, 238))	('dacarbazine', 'Chemical', 'MESH:D003606', (316, 327))	('patients', 'Species', '9606', (210, 218))	('p.V600E', 'Mutation', 'rs113488022', (242, 249))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
70244	33260892	In another phase III, randomized, controlled clinical trial, in which the efficacy of dacarbazine was compared with the BRAF inhibitor dabrafenib, similar results were obtained in terms of PFS and OS in advanced-stage previously untreated melanoma patients harboring BRAF exon 15 p.V600 point mutations (p.V600E and p.V600K).	('BRAF exon 15', 'Gene', (267, 279))	('p.V600E', 'Mutation', 'rs113488022', (304, 311))	('p.V600K', 'Var', (316, 323))	('p.V600K', 'Mutation', 'rs121913227', (316, 323))	('p.V600E', 'Var', (304, 311))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('p.V600 point', 'Var', (280, 292))	('dacarbazine', 'Chemical', 'MESH:D003606', (86, 97))	('patients', 'Species', '9606', (248, 256))	('dabrafenib', 'Chemical', 'MESH:C561627', (135, 145))
70247	33260892	In advanced-stage previously untreated melanoma patients harboring BRAF exon 15 p.V600 point mutations (p.V600E and p.V600K), such a combination significantly improved PFS (11.0 versus 8.8 months, respectively), OS (25.1 versus 18.7 months, respectively), and overall response rates (69.0% versus 53.0%, respectively) compared with dabrafenib alone.	('p.V600K', 'Mutation', 'rs121913227', (116, 123))	('PFS', 'MPA', (168, 171))	('improved', 'PosReg', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('dabrafenib', 'Chemical', 'MESH:C561627', (332, 342))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('p.V600E', 'Mutation', 'rs113488022', (104, 111))	('p.V600 point', 'Var', (80, 92))	('patients', 'Species', '9606', (48, 56))	('p.V600E', 'Var', (104, 111))	('p.V600K', 'Var', (116, 123))
70250	33260892	Even in this case, the combination of the two drugs significantly improved OS and PFS rates in previously untreated advanced-stage BRAF exon 15 p.V600-mutated melanoma patients treated with the combination therapy compared with vemurafenib plus placebo (control group).	('p.V600-mutated', 'Var', (144, 158))	('melanoma', 'Disease', (159, 167))	('PFS rates', 'MPA', (82, 91))	('improved', 'PosReg', (66, 74))	('vemurafenib', 'Chemical', 'MESH:D000077484', (228, 239))	('patients', 'Species', '9606', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
70252	33260892	In the COLUMBUS phase III clinical trial, previously treated or untreated advanced-stage melanoma patients harboring BRAF exon 15 p.V600E or p.V600K point mutations were randomly assigned to receive the combination regimen or single BRAF inhibitor therapies (vemurafenib or encorafenib).	('p.V600E', 'Mutation', 'rs113488022', (130, 137))	('men', 'Species', '9606', (219, 222))	('encorafenib', 'Chemical', 'MESH:C000601108', (274, 285))	('p.V600E', 'Var', (130, 137))	('patients', 'Species', '9606', (98, 106))	('p.V600K', 'Mutation', 'rs121913227', (141, 148))	('p.V600K point mutations', 'Var', (141, 164))	('BRAF exon 15', 'Gene', (117, 129))	('vemurafenib', 'Chemical', 'MESH:D000077484', (259, 270))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
70254	33260892	Interestingly, the association of BRAF and MEK inhibitors demonstrated a higher PFS (8 versus 3.7 months, respectively) and OS (17.3 versus 7.3 months, respectively) with respect to BRAF inhibitors alone in patients harboring rare BRAF non-p.V600 point mutations.	('MEK', 'Gene', '5609', (43, 46))	('patients', 'Species', '9606', (207, 215))	('BRAF', 'Gene', (231, 235))	('non-p.V600 point mutations', 'Var', (236, 262))	('MEK', 'Gene', (43, 46))	('BRAF', 'Gene', (34, 38))	('PFS', 'MPA', (80, 83))	('association', 'Interaction', (19, 30))
70256	33260892	In murine models, in fact, TKIs favor immunotherapy activity by increasing tumor-infiltrating lymphocytes.	('increasing', 'PosReg', (64, 74))	('TKIs', 'Var', (27, 31))	('favor', 'PosReg', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('immunotherapy activity', 'CPA', (38, 60))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
70259	33260892	Based on the results of the phase-III clinical trial IMspire 150, the FDA approved the use of the latter triple combination for advanced-stage melanoma patients harboring BRAF exon 15 p.V600 point mutations.	('p.V600 point mutations', 'Var', (184, 206))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('patients', 'Species', '9606', (152, 160))
70261	33260892	The efficacy of the combination strategy with debrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) was strongly demonstrated in NCI-MATCH Trial Subprotocol H. Overall, in this study, which enrolled patients with different cancer types harboring BRAF exon 15 p.V600 mutations, an ORR of 38% was reached.	('patients', 'Species', '9606', (204, 212))	('debrafenib', 'Chemical', '-', (46, 56))	('cancer', 'Disease', (228, 234))	('BRAF exon 15', 'Gene', (251, 263))	('trametinib', 'Chemical', 'MESH:C560077', (78, 88))	('MEK', 'Gene', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('MEK', 'Gene', '5609', (90, 93))	('p.V600 mutations', 'Var', (264, 280))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
70263	33260892	However, as previously reported, BRAF exon 15 p.V600E-mutated thyroid carcinomas are resistant to the radioiodine treatment approach.	('p.V600E', 'Mutation', 'rs113488022', (46, 53))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('p.V600E-mutated', 'Var', (46, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (62, 80))	('radioiodine', 'Chemical', 'MESH:C000614965', (102, 113))	('men', 'Species', '9606', (119, 122))	('thyroid carcinomas', 'Disease', (62, 80))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (62, 80))
70265	33260892	More recently, the efficacy of BRAF inhibitors vemurafenib for advanced-stage BRAF exon 15 p.V600E-mutated thyroid cancer patients refractory to radioiodine treatment and dabrafenib for BRAF exon 15 p.V600E-mutated metastatic PTC patients has been demonstrated.	('thyroid cancer', 'Disease', (107, 121))	('metastatic PTC', 'Disease', (215, 229))	('BRAF exon 15', 'Gene', (78, 90))	('p.V600E', 'Mutation', 'rs113488022', (91, 98))	('thyroid cancer', 'Phenotype', 'HP:0002890', (107, 121))	('radioiodine', 'Chemical', 'MESH:C000614965', (145, 156))	('thyroid cancer', 'Disease', 'MESH:D013964', (107, 121))	('men', 'Species', '9606', (162, 165))	('dabrafenib', 'Chemical', 'MESH:C561627', (171, 181))	('p.V600E-mutated', 'Var', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (122, 130))	('p.V600E', 'Mutation', 'rs113488022', (199, 206))	('p.V600E-mutated', 'Var', (199, 214))	('PTC', 'Phenotype', 'HP:0002895', (226, 229))	('vemurafenib', 'Chemical', 'MESH:D000077484', (47, 58))
70267	33260892	Conversely, the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib showed promising results and tolerability in BRAF exon 15 p.V600E-mutated unresectable or metastatic anaplastic thyroid carcinoma patients and obtained FDA approval.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (206, 223))	('p.V600E-mutated', 'Var', (152, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('MEK', 'Gene', (69, 72))	('dabrafenib', 'Chemical', 'MESH:C561627', (50, 60))	('MEK', 'Gene', '5609', (69, 72))	('unresectable', 'Disease', (168, 180))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (195, 223))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (195, 223))	('trametinib', 'Chemical', 'MESH:C560077', (83, 93))	('anaplastic thyroid carcinoma', 'Disease', (195, 223))	('patients', 'Species', '9606', (224, 232))	('p.V600E', 'Mutation', 'rs113488022', (152, 159))
70269	33260892	The combination strategy approach seemed to be more effective in CRC patients harboring a BRAF exon 15 p.V600E point mutation with respect to single-agent regimens.	('p.V600E point', 'Var', (103, 116))	('men', 'Species', '9606', (159, 162))	('CRC', 'Disease', 'MESH:D015179', (65, 68))	('p.V600E', 'Mutation', 'rs113488022', (103, 110))	('BRAF exon 15', 'Gene', (90, 102))	('patients', 'Species', '9606', (69, 77))	('CRC', 'Disease', (65, 68))
70270	33260892	In the BEACON CRC phase III clinical trial, metastatic CRC patients harboring a BRAF exon 15 p.V600E point mutation, with disease progression after one or two previous treatment regimens, were randomized to receive encorafenib (BRAF inhibitor), binimetinib (MEK inhibitor), and cetuximab (anti-EGFR) or encorafenib and cetuximab, or other treatment approaches, including cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan).	('cetuximab', 'Chemical', 'MESH:D000068818', (278, 287))	('men', 'Species', '9606', (344, 347))	('CRC', 'Disease', 'MESH:D015179', (55, 58))	('irinotecan', 'Chemical', 'MESH:D000077146', (385, 395))	('cetuximab', 'Chemical', 'MESH:D000068818', (371, 380))	('p.V600E', 'Mutation', 'rs113488022', (93, 100))	('cetuximab', 'Chemical', 'MESH:D000068818', (319, 328))	('binimetinib', 'Chemical', 'MESH:C581313', (245, 256))	('MEK', 'Gene', '5609', (258, 261))	('CRC', 'Disease', 'MESH:D015179', (14, 17))	('fluorouracil', 'Chemical', 'MESH:D005472', (436, 448))	('patients', 'Species', '9606', (59, 67))	('encorafenib', 'Chemical', 'MESH:C000601108', (303, 314))	('irinotecan', 'Chemical', 'MESH:D000077146', (454, 464))	('men', 'Species', '9606', (182, 185))	('EGFR', 'Gene', (294, 298))	('folinic acid', 'Chemical', 'MESH:D002955', (422, 434))	('encorafenib', 'Chemical', 'MESH:C000601108', (215, 226))	('MEK', 'Gene', (258, 261))	('men', 'Species', '9606', (173, 176))	('CRC', 'Disease', (55, 58))	('FOLFIRI', 'Chemical', '-', (413, 420))	('p.V600E point', 'Var', (93, 106))	('cetuximab', 'Chemical', 'MESH:D000068818', (399, 408))	('EGFR', 'Gene', '1956', (294, 298))	('BRAF exon 15', 'Gene', (80, 92))	('CRC', 'Disease', (14, 17))
70272	33260892	These data demonstrated the clinical efficacy of the combination strategy (encorafenib, binimetinib, and cetuximab) in previously treated metastatic CRC patients harboring a BRAF exon 15 p.V600E point mutation.	('CRC', 'Disease', (149, 152))	('encorafenib', 'Chemical', 'MESH:C000601108', (75, 86))	('patients', 'Species', '9606', (153, 161))	('p.V600E', 'Var', (187, 194))	('CRC', 'Disease', 'MESH:D015179', (149, 152))	('binimetinib', 'Chemical', 'MESH:C581313', (88, 99))	('cetuximab', 'Chemical', 'MESH:D000068818', (105, 114))	('p.V600E', 'Mutation', 'rs113488022', (187, 194))
70273	33260892	The combination strategy, with the BRAF inhibitor dabrafenib plus MEK inhibitor trametinib, demonstrated promising efficacy in patients with recurrent or refractory BRAF exon 15 p.V600E-mutated high-grade and low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('p.V600E', 'Mutation', 'rs113488022', (178, 185))	('MEK', 'Gene', (66, 69))	('dabrafenib', 'Chemical', 'MESH:C561627', (50, 60))	('MEK', 'Gene', '5609', (66, 69))	('patients', 'Species', '9606', (127, 135))	('gliomas', 'Disease', (219, 226))	('p.V600E-mutated', 'Var', (178, 193))	('trametinib', 'Chemical', 'MESH:C560077', (80, 90))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))
70274	33260892	BRAF mutations are reported in about 7% of solid tumors, with a high prevalence in PTC, melanoma, colorectal cancer, and lung cancer.	('colorectal cancer', 'Disease', (98, 115))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('reported', 'Reg', (19, 27))	('BRAF', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (43, 55))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('mutations', 'Var', (5, 14))	('lung cancer', 'Disease', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PTC', 'Disease', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('solid tumors', 'Disease', 'MESH:D009369', (43, 55))	('PTC', 'Phenotype', 'HP:0002895', (83, 86))
70275	33260892	Located at codon 600 of exon 15, most of these mutations result in an amino acid substitution of valine to glutamic acid (p.V600E).	('glutamic acid', 'Chemical', 'MESH:D018698', (107, 120))	('valine', 'Chemical', 'MESH:D014633', (97, 103))	('result in', 'Reg', (57, 66))	('mutations', 'Var', (47, 56))	('p.V600E', 'Mutation', 'rs113488022', (122, 129))	('p.V600E', 'Var', (122, 129))
70276	33260892	Overall, about 200 BRAF mutant variants have been described in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('variants', 'Var', (31, 39))	('human', 'Species', '9606', (63, 68))	('mutant variants', 'Var', (24, 39))	('BRAF', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
70277	33260892	In fact, although BRAF mutations are typically associated with a negative prognostic role especially in, lung cancer, melanoma, thyroid, and CRC, their positive predictive role has recently emerged in melanoma, lung cancer, thyroid carcinoma, CRC, and other cancers, such as glioma patients.	('glioma', 'Disease', (275, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('CRC', 'Disease', (243, 246))	('CRC', 'Disease', 'MESH:D015179', (141, 144))	('glioma', 'Disease', 'MESH:D005910', (275, 281))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('thyroid', 'Disease', (128, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (224, 241))	('mutations', 'Var', (23, 32))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('cancers', 'Disease', 'MESH:D009369', (258, 265))	('patients', 'Species', '9606', (282, 290))	('lung cancer', 'Disease', (211, 222))	('thyroid carcinoma', 'Disease', (224, 241))	('CRC', 'Disease', 'MESH:D015179', (243, 246))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CRC', 'Disease', (141, 144))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (224, 241))	('lung cancer', 'Disease', (105, 116))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma', 'Disease', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('BRAF', 'Gene', (18, 22))	('cancers', 'Disease', (258, 265))
70278	33260892	For this reason, implementing BRAF mutational analysis, alongside other clinically relevant gene alterations, is pivotal in selecting patients for targeted treatments.	('patients', 'Species', '9606', (134, 142))	('BRAF', 'Gene', (30, 34))	('men', 'Species', '9606', (22, 25))	('mutational analysis', 'Var', (35, 54))	('men', 'Species', '9606', (161, 164))
70279	33260892	Noticeably, our research team at the Predictive Molecular Laboratory (Department of Public Health, University of Naples Federico II, Naples, Italy) has designed, developed, and validated a narrow NGS custom panel, named SiRe , that is able to cover 568 mutations in six genes of clinical interest involved in four solid tumors: NSCLCs, CRCs, melanomas, and gastrointestinal stromal tumors.	('men', 'Species', '9606', (76, 79))	('melanoma', 'Phenotype', 'HP:0002861', (342, 350))	('NSCLCs', 'Disease', (328, 334))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (357, 388))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (357, 388))	('mutations', 'Var', (253, 262))	('CRC', 'Disease', (336, 339))	('melanomas', 'Disease', 'MESH:D008545', (342, 351))	('solid tumors', 'Disease', (314, 326))	('melanomas', 'Disease', (342, 351))	('NSCLCs', 'Disease', 'MESH:D002289', (328, 334))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('gastrointestinal stromal tumors', 'Disease', (357, 388))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('NSCLC', 'Phenotype', 'HP:0030358', (328, 333))	('solid tumors', 'Disease', 'MESH:D009369', (314, 326))	('CRC', 'Disease', 'MESH:D015179', (336, 339))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('melanomas', 'Phenotype', 'HP:0002861', (342, 351))	('tumors', 'Phenotype', 'HP:0002664', (382, 388))	('involved', 'Reg', (297, 305))
70282	33260892	Indeed, besides its well-documented prognostic role, BRAF mutations are emerging as crucial predictive markers in personalized cancer therapy.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRAF', 'Gene', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('men', 'Species', '9606', (29, 32))	('cancer', 'Disease', (127, 133))
70284	33260892	Therefore, correct identification of BRAF mutations, together with other types of aberrant molecular markers, is key to selecting patients for target treatments.	('patients', 'Species', '9606', (130, 138))	('men', 'Species', '9606', (155, 158))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', (37, 41))
70286	33260892	However, the efficacy, as well as safety profiles, of these treatments may vary among the different subsets of mutant BRAF tumors.	('BRAF tumors', 'Disease', (118, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('men', 'Species', '9606', (65, 68))	('mutant', 'Var', (111, 117))	('BRAF tumors', 'Disease', 'MESH:D009369', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
70298	31827999	In cancers of indistinct histology, variants can define subsets of tumors that have distinctive biological features and clinical characteristics which then inform prognosis.	('inform', 'Reg', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('variants', 'Var', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
70300	31827999	Detection of variants that confirm a cancer predisposition syndrome may inform the need for ongoing cancer surveillance and testing of family members.	('variants', 'Var', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
70301	31827999	While many variants have known clinical implications, the prognostic significance of recurring genomic lesions for many cancers remains undefined.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('variants', 'Var', (11, 19))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
70303	31827999	Consequently, only a few variants implicated in pediatric tumors have an approved targeted therapy in any tumor type.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('variants', 'Var', (25, 33))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
70315	31827999	Actionable mutations were defined as those which altered diagnosis, altered treatment, or diagnosed a cancer predisposition syndrome.	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('altered', 'Reg', (49, 56))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('diagnosed', 'Reg', (90, 99))	('altered', 'Reg', (68, 75))
70326	31827999	Interestingly, one patient with 186 VUS had a presumptive history of neurofibromatosis type 1 (NF1) based on cutaneous stigmata but was found instead to have congenital mismatch repair deficiency (CMMRD) with an MSH6 mutation.	('deficiency', 'Disease', 'MESH:D007153', (185, 195))	('patient', 'Species', '9606', (19, 26))	('MSH6', 'Gene', '2956', (212, 216))	('NF1', 'Gene', (95, 98))	('NF1', 'Gene', '4763', (95, 98))	('neurofibromatosis type 1', 'Gene', '4763', (69, 93))	('neurofibromatosis type 1', 'Gene', (69, 93))	('mutation', 'Var', (217, 225))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (69, 86))	('MSH6', 'Gene', (212, 216))	('deficiency', 'Disease', (185, 195))
70328	31827999	The remaining patients all had low TMB (seven or fewer mutations per megabase).	('TMB', 'MPA', (35, 38))	('mutations', 'Var', (55, 64))	('TMB', 'Chemical', '-', (35, 38))	('low', 'NegReg', (31, 34))	('patients', 'Species', '9606', (14, 22))
70335	31827999	Detectable mutations by NGS in patients with low-grade gliomas included V600E (N = 2), BRAF KIAA-1549 (N = 3) EGFR (N = 1), PDGFR (N = 1) and Gli 1 (N = 1).	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('NGS', 'Gene', (24, 27))	('PDGFR', 'Gene', (124, 129))	('gliomas', 'Disease', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('EGFR', 'Gene', '1956', (110, 114))	('Gli 1', 'Gene', '2735', (142, 147))	('EGFR', 'Gene', (110, 114))	('PDGFR', 'Gene', '5159', (124, 129))	('V600E', 'Var', (72, 77))	('Gli 1', 'Gene', (142, 147))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('patients', 'Species', '9606', (31, 39))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))	('V600E', 'Mutation', 'rs113488022', (72, 77))
70337	31827999	Tumor NGS demonstrated mutations that were consistent with a previously suspected but unconfirmed cancer predisposition syndrome in four cases (NF1, neurofibromatosis type 2, Von Hippel Lindau syndrome, and Gorlin syndrome), confirmed CMMRD in one patient previously thought to have NF1 and helped exclude Carney complex, tuberous sclerosis complex, and NF1 in three cases.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Von Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (175, 201))	('tuberous sclerosis', 'Disease', (322, 340))	('cancer', 'Disease', (98, 104))	('patient', 'Species', '9606', (248, 255))	('NF1', 'Gene', (144, 147))	('CMMRD', 'Gene', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NF1', 'Gene', '4763', (354, 357))	('Carney complex', 'Disease', (306, 320))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (149, 166))	('mutations', 'Var', (23, 32))	('NF1', 'Gene', '4763', (283, 286))	('NF1', 'Gene', (354, 357))	('neurofibromatosis', 'Disease', 'MESH:C537392', (149, 166))	('NF1', 'Gene', (283, 286))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Von Hippel Lindau syndrome', 'Disease', (175, 201))	('neurofibromatosis', 'Disease', (149, 166))	('confirmed', 'Reg', (225, 234))	('NF1', 'Gene', '4763', (144, 147))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (322, 340))
70342	31827999	Approximately half of high-grade diffuse gliomas show epidermal growth factor receptor (EGFR) 7p12 amplification, and a subset of them (approximately 20%) have an intragenic deletion of exons 2-7 (EGFRvIII variant), which leads to a constitutively activated truncated receptor.	('leads to', 'Reg', (222, 230))	('constitutively activated truncated receptor', 'MPA', (233, 276))	('epidermal growth factor receptor', 'Gene', '1956', (54, 86))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('gliomas', 'Disease', (41, 48))	('deletion', 'Var', (174, 182))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', '1956', (197, 201))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('epidermal growth factor receptor', 'Gene', (54, 86))	('EGFR', 'Gene', (88, 92))	('EGFR', 'Gene', (197, 201))
70344	31827999	Additionally, five patients had mutations detected in the tumor suggesting a cancer predisposition syndrome (Von Hippel Lindau syndrome, Gorlin syndrome, NF1 and NF2, and CMMRD), which were then confirmed in the germline.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patients', 'Species', '9606', (19, 27))	('cancer', 'Disease', (77, 83))	('NF1', 'Gene', (154, 157))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('NF1', 'Gene', '4763', (154, 157))	('NF2', 'Gene', (162, 165))	('mutations', 'Var', (32, 41))	('Gorlin syndrome', 'Disease', (137, 152))	('Von Hippel Lindau syndrome', 'Disease', (109, 135))	('Von Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (109, 135))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('NF2', 'Gene', '4771', (162, 165))
70346	31827999	There may be unrecognized novel cancer predisposition mutations that are therefore not confirmed in the germline, as was seen in a prior study.	('cancer', 'Disease', (32, 38))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))
70351	31827999	For example, the now well-known driver genetic alterations for pilocytic astrocytoma and pilomyxoid astrocytoma have been characterized in the MAPK pathway (most commonly BRAF-KIAA1459 fusion, but also NF1 mutations, BRAF V600E mutation, BRAF intragenic deletions, and BRAF fusions with other partners).	('BRAF', 'Gene', '673', (238, 242))	('BRAF', 'Gene', (238, 242))	('pilocytic astrocytoma and pilomyxoid astrocytoma', 'Disease', 'MESH:D001254', (63, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('fusions', 'Var', (274, 281))	('NF1', 'Gene', '4763', (202, 205))	('BRAF', 'Gene', '673', (269, 273))	('MAPK pathway', 'Pathway', (143, 155))	('mutations', 'Var', (206, 215))	('BRAF', 'Gene', (269, 273))	('V600E mutation', 'Var', (222, 236))	('deletions', 'Var', (254, 263))	('BRAF', 'Gene', '673', (171, 175))	('NF1', 'Gene', (202, 205))	('BRAF', 'Gene', (171, 175))	('V600E', 'Mutation', 'rs113488022', (222, 227))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('BRAF', 'Gene', '673', (217, 221))	('BRAF', 'Gene', (217, 221))
70355	31827999	While the more common BRAF V600E and BRAF-KIAA1459 fusion mutations can be detected through non-sequencing technologies such as fluorescence in situ hybridization (FISH) or immunohistochemistry, these techniques will not detect the less common mutations observed in low-grade gliomas such as EGFR mutations or less common BRAF mutations.	('EGFR', 'Gene', '1956', (292, 296))	('V600E', 'Var', (27, 32))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (322, 326))	('BRAF', 'Gene', '673', (322, 326))	('EGFR', 'Gene', (292, 296))	('gliomas', 'Disease', (276, 283))	('mutations', 'Var', (297, 306))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', '673', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (276, 283))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('BRAF', 'Gene', (22, 26))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))
70377	31827999	Variants in the relapsed tumor may arise through tumor evolution that could indicate a new targetable lesion or resistance to specific treatment options.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Variants', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
70378	31827999	The time elapsed between tumor resection and molecular profiling may impact the clinical relevance of detected variants proportionate to tumor grade, with high-grade tumors evolving more rapidly.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (166, 171))	('variants', 'Var', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('impact', 'Reg', (69, 75))	('tumors', 'Disease', (166, 172))	('clinical relevance', 'MPA', (80, 98))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
70382	31827999	NGS enabled comprehensive identification of targetable mutations, nuanced histopathologic diagnosis, informed prognosis, suggested constitutional and familial testing for cancer predisposition syndromes, and suggested molecular targets worthy of further study.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutations', 'Var', (55, 64))
70387	31827999	NGS led to a change in diagnosis, the discovery of a cancer predisposition syndrome, and altered the course of treatment in a significant proportion of cases.	('change', 'Reg', (13, 19))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('diagnosis', 'MPA', (23, 32))	('NGS', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('altered', 'Reg', (89, 96))
70449	31725652	This might be the reason why high b-value DWI maps are more effective in malignancy grading of tumors than normal b-value DWI maps.	('high b-value', 'Var', (29, 41))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('malignancy', 'Disease', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
70462	30351999	BRAF Inhibition in BRAFV600-Mutant Gliomas: Results From the VE-BASKET Study BRAFV600 mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (235, 247))	('BRAF', 'Gene', '673', (0, 4))	('glioma', 'Disease', (202, 208))	('BRAF', 'Gene', (0, 4))	('Gliomas', 'Disease', 'MESH:D005910', (35, 42))	('glioblastoma', 'Disease', (235, 247))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioblastoma', 'Phenotype', 'HP:0012174', (235, 247))	('Gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('mutations', 'Var', (86, 95))	('found', 'Reg', (111, 116))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (155, 184))	('glioma', 'Disease', (128, 134))	('BRAF', 'Gene', '673', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('BRAF', 'Gene', (77, 81))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('glioma subtypes', 'Disease', 'MESH:D005910', (128, 143))	('Gliomas', 'Disease', (35, 42))	('BRAF', 'Gene', '673', (19, 23))	('pleomorphic xanthoastrocytoma', 'Disease', (155, 184))	('BRAF', 'Gene', (19, 23))	('glioma subtypes', 'Disease', (128, 143))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))
70463	30351999	We sought to determine the activity of vemurafenib, a selective inhibitor of BRAFV600, in patients with gliomas that harbor this mutation.	('gliomas', 'Disease', (104, 111))	('mutation', 'Var', (129, 137))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('patients', 'Species', '9606', (90, 98))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('vemurafenib', 'Chemical', 'MESH:D000077484', (39, 50))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
70486	30351999	Selective targeting of oncogenic mutations has revolutionized the treatment of genomically defined subtypes of non-small-cell lung cancer (NSCLC), breast, gastric, and ovarian cancers, melanoma, and other solid and hematologic cancers.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('mutations', 'Var', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('non-small-cell lung cancer', 'Disease', (111, 137))	('hematologic cancers', 'Disease', (215, 234))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (111, 137))	('ovarian cancers', 'Phenotype', 'HP:0100615', (168, 183))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('breast', 'Disease', (147, 153))	('hematologic cancers', 'Disease', 'MESH:D009369', (215, 234))	('NSCLC', 'Disease', (139, 144))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('gastric', 'Disease', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('ovarian cancers', 'Disease', (168, 183))	('ovarian cancers', 'Disease', 'MESH:D010051', (168, 183))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
70489	30351999	Of importance, BRAFV600 mutations have been identified in several glioma subtypes, specifically in select rare IDH1/2 wild-type gliomas, including PXAs (38% to 100%), gangliogliomas (18% to 57%), anaplastic gangliogliomas (AGGs; 50%), PAs (9%), and less commonly (< 3%) in high-grade gliomas, including GBM.	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('PAs', 'Disease', 'MESH:D011471', (235, 238))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('gliomas', 'Disease', 'MESH:D005910', (284, 291))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('mutations', 'Var', (24, 33))	('PXAs', 'Chemical', '-', (147, 151))	('BRAF', 'Gene', '673', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (284, 290))	('BRAF', 'Gene', (15, 19))	('gangliogliomas', 'Disease', 'MESH:D018303', (167, 181))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('gliomas', 'Phenotype', 'HP:0009733', (284, 291))	('glioma subtypes', 'Disease', 'MESH:D005910', (66, 81))	('PAs', 'Disease', (235, 238))	('gliomas', 'Disease', (128, 135))	('gangliogliomas', 'Disease', 'MESH:D018303', (207, 221))	('gangliogliomas', 'Disease', (167, 181))	('glioma subtypes', 'Disease', (66, 81))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('PXAs', 'Disease', (147, 151))	('gliomas', 'Disease', (174, 181))	('GBM', 'Phenotype', 'HP:0012174', (303, 306))	('gangliogliomas', 'Disease', (207, 221))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('gliomas', 'Disease', (284, 291))	('gliomas', 'Disease', (214, 221))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('identified', 'Reg', (44, 54))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))
70503	30351999	Patients with brain tumors were required to have histologically confirmed glioma (any grade) and confirmation of BRAFV600 mutation in tumor material obtained at any point in treatment.	('BRAF', 'Gene', '673', (113, 117))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('BRAF', 'Gene', (113, 117))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Disease', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('brain tumors', 'Disease', 'MESH:D001932', (14, 26))	('brain tumors', 'Phenotype', 'HP:0030692', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('brain tumors', 'Disease', (14, 26))	('brain tumor', 'Phenotype', 'HP:0030692', (14, 25))	('tumor', 'Disease', (20, 25))
70504	30351999	Testing for BRAFV600 mutation was performed according to local testing procedures in a Clinical Laboratories Improvement Amendment-accredited laboratory or equivalent for sites outside the United States.	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('mutation', 'Var', (21, 29))
70506	30351999	As the clinical trial database did not capture glioma-specific biomarkers (methylguanine-DNA-methyltransferase [MGMT] promoter methylation, IDH1 mutation, or CDKN2A/B deletion), these data, when available, were extracted directly from pathology reports without source verification by the study sponsor.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH1', 'Gene', '3417', (140, 144))	('CDKN2A/B', 'Gene', (158, 166))	('methylguanine-DNA-methyltransferase', 'Gene', (75, 110))	('glioma', 'Disease', (47, 53))	('deletion', 'Var', (167, 175))	('IDH1', 'Gene', (140, 144))	('MGMT', 'Gene', (112, 116))	('CDKN2A/B', 'Gene', '1029;1030', (158, 166))	('methylguanine-DNA-methyltransferase', 'Gene', '4255', (75, 110))	('MGMT', 'Gene', '4255', (112, 116))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('mutation', 'Var', (145, 153))
70552	30351999	The highest response rate was observed in patients with low-grade tumors, particularly PXA, a histology in which BRAFV600 mutations seem to be a common and early genomic event.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (42, 50))	('PXA', 'Disease', (87, 90))
70564	30351999	The incidence of BRAFV600 mutations is age dependent in patients with gangliogliomas, although the etiology that underlies this association is unclear.	('patients', 'Species', '9606', (56, 64))	('BRAF', 'Gene', '673', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('mutations', 'Var', (26, 35))	('BRAF', 'Gene', (17, 21))	('gangliogliomas', 'Disease', (70, 84))	('gangliogliomas', 'Disease', 'MESH:D018303', (70, 84))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
70574	30351999	The clinical trial was not designed to collect glioma biomarkers, such as MGMT promoter methylation, IDH mutation, or CDKN2A/B deletion status, although we were ultimately able to gather available data on most patients.	('CDKN2A/B', 'Gene', '1029;1030', (118, 126))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH', 'Gene', '3417', (101, 104))	('CDKN2A/B', 'Gene', (118, 126))	('glioma', 'Disease', (47, 53))	('MGMT', 'Gene', (74, 78))	('IDH', 'Gene', (101, 104))	('MGMT', 'Gene', '4255', (74, 78))	('patients', 'Species', '9606', (210, 218))	('deletion status', 'Var', (127, 142))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
70578	30351999	Moreover, prior studies have demonstrated mutual exclusivity between IDH and BRAFV600 mutations in gliomas, which indicates that this biomarker might not be relevant in our cohort.	('mutations', 'Var', (86, 95))	('IDH', 'Gene', (69, 72))	('BRAF', 'Gene', '673', (77, 81))	('gliomas', 'Disease', (99, 106))	('BRAF', 'Gene', (77, 81))	('IDH', 'Gene', '3417', (69, 72))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
70587	30351999	Several such studies that permit the enrollment of pediatric or adult patients with glioma are currently ongoing (ClinicalTrials.gov identifiers: NCT01748149, NCT01677741, NCT02124772, NCT02684058, NCT02285439, and NCT03429803).	('patients', 'Species', '9606', (70, 78))	('NCT03429803', 'Var', (215, 226))	('NCT02285439', 'Var', (198, 209))	('NCT01677741', 'Var', (159, 170))	('glioma', 'Disease', (84, 90))	('NCT02684058', 'Var', (185, 196))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('NCT01748149', 'Var', (146, 157))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('NCT02124772', 'Var', (172, 183))
70617	26973806	While the exact role of each subset has not been precisely defined in the context of neovascularization and tumor invasion, it has been shown that BMDCs do in fact help create a niche capable of sustaining tumor growth by breaking down normal structures to promote neovascularization and tumor proliferation.	('tumor', 'Disease', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('neovascularization', 'CPA', (265, 283))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('promote', 'PosReg', (257, 264))	('breaking down', 'NegReg', (222, 235))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('normal structures', 'CPA', (236, 253))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('BMDCs', 'Var', (147, 152))	('breaking down', 'Phenotype', 'HP:0001061', (222, 235))
70650	25469866	Its deregulated high expression is causally linked to many diseases, including heart failure, thrombosis, atherosclerosis, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('heart failure', 'Disease', (79, 92))	('thrombosis', 'Disease', (94, 104))	('atherosclerosis', 'Disease', 'MESH:D050197', (106, 121))	('atherosclerosis', 'Phenotype', 'HP:0002621', (106, 121))	('deregulated', 'Var', (4, 15))	('linked', 'Reg', (44, 50))	('cancer', 'Disease', (127, 133))	('thrombosis', 'Disease', 'MESH:D013927', (94, 104))	('atherosclerosis', 'Disease', (106, 121))	('heart failure', 'Disease', 'MESH:D006333', (79, 92))	('heart failure', 'Phenotype', 'HP:0001635', (79, 92))
70669	25469866	The membranes were blocked for 1 h by 2% milk (Bio-Rad) in PBST (0.1% Tween-20 in PBS) and then incubated with the following antibodies overnight at 4  C: anti-TNC (Abcam), anti-CD133 (Millipore), and anti-beta-actin (Abcam).	('anti-TNC', 'Var', (155, 163))	('anti-CD133', 'Var', (173, 183))	('Tween-20', 'Chemical', 'MESH:D011136', (70, 78))	('beta-actin', 'Gene', (206, 216))	('beta-actin', 'Gene', '728378', (206, 216))
70677	33922264	Moreover, the functional modules formed by the harmful genes were consistently associated with cell cycle in 12 out of the 16 cancer types and pan-cancer, showing that dysregulation of the cell cycle could harm patient prognosis in cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('associated', 'Reg', (79, 89))	('pan', 'Gene', '51816', (143, 146))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (168, 199))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (232, 238))	('cell', 'Disease', (95, 99))	('harm', 'NegReg', (206, 210))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('dysregulation', 'Var', (168, 181))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patient prognosis', 'CPA', (211, 228))	('cancer', 'Disease', (147, 153))	('patient', 'Species', '9606', (211, 218))	('pan', 'Gene', (143, 146))
70700	33922264	We observed that as the p-value increased, the effect size increased at first, and then decreased afterward (Figure 1A,B, left panel).	('pan', 'Gene', (127, 130))	('p-value', 'Var', (24, 31))	('pan', 'Gene', '51816', (127, 130))
70708	33922264	Additionally, we performed the proposed approach to detect SIGs in pan-cancer.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('SIGs', 'Var', (59, 63))	('cancer', 'Disease', (71, 77))	('pan', 'Gene', (67, 70))	('pan', 'Gene', '51816', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
70722	33922264	Moreover, around 90% of harmful and protective genes are in less than two cancer types, and no genes are survival influential in more than eight cancer types (Figure S1).	('cancer', 'Disease', (145, 151))	('genes', 'Var', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
70749	33922264	Through this analysis, we could pinpoint the molecular mechanisms by which the SIGs are involved in carcinogenesis affect patient prognosis.	('carcinogenesis', 'Disease', (100, 114))	('affect', 'Reg', (115, 121))	('patient', 'Species', '9606', (122, 129))	('SIGs', 'Var', (79, 83))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('involved', 'Reg', (88, 96))
70800	33922264	High expression of CDC20 showed an association with tumor recurrence and patient death in bladder cancer and pancreatic cancer.	('bladder cancer', 'Disease', (90, 104))	('death', 'Disease', 'MESH:D003643', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('High', 'Var', (0, 4))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('tumor', 'Disease', (52, 57))	('death', 'Disease', (81, 86))	('CDC20', 'Gene', (19, 24))	('CDC20', 'Gene', '991', (19, 24))	('patient', 'Species', '9606', (73, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('pancreatic cancer', 'Disease', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('association', 'Reg', (35, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
70801	33922264	Additionally, high expression of CDC20 was significantly associated with overall survival in advanced clinical stage (stage III and IV) patients with colorectal cancer.	('colorectal cancer', 'Disease', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CDC20', 'Gene', (33, 38))	('CDC20', 'Gene', '991', (33, 38))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (136, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('associated with', 'Reg', (57, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('overall survival', 'MPA', (73, 89))
70802	33922264	A meta-analysis report from five studies on approximately 700 colorectal patients showed that high expression of PLK1 was associated with worse patient survival.	('PLK1', 'Gene', (113, 117))	('patient', 'Species', '9606', (144, 151))	('colorectal', 'Disease', 'MESH:D015179', (62, 72))	('patient', 'Species', '9606', (73, 80))	('PLK1', 'Gene', '5347', (113, 117))	('patients', 'Species', '9606', (73, 81))	('high', 'Var', (94, 98))	('colorectal', 'Disease', (62, 72))
70803	33922264	Moreover, multivariate cox regression analysis, after adjusting for clinicopathological factors confirmed that high PLK1 expression at the protein level was independently associated with poor outcome in patients with lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (217, 245))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (217, 245))	('expression', 'MPA', (121, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('cox', 'Gene', (23, 26))	('patients', 'Species', '9606', (203, 211))	('lung squamous cell carcinoma', 'Disease', (217, 245))	('PLK1', 'Gene', (116, 120))	('PLK1', 'Gene', '5347', (116, 120))	('cox', 'Gene', '1351', (23, 26))	('associated', 'Reg', (171, 181))	('high', 'Var', (111, 115))
70806	33922264	Finally, we obtained 6584 samples in total (Figure S10A) and around 17,690 detectable genes on average (Figure S10B) across 16 cancer types (Table S5).	('S10B', 'Var', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('S10A', 'Var', (51, 55))	('S10B', 'SUBSTITUTION', 'None', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('S10A', 'SUBSTITUTION', 'None', (51, 55))
70849	31984309	Hypoxia drives transient site-specific copy alterations and increases the mutation frequency of key cancer genes.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('copy alterations', 'Var', (39, 55))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('increases', 'PosReg', (60, 69))	('mutation frequency', 'MPA', (74, 92))
70858	31984309	Hypoxia can also cause resistance to gefitinib in both EGFR mutant and wild-type non-small-cell lung cancer (NSCLC).	('EGFR', 'Gene', '1956', (55, 59))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('Hypoxia', 'Disease', (0, 7))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('EGFR', 'Gene', (55, 59))	('cause', 'Reg', (17, 22))	('resistance', 'MPA', (23, 33))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gefitinib', 'Chemical', 'MESH:C419708', (37, 46))	('mutant', 'Var', (60, 66))	('NSCLC', 'Disease', (109, 114))
70877	31984309	We further excluded kidney renal clear cell carcinoma (KIRC) and colon adenocarcinoma (COAD) samples with relatively high mutation frequency in VHL (>= 5%), which directly regulates HIF1A to induce pseudohypoxia.	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (65, 85))	('kidney renal clear cell carcinoma', 'Disease', (20, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('pseudohypoxia', 'Disease', (198, 211))	('VHL', 'Disease', (144, 147))	('HIF1A', 'Gene', (182, 187))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (20, 53))	('pseudohypoxia', 'Disease', 'None', (198, 211))	('HIF1A', 'Gene', '3091', (182, 187))	('VHL', 'Disease', 'MESH:D006623', (144, 147))	('regulates', 'Reg', (172, 181))	('mutation frequency', 'Var', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('colon adenocarcinoma', 'Disease', (65, 85))
70950	31984309	For example, miR-375 positively correlated (drug-resistant) to A-443654 (Rs = 0.37, FDR = 9.0 x 10-4), PLX4720 (Rs = 0.39, FDR = 9.4 x 10-5) and vinblastine (Rs = 0.35, FDR = 8.5 x 10-4), and miR-200a-3p positively correlated (drug-resistant) to A-443654 (Rs = 0.35, FDR = 1.3 x 10-4), PLX4720 (Rs = 0.29, FDR = 6.1 x 10-3) and vinblastine (Rs = 0.44, FDR = 1.2 x 10-5).	('A-443654', 'Chemical', 'MESH:C504035', (246, 254))	('A-443654', 'Var', (63, 71))	('PLX4720', 'Chemical', 'MESH:C528407', (286, 293))	('miR', 'Gene', (13, 16))	('PLX4720', 'Chemical', 'MESH:C528407', (103, 110))	('miR', 'Gene', (192, 195))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', '220972', (192, 195))	('vinblastine', 'Chemical', 'MESH:D014747', (145, 156))	('miR-375', 'Gene', '494324', (13, 20))	('A-443654', 'Chemical', 'MESH:C504035', (63, 71))	('A-443654', 'Var', (246, 254))	('vinblastine', 'Chemical', 'MESH:D014747', (328, 339))	('miR-375', 'Gene', (13, 20))	('PLX4720', 'Var', (286, 293))
70951	31984309	For 29 genes overexpressed in hypoxia score-low samples, we also observed a similar regulatory network in that the downregulation of gene expression was consistent with hypermethylation of promoter regions and upregulation of miRNAs, and highly correlated to response to anti-cancer drugs (Supplementary Fig.	('hypoxia', 'Disease', (30, 37))	('hypermethylation', 'Var', (169, 185))	('gene expression', 'MPA', (133, 148))	('cancer', 'Disease', (276, 282))	('hypoxia', 'Disease', 'MESH:D000860', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('miR', 'Gene', '220972', (226, 229))	('miR', 'Gene', (226, 229))	('upregulation', 'PosReg', (210, 222))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('downregulation', 'NegReg', (115, 129))
70954	31984309	For example, TP53 had significantly higher mutation frequency in hypoxia score-high tumors across multiple cancer types: 62.3% (137/220) and 73.5% (83/113) of samples had TP53 mutations in hypoxia score-high BCRA and LUAD, while only 8.0% (19/236) and 34.6% (44/127) of samples had TP53 mutations in hypoxia score-low BRCA and LUAD, respectively (Fig.	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (176, 185))	('hypoxia score-high tumors across multiple cancer', 'Disease', 'MESH:D009369', (65, 113))	('LUAD', 'Phenotype', 'HP:0030078', (217, 221))	('LUAD', 'Phenotype', 'HP:0030078', (327, 331))	('cancer type', 'Disease', (107, 118))	('hypoxia', 'Disease', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('cancer type', 'Disease', 'MESH:D009369', (107, 118))	('TP53', 'Gene', (171, 175))	('LUAD', 'Disease', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TP53', 'Gene', (282, 286))	('hypoxia', 'Disease', 'MESH:D000860', (65, 72))	('TP53', 'Gene', '7157', (13, 17))	('hypoxia', 'Disease', (300, 307))	('BRCA and LUAD', 'Gene', '672', (318, 331))	('hypoxia', 'Disease', 'MESH:D000860', (300, 307))	('hypoxia', 'Disease', (189, 196))	('TP53', 'Gene', '7157', (171, 175))	('TP53', 'Gene', '7157', (282, 286))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('hypoxia', 'Disease', 'MESH:D000860', (189, 196))	('hypoxia score-high tumors across multiple cancer', 'Disease', (65, 113))
70955	31984309	This is consistent with previous reports that mutations of p53 contribute to diminished oxygen consumption.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutations', 'Var', (46, 55))	('diminished', 'NegReg', (77, 87))	('oxygen', 'Chemical', 'MESH:D010100', (88, 94))	('oxygen consumption', 'MPA', (88, 106))
70956	31984309	We further observed that TP53 mutations were associated with reduced drug response to the BRAF inhibitor, AZ-628 (FDR = 5.0 x 10-4; Fig.	('BRAF', 'Gene', (90, 94))	('TP53', 'Gene', (25, 29))	('drug response to the', 'MPA', (69, 89))	('AZ-628', 'Chemical', 'MESH:C000592454', (106, 112))	('mutations', 'Var', (30, 39))	('reduced drug response', 'Phenotype', 'HP:0020173', (61, 82))	('BRAF', 'Gene', '673', (90, 94))	('TP53', 'Gene', '7157', (25, 29))	('reduced', 'NegReg', (61, 68))
70958	31984309	In contrast, IDH1 has 95.5% (63/66) mutation frequency in hypoxia score-low samples, while it only has 38.1% (32/84) in hypoxia score-high samples in LGG.	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('hypoxia', 'Disease', (120, 127))	('IDH1', 'Gene', (13, 17))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('IDH1', 'Gene', '3417', (13, 17))	('mutation', 'Var', (36, 44))
70959	31984309	Mutation of IDH1 promotes the degradation of HIF1alpha, thus reducing the hypoxic effects in tumors and leading to better patient survival times (log-rank test, p = 2.6 x 10-13, Supplementary Fig.	('reducing', 'NegReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1', 'Gene', (12, 16))	('patient', 'Species', '9606', (122, 129))	('Mutation', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('HIF1alpha', 'Gene', (45, 54))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('better', 'PosReg', (115, 121))	('degradation', 'MPA', (30, 41))	('hypoxic', 'Disease', 'MESH:D000860', (74, 81))	('IDH1', 'Gene', '3417', (12, 16))	('tumors', 'Disease', (93, 99))	('HIF1alpha', 'Gene', '3091', (45, 54))	('hypoxic', 'Disease', (74, 81))	('patient survival times', 'CPA', (122, 144))
70960	31984309	Hypoxia can induce transient site-specific copy number gains in tumor cells.	('gains', 'PosReg', (55, 60))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('tumor', 'Disease', (64, 69))	('Hypoxia', 'Disease', (0, 7))	('copy number', 'Var', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
70966	31984309	Deletion of 2q37.3 (FDR = 4.2 x 10-3) occurred more frequently in hypoxia score-high samples.	('2q37.3', 'Gene', (12, 18))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('occurred', 'Reg', (38, 46))	('Deletion', 'Var', (0, 8))
70969	31984309	For example, 7q31.2 amplification, which harbors MET, occurred more frequently in hypoxia score-low KIRP (FDR = 5.3 x 10-3).	('7q31.2', 'Gene', (13, 19))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('occurred', 'Reg', (54, 62))	('amplification', 'Var', (20, 33))
70970	31984309	Deletion of 9p23, which harbors CDKN2A and CDKN2B, occurred more frequently in hypoxia score-low BRCA (FDR = 0.014).	('CDKN2A', 'Gene', (32, 38))	('CDKN2B', 'Gene', (43, 49))	('BRCA', 'Gene', '672', (97, 101))	('CDKN2A', 'Gene', '1029', (32, 38))	('CDKN2B', 'Gene', '1030', (43, 49))	('BRCA', 'Gene', (97, 101))	('hypoxia', 'Disease', (79, 86))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('occurred', 'Reg', (51, 59))	('Deletion', 'Var', (0, 8))
70974	31984309	For example, EGFR was biased in hypoxia score-high samples with overexpression of total proteins or phosphorylated proteins in eight cancer types (e.g., ESCA, diff = 0.54, FDR = 5.5 x 10-5; BLCA, diff = 0.42, FDR = 7.1 x 10-3), amplification in two cancer types (STAD, FDR = 0.022; LGG, FDR = 6.5 x 10-5) and hypomethylation in two cancer types (cervical squamous cell carcinoma and endocervical adenocarcinoma [CESC], diff = -0.29, FDR = 1.8 x 10-8; ESCA, diff = -0.24, FDR = 4.5 x 10-8).	('cervical squamous cell carcinoma', 'Disease', (346, 378))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (346, 378))	('cancer type', 'Disease', (249, 260))	('EGFR', 'Gene', '1956', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (355, 378))	('hypoxia', 'Disease', (32, 39))	('cancer type', 'Disease', 'MESH:D009369', (249, 260))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (383, 410))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('ESCA', 'Phenotype', 'HP:0011459', (153, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (401, 410))	('EGFR', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancer type', 'Disease', (133, 144))	('cancer type', 'Disease', (332, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('hypomethylation', 'Var', (309, 324))	('cancer type', 'Disease', 'MESH:D009369', (133, 144))	('cancer type', 'Disease', 'MESH:D009369', (332, 343))	('ESCA', 'Phenotype', 'HP:0011459', (451, 455))	('endocervical adenocarcinoma', 'Disease', (383, 410))
71002	31984309	These molecular alterations that are driven by the hypoxia microenvironment will likely impact a broad range of biological processes, including metabolic reprogramming, angiogenesis, apoptosis, and multiple signaling pathways.	('impact', 'Reg', (88, 94))	('angiogenesis', 'CPA', (169, 181))	('alterations', 'Var', (16, 27))	('metabolic reprogramming', 'CPA', (144, 167))	('hypoxia', 'Disease', (51, 58))	('hypoxia', 'Disease', 'MESH:D000860', (51, 58))	('apoptosis', 'CPA', (183, 192))
71028	31984309	We kept 24 cancer types with sample size >= 100, and filtered KIRC and COAD samples with relatively high mutation frequency in VHL (>= 5%) to avoid effects of pseudohypoxia in the tumors.	('mutation', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('VHL', 'Disease', 'MESH:D006623', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer type', 'Disease', (11, 22))	('VHL', 'Disease', (127, 130))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('pseudohypoxia in the tumors', 'Disease', (159, 186))	('pseudohypoxia in the tumors', 'Disease', 'MESH:D009369', (159, 186))	('cancer type', 'Disease', 'MESH:D009369', (11, 22))
71043	31984309	A549 and H1299 were purchased from the American Type Culture Collection (ATCC) and Characterized Cell Line Core Facility (MD Anderson Cancer Center) and were cultured in DMEM supplemented with 10% FBS (Gibco) at 37  C in 5% CO2 (v/v).	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('H1299', 'CellLine', 'CVCL:0060', (9, 14))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MD Anderson Cancer Center', 'Disease', 'MESH:D009369', (122, 147))	('MD Anderson Cancer Center', 'Disease', (122, 147))	('CO2', 'Chemical', 'MESH:D002245', (224, 227))	('H1299', 'Var', (9, 14))
71044	31984309	AKT-inhibitor-VIII (612847-09-3) was purchased from Cayman Chemical; PHA-665752 (S1070), camptothecin (S1288) and bexarotene (S2098) were purchased from Selleckchem.	('AKT', 'Gene', (0, 3))	('S1070', 'Chemical', 'MESH:C104856', (81, 86))	('S2098', 'Chemical', 'MESH:C574489', (126, 131))	('camptothecin', 'Chemical', 'MESH:D002166', (89, 101))	('bexarotene', 'Chemical', 'MESH:C095105', (114, 124))	('S2098', 'Var', (126, 131))	('PHA-665752', 'Chemical', 'MESH:C480541', (69, 79))	('S1288', 'Chemical', 'MESH:D002117', (103, 108))	('AKT', 'Gene', '207', (0, 3))	('S1070', 'Var', (81, 86))	('S1288', 'Var', (103, 108))
71045	31984309	Plates were incubated in normoxic conditions (37 C, 5% CO2, 21% O2) or in hypoxic conditions (37 C, 5% CO2, 1% O2).	('O2', 'Chemical', 'MESH:D013481', (56, 58))	('O2', 'Chemical', 'MESH:D013481', (104, 106))	('hypoxic conditions', 'Disease', 'MESH:D009135', (74, 92))	('O2', 'Chemical', 'MESH:D013481', (111, 113))	('CO2', 'Chemical', 'MESH:D002245', (55, 58))	('O2', 'Chemical', 'MESH:D013481', (64, 66))	('CO2', 'Chemical', 'MESH:D002245', (103, 106))	('hypoxic conditions', 'Disease', (74, 92))	('37 C, 5% CO2', 'Var', (94, 106))
71055	28781988	LGGs are classified into molecular subtypes based on alterations in TP53, isocitrate dehydrogenase (IDH) 1 or 2, telomerase reverse transcriptase (TERT), and the transcriptional regulator ATRX: the mutational status of these genes correlates with clinical responses and outcomes.	('LGGs', 'Disease', (0, 4))	('TERT', 'Gene', (147, 151))	('ATRX', 'Gene', '546', (188, 192))	('isocitrate dehydrogenase (IDH) 1 or 2', 'Gene', '3417;3418', (74, 111))	('alterations', 'Var', (53, 64))	('mutational', 'Var', (198, 208))	('TERT', 'Gene', '7015', (147, 151))	('telomerase reverse transcriptase', 'Gene', (113, 145))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('ATRX', 'Gene', (188, 192))	('telomerase reverse transcriptase', 'Gene', '7015', (113, 145))
71060	28781988	In a xenograft mouse model, genetic changes in the tumor resulted in radiologic effects.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('genetic changes', 'Var', (28, 43))	('tumor', 'Disease', (51, 56))	('radiologic effects', 'MPA', (69, 87))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
71069	28781988	For example, tumor localization to the frontal lobes was positively correlated with abundance of MYH11, and was negatively associated with eIF4E expression.	('tumor', 'Disease', (13, 18))	('eIF4E', 'Gene', '1977', (139, 144))	('MYH11', 'Gene', '4629', (97, 102))	('eIF4E', 'Gene', (139, 144))	('positively', 'PosReg', (57, 67))	('expression', 'MPA', (145, 155))	('negatively', 'NegReg', (112, 122))	('MYH11', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('abundance', 'Var', (84, 93))	('correlated', 'Interaction', (68, 78))
71070	28781988	The T1/FLAIR ratio, MRI Necrosis, leptomeningeal reaction, mild enhancement quality, edema, cysts, and tumor localization in the parietal lobe were relatively strongly associated with unique patterns of pathway activation and suppression based on their signifi correlation with unique patterns of protein expression (Table 2 and Figure 1B).	('MRI', 'Disease', (20, 23))	('leptomeningeal reaction', 'Phenotype', 'HP:0032070', (34, 57))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('edema', 'Disease', (85, 90))	('T1/FLAIR', 'Var', (4, 12))	('tumor', 'Disease', (103, 108))	('Necrosis', 'Disease', 'MESH:D009336', (24, 32))	('activation', 'PosReg', (211, 221))	('Necrosis', 'Disease', (24, 32))	('MRI Necrosis', 'Phenotype', 'HP:0010885', (20, 32))	('edema', 'Disease', 'MESH:D004487', (85, 90))	('edema', 'Phenotype', 'HP:0000969', (85, 90))	('cysts', 'Disease', (92, 97))	('suppression', 'NegReg', (226, 237))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('pathway', 'Pathway', (203, 210))	('leptomeningeal', 'Disease', (34, 48))
71071	28781988	Leptomeningeal reaction, edema, mild enhancement quality, cysts, T1/FLAIR ratio, MRI necrosis, and localization of anatomic center of the tumor to the parietal lobes tended to have lower p-values for each IPA canonical pathway (Figure 1A).	('edema', 'Disease', 'MESH:D004487', (25, 30))	('tumor', 'Disease', (138, 143))	('p-values', 'MPA', (187, 195))	('edema', 'Disease', (25, 30))	('parietal lobes', 'Disease', 'MESH:C566826', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('Leptomeningeal reaction', 'CPA', (0, 23))	('necrosis', 'Disease', 'MESH:D009336', (85, 93))	('parietal lobes', 'Disease', (151, 165))	('enhancement', 'PosReg', (37, 48))	('Leptomeningeal reaction', 'Phenotype', 'HP:0032070', (0, 23))	('necrosis', 'Disease', (85, 93))	('mild', 'Var', (32, 36))	('cysts', 'Disease', (58, 63))	('T1/FLAIR', 'MPA', (65, 73))	('MRI necrosis', 'Phenotype', 'HP:0010885', (81, 93))	('edema', 'Phenotype', 'HP:0000969', (25, 30))	('lower', 'NegReg', (181, 186))	('IPA canonical pathway', 'Pathway', (205, 226))
71083	28781988	MAPK phosphorylation participates in signaling cell growth and proliferation, and pathways which include these kinases are frequently over-active in tumor cells.	('signaling cell growth', 'CPA', (37, 58))	('MAPK', 'Gene', '5594', (0, 4))	('proliferation', 'CPA', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('pathways', 'Pathway', (82, 90))	('MAPK', 'Gene', (0, 4))	('over-active', 'PosReg', (134, 145))	('phosphorylation', 'Var', (5, 20))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('participates', 'Reg', (21, 33))
71085	28781988	The downstream effects of these gene expression changes were consistent with the current understanding of tumor biology.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('changes', 'Var', (48, 55))
71114	27867928	3), and positive for the isocitrate dehydrogenase 1 mutation at residue 132:pR132H (tumor proportion of the tested tissue: 70%) (Fig.	('pR132H', 'Var', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
71202	26847705	The mean voxel count was greater in the MFG compared to BA (314.8 vs 216.2, p < 0.001, signed-rank test).	('greater', 'PosReg', (25, 32))	('MFG', 'Chemical', '-', (40, 43))	('MFG', 'Var', (40, 43))	('voxel count', 'CPA', (9, 20))
71218	26847705	Of the three cases that underwent DCS in putative language areas, all of them elicited speech arrest in the left hemisphere.	('speech', 'MPA', (87, 93))	('DCS', 'Chemical', '-', (34, 37))	('elicited', 'Reg', (78, 86))	('DCS', 'Var', (34, 37))
71232	26847705	Another study of temporal lobe epilepsy patients found that asymmetric activation in the MFG correlated with WADA determination of language hemispheric dominance.	('epilepsy', 'Phenotype', 'HP:0001250', (31, 39))	('correlated', 'Reg', (93, 103))	('patients', 'Species', '9606', (40, 48))	('activation', 'PosReg', (71, 81))	('language hemispheric dominance', 'Phenotype', 'HP:0002463', (131, 161))	('asymmetric', 'Var', (60, 70))	('MFG', 'Gene', (89, 92))	('temporal lobe epilepsy', 'Disease', 'MESH:D004833', (17, 39))	('temporal lobe epilepsy', 'Disease', (17, 39))	('MFG', 'Chemical', '-', (89, 92))
71309	24589977	NF1 is characterized by a germline mutation of neurofibromin 1 (NF1), located on chromosome 17q, which results in activation of the RAS/MAPK signaling pathway.	('activation', 'PosReg', (114, 124))	('neurofibromin 1', 'Gene', (47, 62))	('germline mutation', 'Var', (26, 43))	('NF1', 'Gene', (64, 67))	('neurofibromin 1', 'Gene', '4763', (47, 62))	('NF1', 'Gene', '4763', (64, 67))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))	('RAS/MAPK signaling pathway', 'Pathway', (132, 158))
71313	24589977	TS is caused by mutations in two tumor suppressor genes, TSC1 (hamartin, on chromosome 9q34) and TSC2 (tuberin, on chromosome 16p13).	('TSC1', 'Gene', '7248', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tuberin', 'Gene', (103, 110))	('TSC1', 'Gene', (57, 61))	('mutations', 'Var', (16, 25))	('TSC2', 'Gene', (97, 101))	('TSC2', 'Gene', '7249', (97, 101))	('hamartin', 'Gene', '7248', (63, 71))	('hamartin', 'Gene', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('caused by', 'Reg', (6, 15))	('tuberin', 'Gene', '7249', (103, 110))
71325	24589977	Grade I PLGGs are typically well-circumscribed tumors, with T1-hypointensity and T2-hyperintensity on MRI imaging.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('T1-hypointensity', 'Var', (60, 76))	('T2-hyperintensity', 'Var', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
71332	24589977	Similar to astrocytomas and oligodendroglial tumors, they appear T1-hypointense and T2-hyperintense on MRIs.	('T2-hyperintense', 'Var', (84, 99))	('T1-hypointense', 'Var', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('astrocytomas and oligodendroglial tumors', 'Disease', 'MESH:D001254', (11, 51))
71354	24589977	A prospective randomized clinical trial comparing outcomes of vincristine/carboplatin versus TPCV revealed that treatment with TPCV had a trend towards superior 5-year event-free survival (EFS) compared to vincristine/carboplatin (52% vs 39%, respectively), although this did not reach statistical significance.	('superior', 'PosReg', (152, 160))	('carboplatin', 'Chemical', 'MESH:D016190', (218, 229))	('vincristine', 'Chemical', 'MESH:D014750', (206, 217))	('TPCV', 'Chemical', '-', (93, 97))	('vincristine', 'Chemical', 'MESH:D014750', (62, 73))	('TPCV', 'Var', (127, 131))	('event-free', 'MPA', (168, 178))	('TPCV', 'Chemical', '-', (127, 131))	('carboplatin', 'Chemical', 'MESH:D016190', (74, 85))
71369	24589977	Concomitant deletion of chromosome 1p and 19q is one of the most frequent recurrent genetic alterations in adult oligodendrogliomas, aiding in diagnosis as well as serving as a favorable prognostic marker.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('deletion', 'Var', (12, 20))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (113, 131))	('aiding', 'Reg', (133, 139))	('oligodendrogliomas', 'Disease', (113, 131))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))
71370	24589977	In contrast, concomitant deletion of chromosome 1p and 19q is rare in children with oligodendrogliomas, and does not confer similar chemosensitivity when present.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('oligodendrogliomas', 'Disease', (84, 102))	('children', 'Species', '9606', (70, 78))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('deletion', 'Var', (25, 33))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (84, 102))
71371	24589977	Similarly, mutations in TP53, a tumor suppressor gene that codes for a nuclear phosphoprotein and regulates cycle cell arrest, apoptosis, and genetic stability, are frequently found in adult but rarely in pediatric LGGs.	('mutations', 'Var', (11, 20))	('genetic stability', 'CPA', (142, 159))	('TP53', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('apoptosis', 'CPA', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('found', 'Reg', (176, 181))	('TP53', 'Gene', '7157', (24, 28))
71372	24589977	IDH1 and IDH2 mutations are also rarely observed in PLGGs while they are frequent in adults.	('IDH2', 'Gene', (9, 13))	('IDH2', 'Gene', '3418', (9, 13))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
71373	24589977	In a recent study examining IDH1 and IDH2 in 445 CNS tumors and 494 non-CNS tumors, IDH1/2 mutations were described to occur with a frequency of more than 70% in adult patients across a variety of glial tumors including low-grade astrocytomas, anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas and secondary glioblastomas derived from the lower-grade gliomas.	('IDH1', 'Gene', '3417', (28, 32))	('astrocytomas', 'Disease', (230, 242))	('IDH1/2', 'Gene', '3417;3418', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (297, 308))	('CNS tumors', 'Disease', 'MESH:D009369', (72, 82))	('CNS tumors', 'Disease', (49, 59))	('astrocytomas', 'Disease', 'MESH:D001254', (297, 309))	('CNS tumors', 'Disease', (72, 82))	('IDH1/2', 'Gene', (84, 90))	('glial tumors', 'Disease', (197, 209))	('CNS tumors', 'Disease', 'MESH:D009369', (49, 59))	('glioblastomas', 'Disease', (324, 337))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('IDH2', 'Gene', (37, 41))	('oligoastrocytomas', 'Disease', (292, 309))	('astrocytomas', 'Disease', 'MESH:D001254', (255, 267))	('astrocytoma', 'Phenotype', 'HP:0009592', (255, 266))	('gliomas', 'Disease', (280, 287))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (292, 309))	('IDH2', 'Gene', '3418', (37, 41))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (269, 287))	('gliomas', 'Disease', (367, 374))	('glioblastomas', 'Disease', 'MESH:D005909', (324, 337))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('astrocytomas', 'Disease', 'MESH:D001254', (230, 242))	('gliomas', 'Disease', 'MESH:D005910', (280, 287))	('IDH1', 'Gene', (84, 88))	('astrocytoma', 'Phenotype', 'HP:0009592', (230, 241))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('gliomas', 'Disease', 'MESH:D005910', (367, 374))	('glioma', 'Phenotype', 'HP:0009733', (280, 286))	('IDH1', 'Gene', (28, 32))	('oligodendrogliomas', 'Disease', (269, 287))	('glioma', 'Phenotype', 'HP:0009733', (367, 373))	('astrocytomas', 'Disease', (297, 309))	('gliomas', 'Phenotype', 'HP:0009733', (280, 287))	('astrocytomas', 'Disease', (255, 267))	('mutations', 'Var', (91, 100))	('glial tumors', 'Disease', 'MESH:D005910', (197, 209))	('IDH1', 'Gene', '3417', (84, 88))	('patients', 'Species', '9606', (168, 176))	('gliomas', 'Phenotype', 'HP:0009733', (367, 374))	('glioblastomas', 'Phenotype', 'HP:0012174', (324, 337))
71374	24589977	In contrast, IDH1/2 mutations are rare in children, although when found in adolescent patients they may be a harbinger of the adult form of the disease, meriting concordant treatment recommendations.	('children', 'Species', '9606', (42, 50))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('IDH1/2', 'Gene', (13, 19))	('mutations', 'Var', (20, 29))	('patients', 'Species', '9606', (86, 94))
71375	24589977	The increased risk of LGGs in children with NF1 was one of the first clues that dysregulation of the mitogen-activated protein kinases (MAPK) pathway may be important in the pathogenesis of PLGGs.	('children', 'Species', '9606', (30, 38))	('NF1', 'Gene', (44, 47))	('NF1', 'Gene', '4763', (44, 47))	('PLGGs', 'Disease', (190, 195))	('dysregulation', 'Var', (80, 93))	('LGGs', 'Disease', (22, 26))
71378	24589977	In neurofibromatosis, NF1 mutations produce a loss of function of neurofibromin that leads to the constitutive activation of the Ras pathway and results in proliferation of astrocytes, among other phenotypes.	('activation', 'PosReg', (111, 121))	('NF1', 'Gene', (22, 25))	('proliferation of astrocytes', 'Phenotype', 'HP:0002446', (156, 183))	('Ras pathway', 'Pathway', (129, 140))	('neurofibromin', 'Gene', '4763', (66, 79))	('NF1', 'Gene', '4763', (22, 25))	('astrocytes', 'CPA', (173, 183))	('neurofibromatosis', 'Gene', '4763', (3, 20))	('mutations', 'Var', (26, 35))	('neurofibromin', 'Gene', (66, 79))	('proliferation', 'PosReg', (156, 169))	('neurofibromatosis', 'Gene', (3, 20))	('loss of function', 'NegReg', (46, 62))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (3, 20))
71381	24589977	Genetic rearrangements of the oncogene BRAF are the most common genomic alterations found in sporadic PLGGs.	('BRAF', 'Gene', (39, 43))	('BRAF', 'Gene', '673', (39, 43))	('Genetic rearrangements', 'Var', (0, 22))
71382	24589977	Early studies utilizing comparative genomic hybridization (CGH) identified a gain of the specific chromosomal region 7q34 containing the BRAF locus as the most frequent copy number alteration in PLGGs, involving 50-100% of pediatric PAs.	('PLGGs', 'Gene', (195, 200))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('alteration', 'Var', (181, 191))	('gain', 'PosReg', (77, 81))
71383	24589977	The BRAF duplication is found more frequently in cerebellar and hypothalamic-chiasmatic tumors.	('hypothalamic-chiasmatic tumors', 'Disease', 'MESH:D007029', (64, 94))	('cerebellar', 'Disease', (49, 59))	('duplication', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('found', 'Reg', (24, 29))	('hypothalamic-chiasmatic tumors', 'Disease', (64, 94))
71384	24589977	The 7q34 gain has been characterized to represent a duplication of BRAF with a tandem insertion in the KIAA1549 gene.	('7q34', 'Var', (4, 8))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (67, 71))	('KIAA1549', 'Gene', (103, 111))	('gain', 'PosReg', (9, 13))	('KIAA1549', 'Gene', '57670', (103, 111))
71385	24589977	This BRAF duplication results in the activation of the downstream effectors of the MAPK pathway, MEK and ERK.	('BRAF', 'Gene', '673', (5, 9))	('MAPK pathway', 'Pathway', (83, 95))	('ERK', 'Gene', '5594', (105, 108))	('activation', 'PosReg', (37, 47))	('BRAF', 'Gene', (5, 9))	('ERK', 'Gene', (105, 108))	('MEK', 'Gene', (97, 100))	('duplication', 'Var', (10, 21))	('MEK', 'Gene', '5609', (97, 100))
71386	24589977	Subsequently, variants of the fusion transcript involving BRAF gene have been described, involving not only KIAA1549 but also other fusion partners, SRGAP3, FAM131B, MACF1, RNF130, CLCN6, MKRN1 and GNAI1 (Table 5).	('GNAI1', 'Gene', '2770', (198, 203))	('SRGAP3', 'Gene', '9901', (149, 155))	('KIAA1549', 'Gene', '57670', (108, 116))	('MACF1', 'Gene', (166, 171))	('RNF130', 'Gene', '55819', (173, 179))	('KIAA1549', 'Gene', (108, 116))	('SRGAP3', 'Gene', (149, 155))	('CLCN6', 'Gene', '1185', (181, 186))	('MKRN1', 'Gene', (188, 193))	('MKRN1', 'Gene', '23608', (188, 193))	('RNF130', 'Gene', (173, 179))	('BRAF', 'Gene', (58, 62))	('FAM131B', 'Gene', (157, 164))	('variants', 'Var', (14, 22))	('FAM131B', 'Gene', '9715', (157, 164))	('CLCN6', 'Gene', (181, 186))	('BRAF', 'Gene', '673', (58, 62))	('GNAI1', 'Gene', (198, 203))	('MACF1', 'Gene', '23499', (166, 171))
71387	24589977	RAF1, which encodes a protein that leads to the stabilization and activation of BRAF, has also been described to harbor gene fusions with SRGAP3 and QK1, leading to the constitutive activation of MAPK pathway.	('BRAF', 'Gene', (80, 84))	('QK1', 'Gene', '9444', (149, 152))	('fusions', 'Var', (125, 132))	('RAF1', 'Gene', '5894', (0, 4))	('SRGAP3', 'Gene', '9901', (138, 144))	('RAF1', 'Gene', (0, 4))	('constitutive', 'MPA', (169, 181))	('BRAF', 'Gene', '673', (80, 84))	('QK1', 'Gene', (149, 152))	('MAPK pathway', 'Pathway', (196, 208))	('SRGAP3', 'Gene', (138, 144))
71388	24589977	These BRAF rearrangements tend to occur frequently in cerebellar lesions, Strikingly, all of the fusion protein variants are characterized by loss of the N-terminal inhibitory domains of BRAF, resulting in constitutive activation of the BRAF kinase and downstream activation of MAPK and its effectors, MEK and ERK.	('MAPK', 'Enzyme', (278, 282))	('loss', 'NegReg', (142, 146))	('activation', 'PosReg', (264, 274))	('ERK', 'Gene', '5594', (310, 313))	('ERK', 'Gene', (310, 313))	('BRAF', 'Gene', '673', (187, 191))	('activation', 'PosReg', (219, 229))	('MEK', 'Gene', (302, 305))	('cerebellar lesions', 'Disease', (54, 72))	('N-terminal inhibitory domains', 'MPA', (154, 183))	('MEK', 'Gene', '5609', (302, 305))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', '673', (237, 241))	('BRAF', 'Gene', (6, 10))	('cerebellar lesions', 'Disease', 'MESH:D002526', (54, 72))	('BRAF', 'Gene', (237, 241))	('variants', 'Var', (112, 120))	('BRAF', 'Gene', (187, 191))
71391	24589977	This has led to the hypothesis that tandem duplications of the RAF gene might be generated by microhomology-mediated break-induced replication.	('RAF', 'Gene', (63, 66))	('RAF', 'Gene', '22882', (63, 66))	('tandem duplications', 'Var', (36, 55))
71394	24589977	Taken together, BRAF and RAF1 fusion transcripts, leading to constitutive activation of MAPK pathway, may play a crucial role in the pathogenesis of sporadic PAs and may also present potential therapeutic targets for PLGGs.	('sporadic PAs', 'Disease', (149, 161))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('fusion transcripts', 'Var', (30, 48))	('RAF1', 'Gene', (25, 29))	('play', 'Reg', (106, 110))	('RAF1', 'Gene', '5894', (25, 29))	('activation', 'PosReg', (74, 84))	('MAPK pathway', 'Pathway', (88, 100))
71396	24589977	This mutation has been described in other cancer subtypes, including melanoma, colorectal cancer, leukemia, and high-grade gliomas.	('leukemia', 'Disease', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('leukemia', 'Disease', 'MESH:D007938', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gliomas', 'Disease', (123, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('colorectal cancer', 'Disease', (79, 96))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('melanoma', 'Disease', (69, 77))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('described', 'Reg', (23, 32))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (90, 96))	('mutation', 'Var', (5, 13))
71398	24589977	The BRAF V600E point mutation occurs most commonly in PXAs, GGs, DAs, and PMAs and is only rarely detected in PAs.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('PXAs', 'Disease', (54, 58))	('V600E', 'Var', (9, 14))	('GGs', 'Disease', (60, 63))	('DAs', 'Disease', (65, 68))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('PMAs', 'Disease', (74, 78))
71399	24589977	Thus BRAF duplications and V600E point mutation are almost always mutually exclusive.	('BRAF', 'Gene', '673', (5, 9))	('V600E point mutation', 'Var', (27, 47))	('BRAF', 'Gene', (5, 9))	('duplications', 'Var', (10, 22))	('V600E', 'Mutation', 'rs113488022', (27, 32))
71400	24589977	The BRAF V600E alteration confers constitutive BRAF kinase activation, and transforms NIH3T3 fibroblasts in vitro.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('NIH3T3', 'CellLine', 'CVCL:0594', (86, 92))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('transforms', 'Reg', (75, 85))	('activation', 'PosReg', (59, 69))
71401	24589977	Other rare forms of small amino-acid insertions in BRAF have been identified in PAs.	('BRAF', 'Gene', (51, 55))	('BRAF', 'Gene', '673', (51, 55))	('small amino-acid insertions', 'Var', (20, 47))	('PAs', 'Disease', (80, 83))
71402	24589977	The BRAF V600E mutation has been shown to promote transformation of human neural stem cells, followed by senescence.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('human', 'Species', '9606', (68, 73))	('senescence', 'CPA', (105, 115))	('V600E', 'Var', (9, 14))	('promote', 'PosReg', (42, 49))	('transformation', 'CPA', (50, 64))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))
71404	24589977	FGFR1 genomic alterations have also been described in breast cancer, lung cancer, and glioblastomas.	('breast cancer', 'Disease', (54, 67))	('glioblastomas', 'Disease', (86, 99))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('genomic alterations', 'Var', (6, 25))	('described', 'Reg', (41, 50))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('lung cancer', 'Disease', (69, 80))	('glioblastomas', 'Phenotype', 'HP:0012174', (86, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('glioblastomas', 'Disease', 'MESH:D005909', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
71405	24589977	FGFR1 point mutations (N546K and K656E) were found in 5% of supra-tentorial PAs.	('K656E', 'Mutation', 'rs869320694', (33, 38))	('K656E', 'Var', (33, 38))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('supra-tentorial PAs', 'Disease', 'MESH:D011471', (60, 79))	('N546K', 'Mutation', 'rs779707422', (23, 28))	('supra-tentorial PAs', 'Disease', (60, 79))	('N546K', 'Var', (23, 28))	('found', 'Reg', (45, 50))
71406	24589977	In 2% of cases, FGFR1 mutations were associated with the presence of a PTPN11 mutation, another downstream effector of FGFR1.	('mutation', 'Var', (78, 86))	('FGFR1', 'Gene', '2260', (16, 21))	('FGFR1', 'Gene', (119, 124))	('FGFR1', 'Gene', '2260', (119, 124))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (37, 47))	('PTPN11', 'Gene', '5781', (71, 77))	('PTPN11', 'Gene', (71, 77))	('FGFR1', 'Gene', (16, 21))
71407	24589977	In the same study, one PA possessed a tandem duplication of FGFR1.	('FGFR1', 'Gene', (60, 65))	('tandem duplication', 'Var', (38, 56))	('FGFR1', 'Gene', '2260', (60, 65))
71409	24589977	Additionally, FGFR1 mutations and duplication of its tyrosine kinase domain have also been described in PAs, DAs, and DNTs.	('DAs', 'Disease', (109, 112))	('duplication', 'Var', (34, 45))	('FGFR1', 'Gene', (14, 19))	('DNTs', 'Chemical', '-', (118, 122))	('FGFR1', 'Gene', '2260', (14, 19))	('DNTs', 'Disease', (118, 122))	('PAs', 'Disease', (104, 107))	('tyrosine kinase domain', 'MPA', (53, 75))	('described', 'Reg', (91, 100))	('mutations', 'Var', (20, 29))
71410	24589977	These include genomic alterations affecting the kinase domain of neurotrophic tyrosine kinase type 2 (NTRK2), which have been described in pediatric PAs.	('kinase domain', 'MPA', (48, 61))	('affecting', 'Reg', (34, 43))	('genomic alterations', 'Var', (14, 33))	('NTRK2', 'Gene', (102, 107))	('neurotrophic tyrosine kinase type 2', 'Gene', '4915', (65, 100))	('NTRK2', 'Gene', '4915', (102, 107))	('neurotrophic tyrosine kinase type 2', 'Gene', (65, 100))	('described', 'Reg', (126, 135))
71413	24589977	PI3K is an intracellular protein that is recruited to the cell membrane after stimulation of a transmembrane growth receptor such as EGFR or platelet derived growth factor receptor A (PDGFRA - which also signals along the Ras-Raf-MEK-MAPK pathway), resulting in activation of downstream effectors, such as AKT and mTOR, to induce cell proliferation and inhibition of apoptosis.	('AKT', 'Gene', '207', (306, 309))	('PI3K', 'Var', (0, 4))	('Raf', 'Gene', '22882', (226, 229))	('MEK', 'Gene', (230, 233))	('MEK', 'Gene', '5609', (230, 233))	('apoptosis', 'CPA', (367, 376))	('PDGFRA', 'Gene', (184, 190))	('AKT', 'Gene', (306, 309))	('mTOR', 'Gene', '2475', (314, 318))	('cell proliferation', 'CPA', (330, 348))	('mTOR', 'Gene', (314, 318))	('Raf', 'Gene', (226, 229))	('PDGFRA', 'Gene', '5156', (184, 190))	('activation', 'PosReg', (262, 272))	('EGFR', 'Gene', '1956', (133, 137))	('induce', 'PosReg', (323, 329))	('inhibition', 'NegReg', (353, 363))	('EGFR', 'Gene', (133, 137))
71414	24589977	As initially suggested by early studies of tuberous sclerosis, activation of mTOR through mutations of its upstream inhibitor result in increased predisposition for PLGGs, in particular the SEGA subtype.	('PLGGs', 'Disease', (165, 170))	('mutations', 'Var', (90, 99))	('SEGA', 'Disease', (190, 194))	('mTOR', 'Gene', '2475', (77, 81))	('tuberous sclerosis', 'Disease', (43, 61))	('mTOR', 'Gene', (77, 81))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (43, 61))	('activation', 'PosReg', (63, 73))
71418	24589977	In contrast, MEK1/2 knockdown in mice results in the absence of glial cell differentiation and proliferation.	('glial cell differentiation', 'CPA', (64, 90))	('mice', 'Species', '10090', (33, 37))	('knockdown', 'Var', (20, 29))	('proliferation', 'CPA', (95, 108))	('absence', 'NegReg', (53, 60))	('MEK1/2', 'Gene', (13, 19))
71421	24589977	This led to speculation that deregulation of the EGFR pathway may play a role in the pathogenesis of disseminated PLGGs.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('disseminated PLGGs', 'Disease', (101, 119))	('deregulation', 'Var', (29, 41))	('play', 'Reg', (66, 70))
71422	24589977	Additionally, rare mutations of PDGFRA have been reported in PAs, GGs, and LGG-NOS tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PAs', 'Disease', (61, 64))	('LGG-NOS tumors', 'Disease', 'MESH:D009369', (75, 89))	('reported', 'Reg', (49, 57))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (19, 28))	('PDGFRA', 'Gene', (32, 38))	('PDGFRA', 'Gene', '5156', (32, 38))	('LGG-NOS tumors', 'Disease', (75, 89))	('GGs', 'Disease', (66, 69))
71430	24589977	These include MYB amplification in DAs and focal deletions of MYB in AGs.	('MYB', 'Gene', (14, 17))	('amplification', 'MPA', (18, 31))	('deletions', 'Var', (49, 58))	('MYB', 'Gene', '4602', (62, 65))	('MYB', 'Gene', (62, 65))	('MYB', 'Gene', '4602', (14, 17))
71435	24589977	Importantly, this specific duplication-truncation of MYBL1 has demonstrated tumorigenic properties in vitro.	('MYBL1', 'Gene', (53, 58))	('duplication-truncation', 'Var', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('MYBL1', 'Gene', '4603', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
71436	24589977	Aberrant epigenetic regulation has been increasingly described in human cancers and has become a major focus in a number of pediatric cancers .	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Disease', (134, 141))	('pediatric cancers', 'Disease', 'MESH:D009369', (124, 141))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('pediatric cancers', 'Disease', (124, 141))	('Aberrant epigenetic regulation', 'Var', (0, 30))	('cancers', 'Disease', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
71437	24589977	The frequency of alterations in epigenetic modifiers in cancer has been shown in multiple cancer types including hematologic tumors, Wilm's tumors, retinoblastoma, neuroblastoma, thyroid carcinoma, hepatocellular carcinoma, sarcoma, and brain tumors such as medulloblastoma and Atypical teratoid rhabdoid tumors (ATRTs) with SMARCB1 mutations.	('brain tumors', 'Disease', (237, 249))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('retinoblastoma', 'Disease', 'MESH:D012175', (148, 162))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (179, 196))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (198, 222))	('cancer', 'Disease', (56, 62))	('thyroid carcinoma', 'Disease', (179, 196))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	("Wilm's tumors", 'Phenotype', 'HP:0002667', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('brain tumor', 'Phenotype', 'HP:0030692', (237, 248))	('retinoblastoma', 'Phenotype', 'HP:0009919', (148, 162))	('mutations', 'Var', (333, 342))	('alterations', 'Var', (17, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('hepatocellular carcinoma', 'Disease', (198, 222))	('Atypical teratoid rhabdoid tumors', 'Disease', 'MESH:C000597569', (278, 311))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (179, 196))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	("Wilm's tumors", 'Disease', (133, 146))	('Atypical teratoid rhabdoid tumors', 'Disease', (278, 311))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('hematologic tumors', 'Disease', 'MESH:D006402', (113, 131))	('SMARCB1', 'Gene', '6598', (325, 332))	('hematologic tumors', 'Disease', (113, 131))	('retinoblastoma', 'Disease', (148, 162))	('medulloblastoma', 'Disease', 'MESH:D008527', (258, 273))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('SMARCB1', 'Gene', (325, 332))	('medulloblastoma', 'Phenotype', 'HP:0002885', (258, 273))	('brain tumors', 'Disease', 'MESH:D001932', (237, 249))	('brain tumors', 'Phenotype', 'HP:0030692', (237, 249))	('sarcoma', 'Disease', 'MESH:D012509', (224, 231))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('neuroblastoma', 'Disease', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('medulloblastoma', 'Disease', (258, 273))	('sarcoma', 'Disease', (224, 231))	('neuroblastoma', 'Phenotype', 'HP:0003006', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (198, 222))	('neuroblastoma', 'Disease', 'MESH:D009447', (164, 177))	("Wilm's tumors", 'Disease', 'MESH:D009396', (133, 146))	('cancer', 'Disease', (90, 96))
71438	24589977	The evidence that epigenetics is a major factor in pediatric glioma biology is extremely strong.	('epigenetics', 'Var', (18, 29))	('pediatric glioma', 'Disease', (51, 67))	('pediatric glioma', 'Disease', 'MESH:D005910', (51, 67))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))
71440	24589977	This suggests that dysregulation of chromatin remodeling effectors are also acting with genomic alterations in the tumorigenesis of a subset of PLGGs.	('dysregulation', 'Var', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('PLGGs', 'Disease', (144, 149))
71442	24589977	The role of epigenetic dysregulation of tumor suppressor gene expression has been described in multiple adult LGGs.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('adult LGGs', 'Disease', (104, 114))	('epigenetic dysregulation', 'Var', (12, 36))	('tumor', 'Disease', (40, 45))
71443	24589977	First, the spectrum and frequency of mutations in PLGGs is limited, compared to adult tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('adult tumors', 'Disease', (80, 92))	('PLGGs', 'Gene', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (37, 46))	('adult tumors', 'Disease', 'MESH:C538052', (80, 92))
71444	24589977	Recent in vivo studies suggest that BRAF alterations in gliomas are not sufficient to induce tumor formation.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('BRAF', 'Gene', (36, 40))	('gliomas', 'Disease', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('BRAF', 'Gene', '673', (36, 40))	('alterations', 'Var', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
71447	24589977	Thus, epigenetic profiling of PLGGs presents great potential to further the understanding of the pathophysiology underlying these heterogenic and poorly understood tumors.	('epigenetic profiling', 'Var', (6, 26))	('PLGGs', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Disease', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
71448	24589977	A multivariate analysis of 146 patients reported that the presence of KIAA1549-BRAF fusion protein was the most significant favorable prognostic factor in pediatric PAs following subtotal resection.	('presence', 'Var', (58, 66))	('KIAA1549-BRAF', 'Disease', (70, 83))	('patients', 'Species', '9606', (31, 39))	('pediatric PAs', 'Disease', (155, 168))	('KIAA1549-BRAF', 'Disease', 'None', (70, 83))
71451	24589977	It has been hypothesized that improved outcome in PAs conferred by the BRAF duplication may be due to oncogene-induced senescence (OIS), which occurs through the activation of p16Ink4a pathway.	('PAs', 'Disease', (50, 53))	('p16Ink4a', 'Gene', (176, 184))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', (71, 75))	('p16Ink4a', 'Gene', '1029', (176, 184))	('duplication', 'Var', (76, 87))	('improved', 'PosReg', (30, 38))
71454	24589977	Similarly, a recent study performed on GGs has showed that the presence of the V600E point mutation was associated with significant lower recurrence-free survival.	('lower', 'NegReg', (132, 137))	('V600E', 'Var', (79, 84))	('recurrence-free survival', 'CPA', (138, 162))	('V600E', 'Mutation', 'rs113488022', (79, 84))
71455	24589977	The recent discovery of other genomic alterations such as FGFR1 mutations will also enlarge the field of exploration between clinical outcome and biology.	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))	('mutations', 'Var', (64, 73))
71456	24589977	Identification of frequent and recurrent alterations of BRAF resulting in MAPK pathway activation across many PLGGs offers great potential as a therapeutic target.	('activation', 'PosReg', (87, 97))	('BRAF', 'Gene', (56, 60))	('MAPK pathway', 'Pathway', (74, 86))	('alterations', 'Var', (41, 52))	('BRAF', 'Gene', '673', (56, 60))
71459	24589977	Based on the known MAPK feedback loops that regulate BRAF inhibition, patients with the V600E mutation, which signal as monomers, should be very sensitive to BRAF inhibitors.	('patients', 'Species', '9606', (70, 78))	('BRAF', 'Gene', '673', (53, 57))	('V600E', 'Mutation', 'rs113488022', (88, 93))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (158, 162))	('V600E', 'Var', (88, 93))	('BRAF', 'Gene', (158, 162))
71462	24589977	The second group, MEK1/2 inhibitor, which prevent the feedback inhibitory loop that results from BRAF targeted agents as discussed above, are currently being evaluated in early phase clinical trials for PLGGs with the BRAF duplication.	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('duplication', 'Var', (223, 234))	('BRAF', 'Gene', '673', (97, 101))	('feedback inhibitory loop', 'MPA', (54, 78))	('BRAF', 'Gene', (97, 101))
71468	24589977	The recent discovery of FGFR1 alterations in PAs and other PLGG subtypes represents another potential target in the treatment of those tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PAs', 'Disease', (45, 48))	('FGFR1', 'Gene', (24, 29))	('alterations', 'Var', (30, 41))	('FGFR1', 'Gene', '2260', (24, 29))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
71473	24589977	The striking predominance of the RAS/RAF/MAPK pathway alteration in PLGG tumorigenesis may help redefine traditional histopathological classifications and also represents exciting new avenues for the development of novel targeted therapies.	('alteration', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PLGG', 'Disease', (68, 72))	('tumor', 'Disease', (73, 78))	('RAF', 'Gene', '22882', (37, 40))	('RAF', 'Gene', (37, 40))
71476	33922649	MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas.	('gliomas', 'Disease', (77, 84))	('MicroRNA-542-3p', 'Var', (0, 15))	('miR-542-3p', 'Chemical', '-', (17, 27))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('implicated', 'Reg', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('tumors', 'Disease', (60, 66))
71478	33922649	We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('human', 'Species', '9606', (79, 84))	('miR-542-3p', 'Var', (39, 49))	('glioma', 'Disease', (85, 91))	('miR-542-3p', 'Chemical', '-', (39, 49))	('glycolytic activity', 'MPA', (16, 35))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
71479	33922649	We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis; (3) Results: We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells.	('miR-542-3p', 'Chemical', '-', (26, 36))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Disease', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('patients', 'Species', '9606', (68, 76))	('miR-542-3p', 'Var', (173, 183))	('miR-542-3p', 'Chemical', '-', (173, 183))	('gliomas', 'Disease', (102, 109))	('human', 'Species', '9606', (235, 240))	('glioma', 'Disease', (102, 108))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('suppressed', 'NegReg', (198, 208))	('glioma', 'Disease', (241, 247))
71480	33922649	Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells.	('glioma', 'Disease', (76, 82))	('HK2-induced', 'Protein', (35, 46))	('miR-542-3p', 'Chemical', '-', (13, 23))	('suppressed', 'NegReg', (24, 34))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('human', 'Species', '9606', (70, 75))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('miR-542-3p', 'Var', (13, 23))
71481	33922649	Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells.	('human', 'Species', '9606', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('over-expression', 'PosReg', (14, 29))	('glycolytic activity', 'MPA', (66, 85))	('miR-542-3p', 'Var', (33, 43))	('glioma', 'Disease', (95, 101))	('miR-542-3p', 'Chemical', '-', (33, 43))	('increased', 'PosReg', (44, 53))	('HK2-induced', 'Protein', (54, 65))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
71482	33922649	The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('high-grade', 'Var', (96, 106))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('gliomas', 'Disease', (145, 152))	('elevated', 'PosReg', (52, 60))	('glioma', 'Disease', (145, 151))	('gliomas', 'Disease', (107, 114))	('HK2', 'Protein', (29, 32))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('patients', 'Species', '9606', (82, 90))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('miR-542-3p', 'Protein', (14, 24))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('miR-542-3p', 'Chemical', '-', (14, 24))	('glioma', 'Disease', (107, 113))
71484	33922649	Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database; (4) Conclusions: miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.	('miR-542-3p', 'Chemical', '-', (119, 129))	('glioma', 'Disease', (197, 203))	('miR-542-3p', 'Chemical', '-', (29, 39))	('HK2-mediated high glycolytic phenotype', 'MPA', (149, 187))	('human', 'Species', '9606', (191, 196))	('miR-542-3p', 'Var', (119, 129))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
71502	33922649	Among various miRNAs, the role of miR-542-3p has been implicated in various tumors including astrocytoma, neuroblastoma, breast cancer, and colorectal cancer.	('miR-542-3p', 'Chemical', '-', (34, 44))	('neuroblastoma', 'Disease', 'MESH:D009447', (106, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('miR-542-3p', 'Var', (34, 44))	('astrocytoma', 'Disease', 'MESH:D001254', (93, 104))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('astrocytoma', 'Disease', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('colorectal cancer', 'Disease', (140, 157))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('implicated', 'Reg', (54, 64))	('neuroblastoma', 'Disease', (106, 119))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('breast cancer', 'Disease', (121, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (106, 119))
71504	33922649	Here, we show that the knockdown of miR-542-3p suppressed cellular proliferation in human glioma cells.	('suppressed', 'NegReg', (47, 57))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('human', 'Species', '9606', (84, 89))	('miR-542-3p', 'Var', (36, 46))	('miR-542-3p', 'Chemical', '-', (36, 46))
71505	33922649	Knockdown of miR-542-3p suppressed HK2-mediated glycolytic activity via the reduction of HK2 expression.	('reduction', 'NegReg', (76, 85))	('miR-542-3p', 'Chemical', '-', (13, 23))	('suppressed', 'NegReg', (24, 34))	('miR-542-3p', 'Var', (13, 23))	('expression', 'MPA', (93, 103))	('HK2', 'Protein', (89, 92))	('HK2-mediated glycolytic activity', 'MPA', (35, 67))
71506	33922649	Consistently, the over-expression of miR-542-3p increased HK2-mediated glycolytic activity.	('increased', 'PosReg', (48, 57))	('HK2-mediated', 'Enzyme', (58, 70))	('over-expression', 'PosReg', (18, 33))	('miR-542-3p', 'Var', (37, 47))	('miR-542-3p', 'Chemical', '-', (37, 47))
71507	33922649	The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas compared to those with low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('high-grade', 'Var', (96, 106))	('gliomas', 'Disease', (148, 155))	('glioma', 'Disease', (148, 154))	('miR-542-3p', 'Var', (14, 24))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('elevated', 'PosReg', (52, 60))	('gliomas', 'Disease', (107, 114))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('HK2', 'Protein', (29, 32))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('patients', 'Species', '9606', (82, 90))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('miR-542-3p', 'Chemical', '-', (14, 24))	('glioma', 'Disease', (107, 113))
71509	33922649	Moreover, the high levels of miR-542-3p were associated with poor prognosis in patients with gliomas using analysis of the TCGA database.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('miR-542-3p', 'Var', (29, 39))	('patients', 'Species', '9606', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('miR-542-3p', 'Chemical', '-', (29, 39))
71510	33922649	Our results suggest that miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.	('contributes', 'Reg', (36, 47))	('miR-542-3p', 'Var', (25, 35))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('miR-542-3p', 'Chemical', '-', (25, 35))	('human', 'Species', '9606', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('HK2-mediated', 'Protein', (55, 67))	('high glycolytic phenotype', 'MPA', (68, 93))	('glioma', 'Disease', (103, 109))
71520	33922649	PS100010, Origene, Rockville, MD, USA) as a positive control for transfection using lipofectamine LTX with Plus reagent (15338100, Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer's instructions.	('lipofectamine LTX', 'Chemical', '-', (84, 101))	('PS100010', 'Var', (0, 8))	('15338100', 'Var', (121, 129))
71551	33922649	Linear regression was performed to confirm the relationship between miR-542-3p and HK2 expression level.	('miR-542-3p', 'Var', (68, 78))	('miR-542-3p', 'Chemical', '-', (68, 78))	('expression level', 'MPA', (87, 103))	('HK2', 'Protein', (83, 86))
71553	33922649	We examined whether the knockdown of miR-542-3p could suppress cellular proliferation in human glioma cells.	('human', 'Species', '9606', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('suppress', 'NegReg', (54, 62))	('glioma', 'Disease', (95, 101))	('miR-542-3p', 'Var', (37, 47))	('miR-542-3p', 'Chemical', '-', (37, 47))	('knockdown', 'Var', (24, 33))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
71554	33922649	We first analyzed the morphologic changes by miR-542-3p knockdown in human glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('miR-542-3p', 'Var', (45, 55))	('human', 'Species', '9606', (69, 74))	('glioma', 'Disease', (75, 81))	('miR-542-3p', 'Chemical', '-', (45, 55))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
71555	33922649	Knockdown of miR-542-3p (miR-542-3p KO) resulted in the reduction of cell body size and the condensation of cells compared to that in cells treated with microRNA hairpin inhibitor negative control (Control) (Figure 1A).	('condensation of cells', 'CPA', (92, 113))	('miR-542-3p (miR-542-3p KO', 'Var', (13, 38))	('miR-542-3p', 'Chemical', '-', (13, 23))	('miR-542-3p', 'Chemical', '-', (25, 35))	('cell body size', 'CPA', (69, 83))	('reduction', 'NegReg', (56, 65))
71556	33922649	The length of the cell body was significantly decreased by miR-542-3p knockdown relative to that in control (Figure 1B).	('miR-542-3p knockdown', 'Var', (59, 79))	('miR-542-3p', 'Chemical', '-', (59, 69))	('knockdown', 'Var', (70, 79))	('decreased', 'NegReg', (46, 55))
71558	33922649	Notably, knockdown of miR-542-3p significantly suppressed the cellular proliferation in a time-dependent manner compared to that in control (Figure 1C).	('suppressed', 'NegReg', (47, 57))	('knockdown', 'Var', (9, 18))	('cellular proliferation', 'CPA', (62, 84))	('miR-542-3p', 'Var', (22, 32))	('miR-542-3p', 'Chemical', '-', (22, 32))
71559	33922649	These results suggest the knockdown of miR-542-3p suppresses cellular proliferation in human glioma cells.	('glioma', 'Disease', (93, 99))	('human', 'Species', '9606', (87, 92))	('suppresses', 'NegReg', (50, 60))	('miR-542-3p', 'Var', (39, 49))	('knockdown', 'Var', (26, 35))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('miR-542-3p', 'Chemical', '-', (39, 49))
71560	33922649	Next, we investigated the mechanisms by which miR-542-3p regulates cellular proliferation in glioma.	('regulates', 'Reg', (57, 66))	('glioma', 'Disease', (93, 99))	('cellular proliferation', 'CPA', (67, 89))	('miR-542-3p', 'Var', (46, 56))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('miR-542-3p', 'Chemical', '-', (46, 56))
71561	33922649	Since the high-glycolytic phenotype is linked to cellular proliferation, we examined whether the knockdown of miR-542-3p could regulate the high glycolytic phenotype in human glioma cells.	('miR-542-3p', 'Var', (110, 120))	('regulate', 'Reg', (127, 135))	('human', 'Species', '9606', (169, 174))	('glioma', 'Disease', (175, 181))	('miR-542-3p', 'Chemical', '-', (110, 120))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('high glycolytic phenotype', 'MPA', (140, 165))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
71564	33922649	The knockdown of miR-542-3p (miR-542-3p) significantly reduced the levels of ECAR compared to that in cells treated with microRNA hairpin inhibitor negative control (Control) (Figure 2A).	('miR-542-3p', 'Var', (17, 27))	('reduced', 'NegReg', (55, 62))	('miR-542-3p', 'Chemical', '-', (17, 27))	('miR-542-3p', 'Chemical', '-', (29, 39))	('levels of ECAR', 'MPA', (67, 81))
71565	33922649	Notably, the knockdown of miR-542-3p significantly suppressed the levels of ECAR in response to glucose relative to that in control (Figure 2A).	('miR-542-3p', 'Chemical', '-', (26, 36))	('levels of ECAR in response to glucose', 'MPA', (66, 103))	('suppressed', 'NegReg', (51, 61))	('miR-542-3p', 'Gene', (26, 36))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('knockdown', 'Var', (13, 22))
71566	33922649	In addition, the levels of ECAR in response to oligomycin were reduced by the knockdown of miR-542-3p compared to that in control (Figure 2A).	('response to oligomycin', 'MPA', (35, 57))	('reduced', 'NegReg', (63, 70))	('oligomycin', 'Chemical', 'MESH:D009840', (47, 57))	('knockdown', 'Var', (78, 87))	('levels of ECAR', 'MPA', (17, 31))	('miR-542-3p', 'Var', (91, 101))	('miR-542-3p', 'Chemical', '-', (91, 101))
71567	33922649	Next, we investigated the molecular target of miR-542-3p in the regulation of glycolytic activity in human glioma cells.	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('human', 'Species', '9606', (101, 106))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('miR-542-3p', 'Var', (46, 56))	('miR-542-3p', 'Chemical', '-', (46, 56))	('glioma', 'Disease', (107, 113))
71569	33922649	Similarly to the levels of ECAR, the knockdown of miR-542-3p significantly reduced the protein levels of HK2 compared to control (Figure 2B).	('knockdown', 'Var', (37, 46))	('reduced', 'NegReg', (75, 82))	('HK2', 'Protein', (105, 108))	('miR-542-3p', 'Var', (50, 60))	('protein levels', 'MPA', (87, 101))	('miR-542-3p', 'Chemical', '-', (50, 60))
71570	33922649	In addition, the knockdown of miR-542-3p decreased the protein levels of LDH-A relative to that of control (Figure 2B).	('miR-542-3p', 'Chemical', '-', (30, 40))	('protein levels', 'MPA', (55, 69))	('LDH-A', 'Protein', (73, 78))	('decreased', 'NegReg', (41, 50))	('miR-542-3p', 'Var', (30, 40))	('knockdown', 'Var', (17, 26))
71571	33922649	In contrast, the protein levels of other glycolytic enzymes such as phosphofructokinase (PFKP) and pyruvate kinase isozymes M2 (PKM2) were unchanged by miR-542-3p knockdown (Figure 2B).	('knockdown', 'Var', (163, 172))	('pyruvate kinase isozymes M2', 'Gene', '5315', (99, 126))	('phosphofructokinase', 'Enzyme', (68, 87))	('miR-542-3p knockdown', 'Var', (152, 172))	('protein levels', 'MPA', (17, 31))	('miR-542-3p', 'Chemical', '-', (152, 162))	('pyruvate kinase isozymes M2', 'Gene', (99, 126))
71572	33922649	Consistently, over-expression of miR-542-3p (miR-542-3p KO) significantly increased the glycolytic activity in response to glucose compared to that in control (Control) (Figure 2C).	('over-expression', 'PosReg', (14, 29))	('miR-542-3p', 'Var', (33, 43))	('increased', 'PosReg', (74, 83))	('glycolytic activity in response to glucose', 'MPA', (88, 130))	('miR-542-3p', 'Chemical', '-', (45, 55))	('miR-542-3p', 'Chemical', '-', (33, 43))	('glucose', 'Chemical', 'MESH:D005947', (123, 130))
71573	33922649	Moreover, over-expression of miR-542-3p increased the protein levels of HK2 and LDH-A relative to that in cells treated with microRNA mimic negative control (Control) (Figure 2D).	('over-expression', 'PosReg', (10, 25))	('HK2', 'Protein', (72, 75))	('protein levels', 'MPA', (54, 68))	('LDH-A', 'Gene', (80, 85))	('miR-542-3p', 'Var', (29, 39))	('increased', 'PosReg', (40, 49))	('miR-542-3p', 'Chemical', '-', (29, 39))
71574	33922649	The protein levels of other glycolytic enzymes including PFKP and PKM2 were not changed by the over-expression of miR-542-3p (Figure 2D).	('PFKP', 'Enzyme', (57, 61))	('protein levels', 'MPA', (4, 18))	('miR-542-3p', 'Var', (114, 124))	('miR-542-3p', 'Chemical', '-', (114, 124))	('PKM2', 'Enzyme', (66, 70))
71575	33922649	These results suggest that miR-542-3p regulates the HK2-mediated high glycolytic phenotype in human glioma cells.	('glioma', 'Disease', (100, 106))	('miR-542-3p', 'Var', (27, 37))	('high glycolytic phenotype', 'MPA', (65, 90))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('regulates', 'Reg', (38, 47))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('miR-542-3p', 'Chemical', '-', (27, 37))	('human', 'Species', '9606', (94, 99))	('HK2-mediated', 'Protein', (52, 64))
71579	33922649	ISH analysis revealed that the intensity of miR-542-3p-positive staining was significantly elevated in patients with high-grade gliomas (grade III and IV) compared to that in patients with low-grade gliomas (grade I and II) (Figure 3A,B).	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('gliomas', 'Disease', (128, 135))	('elevated', 'PosReg', (91, 99))	('miR-542-3p-positive', 'Var', (44, 63))	('miR-542-3p', 'Chemical', '-', (44, 54))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('patients', 'Species', '9606', (175, 183))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('patients', 'Species', '9606', (103, 111))	('gliomas', 'Disease', (199, 206))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))
71582	33922649	We performed the Kaplan-Meier estimation test and Cox-regression analysis of patients with low and high levels of miR-542-3p using the datasets from The Cancer Genome Atlas (TCGA) (Figure 3C).	('Cancer', 'Disease', 'MESH:D009369', (153, 159))	('miR-542-3p', 'Var', (114, 124))	('patients', 'Species', '9606', (77, 85))	('miR-542-3p', 'Chemical', '-', (114, 124))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Disease', (153, 159))
71583	33922649	The high levels of miR-542-3p were associated with poor survival rate in the GBM and LGG datasets from the TCGA by median survival rate with log-rank test (Log-rank p = 0.0037, Cox-regression p = 0.004, hazard ratio: 1.7 (Confidence interval: 1.18-2.43), and C-index with Cox-regression analysis: 0.6 (standard error: 0.02)) (Figure 3C).	('miR-542-3p', 'Var', (19, 29))	('poor', 'NegReg', (51, 55))	('miR-542-3p', 'Chemical', '-', (19, 29))	('survival', 'CPA', (56, 64))
71584	33922649	These results suggest that the levels of miR-542-3p were elevated and were associated with poor survival rates in patients with gliomas.	('survival rates', 'CPA', (96, 110))	('miR-542-3p', 'Var', (41, 51))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('miR-542-3p', 'Chemical', '-', (41, 51))	('elevated', 'PosReg', (57, 65))	('poor', 'NegReg', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('patients', 'Species', '9606', (114, 122))
71593	33922649	Our results demonstrate that miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.	('HK2-mediated', 'Protein', (59, 71))	('high glycolytic phenotype', 'MPA', (72, 97))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('human', 'Species', '9606', (101, 106))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('miR-542-3p', 'Var', (29, 39))	('miR-542-3p', 'Chemical', '-', (29, 39))	('contributes', 'Reg', (40, 51))	('glioma', 'Disease', (107, 113))
71594	33922649	We suggest that miR-542-3p regulates HK2-mediated high glycolytic activity.	('HK2-mediated', 'Protein', (37, 49))	('high glycolytic activity', 'MPA', (50, 74))	('regulates', 'Reg', (27, 36))	('miR-542-3p', 'Var', (16, 26))	('miR-542-3p', 'Chemical', '-', (16, 26))
71595	33922649	Knockdown of miR-542-3p suppresses cellular proliferation.	('miR-542-3p', 'Chemical', '-', (13, 23))	('miR-542-3p', 'Var', (13, 23))	('suppresses', 'NegReg', (24, 34))	('cellular proliferation', 'CPA', (35, 57))
71597	33922649	The levels of miR-542-3p were positively correlated with the levels of HK in the TCGA.	('miR-542-3p', 'Chemical', '-', (14, 24))	('levels', 'MPA', (61, 67))	('HK', 'Gene', '3098', (71, 73))	('miR-542-3p', 'Var', (14, 24))
71598	33922649	The high levels of miR-542-3p contribute to poor prognosis in patients with gliomas.	('miR-542-3p', 'Chemical', '-', (19, 29))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('patients', 'Species', '9606', (62, 70))	('miR-542-3p', 'Var', (19, 29))
71599	33922649	Our findings suggest that miR-542-3p regulates the high glycolytic phenotype via HK2-mediated glycolysis in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('HK2-mediated glycolysis', 'MPA', (81, 104))	('miR-542-3p', 'Chemical', '-', (26, 36))	('gliomas', 'Disease', (108, 115))	('regulates', 'Reg', (37, 46))	('high glycolytic phenotype', 'MPA', (51, 76))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('miR-542-3p', 'Var', (26, 36))
71613	33922649	Consistent with previous studies, we showed that miR-542-3p promotes the expression of HK2 and HK2-dependent high glycolytic activity in human glioma cells.	('promotes', 'PosReg', (60, 68))	('human', 'Species', '9606', (137, 142))	('miR-542-3p', 'Var', (49, 59))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('HK2', 'Protein', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('miR-542-3p', 'Chemical', '-', (49, 59))	('expression', 'MPA', (73, 83))	('high glycolytic activity', 'MPA', (109, 133))	('glioma', 'Disease', (143, 149))
71615	33922649	Our results suggest that miR-542-3p plays an oncogenesis role through the regulation of glycolytic activity in gliomas.	('gliomas', 'Disease', (111, 118))	('miR-542-3p', 'Var', (25, 35))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('glycolytic activity', 'MPA', (88, 107))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('miR-542-3p', 'Chemical', '-', (25, 35))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('regulation', 'MPA', (74, 84))
71622	33922649	In our study, we showed the elevation of miR-542-3p in tumor tissues of patients with high-grade gliomas.	('miR-542-3p', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR-542-3p', 'Chemical', '-', (41, 51))	('gliomas', 'Disease', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('tumor', 'Disease', (55, 60))	('elevation', 'PosReg', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('patients', 'Species', '9606', (72, 80))
71623	33922649	Moreover, we showed the levels of miR-542-3p positively correlated with HK2 levels in analysis of the GBM and LGG datasets from the TCGA.	('miR-542-3p', 'Var', (34, 44))	('miR-542-3p', 'Chemical', '-', (34, 44))	('correlated', 'Reg', (56, 66))	('HK2', 'MPA', (72, 75))
71626	33922649	Here, we suggest that miR-542-3p might be a critical factor for the high glycolytic phenotype in glioma.	('glioma', 'Disease', (97, 103))	('miR-542-3p', 'Var', (22, 32))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('miR-542-3p', 'Chemical', '-', (22, 32))
71627	33922649	We also suggest the potential role of miR-542-3p as a metabolic alteration regulator in glioma.	('miR-542-3p', 'Var', (38, 48))	('miR-542-3p', 'Chemical', '-', (38, 48))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
71628	33922649	Our findings suggest that miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.	('miR-542-3p', 'Chemical', '-', (26, 36))	('contributes', 'Reg', (37, 48))	('high glycolytic phenotype', 'MPA', (69, 94))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('HK2-mediated', 'Protein', (56, 68))	('human', 'Species', '9606', (98, 103))	('glioma', 'Disease', (104, 110))	('miR-542-3p', 'Var', (26, 36))
71629	33922649	In addition, our results suggest that miR-542-3p is associated with poor prognosis in patients with gliomas.	('miR-542-3p', 'Var', (38, 48))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('miR-542-3p', 'Chemical', '-', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('gliomas', 'Disease', (100, 107))	('patients', 'Species', '9606', (86, 94))
71664	30319400	Combinations of thalidomide/celecoxib with alternating LD etoposide/cyclophosphamide showed prolonged disease stabilizations in especially CNS-tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('celecoxib', 'Chemical', 'MESH:D000068579', (28, 37))	('Combinations', 'Var', (0, 12))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (68, 84))	('CNS-tumors', 'Disease', (139, 149))	('CNS-tumors', 'Disease', 'MESH:D009369', (139, 149))	('LD', 'Chemical', '-', (55, 57))	('thalidomide', 'Chemical', 'MESH:D013792', (16, 27))	('etoposide', 'Chemical', 'MESH:D005047', (58, 67))
71805	27246909	The most common genetic alteration in diffuse astrocytoma is mutations of the TP53 and IDH1/2 genes in 32% cases, 1p/19q loss and IDH1/2 mutation in 37% cases and only IDH1/2 mutation in 17% cases.	('IDH1/2', 'Gene', (87, 93))	('mutation', 'Var', (137, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (46, 57))	('loss', 'NegReg', (121, 125))	('common', 'Reg', (9, 15))	('IDH1/2', 'Gene', '3417;3418', (168, 174))	('IDH1/2', 'Gene', (130, 136))	('mutations', 'Var', (61, 70))	('astrocytoma', 'Disease', 'MESH:D001254', (46, 57))	('1p/19q', 'Var', (114, 120))	('astrocytoma', 'Disease', (46, 57))	('IDH1/2', 'Gene', '3417;3418', (87, 93))	('IDH1/2', 'Gene', (168, 174))	('TP53', 'Gene', (78, 82))	('TP53', 'Gene', '7157', (78, 82))	('IDH1/2', 'Gene', '3417;3418', (130, 136))
71867	27246909	Changes at the chromosome levels such as mutations, copy number variations are important factors that may affect downstream events relevant to tumor development.	('mutations', 'Var', (41, 50))	('copy number variations', 'Var', (52, 74))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('affect', 'Reg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
71875	27246909	In a recent study by TCGA group, genomic alterations including mutation, copy number variations and fusion transcript profiles, showed PI3K/AKT/mTOR signaling to be one of the major drivers for diffuse glioma.	('AKT', 'Gene', (140, 143))	('copy number variations', 'Var', (73, 95))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('mutation', 'Var', (63, 71))	('AKT', 'Gene', '207', (140, 143))	('glioma', 'Disease', (202, 208))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))
71887	27246909	It is linked to the malignant transformation of these tumours through mutations and copy number variations as well as overexpression at RNA and protein level.	('malignant transformation', 'CPA', (20, 44))	('mutations', 'Var', (70, 79))	('linked', 'Reg', (6, 12))	('copy number variations', 'Var', (84, 106))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
71932	32776110	The effects of silencing HAS2-AS1 on the migration and invasion of cancer cells were verified by wound healing and Transwell invasion assays.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('migration', 'CPA', (41, 50))	('cancer', 'Disease', (67, 73))	('HAS2-AS1', 'Gene', (25, 33))	('silencing', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('invasion', 'CPA', (55, 63))	('HAS2-AS1', 'Gene', '594842;3037;5729', (25, 33))
71935	32776110	Silencing HAS2-AS1 expression inhibited glioma cell migration, invasion and EMT.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('EMT', 'CPA', (76, 79))	('inhibited', 'NegReg', (30, 39))	('glioma', 'Disease', (40, 46))	('HAS2-AS1', 'Gene', (10, 18))	('invasion', 'CPA', (63, 71))	('Silencing', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('HAS2-AS1', 'Gene', '594842;3037;5729', (10, 18))
71946	32776110	For example, linc00319 expresses at a high level in glioma and is significantly associated with poor prognosis of glioma patients, while knockdown of linc00319 impairs cell proliferation, arrests cell cycle and induces cell apoptosis of glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('linc00319', 'Gene', (13, 22))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('linc00319', 'Gene', '284836', (150, 159))	('arrests', 'NegReg', (188, 195))	('associated', 'Reg', (80, 90))	('glioma', 'Disease', (114, 120))	('cell proliferation', 'CPA', (168, 186))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('knockdown', 'Var', (137, 146))	('linc00319', 'Gene', '284836', (13, 22))	('induces', 'Reg', (211, 218))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Disease', (237, 243))	('linc00319', 'Gene', (150, 159))	('patients', 'Species', '9606', (121, 129))	('impairs', 'NegReg', (160, 167))	('cell cycle', 'CPA', (196, 206))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('cell apoptosis', 'CPA', (219, 233))	('glioma', 'Disease', (52, 58))
71952	32776110	Silencing of HAS2-AS1 mediates PI3K/Akt signaling pathway to inhibit cell proliferation, migration, and invasion of glioma.	('glioma', 'Disease', (116, 122))	('HAS2-AS1', 'Gene', (13, 21))	('Akt', 'Gene', (36, 39))	('HAS2-AS1', 'Gene', '594842;3037;5729', (13, 21))	('inhibit', 'NegReg', (61, 68))	('cell proliferation', 'CPA', (69, 87))	('mediates', 'Reg', (22, 30))	('invasion', 'CPA', (104, 112))	('migration', 'CPA', (89, 98))	('Silencing', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('Akt', 'Gene', '207', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
71967	32776110	Human glioma cell lines U87 (BNCC352184) and U251 (BNCC337874) were cultured in Dulbecco's modified Eagle's medium (DMEM)/hyperglycemia with 10% FBS.	('Human', 'Species', '9606', (0, 5))	('BNCC337874', 'Var', (51, 61))	('hyperglycemia', 'Disease', 'MESH:D006943', (122, 135))	('U87', 'Gene', '641648', (24, 27))	('hyperglycemia', 'Phenotype', 'HP:0003074', (122, 135))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (80, 114))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('hyperglycemia', 'Disease', (122, 135))	('BNCC352184', 'Var', (29, 39))	('U87', 'Gene', (24, 27))	('glioma', 'Disease', (6, 12))	('DMEM', 'Chemical', '-', (116, 120))
71978	32776110	The primary antibodies used in the experiment were N-cadherin rabbit polyclonal antibody (ab76057, 1:1000, Abcam, Cambridge, U.K.), E-cadherin rabbit polyclonal antibody (ab15148, 1:500, Abcam, Cambridge, U.K.), Vimentin rabbit polyclonal antibody (ab137321, 1:2000, Abcam, Cambridge, U.K.) and GADPH rabbit polyclonal antibody (ab9485, 1:2500, Abcam, Cambridge, U.K.).	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('Vimentin', 'Gene', '7431', (212, 220))	('N-cadherin', 'Gene', (51, 61))	('ab76057', 'Var', (90, 97))	('Vimentin', 'Gene', (212, 220))	('N-cadherin', 'Gene', '1000', (51, 61))
71992	32776110	It could be seen from the results that silencing HAS2-AS1 inhibited EMT of glioma cells (Figure 1F).	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('glioma', 'Disease', (75, 81))	('HAS2-AS1', 'Gene', (49, 57))	('silencing', 'Var', (39, 48))	('inhibited', 'NegReg', (58, 67))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('HAS2-AS1', 'Gene', '594842;3037;5729', (49, 57))
71993	32776110	These results indicated that silencing HAS2-AS1 could inhibit the invasion and migration of glioma cells.	('inhibit', 'NegReg', (54, 61))	('HAS2-AS1', 'Gene', (39, 47))	('silencing', 'Var', (29, 38))	('glioma', 'Disease', (92, 98))	('HAS2-AS1', 'Gene', '594842;3037;5729', (39, 47))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
72010	32776110	Then, we divided the two glioma cell lines into three groups: si-NC+oe-NC, si-USF1+oe-NC, and si-USF1+oe-HAS2-AS1.	('USF1', 'Gene', '7391', (78, 82))	('USF1', 'Gene', (97, 101))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('USF1', 'Gene', (78, 82))	('HAS2-AS1', 'Gene', '594842;3037;5729', (105, 113))	('USF1', 'Gene', '7391', (97, 101))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('si-NC+oe-NC', 'Var', (62, 73))	('glioma', 'Disease', (25, 31))	('HAS2-AS1', 'Gene', (105, 113))
72012	32776110	It was observed that silencing USF1 inhibited the expression of HAS2-AS1, but the results were reversed after the simultaneous transfection of HAS2-AS1 overexpression vector (Figure 3B).	('USF1', 'Gene', (31, 35))	('inhibited', 'NegReg', (36, 45))	('HAS2-AS1', 'Gene', (64, 72))	('HAS2-AS1', 'Gene', (143, 151))	('silencing', 'Var', (21, 30))	('USF1', 'Gene', '7391', (31, 35))	('HAS2-AS1', 'Gene', '594842;3037;5729', (64, 72))	('HAS2-AS1', 'Gene', '594842;3037;5729', (143, 151))	('expression', 'MPA', (50, 60))
72013	32776110	The results showed that silencing USF1 dramatically inhibited migration and invasion abilities of glioma.	('USF1', 'Gene', '7391', (34, 38))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('inhibited', 'NegReg', (52, 61))	('glioma', 'Disease', (98, 104))	('USF1', 'Gene', (34, 38))	('silencing', 'Var', (24, 33))
72017	32776110	These results indicated that silencing USF1 could inhibit the expression of HAS2-AS1, thus inhibiting the invasion and migration of glioma cells.	('inhibiting', 'NegReg', (91, 101))	('glioma', 'Disease', (132, 138))	('silencing', 'Var', (29, 38))	('inhibit', 'NegReg', (50, 57))	('HAS2-AS1', 'Gene', '594842;3037;5729', (76, 84))	('expression', 'MPA', (62, 72))	('USF1', 'Gene', (39, 43))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('USF1', 'Gene', '7391', (39, 43))	('HAS2-AS1', 'Gene', (76, 84))
72027	32776110	The results discovered that silencing HAS2-AS1 significantly inhibited the migration and invasion of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('inhibited', 'NegReg', (61, 70))	('cancer', 'Disease', (101, 107))	('HAS2-AS1', 'Gene', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('silencing', 'Var', (28, 37))	('HAS2-AS1', 'Gene', '594842;3037;5729', (38, 46))
72028	32776110	Meanwhile, the expressions of EMT-related proteins in each group further confirmed the above result, and silencing HAS2-AS1 inhibited the occurrence of EMT.	('silencing', 'Var', (105, 114))	('HAS2-AS1', 'Gene', '594842;3037;5729', (115, 123))	('inhibited', 'NegReg', (124, 133))	('HAS2-AS1', 'Gene', (115, 123))
72029	32776110	These studies fully demonstrated that silencing HAS2-AS1 could inhibit the development of glioma, and HAS2-AS1 might be a potential target for glioma treatment.	('HAS2-AS1', 'Gene', '594842;3037;5729', (48, 56))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('HAS2-AS1', 'Gene', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('HAS2-AS1', 'Gene', (48, 56))	('glioma', 'Disease', (143, 149))	('HAS2-AS1', 'Gene', '594842;3037;5729', (102, 110))	('inhibit', 'NegReg', (63, 70))	('silencing', 'Var', (38, 47))
72037	32776110	found that knockout of USF1 inhibits the vasculogenic mimicry of glioma cells via stimulating small nucleolar RNA host gene 16 (SNHG16)/miR-212-3p and Linc00667/miR-429 axis.	('glioma', 'Disease', (65, 71))	('inhibits', 'NegReg', (28, 36))	('small nucleolar RNA host gene 16', 'Gene', (94, 126))	('Linc00667', 'Gene', (151, 160))	('stimulating', 'PosReg', (82, 93))	('miR-429', 'Gene', '554210', (161, 168))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('USF1', 'Gene', (23, 27))	('Linc00667', 'Gene', '339290', (151, 160))	('miR-429', 'Gene', (161, 168))	('SNHG16', 'Gene', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('SNHG16', 'Gene', '100507246', (128, 134))	('small nucleolar RNA host gene 16', 'Gene', '100507246', (94, 126))	('knockout', 'Var', (11, 19))	('USF1', 'Gene', '7391', (23, 27))
72040	32776110	Inhibiting the expression of USF1 could reduce the migration and invasion abilities of glioma cells, while overexpressing HAS2-AS1 could recover the inhibitory effects of USF1 on glioma cells to a certain extent.	('glioma', 'Disease', (87, 93))	('Inhibiting', 'Var', (0, 10))	('USF1', 'Gene', '7391', (171, 175))	('USF1', 'Gene', (29, 33))	('reduce', 'NegReg', (40, 46))	('HAS2-AS1', 'Gene', (122, 130))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('USF1', 'Gene', (171, 175))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('USF1', 'Gene', '7391', (29, 33))	('HAS2-AS1', 'Gene', '594842;3037;5729', (122, 130))	('glioma', 'Disease', (179, 185))
72118	32134389	This means that eReferrals led to a decrease in the time and number of tasks needed for MDT preparation, which gave nurse specialists, and other professionals, more time to spend with other clinical tasks, while preserving an optimal MDT preparation process.	('time', 'MPA', (52, 56))	('MDT', 'Chemical', '-', (234, 237))	('eReferrals', 'Var', (16, 26))	('MDT preparation process', 'MPA', (234, 257))	('decrease', 'NegReg', (36, 44))	('MDT', 'Chemical', '-', (88, 91))
72133	29780667	Modulation of transcriptional activity in brain lower grade glioma by alternative splicing Proteins that modify the activity of transcription factors (TFs) are often called modulators and play a vital role in gene transcriptional regulation.	('alternative splicing', 'Var', (70, 90))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('transcriptional', 'MPA', (14, 29))	('glioma', 'Disease', (60, 66))	('activity', 'MPA', (116, 124))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
72137	29780667	As AS affects numerous genes and is highly important for regulating the normal expression and tissue specificity of a given gene, it is not surprising that changes in AS are frequently associated with human disease, such as cancers and neurodegenerative diseases.	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (236, 262))	('changes', 'Var', (156, 163))	('associated', 'Reg', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('neurodegenerative diseases', 'Disease', (236, 262))	('human', 'Species', '9606', (201, 206))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (236, 262))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancers', 'Disease', (224, 231))
72159	29780667	The results showed that more than 80% of the splicing proteins related to cancer were enriched, and most of the enriched canonical pathways overlapped with certain genes.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('canonical pathways', 'Pathway', (121, 139))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('splicing', 'Var', (45, 53))
72165	29780667	The isoforms range in length from 639 to 770 amino acids, and certain isoforms are preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease.	('associated', 'Reg', (178, 188))	('changes', 'Var', (120, 127))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (194, 213))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (194, 213))	("Alzheimer's disease", 'Disease', (194, 213))
72170	29780667	However, when APP interacts with ELK1 as a modulator, the original transcriptional activity of ELK1 changes: APP attenuates the inhibitory role of ELK1 for 164 targets, inverts its inhibitory activity for eight targets, and enhances activation for 14 targets.	('inhibitory activity', 'MPA', (181, 200))	('inhibitory role', 'MPA', (128, 143))	('ELK1', 'Gene', '2002', (147, 151))	('APP', 'Var', (109, 112))	('activation', 'MPA', (233, 243))	('inverts', 'NegReg', (169, 176))	('ELK1', 'Gene', (33, 37))	('ELK1', 'Gene', '2002', (33, 37))	('enhances', 'PosReg', (224, 232))	('ELK1', 'Gene', (95, 99))	('ELK1', 'Gene', '2002', (95, 99))	('ELK1', 'Gene', (147, 151))	('attenuates', 'NegReg', (113, 123))
72176	29780667	Figure 5A shows examples of APP-modulated ELK1 target genes and the corresponding action modes.	('ELK1', 'Gene', (42, 46))	('ELK1', 'Gene', '2002', (42, 46))	('APP-modulated', 'Var', (28, 41))
72191	29780667	The specific alternatively spliced exon of STK16 encodes a kinase domain, and thus it is not surprising that the loss of this exon will cause a change in protein function and may ultimately influence numerous normal gene functions.	('STK16', 'Gene', (43, 48))	('change', 'Reg', (144, 150))	('cause', 'Reg', (136, 141))	('protein function', 'MPA', (154, 170))	('STK16', 'Gene', '8576', (43, 48))	('loss', 'Var', (113, 117))	('influence', 'Reg', (190, 199))
72213	29780667	Mutations in this gene have been implicated in autosomal dominant Alzheimer's disease and cerebroarterial amyloidosis.	('amyloidosis', 'Phenotype', 'HP:0011034', (106, 117))	("autosomal dominant Alzheimer's disease", 'Disease', 'MESH:D000544', (47, 85))	('implicated', 'Reg', (33, 43))	('cerebroarterial amyloidosis', 'Disease', 'MESH:D028243', (90, 117))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (66, 85))	('Mutations', 'Var', (0, 9))	('cerebroarterial amyloidosis', 'Disease', (90, 117))	("autosomal dominant Alzheimer's disease", 'Disease', (47, 85))
72215	29780667	The splice isoforms that contain the BPTI domain possess protease inhibitor activity that induces an AGER-dependent pathway involving activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons.	('mitochondrial dysfunction', 'Disease', (226, 251))	('internalization', 'MPA', (171, 186))	('leading to', 'Reg', (215, 225))	('activation', 'PosReg', (134, 144))	('AGER', 'Gene', (101, 105))	('induces', 'Reg', (90, 97))	('BPTI domain', 'Var', (37, 48))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (226, 251))	('AGER', 'Gene', '177', (101, 105))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (226, 251))	('p38 MAPK', 'Pathway', (148, 156))
72248	19333441	Special emphasis will be put on the introduction of those molecular biomarkers that have been established in glioma diagnostics, namely MGMT promoter hypermethylation in glioblastomas and deletion of chromosome arms 1p and 19q in patients with oligodendroglial tumors.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('glioblastomas', 'Disease', (170, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('arms 1p', 'Gene', '3075', (211, 218))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('arms 1p', 'Gene', (211, 218))	('deletion', 'Var', (188, 196))	('glioma', 'Disease', (109, 115))	('patients', 'Species', '9606', (230, 238))	('glioblastomas', 'Phenotype', 'HP:0012174', (170, 183))	('MGMT', 'Gene', '4255', (136, 140))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (244, 267))	('MGMT', 'Gene', (136, 140))	('oligodendroglial tumors', 'Disease', (244, 267))	('glioblastomas', 'Disease', 'MESH:D005909', (170, 183))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
72252	19333441	The most common chromosomal abnormality in diffuse astrocytomas of WHO grade II is trisomy 7 or at least a gain of 7q, which has been detected by comparative genomic hybridization in 50% of the cases.	('trisomy 7', 'Var', (83, 92))	('astrocytomas', 'Disease', 'MESH:D001254', (51, 63))	('gain', 'PosReg', (107, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (51, 62))	('astrocytomas', 'Disease', (51, 63))
72253	19333441	The most common molecular alterations are mutations of the TP53 tumor suppressor gene at 17q13.1 in about 60% of cases as well as the just recently identified codon 132 mutations of the isocitrate dehydrogenase 1 (IDH1) gene in about 70% of diffuse astrocytomas (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TP53', 'Gene', '7157', (59, 63))	('tumor', 'Disease', (64, 69))	('TP53', 'Gene', (59, 63))	('astrocytoma', 'Phenotype', 'HP:0009592', (249, 260))	('astrocytomas', 'Disease', (249, 261))	('IDH1', 'Gene', (214, 218))	('mutations', 'Var', (42, 51))	('IDH1', 'Gene', '3417', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('isocitrate dehydrogenase 1', 'Gene', (186, 212))	('astrocytomas', 'Disease', 'MESH:D001254', (249, 261))	('isocitrate dehydrogenase 1', 'Gene', '3417', (186, 212))
72254	19333441	Even higher frequencies of TP53 mutations of up to 80% are detectable in the gemistocytic astrocytoma variant.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('astrocytoma', 'Disease', 'MESH:D001254', (90, 101))	('astrocytoma', 'Disease', (90, 101))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('mutations', 'Var', (32, 41))
72255	19333441	TP53 mutations are regarded as one of the earliest events in the tumorigenesis of diffuse astrocytomas, since in most cases they are already present in the first biopsy and their frequency does not increase in recurrences.	('astrocytomas', 'Disease', (90, 102))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', (65, 70))	('mutations', 'Var', (5, 14))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
72256	19333441	TP53 mutations in diffuse astrocytomas are commonly associated with loss of heterozygosity (LOH) at polymorphic loci on 17p resulting in complete loss of wild-type p53 in the tumor cells.	('loss', 'NegReg', (146, 150))	('TP53', 'Gene', '7157', (0, 4))	('tumor', 'Disease', (175, 180))	('TP53', 'Gene', (0, 4))	('astrocytomas', 'Disease', 'MESH:D001254', (26, 38))	('mutations', 'Var', (5, 14))	('astrocytomas', 'Disease', (26, 38))	('loss', 'NegReg', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('p53', 'Gene', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (26, 37))	('p53', 'Gene', '7157', (164, 167))
72259	19333441	Interestingly, MGMT hypermethylation was found to be associated with TP53 mutation but is mutually exclusive to p14ARF hypermethylation.	('p14ARF', 'Gene', (112, 118))	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('MGMT', 'Gene', '4255', (15, 19))	('MGMT', 'Gene', (15, 19))	('p14ARF', 'Gene', '1029', (112, 118))	('associated', 'Reg', (53, 63))
72261	19333441	Anaplastic astrocytomas show gains of chromosome 7 and TP53 mutations as well as IDH1 mutations at a similar frequency as diffuse astrocytomas.	('mutations', 'Var', (86, 95))	('Anaplastic astrocytomas', 'Disease', 'MESH:D001254', (0, 23))	('IDH1', 'Gene', '3417', (81, 85))	('astrocytomas', 'Disease', (11, 23))	('astrocytomas', 'Disease', 'MESH:D001254', (130, 142))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('gains', 'PosReg', (29, 34))	('astrocytomas', 'Disease', 'MESH:D001254', (11, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('astrocytomas', 'Disease', (130, 142))	('IDH1', 'Gene', (81, 85))	('chromosome 7', 'Gene', (38, 50))	('mutations', 'Var', (60, 69))	('Anaplastic astrocytomas', 'Disease', (0, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (130, 141))
72262	19333441	In addition, these tumors bear frequent allelic losses on chromosomes 6, 9p, 11p, 19q and 22q.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('allelic losses', 'Var', (40, 54))
72263	19333441	The CDKN2A, p14ARF and CDKN2B tumor suppressor genes are important targets for genetic and or epigenetic inactivation, with inactivation of p14ARF serving as an alternative means to impair the p53 pathway in cases without TP53 mutations.	('impair', 'NegReg', (182, 188))	('p53', 'Gene', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('inactivation', 'Var', (124, 136))	('p14ARF', 'Gene', '1029', (12, 18))	('CDKN2A', 'Gene', (4, 10))	('p14ARF', 'Gene', (140, 146))	('CDKN2B', 'Gene', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('inactivation', 'Var', (105, 117))	('TP53', 'Gene', '7157', (222, 226))	('CDKN2A', 'Gene', '1029', (4, 10))	('tumor', 'Disease', (30, 35))	('p14ARF', 'Gene', (12, 18))	('CDKN2B', 'Gene', '1030', (23, 29))	('epigenetic', 'Var', (94, 104))	('p53', 'Gene', '7157', (193, 196))	('p14ARF', 'Gene', '1029', (140, 146))	('TP53', 'Gene', (222, 226))
72268	19333441	In addition, about 25% of anaplastic astrocytomas carry mutations in the retinoblastoma gene (RB1) (Figure 1).	('mutations', 'Var', (56, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (37, 48))	('RB1', 'Gene', (94, 97))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (26, 49))	('retinoblastoma', 'Gene', (73, 87))	('retinoblastoma', 'Gene', '5925', (73, 87))	('RB1', 'Gene', '5925', (94, 97))	('anaplastic astrocytomas', 'Disease', (26, 49))	('retinoblastoma', 'Phenotype', 'HP:0009919', (73, 87))
72269	19333441	In contrast to glioblastomas, allelic losses on 10q and mutation of the PTEN tumor suppressor gene on 10q23 are rare in anaplastic astrocytomas (<10% of cases).	('PTEN', 'Gene', (72, 76))	('glioblastomas', 'Disease', (15, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (15, 27))	('PTEN', 'Gene', '5728', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (120, 143))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('allelic losses on', 'Var', (30, 47))	('anaplastic astrocytomas', 'Disease', (120, 143))	('mutation', 'Var', (56, 64))	('tumor', 'Disease', (77, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('glioblastomas', 'Phenotype', 'HP:0012174', (15, 28))	('glioblastomas', 'Disease', 'MESH:D005909', (15, 28))
72270	19333441	However, when present, PTEN mutation indicates a poor prognosis.	('mutation', 'Var', (28, 36))	('PTEN', 'Gene', '5728', (23, 27))	('PTEN', 'Gene', (23, 27))
72275	19333441	Primary glioblastomas exhibit frequent EGFR amplification, homozygous deletion of CDKN2A and p14ARF, CDK4 amplification, MDM2 or MDM4 amplification, RB1 mutation/homozygous deletion, monosomy 10 and PTEN mutation.	('PTEN', 'Gene', '5728', (199, 203))	('CDK4', 'Gene', (101, 105))	('RB1', 'Gene', (149, 152))	('p14ARF', 'Gene', '1029', (93, 99))	('Primary glioblastomas', 'Disease', (0, 21))	('EGFR', 'Gene', '1956', (39, 43))	('mutation/homozygous', 'Var', (153, 172))	('CDK4', 'Gene', '1019', (101, 105))	('CDKN2A', 'Gene', (82, 88))	('RB1', 'Gene', '5925', (149, 152))	('mutation', 'Reg', (204, 212))	('Primary glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('p14ARF', 'Gene', (93, 99))	('MDM2', 'Gene', (121, 125))	('deletion', 'Var', (70, 78))	('amplification', 'Reg', (44, 57))	('monosomy', 'Disease', (183, 191))	('CDKN2A', 'Gene', '1029', (82, 88))	('EGFR', 'Gene', (39, 43))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('MDM2', 'Gene', '4193', (121, 125))	('PTEN', 'Gene', (199, 203))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('MDM4', 'Gene', '4194', (129, 133))	('MDM4', 'Gene', (129, 133))
72276	19333441	EGFR amplification is particularly frequent in primary glioblastomas with a small cell, highly anaplastic histological phenotype.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('primary glioblastomas', 'Disease', 'MESH:D005909', (47, 68))	('primary glioblastomas', 'Disease', (47, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))	('glioblastomas', 'Phenotype', 'HP:0012174', (55, 68))	('frequent', 'Reg', (35, 43))	('EGFR', 'Gene', '1956', (0, 4))
72277	19333441	TP53 mutation is found in less than 30% of primary glioblastomas.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('primary glioblastomas', 'Disease', 'MESH:D005909', (43, 64))	('primary glioblastomas', 'Disease', (43, 64))	('glioblastomas', 'Phenotype', 'HP:0012174', (51, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('mutation', 'Var', (5, 13))
72278	19333441	In contrast, secondary glioblastomas arise from a lower-grade precursor lesion and carry TP53 and IDH1 mutations in more than two thirds of the cases.	('TP53', 'Gene', '7157', (89, 93))	('mutations', 'Var', (103, 112))	('TP53', 'Gene', (89, 93))	('glioblastomas', 'Disease', 'MESH:D005909', (23, 36))	('glioblastomas', 'Disease', (23, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('IDH1', 'Gene', (98, 102))	('IDH1', 'Gene', '3417', (98, 102))	('glioblastomas', 'Phenotype', 'HP:0012174', (23, 36))
72279	19333441	Also, allelic losses on 19q and 13q, promoter hypermethylation of the RB1 gene, and overexpression of PDGFRA are more common in secondary glioblastomas.	('PDGFRA', 'Gene', '5156', (102, 108))	('glioblastomas', 'Disease', (138, 151))	('PDGFRA', 'Gene', (102, 108))	('overexpression', 'PosReg', (84, 98))	('RB1', 'Gene', (70, 73))	('allelic losses', 'Var', (6, 20))	('glioblastomas', 'Phenotype', 'HP:0012174', (138, 151))	('RB1', 'Gene', '5925', (70, 73))	('promoter', 'MPA', (37, 45))	('glioblastomas', 'Disease', 'MESH:D005909', (138, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))
72280	19333441	Amplification of EGFR or MDM2, PTEN mutation as well as homozygous CDKN2A or p14ARF deletions are all rare in secondary glioblastomas.	('PTEN', 'Gene', (31, 35))	('p14ARF', 'Gene', (77, 83))	('CDKN2A', 'Gene', (67, 73))	('PTEN', 'Gene', '5728', (31, 35))	('glioblastomas', 'Phenotype', 'HP:0012174', (120, 133))	('MDM2', 'Gene', '4193', (25, 29))	('CDKN2A', 'Gene', '1029', (67, 73))	('MDM2', 'Gene', (25, 29))	('glioblastomas', 'Disease', 'MESH:D005909', (120, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('p14ARF', 'Gene', '1029', (77, 83))	('EGFR', 'Gene', '1956', (17, 21))	('glioblastomas', 'Disease', (120, 133))	('deletions', 'Var', (84, 93))	('mutation', 'Var', (36, 44))	('EGFR', 'Gene', (17, 21))
72281	19333441	Also epigenetic silencing of various genes has been described as overrepresented in either primary (NDRG2) or secondary (MGMT and EMP3) glioblastomas.	('NDRG2', 'Gene', (100, 105))	('MGMT', 'Gene', '4255', (121, 125))	('EMP3', 'Gene', '2014', (130, 134))	('MGMT', 'Gene', (121, 125))	('glioblastomas', 'Phenotype', 'HP:0012174', (136, 149))	('glioblastomas', 'Disease', 'MESH:D005909', (136, 149))	('overrepresented', 'PosReg', (65, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('epigenetic silencing', 'Var', (5, 25))	('glioblastomas', 'Disease', (136, 149))	('EMP3', 'Gene', (130, 134))	('NDRG2', 'Gene', '57447', (100, 105))
72283	19333441	The fact that the different molecular alterations converge on the same downstream cellular pathways, namely the p53, pRb1, PTEN/PI3K/AKT and mitogen-activated protein kinase pathways, and thereby lead to similar functional consequences, may explain this phenomenon.	('pRb1', 'Gene', '5542', (117, 121))	('AKT', 'Gene', '207', (133, 136))	('mitogen-activated protein kinase pathways', 'Pathway', (141, 182))	('p53', 'Gene', (112, 115))	('pRb1', 'Gene', (117, 121))	('PTEN', 'Gene', (123, 127))	('alterations', 'Var', (38, 49))	('AKT', 'Gene', (133, 136))	('PTEN', 'Gene', '5728', (123, 127))	('p53', 'Gene', '7157', (112, 115))
72285	19333441	Chemotherapy-induced alkylation in this location triggers cytotoxicity and apoptosis.	('alkylation', 'Var', (21, 31))	('apoptosis', 'CPA', (75, 84))	('cytotoxicity', 'Disease', (58, 70))	('triggers', 'Reg', (49, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))	('Chemotherapy-induced', 'Var', (0, 20))
72287	19333441	Epigenetic silencing of MGMT by means of promoter hypermethylation is present in about 40% of primary glioblastomas and has been identified as the main mechanism reducing MGMT expression and thereby diminishing its DNA repair activity.	('promoter', 'MPA', (41, 49))	('MGMT', 'Gene', '4255', (24, 28))	('diminishing', 'NegReg', (199, 210))	('glioblastomas', 'Phenotype', 'HP:0012174', (102, 115))	('primary glioblastomas', 'Disease', (94, 115))	('DNA repair activity', 'MPA', (215, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('expression', 'MPA', (176, 186))	('Epigenetic silencing', 'Var', (0, 20))	('reducing', 'NegReg', (162, 170))	('MGMT', 'Gene', '4255', (171, 175))	('MGMT', 'Gene', (171, 175))	('MGMT', 'Gene', (24, 28))	('primary glioblastomas', 'Disease', 'MESH:D005909', (94, 115))
72289	19333441	Based on MGMT promoter methylation analysis in glioblastomas from patients treated in a large prospective clinical trial, patients whose tumors had a methylated MGMT promoter survived significantly longer as compared to patients whose tumors lacked MGMT promoter methylation when treated with combined radio-/ chemotherapy.	('tumors', 'Disease', (137, 143))	('MGMT', 'Gene', '4255', (9, 13))	('glioblastomas', 'Disease', (47, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('patients', 'Species', '9606', (220, 228))	('methylated', 'Var', (150, 160))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('glioblastomas', 'Disease', 'MESH:D005909', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('MGMT', 'Gene', (249, 253))	('MGMT', 'Gene', (161, 165))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('MGMT', 'Gene', (9, 13))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (66, 74))	('tumors', 'Disease', (235, 241))	('longer', 'PosReg', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('glioblastomas', 'Phenotype', 'HP:0012174', (47, 60))	('MGMT', 'Gene', '4255', (249, 253))	('MGMT', 'Gene', '4255', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
72292	19333441	Giant cell glioblastomas carry TP53 mutations in up to 90% and PTEN mutations in 30-40% of cases, thus combining molecular features of both primary and secondary glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('PTEN', 'Gene', '5728', (63, 67))	('TP53', 'Gene', '7157', (31, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (11, 23))	('TP53', 'Gene', (31, 35))	('glioblastomas', 'Phenotype', 'HP:0012174', (11, 24))	('mutations', 'Var', (36, 45))	('glioblastoma', 'Disease', (11, 23))	('glioblastomas', 'Disease', 'MESH:D005909', (11, 24))	('glioblastoma', 'Disease', (162, 174))	('mutations', 'Var', (68, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('glioblastomas', 'Disease', (11, 24))	('PTEN', 'Gene', (63, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (11, 23))
72298	19333441	Chromosomal comparative genomic hybridization (CGH) studies in 48 pilocytic astrocytomas revealed chromosomal imbalances only in a small subgroup of seven neoplasms with gain of 9q34.1-qter constituting the most common abnormality.	('neoplasms', 'Disease', 'MESH:D009369', (155, 164))	('pilocytic astrocytomas', 'Disease', (66, 88))	('neoplasms', 'Disease', (155, 164))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (66, 88))	('imbalance', 'Phenotype', 'HP:0002172', (110, 119))	('gain of 9q34.1-qter', 'Var', (170, 189))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('imbalances', 'Phenotype', 'HP:0002172', (110, 120))	('neoplasms', 'Phenotype', 'HP:0002664', (155, 164))
72299	19333441	Recurrent trisomies of chromosomes 5 and chromosome 7 have been reported in another study employing array-CGH on 53 pilocytic astrocytomas (Figure 2).	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('trisomies', 'Var', (10, 19))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (116, 138))	('pilocytic astrocytomas', 'Disease', (116, 138))
72301	19333441	In this setting, pilocytic astrocytomas are typically located in the optic nerve, often bilaterally, and carry allelic losses at the NF1 tumor suppressor gene locus at 17q11.2.	('tumor', 'Disease', (137, 142))	('pilocytic astrocytomas', 'Disease', (17, 39))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (17, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('NF1', 'Gene', (133, 136))	('allelic losses', 'Var', (111, 125))	('NF1', 'Gene', '4763', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
72303	19333441	Furthermore, neither NF1 mutations nor loss of NF1 mRNA expression were found in sporadic pilocytic astrocytomas.	('mutations', 'Var', (25, 34))	('pilocytic astrocytomas', 'Disease', (90, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (90, 112))	('NF1', 'Gene', (47, 50))	('NF1', 'Gene', (21, 24))	('NF1', 'Gene', '4763', (47, 50))	('NF1', 'Gene', '4763', (21, 24))	('mRNA expression', 'MPA', (51, 66))
72304	19333441	Losses on 17p and mutations in the TP53 tumor suppressor genes that are observed in diffuse astrocytomas are not a common feature in pilocytic astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (92, 104))	('Losses', 'NegReg', (0, 6))	('astrocytomas', 'Disease', 'MESH:D001254', (143, 155))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (133, 155))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('astrocytomas', 'Disease', (92, 104))	('diffuse', 'Disease', (84, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('astrocytomas', 'Disease', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('pilocytic astrocytomas', 'Disease', (133, 155))	('mutations', 'Var', (18, 27))
72306	19333441	BRAF duplication results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene with constitutive BRAF kinase activity.	('duplication', 'Var', (5, 16))	('BRAF', 'Gene', '673', (91, 95))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('BRAF', 'Gene', (91, 95))	('BRAF', 'Gene', '673', (0, 4))	('results in', 'Reg', (17, 27))	('kinase', 'MPA', (70, 76))	('BRAF', 'Gene', (0, 4))
72307	19333441	A small subset of tumors alternatively carries activating BRAF mutations, thus implicating this gene as an important proto-oncogene in these tumors (Figure 2).	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('activating', 'PosReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
72313	19333441	Loss on chromosome 9 is the most common genomic imbalance in pleomorphic xanthoastrocytoma (PXA), which is detectable by CGH analysis in 50% of cases.	('imbalance', 'Phenotype', 'HP:0002172', (48, 57))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (61, 90))	('Loss on chromosome', 'Var', (0, 18))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('pleomorphic xanthoastrocytoma', 'Disease', (61, 90))
72314	19333441	TP53 mutations are seen in a small fraction of tumors (<10% of cases), while 1p/19q losses as well as amplification of EGFR, CDK4 and MDM2 are absent.	('CDK4', 'Gene', (125, 129))	('tumors', 'Disease', (47, 53))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('CDK4', 'Gene', '1019', (125, 129))	('losses', 'NegReg', (84, 90))	('MDM2', 'Gene', '4193', (134, 138))	('mutations', 'Var', (5, 14))	('MDM2', 'Gene', (134, 138))	('EGFR', 'Gene', '1956', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('EGFR', 'Gene', (119, 123))
72317	19333441	Biallelic inactivation of either the TSC1 or the TSC2 tumor suppressor gene is a hallmark for these tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('TSC2', 'Gene', '7249', (49, 53))	('TSC1', 'Gene', '7248', (37, 41))	('TSC2', 'Gene', (49, 53))	('tumor', 'Disease', (100, 105))	('TSC1', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('Biallelic inactivation', 'Var', (0, 22))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
72318	19333441	Since the corresponding gene products have an inhibitory function on the mTOR pathway, their mutational inactivation leads to aberrant activation of mTOR signaling, which in turn represents an interesting novel target for specific pharmacologic inhibition.	('mTOR', 'Gene', '2475', (73, 77))	('activation', 'PosReg', (135, 145))	('mTOR', 'Gene', (73, 77))	('mutational', 'Var', (93, 103))	('mTOR', 'Gene', '2475', (149, 153))	('mTOR', 'Gene', (149, 153))
72329	19333441	Both oligodendrogliomas of WHO grade II as well as anaplastic oligodendrogliomas (WHO grade III) share the high frequency of IDH1 mutations (~70%) with astrocytic gliomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (5, 23))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (51, 80))	('oligodendrogliomas', 'Disease', (5, 23))	('anaplastic oligodendrogliomas', 'Disease', (51, 80))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (62, 80))	('IDH1', 'Gene', '3417', (125, 129))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (152, 170))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('mutations', 'Var', (130, 139))	('astrocytic gliomas', 'Disease', (152, 170))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('oligodendrogliomas', 'Disease', (62, 80))	('IDH1', 'Gene', (125, 129))
72330	19333441	Allelic losses on 17p and TP53 gene mutations are rare in low-grade oligodendrogliomas as they are mutually exclusive to the frequent 1p/19q losses.	('TP53', 'Gene', (26, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (68, 86))	('mutations', 'Var', (36, 45))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('oligodendrogliomas', 'Disease', (68, 86))	('TP53', 'Gene', '7157', (26, 30))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
72331	19333441	Nevertheless functional inactivation of the p53 pathway in oligodendrogliomas may be achieved by means of epigenetic silencing of the p14ARF gene, which thereby loses its ability to bind Mdm2 and to prevent the Mdm2-mediated degradation of p53.	('Mdm2', 'Gene', (211, 215))	('p14ARF', 'Gene', (134, 140))	('p53', 'Gene', '7157', (240, 243))	('ability', 'MPA', (171, 178))	('prevent', 'NegReg', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('oligodendrogliomas', 'Disease', (59, 77))	('p53', 'Gene', (240, 243))	('loses', 'NegReg', (161, 166))	('Mdm2', 'Gene', '4193', (187, 191))	('inactivation', 'NegReg', (24, 36))	('Mdm2', 'Gene', '4193', (211, 215))	('degradation', 'MPA', (225, 236))	('p53', 'Gene', '7157', (44, 47))	('p14ARF', 'Gene', '1029', (134, 140))	('bind', 'Interaction', (182, 186))	('epigenetic silencing', 'Var', (106, 126))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (59, 77))	('p53', 'Gene', (44, 47))	('Mdm2', 'Gene', (187, 191))
72335	19333441	Initially reported by Cairncross and colleagues in 1998, several retrospective studies have confirmed combined deletions of 1p and 19q as an independent marker of favorable response to radio- and chemotherapy as well as prolonged survival in patients with high-grade oligodendroglial tumors.	('19q', 'Gene', (131, 134))	('prolonged', 'PosReg', (220, 229))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (267, 290))	('oligodendroglial tumors', 'Disease', (267, 290))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('deletions', 'Var', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('patients', 'Species', '9606', (242, 250))
72336	19333441	Also, two prospective and randomized phase III trials involving 368 patients and 289 patients, respectively, confirmed the prognostic value of 1p/19q deletion in patients with anaplastic oligodendroglial tumors.	('patients', 'Species', '9606', (162, 170))	('1p/19q deletion', 'Var', (143, 158))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (176, 210))	('anaplastic oligodendroglial tumors', 'Disease', (176, 210))
72338	19333441	Thus, it is likely that molecular testing for 1p/19q deletion will become a routine adjunct to histology in the diagnostic assessment of anaplastic gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('1p/19q deletion', 'Var', (46, 61))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (137, 155))	('anaplastic gliomas', 'Disease', (137, 155))
72340	19333441	Several recent studies independently reported that 1p deletion or 1p/19q co-deletion were also associated with a trend towards longer survival in low-grade oligodendroglioma patients, and that in patients treated with temozolomide 1p loss was associated with objective treatment response.	('temozolomide', 'Chemical', 'MESH:D000077204', (218, 230))	('1p deletion', 'Var', (51, 62))	('oligodendroglioma', 'Disease', (156, 173))	('1p/19q co-deletion', 'Var', (66, 84))	('longer', 'PosReg', (127, 133))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (196, 204))	('oligodendroglioma', 'Disease', 'MESH:D009837', (156, 173))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))
72347	19333441	Anaplastic oligodendrogliomas share the frequent loss of alleles on 1p and 19q with low-grade oligodendrogliomas, but additionally show frequent deletions on 9p and/or on chromosome 10 (Figure 3).	('Anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 29))	('oligodendrogliomas', 'Disease', (11, 29))	('loss', 'NegReg', (49, 53))	('oligodendrogliomas', 'Disease', (94, 112))	('Anaplastic oligodendrogliomas', 'Disease', (0, 29))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (11, 29))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (94, 112))	('deletions', 'Var', (145, 154))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
72348	19333441	On 9p21, the tumor suppressor genes CDKN2A, p14ARF and CDKN2B are homozygously deleted in up to one third of anaplastic oligodendrogliomas.	('p21', 'Gene', (4, 7))	('CDKN2B', 'Gene', (55, 61))	('tumor', 'Disease', (13, 18))	('CDKN2A', 'Gene', (36, 42))	('p14ARF', 'Gene', (44, 50))	('p21', 'Gene', '1026', (4, 7))	('CDKN2B', 'Gene', '1030', (55, 61))	('CDKN2A', 'Gene', '1029', (36, 42))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('deleted', 'Var', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('p14ARF', 'Gene', '1029', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (109, 138))	('anaplastic oligodendrogliomas', 'Disease', (109, 138))
72349	19333441	Such deletions are particularly common in anaplastic oligodendrogliomas without 1p and 19q losses, but may also be present in 1p/19q-deleted cases.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (42, 71))	('anaplastic oligodendrogliomas', 'Disease', (42, 71))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('common', 'Reg', (32, 38))	('deletions', 'Var', (5, 14))
72350	19333441	PTEN mutations occur in only about half of the cases with 10q loss, suggesting that there might be another progression-related target gene in this region.	('loss', 'NegReg', (62, 66))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('mutations', 'Var', (5, 14))
72351	19333441	PTEN mutations and 10q deletions are more common in anaplastic oligodendrogliomas without 1p and 19q losses.	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (52, 81))	('mutations', 'Var', (5, 14))	('anaplastic oligodendrogliomas', 'Disease', (52, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('PTEN', 'Gene', (0, 4))	('common', 'Reg', (42, 48))	('PTEN', 'Gene', '5728', (0, 4))
72352	19333441	Rare anaplastic oligodendrogliomas carry activating mutations in the PIK3CA gene.	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('PIK3CA', 'Gene', (69, 75))	('activating mutations', 'Var', (41, 61))	('PIK3CA', 'Gene', '5290', (69, 75))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (5, 34))	('anaplastic oligodendrogliomas', 'Disease', (5, 34))
72358	19333441	Roughly half of the oligoastrocytomas show allelic losses on 1p and 19q.	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (20, 37))	('allelic losses', 'Var', (43, 57))	('oligoastrocytomas', 'Disease', (20, 37))
72361	19333441	TP53 mutation and loss of heterozygosity on 17p.	('TP53', 'Gene', '7157', (0, 4))	('loss', 'NegReg', (18, 22))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
72362	19333441	Those oligoastrocytomas with TP53 mutation and 17p loss do not have LOH on 1p and 19q, and vice versa.	('oligoastrocytomas', 'Disease', (6, 23))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (6, 23))	('mutation', 'Var', (34, 42))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('loss', 'NegReg', (51, 55))
72365	19333441	While rare in classic glioblastomas (less than 10% of the cases), 1p/19q deletions may be more common in glioblastomas with an oligodendroglial component, which in part may account for the better survival associated with this particular glioblastoma subgroup.	('glioblastomas', 'Phenotype', 'HP:0012174', (22, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('oligodendroglial component', 'Disease', (127, 153))	('1p/19q deletions', 'Var', (66, 82))	('glioblastoma', 'Disease', (237, 249))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('oligodendroglial component', 'Disease', 'MESH:C562869', (127, 153))	('glioblastoma', 'Disease', (22, 34))	('glioblastomas', 'Disease', (22, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('glioblastoma', 'Disease', (105, 117))	('glioblastomas', 'Disease', (105, 118))	('glioblastomas', 'Disease', 'MESH:D005909', (22, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('glioblastomas', 'Disease', 'MESH:D005909', (105, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (237, 249))	('common', 'Reg', (95, 101))
72367	19333441	Recent studies using CGH analysis reported on distinct patterns of chromosomal aberrations being linked to certain clinical and pathological features of ependymomas, such as patient age, tumor location, and histological subtype or WHO grade.	('ependymoma', 'Phenotype', 'HP:0002888', (153, 163))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (67, 90))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('patient', 'Species', '9606', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('ependymomas', 'Disease', 'MESH:D004806', (153, 164))	('linked', 'Reg', (97, 103))	('tumor', 'Disease', (187, 192))	('chromosomal aberrations', 'Var', (67, 90))	('ependymomas', 'Disease', (153, 164))
72368	19333441	Losses on 22q and gains of chromosome 4 were more common in adult tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('adult tumors', 'Disease', (60, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('gains', 'Var', (18, 23))	('Losses on', 'Var', (0, 9))	('adult tumors', 'Disease', 'MESH:C538052', (60, 72))	('22q', 'Protein', (10, 13))
72372	19333441	Molecular genetic studies on selected candidate genes revealed frequent NF2 gene mutations in intramedullary spinal ependymomas, while deletions of the CDKN2A gene were frequent in intracranial supratentorial ependymomas but rare in ependymomas from other locations (Figure 5).	('CDKN2A', 'Gene', (152, 158))	('ependymomas', 'Disease', 'MESH:D004806', (233, 244))	('ependymomas', 'Disease', (209, 220))	('CDKN2A', 'Gene', '1029', (152, 158))	('spinal ependymomas', 'Disease', (109, 127))	('ependymomas', 'Disease', (116, 127))	('ependymomas', 'Disease', (233, 244))	('ependymoma', 'Phenotype', 'HP:0002888', (209, 219))	('ependymoma', 'Phenotype', 'HP:0002888', (116, 126))	('NF2', 'Gene', (72, 75))	('spinal ependymomas', 'Disease', 'MESH:D004806', (109, 127))	('mutations', 'Var', (81, 90))	('ependymoma', 'Phenotype', 'HP:0002888', (233, 243))	('NF2', 'Gene', '4771', (72, 75))	('deletions', 'Var', (135, 144))	('ependymomas', 'Disease', 'MESH:D004806', (116, 127))	('ependymomas', 'Disease', 'MESH:D004806', (209, 220))
72373	19333441	Mutations in the TP53, PTEN and INI1 tumor suppressor genes are not a common feature in ependymomas.	('INI1', 'Gene', (32, 36))	('INI1', 'Gene', '6598', (32, 36))	('ependymomas', 'Disease', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ependymoma', 'Phenotype', 'HP:0002888', (88, 98))	('PTEN', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (37, 42))	('PTEN', 'Gene', '5728', (23, 27))	('ependymomas', 'Disease', 'MESH:D004806', (88, 99))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
72374	19333441	The tumors suppressor genes RASSF1, CDKN2A, CDKN2B, p14ARF and TP73, as well as other genes potentially involved in the tumorigenesis of ependymomas, such as CASP1, MGMT, TIMP3 and THBS1 are epigenetically silenced by aberrant promoter methylation in subsets of ependymomas.	('tumor', 'Disease', (4, 9))	('ependymomas', 'Disease', 'MESH:D004806', (137, 148))	('p14ARF', 'Gene', '1029', (52, 58))	('CDKN2A', 'Gene', (36, 42))	('TP73', 'Gene', '7161', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('TP73', 'Gene', (63, 67))	('ependymomas', 'Disease', (137, 148))	('CDKN2A', 'Gene', '1029', (36, 42))	('ependymomas', 'Disease', 'MESH:D004806', (262, 273))	('RASSF1', 'Gene', '11186', (28, 34))	('p14ARF', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('aberrant promoter methylation', 'Var', (218, 247))	('tumor', 'Disease', (120, 125))	('RASSF1', 'Gene', (28, 34))	('THBS1', 'Gene', (181, 186))	('MGMT', 'Gene', '4255', (165, 169))	('THBS1', 'Gene', '7057', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('CDKN2B', 'Gene', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CASP1', 'Gene', (158, 163))	('ependymomas', 'Disease', (262, 273))	('tumors', 'Disease', (4, 10))	('TIMP3', 'Gene', (171, 176))	('CASP1', 'Gene', '834', (158, 163))	('TIMP3', 'Gene', '7078', (171, 176))	('ependymoma', 'Phenotype', 'HP:0002888', (262, 272))	('ependymoma', 'Phenotype', 'HP:0002888', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CDKN2B', 'Gene', '1030', (44, 50))	('MGMT', 'Gene', (165, 169))
72378	19333441	In an analysis of 23 anaplastic ependymomas, loss of chromosome arm 10q appeared overrepresented.	('ependymoma', 'Phenotype', 'HP:0002888', (32, 42))	('anaplastic ependymomas', 'Phenotype', 'HP:0030066', (21, 43))	('anaplastic ependymomas', 'Disease', (21, 43))	('anaplastic ependymomas', 'Disease', 'MESH:D004806', (21, 43))	('loss', 'Var', (45, 49))
72379	19333441	Also, gain of 1q, with DUSP12 on 1q23 as a potential target gene, as well as losses of 9 and 13 were associated with WHO grade III lesions (Figure 5).	('WHO grade III lesions', 'Disease', (117, 138))	('gain', 'PosReg', (6, 10))	('DUSP12', 'Gene', (23, 29))	('DUSP12', 'Gene', '11266', (23, 29))	('losses', 'Var', (77, 83))
72382	19333441	In spite of their benign clinical behavior, myxopapillary ependymomas are often aneuploid or tetraploid and carry numerous chromosomal imbalances, as determined by CGH analysis.	('aneuploid', 'Var', (80, 89))	('myxopapillary ependymomas', 'Disease', 'MESH:D004806', (44, 69))	('imbalance', 'Phenotype', 'HP:0002172', (135, 144))	('numerous chromosomal imbalances', 'Phenotype', 'HP:0040012', (114, 145))	('carry', 'Reg', (108, 113))	('ependymoma', 'Phenotype', 'HP:0002888', (58, 68))	('imbalances', 'Phenotype', 'HP:0002172', (135, 145))	('myxopapillary ependymomas', 'Disease', (44, 69))
72383	19333441	In fact, the average number of chromosomal aberrations per tumor is considerably higher than that in ependymomas and anaplastic ependymomas.	('ependymoma', 'Phenotype', 'HP:0002888', (128, 138))	('tumor', 'Disease', (59, 64))	('ependymoma', 'Phenotype', 'HP:0002888', (101, 111))	('chromosomal aberrations', 'Var', (31, 54))	('higher', 'PosReg', (81, 87))	('ependymomas', 'Disease', 'MESH:D004806', (128, 139))	('ependymomas', 'Disease', 'MESH:D004806', (101, 112))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (31, 54))	('anaplastic ependymomas', 'Disease', (117, 139))	('anaplastic ependymomas', 'Phenotype', 'HP:0030066', (117, 139))	('anaplastic ependymomas', 'Disease', 'MESH:D004806', (117, 139))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('ependymomas', 'Disease', (128, 139))	('ependymomas', 'Disease', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
72387	19333441	Individual cases studied for allelic losses on chromosome arms 10q and 22q, as well as for mutations in the hSNF5/INI1, NF2 and PTEN genes also did not show any aberrations.	('INI1', 'Gene', (114, 118))	('hSNF5', 'Gene', (108, 113))	('INI1', 'Gene', '6598', (114, 118))	('PTEN', 'Gene', (128, 132))	('losses', 'NegReg', (37, 43))	('PTEN', 'Gene', '5728', (128, 132))	('NF2', 'Gene', '4771', (120, 123))	('mutations', 'Var', (91, 100))	('hSNF5', 'Gene', '6598', (108, 113))	('NF2', 'Gene', (120, 123))
72388	19333441	In this regard, the undisputably most important molecular alterations are hypermethylation of the MGMT gene in glioblastomas (Breakout Box 1) and combined deletions of chromosome arms 1p and 19q in oligodendrogliomas (Breakout Box 2).	('glioblastomas', 'Disease', (111, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('oligodendrogliomas', 'Disease', (198, 216))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('gliomas', 'Phenotype', 'HP:0009733', (209, 216))	('hypermethylation', 'Var', (74, 90))	('MGMT', 'Gene', (98, 102))	('deletions', 'Var', (155, 164))	('glioblastomas', 'Phenotype', 'HP:0012174', (111, 124))	('MGMT', 'Gene', '4255', (98, 102))	('alterations', 'Reg', (58, 69))	('arms 1p', 'Gene', '3075', (179, 186))	('glioblastomas', 'Disease', 'MESH:D005909', (111, 124))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (198, 216))	('arms 1p', 'Gene', (179, 186))
72389	19333441	MGMT hypermethylation has been clearly identified as a predictive marker for the response of glioblastomas to alkylating chemotherapy with nitrosourea, temozolomide, or a combination of both.	('glioblastomas', 'Disease', (93, 106))	('MGMT', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('glioblastomas', 'Phenotype', 'HP:0012174', (93, 106))	('alkylating chemotherapy', 'MPA', (110, 133))	('nitrosourea', 'Chemical', 'MESH:D009607', (139, 150))	('hypermethylation', 'Var', (5, 21))	('temozolomide', 'Chemical', 'MESH:D000077204', (152, 164))	('glioblastomas', 'Disease', 'MESH:D005909', (93, 106))	('MGMT', 'Gene', '4255', (0, 4))
72393	19333441	Several studies on low-grade WHO grade II oligodendroglioma patients who were initially treated with surgery alone reported an association of 1p/19q deletions with a trend towards longer survival.	('association', 'Interaction', (127, 138))	('oligodendroglioma', 'Disease', 'MESH:D009837', (42, 59))	('patients', 'Species', '9606', (60, 68))	('1p/19q deletions', 'Var', (142, 158))	('longer', 'PosReg', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('oligodendroglioma', 'Disease', (42, 59))
72398	19333441	Furthermore, one may speculate that not primarily the presence of 1p/19q loss but rather the absence of other prognostically unfavorable genetic alterations in 1p/19q-deleted tumors, e.g.	('loss', 'NegReg', (73, 77))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('1p/19q', 'Gene', (66, 72))	('1p/19q-deleted', 'Var', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
72400	19333441	While immunohistochemistry using antibodies against a number of distinct antigens may support the histological classification, only few of the above described genetic alterations are consistently enough associated with defined glioma subtypes to qualify as auxiliary molecular diagnostic markers.	('glioma subtypes', 'Disease', (227, 242))	('genetic alterations', 'Var', (159, 178))	('associated', 'Reg', (203, 213))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('glioma subtypes', 'Disease', 'MESH:D005910', (227, 242))
72401	19333441	Analysis for losses on 1p and 19q as well as mutations of the TP53 gene might help in the differential diagnosis between oligodendroglial and astrocytic gliomas.	('TP53', 'Gene', '7157', (62, 66))	('mutations', 'Var', (45, 54))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('help', 'Reg', (78, 82))	('TP53', 'Gene', (62, 66))	('oligodendroglial and astrocytic gliomas', 'Disease', 'MESH:D001254', (121, 160))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('losses', 'Var', (13, 19))
72402	19333441	While oligodendrogliomas exhibit deletions on 1p and 19q in about two-thirds of cases, mutations of the TP53 gene are a hallmark genetic alteration found in about 60% of diffusely infiltrating astrocytic gliomas.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (6, 24))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (193, 211))	('deletions', 'Var', (33, 42))	('astrocytic gliomas', 'Disease', (193, 211))	('oligodendrogliomas', 'Disease', (6, 24))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('mutations', 'Var', (87, 96))
72403	19333441	Thus, the demonstration of allelic losses on 1p and 19q argues in favor of an oligodendroglioma, whereas TP53 mutation or the immunohistochemical detection of a nuclear accumulation of the p53 protein supports the diagnosis of a diffuse astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (237, 248))	('astrocytoma', 'Disease', (237, 248))	('p53', 'Gene', '7157', (189, 192))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('astrocytoma', 'Phenotype', 'HP:0009592', (237, 248))	('allelic losses', 'Var', (27, 41))	('TP53', 'Gene', '7157', (105, 109))	('mutation', 'Var', (110, 118))	('TP53', 'Gene', (105, 109))	('oligodendroglioma', 'Disease', (78, 95))	('oligodendroglioma', 'Disease', 'MESH:D009837', (78, 95))	('p53', 'Gene', (189, 192))
72404	19333441	However, the sensitivity of both molecular alterations as differential diagnostic markers is not very high, indicated by the fact that about one third of oligodendrogliomas retain 1p/19 and about 40% of diffuse astrocytomas lack TP53 mutations and nuclear p53 accumulation.	('accumulation', 'PosReg', (260, 272))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (154, 172))	('astrocytoma', 'Phenotype', 'HP:0009592', (211, 222))	('lack', 'NegReg', (224, 228))	('1p/19', 'Var', (180, 185))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('TP53', 'Gene', '7157', (229, 233))	('astrocytomas', 'Disease', 'MESH:D001254', (211, 223))	('p53', 'Gene', (256, 259))	('oligodendrogliomas', 'Disease', (154, 172))	('p53', 'Gene', '7157', (256, 259))	('TP53', 'Gene', (229, 233))	('mutations', 'Var', (234, 243))	('astrocytomas', 'Disease', (211, 223))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
72408	19333441	In addition to frequent TP53 mutations, a recent integrated genomic analysis identified the isocitrate dehydrogenase 1 (IDH1) gene as frequently mutated in diffusely infiltrating astrocytic gliomas.	('mutated', 'Var', (145, 152))	('isocitrate dehydrogenase 1', 'Gene', (92, 118))	('isocitrate dehydrogenase 1', 'Gene', '3417', (92, 118))	('TP53', 'Gene', (24, 28))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('IDH1', 'Gene', (120, 124))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('IDH1', 'Gene', '3417', (120, 124))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (179, 197))	('astrocytic gliomas', 'Disease', (179, 197))	('TP53', 'Gene', '7157', (24, 28))
72409	19333441	Interestingly, in an initial screen on 22 glioblastoma patients, mutations in the active site of IDH1 occurred in a large fraction of young patients and were associated with an increased overall survival in secondary glioblastoma patients.	('overall survival', 'MPA', (187, 203))	('IDH1', 'Gene', (97, 101))	('associated', 'Reg', (158, 168))	('IDH1', 'Gene', '3417', (97, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (217, 229))	('glioblastoma', 'Disease', (217, 229))	('increased', 'PosReg', (177, 186))	('glioblastoma', 'Disease', (42, 54))	('patients', 'Species', '9606', (230, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('patients', 'Species', '9606', (140, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('patients', 'Species', '9606', (55, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('mutations', 'Var', (65, 74))
72410	19333441	A follow-up study analyzed IDH1 codon 132 mutations in a large series of 685 brain tumors comprising all major glioma subtypes and reported IDH1 mutation frequencies of up to 70% in diffuse astrocytomas, while virtually no mutations were detected in pilocytic astrocytomas.	('IDH1', 'Gene', '3417', (140, 144))	('astrocytomas', 'Disease', 'MESH:D001254', (260, 272))	('glioma subtypes', 'Disease', (111, 126))	('brain tumors', 'Disease', (77, 89))	('astrocytomas', 'Disease', (190, 202))	('pilocytic astrocytomas', 'Disease', (250, 272))	('mutation', 'Var', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('astrocytomas', 'Disease', (260, 272))	('IDH1', 'Gene', (140, 144))	('astrocytomas', 'Disease', 'MESH:D001254', (190, 202))	('IDH1', 'Gene', (27, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (190, 201))	('astrocytoma', 'Phenotype', 'HP:0009592', (260, 271))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (250, 272))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))	('glioma subtypes', 'Disease', 'MESH:D005910', (111, 126))	('mutations', 'Var', (42, 51))	('IDH1', 'Gene', '3417', (27, 31))
72411	19333441	In contrast, pilocytic astrocytomas -as recently indicated- are molecularly characterized by gene duplication/fusion or mutation of the BRAF gene on 7q34.	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (13, 35))	('astrocytoma', 'Phenotype', 'HP:0009592', (23, 34))	('gene duplication/fusion', 'Var', (93, 116))	('BRAF', 'Gene', '673', (136, 140))	('mutation', 'Var', (120, 128))	('BRAF', 'Gene', (136, 140))	('pilocytic astrocytomas', 'Disease', (13, 35))
72412	19333441	These BRAF gene alterations occur in about 60-80% of pilocytic astrocytomas but are infrequent in diffusely infiltrating low-grade astrocytomas.	('astrocytomas', 'Disease', (131, 143))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (53, 75))	('occur', 'Reg', (28, 33))	('alterations', 'Var', (16, 27))	('astrocytomas', 'Disease', 'MESH:D001254', (63, 75))	('pilocytic astrocytomas', 'Disease', (53, 75))	('BRAF', 'Gene', '673', (6, 10))	('astrocytomas', 'Disease', 'MESH:D001254', (131, 143))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('astrocytomas', 'Disease', (63, 75))	('BRAF', 'Gene', (6, 10))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))
72413	19333441	Tumors with duplications or activating mutations of the BRAF proto-oncogene showed significantly increased mRNA levels of BRAF and its downstream target, CCND1, as compared to tumors without these molecular alterations.	('CCND1', 'Gene', '595', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('increased', 'PosReg', (97, 106))	('mRNA levels', 'MPA', (107, 118))	('BRAF', 'Gene', '673', (56, 60))	('BRAF', 'Gene', '673', (122, 126))	('activating', 'PosReg', (28, 38))	('CCND1', 'Gene', (154, 159))	('tumors', 'Disease', (176, 182))	('BRAF', 'Gene', (122, 126))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('duplications', 'Var', (12, 24))	('BRAF', 'Gene', (56, 60))
72415	19333441	Thus, pharmacological inhibition of the MAPK pathway may serve as a potential treatment option in pediatric low-grade astrocytoma patients.	('astrocytoma', 'Disease', 'MESH:D001254', (118, 129))	('astrocytoma', 'Disease', (118, 129))	('pharmacological', 'Var', (6, 21))	('MAPK pathway', 'Pathway', (40, 52))	('patients', 'Species', '9606', (130, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))
72424	19333441	Parsons and colleagues investigated 22 human glioblastoma samples for genome-wide DNA copy number and gene expression aberrations as well as somatic mutations in 20,661 protein coding genes.	('mutations', 'Var', (149, 158))	('glioblastoma', 'Disease', (45, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('human', 'Species', '9606', (39, 44))
72425	19333441	In addition to the identification of yet unknown IDH1 mutations, integrative data analysis identified a set of glioblastoma candidiate cancer genes that mainly functioned within the TP53, RB1 and PI3K/PTEN signaling pathways (Figure 6).	('candidiate cancer', 'Phenotype', 'HP:0005411', (124, 141))	('RB1', 'Gene', '5925', (188, 191))	('TP53', 'Gene', '7157', (182, 186))	('IDH1', 'Gene', '3417', (49, 53))	('TP53', 'Gene', (182, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('PTEN', 'Gene', (201, 205))	('glioblastoma candidiate cancer', 'Disease', 'MESH:D005909', (111, 141))	('glioblastoma candidiate cancer', 'Disease', (111, 141))	('mutations', 'Var', (54, 63))	('PTEN', 'Gene', '5728', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('RB1', 'Gene', (188, 191))	('IDH1', 'Gene', (49, 53))
72428	19333441	Large-scale sequencing in a subset of 91 human glioblastomas for mutations in 601 selected genes additionally revealed ERBB2 gene mutations in 8% of glioblastomas, NF1 gene mutations in 14% and PIK3R1 mutations in closely 10% of glioblastomas, i.e.	('glioblastomas', 'Disease', (229, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (229, 241))	('glioblastomas', 'Disease', (47, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('NF1', 'Gene', '4763', (164, 167))	('PIK3R1', 'Gene', (194, 200))	('glioblastomas', 'Disease', 'MESH:D005909', (229, 242))	('glioblastomas', 'Disease', (149, 162))	('glioblastomas', 'Disease', 'MESH:D005909', (47, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('ERBB2', 'Gene', (119, 124))	('human', 'Species', '9606', (41, 46))	('NF1', 'Gene', (164, 167))	('glioblastomas', 'Disease', 'MESH:D005909', (149, 162))	('ERBB2', 'Gene', '2064', (119, 124))	('mutations', 'Var', (173, 182))	('PIK3R1', 'Gene', '5295', (194, 200))	('glioblastomas', 'Phenotype', 'HP:0012174', (229, 242))	('mutations', 'Var', (201, 210))	('glioblastomas', 'Phenotype', 'HP:0012174', (47, 60))	('mutations', 'Var', (130, 139))	('glioblastomas', 'Phenotype', 'HP:0012174', (149, 162))
72429	19333441	For example, as PIK3R1 encodes the regulatory protein p85a subunit, response to PI3K inhibitors may depend on whether the tumors bear mutations in this specific gene or not.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('p85a', 'Gene', '5295', (54, 58))	('p85a', 'Gene', (54, 58))	('PIK3R1', 'Gene', '5295', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutations', 'Var', (134, 143))	('PIK3R1', 'Gene', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
72431	19333441	MGMT methylation in conjunction with temozolomide treatment may lead to a loss of mismatch repair function by introduction of mutations in mismatch repair genes.	('MGMT', 'Gene', (0, 4))	('mismatch repair function', 'MPA', (82, 106))	('temozolomide', 'Chemical', 'MESH:D000077204', (37, 49))	('loss', 'NegReg', (74, 78))	('mutations', 'Var', (126, 135))	('mismatch repair genes', 'Gene', (139, 160))	('MGMT', 'Gene', '4255', (0, 4))
72433	19333441	As a consequence, selective strategies targeting mismatch-repair-deficient cells would represent a rational upfront combination with alkylating agents to prevent or minimize resistence to temozolomide.	('resistence to temozolomide', 'MPA', (174, 200))	('mismatch-repair-deficient', 'Var', (49, 74))	('temozolomide', 'Chemical', 'MESH:D000077204', (188, 200))
72446	32536029	Next, we analyzed the correlation between expression and methylation of CAPG in LGG tumors and found that the methylation levels of five methylation sites (cg04881903, cg26476820, cg27139457, cg19627006, and cg07215695) were strongly negatively correlated with CAPG expression, whereas one (cg27090078) showed weak negative association (Figure S2A).	('expression', 'MPA', (266, 276))	('correlated', 'Reg', (245, 255))	('cg27139457', 'Var', (180, 190))	('negatively', 'NegReg', (234, 244))	('CAPG', 'Gene', (261, 265))	('CAPG', 'Gene', '822', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('LGG tumors', 'Disease', (80, 90))	('cg26476820', 'Var', (168, 178))	('CAPG', 'Gene', (72, 76))	('cg19627006', 'Var', (192, 202))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('cg07215695', 'Var', (208, 218))	('LGG tumors', 'Disease', 'MESH:D009369', (80, 90))	('methylation levels', 'MPA', (110, 128))	('cg04881903', 'Var', (156, 166))	('CAPG', 'Gene', '822', (72, 76))
72447	32536029	Survival analysis results suggested that high levels of methylation in these six sites were associated with better survival in LGG patients (Figure S2B).	('patients', 'Species', '9606', (131, 139))	('LGG', 'Disease', (127, 130))	('survival', 'MPA', (115, 123))	('high', 'Var', (41, 45))	('better', 'PosReg', (108, 114))	('methylation', 'Var', (56, 67))
72450	32536029	The results suggested that gene alteration of CAPG and IDH1 was mutually exclusive (q < .001 in TCGA PanCancer Atlas) (Figure 1).	('alteration', 'Var', (32, 42))	('IDH1', 'Gene', '3417', (55, 59))	('CAPG', 'Gene', (46, 50))	('PanCancer Atlas', 'Disease', 'None', (101, 116))	('PanCancer Atlas', 'Disease', (101, 116))	('CAPG', 'Gene', '822', (46, 50))	('IDH1', 'Gene', (55, 59))
72468	32536029	Interestingly, we found that gene alterations of CAPG and IDH1 were mutually exclusive in LGG, which indicates that CAPG might be used as a new marker for subtype classification of LGG.	('IDH1', 'Gene', '3417', (58, 62))	('CAPG', 'Gene', (49, 53))	('gene alterations', 'Var', (29, 45))	('CAPG', 'Gene', '822', (116, 120))	('LGG', 'Disease', (90, 93))	('CAPG', 'Gene', '822', (49, 53))	('CAPG', 'Gene', (116, 120))	('IDH1', 'Gene', (58, 62))
72474	26824661	Whole genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length.	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('increased', 'PosReg', (111, 120))	('telomere length', 'CPA', (121, 136))	('ATRX', 'Gene', '546', (54, 58))	('mutations', 'Var', (81, 90))	('increased telomere length', 'Phenotype', 'HP:0031413', (111, 136))	('ATRX', 'Gene', (54, 58))
72481	26824661	For example, mutations in the isocitrate dehydrogenase genes 1 and 2 (IDH1/IDH2) define a distinct subset of glioblastoma (GBM) with a hypermethylation phenotype (G-CIMP) with favorable outcome.	('glioblastoma', 'Disease', (109, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('G-CIMP', 'Chemical', '-', (163, 169))	('IDH1', 'Gene', '3417', (70, 74))	('IDH2', 'Gene', (75, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('IDH2', 'Gene', '3418', (75, 79))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', (70, 74))
72482	26824661	Conversely, the absence of IDH mutations in LGG marks a distinct IDH-wildtype subgroup characterized by poor, GBM-like prognosis.	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (31, 40))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (27, 30))	('IDH', 'Gene', '3417', (65, 68))	('LGG', 'Gene', (44, 47))	('GBM', 'Phenotype', 'HP:0012174', (110, 113))
72483	26824661	Recent work by us and others has proposed classification of glioma into IDH wildtype cases, IDH mutant samples additionally carrying codeletion of chromosome arm 1p and 19q (IDH mutant-codel) and samples with euploid 1p/19q (IDH-mutant-non-codel), regardless of grade and histology.	('IDH', 'Gene', '3417', (174, 177))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('euploid 1p/19q', 'Var', (209, 223))	('IDH', 'Gene', (225, 228))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('glioma', 'Disease', (60, 66))	('IDH', 'Gene', '3417', (225, 228))	('IDH', 'Gene', (92, 95))	('IDH', 'Gene', (174, 177))	('IDH', 'Gene', '3417', (92, 95))	('codeletion', 'Var', (133, 143))
72484	26824661	Mutation of the TERT promoter, which has been reported with high frequency across glioma, may be an additional defining feature.	('TERT', 'Gene', (16, 20))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('TERT', 'Gene', '7015', (16, 20))	('Mutation', 'Var', (0, 8))	('glioma', 'Disease', (82, 88))
72498	26824661	Conversely, we found that a set of 36 genes involved in chromatin modification was targeted by genetic alterations in 423 tumors (54%, n = 36 genes), most of which belonged to the IDH-mutant-non-codel group (n = 230, 87%).	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', (122, 128))	('targeted', 'Reg', (83, 91))	('IDH', 'Gene', (180, 183))	('genetic alterations', 'Var', (95, 114))	('IDH', 'Gene', '3417', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
72499	26824661	In order to identify new somatically altered glioma genes, we used MutComFocal to nominate candidates altered by mutation as well as copy number alteration.	('mutation', 'Var', (113, 121))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('copy number alteration', 'Var', (133, 155))	('glioma', 'Disease', (45, 51))
72502	26824661	Alterations in the cohesin pathway have been reported in 12% of acute myeloid leukemias.	('reported', 'Reg', (45, 53))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (64, 87))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (70, 87))	('Alterations', 'Var', (0, 11))	('leukemias', 'Phenotype', 'HP:0001909', (78, 87))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (64, 87))	('cohesin pathway', 'Pathway', (19, 34))	('acute myeloid leukemias', 'Disease', (64, 87))
72503	26824661	Mutations of the cohesin complex gene STAG2 had been previously reported in GBM.	('STAG2', 'Gene', (38, 43))	('Mutations', 'Var', (0, 9))	('reported', 'Reg', (64, 72))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('STAG2', 'Gene', '10735', (38, 43))
72504	26824661	Taken together, 16% of the LGG/GBM showed mutations and/or CNAs in multiple genes involved in the cohesin complex, thus nominating this process as a prominent pathway involved in gliomagenesis.	('CNAs', 'MPA', (59, 63))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('mutations', 'Var', (42, 51))	('glioma', 'Disease', (179, 185))
72505	26824661	Mutations in the TERT promoter (TERTp) have been reported in 80% of GBM.	('TERT', 'Gene', '7015', (32, 36))	('reported', 'Reg', (49, 57))	('TERT', 'Gene', (17, 21))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('TERT', 'Gene', '7015', (17, 21))	('Mutations', 'Var', (0, 9))	('TERTp', 'Gene', (32, 37))	('TERTp', 'Gene', '7015', (32, 37))	('GBM', 'Disease', (68, 71))	('TERT', 'Gene', (32, 36))
72507	26824661	TERTp mutations are nearly mutually exclusive with mutations in ATRX, which was confirmed in our cohort.	('TERTp', 'Gene', '7015', (0, 5))	('ATRX', 'Gene', (64, 68))	('ATRX', 'Gene', '546', (64, 68))	('mutations', 'Var', (6, 15))	('TERTp', 'Gene', (0, 5))
72508	26824661	Overall, 85% of diffuse gliomas harbored mutations of TERTp (n=157, 48%) or ATRX (n=120, 37%).	('mutations', 'Var', (41, 50))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('ATRX', 'Gene', '546', (76, 80))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('ATRX', 'Gene', (76, 80))	('TERTp', 'Gene', (54, 59))	('gliomas', 'Disease', (24, 31))	('TERTp', 'Gene', '7015', (54, 59))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
72509	26824661	TERTp mutations activate TERT mRNA expression through the creation of a de novo ETS transcription factor-binding site and we observed significant TERT upregulation in TERTp mutant cases (p-value < 0.0001, Figure S1A).	('TERTp', 'Gene', '7015', (167, 172))	('TERT', 'Gene', (167, 171))	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', (25, 29))	('TERT', 'Gene', '7015', (167, 171))	('TERT', 'Gene', (0, 4))	('mutant', 'Var', (173, 179))	('TERT', 'Gene', '7015', (25, 29))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', (167, 172))	('TERT', 'Gene', (146, 150))	('upregulation', 'PosReg', (151, 163))	('TERT', 'Gene', '7015', (146, 150))	('activate', 'PosReg', (16, 24))	('mutations', 'Var', (6, 15))	('TERTp', 'Gene', (0, 5))
72511	26824661	We correlated TERTp status with glioma driving alterations and observed that nearly all IDH-wildtype cases with chromosome 7 gain and chromosome 10 loss harbored TERTp mutations or upregulated TERT expression (n=52/53 and n = 134/147, respectively; Figure 1A).	('TERTp', 'Gene', (14, 19))	('loss', 'NegReg', (148, 152))	('TERTp', 'Gene', '7015', (14, 19))	('upregulated', 'PosReg', (181, 192))	('TERT', 'Gene', (14, 18))	('TERT', 'Gene', '7015', (14, 18))	('IDH', 'Gene', (88, 91))	('mutations', 'Var', (168, 177))	('TERTp', 'Gene', (162, 167))	('TERTp', 'Gene', '7015', (162, 167))	('TERT', 'Gene', (162, 166))	('TERT', 'Gene', (193, 197))	('TERT', 'Gene', '7015', (162, 166))	('IDH', 'Gene', '3417', (88, 91))	('TERT', 'Gene', '7015', (193, 197))	('chromosome 7', 'Gene', (112, 124))	('glioma', 'Disease', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('gain', 'PosReg', (125, 129))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
72513	26824661	Thus, TERTp mutations may precede the chr 7/chr 10 alterations which have been implicated in glioma initiation.	('TERTp', 'Gene', '7015', (6, 11))	('mutations', 'Var', (12, 21))	('glioma initiation', 'Disease', 'MESH:D005910', (93, 110))	('glioma initiation', 'Disease', (93, 110))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('TERTp', 'Gene', (6, 11))
72516	26824661	Glioma samples harboring ATRX mutations showed significantly longer telomeres compared to TERTp mutant samples (t-test p-value < 0.0001; Figure 1C).	('longer', 'PosReg', (61, 67))	('telomeres', 'CPA', (68, 77))	('ATRX', 'Gene', (25, 29))	('TERTp', 'Gene', (90, 95))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('TERTp', 'Gene', '7015', (90, 95))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('mutations', 'Var', (30, 39))	('ATRX', 'Gene', '546', (25, 29))	('Glioma', 'Disease', (0, 6))
72519	26824661	Mutations in DAXX and H3F3A were identified in only two samples in our WGS dataset.	('H3F3A', 'Gene', (22, 27))	('DAXX', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('DAXX', 'Gene', '1616', (13, 17))	('H3F3A', 'Gene', '3020', (22, 27))
72521	26824661	As demonstrated by the identification of TERTp mutations, somatic variants affecting regulatory regions may play a role in gliomagenesis.	('play', 'Reg', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('TERTp', 'Gene', (41, 46))	('TERTp', 'Gene', '7015', (41, 46))	('role', 'Reg', (115, 119))	('mutations', 'Var', (47, 56))	('glioma', 'Disease', (123, 129))
72528	26824661	The LGm1/LGm2/LGm3 DNA methylation macro-group carried IDH1 or IDH2 mutations (449 of 450, 99%) and was enriched for LGG (421/454, 93%) while LGm4/LGm5/LGm6 were IDH-wildtype (429/430, 99%) and enriched for GBM (383/478, 80%).	('IDH2', 'Gene', '3418', (63, 67))	('IDH1', 'Gene', '3417', (55, 59))	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', (55, 58))	('IDH', 'Gene', (162, 165))	('mutations', 'Var', (68, 77))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', '3417', (55, 58))	('IDH', 'Gene', '3417', (162, 165))	('IDH2', 'Gene', (63, 67))	('GBM', 'Phenotype', 'HP:0012174', (207, 210))	('IDH1', 'Gene', (55, 59))
72529	26824661	LGm1-3 showed genome wide hypermethylation compared to LGm4-6 clusters (Figure S2A), documenting the association between IDH mutation and increased DNA methylation.	('increased', 'PosReg', (138, 147))	('mutation', 'Var', (125, 133))	('IDH', 'Gene', (121, 124))	('IDH', 'Gene', '3417', (121, 124))	('DNA methylation', 'MPA', (148, 163))
72530	26824661	The gene expression clusters LGr1-3 harbored IDH1 or IDH2 mutations (438 of 553, 82%) and were enriched for LGG (436/563, 77%) while the LGr4 was exclusively IDH-wildtype (376 of 387, 97%) and enriched for GBM (399/476, 84%).	('IDH1', 'Gene', '3417', (45, 49))	('mutations', 'Var', (58, 67))	('IDH', 'Gene', '3417', (158, 161))	('LGr4', 'Gene', '55366', (137, 141))	('IDH', 'Gene', (45, 48))	('LGr1', 'Gene', (29, 33))	('IDH2', 'Gene', (53, 57))	('LGr4', 'Gene', (137, 141))	('IDH', 'Gene', '3417', (45, 48))	('GBM', 'Phenotype', 'HP:0012174', (206, 209))	('IDH2', 'Gene', '3418', (53, 57))	('IDH', 'Gene', (53, 56))	('IDH1', 'Gene', (45, 49))	('LGr1', 'Gene', '2492', (29, 33))	('IDH', 'Gene', (158, 161))	('IDH', 'Gene', '3417', (53, 56))
72534	26824661	The fCN signature clustered gliomas into three macro-clusters, LGfc1-3, strongly associated with IDH and 1p/19q status (Figure S2D).	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('1p/19q status', 'Var', (105, 118))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH', 'Gene', (97, 100))	('IDH', 'Gene', '3417', (97, 100))	('associated', 'Reg', (81, 91))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
72545	26824661	The three epigenetic subtypes defined by clustering IDH-mutant glioma separated samples harboring the 1p/19q co-deletion into a single cluster and non-codel glioma into two clusters (Figure S3A).	('1p/19q co-deletion', 'Var', (102, 120))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('IDH', 'Gene', (52, 55))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('IDH', 'Gene', '3417', (52, 55))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Disease', (157, 163))	('glioma', 'Disease', (63, 69))
72546	26824661	Conversely, non-codel glioma grouped nearly exclusively into a single expression cluster and codels were split in two separated expression clusters (Figure S3A).	('non-codel', 'Var', (12, 21))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (22, 28))	('glioma', 'Disease', (22, 28))
72555	26824661	The newly identified G-CIMP-low group of glioma was associated with significantly worse survival as compared to the G-CIMP-high and Codel groups (Figure S3D).	('G-CIMP', 'Chemical', '-', (21, 27))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('G-CIMP', 'Chemical', '-', (116, 122))	('survival', 'MPA', (88, 96))	('G-CIMP-low', 'Var', (21, 31))	('worse', 'NegReg', (82, 87))	('glioma', 'Disease', (41, 47))
72557	26824661	We compared the frequencies of glioma driver gene alterations between the three types of IDH-mutant glioma and found that 15 of 18 G-CIMP-low cases carried abnormalities in cell cycle pathway genes such as CDK4 and CDKN2A, relative to 36/241 and 2/172 for G-CIMP-high and Codels, respectively (Figure 3D).	('glioma', 'Disease', (100, 106))	('cell cycle pathway genes', 'Gene', (173, 197))	('CDKN2A', 'Gene', (215, 221))	('G-CIMP', 'Chemical', '-', (131, 137))	('abnormalities', 'Var', (156, 169))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('CDKN2A', 'Gene', '1029', (215, 221))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('G-CIMP', 'Chemical', '-', (256, 262))	('abnormalities in cell cycle', 'Phenotype', 'HP:0011018', (156, 183))	('CDK4', 'Gene', (206, 210))	('IDH', 'Gene', (89, 92))	('CDK4', 'Gene', '1019', (206, 210))	('glioma', 'Disease', (31, 37))	('IDH', 'Gene', '3417', (89, 92))	('G-CIMP-low', 'Var', (131, 141))
72559	26824661	We mapped the 943 deregulated genes to 767 nearest CpG probes (max distance 1kb) and found the majority of the CpG probes (486/767, 63%) to show a significant methylation difference (FDR<0.05, difference in mean methylation beta-value > 0.01) between G-CIMP-low and G-CIMP-high, suggesting a mechanistic relation between loss of methylation and increased transcript levels.	('G-CIMP', 'Chemical', '-', (251, 257))	('CpG', 'Var', (111, 114))	('methylation', 'MPA', (159, 170))	('methylation beta-value', 'MPA', (212, 234))	('G-CIMP', 'Chemical', '-', (266, 272))	('transcript', 'MPA', (355, 365))	('G-CIMP-low', 'Var', (251, 261))
72560	26824661	Recent analysis of epigenetic profiles derived from colon cancers showed that transcription factors may bind to regions of demethylated DNA.	('demethylated', 'Var', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colon cancers', 'Phenotype', 'HP:0003003', (52, 65))	('colon cancers', 'Disease', 'MESH:D015179', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('colon cancers', 'Disease', (52, 65))	('bind', 'Interaction', (104, 108))
72565	26824661	This observation was corroborated by the higher expression levels of SOX2 as well as 17 out of 20 other known SOX family members in G-CIMP-low compared to G-CIMP-high (fold difference > 2).	('SOX2', 'Gene', (69, 73))	('G-CIMP', 'Chemical', '-', (155, 161))	('expression levels', 'MPA', (48, 65))	('SOX2', 'Gene', '6657', (69, 73))	('G-CIMP-low', 'Var', (132, 142))	('G-CIMP', 'Chemical', '-', (132, 138))	('higher', 'PosReg', (41, 47))
72568	26824661	Supervised gene expression pathway analysis of the genes activated in the G-CIMP-low group as opposed to G-CIMP-high group revealed activation of genes involved in cell cycle and cell division consistent with the role of SOX in promoting cell proliferation (Figure S3E).	('activation', 'PosReg', (132, 142))	('cell cycle', 'CPA', (164, 174))	('G-CIMP-low', 'Var', (74, 84))	('G-CIMP', 'Chemical', '-', (105, 111))	('promoting', 'PosReg', (228, 237))	('cell proliferation', 'CPA', (238, 256))	('G-CIMP', 'Chemical', '-', (74, 80))	('cell division', 'CPA', (179, 192))
72569	26824661	The enrichment in cell cycle gene expression provides additional support to the notion that development of the G-CIMP-low subtype is associated with activation of cell cycle progression and may be mediated by a loss of CpG methylation and binding of SOX factors to candidate genomic enhancer elements.	('G-CIMP', 'Chemical', '-', (111, 117))	('loss', 'NegReg', (211, 215))	('methylation', 'Var', (223, 234))	('cell cycle progression', 'CPA', (163, 185))	('CpG', 'Protein', (219, 222))	('activation', 'PosReg', (149, 159))	('binding', 'Interaction', (239, 246))	('cell cycle gene', 'Gene', (18, 33))
72588	26824661	Pilocytic astrocytomas are characterized by frequent alterations in the MAPK pathway, such as FGFR1 mutations, KIAA1549-BRAF and NTRK2 fusions.	('Pilocytic astrocytomas', 'Disease', (0, 22))	('mutations', 'Var', (100, 109))	('FGFR1', 'Gene', '2260', (94, 99))	('NTRK2', 'Gene', (129, 134))	('MAPK pathway', 'Pathway', (72, 84))	('fusions', 'Var', (135, 142))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('NTRK2', 'Gene', '4915', (129, 134))	('KIAA1549-BRAF', 'Disease', (111, 124))	('alterations', 'Reg', (53, 64))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('FGFR1', 'Gene', (94, 99))	('KIAA1549-BRAF', 'Disease', 'None', (111, 124))
72589	26824661	The frequency of mutations, fusions and amplifications in eight PA-associated genes (BRAF, NF1, NTRK1, NTRK2, FGFR1, and FGFR2) rated from 11% (n=12/113) of Classic-like, 13% (n=21/158) of Mesenchymal-like IDH-wildtype tumors to 32% (n=7/22) of LGm6-GBM and 52% (n=13/25) of PA-like LGG (Fisher Exact Test (FET) p-value < 0.0001; Figure 4C).	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (206, 225))	('mutations', 'Var', (17, 26))	('GBM', 'Phenotype', 'HP:0012174', (250, 253))	('amplifications', 'Var', (40, 54))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('FGFR2', 'Gene', (121, 126))	('NF1', 'Gene', '4763', (91, 94))	('IDH-wildtype tumors', 'Disease', (206, 225))	('NTRK1', 'Gene', '4914', (96, 101))	('fusions', 'Var', (28, 35))	('FGFR1', 'Gene', (110, 115))	('NTRK2', 'Gene', '4915', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('NF1', 'Gene', (91, 94))	('NTRK1', 'Gene', (96, 101))	('FGFR2', 'Gene', '2263', (121, 126))	('PA-like LGG', 'Disease', (275, 286))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('NTRK2', 'Gene', (103, 108))	('FGFR1', 'Gene', '2260', (110, 115))
72591	26824661	The PA-like group was characterized by relatively low frequency of typical GBM alterations, in genes such as EGFR, CDKN2A/B, and PTEN and displayed euploid DNA copy number profiles (Figure S4E).	('alterations', 'Var', (79, 90))	('PA-like', 'Disease', (4, 11))	('CDKN2A/B', 'Gene', '1029;1030', (115, 123))	('PTEN', 'Gene', (129, 133))	('EGFR', 'Gene', '1956', (109, 113))	('CDKN2A/B', 'Gene', (115, 123))	('PTEN', 'Gene', '5728', (129, 133))	('EGFR', 'Gene', (109, 113))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))
72597	26824661	Age at diagnosis, histology, IDH/codel subtype, TERT expression and epigenetic subtype all contribute to survival in single-predictor analysis (log-rank p-value < 0.05, Table S4).	('TERT', 'Gene', '7015', (48, 52))	('contribute', 'Reg', (91, 101))	('survival', 'MPA', (105, 113))	('TERT', 'Gene', (48, 52))	('IDH', 'Gene', (29, 32))	('epigenetic', 'Var', (68, 78))	('IDH', 'Gene', '3417', (29, 32))
72600	26824661	This generalization of our model supports the epigenetic subtypes as a means to improve the prognostication of glioma.	('glioma', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('epigenetic subtypes', 'Var', (46, 65))	('improve', 'PosReg', (80, 87))
72601	26824661	Gene Set Enrichment Analysis of the genes activated in G-CIMP GBM as opposed to the IDH-mutant-non-codel within LGr3 (Figure 2B) revealed four major groups, including cell cycle and hyperproliferation, DNA metabolic processes, response to stress, and angiogenesis (Figure S5A, Table S5).	('LGr3', 'Gene', '7253', (112, 116))	('G-CIMP', 'Chemical', '-', (55, 61))	('G-CIMP', 'Var', (55, 61))	('LGr3', 'Gene', (112, 116))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('DNA metabolic processes', 'CPA', (202, 225))	('angiogenesis', 'CPA', (251, 263))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', (84, 87))	('activated', 'PosReg', (42, 51))	('response', 'CPA', (227, 235))	('hyperproliferation', 'CPA', (182, 200))	('cell cycle', 'CPA', (167, 177))
72613	26824661	In particular, the identification of the G-CIMP-low subset, characterized by activation of cell cycle genes mediated by SOX binding at hypomethylated functional genomic elements and unfavorable clinical outcome is an important finding that will guide more accurate segregation and therapeutic assessment in a group of patients in which correlations of conventional grading with outcome are modest.	('patients', 'Species', '9606', (318, 326))	('activation', 'PosReg', (77, 87))	('cell cycle genes', 'Gene', (91, 107))	('G-CIMP-low', 'Var', (41, 51))	('G-CIMP', 'Chemical', '-', (41, 47))
72614	26824661	The finding that G-CIMP-high tumors can emerge as G-CIMP-low glioma at recurrence identify variations in DNA methylation as crucial determinants for glioma progression and provides a clue to the mechanisms driving evolution of glioma.	('variations', 'Var', (91, 101))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('glioma', 'Disease', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('G-CIMP', 'Chemical', '-', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('tumors', 'Disease', (29, 35))	('G-CIMP', 'Chemical', '-', (17, 23))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('glioma', 'Disease', (227, 233))
72620	26824661	Cohesin mutant tumors may infer increased sensitivity to DNA damage agents and PARP inhibitors suggesting that gliomas with genetic alterations of key cohesin regulatory factors may represent biomarkers and therapeutic opportunities.	('gliomas', 'Disease', (111, 118))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PARP', 'Gene', '1302', (79, 83))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('Cohesin', 'Gene', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('sensitivity', 'MPA', (42, 53))	('mutant', 'Var', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PARP', 'Gene', (79, 83))	('increased', 'PosReg', (32, 41))	('tumors', 'Disease', (15, 21))
72621	26824661	Overexpression of TERT mRNA was found to be associated with increased telomere length in urothelial cancer.	('increased telomere length', 'Phenotype', 'HP:0031413', (60, 85))	('urothelial cancer', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('telomere length', 'MPA', (70, 85))	('urothelial cancer', 'Disease', 'MESH:D014523', (89, 106))	('TERT', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('TERT', 'Gene', '7015', (18, 22))	('increased', 'PosReg', (60, 69))
72622	26824661	Our results revealed that in gliomas, increased telomere length is associated with ATRX mutations, suggesting an ALT mechanism.	('ATRX', 'Gene', (83, 87))	('telomere length', 'MPA', (48, 63))	('gliomas', 'Disease', (29, 36))	('mutations', 'Var', (88, 97))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('increased telomere length', 'Phenotype', 'HP:0031413', (38, 63))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('ATRX', 'Gene', '546', (83, 87))	('increased', 'PosReg', (38, 47))
72624	26824661	In summary, our pan-glioma analysis has expanded our knowledge of the glioma somatic alteration landscape, emphasized the relevance of DNA methylation profiles as a modality for clinical classification, and quantitatively linked somatic TERT pathway alterations to telomere maintenance.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('TERT', 'Gene', '7015', (237, 241))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('alterations', 'Var', (250, 261))	('glioma', 'Disease', (20, 26))	('linked', 'Reg', (222, 228))	('TERT', 'Gene', (237, 241))
72658	34011400	IF staining was performed on 5-mum sections using anti-MARCO (1:100, PA5-64134, Invitrogen (Carlsbad, CA)) followed by biotinylated goat anti-rabbit IgG (1:200, BA1000, Vector Laboratories) and streptavidin-conjugated 594 (1:1000, S11127, Invitrogen), as well as anti-CD163 (1:100, 10D6, Biocare Medical (Pacheco, CA)) followed by biotinylated horse anti-mouse IgG (1:200, BA2000, Vector Laboratories) and streptavidin-conjugated 488 (1:300, Invitrogen).	('1:100', 'Var', (275, 280))	('mouse', 'Species', '10090', (355, 360))	('anti-CD163', 'Var', (263, 273))
72672	34011400	Since most LGGs are IDH1-mutated, we examined MARCO expression in the 4 GBM cases with IDH1 mutations.	('IDH1', 'Gene', '3417', (20, 24))	('examined', 'Reg', (37, 45))	('IDH1', 'Gene', '3417', (87, 91))	('mutations', 'Var', (92, 101))	('IDH1', 'Gene', (87, 91))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('IDH1', 'Gene', (20, 24))
72683	34011400	However, given the aforementioned association of MARCO with IDH1 and the strong impact of IDH1 mutations on survival, we repeated the analysis with only the 437 GBMs with known IDH1-wild-type status, and the effect persisted (OS: p = 0.0084, n = 437 patients; DFS: p = 0.035, n = 267 patients, log-rank test, Fig.	('IDH1', 'Gene', (90, 94))	('patients', 'Species', '9606', (284, 292))	('IDH1', 'Gene', '3417', (90, 94))	('IDH1', 'Gene', (60, 64))	('IDH1', 'Gene', (177, 181))	('MARCO', 'Disease', (49, 54))	('patients', 'Species', '9606', (250, 258))	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('mutations', 'Var', (95, 104))	('IDH1', 'Gene', '3417', (177, 181))	('IDH1', 'Gene', '3417', (60, 64))
72684	34011400	Continuing this analysis with the IDH1-wild-type cohort, we treated MARCO expression as a continuous variable and found that the effect of MARCO in a univariable Cox model was also significantly detrimental to survival (p = 0.00057 for OS, n = 437 patients, hazard ratio = 1.19; p = 0.0047 for DFS, n = 267 patients, hazard ratio 1.19; Wald test).	('IDH1', 'Gene', '3417', (34, 38))	('MARCO', 'Var', (139, 144))	('effect', 'Var', (129, 135))	('detrimental', 'NegReg', (195, 206))	('IDH1', 'Gene', (34, 38))	('patients', 'Species', '9606', (248, 256))	('patients', 'Species', '9606', (307, 315))	('survival', 'MPA', (210, 218))
72686	34011400	Recapitulating the single-cell results, we found an association of IDH1 mutations with decreased MARCO expression in bulk data (p = 0.0039, n = 482 patients, Mann-Whitney U test, Fig.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (148, 156))	('decreased', 'NegReg', (87, 96))	('MARCO', 'Gene', (97, 102))	('IDH1', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (67, 71))
72711	34011400	S10B), suggesting that these changes in MARCO are specific to immunotherapy.	('S10B', 'SUBSTITUTION', 'None', (0, 4))	('MARCO', 'Disease', (40, 45))	('S10B', 'Var', (0, 4))
72723	34011400	In fact, the remarkable downregulation of HLA class II genes on MARCO+ macrophages is consistent with murine studies where MARCO expression is associated with a decrease of antigen internalization capacity.	('decrease', 'NegReg', (161, 169))	('MARCO expression', 'Var', (123, 139))	('downregulation', 'NegReg', (24, 38))	('murine', 'Species', '10090', (102, 108))	('HLA', 'Gene', '3123', (42, 45))	('antigen internalization capacity', 'MPA', (173, 205))	('HLA', 'Gene', (42, 45))
72733	34011400	Previously, we had shown that mutations in MAPK genes and loss of PTEN predict response to anti-PD1 immunotherapy.	('PD1', 'Gene', (96, 99))	('loss', 'NegReg', (58, 62))	('PTEN', 'Gene', (66, 70))	('PD1', 'Gene', '9825', (96, 99))	('PTEN', 'Gene', '5728', (66, 70))	('predict', 'Reg', (71, 78))	('mutations', 'Var', (30, 39))	('MAPK genes', 'Gene', (43, 53))
72749	33190170	Mechanistic research demonstrated that overexpression of Smarcd1 decreased the expression of Notch1, while knockdown of Notch1 increased the expression of Smarcd1 through Hes1 suppression.	('knockdown', 'Var', (107, 116))	('Notch1', 'Gene', '4851', (120, 126))	('expression', 'MPA', (79, 89))	('decreased', 'NegReg', (65, 74))	('suppression', 'NegReg', (176, 187))	('Hes1', 'Gene', (171, 175))	('Notch1', 'Gene', (93, 99))	('expression', 'MPA', (141, 151))	('Hes1', 'Gene', '3280', (171, 175))	('Smarcd1', 'Gene', (155, 162))	('Notch1', 'Gene', '4851', (93, 99))	('Notch1', 'Gene', (120, 126))	('increased', 'PosReg', (127, 136))
72751	33190170	Furthermore, targeting Smarcd1 could be a potential strategy for human glioblastoma treatment.	('human', 'Species', '9606', (65, 70))	('glioblastoma', 'Disease', (71, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('Smarcd1', 'Gene', (23, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('targeting', 'Var', (13, 22))
72761	33190170	Hong and his colleagues demonstrated that the expression of Smarcd1 sensitized lung cancer cells to chemotherapy drug-induced apoptosis via the inhibition of miR-7.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('expression', 'Var', (46, 56))	('Smarcd1', 'Gene', (60, 67))	('miR-7', 'Gene', '10859', (158, 163))	('chemotherapy drug-induced', 'MPA', (100, 125))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('inhibition', 'NegReg', (144, 154))	('miR-7', 'Gene', (158, 163))	('sensitized', 'Reg', (68, 78))
72765	33190170	Ahmad and his colleagues have found that knockdown of the core subunit of SWI/SNF complex, BRG1, significantly reduced the transcriptional activation of targeted genes, whereas Smarcd1 and BRG1 are evolutionary conserved and structurally integrated subunits in the SWI/SNF family.	('BRG1', 'Gene', '6597', (189, 193))	('reduced', 'NegReg', (111, 118))	('BRG1', 'Gene', (91, 95))	('BRG1', 'Gene', (189, 193))	('BRG1', 'Gene', '6597', (91, 95))	('transcriptional activation', 'MPA', (123, 149))	('knockdown', 'Var', (41, 50))
72809	33190170	The results showed that U87 and U251 kd-sm groups were more proliferative than corresponding kd-nc groups (Fig.	('U251 kd-sm', 'Var', (32, 42))	('U251', 'CellLine', 'CVCL:0021', (32, 36))	('proliferative', 'CPA', (60, 73))	('kd-sm', 'Chemical', '-', (37, 42))	('more', 'PosReg', (55, 59))	('U87', 'Var', (24, 27))
72811	33190170	Besides, we found that at the point of day 4 in U87 cells, the kd-sm group had slowed growth as compared to the kd-nc group, which may be due to the intensive attachment inhibition.	('slowed growth', 'Phenotype', 'HP:0001510', (79, 92))	('kd-sm', 'Var', (63, 68))	('slowed', 'NegReg', (79, 85))	('growth', 'MPA', (86, 92))	('kd-sm', 'Chemical', '-', (63, 68))
72813	33190170	2c, the size and the number of colonies were much smaller in the over-sm groups than the control groups and kd-sm groups showed better colony-forming capacity.	('over-sm', 'Var', (65, 72))	('colony-forming capacity', 'CPA', (135, 158))	('kd-sm', 'Chemical', '-', (108, 113))	('smaller', 'NegReg', (50, 57))
72815	33190170	Inversely, glioma cells in the kd-sm group were prone to grow bigger than control, albeit no overt change in the total body weight of nude mice.	('grow', 'CPA', (57, 61))	('kd-sm', 'Chemical', '-', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('nude mice', 'Species', '10090', (134, 143))	('glioma', 'Disease', (11, 17))	('kd-sm', 'Var', (31, 36))
72822	33190170	The observations from the western blot bands illustrated that overexpression of Smarcd1 obviously decreased the levels of CDK4 and cyclin D1, while knockdown of Smarcd1 promoted CDK4 and cyclin D1 expression (Fig.	('promoted', 'PosReg', (169, 177))	('cyclin D1', 'Gene', (131, 140))	('cyclin D1', 'Gene', '595', (187, 196))	('cyclin D1', 'Gene', '595', (131, 140))	('cyclin D1', 'Gene', (187, 196))	('CDK4', 'Gene', '1019', (178, 182))	('Smarcd1', 'Gene', (161, 168))	('CDK4', 'Gene', (122, 126))	('CDK4', 'Gene', '1019', (122, 126))	('decreased', 'NegReg', (98, 107))	('CDK4', 'Gene', (178, 182))	('expression', 'MPA', (197, 207))	('knockdown', 'Var', (148, 157))	('Smarcd1', 'Gene', (80, 87))
72831	33190170	4c and d), we could also draw the conclusion that Smarcd1 inhibited the ability of invasion in glioma cells by combination of the transwell assays and the protein expression tendency.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('Smarcd1', 'Var', (50, 57))	('glioma', 'Disease', (95, 101))	('inhibited', 'NegReg', (58, 67))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
72833	33190170	A number of patients suffer from TMZ chemoresistance partially due to hypomethylation of MGMT promoter.	('MGMT', 'Gene', (89, 93))	('patients', 'Species', '9606', (12, 20))	('suffer from', 'Reg', (21, 32))	('hypomethylation', 'Var', (70, 85))	('TMZ chemoresistance', 'Disease', (33, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (33, 36))	('MGMT', 'Gene', '4255', (89, 93))
72838	33190170	Surprisingly, we observed that high expression of Smarcd1 showed more sensitivity to TMZ administration for 48 h with a significant increase in apoptotic rate than the control group in both U87 (Fig.	('Smarcd1', 'Gene', (50, 57))	('apoptotic rate', 'CPA', (144, 158))	('increase', 'PosReg', (132, 140))	('sensitivity', 'MPA', (70, 81))	('more', 'PosReg', (65, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (85, 88))	('high expression', 'Var', (31, 46))
72846	33190170	5g and h, knockdown of Smarcd1 led to a decreased expression of P53 and the downstream target P21 in the input U87 and U251 cell lysates, meanwhile the same tendency was found in overexpression of Smarcd1.	('knockdown', 'Var', (10, 19))	('P21', 'Gene', (94, 97))	('P53', 'Gene', (64, 67))	('Smarcd1', 'Gene', (23, 30))	('P53', 'Gene', '7157', (64, 67))	('P21', 'Gene', '644914', (94, 97))	('decreased', 'NegReg', (40, 49))	('expression', 'MPA', (50, 60))	('U251', 'CellLine', 'CVCL:0021', (119, 123))
72851	33190170	After knockdown of Smarcd1, P53 pathway was inactivated, which might stand reason to the decreased apoptosis and augmented chemoresistance of gliomas after TMZ treatment.	('augmented', 'PosReg', (113, 122))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('Smarcd1', 'Gene', (19, 26))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('TMZ', 'Chemical', 'MESH:D000077204', (156, 159))	('apoptosis', 'CPA', (99, 108))	('chemoresistance', 'CPA', (123, 138))	('P53', 'Gene', (28, 31))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('knockdown', 'Var', (6, 15))	('inactivated', 'NegReg', (44, 55))	('P53', 'Gene', '7157', (28, 31))	('decreased', 'NegReg', (89, 98))
72857	33190170	Also, we found that BRG1, the catalytic subunit of SWI/SNF complex, was not overtly influenced when expression of Smarcd1 changed, which indicated that Smarcd1 induced the inactivation of Notch1 pathway which was independent of the cross-link to BRG1 (Fig.	('BRG1', 'Gene', '6597', (20, 24))	('Notch1', 'Gene', '4851', (188, 194))	('inactivation', 'NegReg', (172, 184))	('BRG1', 'Gene', (246, 250))	('BRG1', 'Gene', '6597', (246, 250))	('BRG1', 'Gene', (20, 24))	('Notch1', 'Gene', (188, 194))	('Smarcd1', 'Var', (152, 159))
72861	33190170	6d-f, knockdown of Smarcd1 increased the U251 cell viability and migration, which was consistent with Figs.	('migration', 'CPA', (65, 74))	('U251 cell viability', 'CPA', (41, 60))	('increased', 'PosReg', (27, 36))	('U251', 'CellLine', 'CVCL:0021', (41, 45))	('Smarcd1', 'Gene', (19, 26))	('knockdown', 'Var', (6, 15))
72862	33190170	However, treatment with Notch1 inhibitor DAPT restored the proliferation and migration abilities induced by low expression of Smarcd1, suggesting that downregulated Smarcd1 aggravated glioblastoma malignancy potentially via enabled Notch1 pathway.	('glioblastoma', 'Phenotype', 'HP:0012174', (184, 196))	('Notch1', 'Gene', '4851', (24, 30))	('aggravated', 'PosReg', (173, 183))	('glioblastoma malignancy', 'Disease', 'MESH:D005909', (184, 207))	('DAPT', 'Chemical', '-', (41, 45))	('Smarcd1', 'Gene', (165, 172))	('migration', 'CPA', (77, 86))	('downregulated', 'Var', (151, 164))	('Notch1', 'Gene', (24, 30))	('Notch1', 'Gene', '4851', (232, 238))	('Notch1', 'Gene', (232, 238))	('glioblastoma malignancy', 'Disease', (184, 207))
72867	33190170	The immunofluorescence assay showed that inactivation of Notch1 reduced the Hes1 red fluorescence and heightened the density of Smarcd1 green fluorescence, where the merged figures show differential densities as we can distinguish compared to relative control groups (Fig.	('heightened', 'PosReg', (102, 112))	('Hes1', 'Gene', (76, 80))	('Hes1', 'Gene', '3280', (76, 80))	('inactivation', 'Var', (41, 53))	('reduced', 'NegReg', (64, 71))	('Notch1', 'Gene', (57, 63))	('Notch1', 'Gene', '4851', (57, 63))	('Smarcd1 green fluorescence', 'MPA', (128, 154))	('density', 'MPA', (117, 124))
72871	33190170	Immunofluorescence assay of Hes1 knockdown showed the same results (Fig.	('knockdown', 'Var', (33, 42))	('Hes1', 'Gene', '3280', (28, 32))	('Hes1', 'Gene', (28, 32))
72875	33190170	Inhibition of Notch1 could restore the enhanced proliferation and migration which were induced by knockdown of Smarcd1.	('Smarcd1', 'Gene', (111, 118))	('migration', 'CPA', (66, 75))	('proliferation', 'CPA', (48, 61))	('knockdown', 'Var', (98, 107))	('Notch1', 'Gene', (14, 20))	('Notch1', 'Gene', '4851', (14, 20))	('Inhibition', 'Var', (0, 10))	('enhanced', 'PosReg', (39, 47))
72878	33190170	More than 20% of human cancers reported are associated with mutations in SWI/SNF encoded genes.	('associated', 'Reg', (44, 54))	('human', 'Species', '9606', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('SWI/SNF encoded', 'Gene', (73, 88))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
72885	33190170	The expression of MGMT mainly accounts for TMZ resistance and other factors including nucleotide base mismatch repair, base excision repair, P53 mutation and autophagy changes.	('autophagy changes', 'CPA', (158, 175))	('MGMT', 'Gene', (18, 22))	('base excision repair', 'MPA', (119, 139))	('MGMT', 'Gene', '4255', (18, 22))	('accounts', 'Reg', (30, 38))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('P53', 'Gene', (141, 144))	('P53', 'Gene', '7157', (141, 144))	('mutation', 'Var', (145, 153))
72889	33190170	More concretely, the N-terminal residues of Smarcd1 could bind with the tetramerization domain of P53, and in LNCaP cell line, knockdown of Smarcd1 suppressed the transcriptional ability of P53, resulting in reduced P53-dependent tumor apoptosis.	('P53', 'Gene', (190, 193))	('bind', 'Interaction', (58, 62))	('tumor', 'Disease', (230, 235))	('LNCaP', 'CellLine', 'CVCL:0395', (110, 115))	('P53', 'Gene', '7157', (190, 193))	('P53', 'Gene', (98, 101))	('Smarcd1', 'Gene', (140, 147))	('P53', 'Gene', (216, 219))	('P53', 'Gene', '7157', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('reduced', 'NegReg', (208, 215))	('P53', 'Gene', '7157', (216, 219))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('transcriptional ability', 'MPA', (163, 186))	('knockdown', 'Var', (127, 136))	('suppressed', 'NegReg', (148, 158))
72894	33190170	In glioblastoma, Notch1 pathway is involved in tumorigenesis and maintenance, and as a consequence, inhibition of Notch1 led to decreased cell viability, proliferation and a more differentiated morphology.	('Notch1', 'Gene', (17, 23))	('Notch1', 'Gene', '4851', (17, 23))	('involved', 'Reg', (35, 43))	('cell viability', 'CPA', (138, 152))	('more', 'PosReg', (174, 178))	('glioblastoma', 'Disease', (3, 15))	('Notch1', 'Gene', (114, 120))	('decreased', 'NegReg', (128, 137))	('inhibition', 'Var', (100, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Notch1', 'Gene', '4851', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('proliferation', 'CPA', (154, 167))	('tumor', 'Disease', (47, 52))
72897	33190170	The histone acetylases p300 can be recruited to NICD and then catalyze H3K27 into H3K27ac which facilitates chromatin loosening of the enhancer region and then stimulates transcription.	('transcription', 'MPA', (171, 184))	('stimulates', 'PosReg', (160, 170))	('H3K27', 'Var', (71, 76))	('p300', 'Gene', '2033', (23, 27))	('facilitates', 'PosReg', (96, 107))	('chromatin', 'MPA', (108, 117))	('H3K27ac', 'Var', (82, 89))	('p300', 'Gene', (23, 27))
72898	33190170	Histone demethylase Kdm5a catalyzes H3K4me3, which is considered to open chromatin structure, to the repressive form of H3K4.	('H3K4me3', 'Var', (36, 43))	('Kdm5a', 'Gene', '5927', (20, 25))	('Kdm5a', 'Gene', (20, 25))
72899	33190170	Alajem and his colleagues reported that knockdown of Smarcd1 in embryonic stem cells redistributed H3K27me3 and H3K4me3 in the TSS of Klf4 gene.	('Klf4', 'Gene', (134, 138))	('Smarcd1', 'Gene', (53, 60))	('H3K4me3', 'Var', (112, 119))	('H3K27me3', 'Protein', (99, 107))	('Klf4', 'Gene', '9314', (134, 138))	('knockdown', 'Var', (40, 49))
72900	33190170	Meanwhile, in HepG2 cells, the expression of Smarcd1 boosted the level of histone H3 acetylation and H3K4me3 proximal to Bmal1 promoter.	('histone H3 acetylation', 'MPA', (74, 96))	('Smarcd1', 'Gene', (45, 52))	('HepG2', 'CellLine', 'CVCL:0027', (14, 19))	('boosted', 'PosReg', (53, 60))	('expression', 'Var', (31, 41))	('H3K4me3', 'MPA', (101, 108))
72903	33190170	Furthermore, we demonstrated that inhibition of Notch1 decreased Smarcd1 expression by downstream targets Hes1 in the present study.	('Notch1', 'Gene', (48, 54))	('inhibition', 'Var', (34, 44))	('Notch1', 'Gene', '4851', (48, 54))	('Hes1', 'Gene', (106, 110))	('decreased', 'NegReg', (55, 64))	('expression', 'MPA', (73, 83))	('Hes1', 'Gene', '3280', (106, 110))	('Smarcd1', 'Gene', (65, 72))
72905	33190170	Silencing Hes1 expression in GSCs induced G1 phase arrest, inhibitory proliferation, and a more mature cell phenotype.	('inhibitory proliferation', 'CPA', (59, 83))	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('more mature cell phenotype', 'CPA', (91, 117))	('arrest', 'Disease', (51, 57))	('Hes1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('Hes1', 'Gene', '3280', (10, 14))
72912	33190170	Therefore, it is reasonable that the crosstalk between Smarcd1 and Notch1 contributes to glioma chemoresistance potentially via the existence of GSCs, and strategies targeting pathways involving GSC to break up TMZ chemoresistance are the latest frontier of current GBM treatment.	('contributes', 'Reg', (74, 85))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (211, 214))	('crosstalk', 'Var', (37, 46))	('glioma', 'Disease', (89, 95))	('Notch1', 'Gene', (67, 73))	('break up', 'Phenotype', 'HP:0001061', (202, 210))	('Smarcd1', 'Gene', (55, 62))	('Notch1', 'Gene', '4851', (67, 73))
72915	33190170	Breaking up the malignant feedback loop between Smarcd1 and Notch1 may be a potential target in treating glioblastoma.	('malignant feedback loop', 'MPA', (16, 39))	('Notch1', 'Gene', '4851', (60, 66))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('Breaking', 'Var', (0, 8))	('Breaking up', 'Phenotype', 'HP:0001061', (0, 11))	('Notch1', 'Gene', (60, 66))	('glioblastoma', 'Disease', (105, 117))	('Smarcd1', 'Gene', (48, 55))
72919	33029523	Furthermore, knockdown of EEF1D could reduce cell proliferation and impaired epithelial-mesenchymal transition (EMT) phenotypes, including cell invasion.	('EEF1D', 'Gene', (26, 31))	('EEF1D', 'Gene', '1936', (26, 31))	('cell proliferation', 'CPA', (45, 63))	('impaired', 'NegReg', (68, 76))	('cell invasion', 'CPA', (139, 152))	('reduce', 'NegReg', (38, 44))	('knockdown', 'Var', (13, 22))
72941	33029523	The membranes were blocked with 5% BSA and then incubated with primary antibodies, including EEF1D (PTG, USA); E-cadherin, N-cadherin, beta-catenin, slug, snail, and vimentin (Cell Signaling Technology, USA); PI3K and PI3K (phosopho-Tyr467/199); Akt and p-Akt (phosphor-Ser473) (SAB, USA); and GAPDH (CWbio, China), overnight at 4 C and then incubated with horseradish peroxidase-conjugated secondary antibody for 1 h under room temperature.	('Akt', 'Gene', '207', (246, 249))	('snail', 'Gene', '6615', (155, 160))	('slug', 'Gene', (149, 153))	('N-cadherin', 'Gene', (123, 133))	('beta-catenin', 'Gene', (135, 147))	('N-cadherin', 'Gene', '1000', (123, 133))	('beta-catenin', 'Gene', '1499', (135, 147))	('GAPDH', 'Gene', '2597', (294, 299))	('phosopho-Tyr467/199', 'Var', (224, 243))	('vimentin', 'Gene', '7431', (166, 174))	('snail', 'Gene', (155, 160))	('vimentin', 'Gene', (166, 174))	('Akt', 'Gene', (256, 259))	('horseradish', 'Species', '3704', (357, 368))	('E-cadherin', 'Gene', (111, 121))	('EEF1D', 'Gene', '1936', (93, 98))	('E-cadherin', 'Gene', '999', (111, 121))	('GAPDH', 'Gene', (294, 299))	('Akt', 'Gene', '207', (256, 259))	('Akt', 'Gene', (246, 249))	('slug', 'Gene', '6591', (149, 153))	('EEF1D', 'Gene', (93, 98))
72967	33029523	Transwell assay further determined that depletion of EEF1D could impair the migration capacity of U87 and A172 cells (Figures 3(e) and 3(f)) and resulted in lower invasion capacity compared to negative control group, as Boyden assays have shown (Figures 3(g) and 3(h)).	('EEF1D', 'Gene', (53, 58))	('depletion', 'Var', (40, 49))	('EEF1D', 'Gene', '1936', (53, 58))	('migration capacity', 'CPA', (76, 94))	('impair', 'NegReg', (65, 71))	('invasion capacity', 'CPA', (163, 180))	('lower', 'NegReg', (157, 162))
72968	33029523	In summary, these results proposed that inhibition of EEF1D could suppress the cell growth and reduce the malignant phenotype-like proliferation, migratory, and invasion of glioma cells.	('inhibition', 'Var', (40, 50))	('suppress', 'NegReg', (66, 74))	('malignant phenotype-like proliferation', 'CPA', (106, 144))	('reduce', 'NegReg', (95, 101))	('glioma', 'Disease', (173, 179))	('EEF1D', 'Gene', (54, 59))	('EEF1D', 'Gene', '1936', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('cell growth', 'CPA', (79, 90))	('migratory', 'CPA', (146, 155))
72970	33029523	As shown in Figures 4(a) and 4(b), levels of the epithelial marker E-cadherin were slightly promoted, whereas the expression of mesenchymal markers including N-cadherin and Snail was significantly downregulated in U87 and A172 glioma cells following EEF1D-siRNA transfection.	('Snail', 'Gene', '6615', (173, 178))	('N-cadherin', 'Gene', (158, 168))	('downregulated', 'NegReg', (197, 210))	('EEF1D', 'Gene', (250, 255))	('E-cadherin', 'Gene', (67, 77))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('E-cadherin', 'Gene', '999', (67, 77))	('promoted', 'PosReg', (92, 100))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('EEF1D', 'Gene', '1936', (250, 255))	('N-cadherin', 'Gene', '1000', (158, 168))	('transfection', 'Var', (262, 274))	('Snail', 'Gene', (173, 178))	('expression', 'MPA', (114, 124))	('glioma', 'Disease', (227, 233))
72971	33029523	Further, beta-catenin, a critical transcriptional factor of the EMT process, was also decreased after EEF1D knockdown.	('knockdown', 'Var', (108, 117))	('beta-catenin', 'Gene', (9, 21))	('EEF1D', 'Gene', (102, 107))	('EEF1D', 'Gene', '1936', (102, 107))	('decreased', 'NegReg', (86, 95))	('beta-catenin', 'Gene', '1499', (9, 21))
72972	33029523	Taken together, these findings suggested that EEF1D was closely associated with the modulation of EMT progress in glioma cells, and inhibition of EEF1D could reverse the EMT characteristics of glioma cells.	('associated', 'Reg', (64, 74))	('glioma', 'Disease', (114, 120))	('EEF1D', 'Gene', (146, 151))	('glioma', 'Disease', (193, 199))	('EEF1D', 'Gene', '1936', (146, 151))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('EMT progress', 'CPA', (98, 110))	('EEF1D', 'Gene', (46, 51))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('reverse', 'NegReg', (158, 165))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('inhibition', 'Var', (132, 142))	('EEF1D', 'Gene', '1936', (46, 51))
72974	33029523	In the present study, Western blot results revealed that PI3K, p-PI3K, Akt, and p-Akt in glioma cells transfected with EEF1D-siRNA were significantly lower than those transfected with NC-siRNA (P < 0.05; Figure 4(c)).	('lower', 'NegReg', (150, 155))	('Akt', 'Gene', '207', (71, 74))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('Akt', 'Gene', '207', (82, 85))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('Akt', 'Gene', (71, 74))	('EEF1D', 'Gene', (119, 124))	('EEF1D', 'Gene', '1936', (119, 124))	('glioma', 'Disease', (89, 95))	('Akt', 'Gene', (82, 85))	('PI3K', 'Var', (57, 61))	('NC-siRNA', 'Disease', (184, 192))	('NC-siRNA', 'Disease', 'OMIM:617025', (184, 192))	('p-PI3K', 'Var', (63, 69))
72985	33029523	Proteomic analysis shows that EEF1D is overexpressed in right-sided colon cancer and correlates with the invasive status of Adriamycin-resistant variants of DLKP, a squamous lung and cancer cell line.	('cancer', 'Disease', (183, 189))	('EEF1D', 'Gene', (30, 35))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('EEF1D', 'Gene', '1936', (30, 35))	('cancer', 'Disease', (74, 80))	('variants', 'Var', (145, 153))	('DLKP', 'Gene', (157, 161))	('squamous lung', 'Disease', (165, 178))	('squamous lung', 'Disease', 'MESH:D002294', (165, 178))	('colon cancer', 'Disease', (68, 80))	('Adriamycin', 'Chemical', 'MESH:D004317', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('overexpressed', 'PosReg', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
73002	33029523	Alteration of the processes induced by aberrant expression of EEF1D may impair the indispensable nucleic acid metabolism and translational deregulation and finally impede tumor cell survival and progression including glioma.	('aberrant expression', 'Var', (39, 58))	('glioma', 'Disease', 'MESH:D005910', (217, 223))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('impair', 'NegReg', (72, 78))	('EEF1D', 'Gene', (62, 67))	('glioma', 'Disease', (217, 223))	('impede', 'NegReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('EEF1D', 'Gene', '1936', (62, 67))
73005	33029523	Therefore, blocking EEF1D could restrain EMT and PI3K/Akt activity resulting in the suppression of cell growth and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Akt', 'Gene', '207', (54, 57))	('tumor', 'Disease', (115, 120))	('restrain', 'NegReg', (32, 40))	('EEF1D', 'Gene', (20, 25))	('Akt', 'Gene', (54, 57))	('blocking', 'Var', (11, 19))	('EEF1D', 'Gene', '1936', (20, 25))	('suppression', 'NegReg', (84, 95))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('EMT', 'CPA', (41, 44))
73009	32323804	GSK-3 inhibitor CHIR99021 enriches glioma stem-like cells Glioblastoma (GBM) is the most prevalent and lethal primary intrinsic brain cancer.	('glioma', 'Disease', (35, 41))	('Glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('Glioblastoma', 'Disease', (58, 70))	('brain cancer', 'Disease', (128, 140))	('GSK-3', 'Gene', '56637', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('Glioblastoma', 'Disease', 'MESH:D005909', (58, 70))	('brain cancer', 'Disease', 'MESH:D001932', (128, 140))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('CHIR99021', 'Var', (16, 25))	('brain cancer', 'Phenotype', 'HP:0030692', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GSK-3', 'Gene', (0, 5))
73018	32323804	CHIR99021 could stably enhance GSLC properties in patient-derived glioma samples.	('glioma', 'Disease', (66, 72))	('patient', 'Species', '9606', (50, 57))	('GSLC properties', 'MPA', (31, 46))	('GSLC', 'Chemical', '-', (31, 35))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('enhance', 'PosReg', (23, 30))	('CHIR99021', 'Var', (0, 9))
73027	32323804	CHIR99021 is a chemical compound that acts as an inhibitor of GSK-3.	('GSK-3', 'Gene', '56637', (62, 67))	('CHIR99021', 'Var', (0, 9))	('GSK-3', 'Gene', (62, 67))
73029	32323804	However, there is no evidence that CHIR99021 can transform primary low-grade glioma cells into GSLCs.	('GSLCs', 'Chemical', '-', (95, 100))	('CHIR99021', 'Var', (35, 44))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
73039	32323804	Flow cytometry was used in order to find a suitable concentration of CHIR99021 for cell survival and to detect the expression level of stem cell markers in the two groups.	('expression', 'MPA', (115, 125))	('CHIR99021', 'Var', (69, 78))	('rat', 'Species', '10116', (59, 62))
73092	32323804	The expression levels of the related proteins (PI3K, AKT and mTOR) were also enhanced in the GSLCs compared to the PGBCs (Fig.	('mTOR', 'MPA', (61, 65))	('enhanced', 'PosReg', (77, 85))	('PGBCs', 'Chemical', '-', (115, 120))	('GSLCs', 'Chemical', '-', (93, 98))	('GSLCs', 'Var', (93, 98))	('expression levels of', 'MPA', (4, 24))
73094	32323804	Western blot analysis revealed that the expression of STAT3, p-STAT3, VEGF, and NF-kappaB was significantly increased in the GSLCs compared to the PGBCs (Fig.	('expression', 'MPA', (40, 50))	('VEGF', 'Gene', (70, 74))	('increased', 'PosReg', (108, 117))	('p-STAT3', 'Var', (61, 68))	('GSLCs', 'Chemical', '-', (125, 130))	('STAT3', 'Gene', (54, 59))	('PGBCs', 'Chemical', '-', (147, 152))	('NF-kappaB', 'Gene', (80, 89))
73096	32323804	In addition, the knockdown effect of STAT3 in the GSLCs was also detected by western blotting.	('GSLCs', 'Chemical', '-', (50, 55))	('STAT3', 'Gene', (37, 42))	('knockdown', 'Var', (17, 26))
73110	32323804	Moreover, the NF-kappaB and VEGF protein levels were significantly increased in the GSLC-transplanted mice than in the PGBC- and saline-injected mice (Fig.	('mice', 'Species', '10090', (102, 106))	('saline', 'Chemical', 'MESH:D012965', (129, 135))	('PGBC', 'Chemical', '-', (119, 123))	('GSLC-transplanted', 'Var', (84, 101))	('increased', 'PosReg', (67, 76))	('GSLC', 'Chemical', '-', (84, 88))	('mice', 'Species', '10090', (145, 149))	('NF-kappaB', 'Protein', (14, 23))
73111	32323804	A western blot assay revealed that the expression of the STAT3, NF-kappaB, VEGF, and mTOR protein levels were significantly upregulated in the GSLC-transplanted mice compared to the saline- and PGBC-injected mice (Fig.	('mice', 'Species', '10090', (161, 165))	('mTOR protein levels', 'MPA', (85, 104))	('saline', 'Chemical', 'MESH:D012965', (182, 188))	('GSLC-transplanted', 'Var', (143, 160))	('VEGF', 'MPA', (75, 79))	('NF-kappaB', 'Gene', (64, 73))	('STAT3', 'Gene', (57, 62))	('expression', 'MPA', (39, 49))	('upregulated', 'PosReg', (124, 135))	('PGBC', 'Chemical', '-', (194, 198))	('mice', 'Species', '10090', (208, 212))	('GSLC', 'Chemical', '-', (143, 147))
73115	32323804	The results of the present study revealed that CHIR99021, in a concentration of 100 nM, could enrich primary low-grade glioma cells with CD133-positive GSLC properties.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('rat', 'Species', '10116', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('GSLC', 'Chemical', '-', (152, 156))	('glioma', 'Disease', (119, 125))	('CHIR99021', 'Var', (47, 56))
73118	32323804	Another study reported that CHIR99021 activated the Wnt/beta-catenin signaling pathway and then initiated the differentiation of human embryonic stem cells (hESCs) by inhibiting the degradation of beta-catenin.	('inhibiting', 'NegReg', (167, 177))	('Wnt/beta-catenin signaling pathway', 'Pathway', (52, 86))	('differentiation', 'CPA', (110, 125))	('human', 'Species', '9606', (129, 134))	('activated', 'PosReg', (38, 47))	('degradation', 'MPA', (182, 193))	('CHIR99021', 'Var', (28, 37))
73123	32323804	These changes indicated that the proliferation and migration abilities of the GSLCs were enhanced by CHIR99021, which was consistent with the expression of related genes and proteins in the PI3K/AKT/mTOR signaling pathway.	('enhanced', 'PosReg', (89, 97))	('rat', 'Species', '10116', (40, 43))	('rat', 'Species', '10116', (54, 57))	('CHIR99021', 'Var', (101, 110))	('GSLCs', 'Chemical', '-', (78, 83))	('migration abilities', 'CPA', (51, 70))
73125	32323804	CHIR99021 specifically inhibits GSK-3, while AKT inactivates GSK-3 through its Ser9 phosphorylation.	('GSK-3', 'Gene', '56637', (32, 37))	('Ser9 phosphorylation', 'MPA', (79, 99))	('GSK-3', 'Gene', '56637', (61, 66))	('GSK-3', 'Gene', (32, 37))	('GSK-3', 'Gene', (61, 66))	('inhibits', 'NegReg', (23, 31))	('Ser9', 'Chemical', '-', (79, 83))	('inactivates', 'NegReg', (49, 60))	('CHIR99021', 'Var', (0, 9))
73126	32323804	In the present study, qRT-PCR and western blot analysis were used to demonstrate that AKT was activated by CHIR99021 in the GSLCs.	('rat', 'Species', '10116', (76, 79))	('CHIR99021', 'Var', (107, 116))	('GSLCs', 'Chemical', '-', (124, 129))	('AKT', 'Pathway', (86, 89))	('activated', 'PosReg', (94, 103))
73141	32323804	Furthermore, although the present study provided evidence that CHIR99021 could enhance the expression of malignancy-related biological features, only the well-known PI3K/ATK pathway and STAT3 were explored.	('expression', 'MPA', (91, 101))	('CHIR99021', 'Var', (63, 72))	('enhance', 'PosReg', (79, 86))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))
73143	32323804	CHIR99021 has the potential to promote the migration and invasiveness of induced GSLCs both in vitro and in vivo, possibly by regulating the PI3K/AKT signaling pathway and activating STAT3.	('rat', 'Species', '10116', (46, 49))	('activating', 'PosReg', (172, 182))	('regulating', 'Reg', (126, 136))	('PI3K/AKT signaling pathway', 'Pathway', (141, 167))	('promote', 'PosReg', (31, 38))	('STAT3', 'MPA', (183, 188))	('migration', 'CPA', (43, 52))	('invasiveness', 'CPA', (57, 69))	('GSLCs', 'Chemical', '-', (81, 86))	('CHIR99021', 'Var', (0, 9))
73145	32323804	In conclusion, CHIR99021 may provide a useful GSLC model, generated from patient-derived low-grade glioma samples, for further study, helping to understand the pathogenesis of therapeutic resistance and to screen for potential drug candidates.	('CHIR99021', 'Var', (15, 24))	('GSLC', 'Chemical', '-', (46, 50))	('glioma', 'Disease', (99, 105))	('patient', 'Species', '9606', (73, 80))	('rat', 'Species', '10116', (62, 65))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
73155	30878893	The crosstabs chi-square test of independence was performed to calculate contingency coefficient (C) and Cramer V coefficient to assess the correlation between perfusion and IDH1 genotypes and 1p/19q status of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (210, 217))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('IDH1', 'Gene', (174, 178))	('IDH1', 'Gene', '3417', (174, 178))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))	('1p/19q status', 'Var', (193, 206))
73157	30878893	There was no significant association between 1p/19q codeletion and perfusion in grade II and III gliomas.	('1p/19q codeletion', 'Var', (45, 62))	('II gliomas', 'Disease', 'MESH:D005910', (94, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('II gliomas', 'Disease', (94, 104))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
73167	30878893	IDH mutations that occur in gliomas include IDH1 and IDH2 mutations, with the former accounting for the vast majority.	('mutations', 'Var', (58, 67))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('IDH', 'Gene', (0, 3))	('IDH2', 'Gene', (53, 57))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH1', 'Gene', (44, 48))	('IDH', 'Gene', '3417', (0, 3))	('IDH2', 'Gene', '3418', (53, 57))	('IDH1', 'Gene', '3417', (44, 48))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (53, 56))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', '3417', (53, 56))	('gliomas', 'Disease', (28, 35))
73168	30878893	Previous studies have shown that the presence or absence of IDH mutation and 1p/19q codeletion affects the prognosis of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('mutation', 'Var', (64, 72))	('affects', 'Reg', (95, 102))	('IDH', 'Gene', (60, 63))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('1p/19q codeletion', 'Var', (77, 94))	('gliomas', 'Disease', (120, 127))	('IDH', 'Gene', '3417', (60, 63))
73176	30878893	In addition, we preliminarily explored the association of perfusion parameters with IDH1 genotypes and 1p/19q status of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('association', 'Interaction', (43, 54))	('IDH1', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (84, 88))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))	('genotypes', 'Var', (89, 98))
73198	30878893	Molecular markers included IDH1 genotype (IDH1 mutant or wild-type) and 1p/19q status (1p/19q codeleted or non-codeleted).	('IDH1', 'Gene', '3417', (42, 46))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', (42, 46))	('mutant', 'Var', (47, 53))	('IDH1', 'Gene', '3417', (27, 31))
73202	30878893	The quantitative perfusion parameters were compared between IDH1 mutant and wild-type groups, and between 1p/19q codeleted and non-codeleted group by using the Mann-Whitney U test or t test according to the normality of data.	('IDH1', 'Gene', (60, 64))	('mutant', 'Var', (65, 71))	('IDH1', 'Gene', '3417', (60, 64))
73203	30878893	For qualitative analysis, crosstabs chi-square test of independence was performed to calculate contingency coefficient (C) and Cramer V coefficient to assess the correlation between perfusion parameters and IDH1 genotypes and 1p/19q status of gliomas.	('genotypes', 'Var', (212, 221))	('IDH1', 'Gene', (207, 211))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('IDH1', 'Gene', '3417', (207, 211))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('gliomas', 'Disease', (243, 250))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))
73215	30878893	Regardless of grades and 1p/19q status, rmeanCBF was lower in IDH1 mutant group than in IDH1 wild-type group (P = .047); the other parameters did not show statistical differences between IDH1 mutant and wild-type groups (P = .097, .455, and .282, respectively, for meanCBF, maxCBF, and rmaxCBF).	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', (88, 92))	('IDH1', 'Gene', '3417', (187, 191))	('mutant', 'Var', (67, 73))	('IDH1', 'Gene', '3417', (88, 92))	('lower', 'NegReg', (53, 58))	('IDH1', 'Gene', (62, 66))	('rmeanCBF', 'MPA', (40, 48))	('IDH1', 'Gene', (187, 191))
73217	30878893	There were only two cases with IDH1 wild-type gliomas in the low-grade group, and there were 12 cases with IDH1 mutant and 23 cases with IDH1 wild-type gliomas in the high-grade group.	('IDH1', 'Gene', (107, 111))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('IDH1', 'Gene', '3417', (31, 35))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('IDH1', 'Gene', '3417', (107, 111))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('IDH1', 'Gene', (137, 141))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('mutant', 'Var', (112, 118))	('IDH1', 'Gene', '3417', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('IDH1', 'Gene', (31, 35))
73219	30878893	However, none of the perfusion parameters showed statistical differences between IDH1 mutant and wild-type gliomas in the high-grade group.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('mutant', 'Var', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (81, 85))
73222	30878893	A moderate correlation was shown between perfusion and IDH1 genotype of gliomas (C = 0.354, Cramer V = 0.378, P = .014).	('genotype', 'Var', (60, 68))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('perfusion', 'MPA', (41, 50))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
73223	30878893	As a characteristic feature of oligodendroglioma, 1p/19q codeletion was shown in three patients with oligodendroglioma and six patients with anaplastic oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('oligodendroglioma', 'Disease', (31, 48))	('shown', 'Reg', (72, 77))	('oligodendroglioma', 'Disease', (152, 169))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (141, 169))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('oligodendroglioma', 'Disease', (101, 118))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('patients', 'Species', '9606', (127, 135))	('oligodendroglioma', 'Disease', 'MESH:D009837', (31, 48))	('1p/19q codeletion', 'Var', (50, 67))	('oligodendroglioma', 'Disease', 'MESH:D009837', (152, 169))	('oligodendroglioma', 'Disease', 'MESH:D009837', (101, 118))	('anaplastic oligodendroglioma', 'Disease', (141, 169))	('patients', 'Species', '9606', (87, 95))
73228	30878893	Previous studies declared that rmaxCBF rather than rmeanCBF of gliomas had higher diagnostic efficiency for distinguishing high- from low-grade gliomas.	('rmaxCBF', 'Var', (31, 38))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('high-', 'Disease', (123, 128))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
73249	30878893	A mild correlation was showed between perfusion and IDH1 genotype regardless of grades and 1p/19q status, and a similar result was also found in astrocytoma.	('IDH1', 'Gene', '3417', (52, 56))	('astrocytoma', 'Disease', 'MESH:D001254', (145, 156))	('genotype', 'Var', (57, 65))	('astrocytoma', 'Disease', (145, 156))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('perfusion', 'MPA', (38, 47))	('IDH1', 'Gene', (52, 56))
73253	30878893	Since 1p/19q codeletion is a distinguishing feature of oligodendrogliomas, our study explored the correlation between 1p/19q codeletion and perfusion.	('1p/19q codeletion', 'Var', (6, 23))	('oligodendrogliomas', 'Disease', (55, 73))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (55, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))
73255	30878893	Third, it will be very valuable to enlarge the sample size to explore the association of perfusion with IDH1 genotype and 1p/19q status.	('1p/19q status', 'Var', (122, 135))	('IDH1', 'Gene', (104, 108))	('IDH1', 'Gene', '3417', (104, 108))
73259	30878893	Preliminary results showed a mild correlation between IDH1 genotypes and perfusion in astrocytoma, but no significant association was found between 1p/19q status and perfusion of gliomas.	('genotypes', 'Var', (59, 68))	('astrocytoma', 'Disease', 'MESH:D001254', (86, 97))	('IDH1', 'Gene', (54, 58))	('astrocytoma', 'Disease', (86, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('IDH1', 'Gene', '3417', (54, 58))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('gliomas', 'Disease', (179, 186))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))
73276	23096411	Molecular biomarkers most commonly used to evaluate adult malignant gliomas from biopsies include 1p/19q co-deletion, methylation of the O-6 methylguanine-DNA methyltransferase (MGMT) gene promoter, alterations in the epidermal growth factor receptor (EGFR) pathway, and isocitrate dehydrogenase 1 (IDH1) and IDH2 gene mutations.	('malignant gliomas', 'Disease', (58, 75))	('MGMT', 'Gene', '4255', (178, 182))	('mutations', 'Var', (319, 328))	('methylation', 'Var', (118, 129))	('O-6 methylguanine-DNA methyltransferase', 'Gene', (137, 176))	('O-6 methylguanine-DNA methyltransferase', 'Gene', '4255', (137, 176))	('rat', 'Species', '10116', (277, 280))	('EGFR', 'Gene', '1956', (252, 256))	('IDH1', 'Gene', (299, 303))	('MGMT', 'Gene', (178, 182))	('alterations', 'Reg', (199, 210))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('isocitrate dehydrogenase 1', 'Gene', (271, 297))	('isocitrate dehydrogenase 1', 'Gene', '3417', (271, 297))	('rat', 'Species', '10116', (203, 206))	('epidermal growth factor receptor', 'Gene', (218, 250))	('IDH1', 'Gene', '3417', (299, 303))	('epidermal growth factor receptor', 'Gene', '1956', (218, 250))	('malignant gliomas', 'Disease', 'MESH:D005910', (58, 75))	('IDH2', 'Gene', (309, 313))	('EGFR', 'Gene', (252, 256))	('IDH2', 'Gene', '3418', (309, 313))
73284	23096411	In more obscure roles, variations in ELTD1 have been associated as a risk factor for cannabis use disorders, tick burden in cattle, and subcutaneous fat thickness.	('risk factor', 'Reg', (69, 80))	('cattle', 'Species', '9913', (124, 130))	('ELTD1', 'Gene', (37, 42))	('cannabis use disorders', 'Disease', (85, 107))	('associated', 'Reg', (53, 63))	('variations', 'Var', (23, 33))	('tick burden', 'Disease', (109, 120))
73328	23096411	MRI was performed for the purpose of determining the incidence, number, growth rate, and volume of each tumor for the F98 gliomas.	('F98', 'Var', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('MR', 'Gene', '50771', (0, 2))	('gliomas', 'Disease', (122, 129))	('rat', 'Species', '10116', (79, 82))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
73391	23096411	Co-localization analysis indicated that the Pearson co-localization coefficients were 0.8089 (1.0000 would be 100% co-localization) (Bii) and 0.7929 (Ci) for ELTD1 and CD31 in glioma tissue, indicating a high association of ELTD1 with endothelial cells.	('glioma', 'Disease', (176, 182))	('association', 'Interaction', (209, 220))	('0.7929', 'Var', (142, 148))	('Bii', 'Gene', (133, 136))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('CD31', 'Gene', (168, 172))	('Bii', 'Gene', '777', (133, 136))
73414	23096411	F98 gliomas are classified as anaplastic malignant tumors, which have an infiltrative pattern of growth, which is an attribute associated with human GBM.	('gliomas', 'Phenotype', 'HP:0009733', (4, 11))	('anaplastic malignant tumors', 'Disease', (30, 57))	('human', 'Species', '9606', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('anaplastic malignant tumors', 'Disease', 'MESH:D002277', (30, 57))	('F98', 'Var', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('rat', 'Species', '10116', (79, 82))	('gliomas', 'Disease', (4, 11))	('gliomas', 'Disease', 'MESH:D005910', (4, 11))
73415	23096411	MRI techniques have been used in our group to demonstrate the aggressive nature of F98 gliomas.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('rat', 'Species', '10116', (53, 56))	('MR', 'Gene', '50771', (0, 2))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('F98', 'Var', (83, 86))	('gliomas', 'Disease', (87, 94))
73416	23096411	With the use of diffusion tensor imaging, we were able to demonstrate that the F98 glioma model is much more infiltrative than the rat C6 glioma model.	('glioma', 'Disease', (83, 89))	('rat', 'Species', '10116', (131, 134))	('rat', 'Species', '10116', (115, 118))	('glioma', 'Disease', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('C6 glioma', 'Disease', 'MESH:C567307', (135, 144))	('C6 glioma', 'Disease', (135, 144))	('F98', 'Var', (79, 82))	('rat', 'Species', '10116', (65, 68))
73417	23096411	With the use of MR angiography, we have shown that the F98 model predominantly uses pre-existing blood vessels in tumor angiogenesis, but has longer and thicker new blood vessels compared to other glioma models.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MR', 'Gene', '50771', (16, 18))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('glioma', 'Disease', (197, 203))	('tumor', 'Disease', (114, 119))	('F98', 'Var', (55, 58))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
73418	23096411	In this study within the F98 glioma model, we were also able to demonstrate, with the use of mMRI and an anti-ELTD1 probe, that substantial levels of ELTD1 are found in the tumor tissue of F98 glioma-bearing animals.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('glioma', 'Disease', (29, 35))	('rat', 'Species', '10116', (71, 74))	('glioma', 'Disease', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('MR', 'Gene', '50771', (94, 96))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('F98', 'Var', (189, 192))
73436	23096411	In another study, within U87MG xenograft tumors in nude mice, RGD-labeled ultrasmall superparamagnetic iron oxide (USPIO) probes were found to accumulate only within the neovasculature associated with tumors, and not within tumor cells.	('accumulate', 'PosReg', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (41, 47))	('iron oxide', 'Chemical', 'MESH:C000499', (103, 113))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', (201, 206))	('U87MG', 'CellLine', 'CVCL:0022', (25, 30))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('U87MG', 'Var', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('nude mice', 'Species', '10090', (51, 60))
73452	33228806	TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas.	('1p/19q codeletion', 'Var', (179, 196))	('TERT', 'Gene', (126, 130))	('IDH', 'Gene', (200, 203))	('19q', 'Chemical', '-', (68, 71))	('TERT', 'Gene', '7015', (126, 130))	('IDH1/2', 'Gene', '3417;3418', (109, 115))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('1p', 'Chemical', '-', (179, 181))	('IDH1/2', 'Gene', (109, 115))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('IDH', 'Gene', '3417', (200, 203))	('IDH', 'Gene', (109, 112))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('gliomas', 'Disease', (96, 103))	('1p', 'Chemical', '-', (65, 67))	('associated', 'Reg', (163, 173))	('mutations', 'Var', (116, 125))	('19q', 'Chemical', '-', (182, 185))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('IDH', 'Gene', '3417', (109, 112))	('TERT', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('TERT', 'Gene', '7015', (0, 4))	('gliomas', 'Disease', (212, 219))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))
73453	33228806	However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown.	('1p', 'Chemical', '-', (83, 85))	('mutations', 'Var', (23, 32))	('patient', 'Species', '9606', (51, 58))	('impact', 'Reg', (41, 47))	('19q', 'Chemical', '-', (86, 89))
73457	33228806	A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p < 0.05).	('1p/19q codeletion', 'Var', (212, 229))	('1p', 'Chemical', '-', (212, 214))	('TERT', 'Gene', (188, 192))	('TERT', 'Gene', '7015', (188, 192))	('19q', 'Chemical', '-', (215, 218))
73459	33228806	Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation.	('TERT', 'Gene', (152, 156))	('TERT', 'Gene', '7015', (152, 156))	('mutation', 'Var', (166, 174))	('patient', 'Species', '9606', (23, 30))
73460	33228806	Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032).	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('19q', 'Chemical', '-', (226, 229))	('IDH', 'Gene', '3417', (81, 84))	('19q', 'Chemical', '-', (116, 119))	('IDH', 'Gene', (182, 185))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('TERT', 'Gene', (85, 89))	('TERT', 'Gene', '7015', (85, 89))	('intact', 'Var', (106, 112))	('patients', 'Species', '9606', (30, 38))	('1p', 'Chemical', '-', (113, 115))	('1p', 'Chemical', '-', (223, 225))	('IDH', 'Gene', '3417', (182, 185))	('survival', 'MPA', (157, 165))	('longer', 'PosReg', (150, 156))	('TERT', 'Gene', (206, 210))	('glioma', 'Disease', (23, 29))	('TERT', 'Gene', '7015', (206, 210))	('IDH', 'Gene', (81, 84))
73462	33228806	Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (210, 217))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('IDH', 'Gene', (51, 54))	('mutation', 'Var', (122, 130))	('IDH', 'Gene', '3417', (51, 54))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('glioma', 'Disease', (60, 66))	('TERT', 'Gene', (108, 112))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))	('TERT', 'Gene', '7015', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('glioma', 'Disease', (210, 216))
73465	33228806	IDH mutation and 1p/19q codeletion are necessary and sufficient to make the diagnosis of oligodendrogliomas regardless of the histology.	('IDH', 'Gene', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('mutation', 'Var', (4, 12))	('oligodendrogliomas regardless', 'Disease', (89, 118))	('and 1p', 'Gene', '11169', (13, 19))	('19q', 'Chemical', '-', (20, 23))	('oligodendrogliomas regardless', 'Disease', 'MESH:D009837', (89, 118))	('and 1p', 'Gene', (13, 19))
73468	33228806	TERT promoter mutations are common in oligodendrogliomas and glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (61, 74))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('common', 'Reg', (28, 34))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (38, 56))	('glioblastomas', 'Disease', 'MESH:D005909', (61, 74))	('TERT', 'Gene', (0, 4))	('glioblastomas', 'Disease', (61, 74))	('TERT', 'Gene', '7015', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('oligodendrogliomas', 'Disease', (38, 56))	('mutations', 'Var', (14, 23))
73469	33228806	We and others have shown that TERT promoter mutations are frequently observed (> 90%) in oligodendrogliomas with mutant IDH and 1p/19q codeletion, and that the presence of TERT promoter mutations is associated with favorable outcomes in IDH-mutated gliomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (89, 107))	('mutant', 'Var', (113, 119))	('IDH', 'Gene', (237, 240))	('IDH', 'Gene', (120, 123))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('TERT', 'Gene', (30, 34))	('19q', 'Chemical', '-', (131, 134))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('gliomas', 'Disease', (249, 256))	('TERT', 'Gene', '7015', (30, 34))	('oligodendrogliomas', 'Disease', (89, 107))	('TERT', 'Gene', (172, 176))	('IDH and 1p/19', 'Gene', '3417', (120, 133))	('TERT', 'Gene', '7015', (172, 176))	('observed', 'Reg', (69, 77))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH', 'Gene', '3417', (120, 123))	('IDH', 'Gene', '3417', (237, 240))	('gliomas', 'Disease', 'MESH:D005910', (249, 256))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('gliomas', 'Phenotype', 'HP:0009733', (249, 256))	('mutations', 'Var', (44, 53))	('gliomas', 'Disease', (100, 107))
73471	33228806	Another aspect of TERT promoter mutation is that this alteration without accompanying IDH mutation suggests clinically and biologically aggressive characteristics comparable with those of glioblastomas when found in histologically diagnosed as diffuse gliomas.	('IDH', 'Gene', (86, 89))	('glioblastomas', 'Phenotype', 'HP:0012174', (188, 201))	('IDH', 'Gene', '3417', (86, 89))	('gliomas', 'Disease', 'MESH:D005910', (252, 259))	('glioblastomas', 'Disease', 'MESH:D005909', (188, 201))	('gliomas', 'Phenotype', 'HP:0009733', (252, 259))	('gliomas', 'Disease', (252, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('TERT', 'Gene', (18, 22))	('glioblastomas', 'Disease', (188, 201))	('TERT', 'Gene', '7015', (18, 22))	('mutation', 'Var', (32, 40))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))
73472	33228806	The presence of the TERT promoter mutation indicates the underestimation of the tumor grades when observed in grade II-III diffuse gliomas without IDH mutation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IDH', 'Gene', '3417', (147, 150))	('gliomas', 'Disease', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', (80, 85))	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('IDH', 'Gene', (147, 150))
73473	33228806	cIMPACT-NOW Update 3 recommended TERT promoter mutations as one of the three criteria (the other two being either EGFR amplification or combined whole chromosome 7 gain/chromosome 10 loss) to diagnosis "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV".	('IDH', 'Gene', (230, 233))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('IDH', 'Gene', '3417', (230, 233))	('astrocytic glioma', 'Disease', (211, 228))	('glioblastoma', 'Disease', (271, 283))	('astrocytic glioma', 'Disease', 'MESH:D001254', (211, 228))	('mutations', 'Var', (47, 56))	('EGFR', 'Gene', '1956', (114, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (271, 283))	('glioblastoma', 'Phenotype', 'HP:0012174', (271, 283))	('EGFR', 'Gene', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
73476	33228806	The bivalent impact of TERT promoter mutations on glioma biology depends on the IDH status, as such, we have previously proposed a molecular classification based on the IDH and TERT status, which can efficiently identify diffuse astrocytomas and oligodendrogliomas.	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('gliomas', 'Phenotype', 'HP:0009733', (257, 264))	('TERT', 'Gene', '7015', (177, 181))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('IDH', 'Gene', (80, 83))	('IDH', 'Gene', (169, 172))	('glioma', 'Disease', (50, 56))	('mutations', 'Var', (37, 46))	('IDH', 'Gene', '3417', (169, 172))	('IDH', 'Gene', '3417', (80, 83))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (229, 264))	('astrocytoma', 'Phenotype', 'HP:0009592', (229, 240))	('glioma', 'Disease', (257, 263))	('TERT', 'Gene', (177, 181))
73481	33228806	Out of the 951 cases analyzed in the previous study, 286 cases with IDH mutations from 13 institutions were enrolled in this study, and their clinical data were updated.	('IDH', 'Gene', (68, 71))	('mutations', 'Var', (72, 81))	('IDH', 'Gene', '3417', (68, 71))
73489	33228806	Briefly, the mutational status of IDH1/2 and TERT promoter was tested by Sanger sequencing and/or pyrosequencing.	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('TERT', 'Gene', (45, 49))	('IDH1/2', 'Gene', (34, 40))	('TERT', 'Gene', '7015', (45, 49))	('mutational', 'Var', (13, 23))	('tested', 'Reg', (63, 69))
73496	33228806	A total of 560 diffuse glioma patients with confirmed IDH mutations were analyzed in the present study.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('mutations', 'Var', (58, 67))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('glioma', 'Disease', (23, 29))	('IDH', 'Gene', (54, 57))	('patients', 'Species', '9606', (30, 38))	('IDH', 'Gene', '3417', (54, 57))
73503	33228806	Infratentorial tumors with IDH mutation were extremely rare (n = 3) and harbored neither of TERT promoter mutation nor 1p/19q codeletion.	('1p', 'Chemical', '-', (119, 121))	('IDH', 'Gene', (27, 30))	('TERT', 'Gene', (92, 96))	('TERT', 'Gene', '7015', (92, 96))	('IDH', 'Gene', '3417', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutation', 'Var', (31, 39))	('Infratentorial tumors', 'Disease', 'MESH:D015192', (0, 21))	('19q', 'Chemical', '-', (122, 125))	('Infratentorial tumors', 'Disease', (0, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
73505	33228806	KPS score, WHO grade, TERT promoter status, 1p/19q status, adjuvant radiation therapy, and EOR were significantly associated with survival.	('TERT', 'Gene', (22, 26))	('1p', 'Chemical', '-', (44, 46))	('1p/19q status', 'Var', (44, 57))	('TERT', 'Gene', '7015', (22, 26))	('associated with', 'Reg', (114, 129))	('19q', 'Chemical', '-', (47, 50))	('KPS score', 'Gene', (0, 9))	('survival', 'MPA', (130, 138))
73524	33228806	On the other hand, neither 1p/19q codeletion nor TERT promoter mutation was associated with a favorable prognosis in subgroups with a lower KPS score (< 90) (Fig.	('lower', 'NegReg', (134, 139))	('1p/19q codeletion', 'Var', (27, 44))	('1p', 'Chemical', '-', (27, 29))	('19q', 'Chemical', '-', (30, 33))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))
73530	33228806	CDKN2A homozygous deletion was observed in all molecular groups; however, the majority of deletions were found in those with TERT-wildtype-1p/19q intact tumors (Table 1).	('19q', 'Chemical', '-', (142, 145))	('1p', 'Chemical', '-', (139, 141))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('TERT', 'Gene', (125, 129))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('CDKN2A', 'Gene', (0, 6))	('deletions', 'Var', (90, 99))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('TERT', 'Gene', '7015', (125, 129))	('CDKN2A', 'Gene', '1029', (0, 6))
73534	33228806	When confined to the cases for which CDKN2A status was available, an unfavorable prognosis for WHO grade IV cases was retained even after excluding cases with CDKN2A homozygous deletion (Additional file 2: Fig.	('CDKN2A', 'Gene', '1029', (159, 165))	('CDKN2A', 'Gene', (37, 43))	('homozygous', 'Var', (166, 176))	('CDKN2A', 'Gene', '1029', (37, 43))	('CDKN2A', 'Gene', (159, 165))
73536	33228806	We confirmed that majority of the TERT promoter mutations coincided with 1p/19q codeletion in IDH-mutated gliomas.	('19q', 'Chemical', '-', (76, 79))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('IDH', 'Gene', (94, 97))	('TERT', 'Gene', (34, 38))	('IDH', 'Gene', '3417', (94, 97))	('1p', 'Chemical', '-', (73, 75))	('TERT', 'Gene', '7015', (34, 38))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('mutations', 'Var', (48, 57))
73537	33228806	However, there were notable exceptions, that is, 24 IDH-mutated tumors had TERT promoter mutations but not 1p/19q codeletion, whereas six tumors had 1p/19q codeletion without TERT promoter mutations.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('1p', 'Chemical', '-', (107, 109))	('IDH', 'Gene', '3417', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('19q', 'Chemical', '-', (152, 155))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('19q', 'Chemical', '-', (110, 113))	('TERT', 'Gene', (175, 179))	('IDH', 'Gene', (52, 55))	('TERT', 'Gene', '7015', (175, 179))	('tumors', 'Disease', (138, 144))	('1p', 'Chemical', '-', (149, 151))
73538	33228806	Multivariable analysis incorporating clinical background revealed that the prognostic impact of TERT promoter mutations was independent from that of 1p/19q codeletion (Table 2).	('19q', 'Chemical', '-', (152, 155))	('mutations', 'Var', (110, 119))	('TERT', 'Gene', (96, 100))	('1p', 'Chemical', '-', (149, 151))	('TERT', 'Gene', '7015', (96, 100))
73540	33228806	A favorable prognostic impact of TERT promoter mutation in lower grade gliomas with an IDH mutation has been reported in several studies.	('TERT', 'Gene', (33, 37))	('mutation', 'Var', (91, 99))	('TERT', 'Gene', '7015', (33, 37))	('gliomas', 'Disease', (71, 78))	('IDH', 'Gene', (87, 90))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('IDH', 'Gene', '3417', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))
73546	33228806	Another study involving over 300 IDH-mutated glioma cases also reported that survival of patients with IDH-TERT co-mutated tumors and grade II-III histology did not differ according to 1p/19q status.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('1p/19q', 'Var', (185, 191))	('IDH', 'Gene', (103, 106))	('1p', 'Chemical', '-', (185, 187))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('IDH', 'Gene', '3417', (33, 36))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH', 'Gene', '3417', (103, 106))	('19q', 'Chemical', '-', (188, 191))	('patients', 'Species', '9606', (89, 97))	('IDH', 'Gene', (33, 36))	('TERT', 'Gene', (107, 111))	('TERT', 'Gene', '7015', (107, 111))	('glioma', 'Disease', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
73548	33228806	Significantly longer overall survival was seen in the TERT-mutated, 1p/19q intact, and IDH-mutated cases than in the TERT-wildtype, 1p/19q intact, and IDH-mutated cases, among patients with a high KPS score (90-100) in our study.	('patients', 'Species', '9606', (176, 184))	('TERT', 'Gene', (54, 58))	('IDH', 'Gene', '3417', (151, 154))	('TERT', 'Gene', '7015', (54, 58))	('19q', 'Chemical', '-', (135, 138))	('IDH', 'Gene', (87, 90))	('19q', 'Chemical', '-', (71, 74))	('1p', 'Chemical', '-', (68, 70))	('1p', 'Chemical', '-', (132, 134))	('IDH', 'Gene', '3417', (87, 90))	('TERT', 'Gene', (117, 121))	('1p/19q intact', 'Var', (68, 81))	('TERT', 'Gene', '7015', (117, 121))	('longer', 'PosReg', (14, 20))	('overall survival', 'MPA', (21, 37))	('IDH', 'Gene', (151, 154))
73550	33228806	Although the TERT-mutated, 1p/19q intact, and IDH-mutated cases showed comparable survival with that of the triple-positive cases, the histology of the former varied.	('1p', 'Chemical', '-', (27, 29))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('IDH', 'Gene', (46, 49))	('19q', 'Chemical', '-', (30, 33))	('IDH', 'Gene', '3417', (46, 49))	('1p/19q intact', 'Var', (27, 40))
73555	33228806	The present study and other studies have reported that 1p/19q codeletion without accompanying TERT promoter mutations does not have prognostic benefit.	('1p/19q codeletion', 'Var', (55, 72))	('1p', 'Chemical', '-', (55, 57))	('19q', 'Chemical', '-', (58, 61))	('TERT', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (94, 98))
73557	33228806	The combination of TERT promoter mutations and IDH mutations is a highly specific biomarker.	('TERT', 'Gene', (19, 23))	('IDH', 'Gene', '3417', (47, 50))	('mutations', 'Var', (51, 60))	('TERT', 'Gene', '7015', (19, 23))	('mutations', 'Var', (33, 42))	('IDH', 'Gene', (47, 50))
73560	33228806	Our results showed that the survival of patients with IDH-mutated 1p/19q codeleted gliomas did not differ between WHO grade II and III cases (Additional file 2: Fig.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('1p', 'Chemical', '-', (66, 68))	('1p/19q', 'Var', (66, 72))	('patients', 'Species', '9606', (40, 48))	('IDH', 'Gene', (54, 57))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH', 'Gene', '3417', (54, 57))	('19q', 'Chemical', '-', (69, 72))
73565	33228806	Attempts to molecularly define the aggressive type of diffuse astrocytomas have suggested several genetic markers such as RB1 pathway alterations (e.g., CDKN2A/B homozygous deletion or CDK4 amplification), PIK3R1 mutation, PDGFRA amplification, or G-CIMP low type in the methylation cluster.	('RB1', 'Gene', '5925', (122, 125))	('G-CIMP', 'Chemical', '-', (248, 254))	('CDKN2A/B', 'Gene', (153, 161))	('PIK3R1', 'Gene', '5295', (206, 212))	('CDK4', 'Gene', (185, 189))	('astrocytomas', 'Disease', (62, 74))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('CDKN2A/B', 'Gene', '1029;1030', (153, 161))	('amplification', 'Var', (230, 243))	('RB1', 'Gene', (122, 125))	('CDK4', 'Gene', '1019', (185, 189))	('PDGFRA', 'Gene', (223, 229))	('G-CIMP low type', 'Var', (248, 263))	('PDGFRA', 'Gene', '5156', (223, 229))	('PIK3R1', 'Gene', (206, 212))	('methylation', 'Var', (271, 282))	('mutation', 'Var', (213, 221))	('astrocytomas', 'Disease', 'MESH:D001254', (62, 74))	('alterations', 'Reg', (134, 145))
73575	33228806	TERT promoter mutations may not serve as diagnostic markers on their own as there are other types of IDH-wildtype glial neoplasms that may harbor TERT promoter mutations, including pleomorphic xanthoastrocytoma, ganglioglioma, anaplastic glioma with piloid features, and ependymoma.	('anaplastic glioma', 'Disease', (227, 244))	('mutations', 'Var', (160, 169))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (181, 210))	('IDH-wildtype glial neoplasms', 'Disease', (101, 129))	('ependymoma', 'Disease', 'MESH:D004806', (271, 281))	('IDH-wildtype glial neoplasms', 'Disease', 'MESH:D004194', (101, 129))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('ganglioglioma', 'Disease', 'MESH:D018303', (212, 225))	('TERT', 'Gene', (146, 150))	('TERT', 'Gene', '7015', (146, 150))	('pleomorphic xanthoastrocytoma', 'Disease', (181, 210))	('astrocytoma', 'Phenotype', 'HP:0009592', (199, 210))	('neoplasms', 'Phenotype', 'HP:0002664', (120, 129))	('ependymoma', 'Disease', (271, 281))	('ganglioglioma', 'Disease', (212, 225))	('TERT', 'Gene', (0, 4))	('anaplastic glioma', 'Disease', 'MESH:D005910', (227, 244))	('TERT', 'Gene', '7015', (0, 4))	('ependymoma', 'Phenotype', 'HP:0002888', (271, 281))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))
73579	33228806	Given the current trend of using molecular and biological markers for diagnosis, it is worthwhile to consider TERT promoter mutation as a diagnostic as well as prognostic marker.	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('mutation', 'Var', (124, 132))
73606	32429325	Class II is commonly subdivided into two sub-classes (Table 1) based on sequence analysis: IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10).	('HDAC10', 'Gene', '83933', (147, 153))	('HDAC5', 'Gene', '10014', (103, 108))	('IIb', 'Gene', (132, 135))	('HDAC5', 'Gene', (103, 108))	('HDAC7', 'Gene', '51564', (110, 115))	('HDAC6', 'Gene', '10013', (137, 142))	('HDAC6', 'Gene', (137, 142))	('IIb', 'Gene', '5658173', (132, 135))	('HDAC7', 'Gene', (110, 115))	('HDAC4', 'Var', (96, 101))	('HDAC10', 'Gene', (147, 153))	('HDAC9', 'Gene', '9734', (121, 126))	('HDAC9', 'Gene', (121, 126))
73624	32429325	Drosophila melanogaster (fruit fly) carries a total of 5 HDAC genes, translated in the following protein products: NP_001259507.1 located in Class IIa, NP_001259569.1 in Class IIb, NP_733048.1 in Class IV and two Class I HDACs: NP_647918.2 and NP_651978.2.	('NP_651978.2', 'Var', (244, 255))	('IIb', 'Gene', (176, 179))	('NP_733048.1', 'Var', (181, 192))	('IIb', 'Gene', '5658173', (176, 179))	('Drosophila melanogaster', 'Species', '7227', (0, 23))	('fruit fly', 'Species', '7227', (25, 34))	('HDAC genes', 'Gene', (57, 67))	('NP_001259569.1', 'Var', (152, 166))	('NP_001259507.1', 'Var', (115, 129))
73629	32429325	Arabidopsis in particular carries the largest number of HDAC genes in all species investigated (14, Table 2); this is the result of recent HDAC expansion, as this plant carries a cluster of three recently duplicated Class I HDAC loci, which are located in succession on its genome: NP_190052.1 (encoded by gene At3g44660), NP_190054.2 (At3g44680), and NP_190035.1 (At3g44490).	('At3', 'Species', '1239833', (311, 314))	('Arabidopsis', 'Species', '3702', (0, 11))	('At3g44660', 'Var', (311, 320))	('At3', 'Species', '1239833', (336, 339))	('At3g44680', 'Var', (336, 345))	('At3g44490', 'Var', (365, 374))	('At3', 'Species', '1239833', (365, 368))
73630	32429325	Two more highly homologous Arabidopsis Class I HDAC loci, represented by protein NP_198410.1 (gene At5g35600) and NP_201116.1 (gene At5g63110) are separated instead by more than 10 million nucleotides on the plant chromosome 5.	('At5', 'Species', '1239833', (99, 102))	('Arabidopsis', 'Species', '3702', (27, 38))	('gene At5g35600', 'Var', (94, 108))	('At5', 'Species', '1239833', (132, 135))	('gene At5g63110', 'Var', (127, 141))
73632	32429325	Sequences NP_563817.1 (Arabidopsis) and XP_015638622.1 (rice), dubbed HDAC8 by the NCBI annotation and in our tree (Figure 1, between Class IV and Class IIb) are even more separated from the rest of the organisms, and appear as a completely unique class of plant-specific HDACs.	('NP_563817.1', 'Var', (10, 21))	('Arabidopsis', 'Species', '3702', (23, 34))	('HDAC8', 'Gene', (70, 75))	('IIb', 'Gene', (153, 156))	('IIb', 'Gene', '5658173', (153, 156))	('HDAC8', 'Gene', '55869', (70, 75))	('XP_015638622.1', 'Var', (40, 54))	('rice', 'Species', '4530', (56, 60))	('S', 'Chemical', 'MESH:D012694', (0, 1))
73634	32429325	Schizosaccharomyces pombe (fission yeast) HDACs appear very similar to S.cerevisiae, with clear orthologs of Rpd3 (NP_595333.1), Hos2 (NP_594079.1) and Hda1 (NP_595104.1).	('Hda1', 'Gene', (152, 156))	('fission yeast', 'Species', '4896', (27, 40))	('Hos2', 'Gene', (129, 133))	('NP_595333.1', 'Var', (115, 126))	('NP_594079.1', 'Var', (135, 146))	('Hda1', 'Gene', '855710', (152, 156))	('Schizosaccharomyces pombe', 'Species', '4896', (0, 25))	('Hos2', 'Gene', '852681', (129, 133))	('S.cerevisiae', 'Species', '4932', (71, 83))
73668	32429325	These methodologies were applied for the identification of HDAC8 candidate substrates using, respectively, the specific HDAC8 inhibitor PCI-34051 and a recombinant HDAC8 protein in which tyrosine 100 is replaced with a p-benzoyl-L-phenylalanine (Bpa).	('tyrosine', 'Chemical', 'MESH:D014443', (187, 195))	('HDAC8', 'Gene', '55869', (59, 64))	('HDAC8', 'Gene', '55869', (120, 125))	('Bpa', 'Chemical', 'MESH:C488060', (246, 249))	('HDAC8', 'Gene', '55869', (164, 169))	('HDAC8', 'Gene', (120, 125))	('tyrosine 100', 'Var', (187, 199))	('HDAC8', 'Gene', (164, 169))	('HDAC8', 'Gene', (59, 64))	('p-benzoyl-L-phenylalanine', 'Chemical', 'MESH:C488060', (219, 244))
73676	32429325	HDAC8 has been shown to deacetylate ERRalpha, which results in an enhancement of the transcription factor function, and SMC3, one of the components of the cohesin complex, the deacetylation of which facilitates renewal of cohesin following its removal from chromatin during prophase or anaphase.	('acetyl', 'Chemical', '-', (26, 32))	('HDAC8', 'Gene', '55869', (0, 5))	('ERRalpha', 'Gene', '2101', (36, 44))	('deacetylate', 'Var', (24, 35))	('transcription factor function', 'MPA', (85, 114))	('facilitates', 'PosReg', (199, 210))	('acetyl', 'Chemical', '-', (178, 184))	('SMC3', 'Gene', '9126', (120, 124))	('deacetylation', 'Var', (176, 189))	('renewal', 'MPA', (211, 218))	('SMC3', 'Gene', (120, 124))	('cohesin', 'Protein', (222, 229))	('HDAC8', 'Gene', (0, 5))	('ERRalpha', 'Gene', (36, 44))	('enhancement', 'PosReg', (66, 77))
73680	32429325	For example, HDAC1 decrotonylates H3K4cr, H3K9cr, H3K23cr, H4K8cr, and H4K12cr in vitro; H3K8cr can be also decrotonylated by HDAC2 and HDAC8.	('HDAC2', 'Gene', (126, 131))	('HDAC8', 'Gene', '55869', (136, 141))	('HDAC2', 'Gene', '3066', (126, 131))	('H3K23cr', 'Var', (50, 57))	('H3K9cr', 'Var', (42, 48))	('H4K8cr', 'Var', (59, 65))	('HDAC8', 'Gene', (136, 141))	('H3K8cr', 'Var', (89, 95))	('H4K12cr', 'Var', (71, 78))	('H3K4cr', 'Var', (34, 40))
73683	32429325	About the catalytic activity, for vertebrate Class IIa HDACs, the catalytic Tyrosine 345 residue is replaced by a histidine side chain, which is too short to reach into the active site (Figure 3A).	('histidine', 'Chemical', 'MESH:D006639', (114, 123))	('Tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('catalytic', 'MPA', (66, 75))	('Tyrosine 345', 'Var', (76, 88))
73684	32429325	Due to the Y-H substitution, the catalytic activity of those enzymes on acetylated lysines of histone tail peptides is very low when compared to that of Class I HDACs.	('lysines', 'Chemical', 'MESH:D008239', (83, 90))	('catalytic activity', 'MPA', (33, 51))	('peptides', 'Chemical', 'MESH:D010455', (107, 115))	('Y-H substitution', 'Var', (11, 27))	('low', 'NegReg', (124, 127))	('acetyl', 'Chemical', '-', (72, 78))
73685	32429325	This property is independent from the Y-H catalytic residue as replacement of H with a Y in Class IIa HDACs promotes deacetylation of acetylated histone tail peptides, but it does not impact on transcriptional repression.	('peptides', 'Chemical', 'MESH:D010455', (158, 166))	('acetyl', 'Chemical', '-', (134, 140))	('replacement', 'Var', (63, 74))	('acetyl', 'Chemical', '-', (119, 125))	('promotes', 'PosReg', (108, 116))	('deacetylation of acetylated histone tail peptides', 'MPA', (117, 166))
73714	32429325	Since simultaneous deletion of HDAC1 and 2 genes results in early embryonic lethality conditional mutants were produced to investigate their role during development.	('results in', 'Reg', (49, 59))	('deletion', 'Var', (19, 27))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('embryonic lethality', 'Disease', (66, 85))	('HDAC1', 'Gene', (31, 36))	('S', 'Chemical', 'MESH:D012694', (0, 1))
73720	32429325	In adult individuals, deletion of HDAC3 in hepatocytes causes an increase of adipogenesis leading to hepatosteatosis whereas its loss in the heart cause interstitial fibrosis.	('increase', 'PosReg', (65, 73))	('HDAC3', 'Gene', '8841', (34, 39))	('hepatosteatosis', 'Disease', 'None', (101, 116))	('leading to', 'Reg', (90, 100))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (153, 174))	('HDAC3', 'Gene', (34, 39))	('deletion', 'Var', (22, 30))	('loss', 'NegReg', (129, 133))	('fibrosis', 'Disease', (166, 174))	('hepatosteatosis', 'Disease', (101, 116))	('fibrosis', 'Disease', 'MESH:D005355', (166, 174))	('adipogenesis', 'MPA', (77, 89))
73730	32429325	Its deletions in mouse knockout models has been linked to cardiac defects, mainly depending on deregulation of one of its targets, transcription factor MEF2.	('cardiac defects', 'Disease', 'MESH:D006331', (58, 73))	('mouse', 'Species', '10090', (17, 22))	('deletions', 'Var', (4, 13))	('cardiac defects', 'Disease', (58, 73))	('deregulation', 'MPA', (95, 107))	('MEF2', 'Gene', (152, 156))	('linked', 'Reg', (48, 54))
73736	32429325	However, deletion of HDAC6 led to no evident defects in animal models, possibly due to redundancy of functions shared with HDAC10.	('deletion', 'Var', (9, 17))	('HDAC6', 'Gene', '10013', (21, 26))	('HDAC10', 'Gene', (123, 129))	('HDAC6', 'Gene', (21, 26))	('HDAC10', 'Gene', '83933', (123, 129))
73740	32429325	It is thought to have a role in immune cells development, and it has been recently shown that HDAC10 deletion improves Foxp3+ Treg cells suppressive function in vivo.	('deletion', 'Var', (101, 109))	('Foxp3', 'Gene', (119, 124))	('HDAC10', 'Gene', '83933', (94, 100))	('improves', 'PosReg', (110, 118))	('Foxp3', 'Gene', '50943', (119, 124))	('HDAC10', 'Gene', (94, 100))
73752	32429325	The interaction of SIN3A/HDAC1 complex with cell cycle regulators such as Rb and the Mxd1 family suggests that loss of SIN3A would cause an uncontrollably cell cycle progression.	('interaction', 'Interaction', (4, 15))	('SIN3A', 'Gene', (119, 124))	('loss', 'Var', (111, 115))	('Mxd1', 'Gene', (85, 89))	('cause', 'Reg', (131, 136))	('uncontrollably', 'MPA', (140, 154))	('Mxd1', 'Gene', '4084', (85, 89))
73789	32429325	After that, LSD1 demethylates H3-K4Me1-2 causing the reversibly transcriptional repression of the gene locus.	('H3-K4Me1-2', 'Var', (30, 40))	('demethylates H3-K4Me1-2', 'Var', (17, 40))	('LSD1', 'Gene', (12, 16))	('LSD1', 'Gene', '23028', (12, 16))	('reversibly transcriptional repression', 'MPA', (53, 90))
73790	32429325	Finally, the recruitment of histone methyltransferase such as G9a or SUV39H1 and methylation of "repressive" sites like H3-K9 induces a stable long-term silencing of targets through the binding to K9-methyl residues of the heterochromatin protein 1 (HP1) that generate the heterochromatinization of the locus.	('SUV39H1', 'Gene', (69, 76))	('methylation', 'Var', (81, 92))	('H3-K9', 'Gene', (120, 125))	('SUV39H1', 'Gene', '6839', (69, 76))	('silencing', 'NegReg', (153, 162))	('HP1', 'Gene', (250, 253))	('HP1', 'Gene', '23468', (250, 253))	('G9a', 'Gene', '10919', (62, 65))	('heterochromatin protein 1', 'Gene', '23468', (223, 248))	('G9a', 'Gene', (62, 65))	('binding', 'Interaction', (186, 193))	('heterochromatin protein 1', 'Gene', (223, 248))
73797	32429325	An aberrant protein levels of ZNF217 has been reported in many cancer cell lines and may cause unregulated targeting by the CoREST-LSD1 complex, with a profound effect on cancer progression.	('unregulated targeting', 'MPA', (95, 116))	('cause', 'Reg', (89, 94))	('protein levels', 'MPA', (12, 26))	('aberrant', 'Var', (3, 11))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('LSD1', 'Gene', '23028', (131, 135))	('CoREST', 'Gene', '23186', (124, 130))	('cancer', 'Disease', (171, 177))	('LSD1', 'Gene', (131, 135))	('CoREST', 'Gene', (124, 130))	('reported', 'Reg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ZNF217', 'Gene', (30, 36))	('ZNF217', 'Gene', '7764', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (63, 69))	('effect', 'Reg', (161, 167))
73806	32429325	In particular, it has been demonstrated that NuRD complex binds methylated DNA in correspondence to the pericentric heterochromatin containing MBD2 proteins.	('methylated', 'Var', (64, 74))	('MBD2', 'Gene', (143, 147))	('rice', 'Species', '4530', (106, 110))	('MBD2', 'Gene', '8932', (143, 147))
73809	32429325	PWWP2A was correlated to H3K36me3 marked genes and PWWP2B to active promoters and enhancers.	('H3K36me3 marked', 'Var', (25, 40))	('PWWP2A', 'Gene', '70802', (0, 6))	('PWWP2B', 'Gene', (51, 57))	('PWWP2B', 'Gene', '101631', (51, 57))	('PWWP2A', 'Gene', (0, 6))
73811	32429325	Specifically, MBD2 and MBD3 mediates NuRD recruitment to methylated or hemi-methylated DNA, respectively.	('MBD3', 'Gene', (23, 27))	('mediates', 'Reg', (28, 36))	('MBD3', 'Gene', '53615', (23, 27))	('MBD2', 'Gene', '8932', (14, 18))	('hemi-methylated', 'Var', (71, 86))	('MBD2', 'Gene', (14, 18))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('methylated', 'Var', (57, 67))
73813	32429325	Furthermore, WDR529 and UpSET30 recruits the complex to promoter regions.	('S', 'Chemical', 'MESH:D012694', (26, 27))	('UpSET30', 'Var', (24, 31))	('complex', 'MPA', (45, 52))	('WDR529', 'Var', (13, 19))
73815	32429325	For instance, in mESCs, it has been reported that after H3K36me3 deposition by SET2 on specific promoters of active genes, NuRD/HDAC complex are recruited to the action of PWWP2A/B and the deacetylation of H3K9ac by HDAC2 facilitates RNA Pol II transcriptional elongation.	('recruited', 'PosReg', (145, 154))	('facilitates', 'PosReg', (222, 233))	('SET2', 'Gene', (79, 83))	('deacetylation', 'Var', (189, 202))	('PWWP2A', 'Gene', '70802', (172, 178))	('HDAC2', 'Gene', (216, 221))	('HDAC2', 'Gene', '3066', (216, 221))	('S', 'Chemical', 'MESH:D012694', (79, 80))	('S', 'Chemical', 'MESH:D012694', (19, 20))	('H3K36me3', 'Var', (56, 64))	('RNA Pol II transcriptional', 'Enzyme', (234, 260))	('SET2', 'Gene', '29072', (79, 83))	('PWWP2A', 'Gene', (172, 178))	('acetyl', 'Chemical', '-', (191, 197))
73823	32429325	Specifically, the knockdown of CHD4, an ATPase subunit of NuRD complex (Figure 5), dramatically upregulates C4B expression, a critical component of the complement system, and this can trigger proliferation and tumor progression.	('C4B', 'Gene', '721', (108, 111))	('knockdown', 'Var', (18, 27))	('CHD4', 'Gene', (31, 35))	('trigger', 'Reg', (184, 191))	('expression', 'MPA', (112, 122))	('proliferation', 'CPA', (192, 205))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('CHD4', 'Gene', '1108', (31, 35))	('upregulates', 'PosReg', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('C4B', 'Gene', (108, 111))
73853	32429325	Although, the production of the aberrant PML-RARalpha protein causes an increase in the binding affinity between RARalpha and NCoR/SMRT complex.	('SMRT', 'Gene', (131, 135))	('PML-RAR', 'Gene', (41, 48))	('increase', 'PosReg', (72, 80))	('RARalpha', 'Gene', '5914', (45, 53))	('NCoR', 'Gene', (126, 130))	('binding affinity', 'Interaction', (88, 104))	('RARalpha', 'Gene', (45, 53))	('PML-RAR', 'Gene', '84106', (41, 48))	('RARalpha', 'Gene', '5914', (113, 121))	('aberrant', 'Var', (32, 40))	('SMRT', 'Gene', '9612', (131, 135))	('RARalpha', 'Gene', (113, 121))	('NCoR', 'Gene', '9611', (126, 130))
73866	32429325	In mice, deletion of HDAC4 in the forebrain resulted in the impairment of memory, behavioral learning, and long-term synaptic plasticity.	('impairment of memory', 'Disease', 'MESH:D008569', (60, 80))	('impairment of memory', 'Disease', (60, 80))	('long-term synaptic plasticity', 'CPA', (107, 136))	('deletion', 'Var', (9, 17))	('mice', 'Species', '10090', (3, 7))	('HDAC4', 'Gene', (21, 26))	('impairment of memory', 'Phenotype', 'HP:0002354', (60, 80))	('behavioral learning', 'CPA', (82, 101))
73867	32429325	In human, the HDAC4 locus is deleted or mutated in patients with brachydactyly mental retardation (BDMR) syndrome, which is characterized by intellectual disabilities, developmental delays, behavioral abnormalities, and skeletal abnormalities.	('developmental delays', 'Disease', 'MESH:D002658', (168, 188))	('behavioral abnormalities', 'Disease', 'MESH:D001523', (190, 214))	('behavioral abnormalities', 'Phenotype', 'HP:0000708', (190, 214))	('human', 'Species', '9606', (3, 8))	('skeletal abnormalities', 'Disease', (220, 242))	('developmental delays', 'Disease', (168, 188))	('developmental delays', 'Phenotype', 'HP:0001263', (168, 188))	('brachydactyly', 'Phenotype', 'HP:0001156', (65, 78))	('behavioral abnormalities', 'Disease', (190, 214))	('brachydactyly mental retardation (BDMR) syndrome', 'Disease', 'MESH:C538317', (65, 113))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (141, 166))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (220, 242))	('mutated', 'Var', (40, 47))	('patients', 'Species', '9606', (51, 59))	('mental retardation', 'Phenotype', 'HP:0001249', (79, 97))	('HDAC4', 'Gene', (14, 19))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (220, 242))
73883	32429325	HDAC11 was shown to de-acetylate Lys24 and Lys49 at the N-terminus of the chromatin licensing and DNA replication factor 1 (Cdt1) and affect its proteasomal degradation.	('de-acetylate', 'NegReg', (20, 32))	('Lys49', 'Chemical', '-', (43, 48))	('Cdt1', 'Gene', '81620', (124, 128))	('acetyl', 'Chemical', '-', (23, 29))	('Cdt1', 'Gene', (124, 128))	('proteasomal degradation', 'MPA', (145, 168))	('affect', 'Reg', (134, 140))	('Lys24', 'Var', (33, 38))	('Lys49', 'Var', (43, 48))	('HDAC11', 'Gene', (0, 6))	('Lys24', 'Chemical', '-', (33, 38))
73887	32429325	However, deregulation of HDACs has been reported a role in the development and progression of several cancer types.	('role', 'Reg', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('deregulation', 'Var', (9, 21))	('HDACs', 'Protein', (25, 30))
73894	32429325	Silencing or inhibition of HDAC1 was proven to be effective in reducing acquired chemoresistance and aggressiveness in cellular models of ovarian and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('reducing', 'NegReg', (63, 71))	('inhibition', 'Var', (13, 23))	('ovarian and lung cancers', 'Disease', 'MESH:D055370', (138, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (150, 162))	('HDAC1', 'Gene', (27, 32))	('acquired chemoresistance', 'CPA', (72, 96))	('aggressiveness', 'Disease', 'MESH:D001523', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('Silencing', 'Var', (0, 9))	('aggressiveness', 'Disease', (101, 115))	('S', 'Chemical', 'MESH:D012694', (0, 1))
73915	32429325	Overexpression of HDAC8 and 3 was associated with an improved survival in stage IV metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('HDAC8', 'Gene', '55869', (18, 23))	('Overexpression', 'Var', (0, 14))	('improved', 'PosReg', (53, 61))	('HDAC8', 'Gene', (18, 23))
73931	32429325	Survival analysis reported several significant associations in different tumor subtypes: high transcript levels are associated with a reduced OS in CESC, GBM, LGG, and KIRP, while it is a good prognostic factor in BLCA, DLBC, KICH, NBL, and THYM (Figure 6B).	('KICH', 'Disease', (226, 230))	('DLBC', 'Disease', (220, 224))	('KIRP', 'Disease', (168, 172))	('CESC', 'Disease', (148, 152))	('NBL', 'Gene', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('NBL', 'Gene', '9253', (232, 235))	('BLCA', 'Disease', (214, 218))	('LGG', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('KICH', 'Disease', 'None', (226, 230))	('high', 'Var', (89, 93))	('tumor', 'Disease', (73, 78))	('GBM', 'Disease', (154, 157))	('reduced', 'NegReg', (134, 141))	('S', 'Chemical', 'MESH:D012694', (150, 151))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('S', 'Chemical', 'MESH:D012694', (143, 144))
73934	32429325	Overexpression of HDAC7 is frequently reported in several hematologic malignancies like ALL and CLL, often correlated with poor outcomes.	('CLL', 'Phenotype', 'HP:0005550', (96, 99))	('CLL', 'Disease', (96, 99))	('ALL', 'Phenotype', 'HP:0006721', (88, 91))	('reported', 'Reg', (38, 46))	('HDAC7', 'Gene', (18, 23))	('hematologic malignancies', 'Disease', 'MESH:D019337', (58, 82))	('Overexpression', 'Var', (0, 14))	('hematologic malignancies', 'Disease', (58, 82))	('ALL', 'Disease', (88, 91))	('HDAC7', 'Gene', '51564', (18, 23))
73937	32429325	Low expression is associated with a significantly poorer OS in ACC and CHOL.	('ACC', 'Disease', (63, 66))	('S', 'Chemical', 'MESH:D012694', (58, 59))	('CHOL', 'Disease', (71, 75))	('Low expression', 'Var', (0, 14))	('CHOL', 'Disease', 'None', (71, 75))	('poorer', 'NegReg', (50, 56))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))
73951	32429325	It has been found in cervical cancers as metastasis suppressor, and low expression is associated to a bad prognosis in lung and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('expression', 'MPA', (72, 82))	('low', 'Var', (68, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('gastric cancers', 'Disease', 'MESH:D013274', (128, 143))	('gastric cancers', 'Phenotype', 'HP:0012126', (128, 143))	('gastric cancers', 'Disease', (128, 143))	('lung', 'Disease', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
73952	32429325	In the TCGA cohort, low expression is associated with a bad OS in BLCA and PCPG, while better outcomes are expected in HDAC10 low-expressing KIRC and THCA patients (Figure 6B).	('PCPG', 'Disease', (75, 79))	('THCA', 'Chemical', '-', (150, 154))	('low expression', 'Var', (20, 34))	('HDAC10', 'Gene', '83933', (119, 125))	('HDAC10', 'Gene', (119, 125))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('patients', 'Species', '9606', (155, 163))	('BLCA', 'Disease', (66, 70))
73957	32429325	Low-expressing LUAD, NBL, and UVM patients experience worse OS (Figure 6B).	('Low-expressing', 'Var', (0, 14))	('LUAD', 'Disease', (15, 19))	('patients', 'Species', '9606', (34, 42))	('NBL', 'Gene', '9253', (21, 24))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('NBL', 'Gene', (21, 24))
73970	32429325	Cell cycle blocks is mainly caused by the mis-regulation of key genes such as CDKN1A and AKT and by the hyperacetylation/activation of the tumor suppressor p53.	('caused', 'Reg', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mis-regulation', 'Var', (42, 56))	('acetyl', 'Chemical', '-', (109, 115))	('CDKN1A', 'Gene', (78, 84))	('hyperacetylation/activation', 'PosReg', (104, 131))	('p53', 'Gene', (156, 159))	('AKT', 'Gene', '207', (89, 92))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Disease', (139, 144))	('CDKN1A', 'Gene', '1026', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AKT', 'Gene', (89, 92))	('Cell cycle blocks', 'CPA', (0, 17))
73972	32429325	Ideally, the chemical pan-inhibition of HDACs should trigger a global hyperacetylation and, consequentially, an hyperactivation of many genes across the genome.	('trigger', 'Reg', (53, 60))	('acetyl', 'Chemical', '-', (75, 81))	('global hyperacetylation', 'MPA', (63, 86))	('hyperactivation', 'PosReg', (112, 127))	('pan-inhibition', 'Var', (22, 36))
73976	32429325	In vitro and in vivo studies have revealed an important link between ARID1A mutation status and SAHA sensitivity in ovarian cancer.	('SAHA sensitivity in ovarian cancer', 'Disease', 'MESH:D003807', (96, 130))	('ARID1A', 'Gene', '8289', (69, 75))	('SAHA sensitivity in ovarian cancer', 'Disease', (96, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ARID1A', 'Gene', (69, 75))	('mutation', 'Var', (76, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
73981	32429325	The loss of Crebbp leads to reduced H3K27Ac and transcriptional downregulation of CDH1 which, in turn, promotes cell transformation.	('reduced', 'NegReg', (28, 35))	('downregulation', 'NegReg', (64, 78))	('Crebbp', 'Gene', (12, 18))	('CDH1', 'Gene', '999', (82, 86))	('cell transformation', 'CPA', (112, 131))	('promotes', 'PosReg', (103, 111))	('CDH1', 'Gene', (82, 86))	('H3K27Ac', 'Protein', (36, 43))	('loss', 'Var', (4, 8))
73982	32429325	Pracinostat treatment of DMS53 (human SCLC cells with CRISPR-generated CREBBP deletion) resulted in a widely increase in H3K27Ac, H3K18Ac, and increased CDH1 RNA and protein expression.	('Pracinostat', 'Chemical', 'MESH:C557525', (0, 11))	('CREBBP', 'Gene', (71, 77))	('increased', 'PosReg', (143, 152))	('S', 'Chemical', 'MESH:D012694', (27, 28))	('S', 'Chemical', 'MESH:D012694', (38, 39))	('DMS53', 'Chemical', '-', (25, 30))	('increase', 'PosReg', (109, 117))	('CREBBP', 'Gene', '1387', (71, 77))	('CDH1', 'Gene', (153, 157))	('S', 'Chemical', 'MESH:D012694', (57, 58))	('CDH1', 'Gene', '999', (153, 157))	('human', 'Species', '9606', (32, 37))	('DMS53', 'Var', (25, 30))	('H3K27Ac', 'Protein', (121, 128))	('H3K18Ac', 'Protein', (130, 137))
73986	32429325	Specifically, LBH589 treatment seems to induce a depletion of histone H2B ubiquitination via misregulation of the RNF20/RNF40/WAC E3 ligase complex axis.	('RNF40', 'Gene', (120, 125))	('ubiquitination', 'MPA', (74, 88))	('depletion', 'MPA', (49, 58))	('RNF40', 'Gene', '9810', (120, 125))	('RNF20', 'Gene', (114, 119))	('LBH589', 'Chemical', 'MESH:D000077767', (14, 20))	('histone H2B', 'Protein', (62, 73))	('misregulation', 'Var', (93, 106))	('LBH589', 'Var', (14, 20))	('RNF20', 'Gene', '56254', (114, 119))	('S', 'Chemical', 'MESH:D012694', (0, 1))
74008	32429325	Mocetinostat (MGCD0103), Entinostat (MS275), Chidamide (HBI-8000), K560, and K560(1a) are the best characterized HDACi benzamide compounds able to interfere in tumor cell growth of many types of tumor.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('K560', 'Chemical', '-', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('benzamide', 'Chemical', 'MESH:C037689', (119, 128))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('K560', 'Chemical', '-', (77, 81))	('Entinostat', 'Chemical', 'MESH:C118739', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Chidamide', 'Chemical', 'MESH:C547816', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('HBI-8000', 'Chemical', 'MESH:C000613826', (56, 64))	('K560', 'Var', (77, 81))	('tumor', 'Disease', (160, 165))	('MGCD0103', 'Chemical', 'MESH:C523184', (14, 22))	('interfere', 'NegReg', (147, 156))	('MS275', 'Chemical', 'MESH:C118739', (37, 42))
74015	32429325	Interestingly, Entinostat stimulate MHCII pathway only in the immunocompetent C57BL/6 mouse model, suggesting a strong coordination between the epigenetic modulation exerted by MS275 treatment and the consequent stimulation of adaptive immunity.	('Entinostat', 'Chemical', 'MESH:C118739', (15, 25))	('MHCII', 'Gene', '111364', (36, 41))	('adaptive immunity', 'CPA', (227, 244))	('stimulation', 'PosReg', (212, 223))	('mouse', 'Species', '10090', (86, 91))	('MS275', 'Var', (177, 182))	('epigenetic modulation', 'MPA', (144, 165))	('MHCII', 'Gene', (36, 41))	('MS275', 'Chemical', 'MESH:C118739', (177, 182))
74018	32429325	Specifically, cytofluorimetric and biochemical assays have revealed that MS275 and 5-fluorouracil co-treatment exert a synergistic effect triggering apoptosis via deregulation of key cell cycle related genes such as p53, CDKN1A, and cyclin A.	('CDKN1A', 'Gene', (221, 227))	('apoptosis', 'CPA', (149, 158))	('MS275', 'Var', (73, 78))	('CDKN1A', 'Gene', '1026', (221, 227))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('cyclin A', 'Gene', (233, 241))	('deregulation', 'PosReg', (163, 175))	('S', 'Chemical', 'MESH:D012694', (74, 75))	('p53', 'Gene', '7157', (216, 219))	('triggering', 'Reg', (138, 148))	('MS275', 'Chemical', 'MESH:C118739', (73, 78))	('cyclin A', 'Gene', '890', (233, 241))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (83, 97))	('p53', 'Gene', (216, 219))
74022	32429325	In two recent studies, two putative HDAC1,2 benzamide specific inhibitors, K560 and K560(1a), were developed and tested for their neuroprotective abilities.	('neuroprotective abilities', 'CPA', (130, 155))	('K560', 'Chemical', '-', (84, 88))	('benzamide', 'Chemical', 'MESH:C037689', (44, 53))	('K560', 'Var', (84, 88))	('K560', 'Chemical', '-', (75, 79))	('K560', 'Var', (75, 79))
74023	32429325	Authors have shown how K560 benzamide drugs can exert neuroprotective abilities in MPP+ induced toxicity on in vitro SH-SY5Y retinoic acid differentiated cells.	('neuroprotective abilities', 'CPA', (54, 79))	('toxicity', 'Disease', 'MESH:D064420', (96, 104))	('K560', 'Chemical', '-', (23, 27))	('toxicity', 'Disease', (96, 104))	('benzamide', 'Chemical', 'MESH:C037689', (28, 37))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (117, 124))	('K560', 'Var', (23, 27))	('retinoic acid', 'Chemical', 'MESH:D014212', (125, 138))	('MPP+', 'Chemical', 'MESH:C044202', (83, 87))
74024	32429325	Specifically, K560 treatment stimulates HDAC1,2 protein expression and abrogates the cell death effect of MPP+ by modulating key apoptosis-related factors such as claspin, XIAP, and livin, and observed an increased p53 activation through phosphorylation.	('claspin', 'Gene', (163, 170))	('K560', 'Var', (14, 18))	('cell death effect', 'CPA', (85, 102))	('livin', 'Gene', (182, 187))	('XIAP', 'Gene', (172, 176))	('XIAP', 'Gene', '331', (172, 176))	('abrogates', 'NegReg', (71, 80))	('MPP+', 'Chemical', 'MESH:C044202', (106, 110))	('p53', 'Gene', (215, 218))	('livin', 'Gene', '79444', (182, 187))	('p53', 'Gene', '7157', (215, 218))	('activation', 'PosReg', (219, 229))	('modulating', 'Reg', (114, 124))	('K560', 'Chemical', '-', (14, 18))	('phosphorylation', 'MPA', (238, 253))	('claspin', 'Gene', '63967', (163, 170))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('stimulates', 'PosReg', (29, 39))
74042	32429325	Among these, FR901375 chromopeptide A, FR901375, largazole, spiruchostatin A, HC-toxin, trapoxin, and azumamide are currently investigated for their anti-tumorigenic potential.	('FR901375', 'Chemical', 'MESH:C482963', (39, 47))	('azumamide', 'Chemical', '-', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('FR901375', 'Chemical', 'MESH:C482963', (13, 21))	('HC-toxin', 'Disease', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('largazole', 'Chemical', 'MESH:C527895', (49, 58))	('trapoxin', 'Chemical', 'MESH:C067070', (88, 96))	('HC-toxin', 'Disease', 'MESH:D065766', (78, 86))	('FR901375', 'Var', (39, 47))	('FR901375 chromopeptide A', 'Chemical', '-', (13, 37))	('FR901375', 'Var', (13, 21))	('tumor', 'Disease', (154, 159))
74052	32429325	For example, inhibition of HDACs could modulate their action in genomic instability, often observed in cancer in the form of amplifications/deletions, chromosomic rearrangements, and chromothripsis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genomic instability', 'MPA', (64, 83))	('inhibition', 'Var', (13, 23))	('chromothripsis', 'Disease', (183, 197))	('modulate', 'Reg', (39, 47))	('chromothripsis', 'Disease', 'MESH:D000072837', (183, 197))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HDACs', 'Protein', (27, 32))
74206	28390530	Several PET radiotracers that bind tau with high affinity are available including 11C -PBB3, 18F -T807(AV-1451), 18F -1808, 18F -THK-5105, and 18F -THK-5117.	('18F -T807', 'Var', (93, 102))	('18F', 'Chemical', 'MESH:C000615276', (93, 96))	('18F', 'Chemical', 'MESH:C000615276', (124, 127))	('18F -THK-5105', 'Var', (124, 137))	('18F', 'Chemical', 'MESH:C000615276', (113, 116))	('18F', 'Chemical', 'MESH:C000615276', (143, 146))	('18F -THK-5117', 'Var', (143, 156))	('11C', 'Chemical', 'MESH:C000615233', (82, 85))
74208	28390530	Tau-PET is closely associated with clinical severity of dementia and has a high association with neurodegeneration seen at autopsy.	('associated', 'Reg', (19, 29))	('dementia', 'Disease', 'MESH:D003704', (56, 64))	('Tau-PET', 'Var', (0, 7))	('neurodegeneration', 'Disease', (97, 114))	('neurodegeneration', 'Disease', 'MESH:D019636', (97, 114))	('association', 'Interaction', (80, 91))	('dementia', 'Phenotype', 'HP:0000726', (56, 64))	('dementia', 'Disease', (56, 64))	('neurodegeneration', 'Phenotype', 'HP:0002180', (97, 114))
74214	28390530	18F-FDG PET predicts a decline from MCI to AD with sensitivity and specificity ranging from 75% to 100% and predicts early AD with high sensitivity (approximately 90%).	('AD', 'Disease', 'MESH:D000544', (43, 45))	('MCI', 'Phenotype', 'HP:0001256', (36, 39))	('AD', 'Phenotype', 'HP:0002511', (43, 45))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('AD', 'Disease', (43, 45))	('AD', 'Disease', 'MESH:D000544', (123, 125))	('AD', 'Disease', (123, 125))	('AD', 'Phenotype', 'HP:0002511', (123, 125))	('decline', 'NegReg', (23, 30))	('18F-FDG PET', 'Var', (0, 11))
74254	27001312	Functionally, B7-H4 transmits negative signals to T cells to effectively inhibit activation, proliferation and clonal expansion of CD4+ and CD8+ T cells.	('proliferation', 'CPA', (93, 106))	('CD8', 'Gene', (140, 143))	('B7-H4', 'Var', (14, 19))	('CD8', 'Gene', '925', (140, 143))	('activation', 'CPA', (81, 91))	('CD4', 'Gene', (131, 134))	('CD4', 'Gene', '12504', (131, 134))	('clonal expansion', 'CPA', (111, 127))	('inhibit', 'NegReg', (73, 80))
74256	27001312	We have recently determined the crystal structure of human B7x IgV functional domain and further developed a new cancer immunotherapy with mAbs targeting the B7x IgV.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('human', 'Species', '9606', (53, 58))	('B7x', 'Var', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
74272	27001312	To detect surface B7-H4, CD11b or CD133 expression, cells were incubated on ice for 30min with appropriate antibodies or isotype controls (PE-B7-H4, PE-mouse IgG1, APC-CD11b, APC-CD133, APC-mouse IgG1, all from eBioscience, 1:5), washed twice with FACS buffer (PBS containing 0.1% NaN3 and 5% fetal bovine serum), and resuspended in 0.5 ml 1% formalin/PBS.	('NaN3', 'Chemical', 'MESH:D019810', (281, 285))	('FACS', 'Gene', (248, 252))	('FACS', 'Gene', '14081', (248, 252))	('CD11b', 'Gene', (25, 30))	('formalin', 'Chemical', 'MESH:D005557', (343, 351))	('mouse', 'Species', '10090', (152, 157))	('PBS', 'Chemical', 'MESH:D007854', (261, 264))	('bovine', 'Species', '9913', (299, 305))	('mouse', 'Species', '10090', (190, 195))	('CD133', 'Gene', (34, 39))	('PE-B7-H4', 'Var', (139, 147))	('PBS', 'Chemical', 'MESH:D007854', (352, 355))
74294	27001312	Flow cytometry was used to assess glioma tissues, B7-H4+CD11b+ Mphis/microglia in LGG and HGG were 24.5% and 69.9% (Fig.	('B7-H4+CD11b+', 'Var', (50, 62))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('glioma tissue', 'Disease', 'MESH:D005910', (34, 47))	('glioma tissue', 'Disease', (34, 47))
74304	27001312	B7-H4+ GIMs (Iba1+ Mphis) were identified primarily at the glioma tumor boundary.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Iba1', 'Gene', '114737', (13, 17))	('Iba1', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('glioma tumor', 'Disease', (59, 71))	('B7-H4+ GIMs', 'Var', (0, 11))	('glioma tumor', 'Disease', 'MESH:D005910', (59, 71))
74312	27001312	Enhanced MRI images-guided brain tissue biopsies taken from these locations were sectioned to include both regions of interest and then employed IHC with anti-B7-H4, cell-specific, anti-Iba1, and anti-CD8 Abs for GIMs (Mphis/microglia) and CTLs, respectively.	('anti-B7-H4', 'Var', (154, 164))	('CD8', 'Gene', (201, 204))	('CD8', 'Gene', '925', (201, 204))	('Iba1', 'Gene', '114737', (186, 190))	('Iba1', 'Gene', (186, 190))
74313	27001312	The IHC analysis revealed higher amounts of B7-H4 on GIMs in the peritumoral regions (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('B7-H4', 'Var', (44, 49))	('amounts', 'MPA', (33, 40))	('higher', 'PosReg', (26, 32))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
74321	27001312	Finally, we used a cell migration assays to examine if CD133+ GBM cells could initiate recruitment of Mphis/monocytes into the tumor environment.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('recruitment', 'MPA', (87, 98))	('CD133+', 'Var', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
74327	27001312	To further determine whether the expression of B7-H4 was regulated by the Stat3 pathway, four pairs of STAT3 shRNAs were individually transduced into BV2 cells to knock down endogenous STAT3.	('knock down', 'Var', (163, 173))	('BV2', 'CellLine', 'CVCL:0182', (150, 153))	('Stat3', 'Gene', (74, 79))	('Stat3', 'Gene', '20848', (74, 79))
74329	27001312	Because STAT3 protein was remarkably decreased in the BV2 cells that were transduced with shRNA3, we chose to use shRNA3 for the subsequent experiments.	('BV2', 'CellLine', 'CVCL:0182', (54, 57))	('transduced', 'Var', (74, 84))	('STAT3 protein', 'Protein', (8, 21))	('decreased', 'NegReg', (37, 46))	('shRNA3', 'Gene', (90, 96))
74337	27001312	Correspondingly, the B7-H4 silencing also reduced T cells that did not produce IL-2 or IFN-gamma (Fig.	('reduced', 'NegReg', (42, 49))	('IFN-gamma', 'Gene', (87, 96))	('silencing', 'Var', (27, 36))	('IL-2', 'Gene', '16183', (79, 83))	('T cells', 'CPA', (50, 57))	('IL-2', 'Gene', (79, 83))	('B7-H4', 'Protein', (21, 26))	('IFN-gamma', 'Gene', '15978', (87, 96))
74338	27001312	Furthermore, B7-H4+ Mphis cultured in CD133+ supernatant inhibited CTL-cytotoxic activity against U87MG glioma cells.	('inhibited', 'NegReg', (57, 66))	('U87MG', 'CellLine', 'CVCL:0022', (98, 103))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('U87MG', 'Var', (98, 103))	('CTL-cytotoxic activity', 'CPA', (67, 89))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('B7-H4+ Mphis', 'Var', (13, 25))	('glioma', 'Disease', (104, 110))
74340	27001312	GL261 tumor cells derived from mouse glioma contained CD133+ cells and were able to inhibit both CD8+ and CD4+ T cell function in vitro (Supplementary Fig.	('CD4', 'Gene', (106, 109))	('CD133+', 'Var', (54, 60))	('CD8', 'Gene', '925', (97, 100))	('glioma', 'Disease', (37, 43))	('inhibit', 'NegReg', (84, 91))	('mouse', 'Species', '10090', (31, 36))	('CD4', 'Gene', '12504', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('CD8', 'Gene', (97, 100))	('GL261', 'Chemical', '-', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
74343	27001312	We observed tumor growth inhibition in mice injected together with CTL+ M and CTL+ GCM+ sh1-B7-H4 Mphis, while the other two groups showed rapid progression of nearly 200 mm3 per day (Fig.	('sh1', 'Gene', (88, 91))	('mice', 'Species', '10090', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('sh1', 'Gene', '100125848', (88, 91))	('tumor', 'Disease', (12, 17))	('CTL+ M', 'Var', (67, 73))
74344	27001312	To determine whether B7-H4 could serve as a predictor of prognosis, we infused CTLs with CD133+ Glioma initiating cells-conditioned sh1-mock or sh-B7-H4 Mphis via a caudal vein injection of mice with U87MG-derived intracranial tumor.	('U87MG', 'CellLine', 'CVCL:0022', (200, 205))	('intracranial tumor', 'Disease', 'MESH:D001932', (214, 232))	('sh1', 'Gene', '100125848', (132, 135))	('intracranial tumor', 'Disease', (214, 232))	('Glioma', 'Disease', 'MESH:D005910', (96, 102))	('Glioma', 'Phenotype', 'HP:0009733', (96, 102))	('sh-B7-H4', 'Var', (144, 152))	('mice', 'Species', '10090', (190, 194))	('Glioma', 'Disease', (96, 102))	('sh1', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
74355	27001312	Our studies characterizing the immunological roles of GIMs, tumor derived cytokines, and tissue-derived Glioma initiating cells have revealed evidence for an immunosuppressive role of B7-H4 in human malignant glioma.	('B7-H4', 'Var', (184, 189))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Glioma', 'Disease', 'MESH:D005910', (104, 110))	('Glioma', 'Phenotype', 'HP:0009733', (104, 110))	('Glioma', 'Disease', (104, 110))	('malignant glioma', 'Disease', 'MESH:D005910', (199, 215))	('tumor', 'Disease', (60, 65))	('malignant glioma', 'Disease', (199, 215))	('human', 'Species', '9606', (193, 198))	('immunosuppressive', 'MPA', (158, 175))
74364	27001312	B7-H4 in the tumor microenvironment, surrounding stroma and invasive edge, may contribute to the escape from immune surveillance during tumor cell invasion into adjacent brain tissue.	('tumor', 'Disease', (13, 18))	('B7-H4', 'Var', (0, 5))	('immune surveillance', 'MPA', (109, 128))	('contribute', 'Reg', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('stroma', 'Disease', (49, 55))	('escape', 'MPA', (97, 103))	('stroma', 'Disease', 'None', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (136, 141))
74369	27001312	Our studies showed Glioma initiating cells mediated expression of B7-H4 on Mphis.	('Glioma', 'Disease', (19, 25))	('Glioma', 'Phenotype', 'HP:0009733', (19, 25))	('Glioma', 'Disease', 'MESH:D005910', (19, 25))	('B7-H4', 'Var', (66, 71))
74382	27001312	The blood-brain barrier (BBB) normally allows the permeability of small molecules (400-500 Da) and some small lipid-soluble proteins, B7-H4 (50 kDa - 80 kDa) may be too large to pass across this natural barrier.	('400-500 Da', 'Var', (83, 93))	('permeability', 'MPA', (50, 62))	('lipid', 'Chemical', 'MESH:D008055', (110, 115))
74383	27001312	Considering CSF comes in direct contact with the extracellular compartment of the central nervous system and the existence of BBB, CSF sB7-H4 may be a better potential immunity-associated marker for supratentorial tumors like gliomas when compared to serum sB7-H4.	('supratentorial tumors', 'Disease', (199, 220))	('sB7-H4', 'Var', (135, 141))	('supratentorial tumors', 'Disease', 'MESH:D015173', (199, 220))	('supratentorial tumors', 'Phenotype', 'HP:0030693', (199, 220))	('sB7-H4', 'Chemical', '-', (257, 263))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('sB7-H4', 'Chemical', '-', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', (226, 233))
74390	27001312	Specifically the results identified that B7-H4+ glioma infiltrated macrophages (Mphis)/microglia showed immunosuppressive activity which could be auto-regulated by IL-6 production.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('B7-H4+', 'Var', (41, 47))	('immunosuppressive activity', 'CPA', (104, 130))	('glioma', 'Disease', (48, 54))
74398	30894197	In both the GBM and LGG cohort study, most of the patients in the high-risk group had the IDH1 wild-type gene, and those in the low-risk group had IDH1 mutations.	('IDH1', 'Gene', (90, 94))	('patients', 'Species', '9606', (50, 58))	('IDH1', 'Gene', '3417', (90, 94))	('mutations', 'Var', (152, 161))	('IDH1', 'Gene', (147, 151))	('IDH1', 'Gene', '3417', (147, 151))
74399	30894197	Moreover, most of the high-risk patients with LGG possessed a 1p/19q-noncodeletion.	('1p/19q-noncodeletion', 'Var', (62, 82))	('LGG', 'Disease', (46, 49))	('patients', 'Species', '9606', (32, 40))
74455	30894197	Therefore, it was seen that the 104 genes affected the survival durations of patients with GBM and LGG to a certain extent.	('survival durations', 'CPA', (55, 73))	('genes', 'Var', (36, 41))	('patients', 'Species', '9606', (77, 85))	('affected', 'Reg', (42, 50))	('LGG', 'Disease', (99, 102))
74484	30894197	Recent studies have demonstrated that gliomas could be divided into multiple subtypes based on various molecular features such as IDH1 mutation/wild type and chromosome 1p/19q noncodeletion/codeletion.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('chromosome 1p/19q noncodeletion/codeletion', 'Var', (158, 200))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH1', 'Gene', (130, 134))	('noncodeletion/codeletion', 'Var', (176, 200))	('IDH1', 'Gene', '3417', (130, 134))	('mutation/wild', 'Var', (135, 148))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
74485	30894197	Generally, IDH1 mutation and 1p/19q codeletion are favorable prognostic factors for patients with gliomas.	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('patients', 'Species', '9606', (84, 92))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('IDH1', 'Gene', (11, 15))
74487	30894197	In the low-risk group (n = 19) of GBM, as identified using the logistic regression model, 8 patients had the IDH1 mutant.	('IDH1', 'Gene', '3417', (109, 113))	('IDH1', 'Gene', (109, 113))	('patients', 'Species', '9606', (92, 100))	('mutant', 'Var', (114, 120))
74488	30894197	This result indicated that 80% of patients with IDH1 mutation would be clustered into the relative low-risk group of GBM against the risk prediction model.	('mutation', 'Var', (53, 61))	('IDH1', 'Gene', '3417', (48, 52))	('GBM', 'Disease', (117, 120))	('patients', 'Species', '9606', (34, 42))	('IDH1', 'Gene', (48, 52))
74489	30894197	Unlike GBM, IDH1 was mutated in most patients (n = 419) and fewer patients (n = 94) had the wild-type IDH1 in the LGG (n = 516) datasets from TCGA.	('IDH1', 'Gene', (12, 16))	('patients', 'Species', '9606', (37, 45))	('IDH1', 'Gene', (102, 106))	('IDH1', 'Gene', '3417', (12, 16))	('IDH1', 'Gene', '3417', (102, 106))	('mutated', 'Var', (21, 28))	('patients', 'Species', '9606', (66, 74))
74491	30894197	According to the relative high-risk group (n = 121) of LGG clustered by our constructed model, most of patients had wild-type IDH1 (n = 73) and 1p/19q-noncodeletion (n = 108), accounting for 60.3 and 89.3% of the cases, respectively (Table 7).	('IDH1', 'Gene', '3417', (126, 130))	('wild-type', 'Var', (116, 125))	('IDH1', 'Gene', (126, 130))	('1p/19q-noncodeletion', 'Var', (144, 164))	('patients', 'Species', '9606', (103, 111))
74493	30894197	For instance, 22.3% (n = 21) and 77.7% (n = 73) of patients with wild-type IDH1 in the LGG cohort (n = 94) were identified as low and high risk, respectively (Table 7); the survival curves of both risk groups could not be separated significantly, especially those representing less than 750 days of survival durations (Fig.	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', (75, 79))	('patients', 'Species', '9606', (51, 59))	('wild-type', 'Var', (65, 74))
74495	30894197	However, the risk model could classify patients with mutant-type IDH1 into different risk groups well in LGG cohort (n = 419).	('IDH1', 'Gene', '3417', (65, 69))	('IDH1', 'Gene', (65, 69))	('mutant-type', 'Var', (53, 64))	('patients', 'Species', '9606', (39, 47))
74497	30894197	The high-risk group of patients with IDH1 mutation might be associated with DNA methylation, which has indicated in the study based on the molecular profiling analysis.	('patients', 'Species', '9606', (23, 31))	('IDH1', 'Gene', (37, 41))	('DNA methylation', 'MPA', (76, 91))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('associated', 'Reg', (60, 70))
74498	30894197	The OS duration of patients decreased upon high gene expression but increased upon low gene expression.	('high gene expression', 'Var', (43, 63))	('decreased', 'NegReg', (28, 37))	('patients', 'Species', '9606', (19, 27))	('OS', 'Gene', '17451', (4, 6))	('increased', 'PosReg', (68, 77))	('low', 'NegReg', (83, 86))
74504	30894197	Moreover, the expression profiles of these potential biomarkers could be correlated to the molecular subtypes of patients, such as IDH1/2 mutation/wild type and chromosome 1p/19q codeletion/noncodeletion.	('IDH1/2', 'Gene', (131, 137))	('correlated', 'Reg', (73, 83))	('patients', 'Species', '9606', (113, 121))	('IDH1/2', 'Gene', '3417;3418', (131, 137))	('mutation/wild', 'Var', (138, 151))	('chromosome 1p/19q codeletion/noncodeletion', 'Var', (161, 203))
74518	30253793	BRAF duplication (a marker of KIAA1549-BRAF fusion) and BRAF V600E mutation were detected in 25% and 7.7%, respectively.	('duplication', 'Var', (5, 16))	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', '673', (56, 60))	('KIAA1549-BRAF fusion', 'Disease', (30, 50))	('BRAF', 'Gene', (39, 43))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (61, 66))	('BRAF', 'Gene', (0, 4))	('KIAA1549-BRAF fusion', 'Disease', 'MESH:D000069337', (30, 50))	('BRAF', 'Gene', (56, 60))
74519	30253793	No case had histone H3 K27M mutation.	('histone', 'Protein', (12, 19))	('K27M mutation', 'Var', (23, 36))	('K27M', 'Mutation', 'p.K27M', (23, 27))
74533	30253793	For immunohistochemistry, we used antibodies against GFAP (Ventana, 760-4345, prediluted), Olig2 (Cell Marque, 387 M-15, diluted 1:50), neurofilament (Ventana, 760-2661, prediluted), and Ki67 (Dako, M7240, diluted 1:100).	('Olig2', 'Gene', '10215', (91, 96))	('GFAP', 'Gene', (53, 57))	('GFAP', 'Gene', '2670', (53, 57))	('Ventana', 'Var', (151, 158))	('Olig2', 'Gene', (91, 96))
74535	30253793	BRAF V600E mutant protein was detected with a mouse monoclonal antibody (Ventana, 790-4855, prediluted).	('V600E', 'Mutation', 'rs113488022', (5, 10))	('mouse', 'Species', '10090', (46, 51))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
74583	30253793	BRAF duplication consistent with the presence of KIAA1549-BRAF fusion was present in 6/24 samples (25%), whereas BRAF V600E mutation was detected in 2/26 samples (7.7%).	('BRAF', 'Gene', '673', (113, 117))	('KIAA1549-BRAF fusion', 'Disease', 'MESH:D000069337', (49, 69))	('BRAF', 'Gene', (113, 117))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (118, 123))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (0, 4))	('KIAA1549-BRAF fusion', 'Disease', (49, 69))	('BRAF', 'Gene', (58, 62))
74584	30253793	All eight samples with BRAF alterations exhibited a PA-like growth pattern.	('PA-like growth pattern', 'CPA', (52, 74))	('BRAF', 'Gene', '673', (23, 27))	('alterations', 'Var', (28, 39))	('BRAF', 'Gene', (23, 27))	('exhibited', 'Reg', (40, 49))
74586	30253793	The prognostic value of BRAF alterations could not be meaningfully interpreted with the limited sample size.	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('alterations', 'Var', (29, 40))
74613	30253793	In our study, we for the first time interrogated the molecular distinctiveness of TG by performing targeted studies (of BRAF alterations and histone mutations) and genome-wide DNA methylation profiling.	('mutations', 'Var', (149, 158))	('BRAF', 'Gene', '673', (120, 124))	('alterations', 'Var', (125, 136))	('BRAF', 'Gene', (120, 124))	('TG', 'Chemical', '-', (82, 84))
74614	30253793	The frequency of KIAA1549-BRAF fusion (by the presence of BRAF locus duplication on iFISH) in TG (25%) appeared to be lower than that in PAs from the cerebellum (92%) and supratentorium (59%), whereas the frequency of BRAF V600E mutation (7.7%) appeared to be intermediate between the two (0% and 10% respectively).	('V600E', 'Var', (223, 228))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('BRAF', 'Gene', '673', (26, 30))	('TG', 'Chemical', '-', (94, 96))	('BRAF', 'Gene', (26, 30))	('KIAA1549-BRAF fusion', 'Disease', (17, 37))	('KIAA1549-BRAF fusion', 'Disease', 'MESH:D000069337', (17, 37))	('PAs', 'Chemical', 'MESH:D011478', (137, 140))	('BRAF', 'Gene', '673', (58, 62))	('lower', 'NegReg', (118, 123))	('V600E', 'Mutation', 'rs113488022', (223, 228))	('BRAF', 'Gene', (58, 62))
74615	30253793	Despite the extra-tectal extension of a proportion of tumors, the lack of histone H3 K27M mutations in all 24 samples supported the biological distinctiveness of TG from other midline diffuse gliomas of the brainstem, which are often characterized by such histone mutations and a more aggressive clinical course.	('midline diffuse gliomas', 'Disease', (176, 199))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('K27M', 'Mutation', 'p.K27M', (85, 89))	('TG', 'Chemical', '-', (162, 164))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('histone H3', 'Protein', (74, 84))	('midline diffuse gliomas', 'Disease', 'MESH:D005910', (176, 199))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('K27M', 'Var', (85, 89))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
74634	29306321	Similarly, as compared with biopsy(BX), the 5-year and 10-year OS were higher after either GTR (5-year: OR, 5.43; 95%CI, 3.57~8.26; P < 0.01; Z = Z = 7.9; 10-year: OR, 10.17; 95%CI, 4.02~25.71; P < 0.00001; Z = 4.9) or STR (5-year: OR, 2.59; 95%CI, 1.81~ - 3.71; P < 0.00001; Z = 5.19; 10-year: OR, 2.21; 95%CI, 1.164.25; P = 0.02; Z = 2.39).	('higher', 'PosReg', (71, 77))	('GTR', 'Chemical', '-', (91, 94))	('GTR', 'Var', (91, 94))	('OS', 'Chemical', '-', (63, 65))
74648	29306321	There are explicit first-level evidences indicating that a gross total resection (GTR) can significantly increase the overall survival (OS) and progression-free survival (PFS) of patients as compared with a subtotal resection (STR) or biopsy(BX).	('progression-free survival', 'CPA', (144, 169))	('overall survival', 'CPA', (118, 134))	('increase', 'PosReg', (105, 113))	('OS', 'Chemical', '-', (136, 138))	('patients', 'Species', '9606', (179, 187))	('GTR', 'Chemical', '-', (82, 85))	('gross', 'Var', (59, 64))
74666	29306321	The pooled results indicated that, as compared with biopsy, GTR could significantly increase the 5-year survival of patients with low-grade gliomas (OR, 5.43; 95%CI,3.57~8.26) and there was nearly no heterogeneity between studies (P = 0.23).	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('patients', 'Species', '9606', (116, 124))	('GTR', 'Var', (60, 63))	('increase', 'PosReg', (84, 92))	('GTR', 'Chemical', '-', (60, 63))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('5-year survival', 'CPA', (97, 112))	('gliomas', 'Disease', (140, 147))
74671	29306321	The combined results indicated that, as compared with biopsy, GTR considerably increased the 10-year survival (OR,10.17; 95%CI,4.02~25.71) and there was no heterogeneity between studies (P = 0.55) (Fig.	('GTR', 'Var', (62, 65))	('increased', 'PosReg', (79, 88))	('10-year survival', 'CPA', (93, 109))	('GTR', 'Chemical', '-', (62, 65))
74677	29306321	Surgical resection of low-grade gliomas may lead to dysfunction and impairment of patients' quality of life (QOL).	('lead to', 'Reg', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('patients', 'Species', '9606', (82, 90))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('dysfunction', 'MPA', (52, 63))	('low-grade', 'Var', (22, 31))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('impairment', 'NegReg', (68, 78))
74703	29306321	We believe that, as compared with STR and biopsy, GTR could significantly increase the 5-year and 10-year survival of patients with low-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('increase', 'PosReg', (74, 82))	('GTR', 'Var', (50, 53))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('GTR', 'Chemical', '-', (50, 53))	('patients', 'Species', '9606', (118, 126))
74730	27742110	Finally, with the recent discovery of the isocitrate dehydrogenase (IDH) mutation, the most common mutation in oligodendroglioma and astrocytoma tumors, elevated levels of 2-hydroxyglutarate (2-HG), which is produced from alpha-ketoglutarate by mutant IDH, serve as a clear metabolic indicator for the presence of the mutation within a tumor and can also be detected by 1H MRS when the mutation is present.	('IDH', 'Gene', '3417', (68, 71))	('astrocytoma tumors', 'Disease', 'MESH:D001254', (133, 151))	('tumor', 'Disease', (336, 341))	('astrocytoma tumors', 'Disease', (133, 151))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumor', 'Disease', (145, 150))	('IDH', 'Gene', (252, 255))	('oligodendroglioma', 'Disease', 'MESH:D009837', (111, 128))	('mutation', 'Var', (73, 81))	('elevated levels of 2-hydroxyglutarate', 'Phenotype', 'HP:0012402', (153, 190))	('isocitrate dehydrogenase', 'Gene', '3417', (42, 66))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('1H', 'Chemical', '-', (370, 372))	('oligodendroglioma', 'Disease', (111, 128))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('mutant', 'Var', (245, 251))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3417', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('MRS', 'Disease', 'MESH:D008556', (373, 376))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('levels', 'MPA', (162, 168))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (222, 241))	('MRS', 'Disease', (373, 376))	('isocitrate dehydrogenase', 'Gene', (42, 66))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (172, 190))
74733	27742110	Labeling of glucose-derived [3-13C] Lac, [4-13C] Glu, [4-13C] Gln and [1-13C] glycogen could all be detected.	('[4-13C] Gln', 'Chemical', '-', (54, 65))	('Glu', 'Chemical', 'MESH:D018698', (49, 52))	('[4-13C]', 'Chemical', '-', (54, 61))	('[4-13C]', 'Var', (41, 48))	('glucose', 'Chemical', 'MESH:D005947', (12, 19))	('[4-13C] Gln', 'Var', (54, 65))	('3-13C', 'Chemical', '-', (29, 34))	('[4-13C]', 'Chemical', '-', (41, 48))	('Lac', 'Chemical', 'MESH:D019344', (36, 39))	('[1-13C] glycogen', 'Chemical', '-', (70, 86))
74762	27742110	analyzed cerebrospinal fluid (CSF) from glioma patients using gas chromatography/mass spectrometry (GC/MS) in order to correlate metabolomic profiles with World Health Organization (WHO) tumor grades, tumor location, contrast in magnetic resonance (MR) images, and isocitrate dehydrogenase (IDH) mutations.	('IDH', 'Gene', '3417', (291, 294))	('spin', 'Gene', (16, 20))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('isocitrate dehydrogenase', 'Gene', (265, 289))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('spin', 'Gene', '10927', (16, 20))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('glioma', 'Disease', (40, 46))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (201, 206))	('IDH', 'Gene', (291, 294))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('mutations', 'Var', (296, 305))	('isocitrate dehydrogenase', 'Gene', '3417', (265, 289))
74775	27742110	Several amino acids were found in larger quantities in the tumor relative to the BAT including the essential amino acids, L-threonine, allothreonine, L-tryptophan, L-arginine, L-lysine, and L-valine.	('L-tryptophan', 'Chemical', 'MESH:D014364', (150, 162))	('allothreonine', 'MPA', (135, 148))	('L-arginine', 'Var', (164, 174))	('tumor', 'Disease', (59, 64))	('L-lysine', 'Chemical', 'MESH:D008239', (176, 184))	('L-threonine', 'Var', (122, 133))	('L-valine', 'Var', (190, 198))	('L-lysine', 'Var', (176, 184))	('L-valine', 'Chemical', 'MESH:D014633', (190, 198))	('L-arginine', 'Chemical', 'MESH:D001120', (164, 174))	('L-tryptophan', 'MPA', (150, 162))	('allothreonine', 'Chemical', '-', (135, 148))	('essential amino acids', 'Chemical', 'MESH:D000601', (99, 120))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('L-threonine', 'Chemical', 'MESH:D013912', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
74810	27742110	The novel hyperpolarized 13C MRS is thus more promising for interrogating the cancer metabolism of a tumor in real-time and monitoring the efficacy and prognosis after therapy to help to tailor treatment for each individual patient.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MRS', 'Disease', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Disease', (78, 84))	('tumor', 'Disease', (101, 106))	('patient', 'Species', '9606', (224, 231))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('MRS', 'Disease', 'MESH:D008556', (29, 32))	('13C', 'Chemical', 'MESH:C000615229', (25, 28))	('hyperpolarized', 'Var', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
74811	27742110	Mutations in isocitrate dehydrogenase (IDH) 1 and 2 present in 70% of low-grade gliomas and secondary high-grade gliomas in adults.	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (13, 51))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('gliomas', 'Disease', (113, 120))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
74812	27742110	These mutations are associated with the production of the oncometabolite, 2-hydroxyglutarate (2-HG) instead of alpha-KG in the brain tumor, which contributes to the formation and malignant progression of gliomas.	('associated', 'Reg', (20, 30))	('brain tumor', 'Disease', (127, 138))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('alpha-KG', 'Chemical', '-', (111, 119))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('brain tumor', 'Disease', 'MESH:D001932', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('brain tumor', 'Phenotype', 'HP:0030692', (127, 138))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (74, 92))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('mutations', 'Var', (6, 15))
74864	27742110	Everolimus and LY294002 are drugs that target the PI3K/AKT/mTOR pathway which regulates the cell cycle.	('LY294002', 'Chemical', 'MESH:C085911', (15, 23))	('AKT', 'Gene', (55, 58))	('LY294002', 'Var', (15, 23))	('AKT', 'Gene', '207', (55, 58))	('mTOR', 'Gene', '2475', (59, 63))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))	('mTOR', 'Gene', (59, 63))
74867	27742110	Treatment with TMZ was found to decrease the hyperpolarized pyruvate/lactate ratio in an orthotopic rat model of human GBM.	('hyperpolarized pyruvate/lactate ratio', 'MPA', (45, 82))	('TMZ', 'Var', (15, 18))	('rat', 'Species', '10116', (77, 80))	('TMZ', 'Chemical', 'MESH:D000077204', (15, 18))	('decrease', 'NegReg', (32, 40))	('human', 'Species', '9606', (113, 118))	('lactate', 'Chemical', 'MESH:D019344', (69, 76))	('pyruvate', 'Chemical', 'MESH:D019289', (60, 68))	('rat', 'Species', '10116', (100, 103))
74870	27742110	TMZ-treated cells showed a decrease in conversion of hyperpolarized pyruvate to lactate compared to untreated cells.	('lactate', 'Chemical', 'MESH:D019344', (80, 87))	('pyruvate', 'Chemical', 'MESH:D019289', (68, 76))	('decrease', 'NegReg', (27, 35))	('conversion of hyperpolarized pyruvate to lactate', 'MPA', (39, 87))	('TMZ-treated', 'Var', (0, 11))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
74871	27742110	Additionally, the authors of the study found that treatment with TMZ correlated with a decrease in pyruvate kinase (PKM2), which is a glycolytic enzyme that indirectly controls pyruvate to lactate conversion.	('PKM2', 'Gene', (116, 120))	('PKM2', 'Gene', '5315', (116, 120))	('pyruvate', 'Chemical', 'MESH:D019289', (99, 107))	('TMZ', 'Var', (65, 68))	('decrease', 'NegReg', (87, 95))	('pyruvate', 'Chemical', 'MESH:D019289', (177, 185))	('lactate', 'Chemical', 'MESH:D019344', (189, 196))	('TMZ', 'Chemical', 'MESH:D000077204', (65, 68))
74883	27742110	A bioreactor study of glioblastoma cells with mutated IDH1 showed elevated levels of hyperpolarized 2-HG compared to glioblastoma cells with wild-type IDH1.	('IDH1', 'Gene', (54, 58))	('glioblastoma', 'Disease', (22, 34))	('levels of hyperpolarized 2-HG', 'MPA', (75, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('mutated', 'Var', (46, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('IDH1', 'Gene', (151, 155))	('IDH1', 'Gene', '3417', (54, 58))	('glioblastoma', 'Disease', (117, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))	('IDH1', 'Gene', '3417', (151, 155))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))	('elevated', 'PosReg', (66, 74))
74884	27742110	IDH mutation was also found to correlate with decreased activity of branched chain amino acid transaminase (BCAT).	('IDH', 'Gene', (0, 3))	('activity', 'MPA', (56, 64))	('branched chain amino acid transaminase', 'MPA', (68, 106))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('decreased', 'NegReg', (46, 55))
74886	27742110	Thus, in cells with IDH1 mutation, a decrease in BCAT activity is expected to correlate with decreased glutamate production.	('IDH1', 'Gene', '3417', (20, 24))	('decrease', 'NegReg', (37, 45))	('mutation', 'Var', (25, 33))	('glutamate', 'Chemical', 'MESH:D018698', (103, 112))	('decreased', 'NegReg', (93, 102))	('glutamate production', 'MPA', (103, 123))	('decreased glutamate production', 'Phenotype', 'HP:0500150', (93, 123))	('IDH1', 'Gene', (20, 24))	('BCAT activity', 'MPA', (49, 62))
74887	27742110	This was found to be the case in a bioreactor study of GBM cells with IDH1 mutation; hyperpolarized 13C-glutamate production was decreased in mutant cells compared to wild-type.	('hyperpolarized 13C-glutamate production', 'MPA', (85, 124))	('mutation', 'Var', (75, 83))	('IDH1', 'Gene', '3417', (70, 74))	('mutant', 'Var', (142, 148))	('13C-glutamate', 'Chemical', '-', (100, 113))	('decreased', 'NegReg', (129, 138))	('IDH1', 'Gene', (70, 74))
74888	27742110	As biomarkers of metabolic imaging, hyperpolarized 2-HG and glutamate may potentially provide useful information in regards to detecting IDH1 mutation and treatment monitoring of brain tumors with IDH1 mutation.	('glutamate', 'Chemical', 'MESH:D018698', (60, 69))	('IDH1', 'Gene', (197, 201))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('IDH1', 'Gene', (137, 141))	('brain tumor', 'Phenotype', 'HP:0030692', (179, 190))	('mutation', 'Var', (202, 210))	('brain tumors', 'Disease', 'MESH:D001932', (179, 191))	('brain tumors', 'Phenotype', 'HP:0030692', (179, 191))	('IDH1', 'Gene', '3417', (197, 201))	('mutation', 'Var', (142, 150))	('IDH1', 'Gene', '3417', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('brain tumors', 'Disease', (179, 191))
74950	27742110	So the entire Z-spectrums for each pixel must be acquired for Lorentzian spectral fitting (5 components: free water, bound water, CrEST ~2 ppm, MT and CEST), which could lead to greatly increased scan time (~30 mins for the brain).	('water', 'Chemical', 'MESH:D014867', (110, 115))	('scan time', 'MPA', (196, 205))	('CrEST ~2 ppm', 'Var', (130, 142))	('Cr', 'Chemical', 'MESH:D002857', (130, 132))	('increased', 'PosReg', (186, 195))	('water', 'Chemical', 'MESH:D014867', (123, 128))
74962	27742110	One example of paraCEST agent for in vivo glioma detection is based on dendrimer labeled with Europium CEST agents and fluorescent labels for dual modality imaging ([DyLight 680]-Eu-G5PAMAM).	('glioma', 'Disease', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('[DyLight 680]-Eu-G5PAMAM', 'Var', (165, 189))
74966	27742110	injection (0.3 mg/kg), SPION-EGF showed much better accumulation inside the tumor region compared to bare SPIONs; reflected laser scanning revealed internalization of SPION-EGF inside the glioma cell cytoplasm.	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('SPION-EGF', 'Var', (167, 176))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('internalization', 'MPA', (148, 163))	('glioma', 'Disease', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
74977	27742110	Importantly, 129Xe possesses an incredibly sensitive chemical shift range (delta>7,500 ppm), which makes it well-suited to function as a spectroscopic chemical sensor.	('Xe', 'Chemical', 'MESH:D014978', (16, 18))	('sensitive chemical shift range', 'MPA', (43, 73))	('129Xe', 'Var', (13, 18))
74978	27742110	Indeed, differences in chemical shift have been shown to distinguish 129Xe inside Cryptophane cages that are linked to different biological targets.	('chemical shift', 'MPA', (23, 37))	('129Xe', 'Var', (69, 74))	('Xe', 'Chemical', 'MESH:D014978', (72, 74))	('Cryptophane', 'Chemical', 'MESH:C523242', (82, 93))	('differences', 'Reg', (8, 19))
74983	27742110	This results in a build-up of 129Xe nuclear spin polarization, which creates MR signal enhancement values of 4-5 orders of magnitude compared to thermal equilibrium:allowing 129Xe MRS/MRI for biomedical studies.	('spin', 'Gene', (44, 48))	('MRS', 'Disease', (180, 183))	('Xe', 'Chemical', 'MESH:D014978', (33, 35))	('Xe', 'Chemical', 'MESH:D014978', (177, 179))	('enhancement', 'PosReg', (87, 98))	('MR signal', 'MPA', (77, 86))	('spin', 'Gene', '10927', (44, 48))	('MRS', 'Disease', 'MESH:D008556', (180, 183))	('129Xe', 'Var', (174, 179))
74986	27742110	Hyperpolarized 129Xe can be administered to patients through either inhalation or intravenous injection, and it has been shown that both methods lead to comparable 129Xe concentrations in the brain.	('patients', 'Species', '9606', (44, 52))	('rat', 'Species', '10116', (177, 180))	('Xe', 'Chemical', 'MESH:D014978', (167, 169))	('129Xe', 'MPA', (164, 169))	('Xe', 'Chemical', 'MESH:D014978', (18, 20))	('Hyperpolarized', 'Var', (0, 14))
74992	27742110	When held in pristine laboratory conditions, hyperpolarized 129Xe will last for hours.	('rat', 'Species', '10116', (26, 29))	('129Xe', 'Protein', (60, 65))	('hyperpolarized', 'Var', (45, 59))	('Xe', 'Chemical', 'MESH:D014978', (63, 65))
74997	27742110	Since the initial demonstration of hyperpolarized 129Xe MRI in a rat brain and 129Xe MRS in a human brain in 1997, the field has grown steadily.	('Xe', 'Chemical', 'MESH:D014978', (53, 55))	('Xe', 'Chemical', 'MESH:D014978', (82, 84))	('MRS', 'Disease', (85, 88))	('human', 'Species', '9606', (94, 99))	('rat', 'Species', '10116', (25, 28))	('hyperpolarized', 'Var', (35, 49))	('MRS', 'Disease', 'MESH:D008556', (85, 88))	('rat', 'Species', '10116', (65, 68))
74998	27742110	129Xe brain MRS typically displays a handful of discernable peaks that can be attributed to 129Xe in the gas phase, dissolved in blood, and dissolved in different brain tissues (i.e., gray and white matter).	('MRS', 'Disease', (12, 15))	('129Xe', 'Var', (92, 97))	('Xe', 'Chemical', 'MESH:D014978', (95, 97))	('attributed', 'Reg', (78, 88))	('MRS', 'Disease', 'MESH:D008556', (12, 15))	('129Xe', 'Var', (0, 5))	('Xe', 'Chemical', 'MESH:D014978', (3, 5))
75009	27742110	One way around this is through a technique called 'HyperCEST' (Hyperpolarized Chemical Exchange Saturation Transfer), which saturates the "129Xe in Cryptophane" resonance while monitoring the increased depletion of the "129Xe gas resonance" as the xenon transfers between the targeted cage complex and the spin reservoir.	('Xe', 'Chemical', 'MESH:D014978', (142, 144))	('saturates', 'Var', (124, 133))	('Cryptophane', 'Chemical', 'MESH:C523242', (148, 159))	('rat', 'Species', '10116', (128, 131))	('Xe', 'Chemical', 'MESH:D014978', (223, 225))	('spin', 'Gene', (306, 310))	('xenon', 'Chemical', 'MESH:D014978', (248, 253))	('Cryptophane" resonance', 'MPA', (148, 170))	('rat', 'Species', '10116', (100, 103))	('depletion', 'MPA', (202, 211))	('spin', 'Gene', '10927', (306, 310))
75021	33356508	In normal conditions, glial cells are there to support and protect nerve cells but, in NF1-OPG, glial cells have a genetic defect and grow out of control forming a tumor called a glioma.	('OPG', 'Chemical', '-', (91, 94))	('tumor', 'Disease', (164, 169))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('OPG', 'Phenotype', 'HP:0009734', (91, 94))	('genetic defect', 'Disease', 'MESH:D030342', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('genetic defect', 'Disease', (115, 129))	('glioma', 'Disease', (179, 185))	('NF1-OPG', 'Var', (87, 94))
75030	33356508	Numerous inherited disorders can cause tumor in vision system including retinoblastoma that is caused by germline mutations in RB1 genes, retinal hemangioblastoma in von Hippel-Lindau, or neurofibromatosis.	('retinoblastoma', 'Disease', (72, 86))	('cause', 'Reg', (33, 38))	('mutations', 'Var', (114, 123))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (146, 162))	('RB1', 'Gene', '24708', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (188, 205))	('RB1', 'Gene', (127, 130))	('neurofibromatosis', 'Disease', 'MESH:C537392', (188, 205))	('caused', 'Reg', (95, 101))	('neurofibroma', 'Phenotype', 'HP:0001067', (188, 200))	('retinoblastoma', 'Disease', 'MESH:D012175', (72, 86))	('von Hippel-Lindau', 'Disease', (166, 183))	('neurofibromatosis', 'Disease', (188, 205))	('retinal hemangioblastoma', 'Disease', 'MESH:D018325', (138, 162))	('tumor', 'Disease', (39, 44))	('Numerous inherited disorders', 'Disease', (0, 28))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('retinal hemangioblastoma', 'Disease', (138, 162))	('retinal hemangioblastoma', 'Phenotype', 'HP:0009711', (138, 162))	('retinoblastoma', 'Phenotype', 'HP:0009919', (72, 86))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (166, 183))	('Numerous inherited disorders', 'Disease', 'MESH:D030342', (0, 28))
75034	33356508	The OPG grows near the vital sections of the brain involved in hormone secretion and homeostasis and therefore can interfere with the body's endocrine functions, such as hormone production, salt and water balance, appetite, and sleep.	('OPG', 'Var', (4, 7))	('water balance', 'Phenotype', 'HP:0000969', (199, 212))	('OPG', 'Phenotype', 'HP:0009734', (4, 7))	('water', 'Chemical', 'MESH:D014867', (199, 204))	('OPG', 'Chemical', '-', (4, 7))	('appetite', 'CPA', (214, 222))	('salt and water balance', 'Phenotype', 'HP:0000127', (190, 212))	('endocrine functions', 'MPA', (141, 160))	('sleep', 'CPA', (228, 233))	('hormone production', 'MPA', (170, 188))	('interfere', 'NegReg', (115, 124))
75089	33356508	Blocked cells were seeded onto a flat bottom 96-well plate (polystyrene, Thomas Scientific, USA) and labeled overnight at room temperature with the following conjugated primary antibodies: S100-FITC, Vimentin-FTIC, CD45-APC, Ki67-APC, and GFAP-APC.	('S100-FITC', 'Var', (189, 198))	('GFAP', 'Gene', '24387', (239, 243))	('rat', 'Species', '10116', (132, 135))	('Vimentin', 'Gene', '81818', (200, 208))	('GFAP', 'Gene', (239, 243))	('polystyrene', 'Chemical', 'MESH:D011137', (60, 71))	('Vimentin', 'Gene', (200, 208))	('FITC', 'Chemical', '-', (194, 198))	('CD45-APC', 'Var', (215, 223))
75166	33356508	Postsectioning, H&E was performed and showed massive infiltration of cells with hyperchromatism and pleomorphism markers.	('hyperchromatism', 'Disease', (80, 95))	('and', 'Var', (96, 99))	('H&E', 'Chemical', '-', (16, 19))	('rat', 'Species', '10116', (59, 62))	('hyperchromatism', 'Disease', 'None', (80, 95))
75221	33408717	This study acquired 20 glioma samples and 15 control samples from four datasets downloaded from NCBI Gene Expression Omnibus(GEO), including GSE80338, GSE115397, GSE135437, and GSE84465.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('GSE115397', 'Var', (151, 160))	('GSE80338', 'Var', (141, 149))	('GSE84465', 'Var', (177, 185))	('glioma', 'Disease', (23, 29))	('GSE135437', 'Var', (162, 171))
75230	33408717	We first screened the GEO database and collected three datasets of TAMs in glioma, the GSE80338 and GSE115397 collected CD11b+ microglia/macrophages from glioma and normal brain tissue and sequenced using RNA sequencing, while the GSE135437 was using FACS sorted on lineage-negative live CD45-positive cells and sequenced using the mCEL-Seq2 protocol.	('CD45', 'Gene', '5788', (288, 292))	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('GSE115397', 'Var', (100, 109))	('glioma', 'Disease', (75, 81))	('CD45', 'Gene', (288, 292))	('glioma', 'Disease', (154, 160))	('CD11b', 'Gene', '3684', (120, 125))	('TAMs', 'Chemical', '-', (67, 71))	('CD11b', 'Gene', (120, 125))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
75238	33408717	In GSE84465, P2RY12 was mainly expression in M1 macrophages, but in another dataset, it expressed in both M1 and M2 macrophages.	('P2RY12', 'Gene', (13, 19))	('GSE84465', 'Var', (3, 11))	('P2RY12', 'Gene', '64805', (13, 19))
75256	33408717	The analysis of TCGA LGG revealed that patients whose glioma expression high or low of LPAR5 had different outcomes, and consistent with LPAR5, the expression of other five genes all had a relationship with outcomes.	('LPAR5', 'Gene', '57121', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('low', 'NegReg', (80, 83))	('LPAR5', 'Gene', (137, 142))	('patients', 'Species', '9606', (39, 47))	('LPAR5', 'Gene', '57121', (87, 92))	('LPAR5', 'Gene', (87, 92))	('glioma', 'Disease', (54, 60))	('relationship', 'Reg', (189, 201))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('high', 'Var', (72, 76))
75390	33178973	2HG accumulation results from isocitrate dehydrogenase (IDH) genetic mutation in LGGs and this, combined with the integration of IDH mutation status in the WHO 2016 gliomas' reclassification, suggests that the metabolite could be used as a state-of-the-art biomarker for IDH-mutant gliomas.	('rat', 'Species', '10116', (119, 122))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('IDH', 'Gene', '3417', (129, 132))	('IDH', 'Gene', '3417', (271, 274))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('isocitrate dehydrogenase', 'Gene', (30, 54))	('IDH', 'Gene', (56, 59))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('rat', 'Species', '10116', (36, 39))	('IDH', 'Gene', '3417', (56, 59))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('LGGs', 'Gene', (81, 85))	('mutation', 'Var', (69, 77))	('isocitrate dehydrogenase', 'Gene', '3417', (30, 54))	('IDH', 'Gene', (129, 132))	('gliomas', 'Disease', (165, 172))	('IDH', 'Gene', (271, 274))
75421	33178973	3, 4-dihydroxy-6-F-flu-l-phenylalanine (FDOPA), 11C-methyl-L-methionine (MET) and 18F-fluethyl-L-tyrosine (FET) are the most frequently used non-FDG amino-acid agents (Figure 11).	('FET', 'Chemical', '-', (107, 110))	('FDOPA', 'Chemical', 'MESH:C043437', (40, 45))	('FDG', 'Chemical', 'MESH:D019788', (145, 148))	('MET', 'Gene', '79811', (73, 76))	('MET', 'Gene', (73, 76))	('3, 4-dihydroxy-6-F-flu-l-phenylalanine', 'Chemical', '-', (0, 38))	('18F-fluethyl-L-tyrosine', 'Chemical', '-', (82, 105))	('11C-methyl-L-methionine', 'Chemical', '-', (48, 71))	('18F-fluethyl-L-tyrosine', 'Var', (82, 105))
75448	32127518	Pseudogenes, once considered to be non-functional relics of evolution, are emerging as a critical factor in human tumorigenesis and progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Pseudogenes', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('human', 'Species', '9606', (108, 113))
75452	32127518	Further studies revealed that PDIA3P1 functions as a ceRNA, sponging miR-124-3p to modulate RELA expression and activate the downstream NF-kappaB pathway, thus promoting the MES transition of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('NF-kappaB', 'Gene', '4790', (136, 145))	('miR-124-3p', 'Gene', '406909', (69, 79))	('RELA', 'Gene', (92, 96))	('RELA', 'Gene', '5970', (92, 96))	('miR-124-3p', 'Gene', (69, 79))	('NF-kappaB', 'Gene', (136, 145))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('modulate', 'MPA', (83, 91))	('promoting', 'PosReg', (160, 169))	('PDIA3P1', 'Var', (30, 37))	('glioma', 'Disease', (192, 198))	('MES', 'Chemical', '-', (174, 177))	('activate', 'PosReg', (112, 120))
75460	32127518	However, increasing evidence has revealed the multifunctional character of pseudogenes in contribution to tumor progression.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('pseudogenes', 'Var', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
75462	32127518	Lack of oxygen alters the expression properties of tumor cells, which activate downstream genes to facilitate tumor growth, angiogenesis, and metastasis.	('expression', 'MPA', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Lack', 'Var', (0, 4))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (110, 115))	('metastasis', 'CPA', (142, 152))	('oxygen', 'Chemical', 'MESH:D010100', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('activate', 'PosReg', (70, 78))	('angiogenesis', 'CPA', (124, 136))	('facilitate', 'PosReg', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
75466	32127518	Further analysis using The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) database showed that high PDIA3P1 expression represents a more malignant tumor type and results in poorer outcomes in glioma patients.	('PDIA3P1', 'Gene', (123, 130))	('high', 'Var', (118, 122))	('poorer', 'NegReg', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('patients', 'Species', '9606', (222, 230))	('Cancer', 'Disease', (27, 33))	('glioma', 'Disease', (215, 221))	('expression', 'MPA', (131, 141))	('malignant tumor', 'Disease', (160, 175))	('outcomes', 'MPA', (203, 211))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('malignant tumor', 'Disease', 'MESH:D009369', (160, 175))	('Glioma', 'Disease', 'MESH:D005910', (70, 76))	('Glioma', 'Disease', (70, 76))	('Glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))
75467	32127518	PDIA3P1 overexpression or knockdown changed the migration and invasion capacity of glioma cells.	('glioma', 'Disease', (83, 89))	('migration', 'CPA', (48, 57))	('changed', 'Reg', (36, 43))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('knockdown', 'Var', (26, 35))	('PDIA3P1', 'Gene', (0, 7))
75479	32127518	The si-PDIA3P1, si-RELA, miR-124-3p mimics, miR-124-3p inhibitors, and negative controls were purchased from Genepharma (Shanghai, China).	('RELA', 'Gene', '5970', (19, 23))	('miR-124-3p', 'Gene', (25, 35))	('si-PDIA3P1', 'Var', (4, 14))	('miR-124-3p', 'Gene', '406909', (44, 54))	('miR-124-3p', 'Gene', '406909', (25, 35))	('miR-124-3p', 'Gene', (44, 54))	('RELA', 'Gene', (19, 23))
75506	32127518	Here, we found 41 upregulated pseudogenes in hypoxia-treated U87MG cells (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (61, 66))	('hypoxia', 'Disease', 'MESH:D000860', (45, 52))	('hypoxia', 'Disease', (45, 52))	('upregulated', 'PosReg', (18, 29))	('pseudogenes', 'Var', (30, 41))
75523	32127518	Therefore, we knocked down PDIA3P1 in U87MG and A172 cells and P3 primary GBM cells, and overexpressed PDIA3P1 in U251, U87MG, and A172 cells (Supplementary Fig.	('PDIA3P1', 'Gene', (27, 34))	('PDIA3P1', 'Gene', (103, 110))	('U87MG', 'CellLine', 'CVCL:0022', (120, 125))	('U87MG', 'CellLine', 'CVCL:0022', (38, 43))	('U251', 'CellLine', 'CVCL:0021', (114, 118))	('knocked', 'Var', (14, 21))	('overexpressed', 'PosReg', (89, 102))
75525	32127518	Similarly, high PDIA3P1 levels in U87MG cells resulted in a larger invasion area in the 3D tumor spheroid invasion assay (Fig.	('tumor', 'Disease', (91, 96))	('PDIA3P1 levels', 'MPA', (16, 30))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('larger', 'PosReg', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('U87MG', 'CellLine', 'CVCL:0022', (34, 39))	('U87MG', 'Var', (34, 39))
75531	32127518	As expected, increased PDIA3P1 levels in U87MG cells also resulted in shorter overall survival in xenograft mice (Fig.	('PDIA3P1 levels', 'MPA', (23, 37))	('shorter', 'NegReg', (70, 77))	('increased PDIA3P1 levels', 'Phenotype', 'HP:0003240', (13, 37))	('mice', 'Species', '10090', (108, 112))	('U87MG cells', 'Var', (41, 52))	('overall survival', 'CPA', (78, 94))	('U87MG', 'CellLine', 'CVCL:0022', (41, 46))	('increased', 'PosReg', (13, 22))
75533	32127518	H&E staining showed obscure tumor borders and tenuous ECM in PDIA3P1 overexpressing samples, however, samples in the control group exhibited a clear tumor border and dense ECM (Fig.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('obscure tumor borders', 'Disease', 'MESH:D001882', (20, 41))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('obscure tumor borders', 'Disease', (20, 41))	('PDIA3P1', 'Var', (61, 68))
75539	32127518	RT-qPCR was performed to verify their expression in PDIA3P1 overexpressing or knockdown U87MG and A172 cells.	('PDIA3P1', 'Gene', (52, 59))	('knockdown', 'Var', (78, 87))	('U87MG', 'CellLine', 'CVCL:0022', (88, 93))
75544	32127518	To further confirm our results, dual luciferase reporter plasmids were constructed which contained the wildtype (WT) or mutant type (MUT) sequences based on the putative miR-124-3p binding site in PDIA3P1 (Fig.	('miR-124-3p', 'Gene', (170, 180))	('miR-124-3p', 'Gene', '406909', (170, 180))	('mutant', 'Var', (120, 126))	('PDIA3P1', 'Gene', (197, 204))
75545	32127518	As expected, miR-124-3p overexpression significantly suppressed luciferase activity in HEK-293T cells transfected with the WT plasmids, but this was abolished by the mutation of the predicted binding site (Fig.	('miR-124-3p', 'Gene', (13, 23))	('suppressed', 'NegReg', (53, 63))	('luciferase', 'Enzyme', (64, 74))	('miR-124-3p', 'Gene', '406909', (13, 23))	('activity', 'MPA', (75, 83))	('mutation', 'Var', (166, 174))	('HEK-293T', 'CellLine', 'CVCL:0063', (87, 95))
75547	32127518	Figure 3j showed that the RNA level PDIA3P1 was significantly increased in the miR-124-3p pull-down product isolated from U87MG and U251 cells.	('miR-124-3p', 'Gene', (79, 89))	('increased', 'PosReg', (62, 71))	('U87MG', 'CellLine', 'CVCL:0022', (122, 127))	('U251', 'CellLine', 'CVCL:0021', (132, 136))	('PDIA3P1', 'Var', (36, 43))	('miR-124-3p', 'Gene', '406909', (79, 89))	('RNA level', 'MPA', (26, 35))
75556	32127518	Then, the expression of 13 potential targets was tested using RT-qPCR in PDIA3P1 overexpressing or knockdown U87MG and A172 cells, and PDIA3P1 overexpressing U251 cells.	('U251', 'CellLine', 'CVCL:0021', (158, 162))	('PDIA3P1', 'Gene', (73, 80))	('U87MG', 'CellLine', 'CVCL:0022', (109, 114))	('knockdown', 'Var', (99, 108))	('tested', 'Reg', (49, 55))
75570	32127518	5a, b, both KEGG enrichment and GSEA analysis demonstrated that the NF-kappaB pathway was activated in high-PDIA3P1 samples.	('activated', 'PosReg', (90, 99))	('NF-kappaB', 'Gene', '4790', (68, 77))	('GSEA', 'Chemical', '-', (32, 36))	('NF-kappaB', 'Gene', (68, 77))	('high-PDIA3P1', 'Var', (103, 115))
75574	32127518	Considering the possibility that PDIA3P1 may activate the NF-kappaB pathway and promote glioma MES transition through increasing RELA expression, we knocked down RELA using small interfering RNAs (siRNAs) in U87MG, A172, and U251 cells and determined the protein levels of CD44, beta-catenin, N-cadherin, Vimentin, and MMP14.	('N-cadherin', 'Gene', '1000', (293, 303))	('beta-catenin', 'Gene', (279, 291))	('CD44', 'Gene', '960', (273, 277))	('beta-catenin', 'Gene', '1499', (279, 291))	('NF-kappaB', 'Gene', '4790', (58, 67))	('activate', 'PosReg', (45, 53))	('CD44', 'Gene', (273, 277))	('U251', 'CellLine', 'CVCL:0021', (225, 229))	('PDIA3P1', 'Var', (33, 40))	('increasing', 'PosReg', (118, 128))	('U87MG', 'CellLine', 'CVCL:0022', (208, 213))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('RELA', 'Gene', (162, 166))	('RELA', 'Gene', '5970', (162, 166))	('promote', 'PosReg', (80, 87))	('RELA', 'Gene', (129, 133))	('RELA', 'Gene', '5970', (129, 133))	('MES', 'Chemical', '-', (95, 98))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('Vimentin', 'Gene', '7431', (305, 313))	('MMP14', 'Gene', '4323', (319, 324))	('MMP14', 'Gene', (319, 324))	('N-cadherin', 'Gene', (293, 303))	('Vimentin', 'Gene', (305, 313))	('NF-kappaB', 'Gene', (58, 67))
75575	32127518	As expected, RELA knockdown significantly inhibited NF-kappaB activity and the downstream protein levels of MES markers in glioma cells (Fig.	('knockdown', 'Var', (18, 27))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('activity', 'MPA', (62, 70))	('MES', 'Chemical', '-', (108, 111))	('RELA', 'Gene', (13, 17))	('RELA', 'Gene', '5970', (13, 17))	('NF-kappaB', 'Gene', '4790', (52, 61))	('inhibited', 'NegReg', (42, 51))	('NF-kappaB', 'Gene', (52, 61))	('glioma', 'Disease', (123, 129))	('protein levels of MES markers', 'MPA', (90, 119))
75576	32127518	Further, the results of the transwell assay showed that RELA knockdown indeed suppressed the migration and invasion capacity of U87MG and U251 cells (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (128, 133))	('suppressed', 'NegReg', (78, 88))	('migration', 'CPA', (93, 102))	('U251', 'CellLine', 'CVCL:0021', (138, 142))	('invasion capacity', 'CPA', (107, 124))	('knockdown', 'Var', (61, 70))	('RELA', 'Gene', (56, 60))	('RELA', 'Gene', '5970', (56, 60))
75579	32127518	5k, the NF-kappaB p65 and phosphorylated p65 (S536) were higher in PDIA3P1 overexpressing samples, indicating that PDIA3P1 promotes glioma MES transition by activating the NF-kappaB pathway in vitro and in vivo.	('glioma', 'Disease', (132, 138))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('NF-kappaB', 'Gene', (8, 17))	('promotes', 'PosReg', (123, 131))	('p65', 'Gene', (41, 44))	('MES', 'Chemical', '-', (139, 142))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('p65', 'Gene', (18, 21))	('NF-kappaB', 'Gene', '4790', (8, 17))	('activating', 'PosReg', (157, 167))	('NF-kappaB p65', 'Gene', (8, 21))	('PDIA3P1', 'Gene', (67, 74))	('NF-kappaB p65', 'Gene', '5970', (8, 21))	('NF-kappaB', 'Gene', (172, 181))	('p65', 'Gene', '5970', (41, 44))	('p65', 'Gene', '5970', (18, 21))	('higher', 'PosReg', (57, 63))	('NF-kappaB', 'Gene', '4790', (172, 181))	('PDIA3P1', 'Var', (115, 122))
75584	32127518	Alternatively, miR-124-3p expression was significantly increased in HIF1A knockdown hypoxia-treated glioma cells (Fig.	('expression', 'MPA', (26, 36))	('glioma', 'Disease', (100, 106))	('hypoxia', 'Disease', (84, 91))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('HIF1A', 'Gene', (68, 73))	('HIF1A', 'Gene', '3091', (68, 73))	('miR-124-3p', 'Gene', '406909', (15, 25))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('increased', 'PosReg', (55, 64))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('miR-124-3p', 'Gene', (15, 25))	('knockdown', 'Var', (74, 83))
75587	32127518	In addition, western-blot assay verified that HIF1A overexpression activated the NF-kappaB pathway and its downstream MES markers, however this effect was suppressed or even reversed by PDIA3P1 inhibition in U87MG and U251 cells (Fig.	('NF-kappaB', 'Gene', '4790', (81, 90))	('activated', 'PosReg', (67, 76))	('overexpression', 'Var', (52, 66))	('U87MG', 'CellLine', 'CVCL:0022', (208, 213))	('NF-kappaB', 'Gene', (81, 90))	('MES', 'Chemical', '-', (118, 121))	('HIF1A', 'Gene', (46, 51))	('HIF1A', 'Gene', '3091', (46, 51))	('U251', 'CellLine', 'CVCL:0021', (218, 222))
75590	32127518	As there were two putative binding sites located between -1108 and -887, three plasmids were constructed containing the deletion of site 999-991 (pGL3-Del-1), site 899-891 (pGL3-Del-2), and both sites (pGL3-Del-3) (Fig.	('pGL3', 'Gene', (146, 150))	('pGL3', 'Gene', '6391', (173, 177))	('pGL3', 'Gene', '6391', (202, 206))	('pGL3', 'Gene', (173, 177))	('Del-1', 'Gene', '10085', (151, 156))	('pGL3', 'Gene', '6391', (146, 150))	('deletion', 'Var', (120, 128))	('pGL3', 'Gene', (202, 206))	('site 999-991', 'Var', (132, 144))	('Del-1', 'Gene', (151, 156))
75591	32127518	Deletion plasmids were co-transfected with HIF1A-overexpressing plasmids or control vector into HEK-293 cells.	('HIF1A', 'Gene', (43, 48))	('HEK-293', 'CellLine', 'CVCL:0045', (96, 103))	('HIF1A', 'Gene', '3091', (43, 48))	('Deletion', 'Var', (0, 8))
75593	32127518	DNA fragments were collected from hypoxia-cultured U251 cells and immunoprecipitated using anti-IgG, anti-HIF-1alpha and anti-HIF-1beta.	('HIF-1alpha', 'Gene', (106, 116))	('U251', 'CellLine', 'CVCL:0021', (51, 55))	('HIF-1beta', 'Gene', (126, 135))	('HIF-1alpha', 'Gene', '3091', (106, 116))	('HIF-1beta', 'Gene', '3091', (126, 135))	('hypoxia', 'Disease', (34, 41))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('anti-IgG', 'Var', (91, 99))
75598	32127518	found that PDIA3P1 knockdown decreased the migration, invasion, and proliferation of HCC cells by affecting the p53 pathway, but the detailed mechanisms were not studied in detail.	('proliferation', 'CPA', (68, 81))	('invasion', 'CPA', (54, 62))	('PDIA3P1', 'Gene', (11, 18))	('affecting', 'Reg', (98, 107))	('knockdown', 'Var', (19, 28))	('p53', 'Gene', (112, 115))	('decreased', 'NegReg', (29, 38))	('migration', 'CPA', (43, 52))	('HCC', 'CellLine', 'CVCL:0C54', (85, 88))	('p53', 'Gene', '7157', (112, 115))
75619	32127518	This effect was partly reversed by RELA knockdown, indicating that PDIA3P1 is an important connection between hypoxia and the NF-kappaB pathway.	('NF-kappaB', 'Gene', '4790', (126, 135))	('PDIA3P1', 'Var', (67, 74))	('NF-kappaB', 'Gene', (126, 135))	('hypoxia', 'Disease', (110, 117))	('hypoxia', 'Disease', 'MESH:D000860', (110, 117))	('RELA', 'Gene', (35, 39))	('RELA', 'Gene', '5970', (35, 39))
75648	24946857	Because of these extensive fields of associating proteins, mutations in filamin genes result in a wide range of cell and tissue anomalies.	('filamin', 'Gene', '2318', (72, 79))	('result in', 'Reg', (86, 95))	('filamin', 'Gene', (72, 79))	('anomalies', 'Disease', (128, 137))	('mutations', 'Var', (59, 68))	('anomalies', 'Disease', 'MESH:D000014', (128, 137))
75649	24946857	Furthermore, Filamin genes mutations are common in human breast and colon cancers .	('mutations', 'Var', (27, 36))	('breast and colon cancers', 'Disease', 'MESH:D001943', (57, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('colon cancers', 'Phenotype', 'HP:0003003', (68, 81))	('Filamin', 'Gene', (13, 20))	('human', 'Species', '9606', (51, 56))	('Filamin', 'Gene', '2318', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('common', 'Reg', (41, 47))
75720	24946857	In spite of the immunological privileged nature of the brain, the aberrant FLNC production could induce immune reaction.	('FLNC', 'Gene', (75, 79))	('induce', 'Reg', (97, 103))	('aberrant', 'Var', (66, 74))	('immune reaction', 'CPA', (104, 119))	('FLNC', 'Gene', '2318', (75, 79))
75943	32457836	In addition, HIST1H2BK was an independent prognostic indicator for patients with glioma.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('patients', 'Species', '9606', (67, 75))	('HIST1H2BK', 'Var', (13, 22))	('glioma', 'Disease', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
75945	32457836	The results showed that HIST1H2BK was associated with intensity of immune infiltration in glioma.	('HIST1H2BK', 'Var', (24, 33))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))
75946	32457836	The results showed that HIST1H2BK was positively correlated with HIST1H2AG, HIST2H2AA4, HIST1H2BJ, HIST2H2BE, and HIST1H2AC, and negatively correlated with PDZD4, CRY2, GABBR1, rp5-1119a7.17, and KCNJ11.	('CRY2', 'Gene', '1408', (163, 167))	('HIST2H2AA4', 'Gene', '723790', (76, 86))	('HIST1H2BK', 'Var', (24, 33))	('HIST1H2AG', 'Gene', '8969', (65, 74))	('KCNJ11', 'Gene', (196, 202))	('CRY2', 'Gene', (163, 167))	('HIST1H2AG', 'Gene', (65, 74))	('PDZD4', 'Gene', '57595', (156, 161))	('negatively', 'NegReg', (129, 139))	('GABBR1', 'Gene', '2550', (169, 175))	('HIST1H2BJ', 'Gene', (88, 97))	('HIST2H2BE', 'Gene', '8349', (99, 108))	('HIST2H2BE', 'Gene', (99, 108))	('PDZD4', 'Gene', (156, 161))	('HIST1H2BJ', 'Gene', '8970', (88, 97))	('HIST1H2AC', 'Gene', (114, 123))	('HIST1H2AC', 'Gene', '8334', (114, 123))	('KCNJ11', 'Gene', '3767', (196, 202))	('GABBR1', 'Gene', (169, 175))	('HIST2H2AA4', 'Gene', (76, 86))
75949	32457836	In the revised fourth edition of the WHO Classification of CNS tumors published in 2016, classification of gliomas was fundamentally changed: for the first time, a large subset of these tumors is now defined based on presence/absence of IDH mutation and 1p/19q codeletion.	('CNS tumors', 'Disease', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IDH', 'Gene', (237, 240))	('gliomas', 'Disease', (107, 114))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('presence/absence', 'NegReg', (217, 233))	('CNS tumors', 'Disease', 'MESH:D016543', (59, 69))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('tumors', 'Disease', (63, 69))	('1p/19q codeletion', 'Var', (254, 271))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('IDH', 'Gene', '3417', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('presence/absence', 'Var', (217, 233))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
75965	32457836	Considering the dependency of HIST1H2BK expression level on cell replication, the predictive value of HIST1H2BK was compared with that of Ki-67, a positive marker of the cell cycle.	('Ki-67', 'Gene', '17345', (138, 143))	('HIST1H2BK', 'Var', (102, 111))	('Ki-67', 'Gene', (138, 143))
75968	32457836	Then, GSEA was used to identify survival differences between the high and low HIST1H2BK groups.	('low', 'Var', (74, 77))	('HIST1H2BK', 'Gene', (78, 87))	('GSEA', 'Chemical', '-', (6, 10))	('high', 'Var', (65, 69))
75976	32457836	Univariate Cox analysis showed that HIST1H2BK (HR = 1.808; 95% CI = 1.669-1.959; P < 0.001), PRS type, histology, grade, age, and chemo were high-risk factors, and IDH mutation and 1p19qcodeletion were low-risk factors (Figure 1B).	('IDH', 'Gene', '3417', (164, 167))	('IDH', 'Gene', (164, 167))	('HIST1H2BK', 'Var', (36, 45))
75977	32457836	Multivariate Cox analysis showed that HIST1H2BK (HR = 1.298; 95% CI = 1.170-1.440; P < 0.001) was independently associated with overall survival, which suggested that HIST1H2BK could be an independent prognostic indicator for glioma.	('overall survival', 'MPA', (128, 144))	('HIST1H2BK', 'Var', (167, 176))	('glioma', 'Disease', 'MESH:D005910', (226, 232))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('HIST1H2BK', 'Var', (38, 47))	('glioma', 'Disease', (226, 232))	('associated', 'Reg', (112, 122))
75978	32457836	In addition, PRS type, grade, age, chemo, IDH mutation, and 1p19q codeletion may also be independent prognostic factors (Figure 1C).	('IDH', 'Gene', '3417', (42, 45))	('1p19q codeletion', 'Var', (60, 76))	('IDH', 'Gene', (42, 45))
75980	32457836	The predictive value of Ki-67 was lower than that of HIST1H2BK, which further demonstrated that HIST1H2BK was a good predictive marker.	('Ki-67', 'Gene', '17345', (24, 29))	('Ki-67', 'Gene', (24, 29))	('HIST1H2BK', 'Var', (96, 105))
75981	32457836	Prognostic analysis revealed that high expression of HIST1H2BK would lead to a short overall survival in patients with LGG (Figure 2C, P < 0.05), and the expression level of HIST1H2BK was not associated with the prognosis of patients with GBM (Figure 2D, P > 0.05).	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (225, 233))	('short', 'NegReg', (79, 84))	('high', 'PosReg', (34, 38))	('overall survival', 'MPA', (85, 101))	('LGG', 'Disease', (119, 122))	('HIST1H2BK', 'Var', (53, 62))
75982	32457836	In addition, the protein level of HIST1H2BK was significantly higher in LGG tissues compared with normal tissues based on HPA (Figures 2E,F).	('protein level', 'MPA', (17, 30))	('HIST1H2BK', 'Var', (34, 43))	('HPA', 'Disease', 'MESH:D010661', (122, 125))	('HPA', 'Disease', (122, 125))	('LGG', 'Disease', (72, 75))	('higher', 'PosReg', (62, 68))
75984	32457836	Analysis of 1,018 samples from the CGGA database (including LGG and GBM) showed that differential expression of HIST1H2BK was significantly associated with PRS type, histology, grade, age, chemo status, IDH mutation status, and 1p19q codeletion status (Figure 3, Supplementary Figure 1).	('IDH', 'Gene', (203, 206))	('associated', 'Reg', (140, 150))	('histology', 'Disease', (166, 175))	('PRS type', 'Disease', (156, 164))	('1p19q codeletion', 'Var', (228, 244))	('IDH', 'Gene', '3417', (203, 206))	('HIST1H2BK', 'Gene', (112, 121))
75985	32457836	Gene set enrichment analysis was used to identify GO and signaling pathways that were differentially expressed in glioma (LGG+GBM) between the low and high HIST1H2BK expression groups.	('glioma', 'Disease', (114, 120))	('high', 'Var', (151, 155))	('low', 'Var', (143, 146))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('HIST1H2BK', 'Gene', (156, 165))
75987	32457836	Analysis using TIMER showed that HIST1H2BK was negatively associated with purity and CD8+ T cells, and was positively correlated with dendritic cells in GBM.	('CD8', 'Gene', (85, 88))	('CD8', 'Gene', '925', (85, 88))	('correlated', 'Interaction', (118, 128))	('associated', 'Interaction', (58, 68))	('purity', 'CPA', (74, 80))	('negatively', 'NegReg', (47, 57))	('positively', 'PosReg', (107, 117))	('dendritic cells', 'CPA', (134, 149))	('HIST1H2BK', 'Var', (33, 42))
75988	32457836	In low grade glioma (LGG), HIST1H2BK was inversely related to tumor purity, and was positively correlated with B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells (Figure 5 and Table 1).	('CD4', 'Gene', (120, 123))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CD8', 'Gene', (134, 137))	('CD4', 'Gene', '920', (120, 123))	('tumor', 'Disease', (62, 67))	('CD8', 'Gene', '925', (134, 137))	('HIST1H2BK', 'Var', (27, 36))	('glioma', 'Disease', (13, 19))	('correlated', 'Interaction', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
75990	32457836	Multivariate Cox survival analysis showed that age, macrophages, and HIST1H2BK were independent prognostic indicators for patients with LGG (Table 3), and age and dendritic cells were independent prognostic indicators for patients with GBM (Table 4).	('HIST1H2BK', 'Var', (69, 78))	('LGG', 'Disease', (136, 139))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (122, 130))
75992	32457836	These results showed that HIST1H2BK was associated with immune infiltration in glioma using external data analysis.	('HIST1H2BK', 'Var', (26, 35))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('immune infiltration', 'Disease', (56, 75))	('associated', 'Reg', (40, 50))
75994	32457836	These findings indicated that HIST1H2BK might be a prognostic biomarker of glioma, and may be a target for immunotherapy.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('HIST1H2BK', 'Var', (30, 39))	('glioma', 'Disease', (75, 81))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
75995	32457836	The results showed that HIST1H2BK was positively associated with HIST1H2AG, HIST2H2AA4, HIST1H2BJ, HIST2H2BE, and HIST1H2AC, and was negatively associated with PDZD4, CRY2, GABBR1, rp5-1119a7.17, and KCNJ11 (Supplementary Table 5).	('GABBR1', 'Gene', '2550', (173, 179))	('HIST2H2AA4', 'Gene', '723790', (76, 86))	('HIST1H2BK', 'Var', (24, 33))	('HIST1H2AG', 'Gene', '8969', (65, 74))	('PDZD4', 'Gene', (160, 165))	('KCNJ11', 'Gene', '3767', (200, 206))	('HIST1H2AG', 'Gene', (65, 74))	('CRY2', 'Gene', '1408', (167, 171))	('KCNJ11', 'Gene', (200, 206))	('CRY2', 'Gene', (167, 171))	('GABBR1', 'Gene', (173, 179))	('HIST1H2BJ', 'Gene', (88, 97))	('HIST2H2BE', 'Gene', '8349', (99, 108))	('HIST2H2BE', 'Gene', (99, 108))	('HIST1H2BJ', 'Gene', '8970', (88, 97))	('PDZD4', 'Gene', '57595', (160, 165))	('HIST1H2AC', 'Gene', (114, 123))	('HIST1H2AC', 'Gene', '8334', (114, 123))	('HIST2H2AA4', 'Gene', (76, 86))	('negatively', 'NegReg', (133, 143))
76006	32457836	We showed that HIST1H2BK was a high-risk factor, and could be an independent prognostic indicator in patients with glioma using comprehensive univariate and multivariate Cox analyses.	('patients', 'Species', '9606', (101, 109))	('glioma', 'Disease', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('HIST1H2BK', 'Var', (15, 24))
76008	32457836	Taken altogether, these results indicated that HIST1H2BK was upregulated in LGG and GBM, and HIST1H2BK had prognostic value in LGG, indicating that HIST1H2BK had important regulatory functions in gliomas.	('LGG', 'Disease', (127, 130))	('upregulated', 'PosReg', (61, 72))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('HIST1H2BK', 'Gene', (47, 56))	('LGG', 'Disease', (76, 79))	('GBM', 'Disease', (84, 87))	('HIST1H2BK', 'Var', (93, 102))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))
76009	32457836	With The Human Protein Atlas (https://www.proteinatlas.org/), an online tool containing survival data from TCGA and giving users the ability to create publication-quality Kaplan-Meier plots, HIST1H2BK was identified to be a biomarker for renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('renal cancer', 'Disease', (238, 250))	('Human', 'Species', '9606', (9, 14))	('renal cancer', 'Disease', 'MESH:D007680', (238, 250))	('renal cancer', 'Phenotype', 'HP:0009726', (238, 250))	('HIST1H2BK', 'Var', (191, 200))
76011	32457836	We speculated that HIST1H2BK may be used as a prognostic indicator for a variety of cancers, and we will explore the protein in a multi-disciplinary way in the future, hoping to find a molecular predictor with great clinical value.	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('HIST1H2BK', 'Var', (19, 28))
76015	32457836	We speculated that the high levels of HIST1H2BK would increase the aggressiveness in glioma via LIFR-JAK1-STAT3 signaling pathway.	('aggressiveness', 'Disease', (67, 81))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('JAK1', 'Gene', '3716', (101, 105))	('aggressiveness', 'Phenotype', 'HP:0000718', (67, 81))	('HIST1H2BK', 'Var', (38, 47))	('increase', 'PosReg', (54, 62))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', (85, 91))	('STAT3', 'Gene', '6774', (106, 111))	('aggressiveness', 'Disease', 'MESH:D001523', (67, 81))	('LIFR', 'Gene', '3977', (96, 100))	('LIFR', 'Gene', (96, 100))	('STAT3', 'Gene', (106, 111))	('JAK1', 'Gene', (101, 105))
76020	32457836	The results of GSEA showed that HIST1H2BK might be involved in tumor progression by regulating the B lymphocyte.	('B lymphocyte', 'CPA', (99, 111))	('HIST1H2BK', 'Var', (32, 41))	('tumor', 'Disease', (63, 68))	('GSEA', 'Chemical', '-', (15, 19))	('involved', 'Reg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('regulating', 'Reg', (84, 94))
76021	32457836	Finally, co-expression analysis showed that HIST1H2BK was positively associated with HIST1H2AG, HIST2H2AA4, HIST1H2BJ, HIST2H2BE, and HIST1H2AC, and was negatively associated with PDZD4, CRY2, GABBR1, RP5-1119A7.17, and KCNJ11.	('HIST2H2BE', 'Gene', (119, 128))	('HIST2H2BE', 'Gene', '8349', (119, 128))	('HIST1H2AC', 'Gene', (134, 143))	('associated', 'Interaction', (69, 79))	('KCNJ11', 'Gene', (220, 226))	('HIST1H2AC', 'Gene', '8334', (134, 143))	('PDZD4', 'Gene', (180, 185))	('HIST1H2BJ', 'Gene', (108, 117))	('HIST2H2AA4', 'Gene', (96, 106))	('HIST1H2BJ', 'Gene', '8970', (108, 117))	('HIST2H2AA4', 'Gene', '723790', (96, 106))	('GABBR1', 'Gene', '2550', (193, 199))	('HIST1H2BK', 'Var', (44, 53))	('CRY2', 'Gene', '1408', (187, 191))	('HIST1H2AG', 'Gene', '8969', (85, 94))	('CRY2', 'Gene', (187, 191))	('KCNJ11', 'Gene', '3767', (220, 226))	('HIST1H2AG', 'Gene', (85, 94))	('PDZD4', 'Gene', '57595', (180, 185))	('GABBR1', 'Gene', (193, 199))
76026	32457836	Our study showed HIST1H2BK to be associated with HIST2H2BE and CRY, which indicated that HIST1H2BK might be associated with cellular immunity.	('HIST1H2BK', 'Var', (17, 26))	('CRY', 'Disease', (63, 66))	('associated', 'Reg', (108, 118))	('associated', 'Reg', (33, 43))	('HIST2H2BE', 'Gene', (49, 58))	('HIST2H2BE', 'Gene', '8349', (49, 58))
76027	32457836	In conclusion, this study investigated the relationship between HIST1H2BK and glioma prognosis.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('HIST1H2BK', 'Var', (64, 73))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
76028	32457836	The results show that high expression of HIST1H2BK was associated with worse prognosis, and HIST1H2BK was a high-risk factor and could be used as an independent prognostic indicator for patients with glioma.	('glioma', 'Disease', (200, 206))	('high expression', 'Var', (22, 37))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('HIST1H2BK', 'Gene', (41, 50))	('patients', 'Species', '9606', (186, 194))	('HIST1H2BK', 'Var', (92, 101))
76030	32457836	The results showed that HIST1H2BK could affect the level of immune infiltration in glioma and that upregulation of HIST1H2BK in glioma indicates poor prognosis.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', (128, 134))	('upregulation', 'PosReg', (99, 111))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('HIST1H2BK', 'Var', (115, 124))	('affect', 'Reg', (40, 46))	('level of immune infiltration', 'MPA', (51, 79))
76031	32457836	Few studies have shown the association between HIST1H2BK and glioma or other cancers, which suggests that this study may provide a scaffold for future development of therapeutic strategies for glioma.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('glioma', 'Disease', (193, 199))	('association', 'Interaction', (27, 38))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('HIST1H2BK', 'Var', (47, 56))
76211	27651330	12 and 13 illustrate that the segmented tumour boundary from ERT (d1) is closer to the manual annotation, compared to that of SVM (c1).	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Disease', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('ERT (d1', 'Var', (61, 68))
76240	26945349	Isocitrate Dehydrogenase (IDH)1/2 Mutations as Prognostic Markers in Patients With Glioblastomas The purpose of this study was to perform a meta-analysis examining the association of isocitrate dehydrogenase (IDH)1/2 mutations with overall survival (OS) and progression-free survival (PFS) in patients with glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (307, 319))	('overall', 'Disease', (232, 239))	('Isocitrate Dehydrogenase (IDH)1', 'Gene', '3417', (0, 31))	('association', 'Interaction', (168, 179))	('progression-free survival', 'CPA', (258, 283))	('patients', 'Species', '9606', (293, 301))	('IDH)1', 'Gene', '3417', (209, 214))	('glioblastomas', 'Phenotype', 'HP:0012174', (307, 320))	('isocitrate', 'Chemical', 'MESH:C034219', (183, 193))	('Glioblastomas', 'Disease', 'MESH:D005909', (83, 96))	('Glioblastomas', 'Disease', (83, 96))	('glioblastomas', 'Disease', 'MESH:D005909', (307, 320))	('IDH)1', 'Gene', '3417', (26, 31))	('mutations', 'Var', (217, 226))	('Glioblastomas', 'Phenotype', 'HP:0012174', (83, 96))	('Patients', 'Species', '9606', (69, 77))	('glioblastomas', 'Disease', (307, 320))
76243	26945349	OS and PFS were used to evaluate the association of IDH1 and IDH1/2 mutations and prognosis.	('association', 'Interaction', (37, 48))	('IDH1', 'Gene', '3417', (52, 56))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', (61, 65))	('mutations', 'Var', (68, 77))	('IDH1', 'Gene', (52, 56))
76245	26945349	The pooled HR of 0.358 (95% CI 0.264-0.487, P < 0.001) indicated that IDH mutations were associated with better OS.	('IDH', 'Gene', '3417', (70, 73))	('IDH', 'Gene', (70, 73))	('better OS', 'Disease', (105, 114))	('mutations', 'Var', (74, 83))
76246	26945349	Similarly, the pooled HR of 0.322 (95% CI 0.24200.455, P < 0.001) indicated that IDH mutations were associated with better PFS.	('mutations', 'Var', (85, 94))	('IDH', 'Gene', '3417', (81, 84))	('IDH', 'Gene', (81, 84))
76247	26945349	When patients were stratified by surgery versus no surgery or IDH1 versus IDH1/2 mutations, the results also indicated that the presence of IDH mutations was associated with better OS and PFS.	('IDH', 'Gene', (140, 143))	('presence', 'Var', (128, 136))	('IDH', 'Gene', '3417', (62, 65))	('IDH', 'Gene', '3417', (140, 143))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', (74, 78))	('patients', 'Species', '9606', (5, 13))	('IDH', 'Gene', (74, 77))	('IDH1', 'Gene', '3417', (74, 78))	('IDH1', 'Gene', (62, 66))	('mutations', 'Var', (144, 153))	('better OS', 'CPA', (174, 183))	('IDH', 'Gene', (62, 65))	('IDH', 'Gene', '3417', (74, 77))
76248	26945349	The IDH mutations are associated with improved survival in patients with glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('improved', 'PosReg', (38, 46))	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (4, 7))	('mutations', 'Var', (8, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (73, 86))	('survival', 'MPA', (47, 55))	('patients', 'Species', '9606', (59, 67))	('glioblastomas', 'Disease', 'MESH:D005909', (73, 86))	('glioblastomas', 'Disease', (73, 86))
76254	26945349	Mutations in IDH1 associated with glioblastomas map to the highly conserved residue R132 in the enzyme active site, and usually result in an Arg to His substitution, although other substitutions can also occur.	('substitution', 'Var', (152, 164))	('result in', 'Reg', (128, 137))	('Arg', 'Chemical', 'MESH:D001120', (141, 144))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('R132', 'Var', (84, 88))	('IDH1', 'Gene', (13, 17))	('glioblastomas', 'Disease', 'MESH:D005909', (34, 47))	('associated', 'Reg', (18, 28))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('glioblastomas', 'Disease', (34, 47))	('Arg', 'MPA', (141, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('map', 'Reg', (48, 51))
76258	26945349	Both the IDH1-R132 and IDH2-R172 mutations are thought to result in an accumulation of the oncometabolite 2-hydroxyglutarate instead of alpha-ketogluterate.	('alpha-ketogluterate', 'Chemical', '-', (136, 155))	('accumulation', 'PosReg', (71, 83))	('IDH1', 'Gene', (9, 13))	('IDH2', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (9, 13))	('mutations', 'Var', (33, 42))	('IDH2', 'Gene', '3418', (23, 27))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (106, 124))	('oncometabolite 2-hydroxyglutarate', 'MPA', (91, 124))
76259	26945349	It is unclear how a tumor's biology is affected by IDH1/2 mutations.	('mutations', 'Var', (58, 67))	('IDH1', 'Gene', '3417', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH1', 'Gene', (51, 55))	('tumor', 'Disease', (20, 25))
76260	26945349	IDH1/2 mutations may result in genome-wide epigenetic changes in human gliomas.	('epigenetic changes', 'MPA', (43, 61))	('human', 'Species', '9606', (65, 70))	('IDH1', 'Gene', '3417', (0, 4))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH1', 'Gene', (0, 4))	('result in', 'Reg', (21, 30))	('mutations', 'Var', (7, 16))
76261	26945349	Another hypothesis is that the mutations reduce the capacity of cells to produce NADPH, and consequently lowers the ability of the cell to scavenge oxygen species, making the tumor cells more susceptible to irradiation and chemotherapy.	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (175, 180))	('NADPH', 'MPA', (81, 86))	('ability', 'MPA', (116, 123))	('reduce', 'NegReg', (41, 47))	('oxygen', 'Chemical', 'MESH:D010100', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('more', 'PosReg', (187, 191))	('lowers', 'NegReg', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('NADPH', 'Chemical', 'MESH:D009249', (81, 86))
76263	26945349	A number of studies have found that IDH1-R132 and IDH2-R172 mutations are linked to the genomic profile of the tumor, and are important prognostic markers in grade II to IV gliomas.	('IDH2', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH1', 'Gene', (36, 40))	('gliomas', 'Disease', (173, 180))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('IDH2', 'Gene', '3418', (50, 54))	('tumor', 'Disease', (111, 116))	('grade II', 'Disease', (158, 166))	('IDH1', 'Gene', '3417', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('mutations', 'Var', (60, 69))	('linked', 'Reg', (74, 80))
76264	26945349	However, other studies have not found an association of IDH1/2 mutations with prognosis in low-grade tumors.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('IDH1', 'Gene', '3417', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('IDH1', 'Gene', (56, 60))
76265	26945349	The purpose of the current study was to perform a meta-analysis to examine the association of IDH1/2 mutations with overall survival (OS) and progression-free survival (PFS) in patients with glioblastomas.	('IDH1', 'Gene', (94, 98))	('mutations', 'Var', (101, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('glioblastomas', 'Disease', 'MESH:D005909', (191, 204))	('patients', 'Species', '9606', (177, 185))	('IDH1', 'Gene', '3417', (94, 98))	('association', 'Interaction', (79, 90))	('glioblastomas', 'Disease', (191, 204))	('glioblastomas', 'Phenotype', 'HP:0012174', (191, 204))	('overall', 'MPA', (116, 123))
76269	26945349	Overall survival and PFS were used to evaluate the association of IDH1 and IDH1/2 mutations, and prognosis for patients with malignant brain tumors.	('malignant brain tumors', 'Disease', (125, 147))	('IDH1', 'Gene', '3417', (66, 70))	('brain tumors', 'Phenotype', 'HP:0030692', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('brain tumor', 'Phenotype', 'HP:0030692', (135, 146))	('association', 'Interaction', (51, 62))	('IDH1', 'Gene', (75, 79))	('mutations', 'Var', (82, 91))	('IDH1', 'Gene', '3417', (75, 79))	('malignant brain tumors', 'Disease', 'MESH:D001932', (125, 147))	('IDH1', 'Gene', (66, 70))	('patients', 'Species', '9606', (111, 119))
76271	26945349	A HR value equal to 1 indicates there was no significant association of IDH1 or IDH1/2 mutations with OS or PFS.	('PFS', 'Disease', (108, 111))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (80, 84))	('IDH1', 'Gene', '3417', (72, 76))	('association', 'Interaction', (57, 68))	('mutations', 'Var', (87, 96))
76273	26945349	The pooled HR of 0.358 (95% CI 0.264-0.487, P < 0.001) indicated that IDH1 or IDH1/2 mutations were associated with better OS (Figure 2).	('better OS', 'Disease', (116, 125))	('IDH1', 'Gene', (78, 82))	('IDH1', 'Gene', '3417', (70, 74))	('mutations', 'Var', (85, 94))	('IDH1', 'Gene', '3417', (78, 82))	('IDH1', 'Gene', (70, 74))
76274	26945349	When patients were stratified by surgery versus no surgery or IDH1 versus IDH1/2 mutations, the results also indicated that the presence of IDH mutations was associated with better OS.	('IDH', 'Gene', (140, 143))	('presence', 'Var', (128, 136))	('IDH', 'Gene', '3417', (62, 65))	('IDH', 'Gene', '3417', (140, 143))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', (74, 78))	('patients', 'Species', '9606', (5, 13))	('IDH', 'Gene', (74, 77))	('better', 'Disease', (174, 180))	('IDH1', 'Gene', '3417', (74, 78))	('IDH1', 'Gene', (62, 66))	('mutations', 'Var', (144, 153))	('IDH', 'Gene', (62, 65))	('IDH', 'Gene', '3417', (74, 77))
76275	26945349	The pooled HR of 0.322 (95% CI 0.242-0.455, P < 0.001) indicated that IDH1 or IDH1/2 mutations were associated with better PFS (Figure 3).	('IDH1', 'Gene', (78, 82))	('IDH1', 'Gene', '3417', (70, 74))	('mutations', 'Var', (85, 94))	('IDH1', 'Gene', '3417', (78, 82))	('PFS', 'Disease', (123, 126))	('IDH1', 'Gene', (70, 74))
76276	26945349	When patients were stratified by surgery versus no surgery or IDH1 versus IDH1/2 mutations, the results also indicated that the presence of IDH mutations was associated with better PFS.	('IDH', 'Gene', (140, 143))	('presence', 'Var', (128, 136))	('IDH', 'Gene', '3417', (62, 65))	('IDH', 'Gene', '3417', (140, 143))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', (74, 78))	('patients', 'Species', '9606', (5, 13))	('PFS', 'CPA', (181, 184))	('IDH', 'Gene', (74, 77))	('IDH1', 'Gene', '3417', (74, 78))	('IDH1', 'Gene', (62, 66))	('mutations', 'Var', (144, 153))	('IDH', 'Gene', (62, 65))	('IDH', 'Gene', '3417', (74, 77))
76278	26945349	The purpose of this meta-analysis was to evaluate the prognostic value of IDH1/2 mutations with respect to OS and PFS in patients with glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('IDH1', 'Gene', (74, 78))	('mutations', 'Var', (81, 90))	('IDH1', 'Gene', '3417', (74, 78))	('glioblastoma', 'Disease', (135, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('patients', 'Species', '9606', (121, 129))
76279	26945349	The results showed that the presence of IDH1/2 mutations was associated with longer OS and PFS, and this result was seen in both patients treated with surgery and those treated nonsurgically (e.g., radiotherapy), as well as in patients with IDH1 and IDH1/2 mutations.	('PFS', 'CPA', (91, 94))	('IDH1', 'Gene', (40, 44))	('patients', 'Species', '9606', (129, 137))	('IDH1', 'Gene', '3417', (241, 245))	('mutations', 'Var', (47, 56))	('IDH1', 'Gene', '3417', (40, 44))	('IDH1', 'Gene', (250, 254))	('IDH1', 'Gene', '3417', (250, 254))	('longer OS', 'CPA', (77, 86))	('IDH1', 'Gene', (241, 245))	('patients', 'Species', '9606', (227, 235))
76280	26945349	IDH1 mutations have been reported in secondary GBM, diffuse astrocytoma, oligodendrogliomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas, and rarely in primary GBM, and have not been reported in pilocytic astrocytomas, ependymonmas, and medulloblastomas.	('astrocytomas', 'Disease', (169, 181))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (129, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (118, 147))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (73, 91))	('IDH1', 'Gene', (0, 4))	('medulloblastomas', 'Disease', (282, 298))	('anaplastic oligodendrogliomas', 'Disease', (118, 147))	('anaplastic oligoastrocytomas', 'Disease', (153, 181))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('reported', 'Reg', (25, 33))	('astrocytomas', 'Disease', 'MESH:D001254', (104, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (250, 261))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('astrocytoma', 'Disease', 'MESH:D001254', (250, 261))	('oligodendrogliomas', 'Disease', (129, 147))	('astrocytoma', 'Disease', (250, 261))	('astrocytoma', 'Disease', 'MESH:D001254', (60, 71))	('astrocytomas', 'Disease', 'MESH:D001254', (169, 181))	('astrocytoma', 'Disease', (60, 71))	('anaplastic astrocytoma', 'Disease', (93, 115))	('pilocytic astrocytomas', 'Disease', (240, 262))	('oligodendrogliomas', 'Disease', (73, 91))	('IDH1', 'Gene', '3417', (0, 4))	('astrocytomas', 'Disease', (250, 262))	('astrocytoma', 'Disease', 'MESH:D001254', (169, 180))	('medulloblastomas', 'Disease', 'MESH:D008527', (282, 298))	('mutations', 'Var', (5, 14))	('astrocytoma', 'Disease', (169, 180))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('secondary GBM', 'Disease', (37, 50))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('ependymonmas', 'Disease', (264, 276))	('astrocytoma', 'Disease', 'MESH:D001254', (104, 115))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (240, 262))	('anaplastic oligoastrocytomas', 'Disease', 'MESH:D001254', (153, 181))	('ependymonmas', 'Disease', 'None', (264, 276))	('astrocytoma', 'Disease', (104, 115))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (93, 115))	('astrocytomas', 'Disease', (104, 116))	('astrocytomas', 'Disease', 'MESH:D001254', (250, 262))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))
76281	26945349	Mutations have also been reported in other cancers including acute myeloid leukemia and colorectal and prostate cancer.	('reported', 'Reg', (25, 33))	('acute myeloid leukemia', 'Disease', (61, 83))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (67, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('cancers', 'Disease', (43, 50))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (61, 83))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (61, 83))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal and prostate cancer', 'Disease', 'MESH:D015179', (88, 118))
76282	26945349	Prior studies have found that IDH1/2 mutations may influence the prognosis of patients with secondary or greater than grade II gliomas; however, these studies have differed in design and the results have not always been consistent.	('II gliomas', 'Disease', 'MESH:D005910', (124, 134))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('patients', 'Species', '9606', (78, 86))	('IDH1', 'Gene', (30, 34))	('mutations', 'Var', (37, 46))	('II gliomas', 'Disease', (124, 134))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('influence', 'Reg', (51, 60))	('IDH1', 'Gene', '3417', (30, 34))
76283	26945349	Evidence has generally shown that IDH1 mutations are associated with improved OS and PFS, particularly in patients with high-grade gliomas.	('IDH1', 'Gene', '3417', (34, 38))	('gliomas', 'Disease', (131, 138))	('improved', 'PosReg', (69, 77))	('PFS', 'CPA', (85, 88))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (106, 114))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('IDH1', 'Gene', (34, 38))
76285	26945349	For example, Sanson et al showed that the IDH1 mutation had a significant prognostic value for OS in gliomas, whereas Kim et al reported the IDH1/IDH2 mutation was of no prognostic value in 360 low-grade gliomas.	('IDH1', 'Gene', (141, 145))	('gliomas', 'Disease', (101, 108))	('IDH2', 'Gene', '3418', (146, 150))	('IDH1', 'Gene', '3417', (42, 46))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('mutation', 'Var', (47, 55))	('gliomas', 'Disease', (204, 211))	('IDH1', 'Gene', '3417', (141, 145))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('IDH1', 'Gene', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH2', 'Gene', (146, 150))
76286	26945349	Interestingly, although IDH1 mutations have generally been shown to be a prognostic indicator, their presence is not necessarily predictive of response to therapy.	('IDH1', 'Gene', '3417', (24, 28))	('mutations', 'Var', (29, 38))	('IDH1', 'Gene', (24, 28))
76287	26945349	Reasons for these findings may have to do with the association of IDH1 mutations with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.	('IDH1', 'Gene', '3417', (66, 70))	('O6-methylguanine-DNA methyltransferase', 'Gene', (86, 124))	('association', 'Interaction', (51, 62))	('mutations', 'Var', (71, 80))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (86, 124))	('MGMT', 'Gene', (126, 130))	('IDH1', 'Gene', (66, 70))	('MGMT', 'Gene', '4255', (126, 130))
76288	26945349	For example, Molenaar et al reported that the combination of IDH1 mutations and MGMT methylation status predicted survival in patients with glioblastomas better than either IDH1 or MGMT status alone.	('mutations', 'Var', (66, 75))	('glioblastomas', 'Disease', (140, 153))	('MGMT', 'Gene', '4255', (80, 84))	('glioblastomas', 'Phenotype', 'HP:0012174', (140, 153))	('predicted', 'Reg', (104, 113))	('MGMT', 'Gene', (80, 84))	('IDH1', 'Gene', (173, 177))	('IDH1', 'Gene', (61, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (140, 153))	('IDH1', 'Gene', '3417', (173, 177))	('survival', 'Disease', (114, 122))	('patients', 'Species', '9606', (126, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('IDH1', 'Gene', '3417', (61, 65))	('MGMT', 'Gene', (181, 185))	('MGMT', 'Gene', '4255', (181, 185))
76289	26945349	Though the reasons for the associations between survival, and IDH1 and MGMT methylation status remain to be determined, it has been suggested there may be mechanistic link between IDH1 mutations and MGMT methylation.	('MGMT', 'Gene', '4255', (199, 203))	('IDH1', 'Gene', (180, 184))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', '3417', (180, 184))	('MGMT', 'Gene', '4255', (71, 75))	('MGMT', 'Gene', (71, 75))	('mutations', 'Var', (185, 194))	('IDH1', 'Gene', (62, 66))	('MGMT', 'Gene', (199, 203))
76291	26945349	Among the studies included in the current analysis, Okita et al suggested IDH1/2 mutations were predictive for response to chemoradiotherapy, but not radiotherapy alone in patients with grade II gliomas.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('II gliomas', 'Disease', (192, 202))	('IDH1', 'Gene', (74, 78))	('mutations', 'Var', (81, 90))	('IDH1', 'Gene', '3417', (74, 78))	('II gliomas', 'Disease', 'MESH:D005910', (192, 202))	('patients', 'Species', '9606', (172, 180))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))
76292	26945349	However, van den Bent et al reported that IDH1 mutations were predictive of both OS and PFS for patients treated with radiotherapy and radiotherapy/PVC.	('IDH1', 'Gene', '3417', (42, 46))	('mutations', 'Var', (47, 56))	('PFS', 'Disease', (88, 91))	('patients', 'Species', '9606', (96, 104))	('IDH1', 'Gene', (42, 46))
76294	26945349	In the current meta-analysis, we did not evaluate the predictive value of IDH1/2 mutations with respect to radiotherapy, chemotherapy, or chemoradiotherapy.	('IDH1', 'Gene', (74, 78))	('mutations', 'Var', (81, 90))	('IDH1', 'Gene', '3417', (74, 78))
76295	26945349	Other prior meta-analyses have evaluated the association of IDH mutations and survival in patients with glioblastomas.	('association', 'Interaction', (45, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('IDH', 'Gene', (60, 63))	('mutations', 'Var', (64, 73))	('glioblastomas', 'Phenotype', 'HP:0012174', (104, 117))	('IDH', 'Gene', '3417', (60, 63))	('patients', 'Species', '9606', (90, 98))	('glioblastomas', 'Disease', 'MESH:D005909', (104, 117))	('glioblastomas', 'Disease', (104, 117))
76296	26945349	An analysis by Cheng et al included 9 studies with a total of 1669 patients with glioblastomas, and, similar to our results, found that IDH1 mutations were associated with improved OS.	('glioblastomas', 'Phenotype', 'HP:0012174', (81, 94))	('improved', 'PosReg', (172, 180))	('mutations', 'Var', (141, 150))	('patients', 'Species', '9606', (67, 75))	('glioblastomas', 'Disease', 'MESH:D005909', (81, 94))	('IDH1', 'Gene', (136, 140))	('glioblastomas', 'Disease', (81, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('IDH1', 'Gene', '3417', (136, 140))
76297	26945349	Zou et al performed a meta-analysis including 12 studies with a total of 2190 patients, and reported HRs for OS and PFS in patients with IDH mutations were 0.33 (95% CI 0.25-0.42) and 0.38 (95% CI 0.21-0.68), respectively, as compared with glioma patients with the wild-type IDH gene.	('IDH', 'Gene', (275, 278))	('IDH', 'Gene', '3417', (137, 140))	('mutations', 'Var', (141, 150))	('IDH', 'Gene', '3417', (275, 278))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (123, 131))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('patients', 'Species', '9606', (247, 255))	('glioma', 'Disease', (240, 246))	('IDH', 'Gene', (137, 140))
76298	26945349	Subgroup analyses based on tumor grade also showed that the presence of IDH mutations was associated with better outcomes.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (27, 32))	('presence', 'Var', (60, 68))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
76299	26945349	We did not evaluate whether the histological subtype or tumor grade influenced the association of IDH1/2 mutations with the survival outcomes of patients with secondary GBM.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('association', 'Interaction', (83, 94))	('mutations', 'Var', (105, 114))	('IDH1', 'Gene', (98, 102))	('IDH1', 'Gene', '3417', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
76300	26945349	As mentioned above, we also did not evaluate whether the type of treatment regimen influenced the prognostic value of IDH1/2 mutations of patients with secondary GBM.	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (138, 146))	('IDH1', 'Gene', '3417', (118, 122))	('IDH1', 'Gene', (118, 122))
76302	26945349	In summary, the results of this meta-analysis indicate that IDH1/2 mutations are associated with improved survival in patients with glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('glioblastomas', 'Disease', (132, 145))	('IDH1', 'Gene', (60, 64))	('improved', 'PosReg', (97, 105))	('mutations', 'Var', (67, 76))	('IDH1', 'Gene', '3417', (60, 64))	('glioblastomas', 'Phenotype', 'HP:0012174', (132, 145))	('survival', 'MPA', (106, 114))	('patients', 'Species', '9606', (118, 126))	('glioblastomas', 'Disease', 'MESH:D005909', (132, 145))
76349	23922804	With compensatory plasticity, synaptic conductance was increased with connection loss, increasing within the fiber tract from the tumor edge towards the tumor center.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('synaptic conductance', 'MPA', (30, 50))	('increased', 'PosReg', (55, 64))	('connection', 'Var', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('loss', 'NegReg', (81, 85))	('increasing', 'PosReg', (87, 97))	('tumor', 'Disease', (130, 135))
76353	23922804	In the simulation sets with plasticity and variable noise, the noise levels were increased by 25% or 50% at the center of the tumor (but outside the fiber) and linearly decreased to 0% (baseline) at the tumor edge.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('plasticity', 'Var', (28, 38))	('noise levels', 'MPA', (63, 75))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('increased', 'PosReg', (81, 90))	('tumor', 'Disease', (126, 131))
76405	23922804	In other words, micro-environmental and extra-cellular ion concentration changes around the tumor may increase neuronal excitability.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('neuronal', 'CPA', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('increase', 'PosReg', (102, 110))	('tumor', 'Disease', (92, 97))	('changes', 'Var', (73, 80))
76455	21438658	The following 5 diagnostic variables were calculated to determine the diagnostic variable with the best classification efficiency: CPpIX, A615, A660, P635, and P710.	('A615', 'Var', (138, 142))	('A660', 'Var', (144, 148))	('CPpIX', 'Chemical', '-', (131, 136))	('P710', 'Var', (160, 164))	('CPpIX', 'Disease', (131, 136))	('P635', 'Var', (150, 154))
76465	21438658	In fact, CPpIX discriminated abnormal from normal tissue with a mean AUC of 0.95 +- 0.02 compared with mean AUCs of 0.54 +- 0.06, 0.54 +- 0.06, 0.60 +- 0.06, and 0.57 +- 0.06 (+- SE) for A615, A660, P635 and P710, respectively.	('AUC', 'MPA', (69, 72))	('A615', 'Var', (187, 191))	('CPpIX', 'Chemical', '-', (9, 14))	('P710', 'Var', (208, 212))	('CPpIX', 'Gene', (9, 14))	('A660', 'Var', (193, 197))	('P635', 'Var', (199, 203))
76492	21438658	Generalization to N fluorescent biomarkers, each with different spectra, is possible by forming a basis matrix, B = [b1 b2 ... bN], composed of the individual basis spectra for each fluorescent biomarker, and calculating biomarker concentrations, c = [c1 c2 ... cN]T. ALA delta-aminolevulinic acid AUC area under the curve A615 total light intensity associated with the integration of the fluorescence emission spectrum from lambda = 615 to 740 nm A660 total light intensity associated with the integration of the fluorescence emission spectrum from lambda = 660 to 740 nm CPpIX absolute concentration of PpIX HGG high-grade glioma LGG low-grade glioma NPV negative predictive value PpIX protoporphyrin IX PPV positive predictive value P635 peak intensity of the fluorescence emission spectrum at lambda = 635 nm P710 peak intensity of the fluorescence emission spectrum at lambda = 710 nm ROC receiver operating characteristic	('CPpIX', 'Chemical', '-', (573, 578))	('LGG low', 'Phenotype', 'HP:0004315', (632, 639))	('ALA', 'Chemical', 'MESH:D000622', (268, 271))	('P635', 'Var', (736, 740))	('glioma', 'Disease', 'MESH:D005910', (646, 652))	('HGG high', 'Phenotype', 'HP:0003237', (610, 618))	('glioma', 'Phenotype', 'HP:0009733', (646, 652))	('glioma', 'Disease', 'MESH:D005910', (625, 631))	('PpIX', 'Chemical', 'MESH:C028025', (683, 687))	('protoporphyrin IX', 'Chemical', 'MESH:C028025', (688, 705))	('glioma', 'Phenotype', 'HP:0009733', (625, 631))	('PpIX', 'Chemical', 'MESH:C028025', (574, 578))	('PpIX', 'Chemical', 'MESH:C028025', (605, 609))	('glioma', 'Disease', (646, 652))	('glioma', 'Disease', (625, 631))	('delta-aminolevulinic acid', 'Chemical', 'MESH:D000622', (272, 297))
76494	33926464	In this study, the role of long non-coding RNAs in association with the poor-prognosis G-CMIP-low phenotype and the good-prognosis G-CMIP-high phenotype was investigated.	('CMIP', 'Gene', '80790', (89, 93))	('CMIP', 'Gene', (89, 93))	('CMIP', 'Gene', '80790', (133, 137))	('long non-coding RNAs', 'Var', (27, 47))	('CMIP', 'Gene', (133, 137))
76496	33926464	RNA-seq data on 250 samples from TCGA's Pan-Glioma study, quantified for lncRNA and mRNAs (GENCODE v28), were analyzed for differential expression between G-CIMP-low and G-CIMP-high phenotypes.	('G-CIMP', 'Chemical', '-', (155, 161))	('Glioma', 'Disease', 'MESH:D005910', (44, 50))	('Glioma', 'Phenotype', 'HP:0009733', (44, 50))	('Glioma', 'Disease', (44, 50))	('G-CIMP', 'Chemical', '-', (170, 176))	('G-CIMP-low', 'Var', (155, 165))
76506	33926464	Recently, the World Health Organization (WHO) added the presence of one of the recurrent point mutations in the isocitrate dehydrogenase genes (IDH1 or IDH2) and co-deletion of chromosomal arms 1p/19q to the glioma diagnosis criteria.	('IDH', 'Gene', (144, 147))	('glioma', 'Disease', (208, 214))	('IDH', 'Gene', '3417', (144, 147))	('point mutations', 'Var', (89, 104))	('co-deletion', 'Var', (162, 173))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', '3417', (152, 155))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))
76513	33926464	This IDH-mutant G-CIMP positive subtype has now been further refined into two distinct subgroups, G-CIMP-low (10% of IDH-mutant, 1p/19q intact tumor) and G-CIMP-high (90% of IDH-mutant, 1p/19q intact tumors), with 'low' and 'high' designations determined by a low or high degree of DNA methylation, respectively.	('G-CIMP', 'Chemical', '-', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('IDH', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (200, 205))	('1p/19q', 'Var', (186, 192))	('IDH', 'Gene', '3417', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('IDH', 'Gene', (117, 120))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('G-CIMP', 'Chemical', '-', (154, 160))	('IDH', 'Gene', (5, 8))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('IDH', 'Gene', '3417', (117, 120))	('tumors', 'Disease', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('G-CIMP', 'Chemical', '-', (98, 104))	('IDH', 'Gene', '3417', (5, 8))
76541	33926464	The distribution of the influence of miRNA on the lncRNA:mRNA correlation, specifically Sz = rx,y:rx,y z, is plotted in Additional file 1: Fig S1.	('miR', 'Gene', '22877', (37, 40))	('miR', 'Gene', (37, 40))	('y:rx', 'Var', (96, 100))
76550	33926464	Mutation of TP53 is associated with a variety of human cancers including gliomas, and is found in 94 percent of IDH mutant, 1p/19q non-codeleted, glioma.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('IDH', 'Gene', (112, 115))	('glioma', 'Disease', (146, 152))	('human', 'Species', '9606', (49, 54))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('found', 'Reg', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('TP53', 'Gene', (12, 16))	('IDH', 'Gene', '3417', (112, 115))	('cancers', 'Disease', (55, 62))	('gliomas', 'Disease', (73, 80))	('associated', 'Reg', (20, 30))	('glioma', 'Disease', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('Mutation', 'Var', (0, 8))	('TP53', 'Gene', '7157', (12, 16))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))
76551	33926464	High expression of PVT1, a long non-coding RNA located at chromosome 8a24.21, has been associated with several mutations of TP53 in diffuse glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('mutations', 'Var', (111, 120))	('PVT1', 'Gene', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('TP53', 'Gene', '7157', (124, 128))	('PVT1', 'Gene', '5820', (19, 23))	('TP53', 'Gene', (124, 128))	('associated', 'Reg', (87, 97))	('glioma', 'Disease', (140, 146))
76555	33926464	The role of MYC in glioma has been well established, both in vivo and in vitro, such that MYC inhibition suppresses glioma formation, restricts glioma cell proliferation and improves survival.	('restricts', 'NegReg', (134, 143))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('suppresses', 'NegReg', (105, 115))	('MYC', 'Gene', (90, 93))	('improves', 'PosReg', (174, 182))	('glioma', 'Disease', (116, 122))	('glioma', 'Disease', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('MYC', 'Gene', (12, 15))	('glioma', 'Disease', (144, 150))	('survival', 'CPA', (183, 191))	('MYC', 'Gene', '4609', (90, 93))	('inhibition', 'Var', (94, 104))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('MYC', 'Gene', '4609', (12, 15))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
76557	33926464	PANDAR is a promoter of CDKN1A antisense DNA damage activated RNA and increased expression of PANDAR has been indicated to predict poor prognosis in cervical and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('increased', 'PosReg', (70, 79))	('PANDAR', 'Gene', '101154753', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('PANDAR', 'Gene', (0, 6))	('PANDAR', 'Gene', '101154753', (94, 100))	('CDKN1A', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cervical', 'Disease', (149, 157))	('CDKN1A', 'Gene', '1026', (24, 30))	('expression', 'MPA', (80, 90))	('activated', 'PosReg', (52, 61))	('PANDAR', 'Gene', (94, 100))	('antisense', 'Var', (31, 40))	('gastric cancer', 'Disease', (162, 176))	('RNA', 'MPA', (62, 65))
76558	33926464	Recently, a study published showed CDKN2A, a gene which belongs to same family as CDKN1A, often deleted in G-CIMP-low tumors as compared to G-CIMP-high.	('G-CIMP', 'Chemical', '-', (107, 113))	('deleted', 'NegReg', (96, 103))	('CDKN2A', 'Gene', '1029', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CDKN1A', 'Gene', (82, 88))	('G-CIMP', 'Chemical', '-', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('CDKN1A', 'Gene', '1026', (82, 88))	('tumors', 'Disease', (118, 124))	('G-CIMP-low', 'Var', (107, 117))	('CDKN2A', 'Gene', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
76560	33926464	Cell death is one of the primary mechanisms studied in cancer as disruption of this process can facilitate tumorigenesis, promote proliferation, and lead to resistance to anticancer therapy.	('death', 'Disease', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('facilitate', 'PosReg', (96, 106))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('promote', 'PosReg', (122, 129))	('disruption', 'Var', (65, 75))	('proliferation', 'CPA', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('lead to', 'Reg', (149, 156))	('cancer', 'Disease', (55, 61))	('death', 'Disease', 'MESH:D003643', (5, 10))
76564	33926464	Several studies during recent years reported dysregulated NOTCH signaling activity (NOTCH 1-4) in human brain tumors.	('dysregulated', 'Var', (45, 57))	('brain tumors', 'Phenotype', 'HP:0030692', (104, 116))	('NOTCH 1-4', 'Gene', (84, 93))	('NOTCH 1-4', 'Gene', '4851;4853;4854;4855', (84, 93))	('NOTCH', 'Gene', (84, 89))	('NOTCH', 'Gene', '4851;4853;4854;4855', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('NOTCH', 'Gene', '4851;4853;4854;4855', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (98, 103))	('brain tumors', 'Disease', 'MESH:D001932', (104, 116))	('NOTCH', 'Gene', (58, 63))	('brain tumors', 'Disease', (104, 116))
76569	33926464	The increased expression of PVT1, CYTOR, FOXD2-AS1, and CRNDE were seen in various cancers, similarly these lncRNAs were all up-regulated in G-CIMP-low suggesting their more oncogenic activity leads to poor prognosis compared to G-CIMP-high.	('CYTOR', 'Gene', '112597', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('AS1', 'Gene', (47, 50))	('FOXD2', 'Gene', (41, 46))	('G-CIMP-low', 'Var', (141, 151))	('increased', 'PosReg', (4, 13))	('G-CIMP', 'Chemical', '-', (141, 147))	('up-regulated', 'PosReg', (125, 137))	('G-CIMP', 'Chemical', '-', (229, 235))	('oncogenic activity', 'CPA', (174, 192))	('CRNDE', 'Gene', '643911', (56, 61))	('CRNDE', 'Gene', (56, 61))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('CYTOR', 'Gene', (34, 39))	('PVT1', 'Gene', (28, 32))	('AS1', 'Gene', '5729', (47, 50))	('PVT1', 'Gene', '5820', (28, 32))	('FOXD2', 'Gene', '2306', (41, 46))	('expression', 'MPA', (14, 24))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
76576	33926464	MiR-4425 is up-regulated in glioma tissues and a high expression of miR-4425 is associated with an unfavorable prognosis in glioma.	('miR-4425', 'Gene', '100616365', (68, 76))	('glioma', 'Disease', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('up-regulated', 'PosReg', (12, 24))	('glioma', 'Disease', (28, 34))	('miR-4425', 'Gene', (68, 76))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('associated with', 'Reg', (80, 95))	('high', 'Var', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('MiR-4425', 'Gene', '100616365', (0, 8))	('MiR-4425', 'Gene', (0, 8))
76578	33926464	LncRNA PART-1 has been shown to have oncogenic activity in colorectal cancer, but was identified as positively associated with GBM prognosis, such that decreased PART-1 predicted decreased survival time.	('decreased', 'NegReg', (179, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('PART-1', 'Gene', (162, 168))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('associated', 'Reg', (111, 121))	('survival time', 'CPA', (189, 202))	('colorectal cancer', 'Disease', (59, 76))	('LncRNA PART-1', 'Gene', (0, 13))	('oncogenic activity', 'MPA', (37, 55))	('decreased', 'Var', (152, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))
76601	33926464	Data had been aligned and quantified by Broad, reporting log2 reads per million (RPM) for 2588 miRNAs.	('log2 reads', 'Var', (57, 67))	('miR', 'Gene', (95, 98))	('miR', 'Gene', '22877', (95, 98))
76605	33926464	Then a lncRNA was nominated as having a sponge function in the lncRNA:miRNA:mRNA trio if Sz = rx,y:rx,y z was high; here we use Sz > 0.2.	('miR', 'Gene', (70, 73))	('miR', 'Gene', '22877', (70, 73))	('Sz = rx', 'Var', (89, 96))
76607	32220051	MicroRNA-155-3p promotes glioma progression and temozolomide resistance by targeting Six1 The prognosis of glioma is generally poor and is the cause of primary malignancy in the brain.	('malignancy', 'Disease', (160, 170))	('promotes', 'PosReg', (16, 24))	('Six1', 'Gene', (85, 89))	('targeting', 'Var', (75, 84))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('MicroRNA-155-3p', 'Var', (0, 15))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('temozolomide', 'Chemical', 'MESH:D000077204', (48, 60))	('glioma', 'Disease', (25, 31))	('malignancy in the brain', 'Phenotype', 'HP:0030692', (160, 183))	('glioma', 'Disease', (107, 113))
76612	32220051	Bioinformatics analyses, and assays using luciferase reporter, and immunoblotting revealed that miR-155-3p targets Six1 and that the relationship between glioma and healthy brain tissues was significantly inverse.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('targets', 'Reg', (107, 114))	('miR-155-3p', 'Chemical', '-', (96, 106))	('glioma', 'Disease', (154, 160))	('Six1', 'Gene', (115, 119))	('miR-155-3p', 'Var', (96, 106))
76613	32220051	In rescue experiments, overexpressed Six1 revoked the changes in cell cycle distribution, proliferation and resistance to temozolomide estimated by apoptosis induced by overexpressed miR-155-3p.	('miR-155-3p', 'Var', (183, 193))	('temozolomide', 'Chemical', 'MESH:D000077204', (122, 134))	('proliferation', 'CPA', (90, 103))	('cell cycle', 'CPA', (65, 75))	('resistance to temozolomide', 'MPA', (108, 134))	('miR-155-3p', 'Chemical', '-', (183, 193))
76615	32220051	Thus, miR-155-3p modulates Six1 expression and facilitates the progression of glioblastoma and resistance to temozolomide and may act as a novel diagnostic biomarker and a target for glioma treatment.	('temozolomide', 'Chemical', 'MESH:D000077204', (109, 121))	('glioblastoma', 'Disease', (78, 90))	('facilitates', 'PosReg', (47, 58))	('modulates', 'Reg', (17, 26))	('glioma', 'Disease', (183, 189))	('Six1', 'Gene', (27, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('miR-155-3p', 'Chemical', '-', (6, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('miR-155-3p', 'Var', (6, 16))	('progression', 'CPA', (63, 74))	('expression', 'MPA', (32, 42))	('resistance to temozolomide', 'MPA', (95, 121))
76624	32220051	14 ,  15 ,  16  More than half of the known miRNAs participate in tumorigenesis by targeting tumour suppressor genes or oncogenes directly.	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('oncogenes', 'Gene', (120, 129))	('targeting', 'Reg', (83, 92))	('miRNAs', 'Var', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumorigenesis', 'CPA', (66, 79))	('participate', 'Reg', (51, 62))
76625	32220051	14 ,  17  Previous studies have shown that miRNAs play a key role in glioma, such as miR-30a decrease tumorigenicity of glioma stem cells by targeting NT5E-dependent AKT pathway 18 ; miR-1254 inhibits glioma progression by targeting CSF-1 19 ; and miR-769-3p inhibits glioma tumour progression by suppressing ZEB2 and regulating Wnt signalling pathway.	('glioma', 'Disease', (69, 75))	('glioma', 'Disease', (268, 274))	('miR-30a', 'Gene', (85, 92))	('NT5E', 'Gene', '4907', (151, 155))	('glioma tumour', 'Disease', 'MESH:D005910', (268, 281))	('ZEB2', 'Gene', '9839', (309, 313))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('AKT', 'Gene', (166, 169))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('glioma', 'Disease', 'MESH:D005910', (268, 274))	('decrease', 'NegReg', (93, 101))	('suppressing', 'NegReg', (297, 308))	('glioma', 'Disease', (201, 207))	('miR-1254', 'Gene', '100302273', (183, 191))	('inhibits', 'NegReg', (259, 267))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('glioma', 'Disease', (120, 126))	('NT5E', 'Gene', (151, 155))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('CSF-1', 'Gene', (233, 238))	('miR-1254', 'Gene', (183, 191))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('AKT', 'Gene', '207', (166, 169))	('miR-30a', 'Gene', '407029', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('glioma tumour', 'Disease', (268, 281))	('inhibits', 'NegReg', (192, 200))	('miR-769-3p', 'Var', (248, 258))	('regulating', 'Reg', (318, 328))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Wnt signalling pathway', 'Pathway', (329, 351))	('miR-769-3p', 'Chemical', '-', (248, 258))	('targeting', 'Reg', (141, 150))	('ZEB2', 'Gene', (309, 313))
76629	32220051	23 ,  24   In this study, we showed an increase in the oncogenic capacity of miR-155-3p in clinical samples of glioma and correlated with the grades defined by WHO.	('glioma', 'Disease', (111, 117))	('miR-155-3p', 'Var', (77, 87))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('increase', 'PosReg', (39, 47))	('oncogenic capacity', 'MPA', (55, 73))	('miR-155-3p', 'Chemical', '-', (77, 87))
76630	32220051	Further, we found that Six1 is targeted directly by miR-155-3p and in an inverse relationship in glioma.	('glioma', 'Disease', (97, 103))	('miR-155-3p', 'Chemical', '-', (52, 62))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('miR-155-3p', 'Var', (52, 62))
76632	32220051	Our findings implicate miR-155-3p as an important biomolecule in the treatment of glioma.	('miR-155-3p', 'Chemical', '-', (23, 33))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('miR-155-3p', 'Var', (23, 33))	('glioma', 'Disease', (82, 88))
76646	32220051	The anti-miR155-3p or anti-miR-con (negative control, anti-miR) harbouring lentivirus was packaged in 293T cells (human embryonic kidney cells) using the Genechem lentiviral packaging kit for two full days and harvested as per instructions.	('293T', 'CellLine', 'CVCL:0063', (102, 106))	('embryonic kidney', 'Disease', 'MESH:D007674', (120, 136))	('kit', 'Gene', '3815', (184, 187))	('miR155', 'Gene', (9, 15))	('miR155', 'Gene', '406947', (9, 15))	('miR-con', 'Chemical', '-', (27, 34))	('kit', 'Gene', (184, 187))	('human', 'Species', '9606', (114, 119))	('anti-miR-con', 'Var', (22, 34))	('embryonic kidney', 'Disease', (120, 136))
76655	32220051	The primary antibodies used are listed as follows: cleaved caspase 3 (#9661, Cell Signaling Technology), beta-actin (A5441, Sigma), Six1 (ab211359, Abcam), p21 (ab109520, Abcam), Bcl-2 (ab32124, Abcam) and bax (ab32503, Abcam).	('beta-actin', 'Protein', (105, 115))	('bax', 'Gene', (206, 209))	('ab32124', 'Var', (186, 193))	('ab211359', 'Var', (138, 146))	('p21', 'Gene', (156, 159))	('bax', 'Gene', '581', (206, 209))	('p21', 'Gene', '644914', (156, 159))	('A5441', 'Var', (117, 122))	('Bcl-2', 'Gene', (179, 184))	('Bcl-2', 'Gene', '596', (179, 184))
76663	32220051	PCR amplification of seed-matching sites of mutated putative miR-155-3p and wild-type (WT) in Six1 3'-UTR (untranslated regions) was done using human cDNA and cloned using restriction enzyme Hind III and Sac I at their sites in the Report vector for pmiRNA from Genechem.	('miR-155-3p', 'Gene', (61, 71))	('human', 'Species', '9606', (144, 149))	('miR-155-3p', 'Chemical', '-', (61, 71))	('mutated', 'Var', (44, 51))
76666	32220051	To carry out xenograft studies, glioma cells (stably expressing 2 x 105 cells) intracranial injection of anti-miR-con or anti-miR-155-3p were done in the 4- to 6-week-old female SCID/NOD mice.	('miR-155-3p', 'Chemical', '-', (126, 136))	('glioma', 'Disease', (32, 38))	('mice', 'Species', '10090', (187, 191))	('anti-miR-con', 'Var', (105, 117))	('SCID', 'Disease', 'MESH:D053632', (178, 182))	('miR-con', 'Chemical', '-', (110, 117))	('anti-miR-155-3p', 'Var', (121, 136))	('SCID', 'Disease', (178, 182))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
76678	32220051	Clinical glioma and glioma tissues were analysed by the Kaplan-Meier survival curve using the CGGA database and found that higher expression of miR-155-3p (greater than the medium value) correlated with the decline in survival compared to those who contributed samples with low miR-155-3p levels, as presented in Figure 1C.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('expression', 'MPA', (130, 140))	('glioma', 'Disease', (9, 15))	('miR-155-3p', 'Chemical', '-', (144, 154))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('miR-155-3p', 'Chemical', '-', (278, 288))	('higher', 'PosReg', (123, 129))	('miR-155-3p', 'Var', (144, 154))	('survival', 'MPA', (218, 226))	('decline', 'NegReg', (207, 214))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('glioma', 'Disease', (20, 26))
76680	32220051	Our findings indicate that miR-155-3p increase in glioma and relative to poor survival.	('increase', 'PosReg', (38, 46))	('miR-155-3p', 'Chemical', '-', (27, 37))	('glioma', 'Disease', (50, 56))	('miR-155-3p', 'Var', (27, 37))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
76684	32220051	The anti-miR-155-3p transfected U87 and A172 cells exhibited a lower EDU-positive rate than the control group (Figure 2F), indicating suppression of glioma cell proliferation on inhibiting miR-155-3p.	('glioma', 'Disease', (149, 155))	('lower', 'NegReg', (63, 68))	('inhibiting', 'NegReg', (178, 188))	('EDU-positive rate', 'CPA', (69, 86))	('miR-155-3p', 'Protein', (189, 199))	('EDU', 'Chemical', '-', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('miR-155-3p', 'Chemical', '-', (189, 199))	('miR-155-3p', 'Chemical', '-', (9, 19))	('suppression', 'NegReg', (134, 145))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('anti-miR-155-3p', 'Var', (4, 19))
76686	32220051	The results of flow cytometry evaluation revealed that miR-155-3p knock-down enhanced the rate of apoptosis, induced cell arrest at the G1/S phase and reduced the percentage of S-phase cells (Figure 2H,I).	('enhanced', 'PosReg', (77, 85))	('apoptosis', 'CPA', (98, 107))	('reduced', 'NegReg', (151, 158))	('miR-155-3p knock-down', 'Var', (55, 76))	('induced', 'Reg', (109, 116))	('cell arrest', 'Disease', (117, 128))	('miR-155-3p', 'Chemical', '-', (55, 65))	('knock-down', 'Var', (66, 76))	('cell arrest', 'Disease', 'MESH:D006323', (117, 128))
76687	32220051	MiR-155-3p inhibition as a result of chemotherapy was explored, after transiently transfecting anti-miR-155-3p or anti-miR-con into A172/TMZ resistance (TMZ-R) and U87/TMZ-resistant cells.	('miR-con', 'Chemical', '-', (119, 126))	('anti-miR-con', 'Var', (114, 126))	('anti-miR-155-3p', 'Var', (95, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (153, 156))	('miR-155-3p', 'Chemical', '-', (100, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (137, 140))	('TMZ', 'Chemical', 'MESH:D000077204', (168, 171))	('MiR-155-3p', 'Chemical', '-', (0, 10))
76690	32220051	A significant increase in chemosensitivity to TMZ was observed after knock-down of miR-155-3p in A172/TR and U87/TR, with a remarkably suppressed cell viability, exhibiting an inverse relationship with TMZ concentrations relative to the observations in miR-con group (Figure 3B,C).	('chemosensitivity to TMZ', 'MPA', (26, 49))	('miR-con', 'Chemical', '-', (253, 260))	('TMZ', 'Chemical', 'MESH:D000077204', (46, 49))	('miR-155-3p', 'Chemical', '-', (83, 93))	('knock-down', 'Var', (69, 79))	('cell viability', 'CPA', (146, 160))	('suppressed', 'NegReg', (135, 145))	('TMZ', 'Chemical', 'MESH:D000077204', (202, 205))	('miR-155-3p', 'Var', (83, 93))	('increase', 'PosReg', (14, 22))
76691	32220051	Similar results were observed on cell proliferation by evaluating the effect of miR-155-3p along with TMZ by EDU cell image and colony formation assays (Figure 3D-F).	('miR-155-3p', 'Var', (80, 90))	('miR-155-3p', 'Chemical', '-', (80, 90))	('TMZ', 'Chemical', 'MESH:D000077204', (102, 105))	('cell proliferation', 'CPA', (33, 51))	('EDU', 'Chemical', '-', (109, 112))
76692	32220051	Our findings also shown that miR-155-3p inhibitor enhances TMZ-induced apoptosis in the TMZ resistance cells (Figure 3G, H).	('enhances', 'PosReg', (50, 58))	('TMZ', 'Chemical', 'MESH:D000077204', (88, 91))	('miR-155-3p inhibitor', 'Var', (29, 49))	('miR-155-3p', 'Chemical', '-', (29, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
76694	32220051	Nearly 80% reduction in relative luciferase activity of WT-Six1 by miR-155-3p mimics was observed, whereas minimal inhibition was observed in cells transfected Mut-Six1 luciferase reported (Figure 4B,C) implicating that Six1 is targeted directly by miR-155-3p.	('reduction', 'NegReg', (11, 20))	('miR-155-3p', 'Chemical', '-', (249, 259))	('luciferase', 'Enzyme', (33, 43))	('miR-155-3p mimics', 'Var', (67, 84))	('activity', 'MPA', (44, 52))	('miR-155-3p', 'Chemical', '-', (67, 77))
76695	32220051	We further observed that miR-155-3p knock-down in both A172 and U87 glioma cells increased endogenous Six1 levels and its downstream proteins, but no notable change was observed in the transcript levels (Figure 4D), thus indicating the inhibition of Six1 by miR-155-3p at the translational and not transcription level.	('knock-down', 'Var', (36, 46))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('miR-155-3p', 'Chemical', '-', (258, 268))	('inhibition', 'NegReg', (236, 246))	('miR-155-3p', 'Chemical', '-', (25, 35))	('endogenous Six1 levels', 'MPA', (91, 113))	('proteins', 'MPA', (133, 141))	('glioma', 'Disease', (68, 74))	('increased', 'PosReg', (81, 90))	('miR-155-3p', 'Gene', (25, 35))
76701	32220051	As shown in Figure 5B-H, the activities of miR-155-3p on cell cycle distribution and cell proliferation were inhibited by overexpressing Six1.	('Six1', 'Gene', (137, 141))	('cell proliferation', 'CPA', (85, 103))	('miR-155-3p', 'Var', (43, 53))	('cell cycle distribution', 'CPA', (57, 80))	('inhibited', 'NegReg', (109, 118))	('activities', 'MPA', (29, 39))	('overexpressing', 'PosReg', (122, 136))	('miR-155-3p', 'Chemical', '-', (43, 53))
76703	32220051	A reduction in BAX and p21 expression was rescued by abnormal Six1 expression and rescued miR-155-3p mimic-induced enhanced BAX and p21 levels in both A172 and U87 cells (Figure 5I-J).	('p21', 'Gene', '644914', (23, 26))	('p21', 'Gene', (132, 135))	('Six1', 'Gene', (62, 66))	('BAX', 'Gene', (124, 127))	('enhanced', 'PosReg', (115, 123))	('miR-155-3p', 'Chemical', '-', (90, 100))	('abnormal', 'Var', (53, 61))	('BAX', 'Gene', '581', (124, 127))	('p21', 'Gene', '644914', (132, 135))	('p21', 'Gene', (23, 26))	('miR-155-3p mimic-induced', 'Gene', (90, 114))	('BAX', 'Gene', '581', (15, 18))	('BAX', 'Gene', (15, 18))
76704	32220051	Thus, the function of Six1 is targeted by miR-155-3p in glioma cells.	('glioma', 'Disease', (56, 62))	('miR-155-3p', 'Chemical', '-', (42, 52))	('function', 'MPA', (10, 18))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('miR-155-3p', 'Var', (42, 52))	('targeted', 'Reg', (30, 38))	('Six1', 'Gene', (22, 26))
76706	32220051	MiR-155-3p-mediated stimulation of proliferative capacity and apoptotic inhibition was repressed by overexpressing Six1 in the medium containing TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (145, 148))	('apoptotic inhibition', 'CPA', (62, 82))	('stimulation', 'PosReg', (20, 31))	('MiR-155-3p', 'Chemical', '-', (0, 10))	('MiR-155-3p-mediated', 'Var', (0, 19))	('proliferative capacity', 'CPA', (35, 57))
76709	32220051	Further, in an in vivo experiment on the U87 xenograft mice model (6 mice/group), the introduction of xenografted tumours was done by U87 glioma cells either with anti-miR-con or with anti-miR-155-3p, in the presence or absence of TMZ.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumours', 'Disease', (114, 121))	('glioma', 'Disease', (138, 144))	('anti-miR-155-3p', 'Var', (184, 199))	('anti-miR-con', 'Var', (163, 175))	('mice', 'Species', '10090', (55, 59))	('TMZ', 'Chemical', 'MESH:D000077204', (231, 234))	('miR-155-3p', 'Chemical', '-', (189, 199))	('miR-con', 'Chemical', '-', (168, 175))	('mice', 'Species', '10090', (69, 73))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))
76710	32220051	The anti-miR-155-3p group exhibited a significant intracranial tumour volume reduction in comparison with the anti-miR-con group in these models (Figure 7A,B).	('intracranial tumour', 'Disease', 'MESH:D001932', (50, 69))	('reduction', 'NegReg', (77, 86))	('intracranial tumour', 'Disease', (50, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('miR-155-3p', 'Chemical', '-', (9, 19))	('anti-miR-155-3p', 'Var', (4, 19))	('miR-con', 'Chemical', '-', (115, 122))
76711	32220051	Anti-miR-155-3p sensitized U87 tumour to TMZ (Figure 7A,B).	('miR-155-3p', 'Chemical', '-', (5, 15))	('Anti-miR-155-3p', 'Var', (0, 15))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('sensitized', 'Reg', (16, 26))	('TMZ', 'Chemical', 'MESH:D000077204', (41, 44))	('tumour', 'Disease', (31, 37))
76712	32220051	Consistent with in vitro results, Western blotting and immunohistochemistry revealed enhanced expression of Six1 in anti-miR-155-3p tumours (Figure 7D,E).	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumours', 'Disease', (132, 139))	('enhanced', 'PosReg', (85, 93))	('Six1', 'Gene', (108, 112))	('miR-155-3p', 'Chemical', '-', (121, 131))	('anti-miR-155-3p', 'Var', (116, 131))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (94, 104))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))
76713	32220051	Thus, miR-155-3p activates the growth of glioma cells and increases the sensitivity of tumours to TMZ in vivo.	('increases', 'PosReg', (58, 67))	('tumours', 'Disease', (87, 94))	('growth', 'CPA', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('miR-155-3p', 'Chemical', '-', (6, 16))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('miR-155-3p', 'Var', (6, 16))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('glioma', 'Disease', (41, 47))	('activates', 'PosReg', (17, 26))
76719	32220051	37  Further, miR-155 knock-down clearly reduced viability and promoted apoptosis of breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('apoptosis', 'CPA', (71, 80))	('knock-down', 'Var', (21, 31))	('miR-155', 'Gene', (13, 20))	('viability', 'CPA', (48, 57))	('reduced', 'NegReg', (40, 47))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('promoted', 'PosReg', (62, 70))	('breast cancer', 'Disease', (84, 97))
76720	32220051	38 ,  39  Likewise, in this study, we found increased miR-155-3p in a higher grade glioblastoma and its knock-down in glioblastoma cells stalled proliferation, induced apoptosis, led to arrest of the cell cycle and resistance to TMZ.	('miR-155-3p', 'Chemical', '-', (54, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('arrest', 'Disease', 'MESH:D006323', (186, 192))	('induced', 'Reg', (160, 167))	('TMZ', 'Chemical', 'MESH:D000077204', (229, 232))	('miR-155-3p', 'Var', (54, 64))	('stalled', 'NegReg', (137, 144))	('proliferation', 'CPA', (145, 158))	('arrest', 'Disease', (186, 192))	('resistance to TMZ', 'CPA', (215, 232))	('apoptosis', 'CPA', (168, 177))	('glioblastoma', 'Disease', (83, 95))	('knock-down', 'Var', (104, 114))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
76722	32220051	We could also show that miR-155-3p overexpression in glioma cells caused decrease in Bax and p21 and expression by directly targeting the Six1 3'-UTR.	('glioma', 'Disease', (53, 59))	('miR-155-3p', 'Chemical', '-', (24, 34))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('p21', 'Gene', (93, 96))	('Bax', 'Gene', (85, 88))	('p21', 'Gene', '644914', (93, 96))	('decrease', 'NegReg', (73, 81))	('miR-155-3p', 'Var', (24, 34))	('overexpression', 'PosReg', (35, 49))	('expression', 'MPA', (101, 111))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('Bax', 'Gene', '581', (85, 88))
76723	32220051	40  Mouse embryos with Six1-/- exhibit defects in the survival of the precursor cells of multiple organs as well as in proliferation and, ultimately, die during birth.	('Six1-/-', 'Var', (23, 30))	('defects', 'NegReg', (39, 46))	('survival of the precursor cells of multiple organs', 'CPA', (54, 104))	('Mouse', 'Species', '10090', (4, 9))	('proliferation', 'CPA', (119, 132))
76731	32220051	Our results show therefore the tumour-promoting activity of miR-155-3p through various mechanisms, including apoptotic inhibition, tumour cell growth promotion and initiation of cell cycle arrest.	('apoptotic inhibition', 'CPA', (109, 129))	('tumour', 'Disease', (131, 137))	('miR-155-3p', 'Chemical', '-', (60, 70))	('arrest', 'Disease', 'MESH:D006323', (189, 195))	('arrest', 'Disease', (189, 195))	('miR-155-3p', 'Var', (60, 70))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (178, 195))	('tumour', 'Disease', (31, 37))
76732	32220051	While the Six1 level decreased in U87 and A172 cells with miR-155-3p transfection.	('miR-155-3p transfection', 'Var', (58, 81))	('Six1 level', 'MPA', (10, 20))	('miR-155-3p', 'Chemical', '-', (58, 68))	('decreased', 'NegReg', (21, 30))
76733	32220051	While U87 and A172 cells are Six1 mutation cell lines and cell lines U87 and A172 were of Six1 wild-type, MiR-155-3p decreased expression of Six1 in U87 and A172 cells could not efficiently promote U87 and A172 cells growth.	('expression', 'MPA', (127, 137))	('MiR-155-3p', 'Chemical', '-', (106, 116))	('decreased', 'NegReg', (117, 126))	('MiR-155-3p', 'Var', (106, 116))
76734	32220051	Here, miR-155-3p knock-down enhanced TMZ sensitivity in human glioma cells and induced apoptosis in glioma cells.	('glioma', 'Disease', (100, 106))	('miR-155-3p knock-down', 'Var', (6, 27))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('enhanced', 'PosReg', (28, 36))	('miR-155-3p', 'Chemical', '-', (6, 16))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('human', 'Species', '9606', (56, 61))	('TMZ', 'Chemical', 'MESH:D000077204', (37, 40))	('induced', 'Reg', (79, 86))	('TMZ sensitivity', 'MPA', (37, 52))	('glioma', 'Disease', (62, 68))
76737	32220051	Thus, we hypothesize that the anti-miR-155-3p and TMZ combination could be a promising treatment strategy to suppress glioma growth.	('glioma', 'Disease', (118, 124))	('suppress', 'NegReg', (109, 117))	('anti-miR-155-3p', 'Var', (30, 45))	('miR-155-3p', 'Chemical', '-', (35, 45))	('TMZ', 'Chemical', 'MESH:D000077204', (50, 53))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
76738	32220051	In conclusion, our current study provides significant insights into tumorigenesis and miR-155-3p relationship in human glioma.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('miR-155-3p', 'Chemical', '-', (86, 96))	('glioma', 'Disease', (119, 125))	('miR-155-3p', 'Var', (86, 96))	('human', 'Species', '9606', (113, 118))
76739	32220051	We could show that miR-155-3p acts as a promoter of tumours by targeting Six1 and inhibiting Six1-associated pathways.	('inhibiting', 'NegReg', (82, 92))	('tumours', 'Disease', (52, 59))	('miR-155-3p', 'Var', (19, 29))	('Six1', 'Protein', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('targeting', 'Reg', (63, 72))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('Six1-associated pathways', 'Pathway', (93, 117))	('miR-155-3p', 'Chemical', '-', (19, 29))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
76740	32220051	Interestingly, we found that the glioma cell resistance to TMZ treatment is enhanced by miR-155-3p treatment.	('miR-155-3p', 'Var', (88, 98))	('glioma', 'Disease', (33, 39))	('enhanced', 'PosReg', (76, 84))	('miR-155-3p', 'Chemical', '-', (88, 98))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
76741	32220051	Despite being in preliminary stages of development, miRNA-based therapeutics are promising, and our findings give a potential indication of the role of miR-155-3p as potential prognostic/diagnostic marker and a possible target for glioma treatment.	('miR-155-3p', 'Var', (152, 162))	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('glioma', 'Disease', (231, 237))	('miR-155-3p', 'Chemical', '-', (152, 162))	('glioma', 'Disease', 'MESH:D005910', (231, 237))
76756	28283800	In GBM cell lines, celecoxib induced apoptosis and inhibited cell proliferation and angiogenesis.	('angiogenesis', 'CPA', (84, 96))	('celecoxib', 'Var', (19, 28))	('apoptosis', 'CPA', (37, 46))	('celecoxib', 'Chemical', 'MESH:C105934', (19, 28))	('inhibited', 'NegReg', (51, 60))	('cell proliferation', 'CPA', (61, 79))
76769	28283800	Human glioma- and GBM cell lines (1321N1, SW1088, U87MG, U251MG, and NHA) were purchased from the European Collection of Cell Cultures (Salisbury, Wiltshire, UK), American Type Culture Collection (Manassas, VA, USA), the Health Science Research Resources Bank (Osaka, Japan), and Lonza Japan Co. (Tokyo, Japan).	('1321N1', 'Var', (34, 40))	('Human', 'Species', '9606', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('U87MG', 'Var', (50, 55))	('glioma', 'Disease', (6, 12))	('U251MG', 'Var', (57, 63))
76792	28283800	The expression of COX-2 protein in glioma cell lines (1321N1, SW1088, U87MG, U251MG) was higher than in NHA; its expression also increased with the glioma grade (Fig.	('U87MG', 'Var', (70, 75))	('expression', 'MPA', (113, 123))	('COX-2', 'Gene', '5743', (18, 23))	('protein', 'Protein', (24, 31))	('glioma', 'Disease', (148, 154))	('expression', 'MPA', (4, 14))	('increased', 'PosReg', (129, 138))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('higher', 'PosReg', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('1321N1', 'Var', (54, 60))	('COX-2', 'Gene', (18, 23))	('glioma', 'Disease', (35, 41))
76808	28283800	The expression of Akt2 protein, Akt2 and Akt phosphorylation, survivin expression were lower in both cell lines treated with celecoxib than celecoxib-untreated controls (Fig.	('expression', 'MPA', (71, 81))	('survivin', 'Protein', (62, 70))	('Akt', 'Gene', '207', (32, 35))	('Akt2', 'Gene', (32, 36))	('Akt', 'Gene', (18, 21))	('celecoxib', 'Chemical', 'MESH:C105934', (125, 134))	('lower', 'NegReg', (87, 92))	('Akt', 'Gene', (32, 35))	('Akt2', 'Gene', '208', (32, 36))	('expression', 'MPA', (4, 14))	('Akt', 'Gene', '207', (41, 44))	('phosphorylation', 'MPA', (45, 60))	('Akt', 'Gene', '207', (18, 21))	('Akt2', 'Gene', (18, 22))	('Akt', 'Gene', (41, 44))	('celecoxib', 'Var', (125, 134))	('Akt2', 'Gene', '208', (18, 22))	('celecoxib', 'Chemical', 'MESH:C105934', (140, 149))
76814	28283800	Akt phosphorylation and the expression of survivin and ID3 were decreased by LY294002 without affecting Smad-1, -5, and -8 phosphorylation.	('ID3', 'Gene', (55, 58))	('survivin', 'Protein', (42, 50))	('expression', 'MPA', (28, 38))	('LY294002', 'Chemical', 'MESH:C085911', (77, 85))	('Akt', 'Gene', '207', (0, 3))	('ID3', 'Gene', '3399', (55, 58))	('Akt', 'Gene', (0, 3))	('LY294002', 'Var', (77, 85))	('decreased', 'NegReg', (64, 73))
76831	28283800	Our and studies by others have shown that the inhibition of Akt2 and Akt3 activates the intrinsic apoptotic pathway mediated by mitochondria in GBM cell lines.	('inhibition', 'Var', (46, 56))	('Akt3', 'Gene', (69, 73))	('Akt2', 'Gene', (60, 64))	('activates', 'PosReg', (74, 83))	('Akt2', 'Gene', '208', (60, 64))	('Akt3', 'Gene', '10000', (69, 73))	('intrinsic apoptotic pathway', 'Pathway', (88, 115))
76836	28283800	ID3 knockdown decreased the proliferation and increased apoptosis of medulloblastoma cells and ID3 was associated with the EGFR-Akt pathway.	('EGFR', 'Gene', (123, 127))	('ID3', 'Gene', '3399', (95, 98))	('decreased', 'NegReg', (14, 23))	('associated', 'Reg', (103, 113))	('Akt', 'Gene', (128, 131))	('increased', 'PosReg', (46, 55))	('ID3', 'Gene', (95, 98))	('ID3', 'Gene', '3399', (0, 3))	('medulloblastoma', 'Disease', 'MESH:D008527', (69, 84))	('Akt', 'Gene', '207', (128, 131))	('medulloblastoma', 'Phenotype', 'HP:0002885', (69, 84))	('EGFR', 'Gene', '1956', (123, 127))	('apoptosis', 'CPA', (56, 65))	('knockdown', 'Var', (4, 13))	('medulloblastoma', 'Disease', (69, 84))	('ID3', 'Gene', (0, 3))
76837	28283800	In our study celecoxib inhibited the expression of ID3 through Akt phosphorylation but it did not inhibit EGFR and the other ID family proteins, suggesting the EGFR-independent regulation of Akt downstream by celecoxib in LGG cells (Fig.	('ID3', 'Gene', (51, 54))	('Akt', 'Gene', '207', (191, 194))	('celecoxib', 'Chemical', 'MESH:C105934', (13, 22))	('inhibited', 'NegReg', (23, 32))	('LGG', 'Disease', 'MESH:D008228', (222, 225))	('Akt', 'Gene', (191, 194))	('EGFR', 'Gene', '1956', (160, 164))	('ID3', 'Gene', '3399', (51, 54))	('Akt', 'Gene', (63, 66))	('EGFR', 'Gene', (160, 164))	('celecoxib', 'Var', (13, 22))	('Akt', 'Gene', '207', (63, 66))	('EGFR', 'Gene', '1956', (106, 110))	('expression', 'MPA', (37, 47))	('LGG', 'Disease', (222, 225))	('celecoxib', 'Chemical', 'MESH:C105934', (209, 218))	('EGFR', 'Gene', (106, 110))
76861	31179243	One previous study has indicated that signal intensity on high b-value DWI may be able to directly reflect water diffusivity.	('high b-value', 'Var', (58, 70))	('water', 'Chemical', 'MESH:D014867', (107, 112))	('signal intensity', 'MPA', (38, 54))	('water diffusivity', 'MPA', (107, 124))
76939	30957015	To the best of our knowledge, this is the first study that links transcriptional profiles of astrocyte subpopulations with glioma genomic mutations.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('glioma', 'Disease', (123, 129))	('mutations', 'Var', (138, 147))
76950	30957015	For example, given the plethora of genomic data available for human glioma, whether key genetic mutations associated with glioma are also associated with specific astrocyte/glioma subpopulation remains unknown.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('plethora', 'Phenotype', 'HP:0001050', (23, 31))	('glioma', 'Disease', (173, 179))	('human', 'Species', '9606', (62, 67))	('glioma', 'Disease', (122, 128))	('associated', 'Reg', (138, 148))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('mutations', 'Var', (96, 105))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
76954	30957015	For example, astrocyte subpopulations B and C in all brain regions are significantly correlated with amplification of the gene encoding EGFR (epidermal growth factor receptor).	('astrocyte subpopulations B', 'CPA', (13, 39))	('amplification', 'Var', (101, 114))	('epidermal growth factor receptor', 'Gene', (142, 174))	('correlated', 'Reg', (85, 95))	('epidermal growth factor receptor', 'Gene', '1956', (142, 174))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
76955	30957015	Additionally, astrocyte subpopulations D and E were among the gene signatures highly correlated with LGG samples bearing both mutation in IDH gene and 1p/19q codeletion.	('1p/19q codeletion', 'Var', (151, 168))	('IDH', 'Gene', (138, 141))	('mutation', 'Var', (126, 134))	('IDH', 'Gene', '3417', (138, 141))	('LGG', 'Disease', (101, 104))	('correlated', 'Reg', (85, 95))
76969	30957015	The genomic features used for GBM samples included transcriptional subtype; mutations in genes encoding TP53, EGFR, PTEN, NF1, PIK3R1, RB1, ATRX, IDH1, APOB, or PDGFRA; amplifications of genes encoding EGFR, PDGFRA, or CDK4; and deletions of genes encoding MTAP, PTEN, QKI, or RB1.	('EGFR', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (104, 108))	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('EGFR', 'Gene', '1956', (110, 114))	('IDH1', 'Gene', '3417', (146, 150))	('RB1', 'Gene', (135, 138))	('RB1', 'Gene', (277, 280))	('PTEN', 'Gene', (116, 120))	('CDK4', 'Gene', (219, 223))	('APOB', 'Gene', '338', (152, 156))	('PIK3R1', 'Gene', '5295', (127, 133))	('ATRX', 'Gene', (140, 144))	('ATRX', 'Gene', '546', (140, 144))	('RB1', 'Gene', '5925', (135, 138))	('QKI', 'Gene', '9444', (269, 272))	('EGFR', 'Gene', '1956', (202, 206))	('PTEN', 'Gene', '5728', (116, 120))	('CDK4', 'Gene', '1019', (219, 223))	('RB1', 'Gene', '5925', (277, 280))	('TP53', 'Gene', (104, 108))	('EGFR', 'Gene', (110, 114))	('PDGFRA', 'Gene', (208, 214))	('PTEN', 'Gene', (263, 267))	('QKI', 'Gene', (269, 272))	('PDGFRA', 'Gene', '5156', (208, 214))	('NF1', 'Gene', '4763', (122, 125))	('APOB', 'Gene', (152, 156))	('deletions', 'Var', (229, 238))	('IDH1', 'Gene', (146, 150))	('PDGFRA', 'Gene', (161, 167))	('mutations', 'Var', (76, 85))	('PDGFRA', 'Gene', '5156', (161, 167))	('PIK3R1', 'Gene', (127, 133))	('PTEN', 'Gene', '5728', (263, 267))	('amplifications', 'Var', (169, 183))	('NF1', 'Gene', (122, 125))	('MTAP', 'Gene', (257, 261))	('MTAP', 'Gene', '4507', (257, 261))
76970	30957015	Similarly, for LGG, the genomic features queried included tumor grade, histologic subtype, mutation in the IDH gene, codeletion of 1p/19q loci, mutations in genes encoding TP53, EGFR, PTEN, ATRX, IDH1, IDH2, CIC, NOTCH1, FUBP1, PIK3CA, NF1, PIK3R1, SMARCA4, ARID1A, TCF12, ZBTB20, PTPN11, PLCG1, or ZCCHC12; deletions of genes encoding PTEN, NF1, CDKN2C, and CDKN2A; and amplifications of genes encoding PIK3CA, PIK3C2B, PDGFRA, MDM4, MDM2, EGFR, or CDK4.	('ATRX', 'Gene', '546', (190, 194))	('ARID1A', 'Gene', '8289', (258, 264))	('IDH', 'Gene', '3417', (202, 205))	('NF1', 'Gene', '4763', (236, 239))	('MDM2', 'Gene', (435, 439))	('ZCCHC12', 'Gene', (299, 306))	('NF1', 'Gene', (342, 345))	('IDH', 'Gene', '3417', (107, 110))	('NOTCH1', 'Gene', (213, 219))	('ZBTB20', 'Gene', (273, 279))	('PIK3C2B', 'Gene', '5287', (412, 419))	('CDK4', 'Gene', '1019', (450, 454))	('PLCG1', 'Gene', '5335', (289, 294))	('mutations', 'Var', (144, 153))	('CDKN2A', 'Gene', (359, 365))	('MDM4', 'Gene', '4194', (429, 433))	('tumor', 'Disease', (58, 63))	('MDM2', 'Gene', '4193', (435, 439))	('MDM4', 'Gene', (429, 433))	('TP53', 'Gene', (172, 176))	('PIK3R1', 'Gene', (241, 247))	('EGFR', 'Gene', (178, 182))	('NF1', 'Gene', (236, 239))	('NOTCH1', 'Gene', '4851', (213, 219))	('CIC', 'Gene', '23152', (208, 211))	('IDH2', 'Gene', (202, 206))	('EGFR', 'Gene', '1956', (441, 445))	('CDKN2C', 'Gene', (347, 353))	('IDH1', 'Gene', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PTEN', 'Gene', (336, 340))	('IDH2', 'Gene', '3418', (202, 206))	('FUBP1', 'Gene', (221, 226))	('IDH', 'Gene', (196, 199))	('PIK3CA', 'Gene', '5290', (228, 234))	('SMARCA4', 'Gene', '6597', (249, 256))	('CDKN2A', 'Gene', '1029', (359, 365))	('ZCCHC12', 'Gene', '170261', (299, 306))	('PTPN11', 'Gene', (281, 287))	('PTEN', 'Gene', (184, 188))	('PIK3CA', 'Gene', '5290', (404, 410))	('amplifications', 'Var', (371, 385))	('ZBTB20', 'Gene', '26137', (273, 279))	('PLCG1', 'Gene', (289, 294))	('PTPN11', 'Gene', '5781', (281, 287))	('PTEN', 'Gene', '5728', (336, 340))	('IDH1', 'Gene', '3417', (196, 200))	('IDH', 'Gene', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('deletions', 'Var', (308, 317))	('EGFR', 'Gene', '1956', (178, 182))	('CDKN2C', 'Gene', '1031', (347, 353))	('IDH', 'Gene', '3417', (196, 199))	('PIK3R1', 'Gene', '5295', (241, 247))	('TP53', 'Gene', '7157', (172, 176))	('ARID1A', 'Gene', (258, 264))	('PTEN', 'Gene', '5728', (184, 188))	('TCF12', 'Gene', (266, 271))	('IDH', 'Gene', (107, 110))	('CIC', 'Gene', (208, 211))	('FUBP1', 'Gene', '8880', (221, 226))	('PIK3C2B', 'Gene', (412, 419))	('PDGFRA', 'Gene', '5156', (421, 427))	('PDGFRA', 'Gene', (421, 427))	('NF1', 'Gene', '4763', (342, 345))	('EGFR', 'Gene', (441, 445))	('ATRX', 'Gene', (190, 194))	('TCF12', 'Gene', '6938', (266, 271))	('SMARCA4', 'Gene', (249, 256))	('CDK4', 'Gene', (450, 454))	('PIK3CA', 'Gene', (228, 234))	('PIK3CA', 'Gene', (404, 410))
76976	30957015	Classical GBM samples with EGFR amplification and LGG samples with astrocytoma histology were used for survival analyses.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('astrocytoma', 'Disease', 'MESH:D001254', (67, 78))	('amplification', 'Var', (32, 45))	('GBM', 'Phenotype', 'HP:0012174', (10, 13))	('astrocytoma', 'Disease', (67, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))
76978	30957015	Furthermore, to determine the association of IDH mutations with the survival of samples correlated with astrocyte gene signatures we constructed contingency tables and performed Fisher's tests.	('IDH', 'Gene', '3417', (45, 48))	('IDH', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))
76983	30957015	The sections were then incubated in PBS with 0.1% Triton X-100 containing chicken anti-GFAP (1:500; Abcam) combined with either rabbit anti-Adcy7 (1:100; Bioss), mouse anti-Serping1 (1:50; Santa Cruz Biotechnology), or rabbit anti-Emp1 (1:50; Abcam) overnight at 4 C. After incubation with secondary antibodies conjugated with AlexaFluor 488 and AlexaFluor 568 or AlexaFluor 647 (1:500; Invitrogen) for 1 h at room temperature, the tissues were counterstained with DAPI (Sigma-Aldrich) solution and mounted with mounting media (Vector Laboratories).	('AlexaFluor', 'Var', (346, 356))	('AlexaFluor', 'Var', (364, 374))	('mouse', 'Species', '10090', (162, 167))	('PBS', 'Chemical', 'MESH:D007854', (36, 39))
76997	30957015	Similarly, a set of DE lncRNAs in cortex subpopulation B with the highest expression compared with non-astrocyte samples include, for example, Gm37524, Gm3764, and Junos.	('Gm3764', 'Var', (152, 158))	('expression', 'MPA', (74, 84))	('Gm37524', 'Var', (143, 150))	('Gm37524', 'Chemical', '-', (143, 150))	('Gm3764', 'Chemical', '-', (152, 158))
77000	30957015	DE lncRNAs enriched in cortex subpopulation C include Gm13872, Gm26672, and Gm37885.	('Gm13872', 'Var', (54, 61))	('Gm37885', 'Chemical', '-', (76, 83))	('Gm26672', 'Chemical', '-', (63, 70))	('Gm13872', 'Chemical', '-', (54, 61))	('Gm37885', 'Var', (76, 83))	('Gm26672', 'Var', (63, 70))
77012	30957015	Nearly 77% (36 of 47) of the glioblastoma samples within the classical subtype exhibited EGFR gene amplification.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('EGFR', 'Gene', (89, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioblastoma', 'Disease', (29, 41))	('amplification', 'Var', (99, 112))	('EGFR', 'Gene', '1956', (89, 93))	('exhibited', 'Reg', (79, 88))
77013	30957015	The top five positively enriched gene signatures with the highest number of classical subtype samples carrying an EGFR amplification were amygdala_top50, striatum_top50, hippocampus_top240, PopC_olfactory_bulb, and PopA_brainstem.	('EGFR', 'Gene', (114, 118))	('amplification', 'Var', (119, 132))	('EGFR', 'Gene', '1956', (114, 118))
77015	30957015	No significant positive correlations were found for GBM samples with TP53 mutations.	('TP53', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('TP53', 'Gene', '7157', (69, 73))
77016	30957015	A large proportion of astrocyte gene signatures were significantly positively correlated with samples carrying amplifications of the gene encoding EGFR (62%, 26 of 42) and deletions of the genes encoding CDKN2A and MTAP (50 and 45%).	('correlated', 'Interaction', (78, 88))	('EGFR', 'Gene', (147, 151))	('CDKN2A', 'Gene', '1029', (204, 210))	('MTAP', 'Gene', (215, 219))	('amplifications', 'Var', (111, 125))	('deletions', 'Var', (172, 181))	('astrocyte gene signatures', 'MPA', (22, 47))	('MTAP', 'Gene', '4507', (215, 219))	('EGFR', 'Gene', '1956', (147, 151))	('CDKN2A', 'Gene', (204, 210))
77017	30957015	Gene signatures of subpopulations A, B, and C, brainstem (subpopulations A, C), olfactory bulb (subpopulations A, B, C, E), cortex (subpopulations B, C), amygdala, striatum, hippocampus, reactive astrocytes (RAs), and scar-forming astrocytes (SAs) in SCI had significant positive correlations with GBM samples with a combined set of genomic features that included amplification of the EGFR gene and deletions of the CDKN2A and MTAP genes.	('GBM', 'Phenotype', 'HP:0012174', (298, 301))	('EGFR', 'Gene', (385, 389))	('MTAP', 'Gene', (427, 431))	('SCI', 'Phenotype', 'HP:0100561', (251, 254))	('scar', 'Phenotype', 'HP:0100699', (218, 222))	('MTAP', 'Gene', '4507', (427, 431))	('CDKN2A', 'Gene', '1029', (416, 422))	('deletions', 'Var', (399, 408))	('CDKN2A', 'Gene', (416, 422))	('amplification', 'Var', (364, 377))	('EGFR', 'Gene', '1956', (385, 389))
77019	30957015	Gene signatures of subpopulations A and C from brainstem and olfactory bulb, and from cortex subpopulation B, were positively correlated with EGFR amplifications with p < 0.001.	('amplifications', 'Var', (147, 161))	('EGFR', 'Gene', '1956', (142, 146))	('correlated', 'Reg', (126, 136))	('EGFR', 'Gene', (142, 146))
77025	30957015	As previously demonstrated, the mixture of astrocytoma and oligoastrocytoma samples is characterized modestly by mutations of IDH without codeletions of 1p/19q loci, TP53 mutations, and ATRX mutations.	('astrocytoma', 'Phenotype', 'HP:0009592', (64, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('IDH', 'Gene', '3417', (126, 129))	('TP53', 'Gene', '7157', (166, 170))	('astrocytoma and oligoastrocytoma', 'Disease', 'MESH:D001254', (43, 75))	('mutations', 'Var', (113, 122))	('TP53', 'Gene', (166, 170))	('mutations', 'Var', (171, 180))	('ATRX', 'Gene', (186, 190))	('IDH', 'Gene', (126, 129))	('ATRX', 'Gene', '546', (186, 190))
77026	30957015	The oligodendroglioma group is enriched in samples carrying mutations of IDH gene combined with codeletions of 1p/19q loci, and mutations in the TERT promoter.	('oligodendroglioma', 'Disease', 'MESH:D009837', (4, 21))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (73, 76))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('mutations', 'Var', (60, 69))	('oligodendroglioma', 'Disease', (4, 21))	('TERT', 'Gene', (145, 149))	('TERT', 'Gene', '7015', (145, 149))
77031	30957015	Mutation in the gene encoding IDH1 or IDH2 and complete deletion of both the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q codeletion) are markers frequently used in clinical practice for classification of LGG samples.	('short arm', 'Phenotype', 'HP:0009824', (77, 86))	('Mutation', 'Var', (0, 8))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', (38, 42))	('LGG samples', 'Disease', (228, 239))	('IDH2', 'Gene', '3418', (38, 42))	('IDH1', 'Gene', '3417', (30, 34))
77032	30957015	We used IDH status as a genomic feature with the following categories: wild-type IDH, mutant IDH with codeletion of 1p/19q, and mutant IDH with no codeletion of 1p/19q.	('mutant', 'Var', (86, 92))	('IDH', 'Gene', (8, 11))	('IDH', 'Gene', (93, 96))	('IDH', 'Gene', '3417', (8, 11))	('IDH', 'Gene', (135, 138))	('IDH', 'Gene', '3417', (135, 138))	('IDH', 'Gene', '3417', (93, 96))	('IDH', 'Gene', (81, 84))	('codeletion of 1p/19q', 'Var', (102, 122))	('IDH', 'Gene', '3417', (81, 84))
77033	30957015	~45% and 40% of the gene signatures were positively correlated with wild-type IDH samples and mutant IDH samples with no 1p/19q codeletion, respectively.	('mutant', 'Var', (94, 100))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', '3417', (101, 104))	('IDH', 'Gene', '3417', (78, 81))
77034	30957015	Subpopulation B, brainstem (subpopulations A, B), olfactory bulb (subpopulations A, B, D, E), cortex (subpopulations B, E), hemisection, transection, hippocampus (ASTRO1), and RA SCI astrocyte gene signatures correlated significantly with both wild-type IDH and mutant IDH samples with no1p/19q codeletion.	('IDH', 'Gene', (254, 257))	('IDH', 'Gene', (269, 272))	('mutant', 'Var', (262, 268))	('IDH', 'Gene', '3417', (254, 257))	('SCI', 'Phenotype', 'HP:0100561', (179, 182))	('IDH', 'Gene', '3417', (269, 272))	('correlated', 'Reg', (209, 219))
77035	30957015	Figure 4C shows a heatmap displaying the proportion of samples featuring each IDH status variant with positive enrichment scores for 21 representative astrocyte gene signatures (Extended data Fig.	('IDH', 'Gene', '3417', (78, 81))	('IDH', 'Gene', (78, 81))	('variant', 'Var', (89, 96))
77036	30957015	Extended data Figure 4-2A-C shows the enrichment score matrices obtained with each IDH status variant.	('IDH', 'Gene', (83, 86))	('variant', 'Var', (94, 101))	('IDH', 'Gene', '3417', (83, 86))
77038	30957015	Mutant IDH samples without the 1p/19q codeletion had high enrichment scores with amygdala gene signatures (AS1-AS3).	('Mutant', 'Var', (0, 6))	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))
77039	30957015	Mutant IDH samples carrying the 1p/19q codeletion had high enrichment scores with subpopulations D and E, cortex subpopulation A, cortex injury (B2), cortex development (A1, A2), and SA SCI gene signatures.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('cortex injury', 'Disease', (130, 143))	('1p/19q', 'Var', (32, 38))	('cortex development', 'CPA', (150, 168))	('cortex injury', 'Disease', 'MESH:D001480', (130, 143))	('SCI', 'Phenotype', 'HP:0100561', (186, 189))
77042	30957015	Extended data Figure 4-3A shows the enrichment scores for LGG samples with an astrocytic histology and wild-type IDH or mutant IDH with no 1p/19q codeletion.	('IDH', 'Gene', (127, 130))	('LGG', 'Disease', (58, 61))	('IDH', 'Gene', '3417', (113, 116))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (113, 116))	('mutant', 'Var', (120, 126))
77043	30957015	Mutations in the promoter of the gene encoding TERT were positively correlated with astrocyte gene signatures (cortex development, cortex injury, SA SCI) in 12% of the LGG samples.	('TERT', 'Gene', (47, 51))	('cortex injury', 'Disease', (131, 144))	('cortex injury', 'Disease', 'MESH:D001480', (131, 144))	('TERT', 'Gene', '7015', (47, 51))	('SCI', 'Phenotype', 'HP:0100561', (149, 152))	('Mutations in', 'Var', (0, 12))	('correlated', 'Reg', (68, 78))
77044	30957015	Positive correlations were found in 36% of the gene signatures for LGG samples carrying mutations in the CIC gene.	('CIC', 'Gene', '23152', (105, 108))	('mutations', 'Var', (88, 97))	('CIC', 'Gene', (105, 108))
77045	30957015	Astrocyte subpopulation gene signatures (PopD, PopE, Cortex, and PopA cortex) clustered a subset of LGG samples into oligodendrogliomas with IDH mutation and 1p/19q codeletion, TERT promoter mutations, and CIC gene mutations.	('TERT', 'Gene', (177, 181))	('IDH', 'Gene', (141, 144))	('TERT', 'Gene', '7015', (177, 181))	('IDH', 'Gene', '3417', (141, 144))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (117, 135))	('mutations', 'Var', (215, 224))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('CIC', 'Gene', '23152', (206, 209))	('CIC', 'Gene', (206, 209))	('oligodendrogliomas', 'Disease', (117, 135))
77046	30957015	The heatmap in Extended data Figure 4-3B contains the enrichment scores of samples with an oligodendroglioma histology, mutant TERT promoter, mutant CIC gene, and mutant IDH gene combined with the 1p/19q codeletion.	('oligodendroglioma', 'Disease', 'MESH:D009837', (91, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('TERT', 'Gene', (127, 131))	('CIC', 'Gene', (149, 152))	('TERT', 'Gene', '7015', (127, 131))	('mutant', 'Var', (163, 169))	('mutant', 'Var', (142, 148))	('IDH', 'Gene', (170, 173))	('oligodendroglioma', 'Disease', (91, 108))	('IDH', 'Gene', '3417', (170, 173))	('CIC', 'Gene', '23152', (149, 152))	('mutant', 'Var', (120, 126))
77056	30957015	Then we used Fisher's test to determine whether the proportion of samples classified as High or Low was different depending on the number of samples with and without IDH mutations.	('mutations', 'Var', (170, 179))	('IDH', 'Gene', '3417', (166, 169))	('IDH', 'Gene', (166, 169))
77057	30957015	We found that for some gene signatures (brainstem subpopulation A, cortex subpopulation A, and cortex subpopulation D) the p value of Fisher's test was not significant (p values = 0.4606, 0.09365, and 0.08331, respectively), therefore there is no statistical evidence to demonstrate that there are differences in the enrichment scores between IDHwt and mutated IDH.	('IDH', 'Gene', (361, 364))	('IDH', 'Gene', '3417', (361, 364))	('IDH', 'Gene', (343, 346))	('mutated', 'Var', (353, 360))	('IDH', 'Gene', '3417', (343, 346))
77058	30957015	However, for subpopulation D and olfactory bulb subpopulation D, the p values were 0.04211 and 0.001592, respectively, thus, the correlation between survival and enrichment scores among these samples could possibly be affected by mutations of IDH.	('0.001592', 'Var', (95, 103))	('affected', 'Reg', (218, 226))	('mutations', 'Var', (230, 239))	('IDH', 'Gene', (243, 246))	('IDH', 'Gene', '3417', (243, 246))
77088	30957015	The dysfunction of SLC1A2 (commonly observed in neurodegenerative diseases) causes elevated levels of glutamate, which yield neuronal damage.	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (48, 73))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (48, 74))	('yield', 'Reg', (119, 124))	('dysfunction', 'Var', (4, 15))	('neuronal damage', 'Disease', 'MESH:D009410', (125, 140))	('SLC1A2', 'Gene', '6506', (19, 25))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (48, 74))	('elevated', 'PosReg', (83, 91))	('neuronal damage', 'Disease', (125, 140))	('SLC1A2', 'Gene', (19, 25))	('glutamate', 'Chemical', 'MESH:D018698', (102, 111))	('levels of glutamate', 'MPA', (92, 111))	('neurodegenerative diseases', 'Disease', (48, 74))
77107	30957015	We correlated astrocyte gene signatures with copy-number variations that are known to play a role in tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('copy-number variations', 'Var', (45, 67))
77108	30957015	For example, amplifications of the EGFR gene are known to lead to tumor growth through enhancement of cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('enhancement', 'PosReg', (87, 98))	('amplifications', 'Var', (13, 27))	('tumor', 'Disease', (66, 71))	('EGFR', 'Gene', '1956', (35, 39))	('lead to', 'Reg', (58, 65))	('EGFR', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cell proliferation', 'CPA', (102, 120))
77110	30957015	A total of 18 astrocyte gene signatures were significantly correlated with GBM samples harboring a combination of copy-number variations including EGFR amplification, CDKN2A deletion, and MTAP deletion.	('EGFR', 'Gene', (147, 151))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('deletion', 'Var', (174, 182))	('MTAP', 'Gene', (188, 192))	('MTAP', 'Gene', '4507', (188, 192))	('EGFR', 'Gene', '1956', (147, 151))	('correlated', 'Reg', (59, 69))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))
77112	30957015	Our results indicate that more than half of the gene signatures were positively correlated with samples classified either as wild-type or mutated IDH with no 1p/19q codeletion.	('IDH', 'Gene', '3417', (146, 149))	('IDH', 'Gene', (146, 149))	('mutated', 'Var', (138, 145))
77113	30957015	The high positive correlation of gene profiles with wild-type and mutant IDH samples without the 1p/19q codeletion is most likely because of the astrocyte origin of these gene signatures.	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', (73, 76))	('mutant', 'Var', (66, 72))
77116	30957015	Our results also show that amygdala gene signatures (AS1-AS3) were strongly correlated with samples with mutant IDH and no 1p/19q codeletion.	('amygdala gene signatures', 'Gene', (27, 51))	('mutant', 'Var', (105, 111))	('IDH', 'Gene', '3417', (112, 115))	('IDH', 'Gene', (112, 115))
77117	30957015	The gene signatures of subpopulations D and E, cortex subpopulation A, cortex development (A1 and A2), and cortex injury (B2) were most highly correlated with LGG samples bearing the IDH mutation and the 1p/19q codeletion; they are also positively associated with oligodendroglioma histology.	('cortex injury', 'Disease', 'MESH:D001480', (107, 120))	('oligodendroglioma', 'Disease', (264, 281))	('cortex development', 'CPA', (71, 89))	('1p/19q codeletion', 'Var', (204, 221))	('IDH', 'Gene', (183, 186))	('associated', 'Reg', (248, 258))	('oligodendroglioma', 'Disease', 'MESH:D009837', (264, 281))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('mutation', 'Var', (187, 195))	('IDH', 'Gene', '3417', (183, 186))	('cortex injury', 'Disease', (107, 120))	('correlated', 'Reg', (143, 153))
77120	30957015	Kaplan-Meier plots suggest that patients with an astrocytic LGG and a gene profile similar to that of astrocyte subpopulation A in brainstem are not correlated with mutations of IDH and have a better prognosis.	('patients', 'Species', '9606', (32, 40))	('IDH', 'Gene', '3417', (178, 181))	('astrocytic', 'Disease', (49, 59))	('mutations', 'Var', (165, 174))	('IDH', 'Gene', (178, 181))
77121	30957015	On the other hand, the survival of LGG patients associated with subpopulation D and olfactory bulb subpopulation D gene signatures could possibly be affected by mutations of IDH correlated with subtypes of these LGG samples.	('IDH', 'Gene', '3417', (174, 177))	('patients', 'Species', '9606', (39, 47))	('LGG', 'Disease', (35, 38))	('mutations', 'Var', (161, 170))	('IDH', 'Gene', (174, 177))	('affected', 'Reg', (149, 157))
77131	30957015	GFAP + astrocytes in AD cortices also exhibit significantly increased Adcy7 protein expression.	('GFAP +', 'Var', (0, 6))	('Adcy7 protein', 'Protein', (70, 83))	('AD', 'Disease', 'MESH:D000544', (21, 23))	('AD', 'Disease', (21, 23))	('AD', 'Phenotype', 'HP:0002511', (21, 23))	('increased', 'PosReg', (60, 69))
77151	29844871	We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH.	('SLUG', 'Gene', '6591', (78, 82))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('SLUG', 'Gene', (78, 82))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('R132H', 'Mutation', 'rs121913500', (213, 218))	('IDH-1', 'Gene', '3417', (206, 211))	('IDH-1', 'Gene', (206, 211))	('EGFR', 'Gene', '1956', (186, 190))	('EGFR', 'Gene', (186, 190))	('patients', 'Species', '9606', (27, 35))	('glioma', 'Disease', (20, 26))	('TWIST', 'Gene', '7291', (87, 92))	('1p/19q LOH', 'Var', (233, 243))	('TWIST', 'Gene', (87, 92))
77158	29844871	The reactivation of EMT genes is associated with worse patient prognosis in carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinomas', 'Disease', (76, 86))	('carcinomas', 'Disease', 'MESH:D002277', (76, 86))	('EMT genes', 'Gene', (20, 29))	('patient', 'Species', '9606', (55, 62))	('reactivation', 'Var', (4, 16))
77181	29844871	In secondary glioblastomas IDH-1 (R132H) mutated glioma cells were completely devoid of the EMT transcription factors SLUG (Figure 3A) and TWIST (Figure 3B) while vascular proliferations were constantly positive for those factors.	('mutated', 'Var', (41, 48))	('R132H', 'Mutation', 'rs121913500', (34, 39))	('TWIST', 'Gene', '7291', (139, 144))	('TWIST', 'Gene', (139, 144))	('glioblastomas', 'Phenotype', 'HP:0012174', (13, 26))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioblastomas IDH-1', 'Disease', (13, 32))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('devoid', 'NegReg', (78, 84))	('glioblastomas IDH-1', 'Disease', 'MESH:D005909', (13, 32))	('SLUG', 'Gene', '6591', (118, 122))	('glioma', 'Disease', (49, 55))	('SLUG', 'Gene', (118, 122))
77182	29844871	Of note, SLUG (median test: p=0.0098) and TWIST (median test: p=0.0315) expression were significantly higher in IDH-1-wildtype as compared to IDH-1-mutant (R132H) glioblastomas, most probably related to the a priori more prominent neoangiogenesis in primary glioblastoma (data not shown).	('IDH-1', 'Gene', (142, 147))	('primary glioblastoma', 'Disease', (250, 270))	('glioblastomas', 'Phenotype', 'HP:0012174', (163, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('higher', 'PosReg', (102, 108))	('expression', 'MPA', (72, 82))	('primary glioblastoma', 'Disease', 'MESH:D005909', (250, 270))	('R132H', 'Var', (156, 161))	('IDH-1', 'Gene', '3417', (112, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (258, 270))	('glioblastomas', 'Disease', (163, 176))	('IDH-1', 'Gene', '3417', (142, 147))	('TWIST', 'Gene', (42, 47))	('glioblastomas', 'Disease', 'MESH:D005909', (163, 176))	('IDH-1', 'Gene', (112, 117))	('TWIST', 'Gene', '7291', (42, 47))	('SLUG', 'Gene', '6591', (9, 13))	('R132H', 'Mutation', 'rs121913500', (156, 161))	('SLUG', 'Gene', (9, 13))
77183	29844871	In contrast, IDH-1-mutant (R132H) glioblastomas mainly present as secondary glioblastoma deriving from lower grade gliomas that - per definition - do not display vascular proliferations.	('IDH-1', 'Gene', (13, 18))	('R132H', 'Var', (27, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('gliomas', 'Disease', (115, 122))	('R132H', 'Mutation', 'rs121913500', (27, 32))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioblastomas', 'Disease', 'MESH:D005909', (34, 47))	('glioblastoma', 'Disease', (34, 46))	('glioblastomas', 'Disease', (34, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('glioblastoma', 'Disease', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('IDH-1', 'Gene', '3417', (13, 18))
77184	29844871	In lower grade IDH-1 (R132H) mutated astrocytomas without signs of neo-angiogenesis, SLUG (Supplementary Figure 1A) and TWIST (Supplementary Figure 1B) were absent on both IDH-1 (R132H)-mutated glioma cells and tumor-associated blood vessels.	('astrocytoma', 'Phenotype', 'HP:0009592', (37, 48))	('glioma', 'Disease', (194, 200))	('Supplementary Figure 1B', 'Disease', (127, 150))	('IDH-1', 'Gene', '3417', (172, 177))	('TWIST', 'Gene', '7291', (120, 125))	('tumor', 'Disease', (211, 216))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('IDH-1', 'Gene', (15, 20))	('absent', 'NegReg', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('mutated', 'Var', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('SLUG', 'Gene', '6591', (85, 89))	('astrocytomas', 'Disease', (37, 49))	('IDH-1', 'Gene', (172, 177))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (127, 150))	('SLUG', 'Gene', (85, 89))	('IDH-1', 'Gene', '3417', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('R132H', 'Mutation', 'rs121913500', (22, 27))	('R132H', 'Mutation', 'rs121913500', (179, 184))	('TWIST', 'Gene', (120, 125))	('astrocytomas', 'Disease', 'MESH:D001254', (37, 49))
77187	29844871	Finally, in oligodendrogliomas with 1p/19q LOH, SLUG- and TWIST-positive cells were only encountered in perivascular cells displaying 2 copies for both the short as well as the long arm on chromosomes 1 and 19 (data not shown).	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('oligodendrogliomas', 'Disease', (12, 30))	('SLUG', 'Gene', '6591', (48, 52))	('TWIST', 'Gene', '7291', (58, 63))	('1p/19q LOH', 'Var', (36, 46))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (12, 30))	('SLUG', 'Gene', (48, 52))	('TWIST', 'Gene', (58, 63))
77214	29844871	More recently, it has been shown that gliomas with a proneural gene expression signature displayed a distinct underlying (epi-)genetic phenotype consisting of a specific glioma-CpG island methylation phenotype (G-CIMP) related to IDH1 mutations.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Disease', (170, 176))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('mutations', 'Var', (235, 244))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH1', 'Gene', (230, 234))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Disease', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('gliomas', 'Disease', (38, 45))	('IDH1', 'Gene', '3417', (230, 234))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
77215	29844871	Gliomas harbouring IDH1 mutations belong to the group of WHO grade II and III gliomas typically lacking vascular proliferations or account for only approximately 5% of secondary glioblastomas.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH1', 'Gene', (19, 23))	('lacking', 'NegReg', (96, 103))	('glioblastomas', 'Phenotype', 'HP:0012174', (178, 191))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('IDH1', 'Gene', '3417', (19, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('glioblastomas', 'Disease', 'MESH:D005909', (178, 191))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('Gliomas', 'Disease', (0, 7))	('mutations', 'Var', (24, 33))	('glioblastomas', 'Disease', (178, 191))
77226	29844871	Therefore, we also analysed glioma VAMCs, constituting the cellular source of EMT transcription factors in our cohort, for the most frequent and specific glioma-associated genetic aberrations namely IDH1 mutation, 1p/19q LOH as well as EGFR amplification (Figure 3).	('mutation', 'Var', (204, 212))	('glioma VAMCs', 'Disease', 'MESH:D005910', (28, 40))	('IDH1', 'Gene', '3417', (199, 203))	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glioma VAMCs', 'Disease', (28, 40))	('1p/19q LOH', 'Var', (214, 224))	('glioma', 'Disease', (154, 160))	('EGFR', 'Gene', '1956', (236, 240))	('IDH1', 'Gene', (199, 203))	('glioma', 'Disease', (28, 34))	('EGFR', 'Gene', (236, 240))
77276	22270850	Thus far, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been the only confirmed molecular predictive factor in glioblastoma.	('MGMT', 'Gene', '4255', (69, 73))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (29, 67))	('MGMT', 'Gene', (69, 73))	('glioblastoma', 'Disease', (143, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('O6-methylguanine-DNA methyltransferase', 'Gene', (29, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('methylation', 'Var', (10, 21))
77277	22270850	Novel "genome-wide" techniques have identified additional important molecular alterations as mutations in isocitrate dehydrogenase 1 (IDH1) and its prognostic importance.	('mutations', 'Var', (93, 102))	('isocitrate dehydrogenase 1', 'Gene', (106, 132))	('isocitrate dehydrogenase 1', 'Gene', '3417', (106, 132))	('IDH1', 'Gene', (134, 138))	('IDH1', 'Gene', '3417', (134, 138))
77295	22270850	Cytogenetic studies of glioblastoma have shown that most tumors are near-diploid, and that numerical and structural chromosomal abnormalities are common.	('chromosomal abnormalities', 'Disease', (116, 141))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (116, 141))	('near-diploid', 'Var', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('glioblastoma', 'Disease', (23, 35))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
77296	22270850	MSI is rarely observed for non-inherited newly diagnosed glioblastomas, because of inactivation of mismatch repair (MMR) genes.	('glioblastomas', 'Disease', 'MESH:D005909', (57, 70))	('inactivation', 'Var', (83, 95))	('glioblastomas', 'Disease', (57, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('MMR) genes', 'Gene', (116, 126))	('MSI', 'Gene', (0, 3))	('MSI', 'Gene', '5928', (0, 3))	('glioblastomas', 'Phenotype', 'HP:0012174', (57, 70))
77297	22270850	However, in recurrent glioblastomas after TMZ treatment, inactivating mutations have been observed in MSH6, one of the MMR genes.	('glioblastomas', 'Phenotype', 'HP:0012174', (22, 35))	('MSH6', 'Gene', '2956', (102, 106))	('MSH6', 'Gene', (102, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (22, 35))	('glioblastomas', 'Disease', (22, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('inactivating mutations', 'Var', (57, 79))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))
77298	22270850	MSH6 mutations have not been associated with detectable MSI as manifested by changes in the length of microsatellite sequences, but with a hypermutator phenotype.	('MSI', 'Gene', (56, 59))	('MSI', 'Gene', '5928', (56, 59))	('MSH6', 'Gene', '2956', (0, 4))	('mutations', 'Var', (5, 14))	('MSH6', 'Gene', (0, 4))
77303	22270850	Amplification of the epidermal growth factor receptor (EGFR) gene is a characteristic finding in primary glioblastoma (Table 1).	('EGFR', 'Gene', '1956', (55, 59))	('Amplification', 'Var', (0, 13))	('epidermal growth factor receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('primary glioblastoma', 'Disease', (97, 117))	('primary glioblastoma', 'Disease', 'MESH:D005909', (97, 117))	('epidermal growth factor receptor', 'Gene', '1956', (21, 53))
77305	22270850	Focal amplification of EGFR correlates with EGFR overexpression or mutations and deletions in the EGFR gene, and subsequent activation of the PI3K/AKT pathway.	('EGFR', 'Gene', (98, 102))	('activation', 'PosReg', (124, 134))	('deletions', 'Var', (81, 90))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (67, 76))	('EGFR', 'Gene', '1956', (23, 27))	('AKT', 'Gene', '207', (147, 150))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('overexpression', 'PosReg', (49, 63))	('EGFR', 'Gene', (23, 27))	('AKT', 'Gene', (147, 150))
77307	22270850	Amplification of the complete chromosome 7, containing EGFR, MET, and its ligand HGF, has been found to correlate with activation of the MET axis.	('EGFR', 'Gene', '1956', (55, 59))	('Amplification', 'Var', (0, 13))	('HGF', 'Gene', '3082', (81, 84))	('MET', 'Gene', (61, 64))	('EGFR', 'Gene', (55, 59))	('activation', 'PosReg', (119, 129))	('HGF', 'Gene', (81, 84))	('MET axis', 'CPA', (137, 145))
77309	22270850	Remarkably, gain of chromosome 7 and amplification of EGFR have been found more frequently in short-term survivors, however EGFR alterations are not of prognostic importance in glioblastoma.	('glioblastoma', 'Disease', (177, 189))	('EGFR', 'Gene', '1956', (124, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (177, 189))	('amplification', 'Var', (37, 50))	('EGFR', 'Gene', (124, 128))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('EGFR', 'Gene', '1956', (54, 58))	('gain', 'PosReg', (12, 16))	('EGFR', 'Gene', (54, 58))
77310	22270850	Amplification of 12q13-15, where the oncogenes CDK4 and MDM2 are located, results in the disruption of both the RB and P53 pathways.	('Amplification', 'Var', (0, 13))	('P53', 'Gene', (119, 122))	('CDK4', 'Gene', (47, 51))	('P53', 'Gene', '7157', (119, 122))	('disruption', 'NegReg', (89, 99))	('CDK4', 'Gene', '1019', (47, 51))	('MDM2', 'Gene', '4193', (56, 60))	('MDM2', 'Gene', (56, 60))
77313	22270850	LOH of chromosome 10q is the most common genomic alteration found in both primary and secondary glioblastomas (Table 1) and is associated with poor survival.	('glioblastomas', 'Disease', (96, 109))	('primary', 'Disease', (74, 81))	('glioblastomas', 'Phenotype', 'HP:0012174', (96, 109))	('LOH of chromosome 10q', 'Var', (0, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('glioblastomas', 'Disease', 'MESH:D005909', (96, 109))
77318	22270850	Deletion of CDKN2A and CDKN2B is often accompanied by deletion of CDKN2C on chromosome 1p32, which encodes another cell cycle protein p18INK4C.	('p18INK4C', 'Gene', '1031', (134, 142))	('CDKN2C', 'Gene', '1031', (66, 72))	('CDKN2A', 'Gene', (12, 18))	('deletion', 'Var', (54, 62))	('CDKN2A', 'Gene', '1029', (12, 18))	('p18INK4C', 'Gene', (134, 142))	('CDKN2B', 'Gene', (23, 29))	('CDKN2B', 'Gene', '1030', (23, 29))	('CDKN2C', 'Gene', (66, 72))	('accompanied', 'Reg', (39, 50))	('Deletion', 'Var', (0, 8))
77321	22270850	Co-deletion of 1p and 19q is frequently seen in oligodendrogliomas and is, in those, associated with prolonged survival and translocations.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (48, 66))	('Co-deletion', 'Var', (0, 11))	('associated', 'Reg', (85, 95))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('oligodendrogliomas', 'Disease', (48, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
77323	22270850	Isolated LOH 19q, however, is frequently observed in secondary glioblastoma and may be a marker of longer survival.	('glioblastoma', 'Disease', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('Isolated LOH 19q', 'Var', (0, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))
77324	22270850	In addition to amplifications and deletions, genes implicated in glioblastoma can be affected by somatic mutations.	('affected', 'Reg', (85, 93))	('glioblastoma', 'Disease', (65, 77))	('mutations', 'Var', (105, 114))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
77327	22270850	Furthermore, glioblastoma-specific mutations are seen; the EGFRvIII mutant lacks 267 amino acids in the extracellular part, resulting in a constitutively activated receptor that no longer requires its ligand EGF to signal downstream.	('EGF', 'Gene', '1950', (59, 62))	('EGF', 'Gene', (208, 211))	('EGFR', 'Gene', (59, 63))	('glioblastoma', 'Disease', (13, 25))	('EGF', 'Gene', '1950', (208, 211))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('EGF', 'Gene', (59, 62))	('EGFR', 'Gene', '1956', (59, 63))	('constitutively activated receptor', 'MPA', (139, 172))	('267 amino acids in the', 'MPA', (81, 103))	('lacks', 'NegReg', (75, 80))	('mutant', 'Var', (68, 74))
77328	22270850	EGFR point mutations have also been identified in glioblastoma, in the extracellular domain, whereas they are predominantly found in the kinase domain in other tumor types, for example lung cancer.	('point mutations', 'Var', (5, 20))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('EGFR', 'Gene', (0, 4))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('lung cancer', 'Disease', (185, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('EGFR', 'Gene', '1956', (0, 4))	('tumor', 'Disease', (160, 165))	('glioblastoma', 'Disease', (50, 62))
77329	22270850	Two extensive mutational studies have provided an overview of the most common mutations affecting glioblastoma (Table 2).	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('mutations', 'Var', (78, 87))
77330	22270850	Although mutations in "common" cancer genes, for example BRAF and the RAS genes, have rarely been observed in gliomas (<5%), inactivating mutations and deletions have been identified in their inhibitory tumor suppressor gene NF1.	('RAS genes', 'Gene', (70, 79))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('BRAF', 'Gene', '673', (57, 61))	('NF1', 'Gene', (225, 228))	('inactivating mutations', 'Var', (125, 147))	('NF1', 'Gene', '4763', (225, 228))	('BRAF', 'Gene', (57, 61))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('deletions', 'Var', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (31, 37))
77331	22270850	Mutations in PIK3CA and PIK3R1, coding, respectively, for the PI3K catalytic subunit p110alpha and regulatory subunit P85alpha, have been described.	('PIK3R1', 'Gene', '5295', (24, 30))	('PIK3R1', 'Gene', (24, 30))	('PIK3CA', 'Gene', (13, 19))	('P85alpha', 'Gene', (118, 126))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('P85alpha', 'Gene', '5295', (118, 126))
77332	22270850	The incidence of mutation in glioblastoma is lower than in other solid tumors, with the exception of the hypermutator phenotype, which, as described above, is found in recurrent glioblastomas after treatment with alkylating agents.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('found', 'Reg', (159, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioblastoma', 'Disease', (178, 190))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('mutation', 'Var', (17, 25))	('glioblastomas', 'Phenotype', 'HP:0012174', (178, 191))	('solid tumors', 'Disease', (65, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (178, 191))	('solid tumors', 'Disease', 'MESH:D009369', (65, 77))	('glioblastomas', 'Disease', (178, 191))	('glioblastoma', 'Disease', (29, 41))
77333	22270850	This may be caused by MGMT methylation or mutational inactivation of DNA-repair enzymes, for example MSH6.	('caused by', 'Reg', (12, 21))	('MSH6', 'Gene', (101, 105))	('MGMT', 'Gene', (22, 26))	('MSH6', 'Gene', '2956', (101, 105))	('mutational inactivation', 'Var', (42, 65))	('MGMT', 'Gene', '4255', (22, 26))
77334	22270850	An interesting gene found to contain mutations in glioblastoma is IDH1, which encodes isocitrate dehydrogenase 1 and is involved in energy metabolism.	('IDH1', 'Gene', '3417', (66, 70))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('IDH1', 'Gene', (66, 70))	('mutations', 'Var', (37, 46))	('isocitrate dehydrogenase 1', 'Gene', (86, 112))	('isocitrate dehydrogenase 1', 'Gene', '3417', (86, 112))	('glioblastoma', 'Disease', (50, 62))
77335	22270850	IDH1 mutations have been predominantly identified in secondary glioblastomas and low-grade gliomas, with mutations in more than 70% of cases; they are found only sporadically in primary glioblastomas.	('primary glioblastoma', 'Disease', (178, 198))	('glioblastomas', 'Disease', (186, 199))	('glioblastomas', 'Disease', 'MESH:D005909', (186, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('gliomas', 'Disease', (91, 98))	('glioblastomas', 'Phenotype', 'HP:0012174', (63, 76))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('mutations', 'Var', (5, 14))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('identified', 'Reg', (39, 49))	('glioblastomas', 'Disease', 'MESH:D005909', (63, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('IDH1', 'Gene', (0, 4))	('glioblastomas', 'Phenotype', 'HP:0012174', (186, 199))	('glioblastomas', 'Disease', (63, 76))	('primary glioblastoma', 'Disease', 'MESH:D005909', (178, 198))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('IDH1', 'Gene', '3417', (0, 4))
77336	22270850	Because patients with IDH1 mutated primary glioblastomas are generally younger and have longer median survival and wild-type EGFR, which are characteristics of secondary glioblastomas, it is hypothesized that these are in fact secondary glioblastomas for which no histological evidence of evolution from a less malignant glioma is found.	('malignant glioma', 'Disease', 'MESH:D005910', (311, 327))	('glioblastomas', 'Phenotype', 'HP:0012174', (170, 183))	('malignant glioma', 'Disease', (311, 327))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('glioblastomas', 'Phenotype', 'HP:0012174', (43, 56))	('glioblastomas', 'Disease', (237, 250))	('EGFR', 'Gene', '1956', (125, 129))	('primary glioblastoma', 'Disease', (35, 55))	('glioblastomas', 'Disease', 'MESH:D005909', (237, 250))	('longer', 'PosReg', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (321, 327))	('mutated', 'Var', (27, 34))	('glioblastomas', 'Disease', (170, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('primary glioblastoma', 'Disease', 'MESH:D005909', (35, 55))	('glioblastomas', 'Disease', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('IDH1', 'Gene', (22, 26))	('glioblastomas', 'Disease', 'MESH:D005909', (170, 183))	('patients', 'Species', '9606', (8, 16))	('glioblastomas', 'Disease', 'MESH:D005909', (43, 56))	('glioblastomas', 'Phenotype', 'HP:0012174', (237, 250))	('EGFR', 'Gene', (125, 129))	('IDH1', 'Gene', '3417', (22, 26))
77338	22270850	In different glioblastoma studies IDH1 mutations have been found to be an independent positive prognostic marker.	('IDH1', 'Gene', '3417', (34, 38))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('mutations', 'Var', (39, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('IDH1', 'Gene', (34, 38))
77339	22270850	IDH1 mutations have been shown to inactivate the enzyme with subsequent HIF-1a induction.	('HIF-1a', 'Gene', '3091', (72, 78))	('HIF-1a', 'Gene', (72, 78))	('mutations', 'Var', (5, 14))	('inactivate', 'NegReg', (34, 44))	('enzyme', 'Enzyme', (49, 55))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
77340	22270850	In addition, the mutations result in gain of function to catalyze alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG).	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (100, 118))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (66, 85))	('function', 'MPA', (45, 53))	('gain', 'PosReg', (37, 41))	('catalyze', 'MPA', (57, 65))	('mutations', 'Var', (17, 26))	('alpha-KG', 'Chemical', 'MESH:D007656', (87, 95))
77342	22270850	This suggests that mutations in IDH1 change the expression of a potentially large number of genes.	('IDH1', 'Gene', (32, 36))	('mutations', 'Var', (19, 28))	('IDH1', 'Gene', '3417', (32, 36))	('expression of', 'MPA', (48, 61))	('change', 'Reg', (37, 43))
77343	22270850	Given that mutations in IDH1 are an early event in gliomagenesis (Fig.	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (24, 28))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('IDH1', 'Gene', (24, 28))
77344	22270850	2), this may implicate widespread alteration of epigenetic control as the key mechanism in gliomagenesis in IDH1 mutated tumors.	('IDH1', 'Gene', '3417', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('implicate', 'Reg', (13, 22))	('tumors', 'Disease', (121, 127))	('glioma', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutated', 'Var', (113, 120))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('IDH1', 'Gene', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
77345	22270850	Furthermore, it might explain the extensive and fundamental differences between mutated and wildtype IDH1 glioblastoma.	('IDH1 glioblastoma', 'Disease', (101, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('IDH1 glioblastoma', 'Disease', 'MESH:D005909', (101, 118))	('mutated', 'Var', (80, 87))
77347	22270850	SNPs have been linked to susceptibility to glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (43, 56))	('glioblastomas', 'Disease', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('SNPs', 'Var', (0, 4))	('linked', 'Reg', (15, 21))	('glioblastomas', 'Phenotype', 'HP:0012174', (43, 56))
77348	22270850	In particular, allergies and asthma's inverse association with glioblastoma have been observed in different studies and have been linked with polymorphisms in HLA and interleukins.	('allergies', 'Disease', (15, 24))	('HLA', 'Protein', (159, 162))	('glioblastoma', 'Disease', (63, 75))	('asthma', 'Disease', (29, 35))	('polymorphisms', 'Var', (142, 155))	('asthma', 'Disease', 'MESH:D001249', (29, 35))	('asthma', 'Phenotype', 'HP:0002099', (29, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('inverse', 'NegReg', (38, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('allergies', 'Disease', 'MESH:D004342', (15, 24))	('allergies', 'Phenotype', 'HP:0012393', (15, 24))
77350	22270850	SNP309 in MDM2 has been associated with an increased risk of various types of cancer, but has not been associated as a risk or prognostic factor in respect of glioblastoma in large studies.	('SNP309', 'Var', (0, 6))	('associated', 'Reg', (24, 34))	('SNP309', 'Chemical', '-', (0, 6))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('MDM2', 'Gene', '4193', (10, 14))	('glioblastoma', 'Disease', (159, 171))	('MDM2', 'Gene', (10, 14))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))
77351	22270850	SNPs in CDKN2B, TERT, and RTEL1 have been described in independent studies as susceptibility loci for high-grade glioma.	('TERT', 'Gene', (16, 20))	('CDKN2B', 'Gene', (8, 14))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('susceptibility', 'Reg', (78, 92))	('RTEL1', 'Gene', '51750', (26, 31))	('TERT', 'Gene', '7015', (16, 20))	('CDKN2B', 'Gene', '1030', (8, 14))	('RTEL1', 'Gene', (26, 31))	('SNPs', 'Var', (0, 4))	('glioma', 'Disease', (113, 119))
77352	22270850	In a follow-up study, SNPs in DNA double-strand break repair enzymes, for example RTEL1, have been found to correlate with glioblastoma survival.	('glioblastoma', 'Disease', (123, 135))	('SNPs', 'Var', (22, 26))	('RTEL1', 'Gene', '51750', (82, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('RTEL1', 'Gene', (82, 87))	('correlate with', 'Reg', (108, 122))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))
77367	22270850	Interestingly, survival was similar for patients in the low-risk group with wildtype IDH1 and patients in the high-risk group with mutated IDH1.	('IDH1', 'Gene', (139, 143))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (40, 48))	('mutated', 'Var', (131, 138))	('wildtype', 'Var', (76, 84))	('IDH1', 'Gene', '3417', (139, 143))	('IDH1', 'Gene', (85, 89))	('IDH1', 'Gene', '3417', (85, 89))
77370	22270850	Proneural glioblastomas are characterized by IDH1 mutations, and TP53 and PDGFRA alterations, and correlate with a better prognosis and younger age.	('IDH1', 'Gene', '3417', (45, 49))	('PDGFRA', 'Gene', (74, 80))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('mutations', 'Var', (50, 59))	('glioblastomas', 'Phenotype', 'HP:0012174', (10, 23))	('glioblastomas', 'Disease', 'MESH:D005909', (10, 23))	('alterations', 'Var', (81, 92))	('PDGFRA', 'Gene', '5156', (74, 80))	('IDH1', 'Gene', (45, 49))	('glioblastomas', 'Disease', (10, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
77371	22270850	Classic glioblastomas are differentiated on the basis of high-level amplification of EGFR, monosomy of chromosome 10, and deletion of CDKN2A.	('EGFR', 'Gene', (85, 89))	('Classic glioblastomas', 'Disease', (0, 21))	('monosomy', 'Var', (91, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('CDKN2A', 'Gene', (134, 140))	('Classic glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('deletion', 'Var', (122, 130))	('CDKN2A', 'Gene', '1029', (134, 140))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('EGFR', 'Gene', '1956', (85, 89))
77373	22270850	Mesenchymal glioblastomas are known for NF1 deletion or mutation and expression of YKL-40/CHI3L1 and MET.	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('glioblastomas', 'Disease', 'MESH:D005909', (12, 25))	('CHI3L1', 'Gene', '1116', (90, 96))	('deletion', 'Var', (44, 52))	('glioblastomas', 'Disease', (12, 25))	('NF1', 'Gene', (40, 43))	('CHI3L1', 'Gene', (90, 96))	('YKL-40', 'Gene', '1116', (83, 89))	('NF1', 'Gene', '4763', (40, 43))	('glioblastomas', 'Phenotype', 'HP:0012174', (12, 25))	('mutation', 'Var', (56, 64))	('YKL-40', 'Gene', (83, 89))
77374	22270850	Different subtypes of glioblastoma have been shown to behave differently in response to treatment; Classic and mesenchymal subtypes have a survival advantage after TMZ and RT, whereas the proneural subtype of glioblastomas, with relative good prognostic, does not.	('glioblastomas', 'Phenotype', 'HP:0012174', (209, 222))	('glioblastoma', 'Disease', (209, 221))	('glioblastoma', 'Disease', (22, 34))	('TMZ', 'Var', (164, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('glioblastomas', 'Disease', 'MESH:D005909', (209, 222))	('survival advantage', 'CPA', (139, 157))	('glioblastoma', 'Disease', 'MESH:D005909', (209, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (209, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (164, 167))	('glioblastomas', 'Disease', (209, 222))
77375	22270850	Stratified clinical trials in which patient inclusion is based on the genetic alterations that have been identified in their tumor samples are necessary to further increase our understanding of the clinical possibilities of these subgroups.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('patient', 'Species', '9606', (36, 43))	('genetic alterations', 'Var', (70, 89))
77376	22270850	Epigenetic silencing of tumor suppressor genes is a common phenomenon of genomic instability in cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Disease', (96, 102))
77377	22270850	Examples are promoter hypermethylation, histone deacetylation, histone methylation, other histone modifications which can alter chromatin structure (in)directly, and RNA-silencing mechanisms such as RNA interference and microRNA (miRNA or miR) regulation of gene expression.	('RNA', 'MPA', (199, 202))	('miR', 'Gene', (239, 242))	('histone deacetylation', 'MPA', (40, 61))	('alter', 'Reg', (122, 127))	('miR', 'Gene', (230, 233))	('miR', 'Gene', '22877', (239, 242))	('chromatin structure', 'MPA', (128, 147))	('modifications', 'Var', (98, 111))	('histone methylation', 'MPA', (63, 82))	('RNA-silencing', 'MPA', (166, 179))	('promoter', 'MPA', (13, 21))	('miR', 'Gene', '22877', (230, 233))
77381	22270850	Tumor-suppressor genes frequently found to be silenced by hypermethylation in glioblastoma include CDKN2A, CDKN2B, RB1, PTEN, and TP53.	('CDKN2B', 'Gene', '1030', (107, 113))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioblastoma', 'Disease', (78, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('CDKN2A', 'Gene', (99, 105))	('silenced', 'NegReg', (46, 54))	('RB1', 'Gene', (115, 118))	('hypermethylation', 'Var', (58, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('CDKN2A', 'Gene', '1029', (99, 105))	('PTEN', 'Gene', (120, 124))	('RB1', 'Gene', '5925', (115, 118))	('PTEN', 'Gene', '5728', (120, 124))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('CDKN2B', 'Gene', (107, 113))
77383	22270850	Particularly important in glioblastoma is the methylation status of MGMT, which is a predictive factor for therapy response and hence survival of glioblastoma patients treated with TMZ and RT.	('methylation', 'Var', (46, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('glioblastoma', 'Disease', (26, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('MGMT', 'Gene', '4255', (68, 72))	('MGMT', 'Gene', (68, 72))	('glioblastoma', 'Disease', (146, 158))	('patients', 'Species', '9606', (159, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('TMZ', 'Chemical', 'MESH:D000077204', (181, 184))
77385	22270850	MGMT methylation has been found to be more frequent in secondary glioblastomas, in females, and in long-term survivors (LTS), whereas it is rare (5%) in recurrent glioblastomas.	('MGMT', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('glioblastomas', 'Disease', (163, 176))	('frequent', 'Reg', (43, 51))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioblastomas', 'Phenotype', 'HP:0012174', (163, 176))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('MGMT', 'Gene', '4255', (0, 4))	('glioblastomas', 'Disease', 'MESH:D005909', (163, 176))
77386	22270850	Conflicting results have been reported regarding the methylation status of MGMT as a positive prognostic marker.	('MGMT', 'Gene', (75, 79))	('MGMT', 'Gene', '4255', (75, 79))	('methylation status', 'Var', (53, 71))
77392	22270850	MGMT methylation is also associated with pseudo-progression after concomitant radiochemotherapy for newly diagnosed glioblastoma patients.	('MGMT', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('associated with', 'Reg', (25, 40))	('glioblastoma', 'Disease', (116, 128))	('patients', 'Species', '9606', (129, 137))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('pseudo-progression', 'Disease', (41, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('MGMT', 'Gene', '4255', (0, 4))
77395	22270850	These G-CIMP tumors cluster into the aforementioned proneural subgroup, are strongly associated with IDH1 mutations, and generally affect younger patients with improved prognosis.	('IDH1', 'Gene', (101, 105))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('IDH1', 'Gene', '3417', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('patients', 'Species', '9606', (146, 154))	('associated', 'Reg', (85, 95))
77396	22270850	Furthermore, inhibition of histone demethylases and TET 5-methylcytosine hydroxylases by mutated IDH1 potentially implies the methylation of an even greater number of genes in this subgroup.	('IDH1', 'Gene', (97, 101))	('methylation', 'MPA', (126, 137))	('histone demethylases', 'Enzyme', (27, 47))	('IDH1', 'Gene', '3417', (97, 101))	('TET 5-methylcytosine hydroxylases', 'MPA', (52, 85))	('inhibition', 'NegReg', (13, 23))	('mutated', 'Var', (89, 96))
77421	22270850	Primary glioblastomas have a greater prevalence of EGFR alterations, MDM2 duplications, PTEN mutations, and homozygous deletions of CDKN2A.	('CDKN2A', 'Gene', (132, 138))	('duplications', 'Var', (74, 86))	('mutations', 'Var', (93, 102))	('Primary glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('alterations', 'Var', (56, 67))	('EGFR', 'Gene', (51, 55))	('CDKN2A', 'Gene', '1029', (132, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('Primary glioblastomas', 'Disease', (0, 21))	('PTEN', 'Gene', (88, 92))	('PTEN', 'Gene', '5728', (88, 92))	('MDM2', 'Gene', '4193', (69, 73))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('MDM2', 'Gene', (69, 73))	('EGFR', 'Gene', '1956', (51, 55))
77422	22270850	MET amplification, overexpression of PDGFRA, and mutations in IDH1 and TP53 are more prevalent in secondary glioblastomas.	('overexpression', 'PosReg', (19, 33))	('glioblastomas', 'Disease', 'MESH:D005909', (108, 121))	('MET amplification', 'Var', (0, 17))	('mutations', 'Var', (49, 58))	('IDH1', 'Gene', '3417', (62, 66))	('glioblastomas', 'Disease', (108, 121))	('glioblastomas', 'Phenotype', 'HP:0012174', (108, 121))	('PDGFRA', 'Gene', (37, 43))	('prevalent', 'Reg', (85, 94))	('TP53', 'Gene', '7157', (71, 75))	('IDH1', 'Gene', (62, 66))	('TP53', 'Gene', (71, 75))	('PDGFRA', 'Gene', '5156', (37, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
77425	22270850	In contrast, PTEN mutations and LOH 10q are thought to be important in glioma progression, but not initiation.	('glioma', 'Disease', (71, 77))	('LOH 10q', 'Var', (32, 39))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('mutations', 'Var', (18, 27))
77427	22270850	The good news is, however, that many of the alterations identified in glioblastoma cluster in three pathways, the P53 (64-87%), RB (68-78%), and the PI3K/AKT (50%), downstream of the receptor tyrosine kinases (altered 88% in total; Fig.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('AKT', 'Gene', '207', (154, 157))	('glioblastoma cluster', 'Disease', (70, 90))	('alterations', 'Var', (44, 55))	('AKT', 'Gene', (154, 157))	('P53', 'Gene', (114, 117))	('P53', 'Gene', '7157', (114, 117))	('glioblastoma cluster', 'Disease', 'MESH:D005909', (70, 90))
77428	22270850	Most alterations occur in a mutually exclusive fashion: alterations within one tumor affect only a single gene in a pathway, suggesting that different genes in a pathway are functionally equivalent.	('tumor', 'Disease', (79, 84))	('alterations', 'Var', (56, 67))	('affect', 'Reg', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
77436	22270850	The clinical response of recurrent glioblastomas to EGFR inhibitors was found, in one study, to be associated with co-expression of EGFRvIII and PTEN or pAkt, but not in combination with TMZ and RT for newly diagnosed glioblastomas or in glioblastomas treated with erlotinib and TMZ.	('glioblastomas', 'Disease', 'MESH:D005909', (35, 48))	('glioblastomas', 'Disease', (238, 251))	('EGFR', 'Gene', (52, 56))	('erlotinib', 'Chemical', 'MESH:D000069347', (265, 274))	('glioblastomas', 'Phenotype', 'HP:0012174', (218, 231))	('glioblastomas', 'Disease', 'MESH:D005909', (238, 251))	('EGFR', 'Gene', '1956', (132, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('co-expression', 'Var', (115, 128))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))	('TMZ', 'Chemical', 'MESH:D000077204', (187, 190))	('PTEN', 'Gene', (145, 149))	('EGFR', 'Gene', '1956', (52, 56))	('glioblastomas', 'Disease', (218, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('glioblastomas', 'Phenotype', 'HP:0012174', (238, 251))	('associated', 'Reg', (99, 109))	('glioblastomas', 'Disease', (35, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('PTEN', 'Gene', '5728', (145, 149))	('glioblastomas', 'Disease', 'MESH:D005909', (218, 231))	('EGFR', 'Gene', (132, 136))	('TMZ', 'Chemical', 'MESH:D000077204', (279, 282))
77458	29110682	Our findings indicate that TAGLN2 exerts a role in promoting the development of human glioma.	('glioma', 'Disease', (86, 92))	('promoting', 'PosReg', (51, 60))	('TAGLN2', 'Var', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('development of human', 'CPA', (65, 85))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('human', 'Species', '9606', (80, 85))
77465	29110682	More recently, the dysregulation of TAGLN2 in a variety of malignant tumor types, including colorectal cancer, bladder cancer, lung cancer, uterine cervical squamous cell carcinoma, and breast cancer, has been discovered through proteomic analysis, and thus reveals an important role for TAGLN2 in tumor progression.	('squamous cell carcinoma', 'Disease', (157, 180))	('lung cancer', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('dysregulation', 'Var', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('bladder cancer', 'Disease', (111, 125))	('tumor', 'Disease', (298, 303))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('TAGLN2', 'Gene', (36, 42))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('malignant tumor', 'Disease', (59, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('malignant tumor', 'Disease', 'MESH:D018198', (59, 74))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('breast cancer', 'Disease', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 180))	('colorectal cancer', 'Disease', (92, 109))	('tumor', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
77468	29110682	Our findings indicate that TAGLN2 might be a significant prognostic indicator and a potential therapeutic target for human gliomas.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('human', 'Species', '9606', (117, 122))	('TAGLN2', 'Var', (27, 33))	('gliomas', 'Disease', (123, 130))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))
77502	29110682	To establish intracranial gliomas, U87MG and U251 cells (1 x 106) were infected with Lenti-si-TAGLN2 or Lenti-Control virus and then implanted stereotactically into the brain of 4-week-old nude mice (SLAC laboratory animal Center; Shanghai, China).	('U251', 'CellLine', 'CVCL:0021', (45, 49))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('Lenti-si-TAGLN2', 'Var', (85, 100))	('intracranial gliomas', 'Disease', (13, 33))	('nude mice', 'Species', '10090', (189, 198))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('intracranial gliomas', 'Disease', 'MESH:D005910', (13, 33))	('U87MG', 'CellLine', 'CVCL:0022', (35, 40))
77504	29110682	The expression pattern of TAGLN2 in different glioma subtypes and the associations of TAGLN2 with isocitrate dehydrogenase 1 (IDH1) mutation, methylation of O-methylguanine-DNA methyltransferase (MGMT) promoter, codeletion of 1p/19q, telomerase reverse transcriptase (TERT) loss, and alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutation were performed using the TCGA dataset.	('ATRX', 'Gene', (340, 344))	('TAGLN2', 'Gene', (86, 92))	('glioma subtype', 'Disease', 'MESH:D005910', (46, 60))	('O-methylguanine-DNA methyltransferase', 'Gene', '4255', (157, 194))	('TERT', 'Gene', (268, 272))	('ATRX', 'Gene', '546', (340, 344))	('glioma subtype', 'Disease', (46, 60))	('TERT', 'Gene', '7015', (268, 272))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('isocitrate dehydrogenase 1', 'Gene', (98, 124))	('isocitrate dehydrogenase 1', 'Gene', '3417', (98, 124))	('telomerase reverse transcriptase', 'Gene', '7015', (234, 266))	('IDH1', 'Gene', (126, 130))	('MGMT', 'Gene', '4255', (196, 200))	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (284, 338))	('TAGLN2', 'Gene', (26, 32))	('mental retardation', 'Phenotype', 'HP:0001249', (302, 320))	('IDH1', 'Gene', '3417', (126, 130))	('O-methylguanine-DNA methyltransferase', 'Gene', (157, 194))	('mutation', 'Var', (132, 140))	('MGMT', 'Gene', (196, 200))	('telomerase reverse transcriptase', 'Gene', (234, 266))
77508	29110682	TAGLN2 was high in the mesenchymal subtype in TCGA, CGGA and GSE4271 databases and low in the proneural subtype (Table 1; Fig.	('low', 'NegReg', (83, 86))	('GSE4271', 'Chemical', '-', (61, 68))	('TAGLN2', 'Var', (0, 6))	('mesenchymal subtype', 'CPA', (23, 42))
77509	29110682	Meanwhile, GSEA analysis showed that mesenchymal related gene signatures were significantly enriched in high TAGLN2 expression samples (Additional file 2: Fig.	('expression', 'MPA', (116, 126))	('GSEA', 'Chemical', '-', (11, 15))	('high', 'Var', (104, 108))	('mesenchymal related gene signatures', 'Gene', (37, 72))	('TAGLN2', 'Gene', (109, 115))
77512	29110682	Thus, TAGLN2 was positively correlated with increasing tumor grade both in the publicly available databases and in our cohort of primary tumor specimens.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('increasing', 'PosReg', (44, 54))	('TAGLN2', 'Var', (6, 12))	('tumor', 'Disease', (55, 60))	('primary tumor', 'Disease', (129, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('primary tumor', 'Disease', 'MESH:D009369', (129, 142))
77515	29110682	Some molecular genetic features including IDH1/2 mutation, MGMT promotor methylation, codeletion of 1p/19q, TERT loss, and ATRX mutation have been reported to be associated with favorable prognosis in gliomas.	('ATRX', 'Gene', (123, 127))	('gliomas', 'Disease', (201, 208))	('IDH1', 'Gene', '3417', (42, 46))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('mutation', 'Var', (49, 57))	('associated', 'Reg', (162, 172))	('ATRX', 'Gene', '546', (123, 127))	('IDH1', 'Gene', (42, 46))	('TERT', 'Gene', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('TERT', 'Gene', '7015', (108, 112))	('mutation', 'Var', (128, 136))	('MGMT', 'Gene', (59, 63))	('MGMT', 'Gene', '4255', (59, 63))
77516	29110682	Patients with wild type IDH1 exhibited higher expression of TAGLN2 than those with mutated IDH1.	('TAGLN2', 'Var', (60, 66))	('IDH1', 'Gene', '3417', (24, 28))	('higher', 'PosReg', (39, 45))	('IDH1', 'Gene', (91, 95))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (91, 95))	('expression', 'MPA', (46, 56))
77517	29110682	Low TAGLN2 was also associated with other molecular characteristics, including methylated MGMT, 1p/19q codeletion, loss of TERT and mutated ATRX in tumors (P < 0.001; respectively).	('TERT', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('loss', 'NegReg', (115, 119))	('MGMT', 'Gene', (90, 94))	('1p/19q codeletion', 'Var', (96, 113))	('methylated', 'Var', (79, 89))	('ATRX', 'Gene', (140, 144))	('MGMT', 'Gene', '4255', (90, 94))	('mutated', 'Var', (132, 139))	('Low TAGLN2', 'Var', (0, 10))	('TERT', 'Gene', '7015', (123, 127))	('tumors', 'Disease', (148, 154))	('ATRX', 'Gene', '546', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
77520	29110682	S1C), confirming that high TAGLN2 was statistically related to shorter OS.	('shorter OS', 'Disease', (63, 73))	('high TAGLN2', 'Var', (22, 33))	('related', 'Reg', (52, 59))	('OS', 'Chemical', '-', (71, 73))
77521	29110682	Furthermore, TAGLN2 expression was validated as an independent indicator of OS after multivariate Cox regression analysis (HR = 1.713, 95% CI = 1.384 to 2.119, P < 0.0001; Table 2).	('TAGLN2', 'Var', (13, 19))	('Cox', 'Gene', '1351', (98, 101))	('Cox', 'Gene', (98, 101))	('OS', 'Chemical', '-', (76, 78))
77522	29110682	TAGLN2 might therefore be a novel prognostic biomarker in gliomas.	('TAGLN2', 'Var', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
77524	29110682	KEGG analysis demonstrated that TAGLN2 was enriched in pathways in cancer, focal adhesion and regulation of the actin cytoskeleton.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TAGLN2', 'Var', (32, 38))	('focal adhesion', 'CPA', (75, 89))
77525	29110682	Finally, GSEA analysis revealed that high levels of TAGLN2 were significantly related to EMT, cancer metastasis, and the G1-S phase transition of cell cycle progression (Fig.	('TAGLN2', 'Var', (52, 58))	('related', 'Reg', (78, 85))	('G1-S phase transition of cell cycle progression', 'CPA', (121, 168))	('GSEA', 'Chemical', '-', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer metastasis', 'Disease', (94, 111))	('EMT', 'CPA', (89, 92))	('cancer metastasis', 'Disease', 'MESH:D009362', (94, 111))
77526	29110682	Altogether, these data further implicated the malignant property of TAGLN2 in gliomagenesis.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('TAGLN2', 'Var', (68, 74))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
77528	29110682	Silencing TAGLN2 with a single siRNA reduced the area invaded by U87MG, U251, as well as primary GBM#P3 spheroids relative to controls, respectively (Fig.	('U251', 'Var', (72, 76))	('TAGLN2', 'Gene', (10, 16))	('area invaded', 'CPA', (49, 61))	('U251', 'CellLine', 'CVCL:0021', (72, 76))	('U87MG', 'CellLine', 'CVCL:0022', (65, 70))	('reduced', 'NegReg', (37, 44))	('Silencing', 'Var', (0, 9))	('U87MG', 'Var', (65, 70))
77530	29110682	We therefore investigated whether TAGLN2 regulated EMT in glioma cells.	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Disease', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('TAGLN2', 'Var', (34, 40))
77531	29110682	Western blot analysis revealed that knockdown of TAGLN2 led to decreases in several mesenchymal factors, including N-cadherin, beta-catenin, Snail, Slug, and Twist, and significant increases in the epithelial marker (E-cadherin) compared to controls (Fig.	('decreases', 'NegReg', (63, 72))	('TAGLN2', 'Gene', (49, 55))	('knockdown', 'Var', (36, 45))	('Slug', 'Gene', '6591', (148, 152))	('mesenchymal factors', 'CPA', (84, 103))	('N-cadherin', 'Gene', (115, 125))	('epithelial marker', 'CPA', (198, 215))	('Twist', 'CPA', (158, 163))	('Snail', 'Gene', (141, 146))	('Slug', 'Gene', (148, 152))	('E-cadherin', 'Gene', (217, 227))	('beta-catenin', 'Gene', (127, 139))	('E-cadherin', 'Gene', '999', (217, 227))	('Snail', 'Gene', '6615', (141, 146))	('N-cadherin', 'Gene', '1000', (115, 125))	('increases', 'PosReg', (181, 190))	('beta-catenin', 'Gene', '1499', (127, 139))
77533	29110682	Thus, TAGLN2 may contribute to invasiveness in glioma cells by promoting EMT and the formation of invadopodia in glioma cell lines.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('promoting', 'PosReg', (63, 72))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('EMT', 'CPA', (73, 76))	('TAGLN2', 'Var', (6, 12))	('glioma', 'Disease', (47, 53))	('glioma', 'Disease', (113, 119))	('contribute', 'Reg', (17, 27))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
77534	29110682	We found that knocking down of TAGLN2 lead to the suppression of neurosphere formation ability and cell growth of GBM#P3 cells, accompanied with the reduction of key mesenchymal markers, including CD44, CHI3L1, N-cadherin and beta-catenin (Additional file 3: Fig.	('neurosphere formation ability', 'CPA', (65, 94))	('beta-catenin', 'Gene', '1499', (226, 238))	('reduction', 'NegReg', (149, 158))	('CHI3L1', 'Gene', (203, 209))	('knocking down', 'Var', (14, 27))	('N-cadherin', 'Gene', '1000', (211, 221))	('CD44', 'Gene', '960', (197, 201))	('TAGLN2', 'Gene', (31, 37))	('CD44', 'Gene', (197, 201))	('beta-catenin', 'Gene', (226, 238))	('cell growth', 'CPA', (99, 110))	('CHI3L1', 'Gene', '1116', (203, 209))	('suppression', 'NegReg', (50, 61))	('N-cadherin', 'Gene', (211, 221))
77535	29110682	To directly test the role of TAGLN2 in glioma cell survival and proliferation, cells were transfected with siRNA to knock down TAGLN2, and EdU as well as CCK-8 assays were performed.	('glioma', 'Disease', (39, 45))	('TAGLN2', 'Gene', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('knock down', 'Var', (116, 126))	('test', 'Reg', (12, 16))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
77537	29110682	Cell cycle analysis also demonstrated that knockdown of TAGLN2 increased the population of the U87MG and U251 cells in the G0/G1 phase by ~ 15.5% and 10.5%, respectively (Fig.	('increased', 'PosReg', (63, 72))	('TAGLN2', 'Gene', (56, 62))	('knockdown', 'Var', (43, 52))	('U87MG', 'CellLine', 'CVCL:0022', (95, 100))	('U251', 'CellLine', 'CVCL:0021', (105, 109))
77538	29110682	Futhermore, TAGLN2 silencing promoted apoptotic cell death by ~ three- and two-fold compared with controls in U87MG and U251 cell lines, respectively (P < 0.001 and P < 0.01, respectively; Fig.	('promoted', 'PosReg', (29, 37))	('U251', 'CellLine', 'CVCL:0021', (120, 124))	('silencing', 'Var', (19, 28))	('apoptotic cell death', 'CPA', (38, 58))	('TAGLN2', 'Gene', (12, 18))	('U87MG', 'CellLine', 'CVCL:0022', (110, 115))
77539	29110682	TAGLN2 knockdown significantly decreased the level of Fork head box M1 (FoxM1), an oncogenic transcription factor essential for cancer progression in various types of cancers including gliomas (Fig.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('TAGLN2', 'Gene', (0, 6))	('cancer', 'Disease', (167, 173))	('level', 'MPA', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('FoxM1', 'Gene', '2305', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gliomas', 'Disease', (185, 192))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('decreased', 'NegReg', (31, 40))	('Fork head box M1', 'Gene', (54, 70))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('FoxM1', 'Gene', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Fork head box M1', 'Gene', '2305', (54, 70))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('knockdown', 'Var', (7, 16))
77541	29110682	In contrast, cyclin-dependent kinase inhibitors, including p21 and p27 which were identified as tumor suppressors, were increased in the si-TAGLN2 group.	('si-TAGLN2', 'Var', (137, 146))	('p21', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('p21', 'Gene', '644914', (59, 62))	('p27', 'Gene', '10534', (67, 70))	('cyclin-dependent kinase inhibitors', 'MPA', (13, 47))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('increased', 'PosReg', (120, 129))	('p27', 'Gene', (67, 70))
77542	29110682	Furthermore, a marked reduction in c-Myc and Survivin, downstream targets of p21, were observed after TAGLN2 knockdown.	('c-Myc', 'Gene', '4609', (35, 40))	('reduction', 'NegReg', (22, 31))	('TAGLN2 knockdown', 'Var', (102, 118))	('c-Myc', 'Gene', (35, 40))	('knockdown', 'Var', (109, 118))	('p21', 'Gene', (77, 80))	('Survivin', 'Protein', (45, 53))	('p21', 'Gene', '644914', (77, 80))
77543	29110682	Taken together, these results indicated that loss of TAGLN2 suppressed cell cycle progression and induced apoptosis in glioma cells.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('suppressed', 'NegReg', (60, 70))	('induced', 'Reg', (98, 105))	('apoptosis', 'CPA', (106, 115))	('glioma', 'Disease', (119, 125))	('cell cycle progression', 'CPA', (71, 93))	('TAGLN2', 'Gene', (53, 59))	('loss', 'Var', (45, 49))
77552	29110682	In the presence of TGFbeta2, TAGLN2 expression was decreased in Smad2 knockdown cells compared with control group (Fig.	('knockdown', 'Var', (70, 79))	('TGFbeta2', 'Gene', '7042', (19, 27))	('decreased', 'NegReg', (51, 60))	('Smad2', 'Gene', (64, 69))	('Smad2', 'Gene', '4087', (64, 69))	('TGFbeta2', 'Gene', (19, 27))	('TAGLN2 expression', 'MPA', (29, 46))
77554	29110682	To further examine the function of TAGLN2 protein in human gliomas, growth of cells depleted of the protein was assessed in vivo.	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TAGLN2', 'Var', (35, 41))	('human', 'Species', '9606', (53, 58))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
77555	29110682	Glioma cells were transduced with lentiviral constructs expressing TAGLN2-targeting shRNA or control shRNA.	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', (0, 6))	('TAGLN2-targeting', 'Var', (67, 83))
77557	29110682	Animals bearing sh-TAGLN2 cells displayed significantly reduced tumor size (Fig.	('tumor', 'Disease', (64, 69))	('sh-TAGLN2 cells', 'Var', (16, 31))	('reduced', 'NegReg', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
77559	29110682	These results demonstrated that TAGLN2 knockdown led to reduced growth and invasion of glioma cells in vivo.	('glioma', 'Disease', (87, 93))	('reduced', 'NegReg', (56, 63))	('knockdown', 'Var', (39, 48))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('TAGLN2', 'Gene', (32, 38))
77562	29110682	High TAGLN2 expression was associated with the mesenchymal molecular phenotype in human gliomas and thus poor prognosis in glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (88, 94))	('associated', 'Reg', (27, 37))	('gliomas', 'Disease', (88, 95))	('mesenchymal molecular phenotype', 'CPA', (47, 78))	('patients', 'Species', '9606', (130, 138))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Disease', (123, 129))	('High TAGLN2', 'Var', (0, 11))	('TAGLN2', 'Var', (5, 11))	('human', 'Species', '9606', (82, 87))
77563	29110682	In contrast, low TAGLN2 mRNA levels were linked to other positive prognostic markers, including IDH1 and ATRX mutations, methylated MGMT, 1p/19q codeletion, and loss of TERT.	('TERT', 'Gene', '7015', (169, 173))	('1p/19q codeletion', 'Var', (138, 155))	('IDH1', 'Gene', '3417', (96, 100))	('mutations', 'Var', (110, 119))	('ATRX', 'Gene', '546', (105, 109))	('low', 'NegReg', (13, 16))	('MGMT', 'Gene', '4255', (132, 136))	('MGMT', 'Gene', (132, 136))	('loss', 'Var', (161, 165))	('methylated', 'Var', (121, 131))	('ATRX', 'Gene', (105, 109))	('TERT', 'Gene', (169, 173))	('IDH1', 'Gene', (96, 100))	('TAGLN2 mRNA levels', 'MPA', (17, 35))
77567	29110682	Here, we observed that TAGLN2 depletion significantly decreased glioma cell invasiveness and reversed EMT features, including changes in epithelial (E-cadherin) and mesenchymal markers (N-cadherin, Snail, Slug, Twist) in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('depletion', 'Var', (30, 39))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('N-cadherin', 'Gene', (186, 196))	('Slug', 'Gene', (205, 209))	('glioma cell invasiveness', 'Disease', (64, 88))	('N-cadherin', 'Gene', '1000', (186, 196))	('TAGLN2', 'Gene', (23, 29))	('Snail', 'Gene', '6615', (198, 203))	('mesenchymal markers', 'CPA', (165, 184))	('changes', 'Reg', (126, 133))	('decreased', 'NegReg', (54, 63))	('Slug', 'Gene', '6591', (205, 209))	('EMT features', 'CPA', (102, 114))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('Snail', 'Gene', (198, 203))	('glioma', 'Disease', (221, 227))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('glioma cell invasiveness', 'Disease', 'MESH:D005910', (64, 88))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
77569	29110682	TAGLN2 silencing appeared to specifically suppress the F-actin-rich leading edge in glioma cells, thus reducing the formation of invadopodia during cell invasion.	('suppress', 'NegReg', (42, 50))	('F-actin-rich leading', 'MPA', (55, 75))	('TAGLN2 silencing', 'Var', (0, 16))	('glioma', 'Disease', (84, 90))	('formation of invadopodia', 'MPA', (116, 140))	('reducing', 'NegReg', (103, 111))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
77570	29110682	According to the study by Na et al., TAGLN2 blocks actin depolymerization and competes with cofilin to protect F-actin during the formation of immunological synapse in T cells, and knockout of TAGLN2 significantly destabilized F-actin ring formation, resulting in decreased cell adhesion and spreading.	('cofilin', 'Gene', (92, 99))	('blocks', 'NegReg', (44, 50))	('destabilized', 'NegReg', (214, 226))	('decreased', 'NegReg', (264, 273))	('TAGLN2', 'Gene', (193, 199))	('spreading', 'CPA', (292, 301))	('F-actin ring', 'MPA', (227, 239))	('actin depolymerization', 'MPA', (51, 73))	('knockout', 'Var', (181, 189))	('cofilin', 'Gene', '1072', (92, 99))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (264, 287))	('cell adhesion', 'CPA', (274, 287))
77571	29110682	Therefore, we hypothesize that TAGLN2 may promote invadopodia formation of glioma cells via competing with cofilin and suppressing actin depolymerization.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('actin depolymerization', 'MPA', (131, 153))	('suppressing', 'NegReg', (119, 130))	('TAGLN2', 'Var', (31, 37))	('cofilin', 'Gene', '1072', (107, 114))	('glioma', 'Disease', (75, 81))	('promote', 'PosReg', (42, 49))	('invadopodia formation', 'CPA', (50, 71))	('cofilin', 'Gene', (107, 114))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
77572	29110682	Altogether, these results indicated that TAGLN2 may serve as a crucial regulator of invasion and aggressiveness by inducing mesenchymal-like properties in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('mesenchymal-like properties', 'CPA', (124, 151))	('aggressiveness', 'Phenotype', 'HP:0000718', (97, 111))	('TAGLN2', 'Var', (41, 47))	('inducing', 'PosReg', (115, 123))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('aggressiveness', 'Disease', 'MESH:D001523', (97, 111))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('aggressiveness', 'Disease', (97, 111))
77574	29110682	GO and GSEA analysis indicated that TAGLN2 might indeed promote growth through functions in cell cycle progression and cell survival.	('GSEA', 'Chemical', '-', (7, 11))	('cell cycle progression', 'CPA', (92, 114))	('TAGLN2', 'Var', (36, 42))	('promote', 'PosReg', (56, 63))	('growth', 'CPA', (64, 70))	('cell survival', 'CPA', (119, 132))
77575	29110682	TAGLN2 knockdown in glioma cells induced cell cycle arrest at G0-G1 and cell apoptosis, and reduced growth in orthotopic xenografts.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('TAGLN2', 'Gene', (0, 6))	('growth in orthotopic xenografts', 'CPA', (100, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (41, 58))	('glioma', 'Disease', (20, 26))	('cell apoptosis', 'CPA', (72, 86))	('reduced', 'NegReg', (92, 99))	('knockdown', 'Var', (7, 16))	('cell cycle arrest at G0-G1', 'CPA', (41, 67))
77579	29110682	In the present study, TAGLN2 knockdown led to significantly reduced levels of FoxM1, as well as downstream oncogenic factors including CDK2, cyclin B1, and cyclin D1, c-Myc and Survivin.	('FoxM1', 'Gene', '2305', (78, 83))	('CDK2', 'Gene', '1017', (135, 139))	('cyclin D1', 'Gene', (156, 165))	('knockdown', 'Var', (29, 38))	('Survivin', 'Protein', (177, 185))	('FoxM1', 'Gene', (78, 83))	('cyclin B1', 'Gene', (141, 150))	('cyclin D1', 'Gene', '595', (156, 165))	('cyclin B1', 'Gene', '891', (141, 150))	('c-Myc', 'Gene', '4609', (167, 172))	('CDK2', 'Gene', (135, 139))	('reduced', 'NegReg', (60, 67))	('TAGLN2', 'Gene', (22, 28))	('levels', 'MPA', (68, 74))	('c-Myc', 'Gene', (167, 172))
77580	29110682	Meanwhile, tumor suppressor p21 and p27 were induced after TAGLN2 depletion.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('TAGLN2 depletion', 'Var', (59, 75))	('induced', 'PosReg', (45, 52))	('tumor', 'Disease', (11, 16))	('p21', 'Gene', (28, 31))	('p21', 'Gene', '644914', (28, 31))	('p27', 'Gene', '10534', (36, 39))	('p27', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
77581	29110682	These data suggest that TAGLN2 activates FoxM1 signaling during gliomagenesis.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('activates', 'PosReg', (31, 40))	('TAGLN2', 'Var', (24, 30))	('FoxM1', 'Gene', '2305', (41, 46))	('glioma', 'Disease', (64, 70))	('FoxM1', 'Gene', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
77582	29110682	However, further investigation is necessary to elucidate the mechanism of TAGLN2 regulation of FoxM1 axis in glioma.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('TAGLN2', 'Var', (74, 80))	('FoxM1', 'Gene', '2305', (95, 100))	('FoxM1', 'Gene', (95, 100))	('glioma', 'Disease', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
77584	29110682	For example, high expression of TAGLN2 in tumor-derived lung cancer endothelial cells was associated with clinical stage, tumor size, and tumor development in lung cancer tissues.	('tumor', 'Disease', (138, 143))	('clinical', 'Disease', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('lung cancer', 'Disease', (56, 67))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (42, 47))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('associated', 'Reg', (90, 100))	('lung cancer', 'Disease', (159, 170))	('TAGLN2', 'Var', (32, 38))	('clinical', 'Species', '191496', (106, 114))
77587	29110682	However, in gynecological malignancies, decreased expression of TAGLN2 was found in metastatic cells in comparison to primary tumors.	('malignancies', 'Disease', 'MESH:D009369', (26, 38))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('malignancies', 'Disease', (26, 38))	('primary tumor', 'Disease', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('primary tumor', 'Disease', 'MESH:D009369', (118, 131))	('decreased', 'NegReg', (40, 49))	('expression', 'MPA', (50, 60))	('TAGLN2', 'Var', (64, 70))
77589	29110682	These contradictory results reveal a complex role of TAGLN2 in tumorigenesis, urging further investigation.	('TAGLN2', 'Var', (53, 59))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
77592	29110682	In addition, studies have shown that TGFbeta2 overexpression promotes motility, invasion and EMT in cells from some cancer types, thus indicating a role for the TGFbeta2/Smad signaling pathway in tumorigenesis.	('invasion', 'CPA', (80, 88))	('tumor', 'Disease', (196, 201))	('EMT', 'CPA', (93, 96))	('cancer', 'Disease', (116, 122))	('promotes', 'PosReg', (61, 69))	('TGFbeta2', 'Gene', '7042', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('motility', 'CPA', (70, 78))	('TGFbeta2', 'Gene', '7042', (161, 169))	('TGFbeta2', 'Gene', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('overexpression', 'Var', (46, 60))	('TGFbeta2', 'Gene', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
77595	29110682	However, the precise molecular mechanisms of the cross-talk between TAGLN2 and TGFbeta2 signaling in gliomas require further investigation.	('TAGLN2', 'Var', (68, 74))	('TGFbeta2', 'Gene', (79, 87))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('TGFbeta2', 'Gene', '7042', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
77598	29110682	TAGLN2 may therefore serve as a novel biomarker and a potential therapeutic target in the treatment of human GBM.	('TAGLN2', 'Var', (0, 6))	('human', 'Species', '9606', (103, 108))	('human GBM', 'Disease', (103, 112))
77602	27295313	Somatic mutations in isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways are key oncogenic events in diffuse gliomas, including lower grade (grade II and III) gliomas (LGG) and the highly lethal brain tumor glioblastoma (GBM) respectively, where they reprogram the epigenome, transcriptome and metabolome to drive tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('gliomas', 'Disease', (132, 139))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('tumor', 'Disease', (337, 342))	('brain tumor', 'Phenotype', 'HP:0030692', (218, 229))	('RTK', 'Gene', (82, 85))	('GBM', 'Phenotype', 'HP:0012174', (244, 247))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('RTK', 'Gene', '5979', (82, 85))	('mutations', 'Var', (8, 17))	('isocitrate dehydrogenase', 'Gene', (21, 45))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('IDH', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('tumor', 'Disease', (224, 229))	('brain tumor glioblastoma', 'Disease', 'MESH:D005909', (218, 242))	('receptor tyrosine kinase', 'Gene', '5979', (56, 80))	('gliomas', 'Disease', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('IDH', 'Gene', '3417', (47, 50))	('brain tumor glioblastoma', 'Disease', (218, 242))	('receptor tyrosine kinase', 'Gene', (56, 80))	('isocitrate dehydrogenase', 'Gene', '3417', (21, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (230, 242))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))
77605	27295313	Here we describe a set of recent discoveries on cancer metabolism driven by IDH mutation and mutations in RTK pathways, highlighting the integration of genetic mutations, metabolic reprogramming and epigenetic shifts, potentially providing new therapeutic opportunities.	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RTK', 'Gene', '5979', (106, 109))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', '3417', (76, 79))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('RTK', 'Gene', (106, 109))	('mutation', 'Var', (80, 88))	('driven', 'Reg', (66, 72))
77606	27295313	The identification of distinct genetic and epigenetic profiles in different types of gliomas has revealed novel diagnostic, prognostic, and predictive molecular biomarkers for refining glioma classification.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('gliomas', 'Disease', (85, 92))	('epigenetic', 'Var', (43, 53))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('glioma', 'Disease', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', (185, 191))
77616	27295313	In addition, mutations in enzymes that regulate metabolite flux are also implicated in cancer development, as highlighted by the discovery of isocitrate dehydrogenase 1 (IDH1), or less commonly IDH2 gene mutations in more than 70% of diffusely infiltrating World Health Organization (WHO) grade II and grade III astrocytic and oligodendroglial gliomas, as well as in a small fraction of glioblastomas (GBMs), particularly those that develop from lower grade gliomas (LGGs).	('oligodendroglial gliomas', 'Disease', (327, 351))	('gliomas', 'Disease', 'MESH:D005910', (458, 465))	('IDH1', 'Gene', '3417', (170, 174))	('GBM', 'Phenotype', 'HP:0012174', (402, 405))	('glioblastoma', 'Phenotype', 'HP:0012174', (387, 399))	('glioblastomas', 'Disease', (387, 400))	('oligodendroglial gliomas', 'Disease', 'MESH:D005910', (327, 351))	('glioma', 'Phenotype', 'HP:0009733', (458, 464))	('gliomas', 'Phenotype', 'HP:0009733', (458, 465))	('gliomas', 'Disease', (344, 351))	('glioblastomas', 'Disease', 'MESH:D005909', (387, 400))	('GBMs', 'Phenotype', 'HP:0012174', (402, 406))	('cancer', 'Disease', (87, 93))	('IDH2', 'Gene', (194, 198))	('gliomas', 'Disease', 'MESH:D005910', (344, 351))	('mutations', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('IDH2', 'Gene', '3418', (194, 198))	('isocitrate dehydrogenase 1', 'Gene', (142, 168))	('glioma', 'Phenotype', 'HP:0009733', (344, 350))	('isocitrate dehydrogenase 1', 'Gene', '3417', (142, 168))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', (170, 174))	('gliomas', 'Disease', (458, 465))	('gliomas', 'Phenotype', 'HP:0009733', (344, 351))	('glioblastomas', 'Phenotype', 'HP:0012174', (387, 400))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
77617	27295313	Therefore, unraveling the molecular mechanisms by which mutations in the growth factor receptor signaling system and IDH reprogram glioma cell metabolism will shed new light on the contribution of genetic aberrations to the glioma pathogenesis.	('glioma', 'Disease', (131, 137))	('mutations', 'Var', (56, 65))	('IDH', 'Gene', (117, 120))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('IDH', 'Gene', '3417', (117, 120))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('glioma', 'Disease', (224, 230))
77618	27295313	Here we review a set of recent discoveries on cancer metabolism involving IDH-mutated LGGs and IDH wild-type GBMs primarily driven by mutations in receptor tyrosine kinase (RTK) pathways.	('receptor tyrosine kinase', 'Gene', '5979', (147, 171))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('RTK', 'Gene', (173, 176))	('cancer', 'Disease', (46, 52))	('GBMs', 'Phenotype', 'HP:0012174', (109, 113))	('LGGs', 'Disease', (86, 90))	('driven by', 'Reg', (124, 133))	('IDH', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (134, 143))	('IDH', 'Gene', (95, 98))	('RTK', 'Gene', '5979', (173, 176))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', '3417', (74, 77))	('receptor tyrosine kinase', 'Gene', (147, 171))
77619	27295313	These highlight the integration of genetic aberrations with altered signaling, metabolic reprogramming, and epigenetic changes downstream of common cancer mutations, potentially providing new therapeutic opportunities for these deadly types of brain tumors.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('brain tumor', 'Phenotype', 'HP:0030692', (244, 255))	('genetic aberrations', 'Var', (35, 54))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('brain tumors', 'Disease', 'MESH:D001932', (244, 256))	('brain tumors', 'Phenotype', 'HP:0030692', (244, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('altered', 'Reg', (60, 67))	('epigenetic changes', 'Var', (108, 126))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('brain tumors', 'Disease', (244, 256))
77621	27295313	The tumorigenic potential of mutant IDH is primarily associated with a metabolic shift in glioma cells (Fig.	('tumor', 'Disease', (4, 9))	('glioma', 'Disease', (90, 96))	('mutant', 'Var', (29, 35))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('IDH', 'Gene', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('metabolic', 'MPA', (71, 80))	('associated', 'Reg', (53, 63))	('IDH', 'Gene', '3417', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
77622	27295313	It has been shown that mutant IDH acquires a neomorphic activity that converts alpha-KG to D(R)-2-hydroxyglutarate (D-2-HG) in an NADPH-consuming reduction, leading to the intriguing idea that D-2-HG acts as "oncometabolites."	('NADPH', 'Chemical', 'MESH:D009249', (130, 135))	('D(R)-2-hydroxyglutarate', 'Chemical', '-', (91, 114))	('neomorphic activity', 'MPA', (45, 64))	('D-2-HG', 'Chemical', '-', (193, 199))	('D-2-HG', 'Chemical', '-', (116, 122))	('IDH', 'Gene', (30, 33))	('alpha-KG', 'Chemical', 'MESH:D007656', (79, 87))	('IDH', 'Gene', '3417', (30, 33))	('mutant', 'Var', (23, 29))
77625	27295313	Additionally, IDH mutation decreases intracellular NADPH levels required for the reduction of glutathione disulfide (GSSG) to GSH, thereby causing increased oxidative stress that promotes tumorigenesis but also increases therapy sensitivity.	('tumor', 'Disease', (188, 193))	('intracellular NADPH levels required', 'MPA', (37, 72))	('NADPH', 'Chemical', 'MESH:D009249', (51, 56))	('GSSG', 'Chemical', 'MESH:D019803', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('increases', 'PosReg', (211, 220))	('GSH', 'Chemical', '-', (126, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (157, 173))	('promotes', 'PosReg', (179, 187))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (147, 173))	('mutation', 'Var', (18, 26))	('glutathione disulfide', 'Chemical', 'MESH:D019803', (94, 115))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('IDH', 'Gene', (14, 17))	('increased', 'PosReg', (147, 156))	('glutathione disulfide', 'MPA', (94, 115))	('decreases', 'NegReg', (27, 36))	('IDH', 'Gene', '3417', (14, 17))	('oxidative stress', 'MPA', (157, 173))	('therapy sensitivity', 'CPA', (221, 240))
77626	27295313	In line with this hypothesis, oxidative stress may promote further genetic changes, such as TP53 mutation or t(1;19) translocation, leading to development of either astrocytoma or oligodendroglioma, and IDH mutation is associated with better response to cytotoxic therapy and longer survival in malignant glioma patients.	('astrocytoma or oligodendroglioma', 'Disease', 'MESH:D009837', (165, 197))	('IDH', 'Gene', (203, 206))	('leading to', 'Reg', (132, 142))	('mutation', 'Var', (97, 105))	('IDH', 'Gene', '3417', (203, 206))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('patients', 'Species', '9606', (312, 320))	('oxidative stress', 'Phenotype', 'HP:0025464', (30, 46))	('astrocytoma or oligodendroglioma', 'Disease', (165, 197))	('malignant glioma', 'Disease', (295, 311))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('t(1;19', 'Gene', (109, 115))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('malignant glioma', 'Disease', 'MESH:D005910', (295, 311))	('mutation', 'Var', (207, 215))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))
77627	27295313	The specific nature of IDH mutation in gliomas may be further exploited for 2-HG-targeting diagnostics and mutant IDH-targeting therapeutics.	('IDH', 'Gene', (114, 117))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('mutation', 'Var', (27, 35))	('gliomas', 'Disease', (39, 46))	('IDH', 'Gene', '3417', (114, 117))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('IDH', 'Gene', (23, 26))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH', 'Gene', '3417', (23, 26))
77635	27295313	Among these, the genomic characterization of IDH wild-type GBM reveals frequent genetic alterations of key components of the growth factor receptor-PI3K-Akt signaling pathway that activate mechanistic target of rapamycin (mTOR) signaling.	('genetic alterations', 'Var', (80, 99))	('IDH', 'Gene', (45, 48))	('Akt', 'Gene', '207', (153, 156))	('IDH', 'Gene', '3417', (45, 48))	('Akt', 'Gene', (153, 156))	('alterations', 'Var', (88, 99))	('mTOR', 'Gene', '2475', (222, 226))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('activate', 'PosReg', (180, 188))	('mechanistic target of rapamycin', 'Gene', (189, 220))	('mTOR', 'Gene', (222, 226))	('mechanistic target of rapamycin', 'Gene', '2475', (189, 220))
77638	27295313	Only recently has it been determined how the mutations in growth factor receptor signaling pathways, such as epidermal growth factor receptor (EGFR) mutations which are most commonly detected in IDH wild-type GBM, cooperate with c-Myc to promote tumorigenesis.	('cooperate', 'Reg', (214, 223))	('EGFR', 'Gene', (143, 147))	('IDH', 'Gene', (195, 198))	('mutations', 'Var', (45, 54))	('mutations', 'Var', (149, 158))	('GBM', 'Phenotype', 'HP:0012174', (209, 212))	('epidermal growth factor receptor', 'Gene', '1956', (109, 141))	('IDH', 'Gene', '3417', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (246, 251))	('c-Myc', 'Gene', '4609', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('c-Myc', 'Gene', (229, 234))	('EGFR', 'Gene', '1956', (143, 147))	('epidermal growth factor receptor', 'Gene', (109, 141))	('promote', 'PosReg', (238, 245))
77642	27295313	Importantly, failure to inhibit mTOR signaling can render GBM cells resistant to PI3K or Akt targeted therapies by maintaining elevated levels of c-Myc.	('c-Myc', 'Gene', '4609', (146, 151))	('mTOR', 'Gene', '2475', (32, 36))	('Akt', 'Gene', '207', (89, 92))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('mTOR', 'Gene', (32, 36))	('c-Myc', 'Gene', (146, 151))	('failure', 'Var', (13, 20))	('elevated', 'PosReg', (127, 135))	('Akt', 'Gene', (89, 92))
77646	27295313	Cancer metabolic reprogramming has been shown to be a consequence of upstream mutations in IDH in LGGs and the RTK signaling network in IDH wild-type GBM.	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('RTK', 'Gene', (111, 114))	('mutations', 'Var', (78, 87))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('IDH', 'Gene', (91, 94))	('RTK', 'Gene', '5979', (111, 114))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('IDH', 'Gene', '3417', (91, 94))
77648	27295313	Mutations in IDH, which were identified as early genetic events in gliomagenesis, play an important role in gliomas through neomorphic activity that converts alpha-KG to 2-HG as aforementioned, which inhibits alpha-KG-dependent dioxygenases including histone demethylases and the TET family of 5'-methlycytosine hydroxylases.	('gliomas', 'Disease', (108, 115))	('glioma', 'Disease', (108, 114))	('glioma', 'Disease', (67, 73))	('oxygen', 'Chemical', 'MESH:D010100', (230, 236))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('histone demethylases', 'Enzyme', (251, 271))	('alpha-KG-dependent', 'Enzyme', (209, 227))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('alpha-KG', 'Chemical', 'MESH:D007656', (209, 217))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH', 'Gene', (13, 16))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	("TET family of 5'-methlycytosine hydroxylases", 'Enzyme', (280, 324))	('IDH', 'Gene', '3417', (13, 16))	('inhibits', 'NegReg', (200, 208))	('alpha-KG', 'Chemical', 'MESH:D007656', (158, 166))
77649	27295313	The presence of IDH mutations thus leads to a distinct subgroup of glioma with a CpG island methylator phenotype (G-CIMP) and aberrant histone methylation, which possibly locks differentiation-related genes in an inactive state, disrupts chromosomal topology and changes the landscape of enhancers, eventually contributing to tumorigenesis.	('changes', 'Reg', (263, 270))	('glioma', 'Disease', (67, 73))	('IDH', 'Gene', (16, 19))	('landscape of enhancers', 'MPA', (275, 297))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('contributing to', 'Reg', (310, 325))	('disrupts', 'NegReg', (229, 237))	('histone', 'Protein', (135, 142))	('IDH', 'Gene', '3417', (16, 19))	('tumor', 'Disease', (326, 331))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('aberrant', 'Var', (126, 134))	('chromosomal topology', 'MPA', (238, 258))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('presence', 'Var', (4, 12))	('mutations', 'Var', (20, 29))	('leads to', 'Reg', (35, 43))	('G-CIMP', 'Chemical', '-', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))
77650	27295313	Subsequent discovery of germline or somatic mutations in genes coding for metabolic enzymes (succinate dehydrogenase and fumarate hydratase) that are associated with tumor susceptibility by altering the epigenome further supports the idea of oncometabolites to "tailor the genetics".	('associated', 'Reg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('epigenome', 'MPA', (203, 212))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('fumarate hydratase', 'Gene', '2271', (121, 139))	('mutations', 'Var', (44, 53))	('altering', 'Reg', (190, 198))	('fumarate hydratase', 'Gene', (121, 139))
77651	27295313	On the other hand, in EGFR-mutant GBMs which do not usually possess the mutations in IDH or H3 histone family 3A (H3F3A) to potentially change the epigenetics, constitutive PI3K activation could engage the epigenetic machinery through several complementary routes.	('change', 'Reg', (136, 142))	('mutations', 'Var', (72, 81))	('IDH', 'Gene', '3417', (85, 88))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('engage', 'Reg', (195, 201))	('epigenetics', 'MPA', (147, 158))	('H3 histone family 3A', 'Gene', '3020', (92, 112))	('H3F3A', 'Gene', '3020', (114, 119))	('EGFR', 'Gene', '1956', (22, 26))	('GBMs', 'Phenotype', 'HP:0012174', (34, 38))	('IDH', 'Gene', (85, 88))	('H3 histone family 3A', 'Gene', (92, 112))	('H3F3A', 'Gene', (114, 119))	('EGFR', 'Gene', (22, 26))
77653	27295313	Interestingly, epigenetic regulation of c-Myc may be a central mechanism for its overexpression in GBM.	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('epigenetic regulation', 'Var', (15, 36))	('overexpression', 'PosReg', (81, 95))	('c-Myc', 'Gene', '4609', (40, 45))	('GBM', 'Disease', (99, 102))	('c-Myc', 'Gene', (40, 45))
77655	27295313	In addition to the change in intracellular nutrient, we recently made the surprising discovery that exogenous glucose or acetate, two "fuel sources" that are widely available in the brain and readily taken up by tumor cells, are required for mutant EGFR signaling.	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (249, 253))	('mutant', 'Var', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('acetate', 'Chemical', 'MESH:D000085', (121, 128))	('tumor', 'Disease', (212, 217))
77664	27295313	This notion has been further supported by a recent large-scale genomic, epigenomic, transcriptomic and proteomic analysis of diffuse gliomas, demonstrating that methylome, transcriptome and functional copy number variations connect to the status of IDH mutations (i.e.	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('copy number variations', 'Var', (201, 223))	('IDH', 'Gene', '3417', (249, 252))	('connect', 'Reg', (224, 231))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('IDH', 'Gene', (249, 252))
77668	27295313	The biochemical environment can shape the behavior of tumor cells in a genotype-specific fashion, potentially by altering the relative fitness of cells bearing a mutation to grow within that metabolic niche and also by directly regulating downstream signaling.	('regulating', 'Reg', (228, 238))	('altering', 'Reg', (113, 121))	('signaling', 'MPA', (250, 259))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutation', 'Var', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('shape', 'Reg', (32, 37))	('tumor', 'Disease', (54, 59))
77670	27295313	Future studies are needed to determine precisely how chief genetic mutations specific in each glioma entity facilitate cancer metabolic reprogramming and how at the same time extracellular nutrients modulate oncogenic signaling, in order to translate these insights into more effective treatments for glioma patients.	('oncogenic', 'MPA', (208, 217))	('glioma', 'Disease', (94, 100))	('patients', 'Species', '9606', (308, 316))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (67, 76))	('facilitate', 'PosReg', (108, 118))	('cancer', 'Disease', (119, 125))	('glioma', 'Disease', (301, 307))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('modulate', 'Reg', (199, 207))	('glioma', 'Phenotype', 'HP:0009733', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('glioma', 'Disease', 'MESH:D005910', (301, 307))
77679	27651314	Furthermore, high IDO expression correlates with poor clinical prognosis in several human cancers and plays an immunosuppressive role in the context of immunotherapies.	('in t', 'Gene', (134, 138))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('high', 'Var', (13, 17))	('in t', 'Gene', '27152', (134, 138))	('IDO', 'Gene', '3620', (18, 21))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('poor', 'NegReg', (49, 53))	('IDO', 'Gene', (18, 21))	('expression', 'MPA', (22, 32))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
77683	27651314	While it is known that in T cells, IDO-mediated tryptophan depletion induces a GCN2-dependent proliferative arrest, inhibiting the G1-to-S phase transition, the molecular mechanisms by which IDO- and TDO-expressing cancer cells remain resistant to local tryptophan depletion remain largely unknown.	('tryptophan', 'Var', (48, 58))	('inhibiting', 'NegReg', (116, 126))	('tryptophan', 'Chemical', 'MESH:D014364', (48, 58))	('tryptophan', 'Chemical', 'MESH:D014364', (254, 264))	('G1-to-S phase transition', 'CPA', (131, 155))	('GCN2-dependent', 'MPA', (79, 93))	('IDO', 'Gene', (191, 194))	('IDO', 'Gene', '3620', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('IDO', 'Gene', '3620', (191, 194))	('IDO', 'Gene', (35, 38))
77713	27651314	IFNgamma-treated WT, IDO1-transduced HeLa, as well as HeLa cells overexpressing the tryptophan-degrading enzyme TDO exhibited increased expression of all three SLC1A5 variants (Fig.	('variants', 'Var', (167, 175))	('expression', 'MPA', (136, 146))	('WT, IDO1', 'Gene', '3620', (17, 25))	('HeLa', 'CellLine', 'CVCL:0030', (54, 58))	('SLC', 'Gene', '6366', (160, 163))	('tryptophan', 'Chemical', 'MESH:D014364', (84, 94))	('HeLa', 'CellLine', 'CVCL:0030', (37, 41))	('SLC', 'Gene', (160, 163))	('increased', 'PosReg', (126, 135))
77726	27651314	Furthermore, SLC1A5 knockdown resulted in a significant impairment of HeLa cell proliferation under amino acid sufficient conditions (Fig.	('knockdown', 'Var', (20, 29))	('HeLa cell proliferation', 'CPA', (70, 93))	(', SLC', 'Gene', '6366', (11, 16))	('impairment', 'NegReg', (56, 66))
77749	27651314	While ATF4 protein was almost undetectable in complete medium, its expression increased markedly in tumor cells cultured in the absence of tryptophan, glutamine, and, to a lesser extent, arginine and isoleucine (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tryptophan', 'MPA', (139, 149))	('protein', 'Protein', (11, 18))	('isoleucine', 'Chemical', 'MESH:D007532', (200, 210))	('in t', 'Gene', (97, 101))	('arginine', 'Var', (187, 195))	('in t', 'Gene', (121, 125))	('increased', 'PosReg', (78, 87))	('tryptophan', 'Chemical', 'MESH:D014364', (139, 149))	('expression', 'MPA', (67, 77))	('ATF4', 'Gene', (6, 10))	('arginine', 'Chemical', 'MESH:D001120', (187, 195))	('in t', 'Gene', '27152', (97, 101))	('glutamine', 'Protein', (151, 160))	('glutamine', 'Chemical', 'MESH:D005973', (151, 160))	('in t', 'Gene', '27152', (121, 125))	('isoleucine', 'Var', (200, 210))
77753	27651314	To determine the role of the ATF4 pathway in regulation of SLC1A5 expression under tryptophan-deficient conditions, we knocked down ATF4 from HeLa cells using a lentiviral CRISPR construct.	('SLC', 'Gene', (59, 62))	('knocked', 'Var', (119, 126))	('tryptophan-deficient conditions', 'Disease', 'MESH:D016603', (83, 114))	('SLC', 'Gene', '6366', (59, 62))	('tryptophan-deficient conditions', 'Disease', (83, 114))	('ATF4', 'Gene', (132, 136))
77764	27651314	In line with these results, pharmacological inhibition of SLC1A5 reduced mTOR activation in stimulated T cells (Fig.	('mTOR activation', 'MPA', (73, 88))	('reduced', 'NegReg', (65, 72))	(' cel', 'Gene', (104, 108))	('pharmacological inhibition', 'Var', (28, 54))	('SLC', 'Gene', '6366', (58, 61))	(' cel', 'Gene', '1056', (104, 108))	('SLC', 'Gene', (58, 61))
77791	27651314	6A), high expression of SLC1A5 was significantly associated with decreased patient survival (Hazard ratio=0.40526; log-rank test p-value=0.00006) (Fig.	('SLC', 'Gene', '6366', (24, 27))	('patient survival', 'CPA', (75, 91))	('SLC', 'Gene', (24, 27))	('high expression', 'Var', (5, 20))	('decreased', 'NegReg', (65, 74))	('patient', 'Species', '9606', (75, 82))
77792	27651314	We also observed a similar association between survival and high IDO1 expression in this tumor type (Hazard ratio=0.46179; log-rank test p-value=0.00053) (Fig.	('in t', 'Gene', (81, 85))	('high', 'Var', (60, 64))	('IDO1', 'Gene', (65, 69))	('in t', 'Gene', '27152', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('expression', 'MPA', (70, 80))	('IDO1', 'Gene', '3620', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
77797	27651314	Up-regulation of SLC1A5 (and its splice variants), in addition to enhancing the uptake of glutamine, also improves tryptophan transport, which can be blocked by the SLC1A5-specific inhibitor BenSer or by deleting expression of LAT1 (SLC7A5) - a component of the ubiquitous amino acid transporter System L, which constitutes the major neutral amino acid transport system, importing large hydrophobic amino acids with branched or aromatic side chains, such as leucine and tryptophan.	('deleting', 'Var', (204, 212))	('SLC', 'Gene', (17, 20))	('s tr', 'Gene', (113, 117))	('LAT1', 'Gene', (227, 231))	('SLC', 'Gene', (165, 168))	('s tr', 'Gene', '6779', (113, 117))	('LAT1', 'Gene', '8140', (227, 231))	('glutamine', 'Chemical', 'MESH:D005973', (90, 99))	('tryptophan', 'Chemical', 'MESH:D014364', (115, 125))	('SLC', 'Gene', '6366', (165, 168))	('tryptophan', 'Chemical', 'MESH:D014364', (470, 480))	('uptake of glutamine', 'MPA', (80, 99))	('enhancing', 'PosReg', (66, 75))	('Up-regulation', 'PosReg', (0, 13))	('leucine', 'Chemical', 'MESH:D007930', (458, 465))	('SLC', 'Gene', '6366', (233, 236))	('SLC', 'Gene', '6366', (17, 20))	('SLC', 'Gene', (233, 236))
77831	27651314	Our observations complement previous studies, which have proposed high SLC1A5 expression as a marker of poor prognosis in MYCN-driven neuroblastoma, non-small cell lung cancer and breast cancer.	('non-small cell lung cancer', 'Disease', (149, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (153, 175))	('SLC', 'Gene', '6366', (71, 74))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('SLC', 'Gene', (71, 74))	('neuroblastoma', 'Disease', 'MESH:D009447', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('high', 'Var', (66, 70))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (149, 175))	('neuroblastoma', 'Disease', (134, 147))	('neuroblastoma', 'Phenotype', 'HP:0003006', (134, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (149, 175))
77836	33169458	A functional variant on 20q13.33 related to glioma risk alters enhancer activity and modulates expression of multiple genes Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with glioma risk on 20q13.33, but the biological mechanisms underlying this association are unknown.	('modulates', 'Reg', (85, 94))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('variant', 'Var', (13, 20))	('glioma', 'Disease', (44, 50))	('alters', 'Reg', (56, 62))	('single-nucleotide polymorphisms', 'Var', (179, 210))	('enhancer activity', 'MPA', (63, 80))	('glioma', 'Disease', (234, 240))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('expression', 'MPA', (95, 105))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
77838	33169458	Putative enhancers containing candidate functional SNPs were tested for allele-specific effects in luciferase enhancer activity assays against glioblastoma multiforme (GBM) cell lines.	('enhancer', 'PosReg', (110, 118))	('glioblastoma multiforme', 'Disease', (143, 166))	('luciferase', 'Enzyme', (99, 109))	('SNPs', 'Var', (51, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('activity', 'MPA', (119, 127))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (143, 166))
77839	33169458	An enhancer containing SNP rs3761124 exhibited allele-specific effects on activity.	('rs3761124', 'Mutation', 'rs3761124', (27, 36))	('SNP rs3761124', 'Var', (23, 36))	('activity', 'MPA', (74, 82))
77840	33169458	Deletion of this enhancer by CRISPR-Cas9 editing in GBM cell lines correlated with an altered expression of multiple genes, including STMN3, RTEL1, RTEL1-TNFRSF6B, GMEB2, and SRMS.	('RTEL1', 'Gene', (141, 146))	('altered', 'Reg', (86, 93))	('TNFRSF6B', 'Gene', '8771', (154, 162))	('GMEB2', 'Gene', '26205', (164, 169))	('Deletion', 'Var', (0, 8))	('SRMS', 'Gene', (175, 179))	('TNFRSF6B', 'Gene', (154, 162))	('SRMS', 'Gene', '6725', (175, 179))	('GMEB2', 'Gene', (164, 169))	('expression', 'MPA', (94, 104))	('STMN3', 'Gene', '50861', (134, 139))	('STMN3', 'Gene', (134, 139))	('RTEL1', 'Gene', '51750', (148, 153))	('RTEL1', 'Gene', '51750', (141, 146))	('RTEL1', 'Gene', (148, 153))
77841	33169458	Expression quantitative trait loci (eQTL) analyses using nondiseased brain samples, isocitrate dehydrogenase 1 (IDH1) wild-type glioma, and neurodevelopmental tissues showed STMN3 to be a consistent significant eQTL with rs3761124.	('STMN3', 'Gene', '50861', (174, 179))	('STMN3', 'Gene', (174, 179))	('isocitrate dehydrogenase 1', 'Gene', '3417', (84, 110))	('glioma', 'Disease', (128, 134))	('IDH1', 'Gene', (112, 116))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('rs3761124', 'Mutation', 'rs3761124', (221, 230))	('IDH1', 'Gene', '3417', (112, 116))	('isocitrate dehydrogenase 1', 'Gene', (84, 110))	('rs3761124', 'Var', (221, 230))
77843	33169458	We provide evidence that rs3761124 is a functional variant on 20q13.33 related to glioma/GBM risk that modulates the expression of STMN3 and potentially other genes across diverse cellular contexts.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('related', 'Reg', (71, 78))	('expression', 'MPA', (117, 127))	('modulates', 'Reg', (103, 112))	('STMN3', 'Gene', (131, 136))	('STMN3', 'Gene', '50861', (131, 136))	('rs3761124', 'Mutation', 'rs3761124', (25, 34))	('glioma', 'Disease', (82, 88))	('rs3761124', 'Var', (25, 34))
77848	33169458	The discovery of the biological mechanism underlying these risk variants has the potential to reveal novel insights into glioma development.	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('variants', 'Var', (64, 72))	('glioma', 'Disease', (121, 127))
77850	33169458	In the first two GWAS conducted on glioma, several risk variants were identified that reached genome-wide significance in 20q13.33, with rs6010620 (NC_000020.10:g.62309839A>G) being the common risk SNP between the two studies (Shete et al., 2009; Wrensch et al., 2009).	('g.62309839A>G', 'Var', (161, 174))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('rs6010620', 'Var', (137, 146))	('rs6010620', 'Mutation', 'rs6010620', (137, 146))	('NC_000020.10:g.62309839A>G', 'Mutation', 'rs6010620', (148, 174))	('glioma', 'Disease', (35, 41))
77851	33169458	Subsequent GWAS further confirmed 20q13.33 as a risk locus (Kinnersley et al., 2015; Rajaraman et al., 2012), with the most recent and largest Glioma International Case-Control (GICC) GWAS meta-analysis (cases: 12,496, controls: 18,190) again confirming the association between a polymorphism in 20q13.33 and glioma, and the top GWAS SNP as rs2297440 (GICC GWAS meta-analysis p = 1.16E-38; NC_000020.10:g.62312299T>C; Melin et al., 2017), where the association was strongest with GBM.	('glioma', 'Disease', (309, 315))	('rs2297440', 'Mutation', 'rs2297440', (341, 350))	('NC_000020.10:g.62312299T>C', 'Mutation', 'rs2297440', (390, 416))	('rs2297440', 'Var', (341, 350))	('20q13.33', 'Gene', (296, 304))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('Glioma', 'Disease', 'MESH:D005910', (143, 149))	('association', 'Interaction', (258, 269))	('glioma', 'Disease', 'MESH:D005910', (309, 315))	('Glioma', 'Disease', (143, 149))	('polymorphism', 'Var', (280, 292))	('Glioma', 'Phenotype', 'HP:0009733', (143, 149))	('g.62312299T>C', 'Var', (403, 416))
77853	33169458	The top GWAS SNP at 20q13.33, rs2297440, maps to Intron 14 of the regulator of telomere elongation helicase 1 (RTEL1).	('regulator of telomere elongation helicase 1', 'Gene', '51750', (66, 109))	('rs2297440', 'Mutation', 'rs2297440', (30, 39))	('regulator of telomere elongation helicase 1', 'Gene', (66, 109))	('rs2297440', 'Var', (30, 39))	('RTEL1', 'Gene', '51750', (111, 116))	('RTEL1', 'Gene', (111, 116))
77856	33169458	Several candidate target genes of this enhancer were identified after CRISPR-Cas9 deletion including stathmin 3 (STMN3).	('CRISPR-Cas9', 'Gene', (70, 81))	('stathmin 3', 'Gene', (101, 111))	('deletion', 'Var', (82, 90))	('stathmin 3', 'Gene', '50861', (101, 111))	('STMN3', 'Gene', '50861', (113, 118))	('STMN3', 'Gene', (113, 118))
77857	33169458	We further demonstrated that this variant correlated with the expression of several cis genes using eQTL analysis, including STMN3 as the most consistent target gene across different cellular contexts.	('STMN3', 'Gene', '50861', (125, 130))	('STMN3', 'Gene', (125, 130))	('expression', 'MPA', (62, 72))	('variant', 'Var', (34, 41))	('correlated', 'Reg', (42, 52))
77858	33169458	Several GWAS have shown an association between SNPs mapping to chromosome 20q13.33 and glioma risk (Kinnersley et al., 2015; Melin et al., 2017; Rajaraman et al., 2012; Shete et al., 2009).	('glioma', 'Disease', (87, 93))	('SNPs mapping', 'Var', (47, 59))	('association', 'Interaction', (27, 38))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))
77861	33169458	To identify candidate functional SNPs, we used University of California Santa Cruz Genome Browser (http://genome.ucsc.edu/; Kent et al., 2002) to overlay the SNPs in LD with rs2297440 with physiologically relevant histone ChIP-Seq peaks for H3K4me1 (from Encyclopedia of DNA Elements [ENCODE] normal human astrocyte cell line GSM733710) and H3K27ac (from ENCODE normal human astrocyte cell line GSM733763 and ENCODE GBM cell line GSM1121878; Figure 1).	('H3K4me1', 'Var', (241, 248))	('California Santa Cruz', 'Disease', (61, 82))	('human', 'Species', '9606', (300, 305))	('California Santa Cruz', 'Disease', 'MESH:D004670', (61, 82))	('H3K27ac', 'Var', (341, 348))	('rs2297440', 'Mutation', 'rs2297440', (174, 183))	('rs2297440', 'Var', (174, 183))	('human', 'Species', '9606', (369, 374))
77862	33169458	All cloned candidate enhancer regions contained at least one SNP in LD (r 2 > = .6) with the lead SNP (rs2297440) and coincided with peaks of chromatin marks of enhancers in at least two relevant ChIP-seq datasets.	('rs2297440', 'Var', (103, 112))	('chromatin', 'MPA', (142, 151))	('rs2297440', 'Mutation', 'rs2297440', (103, 112))
77863	33169458	Additional histone ChIP-Seq peaks for enhancer elements derived from normal human astrocytes, human glioblastoma cancer stem cells, and human glioblastoma cell lines were also used in these analyses (GSM1121881, GSM894065, GSM1515744, GSM2500170, GSM1121859, and GSM1121869; data are not shown).	('human', 'Species', '9606', (136, 141))	('GSM894065', 'Var', (212, 221))	('GSM1121859', 'Var', (247, 257))	('glioblastoma cancer', 'Disease', 'MESH:D009369', (100, 119))	('GSM1121881', 'Var', (200, 210))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('glioblastoma', 'Disease', (100, 112))	('GSM1515744', 'Var', (223, 233))	('glioblastoma cancer', 'Disease', (100, 119))	('human', 'Species', '9606', (76, 81))	('human', 'Species', '9606', (94, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('glioblastoma', 'Disease', (142, 154))	('glioblastoma', 'Disease', 'MESH:D005909', (142, 154))	('GSM2500170', 'Var', (235, 245))	('GSM1121869', 'Var', (263, 273))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
77881	33169458	The association between rs3761124 and expression of cis genes was evaluated in adult brains without neurological diseases, during early neurological development, and in IDH1 wild-type adult glioma.	('IDH1', 'Gene', (169, 173))	('glioma', 'Disease', (190, 196))	('rs3761124', 'Mutation', 'rs3761124', (24, 33))	('IDH1', 'Gene', '3417', (169, 173))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('rs3761124', 'Var', (24, 33))	('neurological diseases', 'Disease', 'MESH:D020271', (100, 121))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('neurological diseases', 'Disease', (100, 121))
77886	33169458	Linear regression was used to evaluate the association between rs3761124 and specific target genes discovered by quantitative RT-PCR, with age, gender, RIN scores, the first three principal components of genotype, and RNA-seq expression residuals as covariates.	('rs3761124', 'Mutation', 'rs3761124', (63, 72))	('association', 'Interaction', (43, 54))	('rs3761124', 'Var', (63, 72))
77900	33169458	A high PP4 (>0.8) and low PP3 (<0.2) indicate that a single variant (rs3761124) is responsible for both the GWAS and eQTL signals.	('PP3', 'Chemical', '-', (26, 29))	('rs3761124', 'Mutation', 'rs3761124', (69, 78))	('rs3761124', 'Var', (69, 78))	('PP4', 'Gene', '5531', (7, 10))	('responsible', 'Reg', (83, 94))	('PP4', 'Gene', (7, 10))
77904	33169458	There were a total of six SNPs (r 2 of >= .6 with rs2297440) within these three enhancer regions (rs3761124 [NC_000020.10:g.62288752T>C] in Region 2, rs1291209 [NC_000020.10:g.62330439T>C] and rs1295810 [NC_000020.10:g.62330484G>A] in Region 3, and rs1741708 [NC_000020.10:g.62372041G>T], rs2253823 [NC_000020.10:g.62372956C>T], and rs2253829 [NC_000020.10:g.62373079G>C] in Region 4), but only one, rs3761124, in the enhancer Region 2 (Figure 1) demonstrated allele-specific effects.	('rs2253823 [NC_000020.10', 'Var', (289, 312))	('NC_000020.10:g.62330439T>C', 'Mutation', 'rs1291209', (161, 187))	('rs1741708', 'Mutation', 'rs1741708', (249, 258))	('NC_000020.10:g.62372956C>T', 'Mutation', 'rs2253823', (300, 326))	('rs1741708 [', 'Var', (249, 260))	('rs2253829', 'Mutation', 'rs2253829', (333, 342))	('NC_000020.10:g.62330484G>A', 'Mutation', 'rs1295810', (204, 230))	('NC_000020.10:g.62288752T>C', 'Mutation', 'rs3761124', (109, 135))	('NC_000020.10:g.62373079G>C', 'Mutation', 'rs2253829', (344, 370))	('rs3761124', 'Mutation', 'rs3761124', (400, 409))	('rs1291209 [', 'Var', (150, 161))	('rs2253823', 'Mutation', 'rs2253823', (289, 298))	('rs3761124', 'Mutation', 'rs3761124', (98, 107))	('rs2297440', 'Mutation', 'rs2297440', (50, 59))	('rs2253829 [', 'Var', (333, 344))	('rs1295810', 'Mutation', 'rs1295810', (193, 202))	('g.62330484G>A]', 'Var', (217, 231))	('NC_000020.10:g.62372041G>T', 'Mutation', 'rs1741708', (260, 286))	('rs1295810 [', 'Var', (193, 204))	('rs1291209', 'Mutation', 'rs1291209', (150, 159))
77905	33169458	rs3761124 is 23.7 kb away from the top GWAS SNP, rs2297440, and is in high LD with it (r 2 of .92 in the European population).	('rs3761124', 'Var', (0, 9))	('rs2297440', 'Mutation', 'rs2297440', (49, 58))	('rs3761124', 'Mutation', 'rs3761124', (0, 9))	('rs2297440', 'Var', (49, 58))
77906	33169458	Whereas the candidate enhancer in Region 2 demonstrated activity in luciferase assays in both directions, rs3761124 showed allele-specific effects on enhancer activity in the forward orientation only (Figure 2), and not the reverse orientation in either cell line (data not shown).	('enhancer', 'PosReg', (150, 158))	('activity', 'MPA', (56, 64))	('activity', 'MPA', (159, 167))	('rs3761124', 'Mutation', 'rs3761124', (106, 115))	('luciferase', 'Enzyme', (68, 78))	('rs3761124', 'Var', (106, 115))
77907	33169458	rs201497780 (NC_000020.10:g.62284926_62284927delGA) within Region 1 did not demonstrate enhancer activity in cell lines (Figure 1).	('NC_000020.10:g.62284926_62284927delGA', 'Mutation', 'rs201497780', (13, 50))	('g.62284926_62284927delGA', 'Var', (26, 50))	('rs201497780', 'Mutation', 'rs201497780', (0, 11))	('rs201497780', 'Var', (0, 11))
77908	33169458	To provide evidence that the candidate functional SNP rs3761124 identified in our cell-based luciferase assays correlated with the altered expression of genes mapping in cis, we used CRISPR-Cas9 genome editing to delete the region containing SNP rs3761124.	('rs3761124', 'Mutation', 'rs3761124', (246, 255))	('correlated', 'Reg', (111, 121))	('rs3761124', 'Var', (54, 63))	('SNP', 'Var', (242, 245))	('expression', 'MPA', (139, 149))	('rs3761124', 'Mutation', 'rs3761124', (54, 63))
77909	33169458	The GBM cell lines LN-229 and U-87 MG were chosen for these experiments because they both expressed detectable levels of many of the potential target genes in the region and due to the demonstrated enhancer activity of the fragment containing rs3761124 in these cell lines.	('rs3761124', 'Mutation', 'rs3761124', (243, 252))	('U-87 MG', 'CellLine', 'CVCL:0022', (30, 37))	('enhancer activity', 'PosReg', (198, 215))	('rs3761124', 'Var', (243, 252))	('LN-229', 'CellLine', 'CVCL:0393', (19, 25))
77910	33169458	We designed guide RNAs (gRNA1 and gRNA2) to delete an approximately 500-bp fragment containing the enhancer and SNP rs3761124 (Figure 3a).	('rs3761124', 'Mutation', 'rs3761124', (116, 125))	('rs3761124', 'Var', (116, 125))	('enhancer', 'PosReg', (99, 107))
77912	33169458	Deletion efficiency was measured by PCR using primers designed to amplify an approximately 2-kb region across the putative enhancer containing the candidate functional SNP rs3761124 (PCR Forward and PCR Reverse in Figure 3a).	('rs3761124', 'Mutation', 'rs3761124', (172, 181))	('SNP', 'Var', (168, 171))	('rs3761124', 'Var', (172, 181))
77914	33169458	We hypothesized that CRISPR-Cas9 mediated disruption of the region containing the candidate functional SNP rs3761124 may affect the expression of multiple genes.	('rs3761124', 'Var', (107, 116))	('affect', 'Reg', (121, 127))	('rs3761124', 'Mutation', 'rs3761124', (107, 116))	('disruption', 'NegReg', (42, 52))	('expression', 'MPA', (132, 142))
77920	33169458	STMN3 was a significant eQTL with the candidate functional SNP rs3761124 in all three datasets.	('rs3761124', 'Mutation', 'rs3761124', (63, 72))	('rs3761124', 'Var', (63, 72))	('STMN3', 'Gene', '50861', (0, 5))	('STMN3', 'Gene', (0, 5))
77923	33169458	Therefore, STMN3 is a consistent eQTL for rs3761124 in early neurological development, in the normal adult brain and in glioma or during gliomagenesis, whereas the RTEL1 expression correlated with rs3761124 only during early neurological development and in IDH1 wild-type glioma.	('IDH1', 'Gene', '3417', (257, 261))	('STMN3', 'Gene', '50861', (11, 16))	('glioma', 'Disease', (272, 278))	('rs3761124', 'Mutation', 'rs3761124', (197, 206))	('rs3761124', 'Var', (197, 206))	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('glioma', 'Disease', (120, 126))	('RTEL1', 'Gene', (164, 169))	('glioma', 'Disease', (137, 143))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('STMN3', 'Gene', (11, 16))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('rs3761124', 'Mutation', 'rs3761124', (42, 51))	('IDH1', 'Gene', (257, 261))	('rs3761124', 'Var', (42, 51))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('RTEL1', 'Gene', '51750', (164, 169))
77927	33169458	It shows interactions, demonstrated as peaks, between the region containing rs3761124 and promoters of STMN3 and RTEL1.	('STMN3', 'Gene', '50861', (103, 108))	('STMN3', 'Gene', (103, 108))	('RTEL1', 'Gene', '51750', (113, 118))	('RTEL1', 'Gene', (113, 118))	('interactions', 'Interaction', (9, 21))	('rs3761124', 'Mutation', 'rs3761124', (76, 85))	('rs3761124', 'Var', (76, 85))
77929	33169458	We show that rs3761124 had allele-specific effects on enhancer activity in the forward direction only.	('enhancer activity in the forward direction', 'MPA', (54, 96))	('rs3761124', 'Mutation', 'rs3761124', (13, 22))	('rs3761124', 'Var', (13, 22))
77931	33169458	We further show that this SNP affects glioma risk potentially through the altered expression of STMN3, RTEL1, GMEB2, and several other genes based on CRISPR deletion of the risk enhancer.	('GMEB2', 'Gene', (110, 115))	('expression', 'MPA', (82, 92))	('STMN3', 'Gene', (96, 101))	('affects', 'Reg', (30, 37))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('STMN3', 'Gene', '50861', (96, 101))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('deletion', 'Var', (157, 165))	('RTEL1', 'Gene', '51750', (103, 108))	('GMEB2', 'Gene', '26205', (110, 115))	('altered', 'Reg', (74, 81))	('glioma', 'Disease', (38, 44))	('RTEL1', 'Gene', (103, 108))
77932	33169458	The complementary methods of eQTL mapping and Hi-C interaction data support STMN3, being the most consistent target gene across biological models, whereas RTEL1 and GMEB2 expression correlated with rs3761124 only in glioma and/or during early neurological development but not in the adult normal brain.	('RTEL1', 'Gene', (155, 160))	('GMEB2', 'Gene', '26205', (165, 170))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('rs3761124', 'Mutation', 'rs3761124', (198, 207))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('rs3761124', 'Var', (198, 207))	('STMN3', 'Gene', '50861', (76, 81))	('STMN3', 'Gene', (76, 81))	('RTEL1', 'Gene', '51750', (155, 160))	('GMEB2', 'Gene', (165, 170))	('correlated', 'Reg', (182, 192))	('glioma', 'Disease', (216, 222))
77933	33169458	A previous report identified rs73001406 as a candidate functional variant for glioma on 11q23.3, with PHLDB1 and DDX6 as potential target genes (Baskin et al., 2015).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('rs73001406', 'Var', (29, 39))	('rs73001406', 'Mutation', 'rs73001406', (29, 39))	('DDX6', 'Gene', (113, 117))	('glioma', 'Disease', (78, 84))	('DDX6', 'Gene', '1656', (113, 117))	('PHLDB1', 'Gene', '23187', (102, 108))	('PHLDB1', 'Gene', (102, 108))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
77941	33169458	Another study reported that high-resolution chromosome conformation capture (Hi-C) data generated in H1 embryonic stem cell and neuronal progenitor cell lines revealed a physical interaction between the STMN3 promoter and the top GWAS SNP rs2297440 (Dixon et al., 2015; Labreche et al., 2018), which is in high LD (r 2 = .92) with the functional SNP rs3761124.	('interaction', 'Interaction', (179, 190))	('STMN3', 'Gene', (203, 208))	('STMN3', 'Gene', '50861', (203, 208))	('rs3761124', 'Mutation', 'rs3761124', (350, 359))	('rs2297440', 'Mutation', 'rs2297440', (239, 248))	('rs2297440', 'Var', (239, 248))	('H1', 'CellLine', 'CVCL:Z499', (101, 103))
77944	33169458	CRISPR deletion of the risk enhancer containing rs3761124 in the U-87 MG and LN-229 GBM cell lines (which are both IDH1 wild type) correlated with altered expression of both genes.	('LN-229', 'CellLine', 'CVCL:0393', (77, 83))	('IDH1', 'Gene', (115, 119))	('rs3761124', 'Mutation', 'rs3761124', (48, 57))	('expression', 'MPA', (155, 165))	('altered', 'Reg', (147, 154))	('IDH1', 'Gene', '3417', (115, 119))	('U-87 MG', 'CellLine', 'CVCL:0022', (65, 72))	('rs3761124', 'Var', (48, 57))
77945	33169458	Consistent with this, rs3761124 correlated with altered expression of RTEL1 in IDH1 wild-type glioma and during early brain development but not in the CMC brain tissues.	('IDH1', 'Gene', '3417', (79, 83))	('glioma', 'Disease', (94, 100))	('altered', 'Reg', (48, 55))	('rs3761124', 'Var', (22, 31))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('expression', 'MPA', (56, 66))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('RTEL1', 'Gene', '51750', (70, 75))	('IDH1', 'Gene', (79, 83))	('rs3761124', 'Mutation', 'rs3761124', (22, 31))	('RTEL1', 'Gene', (70, 75))
77948	33169458	Therefore, our candidate functional variant rs3761124 may impact genomic stability through changes in activity of its risk enhancer, modulating the expression of RTEL1.	('changes', 'Reg', (91, 98))	('genomic stability', 'CPA', (65, 82))	('rs3761124', 'Mutation', 'rs3761124', (44, 53))	('impact', 'Reg', (58, 64))	('rs3761124', 'Var', (44, 53))	('activity', 'MPA', (102, 110))	('expression', 'MPA', (148, 158))	('RTEL1', 'Gene', '51750', (162, 167))	('modulating', 'Reg', (133, 143))	('RTEL1', 'Gene', (162, 167))
77953	33169458	Two additional genes were identified as potential target genes of the putative risk enhancer on 20q13.33 after CRISPR-Cas9 deletion including RTEL1-TNFRSF6B and SRMS.	('deletion', 'Var', (123, 131))	('CRISPR-Cas9', 'Gene', (111, 122))	('SRMS', 'Gene', '6725', (161, 165))	('enhancer', 'PosReg', (84, 92))	('SRMS', 'Gene', (161, 165))	('RTEL1', 'Gene', '51750', (142, 147))	('TNFRSF6B', 'Gene', '8771', (148, 156))	('TNFRSF6B', 'Gene', (148, 156))	('RTEL1', 'Gene', (142, 147))
77955	33169458	SRMS belongs to a family of nonreceptor tyrosine kinases that have been involved in a number of cancers, including fibrosarcoma (Lin et al., 2013), eosinophilic variant of chromophobe renal cell carcinoma (Pagano et al., 2018), and breast cancer (Fan et al., 2015), but its function in gliomagenesis remains unknown.	('breast cancer', 'Disease', (232, 245))	('fibrosarcoma', 'Disease', 'MESH:D005354', (115, 127))	('chromophobe renal cell carcinoma', 'Disease', (172, 204))	('fibrosarcoma', 'Disease', (115, 127))	('SRMS', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('eosinophilic variant', 'Var', (148, 168))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('involved', 'Reg', (72, 80))	('SRMS', 'Gene', '6725', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('glioma', 'Disease', (286, 292))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('glioma', 'Disease', 'MESH:D005910', (286, 292))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (172, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (115, 127))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))
77959	33169458	In summary, we report identification and characterization of a functional SNP, rs3761124, that affects the activity of an enhancer on 20q13.33 that leads to modulated expression of multiple genes implicated in glioma risk.	('activity', 'MPA', (107, 115))	('affects', 'Reg', (95, 102))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('rs3761124', 'Mutation', 'rs3761124', (79, 88))	('modulated', 'Reg', (157, 166))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('rs3761124', 'Var', (79, 88))	('expression', 'MPA', (167, 177))	('glioma', 'Disease', (210, 216))
77973	33330055	There was a strong correlation between the increased survival in LGG and complementarity of the IDH1 mutant to the CDR3 domain of the T-cell receptor beta chain.	('mutant', 'Var', (101, 107))	('IDH1', 'Gene', '3417', (96, 100))	('IDH1', 'Gene', (96, 100))	('increased', 'PosReg', (43, 52))
78031	33330055	Studies show that many lncNRAs had important effects on the immune microenvironment of gliomas, for example, lncRNA H19 could affect the level of immune infiltration of gliomas, as a result of affecting the prognosis of patients.	('gliomas', 'Disease', (169, 176))	('effects', 'Reg', (45, 52))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('lncRNA H19', 'Var', (109, 119))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('affecting', 'Reg', (193, 202))	('patients', 'Species', '9606', (220, 228))	('level of immune infiltration', 'MPA', (137, 165))	('affect', 'Reg', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('gliomas', 'Disease', (87, 94))
78041	33330055	Among 11 immune-related lncRNAs, AC012558.1, LINC00641, AC126407.1, DGCR9, AC021739.2, FLJ16779, AC124016.2, AL645608.6, AL355916.1, and AC074286 were risk factors for the prognosis of LGG, while AL391422.4 was a protective factor.	('AL645608', 'Chemical', '-', (109, 117))	('DGCR9', 'Gene', '25787', (68, 73))	('LGG', 'Disease', (185, 188))	('AC124016.2', 'Var', (97, 107))	('LINC00641', 'Gene', '283624', (45, 54))	('AC012558.1', 'Var', (33, 43))	('AL645608.6', 'Var', (109, 119))	('AL355916.1', 'Var', (121, 131))	('FLJ16779', 'Var', (87, 95))	('AC126407.1', 'Var', (56, 66))	('LINC00641', 'Gene', (45, 54))	('AC074286', 'Var', (137, 145))	('AC021739.2', 'Var', (75, 85))	('AL391422', 'Chemical', '-', (196, 204))	('AL355916', 'Chemical', '-', (121, 129))	('DGCR9', 'Gene', (68, 73))
78048	33330055	obtained that LncRNA-135528 up-regulates the expression of CXCL10 through JAK/STAT signaling pathway, thereby inhibiting the development of glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('LncRNA-135528', 'Var', (14, 27))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('STAT', 'Gene', '6774', (78, 82))	('up-regulates', 'PosReg', (28, 40))	('STAT', 'Gene', (78, 82))	('expression', 'MPA', (45, 55))	('inhibiting', 'NegReg', (110, 120))	('CXCL10', 'Gene', '3627', (59, 65))	('glioma', 'Disease', (140, 146))	('CXCL10', 'Gene', (59, 65))
78049	33330055	Dp44mT (an Iron Chelator) could restrain the progress of glioma by targeting RORA-mediated activation of ndrg2-IL-6/JAK2/STAT3 signaling pathway.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('JAK2', 'Gene', '3717', (116, 120))	('STAT3', 'Gene', '6774', (121, 126))	('ndrg2', 'Gene', '57447', (105, 110))	('IL-6', 'Gene', '3569', (111, 115))	('STAT3', 'Gene', (121, 126))	('glioma', 'Disease', (57, 63))	('activation', 'PosReg', (91, 101))	('Dp44mT', 'Var', (0, 6))	('RORA', 'Gene', (77, 81))	('restrain', 'NegReg', (32, 40))	('JAK2', 'Gene', (116, 120))	('ndrg2', 'Gene', (105, 110))	('RORA', 'Gene', '6095', (77, 81))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('Iron', 'Chemical', 'MESH:D007501', (11, 15))	('IL-6', 'Gene', (111, 115))
78055	30530503	Drak/STK17A drives neoplastic glial proliferation through modulation of MRLC signaling Glioblastoma (GBM) and lower grade gliomas (LGG) are the most common primary malignant brain tumors and are resistant to current therapies.	('Glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('STK17A', 'Gene', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('malignant brain tumors', 'Disease', (164, 186))	('MRLC', 'Gene', '31554', (72, 76))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('modulation', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Glioblastoma', 'Disease', (87, 99))	('brain tumors', 'Phenotype', 'HP:0030692', (174, 186))	('malignant brain tumors', 'Disease', 'MESH:D001932', (164, 186))	('neoplastic glial proliferation', 'CPA', (19, 49))	('brain tumor', 'Phenotype', 'HP:0030692', (174, 185))	('gliomas', 'Disease', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('MRLC', 'Gene', (72, 76))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('Glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('STK17A', 'Gene', '9263', (5, 11))
78056	30530503	Genomic analyses reveal that signature genetic lesions in GBM and LGG include copy gain and amplification of chromosome 7, amplification, mutation, and overexpression of receptor tyrosine kinases (RTK) such as EGFR, and activating mutations in components of the PI-3 kinase (PI3K) pathway.	('overexpression', 'PosReg', (152, 166))	('activating', 'PosReg', (220, 230))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('RTK', 'Gene', (197, 200))	('chromosome', 'Gene', (109, 119))	('copy gain', 'Var', (78, 87))	('amplification', 'Var', (92, 105))	('PI-3 kinase', 'Gene', '5293', (262, 273))	('RTK', 'Gene', '38559', (197, 200))	('mutation', 'Var', (138, 146))	('amplification', 'Var', (123, 136))	('PI-3 kinase', 'Gene', (262, 273))
78059	30530503	Drak was necessary for glial neoplasia, but not for normal glial proliferation and development, and Drak cooperated with EGFR to promote glial cell transformation.	('promote', 'PosReg', (129, 136))	('glial neoplasia', 'Disease', 'MESH:D009369', (23, 38))	('neoplasia', 'Phenotype', 'HP:0002664', (29, 38))	('glial cell transformation', 'CPA', (137, 162))	('Drak', 'Var', (100, 104))	('glial neoplasia', 'Disease', (23, 38))
78067	30530503	To understand their genesis, these tumors have been subject to extensive genomic analyses, which show that signature genetic lesions in LGG and GBM include copy gain and amplification of chromosome 7, amplification, mutation, and/or overexpression of receptor tyrosine kinases (RTKs), such as EGFR, and activating mutations in components of the PI-3 kinase (PI3K) pathway.	('amplification', 'Var', (170, 183))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('amplification', 'Var', (201, 214))	('copy gain', 'Var', (156, 165))	('PI-3 kinase', 'Gene', '5293', (345, 356))	('RTK', 'Gene', '38559', (278, 281))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('mutation', 'Var', (216, 224))	('GBM', 'Phenotype', 'HP:0012174', (144, 147))	('overexpression', 'PosReg', (233, 247))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('LGG', 'Gene', (136, 139))	('activating', 'PosReg', (303, 313))	('lesions', 'Var', (125, 132))	('PI-3 kinase', 'Gene', (345, 356))	('RTK', 'Gene', (278, 281))
78068	30530503	The most prevalent EGFR mutant variant in GBM is EGFRVIII, in which exon2-7 deletion confers constitutive kinase activity, which potently drives tumorigenesis.	('mutant', 'Var', (24, 30))	('deletion', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('constitutive kinase activity', 'MPA', (93, 121))	('drives', 'PosReg', (138, 144))	('tumor', 'Disease', (145, 150))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('EGFR', 'Gene', (19, 23))
78098	30530503	To create UAS-Drak and UAS-DrakKD (kinase dead) constructs, the RE12147 Drak cDNA was cloned into pUAS-T, site directed mutagenesis was used to convert Lys-66 to Ala, and the resulting DNA was injected into embryos and stocks for each construct were established and sequence verified.	('Lys-66', 'Gene', (152, 158))	('stocks', 'Species', '3724', (219, 225))	('convert', 'Var', (144, 151))	('Lys-66 to Ala', 'Mutation', 'p.K66A', (152, 165))
78115	30530503	The following antibodies were used: anti-STK17A (1:1000, Sigma HPA037979), anti-ANLN (1:50, Sigma, HPA005680), anti-phospho-S19-MRLC (1:200, Abcam, ab2480), anti-EGFR (1:50, Cell Signaling Technology, 4267).	('STK17A', 'Gene', '9263', (41, 47))	('MRLC', 'Gene', '31554', (128, 132))	('MRLC', 'Gene', (128, 132))	('STK17A', 'Gene', (41, 47))	('anti-ANLN', 'Var', (75, 84))
78117	30530503	The model uses the glial-specific repo-Gal4 transcriptional driver to co-overexpress constitutively active versions of dEGFR (dEGFRlambda) and dp110 (dp110CAAX), the catalytic subunit of PI3K, that together drive malignant transformation of post-embryonic larval glia.	('embryonic larval glia', 'Disease', (246, 267))	('dp110', 'Var', (143, 148))	('dEGFR', 'Gene', '37455', (126, 131))	('dEGFR', 'Gene', '37455', (119, 124))	('Gal4', 'Gene', (39, 43))	('dEGFR', 'Gene', (126, 131))	('dEGFR', 'Gene', (119, 124))	('malignant transformation', 'CPA', (213, 237))	('embryonic larval glia', 'Disease', 'MESH:D020964', (246, 267))	('drive', 'Reg', (207, 212))	('Gal4', 'Gene', '3960', (39, 43))
78120	30530503	Glial-specific Drak RNAi reduced neoplastic glial proliferation and altered glial morphogenesis, with DrakdsRNA#1 yielding significantly reduced brain sizes and glial cell numbers compared to dEGFRlambda-dp110CAAX (Figure 1A-C, 1D-I).	('reduced', 'NegReg', (25, 32))	('dEGFR', 'Gene', '37455', (192, 197))	('neoplastic glia', 'Disease', 'MESH:D009386', (33, 48))	('neoplastic glia', 'Disease', (33, 48))	('dEGFR', 'Gene', (192, 197))	('brain sizes', 'CPA', (145, 156))	('glial morphogenesis', 'CPA', (76, 95))	('DrakdsRNA', 'Var', (102, 111))	('glial cell numbers', 'CPA', (161, 179))	('altered', 'Reg', (68, 75))	('reduced', 'NegReg', (137, 144))
78121	30530503	The transforming effects of EGFR-PI3K signaling were also reduced in Drak null mutants (Draknull) or by co-overexpression of kinase-dead Drak (DrakKD): such mutants showed near wild-type brain sizes and reduced glial cell numbers compared to dEGFRlambda-dp110CAAX controls (Figure 1A-C, 1D-I), indicating that Drak catalytic activity is essential for proliferation of dEGFRlambda-dp110CAAX-mutant glia.	('dEGFR', 'Gene', (242, 247))	('mutants', 'Var', (79, 86))	('dEGFR', 'Gene', '37455', (368, 373))	('glial cell numbers', 'CPA', (211, 229))	('reduced', 'NegReg', (203, 210))	('brain sizes', 'CPA', (187, 198))	('mutants', 'Var', (157, 164))	('dEGFR', 'Gene', (368, 373))	('dEGFR', 'Gene', '37455', (242, 247))	('reduced', 'NegReg', (58, 65))	('Drak', 'Gene', (69, 73))
78122	30530503	Growth inhibition of neoplastic glia induced by Drak knockdown or loss-of-function was not due to nonspecific glial lethality: Drak is a nonessential gene and homozygous null mutants are viable and show normal brain morphology and glial development, and Drak RNAi in wild-type larval glia caused no obvious defects (Supplemental Figure S1A-B).	('glial development', 'CPA', (231, 248))	('Drak', 'Gene', (127, 131))	('brain morphology', 'CPA', (210, 226))	('neoplastic glia', 'Disease', 'MESH:D009386', (21, 36))	('neoplastic glia', 'Disease', (21, 36))	('Drak', 'Var', (254, 258))
78124	30530503	Because reduced Drak function had a dramatic effect on dEGFRlambda-dp110CAAX mutant neoplastic glia, and because Drak functions downstream of EGFR in epithelia, we predicted that Drak may function downstream of EGFR in neoplastic glia.	('neoplastic glia', 'Disease', 'MESH:D009386', (84, 99))	('dEGFR', 'Gene', '37455', (55, 60))	('Drak function', 'MPA', (16, 29))	('reduced', 'NegReg', (8, 15))	('neoplastic glia', 'Disease', 'MESH:D009386', (219, 234))	('neoplastic glia', 'Disease', (84, 99))	('neoplastic glia', 'Disease', (219, 234))	('mutant', 'Var', (77, 83))	('dEGFR', 'Gene', (55, 60))
78128	30530503	We found that RhoA loss-of-function caused a significant reduction in dEGFRlambda-dp110CAAX mutant glial proliferation, but did not obviously affect wild-type glia proliferation (Figure 1A-C, 1D-I, Supplemental Table 1).	('reduction', 'NegReg', (57, 66))	('dEGFR', 'Gene', '37455', (70, 75))	('mutant', 'Var', (92, 98))	('dEGFR', 'Gene', (70, 75))	('RhoA', 'Gene', (14, 18))	('loss-of-function', 'NegReg', (19, 35))
78134	30530503	We previously showed that overexpression of human EGFRvIII (hEGFRvIII), an oncogenic constitutively active mutant variant of EGFR found in GBM, cooperates with dp110CAAX to drive neoplastic glial transformation, which was suppressed by Drak RNAi.	('human', 'Species', '9606', (44, 49))	('variant', 'Var', (114, 121))	('neoplastic glial transformation', 'Disease', 'MESH:D002471', (179, 210))	('EGFR', 'Gene', (125, 129))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))	('neoplastic glial transformation', 'Disease', (179, 210))	('mutant variant', 'Var', (107, 121))	('drive', 'PosReg', (173, 178))
78140	30530503	Phosphorylated Sqh binds to and stimulates the ATPase-dependent motor activity of Zipper, the sole NMII ortholog, which functions in cellular processes that require cytoskeletal contractility, such as cell migration, cytokinesis, and morphogenesis; all processes that play pivotal roles in tumorigenesis.	('Phosphorylated', 'Var', (0, 14))	('ATPase-dependent motor activity', 'MPA', (47, 78))	('Sqh', 'Gene', '31554', (15, 18))	('Sqh', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('cell migration', 'CPA', (201, 215))	('tumor', 'Disease', (290, 295))	('stimulates', 'PosReg', (32, 42))
78141	30530503	We found that, similar to Drak knockdown, glial-specific sqh knockdown significantly reduced glial cell numbers and rescued brain size in dEGFRlambda-dp110CAAX mutants (Figure 3A-F), which suggests that Drak activates Sqh by phosphorylation in transformed glia.	('brain size', 'CPA', (124, 134))	('dEGFR', 'Gene', '37455', (138, 143))	('Sqh', 'Gene', '31554', (218, 221))	('rescued', 'PosReg', (116, 123))	('sqh', 'Gene', '31554', (57, 60))	('mutants', 'Var', (160, 167))	('dEGFR', 'Gene', (138, 143))	('Sqh', 'Gene', (218, 221))	('sqh', 'Gene', (57, 60))	('glial cell numbers', 'CPA', (93, 111))	('reduced', 'NegReg', (85, 92))
78148	30530503	These data are consistent with a model in which Drak increases the amount of activated, phosphorylated Sqh, which in turn supports EGFR-dependent tumorigenesis.	('Drak', 'Var', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Sqh', 'Gene', (103, 106))	('supports', 'PosReg', (122, 130))	('tumor', 'Disease', (146, 151))	('amount', 'MPA', (67, 73))	('increases', 'PosReg', (53, 62))	('Sqh', 'Gene', '31554', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
78149	30530503	If Sqh phosphorylation promotes EGFR-dependent neoplasia, then overexpression of a phospho-mimetic version of Sqh should enhance oncogenic EGFR.	('neoplasia', 'Phenotype', 'HP:0002664', (47, 56))	('EGFR-dependent', 'Disease', (32, 46))	('Sqh', 'Gene', (110, 113))	('oncogenic EGFR', 'CPA', (129, 143))	('promotes', 'PosReg', (23, 31))	('neoplasia', 'Disease', (47, 56))	('Sqh', 'Gene', '31554', (3, 6))	('enhance', 'PosReg', (121, 128))	('phosphorylation', 'Var', (7, 22))	('neoplasia', 'Disease', 'MESH:D009369', (47, 56))	('Sqh', 'Gene', '31554', (110, 113))	('Sqh', 'Gene', (3, 6))
78158	30530503	To determine if Anillin is an effector of dEGFR-Drak-Sqh signaling, we tested glial-specific anillin knockdown in either dEGFRlambda;DrakOE or dEGFRlambda;sqhD20D21 mutant glia, and observed a significant reduction in glial proliferation (Supplemental Figure S3A-G), indicating that Anillin operates downstream of dEGFR-Drak-Sqh signaling.	('dEGFR', 'Gene', (314, 319))	('tested', 'Reg', (71, 77))	('Sqh', 'Gene', '31554', (325, 328))	('reduction', 'NegReg', (205, 214))	('glial proliferation', 'CPA', (218, 237))	('dEGFR', 'Gene', (42, 47))	('dEGFR', 'Gene', (121, 126))	('dEGFR', 'Gene', '37455', (143, 148))	('sqh', 'Gene', (155, 158))	('Sqh', 'Gene', (53, 56))	('sqh', 'Gene', '31554', (155, 158))	('Sqh', 'Gene', '31554', (53, 56))	('dEGFR', 'Gene', (143, 148))	('dEGFR', 'Gene', '37455', (314, 319))	('anillin', 'Gene', '54443', (93, 100))	('mutant', 'Var', (165, 171))	('anillin', 'Gene', (93, 100))	('dEGFR', 'Gene', '37455', (42, 47))	('dEGFR', 'Gene', '37455', (121, 126))	('Sqh', 'Gene', (325, 328))	('knockdown', 'Var', (101, 110))
78159	30530503	In contrast, anillin knockdown in wild-type glia had no impact on glial cell proliferation compared to wild-type controls (Supplemental Figure S3A-G), showing a differential requirement for the Drak-Sqh-Anillin pathway in neoplastic glia, but not wild-type glia.	('Sqh', 'Gene', (199, 202))	('neoplastic glia', 'Disease', 'MESH:D009386', (222, 237))	('anillin', 'Gene', '54443', (13, 20))	('Sqh', 'Gene', '31554', (199, 202))	('neoplastic glia', 'Disease', (222, 237))	('knockdown', 'Var', (21, 30))	('anillin', 'Gene', (13, 20))	('glial cell proliferation', 'CPA', (66, 90))
78160	30530503	MRLC phosphorylation mediates cellular processes that require NMII-dependent cytoskeletal contractility, including mitosis and cytokinesis.	('mitosis', 'CPA', (115, 122))	('MRLC', 'Gene', '31554', (0, 4))	('MRLC', 'Gene', (0, 4))	('phosphorylation', 'Var', (5, 20))	('cytokinesis', 'CPA', (127, 138))	('mediates', 'Reg', (21, 29))
78165	30530503	Thus, our data support a model wherein Drak-dependent phosphorylation of Sqh promotes Anillin binding to coordinately drive cytokinesis and proliferation in neoplastic glia.	('drive', 'PosReg', (118, 123))	('proliferation', 'CPA', (140, 153))	('Sqh', 'Gene', (73, 76))	('promotes', 'PosReg', (77, 85))	('cytokinesis', 'MPA', (124, 135))	('binding', 'Interaction', (94, 101))	('neoplastic glia', 'Disease', 'MESH:D009386', (157, 172))	('phosphorylation', 'Var', (54, 69))	('neoplastic glia', 'Disease', (157, 172))	('Anillin', 'Protein', (86, 93))	('Sqh', 'Gene', '31554', (73, 76))
78168	30530503	Compared to cultured normal human neural progenitor cells (HNPCs), EGFRvIII-positive and EGFR-mutant GSC cultures express higher levels of STK17A and ANLN (Figure 6A).	('human', 'Species', '9606', (28, 33))	('higher', 'PosReg', (122, 128))	('STK17A', 'Gene', '9263', (139, 145))	('EGFR-mutant', 'Var', (89, 100))	('ANLN', 'MPA', (150, 154))	('EGFR-mutant', 'Gene', (89, 100))	('STK17A', 'Gene', (139, 145))
78172	30530503	Consistent with prior reports, we found that, in serum cultured lines, STK17A is required for proliferation, with STK17A knockdown inducing slower proliferation, apoptosis, reduced MRLC-S19-P levels, and altered cell shape and adhesion (Figure 6B, Supplemental Figure S4A-B), which is consistent with alterations in MRLC regulation.	('knockdown', 'Var', (121, 130))	('cell shape', 'CPA', (212, 222))	('slower proliferation', 'CPA', (140, 160))	('adhesion', 'CPA', (227, 235))	('STK17A', 'Gene', (71, 77))	('reduced', 'NegReg', (173, 180))	('MRLC', 'Gene', (181, 185))	('MRLC', 'Gene', '31554', (181, 185))	('inducing', 'Reg', (131, 139))	('MRLC', 'Gene', '31554', (316, 320))	('STK17A', 'Gene', '9263', (114, 120))	('MRLC', 'Gene', (316, 320))	('altered', 'Reg', (204, 211))	('apoptosis', 'CPA', (162, 171))	('STK17A', 'Gene', '9263', (71, 77))	('STK17A', 'Gene', (114, 120))
78173	30530503	We examined the effects of STK17A loss in GSCs treated with or without ZVAD to control for the effects of apoptosis, and we found that STK17A knockdown caused GSC adhesion defects, slower proliferation, apoptosis, and reduced levels of MRLC-S19-P and ANLN levels relative to control GSCs (Figure 6C-D, Supplemental Figure S4C-D).	('MRLC', 'Gene', '31554', (236, 240))	('slower proliferation', 'CPA', (181, 201))	('STK17A', 'Gene', (135, 141))	('MRLC', 'Gene', (236, 240))	('ZVAD', 'Chemical', '-', (71, 75))	('STK17A', 'Gene', '9263', (27, 33))	('apoptosis', 'CPA', (203, 212))	('defects', 'NegReg', (172, 179))	('STK17A', 'Gene', (27, 33))	('reduced', 'NegReg', (218, 225))	('levels', 'MPA', (226, 232))	('STK17A', 'Gene', '9263', (135, 141))	('ANLN levels', 'MPA', (251, 262))	('knockdown', 'Var', (142, 151))	('GSC adhesion', 'CPA', (159, 171))
78174	30530503	We also observed that total MRLC levels were reduced upon STK17A knockdown, suggesting that phosphorylation may regulate total MRLC protein in GBM cells.	('MRLC', 'Gene', '31554', (127, 131))	('MRLC', 'Gene', (127, 131))	('reduced', 'NegReg', (45, 52))	('GBM', 'Phenotype', 'HP:0012174', (143, 146))	('regulate', 'Reg', (112, 120))	('total', 'MPA', (121, 126))	('STK17A', 'Gene', '9263', (58, 64))	('MRLC', 'Gene', '31554', (28, 32))	('MRLC', 'Gene', (28, 32))	('STK17A', 'Gene', (58, 64))	('knockdown', 'Var', (65, 74))
78183	30530503	We used cBioportal to process genomic data catalogued by The Cancer Genome Atlas (TCGA) to assess prevalence of STK17A mRNA expression and copy gain alterations and to examine relationships between STK17A alterations and well-characterized genetic lesions in gliomas.	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('alterations', 'Var', (149, 160))	('Cancer', 'Disease', (61, 67))	('STK17A', 'Gene', (198, 204))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('gliomas', 'Disease', (259, 266))	('STK17A', 'Gene', (112, 118))	('gliomas', 'Disease', 'MESH:D005910', (259, 266))	('mRNA', 'MPA', (119, 123))	('gliomas', 'Phenotype', 'HP:0009733', (259, 266))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('copy', 'MPA', (139, 143))	('STK17A', 'Gene', '9263', (112, 118))	('STK17A', 'Gene', '9263', (198, 204))
78184	30530503	Well-characterized lesions include full or partial amplification of chromosome 7, which includes regions encoding both EGFR and STK17A, and focal EGFR amplification and mutation.	('mutation', 'Var', (169, 177))	('EGFR', 'Gene', (146, 150))	('STK17A', 'Gene', '9263', (128, 134))	('partial amplification', 'Var', (43, 64))	('amplification', 'Var', (151, 164))	('EGFR', 'Gene', (119, 123))	('STK17A', 'Gene', (128, 134))
78185	30530503	In TCGA cohorts of LGGs and GBMs, STK17A mRNA expression was significantly correlated with copy number gain in 13p on chromosome 7 (7p13) (Figure7C-D).	('STK17A', 'Gene', '9263', (34, 40))	('copy number gain', 'Var', (91, 107))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('STK17A', 'Gene', (34, 40))	('mRNA expression', 'MPA', (41, 56))
78188	30530503	NACAD) showed no statistically significant difference in mRNA expression between LGG specimens with chromosome 7 copy gain compared to LGG specimens with no observable copy number alterations in the same region of chromosome 7 (Figure 7E), indicating that STK17A mRNA expression may be selectively upregulated.	('NACAD', 'Gene', (0, 5))	('copy', 'Var', (113, 117))	('mRNA expression', 'MPA', (57, 72))	('mRNA expression', 'MPA', (263, 278))	('upregulated', 'PosReg', (298, 309))	('STK17A', 'Gene', (256, 262))	('gain', 'PosReg', (118, 122))	('NACAD', 'Gene', '23148', (0, 5))	('STK17A', 'Gene', '9263', (256, 262))
78191	30530503	IDH1 mutation is a common genetic alteration in LGG, and patients who harbor IDH1 mutations have a better prognosis than those with wild-type IDH1.	('IDH1', 'Gene', '3417', (142, 146))	('patients', 'Species', '9606', (57, 65))	('LGG', 'Disease', (48, 51))	('IDH1', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', (142, 146))	('IDH1', 'Gene', '3417', (0, 4))
78192	30530503	LGG patients with wild-type IDH1 have more aggressive tumors that behave much like primary GBMs.	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('IDH1', 'Gene', '3417', (28, 32))	('aggressive tumors', 'Disease', 'MESH:D001523', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('aggressive tumors', 'Disease', (43, 60))	('patients', 'Species', '9606', (4, 12))	('wild-type', 'Var', (18, 27))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('IDH1', 'Gene', (28, 32))
78195	30530503	In IDH1 mutant LGGs, there was not a statistically significant difference between STK17A mRNA expression between tumors with or without chromosome 7 gain (Figure 7G), suggesting that STK17A levels are not as relevant to progression in IDH1 mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('STK17A', 'Gene', (183, 189))	('tumors', 'Disease', (247, 253))	('IDH1', 'Gene', (235, 239))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('STK17A', 'Gene', '9263', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('mutant', 'Var', (8, 14))	('IDH1', 'Gene', '3417', (235, 239))	('STK17A', 'Gene', (82, 88))	('STK17A', 'Gene', '9263', (183, 189))	('IDH1', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IDH1', 'Gene', '3417', (3, 7))
78197	30530503	To investigate associations between STK17A expression and patient survival, we analyzed cBioportal TCGA data to find that LGG and GBM patients with at least two-fold STK17A copy gain showed worse overall survival compared to patients with no STK17A copy gain (Supplemental Figure S5A-B).	('STK17A', 'Gene', (166, 172))	('gain', 'PosReg', (178, 182))	('STK17A', 'Gene', (242, 248))	('copy', 'Var', (173, 177))	('patients', 'Species', '9606', (225, 233))	('patient', 'Species', '9606', (58, 65))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('STK17A', 'Gene', (36, 42))	('patients', 'Species', '9606', (134, 142))	('worse', 'NegReg', (190, 195))	('STK17A', 'Gene', '9263', (166, 172))	('STK17A', 'Gene', '9263', (242, 248))	('overall survival', 'MPA', (196, 212))	('patient', 'Species', '9606', (225, 232))	('patient', 'Species', '9606', (134, 141))	('STK17A', 'Gene', '9263', (36, 42))
78201	30530503	We developed a Drosophila melanogaster GBM model based on co-activation of EGFR and PI3K in glia in order to gain insight into genetic and cellular mechanisms underlying gliomas.	('Drosophila melanogaster', 'Species', '7227', (15, 38))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('gliomas', 'Disease', (170, 177))	('PI3K', 'Var', (84, 88))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('EGFR', 'Gene', (75, 79))
78207	30530503	We show that, in Drosophila and human tumor cells, Sqh/MRLC is a key mediator of Drak/STK17A: Sqh/MRLC is phosphorylated at equivalent conserved sites in EGFR-PI3K mutant tumor cells in a Drak/STK17A-dependent manner, and is necessary for neoplastic growth.	('EGFR-PI3K', 'Gene', (154, 163))	('Sqh', 'Gene', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('MRLC', 'Gene', '31554', (55, 59))	('STK17A', 'Gene', '9263', (193, 199))	('Sqh', 'Gene', '31554', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('MRLC', 'Gene', (98, 102))	('STK17A', 'Gene', (193, 199))	('human', 'Species', '9606', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('Sqh', 'Gene', (51, 54))	('MRLC', 'Gene', (55, 59))	('Drosophila', 'Species', '7227', (17, 27))	('STK17A', 'Gene', '9263', (86, 92))	('Sqh', 'Gene', '31554', (51, 54))	('STK17A', 'Gene', (86, 92))	('tumor', 'Disease', (38, 43))	('mutant', 'Var', (164, 170))	('MRLC', 'Gene', '31554', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (171, 176))
78215	30530503	We observed that phosphorylated Sqh and Anillin co-localize in a Drak-dependent manner at the cleavage furrow in EGFR-PI3K mutant glia undergoing cytokinesis.	('EGFR-PI3K', 'Gene', (113, 122))	('Sqh', 'Gene', (32, 35))	('glia', 'CPA', (130, 134))	('mutant', 'Var', (123, 129))	('Sqh', 'Gene', '31554', (32, 35))
78223	30530503	Further work is needed to determine mechanisms of Drak/STK17A dependent regulation of cytokinesis, and whether defective cytokinesis actively provokes growth arrest and apoptosis in GBM cells.	('regulation', 'MPA', (72, 82))	('growth arrest', 'Phenotype', 'HP:0001510', (151, 164))	('apoptosis', 'CPA', (169, 178))	('GBM', 'Phenotype', 'HP:0012174', (182, 185))	('provokes', 'Reg', (142, 150))	('STK17A', 'Gene', '9263', (55, 61))	('defective', 'Var', (111, 120))	('growth arrest', 'Disease', (151, 164))	('growth arrest', 'Disease', 'MESH:D006323', (151, 164))	('STK17A', 'Gene', (55, 61))
78245	32472232	In particular, [18F]-F-DOPA PET was found to detect glioma recurrence with an accuracy as high as 82% in a retrospective study of 110 patients, in which the lesion-to-normal-tissue ratio was additionally predictive of PFS.	('[18F]-F-DOPA', 'Var', (15, 27))	('[18F]-F-DOPA', 'Chemical', '-', (15, 27))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('patients', 'Species', '9606', (134, 142))	('glioma', 'Disease', (52, 58))
78253	32472232	The aim of the present study was thus to assess the performances of [18F]-F-DOPA PET with both static and dynamic parameters in detecting patients with progressive or recurrent glioma and for assessing further relationships with patient outcome.	('glioma', 'Disease', (177, 183))	('[18F]-F-DOPA', 'Chemical', '-', (68, 80))	('patient', 'Species', '9606', (138, 145))	('[18F', 'Var', (68, 72))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('patients', 'Species', '9606', (138, 146))	('patient', 'Species', '9606', (229, 236))
78264	32472232	IDH mutation status was assessed by immunohistochemistry with IDH1 R132H protein expression (Dianova, clone H09), or by Sanger sequencing in case of ATRX immunohistochemical loss without IDH1 R132H staining.	('R132H', 'Mutation', 'rs121913500', (192, 197))	('IDH', 'Gene', (0, 3))	('ATRX', 'Gene', '546', (149, 153))	('IDH', 'Gene', '3417', (62, 65))	('IDH1', 'Gene', '3417', (62, 66))	('protein', 'Protein', (73, 80))	('IDH', 'Gene', (187, 190))	('IDH', 'Gene', '3417', (0, 3))	('IDH1', 'Gene', '3417', (187, 191))	('IDH', 'Gene', '3417', (187, 190))	('R132H', 'Var', (67, 72))	('ATRX', 'Gene', (149, 153))	('IDH1', 'Gene', (62, 66))	('loss', 'NegReg', (174, 178))	('R132H', 'Mutation', 'rs121913500', (67, 72))	('IDH', 'Gene', (62, 65))	('IDH1', 'Gene', (187, 191))
78269	32472232	The choice of this acquisition time frame was based on previous studies performed with [18F]-FET PET (from 0 to 40 min post-injection with a reconstructed 20- to 40-min static image) and on the maximum observed uptake of [18F]-F-DOPA in a PET study involving high-grade and low-grade gliomas (respectively 8 and 10 min post-injection).	('glioma', 'Phenotype', 'HP:0009733', (284, 290))	('[18F]-F-DOPA', 'Chemical', '-', (221, 233))	('gliomas', 'Disease', (284, 291))	('gliomas', 'Disease', 'MESH:D005910', (284, 291))	('gliomas', 'Phenotype', 'HP:0009733', (284, 291))	('[18F', 'Var', (87, 91))
78279	32472232	According to the 2016 WHO classification for gliomas, 8 gliomas (16%) had been initially classified as IDH-mutant astrocytomas (including 2 with anaplastic component), 6 (12%) as IDH-wildtype astrocytomas (including 2 with anaplastic component), 12 (24%) as IDH-mutant and 1p/19q co-deleted oligodendrogliomas (including 4 with anaplastic component), 22 (43%) as IDH-wildtype glioblastomas (GBM), and 3 (6%) as IDH-mutant GBM.	('gliomas', 'Phenotype', 'HP:0009733', (302, 309))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('IDH', 'Gene', '3417', (179, 182))	('IDH-wildtype astrocytomas', 'Disease', (179, 204))	('astrocytomas', 'Disease', 'MESH:D001254', (114, 126))	('IDH', 'Gene', '3417', (258, 261))	('glioblastomas', 'Phenotype', 'HP:0012174', (376, 389))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('astrocytomas', 'Disease', 'MESH:D001254', (192, 204))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('IDH-wildtype astrocytomas', 'Disease', 'MESH:D001254', (179, 204))	('IDH', 'Gene', (103, 106))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH', 'Gene', (363, 366))	('gliomas', 'Disease', (302, 309))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (291, 309))	('IDH', 'Gene', (411, 414))	('glioblastoma', 'Phenotype', 'HP:0012174', (376, 388))	('glioblastomas', 'Disease', (376, 389))	('GBM', 'Phenotype', 'HP:0012174', (391, 394))	('GBM', 'Phenotype', 'HP:0012174', (422, 425))	('IDH', 'Gene', '3417', (103, 106))	('astrocytomas', 'Disease', (114, 126))	('glioblastomas', 'Disease', 'MESH:D005909', (376, 389))	('gliomas', 'Disease', 'MESH:D005910', (302, 309))	('IDH', 'Gene', '3417', (363, 366))	('IDH', 'Gene', (179, 182))	('gliomas', 'Disease', (56, 63))	('IDH', 'Gene', (258, 261))	('IDH', 'Gene', '3417', (411, 414))	('astrocytomas', 'Disease', (192, 204))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('oligodendrogliomas', 'Disease', (291, 309))	('glioma', 'Phenotype', 'HP:0009733', (302, 308))	('1p/19q co-deleted', 'Var', (273, 290))	('gliomas', 'Disease', (45, 52))
78338	32003759	Aberrant LSP1 overexpression leads to reduced motility of neutrophils in the patients with neutrophil actin dysfunction.	('motility of neutrophils', 'CPA', (46, 69))	('Aberrant', 'Var', (0, 8))	('reduced', 'NegReg', (38, 45))	('reduced motility of neutrophils', 'Phenotype', 'HP:0005400', (38, 69))	('LSP1', 'Gene', (9, 13))	('patients', 'Species', '9606', (77, 85))	('overexpression', 'PosReg', (14, 28))	('LSP1', 'Gene', '4046', (9, 13))
78339	32003759	LSP1 deficiency leads to enhanced T cell migration, and contributes to the development of rheumatoid arthritis.	('T cell migration', 'CPA', (34, 50))	('rheumatoid arthritis', 'Disease', (90, 110))	('deficiency', 'Var', (5, 15))	('enhanced', 'PosReg', (25, 33))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (90, 110))	('arthritis', 'Phenotype', 'HP:0001369', (101, 110))	('enhanced T cell', 'Phenotype', 'HP:0100828', (25, 40))	('LSP1', 'Gene', '4046', (0, 4))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (90, 110))	('LSP1', 'Gene', (0, 4))	('contributes', 'Reg', (56, 67))
78364	32003759	Furthermore, we verified this result in clinical glioma samples with qPCR, western blot and IHC, and similar result was obtained (Figure 2C-2E).	('qPCR', 'Var', (69, 73))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('clinical', 'Species', '191496', (40, 48))	('glioma', 'Disease', (49, 55))
78369	32003759	Taken together, these data indicate the potential of LSP1 as an independent predicative factor for progressive malignancy in glioma and high LSP1 expression predicts unfavorable survival in glioma.	('malignancy in glioma', 'Disease', 'MESH:D005910', (111, 131))	('glioma', 'Disease', (125, 131))	('LSP1', 'Gene', (141, 145))	('LSP1', 'Gene', '4046', (53, 57))	('progressive malignancy in glioma', 'Phenotype', 'HP:0012174', (99, 131))	('high', 'Var', (136, 140))	('glioma', 'Disease', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('LSP1', 'Gene', (53, 57))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('malignancy in glioma', 'Disease', (111, 131))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('LSP1', 'Gene', '4046', (141, 145))	('expression', 'MPA', (146, 156))
78371	32003759	Mutation in IDH1 is a stable marker for better prognosis in both lower-grade glioma (LGG) and glioblastoma multiforme (GBM).	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (94, 117))	('IDH1', 'Gene', (12, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('Mutation', 'Var', (0, 8))	('glioma', 'Disease', (77, 83))	('IDH1', 'Gene', '3417', (12, 16))	('glioblastoma multiforme', 'Disease', (94, 117))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
78372	32003759	As the earliest detectable genetic alteration in gliomagenesis, IDH1 heterozygous missense mutations in codon 132 cause an arginine-to-histidine substitution in 80-90 % of cases (R132H) that leads to a distinct metabolism and hypermethylation phenotype in gliomas.	('R132H', 'Mutation', 'rs121913500', (179, 184))	('gliomas', 'Disease', (256, 263))	('IDH1', 'Gene', (64, 68))	('metabolism', 'MPA', (211, 221))	('gliomagenesis', 'Disease', 'None', (49, 62))	('missense mutations', 'Var', (82, 100))	('gliomas', 'Disease', 'MESH:D005910', (256, 263))	('arginine-to-histidine substitution in 80', 'Mutation', 'p.R80H', (123, 163))	('gliomas', 'Phenotype', 'HP:0009733', (256, 263))	('IDH1', 'Gene', '3417', (64, 68))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('hypermethylation', 'MPA', (226, 242))	('gliomagenesis', 'Disease', (49, 62))	('arginine-to-histidine', 'MPA', (123, 144))	('leads to', 'Reg', (191, 199))	('cause', 'Reg', (114, 119))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('R132H', 'Var', (179, 184))
78373	32003759	IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('down-regulation', 'NegReg', (22, 37))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (94, 99))	('repression', 'NegReg', (76, 86))	('IDH1', 'Gene', (0, 4))	('leukocyte chemotaxis', 'CPA', (41, 61))	('IDH1', 'Gene', '3417', (0, 4))
78374	32003759	Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, lymphocyte, and neutrophils is linked to poor prognosis in many cancer types, these disrupted immune infiltrates in IDH1 mutation glioma tumors may contribute to the different aggressiveness of these two glioma types.	('glioma', 'Disease', (299, 305))	('glioma tumors', 'Disease', (225, 238))	('glioma', 'Disease', 'MESH:D005910', (299, 305))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('glioma', 'Disease', (225, 231))	('aggressiveness', 'Disease', (271, 285))	('mutation', 'Var', (216, 224))	('glioma tumors', 'Disease', 'MESH:D005910', (225, 238))	('glioma', 'Phenotype', 'HP:0009733', (299, 305))	('aggressiveness', 'Phenotype', 'HP:0000718', (271, 285))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('aggressiveness', 'Disease', 'MESH:D001523', (271, 285))	('IDH1', 'Gene', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('IDH1', 'Gene', '3417', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))
78375	32003759	Therefore, we compared LSP1 expression between IDH1 mutation and wild type.	('LSP1', 'Gene', '4046', (23, 27))	('compared', 'Reg', (14, 22))	('IDH1', 'Gene', (47, 51))	('expression', 'MPA', (28, 38))	('LSP1', 'Gene', (23, 27))	('mutation', 'Var', (52, 60))	('IDH1', 'Gene', '3417', (47, 51))
78385	32003759	Moreover, according to treatment strategies (whether to receive radiation therapy) and LSP1 expression, we divided the samples in CGGA and TCGA into four groups, including high LSP1 expression with or without radiotherapy and low LSP1 expression with or without radiotherapy.	('expression', 'MPA', (235, 245))	('expression', 'MPA', (182, 192))	('LSP1', 'Gene', '4046', (177, 181))	('LSP1', 'Gene', '4046', (230, 234))	('LSP1', 'Gene', (177, 181))	('low', 'Var', (226, 229))	('high', 'Var', (172, 176))	('LSP1', 'Gene', '4046', (87, 91))	('LSP1', 'Gene', (230, 234))	('LSP1', 'Gene', (87, 91))
78394	32003759	The result showed that the low LSP1 group had a survival advantage compared to high group with methylated MGMT promoter (Figure 3C and Supplementary Figure 3F, 3G).	('survival advantage', 'CPA', (48, 66))	('LSP1', 'Gene', (31, 35))	('low', 'Var', (27, 30))	('LSP1', 'Gene', '4046', (31, 35))	('MGMT', 'Gene', '4255', (106, 110))	('MGMT', 'Gene', (106, 110))
78396	32003759	Lastly, the analyses with the data from three TCGA datasets showed that high LSP1 expression with methylated MGMT promoter had no significant survival advantage over unmethylated group in chemotherapy patients (Figure 3D and Supplementary Figure 3H, 3I).	('patients', 'Species', '9606', (201, 209))	('LSP1', 'Gene', '4046', (77, 81))	('expression', 'MPA', (82, 92))	('MGMT', 'Gene', (109, 113))	('LSP1', 'Gene', (77, 81))	('MGMT', 'Gene', '4255', (109, 113))	('methylated', 'Var', (98, 108))	('high', 'Var', (72, 76))
78403	32003759	Additionally, in consistent with the above data, the results of GSVA showed the enrichment of leukocyte migration, inflammatory response, and the regulation of immune response phenotypes in samples with high LSP1 expression (Figure 4C, 4D).	('LSP1', 'Gene', '4046', (208, 212))	('inflammatory response', 'CPA', (115, 136))	('regulation', 'MPA', (146, 156))	('GSVA', 'Chemical', '-', (64, 68))	('LSP1', 'Gene', (208, 212))	('high', 'Var', (203, 207))	('leukocyte migration', 'CPA', (94, 113))
78433	32003759	We found that LAIR1, OSMR, PD1, and LILRB3 had the prognosis value of the combination with LSP1 in the CGGA and TCGA datasets in GBM, and the co-upregulation of LSP1 and these genes is a predictor of poor survival in GBM patients, respectively (Figure 6D-6K).	('LILRB3', 'Gene', '11025', (36, 42))	('patients', 'Species', '9606', (221, 229))	('GBM', 'Disease', (217, 220))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('co-upregulation', 'Var', (142, 157))	('LAIR1', 'Gene', '3903', (14, 19))	('LSP1', 'Gene', '4046', (91, 95))	('LSP1', 'Gene', '4046', (161, 165))	('GBM', 'Phenotype', 'HP:0012174', (217, 220))	('LILRB3', 'Gene', (36, 42))	('OSMR', 'Gene', (21, 25))	('LSP1', 'Gene', (91, 95))	('LSP1', 'Gene', (161, 165))	('LAIR1', 'Gene', (14, 19))	('OSMR', 'Gene', '9180', (21, 25))	('PD1', 'Gene', (27, 30))	('combination', 'Var', (74, 85))
78445	32003759	It is well known that the wild type and mutant form of IDH1 have important impact on the regulation of local immune response and tumorigenesis in glioma.	('IDH1', 'Gene', '3417', (55, 59))	('impact', 'Reg', (75, 81))	('glioma', 'Disease', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('local immune response', 'MPA', (103, 124))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('regulation', 'MPA', (89, 99))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('mutant', 'Var', (40, 46))	('tumor', 'Disease', (129, 134))	('IDH1', 'Gene', (55, 59))
78446	32003759	The mutant form of IDH1 attenuated leukocyte chemotaxis, resulting in the repression of local immune system and leaded to immune suppression in GBM TME.	('attenuated', 'NegReg', (24, 34))	('leukocyte chemotaxis', 'CPA', (35, 55))	('mutant', 'Var', (4, 10))	('immune', 'MPA', (122, 128))	('IDH1', 'Gene', (19, 23))	('repression', 'NegReg', (74, 84))	('leaded to', 'Reg', (112, 121))	('IDH1', 'Gene', '3417', (19, 23))	('GBM', 'Phenotype', 'HP:0012174', (144, 147))	('local immune', 'Protein', (88, 100))
78447	32003759	Our results revealed that LSP1 had a low expression in IDH1 mutant GBM, which reached the same conclusion with the above report.	('IDH1', 'Gene', '3417', (55, 59))	('low', 'NegReg', (37, 40))	('expression', 'MPA', (41, 51))	('LSP1', 'Gene', '4046', (26, 30))	('LSP1', 'Gene', (26, 30))	('mutant', 'Var', (60, 66))	('IDH1', 'Gene', (55, 59))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
78460	32003759	The migration of M0 macrophages was also increased by LSP1 overexpression.	('increased', 'PosReg', (41, 50))	('LSP1', 'Gene', '4046', (54, 58))	('migration of M0 macrophages', 'CPA', (4, 31))	('overexpression', 'Var', (59, 73))	('LSP1', 'Gene', (54, 58))
78515	30725238	One notable association is that of multiple meningiomas arising in patients with neurofibromatosis type 2 (NF2) gene mutations.	('mutations', 'Var', (117, 126))	('meningiomas', 'Phenotype', 'HP:0002858', (44, 55))	('patients', 'Species', '9606', (67, 75))	('meningioma', 'Phenotype', 'HP:0002858', (44, 54))	('neurofibromatosis type 2', 'Gene', '4771', (81, 105))	('NF2', 'Gene', (107, 110))	('multiple meningiomas', 'Disease', 'MESH:D008577', (35, 55))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (81, 98))	('multiple meningiomas', 'Disease', (35, 55))	('NF2', 'Gene', '4771', (107, 110))	('neurofibromatosis type 2', 'Gene', (81, 105))
78568	30725238	Lesions are usually isointense or hypointense on T1-weighted MR images (T1WI), but are variable on T2-weighted MR images (T2WI), sometimes being predominantly hyper- or hypointense.	('hypointense', 'Var', (34, 45))	('hyper', 'Disease', 'MESH:D053307', (159, 164))	('hyper', 'Disease', (159, 164))
78592	30725238	In contrast to meningiomas, low-grade SFTs do not invade or occlude nearby venous sinuses.	('meningioma', 'Phenotype', 'HP:0002858', (15, 25))	('meningiomas', 'Phenotype', 'HP:0002858', (15, 26))	('low-grade', 'Var', (28, 37))	('meningiomas', 'Disease', 'MESH:D008577', (15, 26))	('meningiomas', 'Disease', (15, 26))	('occlude', 'NegReg', (60, 67))
78643	30725238	Melanoma CNS metastases, when occurring peripherally, particularly around the cerebellopontine junction and internal auditory canal, mimic the MR appearances of meningiomas, often being isointense on T1WI and slightly hyperintense on T2WI.	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('meningiomas', 'Phenotype', 'HP:0002858', (161, 172))	('hyper', 'Disease', 'MESH:D053307', (218, 223))	('T1WI', 'MPA', (200, 204))	('internal auditory canal', 'Phenotype', 'HP:0004458', (108, 131))	('Melanoma CNS metastases', 'Disease', (0, 23))	('meningioma', 'Phenotype', 'HP:0002858', (161, 171))	('meningiomas', 'Disease', 'MESH:D008577', (161, 172))	('hyper', 'Disease', (218, 223))	('T2WI', 'MPA', (234, 238))	('meningiomas', 'Disease', (161, 172))	('isointense', 'Var', (186, 196))	('Melanoma CNS metastases', 'Disease', 'MESH:D009362', (0, 23))
78685	30725238	While best seen on CT, this is also evident as bone hypointensity on T1WI and T2WI.	('bone hypointensity', 'Disease', 'MESH:D001847', (47, 65))	('bone hypointensity', 'Disease', (47, 65))	('T2WI', 'Var', (78, 82))	('T1WI', 'Var', (69, 73))
78695	30725238	En plaque thickening may involve cranial nerves causing cranial nerve palsies.	('thickening', 'Var', (10, 20))	('cranial nerve', 'Phenotype', 'HP:0001291', (56, 69))	('cranial nerve palsies', 'Disease', (56, 77))	('cranial nerve palsies', 'Phenotype', 'HP:0006824', (56, 77))	('involve cranial nerves', 'Phenotype', 'HP:0001291', (25, 47))	('cranial nerve', 'Phenotype', 'HP:0001291', (33, 46))	('cranial nerve palsies', 'Disease', 'MESH:D003389', (56, 77))
78757	30725238	MRS, while not currently used routinely in clinical practice, is useful in differentiating meningiomas in some cases with high alanine and low NAA in meningiomas, high lipid/lactate in metastases and high myoinositol in solitary fibrous tumours.	('myoinositol', 'Chemical', 'MESH:D007294', (205, 216))	('meningioma', 'Phenotype', 'HP:0002858', (91, 101))	('lactate', 'Chemical', 'MESH:D019344', (174, 181))	('meningiomas', 'Disease', 'MESH:D008577', (91, 102))	('metastases', 'Disease', (185, 195))	('meningiomas', 'Phenotype', 'HP:0002858', (91, 102))	('high alanine', 'Phenotype', 'HP:0003348', (122, 134))	('meningiomas', 'Disease', (91, 102))	('alanine', 'Chemical', 'MESH:D000409', (127, 134))	('high lipid/lactate', 'MPA', (163, 181))	('lipid', 'Chemical', 'MESH:D008055', (168, 173))	('tumours', 'Phenotype', 'HP:0002664', (237, 244))	('solitary fibrous tumours', 'Disease', (220, 244))	('meningiomas', 'Disease', 'MESH:D008577', (150, 161))	('meningioma', 'Phenotype', 'HP:0002858', (150, 160))	('low NAA', 'MPA', (139, 146))	('meningiomas', 'Phenotype', 'HP:0002858', (150, 161))	('NAA', 'Chemical', 'MESH:C000179', (143, 146))	('MRS', 'Disease', 'MESH:D008556', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('high', 'Var', (122, 126))	('solitary fibrous tumours', 'Disease', 'MESH:D054364', (220, 244))	('MRS', 'Disease', (0, 3))	('meningiomas', 'Disease', (150, 161))	('high', 'Var', (200, 204))	('metastases', 'Disease', 'MESH:D009362', (185, 195))
78791	28427185	The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer.	('dysregulation', 'Var', (4, 17))	('associated', 'Reg', (49, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
78803	28427185	Lawrence et al analyzed 27 cancer types and found that the median frequency of non-synonymous mutations varied by more than 1,000-fold across different cancer types.	('cancer', 'Disease', (152, 158))	('non-synonymous mutations', 'Var', (79, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
78805	28427185	Zack et al analyzed the copy number profiles of 4,934 primary cancer specimens across 11 cancer types and found that the mean rate of somatic copy number alterations (SCNAs) varied across different cancer types with ovarian, cervix, breast and bladder cancers having a large number of SCNAs while leukemia and kidney cancers very few SCNAs.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (89, 95))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (198, 204))	('kidney cancers', 'Disease', (310, 324))	('cervix', 'Disease', (225, 231))	('kidney cancers', 'Disease', 'MESH:D007680', (310, 324))	('cancer', 'Disease', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('cancer', 'Disease', (317, 323))	('copy number', 'Var', (142, 153))	('ovarian', 'Disease', (216, 223))	('leukemia', 'Disease', 'MESH:D007938', (297, 305))	('ovarian', 'Disease', 'MESH:D010051', (216, 223))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('kidney cancers', 'Phenotype', 'HP:0009726', (310, 324))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('kidney cancer', 'Phenotype', 'HP:0009726', (310, 323))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('leukemia', 'Phenotype', 'HP:0001909', (297, 305))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('leukemia', 'Disease', (297, 305))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
78924	28427185	Likewise, we found a number of genes whose expression follows this pattern: late-stage cancers < early-stage cancers < normal tissue (Figure 7C), such as ADHFE1, LOC653501, NT5DC1, RSBN1, SOCS2 and TAPT1 in five cancer types.	('RSBN1', 'Gene', '54665', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('LOC653501', 'Var', (162, 171))	('late-stage cancers', 'Disease', 'MESH:D009369', (76, 94))	('ADHFE1', 'Gene', '137872', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('RSBN1', 'Gene', (181, 186))	('NT5DC1', 'Gene', '221294', (173, 179))	('NT5DC1', 'Gene', (173, 179))	('SOCS2', 'Gene', '8835', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('SOCS2', 'Gene', (188, 193))	('cancer', 'Disease', (87, 93))	('cancers', 'Disease', (87, 94))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('late-stage cancers', 'Disease', (76, 94))	('cancer', 'Disease', (212, 218))	('TAPT1', 'Gene', '202018', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('TAPT1', 'Gene', (198, 203))	('ADHFE1', 'Gene', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
78946	28427185	These results demonstrate that there exist common genes and pathways whose dysregulations lead to the development of different types of cancer.	('dysregulations', 'Var', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('lead to', 'Reg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
78977	28427185	In addition, many upstream factors may affect expression of mRNAs (genes) in cancers such as gene mutations, DNA copy number alterations, DNA methylation, microRNA expression, and expression change of regulators.	('expression', 'MPA', (46, 56))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('affect', 'Reg', (39, 45))	('expression', 'MPA', (180, 190))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('methylation', 'Var', (142, 153))	('microRNA', 'MPA', (155, 163))	('copy number alterations', 'Var', (113, 136))
79054	31879461	Scores of 11 or more on either subscale are considered to be a significant "case" of psychological morbidity, while scores of 8-10 represent a "mood disorder."	('mood disorder', 'Disease', 'MESH:D019964', (144, 157))	('Scores of 11', 'Var', (0, 12))	('mood disorder', 'Disease', (144, 157))	('psychological morbidity', 'Phenotype', 'HP:0001575', (85, 108))
79126	31106606	Several studies have shown a survival advantage when patients undergo gross total resection of the tumor compared with biopsies.	('tumor', 'Disease', (99, 104))	('patients', 'Species', '9606', (53, 61))	('gross total', 'Var', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
79131	31106606	For example, mutation of isocitrate dehydrogenase (IDH) is frequently seen in low-grade and anaplastic glioma and is a marker of better prognosis.	('IDH', 'Gene', (51, 54))	('low-grade', 'Disease', (78, 87))	('mutation', 'Var', (13, 21))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('IDH', 'Gene', '3417', (51, 54))	('seen', 'Reg', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('isocitrate dehydrogenase', 'Gene', (25, 49))	('glioma', 'Disease', (103, 109))	('isocitrate dehydrogenase', 'Gene', '3417', (25, 49))
79132	31106606	Most glioblastomas on the other hand have wild type IDH; the presence of IDH mutation in glioblastoma suggests an overall better prognosis or indicates progression of a lower grade astrocytoma to a secondary GBM.	('glioblastoma', 'Disease', 'MESH:D005909', (5, 17))	('mutation', 'Var', (77, 85))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (52, 55))	('progression', 'PosReg', (152, 163))	('astrocytoma', 'Disease', 'MESH:D001254', (181, 192))	('glioblastoma', 'Disease', (5, 17))	('better', 'PosReg', (122, 128))	('astrocytoma', 'Disease', (181, 192))	('glioblastomas', 'Disease', (5, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (5, 17))	('IDH', 'Gene', '3417', (73, 76))	('glioblastomas', 'Disease', 'MESH:D005909', (5, 18))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('presence', 'Var', (61, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (181, 192))	('glioblastoma', 'Disease', (89, 101))	('IDH', 'Gene', (52, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('glioblastomas', 'Phenotype', 'HP:0012174', (5, 18))
79139	31106606	The survival benefit of adding TMZ was predominantly seen in patients with methylated MGMT.	('methylated', 'Var', (75, 85))	('MGMT', 'Gene', (86, 90))	('MGMT', 'Gene', '4255', (86, 90))	('patients', 'Species', '9606', (61, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (31, 34))
79153	31106606	Interim analysis of the ongoing CATNON study which compares the efficacy of four treatment arms (radiation alone, radiation with concurrent temozolomide, radiation followed by temozolomide and radiation with concurrent and adjuvant temozolomide) in patients with 1p/19q non-codeleted anaplastic gliomas, showed that the arms with adjuvant temozolomide showed improved survival compared to those without leading to the termination of the arms without adjuvant temozolomide.	('glioma', 'Phenotype', 'HP:0009733', (295, 301))	('survival', 'MPA', (368, 376))	('temozolomide', 'Chemical', 'MESH:D000077204', (232, 244))	('temozolomide', 'Chemical', 'MESH:D000077204', (140, 152))	('patients', 'Species', '9606', (249, 257))	('temozolomide', 'Chemical', 'MESH:D000077204', (339, 351))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (284, 302))	('improved', 'PosReg', (359, 367))	('1p/19q', 'Var', (263, 269))	('temozolomide', 'Chemical', 'MESH:D000077204', (176, 188))	('anaplastic gliomas', 'Disease', (284, 302))	('gliomas', 'Phenotype', 'HP:0009733', (295, 302))	('temozolomide', 'Chemical', 'MESH:D000077204', (459, 471))
79162	31106606	The diversity of mutations has been an obstacle in developing glioma animal models that can closely approximate human glioma disease and consequently, has caused a universal clinical treatment plan to be elusive.	('glioma disease', 'Disease', 'MESH:D005910', (118, 132))	('glioma', 'Disease', (118, 124))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('human', 'Species', '9606', (112, 117))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioma disease', 'Disease', (118, 132))	('mutations', 'Var', (17, 26))	('glioma', 'Disease', (62, 68))
79163	31106606	The biological consequences of the genetic and epigenetic alterations gliomas that underlie their increased survival and malignant transformation include unrestricted proliferation, invasion, neovascularization, necrosis, and resistance to apoptosis.	('neovascularization', 'CPA', (192, 210))	('necrosis', 'Disease', 'MESH:D009336', (212, 220))	('unrestricted proliferation', 'CPA', (154, 180))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('genetic', 'Var', (35, 42))	('resistance to apoptosis', 'CPA', (226, 249))	('invasion', 'CPA', (182, 190))	('necrosis', 'Disease', (212, 220))	('epigenetic alterations gliomas', 'Disease', (47, 77))	('epigenetic alterations gliomas', 'Disease', 'MESH:D005910', (47, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
79167	31106606	Pediatric LGG show alterations in FGFR1 and BRAF genes, and adult LGG are characterized by IDH1/2 mutations, ATRX mutations, and 1p/19q codeletion.	('BRAF', 'Gene', '673', (44, 48))	('mutations', 'Var', (114, 123))	('BRAF', 'Gene', (44, 48))	('IDH1/2', 'Gene', (91, 97))	('alterations', 'Reg', (19, 30))	('FGFR1', 'Gene', (34, 39))	('mutations', 'Var', (98, 107))	('1p/19q codeletion', 'Var', (129, 146))	('FGFR1', 'Gene', '2260', (34, 39))	('ATRX', 'Gene', (109, 113))	('IDH1/2', 'Gene', '3417;3418', (91, 97))
79170	31106606	A point mutation in BRAF with valine to glutamate at position 600 (V600E), has been identified as the key oncogenic mutations in several cancers, especially in melanoma; these mutations are believed to change the protein conformation to a constitutively active state driving the downstream MAPK pathways and resulting in increased proliferation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('valine to glutamate at position 600', 'Mutation', 'rs113488022', (30, 65))	('mutations', 'Var', (176, 185))	('driving', 'PosReg', (267, 274))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('change', 'Reg', (202, 208))	('proliferation', 'CPA', (331, 344))	('V600E', 'Mutation', 'rs113488022', (67, 72))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('BRAF', 'Gene', '673', (20, 24))	('increased', 'PosReg', (321, 330))	('cancers', 'Disease', (137, 144))	('BRAF', 'Gene', (20, 24))	('MAPK pathways', 'Pathway', (290, 303))	('protein', 'Protein', (213, 220))
79174	31106606	While BRAF mutations are frequently seen in the subtypes of gliomas outlined above, other alterations in BRAF driven signaling pathway such as the fusion of the can also provide oncogenic pressure in the setting of certain gliomas.	('alterations', 'Var', (90, 101))	('mutations', 'Var', (11, 20))	('BRAF', 'Gene', '673', (105, 109))	('provide', 'Reg', (170, 177))	('gliomas', 'Disease', 'MESH:D005910', (223, 230))	('gliomas', 'Phenotype', 'HP:0009733', (223, 230))	('BRAF', 'Gene', (105, 109))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('oncogenic pressure', 'CPA', (178, 196))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('gliomas', 'Disease', (223, 230))
79176	31106606	In addition, rates of BRAF fusion appear to vary depending on tumor location in the central nervous system (CNS); ~75% of cerebellar pilocytic astrocytomas exhibit BRAF-KIAA1549 fusions in contrast with only 33% of supratentorial astrocytomas harboring this alteration Several other novel BRAF fusions have been described and although their incidence is small, their biological behavior is believed to be similar to BRAF-KIAA1549 fusions.	('astrocytomas', 'Disease', (143, 155))	('astrocytomas', 'Disease', (230, 242))	('cerebellar pilocytic astrocytomas', 'Disease', (122, 155))	('cerebellar pilocytic astrocytomas', 'Disease', 'MESH:D001254', (122, 155))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('fusions', 'Var', (178, 185))	('astrocytomas', 'Disease', 'MESH:D001254', (143, 155))	('astrocytomas', 'Disease', 'MESH:D001254', (230, 242))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('BRAF', 'Gene', '673', (22, 26))	('astrocytoma', 'Phenotype', 'HP:0009592', (230, 241))	('BRAF', 'Gene', '673', (164, 168))	('BRAF', 'Gene', (22, 26))	('KIAA1549', 'Gene', '57670', (421, 429))	('BRAF', 'Gene', (164, 168))	('BRAF', 'Gene', '673', (289, 293))	('KIAA1549', 'Gene', '57670', (169, 177))	('BRAF', 'Gene', (289, 293))	('KIAA1549', 'Gene', (169, 177))	('tumor location in the central nervous system', 'Phenotype', 'HP:0100006', (62, 106))	('tumor', 'Disease', (62, 67))	('BRAF', 'Gene', '673', (416, 420))	('BRAF', 'Gene', (416, 420))	('KIAA1549', 'Gene', (421, 429))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
79177	31106606	Genome-wide profiling studies unexpectedly identified heterozygous mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) in >70% of grade II and grade III gliomas and more than 90% of secondary GBM bringing to light the involvement of metabolic genes in the pathogenesis of lower grade infiltrative gliomas.	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('IDH1/2', 'Gene', (136, 142))	('isocitrate dehydrogenase', 'Gene', (102, 126))	('gliomas', 'Disease', (322, 329))	('III gliomas', 'Disease', 'MESH:D005910', (174, 185))	('gliomas', 'Disease', 'MESH:D005910', (322, 329))	('heterozygous mutations', 'Var', (54, 76))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('isocitrate dehydrogenase', 'Gene', '3417', (102, 126))	('gliomas', 'Disease', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (322, 329))	('III gliomas', 'Disease', (174, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('glioma', 'Phenotype', 'HP:0009733', (322, 328))	('IDH1/2', 'Gene', '3417;3418', (136, 142))
79178	31106606	Such mutations were notably absent in the majority of grade 1 gliomas, ependymomas and primary glioblastomas.	('absent', 'NegReg', (28, 34))	('glioblastomas', 'Phenotype', 'HP:0012174', (95, 108))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioblastomas', 'Disease', 'MESH:D005909', (95, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('mutations', 'Var', (5, 14))	('glioblastomas', 'Disease', (95, 108))	('ependymomas', 'Disease', 'MESH:D004806', (71, 82))	('gliomas', 'Disease', (62, 69))	('ependymomas', 'Disease', (71, 82))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
79180	31106606	The mutations occur in the isocitrate binding pocket of the IDH protein resulting in neomorphic enzyme activity changing its specificity to alpha-ketoglutarate and generating high levels of 2-hydroxyglutarate (2-HG), an oncometabolite that drives pathological alterations in a variety of cellular processes especially -ketoglutarate-dependent dioxygenases, including the TET group of DNA demethylases.	('IDH', 'Gene', '3417', (60, 63))	('TET', 'Chemical', 'MESH:C010349', (371, 374))	('neomorphic enzyme', 'Enzyme', (85, 102))	('activity', 'MPA', (103, 111))	('isocitrate', 'Chemical', 'MESH:C034219', (27, 37))	('specificity to alpha-ketoglutarate', 'MPA', (125, 159))	('2-HG', 'Chemical', 'MESH:C019417', (210, 214))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (190, 208))	('changing', 'Reg', (112, 120))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (140, 159))	('IDH', 'Gene', (60, 63))	('mutations', 'Var', (4, 13))	('DNA demethylases', 'Enzyme', (384, 400))
79182	31106606	Recent studies have shown that IDH1/2 mutations cause genome-wide changes in multiple histone marks causing altered chromatin structure which after sustained exposure leads to irreversible genomic and epigenetic alterations in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('leads to', 'Reg', (167, 175))	('gliomas', 'Disease', (227, 234))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('altered', 'Reg', (108, 115))	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('changes', 'Reg', (66, 73))	('mutations', 'Var', (38, 47))	('IDH1/2', 'Gene', (31, 37))	('multiple histone marks', 'MPA', (77, 99))	('chromatin structure', 'MPA', (116, 135))
79183	31106606	Further, it was seen that mutant IDH1 can result in the generation of a CD24+ stem like cell population that can drive tumor growth.	('tumor', 'Disease', (119, 124))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutant', 'Var', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('result in', 'Reg', (42, 51))	('CD24', 'Gene', '100133941', (72, 76))	('CD24', 'Gene', (72, 76))
79184	31106606	Additional gene expression analysis studies have provided These findings have resulted in a focused effort to develop inhibitors of IDH1/2 although it remains to be seen if such targeting may be aiming at an early oncogenic event whose relevance may be overshadowed by subsequent changes that maintain tumor growth or drive tumor progression to more malignant states through downstream genetic and epigenetic alterations.	('inhibitors', 'Var', (118, 128))	('IDH1/2', 'Gene', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('tumor', 'Disease', (302, 307))	('IDH1/2', 'Gene', '3417;3418', (132, 138))	('epigenetic alterations', 'Var', (398, 420))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
79185	31106606	Oligodendrogliomas were recognized initially as a chemo-sensitive subtype of gliomas; subsequent studies showed that approximately 70% of gliomas that are morphologically consistent with oligodendrogliomas harbored co-deletions of chromosomes 1p and 19q which correlated with their sensitivity to treatment.	('oligodendrogliomas', 'Disease', (187, 205))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('Oligodendrogliomas', 'Disease', (0, 18))	('gliomas', 'Disease', (11, 18))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Disease', (138, 145))	('co-deletions', 'Var', (215, 227))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (187, 205))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('gliomas', 'Disease', (77, 84))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('gliomas', 'Disease', (198, 205))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))
79186	31106606	Given the strong association of 1p/19q codeletion with a classical oligodendroglial morphology as well as to treatment sensitivity, molecular reclassification of gliomas currently defines oligodendrogliomas by the combined presence of IDH mutation and 1p/19q codeletion.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('gliomas', 'Disease', (162, 169))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (188, 206))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('oligodendroglial morphology', 'Phenotype', 'HP:0100709', (67, 94))	('presence', 'Reg', (223, 231))	('IDH', 'Gene', '3417', (235, 238))	('oligodendrogliomas', 'Disease', (188, 206))	('1p/19q codeletion', 'Var', (252, 269))	('1p/19q codeletion', 'Var', (32, 49))	('IDH', 'Gene', (235, 238))	('gliomas', 'Disease', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))
79187	31106606	The association of 1p/19q codeletion with other mutations such as in CIC, FUBP1 and TERT promoter has further refined the molecular assessment of oligodendroglial tumors.	('CIC', 'Gene', (69, 72))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (146, 169))	('TERT', 'Gene', (84, 88))	('oligodendroglial tumors', 'Disease', (146, 169))	('TERT', 'Gene', '7015', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('1p/19q codeletion', 'Var', (19, 36))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('FUBP1', 'Gene', '8880', (74, 79))	('CIC', 'Gene', '23152', (69, 72))	('FUBP1', 'Gene', (74, 79))
79189	31106606	Large scale genome sequencing of glioblastoma in pediatric and young adult population identified mutations in ATRX in astrocytic gliomas; mutations in components of this complex including ATRX, H3.3 and DAXX were seen to facilitate alternative lengthening of telomeres (ALT) in malignant cells which can result in preservation of telomere length and enhanced tumor cell survival.	('mutations', 'Var', (97, 106))	('telomere length', 'MPA', (330, 345))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (118, 136))	('astrocytic gliomas', 'Disease', (118, 136))	('enhanced', 'PosReg', (350, 358))	('H3.3', 'Gene', (194, 198))	('tumor', 'Disease', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('mutations', 'Var', (138, 147))	('glioblastoma', 'Disease', (33, 45))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('ATRX', 'Gene', (110, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('facilitate', 'PosReg', (221, 231))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('H3.3', 'Gene', '109836', (194, 198))	('ATRX', 'Gene', (188, 192))
79190	31106606	ATRX mutations were also noted in adult diffuse astrocytomas with IDH1 and TP53 mutations being seen in 33% of low grade astrocytomas, 46% of anaplastic astrocytomas and 80% of secondary glioblastoma.	('astrocytomas', 'Disease', (153, 165))	('astrocytoma', 'Phenotype', 'HP:0009592', (121, 132))	('astrocytoma', 'Phenotype', 'HP:0009592', (153, 164))	('glioblastoma', 'Disease', (187, 199))	('astrocytomas', 'Disease', (48, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('IDH1', 'Gene', '3417', (66, 70))	('mutations', 'Var', (80, 89))	('astrocytomas', 'Disease', 'MESH:D001254', (121, 133))	('astrocytomas', 'Disease', 'MESH:D001254', (153, 165))	('IDH1', 'Gene', (66, 70))	('TP53', 'Gene', (75, 79))	('seen', 'Reg', (96, 100))	('mutations', 'Var', (5, 14))	('astrocytomas', 'Disease', 'MESH:D001254', (48, 60))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (142, 165))	('anaplastic astrocytomas', 'Disease', (142, 165))	('glioblastoma', 'Disease', 'MESH:D005909', (187, 199))	('TP53', 'Gene', '7157', (75, 79))	('astrocytomas', 'Disease', (121, 133))
79191	31106606	ATRX loss by immunohistochemistry which is associated with ATRX mutations has hence served as a marker of a astrocytic gliomas and is mutually exclusive from 1p/19q codeletions.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('ATRX', 'Gene', (0, 4))	('ATRX', 'Gene', (59, 63))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (108, 126))	('astrocytic gliomas', 'Disease', (108, 126))	('loss', 'NegReg', (5, 9))	('mutations', 'Var', (64, 73))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))
79194	31106606	Cancer cells are characterized by reactivation of telomeres resulting in replicative immortality mostly driven by point mutations in the promoter region of TERT) gene which increases telomerase expression, thereby maintaining telomere length and enabling repeated cell division.	('driven', 'Reg', (104, 110))	('telomere length', 'MPA', (226, 241))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('repeated cell division', 'CPA', (255, 277))	('maintaining', 'PosReg', (214, 225))	('increases', 'PosReg', (173, 182))	('point mutations', 'Var', (114, 129))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mortality', 'Disease', (87, 96))	('enabling', 'PosReg', (246, 254))	('TERT', 'Gene', (156, 160))	('telomerase expression', 'MPA', (183, 204))	('TERT', 'Gene', '7015', (156, 160))
79195	31106606	These mutations have been identified in glioblastomas and LGG; in LGG, TERT promoter mutations are predominantly observed in oligodendrogliomas (63-78%) and less frequently (0-32%) in diffuse astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (192, 204))	('glioblastomas', 'Phenotype', 'HP:0012174', (40, 53))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (71, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (192, 203))	('glioblastomas', 'Disease', 'MESH:D005909', (40, 53))	('astrocytomas', 'Disease', (192, 204))	('observed', 'Reg', (113, 121))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (125, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('mutations', 'Var', (85, 94))	('glioblastomas', 'Disease', (40, 53))	('oligodendrogliomas', 'Disease', (125, 143))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
79196	31106606	The clinical impact of TERT promoter mutations in lower grade and anaplastic gliomas appear to depend on the IDH status; in IDH mutated astrocytomas, TERT promoter mutations appear to confer a longer progression free and overall survival.	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('TERT', 'Gene', (150, 154))	('overall survival', 'CPA', (221, 237))	('TERT', 'Gene', '7015', (150, 154))	('astrocytomas', 'Disease', (136, 148))	('progression free', 'CPA', (200, 216))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('IDH', 'Gene', (109, 112))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (66, 84))	('longer', 'PosReg', (193, 199))	('anaplastic gliomas', 'Disease', (66, 84))	('IDH', 'Gene', (124, 127))	('astrocytomas', 'Disease', 'MESH:D001254', (136, 148))	('mutations', 'Var', (37, 46))	('IDH', 'Gene', '3417', (109, 112))	('lower grade', 'Disease', (50, 61))	('IDH', 'Gene', '3417', (124, 127))
79197	31106606	Conversely, patients with IDH wild type astrocytomas which also exhibited TERT promoter mutations have a shorter progression free and overall survival.	('astrocytomas', 'Disease', (40, 52))	('patients', 'Species', '9606', (12, 20))	('overall survival', 'CPA', (134, 150))	('astrocytoma', 'Phenotype', 'HP:0009592', (40, 51))	('TERT', 'Gene', '7015', (74, 78))	('mutations', 'Var', (88, 97))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (26, 29))	('shorter', 'NegReg', (105, 112))	('astrocytomas', 'Disease', 'MESH:D001254', (40, 52))	('TERT', 'Gene', (74, 78))
79201	31106606	The proneural subtype is characterized by PDGFRA alterations, TP53 mutations, IDH1 mutations and PIK3CA/PIK3R1 mutations and is associated with longer median survival.	('mutations', 'Var', (83, 92))	('mutations', 'Var', (111, 120))	('TP53', 'Gene', '7157', (62, 66))	('alterations', 'Var', (49, 60))	('PDGFRA', 'Gene', (42, 48))	('PDGFRA', 'Gene', '5156', (42, 48))	('longer', 'PosReg', (144, 150))	('IDH1', 'Gene', (78, 82))	('TP53', 'Gene', (62, 66))	('PIK3R1', 'Gene', '5295', (104, 110))	('mutations', 'Var', (67, 76))	('PIK3R1', 'Gene', (104, 110))	('proneural', 'Disease', (4, 13))	('IDH1', 'Gene', '3417', (78, 82))	('PIK3CA', 'Gene', (97, 103))	('PIK3CA', 'Gene', '5290', (97, 103))
79202	31106606	The classical subtype demonstrates EGFR overexpression, EGFRvIII mutation and CDKN2A loss.	('overexpression', 'PosReg', (40, 54))	('CDKN2A', 'Gene', (78, 84))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('CDKN2A', 'Gene', '1029', (78, 84))	('EGFR', 'Gene', (56, 60))	('mutation', 'Var', (65, 73))	('loss', 'NegReg', (85, 89))
79203	31106606	Similar in survival to the classical subtype is the mesenchymal subtype which shows NF1 loss or mutations, expression of genes associated with epithelial-to-mesenchymal transformation and the presence of inflammatory infiltrates and angiogenesis.	('NF1', 'Gene', (84, 87))	('expression', 'MPA', (107, 117))	('loss', 'NegReg', (88, 92))	('NF1', 'Gene', '4763', (84, 87))	('epithelial-to-mesenchymal transformation', 'CPA', (143, 183))	('angiogenesis', 'CPA', (233, 245))	('mutations', 'Var', (96, 105))
79205	31106606	Hypermethylation of the MGMT gene promoter results in epigenetic silencing of the gene and is predicted to decrease the levels of the protein thus reducing the ability of the cell to repair DNA lesions from monofunctional alkylating agents such as temozolomide.	('MGMT', 'Gene', '4255', (24, 28))	('results in', 'Reg', (43, 53))	('reducing', 'NegReg', (147, 155))	('Hypermethylation', 'Var', (0, 16))	('temozolomide', 'Chemical', 'MESH:D000077204', (248, 260))	('levels of the protein', 'MPA', (120, 141))	('epigenetic silencing', 'MPA', (54, 74))	('decrease', 'NegReg', (107, 115))	('MGMT', 'Gene', (24, 28))	('ability', 'MPA', (160, 167))
79208	31106606	The prognostic relevance of a methylated MGMT promoter has also been shown in elderly GBM patients as well as those with unresectable GBM.	('methylated', 'Var', (30, 40))	('GBM', 'Disease', (86, 89))	('MGMT', 'Gene', '4255', (41, 45))	('patients', 'Species', '9606', (90, 98))	('MGMT', 'Gene', (41, 45))
79210	31106606	As noted in the previous sections, point mutations in the IDH1 and IDH2 genes are uncommon in primary glioblastomas but are frequently seen in secondary glioblastoma.	('IDH1', 'Gene', '3417', (58, 62))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('glioblastomas', 'Phenotype', 'HP:0012174', (102, 115))	('glioblastoma', 'Disease', (102, 114))	('IDH2', 'Gene', (67, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('secondary', 'Disease', (143, 152))	('glioblastomas', 'Disease', 'MESH:D005909', (102, 115))	('seen', 'Reg', (135, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('IDH2', 'Gene', '3418', (67, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('point mutations', 'Var', (35, 50))	('glioblastomas', 'Disease', (102, 115))	('glioblastoma', 'Disease', (153, 165))	('IDH1', 'Gene', (58, 62))
79211	31106606	However, IDH1/2 mutations are associated with the gCIMP subtype of glioblastoma and by their effect on alpha-ketoglutarate dependent dioxygenases such as TET demethylases which may be causative of the increased methylation seen in this subtype of glioblastoma.	('associated', 'Reg', (30, 40))	('IDH1/2', 'Gene', (9, 15))	('glioblastoma', 'Disease', (67, 79))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (103, 122))	('alpha-ketoglutarate', 'MPA', (103, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('glioblastoma', 'Disease', (247, 259))	('effect', 'Reg', (93, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('mutations', 'Var', (16, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (247, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (247, 259))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('gCIMP subtype', 'Disease', (50, 63))	('TET', 'Chemical', 'MESH:C010349', (154, 157))
79212	31106606	Gliomas with a mutated IDH1 or IDH2 are associated with better prognosis compared to their wild-type counterparts.	('IDH2', 'Gene', '3418', (31, 35))	('IDH1', 'Gene', (23, 27))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('mutated', 'Var', (15, 22))	('IDH1', 'Gene', '3417', (23, 27))	('Gliomas', 'Disease', (0, 7))	('IDH2', 'Gene', (31, 35))
79213	31106606	However, a recent report analyzing IDH mutant GBM (comprising of ~10% of the tumors) reported a poorer prognosis for patients of male gender and those with IDH mutant tumors which had wild type TERT promoter, suggesting further nuances in the implications of IDH mutation in patients with GBM.	('IDH', 'Gene', '3417', (35, 38))	('patients', 'Species', '9606', (275, 283))	('patients', 'Species', '9606', (117, 125))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mutant', 'Var', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutant', 'Var', (39, 45))	('tumors', 'Disease', (77, 83))	('TERT', 'Gene', (194, 198))	('TERT', 'Gene', '7015', (194, 198))	('poorer', 'NegReg', (96, 102))	('IDH', 'Gene', (156, 159))	('IDH', 'Gene', (259, 262))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('IDH', 'Gene', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('IDH', 'Gene', '3417', (156, 159))	('tumors', 'Disease', (167, 173))	('IDH', 'Gene', '3417', (259, 262))
79214	31106606	Alterations of EGFR, a membrane bound tyrosine kinase, are among the most common tumor-specific genetic changes seen in GBM.	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
79216	31106606	Additionally about 30% of primary GBM also express the EFGR variant III (EGFRvIII) which results from deletion of exon 2-7 of EGFR and is a constitutively activated mutant receptor which cannot bind any known ligand.	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (126, 130))	('results from', 'Reg', (89, 101))	('EGFR', 'Gene', (73, 77))	('deletion of', 'Var', (102, 113))	('EGFR', 'Gene', '1956', (126, 130))
79243	31106606	Gene expression profiling of GBM through the Cancer Genome Atlas project demonstrated a high degree of heterogeneity as a result of several genetic and epigenetic alterations including amplification, gain-of-function mutations, copy number loss or gain and methylation that promote growth factor receptor signaling, and loss-of-function mutations in tumor suppressor genes (e.g.	('mutations', 'Var', (337, 346))	('promote', 'PosReg', (274, 281))	('amplification', 'MPA', (185, 198))	('loss-of-function', 'NegReg', (320, 336))	('gain', 'PosReg', (248, 252))	('methylation', 'Var', (257, 268))	('tumor', 'Disease', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('copy number loss', 'Var', (228, 244))	('Cancer', 'Disease', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('growth factor receptor signaling', 'MPA', (282, 314))	('mutations', 'Var', (217, 226))	('gain-of-function', 'PosReg', (200, 216))
79254	31106606	Subgroup analysis, however, suggested possible benefit in patients with residual tumor with unmethylated MGMT promoter.	('benefit', 'PosReg', (47, 54))	('MGMT', 'Gene', '4255', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('MGMT', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patients', 'Species', '9606', (58, 66))	('unmethylated', 'Var', (92, 104))	('tumor', 'Disease', (81, 86))
79261	31106606	Interestingly, mutation and loss of PTEN as well as PTEN phosphorylation mediated by both FGFR and Src-family kinases (SFKs) were linked to EGFR TKI resistance in GBM patients.	('mutation', 'Var', (15, 23))	('SFKs', 'Disease', 'None', (119, 123))	('PTEN', 'Gene', (52, 56))	('EGFR', 'Gene', (140, 144))	('PTEN', 'Gene', '5728', (52, 56))	('FGFR', 'Gene', (90, 94))	('patients', 'Species', '9606', (167, 175))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('linked', 'Reg', (130, 136))	('SFKs', 'Disease', (119, 123))	('phosphorylation', 'MPA', (57, 72))	('EGFR', 'Gene', '1956', (140, 144))	('loss', 'NegReg', (28, 32))
79266	31106606	The Cancer Genome Atlas Research Network further reported PDGFR amplification in 13.1% in GBM samples.	('GBM', 'Disease', (90, 93))	('amplification', 'Var', (64, 77))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('PDGFR', 'Gene', (58, 63))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('PDGFR', 'Gene', '5159', (58, 63))
79276	31106606	Such targets have included p53, a key regulator of DNA repair and cellular decisions to activate apoptosis, which is commonly dysregulated in GBM either through mutations or loss.	('p53', 'Gene', '7157', (27, 30))	('activate', 'PosReg', (88, 96))	('mutations', 'Var', (161, 170))	('loss', 'NegReg', (174, 178))	('apoptosis', 'CPA', (97, 106))	('p53', 'Gene', (27, 30))
79277	31106606	Relevant to p53 function, its cellular inhibitory partners, MDM1, 2 and 4 are noted to be overexpressed through amplification and cause inactivation of p53 function.	('inactivation', 'NegReg', (136, 148))	('p53', 'Gene', (152, 155))	('amplification', 'Var', (112, 125))	('p53', 'Gene', '7157', (152, 155))	('overexpressed', 'PosReg', (90, 103))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('function', 'MPA', (156, 164))	('MDM1, 2 and 4', 'Gene', '56890;4193;4194', (60, 73))
79278	31106606	Preclinical studies of MDM2 inhibitors have shown promising activity in glioma models.	('glioma', 'Disease', (72, 78))	('MDM2', 'Gene', '4193', (23, 27))	('MDM2', 'Gene', (23, 27))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('inhibitors', 'Var', (28, 38))	('activity', 'MPA', (60, 68))
79279	31106606	Similarly, preclinical efforts to target mutant IDH1 and MYC amplification have been translated to early trials which are ongoing.	('IDH1', 'Gene', '3417', (48, 52))	('mutant', 'Var', (41, 47))	('MYC', 'Gene', '4609', (57, 60))	('IDH1', 'Gene', (48, 52))	('MYC', 'Gene', (57, 60))
79280	31106606	Mutations of H3.3 histones, not observed in the Cancer Genome Atlas Project, were nevertheless identified independently in midline and brain stem gliomas and constitute new targets in gliomas for development of therapies.	('brain stem gliomas', 'Phenotype', 'HP:0010796', (135, 153))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('gliomas', 'Disease', 'MESH:D005910', (184, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('gliomas', 'Disease', (184, 191))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('Mutations', 'Var', (0, 9))	('H3.3', 'Gene', (13, 17))	('midline', 'Disease', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('identified', 'Reg', (95, 105))	('H3.3', 'Gene', '109836', (13, 17))
79316	31106606	In this system, T-cells are engineered to recognize antigens on tumors by fusing an extracellular binding domain to the intra-cellular signaling domain of the T cell receptor.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('fusing', 'Var', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
79323	31106606	In addition, both spatial and temporal genetic heterogeneity seems to be critical to such adaptations with accumulation of specific genetic alterations that provide new pathways for tumor survival both during spontaneous evolution as well as in response to therapy.	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('alterations', 'Var', (140, 151))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
79339	31106606	This is highlighted by recent promising results seen with pre-treatment of surgical patients with recurrent GBM with pembrolizumab followed by resection and continued checkpoint blockade who had near doubling of survival compared to those who received pembrolizumab after surgery alone.	('pembrolizumab', 'Chemical', 'MESH:C582435', (117, 130))	('pembrolizumab', 'Var', (117, 130))	('patients', 'Species', '9606', (84, 92))	('GBM', 'Disease', (108, 111))	('pembrolizumab', 'Chemical', 'MESH:C582435', (252, 265))	('survival', 'MPA', (212, 220))
79343	31106606	Such strategies include developing treatments that are selective for specific genetic or epigenetic vulnerabilities of GBM in smaller subsets of selected patients and targeting metabolic or immunological aspects of tumors that bypass the heterogeneity of these tumors.	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('epigenetic', 'Var', (89, 99))	('GBM', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
79346	31106606	The results of IDH1/2 inhibitor trials are also eagerly awaited given that IDH mutations are believed to be the initial event in tumorigenesis of IDH mutant gliomas and invariably exist across the lifetime of IDH mutant gliomas although it remains to be seen if the benefits of such targeting may be negated by subsequent changes that maintain tumor growth through downstream genetic and epigenetic alterations.	('IDH', 'Gene', '3417', (146, 149))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('tumor', 'Disease', (129, 134))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('IDH1/2', 'Gene', '3417;3418', (15, 21))	('IDH1/2', 'Gene', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (344, 349))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('IDH', 'Gene', (15, 18))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('mutant', 'Var', (150, 156))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (15, 18))	('IDH', 'Gene', (209, 212))	('IDH', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('gliomas', 'Disease', (157, 164))	('IDH', 'Gene', '3417', (75, 78))	('IDH', 'Gene', '3417', (209, 212))	('gliomas', 'Disease', (220, 227))
79399	31355268	Phosphorylation of beta-catenin at S33 and S37 promotes its degradation, and its downstream target genes c-myc and cyclin D1 are responsible for tumor proliferation or malignant progression.	('cyclin D1', 'Gene', '595', (115, 124))	('cyclin D1', 'Gene', (115, 124))	('S37', 'Var', (43, 46))	('Phosphorylation', 'Var', (0, 15))	('promotes', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('beta-catenin', 'Protein', (19, 31))	('at S33', 'Var', (32, 38))	('degradation', 'MPA', (60, 71))	('c-myc', 'Gene', '4609', (105, 110))	('c-myc', 'Gene', (105, 110))
79406	31355268	It has been reported that CKIP-1 expression suppresses osteosarcoma and human epithelial carcinoma formation in nude mice.	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (78, 98))	('epithelial carcinoma', 'Disease', (78, 98))	('expression', 'Var', (33, 43))	('suppresses', 'NegReg', (44, 54))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (78, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('nude mice', 'Species', '10090', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('CKIP-1', 'Gene', (26, 32))
79415	27748711	Alterations in many metabolic pathways support the requirement for cellular building blocks that are essential for cancer cell proliferation.	('cancer', 'Disease', (115, 121))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rat', 'Species', '10116', (134, 137))	('metabolic pathways', 'Pathway', (20, 38))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
79418	27748711	In the case of glioma, preclinical cell and animal studies have shown that the hyperpolarized 13C MRS metabolic imaging signature is specific to tumor type and can distinguish between mutant IDH1 glioma and primary glioblastoma.	('IDH1', 'Gene', (191, 195))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('mutant', 'Var', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('13C', 'Chemical', '-', (94, 97))	('IDH1', 'Gene', '3417', (191, 195))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('tumor', 'Disease', (145, 150))	('MRS', 'Disease', 'MESH:D008556', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MRS', 'Disease', (98, 101))	('primary glioblastoma', 'Disease', (207, 227))	('distinguish', 'Reg', (164, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('glioma', 'Disease', (15, 21))	('primary glioblastoma', 'Disease', 'MESH:D005909', (207, 227))	('glioma', 'Disease', (196, 202))	('glioma', 'Disease', 'MESH:D005910', (15, 21))
79432	27748711	Primary GBM are driven by multiple genetic alterations such as loss of the phosphatase and tensin homolog (PTEN) gene, amplification or mutation of the epidermal growth factor receptor (EGFR), and increased signaling via the phosphatidylinositol-3-kinase (PI3K)/Akt pathway .	('PTEN', 'Gene', (107, 111))	('epidermal growth factor receptor', 'Gene', '1956', (152, 184))	('PTEN', 'Gene', '5728', (107, 111))	('phosphatidylinositol-3-kinase', 'Gene', (225, 254))	('mutation', 'Var', (136, 144))	('EGFR', 'Gene', '1956', (186, 190))	('rat', 'Species', '10116', (47, 50))	('EGFR', 'Gene', (186, 190))	('increased', 'PosReg', (197, 206))	('Primary GBM', 'Disease', (0, 11))	('phosphatidylinositol-3-kinase', 'Gene', '5294', (225, 254))	('amplification', 'Var', (119, 132))	('epidermal growth factor receptor', 'Gene', (152, 184))	('GBM', 'Phenotype', 'HP:0012174', (8, 11))	('loss', 'NegReg', (63, 67))	('signaling', 'MPA', (207, 216))
79433	27748711	In contrast, 70-90% of grade II/III glioma and secondary GBM harbor a mutation in the cytosolic isocitrate dehydrogenase 1 gene (IDH1) .	('IDH1', 'Gene', (129, 133))	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('isocitrate', 'Chemical', 'MESH:C034219', (96, 106))	('glioma', 'Disease', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('IDH1', 'Gene', '3417', (129, 133))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('mutation', 'Var', (70, 78))	('secondary GBM', 'Disease', (47, 60))
79436	27748711	However, mutant IDH1 inhibits the wild-type form and establishes a new function converting alpha-KG to 2-hydroxyglutarate (2-HG).	('inhibits', 'NegReg', (21, 29))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (103, 121))	('alpha-KG', 'Chemical', 'MESH:D007656', (91, 99))	('mutant', 'Var', (9, 15))	('IDH1', 'Gene', (16, 20))	('IDH1', 'Gene', '3417', (16, 20))
79438	27748711	In addition to the IDH1 mutation, over 70% of grade II/III astrocytomas and oligodendrogliomas have a mutation in the TP53 tumor suppressor gene and a co-deletion of chromosome arms 1p/19q respectively .	('oligodendrogliomas', 'Disease', (76, 94))	('tumor', 'Disease', (123, 128))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('astrocytomas', 'Disease', 'MESH:D001254', (59, 71))	('mutation', 'Var', (102, 110))	('IDH1', 'Gene', (19, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('IDH1', 'Gene', '3417', (19, 23))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (76, 94))	('TP53', 'Gene', (118, 122))	('astrocytomas', 'Disease', (59, 71))	('TP53', 'Gene', '7157', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
79444	27748711	Recently, using 1H MRS, the oncometabolite 2-HG produced by mutant IDH1 was detected in vivo in glioma patients harboring the IDH1 mutation  as well as ex vivo in glioma biopsies .	('IDH1', 'Gene', '3417', (126, 130))	('glioma', 'Disease', (163, 169))	('detected', 'Reg', (76, 84))	('IDH1', 'Gene', (67, 71))	('MRS', 'Disease', (19, 22))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH1', 'Gene', '3417', (67, 71))	('IDH1', 'Gene', (126, 130))	('patients', 'Species', '9606', (103, 111))	('MRS', 'Disease', 'MESH:D008556', (19, 22))	('mutant', 'Var', (60, 66))	('1H', 'Chemical', '-', (16, 18))	('glioma', 'Disease', (96, 102))	('mutation', 'Var', (131, 139))
79447	27748711	The natural abundance of 13C is only 1.1% and its gyromagnetic ratio, gamma13C=10.705 MHz/T, is ~ 4 times lower than gamma1H.	('13C', 'Chemical', '-', (25, 28))	('lower', 'NegReg', (106, 111))	('gamma1H', 'Chemical', '-', (117, 124))	('rat', 'Species', '10116', (63, 66))	('gamma13C=10.705', 'Var', (70, 85))	('13C', 'Chemical', '-', (75, 78))	('gamma13C', 'Chemical', '-', (70, 78))	('gyromagnetic ratio', 'MPA', (50, 68))
79449	27748711	The emergence of hyperpolarized 13C MRS has opened a range of new possibilities for novel metabolic imaging studies that are translatable to the clinic and can serve to characterize brain tumors and their response to therapy .	('MRS', 'Disease', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('brain tumors', 'Phenotype', 'HP:0030692', (182, 194))	('hyperpolarized', 'Var', (17, 31))	('MRS', 'Disease', 'MESH:D008556', (36, 39))	('brain tumors', 'Disease', 'MESH:D001932', (182, 194))	('13C', 'Chemical', '-', (32, 35))	('brain tumors', 'Disease', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('brain tumor', 'Phenotype', 'HP:0030692', (182, 193))
79464	27748711	Inhibition of PDH, in turn, blocks the entry of pyruvate into the tricarboxylic acid (TCA) cycle and therefore limits glucose-dependent TCA metabolism .	('limits', 'NegReg', (111, 117))	('PDH', 'Gene', '54704', (14, 17))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('TCA', 'Chemical', 'MESH:D014233', (136, 139))	('blocks', 'NegReg', (28, 34))	('glucose-dependent TCA metabolism', 'MPA', (118, 150))	('TCA', 'Chemical', 'MESH:D014233', (86, 89))	('pyruvate', 'Chemical', 'MESH:D019289', (48, 56))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (66, 84))	('PDH', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))
79473	27748711	As mentioned above, primary GBM differ genetically from mutant IDH1-driven low-grade gliomas (astrocytoma and oligodendroglioma) and secondary GBM.	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (94, 127))	('IDH1', 'Gene', '3417', (63, 67))	('GBM', 'Phenotype', 'HP:0012174', (143, 146))	('mutant', 'Var', (56, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('gliomas', 'Disease', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('IDH1', 'Gene', (63, 67))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
79476	27748711	However, more recent studies looking at events specifically associated with the IDH1 mutation, have demonstrated that GPC levels are elevated in these cells and that PC levels are reduced compared to wild-type IDH1 cells .	('IDH1', 'Gene', '3417', (210, 214))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('PC', 'Chemical', 'MESH:D010767', (166, 168))	('elevated', 'PosReg', (133, 141))	('reduced', 'NegReg', (180, 187))	('mutation', 'Var', (85, 93))	('GPC', 'Gene', '2995', (118, 121))	('PC', 'Chemical', 'MESH:D010767', (119, 121))	('PC levels', 'MPA', (166, 175))	('GPC', 'Gene', (118, 121))	('IDH1', 'Gene', (210, 214))	('rat', 'Species', '10116', (107, 110))
79477	27748711	The link to mutant IDH1 remains to be determined.	('mutant', 'Var', (12, 18))	('IDH1', 'Gene', (19, 23))	('IDH1', 'Gene', '3417', (19, 23))
79478	27748711	Other metabolic alterations detected in mutant IDH1 gliomas have been directly linked to elevated 2-HG levels.	('gliomas', 'Disease', (52, 59))	('linked', 'Reg', (79, 85))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH1', 'Gene', (47, 51))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('elevated', 'PosReg', (89, 97))	('metabolic alterations', 'MPA', (6, 27))	('rat', 'Species', '10116', (20, 23))	('mutant', 'Var', (40, 46))	('2-HG levels', 'MPA', (98, 109))	('IDH1', 'Gene', '3417', (47, 51))
79480	27748711	The IDH1 mutation also leads to the hypermethylation and consequently silencing of lactate dehydrogenase A (LDHA), the enzyme that converts pyruvate to lactate .	('mutation', 'Var', (9, 17))	('lactate', 'Chemical', 'MESH:D019344', (152, 159))	('IDH1', 'Gene', '3417', (4, 8))	('lactate dehydrogenase A', 'Gene', (83, 106))	('silencing', 'NegReg', (70, 79))	('hypermethylation', 'MPA', (36, 52))	('lactate dehydrogenase A', 'Gene', '3939', (83, 106))	('pyruvate', 'Chemical', 'MESH:D019289', (140, 148))	('IDH1', 'Gene', (4, 8))	('lactate', 'Chemical', 'MESH:D019344', (83, 90))
79481	27748711	Additionally, reduced expression of MCT1 and MCT4 is observed in mutant IDH tumors .	('MCT1', 'Gene', '6566', (36, 40))	('reduced', 'NegReg', (14, 21))	('IDH tumors', 'Disease', 'MESH:D009369', (72, 82))	('mutant', 'Var', (65, 71))	('MCT4', 'Gene', '9123', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('IDH tumors', 'Disease', (72, 82))	('MCT4', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('MCT1', 'Gene', (36, 40))	('expression', 'MPA', (22, 32))
79483	27748711	Finally, as a result of the reduced activity of wild-type IDH1, and the increased activity of NADPH-dependent mutant IDH1, levels of NADPH are also diminished in mutant IDH1 glioma cells as are the levels of glutathione (GSH), leading to elevated levels of reactive oxygen species (ROS) .	('reduced', 'NegReg', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('IDH1', 'Gene', (169, 173))	('mutant', 'Var', (162, 168))	('GSH', 'Chemical', 'MESH:D005978', (221, 224))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (238, 280))	('IDH1', 'Gene', '3417', (58, 62))	('IDH1', 'Gene', '3417', (169, 173))	('elevated', 'PosReg', (238, 246))	('IDH1', 'Gene', (117, 121))	('glutathione', 'Chemical', 'MESH:D005978', (208, 219))	('levels of reactive oxygen species', 'MPA', (247, 280))	('activity', 'MPA', (36, 44))	('mutant', 'Var', (110, 116))	('glioma', 'Disease', (174, 180))	('NADPH', 'Gene', (133, 138))	('levels', 'MPA', (123, 129))	('NADPH', 'Gene', '1666', (133, 138))	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('increased', 'PosReg', (72, 81))	('levels of glutathione', 'MPA', (198, 219))	('IDH1', 'Gene', '3417', (117, 121))	('ROS', 'Chemical', 'MESH:D017382', (282, 285))	('NADPH', 'Gene', (94, 99))	('activity', 'MPA', (82, 90))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (257, 280))	('NADPH', 'Gene', '1666', (94, 99))	('diminished', 'NegReg', (148, 158))	('IDH1', 'Gene', (58, 62))
79497	27748711	In contrast, in low-grade mutant IDH1 tumors, LDHA is silenced .	('IDH1 tumors', 'Disease', 'MESH:D009369', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('IDH1 tumors', 'Disease', (33, 44))	('mutant', 'Var', (26, 32))
79505	27748711	In contrast, in a low-grade IDH1 mutant orthotopic tumor model where LDHA is silenced , very low production of hyperpolarized [1-13C]-lactate was observed .	('silenced', 'Var', (77, 85))	('production of hyperpolarized [1-13C]-lactate', 'MPA', (97, 141))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('IDH1', 'Gene', '3417', (28, 32))	('LDHA', 'Gene', (69, 73))	('tumor', 'Disease', (51, 56))	('low', 'NegReg', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('IDH1', 'Gene', (28, 32))
79507	27748711	Additionally, in a recent study, hyperpolarized [1-13C]-pyruvate was used as an imaging marker to monitor decreased expression of MCT1 (responsible primarily for pyruvate cellular influx) and MCT4 (responsible primarily for lactate cellular efflux) in immortalized normal human astrocytes (NHAs) harboring the IDH1 mutation as compared to the IDH1 wild-type NHAs .	('decreased', 'NegReg', (106, 115))	('IDH1', 'Gene', (310, 314))	('expression', 'MPA', (116, 126))	('pyruvate', 'MPA', (162, 170))	('MCT1', 'Gene', (130, 134))	('human', 'Species', '9606', (272, 277))	('MCT1', 'Gene', '6566', (130, 134))	('IDH1', 'Gene', (343, 347))	('mutation', 'Var', (315, 323))	('IDH1', 'Gene', '3417', (310, 314))	('MCT4', 'Gene', (192, 196))	('pyruvate', 'Chemical', 'MESH:D019289', (162, 170))	('IDH1', 'Gene', '3417', (343, 347))	('pyruvate', 'Chemical', 'MESH:D019289', (56, 64))	('[1-13C]-pyruvate', 'Chemical', '-', (48, 64))	('lactate', 'Chemical', 'MESH:D019344', (224, 231))	('MCT4', 'Gene', '9123', (192, 196))
79509	27748711	A decrease in hyperpolarized [1-13C]-lactate/[1-13C]-pyruvate ratio was correlated with a drop in LDHA expression and HIF-1alpha activity in response to Everolimus, a first-generation mTOR inhibitor, and in response to LY294002, a PI3K inhibitor, in GS-2 GBM cells  and in a GS-2 rat orthotopic tumor model .	('GS-2', 'Disease', 'MESH:D011125', (275, 279))	('LY294002', 'Var', (219, 227))	('rat', 'Species', '10116', (62, 65))	('GS-2', 'Disease', (275, 279))	('drop', 'NegReg', (90, 94))	('LY294002', 'Chemical', 'MESH:C085911', (219, 227))	('GS-2', 'Disease', 'MESH:D011125', (250, 254))	('tumor', 'Disease', (295, 300))	('LDHA', 'Protein', (98, 102))	('Everolimus', 'Chemical', 'MESH:D000068338', (153, 163))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('[1-13C]-pyruvate', 'Chemical', '-', (45, 61))	('GBM', 'Phenotype', 'HP:0012174', (255, 258))	('GS-2', 'Disease', (250, 254))	('HIF-1alpha', 'Enzyme', (118, 128))	('decrease', 'NegReg', (2, 10))	('rat', 'Species', '10116', (177, 180))	('rat', 'Species', '10116', (280, 283))	('activity', 'MPA', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))
79516	27748711	In contrast, in mutant IDH1 tumors, recent studies in our lab demonstrate that response to TMZ-treatment and tumor shrinkage did not lead to a detectable drop in hyperpolarized [1-13C]-lactate production .	('IDH1 tumors', 'Disease', 'MESH:D009369', (23, 34))	('tumor', 'Disease', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('hyperpolarized [1-13C]-lactate production', 'MPA', (162, 203))	('mutant', 'Var', (16, 22))	('IDH1 tumors', 'Disease', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rat', 'Species', '10116', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (109, 114))
79520	27748711	Similarly, in models of mutant IDH1 cells, lower hyperpolarized [5-13C]-glutamate production following [2-13C]-pyruvate injection was observed in two genetically engineered cell models (U87 and NHAs) expressing the IDH1 mutation as compared to cells expressing wild-type IDH1 associated with a HIF-1alpha-mediated decrease in PDH activity .	('mutant', 'Var', (24, 30))	('IDH1', 'Gene', '3417', (271, 275))	('[5-13C]-glutamate', 'Chemical', '-', (64, 81))	('IDH1', 'Gene', (31, 35))	('IDH1', 'Gene', (215, 219))	('PDH', 'Gene', (326, 329))	('IDH1', 'Gene', '3417', (31, 35))	('U87', 'Gene', (186, 189))	('hyperpolarized [5-13C]-glutamate production', 'MPA', (49, 92))	('IDH1', 'Gene', '3417', (215, 219))	('[2-13C]-pyruvate', 'Chemical', '-', (103, 119))	('mutation', 'Var', (220, 228))	('IDH1', 'Gene', (271, 275))	('U87', 'Gene', '641648', (186, 189))	('PDH', 'Gene', '54704', (326, 329))	('decrease', 'NegReg', (314, 322))	('lower', 'NegReg', (43, 48))
79522	27748711	This points to one metabolic event that is similar in primary GBM and mutant IDH1 glioma cells.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutant', 'Var', (70, 76))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('IDH1', 'Gene', (77, 81))	('IDH1', 'Gene', '3417', (77, 81))	('glioma', 'Disease', (82, 88))
79523	27748711	As mentioned previously, the IDH1 mutation leads to elevated levels of 2-HG production.	('IDH1', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('IDH1', 'Gene', '3417', (29, 33))	('levels of 2-HG production', 'MPA', (61, 86))	('elevated', 'PosReg', (52, 60))
79525	27748711	Recently, following the optimization of [1-13C]-alpha-KG as an hyperpolarized agent with sufficiently long T1 and adequate polarization (T1~52s at 3T and polarization level~16% ), our group showed the accumulation of [1-13C]-2-HG (Figure 1) both in vitro and in an orthotopic preclinical model engineered to express mutant IDH1 .	('mutant', 'Var', (316, 322))	('T1', 'Chemical', 'MESH:C103828', (137, 139))	('IDH1', 'Gene', '3417', (323, 327))	('T1', 'Chemical', 'MESH:C103828', (107, 109))	('[1-13C]', 'Chemical', '-', (40, 47))	('IDH1', 'Gene', (323, 327))	('[1-13C]', 'Chemical', '-', (217, 224))
79535	27748711	LDHB is highly expressed in the brain; therefore following changes in LDHB could be of great interest, particularly in low-grade tumors expressing the IDH1 mutation and wherein LDHA is silenced .	('LDHB', 'Gene', (0, 4))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('LDHB', 'Gene', '3945', (0, 4))	('LDHB', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IDH1', 'Gene', (151, 155))	('LDHB', 'Gene', '3945', (70, 74))	('IDH1', 'Gene', '3417', (151, 155))	('mutation', 'Var', (156, 164))
79544	27748711	The detection of the conversion of hyperpolarized [1-13C]-DHA into [1-13C]-vitamin C in normal rat brain as well as the modulation of this reaction in a model of prostate cancer illustrated the potential of this agent .	('DHA', 'Chemical', 'MESH:D003683', (58, 61))	('[1-13C]-vitamin C', 'Chemical', '-', (67, 84))	('rat', 'Species', '10116', (184, 187))	('[1-13C]-DHA', 'Var', (50, 61))	('rat', 'Species', '10116', (95, 98))	('modulation', 'Reg', (120, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (162, 177))	('[1-13C]', 'Chemical', '-', (67, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('[1-13C]', 'Chemical', '-', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('prostate cancer', 'Disease', (162, 177))
79545	27748711	DHA is transported into cells through the glucose transporter , making it a good candidate for in vivo brain studies and particularly interesting for the study of mutant IDH1 tumors wherein redox status is likely altered.	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('DHA', 'Chemical', 'MESH:D003683', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('mutant', 'Var', (163, 169))	('IDH1 tumors', 'Disease', (170, 181))	('IDH1 tumors', 'Disease', 'MESH:D009369', (170, 181))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))
79558	27748711	However, in the case of GBM, where the entry of fumarate is facilitated by the disruption of the BBB, hyperpolarized [1,4-13C2]-fumarate could potentially detect cell death.	('detect', 'Reg', (155, 161))	('disruption', 'MPA', (79, 89))	('facilitated', 'PosReg', (60, 71))	('BBB', 'Protein', (97, 100))	('entry of fumarate', 'MPA', (39, 56))	('[1,4-13C2]-fumarate', 'Chemical', '-', (117, 136))	('fumarate', 'Chemical', 'MESH:D005650', (48, 56))	('GBM', 'Phenotype', 'HP:0012174', (24, 27))	('cell death', 'CPA', (162, 172))	('fumarate', 'Chemical', 'MESH:D005650', (128, 136))	('hyperpolarized [', 'Var', (102, 118))
79564	27748711	Hyperpolarized [13C]-urea has been well studied in the context of prostate, liver and kidney cancers .	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('kidney cancers', 'Phenotype', 'HP:0009726', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('urea', 'Chemical', 'MESH:D014508', (21, 25))	('liver and kidney cancers', 'Disease', 'MESH:D006528', (76, 100))	('13C', 'Chemical', '-', (16, 19))	('prostate', 'Disease', (66, 74))	('Hyperpolarized', 'Var', (0, 14))
79566	27748711	Recently, two novel hyperpolarized agents were developed, [13C]-hydroxymethyl cyclopropane (HMCP) and [13C]-t-butanol, with the latest diffusing freely into normal brain tissue .	('[13C]-hydroxymethyl cyclopropane', 'Chemical', '-', (58, 90))	('HMCP', 'Chemical', '-', (92, 96))	('[13C', 'Var', (58, 62))	('[13C]-t-butanol', 'Var', (102, 117))	('[13C]-t-butanol', 'Chemical', '-', (102, 117))
79592	21603237	In general, the chemosensitivity of oligodendroglial tumors is higher than of astrocytic tumors, being associated with the loss of heterozygosity (LOH) on chromosome 1p and 19q.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (36, 59))	('oligodendroglial tumors', 'Disease', (36, 59))	('loss of heterozygosity', 'Var', (123, 145))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('astrocytic tumors', 'Disease', (78, 95))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('astrocytic tumors', 'Disease', 'MESH:D001254', (78, 95))
79736	33451333	However, only about ten clinical trials using inhibitors specifically targeting AURKB and most of them are still in phase I stage.	('inhibitors', 'Var', (46, 56))	('AURKB', 'Gene', (80, 85))	('AURKB', 'Gene', '9212', (80, 85))
79740	33451333	Gene amplification, transcriptional activation and inhibition of protein degradation could contribute to the elevated levels of AURKA expression in cancer tissues.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('expression', 'MPA', (134, 144))	('levels', 'MPA', (118, 124))	('elevated', 'PosReg', (109, 117))	('protein degradation', 'MPA', (65, 84))	('AURKA', 'Gene', '6790', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('activation', 'PosReg', (36, 46))	('Gene amplification', 'Var', (0, 18))	('AURKA', 'Gene', (128, 133))
79742	33451333	Given that overexpression and gene amplification of AURKA have been identified in diverse cancers, small molecule kinase inhibitors of AURKA have attracted considerable interest.	('AURKA', 'Gene', '6790', (52, 57))	('cancers', 'Disease', (90, 97))	('AURKA', 'Gene', '6790', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AURKA', 'Gene', (52, 57))	('AURKA', 'Gene', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('overexpression', 'PosReg', (11, 25))	('gene amplification', 'Var', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
79743	33451333	A series of AURKA kinase inhibitors (AKIs) have been produced over the past decades; inhibition of the expression or activity of AURKA by AKIs suppresses cancer cell proliferation, migration and invasion.	('AKIs suppresses cancer', 'Disease', 'MESH:D009369', (138, 160))	('activity', 'MPA', (117, 125))	('expression', 'MPA', (103, 113))	('inhibition', 'Var', (85, 95))	('AURKA', 'Gene', '6790', (12, 17))	('AURKA', 'Gene', '6790', (129, 134))	('AURKA', 'Gene', (129, 134))	('AURKA', 'Gene', (12, 17))	('AKIs suppresses cancer', 'Disease', (138, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
79762	33451333	There is overwhelming evidence of overexpression and gene amplification of AURKA in a wide range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('overexpression', 'PosReg', (34, 48))	('AURKA', 'Gene', '6790', (75, 80))	('gene amplification', 'Var', (53, 71))	('AURKA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
79763	33451333	The underlying mechanisms for AURKA upregulation in cancer include gene amplification, gene mutation, microRNA regulation, transcriptional or posttranscriptional modification, and others.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('microRNA regulation', 'MPA', (102, 121))	('upregulation', 'PosReg', (36, 48))	('AURKA', 'Gene', '6790', (30, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene mutation', 'Var', (87, 100))	('gene amplification', 'Var', (67, 85))	('AURKA', 'Gene', (30, 35))
79790	33451333	Likewise, NEDD9 and PUM2 not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh.	('disassociation', 'Var', (144, 158))	('AURKA', 'Gene', '6790', (86, 91))	('AURKA', 'Gene', '6790', (111, 116))	('cdh', 'Protein', (164, 167))	('PUM2', 'Gene', (20, 24))	('autophosphorylation', 'MPA', (44, 63))	('stabilize', 'PosReg', (101, 110))	('AURKA', 'Gene', (111, 116))	('AURKA', 'Gene', (86, 91))	('stimulate', 'PosReg', (34, 43))	('autoactivation', 'MPA', (68, 82))	('expression', 'MPA', (125, 135))	('NEDD9', 'Gene', (10, 15))	('PUM2', 'Gene', '23369', (20, 24))	('NEDD9', 'Gene', '4739', (10, 15))
79793	33451333	These regulators are usually tumor suppressors, and inhibition of AURKA is one of the mechanisms explaining their tumor-suppressive functions.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AURKA', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (114, 119))	('inhibition', 'Var', (52, 62))	('tumor', 'Disease', (29, 34))
79801	33451333	GSK-3beta interacts with AURKA and phosphorylates AURKA at Ser290/291 in vitro, after which autophosphorylation occurs at Ser349, which is an AURKA activity-inhibiting phosphorylation site.	('Ser349', 'Chemical', '-', (122, 128))	('AURKA', 'Gene', '6790', (142, 147))	('AURKA', 'Gene', '6790', (25, 30))	('Ser349', 'Var', (122, 128))	('autophosphorylation', 'MPA', (92, 111))	('Ser290', 'Chemical', '-', (59, 65))	('AURKA', 'Gene', (142, 147))	('AURKA', 'Gene', (25, 30))	('AURKA', 'Gene', '6790', (50, 55))	('interacts', 'Interaction', (10, 19))	('GSK-3beta', 'Gene', '2931', (0, 9))	('AURKA', 'Gene', (50, 55))	('GSK-3beta', 'Gene', (0, 9))
79809	33451333	Phosphorylation of AURKA by IKK2 targets it for beta-TRCP-mediated degradation and serves to maintain appropriate levels of AURKA to assure proper bipolar spindle assembly and mitotic progression.	('IKK2', 'Gene', (28, 32))	('levels', 'MPA', (114, 120))	('AURKA', 'Gene', '6790', (124, 129))	('AURKA', 'Gene', '6790', (19, 24))	('beta-TRCP', 'Gene', '8945', (48, 57))	('Phosphorylation', 'Var', (0, 15))	('beta-TRCP', 'Gene', (48, 57))	('targets', 'Reg', (33, 40))	('AURKA', 'Gene', (124, 129))	('mitotic progression', 'CPA', (176, 195))	('AURKA', 'Gene', (19, 24))	('IKK2', 'Gene', '3551', (28, 32))	('bipolar spindle assembly', 'CPA', (147, 171))
79815	33451333	VHL is an E3 ligase that multi-monoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions.	('AURKA', 'Gene', '6790', (49, 54))	('AURKA', 'Gene', (49, 54))	('proteasome-mediated degradation', 'MPA', (93, 124))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (149, 167))	('hypoxic conditions', 'Disease', (149, 167))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('multi-monoubiquitinates', 'Var', (25, 48))
79826	33451333	Many of the substrates regulated by AURKA coordinate with AURKA to control mitotic progression, and aberrant expression of AURKA in a variety of human cancers has been linked with mitotic defects.	('linked', 'Reg', (168, 174))	('AURKA', 'Gene', (123, 128))	('AURKA', 'Gene', '6790', (58, 63))	('mitotic progression', 'CPA', (75, 94))	('AURKA', 'Gene', (58, 63))	('mitotic defects', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('AURKA', 'Gene', '6790', (36, 41))	('aberrant expression', 'Var', (100, 119))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('AURKA', 'Gene', '6790', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('AURKA', 'Gene', (36, 41))	('cancers', 'Disease', (151, 158))	('mitotic defects', 'Disease', 'MESH:C536987', (180, 195))
79833	33451333	ASAP is also a spindle-associated protein, deregulation of which induces severe mitotic defects.	('ASAP', 'Gene', '79884', (0, 4))	('ASAP', 'Gene', (0, 4))	('induces', 'Reg', (65, 72))	('mitotic defects', 'Disease', 'MESH:C536987', (80, 95))	('deregulation', 'Var', (43, 55))	('mitotic defects', 'Disease', (80, 95))
79835	33451333	The AURKA activator TPX2 is an AURKA substrate with phosphorylation sites at Ser121 and Ser125.	('Ser121', 'Var', (77, 83))	('AURKA', 'Gene', (4, 9))	('AURKA', 'Gene', '6790', (31, 36))	('Ser125', 'Chemical', '-', (88, 94))	('AURKA', 'Gene', (31, 36))	('TPX2', 'Gene', (20, 24))	('Ser121', 'Chemical', '-', (77, 83))	('Ser125', 'Var', (88, 94))	('AURKA', 'Gene', '6790', (4, 9))	('TPX2', 'Gene', '22974', (20, 24))
79845	33451333	Research has shown that AURKA phosphorylation of Twist at Ser123, Thr148 and Ser184 facilitates Twist-mediated promotion of EMT and chemoresistance in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('AURKA', 'Gene', (24, 29))	('Thr148', 'Chemical', '-', (66, 72))	('Thr148', 'Var', (66, 72))	('promotion', 'PosReg', (111, 120))	('Twist', 'Gene', '7291', (96, 101))	('Twist', 'Gene', '7291', (49, 54))	('Ser184', 'Var', (77, 83))	('Twist', 'Gene', (96, 101))	('Twist', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('Ser123', 'Chemical', '-', (58, 64))	('Ser184', 'Chemical', '-', (77, 83))	('AURKA', 'Gene', '6790', (24, 29))	('facilitates', 'PosReg', (84, 95))	('pancreatic cancer', 'Disease', (151, 168))
79854	33451333	Phosphorylation of LDHB by AURKA at Ser162 amplifies its activity in reducing pyruvate to lactate, thus promoting glycolysis and biosynthesis and promoting tumor growth.	('glycolysis', 'MPA', (114, 124))	('AURKA', 'Gene', '6790', (27, 32))	('reducing pyruvate to lactate', 'MPA', (69, 97))	('biosynthesis', 'MPA', (129, 141))	('promoting', 'PosReg', (104, 113))	('promoting', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AURKA', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Phosphorylation', 'MPA', (0, 15))	('Ser162', 'Var', (36, 42))	('Ser162', 'Chemical', '-', (36, 42))	('LDHB', 'Gene', (19, 23))	('tumor', 'Disease', (156, 161))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('LDHB', 'Gene', '3945', (19, 23))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))
79855	33451333	Recently, our research has indicated that phosphorylation of the scaffold and oncogenic protein SDCBP by AURKA maintains its protein stability and pro-proliferative functions.	('SDCBP', 'Gene', (96, 101))	('pro-proliferative functions', 'CPA', (147, 174))	('maintains', 'PosReg', (111, 120))	('protein stability', 'MPA', (125, 142))	('SDCBP', 'Gene', '6386', (96, 101))	('AURKA', 'Gene', '6790', (105, 110))	('phosphorylation', 'Var', (42, 57))	('AURKA', 'Gene', (105, 110))
79858	33451333	HURP protein stability and serum-independent growth are enhanced after phosphorylation.	('phosphorylation', 'Var', (71, 86))	('HURP', 'Gene', '9787', (0, 4))	('enhanced', 'PosReg', (56, 64))	('serum-independent growth', 'CPA', (27, 51))	('HURP', 'Gene', (0, 4))
79862	33451333	AURKA regulates LIMK2 kinase activity, subcellular localization and protein levels by directly phosphorylating LIMK2 at Ser283, Thr494 and Thr505.	('AURKA', 'Gene', (0, 5))	('LIMK2', 'Gene', '3985', (111, 116))	('LIMK2', 'Gene', (111, 116))	('LIMK2', 'Gene', '3985', (16, 21))	('activity', 'MPA', (29, 37))	('regulates', 'Reg', (6, 15))	('Ser283', 'Var', (120, 126))	('LIMK2', 'Gene', (16, 21))	('Thr494', 'Var', (128, 134))	('Thr505', 'Var', (139, 145))	('Thr494', 'Chemical', '-', (128, 134))	('protein levels', 'MPA', (68, 82))	('AURKA', 'Gene', '6790', (0, 5))	('Ser283', 'Chemical', '-', (120, 126))	('Thr505', 'Chemical', '-', (139, 145))	('subcellular localization', 'MPA', (39, 63))
79863	33451333	The small GTPase RalA is also a target of AURKA; phosphorylation of RalA at Ser194 enhances cell migration and anchorage-independent growth.	('anchorage-independent growth', 'CPA', (111, 139))	('AURKA', 'Gene', (42, 47))	('RalA', 'Gene', (68, 72))	('RalA', 'Gene', (17, 21))	('Ser194', 'Chemical', '-', (76, 82))	('RalA', 'Gene', '5898', (68, 72))	('enhances', 'PosReg', (83, 91))	('RalA', 'Gene', '5898', (17, 21))	('cell migration', 'CPA', (92, 106))	('AURKA', 'Gene', '6790', (42, 47))	('phosphorylation', 'Var', (49, 64))
79864	33451333	ALDH1A1 is an AURKA substrate enzyme whose phosphorylation by AURKA at Thr267, Thr442 and Thr493 regulates ALDH1A1 protein stability, enhancing the role of this protein in the process of EMT.	('enhancing', 'PosReg', (134, 143))	('Thr267', 'Chemical', '-', (71, 77))	('Thr493', 'Var', (90, 96))	('Thr442', 'Chemical', '-', (79, 85))	('phosphorylation', 'MPA', (43, 58))	('AURKA', 'Gene', (14, 19))	('AURKA', 'Gene', (62, 67))	('ALDH1A1', 'Gene', '216', (0, 7))	('ALDH1A1', 'Gene', (107, 114))	('protein stability', 'MPA', (115, 132))	('ALDH1A1', 'Gene', '216', (107, 114))	('Thr493', 'Chemical', '-', (90, 96))	('regulates', 'Reg', (97, 106))	('ALDH1A1', 'Gene', (0, 7))	('AURKA', 'Gene', '6790', (14, 19))	('AURKA', 'Gene', '6790', (62, 67))
79867	33451333	However, Ser106 residue phosphorylation by AURKA has the opposite effect.	('Ser106', 'Chemical', '-', (9, 15))	('AURKA', 'Gene', '6790', (43, 48))	('AURKA', 'Gene', (43, 48))	('Ser106 residue', 'Var', (9, 23))
79869	33451333	Another study has revealed that the p53 Ser215 site is phosphorylated by AURKA.	('AURKA', 'Gene', '6790', (73, 78))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('AURKA', 'Gene', (73, 78))	('Ser215', 'Var', (40, 46))	('Ser215', 'Chemical', '-', (40, 46))
79872	33451333	Phosphorylation of RASSF1A by AURKA at Ser203 and Thr202 removes the ability of RASSF1A to interact with microtubules and induce M-phase cell cycle arrest.	('removes', 'NegReg', (57, 64))	('RASSF1A', 'Gene', '11186', (19, 26))	('RASSF1A', 'Gene', '11186', (80, 87))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('Thr202', 'Var', (50, 56))	('Phosphorylation', 'Var', (0, 15))	('interact', 'Interaction', (91, 99))	('RASSF1A', 'Gene', (80, 87))	('arrest', 'Disease', (148, 154))	('AURKA', 'Gene', '6790', (30, 35))	('Thr202', 'Chemical', '-', (50, 56))	('induce', 'Reg', (122, 128))	('Ser203', 'Chemical', '-', (39, 45))	('ability', 'MPA', (69, 76))	('RASSF1A', 'Gene', (19, 26))	('microtubules', 'Protein', (105, 117))	('AURKA', 'Gene', (30, 35))
79876	33451333	Phosphorylation of LKB1 at Ser299 causes LKB1 to dissociate from AMPK, resulting in impairment of the AMPK signaling pathway and facilitating non-small-cell lung cancer (NSCLC) growth and migration.	('LKB1', 'Gene', '6794', (19, 23))	('LKB1', 'Gene', '6794', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Phosphorylation', 'Var', (0, 15))	('facilitating', 'PosReg', (129, 141))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (146, 168))	('AMPK', 'Gene', (65, 69))	('LKB1', 'Gene', (19, 23))	('AMPK', 'Gene', '5564', (65, 69))	('small-cell lung cancer', 'Disease', (146, 168))	('Ser299', 'Var', (27, 33))	('LKB1', 'Gene', (41, 45))	('NSCLC', 'Disease', (170, 175))	('Ser299', 'Chemical', '-', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('AMPK', 'Gene', (102, 106))	('impairment', 'NegReg', (84, 94))	('AMPK', 'Gene', '5564', (102, 106))
79883	33451333	Once YY1 is phosphorylated by AURKA at Ser365, its DNA-binding activity and transcriptional activity are abolished.	('YY1', 'Gene', '7528', (5, 8))	('DNA-binding', 'Interaction', (51, 62))	('YY1', 'Gene', (5, 8))	('Ser365', 'Var', (39, 45))	('transcriptional activity', 'MPA', (76, 100))	('AURKA', 'Gene', '6790', (30, 35))	('Ser365', 'Chemical', '-', (39, 45))	('abolished', 'NegReg', (105, 114))	('AURKA', 'Gene', (30, 35))
79886	33451333	AURKA-mediated phosphorylation of CHIP at Ser273 promotes androgen degradation in castration-resistant prostate cancer.	('AURKA', 'Gene', (0, 5))	('phosphorylation', 'Var', (15, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('promotes', 'PosReg', (49, 57))	('Ser273', 'Chemical', '-', (42, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('AURKA', 'Gene', '6790', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('androgen degradation', 'MPA', (58, 78))	('prostate cancer', 'Disease', (103, 118))
79888	33451333	Phosphorylation by AURKA at Ser243 may account for the cancer-promoting effects of KCTD12.	('KCTD12', 'Gene', '115207', (83, 89))	('AURKA', 'Gene', '6790', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Ser243', 'Chemical', '-', (28, 34))	('Ser243', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Phosphorylation', 'MPA', (0, 15))	('AURKA', 'Gene', (19, 24))	('KCTD12', 'Gene', (83, 89))	('cancer', 'Disease', (55, 61))
79898	33451333	In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668, BPR1K0609S1, LDD970, MK-8745, AKI603 and CYC3.	('BPR1K0609S1', 'Var', (161, 172))	('AURKA', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('LDD970', 'Var', (174, 180))	('LDD970', 'CellLine', 'CVCL:7312', (174, 180))	('MK-8745', 'Var', (182, 189))	('AKI603', 'Var', (191, 197))	('LY3295668', 'Var', (150, 159))	('LY3295668', 'Chemical', '-', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AURKA', 'Gene', '6790', (65, 70))
79900	33451333	The common dose-limiting toxicity of specific AKIs, including MLN8237 and ENMD-2076, are neutropenia, somnolence and mucisitis.	('neutropenia', 'Phenotype', 'HP:0001875', (89, 100))	('neutropenia', 'Disease', 'MESH:D009503', (89, 100))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('toxicity', 'Disease', (25, 33))	('somnolence', 'Disease', (102, 112))	('MLN8237', 'Chemical', 'MESH:C550258', (62, 69))	('somnolence', 'Disease', 'MESH:D006970', (102, 112))	('mucisitis', 'Disease', (117, 126))	('MLN8237', 'Var', (62, 69))	('neutropenia', 'Disease', (89, 100))
79901	33451333	MLN8237 is a highly selective small molecule inhibitor of AURKA with an IC50 of 1 nM.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (58, 63))	('AURKA', 'Gene', (58, 63))
79902	33451333	MLN8237 was developed as an enhancement of its predecessor, MLN8054, development of which was terminated after phase I studies due to central nervous system side effects, including dose-limiting somnolence.	('somnolence', 'Disease', (195, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('somnolence', 'Disease', 'MESH:D006970', (195, 205))	('MLN8237', 'Var', (0, 7))	('MLN8054', 'Chemical', 'MESH:C518940', (60, 67))
79903	33451333	MLN8237 has been shown to inhibit cell proliferation by impairing mitosis, inducing cell cycle arrest and autophagy, and accelerating cancer cell apoptosis and senescence in multiple cancer types.	('cancer', 'Disease', (183, 189))	('impairing mitosis', 'Disease', (56, 73))	('cell proliferation', 'CPA', (34, 52))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('senescence', 'CPA', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MLN8237', 'Var', (0, 7))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('impairing mitosis', 'Disease', 'MESH:D060825', (56, 73))	('accelerating', 'PosReg', (121, 133))	('inducing', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('autophagy', 'CPA', (106, 115))	('arrest', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
79904	33451333	The EMT process is also impeded by MLN8237 treatment in human epithelial ovarian and pancreatic cancer cells.	('epithelial ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (62, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('human', 'Species', '9606', (56, 61))	('MLN8237 treatment', 'Var', (35, 52))	('EMT process', 'CPA', (4, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('impeded', 'NegReg', (24, 31))
79905	33451333	Importantly, MLN8237 significantly increases the sensitivity of tumor cells to chemotherapy drugs or radiation.	('tumor', 'Disease', (64, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('increases', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('MLN8237', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
79906	33451333	Mechanistic studies have revealed that MLN8237 induces proteasomal degradation of N-myc in childhood neuroblastoma.	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('induces', 'Reg', (47, 54))	('MLN8237', 'Var', (39, 46))	('neuroblastoma', 'Disease', (101, 114))	('proteasomal degradation', 'MPA', (55, 78))	('N-myc', 'Gene', '4613', (82, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('N-myc', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (101, 114))
79907	33451333	In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('AURKA', 'Gene', (38, 43))	('MLN8237', 'Var', (15, 22))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', '4609', (67, 72))	('c-Myc', 'Gene', (32, 37))	('c-Myc', 'Gene', (67, 72))	('AURKA', 'Gene', '6790', (38, 43))	('disrupts', 'NegReg', (23, 31))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
79908	33451333	MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma, bladder cancer, esophageal adenocarcinoma, multiple myeloma, neuroblastoma and colon cancer.	('multiple myeloma', 'Disease', (185, 201))	('numerous tumor', 'Disease', (96, 110))	('MLN8237', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (158, 183))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('numerous tumor', 'Disease', 'MESH:D009369', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('patient', 'Species', '9606', (54, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('glioblastoma', 'Disease', (128, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neuroblastoma and colon cancer', 'Disease', 'MESH:D015179', (203, 233))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
79909	33451333	Due to its potent efficiency in preclinical studies, MLN8237 has been tested in clinical trials for multiple cancers and is the only AURKA inhibitor that has proceeded to phase III evaluation.	('MLN8237', 'Var', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AURKA', 'Gene', '6790', (133, 138))	('AURKA', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
79913	33451333	One phase II trial of MLN8237 in patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma, acute myelogenous leukemia and high-grade myelodysplastic syndrome showed that MLN8237 has modest single-agent antitumor activity.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('acute myelogenous leukemia', 'Disease', (108, 134))	('fallopian tube cancer', 'Disease', (63, 84))	('myelodysplastic syndrome', 'Disease', (150, 174))	('peritoneal carcinoma', 'Disease', (86, 106))	('MLN8237', 'Var', (22, 29))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (108, 134))	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (86, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('MLN8237', 'Var', (187, 194))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (63, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('tumor', 'Disease', (223, 228))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (150, 174))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('MLN8237', 'Chemical', 'MESH:C550258', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (150, 174))	('patients', 'Species', '9606', (33, 41))	('ovarian cancer', 'Disease', (47, 61))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (108, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
79914	33451333	In a multicenter phase II study, MLN8237 treatment obtained an objective response in 18% of 49 women with breast cancer and 21% of 48 participants with small-cell lung cancer.	('small-cell lung cancer', 'Disease', (152, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('participants', 'Species', '9606', (134, 146))	('women', 'Species', '9606', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('MLN8237 treatment', 'Var', (33, 50))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
79915	33451333	In another phase II study of MLN8237 in advanced/metastatic sarcoma, occasional responses and prolonged stable disease were observed, and progression-free survival (PFS) was promising.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MLN8237', 'Var', (29, 36))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
79916	33451333	In castration-resistant neuroendocrine prostate cancer patients, those with AURKA and N-myc activation achieve significant clinical benefit from single-agent MLN8237 treatment.	('MLN8237 treatment', 'Var', (158, 175))	('AURKA', 'Gene', '6790', (76, 81))	('activation', 'PosReg', (92, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AURKA', 'Gene', (76, 81))	('N-myc', 'Gene', (86, 91))	('benefit', 'PosReg', (132, 139))	('neuroendocrine prostate cancer', 'Disease', (24, 54))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (24, 54))	('patients', 'Species', '9606', (55, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('N-myc', 'Gene', '4613', (86, 91))
79917	33451333	Another phase II study has shown that in relapsed or refractory peripheral T-cell NHL (PTCL) patients, MLN8237 has antitumor activity with an overall response rate of 30%.	('tumor', 'Disease', (119, 124))	('NHL', 'Gene', '51750', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('MLN8237', 'Var', (103, 110))	('NHL', 'Gene', (82, 85))	('patients', 'Species', '9606', (93, 101))
79918	33451333	In a recently reported phase III study conducted in patients with PTCL, although MLN8237 did not demonstrate superior efficacy over comparators, it did show antitumor activity and acceptable tolerability and safety.	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (52, 60))
79919	33451333	All these encouraging outcomes make MLN8237 a promising agent for cancer treatment.	('MLN8237', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('cancer', 'Disease', (66, 72))
79920	33451333	ENMD-2076, a novel, orally bioavailable multitarget inhibitor whose main targets are FLT3 (IC50 = 3 nM) and AURKA (IC50 = 14 nM), exhibits much greater potency against AURKA than against AURKB (IC50 = 350 nM).	('AURKA', 'Gene', (168, 173))	('ENMD-2076', 'Var', (0, 9))	('greater', 'PosReg', (144, 151))	('AURKA', 'Gene', '6790', (108, 113))	('FLT3', 'Gene', '2322', (85, 89))	('AURKB', 'Gene', '9212', (187, 192))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (168, 173))	('FLT3', 'Gene', (85, 89))	('potency', 'MPA', (152, 159))	('AURKB', 'Gene', (187, 192))
79921	33451333	Because of its multitarget properties, ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines, with IC50 values ranging from 0.025 to 0.7 muM.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth', 'CPA', (62, 68))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (100, 105))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ENMD-2076', 'Var', (39, 48))
79922	33451333	ENMD-2076 shows antitumor activity in colorectal cancer, multiple myeloma and triple-negative breast cancer both in vitro and in vivo.	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', (57, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (20, 25))
79924	33451333	MK-5108 is a novel small molecule that shows robust selectivity for AURKA over AURKB (220-fold greater selectivity) and AURKC (190-fold greater selectivity).	('AURKC', 'Gene', (120, 125))	('AURKA', 'Gene', (68, 73))	('AURKB', 'Gene', '9212', (79, 84))	('AURKB', 'Gene', (79, 84))	('AURKC', 'Gene', '6795', (120, 125))	('MK-5108', 'Var', (0, 7))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('AURKA', 'Gene', '6790', (68, 73))
79926	33451333	In EOC stem cells, MK-5108 induces cell cycle arrest by affecting the NF-kB pathway.	('MK-5108', 'Var', (19, 26))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('NF-kB pathway', 'Pathway', (70, 83))	('affecting', 'Reg', (56, 65))	('MK-5108', 'Chemical', 'MESH:C547876', (19, 26))	('arrest', 'Disease', (46, 52))
79927	33451333	MK-5108 also decreases the rate of proliferation and increases intratumoral apoptosis in uterine leiomyosarcoma xenografts.	('decreases', 'NegReg', (13, 22))	('tumor', 'Disease', (68, 73))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('MK-5108', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (89, 111))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('increases', 'PosReg', (53, 62))	('leiomyosarcoma', 'Disease', (97, 111))
79930	33451333	Even though the selective AURKA inhibitors might be less toxic than pan-inhibitors, it may also lead to drug resistance more easily, so it is necessary to develop broad Aurora kinase inhibitors to obtain drugs with greater potency for cancer treatment.	('inhibitors', 'Var', (32, 42))	('drug', 'MPA', (104, 108))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('AURKA', 'Gene', '6790', (26, 31))	('lead to', 'Reg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('AURKA', 'Gene', (26, 31))
79931	33451333	AT9283 exhibits strong activity against several kinases.	('activity', 'MPA', (23, 31))	('AT9283', 'Var', (0, 6))	('kinases', 'Pathway', (48, 55))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
79932	33451333	The ability of AT9283 to inhibit the growth and survival of tumor cells as well as xenografts has been demonstrated in imatinib-resistant BCR-ABL-positive leukemic cells, aggressive B-cell lymphoma and medulloblastoma.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (182, 197))	('tumor', 'Disease', (60, 65))	('AT9283', 'Var', (15, 21))	('medulloblastoma', 'Disease', 'MESH:D008527', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (184, 197))	('AT9283', 'Chemical', 'MESH:C535237', (15, 21))	('medulloblastoma', 'Phenotype', 'HP:0002885', (202, 217))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('BCR-ABL', 'Gene', '25', (138, 145))	('BCR-ABL', 'Gene', (138, 145))	('medulloblastoma', 'Disease', (202, 217))	('B-cell lymphoma', 'Disease', (182, 197))
79935	33451333	MK-0457, a pyrazoloquinazoline compound, inhibits all three Aurora kinases and inhibits FLT-3 and Abl kinases.	('Abl', 'Gene', '25', (98, 101))	('pyrazoloquinazoline', 'Chemical', '-', (11, 30))	('inhibits', 'NegReg', (41, 49))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('inhibits', 'NegReg', (79, 87))	('MK-0457', 'Var', (0, 7))	('Abl', 'Gene', (98, 101))	('FLT-3', 'Gene', (88, 93))	('FLT-3', 'Gene', '2322', (88, 93))	('Aurora', 'Enzyme', (60, 66))
79938	33451333	MK-0457 induces accumulation of cells with >=4 N DNA content, inhibits cell cycle progression and induces apoptosis of anaplastic THCA cells.	('THCA', 'Phenotype', 'HP:0002890', (130, 134))	('induces', 'Reg', (98, 105))	('inhibits', 'NegReg', (62, 70))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('cells with >=4 N DNA content', 'MPA', (32, 60))	('MK-0457', 'Var', (0, 7))	('apoptosis', 'CPA', (106, 115))	('cell cycle progression', 'CPA', (71, 93))	('accumulation', 'PosReg', (16, 28))
79940	33451333	The activity of MK-0457 was also assessed in two other phase I/II studies, both of which showed promising outcomes in patients with BCR-ABL T315I leukemia.	('BCR-ABL', 'Gene', (132, 139))	('BCR-ABL', 'Gene', '25', (132, 139))	('T315I', 'Var', (140, 145))	('T315I', 'Mutation', 'rs121913459', (140, 145))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MK-0457', 'Chemical', 'MESH:C484810', (16, 23))	('leukemia', 'Disease', (146, 154))	('patients', 'Species', '9606', (118, 126))
79942	33451333	PHA-739358 exhibits strong antiproliferative activity in BCR-ABL-positive leukemia cells, including those harboring the T315I mutation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('T315I', 'Var', (120, 125))	('T315I', 'Mutation', 'rs121913459', (120, 125))	('BCR-ABL', 'Gene', (57, 64))	('BCR-ABL', 'Gene', '25', (57, 64))	('leukemia', 'Disease', (74, 82))	('antiproliferative activity', 'MPA', (27, 53))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
79943	33451333	The crystal structure of the Abl-T315I-PHA-739358 complex provides a possible structural explanation for the activity of PHA-739358 on the T315I mutation.	('Abl', 'Gene', (29, 32))	('activity', 'MPA', (109, 117))	('T315I', 'Var', (139, 144))	('Abl', 'Gene', '25', (29, 32))	('T315I', 'Mutation', 'rs121913459', (33, 38))	('T315I', 'Mutation', 'rs121913459', (139, 144))
79944	33451333	PHA-739358 also induces cell cycle arrest, apoptosis and autophagy and suppresses the EMT process.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('suppresses', 'NegReg', (71, 81))	('apoptosis', 'CPA', (43, 52))	('PHA-739358', 'Var', (0, 10))	('arrest', 'Disease', (35, 41))	('EMT process', 'CPA', (86, 97))	('autophagy', 'CPA', (57, 66))	('induces', 'Reg', (16, 23))
79945	33451333	In one study, PHA-739358 inhibited liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('PHA-739358', 'Var', (14, 24))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (57, 101))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (57, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inhibited', 'NegReg', (25, 34))	('metastases', 'Disease', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
79946	33451333	In another study, PHA-739358 inhibited early-stage bone metastases based on an ex vivo model named the 'bone-in-culture array'.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('inhibited', 'NegReg', (29, 38))	('PHA-739358', 'Var', (18, 28))	('metastases', 'Disease', (56, 66))
79947	33451333	Several phase I/II clinical evaluations have been performed on PHA-739358 due to its encouraging antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PHA-739358', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
79948	33451333	Other drugs including AMG900, AS703569, BI-847325, CYC116, PF-03814735, and SNS-314 are also in phase I clinical trials.	('SNS-314', 'Chemical', 'MESH:C532454', (76, 83))	('AMG900', 'Chemical', 'MESH:C555658', (22, 28))	('PF-03814735', 'Chemical', 'MESH:C550549', (59, 70))	('CYC116', 'Var', (51, 57))	('PF-03814735', 'Var', (59, 70))	('BI-847325', 'Var', (40, 49))	('BI-847325', 'Chemical', 'MESH:C000606531', (40, 49))	('AS703569', 'Var', (30, 38))	('AS703569', 'Chemical', 'MESH:C000592140', (30, 38))
79956	33451333	In patients with solid tumors, AS703569 in combination with the standard dose of gemcitabine produces preliminary signs of efficacy.	('solid tumors', 'Disease', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('AS703569', 'Var', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('AS703569', 'Chemical', 'MESH:C000592140', (31, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
79959	33451333	In addition, MLN8237 has a synergistic effect in association with vincristine and rituximab in aggressive B-cell NHL.	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('vincristine', 'Chemical', 'MESH:D014750', (66, 77))	('NHL', 'Gene', '51750', (113, 116))	('MLN8237', 'Var', (13, 20))	('NHL', 'Gene', (113, 116))	('rituximab', 'Chemical', 'MESH:D000069283', (82, 91))
79963	33451333	In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival.	('lymphoma', 'Disease', 'MESH:D008223', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('survival', 'CPA', (174, 182))	('tumor', 'Disease', (117, 122))	('MLN8237', 'Var', (92, 99))	('Myc', 'Gene', (14, 17))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('Myc', 'Gene', '17869', (14, 17))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvements', 'PosReg', (158, 170))	('lymphoma', 'Disease', (33, 41))
79966	33451333	Combined treatment with MLN8237 and eribulin leads to a synergistic increase in apoptosis in mammary tumors as well as cytotoxic autophagy in metastases through the LC3B/p62 axis and Akt pathway.	('LC3B', 'Gene', (165, 169))	('Akt', 'Gene', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('metastases', 'Disease', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Akt', 'Gene', '207', (183, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('p62', 'Gene', '23636', (170, 173))	('increase', 'PosReg', (68, 76))	('LC3B', 'Gene', '81631', (165, 169))	('MLN8237', 'Var', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('p62', 'Gene', (170, 173))	('apoptosis', 'CPA', (80, 89))	('tumors', 'Disease', (101, 107))
79967	33451333	In multiple myeloma, studies on combined treatment with AT9283 and lenalidomide have shown significant synergistic antitumor effects of this regimen both in vitro and in vivo.	('AT9283', 'Chemical', 'MESH:C535237', (56, 62))	('multiple myeloma', 'Disease', (3, 19))	('tumor', 'Disease', (119, 124))	('AT9283', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lenalidomide', 'Chemical', 'MESH:D000077269', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
79970	33451333	PHA680632 treatment prior to radiation treatment leads to an additive effect in cancer cells, especially in p53-deficient cells in vitro or in vivo.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('additive effect', 'MPA', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PHA680632', 'Chemical', 'MESH:C524543', (0, 9))	('PHA680632', 'Var', (0, 9))	('cancer', 'Disease', (80, 86))
79971	33451333	Another AURKA inhibitor, MLN8054, sensitizes androgen-insensitive prostate cancer to radiation; this sensitization is associated with sustained DNA double-strand breaks.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MLN8054', 'Chemical', 'MESH:C518940', (25, 32))	('AURKA', 'Gene', '6790', (8, 13))	('sensitizes', 'Reg', (34, 44))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AURKA', 'Gene', (8, 13))	('MLN8054', 'Var', (25, 32))
79972	33451333	Two other AURKA inhibitors, MLN8237 and ENMD-2076, also enhance radiation sensitivity in cancer cells.	('ENMD-2076', 'Var', (40, 49))	('AURKA', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('enhance', 'PosReg', (56, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('cancer', 'Disease', (89, 95))	('MLN8237', 'Var', (28, 35))	('AURKA', 'Gene', '6790', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
79977	33451333	In addition, vorinostat and MK-0457 or MK-5108 combination treatment enhances lymphoma cell killing with reductions in c-Myc, hTERT, and microRNA levels.	('hTERT', 'Gene', (126, 131))	('lymphoma', 'Disease', (78, 86))	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('MK-5108', 'Gene', (39, 46))	('MK-0457', 'Chemical', 'MESH:C484810', (28, 35))	('lymphoma', 'Disease', 'MESH:D008223', (78, 86))	('MK-0457', 'Var', (28, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('microRNA levels', 'MPA', (137, 152))	('reductions', 'NegReg', (105, 115))	('MK-5108', 'Chemical', 'MESH:C547876', (39, 46))	('enhances', 'PosReg', (69, 77))	('c-Myc', 'Gene', '4609', (119, 124))	('hTERT', 'Gene', '7015', (126, 131))	('c-Myc', 'Gene', (119, 124))
79981	33451333	EGFR inhibitors have been a major breakthrough for NSCLC treatment.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (51, 56))	('inhibitors', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', '1956', (0, 4))
79985	33451333	Both BRD4 and AURKA are regulators of the MYC gene at the translational and posttranslational levels, respectively, and targeting both of them simultaneously may produce synergistic antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('produce', 'Reg', (162, 169))	('BRD4', 'Gene', (5, 9))	('AURKA', 'Gene', (14, 19))	('MYC', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('targeting', 'Var', (120, 129))	('tumor', 'Disease', (186, 191))	('BRD4', 'Gene', '23476', (5, 9))	('MYC', 'Gene', '4609', (42, 45))	('AURKA', 'Gene', '6790', (14, 19))
79986	33451333	JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells.	('glioblastoma', 'Disease', (133, 145))	('BRD4', 'Gene', '23476', (25, 29))	('human', 'Species', '9606', (127, 132))	('MLN8237', 'Var', (53, 60))	('c-Myc', 'Gene', '4609', (110, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('BRD4', 'Gene', (25, 29))	('c-Myc', 'Gene', (110, 115))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('promotes', 'PosReg', (87, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('activity', 'MPA', (30, 38))
79989	33451333	One study showed that AURKA and MDM2 antagonism with MLN8237 and Nutlin-3 halted melanoma growth by inducing growth arrest and senescence, limiting the lifespans of senescent cells, and enhancing tumor immune infiltration and clearance.	('tumor', 'Disease', (196, 201))	('growth arrest', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('Nutlin-3', 'Chemical', 'MESH:C482205', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('senescence', 'CPA', (127, 137))	('lifespans', 'CPA', (152, 161))	('MLN8237', 'Var', (53, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MDM2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('halted', 'NegReg', (74, 80))	('growth arrest', 'Phenotype', 'HP:0001510', (109, 122))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('enhancing', 'PosReg', (186, 195))	('MDM2', 'Gene', '4193', (32, 36))	('clearance', 'CPA', (226, 235))	('inducing', 'PosReg', (100, 108))	('growth arrest', 'Disease', 'MESH:D006323', (109, 122))	('AURKA', 'Gene', '6790', (22, 27))	('limiting', 'NegReg', (139, 147))	('AURKA', 'Gene', (22, 27))
79990	33451333	The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53-dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML.	('MK-0457', 'Var', (37, 44))	('mitochondrial apoptosis', 'CPA', (178, 201))	('AML', 'Disease', (205, 208))	('p53', 'Gene', (160, 163))	('postmitotic checkpoints at pseudo-G1 phase', 'CPA', (92, 134))	('activated', 'PosReg', (68, 77))	('p53', 'Gene', (78, 81))	('induced', 'PosReg', (139, 146))	('p53', 'Gene', '7157', (160, 163))	('Nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Gene', '7157', (78, 81))	('MK-0457', 'Chemical', 'MESH:C484810', (37, 44))	('AML', 'Disease', 'MESH:D015470', (205, 208))
79993	33451333	In human neuroblastoma cells, MK-5108 increases the efficacy of an anti-ganglioside (GD2) 14G2a antibody, which is related to a reduction in N-Myc expression and an increase in PHLDA1 and p53 protein levels.	('MK-5108', 'Var', (30, 37))	('neuroblastoma', 'Disease', (9, 22))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (147, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('ganglioside', 'Chemical', 'MESH:D005732', (72, 83))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('efficacy', 'MPA', (52, 60))	('increase', 'PosReg', (165, 173))	('PHLDA1', 'Gene', '22822', (177, 183))	('N-Myc', 'Gene', (141, 146))	('p53', 'Gene', '7157', (188, 191))	('GD2', 'Gene', (85, 88))	('N-Myc', 'Gene', '4613', (141, 146))	('p53', 'Gene', (188, 191))	('increases', 'PosReg', (38, 47))	('PHLDA1', 'Gene', (177, 183))	('reduction', 'NegReg', (128, 137))	('MK-5108', 'Chemical', 'MESH:C547876', (30, 37))
79994	33451333	In addition, combined treatment with an anti-GD2 14G2a antibody and MK-5108 leads to enhancement of the autophagy process in IMR-32 neuroblastoma cells.	('neuroblastoma', 'Disease', (132, 145))	('MK-5108', 'Gene', (68, 75))	('autophagy process', 'CPA', (104, 121))	('IMR-32', 'CellLine', 'CVCL:0346', (125, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))	('MK-5108', 'Chemical', 'MESH:C547876', (68, 75))	('enhancement', 'PosReg', (85, 96))	('combined', 'Interaction', (13, 21))	('anti-GD2 14G2a', 'Var', (40, 54))	('anti-GD2', 'Gene', (40, 48))
79995	33451333	A death receptor 5 agonist antibody has been found to initiate significant apoptosis in tumor cells undergoing therapy-induced senescence induced by MLN8237 treatment.	('death receptor 5', 'Gene', '8795', (2, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MLN8237 treatment', 'Var', (149, 166))	('death receptor 5', 'Gene', (2, 18))	('tumor', 'Disease', (88, 93))
80013	33451333	This drug delivery technology has been applied to MLN8237 and the polysaccharide nanovesicle efficiently delivers low concentrations of MLN8237 to inhibit AURKA and disrupt the anchorage-independent growth of MCF-7 cell than free MLN8237.	('AURKA', 'Gene', '6790', (155, 160))	('disrupt', 'NegReg', (165, 172))	('MLN8237', 'Chemical', 'MESH:C550258', (136, 143))	('polysaccharide', 'Chemical', 'MESH:D011134', (66, 80))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('AURKA', 'Gene', (155, 160))	('MLN8237', 'Var', (136, 143))	('MLN8237', 'Chemical', 'MESH:C550258', (230, 237))	('inhibit', 'NegReg', (147, 154))	('anchorage-independent growth', 'CPA', (177, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
80022	33451333	Furthermore, due to the fact that AURKA exerts its function through specific substrates in certain cancers, inhibition of AURKA substrates instead of targeting AURKA kinase activity may decrease the adverse effects.	('AURKA', 'Gene', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('function', 'MPA', (51, 59))	('cancers', 'Disease', (99, 106))	('AURKA', 'Gene', '6790', (160, 165))	('AURKA', 'Gene', '6790', (122, 127))	('AURKA', 'Gene', '6790', (34, 39))	('inhibition', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('AURKA', 'Gene', (160, 165))	('AURKA', 'Gene', (122, 127))
80026	33451333	Furthermore, in the triple-negative breast cancer cells, cell lines with a p53 mutation and increased p53 expression are more sensitive to ENMD-2076 than cell lines with decreased p53 expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (180, 183))	('expression', 'MPA', (106, 116))	('p53', 'Gene', '7157', (180, 183))	('sensitive', 'MPA', (126, 135))	('increased', 'PosReg', (92, 101))	('mutation', 'Var', (79, 87))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
80038	32856872	Low WT1 scores in grade II and III diffuse astrocytomas were linked to the high frequency of IDH1 positivity, and were associated with low Bcl2 and Ki67 labelling indices.	('Bcl2', 'Gene', '596', (139, 143))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('WT1', 'Gene', '7490', (4, 7))	('astrocytomas', 'Disease', (43, 55))	('IDH', 'Gene', (93, 96))	('WT1', 'Gene', (4, 7))	('IDH', 'Gene', '3417', (93, 96))	('Bcl2', 'Gene', (139, 143))	('Ki67', 'Chemical', '-', (148, 152))	('Low', 'NegReg', (0, 3))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))	('positivity', 'Var', (98, 108))
80053	32856872	Although the IHC method to assess WT1 mutation appears to be more suitable for routine use on clinical practice, thus far it has not been validated and controversies still exist on its competence (Manocha and Jain, 2019).	('WT1', 'Gene', '7490', (34, 37))	('WT1', 'Gene', (34, 37))	('mutation', 'Var', (38, 46))
80121	32856872	For Ki67, a median score of 12% was noticed in WT1 score +3 tumors, in contrast to the overtly lower median Ki67 scores (0, 1, 2% respectively) observed in 0, +1 and +2 WT1 scores (p<0.001).	('WT1', 'Gene', '7490', (47, 50))	('Ki67', 'Var', (4, 8))	('WT1', 'Gene', (47, 50))	('Ki67', 'Chemical', '-', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('WT1', 'Gene', '7490', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Ki67', 'Chemical', '-', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('WT1', 'Gene', (169, 172))	('tumors', 'Disease', (60, 66))
80122	32856872	Correspondingly, the Ki67 labelling index was significantly associated with the WT1 score (p=0.034) and most of the low proliferation index tumors (41.7%) lied in the +1 WT1 category, while most tumors of intermediate (41.7%) and high (77.8%) proliferation indices exhibited a +3WT1 score.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('Ki67', 'Var', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Ki67', 'Chemical', '-', (21, 25))	('WT1', 'Gene', '7490', (279, 282))	('low', 'NegReg', (116, 119))	('WT1', 'Gene', (279, 282))	('WT1', 'Gene', '7490', (80, 83))	('WT1', 'Gene', '7490', (170, 173))	('WT1', 'Gene', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('WT1', 'Gene', (170, 173))	('associated', 'Reg', (60, 70))
80152	32856872	Likewise, not all TP53 gene mutations result in immunohistochemically detectable p53 (Schittenhelm et al., 2008; Ambroise et al., 2010; Bourne et al., 2010; Camelo-Piragua et al., 2010; Shao et al., 2016).	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('mutations', 'Var', (28, 37))
80154	32856872	Recently, IHC for R132H-mutant IDH1 was proposed to distinguish neoplastic from reactive astrocytes.	('IDH', 'Gene', (31, 34))	('R132H', 'SUBSTITUTION', 'None', (18, 23))	('IDH', 'Gene', '3417', (31, 34))	('neoplastic', 'Disease', (64, 74))	('R132H', 'Var', (18, 23))
80155	32856872	Nonetheless, IDH mutations in low-grade diffuse astrocytomas ranges from 57 to 88% and almost all pilocytic astrocytomas and primary glioblastomas stains IDH-negative (Camelo-Piragua et al., 2010; Cai et al., 2016; Louis et al., 2016).	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', (154, 157))	('glioblastomas', 'Disease', 'MESH:D005909', (133, 146))	('glioblastomas', 'Phenotype', 'HP:0012174', (133, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('astrocytomas', 'Disease', 'MESH:D001254', (108, 120))	('glioblastomas', 'Disease', (133, 146))	('astrocytomas', 'Disease', 'MESH:D001254', (48, 60))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('pilocytic astrocytomas', 'Disease', (98, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (98, 120))	('astrocytomas', 'Disease', (108, 120))	('IDH', 'Gene', (13, 16))	('astrocytomas', 'Disease', (48, 60))	('mutations', 'Var', (17, 26))	('IDH', 'Gene', '3417', (154, 157))
80192	32856872	Ki67 score and labelling index were significantly associated with the WT1 score (p<0.001 and=0.034 respectively) and most tumors of intermediate and high proliferation indices exhibited a +3WT1 score.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('exhibited', 'Reg', (176, 185))	('associated', 'Interaction', (50, 60))	('labelling', 'MPA', (15, 24))	('Ki67', 'Chemical', '-', (0, 4))	('Ki67', 'Var', (0, 4))	('WT1', 'Gene', '7490', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('WT1', 'Gene', (70, 73))	('WT1', 'Gene', '7490', (190, 193))	('WT1', 'Gene', (190, 193))
80212	32856872	Despite the uncertain histogenesis, SEGA was suggested to arise from neuroglial progenitor cell carrying a biallelic inactivation of Tuberous Sclerosis genes.	('SEGA', 'Disease', (36, 40))	('Tuberous Sclerosis', 'Disease', 'MESH:D014402', (133, 151))	('biallelic inactivation', 'Var', (107, 129))	('Tuberous Sclerosis', 'Disease', (133, 151))
80213	32856872	Moreover, gemistocytic astrocytes exhibit a high frequency TP53 mutation and gemistocytic astrocytomas more likely undergo progression to anaplastic astrocytoma and glioblastoma (Louis et al., 2016).	('anaplastic astrocytoma', 'Disease', (138, 160))	('astrocytomas', 'Disease', (90, 102))	('TP53', 'Gene', (59, 63))	('progression', 'PosReg', (123, 134))	('mutation', 'Var', (64, 72))	('astrocytoma and glioblastoma', 'Disease', 'MESH:D005909', (149, 177))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (138, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (165, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('undergo', 'Reg', (115, 122))	('TP53', 'Gene', '7157', (59, 63))
80218	32856872	In grade I, the most important observations were the occurrence of WT1 low scores in older age patients, the association between the rare IDH1 positivity and +3 WT1 score, the association of intermediate or high Bcl2 and Ki67 indices with +3 WT1 score.	('low', 'NegReg', (71, 74))	('Bcl2', 'Gene', (212, 216))	('WT1', 'Gene', '7490', (161, 164))	('positivity', 'Var', (143, 153))	('IDH', 'Gene', (138, 141))	('patients', 'Species', '9606', (95, 103))	('WT1', 'Gene', (161, 164))	('IDH', 'Gene', '3417', (138, 141))	('Bcl2', 'Gene', '596', (212, 216))	('WT1', 'Gene', '7490', (67, 70))	('Ki67', 'Chemical', '-', (221, 225))	('WT1', 'Gene', '7490', (242, 245))	('WT1', 'Gene', (242, 245))	('WT1', 'Gene', (67, 70))
80221	32856872	Furthermore, Manocha and Jain (2019), attributed the lower WT1 scores in grade II astrocytomas to the high frequency of IDH1 positivity.	('IDH', 'Gene', '3417', (120, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('astrocytomas', 'Disease', (82, 94))	('WT1', 'Gene', '7490', (59, 62))	('astrocytomas', 'Disease', 'MESH:D001254', (82, 94))	('positivity', 'Var', (125, 135))	('WT1', 'Gene', (59, 62))	('lower', 'NegReg', (53, 58))	('IDH', 'Gene', (120, 123))
80225	32856872	Taken together, we can confirm that WT1 correlates with old age and IDH1 negativity in grade IV astrocytomas indicating a poor outcome and that, absent/low WT1 expression in high-grade astrocytic tumors is associated with younger age and presence of IDH1 mutation (Rauscher et al., 2014), signifying a favorable prognosis for the latter group (Manocha and Jain, 2019).	('IDH', 'Gene', '3417', (68, 71))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (185, 201))	('astrocytic tumors', 'Disease', 'MESH:D001254', (185, 202))	('Manocha', 'Disease', (344, 351))	('WT1', 'Gene', '7490', (156, 159))	('WT1', 'Gene', (36, 39))	('WT1', 'Gene', '7490', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('astrocytomas', 'Disease', 'MESH:D001254', (96, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('mutation', 'Var', (255, 263))	('absent/low', 'NegReg', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('expression', 'MPA', (160, 170))	('IDH', 'Gene', (250, 253))	('IDH', 'Gene', (68, 71))	('astrocytomas', 'Disease', (96, 108))	('astrocytic tumors', 'Disease', (185, 202))	('IDH', 'Gene', '3417', (250, 253))	('WT1', 'Gene', (156, 159))
80226	32856872	The inverse relation between WT1 and IDH1 can be simply explained on molecular basis, while IDH1 mutation occurs with increased DNA methylation (hypermethylation phenotype), WT1 was conversely found to be involved in the TET/oxi-mCs (ten eleven translocation/ oxidize 5-methylcytosines)-related demethylation and transcriptional repression resulting in methylome reprogramming and ultimately, tumorigenesis (Cohen et al., 2013; Ramsawhook et al., 2018).	('methylome reprogramming', 'CPA', (353, 376))	('WT1', 'Gene', '7490', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('WT1', 'Gene', (174, 177))	('IDH', 'Gene', '3417', (37, 40))	('demethylation', 'Var', (295, 308))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('increased', 'PosReg', (118, 127))	('5-methylcytosines', 'Chemical', 'MESH:D044503', (268, 285))	('tumor', 'Disease', (393, 398))	('IDH', 'Gene', (92, 95))	('mutation', 'Var', (97, 105))	('IDH', 'Gene', (37, 40))	('WT1', 'Gene', '7490', (29, 32))	('IDH', 'Gene', '3417', (92, 95))	('WT1', 'Gene', (29, 32))
80235	32856872	Nonetheless, low WT1 scores in grade II and III tumors can be linked to high frequency of IDH1 positivity and low Bcl2 and Ki67 labelling indices.	('Bcl2', 'Gene', '596', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Ki67', 'Chemical', '-', (123, 127))	('III tumors', 'Disease', (44, 54))	('IDH', 'Gene', (90, 93))	('WT1', 'Gene', '7490', (17, 20))	('low', 'NegReg', (13, 16))	('WT1', 'Gene', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('IDH', 'Gene', '3417', (90, 93))	('Bcl2', 'Gene', (114, 118))	('III tumors', 'Disease', 'MESH:D009369', (44, 54))	('low', 'NegReg', (110, 113))	('positivity', 'Var', (95, 105))
80239	33115448	TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors.	('Capicua', 'Gene', (16, 23))	('Capicua', 'Gene', (97, 104))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('ERK', 'Gene', '5594', (53, 56))	('ATXN1', 'Gene', (75, 80))	('TRIM25', 'Gene', '7706', (0, 6))	('Capicua', 'Gene', '23152', (16, 23))	('derepression', 'PosReg', (216, 228))	('ERK', 'Gene', (53, 56))	('Capicua', 'Gene', '23152', (97, 104))	('ATXN1', 'Gene', '6310', (75, 80))	('Aberrations', 'Var', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('TRIM25', 'Gene', (0, 6))
80241	33115448	Functional in vitro studies utilizing ATXN1LKO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome.	('polyubiquitinated CIC', 'Disease', (122, 143))	('polyubiquitinated CIC', 'Disease', 'None', (122, 143))	('accumulation', 'PosReg', (106, 118))	('promoting', 'PosReg', (153, 162))	('loss', 'Var', (78, 82))	('ATXN1LKO', 'Gene', '342371', (38, 46))	('degradation', 'MPA', (167, 178))	('human', 'Species', '9606', (47, 52))	('ATXN1L', 'Gene', (86, 92))	('ATXN1LKO', 'Gene', (38, 46))
80248	33115448	In general, CIC acts as a repressor of receptor tyrosine kinase (RTK)-responsive genes and is inactivated through phosphorylation by ERK, a member of the mitogen-activated protein kinase (MAPK) cascade.	('repressor', 'MPA', (26, 35))	('RTK)-responsive genes', 'Gene', (65, 86))	('CIC', 'Gene', (12, 15))	('inactivated', 'NegReg', (94, 105))	('ERK', 'Gene', (133, 136))	('receptor tyrosine kinase', 'Gene', (39, 63))	('receptor tyrosine kinase', 'Gene', '5979', (39, 63))	('phosphorylation', 'Var', (114, 129))
80250	33115448	Mutations in CIC were first identified in type I low-grade glioma (LGG) (50-70%), a subtype of LGG defined by simultaneous IDH mutation and 1p19q codeletion.	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (123, 126))	('CIC', 'Gene', (13, 16))	('IDH', 'Gene', '3417', (123, 126))
80251	33115448	More recently, dysregulation of CIC activity has been associated with negative prognostic features and/or oncogenesis in several human cancer types including sarcoma, glioblastoma, hepatocellular carcinoma lung adenocarcinoma, and pancreatic adenocarcinoma.	('hepatocellular carcinoma lung adenocarcinoma', 'Disease', 'MESH:D000077192', (181, 225))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (206, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('pancreatic adenocarcinoma', 'Disease', (231, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('hepatocellular carcinoma lung adenocarcinoma', 'Disease', (181, 225))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (167, 179))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (231, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('dysregulation', 'Var', (15, 28))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (231, 256))	('glioblastoma', 'Disease', (167, 179))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('human', 'Species', '9606', (129, 134))	('sarcoma', 'Disease', (158, 165))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (181, 205))
80257	33115448	However, these studies have also highlighted that loss of ATXN1L affected CIC function much more profoundly and robustly compared to the loss of ATXN1, which is also consistent in cancer.	('CIC function', 'MPA', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('loss', 'Var', (50, 54))	('affected', 'Reg', (65, 73))	('ATXN1L', 'Gene', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
80266	33115448	Similarly, using proximity ligation assay (PLA), the interaction between CIC and ubiquitin was observed to increase following treatment with MG132 in ATXN1LKO (Additional file 1: Figure S1C, D) or siRNA knockdown of ATXN1L in ATXN1LWT cells (Fig.	('increase', 'PosReg', (107, 115))	('MG132', 'Chemical', 'MESH:C072553', (141, 146))	('ATXN1LKO', 'Gene', '342371', (150, 158))	('ATXN1LKO', 'Gene', (150, 158))	('MG132', 'Var', (141, 146))	('interaction', 'Interaction', (53, 64))	('ubiquitin', 'Protein', (81, 90))	('knockdown', 'Var', (203, 212))
80269	33115448	Phosphorylated ERK (pThr202/Tyr204) was found to be decreased in our ATXN1LKO cell lines compared to the ATXN1LWT cell lines, detected using ELISA (Fig.	('Phosphorylated', 'MPA', (0, 14))	('decreased', 'NegReg', (52, 61))	('Tyr204', 'Chemical', '-', (28, 34))	('ERK', 'Protein', (15, 18))	('ATXN1LKO', 'Gene', '342371', (69, 77))	('pThr202/Tyr204', 'Var', (20, 34))	('ATXN1LKO', 'Gene', (69, 77))
80271	33115448	Further, dual inhibition of MEK and ERK using the small molecule inhibitors trametinib and LY3214996, respectively, did not rescue CIC protein expression in ATXN1LKO cell lines (Fig.	('LY3214996', 'Chemical', '-', (91, 100))	('ATXN1LKO', 'Gene', '342371', (157, 165))	('CIC protein', 'Protein', (131, 142))	('MEK', 'Gene', (28, 31))	('MEK', 'Gene', '5609', (28, 31))	('trametinib', 'Chemical', 'MESH:C560077', (76, 86))	('ATXN1LKO', 'Gene', (157, 165))	('LY3214996', 'Var', (91, 100))
80282	33115448	Using CICKO cell lines with stably expressing FLAG-tagged CIC-S, CIC interaction with 14-3-3 regulatory proteins and the nuclear pore protein TPR was observed to increase following siRNA knockdown of ATXN1L using PLA (Additional file 5: Figure S4A, B, C).	('increase', 'PosReg', (162, 170))	('knockdown', 'Var', (187, 196))	('14-3-3', 'Gene', '10971', (86, 92))	('interaction', 'Interaction', (69, 80))	('TPR', 'Gene', (142, 145))	('CIC', 'MPA', (65, 68))	('TPR', 'Gene', '7175', (142, 145))	('14-3-3', 'Gene', (86, 92))
80289	33115448	Ectopic overexpression of FLAG-tagged TRIM25 resulted in a further decrease in CIC protein expression in ATXN1LKO cells (Fig.	('overexpression', 'PosReg', (8, 22))	('ATXN1LKO', 'Gene', '342371', (105, 113))	('CIC protein', 'Protein', (79, 90))	('decrease', 'NegReg', (67, 75))	('ATXN1LKO', 'Gene', (105, 113))	('FLAG-tagged', 'Var', (26, 37))	('TRIM25', 'Gene', '7706', (38, 44))	('TRIM25', 'Gene', (38, 44))
80297	33115448	Similarly, knockdown of ATXN1L did result in decreased CIC protein expression in both GBM (Additional file 7: Figure S6B) and BTIC (Fig.	('BTIC', 'Chemical', '-', (126, 130))	('decreased CIC', 'Disease', 'MESH:D002303', (45, 58))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('ATXN1L', 'Gene', (24, 30))	('expression', 'MPA', (67, 77))	('knockdown', 'Var', (11, 20))	('decreased CIC', 'Disease', (45, 58))
80298	33115448	Derepression of CIC target genes (ETV1/4/5, DUSP6, SPRY4) was also observed following siRNA knockdown of ATXN1L in GBM (Fig.	('knockdown', 'Var', (92, 101))	('SPRY4', 'Gene', (51, 56))	('DUSP6', 'Gene', (44, 49))	('ETV1/4/5', 'Gene', '2115;2118;2119', (34, 42))	('DUSP6', 'Gene', '1848', (44, 49))	('GBM', 'Phenotype', 'HP:0012174', (115, 118))	('SPRY4', 'Gene', '81848', (51, 56))	('ETV1/4/5', 'Gene', (34, 42))
80299	33115448	5g, Additional file 7: Figure S6C) and BTIC (Additional file 7: Figure S6D) cell lines, while siRNA knockdown of TRIM25 resulted in further repression.	('BTIC', 'Chemical', '-', (39, 43))	('knockdown', 'Var', (100, 109))	('TRIM25', 'Gene', '7706', (113, 119))	('TRIM25', 'Gene', (113, 119))	('repression', 'MPA', (140, 150))
80300	33115448	Dual inhibition of MEK and ERK was not sufficient to rescue decreases in CIC protein expression following siRNA knockdown of ATXN1L (Fig.	('decreases', 'NegReg', (60, 69))	('CIC protein', 'Protein', (73, 84))	('MEK', 'Gene', '5609', (19, 22))	('knockdown', 'Var', (112, 121))	('MEK', 'Gene', (19, 22))
80301	33115448	5h, Additional file 7: Figure S6E), whereas concurrent knockdown of ATXN1L and TRIM25 was able to rescue decreased CIC protein (Fig.	('knockdown', 'Var', (55, 64))	('decreased CIC', 'Disease', (105, 118))	('ATXN1L', 'Gene', (68, 74))	('decreased CIC', 'Disease', 'MESH:D002303', (105, 118))	('TRIM25', 'Gene', '7706', (79, 85))	('TRIM25', 'Gene', (79, 85))
80302	33115448	Probing the TCGA database, alterations in TRIM25 were observed in several cancer types, most notably amplifications in the invasive breast carcinoma (BRCA) and mesothelioma datasets (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (160, 172))	('BRCA', 'Phenotype', 'HP:0003002', (150, 154))	('breast carcinoma', 'Phenotype', 'HP:0003002', (132, 148))	('BRCA', 'Gene', (150, 154))	('invasive breast carcinoma', 'Disease', (123, 148))	('BRCA', 'Gene', '672', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('observed', 'Reg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('TRIM25', 'Gene', '7706', (42, 48))	('mesothelioma', 'Disease', (160, 172))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (123, 148))	('amplifications', 'Var', (101, 115))	('TRIM25', 'Gene', (42, 48))	('alterations', 'Var', (27, 38))
80303	33115448	To determine if TRIM25 may regulate the transcription factor functions of CIC, differentially expressed (DE) genes using published gene expression data of TRIM25 knockdown in breast cancer cell lines (BT549 and MDA-MB-231, Additional file 8: Table S2) from Walsh et al.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('TRIM25', 'Gene', '7706', (16, 22))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('transcription factor functions', 'MPA', (40, 70))	('breast cancer', 'Disease', (175, 188))	('TRIM25', 'Gene', (16, 22))	('regulate', 'Reg', (27, 35))	('BT549', 'CellLine', 'CVCL:1092', (201, 206))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (211, 221))	('TRIM25', 'Gene', '7706', (155, 161))	('knockdown', 'Var', (162, 171))	('TRIM25', 'Gene', (155, 161))
80305	33115448	As TRIM25 was knocked down, we expected directional discordance between DE genes identified in TRIM25 knockdown versus CICKO/ATXN1LKO.	('TRIM25', 'Gene', '7706', (95, 101))	('ATXN1LKO', 'Gene', '342371', (125, 133))	('ATXN1LKO', 'Gene', (125, 133))	('TRIM25', 'Gene', '7706', (3, 9))	('knockdown', 'Var', (102, 111))	('TRIM25', 'Gene', (95, 101))	('TRIM25', 'Gene', (3, 9))
80307	33115448	To further validate the relationship between TRIM25 and CIC, differential expression analysis was performed using the TCGA BRCA cohort comparing samples with TRIM25 amplification versus samples with copy number neutral TRIM25.	('BRCA', 'Gene', (123, 127))	('TRIM25', 'Gene', '7706', (158, 164))	('TRIM25', 'Gene', '7706', (219, 225))	('TRIM25', 'Gene', '7706', (45, 51))	('amplification', 'Var', (165, 178))	('TRIM25', 'Gene', (158, 164))	('BRCA', 'Phenotype', 'HP:0003002', (123, 127))	('TRIM25', 'Gene', (219, 225))	('BRCA', 'Gene', '672', (123, 127))	('TRIM25', 'Gene', (45, 51))
80311	33115448	BRCA patients which expressed high TRIM25 expression (top 25%) also showed decreased overall survival (Fig.	('patients', 'Species', '9606', (5, 13))	('BRCA', 'Gene', (0, 4))	('high', 'Var', (30, 34))	('BRCA', 'Gene', '672', (0, 4))	('decreased', 'NegReg', (75, 84))	('TRIM25', 'Gene', '7706', (35, 41))	('overall survival', 'MPA', (85, 101))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('TRIM25', 'Gene', (35, 41))
80313	33115448	Similar to the BRCA cohort, LIHC patients with high TRIM25 expression (top 25%) were found to have higher expression of the CIC target genes ETV1/4/5 (Fig.	('patients', 'Species', '9606', (33, 41))	('higher', 'PosReg', (99, 105))	('high', 'Var', (47, 51))	('expression', 'MPA', (106, 116))	('BRCA', 'Phenotype', 'HP:0003002', (15, 19))	('ETV1/4/5', 'Gene', (141, 149))	('BRCA', 'Gene', (15, 19))	('TRIM25', 'Gene', '7706', (52, 58))	('BRCA', 'Gene', '672', (15, 19))	('TRIM25', 'Gene', (52, 58))	('ETV1/4/5', 'Gene', '2115;2118;2119', (141, 149))
80317	33115448	This can be evidenced by the temporal differences in CIC inactivation following the loss of ATXN1L (hours) versus phosphorylation by ERK (minutes), which may suggest that CIC instability resulting from the loss of ATXN1L may be due to an increased rate of normal CIC turnover.	('ATXN1L', 'Gene', (214, 220))	('loss', 'Var', (206, 210))	('CIC inactivation', 'MPA', (53, 69))	('CIC turnover', 'Disease', 'MESH:D001851', (263, 275))	('CIC instability', 'Disease', (171, 186))	('ATXN1L', 'Gene', (92, 98))	('CIC instability', 'Disease', 'MESH:D043171', (171, 186))	('CIC turnover', 'Disease', (263, 275))	('loss', 'Var', (84, 88))
80321	33115448	Overexpression of TRIM25 was able to reduce CIC protein expression while siRNA knockdown of TRIM25 was able to stabilize CIC and promote its tumor suppressor function.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('reduce', 'NegReg', (37, 43))	('TRIM25', 'Gene', '7706', (92, 98))	('TRIM25', 'Gene', (18, 24))	('stabilize', 'MPA', (111, 120))	('promote', 'PosReg', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('TRIM25', 'Gene', (92, 98))	('CIC protein', 'Protein', (44, 55))	('knockdown', 'Var', (79, 88))	('TRIM25', 'Gene', '7706', (18, 24))
80337	33115448	Wild-type IDH1-stable NHA cell line was purchased from Applied Biological Materials (ABM) Inc. (T3022, Richmond, BC, Canada).	('NHA', 'Chemical', '-', (22, 25))	('IDH1', 'Gene', '3417', (10, 14))	('IDH1', 'Gene', (10, 14))	('T3022', 'Var', (96, 101))
80345	33115448	FLAG-tagged ATXN1L (#33242) and FLAG-tagged TRIM25 (#12449) constructs were purchased from Addgene.	('TRIM25', 'Gene', '7706', (44, 50))	('TRIM25', 'Gene', (44, 50))	('#33242', 'Var', (20, 26))	('#12449', 'Var', (52, 58))
80348	33115448	LY3214996 was used for ERK inhibition at a concentration of 10 nM.	('LY3214996', 'Chemical', '-', (0, 9))	('ERK', 'Enzyme', (23, 26))	('LY3214996', 'Var', (0, 9))
80367	33115448	Only BRCA samples with no TRIM25 copy number variations were considered wild-type (n = 449), and BRCA samples with a copy number of 2 or greater were considered amplified (n = 73).	('TRIM25', 'Gene', '7706', (26, 32))	('copy number variations', 'Var', (33, 55))	('BRCA', 'Phenotype', 'HP:0003002', (97, 101))	('TRIM25', 'Gene', (26, 32))	('BRCA', 'Gene', '672', (97, 101))	('BRCA', 'Phenotype', 'HP:0003002', (5, 9))	('BRCA', 'Gene', '672', (5, 9))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', (5, 9))
80392	32859926	Comparative studies between responders and non-responders indicate that multiple factors, including pre-existing T-cell infiltration, checkpoint molecule expression within the tumor, and mutational burden with consequent production of neoantigens correlate with response to immune therapy.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutational', 'Var', (187, 197))	('tumor', 'Disease', (176, 181))	('checkpoint', 'MPA', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
80393	32859926	For instance, colorectal cancer of the molecular subtype CMS1 are characterized by DNA mismatch-repair defects, microsatellite instability, and hypermutation with accompanying infiltration of CD8+ T-cells and expression of immune checkpoint proteins CTLA-4, PD-1, PDL1, and IDO-1.	('CTLA-4', 'Gene', '1493', (250, 256))	('IDO-1', 'Gene', (274, 279))	('IDO-1', 'Gene', '3620', (274, 279))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('CTLA-4', 'Gene', (250, 256))	('PD-1', 'Gene', (258, 262))	('PD-1', 'Gene', '5133', (258, 262))	('microsatellite instability', 'Disease', 'MESH:D053842', (112, 138))	('infiltration', 'PosReg', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('CD8', 'Gene', (192, 195))	('microsatellite instability', 'Disease', (112, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (14, 31))	('defects', 'Var', (103, 110))	('hypermutation', 'Var', (144, 157))	('colorectal cancer', 'Disease', (14, 31))	('PDL1', 'Gene', (264, 268))	('CD8', 'Gene', '925', (192, 195))	('PDL1', 'Gene', '29126', (264, 268))
80454	32859926	Further associations between infiltrating cell estimations and clinico-pathological variables (within the four classic subgroups) were examined includingthe following: MYC/MYCN amplification, TP53 mutation, and metastatic stage (see Supplementary Data 1).	('MYC', 'Gene', (172, 175))	('MYC', 'Gene', (168, 171))	('TP53', 'Gene', '7157', (192, 196))	('MYCN', 'Gene', (172, 176))	('MYCN', 'Gene', '4613', (172, 176))	('MYC', 'Gene', '4609', (168, 171))	('MYC', 'Gene', '4609', (172, 175))	('metastatic stage', 'CPA', (211, 227))	('TP53', 'Gene', (192, 196))	('mutation', 'Var', (197, 205))
80463	32859926	We next ran our methylCIBERSORT on a set of 229 malignant rhabdoid tumor (MRT) methylation profiles from a previously published study and supplemented with 79 previously unpublished profiles.	('malignant rhabdoid tumor', 'Disease', (48, 72))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (48, 72))	('methylation', 'Var', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))
80474	32859926	No significant differences in immune infiltration are seen with respect to age category (<2 vs. >2 years), the presence of metastases at diagnosis, and type of SMARCB1 mutation (Supplementary Data 1).	('SMARCB1', 'Gene', '6598', (160, 167))	('SMARCB1', 'Gene', (160, 167))	('mutation', 'Var', (168, 176))	('metastases', 'Disease', (123, 133))	('metastases', 'Disease', 'MESH:D009362', (123, 133))
80483	32859926	Post hoc testing shows significantly greater monocytes in WT-A vs. other subgroups (2.9-fold, all comparisons p < 0.001), significantly greater CD8T in GBM with G34 mutations (1.7-fold, all comparisons p < 0.05), and significantly less eosinophils in GBM with G34 mutations (2.3-fold less, all comparisons p < 0.001).	('G34', 'Gene', (161, 164))	('mutations', 'Var', (264, 273))	('less', 'NegReg', (231, 235))	('CD8', 'Gene', (144, 147))	('monocytes', 'CPA', (45, 54))	('eosinophils', 'CPA', (236, 247))	('CD8', 'Gene', '925', (144, 147))	('mutations', 'Var', (165, 174))	('greater', 'PosReg', (136, 143))	('greater', 'PosReg', (37, 44))
80484	32859926	The WT-A subgroup generally contains pHGG, otherwise referred to as PXA or LGG-like; they are also enriched for mitogen-activated protein kinase (MAPK) mutations (genes NF1, FGFR1, NTRK2, BRAF, see Supplementary Data 1).	('NF1', 'Gene', (169, 172))	('mutations', 'Var', (152, 161))	('NF1', 'Gene', '4763', (169, 172))	('BRAF', 'Gene', '673', (188, 192))	('BRAF', 'Gene', (188, 192))	('NTRK2', 'Gene', (181, 186))	('FGFR1', 'Gene', (174, 179))	('FGFR1', 'Gene', '2260', (174, 179))	('MAPK', 'Gene', (146, 150))	('pHGG', 'Disease', (37, 41))	('NTRK2', 'Gene', '4915', (181, 186))
80489	32859926	Clinico-pathological/biological features examined for association with estimated cell types include WHO stage, gender, age <1 year or age <3 years, and the presence of BRAF and/or other MAPK mutation.	('BRAF', 'Gene', '673', (168, 172))	('MAPK', 'Gene', (186, 190))	('presence', 'Reg', (156, 164))	('BRAF', 'Gene', (168, 172))	('mutation', 'Var', (191, 199))
80490	32859926	As previously noted, the presence of MAPK mutations was associated with higher immune cell infiltration, specifically of monocytes and CD4T cells (W = 3614 and W = 3453, respectively, both p < 0.001).	('CD4', 'Gene', (135, 138))	('immune cell infiltration', 'CPA', (79, 103))	('higher', 'PosReg', (72, 78))	('CD4', 'Gene', '920', (135, 138))	('mutations', 'Var', (42, 51))	('MAPK', 'Gene', (37, 41))
80502	32859926	Third, that key molecular features recognized as molecular drivers, such as MYC amplification in MB or H3.3G34 mutations in HGG, are associated with distinct TIMEs and particular infiltrating cell types raising the possibility that these mutations are directly influencing the tumor microenvironment, perhaps as an adjunct to their intrinsic oncogenic mechanism.	('mutations', 'Var', (111, 120))	('influencing', 'Reg', (261, 272))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('MYC', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('HGG', 'Gene', (124, 127))	('tumor', 'Disease', (277, 282))	('MYC', 'Gene', '4609', (76, 79))
80526	32859926	The pattern of large beta-value variations within the reference cell types and small variations between the CNS tumor types is consistent with these CpGs correctly representing a minor infiltrating population within a uniform majority cancer cell population.	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('beta-value', 'MPA', (21, 31))	('variations', 'Var', (32, 42))	('CNS tumor', 'Phenotype', 'HP:0100006', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
80532	32859926	To define microglia, we used the following genes: ENSG00000181631 (P2RY13), ENSG00000169313 (P2RY12), ENSG00000171659 (GPR34), ENSG00000142583 (SLC2A5), ENSG00000116774 (OLFML3), and ENSG00000183160 (TMEM119).	('ENSG00000183160', 'Var', (183, 198))	('P2RY12', 'Gene', '64805', (93, 99))	('OLFML3', 'Gene', (170, 176))	('TMEM119', 'Gene', (200, 207))	('ENSG00000171659', 'Var', (102, 117))	('P2RY13', 'Gene', '53829', (67, 73))	('SLC2A5', 'Gene', '6518', (144, 150))	('P2RY12', 'Gene', (93, 99))	('GPR34', 'Gene', '2857', (119, 124))	('ENSG00000169313', 'Var', (76, 91))	('P2RY13', 'Gene', (67, 73))	('TMEM119', 'Gene', '338773', (200, 207))	('ENSG00000181631', 'Var', (50, 65))	('ENSG00000116774', 'Var', (153, 168))	('GPR34', 'Gene', (119, 124))	('OLFML3', 'Gene', '56944', (170, 176))	('ENSG00000142583', 'Var', (127, 142))	('SLC2A5', 'Gene', (144, 150))
80533	32859926	To define peripheral macrophages, we used the following: ENSG00000126218 (F10), ENSG00000132205 (EMILIN2), ENSG00000198734 (F5), ENSG00000125730 (C3), ENSG00000119125 (GDA), ENSG00000188404 (SELL), and ENSG00000257017 (HP).	('ENSG00000132205', 'Var', (80, 95))	('EMILIN2', 'Gene', '84034', (97, 104))	('ENSG00000198734', 'Var', (107, 122))	('EMILIN2', 'Gene', (97, 104))	('ENSG00000126218', 'Var', (57, 72))	('ENSG00000119125', 'Var', (151, 166))	('ENSG00000125730', 'Var', (129, 144))	('GDA', 'Gene', (168, 171))	('ENSG00000257017', 'Var', (202, 217))	('GDA', 'Gene', '9615', (168, 171))	('ENSG00000188404', 'Var', (174, 189))
80534	32859926	To define all monocytes of whichever type, we used the following genes: (ENSG00000169896 (CD11B) and ENSG00000081237 (CD45).	('ENSG00000169896', 'Var', (73, 88))	('CD11B', 'Gene', '3684', (90, 95))	('CD45', 'Gene', (118, 122))	('CD11B', 'Gene', (90, 95))	('ENSG00000081237', 'Var', (101, 116))	('CD45', 'Gene', '5788', (118, 122))
80542	32859926	For the tumor cohorts: GEO datasets GSE70460, GSE109381, GSE60274, GSE93646, GSE85212, and GSE130051; ArrayExpress datasets E-MTAB-5528, E-MTAB-5552, and E-MTAB-6708.	('GSE93646', 'Var', (67, 75))	('GSE85212', 'Var', (77, 85))	('GSE60274', 'Var', (57, 65))	('E-MTAB-5528', 'Var', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('GSE130051', 'Var', (91, 100))	('GSE70460', 'Var', (36, 44))	('tumor', 'Disease', (8, 13))
80565	31908526	Mutations in let-7, which was first discovered in Caenorhabditis elegans, can lead to abnormal larval growth and are therefore lethal to these organisms.	('larval growth', 'CPA', (95, 108))	('lead to', 'Reg', (78, 85))	('let-7', 'Gene', '266952', (13, 18))	('Caenorhabditis elegans', 'Species', '6239', (50, 72))	('Mutations', 'Var', (0, 9))	('let-7', 'Gene', (13, 18))
80587	31908526	The DNA synthesis of glioma cells transfected with the si-GALE, miR-Let7i-5p or NC constructs in the 24-well culture plate was detected with an EdU Apollo 567 In Vitro Kit (Cell-Light).	('N', 'Chemical', 'MESH:D009584', (5, 6))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('Let7i', 'Gene', (68, 73))	('nt', 'Chemical', 'MESH:D009711', (10, 12))	('DNA synthesis', 'MPA', (4, 17))	('si-GALE', 'Var', (55, 62))	('glioma', 'Disease', (21, 27))	('Let7i', 'Gene', '406891', (68, 73))	('N', 'Chemical', 'MESH:D009584', (80, 81))
80591	31908526	Cells (1x105) were inoculated into 6-well plates overnight and transfected with the si-GALE, miR-Let7i-5p or NC construct.	('si-GALE', 'Var', (84, 91))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('Let7i', 'Gene', '406891', (97, 102))	('nt', 'Chemical', 'MESH:D009711', (31, 33))	('Let7i', 'Gene', (97, 102))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))
80631	31908526	Therefore, GALE was positively associated with a high tumor grade in both the public database and our primary tumor sample cohort.	('GALE', 'Var', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
80633	31908526	Compared with LGG (P<0.001) and GBM (P<0.05) patients in the TCGA (n=667), patients with high GALE expression had a significantly worse prognosis (Figure 1B and C).	('expression', 'MPA', (99, 109))	('patients', 'Species', '9606', (75, 83))	('nt', 'Chemical', 'MESH:D009711', (125, 127))	('GBM', 'Disease', (32, 35))	('high', 'Var', (89, 93))	('nt', 'Chemical', 'MESH:D009711', (80, 82))	('patients', 'Species', '9606', (45, 53))	('GALE', 'Protein', (94, 98))	('GBM', 'Disease', 'MESH:D005909', (32, 35))	('nt', 'Chemical', 'MESH:D009711', (50, 52))
80641	31908526	These results show that the knockdown of GALE significantly inhibited the migration ability of GBM cell lines.	('inhibited', 'NegReg', (60, 69))	('nt', 'Chemical', 'MESH:D009711', (55, 57))	('GBM', 'Disease', (95, 98))	('knockdown', 'Var', (28, 37))	('GBM', 'Disease', 'MESH:D005909', (95, 98))	('GALE', 'Gene', (41, 45))
80643	31908526	GALE gene knockout significantly reduced the levels of N-CAD, MMP-2, and several genes/pathways critical for the progression of various types of cancer, including glioma (Figure 4H and I).	('cancer', 'Disease', (145, 151))	('GALE', 'Gene', (0, 4))	('N-CAD', 'Gene', (55, 60))	('glioma', 'Disease', (163, 169))	('N-CAD', 'Gene', '1000', (55, 60))	('MMP-2', 'Gene', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('nt', 'Chemical', 'MESH:D009711', (28, 30))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('knockout', 'Var', (10, 18))	('genes/pathways', 'Gene', (81, 95))	('reduced', 'NegReg', (33, 40))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('MMP-2', 'Gene', '4313', (62, 67))
80644	31908526	Cell cycle analysis by flow cytometry also showed that GALE knockdown increased the number of U87 and U251 cells in the G1 phase (Figure 4A-C).	('GALE', 'Gene', (55, 59))	('increased', 'PosReg', (70, 79))	('U87', 'CellLine', 'CVCL:0022', (94, 97))	('knockdown', 'Var', (60, 69))	('U251', 'CellLine', 'CVCL:0021', (102, 106))
80645	31908526	In addition, in U87 and U251 cells, silencing GALE promoted apoptotic cell death compared with that in the corresponding control (Figure 4D and E).	('U251', 'CellLine', 'CVCL:0021', (24, 28))	('apoptotic cell death', 'CPA', (60, 80))	('nt', 'Chemical', 'MESH:D009711', (123, 125))	('GALE', 'Gene', (46, 50))	('silencing', 'Var', (36, 45))	('promoted', 'PosReg', (51, 59))	('U87', 'CellLine', 'CVCL:0022', (16, 19))
80647	31908526	In contrast, the bax and cleaved caspase-3 expression levels were increased in the si-GALE group (Figure 4F and G).	('nt', 'Chemical', 'MESH:D009711', (5, 7))	('increased', 'PosReg', (66, 75))	('bax', 'Gene', '581', (17, 20))	('cleaved caspase-3 expression levels', 'MPA', (25, 60))	('si-GALE', 'Var', (83, 90))	('bax', 'Gene', (17, 20))
80648	31908526	In summary, these results suggest that the absence of GALE inhibits the progression of the glioma cell cycle and induces the apoptosis of glioma cells.	('induces', 'Reg', (113, 120))	('glioma', 'Disease', (138, 144))	('inhibits', 'NegReg', (59, 67))	('absence', 'Var', (43, 50))	('glioma', 'Disease', (91, 97))	('GALE', 'Gene', (54, 58))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('apoptosis', 'CPA', (125, 134))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
80669	31908526	These results suggest that GALE knockdown results in the reduced growth and invasion of glioma cells in the body.	('growth', 'CPA', (65, 71))	('glioma', 'Disease', (88, 94))	('knockdown', 'Var', (32, 41))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('reduced', 'NegReg', (57, 64))	('GALE', 'Gene', (27, 31))
80671	31908526	Here, we studied the function of GALE, a gene that is highly expressed in GBM compared to LGG, and high GALE expression was associated with a poor prognosis in glioma patients.	('GALE', 'Gene', (104, 108))	('expression', 'MPA', (109, 119))	('glioma', 'Disease', (160, 166))	('patients', 'Species', '9606', (167, 175))	('high', 'Var', (99, 103))	('associated', 'Reg', (124, 134))	('GBM', 'Disease', (74, 77))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('GBM', 'Disease', 'MESH:D005909', (74, 77))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
80673	31908526	Many genetic changes lead to uncontrolled growth through the maladjustment of proteins directly involved in cell cycle progression and apoptosis.	('changes', 'Var', (13, 20))	('maladjustment', 'Var', (61, 74))	('lead to', 'Reg', (21, 28))	('nt', 'Chemical', 'MESH:D009711', (72, 74))	('proteins', 'Protein', (78, 86))	('uncontrolled growth', 'MPA', (29, 48))	('genetic changes', 'Var', (5, 20))	('nt', 'Chemical', 'MESH:D009711', (33, 35))
80675	31908526	Defects in the conversion of UDP-galactose to UDP-glucose have been reported to result in common characteristics of galactosemia, including vomiting, hypotension, epileptic seizures, jaundice, galactosuria, and hepatomegaly.	('seizures', 'Phenotype', 'HP:0001250', (173, 181))	('result', 'Reg', (80, 86))	('vomiting', 'Disease', 'MESH:D014839', (140, 148))	('hypotension', 'Disease', (150, 161))	('jaundice, galactosuria', 'Disease', 'MESH:D007565', (183, 205))	('galactosemia', 'Phenotype', 'HP:0012024', (116, 128))	('jaundice', 'Phenotype', 'HP:0000952', (183, 191))	('galactosemia', 'Disease', (116, 128))	('galactosuria', 'Phenotype', 'HP:0012023', (193, 205))	('vomiting', 'Phenotype', 'HP:0002013', (140, 148))	('UDP-glucose', 'Chemical', 'MESH:D014532', (46, 57))	('hypotension', 'Disease', 'MESH:D007022', (150, 161))	('hepatomegaly', 'Disease', (211, 223))	('Defects', 'Var', (0, 7))	('vomiting', 'Disease', (140, 148))	('epileptic seizures', 'Disease', (163, 181))	('UDP-galactose', 'Chemical', 'MESH:D014531', (29, 42))	('hypotension', 'Phenotype', 'HP:0002615', (150, 161))	('hepatomegaly', 'Disease', 'MESH:D006529', (211, 223))	('galactosemia', 'Disease', 'MESH:D005693', (116, 128))	('hepatomegaly', 'Phenotype', 'HP:0002240', (211, 223))	('epileptic seizures', 'Disease', 'MESH:D004827', (163, 181))
80677	31908526	GALE gene knockout reduced cell proliferation and migration in vitro and in vivo, induced G1 cell cycle arrest, promoted cell apoptosis, and reduced the growth of in situ xenotransplantation.	('GALE', 'Gene', (0, 4))	('reduced', 'NegReg', (141, 148))	('cell proliferation', 'CPA', (27, 45))	('promoted', 'PosReg', (112, 120))	('induced', 'Reg', (82, 89))	('G1 cell cycle arrest', 'CPA', (90, 110))	('knockout', 'Var', (10, 18))	('nt', 'Chemical', 'MESH:D009711', (183, 185))	('reduced', 'NegReg', (19, 26))	('growth of in situ xenotransplantation', 'CPA', (153, 190))	('cell apoptosis', 'CPA', (121, 135))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))
80689	31908526	Moreover, the tumor suppressors bax and p53 were induced after GALE knockdown.	('tumor', 'Disease', (14, 19))	('induced', 'PosReg', (49, 56))	('p53', 'Gene', (40, 43))	('bax', 'Gene', (32, 35))	('knockdown', 'Var', (68, 77))	('p53', 'Gene', '7157', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('bax', 'Gene', '581', (32, 35))
80702	31062529	von Willebrand Factor Gene Expression in Primary Lower Grade Glioma: Mutually Co-Occurring Mutations in von Willebrand Factor, ATRX, and TP53 Venous thromboembolism is a common complication in patients with glioma.	('Glioma', 'Phenotype', 'HP:0009733', (61, 67))	('patients', 'Species', '9606', (193, 201))	('ATRX', 'Gene', (127, 131))	('Glioma', 'Disease', 'MESH:D005910', (61, 67))	('thromboembolism', 'Phenotype', 'HP:0001907', (149, 164))	('Glioma', 'Disease', (61, 67))	('glioma', 'Disease', (207, 213))	('von Willebrand Factor', 'Gene', (0, 21))	('ATRX', 'Gene', '546', (127, 131))	('von Willebrand Factor', 'Gene', '7450', (0, 21))	('Mutations', 'Var', (91, 100))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('Venous thromboembolism', 'Disease', 'MESH:D054556', (142, 164))	('von Willebrand Factor', 'Gene', (104, 125))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('Venous thromboembolism', 'Disease', (142, 164))	('von Willebrand Factor', 'Gene', '7450', (104, 125))	('TP53', 'Gene', (137, 141))
80708	31062529	When we analyzed the data with Cox regression, VWF expression had a significant effect on survival (p=0.02) that was unrelated to the effect of IDH1 expression (p=0.062), TP53 expression (p=0.135), independent of ATRX expression (p=0.021) and histology (astrocytoma versus oligoastrocytoma and oligodendroglioma, p=0.002).	('TP53', 'Gene', (171, 175))	('VWF', 'Gene', (47, 50))	('Cox', 'Gene', '1351', (31, 34))	('ATRX', 'Gene', (213, 217))	('TP53', 'Gene', '7157', (171, 175))	('astrocytoma', 'Phenotype', 'HP:0009592', (254, 265))	('Cox', 'Gene', (31, 34))	('astrocytoma versus oligoastrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (254, 311))	('astrocytoma', 'Phenotype', 'HP:0009592', (278, 289))	('IDH1', 'Gene', (144, 148))	('survival', 'Disease', (90, 98))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))	('expression', 'Var', (51, 61))	('IDH1', 'Gene', '3417', (144, 148))	('ATRX', 'Gene', '546', (213, 217))
80709	31062529	VWF mutations significantly co-occur with mutations in TP53 and ATRX (p<0.001).	('ATRX', 'Gene', (64, 68))	('ATRX', 'Gene', '546', (64, 68))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('VWF', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('mutations', 'Var', (42, 51))
80710	31062529	The deleterious prognostic effect of VWF expression and its co-occurrent mutations with TP53 and ATRX in lower grade gliomas are not surprising, given VWF's role in other cancers.	('ATRX', 'Gene', '546', (97, 101))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('TP53', 'Gene', '7157', (88, 92))	('ATRX', 'Gene', (97, 101))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TP53', 'Gene', (88, 92))	('mutations', 'Var', (73, 82))	('VWF', 'Gene', (37, 40))
80734	31062529	VWF was most often mutated and amplified in diffuse gliomas (grade II gliomas, also known as diffuse low-grade glioma) (Fig.	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('gliomas', 'Disease', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('II gliomas', 'Disease', (67, 77))	('glioma', 'Disease', (111, 117))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('VWF', 'Gene', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('mutated', 'Var', (19, 26))	('gliomas', 'Disease', (70, 77))	('glioma', 'Disease', (70, 76))	('amplified', 'Var', (31, 40))	('II gliomas', 'Disease', 'MESH:D005910', (67, 77))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma', 'Disease', (52, 58))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
80737	31062529	Note that in the 2016 CNS WHO classifications, oligodendrogliomas must carry both an isocitrate dehydrogenase (IDH) mutation and a 1p/19q codeletion.	('mutation', 'Var', (116, 124))	('oligodendrogliomas', 'Disease', (47, 65))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (47, 65))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH', 'Gene', (111, 114))	('isocitrate dehydrogenase', 'Gene', (85, 109))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('IDH', 'Gene', '3417', (111, 114))	('isocitrate dehydrogenase', 'Gene', '3417', (85, 109))
80739	31062529	IDH1, TP53 and ATRX mutations are present in 40% or more adult lower grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('TP53', 'Gene', '7157', (6, 10))	('ATRX', 'Gene', '546', (15, 19))	('TP53', 'Gene', (6, 10))	('present', 'Reg', (34, 41))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('ATRX', 'Gene', (15, 19))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (20, 29))	('IDH1', 'Gene', '3417', (0, 4))
80741	31062529	VWF mutations significantly co-occur with mutations in TP53 and ATRX (p<0.001) (Table 3, Fig.	('ATRX', 'Gene', (64, 68))	('ATRX', 'Gene', '546', (64, 68))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('VWF', 'Gene', (0, 3))	('co-occur', 'Reg', (28, 36))	('mutations', 'Var', (4, 13))	('mutations', 'Var', (42, 51))
80747	31062529	IDH1 versus VWF mRNA expression by mutation status is shown in Fig.	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (35, 43))	('IDH1', 'Gene', '3417', (0, 4))
80754	31062529	Recently, tumor genome has proven to be a prognostic factor, as well as F13A1 copy number segments.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('copy number segments', 'Var', (78, 98))	('F13A1', 'Gene', '2162', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('F13A1', 'Gene', (72, 77))
80757	31062529	Recent findings suggest that genetic pathways within tumor cells might trigger thrombotic phenomena, worsening prognosis.	('trigger', 'Reg', (71, 78))	('thrombotic phenomena', 'Phenotype', 'HP:0001907', (79, 99))	('thrombotic', 'Disease', 'MESH:D013927', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('worsening', 'Reg', (101, 110))	('prognosis', 'MPA', (111, 120))	('thrombotic', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('genetic pathways', 'Var', (29, 45))
80760	31062529	Mutations of certain cancer genes tend to co-occur, indicating that they may work in tandem to drive tumor formation and development.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('drive', 'PosReg', (95, 100))	('tumor', 'Disease', (101, 106))	('Mutations', 'Var', (0, 9))	('development', 'CPA', (121, 132))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
80761	31062529	This appears to be the case with the co-occurring VWF, ATRX, and TP53 mutations.	('VWF', 'Disease', (50, 53))	('TP53', 'Gene', '7157', (65, 69))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', (65, 69))	('ATRX', 'Gene', (55, 59))	('ATRX', 'Gene', '546', (55, 59))
80762	31062529	The deleterious prognostic effect of VWF expression in lower grade gliomas is not surprising, given its role in other cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('gliomas', 'Disease', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Var', (41, 51))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('VWF', 'Gene', (37, 40))
80764	31062529	An analysis of lower grade glioma in TCGA has shown IDH, 1p/19q, and TP53 status to be more indicative of prognosis than histologic class.	('glioma', 'Disease', (27, 33))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('1p/19q', 'Var', (57, 63))
80765	31062529	Moreover, lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation.	('IDH', 'Gene', (38, 41))	('1p/19q codeletion', 'Var', (62, 79))	('gliomas', 'Disease', (22, 29))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('IDH', 'Gene', '3417', (38, 41))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('mutation', 'Var', (42, 50))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))
80775	29730475	In functional assays performed with RNA knockdown, loss of STEAP3 attenuated aggressive phenotypes in glioma cells, including cell proliferation, invasion, and sphere formation in vitro and tumor growth in vivo.	('STEAP3', 'Gene', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('loss', 'Var', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('cell proliferation', 'CPA', (126, 144))	('attenuated', 'NegReg', (66, 76))	('sphere formation', 'CPA', (160, 176))	('si', 'Chemical', 'MESH:D012825', (150, 152))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('glioma', 'Disease', (102, 108))	('aggressive phenotypes', 'CPA', (77, 98))	('invasion', 'CPA', (146, 154))
80784	29730475	It is indispensable for the synthesis/function of proteins or enzymes that regulate respiratory complexes, DNA, hemesynthesis, mitosis, and epigenetic modifications, all of which are abnormal in cancer.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('cancer', 'Disease', (195, 201))	('epigenetic modifications', 'Var', (140, 164))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('mitosis', 'Disease', (127, 134))	('mitosis', 'Disease', 'None', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
80789	29730475	Fe3+ binds to transferrin in order to form holo-transferrin, which can then be taken up by TfR located on the cell membrane.	('transferrin', 'Gene', '7018', (14, 25))	('transferrin', 'Gene', (14, 25))	('TfR', 'Gene', (91, 94))	('transferrin', 'Gene', '7018', (48, 59))	('Fe3+', 'Chemical', '-', (0, 4))	('transferrin', 'Gene', (48, 59))	('TfR', 'Gene', '7037', (91, 94))	('Fe3+', 'Var', (0, 4))
80882	29730475	STEAP3 was also found to be negatively correlated with OS in IDH wild-type LGG (P < .05; Supplementary Figure S2B).	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))	('STEAP3', 'Var', (0, 6))	('negatively', 'NegReg', (28, 38))
80887	29730475	GO analysis indicated that STEAP3 was strongly associated with several biological processes, including cell adhesion, promotion of cell proliferation, extracellular matrix organization, proteolysis, and regulation of the immune response (Figure 2E).	('extracellular matrix organization', 'CPA', (151, 184))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('proteolysis', 'MPA', (186, 197))	('cell adhesion', 'CPA', (103, 116))	('promotion', 'PosReg', (118, 127))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('si', 'Chemical', 'MESH:D012825', (194, 196))	('STEAP3', 'Var', (27, 33))	('cell proliferation', 'CPA', (131, 149))	('associated', 'Reg', (47, 57))
80891	29730475	Knockdown with si-STEAP3 significantly reduced cell growth in both GBM#01 and GBM#P3 GSC compared to the si-Ctrl group (P < .001, si-Ctrl vs si-STEAP3, respectively; Figure 3B).	('si-STEAP3', 'Var', (15, 24))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('cell growth', 'CPA', (47, 58))	('reduced', 'NegReg', (39, 46))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
80892	29730475	To investigate whether loss of STEAP3 influences stem cell-associated properties, we performed tumor sphere formation and extreme limiting dilution assays (ELDA) with GBM#01- and GBM#P3-si-STEAP3 GSCs.	('tumor', 'Disease', (95, 100))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('GBM', 'Var', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('loss', 'Var', (23, 27))	('si', 'Chemical', 'MESH:D012825', (186, 188))
80896	29730475	Classical and mesenchymal subtypes are associated with poorer survival outcomes relative to proneural and neural subtypes which are often IDH1/2 mutated.	('mutated', 'Var', (145, 152))	('poorer', 'NegReg', (55, 61))	('IDH1/2', 'Gene', '3417;3418', (138, 144))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('IDH1/2', 'Gene', (138, 144))
80907	29730475	Because high STEAP3 expression was associated with the GBM mesenchymal molecular subtype, we explored whether molecular markers involved in the mesenchymal transition were correspondingly regulated.	('high', 'Var', (8, 12))	('GBM', 'Disease', (55, 58))	('expression', 'MPA', (20, 30))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('associated', 'Reg', (35, 45))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('STEAP3', 'Gene', (13, 19))
80908	29730475	Western blot analysis revealed that knockdown of STEAP3 led to decreased expression of molecular markers of the mesenchymal transition, such as CDH2, Snail, Slug, and matrix metalloproteinase-2 (MMP-2).	('si', 'Chemical', 'MESH:D012825', (79, 81))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('MMP-2', 'Gene', (195, 200))	('STEAP3', 'Gene', (49, 55))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('Slug', 'Gene', (157, 161))	('decreased', 'NegReg', (63, 72))	('matrix metalloproteinase-2', 'Gene', (167, 193))	('matrix metalloproteinase-2', 'Gene', '4313', (167, 193))	('knockdown', 'Var', (36, 45))	('expression', 'MPA', (73, 83))	('CDH2', 'Gene', (144, 148))	('MMP-2', 'Gene', '4313', (195, 200))	('CDH2', 'Gene', '1000', (144, 148))	('Slug', 'Gene', '6591', (157, 161))
80910	29730475	Altogether, our findings indicated that STEAP3 might promote invasion of human glioma cells by inducing the mesenchymal transition.	('glioma', 'Disease', (79, 85))	('STEAP3', 'Var', (40, 46))	('mesenchymal transition', 'CPA', (108, 130))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('invasion', 'CPA', (61, 69))	('human', 'Species', '9606', (73, 78))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('inducing', 'Reg', (95, 103))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('promote', 'PosReg', (53, 60))
80918	29730475	We also found TfR to be one of the top five proteins (annexin.1, p62.LCK.ligand, PAI.1, stathmin, TfR) with increased expression in STEAP3high GBM patients compared to STEAP3low GBM patients based on TCGA RPPA data (P < .0001; Figure 6B, supplementary Table S5).	('PAI.1', 'Gene', '5054', (81, 86))	('annexin.1', 'Gene', (54, 63))	('LCK', 'Gene', (69, 72))	('patients', 'Species', '9606', (182, 190))	('TfR', 'Gene', (14, 17))	('PAI.1', 'Gene', (81, 86))	('increased', 'PosReg', (108, 117))	('GBM', 'Phenotype', 'HP:0012174', (178, 181))	('stathmin', 'Gene', (88, 96))	('patients', 'Species', '9606', (147, 155))	('stathmin', 'Gene', '3925', (88, 96))	('TfR', 'Gene', '7037', (14, 17))	('TfR', 'Gene', (98, 101))	('LCK', 'Gene', '3932', (69, 72))	('STEAP3high', 'Var', (132, 142))	('expression', 'MPA', (118, 128))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('p62', 'Gene', '8878', (65, 68))	('GBM', 'Phenotype', 'HP:0012174', (143, 146))	('p62', 'Gene', (65, 68))	('annexin.1', 'Gene', '301', (54, 63))	('TfR', 'Gene', '7037', (98, 101))
80925	29730475	Second, siRNA knockdown of STEAP3 led to decreased expression of TfR and Ferritin in GBM#P3 GSCs (Figure 6E; Supplementary Figure S7).	('Ferritin', 'Protein', (73, 81))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('TfR', 'Gene', '7037', (65, 68))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('decreased', 'NegReg', (41, 50))	('expression', 'MPA', (51, 61))	('knockdown', 'Var', (14, 23))	('TfR', 'Gene', (65, 68))	('STEAP3', 'Gene', (27, 33))
80926	29730475	Third, a previous study reported that depleting Ferritin disrupted mitotic progression in cancer stem cells through the STAT3-FoxM1 regulatory axis.	('Ferritin', 'Protein', (48, 56))	('depleting', 'Var', (38, 47))	('disrupted', 'NegReg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('FoxM1', 'Gene', '2305', (126, 131))	('FoxM1', 'Gene', (126, 131))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('STAT3', 'Gene', '6774', (120, 125))	('STAT3', 'Gene', (120, 125))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('mitotic progression', 'CPA', (67, 86))
80927	29730475	We therefore investigated whether STEAP3 knockdown influenced protein levels of STAT3 and FoxM1.	('investigated', 'Reg', (13, 25))	('FoxM1', 'Gene', (90, 95))	('knockdown', 'Var', (41, 50))	('STAT3', 'Gene', '6774', (80, 85))	('STAT3', 'Gene', (80, 85))	('STEAP3', 'Gene', (34, 40))	('FoxM1', 'Gene', '2305', (90, 95))	('protein levels', 'MPA', (62, 76))	('influenced', 'Reg', (51, 61))
80928	29730475	STEAP3 siRNA knockdown led to decreased FoxM1 and phosphorylated STAT3, as well as total STAT3 protein levels (Figure 6E).	('STEAP3', 'Gene', (0, 6))	('FoxM1', 'Gene', '2305', (40, 45))	('FoxM1', 'Gene', (40, 45))	('STAT3', 'Gene', '6774', (89, 94))	('STAT3', 'Gene', '6774', (65, 70))	('knockdown', 'Var', (13, 22))	('si', 'Chemical', 'MESH:D012825', (7, 9))	('STAT3', 'Gene', (89, 94))	('STAT3', 'Gene', (65, 70))	('decreased', 'NegReg', (30, 39))
80929	29730475	Finally, we used siRNA knockdown of TfR to characterize its functional relationship with STEAP3.	('TfR', 'Gene', '7037', (36, 39))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('knockdown', 'Var', (23, 32))	('TfR', 'Gene', (36, 39))
80930	29730475	Si-RNA-induced knockdown of TfR significantly abrogated STEAP3 induced cell proliferation and invasion in GBM#01-STEAP3 GSCs (Figure 6, F and G, Supplementary Figure S8).	('invasion', 'CPA', (94, 102))	('STEAP3', 'Gene', (56, 62))	('TfR', 'Gene', '7037', (28, 31))	('knockdown', 'Var', (15, 24))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('abrogated', 'NegReg', (46, 55))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('TfR', 'Gene', (28, 31))	('cell proliferation', 'CPA', (71, 89))
80931	29730475	These results indicated that STEAP3 might contribute to cancer progression by activating TfR and the downstream Ferritin-STAT3 pathway.	('STAT3', 'Gene', '6774', (121, 126))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('activating', 'PosReg', (78, 88))	('STAT3', 'Gene', (121, 126))	('TfR', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('contribute', 'Reg', (42, 52))	('TfR', 'Gene', '7037', (89, 92))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('STEAP3', 'Var', (29, 35))
80934	29730475	Here, we found that STEAP3, an enzyme involved in iron metabolism, was one of the top three genes with increased expression in GBM compared to LGG, correlated with poor clinical prognosis.	('si', 'Chemical', 'MESH:D012825', (184, 186))	('expression', 'MPA', (113, 123))	('increased', 'PosReg', (103, 112))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('GBM', 'Var', (127, 130))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('iron', 'Chemical', 'MESH:D007501', (50, 54))	('STEAP3', 'Gene', (20, 26))
80935	29730475	Silencing STEAP3 in glioma cell cultures attenuated many biological processes associated with cancer development, including tumor growth and invasion, as well as mesenchymal transition.	('invasion', 'CPA', (141, 149))	('si', 'Chemical', 'MESH:D012825', (145, 147))	('attenuated', 'NegReg', (41, 51))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('mesenchymal transition', 'CPA', (162, 184))	('tumor', 'Disease', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('cancer', 'Disease', (94, 100))	('glioma', 'Disease', (20, 26))	('Silencing', 'Var', (0, 9))	('STEAP3', 'Gene', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
80936	29730475	Furthermore, stem cell-like properties, such as tumor sphere formation and expression of stem cell markers, were also inhibited in human glioma cells transfected with si-STEAP3.	('inhibited', 'NegReg', (118, 127))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('si-STEAP3', 'Var', (167, 176))	('stem cell-like properties', 'CPA', (13, 38))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('human', 'Species', '9606', (131, 136))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('glioma', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('expression', 'MPA', (75, 85))
80952	29730475	Finally, we demonstrated that STEAP3 activates the TfR-STAT3 pathway in GBM, and that knockdown of TfR significantly influences the impact of STEAP3 overexpression on malignant phenotypes in GSC.	('si', 'Chemical', 'MESH:D012825', (159, 161))	('knockdown', 'Var', (86, 95))	('STAT3', 'Gene', (55, 60))	('TfR', 'Gene', '7037', (51, 54))	('TfR', 'Gene', (99, 102))	('influences', 'Reg', (117, 127))	('GSC', 'Disease', (191, 194))	('activates', 'PosReg', (37, 46))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('TfR', 'Gene', '7037', (99, 102))	('TfR', 'Gene', (51, 54))	('STAT3', 'Gene', '6774', (55, 60))
80959	29730475	These results suggest that STEAP3 might contribute to cancer progression through interaction with TfR and regulation of downstream Ferritin-FoxM1-STAT3 signaling.	('si', 'Chemical', 'MESH:D012825', (152, 154))	('contribute', 'Reg', (40, 50))	('STAT3', 'Gene', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('FoxM1', 'Gene', '2305', (140, 145))	('TfR', 'Gene', (98, 101))	('FoxM1', 'Gene', (140, 145))	('cancer', 'Disease', (54, 60))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('STEAP3', 'Var', (27, 33))	('TfR', 'Gene', '7037', (98, 101))	('STAT3', 'Gene', '6774', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('interaction', 'Interaction', (81, 92))
80966	29730475	In our study, we found that STEAP3 not only promotes malignant progression of human glioma but is also a prognostic marker of glioma patients.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('promotes', 'PosReg', (44, 52))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('malignant progression', 'CPA', (53, 74))	('glioma', 'Disease', (84, 90))	('patients', 'Species', '9606', (133, 141))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('STEAP3', 'Var', (28, 34))	('glioma', 'Disease', (126, 132))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('human', 'Species', '9606', (78, 83))
80970	29730475	conceived and designed the experiments; M.H, R.X., Y.X., C.Z., Y.W., X.Z.	('Y.X.', 'Var', (51, 55))	('Y.W.', 'Var', (63, 67))	('R.X.', 'Var', (45, 49))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('M.H', 'Var', (40, 43))	('C.Z.', 'Var', (57, 61))
80972	29619216	Mutant IDH1 gliomas downregulate phosphocholine and phosphoethanolamine synthesis in a 2-hydroxyglutarate-dependent manner Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer.	('gliomas', 'Disease', (12, 19))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (52, 71))	('phosphocholine', 'Chemical', 'MESH:D010767', (33, 47))	('PE', 'Chemical', 'MESH:C005448', (276, 278))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('downregulate', 'NegReg', (20, 32))	('phosphocholine', 'Chemical', 'MESH:D010767', (231, 245))	('elevated', 'PosReg', (185, 193))	('PC', 'Chemical', 'MESH:D010767', (247, 249))	('metabolic hallmarks of cancer', 'Disease', (283, 312))	('IDH1', 'Gene', (7, 11))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (255, 274))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (87, 105))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('Mutant', 'Var', (0, 6))	('metabolic hallmarks of cancer', 'Disease', 'MESH:D009369', (283, 312))	('IDH1', 'Gene', '3417', (7, 11))	('phospholipid', 'Chemical', 'MESH:D010743', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))
80973	29619216	Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH', 'Gene', (183, 186))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('isocitrate dehydrogenase 1', 'Gene', (59, 85))	('isocitrate dehydrogenase 1', 'Gene', '3417', (59, 85))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('reduced', 'NegReg', (41, 48))	('IDH1', 'Gene', '3417', (183, 187))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (183, 186))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('PE', 'Chemical', 'MESH:C005448', (27, 29))	('IDH', 'Gene', (189, 192))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (135, 153))	('gliomas', 'Disease', (95, 102))	('IDH', 'Gene', '3417', (87, 90))	('mutant', 'Var', (52, 58))	('IDH', 'Gene', '3417', (189, 192))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('PC', 'Chemical', 'MESH:D010767', (20, 22))	('gliomas', 'Disease', (196, 203))	('IDH1', 'Gene', (183, 187))
80982	29619216	Pharmacological manipulation of 2-HG levels established that 2-HG was responsible for reduced CK activity, EK activity, PC and PE.	('EK', 'Gene', '1119', (107, 109))	('reduced', 'NegReg', (86, 93))	('PC', 'Chemical', 'MESH:D010767', (120, 122))	('2-HG', 'Var', (61, 65))	('PE', 'Chemical', 'MESH:C005448', (127, 129))
80984	29619216	Silencing HIF-1alpha in IDHmut cells restored CK activity, EK activity, PC and PE to IDHwt levels.	('PC', 'Chemical', 'MESH:D010767', (72, 74))	('IDH', 'Gene', '3417', (85, 88))	('PE', 'Chemical', 'MESH:C005448', (79, 81))	('IDH', 'Gene', (24, 27))	('activity', 'MPA', (62, 70))	('HIF-1alpha', 'Gene', (10, 20))	('Silencing', 'Var', (0, 9))	('HIF-1alpha', 'Gene', '3091', (10, 20))	('restored', 'PosReg', (37, 45))	('IDH', 'Gene', '3417', (24, 27))	('IDH', 'Gene', (85, 88))	('CK activity', 'MPA', (46, 57))	('EK', 'Gene', '1119', (59, 61))
80988	29619216	Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas and secondary upgraded glioblastomas.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('glioblastomas', 'Disease', (110, 123))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('isocitrate dehydrogenase 1', 'Gene', '3417', (13, 39))	('Mutations', 'Var', (0, 9))	('isocitrate dehydrogenase 1', 'Gene', (13, 39))	('IDH1', 'Gene', (41, 45))	('glioblastomas', 'Phenotype', 'HP:0012174', (110, 123))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('IDH1', 'Gene', '3417', (41, 45))	('glioblastomas', 'Disease', 'MESH:D005909', (110, 123))
80989	29619216	The wild-type IDH1 (IDHwt) enzyme converts isocitrate to alpha-ketoglutarate (alpha-KG), while the mutant IDH1 (IDHmut) enzyme converts alpha-KG to the oncometabolite 2-hydroxyglutarate (2-HG).	('IDH', 'Gene', '3417', (20, 23))	('IDH', 'Gene', (112, 115))	('IDH1', 'Gene', '3417', (106, 110))	('IDH', 'Gene', '3417', (106, 109))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (167, 185))	('IDH1', 'Gene', (14, 18))	('IDH', 'Gene', '3417', (112, 115))	('IDH', 'Gene', (14, 17))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (57, 76))	('alpha-KG', 'Chemical', 'MESH:D007656', (136, 144))	('IDH1', 'Gene', '3417', (14, 18))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (14, 17))	('alpha-KG', 'Chemical', 'MESH:D007656', (78, 86))	('IDH1', 'Gene', (106, 110))	('isocitrate', 'MPA', (43, 53))	('isocitrate', 'Chemical', 'MESH:C034219', (43, 53))	('mutant', 'Var', (99, 105))	('IDH', 'Gene', (106, 109))
80991	29619216	The IDH1 mutation also induces metabolic reprogramming that often differs from that observed in IDHwt gliomas.	('induces', 'Reg', (23, 30))	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (96, 109))	('IDHwt gliomas', 'Disease', (96, 109))	('IDH1', 'Gene', (4, 8))	('metabolic reprogramming', 'CPA', (31, 54))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))
81011	29619216	The generation and characterization of U87 and NHA cells expressing IDHwt (U87IDHwt and NHAIDHwt) or IDH1 R132H mutant enzyme (U87IDHmut and NHAIDHmut) have been previously described.	('IDH', 'Gene', '3417', (68, 71))	('R132H mutant', 'Var', (106, 118))	('U87', 'Gene', '641648', (39, 42))	('IDH', 'Gene', (144, 147))	('IDH', 'Gene', '3417', (130, 133))	('U87', 'Gene', (127, 130))	('IDH', 'Gene', (78, 81))	('U87', 'Gene', '641648', (75, 78))	('IDH1', 'Gene', (101, 105))	('IDH', 'Gene', '3417', (144, 147))	('U87', 'Gene', (39, 42))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', (91, 94))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3417', (78, 81))	('IDH1', 'Gene', '3417', (101, 105))	('U87', 'Gene', (75, 78))	('U87', 'Gene', '641648', (127, 130))	('IDH', 'Gene', '3417', (101, 104))	('IDH', 'Gene', (130, 133))	('IDH', 'Gene', '3417', (91, 94))	('R132H', 'Mutation', 'rs121913500', (106, 111))
81020	29619216	SMARTpool siRNA (Dharmacon, GE) against human HIF-1alpha (M-004018-05) and non-targeting siRNA pool #2 (D-001206-14-05) were transfected according to manufacturer's instructions.	('HIF-1alpha', 'Gene', '3091', (46, 56))	('human', 'Species', '9606', (40, 45))	('M-004018-05', 'Var', (58, 69))	('HIF-1alpha', 'Gene', (46, 56))
81045	29619216	When the tumors reached ~ 100 mm3, the animals were sacrificed and tumor tissue snap frozen for metabolic and biochemical analysis (n = 5 for U87IDHwt, n = 7 for U87IDHmut).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (9, 14))	('U87IDHwt', 'Var', (142, 150))	('tumor', 'Disease', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('U87IDHmut', 'Var', (162, 171))
81061	29619216	We also confirmed that steady-state PC pool sizes as determined by 31P-MRS matched the values previously determined by 1H-MRS in both our NHA and U87 models (Additional file 1: Figure S1C-D).	('1H', 'Chemical', '-', (119, 121))	('U87', 'Gene', (146, 149))	('U87', 'Gene', '641648', (146, 149))	('31P', 'Chemical', '-', (67, 70))	('PC', 'Chemical', 'MESH:D010767', (36, 38))	('31P-MRS', 'Var', (67, 74))	('PC pool', 'MPA', (36, 43))
81067	29619216	Similarly, the pseudo-first-order rate constant for EK decreased significantly by 50% from 0.06 +- 0.005 h-1 to 0.03 +- 0.004 h-1 in the NHA model and by 40% from 0.08 +- 0.005 h-1 to 0.05 +- 0.003 h-1 in the U87 model.	('EK', 'Gene', '1119', (52, 54))	('0.03', 'Var', (112, 116))	('0.06 +- 0.005', 'Var', (91, 104))	('pseudo-first-order', 'MPA', (15, 33))	('U87', 'Gene', (209, 212))	('decreased', 'NegReg', (55, 64))	('U87', 'Gene', '641648', (209, 212))
81079	29619216	In an effort to link our results to the IDH1 mutation, we pharmacologically manipulated the presence of 2-HG and examined choline and ethanolamine metabolism in IDHwt cells incubated with 2-HG or in IDHmut cells treated with the IDHmut enzyme inhibitor AGI-5198.	('IDH', 'Gene', '3417', (161, 164))	('examined', 'Reg', (113, 121))	('choline', 'Chemical', 'MESH:D002794', (122, 129))	('IDH', 'Gene', '3417', (199, 202))	('IDH1', 'Gene', (40, 44))	('ethanolamine', 'Chemical', 'MESH:D019856', (134, 146))	('IDH1', 'Gene', '3417', (40, 44))	('IDH', 'Gene', (229, 232))	('IDH', 'Gene', (40, 43))	('mutation', 'Var', (45, 53))	('IDH', 'Gene', '3417', (229, 232))	('IDH', 'Gene', '3417', (40, 43))	('IDH', 'Gene', (161, 164))	('IDH', 'Gene', (199, 202))
81083	29619216	Concomitantly, CKalpha expression, CK activity, and EK activity were reduced in a manner linked to the presence of 2-HG in both NHA (Fig.	('presence', 'Var', (103, 111))	('activity', 'MPA', (55, 63))	('EK', 'Gene', '1119', (52, 54))	('reduced', 'NegReg', (69, 76))	('CKalpha expression', 'MPA', (15, 33))
81093	29619216	Silencing HIF-1alpha did not alter PC, PE, CKalpha expression, CK activity, or EK activity in IDHwt cells in both NHA (Fig.	('CKalpha', 'Enzyme', (43, 50))	('EK', 'Gene', '1119', (79, 81))	('IDH', 'Gene', (94, 97))	('HIF-1alpha', 'Gene', (10, 20))	('activity', 'MPA', (66, 74))	('HIF-1alpha', 'Gene', '3091', (10, 20))	('PE', 'Chemical', 'MESH:C005448', (39, 41))	('IDH', 'Gene', '3417', (94, 97))	('Silencing', 'Var', (0, 9))	('PC', 'Chemical', 'MESH:D010767', (35, 37))
81095	29619216	In contrast, HIF-1alpha silencing restored PC, PE, CKalpha expression, CK activity, and EK activity to levels similar to those observed in IDHwt cells in both NHA (Fig.	('restored', 'PosReg', (34, 42))	('PC', 'Chemical', 'MESH:D010767', (43, 45))	('HIF-1alpha', 'Gene', '3091', (13, 23))	('activity', 'MPA', (91, 99))	('EK', 'Gene', '1119', (88, 90))	('silencing', 'Var', (24, 33))	('IDH', 'Gene', (139, 142))	('CKalpha expression', 'MPA', (51, 69))	('IDH', 'Gene', '3417', (139, 142))	('PE', 'Chemical', 'MESH:C005448', (47, 49))	('HIF-1alpha', 'Gene', (13, 23))	('CK activity', 'MPA', (71, 82))
81099	29619216	Finally, 2-HG can alter gene expression in glioma cells via DNA hypermethylation.	('glioma', 'Disease', (43, 49))	('DNA', 'Var', (60, 63))	('alter', 'Reg', (18, 23))	('gene expression', 'MPA', (24, 39))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
81101	29619216	There was no significant difference in the Deltabeta value (difference in % methylation between IDHmut and IDHwt cells) of these genes in our NHA (Deltabeta = 0.02, p = 0.4, probe cg27431247 for CHKA, Deltabeta = 0.01, p = 0.5, probe cg25881344 for ETNK1, and Deltabeta = 0.03, p = 0.2, probe cg08114257 for ETNK2) or U87 (Deltabeta = 0.04, p = 0.1, probe cg27431247 for CHKA, Deltabeta = 0.03, p = 0.3, probe cg25881344 for ETNK1, and Deltabeta = 0.01, p = 0.2, probe cg08114257 for ETNK2) models.	('ETNK1', 'Gene', '55500', (425, 430))	('ETNK2', 'Gene', (484, 489))	('probe cg27431247', 'Var', (350, 366))	('IDH', 'Gene', '3417', (107, 110))	('CHKA', 'Gene', '1119', (371, 375))	('ETNK1', 'Gene', '55500', (249, 254))	('CHKA', 'Gene', (195, 199))	('ETNK2', 'Gene', (308, 313))	('IDH', 'Gene', '3417', (96, 99))	('U87', 'Gene', (318, 321))	('ETNK1', 'Gene', (425, 430))	('CHKA', 'Gene', '1119', (195, 199))	('ETNK1', 'Gene', (249, 254))	('probe cg25881344', 'Var', (404, 420))	('ETNK2', 'Gene', '55224', (484, 489))	('IDH', 'Gene', (107, 110))	('ETNK2', 'Gene', '55224', (308, 313))	('U87', 'Gene', '641648', (318, 321))	('CHKA', 'Gene', (371, 375))	('IDH', 'Gene', (96, 99))
81102	29619216	These results potentially rule out epigenetic effects of 2-HG on CK and EK expression in our models and suggest that the effect of 2-HG on PC and PE levels is primarily mediated by HIF-1alpha.	('2-HG', 'Var', (131, 135))	('EK', 'Gene', '1119', (72, 74))	('PC', 'Chemical', 'MESH:D010767', (139, 141))	('HIF-1alpha', 'Gene', '3091', (181, 191))	('PE', 'Chemical', 'MESH:C005448', (146, 148))	('HIF-1alpha', 'Gene', (181, 191))
81106	29619216	Importantly, silencing HIF-1alpha (Fig.	('HIF-1alpha', 'Gene', '3091', (23, 33))	('HIF-1alpha', 'Gene', (23, 33))	('silencing', 'Var', (13, 22))
81111	29619216	6b, c, PC and PE levels were reduced in U87IDHmut tumors relative to U87IDHwt.	('PE', 'Chemical', 'MESH:C005448', (14, 16))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('U87IDHmut', 'Var', (40, 49))	('reduced', 'NegReg', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PC', 'Chemical', 'MESH:D010767', (7, 9))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
81113	29619216	6f) were reduced in U87IDHmut tumors relative to U87IDHwt.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('reduced', 'NegReg', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('U87IDHmut', 'Var', (20, 29))
81114	29619216	As in the case of our cell models, these metabolic changes were accompanied by higher levels of HIF-1alpha in U87IDHmut tumors relative to U87IDHwt (Fig.	('U87IDHmut', 'Var', (110, 119))	('HIF-1alpha', 'Gene', (96, 106))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('levels', 'MPA', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('HIF-1alpha', 'Gene', '3091', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('higher', 'PosReg', (79, 85))
81167	29619216	Our findings thus expand our understanding of the unique metabolic reprogramming associated with the IDH1 mutation.	('IDH1', 'Gene', (101, 105))	('mutation', 'Var', (106, 114))	('IDH1', 'Gene', '3417', (101, 105))
81168	29619216	2-HG 2-Hydroxyglutarate CK Choline kinase DMEM Dulbecco's modified Eagle's medium EK Ethanolamine kinase GPC Glycerophosphocholine GPE Glycerophosphoethanolamine HIF-1alpha Hypoxia inducible factor-1alpha IDH Isocitrate dehydrogenase IDHmut Mutant isocitrate dehydrogenase 1 IDHwt Wild-type isocitrate dehydrogenase 1 MRS Magnetic resonance spectroscopy NHA Immortalized normal human astrocytes PC Phosphocholine PE Phosphoethanolamine tCho Total choline WHO World Health Organization alpha-KG alpha-Ketoglutarate PV and SMR conceived the research and designed experiments.	('isocitrate dehydrogenase 1', 'Gene', (291, 317))	('choline', 'Chemical', 'MESH:D002794', (405, 412))	('isocitrate dehydrogenase 1', 'Gene', '3417', (291, 317))	('IDH', 'Gene', '3417', (234, 237))	('Glycerophosphocholine', 'Chemical', 'MESH:D005997', (109, 130))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (47, 81))	('Mutant', 'Var', (241, 247))	('Phosphocholine', 'Chemical', 'MESH:D010767', (398, 412))	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (5, 23))	('HIF-1alpha', 'Gene', (162, 172))	('DMEM', 'Chemical', '-', (42, 46))	('PE', 'Chemical', 'MESH:C005448', (132, 134))	('IDH', 'Gene', (205, 208))	('alpha-Ketoglutarate', 'Chemical', 'MESH:D007656', (494, 513))	('alpha-KG', 'Chemical', 'MESH:D007656', (485, 493))	('GPE', 'Chemical', 'MESH:C002449', (131, 134))	('isocitrate dehydrogenase 1', 'Gene', (248, 274))	('isocitrate dehydrogenase 1', 'Gene', '3417', (248, 274))	('PC', 'Chemical', 'MESH:D010767', (106, 108))	('SMR', 'Gene', '147719', (521, 524))	('IDH', 'Gene', (275, 278))	('choline', 'Chemical', 'MESH:D002794', (447, 454))	('choline', 'Chemical', 'MESH:D002794', (123, 130))	('Hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('PC', 'Chemical', 'MESH:D010767', (395, 397))	('IDH', 'Gene', '3417', (205, 208))	('Hypoxia', 'Disease', (173, 180))	('IDH', 'Gene', (234, 237))	('GPC', 'Chemical', 'MESH:D005997', (105, 108))	('human', 'Species', '9606', (378, 383))	('IDH', 'Gene', '3417', (275, 278))	('tCho', 'Chemical', '-', (436, 440))	('PE', 'Chemical', 'MESH:C005448', (413, 415))	('SMR', 'Gene', (521, 524))	('EK', 'Gene', '1119', (82, 84))	('HIF-1alpha', 'Gene', '3091', (162, 172))	('Glycerophosphoethanolamine', 'Chemical', 'MESH:C002449', (135, 161))	('Phosphoethanolamine', 'Chemical', 'MESH:C005448', (416, 435))
81196	33599882	The overall direction of amino acid PET imaging favors the use of 18F-fluoroethyltyrosine (FET) given its additional well characterized properties for both static and dynamic tumor imaging.	('FET', 'Chemical', 'MESH:C545932', (91, 94))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('18F-fluoroethyltyrosine', 'Var', (66, 89))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('18F-fluoroethyltyrosine', 'Chemical', 'MESH:C545932', (66, 89))
81214	33599882	DSC further dissociated between isocitrate dehydrogenase (IDH) wild-type and mutant gliomas and characterized additional molecular and genomic profiles along with textural analysis.	('isocitrate dehydrogenase', 'Gene', (32, 56))	('IDH', 'Gene', '3417', (58, 61))	('isocitrate dehydrogenase', 'Gene', '3417', (32, 56))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('mutant', 'Var', (77, 83))	('IDH', 'Gene', (58, 61))	('dissociated', 'Reg', (12, 23))
81232	33599882	2HG is an oncometabolite that is an important biomarker for glioma with IDH mutations, and it can predict tumor grade, tumor progression and the likelihood of treatment response.	('tumor', 'Disease', (119, 124))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('mutations', 'Var', (76, 85))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('glioma', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('predict', 'Reg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('tumor', 'Disease', (106, 111))
81251	33599882	DWI has been shown to predict prognosis within three weeks of therapy initiation and was also predictive of treatment response to bevacizumab.	('DWI', 'Var', (0, 3))	('prognosis', 'MPA', (30, 39))	('bevacizumab', 'Chemical', 'MESH:D000068258', (130, 141))	('predict', 'Reg', (22, 29))
81264	33599882	In comparison to metallic contrast agents (i.e., gadolinium or iron oxide), CEST does not negatively impact the intrinsic MRI properties of tissues nor induces a tissue toxicity potential.	('CEST', 'Chemical', '-', (76, 80))	('CEST', 'Var', (76, 80))	('intrinsic MRI properties', 'MPA', (112, 136))	('gadolinium', 'Chemical', 'MESH:D005682', (49, 59))	('iron oxide', 'Chemical', 'MESH:C000499', (63, 73))	('induces', 'Reg', (152, 159))	('toxicity', 'Disease', 'MESH:D064420', (169, 177))	('toxicity', 'Disease', (169, 177))
81271	33599882	Finally, amide-CEST MRI has potential for identifying IDH mutation status in low-grade tumors as well as MGMT methylation status in high-grade tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('MGMT', 'Gene', '4255', (105, 109))	('mutation', 'Var', (58, 66))	('MGMT', 'Gene', (105, 109))	('IDH', 'Gene', (54, 57))	('amide-CEST', 'Chemical', '-', (9, 19))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('IDH', 'Gene', '3417', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
81285	33599882	Technique modifications have attempted to offset the difficulty of FDG to delineate tumor borders and overcome nonspecific uptake in other processes such as with inflammation.	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('inflammation', 'Disease', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('nonspecific uptake', 'MPA', (111, 129))	('FDG', 'Chemical', 'MESH:D019788', (67, 70))	('tumor', 'Disease', (84, 89))	('modifications', 'Var', (10, 23))
81292	33599882	Despite the limitations of using FDG in brain tumor detection, hybrid FDG PET/MRI appears to improve diagnosis.	('brain tumor', 'Disease', (40, 51))	('diagnosis', 'MPA', (101, 110))	('brain tumor', 'Disease', 'MESH:D001932', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('FDG', 'Chemical', 'MESH:D019788', (70, 73))	('hybrid', 'Var', (63, 69))	('brain tumor', 'Phenotype', 'HP:0030692', (40, 51))	('FDG', 'Chemical', 'MESH:D019788', (33, 36))	('improve', 'PosReg', (93, 100))
81332	33599882	HSVs generated with amide-CEST in GBM patients were larger than for FET or DSC HSVs.	('GBM', 'Disease', (34, 37))	('amide-CEST', 'Chemical', '-', (20, 30))	('FET', 'Chemical', 'MESH:C545932', (68, 71))	('amide-CEST', 'Var', (20, 30))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('HSVs', 'MPA', (0, 4))	('patients', 'Species', '9606', (38, 46))
81338	33599882	The most important finding was that tumor volumes were significantly larger using FET TBR maps compared to rCBV maps.	('larger', 'PosReg', (69, 75))	('FET TBR', 'Chemical', '-', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('FET', 'Var', (82, 85))	('tumor', 'Disease', (36, 41))
81381	33599882	Either IDH1 or IDH2 mutations are a defining classification for adult gliomas, with vast majority of gliomas as IDH1 mutations.	('IDH1', 'Gene', '3417', (7, 11))	('IDH2', 'Gene', (15, 19))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('IDH1', 'Gene', (112, 116))	('IDH2', 'Gene', '3418', (15, 19))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('gliomas', 'Disease', (70, 77))	('IDH1', 'Gene', '3417', (112, 116))	('IDH1', 'Gene', (7, 11))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('mutations', 'Var', (20, 29))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
81382	33599882	IDH1/2 mutant tumors generally having longer progression-free survival and overall survival whether in low-grade glial tumors compared to high-grade GBM.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutant', 'Var', (7, 13))	('progression-free survival', 'CPA', (45, 70))	('glial tumors', 'Disease', (113, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('tumors', 'Disease', (14, 20))	('longer', 'PosReg', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('glial tumors', 'Disease', 'MESH:D005910', (113, 125))	('IDH1/2', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
81383	33599882	In addition, IDH mutation with chromosome 1p and 19q co-deletion is the molecular signature for oligodendroglioma, all but removing oligoastrocytoma as a histopathologic diagnosis.	('IDH', 'Gene', '3417', (13, 16))	('oligodendroglioma', 'Disease', (96, 113))	('mutation', 'Var', (17, 25))	('oligodendroglioma', 'Disease', 'MESH:D009837', (96, 113))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (132, 148))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('oligoastrocytoma', 'Disease', (132, 148))	('IDH', 'Gene', (13, 16))
81385	33599882	In addition, both MGMT promoter methylation and IDH mutation are independent factors favoring pseudoprogression over tumor progression in high-grade glioma using standard therapies.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MGMT', 'Gene', (18, 22))	('IDH', 'Gene', (48, 51))	('glioma', 'Disease', (149, 155))	('MGMT', 'Gene', '4255', (18, 22))	('tumor', 'Disease', (117, 122))	('IDH', 'Gene', '3417', (48, 51))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('favoring', 'Reg', (85, 93))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('mutation', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('pseudoprogression', 'CPA', (94, 111))
81386	33599882	In both lower grade gliomas and GBM, multiple textural feature analysis shows a range of 72-95% predictive accuracy for IDH mutation with T1 contrast enhancement and FLAIR images providing the most discriminating information.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('IDH', 'Gene', '3417', (120, 123))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))	('mutation', 'Var', (124, 132))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('IDH', 'Gene', (120, 123))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
81388	33599882	1p/19q co-deletion accuracy was 92% and MGMT yielded 61-83% accuracy.	('co-deletion', 'Var', (7, 18))	('1p/19q co-deletion', 'Var', (0, 18))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))
81392	33599882	They were able to find area under the curve measurements of 75.7% for MGMT promoter methylation, 88.7% IDH mutation, and 97.8% for 1p19q co-deletion.	('MGMT', 'Gene', (70, 74))	('IDH', 'Gene', (103, 106))	('MGMT', 'Gene', '4255', (70, 74))	('IDH', 'Gene', '3417', (103, 106))	('1p19q co-deletion', 'Var', (131, 148))
81394	33599882	Utilization of advanced MRI, hybrid PET/MRI, and radiomics present a considerable opportunity to improve patient outcomes in the field of neuro-oncology.	('oncology', 'Phenotype', 'HP:0002664', (144, 152))	('patient', 'Species', '9606', (105, 112))	('improve', 'PosReg', (97, 104))	('hybrid', 'Var', (29, 35))
81407	33483471	GBM not only causes serious physical and psychological harm to the patients, but also imposes an economic burden on the whole society.	('GBM', 'Var', (0, 3))	('physical', 'CPA', (28, 36))	('patients', 'Species', '9606', (67, 75))
81410	33483471	LncRNA dysregulation has been proved to modulate the development of various human diseases, including cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('modulate', 'Reg', (40, 48))	('human', 'Species', '9606', (76, 81))	('LncRNA', 'Protein', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('dysregulation', 'Var', (7, 20))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
81413	33483471	LncRNA ENST457720 can function as an oncogene in non-small cell lung cancer.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('LncRNA ENST457720', 'Var', (0, 17))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))
81445	33483471	After sealing in 5% nonfat milk, membranes were probed all night at 4  C with primary antibodies against the internal control GAPDH (ab8245, Abcam) or Tubulin (ab7291, Abcam), as well as MAML2 (ab245612, Abcam), p21 (ab218311, Abcam), HES-1 (ab71559, Abcam), SRSF1 (ab38017, Abcam), ADAR (ab88574, Abcam) and RBPJ (ab25949, Abcam).	('GAPDH', 'Gene', (126, 131))	('ab88574', 'Var', (289, 296))	('p21', 'Gene', (212, 215))	('SRSF1', 'Gene', (259, 264))	('p21', 'Gene', '644914', (212, 215))	('RBPJ', 'Gene', '3516', (309, 313))	('HES-1', 'Gene', (235, 240))	('SRSF1', 'Gene', '6426', (259, 264))	('ADAR', 'Gene', '103', (283, 287))	('HES-1', 'Gene', '3280', (235, 240))	('ADAR', 'Gene', (283, 287))	('GAPDH', 'Gene', '2597', (126, 131))	('RBPJ', 'Gene', (309, 313))	('ab245612', 'Var', (194, 202))
81446	33483471	LINC01152 or MAML2 fragments covering miR-466 binding sites (wild-type and mutant) were inserted into pmirGLO luciferase vector (Promega, Madison, WI), and the indicated recombinant plasmid was then co-transfected into T98G and U343 cells with miR-466 mimics or NC mimics for 48 h. Besides, these cells were also co-transfected with pGL3 luciferase vector (Promega) containing wild-type or mutant LINC01152 promoter and indicated plasmids for gene transcription analysis.	('LINC01152', 'Gene', (0, 9))	('pGL3', 'Gene', '6391', (333, 337))	('LINC01152', 'Gene', '102606463', (0, 9))	('miR-466', 'Gene', (38, 45))	('miR-466', 'Gene', (244, 251))	('mutant', 'Var', (390, 396))	('miR-466', 'Gene', '100423038', (244, 251))	('miR-466', 'Gene', '100423038', (38, 45))	('U343', 'CellLine', 'CVCL:S471', (228, 232))	('LINC01152', 'Gene', (397, 406))	('LINC01152', 'Gene', '102606463', (397, 406))	('pGL3', 'Gene', (333, 337))
81465	33483471	Notably, the results of EdU assay and colony formation assay delineated that the rate of EdU positive cells and the number of colonies were both reduced by silenced LINC01152 (Fig.	('reduced', 'NegReg', (145, 152))	('LINC01152', 'Gene', (165, 174))	('EdU positive cells', 'CPA', (89, 107))	('LINC01152', 'Gene', '102606463', (165, 174))	('silenced', 'Var', (156, 164))	('rate', 'CPA', (81, 85))	('EdU', 'Chemical', '-', (89, 92))	('EdU', 'Chemical', '-', (24, 27))
81468	33483471	Results showed that tumor growth rate and weight were both reduced when the tumors were originated from cells with silenced LINC01152 (Fig.	('reduced', 'NegReg', (59, 66))	('weight', 'CPA', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('LINC01152', 'Gene', (124, 133))	('silenced', 'Var', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('LINC01152', 'Gene', '102606463', (124, 133))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
81475	33483471	Importantly, we proved that the mRNA and protein levels of MAML2 were both declined when LINC01152 was silenced in T98G and U343 cells (Fig.	('LINC01152', 'Gene', (89, 98))	('silenced', 'Var', (103, 111))	('LINC01152', 'Gene', '102606463', (89, 98))	('declined', 'NegReg', (75, 83))	('U343', 'CellLine', 'CVCL:S471', (124, 128))
81476	33483471	Cell growth of T98G and U343 cells was found to be inhibited in response to MAML2 depletion (Fig.	('T98G', 'Var', (15, 19))	('U343', 'CellLine', 'CVCL:S471', (24, 28))	('Cell growth', 'CPA', (0, 11))	('inhibited', 'NegReg', (51, 60))	('MAML2 depletion', 'MPA', (76, 91))
81479	33483471	Results indicated that the absence of LINC01152 had no obvious influence on the luciferase activity of MAML2 promoter (Fig.	('LINC01152', 'Gene', (38, 47))	('LINC01152', 'Gene', '102606463', (38, 47))	('activity', 'MPA', (91, 99))	('absence', 'Var', (27, 34))	('luciferase', 'Enzyme', (80, 90))
81500	33483471	It was validated that the mRNA expression and protein level of MAML2 in T98G and U343 cells were both inhibited by silenced LINC01152 and then partially regained via knockdown of miR-466 (Fig.	('knockdown', 'Var', (166, 175))	('MAML2', 'Gene', (63, 68))	('regained', 'PosReg', (153, 161))	('mRNA expression', 'MPA', (26, 41))	('U343', 'CellLine', 'CVCL:S471', (81, 85))	('inhibited', 'NegReg', (102, 111))	('miR-466', 'Gene', (179, 186))	('protein level', 'MPA', (46, 59))	('LINC01152', 'Gene', (124, 133))	('silenced', 'Var', (115, 123))	('miR-466', 'Gene', '100423038', (179, 186))	('LINC01152', 'Gene', '102606463', (124, 133))
81501	33483471	Also, cell proliferation was reduced by LINC01152 depletion and partially offset under miR-466 inhibition, according to the results of EdU assay and colony formation assay (Fig.	('cell proliferation', 'CPA', (6, 24))	('LINC01152', 'Gene', '102606463', (40, 49))	('EdU', 'Chemical', '-', (135, 138))	('miR-466', 'Gene', (87, 94))	('reduced', 'NegReg', (29, 36))	('miR-466', 'Gene', '100423038', (87, 94))	('depletion', 'Var', (50, 59))	('LINC01152', 'Gene', (40, 49))
81502	33483471	Meanwhile, cell apoptosis elevated by silenced LINC01152 was partially countervailed after inhibiting miR-466, as evidenced by the outcomes of TUNEL assay and flow cytometry analysis (Fig.	('inhibiting', 'NegReg', (91, 101))	('LINC01152', 'Gene', '102606463', (47, 56))	('miR-466', 'Gene', (102, 109))	('silenced', 'Var', (38, 46))	('miR-466', 'Gene', '100423038', (102, 109))	('cell apoptosis', 'CPA', (11, 25))	('LINC01152', 'Gene', (47, 56))
81515	33483471	Interestingly, we discovered that both mRNA and protein levels of p21 were enhanced whereas the expression of HES-1 were decreased by silenced LINC01152 or MAML2 (Fig.	('p21', 'Gene', (66, 69))	('LINC01152', 'Gene', (143, 152))	('silenced', 'Var', (134, 142))	('enhanced', 'PosReg', (75, 83))	('HES-1', 'Gene', (110, 115))	('expression', 'MPA', (96, 106))	('p21', 'Gene', '644914', (66, 69))	('decreased', 'NegReg', (121, 130))	('LINC01152', 'Gene', '102606463', (143, 152))	('HES-1', 'Gene', '3280', (110, 115))	('MAML2', 'Gene', (156, 161))
81518	33483471	Intriguingly, we proved that inhibition of NOTCH1 led to declined level of LINC01152 in both T98G and U343 cells (Fig.	('U343', 'CellLine', 'CVCL:S471', (102, 106))	('LINC01152', 'Gene', (75, 84))	('LINC01152', 'Gene', '102606463', (75, 84))	('NOTCH1', 'Gene', '4851', (43, 49))	('NOTCH1', 'Gene', (43, 49))	('level of', 'MPA', (66, 74))	('declined', 'NegReg', (57, 65))	('inhibition', 'Var', (29, 39))
81519	33483471	Additionally, the level of active NOTCH1 protein val1744 was enhanced in GBM cells but not in LGG cells (Fig.	('level of active', 'MPA', (18, 33))	('enhanced', 'PosReg', (61, 69))	('NOTCH1', 'Gene', '4851', (34, 40))	('val1744', 'Var', (49, 56))	('NOTCH1', 'Gene', (34, 40))
81529	33483471	In the outcomes of luciferase reporter assay, we found the luciferase activity of wild type LINC01152 promoter not the mutant promoter was obviously increased by overexpressed RBPJ and MAML2 (Fig.	('activity', 'MPA', (70, 78))	('increased', 'PosReg', (149, 158))	('RBPJ', 'Gene', (176, 180))	('RBPJ', 'Gene', '3516', (176, 180))	('luciferase', 'Enzyme', (59, 69))	('mutant', 'Var', (119, 125))	('LINC01152', 'Gene', (92, 101))	('LINC01152', 'Gene', '102606463', (92, 101))
81533	33483471	It was proved that MAML2 expression at both mRNA and protein levels was reduced by silenced LINC01152 and fully regained after overexpressing MAML2 (Fig.	('reduced', 'NegReg', (72, 79))	('expression', 'MPA', (25, 35))	('silenced', 'Var', (83, 91))	('MAML2', 'Gene', (19, 24))	('LINC01152', 'Gene', (92, 101))	('LINC01152', 'Gene', '102606463', (92, 101))
81534	33483471	In addition, the inhibition on cell proliferation by silenced LINC01152 was fully countervailed by overexpressed MAML2 (Fig.	('LINC01152', 'Gene', (62, 71))	('cell proliferation', 'CPA', (31, 49))	('LINC01152', 'Gene', '102606463', (62, 71))	('silenced', 'Var', (53, 61))	('inhibition', 'NegReg', (17, 27))
81549	33483471	Meanwhile, the outcomes of in vivo experiments indicated that GBM tumor formation ability was obviously inhibited by LINC01152 depletion.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('depletion', 'Var', (127, 136))	('LINC01152', 'Gene', (117, 126))	('LINC01152', 'Gene', '102606463', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibited', 'NegReg', (104, 113))
81553	33483471	Furthermore, we found that LINC01152 depletion could reduce the expression of MAML2 in GBM cells at post-transcriptional level.	('reduce', 'NegReg', (53, 59))	('expression', 'MPA', (64, 74))	('depletion', 'Var', (37, 46))	('LINC01152', 'Gene', (27, 36))	('LINC01152', 'Gene', '102606463', (27, 36))	('MAML2', 'Gene', (78, 83))
81558	33483471	Also, LINC00483 can modulate cell growth and apoptosis in gastric cancer by sponging miR-30a-3p to upregulate SPAG9 and activate MAPK pathway.	('miR-30a-3p', 'Gene', (85, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('activate', 'PosReg', (120, 128))	('LINC00483', 'Gene', (6, 15))	('LINC00483', 'Gene', '55018', (6, 15))	('cell growth', 'CPA', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SPAG9', 'Gene', (110, 115))	('upregulate', 'PosReg', (99, 109))	('sponging', 'Var', (76, 84))	('SPAG9', 'Gene', '9043', (110, 115))	('MAPK pathway', 'Pathway', (129, 141))	('modulate', 'Reg', (20, 28))	('gastric cancer', 'Disease', (58, 72))	('apoptosis', 'CPA', (45, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))
81560	33483471	However, inhibiting miR-466 could only partly rescue the effect of depleted LINC01152 on GBM cellular functions, indicating the ceRNA network was not the only mechanism involved in the modulation of LINC01152 on MAML2.	('LINC01152', 'Gene', (199, 208))	('GBM cellular functions', 'CPA', (89, 111))	('LINC01152', 'Gene', '102606463', (199, 208))	('miR-466', 'Gene', (20, 27))	('LINC01152', 'Gene', (76, 85))	('miR-466', 'Gene', '100423038', (20, 27))	('LINC01152', 'Gene', '102606463', (76, 85))	('depleted', 'Var', (67, 75))
81566	33483471	In our study, we found that inhibiting MAML2 and LINC01152 could inactivate Notch signaling pathway significantly.	('inhibiting', 'Var', (28, 38))	('LINC01152', 'Gene', (49, 58))	('LINC01152', 'Gene', '102606463', (49, 58))	('Notch signaling pathway', 'Pathway', (76, 99))	('MAML2', 'Gene', (39, 44))	('inactivate', 'NegReg', (65, 75))
81567	33483471	In turn, suppressing NOTCH1 could also lead to silenced LINC01152, so as to reverse the facilitating function of overexpressed LINC01152 in GBM.	('LINC01152', 'Gene', (127, 136))	('lead', 'Reg', (39, 43))	('LINC01152', 'Gene', (56, 65))	('facilitating', 'MPA', (88, 100))	('LINC01152', 'Gene', '102606463', (127, 136))	('LINC01152', 'Gene', '102606463', (56, 65))	('NOTCH1', 'Gene', '4851', (21, 27))	('NOTCH1', 'Gene', (21, 27))	('suppressing', 'NegReg', (9, 20))	('silenced', 'Var', (47, 55))
81590	31839882	Consistent with that study were previous publications showing that high expression of immune gene signatures was associated with favorable prognosis in breast and colorectal cancer.	('high', 'Var', (67, 71))	('breast and colorectal cancer', 'Disease', 'MESH:D001943', (152, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('immune gene signatures', 'Gene', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
81615	31839882	CTNNB1 gene mutation has been shown to be associated with low immune response.	('CTNNB1', 'Gene', '1499', (0, 6))	('low immune response', 'CPA', (58, 77))	('low immune response', 'Phenotype', 'HP:0002721', (58, 77))	('CTNNB1', 'Gene', (0, 6))	('mutation', 'Var', (12, 20))
81616	31839882	On the other hand, patients with POLE gene mutations had higher immune activity and were associated with favorable prognosis compared with patients without POLE mutations.	('patients', 'Species', '9606', (19, 27))	('immune activity', 'MPA', (64, 79))	('higher', 'PosReg', (57, 63))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (43, 52))	('POLE gene', 'Gene', (33, 42))
81653	31839882	MHC class I molecules, including HLA-A, -B, and -C, present peptides from inside the cell to T lymphocytes, while MHC class II molecules (HLA-DP, -DM, -DO, -DQ, and -DR) present antigens from outside the cell.	('peptides', 'MPA', (60, 68))	('HLA-DP', 'Var', (138, 144))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (33, 50))
81690	29923053	Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown.	('gliomas', 'Disease', (111, 118))	('1p19q codeleted', 'Var', (63, 78))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Disease', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('Reduced', 'NegReg', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('1p19q codeletion', 'Var', (165, 181))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('expression', 'MPA', (8, 18))	('DNA repair genes', 'Gene', (22, 38))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('chemosensitivity', 'MPA', (197, 213))
81692	29923053	Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line.	('MTS', 'Gene', (78, 81))	('HS683', 'CellLine', 'CVCL:0844', (110, 115))	('MTS', 'Gene', '8201', (78, 81))	('U251', 'CellLine', 'CVCL:0021', (130, 134))	('knocked', 'Var', (48, 55))
81693	29923053	The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n = 175) than in tumors without the codeletion (n = 337) (p < 0.001).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('expression', 'MPA', (4, 14))	('lower', 'NegReg', (69, 74))	('1p19q-codeleted', 'Var', (78, 93))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
81694	29923053	In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS.	('RAD54L', 'Var', (82, 88))	('PNKP', 'Gene', (76, 80))	('PFS', 'Disease', (126, 129))	('LIG1', 'Gene', '3978', (63, 67))	('LIG1', 'Gene', (63, 67))	('expression', 'MPA', (49, 59))	('PNKP', 'Gene', '11284', (76, 80))	('MUTYH', 'Gene', (93, 98))	('MUTYH', 'Gene', '4595', (93, 98))	('POLD1', 'Gene', '5424', (69, 74))	('POLD1', 'Gene', (69, 74))	('patients', 'Species', '9606', (7, 15))	('lower', 'NegReg', (43, 48))
81695	29923053	MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p < 0.001).	('LIG1', 'Gene', '3978', (53, 57))	('PNKP', 'Gene', (66, 70))	('temozolomide', 'Chemical', 'MESH:D000077204', (137, 149))	('recovery', 'MPA', (113, 121))	('RAD54L', 'Gene', (72, 78))	('knockdown', 'Var', (23, 32))	('PNKP', 'Gene', '11284', (66, 70))	('MUTYH', 'Gene', (83, 88))	('response to temozolomide', 'MPA', (125, 149))	('inhibited', 'NegReg', (103, 112))	('MUTYH', 'Gene', '4595', (83, 88))	('MTS', 'Gene', (0, 3))	('POLD1', 'Gene', (59, 64))	('POLD1', 'Gene', '5424', (59, 64))	('LIG1', 'Gene', (53, 57))	('MTS', 'Gene', '8201', (0, 3))
81701	29923053	A study including 615 grade II and III gliomas from the Cancer Genome Atlas (TCGA) suggested that IDH mutation and 1p19q codeletion status can better predict prognosis than histological grading.	('II gliomas', 'Disease', (36, 46))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('II gliomas', 'Disease', 'MESH:D005910', (36, 46))	('1p19q', 'Var', (115, 120))	('IDH', 'Gene', (98, 101))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('Cancer Genome Atlas', 'Disease', (56, 75))	('IDH', 'Gene', '3417', (98, 101))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (56, 75))
81702	29923053	In a randomized controlled trial comparing RT alone to RT followed by chemotherapy for the treatment of anaplastic oligodendroglioma, adjuvant chemotherapy was more beneficial for tumors with 1p19q-codeletion.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (104, 132))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('1p19q-codeletion', 'Var', (192, 208))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (180, 186))	('anaplastic oligodendroglioma', 'Disease', (104, 132))
81709	29923053	Univariate Cox proportional hazard regression was performed to evaluate the association of WHO tumor grade, IDH1 mutation, TERT mutation, TP53, H3F3A, 1p19q status, histological type, extent of resection, receipt of RT (as categorical variables), and age, KPS and gene expression (as continuous variables) with PFS and OS in each group.	('mutation', 'Var', (113, 121))	('TERT', 'Gene', (123, 127))	('H3F3A', 'Gene', '3020', (144, 149))	('TP53', 'Gene', '7157', (138, 142))	('IDH1', 'Gene', '3417', (108, 112))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('KPS', 'Disease', (256, 259))	('TERT', 'Gene', '7015', (123, 127))	('PFS', 'Disease', (311, 314))	('TP53', 'Gene', (138, 142))	('H3F3A', 'Gene', (144, 149))	('association', 'Interaction', (76, 87))	('KPS', 'Disease', 'None', (256, 259))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IDH1', 'Gene', (108, 112))	('tumor', 'Disease', (95, 100))
81725	29923053	Among the 512 patients in the TCGA LGG cohort with information on 1p19q codeletion status, 175 patients had 1p19q codeleted tumors, while 337 patients had tumors without the codeletion.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('patients', 'Species', '9606', (95, 103))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('1p19q', 'Var', (108, 113))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (142, 150))
81726	29923053	The expression of all 9 DNA repair genes on chromosome arms 1p and 19q was significantly lower in patients with 1p19q codeletion than in those without the codeletion (p < 0.001) (Fig.	('lower', 'NegReg', (89, 94))	('expression', 'MPA', (4, 14))	('patients', 'Species', '9606', (98, 106))	('1p19q codeletion', 'Var', (112, 128))
81727	29923053	For the 5 DNA repair genes on chromosome arms 1q and 19p, expression was significantly higher in the 1p19q codeleted group for XAB2 (p < 0.001), significantly lower for CHAF1A and EXO1 (p < 0.05), and not significantly different for CLK2 and PARP1 (p > 0.05) (Supplementary Fig.	('XAB2', 'Gene', (127, 131))	('CHAF1A', 'Gene', (169, 175))	('CLK2', 'Gene', (233, 237))	('expression', 'MPA', (58, 68))	('EXO1', 'Gene', '9156', (180, 184))	('CLK2', 'Gene', '1196', (233, 237))	('CHAF1A', 'Gene', '10036', (169, 175))	('lower', 'NegReg', (159, 164))	('PARP1', 'Gene', '142', (242, 247))	('EXO1', 'Gene', (180, 184))	('PARP1', 'Gene', (242, 247))	('1p19q', 'Var', (101, 106))	('XAB2', 'Gene', '56949', (127, 131))	('higher', 'PosReg', (87, 93))
81728	29923053	The expression of the five most upregulated non-DNA repair genes (ID3, APOC1, RPS19, GNAI3, RPS9) on chromosome arms 1p and 19q in LGG compared to non-glioma tissue was significantly lower in patients with 1p19q codeletion than in those without the codeletion (p < 0.001) (Supplementary Fig.	('RPS19', 'Gene', '6223', (78, 83))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('APOC1', 'Gene', (71, 76))	('RPS19', 'Gene', (78, 83))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioma', 'Disease', (151, 157))	('expression', 'MPA', (4, 14))	('patients', 'Species', '9606', (192, 200))	('ID3', 'Gene', '3399', (66, 69))	('APOC1', 'Gene', '341', (71, 76))	('1p19q codeletion', 'Var', (206, 222))	('RPS9', 'Gene', '6203', (92, 96))	('RPS9', 'Gene', (92, 96))	('lower', 'NegReg', (183, 188))	('GNAI3', 'Gene', (85, 90))	('ID3', 'Gene', (66, 69))	('GNAI3', 'Gene', '2773', (85, 90))	('upregulated', 'PosReg', (32, 43))
81729	29923053	For the most downregulated non-DNA repair genes on chromosome arms 1p and 19q, expression was significantly higher in the 1p19q codeleted group for FUT1 (p = 0.02) and EXTL1 (p = 0.02), and not significantly different for PRKCZ, SPINT2 and RIMS3 (p > 0.05) (Supplementary Fig.	('expression', 'MPA', (79, 89))	('1p19q', 'Var', (122, 127))	('EXTL1', 'Gene', (168, 173))	('SPINT2', 'Gene', (229, 235))	('downregulated', 'NegReg', (13, 26))	('EXTL1', 'Gene', '2134', (168, 173))	('SPINT2', 'Gene', '10653', (229, 235))	('RIMS3', 'Gene', (240, 245))	('FUT1', 'Gene', (148, 152))	('RIMS3', 'Gene', '9783', (240, 245))	('PRKCZ', 'Gene', (222, 227))	('FUT1', 'Gene', '2523', (148, 152))	('non-DNA repair genes', 'Gene', (27, 47))	('PRKCZ', 'Gene', '5590', (222, 227))	('higher', 'PosReg', (108, 114))
81732	29923053	In the univariate Cox regression analysis, age, KPS, IDH1 mutant status, 1p19q codeletion status, and histological type were significant predictors of PFS.	('IDH1', 'Gene', (53, 57))	('Cox', 'Gene', '1351', (18, 21))	('KPS', 'Disease', 'None', (48, 51))	('IDH1', 'Gene', '3417', (53, 57))	('Cox', 'Gene', (18, 21))	('KPS', 'Disease', (48, 51))	('1p19q codeletion status', 'Var', (73, 96))	('mutant status', 'Var', (58, 71))	('PFS', 'Disease', (151, 154))
81733	29923053	Higher expression of LIG1 (p = 0.009), POLD1 (p = 0.045), PNKP (p = 0.005), RAD54L (p = 0.017) and MUTYH (p = 0.001) were associated with shorter PFS (n = 268) on multivariate analysis (Table 1 and Supplementary Table 5).	('PNKP', 'Gene', (58, 62))	('LIG1', 'Gene', (21, 25))	('MUTYH', 'Gene', (99, 104))	('RAD54L', 'Var', (76, 82))	('MUTYH', 'Gene', '4595', (99, 104))	('POLD1', 'Gene', (39, 44))	('LIG1', 'Gene', '3978', (21, 25))	('shorter', 'NegReg', (138, 145))	('POLD1', 'Gene', '5424', (39, 44))	('expression', 'MPA', (7, 17))	('PNKP', 'Gene', '11284', (58, 62))	('Higher', 'PosReg', (0, 6))	('PFS', 'MPA', (146, 149))
81734	29923053	In the univariate Cox regression analysis, age, KPS, IDH1 mutant status, TP53, 1p19q codeletion, status, histological type and tumor grade were significant predictors of OS.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TP53', 'Gene', '7157', (73, 77))	('tumor', 'Disease', (127, 132))	('IDH1', 'Gene', (53, 57))	('TP53', 'Gene', (73, 77))	('Cox', 'Gene', '1351', (18, 21))	('KPS', 'Disease', 'None', (48, 51))	('IDH1', 'Gene', '3417', (53, 57))	('Cox', 'Gene', (18, 21))	('1p19q codeletion', 'Var', (79, 95))	('KPS', 'Disease', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mutant status', 'Var', (58, 71))
81735	29923053	Higher expression of LIG1 (p = 0.024), POLD1 (p = 0.013), PNKP (p = 0.047), RAD54L (p = 0.001) and MUTYH (p = 0.001) was associated with shorter OS (n = 280) on multivariate analysis (Table 1 and Supplementary Table 5).	('PNKP', 'Gene', (58, 62))	('LIG1', 'Gene', (21, 25))	('MUTYH', 'Gene', (99, 104))	('RAD54L', 'Var', (76, 82))	('MUTYH', 'Gene', '4595', (99, 104))	('POLD1', 'Gene', (39, 44))	('LIG1', 'Gene', '3978', (21, 25))	('POLD1', 'Gene', '5424', (39, 44))	('expression', 'MPA', (7, 17))	('PNKP', 'Gene', '11284', (58, 62))	('Higher', 'PosReg', (0, 6))	('shorter OS', 'Disease', (137, 147))
81739	29923053	However, GNAI3 expression was also significantly associated with OS in patients who did not receive chemotherapy (Supplementary Table 11).	('expression', 'Var', (15, 25))	('GNAI3', 'Gene', (9, 14))	('patients', 'Species', '9606', (71, 79))	('GNAI3', 'Gene', '2773', (9, 14))	('associated with', 'Reg', (49, 64))
81741	29923053	Cells with DNA repair gene RAD54L, MUTYH, LIG1, PNKP and POLD1 knocked down had significantly lower proliferation than control group at 72 h after adding TMZ of 2 mg/L in HS683 cell line (Fig.	('RAD54L', 'Var', (27, 33))	('PNKP', 'Gene', '11284', (48, 52))	('proliferation', 'CPA', (100, 113))	('POLD1', 'Gene', (57, 62))	('POLD1', 'Gene', '5424', (57, 62))	('knocked down', 'Var', (63, 75))	('LIG1', 'Gene', (42, 46))	('LIG1', 'Gene', '3978', (42, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (154, 157))	('lower', 'NegReg', (94, 99))	('MUTYH', 'Gene', (35, 40))	('MUTYH', 'Gene', '4595', (35, 40))	('HS683', 'CellLine', 'CVCL:0844', (171, 176))	('PNKP', 'Gene', (48, 52))
81744	29923053	The deletion of chromosomes 1p and 19q is found in 70% of oligodendrogliomas and 50% of mixed oligoastrocytomas.	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (58, 76))	('oligoastrocytomas', 'Disease', (94, 111))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('deletion', 'Var', (4, 12))	('found', 'Reg', (42, 47))	('oligodendrogliomas', 'Disease', (58, 76))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (94, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
81745	29923053	Deregulation of DNA repair system plays an important role in cancer therapy, and many chemotherapy drugs work through disruption of DNA repair pathways.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Deregulation', 'Var', (0, 12))	('disruption', 'NegReg', (118, 128))	('cancer', 'Disease', (61, 67))	('DNA repair pathways', 'Pathway', (132, 151))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
81747	29923053	For example, in a study of 206 glioblastoma patients, those with silenced O-6-methylgua-nine-DNA methyltransferase (MGMT), which encodes a DNA repair protein, benefited from alkylating agents while those without silenced MGMT did not.	('O-6-methylgua-nine-DNA methyltransferase', 'Gene', (74, 114))	('patients', 'Species', '9606', (44, 52))	('O-6-methylgua-nine-DNA methyltransferase', 'Gene', '4255', (74, 114))	('silenced', 'Var', (65, 73))	('MGMT', 'Gene', (221, 225))	('benefited', 'PosReg', (159, 168))	('MGMT', 'Gene', '4255', (221, 225))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('MGMT', 'Gene', (116, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('MGMT', 'Gene', '4255', (116, 120))	('alkylating agents', 'MPA', (174, 191))
81751	29923053	found that IDH1 mutation results in a gain-of-function mutation leading to accumulation of the onco-metabolite 2-hydroxy-glutarate (2HG).	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('2-hydroxy-glutarate', 'Chemical', 'MESH:C019417', (111, 130))	('gain-of-function', 'PosReg', (38, 54))	('mutation', 'Var', (55, 63))	('IDH1', 'Gene', (11, 15))
81752	29923053	demonstrated that 2HG impairs DNA double-strand break repair and thereby increases sensitivity to poly (adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors.	('increases', 'PosReg', (73, 82))	('PARP', 'Gene', '142', (149, 153))	('DNA double-strand break repair', 'MPA', (30, 60))	('2HG', 'Var', (18, 21))	('PARP', 'Gene', (149, 153))	('impairs', 'NegReg', (22, 29))
81753	29923053	In our study, we showed that lower expression of specific DNA repair genes in 1p19q codeletion (LIG1, POLD1, PNKP, RAD54L and MUTYH) only prolonged PFS and OS in LGG patients who received TMZ, but not in patients who did not receive TMZ.	('expression', 'MPA', (35, 45))	('POLD1', 'Gene', '5424', (102, 107))	('PFS', 'MPA', (148, 151))	('1p19q', 'Var', (78, 83))	('patients', 'Species', '9606', (204, 212))	('MUTYH', 'Gene', (126, 131))	('TMZ', 'Var', (188, 191))	('LIG1', 'Gene', '3978', (96, 100))	('PNKP', 'Gene', (109, 113))	('LIG1', 'Gene', (96, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (188, 191))	('MUTYH', 'Gene', '4595', (126, 131))	('prolonged', 'PosReg', (138, 147))	('POLD1', 'Gene', (102, 107))	('TMZ', 'Chemical', 'MESH:D000077204', (233, 236))	('LGG', 'Disease', (162, 165))	('PNKP', 'Gene', '11284', (109, 113))	('lower', 'NegReg', (29, 34))	('patients', 'Species', '9606', (166, 174))
81754	29923053	The results of vitro experiments in HS683 and U251 supported our hypothesis that these genes may account for chemosensitivity to TMZ in 1p19q codeleted lower-grade glioma patients.	('HS683', 'CellLine', 'CVCL:0844', (36, 41))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('1p19q codeleted', 'Var', (136, 151))	('account', 'Reg', (97, 104))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('patients', 'Species', '9606', (171, 179))	('U251', 'CellLine', 'CVCL:0021', (46, 50))	('TMZ', 'Chemical', 'MESH:D000077204', (129, 132))	('glioma', 'Disease', (164, 170))
81759	29923053	Some previous research has suggested that abnormalities in copy number of ERCC1 or ERCC2 is not associated with response to therapy or survival in patients with gliomas.	('abnormalities', 'Var', (42, 55))	('associated', 'Reg', (96, 106))	('ERCC2', 'Gene', (83, 88))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('copy number', 'Var', (59, 70))	('patients', 'Species', '9606', (147, 155))	('gliomas', 'Disease', (161, 168))	('ERCC1', 'Gene', '2067', (74, 79))	('ERCC1', 'Gene', (74, 79))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('ERCC2', 'Gene', '2068', (83, 88))
81764	29923053	There is evidence to suggest that POLD1 knockdown increases sensitivity to ATR inhibitors in colorectal cancer cells.	('ATR', 'Gene', '545', (75, 78))	('ATR', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('knockdown', 'Var', (40, 49))	('increases', 'PosReg', (50, 59))	('colorectal cancer', 'Disease', (93, 110))	('POLD1', 'Gene', (34, 39))	('POLD1', 'Gene', '5424', (34, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
81766	29923053	In mice, RAD54L deficiency may be associated with sensitivity to clastogens, and the loss of RAD54L can result in increased sensitivity to DNA-damaging agents.	('loss', 'Var', (85, 89))	('associated', 'Reg', (34, 44))	('sensitivity to DNA-damaging agents', 'MPA', (124, 158))	('RAD54L deficiency', 'Disease', 'MESH:D007153', (9, 26))	('mice', 'Species', '10090', (3, 7))	('increased', 'PosReg', (114, 123))	('RAD54L', 'Gene', (93, 99))	('RAD54L deficiency', 'Disease', (9, 26))	('sensitivity', 'CPA', (50, 61))
81772	29923053	Reduced expression of DNA repair genes on chromosome arms 1p and 19q, particularly LIG1, POLD1, PNKP, RAD54L and MUTYH, may account for the increased chemosensitivity of LGGs with 1p19q codeletion.	('MUTYH', 'Gene', (113, 118))	('MUTYH', 'Gene', '4595', (113, 118))	('LIG1', 'Gene', '3978', (83, 87))	('Reduced', 'NegReg', (0, 7))	('LIG1', 'Gene', (83, 87))	('PNKP', 'Gene', '11284', (96, 100))	('expression', 'MPA', (8, 18))	('POLD1', 'Gene', (89, 94))	('POLD1', 'Gene', '5424', (89, 94))	('PNKP', 'Gene', (96, 100))	('DNA repair genes', 'Gene', (22, 38))	('1p19q codeletion', 'Var', (180, 196))
81773	27217440	BRAF status in personalizing treatment approaches for pediatric gliomas Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGG) and mTOR activation has been documented in the majority of these tumors.	('BRAF', 'Gene', (90, 94))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('BRAF', 'Gene', '109880', (0, 4))	('Alteration', 'Var', (72, 82))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('BRAF', 'Gene', '109880', (90, 94))	('BRAF', 'Gene', (0, 4))	('gliomas', 'Disease', (151, 158))	('tumors', 'Disease', (231, 237))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
81774	27217440	We investigated combinations of MEK1/2, BRAFV600E and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('genetic alterations', 'Var', (99, 118))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('BRAFV600E', 'Var', (40, 49))	('gliomas', 'Disease', (73, 80))
81776	27217440	Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK1/2).	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('AZD6244', 'Var', (74, 81))	('PLX4720', 'Var', (49, 56))	('AZD6244', 'Chemical', 'MESH:C517975', (74, 81))	('everolimus', 'Chemical', 'MESH:D000068338', (30, 40))	('everolimus', 'Disease', (30, 40))	('PLX4720', 'Chemical', 'MESH:C528407', (49, 56))
81781	27217440	In vivo experiments in the BRAFV600E pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244+PLX4720 (p<0.01).	('AZD6244', 'Chemical', 'MESH:C517975', (128, 135))	('BRAFV600E', 'Mutation', 'rs113488022', (27, 36))	('mice', 'Species', '10090', (110, 114))	('survival advantage', 'CPA', (88, 106))	('PLX4720', 'Chemical', 'MESH:C528407', (136, 143))	('AZD6244+PLX4720', 'Var', (128, 143))
81782	27217440	In BRAFV600E tumors, combination of AZD6244+PLX4720 is superior to monotherapy and to other combinatorial approaches.	('AZD6244+PLX4720', 'Var', (36, 51))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('AZD6244+PLX4720', 'Gene', (36, 51))	('PLX4720', 'Chemical', 'MESH:C528407', (44, 51))	('AZD6244', 'Chemical', 'MESH:C517975', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BRAFV600E', 'Var', (3, 12))	('BRAFV600E', 'Mutation', 'rs113488022', (3, 12))
81788	27217440	Despite the known heterogeneity of PLGGs and characterized driver mutations that together offer the ideal, timely platform for personalized approaches to therapy, most children are still treated with standard chemotherapy protocols in a "one treatment fits all" approach.	('mutations', 'Var', (66, 75))	('children', 'Species', '9606', (168, 176))	('fits', 'Disease', (252, 256))	('PLGGs', 'Gene', (35, 40))	('fits', 'Disease', 'MESH:D012640', (252, 256))
81789	27217440	The majority of pilocytic astrocytomas (PA) carry the BRAF fusion protein KIAA1549:BRAF leading to MAPK signaling activation.	('activation', 'PosReg', (114, 124))	('BRAF', 'Var', (83, 87))	('pilocytic astrocytomas', 'Disease', (16, 38))	('MAPK signaling', 'MPA', (99, 113))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (16, 38))
81790	27217440	Clinical studies are currently investigating effects of specific inhibitors of the MAPK pathway, such as the MEK1/2 inhibitor AZD62444, for the treatment of PLGGs (ClinicalTrials.gov; Identifier NCT01089101).	('AZD62444', 'Var', (126, 134))	('PLGGs', 'Disease', (157, 162))	('MAPK pathway', 'Pathway', (83, 95))	('AZD62444', 'Chemical', '-', (126, 134))
81791	27217440	Activating BRAFV600E point mutations are present in 6-10% of PAs with higher incidences reported in other LGG subtypes such as pleomorphic xanthoastrocytoma (51-66%) and ganglioglioma (11-21%).	('Activating', 'PosReg', (0, 10))	('BRAFV600E', 'Var', (11, 20))	('BRAFV600E', 'Mutation', 'rs113488022', (11, 20))	('PAs', 'Disease', (61, 64))	('ganglioglioma', 'Disease', (170, 183))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (127, 156))	('PAs', 'Chemical', 'MESH:D011478', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('pleomorphic xanthoastrocytoma', 'Disease', (127, 156))	('ganglioglioma', 'Disease', 'MESH:D018303', (170, 183))
81792	27217440	As this specific BRAFV600E mutation is also common in adult patients with melanoma, several inhibitors are now clinically available, including vermurafenib and dabrafenib.	('vermurafenib', 'Chemical', '-', (143, 155))	('patients', 'Species', '9606', (60, 68))	('dabrafenib', 'Chemical', 'MESH:C561627', (160, 170))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('BRAFV600E', 'Var', (17, 26))	('BRAFV600E', 'Mutation', 'rs113488022', (17, 26))
81793	27217440	Ongoing clinical trials are testing these inhibitors in children with recurrent/progressive BRAFV600E-mutated tumors (ClinicalTrials.gov Identifier NCT01748149).	('children', 'Species', '9606', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('BRAFV600E', 'Mutation', 'rs113488022', (92, 101))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('BRAFV600E-mutated', 'Var', (92, 109))
81796	27217440	We address this impediment by assessing effects of MEK, BRAFV600E and mTOR inhibitors as single agents and as combination therapies in models of pediatric gliomas carrying the most commonly found genetic alterations.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('BRAFV600E', 'Var', (56, 65))	('BRAFV600E', 'Mutation', 'rs113488022', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('pediatric gliomas', 'Disease', 'MESH:D005910', (145, 162))	('pediatric gliomas', 'Disease', (145, 162))
81798	27217440	SF9427 and SF8628 were established from pediatric high-grade gliomas as described previously (Supplemental Table1).	('SF8628', 'Var', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))
81801	27217440	The isogenic system of murine brain tumors differing only in BRAFV600E status was generated as described.	('BRAFV600E status', 'Var', (61, 77))	('brain tumors', 'Disease', 'MESH:D001932', (30, 42))	('murine', 'Species', '10090', (23, 29))	('brain tumors', 'Phenotype', 'HP:0030692', (30, 42))	('brain tumors', 'Disease', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('BRAFV600E', 'Mutation', 'rs113488022', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
81802	27217440	The genotypes used in this study are BRafCA/WT Ink4a-arf lox/lox (6390, 6392) and BRafWT/WT Ink4a-arf lox/lox (6387, 6393).	('6387', 'Var', (111, 115))	('Ink4a-arf', 'Gene', (47, 56))	('lox', 'Gene', (57, 60))	('lox', 'Gene', (102, 105))	('lox', 'Gene', (61, 64))	('lox', 'Gene', (106, 109))	('Ink4a-arf', 'Gene', '12578', (92, 101))	('lox', 'Gene', '16948', (61, 64))	('Ink4a-arf', 'Gene', '12578', (47, 56))	('lox', 'Gene', '16948', (57, 60))	('lox', 'Gene', '16948', (102, 105))	('lox', 'Gene', '16948', (106, 109))	('Ink4a-arf', 'Gene', (92, 101))
81806	27217440	To induce BRAFV600E expression and deletion of Ink4a-arf, SVZ neurospheres were transduced in vitro with adenovirus-Cre-GFP (Vector Biolabs) for 12-18 hours.	('induce', 'Reg', (3, 9))	('Ink4a-arf', 'Gene', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (10, 19))	('expression', 'MPA', (20, 30))	('BRAFV600E', 'Gene', (10, 19))	('Ink4a-arf', 'Gene', '12578', (47, 56))	('deletion', 'Var', (35, 43))
81816	27217440	Protein lysates were separated by SDS-PAGE and transferred to polyvinyllidene difluoride membranes, then incubated with antibodies against p-Akt, total Akt, p-MEK1/2, p-Erk, p-S6, total S6, beta-actin (Cell Signaling, Beverly, MA).	('beta-actin', 'Gene', (190, 200))	('p-Erk', 'Gene', (167, 172))	('beta-actin', 'Gene', '11461', (190, 200))	('Akt', 'Gene', (152, 155))	('polyvinyllidene difluoride', 'Chemical', '-', (62, 88))	('p-S6', 'Gene', (174, 178))	('p-S6', 'Gene', '338413', (174, 178))	('total S6', 'Var', (180, 188))	('p-MEK1/2', 'Var', (157, 165))	('SDS', 'Chemical', 'MESH:D012967', (34, 37))	('Akt', 'Gene', '11651', (141, 144))	('p-Erk', 'Gene', '13666', (167, 172))	('Akt', 'Gene', '11651', (152, 155))	('Akt', 'Gene', (141, 144))
81824	27217440	For the final analysis the following numbers of animals were included: control n=6, AZD6244 n=7, everolimus n=7, PLX4720 n=7, everolimus + PLX4720=9, AZD6244 + PLX4720=7, and AZD6244 + everolmius n=7.	('AZD6244 + PLX4720=7', 'Var', (150, 169))	('AZD6244', 'Var', (84, 91))	('everolimus', 'Chemical', 'MESH:D000068338', (97, 107))	('PLX4720', 'Chemical', 'MESH:C528407', (160, 167))	('AZD6244', 'Chemical', 'MESH:C517975', (84, 91))	('PLX4720', 'Chemical', 'MESH:C528407', (139, 146))	('PLX4720', 'Chemical', 'MESH:C528407', (113, 120))	('everolimus', 'Chemical', 'MESH:D000068338', (126, 136))	('AZD6244', 'Chemical', 'MESH:C517975', (150, 157))	('AZD6244', 'Chemical', 'MESH:C517975', (175, 182))
81831	27217440	We assessed effects of MEK1/2- (AZD6244), mTOR- (everolimus) or BRAFV600E-inhibitions (PLX4720) as monotherapy as well as in combination in BRAFV600E mutated glioma cells DBTRG and AM-38.	('BRAFV600E', 'Mutation', 'rs113488022', (140, 149))	('everolimus', 'Chemical', 'MESH:D000068338', (49, 59))	('PLX4720', 'Chemical', 'MESH:C528407', (87, 94))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('AZD6244', 'Chemical', 'MESH:C517975', (32, 39))	('BRAFV600E mutated', 'Var', (140, 157))	('glioma', 'Disease', (158, 164))	('DBTRG', 'Chemical', '-', (171, 176))	('BRAFV600E', 'Mutation', 'rs113488022', (64, 73))
81832	27217440	As shown in Figure 1A-C (DBTRG) and D-F (AM-38), the three possible doublet combinations of AZD6244, everolimus and PLX4720, led to significant decreases in cell proliferation compared to the respective single agents.	('decreases', 'NegReg', (144, 153))	('DBTRG', 'Chemical', '-', (25, 30))	('cell proliferation', 'CPA', (157, 175))	('everolimus', 'Chemical', 'MESH:D000068338', (101, 111))	('PLX4720', 'Var', (116, 123))	('AZD6244', 'Chemical', 'MESH:C517975', (92, 99))	('combinations', 'Interaction', (76, 88))	('AZD6244', 'Gene', (92, 99))	('PLX4720', 'Chemical', 'MESH:C528407', (116, 123))
81837	27217440	Treatment with PLX4720 or AZD6244 reduced expression of p-ERK, although AZD6244 was more effective in down-regulating p-ERK.	('reduced', 'NegReg', (34, 41))	('p-ERK', 'Gene', (56, 61))	('p-ERK', 'Gene', '13666', (56, 61))	('expression', 'MPA', (42, 52))	('AZD6244', 'Var', (26, 33))	('AZD6244', 'Chemical', 'MESH:C517975', (26, 33))	('p-ERK', 'Gene', (118, 123))	('p-ERK', 'Gene', '13666', (118, 123))	('PLX4720', 'Chemical', 'MESH:C528407', (15, 22))	('down-regulating', 'NegReg', (102, 117))	('AZD6244', 'Var', (72, 79))	('AZD6244', 'Chemical', 'MESH:C517975', (72, 79))
81839	27217440	Treatment of BRAFV600E-mutant DBTRG cells with all examined single agents and combinations led to up-regulation of p-AKT (Figure 1G).	('BRAFV600E-mutant', 'Var', (13, 29))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('AKT', 'Gene', (117, 120))	('up-regulation', 'PosReg', (98, 111))	('DBTRG', 'Chemical', '-', (30, 35))	('DBTRG', 'Gene', (30, 35))	('AKT', 'Gene', '11651', (117, 120))
81842	27217440	Similar results were also seen in SF8628 (Figure 2B) and SF9427 BRAFWT glioma cells (Figure 2C).	('glioma', 'Disease', (71, 77))	('SF9427', 'Var', (57, 63))	('SF8628', 'Var', (34, 40))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
81843	27217440	In addition, SF188 cells treated with AZD6244 + everolimus exhibited significantly greater apoptosis compared to single agent treatments (Figure 2D), a finding documented in SF8628 cells as well (Supplemental Figure 4A).	('apoptosis', 'CPA', (91, 100))	('greater', 'PosReg', (83, 90))	('everolimus', 'Chemical', 'MESH:D000068338', (48, 58))	('AZD6244', 'Chemical', 'MESH:C517975', (38, 45))	('AZD6244 +', 'Var', (38, 47))
81844	27217440	In addition to combinatorial effects on apoptosis and proliferation, we observed decreased S and G2 phase accumulation in SF188 and SF8628 cells treated with combination of AZD6244 + everolimus compared to the respective single agent treated cells (Figure 2E, Supplemental Figure 4B).	('decreased', 'NegReg', (81, 90))	('AZD6244', 'Var', (173, 180))	('AZD6244', 'Chemical', 'MESH:C517975', (173, 180))	('everolimus', 'Chemical', 'MESH:D000068338', (183, 193))	('SF8628', 'Var', (132, 138))	('SF188', 'Gene', (122, 127))
81845	27217440	Western blot analyses (Figure 2F) revealed expected pathway modulations, including down-regulation of p-ERK by AZD6244, reduction in p-S6 by everolimus, and up-regulation of p-Akt by AZD6244, everolimus and their combination.	('AZD6244', 'Var', (183, 190))	('AZD6244', 'Var', (111, 118))	('everolimus', 'Chemical', 'MESH:D000068338', (141, 151))	('p-ERK', 'Gene', '13666', (102, 107))	('AZD6244', 'Chemical', 'MESH:C517975', (183, 190))	('Akt', 'Gene', (176, 179))	('p-S6', 'Gene', '338413', (133, 137))	('AZD6244', 'Chemical', 'MESH:C517975', (111, 118))	('reduction', 'NegReg', (120, 129))	('p-S6', 'Gene', (133, 137))	('everolimus', 'Chemical', 'MESH:D000068338', (192, 202))	('up-regulation', 'PosReg', (157, 170))	('Akt', 'Gene', '11651', (176, 179))	('down-regulation', 'NegReg', (83, 98))	('p-ERK', 'Gene', (102, 107))
81848	27217440	Comparing inhibitor combinations, each of the three combinations was superior to single agents in reducing cell proliferation in BRAFV600E-mutated cells (Figure 3A).	('reducing', 'NegReg', (98, 106))	('BRAFV600E-mutated', 'Var', (129, 146))	('BRAFV600E', 'Mutation', 'rs113488022', (129, 138))	('cell proliferation', 'CPA', (107, 125))
81850	27217440	The combination index of PLX4720 + AZD6244 was indicative of strong synergism at all dose levels.	('PLX4720', 'Var', (25, 32))	('PLX4720', 'Chemical', 'MESH:C528407', (25, 32))	('AZD6244', 'Chemical', 'MESH:C517975', (35, 42))	('AZD6244', 'Var', (35, 42))
81851	27217440	As expected, western blot analyses in BRAFV600E-mutated cells revealed down-regulation of p-ERK by AZD6244 or PLX4720 and down-regulation of p-S6 at 6 hours by everolimus (Figure 3B).	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('PLX4720', 'Chemical', 'MESH:C528407', (110, 117))	('p-S6', 'Gene', (141, 145))	('down-regulation', 'NegReg', (71, 86))	('AZD6244', 'Var', (99, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (160, 170))	('p-ERK', 'Gene', (90, 95))	('AZD6244', 'Chemical', 'MESH:C517975', (99, 106))	('p-ERK', 'Gene', '13666', (90, 95))	('down-regulation', 'NegReg', (122, 137))	('PLX4720', 'Var', (110, 117))	('p-S6', 'Gene', '338413', (141, 145))
81852	27217440	In BRAFWT murine glioma cells, combination of AZD6244 + everolimus enhanced anti-proliferative effects compared to single agents (Figure 3C), with CI values below one, indicating synergistic effects of this combinatorial approach (data not shown).	('anti-proliferative effects', 'MPA', (76, 102))	('AZD6244', 'Var', (46, 53))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('AZD6244', 'Chemical', 'MESH:C517975', (46, 53))	('glioma', 'Disease', (17, 23))	('murine', 'Species', '10090', (10, 16))	('combination', 'Interaction', (31, 42))	('everolimus', 'Chemical', 'MESH:D000068338', (56, 66))	('enhanced', 'PosReg', (67, 75))
81853	27217440	Western blot analyses revealed expected down-regulation of p-ERK by AZD6244 and of p-S6 by everolimus (Figure 3D) and only the combination treatment effectively inhibited both the MAPK and mTOR pathways.	('p-S6', 'Gene', (83, 87))	('p-ERK', 'Gene', (59, 64))	('p-ERK', 'Gene', '13666', (59, 64))	('mTOR pathways', 'Pathway', (189, 202))	('inhibited', 'NegReg', (161, 170))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('down-regulation', 'NegReg', (40, 55))	('AZD6244', 'Var', (68, 75))	('AZD6244', 'Chemical', 'MESH:C517975', (68, 75))	('p-S6', 'Gene', '338413', (83, 87))
81859	27217440	In KIAA1549:BRAF cells, regardless of serum levels, AZD6244 reduced p-ERK and everolimus decreased p-S6, but complete inhibition of both the MAPK and mTOR pathways was evident only in the combined treatment arm (Figure 4D, H).	('AZD6244', 'Var', (52, 59))	('mTOR pathways', 'Pathway', (150, 163))	('AZD6244', 'Chemical', 'MESH:C517975', (52, 59))	('MAPK', 'Pathway', (141, 145))	('p-S6', 'Gene', '338413', (99, 103))	('reduced', 'NegReg', (60, 67))	('everolimus', 'Chemical', 'MESH:D000068338', (78, 88))	('p-S6', 'Gene', (99, 103))	('p-ERK', 'Gene', (68, 73))	('p-ERK', 'Gene', '13666', (68, 73))	('decreased', 'NegReg', (89, 98))
81861	27217440	Mice treated with a combination of AZD6244 plus everolimus or PLX4720 showed significantly prolonged survival and tumor volume reduction compared to single agent treatment, with AZD6244 + PLX4720 appearing superior to AZD6244 + everolimus (Figure 5A-C).	('PLX4720', 'Chemical', 'MESH:C528407', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('prolonged', 'PosReg', (91, 100))	('reduction', 'NegReg', (127, 136))	('AZD6244', 'Chemical', 'MESH:C517975', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('everolimus', 'Chemical', 'MESH:D000068338', (228, 238))	('tumor', 'Disease', (114, 119))	('AZD6244', 'Chemical', 'MESH:C517975', (178, 185))	('Mice', 'Species', '10090', (0, 4))	('AZD6244', 'Chemical', 'MESH:C517975', (218, 225))	('survival', 'CPA', (101, 109))	('AZD6244', 'Var', (35, 42))	('AZD6244 + PLX4720', 'Var', (178, 195))	('PLX4720', 'Chemical', 'MESH:C528407', (62, 69))	('everolimus', 'Chemical', 'MESH:D000068338', (48, 58))
81862	27217440	As observed in our in vitro studies, we found reduced expression of Ki67, a marker of proliferation, in xenografts from mice treated with everolimus, AZD6244, PLX4720 or combinations thereof, with the greatest reduction of Ki67 documented in mice treated with the combination of PLX4720 + AZD6244 (Figure 5D, E).	('expression', 'MPA', (54, 64))	('PLX4720', 'Var', (159, 166))	('PLX4720', 'Chemical', 'MESH:C528407', (159, 166))	('PLX4720', 'Chemical', 'MESH:C528407', (279, 286))	('mice', 'Species', '10090', (120, 124))	('AZD6244', 'Chemical', 'MESH:C517975', (289, 296))	('Ki67', 'Gene', '17345', (223, 227))	('everolimus', 'Chemical', 'MESH:D000068338', (138, 148))	('Ki67', 'Gene', (68, 72))	('AZD6244', 'Var', (150, 157))	('AZD6244', 'Chemical', 'MESH:C517975', (150, 157))	('reduced', 'NegReg', (46, 53))	('Ki67', 'Gene', (223, 227))	('Ki67', 'Gene', '17345', (68, 72))	('mice', 'Species', '10090', (242, 246))
81864	27217440	Treatment with AZD6244 and PLX4720 reduced p-ERK expression in xenografts, as anticipated, an effect that was significantly more pronounced after AZD6244 than after PLX4720 treatment (Figure 5D, G).	('PLX4720', 'Chemical', 'MESH:C528407', (27, 34))	('reduced', 'NegReg', (35, 42))	('AZD6244', 'Chemical', 'MESH:C517975', (146, 153))	('expression', 'MPA', (49, 59))	('AZD6244', 'Chemical', 'MESH:C517975', (15, 22))	('PLX4720', 'Var', (27, 34))	('p-ERK', 'Gene', (43, 48))	('p-ERK', 'Gene', '13666', (43, 48))	('PLX4720', 'Chemical', 'MESH:C528407', (165, 172))	('AZD6244', 'Var', (146, 153))
81866	27217440	Although BRAFV600E-specific inhibitors such as vemurafenib and dabrafenib have only recently entered clinical practice for children whose tumors carry this mutation, initial reports are encouraging.	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))	('tumors', 'Disease', (138, 144))	('BRAFV600E-specific', 'Var', (9, 27))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('children', 'Species', '9606', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('dabrafenib', 'Chemical', 'MESH:C561627', (63, 73))	('vemurafenib', 'Chemical', 'MESH:D000077484', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
81870	27217440	Furthermore, combination of MEK- and BRAFV600E-inhibition improves tolerability with decreased frequency of squamous cell carcinomas, a rare but serious side effect of vemurafenib.	('vemurafenib', 'Chemical', 'MESH:D000077484', (168, 179))	('decreased', 'NegReg', (85, 94))	('MEK-', 'Var', (28, 32))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 132))	('BRAFV600E-inhibition', 'Var', (37, 57))	('improves', 'PosReg', (58, 66))	('squamous cell carcinomas', 'Disease', (108, 132))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (108, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('tolerability', 'MPA', (67, 79))
81871	27217440	In all our model systems of BRAFV600E mutated gliomas [isogenic murine, BRAFV600E PLGG (BT40) and BRAFV600E adult high-grade glioma (DBTRG, AM-38)], whether in vitro or in vivo, treatments with the three possible doublet combinations of AZD6244, everolimus and PLX4720 were superior to their respective mono-therapies, with PLX4720 + AZD6244 appearing the superior combination overall, showing consistently reduced cell viability, increased apoptosis and cell cycle arrest in vitro and most prominently prolonged survival and reduced tumor growth in vivo.	('reduced', 'NegReg', (526, 533))	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (455, 472))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('murine', 'Species', '10090', (64, 70))	('reduced', 'NegReg', (407, 414))	('BRAFV600E', 'Var', (98, 107))	('tumor', 'Disease', (534, 539))	('AZD6244', 'Var', (334, 341))	('arrest', 'Disease', (466, 472))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('AZD6244', 'Chemical', 'MESH:C517975', (334, 341))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('survival', 'CPA', (513, 521))	('DBTRG', 'Chemical', '-', (133, 138))	('AZD6244', 'Chemical', 'MESH:C517975', (237, 244))	('BRAFV600E', 'Mutation', 'rs113488022', (28, 37))	('BRAFV600E', 'Var', (72, 81))	('apoptosis', 'CPA', (441, 450))	('everolimus', 'Chemical', 'MESH:D000068338', (246, 256))	('arrest', 'Disease', 'MESH:D006323', (466, 472))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('PLX4720 + AZD6244', 'Var', (324, 341))	('BRAFV600E', 'Mutation', 'rs113488022', (98, 107))	('increased', 'PosReg', (431, 440))	('prolonged', 'PosReg', (503, 512))	('PLX4720', 'Chemical', 'MESH:C528407', (261, 268))	('glioma', 'Disease', (125, 131))	('PLX4720', 'Chemical', 'MESH:C528407', (324, 331))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Disease', (46, 52))	('gliomas', 'Disease', (46, 53))	('cell viability', 'CPA', (415, 429))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('BRAFV600E', 'Var', (28, 37))
81874	27217440	However, BT40, the only available pediatric model that carries the BRAFV600E mutation, only grows as a flank tumor and there are no intracranial models currently available to study PLGG.	('flank tumor', 'Disease', (103, 114))	('BRAFV600E', 'Var', (67, 76))	('BRAFV600E', 'Mutation', 'rs113488022', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('flank tumor', 'Disease', 'MESH:D021501', (103, 114))
81876	27217440	In examining responses in BRAFWT pediatric high-grade gliomas, we show that the combination of AZD6244 + everolimus was superior to either single agent therapy, as assessed by cell proliferation, cell cycle arrest and induction of apoptosis.	('apoptosis', 'CPA', (231, 240))	('AZD6244', 'Var', (95, 102))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('arrest', 'Disease', 'MESH:D006323', (207, 213))	('everolimus', 'Chemical', 'MESH:D000068338', (105, 115))	('cell proliferation', 'CPA', (176, 194))	('arrest', 'Disease', (207, 213))	('AZD6244', 'Chemical', 'MESH:C517975', (95, 102))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (196, 213))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
81883	27217440	We have shown in vivo and in vitro that BRAF-fusion expressing lines display robust resistance to and enhanced paradoxical activation by PLX4720.	('enhanced', 'PosReg', (102, 110))	('PLX4720', 'Var', (137, 144))	('PLX4720', 'Chemical', 'MESH:C528407', (137, 144))	('resistance', 'CPA', (84, 94))	('paradoxical activation', 'MPA', (111, 133))
81889	27217440	Our results support treatment of BRAFV600E positive PLGGs with a combination of PLX4720 + AZD6244, although AZD6244 + everolimus also shows marked combinatorial activity.	('AZD6244', 'Chemical', 'MESH:C517975', (90, 97))	('PLX4720', 'Var', (80, 87))	('AZD6244', 'Chemical', 'MESH:C517975', (108, 115))	('BRAFV600E positive', 'Var', (33, 51))	('PLGGs', 'Disease', (52, 57))	('PLX4720', 'Chemical', 'MESH:C528407', (80, 87))	('everolimus', 'Chemical', 'MESH:D000068338', (118, 128))	('BRAFV600E', 'Mutation', 'rs113488022', (33, 42))
81898	23892663	In the past year, new mutations in medulloblastoma and driver mutations in histone H3.3 and chromatin-remodeling factor genes in pediatric glioblastoma have been identified, providing key insights for the development of novel treatments for affected patients.	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('mutations', 'Var', (62, 71))	('pediatric glioblastoma', 'Disease', (129, 151))	('patients', 'Species', '9606', (250, 258))	('medulloblastoma', 'Disease', 'MESH:D008527', (35, 50))	('medulloblastoma', 'Phenotype', 'HP:0002885', (35, 50))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (129, 151))	('medulloblastoma', 'Disease', (35, 50))	('histone', 'Gene', (75, 82))
81906	23892663	They further identified new rearrangements and amplifications of MYB in 25% of diffuse cerebral gliomas.	('cerebral gliomas', 'Disease', (87, 103))	('MYB', 'Gene', (65, 68))	('MYB', 'Gene', '4602', (65, 68))	('rearrangements', 'Var', (28, 42))	('cerebral gliomas', 'Disease', 'MESH:C564230', (87, 103))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('amplifications', 'Var', (47, 61))
81907	23892663	Intriguingly, they found recurrent intragenic duplications of the region of FGFR1 encoding the tyrosine kinase domain (TKD) in 24% of diffuse grade II cerebral gliomas.	('II cerebral gliomas', 'Disease', 'MESH:C564230', (148, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('II cerebral gliomas', 'Disease', (148, 167))	('FGFR1', 'Gene', (76, 81))	('duplications', 'Var', (46, 58))
81908	23892663	When the investigators orthotopically transplanted Tp53-null astrocytes expressing TKD-duplicated FGFR1, all mice developed high-grade astrocytomas with complete penetrance.	('FGFR1', 'Gene', (98, 103))	('astrocytomas', 'Disease', (135, 147))	('Tp53', 'Gene', (51, 55))	('Tp53', 'Gene', '22059', (51, 55))	('TKD-duplicated', 'Var', (83, 97))	('developed', 'Reg', (114, 123))	('astrocytomas', 'Disease', 'MESH:D001254', (135, 147))	('mice', 'Species', '10090', (109, 113))
81910	23892663	Likewise, ectopic expression of TKD-duplicated FGFR1 in vitro resulted in FGFR1 autophosphorylation and activation of both MAPK-ERK and PI3K pathways.	('activation', 'PosReg', (104, 114))	('MAPK', 'Gene', (123, 127))	('FGFR1', 'Gene', (47, 52))	('TKD-duplicated', 'Var', (32, 46))	('ERK', 'Gene', (128, 131))	('ERK', 'Gene', '5594', (128, 131))	('autophosphorylation', 'MPA', (80, 99))	('MAPK', 'Gene', '5594', (123, 127))	('FGFR1', 'Gene', (74, 79))
81911	23892663	In addition to duplications, missense mutations in FGFR1 and FGFR-TACC fusions were also identified that can activate the MAPK-ERK and PI3K pathways.	('MAPK', 'Gene', (122, 126))	('FGFR-TACC', 'Gene', (61, 70))	('ERK', 'Gene', '5594', (127, 130))	('FGFR1', 'Gene', (51, 56))	('ERK', 'Gene', (127, 130))	('activate', 'PosReg', (109, 117))	('MAPK', 'Gene', '5594', (122, 126))	('missense mutations', 'Var', (29, 47))
81913	23892663	They reported the presence of KIAA1549-BRAF fusion variants, along with four new BRAF fusions and a single three-amino-acid insertion in the interdomain cleft of BRAF, which increased ERK phosphorylation as effectively as the BRAFV600E mutation.	('KIAA1549-BRAF', 'Disease', (30, 43))	('BRAF', 'Gene', '673', (39, 43))	('ERK', 'Gene', '5594', (184, 187))	('BRAF', 'Gene', (39, 43))	('variants', 'Var', (51, 59))	('ERK', 'Gene', (184, 187))	('BRAF', 'Gene', '673', (226, 230))	('BRAF', 'Gene', '673', (81, 85))	('KIAA1549-BRAF', 'Disease', 'None', (30, 43))	('BRAF', 'Gene', (226, 230))	('BRAF', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (162, 166))	('BRAFV600E', 'Mutation', 'rs113488022', (226, 235))	('increased', 'PosReg', (174, 183))	('BRAF', 'Gene', (162, 166))
81914	23892663	Interestingly, in the 19% of non-cerebellar tumors that lacked an alteration in BRAF or KRAS, new NTRK2 gene fusions affecting its kinase domain were identified.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('BRAF', 'Gene', (80, 84))	('NTRK2', 'Gene', (98, 103))	('kinase domain', 'MPA', (131, 144))	('fusions', 'Var', (109, 116))	('KRAS', 'Gene', (88, 92))	('NTRK2', 'Gene', '4915', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('KRAS', 'Gene', '3845', (88, 92))	('affecting', 'Reg', (117, 126))	('non-cerebellar tumors', 'Disease', (29, 50))	('BRAF', 'Gene', '673', (80, 84))	('non-cerebellar tumors', 'Disease', 'MESH:D002528', (29, 50))
81915	23892663	The resulting chimeric tyrosine kinases probably mediate ligand-independent dimerization, leading to a dominantly acting oncoprotein and potentially activating the MAPK pathway.	('MAPK', 'Gene', '5594', (164, 168))	('MAPK', 'Gene', (164, 168))	('activating', 'Reg', (149, 159))	('oncoprotein', 'MPA', (121, 132))	('chimeric', 'Var', (14, 22))
81916	23892663	also uncovered FGFR1 aberrations and identified mutations and duplications affecting the kinase domain of FGFR1, along with mutations in the tyrosine phosphatase PTPN11.	('FGFR1', 'Gene', (15, 20))	('FGFR1', 'Gene', (106, 111))	('PTPN11', 'Gene', '5781', (162, 168))	('duplications', 'Var', (62, 74))	('PTPN11', 'Gene', (162, 168))	('kinase domain', 'MPA', (89, 102))	('mutations', 'Var', (48, 57))
81917	23892663	Notably, PTPN11 alterations were only present in a subset of FGFR1-mutant tumors, suggesting a cooperative role for these factors in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('FGFR1-mutant', 'Var', (61, 73))	('PTPN11', 'Gene', '5781', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('FGFR1-mutant', 'Gene', (61, 73))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (133, 138))	('PTPN11', 'Gene', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
81918	23892663	Notably, all of the pilocytic astrocytomas harbored a MAPK pathway alteration, and, with the exception of the co-occurrence of mutations in FGFR1 and PTPN11, each case harbored only one alteration in the pathway per tumor.	('pilocytic astrocytomas', 'Disease', (20, 42))	('harbored', 'Reg', (43, 51))	('tumor', 'Disease', (216, 221))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (20, 42))	('PTPN11', 'Gene', (150, 156))	('FGFR1', 'Gene', (140, 145))	('alteration', 'Reg', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('MAPK', 'Gene', '5594', (54, 58))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PTPN11', 'Gene', '5781', (150, 156))	('MAPK', 'Gene', (54, 58))
81919	23892663	Both studies indicated that, unlike adult LGGs, in which hotspot mutations in IDH1 or IDH2 are found in more than 70% of tumors and tend to co-occur with TP53 and ATRX mutations or with 1p or 19q loss, pediatric LGGs are mainly driven by genetic aberrations that activate kinase signaling.	('IDH2', 'Gene', (86, 90))	('ATRX', 'Gene', '546', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('co-occur', 'Reg', (140, 148))	('TP53', 'Gene', (154, 158))	('IDH2', 'Gene', '3418', (86, 90))	('IDH1', 'Gene', (78, 82))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('IDH1', 'Gene', '3417', (78, 82))	('loss', 'NegReg', (196, 200))	('ATRX', 'Gene', (163, 167))	('TP53', 'Gene', '7157', (154, 158))	('mutations', 'Var', (65, 74))
81920	23892663	At least, from what we know so far, driver mutations in the epigenetic machinery seem to be reserved for higher grade pediatric glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (128, 141))	('pediatric glioblastoma', 'Disease', (118, 140))	('glioblastomas', 'Disease', (128, 141))	('epigenetic', 'Gene', (60, 70))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (118, 140))	('mutations', 'Var', (43, 52))	('glioblastomas', 'Phenotype', 'HP:0012174', (128, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
81921	23892663	identified only one FGFR1-mutant tumor that also had a mutation affecting histone H3.3.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('mutation', 'Var', (55, 63))	('histone H3.3', 'Protein', (74, 86))	('FGFR1-mutant', 'Gene', (20, 32))
81926	23892663	converge on the hypothesis that, despite the mutational heterogeneity among different tumors, genetic alterations in LGGs commonly lead to the activation of the MAPK-ERK and PI3K pathways.	('LGGs', 'Gene', (117, 121))	('MAPK', 'Gene', '5594', (161, 165))	('genetic alterations', 'Var', (94, 113))	('ERK', 'Gene', '5594', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('MAPK', 'Gene', (161, 165))	('ERK', 'Gene', (166, 169))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('activation', 'PosReg', (143, 153))	('lead to', 'Reg', (131, 138))
81930	26485760	IDH1 mutation detection by droplet digital PCR in glioma Glioma is the most frequent central nervous system tumor in adults.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('IDH1', 'Gene', '3417', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('central nervous system tumor', 'Phenotype', 'HP:0100006', (85, 113))	('glioma', 'Disease', (50, 56))	('tumor', 'Disease', (108, 113))	('Glioma', 'Phenotype', 'HP:0009733', (57, 63))	('nervous system tumor', 'Phenotype', 'HP:0004375', (93, 113))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('Glioma', 'Disease', 'MESH:D005910', (57, 63))	('mutation', 'Var', (5, 13))	('Glioma', 'Disease', (57, 63))
81933	26485760	Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('IDH', 'Gene', '3417', (13, 16))	('gliomas', 'Disease', (61, 68))	('glioblastoma', 'Disease', (87, 99))	('Mutations', 'Var', (0, 9))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('observed', 'Reg', (27, 35))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('IDH', 'Gene', (13, 16))
81934	26485760	As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients.	('R132H', 'SUBSTITUTION', 'None', (36, 41))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('patients', 'Species', '9606', (92, 100))	('glioma', 'Disease', (85, 91))	('R132H', 'Var', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('IDH1', 'Gene', (31, 35))
81935	26485760	In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR).	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (90, 94))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('mutations', 'Var', (95, 104))	('detected', 'Reg', (81, 89))	('glioma', 'Disease', (38, 44))
81936	26485760	Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation.	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (86, 89))	('mutation', 'Var', (90, 98))
81944	26485760	Mutations in IDH genes (IDH1 and IDH2) are observed in over 70% of low-grade gliomas and some GBM.	('IDH', 'Gene', '3417', (13, 16))	('IDH1', 'Gene', '3417', (24, 28))	('IDH2', 'Gene', (33, 37))	('IDH', 'Gene', (24, 27))	('gliomas', 'Disease', (77, 84))	('observed', 'Reg', (43, 51))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('IDH', 'Gene', '3417', (24, 27))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('IDH2', 'Gene', '3418', (33, 37))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (24, 28))	('IDH', 'Gene', (33, 36))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', '3417', (33, 36))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
81945	26485760	The most frequent mutation (over 95%) is the G to A mutation on amino acid 132 (CGT > CAT, R132H) at exon 4.	('CGT', 'Gene', (80, 83))	('R132H', 'Var', (91, 96))	('CGT', 'Gene', '7368', (80, 83))	('CAT', 'Gene', (86, 89))	('CAT', 'Gene', '847', (86, 89))	('R132H', 'Mutation', 'rs121913500', (91, 96))
81946	26485760	The following mutation patterns were also identified: R132C (CGT > TGT), R132L (CGT > CTT), R132S (CGT > AGT), and R132G (CGT > GGT).	('TGT', 'Gene', '81890', (67, 70))	('CGT', 'Gene', '7368', (122, 125))	('CGT', 'Gene', (122, 125))	('CGT', 'Gene', '7368', (80, 83))	('R132G', 'Mutation', 'rs121913499', (115, 120))	('TGT', 'Gene', (67, 70))	('R132C', 'Var', (54, 59))	('CGT', 'Gene', (80, 83))	('R132C', 'Mutation', 'rs121913499', (54, 59))	('R132L', 'Var', (73, 78))	('AGT', 'Gene', '183', (105, 108))	('R132S', 'Var', (92, 97))	('R132S', 'Mutation', 'rs121913499', (92, 97))	('CGT', 'Gene', '7368', (99, 102))	('CGT', 'Gene', '7368', (61, 64))	('CGT', 'Gene', (99, 102))	('CGT', 'Gene', (61, 64))	('AGT', 'Gene', (105, 108))	('R132L', 'Mutation', 'rs121913500', (73, 78))
81947	26485760	Wild-type IDH1 converts isocitrate to alpha-ketoglutarate (a potential oncometabolite), whereas the mutant IDH1 yields a neomorphic enzymatic function and catalyzes alpha-ketoglutarate into alpha-hydroxyglutarate, which is an oncometabolite that is related to genomic hypertension, genetic instability, and malignant transformation.	('yields', 'Reg', (112, 118))	('IDH1', 'Gene', (107, 111))	('IDH1', 'Gene', '3417', (10, 14))	('isocitrate', 'Chemical', 'MESH:C034219', (24, 34))	('mutant', 'Var', (100, 106))	('IDH1', 'Gene', '3417', (107, 111))	('alpha-hydroxyglutarate', 'Chemical', 'MESH:C019417', (190, 212))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (38, 57))	('hypertension', 'Disease', 'MESH:D006973', (268, 280))	('IDH1', 'Gene', (10, 14))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (165, 184))	('hypertension', 'Disease', (268, 280))	('hypertension', 'Phenotype', 'HP:0000822', (268, 280))
81948	26485760	The IDH1 mutation is one of the most common and earliest genetic alterations in glioma and is an effective diagnostic and predictive marker in glioma patients.	('glioma', 'Disease', (80, 86))	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('patients', 'Species', '9606', (150, 158))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('IDH1', 'Gene', (4, 8))	('glioma', 'Disease', (143, 149))
81949	26485760	investigated The Cancer Genome Atlas (TCGA) data and found that the level of pyruvate carboxylase was higher in human gliomas containing the IDH1 mutation than in those with wild-type IDH1.	('IDH1', 'Gene', (141, 145))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('IDH1', 'Gene', (184, 188))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('IDH1', 'Gene', '3417', (141, 145))	('pyruvate carboxylase', 'Gene', (77, 97))	('IDH1', 'Gene', '3417', (184, 188))	('higher', 'PosReg', (102, 108))	('Cancer Genome Atlas', 'Disease', (17, 36))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (17, 36))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('mutation', 'Var', (146, 154))	('human', 'Species', '9606', (112, 117))	('pyruvate carboxylase', 'Gene', '5091', (77, 97))
81950	26485760	The fractional flux, which depends on the activity of pyruvate carboxylase, is therefore increased in cells with the IDH1 mutation.	('pyruvate carboxylase', 'Gene', '5091', (54, 74))	('fractional flux', 'MPA', (4, 19))	('pyruvate carboxylase', 'Gene', (54, 74))	('IDH1', 'Gene', '3417', (117, 121))	('mutation', 'Var', (122, 130))	('increased', 'PosReg', (89, 98))	('IDH1', 'Gene', (117, 121))
81951	26485760	demonstrated that the mutated IDH1 (R132H) is involved in phosphoethanolamine and glycerophosphocholine and subsequently alters phospholipid metabolism in glioma.	('phospholipid metabolism', 'MPA', (128, 151))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (58, 77))	('glycerophosphocholine', 'Chemical', 'MESH:D005997', (82, 103))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('mutated', 'Var', (22, 29))	('alters', 'Reg', (121, 127))	('IDH1', 'Gene', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('R132H', 'Var', (36, 41))	('involved', 'Reg', (46, 54))	('phospholipid', 'Chemical', 'MESH:D010743', (128, 140))	('R132H', 'Mutation', 'rs121913500', (36, 41))	('IDH1', 'Gene', '3417', (30, 34))	('glioma', 'Disease', (155, 161))
81952	26485760	Thus, the importance of the IDH mutation in the early development of glioma was confirmed.	('glioma', 'Disease', (69, 75))	('IDH', 'Gene', (28, 31))	('IDH', 'Gene', '3417', (28, 31))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('mutation', 'Var', (32, 40))
81953	26485760	In addition to the important role in glioma, IDH mutations were found in myeloid neoplasia, peripheral T-cell lymphoma, chondrosarcoma, chonangiocarcinoma, prostate cancer, and other cancers.	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('mutations', 'Var', (49, 58))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cell lymphoma', 'Phenotype', 'HP:0012191', (105, 118))	('chonangiocarcinoma, prostate cancer', 'Disease', 'MESH:D011471', (136, 171))	('neoplasia', 'Phenotype', 'HP:0002664', (81, 90))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (103, 118))	('myeloid neoplasia', 'Phenotype', 'HP:0012324', (73, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (110, 118))	('myeloid neoplasia', 'Disease', (73, 90))	('IDH', 'Gene', (45, 48))	('myeloid neoplasia', 'Disease', 'MESH:D009369', (73, 90))	('peripheral T-cell lymphoma', 'Disease', 'MESH:D016411', (92, 118))	('found', 'Reg', (64, 69))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('glioma', 'Disease', (37, 43))	('IDH', 'Gene', '3417', (45, 48))	('peripheral T-cell lymphoma', 'Disease', (92, 118))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('chondrosarcoma', 'Disease', (120, 134))	('chondrosarcoma', 'Disease', 'MESH:D002813', (120, 134))	('glioma', 'Disease', 'MESH:D005910', (37, 43))
81954	26485760	As an "ultra-sensitive detection method", ddPCR was applied in the pretreatment of EGFR T790M mutations in non-small cell lung cancer patients.	('EGFR', 'Gene', '1956', (83, 87))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('T790M', 'Mutation', 'rs121434569', (88, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('EGFR', 'Gene', (83, 87))	('T790M', 'Var', (88, 93))	('patients', 'Species', '9606', (134, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('cell lung cancer', 'Disease', (117, 133))	('cell lung cancer', 'Disease', 'MESH:D008175', (117, 133))
81955	26485760	Detection of HER2 amplification in gastric cancer by ddPCR was as effective as immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) and may become a standard method for analyzing formalin-fixed paraffin-embedded (FFPE) samples.	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('HER2', 'Gene', (13, 17))	('amplification', 'Var', (18, 31))	('paraffin', 'Chemical', 'MESH:D010232', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('HER2', 'Gene', '2064', (13, 17))	('gastric cancer', 'Disease', (35, 49))	('ddPCR', 'Var', (53, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))	('formalin', 'Chemical', 'MESH:D005557', (193, 201))
81956	26485760	In glioma, ddPCR successfully measured the IDH1 mutations in extracellular vesicles and cerebrospinal fluid.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('IDH1', 'Gene', (43, 47))	('measured', 'Reg', (30, 38))	('glioma', 'Disease', (3, 9))	('IDH1', 'Gene', '3417', (43, 47))	('mutations', 'Var', (48, 57))
81957	26485760	In the current study, we collected 62 glioma patient tumor samples and detected IDH1(R132H) mutation with ddPCR and qRT-PCR.	('IDH1', 'Gene', (80, 84))	('R132H', 'SUBSTITUTION', 'None', (85, 90))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('R132H', 'Var', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ddPCR', 'Disease', (106, 111))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('patient', 'Species', '9606', (45, 52))	('detected', 'Reg', (71, 79))	('tumor', 'Disease', (53, 58))	('glioma', 'Disease', (38, 44))
81958	26485760	We also analyzed the role of IDH1(R132H) mutations in the prognosis of low-grade glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH1', 'Gene', (29, 33))	('R132H', 'SUBSTITUTION', 'None', (34, 39))	('patients', 'Species', '9606', (88, 96))	('glioma', 'Disease', (81, 87))	('R132H', 'Var', (34, 39))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
81965	26485760	1C, and the sample with heterogeneous wild-type IDH1 and R132H mutations is shown in Fig.	('IDH1', 'Gene', '3417', (48, 52))	('IDH1', 'Gene', (48, 52))	('R132H', 'Var', (57, 62))	('R132H', 'Mutation', 'rs121913500', (57, 62))
81970	26485760	Sequencing data showed that 19 of the 62 glioma patients (30.65%) had a IDH1(R132H) mutation in our cohort, whereas the detection rates of ddPCR and qRT-PCR were 33.87% and 27.42%, respectively.	('mutation', 'Var', (84, 92))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('R132H', 'Var', (77, 82))	('glioma', 'Disease', (41, 47))	('patients', 'Species', '9606', (48, 56))	('R132H', 'SUBSTITUTION', 'None', (77, 82))
81972	26485760	To determine the difference in the detection sensitivity of a low-concentration template, we performed ddPCR and qRT-PCR with diluted samples (Sample No.19, with IDH1(R132H) mutation).	('R132H', 'SUBSTITUTION', 'None', (167, 172))	('R132H', 'Var', (167, 172))	('IDH1', 'Gene', (162, 166))
81973	26485760	We first investigated the frequency of IDH1 mutations in our cohort.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))
81974	26485760	The distribution of IDH1 mutations among Grade II to IV samples was significantly different based on two-sided Fisher's exact test (p = 0.043, Table 3).	('IDH1', 'Gene', '3417', (20, 24))	('IDH1', 'Gene', (20, 24))	('mutations', 'Var', (25, 34))
81975	26485760	Our data thus confirmed that the IDH1 mutation more frequently occurred in low-grade gliomas (Grade II and III) than in high-grade gliomas (Grade IV), in accordance with previous reports.	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('IDH1', 'Gene', (33, 37))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('gliomas', 'Disease', (85, 92))	('IDH1', 'Gene', '3417', (33, 37))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('mutation', 'Var', (38, 46))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('occurred', 'Reg', (63, 71))
81976	26485760	It has been reported that the IDH mutation is a positive prognostic biomarker of low-grade gliomas (Grade II and III).	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('mutation', 'Var', (34, 42))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (30, 33))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
81978	26485760	At a median follow-up of 57.6 months (range from 17.2-139.40 months), the 5-year survival rates were 66.67% and 37.50%, for patients with or without IDH1 mutation, respectively (p = 0.048, Table 4).	('IDH1', 'Gene', (149, 153))	('mutation', 'Var', (154, 162))	('patients', 'Species', '9606', (124, 132))	('IDH1', 'Gene', '3417', (149, 153))
81979	26485760	We used two Kaplan-Meier survival analysis methods, the Log-rank and Breslow tests, to evaluate the role of the IDH1 mutation in the prognosis of glioma patients (Grade II and III).	('patients', 'Species', '9606', (153, 161))	('glioma', 'Disease', (146, 152))	('IDH1', 'Gene', (112, 116))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('mutation', 'Var', (117, 125))	('IDH1', 'Gene', '3417', (112, 116))
81980	26485760	The overall survival rate of patients with wild-type and mutant IDH1 was 28.13% and 50.00% respectively, which was significantly different by Breslow analysis (p = 0.038), but not by Log-rank analysis (p = 0.132, Table 4, Figure 4).	('IDH1', 'Gene', '3417', (64, 68))	('mutant', 'Var', (57, 63))	('IDH1', 'Gene', (64, 68))	('patients', 'Species', '9606', (29, 37))
81981	26485760	Furthermore, we detected only the mutations on IDH1 but not on IDH2, which may have led to the inconsistency in the correlation analysis.	('IDH2', 'Gene', '3418', (63, 67))	('IDH1', 'Gene', (47, 51))	('detected', 'Reg', (16, 24))	('IDH2', 'Gene', (63, 67))	('IDH1', 'Gene', '3417', (47, 51))	('mutations', 'Var', (34, 43))
81982	26485760	We therefore confirmed that the IDH1 mutation is a positive prognosis marker in low-grade glioma patients.	('glioma', 'Disease', (90, 96))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('IDH1', 'Gene', '3417', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('patients', 'Species', '9606', (97, 105))
81983	26485760	Publications in the 2015 New England Journal of Medicine and Nature Genetics confirmed the positive role of mutant IDH in glioma evolution and prognosis.	('positive', 'PosReg', (91, 99))	('glioma', 'Disease', (122, 128))	('mutant', 'Var', (108, 114))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
81985	26485760	They then classified low-grade gliomas into following types: type I, with both IDH mutant and 1p19q codeletion; type II, with IDH mutant only; and type III, with wild-type IDH.	('1p19q codeletion', 'Var', (94, 110))	('IDH', 'Gene', (172, 175))	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', '3417', (126, 129))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('IDH', 'Gene', '3417', (172, 175))	('IDH', 'Gene', '3417', (79, 82))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('IDH', 'Gene', (126, 129))	('gliomas', 'Disease', (31, 38))
81987	26485760	These two studies yielded consistent results and revealed that IDH1 mutation correlated with both the specific mutation profiles and distinctive clinical behaviors better than traditional histology-based grouping.	('mutation', 'Var', (68, 76))	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (63, 67))
81988	26485760	scored tumors according to the IDH mutation, mutations in the TERT (telomerase reverse transcriptase) promoter, and the codeletion of 1p19q in 1087 gliomas and 11590 controls.	('IDH', 'Gene', (31, 34))	('gliomas', 'Disease', (148, 155))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('IDH', 'Gene', '3417', (31, 34))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('TERT', 'Gene', (62, 66))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('telomerase reverse transcriptase', 'Gene', (68, 100))	('TERT', 'Gene', '7015', (62, 66))	('mutations in', 'Var', (45, 57))	('telomerase reverse transcriptase', 'Gene', '7015', (68, 100))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
81991	26485760	These molecular classifications reveal that the metabolic reprogramming caused by mutant IDH may occur early in glioma development.	('metabolic reprogramming', 'CPA', (48, 71))	('glioma', 'Disease', (112, 118))	('IDH', 'Gene', (89, 92))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('IDH', 'Gene', '3417', (89, 92))	('mutant', 'Var', (82, 88))
81992	26485760	Accordingly, the critical role of IDH mutations in molecular diagnosis, determination of therapeutic strategy, and prediction of prognosis was established.	('mutations', 'Var', (38, 47))	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))
81996	26485760	Early detection of the ESR1 mutation with ddPCR in breast cancer biopsies allowed for the cessation of ineffective endocrine therapies and the initiation of other treatments without the need for tissue biopsy.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ESR1', 'Gene', '2099', (23, 27))	('mutation', 'Var', (28, 36))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('ESR1', 'Gene', (23, 27))
82001	26485760	We successfully applied ddPCR to detect the frequent mutation of IDH1 in glioma patient tissue samples in the current study.	('IDH1', 'Gene', '3417', (65, 69))	('glioma', 'Disease', (73, 79))	('mutation', 'Var', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH1', 'Gene', (65, 69))	('patient', 'Species', '9606', (80, 87))
82002	26485760	Compared with Sanger direct sequencing and qRT-PCR, ddPCR is a simple and sensitive method with which to detect site mutations and could be widely applied in cancer to detect, for example, mutations, copy number variations, and circulating nucleic acids.	('copy number variations', 'Var', (200, 222))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('mutations', 'Var', (189, 198))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
82017	26485760	A sample with a strong mutant IDH1(R132H) signal was chosen and diluted with double-distilled water at the following ratios: 1:8, 1:16, 1:32, 1:64, 1:128, 1:256, and 1:512.	('IDH1', 'Gene', (30, 34))	('R132H', 'SUBSTITUTION', 'None', (35, 40))	('water', 'Chemical', 'MESH:D014867', (94, 99))	('R132H', 'Var', (35, 40))
82018	26485760	The overall survival of glioma patients (Grade II and III) with wild-type or mutant IDH1 was investigated by Kaplan-Meier survival analysis, including the Log-rank (Mantel Cox) and Breslow tests.	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH1', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (84, 88))	('patients', 'Species', '9606', (31, 39))	('glioma', 'Disease', (24, 30))	('mutant', 'Var', (77, 83))
82019	26485760	Five-year survival rate of patients (Grade II and III) were analyzed by Chi-square test between those with or without IDH1 mutation.	('patients', 'Species', '9606', (27, 35))	('IDH1', 'Gene', '3417', (118, 122))	('mutation', 'Var', (123, 131))	('IDH1', 'Gene', (118, 122))
82027	25714806	The area under the receiver operating characteristic curve for the SUVgluc (0.8933) was better than that for the SUVmax (0.8266) (P<0.01) and was similar to those of the GMR (0.8622), SUVRc (0.8606), and SUVRw (0.8981).	('better', 'PosReg', (88, 94))	('GMR', 'Chemical', '-', (170, 173))	('0.8933', 'Var', (76, 82))
82126	25714806	In-vivo and in-vitro studies have shown that metformin stimulates the insulin-induced glucose uptake into skeletal muscle and adipocytes in both diabetic individuals and animal models.	('diabetic', 'Disease', (145, 153))	('insulin', 'Gene', '3630', (70, 77))	('metformin', 'Var', (45, 54))	('insulin', 'Gene', (70, 77))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('diabetic', 'Disease', 'MESH:D003920', (145, 153))	('stimulates', 'PosReg', (55, 65))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))
82127	25714806	It has also been shown that insulin-mediated visceral fat glucose uptake is enhanced by metformin monotherapy, which is believed to be related to enhancement in visceral fat insulin sensitivity.	('monotherapy', 'Var', (98, 109))	('metformin monotherapy', 'Var', (88, 109))	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('insulin', 'Gene', (174, 181))	('insulin', 'Gene', '3630', (174, 181))	('insulin', 'Gene', (28, 35))	('enhanced', 'PosReg', (76, 84))	('glucose', 'Chemical', 'MESH:D005947', (58, 65))	('insulin', 'Gene', '3630', (28, 35))
82129	25714806	We excluded three lesions in patients who were on metformin and had a high blood glucose level (>170 mg/dl) because metformin produces a dose-dependent increase in tumor glucose uptake and the high blood glucose level causes the SUVgluc to be overcorrected.	('tumor glucose uptake', 'Disease', 'MESH:C536778', (164, 184))	('metformin', 'Var', (116, 125))	('causes', 'Reg', (218, 224))	('metformin', 'Chemical', 'MESH:D008687', (50, 59))	('patients', 'Species', '9606', (29, 37))	('increase', 'PosReg', (152, 160))	('metformin', 'Chemical', 'MESH:D008687', (116, 125))	('blood glucose', 'Chemical', 'MESH:D001786', (198, 211))	('blood glucose', 'Chemical', 'MESH:D001786', (75, 88))	('high blood glucose', 'Phenotype', 'HP:0003074', (70, 88))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor glucose uptake', 'Disease', (164, 184))	('high blood glucose', 'Phenotype', 'HP:0003074', (193, 211))
82233	23618919	Besides SWI, there is substantial material available in the current literature on the use of other physiologic MR sequences for grading gliomas, namely DWI, proton MR spectroscopy (1HMRS) and PWI.	('MRS', 'Disease', (183, 186))	('DWI', 'Disease', (152, 155))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('gliomas', 'Disease', (136, 143))	('MRS', 'Disease', 'MESH:D008556', (183, 186))	('PWI', 'Var', (192, 195))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
82262	32009124	Patient clinical, radiological, and pathological data were stratified based on the following 16 variables: age, sex, location of tumor, existence of the preoperative seizure, extent of resection, administration of temozolomide, radiation therapy, recurrence, Karnofsky performance scale, isocitrate dehydrogenase 1, 1p/19q co-deletion, Olig2, platelet-derived growth factor receptor alpha, p53, ATRX, and Ki67.	('Olig2', 'Gene', '10215', (336, 341))	('seizure', 'Phenotype', 'HP:0001250', (166, 173))	('ATRX', 'Gene', (395, 399))	('Ki67', 'Var', (405, 409))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('isocitrate dehydrogenase 1', 'Gene', (288, 314))	('p53', 'Gene', (390, 393))	('isocitrate dehydrogenase 1', 'Gene', '3417', (288, 314))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('seizure', 'Disease', (166, 173))	('temozolomide', 'Chemical', 'MESH:D000077204', (214, 226))	('ATRX', 'Gene', '546', (395, 399))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (343, 388))	('seizure', 'Disease', 'MESH:D012640', (166, 173))	('tumor', 'Disease', (129, 134))	('platelet-derived growth factor receptor alpha', 'Gene', (343, 388))	('Patient', 'Species', '9606', (0, 7))	('Olig2', 'Gene', (336, 341))
82265	32009124	Neither clinical nor radiological characteristics were significantly different between these two groups, though p53 immunodetection levels were significantly higher, and the frequency of 1p/19q co-deletion was significantly lower in the group with drug-resistant seizures than in the well-controlled group.	('p53 immunodetection levels', 'MPA', (112, 138))	('seizures', 'Phenotype', 'HP:0001250', (263, 271))	('seizures', 'Disease', (263, 271))	('seizure', 'Phenotype', 'HP:0001250', (263, 270))	('higher', 'PosReg', (158, 164))	('lower', 'NegReg', (224, 229))	('co-deletion', 'Var', (194, 205))	('seizures', 'Disease', 'MESH:D012640', (263, 271))	('1p/19q co-deletion', 'Var', (187, 205))
82280	32009124	It has been reported that isocitrate dehydrogenase 1 (IDH-1) mutation, 1p/19q co-deletion, and high expression levels of Ki67 are associated with seizure occurrence.	('seizure', 'Phenotype', 'HP:0001250', (146, 153))	('isocitrate dehydrogenase 1', 'Gene', (26, 52))	('isocitrate dehydrogenase 1', 'Gene', '3417', (26, 52))	('expression levels', 'MPA', (100, 117))	('associated', 'Reg', (130, 140))	('mutation', 'Var', (61, 69))	('seizure', 'Disease', (146, 153))	('seizure', 'Disease', 'MESH:D012640', (146, 153))	('IDH-1', 'Gene', '3417', (54, 59))	('IDH-1', 'Gene', (54, 59))
82286	32009124	Consequently, patients diagnosed with diffuse astrocytoma with IDH-1 mutation, oligodendroglioma with IDH-1 mutation and 1p/19q co-deletion, diffuse astrocytoma with wild-type IDH-1, and oligodendroglioma not-otherwise-specified (NOS) were included.	('IDH-1', 'Gene', (63, 68))	('astrocytoma', 'Disease', 'MESH:D001254', (149, 160))	('astrocytoma', 'Disease', (149, 160))	('astrocytoma', 'Disease', 'MESH:D001254', (46, 57))	('oligodendroglioma', 'Disease', (187, 204))	('astrocytoma', 'Disease', (46, 57))	('patients', 'Species', '9606', (14, 22))	('IDH-1', 'Gene', (102, 107))	('IDH-1', 'Gene', '3417', (176, 181))	('oligodendroglioma', 'Disease', 'MESH:D009837', (79, 96))	('IDH-1', 'Gene', '3417', (63, 68))	('oligodendroglioma', 'Disease', (79, 96))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (46, 57))	('IDH-1', 'Gene', '3417', (102, 107))	('oligodendroglioma', 'Disease', 'MESH:D009837', (187, 204))	('IDH-1', 'Gene', (176, 181))	('mutation', 'Var', (69, 77))	('mutation', 'Var', (108, 116))
82306	32009124	In terms of pathological diagnosis, 26 cases carried an IDH-1 mutation and 10 cases did not.	('IDH-1', 'Gene', '3417', (56, 61))	('IDH-1', 'Gene', (56, 61))	('mutation', 'Var', (62, 70))
82307	32009124	Of the 26 cases with the IDH-1 mutation, 13 cases carried the 1p/19q co-deletion and 13 cases did not.	('IDH-1', 'Gene', '3417', (25, 30))	('IDH-1', 'Gene', (25, 30))	('1p/19q co-deletion', 'Var', (62, 80))	('mutation', 'Var', (31, 39))
82308	32009124	Pathological diagnosis according to the 2016 WHO guidelines was diffuse astrocytoma with IDH-1 mutation in 14 cases, diffuse astrocytoma with wild-type IDH in eight cases, oligodendroglioma with IDH-1 mutation and 1p/19q co-deletion in 13 cases, and oligodendroglioma with NOS in one case.	('diffuse', 'Disease', (117, 124))	('oligodendroglioma', 'Disease', 'MESH:D009837', (250, 267))	('IDH-1', 'Gene', (89, 94))	('oligodendroglioma', 'Disease', (172, 189))	('IDH-1', 'Gene', '3417', (195, 200))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', (152, 155))	('oligodendroglioma', 'Disease', (250, 267))	('mutation', 'Var', (201, 209))	('IDH', 'Gene', '3417', (89, 92))	('astrocytoma', 'Disease', 'MESH:D001254', (125, 136))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('astrocytoma', 'Disease', (125, 136))	('IDH', 'Gene', '3417', (152, 155))	('IDH-1', 'Gene', '3417', (89, 94))	('mutation', 'Var', (95, 103))	('IDH-1', 'Gene', (195, 200))	('IDH', 'Gene', (195, 198))	('astrocytoma', 'Disease', 'MESH:D001254', (72, 83))	('astrocytoma', 'Disease', (72, 83))	('oligodendroglioma', 'Disease', 'MESH:D009837', (172, 189))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('IDH', 'Gene', (89, 92))
82310	32009124	Mortality was observed at 1841 days, 2050 days, and 745 days after diagnosis in one case of diffuse astrocytoma with IDH-1 mutation and two cases of diffuse astrocytoma with wild-type IDH-1, respectively.	('astrocytoma', 'Disease', 'MESH:D001254', (100, 111))	('mutation', 'Var', (123, 131))	('astrocytoma', 'Disease', (157, 168))	('IDH-1', 'Gene', '3417', (117, 122))	('IDH-1', 'Gene', (117, 122))	('astrocytoma', 'Disease', (100, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('IDH-1', 'Gene', '3417', (184, 189))	('IDH-1', 'Gene', (184, 189))	('astrocytoma', 'Disease', 'MESH:D001254', (157, 168))
82330	32009124	On the other hand, eight cases (57.1%) in well-controlled group and two cases (15.4%) in the drug-resistant seizure group had the 1p/19q co-deletion and this difference was statistically significant (P = 0.046), indicating that the patients without 1p/19q co-deletion mostly had drug-resistant seizures.	('seizure', 'Disease', (294, 301))	('1p/19q co-deletion', 'Var', (130, 148))	('seizure', 'Disease', 'MESH:D012640', (294, 301))	('seizures', 'Phenotype', 'HP:0001250', (294, 302))	('patients', 'Species', '9606', (232, 240))	('seizures', 'Disease', (294, 302))	('seizure', 'Disease', (108, 115))	('seizure', 'Phenotype', 'HP:0001250', (294, 301))	('seizure', 'Disease', 'MESH:D012640', (108, 115))	('seizures', 'Disease', 'MESH:D012640', (294, 302))	('1p/19q co-deletion', 'Var', (249, 267))	('seizure', 'Phenotype', 'HP:0001250', (108, 115))
82333	32009124	Consequently, the presence of p53 and 1p/19q co-deletion were identified to have a statistically significant association with seizure control.	('seizure', 'Disease', (126, 133))	('p53', 'Var', (30, 33))	('1p/19q co-deletion', 'Var', (38, 56))	('seizure', 'Disease', 'MESH:D012640', (126, 133))	('association', 'Reg', (109, 120))	('seizure', 'Phenotype', 'HP:0001250', (126, 133))
82335	32009124	In the univariate analysis, the prevalence of drug resistant seizure was associated with neurological symptoms (OR, 11.143; 95% CI, 1.108-112.012; P = 0.041), 1p/19q co-deletion (OR, 0.136; 95% CI, 0.022-0.860; P = 0.034) and p53 (OR, 21.600; 95% CI, 2.135-218.579; P = 0.009).	('seizure', 'Disease', (61, 68))	('seizure', 'Disease', 'MESH:D012640', (61, 68))	('associated', 'Reg', (73, 83))	('neurological symptoms', 'Disease', (89, 110))	('co-deletion', 'Var', (166, 177))	('p53', 'Var', (226, 229))	('seizure', 'Phenotype', 'HP:0001250', (61, 68))	('1p/19q co-deletion', 'Var', (159, 177))
82338	32009124	The mean periods between seizure recurrence were 63.0 months (95% CI, 41.3-84.7) in the patients with the 1p/19q co-deletion versus 19.5 months (95% CI, 10.3-28.7) in the patients without 1p/19q co-deletion (P = 0.016).	('1p/19q co-deletion', 'Var', (106, 124))	('seizure', 'Disease', (25, 32))	('patients', 'Species', '9606', (88, 96))	('seizure', 'Disease', 'MESH:D012640', (25, 32))	('seizure', 'Phenotype', 'HP:0001250', (25, 32))	('patients', 'Species', '9606', (171, 179))	('co-deletion', 'Var', (113, 124))
82341	32009124	The results of our study indicated that the control of seizures in diffuse astrocytoma and oligodendroglioma is associated with p53 immunopositivity.	('p53 immunopositivity', 'Var', (128, 148))	('seizures', 'Disease', 'MESH:D012640', (55, 63))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (75, 108))	('seizures', 'Disease', (55, 63))	('seizures', 'Phenotype', 'HP:0001250', (55, 63))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('associated', 'Reg', (112, 122))	('seizure', 'Phenotype', 'HP:0001250', (55, 62))
82344	32009124	Many types of cancer present abnormalities in p53 such as loss and mutation.	('cancer', 'Disease', (14, 20))	('mutation', 'Var', (67, 75))	('p53', 'Gene', (46, 49))	('loss', 'Disease', 'MESH:D015431', (58, 62))	('loss', 'Disease', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
82345	32009124	In gliomas, immunodetection of p53 upregulation is indicative of the presence of p53 abnormalities and poor prognosis.	('p53', 'Gene', (31, 34))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('abnormalities', 'Var', (85, 98))	('gliomas', 'Disease', (3, 10))	('upregulation', 'PosReg', (35, 47))
82349	32009124	p53 is associated with neuronal death.	('associated', 'Reg', (7, 17))	('neuronal death', 'Disease', (23, 37))	('p53', 'Var', (0, 3))	('neuronal death', 'Disease', 'MESH:D009410', (23, 37))
82351	32009124	Indeed, in human temporal epilepsy and animal temporal epilepsy models, the levels of normal p53 were elevated in the hippocampus, and the absence of p53 was related to worse seizure outcomes because of seizure-induced neuronal death.	('human', 'Species', '9606', (11, 16))	('absence', 'Var', (139, 146))	('seizure', 'Disease', (203, 210))	('seizure', 'Disease', 'MESH:D012640', (175, 182))	('p53', 'Gene', (150, 153))	('neuronal death', 'Disease', 'MESH:D009410', (219, 233))	('seizure', 'Phenotype', 'HP:0001250', (175, 182))	('epilepsy', 'Disease', 'MESH:D004827', (26, 34))	('levels', 'MPA', (76, 82))	('p53', 'Protein', (93, 96))	('epilepsy', 'Disease', 'MESH:D004827', (55, 63))	('seizure', 'Disease', (175, 182))	('epilepsy', 'Phenotype', 'HP:0001250', (26, 34))	('epilepsy', 'Phenotype', 'HP:0001250', (55, 63))	('neuronal death', 'Disease', (219, 233))	('elevated', 'PosReg', (102, 110))	('epilepsy', 'Disease', (26, 34))	('epilepsy', 'Disease', (55, 63))	('seizure', 'Disease', 'MESH:D012640', (203, 210))	('seizure', 'Phenotype', 'HP:0001250', (203, 210))
82353	32009124	Therefore, p53 abnormalities might facilitate further intractability of seizures when epileptogenesis is established.	('p53', 'Gene', (11, 14))	('facilitate', 'PosReg', (35, 45))	('abnormalities', 'Var', (15, 28))	('seizures', 'Disease', 'MESH:D012640', (72, 80))	('seizure', 'Phenotype', 'HP:0001250', (72, 79))	('seizures', 'Phenotype', 'HP:0001250', (72, 80))	('seizures', 'Disease', (72, 80))
82354	32009124	Our results demonstrated that the good control of seizures was also associated with 1p/19q co-deletion.	('seizure', 'Phenotype', 'HP:0001250', (50, 57))	('seizures', 'Disease', (50, 58))	('seizures', 'Phenotype', 'HP:0001250', (50, 58))	('seizures', 'Disease', 'MESH:D012640', (50, 58))	('1p/19q co-deletion', 'Var', (84, 102))
82355	32009124	With regard to the histopathology of the tumor, reciprocal characteristics between p53 mutation and 1p/19q co-deletion seem to exist, which can be adapted for the design of seizure control treatments.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('seizure', 'Phenotype', 'HP:0001250', (173, 180))	('p53', 'Gene', (83, 86))	('tumor', 'Disease', (41, 46))	('men', 'Species', '9606', (194, 197))	('seizure', 'Disease', (173, 180))	('seizure', 'Disease', 'MESH:D012640', (173, 180))	('mutation', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
82356	32009124	Only p53 was selected in the multivariate analysis, which revealed that p53 is a strong factor for seizure control.	('seizure', 'Disease', (99, 106))	('seizure', 'Disease', 'MESH:D012640', (99, 106))	('seizure', 'Phenotype', 'HP:0001250', (99, 106))	('p53', 'Var', (72, 75))
82359	32009124	Furthermore, it is reported that 80% of ATRX immunopositivity was detected in p53-positive diffuse astrocytoma and oligodendroglioma and, in our study ATRX immunodetection was not significantly related to the drug-resistance of seizures.	('ATRX', 'Gene', '546', (40, 44))	('seizure', 'Phenotype', 'HP:0001250', (228, 235))	('seizures', 'Phenotype', 'HP:0001250', (228, 236))	('ATRX', 'Gene', (151, 155))	('p53-positive', 'Var', (78, 90))	('seizures', 'Disease', (228, 236))	('detected', 'Reg', (66, 74))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (99, 132))	('ATRX', 'Gene', '546', (151, 155))	('ATRX', 'Gene', (40, 44))	('drug-resistance', 'Phenotype', 'HP:0020174', (209, 224))	('seizures', 'Disease', 'MESH:D012640', (228, 236))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
82372	32009124	In seizure control, there was a reciprocal association between p53 mutation and 1p/19q co-deletion as evidenced by the pathological characteristics of the tumors.	('seizure', 'Disease', (3, 10))	('p53', 'Gene', (63, 66))	('mutation', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('seizure', 'Disease', 'MESH:D012640', (3, 10))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('seizure', 'Phenotype', 'HP:0001250', (3, 10))	('1p/19q', 'Gene', (80, 86))
82416	28969094	Glial tumors arising in midline CNS structures should therefore always be tested for histone H3 mutations, possible also by a mutation-specific H3 (K27M) antibody.	('histone H3', 'Protein', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tested', 'Reg', (74, 80))	('Glial tumors', 'Disease', 'MESH:D005910', (0, 12))	('Glial tumors', 'Disease', (0, 12))	('K27M', 'Mutation', 'p.K27M', (148, 152))	('mutations', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('K27M', 'Var', (148, 152))
82421	28969094	Pediatric HGG exhibit broad chromosomal abnormalities at a much lower frequency compared to adult HGG, with chromosome 1q gains being the most common aberration while 7q gain and 10q loss are less commonly encountered.	('chromosome', 'Var', (108, 118))	('broad chromosomal abnormalities', 'Phenotype', 'HP:0040012', (22, 53))	('chromosomal abnormalities', 'Disease', (28, 53))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (28, 53))	('gains', 'PosReg', (122, 127))
82422	28969094	observed recurrent 1q gains in 29% of cases and focal platelet-derived growth factor receptor alpha (PDGFRA) amplifications in 12% of tumors in their report on 78 pediatric HGGs.	('tumors', 'Disease', (134, 140))	('amplifications', 'Var', (109, 123))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (54, 99))	('gains', 'PosReg', (22, 27))	('PDGFRA', 'Gene', (101, 107))	('platelet-derived growth factor receptor alpha', 'Gene', (54, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PDGFRA', 'Gene', '5156', (101, 107))
82424	28969094	Unlike adult HGG, PDGFRA amplifications in pediatric HGG had no prognostic significance.	('amplifications', 'Var', (25, 39))	('PDGFRA', 'Gene', '5156', (18, 24))	('PDGFRA', 'Gene', (18, 24))
82425	28969094	reported worse outcome in correlation with PDGFRA mutations and not amplifications.	('mutations', 'Var', (50, 59))	('PDGFRA', 'Gene', '5156', (43, 49))	('PDGFRA', 'Gene', (43, 49))
82427	28969094	In a recent study investigating the molecular features of 35 HGG from very young children, cytogenetic alterations were in general less frequent compared with HGG from older pediatric and adult patients but included some alterations which are commonly seen in HGG (gains of 1q and 7q or losses of 10q, 13q and 14q).	('patients', 'Species', '9606', (194, 202))	('losses', 'NegReg', (287, 293))	('HGG', 'Disease', (260, 263))	('gains of 1q', 'Var', (265, 276))	('children', 'Species', '9606', (81, 89))
82428	28969094	Losses of 13q and 14q as well as focal amplifications of PDGFRA or EGFR were absent, while cyclin dependent kinase inhibitor -2A (CDKN2A) deletions were seen in two cases.	('cyclin dependent kinase inhibitor -2A', 'Gene', (91, 128))	('Losses', 'NegReg', (0, 6))	('CDKN2A', 'Gene', (130, 136))	('CDKN2A', 'Gene', '1029', (130, 136))	('cyclin dependent kinase inhibitor -2A', 'Gene', '1029', (91, 128))	('PDGFRA', 'Gene', (57, 63))	('deletions', 'Var', (138, 147))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('PDGFRA', 'Gene', '5156', (57, 63))
82429	28969094	Genomic alterations were more frequently seen in children older than nine months, which might imply an association between older age at diagnosis and accumulation of genetic alterations.	('Genomic alterations', 'Var', (0, 19))	('children', 'Species', '9606', (49, 57))	('seen', 'Reg', (41, 45))
82435	28969094	identified recurrent fusion genes involving the kinase domain of the neurotrophin tyrosine receptor kinase gene (NTRK) in 4% of brainstem and 10% of non-brainstem HGG, being observed in 40% (4/10) of HGG in very young children.	('fusion genes', 'Var', (21, 33))	('NTRK', 'Gene', (113, 117))	('children', 'Species', '9606', (218, 226))
82436	28969094	Recently, recurrent NTRK fusion genes were reported in adult HGG as well as pediatric LGG, and later shown to induce HGG in mice by injection of astrocytes transduced with retroviral vectors carrying NTRK fusion genes.	('HGG', 'Disease', (117, 120))	('fusion genes', 'Var', (25, 37))	('LGG', 'Disease', (86, 89))	('mice', 'Species', '10090', (124, 128))	('induce', 'Reg', (110, 116))	('HGG', 'Disease', (61, 64))	('NTRK', 'Gene', (20, 24))
82437	28969094	The authors suggested a significant oncogenic effect of NTRK fusion genes in very young children based on their high frequency in that age group, lack of other significant mutations, as well as rapid tumor induction in their animal model.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('NTRK', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('oncogenic effect', 'MPA', (36, 52))	('tumor', 'Disease', (200, 205))	('children', 'Species', '9606', (88, 96))	('fusion genes', 'Var', (61, 73))
82438	28969094	Specific mutations in H3F3A coding for H3.3 and HIST1H3B/C coding for H3.1 were recently recognized in pediatric HGG as the first reported histone mutations associated with human malignancies.	('H3F3A', 'Gene', (22, 27))	('associated', 'Reg', (157, 167))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('mutations', 'Var', (9, 18))	('H3.1', 'Gene', (70, 74))	('malignancies', 'Disease', (179, 191))	('HIST1H3B', 'Gene', (48, 56))	('HIST1H3B', 'Gene', '8358', (48, 56))	('H3.1', 'Gene', '8353', (70, 74))	('H3F3A', 'Gene', '3020', (22, 27))	('human', 'Species', '9606', (173, 178))
82439	28969094	Initial reports identified two distinct single-nucleotide variant mutations, methionine replacing lysine 27 (K27M) frequently involving H3F3A and to a lesser extent HIST1H3B, and arginine (or less frequently valine) replacing glycine 34 (G34R/V) in H3F3A.	('methionine replacing', 'Var', (77, 97))	('arginine', 'Var', (179, 187))	('methionine replacing lysine 27', 'Mutation', 'p.K27M', (77, 107))	('glycine', 'Chemical', 'MESH:D005998', (226, 233))	('valine', 'Chemical', 'MESH:D014633', (208, 214))	('H3F3A', 'Gene', (136, 141))	('involving', 'Reg', (126, 135))	('HIST1H3B', 'Gene', (165, 173))	('arginine', 'Chemical', 'MESH:D001120', (179, 187))	('HIST1H3B', 'Gene', '8358', (165, 173))	('G34R', 'SUBSTITUTION', 'None', (238, 242))	('H3F3A', 'Gene', '3020', (249, 254))	('G34R', 'Var', (238, 242))	('H3F3A', 'Gene', '3020', (136, 141))	('K27M', 'Mutation', 'p.K27M', (109, 113))	('H3F3A', 'Gene', (249, 254))
82440	28969094	When other gliomas of different grades and across all ages were examined for these mutations, they were identified exclusively in HGG with the vast majority of them occurring in children and adolescents.	('mutations', 'Var', (83, 92))	('identified', 'Reg', (104, 114))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('HGG', 'Disease', (130, 133))	('children', 'Species', '9606', (178, 186))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
82441	28969094	The anatomical tumor locations and age distribution of patients for each group of histone mutations differed largely.	('mutations', 'Var', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('histone', 'Gene', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('patients', 'Species', '9606', (55, 63))
82442	28969094	All G34R/V mutated tumors were found in non-midline cortical locations (hemispheric) and mainly affect young adults and adolescents.	('tumors', 'Disease', (19, 25))	('affect', 'Reg', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('G34R', 'SUBSTITUTION', 'None', (4, 8))	('G34R', 'Var', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('non-midline cortical locations', 'Disease', 'MESH:C580335', (40, 70))	('non-midline cortical locations', 'Disease', (40, 70))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutated', 'Var', (11, 18))
82444	28969094	found H3F3A K27M mutations only in two cases of their cohort of very young children with HGG (6%).	('H3F3A', 'Gene', '3020', (6, 11))	('H3F3A', 'Gene', (6, 11))	('K27M', 'Var', (12, 16))	('children', 'Species', '9606', (75, 83))	('K27M', 'Mutation', 'p.K27M', (12, 16))
82446	28969094	Only five cases - including those two with H3F3A K27M mutations - were midline tumors, while the majority of patients (30/35, 86%) had supratentorial hemispheric tumors.	('midline tumors', 'Disease', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('midline tumors', 'Disease', 'MESH:D009369', (71, 85))	('H3F3A', 'Gene', (43, 48))	('patients', 'Species', '9606', (109, 117))	('K27M mutations -', 'Var', (49, 65))	('K27M', 'Mutation', 'p.K27M', (49, 53))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('H3F3A', 'Gene', '3020', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
82447	28969094	However, the authors did not report H3F3A G34R/V mutations in any of the thirty hemispheric tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('G34R', 'SUBSTITUTION', 'None', (42, 46))	('H3F3A', 'Gene', (36, 41))	('G34R', 'Var', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('H3F3A', 'Gene', '3020', (36, 41))
82449	28969094	found marked overlap of TP53 mutation (more than half of cases) with other mutations in H3F3A, the alpha thalassemia/mental retardation syndrome X-Linked (ATRX) gene, and the death-domain-associated protein (DAXX) gene.	('mutation', 'Var', (29, 37))	('H3F3A', 'Gene', (88, 93))	('TP53', 'Gene', (24, 28))	('DAXX', 'Gene', '1616', (208, 212))	('ATRX', 'Gene', (155, 159))	('mental retardation', 'Phenotype', 'HP:0001249', (117, 135))	('death-domain-associated protein', 'Gene', (175, 206))	('DAXX', 'Gene', (208, 212))	('alpha thalassemia/mental retardation syndrome X-Linked', 'Gene', '546', (99, 153))	('H3F3A', 'Gene', '3020', (88, 93))	('death-domain-associated protein', 'Gene', '1616', (175, 206))	('ATRX', 'Gene', '546', (155, 159))	('TP53', 'Gene', '7157', (24, 28))
82450	28969094	Loss of ATRX protein expression in their samples was strongly associated with alternative lengthening of telomere (ALT), particularly in cases with simultaneous ATRX, H3F3A and TP53 mutations.	('ATRX', 'Gene', (161, 165))	('alternative lengthening of telomere', 'MPA', (78, 113))	('ATRX', 'Gene', '546', (8, 12))	('H3F3A', 'Gene', (167, 172))	('expression', 'MPA', (21, 31))	('Loss', 'NegReg', (0, 4))	('TP53', 'Gene', '7157', (177, 181))	('ATRX', 'Gene', '546', (161, 165))	('ATRX', 'Gene', (8, 12))	('TP53', 'Gene', (177, 181))	('H3F3A', 'Gene', '3020', (167, 172))	('mutations', 'Var', (182, 191))
82454	28969094	However, 40% of their cases had either loss of ATRX protein expression or H3F3A mutation or p53 accumulation, pointing to the importance of the H3F3A/ATRX/DAXX pathway in a subgroup of HGG in very young children.	('ATRX', 'Gene', (47, 51))	('expression', 'MPA', (60, 70))	('H3F3A', 'Gene', (74, 79))	('H3F3A', 'Gene', '3020', (144, 149))	('DAXX', 'Gene', '1616', (155, 159))	('children', 'Species', '9606', (203, 211))	('ATRX', 'Gene', (150, 154))	('accumulation', 'PosReg', (96, 108))	('ATRX', 'Gene', '546', (47, 51))	('H3F3A', 'Gene', (144, 149))	('DAXX', 'Gene', (155, 159))	('loss', 'NegReg', (39, 43))	('p53', 'Gene', (92, 95))	('ATRX', 'Gene', '546', (150, 154))	('H3F3A', 'Gene', '3020', (74, 79))	('p53', 'Gene', '7157', (92, 95))	('mutation', 'Var', (80, 88))
82456	28969094	One subgroup, receptor tyrosine kinase 1 (RTK-I), was characterized by predominant PDGFRA amplification and included patients from a wide age range.	('PDGFRA', 'Gene', (83, 89))	('PDGFRA', 'Gene', '5156', (83, 89))	('included', 'Reg', (108, 116))	('patients', 'Species', '9606', (117, 125))	('amplification', 'Var', (90, 103))
82457	28969094	The other two subgroups correspond to the two H3F3A mutations (K27M and G34V/R).	('H3F3A', 'Gene', '3020', (46, 51))	('K27M', 'Mutation', 'p.K27M', (63, 67))	('G34V', 'SUBSTITUTION', 'None', (72, 76))	('H3F3A', 'Gene', (46, 51))	('K27M', 'Var', (63, 67))	('G34V', 'Var', (72, 76))
82458	28969094	Among adolescents and young adult HGG, one of the identified subgroups was strictly related to IDH1 mutations.	('IDH1', 'Gene', '3417', (95, 99))	('mutations', 'Var', (100, 109))	('IDH1', 'Gene', (95, 99))	('related', 'Reg', (84, 91))
82460	28969094	The majority of those cases were of cortical location (around 75%), had better overall outcome (5-year OS > 90% for LGG-like and ~ 60% for PXA-like cases) and frequently harbored BRAF-V600E mutations (48% in PXA-like and 31% in LGG-like).	('LGG-like', 'Disease', (228, 236))	('PXA-like', 'Disease', (208, 216))	('BRAF-V600E', 'Var', (179, 189))	('LGG-like', 'Disease', (116, 124))	('V600E', 'Mutation', 'p.V600E', (184, 189))	('harbored', 'Reg', (170, 178))
82500	28969094	Although patient numbers may be smaller, pediatric HGG patients appear also to benefit from GTR of the tumor with an improvement of survival.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('improvement', 'PosReg', (117, 128))	('benefit', 'PosReg', (79, 86))	('tumor', 'Disease', (103, 108))	('survival', 'MPA', (132, 140))	('GTR', 'Var', (92, 95))	('patients', 'Species', '9606', (55, 63))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('HGG', 'Disease', (51, 54))
82503	28969094	Whereas some analyses showed evidence for a better survival after GTR of the tumor, other studies could not confirm this survival advantage.	('better', 'PosReg', (44, 50))	('GTR', 'Var', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('survival', 'MPA', (51, 59))
82554	28629182	Magnetic Resonance Spectroscopy for Detection of 2-Hydroxyglutarate as a Biomarker for IDH Mutation in Gliomas Mutations in the isocitrate dehydrogenase (IDH)1/2 genes are highly prevalent in gliomas and have been suggested to play an important role in the development and progression of the disease.	('Gliomas', 'Disease', (103, 110))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('Gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('IDH', 'Gene', (87, 90))	('isocitrate dehydrogenase (IDH)1', 'Gene', '3417', (128, 159))	('gliomas', 'Disease', (192, 199))	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (49, 67))	('IDH', 'Gene', '3417', (87, 90))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('prevalent', 'Reg', (179, 188))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('IDH', 'Gene', (154, 157))	('Gliomas', 'Disease', 'MESH:D005910', (103, 110))	('Mutations', 'Var', (111, 120))	('IDH', 'Gene', '3417', (154, 157))
82555	28629182	Tumours harbouring these mutations exhibit a significant alteration in their metabolism resulting in the aberrant accumulation of the oncometabolite 2-hydroxygluarate (2-HG).	('mutations', 'Var', (25, 34))	('rat', 'Species', '10116', (162, 165))	('2-hydroxygluarate', 'Chemical', '-', (149, 166))	('alteration', 'Reg', (57, 67))	('rat', 'Species', '10116', (61, 64))	('metabolism', 'MPA', (77, 87))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
82558	28629182	The field of neuro-oncology has undergone a significant paradigm shift following the identification of mutations in the isocitrate dehydrogenase (IDH) one and two genes in glioma and gliomagenesis.	('mutations', 'Var', (103, 112))	('oncology', 'Phenotype', 'HP:0002664', (19, 27))	('glioma', 'Disease', (183, 189))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('IDH', 'Gene', (146, 149))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('isocitrate dehydrogenase', 'Gene', (120, 144))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('isocitrate dehydrogenase', 'Gene', '3417', (120, 144))	('glioma', 'Disease', (172, 178))
82559	28629182	Such mutations have been suggested to play an important role in the development and progression of intracranial gliomas, often marking the first genetic transformation to occur, and imparting a range of downstream effects on a myriad of cellular processes.	('mutations', 'Var', (5, 14))	('intracranial gliomas', 'Disease', (99, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('effects', 'Reg', (214, 221))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('intracranial gliomas', 'Disease', 'MESH:D005910', (99, 119))
82560	28629182	Mutations in IDH1/2 genes have been identified in 70-80% of World Health Organization (WHO) grade II-III gliomas, and these mutations are particularly prevalent in grade IV secondary glioblastomas (GBM) arising as a progression from lower grade tumours, suggesting such mutations may act as a driving force behind malignant progression.	('GBM', 'Phenotype', 'HP:0012174', (198, 201))	('glioblastomas', 'Disease', (183, 196))	('glioblastomas', 'Disease', 'MESH:D005909', (183, 196))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('II gliomas', 'Disease', (102, 112))	('grade', 'Disease', (164, 169))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('prevalent', 'Reg', (151, 160))	('tumours', 'Disease', (245, 252))	('II gliomas', 'Disease', 'MESH:D005910', (102, 112))	('glioblastomas', 'Phenotype', 'HP:0012174', (183, 196))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('mutations', 'Var', (124, 133))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('identified', 'Reg', (36, 46))
82561	28629182	Mutations in IDH1/2 confer a gain-of-function neomorphic enzymatic activity, resulting in the aberrant production and subsequent accumulation of 2-hydroxygluarate (2-HG), which has been suggested to be an oncometabolite for this genetic mutation.	('gain-of-function', 'PosReg', (29, 45))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('2-hydroxygluarate', 'Chemical', '-', (145, 162))	('neomorphic enzymatic activity', 'MPA', (46, 75))	('IDH1/2', 'Gene', (13, 19))	('production', 'MPA', (103, 113))	('Mutations', 'Var', (0, 9))	('accumulation', 'PosReg', (129, 141))
82563	28629182	Alongside diagnostic applications, non-invasive detection and quantification of 2-HG levels within the mutant gliomas is highly desirable for the development of targeted treatment and response monitoring.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('mutant', 'Var', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))
82565	28629182	IDH is known to occur in three structural isoforms, namely IDH1, 2 and 3; however, only mutations in IDH1/2 have been identified in human gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('gliomas', 'Disease', (138, 145))	('IDH1/2', 'Gene', (101, 107))	('IDH1, 2 and 3', 'Gene', '3417;3418', (59, 72))	('mutations', 'Var', (88, 97))	('identified', 'Reg', (118, 128))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('IDH1/2', 'Gene', '3417;3418', (101, 107))	('human', 'Species', '9606', (132, 137))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))
82568	28629182	Mutations in both IDH1 and IDH2 are ubiquitously expressed within the tumour tissue; moreover, they consistently occur in a heterozygous manner and are most commonly observed in the IDH1 isoform.	('observed', 'Reg', (166, 174))	('IDH1', 'Gene', '3417', (182, 186))	('IDH2', 'Gene', '3418', (27, 31))	('IDH1', 'Gene', '3417', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('IDH2', 'Gene', (27, 31))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('IDH1', 'Gene', (182, 186))	('IDH1', 'Gene', (18, 22))	('tumour', 'Disease', (70, 76))	('occur', 'Reg', (113, 118))
82569	28629182	Remarkably, within gliomas, less than 90% of these point mutations occur at a single residue within the active site of the IDH1 isoform, where the Arginine 132 residue is replaced with a histidine (IDH1R132H).	('Arginine', 'Chemical', 'MESH:D001120', (147, 155))	('histidine', 'Chemical', 'MESH:D006639', (187, 196))	('Arginine 132', 'Var', (147, 159))	('IDH1', 'Gene', (198, 202))	('IDH1', 'Gene', (123, 127))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('IDH1', 'Gene', '3417', (198, 202))	('IDH1', 'Gene', '3417', (123, 127))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
82570	28629182	The much less frequent mutations in the IDH2 analog occur at Arginine 172, where the most common mutation is IDH2R172K.	('IDH2', 'Gene', (40, 44))	('Arginine', 'Chemical', 'MESH:D001120', (61, 69))	('IDH2', 'Gene', (109, 113))	('IDH2', 'Gene', '3418', (40, 44))	('Arginine 172', 'Var', (61, 73))	('IDH2', 'Gene', '3418', (109, 113))
82571	28629182	Alterations in the conformation of the catalytic site of the enzyme confer a gain-of-function neomorphic enzymatic activity, whereby mutant IDH1/2 catalyses the reduction of alphaKG into the oncometabolite 2-HG (Figure 1).	('IDH1/2', 'Gene', '3417;3418', (140, 146))	('alphaKG', 'Protein', (174, 181))	('neomorphic', 'CPA', (94, 104))	('gain-of-function', 'PosReg', (77, 93))	('IDH1/2', 'Gene', (140, 146))	('conformation', 'MPA', (19, 31))	('reduction', 'NegReg', (161, 170))	('rat', 'Species', '10116', (4, 7))	('mutant', 'Var', (133, 139))
82572	28629182	The full impact of accumulation of 2-HG within tumour cells is yet to be elucidated, but recent work suggests that it may have a pivotal role in altering the genetic, epigenetic and metabolic profile of the IDH mutant cells, driving the phenotype towards a more malignant state.	('epigenetic', 'MPA', (167, 177))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('genetic', 'MPA', (158, 165))	('more', 'PosReg', (257, 261))	('tumour', 'Disease', (47, 53))	('driving', 'Reg', (225, 232))	('IDH', 'Gene', (207, 210))	('metabolic profile', 'MPA', (182, 199))	('mutant', 'Var', (211, 217))	('altering', 'Reg', (145, 153))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
82573	28629182	One well-established mechanism of phenotypic alteration is inhibition of alpha-ketogluarate-dependant deoxygenases and histone demethylases, including the Ten Eleven Translocation (TET) family of 5-methlycytosine hydroxylases, leading to genome-wide alterations in methylation and histone patterns.	('methylation', 'MPA', (265, 276))	('alterations', 'Reg', (250, 261))	('TET', 'Chemical', '-', (181, 184))	('oxygen', 'Chemical', 'MESH:D010100', (104, 110))	('rat', 'Species', '10116', (254, 257))	('inhibition', 'Var', (59, 69))	('rat', 'Species', '10116', (49, 52))	('histone patterns', 'MPA', (281, 297))	('rat', 'Species', '10116', (87, 90))
82576	28629182	Interestingly, the occurrence of IDH mutations is highly restricted to a narrow spectrum, encompassing an exclusive list of malignancies.	('mutations', 'Var', (37, 46))	('malignancies', 'Disease', 'MESH:D009369', (124, 136))	('IDH', 'Gene', (33, 36))	('malignancies', 'Disease', (124, 136))
82577	28629182	For example, these mutations are frequently observed in grades II to III gliomas and secondary GBM but not in primary GBM.	('II gliomas', 'Disease', 'MESH:D005910', (70, 80))	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('observed', 'Reg', (44, 52))	('mutations', 'Var', (19, 28))	('II gliomas', 'Disease', (70, 80))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('grades II', 'Disease', (56, 65))	('secondary GBM', 'Disease', (85, 98))	('GBM', 'Phenotype', 'HP:0012174', (118, 121))
82578	28629182	The observed pattern in mutation occurrence suggests that its involvement in tumourgenesis may be linked to prevention of histone demethylation normally required for linage specific differentiation into terminally differentiated progenitors, in addition to altering the activity of chromosomal topological-regulating proteins.	('prevention', 'NegReg', (108, 118))	('altering', 'Reg', (257, 265))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('histone', 'Protein', (122, 129))	('activity', 'MPA', (270, 278))	('involvement', 'Reg', (62, 73))	('mutation', 'Var', (24, 32))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
82579	28629182	A further molecular mechanism by which mutations in the IDH1/2 genes have been suggested to contribute to tumourgenesis is via the ability of accumulated 2-HG to stimulate activity of the egl-9 family hypoxia inducible factor (EGLN) prolyl 4-hydroxylases.	('hypoxia', 'Disease', (201, 208))	('activity', 'MPA', (172, 180))	('hypoxia', 'Disease', 'MESH:D000860', (201, 208))	('contribute', 'Reg', (92, 102))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('mutations', 'Var', (39, 48))	('stimulate', 'PosReg', (162, 171))	('tumour', 'Disease', (106, 112))	('IDH1/2', 'Gene', (56, 62))
82581	28629182	2-HG has also been suggested to indirectly contribute to increased exposure to oxidative stress, as the conferred neomorphic enzymatic activity observed in mutant cells incurs a reduction in NADPH levels, a molecule that normally functions as a prerequisite for the reduction of glutathione disulphide into the antioxidant glutathione (Figure 1).	('neomorphic', 'CPA', (114, 124))	('NADPH levels', 'MPA', (191, 203))	('glutathione', 'Chemical', 'MESH:D005978', (279, 290))	('oxidative stress', 'Phenotype', 'HP:0025464', (79, 95))	('reduction', 'NegReg', (178, 187))	('glutathione', 'Chemical', 'MESH:D005978', (323, 334))	('glutathione disulphide', 'Chemical', 'MESH:D019803', (279, 301))	('mutant', 'Var', (156, 162))	('NADPH', 'Chemical', 'MESH:D009249', (191, 196))
82583	28629182	One approach that has been adopted for probing IDH mutation uses 13C MRS to monitor the production of 2-HG from its substrate alphaKG in a rat glioma model.	('13C', 'Chemical', '-', (65, 68))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('rat', 'Species', '10116', (139, 142))	('MRS', 'Disease', 'MESH:D008556', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('mutation', 'Var', (51, 59))	('glioma', 'Disease', (143, 149))	('MRS', 'Disease', (69, 72))	('rat', 'Species', '10116', (121, 124))
82585	28629182	It was demonstrated that the injected hyperpolarized 1-13C alphaKG was converted to hyperpolarized 1-13C 2-HG in both cell lysates and in vivo in orthotopic tumours.	('1-13C', 'Chemical', '-', (53, 58))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('orthotopic tumours', 'Disease', 'MESH:D009369', (146, 164))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('1-13C', 'Chemical', '-', (99, 104))	('orthotopic tumours', 'Disease', (146, 164))	('rat', 'Species', '10116', (14, 17))	('1-13C', 'Var', (53, 58))
82589	28629182	The monitoring of active mutant IDH enzymes, as well as 2-HG synthesis, confirms the proposed biochemical pathway leading to the accumulation of 2-HG within glioma cells.	('mutant', 'Var', (25, 31))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('IDH', 'Gene', (32, 35))	('glioma', 'Disease', (157, 163))
82592	28629182	Although the downstream consequences of metabolic reprogramming observed in IDH mutated gliomas are yet to be fully elucidated, the incorporation of IDH status into the WHO diagnostic criteria indicate a significant diagnostic and prognostic role of the genetic abnormality.	('rat', 'Species', '10116', (139, 142))	('IDH', 'Gene', (76, 79))	('gliomas', 'Disease', (88, 95))	('mutated', 'Var', (80, 87))	('genetic abnormality', 'Disease', 'MESH:D030342', (254, 273))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('genetic abnormality', 'Disease', (254, 273))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
82596	28629182	The D-R-2-HG stereoisomer is the metabolite that is produced by the neomorph enzymes resulting from IDH mutation, whereas the L-S-2-HG isomer is produced as a result of limited oxygen availability within a tissue.	('IDH', 'Gene', (100, 103))	('mutation', 'Var', (104, 112))	('oxygen', 'Chemical', 'MESH:D010100', (177, 183))
82601	28629182	Mutations in IDH1/2 within LGGs are highly prevalent, and can be observed at a rate of 70-80% in all tumours within this subgroup.	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('tumours', 'Disease', (101, 108))	('prevalent', 'Reg', (43, 52))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('rat', 'Species', '10116', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
82602	28629182	The influence of IDH mutation on LGG patients has been highlighted in the stratification of oligodendroglioma, astrocytoma and mixed glioma.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('oligodendroglioma', 'Disease', 'MESH:D009837', (92, 109))	('rat', 'Species', '10116', (76, 79))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('patients', 'Species', '9606', (37, 45))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('astrocytoma', 'Disease', 'MESH:D001254', (111, 122))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('mutation', 'Var', (21, 29))	('astrocytoma', 'Disease', (111, 122))	('oligodendroglioma', 'Disease', (92, 109))	('influence', 'Reg', (4, 13))	('glioma', 'Disease', (133, 139))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('glioma', 'Disease', (103, 109))	('IDH', 'Gene', (17, 20))
82603	28629182	The study evaluated the accumulation of a number of additional genetic aberrations alongside IDH mutation, including hypermethylation of O-6-methylguanine DNA methyltransferase (MGMT) promotor region, 1p/19q co-deletion and TP53 mutation.	('hypermethylation', 'MPA', (117, 133))	('mutation', 'Var', (229, 237))	('MGMT', 'Gene', '4255', (178, 182))	('TP53', 'Gene', (224, 228))	('rat', 'Species', '10116', (75, 78))	('O-6-methylguanine DNA methyltransferase', 'Gene', (137, 176))	('O-6-methylguanine DNA methyltransferase', 'Gene', '4255', (137, 176))	('MGMT', 'Gene', (178, 182))	('TP53', 'Gene', '7157', (224, 228))	('1p/19q co-deletion', 'Var', (201, 219))
82605	28629182	Although LGG have been stratified with regards to the prognostic influence of IDH mutation, the importance of the genetic abnormality in this subset of tumours is still a topic of debate, as others have failed to identify such a significant correlation.	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (152, 159))	('mutation', 'Var', (82, 90))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('IDH', 'Gene', (78, 81))	('genetic abnormality', 'Disease', 'MESH:D030342', (114, 133))	('rat', 'Species', '10116', (25, 28))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('genetic abnormality', 'Disease', (114, 133))
82606	28629182	observed a significant increase in OS in patients harbouring an IDH mutation.	('mutation', 'Var', (68, 76))	('patients', 'Species', '9606', (41, 49))	('increase', 'PosReg', (23, 31))	('IDH', 'Gene', (64, 67))
82609	28629182	This investigation did, however, identify that a higher rate of patients with mutated IDH were to develop into a secondary high grade glioma.	('develop', 'Reg', (98, 105))	('IDH', 'Gene', (86, 89))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('rat', 'Species', '10116', (56, 59))	('patients', 'Species', '9606', (64, 72))	('glioma', 'Disease', (134, 140))	('mutated', 'Var', (78, 85))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
82610	28629182	A comprehensive analysis of cellular tricarboxylic acid cycle metabolites was conducted on a range of glioma and non-glioma patients, with both IDH mutant and WT genetic profiles.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (37, 55))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('non-glioma', 'Disease', (113, 123))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mutant', 'Var', (148, 154))	('non-glioma', 'Disease', 'MESH:D005910', (113, 123))	('glioma', 'Disease', (102, 108))	('glioma', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))
82612	28629182	Whilst the influence of IDH mutation on the malignant progression of grade II gliomas is yet to be fully understood, the favourable impact on patient outcome for grade III gliomas is recognised.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('II gliomas', 'Disease', (75, 85))	('II gliomas', 'Disease', 'MESH:D005910', (169, 179))	('IDH', 'Gene', (24, 27))	('II gliomas', 'Disease', 'MESH:D005910', (75, 85))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('mutation', 'Var', (28, 36))	('patient', 'Species', '9606', (142, 149))	('II gliomas', 'Disease', (169, 179))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))
82613	28629182	A number of studies have outlined the prognostic, rather than predictive influence of IDH mutation on grade III gliomas.	('IDH', 'Gene', (86, 89))	('II gliomas', 'Disease', (109, 119))	('rat', 'Species', '10116', (50, 53))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('II gliomas', 'Disease', 'MESH:D005910', (109, 119))	('mutation', 'Var', (90, 98))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
82614	28629182	A prospective study by the European Organization for Research and Treatment of Cancer (EORTC) determining the prognostic significance of IDH mutation in anaplastic oligodendroglioma patients found that IDH mutant oligodendrogliomas had a better OS.	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (213, 231))	('oligodendroglioma', 'Disease', 'MESH:D009837', (213, 230))	('oligodendroglioma', 'Disease', 'MESH:D009837', (164, 181))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('IDH mutant', 'Var', (202, 212))	('oligodendrogliomas', 'Disease', (213, 231))	('patients', 'Species', '9606', (182, 190))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('oligodendroglioma', 'Disease', (213, 230))	('oligodendroglioma', 'Disease', (164, 181))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
82616	28629182	Such analyses highlight the suggested molecular progression through grade classification, initiated by mutation in IDH1/2 and acquisition of the CpG island methylator phenotype.	('mutation', 'Var', (103, 111))	('IDH1/2', 'Gene', (115, 121))	('IDH1/2', 'Gene', '3417;3418', (115, 121))
82617	28629182	In WHO grade IV GBM, IDH mutation has been repeatedly shown to be predictive of improved response to temozolomide treatment and radiotherapy in secondary GBM malignancies that have transformed from lower grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (210, 217))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('mutation', 'Var', (25, 33))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('malignancies', 'Disease', (158, 170))	('improved', 'PosReg', (80, 88))	('response', 'MPA', (89, 97))	('temozolomide', 'Chemical', 'MESH:D000077204', (101, 113))	('GBM', 'Phenotype', 'HP:0012174', (16, 19))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
82618	28629182	Secondary GBM that also harbour hypermethylation of the MGMT promoter region alongside IDH1/2 mutation have the best prognosis.	('IDH1/2', 'Gene', (87, 93))	('MGMT', 'Gene', (56, 60))	('MGMT', 'Gene', '4255', (56, 60))	('GBM', 'Phenotype', 'HP:0012174', (10, 13))	('hypermethylation', 'Var', (32, 48))	('IDH1/2', 'Gene', '3417;3418', (87, 93))	('mutation', 'Var', (94, 102))
82619	28629182	Although the underlying molecular mechanisms behind IDH mutation and its proposed influences on diagnosis, prognosis and the suggested predictive capacity of the mutation are yet to be identified, there appears to be overwhelming evidence that this genetic alteration has a significant role to play in understanding the underlying pathology of gliomagenesis and tumour progression.	('gliomagenesis and tumour', 'Disease', 'MESH:D009369', (344, 368))	('IDH', 'Gene', (52, 55))	('glioma', 'Phenotype', 'HP:0009733', (344, 350))	('tumour', 'Phenotype', 'HP:0002664', (362, 368))	('mutation', 'Var', (56, 64))	('rat', 'Species', '10116', (261, 264))
82621	28629182	The markedly increased concentration of 2-HG in IDH mutant tumours has been demonstrated to correlate with tumour cellularity, and its accumulation may also be applied as a surgical adjunct to guide tissue sampling.	('rat', 'Species', '10116', (83, 86))	('IDH', 'Gene', (48, 51))	('mutant', 'Var', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('rat', 'Species', '10116', (30, 33))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', (59, 66))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('concentration', 'MPA', (23, 36))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))	('increased', 'PosReg', (13, 22))	('tumour', 'Disease', (107, 113))
82633	28629182	Cho levels were found to be further elevated in mutant tumours when compared to WT, a measurement validated via LC-MS, and a finding in line with previous studies that have examined metabolome-wide alterations seen in IDH mutated tumours.	('tumours', 'Disease', (55, 62))	('mutant', 'Var', (48, 54))	('elevated', 'PosReg', (36, 44))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('tumours', 'Disease', 'MESH:D009369', (230, 237))	('Cho', 'Chemical', 'MESH:D002794', (0, 3))	('Cho levels', 'MPA', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', (230, 237))	('rat', 'Species', '10116', (202, 205))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
82634	28629182	Elevated Cho levels seen in IDH mutant tumours are suggested to reflect the increased cell density of mutant malignancies due to an IDH-mediated increase in cell proliferation.	('rat', 'Species', '10116', (169, 172))	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('IDH', 'Gene', (28, 31))	('Cho', 'Chemical', 'MESH:D002794', (9, 12))	('malignancies', 'Disease', (109, 121))	('cell proliferation', 'CPA', (157, 175))	('increased', 'PosReg', (76, 85))	('increase', 'PosReg', (145, 153))	('cell density', 'CPA', (86, 98))	('tumours', 'Disease', 'MESH:D009369', (39, 46))	('tumours', 'Disease', (39, 46))	('Elevated', 'PosReg', (0, 8))	('mutant', 'Var', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('Cho levels', 'MPA', (9, 19))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
82657	28629182	2D L-COSY MRS at 7T has been used to not only identify the resonant peaks of 2-HG, but to further assess and resolve the spectra of other brain metabolites that may experience a change in concentration in the presence of IDH mutation (Figure 5).	('MRS', 'Disease', 'MESH:D008556', (10, 13))	('change', 'Reg', (178, 184))	('IDH', 'Gene', (221, 224))	('rat', 'Species', '10116', (195, 198))	('MRS', 'Disease', (10, 13))	('mutation', 'Var', (225, 233))
82663	28629182	An alternative non-invasive method for detection of 2-HG utilizes an optimized semi-localization by an adiabatic selective refocusing (semi-LASER) sequence at 7T capable of providing quantitative measurements adequate enough to differentiate between cytosolic IDH1 mutant and mitochondrial IDH2 mutant.	('IDH2', 'Gene', (290, 294))	('mutant', 'Var', (265, 271))	('IDH2', 'Gene', '3418', (290, 294))	('IDH1', 'Gene', (260, 264))	('mutant', 'Var', (295, 301))	('IDH1', 'Gene', '3417', (260, 264))
82664	28629182	Spectral changes induced by the presence of IDH mutation were characterised, and feature abnormalities were input into Fisher Linear Discriminant Analysis, where the resulting plot categorised two distinct cluster patterns, pertaining to IDH1 and IDH2 mutation.	('feature abnormalities', 'Disease', 'MESH:D000013', (81, 102))	('IDH1', 'Gene', (238, 242))	('IDH2', 'Gene', (247, 251))	('IDH1', 'Gene', '3417', (238, 242))	('mutation', 'Var', (48, 56))	('IDH', 'Gene', (44, 47))	('IDH2', 'Gene', '3418', (247, 251))	('feature abnormalities', 'Disease', (81, 102))
82668	28629182	The mutated IDH pathway represents a possible target for novel glioma therapies, and, as such, there has begun a significant shift towards development of imaging strategies for the reliable longitudinal assessment and quantification of 2-HG levels during treatment and throughout clinical trials.	('mutated', 'Var', (4, 11))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH pathway', 'Pathway', (12, 23))	('rat', 'Species', '10116', (164, 167))	('glioma', 'Disease', (63, 69))
82671	28629182	In addition to the in vivo detection methods described above, efforts to characterize the metabolic profile of IDH1 mutated gliomas using ex vivo spectroscopic techniques have also been correlated with in vivo MRI parameters.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('IDH1', 'Gene', '3417', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('mutated', 'Var', (116, 123))	('IDH1', 'Gene', (111, 115))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
82677	28629182	The strong correlations bewteen 2-HG and increased cellularity of IDH mutant tumours fall in line with the hypothesis that there is increased cellularity in tumours where 2-HG is present.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('IDH', 'Gene', (66, 69))	('increased', 'PosReg', (41, 50))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('fall', 'Phenotype', 'HP:0002527', (85, 89))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('mutant', 'Var', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('tumours', 'Disease', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (157, 164))	('tumours', 'Disease', (157, 164))	('cellularity', 'MPA', (51, 62))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
82680	28629182	The emergence of IDH mutation and its role in glioma formation and progression has opened up the field of alteration of metabolism as a theraputic strategy once again.	('rat', 'Species', '10116', (149, 152))	('rat', 'Species', '10116', (110, 113))	('glioma', 'Disease', (46, 52))	('mutation', 'Var', (21, 29))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('IDH', 'Gene', (17, 20))
82683	28629182	Such compounds offer integral tools for the study of IDH mutations in glioma growth, where a further understanding can provide avenues for targeted therapies.	('mutations', 'Var', (57, 66))	('glioma growth', 'Disease', (70, 83))	('glioma growth', 'Disease', 'MESH:D005910', (70, 83))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))
82685	28629182	It was illustrated that administration of the non-cytotoxic, epigenetically targeted agent reversed DNA methylation marks associated with IDH mutation and promoted re-expression of genes associated with differentiation to control tumour growth.	('IDH', 'Gene', (138, 141))	('rat', 'Species', '10116', (32, 35))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('DNA methylation marks', 'MPA', (100, 121))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('rat', 'Species', '10116', (13, 16))	('promoted', 'PosReg', (155, 163))	('mutation', 'Var', (142, 150))	('re-expression of genes', 'MPA', (164, 186))	('tumour', 'Disease', (230, 236))	('reversed', 'NegReg', (91, 99))
82686	28629182	With the emergence of targeted compounds, the need for a robust, reliable and clinically applicable method for probing IDH mutation in glioma becomes increasingly relevant.	('glioma', 'Disease', (135, 141))	('mutation', 'Var', (123, 131))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('IDH', 'Gene', (119, 122))
82687	28629182	In addition to targeting the mutated pathway itself to manipulate the proposed oncogenic properties of mutant IDH and its products, recent studies have investigated the potential exploitation of the mutation in immunotherapeutic strategies.	('mutant', 'Var', (103, 109))	('rat', 'Species', '10116', (231, 234))	('IDH', 'Gene', (110, 113))
82688	28629182	The rationale behind such an approach lies in IDH mutation acting as a tumour-specific neo-antigen, due to the ubiquitous expression and homogenous occurrence.	('tumour', 'Disease', (71, 77))	('IDH', 'Gene', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('rat', 'Species', '10116', (4, 7))	('mutation', 'Var', (50, 58))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
82689	28629182	The immunogenicity of an IDH1R132 vaccine was confirmed in mice by induction of CD4+ Major Histocompatibility Complex II-restricted mutation-specific antitumor immune response against cells expressing the IDH1R132 point mutation.	('IDH1', 'Gene', (205, 209))	('mice', 'Species', '10090', (59, 63))	('IDH1', 'Gene', '3417', (205, 209))	('CD4', 'Gene', (80, 83))	('point mutation', 'Var', (214, 228))	('IDH1', 'Gene', (25, 29))	('CD4', 'Gene', '12504', (80, 83))	('IDH1', 'Gene', '3417', (25, 29))
82690	28629182	Other investigations exploring immunotherapeutic treatments have demonstrated the effectiveness in murine models, whereby administration of IDH1R132 specific vaccine caused a reduction in glioma growth rate.	('vaccine', 'Var', (158, 165))	('glioma growth', 'Disease', 'MESH:D005910', (188, 201))	('IDH1', 'Gene', '3417', (140, 144))	('rat', 'Species', '10116', (72, 75))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('murine', 'Species', '10090', (99, 105))	('reduction', 'NegReg', (175, 184))	('IDH1', 'Gene', (140, 144))	('rat', 'Species', '10116', (130, 133))	('rat', 'Species', '10116', (202, 205))	('glioma growth', 'Disease', (188, 201))
82696	26806352	We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse.	('Tv-a', 'Chemical', 'MESH:C050413', (100, 104))	('PDGF-B', 'Gene', (125, 131))	('mouse', 'Species', '10090', (244, 249))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('overexpression', 'PosReg', (132, 146))	('RCAS', 'Chemical', '-', (95, 99))	('p53', 'Gene', (148, 151))	('loss', 'NegReg', (152, 156))	('mouse', 'Species', '10090', (52, 57))	('glioma', 'Disease', (78, 84))	('H3.3K27M mutation', 'Var', (162, 179))	('K27M', 'Mutation', 'p.K27M', (166, 170))	('brainstem glioma', 'Phenotype', 'HP:0010796', (68, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
82701	26806352	Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors.	('tumors', 'Disease', (78, 84))	('K27M', 'Mutation', 'p.K27M', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('H3K27me3', 'MPA', (52, 60))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('mouse', 'Species', '10090', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('H3.3K27M mutation', 'Var', (18, 35))	('human', 'Species', '9606', (152, 157))	('reduces', 'NegReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
82708	26806352	These alterations include most notably a K27M mutation in the majority of patients occurring in the gene encoding either histone H3.1 or H3.3, with the latter being more common and associating with a worse prognosis.	('K27M', 'Mutation', 'p.K27M', (41, 45))	('patients', 'Species', '9606', (74, 82))	('histone H3.1', 'Gene', (121, 133))	('histone H3.1', 'Gene', '8350', (121, 133))	('K27M', 'Var', (41, 45))
82710	26806352	Mutations have been discovered in ACVR1 in roughly 20% of patients, as well as in ATRX, PPMID, and TP53, the last of which occurs in upwards of 77% of patients.	('TP53', 'Gene', (99, 103))	('ATRX', 'Gene', (82, 86))	('ATRX', 'Gene', '546', (82, 86))	('patients', 'Species', '9606', (151, 159))	('TP53', 'Gene', '7157', (99, 103))	('ACVR1', 'Gene', (34, 39))	('Mutations', 'Var', (0, 9))	('ACVR1', 'Gene', '90', (34, 39))	('patients', 'Species', '9606', (58, 66))
82715	26806352	Transgenic mouse modeling using the RCAS/Tv-a system has shown that Nestin-expressing progenitor cells in the P3-P5 mouse brainstem are capable of serving as a cell of origin for BSG when exposed to ectopic PDGF-B ligand and p53-deficiency as well as overexpression of H3.3K27M.	('p53-deficiency', 'Disease', (225, 239))	('p53-deficiency', 'Disease', 'MESH:D007153', (225, 239))	('mouse', 'Species', '10090', (11, 16))	('K27M', 'Mutation', 'p.K27M', (273, 277))	('PDGF-B', 'Gene', (207, 213))	('H3.3K27M', 'Var', (269, 277))	('overexpression', 'PosReg', (251, 265))	('RCAS', 'Chemical', '-', (36, 40))	('mouse', 'Species', '10090', (116, 121))	('BSG', 'Phenotype', 'HP:0010796', (179, 182))	('Tv-a', 'Chemical', 'MESH:C050413', (41, 45))
82719	26806352	To investigate the potential for these cells to be transformed into glioma, we used the Pax3-Tv-a transgenic mouse line to target PDGF-B, H3.3K27M, and p53 loss to Pax3-expressing cells.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('p53', 'Gene', (152, 155))	('H3.3K27M', 'Var', (138, 146))	('PDGF-B', 'Gene', (130, 136))	('loss', 'NegReg', (156, 160))	('Tv-a', 'Chemical', 'MESH:C050413', (93, 97))	('K27M', 'Mutation', 'p.K27M', (142, 146))	('glioma', 'Disease', (68, 74))	('mouse', 'Species', '10090', (109, 114))
82720	26806352	This combination of genetic alterations leads to BSG of variable grades and latencies, arising anywhere within the brainstem, including the classic DIPG location of the ventral pons.	('DIPG', 'Chemical', '-', (148, 152))	('BSG', 'Disease', (49, 52))	('leads to', 'Reg', (40, 48))	('genetic alterations', 'Var', (20, 39))	('BSG', 'Phenotype', 'HP:0010796', (49, 52))
82754	26806352	We have previously shown that targeting Nestin progenitor cells in the neonatal mouse brainstem with PDGF-B overexpression induces high-grade glioma formation in conjunction with Ink4aARF-loss or p53-loss and H3.3K27M overexpression.	('induces', 'Reg', (123, 130))	('glioma', 'Disease', (142, 148))	('PDGF-B', 'Gene', (101, 107))	('K27M', 'Mutation', 'p.K27M', (213, 217))	('overexpression', 'Var', (108, 122))	('Ink4aARF-loss', 'Disease', (179, 192))	('mouse', 'Species', '10090', (80, 85))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('H3.3K27M', 'Protein', (209, 217))	('Ink4aARF-loss', 'Disease', 'MESH:D015431', (179, 192))
82763	26806352	Based on H&E and Ki67 staining, 10 of 12 mice (83.3%) injected with PDGF-B and Cre developed BSG of variable grades (25% low grade and 58.3% high grade; Figures 4, B and D, and 5A), whereas 11 out of 15 mice (73.3%) injected with PDGF-B, Cre, and H3.3K27M developed glioma (20% low grade and 53.3% high grade; Figures 4, B and E, and 5, B and C).	('BSG', 'Phenotype', 'HP:0010796', (93, 96))	('and', 'Var', (243, 246))	('mice', 'Species', '10090', (41, 45))	('mice', 'Species', '10090', (203, 207))	('K27M', 'Mutation', 'p.K27M', (251, 255))	('glioma', 'Disease', (266, 272))	('Ki67', 'Gene', (17, 21))	('developed', 'Disease', (256, 265))	('H&E', 'Chemical', '-', (9, 12))	('glioma', 'Disease', 'MESH:D005910', (266, 272))	('glioma', 'Phenotype', 'HP:0009733', (266, 272))	('Ki67', 'Gene', '17345', (17, 21))
82764	26806352	Staining for HA (a tag that marks both the RCAS-PDGF-B and RCAS-H3.3K27M constructs) shows primarily cytoplasmic expression in the PDGF-B; p53-deficient tumors (Figure 4D) and predominately nuclear expression in the PDGF-B; H3.3K27M; p53-deficient tumors (Figure 4E), indicating successful expression of the H3.3K27M oncoprotein in the latter tumors.	('tumors', 'Disease', (343, 349))	('K27M', 'Mutation', 'p.K27M', (312, 316))	('tumors', 'Disease', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (343, 349))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('p53-deficient tumors', 'Disease', (234, 254))	('RCAS', 'Chemical', '-', (59, 63))	('p53-deficient tumors', 'Disease', (139, 159))	('p53-deficient tumors', 'Disease', 'MESH:D009369', (234, 254))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('K27M', 'Mutation', 'p.K27M', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('K27M', 'Mutation', 'p.K27M', (68, 72))	('RCAS', 'Chemical', '-', (43, 47))	('p53-deficient tumors', 'Disease', 'MESH:D009369', (139, 159))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('H3.3K27M', 'Var', (308, 316))
82780	26806352	Quantification of the overall levels of H3K27me3 nuclear area relative to total nuclear area per high-powered field in these two groups of tumors showed a significant reduction in H3K27me3-positive nuclear area in H3.3K27M-expressing tumors (PDGF-B+Cre mean = 1.3 +- 0.2% [SE], n = 7; PDGF-B+H3.3K27M+Cre, mean = 0.4 +- 0.15% [SE], n = 7; P = .0056 by unpaired t test; Figure 7C).	('H3K27me3-positive nuclear area', 'MPA', (180, 210))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('reduction', 'NegReg', (167, 176))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('K27M', 'Mutation', 'p.K27M', (296, 300))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('H3.3K27M-expressing', 'Var', (214, 233))	('K27M', 'Mutation', 'p.K27M', (218, 222))
82799	26806352	Although the H3.3K27M oncoprotein is now considered the hallmark of DIPG, it is interesting to note that, in our PDGF-B:p53-deficient model, its ectopic expression globally reduces the H3K27me3 mark but does not further accelerate the gliomagenesis process.	('ectopic expression', 'Var', (145, 163))	('K27M', 'Mutation', 'p.K27M', (17, 21))	('H3K27me3', 'Protein', (185, 193))	('glioma', 'Disease', (235, 241))	('reduces', 'NegReg', (173, 180))	('DIPG', 'Chemical', '-', (68, 72))	('glioma', 'Disease', 'MESH:D005910', (235, 241))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))
82801	26806352	In contrast, a recent in vivo study showed that the H3.3K27M mutation did not alter tumor volume at the onset of symptoms in the Nestin-Tv-a model.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('H3.3K27M', 'Var', (52, 60))	('tumor', 'Disease', (84, 89))	('K27M', 'Mutation', 'p.K27M', (56, 60))	('Tv-a', 'Chemical', 'MESH:C050413', (136, 140))
82804	26806352	K27M-mutant human tumors are also found in the thalamus and spinal cord in addition to the pons, and as shown here, we have found Pax3-expressing cells in the murine pons and thalamus (although the spinal cord was not examined), lending credence to the possibility that Pax3-expressing cells are a potential cell of origin for K27M-mutant glioma.	('murine', 'Species', '10090', (159, 165))	('glioma', 'Disease', 'MESH:D005910', (339, 345))	('glioma', 'Phenotype', 'HP:0009733', (339, 345))	('K27M-mutant', 'Var', (0, 11))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('K27M-mutant', 'Var', (327, 338))	('tumors', 'Disease', (18, 24))	('glioma', 'Disease', (339, 345))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('K27M', 'Mutation', 'p.K27M', (327, 331))	('human', 'Species', '9606', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
82815	26806352	This Pax3-Tv-a model of BSG displays a longer latency and lower penetrance as compared with our previously reported Nestin-Tv-a model with PDGF-B and p53 loss.	('penetrance', 'MPA', (64, 74))	('Pax3-Tv-a', 'Var', (5, 14))	('lower', 'NegReg', (58, 63))	('BSG', 'Disease', (24, 27))	('latency', 'MPA', (46, 53))	('Tv-a', 'Chemical', 'MESH:C050413', (123, 127))	('Tv-a', 'Chemical', 'MESH:C050413', (10, 14))	('BSG', 'Phenotype', 'HP:0010796', (24, 27))
82819	26806352	An important difference already noted between the models, however, is the fact that cerebral cortex injection into Nestin-Tv-a mice leads to cerebral cortex glioma, whereas similar injection into Pax3-Tv-a mice does not, indicating that the Pax3-Tv-a model is a specific tool for the study of DIPG and that Pax3-expressing cells may represent a unique, regionally distinct cell of origin for DIPG.	('mice', 'Species', '10090', (127, 131))	('DIPG', 'Chemical', '-', (293, 297))	('injection', 'Var', (100, 109))	('Tv-a', 'Chemical', 'MESH:C050413', (201, 205))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('mice', 'Species', '10090', (206, 210))	('leads to', 'Reg', (132, 140))	('cerebral cortex glioma', 'Disease', 'MESH:C564230', (141, 163))	('Tv-a', 'Chemical', 'MESH:C050413', (246, 250))	('Tv-a', 'Chemical', 'MESH:C050413', (122, 126))	('DIPG', 'Chemical', '-', (392, 396))	('cerebral cortex glioma', 'Disease', (141, 163))
82821	26806352	This model accurately represents the oligodendroglial/PDGFRA and H3-K27M subsets of DIPG and will be a valuable tool moving forward for DIPG research.	('H3-K27M', 'Var', (65, 72))	('DIPG', 'Chemical', '-', (84, 88))	('DIPG', 'Chemical', '-', (136, 140))	('PDGFRA', 'Gene', '18595', (54, 60))	('PDGFRA', 'Gene', (54, 60))	('K27M', 'Mutation', 'p.K27M', (68, 72))
82900	32620753	Based on the expression of 840 genes, the researchers classified GBM into four distinct subtypes: classical (EGFR amplification and CDKN2A deletion), mesenchymal (NF1 deletion and expression of mesenchymal markers), proneural (PDGFRA amplification, IDH1 mutation and expression of proneural development genes), and neural (expression of neuronal markers).	('NF1', 'Gene', (163, 166))	('CDKN2A', 'Gene', (132, 138))	('deletion', 'Var', (139, 147))	('NF1', 'Gene', '4763', (163, 166))	('IDH1', 'Gene', (249, 253))	('PDGFRA', 'Gene', (227, 233))	('PDGFRA', 'Gene', '5156', (227, 233))	('CDKN2A', 'Gene', '1029', (132, 138))	('IDH1', 'Gene', '3417', (249, 253))	('neural', 'CPA', (315, 321))	('EGFR', 'Gene', '1956', (109, 113))	('deletion', 'Var', (167, 175))	('mutation', 'Var', (254, 262))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('EGFR', 'Gene', (109, 113))
82901	32620753	Despite these efforts, these mutation-based and transcriptome-based approaches have found limited clinical application, and only a few biomarkers, including IDH mutation (favorable prognoses, secondary GBM), MGMT promoter methylation (benefit from temozolomide), and 1p/19q co-deletion (chemosensitivity) are being used in clinic.	('IDH', 'Gene', '3417', (157, 160))	('mutation', 'Var', (161, 169))	('temozolomide', 'Chemical', 'MESH:D000077204', (248, 260))	('MGMT', 'Gene', '4255', (208, 212))	('GBM', 'Phenotype', 'HP:0012174', (202, 205))	('MGMT', 'Gene', (208, 212))	('1p/19q', 'Var', (267, 273))	('IDH', 'Gene', (157, 160))
82912	32620753	These samples displayed broad coverage of major driver mutations, including EGFR, EGFRvIII (deletion in exon 2-7), TP53, RB1, PTEN, and PIK3CA (Fig.	('PIK3CA', 'Gene', (136, 142))	('EGFR', 'Gene', (82, 86))	('RB1', 'Gene', (121, 124))	('TP53', 'Gene', '7157', (115, 119))	('deletion', 'Var', (92, 100))	('PIK3CA', 'Gene', '5290', (136, 142))	('EGFR', 'Gene', '1956', (76, 80))	('RB1', 'Gene', '5925', (121, 124))	('TP53', 'Gene', (115, 119))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (82, 86))	('PTEN', 'Gene', (126, 130))	('PTEN', 'Gene', '5728', (126, 130))
82913	32620753	1a), and copy number alterations (CNAs) in CDKN2A/TP53 (deletion) and EGFR/PDGFRA (amplification) (Supplementary Fig.	('TP53', 'Gene', (50, 54))	('CDKN2A', 'Gene', (43, 49))	('EGFR', 'Gene', '1956', (70, 74))	('CDKN2A', 'Gene', '1029', (43, 49))	('TP53', 'Gene', '7157', (50, 54))	('EGFR', 'Gene', (70, 74))	('PDGFRA', 'Gene', (75, 81))	('copy number alterations', 'Var', (9, 32))	('PDGFRA', 'Gene', '5156', (75, 81))
82924	32620753	Of these sites, the phosphorylation of signal transducer and activator of transcription 1 (STAT1) at serine-727, which is a marker of STAT1 activation, correlated with elevated target protein levels in IDH wild-type tumors (Fig.	('IDH', 'Gene', (202, 205))	('STAT1', 'Gene', '6772', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('target protein levels', 'MPA', (177, 198))	('signal transducer and activator of transcription 1', 'Gene', '6772', (39, 89))	('IDH', 'Gene', '3417', (202, 205))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('serine-727', 'Var', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('phosphorylation', 'MPA', (20, 35))	('elevated', 'PosReg', (168, 176))	('STAT1', 'Gene', (91, 96))	('STAT1', 'Gene', (134, 139))	('serine', 'Chemical', 'MESH:D012694', (101, 107))	('STAT1', 'Gene', '6772', (91, 96))
82925	32620753	Also, IDH mutation status directly affected pSTAT1-S727 levels, as shown in an IDH wild-type and mutant GBM cell line pair in an isogenic U87MG background (Supplementary Fig.	('IDH', 'Gene', (6, 9))	('IDH', 'Gene', (79, 82))	('STAT1', 'Gene', (45, 50))	('IDH', 'Gene', '3417', (6, 9))	('IDH', 'Gene', '3417', (79, 82))	('mutant', 'Var', (97, 103))	('mutation', 'Var', (10, 18))	('affected', 'Reg', (35, 43))	('STAT1', 'Gene', '6772', (45, 50))	('GBM', 'Phenotype', 'HP:0012174', (104, 107))	('U87MG', 'CellLine', 'CVCL:0022', (138, 143))
82937	32620753	Notably, EGFRvIII and PIK3CA mutations were exclusively found in GPC1 tumors, whereas other GBM driver mutations in TP53, NF1, PTEN, RB1, and EGFR (non-vIII) were relatively evenly distributed between the two subtypes (Fig.	('EGFR', 'Gene', '1956', (142, 146))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('RB1', 'Gene', (133, 136))	('vIII', 'Gene', (152, 156))	('mutations', 'Var', (103, 112))	('TP53', 'Gene', (116, 120))	('PTEN', 'Gene', '5728', (127, 131))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('EGFR', 'Gene', (9, 13))	('GPC1 tumors', 'Disease', 'MESH:D009369', (65, 76))	('found', 'Reg', (56, 61))	('RB1', 'Gene', '5925', (133, 136))	('PIK3CA', 'Gene', '5290', (22, 28))	('EGFR', 'Gene', (142, 146))	('mutations', 'Var', (29, 38))	('vIII', 'Gene', '1351', (152, 156))	('vIII', 'Gene', (13, 17))	('PTEN', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (116, 120))	('NF1', 'Gene', '4763', (122, 125))	('GPC1 tumors', 'Disease', (65, 76))	('EGFR', 'Gene', '1956', (9, 13))	('NF1', 'Gene', (122, 125))	('vIII', 'Gene', '1351', (13, 17))	('PIK3CA', 'Gene', (22, 28))
82954	32620753	In GPC1 tumors, we also observed elevations in an active form of cortactin phosphorylated at T364/S368/T401/S405 and its interacting partner, Arp2/3 complex subunits (Fig.	('GPC1 tumors', 'Disease', (3, 14))	('elevations', 'PosReg', (33, 43))	('Arp2/3', 'Gene', (142, 148))	('cortactin', 'Gene', '2017', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('GPC1 tumors', 'Disease', 'MESH:D009369', (3, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('active', 'MPA', (50, 56))	('cortactin', 'Gene', (65, 74))	('Arp2/3', 'Gene', '10097;10096', (142, 148))	('T364/S368/T401/S405', 'Var', (93, 112))
82999	32620753	Taken together, these data suggest that tandutinib, olaparib, crizotinib, and AZD2014 might be a promising targeted therapy for GPC1 tumors and that erismodegib and canertinib might be more promising for GPC2 tumors.	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('GPC2 tumor', 'Disease', 'MESH:D009369', (204, 214))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('canertinib', 'Chemical', 'MESH:C420268', (165, 175))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('GPC2 tumor', 'Disease', (204, 214))	('GPC1 tumors', 'Disease', 'MESH:D009369', (128, 139))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumors', 'Disease', (133, 139))	('AZD2014', 'Var', (78, 85))	('AZD2014', 'Chemical', 'MESH:C585537', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('erismodegib', 'Chemical', 'MESH:C561435', (149, 160))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tandutinib', 'Chemical', 'MESH:C464670', (40, 50))	('GPC1 tumors', 'Disease', (128, 139))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))	('crizotinib', 'Chemical', 'MESH:D000077547', (62, 72))
83004	32620753	Similarly, SRC pS17 and pY419 were associated with sensitivity to bosutinib (Supplementary Fig.	('sensitivity to bosutinib', 'MPA', (51, 75))	('associated', 'Reg', (35, 45))	('SRC pS17', 'Var', (11, 19))	('pY419', 'Var', (24, 29))	('pY419', 'Chemical', '-', (24, 29))	('bosutinib', 'Chemical', 'MESH:C471992', (66, 75))
83009	32620753	Our final investigation aimed to identify targeted agents selective to the most aggressive GBMs, characterized by wild-type IDH, low PHGDH expression, and high FKBP9 expression in our study (Fig.	('PHGDH', 'Gene', (133, 138))	('low', 'NegReg', (129, 132))	('IDH', 'Gene', (124, 127))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('IDH', 'Gene', '3417', (124, 127))	('expression', 'MPA', (166, 176))	('expression', 'MPA', (139, 149))	('FKBP9', 'Gene', '11328', (160, 165))	('high', 'Var', (155, 159))	('FKBP9', 'Gene', (160, 165))	('PHGDH', 'Gene', '26227', (133, 138))
83010	32620753	Here, we found that the most significant correlations with both PHGDH and FKBP9 were found for AZD2014 (Fig.	('PHGDH', 'Gene', '26227', (64, 69))	('PHGDH', 'Gene', (64, 69))	('FKBP9', 'Gene', '11328', (74, 79))	('AZD2014', 'Var', (95, 102))	('FKBP9', 'Gene', (74, 79))	('correlations', 'Interaction', (41, 53))	('AZD2014', 'Chemical', 'MESH:C585537', (95, 102))
83011	32620753	6e), suggesting that AZD2014 might be a promising targeted therapy for the aggressive IDH wild-type GBM subtype.	('AZD2014', 'Var', (21, 28))	('AZD2014', 'Chemical', 'MESH:C585537', (21, 28))	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (86, 89))	('GBM', 'Phenotype', 'HP:0012174', (100, 103))
83023	32620753	IDH mutant proteins produce the oncometabolite D-2-HG and predict a favorable prognosis in glioma.	('IDH', 'Gene', (0, 3))	('proteins', 'Protein', (11, 19))	('mutant', 'Var', (4, 10))	('D-2-HG', 'Chemical', 'MESH:C019417', (47, 53))	('IDH', 'Gene', '3417', (0, 3))	('D-2-HG', 'MPA', (47, 53))	('glioma', 'Disease', (91, 97))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
83025	32620753	Thus, further research may be needed to evaluate whether the canonical PHGDH function or its promiscuous function is associated with favorable prognosis in IDH wild-type GBM.	('GBM', 'Phenotype', 'HP:0012174', (170, 173))	('PHGDH', 'Gene', (71, 76))	('IDH', 'Gene', (156, 159))	('IDH', 'Gene', '3417', (156, 159))	('function', 'Var', (77, 85))	('PHGDH', 'Gene', '26227', (71, 76))
83031	32620753	Phosphorylated cortactin activates the Arp2/3 complex to mediate a mechanism by which cancer cells might facilitate actin filamentation and branching while remodeling the extracellular matrix to gain increased motility and invasiveness.	('Phosphorylated', 'Var', (0, 14))	('branching', 'CPA', (140, 149))	('invasiveness', 'CPA', (223, 235))	('motility', 'CPA', (210, 218))	('Arp2/3', 'Gene', '10097;10096', (39, 45))	('actin filamentation', 'CPA', (116, 135))	('cortactin', 'Gene', (15, 24))	('Arp2/3', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gain increased', 'PosReg', (195, 209))	('cortactin', 'Gene', '2017', (15, 24))	('facilitate', 'PosReg', (105, 115))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
83046	32620753	We also demonstrated that AZD2014, a dual mTORC1 and mTORC2 inhibitor, exhibited strong cytotoxicity toward the most aggressive PHGDH-low and FKBP9-high IDH wild-type GBM-derived PDCs.	('mTORC2', 'Gene', (53, 59))	('cytotoxicity', 'Disease', (88, 100))	('mTORC2', 'Gene', '74343', (53, 59))	('FKBP9', 'Gene', '11328', (142, 147))	('mTORC1', 'Gene', '382056', (42, 48))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('FKBP9', 'Gene', (142, 147))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('AZD2014', 'Var', (26, 33))	('mTORC1', 'Gene', (42, 48))	('AZD2014', 'Chemical', 'MESH:C585537', (26, 33))	('IDH', 'Gene', (153, 156))	('PHGDH', 'Gene', '26227', (128, 133))	('IDH', 'Gene', '3417', (153, 156))	('PHGDH', 'Gene', (128, 133))
83051	32620753	The duplicated reads were removed using Picard (version 1.73), and local realignment was then performed around known insertions and deletions (indels) using SAMtools (version 0.1.18) and the Genome Analysis Tool Kit (GATK version 2.5-2).	('Kit', 'Gene', (212, 215))	('deletions', 'Var', (132, 141))	('insertions', 'Var', (117, 127))	('Kit', 'Gene', '3815', (212, 215))
83055	32620753	Hotspot mutations were annotated using databases downloaded from www.cancerhotspots.org (Hotspot Results V1) and www.3dhotspots.org (3D Hotspot Results).	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (69, 75))
83113	32620753	The parameters used for the MS-GF+ search were as follows: precursor error tolerance, 10 ppm; isotope error range, -1 to 2; fragmentation method, HCD; and instrument, Q-Exactive; variable posttranslational modification (PTM), M-oxidation; and two fixed modifications, C-carbamidomethyl and K/N-term-TMT.	('isotope error', 'Disease', 'MESH:D012030', (94, 107))	('K/N-term-TMT', 'Var', (290, 302))	('isotope error', 'Disease', (94, 107))	('HCD', 'Disease', 'MESH:D065630', (146, 149))	('C-carbamidomethyl', 'Var', (268, 285))	('HCD', 'Disease', (146, 149))	('M-oxidation', 'Var', (226, 237))
83115	32620753	The MODplus search parameters were the following: precursor error tolerance, 10 ppm; fragment ion tolerance, 0.025 Da; isotope error range -1 to 2; instrument, QTOF (equivalent to Q-Exactive with HCD); 46 variable PTMs (this parameter allows identification of modified peptides with multiple modifications within a range of -480 to 470 Da; a list of the variable modifications is provided in Supplementary Data 2); and two fixed modifications, C-carbamidomethyl and K/N-term-TMT.	('C-carbamidomethyl', 'Var', (444, 461))	('PTMs', 'Gene', (214, 218))	('isotope error', 'Disease', (119, 132))	('HCD', 'Disease', 'MESH:D065630', (196, 199))	('HCD', 'Disease', (196, 199))	('K/N-term-TMT', 'Var', (466, 478))	('peptides', 'Chemical', 'MESH:D010455', (269, 277))	('PTMs', 'Gene', '5763', (214, 218))	('isotope error', 'Disease', 'MESH:D012030', (119, 132))
83123	32620753	Five PKM1 isoforms (ENST00000319622, ENST00000389093, ENST00000565154, ENST00000565184, and ENST00000568459) and one PKM2 isoform (ENST00000335181) were used.	('ENST00000319622', 'Var', (20, 35))	('ENST00000565154', 'Var', (54, 69))	('PKM', 'Gene', (117, 120))	('PKM', 'Gene', '5315', (117, 120))	('ENST00000389093', 'Var', (37, 52))	('PKM2', 'Gene', (117, 121))	('ENST00000568459', 'Var', (92, 107))	('PKM2', 'Gene', '5315', (117, 121))	('PKM', 'Gene', '5315', (5, 8))	('ENST00000565184', 'Var', (71, 86))	('PKM', 'Gene', (5, 8))
83146	32620753	SNU466, SNU201, SNU626, A172, HS683, SNU1105, and T98G were purchased from Korean Cell Line Bank.	('SNU201', 'Var', (8, 14))	('A172', 'Var', (24, 28))	('SNU466', 'Var', (0, 6))	('SNU466', 'Chemical', '-', (0, 6))	('SNU201', 'CellLine', 'CVCL:5033', (8, 14))	('SNU626', 'Var', (16, 22))	('SNU1105', 'Var', (37, 44))	('SNU1105', 'CellLine', 'CVCL:5010', (37, 44))
83154	32620753	The pCMV6-GFP-PHGDH (RG203949) was purchased from OriGene.	('RG203949', 'Var', (21, 29))	('PHGDH', 'Gene', (14, 19))	('PHGDH', 'Gene', '26227', (14, 19))
83165	32620753	; proteomic data analyses, S.O., H.K., H.L., M.J.O., and J.H.H., genomic data analyses, S.O., J.K.S., and H.J.C.	('J.H.H', 'CellLine', 'CVCL:Y658', (57, 62))	('S.O.', 'Var', (88, 92))	('J.K.S.', 'Var', (94, 100))
83172	30636076	In this study, we report that CA11 secreted by depolarized cultured neurons within conditioned medium (CM) inhibited the growth of glioma cell lines.	('glioma', 'Disease', (131, 137))	('depolarized', 'Var', (47, 58))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('inhibited', 'NegReg', (107, 116))
83175	30636076	Low CA11 expression of gliomas was associated with short survival in four independent datasets [repository of brain neoplasia data (REMBRANDT), The Cancer Genome Atlas (TCGA) lower grade glioma (LGG), GSE4271, and GSE42669].	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('brain neoplasia', 'Disease', 'MESH:D009369', (110, 125))	('glioma', 'Disease', (187, 193))	('GSE4271', 'Chemical', '-', (201, 208))	('brain neoplasia', 'Phenotype', 'HP:0030692', (110, 125))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('expression', 'MPA', (9, 19))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('Low', 'NegReg', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (148, 167))	('brain neoplasia', 'Disease', (110, 125))	('GSE42669]', 'Var', (214, 223))	('short survival', 'MPA', (51, 65))	('Cancer Genome Atlas', 'Disease', (148, 167))	('gliomas', 'Disease', (23, 30))	('glioma', 'Disease', (23, 29))	('CA11', 'Protein', (4, 8))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))
83176	30636076	CA11 knockdown promoted cell growth, clone formation, and migration; inhibited apoptosis; and increased tumor size in xenografted nude mice.	('promoted', 'PosReg', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CA11', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('migration', 'CPA', (58, 67))	('increased', 'PosReg', (94, 103))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('nude mice', 'Species', '10090', (130, 139))	('rat', 'Species', '10116', (61, 64))	('clone formation', 'CPA', (37, 52))	('apoptosis', 'CPA', (79, 88))	('inhibited', 'NegReg', (69, 78))	('cell growth', 'CPA', (24, 35))
83177	30636076	Similarly, CA10 and CA10 secreted by depolarized cultured neurons also inhibited the growth of glioma cell lines.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('inhibited', 'NegReg', (71, 80))	('depolarized', 'Var', (37, 48))	('CA10', 'Gene', (20, 24))	('glioma', 'Disease', (95, 101))	('CA10', 'Gene', (11, 15))	('CA10', 'Gene', '56934', (20, 24))	('CA10', 'Gene', '56934', (11, 15))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
83197	30636076	In addition, CA11 knockdown promoted aggressive tumor behaviors in various in vitro and in vivo assays.	('knockdown', 'Var', (18, 27))	('aggressive tumor behaviors', 'Disease', (37, 63))	('aggressive tumor behaviors', 'Disease', 'MESH:D001523', (37, 63))	('promoted', 'PosReg', (28, 36))	('CA11', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
83209	30636076	HEK293T from the American Type Culture Collection (ATCC) was maintained in DMEM medium with 10% FBS, 100 U mL-1 penicillin, and 100 mg mL-1 streptomycin.	('FBS', 'Disease', (96, 99))	('penicillin', 'Chemical', 'MESH:D010406', (112, 122))	('FBS', 'Disease', 'MESH:D005198', (96, 99))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('DMEM medium', 'Chemical', '-', (75, 86))	('HEK293T', 'Var', (0, 7))	('streptomycin', 'Chemical', 'MESH:D013307', (140, 152))
83217	30636076	The coding sequences of human CA11 (NM_001217.4) and CA10 (NM_001082533.1) were cloned into pcDNA3.1-B- plasmid, respectively.	('CA11', 'Gene', (30, 34))	('human', 'Species', '9606', (24, 29))	('CA10', 'Gene', '56934', (53, 57))	('NM_001217.4', 'Var', (36, 47))	('NM_001082533.1', 'Var', (59, 73))	('CA10', 'Gene', (53, 57))
83239	30636076	CA11, CA10, BDNF, Neuroligin-3, HA, Akt, and p-Akt (Ser473) antibodies were from Sigma-Aldrich (HPA041778), Sigma-Aldrich (HPA057837; Madison, WI, USA), Abcam (ab203573), Abcam (ab192880), Sigma-Aldrich (H6908), CST (Boston, MA, USA; 4691), and CST (4060), respectively.	('Ser473', 'Chemical', '-', (52, 58))	('Neuroligin-3', 'Gene', '54413', (18, 30))	('HPA041778', 'Var', (96, 105))	('ab203573', 'Var', (160, 168))	('CST', 'Gene', (212, 215))	('Akt', 'Gene', '207', (47, 50))	('CA10', 'Gene', (6, 10))	('CST', 'Gene', '106478911', (245, 248))	('Akt', 'Gene', (36, 39))	('H6908', 'Var', (204, 209))	('CA10', 'Gene', '56934', (6, 10))	('HPA057837;', 'Var', (123, 133))	('Akt', 'Gene', (47, 50))	('CST', 'Gene', '106478911', (212, 215))	('CST', 'Gene', (245, 248))	('Akt', 'Gene', '207', (36, 39))	('Neuroligin-3', 'Gene', (18, 30))
83250	30636076	For GSE4271 and GSE42669, expression data and clinical data were downloaded from GEO database (https://www.ncbi.nlm.nih.gov/geo/).	('GSE42669', 'Var', (16, 24))	('GSE4271', 'Var', (4, 11))	('GSE4271', 'Chemical', '-', (4, 11))	('clinical', 'Species', '191496', (46, 54))
83251	30636076	In each dataset, the patients with CA11 expression higher than the median level were classified as the CA11-high expression group, while the patients with CA11 expression lower than the median level were classified as the CA11-low expression group.	('higher', 'PosReg', (51, 57))	('CA11', 'Var', (35, 39))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (21, 29))
83258	30636076	Surprisingly, CA11 depletion further enhanced cell proliferation, suggesting that neuron-secreted CA11 within CM could inhibit cell proliferation.	('depletion', 'Var', (19, 28))	('CA11', 'Gene', (14, 18))	('rat', 'Species', '10116', (139, 142))	('cell proliferation', 'CPA', (127, 145))	('inhibit', 'NegReg', (119, 126))	('rat', 'Species', '10116', (58, 61))	('enhanced', 'PosReg', (37, 45))	('cell proliferation', 'CPA', (46, 64))
83261	30636076	To test the inhibitory effect of CA11 directly, we prepared CA11-CM from HEK293T cells over-expressing HA-tagged human CA11.	('HA-tagged', 'Var', (103, 112))	('HEK293T', 'CellLine', 'CVCL:0063', (73, 80))	('CA11', 'Gene', (119, 123))	('human', 'Species', '9606', (113, 118))
83264	30636076	The results show that CA11-containing CM inhibited cell proliferation, and CA11 depletion abolished its inhibitory effects (Fig.	('cell proliferation', 'CPA', (51, 69))	('inhibited', 'NegReg', (41, 50))	('rat', 'Species', '10116', (63, 66))	('depletion', 'Var', (80, 89))	('CA11', 'Gene', (75, 79))
83268	30636076	To test directly the effect of CA10 on glioma growth, the CM from HEK293 cell over-expressing HA-tagged CA10 was prepared (Fig.	('CA10', 'Gene', '56934', (104, 108))	('CA10', 'Gene', (104, 108))	('HEK293', 'CellLine', 'CVCL:0045', (66, 72))	('CA10', 'Gene', (31, 35))	('HA-tagged', 'Var', (94, 103))	('glioma growth', 'Disease', (39, 52))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('CA10', 'Gene', '56934', (31, 35))	('glioma growth', 'Disease', 'MESH:D005910', (39, 52))
83272	30636076	Taken together, these results suggest CM from depolarized neurons inhibited glioma CA11 expression.	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('inhibited', 'NegReg', (66, 75))	('expression', 'MPA', (88, 98))	('depolarized', 'Var', (46, 57))
83294	30636076	The results show that patients with low CA11 expression had a significantly shorter survival time than those with high expression in REMBRANDT [hazard ratio (HR) = 0.77, P = 0.0312], TCGA LGG (HR = 0.69, P = 0.042), GSE4271 (HR = 0.62, P = 0.0069), and GSE42669 (HR = 0.55, P = 0.0026) datasets.	('low', 'Var', (36, 39))	('patients', 'Species', '9606', (22, 30))	('CA11', 'Gene', (40, 44))	('rat', 'Species', '10116', (151, 154))	('shorter', 'NegReg', (76, 83))	('survival time', 'CPA', (84, 97))	('GSE4271', 'Chemical', '-', (216, 223))
83302	30636076	The results show that, similar to CA11, low CA10 expression was associated with short survival in REMBRANDT gliomas (HR = 0.55, P < 0.0001), TCGA LGG (HR = 0.83, P = 0.003), and GSE4271 (HR = 0.79, P = 0.035), but not in GSE42669 (P = 0.66) or TCGA GBM (P = 0.927).	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('REMBRANDT glioma', 'Disease', 'MESH:D005910', (98, 114))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('CA10', 'Gene', '56934', (44, 48))	('low', 'Var', (40, 43))	('REMBRANDT glioma', 'Disease', (98, 114))	('expression', 'MPA', (49, 59))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('short survival', 'MPA', (80, 94))	('GSE4271', 'Chemical', '-', (178, 185))	('CA10', 'Gene', (44, 48))
83305	30636076	To explore the potential effects of reduced CA11 expression on the behaviors of gliomas, we investigated the effects of CA11 knockdown on proliferation, clone formation, in vitro migration, apoptosis, and in vivo tumor formation in glioma cell lines.	('glioma', 'Disease', (80, 86))	('tumor', 'Disease', (213, 218))	('knockdown', 'Var', (125, 134))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('glioma', 'Disease', (232, 238))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('rat', 'Species', '10116', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('reduced', 'NegReg', (36, 43))	('CA11', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('rat', 'Species', '10116', (145, 148))	('CA11', 'Gene', (120, 124))
83307	30636076	The effect of CA11 knockdown on cell proliferation was then measured by MTT assay and the results show that CA11 knockdown promoted cell proliferation in these two cell lines (Fig.	('MTT', 'Chemical', '-', (72, 75))	('CA11', 'Gene', (108, 112))	('promoted', 'PosReg', (123, 131))	('rat', 'Species', '10116', (44, 47))	('knockdown', 'Var', (113, 122))	('cell proliferation', 'CPA', (132, 150))	('rat', 'Species', '10116', (144, 147))
83308	30636076	In addition, CA11 knockdown increased cell migration (Fig.	('increased', 'PosReg', (28, 37))	('knockdown', 'Var', (18, 27))	('cell migration', 'CPA', (38, 52))	('rat', 'Species', '10116', (46, 49))	('CA11', 'Gene', (13, 17))
83309	30636076	The effects of CA11 knockdown on apoptosis were measured by Annexin V-PE apoptosis assay, and the results show that CA11 knockdown inhibited apoptosis (Fig.	('knockdown', 'Var', (121, 130))	('Annexin V', 'Gene', (60, 69))	('PE', 'Chemical', '-', (70, 72))	('inhibited', 'NegReg', (131, 140))	('apoptosis', 'CPA', (141, 150))	('CA11', 'Gene', (116, 120))	('Annexin V', 'Gene', '308', (60, 69))
83313	30636076	The results show that the tumor size of CA11 shRNA group was significantly larger than that of scramble group (Fig.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('larger', 'PosReg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('CA11 shRNA', 'Var', (40, 50))
83320	30636076	Here, we first tried to reproduce these results using high KCl-induced depolarization, which greatly enhances neurotrophin secretion from neurons (Nagappan et al., 2009).	('neurotrophin', 'Gene', (110, 122))	('KCl', 'Chemical', 'MESH:D011189', (59, 62))	('neurotrophin', 'Gene', '627', (110, 122))	('high KCl-induced depolarization', 'Var', (54, 85))	('enhances', 'PosReg', (101, 109))
83323	30636076	Here, we unexpectedly found that CA11 secreted by depolarized neurons could reduce neuronal activity-dependent glioma growth.	('depolarized', 'Var', (50, 61))	('glioma growth', 'Disease', (111, 124))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma growth', 'Disease', 'MESH:D005910', (111, 124))	('reduce', 'NegReg', (76, 82))
83326	30636076	We found that CA11 reduction was associated with short survival in patients and CA11 knockdown promoted glioma aggression in various in vitro and in vivo assays.	('CA11', 'Gene', (14, 18))	('promoted', 'PosReg', (95, 103))	('reduction', 'NegReg', (19, 28))	('patients', 'Species', '9606', (67, 75))	('glioma aggression', 'Disease', (104, 121))	('glioma aggression', 'Disease', 'MESH:D005910', (104, 121))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('CA11', 'Gene', (80, 84))	('knockdown', 'Var', (85, 94))	('aggression', 'Phenotype', 'HP:0000718', (111, 121))
83327	30636076	These results support that CA11 also inhibits glioma growth in an autocrine manner.	('glioma growth', 'Disease', 'MESH:D005910', (46, 59))	('glioma growth', 'Disease', (46, 59))	('CA11', 'Var', (27, 31))	('inhibits', 'NegReg', (37, 45))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
83344	30636076	In addition, CA11 knockdown promotes aggressive tumor behaviors in in vitro and in vivo assays.	('knockdown', 'Var', (18, 27))	('promotes', 'PosReg', (28, 36))	('aggressive tumor behaviors', 'Disease', (37, 63))	('aggressive tumor behaviors', 'Disease', 'MESH:D001523', (37, 63))	('CA11', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
83367	30625327	Base-pairing of this region with its mRNA target is essential and sufficient for many miRNAs to function.	('Base-pairing', 'Var', (0, 12))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))
83376	30625327	Several studies have shown that changes in the relative distances between the expected cleavage site, the basal junction, and the apical junction of a pri-miRNA can all affect Drosha cleavage fidelity.	('apical junction', 'Phenotype', 'HP:0032176', (130, 145))	('pri', 'Gene', (151, 154))	('affect', 'Reg', (169, 175))	('pri', 'Gene', '47191', (151, 154))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('Drosha cleavage fidelity', 'CPA', (176, 200))	('changes', 'Var', (32, 39))
83382	30625327	Despite the complete conservation of the mature miR-9 sequence within the upper stems of all three pri-miRNAs, variations occur at other positions that could potentially affect biogenesis.	('pri', 'Gene', '47191', (99, 102))	('affect', 'Reg', (170, 176))	('variations', 'Var', (111, 121))	('biogenesis', 'MPA', (177, 187))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))	('pri', 'Gene', (99, 102))
83391	30625327	We provide evidence that non-canonical Drosha cleavage of other pri-miRNAs may similarly be driven by distortion of the pri-miRNA stems.	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('pri', 'Gene', '47191', (64, 67))	('pri', 'Gene', '47191', (120, 123))	('distortion', 'Var', (102, 112))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))	('driven by', 'Reg', (92, 101))	('pri', 'Gene', (64, 67))	('pri', 'Gene', (120, 123))
83394	30625327	In this assay, Drosha cleavage of the pri-miRNA sequence triggers degradation of the luciferase transcripts and reduces luciferase activity.	('pri', 'Gene', (38, 41))	('pri', 'Gene', '47191', (38, 41))	('luciferase', 'Enzyme', (120, 130))	('activity', 'MPA', (131, 139))	('luciferase', 'Enzyme', (85, 95))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('cleavage', 'Var', (22, 30))	('reduces', 'NegReg', (112, 119))	('degradation', 'MPA', (66, 77))
83445	30625327	To determine which element drives the changes on Drosha cleavage fidelity, we swapped these regions between pri-miR-9-1 and pri-miR-9-2, generating six chimeric pri-miRNAs.	('miR-9-2', 'Gene', (128, 135))	('miR-9-1', 'Gene', (112, 119))	('pri', 'Gene', (161, 164))	('pri', 'Gene', (124, 127))	('pri', 'Gene', (108, 111))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('pri', 'Gene', '47191', (161, 164))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (165, 168))	('miR-9-1', 'Gene', '407046', (112, 119))	('miR', 'Gene', '220972', (128, 131))	('swapped', 'Var', (78, 85))	('miR', 'Gene', (128, 131))	('pri', 'Gene', '47191', (124, 127))	('pri', 'Gene', '47191', (108, 111))	('miR-9-2', 'Gene', '407047', (128, 135))
83448	30625327	However, the fidelity of Drosha cleavage varied: the alternative cleavage is nearly abolished when the lower stem of pri-miR-9-1 is replaced with that of pri-miR-9-2 (F1-LS2-TL1), whereas exchanging the loop (F1-LS1-TL2) or the flanking sequences (F2-LS1-TL1) only partially reduces use of the alternative cleavage site (Figures 3B and S3C).	('pri', 'Gene', '47191', (154, 157))	('pri', 'Gene', (117, 120))	('miR-9-2', 'Gene', '407047', (158, 165))	('TL2', 'Gene', '8743', (216, 219))	('pri', 'Gene', (154, 157))	('TL1', 'Gene', (255, 258))	('alt', 'Gene', '76282', (294, 297))	('alt', 'Gene', (294, 297))	('TL1', 'Gene', (174, 177))	('exchanging', 'Var', (188, 198))	('miR-9-1', 'Gene', '407046', (121, 128))	('miR-9-2', 'Gene', (158, 165))	('abolished', 'NegReg', (84, 93))	('TL1', 'Gene', '9966', (255, 258))	('TL2', 'Gene', (216, 219))	('alt', 'Gene', '76282', (53, 56))	('alt', 'Gene', (53, 56))	('miR-9-1', 'Gene', (121, 128))	('TL1', 'Gene', '9966', (174, 177))	('pri', 'Gene', '47191', (117, 120))
83460	30625327	However, pri-miR-9-2 and pri-miR-9-3 also contain internal loops and mismatches in their lower stems (Figure S4A), making an internal loop per se an unlikely cause of Drosha alternative cleavage.	('alt', 'Gene', (174, 177))	('pri', 'Gene', '47191', (9, 12))	('mismatches', 'Var', (69, 79))	('pri', 'Gene', (25, 28))	('miR-9-3', 'Gene', '407051', (29, 36))	('miR-9-3', 'Gene', (29, 36))	('miR-9-2', 'Gene', '407047', (13, 20))	('pri', 'Gene', '47191', (25, 28))	('alt', 'Gene', '76282', (174, 177))	('miR-9-2', 'Gene', (13, 20))	('pri', 'Gene', (9, 12))
83471	30625327	Deep sequencing analysis revealed that both of the modified pri-miR-9-1 s are nearly free of Drosha-mediated alternative cleavage, instead resulting in a cleavage profile similar to that of pri-miR-9-2 in both HEK293T and HeLa cells (Figures 4D, S4H, and S4I).	('miR-9-1', 'Gene', (64, 71))	('pri', 'Gene', '47191', (190, 193))	('pri', 'Gene', '47191', (60, 63))	('miR-9-2', 'Gene', '407047', (194, 201))	('S4I', 'Mutation', 'p.S4I', (255, 258))	('miR-9-2', 'Gene', (194, 201))	('alt', 'Gene', '76282', (109, 112))	('cleavage profile', 'MPA', (154, 170))	('pri', 'Gene', (190, 193))	('HeLa', 'CellLine', 'CVCL:0030', (222, 226))	('pri', 'Gene', (60, 63))	('miR-9-1', 'Gene', '407046', (64, 71))	('alt', 'Gene', (109, 112))	('modified', 'Var', (51, 59))	('resulting in', 'Reg', (139, 151))	('HEK293T', 'CellLine', 'CVCL:0063', (210, 217))
83475	30625327	We focused on high-confidence 5'-arm-miRNAs (5p) because Drosha cleavages of these miRNAs may produce isomiRs with shifted seed sequences.	('miR', 'Gene', (105, 108))	('produce', 'Reg', (94, 101))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('cleavages', 'Var', (64, 73))	('miR', 'Gene', '220972', (105, 108))
83488	30625327	As expected, pri-miRNAs in the low-fidelity group have a higher average RMSD than these of the high-fidelity group, implying that the overall distortion of a pri-miRNA stem affects Drosha cleavage fidelity.	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('distortion', 'Var', (142, 152))	('pri', 'Gene', '47191', (13, 16))	('pri', 'Gene', '47191', (158, 161))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))	('Drosha cleavage', 'MPA', (181, 196))	('pri', 'Gene', (13, 16))	('pri', 'Gene', (158, 161))	('affects', 'Reg', (173, 180))
83489	30625327	To validate this model, we selected two pri-miRNAs from the low-fidelity group (pri-miR-411 and pri-miR-10b) and corrected the structural distortions on their lower stems by mutating the lower stem sequences in a similar strategy as we did with pri-miR-9-1.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', '220972', (84, 87))	('corrected', 'Reg', (113, 122))	('miR', 'Gene', (100, 103))	('miR', 'Gene', (44, 47))	('miR', 'Gene', (84, 87))	('miR', 'Gene', '220972', (249, 252))	('miR-9-1', 'Gene', '407046', (249, 256))	('pri', 'Gene', '47191', (96, 99))	('miR-411', 'Gene', (84, 91))	('pri', 'Gene', '47191', (40, 43))	('miR', 'Gene', (249, 252))	('pri', 'Gene', (96, 99))	('pri', 'Gene', (40, 43))	('miR-9-1', 'Gene', (249, 256))	('pri', 'Gene', '47191', (80, 83))	('pri', 'Gene', '47191', (245, 248))	('miR', 'Gene', '220972', (100, 103))	('pri', 'Gene', (245, 248))	('miR-411', 'Gene', '693121', (84, 91))	('pri', 'Gene', (80, 83))	('structural distortions', 'Var', (127, 149))	('mutating', 'Var', (174, 182))
83490	30625327	Consistent with the results of pri-miR-9-1, such corrections abolished the Drosha alternative cleavage (Figures 5E and 5F).	('miR-9-1', 'Gene', '407046', (35, 42))	('pri', 'Gene', (31, 34))	('corrections', 'Var', (49, 60))	('alt', 'Gene', '76282', (82, 85))	('miR-9-1', 'Gene', (35, 42))	('pri', 'Gene', '47191', (31, 34))	('abolished', 'NegReg', (61, 70))	('alt', 'Gene', (82, 85))
83501	30625327	Hence, pri-miRNAs with a bent or distorted stem in solution may need to alter its 3D conformation to fit in the Microprocessor complex.	('pri', 'Gene', (7, 10))	('distorted', 'Var', (33, 42))	('miR', 'Gene', '220972', (11, 14))	('alt', 'Gene', (72, 75))	('miR', 'Gene', (11, 14))	('pri', 'Gene', '47191', (7, 10))	('alt', 'Gene', '76282', (72, 75))
83503	30625327	This model aligns well with previous studies of the other mammalian RNase III enzyme (Dicer) in which asymmetrical structural motifs in precursor hairpins, which are likely source of tertiary structure bending, induce Dicer alternative cleavages.	('Dicer', 'Gene', (86, 91))	('mammalian', 'Species', '9606', (58, 67))	('alt', 'Gene', (224, 227))	('RNase III', 'Gene', '29102', (68, 77))	('Dicer', 'Gene', '23405', (218, 223))	('RNase III', 'Gene', (68, 77))	('Dicer', 'Gene', (218, 223))	('induce', 'Reg', (211, 217))	('alt', 'Gene', '76282', (224, 227))	('asymmetrical', 'Var', (102, 114))	('Dicer', 'Gene', '23405', (86, 91))
83504	30625327	Alternatively, pri-miRNAs with distorted stems have higher flexibility, allowing them to fold into several distinct structures when complexing with Drosha.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('pri', 'Gene', '47191', (15, 18))	('flexibility', 'MPA', (59, 70))	('pri', 'Gene', (15, 18))	('higher', 'PosReg', (52, 58))	('distorted', 'Var', (31, 40))
83670	28993810	CT, computed tomography; MRI, magnetic resonance imaging; 2D, two-dimensional; 3D, three-dimensional; PACS, picture archiving and communication system; T1W, T1-weighted; T2W, T2-weighted; VA-MD VTH, Virginia-Maryland Veterinary Teaching Hospital; WHO, World Health Organization.	('T1-weighted; T2W', 'Var', (157, 173))	('PACS', 'Phenotype', 'HP:0006699', (102, 106))	('T2-weighted', 'Var', (175, 186))	('Virginia-Maryland Veterinary Teaching', 'Disease', (199, 236))	('T1W', 'Var', (152, 155))	('T2W', 'Var', (170, 173))	('Virginia-Maryland Veterinary Teaching', 'Disease', 'MESH:D000034', (199, 236))
83673	23289977	Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR).	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('p53', 'Gene', (118, 121))	('protein', 'Protein', (138, 145))	('IDH1', 'Gene', (133, 137))	('p53', 'Gene', '7157', (118, 121))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('IDH1', 'Gene', '3417', (133, 137))	('MGMT', 'Gene', '4255', (192, 196))	('MGMT', 'Gene', (192, 196))	('mutant', 'Var', (126, 132))
83674	23289977	GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions.	('secondary neoplasms', 'Disease', (129, 148))	('PTEN', 'Gene', '5728', (220, 224))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('neoplasms', 'Phenotype', 'HP:0002664', (139, 148))	('neoplasm', 'Phenotype', 'HP:0002664', (139, 147))	('secondary neoplasms', 'Disease', 'MESH:D060085', (129, 148))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('IDH1', 'Gene', '3417', (176, 180))	('GBM-Os', 'Disease', (0, 6))	('mutations', 'Var', (181, 190))	('patients', 'Species', '9606', (24, 32))	('PTEN', 'Gene', (220, 224))	('deletions', 'Var', (225, 234))	('IDH1', 'Gene', (176, 180))
83675	23289977	Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively.	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('longer', 'PosReg', (13, 19))	('patients', 'Species', '9606', (23, 31))	('Survival', 'MPA', (0, 8))	('GBM-Os', 'Var', (37, 43))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))
83676	23289977	Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival.	('1p deletion', 'Var', (59, 70))	('patients', 'Species', '9606', (6, 14))	('GBM', 'Phenotype', 'HP:0012174', (20, 23))	('prolonged', 'PosReg', (107, 116))
83682	23289977	These pathways also have distinctive molecular genetic alterations: EGFR amplification and PTEN deletion are more common in primary GBMs, whereas TP53 and IDH1 mutations are more common in secondary GBMs.	('IDH1', 'Gene', (155, 159))	('TP53', 'Gene', '7157', (146, 150))	('common', 'Reg', (114, 120))	('IDH1', 'Gene', '3417', (155, 159))	('TP53', 'Gene', (146, 150))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('primary GBMs', 'Disease', (124, 136))	('PTEN', 'Gene', '5728', (91, 95))	('EGFR', 'Gene', '1956', (68, 72))	('deletion', 'Var', (96, 104))	('PTEN', 'Gene', (91, 95))	('EGFR', 'Gene', (68, 72))	('GBM', 'Phenotype', 'HP:0012174', (132, 135))	('amplification', 'Var', (73, 86))
83702	23289977	Immunoperoxidase staining for the p53 protein and for the IDH1 mutant protein was performed on formalin-fixed, paraffin-embedded tissue sections, according to the manufacturers' instructions.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('formalin', 'Chemical', 'MESH:D005557', (95, 103))	('IDH1', 'Gene', '3417', (58, 62))	('mutant', 'Var', (63, 69))	('paraffin', 'Chemical', 'MESH:D010232', (111, 119))	('IDH1', 'Gene', (58, 62))
83704	23289977	The R132H antibody (1:80; Dianova, Hamburg, Germany) was used to detect the IDH1 mutant protein.	('IDH1', 'Gene', (76, 80))	('IDH1', 'Gene', '3417', (76, 80))	('mutant', 'Var', (81, 87))	('protein', 'Protein', (88, 95))	('R132H', 'Mutation', 'rs121913500', (4, 9))
83708	23289977	Dual-color FISH was performed for EGFR amplification, PTEN deletion and 1p and 19q deletions.	('EGFR', 'Gene', (34, 38))	('PTEN', 'Gene', (54, 58))	('PTEN', 'Gene', '5728', (54, 58))	('deletion', 'Var', (59, 67))	('EGFR', 'Gene', '1956', (34, 38))
83713	23289977	PTEN deletion and 1p and 19q deletions were considered present if >=10% of cells contained the respective deletions.	('PTEN', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('PTEN', 'Gene', '5728', (0, 4))
83715	23289977	The Vysis LSI PTEN/CEP 10 probe (Catalog # 07J74-001; Abbott Molecular Inc.) was used to detect the PTEN deletion.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', (14, 18))	('deletion', 'Var', (105, 113))	('PTEN', 'Gene', '5728', (14, 18))	('PTEN', 'Gene', '5728', (100, 104))
83716	23289977	FISH was performed on both GBM-Os and GBMs of other types for EGFR amplification and PTEN deletion.	('deletion', 'Var', (90, 98))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('GBM', 'Phenotype', 'HP:0012174', (38, 41))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (85, 89))
83724	23289977	GBM-O patients tended to be male (21 male vs. 7 female; 3:1) and had a higher male: female ratio than did patients with other GBMs (121 male vs. 87 female; 1.4:1), but this difference was not significant (P = 0.102; Table 1).	('higher', 'PosReg', (71, 77))	('GBM-O', 'Var', (0, 5))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (106, 114))
83727	23289977	PTEN deletion was less frequent in GBM-Os, with 10 of 13 (77%) harboring the deletion compared with 93 of 98 (95%) other GBMs (P = 0.05; Table 1).	('deletion', 'Var', (5, 13))	('deletion', 'Var', (77, 85))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
83730	23289977	GBM-Os were more frequently immunoreactive for mutant IDH1 protein (7 of 20, 35%) than other GBMs (10 of 116, 9%) (P = 0.004; Table 1).	('IDH1', 'Gene', (54, 58))	('protein', 'Protein', (59, 66))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('IDH1', 'Gene', '3417', (54, 58))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('immunoreactive', 'MPA', (28, 42))	('mutant', 'Var', (47, 53))
83731	23289977	However, IDH1 positivity was also found to be significantly associated with secondary GBMs, with 10 of 18 (55.6%) secondary GBMs being IDH1 positive compared with only 7 of 118 (5.9%) primary GBMs (P = < 0.0001).	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (192, 195))	('IDH1', 'Gene', '3417', (9, 13))	('IDH1', 'Gene', '3417', (135, 139))	('positivity', 'Var', (14, 24))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('secondary GBMs', 'Disease', (76, 90))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))	('associated', 'Reg', (60, 70))
83732	23289977	Among primary neoplasms, 14.3% of GBM-Os were immunoreactive for mutant IDH1, not significantly different from other GBMs (4.8% of primary GBMs; P = 0.194).	('IDH1', 'Gene', (72, 76))	('neoplasms', 'Disease', 'MESH:D009369', (14, 23))	('neoplasms', 'Disease', (14, 23))	('IDH1', 'Gene', '3417', (72, 76))	('mutant', 'Var', (65, 71))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('neoplasm', 'Phenotype', 'HP:0002664', (14, 22))	('neoplasms', 'Phenotype', 'HP:0002664', (14, 23))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
83733	23289977	Thus, while 32% of GBM-Os in this study arose from a lower grade glioma compared with 8% of other GBMs, the higher frequency of secondary neoplasms among GBM-O may account for the higher frequency of the IDH1 mutation in this group.	('glioma', 'Disease', (65, 71))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('IDH1', 'Gene', (204, 208))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('IDH1', 'Gene', '3417', (204, 208))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (138, 146))	('secondary neoplasms', 'Disease', (128, 147))	('mutation', 'Var', (209, 217))	('arose from', 'Reg', (40, 50))	('neoplasms', 'Phenotype', 'HP:0002664', (138, 147))	('secondary neoplasms', 'Disease', 'MESH:D060085', (128, 147))
83735	23289977	FISH analysis for 1p and 19q was performed on all tumors with an oligodendroglioma component, but not on classic GBMs, since 1p/19q loss is rare in GBM and not prognostically significant.	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('oligodendroglioma component', 'Disease', (65, 92))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('oligodendroglioma component', 'Disease', 'MESH:D009837', (65, 92))	('loss', 'NegReg', (132, 136))	('1p/19q', 'Var', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
83736	23289977	Of the eight GBM-Os that were co-deleted for 1p and 19q, six (75%) were IDH1 mutant.	('mutant', 'Var', (77, 83))	('IDH1', 'Gene', '3417', (72, 76))	('IDH1', 'Gene', (72, 76))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))
83737	23289977	Interestingly, none of the eight GBM-Os that were intact at both 1p and 19q were IDH1 mutant, indicating that there is a strong positive correlation between 1p/19q co-deletion and IDH1 mutation for this tumor type (P = 0.0070).	('IDH1', 'Gene', (180, 184))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('GBM', 'Phenotype', 'HP:0012174', (33, 36))	('IDH1', 'Gene', '3417', (180, 184))	('1p/19q co-deletion', 'Var', (157, 175))	('mutation', 'Var', (185, 193))	('IDH1', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('IDH1', 'Gene', '3417', (81, 85))
83738	23289977	We also found that deletion of 1p (regardless of 19q status) has a statistically significant inverse correlation with p53 overexpression, with 6 of 10 (60%) GBM-Os with 1p and 19q intact demonstrating positivity for p53 compared with only 1 of 11 (9.1%) GBM-Os that were 1p deleted (P = 0.0237).	('GBM', 'Phenotype', 'HP:0012174', (157, 160))	('p53', 'Gene', (118, 121))	('deletion', 'Var', (19, 27))	('overexpression', 'PosReg', (122, 136))	('p53', 'Gene', '7157', (118, 121))	('GBM', 'Phenotype', 'HP:0012174', (254, 257))	('p53', 'Gene', '7157', (216, 219))	('p53', 'Gene', (216, 219))
83740	23289977	One of eight (12.5%) 1p/19q co-deleted GBM-Os was EGFR amplified, whereas 4 of 15 (26.7%) GBM-Os without the co-deletion were EGFR amplified (P = 0.6214).	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('EGFR', 'Gene', (126, 130))	('1p/19q co-deleted', 'Var', (21, 38))	('EGFR', 'Gene', '1956', (50, 54))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (126, 130))
83745	23289977	After multivariate analysis, adjusting for age, MGMT promoter methylation status and secondary GBM status, the presence of an oligodendroglioma component conferred only a marginal survival advantage to patients with GBM-Os over patients with other types of GBMs (P = 0.0788; Table 4).	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('MGMT', 'Gene', (48, 52))	('presence', 'Var', (111, 119))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('MGMT', 'Gene', '4255', (48, 52))	('patients', 'Species', '9606', (228, 236))	('GBM', 'Phenotype', 'HP:0012174', (257, 260))	('patients', 'Species', '9606', (202, 210))	('GBM', 'Phenotype', 'HP:0012174', (216, 219))	('oligodendroglioma component', 'Disease', (126, 153))	('oligodendroglioma component', 'Disease', 'MESH:D009837', (126, 153))
83746	23289977	Within the GBM-O group, patients whose tumors contained the 1p deletion, regardless of the 19q status, were found to have a significant survival advantage over patients whose tumors had intact 1p and 19q chromosomal arms (P = 0.0476; Figure 3 and Table 5).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('patients', 'Species', '9606', (160, 168))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('survival', 'CPA', (136, 144))	('GBM', 'Phenotype', 'HP:0012174', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (24, 32))	('1p deletion', 'Var', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Disease', (39, 45))	('advantage', 'PosReg', (145, 154))
83748	23289977	Median survival rates were similar for patients with GBM-Os on the basis of EGFR amplification (16.2 and 16.8 months; P = 0.4531), MGMT promoter methylation (15.3 and 16.8 months; P = 0.5312), IDH1 mutation (23.5 and 16.2 months; P = 0.2101), p53 expression (18.1 and 23.5 months; P = 0.9224), gender (16.2 and 17.0 months; P = 0.8583) or whether the patient's GBM was primary or secondary (16.8 and 15.3; P = 0.9439) (Table 3).	('IDH1', 'Gene', (193, 197))	('patient', 'Species', '9606', (39, 46))	('patients', 'Species', '9606', (39, 47))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('MGMT', 'Gene', '4255', (131, 135))	('EGFR', 'Gene', '1956', (76, 80))	('MGMT', 'Gene', (131, 135))	('IDH1', 'Gene', '3417', (193, 197))	('EGFR', 'Gene', (76, 80))	('p53', 'Gene', (243, 246))	('p53', 'Gene', '7157', (243, 246))	('patient', 'Species', '9606', (351, 358))	('GBM', 'Phenotype', 'HP:0012174', (361, 364))	('mutation', 'Var', (198, 206))
83751	23289977	EGFR amplification and PTEN deletion, two molecular alterations that are associated with primary GBMs, were seen less frequently in the GBM-O group, albeit with only marginal statistical significance.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('PTEN', 'Gene', (23, 27))	('primary GBMs', 'Disease', (89, 101))	('PTEN', 'Gene', '5728', (23, 27))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))	('deletion', 'Var', (28, 36))	('EGFR', 'Gene', '1956', (0, 4))
83752	23289977	However, it should be noted that the number of GBM-Os with information on PTEN deletion was small and this may have had an impact on statistical significance.	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('impact', 'Reg', (123, 129))	('PTEN', 'Gene', (74, 78))	('PTEN', 'Gene', '5728', (74, 78))	('deletion', 'Var', (79, 87))
83753	23289977	GBM-Os were more frequently positive for the IDH1 mutant protein than other GBMs.	('IDH1', 'Gene', '3417', (45, 49))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('positive', 'Reg', (28, 36))	('mutant', 'Var', (50, 56))	('IDH1', 'Gene', (45, 49))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('protein', 'Protein', (57, 64))
83754	23289977	Mutation of IDH1 is a common event in lower grade gliomas, as well as the secondary GBMs that progress from them, and predicts a more favorable prognosis.	('GBM', 'Phenotype', 'HP:0012174', (84, 87))	('IDH1', 'Gene', (12, 16))	('gliomas', 'Disease', (50, 57))	('Mutation', 'Var', (0, 8))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('IDH1', 'Gene', '3417', (12, 16))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
83755	23289977	Conversely, IDH1 mutation is rarely found in primary GBMs.	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('IDH1', 'Gene', '3417', (12, 16))	('mutation', 'Var', (17, 25))	('IDH1', 'Gene', (12, 16))
83756	23289977	Mutant IDH1 immunoreactivity was found to be strongly associated with secondary GBMs in our study, yet was not appreciably more frequent in primary GBM-Os than other primary GBMs.	('IDH1', 'Gene', '3417', (7, 11))	('GBM', 'Phenotype', 'HP:0012174', (174, 177))	('secondary GBMs', 'Disease', (70, 84))	('Mutant', 'Var', (0, 6))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('IDH1', 'Gene', (7, 11))	('associated', 'Reg', (54, 64))	('GBM', 'Phenotype', 'HP:0012174', (80, 83))
83757	23289977	Therefore, the higher frequency of IDH1 mutation in the GBM-O group was likely because of its enrichment in secondary neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('IDH1', 'Gene', '3417', (35, 39))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('secondary neoplasms', 'Disease', (108, 127))	('GBM', 'Phenotype', 'HP:0012174', (56, 59))	('secondary neoplasms', 'Disease', 'MESH:D060085', (108, 127))
83758	23289977	While the frequency of IDH1 mutation that we found in secondary GBMs by immunohistochemistry is lower than that found in most studies, there is a broad range of frequencies reported (50-84.2%).	('mutation', 'Var', (28, 36))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', (23, 27))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))
83759	23289977	Most studies have shown that immunohistochemistry for mutant IDH1 protein is comparable in sensitivity to sequencing or PCR in detecting the IDH1 mutation.	('IDH1', 'Gene', (141, 145))	('protein', 'Protein', (66, 73))	('IDH1', 'Gene', '3417', (141, 145))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', (61, 65))	('mutant', 'Var', (54, 60))
83760	23289977	Similar to our study, Wang et al found that 31% of GBM-Os contained the IDH1 mutation, compared with less than 5% of conventional GBMs.	('IDH1', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('IDH1', 'Gene', '3417', (72, 76))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))
83762	23289977	Hegi et al also found that GBM-Os were enriched for IDH1 mutations.	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('mutations', 'Var', (57, 66))	('IDH1', 'Gene', '3417', (52, 56))	('IDH1', 'Gene', (52, 56))
83763	23289977	In their study, a second distinct subset of GBM-Os was found to contain EGFR amplification, raising the possibility that IDH1 mutant GBM-Os represent secondary GBMs, while EGFR-amplified GBM-Os represent primary GBMs with potential morphologic overlap with small cell variants of GBM.	('IDH1', 'Gene', (121, 125))	('EGFR', 'Gene', '1956', (172, 176))	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('EGFR', 'Gene', '1956', (72, 76))	('IDH1', 'Gene', '3417', (121, 125))	('EGFR', 'Gene', (172, 176))	('GBM', 'Phenotype', 'HP:0012174', (212, 215))	('EGFR', 'Gene', (72, 76))	('GBM', 'Phenotype', 'HP:0012174', (187, 190))	('mutant', 'Var', (126, 132))
83764	23289977	Our study did not uncover a statistically significant, mutually exclusive relationship between IDH1 mutation and EGFR amplification.	('mutation', 'Var', (100, 108))	('IDH1', 'Gene', (95, 99))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (95, 99))
83765	23289977	Neither did we find a positive relationship between p53 overexpression and IDH1 mutation, although this has been reported previously and is thought to be typical of secondary GBMs.	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('GBM', 'Phenotype', 'HP:0012174', (175, 178))	('IDH1', 'Gene', (75, 79))	('overexpression', 'PosReg', (56, 70))	('IDH1', 'Gene', '3417', (75, 79))	('mutation', 'Var', (80, 88))
83766	23289977	Similar to previous studies, however, we did find that IDH1 mutation was significantly associated with 1p/19q co-deletion in GBM-Os.	('mutation', 'Var', (60, 68))	('IDH1', 'Gene', '3417', (55, 59))	('1p/19q co-deletion', 'Disease', (103, 121))	('associated', 'Reg', (87, 97))	('IDH1', 'Gene', (55, 59))	('GBM', 'Phenotype', 'HP:0012174', (125, 128))
83767	23289977	Co-deletion of 1p/19q was detected in 29.6% (8 of 27) of GBM-Os, considerably lower than the 50-80% frequency seen in oligodendrogliomas, yet in the range of 20-30% reported for mixed oligoastrocytomas and higher than most other studies of GBM-Os.	('1p/19q', 'Gene', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('GBM-Os', 'Disease', (57, 63))	('oligodendrogliomas', 'Disease', (118, 136))	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('Co-deletion', 'Var', (0, 11))	('astrocytoma', 'Phenotype', 'HP:0009592', (189, 200))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('oligoastrocytomas', 'Disease', (184, 201))	('GBM', 'Phenotype', 'HP:0012174', (240, 243))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (118, 136))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (184, 201))	('detected', 'Reg', (26, 34))
83769	23289977	Our findings are most consistent with those of Salvati et al because 1p deletion was found to confer a survival advantage to patients with GBM-Os.	('patients', 'Species', '9606', (125, 133))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))	('survival advantage', 'CPA', (103, 121))	('1p deletion', 'Var', (69, 80))
83770	23289977	We also found that deletion of 1p had a statistically significant inverse correlation with p53 overexpression.	('deletion', 'Var', (19, 27))	('overexpression', 'PosReg', (95, 109))	('p53', 'Gene', '7157', (91, 94))	('inverse', 'NegReg', (66, 73))	('p53', 'Gene', (91, 94))
83771	23289977	This finding, seen in previous studies, may suggest that GBM-Os arise by two separate pathways, one characterized by 1p deletion (or 1p/19q co-deletion) and the other by TP53 mutation.	('1p deletion', 'Var', (117, 128))	('GBM-Os', 'Disease', (57, 63))	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('arise', 'Reg', (64, 69))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', (170, 174))
83776	23289977	Within the GBM-Os, younger patient age and 1p deletion were significant predictors of longer patient survival.	('GBM', 'Phenotype', 'HP:0012174', (11, 14))	('patient', 'Species', '9606', (27, 34))	('longer', 'PosReg', (86, 92))	('patient', 'Species', '9606', (93, 100))	('1p deletion', 'Var', (43, 54))
83778	23289977	We found that these tumors tend to occur in younger individuals, are enriched for IDH1 mutations and 1p/19q co-deletion, and are frequently secondary neoplasms.	('secondary neoplasms', 'Disease', (140, 159))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('neoplasm', 'Phenotype', 'HP:0002664', (150, 158))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('neoplasms', 'Phenotype', 'HP:0002664', (150, 159))	('secondary neoplasms', 'Disease', 'MESH:D060085', (140, 159))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (87, 96))
83783	25664944	Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the MAP kinase-signaling pathway.	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('BRAF', 'Gene', (44, 48))	('pilocytic astrocytomas', 'Disease', (52, 74))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (52, 74))	('astrocytomas', 'Disease', 'MESH:D001254', (108, 120))	('FGFR1', 'Gene', (34, 39))	('FGFR1', 'Gene', (79, 84))	('astrocytomas', 'Disease', 'MESH:D001254', (62, 74))	('alterations', 'Reg', (85, 96))	('alterations', 'Var', (19, 30))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('astrocytomas', 'Disease', (108, 120))	('astrocytomas', 'Disease', (62, 74))
83784	25664944	Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors.	('Adult LGG', 'Disease', (0, 9))	('astrocytic tumors', 'Disease', (70, 87))	('IDH1/2', 'Gene', (92, 98))	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('astrocytic tumors', 'Disease', 'MESH:D001254', (70, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (99, 108))	('mutations', 'Var', (57, 66))	('ATRX', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ATRX', 'Gene', '546', (52, 56))	('mutations', 'Var', (38, 47))	('IDH1/2', 'Gene', '3417;3418', (92, 98))	('IDH1/2', 'Gene', (31, 37))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (135, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('oligodendroglial tumors', 'Disease', (135, 158))
83793	25664944	Several new driver mutations have been described in gliomas and the field has rapidly grown to reflect the emerging complexity of these tumors.	('tumors', 'Disease', (136, 142))	('gliomas', 'Disease', (52, 59))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
83801	25664944	These discoveries include histone mutations in pediatric high-grade astrocytomas and alterations in BRAF, FGFR1 and MYB in astrocytic tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('astrocytic tumors', 'Disease', 'MESH:D001254', (123, 140))	('FGFR1', 'Gene', (106, 111))	('astrocytomas', 'Disease', (68, 80))	('histone', 'Protein', (26, 33))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))	('BRAF', 'Gene', (100, 104))	('MYB', 'Gene', '4602', (116, 119))	('alterations', 'Var', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('astrocytic tumors', 'Disease', (123, 140))	('mutations', 'Var', (34, 43))	('MYB', 'Gene', (116, 119))
83802	25664944	Since many of these findings represent new or relatively new discoveries, data regarding prognosis and potential mechanism of pathogenesis are just beginning to emerge The most frequent alterations in pediatric LGG involve the v-raf murine sarcoma viral oncogene homolog B1 (BRAF).	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (227, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (227, 273))	('alterations', 'Var', (186, 197))	('LGG', 'Disease', (211, 214))
83804	25664944	Pilocytic astrocytomas (grade I) show tandem duplications at chromosome 7q34 resulting in the formation of a fusion gene between the kinase domain of BRAF and KIAA1549 (BRAF-KIAA1549 fusion gene).	('Pilocytic astrocytomas', 'Disease', (0, 22))	('KIAA1549', 'Gene', (174, 182))	('KIAA1549', 'Gene', '57670', (174, 182))	('BRAF-KIAA1549', 'Disease', (169, 182))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('KIAA1549', 'Gene', (159, 167))	('BRAF-KIAA1549', 'Disease', 'None', (169, 182))	('KIAA1549', 'Gene', '57670', (159, 167))	('BRAF', 'Gene', (150, 154))	('tandem duplications', 'Var', (38, 57))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('fusion', 'Var', (109, 115))
83808	25664944	By contrast, only 33% of supratentorial and ~50% of optic nerve pilocytic astrocytomas harbor BRAF fusions.	('supratentorial', 'Disease', (25, 39))	('fusions', 'Var', (99, 106))	('optic nerve pilocytic astrocytomas', 'Disease', 'MESH:D001254', (52, 86))	('BRAF', 'Var', (94, 98))	('optic nerve pilocytic astrocytomas', 'Disease', (52, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))
83809	25664944	Nonsynonymous point mutations in BRAF resulting in a valine to glutamic acid substitution at position 600 (V600E) were first described in melanocytic lesions.	('valine to glutamic acid substitution at position 600', 'Mutation', 'rs113488022', (53, 105))	('valine', 'MPA', (53, 59))	('V600E', 'Var', (107, 112))	('BRAF', 'Gene', (33, 37))	('Nonsynonymous point mutations', 'Var', (0, 29))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('melanocytic lesions', 'Disease', 'MESH:D009508', (138, 157))	('melanocytic lesions', 'Disease', (138, 157))
83810	25664944	Subsequently, BRAF V600E mutations were identified in specific subtypes of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('V600E', 'Var', (19, 24))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('identified', 'Reg', (40, 50))	('BRAF', 'Gene', (14, 18))
83815	25664944	Two groups simultaneously reported LGG alterations in fibroblast growth factor receptor 1 (FGFR1), an RTK and member of the FGF receptor family that binds to the fibroblast growth factor family of proteins.	('FGFR1', 'Gene', (91, 96))	('RTK', 'Gene', '5979', (102, 105))	('fibroblast growth factor receptor 1', 'Gene', (54, 89))	('binds', 'Interaction', (149, 154))	('alterations', 'Var', (39, 50))	('fibroblast growth factor receptor 1', 'Gene', '2260', (54, 89))	('RTK', 'Gene', (102, 105))
83816	25664944	Jones et al reported mutations affecting the TKD of FGFR1 in 14/141 (two sample sets including 5/96 and 9/45 tumors negative for BRAF alterations) pilocytic astrocytomas.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('pilocytic astrocytomas', 'Disease', (147, 169))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (147, 169))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('TKD', 'MPA', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('FGFR1', 'Gene', (52, 57))	('tumors', 'Disease', (109, 115))	('mutations', 'Var', (21, 30))
83817	25664944	Mutations involved two hotspot codons, Asn546 and Lys656.	('involved', 'Reg', (10, 18))	('Lys656', 'Chemical', '-', (50, 56))	('Asn546', 'Chemical', '-', (39, 45))	('Lys656', 'Var', (50, 56))
83818	25664944	Moreover, FGFR1 mutant pilocytic astrocytomas tended toward extracerebellar and midline localization.	('FGFR1', 'Gene', (10, 15))	('pilocytic astrocytomas', 'Disease', (23, 45))	('mutant', 'Var', (16, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (23, 45))
83819	25664944	Interestingly, rare alterations involving the kinase domain of NTRK2 (TrkB), an RTK that binds BDNF, were noted in 2/49 pilocytic astrocytomas resulting in the formation of the fusion genes (QKI-NTRK2 and NACC2-NTRK2).	('TrkB', 'Gene', (70, 74))	('NACC2', 'Gene', (205, 210))	('NTRK2', 'Gene', '4915', (211, 216))	('NACC2', 'Gene', '138151', (205, 210))	('alterations', 'Var', (20, 31))	('BDNF', 'Gene', '627', (95, 99))	('QKI', 'Gene', '9444', (191, 194))	('NTRK2', 'Gene', (195, 200))	('49 pilocytic astrocytomas', 'Disease', 'MESH:D001254', (117, 142))	('NTRK2', 'Gene', '4915', (63, 68))	('QKI', 'Gene', (191, 194))	('NTRK2', 'Gene', (211, 216))	('RTK', 'Gene', (80, 83))	('49 pilocytic astrocytomas', 'Disease', (117, 142))	('RTK', 'Gene', '5979', (80, 83))	('TrkB', 'Gene', '4915', (70, 74))	('formation', 'Reg', (160, 169))	('NTRK2', 'Gene', (63, 68))	('BDNF', 'Gene', (95, 99))	('NTRK2', 'Gene', '4915', (195, 200))	('astrocytoma', 'Phenotype', 'HP:0009592', (130, 141))
83820	25664944	MYB (V-Myb Avian Myeloblastosis Viral Oncogene Homolog) copy number alterations were initially described in 2 diffuse astrocytomas (WHO grade II) and 1 angiocentric glioma (WHO grade II) using Affymetrix SNP arrays and interphase FISH analyses.	('MYB', 'Gene', (0, 3))	('angiocentric glioma', 'Disease', 'MESH:D005910', (152, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('V-Myb Avian Myeloblastosis Viral', 'Disease', (5, 37))	('copy number alterations', 'Var', (56, 79))	('V-Myb Avian Myeloblastosis Viral', 'Disease', 'MESH:D001715', (5, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('astrocytomas', 'Disease', 'MESH:D001254', (118, 130))	('described', 'Reg', (95, 104))	('MYB', 'Gene', '4602', (0, 3))	('angiocentric glioma', 'Disease', (152, 171))	('astrocytomas', 'Disease', (118, 130))
83821	25664944	Subsequent efforts using whole genome sequencing, transcriptome and targeted high-throughput sequencing showed rearrangement of MYBL1 (V-Myb Avian Myeloblastosis Viral Oncogene Homolog-Like 1) in one diffuse astrocytoma and rearrangement or copy number alterations of MYB in 5 diffuse astrocytomas, 2 angiocentric gliomas and 1 oligodendroglioma.	('oligodendroglioma', 'Disease', 'MESH:D009837', (328, 345))	('glioma', 'Phenotype', 'HP:0009733', (339, 345))	('MYB', 'Gene', (128, 131))	('rearrangement', 'Var', (224, 237))	('MYB', 'Gene', (268, 271))	('MYB', 'Gene', '4602', (268, 271))	('gliomas', 'Phenotype', 'HP:0009733', (314, 321))	('rearrangement', 'Var', (111, 124))	('astrocytomas', 'Disease', 'MESH:D001254', (285, 297))	('glioma', 'Phenotype', 'HP:0009733', (314, 320))	('MYB', 'Gene', '4602', (128, 131))	('V-Myb Avian Myeloblastosis Viral Oncogene Homolog-Like 1', 'Gene', '4603', (135, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (285, 296))	('oligodendroglioma', 'Disease', (328, 345))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (301, 321))	('astrocytomas', 'Disease', (285, 297))	('angiocentric gliomas', 'Disease', (301, 321))	('astrocytoma', 'Phenotype', 'HP:0009592', (208, 219))
83823	25664944	Alterations in MYB manifested as episome formation, deletion of the negative regulatory region of MYB or deletion of microRNA-binding sites.	('deletion', 'Var', (105, 113))	('MYB', 'Gene', '4602', (15, 18))	('MYB', 'Gene', (15, 18))	('MYB', 'Gene', '4602', (98, 101))	('episome formation', 'MPA', (33, 50))	('MYB', 'Gene', (98, 101))	('deletion', 'Var', (52, 60))	('microRNA-binding', 'Protein', (117, 133))
83825	25664944	MYBL1 truncation products, but not wild type MYBL1, when transduced into NIH-3T3 cells, were able to generate tumors in vitro in soft agar and as xenografts in vivo.	('agar', 'Chemical', 'MESH:D000362', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MYBL1', 'Gene', (0, 5))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('truncation products', 'Var', (6, 25))	('generate', 'PosReg', (101, 109))	('NIH-3T3', 'CellLine', 'CVCL:0594', (73, 80))
83826	25664944	Interestingly, this group did not identify MYB alterations in diffuse astrocytomas, although two angiocentric gliomas showed 6q23.3 deletions resulting in truncated MYB.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('MYB', 'Gene', (165, 168))	('deletions', 'Var', (132, 141))	('MYB', 'Gene', '4602', (165, 168))	('astrocytomas', 'Disease', 'MESH:D001254', (70, 82))	('MYB', 'Gene', '4602', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (97, 117))	('truncated', 'MPA', (155, 164))	('MYB', 'Gene', (43, 46))	('angiocentric gliomas', 'Disease', (97, 117))	('astrocytomas', 'Disease', (70, 82))
83829	25664944	In the context of LGG, BRAF fusion proteins and the BRAF V600E mutation each result in aberrant activation of the MAP kinase pathway.	('V600E', 'Mutation', 'rs113488022', (57, 62))	('MAP kinase pathway', 'Pathway', (114, 132))	('V600E', 'Var', (57, 62))	('BRAF', 'Gene', (52, 56))	('activation', 'PosReg', (96, 106))
83830	25664944	Furthermore, Tp53-null astrocytes bearing TKD-duplicated FGFR1 when xenografted into mouse brains generated high-grade gliomas.	('mouse', 'Species', '10090', (85, 90))	('FGFR1', 'Gene', (57, 62))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('Tp53', 'Gene', '22059', (13, 17))	('gliomas', 'Disease', (119, 126))	('TKD-duplicated', 'Var', (42, 56))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('Tp53', 'Gene', (13, 17))
83831	25664944	That deregulated MAP kinase pathway signaling serves as a major driver in these tumors is underscored by the identification in LGG, albeit at lower frequency, of mutations in other core pathway components.	('mutations', 'Var', (162, 171))	('deregulated', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('MAP kinase pathway signaling', 'Pathway', (17, 45))
83832	25664944	For instance, mutations in the tyrosine phosphatase PTPN11 were noted in 2/49 pilocytic astrocytomas with FGFR1 mutations.	('49 pilocytic astrocytomas', 'Disease', 'MESH:D001254', (75, 100))	('PTPN11', 'Gene', '5781', (52, 58))	('49 pilocytic astrocytomas', 'Disease', (75, 100))	('FGFR1', 'Gene', (106, 111))	('mutations', 'Var', (112, 121))	('PTPN11', 'Gene', (52, 58))	('noted', 'Reg', (64, 69))	('mutations', 'Var', (14, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))
83834	25664944	Along these lines, mutations in RAS and NF1 (encoding the neurofibromin protein, a negative regulator of RAS) were noted at similar frequencies.	('neurofibromin', 'Gene', '4763', (58, 71))	('NF1', 'Gene', (40, 43))	('mutations', 'Var', (19, 28))	('neurofibromin', 'Gene', (58, 71))	('NF1', 'Gene', '4763', (40, 43))	('RAS', 'Gene', (32, 35))
83839	25664944	These factors underscore the importance of MAP kinase signaling in glial development and suggest that aberrant activation of this pathway mediates tumorigenesis in pediatric LGG.	('LGG', 'Disease', (174, 177))	('activation', 'PosReg', (111, 121))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('aberrant', 'Var', (102, 110))
83840	25664944	The discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in gliomas heralded the genomic era of glioma research.	('mutations', 'Var', (52, 61))	('gliomas', 'Disease', (65, 72))	('glioma', 'Disease', (65, 71))	('dehydrogenase (IDH) 1', 'Gene', '3417', (28, 49))	('isocitrate', 'Chemical', 'MESH:C034219', (17, 27))	('dehydrogenase (IDH) 1', 'Gene', (28, 49))	('glioma', 'Disease', (101, 107))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
83841	25664944	Large profiling studies have identified IDH1/2 mutations in >70% of grade II and grade III gliomas and more than 90% of secondary GBM.	('gliomas', 'Disease', (91, 98))	('IDH1/2', 'Gene', (40, 46))	('grade II', 'Disease', (68, 76))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('mutations', 'Var', (47, 56))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
83843	25664944	IDH mutations are invariably missense and heterozygous, with IDH1 mutations predominating (more than 90%), and involve active site arginine residues, either R132 in IDH1 or R172 in IDH2.	('involve', 'Reg', (111, 118))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', (181, 184))	('IDH', 'Gene', (165, 168))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', '3417', (165, 168))	('IDH2', 'Gene', '3418', (181, 185))	('IDH', 'Gene', '3417', (181, 184))	('IDH', 'Gene', '3417', (0, 3))	('IDH2', 'Gene', (181, 185))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', (165, 169))	('R132', 'Var', (157, 161))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', '3417', (165, 169))	('R172', 'Var', (173, 177))	('IDH', 'Gene', (61, 64))	('arginine', 'Chemical', 'MESH:D001120', (131, 139))
83844	25664944	Mutant IDH1/2 catalyze the generation of the oncometabolite D-2HG from alpha-KG (FIG.	('Mutant', 'Var', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('alpha-KG', 'Chemical', 'MESH:D007656', (71, 79))	('IDH1/2', 'Gene', (7, 13))
83846	25664944	Moreover, the association of IDH1/2 mutation with astrocytomas, oligodendrogliomas and oligoastrocytomas strongly suggests that the event arises early in the pathogenesis of LGG (FIG.	('LGG', 'Disease', (174, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (92, 104))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (64, 82))	('IDH1/2', 'Gene', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('astrocytomas', 'Disease', (92, 104))	('astrocytomas', 'Disease', (50, 62))	('association', 'Interaction', (14, 25))	('oligoastrocytomas', 'Disease', (87, 104))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (87, 104))	('IDH1/2', 'Gene', '3417;3418', (29, 35))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('oligodendrogliomas', 'Disease', (64, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('astrocytomas', 'Disease', 'MESH:D001254', (50, 62))	('mutation', 'Var', (36, 44))
83849	25664944	G-CIMP is strongly associated with mutations in IDH1/2 in LGG.	('associated', 'Reg', (19, 29))	('G-CIMP', 'Chemical', '-', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (48, 54))	('G-CIMP', 'Disease', (0, 6))	('IDH1/2', 'Gene', (48, 54))	('mutations', 'Var', (35, 44))
83850	25664944	Moreover, in both immortalized astrocytes and colon cancer cell lines, expression of IDH1 R132H, the most common glioma-associated IDH mutation, fully recapitulates G-CIMP.	('IDH', 'Gene', '3417', (85, 88))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('G-CIMP', 'Chemical', '-', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('colon cancer', 'Disease', (46, 58))	('R132H', 'Var', (90, 95))	('IDH', 'Gene', (131, 134))	('glioma', 'Disease', (113, 119))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('IDH1', 'Gene', (85, 89))	('IDH', 'Gene', '3417', (131, 134))	('IDH', 'Gene', (85, 88))	('IDH1', 'Gene', '3417', (85, 89))	('colon cancer', 'Disease', 'MESH:D015179', (46, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (46, 58))
83852	25664944	Indeed, astrocytic cell lines expressing mutant IDH1 R132H, and IDH-mutant oligodendrogliomas show increased trimethylation of histone marks such as H3K9, H3K27 and H3K36 (FIG.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (75, 93))	('IDH', 'Gene', '3417', (64, 67))	('H3K27', 'Protein', (155, 160))	('IDH', 'Gene', (48, 51))	('mutant', 'Var', (41, 47))	('IDH1', 'Gene', '3417', (48, 52))	('trimethylation', 'MPA', (109, 123))	('H3K9', 'Protein', (149, 153))	('oligodendrogliomas', 'Disease', (75, 93))	('IDH', 'Gene', '3417', (48, 51))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('H3K36', 'Protein', (165, 170))	('increased', 'PosReg', (99, 108))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('IDH1', 'Gene', (48, 52))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('IDH', 'Gene', (64, 67))
83856	25664944	Mutations in CIC (homolog of the Drosophila gene capicua) on chromosome 19q and FUBP1 (FUSE binding protein 1) on chromosome 1p have been recently described in oligodendrogliomas (FIG.	('described', 'Reg', (147, 156))	('Drosophila', 'Species', '7227', (33, 43))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('capicua', 'Gene', (49, 56))	('oligodendrogliomas', 'Disease', (160, 178))	('FUBP1', 'Gene', '8880', (80, 85))	('capicua', 'Gene', '53560', (49, 56))	('Mutations', 'Var', (0, 9))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('FUBP1', 'Gene', (80, 85))	('CIC', 'Gene', (13, 16))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (160, 178))
83859	25664944	Also consistent with loss-of-fuction, FUBP1 mutations are mainly frameshift and nonsense variants, and occur at lower frequencies (14-22%) than CIC mutations in low-grade oligodendrogliomas (2/14, 2/9, 3/21, 3/17).	('FUBP1', 'Gene', '8880', (38, 43))	('frameshift', 'Var', (65, 75))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (171, 189))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('oligodendrogliomas', 'Disease', (171, 189))	('FUBP1', 'Gene', (38, 43))	('mutations', 'Var', (44, 53))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))
83862	25664944	Nevertheless, establishing the precise mechanisms by which either CIC or FUBP1 mutations contribute to oligodendroglioma pathogenesis will require further study.	('CIC', 'Gene', (66, 69))	('oligodendroglioma', 'Disease', (103, 120))	('FUBP1', 'Gene', '8880', (73, 78))	('contribute', 'Reg', (89, 99))	('oligodendroglioma', 'Disease', 'MESH:D009837', (103, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('FUBP1', 'Gene', (73, 78))	('mutations', 'Var', (79, 88))
83864	25664944	Germline loss-of-function mutations in ATRX are associated with alpha thalassemia mental retardation X-linked (ATR-X) syndrome.	('ATRX', 'Gene', (39, 43))	('ATRX', 'Gene', '546', (39, 43))	('thalassemia mental retardation X-linked (ATR-X) syndrome', 'Disease', 'MESH:D038901', (70, 126))	('mutations', 'Var', (26, 35))	('mental retardation', 'Phenotype', 'HP:0001249', (82, 100))	('loss-of-function', 'NegReg', (9, 25))
83866	25664944	In 2012, ATRX mutations were described in adult and pediatric astrocytic gliomas where they exhibited a strong association with the alternate lengthening of telomeres (ALT) phenotype, a pathological telomere maintenance mechanism though to promote cellular immortality (FIG.	('astrocytic gliomas', 'Disease', 'MESH:D001254', (62, 80))	('mutations', 'Var', (14, 23))	('ATRX', 'Gene', '546', (9, 13))	('astrocytic gliomas', 'Disease', (62, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('cellular immortality', 'CPA', (248, 268))	('alternate lengthening of telomeres', 'MPA', (132, 166))	('association', 'Interaction', (111, 122))	('promote', 'PosReg', (240, 247))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('ATRX', 'Gene', (9, 13))
83867	25664944	In total, ATRX mutations were found in 33%-67% of grade II astrocytic tumors, and occurred in 75-80% of IDH-mutant LGG that did not also exhibit 1p/19q codeletion.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('IDH', 'Gene', (104, 107))	('astrocytic tumors', 'Disease', 'MESH:D001254', (59, 76))	('ATRX', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('found', 'Reg', (30, 35))	('IDH', 'Gene', '3417', (104, 107))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('ATRX', 'Gene', '546', (10, 14))	('astrocytic tumors', 'Disease', (59, 76))
83868	25664944	In fact, ATRX mutation was mutually exclusive with 1p/19q codeletion in glioma and strongly associated with TP53 mutation (FIG.	('glioma', 'Disease', (72, 78))	('mutation', 'Var', (113, 121))	('ATRX', 'Gene', '546', (9, 13))	('TP53', 'Gene', '7157', (108, 112))	('1p/19q codeletion', 'Var', (51, 68))	('TP53', 'Gene', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('mutation', 'Var', (14, 22))	('associated', 'Reg', (92, 102))	('ATRX', 'Gene', (9, 13))
83869	25664944	These data suggest that ATRX mutation, together with TP53 mutation, may delineate a distinct pathogenic route operative in the majority of diffuse astrocytic LGG.	('mutation', 'Var', (29, 37))	('diffuse astrocytic LGG', 'Disease', (139, 161))	('ATRX', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (53, 57))	('ATRX', 'Gene', '546', (24, 28))	('TP53', 'Gene', (53, 57))
83870	25664944	That being said, the precise mechanism(s) by which ATRX mutations drive gliomagenesis remain unclear.	('glioma', 'Disease', (72, 78))	('mutations', 'Var', (56, 65))	('ATRX', 'Gene', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('drive', 'Reg', (66, 71))	('ATRX', 'Gene', '546', (51, 55))
83871	25664944	Point mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were first discovered in melanoma, and are thought to increase telomerase expression, thereby maintaining telomere length and enabling repeated cell division.	('telomerase', 'Protein', (154, 164))	('TERT', 'Gene', '7015', (80, 84))	('enabling', 'PosReg', (217, 225))	('repeated cell division', 'CPA', (226, 248))	('increase', 'PosReg', (145, 153))	('expression', 'MPA', (165, 175))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('telomerase reverse transcriptase', 'Gene', (46, 78))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('telomere length', 'MPA', (197, 212))	('telomerase reverse transcriptase', 'Gene', '7015', (46, 78))	('Point mutations', 'Var', (0, 15))	('TERT', 'Gene', (80, 84))	('maintaining', 'PosReg', (185, 196))
83872	25664944	These mutations have been identified in many CNS tumors, including glioblastomas, medulloblastomas and LGG.	('medulloblastomas', 'Disease', 'MESH:D008527', (82, 98))	('glioblastomas', 'Phenotype', 'HP:0012174', (67, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('medulloblastomas', 'Disease', (82, 98))	('LGG', 'Disease', (103, 106))	('glioblastomas', 'Disease', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('identified', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
83876	25664944	Additionally, TERT promoter mutations are tightly associated (98-100%) with 1p/19q co-deletion and are mutually exclusive with ATRX mutations in LGG (FIG.	('ATRX', 'Gene', (127, 131))	('ATRX', 'Gene', '546', (127, 131))	('1p/19q co-deletion', 'Disease', (76, 94))	('TERT', 'Gene', (14, 18))	('TERT', 'Gene', '7015', (14, 18))	('associated', 'Reg', (50, 60))	('mutations', 'Var', (28, 37))	('LGG', 'Gene', (145, 148))
83877	25664944	These findings emphasize the importance of pathological telomere maintenance in LGG, whether by way of TERT promoter mutations in 1p/19q codeleted tumors (predominantly oligodendroglioma), or ALT in ATRX-mutant tumors (predominantly astrocytoma).	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('astrocytoma', 'Phenotype', 'HP:0009592', (233, 244))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('oligodendroglioma', 'Disease', 'MESH:D009837', (169, 186))	('1p/19q', 'Gene', (130, 136))	('oligodendroglioma', 'Disease', (169, 186))	('LGG', 'Disease', (80, 83))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('ATRX', 'Gene', '546', (199, 203))	('mutations', 'Var', (117, 126))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('ATRX', 'Gene', (199, 203))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))
83879	25664944	Perhaps most notably, the identification of IDH1/2 mutations in both low and high-grade adult gliomas is now of considerable importance, due to the significant prognostic benefit conferred by the genomic alteration.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('low', 'Disease', (69, 72))	('mutations', 'Var', (51, 60))	('IDH1/2', 'Gene', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('IDH1/2', 'Gene', '3417;3418', (44, 50))
83880	25664944	The standard initial approach of many pathology practices is immunohistochemical, using an antibody specifically directed against IDH1 R132H (accounting for more than 95% of all glioma-associated IDH mutations), followed by sequencing-based genotyping in immunonegative cases.	('IDH', 'Gene', '3417', (130, 133))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('IDH', 'Gene', '3417', (196, 199))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('R132H', 'Var', (135, 140))	('IDH1', 'Gene', (130, 134))	('R132H', 'Mutation', 'rs121913500', (135, 140))	('IDH1', 'Gene', '3417', (130, 134))	('IDH', 'Gene', (130, 133))	('glioma', 'Disease', (178, 184))	('IDH', 'Gene', (196, 199))
83882	25664944	The mutual exclusivity of ATRX mutation and 1p/19q codeletions in LGG has prompted the proposal that all diffuse gliomas be classified on the basis of IDH and ATRX mutational status:or a negative staining pattern by IHC (FIG.	('ATRX', 'Gene', '546', (159, 163))	('ATRX', 'Gene', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH', 'Gene', '3417', (151, 154))	('LGG', 'Disease', (66, 69))	('mutation', 'Var', (31, 39))	('gliomas', 'Disease', (113, 120))	('ATRX', 'Gene', '546', (26, 30))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('ATRX', 'Gene', (159, 163))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('IDH', 'Gene', (151, 154))
83885	25664944	CIC and FUBP1 mutations do not bear 100% concurrence with 1p/19q codeletions.	('FUBP1', 'Gene', (8, 13))	('mutations', 'Var', (14, 23))	('CIC', 'Gene', (0, 3))	('FUBP1', 'Gene', '8880', (8, 13))
83886	25664944	Thus, from a diagnostic and prognostic view, assessment of 1p/19q deletion remains superior to CIC and FUBP1 genotyping in the establishment of oligodendroglial lineage.	('FUBP1', 'Gene', '8880', (103, 108))	('1p/19q deletion', 'Var', (59, 74))	('oligodendroglia', 'Disease', 'None', (144, 159))	('FUBP1', 'Gene', (103, 108))	('oligodendroglia', 'Disease', (144, 159))
83888	25664944	In pediatric LGG, the identification of BRAF alterations:by molecular techniques or the BRAF V600E antibody (FIG.	('BRAF', 'Gene', (88, 92))	('LGG', 'Disease', (13, 16))	('V600E', 'Mutation', 'rs113488022', (93, 98))	('V600E', 'Var', (93, 98))
83891	25664944	However, pharmaceutically targeting BRAF V600E has already achieved considerable success in melanoma and V600E inhibitors were effective in preclinical animal models of high-grade glioma and a single case of a 12-year-old patient with GBM.	('BRAF', 'Gene', (36, 40))	('patient', 'Species', '9606', (222, 229))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('V600E', 'Var', (105, 110))	('V600E', 'Mutation', 'rs113488022', (41, 46))	('glioma', 'Disease', (180, 186))
83893	25664944	Recent studies have also shown that mutant IDH1 inhibition is partially effective in xenograft glioma models, although blood-brain barrier permeability remains an issue.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('xenograft glioma', 'Disease', 'MESH:D005910', (85, 101))	('IDH1', 'Gene', (43, 47))	('mutant', 'Var', (36, 42))	('IDH1', 'Gene', '3417', (43, 47))	('inhibition', 'NegReg', (48, 58))	('xenograft glioma', 'Disease', (85, 101))
83894	25664944	Alternatively, vaccine-based approaches against IDH1 R132H have elicited anti-tumor immune responses in tumors bearing the mutation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutation', 'Var', (123, 131))	('IDH1', 'Gene', '3417', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('R132H', 'Var', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('tumor', 'Disease', (78, 83))	('IDH1', 'Gene', (48, 52))	('elicited', 'Reg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
83959	22729482	Evaluation of the p53, CD34 and GFAP expression was divided into four groups according to the percentage of positively stained tumour cells: strong (> 50 %, +++), moderate (10-50 %, ++), mild (< 10 %, +), and negative (-).	('10-50 %', 'Var', (173, 180))	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('CD34', 'Gene', (23, 27))	('CD34', 'Gene', '947', (23, 27))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('GFAP', 'Gene', '2670', (32, 36))	('tumour', 'Disease', (127, 133))	('> 50 %', 'Var', (149, 155))	('GFAP', 'Gene', (32, 36))
83985	22729482	Additional logistic regression analysis undertaken to categorise specimens into tumour or non-tumour tissue, and thereby further define specimens with tumour infiltration, resulted in statistically significant P values for the variable "tumour" of 0.0379 in HGG and 0.0315 in LGG samples.	('tumour', 'Disease', (94, 100))	('HGG', 'Disease', (258, 261))	('non-tumour', 'Disease', 'MESH:D009369', (90, 100))	('LGG', 'Chemical', 'MESH:C038737', (276, 279))	('tumour infiltration', 'Disease', 'MESH:D017254', (151, 170))	('non-tumour', 'Disease', (90, 100))	('men', 'Species', '9606', (141, 144))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('men', 'Species', '9606', (70, 73))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Disease', (237, 243))	('tumour', 'Disease', (151, 157))	('tumour infiltration', 'Disease', (151, 170))	('0.0315', 'Var', (266, 272))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
84147	18394009	By comparing the beta3 subunit at 96 kDa, we found a highly significantly elevated expression in GBMs with 6.18 +- 4.59 compared with LGGs with 1.07 +- 0.549 (P < 0.05; Student's t-test, Table 1).	('GBMs', 'Var', (97, 101))	('GBMs', 'Phenotype', 'HP:0012174', (97, 101))	('beta3', 'Gene', (17, 22))	('elevated', 'PosReg', (74, 82))	('expression', 'MPA', (83, 93))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))	('beta3', 'Gene', '1934', (17, 22))
84189	32620922	Our exploratory analysis moreover showed that the mesial frontal lobes, parahippocampal gyrus, and lateral temporal neocortex were at least twice as likely to be functionally connected with the EL_INST compared to the NEL_INST group (i.e.	('mesial frontal lobes', 'Disease', (50, 70))	('mesial frontal lobes', 'Disease', 'MESH:C566903', (50, 70))	('EL_INST', 'Var', (194, 201))
84198	32620922	At present, it remains unclear why identical lesions in different brain regions have differing propensity to induce seizures.	('seizures', 'Disease', (116, 124))	('seizures', 'Phenotype', 'HP:0001250', (116, 124))	('lesions', 'Var', (45, 52))	('seizure', 'Phenotype', 'HP:0001250', (116, 123))	('induce', 'Reg', (109, 115))	('seizures', 'Disease', 'MESH:D012640', (116, 124))
84238	32620922	The LNM method is an emerging neuroscientific method that can facilitate exploration of network connectivity in individuals with neurological symptoms stemming from lesions in seemingly disparate brain regions.	('lesions', 'Var', (165, 172))	('neurological symptoms', 'Disease', (129, 150))	('neurological symptoms', 'Disease', 'MESH:D009422', (129, 150))
84266	31930623	A protein-centric approach for exome variant aggregation enables sensitive association analysis with clinical outcomes Somatic mutations are early drivers of tumorigenesis and tumor progression.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
84267	31930623	To overcome this challenge, we devised a novel approach called Gene-to-Protein-to-Disease (GPD) which accumulates variants into new sequence units as the degree of genetic assault on structural or functional units of each protein.	('variants', 'Var', (114, 122))	('GPD', 'Gene', '2532', (91, 94))	('GPD', 'Gene', (91, 94))
84272	31930623	Accumulation of mutations in the genome can impair cellular function, lead to abnormal proliferation of cells, and eventually cause cancer.	('abnormal proliferation of cells', 'Phenotype', 'HP:0031377', (78, 109))	('cancer', 'Disease', (132, 138))	('impair', 'NegReg', (44, 50))	('cause', 'Reg', (126, 131))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lead to', 'Reg', (70, 77))	('abnormal proliferation of cells', 'CPA', (78, 109))	('cellular function', 'CPA', (51, 68))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
84273	31930623	Today's massively parallel sequencing technology can detect such variation in the whole genome or exome, and simultaneous analysis of paired tumor and normal samples enables reliable calling of somatic mutations and germline variants.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('variation', 'Var', (65, 74))	('tumor', 'Disease', (141, 146))	('detect', 'Reg', (53, 59))
84275	31930623	The next logical step is to test for the association between cancer genome variants and clinical outcomes such as prognosis and response to first-line therapies.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('association', 'Interaction', (41, 52))	('test', 'Reg', (28, 32))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('variants', 'Var', (75, 83))
84276	31930623	For example, somatic driver mutations are responsible for tumor maintenance, progression, and metastasis, which are robust indicators of patient survival.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('metastasis', 'CPA', (94, 104))	('progression', 'CPA', (77, 88))	('patient', 'Species', '9606', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (28, 37))
84277	31930623	For example, tumors from papillary thyroid carcinoma patients with the missense mutation V600E in the BRAF gene are often associated with more rapid tumor growth and higher death risk than the patients without the mutation, Further, missense mutations affect the transcriptional activity of tumor suppressor TP53 in different ways, as has been shown in a study of ~1,800 primary breast cancer patients.	('tumor', 'Disease', (13, 18))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (25, 52))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('affect', 'Reg', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('papillary thyroid carcinoma', 'Disease', (25, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (379, 392))	('tumor', 'Disease', (291, 296))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (25, 52))	('patients', 'Species', '9606', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('BRAF', 'Gene', '673', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('BRAF', 'Gene', (102, 106))	('TP53', 'Gene', '7157', (308, 312))	('breast cancer', 'Disease', 'MESH:D001943', (379, 392))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('breast cancer', 'Disease', (379, 392))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('death', 'Disease', (173, 178))	('patients', 'Species', '9606', (193, 201))	('tumors', 'Disease', (13, 19))	('patients', 'Species', '9606', (393, 401))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('transcriptional activity', 'MPA', (263, 287))	('missense', 'Var', (71, 79))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (35, 52))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('missense mutations', 'Var', (233, 251))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('death', 'Disease', 'MESH:D003643', (173, 178))	('TP53', 'Gene', (308, 312))	('V600E', 'Var', (89, 94))
84278	31930623	Mutations found within the DNA-binding motif, especially those at codon 179 and 248, are associated with poorer patient survival outcome than mutations at other positions.	('patient survival outcome', 'CPA', (112, 136))	('Mutations', 'Var', (0, 9))	('poorer', 'NegReg', (105, 111))	('patient', 'Species', '9606', (112, 119))
84279	31930623	Other than these well-known examples, however, systematic identification of variants useful for prognosis still remains a major undertaking of cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('variants', 'Var', (76, 84))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
84280	31930623	In the past, a plethora of algorithms have been developed to differentiate truly cancer causing, driver mutations from abundant passenger mutations.	('plethora', 'Phenotype', 'HP:0001050', (15, 23))	('mutations', 'Var', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
84281	31930623	MuSic, OncodriveCLUST, and MutSigCV identify the genes that harbor significantly more mutations than others based on cancer-specific background mutations; SIFT, FATHMM, PolyPhen2, and CHASM identify mutations by evaluating their functional impact; e-Driver and ActiveDriver focus on mutations residing at structurally important sites; and Network-Based Stratification, PARADIGM, TieDIE, and DriverNet prioritize driver mutations using network- and pathway-based approaches.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CHASM', 'Gene', (184, 189))	('CHASM', 'Gene', '219537', (184, 189))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (199, 208))	('cancer', 'Disease', (117, 123))
84283	31930623	applied 26 different computational tools and identified 299 consensus driver genes and ~3,400 mutations across 33 cancer types -- one of the most comprehensive such studies known to date.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))	('mutations', 'Var', (94, 103))
84293	31930623	It successfully recovers a handful of cancer driver mutations as prognostic markers, and also enables identification of interactions between the effects of somatic mutations and germline variants on survival outcomes.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('interactions', 'Interaction', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
84294	31930623	Exome sequencing data for somatic mutations in TCGA datasets were downloaded from the Genomic Data Commons (MC3 Public MAF).	('MAF', 'Gene', '4094', (119, 122))	('MAF', 'Gene', (119, 122))	('MC3', 'Gene', (108, 111))	('MC3', 'Gene', '4159', (108, 111))	('TCGA', 'Gene', (47, 51))	('mutations', 'Var', (34, 43))
84308	31930623	For each cancer, we included sequence units with mutations in three or more patients for all subsequent analyses.	('cancer', 'Disease', (9, 15))	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
84311	31930623	We identified sequence units significantly associated with OS (q-value 0.05) and synthesized up to five principal components (PC) of the selected units and fit another cox proportional hazards model consisting of the covariates Xi = {PC1i, PC2i, PC3i, PC4i, PC5i, TotalMutationi, Agei, Genderi, Racei, Stagei}.	('PC4', 'CellLine', 'CVCL:7090', (252, 255))	('PC5i', 'Var', (258, 262))	('TotalMutationi', 'Var', (264, 278))	('PC4i', 'Var', (252, 256))	('PC2i', 'Var', (240, 244))	('PC3i', 'Var', (246, 250))	('associated', 'Reg', (43, 53))	('PC3', 'CellLine', 'CVCL:0035', (246, 249))
84316	31930623	Figure 1A illustrates the concept of GPD's sequence units through a hypothetical exome with somatic mutations: two mutations occurred within a protein domain (PIU1), one mutation near a protein modification site (PIU2), two mutations in a LU outside the PIUs, and three mutations in the non-coding unit.	('mutations', 'Var', (100, 109))	('mutations', 'Var', (115, 124))	('occurred', 'Reg', (125, 133))	('GPD', 'Gene', (37, 40))	('GPD', 'Gene', '2532', (37, 40))
84317	31930623	Using the protein domains from Pfam database and the protein modification sites from PhosphoSitePlus database as PIUs, GPD mapped all somatic mutations extracted from TCGA to a total of 270,470 PIUs, 17,252 LUs, and 17,266 NCUs in 17,744 human genes, respectively.	('mutations', 'Var', (142, 151))	('human', 'Species', '9606', (238, 243))	('PhosphoSitePlus', 'Disease', (85, 100))	('GPD', 'Gene', (119, 122))	('PhosphoSitePlus', 'Disease', 'None', (85, 100))	('GPD', 'Gene', '2532', (119, 122))
84320	31930623	For example, uterine cancer (UCEC) had on average >1,000 mutations per patient; skin and colon cancers (SKCM and COAD) had on average >500 mutations per patient.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('skin and colon cancers', 'Disease', 'MESH:D012878', (80, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('COAD', 'Disease', 'MESH:D029424', (113, 117))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (21, 27))	('patient', 'Species', '9606', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('COAD', 'Disease', (113, 117))	('patient', 'Species', '9606', (71, 78))	('colon cancers', 'Phenotype', 'HP:0003003', (89, 102))	('uterine cancer', 'Phenotype', 'HP:0010784', (13, 27))
84321	31930623	By contrast, the exomes in many other cancers (e.g.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('exomes', 'Var', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
84324	31930623	While 99% of the genes showed mutations, we found that 68% of PIUs, 96% of LUs, and 98% NCUs, respectively, harbored somatic mutations in two or more patients.	('mutations', 'Var', (125, 134))	('PIUs', 'Disease', (62, 66))	('harbored', 'Reg', (108, 116))	('patients', 'Species', '9606', (150, 158))	('mutations', 'Var', (30, 39))
84329	31930623	For example, the PIU for the DNA-binding domain of TP53 gene showed consistent somatic mutations across the majority of the cancers.	('TP53', 'Gene', (51, 55))	('mutations', 'Var', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('TP53', 'Gene', '7157', (51, 55))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
84330	31930623	Other mutations surrounded the serine phosphorylation site S269 of the protein, which is crucial for the conformational stability of the protein.	('surrounded', 'Reg', (16, 26))	('mutations', 'Var', (6, 15))	('serine', 'Chemical', 'MESH:D012694', (31, 37))
84331	31930623	In another gene, KRAS, we found the highest frequency of somatic mutations in the PIU corresponding to the RAS domain of the protein in pancreas, lung, rectum, and colon cancer (PAAD, LUAD, READ, and COAD).	('COAD', 'Disease', 'MESH:D029424', (200, 204))	('pancreas', 'Disease', (136, 144))	('lung', 'Disease', (146, 150))	('colon cancer', 'Phenotype', 'HP:0003003', (164, 176))	('colon cancer', 'Disease', 'MESH:D015179', (164, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('KRAS', 'Gene', (17, 21))	('COAD', 'Disease', (200, 204))	('PIU', 'Gene', (82, 85))	('KRAS', 'Gene', '3845', (17, 21))	('colon cancer', 'Disease', (164, 176))	('mutations', 'Var', (65, 74))
84332	31930623	The RAS domain also accumulates most mutations in the NRAS gene in 103 non-metastatic skin cancer (SKCM).	('NRAS', 'Gene', (54, 58))	('skin cancer', 'Phenotype', 'HP:0008069', (86, 97))	('mutations', 'Var', (37, 46))	('skin cancer', 'Disease', (86, 97))	('NRAS', 'Gene', '4893', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('skin cancer', 'Disease', 'MESH:D012878', (86, 97))
84333	31930623	Further, we find frequent mutations in thyroid, skin, and colon cancers (THCA, SKCM, and COAD) in a region in the BRAF gene densely populated with phosphorylation and ubiquitination sites (T599, K601, S602, S605, and K601).	('colon cancers', 'Phenotype', 'HP:0003003', (58, 71))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (58, 70))	('S602', 'Var', (201, 205))	('K601', 'Var', (217, 221))	('SKCM', 'Disease', (79, 83))	('S605', 'Var', (207, 211))	('skin', 'Disease', (48, 52))	('T599', 'Var', (189, 193))	('colon cancers', 'Disease', 'MESH:D015179', (58, 71))	('COAD', 'Disease', (89, 93))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('mutations', 'Reg', (26, 35))	('thyroid', 'Disease', (39, 46))	('colon cancers', 'Disease', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('THCA', 'Chemical', '-', (73, 77))	('K601', 'Var', (195, 199))	('COAD', 'Disease', 'MESH:D029424', (89, 93))
84334	31930623	Similarly, the cancer gene PTEN accumulated mutations around lysine acetylation sites K125 and K128.	('K125', 'Var', (86, 90))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('K128', 'Var', (95, 99))	('lysine acetylation', 'MPA', (61, 79))	('lysine', 'Chemical', 'MESH:D008239', (61, 67))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
84337	31930623	We found that the somatic mutation frequencies in the sequence units are highly reproducible between the TCGA and MSK-IMPACT cohorts (Figure 1E), suggesting that somatic mutations have the propensity to be enriched in specific GPD units within each gene.	('GPD', 'Gene', (227, 230))	('mutations', 'Var', (170, 179))	('GPD', 'Gene', '2532', (227, 230))
84348	31930623	Mutations mapped to the peptidase domain in FURIN, LGNM and CASP10 genes in UCEC patients, and in TINAG gene in breast cancer (BRCA) patients are also associated with poorer survival outcomes, highly likely by interfering with the catabolism of peptides into amino acids.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('LGNM', 'Gene', (51, 55))	('TINAG', 'Gene', '27283', (98, 103))	('patients', 'Species', '9606', (133, 141))	('interfering', 'Reg', (210, 221))	('catabolism of peptides into amino acids', 'MPA', (231, 270))	('CASP10', 'Gene', '843', (60, 66))	('FURIN', 'Gene', '5045', (44, 49))	('CASP10', 'Gene', (60, 66))	('associated', 'Reg', (151, 161))	('Mutations', 'Var', (0, 9))	('TINAG', 'Gene', (98, 103))	('poorer', 'NegReg', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('BRCA', 'Gene', '672', (127, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('patients', 'Species', '9606', (81, 89))	('FURIN', 'Gene', (44, 49))	('survival outcomes', 'CPA', (174, 191))	('BRCA', 'Gene', (127, 131))
84354	31930623	In most cases, the frequent missense mutation converts the arginine residue to histidine.	('missense mutation', 'Var', (28, 45))	('converts', 'Reg', (46, 54))	('arginine residue', 'MPA', (59, 75))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('histidine', 'Chemical', 'MESH:D006639', (79, 88))
84356	31930623	Epidermal growth factor receptor EGFR is also highly mutated in different sequence regions in LGG patients.	('Epidermal', 'Protein', (0, 9))	('LGG', 'Disease', (94, 97))	('patients', 'Species', '9606', (98, 106))	('EGFR', 'Gene', '1956', (33, 37))	('mutated', 'Var', (53, 60))	('EGFR', 'Gene', (33, 37))
84357	31930623	19 out of 457 patients have mutations in the Furin-like domain, 6 in GF_recep_IV domain and 5 in Recep_L domain.	('Furin', 'Gene', '5045', (45, 50))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (28, 37))	('Furin', 'Gene', (45, 50))
84363	31930623	32 missense driver mutations were found in seven prognostic units, including Furin-like domain, Receptor L-domain and GF_recep domain in EGFR, phosphorylation site T211 and methylation site R213 in TP53, Iso_dh domain and phosphorylation site Y135 in IDH1.	('EGFR', 'Gene', (137, 141))	('methylation', 'Var', (173, 184))	('IDH1', 'Gene', '3417', (251, 255))	('Furin', 'Gene', (77, 82))	('Furin', 'Gene', '5045', (77, 82))	('TP53', 'Gene', '7157', (198, 202))	('IDH1', 'Gene', (251, 255))	('EGFR', 'Gene', '1956', (137, 141))	('TP53', 'Gene', (198, 202))
84367	31930623	We have shown that GPD allows for detection of sequence units enriched with variants that are associated with OS.	('variants', 'Var', (76, 84))	('associated', 'Reg', (94, 104))	('GPD', 'Gene', '2532', (19, 22))	('GPD', 'Gene', (19, 22))
84369	31930623	We surveyed all sequence units in the eight cancer types, for which at least three patients have both somatic mutations in each sequence unit and germline variants in the gene containing the unit.	('mutations', 'Var', (110, 119))	('variants', 'Var', (155, 163))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
84373	31930623	For example, there were multiple occurrences of both germline variants and somatic mutations in the PIU surrounding the arginine methylation site R110 of the TP53 gene.	('TP53', 'Gene', '7157', (158, 162))	('mutations', 'Var', (83, 92))	('TP53', 'Gene', (158, 162))	('arginine', 'Chemical', 'MESH:D001120', (120, 128))
84377	31930623	In comparison, as seen in the bottom panel of Figure 4B, having very few germline variants along with a somatic mutation decreased the hazard ratio and elevated the risk of death substantially in patients with more germline variants.	('variants', 'Var', (82, 90))	('elevated', 'PosReg', (152, 160))	('decreased', 'NegReg', (121, 130))	('patients', 'Species', '9606', (196, 204))	('hazard ratio', 'MPA', (135, 147))	('death', 'Disease', 'MESH:D003643', (173, 178))	('death', 'Disease', (173, 178))
84378	31930623	In sum, these findings suggest that substantial germline variation near the sequence units predisposes patients to a higher risk of death.	('predisposes', 'Reg', (91, 102))	('germline variation', 'Var', (48, 66))	('patients', 'Species', '9606', (103, 111))	('death', 'Disease', 'MESH:D003643', (132, 137))	('death', 'Disease', (132, 137))
84379	31930623	We present a new approach, GPD, which summarizes sequence variation and mutations as their frequency in small sequence units, providing two main advantages over alternative approaches.	('mutations', 'Var', (72, 81))	('GPD', 'Gene', '2532', (27, 30))	('GPD', 'Gene', (27, 30))
84381	31930623	Second, GPD exploits the fact that variant data are not randomly distributed across a gene's sequence but accumulates in specific regions.	('variant', 'Var', (35, 42))	('GPD', 'Gene', (8, 11))	('GPD', 'Gene', '2532', (8, 11))
84384	31930623	We first validated our findings through their reproducibility across a different large-scale dataset (MSK-IMPACT) collected from the same target population, confirmation by well-known cancer mutations, enrichment in protein domains implicated in cancer-related processes amongst survival associated genes, and overlap with an independently identified set of driver mutations.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('protein', 'Protein', (216, 223))	('cancer', 'Disease', (246, 252))	('mutations', 'Var', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
84385	31930623	Furthermore, most sequence units with somatic mutations were highly patient-specific: they occurred in a small percentage of samples across cancers, suggesting that a large proportion of these mutations are likely passenger events.	('mutations', 'Var', (46, 55))	('patient', 'Species', '9606', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
84390	31930623	This finding implies that genetic predisposition represented by germline variants affects the impact of subsequent somatic mutation events on a gene and their indirect impact on patient survival -- highlighting a new avenue for individualized treatment based on the patient's exome data.	('patient', 'Species', '9606', (266, 273))	('impact', 'MPA', (94, 100))	('patient', 'Species', '9606', (178, 185))	('affects', 'Reg', (82, 89))	('germline variants', 'Var', (64, 81))
84400	31701625	In an independent cohort, we confirmed that RSK1hi GBMs exclude long survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells.	('CD68', 'Gene', (244, 248))	('high protein levels of the', 'MPA', (120, 146))	('CD68', 'Gene', '968', (244, 248))	('lysosomal protein transmembrane 5', 'Gene', '7805', (174, 207))	('RSK1hi', 'Gene', (44, 50))	('expression', 'Var', (89, 99))	('expression', 'MPA', (230, 240))	('RSK1', 'Gene', (44, 48))	('associated', 'Reg', (104, 114))	('RSK1', 'Gene', (84, 88))	('RSK1', 'Gene', '6195', (44, 48))	('lysosomal protein transmembrane 5', 'Gene', (174, 207))	('RSK1', 'Gene', '6195', (84, 88))	('RSK1hi', 'Gene', '6195', (44, 50))	('GBMs', 'Phenotype', 'HP:0012174', (51, 55))
84419	31701625	The isocitrate dehydrogenase gene 1 and 2 (IDH1/IDH2) mutational status and the hypermethylator phenotype [glioma CpG island methylator phenotype (G-CIMP)], both characteristic of secondary GBMs and associated with longer survival times, were then considered to improve the TCGA classification (Noushmehr et al., 2010; Turkalp et al., 2014).	('TCGA', 'Disease', (274, 278))	('GBMs', 'Phenotype', 'HP:0012174', (190, 194))	('IDH2', 'Gene', '3418', (48, 52))	('IDH1', 'Gene', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('isocitrate', 'Chemical', 'MESH:D007523', (4, 14))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH2', 'Gene', (48, 52))	('improve', 'PosReg', (262, 269))	('mutational', 'Var', (54, 64))	('IDH1', 'Gene', '3417', (43, 47))	('glioma', 'Disease', (107, 113))
84422	31701625	A few prognostic markers are considered for GBM, including IDH1 mutation status (Turkalp et al., 2014).	('IDH1', 'Gene', '3417', (59, 63))	('IDH1', 'Gene', (59, 63))	('mutation', 'Var', (64, 72))
84430	31701625	It was reported that mesenchymal subtype GBMs showed a marginal increase in phosphorylated RSK1 (T359/S363) relative to proneural GBMs (Brennan et al., 2013).	('mesenchymal subtype GBMs', 'CPA', (21, 45))	('phosphorylated', 'MPA', (76, 90))	('increase', 'PosReg', (64, 72))	('RSK1', 'Gene', (91, 95))	('T359/S363', 'Var', (97, 106))	('RSK1', 'Gene', '6195', (91, 95))	('GBMs', 'Phenotype', 'HP:0012174', (130, 134))	('GBMs', 'Phenotype', 'HP:0012174', (41, 45))
84431	31701625	RSK2 is thought to be a target of miR-218 and a regulator of GBM migration and invasion (Mathew et al., 2015; Sulzmaier et al., 2016).	('RSK2', 'Gene', '6197', (0, 4))	('RSK2', 'Gene', (0, 4))	('miR-218', 'Var', (34, 41))
84432	31701625	Moreover, the use of a nonspecific RSK inhibitor (BI-D1870 (Roffe et al., 2015)) could mislead the correct interpretation of RSK2 involvement (Sulzmaier et al., 2016).	('BI-D1870', 'Var', (50, 58))	('mislead', 'Reg', (87, 94))	('RSK2', 'Gene', (125, 129))	('RSK2', 'Gene', '6197', (125, 129))
84446	31701625	The antibodies for RSK1, RSK2, RSK3, and P(S380)-RSK were the same of the IHC.	('P(S380)-RSK', 'Var', (41, 52))	('RSK2', 'Gene', (25, 29))	('RSK1', 'Gene', (19, 23))	('RSK3', 'Gene', '6196', (31, 35))	('RSK1', 'Gene', '6195', (19, 23))	('RSK2', 'Gene', '6197', (25, 29))	('RSK3', 'Gene', (31, 35))
84447	31701625	Additional antibodies were as follows: RSK4 (sc-100424; Santa Cruz), P(S227)-RSK2 (#9341; Cell Signaling), PTEN (#9559; Cell Signaling), and ERK1/2 (#9102; Cell Signaling).	('RSK2', 'Gene', (77, 81))	('PTEN', 'Gene', (107, 111))	('ERK1/2', 'Gene', (141, 147))	('PTEN', 'Gene', '5728', (107, 111))	('RSK4', 'Gene', '27330', (39, 43))	('ERK1/2', 'Gene', '5595;5594', (141, 147))	('RSK2', 'Gene', '6197', (77, 81))	('#9341', 'Var', (83, 88))	('RSK4', 'Gene', (39, 43))	('#9559', 'Var', (113, 118))	('#9102', 'Var', (149, 154))
84488	31701625	The IDH1 mutation occurs frequently in grade II and III gliomas, and indeed, when considering only the samples positive for IDH1R132H (Fig.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('grade II', 'Disease', (39, 47))	('IDH1', 'Gene', '3417', (124, 128))	('II gliomas', 'Disease', 'MESH:D005910', (53, 63))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH1', 'Gene', (4, 8))	('IDH1', 'Gene', (124, 128))	('II gliomas', 'Disease', (53, 63))
84489	31701625	S1E), the median RSK1 levels were also higher in GBMs than in LGG (Fig.	('higher', 'PosReg', (39, 45))	('RSK1', 'Gene', '6195', (17, 21))	('RSK1', 'Gene', (17, 21))	('GBMs', 'Var', (49, 53))	('GBMs', 'Phenotype', 'HP:0012174', (49, 53))
84490	31701625	Also in IDH1 mutant samples, the levels of RSK2 and RSK3 were comparable between the grades (Fig.	('mutant', 'Var', (13, 19))	('IDH1', 'Gene', (8, 12))	('RSK2', 'Gene', '6197', (43, 47))	('RSK3', 'Gene', '6196', (52, 56))	('IDH1', 'Gene', '3417', (8, 12))	('RSK3', 'Gene', (52, 56))	('RSK2', 'Gene', (43, 47))
84494	31701625	Median levels of RSK phosphorylation (S380) did not differ significantly among NB and the various grades of gliomas (Fig.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('S380', 'Var', (38, 42))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))
84495	31701625	However, high levels of P(S380)-RSK were detected in a subgroup of GBMs, consistent with the high levels of RSK1 observed.	('RSK1', 'Gene', (108, 112))	('GBMs', 'Phenotype', 'HP:0012174', (67, 71))	('P(S380)-RSK', 'Var', (24, 35))	('RSK1', 'Gene', '6195', (108, 112))
84519	31701625	In conclusion, for this cohort, high levels of RSK1 were associated with the absence of long survivors and RSK2 was an independent predictor of poor survival.	('RSK2', 'Gene', '6197', (107, 111))	('long survivors', 'CPA', (88, 102))	('absence', 'NegReg', (77, 84))	('RSK2', 'Gene', (107, 111))	('high levels', 'Var', (32, 43))	('RSK1', 'Gene', (47, 51))	('RSK1', 'Gene', '6195', (47, 51))
84523	31701625	On the other hand, 15/29 (51.7%) of RSK2hi GBMs were also P(S380)-RSKhi and 14/45 (31.1%) of P(S380)-RSKlo GBMs were RSK2hi (Fig.	('GBMs', 'Phenotype', 'HP:0012174', (107, 111))	('RSK2', 'Gene', '6197', (36, 40))	('P(S380)-RSKlo', 'Chemical', 'MESH:C012966', (93, 106))	('GBMs', 'Phenotype', 'HP:0012174', (43, 47))	('P(S380)-RSKlo', 'Var', (93, 106))	('RSK2', 'Gene', (117, 121))	('P(S380)-RSKhi', 'Var', (58, 71))	('RSK2', 'Gene', (36, 40))	('RSK2', 'Gene', '6197', (117, 121))
84524	31701625	Interestingly, 12/15 (80%) GBMs belonging to both RSK1hi and RSK2hi groups at the same time (RSK1hi-RSK2hi) were P(S380)-RSKhi, in contrast to the representation of P(S380)-RSKhi GBMs in RSK1hi-RSK2lo (3/10 or 30%), RSK1lo-RSK2hi (2/13 or 15.4%), and RSK1lo-RSK2lo (8/32 or 25%; Fig.	('RSK2', 'Gene', (61, 65))	('RSK1hi', 'Gene', '6195', (50, 56))	('RSK2', 'Gene', (258, 262))	('RSK1', 'Gene', (251, 255))	('RSK2', 'Gene', '6197', (100, 104))	('RSK2', 'Gene', (194, 198))	('RSK1', 'Gene', (187, 191))	('RSK1hi', 'Gene', (50, 56))	('RSK1', 'Gene', (93, 97))	('RSK2', 'Gene', '6197', (61, 65))	('GBMs', 'Phenotype', 'HP:0012174', (27, 31))	('GBMs', 'Phenotype', 'HP:0012174', (179, 183))	('RSK2', 'Gene', '6197', (258, 262))	('RSK1', 'Gene', '6195', (251, 255))	('RSK1', 'Gene', '6195', (93, 97))	('RSK1', 'Gene', (50, 54))	('RSK2', 'Gene', '6197', (223, 227))	('RSK2', 'Gene', (223, 227))	('RSK1', 'Gene', '6195', (187, 191))	('RSK2', 'Gene', '6197', (194, 198))	('P(S380)-RSKhi', 'Var', (113, 126))	('RSK1', 'Gene', (216, 220))	('RSK1hi', 'Gene', '6195', (187, 193))	('RSK1', 'Gene', '6195', (50, 54))	('RSK2', 'Gene', (100, 104))	('RSK1hi', 'Gene', '6195', (93, 99))	('RSK1', 'Gene', '6195', (216, 220))	('RSK1hi', 'Gene', (93, 99))	('RSK1hi', 'Gene', (187, 193))
84526	31701625	As mentioned above, P(T359/S363)-RSK1 levels (RPPA experiment:TCGA) in GBMs can be considered a measure of RSK1 activation.	('P(T359/S363', 'Var', (20, 31))	('RSK1', 'Gene', (107, 111))	('RSK1', 'Gene', '6195', (107, 111))	('activation', 'PosReg', (112, 122))	('GBMs', 'Phenotype', 'HP:0012174', (71, 75))	('RSK1', 'Gene', (33, 37))	('RSK1', 'Gene', '6195', (33, 37))
84528	31701625	In conclusion, high P(S380)-RSK levels (i.e., RSK activation) in GBMs were associated with high levels of both RSK1 and RSK2; however, the contribution of RSK1 was more important.	('RSK1', 'Gene', (111, 115))	('RSK2', 'Gene', (120, 124))	('P(S380)-RSK', 'Var', (20, 31))	('RSK1', 'Gene', (155, 159))	('RSK1', 'Gene', '6195', (155, 159))	('RSK1', 'Gene', '6195', (111, 115))	('RSK2', 'Gene', '6197', (120, 124))	('GBMs', 'Phenotype', 'HP:0012174', (65, 69))
84567	31701625	Alike the ACCCC cohort, IDH1 mutation was present in RSK1hi GBMs (Fig.	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (24, 28))	('RSK1hi', 'Gene', '6195', (53, 59))	('GBMs', 'Phenotype', 'HP:0012174', (60, 64))	('IDH1', 'Gene', (24, 28))	('RSK1hi', 'Gene', (53, 59))
84588	31701625	In the case of the Gravendeel dataset, cases with IDH1 mutation were present in GBMs with higher GSVA scores, but in a low proportion (Fig.	('GBMs', 'Phenotype', 'HP:0012174', (80, 84))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))
84590	31701625	However, in TCGA dataset, cases with IDH1 mutation were underrepresented in GBMs with higher GSVA scores (Fig.	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('IDH1', 'Gene', (37, 41))	('GBMs', 'Phenotype', 'HP:0012174', (76, 80))
84592	31701625	This apparent discrepancy can be the result of the selection of primary GBMs by the TCGA making IDH1 mutation infrequent in this cohort (Brennan et al., 2013).	('IDH1', 'Gene', '3417', (96, 100))	('GBMs', 'Phenotype', 'HP:0012174', (72, 76))	('mutation', 'Var', (101, 109))	('IDH1', 'Gene', (96, 100))
84615	31701625	Confirming those observations, RSK1 protein levels highly correlated with the presence of CD68 in an independent GBM cohort.	('RSK1', 'Gene', (31, 35))	('RSK1', 'Gene', '6195', (31, 35))	('CD68', 'Gene', (90, 94))	('CD68', 'Gene', '968', (90, 94))	('protein', 'Protein', (36, 43))	('presence', 'Var', (78, 86))	('correlated', 'Reg', (58, 68))
84630	31701625	However, a recent report suggested that LAPTM5 is downregulated in human cancers, such as neuroblastoma, and that low levels of LAPTM5 are associated with poor prognosis (Nuylan et al., 2016).	('cancers', 'Disease', (73, 80))	('LAPTM5', 'Gene', '7805', (40, 46))	('neuroblastoma', 'Disease', (90, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (90, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('associated', 'Reg', (139, 149))	('LAPTM5', 'Gene', (128, 134))	('low levels', 'Var', (114, 124))	('downregulated', 'NegReg', (50, 63))	('LAPTM5', 'Gene', '7805', (128, 134))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('LAPTM5', 'Gene', (40, 46))
84646	31701625	The levels of P(S380)-RSK were higher in RSK1hi and, to a lesser extent, in RSK2hi GBMs; however, the samples showing the highest phosphorylation levels were those bearing high RSK1 and RSK2 expression at the same time.	('RSK2', 'Gene', '6197', (76, 80))	('RSK2', 'Gene', (76, 80))	('levels', 'MPA', (4, 10))	('P(S380)-RSK', 'Var', (14, 25))	('RSK2', 'Gene', '6197', (186, 190))	('RSK1', 'Gene', '6195', (41, 45))	('RSK1', 'Gene', (177, 181))	('RSK1hi', 'Gene', (41, 47))	('RSK1', 'Gene', '6195', (177, 181))	('RSK2', 'Gene', (186, 190))	('higher', 'PosReg', (31, 37))	('RSK1', 'Gene', (41, 45))	('GBMs', 'Phenotype', 'HP:0012174', (83, 87))	('RSK1hi', 'Gene', '6195', (41, 47))
84647	31701625	This observation could be related to the proposed cross-reactivity of the P(S380)-RSK with P(S386)-RSK2, which precludes the determination of RSK activation at the isoform level.	('P(S380)-RSK', 'Var', (74, 85))	('RSK2', 'Gene', '6197', (99, 103))	('RSK2', 'Gene', (99, 103))
84687	31171919	Along with the discovery of the significant clinical implications of isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion in stratifying the gliomas, these two molecular markers have been combined with the traditional histopathological examination to form an integrated diagnosis for diffuse gliomas in the 2016 Classification of Tumors of the Central Nervous System.	('isocitrate dehydrogenase', 'Gene', '3417', (69, 93))	('gliomas', 'Disease', 'MESH:D005910', (301, 308))	('Tumors of the Central Nervous', 'Disease', 'MESH:D016543', (339, 368))	('Tumors', 'Phenotype', 'HP:0002664', (339, 345))	('gliomas', 'Disease', (301, 308))	('gliomas', 'Phenotype', 'HP:0009733', (301, 308))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('Tumors of the Central Nervous System', 'Phenotype', 'HP:0100006', (339, 375))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('mutation', 'Var', (100, 108))	('Tumors of the Central Nervous', 'Disease', (339, 368))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('glioma', 'Phenotype', 'HP:0009733', (301, 307))	('isocitrate dehydrogenase', 'Gene', (69, 93))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
84688	31171919	The IDH-mutant and 1p/19q codeletion LGG has the best prognosis among all the subgroups of the integrated diagnosis.	('1p/19q codeletion', 'Var', (19, 36))	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (4, 7))
84689	31171919	Compared with gliomas in other subgroups, the decreased expression of genes located on chromosomes 1p and 19q is a significant characteristic for the IDH-mutant and 1p/19q codeletion LGG, indicating some of these genes may affect the prognosis of gliomas.	('affect', 'Reg', (223, 229))	('1p/19q codeletion', 'Var', (165, 182))	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('expression', 'MPA', (56, 66))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('gliomas', 'Disease', (247, 254))	('IDH', 'Gene', (150, 153))	('decreased', 'NegReg', (46, 55))	('gliomas', 'Disease', 'MESH:D005910', (247, 254))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))	('IDH', 'Gene', '3417', (150, 153))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('gliomas', 'Disease', (14, 21))
84695	31171919	Therefore, the aberrant expression of eIF3 subunits has been thought of important candidate biomarkers for cancer prognosis and target-therapy.	('eIF3', 'Gene', (38, 42))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('eIF3', 'Gene', '8661', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('aberrant', 'Var', (15, 23))	('cancer', 'Disease', (107, 113))
84729	31171919	The combined expression of eIF3i and eIF3k = eIF3i expression*1.048 + eIF3k expression * 0.797, and the 1.048 and 0.797 were the log2 of HR values for eIF3i and eIF3k in COX regression, respectively.	('eIF3i', 'Gene', '8668', (151, 156))	('eIF3k', 'Gene', '27335', (161, 166))	('1.048', 'Var', (104, 109))	('COX', 'Gene', '1351', (170, 173))	('eIF3k', 'Gene', (161, 166))	('eIF3k', 'Gene', (70, 75))	('eIF3k', 'Gene', (37, 42))	('COX', 'Gene', (170, 173))	('eIF3k', 'Gene', '27335', (70, 75))	('eIF3i', 'Gene', '8668', (45, 50))	('eIF3i', 'Gene', '8668', (27, 32))	('eIF3i', 'Gene', (27, 32))	('eIF3k', 'Gene', '27335', (37, 42))	('0.797', 'Var', (114, 119))	('eIF3i', 'Gene', (45, 50))	('eIF3i', 'Gene', (151, 156))
84730	31171919	The LGG included IDH-wildtype LGG (IDH-wildtype astrocytoma) and IDH-mutant LGG, and the IDH-mutant LGG could be further stratified as 1p/19q codeletion IDH-mutant oligodendroglioma and IDH-mutant astrocytoma (1p/19q non-codeletion).	('IDH', 'Gene', (65, 68))	('astrocytoma', 'Disease', 'MESH:D001254', (48, 59))	('astrocytoma', 'Disease', (48, 59))	('IDH', 'Gene', '3417', (35, 38))	('astrocytoma', 'Disease', 'MESH:D001254', (197, 208))	('IDH', 'Gene', '3417', (186, 189))	('astrocytoma', 'Disease', (197, 208))	('IDH', 'Gene', (153, 156))	('IDH-wildtype astrocytoma', 'Disease', (35, 59))	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', '3417', (17, 20))	('IDH', 'Gene', '3417', (65, 68))	('IDH', 'Gene', '3417', (153, 156))	('oligodendroglioma', 'Disease', (164, 181))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (197, 208))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('IDH', 'Gene', (35, 38))	('oligodendroglioma', 'Disease', 'MESH:D009837', (164, 181))	('1p/19q', 'Var', (135, 141))	('IDH', 'Gene', (186, 189))	('IDH', 'Gene', (89, 92))	('IDH-wildtype astrocytoma', 'Disease', 'MESH:D001254', (35, 59))	('IDH', 'Gene', (17, 20))
84736	31171919	The results showed that the expression of eIF3i had the superior predictive efficiency compared with eIF3k expression, combined expression of eIF3i and eIF3k, WHO grade and subgroups of WHO 2016 for predicting survival of patients with 1p/19q non-codeletion glioma in the CGGA dataset (Fig.	('eIF3i', 'Gene', '8668', (142, 147))	('glioma', 'Disease', 'MESH:D005910', (258, 264))	('patients', 'Species', '9606', (222, 230))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('eIF3k', 'Gene', (101, 106))	('eIF3k', 'Gene', (152, 157))	('eIF3i', 'Gene', '8668', (42, 47))	('1p/19q', 'Var', (236, 242))	('eIF3i', 'Gene', (42, 47))	('eIF3k', 'Gene', '27335', (101, 106))	('glioma', 'Disease', (258, 264))	('eIF3k', 'Gene', '27335', (152, 157))	('eIF3i', 'Gene', (142, 147))
84749	31171919	We observed that the expression of eIF3i was significantly decreased in 1p/19q codeletion and IDH-mutant LGG in both the CGGA (P < 0.0001, Additional file 1: Fig.	('eIF3i', 'Gene', (35, 40))	('decreased', 'NegReg', (59, 68))	('IDH', 'Gene', (94, 97))	('1p/19q codeletion', 'Var', (72, 89))	('expression', 'MPA', (21, 31))	('LGG', 'Gene', (105, 108))	('IDH', 'Gene', '3417', (94, 97))	('eIF3i', 'Gene', '8668', (35, 40))
84759	31171919	In LGGs, though patients with IDH-wildtype astrocytoma in low-expression group had longer (P = 0.059) OS than that of high-expression group in the CGGA database (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('IDH-wildtype astrocytoma', 'Disease', 'MESH:D001254', (30, 54))	('low-expression', 'Var', (58, 72))	('IDH-wildtype astrocytoma', 'Disease', (30, 54))	('patients', 'Species', '9606', (16, 24))	('longer', 'PosReg', (83, 89))
84767	31171919	AUCs of eIF3i, WHO grade and 1p/19q codeletion status were 80.1%, 69.3% and 61.2% respectively for 3 year's survival; 85.2%, 66.9% and 70.5% respectively for 5 year's survival.	('eIF3i', 'Gene', (8, 13))	('1p/19q', 'Var', (29, 35))	('eIF3i', 'Gene', '8668', (8, 13))
84768	31171919	4j), AUCs of eIF3i, WHO grade and 1p/19q codeletion status were 58.8%, 63.3% and 46.7% respectively for 3 year's survival; 72.4%, 66.0% and 64.7% respectively for 5 year's survival.	('1p/19q codeletion status', 'Var', (34, 58))	('eIF3i', 'Gene', (13, 18))	('eIF3i', 'Gene', '8668', (13, 18))
84790	31171919	This is consistent with the reports that elevated eIF3i could promote cell proliferation and angiogenesis in tumorigenesis through up-regulated VEGFA translation.	('cell proliferation', 'CPA', (70, 88))	('eIF3i', 'Gene', '8668', (50, 55))	('up-regulated', 'PosReg', (131, 143))	('eIF3i', 'Gene', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('VEGFA', 'Gene', '7422', (144, 149))	('promote', 'PosReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('VEGFA', 'Gene', (144, 149))	('elevated', 'Var', (41, 49))	('tumor', 'Disease', (109, 114))	('angiogenesis', 'CPA', (93, 105))
84791	31171919	IDH mutant and 1p/19q codeletion LGGs are less invasive and have better prognosis than other gliomas.	('gliomas', 'Disease', (93, 100))	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('mutant', 'Var', (4, 10))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH', 'Gene', '3417', (0, 3))	('1p/19q codeletion', 'Var', (15, 32))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
84792	31171919	Here, we noticed that the expression of eIF3i could predict the 1p/19q codeletion status in IDH-mutant LGGs, and the eIF3i expression was significantly decreased in IDH-mutant and 1p/19q codeletion LGGs.	('IDH', 'Gene', (165, 168))	('expression', 'MPA', (123, 133))	('predict', 'Reg', (52, 59))	('IDH', 'Gene', '3417', (165, 168))	('1p/19q codeletion', 'Var', (180, 197))	('eIF3i', 'Gene', (40, 45))	('1p/19q codeletion status', 'MPA', (64, 88))	('decreased', 'NegReg', (152, 161))	('eIF3i', 'Gene', '8668', (40, 45))	('IDH', 'Gene', (92, 95))	('IDH', 'Gene', '3417', (92, 95))	('eIF3i', 'Gene', '8668', (117, 122))	('eIF3i', 'Gene', (117, 122))
84793	31171919	Considering the vital roles of eIF3i in tumor progression mentioned above, the decreased expression of eIF3i may be one of the mechanisms underlying the better prognosis of IDH-mutant and 1p/19q codeletion LGGs.	('expression', 'MPA', (89, 99))	('decreased', 'NegReg', (79, 88))	('IDH', 'Gene', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('IDH', 'Gene', '3417', (173, 176))	('1p/19q codeletion', 'Var', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('eIF3i', 'Gene', '8668', (103, 108))	('eIF3i', 'Gene', '8668', (31, 36))	('eIF3i', 'Gene', (103, 108))	('eIF3i', 'Gene', (31, 36))
84796	31171919	Considering that abnormal expression of these factors have been reported to be involved in various pathological conditions, including cancers, our findings supplied basic information for future investigating the roles of these eIF3 subunits in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('eIF3', 'Gene', (227, 231))	('cancers', 'Disease', (134, 141))	('involved', 'Reg', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('eIF3', 'Gene', '8661', (227, 231))	('gliomas', 'Disease', (244, 251))	('abnormal', 'Var', (17, 25))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))
84804	28147343	The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types For many years, defects in the ribosome have been associated to cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RPL5', 'Gene', '6125', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('associated', 'Reg', (147, 157))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('haploinsufficient tumor', 'Disease', (37, 60))	('defects', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (161, 167))	('RPL5', 'Gene', (27, 31))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (37, 60))
84805	28147343	Recently, somatic mutations and deletions affecting ribosomal protein genes were identified in a few leukemias and solid tumor types.	('deletions', 'Var', (32, 41))	('leukemias', 'Phenotype', 'HP:0001909', (101, 110))	('leukemias', 'Disease', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('ribosomal protein genes', 'Gene', (52, 75))	('leukemias', 'Disease', 'MESH:D007938', (101, 110))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('identified', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
84808	28147343	RPL5 was located at a significant peak of heterozygous deletion or mutated in 11% of glioblastoma, 28% of melanoma and 34% of breast cancer samples.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('glioblastoma', 'Disease', (85, 97))	('breast cancer', 'Disease', (126, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('mutated', 'Var', (67, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
84809	28147343	Moreover, patients with low RPL5 expression displayed worse overall survival in glioblastoma and in one breast cancer cohort.	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('one breast', 'Phenotype', 'HP:0012813', (100, 110))	('RPL5', 'Protein', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('overall survival', 'MPA', (60, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('patients', 'Species', '9606', (10, 18))	('low', 'Var', (24, 27))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('worse', 'NegReg', (54, 59))
84812	28147343	In conclusion, RPL5 heterozygous inactivation occurs at high incidence (11-34%) in multiple tumor types, currently representing the most common somatic ribosomal protein defect in cancer, and we demonstrate a tumor suppressor role for RPL5 in breast cancer.	('breast cancer', 'Disease', (243, 256))	('protein defect in cancer', 'Disease', (162, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('tumor', 'Disease', (209, 214))	('a tumor', 'Disease', 'MESH:D009369', (207, 214))	('a tumor', 'Disease', (207, 214))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('RPL5', 'Gene', (15, 19))	('RPL5', 'Gene', (235, 239))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('protein defect in cancer', 'Disease', 'MESH:D009369', (162, 186))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (92, 97))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('heterozygous inactivation', 'Var', (20, 45))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
84813	28147343	Cancers contain a variety of genomic lesions including mutations, translocations, copy number alterations and epigenetic changes that can result in altered protein functions.	('copy number alterations', 'Var', (82, 105))	('translocations', 'Var', (66, 80))	('Cancers', 'Disease', (0, 7))	('mutations', 'Var', (55, 64))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('protein functions', 'MPA', (156, 173))	('altered', 'Reg', (148, 155))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('result', 'Reg', (138, 144))	('epigenetic changes', 'Var', (110, 128))
84817	28147343	Somatic mutations and deletions affecting ribosomal protein genes occur in up to 20% of acute T-cell leukemia (T-ALL) cases, with the most frequent defects affecting RPL10 (also known as uL16; 7.9% of pediatric T-ALL cases) and RPL22 (eL22; 10%) and with rare defects in RPL5 (uL18) and RPL11 (uL5).	('RPL22', 'Gene', (228, 233))	('deletions', 'Var', (22, 31))	('ribosomal protein genes', 'Gene', (42, 65))	('RPL22', 'Gene', '6146', (228, 233))	('RPL11', 'Gene', '6135', (287, 292))	('RPL10', 'Gene', (166, 171))	('RPL10', 'Gene', '6134', (166, 171))	('acute T-cell leukemia', 'Disease', 'MESH:D054218', (88, 109))	('affecting', 'Reg', (156, 165))	('RPL5', 'Gene', (271, 275))	('RPL11', 'Gene', (287, 292))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute T-cell leukemia', 'Disease', (88, 109))
84819	28147343	The Cancer Genome Atlas (TCGA) pan-cancer analyses identified RPL5 and RPL22 as significantly mutated in glioblastoma multiforme (GBM, 2.8%) and uterine corpus endometrial carcinoma (UCEC, 10.9%) respectively, and inactivating RPL22 mutations have also been described in colorectal and gastric cancer.	('mutated', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('RPL22', 'Gene', '6146', (71, 76))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('RPL22', 'Gene', (71, 76))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('RPL5', 'Gene', (62, 66))	('RPL22', 'Gene', '6146', (227, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (286, 300))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('inactivating', 'Var', (214, 226))	('RPL22', 'Gene', (227, 232))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (160, 181))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (271, 300))	('corpus endometrial carcinoma', 'Disease', (153, 181))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (153, 181))	('glioblastoma multiforme', 'Disease', (105, 128))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (105, 128))	('Cancer Genome Atlas', 'Disease', (4, 23))	('mutations', 'Var', (233, 242))	('cancer', 'Disease', (35, 41))
84821	28147343	Mutations reported for RPL10 in T-ALL are all missense mutations, with a strong mutational hotspot at residue arginine 98 (R98S), indicating an oncogenic role for these mutations.	('R98S', 'Mutation', 'p.R98S', (123, 127))	('Mutations', 'Var', (0, 9))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('RPL10', 'Gene', '6134', (23, 28))	('RPL10', 'Gene', (23, 28))
84822	28147343	In contrast, all other somatic defects that have been identified so far in ribosomal protein genes are heterozygous and many of them are clearly inactivating mutations or deletions, suggesting roles as haploinsufficient tumor suppressors for these proteins in cancer.	('ribosomal protein', 'Gene', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('inactivating', 'NegReg', (145, 157))	('deletions', 'Var', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (202, 225))	('cancer', 'Disease', (260, 266))	('haploinsufficient tumor', 'Disease', (202, 225))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
84823	28147343	Congenital heterozygous inactivating mutations and deletions affecting RPL5, RPL11 and RPS15 have also been described in Diamond Blackfan Anemia (DBA), a congenital syndrome belonging to a family of human disorders, ribosomopathies, caused by impaired ribosome biogenesis and function.	('Anemia', 'Disease', (138, 144))	('ribosomopathies', 'Disease', 'None', (216, 231))	('ribosomopathies', 'Disease', (216, 231))	('RPS15', 'Gene', '6209', (87, 92))	('human', 'Species', '9606', (199, 204))	('Anemia', 'Disease', 'MESH:D000740', (138, 144))	('RPS15', 'Gene', (87, 92))	('described', 'Reg', (108, 117))	('RPL5', 'Gene', (71, 75))	('congenital syndrome belonging', 'Disease', 'MESH:D000013', (154, 183))	('deletions', 'Var', (51, 60))	('RPL11', 'Gene', (77, 82))	('RPL11', 'Gene', '6135', (77, 82))	('congenital syndrome belonging', 'Disease', (154, 183))	('Anemia', 'Phenotype', 'HP:0001903', (138, 144))
84826	28147343	Besides the identification of somatic ribosome defects in cancer and the elevated cancer risks of ribosomopathy patients, the link between ribosome defects and cancer is supported by the observation that heterozygous inactivation of certain ribosomal protein genes induces tumor development in zebrafish.	('ribosome defects', 'Disease', 'MESH:D005128', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (82, 88))	('tumor', 'Disease', (273, 278))	('elevated cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ribosome defects', 'Disease', (139, 155))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('ribosomal protein', 'Gene', (241, 258))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('ribosomopathy', 'Disease', 'None', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ribosomopathy', 'Disease', (98, 111))	('zebrafish', 'Species', '7955', (294, 303))	('elevated cancer', 'Disease', 'MESH:D009369', (73, 88))	('heterozygous inactivation', 'Var', (204, 229))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ribosome defects', 'Disease', 'MESH:D005128', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('induces', 'PosReg', (265, 272))	('patients', 'Species', '9606', (112, 120))	('ribosome defects', 'Disease', (38, 54))	('cancer', 'Disease', (58, 64))
84827	28147343	Moreover, Rpl11 and Rpl22 haploinsufficiency accelerates mouse lymphoma development and loss of one copy of Rpl5 or Rps24 (eS24) has been linked to development of rare soft tissue sarcomas in mice.	('Rpl22', 'Gene', '19934', (20, 25))	('linked', 'Reg', (138, 144))	('Rpl11', 'Gene', '67025', (10, 15))	('Rpl11', 'Gene', (10, 15))	('haploinsufficiency', 'Disease', 'MESH:D058495', (26, 44))	('eS24', 'Gene', '103943', (123, 127))	('eS24', 'Gene', (123, 127))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('haploinsufficiency', 'Disease', (26, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcomas', 'Disease', (180, 188))	('Rpl5', 'Gene', (108, 112))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('mice', 'Species', '10090', (192, 196))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (168, 188))	('Rps24', 'Gene', (116, 121))	('accelerates', 'PosReg', (45, 56))	('Rpl22', 'Gene', (20, 25))	('Rps24', 'Gene', '20088', (116, 121))	('lymphoma', 'Disease', (63, 71))	('loss', 'Var', (88, 92))	('lymphoma', 'Disease', 'MESH:D008223', (63, 71))	('Rpl5', 'Gene', '100503670', (108, 112))	('mouse', 'Species', '10090', (57, 62))
84833	28147343	RPL22 inactivation was reported to indirectly activate c-MYC expression, via an NF-kB - Lin28B - Let7 miRNA axis.	('inactivation', 'Var', (6, 18))	('c-MYC', 'Gene', (55, 60))	('RPL22', 'Gene', (0, 5))	('Lin28B', 'Gene', '389421', (88, 94))	('activate', 'PosReg', (46, 54))	('c-MYC', 'Gene', '4609', (55, 60))	('RPL22', 'Gene', '6146', (0, 5))	('Lin28B', 'Gene', (88, 94))
84837	28147343	We analyzed mutations from 4 926 tumors and copy number changes from 7 322 tumors across 16 different tumor types for the 81 genes encoding ribosomal proteins.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', (33, 39))	('tumor', 'Disease', (75, 80))
84840	28147343	Whereas somatic mutations in RPL5 had been described in 3% of GBM samples, we found that RPL5 heterozygous inactivation currently represents the most common somatic ribosome defect in human cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('RPL5', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('heterozygous', 'Var', (94, 106))	('RPL5', 'Gene', (89, 93))	('human', 'Species', '9606', (184, 189))
84843	28147343	Overall, the frequency of such defects in individual ribosomal protein genes was below 3% in all cancer types (Supplementary Table 2).	('defects', 'Var', (31, 38))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ribosomal protein', 'Protein', (53, 70))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
84844	28147343	However, mutational frequency represents only one criterium to discriminate functional cancer drivers.	('mutational', 'Var', (9, 19))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
84848	28147343	RPSA was identified in Stomach Adenocarcinoma (STAD) because of a significant cluster of mutations (q-value: 0.004; OncodriveCLUST ) (Figure 1A-1B; Supplementary Figure 1).	('RPSA', 'Gene', (0, 4))	('RPSA', 'Gene', '3921', (0, 4))	('Stomach Adenocarcinoma', 'Disease', (23, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutations', 'Var', (89, 98))	('Stomach Adenocarcinoma', 'Disease', 'MESH:D013274', (23, 45))
84849	28147343	RPS5 and RPS20 show an accumulation of high functional impact mutations, in STAD and UCEC respectively (q-values: 0.026 and 0.042; Oncodrive FM).	('mutations', 'Var', (62, 71))	('RPS5', 'Gene', '6193', (0, 4))	('RPS5', 'Gene', (0, 4))	('RPS20', 'Gene', (9, 14))	('RPS20', 'Gene', '6224', (9, 14))
84850	28147343	Accumulation of high functional impact mutations was also found for RPL5 in GBM (q-value: 0.0002) and SKCM (q-value: 0.004) and for RPL11 in SKCM (q-value: 0.0007).	('RPL11', 'Gene', '6135', (132, 137))	('RPL11', 'Gene', (132, 137))	('RPL5', 'Var', (68, 72))	('mutations', 'Var', (39, 48))
84851	28147343	Some of these mutations were clearly inactivating frameshift, nonsense or splice site mutations (Figure 1B), indicative of a tumor suppressor function.	('inactivating', 'NegReg', (37, 49))	('nonsense or splice site', 'Var', (62, 85))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('frameshift', 'Var', (50, 60))	('a tumor', 'Disease', 'MESH:D009369', (123, 130))	('a tumor', 'Disease', (123, 130))	('mutations', 'Var', (14, 23))
84853	28147343	Because these defects often encompass many genes, we increased the specificity of our screening for driver events by applying additional filtering criteria: i) that the ribosomal protein gene was included in the region of the deletion (or amplification) that is predicted to contain the cancer driving target gene; ii) that the same region does not include other known cancer genes; iii) that the ribosomal protein gene was also affected by mutations, in addition to the significant copy number change.	('ribosomal protein gene', 'Gene', (397, 419))	('cancer', 'Disease', (369, 375))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('mutations', 'Var', (441, 450))	('affected', 'Reg', (429, 437))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (369, 375))
84862	28147343	However, a closer analysis showed that the known cancer genes are more than 7 Mbp away from RPL5 and also in this tumor type RPL5 was located in a pronounced deletion peak (Figure 2C).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (114, 119))	('RPL5', 'Var', (125, 129))	('Mbp', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Mbp', 'Gene', '4155', (78, 81))	('cancer', 'Disease', (49, 55))
84863	28147343	RPL5 deletions were associated with 29-38% lower average RPL5 mRNA expression levels in GBM (p = 0.016), SKCM (p = 2.36e-04) and BRCA (p = 2.2e-16) (Figure 2D).	('BRCA', 'Gene', '672', (129, 133))	('RPL5', 'Gene', (0, 4))	('BRCA', 'Gene', (129, 133))	('RPL5 mRNA expression levels', 'MPA', (57, 84))	('deletions', 'Var', (5, 14))	('lower', 'NegReg', (43, 48))
84865	28147343	RPL5, the most commonly altered ribosomal protein we detected, was significantly mutated and deleted in GBM (11%) and SKCM (28%) and significantly deleted in BRCA (34%).	('BRCA', 'Gene', (158, 162))	('altered', 'Reg', (24, 31))	('deleted', 'Var', (93, 100))	('ribosomal', 'Protein', (32, 41))	('RPL5', 'Gene', (0, 4))	('BRCA', 'Gene', '672', (158, 162))
84871	28147343	Because RPL5 has been functionally linked to TP53 and c-MYC, we tested for an association between RPL5 defects and defects in c-MYC, TP53, or the negative TP53 regulators MDM4 and MDM2 (Figure 4 and Supplementary Figure 4).	('MDM2', 'Gene', '4193', (180, 184))	('MDM4', 'Gene', '4194', (171, 175))	('MDM4', 'Gene', (171, 175))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('c-MYC', 'Gene', '4609', (126, 131))	('defects', 'Var', (103, 110))	('TP53', 'Gene', '7157', (155, 159))	('defects', 'Var', (115, 122))	('c-MYC', 'Gene', '4609', (54, 59))	('tested', 'Reg', (64, 70))	('TP53', 'Gene', (155, 159))	('RPL5', 'Gene', (98, 102))	('c-MYC', 'Gene', (54, 59))	('TP53', 'Gene', '7157', (133, 137))	('c-MYC', 'Gene', (126, 131))	('TP53', 'Gene', (133, 137))	('MDM2', 'Gene', (180, 184))
84872	28147343	In BRCA, significant co-occurrence of RPL5 defects and TP53 pathway inactivation by TP53 inactivation or by mutation/amplification of MDM2 or MDM4 was detected.	('RPL5 defects', 'Gene', (38, 50))	('BRCA', 'Gene', (3, 7))	('inactivation', 'Var', (89, 101))	('MDM4', 'Gene', '4194', (142, 146))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('BRCA', 'Gene', '672', (3, 7))	('MDM2', 'Gene', '4193', (134, 138))	('MDM4', 'Gene', (142, 146))	('MDM2', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (84, 88))	('TP53', 'Gene', (84, 88))	('inactivation', 'NegReg', (68, 80))	('mutation/amplification', 'Var', (108, 130))
84878	28147343	It represents a candidate tumor suppressor, based on its heterozygous inactivating mutations and focal deletions and based on the correlation of lower RPL5 expression with worse survival.	('RPL5', 'Protein', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('deletions', 'Var', (103, 112))	('lower', 'NegReg', (145, 150))	('expression', 'MPA', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
84881	28147343	Triple negative breast cancer cell lines MCF7 (TP53 WT, RPL5 WT) and MDA-MB-231 (TP53 homozygous R280K missense mutation, RPL5 WT) were transduced with lentiviral vectors allowing inducible RPL5 protein knockdown of 30-50% (Figure 5A, Supplementary Figure 6, MCF7 p < 0.001 and MDA-MB-231 p = 0.001).	('breast cancer', 'Disease', (16, 29))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (278, 288))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (69, 79))	('MCF7', 'CellLine', 'CVCL:0031', (259, 263))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('TP53', 'Gene', '7157', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('MCF7', 'CellLine', 'CVCL:0031', (41, 45))	('R280K', 'Mutation', 'rs121912660', (97, 102))	('knockdown', 'Var', (203, 212))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (47, 51))	('TP53', 'Gene', (81, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
84885	28147343	In both subcutaneous breast cancer models, RPL5 knockdown significantly increased the tumor weight when sacrificing the animals (Figure 6A, MCF7 p = 0.009 and MDA-MB-231 p = 0.044).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('tumor', 'Disease', (86, 91))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (159, 169))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('RPL5', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('MCF7', 'CellLine', 'CVCL:0031', (140, 144))	('knockdown', 'Var', (48, 57))
84890	28147343	In addition, the shRPL5 induced mouse tumors showed reduced phosphorylation of CDK1/CDC2 at tyrosine 15, a dephosphoryation that is required for cell cycle progression from G2 to mitosis (Figure 6C, MCF7 p < 0.001 and MDA-MB-231 p = 0.001).	('phosphorylation', 'MPA', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('reduced', 'NegReg', (52, 59))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('shRPL5', 'Var', (17, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (92, 100))	('mouse', 'Species', '10090', (32, 37))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (218, 228))	('CDK1/CDC2', 'Gene', (79, 88))	('mitosis', 'Disease', (179, 186))	('MCF7', 'CellLine', 'CVCL:0031', (199, 203))	('mitosis', 'Disease', 'None', (179, 186))
84891	28147343	These results are consistent with the enhanced proliferation associated with RPL5 knockdown in the cell culture experiments and the increased tumor weights in vivo.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('enhanced', 'PosReg', (38, 46))	('tumor', 'Disease', (142, 147))	('knockdown', 'Var', (82, 91))	('RPL5', 'Gene', (77, 81))	('increased', 'PosReg', (132, 141))	('proliferation', 'CPA', (47, 60))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
84892	28147343	Changes in TP53, MDM2 and c-MYC protein levels upon RPL5 knockdown were assessed by immunoblotting, in vitro and in vivo (Figure 5C, Figure 6D-6E and Supplementary Figure 8).	('RPL5', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (11, 15))	('c-MYC', 'Gene', '4609', (26, 31))	('TP53', 'Gene', (11, 15))	('MDM2', 'Gene', '4193', (17, 21))	('knockdown', 'Var', (57, 66))	('MDM2', 'Gene', (17, 21))	('c-MYC', 'Gene', (26, 31))	('Changes', 'Reg', (0, 7))
84894	28147343	MDM2 expression did not differ in vivo and it was upregulated in vitro only for MDA-MB-231.	('upregulated', 'PosReg', (50, 61))	('expression', 'MPA', (5, 15))	('MDA-MB-231', 'Var', (80, 90))	('MDM2', 'Gene', '4193', (0, 4))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (80, 90))	('MDM2', 'Gene', (0, 4))
84897	28147343	We aimed to identify novel ribosomal protein genes which are significantly targeted by genetic alterations and represent potential causative cancer genes.	('genetic alterations', 'Var', (87, 106))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ribosomal protein genes', 'Gene', (27, 50))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
84900	28147343	RPL22 was found to be significantly mutated in UCEC, according to a TCGA pan-cancer analysis.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('UCEC', 'Disease', (47, 51))	('RPL22', 'Gene', (0, 5))	('mutated', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('RPL22', 'Gene', '6146', (0, 5))
84901	28147343	However, most RPL22 mutations detected in TCGA UCEC are potentially caused by misalignment of reads to homologous regions in the genome.	('caused by', 'Reg', (68, 77))	('RPL22', 'Gene', '6146', (14, 19))	('mutations', 'Var', (20, 29))	('RPL22', 'Gene', (14, 19))
84903	28147343	RPS15 and RPL10 mutations have been reported in CLL and T-ALL, which are not represented in the TCGA dataset analyzed here.	('T-ALL', 'Disease', (56, 61))	('RPL10', 'Gene', '6134', (10, 15))	('CLL', 'Disease', (48, 51))	('mutations', 'Var', (16, 25))	('RPL10', 'Gene', (10, 15))	('reported', 'Reg', (36, 44))	('RPS15', 'Gene', '6209', (0, 5))	('RPS15', 'Gene', (0, 5))
84906	28147343	Other mechanisms such as methylation, regulation by microRNAs or long non-coding RNAs might further cause ribosomal protein dysregulation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('protein dysregulation', 'Disease', 'MESH:D021081', (116, 137))	('microRNAs', 'Var', (52, 61))	('methylation', 'Var', (25, 36))	('protein dysregulation', 'Disease', (116, 137))	('long non-coding RNAs', 'Var', (65, 85))	('cause', 'Reg', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
84913	28147343	RPS5 and RPS20 show accumulation of high functional impact mutations, some of which may disrupt RNA interactions.	('disrupt', 'NegReg', (88, 95))	('RPS5', 'Gene', '6193', (0, 4))	('RNA interactions', 'Interaction', (96, 112))	('RPS5', 'Gene', (0, 4))	('RPS20', 'Gene', (9, 14))	('mutations', 'Var', (59, 68))	('RPS20', 'Gene', '6224', (9, 14))
84914	28147343	Most interestingly, both RPL11 and RPL5 present inactivating mutations and emerge as candidate cancer drivers in the same cancer type (SKCM).	('inactivating mutations', 'Var', (48, 70))	('RPL11', 'Gene', '6135', (25, 30))	('RPL5', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (122, 128))	('RPL11', 'Gene', (25, 30))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
84918	28147343	The observation of heterozygous inactivating RPL5 mutations and deletions across multiple tumor types suggested a role as haploinsufficient tumor suppressor gene.	('mutations', 'Var', (50, 59))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (122, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('deletions', 'Var', (64, 73))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('haploinsufficient tumor', 'Disease', (122, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('RPL5', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (140, 145))
84919	28147343	It is interesting to note that the Rabadan group integrated TCGA data with known causative genes in cancer predisposing Mendelian diseases, such as DBA, and that they also pick up RPL5 as candidate tumor suppressor in GBM in their analyses.	('DBA', 'Disease', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Mendelian diseases', 'Disease', (120, 138))	('TCGA', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Mendelian diseases', 'Disease', 'MESH:D030342', (120, 138))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('RPL5', 'Var', (180, 184))	('tumor', 'Disease', (198, 203))
84920	28147343	In the current study, we show that the incidence of RPL5 alterations in GBM is much higher than previously assumed and that heterozygous RPL5 inactivation occurs at high incidence in GBM, SKCM and BRCA.	('alterations', 'Var', (57, 68))	('RPL5', 'Gene', (52, 56))	('BRCA', 'Gene', (197, 201))	('BRCA', 'Gene', '672', (197, 201))
84921	28147343	As such, RPL5 inactivation currently represents the most common somatic ribosome defect in cancer.	('RPL5 inactivation', 'Var', (9, 26))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
84923	28147343	In this context, LUAD, KIRC, STAD and PRAD also show inactivating mutations or deletions in RPL5 (Supplementary Figure 9), suggesting that RPL5 may also act as a tumor suppressor in these tumor types.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('a tumor', 'Disease', 'MESH:D009369', (160, 167))	('tumor', 'Disease', (162, 167))	('deletions', 'Var', (79, 88))	('inactivating mutations', 'Var', (53, 75))	('RPL5', 'Gene', (92, 96))	('a tumor', 'Disease', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
84924	28147343	In addition, RPL5 shows inactivating mutations in 2% of T-ALL samples and we showed that RPL5 is part of a minimal deleted region that is heterozygously deleted in 20-40% of advanced multiple myeloma cases (Supplementary Figure 10).	('inactivating mutations', 'Var', (24, 46))	('multiple myeloma', 'Phenotype', 'HP:0006775', (183, 199))	('multiple myeloma', 'Disease', 'MESH:D009101', (183, 199))	('multiple myeloma', 'Disease', (183, 199))	('RPL5', 'Gene', (13, 17))	('RPL5', 'Gene', (89, 93))
84926	28147343	Knockdown of RPL5 by ~50% in both TP53 WT MCF7 and TP53 mutant MDA-MB-231 breast cancer lines accelerated the tumor growth in vivo.	('TP53', 'Gene', '7157', (51, 55))	('MCF7', 'CellLine', 'CVCL:0031', (42, 46))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', (51, 55))	('mutant', 'Var', (56, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', '7157', (34, 38))	('accelerated', 'PosReg', (94, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
84928	28147343	The MDA-MB-231 cell line did not show significant proliferation changes in vitro upon RPL5 knockdown, although a significant increase in tumor growth was observed in vivo.	('RPL5', 'Gene', (86, 90))	('tumor', 'Disease', (137, 142))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (4, 14))	('increase', 'PosReg', (125, 133))	('knockdown', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
84933	28147343	Loss of RPL5 in human primary lung fibroblasts does not induce cell cycle arrest by checkpoint activation but suppresses cell cycle progression by reducing translation rates, including translation of some cyclins.	('suppresses', 'NegReg', (110, 120))	('reducing', 'NegReg', (147, 155))	('RPL5', 'Gene', (8, 12))	('cell cycle progression', 'CPA', (121, 143))	('translation rates', 'MPA', (156, 173))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('human', 'Species', '9606', (16, 21))	('cyclins', 'Protein', (205, 212))	('Loss', 'Var', (0, 4))	('translation', 'MPA', (185, 196))
84941	28147343	Moreover, we observed increased in vivo tumor volumes upon RPL5 knockdown, both in the TP53 wild type MCF7 and in the TP53 mutant MDA-MB-231 line and no consistent changes were observed in TP53 and MDM2 protein expression upon knock-down of RPL5 in these breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('TP53', 'Gene', (189, 193))	('breast cancer', 'Disease', (255, 268))	('increased', 'PosReg', (22, 31))	('TP53', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (130, 140))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', '7157', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('TP53', 'Gene', '7157', (118, 122))	('tumor', 'Disease', (40, 45))	('MDM2', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('MCF7', 'CellLine', 'CVCL:0031', (102, 106))	('mutant', 'Var', (123, 129))	('MDM2', 'Gene', '4193', (198, 202))
84942	28147343	These results suggest that the RPL5 knockdown phenotype is likely TP53-independent.	('knockdown', 'Var', (36, 45))	('TP53', 'Gene', (66, 70))	('RPL5', 'Gene', (31, 35))	('TP53', 'Gene', '7157', (66, 70))
84945	28147343	c-MYC protein was upregulated in both breast cancer cell lines with RPL5 knockdown in vitro and in MDA-MB-231 tumors in vivo but downregulated in MCF7 tumors.	('downregulated', 'NegReg', (129, 142))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('tumors', 'Disease', (151, 157))	('c-MYC', 'Gene', '4609', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('breast cancer', 'Disease', (38, 51))	('tumors', 'Disease', (110, 116))	('c-MYC', 'Gene', (0, 5))	('knockdown', 'Var', (73, 82))	('MCF7 tumors', 'Disease', (146, 157))	('MCF7 tumors', 'Disease', 'MESH:D009369', (146, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('RPL5', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('upregulated', 'PosReg', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
84947	28147343	However, c-MYC upregulation does not fully explain the proliferation and tumor growth advantage conferred by RPL5 knockdown since it also occurs in MCF7 tumors despite c-MYC downregulation.	('c-MYC', 'Gene', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('MCF7 tumors', 'Disease', 'MESH:D009369', (148, 159))	('RPL5', 'Gene', (109, 113))	('knockdown', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('c-MYC', 'Gene', (9, 14))	('downregulation', 'NegReg', (174, 188))	('tumor', 'Disease', (153, 158))	('c-MYC', 'Gene', '4609', (168, 173))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('c-MYC', 'Gene', '4609', (9, 14))	('MCF7 tumors', 'Disease', (148, 159))
84951	28147343	These results may suggest that alterations targeting the TP53 pathway or c-MYC may co-operate with RPL5 in tumorigenesis, and/or that RPL5 inactivation may facilitate acquisition of these lesions.	('alterations', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('c-MYC', 'Gene', '4609', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('c-MYC', 'Gene', (73, 78))	('facilitate', 'PosReg', (156, 166))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('acquisition', 'MPA', (167, 178))	('RPL5 inactivation', 'Var', (134, 151))
84952	28147343	In summary, we provide the first comprehensive analysis of defects in coding regions of ribosomal proteins across several cancer types using the TCGA platform.	('ribosomal proteins', 'Protein', (88, 106))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('coding regions', 'MPA', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('defects', 'Var', (59, 66))
84959	28147343	A gene was considered as significantly mutated in a cancer type if presenting a significantly high frequency of mutations (MutSig2.0), or a significant mutational clustering in a particular region (OncodriveCLUST), or a significant accumulation of mutations with predicted high impact on protein function (OncodriveFM).	('protein function', 'MPA', (288, 304))	('mutations', 'Var', (248, 257))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutational', 'Var', (152, 162))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
84960	28147343	Mechismo was used to predict the functional impact of residue changes on protein and RNA interactions and TransFIC was used to estimate the functional impact of mutations.	('residue changes', 'Var', (54, 69))	('protein', 'Protein', (73, 80))	('Mechismo', 'Chemical', '-', (0, 8))
84961	28147343	For a gene to be considered significantly deleted (or amplified) in a tumor entity, the following criteria had to be met: i) presence in a significant peak of deletion (or amplification) according to Gistic2.0; ii) presence in the 'wide peak' region predicted by Gistic2.0 that most likely harbors the target genes of the deletion (or amplification); iii) absence of other known cancer genes from Cancer Gene Census in the same 'wide peak'; iv) presence of mutations in at least 2% of samples; v) at least 5 samples in the tumor entity in which the gene is deleted (or amplified).	('cancer', 'Disease', (379, 385))	('Cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('tumor', 'Disease', 'MESH:D009369', (523, 528))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (523, 528))	('tumor', 'Disease', (70, 75))	('a tumor', 'Disease', 'MESH:D009369', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('tumor', 'Disease', (523, 528))	('deleted', 'Var', (557, 564))	('a tumor', 'Disease', (68, 75))	('Cancer', 'Disease', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
84965	28147343	The interaction between RPL5 inactivating mutations and deletions and TP53 inactivating mutations and deletions and with MDM2, MDM4 and c-MYC non inactivating mutations and amplifications was tested in BRCA, GBM and SKCM.	('BRCA', 'Gene', (202, 206))	('deletions', 'Var', (102, 111))	('TP53', 'Gene', '7157', (70, 74))	('c-MYC', 'Gene', '4609', (136, 141))	('deletions', 'Var', (56, 65))	('TP53', 'Gene', (70, 74))	('MDM4', 'Gene', '4194', (127, 131))	('c-MYC', 'Gene', (136, 141))	('RPL5', 'Gene', (24, 28))	('MDM2', 'Gene', '4193', (121, 125))	('BRCA', 'Gene', '672', (202, 206))	('MDM2', 'Gene', (121, 125))	('MDM4', 'Gene', (127, 131))
84983	28147343	For experimental work, a one-tailed T-test was used to determine whether RPL5 knockdown increased breast cancer tumor weights and two-tailed paired Student's t-tests when comparing breast cancer cells in various assays.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (98, 117))	('knockdown', 'Var', (78, 87))	('breast cancer', 'Disease', (181, 194))	('breast cancer tumor', 'Disease', 'MESH:D001943', (98, 117))	('increased', 'PosReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('breast cancer tumor', 'Disease', (98, 117))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RPL5', 'Gene', (73, 77))
84990	30531227	It is now well understood that aberrations of the MAPK pathway are key to oncogenesis in low-grade gliomas.	('aberrations', 'Var', (31, 42))	('MAPK pathway', 'Pathway', (50, 62))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
85002	30531227	Completely resected tumors often require no further therapy, and even subtotal resection may induce tumor quiescence for prolonged periods.	('subtotal resection', 'Var', (70, 88))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', (100, 105))	('induce', 'Reg', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (20, 25))
85008	30531227	They are also at an increased risk of developing a secondary malignancy due to their germline mutation.	('malignancy', 'Disease', (61, 71))	('germline mutation', 'Var', (85, 102))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))
85023	30531227	Rearrangements afflicting the genes BRAF and KIAA1549 are the most frequent somatic driver alterations across all pLGGs, and are enriched within pilocytic astrocytomas.	('Rearrangements', 'Var', (0, 14))	('BRAF', 'Gene', (36, 40))	('frequent', 'Reg', (67, 75))	('pilocytic astrocytomas', 'Disease', (145, 167))	('KIAA1549', 'Gene', (45, 53))	('KIAA1549', 'Gene', '57670', (45, 53))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (145, 167))	('BRAF', 'Gene', '673', (36, 40))
85024	30531227	KIAA1549-BRAF rearrangements result in expression of a fusion protein consisting of the N'-terminal of the KIAA1549 protein and the truncated C'-terminal of BRAF, which contains the BRAF kinase.	('result in', 'Reg', (29, 38))	('BRAF', 'Gene', (9, 13))	('KIAA1549', 'Gene', '57670', (0, 8))	('KIAA1549-BRAF', 'Disease', (0, 13))	('rearrangements', 'Var', (14, 28))	('KIAA1549', 'Gene', (0, 8))	('BRAF', 'Gene', '673', (157, 161))	('KIAA1549', 'Gene', '57670', (107, 115))	('BRAF', 'Gene', '673', (182, 186))	('BRAF', 'Gene', (157, 161))	('KIAA1549', 'Gene', (107, 115))	('expression', 'MPA', (39, 49))	('KIAA1549-BRAF', 'Disease', 'None', (0, 13))	('BRAF', 'Gene', (182, 186))	('BRAF', 'Gene', '673', (9, 13))
85026	30531227	BRAF rearrangements involving other fusion partners including RNF130, CLCN6, GNAI1, GIT2, FXR1 and MKRN1 have also been observed less frequently.	('GNAI1', 'Gene', (77, 82))	('GIT2', 'Gene', (84, 88))	('FXR1', 'Gene', '8087', (90, 94))	('CLCN6', 'Gene', '1185', (70, 75))	('BRAF', 'Gene', '673', (0, 4))	('RNF130', 'Gene', '55819', (62, 68))	('GIT2', 'Gene', '9815', (84, 88))	('MKRN1', 'Gene', '23608', (99, 104))	('RNF130', 'Gene', (62, 68))	('GNAI1', 'Gene', '2770', (77, 82))	('FXR1', 'Gene', (90, 94))	('BRAF', 'Gene', (0, 4))	('MKRN1', 'Gene', (99, 104))	('CLCN6', 'Gene', (70, 75))	('rearrangements', 'Var', (5, 19))
85028	30531227	Diffuse astrocytomas have been shown to be enriched with BRAF mutations or rearrangements involving the MYB (and the related MYBL1) family of transcription factors.	('MYBL1', 'Gene', '4603', (125, 130))	('MYB', 'Gene', '4603', (125, 128))	('BRAF', 'Gene', '673', (57, 61))	('MYB', 'Gene', (104, 107))	('MYB', 'Gene', (125, 128))	('BRAF', 'Gene', (57, 61))	('astrocytomas', 'Disease', 'MESH:D001254', (8, 20))	('rearrangements', 'Var', (75, 89))	('MYB', 'Gene', '4603', (104, 107))	('MYBL1', 'Gene', (125, 130))	('mutations', 'Var', (62, 71))	('astrocytomas', 'Disease', (8, 20))
85029	30531227	These MYB rearrangements result in C' terminal truncation of MYB/MYBL1, with resultant loss of its negative regulatory domain and aberrant expression of the truncated protein product.	('loss', 'NegReg', (87, 91))	('MYB', 'Gene', (6, 9))	('MYB', 'Gene', (65, 68))	('rearrangements', 'Var', (10, 24))	("C' terminal truncation", 'MPA', (35, 57))	('MYB', 'Gene', '4603', (61, 64))	('MYBL1', 'Gene', (65, 70))	('MYB', 'Gene', '4603', (6, 9))	('MYBL1', 'Gene', '4603', (65, 70))	('expression', 'MPA', (139, 149))	('MYB', 'Gene', '4603', (65, 68))	('MYB', 'Gene', (61, 64))	('negative regulatory domain', 'MPA', (99, 125))
85031	30531227	MYB rearrangements involving other fusion partners including PCDHGA1 and MAML2 have also been described; however, their clinical associations remain to be defined.	('MYB', 'Gene', (0, 3))	('PCDHGA1', 'Gene', '56114', (61, 68))	('rearrangements', 'Var', (4, 18))	('MYB', 'Gene', '4603', (0, 3))	('MAML2', 'Gene', '84441', (73, 78))	('MAML2', 'Gene', (73, 78))	('PCDHGA1', 'Gene', (61, 68))
85032	30531227	FGFR1 mutations and rearrangements involving FGFR1 (including duplications of the FGFR1 kinase) occur more commonly in dysembryoplastic neuro-epithelial tumors, which can also be associated with germline FGFR1 alterations.	('FGFR1', 'Gene', (82, 87))	('FGFR1', 'Gene', '2260', (204, 209))	('rearrangements', 'Var', (20, 34))	('neuro-epithelial tumors', 'Phenotype', 'HP:0030063', (136, 159))	('occur', 'Reg', (96, 101))	('dysembryoplastic neuro-epithelial tumors', 'Disease', 'MESH:D002277', (119, 159))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', '2260', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('dysembryoplastic neuro-epithelial tumors', 'Disease', (119, 159))	('FGFR1', 'Gene', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('FGFR1', 'Gene', (204, 209))	('FGFR1', 'Gene', '2260', (45, 50))	('mutations', 'Var', (6, 15))
85033	30531227	While pilocytic astrocytomas are largely defined by BRAF alterations, a subset harbor FGFR1 and NTRK2 rearrangements.	('pilocytic astrocytomas', 'Disease', (6, 28))	('NTRK2', 'Gene', '4915', (96, 101))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (6, 28))	('alterations', 'Var', (57, 68))	('FGFR1', 'Gene', (86, 91))	('BRAF', 'Gene', '673', (52, 56))	('NTRK2', 'Gene', (96, 101))	('FGFR1', 'Gene', '2260', (86, 91))	('BRAF', 'Gene', (52, 56))	('rearrangements', 'Var', (102, 116))
85034	30531227	Finally, while IDH1 mutations are much more commonly associated with adult low-grade gliomas, they are also infrequently observed in young children.	('IDH1', 'Gene', (15, 19))	('children', 'Species', '9606', (139, 147))	('IDH1', 'Gene', '3417', (15, 19))	('gliomas', 'Disease', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('associated', 'Reg', (53, 63))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('mutations', 'Var', (20, 29))
85035	30531227	The clinical significance and natural history of pediatric IDH1 mutant low-grade gliomas remains to be defined.	('IDH1', 'Gene', '3417', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('IDH1', 'Gene', (59, 63))	('mutant', 'Var', (64, 70))
85057	30531227	Dabrafenib and vemurafenib are both orally-bioavailable, potent and selective inhibitors of BRAF kinases that harbor V600 mutations, binding to the ATP-binding domain of mutant BRAF.	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('BRAF', 'Gene', (92, 96))	('ATP', 'Chemical', 'MESH:D000255', (148, 151))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('V600 mutations', 'Var', (117, 131))	('vemurafenib', 'Chemical', 'MESH:D000077484', (15, 26))	('binding', 'Interaction', (133, 140))
85058	30531227	Both dabrafenib and vemurafenib are FDA-approved in the treatment of BFAFV600E/K-mutated melanoma.	('V600E', 'Mutation', 'rs113488022', (73, 78))	('vemurafenib', 'Chemical', 'MESH:D000077484', (20, 31))	('dabrafenib', 'Chemical', 'MESH:C561627', (5, 15))	('BFAFV600E/K-mutated', 'Var', (69, 88))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
85059	30531227	Case reports describing dramatic responses to dabrafenib in infants and children with recurrent LGG that harbor BRAFV600E mutations led to an ongoing multi-institutional phase I/IIa trial (NCT01677741) of dabrafenib in children with recurrent BRAFV600 mutated solid tumors.	('solid tumors', 'Disease', (260, 272))	('dabrafenib', 'Chemical', 'MESH:C561627', (46, 56))	('LGG', 'Disease', (96, 99))	('dabrafenib', 'Chemical', 'MESH:C561627', (205, 215))	('BRAF', 'Gene', '673', (243, 247))	('children', 'Species', '9606', (72, 80))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', (243, 247))	('BRAF', 'Gene', '673', (112, 116))	('solid tumors', 'Disease', 'MESH:D009369', (260, 272))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('mutations', 'Var', (122, 131))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('BRAFV600E', 'Mutation', 'rs113488022', (112, 121))	('infants', 'Species', '9606', (60, 67))	('children', 'Species', '9606', (219, 227))
85062	30531227	Similarly, early reports of promising vemurafenib activity in children with recurrent BRAFV600E mutant pLGG treated led to the ongoing Pacific Neuro-Oncology Consortium (PNOC) phase I trial of vemurafenib in children with recurrent or refractory gliomas containing the BRAFV600E mutation (NCT01748149).	('vemurafenib', 'Chemical', 'MESH:D000077484', (38, 49))	('children', 'Species', '9606', (62, 70))	('pLGG', 'Gene', (103, 107))	('BRAFV600E', 'Var', (269, 278))	('BRAFV600E', 'Mutation', 'rs113488022', (269, 278))	('gliomas', 'Disease', 'MESH:D005910', (246, 253))	('children', 'Species', '9606', (208, 216))	('BRAFV600E', 'Mutation', 'rs113488022', (86, 95))	('gliomas', 'Disease', (246, 253))	('gliomas', 'Phenotype', 'HP:0009733', (246, 253))	('activity', 'MPA', (50, 58))	('vemurafenib', 'Chemical', 'MESH:D000077484', (193, 204))	('BRAFV600E', 'Gene', (86, 95))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))	('Oncology', 'Phenotype', 'HP:0002664', (149, 157))
85063	30531227	Kondyli et al reported that among 6 patients with refractory V600E-mutated pLGG treated with a combination of trametinib and dabrafenib, 4 patients experienced PR, 1 SD and 1 progressive disease (PD).	('progressive disease', 'Disease', (175, 194))	('experienced', 'Reg', (148, 159))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (36, 44))	('PD', 'Disease', 'MESH:D010300', (196, 198))	('V600E-mutated', 'Var', (61, 74))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('SD', 'Disease', 'MESH:D029461', (166, 168))	('pLGG', 'Gene', (75, 79))	('trametinib', 'Chemical', 'MESH:C560077', (110, 120))	('dabrafenib', 'Chemical', 'MESH:C561627', (125, 135))	('progressive disease', 'Disease', 'MESH:D018450', (175, 194))
85068	30531227	In addition, we now understand the importance of tailoring therapy for pLGGs based on a thorough understanding of the distinct mechanisms of action specific to different BRAF alterations.	('BRAF', 'Gene', (170, 174))	('BRAF', 'Gene', '673', (170, 174))	('alterations', 'Var', (175, 186))
85075	30531227	Novel agents targeting BRAF aberrations have demonstrated high response rates, good PFS and overall manageable toxicity in patients with recurrent disease.	('BRAF', 'Gene', '673', (23, 27))	('aberrations', 'Var', (28, 39))	('BRAF', 'Gene', (23, 27))	('patients', 'Species', '9606', (123, 131))	('toxicity', 'Disease', 'MESH:D064420', (111, 119))	('toxicity', 'Disease', (111, 119))	('PFS', 'MPA', (84, 87))
85137	31118022	Intriguingly, we observed that the patients with high expression of COL1A1, ITGB1 and ITGB3 are prone to with significantly poor prognostic outcomes in TCGA LGG datasets (Fig.	('ITGB1', 'Gene', '3688', (76, 81))	('ITGB3', 'Gene', '3690', (86, 91))	('ITGB1', 'Gene', (76, 81))	('high expression', 'Var', (49, 64))	('ITGB3', 'Gene', (86, 91))	('patients', 'Species', '9606', (35, 43))	('COL1A1', 'Gene', '1277', (68, 74))	('COL1A1', 'Gene', (68, 74))	('poor', 'NegReg', (124, 128))
85170	31118022	For instance, the neurite outgrowth inhibitor (Nogo) of RTN4 could play a newfound role in carcinogenesis through AKT signaling pathway, and knockdown of RTN4 could postpone tumor proliferation in mice.	('tumor', 'Disease', (174, 179))	('knockdown', 'Var', (141, 150))	('neurite outgrowth inhibitor', 'Gene', (18, 45))	('postpone', 'NegReg', (165, 173))	('RTN4', 'Gene', (56, 60))	('AKT', 'Gene', '11651', (114, 117))	('carcinogenesis', 'Disease', (91, 105))	('neurite outgrowth inhibitor', 'Gene', '68585', (18, 45))	('AKT', 'Gene', (114, 117))	('Nogo', 'Gene', '68585', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mice', 'Species', '10090', (197, 201))	('RTN4', 'Gene', (154, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))	('Nogo', 'Gene', (47, 51))
85304	27282398	Although DNA copy number and gene expressions were known to differ in glioblastomas arising in children and adults, the key discovery that best illustrates the unique biology of tumors in children was the identification of somatic histone mutations.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastomas', 'Disease', (70, 83))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('children', 'Species', '9606', (95, 103))	('mutations', 'Var', (239, 248))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('children', 'Species', '9606', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))
85305	27282398	Specific recurrent mutations in the genes encoding the H3.3 (H3F3A) and H3.1 (HIST1H3B, HIST1H3C) histone variants result in amino acid substitutions at 2 key residues in the histone tail: lysine-to-methionine at position 27 (K27M) and glycine-to-arginine or -valine at position 34 (G34R/V).	('H3.3', 'Gene', '3020', (55, 59))	('result in', 'Reg', (115, 124))	('lysine-to-methionine at position 27', 'Mutation', 'p.K27M', (189, 224))	('HIST1H3B', 'Gene', (78, 86))	('variants', 'Var', (106, 114))	('HIST1H3B', 'Gene', '8358', (78, 86))	('arginine', 'Chemical', 'MESH:D001120', (247, 255))	('H3.1', 'Gene', (72, 76))	('valine', 'Chemical', 'MESH:D014633', (260, 266))	('G34R', 'SUBSTITUTION', 'None', (283, 287))	('G34R', 'Var', (283, 287))	('H3F3A', 'Gene', '3020', (61, 66))	('HIST1H3C', 'Gene', '8352', (88, 96))	('glycine', 'Chemical', 'MESH:D005998', (236, 243))	('H3.3', 'Gene', (55, 59))	('K27M', 'Mutation', 'p.K27M', (226, 230))	('H3F3A', 'Gene', (61, 66))	('HIST1H3C', 'Gene', (88, 96))	('mutations', 'Var', (19, 28))	('substitutions', 'Var', (136, 149))	('H3.1', 'Gene', '8352', (72, 76))
85306	27282398	These are as yet not found in other cancer types, such as glioblastoma in the elderly population, though similar variants have been reported in rare childhood bone tumors (H3F3A G34W/L in giant cell tumors of bone, H3F3B K36M in chondroblastoma).	('giant cell tumors', 'Disease', 'MESH:D005870', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('K36M', 'SUBSTITUTION', 'None', (221, 225))	('G34W', 'SUBSTITUTION', 'None', (178, 182))	('K36M', 'Var', (221, 225))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('giant cell tumors of bone', 'Phenotype', 'HP:0011847', (188, 213))	('giant cell tumors', 'Disease', (188, 205))	('glioblastoma', 'Disease', 'MESH:D005909', (58, 70))	('H3F3B', 'Gene', '3021', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('chondroblastoma', 'Disease', 'MESH:D002804', (229, 244))	('H3F3B', 'Gene', (215, 220))	('H3F3A', 'Gene', '3020', (172, 177))	('tumors of bone', 'Phenotype', 'HP:0010622', (199, 213))	('bone tumors', 'Disease', (159, 170))	('glioblastoma', 'Disease', (58, 70))	('chondroblastoma', 'Phenotype', 'HP:0030432', (229, 244))	('bone tumors', 'Phenotype', 'HP:0010622', (159, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (36, 42))	('reported', 'Reg', (132, 140))	('bone tumors', 'Disease', 'MESH:D001859', (159, 170))	('G34W', 'Var', (178, 182))	('H3F3A', 'Gene', (172, 177))	('chondroblastoma', 'Disease', (229, 244))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
85307	27282398	These mutually exclusive mutations mark clear subgroups of the disease, as defined by numerous molecular and clinical parameters, including tumors that arise in young adults (20-30 y) (Fig.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
85308	27282398	These distinct origins are also reflected in the anatomical distribution of tumors carrying the mutations, with H3.3 G34R/V found exclusively in the cerebral hemispheres, H3.3 K27M distributed throughout the midline structures (including the thalamus, brainstem, cerebellum, and spine), and H3.1 K27M restricted to the pons (Fig.	('H3.3', 'Gene', '3020', (171, 175))	('G34R', 'SUBSTITUTION', 'None', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('H3.1', 'Gene', '8352', (291, 295))	('G34R', 'Var', (117, 121))	('tumors', 'Disease', (76, 82))	('H3.3', 'Gene', (171, 175))	('H3.3', 'Gene', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('K27M', 'Mutation', 'p.K27M', (296, 300))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('K27M', 'Mutation', 'p.K27M', (176, 180))	('H3.1', 'Gene', (291, 295))	('H3.3', 'Gene', '3020', (112, 116))
85309	27282398	Indeed more than 85% of DIPGs, a nonsurgically resectable glial tumor of the pons which may display histological features ranging from grade II to grade IV, harbor a K27M mutation in one or other histone variant, with H3.1 mutant tumors displaying a younger age, distinct clinicopathological and radiological features, and a slightly longer survival time.	('K27M', 'Var', (166, 170))	('H3.1', 'Gene', '8352', (218, 222))	('tumors', 'Disease', (230, 236))	('DIPGs', 'Disease', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('glial tumor', 'Disease', 'MESH:D005910', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('H3.1', 'Gene', (218, 222))	('DIPGs', 'Chemical', 'MESH:C060938', (24, 29))	('K27M', 'Mutation', 'p.K27M', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('glial tumor', 'Disease', (58, 69))
85312	27282398	A small number of histologically low-grade glioneuronal tumors have been described that harbor both H3 K27M and BRAF V600E mutations, and these may have an improved prognosis compared with typical high-grade K27M tumors (although the numbers remain small).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('BRAF', 'Gene', (112, 116))	('improved', 'PosReg', (156, 164))	('BRAF', 'Gene', '673', (112, 116))	('K27M', 'Mutation', 'p.K27M', (103, 107))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('V600E', 'Mutation', 'rs113488022', (117, 122))	('K27M', 'Mutation', 'p.K27M', (208, 212))	('H3 K27M', 'Var', (100, 107))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (43, 62))
85314	27282398	Although both histone H3 mutations lead to a reduction in DNA methylation throughout the epigenome, K27M globally and G34R/V mostly at subtelomeric regions, there are notable exceptions.	('mutations', 'Var', (25, 34))	('DNA methylation', 'MPA', (58, 73))	('G34R', 'SUBSTITUTION', 'None', (118, 122))	('histone', 'Gene', (14, 21))	('K27M', 'Mutation', 'p.K27M', (100, 104))	('G34R', 'Var', (118, 122))	('reduction', 'NegReg', (45, 54))	('K27M', 'Var', (100, 104))
85315	27282398	Of particular clinical relevance is hypermethylation of the MGMT gene promoter region, which encodes a DNA repair enzyme associated with resistance in adult glioblastoma to alkylating agents such as temozolomide (TMZ).	('adult glioblastoma', 'Disease', (151, 169))	('adult glioblastoma', 'Disease', 'MESH:D005909', (151, 169))	('temozolomide', 'Chemical', 'MESH:D000077204', (199, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('hypermethylation', 'Var', (36, 52))	('MGMT', 'Gene', (60, 64))	('TMZ', 'Chemical', 'MESH:D000077204', (213, 216))	('MGMT', 'Gene', '4255', (60, 64))
85317	27282398	This may be due to MGMT methylation being predominantly found in the H3.3 G34R/V subgroup and less frequent in tumors with K27M mutations, likely contributing to the lack of clinical response to TMZ in most HGG including DIPG across numerous trials.	('DIPG', 'Chemical', '-', (221, 225))	('K27M', 'Mutation', 'p.K27M', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('H3.3', 'Gene', '3020', (69, 73))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('MGMT', 'Gene', '4255', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('MGMT', 'Gene', (19, 23))	('K27M', 'Var', (123, 127))	('G34R', 'SUBSTITUTION', 'None', (74, 78))	('G34R', 'Var', (74, 78))	('H3.3', 'Gene', (69, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (195, 198))
85318	27282398	Aside from possessing a distinct epigenetic profile, these histone-defined subgroups frequently co-segregate with differential secondary genetic alterations, such as ATRX in the H3.3 G34R/V group,FGFR1 in thalamic H3.3 K27M, and seemingly uniquely in human cancer,ACVR1 mutations in H3.1 K27M DIPG, a subgroup in which the otherwise common TP53 mutations are absent (Fig.	('TP53', 'Gene', (340, 344))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('ATRX', 'Gene', (166, 170))	('H3.3', 'Gene', '3020', (214, 218))	('FGFR1', 'Gene', '2260', (196, 201))	('H3.1', 'Gene', '8352', (283, 287))	('mutations', 'Var', (270, 279))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('TP53', 'Gene', '7157', (340, 344))	('H3.3', 'Gene', (178, 182))	('ACVR1', 'Gene', (264, 269))	('FGFR1', 'Gene', (196, 201))	('H3.1', 'Gene', (283, 287))	('DIPG', 'Chemical', '-', (293, 297))	('G34R', 'SUBSTITUTION', 'None', (183, 187))	('human', 'Species', '9606', (251, 256))	('H3.3', 'Gene', '3020', (178, 182))	('K27M', 'Mutation', 'p.K27M', (219, 223))	('G34R', 'Var', (183, 187))	('H3.3', 'Gene', (214, 218))	('ACVR1', 'Gene', '90', (264, 269))	('cancer', 'Disease', (257, 263))	('ATRX', 'Gene', '546', (166, 170))	('K27M', 'Mutation', 'p.K27M', (288, 292))
85319	27282398	Despite the ability to subclassify tumors on the basis of histone H3 mutations, more than half of all childhood diffusely infiltrating gliomas do not fall into these categories.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('fall', 'Phenotype', 'HP:0002527', (150, 154))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('histone H3', 'Protein', (58, 68))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
85320	27282398	A small proportion (<5%) harbor hotspot mutations in the IDH1/2 genes associated with a global hypermethylation ("G-CIMP") and likely represent the younger tail of an age distribution for these tumors, which peaks at around 40-45 years of age, as reviewed elsewhere.	('global hypermethylation', 'MPA', (88, 111))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('IDH1', 'Gene', (57, 61))	('associated', 'Reg', (70, 80))	('mutations', 'Var', (40, 49))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('IDH1', 'Gene', '3417', (57, 61))	('tumors', 'Disease', (194, 200))
85321	27282398	A larger group (5%-10%) of predominantly cortical tumors harbor an activating BRAF V600E mutation, have histological and epigenetic similarities to pleomorphic xanthoastrocytoma, and have a better clinical outcome.	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (148, 177))	('V600E', 'Var', (83, 88))	('BRAF', 'Gene', '673', (78, 82))	('cortical tumors', 'Disease', 'MESH:D016543', (41, 56))	('pleomorphic xanthoastrocytoma', 'Disease', (148, 177))	('BRAF', 'Gene', (78, 82))	('cortical tumors', 'Disease', (41, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('activating', 'PosReg', (67, 77))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
85322	27282398	Unlike lower-grade gliomas with mitogen-activated protein kinase pathway activation, they frequently co-segregate with CDKN2A/B (p16) deletion (Fig.	('p16', 'Gene', (129, 132))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('CDKN2A/B', 'Gene', '1029;1030', (119, 127))	('gliomas', 'Disease', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('deletion', 'Var', (134, 142))	('p16', 'Gene', '1029', (129, 132))	('CDKN2A/B', 'Gene', (119, 127))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
85323	27282398	Patients whose tumors have these mutations are candidates for target-driven clinical trials and provide a paradigm for translational progress in this disease (below).	('tumors', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mutations', 'Var', (33, 42))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
85325	27282398	Mutations in the histone methyltransferase SETD2 may extend the proportion of tumors with dysregulated H3K36 trimethylation, the likely consequence of H3.3 G34R/V mutation, though the functional overlap between these mutations has not been determined.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('SETD2', 'Gene', '29072', (43, 48))	('G34R', 'SUBSTITUTION', 'None', (156, 160))	('SETD2', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Mutations', 'Var', (0, 9))	('H3K36', 'Protein', (103, 108))	('dysregulated', 'MPA', (90, 102))	('G34R', 'Var', (156, 160))	('H3.3', 'Gene', (151, 155))	('H3.3', 'Gene', '3020', (151, 155))
85326	27282398	They otherwise frequently harbor alterations associated with receptor tyrosine kinase activation, most commonly through amplification and/or mutation of PDGFRA (and in contrast to adult glioblastoma, only rarely through EGFR involvement), though this is also often found in association with H3.3 K27M mutation.	('H3.3', 'Gene', '3020', (291, 295))	('adult glioblastoma', 'Disease', (180, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('EGFR', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (220, 224))	('alterations', 'Reg', (33, 44))	('receptor tyrosine kinase activation', 'MPA', (61, 96))	('adult glioblastoma', 'Disease', 'MESH:D005909', (180, 198))	('PDGFRA', 'Gene', (153, 159))	('amplification', 'Var', (120, 133))	('H3.3', 'Gene', (291, 295))	('K27M', 'Mutation', 'p.K27M', (296, 300))	('PDGFRA', 'Gene', '5156', (153, 159))	('mutation', 'Var', (141, 149))
85328	27282398	Together, integrated genetic and epigenetic characterization of pHGG and DIPG may allow for the delineation of distinct prognostic risk groups which will inform future clinical trial interpretation:for instance, a high-risk group based upon K27M mutation and/or amplification of PDGFRA, MYCN, etc, and an intermediate group enriched for G34R/V and IDH1 mutations.	('DIPG', 'Chemical', '-', (73, 77))	('IDH1', 'Gene', (348, 352))	('G34R', 'SUBSTITUTION', 'None', (337, 341))	('PDGFRA', 'Gene', '5156', (279, 285))	('PDGFRA', 'Gene', (279, 285))	('G34R', 'Var', (337, 341))	('IDH1', 'Gene', '3417', (348, 352))	('K27M', 'Mutation', 'p.K27M', (241, 245))	('MYCN', 'Gene', (287, 291))	('MYCN', 'Gene', '4613', (287, 291))	('pHGG', 'Gene', (64, 68))	('amplification', 'Var', (262, 275))	('K27M mutation', 'Var', (241, 254))
85336	27282398	Similarly, in adult gliomas the number of cells in the tumor mass immunopositive for the activated microglia/macrophage marker CD68 increases with increasing tumor grade, and M2 phenotype microglia appear to promote glioblastoma growth.	('M2 phenotype', 'Var', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (158, 163))	('promote', 'PosReg', (208, 215))	('adult gliomas', 'Disease', (14, 27))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('adult gliomas', 'Disease', 'MESH:D005910', (14, 27))	('CD68', 'Gene', (127, 131))	('increases', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('glioblastoma growth', 'Disease', 'MESH:D005909', (216, 235))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('glioblastoma growth', 'Disease', (216, 235))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('CD68', 'Gene', '968', (127, 131))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))
85341	27282398	While our understanding of TAMs in pediatric infiltrating gliomas remains incomplete, the potential of harnessing the power of the immune system in pediatric gliomas is presently under exploration using a variety of immune-modulatory strategies, including blockade of programmed cell death protein 1 (ClinicalTrials.gov identifiers NCT01952769 and NCT02359565) and tumor vaccine strategies (NCT01400672 and NCT00874861).	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('NCT01400672', 'Var', (391, 402))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('pediatric gliomas', 'Disease', 'MESH:D005910', (148, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('gliomas', 'Disease', (58, 65))	('programmed cell death protein 1', 'Gene', (268, 299))	('NCT02359565', 'Var', (348, 359))	('NCT00874861', 'Var', (407, 418))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('NCT01952769', 'Var', (332, 343))	('pediatric gliomas', 'Disease', (148, 165))	('TAMs', 'Chemical', '-', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('tumor', 'Disease', (365, 370))	('programmed cell death protein 1', 'Gene', '5133', (268, 299))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))
85351	27282398	It demonstrated that the strongest factors associated with more favorable outcome were extent of resection (>90% resection), low methylation-inhibited binding protein 1 indices, and non-overexpression of p53.	('p53', 'Gene', '7157', (204, 207))	('non-overexpression', 'Var', (182, 200))	('p53', 'Gene', (204, 207))	('methylation-inhibited binding protein 1 indices', 'MPA', (129, 176))	('low', 'NegReg', (125, 128))
85370	27282398	As described above, the identification of the chromatin mutations, their association with aberrant pathway activation that appears to segregate into different groups, and the identification of a new target not previously associated with any cancer has changed the very landscape by which we think about these tumors.	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumors', 'Disease', (309, 315))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('chromatin', 'Gene', (46, 55))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('aberrant', 'MPA', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('activation', 'PosReg', (107, 117))
85379	27282398	In addition to confirming the relative insensitivity of pHGGs to traditional chemotherapies, such efforts in DIPG have demonstrated the potential therapeutic efficacy of epigenetic modifying agents targeting histone demethylases and histone deacetylases.	('histone', 'Protein', (233, 240))	('epigenetic modifying agents', 'Var', (170, 197))	('DIPG', 'Chemical', '-', (109, 113))	('histone demethylases', 'Protein', (208, 228))
85381	27282398	However, the impact of K27M and G34R/V on the global chromatin landscape is still largely unknown.	('G34R', 'SUBSTITUTION', 'None', (32, 36))	('G34R', 'Var', (32, 36))	('K27M', 'Var', (23, 27))	('K27M', 'Mutation', 'p.K27M', (23, 27))
85382	27282398	For example, it is highly likely that K27me3 loss in K27M causes downstream consequences on other histone marks or chromatin machinery which can be targeted pharmacologically.	('K27M', 'Mutation', 'p.K27M', (53, 57))	('histone marks', 'MPA', (98, 111))	('chromatin machinery', 'MPA', (115, 134))	('K27me3', 'Var', (38, 44))	('K27M', 'Gene', (53, 57))	('loss', 'NegReg', (45, 49))	('consequences', 'Reg', (76, 88))
85384	27282398	This suggests that mechanistic studies of how K27M and G34R/V mutations impact the global epigenetic landscape will provide further insight into prognostic and rational, targeted therapeutic strategies in DIPG.	('K27M', 'Mutation', 'p.K27M', (46, 50))	('DIPG', 'Chemical', '-', (205, 209))	('G34R', 'SUBSTITUTION', 'None', (55, 59))	('K27M', 'Var', (46, 50))	('G34R', 'Var', (55, 59))	('DIPG', 'Disease', (205, 209))	('impact', 'Reg', (72, 78))	('global epigenetic landscape', 'MPA', (83, 110))
85386	27282398	For example, future trials targeting K27M mutant tumors should include patients regardless of anatomical location.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patients', 'Species', '9606', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('K27M mutant', 'Var', (37, 48))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('K27M', 'Mutation', 'p.K27M', (37, 41))
85387	27282398	On the other hand, given that IDH1 mutant tumors are much more common in adults, the inclusion of IDH mutant tumors on pediatric studies without a specific rationale generally makes little sense (and perhaps should be included in a separate stratum of the adult trials).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutant', 'Var', (35, 41))	('IDH1', 'Gene', (30, 34))	('IDH', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', '3417', (98, 101))	('IDH', 'Gene', '3417', (30, 33))	('tumors', 'Disease', (109, 115))	('IDH1', 'Gene', '3417', (30, 34))
85411	33673213	Notwithstanding their initial innocuous facade, some low-grade tumors have the propensity to become more aggressive over time.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('low-grade', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
85428	33673213	The CL subtype is strongly associated with amplification and mutation of epidermal growth factor receptor (EGFR), along with deletion of cyclin-dependent kinase inhibitors (CDKN2A/2B) and gain of chromosome 7, concomitant with loss of chromosome 10, and its overexpression correlates strongly with an astrocytic signature (Figure 3).	('astrocytic signature', 'Disease', (301, 321))	('CDKN2A/2B', 'Gene', (173, 182))	('mutation', 'Var', (61, 69))	('associated', 'Reg', (27, 37))	('amplification', 'Var', (43, 56))	('EGFR', 'Gene', (107, 111))	('overexpression', 'PosReg', (258, 272))	('epidermal growth factor receptor', 'Gene', (73, 105))	('CL subtype', 'Disease', (4, 14))	('epidermal growth factor receptor', 'Gene', '1956', (73, 105))	('CDKN2A/2B', 'Gene', '1029', (173, 182))
85429	33673213	The ME subtype is associated with mutation and deletion of neurofibromin (NF1) and phosphatase and tensin homolog (PTEN), as previously concluded.	('ME', 'Chemical', '-', (4, 6))	('NF1', 'Gene', (74, 77))	('PTEN', 'Gene', (115, 119))	('neurofibromin', 'Gene', (59, 72))	('mutation', 'Var', (34, 42))	('PTEN', 'Gene', '5728', (115, 119))	('NF1', 'Gene', '4763', (74, 77))	('phosphatase and tensin homolog', 'Gene', '5728', (83, 113))	('associated', 'Reg', (18, 28))	('deletion', 'Var', (47, 55))	('neurofibromin', 'Gene', '4763', (59, 72))
85431	33673213	The PN subtype, featuring an oligodendrocytic signature, is associated with younger age and prolonged survival on account of platelet-derived growth factor receptor alpha (PDGFRA) abnormalities and isocitrate dehydrogenase (IDH1) and tumor suppressor TP53 mutations, all of which are characteristics of secondary GBMs.	('IDH1', 'Gene', '3417', (224, 228))	('PDGFRA', 'Gene', (172, 178))	('tumor', 'Disease', (234, 239))	('abnormalities', 'Var', (180, 193))	('TP53', 'Gene', (251, 255))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (125, 170))	('platelet-derived growth factor receptor alpha', 'Gene', (125, 170))	('IDH1', 'Gene', (224, 228))	('mutations', 'Var', (256, 265))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('PN', 'Gene', '79650', (4, 6))	('oligodendrocytic', 'Disease', (29, 45))	('oligodendrocytic', 'Disease', 'MESH:D056784', (29, 45))	('TP53', 'Gene', '7157', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
85432	33673213	Lastly, the contested NE subtype is associated with amplification of EGFR and deletion of PTEN but correlates with neural gene signatures.	('PTEN', 'Gene', (90, 94))	('EGFR', 'Gene', (69, 73))	('deletion', 'Var', (78, 86))	('PTEN', 'Gene', '5728', (90, 94))	('contested', 'Disease', (12, 21))	('amplification', 'Var', (52, 65))
85434	33673213	Of particular importance is the identification of a cluster of GBM tumors characterized by high copy number alterations and altered methylation patterns, referred to as the glioma-CpG island methylator phenotype (G-CIMP).	('high copy number alterations', 'Var', (91, 119))	('methylation patterns', 'MPA', (132, 152))	('GBM tumors', 'Disease', (63, 73))	('GBM tumors', 'Disease', 'MESH:D005910', (63, 73))	('altered', 'Reg', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma-CpG', 'Disease', 'MESH:D005910', (173, 183))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('G-CIMP', 'Chemical', '-', (213, 219))	('glioma-CpG', 'Disease', (173, 183))
85435	33673213	This subset of tumors is strongly associated with mutations in IDH (detailed below) and TP53 and is more often found in younger patients.	('associated', 'Reg', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('IDH', 'Gene', (63, 66))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('IDH', 'Gene', '3417', (63, 66))	('TP53', 'Gene', '7157', (88, 92))	('patients', 'Species', '9606', (128, 136))	('TP53', 'Gene', (88, 92))	('tumors', 'Disease', (15, 21))
85436	33673213	Of note, G-CIMP+ tumors are also enriched in the PN subtype and typically portray a favorable outcome.	('PN', 'Gene', '79650', (49, 51))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('G-CIMP', 'Chemical', '-', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('G-CIMP+', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
85439	33673213	Methylation of the MGMT promoter silences the gene, thereby resulting in inefficient DNA repair.	('Methylation', 'Var', (0, 11))	('DNA repair', 'MPA', (85, 95))	('MGMT', 'Gene', '4255', (19, 23))	('inefficient', 'NegReg', (73, 84))	('MGMT', 'Gene', (19, 23))	('silences', 'NegReg', (33, 41))
85442	33673213	The following well-known oncogenes and tumor suppressors were found to be significantly mutated in GBM: EGFR, IDH1, NF1, PDGFRA, PIK3R1, PIK3CA, PTEN, RB1, and TP53.	('TP53', 'Gene', '7157', (160, 164))	('PIK3CA', 'Gene', '5290', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IDH1', 'Gene', (110, 114))	('EGFR', 'Gene', (104, 108))	('RB1', 'Gene', '5925', (151, 154))	('NF1', 'Gene', '4763', (116, 119))	('PIK3R1', 'Gene', (129, 135))	('PIK3CA', 'Gene', (137, 143))	('IDH1', 'Gene', '3417', (110, 114))	('PTEN', 'Gene', (145, 149))	('PDGFRA', 'Gene', (121, 127))	('NF1', 'Gene', (116, 119))	('TP53', 'Gene', (160, 164))	('tumor', 'Disease', (39, 44))	('GBM: EGFR', 'Gene', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PTEN', 'Gene', '5728', (145, 149))	('mutated', 'Var', (88, 95))	('RB1', 'Gene', (151, 154))	('PIK3R1', 'Gene', '5295', (129, 135))
85445	33673213	Mutations in IDH1 appear to preferentially occur in younger glioblastoma patients (mean age: 33 or 41 years) as opposed to wild-type carriers (mean age: 53 or 56 years) and are mostly detected in patients with secondary GBM.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('IDH1', 'Gene', (13, 17))	('patients', 'Species', '9606', (196, 204))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('patients', 'Species', '9606', (73, 81))	('occur', 'Reg', (43, 48))
85447	33673213	Over 90% of IDH1 mutations reflect an amino acid substitution at an evolutionarily conserved residue (R132H) located within the enzyme's binding site, akin to well-known activating alterations in BRAF, KRAS, and PIK3CA.	('amino acid substitution', 'Var', (38, 61))	('R132H', 'Mutation', 'rs121913500', (102, 107))	('IDH1', 'Gene', (12, 16))	('reflect', 'Reg', (27, 34))	('PIK3CA', 'Gene', (212, 218))	('BRAF', 'Gene', '673', (196, 200))	('KRAS', 'Gene', '3845', (202, 206))	('BRAF', 'Gene', (196, 200))	('IDH1', 'Gene', '3417', (12, 16))	('PIK3CA', 'Gene', '5290', (212, 218))	('KRAS', 'Gene', (202, 206))	('R132H', 'Var', (102, 107))	('mutations', 'Var', (17, 26))
85448	33673213	Additional studies investigating the functional impact of IDH1 mutations proposed that IDH1 may function as a tumor suppressor that, when inactivated by a mutation, likely contributes to tumorigenesis.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('IDH1', 'Gene', '3417', (58, 62))	('IDH1', 'Gene', '3417', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('contributes', 'Reg', (172, 183))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (187, 192))	('inactivated', 'NegReg', (138, 149))	('mutation', 'Var', (155, 163))	('IDH1', 'Gene', (87, 91))	('IDH1', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
85455	33673213	Interestingly, IHC can even be used to determine patient IDH1 mutation status using IDH1-specific antibody recognizing the R132H mutation.	('R132H', 'Mutation', 'rs121913500', (123, 128))	('IDH1', 'Gene', (84, 88))	('patient', 'Species', '9606', (49, 56))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (84, 88))	('IDH1', 'Gene', '3417', (57, 61))	('R132H', 'Var', (123, 128))
85456	33673213	One of the many factors responsible for GBM malignancy is the rapid proliferation of GBM cells, which can be driven by mutations resulting in uncontrolled activation of signaling pathways such as those downstream of EGFR.	('EGFR', 'Gene', (216, 220))	('malignancy', 'Disease', (44, 54))	('uncontrolled', 'MPA', (142, 154))	('malignancy', 'Disease', 'MESH:D009369', (44, 54))	('signaling pathways', 'Pathway', (169, 187))	('mutations', 'Var', (119, 128))	('activation', 'PosReg', (155, 165))
85462	33673213	It is widely believed that the acquisition of mesenchymal features is associated with stemness and that the co-expression of EMT markers with stem cell markers produces a migratory cancer stem cell.	('cancer', 'Disease', (181, 187))	('co-expression', 'Var', (108, 121))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))
85465	33673213	Interestingly, GSCs have an elevated invasive potential compared to non-stem tumor cells and are thought to be more resistant to radiotherapy and chemotherapy than differentiated bulk tumor cells.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('elevated', 'PosReg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('invasive potential', 'CPA', (37, 55))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('GSCs', 'Var', (15, 19))	('tumor', 'Disease', (77, 82))
85470	33673213	Transdifferentiation of GSCs into endothelial cells is yet another strategy that enhances neovascularization and VEGF-A has been shown to be secreted by GSCs in extracellular vesicles.	('VEGF-A', 'Gene', '7422', (113, 119))	('VEGF-A', 'Gene', (113, 119))	('neovascularization', 'CPA', (90, 108))	('enhances', 'PosReg', (81, 89))	('Transdifferentiation', 'Var', (0, 20))
85472	33673213	In GBM (and other cancers), however, the vasculature is disorganized and chaotic, and the lack of pericytes in the periphery results in hyperpermeability or leakiness of blood vessels, leading to edema, which eventually serves as a platform for GBM and endothelial cell migration.	('edema', 'Phenotype', 'HP:0000969', (196, 201))	('GBM', 'Disease', (3, 6))	('hyperpermeability', 'MPA', (136, 153))	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('leakiness', 'Disease', 'MESH:C535298', (157, 166))	('leakiness', 'Disease', (157, 166))	('edema', 'Disease', (196, 201))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leading to', 'Reg', (185, 195))	('lack', 'Var', (90, 94))	('results in', 'Reg', (125, 135))	('edema', 'Disease', 'MESH:D004487', (196, 201))
85476	33673213	In addition to insulin-signaling-related mechanisms that mediate tumor growth and survival, a link between epigenetics and cell metabolism exists and is best highlighted by IDH1 mutations (see Section 2.2), which likely impact metabolism via altered metabolic flux of alpha-ketogluterate and NAPDH, thereby impairing normal biosynthetic pathways.	('alpha-ketogluterate', 'Protein', (268, 287))	('impairing', 'NegReg', (307, 316))	('tumor', 'Disease', (65, 70))	('normal biosynthetic', 'MPA', (317, 336))	('insulin', 'Gene', (15, 22))	('insulin', 'Gene', '3630', (15, 22))	('altered', 'Reg', (242, 249))	('IDH1', 'Gene', (173, 177))	('NAPDH', 'Protein', (292, 297))	('metabolic flux', 'MPA', (250, 264))	('impact', 'Reg', (220, 226))	('IDH1', 'Gene', '3417', (173, 177))	('alpha-ketogluterate', 'Chemical', '-', (268, 287))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (178, 187))	('metabolism', 'MPA', (227, 237))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
85479	33673213	However, in cancer, RTKs are aberrantly activated and thus contribute to the oncogenic phenotype either by (1) stimulating overproduction of growth factors by cancer cells; (2) overexpression and/or amplification of the RTK itself, enabling hypersensitivity to low ligand concentrations; (3) acquiring mutations in their ligand-binding or kinase domains; (4) fusion of kinase domains with motifs of other, unrelated proteins; or (5) chromosomal translocation, giving rise to a chimeric product with enhanced kinase activity.	('cancer', 'Disease', (159, 165))	('kinase activity', 'MPA', (508, 523))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutations', 'Var', (302, 311))	('hypersensitivity', 'Disease', (241, 257))	('chimeric product', 'MPA', (477, 493))	('cancer', 'Disease', (12, 18))	('hypersensitivity', 'Disease', 'MESH:D004342', (241, 257))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('enhanced', 'PosReg', (499, 507))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('fusion', 'Var', (359, 365))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('chromosomal translocation', 'CPA', (433, 458))
85481	33673213	As shown in Figure 4B, we used the Open Targets Platform to highlight disease association scores for RTKs in GBM as well as catalog RTKs that are frequently altered (either in expression, mutation, or copy number changes) in the various subtypes of GBM (Figure 4).	('as c', 'Gene', (121, 125))	('RTKs', 'Var', (101, 105))	('as c', 'Gene', '29108', (121, 125))	('GBM', 'Disease', (109, 112))	('altered', 'Reg', (157, 164))	('disease association', 'Reg', (70, 89))
85485	33673213	Dysregulation, particularly that of EGFR, is known to be associated with a variety of human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('Dysregulation', 'Var', (0, 13))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('EGFR', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('associated', 'Reg', (57, 67))
85491	33673213	Interestingly, protein expression data from Reverse Phase Protein Array (RPPA) shows that EGFR and its phosphorylated variants (pY992, pY1068, and pY1173) are significantly enriched in the CL subtype (Figure 4).	('enriched', 'Reg', (173, 181))	('pY1068', 'Var', (135, 141))	('pY992', 'Chemical', '-', (128, 133))	('pY1173', 'Chemical', '-', (147, 153))	('pY1173', 'Var', (147, 153))	('pY1068', 'Chemical', '-', (135, 141))	('EGFR', 'Gene', (90, 94))	('pY992', 'Var', (128, 133))	('CL subtype', 'Disease', (189, 199))
85496	33673213	In the TCGA-GBM dataset, while ERBB2-4 are not mutated in any of the four subtypes, there was notable copy number loss for ERBB2 in ME samples (23.4%) and ERBB3 in NE and PN samples (12.5% and 20.0%, respectively), suggesting that these receptors may play a more secondary role in GBM compared to EGFR.	('ERBB2-4', 'Gene', (31, 38))	('ERBB2-4', 'Gene', '2064;2065;2066', (31, 38))	('loss', 'NegReg', (114, 118))	('ERBB3', 'Gene', '2065', (155, 160))	('copy number', 'Var', (102, 113))	('ERBB2', 'Gene', '2064', (123, 128))	('PN', 'Gene', '79650', (171, 173))	('ME', 'Chemical', '-', (132, 134))	('ERBB3', 'Gene', (155, 160))	('ERBB2', 'Gene', (123, 128))	('ERBB2', 'Gene', '2064', (31, 36))	('ERBB2', 'Gene', (31, 36))
85497	33673213	RPPA data shows significant enrichment for ErbB2 in the NE subtype, and for its phosphorylated variant pY1248 in the CL subtype, in contrast to phosphorylated ErbB3 protein (pY1298), which is significantly enriched in the PN subtype (data not shown).	('ErbB2', 'Gene', (43, 48))	('pY1248', 'Chemical', '-', (103, 109))	('PN', 'Gene', '79650', (222, 224))	('ErbB2', 'Gene', '2064', (43, 48))	('ErbB3', 'Gene', (159, 164))	('pY1248', 'Var', (103, 109))	('ErbB3', 'Gene', '2065', (159, 164))
85499	33673213	INSR, through its two developmentally regulated isoforms, the fetal variant INSR-A and the adult variant INSR-B, regulates key processes such as glucose metabolism and glycogen synthesis, while IGF1R regulates cell proliferation and differentiation in the developing brain, where it is highly expressed.	('IGF1R', 'Gene', (194, 199))	('INSR', 'Gene', '3643', (0, 4))	('key processes', 'MPA', (123, 136))	('glycogen', 'Chemical', 'MESH:D006003', (168, 176))	('regulates', 'Reg', (113, 122))	('IGF1R', 'Gene', '3480', (194, 199))	('INSR', 'Gene', (0, 4))	('glucose metabolism', 'Disease', 'MESH:D044882', (145, 163))	('cell proliferation', 'CPA', (210, 228))	('INSR', 'Gene', '3643', (76, 80))	('variant', 'Var', (68, 75))	('INSR', 'Gene', '3643', (105, 109))	('glycogen synthesis', 'MPA', (168, 186))	('glucose metabolism', 'Disease', (145, 163))	('regulates', 'Reg', (200, 209))	('INSR', 'Gene', (76, 80))	('INSR', 'Gene', (105, 109))	('differentiation', 'CPA', (233, 248))
85502	33673213	Moreover, high IGF1R expression is associated with chemoresistance to TMZ as well as reduced survival, suggesting that the receptor may be used as a biomarker.	('TMZ', 'Chemical', 'MESH:D000077204', (70, 73))	('IGF1R', 'Gene', (15, 20))	('high IGF1R', 'Phenotype', 'HP:0030269', (10, 20))	('IGF1R', 'Gene', '3480', (15, 20))	('chemoresistance to', 'CPA', (51, 69))	('expression', 'MPA', (21, 31))	('survival', 'CPA', (93, 101))	('high', 'Var', (10, 14))	('reduced', 'NegReg', (85, 92))
85503	33673213	Apart from IGF1R overexpression, IGF1R mutations are rarely observed in GBMs, and in the TCGA-GBM dataset that we analyzed, IGF1R is only minimally mutated in the CL subtype (2.5%) but a significant portion of samples show deletion of the gene in the PN subtype (40%).	('IGF1R', 'Gene', '3480', (11, 16))	('IGF1R', 'Gene', (33, 38))	('IGF1R', 'Gene', '3480', (124, 129))	('IGF1R', 'Gene', '3480', (33, 38))	('IGF1R', 'Gene', (11, 16))	('PN', 'Gene', '79650', (251, 253))	('deletion', 'Var', (223, 231))	('IGF1R', 'Gene', (124, 129))
85517	33673213	In the TCGA-GBM dataset, KIT is mutated in ME (4.3%) and is amplified (32%) and mutated (4%) with significantly elevated mRNA as well as protein expression in the PN subtype.	('protein expression', 'MPA', (137, 155))	('mRNA', 'MPA', (121, 125))	('elevated', 'PosReg', (112, 120))	('mutated', 'Var', (80, 87))	('KIT', 'Gene', '3815', (25, 28))	('ME', 'Chemical', '-', (43, 45))	('KIT', 'Gene', (25, 28))	('PN', 'Gene', '79650', (163, 165))
85522	33673213	GBMs express high levels of VEGF and its receptors, and the increased angiogenesis and dysfunctional vasculature in these tumors is attributed mostly to aberrant VEGFR2 signaling, which regulates survival, proliferation, migration, and vessel permeability.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('survival', 'CPA', (196, 204))	('migration', 'CPA', (221, 230))	('dysfunctional vasculature', 'Disease', (87, 112))	('VEGFR2', 'Gene', '3791', (162, 168))	('increased', 'PosReg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('dysfunctional vasculature', 'Disease', 'MESH:C565633', (87, 112))	('regulates', 'Reg', (186, 195))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('aberrant', 'Var', (153, 161))	('angiogenesis', 'CPA', (70, 82))	('VEGFR2', 'Gene', (162, 168))
85523	33673213	Furthermore, the hypoxic environment of GBM triggers the "angiogenic switch", wherein the production of HIF-1alpha induces transcription of VEGF itself.	('production', 'Var', (90, 100))	('transcription', 'MPA', (123, 136))	('triggers', 'Reg', (44, 52))	('HIF-1alpha', 'Gene', (104, 114))	('induces', 'PosReg', (115, 122))	('VEGF itself', 'Gene', (140, 151))	('HIF-1alpha', 'Gene', '3091', (104, 114))
85528	33673213	Some FGFR aberrations commonly found in GBM are FGFR1 (and FGFR3) translocations that create fusion genes with transforming acidic coiled-coil genes (FGFR-TACC), leading to constitutive receptor activation and aberrant nuclear localization/aneuploidy.	('FGFR3', 'Gene', '2261', (59, 64))	('translocations', 'Var', (66, 80))	('aneuploidy', 'Disease', (240, 250))	('FGFR-TACC', 'Gene', (150, 159))	('FGFR3', 'Gene', (59, 64))	('FGFR1', 'Gene', (48, 53))	('aneuploidy', 'Disease', 'MESH:D000782', (240, 250))	('activation', 'PosReg', (195, 205))	('fusion', 'Var', (93, 99))	('constitutive', 'Protein', (173, 185))
85538	33673213	Intriguingly, there is a strong link between Trk receptor fusions and gliomagenesis in vivo, particularly in pediatric high-grade gliomas, where Trk receptor fusions are reported in diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem tumors.	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('gliomas', 'Disease', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('reported', 'Reg', (170, 178))	('Trk', 'Gene', (145, 148))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('fusions', 'Var', (58, 65))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('Trk', 'Gene', '4914', (45, 48))	('gliomagenesis', 'Disease', 'None', (70, 83))	('gliomas', 'Disease', (208, 215))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('gliomagenesis', 'Disease', (70, 83))	('tumors', 'Disease', (242, 248))	('Trk', 'Gene', '4914', (145, 148))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('Trk', 'Gene', (45, 48))	('fusions', 'Var', (158, 165))	('tumors', 'Disease', 'MESH:D009369', (242, 248))
85540	33673213	NTRK2 has comparable levels of copy number amplification and loss across all subtypes, whereas NTRK3 has notable copy number loss (40%) in PN.	('NTRK3', 'Gene', (95, 100))	('NTRK2', 'Gene', '4915', (0, 5))	('loss', 'NegReg', (125, 129))	('as c', 'Gene', (7, 11))	('PN', 'Gene', '79650', (139, 141))	('copy number', 'MPA', (113, 124))	('NTRK2', 'Gene', (0, 5))	('as c', 'Gene', '29108', (7, 11))	('copy number', 'Var', (31, 42))	('NTRK3', 'Gene', '4916', (95, 100))	('loss', 'NegReg', (61, 65))
85546	33673213	Dysregulation of MET is associated with increased invasion and poor prognosis, making it an excellent prognostic indicator.	('MET', 'Gene', '79811', (17, 20))	('invasion', 'CPA', (50, 58))	('MET', 'Gene', (17, 20))	('Dysregulation', 'Var', (0, 13))	('increased', 'PosReg', (40, 49))
85561	33673213	In the TCGA-GBM dataset, Tie2 alterations primarily manifest as copy number losses in the NE, CL, and ME subtypes, the gene is upregulated (but not significantly) in CL and mutated in ME (4.3%), and it is deleted in all subtypes, including the G-CIMP subset.	('as c', 'Gene', '29108', (61, 65))	('G-CIMP', 'Chemical', '-', (244, 250))	('upregulated', 'PosReg', (127, 138))	('ME', 'Chemical', '-', (184, 186))	('alterations', 'Var', (30, 41))	('as c', 'Gene', (61, 65))	('losses', 'NegReg', (76, 82))	('ME', 'Chemical', '-', (102, 104))	('Tie2', 'Gene', (25, 29))
85567	33673213	Only one case of DDR2-mutated GBM has been reported thus far and the authors speculate that the mutation contributes to invasion by enhancing tumor cell-ECM interactions.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('DDR2', 'Gene', '4921', (17, 21))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('mutation', 'Var', (96, 104))	('invasion', 'CPA', (120, 128))	('DDR2', 'Gene', (17, 21))	('enhancing', 'PosReg', (132, 141))
85570	33673213	Dysregulation of RET contributes to several forms of cancer, including gliomas, where it has been shown to be highly expressed.	('cancer', 'Disease', (53, 59))	('gliomas', 'Disease', (71, 78))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('contributes', 'Reg', (21, 32))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('RET', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('RET', 'Gene', '5979', (17, 20))
85572	33673213	However, RET is significantly elevated in the CL subtype, and a significant portion of samples (upwards of 80%) of all subtypes show copy number loss and 57.1% of G-CIMP samples show deletion of the gene.	('G-CIMP', 'Chemical', '-', (163, 169))	('loss', 'NegReg', (145, 149))	('RET', 'Gene', (9, 12))	('RET', 'Gene', '5979', (9, 12))	('elevated', 'PosReg', (30, 38))	('copy', 'MPA', (133, 137))	('deletion', 'Var', (183, 191))
85575	33673213	However, it is highly expressed in some GBM cell lines as well as in surgical GBM samples, where its expression parallels increasing tumor grade and is associated with hypomethylation of a CpG island in the promoter region.	('hypomethylation', 'Var', (168, 183))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('associated with', 'Reg', (152, 167))	('expression', 'MPA', (101, 111))
85584	33673213	However, in GBM, the pathway is constitutively active due to PTEN alterations, mutations within the gene encoding the p110 catalytic subunit of PI3K (PIK3CA), or Akt amplification.	('PIK3CA', 'Gene', (150, 156))	('Akt', 'Gene', (162, 165))	('PIK3CA', 'Gene', '5290', (150, 156))	('Akt', 'Gene', '207', (162, 165))	('PTEN', 'Gene', (61, 65))	('PTEN', 'Gene', '5728', (61, 65))	('mutations', 'Var', (79, 88))	('alterations', 'Reg', (66, 77))
85589	33673213	Inhibitors such as Y15, which functions to inhibit FAK autophosphorylation at Y397, have been shown to successfully reduce GBM cell growth, especially in combination with TMZ.	('reduce', 'NegReg', (116, 122))	('inhibit', 'NegReg', (43, 50))	('Y397', 'Var', (78, 82))	('GBM cell growth', 'CPA', (123, 138))	('FAK', 'Gene', '5747', (51, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (171, 174))	('FAK', 'Gene', (51, 54))
85596	33673213	As presented above, dysregulation of RTK-dependent Ras/MAPK, PI3K/Akt/PTEN, and FAK/Src signaling pathways promotes GBM malignancy.	('Akt', 'Gene', (66, 69))	('Src', 'Gene', (84, 87))	('FAK', 'Gene', (80, 83))	('malignancy', 'Disease', (120, 130))	('FAK', 'Gene', '5747', (80, 83))	('Src', 'Gene', '6714', (84, 87))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('dysregulation', 'Var', (20, 33))	('Akt', 'Gene', '207', (66, 69))	('promotes', 'PosReg', (107, 115))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('GBM', 'Disease', (116, 119))
85600	33673213	A seminal study 25 years ago made the discovery that application of the GPCR agonists endothelin-1, lysophosphatidic acid, or thrombin to cultured Rat-1 fibroblast cells results in EGFR activation and downstream phosphorylation of MAPK.	('Rat-1', 'CellLine', 'CVCL:0492', (147, 152))	('activation', 'PosReg', (186, 196))	('thrombin', 'Gene', '29251', (126, 134))	('phosphorylation', 'MPA', (212, 227))	('endothelin-1', 'Gene', '24323', (86, 98))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (100, 121))	('thrombin', 'Gene', (126, 134))	('endothelin-1', 'Gene', (86, 98))	('lysophosphatidic acid', 'Var', (100, 121))	('MAPK', 'Protein', (231, 235))	('EGFR', 'Protein', (181, 185))
85605	33673213	Other examples include enhanced chemotaxis and proliferation of human U87 GBM cells resulting from EGFR signaling mediated by formylpeptide receptor (FPR) activation, and increased migration due to GPCR CXC chemokine receptor 4 (CXCR4) activation of PDGFRbeta in human GL15 GBM cells.	('CXCR4', 'Gene', (229, 234))	('FPR', 'Gene', (150, 153))	('PDGFRbeta', 'Gene', (250, 259))	('human', 'Species', '9606', (263, 268))	('GPCR', 'Var', (198, 202))	('migration', 'CPA', (181, 190))	('proliferation', 'CPA', (47, 60))	('increased', 'PosReg', (171, 180))	('PDGFRbeta', 'Gene', '5159', (250, 259))	('chemotaxis', 'CPA', (32, 42))	('enhanced', 'PosReg', (23, 31))	('human', 'Species', '9606', (64, 69))	('formylpeptide receptor', 'Gene', '2357', (126, 148))	('EGFR signaling', 'MPA', (99, 113))	('U87', 'CellLine', 'CVCL:0022', (70, 73))	('formylpeptide receptor', 'Gene', (126, 148))	('FPR', 'Gene', '2357', (150, 153))	('activation', 'PosReg', (236, 246))	('CXCR4', 'Gene', '7852', (229, 234))
85610	33673213	For example, inhibition of IP3Rs with caffeine not only impairs the migration and invasion of GBM cells but also promotes the survival of xenografted mice.	('promotes', 'PosReg', (113, 121))	('mice', 'Species', '10090', (150, 154))	('caffeine', 'Chemical', 'MESH:D002110', (38, 46))	('survival', 'CPA', (126, 134))	('inhibition', 'Var', (13, 23))	('IP3R', 'Gene', '3710', (27, 31))	('IP3R', 'Gene', (27, 31))	('impairs', 'NegReg', (56, 63))
85619	33673213	Efforts to date have helped to uncover several connections between dysregulation of SOCE and different types of cancer.	('dysregulation', 'Var', (67, 80))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SOCE', 'Gene', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
85621	33673213	Furthermore, pharmacological inhibition of SOCE with the small molecule SKF96365 or ORAI1 downregulation by RNA interference were both linked to decreased migration and invasion in GBM cells.	('ORAI1', 'Gene', '84876', (84, 89))	('ORAI1', 'Gene', (84, 89))	('decreased', 'NegReg', (145, 154))	('SKF96365', 'Var', (72, 80))	('SKF96365', 'Chemical', 'MESH:C063159', (72, 80))	('downregulation', 'NegReg', (90, 104))	('RNA interference', 'MPA', (108, 124))
85623	33673213	While SOCE interplay with RTK activity has not been examined in GBM, work performed with a variety of other cancer cell lines offered the tantalizing result that disruption of EGFR/ErbB2 signaling produces an important decrease in SOCE signal amplitude:a finding suggesting that the anticancer effects of RTK inhibitors may be mediated by inhibition of SOCE.	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('ErbB2', 'Gene', (181, 186))	('decrease', 'NegReg', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('SOCE signal amplitude', 'MPA', (231, 252))	('disruption', 'Var', (162, 172))	('ErbB2', 'Gene', '2064', (181, 186))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
85626	33673213	Increased EGFR amplification and/or expression as well as structural mutations within the gene correlate with poor clinical outcome and chemoresistance in GBM patients.	('GBM', 'Disease', (155, 158))	('expression', 'MPA', (36, 46))	('EGFR', 'Gene', (10, 14))	('chemoresistance', 'CPA', (136, 151))	('Increased', 'PosReg', (0, 9))	('structural mutations', 'Var', (58, 78))	('patients', 'Species', '9606', (159, 167))	('amplification', 'MPA', (15, 28))
85631	33673213	However, combination therapy consisting of Afatinib plus TMZ showed a significant reduction in the proliferation and invasion potencies in U87 and U251 cells as well as GSCs isolated from U87 and U87-EGFRvIII cells in addition to reduced tumor burden in preclinical mouse models.	('reduced', 'NegReg', (230, 237))	('invasion potencies', 'CPA', (117, 135))	('Afatinib', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('TMZ', 'Var', (57, 60))	('U87', 'CellLine', 'CVCL:0022', (196, 199))	('reduction', 'NegReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Afatinib', 'Chemical', 'MESH:D000077716', (43, 51))	('tumor', 'Disease', (238, 243))	('TMZ', 'Chemical', 'MESH:D000077204', (57, 60))	('mouse', 'Species', '10090', (266, 271))	('U87', 'CellLine', 'CVCL:0022', (139, 142))	('proliferation', 'CPA', (99, 112))	('U251', 'CellLine', 'CVCL:0021', (147, 151))	('U87', 'CellLine', 'CVCL:0022', (188, 191))
85635	33673213	Initially developed for anti-IGF1R therapy, inhibitors such as BMS-754807 and KW-2450 showed promising activity but they often cross-react with INSR and are thus described as dual IGF1R/INSR inhibitors.	('INSR', 'Gene', '3643', (144, 148))	('IGF1R', 'Gene', '3480', (180, 185))	('IGF1R', 'Gene', (29, 34))	('IGF1R', 'Gene', '3480', (29, 34))	('BMS-754807', 'Var', (63, 73))	('cross-react', 'Reg', (127, 138))	('INSR', 'Gene', (144, 148))	('INSR', 'Gene', '3643', (186, 190))	('IGF1R', 'Gene', (180, 185))	('KW-2450', 'Var', (78, 85))	('INSR', 'Gene', (186, 190))
85641	33673213	Despite these disappointments, other work suggests that Imatinib can increase the radiosensitivity of human glioblastoma cells in vitro and can delay tumor growth in vivo, providing support for combination treatment with fractionated radiotherapy.	('increase', 'PosReg', (69, 77))	('delay tumor', 'Disease', (144, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('glioblastoma', 'Disease', (108, 120))	('delay tumor', 'Disease', 'MESH:D009369', (144, 155))	('Imatinib', 'Var', (56, 64))	('Imatinib', 'Chemical', 'MESH:D000068877', (56, 64))	('radiosensitivity', 'MPA', (82, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('human', 'Species', '9606', (102, 107))
85649	33673213	Numerous studies have now been conducted to investigate the efficacies of small-molecular TKIs which target the VEGFR family.	('small-molecular', 'Var', (74, 89))	('VEGFR', 'Gene', '3791', (112, 117))	('VEGFR', 'Gene', (112, 117))
85655	33673213	Among FGFR1-3 inhibitors are Infigratinib (BGJ398), AZD4547, and Dovitinib, which have been investigated for their efficacies in other cancer types.	('FGFR1-3', 'Gene', '2260;2263;2261', (6, 13))	('cancer', 'Disease', (135, 141))	('AZD4547', 'Var', (52, 59))	('Dovitinib', 'Chemical', 'MESH:C500007', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('AZD4547', 'Chemical', 'MESH:C572463', (52, 59))	('BGJ398', 'Chemical', 'MESH:C568950', (43, 49))	('FGFR1-3', 'Gene', (6, 13))	('BGJ398', 'Gene', (43, 49))	('Infigratinib', 'Chemical', 'MESH:C568950', (29, 41))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
85657	33673213	BLU9931 is an FGFR4-specific inhibitor.	('FGFR4', 'Gene', (14, 19))	('FGFR4', 'Gene', '2264', (14, 19))	('BLU9931', 'Var', (0, 7))
85659	33673213	A multicenter Phase II study investigating Infigratinib in FGFR-altered recurrent GBM patients revealed that Infigratinib was able to elicit a partial response or stable disease in a third of the cohort, with reversible and manageable adverse effects.	('elicit', 'Reg', (134, 140))	('recurrent GBM', 'Disease', (72, 85))	('stable disease', 'MPA', (163, 177))	('Infigratinib', 'Chemical', 'MESH:C568950', (109, 121))	('Infigratinib', 'Var', (109, 121))	('Infigratinib', 'Chemical', 'MESH:C568950', (43, 55))	('partial', 'CPA', (143, 150))	('patients', 'Species', '9606', (86, 94))
85660	33673213	Beyond the importance of TrkB in normal neurobiology, recent studies have reported connections between aberrant BDNF/TrkB activity and various aspects of GBM.	('BDNF', 'Gene', '627', (112, 116))	('TrkB', 'Gene', (117, 121))	('aberrant', 'Var', (103, 111))	('BDNF', 'Gene', (112, 116))	('TrkB', 'Gene', '4915', (25, 29))	('activity', 'MPA', (122, 130))	('connections', 'Interaction', (83, 94))	('GBM', 'Disease', (154, 157))	('TrkB', 'Gene', '4915', (117, 121))	('TrkB', 'Gene', (25, 29))
85670	33673213	The encouraging results obtained with these two TKIs support the ongoing development of second-generation NTRK inhibitors (e.g., LOXO-195-BAY2731954, Repotrectinib-TPX-0005) with lower tendencies to elicit tumor resistance.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('LOXO-195-BAY2731954', 'Var', (129, 148))	('Repotrectinib', 'Chemical', '-', (150, 163))	('tumor', 'Disease', (206, 211))	('elicit', 'Reg', (199, 205))	('TPX', 'Gene', (164, 167))	('inhibitors', 'NegReg', (111, 121))	('TRK', 'Gene', (107, 110))	('TRK', 'Gene', '4914', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('TPX', 'Gene', '7173', (164, 167))
85671	33673213	Because Ang-2 is overexpressed in GBM and also functions as a chemoattractant for TEMs that drive tumor vessel formation and metastasis, targeting the Ang-2/Tie2 signaling pathway has been shown to inhibit tumor growth and invasion in GBM.	('TEMs', 'Disease', 'None', (82, 86))	('TEMs', 'Disease', (82, 86))	('targeting', 'Var', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('inhibit', 'NegReg', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Ang-2', 'Gene', '285', (151, 156))	('Ang-2', 'Gene', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('invasion', 'CPA', (223, 231))	('Ang-2', 'Gene', '285', (8, 13))	('tumor', 'Disease', (98, 103))	('Ang-2', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
85673	33673213	Selective Tie2 inhibitors such as Rebastinib have also been demonstrated to inhibit the growth, invasion, and metastasis of breast cancer cells by an "allosteric switch control" mechanism.	('metastasis of breast cancer', 'Disease', (110, 137))	('inhibit', 'NegReg', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Rebastinib', 'Chemical', 'MESH:C000627803', (34, 44))	('growth', 'CPA', (88, 94))	('invasion', 'CPA', (96, 104))	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (110, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('inhibitors', 'Var', (15, 25))	('Tie2', 'Gene', (10, 14))
85702	28458946	Recent years showed that co-deletion of 1p19q makes oligodendroglioma more responsive to chemotherapy; thus, as a routine, such gliomas are now treated by surgery and chemotherapy.	('co-deletion', 'Var', (25, 36))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('oligodendroglioma', 'Disease', (52, 69))	('oligodendroglioma', 'Disease', 'MESH:D009837', (52, 69))	('1p19q', 'Gene', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('more', 'PosReg', (70, 74))	('responsive to chemotherapy', 'MPA', (75, 101))
85772	26050588	By utilizing these techniques either alone or in combination, patients harboring low-grade gliomas have a better prognosis with less surgical morbidity following tumor resection.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('gliomas', 'Disease', (91, 98))	('tumor', 'Disease', (162, 167))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('patients', 'Species', '9606', (62, 70))	('low-grade', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
85779	26050588	The evidence prior to 1990 is ambivalent; although, many studies demonstrated a trend toward greater overall survival in patients who received gross total resection, these trends did not reach statistical significance.	('gross total resection', 'Var', (143, 164))	('greater', 'PosReg', (93, 100))	('patients', 'Species', '9606', (121, 129))	('overall survival', 'MPA', (101, 117))
85826	26050588	Complete resection of contrast-enhancing tumor was achieved in 90% of patients receiving 5-ALA compared to 36% of patients in the white-light group.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('patients', 'Species', '9606', (70, 78))	('5-ALA', 'Chemical', 'MESH:C000614854', (89, 94))	('tumor', 'Disease', (41, 46))	('5-ALA', 'Var', (89, 94))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
85827	26050588	The 5-ALA group had a statistically significant greater 6-month progression-free survival (41%) compared to the white-light group (21%).	('progression-free survival', 'CPA', (64, 89))	('greater', 'PosReg', (48, 55))	('5-ALA', 'Var', (4, 9))	('5-ALA', 'Chemical', 'MESH:C000614854', (4, 9))
85871	26050588	The study demonstrated a significant decrease in post-operative motor deterioration in patients using DTI-based functional neuronavigation (9.8%) compared to standard neuronavigation (18.6%) in patients with LGG.	('decrease', 'NegReg', (37, 45))	('patients', 'Species', '9606', (194, 202))	('DTI-based', 'Var', (102, 111))	('motor deterioration', 'Phenotype', 'HP:0002333', (64, 83))	('patients', 'Species', '9606', (87, 95))
85916	33858847	PD-L1 expression can also be attenuated by the loss of CDK5, a key enzyme associated with interferon gamma (IFN-gamma) and PD-L1 upregulation.	('CDK5', 'Gene', '1020', (55, 59))	('expression', 'MPA', (6, 16))	('PD-L1', 'Gene', (0, 5))	('attenuated', 'NegReg', (29, 39))	('loss', 'Var', (47, 51))	('CDK5', 'Gene', (55, 59))	('interferon gamma (IFN-gamma', 'Gene', '3458', (90, 117))
85940	33858847	Stable TLX knockdown by RNA interference and CRISPR/Cas9 knockout in human and mouse glioma cells were generated as described previously.	('mouse', 'Species', '10090', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('TLX', 'Gene', (7, 10))	('CRISPR', 'Gene', (45, 51))	('human', 'Species', '9606', (69, 74))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('TLX', 'Gene', '4179', (7, 10))	('glioma', 'Disease', (85, 91))	('CRISPR', 'Gene', '70873', (45, 51))	('RNA interference', 'MPA', (24, 40))	('knockdown', 'Var', (11, 20))
85947	33858847	Tumor cells were gated as CD45- populations; for lymphocytes, CD45+ cells were first gated by CD3+ and subsequently gated for CD4+, CD8+ and PD-1+ cells; for myeloid-associated cells, mouse macrophages were first gated by F4/80, M1 macrophages were then gated by F4/80+CD86+ and M2 macrophages by F4/80+CD206+ or F4/80+CD163+; PD-L1+ and PD-1+ cells were further characterized under the CD206+ population.	('CD4', 'Gene', '404704', (26, 29))	('CD4', 'Gene', (126, 129))	('CD4', 'Gene', (62, 65))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('F4/80+CD206+', 'Var', (297, 309))	('CD4', 'Gene', '404704', (62, 65))	('CD4', 'Gene', '404704', (126, 129))	('mouse', 'Species', '10090', (184, 189))	('CD8', 'Gene', (269, 272))	('CD4', 'Gene', (26, 29))	('CD8', 'Gene', '925', (269, 272))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))
85962	33858847	Moreover, comparison of the ssGSEA scores for TLX_high versus TLX_low, and PD-L1_high versus PD-L1_low populations revealed higher immune cell infiltration levels and more immune-related pathways in TLX_high and PD-L1_high clusters (online supplemental figure S1E, F).	('TLX', 'Gene', (62, 65))	('TLX', 'Gene', (199, 202))	('immune-related pathways', 'Pathway', (172, 195))	('more', 'PosReg', (167, 171))	('immune cell infiltration levels', 'MPA', (131, 162))	('PD-L1_high', 'Var', (212, 222))	('TLX', 'Gene', (46, 49))	('TLX', 'Gene', '4179', (62, 65))	('TLX', 'Gene', '4179', (199, 202))	('higher', 'PosReg', (124, 130))	('TLX', 'Gene', '4179', (46, 49))
85963	33858847	Based on these results, we speculated that high expression of TLX and PD-L1 was positively associated with macrophage-related suppressive immune microenvironment and poor prognosis of gliomas.	('TLX', 'Gene', (62, 65))	('high', 'Var', (43, 47))	('gliomas', 'Disease', 'MESH:D005910', (184, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('gliomas', 'Disease', (184, 191))	('expression', 'MPA', (48, 58))	('TLX', 'Gene', '4179', (62, 65))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('PD-L1', 'Gene', (70, 75))	('associated', 'Reg', (91, 101))
85965	33858847	Bioinformatics analysis of RNA-seq data showed that low TLX expression indicated lower WHO grades, IDH mutant and 1p19q deletion status.	('expression', 'MPA', (60, 70))	('IDH', 'Gene', '3417', (99, 102))	('lower', 'NegReg', (81, 86))	('TLX', 'Gene', (56, 59))	('1p19q deletion status', 'Var', (114, 135))	('IDH', 'Gene', (99, 102))	('low', 'NegReg', (52, 55))	('WHO grades', 'CPA', (87, 97))	('TLX', 'Gene', '4179', (56, 59))
85966	33858847	In contrast, high TLX expression was associated with an unfavorable prognosis, higher WHO grades, a wild-type IDH and 1p19q with no obvious correlation with MGMT methylation status (figure 2A and online supplemental figure S2D).	('IDH', 'Gene', (110, 113))	('high', 'Var', (13, 17))	('TLX', 'Gene', (18, 21))	('IDH', 'Gene', '3417', (110, 113))	('TLX', 'Gene', '4179', (18, 21))	('WHO grades', 'CPA', (86, 96))
85973	33858847	Moreover, CD163+ cells were significantly enriched in high-grade gliomas compared with low-grade gliomas (p=0.0187) and normal tissues (p=0.0204; Figure 2D, E).	('gliomas', 'Disease', (65, 72))	('CD163+ cells', 'Var', (10, 22))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
85990	33858847	Results showed that TLX silencing can significantly reduce in vivo subcutaneous and brain orthotopic tumor growth in mice (figure 4B, C, and online supplemental figure S4B).	('TLX', 'Gene', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TLX', 'Gene', '4179', (20, 23))	('mice', 'Species', '10090', (117, 121))	('reduce', 'NegReg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('silencing', 'Var', (24, 33))
85992	33858847	ATRAL treatment markedly inhibited CT2A tumor growth, with no significant effect on body weight (online supplemental figure S5B-E. Cumulatively, these findings showed that repression of TLX could significantly inhibit glioma growth.	('repression', 'Var', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('glioma', 'Disease', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('ATRAL', 'Chemical', 'MESH:C009154', (0, 5))	('tumor', 'Disease', (40, 45))	('TLX', 'Gene', (186, 189))	('S5B', 'Gene', '5711', (124, 127))	('CT2A', 'Mutation', 'rs1478570799', (35, 39))	('inhibited', 'NegReg', (25, 34))	('S5B', 'Gene', (124, 127))	('inhibit', 'NegReg', (210, 217))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('TLX', 'Gene', '4179', (186, 189))
85996	33858847	Moreover, PD-1 expression was detected in both CD8+ T cells (CD3+CD8+PD-1+) and M2 TAMs (CDF4/80+CD206+PD-1+), although no difference in expression was observed in TAMs (figure 4E).	('CDF4/80+CD206+PD-1+', 'Var', (89, 108))	('CD8', 'Gene', (47, 50))	('TAMs', 'Chemical', '-', (83, 87))	('TAMs', 'Chemical', '-', (164, 168))	('PD-1', 'Gene', (10, 14))	('CD8', 'Gene', '925', (47, 50))	('CD8', 'Gene', (65, 68))	('CD8', 'Gene', '925', (65, 68))
85998	33858847	To further illustrate the functional role of TLX in PD-L1 regulation in gliomas, we silenced TLX by shRNA in human glioma A1235 cells.	('glioma', 'Disease', (72, 78))	('human', 'Species', '9606', (109, 114))	('glioma', 'Disease', (115, 121))	('TLX', 'Gene', (45, 48))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('TLX', 'Gene', '4179', (93, 96))	('TLX', 'Gene', (93, 96))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('TLX', 'Gene', '4179', (45, 48))	('silenced', 'Var', (84, 92))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
86009	33858847	Results showed that the transfected TLX significantly boosted the activity of the P3-Luc reporter, but not the P1-Luc or P2-Luc reporters (figure 6A).	('TLX', 'Gene', '4179', (36, 39))	('transfected', 'Var', (24, 35))	('activity', 'MPA', (66, 74))	('TLX', 'Gene', (36, 39))	('P3-Luc', 'Protein', (82, 88))	('boosted', 'PosReg', (54, 61))
86010	33858847	Furthermore, only ectopic intact TLX, not its zine finger (ZF1) truncated mutants, increased the PD-L1-Luc reporter activity dose-dependently in transfected HEK293 cells, indicating that TLX-mediated activation of the CD274 promoter requires both an intact DNA-binding element and ligand-binding domain of TLX (figure 6B).	('increased', 'PosReg', (83, 92))	('TLX', 'Gene', '4179', (33, 36))	('CD274', 'Gene', (218, 223))	('TLX', 'Gene', (306, 309))	('TLX', 'Gene', (187, 190))	('HEK293', 'CellLine', 'CVCL:0045', (157, 163))	('TLX', 'Gene', '4179', (306, 309))	('TLX', 'Gene', (33, 36))	('PD-L1-Luc reporter activity', 'MPA', (97, 124))	('mutants', 'Var', (74, 81))	('TLX', 'Gene', '4179', (187, 190))	('CD274', 'Gene', '29126', (218, 223))	('activation', 'PosReg', (200, 210))
86030	33858847	In the present study, we also observed that TLX and PD-L1 expression correlated with IDH mutation and 1p19q deletion status.	('IDH', 'Gene', '3417', (85, 88))	('correlated', 'Reg', (69, 79))	('TLX', 'Gene', '4179', (44, 47))	('expression', 'MPA', (58, 68))	('1p19q deletion status', 'Var', (102, 123))	('TLX', 'Gene', (44, 47))	('IDH', 'Gene', (85, 88))	('PD-L1', 'Gene', (52, 57))
86031	33858847	That is, low TLX and PD-L1 expression correlated with lower WHO grades, mutated IDH, and 1p19q deletion, whereas high TLX and PD-L1 expression was associated with unfavorable prognosis, higher WHO grades, wild-type IDH, and 1p19q status as per TCGA and CGGA databases.	('TLX', 'Gene', '4179', (13, 16))	('IDH', 'Gene', (80, 83))	('expression', 'MPA', (27, 37))	('TLX', 'Gene', (118, 121))	('IDH', 'Gene', (215, 218))	('lower', 'NegReg', (54, 59))	('PD-L1', 'Gene', (21, 26))	('TLX', 'Gene', '4179', (118, 121))	('IDH', 'Gene', '3417', (80, 83))	('mutated', 'Disease', (72, 79))	('IDH', 'Gene', '3417', (215, 218))	('1p19q deletion', 'Var', (89, 103))	('higher', 'PosReg', (186, 192))	('TLX', 'Gene', (13, 16))	('low', 'NegReg', (9, 12))
86032	33858847	However, whether IDH mutation or 1p19q status influences the effect that TLX-induced transcriptional regulation of PD-L1 has on the TME requires further investigation.	('IDH', 'Gene', '3417', (17, 20))	('TLX', 'Gene', (73, 76))	('1p19q', 'Var', (33, 38))	('influences', 'Reg', (46, 56))	('TLX', 'Gene', '4179', (73, 76))	('IDH', 'Gene', (17, 20))	('PD-L1', 'Gene', (115, 120))
86040	33858847	Our observation of significant PD-1 signaling in M2 macrophages is consistent with recent reports revealing that PD-1 ligation in macrophages subdues their phagocytic capacity, and promotes the differentiation of tolerogenic macrophages, which in turn suppresses T-cell activation and promotes tumor growth.	('ligation', 'Var', (118, 126))	('tumor', 'Disease', (294, 299))	('suppresses', 'NegReg', (252, 262))	('T-cell activation', 'CPA', (263, 280))	('promotes', 'PosReg', (181, 189))	('promotes', 'PosReg', (285, 293))	('differentiation', 'CPA', (194, 209))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('PD-1', 'Gene', (113, 117))
86048	30760578	IDH1-R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response Glioma patients whose tumors carry a mutation in Isocitrate Dehydrogenase 1 (IDH1R132H) are younger at diagnosis and live longer.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (21, 26))	('Isocitrate Dehydrogenase', 'Gene', (152, 176))	('mutation', 'Var', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('R132H', 'Mutation', 'rs121913500', (184, 189))	('IDH1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('DNA damage response', 'MPA', (83, 102))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('Glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Disease', (41, 47))	('IDH1', 'Gene', '3417', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('IDH1', 'Gene', (180, 184))	('Isocitrate Dehydrogenase', 'Gene', '3417', (152, 176))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('Glioma', 'Phenotype', 'HP:0009733', (103, 109))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('IDH1', 'Gene', '3417', (180, 184))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('tumor', 'Disease', (125, 130))	('Glioma', 'Disease', (103, 109))	('patients', 'Species', '9606', (110, 118))
86049	30760578	IDH1 mutations co-occur with other molecular lesions, such as 1p/19q co-deletion, inactivating mutations in the tumor suppressor protein 53 (TP53) gene, and loss of function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX).	('inactivating mutations', 'Var', (82, 104))	('loss of function', 'NegReg', (157, 173))	('alpha thalassemia/mental retardation syndrome X-linked gene', 'Gene', '546', (187, 246))	('mental retardation', 'Phenotype', 'HP:0001249', (205, 223))	('1p/19q co-deletion', 'Disease', (62, 80))	('IDH1', 'Gene', (0, 4))	('TP53', 'Gene', (141, 145))	('ATRX', 'Gene', (248, 252))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor suppressor protein 53', 'Gene', '7157', (112, 139))	('mutations', 'Var', (174, 183))	('tumor suppressor protein 53', 'Gene', (112, 139))
86050	30760578	All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1R132H mutation.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('ATRX', 'Gene', (45, 49))	('loss', 'NegReg', (50, 54))	('IDH1R132H', 'Var', (72, 81))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
86051	30760578	We modelled the molecular glioma subtype which harbors IDH1R132H, and TP53 and ATRX inactivating mutations.	('glioma subtype', 'Disease', 'MESH:D005910', (26, 40))	('ATRX', 'Gene', (79, 83))	('TP53', 'Gene', (70, 74))	('glioma subtype', 'Disease', (26, 40))	('IDH1R132H', 'Var', (55, 64))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
86053	30760578	We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 gene inactivation: (i) increases median survival (MS) in the absence of any treatment, (ii) enhances DNA damage response (DDR) via epigenetic upregulation of the Ataxia-telangiectasia mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance.	('epigenetic', 'Var', (211, 221))	('ATM', 'Gene', (273, 276))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('gene inactivation', 'Var', (80, 97))	('Ataxia-telangiectasia mutated', 'Gene', '472', (242, 271))	('IDH1R132H', 'Var', (19, 28))	('inactivation', 'Var', (85, 97))	('upregulation', 'PosReg', (222, 234))	('Ataxia-telangiectasia mutated', 'Gene', (242, 271))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('TP53', 'Gene', (75, 79))	('DDR', 'Chemical', '-', (202, 205))	('increases', 'PosReg', (103, 112))	('elicits', 'Reg', (307, 314))	('ATM', 'Gene', '472', (273, 276))	('Ataxia', 'Phenotype', 'HP:0001251', (242, 248))	('telangiectasia', 'Phenotype', 'HP:0001009', (249, 263))	('enhances', 'PosReg', (172, 180))	('DNA damage response', 'MPA', (181, 200))	('median survival', 'CPA', (113, 128))	('tumor', 'Disease', (315, 320))
86055	30760578	Translation of these findings to IDH1132H glioma patients harboring TP53 and ATRX loss, could significantly improve the therapeutic efficacy of radiotherapy, and consequently patient survival.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glioma', 'Disease', (42, 48))	('patient', 'Species', '9606', (175, 182))	('patient', 'Species', '9606', (49, 56))	('therapeutic efficacy', 'CPA', (120, 140))	('improve', 'PosReg', (108, 115))	('loss', 'NegReg', (82, 86))	('patients', 'Species', '9606', (49, 57))	('TP53', 'Gene', (68, 72))	('IDH1132H', 'Var', (33, 41))	('ATRX', 'Gene', (77, 81))
86056	30760578	Mutant IDH1 when co-expressed with inactivating TP53 and ATRX mutations in glioma, induces genomic stability and enhanced DNA repair, leading to resistance to genotoxic therapies.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('resistance', 'MPA', (145, 155))	('DNA repair', 'MPA', (122, 132))	('mutations', 'Var', (62, 71))	('induces', 'PosReg', (83, 90))	('TP53', 'Gene', (48, 52))	('glioma', 'Disease', (75, 81))	('IDH1', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('genomic stability', 'CPA', (91, 108))	('enhanced', 'PosReg', (113, 121))	('ATRX', 'Gene', (57, 61))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('inactivating', 'Var', (35, 47))
86057	30760578	Mutated isocitrate dehydrogenase 1 (IDH1R132H) is found in 80 % of LGG (WHO grade II/III), and in a subset of high grade gliomas (WHO grade IV).	('isocitrate dehydrogenase', 'Gene', (8, 32))	('isocitrate dehydrogenase', 'Gene', '3417', (8, 32))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('LGG', 'Disease', (67, 70))	('IDH1R132H', 'Gene', (36, 45))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('Mutated', 'Var', (0, 7))
86058	30760578	Two main molecular subtypes of glioma, which harbor IDH1R132H, have been identified expressing: i) IDH1R132H, 1p/19q co-deletion, and TERT promoter mutations; and ii) IDH1R132H, mutant TP53, and inactivation of ATRX.	('mutant', 'Var', (178, 184))	('inactivation', 'NegReg', (195, 207))	('IDH1R132H', 'Var', (167, 176))	('TP53', 'Gene', (185, 189))	('IDH1R132H', 'Var', (99, 108))	('TERT', 'Gene', (134, 138))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('TERT', 'Gene', '7015', (134, 138))	('IDH1R132H', 'Var', (52, 61))	('ATRX', 'Gene', (211, 215))	('glioma', 'Disease', (31, 37))
86059	30760578	In spite of a better prognosis, 50-75% of IDH1R132H gliomas undergo malignant transformation over time, becoming WHO grade IV glioblastomas.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioblastomas', 'Phenotype', 'HP:0012174', (126, 139))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioblastomas', 'Disease', 'MESH:D005909', (126, 139))	('IDH1R132H', 'Var', (42, 51))	('malignant transformation', 'CPA', (68, 92))	('glioblastomas', 'Disease', (126, 139))
86060	30760578	IDH1R132H has been identified as an early event in glioma development, preceding TP53 and ATRX mutations.	('IDH1R132H', 'Var', (0, 9))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))
86064	30760578	Genomic instability is prevalent in gliomas; it is thought to promote tumorigenesis and an aggressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gliomas', 'Disease', (36, 43))	('tumor', 'Disease', (70, 75))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('promote', 'PosReg', (62, 69))	('Genomic instability', 'Var', (0, 19))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
86067	30760578	Herein we demonstrate that IDH1R132H, in the context of ATRX and TP53 knock down (KD), increases DDR activity, enhancing genomic stability and extending MS in our mIDH1 mouse glioma model.	('knock down', 'Var', (70, 80))	('increases', 'PosReg', (87, 96))	('genomic stability', 'CPA', (121, 138))	('TP53', 'Gene', (65, 69))	('mIDH1', 'Gene', '15926', (163, 168))	('enhancing', 'PosReg', (111, 120))	('DDR', 'Chemical', '-', (97, 100))	('glioma', 'Disease', (175, 181))	('IDH1R132H', 'Var', (27, 36))	('mouse', 'Species', '10090', (169, 174))	('DDR activity', 'MPA', (97, 109))	('mIDH1', 'Gene', (163, 168))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
86068	30760578	We demonstrate that 2HG induces hypermethylation of histone 3 (H3) which elicits epigenetic reprogramming of the tumor cells' trancriptome.	('tumor', 'Disease', (113, 118))	('epigenetic', 'MPA', (81, 91))	('hypermethylation', 'MPA', (32, 48))	('induces', 'Reg', (24, 31))	('elicits', 'Reg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('histone 3 (H3', 'Gene', '126961', (52, 65))	('2HG', 'Var', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
86074	30760578	Pharmacological inhibition of DDR conferred radiosensitivity in mIDH1 tumor-bearing mice, leading to prolonged MS. Our findings highlight that DDR inhibition in combination with radiation could provide a novel therapeutic strategy for IDH1R132H glioma patients harboring ATRX and TP53 inactivating mutations.	('IDH1R132H', 'Var', (235, 244))	('mIDH1', 'Gene', (64, 69))	('DDR', 'Chemical', '-', (143, 146))	('glioma', 'Disease', 'MESH:D005910', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('DDR', 'Gene', (143, 146))	('ATRX', 'Gene', (271, 275))	('patients', 'Species', '9606', (252, 260))	('tumor', 'Disease', (70, 75))	('glioma', 'Disease', (245, 251))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('TP53', 'Gene', (280, 284))	('inhibition', 'NegReg', (147, 157))	('DDR', 'Chemical', '-', (30, 33))	('mIDH1', 'Gene', '15926', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mice', 'Species', '10090', (84, 88))
86075	30760578	We generated a mIDH1 mouse glioma model using the Sleeping Beauty transposase system to uncover the impact of IDH1R132H, in the context of ATRX and TP53 loss.	('glioma', 'Disease', (27, 33))	('mouse', 'Species', '10090', (21, 26))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('loss', 'NegReg', (153, 157))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('mIDH1', 'Gene', '15926', (15, 20))	('mIDH1', 'Gene', (15, 20))	('IDH1R132H', 'Var', (110, 119))
86076	30760578	Gliomas were induced by RTK/RAS/PI3K activation in combination with, shp53, shATRX and IDH1R132H (fig.	('RTK/RAS/PI3K', 'Protein', (24, 36))	('shp53', 'Var', (69, 74))	('activation', 'PosReg', (37, 47))	('induced', 'Reg', (13, 20))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))
86085	30760578	Both, wt-IDH1-NS and mIDH1-NS exhibited alternative lengthening of telomeres (ALT) which was associated with the presence of shATRX, whereas ALT was not detected in control NS or normal mouse brain (fig.	('mIDH1', 'Gene', '15926', (21, 26))	('ALT', 'Gene', (78, 81))	('mIDH1', 'Gene', (21, 26))	('mouse', 'Species', '10090', (186, 191))	('shATRX', 'Var', (125, 131))	('ALT', 'Gene', '76282', (78, 81))	('presence', 'Var', (113, 121))	('ALT', 'Gene', (141, 144))	('ALT', 'Gene', '76282', (141, 144))	('telomeres', 'CPA', (67, 76))	('lengthening', 'PosReg', (52, 63))
86087	30760578	1B), in human glioma cells stably transfected with IDH1R132H (fig.	('glioma', 'Disease', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('IDH1R132H', 'Var', (51, 60))	('human', 'Species', '9606', (8, 13))
86088	30760578	S2C) and in human glioma cells with endogenous expression of IDH1R132H, TP53 and ATRX inactivating mutations (fig.	('ATRX', 'Gene', (81, 85))	('glioma', 'Disease', (18, 24))	('inactivating mutations', 'Var', (86, 108))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('TP53', 'Gene', (72, 76))	('IDH1R132H', 'Gene', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('human', 'Species', '9606', (12, 17))
86096	30760578	Mutant IDH1 tumors exhibited decreased amounts of: i) OLIG2 (2.3-fold; p < 0.05), ii) MBP (9.3-fold, p < 0.001); and iii) GFAP (6.7-fold; p < 0.05) (fig.	('OLIG2', 'Gene', (54, 59))	('MBP', 'Gene', '4155', (86, 89))	('OLIG2', 'Gene', '10215', (54, 59))	('GFAP', 'Gene', (122, 126))	('GFAP', 'Gene', '2670', (122, 126))	('MBP', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('decreased', 'NegReg', (29, 38))	('tumors', 'Disease', (12, 18))	('Mutant', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('IDH1', 'Gene', (7, 11))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
86105	30760578	In vivo analysis for tumor initiating cells (TICs) showed that 100% of animals generated tumors and succumbed due to tumor burden after implantation of 30 x 105, 10 x 105, 3 x 103 and 1 x 103 wt-IDH1 cells, whereas with mIDH1 cells, only 40% of animals generated tumors when implanted with 1 x 103 cells (fig.	('tumors', 'Disease', (89, 95))	('mIDH1', 'Gene', '15926', (220, 225))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TICs', 'Phenotype', 'HP:0100033', (45, 49))	('mIDH1', 'Gene', (220, 225))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('TICs', 'Disease', (45, 49))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('TICs', 'Disease', 'MESH:D020323', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('30 x 105', 'Var', (152, 160))	('tumors', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
86107	30760578	Frequency of mitotic (pH3Ser10+) and actively proliferating (EdU+) glioma cells was higher in wt-IDH1 tumors (p < 0.0001) (fig.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('glioma', 'Disease', (67, 73))	('actively proliferating', 'CPA', (37, 59))	('mitotic', 'CPA', (13, 20))	('wt-IDH1 tumors', 'Disease', 'MESH:D009369', (94, 108))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('wt-IDH1 tumors', 'Disease', (94, 108))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('pH3Ser10+', 'Var', (22, 31))	('higher', 'PosReg', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
86110	30760578	Mutant IDH1 tumor sections exhibited increased amounts of H3K27me3 (4.6-fold; p < 0.001) and H3K36me3 (7.3-fold; p < 0.001) (fig.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('H3K27me3', 'Protein', (58, 66))	('Mutant', 'Var', (0, 6))	('increased', 'PosReg', (37, 46))	('H3K36me3', 'Var', (93, 101))	('tumor', 'Disease', (12, 17))	('IDH1', 'Gene', (7, 11))
86112	30760578	H3 hypermethylation was also observed in human glioma cells harboring IDH1R132H (fig.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('observed', 'Reg', (29, 37))	('human', 'Species', '9606', (41, 46))	('glioma', 'Disease', (47, 53))	('IDH1R132H', 'Var', (70, 79))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
86114	30760578	The average genomic distribution of H3K4me3 and H3K27me3 peaks in mIDH1-NS were around the transcription start sites (TSS) (fig.	('mIDH1', 'Gene', '15926', (66, 71))	('H3K27me3', 'Var', (48, 56))	('mIDH1', 'Gene', (66, 71))	('H3K4me3', 'Protein', (36, 43))
86124	30760578	In human glioma cells, IDH1R132H also increased expression of ATM and RAD51 (Fig.	('ATM', 'Gene', '472', (62, 65))	('glioma', 'Disease', (9, 15))	('RAD51', 'Gene', (70, 75))	('IDH1R132H', 'Var', (23, 32))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (48, 58))	('RAD51', 'Gene', '5888', (70, 75))	('ATM', 'Gene', (62, 65))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('increased', 'PosReg', (38, 47))
86128	30760578	Moreover, using ChIP-qPCR, we found that H3K4me3, but not H3K27me3, was significantly enriched in mIDH1-NS versus wt-IDH1-NS for both Atm (1.8-fold; p < 0.0001) (Fig.	('Atm', 'Gene', '472', (134, 137))	('mIDH1', 'Gene', '15926', (98, 103))	('H3K4me3', 'Var', (41, 48))	('mIDH1', 'Gene', (98, 103))	('Atm', 'Gene', (134, 137))
86130	30760578	Gene expression analysis suggested that IDH1R132H could enhance HR repair and DDR (Fig.	('DDR', 'Chemical', '-', (78, 81))	('IDH1R132H', 'Var', (40, 49))	('HR repair', 'CPA', (64, 73))	('enhance', 'PosReg', (56, 63))
86148	30760578	Human glioma cells expressing IDH1R132H displayed a similar pattern (Fig.	('Human', 'Species', '9606', (0, 5))	('IDH1R132H', 'Var', (30, 39))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('glioma', 'Disease', (6, 12))
86151	30760578	Mutant IDH1-NS display higher transcription rate for Atm and Rad50 (fold change >1.5) compared to wt-IDH1-NS (Fig.	('Rad50', 'Gene', '10111', (61, 66))	('transcription rate', 'MPA', (30, 48))	('higher', 'PosReg', (23, 29))	('Rad50', 'Gene', (61, 66))	('IDH1-NS', 'Gene', (7, 14))	('Atm', 'Gene', (53, 56))	('Mutant', 'Var', (0, 6))	('Atm', 'Gene', '472', (53, 56))
86156	30760578	Brain tumors were induced with RCAS PDGFB, mIDH1 or wt-IDH1, and shP53 in mixed background NTva, Ink4a/Arf-/- mice.	('Brain tumors', 'Disease', 'MESH:D001932', (0, 12))	('Brain tumors', 'Phenotype', 'HP:0030692', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('shP53', 'Var', (65, 70))	('mice', 'Species', '10090', (110, 114))	('RCAS', 'Disease', (31, 35))	('RCAS', 'Disease', 'None', (31, 35))	('NTva', 'Chemical', '-', (91, 95))	('mIDH1', 'Gene', '15926', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('induced', 'Reg', (18, 25))	('Brain tumors', 'Disease', (0, 12))	('mIDH1', 'Gene', (43, 48))
86159	30760578	Likewise, human glioma cells harboring IDH1R132H displayed higher viability in response to IR (2.3-fold; p < 0.0001) (Fig.	('IDH1R132H', 'Var', (39, 48))	('human', 'Species', '9606', (10, 15))	('glioma', 'Disease', (16, 22))	('viability', 'CPA', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('higher', 'PosReg', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (16, 22))
86160	30760578	These results were further validated in human glioma cells with endogenous expression of IDH1R132H in the context of ATRX and TP53 inactivation (SF10602 and LC1035) which showed increased expression of RAD51 and ATM (fig.	('SF10602', 'Var', (145, 152))	('TP53', 'Gene', (126, 130))	('expression', 'MPA', (188, 198))	('RAD51', 'Gene', (202, 207))	('glioma', 'Disease', (46, 52))	('RAD51', 'Gene', '5888', (202, 207))	('ATM', 'Gene', (212, 215))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('IDH1R132H', 'Gene', (89, 98))	('LC1035', 'Var', (157, 163))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('ATM', 'Gene', '472', (212, 215))	('human', 'Species', '9606', (40, 45))	('increased', 'PosReg', (178, 187))
86167	30760578	Collectively, these results indicate that IDH1R132H enhances DDR, imparting radioresistance independently of the presence of RAS activating mutations.	('IDH1R132H', 'Var', (42, 51))	('radioresistance', 'CPA', (76, 91))	('enhances', 'PosReg', (52, 60))	('DDR', 'MPA', (61, 64))	('DDR', 'Chemical', '-', (61, 64))
86180	30760578	5I and fig S14), indicating that inducible DNA repair mechanisms were associated with in vivo radioresistance in the mIDHI glioma model.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('mIDHI glioma', 'Disease', 'MESH:D005910', (117, 129))	('associated', 'Reg', (70, 80))	('radioresistance', 'CPA', (94, 109))	('mIDHI glioma', 'Disease', (117, 129))	('inducible', 'Var', (33, 42))
86187	30760578	CC3 was significantly higher in wt-IDH1-R at 14 and 21 DPI compared to the NT group (>105-fold; p < 0.0001) which correlated with a reduction in tumor size (Fig.	('NT', 'Chemical', '-', (75, 77))	('higher', 'PosReg', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('CC3', 'Gene', (0, 3))	('reduction', 'NegReg', (132, 141))	('CC3', 'Gene', '6358', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('DPI', 'Chemical', '-', (55, 58))	('wt-IDH1-R', 'Var', (32, 41))
86192	30760578	Taken together, these results suggest that IDH1R132H induces radioresistance in vivo by altering gene expression, enhancing DDR and DNA repair mechanisms.	('radioresistance', 'CPA', (61, 76))	('altering', 'Reg', (88, 96))	('IDH1R132H', 'Var', (43, 52))	('DDR', 'MPA', (124, 127))	('DDR', 'Chemical', '-', (124, 127))	('induces', 'PosReg', (53, 60))	('DNA repair mechanisms', 'CPA', (132, 153))	('enhancing', 'PosReg', (114, 123))	('gene expression', 'MPA', (97, 112))
86196	30760578	Similarly, IR combined with specific inhibitors for ATM (KU60019) (Fig.	('ATM', 'Gene', '472', (52, 55))	('KU60019', 'Var', (57, 64))	('ATM', 'Gene', (52, 55))	('KU60019', 'Chemical', 'MESH:C546193', (57, 64))
86202	30760578	However, KU60019 combined with IR improved MS of mIDHl mice (45 days) versus controls (MS = 30 days; p < 0.01) (Fig.	('improved', 'PosReg', (34, 42))	('mice', 'Species', '10090', (55, 59))	('KU60019', 'Var', (9, 16))	('KU60019', 'Chemical', 'MESH:C546193', (9, 16))
86203	30760578	6F), consistent with decreased tumor size in mIDHl animals treated with 20 Gy and KU60019 (Fig.	('KU60019', 'Var', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('decreased tumor', 'Disease', 'MESH:D009369', (21, 36))	('decreased tumor', 'Disease', (21, 36))	('KU60019', 'Chemical', 'MESH:C546193', (82, 89))
86205	30760578	AZD7762 combined with IR significantly increased MS in mIDHl glioma-bearing mice (Fig.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (61, 67))	('mice', 'Species', '10090', (76, 80))	('increased', 'PosReg', (39, 48))	('AZD7762', 'Var', (0, 7))	('AZD7762', 'Chemical', 'MESH:C532363', (0, 7))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
86209	30760578	We also assessed CC3 expression in mIDH1 tumors after treatment with IR combined with KU600l9 or AZD7762 at l4 DPI (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('AZD7762', 'Var', (97, 104))	('CC3', 'Gene', (17, 20))	('AZD7762', 'Chemical', 'MESH:C532363', (97, 104))	('CC3', 'Gene', '6358', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('KU600l9', 'Chemical', '-', (86, 93))	('expression', 'MPA', (21, 31))	('KU600l9', 'Var', (86, 93))	('assessed', 'Reg', (8, 16))	('mIDH1 tumors', 'Disease', 'MESH:D009369', (35, 47))	('DPI', 'Chemical', '-', (111, 114))	('mIDH1 tumors', 'Disease', (35, 47))
86210	30760578	CC3 expression is increased in mIDHl tumors treated with IR plus KU600l9 or AZD7762, suggesting that DDR inhibition in combination with IR induced apoptosis.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('increased', 'PosReg', (18, 27))	('AZD7762', 'Var', (76, 83))	('AZD7762', 'Chemical', 'MESH:C532363', (76, 83))	('CC3', 'Gene', (0, 3))	('CC3', 'Gene', '6358', (0, 3))	('KU600l9', 'Var', (65, 72))	('expression', 'MPA', (4, 14))	('KU600l9', 'Chemical', '-', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('DDR', 'Chemical', '-', (101, 104))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
86211	30760578	In mIDHl human glioma cells, SFl0602 and LCl035, AZD7762 was able to revert radioresistance (Fig.	('SFl0602', 'Var', (29, 36))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('human', 'Species', '9606', (9, 14))	('glioma', 'Disease', (15, 21))	('radioresistance', 'CPA', (76, 91))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('AZD7762', 'Var', (49, 56))	('revert', 'NegReg', (69, 75))	('AZD7762', 'Chemical', 'MESH:C532363', (49, 56))
86212	30760578	Consistent with our results, analysis of TCGA data-base indicated that LGG patients harboring IDHlRl23H with TP53 and ATRX inactivating mutations have higher expression of ATM and RAD50 mRNA than wt-IDH1 GBM (fig.	('expression', 'MPA', (158, 168))	('RAD50', 'Gene', (180, 185))	('RAD50', 'Gene', '10111', (180, 185))	('patients', 'Species', '9606', (75, 83))	('ATM', 'Gene', '472', (172, 175))	('higher', 'PosReg', (151, 157))	('TP53', 'Gene', (109, 113))	('ATM', 'Gene', (172, 175))	('IDHlRl23H', 'Var', (94, 103))	('ATRX', 'Gene', (118, 122))	('inactivating mutations', 'Var', (123, 145))
86216	30760578	Patients harboring IDH1R132H glioma exhibit longer MS (~6.6 years from diagnosis) compared with patients whose tumors express wt-IDH1 (~1.6 years from diagnosis).	('longer', 'PosReg', (44, 50))	('glioma', 'Disease', (29, 35))	('IDH1R132H', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('patients', 'Species', '9606', (96, 104))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
86218	30760578	It was reported that the glioma subgroup harboring IDH1R132H, ATRX, and TP53 loss also exhibits lengthening of telomeres.	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('ATRX', 'Gene', (62, 66))	('TP53', 'Gene', (72, 76))	('loss', 'NegReg', (77, 81))	('IDH1R132H', 'Var', (51, 60))	('glioma', 'Disease', (25, 31))	('lengthening', 'CPA', (96, 107))
86220	30760578	Genomic stability in our mIDH1 glioma model is mediated via increased DDR due to epigenetic reprogramming of the tumor cells' transcriptome (fig.	('tumor', 'Disease', (113, 118))	('mIDH1', 'Gene', '15926', (25, 30))	('DDR', 'MPA', (70, 73))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('DDR', 'Chemical', '-', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('mIDH1', 'Gene', (25, 30))	('epigenetic', 'Var', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Disease', (31, 37))	('increased', 'PosReg', (60, 69))
86223	30760578	Our ChIP-seq data revealed enrichment of H3K4me3 at promoter regions of genes involved in DDR and cell cycle progression.	('DDR', 'Disease', (90, 93))	('H3K4me3', 'Var', (41, 48))	('DDR', 'Chemical', '-', (90, 93))
86224	30760578	ChIP-qPCR showed enrichment of the H3K4me3 mark around Atm TSS, which would increase Atm expression.	('increase', 'PosReg', (76, 84))	('Atm', 'Gene', (55, 58))	('Atm', 'Gene', '472', (55, 58))	('H3K4me3', 'Var', (35, 42))	('Atm', 'Gene', (85, 88))	('Atm', 'Gene', '472', (85, 88))
86225	30760578	Upregulation of ATM was also found in LGG patients harboring IDH1R132H with ATRX and TP53 gene inactivation; this correlates with an increased survival of these patients.	('Upregulation', 'PosReg', (0, 12))	('TP53', 'Gene', (85, 89))	('IDH1R132H', 'Var', (61, 70))	('ATM', 'Gene', (16, 19))	('ATM', 'Gene', '472', (16, 19))	('patients', 'Species', '9606', (161, 169))	('increased', 'PosReg', (133, 142))	('patients', 'Species', '9606', (42, 50))
86226	30760578	We discovered that IDH1R132H induced transcriptional activation of Atm, which resulted in efficient DNA repair activity via HR.	('IDH1R132H', 'Var', (19, 28))	('DNA repair activity', 'CPA', (100, 119))	('Atm', 'Gene', (67, 70))	('transcriptional', 'MPA', (37, 52))	('Atm', 'Gene', '472', (67, 70))
86228	30760578	Mutations in IDH1/2 are also detected in 15% of AML patients, which correlates with unfavorable prognosis.	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('AML', 'Disease', (48, 51))	('detected', 'Reg', (29, 37))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('AML', 'Disease', 'MESH:D015470', (48, 51))	('patients', 'Species', '9606', (52, 60))
86230	30760578	AML-IDH1 mutant cells are more sensitive to chemotherapy and are highly malignant.	('more', 'PosReg', (26, 30))	('mutant', 'Var', (9, 15))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('sensitive', 'MPA', (31, 40))	('AML', 'Disease', (0, 3))
86232	30760578	In the glioma subtype we studied, IDH1R132H is expressed in the context of TP53 and ATRX mutations, differing from AML, where ATRX gene inactivation is not present.	('AML', 'Disease', 'MESH:D015470', (115, 118))	('glioma subtype', 'Disease', (7, 21))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('IDH1R132H', 'Var', (34, 43))	('AML', 'Disease', (115, 118))	('mutations', 'Var', (89, 98))	('glioma subtype', 'Disease', 'MESH:D005910', (7, 21))	('ATRX', 'Gene', (84, 88))	('TP53', 'Gene', (75, 79))
86234	30760578	It appears that IDH1R132H induces genomic stability, which on one hand slows tumor growth, and on the other, increases DNA repair capacity, reducing the efficacy of radiotherapy.	('IDH1R132H', 'Var', (16, 25))	('reducing', 'NegReg', (140, 148))	('DNA repair', 'MPA', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('slows', 'NegReg', (71, 76))	('induces', 'PosReg', (26, 33))	('increases', 'PosReg', (109, 118))	('tumor', 'Disease', (77, 82))	('genomic stability', 'CPA', (34, 51))
86235	30760578	Previous studies used colon cancer cells, HeLa cells, and immortalized cells derived from high-grade gliomas suggest that IDH1R132H suppresses HR repair.	('suppresses', 'NegReg', (132, 142))	('gliomas', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('HR repair', 'CPA', (143, 152))	('IDH1R132H', 'Var', (122, 131))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('colon cancer', 'Disease', (22, 34))	('HeLa', 'CellLine', 'CVCL:0030', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
86236	30760578	None of these cells, however, originated from patient-derived IDH1R132H glioma, harboring concomitant mutations in ATRX and TP53, and no experiments were done orthotopically.	('glioma', 'Disease', (72, 78))	('patient', 'Species', '9606', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('TP53', 'Gene', (124, 128))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('IDH1R132H', 'Var', (62, 71))	('mutations', 'Var', (102, 111))	('ATRX', 'Gene', (115, 119))
86237	30760578	These apparently opposing results reinforce the notion that the effects of IDH1R132H can vary according to tumor type/subtype and should be evaluated in an appropriate cellular and genetic context.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('IDH1R132H', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
86238	30760578	Our results indicating that IDH1R132H decreases radiosensitivity and enhances DDR in glioma were validated in cells derived from glioma patients with endogenous expression of IDH1R132H in the context of TP53 and ATRX inactivation, and in a second mouse glioma model lacking RAS activating mutation.	('decreases', 'NegReg', (38, 47))	('mouse', 'Species', '10090', (247, 252))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('IDH1R132H', 'Var', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('DDR', 'MPA', (78, 81))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))	('DDR', 'Chemical', '-', (78, 81))	('glioma', 'Disease', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('IDH1R132H', 'Var', (175, 184))	('enhances', 'PosReg', (69, 77))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('radiosensitivity', 'MPA', (48, 64))	('decreases radiosensitivity', 'Phenotype', 'HP:0010997', (38, 64))	('glioma', 'Disease', (85, 91))	('patients', 'Species', '9606', (136, 144))	('glioma', 'Disease', (253, 259))	('glioma', 'Disease', 'MESH:D005910', (253, 259))
86239	30760578	In agreement with our results, a recent study using gliomaspheres demonstrated that mIDH1 cultures are less sensitive to IR than wt-IDH1 cultures, however, this work does not distinguish between 1p/19q co-deleted and non-co-deleted mIDH1 glioma subtypes.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('glioma subtype', 'Disease', 'MESH:D005910', (238, 252))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('mIDH1', 'Gene', '15926', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma subtype', 'Disease', (238, 252))	('mIDH1', 'Gene', '15926', (232, 237))	('mIDH1', 'Gene', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('mIDH1', 'Gene', (232, 237))	('1p/19q co-deleted', 'Var', (195, 212))
86240	30760578	Thus, we postulated that inhibiting DDR would restitute glioma radiosensitivity in the mIDH1 glioma subtype under investigation.	('glioma subtype', 'Disease', 'MESH:D005910', (93, 107))	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', (93, 99))	('inhibiting', 'Var', (25, 35))	('mIDH1', 'Gene', '15926', (87, 92))	('glioma subtype', 'Disease', (93, 107))	('mIDH1', 'Gene', (87, 92))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('DDR', 'Chemical', '-', (36, 39))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('DDR', 'Protein', (36, 39))	('glioma radiosensitivity', 'Phenotype', 'HP:0010997', (56, 79))	('restitute', 'NegReg', (46, 55))
86243	30760578	Evidence in favor of IDH1R132H increasing or decreasing tumors' radiosensitivity has been published.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('increasing', 'PosReg', (31, 41))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('IDH1R132H', 'Var', (21, 30))	('decreasing', 'NegReg', (45, 55))	('radiosensitivity', 'MPA', (64, 80))
86244	30760578	Glioma patients expressing IDH1R132H do live longer, but whether this is due to IDH1R132H tumors growing slower, or whether they are more radiosensitive has not yet been conclusively demonstrated.	('slower', 'NegReg', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('IDH1R132H', 'Var', (27, 36))	('Glioma', 'Disease', (0, 6))	('IDH1R132H', 'Var', (80, 89))	('patients', 'Species', '9606', (7, 15))
86247	30760578	Our data also demonstrates that the effects mediated by IDH1R132H on DDR are dependent on the genetic context.	('IDH1R132H', 'Var', (56, 65))	('DDR', 'Chemical', '-', (69, 72))	('DDR', 'Disease', (69, 72))
86249	30760578	Similarly, survival of WHO II glioma patients expressing IDH1R132H treated with TMZ, was not further improved by radiotherapy.	('II glioma', 'Disease', 'MESH:D005910', (27, 36))	('IDH1R132H', 'Var', (57, 66))	('patients', 'Species', '9606', (37, 45))	('II glioma', 'Disease', (27, 36))	('TMZ', 'Chemical', '-', (80, 83))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
86250	30760578	Also, a combination of vincristine, procarbazine, and lomustine WHO II glioma prolong overall survival compared with patients receiving IR alone, suggesting that tumors expressing IDH1R132H remain sensitive to chemotherapy, but not radiotherapy.	('vincristine', 'Chemical', 'MESH:D014750', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('procarbazine', 'Chemical', 'MESH:D011344', (36, 48))	('prolong', 'PosReg', (78, 85))	('tumors', 'Disease', (162, 168))	('lomustine WHO II glioma', 'Disease', (54, 77))	('lomustine WHO II glioma', 'Disease', 'MESH:D005910', (54, 77))	('patients', 'Species', '9606', (117, 125))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('IDH1R132H', 'Var', (180, 189))	('overall survival', 'MPA', (86, 102))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))
86251	30760578	In conclusion, we discovered the mechanism by which IDH1R132H, in the context of TP53 and ATRX inactivation, elicits epigenetic reprogramming of the ATM signaling pathway, which in turn increases DDR and genomic stability (fig.	('DDR', 'MPA', (196, 199))	('DDR', 'Chemical', '-', (196, 199))	('ATM', 'Gene', '472', (149, 152))	('elicits', 'Reg', (109, 116))	('epigenetic', 'MPA', (117, 127))	('increases', 'PosReg', (186, 195))	('genomic stability', 'CPA', (204, 221))	('IDH1R132H', 'Var', (52, 61))	('ATM', 'Gene', (149, 152))
86256	30760578	We also used human glioma cells derived from patients harboring IDH1R132H in the context of TP53 and ATRX inactivating mutations, to confirm the results obtained from our animal models.	('human', 'Species', '9606', (13, 18))	('IDH1R132H', 'Var', (64, 73))	('glioma', 'Disease', (19, 25))	('patients', 'Species', '9606', (45, 53))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
86271	26050590	Multiple reports demonstrated objective shrinkage in 31%-62% of LGGs with TMZ, and median duration of tumor response or stabilization ranges from 10-31 months for recurrent LGGs and may exceed 3 years in patients previously untreated with RT.	('TMZ', 'Var', (74, 77))	('patients', 'Species', '9606', (204, 212))	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('LGGs', 'Disease', (64, 68))	('LGGs', 'Disease', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('shrinkage', 'NegReg', (40, 49))
86274	26050590	Patients of any age with residual T2 abnormality < 2 cm in greatest dimension, patients younger than 40 years with any extent of resection, and patients younger than 50 years with tumor size < 4 cm before resection are all eligible for observation based on a predicted median survival of greater than 10 years.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('abnormality < 2', 'Var', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (79, 87))
86277	26050590	The RTOG and European Organization for Research and Treatment of Cancer (EORTC) both reported long-term outcomes of prospective, randomized trials showing evidence that PCV and RT improved survival compared with RT alone in patients with isocitrate dehydrogenase (IDH) mutations, with or without 1p/19q codeletion.	('survival', 'MPA', (189, 197))	('mutations', 'Var', (269, 278))	('IDH', 'Gene', (264, 267))	('IDH', 'Gene', '3417', (264, 267))	('improved', 'PosReg', (180, 188))	('Cancer', 'Disease', (65, 71))	('patients', 'Species', '9606', (224, 232))	('Cancer', 'Disease', 'MESH:D009369', (65, 71))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EORTC', 'Chemical', '-', (73, 78))
86285	26050590	Although not as well established during this time period, evidence was emerging that 1p/19q codeletion, often seen in oligodendroglial tumors, was associated with improved OS in patients with LGG regardless of treatment suggesting a different natural history in this molecular subtype.	('OS', 'Chemical', '-', (172, 174))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (118, 141))	('oligodendroglial tumors', 'Disease', (118, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('patients', 'Species', '9606', (178, 186))	('improved', 'PosReg', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('LGG', 'Disease', (192, 195))	('1p/19q codeletion', 'Var', (85, 102))
86288	26050590	With a median follow-up of 5.9 years, PCV chemotherapy was found to have significantly prolonged PFS compared with patients assigned to radiation alone.	('PFS', 'MPA', (97, 100))	('patients', 'Species', '9606', (115, 123))	('prolonged', 'PosReg', (87, 96))	('PCV chemotherapy', 'Var', (38, 54))
86303	26050590	The survival benefit associated with the addition of chemotherapy was limited to those patients with 1p/19q codeletions and IDH mutations.	('1p/19q codeletions', 'Var', (101, 119))	('patients', 'Species', '9606', (87, 95))	('IDH', 'Gene', '3417', (124, 127))	('IDH', 'Gene', (124, 127))
86310	26050590	In the intervening decade since the trial's inception, radiation alone is not often the "standard" treatment, and instead chemotherapy alone is considered, especially for tumors with 1p/19q deletion or IDH mutations or both.	('IDH', 'Gene', (202, 205))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('IDH', 'Gene', '3417', (202, 205))	('1p/19q deletion', 'Var', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
86319	26050590	Prolonged PFS was seen in both RT and chemotherapy arms for patients with IDH1 mutations and MGMT promoter hypermethylation.	('MGMT', 'Gene', '4255', (93, 97))	('IDH1', 'Gene', (74, 78))	('MGMT', 'Gene', (93, 97))	('patients', 'Species', '9606', (60, 68))	('PFS', 'MPA', (10, 13))	('IDH1', 'Gene', '3417', (74, 78))	('mutations', 'Var', (79, 88))
86323	26050590	Updated results of this trial demonstrated the 6-year OS for codeleted patients was greater following TMZ +- RT than RT + PCV in RTOG 9402 (82% vs 67%), although the results were not significant.	('patients', 'Species', '9606', (71, 79))	('RT + PCV', 'Chemical', '-', (117, 125))	('TMZ +- RT', 'Chemical', '-', (102, 111))	('TMZ +- RT', 'Var', (102, 111))	('OS', 'Chemical', '-', (54, 56))	('greater', 'PosReg', (84, 91))
86324	26050590	Although it may appear that TMZ may have similar effects in codeleted patients with anaplastic oligodendroglial, the RTOG phase II study was small, with 40 patients enrolled, of which only 23 were codeleted, so caution should be used when drawing comparisons between these results as RTOG 9402 demonstrated no evidence of benefit of PCV in patients with neither 1p/19q codeletion nor IDH mutations.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (70, 78))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('anaplastic oligodendroglial', 'Disease', (84, 111))	('1p/19q codeletion', 'Var', (362, 379))	('patients', 'Species', '9606', (340, 348))	('IDH', 'Gene', (384, 387))	('IDH', 'Gene', '3417', (384, 387))
86332	26050590	The identification of molecular markers such as 1p/19q deletion and IDH mutations that identify subgroups of patients with median survival exceeding 10 years has also resulted in reclassification of patients previously considered "high risk" to patients in whom aggressive treatment is often deferred.	('IDH', 'Gene', '3417', (68, 71))	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (245, 253))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (199, 207))	('IDH', 'Gene', (68, 71))
86341	26050590	The final analysis of both the RTOG and EORTC studies in grade III patients revealed that a statistically significant survival advantage was limited only to patients with 1p/19q or IDH gene deletions.	('IDH', 'Gene', (181, 184))	('patients', 'Species', '9606', (67, 75))	('IDH', 'Gene', '3417', (181, 184))	('EORTC', 'Chemical', '-', (40, 45))	('patients', 'Species', '9606', (157, 165))	('1p/19q', 'Var', (171, 177))
86342	26050590	In a 45-year-old individual with a 1p19q noncodeleted grade II astrocytoma, do the benefits of PCV outweigh the toxicities in comparison with TMZ?	('toxicities', 'Disease', 'MESH:D064420', (112, 122))	('TMZ', 'Chemical', 'MESH:D000077204', (142, 145))	('II astrocytoma', 'Disease', 'MESH:D001254', (60, 74))	('II astrocytoma', 'Disease', (60, 74))	('1p19q', 'Var', (35, 40))	('toxicities', 'Disease', (112, 122))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))
86344	26050590	CODEL, a randomized phase III trial of radiation therapy plus either TMZ or PCV for patients with newly diagnosed 1p/19q codeleted anaplastic gliomas, is ongoing and will likely be modified to include patients with 1p/19q codeleted grade 2 gliomas to answer the question of the optimal chemotherapy regimen.	('patients', 'Species', '9606', (201, 209))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('patients', 'Species', '9606', (84, 92))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('1p/19q', 'Var', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('gliomas', 'Disease', 'MESH:D005910', (240, 247))	('gliomas', 'Phenotype', 'HP:0009733', (240, 247))	('gliomas', 'Disease', (240, 247))
86347	26050590	PFS may be valid in some disease setting; however, PFS did not correlate with OS in radiation alone studies, but PFS and OS were very similar in R9402, EORTC 26951, and R9802.	('R9802', 'Var', (169, 174))	('OS', 'Chemical', '-', (121, 123))	('R9402', 'Var', (145, 150))	('OS', 'Chemical', '-', (78, 80))	('EORTC', 'Chemical', '-', (152, 157))
86362	24574359	In phase III trial for recurrent glioblastomas, NovoTTF-100A was shown to have equivalent efficacy and less toxicity when compared to Best Physician's Choice (BPC) chemotherapy.	('NovoTTF-100A', 'Var', (48, 60))	('BPC', 'Chemical', '-', (159, 162))	('glioblastomas', 'Phenotype', 'HP:0012174', (33, 46))	('glioblastomas', 'Disease', 'MESH:D005909', (33, 46))	('glioblastomas', 'Disease', (33, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))	('toxicity', 'Disease', (108, 116))
86370	24574359	Pearson analysis showed strong correlation between response and OS in NovoTTF-100A (P = 0.0002) but not in BPC cohort (P = 0.2900).	('BPC', 'Chemical', '-', (107, 110))	('OS', 'Chemical', '-', (64, 66))	('correlation', 'Interaction', (31, 42))	('NovoTTF-100A', 'Var', (70, 82))
86385	24574359	The NovoTTF-100A cohort (N = 120) had more responders than the BPC cohort (N = 117) (Table 1).	('NovoTTF-100A', 'Var', (4, 16))	('BPC', 'Chemical', '-', (63, 66))	('responders', 'MPA', (43, 53))
86399	24574359	Therefore, in light of the more frequent low-grade histology and the lower cumulative dexamethasone dose, NovoTTF-100A responders may have more favorable genetic and/or epigenetic characteristics.	('NovoTTF-100A', 'Gene', (106, 118))	('dexamethasone', 'Chemical', 'MESH:D003907', (86, 99))	('epigenetic', 'Var', (169, 179))
86407	24574359	This difference was also notably greater in the NovoTTF-100A than the BPC cohort.	('NovoTTF-100A', 'Var', (48, 60))	('BPC', 'Chemical', '-', (70, 73))	('greater', 'PosReg', (33, 40))
86428	24574359	Because primary and secondary glioblastomas have different genetic alterations, notably EGFR and MDM2 amplifications together with p16 deletion in primary glioblastomas and p53 mutation, IDH1 mutation and PDGFR amplification in secondary glioblastomas, the distinct genetic makeup in these two subtypes of glioblastomas could make secondary glioblastomas more susceptible to NovoTTF-100A treatment.	('glioblastomas', 'Disease', (341, 354))	('glioblastoma', 'Phenotype', 'HP:0012174', (341, 353))	('glioblastomas', 'Disease', (238, 251))	('glioblastomas', 'Phenotype', 'HP:0012174', (30, 43))	('amplification', 'Var', (211, 224))	('glioblastomas', 'Phenotype', 'HP:0012174', (306, 319))	('glioblastomas', 'Disease', 'MESH:D005909', (341, 354))	('glioblastomas', 'Phenotype', 'HP:0012174', (155, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('p16', 'Gene', (131, 134))	('deletion', 'Var', (135, 143))	('glioblastomas', 'Disease', 'MESH:D005909', (238, 251))	('p16', 'Gene', '1029', (131, 134))	('p53', 'Gene', '7157', (173, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('glioblastomas', 'Disease', (30, 43))	('MDM2', 'Gene', (97, 101))	('EGFR', 'Gene', (88, 92))	('IDH1', 'Gene', (187, 191))	('mutation', 'Var', (177, 185))	('glioblastomas', 'Disease', (306, 319))	('glioblastoma', 'Phenotype', 'HP:0012174', (306, 318))	('p53', 'Gene', (173, 176))	('glioblastomas', 'Disease', (155, 168))	('PDGFR', 'Gene', (205, 210))	('PDGFR', 'Gene', '5159', (205, 210))	('glioblastomas', 'Disease', 'MESH:D005909', (30, 43))	('glioblastomas', 'Phenotype', 'HP:0012174', (341, 354))	('MDM2', 'Gene', '4193', (97, 101))	('glioblastomas', 'Disease', 'MESH:D005909', (306, 319))	('glioblastomas', 'Phenotype', 'HP:0012174', (238, 251))	('glioblastomas', 'Disease', 'MESH:D005909', (155, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('IDH1', 'Gene', '3417', (187, 191))	('EGFR', 'Gene', '1956', (88, 92))
86434	24574359	Second, the daily dexamethasone dose used by both NovoTTF-100A and BPC chemotherapy responders was significantly lower than that used by nonresponders.	('NovoTTF-100A', 'Var', (50, 62))	('dexamethasone', 'Chemical', 'MESH:D003907', (18, 31))	('lower', 'NegReg', (113, 118))	('BPC', 'Chemical', '-', (67, 70))
86435	24574359	Indeed, dexamethasone has been associated with profound immunosuppression and increased risk of infection.	('infection', 'Disease', 'MESH:D007239', (96, 105))	('dexamethasone', 'Chemical', 'MESH:D003907', (8, 21))	('infection', 'Disease', (96, 105))	('dexamethasone', 'Var', (8, 21))
86443	24574359	Furthermore, the time interval between peak hazard rates of responders and nonresponders in the BPC cohort is narrower than that for the NovoTTF-100A cohort, suggesting that NovoTTF-100A responders had a slightly more favorable tumor progression profile than BPC chemotherapy responders.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('BPC', 'Chemical', '-', (259, 262))	('NovoTTF-100A', 'Var', (174, 186))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('BPC', 'Chemical', '-', (96, 99))
86446	24574359	Also, this difference is larger in the NovoTTF-100A than the BPC cohort, suggesting that responders possibly experienced a greater efficacy from NovoTTF-100A than responders from BPC chemotherapy.	('NovoTTF-100A', 'Var', (145, 157))	('BPC', 'Chemical', '-', (179, 182))	('greater efficacy', 'PosReg', (123, 139))	('BPC', 'Chemical', '-', (61, 64))
86448	24574359	Notably, Pearson analysis showed that responders to NovoTTF-100A had a stronger correlation than responders to BPC chemotherapy.	('correlation', 'Interaction', (80, 91))	('NovoTTF-100A', 'Var', (52, 64))	('BPC', 'Chemical', '-', (111, 114))
86519	29190914	Genomic copy number gains of ErbB family members predict poor clinical outcomes in glioma patients The aim of this study was to investigate copy number of ErbB family members (including EGFR, HER2, HER3 and HER4) in a cohort of gliomas and benign meningiomas (control subjects), and explore the associations of their copy number with clinicopathological characteristics and clinical outcomes of glioma patients.	('copy', 'Var', (8, 12))	('gliomas and benign meningiomas', 'Disease', 'MESH:D008577', (228, 258))	('glioma', 'Disease', 'MESH:D005910', (395, 401))	('HER3', 'Gene', '2065', (198, 202))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('glioma', 'Disease', (83, 89))	('ErbB', 'Gene', '1956', (29, 33))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('EGF', 'Gene', '1950', (186, 189))	('glioma', 'Phenotype', 'HP:0009733', (395, 401))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('HER2', 'Gene', (192, 196))	('HER4', 'Gene', (207, 211))	('patients', 'Species', '9606', (402, 410))	('ErbB', 'Gene', '1956', (155, 159))	('investigate', 'Reg', (128, 139))	('meningiomas', 'Phenotype', 'HP:0002858', (247, 258))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('HER3', 'Gene', (198, 202))	('patients', 'Species', '9606', (90, 98))	('EGF', 'Gene', (186, 189))	('glioma', 'Disease', (395, 401))	('glioma', 'Disease', (228, 234))	('ErbB', 'Gene', (29, 33))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('HER2', 'Gene', '2064', (192, 196))	('HER4', 'Gene', '2066', (207, 211))	('ErbB', 'Gene', (155, 159))
86524	29190914	Stratified analysis showed that CNG of HER2-4 almost did not influence the survival of male patients, patients with high-grade tumors and patients receiving chemotherapy, but dramatically shortened median survival times of female patients, those with low-grade tumors and those receiving radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('median survival', 'MPA', (198, 213))	('HER2-4', 'Gene', '2064;2065;2066', (39, 45))	('tumors', 'Disease', (127, 133))	('CNG', 'Var', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('shortened', 'NegReg', (188, 197))	('HER2-4', 'Gene', (39, 45))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('patients', 'Species', '9606', (92, 100))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('patients', 'Species', '9606', (230, 238))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('patients', 'Species', '9606', (138, 146))
86529	29190914	Therefore, determining the genetic alterations of classic oncogenes will improve the accuracy of clinical interpretations and the effectiveness of therapeutics for this cancer.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('improve', 'PosReg', (73, 80))	('genetic alterations', 'Var', (27, 46))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
86531	29190914	Copy number variation (CNV) is increasingly linked to the genetic and phenotypic diversity among cancers, and is frequently associated with the activation of oncogenic drivers or the deletion of tumor suppressors.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('tumor', 'Disease', (195, 200))	('cancers', 'Disease', (97, 104))	('Copy number variation', 'Var', (0, 21))	('associated', 'Reg', (124, 134))	('activation', 'PosReg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('linked', 'Reg', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('deletion', 'Var', (183, 191))
86532	29190914	Like other malignancies, the current studies have shed light on molecular events of oncogenes and tumor suppressor genes in gliomas due to numerical chromosomal abnormalities such as genomic gains and losses.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('genomic gains', 'Var', (183, 196))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('losses', 'Var', (201, 207))	('malignancies', 'Disease', 'MESH:D009369', (11, 23))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (149, 174))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('malignancies', 'Disease', (11, 23))	('tumor', 'Disease', (98, 103))	('chromosomal abnormalities', 'Disease', (149, 174))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
86537	29190914	Given that aberrant activation of ErbB receptors is frequently observed in multiple types of cancer, clinical applications have rapidly emerged around attempts to therapeutically inhibit the function of ErbB receptors in different cancers including monoclonal antibodies (mAbs), small-molecule TKIs and other agents like peptides, affibodies, nanobodies, etc.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('small-molecule', 'Var', (279, 293))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancer', 'Disease', (231, 237))	('cancers', 'Disease', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ErbB', 'Gene', (34, 38))	('activation', 'PosReg', (20, 30))	('function', 'MPA', (191, 199))	('ErbB', 'Gene', '1956', (34, 38))	('ErbB', 'Gene', (203, 207))	('inhibit', 'NegReg', (179, 186))	('ErbB', 'Gene', '1956', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
86542	29190914	When a copy number of >=4 of the indicated genes was considered as CNG (or gene amplification), we found that EGFR CNG in 62/127 (48.8%) gliomas, HER2 in 44/127 (34.6%) gliomas, HER3 in 47/127 (37.0%) gliomas, and HER4 in 50/127 (39.4%) gliomas, whereas none was found in control subjects (Table 1).	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('EGF', 'Gene', (110, 113))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('HER4', 'Gene', '2066', (214, 218))	('HER2', 'Gene', (146, 150))	('HER3', 'Gene', (178, 182))	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', (201, 208))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Disease', (237, 244))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('HER4', 'Gene', (214, 218))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('EGF', 'Gene', '1950', (110, 113))	('HER2', 'Gene', '2064', (146, 150))	('HER3', 'Gene', '2065', (178, 182))	('CNG', 'Var', (115, 118))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))
86543	29190914	Also shown in Table 1, IDH1 mutations were found in 45 of 127 (35.4%) patients.	('patients', 'Species', '9606', (70, 78))	('found', 'Reg', (43, 48))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (23, 27))	('mutations', 'Var', (28, 37))
86548	29190914	As shown in Figure 1B, the mRNA levels of these four genes in high-copy group were higher than low-copy group, especially in EGFR (P <0.001).	('high-copy', 'Var', (62, 71))	('EGF', 'Gene', '1950', (125, 128))	('higher', 'PosReg', (83, 89))	('mRNA levels', 'MPA', (27, 38))	('EGF', 'Gene', (125, 128))
86550	29190914	When copy number of >=4 was defined as CNG, the glioma patients were subsequently categorized into CNG- and non-CNG-groups of the indicate genes.	('copy number', 'Var', (5, 16))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('patients', 'Species', '9606', (55, 63))	('glioma', 'Disease', (48, 54))
86551	29190914	As shown in Table 2, by using univariate regression analysis, we found that the risk of cancer-related death was significantly increased by the presence of EGFR CNG (OR =4.14, 95% CI =1.94-8.86, P <0.001), HER3 CNG (OR =2.48, 95% CI =1.15-5.40, P =0.02) and HER4 CNG (OR =2.16, 95% CI =1.02-4.58, P =0.04).	('HER3', 'Gene', (206, 210))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('HER3', 'Gene', '2065', (206, 210))	('EGF', 'Gene', '1950', (156, 159))	('HER4', 'Gene', '2066', (258, 262))	('HER4', 'Gene', (258, 262))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('presence', 'Var', (144, 152))	('increased', 'PosReg', (127, 136))	('EGF', 'Gene', (156, 159))
86553	29190914	HER2 was more likely to be amplified in young patients (OR =0.61, 95% CI =0.40-0.93, P =0.02).	('amplified', 'Var', (27, 36))	('HER2', 'Gene', '2064', (0, 4))	('patients', 'Species', '9606', (46, 54))	('HER2', 'Gene', (0, 4))
86555	29190914	Increasing evidences have demonstrated that IDH1 mutations are important genetic events, and closely associated with survival benefit in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('mutations', 'Var', (49, 58))	('survival benefit', 'CPA', (117, 133))	('IDH1', 'Gene', (44, 48))	('IDH1', 'Gene', '3417', (44, 48))	('gliomas', 'Disease', (137, 144))	('associated', 'Reg', (101, 111))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))
86556	29190914	Our data showed that the association of low copy number of EGFR with IDH1 mutations (Table 2).	('EGF', 'Gene', '1950', (59, 62))	('low copy number', 'Var', (40, 55))	('IDH1', 'Gene', '3417', (69, 73))	('mutations', 'Var', (74, 83))	('EGF', 'Gene', (59, 62))	('IDH1', 'Gene', (69, 73))
86559	29190914	Similar to the findings from univariate analysis, CNG of EGFR (OR =9.61, 95% CI =2.83-32.7, P <0.001), HER3 (OR =4.47, 95% CI =1.35-14.75, P =0.01) and HER4 (OR =5.07, 95% CI =1.50-17.06, P =0.009) was still significantly associated with cancer-related death in glioma patients (Table 3).	('death in glioma', 'Disease', 'MESH:D005910', (253, 268))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('associated with', 'Reg', (222, 237))	('HER3', 'Gene', (103, 107))	('EGF', 'Gene', (57, 60))	('death in glioma', 'Disease', (253, 268))	('CNG', 'Var', (50, 53))	('HER3', 'Gene', '2065', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('EGF', 'Gene', '1950', (57, 60))	('HER4', 'Gene', (152, 156))	('HER4', 'Gene', '2066', (152, 156))	('patients', 'Species', '9606', (269, 277))
86560	29190914	Also shown in Table 3, EGFR (OR =0.56, 95% CI =0.33-0.94, P =0.03), HER3 (OR =0.42, 95% CI =0.24-0.72, P =0.002) and HER4 (OR =0.42, 95% CI =0.24-0.73, P =0.002) genes were more likely to be amplified in the patients with low-grade tumors as compared to those with high-grade tumors, suggesting that CNG of EGFR, HER3 and HER4 may be early-stage genetic events in glioma tumorigenesis.	('HER3', 'Gene', (313, 317))	('tumor', 'Disease', (371, 376))	('glioma', 'Phenotype', 'HP:0009733', (364, 370))	('EGF', 'Gene', '1950', (307, 310))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('EGF', 'Gene', (23, 26))	('HER4', 'Gene', '2066', (117, 121))	('tumor', 'Disease', (232, 237))	('EGF', 'Gene', (307, 310))	('HER3', 'Gene', '2065', (68, 72))	('tumors', 'Disease', (276, 282))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('CNG', 'Var', (300, 303))	('HER4', 'Gene', '2066', (322, 326))	('HER3', 'Gene', '2065', (313, 317))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', (276, 281))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('glioma', 'Disease', (364, 370))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('patients', 'Species', '9606', (208, 216))	('glioma', 'Disease', 'MESH:D005910', (364, 370))	('EGF', 'Gene', '1950', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('HER4', 'Gene', (117, 121))	('HER3', 'Gene', (68, 72))	('HER4', 'Gene', (322, 326))	('tumors', 'Disease', (232, 238))
86563	29190914	As shown in Supplementary Table 2, CNG of EGFR, HER2 and HER3 was positively associated with tumor recurrence, especially EGFR in female patients.	('HER2', 'Gene', '2064', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('EGF', 'Gene', '1950', (42, 45))	('tumor', 'Disease', (93, 98))	('patients', 'Species', '9606', (137, 145))	('HER3', 'Gene', '2065', (57, 61))	('EGF', 'Gene', (122, 125))	('EGF', 'Gene', (42, 45))	('HER3', 'Gene', (57, 61))	('EGF', 'Gene', '1950', (122, 125))	('CNG', 'Var', (35, 38))	('HER2', 'Gene', (48, 52))	('associated with', 'Reg', (77, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
86564	29190914	Moreover, we also found that CNG of EGFR, HER2, HER3 and HER4 was correlated with the risk of cancer-related death in female patients (Supplementary Table 2).	('HER2', 'Gene', '2064', (42, 46))	('HER3', 'Gene', (48, 52))	('correlated', 'Reg', (66, 76))	('HER4', 'Gene', (57, 61))	('HER4', 'Gene', '2066', (57, 61))	('HER3', 'Gene', '2065', (48, 52))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('EGF', 'Gene', '1950', (36, 39))	('CNG', 'Var', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('EGF', 'Gene', (36, 39))	('HER2', 'Gene', (42, 46))	('cancer', 'Disease', (94, 100))	('patients', 'Species', '9606', (125, 133))
86565	29190914	In male patients, our data showed that HER4 was more likely to be amplified in early-stage tumors.	('HER4', 'Gene', (39, 43))	('amplified', 'Var', (66, 75))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('HER4', 'Gene', '2066', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (8, 16))
86568	29190914	Next, multivariable regression analysis demonstrated that EGFR CNG in female patients and CNG of HER3 and HER4 in male patients were still negatively associated with tumor grade (Supplementary Tables 4 and 5).	('associated', 'Reg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('HER3', 'Gene', (97, 101))	('HER4', 'Gene', '2066', (106, 110))	('HER4', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('EGF', 'Gene', (58, 61))	('negatively', 'NegReg', (139, 149))	('HER3', 'Gene', '2065', (97, 101))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', (166, 171))	('patients', 'Species', '9606', (77, 85))	('EGF', 'Gene', '1950', (58, 61))	('CNG', 'Var', (63, 66))
86569	29190914	In addition, we also found that EGFR CNG in both female and male patients and CNG of HER3 and HER4 in male patients were closely associated with increased risk of cancer-related death (Supplementary Tables 4 and 5).	('EGF', 'Gene', (32, 35))	('associated', 'Reg', (129, 139))	('HER3', 'Gene', '2065', (85, 89))	('patients', 'Species', '9606', (107, 115))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('EGF', 'Gene', '1950', (32, 35))	('CNG', 'Var', (37, 40))	('death', 'Disease', 'MESH:D003643', (178, 183))	('death', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CNG', 'Var', (78, 81))	('patients', 'Species', '9606', (65, 73))	('HER4', 'Gene', '2066', (94, 98))	('HER4', 'Gene', (94, 98))	('cancer', 'Disease', (163, 169))	('HER3', 'Gene', (85, 89))
86570	29190914	Also shown in Supplementary Table 5, our data indicated that CNG of HER2-4 was more frequently found in male patients receiving postoperative radiotherapy.	('patients', 'Species', '9606', (109, 117))	('HER2-4', 'Gene', '2064;2065;2066', (68, 74))	('found', 'Reg', (95, 100))	('CNG', 'Var', (61, 64))	('HER2-4', 'Gene', (68, 74))
86573	29190914	As shown in Table 4, EGFR CNG (HR =2.31, 95% CI =1.44-3.69, P =0.001), IDH1 mutations (HR =0.3, 95% CI =0.17-0.53, P <0.001), increasing age (HR =1.52, 95% CI =1.16-1.98, P =0.002), advanced tumor stage (HR =1.92, 95% CI =1.47-2.48, P <0.001) and tumor recurrence (HR =44.86, 95% CI =6.16-327.00, P <0.001) were significantly correlated with poor survival, while the patients receiving radiotherapy (HR =0.47, 95% CI=0.30-0.75, P <0.001) and the patients with epilepsy (HR =0.41, 95% CI=0.25-0.66, P <0.001) were more likely to have a better prognosis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('mutations', 'Var', (76, 85))	('epilepsy', 'Phenotype', 'HP:0001250', (460, 468))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (247, 252))	('poor', 'NegReg', (342, 346))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('IDH1', 'Gene', (71, 75))	('EGF', 'Gene', (21, 24))	('epilepsy', 'Disease', (460, 468))	('patients', 'Species', '9606', (367, 375))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('IDH1', 'Gene', '3417', (71, 75))	('patients', 'Species', '9606', (446, 454))	('epilepsy', 'Disease', 'MESH:D004827', (460, 468))	('EGF', 'Gene', '1950', (21, 24))
86577	29190914	This was supported by the TCGA dataset that high copy number of EGFR was strongly related with worse patient survival as compared to low copy number (P =0.001) (Figure 2B).	('worse', 'NegReg', (95, 100))	('high copy number', 'Var', (44, 60))	('EGF', 'Gene', (64, 67))	('patient survival', 'CPA', (101, 117))	('EGF', 'Gene', '1950', (64, 67))	('patient', 'Species', '9606', (101, 108))
86578	29190914	In addition, the TCGA dataset also showed that high copy number of HER2 (P =0.007) and HER4 (P =0.006) was significantly associated with poor patient survival (Figure 2); however, we did not find significant relationships between CNG of HER2 and HER4 and poor patient survival.	('patient', 'Species', '9606', (260, 267))	('HER2', 'Gene', '2064', (237, 241))	('HER4', 'Gene', (246, 250))	('HER4', 'Gene', '2066', (246, 250))	('associated', 'Reg', (121, 131))	('high copy number', 'Var', (47, 63))	('patient survival', 'CPA', (142, 158))	('HER4', 'Gene', (87, 91))	('poor', 'NegReg', (137, 141))	('HER2', 'Gene', (67, 71))	('HER2', 'Gene', '2064', (67, 71))	('HER4', 'Gene', '2066', (87, 91))	('patient', 'Species', '9606', (142, 149))	('HER2', 'Gene', (237, 241))
86584	29190914	In addition, given that IDH1 mutation lead to a better prognosis of glioma patients, we next evaluated the effect of CNG of these genes on the survival of the patients with different IDH1 mutation status.	('mutation', 'Var', (29, 37))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('IDH1', 'Gene', '3417', (24, 28))	('IDH1', 'Gene', '3417', (183, 187))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('better', 'PosReg', (48, 54))	('patients', 'Species', '9606', (75, 83))	('IDH1', 'Gene', (24, 28))	('glioma', 'Disease', (68, 74))	('patients', 'Species', '9606', (159, 167))	('IDH1', 'Gene', (183, 187))
86589	29190914	As shown in Figure 5 and Table 6, CNG of these genes dramatically shortened median survival times in the patients receiving radiotherapy (EGFR: 36.0 months vs. 67.0 months, P =0.001; HER2: 40.0 months vs. 60.0 months, P =0.04; HER3: 41.5 months vs. 52.1 months, P =0.06; HER4: 41.8 months vs. 52.6 months, P =0.05), but not in those who did not receive radiotherapy except for EGFR (18.1 months vs. 30.3 months, P =0.02).	('EGF', 'Gene', '1950', (138, 141))	('HER3', 'Gene', (227, 231))	('HER2', 'Gene', '2064', (183, 187))	('genes', 'Var', (47, 52))	('patients', 'Species', '9606', (105, 113))	('HER4', 'Gene', (271, 275))	('HER3', 'Gene', '2065', (227, 231))	('HER4', 'Gene', '2066', (271, 275))	('EGF', 'Gene', (377, 380))	('shortened', 'NegReg', (66, 75))	('EGF', 'Gene', (138, 141))	('CNG', 'Var', (34, 37))	('median survival times', 'CPA', (76, 97))	('EGF', 'Gene', '1950', (377, 380))	('HER2', 'Gene', (183, 187))
86594	29190914	Genomic amplification, a common mechanism for oncogene overexpression, is one of the most frequent genomic alterations found in human cancers including gliomas.	('Genomic amplification', 'Var', (0, 21))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('gliomas', 'Disease', (152, 159))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('human', 'Species', '9606', (128, 133))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
86598	29190914	In the present study, we measured copy number of members of ErbB family (including EGFR, HER2, HER3 and HER4) in a cohort of glioma patients and control subjects using real-time qPCR approach and determined their prognostic significance in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('HER2', 'Gene', '2064', (89, 93))	('patients', 'Species', '9606', (132, 140))	('HER3', 'Gene', '2065', (95, 99))	('EGF', 'Gene', '1950', (83, 86))	('ErbB', 'Gene', '1956', (60, 64))	('HER4', 'Gene', (104, 108))	('glioma', 'Disease', (240, 246))	('gliomas', 'Disease', (240, 247))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('HER2', 'Gene', (89, 93))	('EGF', 'Gene', (83, 86))	('HER3', 'Gene', (95, 99))	('gliomas', 'Disease', 'MESH:D005910', (240, 247))	('glioma', 'Disease', (125, 131))	('ErbB', 'Gene', (60, 64))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('copy number', 'Var', (34, 45))	('HER4', 'Gene', '2066', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('gliomas', 'Phenotype', 'HP:0009733', (240, 247))
86600	29190914	This was consistent with a previous study that EGFR amplification was frequently found in gliomas and could be used as a biomarker for the diagnosis of this cancer.	('gliomas', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('EGF', 'Gene', (47, 50))	('found', 'Reg', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('cancer', 'Disease', (157, 163))	('EGF', 'Gene', '1950', (47, 50))	('amplification', 'Var', (52, 65))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
86601	29190914	These observations suggest that CNG of members of ErbB family is more likely involved in glioma tumorigenesis.	('CNG of', 'Var', (32, 38))	('ErbB', 'Gene', (50, 54))	('involved', 'Reg', (77, 85))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('ErbB', 'Gene', '1956', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('glioma', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
86603	29190914	The results demonstrated that CNG of EGFR, HER3 and HER4 significantly increased the risk of cancer-related death in glioma patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (124, 132))	('EGF', 'Gene', (37, 40))	('CNG', 'Var', (30, 33))	('EGF', 'Gene', '1950', (37, 40))	('death in glioma', 'Disease', 'MESH:D005910', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('HER4', 'Gene', (52, 56))	('HER3', 'Gene', (43, 47))	('increased', 'PosReg', (71, 80))	('HER4', 'Gene', '2066', (52, 56))	('HER3', 'Gene', '2065', (43, 47))	('death in glioma', 'Disease', (108, 123))
86605	29190914	For example, CNGs of EGFR, HER2, HER3, and HER4 had strongly associations with poor overall survival in lung adenocarcinoma with EGFR-activating mutations.	('HER4', 'Gene', '2066', (43, 47))	('HER4', 'Gene', (43, 47))	('lung adenocarcinoma', 'Disease', (104, 123))	('EGF', 'Gene', (129, 132))	('mutations', 'Var', (145, 154))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('EGF', 'Gene', (21, 24))	('HER3', 'Gene', (33, 37))	('EGF', 'Gene', '1950', (129, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('HER3', 'Gene', '2065', (33, 37))	('EGF', 'Gene', '1950', (21, 24))	('HER2', 'Gene', (27, 31))	('CNGs', 'Var', (13, 17))	('poor', 'NegReg', (79, 83))	('HER2', 'Gene', '2064', (27, 31))	('associations', 'Reg', (61, 73))
86611	29190914	As expected, our data and the TCGA database showed that CNG of some of these genes was significantly associated with poor patient survival particularly EGFR.	('patient survival', 'CPA', (122, 138))	('poor', 'NegReg', (117, 121))	('EGF', 'Gene', '1950', (152, 155))	('patient', 'Species', '9606', (122, 129))	('associated', 'Reg', (101, 111))	('EGF', 'Gene', (152, 155))	('CNG', 'Var', (56, 59))
86612	29190914	By using stratified analysis, we surprisingly found that CNG of EGFR, HER2 and HER3 remarkably shortened median survival times in female patients, but almost did not influence the survival of male patients except for EGFR.	('median survival', 'MPA', (105, 120))	('HER3', 'Gene', (79, 83))	('HER2', 'Gene', (70, 74))	('patients', 'Species', '9606', (197, 205))	('shortened', 'NegReg', (95, 104))	('HER3', 'Gene', '2065', (79, 83))	('HER2', 'Gene', '2064', (70, 74))	('EGF', 'Gene', (64, 67))	('CNG', 'Var', (57, 60))	('patients', 'Species', '9606', (137, 145))	('EGF', 'Gene', '1950', (64, 67))	('EGF', 'Gene', (217, 220))	('EGF', 'Gene', '1950', (217, 220))
86613	29190914	In addition, our data also showed that CNG of EGFR, HER3 and HER4 significantly shortened median survival times of the patients with early-stage tumors, but had very little effect on the survival of the patients with late-stage tumors, further supporting that these abnormalities may be early genetic events in glioma tumorigenesis.	('median', 'MPA', (90, 96))	('HER3', 'Gene', (52, 56))	('late-stage tumors', 'Disease', 'MESH:D062706', (217, 234))	('HER4', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('EGF', 'Gene', (46, 49))	('late-stage tumors', 'Disease', (217, 234))	('CNG', 'Var', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (145, 150))	('patients', 'Species', '9606', (203, 211))	('glioma', 'Disease', (311, 317))	('tumors', 'Disease', (228, 234))	('tumor', 'Disease', (318, 323))	('glioma', 'Disease', 'MESH:D005910', (311, 317))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('HER3', 'Gene', '2065', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('HER4', 'Gene', '2066', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (311, 317))	('EGF', 'Gene', '1950', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('patients', 'Species', '9606', (119, 127))	('tumors', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('tumor', 'Disease', (228, 233))	('shortened', 'NegReg', (80, 89))
86614	29190914	However, a previous study has demonstrated mutation rate of EGFR in lung cancer differs between races.	('EGF', 'Gene', (60, 63))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mutation', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('EGF', 'Gene', '1950', (60, 63))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
86620	29190914	AC480 is a highly selective and potent small-molecule inhibitor of EGFR/HER kinase family, and inhibit cancer cell proliferation through targeting EGFR and HER2 kinases.	('HER2', 'Gene', (156, 160))	('EGF', 'Gene', '1950', (67, 70))	('HER2', 'Gene', '2064', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('EGF', 'Gene', (147, 150))	('inhibit', 'NegReg', (95, 102))	('AC480', 'Chemical', 'MESH:C545531', (0, 5))	('AC480', 'Var', (0, 5))	('EGF', 'Gene', '1950', (147, 150))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('EGF', 'Gene', (67, 70))
86621	29190914	Moreover, AC480 has been demonstrated to enhance radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo.	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (41, 65))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (87, 124))	('radioresponse', 'CPA', (70, 83))	('enhance', 'PosReg', (41, 48))	('neck squamous cell carcinoma', 'Disease', (96, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('radiosensitivity', 'CPA', (49, 65))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (96, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('AC480', 'Chemical', 'MESH:C545531', (10, 15))	('AC480', 'Var', (10, 15))
86625	29190914	Therefore, we suppose that CNG of members of ErbB family in gliomas induces radiotherapy resistance through activating the PI3K/AKT pathway.	('radiotherapy resistance', 'CPA', (76, 99))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('AKT', 'Gene', (128, 131))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('ErbB', 'Gene', (45, 49))	('CNG', 'Var', (27, 30))	('activating', 'PosReg', (108, 118))	('ErbB', 'Gene', '1956', (45, 49))	('AKT', 'Gene', '207', (128, 131))	('induces', 'PosReg', (68, 75))
86628	29190914	To our knowledge, the present study for the first time demonstrates that CNG of members of ErbB family may contribute to radiotherapy resistance in glioma patients.	('glioma', 'Disease', (148, 154))	('radiotherapy', 'MPA', (121, 133))	('ErbB', 'Gene', (91, 95))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('ErbB', 'Gene', '1956', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('contribute', 'Reg', (107, 117))	('patients', 'Species', '9606', (155, 163))	('CNG of', 'Var', (73, 79))
86629	29190914	Altogether, our findings indicate that the above abnormalities may be a trigger of glioma tumorigenesis, and may be used as potentially prognostic markers for glioma patients.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', (159, 165))	('abnormalities', 'Var', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('trigger', 'Reg', (72, 79))	('patients', 'Species', '9606', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
86630	29190914	In addition, our data also suggest that a combination of anti-ErbB therapeutics and radiotherapy may be an effective strategy for the treatment of glioma patients with CNG or overactivation of members of ErbB family.	('ErbB', 'Gene', (204, 208))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('ErbB', 'Gene', '1956', (204, 208))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('patients', 'Species', '9606', (154, 162))	('overactivation', 'Var', (175, 189))	('ErbB', 'Gene', (62, 66))	('ErbB', 'Gene', '1956', (62, 66))	('glioma', 'Disease', (147, 153))
86643	29190914	A copy number >=4 was defined as gene amplification (or copy number gain).	('copy number gain', 'Disease', (56, 72))	('copy number', 'Var', (2, 13))	('copy number gain', 'Disease', 'MESH:D015430', (56, 72))
86688	27878374	showed a higher GTR rate for the 5-ALA group compared to the group that was operated without 5-ALA (65 vs. 35%).	('GTR rate', 'CPA', (16, 24))	('5-ALA', 'Var', (33, 38))	('GTR', 'Chemical', '-', (16, 19))	('5-ALA', 'Chemical', 'MESH:C000614854', (93, 98))	('rat', 'Species', '10116', (20, 23))	('rat', 'Species', '10116', (79, 82))	('5-ALA', 'Chemical', 'MESH:C000614854', (33, 38))	('higher', 'PosReg', (9, 15))
86774	27878374	A mouse study showed that the CH1055 molecule has a maximal TNR of 5.50 +- 0.36.	('TNR', 'MPA', (60, 63))	('CH1055', 'Var', (30, 36))	('mouse', 'Species', '10090', (2, 7))
86788	27878374	Cross-linked iron oxide (CLIO) labeled with Cy5.5 is a metabolic targeting nanoparticle that is internalized and accumulated in tumor cells within a maximum of 24 h after injection.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CLIO', 'Chemical', '-', (25, 29))	('iron oxide', 'Chemical', 'MESH:C000499', (13, 23))	('Cy5.5', 'Var', (44, 49))	('Cy5', 'Chemical', 'MESH:C085321', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
86797	27878374	Gliomas express the wild-type or mutated forms of EGFR, including the GBM specific EGFRvIII.	('EGFR', 'Gene', (50, 54))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('mutated', 'Var', (33, 40))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))
86802	27878374	In a recent mouse study, the smaller anti-EGFR affibody protein (+-7kDA) had a significantly higher concentration in the tumor periphery than the full antibody (+-150 kDa).	('higher', 'PosReg', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('anti-EGFR', 'Protein', (37, 46))	('concentration', 'MPA', (100, 113))	('tumor', 'Disease', (121, 126))	('+-7kDA', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('mouse', 'Species', '10090', (12, 17))	('rat', 'Species', '10116', (107, 110))
86848	26981778	Leveraging a mouse model of mesenchymal glioblastoma (NPcis), shRNA-mediated Abcg1 knockdown (KD) increased CHOP ER stress protein expression and resulted in greater NPcis glioma cell death in vitro.	('greater', 'PosReg', (158, 165))	('glioma cell death', 'Disease', (172, 189))	('CHOP', 'Gene', (108, 112))	('mouse', 'Species', '10090', (13, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('mesenchymal glioblastoma', 'Disease', (28, 52))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('Abcg1', 'Gene', (77, 82))	('NPcis glioma', 'Disease', (166, 178))	('CHOP', 'Gene', '13198', (108, 112))	('Abcg1', 'Gene', '11307', (77, 82))	('increased CHOP', 'Phenotype', 'HP:0007906', (98, 112))	('increased', 'PosReg', (98, 107))	('NPcis glioma', 'Disease', 'MESH:D005910', (166, 178))	('mesenchymal glioblastoma', 'Disease', 'MESH:D005909', (28, 52))	('knockdown', 'Var', (83, 92))	('glioma cell death', 'Disease', 'MESH:D005910', (172, 189))
86865	26981778	Leveraging a mouse model of mesenchymal glioblastoma (NPcis), characterized by Nf1 and Trp53 loss, we show that shRNA-mediated Abcg1 knockdown increases ER stress-induced apoptosis in vitro as well as improves the survival of immunocompetent mice with glioblastoma in vivo.	('Trp53', 'Gene', (87, 92))	('Nf1', 'Gene', (79, 82))	('loss', 'NegReg', (93, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (252, 264))	('Abcg1', 'Gene', '11307', (127, 132))	('survival', 'CPA', (214, 222))	('ER stress-induced', 'MPA', (153, 170))	('glioblastoma', 'Disease', (252, 264))	('glioblastoma', 'Phenotype', 'HP:0012174', (252, 264))	('Nf1', 'Gene', '18015', (79, 82))	('mice', 'Species', '10090', (242, 246))	('improves', 'PosReg', (201, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('mouse', 'Species', '10090', (13, 18))	('mesenchymal glioblastoma', 'Disease', (28, 52))	('Abcg1', 'Gene', (127, 132))	('glioblastoma', 'Disease', (40, 52))	('increases', 'PosReg', (143, 152))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('knockdown', 'Var', (133, 142))	('Trp53', 'Gene', '22059', (87, 92))	('mesenchymal glioblastoma', 'Disease', 'MESH:D005909', (28, 52))
86869	26981778	Using the one available GEO dataset containing normal reference tissue (astrocytes; GSE15824), we found that ABCG1 expression was increased in glioblastoma tumors (697 +- 554, 230913_at probe set; 428 +- 305, 232081_at probe set) relative to astrocytes (11.5 +- 1.1, 230913_at probe set; 13.9 +- 8.1, 232081_at probe set).	('glioblastoma tumors', 'Disease', 'MESH:D005909', (143, 162))	('glioblastoma tumors', 'Disease', (143, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('expression', 'MPA', (115, 125))	('697 +- 554, 230913_at', 'Var', (164, 185))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('increased', 'PosReg', (130, 139))	('ABCG1', 'Gene', (109, 114))
86873	26981778	However, when the analysis was stratified by glioblastoma molecular subtype, high ABCG1 expression correlated with shorter overall survival only in the mesenchymal subgroup (Figure 1C), a subtype characterized by NF1 gene mutation.	('high', 'Var', (77, 81))	('NF1', 'Gene', (213, 216))	('overall survival', 'MPA', (123, 139))	('shorter', 'NegReg', (115, 122))	('glioblastoma', 'Disease', (45, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('ABCG1', 'Gene', (82, 87))	('NF1', 'Gene', '18015', (213, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('expression', 'MPA', (88, 98))
86876	26981778	In the glioblastoma mesenchymal molecular subtype, NF1 loss is frequently associated with TP53 mutation.	('loss', 'NegReg', (55, 59))	('NF1', 'Gene', '18015', (51, 54))	('TP53', 'Gene', '22059', (90, 94))	('glioblastoma', 'Disease', (7, 19))	('TP53', 'Gene', (90, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (7, 19))	('NF1', 'Gene', (51, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (7, 19))	('associated', 'Reg', (74, 84))	('mutation', 'Var', (95, 103))
86877	26981778	Consistent with this observation, mice harboring germline inactivating mutations in both the Nf1 and Trp53 genes residing on the same chromosome (NPcis mice) spontaneously develop high-grade gliomas.	('mice', 'Species', '10090', (34, 38))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('gliomas', 'Disease', (191, 198))	('develop', 'Reg', (172, 179))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('Trp53', 'Gene', (101, 106))	('Nf1', 'Gene', (93, 96))	('germline inactivating mutations', 'Var', (49, 80))	('mice', 'Species', '10090', (152, 156))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('Trp53', 'Gene', '22059', (101, 106))	('Nf1', 'Gene', '18015', (93, 96))
86881	26981778	Following Abcg1 knockdown, K1861 cells exhibited morphological changes (e.g., rounding) suggestive of cell death (Figure 2B).	('K1861', 'Var', (27, 32))	('Abcg1', 'Gene', (10, 15))	('Abcg1', 'Gene', '11307', (10, 15))	('knockdown', 'Var', (16, 25))
86885	26981778	Following Abcg1 knockdown (45-54% protein reduction) in K1861 and K4622 glioblastoma cells, there was increased CHOP expression (2.3 and 3-fold, respectively) and caspase-3 cleavage (1.5 and 2.2-fold, respectively) relative to controls (Figure 3).	('cleavage', 'MPA', (173, 181))	('caspase-3', 'Gene', (163, 172))	('protein', 'Protein', (34, 41))	('knockdown', 'Var', (16, 25))	('CHOP', 'Gene', (112, 116))	('increased CHOP', 'Phenotype', 'HP:0007906', (102, 116))	('Abcg1', 'Gene', (10, 15))	('glioblastoma', 'Disease', (72, 84))	('Abcg1', 'Gene', '11307', (10, 15))	('increased', 'PosReg', (102, 111))	('caspase-3', 'Gene', '12367', (163, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('reduction', 'NegReg', (42, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))	('CHOP', 'Gene', '13198', (112, 116))
86887	26981778	To determine whether Abcg1 knockdown also decreases glioma growth in vivo, 5.0 x 104 K1861 glioblastoma cells were stereotactically injected in the right striatum of 3-week-old C57Bl/6J mice.	('knockdown', 'Var', (27, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('glioma growth', 'Disease', (52, 65))	('decreases', 'NegReg', (42, 51))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('glioma growth', 'Disease', 'MESH:D005910', (52, 65))	('mice', 'Species', '10090', (186, 190))	('Abcg1', 'Gene', '11307', (21, 26))	('Abcg1', 'Gene', (21, 26))	('glioblastoma', 'Disease', (91, 103))
86889	26981778	We specifically chose to employ the K1861 glioblastoma for these in vivo experiments, based on previous studies demonstrating that K1861-engrafted mice develop large and aggressive intracranial tumors.	('mice', 'Species', '10090', (147, 151))	('K1861-engrafted', 'Var', (131, 146))	('aggressive intracranial tumors', 'Disease', 'MESH:D020765', (170, 200))	('aggressive intracranial tumors', 'Disease', (170, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))
86890	26981778	Whereas all engrafted mice harbored brain tumors, there was reduced tumor growth by BLI in the two K1861 Abcg1 shRNA groups (n = 10 mice/group) relative to control shRNA K1861-implanted mice (n = 10 mice) at 28 days post-injection (Figure 4A) and the bioluminescent signal was significantly reduced in both Abcg1 shRNA groups relative to control shRNA K1861-implanted mice (#1, p = 0.042; #2, p = 0.0098; Figure 4B).	('Abcg1', 'Gene', (307, 312))	('brain tumors', 'Disease', (36, 48))	('mice', 'Species', '10090', (132, 136))	('mice', 'Species', '10090', (22, 26))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (42, 47))	('Abcg1', 'Gene', (105, 110))	('mice', 'Species', '10090', (368, 372))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mice', 'Species', '10090', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Abcg1', 'Gene', '11307', (307, 312))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('brain tumors', 'Disease', 'MESH:D001932', (36, 48))	('brain tumors', 'Phenotype', 'HP:0030692', (36, 48))	('mice', 'Species', '10090', (199, 203))	('Abcg1', 'Gene', '11307', (105, 110))	('brain tumor', 'Phenotype', 'HP:0030692', (36, 47))	('K1861', 'Var', (99, 104))	('reduced', 'NegReg', (60, 67))	('reduced', 'NegReg', (291, 298))
86894	26981778	To determine whether Abcg1 knockdown resulted in increased glioblastoma apoptosis in vivo, Ki67 and TUNEL immunostaining were performed on the tumors following euthanasia.	('knockdown', 'Var', (27, 36))	('increased glioblastoma apoptosis', 'Disease', (49, 81))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('Ki67', 'Gene', (91, 95))	('Abcg1', 'Gene', '11307', (21, 26))	('Abcg1', 'Gene', (21, 26))	('Ki67', 'Gene', '17345', (91, 95))	('increased glioblastoma apoptosis', 'Disease', 'MESH:D005909', (49, 81))
86895	26981778	Consistent with the above in vitro findings, shAbcg1 K1861 tumors had reduced Abcg1 protein expression and fewer Ki67+ cells relative to controls (Figure 5).	('fewer', 'NegReg', (107, 112))	('reduced', 'NegReg', (70, 77))	('K1861', 'Var', (53, 58))	('Abcg1', 'Gene', (78, 83))	('Ki67', 'Gene', (113, 117))	('Abcg1', 'Gene', '11307', (47, 52))	('Abcg1', 'Gene', '11307', (78, 83))	('tumors', 'Disease', (59, 65))	('Abcg1', 'Gene', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('protein', 'Protein', (84, 91))	('Ki67', 'Gene', '17345', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
86896	26981778	In addition, shAbcg1 K1861 tumors had increased cell death (TUNEL+ cells).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Abcg1', 'Gene', (15, 20))	('Abcg1', 'Gene', '11307', (15, 20))	('tumors', 'Disease', (27, 33))	('cell death', 'CPA', (48, 58))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('K1861', 'Var', (21, 26))
86900	26981778	Interestingly, ABCG1 expression was not associated with survival in patients with all molecular subtypes of glioblastoma; however, there was a strong correlation between poor patient survival and high ABCG1 RNA expression in tumors classified in the mesenchymal GBM subtype.	('poor', 'NegReg', (170, 174))	('patient', 'Species', '9606', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('patient', 'Species', '9606', (175, 182))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('high', 'Var', (196, 200))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('ABCG1', 'Gene', (201, 206))	('glioblastoma', 'Disease', (108, 120))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('tumors', 'Disease', (225, 231))	('mesenchymal GBM subtype', 'Disease', (250, 273))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
86901	26981778	In this subtype, one of the signature genetic changes is mutation of the NF1 tumor suppressor gene, which is intriguing, given the prior identification of ABCG1 as a uniquely upregulated transcript in GSCs originating from a mouse model of low-grade glioma harboring biallelic Nf1 gene inactivation.	('mutation', 'Var', (57, 65))	('Nf1', 'Gene', (277, 280))	('ABCG1', 'Gene', (155, 160))	('NF1', 'Gene', '18015', (73, 76))	('glioma', 'Disease', (250, 256))	('upregulated', 'PosReg', (175, 186))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mouse', 'Species', '10090', (225, 230))	('Nf1', 'Gene', '18015', (277, 280))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('tumor', 'Disease', (77, 82))	('glioma', 'Disease', 'MESH:D005910', (250, 256))	('NF1', 'Gene', (73, 76))
86910	26981778	The fact that attenuated ABCG1 expression significantly prolongs mouse survival following glioblastoma implantation supports a critical role for this protein in tumor maintenance.	('attenuated', 'Var', (14, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('prolongs', 'PosReg', (56, 64))	('ABCG1', 'Gene', (25, 30))	('mouse', 'Species', '10090', (65, 70))	('mouse survival', 'CPA', (65, 79))	('glioblastoma implantation', 'Disease', 'MESH:D005909', (90, 115))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('glioblastoma implantation', 'Disease', (90, 115))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('expression', 'Var', (31, 41))	('tumor', 'Disease', (161, 166))
86912	26981778	In these studies, ABCG2 has been implicated in reduced brain penetration of enhancer of zeste homolog 2 (EZH2) inhibitors as well as the anti-tumoral responses to PARP inhibitors (ABT-888) and temozolomide.	('ABCG2', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ABT-888', 'Chemical', 'MESH:C521013', (180, 187))	('ABCG2', 'Gene', '26357', (18, 23))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('brain penetration', 'CPA', (55, 72))	('enhancer of zeste homolog 2', 'Gene', (76, 103))	('temozolomide', 'Chemical', 'MESH:D000077204', (193, 205))	('PARP', 'Gene', (163, 167))	('inhibitors', 'Var', (111, 121))	('EZH2', 'Gene', '14056', (105, 109))	('EZH2', 'Gene', (105, 109))	('reduced', 'NegReg', (47, 54))	('PARP', 'Gene', '11545', (163, 167))	('enhancer of zeste homolog 2', 'Gene', '14056', (76, 103))
86968	21055475	The parameters which were derived from the fluorescence data were I390/440, tau380/440, tau390/440, I390/450, I390/460, I380/370, I440/550, I390/370, I440/370, I450/370, I460/370, I470/370, I480/370, I380/550, I390/550, I440/550, I450/550, I460/550, I470/550, I480/550, tau370, tau380, tau390, tau440, tau450, tau460, tau470, tau480, I380/370, I380/400, I380/440, I380/450, I380/460, I380/470, I380/480, I380/490, I380/500, I380/510, I380/520, I380/530, I380/540, I390/400, I390/440, I390/470, I390/480, I390/490, I390/500, I390/510, I390/520, I390/530, I390/540, I440/380, I440/390, I440/400, I440/450, I440/460, I440/470, I440/480, I440/490, I440/500, I440/510, I440/520, I440/530, I440/540, LEC-1380, LEC-1390, LEC-1440, LEC-1450, LEC-1460, LEC-1470, LEC-1480, LEC-1490.	('LEC-1', 'Gene', (714, 719))	('LEC-1', 'Gene', '23266', (764, 769))	('LEC-1', 'Gene', '23266', (694, 699))	('LEC-1', 'Gene', '23266', (734, 739))	('I390/470', 'Var', (484, 492))	('I380/540', 'Var', (454, 462))	('LEC-1', 'Gene', (704, 709))	('LEC-1', 'Gene', (754, 759))	('I440/500', 'Var', (644, 652))	('LEC-1', 'Gene', '23266', (724, 729))	('LEC-1', 'Gene', '23266', (714, 719))	('I440/520', 'Var', (664, 672))	('I390/480', 'Var', (494, 502))	('LEC-1', 'Gene', (744, 749))	('LEC-1', 'Gene', '23266', (754, 759))	('LEC-1', 'Gene', '23266', (704, 709))	('I390/440', 'Var', (474, 482))	('I390/400', 'Var', (464, 472))	('LEC-1', 'Gene', (734, 739))	('LEC-1', 'Gene', '23266', (744, 749))	('I440/510', 'Var', (654, 662))	('LEC-1', 'Gene', (694, 699))	('LEC-1', 'Gene', (764, 769))	('I440/530', 'Var', (674, 682))	('LEC-1', 'Gene', (724, 729))	('I440/540', 'Var', (684, 692))
87017	21055475	We hypothesize that this difference may be attributed to the IDH-1 mutation in oligodendral tumors, which affects the NADP+dependant isocitrate dehydrogenase leading to an increase in 2-hydroxyglutarate and alpha-ketoglutarate in the cells.	('increase', 'PosReg', (172, 180))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (207, 226))	('mutation', 'Var', (67, 75))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (184, 202))	('oligodendral tumors', 'Disease', (79, 98))	('oligodendral tumors', 'Disease', 'MESH:D009369', (79, 98))	('alpha-ketoglutarate', 'MPA', (207, 226))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('affects', 'Reg', (106, 113))	('NADP', 'Chemical', 'MESH:D009249', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('2-hydroxyglutarate', 'MPA', (184, 202))	('IDH-1', 'Gene', '3417', (61, 66))	('IDH-1', 'Gene', (61, 66))
87092	19965287	The Kaplan-Meier curve demonstrated that progression-free survival within the LGG group with (rCBV < 1.75) and (rCBV > 1.75) rCBV groups was significantly different (p < 0.0001).	('rCBV', 'Chemical', '-', (112, 116))	('rCBV', 'Var', (112, 116))	('rCBV', 'Chemical', '-', (94, 98))	('rCBV', 'Chemical', '-', (125, 129))	('rCBV', 'Var', (94, 98))
87096	19965287	DSC MRI increases the sensitivity and predictive value in predicting glioma grade compared with conventional contrast-enhanced MRI.	('glioma', 'Disease', (69, 75))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('increases', 'PosReg', (8, 17))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('DSC', 'Var', (0, 3))
87108	19965287	As a result there are some instances whereby there are not only spatial differences in the distribution of the rCBV versus permeability but changes in one metric may be better than the other for differentiating between radiation necrosis and recurrent tumor.	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('necrosis', 'Disease', (229, 237))	('changes', 'Var', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('rCBV', 'Chemical', '-', (111, 115))	('tumor', 'Disease', (252, 257))	('necrosis', 'Disease', 'MESH:D009336', (229, 237))
87128	19965287	In addition to the potential for direct antitumor effects, antiangiogenic therapy has been shown to prune abnormal vessels and 'normalize' existing vasculature, which may paradoxically improve drug and oxygen delivery to the tumor for a period of time following drug administration.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('oxygen', 'Chemical', 'MESH:D010100', (202, 208))	('improve', 'PosReg', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (225, 230))	('antiangiogenic therapy', 'Var', (59, 81))	("'normalize'", 'PosReg', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('abnormal vessels', 'Phenotype', 'HP:0002597', (106, 122))	('prune', 'Var', (100, 105))	('tumor', 'Disease', (44, 49))	('abnormal vessel', 'Phenotype', 'HP:0002597', (106, 121))
87130	19965287	In addition, anti-VEGF therapy has been shown to reduce cerebral edema through elimination of VEGF, which may reduce the need for steroid use and have a beneficial impact on neurologic function.	('cerebral edema', 'Disease', 'MESH:D001929', (56, 70))	('cerebral edema', 'Disease', (56, 70))	('VEGF', 'Gene', (94, 98))	('VEGF', 'Gene', '7422', (18, 22))	('elimination', 'Var', (79, 90))	('edema', 'Phenotype', 'HP:0000969', (65, 70))	('VEGF', 'Gene', '7422', (94, 98))	('reduce', 'NegReg', (49, 55))	('cerebral edema', 'Phenotype', 'HP:0002181', (56, 70))	('reduce', 'NegReg', (110, 116))	('steroid', 'Chemical', 'MESH:D013256', (130, 137))	('VEGF', 'Gene', (18, 22))
87193	32867190	MMPs are synthesized as inactive zymogens (pro-MMPs) and their activation involves the proteolytic cleavage either by trypsin, other MMPs, plasmin, by allosteric activation, or by chemical modification elicited for example by reactive oxygen species (ROS); followed by the autocatalytic removal of the pro-peptide.	('plasmin', 'Gene', (139, 146))	('ROS', 'Chemical', 'MESH:D017382', (251, 254))	('MMPs', 'Gene', (133, 137))	('MMPs', 'Gene', (47, 51))	('allosteric', 'MPA', (151, 161))	('MMPs', 'Gene', '4313;4318', (133, 137))	('MMPs', 'Gene', '4313;4318', (47, 51))	('proteolytic cleavage', 'MPA', (87, 107))	('MMPs', 'Gene', (0, 4))	('MMPs', 'Gene', '4313;4318', (0, 4))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (226, 249))	('chemical modification', 'Var', (180, 201))	('plasmin', 'Gene', '5340', (139, 146))
87202	32867190	Importantly, high expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, and ADM in GB was associated with significantly worse overall survival.	('PFKFB4', 'Gene', '5210', (52, 58))	('LDHA', 'Gene', (40, 44))	('SLC2A1', 'Gene', (32, 38))	('overall survival', 'MPA', (136, 152))	('ADM', 'Gene', '133', (86, 89))	('high', 'Var', (13, 17))	('VEGFA', 'Gene', '7422', (65, 70))	('PDK1', 'Gene', '5163', (46, 50))	('worse', 'NegReg', (130, 135))	('SERPINE1', 'Gene', (72, 80))	('PFKFB4', 'Gene', (52, 58))	('LDHA', 'Gene', '3939', (40, 44))	('ADM', 'Gene', (86, 89))	('SERPINE1', 'Gene', '5054', (72, 80))	('HK2', 'Gene', (60, 63))	('HK2', 'Gene', '3099', (60, 63))	('GB', 'Phenotype', 'HP:0012174', (93, 95))	('PDK1', 'Gene', (46, 50))	('VEGFA', 'Gene', (65, 70))
87293	32867190	NDRG1 was highly induced during hypoxia in a time-dependent manner in all GB cells analyzed, with expression levels ranging from 3-18 fold in UP-007, 20-240 fold in UP-029, 7-25 fold in SEBTA-003, 3-55 fold in SEBTA-023 and 10-30 fold in U87 cells compared to their normoxic control cells.	('induced', 'PosReg', (17, 24))	('UP-029', 'Var', (165, 171))	('GB', 'Phenotype', 'HP:0012174', (74, 76))	('NDRG1', 'Gene', '10397', (0, 5))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('U87', 'CellLine', 'CVCL:0022', (238, 241))	('NDRG1', 'Gene', (0, 5))	('hypoxia', 'Disease', (32, 39))	('expression', 'MPA', (98, 108))
87305	32867190	NDRG1 relative expression was 0.1 (-10 fold) in UP-007, 0.015 (-65 fold) in UP-029, 0.2 (-5 fold) in SEBTA-003, 0.005 (-200 fold) in SEBTA-023 and 0.04 (-25 fold) in U87 cells compared to RPLP0.	('RPLP0', 'Gene', (188, 193))	('0.015', 'Var', (56, 61))	('NDRG1', 'Gene', '10397', (0, 5))	('expression', 'MPA', (15, 25))	('U87', 'CellLine', 'CVCL:0022', (166, 169))	('RPLP0', 'Gene', '6175', (188, 193))	('NDRG1', 'Gene', (0, 5))
87307	32867190	ANGPTL4 expression was 0.2 (-5 fold) in SEBTA-003, 0.04-0.06 (-17 to -25 fold) in UP-007, UP-029 and U87 cells and 0.01 (-100 fold) in SEBTA-023 cells compared to RPLP0.	('RPLP0', 'Gene', '6175', (163, 168))	('ANGPTL4', 'Gene', (0, 7))	('ANGPTL4', 'Gene', '51129', (0, 7))	('U87', 'CellLine', 'CVCL:0022', (101, 104))	('RPLP0', 'Gene', (163, 168))	('expression', 'MPA', (8, 18))	('0.04-0.06', 'Var', (51, 60))
87360	32867190	We observed that GB patients showing high expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, and ADM genes had significantly worse overall survival (Figure 8C-K).	('high expression', 'Var', (37, 52))	('SLC2A1', 'Gene', (56, 62))	('PFKFB4', 'Gene', '5210', (76, 82))	('LDHA', 'Gene', (64, 68))	('PDK1', 'Gene', (70, 74))	('overall survival', 'MPA', (144, 160))	('VEGFA', 'Gene', (89, 94))	('SERPINE1', 'Gene', (96, 104))	('GB', 'Phenotype', 'HP:0012174', (17, 19))	('ADM', 'Gene', '133', (110, 113))	('worse', 'NegReg', (138, 143))	('patients', 'Species', '9606', (20, 28))	('SERPINE1', 'Gene', '5054', (96, 104))	('VEGFA', 'Gene', '7422', (89, 94))	('PDK1', 'Gene', '5163', (70, 74))	('LDHA', 'Gene', '3939', (64, 68))	('PFKFB4', 'Gene', (76, 82))	('ADM', 'Gene', (110, 113))	('HK2', 'Gene', (84, 87))	('HK2', 'Gene', '3099', (84, 87))
87383	32867190	EGFR gene amplification and/or overexpression are frequently observed in GB.	('EGFR', 'Gene', (0, 4))	('overexpression', 'PosReg', (31, 45))	('GB', 'Phenotype', 'HP:0012174', (73, 75))	('amplification', 'Var', (10, 23))	('EGFR', 'Gene', '1956', (0, 4))
87384	32867190	The most common EGFR gene mutation being the deletion of exons 2-7, resulting in a truncated and constitutively active, ligand independent receptor, EGFRvIII.	('mutation', 'Var', (26, 34))	('deletion', 'Var', (45, 53))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (149, 153))	('constitutively active', 'MPA', (97, 118))	('EGFR', 'Gene', (16, 20))
87385	32867190	EGFR stimulation either by ligand binding and/or gene amplification results in the activation of the PI3K pathway, leading to increased HIF-1alpha translation and stabilization via the PI3K/AKT/FRAP/mTOR pathway.	('FRAP', 'Gene', '2475', (194, 198))	('mTOR', 'Gene', (199, 203))	('stabilization', 'MPA', (163, 176))	('EGFR', 'Gene', (0, 4))	('HIF-1alpha', 'Gene', '3091', (136, 146))	('AKT', 'Gene', '207', (190, 193))	('PI3K pathway', 'Pathway', (101, 113))	('EGFR', 'Gene', '1956', (0, 4))	('gene amplification', 'Var', (49, 67))	('translation', 'MPA', (147, 158))	('AKT', 'Gene', (190, 193))	('HIF-1alpha', 'Gene', (136, 146))	('FRAP', 'Gene', (194, 198))	('increased', 'PosReg', (126, 135))	('mTOR', 'Gene', '2475', (199, 203))
87408	32867190	A previous study showed the up-regulation of PFKFP, PDK1, PGAM1, ENO1, HK2, ALDOA, and ENO2 during hypoxia in 5 patient derived biopsy cell lines and two commercially available cell lines (U87 and U251) by RT-qPCR.	('PGAM1', 'Gene', (58, 63))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('patient', 'Species', '9606', (112, 119))	('HK2', 'Gene', (71, 74))	('U87', 'CellLine', 'CVCL:0022', (189, 192))	('HK2', 'Gene', '3099', (71, 74))	('hypoxia', 'Disease', (99, 106))	('PFKFP', 'Gene', (45, 50))	('PDK1', 'Gene', '5163', (52, 56))	('ENO2', 'Gene', '2026', (87, 91))	('PDK1', 'Gene', (52, 56))	('RT-qPCR', 'Var', (206, 213))	('ENO2', 'Gene', (87, 91))	('up-regulation', 'PosReg', (28, 41))	('ENO1', 'Gene', (65, 69))
87419	32867190	We also observed that high-expression of VEGFA was associated with significantly worse overall survival in GB patients (Figure 8H).	('VEGFA', 'Gene', (41, 46))	('high-expression', 'Var', (22, 37))	('GB', 'Phenotype', 'HP:0012174', (107, 109))	('VEGFA', 'Gene', '7422', (41, 46))	('worse', 'NegReg', (81, 86))	('patients', 'Species', '9606', (110, 118))	('overall survival', 'MPA', (87, 103))
87427	32867190	A previous publication reported that HIF-1alpha siRNA knockdown led to MMP-2 downregulation in U87, U251, U373 and LN18 GB cells.	('downregulation', 'NegReg', (77, 91))	('knockdown', 'Var', (54, 63))	('MMP-2', 'Gene', '4313', (71, 76))	('HIF-1alpha', 'Gene', (37, 47))	('U87', 'CellLine', 'CVCL:0022', (95, 98))	('MMP-2', 'Gene', (71, 76))	('GB', 'Phenotype', 'HP:0012174', (120, 122))	('HIF-1alpha', 'Gene', '3091', (37, 47))
87443	32867190	High levels of PAI-1 have been associated with shorter overall survival and poor prognosis in many cancers including breast, gastric, colorectal, pancreas, glioma, lung, kidney, prostate, liver, and bone.	('shorter', 'NegReg', (47, 54))	('glioma', 'Disease', (156, 162))	('breast', 'Disease', (117, 123))	('PAI-1', 'Gene', '5054', (15, 20))	('High levels', 'Var', (0, 11))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('PAI-1', 'Gene', (15, 20))	('overall survival', 'MPA', (55, 71))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('colorectal', 'Disease', (134, 144))	('liver', 'Disease', (188, 193))	('pancreas', 'Disease', (146, 154))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('prostate', 'Disease', (178, 186))	('lung', 'Disease', (164, 168))	('colorectal', 'Disease', 'MESH:D015179', (134, 144))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('bone', 'Disease', (199, 203))	('cancers', 'Disease', (99, 106))	('gastric', 'Disease', (125, 132))	('kidney', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
87444	32867190	Here, we confirmed the association of high SERPINE1 expression with significantly worse GB patient overall survival (Figure 8I).	('high', 'Var', (38, 42))	('expression', 'MPA', (52, 62))	('overall survival', 'CPA', (99, 115))	('worse', 'NegReg', (82, 87))	('SERPINE1', 'Gene', (43, 51))	('patient', 'Species', '9606', (91, 98))	('SERPINE1', 'Gene', '5054', (43, 51))	('GB', 'Phenotype', 'HP:0012174', (88, 90))
87473	32867190	Moreover, high expression of ADM in GB was associated with worse overall survival (Figure 8K).	('worse', 'NegReg', (59, 64))	('ADM', 'Gene', (29, 32))	('high', 'Var', (10, 14))	('ADM', 'Gene', '133', (29, 32))	('GB', 'Phenotype', 'HP:0012174', (36, 38))	('overall survival', 'MPA', (65, 81))
87567	29199818	The 2016 CNS WHO classification system incorporated molecular variants of high-grade gliomas, including IDH-wildtype and IDH mutant glioblastoma, and H3.3K27M mutant diffuse midline glioma (which includes tumors previously referred to as diffuse intrinsic pontine glioma, DIPG).	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('H3.3K27M mutant', 'Var', (150, 165))	('IDH', 'Gene', (104, 107))	('DIPG', 'Chemical', 'MESH:C060938', (272, 276))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('IDH', 'Gene', (121, 124))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('glioblastoma', 'Disease', (132, 144))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('midline glioma', 'Disease', (174, 188))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('IDH', 'Gene', '3417', (104, 107))	('IDH', 'Gene', '3417', (121, 124))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('glioma', 'Disease', (264, 270))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('midline glioma', 'Disease', 'MESH:D005910', (174, 188))	('glioma', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('gliomas', 'Disease', (85, 92))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))
87568	29199818	Next-generation sequencing has revealed that somatic mutations in genes encoding histones are characteristic of pediatric high-grade gliomas, specifically H3F3A (replication-independent histone 3 variant H3.3) as well as in histone 3.1, whereas IDH mutant gliomas are extremely rare.	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('gliomas', 'Disease', (256, 263))	('H3F3A', 'Gene', '3020', (155, 160))	('IDH', 'Gene', (245, 248))	('mutations', 'Var', (53, 62))	('gliomas', 'Disease', 'MESH:D005910', (256, 263))	('gliomas', 'Phenotype', 'HP:0009733', (256, 263))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('IDH', 'Gene', '3417', (245, 248))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('H3F3A', 'Gene', (155, 160))
87569	29199818	In addition, ATRX (alpha-thalassemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein) in combination with TP53 mutations are frequently seen in pediatric HGGs.	('DAXX', 'Gene', '1616', (79, 83))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (25, 73))	('ATRX', 'Gene', (13, 17))	('HGGs', 'Disease', (186, 190))	('TP53', 'Gene', '7157', (138, 142))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (25, 73))	('death', 'Disease', 'MESH:D003643', (85, 90))	('ATRX', 'Gene', '546', (13, 17))	('death', 'Disease', (85, 90))	('mental retardation', 'Phenotype', 'HP:0001249', (37, 55))	('TP53', 'Gene', (138, 142))	('DAXX', 'Gene', (79, 83))	('mutations', 'Var', (143, 152))
87570	29199818	Furthermore, approximately 80% of pediatric GBMs demonstrate activation of the PI3K/Akt/mTOR pathway; mutations in epidermal growth factor receptor (EGFR)  and platelet-derived growth factor receptor (PDGFR)  have also been associated.	('epidermal growth factor receptor', 'Gene', '1956', (115, 147))	('Akt', 'Gene', '207', (84, 87))	('platelet-derived growth factor receptor', 'Gene', (160, 199))	('PDGFR', 'Gene', (201, 206))	('EGFR', 'Gene', '1956', (149, 153))	('activation', 'PosReg', (61, 71))	('mTOR', 'Gene', (88, 92))	('Akt', 'Gene', (84, 87))	('mTOR', 'Gene', '2475', (88, 92))	('associated', 'Reg', (224, 234))	('PDGFR', 'Gene', '5159', (201, 206))	('mutations', 'Var', (102, 111))	('epidermal growth factor receptor', 'Gene', (115, 147))	('EGFR', 'Gene', (149, 153))	('platelet-derived growth factor receptor', 'Gene', '5159', (160, 199))	('PI3', 'Gene', '5266', (79, 82))	('PI3', 'Gene', (79, 82))
87574	29199818	Investigators have identified that 80% of diffuse midline glioma cases harbor histone 3.3 or 3.1 mutations, most frequently H3.3K27M.	('H3.3K27M', 'Var', (124, 132))	('histone 3.3', 'Protein', (78, 89))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('midline glioma', 'Disease', 'MESH:D005910', (50, 64))	('midline glioma', 'Disease', (50, 64))
87575	29199818	For example, H3.1 mutations co-occur with ACVR1 mutations most commonly while H3.3 mutations co-occur with p53 and PDGFRA mutations.	('H3.1', 'Gene', '8352', (13, 17))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('PDGFRA', 'Gene', '5156', (115, 121))	('PDGFRA', 'Gene', (115, 121))	('ACVR1', 'Gene', (42, 47))	('co-occur', 'Reg', (28, 36))	('ACVR1', 'Gene', '90', (42, 47))	('mutations', 'Var', (48, 57))	('H3.1', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
87576	29199818	Other accessory driver mutations have been identified including mutations in PIK3R1 and PIK3CA.	('PIK3CA', 'Gene', '5290', (88, 94))	('mutations', 'Var', (64, 73))	('PIK3CA', 'Gene', (88, 94))	('PIK3R1', 'Gene', '5295', (77, 83))	('PIK3R1', 'Gene', (77, 83))
87580	29199818	For instance, neurofibromatosis type 1, a genetic syndrome caused by a mutation in the neurofibromin 1 gene, is associated with pilocytic astrocytoma and diffusely infiltrating astrocytoma and a number of other malignancies that may be amenable to biologically targeted treatments.	('neurofibromin 1', 'Gene', '4763', (87, 102))	('neurofibromin 1', 'Gene', (87, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (138, 149))	('neurofibromatosis type 1', 'Gene', (14, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (177, 188))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (14, 31))	('genetic syndrome', 'Disease', 'MESH:D030342', (42, 58))	('astrocytoma', 'Disease', 'MESH:D001254', (138, 149))	('neurofibromatosis type 1', 'Gene', '4763', (14, 38))	('astrocytoma', 'Disease', (138, 149))	('astrocytoma', 'Disease', 'MESH:D001254', (177, 188))	('malignancies', 'Disease', 'MESH:D009369', (211, 223))	('astrocytoma', 'Disease', (177, 188))	('malignancies', 'Disease', (211, 223))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (128, 149))	('mutation', 'Var', (71, 79))	('pilocytic astrocytoma', 'Disease', (128, 149))	('caused by', 'Reg', (59, 68))	('associated', 'Reg', (112, 122))	('genetic syndrome', 'Disease', (42, 58))
87581	29199818	Pilocytic astrocytomas have been found to harbor mutations in BRAF, neurotrophic tyrosine kinase type 2 (NTRK2), and histone H3; all of which are being specifically targeted in current pediatric clinical trials.	('Pilocytic astrocytomas', 'Disease', (0, 22))	('NTRK2', 'Gene', (105, 110))	('mutations', 'Var', (49, 58))	('neurotrophic tyrosine kinase type 2', 'Gene', '4915', (68, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('neurotrophic tyrosine kinase type 2', 'Gene', (68, 103))	('NTRK2', 'Gene', '4915', (105, 110))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))
87599	29199818	Note that the clinical utility of molecular biomarkers has already been established for a variety of cancers, including glioma, and specific well-established assays have had their analytical validity demonstrated for detection of those mutations in patient samples.	('patient', 'Species', '9606', (249, 256))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('mutations', 'Var', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('glioma', 'Disease', (120, 126))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
87613	29199818	have validated the utility of a pocket-sized nanopore sequencing device that is capable of detecting copy number variants, point mutations, and methylation profiling within just 1 day for the analysis of brain cancer biopsies.	('brain cancer', 'Phenotype', 'HP:0030692', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('brain cancer', 'Disease', (204, 216))	('point mutations', 'Var', (123, 138))	('copy number variants', 'Var', (101, 121))	('brain cancer', 'Disease', 'MESH:D001932', (204, 216))
87614	29199818	Furthermore, this platform was able to distinguish gliomas, medulloblastomas, and brain metastases of different primary sites from patient brain tumor biopsy samples, with copy number and epigenetic profiles that correlated well with matched microarray data.	('gliomas', 'Disease', (51, 58))	('medulloblastoma', 'Phenotype', 'HP:0002885', (60, 75))	('brain tumor', 'Disease', 'MESH:D001932', (139, 150))	('metastases', 'Disease', (88, 98))	('medulloblastomas', 'Disease', (60, 76))	('brain tumor', 'Phenotype', 'HP:0030692', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('copy number', 'Var', (172, 183))	('epigenetic profiles', 'Var', (188, 207))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('patient', 'Species', '9606', (131, 138))	('medulloblastomas', 'Disease', 'MESH:D008527', (60, 76))	('brain tumor', 'Disease', (139, 150))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
87621	29199818	Finally, tumor-associated short noncoding RNAs found in CSF or blood are also thought to provide important insight into brain tumor biology due to the differences found between expression profiles in healthy individuals and patients (Figure 3).	('CSF', 'Gene', '3918', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('brain tumor', 'Disease', 'MESH:D001932', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('short noncoding RNAs', 'Var', (26, 46))	('brain tumor', 'Disease', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (9, 14))	('patients', 'Species', '9606', (224, 232))	('brain tumor', 'Phenotype', 'HP:0030692', (120, 131))	('CSF', 'Gene', (56, 59))	('tumor', 'Disease', (126, 131))
87636	29199818	For instance, Zhang's group has conducted nanoparticle-mediated siRNA knockdown of the DNA repair enzyme apurinic endonuclease 1 (Ape1) in a murine model of glioblastoma  and in pediatric ependymoma and medulloblastoma cells in vitro, reporting improvements in circumventing radiation resistance in these tumors.	('knockdown', 'Var', (70, 79))	('glioblastoma', 'Disease', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('pediatric ependymoma', 'Disease', (178, 198))	('improvements', 'PosReg', (245, 257))	('circumventing', 'MPA', (261, 274))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('medulloblastoma', 'Disease', 'MESH:D008527', (203, 218))	('pediatric ependymoma', 'Disease', 'MESH:D004806', (178, 198))	('ependymoma', 'Phenotype', 'HP:0002888', (188, 198))	('medulloblastoma', 'Phenotype', 'HP:0002885', (203, 218))	('tumors', 'Disease', 'MESH:D009369', (305, 311))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('Ape1', 'Gene', (130, 134))	('murine', 'Species', '10090', (141, 147))	('medulloblastoma', 'Disease', (203, 218))	('tumors', 'Disease', (305, 311))
87646	29199818	As previously mentioned, sequencing of pediatric gliomas have identified mutations in the genes encoding histones 3.1 and 3.3, as well as chromatin modifiers ATRX and DAXX.	('DAXX', 'Gene', (167, 171))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('ATRX', 'Gene', (158, 162))	('pediatric gliomas', 'Disease', (39, 56))	('DAXX', 'Gene', '1616', (167, 171))	('ATRX', 'Gene', '546', (158, 162))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('pediatric gliomas', 'Disease', 'MESH:D005910', (39, 56))	('mutations', 'Var', (73, 82))
87647	29199818	For example, a multihistone deacetylase inhibitor, panobinostat, subsequently showed therapeutic efficacy in H3.3K27M mutant diffuse midline glioma cell culture and xenograft models, and is currently undergoing a phase I trial in children .	('H3.3K27M', 'Gene', (109, 117))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('mutant', 'Var', (118, 124))	('midline glioma', 'Disease', 'MESH:D005910', (133, 147))	('midline glioma', 'Disease', (133, 147))	('children', 'Species', '9606', (230, 238))	('diffuse', 'Disease', (125, 132))
87648	29199818	Another phase I trial is evaluating H3.3K27M peptide vaccine conjugated with tetanus toxoid  in pediatric patients with diffuse midline glioma.	('midline glioma', 'Disease', 'MESH:D005910', (128, 142))	('tetanus toxoid', 'Disease', (77, 91))	('midline glioma', 'Disease', (128, 142))	('tetanus toxoid', 'Disease', 'MESH:D013746', (77, 91))	('H3.3K27M', 'Var', (36, 44))	('patients', 'Species', '9606', (106, 114))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
87654	29199818	A frequent mutation identified in pediatric low-grade gliomas (LGG) involves BRAF, a gene that encodes a crucial enzyme involved in cell survival and growth signaling.	('BRAF', 'Gene', '673', (77, 81))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('BRAF', 'Gene', (77, 81))	('mutation', 'Var', (11, 19))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
87655	29199818	Case reports have suggested some efficacy of vemurafenib against BRAFV600E mutant LGG in children; an early phase I trial is currently underway .	('BRAFV600E', 'Var', (65, 74))	('BRAFV600E', 'Mutation', 'rs113488022', (65, 74))	('vemurafenib', 'Chemical', 'MESH:D000077484', (45, 56))	('LGG', 'Gene', (82, 85))	('children', 'Species', '9606', (89, 97))
87657	29199818	In vitro and in vivo model systems of BRAF mutant LGG lend support to combination regimens such as PLX4720 (a BRAF inhibitor) plus selumetinib, or mTOR with MEK blockade.	('MEK', 'Gene', (157, 160))	('MEK', 'Gene', '5609', (157, 160))	('LGG', 'Gene', (50, 53))	('BRAF', 'Gene', '673', (38, 42))	('selumetinib', 'Chemical', 'MESH:C517975', (131, 142))	('mutant', 'Var', (43, 49))	('BRAF', 'Gene', '673', (110, 114))	('BRAF', 'Gene', (38, 42))	('mTOR', 'Gene', '2475', (147, 151))	('BRAF', 'Gene', (110, 114))	('mTOR', 'Gene', (147, 151))
87668	29199818	Treatment arms that are currently enrolling include larotrectinib (a pan-TRK inhibitor), LY3023414 (a small-molecule inhibitor of class I PI3K isoforms), mTOR, and DNA-PK, plus six other arms.	('DNA-PK', 'Gene', '5591', (164, 170))	('PI3', 'Gene', (138, 141))	('larotrectinib', 'Chemical', 'MESH:C000609083', (52, 65))	('LY3023414', 'Chemical', 'MESH:C000621566', (89, 98))	('PI3', 'Gene', '5266', (138, 141))	('TRK', 'Gene', (73, 76))	('mTOR', 'Gene', (154, 158))	('TRK', 'Gene', '4914', (73, 76))	('mTOR', 'Gene', '2475', (154, 158))	('DNA-PK', 'Gene', (164, 170))	('LY3023414', 'Var', (89, 98))
87681	29199818	In treating patients with glioblastoma, researchers have attempted engineering CAR T-cells to target the tumor-associated antigen interleukin-13 receptor alpha 2; epidermal growth factor receptor variant III-specific CAR T-cells have demonstrated efficacy in a murine model.	('patients', 'Species', '9606', (12, 20))	('glioblastoma', 'Disease', (26, 38))	('interleukin-13', 'Gene', '3596', (130, 144))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('CAR', 'Gene', (217, 220))	('epidermal growth factor receptor', 'Gene', (163, 195))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('CAR', 'Gene', (79, 82))	('CAR', 'Gene', '9970', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CAR', 'Gene', '9970', (79, 82))	('murine', 'Species', '10090', (261, 267))	('variant III-specific', 'Var', (196, 216))	('interleukin-13', 'Gene', (130, 144))	('tumor', 'Disease', (105, 110))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))
87693	29199818	Vaccination therapies composed of peptides against glioma-associated antigens, which were identified to be overexpressed in LGGs, have also shown promise in children with recurrent LGGs.	('LGGs', 'Disease', (181, 185))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('peptides', 'Var', (34, 42))	('children', 'Species', '9606', (157, 165))
87701	29199818	In vivo studies in mice showed successful penetration of the bifunctional aptamers into the brain.	('penetration', 'CPA', (42, 53))	('aptamers', 'Protein', (74, 82))	('bifunctional', 'Var', (61, 73))	('mice', 'Species', '10090', (19, 23))
87703	29199818	In vivo studies were successful in inducing specific toxicity in U87MG GBM cells in mice, and these PNPs effectively cross the BBB to arrive at the target microenvironment.	('inducing', 'Reg', (35, 43))	('mice', 'Species', '10090', (84, 88))	('U87MG', 'Var', (65, 70))	('U87MG', 'CellLine', 'CVCL:0022', (65, 70))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('toxicity', 'Disease', (53, 61))
87728	29098416	Conventionally, pathologists make the histological diagnosis by assessing morphological features of cellular atypia, variation of nuclear size (anisonucleosis), shape (pleomorphism), mitotic activity, cell density, characteristic architectural patterns, vascular properties, and cell necrosis.	('vascular properties', 'CPA', (254, 273))	('nuclear size', 'CPA', (130, 142))	('necrosis', 'Disease', 'MESH:D009336', (284, 292))	('cell', 'CPA', (279, 283))	('cell density', 'CPA', (201, 213))	('variation', 'Var', (117, 126))	('necrosis', 'Disease', (284, 292))	('mitotic activity', 'CPA', (183, 199))	('cellular', 'CPA', (100, 108))
87729	29098416	With the exception of histone-mutant diffuse midline gliomas, these cytoarchitectural characteristics are taken into account when assigning a malignancy grade to the tumour according to the WHO classification scheme.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('midline gliomas', 'Disease', 'MESH:D005910', (45, 60))	('tumour', 'Disease', (166, 172))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('malignancy', 'Disease', 'MESH:D009369', (142, 152))	('histone-mutant', 'Var', (22, 36))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('malignancy', 'Disease', (142, 152))	('midline gliomas', 'Disease', (45, 60))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
87732	29098416	Recent combined efforts by large research consortia have, however, led to the discovery of a number of key mutations, chromosome copy number variations and epigenetic alterations in a range of intrinsic brain tumours, challenging the clinical relevance of the traditional diagnostic approach.	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('mutations', 'Var', (107, 116))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('epigenetic alterations', 'Var', (156, 178))	('brain tumour', 'Phenotype', 'HP:0030692', (203, 215))	('chromosome copy number variations', 'Var', (118, 151))	('brain tumours', 'Phenotype', 'HP:0030692', (203, 216))	('intrinsic brain tumours', 'Disease', (193, 216))	('intrinsic brain tumours', 'Disease', 'MESH:D020919', (193, 216))
87735	29098416	The discovery of mutations in specific genes has revolutionised our understanding of the pathogenesis of many type of glioma and has subsequently led to a biomarker-driven classification which in current practice not only supplements, but increasingly overrides the histological diagnosis.	('glioma', 'Disease', (118, 124))	('led to', 'Reg', (146, 152))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('mutations', 'Var', (17, 26))
87740	29098416	The discovery of mutations in the isocitrate dehydrogenase genes 1 and 2 (IDH1, IDH2) in 2008 was a major breakthrough towards molecular biomarker-driven diagnosis of adult gliomas.	('adult gliomas', 'Disease', 'MESH:D005910', (167, 180))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('IDH1', 'Gene', (74, 78))	('IDH2', 'Gene', '3418', (80, 84))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('adult gliomas', 'Disease', (167, 180))	('IDH1', 'Gene', '3417', (74, 78))	('mutations', 'Var', (17, 26))	('IDH2', 'Gene', (80, 84))
87741	29098416	Mutations on codon 132 or 172 of the IDH1 and IDH2 genes, respectively, results in "neo-enzymatic activity" with the production of the novel oncometabolite 2-hydroxyglutarate causing widespread methylation of the tumour cell DNA and altered regulation of histone methylation.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('results', 'Reg', (72, 79))	('IDH2', 'Gene', (46, 50))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('IDH1', 'Gene', (37, 41))	('IDH2', 'Gene', '3418', (46, 50))	('altered', 'Reg', (233, 240))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', (213, 219))	('IDH1', 'Gene', '3417', (37, 41))	('histone methylation', 'MPA', (255, 274))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (156, 174))	('methylation', 'MPA', (194, 205))	('regulation', 'MPA', (241, 251))
87743	29098416	IDH mutations occur in two classes of gliomas, astrocytomas and oligodendrogliomas.	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (47, 82))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('IDH', 'Gene', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('occur', 'Reg', (14, 19))	('gliomas', 'Disease', (75, 82))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('mutations', 'Var', (4, 13))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
87746	29098416	The majority (90%) of both astrocytomas and oligodendrogliomas carry a specific point mutation (R132H) in the IDH1 gene, which can be detected immunohistochemically with a mutation-specific antibody.	('IDH1', 'Gene', '3417', (110, 114))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('R132H', 'Var', (96, 101))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (27, 62))	('R132H', 'Mutation', 'rs121913500', (96, 101))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH1', 'Gene', (110, 114))
87748	29098416	The presence of an IDH1 or IDH2 mutation is also required for the diagnosis of oligodendroglioma and anaplastic oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('oligodendroglioma and anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (79, 129))	('IDH1', 'Gene', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1', 'Gene', '3417', (19, 23))	('IDH2', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('IDH2', 'Gene', '3418', (27, 31))
87749	29098416	The previously known entity of oligoastrocytoma was defined on histological grounds only and is now extinct, as there is robust evidence that the IDH mutations segregate either with the chromosomal codeletion of 1p/19q in oligodendrogliomas, or with a loss of function mutation in the ATRX gene (alpha thalassaemia/mental retardation syndrome X-linked) in astrocytomas (Fig.	('oligoastrocytoma', 'Disease', (31, 47))	('thalassaemia/mental retardation syndrome X-linked', 'Disease', (302, 351))	('mental retardation', 'Phenotype', 'HP:0001249', (315, 333))	('IDH', 'Gene', '3417', (146, 149))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (222, 240))	('astrocytomas', 'Disease', (356, 368))	('mutations', 'Var', (150, 159))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('thalassaemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (302, 351))	('oligodendrogliomas', 'Disease', (222, 240))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('loss of function', 'NegReg', (252, 268))	('astrocytomas', 'Disease', 'MESH:D001254', (356, 368))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (31, 47))	('IDH', 'Gene', (146, 149))	('astrocytoma', 'Phenotype', 'HP:0009592', (356, 367))	('ATRX', 'Gene', (285, 289))	('ATRX', 'Gene', '546', (285, 289))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))	('mutation', 'Var', (269, 277))
87750	29098416	Mutations in the ATRX gene are routinely tested in most laboratories by immunostaining for the ATRX protein, which detects loss of expression resulting from the majority of ATRX gene mutations.	('ATRX', 'Gene', (95, 99))	('ATRX', 'Gene', (17, 21))	('mutations', 'Var', (183, 192))	('ATRX', 'Gene', '546', (173, 177))	('ATRX', 'Gene', '546', (17, 21))	('ATRX', 'Gene', '546', (95, 99))	('expression', 'MPA', (131, 141))	('loss', 'NegReg', (123, 127))	('ATRX', 'Gene', (173, 177))
87751	29098416	However, a small proportion of mutations in the ATRX gene does not result in the loss of protein expression, and thus are not detectable by immunohistochemistry.	('mutations', 'Var', (31, 40))	('protein expression', 'MPA', (89, 107))	('ATRX', 'Gene', (48, 52))	('loss', 'NegReg', (81, 85))	('ATRX', 'Gene', '546', (48, 52))
87753	29098416	Diagnostically useful is the additional testing for mutations in the promoter region of telomerase reverse transcriptase (TERT), which leads to an upregulation of the telomerase complex activity, increasing tumour cell survival.	('tumour', 'Disease', (207, 213))	('telomerase complex', 'Enzyme', (167, 185))	('TERT', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (122, 126))	('activity', 'MPA', (186, 194))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('increasing', 'PosReg', (196, 206))	('upregulation', 'PosReg', (147, 159))	('telomerase reverse transcriptase', 'Gene', (88, 120))	('telomerase reverse transcriptase', 'Gene', '7015', (88, 120))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('mutations in', 'Var', (52, 64))
87754	29098416	Two hotspots in the TERT promoter (C228T or C250T) are strongly associated with oligodendrogliomas.	('associated', 'Reg', (64, 74))	('C250T', 'Mutation', 'c.250C>T', (44, 49))	('C250T', 'Var', (44, 49))	('C228T', 'Var', (35, 40))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (80, 98))	('C228T', 'Mutation', 'c.228C>T', (35, 40))	('oligodendrogliomas', 'Disease', (80, 98))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
87757	29098416	Of note, IDH mutations also are mutually exclusive with mutations in the BRAF gene (see below and Fig.	('BRAF', 'Gene', '673', (73, 77))	('BRAF', 'Gene', (73, 77))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', '3417', (9, 12))	('mutations', 'Var', (13, 22))
87759	29098416	The combination of IDH mutation and 1p/19q codeletion predicts a favourable response to upfront combined radiochemotherapy.	('1p/19q codeletion', 'Var', (36, 53))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', (19, 22))	('mutation', 'Var', (23, 31))
87760	29098416	The importance of a 1p/19q codeletion, in particular, in anaplastic oligodendrogliomas has been demonstrated in several prospective phase 3 trials.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (68, 86))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('1p/19q', 'Var', (20, 26))	('oligodendrogliomas', 'Disease', (68, 86))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
87770	29098416	Prior to the discovery of IDH mutations as biomarkers of diffuse astrocytomas, such "early" glioblastomas were morphologically indistinguishable from other forms of astrocytomas but showed a rapid progression, posing a significant challenge to the WHO classification system.	('glioblastomas', 'Phenotype', 'HP:0012174', (92, 105))	('astrocytomas', 'Disease', 'MESH:D001254', (165, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (92, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('glioblastomas', 'Disease', (92, 105))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('astrocytomas', 'Disease', (165, 177))	('astrocytomas', 'Disease', (65, 77))	('IDH', 'Gene', '3417', (26, 29))
87771	29098416	Currently, no specific mutation has been identified in IDH-wildtype glioblastomas that could serve as a useful biomarker, in the same way that IDH mutations do for oligodendrogliomas and astrocytomas.	('mutations', 'Var', (147, 156))	('IDH-wildtype glioblastomas', 'Disease', (55, 81))	('IDH', 'Gene', '3417', (143, 146))	('oligodendrogliomas and astrocytomas', 'Disease', 'MESH:D009837', (164, 199))	('IDH', 'Gene', (55, 58))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('IDH', 'Gene', '3417', (55, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('astrocytoma', 'Phenotype', 'HP:0009592', (187, 198))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (55, 81))	('IDH', 'Gene', (143, 146))
87773	29098416	The molecular alterations in IDH-wildtype glioblastomas include mutations in the TERT promoter, chromosome 10q loss, 7p gain or EGFR amplification, (some with an additional EGFR vIII mutation), ID2, MYCN and PDGFRA amplifications and CDKN2A/B deletions.	('deletions', 'Var', (243, 252))	('IDH-wildtype glioblastomas', 'Disease', (29, 55))	('CDKN2A/B', 'Gene', '1029;1030', (234, 242))	('amplifications', 'Var', (215, 229))	('ID2', 'Gene', '3398', (194, 197))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (29, 55))	('ID2', 'Gene', (194, 197))	('EGFR', 'Gene', (128, 132))	('MYCN', 'Gene', '4613', (199, 203))	('glioblastomas', 'Phenotype', 'HP:0012174', (42, 55))	('EGFR', 'Gene', '1956', (173, 177))	('mutations', 'Var', (64, 73))	('PDGFRA', 'Gene', (208, 214))	('gain', 'Disease', 'MESH:D015430', (120, 124))	('PDGFRA', 'Gene', '5156', (208, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('chromosome 10q', 'Gene', (96, 110))	('CDKN2A/B', 'Gene', (234, 242))	('MYCN', 'Gene', (199, 203))	('loss', 'NegReg', (111, 115))	('TERT', 'Gene', (81, 85))	('EGFR', 'Gene', '1956', (128, 132))	('TERT', 'Gene', '7015', (81, 85))	('gain', 'Disease', (120, 124))	('EGFR', 'Gene', (173, 177))	('amplification', 'PosReg', (133, 146))
87774	29098416	Molecular testing for these alterations can be helpful in identifying glioblastomas even in small samples, which do not demonstrate histological diagnostic criteria for glioblastoma (Fig.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastoma', 'Disease', (169, 181))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('glioblastomas', 'Disease', (70, 83))	('alterations', 'Var', (28, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('glioblastoma', 'Disease', (70, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))
87776	29098416	A small proportion of IDH-wildtype glioblastomas harbour a BRAF V600E point mutation (see below) or FGFR-TACC fusions.	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (22, 48))	('BRAF', 'Gene', (59, 63))	('IDH-wildtype glioblastomas', 'Disease', (22, 48))	('BRAF', 'Gene', '673', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('FGFR-TACC', 'Gene', (100, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))	('V600E', 'Var', (64, 69))
87779	29098416	Methylation of the MGMT promoter is thought to silence gene expression and therefore reduce the repair activity of the protein.	('silence', 'NegReg', (47, 54))	('repair activity of the protein', 'MPA', (96, 126))	('Methylation', 'Var', (0, 11))	('reduce', 'NegReg', (85, 91))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('gene expression', 'MPA', (55, 70))
87785	29098416	A decade later, mutations in the BRAF gene, the V600E point mutation in particular, have been demonstrated in a range of low-grade IDH-wildtype glial and glioneuronal tumours, and also are increasingly recognised in malignant variants.	('glioneuronal tumours', 'Disease', 'MESH:D009369', (154, 174))	('glioneuronal tumour', 'Phenotype', 'HP:0025170', (154, 173))	('BRAF', 'Gene', '673', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('BRAF', 'Gene', (33, 37))	('demonstrated', 'Reg', (94, 106))	('IDH', 'Gene', (131, 134))	('glioneuronal tumours', 'Disease', (154, 174))	('glioneuronal tumours', 'Phenotype', 'HP:0025170', (154, 174))	('V600E', 'Mutation', 'rs113488022', (48, 53))	('V600E point', 'Var', (48, 59))	('IDH', 'Gene', '3417', (131, 134))
87786	29098416	Mutations in the BRAF gene activate the MAP kinase pathway cascade, stimulating cell growth.	('stimulating', 'PosReg', (68, 79))	('MAP kinase pathway cascade', 'Pathway', (40, 66))	('activate', 'PosReg', (27, 35))	('BRAF', 'Gene', '673', (17, 21))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('cell growth', 'CPA', (80, 91))
87787	29098416	Tumours in which this point mutation is most commonly found are pleomorphic xanthoastrocytoma (PXA, 60%), ganglioglioma and gangliocytoma (30%), subependymal giant cell astrocytoma (SEGA, 40%), desmoplastic infantile glioma (10%) and pilocytic astrocytoma (5% infratentorial and 20% supratentorial).	('desmoplastic infantile glioma', 'Disease', 'MESH:D005910', (194, 223))	('desmoplastic infantile glioma', 'Disease', (194, 223))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (145, 180))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('ganglioglioma and gangliocytoma', 'Disease', 'MESH:D005729', (106, 137))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (64, 93))	('pilocytic astrocytoma', 'Disease', (234, 255))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (244, 255))	('giant cell astrocytoma', 'Phenotype', 'HP:0009718', (158, 180))	('pleomorphic xanthoastrocytoma', 'Disease', (64, 93))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (234, 255))	('point mutation', 'Var', (22, 36))	('subependymal giant cell astrocytoma', 'Disease', (145, 180))
87788	29098416	Unlike the well-defined molecular classes of IDH-mutant tumours, the V600E point mutation in the BRAF gene occurs only in a subset of these nosological tumour entities.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', '3417', (45, 48))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour entities', 'Disease', 'MESH:D009369', (152, 167))	('tumour entities', 'Disease', (152, 167))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('BRAF', 'Gene', '673', (97, 101))	('V600E point', 'Var', (69, 80))	('BRAF', 'Gene', (97, 101))
87790	29098416	The BRAF V600E mutation has also been documented in a morphological variant of glioblastoma (epithelioid glioblastoma).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('epithelioid glioblastoma', 'Disease', (93, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('V600E', 'Var', (9, 14))	('epithelioid glioblastoma', 'Disease', 'MESH:D005909', (93, 117))	('glioblastoma', 'Disease', (79, 91))	('BRAF', 'Gene', (4, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('BRAF', 'Gene', '673', (4, 8))	('glioblastoma', 'Disease', (105, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))
87794	29098416	Apart from a single substitution V600E mutation, other mutations in the BRAF gene, which can occur in IDH-wildtype gliomas and glioneuronal tumours, include rearrangements, duplications and fusions with other genes and their detection may be diagnostically helpful.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('duplications', 'Var', (173, 185))	('rearrangements', 'Var', (157, 171))	('BRAF', 'Gene', (72, 76))	('IDH-wildtype gliomas and glioneuronal tumours', 'Disease', 'MESH:D005910', (102, 147))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('glioneuronal tumour', 'Phenotype', 'HP:0025170', (127, 146))	('fusions', 'Var', (190, 197))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('V600E', 'Var', (33, 38))	('glioneuronal tumours', 'Phenotype', 'HP:0025170', (127, 147))	('BRAF', 'Gene', '673', (72, 76))
87797	29098416	Those pilocytic astrocytomas which do not harbour KIAA1549-BRAF fusion mutations, have been found to have mutations in genes encoding constituents of the MAP kinase pathway, including FGFR1 and NTRK gene family, NF1, PTPN11, KRAS and RAF1.	('pilocytic astrocytomas', 'Disease', (6, 28))	('KIAA1549-BRAF', 'Disease', 'None', (50, 63))	('NTRK', 'Gene', (194, 198))	('RAF1', 'Gene', '5894', (234, 238))	('KRAS', 'Gene', '3845', (225, 229))	('NF1', 'Gene', '4763', (212, 215))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (6, 28))	('KRAS', 'Gene', (225, 229))	('mutations', 'Var', (71, 80))	('RAF1', 'Gene', (234, 238))	('NF1', 'Gene', (212, 215))	('NTRK', 'Gene', '4915', (194, 198))	('astrocytoma', 'Phenotype', 'HP:0009592', (16, 27))	('MAP', 'Pathway', (154, 157))	('FGFR1', 'Gene', '2260', (184, 189))	('PTPN11', 'Gene', (217, 223))	('KIAA1549-BRAF', 'Disease', (50, 63))	('PTPN11', 'Gene', '5781', (217, 223))	('mutations', 'Var', (106, 115))	('FGFR1', 'Gene', (184, 189))
87798	29098416	Inhibition of the activating effects caused by the BRAF V600E mutation was the rationale for developing inhibitor drugs interrupting the BRAF/MEK component of the MAP kinase pathway.	('BRAF', 'Gene', (137, 141))	('V600E', 'Var', (56, 61))	('MEK', 'Gene', (142, 145))	('MAP kinase pathway', 'Pathway', (163, 181))	('activating effects', 'MPA', (18, 36))	('BRAF', 'Gene', '673', (137, 141))	('MEK', 'Gene', '5609', (142, 145))	('BRAF', 'Gene', '673', (51, 55))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('BRAF', 'Gene', (51, 55))
87799	29098416	Vemurafenib, Dabrafenib) were developed and initially approved for the treatment of BRAF V600E mutant melanomas, and have since been trialled first in malignant, and more recently in low-grade BRAF V600E mutant brain tumours.	('BRAF', 'Gene', (193, 197))	('BRAF', 'Gene', '673', (193, 197))	('brain tumour', 'Phenotype', 'HP:0030692', (211, 223))	('melanomas', 'Disease', (102, 111))	('BRAF', 'Gene', '673', (84, 88))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('V600E', 'Mutation', 'rs113488022', (198, 203))	('brain tumours', 'Phenotype', 'HP:0030692', (211, 224))	('tumours', 'Phenotype', 'HP:0002664', (217, 224))	('brain tumours', 'Disease', (211, 224))	('BRAF', 'Gene', (84, 88))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('brain tumours', 'Disease', 'MESH:D001932', (211, 224))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('mutant', 'Var', (95, 101))	('Dabrafenib', 'Chemical', 'MESH:C561627', (13, 23))
87802	29098416	BRAF fusions have no known prognostic value, however, tumours bearing these mutations may in the future benefit from MAP kinase pathway inhibitors.	('mutations', 'Var', (76, 85))	('benefit', 'PosReg', (104, 111))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('MAP kinase pathway', 'Pathway', (117, 135))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
87803	29098416	Mutations in the histone genes have recently been demonstrated in several malignant tumours, including high-grade gliomas.	('gliomas', 'Disease', (114, 121))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('malignant tumours', 'Disease', 'MESH:D009369', (74, 91))	('malignant tumours', 'Disease', (74, 91))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('demonstrated', 'Reg', (50, 62))	('histone genes', 'Gene', (17, 30))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
87805	29098416	K27M, G34R and G34V).	('G34V', 'Var', (15, 19))	('G34R', 'Var', (6, 10))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('K27M', 'Var', (0, 4))	('G34V', 'SUBSTITUTION', 'None', (15, 19))	('G34R', 'Mutation', 'rs1057519902', (6, 10))
87808	29098416	The H3 K27M mutant diffuse midline gliomas of the brain stem are also known as diffuse intrinsic pontine gliomas (DIPG).	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('K27M', 'Mutation', 'p.K27M', (7, 11))	('DIPG', 'Chemical', '-', (114, 118))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('midline gliomas', 'Disease', (27, 42))	('H3 K27M', 'Var', (4, 11))	('gliomas', 'Disease', (35, 42))	('midline gliomas', 'Disease', 'MESH:D005910', (27, 42))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))
87809	29098416	H3 K27M mutant gliomas correspond to WHO grade IV (i.e.	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('K27M', 'Mutation', 'p.K27M', (3, 7))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('H3 K27M', 'Var', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
87812	29098416	in the cerebral hemispheric regions, more commonly carry the histone H3.3 G34R or rarely G34V mutations.	('H3.3', 'Gene', '3020', (69, 73))	('G34V', 'SUBSTITUTION', 'None', (89, 93))	('G34V', 'Var', (89, 93))	('G34R', 'Mutation', 'rs1057519902', (74, 78))	('G34R', 'Var', (74, 78))	('H3.3', 'Gene', (69, 73))
87813	29098416	The majority of these mutations are found in the H3F3A gene.	('H3F3A', 'Gene', (49, 54))	('mutations', 'Var', (22, 31))	('H3F3A', 'Gene', '3020', (49, 54))
87814	29098416	A proportion of histone-mutant tumours also harbour mutations in the ATRX gene.	('mutations', 'Var', (52, 61))	('histone-mutant', 'Protein', (16, 30))	('ATRX', 'Gene', (69, 73))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('ATRX', 'Gene', '546', (69, 73))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))
87817	29098416	Although as of now, there is no specific treatment available for histone-mutant gliomas, the discovery of mutations in histone genes and ongoing further research into the underlying mechanisms has laid the foundation for the development of targeted therapies with the aim to inhibit histone methylase and demethylase (reviewed in).	('histone methylase', 'Enzyme', (283, 300))	('histone-mutant', 'Var', (65, 79))	('demethylase', 'Gene', (305, 316))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('demethylase', 'Gene', '8932', (305, 316))	('histone genes', 'Gene', (119, 132))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('mutations', 'Var', (106, 115))	('inhibit', 'NegReg', (275, 282))
87827	29098416	They are rare, have a distinctive rosetting histological pattern and harbour mutations in the PIK3CA and FGFR1 genes, but they currently have little diagnostic value as the histology is characteristic and unique in most instances.	('FGFR1', 'Gene', (105, 110))	('FGFR1', 'Gene', '2260', (105, 110))	('distinctive rosetting', 'Phenotype', 'HP:0031925', (22, 43))	('mutations', 'Var', (77, 86))	('PIK3CA', 'Gene', (94, 100))	('PIK3CA', 'Gene', '5290', (94, 100))
87835	29098416	These tumours do not harbour mutations in the IDH, BRAF or histone genes, but instead are characterised by MYBL gene rearrangements, which are thought to be driver mutations.	('rearrangements', 'Var', (117, 131))	('MYBL', 'Disease', 'None', (107, 111))	('IDH', 'Gene', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('BRAF', 'Gene', '673', (51, 55))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('IDH', 'Gene', '3417', (46, 49))	('BRAF', 'Gene', (51, 55))	('tumours', 'Disease', (6, 13))	('MYBL', 'Disease', (107, 111))
87841	29098416	In the supratentorial location, ependymomas with the presence of a fusion gene between C11ORF95 and RELA (ST-EPN-RELA) have a poor prognosis, and in the posterior fossa location the ependymoma group PF-EPN-A is characterised by a poor prognosis.	('ependymoma', 'Phenotype', 'HP:0002888', (32, 42))	('RELA', 'Gene', (113, 117))	('RELA', 'Gene', '5970', (113, 117))	('ST-EPN-RELA', 'Gene', '5970', (106, 117))	('fusion gene', 'Var', (67, 78))	('ependymoma', 'Disease', (32, 42))	('presence', 'Var', (53, 61))	('ependymoma', 'Disease', (182, 192))	('C11ORF95', 'Gene', '65998', (87, 95))	('RELA', 'Gene', (100, 104))	('RELA', 'Gene', '5970', (100, 104))	('ependymoma', 'Disease', 'MESH:D004806', (32, 42))	('ependymomas', 'Disease', 'MESH:D004806', (32, 43))	('ependymoma', 'Phenotype', 'HP:0002888', (182, 192))	('C11ORF95', 'Gene', (87, 95))	('ST-EPN-RELA', 'Gene', (106, 117))	('ependymoma', 'Disease', 'MESH:D004806', (182, 192))	('ependymomas', 'Disease', (32, 43))
87849	29098416	Many of the tumour entities described in this review are now defined by the presence of a mutation that serves as a biomarker, and there is now a consensus that certain brain tumour types should be diagnosed according to distinct biomarker profiles rather than histological features alone.	('brain tumour', 'Disease', 'MESH:D001932', (169, 181))	('tumour entities', 'Disease', 'MESH:D009369', (12, 27))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('brain tumour', 'Disease', (169, 181))	('tumour entities', 'Disease', (12, 27))	('mutation', 'Var', (90, 98))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('brain tumour', 'Phenotype', 'HP:0030692', (169, 181))
87854	29098416	The main clinical relevance of identifying specific (epi) genetic alterations in each tumour is in their potential to serve as target for inhibitor drugs, or for the development of therapies, such as immunotherapy with vaccines aiming at the destruction of cells expressing a mutant protein.	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('protein', 'Protein', (283, 290))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('mutant', 'Var', (276, 282))	('tumour', 'Disease', (86, 92))	('genetic alterations', 'Var', (58, 77))
87856	28064387	Specific gene mutations, structural rearrangements, DNA methylation patterns, and gene expression profiles are now recognized to define molecular subgroups of gliomas that arise in distinct anatomic locations and patient age groups, and also provide a better prediction of clinical outcomes for glioma patients compared to histologic assessment alone.	('glioma', 'Phenotype', 'HP:0009733', (295, 301))	('glioma', 'Disease', (159, 165))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('patient', 'Species', '9606', (213, 220))	('patients', 'Species', '9606', (302, 310))	('patient', 'Species', '9606', (302, 309))	('glioma', 'Disease', (295, 301))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('mutations', 'Var', (14, 23))	('glioma', 'Disease', 'MESH:D005910', (295, 301))
87857	28064387	Understanding the role of these distinctive genetic alterations in gliomagenesis is also important for the development of potential targeted therapeutic interventions.	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('genetic alterations', 'Var', (44, 63))
87858	28064387	Mutations including K27M and G34R/V that affect critical amino acids within the N-terminal tail of the histone H3 variants, H3.3 and H3.1 (encoded by H3F3A and HIST1H3B genes), are prime examples of mutations in diffuse gliomas with characteristic clinical associations that can help diagnostic classification and guide effective patient management.	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('H3F3A', 'Gene', '3020', (150, 155))	('H3', 'Gene', '126961', (150, 152))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('G34R', 'SUBSTITUTION', 'None', (29, 33))	('H3', 'Gene', '126961', (111, 113))	('G34R', 'Var', (29, 33))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('H3', 'Gene', '126961', (133, 135))	('H3F3A', 'Gene', (150, 155))	('H3', 'Gene', '126961', (165, 167))	('H3', 'Gene', '126961', (124, 126))	('patient', 'Species', '9606', (330, 337))	('K27M', 'Var', (20, 24))	('affect', 'Reg', (41, 47))	('K27M', 'Mutation', 'p.K27M', (20, 24))	('HIST1H3B', 'Gene', (160, 168))	('HIST1H3B', 'Gene', '8358', (160, 168))	('gliomas', 'Disease', (220, 227))
87859	28064387	These histone H3 mutations frequently co-occur with inactivating mutations in ATRX in association with alternative lengthening of telomeres.	('ATRX', 'Gene', (78, 82))	('ATRX', 'Gene', '546', (78, 82))	('inactivating mutations', 'Var', (52, 74))	('co-occur', 'Reg', (38, 46))	('H3', 'Gene', '126961', (14, 16))	('mutations', 'Var', (17, 26))
87860	28064387	Telomere length can also be maintained through upregulation of telomerase reverse transcriptase (TERT) expression driven by mutation within the TERT gene promoter region, an alteration most commonly found in oligodendrogliomas and primary glioblastomas arising in adults.	('glioblastomas', 'Phenotype', 'HP:0012174', (239, 252))	('oligodendrogliomas', 'Disease', (208, 226))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('glioblastomas', 'Disease', 'MESH:D005909', (239, 252))	('glioblastoma', 'Phenotype', 'HP:0012174', (239, 251))	('TERT', 'Gene', (144, 148))	('TERT', 'Gene', '7015', (144, 148))	('glioblastomas', 'Disease', (239, 252))	('upregulation', 'PosReg', (47, 59))	('TERT', 'Gene', (97, 101))	('mutation', 'Var', (124, 132))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (208, 226))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('TERT', 'Gene', '7015', (97, 101))
87861	28064387	Interestingly, the genetic alterations perturbing histone and telomere function in pediatric gliomas tend to be different from those present in adult tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('adult tumors', 'Disease', 'MESH:C538052', (144, 156))	('pediatric gliomas', 'Disease', (83, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('pediatric gliomas', 'Disease', 'MESH:D005910', (83, 100))	('genetic alterations', 'Var', (19, 38))	('adult tumors', 'Disease', (144, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('perturbing', 'NegReg', (39, 49))
87862	28064387	We present a review of these mutations affecting the histone code and telomere length, highlighting their importance in prognosis and as targets for novel therapeutics in the treatment of diffuse gliomas.	('affecting', 'Reg', (39, 48))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('mutations', 'Var', (29, 38))	('histone code', 'MPA', (53, 65))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))
87870	28064387	Two hotspot mutations in the promoter region of the TERT gene (chr.5: g.1,295,228C>T and g.1,295,250C>T) were first reported in 71% of sporadic melanomas, and have since been detected in numerous cancers.	('228C>T', 'Mutation', 'c.228C>T', (78, 84))	('g.1,295,250C>T', 'Var', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('numerous cancers', 'Disease', (187, 203))	('250C>T', 'Mutation', 'c.250C>T', (97, 103))	('sporadic melanomas', 'Disease', 'MESH:D008545', (135, 153))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('TERT', 'Gene', (52, 56))	('TERT', 'Gene', '7015', (52, 56))	('sporadic melanomas', 'Disease', (135, 153))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('numerous cancers', 'Disease', 'MESH:D009369', (187, 203))
87871	28064387	These mutations create novel-binding sites for E-twenty-six (ETS) transcription factors, specifically the GABP transcription factor that binds to the mutant promoter, resulting in increased TERT transcription.	('TERT', 'Gene', '7015', (190, 194))	('novel-binding', 'Interaction', (23, 36))	('increased', 'PosReg', (180, 189))	('mutant', 'Var', (150, 156))	('TERT', 'Gene', (190, 194))	('mutations', 'Var', (6, 15))
87872	28064387	In the absence of telomerase activity, telomere length can be maintained by homologous recombination, a mechanism known as alternative lengthening of telomeres (ALT).	('ALT', 'Chemical', '-', (161, 164))	('telomere', 'MPA', (39, 47))	('homologous', 'Var', (76, 86))
87873	28064387	ALT is utilized by approximately 5-15% of human cancers, and is associated with genetic inactivation or loss of expression of the histone H3.3 chaperone proteins ATRX and DAXX.	('loss', 'NegReg', (104, 108))	('cancers', 'Disease', (48, 55))	('DAXX', 'Gene', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('human', 'Species', '9606', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('histone H3.3', 'Gene', '3021', (130, 142))	('DAXX', 'Gene', '1616', (171, 175))	('ATRX', 'Gene', (162, 166))	('histone H3.3', 'Gene', (130, 142))	('ALT', 'Chemical', '-', (0, 3))	('ATRX', 'Gene', '546', (162, 166))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('genetic inactivation', 'Var', (80, 100))	('expression', 'MPA', (112, 122))
87874	28064387	Mutations in genes affecting the histone code and alterations of histone methylation status have been reported in several cancer types.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('alterations', 'Reg', (50, 61))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('reported', 'Reg', (102, 110))
87875	28064387	However mutations directly affecting histone genes were originally described in gliomas, and have been subsequently found in chondroblastomas and giant cell tumors of bone.	('chondroblastomas', 'Disease', (125, 141))	('histone genes', 'Gene', (37, 50))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('chondroblastomas', 'Disease', 'MESH:D002804', (125, 141))	('giant cell tumors', 'Disease', (146, 163))	('gliomas', 'Disease', (80, 87))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('tumors of bone', 'Phenotype', 'HP:0010622', (157, 171))	('giant cell tumors', 'Disease', 'MESH:D005870', (146, 163))	('mutations', 'Var', (8, 17))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('described', 'Reg', (67, 76))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('found', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('giant cell tumors of bone', 'Phenotype', 'HP:0011847', (146, 171))
87876	28064387	Tail mutations of histone H3 at amino acids 27 and 34 leading to K27M (lysine to methionine substitution at codon 27) and G34R/V (glycine to arginine or valine substitution at codon 34) were initially reported in 36% of non-brainstem pediatric high-grade gliomas, with 14% containing G34R/V mutations and 22% containing K27M mutations (Table 1).	('G34R', 'Var', (122, 126))	('K27M', 'Var', (320, 324))	('H3', 'Gene', '126961', (26, 28))	('valine', 'Chemical', 'MESH:D014633', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('lysine to methionine substitution at codon 27', 'Mutation', 'p.K27M', (71, 116))	('arginine', 'Chemical', 'MESH:D001120', (141, 149))	('K27M', 'Mutation', 'p.K27M', (65, 69))	('G34R', 'SUBSTITUTION', 'None', (284, 288))	('glycine', 'Chemical', 'MESH:D005998', (130, 137))	('K27M', 'Mutation', 'p.K27M', (320, 324))	('G34R', 'SUBSTITUTION', 'None', (122, 126))	('K27M', 'Var', (65, 69))	('gliomas', 'Phenotype', 'HP:0009733', (255, 262))	('gliomas', 'Disease', (255, 262))	('G34R', 'Var', (284, 288))	('gliomas', 'Disease', 'MESH:D005910', (255, 262))
87878	28064387	Mutations predominantly occur in the H3F3A gene encoding H3.3, but analogous K27M mutations are also found at lower frequency in histone 3.1 gene HIST1H3B.	('K27M', 'Mutation', 'p.K27M', (77, 81))	('H3F3A', 'Gene', (37, 42))	('occur', 'Reg', (24, 29))	('histone 3', 'Gene', '126961', (129, 138))	('histone 3', 'Gene', (129, 138))	('K27M', 'Var', (77, 81))	('H3', 'Gene', '126961', (151, 153))	('Mutations', 'Var', (0, 9))	('HIST1H3B', 'Gene', (146, 154))	('HIST1H3B', 'Gene', '8358', (146, 154))	('H3F3A', 'Gene', '3020', (37, 42))	('H3', 'Gene', '126961', (37, 39))	('H3', 'Gene', '126961', (57, 59))
87879	28064387	Histone H3.3 K27M and G34R/V mutations are mutually exclusive with each other, with analogous histone 3.1 mutations, and with IDH1/2 mutations.	('IDH1/2', 'Gene', '3417;3418', (126, 132))	('histone 3', 'Gene', '126961', (94, 103))	('K27M', 'Mutation', 'p.K27M', (13, 17))	('histone 3', 'Gene', (94, 103))	('Histone H3.3', 'Gene', (0, 12))	('K27M', 'Var', (13, 17))	('IDH1/2', 'Gene', (126, 132))	('Histone H3.3', 'Gene', '3021', (0, 12))	('G34R', 'SUBSTITUTION', 'None', (22, 26))	('G34R', 'Var', (22, 26))
87880	28064387	H3 K27M mutations characterize diffuse midline gliomas arising in both pediatric and adult patients, while H3 G34R/V mutations are found in diffuse gliomas centered within the cerebral hemispheres arising predominantly in older pediatric patients.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('G34R', 'SUBSTITUTION', 'None', (110, 114))	('gliomas centered within the cerebral', 'Disease', (148, 184))	('patients', 'Species', '9606', (91, 99))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('midline gliomas', 'Disease', (39, 54))	('G34R', 'Var', (110, 114))	('H3', 'Gene', '126961', (0, 2))	('K27M', 'Mutation', 'p.K27M', (3, 7))	('H3', 'Gene', '126961', (107, 109))	('midline gliomas', 'Disease', 'MESH:D005910', (39, 54))	('gliomas centered within the cerebral', 'Disease', 'MESH:D001929', (148, 184))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('patients', 'Species', '9606', (238, 246))
87883	28064387	While pontine K27M mutations are found in younger patients, K27M mutations have been increasingly recognized in diffuse midline gliomas of adolescents and adults, occurring in 52-58% of adult spinal cord, brainstem, and thalamic gliomas.	('K27M', 'Mutation', 'p.K27M', (60, 64))	('thalamic gliomas', 'Disease', 'MESH:D013786', (220, 236))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('K27M mutations', 'Var', (60, 74))	('patients', 'Species', '9606', (50, 58))	('thalamic gliomas', 'Disease', (220, 236))	('midline gliomas of adolescents', 'Disease', (120, 150))	('K27M', 'Mutation', 'p.K27M', (14, 18))	('gliomas', 'Phenotype', 'HP:0009733', (229, 236))	('midline gliomas of adolescents', 'Disease', 'MESH:D005910', (120, 150))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))
87884	28064387	Diffuse gliomas with K27M mutations have been reported in the thalamus and spinal cord with a median age of 24 years, and in the pineal region of a 65-year-old patient.	('gliomas', 'Disease', (8, 15))	('K27M', 'Mutation', 'p.K27M', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('K27M mutations', 'Var', (21, 35))	('Diffuse', 'Disease', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('patient', 'Species', '9606', (160, 167))
87885	28064387	In pediatric diffuse midline gliomas, K27M mutation status correlates with very poor prognosis regardless of histologic grade, whereas K27M mutation in thalamic gliomas of adult patients does not always correlate with worse prognosis.	('patients', 'Species', '9606', (178, 186))	('K27M', 'Mutation', 'p.K27M', (38, 42))	('thalamic gliomas', 'Disease', 'MESH:D013786', (152, 168))	('K27M', 'Mutation', 'p.K27M', (135, 139))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('midline gliomas', 'Disease', (21, 36))	('thalamic gliomas', 'Disease', (152, 168))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('K27M mutation', 'Var', (38, 51))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('midline gliomas', 'Disease', 'MESH:D005910', (21, 36))
87887	28064387	ATRX or DAXX gene mutations have been reported to co-occur with K27M mutations, yet the frequency of co-occurrence is variable across studies with reported co-mutation rates of 30%-60%.	('K27M', 'Mutation', 'p.K27M', (64, 68))	('ATRX', 'Gene', (0, 4))	('K27M mutations', 'Var', (64, 78))	('DAXX', 'Gene', '1616', (8, 12))	('ATRX', 'Gene', '546', (0, 4))	('DAXX', 'Gene', (8, 12))
87888	28064387	Variability in the coexistence of ATRX and K27M mutations may be explained by location specific differences.	('ATRX', 'Gene', (34, 38))	('ATRX', 'Gene', '546', (34, 38))	('K27M', 'Var', (43, 47))	('K27M', 'Mutation', 'p.K27M', (43, 47))
87890	28064387	G34R/V histone H3 mutations are found in diffuse gliomas within the cerebral hemispheres, affect adolescents with a median age of 18, and portend a better prognosis compared to diffuse midline gliomas with H3 K27M mutation.	('G34R', 'SUBSTITUTION', 'None', (0, 4))	('affect', 'Reg', (90, 96))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('G34R', 'Var', (0, 4))	('midline gliomas', 'Disease', 'MESH:D005910', (185, 200))	('H3', 'Gene', '126961', (15, 17))	('diffuse gliomas within the cerebral', 'Disease', 'MESH:D001929', (41, 76))	('K27M', 'Mutation', 'p.K27M', (209, 213))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('H3', 'Gene', '126961', (206, 208))	('diffuse gliomas within the cerebral', 'Disease', (41, 76))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('midline gliomas', 'Disease', (185, 200))	('mutations', 'Var', (18, 27))
87891	28064387	ATRX mutations frequently occur with G34R/V histone mutations, with reported co-mutation rates ranging from 75% to 100%.	('histone', 'Protein', (44, 51))	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('ATRX', 'Gene', '546', (0, 4))	('G34R', 'SUBSTITUTION', 'None', (37, 41))	('occur', 'Reg', (26, 31))	('G34R', 'Var', (37, 41))
87892	28064387	Diffuse gliomas arising in the cerebral hemispheres can alternatively harbor mutations in SETD2, a methyltransferase specific to lysine-36 of the histone 3 tail, making the encoded SETD2 (SET domain containing 2) protein a histone code writer.	('SETD2', 'Gene', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('gliomas', 'Disease', (8, 15))	('histone 3', 'Gene', (146, 155))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('SET domain containing 2', 'Gene', '29072', (188, 211))	('SETD2', 'Gene', '29072', (181, 186))	('SETD2', 'Gene', (181, 186))	('mutations', 'Var', (77, 86))	('lysine', 'Chemical', 'MESH:D008239', (129, 135))	('Diffuse', 'Disease', (0, 7))	('SET domain containing 2', 'Gene', (188, 211))	('SETD2', 'Gene', '29072', (90, 95))	('histone 3', 'Gene', '126961', (146, 155))	('harbor', 'Reg', (70, 76))
87893	28064387	SETD2 mutations have been reported in approximately 15% of pediatric high-grade diffuse gliomas in the cerebral hemispheres.	('reported', 'Reg', (26, 34))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('SETD2', 'Gene', '29072', (0, 5))	('gliomas in the cerebral', 'Disease', (88, 111))	('SETD2', 'Gene', (0, 5))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('gliomas in the cerebral', 'Disease', 'MESH:C564230', (88, 111))	('mutations', 'Var', (6, 15))
87894	28064387	SETD2 mutations often occurred in children above the age of 12 and had very frequent co-occurring ATRX mutations, with similar age range and co-mutation spectrum as G34R/V mutant gliomas.	('mutations', 'Var', (103, 112))	('ATRX', 'Gene', (98, 102))	('G34R', 'Var', (165, 169))	('SETD2', 'Gene', '29072', (0, 5))	('ATRX', 'Gene', '546', (98, 102))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('SETD2', 'Gene', (0, 5))	('occurred', 'Reg', (22, 30))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('gliomas', 'Disease', (179, 186))	('G34R', 'SUBSTITUTION', 'None', (165, 169))	('children', 'Species', '9606', (34, 42))	('mutations', 'Var', (6, 15))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))
87895	28064387	Mutations in SETD2 were mutually exclusive with H3 G34R/V mutations in all gliomas studied to date.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('G34R', 'SUBSTITUTION', 'None', (51, 55))	('G34R', 'Var', (51, 55))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('SETD2', 'Gene', '29072', (13, 18))	('H3', 'Gene', '126961', (48, 50))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (13, 18))
87896	28064387	Mutations affecting the histone code of diffuse gliomas include the following: (1) mutations of the histone tail that directly alter a post-translational modification site, exemplified by the K27M mutation, (2) mutations within the histone tail that are adjacent to and interfere with a post-translational modification site, namely the G34R/V mutations, (3) mutations within enzymes or that affect enzymes involved in writing or erasing the histone code, such as SETD2 mutation or IDH1/2 mutation (Figure 1).	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('K27M', 'Mutation', 'p.K27M', (192, 196))	('post-translational modification site', 'MPA', (135, 171))	('mutation', 'Var', (488, 496))	('SETD2', 'Gene', (463, 468))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('IDH1/2', 'Gene', '3417;3418', (481, 487))	('mutations', 'Var', (358, 367))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', '29072', (463, 468))	('IDH1/2', 'Gene', (481, 487))	('mutation', 'Var', (469, 477))	('alter', 'Reg', (127, 132))	('G34R', 'SUBSTITUTION', 'None', (336, 340))	('affect', 'Reg', (391, 397))	('gliomas', 'Disease', (48, 55))	('mutations', 'Var', (83, 92))	('G34R', 'Var', (336, 340))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))
87897	28064387	The heterozygous K27M mutation in histone H3 impairs methylation at position 27 by two mechanisms.	('K27M', 'Mutation', 'p.K27M', (17, 21))	('methylation at position 27', 'MPA', (53, 79))	('H3', 'Gene', '126961', (42, 44))	('K27M', 'Var', (17, 21))	('impairs', 'NegReg', (45, 52))
87898	28064387	Methionine does not undergo methylation; this substitution directly removes a methylation site from the histone tail.	('removes', 'NegReg', (68, 75))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('methylation site', 'MPA', (78, 94))	('substitution', 'Var', (46, 58))
87899	28064387	Additionally, the K27M-mutant histone 3.3 protein is a dominant-negative inhibitor of K27 methylation by sequestration of the PRC2 complex (polycomb repressive complex 2), which contains the EZH2 (enhancer of zeste) K27 methyltransferase.	('protein', 'Protein', (42, 49))	('methylation', 'MPA', (90, 101))	('K27M-mutant', 'Var', (18, 29))	('sequestration', 'MPA', (105, 118))	('K27M', 'Mutation', 'p.K27M', (18, 22))	('EZH2', 'Gene', (191, 195))	('EZH2', 'Gene', '2146', (191, 195))	('histone 3', 'Gene', (30, 39))	('histone 3', 'Gene', '126961', (30, 39))	('dominant-negative inhibitor', 'NegReg', (55, 82))
87901	28064387	Diffuse gliomas with G34R/V and K27M mutations have distinct hypomethylated genomes, a finding most prominent in G34R/V mutations with particularly pronounced hypomethylation at chromosome ends.	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('gliomas', 'Disease', (8, 15))	('G34R', 'Var', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('G34R', 'SUBSTITUTION', 'None', (113, 117))	('mutations', 'Var', (120, 129))	('K27M', 'Mutation', 'p.K27M', (32, 36))	('G34R', 'Var', (113, 117))	('G34R', 'SUBSTITUTION', 'None', (21, 25))	('K27M mutations', 'Var', (32, 46))
87902	28064387	G34R/V and K27M mutations both show mutation-specific gene expression profiles, with distinctive expression patterns similar to those observed during normal brain development.	('G34R', 'SUBSTITUTION', 'None', (0, 4))	('G34R', 'Var', (0, 4))	('K27M', 'Var', (11, 15))	('K27M', 'Mutation', 'p.K27M', (11, 15))	('expression', 'MPA', (97, 107))
87903	28064387	In particular G34R/V mutant gliomas have gene expression profiles resembling early embryonic and early to mid fetal stages of neocortical and striatum development, while K27M gliomas have gene expression profiles that resemble mid to late fetal stages of thalamic and striatum development.	('G34R', 'SUBSTITUTION', 'None', (14, 18))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('K27M', 'Var', (170, 174))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('G34R', 'Var', (14, 18))	('gene expression', 'MPA', (41, 56))	('embryonic', 'Disease', 'MESH:D009373', (83, 92))	('gliomas', 'Disease', (175, 182))	('K27M', 'Mutation', 'p.K27M', (170, 174))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))	('embryonic', 'Disease', (83, 92))
87904	28064387	Of note, the PRC2 complex that is inhibited by K27M mutation additionally plays a prominent role in the progression of neural precursor cell differentiation.	('K27M', 'Mutation', 'p.K27M', (47, 51))	('K27M mutation', 'Var', (47, 60))	('plays', 'Reg', (74, 79))	('neural precursor cell differentiation', 'CPA', (119, 156))	('PRC2 complex', 'Protein', (13, 25))
87905	28064387	While the exact cell of origin is unknown, K27M and G34R/V mutant gliomas are thought to have a different cell of origin due to their unique gene expression profiles and location predilections.	('G34R', 'SUBSTITUTION', 'None', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('K27M', 'Var', (43, 47))	('G34R', 'Var', (52, 56))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('K27M', 'Mutation', 'p.K27M', (43, 47))
87906	28064387	While G34R/V mutations do not directly occur at a site of post-translation modification, they occur in close proximity to lysine 36 of the histone H3.3 tail, which can be mono-, di-, and tri-methylated or acetylated in association with transcriptionally active or silenced chromatin.	('G34R', 'SUBSTITUTION', 'None', (6, 10))	('histone H3.3', 'Gene', '3021', (139, 151))	('G34R', 'Var', (6, 10))	('histone H3.3', 'Gene', (139, 151))	('lysine', 'Chemical', 'MESH:D008239', (122, 128))	('mutations', 'Var', (13, 22))
87907	28064387	As glycine is a small uncharged amino acid residue, substitution with arginine or valine likely alters the post-translational modifications that occur at lysine 36 through steric inhibition or conformational tail changes, thereby interfering with code writers, erasers, and readers.	('conformational tail', 'MPA', (193, 212))	('interfering', 'Reg', (230, 241))	('code writers', 'CPA', (247, 259))	('post-translational modifications', 'MPA', (107, 139))	('alters', 'Reg', (96, 102))	('valine', 'Chemical', 'MESH:D014633', (82, 88))	('lysine', 'Chemical', 'MESH:D008239', (154, 160))	('steric', 'MPA', (172, 178))	('arginine', 'Chemical', 'MESH:D001120', (70, 78))	('substitution', 'Var', (52, 64))	('glycine', 'Chemical', 'MESH:D005998', (3, 10))
87908	28064387	Decreased histone H3 K36 trimethylation (H3K36me3) is observed within nucleosomes that contain an H3.3 G34R/V mutated tail.	('G34R', 'SUBSTITUTION', 'None', (103, 107))	('H3', 'Gene', '126961', (98, 100))	('G34R', 'Var', (103, 107))	('Decreased', 'NegReg', (0, 9))	('H3', 'Gene', '126961', (41, 43))	('H3', 'Gene', '126961', (18, 20))
87909	28064387	Furthermore, diffuse gliomas in the cerebral hemispheres lacking histone H3 gene mutations but instead harboring inactivating SETD2 mutations also demonstrate a significant decrease in H3K36me3 levels.	('decrease', 'NegReg', (173, 181))	('lacking', 'NegReg', (57, 64))	('SETD2', 'Gene', '29072', (126, 131))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('mutations', 'Var', (132, 141))	('H3', 'Gene', '126961', (185, 187))	('diffuse', 'Disease', (13, 20))	('SETD2', 'Gene', (126, 131))	('H3', 'Gene', '126961', (73, 75))	('gliomas in the cerebral', 'Disease', (21, 44))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('gliomas in the cerebral', 'Disease', 'MESH:C564230', (21, 44))
87910	28064387	Hotspot mutations affecting the IDH1 or IDH2 genes, encoding isocitrate dehydrogenase enzymes of the citric acid cycle, define the vast majority of lower grade diffuse gliomas and secondary glioblastomas arising in adults, but are only rarely seen in gliomas in young children.	('glioblastoma', 'Phenotype', 'HP:0012174', (190, 202))	('IDH1', 'Gene', (32, 36))	('glioblastomas', 'Disease', (190, 203))	('gliomas', 'Disease', 'MESH:D005910', (251, 258))	('glioblastomas', 'Disease', 'MESH:D005909', (190, 203))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('mutations', 'Var', (8, 17))	('IDH1', 'Gene', '3417', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('gliomas', 'Disease', (168, 175))	('citric acid', 'Chemical', 'MESH:D019343', (101, 112))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('glioblastomas', 'Phenotype', 'HP:0012174', (190, 203))	('children', 'Species', '9606', (268, 276))	('IDH2', 'Gene', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('IDH2', 'Gene', '3418', (40, 44))	('gliomas', 'Disease', (251, 258))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))
87911	28064387	These IDH1/2 mutations also affect histone methylation, and in contrast to K27M and G34R/V mutations, are associated with DNA hypermethylation.	('affect', 'Reg', (28, 34))	('K27M', 'Mutation', 'p.K27M', (75, 79))	('associated', 'Reg', (106, 116))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('DNA hypermethylation', 'MPA', (122, 142))	('G34R', 'SUBSTITUTION', 'None', (84, 88))	('histone methylation', 'MPA', (35, 54))	('G34R', 'Var', (84, 88))	('mutations', 'Var', (13, 22))	('IDH1/2', 'Gene', (6, 12))
87912	28064387	The recurrent IDH1 R132H and IDH2 R172H substitution mutations cause a gain-of-function that results in production of the oncometabolite 2-HG (D-2-hydroxyglutarate), which inhibits a wide range of histone demethylases, including those involved in the demethylation of H3K4, H3K9, H3K27, and H3K79.	('IDH2', 'Gene', (29, 33))	('H3', 'Gene', '126961', (274, 276))	('H3', 'Gene', '126961', (280, 282))	('gain-of-function', 'PosReg', (71, 87))	('inhibits', 'NegReg', (172, 180))	('IDH2', 'Gene', '3418', (29, 33))	('R132H', 'Var', (19, 24))	('histone demethylases', 'Enzyme', (197, 217))	('H3', 'Gene', '126961', (291, 293))	('demethylation', 'MPA', (251, 264))	('H3', 'Gene', '126961', (268, 270))	('R172H', 'Mutation', 'p.R172H', (34, 39))	('IDH1', 'Gene', (14, 18))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('2-HG', 'Chemical', 'MESH:C019417', (137, 141))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (143, 163))	('IDH1', 'Gene', '3417', (14, 18))
87913	28064387	Amongst diffuse gliomas in adult patients, TERT promoter mutations are seen in almost all tumors (88-98%) with co-deletion of chromosomes 1p and 19q along with IDH1 or IDH2 mutation, the typical molecular profile of adult-type oligodendroglioma, which demonstrates better overall survival compared to other glioma molecular groups and elevated TERT expression.	('IDH2', 'Gene', '3418', (168, 172))	('oligodendroglioma', 'Disease', (227, 244))	('IDH1', 'Gene', (160, 164))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('glioma', 'Disease', (307, 313))	('mutations', 'Var', (57, 66))	('glioma', 'Disease', 'MESH:D005910', (307, 313))	('IDH1', 'Gene', '3417', (160, 164))	('better', 'PosReg', (265, 271))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('glioma', 'Disease', (238, 244))	('TERT', 'Gene', (43, 47))	('almost all tumors', 'Disease', (79, 96))	('TERT', 'Gene', '7015', (43, 47))	('gliomas', 'Disease', (16, 23))	('glioma', 'Disease', (16, 22))	('co-deletion', 'Var', (111, 122))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('TERT', 'Gene', (344, 348))	('TERT', 'Gene', '7015', (344, 348))	('patients', 'Species', '9606', (33, 41))	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('oligodendroglioma', 'Disease', 'MESH:D009837', (227, 244))	('IDH2', 'Gene', (168, 172))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('almost all tumors', 'Disease', 'MESH:D009369', (79, 96))
87914	28064387	Additionally TERT promoter mutations have been reported in 58-83% of adult primary glioblastomas, with a lower prevalence in secondary glioblastomas (28%).	('mutations', 'Var', (27, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('TERT', 'Gene', (13, 17))	('glioblastomas', 'Disease', (135, 148))	('TERT', 'Gene', '7015', (13, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (83, 96))	('glioblastomas', 'Disease', 'MESH:D005909', (83, 96))	('glioblastomas', 'Phenotype', 'HP:0012174', (135, 148))	('glioblastomas', 'Disease', (83, 96))	('reported', 'Reg', (47, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('glioblastomas', 'Disease', 'MESH:D005909', (135, 148))
87917	28064387	A high frequency of TERT promoter mutations (81%) have been reported in the gliosarcoma variant of glioblastoma.	('glioblastoma', 'Disease', (99, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('gliosarcoma', 'Disease', 'MESH:D018316', (76, 87))	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('gliosarcoma', 'Disease', (76, 87))	('reported', 'Reg', (60, 68))	('mutations', 'Var', (34, 43))
87921	28064387	Although pediatric TERT promoter mutations are rare, a single study has reported TERT promoter hypermethylation in association with increased TERT expression in pediatric high-grade gliomas.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('TERT', 'Gene', '7015', (142, 146))	('TERT', 'Gene', (81, 85))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('TERT', 'Gene', '7015', (81, 85))	('increased', 'PosReg', (132, 141))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('TERT', 'Gene', (142, 146))	('hypermethylation', 'Var', (95, 111))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('gliomas', 'Disease', (182, 189))
87922	28064387	Aberrant TERT promoter methylation with increased TERT expression has been reported in other cancer types.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TERT', 'Gene', '7015', (50, 54))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('increased', 'PosReg', (40, 49))	('TERT', 'Gene', (50, 54))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
87924	28064387	Although ATRX and TERT promoter mutations are usually mutually exclusive, supporting an equivalent selective advantage of mutations maintaining telomere length through either ALT or increased telomerase activity, rare exceptions to this have been observed in adult gliomas.	('ALT', 'MPA', (175, 178))	('increased', 'PosReg', (182, 191))	('gliomas', 'Disease', 'MESH:D005910', (265, 272))	('ATRX', 'Gene', '546', (9, 13))	('gliomas', 'Phenotype', 'HP:0009733', (265, 272))	('glioma', 'Phenotype', 'HP:0009733', (265, 271))	('TERT', 'Gene', (18, 22))	('mutations', 'Var', (122, 131))	('ALT', 'Chemical', '-', (175, 178))	('telomerase', 'Enzyme', (192, 202))	('TERT', 'Gene', '7015', (18, 22))	('ATRX', 'Gene', (9, 13))	('telomere length', 'MPA', (144, 159))	('activity', 'MPA', (203, 211))	('gliomas', 'Disease', (265, 272))
87926	28064387	ATRX or DAXX mutations are present in approximately 30% of pediatric glioblastomas, with mutation and loss of immunostaining occurring much more frequently in ATRX than DAXX, and ALT highly correlating with ATRX loss.	('DAXX', 'Gene', (8, 12))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (59, 82))	('ATRX', 'Gene', '546', (159, 163))	('ATRX', 'Gene', '546', (207, 211))	('pediatric glioblastomas', 'Disease', (59, 82))	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', '1616', (169, 173))	('DAXX', 'Gene', '1616', (8, 12))	('mutation', 'Var', (89, 97))	('glioblastomas', 'Phenotype', 'HP:0012174', (69, 82))	('ATRX', 'Gene', (159, 163))	('ATRX', 'Gene', '546', (0, 4))	('ATRX', 'Gene', (207, 211))	('loss', 'NegReg', (102, 106))	('DAXX', 'Gene', (169, 173))	('loss', 'NegReg', (212, 216))	('ALT', 'Chemical', '-', (179, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
87927	28064387	ALT in high-grade pediatric gliomas with TP53 mutation is associated with increased overall survival.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('pediatric gliomas', 'Disease', 'MESH:D005910', (18, 35))	('increased', 'PosReg', (74, 83))	('overall survival', 'MPA', (84, 100))	('ALT', 'Chemical', '-', (0, 3))	('mutation', 'Var', (46, 54))	('pediatric gliomas', 'Disease', (18, 35))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))
87928	28064387	ATRX mutations have also been reported in 9% of DIPGs, but are not prevalent in pediatric low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('reported', 'Reg', (30, 38))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('ATRX', 'Gene', (0, 4))	('DIPGs', 'Chemical', '-', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('mutations', 'Var', (5, 14))	('DIPGs', 'Disease', (48, 53))	('ATRX', 'Gene', '546', (0, 4))	('gliomas', 'Disease', (100, 107))
87929	28064387	ALT rarely occurred in pediatric low-grade gliomas, an interesting finding due to the corresponding low prevalence of ATRX mutation.	('ATRX', 'Gene', '546', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('mutation', 'Var', (123, 131))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('ALT', 'Chemical', '-', (0, 3))	('ATRX', 'Gene', (118, 122))
87932	28064387	While ATRX mutations in pediatric glioblastomas are associated with TP53 and histone H3 mutations, ATRX mutations in diffuse gliomas within adult patients are associated with concurrent TP53 and IDH1/2 mutations (Figure 3), occurring in greater than 90% of lower-grade diffuse astrocytomas and secondary glioblastoma in the context of IDH1/2 mutation with intact chromosomes 1p and 19q.	('mutations', 'Var', (11, 20))	('ATRX', 'Gene', (6, 10))	('mutations', 'Var', (88, 97))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('associated', 'Reg', (159, 169))	('ATRX', 'Gene', '546', (6, 10))	('TP53', 'Gene', (68, 72))	('IDH1/2', 'Gene', '3417;3418', (195, 201))	('mutations', 'Var', (104, 113))	('glioblastoma', 'Disease', 'MESH:D005909', (304, 316))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('astrocytomas', 'Disease', (277, 289))	('gliomas within adult', 'Disease', (125, 145))	('IDH1/2', 'Gene', (195, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('TP53', 'Gene', (186, 190))	('patients', 'Species', '9606', (146, 154))	('ATRX', 'Gene', (99, 103))	('glioblastoma', 'Disease', (304, 316))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (24, 47))	('H3', 'Gene', '126961', (85, 87))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('associated', 'Reg', (52, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (304, 316))	('glioblastoma', 'Disease', (34, 46))	('ATRX', 'Gene', '546', (99, 103))	('TP53', 'Gene', '7157', (68, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('astrocytomas', 'Disease', 'MESH:D001254', (277, 289))	('IDH1/2', 'Gene', '3417;3418', (335, 341))	('pediatric glioblastomas', 'Disease', (24, 47))	('TP53', 'Gene', '7157', (186, 190))	('IDH1/2', 'Gene', (335, 341))	('gliomas within adult', 'Disease', 'MESH:D001929', (125, 145))	('mutations', 'Var', (202, 211))
87933	28064387	In contrast, ATRX mutations are seen in 4-7% of primary glioblastomas with wild-type IDH1/2 alleles.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('ATRX', 'Gene', (13, 17))	('glioblastomas', 'Disease', (56, 69))	('IDH1/2', 'Gene', (85, 91))	('glioblastomas', 'Disease', 'MESH:D005909', (56, 69))	('ATRX', 'Gene', '546', (13, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (56, 69))	('IDH1/2', 'Gene', '3417;3418', (85, 91))	('mutations', 'Var', (18, 27))
87934	28064387	DAXX mutations are rare in adult lower-grade gliomas at less than 1% frequency.	('DAXX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('DAXX', 'Gene', '1616', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
87936	28064387	ALT is highly associated with ATRX mutations in adult low-grade gliomas and in high-grade astrocytomas of children and adults.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('astrocytomas', 'Disease', (90, 102))	('astrocytomas of children', 'Phenotype', 'HP:0009592', (90, 114))	('ATRX', 'Gene', (30, 34))	('associated', 'Reg', (14, 24))	('ALT', 'Gene', (0, 3))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('ATRX', 'Gene', '546', (30, 34))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('ALT', 'Chemical', '-', (0, 3))	('children', 'Species', '9606', (106, 114))	('mutations', 'Var', (35, 44))
87939	28064387	This is in agreement with the existence of ATRX mutations in adult high-grade gliomas without ALT, although 80% of cases with ATRX mutation had ALT.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('ALT', 'Chemical', '-', (144, 147))	('ALT', 'MPA', (144, 147))	('ATRX', 'Gene', (126, 130))	('mutations', 'Var', (48, 57))	('ATRX', 'Gene', '546', (43, 47))	('ALT', 'Chemical', '-', (94, 97))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('ATRX', 'Gene', '546', (126, 130))	('ATRX', 'Gene', (43, 47))
87940	28064387	The notion that multiple steps are required for the development of ALT is supported by the low frequency at which it arises in immortalized cell lines, and the likely prerequisite mutations of both the G1/S and G2/M checkpoints to be permissive of the genomic instability and altered response to DNA damage seen with ALT.	('response to DNA damage', 'MPA', (284, 306))	('ALT', 'Chemical', '-', (317, 320))	('ALT', 'Chemical', '-', (67, 70))	('mutations', 'Var', (180, 189))
87941	28064387	The G1/S checkpoint is frequently undermined by TP53 mutation in association with ATRX mutation and ALT.	('TP53', 'Gene', '7157', (48, 52))	('ATRX', 'Gene', (82, 86))	('mutation', 'Var', (53, 61))	('ATRX', 'Gene', '546', (82, 86))	('TP53', 'Gene', (48, 52))	('G1/S checkpoint', 'CPA', (4, 19))	('undermined', 'NegReg', (34, 44))	('ALT', 'Chemical', '-', (100, 103))	('mutation', 'Var', (87, 95))	('ALT', 'Disease', (100, 103))
87942	28064387	Functional deficiencies in the G2/M checkpoint have been observed in ALT cell lines, warranting investigation of specific mutations in G2/M checkpoint signaling in ALT.	('Functional deficiencies', 'Disease', 'OMIM:608852', (0, 23))	('Functional deficiencies', 'Disease', (0, 23))	('ALT', 'Chemical', '-', (164, 167))	('mutations', 'Var', (122, 131))	('ALT', 'Chemical', '-', (69, 72))
87945	28064387	The consequences of disrupted H3.3 heterochromatin insertion and altered chromatin remodeling are among the proposed mechanisms for the association of ATRX mutation and altered telomere length.	('telomere', 'MPA', (177, 185))	('ATRX', 'Gene', (151, 155))	('ATRX', 'Gene', '546', (151, 155))	('H3', 'Gene', '126961', (30, 32))	('disrupted', 'Var', (20, 29))	('heterochromatin insertion', 'Var', (35, 60))	('association', 'Interaction', (136, 147))	('mutation', 'Var', (156, 164))
87949	28064387	Mutations affecting the histone code could potentially disrupt the association with ATRX, even in the absence of an ATRX mutation.	('histone code', 'Gene', (24, 36))	('ATRX', 'Gene', (116, 120))	('ATRX', 'Gene', '546', (84, 88))	('ATRX', 'Gene', '546', (116, 120))	('disrupt', 'NegReg', (55, 62))	('Mutations', 'Var', (0, 9))	('association', 'Interaction', (67, 78))	('ATRX', 'Gene', (84, 88))
87950	28064387	ATRX has also been shown to bind GC-rich tandem sequences of telomeres and euchromatin, with mutation of ATRX leading to dysregulation of GC-rich tandem repeat associated genes.	('leading to', 'Reg', (110, 120))	('ATRX', 'Gene', '546', (105, 109))	('GC-rich', 'Gene', (138, 145))	('ATRX', 'Gene', (0, 4))	('ATRX', 'Gene', '546', (0, 4))	('ATRX', 'Gene', (105, 109))	('dysregulation', 'MPA', (121, 134))	('mutation', 'Var', (93, 101))
87951	28064387	Therefore ATRX mutation could indirectly affect telomere length by altering expression of telomere homologous recombination regulatory elements.	('mutation', 'Var', (15, 23))	('ATRX', 'Gene', (10, 14))	('telomere length', 'MPA', (48, 63))	('expression', 'MPA', (76, 86))	('ATRX', 'Gene', '546', (10, 14))	('altering', 'Reg', (67, 75))	('affect', 'Reg', (41, 47))
87952	28064387	Histone methyltransferase or DNA methyltransferase knockout in mouse cell lines results in increased telomere length, suggesting that telomere length can be influenced by either altered histone methylation or altered DNA methylation.	('mouse', 'Species', '10090', (63, 68))	('histone', 'Protein', (186, 193))	('Histone', 'Protein', (0, 7))	('increased telomere length', 'Phenotype', 'HP:0031413', (91, 116))	('telomere length', 'CPA', (101, 116))	('increased', 'PosReg', (91, 100))	('knockout', 'Var', (51, 59))	('altered', 'Reg', (178, 185))	('influenced', 'Reg', (157, 167))	('DNA methyltransferase', 'Gene', (29, 50))
87953	28064387	This is intriguing since ATRX mutations and histone H3 gene mutations are independently associated with altered methylation of subtelomeric regions and chromosome ends.	('ATRX', 'Gene', (25, 29))	('altered', 'Reg', (104, 111))	('H3', 'Gene', '126961', (52, 54))	('mutations', 'Var', (30, 39))	('ATRX', 'Gene', '546', (25, 29))	('associated', 'Reg', (88, 98))	('mutations', 'Var', (60, 69))	('methylation', 'MPA', (112, 123))
87955	28064387	Additionally, loss of ATRX is associated with abnormal retention of the telomere RNA transcript (TERRA) and replication protein A (RPA) at telomere ends after completion of DNA replication.	('ATRX', 'Gene', (22, 26))	('loss', 'Var', (14, 18))	('replication protein A', 'Gene', (108, 129))	('replication protein A', 'Gene', '6117', (108, 129))	('ATRX', 'Gene', '546', (22, 26))	('RPA', 'Gene', (131, 134))	('RPA', 'Gene', '6117', (131, 134))
87957	28064387	Ultimately a downstream consequence of ATRX mutation, when combined with other mutations or epigenetic changes, is highly likely to create an altered telomere chromatin environment that is more permissive of homologous recombination and resultant ALT.	('ALT', 'MPA', (247, 250))	('ATRX', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))	('ATRX', 'Gene', '546', (39, 43))	('create', 'Reg', (132, 138))	('more', 'PosReg', (189, 193))	('ALT', 'Chemical', '-', (247, 250))
87958	28064387	Lack of insertion of histone 3.3, changes to DNA and telomere methylation from ATRX mutation or histone H3 mutation, altered expression of homologous recombination regulatory elements, and retention of TERRA with prolonged recruitment of ATR are all currently proposed mechanisms for the development of ALT.	('histone 3', 'Gene', (21, 30))	('mutation', 'Var', (84, 92))	('altered', 'Reg', (117, 124))	('expression', 'MPA', (125, 135))	('changes', 'Reg', (34, 41))	('ATRX', 'Gene', (79, 83))	('ATR', 'Gene', '545', (79, 82))	('H3', 'Gene', '126961', (104, 106))	('histone 3', 'Gene', '126961', (21, 30))	('ATR', 'Gene', (79, 82))	('ATR', 'Gene', '545', (238, 241))	('ATRX', 'Gene', '546', (79, 83))	('mutation', 'Var', (107, 115))	('ALT', 'Chemical', '-', (303, 306))	('ATR', 'Gene', (238, 241))
87959	28064387	Understanding the role of histone mutations and alterations of the histone code in gliomagenesis has led to the development of potentially targeted therapeutic interventions.	('glioma', 'Disease', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('mutations', 'Var', (34, 43))	('glioma', 'Disease', 'MESH:D005910', (83, 89))
87960	28064387	In particular GSKJ4, a small molecule inhibitor of the histone H3 K27 demethylase JMJD3, resulted in decreased tumor cell viability and increased H3K27me3 levels in K27M glioma cell lines, and significantly extended survival of mice with K27M mutant glioma xenografts.	('extended', 'PosReg', (207, 215))	('K27M mutant', 'Var', (238, 249))	('decreased tumor', 'Disease', 'MESH:D009369', (101, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('glioma', 'Disease', (250, 256))	('mice', 'Species', '10090', (228, 232))	('glioma', 'Disease', 'MESH:D005910', (250, 256))	('glioma', 'Disease', (170, 176))	('JMJD3', 'Gene', (82, 87))	('decreased tumor', 'Disease', (101, 116))	('H3', 'Gene', '126961', (63, 65))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('K27M', 'Mutation', 'p.K27M', (238, 242))	('GSKJ4', 'Chemical', 'MESH:C000593030', (14, 19))	('GSKJ4', 'Gene', (14, 19))	('K27M', 'Mutation', 'p.K27M', (165, 169))	('increased', 'PosReg', (136, 145))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('JMJD3', 'Gene', '216850', (82, 87))	('survival', 'CPA', (216, 224))	('H3', 'Gene', '126961', (146, 148))
87961	28064387	In contrast, GSKJ4 has not shown activity in an H3F3A G34V mutant glioma cell line.	('G34V', 'Var', (54, 58))	('glioma', 'Disease', (66, 72))	('GSKJ4', 'Chemical', 'MESH:C000593030', (13, 18))	('H3F3A', 'Gene', '3020', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('H3F3A', 'Gene', (48, 53))	('G34V', 'Mutation', 'p.G34V', (54, 58))
87962	28064387	Panobinostat, a histone deacetylase inhibitor, resulted in decreased tumor cell viability in both K27M mutant glioma cell lines and in mice with K27M mutant glioma xenografts.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('decreased tumor', 'Disease', (59, 74))	('K27M', 'Mutation', 'p.K27M', (98, 102))	('glioma', 'Disease', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('Panobinostat', 'Chemical', 'MESH:D000077767', (0, 12))	('K27M mutant', 'Var', (98, 109))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('mice', 'Species', '10090', (135, 139))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('K27M', 'Mutation', 'p.K27M', (145, 149))	('glioma', 'Disease', (157, 163))	('decreased tumor', 'Disease', 'MESH:D009369', (59, 74))	('K27M mutant', 'Var', (145, 156))
87964	28064387	Combined use of GSKJ4 and panobinostat produced a synergistic reduction of tumor cell viability in K27M mutant glioma cell lines.	('glioma', 'Disease', (111, 117))	('K27M', 'Mutation', 'p.K27M', (99, 103))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('K27M mutant', 'Var', (99, 110))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('GSKJ4', 'Chemical', 'MESH:C000593030', (16, 21))	('panobinostat', 'Chemical', 'MESH:D000077767', (26, 38))	('reduction', 'NegReg', (62, 71))	('tumor', 'Disease', (75, 80))
87965	28064387	Cancer cell lines with decreased H3K36me3 secondary to inactivating SETD2 mutation, silencing, or knockout are sensitive to WEE1 kinase inhibition, creating the possibility of targeted intervention in diffuse gliomas with SETD2 or G34R/V mutations.	('WEE1', 'Gene', (124, 128))	('gliomas', 'Disease', (209, 216))	('SETD2', 'Gene', (68, 73))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutation', 'Var', (74, 82))	('silencing', 'Var', (84, 93))	('SETD2', 'Gene', '29072', (68, 73))	('gliomas', 'Disease', 'MESH:D005910', (209, 216))	('decreased', 'NegReg', (23, 32))	('inactivating', 'Var', (55, 67))	('WEE1', 'Gene', '7465', (124, 128))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('SETD2', 'Gene', (222, 227))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (209, 216))	('SETD2', 'Gene', '29072', (222, 227))	('Cancer', 'Disease', (0, 6))	('G34R', 'SUBSTITUTION', 'None', (231, 235))	('G34R', 'Var', (231, 235))	('H3', 'Gene', '126961', (33, 35))
87967	28064387	H3K36 trimethylation normally induces transcription of RRM2, and reduced H3K36 methylation causes decreased levels of RRM2.	('levels', 'MPA', (108, 114))	('reduced', 'NegReg', (65, 72))	('transcription', 'MPA', (38, 51))	('RRM2', 'Gene', '6241', (55, 59))	('methylation', 'MPA', (79, 90))	('RRM2', 'Gene', (55, 59))	('H3', 'Gene', '126961', (0, 2))	('RRM2', 'Gene', '6241', (118, 122))	('RRM2', 'Gene', (118, 122))	('H3', 'Gene', '126961', (73, 75))	('decreased', 'NegReg', (98, 107))	('induces', 'Reg', (30, 37))	('trimethylation', 'Var', (6, 20))
87968	28064387	In the setting of reduced H3K36 methylation, the effect of WEE1 inhibition on RRM2 degradation exacerbates already reduced RRM2 levels reaching a critical level of dNTP depletion that inhibits DNA replication and induces apoptosis.	('DNA replication', 'MPA', (193, 208))	('H3', 'Gene', '126961', (26, 28))	('degradation', 'MPA', (83, 94))	('WEE1', 'Gene', '7465', (59, 63))	('induces', 'Reg', (213, 220))	('reduced', 'NegReg', (115, 122))	('apoptosis', 'CPA', (221, 230))	('inhibition', 'Var', (64, 74))	('exacerbates', 'PosReg', (95, 106))	('inhibits', 'NegReg', (184, 192))	('RRM2', 'Gene', '6241', (78, 82))	('WEE1', 'Gene', (59, 63))	('RRM2', 'Gene', (78, 82))	('RRM2', 'Gene', (123, 127))	('dNTP', 'Chemical', 'MESH:D010278', (164, 168))	('RRM2', 'Gene', '6241', (123, 127))
87969	28064387	Additionally, gliomas with G34R/V mutations have been shown to upregulate MYCN, through altered genomic binding of the histone 3 tail at K36.	('MYCN', 'Gene', '4613', (74, 78))	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('G34R', 'Var', (27, 31))	('histone 3', 'Gene', '126961', (119, 128))	('genomic binding', 'MPA', (96, 111))	('G34R', 'SUBSTITUTION', 'None', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('altered', 'Reg', (88, 95))	('MYCN', 'Gene', (74, 78))	('upregulate', 'PosReg', (63, 73))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('histone 3', 'Gene', (119, 128))	('mutations', 'Var', (34, 43))	('gliomas', 'Disease', (14, 21))
87970	28064387	Therefore PI3K/mTOR inhibitors such as NVP-BEZ235, which result in MYCN degradation, may potentially be therapeutic in G34R/V gliomas.	('G34R', 'Var', (119, 123))	('V gliomas', 'Disease', (124, 133))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('V gliomas', 'Disease', 'MESH:D005910', (124, 133))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (15, 19))	('NVP-BEZ235', 'Var', (39, 49))	('G34R', 'SUBSTITUTION', 'None', (119, 123))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('MYCN', 'Gene', (67, 71))	('MYCN', 'Gene', '4613', (67, 71))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
87972	28064387	Additionally inhibitors of the protein kinase ATR, a regulator of homologous recombination with prolonged recruitment to telomere ends in the setting of ATRX mutation, have been found to selectively induce death of cancer cells with ALT.	('ATRX', 'Gene', '546', (153, 157))	('ATR', 'Gene', '545', (153, 156))	('ATR', 'Gene', (153, 156))	('induce', 'Reg', (199, 205))	('death of cancer', 'Disease', (206, 221))	('mutation', 'Var', (158, 166))	('death of cancer', 'Disease', 'MESH:D003643', (206, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ALT', 'Chemical', '-', (233, 236))	('ATRX', 'Gene', (153, 157))	('ATR', 'Gene', '545', (46, 49))	('ATR', 'Gene', (46, 49))
87973	28064387	Pediatric and adult gliomas contain genetic alterations that affect the histone code, most frequently seen by direct mutation of the histone H3 tail in pediatric gliomas and IDH1/2 mutation in adult gliomas.	('pediatric gliomas', 'Disease', (152, 169))	('IDH1/2', 'Gene', '3417;3418', (174, 180))	('IDH1/2', 'Gene', (174, 180))	('affect', 'Reg', (61, 67))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (20, 27))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('gliomas', 'Disease', (162, 169))	('H3', 'Gene', '126961', (141, 143))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('pediatric gliomas', 'Disease', 'MESH:D005910', (152, 169))	('gliomas', 'Disease', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('histone code', 'MPA', (72, 84))	('mutation', 'Var', (117, 125))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))
87974	28064387	Histone H3 tail mutations are mutually exclusive with IDH1/2 mutations and both uniquely alter histone tail methylation.	('Histone', 'Gene', (0, 7))	('IDH1/2', 'Gene', (54, 60))	('H3', 'Gene', '126961', (8, 10))	('mutations', 'Var', (16, 25))	('mutations', 'Var', (61, 70))	('alter', 'Reg', (89, 94))	('histone tail methylation', 'MPA', (95, 119))	('IDH1/2', 'Gene', '3417;3418', (54, 60))
87975	28064387	The K27M and G34R/V mutations are associated with decreased histone tail methylation and DNA hypomethylation, while IDH1/2 mutant gliomas correlate with DNA hypermethylation and 2-HG mediated inhibition of histone demethylation.	('G34R', 'Var', (13, 17))	('2-HG', 'Chemical', 'MESH:C019417', (178, 182))	('DNA hypomethylation', 'MPA', (89, 108))	('IDH1/2', 'Gene', (116, 122))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('decreased', 'NegReg', (50, 59))	('G34R', 'SUBSTITUTION', 'None', (13, 17))	('K27M', 'Var', (4, 8))	('histone tail methylation', 'MPA', (60, 84))	('mutant', 'Var', (123, 129))	('IDH1/2', 'Gene', '3417;3418', (116, 122))
87976	28064387	The prevalence of IDH1/2 or histone H3 mutations within diffuse gliomas emphasizes the delicate balance of histone methylation and the functional importance of the histone code in gliomagenesis of both adults and children.	('H3', 'Gene', '126961', (36, 38))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('mutations', 'Var', (39, 48))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('gliomas', 'Disease', (64, 71))	('IDH1/2', 'Gene', '3417;3418', (18, 24))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Disease', (64, 70))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('children', 'Species', '9606', (213, 221))	('IDH1/2', 'Gene', (18, 24))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('glioma', 'Disease', (180, 186))
87977	28064387	Mutations affecting telomere length are also distinctly different in pediatric and adult gliomas.	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('telomere', 'Gene', (20, 28))	('different', 'Reg', (56, 65))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('pediatric', 'Disease', (69, 78))
87978	28064387	TERT promoter mutations are frequently seen in adult primary glioblastomas and oligodendrogliomas but are extremely rare in pediatric gliomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (61, 74))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('pediatric gliomas', 'Disease', 'MESH:D005910', (124, 141))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('TERT', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('TERT', 'Gene', '7015', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('pediatric gliomas', 'Disease', (124, 141))	('seen', 'Reg', (39, 43))	('mutations', 'Var', (14, 23))	('glioblastomas and oligodendrogliomas', 'Disease', 'MESH:D005909', (61, 97))
87981	28064387	In pediatric high-grade gliomas, ALT and increased TERT expression associated with promoter hypermethylation have been observed.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('increased', 'PosReg', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('TERT', 'Gene', (51, 55))	('ALT', 'Chemical', '-', (33, 36))	('TERT', 'Gene', '7015', (51, 55))	('ALT', 'MPA', (33, 36))	('gliomas', 'Disease', (24, 31))	('promoter hypermethylation', 'Var', (83, 108))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
87983	28064387	Current therapies in development include WEE-1 inhibition for gliomas with SETD2 or G34R/V mutation, demethylase and deacetylase inhibitors for K27M mutant gliomas, PI3K/mTOR inhibitors for G34R/V mutant gliomas, telomerase inhibitors for gliomas with TERT promoter mutation, and ATR inhibitors for gliomas with ALT.	('gliomas', 'Disease', (299, 306))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('gliomas', 'Disease', (156, 163))	('gliomas', 'Disease', (204, 211))	('SETD2', 'Gene', (75, 80))	('mTOR', 'Gene', (170, 174))	('G34R', 'SUBSTITUTION', 'None', (190, 194))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('G34R', 'Var', (190, 194))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('SETD2', 'Gene', '29072', (75, 80))	('TERT', 'Gene', (252, 256))	('ATR', 'Gene', '545', (280, 283))	('K27M', 'Mutation', 'p.K27M', (144, 148))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('TERT', 'Gene', '7015', (252, 256))	('gliomas', 'Disease', 'MESH:D005910', (299, 306))	('mTOR', 'Gene', '2475', (170, 174))	('glioma', 'Phenotype', 'HP:0009733', (299, 305))	('G34R', 'SUBSTITUTION', 'None', (84, 88))	('G34R', 'Var', (84, 88))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('gliomas', 'Phenotype', 'HP:0009733', (299, 306))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (239, 246))	('gliomas', 'Disease', (62, 69))	('WEE-1', 'Gene', '7465', (41, 46))	('ATR', 'Gene', (280, 283))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('ALT', 'Chemical', '-', (312, 315))	('K27M mutant', 'Var', (144, 155))	('WEE-1', 'Gene', (41, 46))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
87987	32698507	14C-2-Deoxy-D-glucose (14C-DG) uptake was measured in vitro using U87MG, U373MG and primary neurons cultured with different concentrations of glucose.	('glucose', 'Chemical', 'MESH:D005947', (142, 149))	('14C-DG', 'Chemical', '-', (23, 29))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))	('U373MG', 'Var', (73, 79))	('U87MG', 'CellLine', 'CVCL:0022', (66, 71))	('U373MG', 'CellLine', 'CVCL:2219', (73, 79))	('U87MG', 'Var', (66, 71))
87998	32698507	Therefore, accurate characterization of the tumor and delineation of the tumor boundary is challenging with 18F-FDG PET/CT.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('18F-FDG', 'Var', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PET/CT', 'Gene', '22095', (116, 122))	('18F-FDG', 'Chemical', 'MESH:D019788', (108, 115))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('PET/CT', 'Gene', (116, 122))
88020	32698507	14C-DG uptake was highest at 0 mM of glucose in all cell types (U87MG, 3.11 +- 0.81, CPM%/mg; U373MG, 2.89 +- 0.41; neuron, 3.54 +- 0.37, CPM%/mg).	('U373MG', 'CellLine', 'CVCL:2219', (94, 100))	('CPM', 'Var', (85, 88))	('14C-DG uptake', 'MPA', (0, 13))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('14C-DG', 'Chemical', '-', (0, 6))	('U87MG', 'CellLine', 'CVCL:0022', (64, 69))	('U373MG', 'Var', (94, 100))
88021	32698507	While 14C-DG uptake decreased as the glucose concentration in the media increased, there were differences in the rates of decrease among the primary neurons, U87MG and U373MG cells (Figure 2a).	('glucose concentration', 'MPA', (37, 58))	('U373MG', 'Var', (168, 174))	('decreased', 'NegReg', (20, 29))	('U373MG', 'CellLine', 'CVCL:2219', (168, 174))	('14C-DG uptake', 'MPA', (6, 19))	('U87MG', 'CellLine', 'CVCL:0022', (158, 163))	('14C-DG', 'Chemical', '-', (6, 12))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('U87MG', 'Var', (158, 163))
88023	32698507	The U373MG tumor-to-neuron ratio of 14C-DG uptake (1.00 at 0 mM; 0.77 at 1 mM; 1.11 at 2.5 mM; 1.56 at 5 mM; 2.23 at 10 mM; 1.71 at 15 mM) had a similar pattern toU87MG.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('U87MG', 'CellLine', 'CVCL:0022', (163, 168))	('14C-DG', 'Chemical', '-', (36, 42))	('toU87MG', 'Var', (161, 168))	('tumor', 'Disease', (11, 16))	('U373MG', 'Var', (4, 10))	('U373MG', 'CellLine', 'CVCL:2219', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
88054	32698507	The SUVmax of the cerebral cortex was reduced by 20, 35, 50, 60, and 65% for blood glucose ranges of 111-120, 121-140, 141-160, 161-200, and greater than 20 mg/dL, respectively.	('glucose', 'Chemical', 'MESH:D005947', (83, 90))	('SUVmax', 'MPA', (4, 10))	('reduced', 'NegReg', (38, 45))	('161-200', 'Var', (128, 135))	('blood glucose', 'MPA', (77, 90))	('121-140', 'Var', (110, 117))	('141-160', 'Var', (119, 126))
88058	32698507	14C-DG uptake of U87MG and U373MG cells showed similar values to neurons at low concentrations of glucose, but higher values than neurons at high concentrations of glucose.	('U373MG', 'Var', (27, 33))	('higher values', 'PosReg', (111, 124))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('U373MG', 'CellLine', 'CVCL:2219', (27, 33))	('14C-DG', 'Chemical', '-', (0, 6))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('U87MG', 'CellLine', 'CVCL:0022', (17, 22))	('high concentrations of glucose', 'Phenotype', 'HP:0003074', (141, 171))	('U87MG', 'Var', (17, 22))
88079	32698507	Although high and variable normal cortical uptake has limited the use of 18F-FDG PET/CT, 18F-FDG has advantages in representing the metabolic hallmarks of malignant tumors.	('PET/CT', 'Gene', (81, 87))	('18F-FDG', 'Chemical', 'MESH:D019788', (89, 96))	('advantages', 'PosReg', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('PET/CT', 'Gene', '22095', (81, 87))	('malignant tumors', 'Disease', (155, 171))	('18F-FDG', 'Chemical', 'MESH:D019788', (73, 80))	('18F-FDG', 'Var', (89, 96))	('malignant tumors', 'Disease', 'MESH:D009369', (155, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
88088	32698507	U87MG (human glioblastoma) cells (5 x 105 in 2 muL phosphate buffered saline [PBS]) were stereotactically implanted into the right frontal lobe of the mice.	('mice', 'Species', '10090', (151, 155))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('human', 'Species', '9606', (7, 12))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('PBS', 'Chemical', '-', (78, 81))	('phosphate buffered saline', 'Chemical', '-', (51, 76))	('U87MG', 'Var', (0, 5))
88130	31652449	Effects of the MAML2 genetic variants in glioma susceptibility and prognosis Background: Abnormal expression of the mastermind-like transcriptional co-activator 2 (MAML2) gene is oncogenic in several human cancers, including glioma.	('human', 'Species', '9606', (200, 205))	('mastermind-like transcriptional co-activator 2', 'Gene', (116, 162))	('MAML2', 'Gene', '84441', (15, 20))	('MAML2', 'Gene', (164, 169))	('glioma', 'Disease', (225, 231))	('Abnormal', 'Var', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('glioma', 'Disease', (41, 47))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('MAML2', 'Gene', '84441', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('mastermind-like transcriptional co-activator 2', 'Gene', '84441', (116, 162))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('variants', 'Var', (29, 37))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('oncogenic', 'Reg', (179, 188))	('MAML2', 'Gene', (15, 20))
88131	31652449	However, the relevance of MAML2 variants with glioma remains unknown.	('MAML2', 'Gene', '84441', (26, 31))	('glioma', 'Disease', (46, 52))	('variants', 'Var', (32, 40))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('MAML2', 'Gene', (26, 31))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
88132	31652449	We aimed to investigate the role of MAML2 polymorphisms in glioma risk and prognosis among the Chinese Han population.	('MAML2', 'Gene', (36, 41))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('polymorphisms', 'Var', (42, 55))	('MAML2', 'Gene', '84441', (36, 41))
88133	31652449	Methods: Seven MAML2 single-nucleotide polymorphisms (SNPs) were genotyped using Agena MassARRAY system among 575 patients with glioma and 500 age- and gender-matched healthy controls.	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('MAML2', 'Gene', (15, 20))	('single-nucleotide polymorphisms', 'Var', (21, 52))	('patients', 'Species', '9606', (114, 122))	('MAML2', 'Gene', '84441', (15, 20))
88134	31652449	Logistic regression was used to estimate the association between MAML2 polymorphisms and glioma risk by calculating odds ratios (ORs) and 95% confidence intervals (CI).	('polymorphisms', 'Var', (71, 84))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('association', 'Interaction', (45, 56))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('MAML2', 'Gene', '84441', (65, 70))	('MAML2', 'Gene', (65, 70))	('glioma', 'Disease', (89, 95))
88135	31652449	Kaplan-Meier survival analysis and univariate, multivariate Cox proportional hazard regression analyses for hazard ratios (HRs) and 95% CIs were performed to evaluate the contribution of MAML2 polymorphisms to glioma prognosis.	('polymorphisms', 'Var', (193, 206))	('Cox', 'Gene', (60, 63))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('MAML2', 'Gene', (187, 192))	('MAML2', 'Gene', '84441', (187, 192))	('glioma', 'Disease', (210, 216))	('Cox', 'Gene', '1351', (60, 63))
88136	31652449	Results: MAML2 rs7938889 and rs485842 polymorphisms were associated with the reduced risk of glioma (OR = 0.69, P=0.023; and OR = 0.81, P=0.032, respectively).	('rs7938889', 'Mutation', 'rs7938889', (15, 24))	('glioma', 'Disease', (93, 99))	('rs485842', 'Var', (29, 37))	('rs485842', 'Mutation', 'rs485842', (29, 37))	('reduced', 'NegReg', (77, 84))	('MAML2', 'Gene', (9, 14))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('MAML2', 'Gene', '84441', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('rs7938889', 'Var', (15, 24))
88137	31652449	Rs7115578 polymorphism had a lower susceptibility to glioma in males (OR = 0.68, P=0.034), while rs4598633 variant with a higher risk in females (OR = 1.66, P=0.016).	('Rs7115578', 'Mutation', 'Rs7115578', (0, 9))	('Rs7115578', 'Var', (0, 9))	('susceptibility', 'MPA', (35, 49))	('glioma', 'Disease', (53, 59))	('rs4598633', 'Var', (97, 106))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('rs4598633', 'Mutation', 'rs4598633', (97, 106))	('lower', 'NegReg', (29, 34))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
88138	31652449	Additionally, rs7115578 AG genotype represented a poorer prognosis of glioma (HR = 1.24, P=0.033) and astrocytoma (log-rank P=0.037, HR = 1.31, P=0.036).	('astrocytoma', 'Disease', (102, 113))	('glioma', 'Disease', (70, 76))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('rs7115578 AG', 'Var', (14, 26))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('rs7115578', 'Mutation', 'rs7115578', (14, 23))	('astrocytoma', 'Disease', 'MESH:D001254', (102, 113))	('poorer', 'NegReg', (50, 56))
88139	31652449	Furthermore, rs11021499 polymorphism had lower overall survival (OS) and progression-free survival (PFS) in patients with low-grade glioma.	('glioma', 'Disease', (132, 138))	('progression-free survival', 'CPA', (73, 98))	('rs11021499', 'Var', (13, 23))	('lower', 'NegReg', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('overall survival', 'MPA', (47, 63))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('patients', 'Species', '9606', (108, 116))	('rs11021499', 'Mutation', 'rs11021499', (13, 23))
88140	31652449	Conclusion: We provided some novel data suggesting MAML2 polymorphisms might contribute to glioma risk and prognosis.	('polymorphisms', 'Var', (57, 70))	('contribute', 'Reg', (77, 87))	('glioma', 'Disease', (91, 97))	('MAML2', 'Gene', '84441', (51, 56))	('MAML2', 'Gene', (51, 56))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
88146	31652449	Recently, a vast number of studies have reported that genetic factors contribute to the development of glioma, which revealed single-nucleotide polymorphisms (SNPs) in cancer-related genes were associated with glioma susceptibility and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('associated', 'Reg', (194, 204))	('men', 'Species', '9606', (95, 98))	('cancer', 'Disease', (168, 174))	('single-nucleotide polymorphisms', 'Var', (126, 157))	('glioma', 'Disease', (103, 109))	('glioma', 'Disease', (210, 216))
88152	31652449	Additionally, epidemiological studies have confirmed that polymorphisms in MAML2, a NOTCH pathway gene, were related to cancer susceptibility and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('related', 'Reg', (109, 116))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('polymorphisms', 'Var', (58, 71))	('MAML2', 'Gene', (75, 80))	('MAML2', 'Gene', '84441', (75, 80))
88153	31652449	However, no previous study has investigated the contribution of MAML2 variants to glioma risk and prognosis.	('MAML2', 'Gene', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('MAML2', 'Gene', '84441', (64, 69))	('variants', 'Var', (70, 78))	('glioma', 'Disease', (82, 88))
88154	31652449	In this hospital-based case-control study, we aimed to investigate the association of MAML2 polymorphisms with the susceptibility of glioma, and the role of these polymorphisms in the prognosis of glioma patients among the Chinese Han population.	('patients', 'Species', '9606', (204, 212))	('investigate', 'Reg', (55, 66))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('polymorphisms', 'Var', (92, 105))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('MAML2', 'Gene', (86, 91))	('glioma', 'Disease', (197, 203))	('MAML2', 'Gene', '84441', (86, 91))	('glioma', 'Disease', (133, 139))	('association', 'Interaction', (71, 82))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
88166	31652449	Seven MAML2 SNPs (rs7107785, rs479825, rs7938889, rs11021499, rs7115578, rs4598633 and rs485842) were selected as candidate SNPs for genotyping in the current study.	('rs7107785', 'Mutation', 'rs7107785', (18, 27))	('MAML2', 'Gene', (6, 11))	('rs4598633', 'Mutation', 'rs4598633', (73, 82))	('rs7938889', 'Var', (39, 48))	('rs7938889', 'Mutation', 'rs7938889', (39, 48))	('rs4598633', 'Var', (73, 82))	('MAML2', 'Gene', '84441', (6, 11))	('rs7115578', 'Var', (62, 71))	('rs485842', 'Var', (87, 95))	('rs485842', 'Mutation', 'rs485842', (87, 95))	('rs11021499', 'Mutation', 'rs11021499', (50, 60))	('rs7115578', 'Mutation', 'rs7115578', (62, 71))	('rs479825', 'Var', (29, 37))	('rs7107785', 'Var', (18, 27))	('rs479825', 'Mutation', 'rs479825', (29, 37))	('rs11021499', 'Var', (50, 60))
88174	31652449	Hazard ratios (HRs) and 95% CIs were calculated from univariate and multivariate Cox proportional hazard regression analyses to evaluate the correlation between MAML2 polymorphisms and glioma prognosis.	('polymorphisms', 'Var', (167, 180))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('glioma', 'Disease', (185, 191))	('Cox', 'Gene', '1351', (81, 84))	('Cox', 'Gene', (81, 84))	('MAML2', 'Gene', '84441', (161, 166))	('MAML2', 'Gene', (161, 166))
88183	31652449	Moreover, the expression of MAMAL2 was particularly associated with the prognosis of lower grade glioma (log-rank P=0.0094, Supplementary Figure S2).	('expression', 'Var', (14, 24))	('glioma', 'Disease', (97, 103))	('MAMAL2', 'Gene', (28, 34))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('associated with', 'Reg', (52, 67))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('men', 'Species', '9606', (130, 133))
88184	31652449	Among the seven MAML2 SNPs, two SNPs (rs7938889 and rs485842) were found to be significantly related to the risk of glioma by an adjustment for age and gender.	('rs485842', 'Var', (52, 60))	('glioma', 'Disease', (116, 122))	('rs7938889', 'Var', (38, 47))	('men', 'Species', '9606', (135, 138))	('rs7938889', 'Mutation', 'rs7938889', (38, 47))	('rs485842', 'Mutation', 'rs485842', (52, 60))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('MAML2', 'Gene', (16, 21))	('related', 'Reg', (93, 100))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('MAML2', 'Gene', '84441', (16, 21))
88185	31652449	The genotype and allele frequencies distribution of rs7938889 and rs485842 and their association with glioma risk are shown in Table 2.	('rs485842', 'Var', (66, 74))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('rs485842', 'Mutation', 'rs485842', (66, 74))	('rs7938889', 'Var', (52, 61))	('rs7938889', 'Mutation', 'rs7938889', (52, 61))	('glioma', 'Disease', (102, 108))	('association', 'Interaction', (85, 96))
88186	31652449	Subjects with rs7938889 TT genotype were associated with a reduced risk of glioma (TT vs. CC, OR = 0.69, 95%: 0.48-0.99, P=0.043; and TT vs. CC-CT, OR = 0.69, 95%: 0.50-0.95, P=0.023).	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('reduced', 'NegReg', (59, 66))	('glioma', 'Disease', (75, 81))	('rs7938889', 'Var', (14, 23))	('rs7938889', 'Mutation', 'rs7938889', (14, 23))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
88187	31652449	Rs485842 polymorphism also displayed a lower risk of developing glioma under allele (OR = 0.81, 95%: 0.67-0.98, P=0.032), homozygote (OR = 0.59, 95%: 0.37-0.96, P=0.033) and additive (OR = 0.81, 95%: 0.67-0.98, P=0.033) models.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioma', 'Disease', (64, 70))	('Rs485842', 'Mutation', 'Rs485842', (0, 8))	('Rs485842', 'Var', (0, 8))	('lower', 'NegReg', (39, 44))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
88188	31652449	Additionally, rs7938889 variant had a relationship with decreasing astrocytoma risk under multiple genetic model (allele, OR = 0.82, P=0.035; homozygote, OR = 0.61, P=0.013; recessive, OR = 0.63, P=0.009; and additive, OR = 0.81, P=0.027).	('astrocytoma', 'Disease', 'MESH:D001254', (67, 78))	('rs7938889', 'Var', (14, 23))	('astrocytoma', 'Disease', (67, 78))	('rs7938889', 'Mutation', 'rs7938889', (14, 23))	('decreasing', 'NegReg', (56, 66))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))
88189	31652449	No statistically significant associations were observed between MAML2 rs7107785, rs479825, rs11021499, rs7115578 and rs4598633 variants and the risk of glioma.	('MAML2', 'Gene', (64, 69))	('rs7107785', 'Var', (70, 79))	('rs479825', 'Var', (81, 89))	('rs11021499', 'Var', (91, 101))	('rs4598633', 'Var', (117, 126))	('rs7115578', 'Var', (103, 112))	('rs7107785', 'Mutation', 'rs7107785', (70, 79))	('MAML2', 'Gene', '84441', (64, 69))	('rs479825', 'Mutation', 'rs479825', (81, 89))	('rs4598633', 'Mutation', 'rs4598633', (117, 126))	('glioma', 'Disease', (152, 158))	('rs11021499', 'Mutation', 'rs11021499', (91, 101))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('rs7115578', 'Mutation', 'rs7115578', (103, 112))
88190	31652449	We also conducted stratification analyses by age and gender (Table 3), and revealed that the effect of both rs7938889 and rs485842 on glioma risk remained significant.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('rs485842', 'Mutation', 'rs485842', (122, 130))	('rs485842', 'Var', (122, 130))	('rs7938889', 'Mutation', 'rs7938889', (108, 117))	('glioma', 'Disease', (134, 140))	('rs7938889', 'Var', (108, 117))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
88191	31652449	The association between glioma risk and rs7938889 genotypes was more profound in the individuals at age <= 40 years (T vs C, OR = 0.75, P=0.020; TT vs CC, OR = 0.56, P=0.031) and males (TT vs CC, OR = 0.59, P=0.032), while rs485842 variant in the subjects at age > 40 years (T vs C, OR = 0.66, P=0.003; TT vs CC, OR = 0.31, P=0.0005).	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('rs7938889', 'Var', (40, 49))	('rs7938889', 'Mutation', 'rs7938889', (40, 49))	('rs485842', 'Mutation', 'rs485842', (223, 231))	('glioma', 'Disease', (24, 30))	('rs485842', 'Var', (223, 231))
88192	31652449	Furthermore, we also found that rs7115578 polymorphism had a lower susceptibility to glioma in males (AG-GG vs AA, OR = 0.68, P=0.034), while rs4598633 variant was associated with a higher risk for glioma in females (CT vs CC, OR = 1.66, P=0.016; CT-TT vs CC, OR = 1.49, P=0.043).	('lower', 'NegReg', (61, 66))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('rs4598633', 'Var', (142, 151))	('rs4598633', 'Mutation', 'rs4598633', (142, 151))	('glioma', 'Disease', (198, 204))	('glioma', 'Disease', (85, 91))	('rs7115578', 'Mutation', 'rs7115578', (32, 41))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('rs7115578', 'Var', (32, 41))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
88193	31652449	We further stratified by the glioma grade, and there was a lower prevalence of rs7115578-GG carriers in the high-grade subgroup (WHO III+IV) than in the low-grade subgroup (WHO I+II) (16.99 vs 24.39%) with a marginal P-value in recessive model (OR = 0.64, 95% CI: 0.41-1.00, P=0.048, Supplementary Table S3), which indicated insufficient evidence for claiming an association and needed further verification.	('glioma', 'Disease', (29, 35))	('lower', 'NegReg', (59, 64))	('rs7115578-GG', 'Var', (79, 91))	('WHO III+IV', 'Chemical', 'MESH:C068574', (129, 139))	('men', 'Species', '9606', (290, 293))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('rs7115578', 'Mutation', 'rs7115578', (79, 88))	('WHO I+II', 'Chemical', 'MESH:C068574', (173, 181))
88197	31652449	We investigated the association between MAML2 polymorphisms and the prognosis of glioma patients using Log-rank tests and univariate Cox regression analysis (Table 4 and Figure 1).	('Cox', 'Gene', '1351', (133, 136))	('Cox', 'Gene', (133, 136))	('MAML2', 'Gene', '84441', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('investigated', 'Reg', (3, 15))	('patients', 'Species', '9606', (88, 96))	('association', 'Interaction', (20, 31))	('glioma', 'Disease', (81, 87))	('polymorphisms', 'Var', (46, 59))	('MAML2', 'Gene', (40, 45))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
88198	31652449	MAML2 rs7115578 polymorphism was only one that affected the prognosis of glioma in the overall.	('MAML2', 'Gene', (0, 5))	('glioma', 'Disease', (73, 79))	('MAML2', 'Gene', '84441', (0, 5))	('affected', 'Reg', (47, 55))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('rs7115578 polymorphism', 'Var', (6, 28))	('rs7115578', 'Mutation', 'rs7115578', (6, 15))
88200	31652449	In astrocytoma, rs7115578 polymorphism also was a predictor for unfavorable prognosis (OS: log-rank P=0.037, HR = 1.31, 95% CI: 1.02-1.69, P=0.036).	('astrocytoma', 'Disease', (3, 14))	('astrocytoma', 'Phenotype', 'HP:0009592', (3, 14))	('rs7115578', 'Mutation', 'rs7115578', (16, 25))	('rs7115578', 'Var', (16, 25))	('astrocytoma', 'Disease', 'MESH:D001254', (3, 14))
88202	31652449	In patients with low-grade glioma, Kaplan-Meier analyses and univariate analyses revealed that rs11021499-GA genotype had lower OS (log-rank P=0.046, HR = 1.30, 95% CI: 1.00-1.68, P=0.047) and PFS (log-rank P=0.024, HR = 1.33, 95% CI: 1.03-1.72, P=0.032) than CC genotype.	('glioma', 'Disease', (27, 33))	('lower', 'NegReg', (122, 127))	('rs11021499-GA', 'Var', (95, 108))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('rs11021499', 'Mutation', 'rs11021499', (95, 105))	('patients', 'Species', '9606', (3, 11))	('PFS', 'MPA', (193, 196))
88204	31652449	The rs7115578 heterozygous was significantly associated with the poorer PFS of glioma (HR = 1.25, 95% CI: 1.02-1.53, P=0.031) and high-grade glioma (HR = 1.45, 95% CI: 1.03-2.03, P=0.032).	('glioma', 'Disease', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('poorer', 'NegReg', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('rs7115578', 'Mutation', 'rs7115578', (4, 13))	('rs7115578', 'Var', (4, 13))	('glioma', 'Disease', (141, 147))
88206	31652449	In the present study, we first investigated the association between MAML2 genetic variants and glioma risk or prognosis among the Chinese Han population.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('genetic variants', 'Var', (74, 90))	('MAML2', 'Gene', (68, 73))	('MAML2', 'Gene', '84441', (68, 73))	('association', 'Interaction', (48, 59))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
88207	31652449	We found that rs7938889, rs485842, rs7115578 and rs4598633 polymorphisms were significantly related to the risk of glioma.	('rs7115578', 'Mutation', 'rs7115578', (35, 44))	('glioma', 'Disease', (115, 121))	('rs485842', 'Mutation', 'rs485842', (25, 33))	('rs4598633', 'Var', (49, 58))	('rs7115578', 'Var', (35, 44))	('related', 'Reg', (92, 99))	('rs4598633', 'Mutation', 'rs4598633', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('rs7938889', 'Var', (14, 23))	('rs7938889', 'Mutation', 'rs7938889', (14, 23))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('rs485842', 'Var', (25, 33))
88208	31652449	Moreover, we demonstrated that rs7115578 and rs11021499 variants represented a poorer prognosis of glioma.	('rs11021499', 'Mutation', 'rs11021499', (45, 55))	('rs7115578', 'Mutation', 'rs7115578', (31, 40))	('rs7115578', 'Var', (31, 40))	('glioma', 'Disease', (99, 105))	('rs11021499', 'Var', (45, 55))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
88209	31652449	To the best of our knowledge, no previous studies have investigated the role of MAML2 variants for glioma.	('variants', 'Var', (86, 94))	('MAML2', 'Gene', '84441', (80, 85))	('glioma', 'Disease', (99, 105))	('MAML2', 'Gene', (80, 85))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
88210	31652449	Our study addressed a gap in knowledge of the MAML2 gene polymorphisms and the susceptibility and prognosis of glioma, indicating that MAML2 genetic variations might play an important role in the development of glioma.	('genetic variations', 'Var', (141, 159))	('glioma', 'Disease', (111, 117))	('men', 'Species', '9606', (203, 206))	('play', 'Reg', (166, 170))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('role', 'Reg', (184, 188))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma', 'Disease', (211, 217))	('MAML2', 'Gene', (135, 140))	('MAML2', 'Gene', (46, 51))	('MAML2', 'Gene', '84441', (46, 51))	('MAML2', 'Gene', '84441', (135, 140))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))
88220	31652449	Previous studies have confirmed that the genetic variability of MAML2, including structural variation, copy number variation and SNPs, were associated with the occurrence and progression of disease.	('MAML2', 'Gene', (64, 69))	('associated with', 'Reg', (140, 155))	('SNPs', 'Var', (129, 133))	('MAML2', 'Gene', '84441', (64, 69))	('progression', 'CPA', (175, 186))	('copy number variation', 'Var', (103, 124))	('genetic variability', 'Var', (41, 60))	('structural variation', 'Var', (81, 101))
88221	31652449	In the present study, four SNPs in MAML2 (rs7938889 and rs485842, rs7115578 and rs4598633) were found to be significantly associated with glioma risk.	('associated', 'Reg', (122, 132))	('rs7115578', 'Mutation', 'rs7115578', (66, 75))	('rs7115578', 'Var', (66, 75))	('glioma', 'Disease', (138, 144))	('rs485842', 'Var', (56, 64))	('rs4598633', 'Var', (80, 89))	('rs4598633', 'Mutation', 'rs4598633', (80, 89))	('MAML2', 'Gene', '84441', (35, 40))	('MAML2', 'Gene', (35, 40))	('rs7938889', 'Mutation', 'rs7938889', (42, 51))	('rs485842', 'Mutation', 'rs485842', (56, 64))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('rs7938889', 'Var', (42, 51))
88222	31652449	Specifically, carriers of the rs7938889 TT and rs485842 TT genotypes reduced the risk of the overall glioma and astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (112, 123))	('reduced', 'NegReg', (69, 76))	('rs7938889', 'Mutation', 'rs7938889', (30, 39))	('rs7938889', 'Var', (30, 39))	('rs485842', 'Var', (47, 55))	('glioma and astrocytoma', 'Disease', 'MESH:D005910', (101, 123))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('rs485842', 'Mutation', 'rs485842', (47, 55))
88223	31652449	Furthermore, the association between glioma risk and rs7938889 genotypes was more profound in the individuals at age <= 40 years, while rs485842 variant in the subjects at age > 40 years.	('rs7938889', 'Var', (53, 62))	('rs485842', 'Mutation', 'rs485842', (136, 144))	('rs7938889', 'Mutation', 'rs7938889', (53, 62))	('glioma', 'Disease', (37, 43))	('rs485842', 'Var', (136, 144))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
88224	31652449	We also found that rs7938889 and rs7115578 polymorphisms had a lower susceptibility to glioma in males, while rs4598633 variant was associated with a higher risk for glioma in females.	('rs7938889', 'Var', (19, 28))	('glioma', 'Disease', (87, 93))	('lower', 'NegReg', (63, 68))	('rs7115578', 'Mutation', 'rs7115578', (33, 42))	('rs4598633', 'Mutation', 'rs4598633', (110, 119))	('glioma', 'Disease', (166, 172))	('susceptibility', 'MPA', (69, 83))	('rs4598633', 'Var', (110, 119))	('rs7115578', 'Var', (33, 42))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('rs7938889', 'Mutation', 'rs7938889', (19, 28))
88226	31652449	This result suggested the risk association of MAML2 polymorphisms with glioma might be dependent on age or gender.	('glioma', 'Disease', (71, 77))	('polymorphisms', 'Var', (52, 65))	('MAML2', 'Gene', (46, 51))	('MAML2', 'Gene', '84441', (46, 51))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
88227	31652449	More importantly, we revealed that rs7115578 AG genotype represented a poorer prognosis of glioma, particularly among astrocytoma and high-grade glioma.	('rs7115578', 'Mutation', 'rs7115578', (35, 44))	('glioma', 'Disease', (145, 151))	('astrocytoma', 'Disease', 'MESH:D001254', (118, 129))	('rs7115578 AG', 'Var', (35, 47))	('glioma', 'Disease', (91, 97))	('astrocytoma', 'Disease', (118, 129))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
88228	31652449	Rs11021499 polymorphism had lower OS and PFS in patients with low-grade glioma.	('glioma', 'Disease', (72, 78))	('PFS', 'MPA', (41, 44))	('lower', 'NegReg', (28, 33))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('Rs11021499', 'Mutation', 'Rs11021499', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('patients', 'Species', '9606', (48, 56))	('Rs11021499', 'Var', (0, 10))
88229	31652449	Although MAML2 polymorphisms were found to be significantly associated with the risk and prognosis of glioma, the mechanism of MAML2 underlying the effect on the glioma risk and patients survival was not identified in the present study, nor has not been reported in the literature.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('MAML2', 'Gene', (127, 132))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glioma', 'Disease', (162, 168))	('MAML2', 'Gene', '84441', (127, 132))	('patients', 'Species', '9606', (178, 186))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('MAML2', 'Gene', '84441', (9, 14))	('MAML2', 'Gene', (9, 14))	('glioma', 'Disease', (102, 108))	('polymorphisms', 'Var', (15, 28))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('associated', 'Reg', (60, 70))
88230	31652449	The online prediction tool Haploreg showed that rs7938889 and rs485842, rs7115578, rs4598633 and rs11021499 polymorphisms, located in the intron region, were associated with the regulation of promoter histone marks, enhancer histone marks, DNAse and/or motifs changed, suggesting their possible functions in glioma patients.	('glioma', 'Disease', 'MESH:D005910', (308, 314))	('motifs', 'MPA', (253, 259))	('rs11021499', 'Mutation', 'rs11021499', (97, 107))	('glioma', 'Phenotype', 'HP:0009733', (308, 314))	('rs11021499', 'Var', (97, 107))	('rs485842', 'Var', (62, 70))	('rs7115578', 'Mutation', 'rs7115578', (72, 81))	('rs7115578', 'Var', (72, 81))	('rs7938889', 'Mutation', 'rs7938889', (48, 57))	('patients', 'Species', '9606', (315, 323))	('rs4598633', 'Var', (83, 92))	('rs485842', 'Mutation', 'rs485842', (62, 70))	('rs7938889', 'Var', (48, 57))	('enhancer', 'PosReg', (216, 224))	('rs4598633', 'Mutation', 'rs4598633', (83, 92))	('promoter histone marks', 'MPA', (192, 214))	('glioma', 'Disease', (308, 314))	('changed', 'Reg', (260, 267))	('DNAse', 'MPA', (240, 245))
88232	31652449	Strengths of the current study include the relatively large sample size considering the rarity of glioma, and the first demonstration on the associations of MAML2 polymorphisms with glioma risk and prognosis among Chinese Han population.	('MAML2', 'Gene', '84441', (157, 162))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('associations', 'Interaction', (141, 153))	('glioma', 'Disease', (98, 104))	('glioma', 'Disease', (182, 188))	('polymorphisms', 'Var', (163, 176))	('MAML2', 'Gene', (157, 162))
88233	31652449	Second, the detailed molecular mechanism under which MAML2 polymorphisms affect glioma risk and prognosis needs further studies to elucidate.	('glioma', 'Disease', (80, 86))	('affect', 'Reg', (73, 79))	('polymorphisms', 'Var', (59, 72))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('MAML2', 'Gene', '84441', (53, 58))	('MAML2', 'Gene', (53, 58))
88234	31652449	In conclusion, these results suggested that MAML2 polymorphisms might contribute to glioma susceptibility and prognosis.	('glioma', 'Disease', (84, 90))	('polymorphisms', 'Var', (50, 63))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('contribute', 'Reg', (70, 80))	('MAML2', 'Gene', '84441', (44, 49))	('MAML2', 'Gene', (44, 49))
88235	31652449	We found that MAML2 rs7938889 and rs485842 polymorphisms were significantly associated with the reduced risk of glioma.	('rs485842', 'Mutation', 'rs485842', (34, 42))	('MAML2', 'Gene', (14, 19))	('rs7938889', 'Mutation', 'rs7938889', (20, 29))	('MAML2', 'Gene', '84441', (14, 19))	('glioma', 'Disease', (112, 118))	('rs7938889', 'Var', (20, 29))	('rs485842', 'Var', (34, 42))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('reduced', 'NegReg', (96, 103))
88237	31652449	Although these data need confirmation by independent studies, our results hint MAML2 genetic variants might play an important role in the development of glioma among Chinese Han population, and add to the body of knowledge surrounding genetic polymorphisms as putative player affecting the risk or prognosis of glioma.	('men', 'Species', '9606', (145, 148))	('glioma', 'Disease', (153, 159))	('MAML2', 'Gene', (79, 84))	('MAML2', 'Gene', '84441', (79, 84))	('variants', 'Var', (93, 101))	('glioma', 'Disease', (311, 317))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('glioma', 'Disease', 'MESH:D005910', (311, 317))	('glioma', 'Phenotype', 'HP:0009733', (311, 317))
88243	31215432	Oligodendroglial tumours: subventricular zone involvement and seizure history are associated with CIC mutation status CIC-mutant oligodendroglial tumours linked to better prognosis.	('CIC', 'Gene', '23152', (118, 121))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('seizure', 'Disease', 'MESH:D012640', (62, 69))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('oligodendroglial tumours', 'Disease', (129, 153))	('seizure', 'Disease', (62, 69))	('CIC', 'Gene', (118, 121))	('CIC', 'Gene', '23152', (98, 101))	('oligodendroglial tumours', 'Disease', 'MESH:D009369', (129, 153))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('seizure', 'Phenotype', 'HP:0001250', (62, 69))	('CIC', 'Gene', (98, 101))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('mutation status', 'Var', (102, 117))	('Oligodendroglial tumours', 'Disease', 'MESH:D009369', (0, 24))	('Oligodendroglial tumours', 'Disease', (0, 24))
88246	31215432	Differences between CIC mutation and CIC wild-type were tested using Chi-square test and binary logistic regression analysis.	('CIC', 'Gene', '23152', (37, 40))	('CIC', 'Gene', (37, 40))	('CIC', 'Gene', '23152', (20, 23))	('mutation', 'Var', (24, 32))	('CIC', 'Gene', (20, 23))
88247	31215432	In univariate analysis, the clinical variables and MR features, which consisted 3 selected features (subventricular zone[SVZ] involvement, volume and seizure history) were associated with CIC mutation status (all p < 0.05).	('seizure', 'Phenotype', 'HP:0001250', (150, 157))	('associated', 'Reg', (172, 182))	('CIC', 'Gene', '23152', (188, 191))	('men', 'Species', '9606', (133, 136))	('mutation status', 'Var', (192, 207))	('CIC', 'Gene', (188, 191))	('seizure', 'Disease', (150, 157))	('seizure', 'Disease', 'MESH:D012640', (150, 157))
88254	31215432	LGG samples with an isocitrate dehydrogenase (IDH) mutation and the codeletion of 1p and 19q had the most favourable outcomes for treatment.	('IDH', 'Gene', (46, 49))	('men', 'Species', '9606', (135, 138))	('isocitrate dehydrogenase', 'Gene', (20, 44))	('IDH', 'Gene', '3417', (46, 49))	('mutation', 'Var', (51, 59))	('isocitrate dehydrogenase', 'Gene', '3417', (20, 44))
88255	31215432	The Capicua transcriptional repressor (CIC) gene is often mutated in oligodendroglial tumours with the codeletion of 1p and 19q.	('Capicua transcriptional repressor', 'Gene', (4, 37))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('CIC', 'Gene', '23152', (39, 42))	('Capicua transcriptional repressor', 'Gene', '23152', (4, 37))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('CIC', 'Gene', (39, 42))	('oligodendroglial tumours', 'Disease', (69, 93))	('oligodendroglial tumours', 'Disease', 'MESH:D009369', (69, 93))	('mutated', 'Var', (58, 65))
88261	31215432	Radiological detection of CIC mutation status may facilitate the preoperative prediction of a patient's prognosis.	('CIC', 'Gene', '23152', (26, 29))	('mutation', 'Var', (30, 38))	('CIC', 'Gene', (26, 29))	('patient', 'Species', '9606', (94, 101))	('facilitate', 'PosReg', (50, 60))
88268	31215432	2015; 372 (26):2481-2498]); and available MR images (T1WI, T2WI, Flair and post-contrast) from TCIA.	('TCIA', 'Chemical', '-', (95, 99))	('T2WI', 'Var', (59, 63))	('T1WI', 'Var', (53, 57))
88274	31215432	Differences between CIC mutation and CIC wild-type were tested using the Chi-square test and binary logistic regression analysis (version 22.0; SPSS Company, Chicago, IL).	('CIC', 'Gene', '23152', (37, 40))	('CIC', 'Gene', (37, 40))	('CIC', 'Gene', '23152', (20, 23))	('mutation', 'Var', (24, 32))	('CIC', 'Gene', (20, 23))
88275	31215432	The area under the receiver operator characteristic curve (AUC) was estimated for prediction of CIC gene mutation status.	('mutation', 'Var', (105, 113))	('CIC', 'Gene', '23152', (96, 99))	('CIC', 'Gene', (96, 99))
88276	31215432	The sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of the model in the prediction of CIC mutations were obtained.	('mutations', 'Var', (136, 145))	('CIC', 'Gene', (132, 135))	('CIC', 'Gene', '23152', (132, 135))
88278	31215432	CIC mutations were found in 10 (16.9%) of 59 patients.	('mutations', 'Var', (4, 13))	('CIC', 'Gene', '23152', (0, 3))	('patients', 'Species', '9606', (45, 53))	('CIC', 'Gene', (0, 3))
88284	31215432	We demonstrated that seizure history (no vs. yes OR: 28.960, 95CI:2.625-319.49, P = 0.006) and subventricular zone involvement (SVZ- vs. SVZ+ OR: 77.092, P = 0.003; 95% CI: 4.578-1298.334) were associated with a higher incidence of CIC mutation status.	('CIC', 'Gene', '23152', (232, 235))	('seizure', 'Disease', (21, 28))	('seizure', 'Disease', 'MESH:D012640', (21, 28))	('CIC', 'Gene', (232, 235))	('mutation status', 'Var', (236, 251))	('seizure', 'Phenotype', 'HP:0001250', (21, 28))	('men', 'Species', '9606', (122, 125))
88285	31215432	The sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of this model in the prediction of CIC mutations were 0.90, 0.71, 3.09 and 0.14, respectively.	('mutations', 'Var', (137, 146))	('CIC', 'Gene', '23152', (133, 136))	('CIC', 'Gene', (133, 136))
88286	31215432	Subventricular zone involvement (-) of oligodendroglial tumours in combination with absence of seizure history may therefore be used to better prognosticate CIC mutation status than the use of each variable alone (Fig.	('seizure', 'Disease', 'MESH:D012640', (95, 102))	('absence of seizure', 'Phenotype', 'HP:0002121', (84, 102))	('oligodendroglial tumours', 'Disease', (39, 63))	('oligodendroglial tumours', 'Disease', 'MESH:D009369', (39, 63))	('mutation', 'Var', (161, 169))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('CIC', 'Gene', '23152', (157, 160))	('seizure', 'Phenotype', 'HP:0001250', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('CIC', 'Gene', (157, 160))	('men', 'Species', '9606', (27, 30))	('seizure', 'Disease', (95, 102))
88290	31215432	Some oligoastrocytomas and most oligodendrogliomas are characterized by a typical and unique unbalanced translocation, der (1, 19), resulting in a 1p/19q co-deletion (codeletion of 1p and 19q).	('1p/19q', 'Var', (147, 153))	('oligodendrogliomas', 'Disease', (32, 50))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (5, 22))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('oligoastrocytomas', 'Disease', (5, 22))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (32, 50))
88296	31215432	Rizzo S found that a pleural effusion related to ALK mutations while nodules located in non-tumour lobes or round lesion shapes were related to a KRAS mutation in subgroups of non-small cell lung cancer patients.	('KRAS', 'Gene', '3845', (146, 150))	('related', 'Reg', (133, 140))	('related', 'Reg', (38, 45))	('non-small cell lung cancer', 'Disease', (176, 202))	('pleural effusion', 'Disease', (21, 37))	('KRAS', 'Gene', (146, 150))	('patients', 'Species', '9606', (203, 211))	('non-tumour lobes', 'Disease', 'MESH:D001932', (88, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('pleural effusion', 'Disease', 'MESH:D010996', (21, 37))	('ALK', 'Gene', '238', (49, 52))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (176, 202))	('mutations', 'Var', (53, 62))	('non-tumour lobes', 'Disease', (88, 104))	('ALK', 'Gene', (49, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (180, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('pleural effusion', 'Phenotype', 'HP:0002202', (21, 37))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (176, 202))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
88298	31215432	This study suggests that SVZ involvement and seizure history can be conveniently used to facilitate the prediction of CIC mutation status.	('CIC', 'Gene', '23152', (118, 121))	('mutation', 'Var', (122, 130))	('seizure', 'Disease', (45, 52))	('CIC', 'Gene', (118, 121))	('seizure', 'Disease', 'MESH:D012640', (45, 52))	('men', 'Species', '9606', (36, 39))	('seizure', 'Phenotype', 'HP:0001250', (45, 52))
88305	31215432	In the present study, we constructed three models for the preoperative prediction of CIC mutation statuses in oligodendroglial tumours.	('oligodendroglial tumours', 'Disease', 'MESH:D009369', (110, 134))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('CIC', 'Gene', '23152', (85, 88))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('mutation', 'Var', (89, 97))	('CIC', 'Gene', (85, 88))	('oligodendroglial tumours', 'Disease', (110, 134))
88311	31215432	In conclusion, this study presents that SVZ involvement (-) and absence of seizure history may therefore be used to facilitate the prediction of CIC mutation status.	('CIC', 'Gene', (145, 148))	('seizure', 'Phenotype', 'HP:0001250', (75, 82))	('men', 'Species', '9606', (51, 54))	('absence of seizure', 'Phenotype', 'HP:0002121', (64, 82))	('mutation', 'Var', (149, 157))	('CIC', 'Gene', '23152', (145, 148))	('seizure', 'Disease', 'MESH:D012640', (75, 82))	('facilitate', 'PosReg', (116, 126))	('seizure', 'Disease', (75, 82))
88317	26424050	Genome-wide association study identifies multiple susceptibility loci for glioma Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Disease', (208, 214))	('common genetic variation', 'Var', (146, 170))	('glioma', 'Disease', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
88319	26424050	After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 x 10-9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 x 10-8), 11q23.2 (rs648044, near ZBTB16, P=6.26 x 10-11), 12q21.2 (rs12230172, P=7.53 x 10-11) and 15q24.2 (rs1801591, near ETFA, P=5.71 x 10-9).	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('rs11196067', 'Mutation', 'rs11196067', (187, 197))	('glioblastoma', 'Disease', (92, 104))	('GBM', 'Phenotype', 'HP:0012174', (171, 174))	('rs1801591', 'Mutation', 'rs1801591', (326, 335))	('VTI1A', 'Gene', (204, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('rs1801591', 'Var', (326, 335))	('rs648044', 'Mutation', 'rs648044', (236, 244))	('POLR3B', 'Gene', (140, 146))	('rs648044', 'Var', (236, 244))	('ETFA', 'Gene', (342, 346))	('ZBTB16', 'Gene', (251, 257))	('rs11196067', 'Var', (187, 197))	('rs12230172', 'Mutation', 'rs12230172', (285, 295))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('rs3851634', 'Mutation', 'rs3851634', (124, 133))	('VTI1A', 'Gene', '143187', (204, 209))	('rs12230172', 'Var', (285, 295))	('ETFA', 'Gene', '2108', (342, 346))	('POLR3B', 'Gene', '55703', (140, 146))	('rs3851634', 'Var', (124, 133))	('ZBTB16', 'Gene', '7704', (251, 257))
88330	26424050	Recovery of untyped genotypes via imputation has enabled fine mapping and refinement of association signals, for example, in identification of rs55705857 as the basis of the 8q24 association signal in glioma.	('glioma', 'Disease', (201, 207))	('rs55705857', 'Mutation', 'rs55705857', (143, 153))	('men', 'Species', '9606', (80, 83))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('rs55705857', 'Var', (143, 153))	('glioma', 'Disease', 'MESH:D005910', (201, 207))
88332	26424050	To identify additional glioma susceptibility loci we conducted a pooled meta-analysis of four GWASs in populations of European ancestry, the UK-GWAS, the French-GWAS, the German-GWAS and the US-GWAS, that were genotyped using either Illumina HumanHap 317, 317+240S, 370Duo, 550, 610 or 1M arrays (Supplementary Table 1).	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('men', 'Species', '9606', (303, 306))	('glioma', 'Disease', (23, 29))	('370Duo', 'Var', (266, 272))
88339	26424050	In contrast we found no significant support for the association between rs1920116 near TERC (3q26.2) and risk of high-grade glioma recently reported by Walsh et al.	('TERC', 'Gene', '7012', (87, 91))	('rs1920116', 'Mutation', 'rs1920116', (72, 81))	('glioma', 'Disease', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('TERC', 'Gene', (87, 91))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('rs1920116', 'Var', (72, 81))
88342	26424050	rs141035288, rs117527984, rs138170678 were not taken forward as there was poor concordance between imputed and sequenced genotypes (Supplementary Table 3), and rs145034266 could not be genotyped as it mapped within a highly repetitive region.	('men', 'Species', '9606', (138, 141))	('rs145034266', 'Var', (160, 171))	('rs138170678', 'Var', (26, 37))	('rs117527984', 'Var', (13, 24))	('rs145034266', 'Mutation', 'rs145034266', (160, 171))	('rs141035288', 'Var', (0, 11))	('rs138170678', 'Mutation', 'rs138170678', (26, 37))	('rs117527984', 'Mutation', 'rs117527984', (13, 24))	('rs141035288', 'Mutation', 'rs141035288', (0, 11))
88344	26424050	In the combined analysis five SNPs showed an association with tumour risk, which was genome-wide significant (Table 1):rs3851634 (12q23.3, PGBM=3.02 x 10-9), rs11196067 (10q25.2, PNon-GBM=4.32 x 10-8), rs648044 (11q23.2, PNon-GBM=6.26 x 10-11), rs12230172 (12q21.2, PNon-GBM=7.53 x 10-11) and rs1801591 (15q24.2, PNon-GBM=5.71 x 10-9).	('GBM', 'Phenotype', 'HP:0012174', (184, 187))	('rs1801591', 'Mutation', 'rs1801591', (293, 302))	('rs648044', 'Var', (202, 210))	('rs11196067', 'Mutation', 'rs11196067', (158, 168))	('GBM', 'Phenotype', 'HP:0012174', (318, 321))	('rs3851634', 'Var', (119, 128))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('GBM', 'Phenotype', 'HP:0012174', (226, 229))	('GBM', 'Phenotype', 'HP:0012174', (271, 274))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('rs3851634', 'Mutation', 'rs3851634', (119, 128))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('rs12230172', 'Mutation', 'rs12230172', (245, 255))	('rs12230172', 'Var', (245, 255))	('tumour', 'Disease', (62, 68))	('rs11196067', 'Var', (158, 168))	('rs648044', 'Mutation', 'rs648044', (202, 210))
88346	26424050	The association signal at 12q23.3 defined by rs3851634 was specific for GBM.	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('rs3851634', 'Mutation', 'rs3851634', (45, 54))	('rs3851634', 'Var', (45, 54))	('GBM', 'Disease', (72, 75))
88347	26424050	The rs3851634 maps to intron 12 of the gene encoding polymerase III, RNA, subunit b (POLR3B; Fig.	('rs3851634', 'Mutation', 'rs3851634', (4, 13))	('POLR3B', 'Gene', (85, 91))	('POLR3B', 'Gene', '55703', (85, 91))	('rs3851634', 'Var', (4, 13))
88349	26424050	The other four SNP associations defined by rs11196067, rs648044, rs12230172 and rs1801591 were specific to non-GBM glioma.	('rs648044', 'Mutation', 'rs648044', (55, 63))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))	('glioma', 'Disease', (115, 121))	('rs648044', 'Var', (55, 63))	('rs12230172', 'Mutation', 'rs12230172', (65, 75))	('rs12230172', 'Var', (65, 75))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('rs11196067', 'Var', (43, 53))	('rs1801591', 'Mutation', 'rs1801591', (80, 89))	('rs11196067', 'Mutation', 'rs11196067', (43, 53))	('rs1801591', 'Var', (80, 89))
88350	26424050	rs11196067 (10q25.2) is located in intron 7 of VTI1A (vesicle transport through interaction with t-SNAREs 1A, Fig.	('rs11196067', 'Var', (0, 10))	('rs11196067', 'Mutation', 'rs11196067', (0, 10))	('VTI1A', 'Gene', (47, 52))	('VTI1A', 'Gene', '143187', (47, 52))	('vesicle transport through interaction with t-SNAREs 1A', 'Gene', '143187', (54, 108))
88351	26424050	Similarly rs648044 (11q23.2) is also intronic mapping within ZBTB16 (zinc finger and BTB domain-containing protein 16, alias PLZF; Fig.	('alias PLZF', 'Disease', (119, 129))	('zinc finger and BTB domain-containing protein 16', 'Gene', '7704', (69, 117))	('rs648044', 'Var', (10, 18))	('ZBTB16', 'Gene', '7704', (61, 67))	('alias PLZF', 'Disease', 'None', (119, 129))	('ZBTB16', 'Gene', (61, 67))	('rs648044', 'Mutation', 'rs648044', (10, 18))
88352	26424050	The rs12230172 (12q21.2) maps within the lincRNA RP11-114H23.1 and is centromeric to the gene encoding PHLDA1 (centromeric pleckstrin homology-like domain, family a, MEMBER 1, Fig.	('RP11', 'Gene', (49, 53))	('RP11', 'Gene', '26121', (49, 53))	('rs12230172', 'Mutation', 'rs12230172', (4, 14))	('rs12230172', 'Var', (4, 14))	('H23.1', 'CellLine', 'CVCL:1547', (57, 62))	('PHLDA1', 'Gene', (103, 109))	('PHLDA1', 'Gene', '22822', (103, 109))
88353	26424050	rs1801591 (15q24.2) is responsible for the p.Thr171Ile substitution in ETFA (electron transfer flavoprotein, alpha polypeptide gene, which resides within a 500-kb region of LD to which ISL2, TYRO3P and SCAPPER genes also map Fig.	('ETFA', 'Gene', (71, 75))	('ETFA', 'Gene', '2108', (71, 75))	('electron transfer flavoprotein, alpha polypeptide', 'Gene', '2108', (77, 126))	('p.Thr171Ile', 'Var', (43, 54))	('TYRO3P', 'Gene', '7302', (191, 197))	('rs1801591', 'Mutation', 'rs1801591', (0, 9))	('ISL2', 'Gene', '64843', (185, 189))	('p.Thr171Ile', 'Mutation', 'rs1801591', (43, 54))	('rs1801591', 'Var', (0, 9))	('ISL2', 'Gene', (185, 189))	('TYRO3P', 'Gene', (191, 197))
88354	26424050	To investigate the impact of the new risk SNPs on glioma subtype we examined rs11196067, rs648044, rs12230172, rs1801591 and rs3851634 genotypes in the French case series for which comprehensive histology and molecular phenotyping had been performed (Supplementary Data 1).	('rs1801591', 'Var', (111, 120))	('men', 'Species', '9606', (257, 260))	('rs12230172', 'Mutation', 'rs12230172', (99, 109))	('rs12230172', 'Var', (99, 109))	('rs648044', 'Var', (89, 97))	('glioma', 'Disease', (50, 56))	('rs3851634', 'Var', (125, 134))	('rs3851634', 'Mutation', 'rs3851634', (125, 134))	('rs1801591', 'Mutation', 'rs1801591', (111, 120))	('rs11196067', 'Var', (77, 87))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('rs648044', 'Mutation', 'rs648044', (89, 97))	('rs11196067', 'Mutation', 'rs11196067', (77, 87))
88355	26424050	The GBM SNP rs3851634 was associated with 10q-deleted glioma (P=0.016).	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('rs3851634', 'Mutation', 'rs3851634', (12, 21))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('glioma', 'Disease', (54, 60))	('rs3851634', 'Var', (12, 21))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('associated', 'Reg', (26, 36))
88356	26424050	In the case of non-GBM SNPs rs11196067 showed the strongest association with grade II glioma (P=3.2 x 10-5) and TP53 non-mutated glioma (P=5.82 x 10-5); rs648044 with grade II oligodendroglioma (P=0.026) and 10q non-deleted glioma (P=0.006); rs1801591 with grade II astrocytoma (P=0.001) and IDH1/IDH2 mutated glioma (P=0.005) and rs12230172 with grade II oligodendroglioma (P=0.009), IDH1/IDH2 mutated (P=0.009) and 10q non-deleted glioma (P=0.003).	('rs1801591', 'Mutation', 'rs1801591', (242, 251))	('IDH1', 'Gene', '3417', (385, 389))	('rs1801591', 'Var', (242, 251))	('II oligodendroglioma', 'Disease', (173, 193))	('glioma', 'Disease', 'MESH:D005910', (433, 439))	('glioma', 'Disease', (187, 193))	('rs11196067', 'Mutation', 'rs11196067', (28, 38))	('II oligodendroglioma', 'Disease', 'MESH:D009837', (353, 373))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('TP53', 'Gene', '7157', (112, 116))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('rs12230172', 'Var', (331, 341))	('rs12230172', 'Mutation', 'rs12230172', (331, 341))	('II astrocytoma', 'Disease', (263, 277))	('II glioma', 'Disease', 'MESH:D005910', (83, 92))	('II glioma', 'Disease', (83, 92))	('II oligodendroglioma', 'Disease', (353, 373))	('glioma', 'Disease', (367, 373))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('glioma', 'Disease', (129, 135))	('IDH1', 'Gene', (292, 296))	('glioma', 'Disease', (224, 230))	('rs11196067', 'Var', (28, 38))	('II astrocytoma', 'Disease', 'MESH:D001254', (263, 277))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (367, 373))	('IDH2', 'Gene', (297, 301))	('glioma', 'Disease', (310, 316))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('IDH2', 'Gene', '3418', (297, 301))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (310, 316))	('IDH1', 'Gene', (385, 389))	('II oligodendroglioma', 'Disease', 'MESH:D009837', (173, 193))	('TP53', 'Gene', (112, 116))	('glioma', 'Disease', (86, 92))	('IDH2', 'Gene', (390, 394))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('IDH1', 'Gene', '3417', (292, 296))	('IDH2', 'Gene', '3418', (390, 394))	('rs648044', 'Mutation', 'rs648044', (153, 161))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('10q', 'Disease', (417, 420))	('glioma', 'Phenotype', 'HP:0009733', (310, 316))	('glioma', 'Disease', (433, 439))	('rs648044', 'Var', (153, 161))	('astrocytoma', 'Phenotype', 'HP:0009592', (266, 277))
88358	26424050	rs1801591, which is responsible for the ETFA p.Thr171Ile substitution, resides within a highly conserved region of the genome (genomic evolutionary rate profiling (GERP)=5.65) and the amino-acid change is predicted to be damaging (PolyPhen=1).	('ETFA', 'Gene', (40, 44))	('ETFA', 'Gene', '2108', (40, 44))	('rs1801591', 'Mutation', 'rs1801591', (0, 9))	('rs1801591', 'Var', (0, 9))	('p.Thr171Ile', 'Mutation', 'rs1801591', (45, 56))	('p.Thr171Ile', 'Var', (45, 56))
88359	26424050	Although rs648044 exhibits low evolutionary conservation (GERP=-9.32) it maps within a strong DNase hypersensitivity site and predicted enhancer/super-enhancer element for multiple tissues including the brain.	('hypersensitivity', 'Disease', 'MESH:D004342', (100, 116))	('hypersensitivity', 'Disease', (100, 116))	('enhancer/super-enhancer', 'PosReg', (136, 159))	('men', 'Species', '9606', (163, 166))	('rs648044', 'Mutation', 'rs648044', (9, 17))	('rs648044', 'Var', (9, 17))
88360	26424050	The region surrounding rs648044 is also predicted to interact with the ZBTB16 promoter, which combined with alteration of a Pax-5 motif is suggestive of direct functional impact.	('Pax-5', 'Gene', '5079', (124, 129))	('ZBTB16', 'Gene', '7704', (71, 77))	('interact', 'Interaction', (53, 61))	('Pax-5', 'Gene', (124, 129))	('rs648044', 'Mutation', 'rs648044', (23, 31))	('ZBTB16', 'Gene', (71, 77))	('rs648044', 'Var', (23, 31))
88361	26424050	rs12230172 localizes within a moderately conserved region (GERP=3.41) and occupies promoter histone marks in the brain as well as enhancers predicted to associate with transcriptional start sites for PHLDA1 and GLIPR1.	('GLIPR1', 'Gene', '11010', (211, 217))	('PHLDA1', 'Gene', (200, 206))	('rs12230172', 'Mutation', 'rs12230172', (0, 10))	('rs12230172', 'Var', (0, 10))	('PHLDA1', 'Gene', '22822', (200, 206))	('GLIPR1', 'Gene', (211, 217))
88362	26424050	rs11196067 in VTI1A, while having a low conservation score (GERP=0.719), occupies enhancer histone marks in embryonic stem cells although not in brain cells.	('rs11196067', 'Var', (0, 10))	('rs11196067', 'Mutation', 'rs11196067', (0, 10))	('enhancer', 'PosReg', (82, 90))	('VTI1A', 'Gene', (14, 19))	('VTI1A', 'Gene', '143187', (14, 19))
88363	26424050	Similarly, rs3851634 maps to a moderately conserved region (GERP=2.37) and occupies enhancer histone marks in 18 organs including the brain.	('rs3851634', 'Var', (11, 20))	('rs3851634', 'Mutation', 'rs3851634', (11, 20))	('enhancer', 'PosReg', (84, 92))
88364	26424050	To gain further insight into the functional basis of rs11196067, rs648044, rs12230172, rs1801591 and rs3851634 associations we performed an expression quantitative trait loci (eQTL) analysis using RNA-Seq expression data on 389 low-grade gliomas (LGGs) and 138 GBMs from The Cancer Genome Atlas (TCGA), together with lymphoblastoid cell line RNA-Seq data on 363 samples from GEUVADIS.	('rs12230172', 'Var', (75, 85))	('rs648044', 'Mutation', 'rs648044', (65, 73))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('gliomas', 'Disease', (238, 245))	('rs648044', 'Var', (65, 73))	('rs3851634', 'Mutation', 'rs3851634', (101, 110))	('GBM', 'Phenotype', 'HP:0012174', (261, 264))	('rs11196067', 'Var', (53, 63))	('Cancer Genome Atlas', 'Disease', (275, 294))	('rs3851634', 'Var', (101, 110))	('Cancer', 'Phenotype', 'HP:0002664', (275, 281))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (275, 294))	('rs1801591', 'Mutation', 'rs1801591', (87, 96))	('rs12230172', 'Mutation', 'rs12230172', (75, 85))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('rs11196067', 'Mutation', 'rs11196067', (53, 63))	('rs1801591', 'Var', (87, 96))
88366	26424050	After adjusting for multiple testing within each region no statistically significant eQTL was seen for rs11196067, rs12230172, rs1801591 or rs3851634.	('rs11196067', 'Var', (103, 113))	('rs3851634', 'Var', (140, 149))	('rs11196067', 'Mutation', 'rs11196067', (103, 113))	('rs12230172', 'Mutation', 'rs12230172', (115, 125))	('rs12230172', 'Var', (115, 125))	('rs1801591', 'Mutation', 'rs1801591', (127, 136))	('rs3851634', 'Mutation', 'rs3851634', (140, 149))	('rs1801591', 'Var', (127, 136))
88367	26424050	The strongest association between rs648044 genotype and gene expression was with ZW10 in LGG (P=5.7 x 10-5), with the risk allele (T) associated with lower expression, remaining significant after adjustment for multiple testing.	('lower', 'NegReg', (150, 155))	('men', 'Species', '9606', (202, 205))	('rs648044', 'Var', (34, 42))	('ZW10', 'Gene', '9183', (81, 85))	('LGG', 'Gene', (89, 92))	('gene expression', 'MPA', (56, 71))	('expression', 'MPA', (156, 166))	('rs648044', 'Mutation', 'rs648044', (34, 42))	('ZW10', 'Gene', (81, 85))
88368	26424050	To explore the possibility that rs648044 is correlated with a SNP exhibiting a stronger association with ZW10, we examined associations with ZW10 expression in LGG tumours in all SNPs in LD (r2>0.4) with rs648044.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('ZW10', 'Gene', '9183', (105, 109))	('ZW10', 'Gene', (141, 145))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('rs648044', 'Mutation', 'rs648044', (32, 40))	('ZW10', 'Gene', (105, 109))	('LGG tumours', 'Disease', 'MESH:D009369', (160, 171))	('rs648044', 'Mutation', 'rs648044', (204, 212))	('LGG tumours', 'Disease', (160, 171))	('rs648044', 'Var', (204, 212))	('rs648044', 'Var', (32, 40))	('associations', 'Interaction', (123, 135))	('ZW10', 'Gene', '9183', (141, 145))
88369	26424050	All of the proxy SNPs examined were more weakly associated with ZW10 than rs648044 (Supplementary Table 6).	('rs648044', 'Var', (74, 82))	('men', 'Species', '9606', (90, 93))	('ZW10', 'Gene', '9183', (64, 68))	('ZW10', 'Gene', (64, 68))	('rs648044', 'Mutation', 'rs648044', (74, 82))	('associated', 'Interaction', (48, 58))
88370	26424050	The risk allele (C) of rs3851634 was associated with significantly lower levels of POLR3B (P=7.49 x 10-6) in peripheral blood analysis with a nominally significant association in skin (P=0.0052).	('rs3851634', 'Var', (23, 32))	('POLR3B', 'Gene', (83, 89))	('POLR3B', 'Gene', '55703', (83, 89))	('levels', 'MPA', (73, 79))	('rs3851634', 'Mutation', 'rs3851634', (23, 32))	('lower', 'NegReg', (67, 72))
88371	26424050	The risk allele (T) of rs1801591, was associated with significantly lower ETFA levels in peripheral blood (P=7.90 x 10-12); there was a nominally significant association in MuTHER lymphoblastoid cell lines (P=0.037).	('rs1801591', 'Mutation', 'rs1801591', (23, 32))	('lower', 'NegReg', (68, 73))	('ETFA', 'Gene', (74, 78))	('ETFA', 'Gene', '2108', (74, 78))	('rs1801591', 'Var', (23, 32))
88383	26424050	Intriguingly recent GWAS have identified associations between the VTI1A SNPs rs7086803 and lung cancer and between rs12241008 and colorectal cancer; rs7086803 and rs12241008 are not correlated with each other (r2=0.22, D'=0.72) and are also not correlated with rs11196067 (r2=0.03/0.00 D' =1.00/0.22, respectively), suggesting the existence of multiple risk loci within the region with different tumour specificities.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('tumour', 'Disease', (396, 402))	('colorectal cancer', 'Disease', (130, 147))	('rs7086803', 'Mutation', 'rs7086803', (149, 158))	('rs7086803', 'Var', (149, 158))	('rs7086803', 'Mutation', 'rs7086803', (77, 86))	('rs7086803', 'Var', (77, 86))	('associations', 'Interaction', (41, 53))	('VTI1A', 'Gene', '143187', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs12241008', 'Mutation', 'rs12241008', (115, 125))	('rs12241008', 'Mutation', 'rs12241008', (163, 173))	('rs12241008', 'Var', (115, 125))	('lung cancer', 'Disease', (91, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('rs12241008', 'Var', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('VTI1A', 'Gene', (66, 71))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('rs11196067', 'Mutation', 'rs11196067', (261, 271))	('tumour', 'Phenotype', 'HP:0002664', (396, 402))	('tumour', 'Disease', 'MESH:D009369', (396, 402))
88384	26424050	ZBTB16 is highly expressed in undifferentiated, multipotential progenitor cells and its expression has been shown to influence resistance to retinoid-mediated re-differentiation in t(11;17)(q23;21) acute promyelocytic leukaemia.	('promyelocytic leukaemia', 'Disease', 'MESH:D015473', (204, 227))	('t(11;17)(q23;21', 'Var', (181, 196))	('retinoid', 'Chemical', 'MESH:D012176', (141, 149))	('resistance to retinoid-mediated re-differentiation', 'MPA', (127, 177))	('ZBTB16', 'Gene', (0, 6))	('influence', 'Reg', (117, 126))	('acute promyelocytic leukaemia', 'Phenotype', 'HP:0004836', (198, 227))	('ZBTB16', 'Gene', '7704', (0, 6))	('promyelocytic leukaemia', 'Disease', (204, 227))
88386	26424050	Although rs648044 lies within an enhancer active in brain and is predicted to interact with the ZBTB16 promoter, providing an attractive functional basis for the 11q23.2 association through differential ZBTB16 expression, we found a strong association between rs648044 and ZW10 expression in LGG (P=5.7 x 10-5).	('ZBTB16', 'Gene', '7704', (96, 102))	('rs648044', 'Var', (9, 17))	('ZBTB16', 'Gene', (203, 209))	('rs648044', 'Var', (260, 268))	('ZW10', 'Gene', '9183', (273, 277))	('expression', 'MPA', (278, 288))	('rs648044', 'Mutation', 'rs648044', (260, 268))	('ZBTB16', 'Gene', (96, 102))	('rs648044', 'Mutation', 'rs648044', (9, 17))	('ZW10', 'Gene', (273, 277))	('ZBTB16', 'Gene', '7704', (203, 209))
88388	26424050	We also observed a strong association between ETFA expression and rs1801591 in peripheral blood (P=7.90 x 10-12).	('ETFA', 'Gene', '2108', (46, 50))	('rs1801591', 'Mutation', 'rs1801591', (66, 75))	('ETFA', 'Gene', (46, 50))	('rs1801591', 'Var', (66, 75))
88390	26424050	Mutations of ETFA have been reported to be a cause of recessive glutaric acidaemia IIA (refs), which features gliosis.	('recessive glutaric acidaemia IIA', 'Disease', (54, 86))	('recessive glutaric acidaemia IIA', 'Disease', 'MESH:D054069', (54, 86))	('gliosis', 'Phenotype', 'HP:0002171', (110, 117))	('gliosis', 'Disease', 'MESH:D005911', (110, 117))	('ETFA', 'Gene', (13, 17))	('glutaric acidaemia', 'Phenotype', 'HP:0003530', (64, 82))	('ETFA', 'Gene', '2108', (13, 17))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (45, 50))	('gliosis', 'Disease', (110, 117))
88391	26424050	While the p.Thr171Ile change is reported to decrease thermal stability of ETFA thereby providing evidence for a direct functional effect the strong eQTL data is consistent with the functional basis for the 15q24.2 association being mediated through differential expression.	('decrease', 'NegReg', (44, 52))	('ETFA', 'Gene', (74, 78))	('ETFA', 'Gene', '2108', (74, 78))	('thermal stability', 'MPA', (53, 70))	('p.Thr171Ile', 'Mutation', 'rs1801591', (10, 21))	('p.Thr171Ile', 'Var', (10, 21))
88393	26424050	Although mutations in POLR3B have been shown to cause recessive hypomyelinating leukoencephalopathy thus far there is no evidence implicating the gene in the development of glioma.	('men', 'Species', '9606', (165, 168))	('glioma', 'Disease', (173, 179))	('mutations', 'Var', (9, 18))	('POLR3B', 'Gene', '55703', (22, 28))	('recessive hypomyelinating leukoencephalopathy', 'Disease', 'MESH:D056784', (54, 99))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (80, 99))	('POLR3B', 'Gene', (22, 28))	('cause', 'Reg', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('recessive hypomyelinating leukoencephalopathy', 'Disease', (54, 99))	('glioma', 'Disease', 'MESH:D005910', (173, 179))
88394	26424050	Albeit in peripheral blood there was a strong association between POLR3B expression and rs3851634 (P=7.49 x 10-6), providing a possible functional basis of the 12q23.2 association.	('POLR3B', 'Gene', (66, 72))	('rs3851634', 'Mutation', 'rs3851634', (88, 97))	('rs3851634', 'Var', (88, 97))	('POLR3B', 'Gene', '55703', (66, 72))
88395	26424050	At 12q21.2 rs12230172 maps within RP11-114H23.1, a lincRNA of currently unknown function.	('RP11', 'Gene', '26121', (34, 38))	('H23.1', 'CellLine', 'CVCL:1547', (42, 47))	('rs12230172', 'Mutation', 'rs12230172', (11, 21))	('rs12230172', 'Var', (11, 21))	('RP11', 'Gene', (34, 38))
88398	26424050	Intriguingly across all of the four GWAS data sets we analysed we did not replicate the association between rs1920116 (near TERC) at 3q26.2 and risk of high-grade glioma recently reported by Walsh et al.	('glioma', 'Disease', (163, 169))	('TERC', 'Gene', '7012', (124, 128))	('rs1920116', 'Mutation', 'rs1920116', (108, 117))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('TERC', 'Gene', (124, 128))	('rs1920116', 'Var', (108, 117))
88400	26424050	While we could not demonstrate a significant association with either subtype we did see an association between rs1920116 and TP53-mutated glioma (P=0.016, Supplementary Data 1) suggesting that the association might be restricted to a specific molecularly defined subtype of glioma.	('glioma', 'Disease', 'MESH:D005910', (274, 280))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('glioma', 'Disease', (138, 144))	('TP53', 'Gene', '7157', (125, 129))	('rs1920116', 'Mutation', 'rs1920116', (111, 120))	('TP53', 'Gene', (125, 129))	('glioma', 'Disease', (274, 280))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('men', 'Species', '9606', (161, 164))	('rs1920116', 'Var', (111, 120))
88404	26424050	By implication, variants with such profiles probably represent a much larger class of susceptibility loci for glioma because of the truly small effect sizes or submaximal LD with tagging SNPs.	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('variants', 'Var', (16, 24))	('glioma', 'Disease', (110, 116))
88406	26424050	For example, if applying an additional Bonferroni correction for GBM and non-GBM subtypes, the rs11196067 (VTI1A) association at P=8.64 x 10-8 would not be declared genome-wide significant.	('VTI1A', 'Gene', '143187', (107, 112))	('rs11196067', 'Mutation', 'rs11196067', (95, 105))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('rs11196067', 'Var', (95, 105))	('VTI1A', 'Gene', (107, 112))
88418	26424050	Genotyping of rs76178334, rs4432939, rs182521816, rs12780046, rs11196067, rs648044, rs12230172, rs3851634, rs1801591 and rs78543262 was performed using competitive allele-specific PCR KASPar chemistry (LGC, Hertfordshire, UK, primer sequences detailed in Supplementary Table 10).	('rs4432939', 'Var', (26, 35))	('rs12780046', 'Mutation', 'rs12780046', (50, 60))	('rs3851634', 'Mutation', 'rs3851634', (96, 105))	('rs76178334', 'Var', (14, 24))	('rs11196067', 'Var', (62, 72))	('rs3851634', 'Var', (96, 105))	('rs78543262', 'Mutation', 'rs78543262', (121, 131))	('rs182521816', 'Var', (37, 48))	('men', 'Species', '9606', (261, 264))	('rs12780046', 'Var', (50, 60))	('rs648044', 'Mutation', 'rs648044', (74, 82))	('rs12230172', 'Mutation', 'rs12230172', (84, 94))	('rs182521816', 'Mutation', 'rs182521816', (37, 48))	('rs4432939', 'Mutation', 'rs4432939', (26, 35))	('rs648044', 'Var', (74, 82))	('rs76178334', 'Mutation', 'rs76178334', (14, 24))	('rs11196067', 'Mutation', 'rs11196067', (62, 72))	('rs12230172', 'Var', (84, 94))	('rs1801591', 'Mutation', 'rs1801591', (107, 116))
88430	26424050	Targeted sequencing for the SNPs rs141035288, rs117527984, rs76178334, rs4432939, rs182521816, rs138170678, rs145034266, rs12780046, rs11196067, rs648044, rs12230172 and rs78543262 was performed by Sanger on an ABI3700 analyser (Applied Biosystems; Supplementary Table 10, conditions are available on request).	('rs76178334', 'Mutation', 'rs76178334', (59, 69))	('rs11196067', 'Mutation', 'rs11196067', (133, 143))	('rs12230172', 'Var', (155, 165))	('rs117527984', 'Mutation', 'rs117527984', (46, 57))	('men', 'Species', '9606', (255, 258))	('rs4432939', 'Var', (71, 80))	('rs138170678', 'Var', (95, 106))	('rs11196067', 'Var', (133, 143))	('rs12780046', 'Var', (121, 131))	('rs76178334', 'Var', (59, 69))	('rs145034266', 'Mutation', 'rs145034266', (108, 119))	('rs141035288', 'Mutation', 'rs141035288', (33, 44))	('rs78543262', 'Mutation', 'rs78543262', (170, 180))	('rs78543262', 'Var', (170, 180))	('rs138170678', 'Mutation', 'rs138170678', (95, 106))	('rs145034266', 'Var', (108, 119))	('rs141035288', 'Var', (33, 44))	('rs182521816', 'Var', (82, 93))	('rs117527984', 'Var', (46, 57))	('rs648044', 'Mutation', 'rs648044', (145, 153))	('rs12230172', 'Mutation', 'rs12230172', (155, 165))	('rs648044', 'Var', (145, 153))	('rs12780046', 'Mutation', 'rs12780046', (121, 131))	('rs4432939', 'Mutation', 'rs4432939', (71, 80))	('rs182521816', 'Mutation', 'rs182521816', (82, 93))
88438	26424050	rs500629 was used as a proxy for rs648044 (r2=0.52, D'=0.85).	('rs648044', 'Mutation', 'rs648044', (33, 41))	('rs648044', 'Var', (33, 41))	('rs500629', 'Var', (0, 8))	('rs500629', 'Mutation', 'rs500629', (0, 8))
88443	30872592	The mRNA expression levels of KIF4A, 9, 18A, and 23 in LGG were significantly increased in the high-histologic-grade group compared with those with a low histologic grade.	('KIF4A', 'Gene', '24137', (30, 35))	('18A', 'Protein', (40, 43))	('high-histologic-grade', 'Var', (95, 116))	('mRNA expression levels', 'MPA', (4, 26))	('increased', 'PosReg', (78, 87))	('KIF4A', 'Gene', (30, 35))
88444	30872592	Genomic analysis showed that the percent of mRNA upregulation of KIF4A, 9, 18A, and 23 was higher than that of other gene alterations, including gene amplification, deep deletion, and missense mutation.	('KIF4A', 'Gene', '24137', (65, 70))	('higher', 'PosReg', (91, 97))	('mRNA', 'MPA', (44, 48))	('gene amplification', 'Var', (145, 163))	('missense mutation', 'Var', (184, 201))	('deep deletion', 'Var', (165, 178))	('upregulation', 'PosReg', (49, 61))	('KIF4A', 'Gene', (65, 70))
88455	30872592	Because the cell cycle is a conserved process necessary for cell growth and development, cell cycle aberrations are a hallmark of cancer.	('aberrations', 'Var', (100, 111))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cell cycle aberrations', 'Phenotype', 'HP:0011018', (89, 111))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cell cycle', 'CPA', (89, 99))
88481	30872592	Specifically, genetic alteration of KIF4A, 9, 18A, and 23 was analyzed and depicted as oncoprints representing amplification, deep deletion, mRNA upregulation, and missense mutation (Fig.	('mRNA', 'MPA', (141, 145))	('missense mutation', 'Var', (164, 181))	('upregulation', 'PosReg', (146, 158))	('KIF4A', 'Gene', (36, 41))	('deep deletion', 'Var', (126, 139))	('KIF4A', 'Gene', '24137', (36, 41))
88483	30872592	The crystal 3D structure of kinesin motor domain in KIF4A, 9, 18A, and 23 was monomeric, homo trimer, hetero trimer and monomeric respectively.	('monomeric', 'MPA', (78, 87))	('KIF4A', 'Gene', (52, 57))	('homo', 'Var', (89, 93))	('KIF4A', 'Gene', '24137', (52, 57))	('hetero', 'MPA', (102, 108))	('kinesin motor domain', 'Protein', (28, 48))
88485	30872592	In particular, missense mutation was identified in KIF4A and 23, but the mutation in kinesin motor domain was only verified in KIF23 (Fig.	('KIF23', 'Gene', '9493', (127, 132))	('KIF4A', 'Gene', (51, 56))	('missense mutation', 'Var', (15, 32))	('KIF23', 'Gene', (127, 132))	('KIF4A', 'Gene', '24137', (51, 56))
88491	30872592	KIF4A, 9, 18A, and 23 in GBM were analyzed and depicted as oncoprints representing amplification, deep deletion, mRNA upregulation, and missense mutation (Fig.	('KIF4A', 'Gene', '24137', (0, 5))	('upregulation', 'PosReg', (118, 130))	('mRNA', 'MPA', (113, 117))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('deep deletion', 'Var', (98, 111))	('KIF4A', 'Gene', (0, 5))	('missense mutation', 'Var', (136, 153))
88505	30872592	In LGG patients, pathways of the G2M checkpoint, E2F targets, mitotic spindle, and Myc target v1 were increased in the high-expression KIF4A, 18A, and 23 groups and had a negative effect on prognosis (Fig.	('LGG', 'Disease', (3, 6))	('G2M checkpoint', 'Gene', (33, 47))	('KIF4A', 'Gene', (135, 140))	('pathways', 'Pathway', (17, 25))	('Myc', 'Gene', '4609', (83, 86))	('high-expression', 'Var', (119, 134))	('mitotic', 'CPA', (62, 69))	('Myc', 'Gene', (83, 86))	('E2F targets', 'Gene', (49, 60))	('increased', 'PosReg', (102, 111))	('KIF4A', 'Gene', '24137', (135, 140))	('patients', 'Species', '9606', (7, 15))
88506	30872592	The pathways of EMT and angiogenesis were increased in the high-expression KIF9 group, with detrimental effects on prognosis.	('increased', 'PosReg', (42, 51))	('KIF9', 'Gene', '64147', (75, 79))	('effects', 'Reg', (104, 111))	('EMT', 'Gene', (16, 19))	('EMT', 'Gene', '3702', (16, 19))	('KIF9', 'Gene', (75, 79))	('high-expression', 'Var', (59, 74))	('angiogenesis', 'CPA', (24, 36))
88508	30872592	However, increased pathway of EMT and decreased pathways of the G2M checkpoint, mitotic spindle, and E2F target were found in the high-expression KIF9 groups (Fig.	('decreased', 'NegReg', (38, 47))	('KIF9', 'Gene', '64147', (146, 150))	('pathways', 'CPA', (48, 56))	('mitotic spindle', 'CPA', (80, 95))	('high-expression', 'Var', (130, 145))	('increased', 'PosReg', (9, 18))	('EMT', 'Gene', (30, 33))	('EMT', 'Gene', '3702', (30, 33))	('KIF9', 'Gene', (146, 150))
88521	30872592	KIFs overexpression disrupts the unique balance of forces associated with normal spindle assembly and function, and thereby leads to the development of spindle defects, genetic instability and tumors.	('disrupts', 'NegReg', (20, 28))	('genetic instability', 'Disease', 'MESH:D030342', (169, 188))	('leads to', 'Reg', (124, 132))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('balance of forces', 'MPA', (40, 57))	('tumors', 'Disease', (193, 199))	('genetic instability', 'Disease', (169, 188))	('overexpression', 'Var', (5, 19))	('spindle defects', 'CPA', (152, 167))
88523	30872592	Genomic analyses revealed that mutations in the kinesin motor domain of KIF4A and KIF23 resulted in abnormalities of KIFs function, but the percent of upregulated mRNA expression was more prominent than the presence of other specific gene alterations, including amplification, deletions, and missense or truncating mutations.	('KIF23', 'Gene', (82, 87))	('deletions', 'Var', (277, 286))	('mutations', 'Var', (31, 40))	('KIF4A', 'Gene', (72, 77))	('missense', 'Var', (292, 300))	('resulted', 'Reg', (88, 96))	('KIFs function', 'MPA', (117, 130))	('upregulated', 'PosReg', (151, 162))	('KIF4A', 'Gene', '24137', (72, 77))	('KIF23', 'Gene', '9493', (82, 87))	('mRNA expression', 'MPA', (163, 178))	('amplification', 'Var', (262, 275))
88524	30872592	We also examined the correlations between gene alterations and overall survival in LGG and GBM patients, finding that those harboring KIF4A, KIF18A, and KIF23 alterations showed a poorer prognosis than those lacking these alterations in LGG.	('KIF18A', 'Gene', (141, 147))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('alterations', 'Var', (159, 170))	('patients', 'Species', '9606', (95, 103))	('KIF18A', 'Gene', '81930', (141, 147))	('KIF4A', 'Gene', (134, 139))	('KIF23', 'Gene', '9493', (153, 158))	('KIF23', 'Gene', (153, 158))	('KIF4A', 'Gene', '24137', (134, 139))
88526	30872592	In survival analysis using Cutoff Finder, the group with high mRNA expression of KIF4A, 9, 18A, and 23 was significantly associated with a poor prognosis in both LGG and GBM patients.	('GBM', 'Phenotype', 'HP:0012174', (170, 173))	('high', 'Var', (57, 61))	('associated', 'Reg', (121, 131))	('patients', 'Species', '9606', (174, 182))	('LGG', 'Disease', (162, 165))	('mRNA expression', 'MPA', (62, 77))	('GBM', 'Disease', (170, 173))	('KIF4A', 'Gene', (81, 86))	('KIF4A', 'Gene', '24137', (81, 86))
88528	30872592	The loss of KIF4A leads to tumor formation, and aneuploidy can act as a primary trigger of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('leads to', 'Reg', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('KIF4A', 'Gene', (12, 17))	('KIF4A', 'Gene', '24137', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aneuploidy', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (91, 96))	('loss', 'Var', (4, 8))
88530	30872592	In this context, high mRNA expression of KIF4A in our study is also associated with poor prognosis in both LGG and GBM.	('mRNA expression', 'MPA', (22, 37))	('KIF4A', 'Gene', (41, 46))	('high', 'Var', (17, 21))	('LGG', 'Disease', (107, 110))	('GBM', 'Disease', (115, 118))	('KIF4A', 'Gene', '24137', (41, 46))	('GBM', 'Phenotype', 'HP:0012174', (115, 118))
88535	30872592	In the present investigation, high KIF18A expression was also significantly associated with poor prognosis and the progression of LGG and GBM.	('KIF18A', 'Gene', (35, 41))	('LGG', 'Disease', (130, 133))	('GBM', 'Disease', (138, 141))	('expression', 'MPA', (42, 52))	('associated', 'Reg', (76, 86))	('high', 'Var', (30, 34))	('GBM', 'Phenotype', 'HP:0012174', (138, 141))	('KIF18A', 'Gene', '81930', (35, 41))
88537	30872592	It was reported that high KIF18A expression is correlated with an unfavorable prognosis and promotes proliferation, invasion, and metastasis by promoting the cell cycle signaling pathway in hepatocellular carcinoma.	('KIF18A', 'Gene', '81930', (26, 32))	('promotes', 'PosReg', (92, 100))	('cell cycle signaling pathway', 'Pathway', (158, 186))	('KIF18A', 'Gene', (26, 32))	('invasion', 'CPA', (116, 124))	('high', 'Var', (21, 25))	('proliferation', 'CPA', (101, 114))	('metastasis', 'CPA', (130, 140))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (190, 214))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (190, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('hepatocellular carcinoma', 'Disease', (190, 214))	('expression', 'MPA', (33, 43))	('promoting', 'PosReg', (144, 153))
88538	30872592	It was also reported that high KIF18A expression is significantly associated with the progression of breast cancer, renal cell carcinoma, and colon cancer.	('colon cancer', 'Disease', (142, 154))	('high', 'Var', (26, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('expression', 'MPA', (38, 48))	('associated with', 'Reg', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('renal cell carcinoma', 'Disease', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('KIF18A', 'Gene', '81930', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('breast cancer', 'Disease', (101, 114))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('KIF18A', 'Gene', (31, 37))
88542	30872592	High expression of KIF23 was also shown to be closely associated with poor survival in lung adenocarcinoma.	('poor', 'NegReg', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('High', 'Var', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('KIF23', 'Gene', '9493', (19, 24))	('KIF23', 'Gene', (19, 24))	('associated', 'Reg', (54, 64))
88543	30872592	However, conflicting results have also been reported, in that hepatocellular carcinoma patients with aberrant expression of KIF23 had longer survival.	('hepatocellular carcinoma', 'Disease', (62, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('longer', 'PosReg', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('KIF23', 'Gene', '9493', (124, 129))	('KIF23', 'Gene', (124, 129))	('patients', 'Species', '9606', (87, 95))	('aberrant expression', 'Var', (101, 120))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))
88549	30872592	In this study, high KIF9 expression was associated with cancer progression and showed significantly poor survival, especially in GBM patients.	('high', 'Var', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('expression', 'MPA', (25, 35))	('survival', 'MPA', (105, 113))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('GBM', 'Disease', (129, 132))	('KIF9', 'Gene', (20, 24))	('poor', 'NegReg', (100, 104))	('cancer', 'Disease', (56, 62))	('KIF9', 'Gene', '64147', (20, 24))	('associated', 'Reg', (40, 50))
88575	30367574	The GDC portal publicly provides dataset of the following genomic experiments of more than 40 tumor types: DNA sequencing, Copy Number Variation, Somatic Mutations, DNA Methylation Gene Expression Quantification, and miRNA Expression Quantification.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Copy Number Variation', 'Var', (123, 144))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('Mutations', 'Var', (154, 163))	('GDC', 'Chemical', '-', (4, 7))
88579	30367574	Example of a logic formula or ("if then" rule) on gene expression data is the following "if ENSG00000167676.3 < 16.15 OR ENSG00000166819.10 < 15.28 then the sample can be classified as tumoral".	('ENSG00000167676.3', 'Var', (92, 109))	('tumoral', 'Disease', (185, 192))	('tumoral', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ENSG00000166819.10 < 15.28', 'Var', (121, 147))
88612	30367574	Previous studies have already shown that mutations within this gene are possible causes of lung cancer (LUSC).	('mutations', 'Var', (41, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('causes', 'Reg', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('lung cancer', 'Disease', (91, 102))
88621	30367574	As the reader can see, the genes COLGALT1 (ENSG00000130309.9) and AC012531.25 (ENSG00000260597.1) is the most frequent couple that appears in the rules occurring 250 times.	('COLGALT1', 'Gene', '79709', (33, 41))	('ENSG00000260597.1', 'Var', (79, 96))	('COLGALT1', 'Gene', (33, 41))	('ENSG00000130309.9', 'Var', (43, 60))
88622	30367574	In particular, AC012531.25 is always extracted together with COLGALT1, because its number of occurrences as single gene is exactly 250.	('AC012531.25', 'Var', (15, 26))	('COLGALT1', 'Gene', '79709', (61, 69))	('COLGALT1', 'Gene', (61, 69))
88627	30367574	Existing studies on the GABRD gene confirm that alterations in its expression can play a key role in differentiating tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('alterations', 'Var', (48, 59))	('tumor', 'Disease', (117, 122))	('play', 'Reg', (82, 86))	('GABRD', 'Gene', '2563', (24, 29))	('GABRD', 'Gene', (24, 29))	('expression', 'MPA', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
88635	30367574	We highlight that previous research confirms the relationship between the alteration of the expression of the first three most occurring genes - SPRY2 (ENSG00000136158.9), VEGFD (ENSG00000165197.4), and MMP11 (ENSG00000099953.8) - and the predisposition to Breast Cancer.	('ENSG00000136158.9', 'Var', (152, 169))	('alteration', 'Var', (74, 84))	('SPRY2', 'Gene', (145, 150))	('MMP11', 'Gene', '4320', (203, 208))	('Breast Cancer', 'Phenotype', 'HP:0003002', (257, 270))	('SPRY2', 'Gene', '10253', (145, 150))	('VEGFD', 'Gene', (172, 177))	('ENSG00000165197.4', 'Var', (179, 196))	('Breast Cancer', 'Disease', (257, 270))	('Breast Cancer', 'Disease', 'MESH:D001943', (257, 270))	('Cancer', 'Phenotype', 'HP:0002664', (264, 270))	('ENSG00000099953.8', 'Var', (210, 227))	('MMP11', 'Gene', (203, 208))	('VEGFD', 'Gene', '2277', (172, 177))
88698	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
88699	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
88737	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))	('cancer', 'Disease', (69, 75))
88776	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
88790	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
88798	29956810	In the present study, we found that high BMI (<=25) is potentially a risk factor for many types of cancer.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('types', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('high', 'Var', (36, 40))	('risk', 'Reg', (69, 73))
88800	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
88861	27923049	Similar to GBMs, LGGs can be categorized into distinct subtypes, IDH1/2 mut, IDH1/2 mut 1p19q codeletion, and IDH1/2 wt, based on IDH1/2 mutational status and the presence of a codeletion of 1p19q.	('IDH1/2 mut', 'Gene', '3417', (65, 75))	('IDH1/2 mut', 'Gene', (130, 140))	('IDH1/2 mut', 'Gene', (77, 87))	('1p19q codeletion', 'Var', (88, 104))	('IDH1/2 mut', 'Gene', '3417', (77, 87))	('IDH1/2 mut', 'Gene', '3417', (130, 140))	('GBMs', 'Phenotype', 'HP:0012174', (11, 15))	('IDH1/2 mut', 'Gene', (65, 75))
88863	27923049	Although knowledge of tumor subtype has clinical utility, the best prognostic indicator for patients with glial tumors is the mutational status of IDH1 and IDH2.	('IDH2', 'Gene', (156, 160))	('glial tumors', 'Disease', 'MESH:D005910', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('glial tumors', 'Disease', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('IDH2', 'Gene', '3418', (156, 160))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('clinical', 'Species', '191496', (40, 48))	('tumor', 'Disease', (22, 27))	('IDH1', 'Gene', (147, 151))	('tumor', 'Disease', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('IDH1', 'Gene', '3417', (147, 151))	('mutational status', 'Var', (126, 143))
88864	27923049	In LGGs, patients with wild-type IDH1/2 have a median survival of 1.7 y, while those with mutant IDH1/2 have a median survival between 6.3 and 8.0 y.	('patients', 'Species', '9606', (9, 17))	('mutant', 'Var', (90, 96))	('IDH1/2', 'Gene', (97, 103))
88877	27923049	The overlap between GBM and LGG differentially expressed lncRNAs was measured using the Jaccard index, a statistic that compares the similarity and divergence of two datasets, defined as the intersection of two datasets divided by the union of the datasets:   To identify lncRNAs associated with individual somatic mutations, we separated patients into two groups based on the presence of nonsynonymous mutation or a non-inframe insertion or deletion in commonly mutated protein-coding genes (prevalence of 5% or greater).	('patients', 'Species', '9606', (339, 347))	('deletion', 'Var', (442, 450))	('nonsynonymous mutation', 'Var', (389, 411))	('non-inframe insertion', 'Var', (417, 438))
88880	27923049	LGGs subtypes were determined by identifying the mutational status of IDH1 or IDH2 from TCGA's preprocessed mutation calling data and identifying LGGs with 1p19q deletions from TCGA's preprocessed CNV data.	('IDH2', 'Gene', (78, 82))	('IDH1', 'Gene', '3417', (70, 74))	('IDH2', 'Gene', '3418', (78, 82))	('1p19q deletions', 'Var', (156, 171))	('IDH1', 'Gene', (70, 74))
88911	27923049	In order to determine what effect these mutations might have on the lncRNA transcriptome, for each commonly mutated gene (S7 Table), we separated patients into groups based on their tumor mutational status and then tested whether the expression of any lncRNA is altered in GBMs and LGGs harboring each common somatic mutation.	('tumor', 'Disease', (182, 187))	('altered', 'Reg', (262, 269))	('tested', 'Reg', (215, 221))	('expression', 'MPA', (234, 244))	('GBMs', 'Phenotype', 'HP:0012174', (273, 277))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
88915	27923049	Furthermore, 1,357, 1,216, and 466 lncRNAs were specifically up- or downregulated in IDH1/2 wt, IDH1/2 mut, and IDH1/2 mut 1p19q codeletion LGGs, respectively (Fig 4B; S5 Table).	('IDH1/2 mut', 'Gene', '3417', (96, 106))	('up-', 'PosReg', (61, 64))	('downregulated', 'NegReg', (68, 81))	('IDH1/2 mut', 'Gene', (112, 122))	('IDH1/2 mut', 'Gene', '3417', (112, 122))	('1p19q codeletion', 'Var', (123, 139))	('IDH1/2 mut', 'Gene', (96, 106))
88916	27923049	Traditionally, GBMs and LGGs have been viewed as distinct oncological entities; however, recent work has begun to suggest that IDH1/2 wt LGGs might be more similar to GBMs than to their IDH1/2 mut LGG counterparts.	('IDH1/2 mut', 'Gene', '3417', (186, 196))	('GBMs', 'Phenotype', 'HP:0012174', (15, 19))	('IDH1/2', 'Var', (127, 133))	('GBMs', 'Phenotype', 'HP:0012174', (167, 171))	('IDH1/2 mut', 'Gene', (186, 196))
88918	27923049	The main prognostic variable for patients with glial tumors is the mutational status of IDH1 or IDH2.	('IDH2', 'Gene', '3418', (96, 100))	('glial tumors', 'Disease', 'MESH:D005910', (47, 59))	('patients', 'Species', '9606', (33, 41))	('IDH1', 'Gene', (88, 92))	('glial tumors', 'Disease', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutational status', 'Var', (67, 84))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('IDH1', 'Gene', '3417', (88, 92))	('IDH2', 'Gene', (96, 100))
88919	27923049	In LGGs, recent work has shown that patients whose tumors also harbor 1p19q codeletions have a slightly better overall survival than patients with IDH1/2 mut tumors without 1p19q codeletions.	('1p19q codeletions', 'Var', (70, 87))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (36, 44))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('overall survival', 'MPA', (111, 127))	('patients', 'Species', '9606', (133, 141))	('tumors', 'Disease', (51, 57))	('better', 'PosReg', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('IDH1/2 mut', 'Gene', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('IDH1/2 mut', 'Gene', '3417', (147, 157))
88932	27923049	Patients with high and low expression of BTAT10 had median survival times of 335 and 485 d, respectively (HR = 1.298, 95% CI = 1.0881-1.548, p = 0.00374) (Fig 6B).	('low', 'NegReg', (23, 26))	('BTAT10', 'Gene', (41, 47))	('expression', 'MPA', (27, 37))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
88946	27923049	Many of these novel lncRNAs were differentially expressed in brain tumors and were associated with clinically relevant mutations.	('brain tumors', 'Disease', 'MESH:D001932', (61, 73))	('brain tumors', 'Phenotype', 'HP:0030692', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (61, 72))	('associated', 'Reg', (83, 93))	('brain tumors', 'Disease', (61, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (119, 128))	('clinical', 'Species', '191496', (99, 107))
88969	26918938	The mutations of IDH and ATRX occur in early stage of gliomagenesis and characterize specific subtypes of gliomas in adults.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('gliomas', 'Disease', (106, 113))	('IDH', 'Gene', '3417', (17, 20))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('ATRX', 'Gene', (25, 29))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('glioma', 'Disease', (54, 60))	('ATRX', 'Gene', '546', (25, 29))	('glioma', 'Disease', (106, 112))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('mutations', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH', 'Gene', (17, 20))
88970	26918938	The majority of oncogenic IDH1 mutations are heterozygous missense mutations with a change of guanine to adenine at position 395 (G395A), leading to the replacement of arginine by histidine at codon 132 (IDH1-R132H) at the enzymatic active site.	('mutations', 'Var', (31, 40))	('R132H', 'Mutation', 'rs121913500', (209, 214))	('IDH1', 'Gene', (204, 208))	('G395A', 'Mutation', 'rs121913500', (130, 135))	('guanine', 'Chemical', 'MESH:D006147', (94, 101))	('IDH1', 'Gene', (26, 30))	('IDH1', 'Gene', '3417', (204, 208))	('replacement', 'Var', (153, 164))	('adenine', 'Chemical', 'MESH:D000225', (105, 112))	('oncogenic', 'Disease', (16, 25))	('IDH1', 'Gene', '3417', (26, 30))	('arginine by histidine at codon 132', 'Mutation', 'rs121913500', (168, 202))
88971	26918938	ATRX mutations or loss, companied by an alternative lengthening of telomeres (ALT) phenotype, impacted biological behaviors of astrocytic tumor cells, associated with favorable survival of patients with astrocytic tumors.	('astrocytic tumor', 'Disease', (127, 143))	('loss', 'NegReg', (18, 22))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (203, 219))	('ATRX', 'Gene', (0, 4))	('astrocytic tumor', 'Disease', 'MESH:D001254', (127, 143))	('astrocytic tumors', 'Disease', 'MESH:D001254', (203, 220))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('astrocytic tumor', 'Disease', 'MESH:D001254', (203, 219))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('biological behaviors', 'CPA', (103, 123))	('ATRX', 'Gene', '546', (0, 4))	('impacted', 'Reg', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (189, 197))	('astrocytic tumors', 'Disease', (203, 220))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (127, 143))
88989	26918938	The AUC of using ATRX loss as a diagnostic biomarker for discriminating between pGBM, oligodendroglioma (WHO grade II/III) and sGBM, astrocytoma (WHO grade II/III) was 0.8241 (sensitivity 76.67%, specificity 88.15%, Figure 3B).	('ATRX', 'Gene', (17, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('oligodendroglioma', 'Disease', (86, 103))	('ATRX', 'Gene', '546', (17, 21))	('oligodendroglioma', 'Disease', 'MESH:D009837', (86, 103))	('loss', 'NegReg', (22, 26))	('pGBM', 'Gene', (80, 84))	('0.8241', 'Var', (168, 174))	('pGBM', 'Chemical', '-', (80, 84))	('astrocytoma', 'Disease', 'MESH:D001254', (133, 144))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('astrocytoma', 'Disease', (133, 144))
89025	26918938	IDH mutation is thought to be an early if not the initial event in the development of low-grade astrocytomas and oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('IDH', 'Gene', (0, 3))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (113, 131))	('IDH', 'Gene', '3417', (0, 3))	('astrocytomas', 'Disease', 'MESH:D001254', (96, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('mutation', 'Var', (4, 12))	('oligodendrogliomas', 'Disease', (113, 131))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('astrocytomas', 'Disease', (96, 108))
89026	26918938	In support of this hypothesis, IDH mutation is found in secondary glioblastomas but rare in primary glioblastomas.	('glioblastomas', 'Disease', (66, 79))	('glioblastomas', 'Disease', (100, 113))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (31, 34))	('found', 'Reg', (47, 52))	('glioblastomas', 'Phenotype', 'HP:0012174', (66, 79))	('glioblastomas', 'Phenotype', 'HP:0012174', (100, 113))	('mutation', 'Var', (35, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('glioblastomas', 'Disease', 'MESH:D005909', (66, 79))	('glioblastomas', 'Disease', 'MESH:D005909', (100, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))
89027	26918938	IDH1 mutations have been shown to alter the enzymatic activity of the encoded protein, leading to up-regulation of hypoxia inducible factor-1alpha (HIF-1alpha).	('hypoxia inducible factor-1alpha', 'Gene', '3091', (115, 146))	('hypoxia inducible factor-1alpha', 'Gene', (115, 146))	('IDH1', 'Gene', (0, 4))	('HIF-1alpha', 'Gene', (148, 158))	('mutations', 'Var', (5, 14))	('alter', 'Reg', (34, 39))	('up-regulation', 'PosReg', (98, 111))	('enzymatic activity', 'MPA', (44, 62))	('HIF-1alpha', 'Gene', '3091', (148, 158))	('IDH1', 'Gene', '3417', (0, 4))
89029	26918938	Although the properties of the IDH1 mutation would promote tumor growth, IDH mutation commonly indicates a favorable prognosis independent of WHO grades.	('IDH', 'Gene', (31, 34))	('tumor', 'Disease', (59, 64))	('IDH1', 'Gene', '3417', (31, 35))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (31, 34))	('IDH', 'Gene', '3417', (73, 76))	('promote', 'PosReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutation', 'Var', (36, 44))	('IDH1', 'Gene', (31, 35))
89030	26918938	Mutations and loss of expression of alphathalassemia/mental retardation syndrome X-linked (ATRX) was first reported in pancreatic neuroendocrine tumors.	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (119, 151))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (130, 151))	('ATRX', 'Gene', (91, 95))	('loss of expression', 'NegReg', (14, 32))	('mental retardation', 'Phenotype', 'HP:0001249', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ATRX', 'Gene', '546', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Mutations', 'Var', (0, 9))	('alphathalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (36, 89))	('pancreatic neuroendocrine tumors', 'Disease', (119, 151))
89031	26918938	ATRX protein plays a variety of key roles at tandem repeat sequences within the genome, including prevention of replication fork stalling, the deposition of a histone variant, and the suppression of a homologous recombination-based pathway of telomere maintenance.	('tandem repeat sequences', 'Var', (45, 68))	('ATRX', 'Gene', (0, 4))	('suppression', 'NegReg', (184, 195))	('variant', 'Var', (167, 174))	('ATRX', 'Gene', '546', (0, 4))	('replication fork stalling', 'CPA', (112, 137))	('histone', 'Protein', (159, 166))
89032	26918938	Recently, mutation/loss of ATRX was identified as a potent biomarker in grade II-III gliomas and was associated with recurrent ones.	('III gliomas', 'Disease', 'MESH:D005910', (81, 92))	('ATRX', 'Gene', (27, 31))	('mutation/loss', 'Var', (10, 23))	('ATRX', 'Gene', '546', (27, 31))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('associated', 'Reg', (101, 111))	('III gliomas', 'Disease', (81, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
89033	26918938	ATRX gene mutations were significantly correlated with ALT positivity.	('ATRX', 'Gene', (0, 4))	('correlated', 'Reg', (39, 49))	('ALT positivity', 'Disease', (55, 69))	('ATRX', 'Gene', '546', (0, 4))	('mutations', 'Var', (10, 19))
89034	26918938	Loss of ATRX in ALT frees macroH2A1.1 to bind and sequester tankyrase 1, thereby preventing resolution of sister telomere cohesion.	('tankyrase 1', 'Gene', '8658', (60, 71))	('ATRX', 'Gene', '546', (8, 12))	('macroH2A1.1', 'Gene', (26, 37))	('preventing', 'NegReg', (81, 91))	('tankyrase 1', 'Gene', (60, 71))	('resolution of sister telomere cohesion', 'MPA', (92, 130))	('ATRX', 'Gene', (8, 12))	('bind', 'Interaction', (41, 45))	('Loss', 'Var', (0, 4))	('macroH2A1.1', 'Gene', '9555', (26, 37))
89038	26918938	In patients with 1p/19q noncodeleted tumors with IDH mutations, those who were ATRX positive might have benefitted more than those who were negative from pre-RT PCV.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('IDH', 'Gene', (49, 52))	('IDH', 'Gene', '3417', (49, 52))	('mutations', 'Var', (53, 62))	('ATRX', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('patients', 'Species', '9606', (3, 11))	('benefitted', 'PosReg', (104, 114))	('tumors', 'Disease', (37, 43))	('ATRX', 'Gene', '546', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
89041	26918938	Similarly, a report depicted how loss of ATRX could affect neuroprogenitor cell apoptosis.	('ATRX', 'Gene', (41, 45))	('ATRX', 'Gene', '546', (41, 45))	('neuroprogenitor cell apoptosis', 'CPA', (59, 89))	('loss', 'Var', (33, 37))	('affect', 'Reg', (52, 58))
89043	26918938	IDH1/2 mutations dominate in WHO grade II/III gliomas (also called as lower grade gliomas) and secondary GBM.	('III gliomas', 'Disease', (42, 53))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('III gliomas', 'Disease', 'MESH:D005910', (42, 53))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('mutations', 'Var', (7, 16))
89046	26918938	In addition, oligodendrogliomas have the 1p/19q codeletion and TERT promoter mutations phenotype, while TP53 and ATRX mutations predominantly occur in grade II/III astrocytoma and secondary GBM.	('astrocytoma', 'Phenotype', 'HP:0009592', (164, 175))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('TP53', 'Gene', '7157', (104, 108))	('ATRX', 'Gene', '546', (113, 117))	('TP53', 'Gene', (104, 108))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (13, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('occur', 'Reg', (142, 147))	('1p/19q codeletion', 'Var', (41, 58))	('secondary GBM', 'Disease', (180, 193))	('TERT', 'Gene', (63, 67))	('TERT', 'Gene', '7015', (63, 67))	('oligodendrogliomas', 'Disease', (13, 31))	('astrocytoma', 'Disease', 'MESH:D001254', (164, 175))	('astrocytoma', 'Disease', (164, 175))	('ATRX', 'Gene', (113, 117))
89048	26918938	The frequency of IDH mutations is rare in primary GBMs that have TERT promoter mutations, EGFR alteration and PTEN loss.	('PTEN', 'Gene', '5728', (110, 114))	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', '3417', (17, 20))	('loss', 'NegReg', (115, 119))	('alteration', 'Var', (95, 105))	('EGFR', 'Gene', '1956', (90, 94))	('TERT', 'Gene', (65, 69))	('TERT', 'Gene', '7015', (65, 69))	('EGFR', 'Gene', (90, 94))	('PTEN', 'Gene', (110, 114))	('mutations', 'Var', (21, 30))
89049	26918938	analyzed IDH1 and IDH2 status at codon 132 of IDH1 and codon 172 of IDH2 by direct sequencing and anti-IDH1-R132H immunohistochemistry in 53 paired samples and their recurrences.	('IDH2', 'Gene', '3418', (18, 22))	('IDH1', 'Gene', '3417', (103, 107))	('IDH1', 'Gene', (9, 13))	('codon', 'Var', (55, 60))	('IDH1', 'Gene', (46, 50))	('IDH2', 'Gene', (68, 72))	('IDH1', 'Gene', '3417', (9, 13))	('R132H', 'Mutation', 'rs121913500', (108, 113))	('IDH1', 'Gene', '3417', (46, 50))	('IDH2', 'Gene', '3418', (68, 72))	('IDH2', 'Gene', (18, 22))	('IDH1', 'Gene', (103, 107))
89080	24482038	Children with PLGGs have been reported to have superior 10-year overall survival (OS) rates compared to adults diagnosed with low-grade gliomas during adulthood (ALGG).	('Children', 'Species', '9606', (0, 8))	('PLGGs', 'Var', (14, 19))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('overall survival', 'MPA', (64, 80))	('superior', 'PosReg', (47, 55))	('gliomas', 'Disease', (136, 143))	('OS', 'Chemical', '-', (82, 84))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
89081	24482038	While children have an excellent 10-year OS, adult patients diagnosed with low-grade gliomas have a more aggressive clinical course and poor long-term survival rates, with a high incidence of malignant transformation and death.	('OS', 'Chemical', '-', (41, 43))	('children', 'Species', '9606', (6, 14))	('gliomas', 'Disease', (85, 92))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('death', 'Disease', 'MESH:D003643', (221, 226))	('patients', 'Species', '9606', (51, 59))	('malignant transformation', 'CPA', (192, 216))	('low-grade', 'Var', (75, 84))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('death', 'Disease', (221, 226))
89122	24482038	Although not significant on univariate analysis, patients with subtotal or no resection had a small but statistically significant increase in risk of disease-related death compared to those with total resection on multivariate analysis (HR = 1.5, 95% CI: 1.01, 2.1, P = 0.04).	('disease-related', 'Disease', (150, 165))	('subtotal', 'Var', (63, 71))	('patients', 'Species', '9606', (49, 57))	('death', 'Disease', 'MESH:D003643', (166, 171))	('death', 'Disease', (166, 171))
89123	24482038	Regardless of the extent of surgical resection, children who were treated with radiation therapy had a worse OS and greater risk of disease death compared to those that were not treated with radiation therapy (HR = 3.9, P < 0.0001; Fig.	('children', 'Species', '9606', (48, 56))	('radiation therapy', 'Var', (79, 96))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('OS', 'Chemical', '-', (109, 111))
89146	24482038	However, in our series, the majority of children with grade II PLGGs also had excellent overall survival, and we did not observe increased rates of death with time as have been reported in low-grade gliomas that arise in adults, and which are prone to undergo malignant transformation.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('grade II', 'Var', (54, 62))	('children', 'Species', '9606', (40, 48))	('death', 'Disease', 'MESH:D003643', (148, 153))	('death', 'Disease', (148, 153))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (199, 206))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))
89155	24482038	Although histologically these tumors have the same characteristics in children and adults, the higher rate of genetic alterations observed in ALGGs compared to pediatric low-grade gliomas suggest a difference in genomic stability.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('children', 'Species', '9606', (70, 78))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('genetic', 'Var', (110, 117))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ALGGs', 'Disease', (142, 147))
89156	24482038	While mutations of IDH and p53 are reported in ALGGs and predict malignant transformation, these are rare in their pediatric counterparts, which more commonly harbor alterations of BRAF.	('malignant transformation', 'CPA', (65, 89))	('p53', 'Gene', '7157', (27, 30))	('ALGGs', 'Disease', (47, 52))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('IDH', 'Gene', (19, 22))	('predict', 'Reg', (57, 64))	('IDH', 'Gene', '3417', (19, 22))	('mutations', 'Var', (6, 15))	('p53', 'Gene', (27, 30))
89157	24482038	It can be hypothesized that normal processes that guide development and maturation of the brain, for example, epigenetic processes, may cause PLGGs to become quiescent as children transition into adulthood.	('children', 'Species', '9606', (171, 179))	('cause', 'Reg', (136, 141))	('epigenetic processes', 'Var', (110, 130))
89178	31119318	Cytotoxic T-lymphocyte-associated protein 4 and programmed death-1, which negatively regulate T-cell activation, represent two specific immune checkpoints that have received recent attention, with inhibitors targeting these immune pathways demonstrating unprecedented clinical activity in multiple tumors.	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('inhibitors', 'Var', (197, 207))	('tumors', 'Disease', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('Cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (0, 43))	('Cytotoxic T-lymphocyte-associated protein 4', 'Gene', (0, 43))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
89181	31119318	Aberrant cellular metabolism is emerging as a novel therapeutic target, and the interplay between metabolic remodeling and immune regulation in cancer represents an active area of investigation.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cellular metabolism', 'MPA', (9, 28))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
89212	31119318	Kynurenine can then be exported to the microenvironment by tumors, contributing towards immune suppression at many levels, with its most notable role in contributing towards materno-fetal immune tolerance.	('Kynurenine', 'Var', (0, 10))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('immune suppression', 'CPA', (88, 106))	('contributing', 'Reg', (153, 165))	('Kynurenine', 'Chemical', 'MESH:D007737', (0, 10))	('contributing', 'Reg', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('materno-fetal immune tolerance', 'CPA', (174, 204))
89213	31119318	Although several recent studies have implicated these enzymes and/or kynurenine in gliomagenesis, its intermediary metabolism has not been studied in detail.	('glioma', 'Disease', (83, 89))	('kynurenine', 'Var', (69, 79))	('implicated', 'Reg', (37, 47))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('kynurenine', 'Chemical', 'MESH:D007737', (69, 79))
89226	31119318	MGMT promoter methylation status and IDH1 mutation represent two of the strongest prognostic factors in glioblastoma.	('MGMT', 'Gene', (0, 4))	('IDH1', 'Gene', (37, 41))	('glioblastoma', 'Disease', (104, 116))	('mutation', 'Var', (42, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('IDH1', 'Gene', '3417', (37, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('MGMT', 'Gene', '4255', (0, 4))
89231	31119318	In addition, a trend in diminished CD8 cells was observed in tryptophan 'high' tumors (Fig.	('diminished', 'NegReg', (24, 34))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('CD8', 'Gene', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CD8', 'Gene', '925', (35, 38))	('tryptophan', 'Var', (61, 71))	('tryptophan', 'Chemical', 'MESH:D014364', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	("'high'", 'PosReg', (72, 78))
89236	31119318	Another novel finding from our studies was the observation of continued metabolism downstream of kynurenine in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))	('kynurenine', 'Var', (97, 107))	('glioblastoma', 'Disease', (111, 123))	('kynurenine', 'Chemical', 'MESH:D007737', (97, 107))	('metabolism', 'MPA', (72, 82))
89251	31119318	Interestingly, similar to what was observed with tryptophan metabolism, mesenchymal and classical molecular subtypes, rather than MGMT methylation or IDH1 mutation status, appeared to display aberrant arginine metabolism in glioblastoma.	('aberrant arginine metabolism', 'Phenotype', 'HP:0010909', (192, 220))	('tryptophan', 'Chemical', 'MESH:D014364', (49, 59))	('MGMT', 'Gene', (130, 134))	('arginine', 'Chemical', 'MESH:D001120', (201, 209))	('glioblastoma', 'Disease', (224, 236))	('MGMT', 'Gene', '4255', (130, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (224, 236))	('mutation', 'Var', (155, 163))	('IDH1', 'Gene', (150, 154))	('arginine metabolism', 'MPA', (201, 220))	('glioblastoma', 'Phenotype', 'HP:0012174', (224, 236))	('IDH1', 'Gene', '3417', (150, 154))
89275	31119318	However, adenosine "high" tumors did appear to confer an immune-suppressive phenotype, consisting of an accumulation of M2 macrophages when analyzed by CIBERSORT (Fig.	('adenosine', 'Var', (9, 18))	('adenosine', 'Chemical', 'MESH:D000241', (9, 18))	('immune-suppressive', 'CPA', (57, 75))	('accumulation', 'PosReg', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))	('M2 macrophages', 'MPA', (120, 134))
89280	31119318	However, similar to what was observed in tumors, an accumulation of adenosine was not observed in our preclinical models in vitro or in vivo Supplementary Fig 5A/B.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('5A/B', 'SUBSTITUTION', 'None', (159, 163))	('adenosine', 'Chemical', 'MESH:D000241', (68, 77))	('5A/B', 'Var', (159, 163))
89290	31119318	One notable finding these integrative analyses offered was that although many of the observed immuno-metabolic phenotypes appeared to be independent of MGMT promoter methylation and IDH1 mutation status, two of the strongest prognostic factors in glioblastoma, they were enriched in the mesenchymal and classical transcriptional subtypes.	('IDH1', 'Gene', '3417', (182, 186))	('glioblastoma', 'Disease', (247, 259))	('MGMT', 'Gene', (152, 156))	('MGMT', 'Gene', '4255', (152, 156))	('glioblastoma', 'Disease', 'MESH:D005909', (247, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (247, 259))	('mutation', 'Var', (187, 195))	('IDH1', 'Gene', (182, 186))
89314	25926297	If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbor cancer-associated somatic variation.	('predisposes', 'Reg', (48, 59))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('harbor', 'Reg', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('germline genetic variation', 'Var', (3, 29))
89317	25926297	Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('genetic alterations', 'Var', (112, 131))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Mendelian disease', 'Disease', (62, 79))	('Mendelian disease', 'Disease', 'MESH:D030342', (62, 79))
89325	25926297	Studies of familial retinoblastoma led to the identification of RB1 as a tumor suppressor, while cases of Li-Fraumeni syndrome showed that germline mutation of TP53 pleiotropically predisposes patients to many cancers.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TP53', 'Gene', '7157', (160, 164))	('RB1', 'Gene', '5925', (64, 67))	('retinoblastoma', 'Phenotype', 'HP:0009919', (20, 34))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('patients', 'Species', '9606', (193, 201))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (11, 34))	('tumor', 'Disease', (73, 78))	('TP53', 'Gene', (160, 164))	('predisposes', 'Reg', (181, 192))	('familial retinoblastoma', 'Disease', (11, 34))	('germline mutation', 'Var', (139, 156))	('Li-Fraumeni syndrome', 'Disease', (106, 126))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('RB1', 'Gene', (64, 67))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (106, 126))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))
89328	25926297	These examples suggest that Mendelian germline mutations could predispose Mendelian disease patients to common cancer by disrupting cellular functions that in the majority of cancer patients are altered by somatic rather than germline genetic events.	('altered', 'Reg', (195, 202))	('Mendelian germline mutations', 'Var', (28, 56))	('Mendelian disease', 'Disease', 'MESH:D030342', (74, 91))	('predispose', 'Reg', (63, 73))	('cancer', 'Disease', (175, 181))	('cellular functions', 'MPA', (132, 150))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('disrupting', 'NegReg', (121, 131))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Mendelian disease', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
89331	25926297	It is possible that genetic variants that cause Mendelian disease with high cancer comorbidity also provide a selective advantage to aberrant cells of a developing tumor, leading to this predisposition to a certain type of cancer.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('high cancer', 'Disease', 'MESH:D009369', (71, 82))	('tumor', 'Disease', (164, 169))	('high cancer', 'Disease', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('variants', 'Var', (28, 36))	('cause', 'Reg', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Mendelian disease', 'Disease', (48, 65))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('Mendelian disease', 'Disease', 'MESH:D030342', (48, 65))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
89347	25926297	For each tumor type we gather sets of genes identified as significantly mutated by MutSig or located in peaks of copy number amplification or deletion by GISTIC2 (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('GISTIC2', 'Gene', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('deletion', 'Var', (142, 150))
89371	25926297	Suppression of the gene is also advantageous for the growing cancer, as it reduces terminal differentiation and senescence in melanocytes.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Suppression', 'Var', (0, 11))	('cancer', 'Disease', (61, 67))	('senescence in melanocytes', 'CPA', (112, 137))	('reduces', 'NegReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('terminal differentiation', 'CPA', (83, 107))
89373	25926297	Of these, MC1R and TYR are associated with oculocutaneous albinism (included in International Classification of Disease, revision 10 (ICD10) billing code E70.2/3, melanoma relative risk 95% confidence interval (CI) = (2.16 - 5.19)).	('MC1R', 'Gene', '4157', (10, 14))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('MC1R', 'Gene', (10, 14))	('melanoma', 'Disease', (163, 171))	('associated', 'Reg', (27, 37))	('TYR', 'Chemical', 'MESH:D014443', (19, 22))	('TYR', 'Var', (19, 22))	('ICD', 'Disease', 'OMIM:252500', (134, 137))	('albinism', 'Phenotype', 'HP:0001022', (58, 66))	('oculocutaneous albinism', 'Disease', (43, 66))	('ICD', 'Disease', (134, 137))
89375	25926297	Germline variants of MC1R, causing red hair, have been implicated as a risk factor for melanoma via both pigmentary and non-pigmentary pathways, and polymorphic variants of TYR, which leads to green eyes, also confer significant, though lesser, risk.	('risk', 'Reg', (71, 75))	('TYR', 'Chemical', 'MESH:D014443', (173, 176))	('MC1R', 'Gene', '4157', (21, 25))	('causing', 'Reg', (27, 34))	('MC1R', 'Gene', (21, 25))	('TYR', 'Gene', (173, 176))	('green eyes', 'Disease', (193, 203))	('melanoma via both pigmentary', 'Disease', 'MESH:D008545', (87, 115))	('green eyes', 'Phenotype', 'HP:0000635', (193, 203))	('leads to', 'Reg', (184, 192))	('red hair', 'Phenotype', 'HP:0002297', (35, 43))	('polymorphic variants', 'Var', (149, 169))	('melanoma via both pigmentary', 'Disease', (87, 115))	('red hair', 'Disease', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
89387	25926297	CREBBP and EP300 defects have also been linked to aberrant TP53 and BCL6 regulation in some lymphomas.	('BCL6', 'Gene', '604', (68, 72))	('TP53', 'Gene', (59, 63))	('CREBBP', 'Gene', '1387', (0, 6))	('EP300', 'Gene', (11, 16))	('EP300', 'Gene', '2033', (11, 16))	('lymphomas', 'Disease', (92, 101))	('lymphomas', 'Disease', 'MESH:D008223', (92, 101))	('BCL6', 'Gene', (68, 72))	('CREBBP', 'Gene', (0, 6))	('linked', 'Reg', (40, 46))	('aberrant', 'Var', (50, 58))	('TP53', 'Gene', '7157', (59, 63))	('lymphomas', 'Phenotype', 'HP:0002665', (92, 101))
89389	25926297	The ectodermal dysplasia disease epidermolysis bullosa can arise from genetic alteration to proteins involved in structural support, tissue integrity, and adhesion in the dermis and epidermis.	('ectodermal dysplasia', 'Phenotype', 'HP:0000968', (4, 24))	('arise from', 'Reg', (59, 69))	('ectodermal dysplasia disease', 'Disease', 'MESH:D004476', (4, 32))	('genetic alteration', 'Var', (70, 88))	('ectodermal dysplasia disease', 'Disease', (4, 32))	('proteins', 'Protein', (92, 100))	('epidermolysis bullosa', 'Disease', (33, 54))
89403	25926297	The deletion of RPL5 is mutually exclusive with amplification of MDM2 (p=0.033, Fig.	('RPL5', 'Gene', (16, 20))	('MDM2', 'Gene', '4193', (65, 69))	('deletion', 'Var', (4, 12))	('MDM2', 'Gene', (65, 69))	('RPL5', 'Gene', '6125', (16, 20))
89404	25926297	3c), supporting the role of RPL5 deletion as an alternative mode of TP53 abrogation.	('deletion', 'Var', (33, 41))	('RPL5', 'Gene', '6125', (28, 32))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('RPL5', 'Gene', (28, 32))
89408	25926297	Defects in genes that regulate cranial-specific components of the sonic hedgehog pathway are responsible for the improper embryonic patterning in holoprosencephalies.	('responsible', 'Reg', (93, 104))	('holoprosencephalies', 'Disease', 'MESH:D016142', (146, 165))	('Defects', 'Var', (0, 7))	('holoprosencephalies', 'Disease', (146, 165))	('genes', 'Gene', (11, 16))
89412	25926297	In the TCGA lower grade glioma cohort, VENTX lesion occurs more in higher grade tumors, and these lesions are anticorrelated with IDH1 mutation.	('VENTX', 'Gene', (39, 44))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('glioma cohort', 'Disease', 'MESH:D005910', (24, 37))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDH1', 'Gene', (130, 134))	('glioma cohort', 'Disease', (24, 37))	('VENTX', 'Gene', '27287', (39, 44))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('IDH1', 'Gene', '3417', (130, 134))	('mutation', 'Var', (135, 143))
89413	25926297	Mutation of IDH1 is associated with good prognosis and particularly co-occurs in subtypes of low grade glioma with either TP53 alteration or 1p19q codeletion.	('TP53', 'Gene', (122, 126))	('IDH1', 'Gene', (12, 16))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('Mutation', 'Var', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('co-occurs', 'Reg', (68, 77))	('IDH1', 'Gene', '3417', (12, 16))	('TP53', 'Gene', '7157', (122, 126))	('glioma', 'Disease', (103, 109))	('1p19q codeletion', 'Var', (141, 157))
89414	25926297	Comparing the IDH1 mutated against the VENTX mutated samples, we find strong differential expression of the holoprosencephaly genes TGIF1, SIX3, ZIC2, GLI2.	('VENTX', 'Gene', (39, 44))	('SIX3', 'Gene', '6496', (139, 143))	('ZIC2', 'Gene', (145, 149))	('SIX3', 'Gene', (139, 143))	('holoprosencephaly', 'Disease', (108, 125))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (108, 125))	('mutated', 'Var', (19, 26))	('ZIC2', 'Gene', '7546', (145, 149))	('VENTX', 'Gene', '27287', (39, 44))	('expression', 'MPA', (90, 100))	('TGIF1', 'Gene', (132, 137))	('GLI2', 'Gene', (151, 155))	('IDH1', 'Gene', (14, 18))	('GLI2', 'Gene', '2736', (151, 155))	('TGIF1', 'Gene', '7050', (132, 137))	('holoprosencephaly', 'Disease', 'MESH:D016142', (108, 125))	('IDH1', 'Gene', '3417', (14, 18))
89415	25926297	As a set, the holoprosencephaly candidate brain neoplasm genes are significantly upregulated in the VENTX mutated tumors (camera p-value = 0.048, GSEA p-value = 0.031, Supplementary Fig.	('upregulated', 'PosReg', (81, 92))	('VENTX', 'Gene', '27287', (100, 105))	('GSEA', 'Chemical', '-', (146, 150))	('brain neoplasm', 'Phenotype', 'HP:0030692', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('holoprosencephaly candidate brain neoplasm', 'Disease', (14, 56))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (14, 31))	('holoprosencephaly candidate brain neoplasm', 'Disease', 'MESH:D016142', (14, 56))	('VENTX', 'Gene', (100, 105))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mutated', 'Var', (106, 113))
89421	25926297	On the other hand, some Mendelian diseases predispose carriers to many cancer types, while others have no relationship with cancer.	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('carriers', 'Var', (54, 62))	('predispose', 'Reg', (43, 53))	('Mendelian diseases', 'Disease', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Mendelian diseases', 'Disease', 'MESH:D030342', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
89433	25926297	These findings suggest that some Mendelian diseases predispose patients to many cancers by genetic alterations affecting pan-cancer processes.	('predispose', 'Reg', (52, 62))	('Mendelian diseases', 'Disease', (33, 51))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('Mendelian diseases', 'Disease', 'MESH:D030342', (33, 51))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('genetic alterations', 'Var', (91, 110))	('pan-cancer', 'Disease', (121, 131))	('affecting', 'Reg', (111, 120))	('patients', 'Species', '9606', (63, 71))	('pan-cancer', 'Disease', 'MESH:C537931', (121, 131))
89437	25926297	For example, the gene B2M is recurrently mutated or deleted in the TCGA melanoma, lung squamous cell carcinoma, and colon adenocarcinoma.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('lung squamous cell carcinoma', 'Disease', (82, 110))	('melanoma', 'Disease', (72, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('deleted', 'Var', (52, 59))	('B2M', 'Gene', '567', (22, 25))	('colon adenocarcinoma', 'Disease', (116, 136))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (116, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('B2M', 'Gene', (22, 25))
89440	25926297	Novel pan-cancer associations include the set of lipoprotein deficiencies, defects in widely expressed proteins that lead to imbalance of blood cholesterols.	('pan-cancer', 'Disease', 'MESH:C537931', (6, 16))	('imbalance', 'Phenotype', 'HP:0002172', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('proteins', 'Protein', (103, 111))	('imbalance of blood cholesterols', 'MPA', (125, 156))	('pan-cancer', 'Disease', (6, 16))	('defects', 'Var', (75, 82))	('lead to', 'Reg', (117, 124))	('cholesterols', 'Chemical', 'MESH:D002784', (144, 156))	('lipoprotein', 'Protein', (49, 60))	('deficiencies', 'Var', (61, 73))
89446	25926297	We have shown that Mendelian diseases that are comorbid with a cancer are likely to involve mutation of genes similar to those that are somatically altered in that cancer.	('Mendelian diseases', 'Disease', 'MESH:D030342', (19, 37))	('Mendelian diseases', 'Disease', (19, 37))	('mutation', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
89451	25926297	Many of our candidate drivers have a bulk of evidence supporting their role: beyond our findings related to comorbidity and genetic similarity, the candidate genes include some recurrently mutated in cancer, and some with identified roles as drivers in other tumors.	('mutated', 'Var', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumors', 'Disease', (259, 265))	('Man', 'Species', '9606', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Disease', (200, 206))
89452	25926297	Additionally, we have used patterns of co-occurrence of candidate mutations across tumor cohorts to demonstrate a likely role for these genes in the tumors.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
89454	25926297	Inactivation of ribosomal protein RPL5, associated with Diamond-Blackfan anemia, has the potential to cause aberrant TP53 degradation in multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (137, 153))	('anemia', 'Disease', (73, 79))	('cause', 'Reg', (102, 107))	('anemia', 'Disease', 'MESH:D000740', (73, 79))	('RPL5', 'Gene', '6125', (34, 38))	('TP53', 'Gene', '7157', (117, 121))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('TP53', 'Gene', (117, 121))	('anemia', 'Phenotype', 'HP:0001903', (73, 79))	('multiple cancers', 'Disease', (137, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('RPL5', 'Gene', (34, 38))	('associated', 'Reg', (40, 50))	('Inactivation', 'Var', (0, 12))
89458	25926297	In contrast, some germline variants predispose patients to a more narrow range of cancers, which can reveal more specific oncogenic processes.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('germline variants', 'Var', (18, 35))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('patients', 'Species', '9606', (47, 55))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('predispose', 'Reg', (36, 46))
89478	25926297	MutSigCV assigns a statistic for evidence of selection for mutation of a gene across a set of tumors.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (59, 67))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
89480	25926297	Each tumor type has from zero to hundreds of associated genes either mutated or copy number altered (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mutated', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('copy number', 'Var', (80, 91))	('altered', 'Reg', (92, 99))
89495	25926297	In the BioGRID binary interaction data set, a curated set of genetic interations and protein interactions, there are 140,402 edges on 14,112 nodes, covering 86% of Mendelian disease genes and all but four of our Mendelian disease sets.	('Mendelian disease', 'Disease', (212, 229))	('Mendelian disease', 'Disease', 'MESH:D030342', (212, 229))	('Mendelian disease', 'Disease', (164, 181))	('genes', 'Var', (182, 187))	('Mendelian disease', 'Disease', 'MESH:D030342', (164, 181))
89509	25484917	We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('K36M', 'Var', (44, 48))	('H3.1', 'Gene', '8352', (60, 64))	('K36M', 'Mutation', 'p.K36M', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('defective', 'NegReg', (237, 246))	('chromatin remodeling', 'CPA', (247, 267))	('increased', 'PosReg', (173, 182))	('H3.1', 'Gene', (60, 64))	('transcriptionally repressive histone methylation', 'MPA', (183, 231))
89511	25484917	Epigenetic control of gene expression dictates cell fate in health and disease, and dysregulation of epigenetic signals is associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('associated', 'Reg', (123, 133))	('dysregulation', 'Var', (84, 97))	('dictates', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Epigenetic', 'Var', (0, 10))	('cell fate', 'CPA', (47, 56))	('cancer', 'Disease', (139, 145))
89512	25484917	Two observations support pharmacological targeting of the 'cancer epigenome': (1) some cancer-associated epigenetic aberrations drive cancer initiation or progression; and (2) unlike genetic information, epigenetic states are reversible.	('cancer', 'Disease', (87, 93))	("'cancer", 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('epigenetic aberrations', 'Var', (105, 127))	('cancer initiation', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	("'cancer", 'Disease', (58, 65))	('progression', 'CPA', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer initiation', 'Disease', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (59, 65))	('drive', 'Reg', (128, 133))
89514	25484917	Cancer associated overexpression, mutation, or aberrant recruitment of chromatin factors (defined here as proteins that participate in the chemical modification of DNA, histones, or control nucleosome occupancy), represent emerging opportunities for cancer therapy.	('aberrant', 'Var', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('recruitment', 'MPA', (56, 67))	('cancer', 'Disease', (250, 256))	('mutation', 'Var', (34, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('overexpression', 'PosReg', (18, 32))
89515	25484917	For instance, inhibitors of EZH2 - a histone 3 lysine 27 (H3K27) methyltransferase that is overexpressed in a number of solid tumors and is the site of recurrent gain-of-function mutations in lymphoma - are raising considerable interest as potential anti-cancer agents, and have recently advanced to the clinic.	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('H3K27', 'Gene', '126961', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('lymphoma', 'Disease', 'MESH:D008223', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('EZH2', 'Gene', '2146', (28, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('EZH2', 'Gene', (28, 32))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('cancer', 'Disease', (255, 261))	('mutations', 'Var', (179, 188))	('inhibitors', 'Var', (14, 24))	('gain-of-function', 'PosReg', (162, 178))	('H3K27', 'Gene', (58, 63))	('lymphoma', 'Disease', (192, 200))
89516	25484917	Chromosomal aberrations and altered expression of chromatin factors that are recurrent in specific cancer types have been reported in the literature, some extensively, and recently reviewed.	('Chromosomal aberrations', 'Var', (0, 23))	('altered', 'Reg', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('expression', 'MPA', (36, 46))
89521	25484917	This systematic and integrated approach identifies many oncogenic aberrations already recorded in the literature, but also uncovers novel alterations recurrently affecting chromatin factors in specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('alterations', 'Var', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('affecting', 'Reg', (162, 171))	('cancer', 'Disease', (202, 208))	('chromatin factors', 'MPA', (172, 189))
89522	25484917	Overall our results provide novel insight into the cancer epigenome revealing a tendency toward alterations predicted to result in greater transcriptional repression, decreased transcriptional activation and reduced chromatin remodeling.	('chromatin remodeling', 'MPA', (216, 236))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('transcriptional activation', 'MPA', (177, 203))	('reduced', 'NegReg', (208, 215))	('greater', 'PosReg', (131, 138))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('transcriptional repression', 'MPA', (139, 165))	('decreased', 'NegReg', (167, 176))
89531	25484917	As shown in Additional file 2: Figure S1 and Table 1, our analysis retrieved a number of known cancer-associated aberrations in chromatin factors.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('chromatin factors', 'Protein', (128, 145))	('aberrations', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
89534	25484917	Other examples include recurrent mutations of the chromatin remodeling protein ATRX in lower grade glioblastoma (40% of patient), or DNMT3A and TET2 in acute myeloid leukemia (25% and 8.6% of patients, respectively), mutations of the H3K4 methyltransferase MLL3 in 7.7% of breast cancer patients, or mutations of the bromodomain containing protein PBRM1 in 28.5% of kidney renal clear cell carcinoma.	('patient', 'Species', '9606', (192, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('acute myeloid leukemia', 'Disease', (152, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('DNMT3A', 'Gene', (133, 139))	('mutations', 'Var', (33, 42))	('TET2', 'Gene', '54790', (144, 148))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (366, 399))	('MLL3', 'Gene', '58508', (257, 261))	('glioblastoma', 'Disease', (99, 111))	('patient', 'Species', '9606', (287, 294))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('patient', 'Species', '9606', (120, 127))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (158, 174))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (152, 174))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (152, 174))	('kidney renal clear cell carcinoma', 'Disease', (366, 399))	('PBRM1', 'Gene', '55193', (348, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('mutations', 'Var', (300, 309))	('patients', 'Species', '9606', (192, 200))	('DNMT3A', 'Gene', '1788', (133, 139))	('MLL3', 'Gene', (257, 261))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('breast cancer', 'Disease', (273, 286))	('TET2', 'Gene', (144, 148))	('PBRM1', 'Gene', (348, 353))	('patients', 'Species', '9606', (287, 295))	('H3', 'Gene', '126961', (234, 236))	('ATRX', 'Gene', (79, 83))	('ATRX', 'Gene', '546', (79, 83))	('mutations', 'Var', (217, 226))
89538	25484917	Another PMT, MLL2, and the HAT EP300 are found mutated in 18% and 7.8% of head and neck tumors, respectively (Table 1).	('head and neck tumors', 'Phenotype', 'HP:0012288', (74, 94))	('neck tumors', 'Disease', (83, 94))	('MLL2', 'Gene', '9757', (13, 17))	('EP300', 'Gene', '2033', (31, 36))	('MLL2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EP300', 'Gene', (31, 36))	('mutated', 'Var', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('neck tumors', 'Disease', 'MESH:D006258', (83, 94))
89544	25484917	Again, the rationale here may be that since chromatin factors control the transcriptional profile of the cancer genome, mutations affecting a single chromatin factor may have a strong impact on the expression of a combination of genes involved in cell fate, survival, or DNA damage response.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('transcriptional', 'MPA', (74, 89))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (198, 208))	('impact', 'Reg', (184, 190))
89550	25484917	It has been proposed that site-specific missense mutations that recur across a sizable cohort of cancer patients are indicative of an oncogenic role for the targeted gene, while genes that are frequently mutated at random positions are more likely to act as tumor suppressors.	('missense mutations', 'Var', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
89551	25484917	For instance, we did not have access to lymphoma data, and failed to retrieve known Y641 mutants that increase the trimethylase activity of EZH2 in this cancer type.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('lymphoma', 'Disease', 'MESH:D008223', (40, 48))	('cancer', 'Disease', (153, 159))	('EZH2', 'Gene', '2146', (140, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (40, 48))	('EZH2', 'Gene', (140, 144))	('trimethylase activity', 'MPA', (115, 136))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('increase', 'PosReg', (102, 110))	('Y641', 'Var', (84, 88))	('lymphoma', 'Disease', (40, 48))
89554	25484917	For instance, genes coding for the histone variant H3.1, are mutated in 17 out of 270 head and neck squamous cell carcinoma samples (HNSC), and four of these mutations replace a lysine with methionine at position 36 (twice in HIST1H3C, once in HIST1H3E and once in HIST1H3I) suggesting that H3K36M is an oncogenic mutation that drives tumor initiation or progression in a fraction of HNSC patients.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('mutations replace', 'Var', (158, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('replace', 'Var', (168, 175))	('HIST1H3C', 'Gene', '8352', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('H3.1', 'Gene', '8352', (51, 55))	('HIST1H3C', 'Gene', (226, 234))	('tumor initiation', 'Disease', 'MESH:D009369', (335, 351))	('HIST1H3E', 'Gene', (244, 252))	('tumor initiation', 'Disease', (335, 351))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('HIST1H3E', 'Gene', '8353', (244, 252))	('HIST1H3I', 'Gene', (265, 273))	('patients', 'Species', '9606', (389, 397))	('H3.1', 'Gene', (51, 55))	('H3K36M', 'Var', (291, 297))	('HIST1H3I', 'Gene', '8354', (265, 273))	('lysine with methionine at position 36', 'Mutation', 'p.K36M', (178, 215))	('head', 'Disease', (86, 90))
89559	25484917	We also found a H3K36M mutation in a colorectal cancer sample, suggesting that this mechanism may extend to other cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('colorectal cancer', 'Disease', (37, 54))	('found', 'Reg', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('H3K36M', 'Var', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('cancer', 'Disease', (114, 120))
89560	25484917	Though statistically significant, we note that the H3K36M mutation rate of 24% out of the 6.2% HNSC samples carrying a mutation at H3.1 remains low.	('mutation', 'Var', (119, 127))	('H3.1', 'Gene', (131, 135))	('H3.1', 'Gene', '8352', (131, 135))	('H3K36M', 'Gene', (51, 57))
89561	25484917	As a comparison, over 40% of cutaneous melanoma samples carry a mutation in BRAF, 90% of which are at the hotspot V600E.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cutaneous melanoma', 'Disease', (29, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (29, 47))	('V600E', 'Mutation', 'rs113488022', (114, 119))
89562	25484917	Another histone, H2B is mutated in seven out of 377 glioblastoma multiform patients, resulting in a G53D mutant in three cases (in HIST1H2BE, HIST1H2BL and HIST1H2BF) (Figure 2A,B).	('H2B', 'Gene', (147, 150))	('H2B', 'Gene', '8349', (136, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('HIST1H2BF', 'Gene', '8343', (156, 165))	('H2B', 'Gene', (161, 164))	('H2B', 'Gene', (17, 20))	('HIST1H2BL', 'Gene', '8340', (142, 151))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('H2B', 'Gene', (136, 139))	('HIST1H2BL', 'Gene', (142, 151))	('patients', 'Species', '9606', (75, 83))	('H2B', 'Gene', '8349', (147, 150))	('HIST1H2BE', 'Gene', (131, 140))	('G53D', 'Mutation', 'p.G53D', (100, 104))	('G53D', 'Var', (100, 104))	('HIST1H2BF', 'Gene', (156, 165))	('H2B', 'Gene', '8349', (161, 164))	('H2B', 'Gene', '8349', (17, 20))	('HIST1H2BE', 'Gene', '8344', (131, 140))
89563	25484917	This mutation places an acidic residue in the minor groove of the DNA wrapped around the histone octamer (Additional file 4: Figure S3), which should destabilize nucleosomal H2B, and possibly nucleosome fluctuation or chromatin architecture.	('nucleosomal', 'MPA', (162, 173))	('destabilize', 'NegReg', (150, 161))	('H2B', 'Gene', '8349', (174, 177))	('mutation', 'Var', (5, 13))	('H2B', 'Gene', (174, 177))
89565	25484917	We find that WHSC1, an H3K36 di-methylase that harbors two PWWP domains, is mutated in eight HNSC samples.	('WHSC1', 'Gene', (13, 18))	('mutated', 'Var', (76, 83))	('H3', 'Gene', '126961', (23, 25))	('WHSC1', 'Gene', '7468', (13, 18))
89566	25484917	In four cases, this produces a frameshift insertion at position G944 of the C-terminal PWWP domain (Figure 2B).	('frameshift', 'Var', (31, 41))	('G944 of the C', 'Mutation', 'rs775942317', (64, 77))	('produces', 'Reg', (20, 28))
89567	25484917	This results in deletion of the C-terminal helix of the WHSC1 PWWP domain, expected to cap the methyl-lysine binding aromatic cage, and may also cause truncation of the methyltransferase domain of WHSC1, located on a downstream exon.	('methyl-lysine binding aromatic cage', 'MPA', (95, 130))	('WHSC1', 'Gene', '7468', (56, 61))	('deletion', 'Var', (16, 24))	('methyltransferase', 'Enzyme', (169, 186))	('WHSC1', 'Gene', (56, 61))	('results in', 'Reg', (5, 15))	('WHSC1', 'Gene', '7468', (197, 202))	('truncation', 'MPA', (151, 161))	('cause', 'Reg', (145, 150))	('methyl-lysine', 'Chemical', '-', (95, 108))	('cap', 'PosReg', (87, 90))	('WHSC1', 'Gene', (197, 202))
89569	25484917	We find that the H3K36M mutation and WHSC1 frameshifts are mutually exclusive in HNSC tumor samples.	('HNSC tumor', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HNSC tumor', 'Disease', (81, 91))	('H3K36M mutation', 'Var', (17, 32))	('WHSC1', 'Gene', '7468', (37, 42))	('frameshifts', 'Var', (43, 54))	('WHSC1', 'Gene', (37, 42))
89570	25484917	Both aberrations are expected to affect H3K36me2 signaling and may represent alternate pathways to the same molecular endpoint.	('affect', 'Reg', (33, 39))	('aberrations', 'Var', (5, 16))	('H3', 'Gene', '126961', (40, 42))
89571	25484917	While mutation hotspots are expected to reveal oncogenes, tumor suppressors are generally targeted by mutations that are more distributed over the gene in cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('targeted', 'Reg', (90, 98))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
89575	25484917	In total, six of the most mutated genes in various cancer types methylate H3K4 or H3K36 (Additional file 2: Figure S1A, Table 1).	('H3', 'Gene', '126961', (82, 84))	('H3', 'Gene', '126961', (74, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('methylate', 'Var', (64, 73))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
89579	25484917	Importantly, we observe that D328 makes critical electrostatic interactions with both H3K4 and H3K9 in the DPF3 complex, and is conserved in MLL3 (corresponding residue: D400 - Figure 2C - Bottom).	('H3', 'Gene', '126961', (95, 97))	('MLL3', 'Gene', '58508', (141, 145))	('D328', 'Chemical', '-', (29, 33))	('electrostatic interactions', 'MPA', (49, 75))	('D328', 'Var', (29, 33))	('H3', 'Gene', '126961', (86, 88))	('DPF3', 'Gene', (107, 111))	('MLL3', 'Gene', (141, 145))	('DPF3', 'Gene', '8110', (107, 111))
89580	25484917	Intriguingly, D400N is one of the three mutations affecting the triple PHD finger of MLL3 in colorectal cancer, and, based on these structural observations, should significantly affect histone binding.	('D400N', 'Mutation', 'p.D400N', (14, 19))	('histone', 'MPA', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('MLL3', 'Gene', (85, 89))	('colorectal cancer', 'Disease', (93, 110))	('D400N', 'Var', (14, 19))	('MLL3', 'Gene', '58508', (85, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('affect', 'Reg', (178, 184))
89583	25484917	The C347G mutation will irremediably affect the structure of this domain, expected to participate in substrate binding.	('structure', 'MPA', (48, 57))	('affect', 'Reg', (37, 43))	('C347G', 'Var', (4, 9))	('participate', 'Reg', (86, 97))	('C347G', 'Mutation', 'rs754368331', (4, 9))
89584	25484917	Somatic mutations affecting MLL3 in colorectal cancer seem therefore to target with high precision residues involved in recruiting the enzyme to appropriately marked loci.	('MLL3', 'Gene', '58508', (28, 32))	('colorectal cancer', 'Disease', (36, 53))	('mutations', 'Var', (8, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('MLL3', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))
89585	25484917	Selective targeting of H3K4 and H3K36 methylation by oncogenic mutations was also observed in other studies that are not yet available from TCGA; for instance, mutations in SETD2 and genes affecting H3K36 methylation are recurrent in high-grade gliomas.	('H3', 'Gene', '126961', (23, 25))	('recurrent', 'Reg', (221, 230))	('mutations', 'Var', (160, 169))	('SETD2', 'Gene', (173, 178))	('gliomas', 'Disease', (245, 252))	('H3', 'Gene', '126961', (199, 201))	('gliomas', 'Disease', 'MESH:D005910', (245, 252))	('gliomas', 'Phenotype', 'HP:0009733', (245, 252))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('H3', 'Gene', '126961', (32, 34))	('SETD2', 'Gene', '29072', (173, 178))
89586	25484917	Together, these results show that H3K36 and H3K4 mediated signaling is highly targeted in cancer via hotspot mutations of oncogenes and random mutation of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('H3', 'Gene', '126961', (44, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('H3', 'Gene', '126961', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('oncogenes', 'Gene', (122, 131))	('mutations', 'Var', (109, 118))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
89587	25484917	To identify cancer-associated chromatin factor alterations that are either synergistic or redundant, we searched for co-occurring and mutually exclusive mutation patterns, respectively (Additional file 5: Table S2).	('cancer', 'Disease', (12, 18))	('alterations', 'Var', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
89588	25484917	We find that mutations are co-occurring in ATRX, TP53, and IDH1, and that these are mutually exlusive with mutations in PTEN and EGFR in glioblatoma multiform (GBM) and lower grade glioma (LGG) (Figure 3; Additional file 5: Table S2).	('IDH1', 'Gene', '3417', (59, 63))	('mutations', 'Var', (107, 116))	('TP53', 'Gene', '7157', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (13, 22))	('ATRX', 'Gene', '546', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioblatoma multiform', 'Disease', (137, 158))	('EGFR', 'Gene', '1956', (129, 133))	('PTEN', 'Gene', (120, 124))	('glioblatoma multiform', 'Disease', 'MESH:D004892', (137, 158))	('PTEN', 'Gene', '5728', (120, 124))	('IDH1', 'Gene', (59, 63))	('EGFR', 'Gene', (129, 133))	('glioma', 'Disease', (181, 187))	('ATRX', 'Gene', (43, 47))
89589	25484917	For example, TP53 is mutated in 50% of all LGG samples, but in 95% of the 80 ATRX-mutated samples.	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (13, 17))	('ATRX', 'Gene', '546', (77, 81))	('LGG', 'Disease', (43, 46))	('mutated', 'Var', (21, 28))	('ATRX', 'Gene', (77, 81))
89591	25484917	Interestingly, it was found that mutations in IDH1, ATRX, or TP53 were recurrent only in glioma-CpG island methylator phenotype-positive tumors (a phenotype probably attributable to the competitive inhibition of TET demethylases, following accumulation of 2-hydroxyglutarate caused by IDH1 mutation), while mutations in EGFR and PTEN were only observed in other tumor subtypes, which is in agreement with the pattern that we observe.	('tumors', 'Disease', (137, 143))	('mutation', 'Var', (290, 298))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (362, 367))	('IDH1', 'Gene', (285, 289))	('TP53', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('IDH1', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('EGFR', 'Gene', (320, 324))	('ATRX', 'Gene', (52, 56))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (256, 274))	('PTEN', 'Gene', (329, 333))	('glioma', 'Disease', (89, 95))	('ATRX', 'Gene', '546', (52, 56))	('IDH1', 'Gene', '3417', (285, 289))	('tumor', 'Disease', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('IDH1', 'Gene', '3417', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PTEN', 'Gene', '5728', (329, 333))	('TP53', 'Gene', '7157', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('EGFR', 'Gene', '1956', (320, 324))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
89592	25484917	An important mutation that is missed in our exome-centric analysis is an upregulating mutation in the promoter of the telomerase reverse transcriptase (TERT), observed in 58% to 84% of primary glioblastomas, suggesting that telomere lengthening plays an important role in tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('TERT', 'Gene', '7015', (152, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (193, 206))	('telomerase reverse transcriptase', 'Gene', (118, 150))	('tumor', 'Disease', (272, 277))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('glioblastomas', 'Disease', (193, 206))	('telomerase reverse transcriptase', 'Gene', '7015', (118, 150))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('upregulating', 'PosReg', (73, 85))	('mutation', 'Var', (86, 94))	('TERT', 'Gene', (152, 156))	('glioblastomas', 'Phenotype', 'HP:0012174', (193, 206))
89593	25484917	Interestingly, ATRX is required for accumulation at telomeres, and ATRX mutations promote telomere lengthening and cellular proliferation.	('mutations', 'Var', (72, 81))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (15, 19))	('cellular proliferation', 'CPA', (115, 137))	('ATRX', 'Gene', '546', (67, 71))	('promote', 'PosReg', (82, 89))	('telomere lengthening', 'CPA', (90, 110))	('ATRX', 'Gene', (15, 19))
89594	25484917	Similarly TP53 deficiency favors telomere lengthening.	('telomere lengthening', 'CPA', (33, 53))	('TP53', 'Gene', (10, 14))	('favors', 'PosReg', (26, 32))	('deficiency', 'Var', (15, 25))	('TP53', 'Gene', '7157', (10, 14))
89595	25484917	This suggests complementary pressures towards an oncogenic pathway depending on telomere lengthening by mutations co-occurring at ATRX, TP53 and (hypothetically) IDH1 in adult brain tumors where the PTEN/EGFR surface signaling axis is not altered.	('PTEN', 'Gene', '5728', (199, 203))	('brain tumors', 'Disease', (176, 188))	('telomere', 'MPA', (80, 88))	('mutations', 'Var', (104, 113))	('ATRX', 'Gene', (130, 134))	('IDH1', 'Gene', '3417', (162, 166))	('brain tumors', 'Disease', 'MESH:D001932', (176, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('brain tumors', 'Phenotype', 'HP:0030692', (176, 188))	('TP53', 'Gene', '7157', (136, 140))	('ATRX', 'Gene', '546', (130, 134))	('EGFR', 'Gene', '1956', (204, 208))	('oncogenic pathway', 'Pathway', (49, 66))	('EGFR', 'Gene', (204, 208))	('TP53', 'Gene', (136, 140))	('PTEN', 'Gene', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('IDH1', 'Gene', (162, 166))
89596	25484917	Other intriguing observations include a mutual exclusion in lower grade glioma between ATRX and CIC, a transcriptional repressor that may play a role in development of the central nervous system, and mutual exclusion in uterine corpus endometrial carcinoma between mutations at TP53 and SWI/SNF remodeling complex protein ARID1A (Additional file 5: Table S2).	('glioma', 'Disease', (72, 78))	('mutations', 'Var', (265, 274))	('TP53', 'Gene', '7157', (278, 282))	('TP53', 'Gene', (278, 282))	('ARID1A', 'Gene', (322, 328))	('ATRX', 'Gene', '546', (87, 91))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('ATRX', 'Gene', (87, 91))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (235, 256))	('CIC', 'Gene', '23152', (96, 99))	('ARID1A', 'Gene', '8289', (322, 328))	('endometrial carcinoma', 'Disease', (235, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('SWI/SNF', 'Gene', (287, 294))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (235, 256))	('CIC', 'Gene', (96, 99))
89598	25484917	We find that some of the changes observed in the cancer epigenome can be associated with a hyperproliferative phenotype, a hallmark of cancer.	('hallmark of cancer', 'Disease', 'MESH:D009369', (123, 141))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (73, 83))	('hyperproliferative phenotype', 'Disease', (91, 119))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('changes', 'Var', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('hallmark of cancer', 'Disease', (123, 141))	('cancer', 'Disease', (49, 55))
89601	25484917	We also find that the only two proteins known to act as direct links between histone methylation and the DNA replication machinery, ORC1 (that binds to H4K20me3 and recruits the origin of replication complex at replication origins) and UHRF1 (that binds H3K9me3 and recruits DNMT1 to hemi-methylated cytosines), are among the five most frequently overexpressed chromatin factors across all cancer types studied (Additional file 2: Figure S1B).	('DNMT1', 'Gene', (275, 280))	('ORC1', 'Gene', '4998', (132, 136))	('UHRF1', 'Gene', (236, 241))	('UHRF1', 'Gene', '29128', (236, 241))	('cancer', 'Disease', 'MESH:D009369', (390, 396))	('DNMT1', 'Gene', '1786', (275, 280))	('cancer', 'Disease', (390, 396))	('H3', 'Gene', '126961', (254, 256))	('ORC1', 'Gene', (132, 136))	('recruits', 'PosReg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('H4K20me3', 'Var', (152, 160))
89602	25484917	Another histone chaperone that is significantly overexpressed - actually the most frequently overexpressed chromatin factor in cancer - is HJURP, a chaperone of the histone H3 variant CENP-A, which facilitates aneuploidy and genome instability, another hallmark of cancer (Additional file 2: Figure S1B; Table 1).	('CENP-A', 'Gene', '1058', (184, 190))	('aneuploidy', 'Disease', (210, 220))	('variant', 'Var', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('genome instability', 'CPA', (225, 243))	('CENP-A', 'Gene', (184, 190))	('HJURP', 'Gene', '55355', (139, 144))	('hallmark of cancer', 'Disease', 'MESH:D009369', (253, 271))	('hallmark of cancer', 'Disease', (253, 271))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('aneuploidy', 'Disease', 'MESH:D000782', (210, 220))	('HJURP', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (265, 271))	('H3', 'Gene', '126961', (173, 175))	('facilitates', 'PosReg', (198, 209))
89611	25484917	Additionally, ATRX is responsible for the incorporation H3.3 at telomeres, and its mutation can cause alternative telomere lengthening, associated with increased genomic instability.	('increased', 'PosReg', (152, 161))	('ATRX', 'Gene', (14, 18))	('H3', 'Gene', '126961', (56, 58))	('mutation', 'Var', (83, 91))	('cause', 'Reg', (96, 101))	('genomic', 'MPA', (162, 169))	('ATRX', 'Gene', '546', (14, 18))	('alternative telomere lengthening', 'MPA', (102, 134))
89612	25484917	These observations strongly suggest that genetic or transcriptional aberrations targeting chromatin factors in cancer favor replication and contribute to genome instability.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('contribute', 'Reg', (140, 150))	('favor', 'PosReg', (118, 123))	('chromatin factors', 'Protein', (90, 107))	('replication', 'CPA', (124, 135))	('aberrations', 'Var', (68, 79))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('genome instability', 'MPA', (154, 172))
89614	25484917	Cancer genomes generally have large numbers of 'passenger' mutations and a small number of driver genetic events.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (59, 68))	("'passenger'", 'PosReg', (47, 58))
89616	25484917	To identify candidate drivers affecting epigenetic mechanisms, we looked for correlations between copy number gains and overexpression of chromatin factors in cancer samples compared with matched normal samples.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('copy number', 'Var', (98, 109))
89619	25484917	Amplification of the SETDB1 gene in lung cancer was recently shown to contribute to lung tumorigenesis, and shRNA-mediated depletion of SETDB1 in amplified cells reduced tumor growth in a mouse xenograft model.	('SETDB1', 'Gene', (136, 142))	('lung cancer', 'Disease', (36, 47))	('mouse', 'Species', '10090', (188, 193))	('Amplification', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('reduced', 'NegReg', (162, 169))	('SETDB1', 'Gene', (21, 27))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (170, 175))	('depletion', 'Var', (123, 132))	('contribute', 'Reg', (70, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
89623	25484917	Interestingly, knockdown of WHSC1L1 results in profound loss of growth survival of 8p11-12 amplified breast cancer cells, but not control MCF10A cells.	('MCF10A', 'CellLine', 'CVCL:0598', (138, 144))	('loss', 'NegReg', (56, 60))	('knockdown', 'Var', (15, 24))	('WHSC1L1', 'Gene', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('WHSC1L1', 'Gene', '54904', (28, 35))	('growth survival', 'CPA', (64, 79))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
89624	25484917	These results suggest that amplification of WHSC1L1 drives cancer in a subset of breast cancer patients.	('cancer', 'Disease', (88, 94))	('WHSC1L1', 'Gene', '54904', (44, 51))	('breast cancer', 'Disease', (81, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('drives', 'Reg', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (59, 65))	('amplification', 'Var', (27, 40))	('WHSC1L1', 'Gene', (44, 51))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
89631	25484917	Together, these results show that overall copy number variation do not appear to drive transcriptional de-regulation of most chromatin factors and are therefore likely to be passenger events in cancer.	('cancer', 'Disease', (194, 200))	('transcriptional', 'MPA', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('copy number variation', 'Var', (42, 63))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
89636	25484917	Specific combinations of post-translational modifications of DNA and histones at distinct genomic elements control chromatin compaction, nucleosome occupancy, and gene activation status: histone acetylation and H3K4 di- or tri-methylation at promoters, H3K4 mono-methylation at enhancers and tri-methylation of H3K36 as well as DNA methylation in gene bodies are associated with transcriptionally active genes.	('associated', 'Reg', (363, 373))	('H3', 'Gene', '126961', (311, 313))	('H3', 'Gene', '126961', (253, 255))	('tri-methylation', 'Var', (292, 307))	('H3', 'Gene', '126961', (211, 213))
89637	25484917	Promoters tri-methylated at H3K4 and H3K27 are thought to be in a state that is transcriptionally repressed, but 'poised' for rapid activation upon demethylation of H3K37.	('H3K27', 'Gene', '126961', (37, 42))	('H3', 'Gene', '126961', (165, 167))	('H3', 'Gene', '126961', (28, 30))	('H3K27', 'Gene', (37, 42))	('H3', 'Gene', '126961', (37, 39))	('tri-methylated', 'Var', (10, 24))
89638	25484917	Finally, tri-methylated H3K9 and methylated DNA at enhancers, or a combination of these two marks with trimethylated H3K27 at promoters, is associated with gene silencing (Figure 6A,B).	('H3K27', 'Gene', (117, 122))	('H3K27', 'Gene', '126961', (117, 122))	('gene', 'MPA', (156, 160))	('H3', 'Gene', '126961', (117, 119))	('H3', 'Gene', '126961', (24, 26))	('methylated', 'Var', (33, 43))
89639	25484917	Intriguingly, we find that enzymes that deposit histone marks associated with gene activation, such as the H3K4 trimethylases MLL1-4 and SETD1A/B, or the H3K36 trimethylase SETD2 are more often repressed and mutated in cancer (Figure 6C).	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('SETD2', 'Gene', (173, 178))	('MLL1', 'Gene', '4297', (126, 130))	('H3', 'Gene', '126961', (154, 156))	('SETD1A/B', 'Gene', (137, 145))	('H3', 'Gene', '126961', (107, 109))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('SETD1A/B', 'Gene', '9739', (137, 145))	('mutated', 'Var', (208, 215))	('cancer', 'Disease', (219, 225))	('MLL1', 'Gene', (126, 130))	('repressed', 'MPA', (194, 203))	('SETD2', 'Gene', '29072', (173, 178))
89647	25484917	Some of the emerging epigenetic drugs, such as bromodomain, protein methyltransferase, or IDH1 inhibitors, are targeting patient group with clear oncogenic chromosomal aberrations such as gene fusions at BRD4 and MLL1, or mutations at IDH1.	('IDH1', 'Gene', (90, 94))	('chromosomal aberrations', 'Disease', (156, 179))	('BRD4', 'Gene', (204, 208))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (156, 179))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (156, 179))	('IDH1', 'Gene', (235, 239))	('IDH1', 'Gene', '3417', (90, 94))	('MLL1', 'Gene', '4297', (213, 217))	('IDH1', 'Gene', '3417', (235, 239))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (156, 178))	('mutations', 'Var', (222, 231))	('BRD4', 'Gene', '23476', (204, 208))	('patient', 'Species', '9606', (121, 128))	('MLL1', 'Gene', (213, 217))
89648	25484917	Translocations are not included in our analysis, but IDH1 mutations are high on our chromatin factor mutation landscape (Additional file 2: Figure S1A).	('mutations', 'Var', (58, 67))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))
89649	25484917	Other peaks, such as ATRX mutations in lower grade glioma or ARID1A mutations in endometrial cancer and stomach adenocarcinoma may represent other points of entry for therapeutic intervention.	('stomach adenocarcinoma', 'Disease', (104, 126))	('endometrial cancer', 'Phenotype', 'HP:0012114', (81, 99))	('glioma', 'Disease', (51, 57))	('ARID1A', 'Gene', (61, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ATRX', 'Gene', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('mutations', 'Var', (26, 35))	('ATRX', 'Gene', '546', (21, 25))	('endometrial cancer', 'Disease', (81, 99))	('mutations', 'Var', (68, 77))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (104, 126))	('ARID1A', 'Gene', '8289', (61, 67))
89654	25484917	It has been proposed that most epigenetic-associated mutations are observed in hematological, in pediatric, or in rare and aggressive variants of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('observed', 'Reg', (67, 75))	('mutations', 'Var', (53, 62))	('hematological', 'Disease', (79, 92))	('solid tumors', 'Disease', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic-associated mutations', 'Var', (31, 62))
89670	25484917	This is in agreement with previous work showing that some cancer types are particularly enriched in false mutation calling.	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('false mutation calling', 'Var', (100, 122))
89677	25484917	GISTIC values are used to evaluate copy number variations relative to the reference genome (hg18 for COAD/READ, LAML and OV; hg19 for all other cancer types).	('COAD', 'Disease', 'MESH:D029424', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('cancer', 'Disease', (144, 150))	('COAD', 'Disease', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('copy number variations', 'Var', (35, 57))
89682	25484917	Mutation hotspots were defined as aminoacids affected by a minimum of three mutations representing at least 20% of non-silent mutations for that gene in a given cancer type.	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))
89692	33402837	Besides, elevated levels of PLOD1 were significantly correlated with high tumor grade, wildtype IDH1/2 status, and 1p19q non-codel in all the four public datasets and in-house cohort.	('elevated', 'PosReg', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('IDH1/2', 'Gene', '3417;3418', (96, 102))	('correlated', 'Reg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('PLOD1', 'Gene', (28, 33))	('IDH1/2', 'Gene', (96, 102))	('1p19q non-codel', 'Var', (115, 130))	('PLOD1', 'Gene', '5351', (28, 33))
89694	33402837	More importantly, patients with IDH1/2 mutations, 1p19q codeletions, and PLOD1 overexpression had the best overall survival.	('1p19q', 'Var', (50, 55))	('PLOD1', 'Gene', '5351', (73, 78))	('IDH1/2', 'Gene', (32, 38))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (18, 26))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('PLOD1', 'Gene', (73, 78))
89696	33402837	Transwell invasion assay, which revealed that inhibiting PLOD1 reduced cell invasion in both U87 and U251 cells.	('U87', 'Gene', (93, 96))	('cell invasion in', 'CPA', (71, 87))	('reduced', 'NegReg', (63, 70))	('PLOD1', 'Gene', (57, 62))	('U251', 'CellLine', 'CVCL:0021', (101, 105))	('PLOD1', 'Gene', '5351', (57, 62))	('U87', 'Gene', '677775', (93, 96))	('inhibiting', 'Var', (46, 56))
89702	33402837	Malignant glioma is a complex disease caused by the accumulation of genetic alterations that cause genome instability.	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('Malignant glioma', 'Disease', 'MESH:D005910', (0, 16))	('genetic alterations', 'Var', (68, 87))	('caused by', 'Reg', (38, 47))	('Malignant glioma', 'Disease', (0, 16))
89705	33402837	Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is a member of the PLOD family of proteins that is responsible for lysyl hydroxylation, and mutations in the PLOD1 gene have been shown to cause Ehlers-Danlos syndrome as well as Bruck syndrome type 2.	('cause', 'Reg', (198, 203))	('PLOD', 'Gene', (168, 172))	('PLOD', 'Gene', '5351', (78, 82))	('PLOD', 'Gene', (52, 56))	('Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1', 'Gene', '5351', (0, 50))	('PLOD1', 'Gene', (168, 173))	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (204, 226))	('Bruck syndrome type 2', 'Disease', (238, 259))	('PLOD', 'Gene', '5351', (168, 172))	('PLOD', 'Gene', (78, 82))	('PLOD', 'Gene', '5351', (52, 56))	('PLOD1', 'Gene', (52, 57))	('Ehlers-Danlos syndrome', 'Disease', (204, 226))	('PLOD1', 'Gene', '5351', (168, 173))	('mutations', 'Var', (151, 160))	('PLOD1', 'Gene', '5351', (52, 57))
89746	33402837	Genetic alteration of PLOD1 in LGG and GBM was analyzed using cBioPortal and the results showed, 25% and 22% genetic alteration of PLOD1 in LGG and GBM, respectively (Figure 1B).	('genetic alteration', 'Var', (109, 127))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('PLOD1', 'Gene', '5351', (131, 136))	('PLOD1', 'Gene', (22, 27))	('PLOD1', 'Gene', '5351', (22, 27))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('PLOD1', 'Gene', (131, 136))
89766	33402837	Besides, high PLOD1 expression predicted worse prognosis in GBM in TCGA, CGGA, and Gravendeel datasets, but no correlation was observed in the Rembrandt dataset (Figure 3).	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('expression', 'MPA', (20, 30))	('worse', 'NegReg', (41, 46))	('PLOD1', 'Gene', (14, 19))	('PLOD1', 'Gene', '5351', (14, 19))	('high', 'Var', (9, 13))
89767	33402837	Histologically, the presence of the 2 mutations, 1p19q and IDH1/2, have been identified as factors associated with a favorable prognosis.	('1p19q', 'Var', (49, 54))	('IDH1/2', 'Gene', (59, 65))	('IDH1/2', 'Gene', '3417;3418', (59, 65))
89768	33402837	Numerous studies have reported that IDH1/2 mutation status and 1p 19q co-deletion status should overrule histological phenotype in tumor classification.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('IDH1/2', 'Gene', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('1p 19q co-deletion', 'Var', (63, 81))	('tumor', 'Disease', (131, 136))	('mutation status', 'Var', (43, 58))	('IDH1/2', 'Gene', '3417;3418', (36, 42))
89769	33402837	In this study, 1p19q and IDH1/2 were detected only in some of the recruited patients.	('patients', 'Species', '9606', (76, 84))	('IDH1/2', 'Gene', (25, 31))	('1p19q', 'Var', (15, 20))	('IDH1/2', 'Gene', '3417;3418', (25, 31))
89771	33402837	Our results showed that patients with IDH1/2 wildtype or 1p/19q non-codeletions had a higher level of PLOD1 expression compared to those with IDH1/2 mutation or 1p/19q codeletions based on the TCGA and CGGA datasets, respectively (Figure 4B-E).	('IDH1/2', 'Gene', (142, 148))	('1p/19q non-codeletions', 'Var', (57, 79))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('PLOD1', 'Gene', (102, 107))	('non-codeletions', 'Var', (64, 79))	('IDH1/2', 'Gene', (38, 44))	('PLOD1', 'Gene', '5351', (102, 107))	('IDH1/2', 'Gene', '3417;3418', (142, 148))	('higher', 'PosReg', (86, 92))	('patients', 'Species', '9606', (24, 32))
89774	33402837	Glioma patients were divided into three survival groups, namely IDH1/2 wild-type, IDH1 mutations with 1p19q codeletion, and IDH1/2 mutations without 1p19q codeletion, as described in a previous study.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('patients', 'Species', '9606', (7, 15))	('IDH1', 'Gene', '3417', (124, 128))	('IDH1', 'Gene', (64, 68))	('1p19q codeletion', 'Var', (102, 118))	('IDH1/2', 'Gene', (64, 70))	('IDH1', 'Gene', (82, 86))	('mutations', 'Var', (87, 96))	('IDH1/2', 'Gene', '3417;3418', (124, 130))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH1', 'Gene', '3417', (64, 68))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('IDH1', 'Gene', '3417', (82, 86))	('Glioma', 'Disease', (0, 6))	('IDH1', 'Gene', (124, 128))	('IDH1/2', 'Gene', (124, 130))
89775	33402837	Patients in the IDH1/2 mutations group and chromosome 1p19q codeletion had the best OS (median survival: 11.19 years, 7.08 years in TCGA and CGGA, respectively, Figure 5A and B), and the IDH1/2 wild-type group had the worst OS (median survival: 1.25years, 1.30 years in TCGA and CGGA, respectively, Figure 5A and B).	('IDH1/2', 'Gene', (187, 193))	('IDH1/2', 'Gene', (16, 22))	('Patients', 'Species', '9606', (0, 8))	('chromosome 1p19q', 'Var', (43, 59))	('IDH1/2', 'Gene', '3417;3418', (187, 193))	('IDH1/2', 'Gene', '3417;3418', (16, 22))	('TCGA', 'Disease', (132, 136))
89778	33402837	However, patients in the IDH1/2 mutation/1p19q codeletion group with low expression of PLOD1 had the longest OS time (Figure 5E and F).	('patients', 'Species', '9606', (9, 17))	('PLOD1', 'Gene', '5351', (87, 92))	('mutation/1p19q', 'Var', (32, 46))	('IDH1/2', 'Gene', '3417;3418', (25, 31))	('IDH1/2', 'Gene', (25, 31))	('PLOD1', 'Gene', (87, 92))
89779	33402837	These results indicated that PLOD1 played an important role in improving prognosis prediction when incorporated together with IDH1 mutation status and chromosome 1p19q codeletion.	('IDH1', 'Gene', '3417', (126, 130))	('PLOD1', 'Gene', (29, 34))	('PLOD1', 'Gene', '5351', (29, 34))	('prognosis', 'MPA', (73, 82))	('IDH1', 'Gene', (126, 130))	('improving', 'PosReg', (63, 72))	('mutation', 'Var', (131, 139))
89789	33402837	PLOD1 knockdown reduced the migration and invasion of glioma cells in vitro (Figure 8A-F).	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('PLOD1', 'Gene', (0, 5))	('reduced', 'NegReg', (16, 23))	('glioma', 'Disease', (54, 60))	('PLOD1', 'Gene', '5351', (0, 5))	('knockdown', 'Var', (6, 15))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
89790	33402837	Besides, inhibiting PLOD1 downregulated the expression of mmp2 and vimentin, which were confirmed by Western blot (Figure 8G and H) and Immunofluorescence staining (Figure 8I).	('downregulated', 'NegReg', (26, 39))	('expression', 'MPA', (44, 54))	('inhibiting', 'Var', (9, 19))	('vimentin', 'Gene', '7431', (67, 75))	('PLOD1', 'Gene', (20, 25))	('mmp2', 'Gene', (58, 62))	('vimentin', 'Gene', (67, 75))	('PLOD1', 'Gene', '5351', (20, 25))	('mmp2', 'Gene', '4313', (58, 62))
89795	33402837	Besides, high PLOD1 expression significantly correlated with poor prognosis in patients with LGG and GBM.	('expression', 'MPA', (20, 30))	('LGG', 'Disease', (93, 96))	('GBM', 'Disease', (101, 104))	('PLOD1', 'Gene', (14, 19))	('patients', 'Species', '9606', (79, 87))	('PLOD1', 'Gene', '5351', (14, 19))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('high', 'Var', (9, 13))
89800	33402837	A previous study found that high PLOD1 expression was observed in clear cell renal cell carcinoma (ccRCC) when compared with normal tissues and a genetic mutant of PLOD1 was associated with a significantly poorer prognosis compared with the wild-type.	('PLOD1', 'Gene', (33, 38))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (66, 97))	('genetic mutant', 'Var', (146, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('PLOD1', 'Gene', '5351', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 97))	('cell renal cell carcinoma', 'Disease', (72, 97))	('PLOD1', 'Gene', (164, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (77, 97))	('expression', 'MPA', (39, 49))	('PLOD1', 'Gene', '5351', (164, 169))
89802	33402837	Another study also demonstrated that compared with normal tissues, PLOD1 was upregulated in gastric cancer tissues and high PLOD1 expression was significantly associated with progression and overall survival.	('expression', 'MPA', (130, 140))	('progression', 'Disease', (175, 186))	('PLOD1', 'Gene', '5351', (124, 129))	('upregulated', 'PosReg', (77, 88))	('PLOD1', 'Gene', (67, 72))	('high', 'Var', (119, 123))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated with', 'Reg', (159, 174))	('PLOD1', 'Gene', '5351', (67, 72))	('overall survival', 'CPA', (191, 207))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('PLOD1', 'Gene', (124, 129))
89809	33402837	In light of the 2016 update by the World Health Organization (WHO) CNS tumor classification, IDH mutations, and 1p19q codeletion status have been considered novel indicators in predicting the outcome of glioma patients.	('mutations', 'Var', (97, 106))	('CNS tumor', 'Phenotype', 'HP:0100006', (67, 76))	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('IDH', 'Gene', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('IDH', 'Gene', '3417', (93, 96))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Disease', (71, 76))	('glioma', 'Disease', (203, 209))
89810	33402837	To improve prognosis prediction, other genes associated with IDH and 1p19q status need to be identified.	('1p19q status', 'Var', (69, 81))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))
89811	33402837	In this study, we revealed that PLOD1 expression was higher in glioma patients with IDH wildtype and 1p19q codeletion.	('patients', 'Species', '9606', (70, 78))	('PLOD1', 'Gene', (32, 37))	('higher', 'PosReg', (53, 59))	('IDH', 'Gene', '3417', (84, 87))	('PLOD1', 'Gene', '5351', (32, 37))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH', 'Gene', (84, 87))	('1p19q codeletion', 'Var', (101, 117))	('glioma', 'Disease', (63, 69))
89815	33402837	Previous studies report that PLOD1 is directly regulated by miR-140-5p in bladder cancer (BC) and knockdown of PLOD1 significantly inhibits the proliferation, migration, and invasion in BC cells.	('BC', 'Phenotype', 'HP:0009725', (186, 188))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('PLOD1', 'Gene', (29, 34))	('PLOD1', 'Gene', '5351', (111, 116))	('PLOD1', 'Gene', '5351', (29, 34))	('knockdown', 'Var', (98, 107))	('invasion', 'CPA', (174, 182))	('migration', 'CPA', (159, 168))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('miR-140', 'Gene', '406932', (60, 67))	('inhibits', 'NegReg', (131, 139))	('bladder cancer', 'Disease', (74, 88))	('PLOD1', 'Gene', (111, 116))	('miR-140', 'Gene', (60, 67))	('BC', 'Phenotype', 'HP:0009725', (90, 92))	('proliferation', 'CPA', (144, 157))
89816	33402837	Aberrant expression of PLOD1 contributes to collagen-related diseases.	('Aberrant expression', 'Var', (0, 19))	('PLOD1', 'Gene', (23, 28))	('collagen-related diseases', 'Disease', (44, 69))	('PLOD1', 'Gene', '5351', (23, 28))	('contributes to', 'Reg', (29, 43))
89824	33402837	Knockdown of PLOD1 was found to alter the migratory and invasive properties of U87 and U251 cells, as confirmed by in vitro transwell assay results.	('Knockdown', 'Var', (0, 9))	('alter', 'Reg', (32, 37))	('U251', 'CellLine', 'CVCL:0021', (87, 91))	('U87', 'Gene', '677775', (79, 82))	('PLOD1', 'Gene', (13, 18))	('PLOD1', 'Gene', '5351', (13, 18))	('U87', 'Gene', (79, 82))	('migratory', 'CPA', (42, 51))
89830	28966033	We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M.	('BCOR', 'Gene', '54880', (144, 148))	('mutations', 'Var', (149, 158))	('K27M', 'Mutation', 'p.K27M', (134, 138))	('FBXW7', 'Gene', (85, 90))	('TOP3A', 'Gene', (106, 111))	('K27M', 'Mutation', 'p.K27M', (166, 170))	('G34R/V', 'Mutation', 'rs1057519902', (98, 104))	('loss', 'NegReg', (77, 81))	('rearrangements', 'Var', (112, 126))	('BCOR', 'Gene', (144, 148))	('FBXW7', 'Gene', '55294', (85, 90))
89834	28966033	Pediatric HGG and DIPG comprise a diverse set of clinical and biological subgroups Somatic coding mutations per tumor range from none to among the highest seen in human cancer Histone mutations co-segregate with distinct alterations and downstream pathways H3/IDH1 WT tumors may resemble low-grade lesions and have targetable alterations  Mackay et al.	('cancer', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('mutations', 'Var', (184, 193))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (268, 273))	('H3/IDH1 WT tumors', 'Disease', (257, 274))	('human', 'Species', '9606', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('H3/IDH1 WT tumors', 'Disease', 'MESH:C536751', (257, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Disease', (112, 117))	('DIPG', 'Chemical', '-', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
89836	28966033	They identify co-segregating mutations in histone-mutant subgroups and show that histone wild-type subgroups are molecularly more similar to lower-grade tumors.	('mutations', 'Var', (29, 38))	('histone-mutant', 'Protein', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('histone-mutant', 'Var', (42, 56))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
89841	28966033	It has become increasingly apparent that pHGG differ from their adult counterparts, with molecular profiling studies carried out over the last 6-7 years having incrementally identified key genetic and epigenetic differences in pHGG associated with distinct ages of onset, anatomical distribution, clinical outcome, and histopathological and radiological features.	('pHGG', 'Chemical', '-', (41, 45))	('pHGG', 'Chemical', '-', (227, 231))	('epigenetic differences', 'Var', (201, 223))	('pHGG', 'Gene', (227, 231))	('associated', 'Reg', (232, 242))
89842	28966033	In particular, the identification of unique recurrent mutations in genes encoding histones H3.3 and H3.1 have demonstrated the distinctiveness of the pediatric disease, with the G34R/V and K27M variants appearing to represent different clinicopathological and biological subgroups.	('H3.1', 'Gene', (100, 104))	('G34R', 'SUBSTITUTION', 'None', (178, 182))	('G34R', 'Var', (178, 182))	('pediatric disease', 'Disease', 'MESH:D063766', (150, 167))	('K27M', 'Mutation', 'p.K27M', (189, 193))	('H3.3', 'Gene', (91, 95))	('pediatric disease', 'Disease', (150, 167))	('H3.3', 'Gene', '3020', (91, 95))	('K27M', 'Var', (189, 193))
89843	28966033	This has been recognized by the World Health Organization (WHO) classification of CNS tumors, with the latest version including the novel entity, diffuse midline glioma with H3K27 mutation.	('K27', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('K27', 'Gene', '342574', (176, 179))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('CNS tumors', 'Disease', 'MESH:D009369', (82, 92))	('midline glioma', 'Disease', 'MESH:D005910', (154, 168))	('CNS tumors', 'Disease', (82, 92))	('midline glioma', 'Disease', (154, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('mutation', 'Var', (180, 188))
89849	28966033	These were predominantly from children but also included young adults, in order to capture more H3F3A G34R/V mutations, as well as to explore an otherwise under-studied population.	('G34R', 'Var', (102, 106))	('children', 'Species', '9606', (30, 38))	('H3F3A', 'Gene', '3020', (96, 101))	('G34R', 'SUBSTITUTION', 'None', (102, 106))	('H3F3A', 'Gene', (96, 101))
89857	28966033	H3.3K27M were spread throughout the midline and pons, where they account for 63.0% DIPG and 59.7% non-brainstem midline tumors.	('H3.3K27M', 'Var', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('DIPG', 'Disease', (83, 87))	('midline tumors', 'Disease', 'MESH:D009369', (112, 126))	('midline tumors', 'Disease', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('DIPG', 'Chemical', '-', (83, 87))
89858	28966033	In all locations (including ten cases reported to present in the cortex), these mutations conferred a significantly shorter time to death from disease (overall median 11 months, 2 year overall survival 4.7%) (Figures S1D-S1F).	('shorter', 'NegReg', (116, 123))	('time', 'MPA', (124, 128))	('mutations', 'Var', (80, 89))	('death', 'Disease', 'MESH:D003643', (132, 137))	('death', 'Disease', (132, 137))
89859	28966033	H3.1/3.2K27M were highly specific to the pons (21.4% total) where they represent a younger age group (median 5.0 years) with a significantly longer overall survival (median 15.0 months) than H3.3K27M (p = 0.00017, log rank test) (Figure S1F).	('overall survival', 'MPA', (148, 164))	('K27M', 'Mutation', 'p.K27M', (195, 199))	('longer', 'PosReg', (141, 147))	('K27M', 'Mutation', 'p.K27M', (8, 12))	('H3.1/3.2K27M', 'Var', (0, 12))
89860	28966033	In multivariate analysis incorporating the histone mutations alongside age, WHO grade, and gender, K27M mutations in both H3.3 and H3.1 are independently associated with shorter survival (p < 0.0001, Cox proportional hazards model).	('K27M mutations', 'Var', (99, 113))	('K27M', 'Mutation', 'p.K27M', (99, 103))	('survival', 'MPA', (178, 186))	('H3.1', 'Gene', (131, 135))	('H3.3', 'Gene', (122, 126))	('shorter', 'NegReg', (170, 177))	('H3.3', 'Gene', '3020', (122, 126))
89861	28966033	BRAF V600E status was available for 535 cases, with mutant cases (n = 32, 6.0%) present only in midline and hemispheric locations, and conferring a significantly improved prognosis (2 year survival 67%, p < 0.0001, log rank test) (Figures S1G-S1I).	('V600E', 'Mutation', 'rs113488022', (5, 10))	('improved', 'PosReg', (162, 170))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
89862	28966033	There was additional annotation for IDH1 R132 mutation status in 640 cases (n = 40, 6.25%), representing a forebrain-restricted, significantly older group of patients (median 17.0 years, p < 0.0001, t test) with longer overall survival (2 year survival 59%, p < 0.0001, log rank test) (Figures S1J-S1L).	('IDH1', 'Gene', (36, 40))	('longer', 'PosReg', (212, 218))	('IDH1', 'Gene', '3417', (36, 40))	('patients', 'Species', '9606', (158, 166))	('mutation', 'Var', (46, 54))	('overall', 'MPA', (219, 226))
89863	28966033	We used the Heidelberg brain tumor classifier to assign tumors into following subgroups: H3G34R/V (n = 51), H3K27M (n = 119), HGG WT (n = 156), IDH1 (n = 36), low-grade glioma (LGG)-like (n = 27), pleomorphic xanthoastrocytoma (PXA)-like (n = 43), and "other" (n = 9) (Figure S2A), visualized by hierarchical clustering (Figure 2A) (Table S2).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (197, 226))	('tumors', 'Disease', (56, 62))	('IDH1', 'Gene', (144, 148))	('H3K27M', 'Var', (108, 114))	('glioma', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('K27M', 'Mutation', 'p.K27M', (110, 114))	('pleomorphic xanthoastrocytoma', 'Disease', (197, 226))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('G34R/V', 'Mutation', 'rs1057519902', (91, 97))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('IDH1', 'Gene', '3417', (144, 148))	('brain tumor', 'Phenotype', 'HP:0030692', (23, 34))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('brain tumor', 'Disease', 'MESH:D001932', (23, 34))	('brain tumor', 'Disease', (23, 34))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
89866	28966033	MGMT promoter methylation was significantly enriched in the H3G34R/V (65.1%, globally hypomethylated) and IDH1 (78.1%, globally hypermethylated) groups, and largely absent from H3K27M tumors (4.5%, all tests versus rest, p < 0.0001 Fisher's exact test) (Figure S2B).	('MGMT', 'Gene', (0, 4))	('absent', 'NegReg', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('H3G34R/V', 'Var', (60, 68))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('IDH1', 'Gene', (106, 110))	('H3K27M tumors', 'Disease', (177, 190))	('IDH1', 'Gene', '3417', (106, 110))	('G34R/V', 'Mutation', 'rs1057519902', (62, 68))	('H3K27M tumors', 'Disease', 'MESH:D009369', (177, 190))	('MGMT', 'Gene', '4255', (0, 4))
89867	28966033	Total methylation was lowest in H3G34R/V (median beta value 0.452), and highest in the IDH subgroup (median beta value 0.520), as reported previously; however it was also found to be significantly elevated in PXA-like tumors (median beta value 0.501, p < 0.0001 t test) (Figure S2C).	('Total methylation', 'MPA', (0, 17))	('lowest', 'NegReg', (22, 28))	('H3G34R/V', 'Var', (32, 40))	('elevated', 'PosReg', (197, 205))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('IDH', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('IDH', 'Gene', '3417', (87, 90))	('G34R/V', 'Mutation', 'rs1057519902', (34, 40))	('highest', 'Reg', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))
89871	28966033	Common large-scale chromosomal alterations with prognostic significance included loss of 17p (n = 156), which targets TP53 at 17p13.1 and confers a shorter overall survival in tumors of all locations and all subgroups (Figure S3B), and gains of 9q (n = 108), more broadly encompassing a region of structural rearrangement on 9q34 in medulloblastoma, and correlating with shorter overall survival in multiple pHGG/DIPG subgroups (Figure S3C).	('alterations', 'Var', (31, 42))	('DIPG', 'Chemical', '-', (413, 417))	('gains', 'Var', (236, 241))	('shorter', 'NegReg', (371, 378))	('medulloblastoma', 'Disease', 'MESH:D008527', (333, 348))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('overall', 'MPA', (379, 386))	('pHGG', 'Chemical', '-', (408, 412))	('overall survival', 'MPA', (156, 172))	('medulloblastoma', 'Phenotype', 'HP:0002885', (333, 348))	('medulloblastoma', 'Disease', (333, 348))	('shorter', 'NegReg', (148, 155))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('TP53', 'Gene', (118, 122))	('TP53', 'Gene', '7157', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('loss', 'Var', (81, 85))
89874	28966033	Amplifications conferred a shorter overall survival, and CDKN2A/CDKN2B deletion a better prognosis, either across the whole cohort or selected subgroups (Figures S3B-S3G).	('better', 'PosReg', (82, 88))	('CDKN2A', 'Gene', (57, 63))	('shorter', 'NegReg', (27, 34))	('CDKN2B', 'Gene', (64, 70))	('deletion', 'Var', (71, 79))	('CDKN2A', 'Gene', '1029', (57, 63))	('Amplifications', 'Var', (0, 14))	('CDKN2B', 'Gene', '1030', (64, 70))	('overall survival', 'MPA', (35, 51))
89877	28966033	Applying GISTIC within these case sets revealed specific focal events enriched within individual subgroups, including AKT1 amplifications in H3.3G34R/V, MYC and CCND2 amplification in H3.3K27M, and MYCN/ID2, MDM4/PIK3C2B, and KRAS amplification in H3 WT (Figure 4B) (Table S4).	('KRAS', 'Gene', '3845', (226, 230))	('MYC', 'Gene', '4609', (198, 201))	('CCND2', 'Gene', (161, 166))	('MDM4', 'Gene', '4194', (208, 212))	('AKT1', 'Gene', '207', (118, 122))	('PIK3C2B', 'Gene', '5287', (213, 220))	('KRAS', 'Gene', (226, 230))	('ID2', 'Gene', '3398', (203, 206))	('CCND2', 'Gene', '894', (161, 166))	('ID2', 'Gene', (203, 206))	('MDM4', 'Gene', (208, 212))	('H3.3G34R/V', 'Var', (141, 151))	('MYC', 'Gene', (153, 156))	('AKT1', 'Gene', (118, 122))	('MYCN', 'Gene', '4613', (198, 202))	('K27M', 'Mutation', 'p.K27M', (188, 192))	('G34R/V', 'Mutation', 'rs1057519902', (145, 151))	('amplification', 'Var', (167, 180))	('MYC', 'Gene', (198, 201))	('MYC', 'Gene', '4609', (153, 156))	('amplifications', 'Var', (123, 137))	('PIK3C2B', 'Gene', (213, 220))	('MYCN', 'Gene', (198, 202))
89878	28966033	These latter events were generally restricted to hemispheric tumors, while MYCN/ID2 were enriched in H3 WT DIPG (Figure S4A).	('ID2', 'Gene', '3398', (80, 83))	('MYCN', 'Gene', (75, 79))	('tumors', 'Disease', (61, 67))	('MYCN', 'Gene', '4613', (75, 79))	('ID2', 'Gene', (80, 83))	('DIPG', 'Chemical', '-', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('H3 WT DIPG', 'Var', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
89879	28966033	H3.1K27M tumors generally lacked amplifications/deletions, but were instead characterized by frequent gains of 1q and the whole of chromosome 2, and the loss of 16q (Figure 4C).	('amplifications/deletions', 'MPA', (33, 57))	('H3.1K27M', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('loss', 'NegReg', (153, 157))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('16q', 'Protein', (161, 164))	('gains', 'PosReg', (102, 107))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('lacked', 'NegReg', (26, 32))
89880	28966033	PXA-like tumors had frequent CDKN2A/B deletions and a unique loss at 1q, associated with shorter overall survival within this group (Figure S4B).	('CDKN2A', 'Gene', (29, 35))	('CDKN2A', 'Gene', '1029', (29, 35))	('overall survival', 'MPA', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('deletions', 'Var', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('loss', 'NegReg', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (89, 96))
89883	28966033	There were also four patients with three different somatic coding mutations identified (below), two truncating and one missense, three of which were in hemispheric tumors, and two with H3F3A G34R (Figure 5B).	('H3F3A', 'Gene', '3020', (185, 190))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('G34R', 'Mutation', 'rs1057519902', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('H3F3A', 'Gene', (185, 190))	('patients', 'Species', '9606', (21, 29))	('missense', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
89885	28966033	Within H3.3K27M tumors, we identified a recurrent amplification at 17p11.2 (n = 17; 170 kb to 11.96 Mb), across multiple platforms and significantly enriched in DIPGs, which appears to target TOP3A within these tumors (Figure 5D).	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('DIPGs', 'Disease', (161, 166))	('H3.3K27M', 'Var', (7, 15))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('K27M', 'Mutation', 'p.K27M', (11, 15))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('17p11.2', 'Gene', (67, 74))	('DIPGs', 'Chemical', 'MESH:C060938', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))
89887	28966033	We further identified a single somatic missense mutation (C658Y) in an additional case of DIPG, and, taken together, TOP3A alterations were mutually exclusive with ATRX deletion/mutations found in H3.3K27M DIPG (0/13).	('DIPG', 'Chemical', '-', (90, 94))	('C658Y', 'Mutation', 'rs1179727459', (58, 63))	('H3.3K27M', 'Var', (197, 205))	('DIPG', 'Chemical', '-', (206, 210))	('C658Y', 'Var', (58, 63))
89889	28966033	IDH1-mutant cases were again excluded (n = 14), with genetic profiles identical to that described in adults for astrocytic tumors (13/14 TP53, 7/14 ATRX mutations), and oligodendroglial tumors (1p19q co-deletion, TERT promoter, CIC, FUBP1 mutations) entirely absent (Figure S6C).	('TERT', 'Gene', (213, 217))	('mutations', 'Var', (239, 248))	('CIC', 'Gene', (228, 231))	('FUBP1', 'Gene', (233, 238))	('astrocytic tumors', 'Disease', (112, 129))	('TERT', 'Gene', '7015', (213, 217))	('IDH1', 'Gene', (0, 4))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (169, 192))	('astrocytic tumors', 'Disease', 'MESH:D001254', (112, 129))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('IDH1', 'Gene', '3417', (0, 4))	('TP53', 'Gene', (137, 141))	('FUBP1', 'Gene', '8880', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('1p19q', 'Gene', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TP53', 'Gene', '7157', (137, 141))	('oligodendroglial tumors', 'Disease', (169, 192))
89891	28966033	As well as known associations such as hemispheric H3.3G34R/V and TP53/ATRX (18/20, 90%; p = 0.0001), midline H3.3K27M and FGFR1 (8/39, 20.5%; p = 0.212, not significant), pontine H3.1K27M and ACVR1 (28/33, 84.8%; p < 0.0001), and PXA-like GBM with BRAF V600E (17/28, 60.7%; p < 0.0001), we also identified previously unrecognized co-segregating mutations including H3.3G34R/V and ARID1B (2/20, 10%; p = 0.0720), H3.3K27M DIPG and ATM and ASXL1 (5/93, 10.7%; p = 0.0473), and H3.1K27M and BCOR (6/37, 16.2%; p = 0.0022, all Fisher's exact test) (Figure S6D).	('K27M', 'Mutation', 'p.K27M', (113, 117))	('H3.3K27M DIPG', 'Var', (412, 425))	('TP53', 'Gene', '7157', (65, 69))	('G34R/V', 'Mutation', 'rs1057519902', (54, 60))	('K27M', 'Mutation', 'p.K27M', (416, 420))	('ACVR1', 'Gene', '90', (192, 197))	('ATM', 'Gene', (430, 433))	('K27M', 'Mutation', 'p.K27M', (183, 187))	('ARID1B', 'Gene', (380, 386))	('G34R/V', 'Mutation', 'rs1057519902', (369, 375))	('ARID1B', 'Gene', '57492', (380, 386))	('FGFR1', 'Gene', '2260', (122, 127))	('TP53', 'Gene', (65, 69))	('ASXL1', 'Gene', '171023', (438, 443))	('DIPG', 'Chemical', '-', (421, 425))	('H3.1K27M', 'Var', (475, 483))	('H3.3G34R/V', 'Var', (365, 375))	('ATM', 'Gene', '472', (430, 433))	('V600E', 'Mutation', 'rs113488022', (253, 258))	('ASXL1', 'Gene', (438, 443))	('BCOR', 'Gene', '54880', (488, 492))	('FGFR1', 'Gene', (122, 127))	('ACVR1', 'Gene', (192, 197))	('BRAF', 'Gene', '673', (248, 252))	('K27M', 'Mutation', 'p.K27M', (479, 483))	('BCOR', 'Gene', (488, 492))	('BRAF', 'Gene', (248, 252))
89893	28966033	These included well-recognized pathways such as DNA repair (198/326, 60.7%), largely driven by TP53 mutations (n = 160), but also by common mutually exclusive (p < 0.0001, Fisher's exact test) activating truncating alterations in PPM1D (n = 18), as well as heterozygous mutations in a diverse set of genes including those involved in homologous recombination (ATM, BRCA2, BLM, ATR, PALB2, RAD50, and RAD51C) and numerous Fancomi anemia genes (BRIP1, FANCM, FANCA, and FANCG), among others (Figure S7A).	('FANCA', 'Gene', (457, 462))	('ATR', 'Gene', '545', (377, 380))	('RAD51C', 'Gene', (400, 406))	('ATM', 'Gene', (360, 363))	('FANCG', 'Gene', (468, 473))	('BRIP1', 'Gene', '83990', (443, 448))	('PPM1D', 'Gene', (230, 235))	('BRCA2', 'Gene', (365, 370))	('RAD50', 'Gene', (389, 394))	('truncating alterations', 'Var', (204, 226))	('numerous Fancomi anemia', 'Disease', (412, 435))	('FANCM', 'Gene', '57697', (450, 455))	('TP53', 'Gene', '7157', (95, 99))	('numerous Fancomi anemia', 'Disease', 'MESH:D000740', (412, 435))	('BLM', 'Gene', (372, 375))	('FANCM', 'Gene', (450, 455))	('ATR', 'Gene', (377, 380))	('RAD50', 'Gene', '10111', (389, 394))	('BRCA2', 'Gene', '675', (365, 370))	('FANCA', 'Gene', '2175', (457, 462))	('FANCG', 'Gene', '2189', (468, 473))	('BRIP1', 'Gene', (443, 448))	('BLM', 'Gene', '641', (372, 375))	('PALB2', 'Gene', (382, 387))	('ATM', 'Gene', '472', (360, 363))	('mutations', 'Var', (100, 109))	('RAD51C', 'Gene', '5889', (400, 406))	('PPM1D', 'Gene', '8493', (230, 235))	('activating', 'PosReg', (193, 203))	('PALB2', 'Gene', '79728', (382, 387))	('anemia', 'Phenotype', 'HP:0001903', (429, 435))	('TP53', 'Gene', (95, 99))
89894	28966033	Although TP53 is almost always found in concert with H3.3G34R/V in the cerebral hemispheres, these additional DNA repair pathway mutations were enriched in H3.3K27M DIPG (36/68, 52.9%).	('DNA repair pathway', 'Pathway', (110, 128))	('G34R/V', 'Mutation', 'rs1057519902', (57, 63))	('TP53', 'Gene', '7157', (9, 13))	('H3.3K27M DIPG', 'Var', (156, 169))	('TP53', 'Gene', (9, 13))	('DIPG', 'Chemical', '-', (165, 169))
89895	28966033	Also co-segregating with H3.3G34R/V and TP53 is ATRX, although mutations/deletions of the latter gene are also frequently found in conjunction with H3.3K27M (28/54, 51.8%).	('TP53', 'Gene', '7157', (40, 44))	('G34R/V', 'Mutation', 'rs1057519902', (29, 35))	('TP53', 'Gene', (40, 44))	('mutations/deletions', 'Var', (63, 82))
89896	28966033	ATRX accounts for a large proportion of the cases harboring mutations in genes coding for chromatin modifiers (54/118, 45.8%); however, there is a diverse set of readers, writers, and erasers also targeted at lower frequency, especially in DIPG, including the previously mentioned BCOR (n = 14) and ASXL1 (n = 6) in addition to SETD2 (n = 8), KDM6B (n = 6), SETD1B (n = 5), and ARID1B (n = 5) among many others (Figure S7B).	('SETD2', 'Gene', '29072', (328, 333))	('SETD1B', 'Gene', '23067', (358, 364))	('KDM6B', 'Gene', (343, 348))	('SETD2', 'Gene', (328, 333))	('DIPG', 'Gene', (240, 244))	('SETD1B', 'Gene', (358, 364))	('BCOR', 'Gene', '54880', (281, 285))	('ARID1B', 'Gene', '57492', (378, 384))	('ASXL1', 'Gene', '171023', (299, 304))	('BCOR', 'Gene', (281, 285))	('KDM6B', 'Gene', '23135', (343, 348))	('mutations', 'Var', (60, 69))	('DIPG', 'Chemical', '-', (240, 244))	('ARID1B', 'Gene', (378, 384))	('ASXL1', 'Gene', (299, 304))
89897	28966033	While CDKN2A/CDKN2B deletions were almost entirely absent from DIPG (1/154, 0.65%), dysregulation of the G1/S cell-cycle checkpoint was common throughout anatomical locations and subgroups (82/326, 25.2%), with amplifications of CCND2 and deletions of CDKN2C predominating in the pons (n = 5/7 and 5/5 DIPG, respectively), in contrast to recurrent homozygous RB1 deletions and CDK6 amplifications (n = 6/7 and 4/6 hemispheric) (Figure S4A) (Figure S7C).	('DIPG', 'Chemical', '-', (302, 306))	('CCND2', 'Gene', (229, 234))	('deletions', 'Var', (363, 372))	('CDK6', 'Gene', (377, 381))	('CDK6', 'Gene', '1021', (377, 381))	('RB1', 'Gene', (359, 362))	('CCND2', 'Gene', '894', (229, 234))	('CDKN2B', 'Gene', '1030', (13, 19))	('CDKN2C', 'Gene', '1031', (252, 258))	('CDKN2B', 'Gene', (13, 19))	('RB1', 'Gene', '5925', (359, 362))	('CDKN2A', 'Gene', (6, 12))	('CDKN2A', 'Gene', '1029', (6, 12))	('deletions', 'Var', (239, 248))	('DIPG', 'Chemical', '-', (63, 67))	('CDKN2C', 'Gene', (252, 258))
89898	28966033	In total, 201/326 (61.7%) cases harbored alterations in any given node; however, for H3.3G34R/V this was predominantly at the RTK level (11/20, n = 9 PDGFRA) (Figure S7D), whereas H3.1K27M cases were enriched for PI3K/mTOR alterations (17/37, n = 9 PIK3CA, n = 5 PIK3R1) (Figure S7E), and H3 WT cases harbored the highest frequency of MAPK alterations (mainly BRAF V600E in PXA-like, n = 5/10 plus one NF1) (Figure S7F).	('PIK3CA', 'Gene', (249, 255))	('V600E', 'Mutation', 'rs113488022', (365, 370))	('PIK3CA', 'Gene', '5290', (249, 255))	('MAPK', 'Gene', (335, 339))	('mTOR', 'Gene', '2475', (218, 222))	('H3.3G34R/V', 'Var', (85, 95))	('PIK3R1', 'Gene', '5295', (263, 269))	('BRAF', 'Gene', (360, 364))	('mTOR', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (360, 364))	('PIK3R1', 'Gene', (263, 269))	('NF1', 'Gene', '4763', (402, 405))	('K27M', 'Mutation', 'p.K27M', (184, 188))	('NF1', 'Gene', (402, 405))	('PDGFRA', 'Gene', '5156', (150, 156))	('PDGFRA', 'Gene', (150, 156))
89899	28966033	NRTK1-NRTK3 fusions were enriched in the infant group (4/6 fusions under 1 year old, median age 3.25 versus 8.5 years, p = 0.00033, t test) (Figure S7D).	('fusions', 'Var', (12, 19))	('infant', 'Species', '9606', (41, 47))	('NRTK1-NRTK3', 'Gene', (0, 11))
89900	28966033	We further identified mutations in genes regulating mTOR signaling, including TSC2 (n = 3), RPTOR, and MTOR itself (both n = 2), as well as a diverse series of SNVs and fusion candidates in MAPKs across all subgroups and locations (MAP2K7, MAP3K15, MAP3K4 and others) (Figure S7F).	('RPTOR', 'Gene', (92, 97))	('MAP3K4', 'Gene', (249, 255))	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('MTOR', 'Gene', '2475', (103, 107))	('RPTOR', 'Gene', '57521', (92, 97))	('MAPKs', 'Gene', (190, 195))	('MAP3K15', 'Gene', '389840', (240, 247))	('MAP2K7', 'Gene', (232, 238))	('MAP2K7', 'Gene', '5609', (232, 238))	('TSC2', 'Gene', '7249', (78, 82))	('mutations', 'Var', (22, 31))	('MAP3K15', 'Gene', (240, 247))	('MAP3K4', 'Gene', '4216', (249, 255))	('TSC2', 'Gene', (78, 82))	('MTOR', 'Gene', (103, 107))
89901	28966033	BMP signaling was significantly enriched in H3.1K27M DIPG due to the strong correlation with ACVR1 mutations; however, alterations in other pathway members such as amplification of ID2 (n = 10) or ID3 (n = 3) and mutations in BMP3 (n = 5), BMP2K (n = 3), and others across locations and subgroups, extends the proportion of tumors for which this pathway may be relevant (62/326, 18.7%) (Figure S7G).	('BMP', 'Gene', (0, 3))	('DIPG', 'Chemical', '-', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('ACVR1', 'Gene', (93, 98))	('BMP', 'Gene', '651', (240, 243))	('ID3', 'Gene', '3399', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('BMP', 'Gene', '651', (0, 3))	('tumors', 'Disease', (324, 330))	('K27M', 'Mutation', 'p.K27M', (48, 52))	('mutations', 'Var', (213, 222))	('ACVR1', 'Gene', '90', (93, 98))	('BMP', 'Gene', (226, 229))	('BMP3', 'Gene', (226, 230))	('ID3', 'Gene', (197, 200))	('BMP2K', 'Gene', (240, 245))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('alterations', 'Var', (119, 130))	('BMP', 'Gene', (240, 243))	('ID2', 'Gene', '3398', (181, 184))	('BMP', 'Gene', '651', (226, 229))	('mutations', 'Var', (99, 108))	('ID2', 'Gene', (181, 184))	('BMP2K', 'Gene', '55589', (240, 245))	('BMP3', 'Gene', '651', (226, 230))
89903	28966033	Uniquely, the accumulated data uncovered a series of additional processes involved in maintenance of DNA replication, genome integrity, or transcriptional fidelity, targeted by infrequent but mutually exclusive alterations in pHGG and DIPG.	('pHGG', 'Chemical', '-', (226, 230))	('pHGG', 'Gene', (226, 230))	('DIPG', 'Chemical', '-', (235, 239))	('alterations', 'Var', (211, 222))	('DIPG', 'Gene', (235, 239))
89904	28966033	These included mutations in splicing factors (SF3A1, SF3A2, SF3A3, SF3B1, SF3B2, and SF3B3, total n = 10), sister chromatid segregation (STAG2, STAG3, and ESPL1, total n = 9), pre-miRNA processing (DICER and DROSHA, total n = 4), DNA polymerases (POLK, POLQ, and POLR1B, total n = 4), as well as genes involved in centromere (CENPB, n = 3) and telomere maintenance (PML, n = 2; TERT, n = 7) (Figure S7I).	('CENPB', 'Gene', (326, 331))	('SF3A2', 'Gene', (53, 58))	('SF3B2', 'Gene', (74, 79))	('SF3A3', 'Gene', (60, 65))	('sister chromatid segregation', 'CPA', (107, 135))	('SF3A3', 'Gene', '10946', (60, 65))	('DICER', 'Gene', (198, 203))	('POLQ', 'Gene', '10721', (253, 257))	('POLK', 'Gene', '51426', (247, 251))	('STAG2', 'Gene', (137, 142))	('DNA', 'Enzyme', (230, 233))	('SF3A1', 'Gene', (46, 51))	('CENPB', 'Gene', '1059', (326, 331))	('SF3B1', 'Gene', '23451', (67, 72))	('mutations', 'Var', (15, 24))	('TERT', 'Gene', (378, 382))	('PML', 'Gene', (366, 369))	('TERT', 'Gene', '7015', (378, 382))	('DROSHA', 'Gene', '29102', (208, 214))	('POLK', 'Gene', (247, 251))	('DROSHA', 'Gene', (208, 214))	('SF3B3', 'Gene', '23450', (85, 90))	('ESPL1', 'Gene', '9700', (155, 160))	('POLQ', 'Gene', (253, 257))	('STAG3', 'Gene', (144, 149))	('POLR1B', 'Gene', '84172', (263, 269))	('POLR1B', 'Gene', (263, 269))	('PML', 'Gene', '5371', (366, 369))	('DICER', 'Gene', '23405', (198, 203))	('SF3B2', 'Gene', '10992', (74, 79))	('ESPL1', 'Gene', (155, 160))	('SF3B3', 'Gene', (85, 90))	('SF3A2', 'Gene', '8175', (53, 58))	('SF3A1', 'Gene', '10291', (46, 51))	('STAG3', 'Gene', '10734', (144, 149))	('STAG2', 'Gene', '10735', (137, 142))	('SF3B1', 'Gene', (67, 72))
89905	28966033	TERT promoter mutations were found in 5/326 (1.5%) cases; however, alternative lengthening of telomeres (ALT) status was only available for 26 cases, although the 5 ALT-positive samples (19.2%) were mutually exclusive with TERT alterations.	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', (223, 227))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', '7015', (223, 227))	('mutations', 'Var', (14, 23))
89913	28966033	These tumors were driven by BRAF V600E, NF1 mutations, or fusions in RTKs including MET, FGFR2, and NTRK2,3 (Figure 8D).	('MET', 'Gene', (84, 87))	('FGFR2', 'Gene', '2263', (89, 94))	('BRAF', 'Gene', '673', (28, 32))	('driven', 'Reg', (18, 24))	('NTRK2', 'Gene', '4915', (100, 105))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('NF1', 'Gene', (40, 43))	('tumors', 'Disease', (6, 12))	('RTKs', 'Gene', (69, 73))	('fusions', 'Var', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (44, 53))	('NTRK2', 'Gene', (100, 105))	('NF1', 'Gene', '4763', (40, 43))	('BRAF', 'Gene', (28, 32))	('FGFR2', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
89917	28966033	A second group of tumors (WT-B) were found in all anatomical compartments, and were distinguished by chromosome 2 gains (Figure 8C) and, most notably, by high-level amplifications in EGFR, CDK6, and MYCN (p = 0.00033, p = 0.0299, p = 0.00037, respectively, Fisher's exact test), with an imperfect overlay to the classifier "GBM_pedRTK" and "GBM_MYCN" groups (Figure 8D).	('MYCN', 'Gene', (199, 203))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('gains', 'PosReg', (114, 119))	('amplifications', 'Var', (165, 179))	('MYCN', 'Gene', '4613', (199, 203))	('tumors', 'Disease', (18, 24))	('CDK6', 'Gene', (189, 193))	('MYCN', 'Gene', (345, 349))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('CDK6', 'Gene', '1021', (189, 193))	('MYCN', 'Gene', '4613', (345, 349))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
89920	28966033	This group was enriched for chromosome 1p and 20q loss, 17q gain (p = 0.00595, p = 0.0286, p = 0.0478, respectively, Fisher's exact test) (Figure 8C), harbored PDGFRA and MET amplifications (p = 0.0159, Fisher's exact test) (Figure 8D), and was strongly associated with the adult GBM-defined "Proneural" gene signature.	('associated', 'Reg', (254, 264))	('loss', 'NegReg', (50, 54))	('PDGFRA', 'Gene', (160, 166))	('gain', 'PosReg', (60, 64))	('PDGFRA', 'Gene', '5156', (160, 166))	('MET', 'Var', (171, 174))
89925	28966033	In adults, the key distinction is between IDH1 mutant (G-CIMP/ATRX/TP53 or 1p19q co-deleted/TERT promoter mutated) and WT (classical, mesenchymal, PA-like), whereas in the childhood setting IDH1 mutations were restricted to a small proportion (6.25%) of tumors mostly in adolescents (representing the tail end of an overwhelmingly adult disease), and harbored only rare examples of the common alterations seen in WT adult GBM (e.g., 4.9% EGFR mutation/amplification).	('1p19q', 'Var', (75, 80))	('TERT', 'Gene', (92, 96))	('tumors', 'Disease', (254, 260))	('TERT', 'Gene', '7015', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('IDH1', 'Gene', (190, 194))	('IDH1', 'Gene', '3417', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('IDH1', 'Gene', '3417', (190, 194))	('EGFR', 'Gene', '1956', (438, 442))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('IDH1', 'Gene', (42, 46))	('EGFR', 'Gene', (438, 442))	('mutant', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
89926	28966033	Instead, most prominent among the differences between pediatric and adult studies is the frequency of hotspot mutations in genes encoding histone H3 variants: 2/820 (0.2%) in adults versus 449/893 (50.3%) in the present pHGG/DIPG series.	('variants', 'Var', (149, 157))	('histone H3', 'Protein', (138, 148))	('pHGG', 'Chemical', '-', (220, 224))	('DIPG', 'Chemical', '-', (225, 229))
89927	28966033	The importance of recurrent H3 mutations in the childhood setting has become increasingly clear since their unexpected discovery in 2012, with clear clinicopathological differences associated with distinct variants, and fundamental insights into mechanisms of epigenetically linked tumorigenesis.	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))
89928	28966033	Data from such a large series of tumors demonstrates the robustness of the histone-defined subgroups in terms of anatomical location, age of incidence, clinical outcome, methylation and gene expression profiles, copy-number changes, co-segregating somatic mutations, and pathway dysregulation.	('copy-number changes', 'Var', (212, 231))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('methylation', 'Var', (170, 181))
89930	28966033	H3.3G34R/V-mutant tumors are restricted to the cerebral hemispheres and co-segregate with ATRX and TP53 mutations; they are also the only pediatric subgroup to harbor frequent MGMT promoter methylation.	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('MGMT', 'Gene', (176, 180))	('MGMT', 'Gene', '4255', (176, 180))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('ATRX', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (99, 103))	('H3.3G34R/V-mutant', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
89934	28966033	H3.3K27M tumors are found in two-thirds of DIPG and non-brainstem midline pHGG alike, where they are associated with a shorter overall survival in both locations, as well as in the small number of cases reported in the cortex.	('shorter', 'NegReg', (119, 126))	('H3.3K27M', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('DIPG', 'Chemical', '-', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('overall survival', 'MPA', (127, 143))	('pHGG', 'Chemical', '-', (74, 78))	('DIPG', 'Disease', (43, 47))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
89935	28966033	Although presumably reflecting a common or overlapping origin, the pattern of co-segregating mutations differ, e.g., PDGFRA alterations predominating in the pons, and FGFR1 variants being largely restricted to the thalamus.	('PDGFRA', 'Gene', (117, 123))	('FGFR1', 'Gene', (167, 172))	('PDGFRA', 'Gene', '5156', (117, 123))	('alterations', 'Var', (124, 135))	('FGFR1', 'Gene', '2260', (167, 172))	('variants', 'Var', (173, 181))
89936	28966033	Our analysis of more than 300 cases further identifies differential amplification of CCND2 (DIPG) and CDK4 (non-brainstem midline), and, most strikingly, an amplification at 17p11.2 involving TOP3A in H3.3K27M DIPG.	('amplification', 'MPA', (68, 81))	('H3.3K27M DIPG', 'Var', (201, 214))	('DIPG', 'Chemical', '-', (92, 96))	('CCND2', 'Gene', (85, 90))	('DIPG', 'Chemical', '-', (210, 214))	('CDK4', 'Gene', (102, 106))	('K27M', 'Mutation', 'p.K27M', (205, 209))	('CDK4', 'Gene', '1019', (102, 106))	('CCND2', 'Gene', '894', (85, 90))
89939	28966033	Notably, TOP3A amplification/mutation was found to be mutually exclusive with ATRX mutation in H3.3K27M DIPG, with depletion by small interfering RNA reducing ALT cell survival, and therefore represents a potential therapeutic target in this subgroup.	('ATRX', 'Gene', (78, 82))	('depletion', 'MPA', (115, 124))	('TOP3A', 'Gene', (9, 14))	('reducing', 'NegReg', (150, 158))	('K27M', 'Mutation', 'p.K27M', (99, 103))	('mutation', 'Var', (83, 91))	('ALT cell survival', 'CPA', (159, 176))	('DIPG', 'Chemical', '-', (104, 108))	('H3.3K27M DIPG', 'Var', (95, 108))
89940	28966033	H3.1K27M tumors by contrast are restricted to the pons, patients are younger and with a slightly longer survival, and are largely defined at the copy-number level by whole chromosomal arm gains and losses.	('patients', 'Species', '9606', (56, 64))	('H3.1K27M', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('longer', 'PosReg', (97, 103))
89941	28966033	They have the well-recognized association with ACVR1 mutation; however, we also identify an enrichment of downstream PI3K pathway mutations (PIK3CA and PIK3R1) in comparison with the largely upstream RTK alterations present in H3.3K27M DIPGs, important in designing stratified trials and combinatorial therapies.	('ACVR1', 'Gene', (47, 52))	('ACVR1', 'Gene', '90', (47, 52))	('PIK3CA', 'Gene', (141, 147))	('mutations', 'Var', (130, 139))	('PIK3R1', 'Gene', '5295', (152, 158))	('DIPGs', 'Chemical', 'MESH:C060938', (236, 241))	('PIK3CA', 'Gene', '5290', (141, 147))	('PIK3R1', 'Gene', (152, 158))	('K27M', 'Mutation', 'p.K27M', (231, 235))
89942	28966033	Further association with mutations of the BCL6 repressor gene BCOR, commonly altered in medulloblastomas, neuroepithelial tumors, and sarcomas, highlights a further avenue for interventional study through its regulation of the SHH pathway.	('medulloblastoma', 'Phenotype', 'HP:0002885', (88, 103))	('SHH', 'Gene', (227, 230))	('BCL6', 'Gene', '604', (42, 46))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (106, 128))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('mutations', 'Var', (25, 34))	('sarcomas', 'Disease', (134, 142))	('altered', 'Reg', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('neuroepithelial tumors', 'Disease', (106, 128))	('medulloblastomas', 'Disease', (88, 104))	('BCOR', 'Gene', '54880', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('SHH', 'Gene', '6469', (227, 230))	('BCOR', 'Gene', (62, 66))	('BCL6', 'Gene', (42, 46))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (106, 128))	('medulloblastomas', 'Disease', 'MESH:D008527', (88, 104))
89944	28966033	These had already been strongly linked with dysregulation of the MAPK pathway (BRAF V600E) along with CDKN2A/CDKN2B deletion.	('MAPK pathway', 'Pathway', (65, 77))	('V600E', 'Mutation', 'rs113488022', (84, 89))	('CDKN2A', 'Gene', (102, 108))	('dysregulation', 'MPA', (44, 57))	('deletion', 'Var', (116, 124))	('CDKN2B', 'Gene', (109, 115))	('CDKN2B', 'Gene', '1030', (109, 115))	('BRAF', 'Gene', '673', (79, 83))	('linked', 'Reg', (32, 38))	('CDKN2A', 'Gene', '1029', (102, 108))	('BRAF', 'Gene', (79, 83))
89945	28966033	However, with molecular markers such as losses at 1q and 17p appearing to confer a worse outcome there may be more than one subgroup within this entity, and a co-clustering group of H3/IDH1 WT tumors appeared distinctly driven by somatic NF1 mutation.	('NF1', 'Gene', '4763', (238, 241))	('driven by', 'Reg', (220, 229))	('H3/IDH1 WT tumors', 'Disease', (182, 199))	('H3/IDH1 WT tumors', 'Disease', 'MESH:C536751', (182, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('losses at 1q', 'Var', (40, 52))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mutation', 'Var', (242, 250))	('NF1', 'Gene', (238, 241))
89968	28966033	Simplified methylation subgroup assignments were then made to incorporate cases carrying G34R/V or K27M mutations in H3 histones, IDH1 mutation at R132, low grade glioma-like profiles (predominantly diffuse infantile ganglioglioma and pilocytic astrocytoma) and those similar to pleomorphic xanthoastrocytoma (PXA).	('G34R', 'SUBSTITUTION', 'None', (89, 93))	('glioma', 'Disease', (163, 169))	('K27M mutations', 'Var', (99, 113))	('H3 histones', 'Protein', (117, 128))	('K27M', 'Mutation', 'p.K27M', (99, 103))	('G34R', 'Var', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('IDH1', 'Gene', '3417', (130, 134))	('ganglioglioma and pilocytic astrocytoma', 'Disease', 'MESH:D001254', (217, 256))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Disease', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('mutation at R132', 'Var', (135, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (245, 256))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (279, 308))	('IDH1', 'Gene', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('infant', 'Species', '9606', (207, 213))	('astrocytoma', 'Phenotype', 'HP:0009592', (297, 308))	('pleomorphic xanthoastrocytoma', 'Disease', (279, 308))
89974	28966033	Somatic variants were identified in regions covered by at least 10 reads in normal and tumor sequences carrying at least 3 variant reads in the tumor and less than 2 in normal sequences.	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('variant', 'Var', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
89975	28966033	Hotspot TERT promoter mutations C228T and C250T were incidentally captured by the various exome platforms as they are located only 114 and 146 bp upstream of the translation start site, and were called even if only covered by a few reads.	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('C228T', 'Mutation', 'c.228C>T', (32, 37))	('C250T', 'Mutation', 'c.250C>T', (42, 47))	('C250T', 'Var', (42, 47))	('C228T', 'Var', (32, 37))
90002	26978735	The aberrant expression of miRNAs has been identified in many diseases, including tumors, and its expression profiles are different in different types of tumor.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('identified', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (154, 159))
90075	26978735	Many genetic and epigenetic alterations have been demonstrated during tumorigenesis.	('tumor', 'Disease', (70, 75))	('epigenetic alterations', 'Var', (17, 39))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
90087	26978735	Indeed, aberrant miR-182 in some tumors is correlated to tumor size, lymph node metastasis, and advanced TNM stage.	('TNM', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('miR-182', 'Gene', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('correlated', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('aberrant', 'Var', (8, 16))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', (33, 38))	('TNM', 'Gene', '10178', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('miR-182', 'Gene', '406958', (17, 24))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', (33, 39))	('lymph node metastasis', 'CPA', (69, 90))
90107	26978735	Since miR-182 may be involved in the early stages of glioma, the blockage of miR-182 may effectively disturb the tumorigenesis and be a potential therapeutic target; therefore, the inhibition of miR-182 may improve glioma outcome.	('disturb', 'NegReg', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('miR-182', 'Gene', (77, 84))	('miR-182', 'Gene', '406958', (77, 84))	('miR-182', 'Gene', (6, 13))	('miR-182', 'Gene', '406958', (6, 13))	('tumor', 'Disease', (113, 118))	('inhibition', 'Var', (181, 191))	('miR-182', 'Gene', (195, 202))	('glioma', 'Disease', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('miR-182', 'Gene', '406958', (195, 202))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('blockage', 'Var', (65, 73))	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('improve', 'PosReg', (207, 214))
90145	20346134	For example, we detected the incorporation ratio of Leu-d3 labeling in a representative Leu-containing peptide (SYELPDGQVITIGNER) of beta-actin.	('Leu-d3', 'Chemical', '-', (52, 58))	('beta-actin', 'Gene', '728378', (133, 143))	('Leu', 'Chemical', 'MESH:D007930', (52, 55))	('beta-actin', 'Gene', (133, 143))	('Leu', 'Chemical', 'MESH:D007930', (88, 91))	('incorporation', 'MPA', (29, 42))	('Leu-d3 labeling', 'Var', (52, 67))
90146	20346134	Because the normal L-leucine (Leu-d0) was gradually replaced with the Leu-d3 into beta-actin during cell growth, the ratio of peptide intensity of the Leu-d3-labeling peptide versus Leu-d0- containing peptide was steadily increased (Figure 1).	('Leu-d3', 'Chemical', '-', (151, 157))	('leucine', 'Chemical', 'MESH:D007930', (21, 28))	('peptide intensity', 'MPA', (126, 143))	('Leu-d3', 'Chemical', '-', (70, 76))	('Leu-d0', 'Chemical', '-', (30, 36))	('ratio', 'MPA', (117, 122))	('beta-actin', 'Gene', '728378', (82, 92))	('beta-actin', 'Gene', (82, 92))	('Leu-d0', 'Chemical', '-', (182, 188))	('increased', 'PosReg', (222, 231))	('Leu-d3-labeling', 'Var', (151, 166))
90157	20346134	Therefore, the HSP27 (IPI00025512), HSP A5 (IPI00003362) and HSP90AB1 (IPI00334775) respectively had 0.48, 0.58 and 0.64-fold downregulation in HGTs compared with that in PBTs.	('IPI00003362', 'Var', (44, 55))	('IPI00025512', 'Var', (22, 33))	('IPI00025512', 'Chemical', '-', (22, 33))	('HSP90AB1', 'Gene', (61, 69))	('downregulation', 'NegReg', (126, 140))	('IPI00003362', 'Chemical', '-', (44, 55))	('IPI00334775', 'Chemical', '-', (71, 82))	('HSP27', 'Gene', (15, 20))	('HSP90AB1', 'Gene', '3326', (61, 69))	('PBTs', 'Chemical', '-', (171, 175))	('HSP27', 'Gene', '3315', (15, 20))	('HSP A5', 'Gene', (36, 42))	('IPI00334775', 'Var', (71, 82))	('HGTs', 'Disease', (144, 148))	('HSP A5', 'Gene', '3309', (36, 42))
90172	20346134	Therefore, under heat shock treatment within 0-3 h, cell survival rate was gradiently diminished corresponding to the variation of HSP27 expression in H4 cells (Figure 7).	('expression', 'MPA', (137, 147))	('cell survival rate', 'CPA', (52, 70))	('HSP27', 'Gene', '3315', (131, 136))	('HSP27', 'Gene', (131, 136))	('shock', 'Phenotype', 'HP:0031273', (22, 27))	('diminished', 'NegReg', (86, 96))	('H4', 'CellLine', 'CVCL:6C19', (151, 153))	('variation', 'Var', (118, 127))
90190	20346134	For example, how did the expression variation of HSP27 regulate cell survival signaling, and it cooperated with other heat shock proteins, including HSPA9, HSP90AB1 and HSPA5?	('shock', 'Phenotype', 'HP:0031273', (123, 128))	('HSP90AB1', 'Gene', '3326', (156, 164))	('HSPA9', 'Gene', (149, 154))	('HSP27', 'Gene', '3315', (49, 54))	('HSP27', 'Gene', (49, 54))	('expression variation', 'Var', (25, 45))	('HSPA9', 'Gene', '3313', (149, 154))	('cell survival signaling', 'MPA', (64, 87))	('HSPA5', 'Gene', '3309', (169, 174))	('regulate', 'Reg', (55, 63))	('HSP90AB1', 'Gene', (156, 164))	('HSPA5', 'Gene', (169, 174))	('cooperated', 'Reg', (96, 106))
90193	20346134	Human glioma cell line H4 was cultured in isotope-labeling 1640 media with 10% dialyzed fetal bovine serum (FBS, GIBCO), which was supplemented with the Leu-d3 (L-leucine-5,5,5-D3, 98%; Cambridge Isotope Laboratories, Inc, U.K.) replaced normal Leu-d0.	('Human', 'Species', '9606', (0, 5))	('FBS', 'Disease', (108, 111))	('Leu-d0', 'Chemical', '-', (245, 251))	('Leu-d3', 'Chemical', '-', (153, 159))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('H4', 'CellLine', 'CVCL:6C19', (23, 25))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('FBS', 'Disease', 'MESH:D005198', (108, 111))	('bovine', 'Species', '9913', (94, 100))	('Leu-d3', 'Var', (153, 159))	('L-leucine-5,5,5-D3', 'Chemical', '-', (161, 179))	('glioma', 'Disease', (6, 12))
90233	32412186	ROC and TimeROC curves were plotted to compare the predictive ability of IDH mutation and the signature.	('mutation', 'Var', (77, 85))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', (73, 76))
90274	32412186	In the test dataset, patients with high five-microRNAs expression have shorter life span and are more likely to die than patients with low five-microRNAs expression (Figure 3B).	('high five-microRNAs expression', 'Var', (35, 65))	('patients', 'Species', '9606', (21, 29))	('life span', 'CPA', (79, 88))	('shorter', 'NegReg', (71, 78))	('patients', 'Species', '9606', (121, 129))
90277	32412186	Considering the important role of IDH mutation in the prognosis prediction of LGG, we performed ROC analysis and compared the area under the ROC curve (AUC) of IDH mutation and the five-microRNA signature to analyse their predictive power.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('mutation', 'Var', (164, 172))	('IDH', 'Gene', (160, 163))	('IDH', 'Gene', '3417', (160, 163))	('LGG', 'Disease', (78, 81))
90278	32412186	17 ,  18  After congregating the TCGA and CGGA sets of data, we found a total of 216 patients with IDH mutation information.	('mutation information', 'Var', (103, 123))	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', (99, 102))	('patients', 'Species', '9606', (85, 93))
90300	32412186	IDH mutations cause a change in enzyme activity, resulting in a large amount of 2-hydroxyglutarate (D2HG) being synthesized and accumulated.	('D2HG', 'Chemical', '-', (100, 104))	('IDH', 'Gene', (0, 3))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (80, 98))	('IDH', 'Gene', '3417', (0, 3))	('enzyme activity', 'MPA', (32, 47))	('accumulated', 'MPA', (128, 139))	('mutations', 'Var', (4, 13))	('change', 'Reg', (22, 28))
90301	32412186	Since the discovery of IDH mutations in diffuse lower-grade glioma, 22  studies have confirmed IDH could be a prognostic biomarker for glioma.	('mutations', 'Var', (27, 36))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('glioma', 'Disease', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', (60, 66))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (95, 98))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('IDH', 'Gene', '3417', (23, 26))
90330	30257451	Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs.	('IDH1', 'Gene', (72, 76))	('IDH1', 'Gene', (184, 188))	('IDH1', 'Gene', (169, 173))	('IDH1', 'Gene', '3417', (72, 76))	('IDH1', 'Gene', '3417', (184, 188))	('hypoxic conditions', 'Disease', 'MESH:D009135', (101, 119))	('IDH1', 'Gene', '3417', (169, 173))	('hypoxic conditions', 'Disease', (101, 119))	('mutant', 'Var', (64, 70))
90340	30257451	This gain of function mutation leads to the production of the onco-metabolite 2-hydroxyglutarate (2HG) which interferes with many pathways and its opposing appearance suggests that IDHmut and IDH1wt glioma are in fact biologically different tumor types.	('IDH', 'Gene', (181, 184))	('mutation', 'Var', (22, 30))	('many pathways', 'Pathway', (125, 138))	('gain of function', 'PosReg', (5, 21))	('tumor', 'Disease', (241, 246))	('IDH', 'Gene', '3417', (192, 195))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (78, 96))	('IDH', 'Gene', '3417', (181, 184))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('IDH1', 'Gene', '3417', (192, 196))	('IDH1', 'Gene', (192, 196))	('glioma', 'Disease', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('IDH', 'Gene', (192, 195))	('interferes', 'NegReg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
90343	30257451	Although the underlying mechanisms have not been fully elucidated the discovery of the IDH mutation had a fundamental impact on glioma research.	('mutation', 'Var', (91, 99))	('glioma', 'Disease', (128, 134))	('IDH', 'Gene', (87, 90))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('IDH', 'Gene', '3417', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('impact', 'Reg', (118, 124))
90356	30257451	A maintained 2HG secretion in the supernatant of all IDH1mut GSCs as a result of the IDH1 mutation could be confirmed by an enzymatic assay with concentrations ranging from 9.4-1792.1 microM, whereas in IDH1wt GSCs 2HG levels were below the detection limit (Table 1).	('IDH1', 'Gene', (53, 57))	('2HG secretion', 'MPA', (13, 26))	('IDH1', 'Gene', '3417', (85, 89))	('IDH1mut GSCs', 'Gene', '3417', (53, 65))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (85, 89))	('IDH1', 'Gene', (203, 207))	('mutation', 'Var', (90, 98))	('result', 'Reg', (71, 77))	('IDH1', 'Gene', '3417', (203, 207))	('IDH1mut GSCs', 'Gene', (53, 65))
90381	30257451	When including age, codel subtype and WHO grade in a multivariate Cox ph analysis we found that a high HRS-score is a highly significant predictor of shorter patient survival independent of age, codel status and WHO grade (Figure 5; HR 5.85 [95% CI 2.89, 11.83] vs. 1.92 [1.16, 3.17], 1.12 [0.65, 1.93], and 1.65 [0.96, 2,82], respectively).	('patient survival', 'CPA', (158, 174))	('Cox', 'Gene', '1351', (66, 69))	('patient', 'Species', '9606', (158, 165))	('high', 'Var', (98, 102))	('Cox', 'Gene', (66, 69))	('HRS', 'Disease', (103, 106))	('shorter', 'NegReg', (150, 157))	('HRS', 'Disease', 'MESH:D020191', (103, 106))
90385	30257451	The discovery of mutations in IDH genes in glioma as compared to their IDH wildtype counterpart has marked a fundamental milestone in the understanding of glioma biology.	('IDH', 'Gene', '3417', (30, 33))	('glioma', 'Disease', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (71, 74))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('mutations', 'Var', (17, 26))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('glioma', 'Disease', (155, 161))
90387	30257451	Most experimental models have synthetically introduced the IDH1 mutation into commonly used IDHwt cell lines such as U87MG or U251.	('IDH1', 'Gene', '3417', (59, 63))	('IDH', 'Gene', (59, 62))	('mutation', 'Var', (64, 72))	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', (92, 95))	('IDH1', 'Gene', (59, 63))	('U87MG', 'CellLine', 'CVCL:0022', (117, 122))	('IDH', 'Gene', '3417', (92, 95))
90388	30257451	A subsequent increase in HIF1alpha expression suggests a possible oncogenic mechanism of the IDH1 mutation by mimicking the tumorigenic effect of the hypoxic microenvironment.	('IDH1', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutation', 'Var', (98, 106))	('IDH1', 'Gene', '3417', (93, 97))	('tumor', 'Disease', (124, 129))	('HIF1alpha', 'Gene', (25, 34))	('expression', 'MPA', (35, 45))	('increase', 'PosReg', (13, 21))	('HIF1alpha', 'Gene', '3091', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
90389	30257451	In contrast, other groups have demonstrated that HIF1alpha or HIF1alpha-responsive genes are either not affected by an IDH mutation or even showed a decrease in the mRNA or protein expression.	('IDH', 'Gene', '3417', (119, 122))	('mutation', 'Var', (123, 131))	('HIF1alpha', 'Gene', (62, 71))	('mRNA or protein expression', 'MPA', (165, 191))	('HIF1alpha', 'Gene', (49, 58))	('HIF1alpha', 'Gene', '3091', (62, 71))	('IDH', 'Gene', (119, 122))	('decrease', 'NegReg', (149, 157))	('HIF1alpha', 'Gene', '3091', (49, 58))
90397	30257451	Using the LASSO algorithm, we were able to create a hypoxia-related survival score incorporating the regulation of five genes, whose upregulation (WNT6, OTP, and PLOD1) and downregulation (LYVE1 and FAM162A) show a worse survival in all molecular and histological subgroups (1p19q co-deletion status and WHO II/III, Supplementary Materials Figure S2).	('PLOD1', 'Gene', '5351', (162, 167))	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('WNT6', 'Gene', '7475', (147, 151))	('OTP', 'Gene', '23440', (153, 156))	('FAM162A', 'Gene', (199, 206))	('upregulation', 'PosReg', (133, 145))	('LYVE1', 'Gene', '10894', (189, 194))	('FAM162A', 'Gene', '26355', (199, 206))	('WNT6', 'Gene', (147, 151))	('LYVE1', 'Gene', (189, 194))	('OTP', 'Gene', (153, 156))	('hypoxia', 'Disease', (52, 59))	('PLOD1', 'Gene', (162, 167))	('1p19q co-deletion status', 'Var', (275, 299))	('downregulation', 'NegReg', (173, 187))
90405	30257451	Targeted deletion of LYVE1 resulted in a decrease of the capability of dendritic cells to prime CD8+ T cell responses in skin-draining lymph nodes.	('deletion', 'Var', (9, 17))	('decrease', 'NegReg', (41, 49))	('CD8', 'Gene', (96, 99))	('LYVE1', 'Gene', '10894', (21, 26))	('CD8', 'Gene', '925', (96, 99))	('LYVE1', 'Gene', (21, 26))
90409	30257451	Most importantly in the multivariate analysis the continuous HRS-score proved to be more robust in prognosticating survival than WHO grade or 1p19q co-deletion subtype in the LGG TCGA cohort as well as in the Rembrandt validation cohort.	('HRS', 'Disease', (61, 64))	('1p19q', 'Var', (142, 147))	('HRS', 'Disease', 'MESH:D020191', (61, 64))
90412	30257451	However, functional experiments investigating selected genes for their causality to tumorigenesis or the IDH mutation would be highly interesting and should be addressed in further studies.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('IDH', 'Gene', (105, 108))	('IDH', 'Gene', '3417', (105, 108))	('mutation', 'Var', (109, 117))
90552	24117271	If the patient is clinically stable and on <= 0.1 mg/kg/d decadron for at least one week, and a repeat MRI indicates that tumor size has returned to less than 25% above pre-event baseline, the patient may restart vaccine and Imiquimod treatment.	('patient', 'Species', '9606', (7, 14))	('<= 0.1', 'Var', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('decadron', 'Chemical', 'MESH:D003907', (58, 66))	('patient', 'Species', '9606', (193, 200))	('restart', 'PosReg', (205, 212))	('tumor', 'Disease', (122, 127))
90593	31981013	Thus, amino acid PET has higher tumor-to-background uptake (i.e.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('amino acid PET', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('higher', 'PosReg', (25, 31))	('tumor', 'Disease', (32, 37))
90599	31981013	Thus, we hypothesized serial changes in 18F-FDOPA PET combined with changes in MRI may be useful as a unique tool for predicting both malignant transformation as well as predicting residual survival in patients with LGG.	('LGG', 'Disease', (216, 219))	('18F-FDOPA', 'Protein', (40, 49))	('changes', 'Var', (29, 36))	('MRI', 'MPA', (79, 82))	('patients', 'Species', '9606', (202, 210))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (40, 49))	('malignant transformation', 'CPA', (134, 158))
90629	31981013	This patient had a WHO II, IDH1 mutant, MGMT methylated diffuse glioma with multi-parametric MR-PET imaging showing increasing tumor extent crossing the midline and an increasing focus of 18F-FDOPA PET uptake over a period of about 1.3 years while on temozolomide.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('focus', 'MPA', (179, 184))	('MGMT', 'Gene', '4255', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('met', 'Gene', '79811', (86, 89))	('met', 'Gene', (86, 89))	('increasing', 'PosReg', (116, 126))	('18F-FDOPA PET uptake', 'MPA', (188, 208))	('mutant', 'Var', (32, 38))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (188, 197))	('met', 'Gene', '79811', (45, 48))	('temozolomide', 'Chemical', 'MESH:D000077204', (251, 263))	('met', 'Gene', (45, 48))	('MGMT', 'Gene', (40, 44))	('glioma', 'Disease', (64, 70))	('IDH1', 'Gene', (27, 31))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('patient', 'Species', '9606', (5, 12))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('IDH1', 'Gene', '3417', (27, 31))
90631	31981013	This patient had a WHO II, IDH1 mutant, unmethylated, 1p19q codeleted oligodendroglioma with a small tumor burden and minimal PET uptake that was relatively stable over 1 year of evaluation while on temozolomide.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('1p19q', 'Var', (54, 59))	('patient', 'Species', '9606', (5, 12))	('oligodendroglioma', 'Disease', (70, 87))	('met', 'Gene', '79811', (42, 45))	('temozolomide', 'Chemical', 'MESH:D000077204', (199, 211))	('met', 'Gene', (42, 45))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('oligodendroglioma', 'Disease', 'MESH:D009837', (70, 87))	('mutant', 'Var', (32, 38))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
90634	31981013	Similarly, we did not observe any significant differences between IDH mutants and wild type gliomas (Fig.	('IDH', 'Gene', (66, 69))	('mutants', 'Var', (70, 77))	('IDH', 'Gene', '3417', (66, 69))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
90635	31981013	2C; FLAIR, P=0.6262, PET, P=0.9623), patients with 1p19q co-deletion and those without co-deletion (Fig.	('patients', 'Species', '9606', (37, 45))	('co-deletion', 'Var', (57, 68))	('1p19q co-deletion', 'Var', (51, 68))
90645	31981013	In patients with IDH status, MGMT methylation status, or 1p19q codeletion status available, no significant association was observed with OS (IDH, P=0.9986; MGMT, P=1.000; 1p19q, P=0.9990).	('IDH', 'Gene', '3417', (17, 20))	('met', 'Gene', (34, 37))	('IDH', 'Gene', (141, 144))	('1p19q', 'Var', (57, 62))	('MGMT', 'Gene', '4255', (156, 160))	('MGMT', 'Gene', '4255', (29, 33))	('MGMT', 'Gene', (156, 160))	('IDH', 'Gene', '3417', (141, 144))	('MGMT', 'Gene', (29, 33))	('patients', 'Species', '9606', (3, 11))	('IDH', 'Gene', (17, 20))	('met', 'Gene', '79811', (34, 37))
90650	31981013	Additionally, patients with increasing rate of both FLAIR volume and PET uptake had significantly shorter OS compared to patients with decreasing FLAIR volume or PET uptake (Fig.	('FLAIR volume', 'Var', (52, 64))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (121, 129))	('shorter', 'NegReg', (98, 105))	('PET uptake', 'Var', (69, 79))
90651	31981013	4C; Log-rank, P=0.0135, HR=2.354), suggesting the combination of both change in FLAIR volume and PET uptake may be meaningful for identifying patients at highest risk.	('patients', 'Species', '9606', (142, 150))	('change', 'Var', (70, 76))	('FLAIR volume', 'MPA', (80, 92))
90764	30735859	Overall, ADC values provided superior separation of low/high grade tumours, compared to CBF.	('ADC', 'Var', (9, 12))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
90768	30735859	However, when the 'whole tumour' ROI was used, particularly for ADCROI-mean/min, the AUC values were markedly lower than those obtained with the smaller ROIs (25 to 100 mm2, Fig.	('AUC values', 'MPA', (85, 95))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('lower', 'NegReg', (110, 115))	('ADCROI-mean/min', 'Var', (64, 79))	('tumour', 'Disease', (25, 31))
90770	30735859	Using combined ADCROI-mean and nCBFROI-max values, the model correctly classified low/high grade status for 92% of the tumours for reader 1, and 96% for reader 2.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('low/high', 'Var', (82, 90))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('tumours', 'Disease', (119, 126))
90771	30735859	Using combined ADCROI-min and nCBFROI-max values, the model correctly classified low/high grade status for 88% of the tumours for reader 1, and 92% for reader 2.	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (118, 125))	('low/high', 'Var', (81, 89))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))
90780	30735859	It has been suggested that regions which demonstrate T2 hypo-intensity in conjunction with postcontrast signal enhancement and diffusion restriction may represent focal anaplasia in these tumours, which may alleviate this issue in future studies.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('hypo-intensity', 'Var', (56, 70))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('T2 hypo-intensity', 'Var', (53, 70))	('tumours', 'Disease', 'MESH:D009369', (188, 195))	('tumours', 'Disease', (188, 195))	('anaplasia', 'Disease', 'MESH:D000708', (169, 178))	('anaplasia', 'Disease', (169, 178))
90809	30465868	The ROC analyses using MDF values resulted in an area under the curve (AUC) of 0.91 (sensitivity 86%, specificity 87%) for T2w FLAIR, 0.94 (87%, 89%) for ADC, 0.98 (93%, 95%) for T1w, and 0.88 (78%, 86%) for T1w+Gd sequences.	('T1w+Gd sequences', 'Var', (208, 224))	('T2w', 'Var', (123, 126))	('ADC', 'Gene', (154, 157))	('T1w', 'Var', (179, 182))	('ADC', 'Gene', '113451', (154, 157))
90812	30465868	Oligodendroglioma has reported to have longer survival than astrocytoma, and 1p/19q co-deletion is also associated with longer survival and is a predictive marker for response to chemotherapy.	('1p/19q co-deletion', 'Var', (77, 95))	('longer', 'PosReg', (120, 126))	('Oligodendroglioma', 'Disease', 'MESH:D009837', (0, 17))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('astrocytoma', 'Disease', 'MESH:D001254', (60, 71))	('astrocytoma', 'Disease', (60, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('Oligodendroglioma', 'Disease', (0, 17))
90819	30465868	The purpose of this study was to evaluate the feasibility of a clinically implementable texture analysis on preoperative MRI conventional images (T2w FLAIR, ADC, T1w and post-gadolinium T1w (T1w+Gd)) to discriminate between astrocytoma and 1p/19q codeleted oligodendroglioma.	('astrocytoma', 'Disease', 'MESH:D001254', (224, 235))	('1p/19q', 'Var', (240, 246))	('oligodendroglioma', 'Disease', (257, 274))	('astrocytoma', 'Disease', (224, 235))	('ADC', 'Gene', '113451', (157, 160))	('gadolinium', 'Chemical', 'MESH:D005682', (175, 185))	('astrocytoma', 'Phenotype', 'HP:0009592', (224, 235))	('oligodendroglioma', 'Disease', 'MESH:D009837', (257, 274))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('ADC', 'Gene', (157, 160))
90821	30465868	The inclusion criteria were: (1) Pathologically-proven (after resection or biopsy) grade II astrocytoma or oligodendroglioma, based on morphologic and genetic analysis regarding IDH and 1p/19q codeletion status, according to the 2016 WHO tumor classification; (2) a pre-operative MRI scan that included T2w FLAIR, ADC, T1w or T1w+Gd sequences.	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('IDH', 'Gene', '3417', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('II astrocytoma', 'Disease', (89, 103))	('oligodendroglioma', 'Disease', (107, 124))	('II astrocytoma', 'Disease', 'MESH:D001254', (89, 103))	('T1w+Gd sequences', 'Var', (326, 342))	('oligodendroglioma', 'Disease', 'MESH:D009837', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('ADC', 'Gene', (314, 317))	('T1w', 'Var', (319, 322))	('tumor', 'Disease', (238, 243))	('ADC', 'Gene', '113451', (314, 317))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('T2w FLAIR', 'Var', (303, 312))	('IDH', 'Gene', (178, 181))
90830	30465868	All segmented ROIs for each image slice on T2w FLAIR, ADC, T1w and T1w+Gd images were loaded into the MaZda package to perform texture analysis; as many as 279 features were generated within each ROI.	('ADC', 'Gene', '113451', (54, 57))	('ADC', 'Gene', (54, 57))	('T2w', 'Var', (43, 46))
90832	30465868	ROIs for T2w FLAIR, ADC, T1w and T1w+Gd images in the testing data were loaded into the MaZda software and processed in the same way as the training data in order to generate the 279 features.	('T1w+Gd', 'Var', (33, 39))	('ADC', 'Gene', '113451', (20, 23))	('T2w', 'Var', (9, 12))	('T1w', 'Var', (25, 28))	('ADC', 'Gene', (20, 23))
90833	30465868	The MDF values and 9 histogram parameters were used to classify the testing samples into a specified group (astrocytoma or 1p/19q codeleted oligodendroglioma) based on the optimal cutoff value predefined in the training data.	('oligodendroglioma', 'Disease', 'MESH:D009837', (140, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('astrocytoma', 'Disease', 'MESH:D001254', (108, 119))	('astrocytoma', 'Disease', (108, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('oligodendroglioma', 'Disease', (140, 157))	('1p/19q', 'Var', (123, 129))
90836	30465868	Detailed group information for the T2w FLAIR, ADC, T1w and T1w+Gd sequences is shown in Fig.	('ADC', 'Gene', '113451', (46, 49))	('ADC', 'Gene', (46, 49))	('T1w+Gd', 'Var', (59, 65))
90837	30465868	In the training data set, the MDF values generated from the LDA model when performing B11 analysis were significantly different between astrocytoma and 1p/19q codeleted oligodendroglioma (all p<0.001).	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('oligodendroglioma', 'Disease', (169, 186))	('astrocytoma', 'Disease', 'MESH:D001254', (136, 147))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('different', 'Reg', (118, 127))	('1p/19q', 'Var', (152, 158))	('astrocytoma', 'Disease', (136, 147))	('oligodendroglioma', 'Disease', 'MESH:D009837', (169, 186))
90841	30465868	Our study demonstrated that texture analysis performed on conventional preoperative MRI images has high sensitivity, specificity, and accuracy in discriminating between astrocytoma and 1p/19q codeleted oligodendroglioma.	('oligodendroglioma', 'Disease', (202, 219))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('1p/19q', 'Var', (185, 191))	('astrocytoma', 'Disease', 'MESH:D001254', (169, 180))	('oligodendroglioma', 'Disease', 'MESH:D009837', (202, 219))	('astrocytoma', 'Disease', (169, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))
90844	30465868	In clinical radiological practice, astrocytomas are usually associated with the presence of moderate to extensive peri-tumoral edema, a lack of ventricular distortion, and a T1w isointense or hyperintense signal, while oligodendroglioma tends to be T1w hypointense, more common to have ventricular distortion, calcification, and has more possibility to locate in cortical or subcortical areas.	('oligodendroglioma', 'Disease', (219, 236))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('astrocytomas', 'Disease', 'MESH:D001254', (35, 47))	('T1w', 'Var', (249, 252))	('astrocytoma', 'Phenotype', 'HP:0009592', (35, 46))	('calcification', 'Disease', (310, 323))	('peri-tumoral edema', 'Disease', (114, 132))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ventricular', 'MPA', (144, 155))	('T1w', 'Var', (174, 177))	('hyperintense signal', 'MPA', (192, 211))	('lack', 'NegReg', (136, 140))	('peri-tumoral edema', 'Disease', 'MESH:D004487', (114, 132))	('astrocytomas', 'Disease', (35, 47))	('associated', 'Reg', (60, 70))	('calcification', 'Disease', 'MESH:D002114', (310, 323))	('ventricular distortion', 'Disease', (286, 308))	('oligodendroglioma', 'Disease', 'MESH:D009837', (219, 236))	('edema', 'Phenotype', 'HP:0000969', (127, 132))
90846	30465868	Recent studies have also shown that 1p/19q co-deletion status has discriminative MRI features; for example 1p/19q codeleted oligodendroglioma has poorly circumscribed borders and is heterogeneous in signal intensity.	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('oligodendroglioma', 'Disease', (124, 141))	('oligodendroglioma', 'Disease', 'MESH:D009837', (124, 141))	('1p/19q', 'Var', (107, 113))
90847	30465868	T1w+Gd, which is valuable for evaluation of tumor enhancement, had the lowest AUC.	('lowest', 'NegReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('AUC', 'MPA', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('T1w+Gd', 'Var', (0, 6))
90858	29718321	Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours.	('tumour', 'Disease', (87, 93))	('involved', 'Reg', (255, 263))	('ALT tumours', 'Disease', (283, 294))	('ALT tumours', 'Disease', (61, 72))	('ALT tumours', 'Disease', 'MESH:D009369', (283, 294))	('ALT tumours', 'Disease', 'MESH:D009369', (61, 72))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('tumour', 'Disease', 'MESH:D009369', (287, 293))	('tumour', 'Disease', (287, 293))	('tumours', 'Phenotype', 'HP:0002664', (287, 294))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('cell cycle control of chromosomal replication', 'CPA', (132, 177))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (20, 29))	('tumour', 'Disease', (65, 71))	('autophagy', 'CPA', (121, 130))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
90861	29718321	The proximal 2 kb region of human telomeres is rich in variant telomere repeats, which are defined as any repeat that differs by a single nucleotide from the canonical TTAGGG repeat, such as TCAGGG, TGAGGG and TTGGGG.	('TCAGGG', 'Chemical', '-', (191, 197))	('variant', 'Var', (55, 62))	('human', 'Species', '9606', (28, 33))	('telomere repeats', 'Protein', (63, 79))
90865	29718321	Specifically, TERT promoter mutations have been identified that generate transcription factor binding motifs and increase hTERT transcription in cancers, while ATRX and DAXX mutations have been found to correlate with ALT activation in both tumours and cell lines.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('hTERT', 'Gene', (122, 127))	('tumours', 'Disease', 'MESH:D009369', (241, 248))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('tumours', 'Phenotype', 'HP:0002664', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('increase', 'PosReg', (113, 121))	('hTERT', 'Gene', '7015', (122, 127))	('transcription', 'MPA', (128, 141))	('transcription factor', 'MPA', (73, 93))	('tumours', 'Disease', (241, 248))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('mutations', 'Var', (28, 37))
90868	29718321	Paradoxically, nine out of ten melanomas with predicted loss-of-function mutations in ATRX were also found to have TERT promoter mutations.	('melanomas', 'Disease', 'MESH:D008545', (31, 40))	('loss-of-function', 'NegReg', (56, 72))	('ATRX', 'Gene', (86, 90))	('melanomas', 'Disease', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('TERT promoter mutations', 'MPA', (115, 138))	('mutations', 'Var', (73, 82))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
90872	29718321	A recent study provided a comprehensive analysis of TERT-activating and loss-of-function ATRX mutations across a large panel of the TCGA tumour dataset using WGS, whole exome sequencing (WXS) and RNA-seq, finding that TERT promoter mutations correlated with increased TERT expression and shorter telomere length, and ATRX deletions correlated with increased telomere length.	('increased telomere length', 'Phenotype', 'HP:0031413', (348, 373))	('deletions', 'Var', (322, 331))	('increased', 'PosReg', (258, 267))	('TERT promoter', 'Gene', (218, 231))	('ATRX', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('shorter telomere length', 'Phenotype', 'HP:0031413', (288, 311))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('increased', 'PosReg', (348, 357))	('tumour', 'Disease', (137, 143))	('mutations', 'Var', (232, 241))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('ATRX', 'Gene', (317, 321))	('TERT expression', 'MPA', (268, 283))	('loss-of-function', 'NegReg', (72, 88))	('telomere', 'MPA', (358, 366))	('TC', 'Chemical', 'MESH:D013667', (132, 134))	('shorter', 'NegReg', (288, 295))
90886	29718321	The presence of C-circles was used to stratify tumours into ALT positive (+ve) and ALT negative (-ve) groups based on the presence or absence of C-circles, respectively.	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumours', 'Disease', (47, 54))	('C-circles', 'Var', (145, 154))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
90889	29718321	The randomForest package version 4.6-12 in R version 3.3.3 was used to generate classifiers using the calculated proportion of variant repeats and relative telomere content (rel.TC), calculated as log2(tumour/normal), as features, with samples classed as ALT +ve or ALT -ve determined by the C-circle assay.	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('TC', 'Chemical', 'MESH:D013667', (178, 180))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('variant', 'Var', (127, 134))	('tumour', 'Disease', (202, 208))	('ALT -ve', 'Chemical', '-', (266, 273))
90891	29718321	Somatic coding single nucleotide variant (SNV) and insertion/deletion (indel) mutation data for the PanNET and melanoma cohorts (, Supplementary Table, Table_S5_somatic_maf, Supplementary Table_S2) were classified using the Ensembl Variant Effect Predictor (VEP) (release 89) using the GRch37 reference genome and default settings.	('insertion/deletion', 'Var', (51, 69))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))
90896	29718321	Enrichment of mutations in genes or pathways with adjusted P-values <0.05 following FDR correction and fold difference >2 in either direction were identified for a dataset consisting of all tumour samples (PAN-CANCER) as well as each of the following individual tumour datasets: PanNET, Mela val, Mela non-val, BRCA, GBM, KICH, LIHC, OV and SARC datasets.	('tumour', 'Disease', (262, 268))	('tumour', 'Disease', (190, 196))	('BRCA', 'Gene', (311, 315))	('CANCER', 'Phenotype', 'HP:0002664', (210, 216))	('KICH', 'Disease', 'None', (322, 326))	('LIHC', 'Disease', (328, 332))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('LIHC', 'Disease', 'None', (328, 332))	('KICH', 'Disease', (322, 326))	('tumour', 'Disease', 'MESH:D009369', (262, 268))	('mutations', 'Var', (14, 23))	('BRCA', 'Gene', '672', (311, 315))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
90908	29718321	We observed a G-strand error rate of 1.2% and 0.8% for TCAGGG and TTAGCG variants, respectively, and a C-strand error rate of 1.2% and 0.8%.	('TTAGCG', 'Gene', (66, 72))	('TTAGCG', 'Chemical', '-', (66, 72))	('variants', 'Var', (73, 81))	('TCAGGG', 'Chemical', '-', (55, 61))	('TCAGGG', 'Gene', (55, 61))	('G-strand', 'CPA', (14, 22))	('C-strand', 'CPA', (103, 111))
90911	29718321	The PanNET dataset consisted of 32 C-circle +ve (ALT +ve) and 54 C-circle -ve (ALT -ve) tumours, while the melanoma dataset consisted of 11 C-circle +ve (ALT +ve) and 70 C-circle -ve (ALT -ve) tumours (Figure 2A).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('tumours', 'Disease', 'MESH:D009369', (193, 200))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('tumours', 'Disease', (193, 200))	('ALT -ve', 'Chemical', '-', (79, 86))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('C-circle +ve', 'Var', (140, 152))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('C-circle +ve', 'Var', (35, 47))	('ALT -ve', 'Chemical', '-', (184, 191))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))
90914	29718321	In the PanNETs, comparisons between ALT +ve and ALT -ve tumour telomeres revealed significant differences in variant repeat content across all but one variant (TTCGGG) (Figure 2C).	('variant', 'Var', (109, 116))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('TC', 'Chemical', 'MESH:D013667', (161, 163))	('ALT -ve', 'Chemical', '-', (48, 55))	('differences', 'Reg', (94, 105))	('tumour', 'Disease', (56, 62))
90915	29718321	The proportion of variant repeats in telomeres varied substantially across the tumour samples with one tumour containing 4.5% of the TTCGGG variant, the highest proportion of a single variant type.	('TTCGGG', 'Gene', (133, 139))	('TC', 'Chemical', 'MESH:D013667', (134, 136))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('variant', 'Var', (140, 147))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (103, 109))	('tumour', 'Disease', (79, 85))
90916	29718321	Overall, ALT -ve tumours contained a higher proportion of variant repeats compared to ALT +ve tumours.	('ALT -ve tumours', 'Disease', (9, 24))	('tumours', 'Disease', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Disease', (17, 24))	('variant repeats', 'Var', (58, 73))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (9, 24))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
90917	29718321	This reflects a higher representation of the variant repeat-dense proximal regions as a proportion of the total telomere in ALT -ve cells, which typically display substantially shorter telomeres compared to ALT +ve cells.	('telomeres', 'MPA', (185, 194))	('shorter', 'NegReg', (177, 184))	('ALT -ve', 'Chemical', '-', (124, 131))	('variant', 'Var', (45, 52))
90918	29718321	This is demonstrated by the observation that the overall proportion of variant repeats in telomeres is negatively correlated (R2 = 0.6231) with rel.TC measured by qMotif (Supplementary Figure S4A).	('TC', 'Chemical', 'MESH:D013667', (148, 150))	('variant repeats', 'Var', (71, 86))	('rel.TC', 'MPA', (144, 150))	('negatively', 'NegReg', (103, 113))
90921	29718321	Overall, the proportion of variant repeats in ALT -ve tumours was lower in the melanoma dataset than in the PanNET dataset.	('ALT -ve tumours', 'Disease', (46, 61))	('lower', 'NegReg', (66, 71))	('variant repeats', 'Var', (27, 42))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('melanoma', 'Disease', (79, 87))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (46, 61))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
90929	29718321	These experiments demonstrate that rel.TC alone provides limited accuracy in stratifying ALT +ve and ALT -ve tumours across different tumour types, but that significant differences in the variant repeat content of telomeres exist between ALT +ve and ALT -ve tumours across both PanNET and melanoma datasets that could improve upon this.	('TC', 'Chemical', 'MESH:D013667', (39, 41))	('ALT -ve tumours', 'Disease', (101, 116))	('melanoma', 'Disease', 'MESH:D008545', (289, 297))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (250, 265))	('ALT -ve tumours', 'Disease', (250, 265))	('melanoma', 'Disease', (289, 297))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('tumour type', 'Disease', (134, 145))	('tumour type', 'Disease', 'MESH:D009369', (134, 145))	('variant', 'Var', (188, 195))	('tumours', 'Phenotype', 'HP:0002664', (258, 265))	('telomeres', 'Gene', (214, 223))	('differences', 'Reg', (169, 180))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (101, 116))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
90936	29718321	The classifier performed slightly worse on the independent melanoma test set, having class accuracies of 90.91% and 75.71% for ALT +ve and ALT -ve, respectively (Figure 3A).	('ALT -ve', 'Chemical', '-', (139, 146))	('ALT +ve', 'Var', (127, 134))	('ALT', 'Var', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
90944	29718321	Interestingly, rel.TC ranked 10th in terms of importance, showing that variant repeat content has more predictive power for detecting ALT than rel.TC.	('variant repeat content', 'Var', (71, 93))	('TC', 'Chemical', 'MESH:D013667', (147, 149))	('TC', 'Chemical', 'MESH:D013667', (19, 21))	('ALT', 'Disease', (134, 137))
90945	29718321	We conclude that by utilising the proportion of individual variant repeats within telomeres, in combination with rel.TC, we can generate a classifier of ALT that can be applied across different tumour types.	('tumour type', 'Disease', 'MESH:D009369', (194, 205))	('tumour type', 'Disease', (194, 205))	('TC', 'Chemical', 'MESH:D013667', (117, 119))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('variant', 'Var', (59, 66))
90956	29718321	Of the 1023 tumours investigated, only 37 had a predicted loss-of-function (high impact) mutation in ATRX or DAXX, with 22/37 (59%) being classified as ALT +ve (Figure 5A).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Disease', (12, 19))	('mutation', 'Var', (89, 97))	('loss-of-function', 'NegReg', (58, 74))	('ATRX', 'Gene', (101, 105))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('DAXX', 'Gene', (109, 113))
90957	29718321	Interestingly, 2/37 of these tumours were validated to be ALT -ve by the C-circle assay, indicating that loss of ATRX or DAXX is not sufficient to confer ALT activity.	('ALT -ve', 'Chemical', '-', (58, 65))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('loss', 'Var', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
90958	29718321	High impact mutations in DAXX were found to be most prevalent in PanNETs, occurring in 15.1% of tumours, with COAD being the only other investigated tumour type found to contain DAXX mutations (in 2.6%).	('tumour type', 'Disease', 'MESH:D009369', (149, 160))	('DAXX', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('PanNETs', 'Disease', (65, 72))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('COAD', 'Disease', (110, 114))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('COAD', 'Disease', 'MESH:D029424', (110, 114))	('tumours', 'Disease', (96, 103))	('tumour type', 'Disease', (149, 160))	('prevalent', 'Reg', (52, 61))
90959	29718321	An additional 37 tumours were found to contain moderate impact mutations, mostly missense, in ATRX or DAXX; however, only six were classified as ALT +ve, indicating that moderate impact mutations in ATRX and DAXX are not robustly associated with ALT activity.	('missense', 'Var', (81, 89))	('DAXX', 'Gene', (102, 106))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('associated', 'Reg', (230, 240))	('ATRX', 'Gene', (94, 98))	('ALT activity', 'MPA', (246, 258))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))
90962	29718321	TERT promoter mutations, specifically C228T and C250T, have been shown to create an ETS binding motif, which results in increased transcription of the gene.	('transcription', 'MPA', (130, 143))	('C250T', 'Mutation', 'c.250C>T', (48, 53))	('C250T', 'Var', (48, 53))	('C228T', 'Mutation', 'c.228C>T', (38, 43))	('increased', 'PosReg', (120, 129))	('C228T', 'Var', (38, 43))	('binding', 'Interaction', (88, 95))
90963	29718321	We identified 157 tumours that contained one of these mutations, with 149 (94.9%) classified as ALT -ve (Figure 5B).	('tumours', 'Disease', (18, 25))	('ALT -ve', 'Chemical', '-', (96, 103))	('mutations', 'Var', (54, 63))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('tumours', 'Disease', 'MESH:D009369', (18, 25))
90964	29718321	This indicates that TERT promoter mutations are important in ALT -ve tumours, consistent with their role in promoting TERT expression.	('ALT -ve tumours', 'Disease', 'MESH:C538347', (61, 76))	('ALT -ve tumours', 'Disease', (61, 76))	('promoting', 'PosReg', (108, 117))	('TERT promoter', 'Gene', (20, 33))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('TERT', 'MPA', (118, 122))	('mutations', 'Var', (34, 43))
90965	29718321	TERT promoter mutations were most prevalent (approximately 50%) in melanomas, BLCA, GBM and LGG, consistent with previous reports.	('melanomas', 'Disease', (67, 76))	('BLCA', 'Disease', (78, 82))	('TERT promoter', 'Gene', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('GBM', 'Disease', (84, 87))	('prevalent', 'Reg', (34, 43))	('mutations', 'Var', (14, 23))	('LGG', 'Disease', (92, 95))
90967	29718321	Another seven tumours with TERT promoter mutations that were classified as ALT +ve may similarly have both TMMs active, or may have been misclassified.	('mutations', 'Var', (41, 50))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('TERT promoter', 'Gene', (27, 40))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))
90968	29718321	Interestingly, one melanoma tumour was found to have both a loss-of-function ATRX mutation as well as a TERT promoter mutation, potentially facilitating activation of both TMMs in the tumour.	('melanoma tumour', 'Disease', 'MESH:D008545', (19, 34))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('activation', 'PosReg', (153, 163))	('mutation', 'Var', (82, 90))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('melanoma tumour', 'Disease', (19, 34))	('tumour', 'Disease', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('loss-of-function', 'NegReg', (60, 76))	('ATRX', 'Gene', (77, 81))
90971	29718321	Only the high and moderate impact variants were used in the analysis for over-representation of mutations in either the ALT +ve or ALT -ve tumour group across each of the ten cancer datasets, using a criterion of >2-fold over-representation and an FDR of 5%.	('tumour', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('ALT -ve', 'Chemical', '-', (131, 138))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (96, 105))
90972	29718321	When considering both high and moderate impact mutations, DAXX and MEN1 were identified as significantly over-represented in ALT +ve tumours in the PAN-CANCER dataset, affecting 18.09% and 19.15% of ALT +ve tumours, respectively (Figure 6A).	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('tumours', 'Disease', (207, 214))	('CANCER', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (47, 56))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('affecting', 'Reg', (168, 177))	('tumours', 'Disease', (133, 140))	('MEN1', 'Gene', '4221', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('MEN1', 'Gene', (67, 71))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))
90975	29718321	ATRX was observed to have an over-representation of mutations in ALT +ve tumours, affecting 10.64%; however, this was not significant (adjusted P-value 0.07), presumably due to an overall low prevalence of ATRX mutations across the tumour types tested in this study.	('mutations', 'Var', (52, 61))	('tumours', 'Disease', (73, 80))	('tumour type', 'Disease', 'MESH:D009369', (232, 243))	('ATRX', 'Gene', (206, 210))	('ATRX', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('tumour type', 'Disease', (232, 243))	('ALT', 'Disease', (65, 68))
90977	29718321	Analysis of both high and moderate impact mutations in the PAN-CANCER dataset revealed two pathways that were significantly over-represented, and 12 pathways that were significantly under-represented in ALT +ve tumours (Figure 6B) (Supplementary Table S6).	('over-represented', 'PosReg', (124, 140))	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('tumours', 'Disease', (211, 218))	('CANCER', 'Phenotype', 'HP:0002664', (63, 69))	('ALT +ve', 'Disease', (203, 210))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('pathways', 'Pathway', (91, 99))	('mutations', 'Var', (42, 51))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('under-represented', 'NegReg', (182, 199))
90985	29718321	Previous studies of glioblastomas have shown that the presence of ALT in the tumour was associated with longer patient survival times.	('ALT', 'MPA', (66, 69))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (20, 33))	('patient survival times', 'CPA', (111, 133))	('tumour', 'Disease', (77, 83))	('presence', 'Var', (54, 62))	('glioblastomas', 'Disease', 'MESH:D005909', (20, 33))	('longer', 'PosReg', (104, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('patient', 'Species', '9606', (111, 118))	('glioblastomas', 'Disease', (20, 33))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
90990	29718321	Application of this pipeline allowed us to identify significant differences in variant repeat sequence content between telomeres derived from ALT +ve and ALT -ve tumours.	('ALT -ve tumours', 'Disease', 'MESH:C538347', (154, 169))	('differences', 'Reg', (64, 75))	('ALT -ve tumours', 'Disease', (154, 169))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('variant', 'Var', (79, 86))
90991	29718321	We observed a greater proportion of variant repeats in the telomeres of ALT -ve tumours, attributed to the higher proportion of proximal variant repeats when overall telomere lengths are shorter.	('variant repeats', 'Var', (36, 51))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (72, 87))	('ALT -ve tumours', 'Disease', (72, 87))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))
90992	29718321	One exception was the TTCGGG variant repeat, which was found to occur at a similar proportion in both the ALT +ve and ALT -ve tumour groups in the PanNETs, indicating that it is being propagated outside of the proximal region in longer telomeres.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('TC', 'Chemical', 'MESH:D013667', (23, 25))	('variant', 'Var', (29, 36))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('ALT -ve', 'Chemical', '-', (118, 125))	('TTCGGG', 'Gene', (22, 28))
90995	29718321	However, by combining the proportion of variant repeats with telomere content, we created a robust classifier capable of stratifying ALT +ve and ALT -ve tumours, with 91.6% accuracy, that can be applied across multiple tumour types to begin to elucidate the molecular signatures associated with the activation of ALT.	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('variant', 'Var', (40, 47))	('tumour type', 'Disease', 'MESH:D009369', (219, 230))	('tumour type', 'Disease', (219, 230))	('ALT', 'Disease', (133, 136))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (145, 160))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('ALT -ve tumours', 'Disease', (145, 160))
91002	29718321	The prevalence of these mutations was also found to be tumour type dependent, and overall very low (19.5%), consistent with a previous study of TCGA tumours.	('tumours', 'Disease', (149, 156))	('TC', 'Chemical', 'MESH:D013667', (144, 146))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour type', 'Disease', (55, 66))	('mutations', 'Var', (24, 33))	('tumour type', 'Disease', 'MESH:D009369', (55, 66))	('tumours', 'Disease', 'MESH:D009369', (149, 156))
91003	29718321	ALT cancers are highly correlated with mutations in ATRX, exemplified by previous studies of cancers of the central nervous system, GBM, oligodendrogliomas, and medulloblastomas.	('medulloblastomas', 'Disease', 'MESH:D008527', (161, 177))	('cancers of the central nervous system', 'Disease', 'MESH:D002494', (93, 130))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (137, 155))	('cancers of the central nervous system', 'Disease', (93, 130))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (39, 48))	('medulloblastomas', 'Disease', (161, 177))	('correlated', 'Reg', (23, 33))	('oligodendrogliomas', 'Disease', (137, 155))	('ATRX', 'Gene', (52, 56))	('ALT cancers', 'Disease', 'MESH:D009369', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('ALT cancers', 'Disease', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers of the central nervous', 'Phenotype', 'HP:0100006', (93, 123))
91004	29718321	In our investigation, mutations in ATRX were not significantly associated with ALT activity across all tumour types.	('tumour type', 'Disease', 'MESH:D009369', (103, 114))	('associated', 'Reg', (63, 73))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('ALT activity', 'MPA', (79, 91))	('mutations', 'Var', (22, 31))	('ATRX', 'Gene', (35, 39))	('tumour type', 'Disease', (103, 114))
91005	29718321	This can be explained by a low representation of tumour types with common ATRX mutations in our extensive dataset.	('mutations', 'Var', (79, 88))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour type', 'Disease', (49, 60))	('tumour type', 'Disease', 'MESH:D009369', (49, 60))	('ATRX', 'Gene', (74, 78))
91006	29718321	Low sample numbers also precluded conclusions regarding the frequency of ATRX mutations in particular tumour types, and limited our ability to elucidate tumour type specific genetic signatures associated with ALT activation.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour type', 'Disease', (102, 113))	('tumour type', 'Disease', 'MESH:D009369', (102, 113))	('ATRX', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('tumour type', 'Disease', 'MESH:D009369', (153, 164))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('particular tumour', 'Disease', (91, 108))	('particular tumour', 'Disease', 'MESH:D009369', (91, 108))	('tumour type', 'Disease', (153, 164))
91009	29718321	Our analysis of pathways under-represented in ALT +ve tumours revealed three pathways (the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways) that were found to have almost no mutations in ALT +ve tumours.	('cell cycle', 'CPA', (102, 112))	('tumours', 'Phenotype', 'HP:0002664', (277, 284))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('tumours', 'Disease', 'MESH:D009369', (277, 284))	('tumours', 'Disease', (277, 284))	('mutations', 'Var', (256, 265))	('autophagy', 'CPA', (91, 100))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (277, 283))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('ALT +ve', 'Disease', (269, 276))
91010	29718321	Autophagy has been shown to act as a tumour-suppressor, with deficiencies leading to induction of oxidative stress, DNA damage and chromatin instability through the accumulation of damaged macromolecules and organelles, while also promoting cell survival in established cancer cells.	('accumulation', 'PosReg', (165, 177))	('tumour', 'Disease', (37, 43))	('cell survival', 'CPA', (241, 254))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('deficiencies', 'Var', (61, 73))	('DNA damage', 'MPA', (116, 126))	('oxidative stress', 'Phenotype', 'HP:0025464', (98, 114))	('promoting', 'PosReg', (231, 240))	('oxidative stress', 'MPA', (98, 114))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('Autophagy', 'CPA', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('chromatin', 'MPA', (131, 140))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('induction', 'Reg', (85, 94))
91014	29718321	We have demonstrated that a machine learning approach can be used to stratify ALT +ve and ALT -ve tumours, using telomere variant repeat content, with an accuracy of 91.6%, and that this classifier can be applied to large scale cancer datasets to elucidate the molecular mechanisms involved in ALT activation.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Disease', (228, 234))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('variant repeat', 'Var', (122, 136))	('ALT', 'Disease', (78, 81))	('ALT -ve tumours', 'Disease', 'MESH:C538347', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ALT -ve tumours', 'Disease', (90, 105))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
91022	25724300	Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined.	('glioblastoma', 'Disease', (178, 190))	('gliomas', 'Disease', (259, 266))	('TMZ', 'Chemical', 'MESH:D000077204', (125, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('Temozolomide', 'Chemical', 'MESH:D000077204', (111, 123))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (259, 266))	('gliomas', 'Phenotype', 'HP:0009733', (259, 266))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('patients', 'Species', '9606', (164, 172))	('increases', 'PosReg', (130, 139))	('temozolomide', 'Chemical', 'MESH:D000077204', (88, 100))	('defects', 'Var', (24, 31))
91023	25724300	DNA hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis.	('O6-methylguanine-DNA methyltransferase', 'Gene', (28, 66))	('inactivation', 'NegReg', (147, 159))	('TMZ', 'Chemical', 'MESH:D000077204', (247, 250))	('response to TMZ treatment', 'MPA', (114, 139))	('TMZ', 'Chemical', 'MESH:D000077204', (126, 129))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (28, 66))	('MGMT', 'Gene', '4255', (68, 72))	('therapeutic resistance', 'Disease', (220, 242))	('MGMT', 'Gene', (68, 72))	('improved', 'PosReg', (105, 113))	('DNA mismatch', 'Pathway', (167, 179))	('hypermethylation', 'Var', (4, 20))
91024	25724300	We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM.	('mTOR', 'Gene', (96, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (32, 35))	('AKT', 'Gene', '207', (92, 95))	('drive', 'Reg', (121, 126))	('malignant progression', 'CPA', (127, 148))	('mutations', 'Var', (68, 77))	('AKT', 'Gene', (92, 95))	('mTOR', 'Gene', '2475', (96, 100))
91025	25724300	To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment naive LGGs and their recurrences.	('genetic alterations', 'Var', (148, 167))	('MMR genes', 'Gene', (178, 187))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('MGMT', 'Gene', (127, 131))	('MGMT', 'Gene', '4255', (127, 131))
91026	25724300	Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences.	('tumors', 'Disease', (113, 119))	('hypermutation', 'Var', (32, 45))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('MGMT', 'Gene', (139, 143))	('increased', 'PosReg', (50, 59))	('TMZ-associated hypermutation', 'Var', (17, 45))	('MGMT', 'Gene', (60, 64))	('MGMT', 'Gene', '4255', (139, 143))	('MGMT', 'Gene', '4255', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TMZ', 'Chemical', 'MESH:D000077204', (17, 20))	('TMZ', 'Chemical', 'MESH:D000077204', (168, 171))	('higher', 'PosReg', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
91027	25724300	A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ treated, hypermutated recurrences.	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('TMZ', 'Chemical', 'MESH:D000077204', (2, 5))	('mutation', 'Var', (17, 25))	('MMR genes', 'Gene', (41, 50))	('observed', 'Reg', (55, 63))	('TMZ-associated', 'Disease', (2, 16))
91028	25724300	In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest.	('MGMT', 'Gene', '4255', (63, 67))	('mutations', 'Var', (117, 126))	('MGMT', 'Gene', (63, 67))	('deletions', 'Var', (40, 49))	('MMR', 'Gene', (75, 78))	('TMZ', 'Chemical', 'MESH:D000077204', (102, 105))
91029	25724300	These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.	('methylated', 'Var', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MGMT', 'Gene', '4255', (55, 59))	('undergo', 'Reg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MGMT', 'Gene', (55, 59))	('tumor', 'Disease', (27, 32))	('MMR deficiency', 'Disease', (130, 144))	('MMR deficiency', 'Disease', 'MESH:C536143', (130, 144))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('positive selection', 'CPA', (72, 90))
91033	25724300	Moreover, postoperative TMZ or irradiation of LGG has been associated with improved quality of life, better seizure control, and longer progression-free survival.	('improved', 'PosReg', (75, 83))	('TMZ', 'Chemical', 'MESH:D000077204', (24, 27))	('LGG', 'Gene', (46, 49))	('irradiation', 'Var', (31, 42))	('quality of life', 'CPA', (84, 99))	('seizure', 'Disease', (108, 115))	('seizure', 'Disease', 'MESH:D012640', (108, 115))	('TMZ', 'Var', (24, 27))	('seizure', 'Phenotype', 'HP:0001250', (108, 115))
91037	25724300	When the MGMT promoter is hypermethylated however, MGMT expression is decreased and TMZ-induced DNA damage persists.	('hypermethylated', 'Var', (26, 41))	('MGMT', 'Gene', '4255', (9, 13))	('decreased', 'NegReg', (70, 79))	('MGMT', 'Gene', (9, 13))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('MGMT', 'Gene', (51, 55))	('MGMT', 'Gene', '4255', (51, 55))
91039	25724300	MSH2 and MSH6 form the MutSalpha complex, which identifies base-base mismatches and small insertion-deletion-loops (IDLs).	('MSH2', 'Gene', (0, 4))	('MSH6', 'Gene', (9, 13))	('MSH2', 'Gene', '4436', (0, 4))	('MSH6', 'Gene', '2956', (9, 13))	('insertion-deletion-loops', 'Var', (90, 114))
91043	25724300	This futile cycling of repair has been linked to DNA double strand breaks and apoptosis, the apparent mechanism of TMZ-induced cytotoxicity.	('apoptosis', 'CPA', (78, 87))	('cytotoxicity', 'Disease', (127, 139))	('TMZ', 'Chemical', 'MESH:D000077204', (115, 118))	('DNA double strand breaks', 'Var', (49, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (127, 139))
91044	25724300	Inactivation of the MMR pathway is a mechanism of resistance to TMZ in primary GBMs and also leads to TMZinduced mutagenesis.	('MMR pathway', 'Pathway', (20, 31))	('leads to', 'Reg', (93, 101))	('TMZ', 'Chemical', 'MESH:D000077204', (102, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (64, 67))	('Inactivation', 'Var', (0, 12))
91049	25724300	We recently identified hypermutation in a subset of TMZ-treated recurrent GBMs that arose from IDH1-mutant astrocytic LGG.	('hypermutation', 'Var', (23, 36))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('IDH1', 'Gene', (95, 99))	('astrocytic', 'Disease', (107, 117))	('IDH1', 'Gene', '3417', (95, 99))	('GBMs', 'Disease', (74, 78))
91050	25724300	Post-TMZ recurrences had a 39-133 fold increase in the mutation rate relative to their treatment naive initial LGG, more than 98% of which C>T/G>A mutations which are associated with TMZ-induced mutagenesis (Supplementary Table S1).	('TMZ', 'Chemical', 'MESH:D000077204', (183, 186))	('TMZ', 'Chemical', 'MESH:D000077204', (5, 8))	('increase', 'PosReg', (39, 47))	('C>T/G>A', 'Var', (139, 146))	('mutation', 'MPA', (55, 63))
91051	25724300	TMZ-associated mutations resulted in deregulation of RB mediated cell cycle control and hyperactivated AKT-mTOR signaling, suggesting TMZ-induced hypermutation may drive malignant progression.	('malignant progression', 'CPA', (170, 191))	('TMZ-associated', 'Gene', (0, 14))	('AKT', 'Gene', '207', (103, 106))	('mTOR', 'Gene', (107, 111))	('mTOR', 'Gene', '2475', (107, 111))	('deregulation', 'MPA', (37, 49))	('hyperactivated', 'PosReg', (88, 102))	('AKT', 'Gene', (103, 106))	('mutations', 'Var', (15, 24))	('drive', 'PosReg', (164, 169))	('TMZ', 'Chemical', 'MESH:D000077204', (134, 137))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
91069	25724300	The identification of MMR pathway alterations was limited to those for which sufficient tumor DNA and matched normal DNA was available for exome sequencing.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('alterations', 'Var', (34, 45))	('MMR pathway', 'Pathway', (22, 33))
91074	25724300	All candidate mutations were subsequently validated with PCR amplification of the target region from tumor and matched normal genomic DNA followed by conventional Sanger sequencing.	('mutations', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
91086	25724300	Relative to the TMZ-HM group, the number of recurrent tumors with GBM histology was variable in the TMZ-non-HM group and non-TMZ group, (ANOVA, p-value 0.013) (Fig.	('TMZ-non-HM', 'Var', (100, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (16, 19))	('TMZ', 'Chemical', 'MESH:D000077204', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('TMZ', 'Chemical', 'MESH:D000077204', (100, 103))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
91102	25724300	Eleven of 23 individual CpGs were significantly more methylated in the recurrent tumors of the subgroups TMZ-HM vs. TMZ-non-HM (CpGs 1-6, 8-10, 12 and 13, p values 0.012-0.044).	('tumors', 'Disease', (81, 87))	('methylated', 'MPA', (53, 63))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('TMZ-HM', 'Var', (105, 111))	('TMZ', 'Chemical', 'MESH:D000077204', (105, 108))	('more', 'PosReg', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('TMZ', 'Chemical', 'MESH:D000077204', (116, 119))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
91104	25724300	In contrast, five of the six TMZ-HM GBMs contained a TMZ-associated mutation in one of the MMR genes, concurrent with deletion of the other allele or deletion encompassing another MMR gene or MGMT (Fig.	('TMZ-associated', 'Disease', (53, 67))	('mutation', 'Var', (68, 76))	('MMR', 'Gene', (91, 94))	('TMZ', 'Chemical', 'MESH:D000077204', (53, 56))	('deletion', 'Var', (150, 158))	('TMZ', 'Chemical', 'MESH:D000077204', (29, 32))	('MGMT', 'Gene', '4255', (192, 196))	('MGMT', 'Gene', (192, 196))	('deletion', 'Var', (118, 126))
91105	25724300	We also identified a clonal TMZ-associated mutation in MGMT of unknown significance in the recurrent tumor of patient 18.	('MGMT', 'Gene', '4255', (55, 59))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('MGMT', 'Gene', (55, 59))	('mutation', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('patient', 'Species', '9606', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
91109	25724300	In these seven cases only one MMR mutation was detected, an MSH3 mutation in the initial tumor but not in the recurrent tumor of patient 07.	('MSH3', 'Gene', (60, 64))	('MSH3', 'Gene', '4437', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mutation', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (120, 125))	('patient', 'Species', '9606', (129, 136))
91111	25724300	Genomic loss affecting the MGMT region was detected in five initial and seven recurrent tumors of the non-TMZ subgroup.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('Genomic loss', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('TMZ', 'Chemical', 'MESH:D000077204', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('MGMT', 'Gene', '4255', (27, 31))	('MGMT', 'Gene', (27, 31))
91112	25724300	Similarly, deletion encompassing an MMR gene was shared between the initial and recurrent tumors of five cases, while four patients acquired a deletion encompassing a MMR gene at recurrence (Supplementary Table S3).	('MMR gene', 'Gene', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MMR', 'Gene', (36, 39))	('patients', 'Species', '9606', (123, 131))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('deletion', 'Var', (11, 19))
91113	25724300	As these patients did not receive TMZ, it is not known how TMZ treatment may have affected MGMT methylation levels at recurrence, or if the identified genetic alterations to MGMT and MMR genes may indicate a susceptibility to hypermutation.	('MGMT', 'Gene', '4255', (174, 178))	('patients', 'Species', '9606', (9, 17))	('MMR', 'Gene', (183, 186))	('hypermutation', 'Disease', (226, 239))	('affected', 'Reg', (82, 90))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))	('TMZ', 'Chemical', 'MESH:D000077204', (34, 37))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))	('MGMT', 'Gene', (174, 178))	('susceptibility', 'Reg', (208, 222))	('genetic alterations', 'Var', (151, 170))
91114	25724300	We compared spontaneous and treatment-associated evolution of DNA repair deficiency in a cohort of 34 initial LGG and their patient-matched recurrences.	('patient', 'Species', '9606', (124, 131))	('deficiency', 'Var', (73, 83))	('LGG', 'Disease', (110, 113))
91115	25724300	Our data suggest MGMT and MMR mediated DNA repair may be compromised by sequential and coincident loss of heterozygosity, methylation, and TMZ-associated mutation, although repair activity could not be tested directly.	('methylation', 'MPA', (122, 133))	('mutation', 'Var', (154, 162))	('TMZ', 'Chemical', 'MESH:D000077204', (139, 142))	('loss', 'NegReg', (98, 102))	('TMZ-associated', 'Gene', (139, 153))	('MGMT', 'Gene', '4255', (17, 21))	('MGMT', 'Gene', (17, 21))	('heterozygosity', 'MPA', (106, 120))
91117	25724300	This putative mechanism is not fully understood, but may be induced directly by the mutagenic action of TMZ on DNA repair genes, in combination with pre-existing and concurrent copy number alterations in cells with a higher level of MGMT methylation.	('MGMT', 'Gene', '4255', (233, 237))	('TMZ', 'Var', (104, 107))	('DNA repair genes', 'Gene', (111, 127))	('MGMT', 'Gene', (233, 237))	('TMZ', 'Chemical', 'MESH:D000077204', (104, 107))
91119	25724300	The sequential acquisition of genetic and epigenetic change in MGMT and MMR genes in the TMZ-HM group differs notably from the patterns in patients that did not receive TMZ, and in TMZ-treated but not hypermutated patients.	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('MMR', 'Gene', (72, 75))	('patients', 'Species', '9606', (214, 222))	('patients', 'Species', '9606', (139, 147))	('TMZ', 'Chemical', 'MESH:D000077204', (169, 172))	('epigenetic change', 'Var', (42, 59))	('TMZ-HM', 'Var', (89, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (89, 92))	('TMZ', 'Chemical', 'MESH:D000077204', (181, 184))
91121	25724300	The apparent positive selection of MGMT hypermethylated cells and a corresponding decrease in MGMT expression may predispose a cell to persistent 0-6-methylguanine lesions and acquisition of MMR gene mutation, enabling hypermutation from subsequent rounds of TMZ treatment (Fig.	('expression', 'MPA', (99, 109))	('enabling', 'PosReg', (210, 218))	('MGMT', 'Gene', '4255', (94, 98))	('decrease', 'NegReg', (82, 90))	('MGMT', 'Gene', (35, 39))	('MGMT', 'Gene', (94, 98))	('MGMT', 'Gene', '4255', (35, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (259, 262))	('hypermutation', 'MPA', (219, 232))	('0-6-methylguanine lesions', 'MPA', (146, 171))	('MMR gene', 'Gene', (191, 199))	('0-6-methylguanine', 'Chemical', '-', (146, 163))	('mutation', 'Var', (200, 208))
91127	25724300	Exposure of cells to a mutagen such as TMZ will result in a different set of mutations in each cell within the population.	('TMZ', 'Chemical', 'MESH:D000077204', (39, 42))	('mutations', 'Var', (77, 86))	('result in', 'Reg', (48, 57))
91129	25724300	Literature on the functionality of these mutations varies, for example somatic mutations MLH1 P648L and P640S in the TMZ-treated recurrent tumors of patients 01 and 10 also occur in the germline of families with hereditary nonpolyposis colon cancer, significantly affect MLH1 protein function, and are predicted to be pathogenic.	('P648L', 'Var', (94, 99))	('MLH1', 'Gene', '4292', (89, 93))	('patients', 'Species', '9606', (149, 157))	('protein', 'Protein', (276, 283))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('function', 'MPA', (284, 292))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('P640S', 'Mutation', 'rs63749792', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('P648L', 'Mutation', 'rs63750610', (94, 99))	('MLH1', 'Gene', (271, 275))	('tumors', 'Disease', (139, 145))	('P640S', 'Var', (104, 109))	('hereditary nonpolyposis colon cancer', 'Disease', (212, 248))	('affect', 'Reg', (264, 270))	('colon cancer', 'Phenotype', 'HP:0003003', (236, 248))	('MLH1', 'Gene', '4292', (271, 275))	('MLH1', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (212, 248))
91132	25724300	The C>T/G>A mutation also occurs spontaneously, however the extreme number of new mutations, the strong bias towards C>T/G>A versus other mutations, and the occurrence of hypermutation after TMZ treatment but not in patient-matched pre-treatment samples suggests TMZ is the predominant source.	('C>T/G>A', 'Var', (4, 11))	('C>T/G>A', 'Var', (117, 124))	('patient', 'Species', '9606', (216, 223))	('TMZ', 'Chemical', 'MESH:D000077204', (191, 194))	('TMZ', 'Chemical', 'MESH:D000077204', (263, 266))
91136	25724300	Rare germline and somatic MSH6 mutations that might affect how cells respond to TMZ have been detected in patients with untreated anaplastic oligodendrogliomas and GBMs.	('MSH6', 'Gene', '2956', (26, 30))	('mutations', 'Var', (31, 40))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('how', 'MPA', (59, 62))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (141, 159))	('patients', 'Species', '9606', (106, 114))	('MSH6', 'Gene', (26, 30))	('oligodendrogliomas', 'Disease', (141, 159))	('affect', 'Reg', (52, 58))
91138	25724300	In three TMZ-HM patients the initial tumor showed deletion of MGMT or an MMR gene.	('MGMT', 'Gene', (62, 66))	('MMR', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('deletion', 'Var', (50, 58))	('MGMT', 'Gene', '4255', (62, 66))	('TMZ', 'Chemical', 'MESH:D000077204', (9, 12))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
91141	25724300	A larger cohort of paired samples will be needed to determine if loss of heterozygosity of MGMT and/or MMR genes in initial tumors has predictive or prognostic value.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MMR', 'Gene', (103, 106))	('loss of heterozygosity', 'Var', (65, 87))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))
91146	25724300	However, because the TMZ-HM group had an increased level of MGMT methylation relative to more variable patterns in the other groups, recurrences in the TMZ-HM group may exhibit greater intratumoral heterogeneity if the initial tumor resection was incomplete and sampling at recurrence included hypermutated and non-hypermutated regions.	('increased', 'PosReg', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('TMZ-HM', 'Var', (152, 158))	('tumor', 'Disease', (227, 232))	('TMZ', 'Chemical', 'MESH:D000077204', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('MGMT', 'Gene', (60, 64))	('tumor', 'Disease', (190, 195))	('MGMT', 'Gene', '4255', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
91148	25724300	Taken together, the data suggest a working model in which a hypermutated tumor arises through clonal expansion of cells with high levels of MGMT methylation, pre-existing loss of heterozygosity of a key MMR gene and/or MGMT, and TMZ-associated mutation in MMR genes.	('MGMT', 'Gene', '4255', (219, 223))	('loss of heterozygosity', 'Var', (171, 193))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TMZ', 'Chemical', 'MESH:D000077204', (229, 232))	('MMR', 'Gene', (256, 259))	('MMR gene', 'Gene', (203, 211))	('tumor', 'Disease', (73, 78))	('mutation', 'Var', (244, 252))	('MGMT', 'Gene', (140, 144))	('MGMT', 'Gene', (219, 223))	('MGMT', 'Gene', '4255', (140, 144))
91171	23376380	With the recent discovery that the majority of pilocytic astrocytomas exhibit alterations in the BRAF gene, most commonly involving translocations between BRAF and KIAA, or activating mutations, such as BRAFv600E, which induces growth signaling through MAP kinase-related pathways, significant interest has been focused on clinical trials of BRAF and MAPK pathway inhibitors, such as AZD6244, which have been launched for children with progressive tumors.	('BRAF', 'Gene', '673', (342, 346))	('BRAF', 'Gene', (342, 346))	('alterations', 'Reg', (78, 89))	('children', 'Species', '9606', (422, 430))	('BRAFv600E', 'Mutation', 'rs113488022', (203, 212))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (47, 69))	('BRAF', 'Gene', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (448, 454))	('tumor', 'Phenotype', 'HP:0002664', (448, 453))	('BRAF', 'Gene', '673', (203, 207))	('BRAF', 'Gene', (203, 207))	('BRAF', 'Gene', '673', (155, 159))	('tumors', 'Disease', (448, 454))	('BRAF', 'Gene', (155, 159))	('translocations', 'Var', (132, 146))	('pilocytic astrocytomas', 'Disease', (47, 69))	('AZD6244', 'Chemical', 'MESH:C517975', (384, 391))	('tumors', 'Disease', 'MESH:D009369', (448, 454))	('BRAF', 'Gene', '673', (97, 101))
91180	21203894	Cancer susceptibility variants and the risk of adult glioma in a US case-control study Malignant gliomas are the most common and deadly brain tumors.	('deadly brain tumors', 'Disease', (129, 148))	('Malignant gliomas', 'Disease', (87, 104))	('adult glioma', 'Disease', 'MESH:D005910', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('Malignant gliomas', 'Disease', 'MESH:D005910', (87, 104))	('deadly brain tumors', 'Disease', 'MESH:D001932', (129, 148))	('brain tumors', 'Phenotype', 'HP:0030692', (136, 148))	('adult glioma', 'Disease', (47, 59))	('Cancer', 'Disease', (0, 6))	('brain tumor', 'Phenotype', 'HP:0030692', (136, 147))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('variants', 'Var', (22, 30))
91181	21203894	We examined variants implicated in recent cancer genome-wide association studies (GWAS) for associations with glioma risk in a US case-control study.	('glioma', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('variants', 'Var', (12, 20))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('associations', 'Interaction', (92, 104))
91182	21203894	We examined a total of 191 susceptibility variants in genes identified in published cancer GWAS including glioma.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('cancer', 'Disease', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('variants', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('glioma', 'Disease', (106, 112))
91184	21203894	Among glioma GWAS-identified variants, we detected associations in CDKN2B, RTEL1, TERT and PHLDB1, whereas we did not find overall associations for CCDC26.	('associations', 'Interaction', (51, 63))	('TERT', 'Gene', (82, 86))	('RTEL1', 'Gene', '51750', (75, 80))	('CDKN2B', 'Gene', (67, 73))	('RTEL1', 'Gene', (75, 80))	('CDKN2B', 'Gene', '1030', (67, 73))	('TERT', 'Gene', '7015', (82, 86))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('variants', 'Var', (29, 37))	('glioma GWAS', 'Disease', 'MESH:D005910', (6, 17))	('CCDC26', 'Gene', '137196', (148, 154))	('PHLDB1', 'Gene', '23187', (91, 97))	('PHLDB1', 'Gene', (91, 97))	('CCDC26', 'Gene', (148, 154))	('glioma GWAS', 'Disease', (6, 17))
91185	21203894	Results showed clear heterogeneity according to histologic subtypes of glioma, with TERT and RTEL variants a feature of astrocytic tumors and glioblastoma (GBM), CCDC26 and PHLDB1 variants a feature of astrocytic and oligodendroglial tumors, and CDKN2B variants most prominent in GBM.	('CDKN2B', 'Gene', (246, 252))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (202, 240))	('GBM', 'Disease', (280, 283))	('astrocytic tumors and glioblastoma', 'Disease', 'MESH:D005909', (120, 154))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (120, 136))	('variants', 'Var', (98, 106))	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('PHLDB1', 'Gene', (173, 179))	('CDKN2B', 'Gene', '1030', (246, 252))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('PHLDB1', 'Gene', '23187', (173, 179))	('CCDC26', 'Gene', '137196', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('GBM', 'Phenotype', 'HP:0012174', (280, 283))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('glioma', 'Disease', (71, 77))	('CCDC26', 'Gene', (162, 168))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('variants', 'Var', (253, 261))	('RTEL', 'Gene', (93, 97))	('variants', 'Var', (180, 188))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('RTEL', 'Gene', '51750', (93, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
91186	21203894	No examined variant in other cancer GWAS was found to be related to risk after adjustment for multiple comparisons.	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (29, 35))	('variant', 'Var', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
91187	21203894	These results suggest that GWAS-identified SNPs in glioma mark different molecular etiologies in glioma.	('glioma', 'Disease', (51, 57))	('SNPs', 'Var', (43, 47))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
91188	21203894	Stratification by broad histological subgroups may shed light on molecular mechanisms and assist in the discovery of novel loci in future studies of genetic susceptibility variants in glioma.	('variants', 'Var', (172, 180))	('glioma', 'Disease', (184, 190))	('glioma', 'Disease', 'MESH:D005910', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))
91194	21203894	The availability of commercial arrays that capture most common variation in the genome has made possible genome-wide association studies (GWAS) which have successfully identified several hundred common genetic variants associated with cancer, some linked to multiple cancer phenotypes.	('multiple cancer', 'Disease', 'MESH:D009369', (258, 273))	('associated', 'Reg', (219, 229))	('cancer', 'Disease', (267, 273))	('variants', 'Var', (210, 218))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('multiple cancer', 'Disease', (258, 273))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
91195	21203894	Two GWAS in glioma concordantly identified variants in CDKN2B, RTEL1 and TERT although results for other loci were not replicated in the two studies.	('CDKN2B', 'Gene', (55, 61))	('CDKN2B', 'Gene', '1030', (55, 61))	('TERT', 'Gene', '7015', (73, 77))	('glioma', 'Disease', (12, 18))	('TERT', 'Gene', (73, 77))	('RTEL1', 'Gene', '51750', (63, 68))	('RTEL1', 'Gene', (63, 68))	('variants', 'Var', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
91196	21203894	involved genotyping 275,895 autosomal variants among 692 adult high-grade glioma (GBM and anaplastic astrocytoma) cases drawn mainly from the San Francisco Adult Glioma Study (AGS) and 3,992 controls.	('AGS', 'Disease', 'MESH:C535607', (176, 179))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('variants', 'Var', (38, 46))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('astrocytoma', 'Disease', 'MESH:D001254', (101, 112))	('glioma', 'Disease', (74, 80))	('astrocytoma', 'Disease', (101, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('Glioma', 'Disease', 'MESH:D005910', (162, 168))	('Glioma', 'Phenotype', 'HP:0009733', (162, 168))	('AGS', 'Disease', (176, 179))	('Glioma', 'Disease', (162, 168))
91203	21203894	Moreover, the impact of these variants across the spectrum of glioma, a heterogenous tumor encompassing glioblastoma (GBM), the most common and aggressive astrocytic tumor, anaplastic and lower grade astrocytomas, oligodendroglioma and mixed oligoastrocytomas, has not yet been examined.	('tumor', 'Disease', (85, 90))	('variants', 'Var', (30, 38))	('astrocytomas', 'Disease', (200, 212))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('astrocytomas', 'Disease', 'MESH:D001254', (247, 259))	('astrocytoma', 'Phenotype', 'HP:0009592', (247, 258))	('glioma', 'Disease', (225, 231))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('astrocytomas', 'Disease', 'MESH:D001254', (200, 212))	('aggressive astrocytic tumor', 'Disease', (144, 171))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('oligodendroglioma', 'Disease', 'MESH:D009837', (214, 231))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (155, 171))	('tumor', 'Disease', (166, 171))	('oligodendroglioma', 'Disease', (214, 231))	('glioblastoma', 'Disease', (104, 116))	('oligoastrocytomas', 'Disease', (242, 259))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('glioma', 'Disease', (62, 68))	('aggressive astrocytic tumor', 'Disease', 'MESH:D001254', (144, 171))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (242, 259))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('astrocytomas', 'Disease', (247, 259))	('GBM', 'Phenotype', 'HP:0012174', (118, 121))
91204	21203894	Finally, the possibility that variants identified in GWAS of other primary cancers might impact glioma risk has not been explored.	('variants', 'Var', (30, 38))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('primary cancers might impact glioma', 'Disease', 'MESH:D005910', (67, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('primary cancers might impact glioma', 'Disease', (67, 102))
91222	21203894	Based on a review of diagnostic pathology reports, the case group was comprised of 354 (55%) GBMs (ICD-O code 9440/3); 153 (24%) lower grade pure astrocytic tumors including 77 grade 3 anaplastic astrocytoma (ICD-O 9401/3) and 76 grade 1 or 2 astrocytomas (ICD-O 9384/1, 9421/1, 9400/3, 9424/3); 99 (16%) mixed oligodendroglial and astrocytic tumors (ICD-O 9382/3) or pure oligodendrogliomas (ICD-O 9450/3, 9451/3), and 33 rare glioma variants (N = 16) or glioma with unspecified histology (N = 13) or unspecified histology and grade, e.g.	('astrocytomas', 'Disease', 'MESH:D001254', (243, 255))	('astrocytoma', 'Phenotype', 'HP:0009592', (243, 254))	('glioma', 'Disease', (384, 390))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('astrocytoma', 'Disease', 'MESH:D001254', (196, 207))	('glioma', 'Disease', (456, 462))	('astrocytoma', 'Disease', (196, 207))	('glioma', 'Disease', 'MESH:D005910', (384, 390))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('glioma', 'Disease', 'MESH:D005910', (456, 462))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (373, 391))	('astrocytic tumors', 'Disease', (332, 349))	('astrocytoma', 'Disease', 'MESH:D001254', (243, 254))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (332, 348))	('astrocytic tumors', 'Disease', 'MESH:D001254', (332, 349))	('ICD-O', 'Var', (351, 356))	('astrocytoma', 'Disease', (243, 254))	('glioma', 'Phenotype', 'HP:0009733', (384, 390))	('glioma', 'Disease', (428, 434))	('astrocytomas', 'Disease', (243, 255))	('ICD-O 9450/3', 'Var', (393, 405))	('glioma', 'Phenotype', 'HP:0009733', (456, 462))	('glioma', 'Disease', 'MESH:D005910', (428, 434))	('unspecified', 'Species', '32644', (502, 513))	('oligodendrogliomas', 'Disease', (373, 391))	('gliomas', 'Phenotype', 'HP:0009733', (384, 391))	('astrocytic tumors', 'Disease', (146, 163))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('unspecified', 'Species', '32644', (468, 479))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (146, 162))	('astrocytoma', 'Phenotype', 'HP:0009592', (196, 207))	('astrocytic tumors', 'Disease', 'MESH:D001254', (146, 163))	('oligodendroglial and astrocytic tumors', 'Disease', 'MESH:D001254', (311, 349))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('glioma', 'Phenotype', 'HP:0009733', (428, 434))
91234	21203894	A nonsynonymous SNP (N124S; rs3848668) located upstream of the GWAS variants was not significantly associated with glioma risk (Ptrend = 0.252).	('glioma', 'Disease', (115, 121))	('associated', 'Reg', (99, 109))	('GWAS', 'Gene', (63, 67))	('N124S; rs3848668', 'Var', (21, 37))	('rs3848668', 'Mutation', 'rs3848668', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('N124S', 'Mutation', 'rs3848668', (21, 26))
91235	21203894	In contrast, one synonymous (D664D; rs6062302) and one nonsynonymous (Q1042H; rs3208008) SNP, in tight linkage dis-equilibrium with 2 of the GWAS SNPs (rs6010620 and rs2297440) had strong associations with glioma risk (Ptrend < 0.001).	('D664D', 'Mutation', 'rs6062302', (29, 34))	('rs2297440', 'Mutation', 'rs2297440', (166, 175))	('rs3208008', 'Mutation', 'rs3208008', (78, 87))	('Q1042H', 'Mutation', 'rs3208008', (70, 76))	('rs2297440', 'Var', (166, 175))	('rs6010620', 'Mutation', 'rs6010620', (152, 161))	('D664D; rs6062302', 'Var', (29, 45))	('rs6010620', 'Var', (152, 161))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('rs6062302', 'Mutation', 'rs6062302', (36, 45))	('associations', 'Interaction', (188, 200))	('glioma', 'Disease', (206, 212))
91240	21203894	PHLDB1 rs498872 was significant only in lower grade astrocytic tumors (Ptrend = 0.001) with a borderline association also observed among the oligodendrogliomas (Ptrend = 0.042).	('astrocytic tumors', 'Disease', (52, 69))	('PHLDB1', 'Gene', '23187', (0, 6))	('PHLDB1', 'Gene', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('rs498872', 'Var', (7, 15))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (52, 68))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('rs498872', 'Mutation', 'rs498872', (7, 15))	('astrocytic tumors', 'Disease', 'MESH:D001254', (52, 69))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (141, 159))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('oligodendrogliomas', 'Disease', (141, 159))
91242	21203894	A case-only analysis (Table 3) showed a deficit of variant alleles in RTEL1 rs4809324 (OR: 0.50; 95% CI 0.28-0.91; Ptrend = 0.023) in oligodendroglial tumors when compared to GBM; the same pattern was observed for all 4 CDKN2B SNPs.	('deficit', 'NegReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('rs4809324', 'Mutation', 'rs4809324', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('GBM', 'Phenotype', 'HP:0012174', (175, 178))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (134, 157))	('oligodendroglial tumors', 'Disease', (134, 157))	('variant', 'Var', (51, 58))	('RTEL1', 'Gene', '51750', (70, 75))	('rs4809324', 'Var', (76, 85))	('CDKN2B', 'Gene', (220, 226))	('CDKN2B', 'Gene', '1030', (220, 226))	('RTEL1', 'Gene', (70, 75))
91243	21203894	In contrast, an excess of variant alleles was observed in CCDC26 rs4809324, rs16904140 and rs4295627 for oligodendroglial and astrocytic tumors when compared to GBM.	('rs4809324', 'Mutation', 'rs4809324', (65, 74))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (126, 142))	('rs16904140', 'Var', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('oligodendroglial and astrocytic tumors', 'Disease', 'MESH:D001254', (105, 143))	('CCDC26', 'Gene', (58, 64))	('CCDC26', 'Gene', '137196', (58, 64))	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('rs4295627', 'Var', (91, 100))	('rs16904140', 'Mutation', 'rs16904140', (76, 86))	('rs4295627', 'Mutation', 'rs4295627', (91, 100))	('rs4809324', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
91244	21203894	Deleterious alleles in PHLDB1 rs498872 were approximately 40% more common for astrocytic tumors than GBM (OR: 1.41; 95% CI 1.04-1.92; Ptrend = 0.028).	('astrocytic tumor', 'Phenotype', 'HP:0009592', (78, 94))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('rs498872', 'Mutation', 'rs498872', (30, 38))	('common', 'Reg', (67, 73))	('astrocytic tumors', 'Disease', (78, 95))	('PHLDB1', 'Gene', '23187', (23, 29))	('PHLDB1', 'Gene', (23, 29))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('astrocytic tumors', 'Disease', 'MESH:D001254', (78, 95))	('rs498872', 'Var', (30, 38))
91247	21203894	The latter included an intergenic SNP (rs7300686) on chromosome 12 (overall Ptrend = 0.012) in which the association was significant only among astrocytic tumors (per allele OR: 1.39; Ptrend = 0.012) and an intergenic SNP (rs1384847) on chromosome 4 (overall Ptrend = 0.043) in which the association was driven mainly by association with GBMs (per allele OR: 1.46; Ptrend = 0.028).	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('astrocytic tumors', 'Disease', 'MESH:D001254', (144, 161))	('rs7300686', 'Mutation', 'rs7300686', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('rs1384847', 'Mutation', 'rs1384847', (223, 232))	('GBMs', 'Disease', (338, 342))	('GBM', 'Phenotype', 'HP:0012174', (338, 341))	('rs1384847', 'Var', (223, 232))	('rs7300686', 'Var', (39, 48))	('astrocytic tumors', 'Disease', (144, 161))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (144, 160))
91248	21203894	which included primarily GBMs: CSF1R rs10079250 on chromosome 5, rs11163687 on chromosome 7 near the gene TTLL7 and rs11823971 on chromosome 11 near the gene PDE2A.	('rs10079250', 'Var', (37, 47))	('rs11163687', 'Var', (65, 75))	('TTLL7', 'Gene', (106, 111))	('rs11163687', 'Mutation', 'rs11163687', (65, 75))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('rs11823971 on', 'Var', (116, 129))	('PDE2A', 'Gene', '5138', (158, 163))	('CSF1R', 'Gene', '1436', (31, 36))	('TTLL7', 'Gene', '79739', (106, 111))	('PDE2A', 'Gene', (158, 163))	('rs11823971', 'Mutation', 'rs11823971', (116, 126))	('rs10079250', 'Mutation', 'rs10079250', (37, 47))	('CSF1R', 'Gene', (31, 36))
91249	21203894	There was no evidence of LD between the SNP on chromosome 5 and the TERT SNPs (R2 = 0.008, D' = 0.37 for rs2736100 in TERT in HapMap) or the SNP on chromosome 11 and the PHLDB1 SNP (R2 = 0.008 and D' = 0.20 in HapMap).	('TERT', 'Gene', '7015', (118, 122))	('TERT', 'Gene', (68, 72))	('rs2736100', 'Mutation', 'rs2736100', (105, 114))	('TERT', 'Gene', '7015', (68, 72))	('rs2736100', 'Var', (105, 114))	('PHLDB1', 'Gene', '23187', (170, 176))	('PHLDB1', 'Gene', (170, 176))	('TERT', 'Gene', (118, 122))
91250	21203894	We did not find evidence of association for these 3 SNPs with glioma risk, overall, or for GBM only, although all 3 variants were uncommon (MAF: 5, 13 and 9% in controls, respectively), limiting our power.	('variants', 'Var', (116, 124))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioma', 'Disease', (62, 68))
91251	21203894	However, we did observe borderline associations within astrocytic tumors for rs11163687 (OR: 0.58; 95% CI 0.36-0.93; Ptrend = 0.024) and rs10079250 (OR: 1.88; 95% CI: 1.09-3.25; Ptrend = 0.023).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('astrocytic tumors', 'Disease', (55, 72))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (55, 71))	('rs10079250', 'Mutation', 'rs10079250', (137, 147))	('rs10079250', 'Var', (137, 147))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('astrocytic tumors', 'Disease', 'MESH:D001254', (55, 72))	('rs11163687', 'Var', (77, 87))	('rs11163687', 'Mutation', 'rs11163687', (77, 87))
91255	21203894	The current study provides evidence that susceptibility variants identified in published glioma GWAS differ among GBM, lower grade astrocytic tumors and oligodendrogliomas and mixed tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('glioma GWAS', 'Disease', 'MESH:D005910', (89, 100))	('GBM', 'Disease', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('oligodendrogliomas', 'Disease', (153, 171))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', (142, 148))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('variants', 'Var', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('astrocytic tumors', 'Disease', (131, 148))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (131, 147))	('astrocytic tumors', 'Disease', 'MESH:D001254', (131, 148))	('glioma GWAS', 'Disease', (89, 100))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (153, 171))
91258	21203894	In the present study, variants in CCDC26 and PHLDB1 were associated primarily with astrocytic and oligodendroglial tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CCDC26', 'Gene', (34, 40))	('PHLDB1', 'Gene', '23187', (45, 51))	('CCDC26', 'Gene', '137196', (34, 40))	('PHLDB1', 'Gene', (45, 51))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (83, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('variants', 'Var', (22, 30))	('associated', 'Reg', (57, 67))
91259	21203894	CCDC26 rs4295627 provided the strongest signal in the Shete GWAS.	('CCDC26', 'Gene', (0, 6))	('CCDC26', 'Gene', '137196', (0, 6))	('Shete GWAS', 'CPA', (54, 64))	('rs4295627', 'Mutation', 'rs4295627', (7, 16))	('rs4295627', 'Var', (7, 16))
91260	21203894	we did not detect association for CCDC26 rs4295627 or 4 other variants in CCDC26 also linked to risk in the Shete GWAS in a combined analysis.	('rs4295627', 'Mutation', 'rs4295627', (41, 50))	('CCDC26', 'Gene', (74, 80))	('CCDC26', 'Gene', '137196', (74, 80))	('CCDC26', 'Gene', (34, 40))	('CCDC26', 'Gene', '137196', (34, 40))	('linked', 'Reg', (86, 92))	('rs4295627', 'Var', (41, 50))
91263	21203894	The SNP rs498872 which maps to the 5'UTR of PHLDB1 provided the fifth-strongest signal in the Shete GWAS.	('rs498872', 'Mutation', 'rs498872', (8, 16))	('rs498872', 'Var', (8, 16))	('signal', 'MPA', (80, 86))	('PHLDB1', 'Gene', '23187', (44, 50))	('PHLDB1', 'Gene', (44, 50))
91266	21203894	In these data, variants in TERT, RTEL and CDKN2B were primarily a feature of astrocytic tumors and GBM.	('RTEL', 'Gene', '51750', (33, 37))	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (77, 93))	('TERT', 'Gene', (27, 31))	('TERT', 'Gene', '7015', (27, 31))	('RTEL', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CDKN2B', 'Gene', (42, 48))	('astrocytic tumors', 'Disease', (77, 94))	('GBM', 'Disease', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('variants', 'Var', (15, 23))	('astrocytic tumors', 'Disease', 'MESH:D001254', (77, 94))	('CDKN2B', 'Gene', '1030', (42, 48))
91267	21203894	TERT rs2736100, CDKN2B rs4977756 and RTEL1 rs6010620 provided the second, third and fourth strongest signal, respectively, in the GWAS of Shete et al.	('rs2736100', 'Mutation', 'rs2736100', (5, 14))	('RTEL1', 'Gene', '51750', (37, 42))	('rs4977756', 'Var', (23, 32))	('RTEL1', 'Gene', (37, 42))	('CDKN2B', 'Gene', (16, 22))	('TERT', 'Gene', (0, 4))	('CDKN2B', 'Gene', '1030', (16, 22))	('TERT', 'Gene', '7015', (0, 4))	('rs6010620', 'Mutation', 'rs6010620', (43, 52))	('rs6010620', 'Var', (43, 52))	('rs4977756', 'Mutation', 'rs4977756', (23, 32))
91269	21203894	In the current study, TERT rs2736100 was significantly associated only with GBM whereas RTEL1 rs6010620 was more strongly associated with the lower grade astrocytic tumors.	('associated', 'Reg', (122, 132))	('TERT', 'Gene', (22, 26))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (154, 170))	('RTEL1', 'Gene', '51750', (88, 93))	('rs6010620', 'Mutation', 'rs6010620', (94, 103))	('RTEL1', 'Gene', (88, 93))	('TERT', 'Gene', '7015', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('rs6010620', 'Var', (94, 103))	('associated', 'Reg', (55, 65))	('GBM', 'Disease', (76, 79))	('rs2736100', 'Mutation', 'rs2736100', (27, 36))	('astrocytic tumors', 'Disease', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('astrocytic tumors', 'Disease', 'MESH:D001254', (154, 171))
91270	21203894	Variants in CDKN2B were most prominent in GBM although odds ratios were nonsignificantly elevated also for astrocytic tumors.	('astrocytic tumors', 'Disease', (107, 124))	('Variants', 'Var', (0, 8))	('GBM', 'Disease', (42, 45))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (107, 123))	('CDKN2B', 'Gene', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('astrocytic tumors', 'Disease', 'MESH:D001254', (107, 124))	('prominent', 'Reg', (29, 38))	('CDKN2B', 'Gene', '1030', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('elevated', 'PosReg', (89, 97))
91271	21203894	The suggestion from these data that genetic variation in TERT, RTEL and CDKN2B play a more prominent role in tumors with astrocyte lineage should be explored in larger studies.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('CDKN2B', 'Gene', '1030', (72, 78))	('RTEL', 'Gene', (63, 67))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('RTEL', 'Gene', '51750', (63, 67))	('genetic variation', 'Var', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CDKN2B', 'Gene', (72, 78))	('tumors', 'Disease', (109, 115))
91272	21203894	We examined association of the variants in these genes (listed in Table 1) with mortality rates in our series of GBM patients and could demonstrate no significant associations.	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('variants', 'Var', (31, 39))	('examined', 'Reg', (3, 11))	('association', 'Interaction', (12, 23))	('patients', 'Species', '9606', (117, 125))
91273	21203894	A recent study suggested that CCDC26 rs10464870 and rs891835 and RTEL1 rs2297440 and rs6010620 predict long-term survival (>=36 months) in GBM.	('rs10464870', 'Var', (37, 47))	('CCDC26', 'Gene', (30, 36))	('CCDC26', 'Gene', '137196', (30, 36))	('rs891835', 'Mutation', 'rs891835', (52, 60))	('rs891835', 'Var', (52, 60))	('rs2297440', 'Mutation', 'rs2297440', (71, 80))	('RTEL1', 'Gene', '51750', (65, 70))	('rs2297440', 'Var', (71, 80))	('GBM', 'Disease', (139, 142))	('rs10464870', 'Mutation', 'rs10464870', (37, 47))	('predict', 'Reg', (95, 102))	('rs6010620', 'Mutation', 'rs6010620', (85, 94))	('RTEL1', 'Gene', (65, 70))	('rs6010620', 'Var', (85, 94))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
91275	21203894	In addition to top-hit variants in these 5 genes, we detected associations in 2 intergenic SNPs identified the Shete GWAS (rs1384847 and rs7300686).	('rs7300686', 'Mutation', 'rs7300686', (137, 146))	('rs1384847', 'Mutation', 'rs1384847', (123, 132))	('associations', 'Reg', (62, 74))	('rs1384847', 'Var', (123, 132))	('rs7300686', 'Var', (137, 146))
91276	21203894	Furthermore, there was no evidence in our data that associations involving these variants were confined to lower grade astrocytic tumors and/or oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('astrocytic tumors', 'Disease', 'MESH:D001254', (119, 136))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (144, 162))	('associations', 'Interaction', (52, 64))	('oligodendrogliomas', 'Disease', (144, 162))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('astrocytic tumors', 'Disease', (119, 136))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (119, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('variants', 'Var', (81, 89))
91277	21203894	Three variants identified uniquely in the Wrensch GWAS were not associated with risk in current study, overall, or among high-grade tumors.	('variants', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
91279	21203894	We examined SNPs identified in GWAS of other cancers published up to Summer 2009 and found modest associations in several variants, although none remained significant after adjustment for multiple comparisons.	('variants', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('associations', 'Interaction', (98, 110))	('cancers', 'Disease', (45, 52))
91281	21203894	An intronic SNP (rs402710) located in CLPTM1L near TERT, identified in lung cancer GWAS, was marginally associated with risk in the current data (Ptrend = 0.039) before adjustment; this SNP is uncorrelated with TERT rs2736100 and TERT rs2853676 (not shown).	('TERT', 'Gene', '7015', (211, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('TERT', 'Gene', (51, 55))	('rs2853676', 'Mutation', 'rs2853676', (235, 244))	('TERT', 'Gene', (230, 234))	('rs2736100', 'Mutation', 'rs2736100', (216, 225))	('TERT', 'Gene', '7015', (230, 234))	('CLPTM1L', 'Gene', '81037', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CLPTM1L', 'Gene', (38, 45))	('TERT', 'Gene', '7015', (51, 55))	('rs402710', 'Mutation', 'rs402710', (17, 25))	('TERT', 'Gene', (211, 215))	('lung cancer', 'Disease', (71, 82))	('rs402710', 'Var', (17, 25))
91283	21203894	The SNP rs6983267 near POU5F1P1 on chromosome 8 is multicancer susceptibility marker linked to prostate, colon, and a range of other cancers.	('colon', 'Disease', (105, 110))	('SNP', 'Var', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('prostate', 'Disease', (95, 103))	('POU5F1P1', 'Gene', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('rs6983267', 'Mutation', 'rs6983267', (8, 17))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('POU5F1P1', 'Gene', '5462', (23, 31))	('colon', 'Disease', 'MESH:D015179', (105, 110))	('cancer', 'Disease', (56, 62))	('linked', 'Reg', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
91285	21203894	Two breast cancer variants in FGFR2 (rs1219648 and rs2981582) were each marginally associated with glioma risk before adjustment; that amplification of FGFR2 has been noted in GBM suggests these variants may have a causal role in glioma and should be examined in larger studies.	('rs2981582', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('glioma', 'Disease', (99, 105))	('FGFR2', 'Gene', '2263', (30, 35))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('rs1219648', 'Var', (37, 46))	('FGFR2', 'Gene', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('rs1219648', 'Mutation', 'rs1219648', (37, 46))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('FGFR2', 'Gene', '2263', (152, 157))	('breast cancer', 'Disease', (4, 17))	('rs2981582', 'Mutation', 'rs2981582', (51, 60))	('GBM', 'Phenotype', 'HP:0012174', (176, 179))	('glioma', 'Disease', (230, 236))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('associated', 'Reg', (83, 93))	('FGFR2', 'Gene', (30, 35))
91287	21203894	Our study had limited power to detect associations with rare variants and those with modest relative risks, and the study size only permitted us to examine associations according to broad histological strata of glioma.	('associations', 'Interaction', (38, 50))	('glioma', 'Disease', (211, 217))	('variants', 'Var', (61, 69))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))
91289	21203894	We note, however, that our results are consistent with those in a recent report that showed distinct patterns of association for the five most prominent SNPs in the Shete GWAS according to WHO grade of glioma.	('association', 'Interaction', (113, 124))	('SNPs', 'Var', (153, 157))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('glioma', 'Disease', (202, 208))
91290	21203894	As in the current study, risk alleles for TERT rs2736100 were strongly correlated with the diagnosis of GBM whereas carrier frequencies of risk alleles of CCDC26 rs4295627 and PHLDB1 rs498872 were inversely correlated with GBM histology (RTEL1 rs6010620 had a stronger association with GBM in that study).	('RTEL1', 'Gene', (238, 243))	('CCDC26', 'Gene', '137196', (155, 161))	('GBM', 'Disease', (104, 107))	('rs498872', 'Var', (183, 191))	('CCDC26', 'Gene', (155, 161))	('rs498872', 'Mutation', 'rs498872', (183, 191))	('rs6010620', 'Mutation', 'rs6010620', (244, 253))	('rs4295627', 'Var', (162, 171))	('RTEL1', 'Gene', '51750', (238, 243))	('GBM', 'Disease', (223, 226))	('GBM', 'Disease', (286, 289))	('correlated', 'Reg', (207, 217))	('correlated', 'Reg', (71, 81))	('TERT', 'Gene', (42, 46))	('GBM', 'Phenotype', 'HP:0012174', (104, 107))	('TERT', 'Gene', '7015', (42, 46))	('PHLDB1', 'Gene', '23187', (176, 182))	('PHLDB1', 'Gene', (176, 182))	('rs2736100', 'Mutation', 'rs2736100', (47, 56))	('GBM', 'Phenotype', 'HP:0012174', (223, 226))	('GBM', 'Phenotype', 'HP:0012174', (286, 289))	('rs4295627', 'Mutation', 'rs4295627', (162, 171))
91291	21203894	In both series, CDKN2B rs4977756 risk allele frequency did not vary strongly by histology in astrocyte lineage tumors.	('rs4977756', 'Var', (23, 32))	('CDKN2B', 'Gene', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('CDKN2B', 'Gene', '1030', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('rs4977756', 'Mutation', 'rs4977756', (23, 32))
91300	21046410	Novel MYB amplifications that upregulate MYB RNA and protein expression were demonstrated in 2/14 diffuse astrocytomas.	('MYB', 'Gene', (6, 9))	('astrocytomas', 'Disease', 'MESH:D001254', (106, 118))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('astrocytomas', 'Disease', (106, 118))	('upregulate', 'PosReg', (30, 40))	('amplifications', 'Var', (10, 24))	('MYB', 'Gene', '4602', (41, 44))	('MYB', 'Gene', '4602', (6, 9))	('MYB', 'Gene', (41, 44))
91301	21046410	In addition, focal deletion of the terminal region of MYB was seen in 1 of 2 angiocentric gliomas (AGs).	('angiocentric gliomas', 'Disease', (77, 97))	('deletion', 'Var', (19, 27))	('MYB', 'Gene', '4602', (54, 57))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('MYB', 'Gene', (54, 57))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (77, 97))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
91304	21046410	Our data suggest that MYB may have a role in a subset of pediatric gliomas, through a variety of mechanisms in addition to MYB amplification and deletion.	('pediatric gliomas', 'Disease', 'MESH:D005910', (57, 74))	('MYB', 'Gene', '4602', (22, 25))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('pediatric gliomas', 'Disease', (57, 74))	('MYB', 'Gene', (22, 25))	('role', 'Reg', (37, 41))	('MYB', 'Gene', '4602', (123, 126))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('MYB', 'Gene', (123, 126))	('deletion', 'Var', (145, 153))
91311	21046410	In adults, mutations affecting the two isocitrate dehydrogenase (IDH) enzymes characterize the majority of WHO grade II-III astrocytomas.	('mutations', 'Var', (11, 20))	('IDH', 'Gene', (65, 68))	('isocitrate dehydrogenase', 'Gene', (39, 63))	('astrocytomas', 'Disease', 'MESH:D001254', (124, 136))	('IDH', 'Gene', '3417', (65, 68))	('isocitrate dehydrogenase', 'Gene', '3417', (39, 63))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('astrocytomas', 'Disease', (124, 136))
91312	21046410	IDH1 mutations have been reported in pediatric DAs, but at a much lower frequency than in adults.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
91313	21046410	TP53 mutations are also common in adult diffuse (fibrillary) astrocytomas (WHO grade II), and the majority of these tumors will undergo further transformation to anaplastic astrocytoma or glioblastoma.	('tumors', 'Disease', (116, 122))	('astrocytomas', 'Disease', 'MESH:D001254', (61, 73))	('TP53', 'Gene', '7157', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', (0, 4))	('anaplastic astrocytoma', 'Disease', (162, 184))	('glioblastoma', 'Disease', (188, 200))	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('astrocytomas', 'Disease', (61, 73))	('mutations', 'Var', (5, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (162, 184))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('undergo', 'Reg', (128, 135))	('common', 'Reg', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
91314	21046410	In contrast, TP53 mutations are rarely seen in pediatric DAs, and less than 10% of these tumors undergo progression to a HGG.	('TP53', 'Gene', (13, 17))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (18, 27))
91315	21046410	Deletions of chromosome arms 1p and 19q are seen in approximately 80% of adult oligodendrogliomas and are associated with a favorable outcome.	('arms 1p', 'Gene', (24, 31))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (79, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('oligodendrogliomas', 'Disease', (79, 97))	('arms 1p', 'Gene', '3075', (24, 31))	('Deletions', 'Var', (0, 9))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
91316	21046410	Oligodendrogliomas in childhood are rare; few contain 1p/19q loss, and no survival advantages are associated with 1p/19q deletions in this age group.	('1p/19q', 'Gene', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('1p/19q deletions', 'Var', (114, 130))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
91322	21046410	Focal deletion of the 3' region of MYB was also found in 1 of 2 angiocentric gliomas (AGs).	('angiocentric gliomas', 'Disease', (64, 84))	('MYB', 'Gene', (35, 38))	('Focal deletion', 'Var', (0, 14))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('found', 'Reg', (48, 53))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (64, 84))	('MYB', 'Gene', '4602', (35, 38))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
91339	21046410	Clones RP11-366H19 and RP11-170P19 were used to probe the regions of possible copy number loss in DA1 and DA2.	('RP11', 'Gene', '26121', (7, 11))	('DA1', 'Gene', (98, 101))	('RP11', 'Gene', (23, 27))	('copy number loss', 'Var', (78, 94))	('RP11', 'Gene', '26121', (23, 27))	('DA1', 'Gene', '28495', (98, 101))	('DA2', 'Gene', (106, 109))	('RP11', 'Gene', (7, 11))
91363	21046410	DA1 showed a large 370Kb region of copy number gain at 6q23 centromeric to MYB, including the non-coding gene AJ606331.	('MYB', 'Gene', '4602', (75, 78))	('DA1', 'Gene', (0, 3))	('MYB', 'Gene', (75, 78))	('gain', 'PosReg', (47, 51))	('copy number', 'Var', (35, 46))	('DA1', 'Gene', '28495', (0, 3))
91367	21046410	Regions of copy number gain within MYB were subsequently confirmed by DNA qPCR.	('MYB', 'Gene', '4602', (35, 38))	('copy number', 'Var', (11, 22))	('gain', 'PosReg', (23, 27))	('MYB', 'Gene', (35, 38))
91371	21046410	Dual-color interphase FISH (iFISH) confirmed amplification of the MYB locus at 6q23 in both DAs with copy number gains.	('MYB', 'Gene', '4602', (66, 69))	('copy number gains', 'Var', (101, 118))	('MYB', 'Gene', (66, 69))	('amplification', 'Var', (45, 58))
91374	21046410	Three LGGs (DA13, OA3, PA12) showed polysomy 6, with 3-8 copies per cell.	('DA1', 'Gene', '28495', (12, 15))	('OA3', 'Gene', '4936', (18, 21))	('polysomy 6', 'Var', (36, 46))	('OA3', 'Gene', (18, 21))	('DA1', 'Gene', (12, 15))
91375	21046410	Further iFISH was performed to investigate the co-amplified regions that included AJ606331 or MAP7/MAP3K5 in DA1 and DA2, respectively.	('DA1', 'Gene', (109, 112))	('MAP7', 'Gene', '9053', (94, 98))	('MAP7', 'Gene', (94, 98))	('MAP3K5', 'Gene', '4217', (99, 105))	('MAP3K5', 'Gene', (99, 105))	('DA1', 'Gene', '28495', (109, 112))	('AJ606331', 'Var', (82, 90))
91377	21046410	Hemizygous deletion was confirmed between the amplified region of MYB and MAP7/MAP3K5 in DA2; however, no deletion was found in the region between AJ606331 and MYB in DA1, where two copies of the target probe were present (data not shown).	('MYB', 'Gene', (66, 69))	('DA1', 'Gene', (167, 170))	('MAP7', 'Gene', '9053', (74, 78))	('MYB', 'Gene', '4602', (160, 163))	('MYB', 'Gene', (160, 163))	('MYB', 'Gene', '4602', (66, 69))	('MAP7', 'Gene', (74, 78))	('MAP3K5', 'Gene', '4217', (79, 85))	('AJ606331', 'Var', (147, 155))	('MAP3K5', 'Gene', (79, 85))	('DA1', 'Gene', '28495', (167, 170))
91409	21046410	Chromosomal instability was investigated as a possible cause for the genetic abnormalities in the two DAs with MYB amplification.	('MYB', 'Gene', '4602', (111, 114))	('amplification', 'Var', (115, 128))	('MYB', 'Gene', (111, 114))	('genetic abnormalities', 'Disease', 'MESH:D030342', (69, 90))	('genetic abnormalities', 'Disease', (69, 90))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))
91418	21046410	Fifty-seven pediatric LGGs were screened for activating mutations at known mutation hotspots in BRAF (exon 15), KRAS (exons 2 and 3) and for somatic mutations known to perturb enzymatic function in IDH1 (exon 4) and IDH2 (exons 4 and 5).	('mutations', 'Var', (56, 65))	('mutations', 'Var', (149, 158))	('perturb', 'NegReg', (168, 175))	('IDH1', 'Gene', (198, 202))	('IDH2', 'Gene', (216, 220))	('activating', 'PosReg', (45, 55))	('IDH1', 'Gene', '3417', (198, 202))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('KRAS', 'Gene', (112, 116))	('KRAS', 'Gene', '3845', (112, 116))	('IDH2', 'Gene', '3418', (216, 220))
91419	21046410	Two samples were found to contain the BRAF p.V600E activating mutation.	('p.V600E', 'Mutation', 'rs113488022', (43, 50))	('BRAF', 'Gene', '673', (38, 42))	('p.V600E', 'Var', (43, 50))	('activating', 'PosReg', (51, 61))	('BRAF', 'Gene', (38, 42))
91421	21046410	This sample had not been screened by SNP array, but showed polysomy at the CDKN2A locus by iFISH.	('CDKN2A', 'Gene', '1029', (75, 81))	('CDKN2A', 'Gene', (75, 81))	('polysomy', 'Var', (59, 67))
91428	21046410	The rate of anaplastic progression in pediatric grade II LGGs is much lower than in their adult counterparts, and the frequency of specific molecular genetic abnormalities, such as TP53 or IDH1 mutations in diffuse astrocytomas and 1p/19q loss in oligodendrogliomas, is much lower in pediatric tumors.	('TP53', 'Gene', (181, 185))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (247, 265))	('astrocytomas', 'Disease', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('genetic abnormalities', 'Disease', 'MESH:D030342', (150, 171))	('pediatric tumors', 'Disease', 'MESH:D063766', (284, 300))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('pediatric tumors', 'Disease', (284, 300))	('genetic abnormalities', 'Disease', (150, 171))	('anaplastic progression', 'CPA', (12, 34))	('oligodendrogliomas', 'Disease', (247, 265))	('IDH1', 'Gene', (189, 193))	('TP53', 'Gene', '7157', (181, 185))	('astrocytomas', 'Disease', 'MESH:D001254', (215, 227))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('loss', 'NegReg', (239, 243))	('1p/19q', 'Var', (232, 238))	('gliomas', 'Phenotype', 'HP:0009733', (258, 265))	('IDH1', 'Gene', '3417', (189, 193))	('mutations', 'Var', (194, 203))	('lower', 'NegReg', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
91430	21046410	Amplifications of MYB, apparently driving upregulation of the gene product, occurred at low frequency in DAs, but not in PAs.	('MYB', 'Gene', '4602', (18, 21))	('MYB', 'Gene', (18, 21))	('Amplifications', 'Var', (0, 14))	('DAs', 'Disease', (105, 108))	('upregulation', 'PosReg', (42, 54))
91449	21046410	Various human neoplasms harbor genomic rearrangements and CNAs within MYB.	('neoplasms', 'Disease', 'MESH:D009369', (14, 23))	('MYB', 'Gene', (70, 73))	('neoplasms', 'Disease', (14, 23))	('MYB', 'Gene', '4602', (70, 73))	('neoplasms', 'Phenotype', 'HP:0002664', (14, 23))	('genomic rearrangements', 'Var', (31, 53))	('human', 'Species', '9606', (8, 13))
91452	21046410	MYB duplications characterize disease in an additional group of T-ALL patients.	('MYB', 'Gene', (0, 3))	('patients', 'Species', '9606', (70, 78))	('characterize', 'Reg', (17, 29))	('disease', 'Disease', (30, 37))	('duplications', 'Var', (4, 16))	('MYB', 'Gene', '4602', (0, 3))
91454	21046410	MYB amplifications have also been identified in several solid tumors.	('MYB', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('amplifications', 'Var', (4, 18))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('MYB', 'Gene', '4602', (0, 3))	('identified', 'Reg', (34, 44))
91455	21046410	High-level amplifications occurred in 29% of hereditary BRCA1 breast cancers, which compares with 2% in sporadic breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancers', 'Disease', (113, 127))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('hereditary BRCA1 breast cancers', 'Disease', (45, 76))	('amplifications', 'Var', (11, 25))	('occurred', 'Reg', (26, 34))	('hereditary BRCA1 breast cancers', 'Disease', 'MESH:D001943', (45, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (113, 127))
91457	21046410	MYB DNA copy number gains have been demonstrated in approximately 10% of pancreatic carcinomas and FISH using the P2 pancreatic cancer cell line confirmed amplification of MYB as homogeneously staining regions.	('MYB', 'Gene', (0, 3))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (73, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('pancreatic carcinomas', 'Disease', (73, 94))	('MYB', 'Gene', '4602', (172, 175))	('MYB', 'Gene', '4602', (0, 3))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('copy number gains', 'Var', (8, 25))	('MYB', 'Gene', (172, 175))
91458	21046410	Studies of CNS tumors using array-based comparative genomic hybridization (CGH) have identified MYB copy number gain in one supratentorial primitive neuroectodermal tumor, a finding validated by semi-quantitative multiplex PCR, and in 5 of 10 medulloblastomas, although these results were not confirmed by another method.	('neuroectodermal tumor', 'Disease', (149, 170))	('MYB', 'Gene', (96, 99))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (139, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('medulloblastomas', 'Disease', (243, 259))	('CNS tumors', 'Disease', 'MESH:D009369', (11, 21))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (149, 170))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (149, 170))	('copy number', 'Var', (100, 111))	('gain', 'PosReg', (112, 116))	('CNS tumors', 'Disease', (11, 21))	('MYB', 'Gene', '4602', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('medulloblastomas', 'Disease', 'MESH:D008527', (243, 259))
91466	21046410	Our data demonstrated two possible genomic mechanisms for MYB upregulation; MYB amplification in two DAs and loss of the 3' region of MYB in a single angiocentric glioma were both associated with increased expression at RNA and protein levels.	('amplification', 'Var', (80, 93))	('angiocentric glioma', 'Disease', (150, 169))	('increased', 'PosReg', (196, 205))	('MYB', 'Gene', '4602', (76, 79))	('MYB', 'Gene', (76, 79))	('expression', 'MPA', (206, 216))	('loss', 'NegReg', (109, 113))	('angiocentric glioma', 'Disease', 'MESH:D005910', (150, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('MYB', 'Gene', '4602', (58, 61))	('MYB', 'Gene', '4602', (134, 137))	('MYB', 'Gene', (134, 137))	('MYB', 'Gene', (58, 61))
91469	21046410	Discrete copy number loss at 6q24-25 by metaphase comparative genomic hybridization (CGH) has previously been reported in 1 of 8 angiocentric gliomas, and this may represent the same region of loss demonstrated here.	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('angiocentric gliomas', 'Disease', (129, 149))	('Discrete copy number loss', 'Var', (0, 25))	('reported', 'Reg', (110, 118))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (129, 149))
91470	21046410	Array data for both DAs with MYB amplification indicated additional regions of amplification on 6q23.	('amplification', 'Var', (33, 46))	('MYB', 'Gene', '4602', (29, 32))	('MYB', 'Gene', (29, 32))
91472	21046410	The amplicon situated centromeric to MYB in DA1 contains the non-coding gene AJ606331.	('MYB', 'Gene', '4602', (37, 40))	('MYB', 'Gene', (37, 40))	('DA1', 'Gene', '28495', (44, 47))	('AJ606331', 'Var', (77, 85))	('DA1', 'Gene', (44, 47))
91477	21046410	Chromosomal instability was considered as a possible cause for the genetic rearrangements in the two DAs with MYB amplification, but no significant differences were found when comparing the number of genetic gains and losses between these cases and a representative group of LGGs with no CNAs.	('MYB', 'Gene', '4602', (110, 113))	('amplification', 'Var', (114, 127))	('MYB', 'Gene', (110, 113))	('genetic gains', 'Disease', 'MESH:D030342', (200, 213))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('genetic gains', 'Disease', (200, 213))
91478	21046410	MYB upregulation was not confined to the diffuse gliomas with MYB amplification or deletion; immunohistochemistry disclosed increased nuclear expression of MYB in 41% of PAs and 19% of HGGs.	('MYB', 'Gene', (0, 3))	('PAs', 'Disease', (170, 173))	('amplification', 'Var', (66, 79))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('MYB', 'Gene', '4602', (156, 159))	('increased', 'PosReg', (124, 133))	('nuclear expression', 'MPA', (134, 152))	('MYB', 'Gene', (156, 159))	('MYB', 'Gene', (62, 65))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('MYB', 'Gene', '4602', (0, 3))	('MYB', 'Gene', '4602', (62, 65))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
91488	21046410	Further, our immunohistochemical data indicate that upregulation of MYB can occur through mechanisms other than gene amplification or deletion of the 3'UTR, and that it can be a feature of other types of LGG and even some HGGs, suggesting a broader role for MYB in gliomagenesis.	('upregulation', 'PosReg', (52, 64))	('MYB', 'Gene', (258, 261))	('glioma', 'Phenotype', 'HP:0009733', (265, 271))	('deletion', 'Var', (134, 142))	('MYB', 'Gene', '4602', (68, 71))	('MYB', 'Gene', (68, 71))	('MYB', 'Gene', '4602', (258, 261))
91491	31550353	We included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant).	('glioma', 'Disease', (69, 75))	('IDH', 'Gene', (279, 282))	('isocitrate dehydrogenase', 'Gene', '3417', (101, 125))	('glioblastoma', 'Disease', (196, 208))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioblastoma', 'Disease', (244, 256))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('astrocytomas', 'Disease', (87, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (244, 256))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (161, 164))	('glioma', 'Disease', (153, 159))	('IDH', 'Gene', '3417', (279, 282))	('oligodendroglioma', 'Disease', 'MESH:D009837', (142, 159))	('IDH', 'Gene', (260, 263))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('IDH', 'Gene', '3417', (127, 130))	('oligodendroglioma', 'Disease', (142, 159))	('isocitrate dehydrogenase', 'Gene', (101, 125))	('astrocytomas', 'Disease', 'MESH:D001254', (87, 99))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('IDH', 'Gene', '3417', (260, 263))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('IDH', 'Gene', (209, 212))	('mutant', 'Var', (132, 138))	('glioma', 'Disease', (236, 242))	('glioblastoma', 'Disease', 'MESH:D005909', (196, 208))	('glioma', 'Disease', 'MESH:D005910', (236, 242))	('glioblastoma', 'Disease', 'MESH:D005909', (244, 256))	('IDH', 'Gene', (161, 164))	('IDH', 'Gene', '3417', (209, 212))
91496	31550353	Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.	('ADC', 'Gene', (10, 13))	('glioma infiltration', 'Disease', (39, 58))	('gliomas', 'Disease', (114, 121))	('ADC', 'Gene', '113451', (10, 13))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('enhancing', 'PosReg', (104, 113))	('[18F]FET PET', 'Var', (18, 30))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma infiltration', 'Disease', 'MESH:D005910', (39, 58))
91498	31550353	Combination of ADC MRI and [18F]FET PET may enable better image-guided surgery/irradiation in enhancing gliomas.	('gliomas', 'Disease', (104, 111))	('ADC', 'Gene', (15, 18))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('ADC', 'Gene', '113451', (15, 18))	('[18F]FET', 'Var', (27, 35))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
91505	31550353	Furthermore, irradiation is guided by T1G MRI abnormalities with centimeter margins and FLAIR MRI abnormalities for enhancing gliomas and T2w or FLAIR MRI abnormalities with centimeter margins for non-enhancing gliomas.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('T1G', 'Mutation', 'c.1T>G', (38, 41))	('gliomas', 'Phenotype', 'HP:0009733', (211, 218))	('gliomas', 'Disease', (211, 218))	('gliomas', 'Disease', 'MESH:D005910', (211, 218))	('T1G', 'Var', (38, 41))	('abnormalities', 'Var', (98, 111))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))
91508	31550353	Furthermore, the Response Assessment in Neuro-Oncology (RANO) working group has recently concluded amino acid PET to be superior to standard MRI for the delineation of diffuse glioma.	('amino acid', 'Var', (99, 109))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('Oncology', 'Phenotype', 'HP:0002664', (46, 54))
91513	31550353	Diffuse gliomas can be subclassified using different biomarkers:for example, imaging markers such as enhancement on T1G MRI, histopathological markers like the World Health Organization (WHO) classification, or molecular markers such as isocitrate dehydrogenase (IDH) mutational status.	('T1G', 'Mutation', 'c.1T>G', (116, 119))	('mutational', 'Var', (268, 278))	('gliomas', 'Disease', (8, 15))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('enhancement', 'PosReg', (101, 112))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('isocitrate dehydrogenase', 'Gene', (237, 261))	('IDH', 'Gene', (263, 266))	('T1G', 'Gene', (116, 119))	('isocitrate dehydrogenase', 'Gene', '3417', (237, 261))	('IDH', 'Gene', '3417', (263, 266))
91520	31550353	For [18F]FET PET, a tumor-to-brain ratio, validated with full kinetic modeling, of the 20-40 minute interval was used, in accordance with European guidelines for brain tumor imaging.	('[18F]FET', 'Var', (4, 12))	('brain tumor', 'Phenotype', 'HP:0030692', (162, 173))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('brain tumor', 'Disease', (162, 173))	('brain tumor', 'Disease', 'MESH:D001932', (162, 173))	('tumor', 'Disease', (20, 25))
91524	31550353	Samples were fixed in formalin, embedded in paraffin, stained with hematoxylin and eosin, and immunohistochemically analyzed with antibodies against Ki-67, p53, and R132H mutant IDH1.	('eosin', 'Chemical', 'MESH:D004801', (83, 88))	('IDH1', 'Gene', '3417', (178, 182))	('R132H', 'Mutation', 'rs121913500', (165, 170))	('formalin', 'Chemical', 'MESH:D005557', (22, 30))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('paraffin', 'Chemical', 'MESH:D010232', (44, 52))	('IDH1', 'Gene', (178, 182))	('hematoxylin', 'Chemical', 'MESH:D006416', (67, 78))	('R132H', 'Var', (165, 170))
91535	31550353	Subgroup analysis was performed for patients with high- or low-grade gliomas, defined by diagnosis according to WHO 2016 criteria, IDH-wildtype or IDH-mutant gliomas, defined by immunohistochemistry for IDH1 R132H mutant protein for all but one case in which the IDH-mutant status was demonstrated by methylation profiling, and [18F]FET positive or negative gliomas, defined as tumoral uptake not exceeding background activity in visual analysis.	('IDH', 'Gene', '3417', (147, 150))	('gliomas', 'Disease', (69, 76))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('gliomas', 'Phenotype', 'HP:0009733', (358, 365))	('IDH', 'Gene', '3417', (203, 206))	('IDH', 'Gene', (263, 266))	('R132H', 'Mutation', 'rs121913500', (208, 213))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('IDH', 'Gene', '3417', (131, 134))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('patients', 'Species', '9606', (36, 44))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH', 'Gene', '3417', (263, 266))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('gliomas', 'Disease', (358, 365))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('R132H', 'Var', (208, 213))	('tumoral', 'Disease', (378, 385))	('gliomas', 'Disease', (158, 165))	('IDH1', 'Gene', (203, 207))	('tumoral', 'Disease', 'MESH:D009369', (378, 385))	('IDH', 'Gene', (147, 150))	('negative', 'NegReg', (349, 357))	('IDH', 'Gene', (203, 206))	('gliomas', 'Disease', 'MESH:D005910', (358, 365))	('IDH', 'Gene', (131, 134))	('glioma', 'Phenotype', 'HP:0009733', (358, 364))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('IDH1', 'Gene', '3417', (203, 207))
91545	31550353	Interobserver agreement between pathologists was moderate, with a kappa of 0.47, and higher in non-enhancing, low-grade, IDH-mutant and [18F]FET negative gliomas (kappa 0.67, 0.66, 0.61, and 0.74, respectively) than in enhancing, high-grade, IDH-wildtype and [18F]FET positive gliomas (kappa 0.39, 0.40, 0.39, and 0.44, respectively).	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('higher', 'PosReg', (85, 91))	('low-grade', 'Var', (110, 119))	('IDH', 'Gene', (121, 124))	('IDH', 'Gene', (242, 245))	('gliomas', 'Disease', 'MESH:D005910', (277, 284))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', (154, 161))	('gliomas', 'Disease', (277, 284))	('IDH', 'Gene', '3417', (121, 124))	('IDH', 'Gene', '3417', (242, 245))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('gliomas', 'Phenotype', 'HP:0009733', (277, 284))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))
91548	31550353	In patients with enhancing glioma, imaging measurements for samples with tumor presence were significantly higher in T2w, FLAIR MRI, ADC, DSC-CBV, MRSI-CNI, and [18F]FET PET, and lower in FA, than for samples without tumor (Supplementary Figure 1A).	('glioma', 'Disease', (27, 33))	('ADC', 'Gene', '113451', (133, 136))	('tumor', 'Disease', (217, 222))	('lower', 'NegReg', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('MRSI-CNI', 'Chemical', '-', (147, 155))	('T2w', 'Disease', (117, 120))	('[18F]FET PET', 'Var', (161, 173))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('patients', 'Species', '9606', (3, 11))	('ADC', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('higher', 'PosReg', (107, 113))
91549	31550353	In patients with non-enhancing glioma, imaging measurements for samples with tumor presence were significantly higher in T2w, FLAIR MRI, ADC, and [18F]FET PET, and significantly lower in T1G MRI and FA, than for samples without tumor Supplementary Figure 1B).	('tumor Supplementary', 'Disease', 'MESH:D017034', (228, 247))	('ADC', 'Gene', '113451', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('T2w', 'MPA', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('ADC', 'Gene', (137, 140))	('[18F]', 'Var', (146, 151))	('lower', 'NegReg', (178, 183))	('T1G', 'Mutation', 'c.1T>G', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor Supplementary', 'Disease', (228, 247))	('non-enhancing', 'Disease', (17, 30))	('patients', 'Species', '9606', (3, 11))	('glioma', 'Disease', (31, 37))	('FLAIR', 'MPA', (126, 131))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('higher', 'PosReg', (111, 117))	('tumor', 'Disease', (228, 233))	('tumor', 'Disease', (77, 82))
91551	31550353	In non-enhancing glioma, ADC with T1G (ADC/T1G), ADC with DSC-CBF and DSC-CBV (ADC/CBF/CBV), and T2w with T1G (T2w/T1G) had the best, second, and third best fits, respectively.	('ADC', 'Gene', '113451', (25, 28))	('ADC', 'Gene', '113451', (49, 52))	('CBF', 'Gene', '10153', (62, 65))	('CBF', 'Gene', (62, 65))	('ADC', 'Gene', (25, 28))	('ADC', 'Gene', (49, 52))	('ADC', 'Gene', '113451', (79, 82))	('glioma', 'Disease', (17, 23))	('ADC', 'Gene', '113451', (39, 42))	('ADC', 'Gene', (79, 82))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('T1G', 'Var', (34, 37))	('T1G', 'Mutation', 'c.1T>G', (115, 118))	('ADC', 'Gene', (39, 42))	('T1G', 'Mutation', 'c.1T>G', (43, 46))	('CBF', 'Gene', '10153', (83, 86))	('T1G', 'Mutation', 'c.1T>G', (106, 109))	('CBF', 'Gene', (83, 86))	('T1G', 'Mutation', 'c.1T>G', (34, 37))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))
91556	31550353	In the subgroup analysis, highest accuracy in high-grade, IDH-wildtype, and [18F]FET positive glioma was found for ADC/FET (0.89, 0.80-0.99; 0.88, 0.78-0.99; and 0.90, 0.84-0.96, respectively), while in low-grade and IDH-mutant glioma, diagnostic accuracy was highest for T2w/T1G (0.89, 0.79-0.99 and 0.91, 0.82-0.99, respectively) and in [18F]FET negative glioma, ADC/FA diagnostic accuracy was highest (1.00, 1.00-1.00).	('IDH', 'Gene', '3417', (58, 61))	('glioma', 'Phenotype', 'HP:0009733', (357, 363))	('IDH', 'Gene', (217, 220))	('ADC', 'Gene', (115, 118))	('T1G', 'Mutation', 'c.1T>G', (276, 279))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('T2w/T1G', 'Var', (272, 279))	('IDH', 'Gene', '3417', (217, 220))	('ADC', 'Gene', '113451', (365, 368))	('ADC', 'Gene', (365, 368))	('IDH', 'Gene', (58, 61))	('glioma', 'Disease', (357, 363))	('glioma', 'Disease', 'MESH:D005910', (357, 363))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', (228, 234))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('ADC', 'Gene', '113451', (115, 118))
91559	31550353	The diagnostic accuracy of [18F]FET PET was significantly higher than T1G MRI (Fig.	('[18F]FET PET', 'Var', (27, 39))	('T1G', 'Mutation', 'c.1T>G', (70, 73))	('higher', 'PosReg', (58, 64))
91562	31550353	In low-grade and IDH-mutant glioma, T2w/T1G diagnostic accuracy was significantly higher than T2w MRI and [18F]FET PET but not FLAIR MRI.	('IDH', 'Gene', '3417', (17, 20))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('T2w/T1G', 'Var', (36, 43))	('higher', 'PosReg', (82, 88))	('T1G', 'Mutation', 'c.1T>G', (40, 43))	('low-grade', 'Disease', (3, 12))	('glioma', 'Disease', (28, 34))	('IDH', 'Gene', (17, 20))
91565	31550353	In [18F]FET PET negative glioma, ADC/FA diagnostic accuracy was higher than FLAIR, but not T2w MRI (Fig.	('higher', 'PosReg', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('ADC', 'Gene', (33, 36))	('glioma', 'Disease', (25, 31))	('ADC', 'Gene', '113451', (33, 36))	('[18F]FET', 'Var', (3, 11))
91571	31550353	The main finding of this prospective study is that glioma infiltration in enhancing glioma is most accurately detected by the combination of ADC and [18F]FET PET.	('ADC', 'Gene', (141, 144))	('[18F]FET PET', 'Var', (149, 161))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', (84, 90))	('glioma infiltration', 'Disease', 'MESH:D005910', (51, 70))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('ADC', 'Gene', '113451', (141, 144))	('glioma infiltration', 'Disease', (51, 70))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
91573	31550353	This is similar in high-grade, IDH-wildtype, and [18F]FET PET positive gliomas.	('[18F]FET', 'Var', (49, 57))	('IDH', 'Gene', (31, 34))	('gliomas', 'Disease', (71, 78))	('IDH', 'Gene', '3417', (31, 34))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))
91574	31550353	The few studies that looked into imaging combinations to detect glioma infiltration all concluded that imaging combinations had a higher diagnostic accuracy than standard MRI.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioma infiltration', 'Disease', 'MESH:D005910', (64, 83))	('combinations', 'Var', (111, 123))	('glioma infiltration', 'Disease', (64, 83))
91575	31550353	Interestingly, all studies with amino acid PET, each with a majority of enhancing gliomas, included PET in their optimal imaging combination.	('enhancing', 'Disease', (72, 81))	('amino acid PET', 'Var', (32, 46))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('PET', 'MPA', (100, 103))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))
91581	31550353	In our study, [18F]FET PET was not found to be a component of the optimal imaging combinations for non-enhancing glioma, and [18F]FET PET diagnostic accuracy was lower than that of FLAIR MRI, even after removing patients without [18F]FET uptake.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('patients', 'Species', '9606', (212, 220))	('lower', 'NegReg', (162, 167))	('glioma', 'Disease', (113, 119))	('[18F]FET PET', 'Var', (125, 137))
91583	31550353	Pauleit et al obtained 15 samples in 7 grade II glioma patients, resulting in a 100% sensitivity and 91% specificity using [18F]FET PET.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('patients', 'Species', '9606', (55, 63))	('[18F]FET', 'Var', (123, 131))	('glioma', 'Disease', (48, 54))
91584	31550353	Kracht et al reported a 25% underestimation of tumor extent based on 26 samples in 5 grade II astrocytoma patients, using [11C]MET PET, which is in line with our results.	('grade', 'Disease', (85, 90))	('astrocytoma', 'Disease', 'MESH:D001254', (94, 105))	('astrocytoma', 'Disease', (94, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('underestimation', 'NegReg', (28, 43))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('11C', 'Chemical', 'MESH:C000615233', (123, 126))	('[11C]MET', 'Var', (122, 130))	('tumor', 'Disease', (47, 52))
91602	31550353	Use of immunohistochemistry for IDH1 R132H mutant protein would have introduced a bias due to the difference in assessment of IDH-wildtype and IDH-mutant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH', 'Gene', '3417', (126, 129))	('IDH', 'Gene', '3417', (143, 146))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('R132H', 'Var', (37, 42))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', (154, 161))	('IDH', 'Gene', (32, 35))	('protein', 'Protein', (50, 57))	('IDH', 'Gene', '3417', (32, 35))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('R132H', 'Mutation', 'rs121913500', (37, 42))	('IDH', 'Gene', (126, 129))	('IDH', 'Gene', (143, 146))
91607	31550353	Study concept and design: O.S.H., F.B., P.J.W.P., J.C.R., J.J.H., W.P.V., P.W., P.C.W.H.	('J.J.H', 'CellLine', 'CVCL:M891', (58, 63))	('P.W.', 'Var', (74, 78))	('P.J.W.P.', 'Var', (40, 48))	('J.C.R.', 'Var', (50, 56))	('J.J.H.', 'Var', (58, 64))	('W.P.V.', 'Var', (66, 72))
91608	31550353	Critical revision of the manuscript for important intellectual content: T.K., O.S.H., A.A.L., F.B., P.J.W.P., J.C.R., J.J.H., A.M.E.B., F.L., W.P.V., R.B., P.W.	('J.J.H.', 'Var', (118, 124))	('R.B.', 'Var', (150, 154))	('P.J.W.P.', 'Var', (100, 108))	('J.C.R.', 'Var', (110, 116))	('J.J.H', 'CellLine', 'CVCL:M891', (118, 123))	('A.M.E.B.', 'Var', (126, 134))
91614	31221203	Therefore, combined targeted therapy for this pathway and associated molecules could be a novel and attractive strategy for the treatment of human glioblastoma.	('targeted', 'Var', (20, 28))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('human', 'Species', '9606', (141, 146))
91622	31221203	Genetic alterations in glioma occur frequently.	('glioma', 'Disease', (23, 29))	('Genetic alterations', 'Var', (0, 19))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('glioma', 'Disease', 'MESH:D005910', (23, 29))
91623	31221203	Apart from histological classification, genetic diagnoses are recommended to identify the status of isocitrate dehydrogenase 1/2 (IDH1/2) mutation, telomerase reverse transcriptase (TERT) promoter mutation, 1p/19q co-deletion, BRAF mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, which can help to estimate the prognosis and direct treatment options.	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (246, 284))	('MGMT', 'Gene', '4255', (286, 290))	('IDH1/2', 'Gene', (130, 136))	('MGMT', 'Gene', (286, 290))	('telomerase reverse transcriptase', 'Gene', (148, 180))	('isocitrate', 'Chemical', 'MESH:C034219', (100, 110))	('telomerase reverse transcriptase', 'Gene', '7015', (148, 180))	('TERT', 'Gene', (182, 186))	('TERT', 'Gene', '7015', (182, 186))	('O6-methylguanine-DNA methyltransferase', 'Gene', (246, 284))	('mutation', 'Var', (138, 146))	('BRAF', 'Gene', '673', (227, 231))	('BRAF', 'Gene', (227, 231))	('IDH1/2', 'Gene', '3417;3418', (130, 136))
91625	31221203	Gene amplifications or mutations are most common among receptor tyrosine kinase (RTK)/RAS/PI3K, p53, and RB signaling pathways, and approximately 86% of glioblastoma samples harbor at least one genetic event in the core RTK/PI3K pathway.	('p53', 'Gene', '7157', (96, 99))	('RTK', 'Gene', (81, 84))	('RB signaling pathways', 'Pathway', (105, 126))	('PI3', 'Gene', '5266', (224, 227))	('harbor', 'Reg', (174, 180))	('RTK', 'Gene', '5979', (81, 84))	('PI3', 'Gene', (90, 93))	('p53', 'Gene', (96, 99))	('mutations', 'Var', (23, 32))	('common', 'Reg', (42, 48))	('PI3', 'Gene', (224, 227))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('receptor tyrosine kinase', 'Gene', '5979', (55, 79))	('Gene amplifications', 'Var', (0, 19))	('RTK', 'Gene', (220, 223))	('glioblastoma', 'Disease', (153, 165))	('receptor tyrosine kinase', 'Gene', (55, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('RTK', 'Gene', '5979', (220, 223))	('PI3', 'Gene', '5266', (90, 93))
91626	31221203	RTKs are cell-surface receptors that are activated by ligands, activating mutations, or other mechanisms of dysregulation, all of which contribute to the malignancy of many solid tumors such as non-small cell lung cancer, breast cancer, gastric cancer, hepatocellular carcinoma, and glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (283, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('non-small cell lung cancer', 'Disease', (194, 220))	('malignancy of many solid tumors', 'Disease', 'MESH:D009369', (154, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (253, 277))	('gastric cancer', 'Disease', (237, 251))	('malignancy of many solid tumors', 'Disease', (154, 185))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('glioblastoma', 'Disease', (283, 295))	('breast cancer', 'Disease', (222, 235))	('glioblastoma', 'Phenotype', 'HP:0012174', (283, 295))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (194, 220))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('hepatocellular carcinoma', 'Disease', (253, 277))	('RTK', 'Gene', (0, 3))	('gastric cancer', 'Disease', 'MESH:D013274', (237, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('RTK', 'Gene', '5979', (0, 3))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (198, 220))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('contribute', 'Reg', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (194, 220))	('gastric cancer', 'Phenotype', 'HP:0012126', (237, 251))	('mutations', 'Var', (74, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (253, 277))
91632	31221203	Gene mutations seem to be the most important and well-studied mechanism underlying the formation of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('gliomas', 'Disease', (100, 107))	('Gene mutations', 'Var', (0, 14))
91633	31221203	The tumor suppressor gene TP53, p16, and phosphatase and tensin homolog (PTEN) phosphatase control cell cycle progression and proliferation, the mutations in or loss of these tumor suppressor genes contribute to the initiation or formation of gliomas, and have been demonstrated to be characteristics of many glioblastoma cell lines.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('gliomas', 'Disease', (243, 250))	('TP53', 'Gene', '7157', (26, 30))	('proliferation', 'CPA', (126, 139))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))	('loss', 'NegReg', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('p16', 'Gene', (32, 35))	('cell cycle progression', 'CPA', (99, 121))	('PTEN', 'Gene', (73, 77))	('tumor', 'Disease', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('p16', 'Gene', '1029', (32, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (309, 321))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('formation', 'CPA', (230, 239))	('mutations in', 'Var', (145, 157))	('TP53', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (73, 77))	('contribute', 'Reg', (198, 208))	('glioblastoma', 'Disease', (309, 321))	('glioblastoma', 'Phenotype', 'HP:0012174', (309, 321))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
91634	31221203	The genes encoding IDH1, and to a lesser extent IDH2, were found to be mutated in lower grade gliomas and a subset of glioblastomas that evolved from lower grade tumors, which results in the decreased production of alpha-ketoglutarate (alpha-KG) from isocitrate and also the conversion of alpha-KG to 2-hydroxyglutarate (2-HG).	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('conversion', 'MPA', (275, 285))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('IDH2', 'Gene', '3418', (48, 52))	('decreased production of alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (191, 234))	('alpha-KG', 'Chemical', 'MESH:D007656', (236, 244))	('IDH1', 'Gene', '3417', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('alpha-KG', 'Chemical', 'MESH:D007656', (289, 297))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('glioblastomas', 'Disease', (118, 131))	('decreased', 'NegReg', (191, 200))	('glioblastomas', 'Disease', 'MESH:D005909', (118, 131))	('2-HG', 'Chemical', 'MESH:C019417', (321, 325))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (301, 319))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('gliomas', 'Disease', (94, 101))	('isocitrate', 'MPA', (251, 261))	('isocitrate', 'Chemical', 'MESH:C034219', (251, 261))	('IDH1', 'Gene', (19, 23))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (215, 234))	('mutated', 'Var', (71, 78))	('IDH2', 'Gene', (48, 52))	('tumors', 'Disease', (162, 168))	('production', 'MPA', (201, 211))	('glioblastomas', 'Phenotype', 'HP:0012174', (118, 131))
91635	31221203	Even through IDH mutations were found to occur earlier than TP53 mutations in low-grade gliomas, the underlying mechanism of this phenomenon is still unclear.	('IDH', 'Gene', '3417', (13, 16))	('gliomas', 'Disease', (88, 95))	('TP53', 'Gene', '7157', (60, 64))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('IDH', 'Gene', (13, 16))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (17, 26))
91636	31221203	Despite the fact that MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation results in its transcriptional silencing and increases chemosensitivity to temozolomide (TMZ), the dismal prognosis associated with many primary glioblastomas without MGMT promoter methylation still has not changed with current therapies.	('O6-methylguanine-DNA methyltransferase', 'Gene', (28, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (234, 246))	('methylation', 'Var', (77, 88))	('transcriptional', 'MPA', (104, 119))	('glioblastomas', 'Phenotype', 'HP:0012174', (234, 247))	('temozolomide', 'Chemical', 'MESH:D000077204', (164, 176))	('glioblastomas', 'Disease', 'MESH:D005909', (234, 247))	('silencing', 'NegReg', (120, 129))	('chemosensitivity to temozolomide', 'MPA', (144, 176))	('MGMT', 'Gene', (22, 26))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (28, 66))	('MGMT', 'Gene', '4255', (256, 260))	('glioblastomas', 'Disease', (234, 247))	('increases', 'PosReg', (134, 143))	('MGMT', 'Gene', (256, 260))	('MGMT', 'Gene', '4255', (22, 26))	('TMZ', 'Chemical', 'MESH:D000077204', (178, 181))
91637	31221203	Moreover, TERT promoter mutations (C228T, C250T) were found to be associated with significantly shorter progression-free survival (PFS) and overall survival (OS) time in grade III and IV glioma patients.	('overall survival', 'CPA', (140, 156))	('C250T', 'SUBSTITUTION', 'None', (42, 47))	('patients', 'Species', '9606', (194, 202))	('shorter', 'NegReg', (96, 103))	('progression-free survival', 'CPA', (104, 129))	('C228T', 'Var', (35, 40))	('glioma', 'Disease', (187, 193))	('C228T', 'Mutation', 'c.228C>T', (35, 40))	('TERT', 'Gene', (10, 14))	('C250T', 'Var', (42, 47))	('grade III', 'Disease', (170, 179))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('TERT', 'Gene', '7015', (10, 14))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('OS', 'Chemical', '-', (158, 160))
91639	31221203	All of these gene variations illustrate the possible mechanisms underlying glioma initiation or formation.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('variations', 'Var', (18, 28))	('glioma initiation', 'Disease', (75, 92))	('glioma initiation', 'Disease', 'MESH:D005910', (75, 92))
91640	31221203	Although receptor tyrosine kinases (RTKs) possess the roles as key regulators of normal cellular processes, the dysregulation of growth factor signaling pathways via amplification and the mutational activation of receptor tyrosine kinase (RTK)-encoding genes has been identified as important events in human glioblastomas, and approximately 86% harbor at least one genetic event in the core RTK/PI3K pathway.	('receptor tyrosine kinase', 'Gene', (213, 237))	('growth factor signaling pathways', 'Pathway', (129, 161))	('glioblastomas', 'Disease', (308, 321))	('PI3', 'Gene', (395, 398))	('glioblastoma', 'Phenotype', 'HP:0012174', (308, 320))	('RTK', 'Gene', (391, 394))	('RTK', 'Gene', '5979', (391, 394))	('glioblastomas', 'Disease', 'MESH:D005909', (308, 321))	('human', 'Species', '9606', (302, 307))	('RTK', 'Gene', (239, 242))	('receptor tyrosine kinase', 'Gene', '5979', (9, 33))	('RTK', 'Gene', '5979', (239, 242))	('cellular', 'Species', '33083', (88, 96))	('PI3', 'Gene', '5266', (395, 398))	('receptor tyrosine kinase', 'Gene', (9, 33))	('glioblastomas', 'Phenotype', 'HP:0012174', (308, 321))	('receptor tyrosine kinase', 'Gene', '5979', (213, 237))	('RTK', 'Gene', (36, 39))	('mutational', 'Var', (188, 198))	('RTK', 'Gene', '5979', (36, 39))
91649	31221203	One study searched for genetic alterations in glioblastomas occurring with or without IDH1 mutations (typical for secondary and primary glioblastoma) using data from The Cancer Genome Atlas (TCGA) and identified 25 genes, of which 21 were located at 7q31-34.	('Cancer Genome Atlas', 'Disease', (170, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('IDH1', 'Gene', (86, 90))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (170, 189))	('glioblastomas', 'Disease', (46, 59))	('glioblastoma', 'Disease', (136, 148))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('IDH1', 'Gene', '3417', (86, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('mutations', 'Var', (91, 100))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))
91651	31221203	Moreover, activating mutations in MET are significant events during the progression of low-grade gliomas to secondary glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('glioblastomas', 'Disease', (118, 131))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('MET', 'Gene', (34, 37))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('activating mutations', 'Var', (10, 30))	('glioblastomas', 'Phenotype', 'HP:0012174', (118, 131))	('glioblastomas', 'Disease', 'MESH:D005909', (118, 131))
91659	31221203	One animal study showed that MET amplification is one of the most significant oncogenic events in transgenic mouse models of glioblastoma formation.	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('glioblastoma', 'Disease', (125, 137))	('MET amplification', 'Var', (29, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))	('mouse', 'Species', '10090', (109, 114))
91660	31221203	Moreover, in clinical specimens, 4% of glioblastomas harbor an amplification in MET resulting in the overexpression and constitutive activation of this kinase.	('glioblastomas', 'Phenotype', 'HP:0012174', (39, 52))	('overexpression', 'PosReg', (101, 115))	('glioblastomas', 'Disease', 'MESH:D005909', (39, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('glioblastomas', 'Disease', (39, 52))	('amplification', 'Var', (63, 76))	('MET', 'Gene', (80, 83))	('constitutive', 'MPA', (120, 132))
91661	31221203	The auto-activating METDelta7-8 mutation represents a novel variant of MET, with a deletion in exon 7 and 8, which was detected in 6% of high-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('METDelta7-8', 'Gene', (20, 31))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('deletion', 'Var', (83, 91))	('auto-activating', 'PosReg', (4, 19))	('mutation', 'Var', (32, 40))
91663	31221203	These MET fusions and activating mutations upregulate mitogen-activated protein kinase (MAPK) signaling, and in cooperation with compromised cell cycle regulation, induce the formation of aggressive glial tumors in vivo.	('upregulate', 'PosReg', (43, 53))	('induce', 'Reg', (164, 170))	('aggressive glial tumors', 'Disease', 'MESH:D005910', (188, 211))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mitogen-activated', 'MPA', (54, 71))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('aggressive glial tumors', 'Disease', (188, 211))
91664	31221203	It would also appear that the detection of MET amplification in glioblastoma depends on both the technique used and the proportion of amplified cells in the tumor.	('tumor', 'Disease', (157, 162))	('glioblastoma', 'Disease', (64, 76))	('MET amplification', 'Var', (43, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
91670	31221203	Phosphorylation events at Tyr1349 and Tyr1356 of the MET kinase domain, which serves as docking sites for intracellular adaptor proteins, are associated with the survival, proliferation, invasion, migration, angiogenesis, and stemness of gliomas.	('Tyr1349', 'Chemical', '-', (26, 33))	('proliferation', 'CPA', (172, 185))	('stemness of gliomas', 'Disease', 'MESH:D005910', (226, 245))	('angiogenesis', 'CPA', (208, 220))	('Tyr1356 of the MET', 'Mutation', 'p.Y1356M', (38, 56))	('stemness of gliomas', 'Disease', (226, 245))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('Phosphorylation', 'MPA', (0, 15))	('migration', 'CPA', (197, 206))	('associated with', 'Reg', (142, 157))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('survival', 'CPA', (162, 170))	('Tyr1356', 'Var', (38, 45))	('cellular', 'Species', '33083', (111, 119))	('invasion', 'CPA', (187, 195))
91672	31221203	Accordingly MET-exon 14-skipping (METex14) results in the omission of exon 14 and the Tyr1003-encoding residue from the MET transcript, which ultimately contributes to prolonged MET stability and constitutive activation.	('Tyr1003', 'Chemical', '-', (86, 93))	('omission', 'NegReg', (58, 66))	('constitutive activation', 'MPA', (196, 219))	('prolonged', 'PosReg', (168, 177))	('contributes to', 'Reg', (153, 167))	('MET stability', 'MPA', (178, 191))	('MET-exon 14-skipping', 'Var', (12, 32))	('exon', 'Gene', (70, 74))
91673	31221203	Moreover, the phosphorylation at Tyr1234/1235 within the activation loop of the kinase domain is critical for the subsequent phosphorylation of tyrosine residues Tyr1349 and Tyr1356 near the -COOH terminus.	('COOH', 'Chemical', 'MESH:D002255', (192, 196))	('Tyr1234/1235', 'Var', (33, 45))	('Tyr1356', 'Var', (174, 181))	('Tyr1349', 'Var', (162, 169))	('Tyr1234', 'Chemical', '-', (33, 40))	('phosphorylation', 'MPA', (125, 140))	('Tyr1356', 'Chemical', '-', (174, 181))	('Tyr1349', 'Chemical', '-', (162, 169))	('tyrosine', 'Chemical', 'MESH:D014443', (144, 152))
91677	31221203	Moreover, in high-grade glioma, higher SPINT2 expression was determined to be associated with better OS.	('higher', 'Var', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('SPINT2', 'Gene', (39, 45))	('SPINT2', 'Gene', '10653', (39, 45))	('OS', 'Chemical', '-', (101, 103))	('glioma', 'Disease', (24, 30))	('expression', 'MPA', (46, 56))
91678	31221203	Basic experimental research also showed that MET phosphorylation levels and glioblastoma tumor growth are reduced by the expression of HAI-2 both in vitro and in intracranial xenografts in nude mice, and that HAI-2 suppresses fibrinolytic activities and inhibits the Matrigel invasion of glioblastoma cell lines.	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (76, 94))	('suppresses', 'NegReg', (215, 225))	('glioblastoma', 'Disease', (288, 300))	('inhibits', 'NegReg', (254, 262))	('MET phosphorylation levels', 'MPA', (45, 71))	('glioblastoma tumor', 'Disease', (76, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (288, 300))	('glioblastoma', 'Phenotype', 'HP:0012174', (288, 300))	('fibrinolytic', 'MPA', (226, 238))	('HAI-2', 'Gene', (135, 140))	('nude mice', 'Species', '10090', (189, 198))	('expression', 'Var', (121, 131))	('glioblastoma', 'Disease', (76, 88))	('HAI-2', 'Var', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('reduced', 'NegReg', (106, 113))
91685	31221203	Thus, the dysregulation of miRNAs or lncRNAs contributes to the aberrant function of MET signaling in glioblastoma.	('glioblastoma', 'Disease', (102, 114))	('dysregulation', 'Var', (10, 23))	('miRNAs', 'Protein', (27, 33))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('MET signaling', 'MPA', (85, 98))
91686	31221203	In addition to activating mutations in MET and the dysregulation of modulators of this RTK, the activation of downstream signaling and cross-talk between MET and other molecules have also been demonstrated in gliomas.	('MET', 'Gene', (39, 42))	('RTK', 'Gene', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('downstream signaling', 'MPA', (110, 130))	('RTK', 'Gene', '5979', (87, 90))	('mutations', 'Var', (26, 35))	('gliomas', 'Disease', (209, 216))	('activating', 'PosReg', (15, 25))	('gliomas', 'Phenotype', 'HP:0009733', (209, 216))	('gliomas', 'Disease', 'MESH:D005910', (209, 216))	('cross-talk', 'Interaction', (135, 145))	('activation', 'PosReg', (96, 106))	('dysregulation', 'MPA', (51, 64))
91694	31221203	first reported that CD44 is a co-stimulator of the MET signaling pathway in glioma cells and attenuated CD44 expression was found to diminish the HGF-induced phosphorylation of Erk1/2 kinase but not that of AKT kinase, suggesting that CD44 preferentially modulates proliferation but not survival signaling pathways activated by HGF growth factors.	('modulates', 'Reg', (255, 264))	('expression', 'Var', (109, 119))	('CD44', 'Gene', '960', (104, 108))	('CD44', 'Gene', (104, 108))	('AKT', 'Gene', '207', (207, 210))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Erk1/2', 'Gene', '5595;5594', (177, 183))	('glioma cell', 'Disease', 'MESH:D005910', (76, 87))	('glioma cell', 'Disease', (76, 87))	('HGF-induced phosphorylation', 'MPA', (146, 173))	('CD44', 'Gene', '960', (235, 239))	('CD44', 'Gene', (235, 239))	('attenuated', 'NegReg', (93, 103))	('proliferation', 'CPA', (265, 278))	('AKT', 'Gene', (207, 210))	('CD44', 'Gene', '960', (20, 24))	('diminish', 'NegReg', (133, 141))	('CD44', 'Gene', (20, 24))	('MET signaling pathway', 'Pathway', (51, 72))	('Erk1/2', 'Gene', (177, 183))
91717	31221203	The dysregulation of MET signaling is associated with WHO grades, therapy resistance, recurrence, and poor outcomes for glioma patients, making this receptor an attractive target for potential treatment.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('therapy resistance', 'CPA', (66, 84))	('associated', 'Reg', (38, 48))	('dysregulation', 'Var', (4, 17))	('patients', 'Species', '9606', (127, 135))	('MET', 'MPA', (21, 24))	('glioma', 'Disease', (120, 126))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
91718	31221203	The humanized monoclonal anti-HGF antibody, YYB-101, suppresses tumor growth in vitro and in an orthotopic mouse model of human glioblastoma; it also downregulates important cellular molecular effectors including p-MET, p-Gab1, p-FAK, MMP2, uPA/plasminogen, and Ki-67.	('human', 'Species', '9606', (122, 127))	('p-MET', 'Var', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('YYB-101', 'Var', (44, 51))	('uPA/plasminogen', 'MPA', (241, 256))	('Gab1', 'Gene', '2549', (222, 226))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('mouse', 'Species', '10090', (107, 112))	('YYB-101', 'Chemical', '-', (44, 51))	('cellular', 'Species', '33083', (174, 182))	('FAK', 'Gene', (230, 233))	('glioblastoma', 'Disease', (128, 140))	('Gab1', 'Gene', (222, 226))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('suppresses', 'NegReg', (53, 63))	('tumor', 'Disease', (64, 69))	('human', 'Species', '9606', (4, 9))	('downregulates', 'NegReg', (150, 163))	('FAK', 'Gene', '5747', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
91719	31221203	Combination treatment with YYB-101 and TMZ was found to decrease tumor growth and increase OS, compared to the effects of either agent alone, in mice bearing human glioblastoma xenografts.	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('TMZ', 'Var', (39, 42))	('tumor', 'Disease', (65, 70))	('human', 'Species', '9606', (158, 163))	('glioblastoma', 'Disease', (164, 176))	('TMZ', 'Chemical', 'MESH:D000077204', (39, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('increase', 'PosReg', (82, 90))	('OS', 'Chemical', '-', (91, 93))	('YYB-101', 'Var', (27, 34))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('decrease', 'NegReg', (56, 64))	('YYB-101', 'Chemical', '-', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
91728	31221203	Nevertheless, to date, there have been only two ongoing phase I clinical trials in recent years to evaluate the safety and activity of crizotinib with TMZ and radiotherapy for newly diagnosed glioblastoma or to evaluate the tolerable dose of crizotinib and dasatinib in pediatric patients with diffuse pontine glioma and high-grade glioma (NCT02270034, NCT01644773).	('patients', 'Species', '9606', (280, 288))	('glioma', 'Disease', (310, 316))	('glioma', 'Disease', 'MESH:D005910', (332, 338))	('crizotinib', 'Chemical', 'MESH:D000077547', (242, 252))	('glioblastoma', 'Disease', (192, 204))	('glioma', 'Phenotype', 'HP:0009733', (332, 338))	('glioblastoma', 'Disease', 'MESH:D005909', (192, 204))	('NCT01644773', 'Var', (353, 364))	('dasatinib', 'Chemical', 'MESH:D000069439', (257, 266))	('glioblastoma', 'Phenotype', 'HP:0012174', (192, 204))	('glioma', 'Disease', 'MESH:D005910', (310, 316))	('glioma', 'Disease', (332, 338))	('glioma', 'Phenotype', 'HP:0009733', (310, 316))	('TMZ', 'Chemical', 'MESH:D000077204', (151, 154))	('NCT02270034', 'Var', (340, 351))	('crizotinib', 'Chemical', 'MESH:D000077547', (135, 145))
91734	31221203	INCB28060 is a potent and selective inhibitor of MET kinase and shows strong anti-tumor activity in MET-dependent mouse tumor models.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mouse', 'Species', '10090', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('INCB28060', 'Chemical', 'MESH:C570853', (0, 9))	('INCB28060', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (120, 125))
91736	31221203	A preclinical study showed that cabozantinib prolongs the survival of mice bearing orthotopic E98-xenografts by inhibiting tumor proliferation and invasion.	('tumor', 'Disease', (123, 128))	('cabozantinib', 'Var', (32, 44))	('survival', 'CPA', (58, 66))	('invasion', 'CPA', (147, 155))	('mice', 'Species', '10090', (70, 74))	('cabozantinib', 'Chemical', 'MESH:C558660', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('prolongs', 'PosReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('inhibiting', 'NegReg', (112, 122))
91744	31221203	It selectively inhibits the proliferation of MET-addicted U87MG cells in vitro and was found to elicit the tumor regression of U87MG xenografts in mice after oral administration at a dose of 60 mg/kg.	('mice', 'Species', '10090', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('proliferation', 'CPA', (28, 41))	('U87MG', 'CellLine', 'CVCL:0022', (58, 63))	('inhibits', 'NegReg', (15, 23))	('elicit', 'PosReg', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('U87MG', 'CellLine', 'CVCL:0022', (127, 132))	('U87MG', 'Var', (127, 132))
91748	31221203	It was previously characterized and demonstrated effective suppression of MET-induced glioma progression in cell lines and xenografts; further, in an open-label phase I clinical trial, the safety and efficacy of PLB-1001 for the treatment of patients with a ZM fusion and/or METex14 was shown.	('glioma', 'Disease', (86, 92))	('PLB-1001', 'Chemical', '-', (212, 220))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('METex14', 'Var', (275, 282))	('PLB-1001', 'Gene', (212, 220))	('patients', 'Species', '9606', (242, 250))
91751	31221203	As is known, aberrant RTK signaling is a key driver of tumorigenesis and resistance to treatment in glioblastoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('RTK', 'Gene', (22, 25))	('tumor', 'Disease', (55, 60))	('glioblastoma', 'Disease', (100, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('RTK', 'Gene', '5979', (22, 25))	('aberrant', 'Var', (13, 21))
91752	31221203	Although EGFR mutations, amplification, and overexpression are common in glioblastoma and gefitinib is well tolerated in patients with malignant gliomas, treatment is not associated with significant improvements in OS or PFS compared to that in the historical control population.	('PFS', 'CPA', (221, 224))	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('common', 'Reg', (63, 69))	('overexpression', 'PosReg', (44, 58))	('malignant gliomas', 'Disease', (135, 152))	('gefitinib', 'Chemical', 'MESH:D000077156', (90, 99))	('glioblastoma', 'Disease', (73, 85))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('malignant gliomas', 'Disease', 'MESH:D005910', (135, 152))	('OS', 'Chemical', '-', (215, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('mutations', 'Var', (14, 23))	('amplification', 'Var', (25, 38))	('patients', 'Species', '9606', (121, 129))
91753	31221203	Of note, inhibition of EGFR induces a MET-driven stem cell population in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('glioblastoma', 'Disease', (73, 85))	('induces', 'Reg', (28, 35))	('EGFR', 'Gene', '1956', (23, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('MET-driven stem cell population', 'CPA', (38, 69))	('EGFR', 'Gene', (23, 27))	('inhibition', 'Var', (9, 19))
91754	31221203	identified a distinct fraction of cells expressing a high level of MET and co-expressing GSC markers in human primary glioblastoma specimens, which were found to be highly clonogenic, tumorigenic, and resistant to radiation.	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('MET', 'Var', (67, 70))	('human', 'Species', '9606', (104, 109))	('tumor', 'Disease', (184, 189))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))
91772	31221203	As presented in this review, the dysregulation of miRNAs (miR449-5b, miR-34a, miR-182, and miR-144-3p) contributes to over-transcription of the MET gene, and HSP90 is essential for the translation and modification of the MET protein (Fig.	('dysregulation', 'Var', (33, 46))	('miR-34a', 'Gene', (69, 76))	('miR-182', 'Gene', (78, 85))	('over-transcription', 'PosReg', (118, 136))	('HSP90', 'Gene', (158, 163))	('HSP90', 'Gene', '3320', (158, 163))	('miR-182', 'Gene', '406958', (78, 85))	('miR-34a', 'Gene', '407040', (69, 76))	('miR449-5b', 'Var', (58, 67))	('miR-144', 'Gene', (91, 98))	('miR-144', 'Gene', '406936', (91, 98))	('MET gene', 'Gene', (144, 152))
91779	31221203	Therefore, it is expected that a further understanding of drug modifications, the selection of targeted sites, the tumor immune microenvironment, the complex network of interactions between different tumor cell populations, and the penetration of proper drugs across the BBB will provide us with more thorough insights to find more effective treatment strategies.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (200, 205))	('modifications', 'Var', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
91789	19705067	Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation.	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('patients', 'Species', '9606', (16, 24))	('methylated', 'Var', (30, 40))
91791	19705067	Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (67, 75))	('p-S6', 'Gene', '338413', (84, 88))	('phospho-S6', 'Var', (36, 46))	('p-S6', 'Gene', (84, 88))
91800	19705067	Notably, in approximately 60% of astrocytomas, there is inactivation of the TP53 locus, while in over 80% of oligodendroglial lesions there is allelic loss of chromosome 1p and 19q.	('astrocytomas', 'Disease', (33, 45))	('TP53', 'Gene', '7157', (76, 80))	('inactivation', 'Var', (56, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('oligodendroglial lesions', 'Disease', (109, 133))	('TP53', 'Gene', (76, 80))	('astrocytomas', 'Disease', 'MESH:D001254', (33, 45))	('loss', 'NegReg', (151, 155))	('oligodendroglial lesions', 'Disease', 'MESH:D051437', (109, 133))
91801	19705067	1p/19q status in oligodendrogliomas also appears to correlate with promoter methylation of the DNA repair enzyme O6-Methylguanine-DNA methyltransferase (MGMT); in patients with 1p/19q deletions, upwards of 85% have concomitant MGMT methylation.	('MGMT', 'Gene', (227, 231))	('patients', 'Species', '9606', (163, 171))	('MGMT', 'Gene', '4255', (227, 231))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (17, 35))	('O6-Methylguanine-DNA methyltransferase', 'Gene', (113, 151))	('MGMT', 'Gene', (153, 157))	('MGMT', 'Gene', '4255', (153, 157))	('oligodendrogliomas', 'Disease', (17, 35))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('1p/19q deletions', 'Var', (177, 193))	('O6-Methylguanine-DNA methyltransferase', 'Gene', '4255', (113, 151))
91803	19705067	More recently, we found PTEN hypermethylation in upwards of 50% of Grade II astrocytomas, oligodendrogliomas, and mixed histologies.	('oligodendrogliomas', 'Disease', (90, 108))	('astrocytomas', 'Disease', (76, 88))	('PTEN', 'Gene', '5728', (24, 28))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (90, 108))	('hypermethylation', 'Var', (29, 45))	('astrocytomas', 'Disease', 'MESH:D001254', (76, 88))	('found', 'Reg', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('PTEN', 'Gene', (24, 28))
91805	19705067	Sitting downstream of PI3K is the mammalian target of rapamycin (mTOR), a 289-kDa serine/threonine kinase that phosphorylates a series of downstream effectors involved in protein biosynthesis, ribosome biogenesis, and the transcription of genes crucial to cell growth.	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('mammalian target of rapamycin', 'Gene', '2475', (34, 63))	('mammalian target of rapamycin', 'Gene', (34, 63))	('PI3K', 'Var', (22, 26))
91809	19705067	Of interest, PTEN hypermethylation was found in approximately 80% of the examined secondary glioblastomas, lesions that themselves result from the malignant transformation of lower-grade lesions.	('glioblastomas', 'Phenotype', 'HP:0012174', (92, 105))	('hypermethylation', 'Var', (18, 34))	('found', 'Reg', (39, 44))	('glioblastomas', 'Disease', 'MESH:D005909', (92, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('glioblastomas', 'Disease', (92, 105))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))
91810	19705067	This enrichment for hypermethylation in the high grade recurrences suggested that this epigenetic modification and the resultant up-regulation of the PI3K-mTOR pathway might play a crucial role in the biology of LGGs and thus have a significant prognostic impact.	('mTOR', 'Gene', '2475', (155, 159))	('hypermethylation', 'Var', (20, 36))	('mTOR', 'Gene', (155, 159))	('up-regulation', 'PosReg', (129, 142))	('epigenetic modification', 'Var', (87, 110))	('play', 'Reg', (174, 178))	('LGGs', 'Disease', (212, 216))
91812	19705067	We hypothesized that those patients with PTEN promoter hypermethylation, phosphorylation of S6, or phosphorylation of PRAS40 (because any of these changes might result in increased flux through the PI3K-mTOR pathway) would have decreased overall survival.	('phosphorylation', 'Var', (73, 88))	('decreased', 'NegReg', (228, 237))	('PRAS40', 'Gene', '84335', (118, 124))	('PTEN', 'Gene', '5728', (41, 45))	('promoter hypermethylation', 'Var', (46, 71))	('phosphorylation', 'Var', (99, 114))	('overall', 'MPA', (238, 245))	('patients', 'Species', '9606', (27, 35))	('PTEN', 'Gene', (41, 45))	('flux', 'MPA', (181, 185))	('increased', 'PosReg', (171, 180))	('mTOR', 'Gene', (203, 207))	('PRAS40', 'Gene', (118, 124))	('mTOR', 'Gene', '2475', (203, 207))
91835	19705067	Following antigen-retrieval, sections were treated with 3% methanol-hydrogen peroxide at 22C  for 16 min for PTEN and MIB-1 and for 32 min for the phospho-PRAS40 and phospho-S6 epitopes.	('methanol', 'Chemical', 'MESH:D000432', (59, 67))	('MIB-1', 'Gene', '57534', (118, 123))	('phospho-S6', 'Var', (166, 176))	('PTEN', 'Gene', (109, 113))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (68, 85))	('PTEN', 'Gene', '5728', (109, 113))	('PRAS40', 'Gene', '84335', (155, 161))	('MIB-1', 'Gene', (118, 123))	('PRAS40', 'Gene', (155, 161))
91841	19705067	Figure 1 illustrates positive staining for each of the four immunohistochemical assays performed; each of the four panels in the figure displays a separate tumor that received a score of 3 for PTEN, phospho-PRAS40, phospho-S6 (Ser235/236), or phospho-S6 (240/244), respectively.	('PRAS40', 'Gene', (207, 213))	('phospho-S6 (Ser235/236', 'Var', (215, 237))	('PTEN', 'Gene', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('PTEN', 'Gene', '5728', (193, 197))	('phospho-S6 (240/244', 'Var', (243, 262))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Ser235', 'Chemical', '-', (227, 233))	('tumor', 'Disease', (156, 161))	('PRAS40', 'Gene', '84335', (207, 213))
91842	19705067	For PTEN methylation, there was no statistically significant relationship between methylation status and overall-survival (OS) (P = 0.128).	('methylation', 'Var', (9, 20))	('PTEN', 'Gene', '5728', (4, 8))	('PTEN', 'Gene', (4, 8))	('overall-survival', 'CPA', (105, 121))	('OS', 'Chemical', '-', (123, 125))
91847	19705067	We assessed the phosphorylation status of two S6 epitopes: Ser-235/236 and Ser-240.	('Ser-240', 'Var', (75, 82))	('Ser', 'Chemical', 'MESH:D012694', (59, 62))	('Ser-235/236', 'Var', (59, 70))	('Ser', 'Chemical', 'MESH:D012694', (75, 78))
91852	19705067	The estimated 5-year survival for patients with phosphorylation of S6 Ser-235/236 was 76%, as compared to 100% for patients without.	('phosphorylation', 'Var', (48, 63))	('patients', 'Species', '9606', (115, 123))	('Ser', 'Chemical', 'MESH:D012694', (70, 73))	('patients', 'Species', '9606', (34, 42))	('S6 Ser-235/236', 'Var', (67, 81))
91855	19705067	Similar to the 235/236 epitope, there were eight deaths in the phosphorylated group and none in the negative group.	('death', 'Disease', (49, 54))	('phosphorylated', 'Var', (63, 77))	('death', 'Disease', 'MESH:D003643', (49, 54))
91861	19705067	Within each histologic subtype, we again found a consistent pattern of decreased survival among patients with Ser-240 phosphorylation even though the log-rank test did not reach statistical significance for either subgroup due to small event number (P = 0.137 and P = 0.301 for astrocytoma and oligodendraglioma, respectively).	('phosphorylation', 'Var', (118, 133))	('Ser', 'Chemical', 'MESH:D012694', (110, 113))	('astrocytoma and oligodendraglioma', 'Disease', 'MESH:D001254', (278, 311))	('astrocytoma', 'Phenotype', 'HP:0009592', (278, 289))	('survival', 'MPA', (81, 89))	('Ser-240', 'Gene', (110, 117))	('patients', 'Species', '9606', (96, 104))	('decreased', 'NegReg', (71, 80))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))
91872	19705067	Among this subset of 23 patients, the trend towards decreased survival among those with p-S6-240 phosphorylation persisted (Fig.	('survival', 'MPA', (62, 70))	('p-S6', 'Gene', '338413', (88, 92))	('phosphorylation', 'Var', (97, 112))	('decreased', 'NegReg', (52, 61))	('p-S6', 'Gene', (88, 92))	('patients', 'Species', '9606', (24, 32))
91873	19705067	It is also noteworthy that the eight patients with p-S6-240 phosphorylation who died all had had subtotal resections.	('phosphorylation', 'Var', (60, 75))	('p-S6', 'Gene', '338413', (51, 55))	('patients', 'Species', '9606', (37, 45))	('p-S6', 'Gene', (51, 55))
91879	19705067	We would expect patients with PTEN promoter hypermethylation to have increased mTOR activity and thus decreased OS.	('mTOR', 'Gene', (79, 83))	('promoter hypermethylation', 'Var', (35, 60))	('mTOR', 'Gene', '2475', (79, 83))	('increased', 'PosReg', (69, 78))	('patients', 'Species', '9606', (16, 24))	('OS', 'Chemical', '-', (112, 114))	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))	('decreased', 'NegReg', (102, 111))
91885	19705067	In univariate analyses, we established a correlation between phosphorylation of these two proteins and OS in LGG; patients whose tumors had evidence of either PRAS40 or S6 phosphorylation had decreased OS.	('OS', 'Chemical', '-', (202, 204))	('S6 phosphorylation', 'Var', (169, 187))	('OS', 'Chemical', '-', (103, 105))	('tumors', 'Disease', (129, 135))	('decreased', 'NegReg', (192, 201))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PRAS40', 'Gene', '84335', (159, 165))	('patients', 'Species', '9606', (114, 122))	('PRAS40', 'Gene', (159, 165))
91888	19705067	Indeed, we found significant positive correlations between S6 phosphorylation and both PRAS40 phosphorylation and PTEN methylation as well as a significant negative correlation between S6 phosphorylation and PTEN expression.	('positive', 'PosReg', (29, 37))	('expression', 'MPA', (213, 223))	('methylation', 'Var', (119, 130))	('PTEN', 'Gene', (208, 212))	('PTEN', 'Gene', (114, 118))	('PTEN', 'Gene', '5728', (208, 212))	('PTEN', 'Gene', '5728', (114, 118))	('negative', 'NegReg', (156, 164))	('PRAS40', 'Gene', '84335', (87, 93))	('PRAS40', 'Gene', (87, 93))
91895	19705067	However, even by looking exclusively at the group of patients with subtotal resections, phospho-S6 expression still portended a worse overall survival, exhibiting a statistical trend nearing significance (P = 0.068).	('patients', 'Species', '9606', (53, 61))	('portended', 'Reg', (116, 125))	('worse', 'NegReg', (128, 133))	('overall survival', 'MPA', (134, 150))	('phospho-S6 expression', 'Var', (88, 109))
91896	19705067	Of note, inhibitors of mTOR have proven largely ineffectual in glioblastoma.	('glioblastoma', 'Disease', (63, 75))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('inhibitors', 'Var', (9, 19))
91898	19705067	In addition, mTOR drives a feedback loop that normally keeps PI3K activity in check and mTOR inhibition can alleviate this negative feedback loop and result in activation of PI3K.	('PI3K', 'Var', (174, 178))	('activation', 'PosReg', (160, 170))	('activity', 'MPA', (66, 74))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('negative feedback loop', 'MPA', (123, 145))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (13, 17))	('alleviate', 'NegReg', (108, 117))	('inhibition', 'Var', (93, 103))
91899	19705067	Therefore, abrogation of this negative loop may impede anti-tumor efficacy of mTOR inhibitors.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mTOR', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mTOR', 'Gene', '2475', (78, 82))	('abrogation', 'Var', (11, 21))	('impede', 'NegReg', (48, 54))	('tumor', 'Disease', (60, 65))
91917	33327771	Many genetic variants related to common and rare epilepsies have been reported.	('epilepsies', 'Disease', 'MESH:D004827', (49, 59))	('variants', 'Var', (13, 21))	('epilepsies', 'Phenotype', 'HP:0001250', (49, 59))	('epilepsies', 'Disease', (49, 59))
91959	33327771	7A, 20 miRNAs, such as miR-240-3p, miR-298-5p, and miR-3473a and 317 target genes were included in the network.	('miR-240-3p', 'Var', (23, 33))	('miR-3473a', 'Var', (51, 60))	('miR-298', 'Gene', '100126296', (35, 42))	('miR-298', 'Gene', (35, 42))
91968	33327771	Up- and downtrend DEGs lead to significant alterations in GO terms and KEGG pathways.	('rat', 'Species', '10116', (47, 50))	('KEGG pathways', 'Pathway', (71, 84))	('alterations', 'Reg', (43, 54))	('GO terms', 'Pathway', (58, 66))	('downtrend', 'NegReg', (8, 17))	('DEGs', 'Var', (18, 22))
91988	33327771	Additionally, PENK was predicted to be regulated by miR-3473a.	('miR-3473a', 'Var', (52, 61))	('regulated', 'Reg', (39, 48))	('PENK', 'Gene', (14, 18))	('PENK', 'Gene', '5179', (14, 18))
91990	33327771	Interestingly, miR-3473a was also involved in the pathway of calcium signaling pathway.	('pathway of calcium signaling', 'Pathway', (50, 78))	('miR-3473a', 'Var', (15, 24))	('calcium', 'Chemical', 'MESH:D002118', (61, 68))	('involved', 'Reg', (34, 42))
91992	33327771	Changes in the expression and biophysical properties of voltage-gated calcium channels can easily lead to epilepsy.	('epilepsy', 'Phenotype', 'HP:0001250', (106, 114))	('lead to', 'Reg', (98, 105))	('epilepsy', 'Disease', (106, 114))	('Changes', 'Var', (0, 7))	('epilepsy', 'Disease', 'MESH:D004827', (106, 114))	('calcium', 'Chemical', 'MESH:D002118', (70, 77))
92000	33327771	Thus, loss of KCNAB2 is associated with epilepsy.	('loss', 'Var', (6, 10))	('epilepsy', 'Disease', (40, 48))	('associated', 'Reg', (24, 34))	('epilepsy', 'Disease', 'MESH:D004827', (40, 48))	('KCNAB2', 'Gene', '8514', (14, 20))	('epilepsy', 'Phenotype', 'HP:0001250', (40, 48))	('KCNAB2', 'Gene', (14, 20))
92001	33327771	Col4a2 encodes one of the six subunits of type IV collagen, mutations of which are associated with neurologic diseases, including epilepsy.	('neurologic diseases', 'Disease', (99, 118))	('epilepsy', 'Phenotype', 'HP:0001250', (130, 138))	('epilepsy', 'Disease', (130, 138))	('associated', 'Reg', (83, 93))	('neurologic diseases', 'Disease', 'MESH:D020271', (99, 118))	('Col4a2', 'Gene', '1284', (0, 6))	('mutations', 'Var', (60, 69))	('Col4a2', 'Gene', (0, 6))	('epilepsy', 'Disease', 'MESH:D004827', (130, 138))
92167	29408716	Overall, SFE showed appreciably higher sensitivity to PpIX in the fluorescent brain areas (30.4+-8.8%) compared to the OPMI Pentero (13.3+-2.7%), P<.01.	('sensitivity', 'MPA', (39, 50))	('PpIX', 'Var', (54, 58))	('PpIX', 'Chemical', 'MESH:C028025', (54, 58))	('higher', 'PosReg', (32, 38))
92209	29408716	High-optical power density of the exciting light may result in a loss of fluorescence, which is relevant for PpIX-guided surgery (see supplemental text, Supplemental Digital Content 7, for further details).	('loss', 'NegReg', (65, 69))	('fluorescence', 'MPA', (73, 85))	('PpIX', 'Chemical', 'MESH:C028025', (109, 113))	('High-optical power', 'Var', (0, 18))
92246	28966837	We have also combined the two subgroups of patches with bad segmentations together to form the bad-quality-segmentation group and trained the classifiers for each cancer type by the two classification methods to differentiate good-quality-segmentation patches from the bad-quality-segmentation ones.	('patches', 'Var', (252, 259))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
92277	27999734	IDH1/2 mutations are the most common mutations in glioma, especially in lower grade glioma and secondary glioblastoma, which developed from a less malignant lesion.	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('malignant lesion', 'Disease', 'MESH:D009369', (147, 163))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioma', 'Disease', (84, 90))	('malignant lesion', 'Disease', (147, 163))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('glioma', 'Disease', (50, 56))	('common', 'Reg', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('glioblastoma', 'Disease', (105, 117))	('mutations', 'Var', (7, 16))
92278	27999734	For CGGA cohort, IDH1/2 mutations were detected by pyrosequencing which has been described in our previous study.	('mutations', 'Var', (24, 33))	('IDH1/2', 'Gene', (17, 23))	('IDH1/2', 'Gene', '3417;3418', (17, 23))
92283	27999734	Moreover, when IDH mutation status was added as a sub-classifier, we found that in IDH wild-type glioblastoma showed significantly distinct pattern of PD-L1 expression from IDH mutant glioblastoma of both CGGA and TCGA data set (Figs.	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('expression', 'MPA', (157, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (184, 196))	('IDH', 'Gene', (83, 86))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', '3417', (83, 86))	('IDH', 'Gene', '3417', (173, 176))	('IDH', 'Gene', (15, 18))	('mutant', 'Var', (177, 183))	('PD-L1', 'Gene', (151, 156))	('IDH', 'Gene', '3417', (15, 18))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', (184, 196))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (184, 196))
92288	27999734	identified a novel mechanism that TP53 could regulate the expression of PD-L1 through microRNA-34 which contributed to immune evasion of tumor.	('contributed', 'Reg', (104, 115))	('tumor', 'Disease', (137, 142))	('TP53', 'Gene', (34, 38))	('microRNA-34', 'Var', (86, 97))	('expression', 'MPA', (58, 68))	('regulate', 'Reg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PD-L1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('TP53', 'Gene', '7157', (34, 38))
92301	27999734	This suggested that PD-L1, together with PD1, CD80 were induced more as immune suppressors in the tumor environment in which inflammatory and immune response were more active.	('CD80', 'Gene', '941', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PD-L1', 'Var', (20, 25))	('tumor', 'Disease', (98, 103))	('CD80', 'Gene', (46, 50))
92312	27999734	Those findings indicated that PD-L1 was a negative prognosticator in glioma due to suppressive effect on T-cell-related immune response.	('glioma', 'Disease', (69, 75))	('T-cell-related immune response', 'CPA', (105, 135))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('PD-L1', 'Var', (30, 35))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('suppressive', 'NegReg', (83, 94))
92321	27999734	Lower expression of PD-L1 usually was companied by IDH mutation, suggesting IDH mutant gliomas were involved in less tumor-induced immune response than that IDH wild-type gliomas.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('IDH', 'Gene', '3417', (51, 54))	('IDH', 'Gene', '3417', (76, 79))	('gliomas', 'Disease', (171, 178))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('mutant', 'Var', (80, 86))	('less', 'NegReg', (112, 116))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('IDH', 'Gene', (157, 160))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('gliomas', 'Disease', (87, 94))	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', '3417', (157, 160))	('tumor', 'Disease', (117, 122))	('IDH', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
92328	27999734	Interestingly, PD-L1 seemed to be correlated with angiogenesis, corresponding to highly vascularization of GBM in contrast to lower grade glioma, which further validated the relationship between PD-L1 expression and malignant process.	('glioma', 'Disease', (138, 144))	('PD-L1', 'Var', (15, 20))	('angiogenesis', 'CPA', (50, 62))	('highly', 'PosReg', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('correlated', 'Reg', (34, 44))
92369	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
92370	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
92374	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'Var', (169, 174))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))
92406	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('SRPX', 'Gene', (9, 13))	('downregulated', 'NegReg', (178, 191))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('DRS', 'Gene', (80, 83))	('ETX1', 'Gene', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
92415	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('ACC', 'Disease', (11, 14))
92416	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mRNA expression', 'MPA', (24, 39))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
92451	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
92459	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('MYC', 'Gene', (43, 46))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('advantage', 'PosReg', (99, 108))
92470	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('GSE120040', 'Var', (141, 150))	('HDAC4', 'Gene', (134, 139))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
92481	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'Gene', '822', (424, 427))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
92493	30519352	According to their expression levels and major target genes, miRNAs may act as oncogenic miRNAs or tumour suppressor miRNAs in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('miRNAs', 'Var', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
92494	30519352	Studies have shown that miRNAs are associated with angiogenesis, invasion, and altered metabolism in gliomas.	('gliomas', 'Disease', (101, 108))	('metabolism', 'MPA', (87, 97))	('altered', 'Reg', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('associated', 'Reg', (35, 45))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('miRNAs', 'Var', (24, 30))	('invasion', 'CPA', (65, 73))	('angiogenesis', 'CPA', (51, 63))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
92506	30519352	In previous studies, we successfully established 8 BSG cell lines (TT10603, TT10728, TT10902, TT11118, TT11201, TT10630, TT10714 and TT11111), and all the patients were diagnosed with high-grade gliomas (3 cases of grade III anaplastic astrocytoma AA, 2 cases of grade III anaplastic oligodendroastrocytoma AOA, and 3 cases of grade IV glioblastoma GBM).	('astrocytoma', 'Disease', (295, 306))	('oligodendroastrocytoma AOA', 'Disease', 'MESH:C538013', (284, 310))	('astrocytoma', 'Disease', 'MESH:D001254', (236, 247))	('IV glioblastoma GBM', 'Disease', 'MESH:D005909', (333, 352))	('astrocytoma', 'Disease', (236, 247))	('patients', 'Species', '9606', (155, 163))	('gliomas', 'Disease', (195, 202))	('TT11118', 'Var', (94, 101))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('TT11111', 'Var', (133, 140))	('gliomas', 'Disease', 'MESH:D005910', (195, 202))	('TT10728', 'Var', (76, 83))	('TT10902', 'Var', (85, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (295, 306))	('glioblastoma', 'Phenotype', 'HP:0012174', (336, 348))	('TT10630', 'Var', (112, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (236, 247))	('diagnosed', 'Reg', (169, 178))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('oligodendroastrocytoma AOA', 'Disease', (284, 310))	('TT10603', 'Var', (67, 74))	('TT11201', 'Var', (103, 110))	('TT10714', 'Var', (121, 128))	('IV glioblastoma GBM', 'Disease', (333, 352))	('astrocytoma', 'Disease', 'MESH:D001254', (295, 306))
92531	30519352	Based on the FC, hsa-miR-1290, hsa-miR-130b-3p and hsa-miR-18a-3p were the top three most upregulated miRNAs and hsa-miR-31-5p, hsa-miR-34a-3p and hsa-miR-34a-5p were the top three most downregulated miRNAs.	('hsa-miR-31', 'Gene', '407035', (113, 123))	('miR-130b', 'Gene', (35, 43))	('miR-34a', 'Gene', '407040', (132, 139))	('hsa-miR-1290', 'Gene', (17, 29))	('hsa-miR-31', 'Gene', (113, 123))	('miR-34a', 'Gene', (132, 139))	('hsa-miR-18a-3p', 'Var', (51, 65))	('hsa-miR-1290', 'Gene', '100302276', (17, 29))	('upregulated', 'PosReg', (90, 101))	('miR-34a', 'Gene', '407040', (151, 158))	('miR-130b', 'Gene', '406920', (35, 43))	('miR-34a', 'Gene', (151, 158))
92538	30519352	Six of the 28 functional DE-miRNAs (hsa-miR-130b-3p, hsa-miR-19a-3p, hsa-miR-20a-5p, hsa-miR-106a-5p, hsa-miR-34a-5p and hsa-miR-195-5p) were proven to be grade-associated functional DE-miRNAs (Figure 5A-F and Table S2).	('hsa-miR-20a-5p', 'Var', (69, 83))	('miR-19a', 'Gene', '406979', (57, 64))	('miR-106a', 'Gene', '406899', (89, 97))	('miR-130b', 'Gene', '406920', (40, 48))	('miR-195', 'Gene', (125, 132))	('miR-195', 'Gene', '406971', (125, 132))	('miR-106a', 'Gene', (89, 97))	('miR-34a', 'Gene', '407040', (106, 113))	('miR-130b', 'Gene', (40, 48))	('miR-34a', 'Gene', (106, 113))	('miR-19a', 'Gene', (57, 64))
92569	30519352	AMPK is a conserved cellular energy sensor that is activated by metabolic stress to promote energy conservation and glucose uptake, and researchers found that activation of AMPK inhibits the growth of EGFRvIII-expressing glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (221, 233))	('growth', 'MPA', (191, 197))	('AMPK', 'Gene', '5562', (173, 177))	('glioblastomas', 'Disease', (221, 234))	('EGFR', 'Gene', '1956', (201, 205))	('AMPK', 'Gene', (173, 177))	('activation', 'Var', (159, 169))	('AMPK', 'Gene', '5562', (0, 4))	('EGFR', 'Gene', (201, 205))	('energy conservation', 'MPA', (92, 111))	('glucose', 'Chemical', 'MESH:D005947', (116, 123))	('glioblastomas', 'Phenotype', 'HP:0012174', (221, 234))	('AMPK', 'Gene', (0, 4))	('glucose uptake', 'CPA', (116, 130))	('glioblastomas', 'Disease', 'MESH:D005909', (221, 234))	('inhibits', 'NegReg', (178, 186))
92573	30519352	The Hippo signalling pathway is considered a key player in the regulation of tumourigenesis, and inactivating the Hippo signalling pathway enhances stem cell-like phenotypes in glioblastoma.	('glioblastoma', 'Disease', (177, 189))	('inactivating', 'Var', (97, 109))	('stem cell-like phenotypes', 'CPA', (148, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (177, 189))	('enhances', 'PosReg', (139, 147))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('Hippo', 'Gene', (114, 119))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
92574	30519352	Extensive studies have shown that aberrant Wnt/beta-catenin signalling plays a key role in the development of glioblastoma, including in cell proliferation, cell apoptosis and cell invasion.	('beta-catenin', 'Gene', '1499', (47, 59))	('cell proliferation', 'CPA', (137, 155))	('aberrant', 'Var', (34, 42))	('cell apoptosis', 'CPA', (157, 171))	('cell invasion', 'CPA', (176, 189))	('glioblastoma', 'Disease', (110, 122))	('beta-catenin', 'Gene', (47, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (110, 122))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))
92575	30519352	Alterations in the MAPK pathway have been found in 88% of adult glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (64, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (64, 77))	('glioblastomas', 'Disease', (64, 77))	('Alterations', 'Var', (0, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('MAPK pathway', 'Pathway', (19, 31))	('found', 'Reg', (42, 47))
92589	30519352	In addition, the target genes of the functional DE-miRNAs were determined to be associated with several significant signalling pathways in BSGs, such as the FoxO signalling pathway, the AMPK signalling pathway, the HIF-1 signalling pathway and the MAPK signalling pathway.	('AMPK', 'Gene', '5562', (186, 190))	('AMPK', 'Gene', (186, 190))	('HIF-1', 'Gene', '3091', (215, 220))	('FoxO signalling pathway', 'Pathway', (157, 180))	('HIF-1', 'Gene', (215, 220))	('BSGs', 'Disease', (139, 143))	('MAPK signalling pathway', 'Pathway', (248, 271))	('DE-miRNAs', 'Var', (48, 57))
92602	30375513	For example, mutational profiling of regulatory proteins shows tissue specificity, while histone modifiers can be mutated similarly across several cancer types.	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutational', 'Var', (13, 23))
92603	30375513	suggests that lung squamous, head and neck, and a subset of bladder cancers form a unique cancer category typified by specific alterations, while copy number, protein expression, somatic mutations and activated pathways divide bladder cancer into different subtypes.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung squamous', 'Disease', (14, 27))	('bladder cancers', 'Phenotype', 'HP:0009725', (60, 75))	('bladder cancers', 'Disease', 'MESH:D001749', (60, 75))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('bladder cancers', 'Disease', (60, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('alterations', 'Var', (127, 138))	('lung squamous', 'Disease', 'MESH:D002294', (14, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (227, 241))	('bladder cancer', 'Disease', (227, 241))	('cancer', 'Disease', (235, 241))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (227, 241))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
92607	30375513	For example, common genetic alterations can predict similar responses to pharmacological therapies across multiple cancer cell lines, thus common molecular and functional profiles could enable the repurposing of therapies from one cancer to another.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('alterations', 'Var', (28, 39))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
92639	30375513	We selected three drugs: BI6727, for targeting the cluster 2 signature gene PLK1; Bortezomib, for targeting proteasome and NF-kappaB pathway; and the PF-00477736 drug, to target the CHK1/2 genes, which play a role in DNA damage response but are not in the signature.	('PF-00477736', 'Var', (150, 161))	('PLK1', 'Gene', (76, 80))	('NF-kappaB', 'Gene', '4790', (123, 132))	('Bortezomib', 'Chemical', 'MESH:D000069286', (82, 92))	('BI6727', 'Chemical', 'MESH:C541363', (25, 31))	('PLK1', 'Gene', '5347', (76, 80))	('NF-kappaB', 'Gene', (123, 132))	('CHK1/2', 'Gene', '1111;11200', (182, 188))	('CHK1/2', 'Gene', (182, 188))
92641	30375513	Both cell lines resulted highly sensitive to Bortezomib, with an IC50 of 200 nM for MCF-7 and 0.6 nM for T98G (Fig.	('sensitive', 'MPA', (32, 41))	('MCF-7', 'CellLine', 'CVCL:0031', (84, 89))	('Bortezomib', 'Chemical', 'MESH:D000069286', (45, 55))	('T98G', 'Var', (105, 109))
92642	30375513	BI6727 treatment reduced viability in a concentration-dependent manner in both models, with the glioblastoma model showing increased responsiveness (IC50 of 69.2 nM versus 1.8 muM for MCF-7).	('BI6727', 'Var', (0, 6))	('glioblastoma', 'Disease', (96, 108))	('BI6727', 'Chemical', 'MESH:C541363', (0, 6))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('MCF-7', 'CellLine', 'CVCL:0031', (184, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('viability', 'MPA', (25, 34))	('reduced', 'NegReg', (17, 24))
92644	30375513	Although the combinations of PF-00477736 with either BI6727 or Bortezomib did not show any additive or synergistic effect in both cell lines, we observed a cooperation effect between BI6727 and Bortezomib (Fig.	('BI6727', 'Chemical', 'MESH:C541363', (53, 59))	('combinations', 'Interaction', (13, 25))	('BI6727', 'Chemical', 'MESH:C541363', (183, 189))	('BI6727', 'Var', (183, 189))	('Bortezomib', 'Chemical', 'MESH:D000069286', (63, 73))	('Bortezomib', 'Chemical', 'MESH:D000069286', (194, 204))	('PF-00477736', 'Var', (29, 40))	('cooperation', 'Interaction', (156, 167))
92654	30375513	However, the clustering also grouped tumours originating from different tissues, according to similarities in genomic alterations, as in the case of BRCA, OV, LUSC, and UCEC, which share common characteristics as presence of TP53 mutations and multiple recurrent chromosomal gains and losses.	('UCEC', 'Disease', (169, 173))	('losses', 'NegReg', (285, 291))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('presence', 'Reg', (213, 221))	('OV', 'Phenotype', 'HP:0012887', (155, 157))	('LUSC', 'Disease', (159, 163))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('TP53', 'Gene', '7157', (225, 229))	('BRCA', 'Phenotype', 'HP:0003002', (149, 153))	('BRCA', 'Gene', '672', (149, 153))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('mutations', 'Var', (230, 239))	('BRCA', 'Gene', (149, 153))	('TP53', 'Gene', (225, 229))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
92660	30375513	The aberrant activity of NF-kappaB may act as survival factor for transformed cells which would otherwise become senescent or apoptotic.	('NF-kappaB', 'Gene', (25, 34))	('NF-kappaB', 'Gene', '4790', (25, 34))	('aberrant activity', 'Var', (4, 21))
92661	30375513	The mutant genotypes may confer beneficial phenotypic traits to cancer cells, such as sustained proliferative signaling and resistance to cell death.	('mutant', 'Var', (4, 10))	('resistance to cell death', 'CPA', (124, 148))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('sustained', 'MPA', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
92665	30375513	Interestingly, the tumours in this cluster usually present high rates (50-90%) of samples with mutated TP53, which is an important sensor for the cell DNA damage response.	('TP53', 'Gene', '7157', (103, 107))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('TP53', 'Gene', (103, 107))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('mutated', 'Var', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
92678	30375513	PF-00477736 drug (a CHK1/2 inhibitor, not in the signature) had poor effect on both cell lines.	('PF-00477736 drug', 'Var', (0, 16))	('CHK1/2', 'Gene', '1111;11200', (20, 26))	('CHK1/2', 'Gene', (20, 26))
92679	30375513	On the contrary, they resulted highly sensitive to the combination of BI6727 (an inhibitor of the signature gene PLK1) and Bortezomib (proteasome activity inhibitor).	('BI6727', 'Var', (70, 76))	('Bortezomib', 'Chemical', 'MESH:D000069286', (123, 133))	('PLK1', 'Gene', (113, 117))	('BI6727', 'Chemical', 'MESH:C541363', (70, 76))	('PLK1', 'Gene', '5347', (113, 117))
92682	30375513	Moreover, we observed a significant synergic action of Bortezomib and PLK1 inhibitors at several dosages on both cell lines, not found when BI6727 was considered in combination with the other two signature-related drugs.	('PLK1', 'Gene', (70, 74))	('inhibitors', 'Var', (75, 85))	('BI6727', 'Chemical', 'MESH:C541363', (140, 146))	('PLK1', 'Gene', '5347', (70, 74))	('Bortezomib', 'Chemical', 'MESH:D000069286', (55, 65))	('synergic', 'Interaction', (36, 44))
92702	30375513	Cells were cultured at a density of 105 cells/ml in RPMI medium plus 10% FBS (plus 5% Sodium orthovanadate for T98G) for 72 h with increasing concentrations of the following drugs: Bortezomib, BI6727, PF-00477736 (Selleckchem), alone or in combination.	('Bortezomib', 'Chemical', 'MESH:D000069286', (181, 191))	('BI6727', 'Var', (193, 199))	('RPMI medium', 'Chemical', '-', (52, 63))	('Sodium orthovanadate', 'Chemical', '-', (86, 106))	('PF-00477736', 'Var', (201, 212))	('BI6727', 'Chemical', 'MESH:C541363', (193, 199))
92709	28713588	High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22.	('monosomy 22', 'Var', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('chromosomal gains', 'Var', (70, 87))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (117, 123))	('losses', 'NegReg', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('elevated rates of chromosomal gains', 'Phenotype', 'HP:0040012', (52, 87))	('meningiomas', 'Phenotype', 'HP:0002858', (11, 22))	('meningioma', 'Phenotype', 'HP:0002858', (11, 21))	('meningiomas', 'Disease', (11, 22))	('meningiomas', 'Disease', 'MESH:D008577', (11, 22))	('elevated', 'PosReg', (52, 60))
92711	28713588	Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas correlated with subsequent progression to a higher grade.	('mutations', 'Var', (83, 92))	('meningiomas', 'Disease', (162, 173))	('meningiomas', 'Disease', 'MESH:D008577', (162, 173))	('meningiomas', 'Phenotype', 'HP:0002858', (162, 173))	('correlated', 'Reg', (174, 184))	('meningioma', 'Phenotype', 'HP:0002858', (162, 172))
92712	28713588	In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor.	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (106, 111))
92713	28713588	While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value.	('meningiomas', 'Disease', 'MESH:D008577', (104, 115))	('meningioma', 'Phenotype', 'HP:0002858', (104, 114))	('mutations', 'Var', (141, 150))	('meningiomas', 'Phenotype', 'HP:0002858', (17, 28))	('meningioma', 'Phenotype', 'HP:0002858', (17, 27))	('meningiomas', 'Phenotype', 'HP:0002858', (104, 115))	('meningiomas', 'Disease', (17, 28))	('meningiomas', 'Disease', 'MESH:D008577', (17, 28))	('meningiomas', 'Disease', (104, 115))
92718	28713588	They found that aggressive tumors were more likely to harbor mutations in the NF2 gene and exhibit widespread genomic disruption.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('aggressive tumors', 'Disease', 'MESH:D001523', (16, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (61, 70))	('aggressive tumors', 'Disease', (16, 33))	('NF2', 'Gene', (78, 81))
92722	28713588	Despite the greater recurrence rates and mortality that results from high-grade meningiomas, our understanding of the genomic aberrations that drive these tumors remains incomplete.	('meningiomas', 'Disease', (80, 91))	('meningiomas', 'Disease', 'MESH:D008577', (80, 91))	('high-grade', 'Var', (69, 79))	('meningioma', 'Phenotype', 'HP:0002858', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('meningiomas', 'Phenotype', 'HP:0002858', (80, 91))
92724	28713588	The discovery that mutation of the NF2 gene was responsible for Neurofibromatosis 2, an inherited genetic disorder characterized by the development of schwannomas and meningiomas, was a substantial step forward in the characterization of the pathobiology of meningioma and marked these tumors as one of the first to be associated with a genomic driver.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('schwannomas', 'Disease', 'MESH:D009442', (151, 162))	('tumors', 'Disease', (286, 292))	('schwannomas', 'Disease', (151, 162))	('meningioma', 'Disease', 'MESH:D008577', (258, 268))	('inherited genetic disorder', 'Disease', (88, 114))	('meningioma', 'Disease', (167, 177))	('mutation', 'Var', (19, 27))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (64, 81))	('meningioma', 'Phenotype', 'HP:0002858', (167, 177))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('Neurofibromatosis 2', 'Disease', (64, 83))	('meningioma', 'Disease', 'MESH:D008577', (167, 177))	('schwannomas', 'Phenotype', 'HP:0100008', (151, 162))	('meningiomas', 'Disease', 'MESH:D008577', (167, 178))	('inherited genetic disorder', 'Disease', 'MESH:D030342', (88, 114))	('NF2', 'Gene', (35, 38))	('meningiomas', 'Phenotype', 'HP:0002858', (167, 178))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('meningioma', 'Disease', (258, 268))	('meningiomas', 'Disease', (167, 178))	('meningioma', 'Phenotype', 'HP:0002858', (258, 268))	('Neurofibromatosis 2', 'Disease', 'MESH:C537392', (64, 83))	('responsible', 'Reg', (48, 59))
92725	28713588	Subsequent analyses of sporadic meningiomas identified inactivating mutations and copy loss of the region on 22q harboring the NF2 gene in approximately 40-60% of cases.	('NF2', 'Gene', (127, 130))	('sporadic meningiomas', 'Disease', 'MESH:D008577', (23, 43))	('meningiomas', 'Phenotype', 'HP:0002858', (32, 43))	('meningioma', 'Phenotype', 'HP:0002858', (32, 42))	('inactivating mutations', 'Var', (55, 77))	('sporadic meningiomas', 'Disease', (23, 43))	('copy loss', 'Var', (82, 91))
92726	28713588	Recently, our group and others used next-generation sequencing methods to identify recurrent mutations in several additional genes besides NF2, including v-Akt murine thymoma viral oncogene homolog 1 (AKT1) and 3 (AKT3), Phosphatidylinositol 3-kinase (PIK3CA), Smoothened (SMO), SUFU negative regulator of hedgehog signaling (SUFU), TNF receptor-associated factor 7 (TRAF7), Kruppel-like factor 4 (KLF4), SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1), RNA polymerase II subunit A (POLR2A) and BRCA1-associated protein 1 (BAP1), in addition to alterations in the promoter region of the Telomerase reverse transcriptase (TERT) gene.	('BRCA1-associated protein 1', 'Gene', (555, 581))	('murine', 'Species', '10090', (160, 166))	('AKT3', 'Gene', (214, 218))	('SMARCB1', 'Gene', (504, 511))	('Telomerase reverse transcriptase', 'Gene', '21752', (647, 679))	('Kruppel-like factor 4', 'Gene', (375, 396))	('Smoothened', 'Gene', (261, 271))	('Kruppel-like factor 4', 'Gene', '16600', (375, 396))	('BRCA1-associated protein 1', 'Gene', '104416', (555, 581))	('SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1', 'Gene', '20587', (405, 502))	('thymoma viral', 'Disease', (167, 180))	('alterations', 'Reg', (605, 616))	('mutations', 'Var', (93, 102))	('POLR2A', 'Gene', (543, 549))	('thymoma viral', 'Disease', 'MESH:D013945', (167, 180))	('thymoma', 'Phenotype', 'HP:0100522', (167, 174))	('Smoothened', 'Gene', '319757', (261, 271))	('Telomerase reverse transcriptase', 'Gene', (647, 679))	('BAP1', 'Gene', (583, 587))	('TERT', 'Gene', '21752', (681, 685))	('POLR2A', 'Gene', '20020', (543, 549))	('TNF receptor-associated factor 7', 'Gene', '224619', (333, 365))	('TNF receptor-associated factor 7', 'Gene', (333, 365))	('AKT3', 'Gene', '23797', (214, 218))	('TERT', 'Gene', (681, 685))
92727	28713588	However, these alterations have been observed predominantly in low-grade meningiomas, while the genomic landscape of high-grade meningiomas remains largely unexplored.	('meningiomas', 'Disease', (73, 84))	('meningiomas', 'Disease', 'MESH:D008577', (128, 139))	('meningiomas', 'Disease', 'MESH:D008577', (73, 84))	('meningiomas', 'Disease', (128, 139))	('observed', 'Reg', (37, 45))	('alterations', 'Var', (15, 26))	('meningiomas', 'Phenotype', 'HP:0002858', (73, 84))	('meningiomas', 'Phenotype', 'HP:0002858', (128, 139))	('meningioma', 'Phenotype', 'HP:0002858', (128, 138))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))
92737	28713588	Across 39 high-grade meningiomas from unique individuals, we observed an average of 23 (range 1-223) nonsynonymous coding alterations.	('nonsynonymous coding alterations', 'Var', (101, 133))	('meningiomas', 'Phenotype', 'HP:0002858', (21, 32))	('meningioma', 'Phenotype', 'HP:0002858', (21, 31))	('meningiomas', 'Disease', (21, 32))	('meningiomas', 'Disease', 'MESH:D008577', (21, 32))
92741	28713588	We also did not identify any mismatch repair pathway alterations in this sample, which have been shown to produce elevated rates of mutations in other cancer types.	('mismatch repair pathway', 'Pathway', (29, 52))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (132, 141))	('alterations', 'Var', (53, 64))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
92744	28713588	Of the 18 NF2 alterations, 89% were inactivating frame-shift, splice site, or nonsense alterations, consistent with the known tumor suppressor role of NF2, compared with only 16% of non-NF2 mutations (p = 6 x 10-10).	('NF2', 'Gene', (10, 13))	('alterations', 'Var', (14, 25))	('splice', 'MPA', (62, 68))	('nonsense', 'Var', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('inactivating frame-shift', 'Var', (36, 60))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
92745	28713588	The average allelic fraction of NF2 alterations was 57% (range 19-84%), in comparison with the cohort-wide average of 25% among all other mutations (p = 3.7 x 10-6), suggesting that NF2 mutations tend to be shared by a larger fraction of cells in the tumor relative to other mutations.	('tumor', 'Disease', (251, 256))	('mutations', 'Var', (186, 195))	('alterations', 'Var', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('NF2', 'Gene', (182, 185))
92747	28713588	Other than NF2, the most frequently mutated genes were CDC27 and LRP1B, mutated in 10 (9%) and 9 (8%) samples, respectively, of the total set of 115 meningiomas (Supplementary Table 4).	('meningiomas', 'Disease', 'MESH:D008577', (149, 160))	('meningioma', 'Phenotype', 'HP:0002858', (149, 159))	('mutated', 'Var', (72, 79))	('meningiomas', 'Disease', (149, 160))	('CDC27', 'Gene', (55, 60))	('LRP1B', 'Gene', (65, 70))	('meningiomas', 'Phenotype', 'HP:0002858', (149, 160))	('CDC27', 'Gene', '996', (55, 60))	('LRP1B', 'Gene', '53353', (65, 70))
92749	28713588	The finding that no genes other than NF2 were significantly mutated in high-grade meningiomas suggests that high-grade meningiomas are much less likely to harbor mutations in known drivers of low-grade meningioma, including TRAF7, KLF4, AKT1, or SMO.	('TRAF7', 'Gene', (224, 229))	('meningioma', 'Disease', (202, 212))	('meningioma', 'Phenotype', 'HP:0002858', (202, 212))	('low-grade', 'Disease', (192, 201))	('meningioma', 'Disease', (82, 92))	('AKT1', 'Gene', (237, 241))	('meningiomas', 'Disease', 'MESH:D008577', (82, 93))	('meningioma', 'Phenotype', 'HP:0002858', (82, 92))	('meningioma', 'Disease', 'MESH:D008577', (202, 212))	('meningiomas', 'Phenotype', 'HP:0002858', (82, 93))	('meningioma', 'Disease', (119, 129))	('meningioma', 'Phenotype', 'HP:0002858', (119, 129))	('meningiomas', 'Disease', 'MESH:D008577', (119, 130))	('meningiomas', 'Disease', (82, 93))	('meningioma', 'Disease', 'MESH:D008577', (82, 92))	('mutations', 'Var', (162, 171))	('meningiomas', 'Phenotype', 'HP:0002858', (119, 130))	('meningiomas', 'Disease', (119, 130))	('meningioma', 'Disease', 'MESH:D008577', (119, 129))
92752	28713588	Mutations in each of these genes occurred significantly less frequently in high-grade meningiomas (p = 0.03 for each, Fig.	('less', 'NegReg', (56, 60))	('meningiomas', 'Disease', (86, 97))	('meningioma', 'Phenotype', 'HP:0002858', (86, 96))	('meningiomas', 'Phenotype', 'HP:0002858', (86, 97))	('Mutations', 'Var', (0, 9))	('meningiomas', 'Disease', 'MESH:D008577', (86, 97))
92753	28713588	Among these genes, TRAF7 was mutated most frequently among the high-grade meningiomas, but only in 10 of the 254 samples (4%).	('meningiomas', 'Phenotype', 'HP:0002858', (74, 85))	('TRAF7', 'Gene', (19, 24))	('meningioma', 'Phenotype', 'HP:0002858', (74, 84))	('meningiomas', 'Disease', (74, 85))	('mutated', 'Var', (29, 36))	('meningiomas', 'Disease', 'MESH:D008577', (74, 85))
92754	28713588	Conversely, alterations in NF2 or chromosome 22 occurred significantly more frequently in high-grade (80%) than low-grade meningiomas (43%, p < 1 x 10-16; Fig.	('chromosome 22', 'Gene', (34, 47))	('NF2', 'Gene', (27, 30))	('alterations', 'Var', (12, 23))	('meningiomas', 'Phenotype', 'HP:0002858', (122, 133))	('meningioma', 'Phenotype', 'HP:0002858', (122, 132))	('meningiomas', 'Disease', 'MESH:D008577', (122, 133))	('meningiomas', 'Disease', (122, 133))	('high-grade', 'Disease', (90, 100))
92755	28713588	Such elevated rates of NF2 driver events may partly explain why non-NF2 driver genes are mutated significantly less frequently in high-grade than low-grade tumors: the non-NF2 drivers are mutated most often in NF2 wild-type tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('NF2', 'Gene', (210, 213))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('mutated', 'Var', (188, 195))	('tumors', 'Disease', (156, 162))
92757	28713588	However, even among high-grade tumors without NF2 alterations, the difference in rates of non-NF2 driver mutations remained statistically significant (p < 3 x 10-5).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('non-NF2', 'Gene', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (105, 114))
92758	28713588	Across the cohort of 702 high-grade and low-grade meningiomas from unique patients, loss of chromosome 22 and mutations in NF2 tended to co-occur (p < 2 x 10-16).	('mutations', 'Var', (110, 119))	('meningiomas', 'Disease', 'MESH:D008577', (50, 61))	('patients', 'Species', '9606', (74, 82))	('meningioma', 'Phenotype', 'HP:0002858', (50, 60))	('meningiomas', 'Disease', (50, 61))	('NF2', 'Gene', (123, 126))	('loss', 'Var', (84, 88))	('meningiomas', 'Phenotype', 'HP:0002858', (50, 61))
92759	28713588	Even in the 309 meningiomas with chromosome 22 loss, these canonical non-NF2 mutations were mutually exclusive with NF2 mutations (p = 0.02), suggesting that loss of chromosome 22 may not be driving bi-allelic inactivation of NF2 in tumors with non-NF2 driver alterations.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('loss', 'Var', (158, 162))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('meningiomas', 'Disease', 'MESH:D008577', (16, 27))	('meningioma', 'Phenotype', 'HP:0002858', (16, 26))	('meningiomas', 'Disease', (16, 27))	('loss', 'NegReg', (47, 51))	('mutations', 'Var', (77, 86))	('meningiomas', 'Phenotype', 'HP:0002858', (16, 27))	('NF2', 'Gene', (226, 229))
92761	28713588	We detected 25 alterations in the mTOR pathway (including mutations in AKT1, PIK3CA, MTOR, TSC2, and RICTOR), 16 alterations in the Hedgehog pathway (including mutations in SMO and SUFU), and two mutations in TP53, which is downstream of KLF4.	('PIK3CA', 'Gene', (77, 83))	('mutations', 'Var', (58, 67))	('TSC2', 'Gene', (91, 95))	('MTOR', 'Gene', '2475', (85, 89))	('TP53', 'Gene', (209, 213))	('mutations', 'Var', (160, 169))	('RICTOR', 'Gene', (101, 107))	('Hedgehog pathway', 'Pathway', (132, 148))	('RICTOR', 'Gene', '253260', (101, 107))	('alterations', 'Reg', (15, 26))	('alterations', 'Reg', (113, 124))	('MTOR', 'Gene', (85, 89))	('TSC2', 'Gene', '7249', (91, 95))	('mutations', 'Reg', (196, 205))	('mTOR', 'Gene', '2475', (34, 38))	('TP53', 'Gene', '7157', (209, 213))	('AKT1', 'Gene', (71, 75))	('mTOR', 'Gene', (34, 38))
92766	28713588	Similar to mutation burden, high-grade meningiomas have significantly higher levels of genomic disruption than low-grade meningiomas (3% vs. 19%, p < 1 x 10-8), and disruption rates comparable to other aggressive systemic and CNS cancers such as glioblastoma (Fig.	('meningiomas', 'Phenotype', 'HP:0002858', (39, 50))	('disruption', 'MPA', (165, 175))	('meningiomas', 'Disease', (39, 50))	('higher', 'PosReg', (70, 76))	('meningioma', 'Phenotype', 'HP:0002858', (121, 131))	('meningiomas', 'Disease', 'MESH:D008577', (121, 132))	('meningiomas', 'Phenotype', 'HP:0002858', (121, 132))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))	('meningiomas', 'Disease', (121, 132))	('high-grade', 'Var', (28, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (246, 258))	('meningioma', 'Phenotype', 'HP:0002858', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('glioblastoma', 'Disease', (246, 258))	('glioblastoma', 'Phenotype', 'HP:0012174', (246, 258))	('genomic disruption', 'MPA', (87, 105))	('meningiomas', 'Disease', 'MESH:D008577', (39, 50))	('cancers', 'Disease', 'MESH:D009369', (230, 237))
92767	28713588	Loss of chromosome 22 was the most frequent arm-level SCNA, observed in 56% of 702 sequenced meningiomas (Fig.	('meningioma', 'Phenotype', 'HP:0002858', (93, 103))	('meningiomas', 'Disease', (93, 104))	('meningiomas', 'Disease', 'MESH:D008577', (93, 104))	('meningiomas', 'Phenotype', 'HP:0002858', (93, 104))	('Loss', 'Var', (0, 4))
92769	28713588	High-grade meningiomas harbored loss of chromosome 22 more frequently (87%) than low-grade meningiomas (58%, p = 0.03), with chromosome 1p loss being the second most common SCNA.	('meningiomas', 'Phenotype', 'HP:0002858', (91, 102))	('meningioma', 'Phenotype', 'HP:0002858', (91, 101))	('loss', 'NegReg', (139, 143))	('meningiomas', 'Disease', (91, 102))	('meningiomas', 'Disease', 'MESH:D008577', (91, 102))	('meningiomas harbored loss', 'Disease', 'MESH:C537062', (11, 36))	('meningiomas', 'Phenotype', 'HP:0002858', (11, 22))	('meningioma', 'Phenotype', 'HP:0002858', (11, 21))	('meningiomas harbored loss', 'Disease', (11, 36))	('meningiomas', 'Disease', (11, 22))	('meningiomas', 'Disease', 'MESH:D008577', (11, 22))	('chromosome', 'Var', (125, 135))
92772	28713588	While there was no significant difference in genomic disruption between NF2-mutant and NF2-wild-type samples, meningiomas with chromosome 22 loss demonstrated increased rates of genomic disruption, even after excluding chromosome 22 (p = 0.05, Fig.	('meningiomas', 'Disease', 'MESH:D008577', (110, 121))	('meningioma', 'Phenotype', 'HP:0002858', (110, 120))	('genomic disruption', 'MPA', (178, 196))	('chromosome 22', 'Gene', (127, 140))	('NF2-mutant', 'Var', (72, 82))	('loss', 'NegReg', (141, 145))	('meningiomas', 'Phenotype', 'HP:0002858', (110, 121))	('meningiomas', 'Disease', (110, 121))
92774	28713588	We detected a median of 21.5 rearrangements per high-grade tumor (range 0-217, SD = 72), compared with five rearrangements per low-grade tumor (range 0-39, SD = 12; p = 0.15), for a total of 446 distinct rearrangements across our cohort (Supplementary Table 5A).	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('rearrangements', 'Var', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
92775	28713588	These included three patients with rearrangements in the microtubule-associated GTPase DNM3, which is likely a fragile site.	('microtubule-associated GTPase', 'Protein', (57, 86))	('rearrangements', 'Var', (35, 49))	('patients', 'Species', '9606', (21, 29))	('DNM3', 'Gene', (87, 91))	('DNM3', 'Gene', '26052', (87, 91))	('GTPase', 'Protein', (80, 86))
92778	28713588	This sample harbored a TP53 G187S mutation, which has been shown to be a recurrent TP53 alteration across cancers.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('G187S', 'Var', (28, 33))	('G187S', 'Mutation', 'rs776167460', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
92779	28713588	Alterations in p53 have not been found to be significantly recurrent in meningioma, but this alteration may explain the significant rates of disruption found in this sample.	('meningioma', 'Disease', 'MESH:D008577', (72, 82))	('Alterations', 'Var', (0, 11))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (15, 18))	('meningioma', 'Disease', (72, 82))	('meningioma', 'Phenotype', 'HP:0002858', (72, 82))
92780	28713588	Previous work analyzing 10 cancer types has suggested that micro-homology-mediated end joining (MMEJ) and non-homologous end joining (NHEJ) are the most frequent drivers of somatic rearrangements (41 and 39%, respectively).	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('micro-homology-mediated', 'Var', (59, 82))	('cancer', 'Disease', (27, 33))
92781	28713588	Using our own rearrangement detection pipeline, we likewise found that the majority (>90%) of observed rearrangements in meningioma have signatures consistent with MMEJ and NHEJ repair processes (Fig.	('meningioma', 'Disease', 'MESH:D008577', (121, 131))	('rearrangements', 'Var', (103, 117))	('meningioma', 'Disease', (121, 131))	('MMEJ', 'Disease', (164, 168))	('meningioma', 'Phenotype', 'HP:0002858', (121, 131))
92782	28713588	Low-grade and high-grade meningiomas did not significantly differ in the composition (inversion, deletion, duplication, or translocation) or inferred mechanistic basis (MMEJ, NHEJ) of the detected rearrangements.	('deletion', 'Var', (97, 105))	('meningiomas', 'Phenotype', 'HP:0002858', (25, 36))	('meningioma', 'Phenotype', 'HP:0002858', (25, 35))	('duplication', 'Var', (107, 118))	('meningiomas', 'Disease', (25, 36))	('meningiomas', 'Disease', 'MESH:D008577', (25, 36))
92791	28713588	The finding that NF2 is the most frequently altered gene in low-grade and high-grade meningiomas, combined with the finding that these mutations tend to have high allelic fractions and nearly always co-occur with loss of the wild-type copy of chromosome 22, has led to the presumption that NF2 mutations are an initiating event in meningioma tumorigenesis.	('meningioma tumor', 'Disease', (331, 347))	('meningiomas', 'Phenotype', 'HP:0002858', (85, 96))	('meningioma', 'Phenotype', 'HP:0002858', (331, 341))	('mutations', 'Var', (135, 144))	('meningioma', 'Phenotype', 'HP:0002858', (85, 95))	('meningioma tumor', 'Disease', 'MESH:D008577', (331, 347))	('meningiomas', 'Disease', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('meningiomas', 'Disease', 'MESH:D008577', (85, 96))	('NF2', 'Gene', (290, 293))	('mutations', 'Var', (294, 303))	('NF2', 'Gene', (17, 20))
92792	28713588	However, we observed three distinct inactivating NF2 alterations across five recurrences in one patient (MEN0045).	('inactivating', 'NegReg', (36, 48))	('NF2', 'Gene', (49, 52))	('alterations', 'Var', (53, 64))	('patient', 'Species', '9606', (96, 103))	('MEN', 'Species', '9606', (105, 108))
92794	28713588	For this patient, the data suggest that NF2 mutation, and thus bi-allelic inactivation, was not the initiating event, but was instead preceded by widespread genomic disruption.	('patient', 'Species', '9606', (9, 16))	('NF2', 'Gene', (40, 43))	('mutation', 'Var', (44, 52))	('preceded by', 'Reg', (134, 145))
92797	28713588	Most low-grade meningioma tended to have few arm-level events other than loss of chromosome 22.	('meningioma', 'Phenotype', 'HP:0002858', (15, 25))	('meningioma', 'Disease', (15, 25))	('loss', 'Var', (73, 77))	('meningioma', 'Disease', 'MESH:D008577', (15, 25))
92803	28713588	It is increasingly appreciated that the driver mutations of meningiomas are associated with particular histopathologic subtypes and with anatomic locations in the cranium.	('meningiomas', 'Phenotype', 'HP:0002858', (60, 71))	('meningioma', 'Phenotype', 'HP:0002858', (60, 70))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (76, 86))	('meningiomas', 'Disease', (60, 71))	('meningiomas', 'Disease', 'MESH:D008577', (60, 71))
92804	28713588	Recent work has shown that a subset of rhabdoid meningiomas, but not meningiomas of other histological subtypes, harbor mutations in the tumor suppressor gene BAP1.	('meningiomas', 'Disease', (69, 80))	('meningiomas', 'Disease', (48, 59))	('meningiomas', 'Disease', 'MESH:D008577', (69, 80))	('tumor', 'Disease', (137, 142))	('meningiomas', 'Disease', 'MESH:D008577', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('rhabdoid meningiomas', 'Disease', (39, 59))	('meningioma', 'Phenotype', 'HP:0002858', (48, 58))	('meningiomas', 'Phenotype', 'HP:0002858', (48, 59))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('meningiomas', 'Phenotype', 'HP:0002858', (69, 80))	('BAP1', 'Gene', (159, 163))	('meningioma', 'Phenotype', 'HP:0002858', (69, 79))	('rhabdoid meningiomas', 'Disease', 'MESH:D018335', (39, 59))
92812	28713588	Relative to low-grade meningiomas, fewer high-grade meningiomas had mutations in these genes (17 vs. 5%; p < 8 x 10-5).	('meningiomas', 'Disease', 'MESH:D008577', (52, 63))	('meningiomas', 'Disease', (52, 63))	('meningioma', 'Phenotype', 'HP:0002858', (22, 32))	('meningiomas', 'Disease', (22, 33))	('meningiomas', 'Disease', 'MESH:D008577', (22, 33))	('meningiomas', 'Phenotype', 'HP:0002858', (52, 63))	('mutations', 'Var', (68, 77))	('meningioma', 'Phenotype', 'HP:0002858', (52, 62))	('meningiomas', 'Phenotype', 'HP:0002858', (22, 33))
92820	28713588	To further elucidate the potential for immune targeting of these neoantigens, we examined our cohort of serial recurrences in which we had shown that the specific mutations vary significantly from recurrence to recurrence in meningioma.	('meningioma', 'Disease', 'MESH:D008577', (225, 235))	('meningioma', 'Disease', (225, 235))	('mutations', 'Var', (163, 172))	('meningioma', 'Phenotype', 'HP:0002858', (225, 235))
92823	28713588	We performed next-generation sequencing on nearly 140 high-grade meningiomas, and found that they harbored elevated rates of mutations and copy number alterations compared with low-grade samples.	('meningiomas', 'Disease', 'MESH:D008577', (65, 76))	('mutations', 'Var', (125, 134))	('meningiomas', 'Disease', (65, 76))	('copy number alterations', 'Var', (139, 162))	('meningiomas', 'Phenotype', 'HP:0002858', (65, 76))	('meningioma', 'Phenotype', 'HP:0002858', (65, 75))
92824	28713588	Our data and previous publications support a model of meningioma formation in which PI3-kinase and Hedgehog pathway alterations are mostly restricted to low-grade tumors, NF2 mutations and genomic disruption are enriched among high-grade tumors, and mutations of chromatin modifiers are observed across grades.	('genomic disruption', 'Var', (189, 207))	('meningioma', 'Disease', (54, 64))	('tumors', 'Disease', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('meningioma', 'Phenotype', 'HP:0002858', (54, 64))	('PI3-kinase', 'Pathway', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('mutations', 'Var', (175, 184))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('meningioma', 'Disease', 'MESH:D008577', (54, 64))	('alterations', 'Reg', (116, 127))	('Hedgehog pathway', 'Pathway', (99, 115))	('NF2', 'Gene', (171, 174))
92825	28713588	The major consistent genetic distinction between high-grade (grade II-III) and low-grade (grade I) meningiomas is the presence of widespread genomic disruption in aggressive meningiomas.	('meningiomas', 'Phenotype', 'HP:0002858', (99, 110))	('meningiomas', 'Phenotype', 'HP:0002858', (174, 185))	('genomic disruption', 'Var', (141, 159))	('meningiomas', 'Disease', 'MESH:D008577', (99, 110))	('meningioma', 'Phenotype', 'HP:0002858', (99, 109))	('meningiomas', 'Disease', (174, 185))	('meningiomas', 'Disease', (99, 110))	('aggressive meningiomas', 'Disease', (163, 185))	('aggressive meningiomas', 'Disease', 'MESH:D008577', (163, 185))	('meningiomas', 'Disease', 'MESH:D008577', (174, 185))	('meningioma', 'Phenotype', 'HP:0002858', (174, 184))
92828	28713588	We have previously shown that the degree of genomic disruption predicts subsequent recurrence in atypical meningioma.	('meningioma', 'Phenotype', 'HP:0002858', (106, 116))	('meningioma', 'Disease', (106, 116))	('meningioma', 'Disease', 'MESH:D008577', (106, 116))	('genomic disruption', 'Var', (44, 62))
92830	28713588	The ability to differentiate the recurrence risk of meningioma by their copy number profiles may help augment traditional histopathological recurrence risk assessment, with consequent impact on management decisions.	('meningioma', 'Disease', 'MESH:D008577', (52, 62))	('meningioma', 'Disease', (52, 62))	('copy number', 'Var', (72, 83))	('impact', 'Reg', (184, 190))	('meningioma', 'Phenotype', 'HP:0002858', (52, 62))
92831	28713588	When present, NF2 alterations are believed to be the initiating event in meningiomagenesis, in part because germline alterations in NF2 cause Neurofibromatosis 2, characterized by frequent meningiomas and schwannomas.	('alterations', 'Var', (117, 128))	('Neurofibromatosis 2', 'Disease', (142, 161))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))	('cause', 'Reg', (136, 141))	('meningioma', 'Disease', 'MESH:D008577', (189, 199))	('meningioma', 'Disease', 'MESH:D008577', (73, 83))	('schwannomas', 'Phenotype', 'HP:0100008', (205, 216))	('Neurofibromatosis 2', 'Disease', 'MESH:C537392', (142, 161))	('NF2', 'Gene', (132, 135))	('meningiomas', 'Phenotype', 'HP:0002858', (189, 200))	('meningioma', 'Disease', (189, 199))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (142, 159))	('meningioma', 'Phenotype', 'HP:0002858', (189, 199))	('meningiomas and schwannomas', 'Disease', 'MESH:D009442', (189, 216))	('meningioma', 'Disease', (73, 83))
92832	28713588	However, genomic disruption tends to occur earlier in tumor evolution than do most mutations, and in one case, we observed three distinct NF2 alterations across multiple recurrences in the setting of an identical copy number profile (Supplementary Fig.	('alterations', 'Var', (142, 153))	('NF2', 'Gene', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
92833	28713588	These findings suggest a model wherein high-grade meningiomas are initiated by widespread genomic disruption, followed by expansion of cells that then acquire NF2 and other mutations.	('meningioma', 'Phenotype', 'HP:0002858', (50, 60))	('NF2', 'Gene', (159, 162))	('meningiomas', 'Disease', 'MESH:D008577', (50, 61))	('meningiomas', 'Disease', (50, 61))	('mutations', 'Var', (173, 182))	('meningiomas', 'Phenotype', 'HP:0002858', (50, 61))
92834	28713588	Further investigation will be necessary to determine whether widespread copy number alterations, or NF2 mutations, tend to be earlier events in sporadic high-grade meningiomas.	('NF2', 'Gene', (100, 103))	('mutations', 'Var', (104, 113))	('meningiomas', 'Phenotype', 'HP:0002858', (164, 175))	('meningioma', 'Phenotype', 'HP:0002858', (164, 174))	('copy number alterations', 'Var', (72, 95))	('meningiomas', 'Disease', (164, 175))	('meningiomas', 'Disease', 'MESH:D008577', (164, 175))
92836	28713588	In line with this hypothesis, we found that mutations in NF2 occur in 75% of meningiomas with loss of chromosome 22, but in less than 1% of samples without such loss.	('meningiomas', 'Phenotype', 'HP:0002858', (77, 88))	('meningioma', 'Phenotype', 'HP:0002858', (77, 87))	('loss', 'NegReg', (94, 98))	('meningiomas', 'Disease', 'MESH:D008577', (77, 88))	('meningiomas', 'Disease', (77, 88))	('mutations', 'Var', (44, 53))	('NF2', 'Gene', (57, 60))
92837	28713588	It is possible that the 25% of meningiomas with chromosome 22 loss that do not exhibit NF2 mutations nevertheless contain cryptic NF2-inactivating events.	('loss', 'NegReg', (62, 66))	('NF2', 'Gene', (87, 90))	('NF2-inactivating events', 'MPA', (130, 153))	('meningiomas', 'Phenotype', 'HP:0002858', (31, 42))	('mutations', 'Var', (91, 100))	('meningioma', 'Phenotype', 'HP:0002858', (31, 41))	('meningiomas', 'Disease', (31, 42))	('meningiomas', 'Disease', 'MESH:D008577', (31, 42))
92838	28713588	Indeed, among meningiomas that had undergone WGS, every meningioma with loss of chromosome 22 exhibited inactivation of NF2.	('meningiomas', 'Disease', (14, 25))	('meningioma', 'Disease', 'MESH:D008577', (14, 24))	('meningioma', 'Disease', 'MESH:D008577', (56, 66))	('meningioma', 'Phenotype', 'HP:0002858', (56, 66))	('inactivation', 'Var', (104, 116))	('meningiomas', 'Phenotype', 'HP:0002858', (14, 25))	('meningioma', 'Phenotype', 'HP:0002858', (14, 24))	('meningioma', 'Disease', (14, 24))	('meningioma', 'Disease', (56, 66))	('NF2', 'Gene', (120, 123))	('meningiomas', 'Disease', 'MESH:D008577', (14, 25))
92841	28713588	Among tumors with chromosome 22 loss, we detected non-NF2 driver mutations at a higher rate in meningiomas without NF2 mutations than in meningiomas with NF2 mutations, suggesting that NF2 was not equivalently inactivated in the two groups.	('non-NF2 driver', 'Gene', (50, 64))	('meningiomas', 'Phenotype', 'HP:0002858', (95, 106))	('meningiomas', 'Phenotype', 'HP:0002858', (137, 148))	('loss', 'NegReg', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('meningioma', 'Phenotype', 'HP:0002858', (95, 105))	('meningiomas', 'Disease', (95, 106))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('NF2', 'Gene', (115, 118))	('meningiomas', 'Disease', 'MESH:D008577', (95, 106))	('meningioma', 'Phenotype', 'HP:0002858', (137, 147))	('meningiomas', 'Disease', (137, 148))	('meningiomas', 'Disease', 'MESH:D008577', (137, 148))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (65, 74))
92844	28713588	Indeed, we observed increased genomic disruption among meningiomas with loss of chromosome 22.	('meningiomas', 'Disease', (55, 66))	('increased', 'PosReg', (20, 29))	('meningiomas', 'Disease', 'MESH:D008577', (55, 66))	('loss', 'Var', (72, 76))	('genomic disruption', 'CPA', (30, 48))	('meningiomas', 'Phenotype', 'HP:0002858', (55, 66))	('meningioma', 'Phenotype', 'HP:0002858', (55, 65))
92847	28713588	The low incidence of such alterations in high-grade tumors means that enrollment in such trials on the basis of these mutations will require large multicenter trials.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))
92848	28713588	Larger cohorts which are powered for detection of low-frequency events will be necessary to determine whether these mutations are also drivers of meningiomagenesis and therefore may represent alternative avenues of therapeutic potential.	('meningioma', 'Disease', (146, 156))	('meningioma', 'Phenotype', 'HP:0002858', (146, 156))	('mutations', 'Var', (116, 125))	('meningioma', 'Disease', 'MESH:D008577', (146, 156))
92850	28713588	Angiomatous meningiomas are typically considered to be grade I, although emerging data suggest the existence of grade II meningiomas with angiomatous features based on the presence of copy number changes such as monosomy 14 that are traditionally found in higher grade meningiomas.	('angiomatous', 'Disease', (138, 149))	('meningiomas', 'Disease', 'MESH:D008577', (12, 23))	('meningioma', 'Phenotype', 'HP:0002858', (12, 22))	('II meningiomas', 'Disease', 'MESH:D008577', (118, 132))	('meningiomas', 'Phenotype', 'HP:0002858', (12, 23))	('meningioma', 'Phenotype', 'HP:0002858', (121, 131))	('angiomatous', 'Disease', 'MESH:D008577', (138, 149))	('meningiomas', 'Disease', 'MESH:D008577', (121, 132))	('meningiomas', 'Disease', (12, 23))	('meningiomas', 'Phenotype', 'HP:0002858', (121, 132))	('meningiomas', 'Disease', (121, 132))	('Angiomatous meningiomas', 'Disease', (0, 23))	('meningioma', 'Phenotype', 'HP:0002858', (269, 279))	('meningiomas', 'Disease', 'MESH:D008577', (269, 280))	('II meningiomas', 'Disease', (118, 132))	('monosomy 14', 'Var', (212, 223))	('Angiomatous meningiomas', 'Disease', 'MESH:D008577', (0, 23))	('meningiomas', 'Phenotype', 'HP:0002858', (269, 280))	('meningiomas', 'Disease', (269, 280))
92862	28713588	In other cancer types, resistance to targeted inhibitors often result from pre-existing clones harboring resistance mutations in a background of additional mutations, and these clones rise to prominence in the population following treatment.	('cancer', 'Disease', (9, 15))	('resistance', 'MPA', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('resistance', 'MPA', (23, 33))	('mutations', 'Var', (116, 125))	('result', 'Reg', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
92866	28713588	We identified a number of mutations in each meningioma that were predicted to be immunogenic.	('meningioma', 'Disease', (44, 54))	('mutations', 'Var', (26, 35))	('meningioma', 'Disease', 'MESH:D008577', (44, 54))	('meningioma', 'Phenotype', 'HP:0002858', (44, 54))
92870	28713588	Our finding that a significant fraction of mutations observed in high-grade meningioma is likely to result in neo-epitope presentation provides additional evidence for this line of therapeutic investigation.	('meningioma', 'Phenotype', 'HP:0002858', (76, 86))	('meningioma', 'Disease', 'MESH:D008577', (76, 86))	('neo-epitope presentation', 'MPA', (110, 134))	('result', 'Reg', (100, 106))	('mutations', 'Var', (43, 52))	('meningioma', 'Disease', (76, 86))
92890	28713588	For each tumor, epitope predictions were made by considering interaction between confidently called HLA alleles and single-residue missense alterations (SNV) or protein-altering indel alterations.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('single-residue missense alterations', 'Var', (116, 151))	('tumor', 'Disease', (9, 14))	('interaction', 'Interaction', (61, 72))
92891	28713588	Separate lists were generated consisting of wild-type and mutant peptides of 8, 9, 10, and 11 amino acids in length for MHC Class I and 15 amino acids in length for MHC Class II, as these are known to be the possible lengths for peptides presented by human MHC.	('mutant', 'Var', (58, 64))	('MHC', 'Gene', '3107', (120, 123))	('MHC', 'Gene', '3107', (165, 168))	('MHC', 'Gene', '3107', (257, 260))	('human', 'Species', '9606', (251, 256))	('MHC', 'Gene', (120, 123))	('MHC', 'Gene', (257, 260))	('MHC', 'Gene', (165, 168))
92919	33105486	Like other cancers, gliomas are characterized by aberrations in several molecular pathways that confer a growth advantage to these tumors.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('aberrations', 'Var', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('growth advantage', 'CPA', (105, 121))	('rat', 'Species', '10116', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('molecular pathways', 'Pathway', (72, 90))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
92928	33105486	It is also reported that exogenous IGF1 induces proliferative and anti-apoptotic signaling through its receptor IGF1R in cultured glioma cells.	('rat', 'Species', '10116', (55, 58))	('proliferative', 'MPA', (48, 61))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('IGF1R', 'Gene', (112, 117))	('glioma', 'Disease', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('IGF1R', 'Gene', '3480', (112, 117))	('induces', 'PosReg', (40, 47))	('IGF1', 'Gene', (35, 39))	('anti-apoptotic signaling', 'MPA', (66, 90))	('exogenous', 'Var', (25, 34))
92932	33105486	Also, the brain of IGF1 transgenic mice shows upregulated IGFBP5 expression.	('transgenic mice', 'Species', '10090', (24, 39))	('expression', 'MPA', (65, 75))	('IGFBP5', 'Gene', (58, 64))	('transgenic', 'Var', (24, 34))	('IGF1', 'Gene', (19, 23))	('upregulated', 'PosReg', (46, 57))
92935	33105486	Silencing IGFBP5 expression impedes invasion but promotes the proliferation of GBM cells in vitro, thus having opposing effects on two cellular hallmarks of neoplastic state.	('invasion', 'CPA', (36, 44))	('IGFBP5', 'Gene', (10, 16))	('proliferation', 'CPA', (62, 75))	('promotes', 'PosReg', (49, 57))	('neoplastic state', 'Phenotype', 'HP:0002664', (157, 173))	('impedes', 'NegReg', (28, 35))	('Silencing', 'Var', (0, 9))	('rat', 'Species', '10116', (69, 72))
92944	33105486	Interestingly, deletions in MN1 have been implicated in patients with neurodevelopmental abnormalities.	('patients', 'Species', '9606', (56, 64))	('neurodevelopmental abnormalities', 'Disease', (70, 102))	('deletions', 'Var', (15, 24))	('MN1', 'Gene', (28, 31))	('MN1', 'Gene', '4330', (28, 31))	('neurodevelopmental abnormalities', 'Phenotype', 'HP:0012759', (70, 102))	('implicated', 'Reg', (42, 52))	('neurodevelopmental abnormalities', 'Disease', 'OMIM:613658', (70, 102))
92951	33105486	None of the LGGs showed MN1 copy number gain.	('copy number', 'Var', (28, 39))	('MN1', 'Gene', (24, 27))	('gain', 'PosReg', (40, 44))	('MN1', 'Gene', '4330', (24, 27))
92953	33105486	Accordingly, MN1 copy number loss contributed considerably (P < 0.0001) to the higher overall CNA seen in HGGs as compared with LGGs.	('MN1', 'Gene', '4330', (13, 16))	('CNA', 'MPA', (94, 97))	('copy number loss', 'Var', (17, 33))	('HGGs', 'Disease', (106, 110))	('higher', 'PosReg', (79, 85))	('MN1', 'Gene', (13, 16))
92964	33105486	2B) between gene's copy number and mRNA expression in gliomas.	('copy number', 'Var', (19, 30))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('mRNA expression', 'MPA', (35, 50))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
92965	33105486	Also, a negative slope (-0.2289) of the regression line suggests that with an increase in MN1 copies, gene expression tends to decrease.	('copies', 'Var', (94, 100))	('gene expression', 'MPA', (102, 117))	('decrease', 'NegReg', (127, 135))	('MN1', 'Gene', (90, 93))	('increase', 'PosReg', (78, 86))	('MN1', 'Gene', '4330', (90, 93))
92966	33105486	This signifies that alteration in MN1 copy number does not imply a relatable change in its expression.	('expression', 'MPA', (91, 101))	('MN1', 'Gene', (34, 37))	('alteration', 'Var', (20, 30))	('MN1', 'Gene', '4330', (34, 37))	('rat', 'Species', '10116', (24, 27))
92974	33105486	Pairwise Wilcoxon test revealed LGGs and HGGs with single copy of the gene had markedly reduced average MN1 expression as compared with cases with normal copy number (P < 0.0001; Fig.	('MN1', 'Gene', (104, 107))	('MN1', 'Gene', '4330', (104, 107))	('single copy', 'Var', (51, 62))	('expression', 'MPA', (108, 118))	('reduced', 'NegReg', (88, 95))
92975	33105486	The reverse was not true, because a gain in MN1 copy number did not signify an increased average expression in LGGs and HGGs (Fig.	('MN1', 'Gene', '4330', (44, 47))	('HGGs', 'Protein', (120, 124))	('copy number', 'Var', (48, 59))	('expression', 'MPA', (97, 107))	('MN1', 'Gene', (44, 47))	('LGGs', 'Gene', (111, 115))
92977	33105486	Since the TCGA dataset validated our findings of altered MN1 expression correlating with LGGs, we wanted to test whether MN1 overexpression can be used to predict survival and assess it in relation to the widely accepted predictors such as Isocitrate dehydrogenase (IDH) mutation and 1p19q co-deletion.	('LGGs', 'Disease', (89, 93))	('MN1', 'Gene', (57, 60))	('altered', 'Var', (49, 56))	('MN1', 'Gene', '4330', (57, 60))	('MN1', 'Gene', (121, 124))	('IDH', 'Gene', (266, 269))	('Isocitrate dehydrogenase', 'Gene', (240, 264))	('MN1', 'Gene', '4330', (121, 124))	('IDH', 'Gene', '3417', (266, 269))	('expression', 'MPA', (61, 71))	('Isocitrate dehydrogenase', 'Gene', '3417', (240, 264))	('correlating', 'Reg', (72, 83))
92978	33105486	IDH mutations seen in gliomas (including grades II and III astrocytomas, grades II and III oligodendrogliomas and GBM) are known to confer survival advantage in patients.	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('GBM', 'Disease', (114, 117))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('III oligodendrogliomas', 'Disease', (87, 109))	('III oligodendrogliomas', 'Disease', 'MESH:D009837', (87, 109))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('III astrocytomas', 'Disease', (55, 71))	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('IDH', 'Gene', '3417', (0, 3))	('patients', 'Species', '9606', (161, 169))	('mutations', 'Var', (4, 13))	('advantage', 'PosReg', (148, 157))	('survival', 'CPA', (139, 147))	('gliomas', 'Disease', (22, 29))	('III astrocytomas', 'Disease', 'MESH:D001254', (55, 71))	('gliomas', 'Disease', (102, 109))
92979	33105486	Also, the co-deletion of chromosome arms 1p and 19q observed in only oligodendrogliomas (grades II and III) is positively associated with survival.	('co-deletion', 'Var', (10, 21))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('associated with', 'Reg', (122, 137))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (69, 87))	('oligodendrogliomas', 'Disease', (69, 87))
92987	33105486	Further, we performed receiver operating characteristic (ROC) analysis to evaluate sensitivity and specificity of 3-month survival prediction for MN1 overexpression, IDH mutation and 1p19q co-deletion in the TCGA retrieved datasets.	('overexpression', 'PosReg', (150, 164))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', '3417', (166, 169))	('MN1', 'Gene', (146, 149))	('rat', 'Species', '10116', (34, 37))	('MN1', 'Gene', '4330', (146, 149))	('1p19q co-deletion', 'Var', (183, 200))	('mutation', 'Var', (170, 178))
93018	33105486	To our knowledge, alterations in MN1 have not been assessed systematically in human gliomas earlier.	('alterations', 'Var', (18, 29))	('MN1', 'Gene', '4330', (33, 36))	('rat', 'Species', '10116', (22, 25))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('human', 'Species', '9606', (78, 83))	('MN1', 'Gene', (33, 36))
93024	33105486	Further, we observed that CNA in MN1 is more frequent in HGGs compared with LGGs.	('MN1', 'Gene', '4330', (33, 36))	('CNA', 'Var', (26, 29))	('HGGs', 'Disease', (57, 61))	('frequent', 'Reg', (45, 53))	('MN1', 'Gene', (33, 36))
93030	33105486	ROC analysis showed that for a 3-month survival prediction in LGGs, high MN1 expression is a good classifier as it had greater AUC values than IDH mutation and 1p19q co-deletion.	('expression', 'MPA', (77, 87))	('AUC values', 'MPA', (127, 137))	('IDH', 'Gene', '3417', (143, 146))	('high', 'Var', (68, 72))	('MN1', 'Gene', (73, 76))	('MN1', 'Gene', '4330', (73, 76))	('greater', 'PosReg', (119, 126))	('IDH', 'Gene', (143, 146))
93065	33105486	We also analyzed meningioma GEO datasets:GSE88720; GSE16581; GSE43290; GSE85133 and GSE77259.	('GSE77259', 'Var', (84, 92))	('meningioma', 'Disease', 'MESH:D008577', (17, 27))	('GSE43290; GSE85133', 'Var', (61, 79))	('meningioma', 'Disease', (17, 27))	('meningioma', 'Phenotype', 'HP:0002858', (17, 27))	('GSE85133', 'Var', (71, 79))	('GSE88720', 'Var', (41, 49))
93085	33105486	Hs02424444_cn; ABI), and TaqMan  RNase P detection (P/N: 4316831; ABI) as the reference gene, on 7500 Real-Time PCR System (ABI) using tumor genomic DNA as the test samples.	('Hs02424444_cn', 'Var', (0, 13))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
93285	27586084	Lower grade (grade II-III) gliomas and secondary grade IV glioblastomas (arising from lower grade gliomas) display mutations in isocitrate dehydrogenase genes (IDH1/2) in 80 % of the cases.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('mutations', 'Var', (115, 124))	('IDH1', 'Gene', (160, 164))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('glioblastomas', 'Phenotype', 'HP:0012174', (58, 71))	('IDH1', 'Gene', '3417', (160, 164))	('gliomas', 'Disease', (27, 34))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('glioblastomas', 'Disease', 'MESH:D005909', (58, 71))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('glioblastomas', 'Disease', (58, 71))
93288	27586084	Pro-neural and neural glioblastomas display IDH1/2 mutations, whereas classical and mesenchymal gliomas often show loss of chromosome 10 (containing the tumor suppressor gene PTEN at 10q23), and/or amplification of chromosome 7 (containing the proto-oncogene EGFR at 7p12).	('glioblastomas', 'Phenotype', 'HP:0012174', (22, 35))	('mutations', 'Var', (51, 60))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('loss', 'NegReg', (115, 119))	('tumor', 'Disease', (153, 158))	('glioblastomas', 'Disease', (22, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('gliomas', 'Disease', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('glioblastomas', 'Disease', 'MESH:D005909', (22, 35))	('IDH1', 'Gene', (44, 48))	('neural', 'CPA', (15, 21))	('PTEN', 'Gene', (175, 179))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH1', 'Gene', '3417', (44, 48))	('amplification', 'CPA', (198, 211))	('PTEN', 'Gene', '5728', (175, 179))
93291	27586084	As a result, in about 90 % of primary glioblastomas the RTK/RAS/PI3K signaling pathway is affected by mutations, underscoring deregulated phosphotyrosine-based signaling as a major driver in glioma etiology.	('phosphotyrosine', 'Chemical', 'MESH:D019000', (138, 153))	('glioblastomas', 'Phenotype', 'HP:0012174', (38, 51))	('glioma', 'Disease', (191, 197))	('mutations', 'Var', (102, 111))	('glioblastomas', 'Disease', 'MESH:D005909', (38, 51))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('RTK/RAS/PI3K signaling pathway', 'Pathway', (56, 86))	('affected', 'Reg', (90, 98))	('glioblastomas', 'Disease', (38, 51))
93295	27586084	A well-known exception is PTEN, the PTP family member that is mutated or deleted in 41 % of primary glioblastomas and whose tumor suppressive action is linked to its phospholipid phosphatase activity.	('glioblastomas', 'Disease', (100, 113))	('PTP', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('deleted', 'Var', (73, 80))	('tumor', 'Disease', (124, 129))	('PTP', 'Gene', '10076', (36, 39))	('glioblastomas', 'Phenotype', 'HP:0012174', (100, 113))	('PTEN', 'Gene', (26, 30))	('phospholipid', 'Chemical', 'MESH:D010743', (166, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('PTEN', 'Gene', '5728', (26, 30))	('glioblastomas', 'Disease', 'MESH:D005909', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
93327	27586084	Third generation lentiviral constructs that drive expression of wildtype (EGFR WT) or variant III (EGFRvIII) epidermal growth factor receptor were generated as follows.	('epidermal growth factor receptor', 'Gene', (109, 141))	('variant III', 'Var', (86, 97))	('expression', 'Species', '29278', (50, 60))	('epidermal growth factor receptor', 'Gene', '1956', (109, 141))
93343	27586084	Individual clones were derived via limiting dilution and tested for successful CRISPR/Cas9-mediated PTEN gene editing using a T7 endonuclease I assay.	('PTEN', 'Gene', (100, 104))	('editing', 'Var', (110, 117))	('PTEN', 'Gene', '5728', (100, 104))
93363	27586084	These represented RNA-seq data of 166 IDH1 WT glioblastoma samples, 9 IDH1 mutant glioblastoma samples, 221 IDH1 mutant lower grade glioma samples and 309 IDH1 WT lower grade glioma samples.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('glioma', 'Disease', (132, 138))	('IDH1', 'Gene', '3417', (155, 159))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('mutant', 'Var', (113, 119))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('glioma', 'Disease', (175, 181))	('IDH1', 'Gene', (38, 42))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('IDH1 WT glioblastoma', 'Disease', 'MESH:D005909', (38, 58))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('IDH1', 'Gene', (108, 112))	('IDH1 WT glioblastoma', 'Disease', (38, 58))	('IDH1', 'Gene', (70, 74))	('glioblastoma', 'Disease', (82, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('IDH1', 'Gene', (155, 159))	('IDH1', 'Gene', '3417', (38, 42))	('IDH1', 'Gene', '3417', (108, 112))	('IDH1', 'Gene', '3417', (70, 74))	('mutant', 'Var', (75, 81))	('glioblastoma', 'Disease', (46, 58))
93392	27586084	EGFR amplification; PTEN deletion) or rather reflect the tumor pathogenesis, including cell of origin.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('reflect', 'Reg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('deletion', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))
93397	27586084	PTEN-inactivating deletions or mutations represent another common aberration in primary glioblastoma samples and could potentially explain the pattern observed on the PTP transcripts.	('glioblastoma', 'Disease', (88, 100))	('mutations', 'Var', (31, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('PTP', 'Gene', (167, 170))	('deletions', 'Var', (18, 27))	('PTP', 'Gene', '10076', (167, 170))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
93400	27586084	We also monitored effects of the oncometabolite 2-hydroxyglutarate (2-HG) that is produced in lower grade gliomas and secondary glioblastomas as a result of the characteristic IDH1R132H mutation and inhibits DNA and histone demethylation.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (48, 66))	('gliomas', 'Disease', (106, 113))	('glioblastomas', 'Disease', 'MESH:D005909', (128, 141))	('inhibits', 'NegReg', (199, 207))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('glioblastomas', 'Disease', (128, 141))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('IDH1R132H', 'Var', (176, 185))	('glioblastomas', 'Phenotype', 'HP:0012174', (128, 141))	('2-HG', 'Chemical', 'MESH:C019417', (68, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
93409	27586084	DUSP26 and PTPRT protein expression of virus - producing HEK293FT was visualized using immunoblotting [see Additional file 5].	('DUSP26', 'Chemical', '-', (0, 6))	('expression', 'Species', '29278', (25, 35))	('HEK293FT', 'CellLine', 'CVCL:6911', (57, 65))	('PTPRT', 'Gene', '11122', (11, 16))	('PTPRT', 'Gene', (11, 16))	('HEK293FT', 'Var', (57, 65))
93415	27586084	Homogeneously-sized spheroids of lentivirally transduced E98 cells, generated using the hanging-drop method, were placed on a layer of mouse astrocytes and the migratory performance of outgrowing fluorescent E98 cells was calculated as the change in radius of the spheroid over 24 h. As compared to GFP-expressing control cells, the expression of either PTPRT or DUSP26 significantly reduced migration of E98 cells from the spheroid edge (Fig.	('E98', 'CellLine', 'CVCL:V748', (208, 211))	('E98', 'CellLine', 'CVCL:V748', (57, 60))	('E98', 'CellLine', 'CVCL:V748', (405, 408))	('migration of E98 cells from the spheroid edge', 'CPA', (392, 437))	('mouse', 'Species', '10090', (135, 140))	('expression', 'Var', (333, 343))	('DUSP26', 'Chemical', '-', (363, 369))	('PTPRT', 'Gene', '11122', (354, 359))	('PTPRT', 'Gene', (354, 359))	('expression', 'Species', '29278', (333, 343))	('reduced', 'NegReg', (384, 391))	('DUSP26', 'Gene', (363, 369))
93426	27586084	We found that experimental introduction of EGFR hyperactivity, or of PTEN inactivation, in a glioblastoma cell line had no effect on overall PTP expression patterns.	('EGFR', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (69, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('expression', 'Species', '29278', (145, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('glioblastoma', 'Disease', (93, 105))	('hyperactivity', 'Disease', 'MESH:D006948', (48, 61))	('hyperactivity', 'Disease', (48, 61))	('hyperactivity', 'Phenotype', 'HP:0000752', (48, 61))	('PTP', 'Gene', (141, 144))	('PTP', 'Gene', '10076', (141, 144))	('inactivation', 'Var', (74, 86))	('PTEN', 'Gene', (69, 73))
93431	27586084	Our data revealing that PTEN expression was low in high grade gliomas concords with literature data on PTEN inactivation or absence in over one-third of high grade gliomas, resulting in increased proliferation and survival through activation of the PI3K/AKT pathway.	('PTEN', 'Gene', '5728', (24, 28))	('PTEN', 'Gene', '5728', (103, 107))	('AKT', 'Gene', (254, 257))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('inactivation', 'Var', (108, 120))	('expression', 'Species', '29278', (29, 39))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('survival', 'CPA', (214, 222))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('increased', 'PosReg', (186, 195))	('absence', 'NegReg', (124, 131))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('AKT', 'Gene', '207', (254, 257))	('activation', 'PosReg', (231, 241))	('gliomas', 'Disease', (62, 69))	('PTEN', 'Gene', (24, 28))	('PTEN', 'Gene', (103, 107))	('gliomas', 'Disease', (164, 171))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))
93439	27586084	In the RNA-seq dataset, a third of the lower grade samples represent astrocytomas while in our sample cohort lower grade tumors consisted mostly of oligodendroglial neoplasms with 1p/19q co-deletion.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('oligodendroglial neoplasms', 'Disease', 'MESH:D009369', (148, 174))	('tumors', 'Disease', (121, 127))	('astrocytomas', 'Disease', 'MESH:D001254', (69, 81))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('oligodendroglial neoplasms', 'Disease', (148, 174))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (165, 174))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('1p/19q co-deletion', 'Var', (180, 198))	('astrocytomas', 'Disease', (69, 81))
93451	27586084	In neuroblastoma cells DUSP26 dephosphorylates and inhibits the tumor suppressor p53.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('tumor', 'Disease', (64, 69))	('inhibits', 'NegReg', (51, 59))	('neuroblastoma', 'Disease', 'MESH:D009447', (3, 16))	('DUSP26', 'Chemical', '-', (23, 29))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('neuroblastoma', 'Disease', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('DUSP26', 'Var', (23, 29))
93452	27586084	Furthermore, DUSP26 amplification has been found in thyroid cancer, and DUSP26 knockdown impeded growth of anaplastic thyroid cancer cells.	('DUSP26', 'Gene', (13, 19))	('DUSP26', 'Chemical', '-', (72, 78))	('thyroid cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('thyroid cancer', 'Phenotype', 'HP:0002890', (52, 66))	('thyroid cancer', 'Disease', (118, 132))	('DUSP26', 'Gene', (72, 78))	('impeded', 'NegReg', (89, 96))	('DUSP26', 'Chemical', '-', (13, 19))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('thyroid cancer', 'Disease', 'MESH:D013964', (52, 66))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (107, 132))	('thyroid cancer', 'Disease', 'MESH:D013964', (118, 132))	('knockdown', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
93461	27586084	The hypermethylation of the PTPRN2 promoter region in glioblastomas and lung adenocarcinomas suggests tumor suppressor roles.	('PTP', 'Gene', '10076', (28, 31))	('glioblastomas', 'Phenotype', 'HP:0012174', (54, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PTP', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('glioblastomas and lung adenocarcinomas', 'Disease', 'MESH:D005909', (54, 92))	('hypermethylation', 'Var', (4, 20))
93462	27586084	In contrast, high PTPRN2 expression has been reported to correlate with poor clinical outcomes in breast cancer cases.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('PTP', 'Gene', '10076', (18, 21))	('expression', 'Species', '29278', (25, 35))	('breast cancer', 'Disease', (98, 111))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PTP', 'Gene', (18, 21))
93467	27586084	Their expression correlated with patient survival probability, and overexpression inhibited glioblastoma cell growth and motility.	('glioblastoma', 'Disease', (92, 104))	('patient', 'Species', '9606', (33, 40))	('expression', 'Species', '29278', (6, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('inhibited', 'NegReg', (82, 91))	('motility', 'CPA', (121, 129))	('expression', 'MPA', (6, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('overexpression', 'Var', (67, 81))	('expression', 'Species', '29278', (71, 81))
93494	33772073	Gross total resection is considered to improve seizures control, prolongs progression-free survival (PFS), overall survival (OS) and delays the malignant transformation.	('delays', 'NegReg', (133, 139))	('seizures', 'Disease', 'MESH:D012640', (47, 55))	('improve', 'PosReg', (39, 46))	('overall survival', 'MPA', (107, 123))	('seizures', 'Disease', (47, 55))	('seizures', 'Phenotype', 'HP:0001250', (47, 55))	('prolongs', 'NegReg', (65, 73))	('progression-free', 'MPA', (74, 90))	('Gross', 'Var', (0, 5))	('malignant transformation', 'CPA', (144, 168))
93564	33772073	It has been reported that low-grade gliomas of the insular region benefit from an EOR > 90%, which further significantly increased 5-year survival rates.	('increased', 'PosReg', (121, 130))	('gliomas', 'Disease', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('EOR', 'Var', (82, 85))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
93707	32153349	proposed and implemented a CNN model to predict isocitrate dehydrogenase (IDH) mutations in glioma patients using preoperative MRI data.	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('men', 'Species', '9606', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('IDH', 'Gene', (74, 77))	('isocitrate dehydrogenase', 'Gene', (48, 72))	('IDH', 'Gene', '3417', (74, 77))	('mutations', 'Var', (79, 88))	('isocitrate dehydrogenase', 'Gene', '3417', (48, 72))
93711	32153349	identified radiographic signatures of extracellular domain missense mutants (i.e., A289V) of the epidermal growth factor receptor (EGFR) suggestive of an invasive and proliferative phenotype, and associated with shorter patient survival.	('missense mutants', 'Var', (59, 75))	('shorter', 'NegReg', (212, 219))	('A289V', 'Mutation', 'rs149840192', (83, 88))	('patient survival', 'CPA', (220, 236))	('EGFR', 'Gene', '1956', (131, 135))	('epidermal growth factor receptor', 'Gene', (97, 129))	('EGFR', 'Gene', (131, 135))	('patient', 'Species', '9606', (220, 227))	('invasive', 'CPA', (154, 162))	('A289V', 'Var', (83, 88))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))
93714	32153349	Another study found an imaging signature in radiology images of the most prevalent mutation of EGFR, namely, EGFRvIII, revealing a complex yet distinct macroscopic GBM radiographic phenotype.	('GBM', 'Disease', (164, 167))	('GBM', 'Disease', 'MESH:D005909', (164, 167))	('mutation', 'Var', (83, 91))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (109, 113))	('EGFR', 'Gene', (95, 99))
93870	31749678	It has been shown that the underlying genetic and molecular heterogeneity can be associated with variations in imaging phenotype such as changes in tumor compartment volumes (Lai et al.,; Grossmann et al.,), contrast enhancement (Carrillo et al.,; Treiber et al.,), radiomic signatures (Gevaert et al.,), and tumor location (Carrillo et al.,; Ellingson et al.,).	('tumor', 'Disease', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('contrast enhancement', 'MPA', (208, 228))	('changes', 'Reg', (137, 144))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('variations', 'Var', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
93877	31749678	Since part of the BraTS dataset is coming from The Cancer Imaging Archive (TCIA) (Bakas et al.,), additional relevant information such as e.g., patient's gender, mutation subtypes [Isocitrate dehydrogenase (IDH), 1p19q co-deletion] and methylation status of MGMT-promotor could potentially be added as well.	('MGMT', 'Gene', '4255', (258, 262))	('MGMT', 'Gene', (258, 262))	('BraTS', 'Disease', (18, 23))	('1p19q co-deletion', 'Var', (213, 230))	('Isocitrate dehydrogenase', 'Gene', (181, 205))	('patient', 'Species', '9606', (144, 151))	('IDH', 'Gene', (207, 210))	('BraTS', 'Disease', 'MESH:D001932', (18, 23))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('IDH', 'Gene', '3417', (207, 210))	('Isocitrate dehydrogenase', 'Gene', '3417', (181, 205))
93930	31749678	However, we presented also exceptions [e.g., BRATS18_2013_21_1 (Figure 4) in section 3.2] which actually profit from training data of opposite tumor grade.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('BRATS18_2013_21_1', 'Var', (45, 62))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
94026	30686996	In Case 3, Ki-67 was the major contributor to the correct decision, while the morphological features such as standard deviation of cells' max axis and standard deviation of cells' perimeter were the second and third contributors.	('Ki-67', 'Chemical', '-', (11, 16))	('standard deviation', 'Var', (151, 169))	('standard deviation', 'Var', (109, 127))
94039	30686996	Case 1 and Case 3 in Figures 5C, 6B endorse the important role that Ki-67 plays in grading decisions, which is in accordance with the clinical fact that Ki-67 PI is positively correlated with the histopathology grades.	('Ki-67', 'Chemical', '-', (68, 73))	('Ki-67', 'Chemical', '-', (153, 158))	('Ki-67', 'Var', (153, 158))	('correlated', 'Reg', (176, 186))
94074	29763414	The aberrant tumor vasculature is permeable and dysfunctional, and contributes to patient morbidity by inducing vasogenic edema in the brain.	('tumor', 'Disease', (13, 18))	('edema', 'Disease', (122, 127))	('patient', 'Species', '9606', (82, 89))	('dysfunctional', 'Disease', (48, 61))	('dysfunctional', 'Disease', 'MESH:D006331', (48, 61))	('aberrant', 'Var', (4, 12))	('inducing', 'Reg', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('edema', 'Disease', 'MESH:D004487', (122, 127))	('edema', 'Phenotype', 'HP:0000969', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('contributes', 'Reg', (67, 78))	('edema in the brain', 'Phenotype', 'HP:0002181', (122, 140))
94077	29763414	Antiangiogenic therapy neutralizing VEGF, or blocking signaling through its cognate receptor VEGFR2, has been approved as second-line treatment for glioblastoma owing to prolonged progression-free survival, although no increase in overall survival is observed.	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('neutralizing', 'Var', (23, 35))	('VEGF', 'Gene', (93, 97))	('VEGF', 'Gene', (36, 40))	('VEGFR2', 'Gene', '16542', (93, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (148, 160))	('VEGF', 'Gene', '22339', (93, 97))	('glioblastoma', 'Disease', (148, 160))	('signaling', 'MPA', (54, 63))	('VEGFR2', 'Gene', (93, 99))	('VEGF', 'Gene', '22339', (36, 40))	('blocking', 'NegReg', (45, 53))
94084	29763414	The extracellular domain can be shed and released during inflammation, and soluble CD93 has been proposed to have a proangiogenic effect through its EGF-like repeats.	('CD93', 'Gene', (83, 87))	('proangiogenic effect', 'MPA', (116, 136))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('soluble', 'Var', (75, 82))	('inflammation', 'Disease', (57, 69))
94090	29763414	CD93 localization in filopodia is stabilized by interaction with the extracellular matrix-binding protein multimerin-2 (MMRN2), which anchors CD93 to fibronectin and inhibits its proteolytic cleavage.	('CD93', 'Gene', (0, 4))	('proteolytic cleavage', 'MPA', (179, 199))	('multimerin-2', 'Gene', (106, 118))	('anchors', 'Interaction', (134, 141))	('interaction', 'Interaction', (48, 59))	('CD93', 'Var', (142, 146))	('inhibits', 'NegReg', (166, 174))	('localization', 'MPA', (5, 17))	('multimerin-2', 'Gene', '105450', (106, 118))
94106	29763414	To investigate whether loss of CD93 affects retinal angiogenesis, we analyzed P6 retinas from CD93-deficient (CD93-/-) mice and WT littermates.	('loss', 'Var', (23, 27))	('mice', 'Species', '10090', (119, 123))	('CD93', 'Gene', (31, 35))	('CD93-deficient', 'Gene', (94, 108))
94107	29763414	In addition, a significant reduction in filopodia protrusions was observed in CD93-/- mice compared with WT mice (Figure 2E, quantified in Figure 2H).	('filopodia protrusions', 'CPA', (40, 61))	('mice', 'Species', '10090', (86, 90))	('mice', 'Species', '10090', (108, 112))	('CD93-/-', 'Var', (78, 85))	('reduction', 'NegReg', (27, 36))
94113	29763414	The only partial reduction of CD93 in filopodia did not result in a decreased number of filopodia in siMMRN2-transfected HDBECs, which is consistent with similar numbers of filopodia in the retinas of CD93+/- and WT mice (Supplemental Figure 4, A and B, and Figure 2, G and H).	('CD93', 'Gene', (30, 34))	('decreased', 'NegReg', (68, 77))	('mice', 'Species', '10090', (216, 220))	('CD93+/-', 'Var', (201, 208))	('reduction', 'NegReg', (17, 26))
94120	29763414	Consistent with these results, decreased fibronectin fibrillogenesis was observed in brain endothelial cells isolated from CD93-/- mice compared with those isolated from WT mice (Figure 6F).	('CD93-/-', 'Var', (123, 130))	('decreased', 'NegReg', (31, 40))	('fibronectin fibrillogenesis', 'MPA', (41, 68))	('decreased fibronectin', 'Phenotype', 'HP:0032463', (31, 52))	('mice', 'Species', '10090', (131, 135))	('mice', 'Species', '10090', (173, 177))
94124	29763414	A striking reduction of active beta1 integrin was observed in endothelial cells when either CD93 or MMRN2 was silenced (Figure 7, A and B).	('reduction', 'NegReg', (11, 20))	('MMRN2', 'Gene', (100, 105))	('active', 'MPA', (24, 30))	('silenced', 'Var', (110, 118))	('CD93', 'Gene', (92, 96))	('beta1', 'Gene', '97440', (31, 36))	('beta1', 'Gene', (31, 36))
94130	29763414	The CD93-alpha5beta1 interaction was further confirmed by PLA showing statistically significant interaction between CD93 and alpha5beta1 as well as CD93 and active beta1 integrin (Figure 7D).	('CD93', 'Gene', (116, 120))	('beta1', 'Gene', (131, 136))	('beta1', 'Gene', (15, 20))	('beta1', 'Gene', '97440', (15, 20))	('interaction', 'Interaction', (96, 107))	('beta1', 'Gene', '97440', (164, 169))	('CD93', 'Var', (148, 152))	('beta1', 'Gene', (164, 169))	('beta1', 'Gene', '97440', (131, 136))
94132	29763414	In line with a requirement of CD93 and MMRN2 for full beta1 integrin activation, we observed reduced FAK activation, monitored as Y397-phosphorylated FAK (p-FAK), in endothelial cells treated with siRNA targeting either CD93 or MMRN2.	('FAK', 'Gene', (101, 104))	('CD93', 'Var', (220, 224))	('FAK', 'Gene', '14083', (150, 153))	('FAK', 'Gene', (150, 153))	('beta1', 'Gene', (54, 59))	('reduced', 'NegReg', (93, 100))	('FAK', 'Gene', (157, 160))	('FAK', 'Gene', '14083', (157, 160))	('beta1', 'Gene', '97440', (54, 59))	('FAK', 'Gene', '14083', (101, 104))
94137	29763414	Given the significant inhibition in endothelial sprouts and endothelial filopodia observed in CD93-/- retinas (Figure 2, D and E), integrin activation and fibronectin fibrillogenesis was assessed during developmental angiogenesis in P6 WT and CD93-/- mouse retinas.	('mouse', 'Species', '10090', (251, 256))	('inhibition', 'NegReg', (22, 32))	('CD93-/-', 'Var', (94, 101))	('endothelial sprouts', 'CPA', (36, 55))	('endothelial filopodia', 'CPA', (60, 81))
94138	29763414	Consistent with a key role of CD93 in beta1 integrin activation, a dramatic inhibition of the active form of beta1 integrin (recognized by the 9EG7 antibody) was observed in the sprouting front and filopodia of CD93-/- retinas compared with WT mice (Figure 8A).	('inhibition', 'NegReg', (76, 86))	('mice', 'Species', '10090', (244, 248))	('beta1', 'Gene', '97440', (109, 114))	('beta1', 'Gene', (109, 114))	('active', 'MPA', (94, 100))	('CD93-/-', 'Var', (211, 218))	('beta1', 'Gene', '97440', (38, 43))	('beta1', 'Gene', (38, 43))
94142	29763414	Similar to our previous observation that CD93 expression is increased in the vasculature of human high-grade glioma (HGG), MMRN2 and fibronectin were significantly elevated in WHO grade III and IV glioma compared with low-grade glioma (LGG; WHO grade II) or control brain samples (Figure 9, C and D).	('CD93', 'Gene', (41, 45))	('expression', 'MPA', (46, 56))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('glioma', 'Disease', (228, 234))	('glioma', 'Disease', (197, 203))	('glioma', 'Disease', (109, 115))	('fibronectin', 'Protein', (133, 144))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('MMRN2', 'Gene', (123, 128))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('elevated', 'PosReg', (164, 172))	('grade III', 'Var', (180, 189))	('increased', 'PosReg', (60, 69))	('human', 'Species', '9606', (92, 97))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
94149	29763414	Notably, a substantial reduction of fibronectin deposition was found in the CD93-/- GL261 tumor, and disrupted fibronectin fibers were observed associated with the tumor vasculature (Figure 10B).	('tumor', 'Disease', (164, 169))	('fibronectin deposition', 'MPA', (36, 58))	('CD93-/- GL261', 'Var', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('reduction', 'NegReg', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
94151	29763414	No obvious differences in fibronectin deposition were found in the normal vasculature of CD93-/- mice compared with WT mice, and fibronectin levels in normal vessels were considerably lower than those in tumor vessels (Supplemental Figure 8B).	('mice', 'Species', '10090', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('fibronectin levels', 'MPA', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mice', 'Species', '10090', (97, 101))	('tumor', 'Disease', (204, 209))	('lower', 'NegReg', (184, 189))	('CD93-/-', 'Var', (89, 96))
94154	29763414	Consistent with our previous report, the mean GL261 tumor area was significantly reduced in CD93-/- mice as compared with WT mice (Figure 10E and ref.).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mice', 'Species', '10090', (100, 104))	('mice', 'Species', '10090', (125, 129))	('GL261', 'Gene', (46, 51))	('reduced', 'NegReg', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CD93-/-', 'Var', (92, 99))
94176	29763414	In CD93-/- mice, there are fewer filopodia in the sprouting front during vascular development in the retina, suggesting that CD93 is important for tip cell behavior.	('mice', 'Species', '10090', (11, 15))	('CD93-/-', 'Var', (3, 10))	('fewer', 'NegReg', (27, 32))	('filopodia in the sprouting front', 'CPA', (33, 65))
94180	29763414	Similarly, CD93 deficiency reduced beta1 integrin activation in murine GL261 glioma tumor vessels in vivo.	('activation', 'MPA', (50, 60))	('reduced', 'NegReg', (27, 34))	('beta1', 'Gene', (35, 40))	('CD93', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('glioma tumor', 'Disease', (77, 89))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('murine', 'Species', '10090', (64, 70))	('glioma tumor', 'Disease', 'MESH:D005910', (77, 89))	('beta1', 'Gene', '97440', (35, 40))	('deficiency', 'Var', (16, 26))
94181	29763414	Inhibition of integrin activation decreases angiogenesis and reduces tumor growth in several models, consistent with our observation of deficient integrin activation and decreased tumor growth observed in CD93-/- mice.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('integrin', 'Protein', (14, 22))	('decreases', 'NegReg', (34, 43))	('mice', 'Species', '10090', (213, 217))	('decreased tumor', 'Disease', 'MESH:D009369', (170, 185))	('angiogenesis', 'CPA', (44, 56))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('decreased tumor', 'Disease', (170, 185))	('Inhibition', 'Var', (0, 10))	('reduces', 'NegReg', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
94183	29763414	Consistent with an important role of alpha5beta1 integrin in fibronectin fibrillogenesis, siRNA knockdown or deficiency of either CD93 or MMRN2 in endothelial cells resulted in disruption of the fibronectin fibrillar network formation in vitro.	('knockdown', 'Var', (96, 105))	('CD93', 'Gene', (130, 134))	('deficiency', 'Var', (109, 119))	('beta1', 'Gene', '97440', (43, 48))	('disruption', 'NegReg', (177, 187))	('fibronectin fibrillar network formation', 'CPA', (195, 234))	('beta1', 'Gene', (43, 48))	('MMRN2', 'Gene', (138, 143))
94217	29763414	Cryosections of human grade IV glioma and murine GL261 glioma sections were stained with anti-CD31 (2H8, Thermo Fisher Scientific, MA3105), anti-CD93 (R&D Systems, AF1696), anti-MMRN2 (MyBioSource, MBS2028221), anti-fibronectin (Abcam, ab2413), and anti-beta1 integrin (9EG7, BD Pharmingen, 553715).	('glioma', 'Disease', (55, 61))	('anti-CD31', 'Var', (89, 98))	('anti-CD93', 'Var', (140, 149))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('beta1', 'Gene', '97440', (254, 259))	('murine', 'Species', '10090', (42, 48))	('beta1', 'Gene', (254, 259))	('human', 'Species', '9606', (16, 21))	('glioma', 'Disease', (31, 37))
94301	26308630	Furthermore, histopathological analysis of intratumoral areas with focal 5-ALA-induced fluorescence showed that fluorescing tumor tissue significantly correlates with an increased proliferation rate and histopathological WHO parameters of anaplasia .	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('proliferation rate', 'CPA', (180, 198))	('tumor', 'Disease', (124, 129))	('increased', 'PosReg', (170, 179))	('anaplasia', 'Disease', 'MESH:D000708', (239, 248))	('anaplasia', 'Disease', (239, 248))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('fluorescing', 'Var', (112, 123))	('5-ALA', 'Chemical', 'MESH:C000614854', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
94309	26308630	During the actual tumor resection, brain shift further compounds the inaccuracy of the neuronavigation system up to several more centimeters .	('inaccuracy', 'MPA', (69, 79))	('tumor', 'Disease', (18, 23))	('brain shift', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
94374	26108672	Quantitative proteomic analysis shows differentially expressed HSPB1 in glioblastoma as a discriminating short from long survival factor and NOVA1 as a differentiation factor between low-grade astrocytoma and oligodendroglioma Gliomas account for more than 60 % of all primary central nervous system neoplasms.	('differentially expressed', 'Var', (38, 62))	('oligodendroglioma', 'Disease', 'MESH:D009837', (209, 226))	('nervous system neoplasms', 'Phenotype', 'HP:0004375', (285, 309))	('central nervous system neoplasms', 'Disease', (277, 309))	('astrocytoma', 'Phenotype', 'HP:0009592', (193, 204))	('Gliomas', 'Disease', 'MESH:D005910', (227, 234))	('oligodendroglioma', 'Disease', (209, 226))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('HSPB1', 'Gene', (63, 68))	('Gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('HSPB1', 'Gene', '3315', (63, 68))	('central nervous system neoplasms', 'Disease', 'MESH:D016543', (277, 309))	('astrocytoma', 'Disease', 'MESH:D001254', (193, 204))	('NOVA1', 'Gene', (141, 146))	('astrocytoma', 'Disease', (193, 204))	('central nervous system neoplasms', 'Phenotype', 'HP:0100006', (277, 309))	('NOVA1', 'Gene', '4857', (141, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('Gliomas', 'Disease', (227, 234))	('glioblastoma', 'Disease', (72, 84))	('neoplasms', 'Phenotype', 'HP:0002664', (300, 309))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
94388	26108672	We have also shown that NPM1 knockdown sensitized GBM cell lines to cell death after treatment with temozolamide.	('knockdown', 'Var', (29, 38))	('cell death', 'CPA', (68, 78))	('NPM1', 'Gene', (24, 28))	('sensitized', 'Reg', (39, 49))	('NPM1', 'Gene', '4869', (24, 28))	('temozolamide', 'Chemical', '-', (100, 112))
94389	26108672	Moreover, when NPM1 expression was silenced, expression of GRP78, a member of the heat shock protein 70 involved in protein unfold response, was concomitantly decreased.	('GRP78', 'Gene', '3309', (59, 64))	('NPM1', 'Gene', (15, 19))	('silenced', 'Var', (35, 43))	('NPM1', 'Gene', '4869', (15, 19))	('expression', 'MPA', (45, 55))	('decreased', 'NegReg', (159, 168))	('GRP78', 'Gene', (59, 64))	('shock', 'Phenotype', 'HP:0031273', (87, 92))
94423	26108672	MS/MS spectra from 20 fractions were searched against the Swiss Prot (Swiss Institute of Bioinformatics) database, taxonomy Homo sapiens (human) using Mascot software (Matrix Science, London, UK; version 2.3), with precursor mass tolerance at 20 ppm, fragment ion mass tolerance at 0.05 Da, trypsin enzyme with 2 miscleavages, methyl methanethiosulfonate of cysteine and iTRAQ 8plex of lysine and the n-terminus as fixed modifications, and deamidation of asparagine and glutamine, oxidation of methionine and iTRAQ 8plex of tyrosine as variable modifications.	('Homo sapiens', 'Species', '9606', (124, 136))	('cysteine', 'Chemical', 'MESH:D003545', (358, 366))	('oxidation', 'MPA', (481, 490))	('glutamine', 'MPA', (470, 479))	('iTRAQ', 'Chemical', '-', (371, 376))	('human', 'Species', '9606', (138, 143))	('methyl methanethiosulfonate', 'Chemical', 'MESH:C014674', (327, 354))	('iTRAQ', 'Var', (509, 514))	('deamidation', 'MPA', (440, 451))	('methyl methanethiosulfonate', 'MPA', (327, 354))	('iTRAQ', 'Chemical', '-', (509, 514))
94455	26108672	On the other hand, IDH1 mutation status (mutated IDH1 compared to wild type) presented HR = 1.35, 95 % CI = 0.64 +- 2.84, p = 0.43.	('IDH1', 'Gene', '3417', (49, 53))	('IDH1', 'Gene', (19, 23))	('IDH1', 'Gene', '3417', (19, 23))	('mutation', 'Var', (24, 32))	('IDH1', 'Gene', (49, 53))
94560	22393407	In order to identify stromal genes important for tumorigenesis, we next looked specifically for genes expressed at much higher levels in GBM TAAs when compared to TAAs from low-grade gliomas.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('gliomas', 'Disease', (183, 190))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('GBM', 'Phenotype', 'HP:0012174', (137, 140))	('GBM', 'Var', (137, 140))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('higher', 'PosReg', (120, 126))	('tumor', 'Disease', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))
94575	22393407	In this orthotopic model, TAAs derived from tumor cells would not express the GFAP-GFP transgene; conversely, TAAs derived from non-tumor cells should express GFP.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (132, 137))	('GFP', 'Var', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
94588	22393407	Using this analysis, most of the genes identified as specific to GBM TAAs when compared to low grade (WHO Grade II) TAAs were also identified as arising only in the stromal compartment of the tumor and not in the Olig2-expressing tumor cells (Figure 4A).	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (192, 197))	('GBM', 'Var', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
94600	22393407	These tumors have hypermethylated promoter CpG islands, which results in transcriptional silencing of the associated genes.	('transcriptional', 'MPA', (73, 88))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('silencing', 'NegReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('hypermethylated', 'Var', (18, 33))
94617	22393407	We will direct some of our future studies towards understanding whether these gene expression changes produces functional differences in tumor pathophysiology.	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('changes', 'Var', (94, 101))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))
94625	22393407	Three of the stromal genes (Rbp1, Lgals3 and Anxa2) were methylated at a significantly higher level in g-CIMP tumors compared to non-CIMP tumors, and even unmethylated genes were significantly downregulated in g-CIMP tumors when compared to non-CIMP tumors.	('Rbp1', 'Gene', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('CIMP', 'Chemical', '-', (245, 249))	('CIMP', 'Chemical', '-', (133, 137))	('CIMP', 'Chemical', '-', (212, 216))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('Lgals3', 'Gene', '3958', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('Anxa2', 'Gene', '302', (45, 50))	('higher', 'PosReg', (87, 93))	('downregulated', 'NegReg', (193, 206))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('g-CIMP', 'Chemical', '-', (210, 216))	('tumors', 'Disease', (110, 116))	('Rbp1', 'Gene', '5947', (28, 32))	('Anxa2', 'Gene', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('g-CIMP', 'Disease', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CIMP', 'Chemical', '-', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('g-CIMP', 'Chemical', '-', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('Lgals3', 'Gene', (34, 40))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('methylated', 'Var', (57, 67))
94633	22393407	Nestin-tv-a (N-tva) transgenic mice were injected with DF1 cells (purchased from ATCC) producing RCAS-PDGFB, RCAS-PDGF-sv40-GFP or RCAS-PDGF-RFP as previously described.	('RCAS', 'Chemical', '-', (131, 135))	('RFP', 'Gene', (141, 144))	('RCAS', 'Chemical', '-', (97, 101))	('RFP', 'Gene', '19720', (141, 144))	('PDGFB', 'Gene', (102, 107))	('PDGFB', 'Gene', '374128', (102, 107))	('RCAS-PDGF-sv40-GFP', 'Var', (109, 127))	('transgenic mice', 'Species', '10090', (20, 35))	('RCAS', 'Chemical', '-', (109, 113))
94638	22393407	DF1 cells overexpressing RCAS-PDGF, RCAS-PDGF-sv40-GFP or RCAS-PDGF-mRFP were maintained in media containing 10% FBS in a humidified atmosphere containing 5% carbon dioxide at 39 degrees.	('FBS', 'Disease', 'MESH:D005198', (113, 116))	('RCAS', 'Chemical', '-', (25, 29))	('RFP', 'Gene', (69, 72))	('carbon dioxide', 'Chemical', 'MESH:D002245', (158, 172))	('RCAS-PDGF', 'Var', (25, 34))	('RCAS', 'Chemical', '-', (58, 62))	('FBS', 'Disease', (113, 116))	('RCAS', 'Chemical', '-', (36, 40))	('RFP', 'Gene', '19720', (69, 72))
94701	33671796	CCNU inhibits the enzymatic function of key enzymes involved in the carbamoylation process of amino acids, interfering with transcription and translation processes.	('enzymatic function', 'MPA', (18, 36))	('interfering', 'NegReg', (107, 118))	('inhibits', 'NegReg', (5, 13))	('CCNU', 'Var', (0, 4))	('CCNU', 'Chemical', 'MESH:D008130', (0, 4))
94703	33671796	Although GBM patients with methylated MGMT and deficient mismatch repair often have a better prognosis with CCNU, the six-months progression-free survival (19%) and median overall survival (7.1 months) remains low, particularly in recurrent GBM patients as demonstrated in phase III clinical trial.	('MGMT', 'Gene', '4255', (38, 42))	('mismatch', 'MPA', (57, 65))	('GBM', 'Disease', (241, 244))	('CCNU', 'Chemical', 'MESH:D008130', (108, 112))	('deficient', 'Var', (47, 56))	('patients', 'Species', '9606', (245, 253))	('patients', 'Species', '9606', (13, 21))	('better', 'PosReg', (86, 92))	('low', 'NegReg', (210, 213))	('rat', 'Species', '10116', (264, 267))	('MGMT', 'Gene', (38, 42))
94712	33671796	However, Tmz is associated with side effects such as nausea, fatigue, significant myelosuppression, thrombocytopenia, severe infections, and myelodysplastic syndrome.	('myelosuppression', 'Disease', 'MESH:D001855', (82, 98))	('Tmz', 'Chemical', 'MESH:D000077204', (9, 12))	('thrombocytopenia', 'Disease', (100, 116))	('myelodysplastic syndrome', 'Disease', (141, 165))	('severe infections', 'Phenotype', 'HP:0032169', (118, 135))	('infections', 'Disease', 'MESH:D007239', (125, 135))	('nausea', 'Phenotype', 'HP:0002018', (53, 59))	('fatigue', 'Disease', (61, 68))	('fatigue', 'Phenotype', 'HP:0012378', (61, 68))	('infections', 'Disease', (125, 135))	('nausea', 'Disease', (53, 59))	('thrombocytopenia', 'Disease', 'MESH:D013921', (100, 116))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (141, 165))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (100, 116))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (141, 165))	('myelosuppression', 'Disease', (82, 98))	('fatigue', 'Disease', 'MESH:D005221', (61, 68))	('Tmz', 'Var', (9, 12))	('nausea', 'Disease', 'MESH:D009325', (53, 59))
94718	33671796	Interestingly, high-grade anaplastic oligodendroglioma patients with 1p/19q co-deletion treated with radiotherapy only or a combination of radiotherapy and PCV exhibited improvement in the overall survival.	('high-grade', 'Disease', (15, 25))	('overall', 'MPA', (189, 196))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('anaplastic oligodendroglioma', 'Disease', (26, 54))	('improvement', 'PosReg', (170, 181))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (26, 54))	('1p/19q co-deletion', 'Var', (69, 87))	('patients', 'Species', '9606', (55, 63))
94719	33671796	Tmz is more tolerable than PCV, and recent clinical trials supported its use for anaplastic oligodendroglioma patients with intact 1p/19q and wild-type IDH1.	('IDH1', 'Gene', (152, 156))	('anaplastic oligodendroglioma', 'Disease', (81, 109))	('IDH1', 'Gene', '3417', (152, 156))	('1p/19q', 'Var', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('Tmz', 'Chemical', 'MESH:D000077204', (0, 3))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (81, 109))	('patients', 'Species', '9606', (110, 118))
94721	33671796	Previously, in a prospective GICNO study, it was reported that co-deletion of 1p/19q is associated with Tmz responses, and MGMT methylation is correlated with co-deletion of chromosome 1p/19q in anaplastic oligodendroglioma.	('1p/19q', 'Gene', (78, 84))	('Tmz responses', 'MPA', (104, 117))	('co-deletion', 'Var', (63, 74))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (195, 223))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('co-deletion', 'Var', (159, 170))	('anaplastic oligodendroglioma', 'Disease', (195, 223))	('MGMT', 'Gene', (123, 127))	('associated', 'Reg', (88, 98))	('correlated', 'Reg', (143, 153))	('Tmz', 'Chemical', 'MESH:D000077204', (104, 107))	('MGMT', 'Gene', '4255', (123, 127))
94722	33671796	Hence, MGMT methylation and 1p/19q co-deletion could confer a favorable prognosis in patients with HGG.	('MGMT', 'Gene', '4255', (7, 11))	('MGMT', 'Gene', (7, 11))	('HGG', 'Disease', (99, 102))	('patients', 'Species', '9606', (85, 93))	('1p/19q co-deletion', 'Var', (28, 46))
94723	33671796	Thus, a complex model integrating 1p/19q co-deletion, MGMT methylation, IDH1 mutations while taking into consideration the patient's age and histopathological diagnosis should be integrated to validate this.	('IDH1', 'Gene', (72, 76))	('patient', 'Species', '9606', (123, 130))	('rat', 'Species', '10116', (184, 187))	('IDH1', 'Gene', '3417', (72, 76))	('MGMT', 'Gene', (54, 58))	('rat', 'Species', '10116', (112, 115))	('MGMT', 'Gene', '4255', (54, 58))	('mutations', 'Var', (77, 86))	('rat', 'Species', '10116', (27, 30))
94725	33671796	This analysis demonstrated a significantly reduced OS association with unmethylated MGMT promoter status.	('OS association', 'MPA', (51, 65))	('MGMT', 'Gene', '4255', (84, 88))	('rat', 'Species', '10116', (21, 24))	('MGMT', 'Gene', (84, 88))	('unmethylated', 'Var', (71, 83))	('reduced', 'NegReg', (43, 50))
94726	33671796	Additionally, this study highlighted MGMT promoter methylation as a potential prognostic tool besides IDH1/2 mutation for LGG.	('LGG', 'Disease', (122, 125))	('IDH1', 'Gene', (102, 106))	('MGMT', 'Gene', '4255', (37, 41))	('MGMT', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (102, 106))	('mutation', 'Var', (109, 117))
94736	33671796	This study also indicated that IDH1 mutation has a favorable prognosis than the methylation of MGMT promoter or 1p/19q co-deletion.	('IDH1', 'Gene', '3417', (31, 35))	('MGMT', 'Gene', '4255', (95, 99))	('MGMT', 'Gene', (95, 99))	('mutation', 'Var', (36, 44))	('IDH1', 'Gene', (31, 35))
94737	33671796	Hence, anaplastic astrocytoma with IDH1 wild-type and MGMT methylation patients may be more suitable treated with chemotherapy and if the MGMT is unmethylated, they are better treated by radiotherapy only.	('anaplastic astrocytoma', 'Disease', (7, 29))	('IDH1', 'Gene', (35, 39))	('MGMT', 'Gene', (138, 142))	('MGMT', 'Gene', '4255', (138, 142))	('IDH1', 'Gene', '3417', (35, 39))	('patients', 'Species', '9606', (71, 79))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (7, 29))	('MGMT', 'Gene', (54, 58))	('astrocytoma', 'Phenotype', 'HP:0009592', (18, 29))	('methylation', 'Var', (59, 70))	('MGMT', 'Gene', '4255', (54, 58))
94739	33671796	Additionally, when the CpG islands located in the promoter regions of MGMT are methylated, it suppresses MGMT transcription.	('MGMT', 'Gene', (70, 74))	('methylated', 'Var', (79, 89))	('MGMT', 'Gene', '4255', (70, 74))	('MGMT', 'Gene', '4255', (105, 109))	('MGMT', 'Gene', (105, 109))	('suppresses', 'NegReg', (94, 104))
94743	33671796	In another study, PCV addition to radiotherapy in anaplastic oligodendroglioma patients is not restricted to tumors with 1p/19q co-deletion but also to ATRX and IDH mutations.	('IDH', 'Gene', '3417', (161, 164))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('anaplastic oligodendroglioma', 'Disease', (50, 78))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (50, 78))	('1p/19q co-deletion', 'Var', (121, 139))	('patients', 'Species', '9606', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ATRX', 'Gene', (152, 156))	('IDH', 'Gene', (161, 164))	('tumors', 'Disease', (109, 115))	('ATRX', 'Gene', '546', (152, 156))
94744	33671796	Anaplastic astrocytoma patients may share similar molecular traits with anaplastic oligodendroglioma patients having 1p/19q co-deletion and low-grade astrocytoma with IDH mutations.	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('patients', 'Species', '9606', (101, 109))	('IDH', 'Gene', '3417', (167, 170))	('astrocytoma', 'Disease', (11, 22))	('astrocytoma', 'Disease', (150, 161))	('patients', 'Species', '9606', (23, 31))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (72, 100))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('1p/19q co-deletion', 'Var', (117, 135))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('astrocytoma', 'Disease', 'MESH:D001254', (11, 22))	('astrocytoma', 'Disease', 'MESH:D001254', (150, 161))	('IDH', 'Gene', (167, 170))	('Anaplastic astrocytoma', 'Disease', (0, 22))	('Anaplastic astrocytoma', 'Disease', 'MESH:D001254', (0, 22))	('anaplastic oligodendroglioma', 'Disease', (72, 100))
94754	33671796	Mutation of IDH renders cells incapable of fully utilizing the citric acid cycle, which creates ATP deprivation, leading to a low cell cycle performance.	('Mutation', 'Var', (0, 8))	('ATP', 'Chemical', 'MESH:D000255', (96, 99))	('low', 'NegReg', (126, 129))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('cell cycle performance', 'CPA', (130, 152))	('citric acid', 'Chemical', 'MESH:D019343', (63, 74))
94759	33671796	However, the PCV regime has been added as part of disease management (based on EORTC 26951 and the RTOG 9402 trials), which demonstrated prolonged survival and better radiographic response rate (93-100%) in 1p/19q co-deletion gliomas than Tmz (35-82%).	('1p/19q co-deletion', 'Var', (207, 225))	('rat', 'Species', '10116', (131, 134))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('Tmz', 'Chemical', 'MESH:D000077204', (239, 242))	('co-deletion', 'Var', (214, 225))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', (226, 233))	('rat', 'Species', '10116', (189, 192))
94764	33671796	Anaplastic astrocytoma patients with 1p/19q co-deletion and IDH mutation often have a better prognosis.	('1p/19q co-deletion', 'Var', (37, 55))	('patients', 'Species', '9606', (23, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('IDH', 'Gene', (60, 63))	('IDH', 'Gene', '3417', (60, 63))	('Anaplastic astrocytoma', 'Disease', (0, 22))	('Anaplastic astrocytoma', 'Disease', 'MESH:D001254', (0, 22))
94765	33671796	In contrast, patients with only IDH mutation and intact 1p/19q have moderate prognoses.	('rat', 'Species', '10116', (72, 75))	('patients', 'Species', '9606', (13, 21))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('mutation', 'Var', (36, 44))
94766	33671796	Although wild-type IDH anaplastic astrocytoma patients tend to have poorer prognoses, they share similar molecular alterations with GBM patients, including EGFR amplification, gain in chromosome 7, and loss in chromosome 10.	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('patients', 'Species', '9606', (46, 54))	('EGFR', 'Gene', '1956', (156, 160))	('IDH anaplastic astrocytoma', 'Disease', 'MESH:D001254', (19, 45))	('gain', 'PosReg', (176, 180))	('rat', 'Species', '10116', (119, 122))	('IDH anaplastic astrocytoma', 'Disease', (19, 45))	('EGFR', 'Gene', (156, 160))	('patients', 'Species', '9606', (136, 144))	('amplification', 'Var', (161, 174))	('loss', 'NegReg', (202, 206))
94772	33671796	Additionally, D-2-HG also competitively inhibits the function of ten-eleven translocation methylcytosine dioxygenase 1 and 2 (TET 1 and TET2).	('D-2-HG', 'Chemical', '-', (14, 20))	('D-2-HG', 'Var', (14, 20))	('oxygen', 'Chemical', 'MESH:D010100', (107, 113))	('TET2', 'Gene', '54790', (136, 140))	('cytosine', 'Chemical', 'MESH:D003596', (96, 104))	('ten-eleven', 'Pathway', (65, 75))	('inhibits', 'NegReg', (40, 48))	('TET 1', 'Gene', (126, 131))	('TET2', 'Gene', (136, 140))	('TET 1', 'Gene', '80312', (126, 131))	('function', 'MPA', (53, 61))
94776	33671796	Increased histone methylation associated with D-2-HG can restrict cell differentiation which is vital in gliomagenesis and cell maintenance.	('glioma', 'Disease', (105, 111))	('cell differentiation', 'CPA', (66, 86))	('Increased', 'PosReg', (0, 9))	('D-2-HG', 'Chemical', '-', (46, 52))	('histone methylation', 'MPA', (10, 29))	('restrict', 'NegReg', (57, 65))	('D-2-HG', 'Var', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
94777	33671796	Furthermore, D-2-HG may affect numerous pathways involved in DNA repair.	('D-2-HG', 'Var', (13, 19))	('D-2-HG', 'Chemical', '-', (13, 19))	('DNA', 'Disease', (61, 64))	('affect', 'Reg', (24, 30))
94778	33671796	It inhibits the alpha-KG-dependent alkB homolog (ALKBH) enzyme, which sensitizes cancers with IDH mutations to DNA alkylating agents.	('alkB', 'Gene', (35, 39))	('ALKBH', 'Gene', '8846', (49, 54))	('inhibits', 'NegReg', (3, 11))	('IDH', 'Gene', (94, 97))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('mutations', 'Var', (98, 107))	('IDH', 'Gene', '3417', (94, 97))	('alkB', 'Gene', '8846', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ALKBH', 'Gene', (49, 54))
94779	33671796	Moreover, mutation to IDH1 downregulates the ataxia-telangiectasia-mutated (ATM) signaling pathway via an alteration to histone proteins' methylation, resulting in enhanced sensitivity towards agents that damage the DNA.	('ATM', 'Gene', (76, 79))	('rat', 'Species', '10116', (110, 113))	('telangiectasia', 'Phenotype', 'HP:0001009', (52, 66))	('enhanced', 'PosReg', (164, 172))	("histone proteins'", 'Protein', (120, 137))	('methylation', 'MPA', (138, 149))	('ataxia-telangiectasia-mutated', 'Gene', (45, 74))	('mutation', 'Var', (10, 18))	('ATM', 'Gene', '472', (76, 79))	('IDH1', 'Gene', (22, 26))	('downregulates', 'NegReg', (27, 40))	('sensitivity towards agents', 'MPA', (173, 199))	('ataxia-telangiectasia-mutated', 'Gene', '472', (45, 74))	('ataxia', 'Phenotype', 'HP:0001251', (45, 51))	('IDH1', 'Gene', '3417', (22, 26))	('alteration', 'Reg', (106, 116))
94780	33671796	Moreover, IDH mutation causes a reduction in NAD+, affecting the poly (ADP-ribose) polymerase-1 (PARP1)-associated DNA repair pathways.	('IDH', 'Gene', (10, 13))	('NAD+', 'MPA', (45, 49))	('PARP1', 'Gene', '142', (97, 102))	('IDH', 'Gene', '3417', (10, 13))	('PARP1', 'Gene', (97, 102))	('NAD+', 'Chemical', 'MESH:D009243', (45, 49))	('reduction', 'NegReg', (32, 41))	('affecting', 'Reg', (51, 60))	('mutation', 'Var', (14, 22))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (65, 95))	('poly (ADP-ribose) polymerase-1', 'Gene', (65, 95))
94798	33671796	Impairment in mismatch repair system contributed by gene mutations such as melanocyte-stimulating hormone 2 (MSH2), MSH6, mutL homolog 1 (MLH1), and post-meiotic segregation-increased Saccharomyces cerevisiae 2 (PMS2).	('MSH2', 'Chemical', '-', (109, 113))	('mismatch repair system', 'MPA', (14, 36))	('MSH2', 'Gene', (109, 113))	('Saccharomyces cerevisiae', 'Species', '4932', (184, 208))	('mutations', 'Var', (57, 66))	('mutL homolog 1', 'Gene', (122, 136))	('mutL homolog 1', 'Gene', '855203', (122, 136))	('MLH1', 'Gene', '855203', (138, 142))	('MSH6', 'Gene', (116, 120))	('MLH1', 'Gene', (138, 142))	('MSH6', 'Gene', '851671', (116, 120))
94802	33671796	The methylation of N7-guanine (60-80%) and N3-adenine (10-20%) represents more than 90% of the methylation by Tmz and is rapidly repaired by base excision repair.	('N3-adenine', 'Chemical', '-', (43, 53))	('methylation', 'MPA', (4, 15))	('N7-guanine', 'Chemical', '-', (19, 29))	('N7-guanine', 'Var', (19, 29))	('methylation', 'MPA', (95, 106))	('Tmz', 'Chemical', 'MESH:D000077204', (110, 113))
94803	33671796	When one or more base excision repair components are mutated, its ability is deficient and contributes to Tmz cytotoxicity.	('deficient', 'NegReg', (77, 86))	('cytotoxicity', 'Disease', 'MESH:D064420', (110, 122))	('mutated', 'Var', (53, 60))	('ability', 'MPA', (66, 73))	('Tmz', 'Chemical', 'MESH:D000077204', (106, 109))	('cytotoxicity', 'Disease', (110, 122))	('Tmz', 'MPA', (106, 109))	('contributes', 'Reg', (91, 102))
94804	33671796	Notably, N3 lesions are lethal if not repaired, as opposed to N7 lesions, which leads to inhibition of PARP-1.	('PARP-1', 'Gene', '142', (103, 109))	('N3 lesions', 'Var', (9, 19))	('PARP-1', 'Gene', (103, 109))
94809	33671796	Generally, Tmz can induce cell cycle arrest and apoptosis via DNA damage in tumors that lack MGMT.	('DNA damage', 'MPA', (62, 72))	('Tmz', 'Var', (11, 14))	('induce', 'PosReg', (19, 25))	('MGMT', 'Gene', '4255', (93, 97))	('MGMT', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('Tmz', 'Chemical', 'MESH:D000077204', (11, 14))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (26, 43))	('arrest', 'Disease', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('apoptosis', 'CPA', (48, 57))
94830	33671796	Alterations in various genes largely drive tumorigenesis.	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('rat', 'Species', '10116', (4, 7))	('tumor', 'Disease', (43, 48))	('drive', 'Reg', (37, 42))
94845	33671796	In a randomized phase III clinical trial (NCT00045968), the addition of DCVax to regular therapy (Tmz) in newly diagnosed GBM patients prolonged the two and three-year survival rate by 66.7% and 46.4% respectively in patients with methylated MGMT, whereas in patients with unmethylated MGMT, the two and three-year survival rate is 32.1% and 11% respectively.	('methylated', 'Var', (231, 241))	('patients', 'Species', '9606', (259, 267))	('rat', 'Species', '10116', (177, 180))	('MGMT', 'Gene', '4255', (286, 290))	('MGMT', 'Gene', (286, 290))	('Tmz', 'Chemical', 'MESH:D000077204', (98, 101))	('MGMT', 'Gene', '4255', (242, 246))	('MGMT', 'Gene', (242, 246))	('prolonged', 'PosReg', (135, 144))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (217, 225))	('DCVax', 'Chemical', '-', (72, 77))	('rat', 'Species', '10116', (324, 327))
94851	33671796	Moreover, even if some patients have the EGFRVIII variant, the natural evolution of the GBM tumor could result in a loss of this variant subtype, thus, causing peptide vaccines to be ineffective, as seen in phase III of the ACT IV trial.	('EGFRVIII', 'Gene', (41, 49))	('variant', 'Var', (50, 57))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('GBM tumor', 'Disease', 'MESH:D005910', (88, 97))	('loss', 'NegReg', (116, 120))	('EGFRVIII', 'Gene', '1351', (41, 49))	('GBM tumor', 'Disease', (88, 97))
94866	33671796	In this cohort study, co-targeting HER2, IL13Ralpha2, and EphA2 overcomes the interpatient variability and activates the immune synapses to improve cytotoxicity and release of cytokines when compared to monospecific and bispecific CAR T cells.	('activates', 'PosReg', (107, 116))	('co-targeting', 'Var', (22, 34))	('HER2', 'Protein', (35, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (148, 160))	('improve', 'PosReg', (140, 147))	('release of cytokines', 'MPA', (165, 185))	('IL13Ralpha2', 'Gene', (41, 52))	('patient', 'Species', '9606', (83, 90))	('IL13Ralpha2', 'Gene', '3598', (41, 52))	('immune synapses', 'CPA', (121, 136))	('cytotoxicity', 'Disease', (148, 160))	('EphA2', 'Var', (58, 63))
94879	33671796	Initial clinical studies in recurrent GBM patients (n = 10), shows that TTF prolonged the median time of disease progression (26.1 months), 6 months progression-free survival rates (50%) and median overall survival (>62 weeks) TTF can enhance Tmz therapeutic efficacy by delaying the repair of damaged DNA in newly diagnosed or recurrent GBM.	('TTF', 'Chemical', '-', (227, 230))	('delaying', 'NegReg', (271, 279))	('TTF', 'Chemical', '-', (72, 75))	('Tmz', 'Chemical', 'MESH:D000077204', (243, 246))	('repair', 'MPA', (284, 290))	('TTF', 'Var', (227, 230))	('rat', 'Species', '10116', (175, 178))	('patients', 'Species', '9606', (42, 50))	('enhance', 'PosReg', (235, 242))
94926	33671796	The use of formulated nanoparticles such as poly(lactic-co-glycolic acid), poly(butyl)cyanoacrylate, and tripalmitin-oleic acid enhance curcumin distribution in vitro and in vivo models.	('poly', 'Var', (75, 79))	('poly(butyl)cyanoacrylate', 'Chemical', 'MESH:D004659', (75, 99))	('curcumin', 'Chemical', 'MESH:D003474', (136, 144))	('tripalmitin-oleic acid', 'Chemical', '-', (105, 127))	('poly(lactic-co-glycolic acid)', 'Chemical', 'MESH:D000077182', (44, 73))	('curcumin distribution', 'MPA', (136, 157))	('enhance', 'PosReg', (128, 135))
94927	33671796	For instance, poly(lactic-co-glycolic acid) demonstrated an increased half-life in male Sprague-Dawley rat (210 +- 10 g body weight) brain tissue from 9 to 15 min.	('rat', 'Species', '10116', (103, 106))	('poly', 'Var', (14, 18))	('half-life', 'MPA', (70, 79))	('Sprague-Dawley rat', 'Species', '10116', (88, 106))	('increased', 'PosReg', (60, 69))	('poly(lactic-co-glycolic acid)', 'Chemical', 'MESH:D000077182', (14, 43))	('rat', 'Species', '10116', (51, 54))
94990	33671796	The use of nanoparticles also faces challenges such as immune response, blood flow, red blood cells hemolysis, and substantial tissue resistance, preventing nanoparticles from being internalized cellularly, particularly in the nano-drug diffusion in vivo model.	('hemolysis', 'Disease', (100, 109))	('preventing', 'NegReg', (146, 156))	('hemolysis', 'Disease', 'MESH:D006461', (100, 109))	('blood cells hemolysis', 'Phenotype', 'HP:0001878', (88, 109))	('nanoparticles', 'Var', (157, 170))
94992	33671796	Similarly, intraperitoneal administration of pegylated liposomal Tmz in glioma bearing male Lewis rats and in vitro study (CNS-1 glioma cancer cells) demonstrated prolonged survival and decreased tumor volume.	('tumor', 'Disease', (196, 201))	('pegylated liposomal', 'Var', (45, 64))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Tmz', 'Chemical', 'MESH:D000077204', (65, 68))	('glioma cancer', 'Disease', 'MESH:D009369', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('rats', 'Species', '10116', (98, 102))	('rat', 'Species', '10116', (157, 160))	('glioma', 'Disease', (129, 135))	('survival', 'CPA', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Disease', (72, 78))	('glioma cancer', 'Disease', (129, 142))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('prolonged', 'PosReg', (163, 172))	('rat', 'Species', '10116', (35, 38))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('decreased', 'NegReg', (186, 195))	('rat', 'Species', '10116', (98, 101))
95007	33671796	For instance, patients with triple-positive mutations (1p/19q codeletion, IDH mutation, and TERT promoter mutation) have a favorable prognosis, while patients with triple-negative mutation often have poorer prognoses.	('TERT', 'Gene', (92, 96))	('TERT', 'Gene', '7015', (92, 96))	('1p/19q codeletion', 'Var', (55, 72))	('patients', 'Species', '9606', (150, 158))	('IDH', 'Gene', (74, 77))	('IDH', 'Gene', '3417', (74, 77))	('patients', 'Species', '9606', (14, 22))
95013	33671796	The therapeutic agents which served as strong candidates for GBM with amplification of the EGFR gene include afatinib, dacomitinib, and propranolol.	('EGFR', 'Gene', (91, 95))	('dacomitinib', 'Chemical', 'MESH:C525726', (119, 130))	('propranolol', 'Chemical', 'MESH:D011433', (136, 147))	('afatinib', 'Chemical', 'MESH:D000077716', (109, 117))	('EGFR', 'Gene', '1956', (91, 95))	('amplification', 'Var', (70, 83))
95020	33671796	For CDKN2A deletion, the therapeutic agent of choice includes cyclin-dependent kinase (CDK) 4/6 inhibitors.	('deletion', 'Var', (11, 19))	('CDKN2A', 'Gene', (4, 10))	('CDKN2A', 'Gene', '1029', (4, 10))	('cyclin-dependent kinase (CDK) 4/6', 'Gene', '1019;1021', (62, 95))
95022	33671796	Using this GBM sample as an example, if an EGFR inhibitor that has activity against EGFRvIII and can penetrate the BBB is coupled with a CDK 4/6 inhibitor, it may serve as a potentially effective treatment strategy in this case.	('rat', 'Species', '10116', (208, 211))	('CDK 4/6', 'Gene', (137, 144))	('CDK 4/6', 'Gene', '1019;1021', (137, 144))	('EGFRvIII', 'Gene', (84, 92))	('inhibitor', 'Var', (48, 57))	('EGFR', 'Gene', '1956', (84, 88))	('activity', 'MPA', (67, 75))	('EGFR', 'Gene', '1956', (43, 47))	('EGFRvIII', 'Gene', '1351', (84, 92))	('rat', 'Species', '10116', (106, 109))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', (43, 47))
95023	33671796	Another recurrent GBM sample exhibited mutation of BRAF V600E gene, deletion of TSC2, FANCA and RECQL5 genes.	('FANCA', 'Gene', '2175', (86, 91))	('TSC2', 'Gene', '7249', (80, 84))	('deletion', 'Var', (68, 76))	('BRAF', 'Gene', '673', (51, 55))	('TSC2', 'Gene', (80, 84))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('RECQL5', 'Gene', '9400', (96, 102))	('RECQL5', 'Gene', (96, 102))	('BRAF', 'Gene', (51, 55))	('FANCA', 'Gene', (86, 91))
95024	33671796	These deletions and mutation can cause the activation of both the MAPK and P13K/mTOR signaling pathways.	('mTOR', 'Gene', (80, 84))	('activation', 'PosReg', (43, 53))	('mTOR', 'Gene', '2475', (80, 84))	('mutation', 'Var', (20, 28))	('deletions', 'Var', (6, 15))	('P13K', 'Mutation', 'p.P13K', (75, 79))	('MAPK', 'Pathway', (66, 70))
95054	30744596	Deficits of some, predominantly low-grade, tumours or differences in their age distribution compared with the United States and Nordic countries are compatible with delayed diagnosis.	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('differences', 'Reg', (54, 65))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', (43, 50))	('low-grade', 'Var', (32, 41))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))
95073	30744596	Definitions for four existing codes were expanded in line with the 2007 WHO Classification: 8290/0 includes spindle-cell oncocytoma, 9471/3 includes medulloblastoma with extensive nodularity, 9474/3 includes anaplastic medulloblastoma, and 9506/1 includes extraventricular neurocytoma and cerebellar liponeurocytoma.	('medulloblastoma', 'Disease', (149, 164))	('neurocytoma', 'Phenotype', 'HP:0030064', (304, 315))	('medulloblastoma', 'Disease', 'MESH:D008527', (219, 234))	('medulloblastoma', 'Phenotype', 'HP:0002885', (219, 234))	('neurocytoma', 'Phenotype', 'HP:0030064', (273, 284))	('9474/3', 'Var', (192, 198))	('spindle-cell oncocytoma', 'Disease', (108, 131))	('medulloblastoma', 'Disease', 'MESH:D008527', (149, 164))	('medulloblastoma', 'Phenotype', 'HP:0002885', (149, 164))	('medulloblastoma', 'Disease', (219, 234))	('neurocytoma and cerebellar liponeurocytoma', 'Disease', 'MESH:D018306', (273, 315))	('9471/3', 'Var', (133, 139))
95239	30744596	some cases of brainstem glioma or diffuse intrinsic pontine glioma could be redefined as diffuse midline glioma H3 K27 M-mutant.	('brainstem glioma', 'Disease', 'MESH:D005910', (14, 30))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('brainstem glioma', 'Phenotype', 'HP:0010796', (14, 30))	('midline glioma', 'Disease', 'MESH:D005910', (97, 111))	('midline glioma', 'Disease', (97, 111))	('glioma', 'Disease', (105, 111))	('glioma', 'Disease', (60, 66))	('brainstem glioma', 'Disease', (14, 30))	('glioma', 'Disease', (24, 30))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('H3 K27 M-mutant', 'Var', (112, 127))	('K27 M', 'Mutation', 'p.K27M', (115, 120))
95251	30524204	Dysregulation of A-to-I editing has been found associated with a number of nervous system diseases.	('Dysregulation', 'Var', (0, 13))	('nervous system diseases', 'Disease', 'MESH:D009422', (75, 98))	('associated', 'Reg', (47, 57))	('A-to-I editing', 'Protein', (17, 31))	('nervous system diseases', 'Disease', (75, 98))
95256	30524204	Moreover, the characteristic of GRIA2Q607R editing in gliomas has been investigated.	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('GRIA2Q607R', 'Var', (32, 42))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
95258	30524204	ADAR3 was characteristically highly expressed in neural subtype and IDH1/2 mutant preference.	('IDH1/2', 'Gene', (68, 74))	('IDH1/2', 'Gene', '3417;3418', (68, 74))	('ADAR3', 'Gene', (0, 5))	('mutant', 'Var', (75, 81))
95259	30524204	Moreover, high expression of ADAR3 predicted a better prognosis in lower-grade glioma (LGG) patients and multivariate analysis suggested ADAR3 expression was an independent prognostic indicator.	('better', 'PosReg', (47, 53))	('glioma', 'Disease', (79, 85))	('patients', 'Species', '9606', (92, 100))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('high', 'Var', (10, 14))	('ADAR3', 'Gene', (29, 34))
95271	30524204	Studies over the past two decades have clarified several genetic alterations in gliomas, such as mutations in IDH1/2, TP53 and ATRX, TERT promoter mutation, MGMT promoter methylation and 1p/19q co-deletion, etc.	('mutations', 'Var', (97, 106))	('ATRX', 'Gene', (127, 131))	('TERT', 'Gene', (133, 137))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('TERT', 'Gene', '7015', (133, 137))	('ATRX', 'Gene', '546', (127, 131))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('IDH1/2', 'Gene', '3417;3418', (110, 116))	('TP53', 'Gene', '7157', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('TP53', 'Gene', (118, 122))	('MGMT', 'Gene', '4255', (157, 161))	('MGMT', 'Gene', (157, 161))	('IDH1/2', 'Gene', (110, 116))	('1p/19q co-deletion', 'Var', (187, 205))
95273	30524204	In the 2016 WHO classification of central nervous system (CNS) tumors, classification of diffuse gliomas (WHO Grade II-IV) has fundamentally changed: for the first time, a large subset of these tumors is now defined based on IDH1 or IDH2 mutation and co-deletion of chromosomal arms 1p and 19q.	('arms 1p', 'Gene', '3075', (278, 285))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IDH1', 'Gene', '3417', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Disease', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('mutation', 'Var', (238, 246))	('arms 1p', 'Gene', (278, 285))	('gliomas', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('IDH2', 'Gene', (233, 237))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (194, 200))	('IDH2', 'Gene', '3418', (233, 237))	('IDH1', 'Gene', (225, 229))	('co-deletion', 'Var', (251, 262))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('central nervous system (CNS) tumors', 'Disease', 'MESH:D016543', (34, 69))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (194, 200))
95276	30524204	The most predominant pattern of RNA editing converts adenosine to inosine (A-to-I) in coding and non-coding RNA sequences, which is mediated by ADAR enzymes.	('adenosine', 'MPA', (53, 62))	('editing', 'Var', (36, 43))	('ADAR', 'Gene', (144, 148))	('adenosine', 'Chemical', 'MESH:D000241', (53, 62))	('inosine', 'Chemical', 'MESH:D007288', (66, 73))	('ADAR', 'Gene', '103', (144, 148))
95278	30524204	Changes in the A-to-I editing have been associated with a number of human diseases, such as amyotrophic lateral sclerosis (ALS), transient forebrain ischemia, epilepsy, metastatic melanoma, glioblastoma (GBM, WHO grade IV) and hepatocellular carcinoma (HCC).	('human', 'Species', '9606', (68, 73))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (190, 202))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (92, 121))	('associated', 'Reg', (40, 50))	('forebrain ischemia', 'Disease', (139, 157))	('epilepsy', 'Disease', 'MESH:D004827', (159, 167))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (227, 251))	('HCC', 'Phenotype', 'HP:0001402', (253, 256))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (92, 121))	('WHO', 'Disease', (209, 212))	('amyotrophic lateral sclerosis', 'Disease', (92, 121))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (227, 251))	('epilepsy', 'Phenotype', 'HP:0001250', (159, 167))	('forebrain ischemia', 'Disease', 'MESH:D007511', (139, 157))	('epilepsy', 'Disease', (159, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (190, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('hepatocellular carcinoma', 'Disease', (227, 251))	('Changes', 'Var', (0, 7))	('ALS', 'Phenotype', 'HP:0007354', (123, 126))	('glioblastoma', 'Disease', (190, 202))
95281	30524204	Recently, ADAR3 was proved to directly compete with ADAR2 for binding to GRIA2 pre-mRNA, inhibiting RNA editing at the Q607R editing site of GRIA2 in GBM cell line.	('Q607R', 'Mutation', 'rs17850674', (119, 124))	('GRIA2', 'Gene', (141, 146))	('GRIA2', 'Gene', (73, 78))	('inhibiting', 'NegReg', (89, 99))	('GRIA2', 'Gene', '2891', (141, 146))	('RNA editing', 'MPA', (100, 111))	('GRIA2', 'Gene', '2891', (73, 78))	('Q607R', 'Var', (119, 124))
95311	30524204	Then we investigated the correlation between ADAR3 mRNA expression level and IDH1 or/and IDH2 (IDH) mutation, which is a canonical indicator of glioma.	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('ADAR3 mRNA expression level', 'MPA', (45, 72))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH', 'Gene', '3418', (89, 92))	('investigated', 'Reg', (8, 20))	('IDH1', 'Gene', (77, 81))	('mutation', 'Var', (100, 108))	('IDH', 'Gene', '3418', (95, 98))	('glioma', 'Disease', (144, 150))	('IDH', 'Gene', (77, 80))	('IDH2', 'Gene', (89, 93))	('IDH', 'Gene', (89, 92))	('IDH', 'Gene', (95, 98))	('IDH1', 'Gene', '3417', (77, 81))	('IDH', 'Gene', '3418', (77, 80))	('IDH2', 'Gene', '3418', (89, 93))
95312	30524204	The patients with mutant IDH (IDH-mut) showed much stronger expression of ADAR3 than those with wildtype IDH (IDH-wt) in CGGA and TCGA datasets (Fig.	('ADAR3', 'Gene', (74, 79))	('expression', 'MPA', (60, 70))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', '3418', (110, 113))	('mutant', 'Var', (18, 24))	('stronger', 'PosReg', (51, 59))	('IDH-wt', 'Gene', (110, 116))	('IDH-wt', 'Gene', '3418', (110, 116))	('IDH', 'Gene', (105, 108))	('IDH', 'Gene', (30, 33))	('patients', 'Species', '9606', (4, 12))	('IDH', 'Gene', '3418', (105, 108))	('IDH', 'Gene', '3418', (30, 33))	('IDH', 'Gene', '3418', (25, 28))
95314	30524204	ADAR3 expression was highest in LGG IDH-mut and 1p/19q codeleted stratified patients (Fig.	('patients', 'Species', '9606', (76, 84))	('1p/19q', 'Var', (48, 54))	('expression', 'MPA', (6, 16))	('highest', 'Reg', (21, 28))	('IDH', 'Gene', (36, 39))	('ADAR3', 'Gene', (0, 5))	('IDH', 'Gene', '3418', (36, 39))
95318	30524204	Consistent with the above results, lower WHO grade, neural subtype and IDH mutants are enriched in higher ADAR3 expression (P < 0.0001).	('higher', 'PosReg', (99, 105))	('mutants', 'Var', (75, 82))	('ADAR3', 'Protein', (106, 111))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3418', (71, 74))	('expression', 'MPA', (112, 122))
95319	30524204	Meanwhile, deletion of 1p or/and 19q, confirming favorable prognostic indicators, aggregated in gliomas with higher ADAR3 expression (P < 0.0001).	('expression', 'MPA', (122, 132))	('ADAR3', 'Gene', (116, 121))	('higher', 'PosReg', (109, 115))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('deletion', 'Var', (11, 19))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
95325	30524204	Moreover, the similar trend was observed in LGG IDH-mut and 1p/19q non-codeleted and LGG IDH-wt patients (P = 6e - 04, P = 0.0043, Fig.	('IDH-wt', 'Gene', (89, 95))	('IDH-wt', 'Gene', '3418', (89, 95))	('IDH', 'Gene', (48, 51))	('IDH', 'Gene', '3418', (48, 51))	('IDH', 'Gene', '3418', (89, 92))	('IDH', 'Gene', (89, 92))	('patients', 'Species', '9606', (96, 104))	('1p/19q', 'Var', (60, 66))
95326	30524204	CDKN2A loss is associated with shorter overall survival in LGG IDH-mut and 1p/19q non-codeleted patients.	('IDH', 'Gene', '3418', (63, 66))	('loss', 'NegReg', (7, 11))	('CDKN2A', 'Gene', '1029', (0, 6))	('IDH', 'Gene', (63, 66))	('shorter', 'NegReg', (31, 38))	('overall survival', 'MPA', (39, 55))	('patients', 'Species', '9606', (96, 104))	('1p/19q', 'Var', (75, 81))	('CDKN2A', 'Gene', (0, 6))
95332	30524204	As shown in Table 2, factors including age at diagnosis, WHO Grade, ADAR3 expression, MGMT promoter methylation, IDH1/2 mutation status and radiotherapy were significantly associated with the OS of glioma patients.	('expression', 'MPA', (74, 84))	('patients', 'Species', '9606', (205, 213))	('MGMT', 'Gene', (86, 90))	('glioma', 'Disease', (198, 204))	('MGMT', 'Gene', '4255', (86, 90))	('ADAR3', 'Gene', (68, 73))	('mutation', 'Var', (120, 128))	('associated with', 'Reg', (172, 187))	('IDH1/2', 'Gene', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('OS', 'Chemical', '-', (192, 194))	('IDH1/2', 'Gene', '3417;3418', (113, 119))
95344	30524204	For analysis relationship between the Q607R editing level and ADAR family expression level in glioma samples, we first calculated the editing level of Q607R site in GRIA2 based on CGGA RNAseq database.	('GRIA2', 'Gene', '2891', (165, 170))	('Q607R', 'Var', (151, 156))	('glioma', 'Disease', (94, 100))	('ADAR', 'Gene', '103', (62, 66))	('Q607R', 'Mutation', 'rs17850674', (38, 43))	('Q607R', 'Mutation', 'rs17850674', (151, 156))	('ADAR', 'Gene', (62, 66))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('GRIA2', 'Gene', (165, 170))
95345	30524204	Compared to Grade II gliomas, the editing level of GRIA2Q607R is lower in Grade IV (P < 0.05, Fig.	('II gliomas', 'Disease', 'MESH:D005910', (18, 28))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('lower', 'NegReg', (65, 70))	('GRIA2Q607R', 'Var', (51, 61))	('II gliomas', 'Disease', (18, 28))	('Grade IV', 'Disease', (74, 82))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('editing level', 'MPA', (34, 47))
95346	30524204	Meanwhile, the Q607R editing is related with different molecular subtype of glioma.	('related', 'Reg', (32, 39))	('glioma', 'Disease', (76, 82))	('Q607R', 'Var', (15, 20))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Q607R', 'Mutation', 'rs17850674', (15, 20))
95347	30524204	Differential editing level at Q607R in GRIA2 has been identified in different TCGA subtypes (Anova, P = 5e-6, Fig.	('Q607R', 'Mutation', 'rs17850674', (30, 35))	('GRIA2', 'Gene', '2891', (39, 44))	('Q607R', 'Var', (30, 35))	('GRIA2', 'Gene', (39, 44))
95348	30524204	And the Q607R editing level is lower in IDH-mut glioma (P < 0.05, Fig.	('editing level', 'MPA', (14, 27))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('Q607R', 'Var', (8, 13))	('lower', 'NegReg', (31, 36))	('IDH', 'Gene', (40, 43))	('IDH', 'Gene', '3418', (40, 43))	('Q607R', 'Mutation', 'rs17850674', (8, 13))	('glioma', 'Disease', (48, 54))
95349	30524204	Moreover, the low Q607R editing level indicted a shorter overall survival time (Log-rank test, P = 0.0425, Fig.	('Q607R', 'Mutation', 'rs17850674', (18, 23))	('overall survival time', 'CPA', (57, 78))	('shorter', 'NegReg', (49, 56))	('low Q607R', 'Var', (14, 23))	('Q607R', 'Var', (18, 23))
95350	30524204	These results indicated that underediting of Q607R site in GRIA2 is a malignant marker for glioma based on a large cohort analysis.	('GRIA2', 'Gene', '2891', (59, 64))	('Q607R', 'Mutation', 'rs17850674', (45, 50))	('GRIA2', 'Gene', (59, 64))	('glioma', 'Disease', (91, 97))	('Q607R site', 'Var', (45, 55))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
95355	30524204	ADAR1 deficient mice die during embryonic development, owing to defective hematopoiesis, widespread apoptosis, liver disintegration and an increasing activity of interferon signaling.	('ADAR1', 'Gene', (0, 5))	('defective hematopoiesis', 'Disease', 'MESH:C536227', (64, 87))	('defective hematopoiesis', 'Phenotype', 'HP:0010972', (64, 87))	('deficient', 'Var', (6, 15))	('interferon', 'Pathway', (162, 172))	('increasing', 'PosReg', (139, 149))	('mice', 'Species', '10090', (16, 20))	('liver disintegration', 'CPA', (111, 131))	('activity', 'MPA', (150, 158))	('defective hematopoiesis', 'Disease', (64, 87))
95358	30524204	Currently, mutations or changes in expression induced disorder of ADAR activity have been linked to a variety of human diseases, ranging from neurological and neurodegenerative diseases, metabolic diseases, viral infections, autoimmune disorders to cancers.	('autoimmune disorders to cancers', 'Disease', 'MESH:D001327', (225, 256))	('mutations', 'Var', (11, 20))	('linked', 'Reg', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (159, 185))	('expression', 'MPA', (35, 45))	('metabolic diseases', 'Disease', (187, 205))	('viral infections', 'Disease', 'MESH:D001102', (207, 223))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (159, 185))	('human', 'Species', '9606', (113, 118))	('ADAR', 'Gene', (66, 70))	('autoimmune disorders to cancers', 'Disease', (225, 256))	('activity', 'MPA', (71, 79))	('viral infections', 'Disease', (207, 223))	('neurodegenerative diseases', 'Disease', (159, 185))	('changes in', 'Var', (24, 34))	('metabolic diseases', 'Disease', 'MESH:D008659', (187, 205))	('ADAR', 'Gene', '103', (66, 70))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (225, 245))
95360	30524204	ADAR2 promotes CDC14B editing and overexpression in astrocytoma cells, leading to Skp2 degradation and upregulation of p21 and p27 proteins, consequently causing cells to accumulate in the G1 phase of the cell cycle.	('Skp2', 'Gene', (82, 86))	('CDC14B', 'Gene', (15, 21))	('p21', 'Gene', '644914', (119, 122))	('upregulation', 'PosReg', (103, 115))	('p27', 'Gene', (127, 130))	('editing', 'Var', (22, 29))	('p27', 'Gene', '3429', (127, 130))	('degradation', 'MPA', (87, 98))	('ADAR2', 'Gene', (0, 5))	('astrocytoma', 'Disease', 'MESH:D001254', (52, 63))	('proteins', 'Protein', (131, 139))	('astrocytoma', 'Disease', (52, 63))	('CDC14B', 'Gene', '8555', (15, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('Skp2', 'Gene', '6502', (82, 86))	('accumulate', 'PosReg', (171, 181))	('p21', 'Gene', (119, 122))
95362	30524204	Meanwhile, the impaired ADAR2 activity in GBM inhibits a subset of onco-miRNAs (miR221, miR222, miR-21, miR-376a and miR-589-3p) editing, leading to tumor cells proliferation, migration and invasion.	('miR221', 'Gene', '407006', (80, 86))	('impaired', 'Var', (15, 23))	('invasion', 'CPA', (190, 198))	('miR-376a', 'Var', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('migration', 'CPA', (176, 185))	('miR-21', 'Gene', (96, 102))	('miR-589', 'Gene', '693174', (117, 124))	('miR222', 'Gene', '407007', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ADAR2 activity', 'Protein', (24, 38))	('miR221', 'Gene', (80, 86))	('inhibits', 'NegReg', (46, 54))	('tumor', 'Disease', (149, 154))	('miR-21', 'Gene', '406991', (96, 102))	('miR222', 'Gene', (88, 94))	('miR-589', 'Gene', (117, 124))	('leading to', 'Reg', (138, 148))
95368	30524204	Moreover, the ADAR3 expression level was significantly highest in the phenotype of known favorable molecular, such as neural subtype and LGG IDH-mut and 1p/19q codeleted stratified patients.	('IDH', 'Gene', (141, 144))	('IDH', 'Gene', '3418', (141, 144))	('ADAR3', 'Gene', (14, 19))	('1p/19q', 'Var', (153, 159))	('patients', 'Species', '9606', (181, 189))	('highest', 'Reg', (55, 62))	('expression level', 'MPA', (20, 36))
95372	30524204	After divided the patients into LGG and GBM subgroup, the high expression of ADAR3 is also a favorable indicator in LGG group, but not in GBM group.	('LGG', 'Disease', (116, 119))	('patients', 'Species', '9606', (18, 26))	('high', 'Var', (58, 62))	('ADAR3', 'Gene', (77, 82))
95373	30524204	Furthermore, the high expression of ADAR3 was associated with longer overall survival time in LGG IDH-mut and 1p/19q non-codeleted and LGG IDH-wt patients.	('IDH', 'Gene', '3418', (139, 142))	('overall survival', 'MPA', (69, 85))	('ADAR3', 'Gene', (36, 41))	('longer', 'PosReg', (62, 68))	('IDH-wt', 'Gene', (139, 145))	('high expression', 'Var', (17, 32))	('IDH-wt', 'Gene', '3418', (139, 145))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', '3418', (98, 101))	('patients', 'Species', '9606', (146, 154))
95379	30524204	The reduced GRIA2 editing at Q607R site has been observed in malignant gliomas, and the unedited GRIA2 protein promotes cell migration and invasion in these cell lines.	('malignant gliomas', 'Disease', 'MESH:D005910', (61, 78))	('invasion', 'CPA', (139, 147))	('reduced', 'NegReg', (4, 11))	('GRIA2', 'Gene', (97, 102))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('GRIA2', 'Gene', (12, 17))	('malignant gliomas', 'Disease', (61, 78))	('GRIA2', 'Gene', '2891', (97, 102))	('promotes', 'PosReg', (111, 119))	('GRIA2', 'Gene', '2891', (12, 17))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('Q607R', 'Mutation', 'rs17850674', (29, 34))	('editing', 'Var', (18, 25))	('cell migration', 'CPA', (120, 134))
95380	30524204	reported that overexpression of ADAR3 inhibited RNA editing at the Q607R site of GRIA2 in astrocyte and astrocytoma cell lines, which indicted the competitive inhibition of ADAR2 with ADAR3 on this site.	('astrocytoma', 'Disease', 'MESH:D001254', (104, 115))	('ADAR3', 'Gene', (32, 37))	('astrocytoma', 'Disease', (104, 115))	('inhibited', 'NegReg', (38, 47))	('Q607R', 'Var', (67, 72))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('GRIA2', 'Gene', (81, 86))	('GRIA2', 'Gene', '2891', (81, 86))	('Q607R', 'Mutation', 'rs17850674', (67, 72))	('RNA editing', 'MPA', (48, 59))
95381	30524204	These results indicated that the regulation of GRIA2 editing in gliomas is a more complex model than previous studies, and the tumor suppressor role of ADAR3 may partly related with the underedited level of Q607R.	('GRIA2 editing in gliomas', 'Disease', 'MESH:D005910', (47, 71))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('ADAR3', 'Gene', (152, 157))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('Q607R', 'Var', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Q607R', 'Mutation', 'rs17850674', (207, 212))	('GRIA2 editing in gliomas', 'Disease', (47, 71))
95392	29164057	MET-PET is not widely used in the United States, though clinical trials from Japan and Germany suggesting the diagnostic ability of MET-PET imaging are superior to FDG-PET imaging for brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (184, 196))	('brain tumors', 'Disease', (184, 196))	('brain tumor', 'Phenotype', 'HP:0030692', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('MET-PET', 'Var', (132, 139))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('FDG', 'Chemical', 'MESH:D019788', (164, 167))	('brain tumors', 'Phenotype', 'HP:0030692', (184, 196))
95412	29164057	Previous studies have reported gliomas are frequently associated with abnormalities in chromosome 9 and the MTAP locus is located at 9p21.3.	('MTAP', 'Gene', (108, 112))	('abnormalities', 'Var', (70, 83))	('MTAP', 'Gene', '4507', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('associated', 'Reg', (54, 64))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
95413	29164057	The shortest region of overlap of the deletions maps in the interval between the centromeric end of the interferon gene cluster and MTAP gene.	('MTAP', 'Gene', (132, 136))	('MTAP', 'Gene', '4507', (132, 136))	('deletions', 'Var', (38, 47))
95418	29164057	In general, GBMs lack expression of the enzyme MTAP, due to either deletion or methylation of the MTAP promoter.	('deletion', 'Var', (67, 75))	('MTAP', 'Gene', (47, 51))	('MTAP', 'Gene', (98, 102))	('methylation', 'Var', (79, 90))	('expression', 'MPA', (22, 32))	('MTAP', 'Gene', '4507', (47, 51))	('MTAP', 'Gene', '4507', (98, 102))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('lack', 'NegReg', (17, 21))
95420	29164057	Copy number assays carried out on U87, U118, LN18, and LN229 GBM cell lines showed a value of "0" for U87, U118, and LN18 and "1" for LN229.	('LN229', 'CellLine', 'CVCL:0393', (55, 60))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('U87', 'Var', (102, 105))	('LN18', 'Var', (117, 121))	('LN229', 'CellLine', 'CVCL:0393', (134, 139))	('U118', 'Var', (107, 111))
95437	29164057	The methionine dependency and its role in cancer growth control can be achieved using the methionine restriction strategy, particularly in cancers that require methionine for survival and proliferation.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('methionine restriction', 'Var', (90, 112))	('methionine', 'Chemical', 'MESH:D008715', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('methionine', 'Chemical', 'MESH:D008715', (4, 14))	('methionine', 'Chemical', 'MESH:D008715', (90, 100))	('cancer', 'Disease', (139, 145))
95449	29164057	Previous studies have shown that methionine has higher specificity and sensitivity in PET imaging than 18F-FDG, which may be helpful for brain tumor detection, tumor delineation, and differential diagnosis of suspected glioma recurrence.	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('brain tumor', 'Disease', (137, 148))	('glioma', 'Disease', 'MESH:D005910', (219, 225))	('brain tumor', 'Disease', 'MESH:D001932', (137, 148))	('methionine', 'Var', (33, 43))	('brain tumor', 'Phenotype', 'HP:0030692', (137, 148))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('specificity', 'MPA', (55, 66))	('tumor delineation', 'Disease', 'MESH:D009369', (160, 177))	('sensitivity', 'MPA', (71, 82))	('tumor delineation', 'Disease', (160, 177))	('glioma', 'Disease', (219, 225))	('18F-FDG', 'Chemical', '-', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('methionine', 'Chemical', 'MESH:D008715', (33, 43))
95452	29164057	FDG-PET portrayed malignant tumors as hot spots but was not able to delineate the extent of the tumor, whereas MET-PET, regardless of the degree of malignancy, outlined the tumors clearly as areas of increased 11C-methionine accumulation.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('11C-methionine accumulation', 'MPA', (210, 237))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('FDG', 'Chemical', 'MESH:D019788', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('MET-PET', 'Var', (111, 118))	('malignancy', 'Disease', 'MESH:D009369', (148, 158))	('tumors', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('methionine accumulation', 'Phenotype', 'HP:0003235', (214, 237))	('malignant tumors', 'Disease', 'MESH:D018198', (18, 34))	('tumors', 'Disease', (28, 34))	('increased', 'PosReg', (200, 209))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('malignancy', 'Disease', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('11C-methionine', 'Chemical', '-', (210, 224))	('malignant tumors', 'Disease', (18, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Disease', (173, 178))
95461	29164057	Methionine was reported as the more sensitive and selective radiotracer in evaluating tumor recurrence by comparing FDG-PET and MET-PET.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('MET-PET', 'Var', (128, 135))	('FDG', 'Chemical', 'MESH:D019788', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('FDG-PET', 'Var', (116, 123))
95471	29164057	Another study demonstrated the potential of combining MET-PET/MRI for assessing suspected primary brain tumors by comparing PET/MRI vs. MRI and reported a significant improvement in diagnostic confidence.	('diagnostic confidence', 'CPA', (182, 203))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('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))	('PET/MRI', 'Var', (124, 131))	('improvement', 'PosReg', (167, 178))	('brain tumor', 'Phenotype', 'HP:0030692', (98, 109))
95473	29164057	Finding from MET-PET imaging significantly correlated with histological grade and IDH1 mutation status.	('IDH1', 'Gene', '3417', (82, 86))	('mutation', 'Var', (87, 95))	('correlated', 'Reg', (43, 53))	('IDH1', 'Gene', (82, 86))
95474	29164057	Meta-analysis of brain tumors MET-PET has excellent diagnostic accuracy in differentiating brain tumors, whereas FDG-PET has limited diagnostic performance.	('brain tumors', 'Disease', 'MESH:D001932', (91, 103))	('brain tumors', 'Phenotype', 'HP:0030692', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('brain tumors', 'Phenotype', 'HP:0030692', (17, 29))	('brain tumors', 'Disease', (91, 103))	('brain tumor', 'Phenotype', 'HP:0030692', (91, 102))	('brain tumors', 'Disease', 'MESH:D001932', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('brain tumors', 'Disease', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('brain tumor', 'Phenotype', 'HP:0030692', (17, 28))	('MET-PET', 'Var', (30, 37))	('FDG', 'Chemical', 'MESH:D019788', (113, 116))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
95482	29164057	However, it is important to note that methionine fulfills the criteria of a brain tumor tracer since it can cross the blood-brain barrier.	('methionine', 'Var', (38, 48))	('methionine', 'Chemical', 'MESH:D008715', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('brain tumor', 'Disease', (76, 87))	('brain tumor', 'Disease', 'MESH:D001932', (76, 87))	('brain tumor', 'Phenotype', 'HP:0030692', (76, 87))
95489	29164057	In 31 pediatric high-grade gliomas, MET-PET delineates non-contrast enhancing tumors and identified regions having increased risk for recurrence and this prognostic power of MET-PET may lead to a better assessment for radiotherapy.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('lead to', 'Reg', (186, 193))	('MET-PET', 'Var', (174, 181))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('gliomas', 'Disease', (27, 34))	('non-contrast', 'MPA', (55, 67))
95492	29164057	By assessing imaging on treatment volumes and clinical outcome, investigators report that MET-PET/CT has a significant impact on radiation therapy planning, and appears to be a predictor of clinical outcome in that group of patients.	('MET-PET/CT', 'Var', (90, 100))	('impact', 'Reg', (119, 125))	('radiation therapy planning', 'CPA', (129, 155))	('patients', 'Species', '9606', (224, 232))
95493	29164057	A study comparing the MET-PET and MRI imaging modalities in a trial of 39 patients with resected gliomas show that MET-PET has a greater specificity to outline the gross tumor volume with greater accuracy.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('MET-PET', 'Var', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
95494	29164057	They have also shown that sparing of normal brain tissue can be achieved by integrating MET-PET in tumor volume delineation.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor volume delineation', 'Disease', (99, 123))	('MET-PET', 'Var', (88, 95))	('tumor volume delineation', 'Disease', 'MESH:D009369', (99, 123))
95495	29164057	Among PET, MET-PET has a greater resolution (3-4 mm) than 123I-alpha-methyl tyrosine-single photon computed emission tomography (7 mm) and is more appropriate for use with high precision radiation techniques.	('123I-alpha-methyl tyrosine', 'Chemical', '-', (58, 84))	('MET-PET', 'Var', (11, 18))	('resolution', 'MPA', (33, 43))
95500	29164057	Methionine can alter translational (protein), transcriptional (RNA), and epigenetic (DNA) status of cells.	('transcriptional', 'MPA', (46, 61))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('Methionine', 'Var', (0, 10))	('epigenetic', 'MPA', (73, 83))	('alter', 'Reg', (15, 20))
95501	29164057	Methionine is the substrate for principle methyl donor S-adenosylmethionine (SAM) and variations in SAM levels can lead to hypo-/hypermethylation of DNA.	('donor', 'Species', '9606', (49, 54))	('DNA', 'Protein', (149, 152))	('SAM', 'Chemical', 'MESH:D012436', (100, 103))	('hypo-/hypermethylation', 'MPA', (123, 145))	('variations', 'Var', (86, 96))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('SAM', 'Chemical', 'MESH:D012436', (77, 80))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (55, 75))	('lead to', 'Reg', (115, 122))
95506	29164057	During methylation, SAM transfers methyl groups and is then converted to S-adenosylhomocysteine (SAH).	('SAM', 'Chemical', 'MESH:D012436', (20, 23))	('S-adenosylhomocysteine', 'Chemical', 'MESH:D012435', (73, 95))	('methylation', 'Var', (7, 18))	('methyl groups', 'MPA', (34, 47))
95509	29164057	Biochemically after methionine uptake, methionine enters the methionine metabolic cycle.	('methionine', 'Chemical', 'MESH:D008715', (39, 49))	('methionine', 'Chemical', 'MESH:D008715', (61, 71))	('methionine', 'Chemical', 'MESH:D008715', (20, 30))	('methionine', 'Var', (39, 49))	('methionine metabolic cycle', 'MPA', (61, 87))
95529	29164057	Any change in the status (hyperactive/hypoactive/inactive states) of enzymes due to the mutations that occur in these enzymes during cancer progression could potentially alter the methionine uptake.	('methionine uptake', 'MPA', (180, 197))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('mutations', 'Var', (88, 97))	('change', 'Reg', (4, 10))	('cancer', 'Disease', (133, 139))	('methionine', 'Chemical', 'MESH:D008715', (180, 190))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('alter', 'Reg', (170, 175))
95538	33459509	Epigenetic modifications in LGGs appear tightly linked to patient clinical outcomes but are not commonly used as clinical tools.	('patient', 'Species', '9606', (58, 65))	('Epigenetic modifications', 'Var', (0, 24))	('LGGs', 'Gene', (28, 32))	('linked', 'Reg', (48, 54))
95540	33459509	The signature was also significantly associated with malignant molecular signatures including wild-type IDH, unmethylated MGMT promoter, and non-codeletion of 1p19q together with linkage to multiple oncogenic pathways.	('IDH', 'Gene', (104, 107))	('malignant molecular signatures', 'MPA', (53, 83))	('IDH', 'Gene', '3417', (104, 107))	('non-codeletion', 'Var', (141, 155))	('associated', 'Reg', (37, 47))	('MGMT', 'Gene', (122, 126))	('MGMT', 'Gene', '4255', (122, 126))
95542	33459509	We report a novel epigenetic gene signature that harbors robust survival prediction value for LGG patients that is tightly linked to activation of multiple oncogenic pathways.	('LGG', 'Disease', (94, 97))	('epigenetic gene', 'Var', (18, 33))	('patients', 'Species', '9606', (98, 106))
95543	33459509	We identified an epigenetic enzyme gene signature in LGG (lower-grade glioma) patients that harbors high predictive value of patient's outcome.	('glioma', 'Disease', (70, 76))	('patient', 'Species', '9606', (78, 85))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('patients', 'Species', '9606', (78, 86))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('LGG', 'Gene', (53, 56))	('patient', 'Species', '9606', (125, 132))	('epigenetic', 'Var', (17, 27))
95553	33459509	Further evidence also shows that codeletion of 1p/19q with hypermethylation of the MGMT promoter is critical prognostic factor in LGGs.	('MGMT', 'Gene', '4255', (83, 87))	('hypermethylation', 'Var', (59, 75))	('MGMT', 'Gene', (83, 87))	('codeletion', 'Var', (33, 43))	('LGGs', 'Disease', (130, 134))
95557	33459509	Epigenetic alterations are now widely recognized as a cancer hallmark.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (54, 60))
95559	33459509	9  Many epigenetic regulators with oncogenic properties have been intensively investigated in past studies, for example, IDH1 mutations in glioma have been linked with a hypermethylation phenotype which induces global gene expression alterations.	('hypermethylation', 'MPA', (170, 186))	('IDH1', 'Gene', (121, 125))	('glioma', 'Disease', (139, 145))	('IDH1', 'Gene', '3417', (121, 125))	('linked', 'Reg', (156, 162))	('induces', 'Reg', (203, 210))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('mutations', 'Var', (126, 135))	('global gene expression alterations', 'MPA', (211, 245))
95560	33459509	10 ,  11  Moreover, accumulating evidence shows that epigenetic modifications are tightly linked with the elevated adaptiveness of cancer cells to the harsh tumor microenvironment, together with their increased invasiveness, therapeutic resistance, and recurrence.	('cancer', 'Disease', (131, 137))	('tumor', 'Disease', (157, 162))	('adaptiveness', 'CPA', (115, 127))	('linked', 'Reg', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('elevated', 'PosReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('epigenetic modifications', 'Var', (53, 77))
95561	33459509	12 ,  13 ,  14  Instructively, studies have also revealed that the cellular plasticity of glioma cells is highly dependent on epigenetic modifications and their intercellular crosstalk within the microenvironment.	('glioma', 'Disease', (90, 96))	('dependent', 'Reg', (113, 122))	('epigenetic modifications', 'Var', (126, 150))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('cellular plasticity', 'CPA', (67, 86))
95562	33459509	The current study focused on deriving an epigenetic gene signature that can predict LGG patient outcomes.	('patient', 'Species', '9606', (88, 95))	('predict', 'Reg', (76, 83))	('epigenetic gene', 'Var', (41, 56))	('LGG', 'Disease', (84, 87))
95574	33459509	In addition, the pathway enrichment analysis showed that the deregulated genes were tightly linked to a variety of oncogenic pathways, including cell cycle, Notch, FoxO, and metabolite-associated pathways (Figure 1B), indicating that intra-tumoral epigenetic status likely plays an important role in LGGs.	('cell cycle', 'Pathway', (145, 155))	('deregulated', 'Var', (61, 72))	('LGGs', 'Disease', (300, 304))	('linked', 'Reg', (92, 98))	('FoxO', 'Pathway', (164, 168))	('Notch', 'Pathway', (157, 162))	('intra-tumoral', 'Disease', 'MESH:D009369', (234, 247))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('metabolite-associated pathways', 'Pathway', (174, 204))	('oncogenic pathways', 'Pathway', (115, 133))	('intra-tumoral', 'Disease', (234, 247))
95581	33459509	ROC analyses comparing the performance of the risk signature against of IDH and 1p19q status (Figure S3A-C) showed that the risk score produced higher AUC values (0.874, 0.85, and 0.866 for 1, 2, and 3 years, respectively).	('AUC values', 'MPA', (151, 161))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('higher', 'PosReg', (144, 150))	('1p19q status', 'Var', (80, 92))
95588	33459509	Clinicopathological and genetic alterations, including age, sex, grade, IDH mutation status, MGMT promoter status, Chr.	('MGMT', 'Gene', '4255', (93, 97))	('MGMT', 'Gene', (93, 97))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (72, 75))	('mutation status', 'Var', (76, 91))
95589	33459509	1p19q status, TERT mutation status, and ATXR mutation status, are summarized in Table 1.	('TERT', 'Gene', '7015', (14, 18))	('TERT', 'Gene', (14, 18))	('1p19q', 'Var', (0, 5))
95590	33459509	As shown in Figure 3A, higher risk scores demonstrated stronger associative trends with older age, higher tumor grade, wild-type (WT) IDH, 1p19q non-codeletion (non-codel), and non-methylation of the MGMT promoter.	('IDH', 'Gene', '3417', (134, 137))	('MGMT', 'Gene', '4255', (200, 204))	('MGMT', 'Gene', (200, 204))	('associative', 'Interaction', (64, 75))	('1p19q non-codeletion', 'Var', (139, 159))	('non-methylation', 'Var', (177, 192))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('IDH', 'Gene', (134, 137))	('tumor', 'Disease', (106, 111))
95591	33459509	In addition, analyses using Pearson's chi-squared test (Table 2) demonstrated that higher risk score was significantly linked to higher tumor grades (grade III, p < 0.001), WT IDH (p < 0.001), non-codel status of 1p19q (p < 0.001), non-methylation status of the MGMT promoter (p < 0.001), and WT status of TERT (p < 0.001).	('MGMT', 'Gene', (262, 266))	('MGMT', 'Gene', '4255', (262, 266))	('non-methylation status', 'Var', (232, 254))	('IDH', 'Gene', (176, 179))	('non-codel status', 'Var', (193, 209))	('higher', 'PosReg', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IDH', 'Gene', '3417', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TERT', 'Gene', (306, 310))	('tumor', 'Disease', (136, 141))	('TERT', 'Gene', '7015', (306, 310))
95592	33459509	The univariate analysis showed that age, grade (II vs. III), IDH mutation status (mutant vs. WT), 1p19q status (codel vs. non-codel), MGMT promoter methylation status (methylated vs. unmethylated), and the risk score all derived significant hazard ratios (HR) in the TCGA data set (Table S3).	('1p19q status', 'Var', (98, 110))	('IDH', 'Gene', '3417', (61, 64))	('mutation', 'Var', (65, 73))	('MGMT', 'Gene', (134, 138))	('IDH', 'Gene', (61, 64))	('MGMT', 'Gene', '4255', (134, 138))	('mutant', 'Var', (82, 88))
95598	33459509	The latter finding suggests that epigenetic status could contribute to intra-tumoral immune heterogeneity, thereby contributing a critical role in the cellular interactions between tumor cells and immune cells.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('contribute', 'Reg', (57, 67))	('cellular', 'MPA', (151, 159))	('intra-tumoral', 'Disease', 'MESH:D009369', (71, 84))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('contributing', 'Reg', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('epigenetic status', 'Var', (33, 50))	('intra-tumoral', 'Disease', (71, 84))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', (77, 82))	('interactions', 'Interaction', (160, 172))
95600	33459509	23  In addition, MDSCs is a well-known cell population tightly linked with immune suppression in glioma, inducing T-cell apoptosis, Treg cell activation, and functional impairment of NK cells and active dendritic cells.	('MDSCs', 'Var', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (97, 103))	('activation', 'PosReg', (142, 152))	('functional impairment', 'CPA', (158, 179))	('inducing', 'PosReg', (105, 113))	('Treg cell', 'CPA', (132, 141))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('T-cell apoptosis', 'CPA', (114, 130))	('NK cells', 'CPA', (183, 191))
95605	33459509	Assessment of the in vitro growth of the U373 glioma cells demonstrated that their proliferative capacity was attenuated after SMYD2 silencing in comparison to the shNT-treated cells (Figure 6B).	('glioma', 'Disease', (46, 52))	('SMYD2', 'Gene', (127, 132))	('attenuated', 'NegReg', (110, 120))	('U373', 'CellLine', 'CVCL:2219', (41, 45))	('silencing', 'Var', (133, 142))	('proliferative capacity', 'CPA', (83, 105))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
95607	33459509	The outcome revealed a significantly prolonged survival time in the shSMYD2 group (Figure 6C) with serial bioluminescent imaging (Figure 6D and 6E) confirming that SMYD2 silencing attenuated the tumor forming ability and progression of xenografted glioma cells.	('survival time', 'CPA', (47, 60))	('glioma', 'Disease', (248, 254))	('tumor', 'Disease', (195, 200))	('silencing', 'Var', (170, 179))	('attenuated', 'NegReg', (180, 190))	('SMYD2', 'Gene', (164, 169))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('prolonged', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
95617	33459509	Recent evidence shows that the epigenetic modifications in tumor cells play a critical role in the progression of many cancers including gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('epigenetic modifications', 'Var', (31, 55))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('role', 'Reg', (87, 91))
95623	33459509	For instance, the mutation status of IDH1 and less commonly IDH2 has been well recognized as crucial factors for classification and prognostic prediction in LGGs.	('IDH2', 'Gene', (60, 64))	('IDH1', 'Gene', (37, 41))	('IDH2', 'Gene', '3418', (60, 64))	('IDH1', 'Gene', '3417', (37, 41))	('mutation', 'Var', (18, 26))	('LGGs', 'Disease', (157, 161))
95624	33459509	The mutation of IDH1 or IDH2 leads to the elevated production of the oncometabolite 2-hydroxyglutarate, which is thought to induce significant epigenetic alterations and promote the initiation and progression of tumor cells.	('production of the', 'MPA', (51, 68))	('progression', 'CPA', (197, 208))	('IDH2', 'Gene', '3418', (24, 28))	('initiation', 'CPA', (182, 192))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (84, 102))	('mutation', 'Var', (4, 12))	('induce', 'Reg', (124, 130))	('IDH1', 'Gene', (16, 20))	('IDH2', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('IDH1', 'Gene', '3417', (16, 20))	('elevated', 'PosReg', (42, 50))	('epigenetic alterations', 'MPA', (143, 165))	('tumor', 'Disease', (212, 217))	('promote', 'PosReg', (170, 177))
95632	33459509	38 ,  39 ,  40  In addition, one study found that positive expression of SMYD2 was associated with poor prognosis in patients with hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('positive expression', 'Var', (50, 69))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('hepatocellular carcinoma', 'Disease', (131, 155))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (131, 155))	('associated', 'Reg', (83, 93))	('patients', 'Species', '9606', (117, 125))	('SMYD2', 'Gene', (73, 78))
95652	32111869	The prediction models of MGMT methylation, IDH mutations, 1p/19q co-deletion, ATRX mutation, and TERT mutations achieve a test performance AUC of 0.83 +- 0.04, 0.84 +- 0.03, 0.80 +- 0.04, 0.70 +- 0.09, and 0.82 +- 0.04, respectively.	('IDH', 'Gene', '3417', (43, 46))	('ATRX', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (97, 101))	('methylation', 'Var', (30, 41))	('ATRX', 'Gene', '546', (78, 82))	('1p/19q', 'Gene', (58, 64))	('mutation', 'Var', (83, 91))	('TERT', 'Gene', (97, 101))	('MGMT', 'Gene', (25, 29))	('MGMT', 'Gene', '4255', (25, 29))	('IDH', 'Gene', (43, 46))
95653	32111869	Furthermore, our analysis shows that the fractal features have a significant effect on the predictive performance of MGMT methylation IDH mutations, 1p/19q co-deletion, and ATRX mutations.	('IDH', 'Gene', '3417', (134, 137))	('MGMT', 'Gene', (117, 121))	('ATRX', 'Gene', '546', (173, 177))	('MGMT', 'Gene', '4255', (117, 121))	('mutations', 'Var', (138, 147))	('ATRX', 'Gene', (173, 177))	('IDH', 'Gene', (134, 137))	('1p/19q co-deletion', 'Var', (149, 167))
95659	32111869	This new classification correlates well with patients' treatment and survival, for example, oligodendroglioma, defined by the 1p/19q co-deletion, are associated with longer survival compared to astrocytoma, which do not harbor the 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (126, 144))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('astrocytoma', 'Disease', 'MESH:D001254', (194, 205))	('oligodendroglioma', 'Disease', (92, 109))	('patients', 'Species', '9606', (45, 53))	('longer', 'PosReg', (166, 172))	('astrocytoma', 'Disease', (194, 205))	('oligodendroglioma', 'Disease', 'MESH:D009837', (92, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (194, 205))
95661	32111869	Isocitrate Dehydrogenase mutations, IDH1, and IDH2 have been found in gliomas, and classifying gliomas based on their molecular profiling of IDH status (mutated vs. wild-type) creates clinically distinct groups.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH2', 'Gene', (46, 50))	('IDH2', 'Gene', '3418', (46, 50))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('Isocitrate Dehydrogenase', 'Gene', (0, 24))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('mutations', 'Var', (25, 34))	('IDH', 'Gene', (141, 144))	('IDH', 'Gene', (46, 49))	('IDH1', 'Gene', (36, 40))	('IDH', 'Gene', '3417', (141, 144))	('IDH', 'Gene', (36, 39))	('gliomas', 'Disease', (95, 102))	('IDH', 'Gene', '3417', (46, 49))	('gliomas', 'Disease', (70, 77))	('Isocitrate Dehydrogenase', 'Gene', '3417', (0, 24))	('found', 'Reg', (61, 66))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('IDH1', 'Gene', '3417', (36, 40))	('IDH', 'Gene', '3417', (36, 39))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
95664	32111869	A 1p/19q co-deletion is considered as a molecular marker of oligodendroglioma and is associated with IDH mutation and improved survival.	('mutation', 'Var', (105, 113))	('improved', 'PosReg', (118, 126))	('oligodendroglioma', 'Disease', (60, 77))	('IDH', 'Gene', (101, 104))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH', 'Gene', '3417', (101, 104))	('oligodendroglioma', 'Disease', 'MESH:D009837', (60, 77))	('associated', 'Reg', (85, 95))
95665	32111869	Another mutation that is strongly associated with 1p/19q co-deletion is the mutations in the promoter region of the telomerase reverse transcriptase (TERT).	('mutations in', 'Var', (76, 88))	('TERT', 'Gene', (150, 154))	('TERT', 'Gene', '7015', (150, 154))	('telomerase reverse transcriptase', 'Gene', (116, 148))	('telomerase reverse transcriptase', 'Gene', '7015', (116, 148))
95668	32111869	In addition, ATRX mutation often occurs with IDH mutations and is almost mutually exclusive with 1p/19q co-deletion.	('occurs', 'Reg', (33, 39))	('IDH', 'Gene', (45, 48))	('ATRX', 'Gene', (13, 17))	('IDH', 'Gene', '3417', (45, 48))	('ATRX', 'Gene', '546', (13, 17))	('mutation', 'Var', (18, 26))
95670	32111869	Patients with a methylated MGMT promoter are associated with better overall survival.	('better', 'PosReg', (61, 67))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (68, 84))	('methylated', 'Var', (16, 26))	('MGMT', 'Gene', '4255', (27, 31))	('MGMT', 'Gene', (27, 31))
95686	32111869	Molecular alterations (IDH mutation, 1p/19q co-deletion, ATRX, and TERT mutation), grade (II and III), and clinical data are downloaded from the Genomic Data Commons Data Portal (https://portal.gdc.cancer.gov/).	('1p/19q co-deletion', 'Var', (37, 55))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('cancer', 'Disease', (198, 204))	('ATRX', 'Gene', '546', (57, 61))	('IDH', 'Gene', (23, 26))	('ATRX', 'Gene', (57, 61))	('IDH', 'Gene', '3417', (23, 26))
95687	32111869	The distribution of the data is as follows: (i) IDH mutation: 85 Mutant (of which 27 cases are co-deleted) and 23 wild-type (WT), (ii) 1p/19q co-deletion: 27 co-deletion and 81 non-co-deletion, (iii) ATRX status: 43 Mutant and 65 WT, (iv) TERT status: 46 Mutant and 62 WT, and (v) O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation: 91 methylated and 14 un-methylated.	('TERT', 'Gene', (239, 243))	('Mutant', 'Var', (65, 71))	('IDH', 'Gene', (48, 51))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (281, 319))	('O6-methylguanine-DNA methyltransferase', 'Gene', (281, 319))	('TERT', 'Gene', '7015', (239, 243))	('IDH', 'Gene', '3417', (48, 51))	('Mutant', 'Var', (255, 261))	('1p/19q', 'Var', (135, 141))	('MGMT', 'Gene', (321, 325))	('methylated', 'Var', (352, 362))	('MGMT', 'Gene', '4255', (321, 325))	('ATRX', 'Gene', (200, 204))	('co-deletion', 'Var', (158, 169))	('Mutant', 'Var', (216, 222))	('ATRX', 'Gene', '546', (200, 204))
95689	32111869	These molecular models include the IDH, 1p/19q co-deletion, MGMT, ATRX, and TERT prediction.	('1p/19q co-deletion', 'Var', (40, 58))	('TERT', 'Gene', '7015', (76, 80))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))	('MGMT', 'Gene', (60, 64))	('ATRX', 'Gene', (66, 70))	('MGMT', 'Gene', '4255', (60, 64))	('TERT', 'Gene', (76, 80))	('ATRX', 'Gene', '546', (66, 70))
95704	32111869	Whereas the tumor correlation associates significantly (ANOVA test, p-value < 0.005) with mutated IDH status as illustrated in Fig.	('mutated', 'Var', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('IDH', 'Gene', (98, 101))	('tumor', 'Disease', (12, 17))	('IDH', 'Gene', '3417', (98, 101))
95706	32111869	The clustering between the mutated IDH and WT IDH is demonstrated using t-Distributed Stochastic Neighbor Embedding (tSNE).	('mutated', 'Var', (27, 34))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (35, 38))	('IDH', 'Gene', '3417', (46, 49))
95717	32111869	Whereas Higher values of histogram mean are associated significantly (ANOVA test, p-value < 0.001) with mutated ATRX.	('Higher', 'PosReg', (8, 14))	('histogram', 'MPA', (25, 34))	('ATRX', 'Gene', (112, 116))	('mutated', 'Var', (104, 111))	('ATRX', 'Gene', '546', (112, 116))
95725	32111869	Molecular classification based on the status of IDH mutations and 1p/19q co-deletion results in distinguishing three LGG molecular subtypes that have a distinct clinical behavior: IDH WT, IDH mutant with 1p/19q co-deleted, and IDH mutant with 1p/19q non-co-deleted.	('IDH', 'Gene', '3417', (188, 191))	('IDH', 'Gene', (48, 51))	('IDH', 'Gene', (227, 230))	('IDH', 'Gene', '3417', (48, 51))	('IDH', 'Gene', (180, 183))	('IDH', 'Gene', '3417', (227, 230))	('1p/19q co-deleted', 'Var', (204, 221))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (188, 191))
95729	32111869	The distribution of the three molecular subtypes is as follows: 23 cases represent IDH WT, 27 cases represent IDH mutant with 1p/19q co-deleted, and 58 cases represent IDH mutant with 1p/19q non-co-deleted.	('1p/19q co-deleted', 'Var', (126, 143))	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', '3417', (168, 171))	('IDH', 'Gene', (83, 86))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', '3417', (83, 86))	('IDH', 'Gene', (168, 171))
95730	32111869	Our analysis using the Chi-square test confirms a significant association (p-value = 0.004) between IDH status and 1p/19q codeletion.	('IDH', 'Gene', '3417', (100, 103))	('IDH', 'Gene', (100, 103))	('1p/19q codeletion', 'Var', (115, 132))
95732	32111869	The association between IDH status and overall survival remains significant after stratifying for 1p/19q codeletion (likelihood ratio test p-value = 0.005).	('overall survival', 'MPA', (39, 55))	('1p/19q codeletion', 'Var', (98, 115))	('IDH', 'Gene', '3417', (24, 27))	('IDH', 'Gene', (24, 27))
95734	32111869	The 2016 WHO classification of diffuse LGGs heavily weighs molecular mutations classifying primary brain tumors with particular importance assigned to IDH mutation, 1p/19q co-deletion, ATRX mutation, TERT mutations, and MGMT methylation.	('MGMT', 'Gene', (220, 224))	('IDH', 'Gene', '3417', (151, 154))	('brain tumors', 'Disease', 'MESH:D001932', (99, 111))	('brain tumors', 'Phenotype', 'HP:0030692', (99, 111))	('ATRX', 'Gene', (185, 189))	('brain tumors', 'Disease', (99, 111))	('1p/19q co-deletion', 'Var', (165, 183))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutation', 'Var', (155, 163))	('ATRX', 'Gene', '546', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('TERT', 'Gene', (200, 204))	('TERT', 'Gene', '7015', (200, 204))	('MGMT', 'Gene', '4255', (220, 224))	('IDH', 'Gene', (151, 154))
95736	32111869	For the fractal and multi-resolution fractal texture model in Table 1, the AUC predictive performance of MGMT, 1p/19q co-deletion, and ATRX models drop to 0.83 +- 0.04, 0.80 +- 0.04, and 0.70 +- 0.09, respectively.	('ATRX', 'Gene', '546', (135, 139))	('ATRX', 'Gene', (135, 139))	('MGMT', 'Gene', '4255', (105, 109))	('MGMT', 'Gene', (105, 109))	('1p/19q co-deletion', 'Var', (111, 129))
95738	32111869	For the non-fractal models in Table 1, the AUC predictive performance of IDH, 1p/19q co-deletion, and TERT models drop to 0.75 +- 0.07, 0.75 +- 0.07, and 0.78 +- 0.07 respectively.	('TERT', 'Gene', (102, 106))	('TERT', 'Gene', '7015', (102, 106))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (73, 76))	('co-deletion', 'Var', (85, 96))
95743	32111869	The study further shows that the size ratio between enhancing tumor and necrosis correlates significantly with un-methylated MGMT, which indicates that the high aggressive MGMT un-methylated LGG, the higher the values of the size ratio.	('LGG', 'Protein', (191, 194))	('MGMT', 'Gene', '4255', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('MGMT', 'Gene', (172, 176))	('MGMT', 'Gene', (125, 129))	('size', 'MPA', (225, 229))	('MGMT', 'Gene', '4255', (125, 129))	('tumor', 'Disease', (62, 67))	('necrosis', 'Disease', (72, 80))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('un-methylated', 'Var', (177, 190))	('higher', 'PosReg', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
95752	32111869	In addition, our IDH mutation prediction model indicates that the tumor correlation associates significantly with mutated IDH and offers HR of 0.562 per standard deviation with a likelihood ratio test p-value = 0.005.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', '3417', (17, 20))	('tumor', 'Disease', (66, 71))	('mutated', 'Var', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('IDH', 'Gene', (17, 20))
95755	32111869	which reports that the enhancement patterns predict the prognosis in IDH1 mutations in Anaplastic gliomas.	('IDH1', 'Gene', (69, 73))	('IDH1', 'Gene', '3417', (69, 73))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('mutations', 'Var', (74, 83))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('Anaplastic gliomas', 'Disease', (87, 105))	('Anaplastic gliomas', 'Disease', 'MESH:D005910', (87, 105))
95765	32111869	This outcome is in agreement with different studies which report that gliomas with 1p/19q co-deletion are associated with the tumor location.	('associated', 'Reg', (106, 116))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('1p/19q co-deletion', 'Var', (83, 101))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('tumor', 'Disease', (126, 131))
95766	32111869	In addition, our analysis shows that higher values of histogram entropy of mBm texture of tumor volume are associated significantly with the existence of 1p/19q co-deletion.	('higher', 'PosReg', (37, 43))	('1p/19q co-deletion', 'Var', (154, 172))	('histogram', 'MPA', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
95769	32111869	(Table 3) utilizes MR imaging features along with patients' age and sex using an SVM classifier to predict 1p/19q co-deletion in LGG patients.	('LGG', 'Disease', (129, 132))	('patients', 'Species', '9606', (133, 141))	('1p/19q co-deletion', 'Var', (107, 125))	('patients', 'Species', '9606', (50, 58))
95771	32111869	Their analysis reveals that the cranial/caudal location of the tumor is one of the most important features in predicting 1p/19q co-deletion.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('1p/19q co-deletion', 'Var', (121, 139))
95776	32111869	In their model, the information measure of correlation is one of the features that is used to predict ATRX mutation.	('mutation', 'Var', (107, 115))	('ATRX', 'Gene', '546', (102, 106))	('ATRX', 'Gene', (102, 106))
95780	32111869	Higher values of these two features are significantly associated with mutated TERT status.	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('associated', 'Reg', (54, 64))	('mutated', 'Var', (70, 77))
95781	32111869	High values of Information measure of correlation are associated with mutated TERT.	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('mutated', 'Var', (70, 77))
95787	32111869	Overall, our analysis shows that the necrosis location and the necrosis volume-related features are very important (most frequently selected features) in MGMT, IDH, and 1p/19q co-deletion prediction.	('necrosis', 'Disease', (63, 71))	('necrosis', 'Disease', 'MESH:D009336', (63, 71))	('IDH', 'Gene', (160, 163))	('necrosis', 'Disease', (37, 45))	('IDH', 'Gene', '3417', (160, 163))	('MGMT', 'Gene', (154, 158))	('1p/19q co-deletion', 'Var', (169, 187))	('necrosis', 'Disease', 'MESH:D009336', (37, 45))	('MGMT', 'Gene', '4255', (154, 158))
95789	32111869	Fractal features have a significant effect on MGMT, IDH, 1p/19q co-deletion, and ATRX prediction models.	('1p/19q co-deletion', 'Var', (57, 75))	('ATRX', 'Gene', (81, 85))	('MGMT', 'Gene', (46, 50))	('MGMT', 'Gene', '4255', (46, 50))	('IDH', 'Gene', (52, 55))	('ATRX', 'Gene', '546', (81, 85))	('IDH', 'Gene', '3417', (52, 55))	('effect', 'Reg', (36, 42))	('co-deletion', 'Var', (64, 75))
95815	27810966	Subjects were eligible for the study if they had imaging findings consistent with a brainstem lowgrade glioma:a well circumscribed or exophytic lesion that is hypointense on T1-weighted images, hyperintense on T2-weighted images and enhancing with contrast, or if there was a histologic confirmation of a low-grade glioma in brainstem.	('glioma', 'Phenotype', 'HP:0009733', (315, 321))	('hyperintense', 'Var', (194, 206))	('enhancing', 'PosReg', (233, 242))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('glioma', 'Disease', (315, 321))	('lowgrade glioma', 'Disease', 'MESH:D005910', (94, 109))	('glioma in brainstem', 'Phenotype', 'HP:0010796', (315, 334))	('lowgrade glioma', 'Disease', (94, 109))	('glioma', 'Disease', (103, 109))	('brainstem lowgrade glioma', 'Phenotype', 'HP:0010796', (84, 109))	('glioma', 'Disease', 'MESH:D005910', (315, 321))
95827	27810966	Together, these cover approximately 98% of KIAA1549-BRAF fusions occurring in pilocytic astrocytoma according to the COSMIC database (http://cancer.sanger.ac.uk/cosmic).	('pilocytic astrocytoma', 'Disease', (78, 99))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (78, 99))	('KIAA1549-BRAF', 'Disease', 'None', (43, 56))	('fusions', 'Var', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('KIAA1549-BRAF', 'Disease', (43, 56))
95836	27810966	Twenty-two patients underwent an initial surgery, either biopsy (3) or surgical resection (19); extent of resection was gross total resection/near total resection (10), subtotal resection (7), partial resection (2) (Table 2).	('patients', 'Species', '9606', (11, 19))	('partial resection', 'Var', (193, 210))	('subtotal', 'Var', (169, 177))
95857	27810966	Determination of tumor BRAF mutation status was attempted in this cohort and was successful in 7 tumors; but tissue was not available/inadequate or of poor quality in the remaining tumors.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (181, 186))	('BRAF', 'Gene', '673', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRAF', 'Gene', (23, 27))	('tumor', 'Disease', (97, 102))	('mutation', 'Var', (28, 36))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
95905	27810966	These include very frequent BRAF gene fusions in pilocytic astrocytomas, as well as other BRAF mutations and various downstream MAP kinase pathway alterations in other low-grade gliomas, depending on location and including brainstem low-grade gliomas.	('BRAF', 'Gene', (90, 94))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('BRAF', 'Gene', '673', (28, 32))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('pilocytic astrocytomas', 'Disease', (49, 71))	('brainstem low-grade gliomas', 'Phenotype', 'HP:0010796', (223, 250))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (49, 71))	('brainstem low-grade glioma', 'Phenotype', 'HP:0010796', (223, 249))	('gliomas', 'Disease', (243, 250))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('mutations', 'Var', (95, 104))	('gliomas', 'Disease', (178, 185))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (90, 94))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))
95906	27810966	Molecular evaluation was possible in 7 tumors in this cohort, 4 of whom had the KIAA1549-BRAF fusion; all 7 patients were negative for the BRAFV600E mutation.	('KIAA1549-BRAF', 'Disease', 'None', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BRAFV600E', 'Var', (139, 148))	('BRAFV600E', 'Mutation', 'rs113488022', (139, 148))	('KIAA1549-BRAF', 'Disease', (80, 93))	('patients', 'Species', '9606', (108, 116))	('tumors', 'Disease', (39, 45))
95923	26424902	Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma.	('better', 'PosReg', (61, 67))	('patients', 'Species', '9606', (94, 102))	('glioma', 'Disease', (108, 114))	('expression', 'Var', (19, 29))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('SASH1', 'Gene', (13, 18))	('postoperative', 'CPA', (68, 81))
95927	26424902	discovered a loss of SASH1 heterozygosity in chromosome 6q24.3, a location where many factors are considered to harbor tumor suppressor function.	('harbor tumor', 'Disease', (112, 124))	('harbor tumor', 'Disease', 'MESH:C537062', (112, 124))	('heterozygosity', 'Var', (27, 41))	('loss', 'NegReg', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SASH1', 'Gene', (21, 26))
95983	31505839	However, much is still to be learnt in this field because tumours in those patients without such resistance mutations become resistant to chemotherapy, suggesting other unknown mechanisms are involved.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('patients', 'Species', '9606', (75, 83))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))
95985	31505839	Primary GBMs usually have one or more mutations in three main molecular pathways: Ras/RTK (receptor tyrosine kinase) pathway, p53 pathway, and the retinoblastoma (Rb) pathway.	('retinoblastoma', 'Disease', (147, 161))	('GBMs', 'Disease', 'MESH:D005909', (8, 12))	('retinoblastoma', 'Phenotype', 'HP:0009919', (147, 161))	('mutations', 'Var', (38, 47))	('tyrosine', 'Chemical', 'None', (100, 108))	('p53', 'Gene', '22059', (126, 129))	('GBMs', 'Disease', (8, 12))	('Rb', 'Disease', 'MESH:D012175', (163, 165))	('p53', 'Gene', (126, 129))	('retinoblastoma', 'Disease', 'MESH:D012175', (147, 161))
95986	31505839	Within the Ras/RTK pathway, epidermal growth factor receptor (EGFR, 30-50% of tumours) and phosphatase and tensin homolog (PTEN, 30%) are the most commonly mutated in GBM, although mutations in NF1 and RAS have also been documented.	('GBM', 'Disease', (167, 170))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('GBM', 'Disease', 'MESH:D005909', (167, 170))	('NF1', 'Gene', (194, 197))	('epidermal growth factor receptor', 'Gene', (28, 60))	('epidermal growth factor receptor', 'Gene', '13649', (28, 60))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', (78, 85))	('mutated', 'Var', (156, 163))	('NF1', 'Gene', '18015', (194, 197))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
95987	31505839	Of the p53 pathway, TP53 (25%) itself is most commonly mutated in GBM.	('TP53', 'Gene', (20, 24))	('GBM', 'Disease', (66, 69))	('p53', 'Gene', '22059', (7, 10))	('mutated', 'Var', (55, 62))	('GBM', 'Disease', 'MESH:D005909', (66, 69))	('p53', 'Gene', (7, 10))
95988	31505839	Mutations in TP53 are thought to have effects such as inhibition of apoptosis, stimulation of cell proliferation and neovascularisation, which are hallmarks of cancer.	('TP53', 'Gene', (13, 17))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (147, 166))	('neovascularisation', 'CPA', (117, 135))	('inhibition', 'NegReg', (54, 64))	('apoptosis', 'CPA', (68, 77))	('Mutations', 'Var', (0, 9))	('hallmarks of cancer', 'Disease', (147, 166))	('stimulation', 'PosReg', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cell proliferation', 'CPA', (94, 112))
95989	31505839	Although a mutation in the Rb pathway is present in most GBMs, the RB gene itself is infrequently mutated, and instead, mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A, 50% of tumours) are particularly common.	('cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (133, 169))	('GBMs', 'Disease', 'MESH:D005909', (57, 61))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumours', 'Disease', (186, 193))	('CDKN2A', 'Gene', '12578', (171, 177))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (133, 169))	('CDKN2A', 'Gene', (171, 177))	('RB', 'Disease', 'MESH:D012175', (67, 69))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('Rb', 'Disease', 'MESH:D012175', (27, 29))	('mutations', 'Var', (120, 129))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('common', 'Reg', (212, 218))	('GBMs', 'Disease', (57, 61))
95991	31505839	In vitro and in vivo models have validated a number of such mutations as driving tumour growth and invasion.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', (81, 87))	('invasion', 'CPA', (99, 107))	('driving', 'PosReg', (73, 80))	('mutations', 'Var', (60, 69))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
95992	31505839	Mouse models have been particularly helpful in demonstrating how mutations in multiple pathways can co-operate together to accelerate tumourigenesis.	('accelerate', 'PosReg', (123, 133))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Disease', (134, 140))	('Mouse', 'Species', '10090', (0, 5))	('mutations', 'Var', (65, 74))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
95993	31505839	The IDH1 (isocitrate dehydrogenase 1) mutation is characteristically found more commonly in secondary GBMs and also in LGGs, and although the mechanism by which this mutation contributes to carcinogenesis is still unclear, it is thought to act epigenetically through abnormal methylation of DNA.	('isocitrate dehydrogenase 1', 'Gene', '15926', (10, 36))	('GBMs', 'Disease', (102, 106))	('GBMs', 'Disease', 'MESH:D005909', (102, 106))	('IDH1', 'Gene', (4, 8))	('abnormal', 'Var', (267, 275))	('mutation', 'Var', (38, 46))	('isocitrate dehydrogenase 1', 'Gene', (10, 36))
95994	31505839	The recent pathological classification of gliomas has been changed to take into account both classical histopathology and key genetic changes, such as IDH1 mutant status, which predicts a better prognosis, and the presence or absence of 1p/19q co-deletions, TERT promoter mutations, and ATRX mutations.	('mutations', 'Var', (292, 301))	('ATRX', 'Gene', (287, 291))	('mutant status', 'Var', (156, 169))	('better', 'PosReg', (188, 194))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('1p/19q', 'Gene', (237, 243))	('IDH1', 'Gene', (151, 155))	('TERT', 'Gene', (258, 262))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('TERT', 'Gene', '21752', (258, 262))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
96010	31505839	Therefore, in postnatal and adult mice carrying nestin-cre, cre is expressed throughout most of the central nervous system, eye, and also the kidneys:this was demonstrated by Dubois and colleagues who showed virtually complete cre-mediated recombination in these tissues by embryonic day 15.5 using LacZ based reporters.	('nestin', 'Gene', '18008', (48, 54))	('nestin', 'Gene', (48, 54))	('mice', 'Species', '10090', (34, 38))	('cre-mediated', 'Var', (227, 239))
96015	31505839	For example, nestin-creERT2 (cre fused to a mutant oestrogen ligand binding domain) and GFAP-creERT2 are inducible cre lines used for this purpose.	('oestrogen', 'Chemical', 'MESH:D004967', (51, 60))	('mutant', 'Var', (44, 50))	('nestin', 'Gene', '18008', (13, 19))	('nestin', 'Gene', (13, 19))
96018	31505839	One of the earliest oncogenes to be discovered in gliomas is the epidermal growth factor receptor (EGFR) gene, which is mutated and/or amplified in 50-60% of primary GBMs.	('EGFR', 'Gene', (99, 103))	('gliomas', 'Disease', (50, 57))	('epidermal growth factor receptor', 'Gene', (65, 97))	('epidermal growth factor receptor', 'Gene', '13649', (65, 97))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('GBMs', 'Disease', (166, 170))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('mutated', 'Var', (120, 127))	('GBMs', 'Disease', 'MESH:D005909', (166, 170))
96020	31505839	In primary GBMs, the variant III mutation of EGFR is particularly common, which is a deletion of exons 2-7 of the gene (the extracellular ligand binding domain) that promotes constitutive signalling from the resulting receptor.	('EGFR', 'Gene', (45, 49))	('GBMs', 'Disease', 'MESH:D005909', (11, 15))	('GBMs', 'Disease', (11, 15))	('constitutive signalling', 'MPA', (175, 198))	('deletion', 'Var', (85, 93))	('promotes', 'PosReg', (166, 174))	('variant III', 'Var', (21, 32))
96021	31505839	An early study, aimed at determining whether excessive EGFR signalling can induce gliomas in vivo, employed the RCAS vector system to introduce an Egfr activating mutation (the EgfrvIII deletion and second deletion that removes the intracellular regulatory kinase domain) in mice expressing the avian tumour virus receptor A (TVA) under control of brain cell specific promoters (nestin and glial fibrillary acidic protein (GFAP)).	('nestin', 'Gene', (379, 385))	('mice', 'Species', '10090', (275, 279))	('Egfr', 'Gene', '13649', (177, 181))	('mutation', 'Var', (163, 171))	('activating', 'PosReg', (152, 162))	('nestin', 'Gene', '18008', (379, 385))	('Egfr', 'Gene', (177, 181))	('gliomas', 'Disease', (82, 89))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (301, 307))	('Egfr', 'Gene', '13649', (147, 151))	('glial fibrillary acidic protein', 'Gene', (390, 421))	('tumour', 'Disease', 'MESH:D009369', (301, 307))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumour', 'Disease', (301, 307))	('glial fibrillary acidic protein', 'Gene', '14580', (390, 421))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('Egfr', 'Gene', (147, 151))	('intracellular', 'MPA', (232, 245))
96023	31505839	In contrast, when an Egfr activating mutation was introduced in the presence of Cdkn2a loss, gliomas arose at a high frequency particularly on the nestin-TVA (Ntv) background.	('gliomas', 'Disease', (93, 100))	('loss', 'NegReg', (87, 91))	('Cdkn2a', 'Gene', (80, 86))	('Egfr', 'Gene', '13649', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('mutation', 'Var', (37, 45))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('nestin', 'Gene', '18008', (147, 153))	('Egfr', 'Gene', (21, 25))	('Cdkn2a', 'Gene', '12578', (80, 86))	('nestin', 'Gene', (147, 153))
96024	31505839	The authors concluded that Egfr activating mutations alone are insufficient to generate gliomas but can cooperate with predisposing mutations such as those of Cdkn2a to produce these tumours.	('Cdkn2a', 'Gene', (159, 165))	('tumours', 'Disease', (183, 190))	('gliomas', 'Disease', (88, 95))	('Egfr', 'Gene', '13649', (27, 31))	('mutations', 'Var', (43, 52))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('Cdkn2a', 'Gene', '12578', (159, 165))	('Egfr', 'Gene', (27, 31))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('tumours', 'Disease', 'MESH:D009369', (183, 190))
96025	31505839	Given the incidence of tumours was higher in Ntv compared with glial-specific GFAP-TVA (Gtv) mice, the authors suggested that the presence of these driving mutations in a neural stem cell lineage is a likely origin for gliomas.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('mutations', 'Var', (156, 165))	('tumours', 'Disease', (23, 30))	('mice', 'Species', '10090', (93, 97))	('gliomas', 'Disease', (219, 226))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))
96028	31505839	However, lesions histologically resembling human GBMs were observed when these mutations were expressed in combination with one other.	('human', 'Species', '9606', (43, 48))	('GBMs', 'Disease', 'MESH:D005909', (49, 53))	('GBMs', 'Disease', (49, 53))	('mutations', 'Var', (79, 88))
96032	31505839	hypothesised that loss-of-function mutations in these two genes cooperate in driving gliomagenesis.	('gliomagenesis', 'Disease', (85, 98))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('loss-of-function', 'NegReg', (18, 34))	('gliomagenesis', 'Disease', 'None', (85, 98))	('mutations', 'Var', (35, 44))
96033	31505839	To explore this, they crossed a hGFAP-cre mouse with Trp53 mutant and Pten knockout mice.	('mouse', 'Species', '10090', (42, 47))	('mutant', 'Var', (59, 65))	('Trp53', 'Gene', (53, 58))	('hGFAP', 'Gene', (32, 37))	('hGFAP', 'Gene', '2670', (32, 37))	('mice', 'Species', '10090', (84, 88))
96035	31505839	Gliomaspheres with neural stem cell-like properties could be generated from these tumours, and the authors demonstrated that activation of myc was crucial in driving tumourigenesis in this model.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('activation', 'Var', (125, 135))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumour', 'Disease', (82, 88))	('myc', 'Protein', (139, 142))	('tumours', 'Disease', (82, 89))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('Gliomas', 'Disease', (0, 7))
96036	31505839	Importantly, although TP53 and PTEN mutations are commonly found in human low-grade gliomas as well as GBMs, all of the tumours generated in these mice were either grade III or IV.	('PTEN', 'Gene', (31, 35))	('mice', 'Species', '10090', (147, 151))	('human', 'Species', '9606', (68, 73))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('gliomas', 'Disease', (84, 91))	('GBMs', 'Disease', (103, 107))	('mutations', 'Var', (36, 45))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('GBMs', 'Disease', 'MESH:D005909', (103, 107))	('found', 'Reg', (59, 64))	('tumours', 'Disease', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('TP53', 'Gene', (22, 26))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
96038	31505839	Zhu and colleagues explored the cooperation between the EGFRvIII mutation and other genes in gliomagenesis by also using transgenic mice.	('EGFRvIII', 'Gene', (56, 64))	('gliomagenesis', 'Disease', 'None', (93, 106))	('mutation', 'Var', (65, 73))	('gliomagenesis', 'Disease', (93, 106))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('transgenic mice', 'Species', '10090', (121, 136))
96039	31505839	They generated both an EGFRvIII transgenic mouse, in which this mutation was overexpressed at the Col1a locus, and an EGFR wild-type transgenic mouse with the human EGFR gene sequence inserted and over-expressed at the Col1a locus.	('mouse', 'Species', '10090', (144, 149))	('mutation', 'Var', (64, 72))	('transgenic', 'Species', '10090', (32, 42))	('human', 'Species', '9606', (159, 164))	('transgenic', 'Species', '10090', (133, 143))	('over-expressed', 'PosReg', (197, 211))	('mouse', 'Species', '10090', (43, 48))
96041	31505839	Neither of these mutations was sufficient to initiate gliomas alone, but when each was expressed in combination with homozygous loss of Pten and Ink4a, both mutations were able to produce high-grade gliomas with a short latency.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('produce', 'Reg', (180, 187))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('Pten', 'Gene', (136, 140))	('Ink4a', 'Gene', '12578', (145, 150))	('mutations', 'Var', (157, 166))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('Ink4a', 'Gene', (145, 150))
96042	31505839	However, the EGFRwt allele produced tumours with a lower incidence and longer latency in comparison with a single EGFRvIII allele.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumours', 'Disease', (36, 43))	('lower', 'NegReg', (51, 56))	('EGFRwt', 'Var', (13, 19))	('incidence', 'MPA', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))
96046	31505839	Crossing this with nestin-cre mice led to pups with perinatal brain haemorrhages, as shown previously.	('mice', 'Species', '10090', (30, 34))	('nestin', 'Gene', '18008', (19, 25))	('nestin', 'Gene', (19, 25))	('brain haemorrhages', 'Disease', 'MESH:D020300', (62, 80))	('brain haemorrhages', 'Phenotype', 'HP:0001342', (62, 80))	('brain haemorrhages', 'Disease', (62, 80))	('Crossing', 'Var', (0, 8))
96049	31505839	This study highlights the importance of using stage-specific cellular recombination, given that an Idh1 mutation led to early gliomagenesis in the adult SVZ but could not be detected from perinatal neural precursor recombination.	('gliomagenesis', 'Disease', 'None', (126, 139))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('gliomagenesis', 'Disease', (126, 139))	('Idh1', 'Gene', '15926', (99, 103))	('mutation', 'Var', (104, 112))	('Idh1', 'Gene', (99, 103))
96050	31505839	It also adds weight to the argument that an IDH1 mutation can be an initiating event in gliomagenesis, explaining the high frequency of clonal IDH1 mutations in human gliomas and their presence in both primary and recurrent gliomas.	('human', 'Species', '9606', (161, 166))	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('mutations', 'Var', (148, 157))	('gliomagenesis', 'Disease', (88, 101))	('presence', 'Reg', (185, 193))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('gliomagenesis', 'Disease', 'None', (88, 101))	('IDH1', 'Gene', (143, 147))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('gliomas', 'Disease', (224, 231))	('gliomas', 'Disease', 'MESH:D005910', (224, 231))
96054	31505839	Although it remains unclear which is the key cell type of origin, evidence suggests that the combination of genetic alterations has a major influence on whether one particular cell type can give rise to a glioma.	('genetic alterations', 'Var', (108, 127))	('influence', 'Reg', (140, 149))	('glioma', 'Disease', (205, 211))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('give rise to', 'Reg', (190, 202))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
96055	31505839	Jacques and colleagues introduced combinations of Trp53/Pten and Rb mutations in adult subventricular zone (SVZ) neural stem cells (NSCs) and in astrocytes of mice by injections of adenovirus expressing cre (with and without the control of the GFAP promoter).	('mutations', 'Var', (68, 77))	('Rb', 'Disease', 'MESH:D012175', (65, 67))	('Trp53/Pten', 'Gene', (50, 60))	('mice', 'Species', '10090', (159, 163))
96057	31505839	Moreover, Trp53 and Pten loss-of-function mutations together induced gliomas, whereas deletion of Rb in addition to Trp53/Pten loss led to primitive neuroectodermal tumours (PNETs) rather than gliomas.	('gliomas', 'Disease', (69, 76))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('Pten', 'Gene', (20, 24))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Disease', (193, 200))	('Rb', 'Disease', 'MESH:D012175', (98, 100))	('loss-of-function', 'NegReg', (25, 41))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('deletion', 'Var', (86, 94))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('loss', 'NegReg', (127, 131))	('neuroectodermal tumours', 'Disease', (149, 172))	('Trp53', 'Gene', (10, 15))	('primitive neuroectodermal tumours', 'Phenotype', 'HP:0030065', (139, 172))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('neuroectodermal tumours', 'Disease', 'MESH:D017599', (149, 172))	('mutations', 'Var', (42, 51))
96058	31505839	Importantly, despite containing the same mutations as those induced in the SVZ, mature astrocytes were unable to form tumours.	('mutations', 'Var', (41, 50))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (118, 125))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))
96059	31505839	A related study into the cellular origin of gliomas investigated the role of Egfr (activation) and Cdkn2a (loss) mutations in various brain cell types.	('Cdkn2a', 'Gene', '12578', (99, 105))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('mutations', 'Var', (113, 122))	('Egfr', 'Gene', (77, 81))	('Cdkn2a', 'Gene', (99, 105))	('Egfr', 'Gene', '13649', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
96061	31505839	These mutated cells were subsequently transplanted into the brain (striatum) of severe combined immunodeficient (SCID) mice.	('immunodeficient', 'Disease', 'MESH:D007153', (96, 111))	('mice', 'Species', '10090', (119, 123))	('immunodeficient', 'Disease', (96, 111))	('mutated', 'Var', (6, 13))
96062	31505839	When these mutations were introduced independently of each other, the cells did not transform into gliomas.	('mutations', 'Var', (11, 20))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
96063	31505839	With these mutations in combination however, gliomas were observed to arise from both astrocytes and neural stem cells.	('mutations', 'Var', (11, 20))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
96064	31505839	These results suggest that this particular combination of mutations rather than the cell type was more important in driving tumour formation.	('mutations', 'Var', (58, 67))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Disease', (124, 130))
96065	31505839	In particular, Cdkn2a loss led to the dedifferentiation of the mature astrocytes, enabling these cells to later be transformed if an activating Egfr mutation was introduced.	('Cdkn2a', 'Gene', '12578', (15, 21))	('Cdkn2a', 'Gene', (15, 21))	('dedifferentiation of the mature astrocytes', 'CPA', (38, 80))	('loss', 'NegReg', (22, 26))	('Egfr', 'Gene', (144, 148))	('mutation', 'Var', (149, 157))	('Egfr', 'Gene', '13649', (144, 148))
96066	31505839	The authors concluded that loss of Cdkn2a was a critical initial step in gliomagenesis that must precede Egfr activation if the latter is to trigger glioma formation, at least from mature astrocytes.	('loss', 'Var', (27, 31))	('glioma', 'Disease', (73, 79))	('glioma', 'Disease', (149, 155))	('gliomagenesis', 'Disease', 'None', (73, 86))	('Egfr', 'Gene', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('Egfr', 'Gene', '13649', (105, 109))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('gliomagenesis', 'Disease', (73, 86))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('Cdkn2a', 'Gene', '12578', (35, 41))	('Cdkn2a', 'Gene', (35, 41))
96067	31505839	To expand on these observations, Friedmann-Morvinski and colleagues performed direct lentiviral vector injections to cause p53/Nf1 knockdown or H-ras overexpression with p53 knockdown in neurons, astrocytes and neural stem cells of mice.	('knockdown', 'Var', (131, 140))	('H-ras', 'Gene', '15461', (144, 149))	('overexpression', 'PosReg', (150, 164))	('p53', 'Gene', (170, 173))	('H-ras', 'Gene', (144, 149))	('p53', 'Gene', '22059', (170, 173))	('p53', 'Gene', (123, 126))	('p53', 'Gene', '22059', (123, 126))	('mice', 'Species', '10090', (232, 236))
96068	31505839	Their models used cre-inducible lentiviral vectors, and Syn1-cre and CamK2a-cre transgenic mouse lines enabled recombination specifically in neurons.	('Syn1', 'Gene', '20964', (56, 60))	('transgenic', 'Species', '10090', (80, 90))	('recombination', 'Var', (111, 124))	('Syn1', 'Gene', (56, 60))	('mouse', 'Species', '10090', (91, 96))
96069	31505839	They found that all of these cell types generated malignant gliomas in mice with these genetic alterations and concluded that the mature cell types undergo dedifferentiation in response to defined oncogenic mutations to neural stem cells or progenitors, enabling tumour initiation and maintenance.	('mice', 'Species', '10090', (71, 75))	('genetic alterations', 'Var', (87, 106))	('enabling', 'PosReg', (254, 262))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('mutations', 'Var', (207, 216))	('malignant gliomas', 'Disease', (50, 67))	('tumour initiation', 'Disease', 'MESH:D009369', (263, 280))	('alterations', 'Var', (95, 106))	('tumour', 'Phenotype', 'HP:0002664', (263, 269))	('tumour initiation', 'Disease', (263, 280))	('malignant gliomas', 'Disease', 'MESH:D005910', (50, 67))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('dedifferentiation', 'CPA', (156, 173))
96073	31505839	It is unclear from this study alone though what the effect of the EGFRvIII mutation in absence of exogenous EGF would be on these cells.	('EGF', 'Gene', '13645', (66, 69))	('EGF', 'Gene', '13645', (108, 111))	('mutation', 'Var', (75, 83))	('EGF', 'Gene', (66, 69))	('EGF', 'Gene', (108, 111))
96074	31505839	A further study elegantly used mosaic analysis with double markers (MADM) in mice with p53/Nf1 inactivation in NSCs.	('mice', 'Species', '10090', (77, 81))	('NSCs', 'Disease', (111, 115))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '22059', (87, 90))	('inactivation', 'Var', (95, 107))
96075	31505839	MADM is a genetic mosaic system that uses cre/Loxp recombination to generate homozygous mutations in a small population of cells, labelling the mutant cells with green-fluorescent protein (GFP) and the wild-type cells with red-fluorescent protein (RFP).	('mutant', 'Var', (144, 150))	('mutations', 'Var', (88, 97))	('RFP', 'Gene', '19720', (248, 251))	('RFP', 'Gene', (248, 251))
96077	31505839	Prior to GBM establishment, MADM-based lineage tracing identified aberrant growth only in oligodendrocyte precursor cells (OPCs), but not in NSCs or other NSC-lineages.	('growth', 'MPA', (75, 81))	('GBM', 'Disease', (9, 12))	('aberrant', 'Var', (66, 74))	('GBM', 'Disease', 'MESH:D005909', (9, 12))	('aberrant growth', 'Phenotype', 'HP:0001507', (66, 81))
96078	31505839	Moreover, induction of p53/Nf1 mutations directly in OPCs caused glioma formation, leading the authors to conclude that OPCs are the origin of glioma in this model, even if the initiating mutations occur in NSCs.	('caused', 'Reg', (58, 64))	('mutations', 'Var', (31, 40))	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '22059', (23, 26))	('glioma', 'Disease', (143, 149))
96079	31505839	To test whether adult committed neural progenitors and adult OPCs can give rise to gliomas, a well-designed study leveraged the Ascl1-creERTM transgenic mouse line to target Nf1, Trp53 and Pten loss-of -function mutations specifically in these cells to the exclusion of neural stem cells.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('Trp53', 'Gene', (179, 184))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('Nf1', 'Gene', (174, 177))	('transgenic', 'Species', '10090', (142, 152))	('loss-of -function', 'NegReg', (194, 211))	('mouse', 'Species', '10090', (153, 158))	('Ascl1', 'Gene', '17172', (128, 133))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('Ascl1', 'Gene', (128, 133))	('mutations', 'Var', (212, 221))	('Pten', 'Gene', (189, 193))
96080	31505839	When mutations in all three genes were present, infiltrative GBMs with gene expression profiles similar to astrocytes were produced (type 1 tumours), whereas in the context of Nf1-/-; Trp53-/- these type 1 tumours were seen in addition to more circumscribed GBMs with expression profiles reflecting OPCs were observed (type 2 tumours).	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (326, 332))	('GBMs', 'Disease', (61, 65))	('tumours', 'Phenotype', 'HP:0002664', (326, 333))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumours', 'Disease', 'MESH:D009369', (326, 333))	('mutations', 'Var', (5, 14))	('GBMs', 'Disease', 'MESH:D005909', (61, 65))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('GBMs', 'Disease', (258, 262))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', (326, 333))	('tumours', 'Disease', (140, 147))	('GBMs', 'Disease', 'MESH:D005909', (258, 262))	('tumours', 'Disease', (206, 213))
96081	31505839	To confirm therefore that type 2 tumours are derived from adult OPCs, the investigators leveraged the NG2-creERTM transgenic line to express the same mutations specifically in adult OPCs only.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('transgenic', 'Species', '10090', (114, 124))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumours', 'Disease', (33, 40))	('mutations', 'Var', (150, 159))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))
96083	31505839	These data together suggest that the cell-of-origin influences the phenotype of GBMs, with adult OPCs and adult neural progenitors being capable of malignant transformation with appropriate mutations.	('GBMs', 'Disease', 'MESH:D005909', (80, 84))	('GBMs', 'Disease', (80, 84))	('mutations', 'Var', (190, 199))	('influences', 'Reg', (52, 62))
96086	31505839	They found that normal SVZ displayed low level driver mutations (1% of tumour mutational burden) that were also present in the GBMs of the same patients in 56.3% of cases.	('tumour', 'Disease', (71, 77))	('GBMs', 'Disease', (127, 131))	('mutations', 'Var', (54, 63))	('GBMs', 'Disease', 'MESH:D005909', (127, 131))	('patients', 'Species', '9606', (144, 152))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
96087	31505839	The introduction of driver mutations in astrocyte-like NSCs in the SVZ in mice led to migration of these cells and formation of GBMs at distant brain regions.	('mutations', 'Var', (27, 36))	('migration', 'CPA', (86, 95))	('GBMs', 'Disease', (128, 132))	('mice', 'Species', '10090', (74, 78))	('GBMs', 'Disease', 'MESH:D005909', (128, 132))
96089	31505839	A powerful platform for functional cancer gene discovery and also transgene insertion is the Sleeping Beauty (SB) transposon system.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('SB', 'Disease', 'MESH:D012893', (110, 112))	('transgene', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('insertion', 'Var', (76, 85))	('cancer', 'Disease', (35, 41))
96091	31505839	When these are present in the same cell, the transposase recognises the inverted repeats of the transposon and excises it from the donor locus.	('donor', 'Species', '9606', (131, 136))	('excises', 'NegReg', (111, 118))	('inverted repeats', 'Var', (72, 88))	('transposon', 'Gene', (96, 106))
96092	31505839	Modifications to the inverted repeats have been made in order to improve transposition efficiency, and site-directed mutagenesis of the SB transposase produced alternative versions of the enzyme with different transposition efficiencies.	('mutagenesis', 'Var', (117, 128))	('improve', 'PosReg', (65, 72))	('Modifications', 'Var', (0, 13))	('transposition', 'MPA', (73, 86))	('SB', 'Disease', 'MESH:D012893', (136, 138))	('different transposition', 'Phenotype', 'HP:0011540', (200, 223))
96104	31505839	One study which employed this conditional SB transposon system for investigating gliomas used a nestin-cre allele on a Trp53-mutant background to drive expression of the SB transposase in mouse neural stem cells, although these did not directly generate tumours in vivo.	('mouse', 'Species', '10090', (188, 193))	('tumours', 'Disease', 'MESH:D009369', (254, 261))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('SB', 'Disease', 'MESH:D012893', (42, 44))	('Trp53-mutant', 'Var', (119, 131))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('tumours', 'Phenotype', 'HP:0002664', (254, 261))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('SB', 'Disease', 'MESH:D012893', (170, 172))	('nestin', 'Gene', '18008', (96, 102))	('nestin', 'Gene', (96, 102))	('tumours', 'Disease', (254, 261))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
96106	31505839	Immortalisation occurred significantly more frequently in cell lines with both Trp53R172H and mobilising SB than those with Trp53R172H alone, but not in lines with neither Trp53R172H nor mobilising SB.	('Immortalisation', 'CPA', (0, 15))	('SB', 'Disease', 'MESH:D012893', (105, 107))	('SB', 'Disease', 'MESH:D012893', (198, 200))	('Trp53R172H', 'Var', (79, 89))
96108	31505839	Through genetic sequencing for the SB insertions, the authors identified 106 CIS genes in the immortalised cell lines and 114 in the tumours, of which 34 CIS genes were present in both cohorts.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('SB', 'Disease', 'MESH:D012893', (35, 37))	('insertions', 'Var', (38, 48))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('tumours', 'Disease', (133, 140))
96110	31505839	The authors were therefore able to categorise SB insertions according to whether they drove cellular proliferation in vitro or in vivo tumour growth or both, as part of a two-step process of cancer evolution.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cellular proliferation', 'CPA', (92, 114))	('vivo tumour', 'Disease', 'MESH:C536830', (130, 141))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('vivo tumour', 'Disease', (130, 141))	('insertions', 'Var', (49, 59))	('SB', 'Disease', 'MESH:D012893', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
96113	31505839	The CIS genes clustered into biological pathways that are thought to underlie gliomagenesis, in particular the Ras-MAPK and PI3K-Akt pathways, confirming that these major pathways that are mutated in human tumours can promote neural stem cell immortalisation in vitro and subcutaneous glioma formation.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('neural stem cell immortalisation in vitro', 'CPA', (226, 267))	('mutated', 'Var', (189, 196))	('glioma', 'Disease', (285, 291))	('promote', 'PosReg', (218, 225))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('glioma', 'Disease', 'MESH:D005910', (285, 291))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('glioma', 'Phenotype', 'HP:0009733', (285, 291))	('gliomagenesis', 'Disease', 'None', (78, 91))	('human', 'Species', '9606', (200, 205))	('glioma', 'Disease', (78, 84))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('tumours', 'Disease', (206, 213))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('gliomagenesis', 'Disease', (78, 91))
96119	31505839	90% of paediatric GBMs carry a K27M mutation in a H3 variant, which is a gain-of-function mutation that leads to inhibition of the Polycomb repressive complex 2 (PRC2).	('inhibition', 'NegReg', (113, 123))	('K27M', 'Mutation', 'p.K27M', (31, 35))	('GBMs', 'Disease', (18, 22))	('GBMs', 'Disease', 'MESH:D005909', (18, 22))	('K27M', 'Var', (31, 35))
96120	31505839	A recent study used in utero electroporation of piggyBac vectors to integrate a H3.3K27M transgene into neural precursor cells (lining the ventricles) in the hindbrain and cerebral cortex of mouse embryos.	('H3.3K27M transgene', 'Var', (80, 98))	('mouse', 'Species', '10090', (191, 196))	('piggyBac vectors', 'Disease', (48, 64))	('piggyBac vectors', 'Disease', 'MESH:D011778', (48, 64))	('K27M', 'Mutation', 'p.K27M', (84, 88))
96121	31505839	When this was done in combination with CRISPR-cas9 induced Trp53 loss, mice developed gliomas in both hindbrain and cortex within 8 months suggesting that H3.3K27M mutation cooperates with Trp53 loss in gliomagenesis when they are present in embryonic neural precursor cells but not in adult neural precursors (given that no tumours were observed when these alleles were expressed under control of nestin and GFAP promoters).	('mice', 'Species', '10090', (71, 75))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('mutation', 'Var', (164, 172))	('loss', 'NegReg', (195, 199))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('H3.3K27M', 'Gene', (155, 163))	('Trp53', 'Gene', (189, 194))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('tumours', 'Disease', (325, 332))	('K27M', 'Mutation', 'p.K27M', (159, 163))	('Trp53', 'Gene', (59, 64))	('loss', 'NegReg', (65, 69))	('tumours', 'Phenotype', 'HP:0002664', (325, 332))	('tumours', 'Disease', 'MESH:D009369', (325, 332))	('nestin', 'Gene', (398, 404))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))	('gliomas', 'Disease', (86, 93))	('gliomagenesis', 'Disease', 'None', (203, 216))	('gliomagenesis', 'Disease', (203, 216))	('nestin', 'Gene', '18008', (398, 404))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))
96125	31505839	For example, in utero electroporation of the developing prosencephalon of multiple plasmids encoding Cas9 together with sgRNAs targeting Nf1, Pten, and Trp53 led to the confirmed loss of these genes, and subsequent development of tumours histologically resembling human GBMs.	('Cas9', 'Gene', (101, 105))	('Nf1', 'Gene', (137, 140))	('GBMs', 'Disease', 'MESH:D005909', (270, 274))	('human', 'Species', '9606', (264, 269))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('Trp53', 'Gene', (152, 157))	('GBMs', 'Disease', (270, 274))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('electroporation', 'Var', (22, 37))	('tumours', 'Disease', 'MESH:D009369', (230, 237))	('tumours', 'Disease', (230, 237))	('loss', 'NegReg', (179, 183))	('Pten', 'Gene', (142, 146))
96131	31505839	With this system, tumours that histologically resemble human GBMs were generated, and deep-sequencing revealed co-occurring mutations such as B2m-Nf1 and Mll3-Nf1 as putative driver combinations.	('Mll3', 'Gene', (154, 158))	('B2m-Nf1', 'Gene', (142, 149))	('mutations', 'Var', (124, 133))	('tumours', 'Disease', (18, 25))	('GBMs', 'Disease', (61, 65))	('human', 'Species', '9606', (55, 60))	('GBMs', 'Disease', 'MESH:D005909', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('Mll3', 'Gene', '58508', (154, 158))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('tumours', 'Disease', 'MESH:D009369', (18, 25))
96135	31505839	As technologies are being refined for engineering mutations found in human gliomas into the precise cell types of interest in the mouse brain, including by cre/LoxP recombination and viral- or transposon-based integration, our tools for investigating the mechanisms and origins of gliomagenesis are reaching new heights.	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('gliomagenesis', 'Disease', (281, 294))	('mutations', 'Var', (50, 59))	('gliomas', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('gliomagenesis', 'Disease', 'None', (281, 294))	('mouse', 'Species', '10090', (130, 135))
96137	31505839	The generation and detailed characterisation of novel cre transgenic mouse lines will enable further targeting of mutations to increasingly specific brain cell types to investigate the glioma cell-of-origin.	('mutations', 'Var', (114, 123))	('mouse', 'Species', '10090', (69, 74))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('transgenic', 'Species', '10090', (58, 68))	('glioma', 'Disease', (185, 191))
96172	28479790	Low ADC values are used as indicators for high-grade gliomas and correlate with poor survival in malignant astrocytomas independent of tumor grade.	('poor', 'NegReg', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('tumor', 'Disease', (135, 140))	('ADC values', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('astrocytomas', 'Disease', 'MESH:D001254', (107, 119))	('high-grade', 'Disease', (42, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('astrocytomas', 'Disease', (107, 119))	('Low', 'Var', (0, 3))
96209	28479790	(0.786, 0.856, 0.931 x 10-3 mm2/s) ANOVA P = 0.023.	('0.786', 'Var', (1, 6))	('mm2', 'Gene', (28, 31))	('mm2', 'Gene', '10687', (28, 31))
96240	28479790	Patients with LGG [Figure 4], anaplastic ODG [Figure 5] and GBM [Figure 6] provided the temporal profile of "minimum ADC" values that mirror the clinical response of the patients.	('patients', 'Species', '9606', (170, 178))	('anaplastic ODG', 'Var', (30, 44))	('ADC"', 'Gene', '113451', (117, 121))	('ADC"', 'Gene', (117, 121))	('GBM', 'Gene', (60, 63))	('Patients', 'Species', '9606', (0, 8))	('LGG', 'Chemical', '-', (14, 17))	('LGG', 'Gene', (14, 17))
96295	27793055	Interestingly, the analysis of the homology networks for patients in whom elimination of HSPA8 leads to most significant changes in complexity revealed similarities in the homology subnetworks despite the differences in tissue type.	('changes', 'Reg', (121, 128))	('complexity', 'MPA', (132, 142))	('patients', 'Species', '9606', (57, 65))	('HSPA8', 'Gene', (89, 94))	('HSPA8', 'Gene', '3312', (89, 94))	('elimination', 'Var', (74, 85))
96310	27793055	The protein neighbors of HSPA8 and HDAC4 have similar, albeit not identical, Gibbs free energy and form part of the persistent homology, as the inhibition of HSPA8 or HDAC4 can drop the network complexity (Betti number) by a comparable amount.	('HDAC4', 'Gene', '9759', (35, 40))	('Betti', 'Chemical', '-', (206, 211))	('HSPA8', 'Gene', (158, 163))	('network complexity', 'MPA', (186, 204))	('inhibition', 'Var', (144, 154))	('HDAC4', 'Gene', (167, 172))	('HSPA8', 'Gene', (25, 30))	('HDAC4', 'Gene', '9759', (167, 172))	('HSPA8', 'Gene', '3312', (158, 163))	('drop', 'NegReg', (177, 181))	('HSPA8', 'Gene', '3312', (25, 30))	('HDAC4', 'Gene', (35, 40))
96321	27793055	While HDAC4 expression has been used to identify patients likely to respond to temozolomide or radiotherapy, and a high HDAC4 expression is a signature of low-grade glioma, it has not been viewed as having a direct therapeutic value to date.	('high', 'Var', (115, 119))	('expression', 'MPA', (126, 136))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('temozolomide', 'Chemical', 'MESH:D000077204', (79, 91))	('HDAC4', 'Gene', '9759', (120, 125))	('HDAC4', 'Gene', '9759', (6, 11))	('HDAC4', 'Gene', (120, 125))	('HDAC4', 'Gene', (6, 11))	('patients', 'Species', '9606', (49, 57))	('glioma', 'Disease', (165, 171))
96327	27793055	Yet, while the frequency of HSPA8 gene alteration may be sufficient for a successful clinical trial, it may not be of benefit for most patients.	('patients', 'Species', '9606', (135, 143))	('alteration', 'Var', (39, 49))	('HSPA8', 'Gene', (28, 33))	('HSPA8', 'Gene', '3312', (28, 33))
96352	27793055	8, 16), the complexity of the subnetwork is also low, and removing any individual protein will drop the Betti number by the same amount resulting in as many as eight or more equivalent targets.	('removing', 'Var', (58, 66))	('Betti number', 'MPA', (104, 116))	('resulting in', 'Reg', (136, 148))	('Betti', 'Chemical', '-', (104, 109))	('protein', 'Protein', (82, 89))	('drop', 'NegReg', (95, 99))
96396	26663561	The steady-state longitudinal magnetization of the water proton pool , which has the equilibrium magnetization  can be simplified to only six parameters (R, Rm, T2m,  , 1/RwT2w, and Deltamw):   where R is the fundamental rate constant describing the magnetization exchange between the two proton pools ( for the exchange from the water pool to semi-solid pool and   for the reverse direction); Rw and Rm are the longitudinal relaxation rate of the free water proton pool and semi-solid macromolecular proton pool, respectively; T2w and T2m are the transverse relaxation times of the free water proton pool and semi-solid macromolecular proton pool, respectively; and   is the fully-relaxed equilibrium magnetization value associated with the semi-solid macromolecular pool.	('water pool', 'Phenotype', 'HP:0000969', (330, 340))	('T2w', 'Var', (528, 531))	('water', 'Chemical', 'MESH:D014867', (330, 335))	('water', 'Chemical', 'MESH:D014867', (453, 458))	('longitudinal', 'MPA', (412, 424))	('water', 'Chemical', 'MESH:D014867', (51, 56))	('T2m', 'Var', (536, 539))	('water', 'Chemical', 'MESH:D014867', (588, 593))
96397	26663561	The RF absorption rate, Rrfm is the rate of loss of longitudinal magnetization by direct saturation of the semi-solid macromolecular pool due to off resonance irradiation of amplitude omega1 and offset frequency Deltaw, which is dependent on absorption lineshape, gm (2piDeltam).	('radiation', 'Disease', 'MESH:D004194', (161, 170))	('loss', 'NegReg', (44, 48))	('radiation', 'Disease', (161, 170))	('longitudinal magnetization', 'MPA', (52, 78))	('Deltaw', 'Var', (212, 218))
96398	26663561	It should be noted that a super-Lorentzian lineshape provides the best fit to semi-solid macromolecular protons in biological tissue:     where Deltam is the frequency offset for the semi-solid macromolecular protons, and Deltamw is the frequency difference between the semi-solid macromolecular protons and the free water protons.	('Deltam', 'Var', (144, 150))	('Deltamw', 'Var', (222, 229))	('water', 'Chemical', 'MESH:D014867', (317, 322))
96431	26663561	However, NOE# maps not only had much higher signals compared to the downfield CEST#, but also showed contrast between the white matter and gray matter probably due to the residual conventional MTC effect.	('NOE', 'Chemical', '-', (9, 12))	('signals', 'MPA', (44, 51))	('higher', 'PosReg', (37, 43))	('NOE#', 'Var', (9, 13))
96435	26663561	Figure 6 quantitatively compares the APT# (3.3 ~ 3.7 ppm), NOE# (-3.3 ~ -3.7 ppm), delta (MT asymmetry, = ZEMR(3.5ppm) - ZEMR(-3.5ppm)) and MTRasym(3.5ppm) signals in the normal tissue and glioma in each grade (grades II to IV).	('glioma', 'Disease', (189, 195))	('APT#', 'Gene', '653639', (37, 41))	('APT#', 'Gene', (37, 41))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('glioma', 'Disease', 'MESH:D005910', (189, 195))	('NOE', 'Chemical', '-', (59, 62))	('-3.3', 'Var', (65, 69))
96495	26771840	Univariate analysis showed that PD-L1 expression was significantly associated with poor OS in the patients with long-time survival or follow up (OS >= 12 months) (P = 0.018), especially in patients with grade IV (P = 0.019).	('PD-L1', 'Gene', (32, 37))	('grade IV', 'Disease', (203, 211))	('patients', 'Species', '9606', (98, 106))	('poor OS', 'Disease', (83, 90))	('expression', 'Var', (38, 48))	('PD-L1', 'Gene', '29126', (32, 37))	('patients', 'Species', '9606', (189, 197))
96503	26771840	In the past decades, molecular targeted therapies are beneficial to improve the prognosis of gliomas, such as bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), nimotuzumab, a monoclonal antibody to epidermal growth factor receptor (EGFR) and several patients of gliomas with silencing of O6-methylguanine DNA methyltransferase (MGMT) could aggrieve more benefits from temozolomide (TMZ).	('gliomas', 'Disease', (93, 100))	('bevacizumab', 'Chemical', 'MESH:D000068258', (110, 121))	('gliomas', 'Disease', (298, 305))	('VEGF', 'Gene', (189, 193))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('EGFR', 'Gene', '1956', (268, 272))	('gliomas', 'Disease', 'MESH:D005910', (298, 305))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('TMZ', 'Chemical', 'MESH:D000077204', (418, 421))	('temozolomide', 'Chemical', 'MESH:D000077204', (404, 416))	('MGMT', 'Gene', '4255', (364, 368))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (324, 362))	('MGMT', 'Gene', (364, 368))	('epidermal growth factor receptor', 'Gene', (234, 266))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('glioma', 'Phenotype', 'HP:0009733', (298, 304))	('epidermal growth factor receptor', 'Gene', '1956', (234, 266))	('gliomas', 'Phenotype', 'HP:0009733', (298, 305))	('vascular endothelial growth factor', 'Gene', '7422', (153, 187))	('EGFR', 'Gene', (268, 272))	('nimotuzumab', 'Chemical', 'MESH:C501466', (196, 207))	('VEGF', 'Gene', '7422', (189, 193))	('vascular endothelial growth factor', 'Gene', (153, 187))	('silencing', 'Var', (311, 320))	('O6-methylguanine DNA methyltransferase', 'Gene', (324, 362))	('patients', 'Species', '9606', (286, 294))
96508	26771840	Blockage of PD-L1 expression on tumor cells might activate tumor-specific T cell to kill tumor cells by mediating tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma).	('TNF-alpha', 'Gene', (143, 152))	('tumor', 'Disease', (59, 64))	('interferon gamma (IFN-gamma', 'Gene', '3458', (158, 185))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor necrosis factor alpha', 'Gene', '7124', (114, 141))	('Blockage', 'Var', (0, 8))	('tumor', 'Disease', (114, 119))	('activate', 'PosReg', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (32, 37))	('tumor necrosis factor alpha', 'Gene', (114, 141))	('PD-L1', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('PD-L1', 'Gene', '29126', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TNF-alpha', 'Gene', '7124', (143, 152))
96525	26771840	A strong tendency towards the statistical significance was demonstrated between PD-L1 expression and better prognosis in the patients with the short-time survival or follow up (P = 0.162, Figure 4A).	('PD-L1', 'Gene', (80, 85))	('prognosis', 'CPA', (108, 117))	('PD-L1', 'Gene', '29126', (80, 85))	('expression', 'Var', (86, 96))	('patients', 'Species', '9606', (125, 133))
96530	26771840	Stratified analysis revealed that PD-L1 expression was significantly associated with adverse OS (P = 0.019, Figure 5A) and DFS (P = 0.014, Figure 5B) for patients with grade IV gliomas during the long-time survival or follow up.	('DFS', 'MPA', (123, 126))	('grade', 'Disease', (168, 173))	('expression', 'Var', (40, 50))	('adverse OS', 'Disease', (85, 95))	('gliomas', 'Disease', (177, 184))	('associated', 'Reg', (69, 79))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('patients', 'Species', '9606', (154, 162))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('PD-L1', 'Gene', (34, 39))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('PD-L1', 'Gene', '29126', (34, 39))
96540	26771840	The additional reason was that the majority of enrolled patients with high-grade gliomas could rarely have gene loss or mutation including PTEN, which contributed to upregulation of PD-L1 expression as well as different response to immune activity in the tumor microenvironment could lead to the non-uniform PD-L1 expression of tumor cells.	('patients', 'Species', '9606', (56, 64))	('lead to', 'Reg', (284, 291))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (328, 333))	('PD-L1', 'Gene', (308, 313))	('upregulation', 'PosReg', (166, 178))	('PTEN', 'Gene', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('gliomas', 'Disease', (81, 88))	('PD-L1', 'Gene', '29126', (308, 313))	('PD-L1', 'Gene', (182, 187))	('PD-L1', 'Gene', '29126', (182, 187))	('tumor', 'Disease', (255, 260))	('mutation', 'Var', (120, 128))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('PTEN', 'Gene', '5728', (139, 143))	('loss', 'NegReg', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('expression', 'MPA', (188, 198))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))
96548	26771840	Some studies demonstrated that PD-L1 expression on tumor cells was significantly associated with adverse prognosis in various malignancies, and other studies revealed that PD-L1 expression on tumor cells was significantly associated with better prognosis in several malignancies.	('PD-L1', 'Gene', '29126', (172, 177))	('expression', 'Var', (37, 47))	('malignancies', 'Disease', (266, 278))	('tumor', 'Disease', (192, 197))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PD-L1', 'Gene', '29126', (31, 36))	('tumor', 'Disease', (51, 56))	('malignancies', 'Disease', (126, 138))	('associated', 'Reg', (222, 232))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('malignancies', 'Disease', 'MESH:D009369', (266, 278))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('better', 'PosReg', (238, 244))	('associated', 'Reg', (81, 91))	('PD-L1', 'Gene', (172, 177))	('PD-L1', 'Gene', (31, 36))
96564	26771840	However, a statistical tendency was found between PD-L1 expression and better prognosis in the patients with short-time survival or follow up.	('PD-L1', 'Gene', (50, 55))	('expression', 'Var', (56, 66))	('PD-L1', 'Gene', '29126', (50, 55))	('patients', 'Species', '9606', (95, 103))
96566	26771840	Therefore, further studies were needed to investigate the complex role of PD-L1 expression and the treatment effect of inhibition of PD-1 and PD-L1 in large scale clinical trials for patients with gliomas.	('PD-1', 'Gene', '5133', (133, 137))	('PD-L1', 'Gene', (74, 79))	('PD-L1', 'Gene', '29126', (142, 147))	('gliomas', 'Disease', (197, 204))	('gliomas', 'Phenotype', 'HP:0009733', (197, 204))	('inhibition', 'Var', (119, 129))	('gliomas', 'Disease', 'MESH:D005910', (197, 204))	('PD-L1', 'Gene', '29126', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('PD-L1', 'Gene', (142, 147))	('patients', 'Species', '9606', (183, 191))	('PD-1', 'Gene', (133, 137))
96586	29846705	IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II-III gliomas) have not been thoroughly investigated.	('II gliomas', 'Disease', (222, 232))	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Disease', (225, 232))	('II gliomas', 'Disease', 'MESH:D005910', (222, 232))	('gliomas', 'Disease', (156, 163))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (225, 232))	('gliomas', 'Disease', (99, 106))	('mutation', 'Var', (4, 12))	('gliomas', 'Phenotype', 'HP:0009733', (225, 232))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
96587	29846705	The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('vascular', 'MPA', (144, 152))	('tumor', 'Disease', (83, 88))	('affects', 'Reg', (136, 143))	('mutation', 'Var', (120, 128))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('isocitrate dehydrogenase', 'Gene', (89, 113))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('isocitrate dehydrogenase', 'Gene', '3417', (89, 113))
96603	29846705	Based on integrative molecular profiling, lower-grade gliomas (LGGs; World Health Organization [WHO] grades II-III) have been classified into 3 molecular subgroups: isocitrate dehydrogenase (IDH) wild-type, IDH-mutated with 1p/19q codeletion (IDH mut-codel), and IDH-mutated without 1p/19q codeletion (IDH mut-noncodel).	('1p/19q codeletion', 'Var', (224, 241))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('IDH', 'Gene', '3417', (263, 266))	('IDH', 'Gene', (302, 305))	('gliomas', 'Disease', (54, 61))	('IDH', 'Gene', (191, 194))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('isocitrate dehydrogenase', 'Gene', '3417', (165, 189))	('isocitrate dehydrogenase', 'Gene', (165, 189))	('IDH', 'Gene', (207, 210))	('IDH', 'Gene', (263, 266))	('IDH', 'Gene', '3417', (302, 305))	('IDH', 'Gene', '3417', (191, 194))	('IDH', 'Gene', (243, 246))	('IDH', 'Gene', '3417', (207, 210))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH', 'Gene', '3417', (243, 246))
96604	29846705	Gliomas that lack IDH mutations are molecularly and clinically similar to primary glioblastomas (WHO grade IV).	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('IDH', 'Gene', (18, 21))	('glioblastomas', 'Disease', 'MESH:D005909', (82, 95))	('IDH', 'Gene', '3417', (18, 21))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('glioblastomas', 'Disease', (82, 95))	('mutations', 'Var', (22, 31))	('Gliomas', 'Disease', (0, 7))
96627	29846705	Use of anonymized biobank material and tumor tissue microarrays was granted by Uppsala County's ethical committee (Ups 03-412/2003-10-02, Dnr 2010/291/2010-11-17, Dnr Ups 02-330, Ups 06-084, Dnr Ki 02-254).	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Ups 03-412/2003-10-02', 'Var', (115, 136))	('Dnr Ups 02-330', 'Var', (163, 177))	('tumor', 'Disease', (39, 44))
96662	29846705	By dichotomizing patients into 2 groups of equal size according to their MV scores, we found that a high MV score was significantly associated with shorter survival (P = 0.0265, log-rank test) (Fig.	('high', 'Var', (100, 104))	('shorter', 'NegReg', (148, 155))	('patients', 'Species', '9606', (17, 25))	('survival', 'MPA', (156, 164))
96664	29846705	To investigate potential differences in tumor angiogenesis in molecular subgroups of LGG, we compared the MV score in each subgroup by combining the dataset from the database of TCGA with published information regarding the presence of IDH mutations and 1p/19q codeletions in these tumors (http://gliovis.bioinfo.cnio.es/).	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (282, 287))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('IDH', 'Gene', (236, 239))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('IDH', 'Gene', '3417', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mutations', 'Var', (240, 249))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
96670	29846705	IDH wild-type gliomas can be subdivided into 3 subgroups with different prognoses: combination of trisomy of whole chromosome 7 and loss of chromosomal arm 10q (+7/-10q), only TERTp mutated (TERTp mut), and unclassified.	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('IDH', 'Gene', (0, 3))	('loss', 'NegReg', (132, 136))	('IDH', 'Gene', '3417', (0, 3))	('TERTp', 'Gene', (176, 181))	('TERTp', 'Gene', '7015', (176, 181))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('TERTp', 'Gene', (191, 196))	('TERTp', 'Gene', '7015', (191, 196))	('trisomy', 'Var', (98, 105))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('gliomas', 'Disease', (14, 21))
96680	29846705	The IDH1-R132H mutation accounts for nearly 80% of all IDH mutations, and by staining of IDH1-R132H, we cannot exclude the presence of other, less common IDH1 mutations or IDH2 mutations.	('IDH1', 'Gene', '3417', (4, 8))	('IDH', 'Gene', '3417', (4, 7))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('IDH1', 'Gene', (89, 93))	('IDH1', 'Gene', '3417', (154, 158))	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', (55, 58))	('IDH2', 'Gene', (172, 176))	('IDH1', 'Gene', '3417', (89, 93))	('IDH', 'Gene', (172, 175))	('IDH2', 'Gene', '3418', (172, 176))	('R132H', 'Mutation', 'rs121913500', (94, 99))	('IDH', 'Gene', '3417', (55, 58))	('IDH1', 'Gene', (4, 8))	('mutations', 'Var', (59, 68))	('IDH', 'Gene', (154, 157))	('IDH', 'Gene', (4, 7))	('IDH', 'Gene', '3417', (172, 175))	('IDH1', 'Gene', (154, 158))	('IDH', 'Gene', (89, 92))	('IDH', 'Gene', '3417', (154, 157))
96696	29846705	However, high SPRY4 expression significantly correlated with poor survival in IDH wild-type LGGs (Fig.	('expression', 'MPA', (20, 30))	('SPRY4', 'Gene', (14, 19))	('poor', 'NegReg', (61, 65))	('SPRY4', 'Gene', '81848', (14, 19))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', '3417', (78, 81))	('high', 'Var', (9, 13))
96697	29846705	4E), and high ANGPT2 expression significantly correlated with poor survival in IDH-mutated tumors (Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', '3417', (79, 82))	('ANGPT2', 'Gene', '285', (14, 20))	('expression', 'MPA', (21, 31))	('ANGPT2', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('poor', 'NegReg', (62, 66))	('high', 'Var', (9, 13))
96722	29846705	Inhibition of TGFbeta signaling altered vascular morphology in mouse models of glioma, and combined TGFbeta and VEGF inhibition suppressed tumor angiogenesis and prolonged survival in GL261 glioma.	('mouse', 'Species', '10090', (63, 68))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('tumor', 'Disease', (139, 144))	('altered', 'Reg', (32, 39))	('inhibition suppressed', 'NegReg', (117, 138))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('GL261', 'CellLine', 'CVCL:Y003', (184, 189))	('TGFbeta', 'Gene', (100, 107))	('glioma', 'Disease', (190, 196))	('survival', 'CPA', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('VEGF', 'Gene', (112, 116))	('prolonged', 'PosReg', (162, 171))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('Inhibition', 'Var', (0, 10))	('vascular', 'MPA', (40, 48))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))
96732	30208924	The treatment experiment was performed in an intracranial orthotopic xenograft model by knockdown of LGR5 or by using the Wnt/beta-catenin pathway inhibitor Wnt-C59.	('p', 'Chemical', 'MESH:D010758', (65, 66))	('p', 'Chemical', 'MESH:D010758', (29, 30))	('knockdown', 'Var', (88, 97))	('p', 'Chemical', 'MESH:D010758', (139, 140))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('LGR5', 'Gene', (101, 105))
96734	30208924	LGR5+ cells possessed stronger stemness properties compared to LGR5- cells.	('stronger', 'PosReg', (22, 30))	('p', 'Chemical', 'MESH:D010758', (40, 41))	('p', 'Chemical', 'MESH:D010758', (12, 13))	('p', 'Chemical', 'MESH:D010758', (43, 44))	('stemness properties', 'CPA', (31, 50))	('p', 'Chemical', 'MESH:D010758', (54, 55))	('LGR5+', 'Var', (0, 5))
96736	30208924	Both LGR5 knockdown and Wnt-C59 reduced tumor invasion and migration and blocked EMT by inhibiting the Wnt/beta-catenin pathway in vitro and suppressed the intracranial orthotopic xenograft growth and prolonged the survival of xenograft mice in vivo.	('p', 'Chemical', 'MESH:D010758', (143, 144))	('mice', 'Species', '10090', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('Wnt-C59 reduced tumor', 'Disease', (24, 45))	('Wnt-C59 reduced tumor', 'Disease', 'MESH:D015354', (24, 45))	('suppressed', 'NegReg', (141, 151))	('inhibiting', 'NegReg', (88, 98))	('migration', 'CPA', (59, 68))	('knockdown', 'Var', (10, 19))	('Wnt/beta-catenin pathway', 'Pathway', (103, 127))	('p', 'Chemical', 'MESH:D010758', (176, 177))	('prolonged', 'PosReg', (201, 210))	('EMT', 'CPA', (81, 84))	('p', 'Chemical', 'MESH:D010758', (201, 202))	('p', 'Chemical', 'MESH:D010758', (144, 145))	('LGR5', 'Gene', (5, 9))	('blocked', 'NegReg', (73, 80))	('p', 'Chemical', 'MESH:D010758', (120, 121))	('intracranial orthotopic xenograft growth', 'CPA', (156, 196))	('survival', 'CPA', (215, 223))
96738	30208924	Glioma patients with high expression of LGR5 showed significantly poorer prognosis.	('LGR5', 'Gene', (40, 44))	('p', 'Chemical', 'MESH:D010758', (28, 29))	('p', 'Chemical', 'MESH:D010758', (7, 8))	('p', 'Chemical', 'MESH:D010758', (66, 67))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('high expression', 'Var', (21, 36))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('p', 'Chemical', 'MESH:D010758', (73, 74))	('Glioma', 'Disease', (0, 6))	('patients', 'Species', '9606', (7, 15))
96749	30208924	Accumulated evidences have suggested that induction of EMT induces CSC phenotype in tumor cells or human mammary epithelial cells and gives rise to invasive and metastatic CSCs.	('CSC phenotype', 'MPA', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('gives rise to', 'Reg', (134, 147))	('induction', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('EMT', 'Gene', (55, 58))	('induces', 'Reg', (59, 66))	('tumor', 'Disease', (84, 89))	('p', 'Chemical', 'MESH:D010758', (114, 115))	('p', 'Chemical', 'MESH:D010758', (78, 79))	('p', 'Chemical', 'MESH:D010758', (71, 72))	('human', 'Species', '9606', (99, 104))
96782	30208924	Parent cells and enriched cells were incubated with LGR5 (#ab75735; Abcam) and an isotype control (#ab171870; Abcam) and subsequently with secondary antibodies (Alexa Fluor 488) for 30 min at room temperature and washed three times in phosphate buffered saline (PBS) after each reaction to detect the proportion of LGR5 expression.	('PBS', 'Disease', 'MESH:D011535', (262, 265))	('PBS', 'Disease', (262, 265))	('saline', 'Chemical', 'MESH:D012965', (254, 260))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('phosphate', 'Chemical', 'MESH:D010710', (235, 244))	('#ab75735', 'Var', (58, 66))	('p', 'Chemical', 'MESH:D010758', (200, 201))	('p', 'Chemical', 'MESH:D010758', (304, 305))	('p', 'Chemical', 'MESH:D010758', (322, 323))	('p', 'Chemical', 'MESH:D010758', (301, 302))	('p', 'Chemical', 'MESH:D010758', (235, 236))	('Alexa Fluor 488', 'Chemical', '-', (161, 176))	('p', 'Chemical', 'MESH:D010758', (239, 240))
96784	30208924	To explore the proportion of reported stem cell markers in both LGR5+ and LGR5- glioma cells, the cells were incubated with APC anti-human CD133 antibody (#130-090-826; Miltenyi), APC anti-human CD44 antibody (#17-0441-82; eBioscience), APC anti-human CD24 antibody (#311118; BioLegend), APC anti-human CD90 antibody (#328114; BioLegend) or APC anti-human EpCAM (#328208; BioLegend) antibody for 30 min at room temperature.	('p', 'Chemical', 'MESH:D010758', (31, 32))	('p', 'Chemical', 'MESH:D010758', (357, 358))	('APC', 'Disease', 'MESH:D011125', (237, 240))	('APC', 'Disease', (237, 240))	('#328114', 'Var', (318, 325))	('#311118', 'Var', (267, 274))	('APC', 'Disease', 'MESH:D011125', (341, 344))	('APC', 'Disease', (341, 344))	('human', 'Species', '9606', (350, 355))	('CD24', 'Gene', (252, 256))	('APC', 'Disease', 'MESH:D011125', (124, 127))	('APC', 'Disease', 'MESH:D011125', (180, 183))	('APC', 'Disease', (124, 127))	('human', 'Species', '9606', (246, 251))	('human', 'Species', '9606', (133, 138))	('EpCAM', 'Gene', (356, 361))	('#328208', 'Var', (363, 370))	('p', 'Chemical', 'MESH:D010758', (5, 6))	('APC', 'Disease', (180, 183))	('glioma', 'Disease', (80, 86))	('EpCAM', 'Gene', '4072', (356, 361))	('CD90', 'Gene', (303, 307))	('human', 'Species', '9606', (189, 194))	('p', 'Chemical', 'MESH:D010758', (18, 19))	('p', 'Chemical', 'MESH:D010758', (414, 415))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('APC', 'Disease', 'MESH:D011125', (288, 291))	('CD90', 'Gene', '7070', (303, 307))	('CD24', 'Gene', '100133941', (252, 256))	('APC', 'Disease', (288, 291))	('CD133', 'Gene', (139, 144))	('CD44', 'Gene', '960', (195, 199))	('CD133', 'Gene', '8842', (139, 144))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('CD44', 'Gene', (195, 199))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('human', 'Species', '9606', (297, 302))
96801	30208924	The multiplicity of infection (MOI) was 5 for U251 and 10 for 8591.	('infection', 'Disease', 'MESH:D007239', (20, 29))	('p', 'Chemical', 'MESH:D010758', (9, 10))	('U251', 'Var', (46, 50))	('infection', 'Disease', (20, 29))
96817	30208924	The sorting glioma cells suspended in 100 muL of DMEM were injected directly into the dorsal areas (left for LGR5- and right for LGR5+) of mice with 5 x 105 cells/mice for U251 or 1 x 106 cells/mice for 8591.	('U251', 'Var', (172, 176))	('DMEM', 'Chemical', '-', (49, 53))	('p', 'Chemical', 'MESH:D010758', (28, 29))	('glioma', 'Disease', (12, 18))	('mice', 'Species', '10090', (163, 167))	('mice', 'Species', '10090', (139, 143))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('mice', 'Species', '10090', (194, 198))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
96824	30208924	All antibodies used were as follows: LGR5 (#TA502948; OriGene), Ki67 (#ab16667; Abcam), CD44 (#15675-1-AP, Proteintech), SOX2 (#ab92494; Abcam), Non-phospho (Active) beta-catenin Ser33/37/Thr41 (#8814; Cell Signaling) and N-cadherin (#bs-1172R; Bioss).	('CD44', 'Gene', '960', (88, 92))	('#TA502948', 'Var', (43, 52))	('N-cadherin', 'Gene', '1000', (222, 232))	('SOX2', 'Gene', (121, 125))	('#bs-1172R;', 'Var', (234, 244))	('SOX2', 'Gene', '6657', (121, 125))	('#15675-1-AP', 'Var', (94, 105))	('CD44', 'Gene', (88, 92))	('Ki67', 'Gene', (64, 68))	('p', 'Chemical', 'MESH:D010758', (149, 150))	('Ser33', 'Chemical', '-', (179, 184))	('Thr41', 'Chemical', '-', (188, 193))	('p', 'Chemical', 'MESH:D010758', (153, 154))	('#ab92494;', 'Var', (127, 136))	('Ki67', 'Gene', '17345', (64, 68))	('N-cadherin', 'Gene', (222, 232))
96832	30208924	The primary antibodies used were as follows: LGR5 (#LS-C98619; Biosciences), LGR5 (#TA502948; OriGene), GFAP (#ab190288; Abcam), SOX2 (#3579; Cell Signaling) and N-cadherin (#13116; Cell Signaling).	('#13116', 'Var', (174, 180))	('p', 'Chemical', 'MESH:D010758', (4, 5))	('GFAP', 'Gene', '2670', (104, 108))	('SOX2', 'Gene', '6657', (129, 133))	('#LS-C98619', 'Var', (51, 61))	('#TA502948', 'Var', (83, 92))	('SOX2', 'Gene', (129, 133))	('#ab190288', 'Var', (110, 119))	('N-cadherin', 'Gene', (162, 172))	('#3579;', 'Var', (135, 141))	('GFAP', 'Gene', (104, 108))	('N-cadherin', 'Gene', '1000', (162, 172))
96854	30208924	These results indicated that LGR5+ cells exhibited stronger tumor initiation and cloning abilities compared to LGR5- cells in vitro.	('tumor initiation', 'Disease', (60, 76))	('tumor initiation', 'Disease', 'MESH:D009369', (60, 76))	('stronger', 'PosReg', (51, 59))	('LGR5+', 'Var', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cloning abilities', 'CPA', (81, 98))	('p', 'Chemical', 'MESH:D010758', (102, 103))
96859	30208924	LGR5+ glioma cells expressed stronger resistance to TMZ than LGR5- glioma cells.	('glioma', 'Disease', (67, 73))	('p', 'Chemical', 'MESH:D010758', (21, 22))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('glioma', 'Disease', (6, 12))	('resistance to TMZ', 'MPA', (38, 55))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('LGR5+', 'Var', (0, 5))	('stronger', 'PosReg', (29, 37))
96860	30208924	We performed invasion and migration assays of LGR5+ and LGR5- U251 cells and found that LGR5+ U251 cells were significantly more invasive and migratory than LGR5- cells (P < 0.001, n = 3; P < 0.001, n = 3, respectively, Fig.	('LGR5+ U251', 'Var', (88, 98))	('p', 'Chemical', 'MESH:D010758', (3, 4))	('invasive', 'CPA', (129, 137))	('migration', 'CPA', (26, 35))	('more', 'PosReg', (124, 128))	('migratory', 'CPA', (142, 151))	('p', 'Chemical', 'MESH:D010758', (209, 210))
96868	30208924	The expression of LGR5 was remarkably higher in LGR5+ xenografts than that in LGR5- xenografts (P < 0.01, n = 5, Fig.	('p', 'Chemical', 'MESH:D010758', (6, 7))	('LGR5+', 'Var', (48, 53))	('expression', 'MPA', (4, 14))	('LGR5', 'Gene', (18, 22))	('higher', 'PosReg', (38, 44))
96869	30208924	The expression level of Ki67, a sign of proliferation for tumor malignancy, was higher in LGR5+ xenografts than that in LGR5- xenografts (P < 0.05, n = 5, Fig.	('expression level', 'MPA', (4, 20))	('p', 'Chemical', 'MESH:D010758', (6, 7))	('Ki67', 'Gene', '17345', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('LGR5+', 'Var', (90, 95))	('tumor malignancy', 'Disease', 'MESH:D018198', (58, 74))	('Ki67', 'Gene', (24, 28))	('p', 'Chemical', 'MESH:D010758', (40, 41))	('higher', 'PosReg', (80, 86))	('tumor malignancy', 'Disease', (58, 74))
96870	30208924	Moreover, the LGR5+ xenografts exhibited significantly higher expression of N-cadherin compared with the LGR5- xenografts (P < 0.01, n = 5, Fig.	('LGR5+', 'Var', (14, 19))	('expression', 'MPA', (62, 72))	('N-cadherin', 'Gene', (76, 86))	('p', 'Chemical', 'MESH:D010758', (90, 91))	('N-cadherin', 'Gene', '1000', (76, 86))	('higher', 'PosReg', (55, 61))	('p', 'Chemical', 'MESH:D010758', (64, 65))
96879	30208924	These results suggest that LGR5+ cells possess stronger tumorigenicity in vivo than LGR5- cells, and LGR5 may thus be implicated in the malignancy, invasiveness and stemness of glioma.	('p', 'Chemical', 'MESH:D010758', (120, 121))	('stemness of glioma', 'Disease', 'MESH:D005910', (165, 183))	('malignancy', 'Disease', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('LGR5+', 'Var', (27, 32))	('stemness of glioma', 'Disease', (165, 183))	('implicated', 'Reg', (118, 128))	('stronger', 'PosReg', (47, 55))	('tumor', 'Disease', (56, 61))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('p', 'Chemical', 'MESH:D010758', (39, 40))	('LGR5', 'Gene', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
96883	30208924	To further reveal the relationship between LGR5 and the reported CSC markers in GSCs, we obtained enriched cells (U251-GSCs, 8591-GSCs) from U251 and 8591 glioma cells (Fig.	('p', 'Chemical', 'MESH:D010758', (58, 59))	('U251', 'Var', (141, 145))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('p', 'Chemical', 'MESH:D010758', (33, 34))	('glioma', 'Disease', (155, 161))
96885	30208924	Immunofluorescence double staining showed that LGR5 and SOX2 were co-expressed in both U251-GSCs and 8591-GSCs (Fig.	('LGR5', 'Gene', (47, 51))	('U251-GSCs', 'Var', (87, 96))	('SOX2', 'Gene', '6657', (56, 60))	('SOX2', 'Gene', (56, 60))	('8591-GSCs', 'Var', (101, 110))	('p', 'Chemical', 'MESH:D010758', (71, 72))
96895	30208924	We found that the invasion and migration capacities of shLGR5 GSCs were weakened as a result of LGR5 knockdown, whereas the invasion and migration capacities of Lenti-LGR5 GSCs were enhanced as a result of LGR5 overexpression (Fig.	('p', 'Chemical', 'MESH:D010758', (217, 218))	('overexpression', 'PosReg', (211, 225))	('LGR5', 'Gene', (96, 100))	('enhanced', 'PosReg', (182, 190))	('p', 'Chemical', 'MESH:D010758', (149, 150))	('LGR5', 'Protein', (206, 210))	('p', 'Chemical', 'MESH:D010758', (43, 44))	('weakened', 'NegReg', (72, 80))	('knockdown', 'Var', (101, 110))
96906	30208924	To test this assumption, we treated U251 and 8591 GSCs with the Wnt/beta-catenin inhibitor Wnt-C59 and found that the expression levels of both the Wnt/beta-catenin pathway and EMT markers were inhibited in U251 and 8591 GSCs except for LGR5 expression level (Fig.	('p', 'Chemical', 'MESH:D010758', (120, 121))	('p', 'Chemical', 'MESH:D010758', (165, 166))	('U251', 'Var', (207, 211))	('inhibited', 'NegReg', (194, 203))	('p', 'Chemical', 'MESH:D010758', (230, 231))	('p', 'Chemical', 'MESH:D010758', (244, 245))	('p', 'Chemical', 'MESH:D010758', (18, 19))	('8591', 'Var', (216, 220))	('expression levels', 'MPA', (118, 135))	('EMT markers', 'CPA', (177, 188))	('Wnt/beta-catenin pathway', 'Pathway', (148, 172))
96912	30208924	The intracranial tumors induced by U251-GSCs were assessed on days 12, 25 and 39 (Fig.	('intracranial tumors', 'Disease', (4, 23))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('U251-GSCs', 'Var', (35, 44))	('intracranial tumors', 'Disease', 'MESH:D001932', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
96916	30208924	A log-rank test of the three groups revealed that the OS of the shLGR5 and Wnt-C59 mice was significantly prolonged compared with that of the shCtrl mice (n = 5; Fig.	('shLGR5', 'Var', (64, 70))	('p', 'Chemical', 'MESH:D010758', (106, 107))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('mice', 'Species', '10090', (83, 87))	('OS', 'Chemical', '-', (54, 56))	('mice', 'Species', '10090', (149, 153))	('p', 'Chemical', 'MESH:D010758', (33, 34))	('prolonged', 'PosReg', (106, 115))
96928	30208924	These results demonstrated that the inhibition of LGR5 could inhibit glioma growth and prolong the survival of the xenograft mice in vivo effectively, indicating that LGR5 might serve as a prospective therapeutic target for glioma.	('glioma', 'Disease', (69, 75))	('p', 'Chemical', 'MESH:D010758', (189, 190))	('inhibition', 'Var', (36, 46))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('prolong', 'PosReg', (87, 94))	('glioma growth', 'Disease', (69, 82))	('glioma growth', 'Disease', 'MESH:D005910', (69, 82))	('p', 'Chemical', 'MESH:D010758', (206, 207))	('survival', 'CPA', (99, 107))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('mice', 'Species', '10090', (125, 129))	('inhibit', 'NegReg', (61, 68))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('p', 'Chemical', 'MESH:D010758', (193, 194))	('glioma', 'Disease', (224, 230))	('LGR5', 'Gene', (50, 54))
96941	30208924	Notably, although there was no statistical significance, patients with high expression of LGR5 (LGR5high) in the HGG group tended to have more severe peritumoral edema (P = 0.079) (Additional file 1: Table S1).	('edema', 'Disease', 'MESH:D004487', (162, 167))	('high expression', 'Var', (71, 86))	('edema', 'Phenotype', 'HP:0000969', (162, 167))	('p', 'Chemical', 'MESH:D010758', (121, 122))	('patients', 'Species', '9606', (57, 65))	('edema', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('p', 'Chemical', 'MESH:D010758', (57, 58))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('p', 'Chemical', 'MESH:D010758', (78, 79))	('LGR5', 'Gene', (90, 94))	('p', 'Chemical', 'MESH:D010758', (150, 151))	('tumor', 'Disease', (154, 159))
96945	30208924	The median PFS and OS were 7.0 and 17.5 months for LGR5high patients and 10.5 and 23.0 months for LGR5low patients, respectively (Additional file 10: Table S3).	('p', 'Chemical', 'MESH:D010758', (106, 107))	('LGR5low', 'Gene', (98, 105))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('p', 'Chemical', 'MESH:D010758', (60, 61))	('patients', 'Species', '9606', (60, 68))	('LGR5low', 'Gene', '8549', (98, 105))	('patients', 'Species', '9606', (106, 114))	('OS', 'Chemical', '-', (19, 21))	('LGR5high', 'Var', (51, 59))
96946	30208924	In the LGG group, LGR5high patients had significantly lower RFS (P = 0.012) than LGR5low patients, while the OS was not statistically significant between LGR5high patients and LGR5low patients (P = 0.058).	('LGR5low', 'Gene', '8549', (176, 183))	('RFS', 'Disease', 'MESH:D005198', (60, 63))	('LGG', 'Disease', (7, 10))	('p', 'Chemical', 'MESH:D010758', (163, 164))	('patients', 'Species', '9606', (27, 35))	('RFS', 'Disease', (60, 63))	('LGR5low', 'Gene', (81, 88))	('patients', 'Species', '9606', (163, 171))	('p', 'Chemical', 'MESH:D010758', (27, 28))	('p', 'Chemical', 'MESH:D010758', (184, 185))	('LGR5low', 'Gene', (176, 183))	('OS', 'Chemical', '-', (109, 111))	('LGR5high', 'Var', (18, 26))	('p', 'Chemical', 'MESH:D010758', (89, 90))	('patients', 'Species', '9606', (184, 192))	('LGR5low', 'Gene', '8549', (81, 88))	('patients', 'Species', '9606', (89, 97))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('lower', 'NegReg', (54, 59))
96950	30208924	Moreover, LGR5 expression, the Karnofsky Performance Scale (KPS), IDH1 mutation and chemoradiotherapy were associated with worse OS according to the log-rank test (Additional file 10: Table S3).	('p', 'Chemical', 'MESH:D010758', (99, 100))	('IDH1', 'Gene', '3417', (66, 70))	('p', 'Chemical', 'MESH:D010758', (17, 18))	('mutation', 'Var', (71, 79))	('LGR5', 'Gene', (10, 14))	('OS', 'Chemical', '-', (129, 131))	('IDH1', 'Gene', (66, 70))
96951	30208924	Multivariate analysis showed that LGR5 expression, IDH1 mutation and chemoradiotherapy were independent indicators of OS (Table 1).	('IDH1', 'Gene', '3417', (51, 55))	('p', 'Chemical', 'MESH:D010758', (96, 97))	('p', 'Chemical', 'MESH:D010758', (41, 42))	('LGR5', 'Gene', (34, 38))	('OS', 'Chemical', '-', (118, 120))	('p', 'Chemical', 'MESH:D010758', (84, 85))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))
96952	30208924	In the LGG group, IDH1 mutation and chemoradiotherapy significantly decreased both RFS and OS, whereas LGR5 expression was only related with shorter PFS but not OS (Additional file 11: Table S4).	('decreased', 'NegReg', (68, 77))	('OS', 'Chemical', '-', (161, 163))	('mutation', 'Var', (23, 31))	('RFS', 'Disease', 'MESH:D005198', (83, 86))	('IDH1', 'Gene', '3417', (18, 22))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('p', 'Chemical', 'MESH:D010758', (110, 111))	('RFS', 'Disease', (83, 86))	('OS', 'Chemical', '-', (91, 93))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('IDH1', 'Gene', (18, 22))
96960	30208924	Moreover, the tumors produced by LGR5+ cells were larger, more invasive and malignant in subcutaneous transplantation experiments than those produced by LGR5- cells.	('p', 'Chemical', 'MESH:D010758', (120, 121))	('p', 'Chemical', 'MESH:D010758', (107, 108))	('p', 'Chemical', 'MESH:D010758', (21, 22))	('malignant', 'CPA', (76, 85))	('tumors', 'Disease', (14, 20))	('p', 'Chemical', 'MESH:D010758', (141, 142))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('more', 'PosReg', (58, 62))	('LGR5+ cells', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('invasive', 'CPA', (63, 71))
96961	30208924	These results strongly indicate that LGR5+ glioma cells possess a stronger stem-like phenotype.	('glioma', 'Disease', (43, 49))	('p', 'Chemical', 'MESH:D010758', (56, 57))	('LGR5+', 'Var', (37, 42))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('stronger', 'PosReg', (66, 74))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('p', 'Chemical', 'MESH:D010758', (85, 86))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
96963	30208924	Our FCM analysis revealed that LGR5+ glioma cells displayed significantly higher expression of these CSCs markers, indicating that LGR5+ glioma cells have stronger stem cell characteristics than LGR5- cells.	('stem cell characteristics', 'CPA', (164, 189))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('p', 'Chemical', 'MESH:D010758', (83, 84))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('higher', 'PosReg', (74, 80))	('LGR5+', 'Var', (131, 136))	('glioma', 'Disease', (37, 43))	('stronger', 'PosReg', (155, 163))	('glioma', 'Disease', (137, 143))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('expression', 'MPA', (81, 91))
96964	30208924	Furthermore, the conjecture that the expression of these CSCs markers in GSCs were modulated by LGR5 was confirmed by results indicating reduced expression of CD133, CD24, CD44 and EpCAM in LGR5 knockdown GSCs.	('p', 'Chemical', 'MESH:D010758', (182, 183))	('CD24', 'Gene', (166, 170))	('CD133', 'Gene', (159, 164))	('EpCAM', 'Gene', '4072', (181, 186))	('CD133', 'Gene', '8842', (159, 164))	('p', 'Chemical', 'MESH:D010758', (147, 148))	('LGR5', 'Gene', (96, 100))	('expression', 'MPA', (145, 155))	('CD44', 'Gene', '960', (172, 176))	('p', 'Chemical', 'MESH:D010758', (39, 40))	('knockdown', 'Var', (195, 204))	('LGR5', 'Gene', (190, 194))	('CD44', 'Gene', (172, 176))	('EpCAM', 'Gene', (181, 186))	('CD24', 'Gene', '100133941', (166, 170))	('reduced', 'NegReg', (137, 144))
96968	30208924	Similarly, our research showed that LGR5+ cells possessed significantly stronger stem cell characteristics in cell proliferation, cloning, tumorigenicity, and even drug resistance.	('cloning', 'CPA', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('drug resistance', 'CPA', (164, 179))	('drug resistance', 'Phenotype', 'HP:0020174', (164, 179))	('p', 'Chemical', 'MESH:D010758', (48, 49))	('p', 'Chemical', 'MESH:D010758', (115, 116))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('LGR5+', 'Var', (36, 41))	('cell proliferation', 'CPA', (110, 128))	('stronger', 'PosReg', (72, 80))
96972	30208924	The tumors derived from LGR5+ cells possessed higher invasive phenotype.	('LGR5+', 'Var', (24, 29))	('higher', 'PosReg', (46, 52))	('p', 'Chemical', 'MESH:D010758', (62, 63))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('invasive phenotype', 'CPA', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('p', 'Chemical', 'MESH:D010758', (36, 37))
96979	30208924	Notably, we found that both LGR5 knockdown and Wnt-C59 significantly inhibited the growth of tumors and prolonged the survival time of mice in intracranial orthotopic xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('inhibited', 'NegReg', (69, 78))	('knockdown', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('p', 'Chemical', 'MESH:D010758', (104, 105))	('p', 'Chemical', 'MESH:D010758', (163, 164))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('LGR5', 'Gene', (28, 32))	('mice', 'Species', '10090', (135, 139))	('prolonged', 'PosReg', (104, 113))	('survival time', 'CPA', (118, 131))	('tumors', 'Disease', (93, 99))
96980	30208924	Additionally, the treatment effect of orthotopic xenografts tended to be more distinct in the LGR5 knockdown group, suggesting the possibility of the involvement of LGR5 with other tumorigenesis-related pathways.	('tumor', 'Disease', (181, 186))	('p', 'Chemical', 'MESH:D010758', (203, 204))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('p', 'Chemical', 'MESH:D010758', (131, 132))	('p', 'Chemical', 'MESH:D010758', (45, 46))	('involvement', 'Reg', (150, 161))	('knockdown', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('p', 'Chemical', 'MESH:D010758', (113, 114))	('LGR5', 'Gene', (94, 98))
96981	30208924	IHC analysis of orthotopic xenografts revealed that the expression levels of Ki67 and Active-beta-catenin were significantly decreased in both the LGR5 knockdown and Wnt-C59 groups.	('Active-beta-catenin', 'MPA', (86, 105))	('knockdown', 'Var', (152, 161))	('p', 'Chemical', 'MESH:D010758', (58, 59))	('p', 'Chemical', 'MESH:D010758', (178, 179))	('Ki67', 'Gene', (77, 81))	('LGR5', 'Gene', (147, 151))	('decreased', 'NegReg', (125, 134))	('expression levels', 'MPA', (56, 73))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('Ki67', 'Gene', '17345', (77, 81))
96985	30208924	In addition, LGR5+ N-cadherin+ cells were mostly observed in the invasive front of human glioma tissues, while glioma cells inside tumors rarely expressed LGR5 and N-cadherin, suggesting a correlation between the two markers and their important role in the high invasion of glioma.	('N-cadherin', 'Gene', (164, 174))	('p', 'Chemical', 'MESH:D010758', (237, 238))	('glioma', 'Disease', (274, 280))	('N-cadherin', 'Gene', '1000', (164, 174))	('glioma', 'Disease', 'MESH:D005910', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('glioma', 'Disease', (89, 95))	('LGR5+', 'Var', (13, 18))	('glioma', 'Disease', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('N-cadherin', 'Gene', (19, 29))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('p', 'Chemical', 'MESH:D010758', (147, 148))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('N-cadherin', 'Gene', '1000', (19, 29))	('tumors', 'Disease', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('human', 'Species', '9606', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
96986	30208924	Furthermore, IDH1 mutation, a favorable predictor of prognosis, was confirmed to be negatively correlated with LGR5 by chi-square tests in both HGG and LGG group.	('negatively', 'NegReg', (84, 94))	('IDH1', 'Gene', (13, 17))	('p', 'Chemical', 'MESH:D010758', (40, 41))	('LGG', 'Disease', (152, 155))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', '3417', (13, 17))	('LGR5', 'Gene', (111, 115))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('HGG', 'Disease', (144, 147))	('p', 'Chemical', 'MESH:D010758', (160, 161))
96987	30208924	This result indicated that IDH1 mutation in LGR5high glioma occurred less frequently than that in LGR5low glioma, suggesting that glioma patients with high expression of LGR5 may have a poor prognosis.	('p', 'Chemical', 'MESH:D010758', (158, 159))	('glioma', 'Disease', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('LGR5high', 'Var', (44, 52))	('p', 'Chemical', 'MESH:D010758', (186, 187))	('glioma', 'Disease', (106, 112))	('mutation', 'Var', (32, 40))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('LGR5low', 'Gene', (98, 105))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('patients', 'Species', '9606', (137, 145))	('IDH1', 'Gene', (27, 31))	('p', 'Chemical', 'MESH:D010758', (137, 138))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('glioma', 'Disease', (53, 59))	('LGR5low', 'Gene', '8549', (98, 105))	('p', 'Chemical', 'MESH:D010758', (191, 192))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('IDH1', 'Gene', '3417', (27, 31))
96992	30208924	The results revealed that LGR5 expression was an independent indicator of postoperative recurrence in both the HGG group and LGG group; moreover, LGR5 expression was also an independent indicator of OS in the HGG group, consistent with the results indicating that LGR5 knockdown prolonged the survival of nude mice in vivo.	('OS', 'Chemical', '-', (199, 201))	('knockdown', 'Var', (269, 278))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('p', 'Chemical', 'MESH:D010758', (217, 218))	('p', 'Chemical', 'MESH:D010758', (178, 179))	('p', 'Chemical', 'MESH:D010758', (79, 80))	('nude mice', 'Species', '10090', (305, 314))	('p', 'Chemical', 'MESH:D010758', (279, 280))	('p', 'Chemical', 'MESH:D010758', (153, 154))	('prolonged', 'PosReg', (279, 288))	('LGR5', 'Gene', (146, 150))	('p', 'Chemical', 'MESH:D010758', (74, 75))	('survival', 'CPA', (293, 301))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('p', 'Chemical', 'MESH:D010758', (33, 34))	('p', 'Chemical', 'MESH:D010758', (133, 134))
96996	30208924	Overall, our finding that LGR5high expression identifies a subset of glioma patients with a poorer survival profile than LGR5low expression might provide aid for clinicians in determining the prognosis of glioma patients.	('glioma', 'Disease', (69, 75))	('LGR5low', 'Gene', '8549', (121, 128))	('patients', 'Species', '9606', (212, 220))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('p', 'Chemical', 'MESH:D010758', (212, 213))	('p', 'Chemical', 'MESH:D010758', (131, 132))	('p', 'Chemical', 'MESH:D010758', (76, 77))	('p', 'Chemical', 'MESH:D010758', (146, 147))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('patients', 'Species', '9606', (76, 84))	('LGR5low', 'Gene', (121, 128))	('p', 'Chemical', 'MESH:D010758', (192, 193))	('glioma', 'Disease', (205, 211))	('LGR5high', 'Var', (26, 34))	('glioma', 'Disease', 'MESH:D005910', (205, 211))
97008	32046730	The dysfunction of Presenilin1 is the main reason for AD pathogenesis.	('AD', 'Phenotype', 'HP:0002511', (54, 56))	('AD', 'Disease', 'MESH:D000544', (54, 56))	('dysfunction', 'Var', (4, 15))	('AD', 'Disease', (54, 56))	('Presenilin1', 'Protein', (19, 30))
97029	32046730	The dysfunction of the Presenilin1 gene leading to aberrant APP cleavage is central to AD pathogenesis.	('AD', 'Phenotype', 'HP:0002511', (87, 89))	('dysfunction', 'Var', (4, 15))	('Presenilin1', 'Gene', (23, 34))	('APP cleavage', 'CPA', (60, 72))	('AD', 'Disease', 'MESH:D000544', (87, 89))	('AD', 'Disease', (87, 89))
97079	32046730	In all grades of glioma patients, using a cutoff value to divide 183 patients into a Presenilin1-high (Presenilin1high) group and a Presenilin1-low (Presenilin1low) group, we found that the 1-year, 2-year and 5-year OS rates of patients in the Presenilin1high group were significantly higher than those in the Presenilin1low group (Fig.	('Presenilin1high', 'Var', (244, 259))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('patients', 'Species', '9606', (228, 236))	('OS rates', 'MPA', (216, 224))	('glioma', 'Disease', (17, 23))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (69, 77))	('higher', 'PosReg', (285, 291))
97082	32046730	We also utilized Kaplan-Meier analysis to observe the correlation of Presenilin1 expression with the recurrence rates of glioma patients and found that the 1-year, 2-year and 5-year recurrence rates in the Presenilin1high group were significantly lower than those in the Presenilin1low group (Fig.	('Presenilin1high', 'Var', (206, 221))	('lower', 'NegReg', (247, 252))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('recurrence', 'CPA', (182, 192))	('patients', 'Species', '9606', (128, 136))	('glioma', 'Disease', (121, 127))
97096	32046730	However, blocking Presenilin1 significantly elevated the positive rate of Edu in U87 and U251 cells (Fig.	('Presenilin1', 'Gene', (18, 29))	('elevated', 'PosReg', (44, 52))	('U251', 'CellLine', 'CVCL:0021', (89, 93))	('Edu', 'CPA', (74, 77))	('positive', 'MPA', (57, 65))	('blocking', 'Var', (9, 17))
97105	32046730	Conversely, the stabilized beta-catenin level was elevated when Presenilin1 was downregulated and reduced when Presenilin1 was upregulated in U87 cells, indicating that Presenilin1 decreased beta-catenin stabilization by promoting degradation-related phosphorylation at Ser45 and Thr41/Ser37/Ser33.	('Ser45', 'Var', (270, 275))	('degradation-related phosphorylation', 'MPA', (231, 266))	('beta-catenin', 'Gene', '1499', (27, 39))	('elevated', 'PosReg', (50, 58))	('Ser', 'Chemical', 'MESH:C530429', (292, 295))	('beta-catenin', 'Gene', (191, 203))	('promoting', 'PosReg', (221, 230))	('Thr', 'Chemical', 'MESH:C055175', (280, 283))	('Thr41/Ser37/Ser33', 'Var', (280, 297))	('Ser', 'Chemical', 'MESH:C530429', (286, 289))	('beta-catenin', 'Gene', '1499', (191, 203))	('downregulated', 'NegReg', (80, 93))	('beta-catenin', 'Gene', (27, 39))	('Ser', 'Chemical', 'MESH:C530429', (270, 273))	('decreased', 'NegReg', (181, 190))
97109	32046730	4e, beta-catenin was primarily localized in the nucleus of U87 cells, and Presenilin1 deficiency distinctly elevated the expression of beta-catenin.	('beta-catenin', 'Gene', '1499', (4, 16))	('beta-catenin', 'Gene', (135, 147))	('expression', 'MPA', (121, 131))	('Presenilin1', 'Gene', (74, 85))	('deficiency', 'Var', (86, 96))	('beta-catenin', 'Gene', '1499', (135, 147))	('elevated', 'PosReg', (108, 116))	('beta-catenin', 'Gene', (4, 16))
97110	32046730	Additionally, we analyzed the colocalization of beta-catenin and DAPI and found that the Pearson index was significantly increased after Presenilin1 repression.	('repression', 'Var', (149, 159))	('beta-catenin', 'Gene', (48, 60))	('increased', 'PosReg', (121, 130))	('beta-catenin', 'Gene', '1499', (48, 60))	('Presenilin1', 'Gene', (137, 148))	('Pearson index', 'MPA', (89, 102))
97111	32046730	In contrast, we observed that the activation of Presenilin1 clearly decreased the expression of beta-catenin and the colocalization of beta-catenin to DAPI, suggesting that the repression of Presenilin1 maintained beta-catenin stabilization and transported it to the nucleus.	('decreased', 'NegReg', (68, 77))	('Presenilin1', 'Gene', (48, 59))	('Presenilin1', 'Gene', (191, 202))	('beta-catenin', 'Gene', '1499', (96, 108))	('expression', 'MPA', (82, 92))	('colocalization', 'MPA', (117, 131))	('repression', 'Var', (177, 187))	('beta-catenin', 'Gene', (135, 147))	('beta-catenin', 'Gene', '1499', (135, 147))	('transported', 'MPA', (245, 256))	('stabilization', 'MPA', (227, 240))	('beta-catenin', 'Gene', (214, 226))	('beta-catenin', 'Gene', '1499', (214, 226))	('beta-catenin', 'Gene', (96, 108))
97115	32046730	We found that the knockout of Presenilin1 significantly promoted the growth of subcutaneous GBM compared to the control (Fig.	('Presenilin1', 'Gene', (30, 41))	('knockout', 'Var', (18, 26))	('GBM', 'Disease', (92, 95))	('promoted', 'PosReg', (56, 64))	('GBM', 'Disease', 'MESH:D005909', (92, 95))
97118	32046730	Western blot and IHC assays indicated that the direct and indirect phosphorylation levels of beta-catenin were significantly elevated in the Lv-PS1 groups and reduced in the Sh-PS1 groups.	('elevated', 'PosReg', (125, 133))	('beta-catenin', 'Gene', (93, 105))	('reduced', 'NegReg', (159, 166))	('beta-catenin', 'Gene', '1499', (93, 105))	('Lv-PS1', 'Var', (141, 147))
97119	32046730	Stabilized beta-catenin was distinctly decreased in the Lv-PS1 groups and increased in the Sh-PS1 groups (Fig.	('beta-catenin', 'Gene', (11, 23))	('beta-catenin', 'Gene', '1499', (11, 23))	('increased', 'PosReg', (74, 83))	('Lv-PS1', 'Var', (56, 62))	('decreased', 'NegReg', (39, 48))
97122	32046730	The tumor value in the Lv-PS1 group was significantly smaller than that in the control group on day 19 after transplantation (Fig.	('tumor', 'Disease', (4, 9))	('Lv-PS1', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('smaller', 'NegReg', (54, 61))
97145	32046730	Additionally, Significant negative associations between Presenilin1 rs165934 genes and OS have been found in Chinese epithelial ovarian cancer (EOC) patients.	('rs165934', 'Mutation', 'rs165934', (68, 76))	('patients', 'Species', '9606', (149, 157))	('EOC', 'Phenotype', 'HP:0025318', (144, 147))	('negative', 'NegReg', (26, 34))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (117, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Presenilin1', 'Gene', (56, 67))	('EOC', 'Disease', 'MESH:D010051', (144, 147))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (117, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('EOC', 'Disease', (144, 147))	('epithelial ovarian cancer', 'Disease', (117, 142))	('rs165934 genes', 'Var', (68, 82))
97150	32046730	reported that orthotopically implanted glioma is significantly reduced in Tg PS1/APPsw mice compared to their wild-type littermate, suggesting that AD does not constitute a favorable environment to support glioma growth.	('Tg PS1/APPsw', 'Var', (74, 86))	('AD', 'Disease', 'MESH:D000544', (148, 150))	('AD', 'Disease', (148, 150))	('reduced', 'NegReg', (63, 70))	('glioma', 'Disease', (39, 45))	('AD', 'Phenotype', 'HP:0002511', (148, 150))	('mice', 'Species', '10090', (87, 91))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', (206, 212))
97151	32046730	However, the tumor volume of Tg PS1/APPsw mice was slightly larger (no significant difference) than that of Tg APPsw mice, implying that PS1 dysregulation could reverse the depression of glioma growth when APP is overproduced.	('tumor', 'Disease', (13, 18))	('depression of glioma', 'Disease', 'MESH:D003866', (173, 193))	('mice', 'Species', '10090', (42, 46))	('depression', 'Phenotype', 'HP:0000716', (173, 183))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('depression of glioma', 'Disease', (173, 193))	('dysregulation', 'Var', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
97160	32046730	Thus, Presenilin1 may cleave P75NTR to relieve the pro-growth function of pro-BDNF.	('P75NTR', 'Gene', '4804', (29, 35))	('BDNF', 'Gene', '627', (78, 82))	('pro-growth function', 'MPA', (51, 70))	('P75NTR', 'Gene', (29, 35))	('BDNF', 'Gene', (78, 82))	('relieve', 'NegReg', (39, 46))	('cleave', 'Var', (22, 28))
97175	28887715	No significant difference was found between median survival among patients with GBM tumors exhibiting high EMP2 expression and survival of those with low EMP2 expression (8.38 vs. 10.98 months, P = 0.39).	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('high', 'Var', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('GBM tumors', 'Disease', (80, 90))	('GBM tumors', 'Disease', 'MESH:D005910', (80, 90))	('EMP2', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (66, 74))
97183	28887715	EMP2 expression is significantly associated with increased Src kinase activation in human samples and results in increased tumor cell invasion in intracranial murine models.	('murine', 'Species', '10090', (159, 165))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (49, 58))	('EMP2', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('Src', 'Gene', (59, 62))	('Src', 'Gene', '6714', (59, 62))	('human', 'Species', '9606', (84, 89))	('increased', 'PosReg', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('activation', 'PosReg', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
97192	28887715	Secondary molecular and genetic markers of interest included antigen Ki-67 positivity, epithelial-like growth factor receptor III (EGFRvIII) expression, isocitrate dehydrogenase 1 (IDH1) mutation and 1p/19q chromosome codeletion.	('1p/19q chromosome codeletion', 'CPA', (200, 228))	('EGFR', 'Gene', '1956', (131, 135))	('IDH1', 'Gene', (181, 185))	('EGFR', 'Gene', (131, 135))	('mutation', 'Var', (187, 195))	('IDH1', 'Gene', '3417', (181, 185))	('isocitrate dehydrogenase 1', 'Gene', (153, 179))	('isocitrate dehydrogenase 1', 'Gene', '3417', (153, 179))
97193	28887715	EGFR is among the most commonly altered genes in high-grade glioma, with the EGFRvIII variant observed in around 25% of cases and strongly associated with tumor aggressiveness.	('associated with', 'Reg', (139, 154))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (155, 175))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('EGFR', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor aggressiveness', 'Disease', (155, 175))	('altered', 'Reg', (32, 39))	('glioma', 'Disease', (60, 66))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', '1956', (0, 4))	('aggressiveness', 'Phenotype', 'HP:0000718', (161, 175))	('variant', 'Var', (86, 93))	('EGFR', 'Gene', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
97194	28887715	IDH1 mutations are observed in around 80% of low-grade or secondary high-grade gliomas and associated with more favorable prognosis.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('observed', 'Reg', (19, 27))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', (0, 4))	('low-grade', 'Disease', (45, 54))	('IDH1', 'Gene', '3417', (0, 4))
97196	28887715	It is closely associated with IDH1 mutation and predicts favorable prognosis.	('IDH1', 'Gene', (30, 34))	('IDH1', 'Gene', '3417', (30, 34))	('associated', 'Reg', (14, 24))	('mutation', 'Var', (35, 43))
97206	28887715	The percentage of lower grade glioma samples with high EMP2 expression was 52.6%, compared to 90.0% of GBM samples with high EMP2 expression (P = 0.001) (Table 2).	('high EMP2 expression', 'Var', (50, 70))	('glioma', 'Disease', (30, 36))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
97209	28887715	Across all 69 glioma cases, EMP2 expression score of >=2 (r = -0.39, P = 0.001) and high Ki-67 positivity (r = -0.42, P = 0.001) were negatively correlated with OS, while EGFRvIII positivity (r = 0.52, P = 0.04), 1p/19q co-deletion (r = 0.50, P = 0.02) and IDH1 mutation (r = 0.42, P = 0.009) were positively correlated with OS.	('EGFR', 'Gene', (171, 175))	('glioma', 'Disease', (14, 20))	('IDH1', 'Gene', '3417', (257, 261))	('correlated', 'Reg', (145, 155))	('1p/19q co-deletion', 'Var', (213, 231))	('EMP2', 'Gene', (28, 32))	('IDH1', 'Gene', (257, 261))	('mutation', 'Var', (262, 270))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('EGFR', 'Gene', '1956', (171, 175))	('negatively', 'NegReg', (134, 144))
97215	28887715	Next, we computed an adjusted mortality hazard ratio (HR) for GBM patients using Cox regression in which patient age, sex, diagnosis (primary, secondary or recurrent GBM), high EMP2 expression, and tumor recurrence were included as explanatory variables (Table 6).	('patient', 'Species', '9606', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('patient', 'Species', '9606', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('high', 'Var', (172, 176))	('tumor', 'Disease', (198, 203))	('EMP2', 'Gene', (177, 181))	('GBM', 'Phenotype', 'HP:0012174', (166, 169))	('patients', 'Species', '9606', (66, 74))
97219	28887715	One well-known example in GBM biology has been the epigenetic silencing of O6-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene, which is associated with better treatment response to alkylating agents.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (75, 113))	('epigenetic silencing', 'Var', (51, 71))	('MGMT', 'Gene', '4255', (115, 119))	('MGMT', 'Gene', (115, 119))	('O6-methylguanine-DNA methyltransferase', 'Gene', (75, 113))
97242	28887715	MGMT, isocitrate dehydrogenase 1 and 2 (IDH1/2), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), loss of heterozygosity of chromosome arms 1p or 19q, and 1p/19q co-deletion have been investigated extensively for their ability to aid clinical management of GBM.	('MGMT', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (83, 87))	('loss of heterozygosity', 'Var', (129, 151))	('GBM', 'Phenotype', 'HP:0012174', (288, 291))	('epidermal growth factor receptor', 'Gene', (49, 81))	('EGFR', 'Gene', (83, 87))	('isocitrate dehydrogenase 1', 'Gene', (6, 32))	('IDH1/2', 'Gene', (40, 46))	('isocitrate dehydrogenase 1', 'Gene', '3417', (6, 32))	('1p/19q', 'Var', (186, 192))	('PTEN', 'Gene', '5728', (122, 126))	('epidermal growth factor receptor', 'Gene', '1956', (49, 81))	('PTEN', 'Gene', (122, 126))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('MGMT', 'Gene', '4255', (0, 4))
97243	28887715	Nevertheless, MGMT promoter methylation, 1p/19q co-deletion and IDH1 mutations have been shown conclusively to confer favorable prognosis in gliomas.	('MGMT', 'Gene', (14, 18))	('mutations', 'Var', (69, 78))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('IDH1', 'Gene', (64, 68))	('1p/19q co-deletion', 'Var', (41, 59))	('IDH1', 'Gene', '3417', (64, 68))	('gliomas', 'Disease', (141, 148))	('MGMT', 'Gene', '4255', (14, 18))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
97244	28887715	To date, the most notable prognostic molecular classifications of GBMs are related to mutations in TERT promoter and IDH, as well as 1p/19q deletions.	('mutations', 'Var', (86, 95))	('TERT', 'Gene', (99, 103))	('IDH', 'Gene', (117, 120))	('TERT', 'Gene', '7015', (99, 103))	('IDH', 'Gene', '3417', (117, 120))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('GBMs', 'Disease', (66, 70))	('1p/19q deletions', 'Var', (133, 149))
97245	28887715	In reviewing associations between glioma biomarkers and OS, we found EMP2 expression scores of >=2 to be as strongly correlated with OS as IDH1 mutation and 1p/19q co-deletion, and in the opposite direction.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH1', 'Gene', (139, 143))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('mutation', 'Var', (144, 152))	('EMP2', 'Gene', (69, 73))	('IDH1', 'Gene', '3417', (139, 143))	('glioma', 'Disease', (34, 40))	('correlated', 'Reg', (117, 127))
97274	28567586	Impairments in NCF negatively influence health-related quality of life (HRQOL) of patients and their partners.	('NCF', 'Gene', (15, 18))	('health-related quality of life', 'MPA', (40, 70))	('patients', 'Species', '9606', (82, 90))	('influence', 'Reg', (30, 39))	('Impairments', 'Var', (0, 11))
97330	28567586	Patients with high-grade glioma more often exhibit cognitive impairments than patients with low-grade glioma (OR 2.50; 95% CI 1.71-3.66).	('cognitive impairments', 'Disease', (51, 72))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('high-grade', 'Var', (14, 24))	('cognitive impairment', 'Phenotype', 'HP:0100543', (51, 71))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('patients', 'Species', '9606', (78, 86))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('Patients', 'Species', '9606', (0, 8))	('cognitive impairments', 'Phenotype', 'HP:0100543', (51, 72))	('glioma', 'Disease', (102, 108))	('glioma', 'Disease', (25, 31))	('cognitive impairments', 'Disease', 'MESH:D003072', (51, 72))
97496	19777070	Many GBMs appear to have lost an entire copy of chromosome 10, but several LOH studies have suggested at least three distinct loci to be deleted (e.g., 10p14-p15, 10q23-24, distal to 10q25).	('10q23-24', 'Var', (163, 171))	('p15', 'Gene', (158, 161))	('p15', 'Gene', '1030', (158, 161))
97498	19777070	Loss of gene dosage from numerous genomic alterations has been documented in GBM, such as entire chromosomal loss, partial chromosomal loss, specific allelic loss, inactivating mutations, and promoter methylation.	('inactivating mutations', 'Var', (164, 186))	('chromosomal loss', 'Disease', 'MESH:D015431', (97, 113))	('chromosomal loss', 'Disease', (123, 139))	('GBM', 'Gene', (77, 80))	('Loss', 'NegReg', (0, 4))	('chromosomal loss', 'Disease', 'MESH:D015431', (123, 139))	('allelic loss', 'Disease', 'MESH:C566065', (150, 162))	('chromosomal loss', 'Disease', (97, 113))	('allelic loss', 'Disease', (150, 162))	('promoter', 'Disease', (192, 200))
97500	19777070	Clearly, the most common oncogenic event is amplification of the epidermal growth factor receptor (EGFR) gene on chromosome 7, often in the form of dmins.	('EGFR', 'Gene', (99, 103))	('dmins', 'Disease', (148, 153))	('epidermal growth factor receptor', 'Gene', (65, 97))	('amplification', 'Var', (44, 57))	('epidermal growth factor receptor', 'Gene', '1956', (65, 97))	('EGFR', 'Gene', '1956', (99, 103))
97502	19777070	Many genetic alterations, such as gene amplification or deletion, represent direct glioma-inducing events, whereas others indirectly affect gliomagenesis through processes such as DNA instability.	('glioma', 'Disease', (83, 89))	('deletion', 'Var', (56, 64))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('affect', 'Reg', (133, 139))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Disease', (140, 146))	('gene amplification', 'Var', (34, 52))
97504	19777070	In addition to many of the genetic events noted above, gliomagenesis likely involves errors in DNA replication, DNA repair, chromosomal segregation, and alteration of numerous signaling cascades not directly attributed to genomic mutations.	('glioma', 'Disease', (55, 61))	('DNA replication', 'Gene', (95, 110))	('alteration', 'Reg', (153, 163))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('errors', 'Var', (85, 91))
97505	19777070	This collection of genetic and cellular alterations gives rise to a tumor cell phenotype, previously described as a "mutator phenotype."	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('alterations', 'Var', (40, 51))
97510	19777070	Repair of O6-alkylguanine adducts by tumor cells has been implicated in drug resistance, since it reduces the cytotoxicity of alkylating chemotherapeutic agents.	('cytotoxicity', 'Disease', 'MESH:D064420', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('O6-alkylguanine', 'Chemical', '-', (10, 25))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('O6-alkylguanine', 'Var', (10, 25))	('cytotoxicity', 'Disease', (110, 122))	('reduces', 'NegReg', (98, 105))
97511	19777070	Loss of MGMT expression may be caused by methylation of promoter CpG islands, which has been observed in gliomas.	('expression', 'MPA', (13, 23))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('methylation', 'Var', (41, 52))	('Loss', 'NegReg', (0, 4))	('MGMT', 'Gene', (8, 12))	('MGMT', 'Gene', '4255', (8, 12))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
97513	19777070	Interestingly, the majority of low-grade gliomas with MGMT methylation (92%) contain a mutation in the tumor suppressor gene p53, whereas only 39% of those without MGMT methylation carry a p53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('MGMT', 'Gene', '4255', (164, 168))	('tumor', 'Disease', (103, 108))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('p53', 'Gene', (125, 128))	('MGMT', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('MGMT', 'Gene', '4255', (54, 58))	('contain', 'Reg', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('mutation', 'Var', (87, 95))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))	('MGMT', 'Gene', (164, 168))
97515	19777070	This association with increased frequency of p53 mutations suggests that loss of MGMT expression due to promoter methylation frequently occurs at an early stage in the pathway leading to secondary GBMs.	('p53', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('MGMT', 'Gene', '4255', (81, 85))	('MGMT', 'Gene', (81, 85))	('secondary GBMs', 'Disease', (187, 201))	('leading to', 'Reg', (176, 186))	('promoter methylation', 'Var', (104, 124))
97521	19777070	In GBM, aberrant EGFR and other tyrosine kinase receptor autocrine signaling pathways may be the most often cited pathways.	('aberrant', 'Var', (8, 16))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
97525	19777070	EGFR amplification and overexpression occur in 40%-60% of primary GBMs, and rarely in secondary GBMs.	('overexpression', 'PosReg', (23, 37))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('primary GBMs', 'Disease', (58, 70))	('EGFR', 'Gene', '1956', (0, 4))
97526	19777070	Amplification of the EGFR gene is often associated with structural alterations in the gene.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('Amplification', 'Var', (0, 13))	('structural', 'MPA', (56, 66))	('associated', 'Reg', (40, 50))
97528	19777070	EGFRvIII results from a nonrandom 801-bp inframe deletion of exons 2-7 of the EGFR gene that occurs at the genomic level leading to expression of aberrant transcripts and proteins.	('EGFR', 'Gene', (0, 4))	('proteins', 'MPA', (171, 179))	('expression', 'MPA', (132, 142))	('aberrant', 'Var', (146, 154))	('deletion', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('results from', 'Reg', (9, 21))	('EGFR', 'Gene', '1956', (0, 4))
97530	19777070	Multiple murine glioma models have confirmed the importance of this aberrant growth factor signaling in gliomagenesis.	('murine', 'Species', '10090', (9, 15))	('growth', 'MPA', (77, 83))	('glioma', 'Disease', (104, 110))	('glioma', 'Disease', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('aberrant growth', 'Phenotype', 'HP:0001507', (68, 83))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('aberrant', 'Var', (68, 76))
97537	19777070	Germline mutations and loss-of-function mutations have been seen in the disease, which includes optic nerve gliomas, astrocytomas, and GBMs.	('loss-of-function', 'NegReg', (23, 39))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('astrocytomas', 'Disease', 'MESH:D001254', (117, 129))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('mutations', 'Var', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('optic nerve gliomas', 'Disease', (96, 115))	('optic nerve gliomas', 'Phenotype', 'HP:0009734', (96, 115))	('astrocytomas', 'Disease', (117, 129))	('optic nerve gliomas', 'Disease', 'MESH:D020339', (96, 115))	('GBMs', 'Disease', (135, 139))
97542	19777070	Similarly, mouse models deficient in NF1 and p53 develop GBM-like tumors with all the characteristic features, including invasion, neovascularity, necrosis, and atypical astrocytes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p53', 'Gene', (45, 48))	('mouse', 'Species', '10090', (11, 16))	('develop', 'PosReg', (49, 56))	('necrosis', 'Disease', 'MESH:D009336', (147, 155))	('neovascularity', 'CPA', (131, 145))	('NF1', 'Gene', (37, 40))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('deficient', 'Var', (24, 33))	('invasion', 'CPA', (121, 129))	('necrosis', 'Disease', (147, 155))
97553	19777070	The majority of malignant brain tumors, including GBM, demonstrate inactivating mutations in either the p53 and/or retinoblastoma (RB) pathways.	('malignant brain tumors', 'Disease', (16, 38))	('malignant brain tumors', 'Disease', 'MESH:D001932', (16, 38))	('RB', 'Gene', '5925', (131, 133))	('brain tumors', 'Phenotype', 'HP:0030692', (26, 38))	('p53', 'Pathway', (104, 107))	('brain tumor', 'Phenotype', 'HP:0030692', (26, 37))	('retinoblastoma', 'Gene', '5925', (115, 129))	('inactivating mutations', 'Var', (67, 89))	('retinoblastoma', 'Gene', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('retinoblastoma', 'Phenotype', 'HP:0009919', (115, 129))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('RB', 'Phenotype', 'HP:0009919', (131, 133))
97556	19777070	P53 is a short-lived transcription factor which is upregulated in response to cellular stress such as radiation exposure, DNA strand breaks, and toxins.	('upregulated', 'PosReg', (51, 62))	('DNA', 'Var', (122, 125))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))
97559	19777070	Loss of p14ARF expression has often been seen in GBMs (76%), and this correlates with homozygous deletion or promoter methylation of the p14ARF gene.	('p14ARF', 'Gene', (137, 143))	('p14ARF', 'Gene', '1029', (8, 14))	('promoter', 'MPA', (109, 117))	('Loss', 'NegReg', (0, 4))	('expression', 'MPA', (15, 25))	('p14ARF', 'Gene', (8, 14))	('p14ARF', 'Gene', '1029', (137, 143))	('deletion', 'Var', (97, 105))
97561	19777070	Analysis of multiple biopsies from the same patient reveals that p14ARF methylation is present in up to a third of lower grade astrocytomas, suggesting an early event in secondary GBMs.	('patient', 'Species', '9606', (44, 51))	('astrocytomas', 'Disease', 'MESH:D001254', (127, 139))	('p14ARF', 'Gene', '1029', (65, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (127, 138))	('astrocytomas', 'Disease', (127, 139))	('methylation', 'Var', (72, 83))	('p14ARF', 'Gene', (65, 71))
97564	19777070	p16INK4a binds to CDK4, inhibits the CDK4/cyclin D1 complex, and thus inhibits the G1 to S transition.	('p16INK4a', 'Var', (0, 8))	('inhibits', 'NegReg', (24, 32))	('inhibits', 'NegReg', (70, 78))	('binds', 'Interaction', (9, 14))	('CDK4', 'Protein', (18, 22))	('G1 to S transition', 'CPA', (83, 101))	('cyclin D1', 'Gene', '595', (42, 51))	('cyclin D1', 'Gene', (42, 51))
97565	19777070	Inactivating mutations in RB1 or the upstream factor p16INK4a (also called inhibitor of CDK4a), or activating mutations in the downstream factors CDK4 or cyclin D, cause dysregulated control of E2F1.	('dysregulated control', 'MPA', (170, 190))	('E2F1', 'Gene', '1869', (194, 198))	('RB', 'Phenotype', 'HP:0009919', (26, 28))	('cyclin', 'Gene', '5111', (154, 160))	('cause', 'Reg', (164, 169))	('cyclin', 'Gene', (154, 160))	('Inactivating mutations', 'Var', (0, 22))	('RB1', 'Gene', (26, 29))	('E2F1', 'Gene', (194, 198))	('p16INK4a', 'Var', (53, 61))
97568	19777070	The genetic locus INK4a/ARF on chromosome 9p21 produces both p14ARF and p16INK4a by alternative splicing.	('p14ARF', 'Gene', (61, 67))	('p21', 'Gene', '1026', (43, 46))	('p16INK4a', 'Var', (72, 80))	('INK4a/ARF', 'Gene', (18, 27))	('INK4a/ARF', 'Gene', '1029', (18, 27))	('p14ARF', 'Gene', '1029', (61, 67))	('p21', 'Gene', (43, 46))
97569	19777070	Since p16INK4a negatively regulates CDK4 and p14ARF (p19ARF in mice) inhibits MDM2, blocking rapid ubiquitin-mediated decay of p53, simultaneous inactivation of both genes by a homozygous deletion dysregulates both the RB1 pathway and the p53 pathway.	('p16INK4a', 'Var', (6, 14))	('CDK4', 'Gene', (36, 40))	('MDM2', 'Gene', (78, 82))	('inhibits', 'NegReg', (69, 77))	('dysregulates', 'Reg', (197, 209))	('negatively', 'NegReg', (15, 25))	('inactivation', 'NegReg', (145, 157))	('deletion', 'Var', (188, 196))	('blocking', 'NegReg', (84, 92))	('p14ARF', 'Gene', (45, 51))	('rapid ubiquitin-mediated decay', 'MPA', (93, 123))	('mice', 'Species', '10090', (63, 67))	('RB', 'Phenotype', 'HP:0009919', (219, 221))	('p53 pathway', 'Pathway', (239, 250))	('RB1 pathway', 'Pathway', (219, 230))	('p14ARF', 'Gene', '1029', (45, 51))
97571	19777070	Up to 50% of malignant human gliomas have homozygous deletions that span the reading frame of both genes.	('deletions', 'Var', (53, 62))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('human', 'Species', '9606', (23, 28))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
97573	19777070	Most GBMs that retain an intact INK4a/ARF locus display mutations in other genes of the p53 and the RB pathways, leading to unchecked cell cycling and apoptotic resistance.	('mutations', 'Var', (56, 65))	('INK4a/ARF', 'Gene', '1029', (32, 41))	('INK4a/ARF', 'Gene', (32, 41))	('RB', 'Gene', '5925', (100, 102))	('apoptotic resistance', 'CPA', (151, 171))	('p53', 'Gene', (88, 91))	('leading to', 'Reg', (113, 123))	('RB', 'Phenotype', 'HP:0009919', (100, 102))	('cyclin', 'Gene', '5111', (139, 145))	('cyclin', 'Gene', (139, 145))
97574	19777070	As alluded to above, p16INK4a is an inhibitor of CDK4, blocks CDK4-dependent phosphorylation of the RB protein and acts as a negative regulator of cell proliferation.	('p16INK4a', 'Var', (21, 29))	('CDK4-dependent', 'MPA', (62, 76))	('RB', 'Gene', '5925', (100, 102))	('blocks', 'NegReg', (55, 61))	('RB', 'Phenotype', 'HP:0009919', (100, 102))
97577	19777070	Mutations of the TSG phosphatase tensin homology (PTEN) on chromosome 10q23, also called MMAC1 and TEP1, occur frequently in familial developmental and cancer syndromes such as Cowden-Bannayan syndrome and Lhermitte-Duclos disease.	('occur', 'Reg', (105, 110))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cowden-Bannayan syndrome', 'Disease', (177, 201))	('MMAC1', 'Gene', (89, 94))	('MMAC1', 'Gene', '5728', (89, 94))	('Lhermitte-Duclos disease', 'Disease', 'MESH:D006223', (206, 230))	('PTEN', 'Gene', (50, 54))	('TEP1', 'Gene', (99, 103))	('Lhermitte-Duclos disease', 'Phenotype', 'HP:0500009', (206, 230))	('PTEN', 'Gene', '5728', (50, 54))	('Lhermitte-', 'Phenotype', 'HP:0032504', (206, 216))	('Mutations', 'Var', (0, 9))	('Cowden-Bannayan syndrome', 'Disease', 'MESH:D006223', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Lhermitte-Duclos disease', 'Disease', (206, 230))	('TEP1', 'Gene', '7011', (99, 103))
97580	19777070	In the case of mutant PTEN, the elevated lipid second messenger PIP3 is used by PI3K to hyperphosphorylate Akt (also known as protein kinase B [PKB]).	('hyperphosphorylate', 'PosReg', (88, 106))	('elevated', 'PosReg', (32, 40))	('PKB', 'Gene', '2185', (144, 147))	('PIP3', 'Chemical', '-', (64, 68))	('elevated lipid', 'Phenotype', 'HP:0003077', (32, 46))	('protein kinase B', 'Gene', '2185', (126, 142))	('PKB', 'Gene', (144, 147))	('Akt', 'Pathway', (107, 110))	('lipid', 'Chemical', 'MESH:D008055', (41, 46))	('PTEN', 'Gene', (22, 26))	('lipid second messenger PIP3', 'MPA', (41, 68))	('PTEN', 'Gene', '5728', (22, 26))	('mutant', 'Var', (15, 21))	('protein kinase B', 'Gene', (126, 142))
97582	19777070	The PTEN C2 domain binds phospholipid membranes and mutations in this domain reduce PTEN's membrane affinity and ability to suppress growth and motility of GBM cells.	('mutations', 'Var', (52, 61))	('PTEN', 'Gene', '5728', (4, 8))	('suppress', 'NegReg', (124, 132))	('reduce', 'NegReg', (77, 83))	('membrane affinity', 'MPA', (91, 108))	('phospholipid', 'Chemical', 'MESH:D010743', (25, 37))	('PTEN', 'Gene', (84, 88))	('PTEN', 'Gene', '5728', (84, 88))	('PTEN', 'Gene', (4, 8))
97584	19777070	In GBM, deletions distal to 10q25 (distal to PTEN) cover DMBT1 and FGFR2 loci, which suggest that acquisition of the GBM phenotype is associated with loss of other putative TSGs.	('DMBT1', 'Gene', (57, 62))	('FGFR2', 'Gene', (67, 72))	('DMBT1', 'Gene', '1755', (57, 62))	('FGFR2', 'Gene', '2263', (67, 72))	('PTEN', 'Gene', (45, 49))	('deletions', 'Var', (8, 17))	('PTEN', 'Gene', '5728', (45, 49))
97586	19777070	PTEN mutations are almost exclusively seen in primary GBMs, but rarely in secondary GBMs.	('seen', 'Reg', (38, 42))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('primary GBMs', 'Disease', (46, 58))
97589	19777070	Nonsense mutations (12%) and deletions or insertions leading to stop codons (32%) appear to be more equally distributed throughout the exons, whereas one-third are missense mutations leading to amino acid changes, preferentially located in exons 1-6, regions homologous to tensin, auxilin, and phosphatases.	('amino', 'MPA', (194, 199))	('auxilin', 'Gene', '9829', (281, 288))	('stop codons', 'MPA', (64, 75))	('missense mutations', 'Var', (164, 182))	('deletions', 'Var', (29, 38))	('auxilin', 'Gene', (281, 288))
97595	19777070	Heterogeneity within a glioma may not necessarily reflect a stem cell origin of the glioma producing different phenotypes, but could be due to mutations inducing self-renewal properties in progenitor cells with more limited differentiation potential.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('glioma', 'Disease', (84, 90))	('glioma', 'Disease', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('inducing', 'Reg', (153, 161))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('self-renewal properties', 'CPA', (162, 185))	('mutations', 'Var', (143, 152))
97615	19777070	Hereditary loss of function mutations in the SHH receptor Patched (PTCH) lead to constitutive activation of the SHH pathway and predisposition to medulloblastoma in Gorlin syndrome.	('medulloblastoma', 'Phenotype', 'HP:0002885', (146, 161))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (165, 180))	('SHH', 'Gene', (45, 48))	('PTCH', 'Gene', '5727', (67, 71))	('medulloblastoma', 'Disease', (146, 161))	('Patched', 'Gene', (58, 65))	('PTCH', 'Gene', (67, 71))	('SHH', 'Gene', '6469', (112, 115))	('loss of function', 'NegReg', (11, 27))	('Patched', 'Gene', '5727', (58, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (146, 161))	('SHH', 'Gene', '6469', (45, 48))	('SHH', 'Gene', (112, 115))	('Gorlin syndrome', 'Disease', (165, 180))	('mutations', 'Var', (28, 37))	('activation', 'PosReg', (94, 104))
97624	19777070	There is much work to be done, but Olig2 and NG2 may be important markers and/or targets for oligodendroglioma stem cells.	('NG2', 'Gene', (45, 48))	('oligodendroglioma', 'Disease', (93, 110))	('NG2', 'Gene', '1464', (45, 48))	('oligodendroglioma', 'Disease', 'MESH:D009837', (93, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('Olig2', 'Var', (35, 40))
97626	19777070	Some of the most common lesions in malignant gliomas are loss-of-function mutations in p16Ink4a and p19ARF negative regulators of the RB signaling pathway.	('p16Ink4a', 'Gene', (87, 95))	('loss-of-function', 'NegReg', (57, 73))	('RB', 'Phenotype', 'HP:0009919', (134, 136))	('p19ARF', 'Gene', (100, 106))	('mutations', 'Var', (74, 83))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('malignant gliomas', 'Disease', (35, 52))	('malignant gliomas', 'Disease', 'MESH:D005910', (35, 52))	('negative', 'NegReg', (107, 115))	('RB', 'Gene', '5925', (134, 136))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))
97627	19777070	Gain-of-function mutations in CDK4 are seen, in GBM, activating the RB pathway.	('RB', 'Gene', '5925', (68, 70))	('RB', 'Phenotype', 'HP:0009919', (68, 70))	('Gain-of-function', 'PosReg', (0, 16))	('CDK4', 'Gene', (30, 34))	('activating', 'PosReg', (53, 63))	('mutations', 'Var', (17, 26))
97628	19777070	Bmi1, a promoter of neural stem cell self-renewal and neural development, is expressed in most gliomas and promotes malignancy in p16Ink4a/p19ARF double-null murine gliomas.	('malignancy', 'Disease', (116, 126))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('Bmi1', 'Gene', '12151', (0, 4))	('Bmi1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('promotes', 'PosReg', (107, 115))	('gliomas', 'Disease', (95, 102))	('p16Ink4a/p19ARF double-null', 'Var', (130, 157))	('murine', 'Species', '10090', (158, 164))	('malignancy', 'Disease', 'MESH:D009369', (116, 126))	('gliomas', 'Disease', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
97630	19777070	Olig2 is required for tumor formation in p16Ink4a/p19ARF double null murine gliomas.	('gliomas', 'Disease', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('p16Ink4a/p19ARF', 'Var', (41, 56))	('tumor', 'Disease', (22, 27))	('murine', 'Species', '10090', (69, 75))
97636	19777070	Mutations of p53, p16INK4a deletion, EGFR amplification, and PTEN mutations show inverse associations with each other, except for a positive correlation between p16INK4a deletion and EGFR amplification.	('p16INK4a', 'Var', (161, 169))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('deletion', 'Var', (27, 35))	('EGFR', 'Gene', '1956', (37, 41))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (61, 65))	('p16INK4a', 'Gene', (18, 26))	('PTEN', 'Gene', '5728', (61, 65))	('p53', 'Gene', (13, 16))	('EGFR', 'Gene', (37, 41))
97663	33406116	The addition of genetic and molecular classification using IDH mutation, 1p19q codeletion, MGMT promoter methylation, ATRX expression loss and epidermal growth factor receptor has improved prognostic precision.	('ATRX', 'Gene', '546', (118, 122))	('IDH', 'Gene', (59, 62))	('expression', 'MPA', (123, 133))	('epidermal growth factor receptor', 'Gene', (143, 175))	('IDH', 'Gene', '3417', (59, 62))	('epidermal growth factor receptor', 'Gene', '1956', (143, 175))	('improved', 'PosReg', (180, 188))	('MGMT', 'Gene', (91, 95))	('loss', 'NegReg', (134, 138))	('MGMT', 'Gene', '4255', (91, 95))	('1p19q codeletion', 'Var', (73, 89))	('ATRX', 'Gene', (118, 122))
97693	33406116	The perfusion parameters on the GE MR scanners (both 1.5 and 3T) were as follows: TR/TE, 1500-2200ms/19.6ms on 3T and 1900-2150mm/20.5 or 80ms on 1.5T; field of view, 260mm x 260mm on 3T and 300mm x 300mm on 1.5T; slice thickness, 5mm; slice gap, 5mm; NEX, 1; matrix, 128 x 128 x 16; time points, 50; flip angle, 60 on 3T and 90 on 1.5T.	('flip angle', 'Disease', (301, 311))	('TR', 'Gene', '2149', (82, 84))	('flip angle', 'Disease', 'MESH:D009464', (301, 311))	('1900-2150mm/20.5 or', 'Var', (118, 137))
97730	33406116	Patients receiving CCRT showed a relatively higher 2-year survival rate than those receiving chemotherapy or radiation alone in the groups with AA (7 out of 10 (70%) vs 2 out of 4 (50%), P = 0.58) and with GBM (5 out of 25 (20%) vs 0 out of 5 (0%), P = 0.556).	('CCRT', 'Var', (19, 23))	('CCRT', 'Chemical', '-', (19, 23))	('higher', 'PosReg', (44, 50))	('GBM', 'Phenotype', 'HP:0012174', (206, 209))	('AA', 'Phenotype', 'HP:0009592', (144, 146))	('2-year survival', 'CPA', (51, 66))	('Patients', 'Species', '9606', (0, 8))
97757	33406116	It has been reported that the variation of fractional anisotropy values on DTI is useful for differentiating low- and high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('variation', 'Var', (30, 39))	('fractional anisotropy values', 'MPA', (43, 71))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('DTI', 'Gene', (75, 78))	('low-', 'Disease', (109, 113))
97765	33406116	We speculate that the tumor components with maximum rCBV variation might reflect regional heterogeneity of histopathology and have more malignant foci.	('variation', 'Var', (57, 66))	('rCBV', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('rCBV', 'Chemical', '-', (52, 56))	('tumor', 'Disease', (22, 27))
97811	31456158	For executive functioning, increased connectivity between DMN and FPN has been associated with better performance (e.g.	('DMN', 'Gene', (58, 61))	('increased', 'PosReg', (27, 36))	('DMN', 'Gene', '23336', (58, 61))	('connectivity', 'Var', (37, 49))	('better performance', 'MPA', (95, 113))
97967	33953611	Of note, this study identified the amplification of genes, such as EGFR and PDGFRA, which were significantly associated with glioblastoma but had not been previously used for clinical classification (P<0.05).	('amplification', 'Var', (35, 48))	('associated', 'Reg', (109, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('PDGFRA', 'Gene', '5156', (76, 82))	('PDGFRA', 'Gene', (76, 82))	('glioblastoma', 'Disease', (125, 137))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
97968	33953611	Compared to the MSKCC database primarily comprised of Caucasians, H3F3A mutations and MET amplifications exhibited higher mutation rates, whereas TERT mutations and EGFR and CDKN2A/B copy number variations presented a lower mutation rate in Chinese patients with glioma (P<0.05).	('EGFR', 'Gene', (165, 169))	('mutations', 'Var', (72, 81))	('EGFR', 'Gene', '1956', (165, 169))	('MET', 'Gene', '79811', (86, 89))	('H3F3A', 'Gene', '3020', (66, 71))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('patients', 'Species', '9606', (249, 257))	('MET', 'Gene', (86, 89))	('glioma', 'Disease', (263, 269))	('CDKN2A', 'Gene', (174, 180))	('H3F3A', 'Gene', (66, 71))	('CDKN2A', 'Gene', '1029', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('TERT', 'Gene', (146, 150))	('higher', 'PosReg', (115, 121))	('TERT', 'Gene', '7015', (146, 150))	('mutation rates', 'MPA', (122, 136))	('lower', 'NegReg', (218, 223))
97969	33953611	Our multigene NGS in the simultaneous evaluation of multiple relevant markers revealed several novel genetic alterations in Chinese patients with glioma.	('glioma', 'Disease', (146, 152))	('genetic alterations', 'Var', (101, 120))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('patients', 'Species', '9606', (132, 140))
97975	33953611	Detection of IDH mutations, 1p/19q codeletion, and H3F3A mutations (midline position) are now recommended according to their histologic diagnosis.	('IDH', 'Gene', '3417', (13, 16))	('1p/19q codeletion', 'Var', (28, 45))	('H3F3A', 'Gene', '3020', (51, 56))	('mutations', 'Var', (57, 66))	('H3F3A', 'Gene', (51, 56))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
97977	33953611	In fact, many key mutations in the TERT, ATRX, TP53, and EGFR genes found in gliomas could be used as diagnostic, prognostic, and therapeutic biomarkers.	('ATRX', 'Gene', (41, 45))	('gliomas', 'Disease', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('EGFR', 'Gene', '1956', (57, 61))	('ATRX', 'Gene', '546', (41, 45))	('TP53', 'Gene', '7157', (47, 51))	('TERT', 'Gene', (35, 39))	('EGFR', 'Gene', (57, 61))	('TP53', 'Gene', (47, 51))	('TERT', 'Gene', '7015', (35, 39))	('mutations', 'Var', (18, 27))
97983	33953611	The panel should have enough gene numbers to cover a wide range of targets and their various types of genetic mutations, which may have diagnostic, prognostic, predictive, and therapeutic significance for the targeted tumors.	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
97986	33953611	We identified frequent and novel genetic alterations in Chinese gliomas.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('genetic alterations', 'Var', (33, 52))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))
97999	33953611	12351-010) and specific primers to detect methylated and unmethylated MGMT promoters.	('methylated', 'Var', (42, 52))	('MGMT', 'Gene', '4255', (70, 74))	('MGMT', 'Gene', (70, 74))
98007	33953611	Notably, all IDH1 mutations replaced the arginine residue on codon 132, all of which were R132H (25/25) (Figure 1).	('R132H', 'Chemical', '-', (90, 95))	('arginine residue', 'MPA', (41, 57))	('IDH1', 'Gene', (13, 17))	('arginine', 'Chemical', 'MESH:D001120', (41, 49))	('IDH1', 'Gene', '3417', (13, 17))	('replaced', 'Reg', (28, 36))	('mutations', 'Var', (18, 27))
98008	33953611	The frequency of H3F3A gene mutations in this study was relatively high (9.64%) (Figure 1).	('H3F3A', 'Gene', (17, 22))	('mutations', 'Var', (28, 37))	('H3F3A', 'Gene', '3020', (17, 22))
98009	33953611	MGMT methylation was positive in 51.81% (43/83), and 1p19q codeletion was positive in 12.05% (10/83) (Figure 1).	('MGMT', 'Gene', (0, 4))	('positive', 'Reg', (21, 29))	('MGMT', 'Gene', '4255', (0, 4))	('1p19q codeletion', 'Var', (53, 69))
98010	33953611	MGMT methylation was found in almost all patients with IDH1 mutations (P<0.0001) (Figure 1).	('MGMT', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (55, 59))	('patients', 'Species', '9606', (41, 49))	('MGMT', 'Gene', '4255', (0, 4))	('found', 'Reg', (21, 26))	('mutations', 'Var', (60, 69))	('IDH1', 'Gene', (55, 59))
98011	33953611	Of the 83 samples, 7 simultaneously had IDH mutations, MGMT methylation, and 1p/19q codeletion (Figure 1).	('MGMT', 'Gene', '4255', (55, 59))	('MGMT', 'Gene', (55, 59))	('IDH', 'Gene', (40, 43))	('1p/19q codeletion', 'Var', (77, 94))	('IDH', 'Gene', '3417', (40, 43))	('had', 'Reg', (36, 39))
98012	33953611	Regarding CNVs, EGFR, PDGFRA, MET, KIT, CDK4 amplification, and CDKN2A deletion were common events (Figure 1).	('CDK4', 'Gene', (40, 44))	('CDKN2A', 'Gene', (64, 70))	('amplification', 'Var', (45, 58))	('CDK4', 'Gene', '1019', (40, 44))	('deletion', 'Var', (71, 79))	('CNVs', 'Disease', (10, 14))	('CDKN2A', 'Gene', '1029', (64, 70))	('EGFR', 'Gene', '1956', (16, 20))	('PDGFRA', 'Gene', '5156', (22, 28))	('PDGFRA', 'Gene', (22, 28))	('MET', 'Gene', '79811', (30, 33))	('EGFR', 'Gene', (16, 20))	('MET', 'Gene', (30, 33))	('KIT', 'Gene', (35, 38))
98015	33953611	There was no significant difference in the frequency of TP53, IDH1, PTEN, ATRX, EGFR, or CIC gene mutations between our cohort of glioma patients and the MSKCC database (Figure 2).	('IDH1', 'Gene', '3417', (62, 66))	('TP53', 'Gene', '7157', (56, 60))	('ATRX', 'Gene', '546', (74, 78))	('glioma', 'Disease', (130, 136))	('CIC', 'Gene', '23152', (89, 92))	('EGFR', 'Gene', '1956', (80, 84))	('patients', 'Species', '9606', (137, 145))	('PTEN', 'Gene', (68, 72))	('mutations', 'Var', (98, 107))	('EGFR', 'Gene', (80, 84))	('TP53', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('CIC', 'Gene', (89, 92))	('IDH1', 'Gene', (62, 66))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('ATRX', 'Gene', (74, 78))
98018	33953611	Previous studies using genomic landscape studies have reported multiple cooccurring or mutually exclusive mutations of genes in different cancer types.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))
98019	33953611	For example, the coexistence of PDGFRA and EGFR gene amplifications is commonly found in glioblastoma (GBM).	('found', 'Reg', (80, 85))	('glioblastoma', 'Disease', (89, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('EGFR', 'Gene', '1956', (43, 47))	('PDGFRA', 'Gene', (32, 38))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('PDGFRA', 'Gene', '5156', (32, 38))	('EGFR', 'Gene', (43, 47))	('amplifications', 'Var', (53, 67))
98020	33953611	In addition, EGFR amplification and IDH1 mutations are mutually exclusive in low-grade gliomas.	('mutations', 'Var', (41, 50))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('IDH1', 'Gene', (36, 40))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('IDH1', 'Gene', '3417', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('amplification', 'Var', (18, 31))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('gliomas', 'Disease', (87, 94))
98022	33953611	Other considerable coexisting genes included ATRX and TP53, PTEN and APC, CIC and MGMT methylation, and 1p/19q codeletion, as well as FUBP1 and TERT and SETD2 (P<0.05) (Figure 3).	('TP53', 'Gene', (54, 58))	('ATRX', 'Gene', (45, 49))	('CIC', 'Gene', '23152', (74, 77))	('PTEN', 'Gene', (60, 64))	('ATRX', 'Gene', '546', (45, 49))	('APC', 'Gene', '324', (69, 72))	('SETD2', 'Gene', (153, 158))	('TP53', 'Gene', '7157', (54, 58))	('PTEN', 'Gene', '5728', (60, 64))	('MGMT', 'Gene', (82, 86))	('SETD2', 'Gene', '29072', (153, 158))	('FUBP1', 'Gene', (134, 139))	('APC', 'Gene', (69, 72))	('1p/19q codeletion', 'Var', (104, 121))	('CIC', 'Gene', (74, 77))	('TERT', 'Gene', (144, 148))	('TERT', 'Gene', '7015', (144, 148))	('FUBP1', 'Gene', '8880', (134, 139))	('MGMT', 'Gene', '4255', (82, 86))
98025	33953611	Copy number variation is a prevalent form of abnormal change in the copy number of several specific genes that commonly occur in tumor development and progression and results in altered gene expression.	('tumor', 'Disease', (129, 134))	('Copy number variation', 'Var', (0, 21))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('copy number', 'MPA', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('altered', 'Reg', (178, 185))	('gene expression', 'MPA', (186, 201))
98029	33953611	Importantly, these studies showed that GBM with EGFR amplification was significantly associated with both worse disease-free survival (DFS) and overall survival (OS) rates.	('worse', 'NegReg', (106, 111))	('EGFR', 'Gene', '1956', (48, 52))	('disease-free survival', 'CPA', (112, 133))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('amplification', 'Var', (53, 66))	('EGFR', 'Gene', (48, 52))	('overall survival', 'CPA', (144, 160))
98031	33953611	In comparison to the 13 genes with the highest CNV in the MSKCC cohort, we found that the frequencies of CNV in MET, EPCAM, ATM, CCNE1, CDK6, and ERBB2 were much higher, while EGFR, CDK4, and CDKN2A were much lower in our cohort (Figure 4B).	('CDK6', 'Gene', '1021', (136, 140))	('EPCAM', 'Gene', (117, 122))	('CDK4', 'Gene', '1019', (182, 186))	('MET', 'Gene', (112, 115))	('CNV', 'Var', (105, 108))	('ATM', 'Gene', '472', (124, 127))	('CDK6', 'Gene', (136, 140))	('CDKN2A', 'Gene', (192, 198))	('EGFR', 'Gene', (176, 180))	('CCNE1', 'Gene', (129, 134))	('CDK4', 'Gene', (182, 186))	('ERBB2', 'Gene', (146, 151))	('CDKN2A', 'Gene', '1029', (192, 198))	('ATM', 'Gene', (124, 127))	('MET', 'Gene', '79811', (112, 115))	('CCNE1', 'Gene', '898', (129, 134))	('EPCAM', 'Gene', '4072', (117, 122))	('higher', 'PosReg', (162, 168))	('EGFR', 'Gene', '1956', (176, 180))	('ERBB2', 'Gene', '2064', (146, 151))
98034	33953611	Similarly, mutations in TP53 (P=0.0101), TERT (P=0.0005), IDH1 (P<0.0001), PIK3CA (P=0.0095), PTEN (P=0.0123), EGFR amplification (P<0.0001), MGMT methylation (P=0.0042), and CNV (P<0.0001) were dominant in GBM compared to the other subtypes (Figure 5) (Table 2).	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', (75, 81))	('MGMT', 'Gene', '4255', (142, 146))	('PTEN', 'Gene', (94, 98))	('MGMT', 'Gene', (142, 146))	('PIK3CA', 'Gene', '5290', (75, 81))	('TP53', 'Gene', (24, 28))	('PTEN', 'Gene', '5728', (94, 98))	('EGFR', 'Gene', '1956', (111, 115))	('IDH1', 'Gene', '3417', (58, 62))	('TERT', 'Gene', (41, 45))	('GBM', 'Disease', (207, 210))	('TERT', 'Gene', '7015', (41, 45))	('EGFR', 'Gene', (111, 115))	('GBM', 'Phenotype', 'HP:0012174', (207, 210))	('IDH1', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (24, 28))
98035	33953611	In addition, GBM also exhibited recurring genetic mutations, including ATRX mutations (6/32, 19%) and PDGFRA amplification (5/32, 16%) (Figure 5) (Table 2).	('PDGFRA', 'Gene', '5156', (102, 108))	('PDGFRA', 'Gene', (102, 108))	('mutations', 'Var', (76, 85))	('ATRX', 'Gene', '546', (71, 75))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))	('ATRX', 'Gene', (71, 75))
98036	33953611	Hence, as expected, among patients with grade II-III A/AA, TP53 mutation was the most common genomic alteration (13/20, 65%), followed by IDH1/2 mutation (11/20, 55%) and ATRX (7/20, 35%) (Table 2).	('ATRX', 'Gene', (171, 175))	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('patients', 'Species', '9606', (26, 34))	('ATRX', 'Gene', '546', (171, 175))	('IDH1/2', 'Gene', '3417;3418', (138, 144))	('AA', 'Phenotype', 'HP:0009592', (55, 57))	('TP53', 'Gene', '7157', (59, 63))	('IDH1/2', 'Gene', (138, 144))
98037	33953611	Moreover, in the Grade II-III O/AO subgroup, IDH1/2 mutation (12/17, 71%), TERT mutation (6/17, 35%), and 1p19q codeletion (10/17, 59%) were the major genetic alterations (Figure 5) (Table 2).	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('1p19q codeletion', 'Var', (106, 122))	('IDH1/2', 'Gene', (45, 51))	('mutation', 'Var', (52, 60))
98038	33953611	Most O/AOs exhibited TERT promoter (6/17, 35%), CIC (6/17, 35%), and FUBP1 (3/17, 18%) mutations (Table 2).	('FUBP1', 'Gene', '8880', (69, 74))	('CIC', 'Gene', (48, 51))	('TERT', 'Gene', (21, 25))	('TERT', 'Gene', '7015', (21, 25))	('FUBP1', 'Gene', (69, 74))	('CIC', 'Gene', '23152', (48, 51))	('mutations', 'Var', (87, 96))
98039	33953611	The H3K28M mutation only occurred in DMG patients.	('H3K28M', 'Var', (4, 10))	('DMG', 'Disease', (37, 40))	('DMG', 'Chemical', '-', (37, 40))	('patients', 'Species', '9606', (41, 49))	('occurred', 'Reg', (25, 33))
98040	33953611	Other common genetic alterations in DMG included TP53 mutation (3/8, 38%), TERT promoter mutation (2/8, 25%), PDGFRA amplification (2/8, 25%), PTEN mutation (1/8, 13%), and ATRX mutation (1/8, 13%), but no mutations were observed in IDH, EGFR, or MGMT methylation (Table 2).	('TP53', 'Gene', '7157', (49, 53))	('IDH', 'Gene', '3417', (233, 236))	('PDGFRA', 'Gene', (110, 116))	('EGFR', 'Gene', '1956', (238, 242))	('PDGFRA', 'Gene', '5156', (110, 116))	('ATRX', 'Gene', (173, 177))	('DMG', 'Chemical', '-', (36, 39))	('ATRX', 'Gene', '546', (173, 177))	('MGMT', 'Gene', (247, 251))	('TP53', 'Gene', (49, 53))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', (238, 242))	('PTEN', 'Gene', (143, 147))	('mutation', 'Var', (54, 62))	('IDH', 'Gene', (233, 236))	('PTEN', 'Gene', '5728', (143, 147))	('mutation', 'Var', (148, 156))	('MGMT', 'Gene', '4255', (247, 251))	('amplification', 'Var', (117, 130))
98043	33953611	Our results found that among 17 patients with oligodendroglial tumors only 10 patients with IDH mutations and 1p19q codeletion.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (46, 69))	('patients', 'Species', '9606', (32, 40))	('oligodendroglial tumors', 'Disease', (46, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (78, 86))	('IDH', 'Gene', (92, 95))	('1p19q', 'Var', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('IDH', 'Gene', '3417', (92, 95))
98046	33953611	The two cases were classified as based on morphology but harbored 1p19q-intacted and TP53 mutation, which is sufficient for the revised diagnosis of IDH mutation type A (2016 WHO CNS criteria).	('TP53', 'Gene', (85, 89))	('IDH', 'Gene', (149, 152))	('IDH', 'Gene', '3417', (149, 152))	('1p19q-intacted', 'Var', (66, 80))	('TP53', 'Gene', '7157', (85, 89))
98047	33953611	Five cases harbored IDH-wild mutation and 1p19q-intacted, but two cases of them mutated in FGFR1, one case mutated in BRAF V600E, and two cases mutated in other mutations (eg, ATM, PDGFRA), which is for the revised diagnosis of FGFR mutation type, BRAF mutation type and NEC diffuse glioma (cIMPACT-NOW update4).	('BRAF', 'Gene', '673', (118, 122))	('FGFR1', 'Gene', (91, 96))	('IDH', 'Gene', (20, 23))	('PDGFRA', 'Gene', (181, 187))	('BRAF', 'Gene', (248, 252))	('BRAF', 'Gene', (118, 122))	('IDH', 'Gene', '3417', (20, 23))	('PDGFRA', 'Gene', '5156', (181, 187))	('glioma', 'Disease', (283, 289))	('ATM', 'Gene', '472', (176, 179))	('FGFR1', 'Gene', '2260', (91, 96))	('mutated', 'Var', (80, 87))	('1p19q-intacted', 'Var', (42, 56))	('V600E', 'Mutation', 'rs113488022', (123, 128))	('glioma', 'Disease', 'MESH:D005910', (283, 289))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('BRAF', 'Gene', '673', (248, 252))	('ATM', 'Gene', (176, 179))
98049	33953611	In this study, targeted sequencing was used to analyze the pattern of mutations frequently associated with high-grade and low-grade gliomas.	('mutations', 'Var', (70, 79))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('high-grade', 'Disease', (107, 117))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('associated', 'Reg', (91, 101))
98050	33953611	We evaluated SNVs, short insertions, deletions, and CNVs of 28 genes in 27 low-grade gliomas (LGGs) and 56 high-grade gliomas (HGGs).	('deletions', 'Var', (37, 46))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Disease', (85, 92))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('short insertions', 'Var', (19, 35))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
98053	33953611	We found that mutations in IDH1/2 (P=0.0019) and CIC (P=0.0017) were more prevalent in low-grade gliomas (Figure 6) (Table 3).	('CIC', 'Gene', (49, 52))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('IDH1/2', 'Gene', '3417;3418', (27, 33))	('prevalent', 'Reg', (74, 83))	('CIC', 'Gene', '23152', (49, 52))	('IDH1/2', 'Gene', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('mutations', 'Var', (14, 23))
98054	33953611	On the other hand, mutations in TERT (P=0.0398), EGFR (P=0.0064), H3F3A (P=0.0388), PDGFRA (P=0.0388), and CNV (P<0.0001) were primarily found in high-grade (III-IV) gliomas (Figure 6) (Table 3).	('EGFR', 'Gene', '1956', (49, 53))	('TERT', 'Gene', '7015', (32, 36))	('CNV', 'Gene', (107, 110))	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('gliomas', 'Disease', (166, 173))	('EGFR', 'Gene', (49, 53))	('H3F3A', 'Gene', '3020', (66, 71))	('mutations', 'Var', (19, 28))	('PDGFRA', 'Gene', '5156', (84, 90))	('PDGFRA', 'Gene', (84, 90))	('H3F3A', 'Gene', (66, 71))	('found', 'Reg', (137, 142))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('TERT', 'Gene', (32, 36))
98056	33953611	Of note, several genomic mutations have been found only in high-grade tumors, including EGFR and MET amplification, PTEN genomic deletion, and PIK3CA mutations, indicating that mutations in these genes may represent biomarkers for predicting poor prognosis in high-grade gliomas.	('MET', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('PIK3CA', 'Gene', (143, 149))	('mutations', 'Var', (177, 186))	('MET', 'Gene', '79811', (97, 100))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('EGFR', 'Gene', '1956', (88, 92))	('mutations', 'Var', (150, 159))	('PIK3CA', 'Gene', '5290', (143, 149))	('PTEN', 'Gene', (116, 120))	('gliomas', 'Disease', (271, 278))	('PTEN', 'Gene', '5728', (116, 120))	('EGFR', 'Gene', (88, 92))	('gliomas', 'Disease', 'MESH:D005910', (271, 278))	('gliomas', 'Phenotype', 'HP:0009733', (271, 278))
98057	33953611	Although high frequencies of IDH1/2 mutations are typically used for the molecular genetic classification of gliomas according to the modern WHO CNS tumor classification, our findings indicated that the mutational frequency of IDH1/2 in LGG (15/27) and HGG (12/56) did not provide high accuracy in the classification for grading gliomas (Table 3).	('mutational', 'Var', (203, 213))	('glioma', 'Phenotype', 'HP:0009733', (329, 335))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH1/2', 'Gene', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('IDH1/2', 'Gene', '3417;3418', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('IDH1/2', 'Gene', '3417;3418', (29, 35))	('gliomas', 'Disease', 'MESH:D005910', (329, 336))	('gliomas', 'Disease', (329, 336))	('gliomas', 'Disease', (109, 116))	('tumor', 'Disease', (149, 154))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (329, 336))	('IDH1/2', 'Gene', (227, 233))	('CNS tumor', 'Phenotype', 'HP:0100006', (145, 154))
98058	33953611	On the other hand, previous reports have documented that amplification of chromosome 7 and deletion of chromosome 10 are the primary tumor-driving events in low-grade gliomas.	('deletion', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('amplification', 'Var', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('tumor', 'Disease', (133, 138))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))
98060	33953611	This suggests that WHO reclassification should consider not only IDH1/IDH2 mutations but also EGFR amplification and ATRX deletion simultaneously for the diagnosis of glioma tumor grading.	('IDH1', 'Gene', '3417', (65, 69))	('IDH2', 'Gene', '3418', (70, 74))	('EGFR', 'Gene', '1956', (94, 98))	('ATRX', 'Gene', '546', (117, 121))	('glioma tumor', 'Disease', (167, 179))	('EGFR', 'Gene', (94, 98))	('deletion', 'Var', (122, 130))	('ATRX', 'Gene', (117, 121))	('mutations', 'Var', (75, 84))	('amplification', 'Var', (99, 112))	('glioma tumor', 'Disease', 'MESH:D005910', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('IDH1', 'Gene', (65, 69))	('IDH2', 'Gene', (70, 74))
98062	33953611	IDH1/2 (P=0.0391), ATRX (P=0.0365), CIC (P<0.0001), MET (P=0.0367), and KIT (P=0.0201) mutations were significantly higher in recurrent gliomas than in gliomas receiving initial treatment (Figure 7) (Table 4).	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('higher', 'Reg', (116, 122))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (87, 96))	('MET', 'Gene', '79811', (52, 55))	('CIC', 'Gene', (36, 39))	('gliomas', 'Disease', (136, 143))	('ATRX', 'Gene', (19, 23))	('ATRX', 'Gene', '546', (19, 23))	('gliomas', 'Disease', (152, 159))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('MET', 'Gene', (52, 55))	('CIC', 'Gene', '23152', (36, 39))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('KIT', 'Gene', (72, 75))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
98064	33953611	To date, the neuropathology diagnostic laboratory has performed individual tests for selected biomarkers, such as IDH1, IDH2, ATRX, and TERT, as well as mutations in H3F3A and BRAF and 1p/19q chromosome deletion.	('IDH1', 'Gene', (114, 118))	('TERT', 'Gene', (136, 140))	('mutations', 'Var', (153, 162))	('ATRX', 'Gene', (126, 130))	('TERT', 'Gene', '7015', (136, 140))	('1p/19q chromosome deletion', 'Var', (185, 211))	('IDH2', 'Gene', (120, 124))	('H3F3A', 'Gene', '3020', (166, 171))	('IDH1', 'Gene', '3417', (114, 118))	('BRAF', 'Gene', '673', (176, 180))	('ATRX', 'Gene', '546', (126, 130))	('IDH2', 'Gene', '3418', (120, 124))	('H3F3A', 'Gene', (166, 171))	('BRAF', 'Gene', (176, 180))
98065	33953611	This involves a variety of detection methods, including the use of mutation-specific antibodies, such as IHC against IDH1-R132H, BRAF-V600E, and H3K28M, conventional Sanger sequencing or tumor DNA pyrosequencing to detect mutations/methylation, and fluorescence or chromogenic in situ hybridization (FISH/CISH) and microsatellite analysis to detect 1p/19q chromosome deletion.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('1p/19q', 'Disease', (349, 355))	('IDH1', 'Gene', '3417', (117, 121))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CISH', 'Gene', '1154', (305, 309))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('tumor', 'Disease', (187, 192))	('mutations/methylation', 'Var', (222, 243))	('CISH', 'Gene', (305, 309))	('R132H', 'Chemical', '-', (122, 127))	('IDH1', 'Gene', (117, 121))
98066	33953611	Our multigene NGS panel simultaneously evaluated multiple mutations, insertions, gene rearrangements, and CNVs associated with gliomas in Chinese patients.	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('insertions', 'Var', (69, 79))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('patients', 'Species', '9606', (146, 154))
98076	33953611	Zacher et al used 20 gene panels to conduct a comprehensive histological and molecular classification of 111 diffuse gliomas, reclassifying OA and GBM based on the status of IDH mutations and identifying tumors with H3F3A mutations.	('IDH', 'Gene', '3417', (174, 177))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('H3F3A', 'Gene', '3020', (216, 221))	('gliomas', 'Disease', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('GBM', 'Phenotype', 'HP:0012174', (147, 150))	('H3F3A', 'Gene', (216, 221))	('diffuse', 'Disease', (109, 116))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mutations', 'Var', (222, 231))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('IDH', 'Gene', (174, 177))	('mutations', 'Var', (178, 187))
98078	33953611	In the subgroup, IDH1/2 mutation (12/17, 71%), TERT mutation (6/17, 35%), and 1p19q codeletion (10/17, 59%) were the major genetic alterations.	('TERT', 'Gene', (47, 51))	('1p19q codeletion', 'Var', (78, 94))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('TERT', 'Gene', '7015', (47, 51))	('IDH1/2', 'Gene', (17, 23))	('mutation', 'Var', (24, 32))
98079	33953611	Except for mutations in IDH1/2 and TERT, O/AO also had CIC and FUBP1 mutations.	('mutations', 'Var', (69, 78))	('CIC', 'Gene', (55, 58))	('FUBP1', 'Gene', '8880', (63, 68))	('IDH1/2', 'Gene', '3417;3418', (24, 30))	('IDH1/2', 'Gene', (24, 30))	('FUBP1', 'Gene', (63, 68))	('CIC', 'Gene', '23152', (55, 58))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))
98080	33953611	Seven patients did not conform to the 2016 WHO CNS classification criteria of IDH mutated and 1p19q codeletion.	('patients', 'Species', '9606', (6, 14))	('IDH', 'Gene', '3417', (78, 81))	('IDH', 'Gene', (78, 81))	('1p19q codeletion', 'Var', (94, 110))
98084	33953611	In contrast, our study found not only similar genetic markers in brain tumors but also additional and novel mutational and genetic alterations used for the classification and prognosis of brain tumors, such as mutations in CIC, FUBP1, TP53, BRAF, PIK3CA, NF1, FGFR, NOTCH1, EGFR, ATM, and PDGFRA amplification.	('CIC', 'Gene', (223, 226))	('mutations', 'Var', (210, 219))	('ATM', 'Gene', (280, 283))	('brain tumors', 'Disease', 'MESH:D001932', (65, 77))	('PIK3CA', 'Gene', '5290', (247, 253))	('BRAF', 'Gene', '673', (241, 245))	('brain tumors', 'Phenotype', 'HP:0030692', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('FUBP1', 'Gene', '8880', (228, 233))	('TP53', 'Gene', (235, 239))	('brain tumor', 'Phenotype', 'HP:0030692', (65, 76))	('EGFR', 'Gene', '1956', (274, 278))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('CIC', 'Gene', '23152', (223, 226))	('brain tumors', 'Disease', (65, 77))	('brain tumors', 'Phenotype', 'HP:0030692', (188, 200))	('PIK3CA', 'Gene', (247, 253))	('NOTCH1', 'Gene', (266, 272))	('PDGFRA', 'Gene', (289, 295))	('FGFR', 'Gene', (260, 264))	('brain tumors', 'Disease', 'MESH:D001932', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('PDGFRA', 'Gene', '5156', (289, 295))	('TP53', 'Gene', '7157', (235, 239))	('brain tumor', 'Phenotype', 'HP:0030692', (188, 199))	('ATM', 'Gene', '472', (280, 283))	('EGFR', 'Gene', (274, 278))	('NF1', 'Gene', '4763', (255, 258))	('FUBP1', 'Gene', (228, 233))	('NOTCH1', 'Gene', '4851', (266, 272))	('brain tumors', 'Disease', (188, 200))	('NF1', 'Gene', (255, 258))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('BRAF', 'Gene', (241, 245))
98085	33953611	These novel and clinically actionable variants could assist in exploring better-targeted therapies for glioma treatment.	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Disease', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('variants', 'Var', (38, 46))
98086	33953611	In this study, the most common mutations in invasive glioma were TP53, TERT, IDH1, PTEN, ATRX, and EGFR, consistent with other reports.	('EGFR', 'Gene', (99, 103))	('mutations', 'Var', (31, 40))	('PTEN', 'Gene', '5728', (83, 87))	('TERT', 'Gene', (71, 75))	('TP53', 'Gene', (65, 69))	('ATRX', 'Gene', (89, 93))	('TP53', 'Gene', '7157', (65, 69))	('TERT', 'Gene', '7015', (71, 75))	('invasive glioma', 'Disease', (44, 59))	('IDH1', 'Gene', (77, 81))	('invasive glioma', 'Disease', 'MESH:D005910', (44, 59))	('ATRX', 'Gene', '546', (89, 93))	('IDH1', 'Gene', '3417', (77, 81))	('common', 'Reg', (24, 30))	('EGFR', 'Gene', '1956', (99, 103))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('PTEN', 'Gene', (83, 87))
98087	33953611	In astrocytoma grade II/III, 10/11 (91%) IDH mutation cases also exhibited TP53 mutations, and 4/4 (100%) IDH1 mutations in GBM also contained TP53 mutations.	('TP53', 'Gene', (143, 147))	('IDH', 'Gene', (41, 44))	('IDH', 'Gene', '3417', (106, 109))	('astrocytoma', 'Disease', (3, 14))	('exhibited', 'Reg', (65, 74))	('mutations', 'Var', (80, 89))	('IDH', 'Gene', '3417', (41, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (3, 14))	('IDH1', 'Gene', '3417', (106, 110))	('IDH', 'Gene', (106, 109))	('IDH1', 'Gene', (106, 110))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))	('TP53', 'Gene', '7157', (143, 147))	('astrocytoma', 'Disease', 'MESH:D001254', (3, 14))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
98088	33953611	Neither grade II/III astrocytoma nor grade IV GBM with IDH1 mutation exhibited EGFR mutations or PDGFRA amplification.	('mutation', 'Var', (60, 68))	('IDH1', 'Gene', '3417', (55, 59))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('astrocytoma', 'Phenotype', 'HP:0009592', (21, 32))	('III astrocytoma', 'Disease', (17, 32))	('mutations', 'Var', (84, 93))	('PDGFRA', 'Gene', (97, 103))	('PDGFRA', 'Gene', '5156', (97, 103))	('III astrocytoma', 'Disease', 'MESH:D001254', (17, 32))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('IDH1', 'Gene', (55, 59))
98090	33953611	Only 2 IDH mutant gliomas had MET amplification comutations, indicating that IDH1/2 and copy numbers rarely cooccur.	('IDH', 'Gene', (7, 10))	('gliomas', 'Disease', (18, 25))	('mutant', 'Var', (11, 17))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('IDH', 'Gene', '3417', (7, 10))	('amplification', 'MPA', (34, 47))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('IDH1/2', 'Gene', (77, 83))	('IDH1/2', 'Gene', '3417;3418', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH', 'Gene', (77, 80))	('MET', 'Gene', '79811', (30, 33))	('IDH', 'Gene', '3417', (77, 80))	('MET', 'Gene', (30, 33))
98091	33953611	IDH2 mutations are rare in GBM.	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('IDH2', 'Gene', '3418', (0, 4))	('IDH2', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
98093	33953611	Our estimated gene amplification events based on NGS coverage data were 0% O (grade II), 10% A/AA (grade II/III), 11.76% AO tumors (grade III), and 56.25% GBM (grade IV), indicating that copy number variation is more frequent in high-grade gliomas.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('AA', 'Phenotype', 'HP:0009592', (95, 97))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('tumors', 'Disease', (124, 130))	('copy number variation', 'Var', (187, 208))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('frequent', 'Reg', (217, 225))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('gliomas', 'Disease', 'MESH:D005910', (240, 247))	('gliomas', 'Phenotype', 'HP:0009733', (240, 247))	('gliomas', 'Disease', (240, 247))
98099	33953611	Obviously, DNA copy number variations, especially amplification on chromosome 7, including EGFR/MET/CDK6, and chromosome 4, including PDGFRA, are commonly observed in gliomas.	('amplification', 'Var', (50, 63))	('EGFR', 'Gene', (91, 95))	('MET', 'Gene', '79811', (96, 99))	('MET', 'Gene', (96, 99))	('CDK6', 'Gene', (100, 104))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('CDK6', 'Gene', '1021', (100, 104))	('gliomas', 'Disease', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('observed', 'Reg', (155, 163))	('EGFR', 'Gene', '1956', (91, 95))	('PDGFRA', 'Gene', '5156', (134, 140))	('PDGFRA', 'Gene', (134, 140))
98100	33953611	IDH mutation is a well-known prognostic factor.	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('mutation', 'Var', (4, 12))
98103	33953611	Previous studies have shown that in terms of OS, loss of CDKN2A is associated with poor treatment response and shorter OS in diffuse glioma.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('CDKN2A', 'Gene', (57, 63))	('loss', 'Var', (49, 53))	('CDKN2A', 'Gene', '1029', (57, 63))	('glioma', 'Disease', (133, 139))	('poor', 'NegReg', (83, 87))
98107	33953611	Our findings implicate gene panel NGS as a promising diagnostic technique that may facilitate integrated histological and molecular glioma classification.	('glioma', 'Disease', (132, 138))	('NGS', 'Var', (34, 37))	('gene panel NGS', 'Var', (23, 37))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
98114	33637608	Although combinatorial therapy targeting BRAF and MEK using dabrafenib and trametinib, respectively, is indicated for tumors harboring a BRAF p.V600E/K mutation, our report demonstrates efficacy of this combination in a non-V600E BRAF-mutated tumor.	('p.V600E', 'Var', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('p.V600E', 'SUBSTITUTION', 'None', (142, 149))	('RAF', 'Gene', (138, 141))	('RAF', 'Gene', '22882', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('RAF', 'Gene', '22882', (231, 234))	('V600E', 'Mutation', 'p.V600E', (144, 149))	('tumor', 'Disease', (243, 248))	('RAF', 'Gene', (42, 45))	('V600E', 'Mutation', 'p.V600E', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('RAF', 'Gene', (231, 234))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumors', 'Disease', (118, 124))	('MEK', 'Gene', '5609', (50, 53))	('trametinib', 'Chemical', 'MESH:C560077', (75, 85))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('MEK', 'Gene', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('RAF', 'Gene', '22882', (138, 141))	('dabrafenib', 'Chemical', 'MESH:C561627', (60, 70))	('tumor', 'Disease', (118, 123))
98115	33637608	The identification of BRAF alterations may assist clinicians in determining alternative targeted treatment strategies, especially considering the paucity of effective treatments for primary brain tumors and the poor prognosis associated with many central nervous system (CNS) diagnoses.	('brain tumors', 'Disease', 'MESH:D001932', (190, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('brain tumors', 'Disease', (190, 202))	('brain tumor', 'Phenotype', 'HP:0030692', (190, 201))	('RAF', 'Gene', '22882', (23, 26))	('RAF', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('brain tumors', 'Phenotype', 'HP:0030692', (190, 202))	('alterations', 'Var', (27, 38))
98116	33637608	Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAF and/or MEK inhibitors in patients whose tumors harbor a BRAF alteration.	('alteration', 'Var', (156, 166))	('MEK', 'Gene', '5609', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('RAF', 'Gene', '22882', (152, 155))	('RAF', 'Gene', (152, 155))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('patients', 'Species', '9606', (120, 128))	('RAF', 'Gene', '22882', (91, 94))	('RAF', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('MEK', 'Gene', (102, 105))
98117	33637608	BRAF alterations are commonly observed in many tumor types, the most frequent of which is BRAF p.Val600Glu (p.V600E).	('p.Val600Glu', 'Var', (95, 106))	('p.Val600Glu', 'Mutation', 'p.V600E', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('RAF', 'Gene', '22882', (1, 4))	('p.V600E', 'Mutation', 'p.V600E', (108, 115))	('RAF', 'Gene', '22882', (91, 94))	('RAF', 'Gene', (1, 4))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('RAF', 'Gene', (91, 94))	('tumor', 'Disease', (47, 52))
98119	33637608	Several other BRAF mutations, including p.Val600Lys (p.V600K) as well as other activating variants occurring within the kinase domain, have been identified as oncogenic drivers in different human cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('p.V600K', 'Mutation', 'p.V600K', (53, 60))	('p.Val600Lys', 'Mutation', 'p.V600K', (40, 51))	('p.Val600Lys', 'Var', (40, 51))	('RAF', 'Gene', '22882', (15, 18))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('RAF', 'Gene', (15, 18))	('cancers', 'Disease', (196, 203))	('human', 'Species', '9606', (190, 195))	('cancers', 'Disease', 'MESH:D009369', (196, 203))
98120	33637608	Specifically, in pediatric low-grade gliomas, BRAF alterations are the most commonly identified molecular event, most of which are p.V600E or KIAA1549-BRAF gene fusions.	('alterations', 'Var', (51, 62))	('p.V600E', 'Var', (131, 138))	('RAF', 'Gene', '22882', (152, 155))	('KIAA1549', 'Gene', '57670', (142, 150))	('RAF', 'Gene', (152, 155))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('KIAA1549', 'Gene', (142, 150))	('gliomas', 'Disease', (37, 44))	('p.V600E', 'Mutation', 'p.V600E', (131, 138))	('RAF', 'Gene', '22882', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('RAF', 'Gene', (47, 50))
98123	33637608	A BRAF p.V600E/K variant results in constitutively activated kinase activity and increased downstream MEK/ERK activation.	('MEK', 'Gene', '5609', (102, 105))	('activation', 'PosReg', (110, 120))	('RAF', 'Gene', (3, 6))	('ERK', 'Gene', (106, 109))	('ERK', 'Gene', '5594', (106, 109))	('RAF', 'Gene', '22882', (3, 6))	('p.V600E', 'Var', (7, 14))	('increased', 'PosReg', (81, 90))	('constitutively', 'MPA', (36, 50))	('p.V600E', 'SUBSTITUTION', 'None', (7, 14))	('MEK', 'Gene', (102, 105))
98125	33637608	In particular, combination therapy with dabrafenib (BRAFi) and trametinib (MEKi) is FDA-approved for use in patients with BRAF p.V600E/K in melanoma, as well as BRAF p.V600E in non-small-cell lung cancer and thyroid cancer.	('p.V600E', 'Var', (166, 173))	('p.V600E', 'SUBSTITUTION', 'None', (166, 173))	('RAF', 'Gene', (162, 165))	('trametinib', 'Chemical', 'MESH:C560077', (63, 73))	('patients', 'Species', '9606', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('MEK', 'Gene', '5609', (75, 78))	('p.V600E', 'Mutation', 'p.V600E', (127, 134))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('BRAFi', 'Chemical', '-', (52, 57))	('thyroid cancer', 'Disease', (208, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('dabrafenib', 'Chemical', 'MESH:C561627', (40, 50))	('p.V600E', 'Var', (127, 134))	('p.V600E', 'Mutation', 'p.V600E', (166, 173))	('MEK', 'Gene', (75, 78))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('thyroid cancer', 'Disease', 'MESH:D013964', (208, 222))	('melanoma', 'Disease', (140, 148))	('RAF', 'Gene', '22882', (53, 56))	('RAF', 'Gene', '22882', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (177, 203))	('lung cancer', 'Disease', (192, 203))	('thyroid cancer', 'Phenotype', 'HP:0002890', (208, 222))	('RAF', 'Gene', '22882', (162, 165))	('p.V600E', 'SUBSTITUTION', 'None', (127, 134))	('RAF', 'Gene', (53, 56))	('RAF', 'Gene', (123, 126))
98126	33637608	This combinatorial therapy has even proven effective with off-label use in patients with BRAF p.V600E-mutated high-grade gliomas.	('p.V600E-mutated', 'Var', (94, 109))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('RAF', 'Gene', (90, 93))	('RAF', 'Gene', '22882', (90, 93))	('patients', 'Species', '9606', (75, 83))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('p.V600E', 'Mutation', 'p.V600E', (94, 101))
98127	33637608	The value of combination targeted therapy aimed at BRAF alterations other than p.V600E/K needs further study and more clinical evidence to determine efficacy of such drugs.	('RAF', 'Gene', (52, 55))	('p.V600E', 'SUBSTITUTION', 'None', (79, 86))	('p.V600E', 'Var', (79, 86))	('RAF', 'Gene', '22882', (52, 55))
98128	33637608	Previously, we described identification of a BRAF variant resulting in duplication of threonine at codon 599 [NM_004333.4:c.1794_1796dup (p.T599dup)] in a pediatric World Health Organization (WHO) grade I ganglioglioma using genome sequencing.	('p.T599dup', 'Mutation', 'p.599dupT', (138, 147))	('ganglioglioma', 'Disease', 'MESH:D018303', (205, 218))	('threonine', 'Chemical', 'MESH:D013912', (86, 95))	('variant', 'Var', (50, 57))	('duplication of threonine', 'MPA', (71, 95))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('RAF', 'Gene', (46, 49))	('RAF', 'Gene', '22882', (46, 49))	('ganglioglioma', 'Disease', (205, 218))	('NM_004333.4:c.1794_1796dup', 'Mutation', 'c.1794_1796dup', (110, 136))
98129	33637608	Prior in vitro studies of p.T599dup demonstrated kinase activity and cellular MEK/ERK activation potential comparable to that of p.V600E.	('p.T599dup', 'Var', (26, 35))	('MEK', 'Gene', (78, 81))	('p.V600E', 'Mutation', 'p.V600E', (129, 136))	('MEK', 'Gene', '5609', (78, 81))	('ERK', 'Gene', '5594', (82, 85))	('p.T599dup', 'Mutation', 'p.599dupT', (26, 35))	('ERK', 'Gene', (82, 85))	('activation', 'PosReg', (86, 96))	('kinase activity', 'MPA', (49, 64))
98135	33637608	Subsequent genome sequencing of the tumor specimen revealed a BRAF p.T599dup mutation.	('RAF', 'Gene', '22882', (63, 66))	('RAF', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p.T599dup', 'Mutation', 'p.599dupT', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('p.T599dup', 'Var', (67, 76))
98143	33637608	We obtained tumor-extracted DNA from this near-complete resection and performed deep, targeted sequencing of the p.T599dup BRAF variant.	('p.T599dup', 'DUPLICATION', 'None', (113, 122))	('p.T599dup', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('BRAF', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
98144	33637608	The allele frequency of the BRAF variant detected in the more recent resection (5.9%) was retained at a slightly higher, but similar, frequency as detected in the patient's initial tumor resection (5.2%).	('tumor', 'Disease', (181, 186))	('variant', 'Var', (33, 40))	('RAF', 'Gene', (29, 32))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('RAF', 'Gene', '22882', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
98152	33637608	Our report demonstrates the sensitivity of a non-V600E BRAF mutation in a low-grade glioma to treatment with combination targeted therapy (BRAFi/MEKi).	('RAF', 'Gene', (140, 143))	('RAF', 'Gene', '22882', (56, 59))	('non-V600E', 'Var', (45, 54))	('glioma', 'Disease', (84, 90))	('V600E', 'Mutation', 'p.V600E', (49, 54))	('RAF', 'Gene', (56, 59))	('BRAFi', 'Chemical', '-', (139, 144))	('MEK', 'Gene', (145, 148))	('MEK', 'Gene', '5609', (145, 148))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('RAF', 'Gene', '22882', (140, 143))
98153	33637608	We identified two other reports in which patients (one with melanoma and one with lung cancer) each harboring the BRAF p.T599dup received dabrafenib/trametinib and demonstrated a positive clinical response including stable disease in the lung cancer case and partial remission in the melanoma case.	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('trametinib', 'Chemical', 'MESH:C560077', (149, 159))	('RAF', 'Gene', (115, 118))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('melanoma', 'Disease', (284, 292))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('patients', 'Species', '9606', (41, 49))	('lung cancer', 'Disease', (82, 93))	('p.T599dup', 'Var', (119, 128))	('stable', 'Disease', (216, 222))	('RAF', 'Gene', '22882', (115, 118))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('lung cancer', 'Disease', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('p.T599dup', 'Mutation', 'p.599dupT', (119, 128))	('dabrafenib', 'Chemical', 'MESH:C561627', (138, 148))
98156	33637608	MEKi are attractive because BRAF alterations resulting in downstream activation of the RAS/MAPK pathway are present in a significant subset of pediatric brain tumors (pilocytic astrocytomas, 10%-15%; pleomorphic xanthoastrocytomas, 50%-60%; gangliogliomas, 20%-60%) and offer a useful target for therapy.	('brain tumor', 'Phenotype', 'HP:0030692', (153, 164))	('gliomas', 'Phenotype', 'HP:0009733', (248, 255))	('MEK', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (200, 230))	('gangliogliomas', 'Disease', 'MESH:D018303', (241, 255))	('activation', 'PosReg', (69, 79))	('RAS/MAPK pathway', 'Pathway', (87, 103))	('brain tumors', 'Disease', 'MESH:D001932', (153, 165))	('brain tumors', 'Phenotype', 'HP:0030692', (153, 165))	('gangliogliomas', 'Disease', (241, 255))	('pleomorphic xanthoastrocytomas', 'Disease', (200, 230))	('brain tumors', 'Disease', (153, 165))	('alterations', 'Var', (33, 44))	('RAF', 'Gene', '22882', (29, 32))	('pilocytic astrocytomas', 'Disease', (167, 189))	('MEK', 'Gene', '5609', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('RAF', 'Gene', (29, 32))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (167, 189))
98158	33637608	A recent investigation of publicly available databases revealed 20 different known activating BRAF mutations reported in pediatric gliomas.	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('RAF', 'Gene', (95, 98))	('mutations', 'Var', (99, 108))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('RAF', 'Gene', '22882', (95, 98))	('activating', 'PosReg', (83, 93))
98160	33637608	Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAFi and/or MEKi in patients whose tumors harbor a BRAF alteration.	('RAF', 'Gene', (143, 146))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('BRAFi', 'Chemical', '-', (90, 95))	('MEK', 'Gene', (103, 106))	('MEK', 'Gene', '5609', (103, 106))	('RAF', 'Gene', '22882', (91, 94))	('alteration', 'Var', (147, 157))	('RAF', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('RAF', 'Gene', '22882', (143, 146))	('patients', 'Species', '9606', (111, 119))
98163	33637608	Genomic DNA (10 ng) was used as a template for polymerase chain reaction (PCR) designed to amplify a 300-bp product that includes the BRAF p.599 position.	('p.599', 'Var', (139, 144))	('RAF', 'Gene', '22882', (135, 138))	('RAF', 'Gene', (135, 138))
98166	33637608	A post-PCR 1.2x SPRIselect cleanup was performed, and libraries were pooled and sequenced on Illumina iSeq100 to achiever average read depth of 200,000x at the BRAF variant site.	('RAF', 'Gene', '22882', (161, 164))	('RAF', 'Gene', (161, 164))	('variant', 'Var', (165, 172))
98172	33668509	Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG).	('IDH', 'Gene', (49, 52))	('Glioma', 'Disease', 'MESH:D005910', (67, 73))	('Glioma', 'Phenotype', 'HP:0009733', (67, 73))	('isocitrate dehydrogenase', 'Gene', (133, 157))	('glioma', 'Disease', (105, 111))	('IDH', 'Gene', '3417', (49, 52))	('IDH1/2', 'Gene', '3417;3418', (163, 169))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('IDH1/2', 'Gene', (163, 169))	('mutant', 'Var', (126, 132))	('Glioma', 'Disease', (67, 73))	('accumulation', 'PosReg', (199, 211))	('IDH', 'Gene', (163, 166))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('2-HG', 'Chemical', 'MESH:C019417', (254, 258))	('isocitrate dehydrogenase', 'Gene', '3417', (133, 157))	('IDH', 'Gene', '3417', (163, 166))	('mutations', 'Var', (178, 187))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (234, 252))
98173	33668509	Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032.	('IDH', 'Gene', (15, 18))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (85, 96))	('AG-881', 'Chemical', '-', (74, 80))	('mutant', 'Var', (8, 14))
98174	33668509	In this study we used high resolution 1H magnetic resonance spectroscopy (1H-MRS) to identify early noninvasive MR (Magnetic Resonance)-detectable metabolic biomarkers of response to mutant IDH inhibition.	('IDH', 'Gene', (190, 193))	('1H', 'Chemical', '-', (38, 40))	('1H', 'Chemical', '-', (74, 76))	('mutant', 'Var', (183, 189))
98175	33668509	In vivo 1H-MRS was performed on mice orthotopically-implanted with either genetically engineered (U87IDHmut) or patient-derived (BT257 and SF10417) mutant IDH1 cells.	('IDH1', 'Gene', (155, 159))	('patient', 'Species', '9606', (112, 119))	('BT257', 'Chemical', '-', (129, 134))	('SF10417', 'Chemical', '-', (139, 146))	('mutant', 'Var', (148, 154))	('mice', 'Species', '10090', (32, 36))	('1H', 'Chemical', '-', (8, 10))
98176	33668509	Treatment with either AG-881 or BAY-1436032 induced a significant reduction in 2-HG.	('2-HG', 'MPA', (79, 83))	('BAY-1436032', 'Var', (32, 43))	('AG-881', 'Chemical', '-', (22, 28))	('2-HG', 'Chemical', 'MESH:C019417', (79, 83))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (32, 43))	('reduction', 'NegReg', (66, 75))
98180	33668509	Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies.	('glioma', 'Disease', (125, 131))	('inhibition', 'NegReg', (110, 120))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('mutant', 'Var', (99, 105))	('IDH', 'Gene', (106, 109))
98181	33668509	Diffuse infiltrative low-grade gliomas (LGGs) are characterized as grade II or III astrocytoma and oligodendroglioma based on histopathological features and genotype including the status of the isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion and ATRX.	('IDH', 'Gene', (220, 223))	('astrocytoma', 'Disease', 'MESH:D001254', (83, 94))	('oligodendroglioma', 'Disease', 'MESH:D009837', (99, 116))	('isocitrate dehydrogenase', 'Gene', (194, 218))	('ATRX', 'Gene', (257, 261))	('astrocytoma', 'Disease', (83, 94))	('isocitrate dehydrogenase', 'Gene', '3417', (194, 218))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('1p/19q codeletion', 'Var', (235, 252))	('ATRX', 'Gene', '546', (257, 261))	('Diffuse', 'Disease', (0, 7))	('oligodendroglioma', 'Disease', (99, 116))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('mutation', 'Var', (225, 233))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
98185	33668509	Over 80% of LGGs harbor somatic mutations in IDH1 or IDH2 leading to a neomorphic enzyme activity that catalyzes the production of the oncometabolite 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate (alpha-KG).	('leading to', 'Reg', (58, 68))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (181, 200))	('IDH2', 'Gene', (53, 57))	('neomorphic', 'MPA', (71, 81))	('mutations', 'Var', (32, 41))	('production of', 'MPA', (117, 130))	('alpha-KG', 'Chemical', 'MESH:D007656', (202, 210))	('2-HG', 'Chemical', 'MESH:C019417', (170, 174))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (150, 168))	('IDH1', 'Gene', (45, 49))	('catalyzes', 'MPA', (103, 112))
98187	33668509	The role of the IDH mutation as an oncogenic driver, and its recognition in 2016 by the World Health Organization as a crucial genetic characteristic of LGGs, have stimulated extensive exploration of therapies that could inhibit 2-HG production and potentially reverse its oncogenic effects.	('inhibit', 'NegReg', (221, 228))	('mutation', 'Var', (20, 28))	('oncogenic effects', 'CPA', (273, 290))	('IDH', 'Gene', (16, 19))	('2-HG', 'Chemical', 'MESH:C019417', (229, 233))	('2-HG production', 'MPA', (229, 244))
98188	33668509	In particular, several promising mutant IDH inhibitors including AG-120, IDH305, AG-881, BAY-1436032, AG-221, and FT-2120 have been developed and are currently in ongoing clinical trials for gliomas either alone or in combination with chemotherapy (NCT02073994, NCT02381886, NCT03343197, NCT02481154, NCT04164901, NCT02746081, NCT02273739, NCT03684811).	('NCT02481154', 'Var', (288, 299))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('AG-881', 'Chemical', '-', (81, 87))	('IDH', 'Gene', (40, 43))	('mutant', 'Var', (33, 39))	('NCT02746081', 'Var', (314, 325))	('NCT02073994', 'Var', (249, 260))	('AG-120', 'Var', (65, 71))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (89, 100))	('NCT04164901', 'Var', (301, 312))	('gliomas', 'Disease', (191, 198))	('AG-120', 'Chemical', 'MESH:C000627630', (65, 71))	('NCT02381886', 'Var', (262, 273))	('NCT03684811', 'Var', (340, 351))	('IDH305', 'Chemical', '-', (73, 79))	('NCT02273739', 'Var', (327, 338))	('BAY-1436032', 'Var', (89, 100))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('NCT03343197', 'Var', (275, 286))
98193	33668509	As a result, since the discovery of the IDH mutation, this method has the potential to play an important role in noninvasive detection of 2-HG and thus tumor characterization.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutation', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('2-HG', 'Chemical', 'MESH:C019417', (138, 142))	('tumor', 'Disease', (152, 157))	('IDH', 'Gene', (40, 43))
98196	33668509	The use of MRS is particularly important because clinical studies to date with three mutant IDH inhibitors, AG-881, IDH305, and AG-120, have all shown that treatment is associated with inhibition of tumor growth and potentially longer patient survival, but no detectable tumor shrinkage has been reported.	('tumor', 'Disease', (199, 204))	('patient', 'Species', '9606', (235, 242))	('AG-881', 'Var', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('patient survival', 'CPA', (235, 251))	('IDH305', 'Chemical', '-', (116, 122))	('tumor', 'Disease', (271, 276))	('IDH305', 'Var', (116, 122))	('AG-120', 'Chemical', 'MESH:C000627630', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('inhibition', 'NegReg', (185, 195))	('IDH', 'Gene', (92, 95))	('AG-120', 'Var', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('AG-881', 'Chemical', '-', (108, 114))	('longer', 'PosReg', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (271, 276))
98198	33668509	Our previous studies in cells have identified the MRS-detectable metabolic alterations characteristic of glioma harboring the IDH1 mutation when compared to wild type IDH1.	('glioma', 'Disease', (105, 111))	('metabolic alterations', 'MPA', (65, 86))	('IDH1', 'Gene', (126, 130))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('mutation', 'Var', (131, 139))
98199	33668509	We also showed that treatment of cells with the IDH inhibitors AG-120 and AG-881 resulted in a partial reversal of the metabolic alterations caused by the mutation.	('metabolic alterations', 'MPA', (119, 140))	('AG-881', 'Chemical', '-', (74, 80))	('AG-120', 'Chemical', 'MESH:C000627630', (63, 69))	('mutation', 'Var', (155, 163))	('AG-881', 'Gene', (74, 80))
98200	33668509	Most notably, we observed that in addition to the expected 1H-MRS detectable drop in 2-HG, there is a significant increase in glutamate (Glu) following mutant IDH inhibition.	('inhibition', 'NegReg', (163, 173))	('IDH', 'Gene', (159, 162))	('increase', 'PosReg', (114, 122))	('2-HG', 'Chemical', 'MESH:C019417', (85, 89))	('glutamate', 'Chemical', 'MESH:D018698', (126, 135))	('1H', 'Chemical', '-', (59, 61))	('mutant', 'Var', (152, 158))	('2-HG', 'MPA', (85, 89))	('Glu', 'Chemical', 'MESH:D018698', (137, 140))
98201	33668509	The goal of this study was to expand upon our previous work in cells, and to assess the impact of mutant IDH inhibitors on the 1H-MRS spectrum of tumors in vivo particularly metabolic changes other than 2-HG.	('1H', 'Chemical', '-', (127, 129))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('2-HG', 'Chemical', 'MESH:C019417', (203, 207))	('pan', 'Gene', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('pan', 'Gene', '51816', (32, 35))	('IDH', 'Gene', (105, 108))	('tumors', 'Disease', (146, 152))	('mutant', 'Var', (98, 104))
98202	33668509	To this end, we investigated three orthotopic mutant IDH1 glioma mouse models and studied the effects of two brain penetrant mutant IDH inhibitors, AG-881 and BAY-1436032, that are currently in clinical trials for glioma patients.	('patients', 'Species', '9606', (221, 229))	('mouse', 'Species', '10090', (65, 70))	('glioma', 'Disease', (214, 220))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1 glioma', 'Disease', 'MESH:D005910', (53, 64))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (159, 170))	('mutant', 'Var', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('glioma', 'Disease', (58, 64))	('IDH1 glioma', 'Disease', (53, 64))	('AG-881', 'Chemical', '-', (148, 154))
98204	33668509	Previous in vitro studies probed the effect of mutant IDH inhibitor AG-881 in U87IDHmut cells that were genetically engineered to express mutant IDH1.	('AG-881', 'Gene', (68, 74))	('IDH1', 'Gene', (145, 149))	('mutant', 'Var', (138, 144))	('AG-881', 'Chemical', '-', (68, 74))	('mutant', 'Var', (47, 53))
98205	33668509	Therefore, prior to investigating patient-derived (BT257 and SF10417) mutant IDH1 glioma models, we first performed a small-scale study investigating the effect of AG-881 treatment on mice with orthotopic U87IDHmut tumors.	('BT257', 'Chemical', '-', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutant', 'Var', (70, 76))	('AG-881', 'Chemical', '-', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('IDH1 glioma', 'Disease', 'MESH:D005910', (77, 88))	('patient', 'Species', '9606', (34, 41))	('SF10417', 'Chemical', '-', (61, 68))	('mice', 'Species', '10090', (184, 188))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))	('IDH1 glioma', 'Disease', (77, 88))
98209	33668509	Figure 2a illustrates the evolution of average U87IDHmut tumor volume in control, AG-881 and BAY-1436032 treated groups.	('U87IDHmut', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('AG-881', 'Chemical', '-', (82, 88))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (93, 104))	('tumor', 'Disease', (57, 62))	('BAY-1436032', 'Var', (93, 104))
98210	33668509	For the duration of our study, no significant changes in tumor volume could be detected following treatment with either of the mutant IDH inhibitors when compared to controls.	('mutant', 'Var', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('IDH', 'Gene', (134, 137))
98211	33668509	Nonetheless, the overall survival of U87IDHmut tumor-bearing mice was significantly enhanced in both treatments.	('mice', 'Species', '10090', (61, 65))	('survival', 'CPA', (25, 33))	('U87IDHmut', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('enhanced', 'PosReg', (84, 92))	('tumor', 'Disease', (47, 52))
98212	33668509	Following AG-881 treatment the median survival was 7.5 days (Chi2-value = 26.9) and following BAY-1436032 treatment median survival was 10 days (Chi2-value = 54.7) compared to 6-day median survival of controls (Figure 2b).	('AG-881', 'Gene', (10, 16))	('BAY-1436032', 'Var', (94, 105))	('AG-881', 'Chemical', '-', (10, 16))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (94, 105))
98213	33668509	We therefore focused only on the spectra acquired at D5 +- 1 of treatment, when tumor volume changes, as a percentage of D0, were 205 +- 106% (n = 10, p-value = 0.799) in the AG-881 treated group and 225 +- 58% (n = 6, p-value = 0.318) in the BAY-1436032 treated group compared to 261 +- 67% in the control group (n = 7) (Figure 2a).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (243, 254))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('AG-881', 'Chemical', '-', (175, 181))	('BAY-1436032', 'Var', (243, 254))	('tumor', 'Disease', (80, 85))
98217	33668509	As expected, the in vivo 1H-MRS experiments revealed a significant decrease in the concentration of 2-HG following treatment with both inhibitors (decrease by 58% in AG-881-treated and by 25% in BAY-1436032-treated) when compared to controls consistent with drug delivery and action via mutant IDH inhibition by D5 +- 1 (Figure 2d).	('AG-881', 'Chemical', '-', (166, 172))	('concentration', 'MPA', (83, 96))	('decrease', 'NegReg', (67, 75))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (195, 206))	('2-HG', 'Chemical', 'MESH:C019417', (100, 104))	('decrease', 'NegReg', (147, 155))	('1H', 'Chemical', '-', (25, 27))	('inhibition', 'NegReg', (298, 308))	('mutant', 'Var', (287, 293))	('IDH', 'Gene', (294, 297))
98219	33668509	GLX levels also increased significantly in response to both AG-881 (increase by 14%) and BAY-1436032 (increase by 16%) when compared to controls (Figure 2d).	('BAY-1436032', 'Chemical', 'MESH:C000622445', (89, 100))	('BAY-1436032', 'Var', (89, 100))	('AG-881', 'Chemical', '-', (60, 66))	('increased', 'PosReg', (16, 25))	('AG-881', 'Gene', (60, 66))	('GLX levels', 'MPA', (0, 10))
98222	33668509	Figure 3 demonstrates T2-weighted images of control, AG-881 and BAY-1436032-treated mice at D0 prior to treatment, D7 +- 2 and D15 +- 1 of treatment for the BT257 model, and D6 +- 2 and D14 +- 2 of treatment for the SF10417 model (Figure 3a,b).	('BAY-1436032', 'Chemical', 'MESH:C000622445', (64, 75))	('AG-881', 'Chemical', '-', (53, 59))	('D7 +- 2', 'Var', (115, 122))	('D14 +- 2', 'Var', (186, 194))	('mice', 'Species', '10090', (84, 88))	('D15 +- 1 of', 'Var', (127, 138))	('BT257', 'Chemical', '-', (157, 162))	('SF10417', 'Chemical', '-', (216, 223))	('D6 +- 2', 'Var', (174, 181))
98224	33668509	However, differences in tumor volume did become significant by D15 +- 1 in the BT257 model (controls: 335 +- 117%, n = 9; AG-881-treated: 202 +- 68%, n = 6, p-value = 0.016) and by D14 +- 2 in the SF10417 model (controls: 381 +- 78%, n = 5; AG-881-treated: 280 +- 41%, n = 5, p-value = 0.042) (Figure 3c,d).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('AG-881', 'Chemical', '-', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('SF10417', 'Chemical', '-', (197, 204))	('AG-881', 'Chemical', '-', (241, 247))	('D15 +- 1', 'Var', (63, 71))	('BT257', 'Chemical', '-', (79, 84))	('D14 +- 2', 'Var', (181, 189))
98225	33668509	Similarly, no significant differences in average tumor volume were observed at the early time point of treatment with BAY-1436032 in the BT257 model at D7 +- 2 (BAY-1436032-treated: 132 +- 28%, n = 5, p-value = 0.142) and in the SF10417 model at D6 +- 2 (BAY-1436032-treated: 166 +- 17%, n = 7, p-value = 0.102).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (161, 172))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (255, 266))	('tumor', 'Disease', (49, 54))	('SF10417', 'Chemical', '-', (229, 236))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (118, 129))	('BT257', 'Chemical', '-', (137, 142))	('BAY-1436032', 'Var', (118, 129))
98226	33668509	But we detected a significant slowdown in tumor growth in response to BAY-1436032 treatment by D15 +- 1 in the BT257 model (BAY-1436032-treated: 174 +- 53%, n = 5, p-value = 0.004) and by D14 +- 2 in the SF10417 model (BAY-1436032-treated: 252 +- 60%, n = 6, p-value = 0.018) when compared to controls (Figure 3c,d).	('BAY-1436032', 'Gene', (70, 81))	('slowdown', 'NegReg', (30, 38))	('tumor', 'Disease', (42, 47))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (219, 230))	('BT257', 'Chemical', '-', (111, 116))	('D15 +- 1', 'Var', (95, 103))	('SF10417', 'Chemical', '-', (204, 211))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (70, 81))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (124, 135))	('D14 +- 2', 'Var', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
98231	33668509	Based on the temporal evolution of average tumor volume described above, we next designed the spectroscopic study such that we investigated the in vivo 1H-MRS metabolic profile of each model in response to treatment at two time points: the early time point, D7 +- 2 for BT257 and D6 +- 2 for SF10417, prior to differences in tumor volume, and the late time point D15 +- 1 for the BT257 model and D14 +- 2 for the SF10417 model, when significant differences in tumor volume were MR-detectable (Figure 1 and Figure 3).	('D14 +- 2', 'Var', (396, 404))	('SF10417', 'Var', (413, 420))	('1H', 'Chemical', '-', (152, 154))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('SF10417', 'Var', (292, 299))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('D15 +- 1', 'Var', (363, 371))	('tumor', 'Disease', (460, 465))	('tumor', 'Disease', 'MESH:D009369', (460, 465))	('D6 +- 2', 'Var', (280, 287))	('BT257', 'Chemical', '-', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('BT257', 'Chemical', '-', (380, 385))	('tumor', 'Disease', (325, 330))	('D7 +- 2', 'Var', (258, 265))	('SF10417', 'Chemical', '-', (413, 420))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (460, 465))	('SF10417', 'Chemical', '-', (292, 299))
98232	33668509	Figure 4 illustrates typical T2-weighted anatomical images and corresponding 1H-MRS spectra acquired from the voxel placed inside the tumor region of the BT257 and SF10417 glioma models (Figure 4a,b).	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('BT257', 'Chemical', '-', (154, 159))	('SF10417', 'Chemical', '-', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('glioma', 'Disease', (172, 178))	('1H', 'Chemical', '-', (77, 79))	('SF10417', 'Var', (164, 171))
98233	33668509	As expected, at the early time point prior to any significant differences in tumor volume, we detected a consistent and significant decrease in 2-HG levels in response to mutant IDH inhibition.	('2-HG', 'Chemical', 'MESH:C019417', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('inhibition', 'NegReg', (182, 192))	('mutant', 'Var', (171, 177))	('tumor', 'Disease', (77, 82))	('decrease', 'NegReg', (132, 140))	('2-HG levels', 'MPA', (144, 155))	('IDH', 'Gene', (178, 181))
98234	33668509	Following treatment with AG-881, 2-HG significantly dropped in both BT257 (decrease by 35%) and SF10417 (decrease by 7%) tumors (Figure 4c,d, Table 2 and Table 3).	('decrease', 'NegReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('SF10417', 'Var', (96, 103))	('tumors', 'Disease', (121, 127))	('BT257', 'Gene', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('BT257', 'Chemical', '-', (68, 73))	('AG-881', 'Chemical', '-', (25, 31))	('dropped', 'NegReg', (52, 59))	('2-HG', 'Chemical', 'MESH:C019417', (33, 37))	('decrease', 'NegReg', (105, 113))	('SF10417', 'Chemical', '-', (96, 103))
98235	33668509	When compared to controls, lower levels of 2-HG were also observed at the later time point when inhibition of tumor growth was detected in both BT257 (decrease by 68% in AG-881-treated) and SF10417 (decrease by 34% in AG-881-treated) models.	('AG-881', 'Chemical', '-', (170, 176))	('AG-881', 'Chemical', '-', (218, 224))	('SF10417', 'Chemical', '-', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('decrease', 'NegReg', (151, 159))	('BT257', 'Gene', (144, 149))	('BT257', 'Chemical', '-', (144, 149))	('SF10417', 'Var', (190, 197))	('inhibition', 'NegReg', (96, 106))	('2-HG', 'Chemical', 'MESH:C019417', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
98237	33668509	Similarly, GLX levels were also significantly increased in both models (in BT257 increase by 15% in AG-881-treated and in SF10417 increase by 57% in AG-881-treated) (Figure 4c,d).	('AG-881', 'Chemical', '-', (149, 155))	('SF10417', 'Gene', (122, 129))	('increased', 'PosReg', (46, 55))	('BT257', 'MPA', (75, 80))	('BT257', 'Chemical', '-', (75, 80))	('increase', 'PosReg', (130, 138))	('increase', 'PosReg', (81, 89))	('AG-881-treated', 'Var', (100, 114))	('SF10417', 'Chemical', '-', (122, 129))	('AG-881', 'Chemical', '-', (100, 106))	('GLX levels', 'MPA', (11, 21))
98238	33668509	The metabolic alterations in Glu (increase by 39% in BT257 and by 32% in SF10417 tumors) and GLX (increase by 16% in BT257 and by 32% in SF10417 tumors) were sustained and remained significant also at the later stages of AG-881 treatment when changes in tumor volume were already MR-detectable (Table 2 and Table 3).	('SF10417', 'Var', (137, 144))	('tumors', 'Disease', (81, 87))	('Glu', 'MPA', (29, 32))	('SF10417', 'Var', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (254, 259))	('AG-881', 'Chemical', '-', (221, 227))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('increase', 'PosReg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('SF10417', 'Chemical', '-', (137, 144))	('increase', 'PosReg', (34, 42))	('Glu', 'Chemical', 'MESH:D018698', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('BT257', 'Chemical', '-', (117, 122))	('GLX', 'MPA', (93, 96))	('SF10417', 'Chemical', '-', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('BT257', 'Chemical', '-', (53, 58))	('tumors', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
98240	33668509	Treatment of BT257 and SF10417 tumors with BAY-1436032 resulted in the same metabolic trends as treatment with AG-881.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (43, 54))	('tumors', 'Disease', (31, 37))	('BAY-1436032', 'Var', (43, 54))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('metabolic', 'MPA', (76, 85))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('SF10417', 'Chemical', '-', (23, 30))	('BT257', 'Chemical', '-', (13, 18))	('AG-881', 'Chemical', '-', (111, 117))
98241	33668509	2-HG levels were significantly decreased in response to BAY-1436032 treatment at the early time point prior to MR-detectable differences in tumor volume in the BT257 (decrease by 20% in BAY-1436032-treated) and in the SF10417 (decrease by 23% in BAY-1436032-treated) models (Figure 4c,d, Table 2 and Table 3).	('2-HG levels', 'MPA', (0, 11))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('decrease', 'NegReg', (167, 175))	('decreased', 'NegReg', (31, 40))	('BT257', 'Chemical', '-', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('SF10417', 'Chemical', '-', (218, 225))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (56, 67))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (246, 257))	('BAY-1436032-treated', 'Var', (186, 205))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (186, 197))	('BAY-1436032', 'Var', (56, 67))	('tumor', 'Disease', (140, 145))
98242	33668509	Significant decrease in the levels of 2-HG was also observed at the later time point in the BT257 (decrease by 50% in BAY-1436032-treated) and in the SF10417 (decrease by 18% in BAY-1436032-treated) models compared to corresponding controls (Table 2 and Table 3).	('levels', 'MPA', (28, 34))	('2-HG', 'Chemical', 'MESH:C019417', (38, 42))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (178, 189))	('BT257', 'Chemical', '-', (92, 97))	('SF10417', 'Chemical', '-', (150, 157))	('decrease', 'NegReg', (99, 107))	('BAY-1436032-treated', 'Var', (118, 137))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (118, 129))	('decrease', 'NegReg', (12, 20))
98243	33668509	Additionally, treatment with BAY-1436032 resulted in a significant increase in the levels of Glu at the early time point in both the BT257 (increase by 48% in BAY-1436032-treated) and the SF10417 (increase by 128% in BAY-1436032-treated) models.	('BAY-1436032', 'Var', (29, 40))	('levels of Glu at the early time point', 'MPA', (83, 120))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (217, 228))	('BT257', 'Chemical', '-', (133, 138))	('BAY-1436032-treated', 'Var', (159, 178))	('Glu', 'Chemical', 'MESH:D018698', (93, 96))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (159, 170))	('increase', 'PosReg', (67, 75))	('SF10417', 'Chemical', '-', (188, 195))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (29, 40))
98244	33668509	GLX was similarly significantly increased with treatment at the early time point in both the BT257 (increase by 24% in BAY-1436032-treated) and in the SF10417 (increase by 85% in BAY-1436032-treated) models when compared to controls (Figure 4c,d, Table 2 and Table 3).	('BT257', 'Chemical', '-', (93, 98))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (119, 130))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (179, 190))	('increase', 'PosReg', (100, 108))	('increased', 'PosReg', (32, 41))	('GLX', 'MPA', (0, 3))	('BAY-1436032-treated', 'Var', (119, 138))	('SF10417', 'Chemical', '-', (151, 158))
98245	33668509	These increases in Glu (increase by 52% in BT257 and by 45% in SF10417 tumors) and GLX (increase by 24% in BT257 and by 95% in SF10417 tumors) were also sustained at the later time point of BAY-1436032 treatment in both models (Table 2 and Table 3).	('SF10417', 'Chemical', '-', (63, 70))	('GLX', 'MPA', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('BT257', 'Chemical', '-', (43, 48))	('tumors', 'Disease', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('SF10417', 'Var', (127, 134))	('SF10417', 'Chemical', '-', (127, 134))	('SF10417', 'Gene', (63, 70))	('Glu', 'MPA', (19, 22))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('increases', 'PosReg', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Glu', 'Chemical', 'MESH:D018698', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('BT257', 'Chemical', '-', (107, 112))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (190, 201))
98246	33668509	Figure 5 provides a summary of the different metabolic alterations observed prior to MR-detectable changes in tumor volume in all three models following mutant IDH inhibition.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutant', 'Var', (153, 159))	('IDH', 'Gene', (160, 163))	('inhibition', 'NegReg', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
98247	33668509	In all of our models, mutant IDH inhibition with either AG-881 or BAY-1436032 led to the expected drop in 2-HG level.	('2-HG', 'Chemical', 'MESH:C019417', (106, 110))	('inhibition', 'NegReg', (33, 43))	('AG-881', 'Gene', (56, 62))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (66, 77))	('2-HG level', 'MPA', (106, 116))	('BAY-1436032', 'Var', (66, 77))	('mutant', 'Var', (22, 28))	('AG-881', 'Chemical', '-', (56, 62))	('drop', 'NegReg', (98, 102))
98250	33668509	Thus, in the U87IDHmut tumors NAA increased following treatment with AG-881 by 48% and following BAY-1436032 treatment by 37% when compared to controls at D5 +- 1 (Table 1).	('AG-881', 'Var', (69, 75))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('NAA', 'Chemical', 'MESH:C000179', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (97, 108))	('U87IDHmut', 'Var', (13, 22))	('increased', 'PosReg', (34, 43))	('AG-881', 'Chemical', '-', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
98251	33668509	Similarly, NAA increased in BT257 tumors following treatment with AG-881 by 33% and following treatment with BAY-1436032 by 57% when compared to controls D7 +- 2 (Table 2).	('tumors', 'Disease', (34, 40))	('AG-881', 'Var', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (109, 120))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('NAA', 'Chemical', 'MESH:C000179', (11, 14))	('increased', 'PosReg', (15, 24))	('BT257', 'Gene', (28, 33))	('BT257', 'Chemical', '-', (28, 33))	('AG-881', 'Chemical', '-', (66, 72))	('NAA', 'MPA', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
98252	33668509	Finally, in the SF10417 model NAA level increased following AG-881 and BAY-1436032 treatment by 27% and 35% respectively compared to controls D6 +- 2 (Table 3).	('SF10417', 'Chemical', '-', (16, 23))	('AG-881', 'Chemical', '-', (60, 66))	('BAY-1436032 treatment', 'Var', (71, 92))	('NAA level increased', 'Phenotype', 'HP:0032273', (30, 49))	('increased', 'PosReg', (40, 49))	('treatment', 'Var', (83, 92))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (71, 82))	('NAA', 'Chemical', 'MESH:C000179', (30, 33))	('AG-881', 'Gene', (60, 66))	('NAA level', 'MPA', (30, 39))
98254	33668509	The relatively recent discovery of the IDH1/2 mutations was a crucial observation that has impacted the way the World Health Organization now classifies gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('mutations', 'Var', (46, 55))	('IDH1/2', 'Gene', (39, 45))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('impacted', 'Reg', (91, 99))	('IDH1/2', 'Gene', '3417;3418', (39, 45))
98255	33668509	This discovery also triggered multiple studies investigating the effect of targeted mutant IDH1/2 inhibition in gliomas and other tumor types, and a number of pan and specific mutant IDH inhibitors are in clinical trials.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('pan', 'Gene', (159, 162))	('pan', 'Gene', '51816', (159, 162))	('IDH1/2', 'Gene', (91, 97))	('inhibition', 'NegReg', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('mutant', 'Var', (84, 90))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('IDH1/2', 'Gene', '3417;3418', (91, 97))
98256	33668509	AG-881 is a first in class, oral, potent inhibitor of mutant IDH1/2.	('mutant', 'Var', (54, 60))	('IDH1/2', 'Gene', '3417;3418', (61, 67))	('IDH1/2', 'Gene', (61, 67))	('AG-881', 'Chemical', '-', (0, 6))
98258	33668509	BAY-1436032 is an oral pan-inhibitor of mutant IDH1.	('BAY-1436032', 'Chemical', 'MESH:C000622445', (0, 11))	('IDH1', 'Gene', (47, 51))	('BAY-1436032', 'Var', (0, 11))	('mutant', 'Var', (40, 46))	('pan', 'Gene', (23, 26))	('pan', 'Gene', '51816', (23, 26))
98259	33668509	It has robust activity in preclinical glioma models showing that BAY-1436032 treatment has led to significantly longer survival of astrocytoma-bearing mice.	('survival', 'CPA', (119, 127))	('mice', 'Species', '10090', (151, 155))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('astrocytoma', 'Disease', 'MESH:D001254', (131, 142))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (65, 76))	('BAY-1436032', 'Var', (65, 76))	('astrocytoma', 'Disease', (131, 142))	('glioma', 'Disease', (38, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('longer', 'PosReg', (112, 118))
98263	33668509	Consistent with these observations, in this study, we found that treatment of both genetically engineered and patient-derived models, with either AG-881 or BAY-1436032, led, at best, to inhibition in tumor growth (BT257 and SF10417) when compared to corresponding controls, but no tumor shrinkage could be observed.	('BAY-1436032', 'Var', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('inhibition', 'NegReg', (186, 196))	('AG-881', 'Var', (146, 152))	('SF10417', 'Var', (224, 231))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('BT257', 'Chemical', '-', (214, 219))	('AG-881', 'Chemical', '-', (146, 152))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('patient', 'Species', '9606', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (156, 167))	('tumor', 'Disease', (281, 286))	('SF10417', 'Chemical', '-', (224, 231))
98264	33668509	Nonetheless, overall survival was significantly longer in all three treated mutant IDH1 models in response to both AG-881 and BAY-1436032 treatments.	('BAY-1436032', 'Chemical', 'MESH:C000622445', (126, 137))	('mutant', 'Var', (76, 82))	('longer', 'PosReg', (48, 54))	('overall survival', 'CPA', (13, 29))	('IDH1', 'Gene', (83, 87))	('AG-881', 'Chemical', '-', (115, 121))
98265	33668509	The lack of frank tumor shrinkage and continued tumor growth, albeit at a slower rate, highlights the need for early noninvasive metabolic biomarkers of drug delivery, drug action, and response to mutant IDH inhibition using complementary noninvasive imaging methods such as 1H-MRS.	('tumor', 'Disease', (48, 53))	('shrinkage', 'NegReg', (24, 33))	('tumor', 'Disease', (18, 23))	('1H', 'Chemical', '-', (275, 277))	('frank tumor', 'Disease', 'MESH:D001946', (12, 23))	('IDH', 'Gene', (204, 207))	('mutant', 'Var', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('frank tumor', 'Disease', (12, 23))
98266	33668509	In this study we investigated three different mutant IDH1 tumor models.	('IDH1 tumor', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutant', 'Var', (46, 52))	('IDH1 tumor', 'Disease', 'MESH:D009369', (53, 63))
98267	33668509	However, the U87IDHmut model is genetically engineered to express mutant IDH1 in U87 glioblastoma cells.	('mutant', 'Var', (66, 72))	('glioblastoma', 'Disease', (85, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('IDH1', 'Gene', (73, 77))
98268	33668509	As such, it would carry oncogenic mutations that are characteristic for glioblastoma, and any observation made in this model could be associated with its glioblastoma background.	('carry', 'Reg', (18, 23))	('glioblastoma', 'Disease', (154, 166))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('mutations', 'Var', (34, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
98274	33668509	The drop in 2-HG reflects drug delivery and mutant IDH inhibition.	('drop', 'NegReg', (4, 8))	('mutant', 'Var', (44, 50))	('2-HG', 'MPA', (12, 16))	('2-HG', 'Chemical', 'MESH:C019417', (12, 16))
98275	33668509	The changes in 2-HG and Glu levels are also in line with our previous observations in the U87IDHmut cells treated with either AG-120 or AG-881 that showed a significant decrease in 2-HG and a significant increase in Glu.	('Glu', 'Chemical', 'MESH:D018698', (216, 219))	('AG-120', 'Chemical', 'MESH:C000627630', (126, 132))	('Glu levels', 'MPA', (24, 34))	('decrease', 'NegReg', (169, 177))	('Glu', 'Chemical', 'MESH:D018698', (24, 27))	('2-HG', 'Chemical', 'MESH:C019417', (181, 185))	('increase', 'PosReg', (204, 212))	('Glu', 'MPA', (216, 219))	('2-HG', 'MPA', (15, 19))	('AG-881', 'Chemical', '-', (136, 142))	('AG-881', 'Var', (136, 142))	('2-HG', 'MPA', (181, 185))	('2-HG', 'Chemical', 'MESH:C019417', (15, 19))
98280	33668509	The increase in Glu observed both in cells and in vivo reflects a reversal of metabolic changes previously reported to be associated with the IDH mutation by our group and others in cell models and in patient samples.	('Glu', 'MPA', (16, 19))	('IDH', 'Gene', (142, 145))	('Glu', 'Chemical', 'MESH:D018698', (16, 19))	('patient', 'Species', '9606', (201, 208))	('metabolic', 'MPA', (78, 87))	('increase', 'PosReg', (4, 12))	('mutation', 'Var', (146, 154))
98281	33668509	Interestingly however, not all 1H-MRS detectable metabolic alterations associated with the IDH1 mutation appear to be reversed with treatment.	('1H', 'Chemical', '-', (31, 33))	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))
98282	33668509	We have shown that cells genetically engineered to express mutant IDH1 increase 2-HG and also decrease Glu, phosphocholine and lactate.	('Glu', 'MPA', (103, 106))	('phosphocholine', 'Chemical', 'MESH:D010767', (108, 122))	('2-HG', 'MPA', (80, 84))	('mutant', 'Var', (59, 65))	('Glu', 'Chemical', 'MESH:D018698', (103, 106))	('2-HG', 'Chemical', 'MESH:C019417', (80, 84))	('increase', 'PosReg', (71, 79))	('lactate', 'Chemical', 'MESH:D019344', (127, 134))	('lactate', 'MPA', (127, 134))	('IDH1', 'Gene', (66, 70))	('decrease', 'NegReg', (94, 102))
98283	33668509	However, our previous study in cells, as well as the results from this in vivo study, observe a drop in 2-HG and an increase in Glu following mutant IDH inhibition, but no significant changes in lactate or a consistent increase in choline-containing metabolites.	('Glu', 'MPA', (128, 131))	('2-HG', 'MPA', (104, 108))	('inhibition', 'NegReg', (153, 163))	('drop', 'NegReg', (96, 100))	('Glu', 'Chemical', 'MESH:D018698', (128, 131))	('2-HG', 'Chemical', 'MESH:C019417', (104, 108))	('mutant', 'Var', (142, 148))	('increase', 'PosReg', (116, 124))	('lactate', 'Chemical', 'MESH:D019344', (195, 202))	('choline', 'Chemical', 'MESH:D002794', (231, 238))
98284	33668509	Our findings therefore point to the complexity of the molecular biological and metabolic changes that occur in mutant IDH1 tumors during their development and in response to treatment.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('IDH1 tumor', 'Disease', 'MESH:D009369', (118, 128))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('mutant', 'Var', (111, 117))	('IDH1 tumor', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
98285	33668509	Most importantly however, the consistency of our metabolic observations across cell and in vivo studies, their association in cells with reduced clonogenic potential, and in vivo with inhibition of tumor growth and enhanced animal survival, point to the value and reliability of reduced 2-HG and elevated Glu and GLX as noninvasive biomarkers of mutant IDH inhibition.	('GLX', 'MPA', (313, 316))	('reduced', 'NegReg', (279, 286))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('2-HG', 'Chemical', 'MESH:C019417', (287, 291))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('2-HG', 'MPA', (287, 291))	('Glu', 'Chemical', 'MESH:D018698', (305, 308))	('mutant', 'Var', (346, 352))	('tumor', 'Disease', (198, 203))	('enhanced', 'PosReg', (215, 223))	('IDH', 'Gene', (353, 356))	('elevated', 'PosReg', (296, 304))	('clonogenic potential', 'CPA', (145, 165))	('reduced', 'NegReg', (137, 144))
98286	33668509	U87IDHmut glioblastoma cells engineered to express the IDH1 R132H mutant gene, courtesy of the Phillips Lab (UCSF), were maintained in culture as described.	('R132H', 'Mutation', 'rs121913500', (60, 65))	('glioblastoma', 'Disease', (10, 22))	('glioblastoma', 'Disease', 'MESH:D005909', (10, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))	('R132H', 'Var', (60, 65))	('IDH1', 'Gene', (55, 59))
98287	33668509	SF10417 patient-derived mutant IDH1 oligodendroglioma, courtesy of the Costello Lab (UCSF), were cultured as described.	('mutant', 'Var', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('oligodendroglioma', 'Disease', 'MESH:D009837', (36, 53))	('patient', 'Species', '9606', (8, 15))	('oligodendroglioma', 'Disease', (36, 53))	('SF10417', 'Chemical', '-', (0, 7))	('IDH1', 'Gene', (31, 35))
98288	33668509	BT257 patient-derived mutant IDH astrocytoma, courtesy of the Weiss lab (University of Calgary), were cultured as described.	('BT257', 'Gene', (0, 5))	('patient', 'Species', '9606', (6, 13))	('BT257', 'Chemical', '-', (0, 5))	('IDH astrocytoma', 'Disease', (29, 44))	('mutant', 'Var', (22, 28))	('IDH astrocytoma', 'Disease', 'MESH:D001254', (29, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))
98291	33668509	6-9 week old female SCID mice (19-21 g; Fox Chase SCID mice, Charles River Laboratories, Wilmington, MA, USA) were intracranially injected with ~1 x 105 of either BT257 or SF10417 cells from serial orthotopic xenografting as described.	('SCID', 'Disease', 'MESH:D053632', (50, 54))	('mice', 'Species', '10090', (25, 29))	('SF10417', 'Var', (172, 179))	('BT257', 'Chemical', '-', (163, 168))	('mice', 'Species', '10090', (55, 59))	('SCID', 'Disease', 'MESH:D053632', (20, 24))	('SCID', 'Disease', (20, 24))	('SF10417', 'Chemical', '-', (172, 179))	('SCID', 'Disease', (50, 54))
98295	33668509	with one of the following: (1) 50 mg/kg AG-881; (2) 150 mg/kg BAY-1436032; (3) 4 mL/kg Ora-plus (for controls).	('BAY-1436032', 'Chemical', 'MESH:C000622445', (62, 73))	('AG-881', 'Chemical', '-', (40, 46))	('BAY-1436032', 'Var', (62, 73))	('Ora-plus', 'Chemical', '-', (87, 95))	('AG-881', 'Gene', (40, 46))
98304	33668509	In this study, we noninvasively monitored metabolic alterations in response to longitudinal mutant IDH inhibition using high resolution 1H-MRS in mutant IDH1 glioma models.	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('IDH1 glioma', 'Disease', 'MESH:D005910', (153, 164))	('mutant', 'Var', (146, 152))	('IDH1 glioma', 'Disease', (153, 164))	('mutant', 'Var', (92, 98))	('IDH', 'Gene', (99, 102))	('1H', 'Chemical', '-', (136, 138))	('inhibition', 'NegReg', (103, 113))
98305	33668509	In the genetically engineered U87IDHmut model as well as in two patient-derived BT257 and SF10417 mutant IDH1 glioma models, treatments with either AG-881 or BAY-1436032 resulted in a consistent reduction in 2-HG, confirming brain penetration and action of the IDH inhibitors.	('BT257', 'Chemical', '-', (80, 85))	('patient', 'Species', '9606', (64, 71))	('AG-881', 'Var', (148, 154))	('SF10417', 'Chemical', '-', (90, 97))	('AG-881', 'Chemical', '-', (148, 154))	('BAY-1436032', 'Var', (158, 169))	('2-HG', 'MPA', (208, 212))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('IDH1 glioma', 'Disease', 'MESH:D005910', (105, 116))	('reduction', 'NegReg', (195, 204))	('2-HG', 'Chemical', 'MESH:C019417', (208, 212))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (158, 169))	('mutant', 'Var', (98, 104))	('IDH1 glioma', 'Disease', (105, 116))
98307	33668509	Our study thus points to the increase in Glu and GLX together with the drop in 2-HG as potential translatable early metabolic biomarkers of glioma response to mutant IDH inhibition, which, in combination with the monitoring of tumor volume, could serve to enhance the reliability of noninvasive monitoring of response to mutant IDH inhibitors.	('2-HG', 'MPA', (79, 83))	('Glu', 'Chemical', 'MESH:D018698', (41, 44))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('tumor', 'Disease', (227, 232))	('mutant', 'Var', (159, 165))	('2-HG', 'Chemical', 'MESH:C019417', (79, 83))	('increase', 'PosReg', (29, 37))	('IDH', 'Gene', (166, 169))	('glioma', 'Disease', (140, 146))	('Glu', 'MPA', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('GLX', 'MPA', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
98308	33668509	This research was funded by National Institute of Health (NIH) R01CA197254 (SMR), NIH R01CA172845 (SMR) and UCSF Loglio collective (SMR).	('SMR', 'Gene', (132, 135))	('R01CA197254', 'CellLine', 'CVCL:5495', (63, 74))	('NIH R01CA172845', 'Var', (82, 97))	('SMR', 'Gene', '147719', (76, 79))	('SMR', 'Gene', '147719', (132, 135))	('SMR', 'Gene', (99, 102))	('SMR', 'Gene', '147719', (99, 102))	('SMR', 'Gene', (76, 79))
98336	33299884	Another study revealed that high body mass index (BMI) was positively associated with the incidence of several types of cancer, while patients with high BMI at the time of initial diagnosis had higher two/five-year survival rates than those with low BMI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (194, 200))	('high BMI', 'Var', (148, 156))	('low BMI', 'Phenotype', 'HP:0045082', (246, 253))	('cancer', 'Disease', (120, 126))	('patients', 'Species', '9606', (134, 142))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('high body mass index', 'Phenotype', 'HP:0031418', (28, 48))	('two/five-year survival rates', 'CPA', (201, 229))
98350	33299884	The patients were divided into four groups based on BMI: normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI<40 kg/m2), and extremely obese (BMI >= 40 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('25 kg/m2 <=', 'Var', (114, 125))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', (191, 196))	('patients', 'Species', '9606', (4, 12))	('30 kg/m2 <=', 'Var', (150, 161))	('obese', 'Disease', (143, 148))
98360	33299884	Mutations, copy number variations (CNVs), and controlling expression levels of obesity-related genes were downloaded from TCGA.	('obesity', 'Phenotype', 'HP:0001513', (79, 86))	('Mutations', 'Var', (0, 9))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('obesity', 'Disease', (79, 86))	('copy number variations', 'Var', (11, 33))
98387	33299884	As displayed in Figure 2(c), for each of the five obesity-related genes (LEPR, MTCH2, MC4R, LEP, and KCTD15), the patients in a high-expression group had a greater cancer survival rate than those in the low/medium-expression groups (P < 0.05).	('KCTD15', 'Gene', '79047', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LEP', 'Gene', '3952', (92, 95))	('KCTD15', 'Gene', (101, 107))	('obesity', 'Disease', (50, 57))	('greater', 'PosReg', (156, 163))	('patients', 'Species', '9606', (114, 122))	('LEP', 'Gene', (92, 95))	('obesity', 'Disease', 'MESH:D009765', (50, 57))	('LEPR', 'Gene', '3953', (73, 77))	('cancer', 'Disease', (164, 170))	('LEP', 'Gene', '3952', (73, 76))	('LEPR', 'Gene', (73, 77))	('MC4R', 'Gene', (86, 90))	('high-expression', 'Var', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTCH2', 'Gene', '23788', (79, 84))	('LEP', 'Gene', (73, 76))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('MC4R', 'Gene', '4160', (86, 90))	('MTCH2', 'Gene', (79, 84))
98390	33299884	For patients with six types of cancer (KIRC, LUAD, LGG, GBM, UCEC, and BLCA), those in the PCSK1 low/medium-expression group had higher survival probability than those in the high-expression group.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('LGG', 'Disease', (51, 54))	('PCSK1', 'Gene', '5122', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (136, 144))	('higher', 'PosReg', (129, 135))	('GBM', 'Disease', (56, 59))	('UCEC', 'Disease', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (4, 12))	('PCSK1', 'Gene', (91, 96))	('cancer', 'Disease', (31, 37))	('low/medium-expression', 'Var', (97, 118))
98391	33299884	However, for patients with SKCM, patients with high expression level of PCSK1 may benefit from a superior survival probability than those with low/medium expression level.	('patients', 'Species', '9606', (33, 41))	('PCSK1', 'Gene', (72, 77))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (13, 21))	('high expression level', 'Var', (47, 68))	('PCSK1', 'Gene', '5122', (72, 77))	('benefit', 'PosReg', (82, 89))
98401	33299884	However, the mutation rates of five obesity-related genes in few cancer tissues were >0.05 (i.e., LEPR in SKCM (0.11), UCEC (0.07), and LUSC (0.07) and PCSK1 in SKCM (0.09) and UCEC (0.06)).	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('mutation', 'Var', (13, 21))	('LEPR', 'Gene', (98, 102))	('PCSK1', 'Gene', (152, 157))	('obesity', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PCSK1', 'Gene', '5122', (152, 157))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LEPR', 'Gene', '3953', (98, 102))
98406	33299884	Then, for each of the 33 types of cancer, the expression levels of the 13 obesity-related genes were divided into different groups based on the seven factors as follows: (1) patients' gender (male or female), (2) patients' race (African-American, Caucasian, and Asian), (3) menopausal status (premenopause, perimenopause, and postmenopause), (4) history of smoking (smoker, nonsmoker, reformed smoker #1 (<=15 years), and reformed smoker #2 (>15 years)), (5) tumor grade (grade 1, grade 2, grade 3, and grade 4), (6) BMI (normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI < 40 kg/m2), and extremely obese (BMI >= 40 kg/m2)), and (7) history of drinking (occasional drinker, social drinker, daily drinker, weekly drinker, and nondrinker).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('menopausal status', 'Phenotype', 'HP:0008209', (274, 291))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('patients', 'Species', '9606', (213, 221))	('obese', 'Disease', (658, 663))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('obesity', 'Disease', (74, 81))	('obese', 'Disease', 'MESH:D009765', (658, 663))	('30 kg/m2 <= BMI < 40 kg/m2', 'Var', (615, 641))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('tumor', 'Disease', (459, 464))	('obese', 'Disease', (608, 613))	('25 kg/m2 <= BMI < 30 kg/m2', 'Var', (579, 605))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('3 obesity', 'Phenotype', 'HP:0025501', (72, 81))	('obese', 'Disease', 'MESH:D009765', (608, 613))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', (34, 40))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))
98453	33299884	For the majority of obesity-related genes, cancer patients who were in low/medium-expression level group had a superior prognosis than those in the high-expression level group.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('low/medium-expression level', 'Var', (71, 98))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('obesity', 'Disease', (20, 27))
98456	33299884	However, for three types of cancer (SKCM, ACC, and LUAD), patients in the high-expression group for GPR120 gene could benefit from a greater prognosis as compared to those in the low/medium-expression level group.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-expression', 'Var', (74, 89))	('benefit', 'PosReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('GPR120', 'Gene', '338557', (100, 106))	('patients', 'Species', '9606', (58, 66))	('GPR120', 'Gene', (100, 106))	('cancer', 'Disease', (28, 34))
98457	33299884	Moreover, for four types of cancer (KIRP, UVM, CESC, and LUSC), patients in the high-expression level group for SH2B1 gene experienced a better prognosis than those in the low/medium-expression level group.	('SH2B1', 'Gene', (112, 117))	('better', 'PosReg', (137, 143))	('high-expression level', 'Var', (80, 101))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('UVM', 'Disease', (42, 45))	('CESC', 'Disease', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('SH2B1', 'Gene', '25970', (112, 117))
98462	33299884	According to the Kaplan-Meier survival curves, patients with kidney cancer in the low/medium-expression level group for each of LEPR and NEGR1 genes had a long-time life expectancy in comparison to those in the high-expression level group.	('NEGR1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('kidney cancer', 'Disease', (61, 74))	('LEPR', 'Gene', '3953', (128, 132))	('patients', 'Species', '9606', (47, 55))	('low/medium-expression level', 'Var', (82, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (61, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (61, 74))	('LEPR', 'Gene', (128, 132))	('NEGR1', 'Gene', '257194', (137, 142))
98463	33299884	However, patients with kidney cancer in the high-expression level group for each of TMEM18 and SH2B1 genes had a long life expectancy than those who in the low/medium-expression level group.	('TMEM18', 'Gene', '129787', (84, 90))	('kidney cancer', 'Disease', (23, 36))	('patients', 'Species', '9606', (9, 17))	('SH2B1', 'Gene', '25970', (95, 100))	('SH2B1', 'Gene', (95, 100))	('TMEM18', 'Gene', (84, 90))	('high-expression level', 'Var', (44, 65))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
98470	33299884	Once mutations or modify alterations occur for obesity gene, microenvironment probably impacts behavior and adaptive evolution of cancer cells.	('behavior', 'CPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('obesity', 'Disease', 'MESH:D009765', (47, 54))	('mutations', 'Var', (5, 14))	('obesity', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impacts', 'Reg', (87, 94))	('obesity', 'Phenotype', 'HP:0001513', (47, 54))
98507	32195924	Recently, the WHO has introduced molecular parameters, such as mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes, and 1p/19q co-deletion, to define glioma entities.	('mutations', 'Var', (63, 72))	('glioma entities', 'Disease', (160, 175))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (80, 118))	('glioma entities', 'Disease', 'MESH:D005910', (160, 175))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
98512	32195924	In addition, SREBPs have been linked to the epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation, which have been shown to promote GBM tumor growth.	('phosphoinositide 3-kinase', 'Gene', '5295', (109, 134))	('epidermal growth factor receptor', 'Gene', '1956', (44, 76))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('GBM', 'Phenotype', 'HP:0012174', (192, 195))	('mutations', 'Var', (84, 93))	('SREBPs', 'Disease', (13, 19))	('promote', 'PosReg', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('linked', 'Reg', (30, 36))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (95, 99))	('phosphoinositide 3-kinase', 'Gene', (109, 134))	('epidermal growth factor receptor', 'Gene', (44, 76))	('EGFR', 'Gene', (95, 99))
98523	32195924	The datasets included RNAseq gene expression, copy number variation (CNV), reverse phase protein array (RPPA) data from TCGA lower grade glioma, and glioblastoma (LGG and GBM, respectively) cohort.	('glioblastoma', 'Disease', (149, 161))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('GBM', 'Phenotype', 'HP:0012174', (171, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('RNAseq', 'Gene', (22, 28))	('glioma', 'Disease', (137, 143))	('copy number variation', 'Var', (46, 67))
98533	32195924	Encouragingly, high expression of SREBP2 transcript also predicted better prognosis in the CGGA dataset, again consistent with results obtained from TCGA glioma cohort (Fig.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('high expression', 'Var', (15, 30))	('prognosis', 'CPA', (74, 83))	('glioma', 'Disease', (154, 160))	('SREBP2', 'Gene', '6721', (34, 40))	('better', 'PosReg', (67, 73))	('SREBP2', 'Gene', (34, 40))
98546	32195924	Furthermore, the number of deletion events of SREBP2 negatively correlated with overall survival (Fig.	('overall survival', 'MPA', (80, 96))	('deletion', 'Var', (27, 35))	('negatively', 'NegReg', (53, 63))	('SREBP2', 'Gene', '6721', (46, 52))	('correlated', 'Reg', (64, 74))	('SREBP2', 'Gene', (46, 52))
98567	32195924	In addition, according to the reverse phase protein array (RPPA) data of the same TCGA cohort, SREBP2-high expression group had higher phosphorylation level of p70 S6K (pT389), PKCalpha (pS657), PKCbetaII (pS660), and PKCdelta (pS664) (Fig.	('SREBP2', 'Gene', '6721', (95, 101))	('pT389', 'Var', (169, 174))	('PKCbetaII', 'Disease', (195, 204))	('p70 S6K', 'Gene', (160, 167))	('PKCalpha', 'Gene', '5578', (177, 185))	('PKCalpha', 'Gene', (177, 185))	('PKCdelta', 'Gene', '5580', (218, 226))	('PKCdelta', 'Gene', (218, 226))	('pS660', 'Var', (206, 211))	('PKCbetaII', 'Disease', 'None', (195, 204))	('phosphorylation level', 'MPA', (135, 156))	('higher', 'PosReg', (128, 134))	('p70 S6K', 'Gene', '6198', (160, 167))	('SREBP2', 'Gene', (95, 101))
98571	32195924	In addition, phosphorylation of EGFR (pY1068 and pY1173), HER2 (pY1248), STAT3 (pY705), p38 (pT180 and pY182), AKT (pS473), Myosin IIA (pS1943), and SRC (pY416) was also highly enriched in SREBP2-low but not in SREBP2-high group (Fig.	('p38', 'Gene', '1432', (88, 91))	('pY1248', 'Var', (64, 70))	('SREBP2', 'Gene', (189, 195))	('STAT3', 'Gene', (73, 78))	('AKT', 'Gene', (111, 114))	('SRC', 'Gene', '6714', (149, 152))	('SREBP2', 'Gene', (211, 217))	('STAT3', 'Gene', '6774', (73, 78))	('pS1943', 'Var', (136, 142))	('pY182', 'Var', (103, 108))	('SREBP2', 'Gene', '6721', (189, 195))	('pY1068', 'Chemical', '-', (38, 44))	('pS473', 'Var', (116, 121))	('pY705', 'Chemical', '-', (80, 85))	('EGFR', 'Gene', (32, 36))	('SREBP2', 'Gene', '6721', (211, 217))	('pY705', 'Var', (80, 85))	('HER2', 'Gene', (58, 62))	('SRC', 'Gene', (149, 152))	('pY1068', 'Var', (38, 44))	('AKT', 'Gene', '207', (111, 114))	('phosphorylation', 'MPA', (13, 28))	('pY1173', 'Chemical', '-', (49, 55))	('p38', 'Gene', (88, 91))	('pY1173', 'Var', (49, 55))	('pT180', 'Var', (93, 98))	('EGFR', 'Gene', '1956', (32, 36))	('HER2', 'Gene', '2064', (58, 62))	('pY1248', 'Chemical', '-', (64, 70))
98572	32195924	Increased copy number amplification and deletion events were observed in SREBP2-low expression group (Fig.	('copy', 'MPA', (10, 14))	('deletion', 'Var', (40, 48))	('SREBP2', 'Gene', '6721', (73, 79))	('Increased', 'PosReg', (0, 9))	('SREBP2', 'Gene', (73, 79))
98573	32195924	Genes with deletion events were associated with humoral immune response, type I interferon signaling and lipid catabolic process (Fig.	('deletion events', 'Var', (11, 26))	('lipid catabolic process', 'MPA', (105, 128))	('associated', 'Reg', (32, 42))	('humoral immune response', 'MPA', (48, 71))	('type I interferon signaling', 'MPA', (73, 100))	('lipid', 'Chemical', 'MESH:D008055', (105, 110))
98589	32195924	This could explain why mRNA expression of CYP46A1, the enzyme that coverts cholesterol to oxysterol, was also lower in GBM than in LGG in our study.	('oxysterol', 'Chemical', 'MESH:D000072376', (90, 99))	('CYP46A1', 'Gene', '10858', (42, 49))	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('GBM', 'Var', (119, 122))	('cholesterol', 'Chemical', 'MESH:D002784', (75, 86))	('mRNA expression', 'MPA', (23, 38))	('lower', 'NegReg', (110, 115))	('CYP46A1', 'Gene', (42, 49))
98593	32195924	Cholesterol metabolism, also, appears to be suppressed in GBMs.	('suppressed', 'NegReg', (44, 54))	('Cholesterol metabolism', 'MPA', (0, 22))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('GBMs', 'Var', (58, 62))
98636	32154177	Operating characteristic (ROC) curves were used to study the prediction efficiency of the risk signature, WHO grade and age for survival, EM1/2 groups, IDH-mutant status, and 1p/19q codeletion status.	('1p/19q codeletion status', 'Var', (175, 199))	('IDH', 'Gene', '3417', (152, 155))	('IDH', 'Gene', (152, 155))
98637	32154177	Univariate and multivariate Cox regression analyses were performed to determine prognostic values for risk scores as well as various clinical and molecular pathological features, including risk scores, age, gender, IDH status, and 1p/19q codel.	('1p/19q codel', 'Var', (231, 243))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('IDH', 'Gene', (215, 218))	('IDH', 'Gene', '3417', (215, 218))
98639	32154177	Because EMT is determined to be closely related to glioma malignancies, we systematically studied the relationship between variables and the pathological characteristics of glioma, including WHO grade, IDH status, and 1p/19q codeletion status.	('IDH', 'Gene', (202, 205))	('glioma malignancies', 'Disease', 'MESH:D005910', (51, 70))	('glioma', 'Disease', (51, 57))	('IDH', 'Gene', '3417', (202, 205))	('1p/19q codeletion status', 'Var', (218, 242))	('glioma', 'Disease', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma malignancies', 'Disease', (51, 70))	('glioma', 'Disease', 'MESH:D005910', (173, 179))
98642	32154177	Next, we investigated the status of IDH and 1p19q in EMT-associated proteins for various grades of gliomas.	('1p19q', 'Var', (44, 49))	('gliomas', 'Disease', (99, 106))	('IDH', 'Gene', (36, 39))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('IDH', 'Gene', '3417', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
98645	32154177	For the 1p19q status, SNAI1, PDGFB, HGF, TGFB1, EGF, CDH1, MET, IGF1, EGFR, ZEB2, and TWIST2 were significantly differentially expressed between LGG with codel-1p19q and LGG with Non-codel 1p19q (Figure 1J).	('EGF', 'Gene', '1950', (70, 73))	('EGF', 'Gene', (48, 51))	('CDH1', 'Gene', '999', (53, 57))	('differentially', 'Reg', (112, 126))	('IGF1', 'Gene', (64, 68))	('PDGFB', 'Gene', '5155', (29, 34))	('EGFR', 'Gene', '1956', (70, 74))	('CDH1', 'Gene', (53, 57))	('EGF', 'Gene', (70, 73))	('ZEB2', 'Gene', (76, 80))	('codel-1p19q', 'Var', (154, 165))	('PDGFB', 'Gene', (29, 34))	('TWIST2', 'Gene', '117581', (86, 92))	('ZEB2', 'Gene', '9839', (76, 80))	('EGF', 'Gene', '1950', (48, 51))	('HGF', 'Gene', '3082', (36, 39))	('SNAI1', 'Gene', '6615', (22, 27))	('TGFB1', 'Gene', '7040', (41, 46))	('SNAI1', 'Gene', (22, 27))	('TWIST2', 'Gene', (86, 92))	('TGFB1', 'Gene', (41, 46))	('EGFR', 'Gene', (70, 74))	('IGF1', 'Gene', '3479', (64, 68))	('HGF', 'Gene', (36, 39))
98646	32154177	In the LGG with mutant-IDH, the expression of SNAI1, PDGFB, TGFB1, EGF, CDH1, HGF, IGF1, EGFR, ZEB2, MET were associated with the status of 1p/19q codeletion (1p/19q codel) (Figure 1K).	('EGF', 'Gene', '1950', (67, 70))	('CDH1', 'Gene', (72, 76))	('ZEB2', 'Gene', (95, 99))	('ZEB2', 'Gene', '9839', (95, 99))	('PDGFB', 'Gene', '5155', (53, 58))	('associated', 'Reg', (110, 120))	('EGF', 'Gene', '1950', (89, 92))	('IDH', 'Gene', (23, 26))	('TGFB1', 'Gene', '7040', (60, 65))	('SNAI1', 'Gene', '6615', (46, 51))	('EGF', 'Gene', (67, 70))	('SNAI1', 'Gene', (46, 51))	('TGFB1', 'Gene', (60, 65))	('EGFR', 'Gene', (89, 93))	('IGF1', 'Gene', '3479', (83, 87))	('HGF', 'Gene', '3082', (78, 81))	('PDGFB', 'Gene', (53, 58))	('MET', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (23, 26))	('HGF', 'Gene', (78, 81))	('EGF', 'Gene', (89, 92))	('IGF1', 'Gene', (83, 87))	('CDH1', 'Gene', '999', (72, 76))	('1p/19q codeletion', 'Var', (140, 157))	('EGFR', 'Gene', '1956', (89, 93))
98652	32154177	In addition, the overall survival (OS) of the EM2 subgroup was found to be shorter than that of the EM1 subgroup (Figure 4D).	('overall survival', 'CPA', (17, 33))	('shorter', 'NegReg', (75, 82))	('EM2', 'Var', (46, 49))	('OS', 'Chemical', '-', (35, 37))
98668	32154177	In both groups, WHO grade (P < 0.001), age (P < 0.05), IDH status (P < 0.001), 1p/19q codel status (P < 0.001), and EM1/2 subgroups were significant (P < 0.001).	('IDH', 'Gene', (55, 58))	('1p/19q codel status', 'Var', (79, 98))	('IDH', 'Gene', '3417', (55, 58))
98669	32154177	Significant differences were observed between the two groups in terms of WHO classification (P < 0.001), 1p / 19q codel status (P < 0.001) age (P < 0.05), and IDH status (P < 0.001) (Figures 7A-F).	('1p / 19q codel status', 'Var', (105, 126))	('IDH', 'Gene', (159, 162))	('IDH', 'Gene', '3417', (159, 162))
98689	32154177	As EMT induction factor, transcription factors, the expression of SNAI1, SNAI2, TWIST1, and PDGFB was significantly higher in high-grade, elderly glioma patients, IDH-wildtype, 1p19q non-codel glioma patients.	('TWIST1', 'Gene', (80, 86))	('SNAI1', 'Gene', '6615', (66, 71))	('SNAI2', 'Gene', (73, 78))	('SNAI1', 'Gene', (66, 71))	('higher', 'PosReg', (116, 122))	('PDGFB', 'Gene', '5155', (92, 97))	('glioma', 'Disease', (193, 199))	('glioma', 'Disease', (146, 152))	('TWIST1', 'Gene', '7291', (80, 86))	('1p19q non-codel', 'Var', (177, 192))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('SNAI2', 'Gene', '6591', (73, 78))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('IDH', 'Gene', (163, 166))	('PDGFB', 'Gene', (92, 97))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (153, 161))	('expression', 'MPA', (52, 62))	('IDH', 'Gene', '3417', (163, 166))
98690	32154177	Whereas ZEB1 and ZEB2 expression were highly expressed in low-grade, IDH-Mutant, 1p19q codel and younger glioma patients, indicating that the potential function of these genes in glioma malignancies.	('ZEB2', 'Gene', '9839', (17, 21))	('glioma malignancies', 'Disease', 'MESH:D005910', (179, 198))	('ZEB1', 'Gene', (8, 12))	('IDH', 'Gene', (69, 72))	('ZEB1', 'Gene', '6935', (8, 12))	('1p19q codel', 'Var', (81, 92))	('glioma', 'Disease', (105, 111))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('patients', 'Species', '9606', (112, 120))	('ZEB2', 'Gene', (17, 21))	('IDH', 'Gene', '3417', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('glioma malignancies', 'Disease', (179, 198))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Disease', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
98748	29238007	Other conventional MR sequences such as CE + T1WI, FLAIR, and T1WI were also used as references for defining tumor position.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('T1WI', 'Var', (62, 66))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
98777	29238007	Similarly, a CT perfusion study distinguishing nonenhancing gliomas as grade II or III achieved 83.3% sensitivity and 90.9% specificity using rTBV and 83.3% sensitivity and 81.8% specificity using rTBF.	('rTBV', 'Species', '10654', (142, 146))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('rTBV', 'Var', (142, 146))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('TBF', 'Chemical', '-', (198, 201))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
98812	27047702	As a result, we now know the most commonly mutated genes in dozens of cancers and can use this information to give patients targeted therapeutics.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', (70, 77))	('mutated', 'Var', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('genes', 'Gene', (51, 56))
98813	27047702	Whereas well established statistical techniques exist for identifying mutations which are drivers instead of simply passengers (mut-drivers), identifying copy number aberrations, methylation changes, or non-coding mutations that alter expression of a gene and result in a growth advantage (epi-drivers) are more difficult to identify and represent a "dark matter" of cancer.	('expression', 'MPA', (235, 245))	('growth advantage', 'CPA', (272, 288))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('copy', 'Var', (154, 158))	('methylation changes', 'Var', (179, 198))	('mutations', 'Var', (214, 223))	('cancer', 'Disease', (367, 373))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('alter', 'Reg', (229, 234))
98876	27047702	To date, different cancers have been compared to each other through mRNA levels, miRNA levels, protein levels, networks, copy number alterations, DNA methylation, somatic mutations or some combination of these.	('miRNA levels', 'MPA', (81, 93))	('networks', 'MPA', (111, 119))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('copy number alterations', 'Var', (121, 144))	('protein levels', 'MPA', (95, 109))	('mRNA levels', 'MPA', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('DNA methylation', 'MPA', (146, 161))
98899	27047702	Our results show that patients with high expression of genes utilizing oxygen survive longer, which underscores the importance of a metabolic shift in this cancer.	('high expression', 'Var', (36, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('genes', 'Var', (55, 60))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))
98915	27047702	For example, currently EGFR inhibitors are recommended for LUAD patients with EGFR mutations, but EGFR mutations are rare in LUSC and patients with mutations do not respond well to tyrosine kinase inhibitors.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (83, 92))	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('patients', 'Species', '9606', (64, 72))	('patients', 'Species', '9606', (134, 142))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', (23, 27))
98927	26317904	MiR-215, an activator of the CTNNBIP1/beta-catenin pathway, is a marker of poor prognosis in human glioma MicroRNA-215 (miR-215) promotes tumor growth in various human malignancies.	('tumor', 'Disease', (138, 143))	('MiR-215', 'Gene', (0, 7))	('glioma', 'Disease', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('MicroRNA-215', 'Gene', '406997', (106, 118))	('CTNNBIP1', 'Gene', (29, 37))	('MiR-215', 'Gene', '406997', (0, 7))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('malignancies', 'Disease', (168, 180))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('beta-catenin', 'Gene', (38, 50))	('miR-215', 'Var', (120, 127))	('promotes', 'PosReg', (129, 137))	('human', 'Species', '9606', (93, 98))	('beta-catenin', 'Gene', '1499', (38, 50))	('MicroRNA-215', 'Gene', (106, 118))	('human', 'Species', '9606', (162, 167))	('CTNNBIP1', 'Gene', '56998', (29, 37))
98932	26317904	These data indicate that miR-215 activates Wnt/beta-catenin signaling by increasing beta-catenin phosphorylation, alpha-SMA expression, and fibronectin expression.	('beta-catenin', 'Gene', '1499', (47, 59))	('a-SMA', 'Gene', (118, 123))	('fibronectin', 'Gene', '2335', (140, 151))	('miR-215', 'Var', (25, 32))	('a-SMA', 'Gene', '58', (118, 123))	('activates', 'PosReg', (33, 42))	('beta-catenin', 'Gene', (84, 96))	('expression', 'MPA', (152, 162))	('beta-catenin', 'Gene', (47, 59))	('increasing', 'PosReg', (73, 83))	('fibronectin', 'Gene', (140, 151))	('beta-catenin', 'Gene', '1499', (84, 96))
98944	26317904	It is also estimated that more than one-third of human genes are regulated by miRNAs with more than 1900 miRNA genes identified in the human genome.	('human', 'Species', '9606', (49, 54))	('human', 'Species', '9606', (135, 140))	('miRNAs', 'Var', (78, 84))	('human genes', 'Gene', (49, 60))	('regulated', 'Reg', (65, 74))
98945	26317904	Many miRNAs have been implicated in the pathogenesis, diagnosis, and therapy of several cancers, including pancreatic cancer, cervical cancer, and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('pancreatic cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('miRNAs', 'Var', (5, 11))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('implicated', 'Reg', (22, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cervical cancer', 'Disease', (126, 141))	('cervical cancer', 'Disease', 'MESH:D002583', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Disease', (147, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
98955	26317904	To explore the effect of miRNAs on human gliomas, we measured the expression of miRNAs in human glioma tissue and found that miR-215 is the most highly expressed.	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('human', 'Species', '9606', (35, 40))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('human', 'Species', '9606', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('miR-215', 'Var', (125, 132))	('glioma', 'Disease', (41, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))	('glioma', 'Disease', (96, 102))
98966	26317904	Also, a correlation was observed between high miR-215 expression, tumor dimension, and tumor recurrence or metastasis (P = 0.012 and 0.042, respectively).	('expression', 'MPA', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('metastasis', 'CPA', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (87, 92))	('high', 'Var', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('miR-215', 'Gene', (46, 53))
98968	26317904	In order to understand the prognostic significance of high miR-215 levels, the survival of patients with high miR-215 expression was compared to that of patients with low expression.	('miR-215', 'Gene', (110, 117))	('high', 'Var', (105, 109))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (153, 161))
98969	26317904	We found that glioma patients with high miR-215 expression had a shorter median overall survival (OS) than those with low expression (44 months vs. 15 months, P = 0.040, Fig.	('glioma', 'Disease', (14, 20))	('miR-215', 'Gene', (40, 47))	('overall survival', 'MPA', (80, 96))	('shorter', 'NegReg', (65, 72))	('patients', 'Species', '9606', (21, 29))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('high', 'Var', (35, 39))
98970	26317904	Also, the median progression free survival was shorter in patients with high expression than those with low expression (41 months vs. 13 months, P = 0.007, Fig.	('progression free survival', 'CPA', (17, 42))	('shorter', 'NegReg', (47, 54))	('patients', 'Species', '9606', (58, 66))	('high expression', 'Var', (72, 87))
98991	26317904	investigated the functional properties and expression of a single miRNA in GBM cell lines and found that inhibition of miR-21 resulted in increased apoptosis.	('increased', 'PosReg', (138, 147))	('miR-21', 'Gene', (119, 125))	('inhibition', 'Var', (105, 115))	('miR-21', 'Gene', '406991', (119, 125))	('apoptosis', 'CPA', (148, 157))
98998	26317904	Here, we observed that miR-215 was the most dramatically increased miRNA in human glioma and that the expression level of miR-215 is correlated with disease stage.	('miR-215', 'Var', (122, 129))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('expression', 'MPA', (102, 112))	('human', 'Species', '9606', (76, 81))	('increased', 'PosReg', (57, 66))	('glioma', 'Disease', (82, 88))	('miR-215', 'Var', (23, 30))	('miRNA', 'MPA', (67, 72))
99003	26317904	Tumor size was larger in nude mice injected with HeLa-miR-215 cells than in those injected with control cells.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor size', 'CPA', (0, 10))	('larger', 'PosReg', (15, 21))	('HeLa-miR-215 cells', 'Var', (49, 67))	('nude mice', 'Species', '10090', (25, 34))	('HeLa', 'CellLine', 'CVCL:0030', (49, 53))
99004	26317904	All of these findings indicate that miR-215 is a marker for the poor prognosis of cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('miR-215', 'Var', (36, 43))	('cervical cancer', 'Disease', (82, 97))	('cervical cancer', 'Disease', 'MESH:D002583', (82, 97))
99007	26317904	We observed that high miR-215 expression is correlated with poor prognosis and advanced tumor stage in glioma patients.	('miR-215', 'Gene', (22, 29))	('expression', 'MPA', (30, 40))	('glioma', 'Disease', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('high', 'Var', (17, 21))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('patients', 'Species', '9606', (110, 118))
99013	26317904	miR-215 also inhibited the expression of BMP-6 through the BMP-6/miR-192 pathway to increase cell proliferation in breast cancer.	('miR-215', 'Var', (0, 7))	('BMP-6', 'Gene', '654', (59, 64))	('BMP-6', 'Gene', (59, 64))	('BMP-6', 'Gene', '654', (41, 46))	('expression', 'MPA', (27, 37))	('BMP-6', 'Gene', (41, 46))	('miR-192', 'Gene', (65, 72))	('increase', 'PosReg', (84, 92))	('cell proliferation', 'CPA', (93, 111))	('inhibited', 'NegReg', (13, 22))	('miR-192', 'Gene', '406967', (65, 72))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
99014	26317904	miR-215 and miR-192 promoted apoptosis through the XIAP pathway in non-small cell lung cancer.	('apoptosis', 'CPA', (29, 38))	('miR-215', 'Var', (0, 7))	('XIAP', 'Gene', '331', (51, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (67, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('non-small cell lung cancer', 'Disease', (67, 93))	('promoted', 'PosReg', (20, 28))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (71, 93))	('miR-192', 'Gene', '406967', (12, 19))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (67, 93))	('miR-192', 'Gene', (12, 19))	('XIAP', 'Gene', (51, 55))
99015	26317904	Importantly, it is reported that miR-215 is involved in the TGF-beta1-induced activation of the beta-catenin pathway by directly targeting and decreasing expression of CTNNBIP1.	('beta-catenin', 'Gene', '1499', (96, 108))	('CTNNBIP1', 'Gene', '56998', (168, 176))	('decreasing', 'NegReg', (143, 153))	('beta-catenin', 'Gene', (96, 108))	('CTNNBIP1', 'Gene', (168, 176))	('targeting', 'Reg', (129, 138))	('TGF-beta1', 'Gene', '7040', (60, 69))	('miR-215', 'Var', (33, 40))	('TGF-beta1', 'Gene', (60, 69))	('expression', 'MPA', (154, 164))
99021	26317904	High miR-215 expression is a potential biomarker for diagnosis and prognosis in human glioma.	('glioma', 'Disease', (86, 92))	('High', 'Var', (0, 4))	('miR-215', 'Gene', (5, 12))	('expression', 'MPA', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('human', 'Species', '9606', (80, 85))
99049	26317904	The following antibodies were used: anti-CTNNBIP1 antibody (1:200; Santa Cruz), anti-beta-Catenin (t-beta-Catenin) antibody (1:200; Product code: ab47426; Abcam), anti-beta-Catenin (phospho T41 + S45, p-beta-Catenin) antibody (1:200; Product code: ab81305; Abcam), anti-alpha-SMA antibody (1:200; Sigma, St. Louis, MO), and anti-fibronectin antibody (1:200; Santa Cruz).	('CTNNBIP1', 'Gene', '56998', (41, 49))	('beta-Catenin', 'Gene', '1499', (101, 113))	('1:200', 'Var', (290, 295))	('fibronectin', 'Gene', '2335', (329, 340))	('a-SMA', 'Gene', (274, 279))	('CTNNBIP1', 'Gene', (41, 49))	('fibronectin', 'Gene', (329, 340))	('beta-Catenin', 'Gene', (85, 97))	('a-SMA', 'Gene', '58', (274, 279))	('beta-Catenin', 'Gene', (203, 215))	('beta-Catenin', 'Gene', '1499', (85, 97))	('beta-Catenin', 'Gene', '1499', (203, 215))	('beta-Catenin', 'Gene', (168, 180))	('beta-Catenin', 'Gene', '1499', (168, 180))	('beta-Catenin', 'Gene', (101, 113))
99056	33565732	COSMIC, cBioPortal, and CCLE were used to examine FZD2 mutations in human cancers.	('human', 'Species', '9606', (68, 73))	('mutations', 'Var', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('CCLE', 'Chemical', '-', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('FZD2', 'Gene', '2535', (50, 54))	('FZD2', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
99086	33565732	The catalog of somatic mutations in cancer (COSMIC) database (https://cancer.sanger.ac.uk/cosmic/) collects millions of coding mutations, noncoding mutations, genome rearrangements, fusion genes, copy number abnormalities, and gene expression variations in the human genome [12].	('fusion genes', 'Var', (182, 194))	('number abnormalities', 'Disease', 'MESH:D007674', (201, 221))	('variations', 'Var', (243, 253))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (36, 42))	('human', 'Species', '9606', (261, 266))	('number abnormalities', 'Disease', (201, 221))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
99087	33565732	In this study, COSMIC was used to examine FZD2 mutations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('FZD2', 'Gene', '2535', (42, 46))	('FZD2', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))
99090	33565732	The Cancer Cell Line Encyclopedia (CCLE) project dataset is a compilation of gene expression data from human cancer cell lines and was used to analyze FZD2 mutations in various cancer cell lines [14].	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FZD2', 'Gene', '2535', (151, 155))	('FZD2', 'Gene', (151, 155))	('human', 'Species', '9606', (103, 108))	('mutations', 'Var', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('CCLE', 'Chemical', '-', (35, 39))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
99091	33565732	Tumor mutation burden (TMB) is defined as the total number of somatic gene coding errors, base substitutions, insertions, or deletions detected per million bases.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMB', 'Chemical', '-', (23, 26))	('insertions', 'Var', (110, 120))	('deletions', 'Var', (125, 134))	('Tumor mutation burden', 'Disease', (0, 21))	('base substitutions', 'Var', (90, 108))
99115	33565732	According to the median expression of FZD2 across the different cancer types, patients were divided into either a high or low expression group; when analyzed, it was found that the survival difference between the high and low expression groups was significant and that patients with high FZD2 expression had earlier recurrence after tumor resection (Fig.	('earlier', 'PosReg', (308, 315))	('tumor', 'Disease', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('high', 'Var', (283, 287))	('FZD2', 'Gene', (38, 42))	('FZD2', 'Gene', '2535', (38, 42))	('cancer', 'Disease', (64, 70))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('FZD2', 'Gene', (288, 292))	('expression', 'MPA', (293, 303))	('FZD2', 'Gene', '2535', (288, 292))	('recurrence', 'CPA', (316, 326))	('patients', 'Species', '9606', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
99116	33565732	COSMIC provides information about FZD2 mutations in different cancers, including missense mutations, nonsense mutations, and synonymous mutations (Figs 3A and Fig.	('missense mutations', 'Var', (81, 99))	('FZD2', 'Gene', (34, 38))	('FZD2', 'Gene', '2535', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (39, 48))	('nonsense mutations', 'Var', (101, 119))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('synonymous mutations', 'Var', (125, 145))	('cancers', 'Disease', (62, 69))
99119	33565732	C>T and G>A mutations were found to be the most common in the FZD2 coding chain, while A>T and T>A mutations were rare.	('G>A mutations', 'Var', (8, 21))	('C>T', 'Var', (0, 3))	('FZD2', 'Gene', '2535', (62, 66))	('FZD2', 'Gene', (62, 66))	('common', 'Reg', (48, 54))
99122	33565732	Among these, the mutation rate was higher in esophagogastric adenocarcinoma and endometrial carcinoma (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutation', 'Var', (17, 25))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 75))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 101))	('higher', 'Reg', (35, 41))
99123	33565732	Missense mutations and silent mutations were also found in cancer cell lines (Fig.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Missense mutations', 'Var', (0, 18))
99158	33565732	In addition, the latest research has found that FZD2 is more highly expressed in hepatocellular carcinoma tissues than in adjacent tissues, and the recurrence-free survival rate of patients with high FZD2 expression is significantly lower than that of patients with low expression.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('recurrence-free survival rate', 'CPA', (148, 177))	('patients', 'Species', '9606', (252, 260))	('FZD2', 'Gene', '2535', (48, 52))	('FZD2', 'Gene', (48, 52))	('highly', 'PosReg', (61, 67))	('lower', 'NegReg', (233, 238))	('FZD2', 'Gene', '2535', (200, 204))	('high', 'Var', (195, 199))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('patients', 'Species', '9606', (181, 189))	('hepatocellular carcinoma', 'Disease', (81, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('FZD2', 'Gene', (200, 204))	('expression', 'MPA', (205, 215))
99159	33565732	Furthermore, FZD2 expression is significantly correlated with the mesenchymal phenotype in HCC cell lines, and knocking out FZD2 can inhibit the migration and invasiveness of liver cancer cells [23].	('liver cancer', 'Phenotype', 'HP:0002896', (175, 187))	('FZD2', 'Gene', '2535', (13, 17))	('FZD2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('knocking out', 'Var', (111, 123))	('invasiveness of liver cancer', 'Disease', (159, 187))	('migration', 'CPA', (145, 154))	('FZD2', 'Gene', '2535', (124, 128))	('FZD2', 'Gene', (124, 128))	('inhibit', 'NegReg', (133, 140))	('invasiveness of liver cancer', 'Disease', 'MESH:D006528', (159, 187))
99167	33565732	Knockout of FZD7 or use of Wnt/beta-catenin inhibitors has been shown to reduce the stemness and chemoresistance of GC cells [33].	('chemoresistance', 'CPA', (97, 112))	('beta-catenin', 'Gene', (31, 43))	('GC', 'Phenotype', 'HP:0012126', (116, 118))	('beta-catenin', 'Gene', '1499', (31, 43))	('Knockout', 'Var', (0, 8))	('FZD7', 'Gene', '8324', (12, 16))	('FZD7', 'Gene', (12, 16))	('reduce', 'NegReg', (73, 79))
99168	33565732	FZD8 is highly expressed in human lung cancer tissue samples and cell lines, and knockout of FZD8 can increase the sensitivity of lung cancer cells to paclitaxel [34].	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('FZD8', 'Gene', '8325', (93, 97))	('paclitaxel', 'Chemical', 'MESH:D017239', (151, 161))	('FZD8', 'Gene', (93, 97))	('lung cancer', 'Disease', (34, 45))	('human', 'Species', '9606', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('knockout', 'Var', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('increase', 'PosReg', (102, 110))	('sensitivity', 'MPA', (115, 126))	('FZD8', 'Gene', '8325', (0, 4))	('lung cancer', 'Disease', (130, 141))	('FZD8', 'Gene', (0, 4))
99184	33565732	Those with high TMB expression have been shown to benefit more from immune checkpoint inhibitor therapy [44].	('TMB', 'Chemical', '-', (16, 19))	('TMB', 'Protein', (16, 19))	('benefit', 'PosReg', (50, 57))	('high', 'Var', (11, 15))
99185	33565732	TMB reflects the total number of replacement and insertion/deletion mutations per megabase in the exon coding region of the evaluated gene in the tumor cell genome.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TMB', 'Chemical', '-', (0, 3))	('insertion/deletion mutations', 'Var', (49, 77))	('tumor', 'Disease', (146, 151))	('replacement', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
99186	33565732	Driving gene mutations can lead to tumors, and a large number of somatic mutations can produce new antigens, which can activate T cells and cause immune responses [45].	('T cells', 'CPA', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cause', 'Reg', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('immune responses', 'CPA', (146, 162))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('lead to', 'Reg', (27, 34))	('mutations', 'Var', (13, 22))	('activate', 'PosReg', (119, 127))	('mutations', 'Var', (73, 82))	('produce', 'Reg', (87, 94))
99189	33565732	Studies have shown that frameshift mutations of AXIN2 and TCF7L2 are common in GC with high MSI, and these mutations may promote the development of GC through the control of Wnt signaling [46].	('mutations', 'Var', (107, 116))	('AXIN2', 'Gene', (48, 53))	('development', 'CPA', (133, 144))	('AXIN2', 'Gene', '8313', (48, 53))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('TCF7L2', 'Gene', (58, 64))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('TCF7L2', 'Gene', '6934', (58, 64))	('promote', 'PosReg', (121, 128))	('frameshift mutations', 'Var', (24, 44))
99191	33565732	It was also found that FZD2 was mutated in breast, endometrial, large intestine, liver, lung, skin, and stomach cancer.	('endometrial', 'Disease', (51, 62))	('skin', 'Disease', (94, 98))	('stomach cancer', 'Disease', 'MESH:D013274', (104, 118))	('stomach cancer', 'Phenotype', 'HP:0012126', (104, 118))	('liver', 'Disease', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('large intestine', 'Disease', (64, 79))	('mutated', 'Var', (32, 39))	('stomach cancer', 'Disease', (104, 118))	('breast', 'Disease', (43, 49))	('lung', 'Disease', (88, 92))	('FZD2', 'Gene', '2535', (23, 27))	('FZD2', 'Gene', (23, 27))
99214	31653812	Importantly, the diagnosis and management of diffuse LGGs have been transformed by the revised 2016 WHO classification of CNS tumors, which for the first time incorporated molecular information to classify diffuse LGG into the following subtypes, in order of worsening prognosis: WHO grade II, IDH-mutant, 1p/19q-codeleted oligodendrogliomas; IDH-mutant astrocytomas; and IDH-wildtype astrocytomas.	('gliomas', 'Phenotype', 'HP:0009733', (334, 341))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('astrocytomas', 'Disease', 'MESH:D001254', (385, 397))	('astrocytoma', 'Phenotype', 'HP:0009592', (385, 396))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('IDH', 'Gene', (294, 297))	('IDH', 'Gene', '3417', (343, 346))	('1p/19q-codeleted', 'Var', (306, 322))	('CNS tumors', 'Disease', 'MESH:D016543', (122, 132))	('IDH', 'Gene', (372, 375))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (323, 341))	('astrocytomas', 'Disease', (354, 366))	('IDH', 'Gene', '3417', (294, 297))	('IDH-wildtype astrocytomas', 'Disease', (372, 397))	('IDH', 'Gene', '3417', (372, 375))	('astrocytomas', 'Disease', (385, 397))	('oligodendrogliomas', 'Disease', (323, 341))	('glioma', 'Phenotype', 'HP:0009733', (334, 340))	('IDH-wildtype astrocytomas', 'Disease', 'MESH:D001254', (372, 397))	('astrocytomas', 'Disease', 'MESH:D001254', (354, 366))	('CNS tumors', 'Disease', (122, 132))	('men', 'Species', '9606', (37, 40))	('astrocytoma', 'Phenotype', 'HP:0009592', (354, 365))	('IDH', 'Gene', (343, 346))
99216	31653812	Patients were eligible for inclusion if they had available preoperative and immediately postoperative MRI studies, as well as molecular data that would enable assignment to one of the 2016 WHO diagnostic categories (i.e., IDH1/2 mutation status, 1p/19q codeletion status, ATRX, and/or p53 mutation status).	('men', 'Species', '9606', (165, 168))	('p53', 'Gene', (285, 288))	('p53', 'Gene', '7157', (285, 288))	('IDH1/2', 'Gene', (222, 228))	('ATRX', 'Gene', (272, 276))	('IDH1/2', 'Gene', '3417;3418', (222, 228))	('Patients', 'Species', '9606', (0, 8))	('mutation status', 'Var', (229, 244))	('ATRX', 'Gene', '546', (272, 276))	('1p/19q codeletion status', 'Var', (246, 270))
99227	31653812	First, a determination of IDH mutational status was made based on immunohistochemistry (IHC) for the common IDH1 Arg132His (R132H) mutation.	('Arg132His', 'Var', (113, 122))	('IDH1', 'Gene', '3417', (108, 112))	('IDH', 'Gene', (108, 111))	('Arg132His', 'SUBSTITUTION', 'None', (113, 122))	('IDH', 'Gene', '3417', (108, 111))	('IDH', 'Gene', (26, 29))	('R132H', 'Mutation', 'rs121913500', (124, 129))	('IDH', 'Gene', '3417', (26, 29))	('IDH1', 'Gene', (108, 112))
99229	31653812	The presence of both IDH gene mutation and combined whole-arm losses of 1p and 19q led to designation as an oligodendroglioma.	('IDH', 'Gene', (21, 24))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('IDH', 'Gene', '3417', (21, 24))	('oligodendroglioma', 'Disease', (108, 125))	('mutation', 'Var', (30, 38))	('oligodendroglioma', 'Disease', 'MESH:D009837', (108, 125))	('losses', 'NegReg', (62, 68))
99230	31653812	The presence of IDH mutation and absence of 1p/19q codeletion signified a diagnosis of IDH-mutant astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (98, 109))	('absence', 'NegReg', (33, 40))	('presence', 'Reg', (4, 12))	('IDH', 'Gene', (87, 90))	('mutation', 'Var', (20, 28))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', '3417', (87, 90))	('IDH', 'Gene', '3417', (16, 19))	('astrocytoma', 'Disease', 'MESH:D001254', (98, 109))	('astrocytoma', 'Disease', (98, 109))
99231	31653812	Absent 1p/19q status, ATRX loss, or mutant p53 by IHC in a diffuse glioma with astrocytic histology also led to designation as an astrocytoma, consistent with the recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy:Not Official WHO (cIMPACT-NOW).	('ATRX', 'Gene', (22, 26))	('1p/19q', 'Protein', (7, 13))	('Tumor', 'Phenotype', 'HP:0002664', (249, 254))	('glioma', 'Disease', (67, 73))	('ATRX', 'Gene', '546', (22, 26))	('astrocytoma', 'Disease', 'MESH:D001254', (130, 141))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('mutant', 'Var', (36, 42))	('astrocytoma', 'Disease', (130, 141))	('p53', 'Gene', (43, 46))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('p53', 'Gene', '7157', (43, 46))	('men', 'Species', '9606', (168, 171))	('CNS Tumor', 'Phenotype', 'HP:0100006', (245, 254))	('loss', 'NegReg', (27, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (130, 141))
99246	31653812	In univariable analysis, postoperative volume was significantly associated with worse OS (HR 1.02 per cm3, 95% CI 1.01-1.03, p < 0.0001), and this association was consistent across all molecular classes (oligodendroglioma HR 1.05 per cm3, 95% CI 1.0-1.09, p = 0.025; IDH-mutant astrocytoma HR 1.02 per cm3, 95% CI 1.01-1.03, p < 0.0001; and IDH-wildtype HR 1.03 per cm3, 95% CI 1.01-1.05, p = 0.001).	('astrocytoma HR', 'Disease', 'MESH:D001254', (278, 292))	('astrocytoma HR', 'Disease', (278, 292))	('IDH', 'Gene', (341, 344))	('oligodendroglioma HR', 'Disease', 'MESH:D009837', (204, 224))	('postoperative', 'Var', (25, 38))	('worse OS', 'Disease', (80, 88))	('IDH', 'Gene', '3417', (341, 344))	('oligodendroglioma HR', 'Disease', (204, 224))	('IDH', 'Gene', (267, 270))	('astrocytoma', 'Phenotype', 'HP:0009592', (278, 289))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('IDH', 'Gene', '3417', (267, 270))
99254	31653812	Prognostic factors associated with worse MPFS in a multivariable CPH model were age at diagnosis (HR 1.02 per year, 95% CI 1.00-1.04, p = 0.033); IDH-mutant (reference oligodendroglioma: HR 5.12, 95% CI 2.83-9.26, p < 0.001) or IDH-wildtype (reference oligodendroglioma: HR 4.44, 95% CI 1.91-10.3, p = 0.001) molecular groups; presence of contrast enhancement (HR 2.04, 95% CI 1.08-3.87, p = 0.029); and increasing preoperative volume (HR 1.01 per cm3, 95% CI 1.0-1.01, p = 0.001) and postoperative residual volume (HR 1.01 per cm3, 95% CI 1.0-1.02, p = 0.029).	('oligodendroglioma', 'Disease', (168, 185))	('oligodendroglioma', 'Disease', 'MESH:D009837', (252, 269))	('increasing', 'PosReg', (404, 414))	('presence', 'Var', (327, 335))	('IDH', 'Gene', (146, 149))	('oligodendroglioma', 'Disease', 'MESH:D009837', (168, 185))	('men', 'Species', '9606', (355, 358))	('IDH', 'Gene', (228, 231))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('IDH', 'Gene', '3417', (146, 149))	('oligodendroglioma', 'Disease', (252, 269))	('IDH', 'Gene', '3417', (228, 231))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))
99263	31653812	Moreover, 1p/19q codeletion imparts higher sensitivity to chemotherapeutic regimens, further lowering the risk of progression in oligodendrogliomas.	('men', 'Species', '9606', (79, 82))	('codeletion', 'Var', (17, 27))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('higher', 'PosReg', (36, 42))	('1p/19q codeletion', 'Var', (10, 27))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (129, 147))	('sensitivity', 'MPA', (43, 54))	('oligodendrogliomas', 'Disease', (129, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('lowering', 'NegReg', (93, 101))
99428	31214496	Radiotherapy may cause damage in the form of radiation necrosis that may appear several months or even years after the treatment.	('Radiotherapy', 'Var', (0, 12))	('radiation necrosis', 'Disease', 'MESH:D004194', (45, 63))	('radiation necrosis', 'Disease', (45, 63))
99430	31214496	Thus, patients treated with high-dose SRS have higher likelihoods of developing radiation necrosis [reported in up to 22% of patients ] which can be difficult to manage.	('radiation necrosis', 'Disease', 'MESH:D004194', (80, 98))	('radiation necrosis', 'Disease', (80, 98))	('high-dose', 'Var', (28, 37))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (125, 133))
99461	31214496	Such tumor-related normal appearing tissue changes have been detected with DTI (increased fractional anisotropy, FA due to destruction of neurons in cNAWM), qMT (increased direct effect of the free water pool, 1/(RaT2a) calculated from qMT measurements in cNAWM), and CEST (altered metabolism measured with decrease in Amide and Amine CEST signals in cNAWM).	('destruction', 'Var', (123, 134))	('water', 'Chemical', 'MESH:D014867', (198, 203))	('Amine', 'Chemical', 'MESH:D000588', (329, 334))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('Amide', 'Chemical', 'MESH:D000577', (319, 324))	('increased', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('water pool', 'Phenotype', 'HP:0000969', (198, 208))	('decrease', 'NegReg', (307, 315))	('tumor', 'Disease', (5, 10))	('fractional anisotropy', 'MPA', (90, 111))	('DTI', 'Gene', (75, 78))	('RaT2a', 'CellLine', 'CVCL:0510', (213, 218))
99492	31088577	Functional experiments showed that HSBP2 appeared to be epigenetically regulated by one identified CpG and was associated with TMZ resistance, but it was not associated with cell proliferation or apoptosis in GBM cell lines.	('HSBP2', 'Gene', (35, 40))	('TMZ resistance', 'MPA', (127, 141))	('associated', 'Reg', (111, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (127, 130))	('epigenetically regulated', 'Var', (56, 80))
99493	31088577	The predictive value of the single CpG methylation of HSBP2 by pyrosequencing was observed in a local cohort of isocitrate dehydrogenase 1 (IDH1) R132H wild-type GBMs.	('IDH1', 'Gene', '3417', (140, 144))	('isocitrate dehydrogenase 1', 'Gene', (112, 138))	('methylation', 'Var', (39, 50))	('R132H', 'Var', (146, 151))	('isocitrate dehydrogenase 1', 'Gene', '3417', (112, 138))	('R132H', 'Mutation', 'rs121913500', (146, 151))	('HSBP2', 'Gene', (54, 59))	('IDH1', 'Gene', (140, 144))	('GBMs', 'Phenotype', 'HP:0012174', (162, 166))
99508	31088577	MGMT promoter methylation status was determined using a logistic regression model based on two Illumina array probes, i.e., cg12434587 and cg12981137.	('MGMT', 'Gene', (0, 4))	('cg12981137', 'Var', (139, 149))	('cg12434587', 'Var', (124, 134))	('MGMT', 'Gene', '4255', (0, 4))
99529	31088577	Inclusion criteria included (1) adult patients (> 18-years old), (2) no prior therapy before surgery, (3) IDH1R132H wild-type tumors, (4) treatment with standard RT plus (adjuvant or concurrent) TMZ or standard RT alone, (5) available OS or progression-free survival (PFS) data, and (6) available FFPE tissue samples.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('IDH1R132H', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (38, 46))	('OS', 'Chemical', '-', (235, 237))	('TMZ', 'Chemical', 'MESH:D000077204', (195, 198))
99533	31088577	Seven CpGs (74-81) in the promoter region of MGMT and the single CpG (cg155227610) at the non-CpGs island (CGI) region of HSPB2 were detected on the PyroMark Q96ID platform (Qiagen).	('HSPB2', 'Gene', (122, 127))	('HSPB2', 'Gene', '3316', (122, 127))	('cg155227610', 'Var', (70, 81))	('MGMT', 'Gene', (45, 49))	('MGMT', 'Gene', '4255', (45, 49))
99540	31088577	Each CpG was significantly associated with OS of non-G-CIMP GBMs treated with RT/TMZ, but not RT alone, which was also independent of age, MGMT promoter methylation status, and other CpG members.	('associated with', 'Reg', (27, 42))	('MGMT', 'Gene', (139, 143))	('G-CIMP', 'Chemical', '-', (53, 59))	('GBMs', 'Phenotype', 'HP:0012174', (60, 64))	('MGMT', 'Gene', '4255', (139, 143))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('OS', 'Chemical', '-', (43, 45))	('RT/TMZ', 'Var', (78, 84))
99542	31088577	The 7-CpG panel was combined using a RISK score model as follows: risk score = (1.095 x beta value of cg23904249) + (1.575 x beta value of cg07490776) + (- 1.365 x beta value of cg24035962) + (- 1.574 x beta value of cg01980222) + (- 1.248 x beta value of cg01980222) + (- 1.120 x beta value of cg15227610) + (- 0.975 x beta value of cg13784557).	('cg15227610) + (-', 'Var', (295, 311))	('7-CpG', 'Chemical', '-', (4, 9))	('cg01980222) + (-', 'Var', (256, 272))	('cg24035962) + (- 1.574', 'Var', (178, 200))	('cg07490776) + (-', 'Var', (139, 155))	('cg01980222) + (-', 'Var', (217, 233))
99549	31088577	The signature accurately predicted OS in the validation cohorts with RT/TMZ: RAUH-GSE22891 (p = 0.0436), GSE50923-RT/TMZ (p = 0.0168), and GSE60274-RT/TMZ (p = 0.0005; Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('RAUH-GSE22891', 'Var', (77, 90))	('predicted', 'Reg', (25, 34))	('OS', 'Chemical', '-', (35, 37))	('TMZ', 'Chemical', 'MESH:D000077204', (72, 75))	('GSE50923-RT/TMZ', 'Var', (105, 120))	('GSE60274-RT/TMZ', 'Var', (139, 154))	('TMZ', 'Chemical', 'MESH:D000077204', (151, 154))
99552	31088577	Cox regression analyses of RAUH-new cohort and TCGA-Brennan et al.-RT/TMZ confirmed the RISK score signature as a significant risk factor that is independent of MGMT methylation status, as well as other variables (e.g., age, treatment schedules, treatment at progression), among non-G-CIMP GBMs with RT/TMZ (Additional file 6: Table S3), instead of RT alone (Additional file 7: Table S4).	('TMZ', 'Chemical', 'MESH:D000077204', (303, 306))	('TMZ', 'Chemical', 'MESH:D000077204', (70, 73))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('GBMs', 'Phenotype', 'HP:0012174', (290, 294))	('RT/TMZ', 'Var', (300, 306))	('G-CIMP', 'Chemical', '-', (283, 289))	('MGMT', 'Gene', (161, 165))	('MGMT', 'Gene', '4255', (161, 165))
99556	31088577	The interaction analyses showed that standard RT/TMZ did confer a clear OS benefit to low-risk patients compared to standard RT, and this treatment was associated with a similar OS in high-risk patients (Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (49, 52))	('OS', 'Chemical', '-', (72, 74))	('patients', 'Species', '9606', (194, 202))	('patients', 'Species', '9606', (95, 103))	('standard', 'Var', (37, 45))	('benefit', 'PosReg', (75, 82))	('OS', 'Chemical', '-', (178, 180))
99558	31088577	and GSE60274 confirmed standard RT/TMZ as a favorable indicator for OS benefit, independent of MGMT methylation status and age, in low-risk patients (Additional file 9: Table S5), but not in high-risk patients (Additional file 10: Table S6).	('patients', 'Species', '9606', (201, 209))	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('patients', 'Species', '9606', (140, 148))	('GSE60274', 'Var', (4, 12))	('MGMT', 'Gene', '4255', (95, 99))	('OS', 'Chemical', '-', (68, 70))	('MGMT', 'Gene', (95, 99))
99561	31088577	To further explore the clinical impact of the epigenetic signature, we also evaluated its performance in cohorts stratified by MGMT methylation status and age.	('MGMT', 'Gene', '4255', (127, 131))	('epigenetic', 'Var', (46, 56))	('MGMT', 'Gene', (127, 131))
99562	31088577	We found that the RISK score signature showed significant discriminating value for OS of patients with each MGMT methylation status in the combined RAUH cohorts (RAUH-two cohorts) and in TCGA-Brennan et al.-RT/TMZ (Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (210, 213))	('MGMT', 'Gene', (108, 112))	('OS', 'Chemical', '-', (83, 85))	('MGMT', 'Gene', '4255', (108, 112))	('patients', 'Species', '9606', (89, 97))	('methylation status', 'Var', (113, 131))
99567	31088577	The single CpG methylation and HSPB2 expression differed regarding the G-CIMP status (or IDH mutations), but they were not significantly altered in GBMs or in IDH mutant gliomas compared to nontumor brains (Fig.	('IDH', 'Gene', (159, 162))	('G-CIMP', 'Chemical', '-', (71, 77))	('GBMs', 'Phenotype', 'HP:0012174', (148, 152))	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', '3417', (159, 162))	('gliomas', 'Disease', (170, 177))	('differed', 'Reg', (48, 56))	('tumor', 'Disease', (193, 198))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('expression', 'MPA', (37, 47))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('mutant', 'Var', (163, 169))	('HSPB2', 'Gene', '3316', (31, 36))	('HSPB2', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('IDH', 'Gene', (89, 92))	('altered', 'Reg', (137, 144))
99569	31088577	Notably, the single CpG methylation was consistently and significantly negatively correlated with HSPB2 expression (Fig.	('single CpG methylation', 'Var', (13, 35))	('HSPB2', 'Gene', '3316', (98, 103))	('correlated', 'Reg', (82, 92))	('expression', 'MPA', (104, 114))	('negatively', 'NegReg', (71, 81))	('HSPB2', 'Gene', (98, 103))
99570	31088577	Demethylation treatment with 5-Aza-dC showed that HSBP2 expression was increased in GBM cells that had the original hypermethylated CpG, e.g., U373 and U251, but not in cells with hypomethylated CpG, e.g., U87 (Fig.	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (29, 37))	('U251', 'Var', (152, 156))	('expression', 'MPA', (56, 66))	('HSBP2', 'Gene', (50, 55))	('increased', 'PosReg', (71, 80))	('U373', 'Var', (143, 147))
99575	31088577	The single CpG methylation of HSPB2 by pyrosequencing predicted OS in patients who received RT/TMZ (log-rank p = 0.0245) but not in those who received RT alone (log-rank p = 0.7733; Fig.	('HSPB2', 'Gene', (30, 35))	('methylation', 'Var', (15, 26))	('patients', 'Species', '9606', (70, 78))	('HSPB2', 'Gene', '3316', (30, 35))	('predicted', 'Reg', (54, 63))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))	('OS', 'Chemical', '-', (64, 66))	('RT/TMZ', 'Var', (92, 98))
99576	31088577	Interaction analyses and Cox analyses both supported an independent predictive potential of the single CpG methylation of HSPB2 to TMZ efficacy in clinically available FFPE samples (Fig.	('HSPB2', 'Gene', (122, 127))	('HSPB2', 'Gene', '3316', (122, 127))	('Cox', 'Gene', '1351', (25, 28))	('Cox', 'Gene', (25, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (131, 134))	('methylation', 'Var', (107, 118))
99577	31088577	Moreover, HSPB2 methylation could optimize the risk classification by MGMT promoter methylation status (Additional file 11: Figure S5C).	('HSPB2', 'Gene', (10, 15))	('MGMT', 'Gene', (70, 74))	('HSPB2', 'Gene', '3316', (10, 15))	('MGMT', 'Gene', '4255', (70, 74))	('optimize', 'Reg', (34, 42))	('methylation', 'Var', (16, 27))
99579	31088577	Epigenetic marks and DNA methylation in particular have long been regarded as the leading candidates for biomarker discovery as they have many advantages over genetic or expression-based information such as having reliable DNA samples, altered patterns that have stability, tolerance of nontumor cell contamination, multilevel biological relevance, and drug-induced reversibility.	('Epigenetic marks', 'Var', (0, 16))	('patterns', 'MPA', (244, 252))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (290, 295))
99594	31088577	In addition, G-CIMP GBMs were excluded from our analyses because those tumors, exclusively carrying IDH mutations, represented a small subtype (~ 10% of all GBMs) and showed a very distinct molecular background and clinical prognosis compared to non-G-CIMP GBMs.	('IDH', 'Gene', (100, 103))	('mutations', 'Var', (104, 113))	('IDH', 'Gene', '3417', (100, 103))	('G-CIMP', 'Chemical', '-', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GBMs', 'Phenotype', 'HP:0012174', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('GBMs', 'Phenotype', 'HP:0012174', (20, 24))	('GBMs', 'Phenotype', 'HP:0012174', (257, 261))	('tumors', 'Disease', (71, 77))	('G-CIMP', 'Chemical', '-', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
99610	31088577	HSPB2 has been reported to be epigenetically or transcriptionally altered in some human cancers, with potential roles in tumor growth, metastasis, and in particular drug resistance.	('metastasis', 'CPA', (135, 145))	('HSPB2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('drug resistance', 'CPA', (165, 180))	('epigenetically', 'Var', (30, 44))	('roles', 'Reg', (112, 117))	('HSPB2', 'Gene', '3316', (0, 5))	('drug resistance', 'Phenotype', 'HP:0020174', (165, 180))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Disease', (121, 126))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
99611	31088577	In this study, the single CpG methylation was found to be negatively correlated with HSPB2 expression, indicating an epigenetic regulatory mechanism for this gene.	('expression', 'MPA', (91, 101))	('HSPB2', 'Gene', '3316', (85, 90))	('methylation', 'Var', (30, 41))	('single CpG methylation', 'Var', (19, 41))	('negatively', 'NegReg', (58, 68))	('HSPB2', 'Gene', (85, 90))
99614	31088577	Together, these data may provide some biological explanations regarding the predictive effects of the multimarker signature:the epigenetic panel might contribute to TMZ resistance via epigenetically regulating the expression levels of drug-resistant genes.	('regulating', 'Reg', (199, 209))	('epigenetic panel', 'Var', (128, 144))	('contribute', 'Reg', (151, 161))	('expression levels', 'MPA', (214, 231))	('TMZ', 'Disease', (165, 168))	('epigenetically', 'Var', (184, 198))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
99618	31088577	Recent studies reported that in addition to a direct alteration in gene expression, cancer-linked DNA methylation abnormalities may have functional impacts via contributing to disrupted heterochromatin, leading to loss of both epigenetic and transcriptional regulatory mechanisms and resulting in hypervariable expression.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('DNA', 'Gene', (98, 101))	('cancer', 'Disease', (84, 90))	('transcriptional regulatory mechanisms', 'MPA', (242, 279))	('abnormalities', 'Var', (114, 127))	('methylation abnormalities', 'Var', (102, 127))	('loss', 'NegReg', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('disrupted', 'NegReg', (176, 185))	('hypervariable expression', 'MPA', (297, 321))	('heterochromatin', 'Protein', (186, 201))
99621	31088577	Validation of the predictive ability of the single CpG methylation of HSPB2 by pyrosequencing in clinically available FFPE samples was reported not only to provide additional validation of the multi-CpG signature at a clinical level, but also to highlight the promising translational potential of the array-based signature to routine clinical testing.	('HSPB2', 'Gene', (70, 75))	('HSPB2', 'Gene', '3316', (70, 75))	('methylation', 'Var', (55, 66))
99624	31088577	In summary, we proposed a RISK score signature comprising 7 CpGs and the single CpG methylation of HSPB2, both with promising predictive values for the outcome of TMZ therapy in non-G-CIMP (or wild-type IDH) GBMs.	('IDH', 'Gene', (203, 206))	('non-G-CIMP', 'Disease', (178, 188))	('HSPB2', 'Gene', '3316', (99, 104))	('methylation', 'Var', (84, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (163, 166))	('GBMs', 'Phenotype', 'HP:0012174', (208, 212))	('IDH', 'Gene', '3417', (203, 206))	('G-CIMP', 'Chemical', '-', (182, 188))	('HSPB2', 'Gene', (99, 104))
99636	30717708	Additionally, high CD133 expression signatures were found in intestinal subtypes and low tumor stage GCs as well as in those with microsatellite instabilities and high mutation burdens.	('expression signatures', 'MPA', (25, 46))	('GCs', 'Phenotype', 'HP:0012126', (101, 104))	('CD133', 'Gene', (19, 24))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('CD133', 'Gene', '8842', (19, 24))	('low tumor', 'Disease', 'MESH:D009800', (85, 94))	('microsatellite', 'Var', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('low tumor', 'Disease', (85, 94))
99642	30717708	Immunohistochemistry (IHC)-based quantification of expressed CD133 protein levels has been proposed as a GC prognostic marker and CD133 positivity indicates poor prognosis as well as chemoresistance and disease progression of GC.	('positivity', 'Var', (136, 146))	('GC', 'Phenotype', 'HP:0012126', (226, 228))	('disease progression', 'CPA', (203, 222))	('chemoresistance', 'CPA', (183, 198))	('CD133', 'Gene', (61, 66))	('CD133', 'Gene', (130, 135))	('CD133', 'Gene', '8842', (130, 135))	('CD133', 'Gene', '8842', (61, 66))	('poor prognosis', 'CPA', (157, 171))	('GC', 'Phenotype', 'HP:0012126', (105, 107))
99646	30717708	In this study, we performed microarray-based transcriptome analyses of CD133+ vs. CD133- cells obtained by cell sorting from three GC cell lines (KATO-III, SNU216 and SNU601).	('CD133', 'Gene', '8842', (71, 76))	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('SNU601', 'Var', (167, 173))	('CD133', 'Gene', (82, 87))	('CD133', 'Gene', '8842', (82, 87))	('CD133', 'Gene', (71, 76))	('SNU216', 'Var', (156, 162))	('SNU216', 'CellLine', 'CVCL:3946', (156, 162))
99671	30717708	To evaluate the gene expression associated with the CD133 stem cell marker in GCs, we performed gene expression profiling of three gastric cancer cell lines (KATO-III, SNU216, and SNU601).	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('CD133', 'Gene', (52, 57))	('CD133', 'Gene', '8842', (52, 57))	('SNU601', 'Var', (180, 186))	('SNU216', 'CellLine', 'CVCL:3946', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('GCs', 'Phenotype', 'HP:0012126', (78, 81))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('gastric cancer', 'Disease', (131, 145))
99709	30717708	Among the major mutations of GC, mutations of TP53, PIK3CA, KRAS, ARID1A, and RHOA were evaluated, whereas only ARID1A mutations were significantly associated with CD133 expression signature (P = 0.0007; Fig.	('ARID1A', 'Gene', (112, 118))	('CD133', 'Gene', '8842', (164, 169))	('RHOA', 'Gene', '387', (78, 82))	('TP53', 'Gene', '7157', (46, 50))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (52, 58))	('ARID1A', 'Gene', '8289', (66, 72))	('ARID1A', 'Gene', (66, 72))	('KRAS', 'Gene', (60, 64))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('TP53', 'Gene', (46, 50))	('associated', 'Reg', (148, 158))	('RHOA', 'Gene', (78, 82))	('KRAS', 'Gene', '3845', (60, 64))	('PIK3CA', 'Gene', '5290', (52, 58))	('ARID1A', 'Gene', '8289', (112, 118))	('CD133', 'Gene', (164, 169))
99761	30717708	In general, IHC-based CD133 positivity in GC has been regarded as a feature associated with high-stage and high-grade tumors with poor prognosis.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('positivity', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('associated', 'Reg', (76, 86))	('high-stage', 'Disease', (92, 102))	('CD133', 'Gene', (22, 27))	('CD133', 'Gene', '8842', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
99825	28915694	Cox regression analyses (enter) were performed to evaluate the association of severe depressive and anxiety symptom severity with 5 year mortality adjusting for patients' age ( < 50 vs. >=50 years), gender (male vs. female), tumor type (primary vs. recurrent), functional status (BI score 100 vs. < 100), extent of resection (complete vs. incomplete or biopsy), adjuvant treatment (yes vs. no), histories of depression (yes vs. no), and tumor laterality, location and grade.	('anxiety', 'Disease', (100, 107))	('Cox', 'Gene', (0, 3))	('men', 'Species', '9606', (376, 379))	('tumor', 'Phenotype', 'HP:0002664', (437, 442))	('tumor', 'Disease', (225, 230))	('anxiety', 'Disease', 'MESH:D001008', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('depression', 'Disease', (408, 418))	('BI score 100', 'Var', (280, 292))	('severe depressive and anxiety symptom severity', 'Phenotype', 'HP:0000716', (78, 124))	('depressive', 'Disease', (85, 95))	('anxiety', 'Phenotype', 'HP:0000739', (100, 107))	('depressive', 'Disease', 'MESH:D000275', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Disease', (437, 442))	('depression', 'Disease', 'MESH:D000275', (408, 418))	('tumor', 'Disease', 'MESH:D009369', (437, 442))	('Cox', 'Gene', '1351', (0, 3))	('depression', 'Phenotype', 'HP:0000716', (408, 418))
99912	26858939	Genetics and Epigenetics of Glioblastoma: Applications and Overall Incidence of IDH1 Mutation Glioblastoma is the most fatal brain cancer found in humans.	('Glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('IDH1', 'Gene', (80, 84))	('brain cancer', 'Disease', (125, 137))	('Glioblastoma', 'Disease', (28, 40))	('IDH1', 'Gene', '3417', (80, 84))	('Glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Mutation', 'Var', (85, 93))	('brain cancer', 'Disease', 'MESH:D001932', (125, 137))	('Glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('Glioblastoma', 'Disease', (94, 106))	('humans', 'Species', '9606', (147, 153))	('brain cancer', 'Phenotype', 'HP:0030692', (125, 137))	('Glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
99916	26858939	Particularly, the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) gene has shed new light on the molecular landscape in glioblastoma.	('mutations', 'Var', (41, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('isocitrate dehydrogenase 1', 'Gene', (58, 84))	('isocitrate dehydrogenase 1', 'Gene', '3417', (58, 84))	('glioblastoma', 'Disease', (146, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))
99917	26858939	Indeed, emerging research on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome and contribute to glioblastoma development.	('affect', 'Reg', (240, 246))	('IDH1', 'Gene', (56, 60))	('influences', 'Reg', (195, 205))	('mutant', 'Var', (49, 55))	('epigenome', 'MPA', (251, 260))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (176, 194))	('IDH1', 'Gene', '3417', (56, 60))	('cellular programs', 'CPA', (217, 234))	('glioblastoma', 'Disease', (279, 291))	('glioblastoma', 'Disease', 'MESH:D005909', (279, 291))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('contribute to', 'Reg', (265, 278))
99918	26858939	One of the exciting observations is the presence of IDH1 mutation in the vast majority of secondary glioblastoma, while it is almost absent in primary glioblastoma.	('mutation', 'Var', (57, 65))	('primary glioblastoma', 'Disease', 'MESH:D005909', (143, 163))	('primary glioblastoma', 'Disease', (143, 163))	('IDH1', 'Gene', '3417', (52, 56))	('secondary glioblastoma', 'Disease', (90, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (90, 112))	('presence', 'Reg', (40, 48))	('IDH1', 'Gene', (52, 56))
99932	26858939	One of the most exciting and clinically relevant observations was the discovery that a high percentage of secondary glioblastomas and a very small percentage of primary glioblastoma harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene.	('primary glioblastoma', 'Disease', (161, 181))	('secondary glioblastoma', 'Disease', (106, 128))	('primary glioblastoma', 'Disease', 'MESH:D005909', (161, 181))	('glioblastomas', 'Phenotype', 'HP:0012174', (116, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('clinical', 'Species', '191496', (29, 37))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (106, 128))	('glioblastomas', 'Disease', (116, 129))	('glioblastomas', 'Disease', 'MESH:D005909', (116, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('isocitrate dehydrogenase 1', 'Gene', (206, 232))	('IDH1', 'Gene', (234, 238))	('isocitrate dehydrogenase 1', 'Gene', '3417', (206, 232))	('mutations', 'Var', (189, 198))	('IDH1', 'Gene', '3417', (234, 238))
99934	26858939	Indeed, IDH1 mutation results in gain of function to catalyze the production of hydroxyglutarate (2-HG), a possible oncometabolite that is thought to influence a range of cellular programs involved in epigenetic control and various processes leading to tumor development.	('2-HG', 'Chemical', 'MESH:C019417', (98, 102))	('gain of function', 'PosReg', (33, 49))	('influence', 'Reg', (150, 159))	('mutation', 'Var', (13, 21))	('IDH1', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('production', 'MPA', (66, 76))	('hydroxyglutarate', 'Chemical', '-', (80, 96))	('IDH1', 'Gene', '3417', (8, 12))	('tumor', 'Disease', (253, 258))	('catalyze', 'MPA', (53, 61))
99936	26858939	In addition, we highlight importance of epigenetic changes that may need to be considered in future diagnostics and therapy for glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('epigenetic changes', 'Var', (40, 58))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
99937	26858939	Initially, the review presents a brief overview on mutations commonly found in glioblastoma, and prunes the consequences of IDH1 mutation on glioblastoma biology to better understand the potential role of this particular mutation in the development of this tumor.	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (257, 262))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('mutation', 'Var', (129, 137))	('IDH1', 'Gene', '3417', (124, 128))	('glioblastoma', 'Disease', (79, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('glioblastoma', 'Disease', (141, 153))	('IDH1', 'Gene', (124, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
99939	26858939	EGFR point mutations have also been identified in glioblastoma.	('point mutations', 'Var', (5, 20))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('EGFR', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('EGFR', 'Gene', '1956', (0, 4))	('identified', 'Reg', (36, 46))	('glioblastoma', 'Disease', (50, 62))
99940	26858939	The EGFRvIII mutant lacks 267 amino acids in the extracellular part, resulting in a constitutively activated receptor that no longer requires its ligand EGF to signal downstream.	('mutant', 'Var', (13, 19))	('lacks', 'NegReg', (20, 25))	('EGFR', 'Gene', (4, 8))	('constitutively activated receptor', 'MPA', (84, 117))	('EGFR', 'Gene', '1956', (4, 8))
99941	26858939	Although mutations in certain cancer genes, such as BRAF and the RAS genes, have rarely been observed in glioblastoma, inactivating mutations and deletions have been identified in their inhibitory tumor-suppressor gene NF1.	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('RAS', 'Gene', (65, 68))	('BRAF', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('NF1', 'Gene', (219, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('deletions', 'Var', (146, 155))	('BRAF', 'Gene', '673', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('glioblastoma', 'Disease', (105, 117))	('inactivating mutations', 'Var', (119, 141))	('tumor', 'Disease', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('NF1', 'Gene', '4763', (219, 222))
99942	26858939	Mutations in PIK3CA and PIK3R1 genes, coding, respectively, for the PI3K catalytic subunit p110alpha and regulatory subunit P85alpha, have also been described.	('PIK3R1', 'Gene', '5295', (24, 30))	('PIK3R1', 'Gene', (24, 30))	('P85alpha', 'Gene', (124, 132))	('PIK3CA', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('P85alpha', 'Gene', '5295', (124, 132))
99943	26858939	An interesting gene found to contain mutations in glioblastoma is IDH1, which encodes IDH1 and is involved in energy metabolism.	('IDH1', 'Gene', '3417', (66, 70))	('IDH1', 'Gene', (86, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('IDH1', 'Gene', (66, 70))	('IDH1', 'Gene', '3417', (86, 90))	('mutations', 'Var', (37, 46))	('glioblastoma', 'Disease', (50, 62))
99944	26858939	This gene shows differential expression between primary and secondary glioblastoma, while PTEN loss, EGFR amplification, and loss of heterozygosity (LOH) of chromosome 10 are associated with primary glioblastoma, and ATRX mutation, loss of p53, and LOH of chromosome 19 are common in secondary glioblastoma.	('associated', 'Reg', (175, 185))	('p53', 'Gene', '7157', (240, 243))	('loss of heterozygosity', 'Var', (125, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('p53', 'Gene', (240, 243))	('secondary glioblastoma', 'Disease', (284, 306))	('EGFR', 'Gene', '1956', (101, 105))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (284, 306))	('amplification', 'Var', (106, 119))	('secondary glioblastoma', 'Disease', (60, 82))	('PTEN', 'Gene', (90, 94))	('ATRX', 'Gene', (217, 221))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (60, 82))	('primary glioblastoma', 'Disease', (191, 211))	('ATRX', 'Gene', '546', (217, 221))	('PTEN', 'Gene', '5728', (90, 94))	('EGFR', 'Gene', (101, 105))	('primary glioblastoma', 'Disease', 'MESH:D005909', (191, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (294, 306))	('glioblastoma', 'Phenotype', 'HP:0012174', (199, 211))	('loss', 'Var', (232, 236))	('loss', 'NegReg', (95, 99))	('LOH', 'Var', (249, 252))
99945	26858939	The IDH1 mutation predicts secondary glioblastoma better than these other mutations predict their respective glioblastoma subtype.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('glioblastoma subtype', 'Disease', (109, 129))	('secondary glioblastoma', 'Disease', (27, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('glioblastoma subtype', 'Disease', 'MESH:D005909', (109, 129))	('IDH1', 'Gene', (4, 8))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (27, 49))
99946	26858939	Indeed, IDH1 mutations have been predominantly identified in secondary glioblastoma and low-grade gliomas, with mutations in more than 70% of cases.	('secondary glioblastoma', 'Disease', (61, 83))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('IDH1', 'Gene', (8, 12))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (61, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('IDH1', 'Gene', '3417', (8, 12))	('gliomas', 'Disease', (98, 105))	('identified', 'Reg', (47, 57))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('mutations', 'Var', (13, 22))
99949	26858939	Therefore, IDH1 mutation could be used to differentiate primary from secondary glioblastoma.	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('IDH1', 'Gene', (11, 15))	('secondary glioblastoma', 'Disease', (69, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('primary', 'Disease', (56, 63))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (69, 91))
99953	26858939	Since 2008, with the discovery of recurrent mutations in the IDH1 coding gene by the Vogelstein group analyzing the DNA sequence of the glioblastoma genome, substantial progress has been made to understand how such genetic modification leads IDH1 to play a role in the tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('glioblastoma', 'Disease', (136, 148))	('IDH1', 'Gene', (242, 246))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('tumor', 'Disease', (269, 274))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (242, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('mutations', 'Var', (44, 53))	('IDH1', 'Gene', '3417', (61, 65))
99954	26858939	The major finding was the discovery that the IDH1 mutation is a gain-of-function mutation, conferring neomorphic activity to IDH1.	('IDH1', 'Gene', '3417', (45, 49))	('neomorphic activity', 'CPA', (102, 121))	('IDH1', 'Gene', '3417', (125, 129))	('IDH1', 'Gene', (45, 49))	('IDH1', 'Gene', (125, 129))	('mutation', 'Var', (50, 58))
99955	26858939	Initially, a pivotal study profiling IDH1 wild-type and mutant glioblastoma cells with liquid chromatography-mass spectrometry has reported high levels of the metabolite 2-HG in mutant cells.	('mutant', 'Var', (178, 184))	('mutant', 'Var', (56, 62))	('glioblastoma', 'Disease', (63, 75))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))	('2-HG', 'Chemical', 'MESH:C019417', (170, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))
99956	26858939	Then, it has been demonstrated that mutant IDH1 catalyzes the reduction of alpha-KG to the R-enantiomer of the metabolite 2-HG (R-2-HG).	('2-HG', 'Chemical', 'MESH:C019417', (122, 126))	('IDH1', 'Gene', (43, 47))	('alpha-KG', 'Chemical', 'MESH:D007656', (75, 83))	('mutant', 'Var', (36, 42))	('IDH1', 'Gene', '3417', (43, 47))	('alpha-KG', 'Protein', (75, 83))	('reduction', 'NegReg', (62, 71))	('2-HG', 'Chemical', 'MESH:C019417', (130, 134))
99957	26858939	Thus, rather than catalyze the NADP+-dependent production of alpha-KG, mutant IDH1 catalyzes the NADPH-dependent reduction of alpha-KG to produce only the R-enantiomer of 2-HG, indicating a gain of neomorphic function.	('2-HG', 'Chemical', 'MESH:C019417', (171, 175))	('IDH1', 'Gene', (78, 82))	('alpha-KG', 'Chemical', 'MESH:D007656', (61, 69))	('NADPH', 'Chemical', 'MESH:D009249', (97, 102))	('NADP+', 'Chemical', 'MESH:D009249', (31, 36))	('mutant', 'Var', (71, 77))	('gain', 'PosReg', (190, 194))	('IDH1', 'Gene', '3417', (78, 82))	('neomorphic function', 'CPA', (198, 217))	('alpha-KG', 'Chemical', 'MESH:D007656', (126, 134))
99958	26858939	Specifically, authors have demonstrated that the mutation reduces the affinity of the IDH1 active site for isocitrate while concomitantly increasing it for NADPH and alpha-KG.	('reduces', 'NegReg', (58, 65))	('IDH1', 'Gene', (86, 90))	('NADPH', 'MPA', (156, 161))	('isocitrate', 'Chemical', 'MESH:C034219', (107, 117))	('increasing', 'PosReg', (138, 148))	('IDH1', 'Gene', '3417', (86, 90))	('mutation', 'Var', (49, 57))	('affinity', 'MPA', (70, 78))	('NADPH', 'Chemical', 'MESH:D009249', (156, 161))	('alpha-KG', 'Chemical', 'MESH:D007656', (166, 174))
99959	26858939	Reduced affinity for isocitrate occurs as a result of alterations to a binding site residue that forms hydrogen bonds between the alpha and beta groups of isocitrate.	('hydrogen', 'Chemical', 'MESH:D006859', (103, 111))	('isocitrate', 'Chemical', 'MESH:C034219', (21, 31))	('isocitrate', 'Chemical', 'MESH:C034219', (155, 165))	('Reduced', 'NegReg', (0, 7))	('alterations', 'Var', (54, 65))	('affinity', 'MPA', (8, 16))	('hydrogen bonds', 'MPA', (103, 117))
99960	26858939	Consequently, the conversion of alpha-KG is favorized, but rather than isocitrate, the mutant enzyme converts alpha-KG into R-2-HG, an oncometabolite that promotes tumorigenesis through inhibition of alpha-KG-dependent (Figure 1).	('tumor', 'Disease', (164, 169))	('inhibition', 'NegReg', (186, 196))	('2-HG', 'Chemical', 'MESH:C019417', (126, 130))	('alpha-KG', 'Chemical', 'MESH:D007656', (32, 40))	('alpha-KG', 'Chemical', 'MESH:D007656', (200, 208))	('mutant', 'Var', (87, 93))	('promotes', 'PosReg', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('isocitrate', 'Chemical', 'MESH:C034219', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('alpha-KG', 'Chemical', 'MESH:D007656', (110, 118))
99961	26858939	Extensive genomic profiling has revealed that about 90% of IDH1 mutations involve exon 4 at codon 132, replacing arginine with histidine (R132H).	('IDH1', 'Gene', '3417', (59, 63))	('arginine', 'Chemical', 'MESH:D001120', (113, 121))	('R132H', 'Chemical', '-', (138, 143))	('arginine', 'MPA', (113, 121))	('histidine', 'Chemical', 'MESH:D006639', (127, 136))	('mutations', 'Var', (64, 73))	('replacing', 'Reg', (103, 112))	('IDH1', 'Gene', (59, 63))
99962	26858939	Of the remaining 10% of IDH1 mutations, 4.7% are due to arginine being replaced with cysteine (R132C), 2.1% with glycine (R132G), 1.7% with serine (R132S), 0.8% with leucine (R132L), and 0.3% with glutamine (R132Q).	('R132L', 'Mutation', 'rs121913500', (175, 180))	('serine', 'Chemical', 'MESH:D012694', (140, 146))	('IDH1', 'Gene', '3417', (24, 28))	('R132C', 'Mutation', 'rs121913499', (95, 100))	('R132G', 'Mutation', 'rs121913499', (122, 127))	('mutations', 'Var', (29, 38))	('glutamine', 'Chemical', 'MESH:D005973', (197, 206))	('leucine', 'Chemical', 'MESH:D007930', (166, 173))	('R132S', 'Mutation', 'rs121913499', (148, 153))	('IDH1', 'Gene', (24, 28))	('arginine', 'Chemical', 'MESH:D001120', (56, 64))	('cysteine', 'Chemical', 'MESH:D003545', (85, 93))	('glycine', 'Chemical', 'MESH:D005998', (113, 120))	('R132Q', 'Mutation', 'p.R132Q', (208, 213))	('arginine', 'MPA', (56, 64))
99963	26858939	Following the first observation of recurrent IDH1 mutation in glioblastoma, several groups have begun to clarify the frequency and distribution of IDH1 mutation across all brain tumors, including gliomas and other subtypes.	('IDH1', 'Gene', '3417', (45, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('IDH1', 'Gene', '3417', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('glioblastoma', 'Disease', (62, 74))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('brain tumors', 'Phenotype', 'HP:0030692', (172, 184))	('IDH1', 'Gene', (147, 151))	('IDH1', 'Gene', (45, 49))	('gliomas', 'Disease', (196, 203))	('brain tumors', 'Disease', 'MESH:D001932', (172, 184))	('mutation', 'Var', (50, 58))	('brain tumors', 'Disease', (172, 184))
99964	26858939	Data summarized from many studies show that only approximately 5.6% of primary glioblastoma are IDH1 mutant, while more than 76% of secondary glioblastomas carry the IDH1 mutation.	('IDH1', 'Gene', (166, 170))	('IDH1', 'Gene', '3417', (96, 100))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (132, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('IDH1', 'Gene', '3417', (166, 170))	('glioblastomas', 'Phenotype', 'HP:0012174', (142, 155))	('mutant', 'Var', (101, 107))	('primary glioblastoma', 'Disease', 'MESH:D005909', (71, 91))	('glioblastomas', 'Disease', 'MESH:D005909', (142, 155))	('secondary glioblastoma', 'Disease', (132, 154))	('primary glioblastoma', 'Disease', (71, 91))	('IDH1', 'Gene', (96, 100))	('glioblastomas', 'Disease', (142, 155))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
99965	26858939	The reported rates of IDH1 mutation in lower-grade gliomas are comparable with those of secondary glioblastoma (Table 2).	('gliomas', 'Disease', (51, 58))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (88, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('secondary glioblastoma', 'Disease', (88, 110))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
99966	26858939	Other brain tumors harboring IDH1 mutations with moderate frequency include gangliogliomas, giant cell glioblastomas, and primitive neuroectodermal tumors, although only small numbers of these tumors have been studied.	('gangliogliomas', 'Disease', (76, 90))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (122, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (132, 154))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('IDH1', 'Gene', (29, 33))	('brain tumors', 'Disease', 'MESH:D001932', (6, 18))	('brain tumors', 'Phenotype', 'HP:0030692', (6, 18))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (132, 154))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioblastomas', 'Phenotype', 'HP:0012174', (103, 116))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (148, 154))	('neuroectodermal tumors', 'Disease', (132, 154))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('IDH1', 'Gene', '3417', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('giant cell glioblastomas', 'Disease', 'MESH:D005909', (92, 116))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', (193, 199))	('gangliogliomas', 'Disease', 'MESH:D018303', (76, 90))	('giant cell glioblastomas', 'Disease', (92, 116))	('brain tumors', 'Disease', (6, 18))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
99967	26858939	Isocitrate dehydrogenase mutations are also present in some tumors originating in cells outside of the central nervous system.	('mutations', 'Var', (25, 34))	('hydrogen', 'Chemical', 'MESH:D006859', (13, 21))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('present', 'Reg', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
99968	26858939	Indeed, about 7.7% of acute myeloid leukemia (AML) possessed the IDH1 mutation, but prevalence rates vary between 15 and 33% if IDH2 are also considered.	('IDH1', 'Gene', '3417', (65, 69))	('IDH2', 'Gene', '3418', (128, 132))	('acute myeloid leukemia', 'Disease', (22, 44))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (28, 44))	('AML', 'Disease', (46, 49))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (22, 44))	('IDH2', 'Gene', (128, 132))	('mutation', 'Var', (70, 78))	('IDH1', 'Gene', (65, 69))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (22, 44))
99969	26858939	Approximately 50% of d-2-hydroxyglutaric aciduria (d-2-HGA), a rare inherited neurometabolic disorder, has also been found to display IDH1 mutations, as well as 10% of intrahepatic cholangiocarcinomas, 5% of myelodysplastic syndrome (MDS), 8.8% of myeloproliferative neoplasms (MPN), and fewer than 10% of secondary AML.	('neoplasms', 'Phenotype', 'HP:0002664', (267, 276))	('inherited neurometabolic disorder', 'Disease', (68, 101))	('myelodysplastic syndrome', 'Disease', (208, 232))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (168, 200))	('2-HG', 'Chemical', 'MESH:C019417', (53, 57))	('MDS', 'Disease', (234, 237))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (248, 276))	('MPN', 'Disease', (278, 281))	('IDH1', 'Gene', (134, 138))	('MPN', 'Phenotype', 'HP:0005547', (278, 281))	('AML', 'Disease', 'MESH:D015470', (316, 319))	('AML', 'Phenotype', 'HP:0004808', (316, 319))	('AML', 'Disease', (316, 319))	('myeloproliferative neoplasms', 'Disease', (248, 276))	('MPN', 'Disease', 'None', (278, 281))	('inherited neurometabolic disorder', 'Disease', 'MESH:D030342', (68, 101))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (208, 232))	('d-2-HGA', 'Phenotype', 'HP:0012321', (51, 58))	('2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0032278', (23, 49))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (248, 276))	('IDH1', 'Gene', '3417', (134, 138))	('d-2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0012321', (21, 49))	('aciduria', 'Phenotype', 'HP:0012072', (41, 49))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (208, 232))	('MDS', 'Phenotype', 'HP:0002863', (234, 237))	('mutations', 'Var', (139, 148))	('intrahepatic cholangiocarcinomas', 'Disease', (168, 200))	('MDS', 'Disease', 'MESH:D009190', (234, 237))
99971	26858939	The same group has also identified IDH1 mutation to occur in patients with Ollier disease and Maffucci syndrome.	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('Ollier disease', 'Disease', (75, 89))	('Ollier disease', 'Phenotype', 'HP:0500045', (75, 89))	('Maffucci syndrome', 'Disease', (94, 111))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (94, 111))	('IDH1', 'Gene', '3417', (35, 39))	('patients', 'Species', '9606', (61, 69))	('occur', 'Reg', (52, 57))	('Ollier disease', 'Disease', 'MESH:D004687', (75, 89))
99972	26858939	The majority of patients exhibited the R132C IDH1 mutation, in contrast to most secondary glioblastoma, which harbor the R132H mutation.	('IDH1', 'Gene', '3417', (45, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('exhibited', 'Reg', (25, 34))	('patients', 'Species', '9606', (16, 24))	('R132H', 'Chemical', '-', (121, 126))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (80, 102))	('R132C', 'Var', (39, 44))	('secondary glioblastoma', 'Disease', (80, 102))	('IDH1', 'Gene', (45, 49))	('R132C', 'Mutation', 'rs121913499', (39, 44))
99973	26858939	In a relatively short time after the discovery of IDH1 mutation in glioblastoma, a tremendous amount of work has been performed on the clinical relevance of this mutation regarding particularly its applications in the diagnosis, prognosis, and treatment of patients suffering from glioblastoma.	('glioblastoma', 'Disease', (67, 79))	('IDH1', 'Gene', (50, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('glioblastoma', 'Disease', (281, 293))	('IDH1', 'Gene', '3417', (50, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (281, 293))	('clinical', 'Species', '191496', (135, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (281, 293))	('patients', 'Species', '9606', (257, 265))	('mutation', 'Var', (55, 63))
99974	26858939	The determination of IDH1 mutation status is highly relevant for the diagnosis of primary brain tumors, and strongly supports the differential diagnosis between an anaplastic glioma and a glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('glioblastoma', 'Disease', (188, 200))	('mutation', 'Var', (26, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('glioma', 'Disease', (175, 181))	('IDH1', 'Gene', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('brain tumors', 'Phenotype', 'HP:0030692', (90, 102))	('IDH1', 'Gene', '3417', (21, 25))	('primary brain tumors', 'Disease', 'MESH:D001932', (82, 102))	('primary brain tumors', 'Disease', (82, 102))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
99977	26858939	Pyrosequencing is an alternative that allows for rapid high-throughput analysis of IDH1 mutation, and has demonstrated an advantage over classic Sanger sequencing in that it can detect mutated allele frequencies down to 5%.	('mutation', 'Var', (88, 96))	('IDH1', 'Gene', '3417', (83, 87))	('IDH1', 'Gene', (83, 87))
99978	26858939	Through COLD PCR combined with HRM, Boisselier and colleagues were able to detect mutant allele concentrations of 0.25% in a span of only 3 h. However, because the technique requires the new mutation to have a melting temperature (Tm) that is lower than IDH1 wild type, it theoretically may not be able to detect R132G mutation.	('IDH1', 'Gene', '3417', (254, 258))	('R132G', 'Mutation', 'rs121913499', (313, 318))	('R132G', 'Var', (313, 318))	('IDH1', 'Gene', (254, 258))	('mutation', 'Var', (191, 199))
99979	26858939	Other technologies currently in use to detect mutations in the IDH1 gene include SNaPshot and Oncomap, both of which can be used with paraffin-embedded tissue, using base pair extension that results in an allele-specific probe that is read out by either fluorescence detection (SNaPshot) or mass spectrometry (Oncomap).	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (63, 67))	('mutations', 'Var', (46, 55))	('paraffin', 'Chemical', 'MESH:D010232', (134, 142))
99980	26858939	In addition to these approaches, Boisselier and colleagues demonstrated evidence of principle in detection of IDH1 mutations from the plasma of patients with mutant glioma.	('IDH1', 'Gene', '3417', (110, 114))	('mutations', 'Var', (115, 124))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('patients', 'Species', '9606', (144, 152))	('IDH1', 'Gene', (110, 114))	('glioma', 'Disease', (165, 171))
99981	26858939	Further work on the nature of circulating tumor material will be necessary to determine whether it will be possible to monitor the IDH1 mutation status in the peripheral blood of all patients with mutant gliomas.	('tumor', 'Disease', (42, 47))	('IDH1', 'Gene', (131, 135))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('IDH1', 'Gene', '3417', (131, 135))	('mutant', 'Var', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('patients', 'Species', '9606', (183, 191))
99982	26858939	Recently, a new technique called amplification-refractory mutation system (ARMS) has been developed to identify R140Q mutations in IDH2 and such novel methods can be of great help in detecting IDH1 mutations.	('IDH1', 'Gene', (193, 197))	('IDH2', 'Gene', (131, 135))	('R140Q', 'Mutation', 'rs121913502', (112, 117))	('IDH2', 'Gene', '3418', (131, 135))	('IDH1', 'Gene', '3417', (193, 197))	('R140Q', 'Var', (112, 117))
99983	26858939	Recently, a novel strategy of PCR clamping was employed for qualitative detection of seven different mutations in IDH1 and five mutations in IDH2 in a single PCR assay.	('IDH1', 'Gene', (114, 118))	('mutations', 'Var', (101, 110))	('IDH2', 'Gene', '3418', (141, 145))	('IDH1', 'Gene', '3417', (114, 118))	('IDH2', 'Gene', (141, 145))
99984	26858939	A monoclonal antibody specific for the IDH-R132H mutation (mIDH1R132H), developed by Capper's group, recognizes the mutant protein with a high degree of sensitivity and specificity.	('R132H', 'Chemical', '-', (64, 69))	('IDH', 'Gene', (60, 63))	('mutant', 'Var', (116, 122))	('IDH', 'Gene', (39, 42))	('R132H', 'Chemical', '-', (43, 48))	('IDH', 'Gene', '3417', (60, 63))	('protein', 'Protein', (123, 130))	('IDH', 'Gene', '3417', (39, 42))
99985	26858939	Using this antibody, 90% of IDH1 mutation can be detected on paraffin sections, and it is recommended to test the remaining 10% by sequencing.	('paraffin', 'Chemical', 'MESH:D010232', (61, 69))	('mutation', 'Var', (33, 41))	('IDH1', 'Gene', '3417', (28, 32))	('IDH1', 'Gene', (28, 32))
99986	26858939	Nevertheless, proponents of immunohistochemistry-based antibody staining argue that the use of mIDH1R132H antibody to identify IDH1 mutation may even be superior to direct sequencing because there are reported cases in which this antibody detects mutations missed by direct sequencing.	('IDH1', 'Gene', '3417', (96, 100))	('mutation', 'Var', (132, 140))	('IDH1', 'Gene', (127, 131))	('IDH1', 'Gene', '3417', (127, 131))	('IDH1', 'Gene', (96, 100))
99988	26858939	Indeed, seeing that IDH1 mutations are specific to gliomas, this antibody can be used to help differentiate between diffuse gliomas and areas of reactive gliosis.	('gliomas', 'Disease', (51, 58))	('gliomas', 'Disease', (124, 131))	('mutations', 'Var', (25, 34))	('IDH1', 'Gene', '3417', (20, 24))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliosis', 'Disease', (154, 161))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('gliosis', 'Phenotype', 'HP:0002171', (154, 161))	('IDH1', 'Gene', (20, 24))	('gliosis', 'Disease', 'MESH:D005911', (154, 161))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
99993	26858939	In theory, sensitive and specific detection of 2-HG is sequence independent in that 2-HG should be present regardless of the type of mutation in IDH1 or IDH2.	('IDH2', 'Gene', (153, 157))	('2-HG', 'Chemical', 'MESH:C019417', (47, 51))	('mutation', 'Var', (133, 141))	('IDH1', 'Gene', (145, 149))	('IDH2', 'Gene', '3418', (153, 157))	('IDH1', 'Gene', '3417', (145, 149))	('2-HG', 'Chemical', 'MESH:C019417', (84, 88))
99998	26858939	Detection of 2-HG by MRS represents a completed non-invasive method with which to determine the presence of IDH mutations in gliomas, irrespective of the sequence of the mutation or the mutation maps to IDH1 or IDH2.	('IDH', 'Gene', (203, 206))	('gliomas', 'Disease', (125, 132))	('IDH2', 'Gene', (211, 215))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (203, 206))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('IDH', 'Gene', (211, 214))	('IDH', 'Gene', '3417', (108, 111))	('mutations', 'Var', (112, 121))	('IDH2', 'Gene', '3418', (211, 215))	('IDH', 'Gene', '3417', (211, 214))	('IDH1', 'Gene', (203, 207))	('IDH1', 'Gene', '3417', (203, 207))	('2-HG', 'Chemical', 'MESH:C019417', (13, 17))
100006	26858939	Extensive research has been performed to determine the prognostic value of IDH1 mutations, and a better prognosis has been generally reported in glioblastoma patients carrying an IDH1 mutation.	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('mutations', 'Var', (80, 89))	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', (75, 79))	('IDH1', 'Gene', (179, 183))	('glioblastoma', 'Disease', (145, 157))	('patients', 'Species', '9606', (158, 166))	('IDH1', 'Gene', '3417', (179, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))	('mutation', 'Var', (184, 192))
100007	26858939	Studies have shown that IDH1 mutation convey an improved prognosis with respect to both overall survival and progression-free survival for the rare glioblastoma patients who express this mutation.	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (24, 28))	('improved', 'PosReg', (48, 56))	('patients', 'Species', '9606', (161, 169))	('IDH1', 'Gene', (24, 28))	('glioblastoma', 'Disease', (148, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (148, 160))
100008	26858939	Indeed, since the publication of the first report on improved survival in glioblastoma patients with mutation by Parsons and colleagues, indicating 45.6 months overall survival in IDH1-mutant versus 13.2 months overall survival in IDH1 wild type, numerous groups have been able to replicate similar findings.	('glioblastoma', 'Disease', (74, 86))	('IDH1', 'Gene', (180, 184))	('IDH1', 'Gene', (231, 235))	('mutation', 'Var', (101, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('IDH1', 'Gene', '3417', (180, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('IDH1', 'Gene', '3417', (231, 235))	('improved', 'PosReg', (53, 61))	('patients', 'Species', '9606', (87, 95))
100009	26858939	were able to demonstrate improved progressive-free survival (PFS) as well in their set of patients with glioblastoma, with 55 months PFS in patients with IDH1 mutation versus 8.8 months PFS in those without this mutation.	('improved', 'PosReg', (25, 33))	('glioblastoma', 'Disease', (104, 116))	('progressive-free survival', 'CPA', (34, 59))	('mutation', 'Var', (159, 167))	('IDH1', 'Gene', (154, 158))	('patients', 'Species', '9606', (140, 148))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('IDH1', 'Gene', '3417', (154, 158))	('patients', 'Species', '9606', (90, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))
100010	26858939	The analysis was extended to anaplastic (WHO grade III) tumors because many groups were readily able to show an improved overall survival in grade III tumors that harbored the IDH1 mutation compared with those that did not in both univariate and multivariate analyses.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('IDH1', 'Gene', '3417', (176, 180))	('tumors', 'Disease', (56, 62))	('overall', 'MPA', (121, 128))	('mutation', 'Var', (181, 189))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('improved', 'PosReg', (112, 120))	('IDH1', 'Gene', (176, 180))
100011	26858939	With anaplastic astrocytomas, patients harboring IDH1 mutation had an overall survival of 65 months compared to 20 months for patients without IDH1 mutation.	('mutation', 'Var', (54, 62))	('IDH1', 'Gene', '3417', (49, 53))	('IDH1', 'Gene', (143, 147))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (5, 28))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (126, 134))	('anaplastic astrocytomas', 'Disease', (5, 28))	('astrocytoma', 'Phenotype', 'HP:0009592', (16, 27))	('IDH1', 'Gene', '3417', (143, 147))	('IDH1', 'Gene', (49, 53))
100012	26858939	The survival benefit also extended to grade II gliomas, showing a median overall survival of 12.6 years in patients with IDH1 mutation versus 5.5 years in patients devoid of this mutation.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('II gliomas', 'Disease', (44, 54))	('IDH1', 'Gene', (121, 125))	('IDH1', 'Gene', '3417', (121, 125))	('grade', 'Disease', (38, 43))	('mutation', 'Var', (126, 134))	('II gliomas', 'Disease', 'MESH:D005910', (44, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (107, 115))
100013	26858939	In a prospective analysis, Wick and colleagues found that grade III astrocytomas that possessed the IDH1 mutation were associated with greater PFS regardless of the treatment.	('mutation', 'Var', (105, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('IDH1', 'Gene', '3417', (100, 104))	('astrocytomas', 'Disease', (68, 80))	('greater', 'PosReg', (135, 142))	('IDH1', 'Gene', (100, 104))	('PFS', 'Disease', (143, 146))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))
100014	26858939	In studies pooling low-grade astrocytomas and oligodendrogliomas, the IDH1 mutation status was prognostic for overall and PFS.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('astrocytomas', 'Disease', (29, 41))	('oligodendrogliomas', 'Disease', (46, 64))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (46, 64))	('mutation', 'Var', (75, 83))	('IDH1', 'Gene', '3417', (70, 74))	('prognostic', 'Reg', (95, 105))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('astrocytoma', 'Phenotype', 'HP:0009592', (29, 40))	('astrocytomas', 'Disease', 'MESH:D001254', (29, 41))	('IDH1', 'Gene', (70, 74))
100015	26858939	In primary glioblastoma, IDH1 mutational status has been reported to be the only factor that showed significant association with patient survival times.	('association', 'Interaction', (112, 123))	('primary glioblastoma', 'Disease', (3, 23))	('IDH1', 'Gene', '3417', (25, 29))	('IDH1', 'Gene', (25, 29))	('mutational status', 'Var', (30, 47))	('primary glioblastoma', 'Disease', 'MESH:D005909', (3, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (11, 23))	('patient', 'Species', '9606', (129, 136))
100016	26858939	However, the evidence for low-grade gliomas and the prognostic value of IDH1 mutation is slightly more controversial.	('IDH1', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('gliomas', 'Disease', (36, 43))	('IDH1', 'Gene', '3417', (72, 76))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
100017	26858939	Two independent groups found that IDH1 mutations in low-grade gliomas were associated with significant improved overall survival, whereas others could not find any significant association.	('IDH1', 'Gene', '3417', (34, 38))	('gliomas', 'Disease', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('improved', 'PosReg', (103, 111))	('mutations', 'Var', (39, 48))	('overall survival', 'MPA', (112, 128))	('IDH1', 'Gene', (34, 38))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
100018	26858939	Nevertheless, the consistent finding of a more favorable outcome of diffuse gliomas patients with IDH1 mutation implies that IDH1 testing might be useful for prognostic considerations in the clinical setting.	('gliomas', 'Disease', (76, 83))	('patients', 'Species', '9606', (84, 92))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('IDH1', 'Gene', '3417', (125, 129))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('clinical', 'Species', '191496', (191, 199))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('more', 'PosReg', (42, 46))	('IDH1', 'Gene', (98, 102))	('mutation', 'Var', (103, 111))	('IDH1', 'Gene', '3417', (98, 102))	('IDH1', 'Gene', (125, 129))
100019	26858939	Isocitrate dehydrogenase 1 mutation was correlated with a higher rate of response to up-front temozolomide in low-grade glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('mutation', 'Var', (27, 35))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('patients', 'Species', '9606', (127, 135))	('response to up-front temozolomide', 'MPA', (73, 106))	('glioma', 'Disease', (120, 126))	('higher', 'PosReg', (58, 64))	('temozolomide', 'Chemical', 'MESH:D000077204', (94, 106))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
100020	26858939	Furthermore, evidence for differential responsiveness to genotoxic therapy of IDH1 mutant versus IDH1 wild-type low-grade gliomas has been provided.	('IDH1', 'Gene', (97, 101))	('mutant', 'Var', (83, 89))	('IDH1', 'Gene', (78, 82))	('IDH1', 'Gene', '3417', (97, 101))	('IDH1', 'Gene', '3417', (78, 82))	('gliomas', 'Disease', (122, 129))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
100021	26858939	Indeed, the presence of IDH1 mutation was associated with favorable progression-free and overall survival in WHO grade II gliomas who received radio- or chemotherapy.	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (24, 28))	('II gliomas', 'Disease', (119, 129))	('presence', 'Var', (12, 20))	('progression-free', 'Disease', (68, 84))	('II gliomas', 'Disease', 'MESH:D005910', (119, 129))	('IDH1', 'Gene', (24, 28))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('favorable', 'PosReg', (58, 67))	('overall survival', 'CPA', (89, 105))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
100022	26858939	Current studies aim to validate and clarify the predictive value of IDH1 mutation in the different glioma types.	('IDH1', 'Gene', (68, 72))	('glioma', 'Disease', (99, 105))	('IDH1', 'Gene', '3417', (68, 72))	('mutation', 'Var', (73, 81))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
100024	26858939	Houillier and colleagues stratified a cohort of low-grade gliomas into three groups based on prognostic factors according to the presence of 1p19q deletion, IDH1 mutation, or both together.	('1p19q deletion', 'Var', (141, 155))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1', 'Gene', (157, 161))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('mutation', 'Var', (162, 170))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('IDH1', 'Gene', '3417', (157, 161))
100026	26858939	Objective response was in 80% with both mutations, 61% of IDH1-mutants without 1p19q deletion, and 17% without either mutation.	('mutations', 'Var', (40, 49))	('IDH1', 'Gene', '3417', (58, 62))	('Objective response', 'CPA', (0, 18))	('IDH1', 'Gene', (58, 62))
100027	26858939	In a similar fashion, Hartman and colleagues found that, in their cohort of patients receiving adjuvant therapy, IDH1 mutation status was the single most important predictor of PFS and overall survival.	('overall survival', 'CPA', (185, 201))	('patients', 'Species', '9606', (76, 84))	('mutation status', 'Var', (118, 133))	('PFS', 'Disease', (177, 180))	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (113, 117))
100029	26858939	These findings support the notion that IDH1 mutation may be an important predictor to treatment response.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
100030	26858939	The identification of IDH1 mutation and the rapid characterization of its protein products present a therapeutic opportunity to treat the IDH1-mutant tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('IDH1', 'Gene', '3417', (138, 142))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('IDH1', 'Gene', '3417', (22, 26))	('IDH1', 'Gene', (138, 142))
100032	26858939	Although there are no published studies to date addressing this possibility, one study performed by Jin and colleagues suggested that mutant tumor cells may depend on the continued expression of the mutant enzyme and/or its resulting 2-HG metabolite.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('2-HG metabolite', 'MPA', (234, 249))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('2-HG', 'Chemical', 'MESH:C019417', (234, 238))	('tumor', 'Disease', (141, 146))	('enzyme', 'Enzyme', (206, 212))	('mutant', 'Var', (134, 140))	('mutant', 'Var', (199, 205))
100033	26858939	In their investigation, the authors showed that a cell line expressing endogenous mutant IDH1 required its expression for survival and anchorage-independent growth, suggesting that pharmacological inhibition of mutant IDH1 may recapitulate this result.	('mutant', 'Var', (82, 88))	('IDH1', 'Gene', (218, 222))	('mutant', 'Var', (211, 217))	('IDH1', 'Gene', '3417', (218, 222))	('IDH1', 'Gene', (89, 93))	('IDH1', 'Gene', '3417', (89, 93))
100035	26858939	It may be anticipated that inhibition of this pathway would increase patient survival.	('inhibition', 'Var', (27, 37))	('patient', 'Species', '9606', (69, 76))	('patient survival', 'CPA', (69, 85))	('increase', 'PosReg', (60, 68))
100036	26858939	Although there has been some discussion of whether it is prudent to inhibit mutant IDH1 because patients with mutant tumors have a better survival than patients with wild-type tumors, it is not expected that inhibiting the mutant enzyme would make mutant tumors behave like their more aggressive wild-type counterparts.	('IDH1', 'Gene', '3417', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (255, 261))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('better', 'PosReg', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutant', 'Var', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumors', 'Disease', (117, 123))	('mutant', 'Var', (110, 116))	('inhibit', 'NegReg', (68, 75))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('survival', 'CPA', (138, 146))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (152, 160))	('IDH1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutant', 'Var', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('tumors', 'Disease', (176, 182))
100038	26858939	Epigenetic is the mitotically heritable changes in gene expression that are not due to changes in the DNA sequence, and has emerged as hallmark of human cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
100039	26858939	Indeed, aberrant epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, or altered non-coding RNA expression, are currently recognized as relevant events in tumor formation.	('DNA methylation', 'Var', (48, 63))	('tumor', 'Disease', (195, 200))	('histone', 'MPA', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
100040	26858939	Until now, most studies about the epigenetic changes in glioblastoma have focused on DNA methylation, including hypermethylation, gene-specific hypomethylation, and genome-wide hypomethylation.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('hypomethylation', 'Var', (144, 159))	('glioblastoma', 'Disease', (56, 68))	('hypermethylation', 'Var', (112, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))
100041	26858939	The leading mechanism attributed to the observed hypermethylation phenotype in IDH1 mutant involves silencing of the alpha-KG-dependent DNA modifying enzyme, Tet methylcytosine dioxygenase 2 (TET2) (Figure 1).	('IDH1', 'Gene', '3417', (79, 83))	('silencing', 'NegReg', (100, 109))	('Tet methylcytosine dioxygenase 2', 'Gene', (158, 190))	('mutant', 'Var', (84, 90))	('TET2', 'Gene', '54790', (192, 196))	('hypermethylation', 'MPA', (49, 65))	('TET2', 'Gene', (192, 196))	('IDH1', 'Gene', (79, 83))	('alpha-KG', 'Chemical', 'MESH:D007656', (117, 125))	('Tet methylcytosine dioxygenase 2', 'Gene', '54790', (158, 190))
100042	26858939	Since the first report demonstrating that a subset of glioblastoma exhibits a global decrease in 5-methylcytosine, subsequent follow-up studies have revealed not only that genome-wide or global hypomethylation occurs at a frequency of 80% in primary glioblastoma, but also that the level of hypomethylation varies between glioblastomas, ranging from near normal levels to approximately 50% of normal in about 20% of cases.	('glioblastoma', 'Disease', (322, 334))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('glioblastoma', 'Disease', 'MESH:D005909', (250, 262))	('glioblastomas', 'Disease', 'MESH:D005909', (322, 335))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('glioblastoma', 'Disease', 'MESH:D005909', (322, 334))	('5-methylcytosine', 'MPA', (97, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (250, 262))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (97, 113))	('glioblastomas', 'Disease', (322, 335))	('primary glioblastoma', 'Disease', 'MESH:D005909', (242, 262))	('decrease', 'NegReg', (85, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (322, 334))	('primary glioblastoma', 'Disease', (242, 262))	('glioblastoma', 'Disease', (250, 262))	('hypomethylation', 'Var', (194, 209))	('glioblastomas', 'Phenotype', 'HP:0012174', (322, 335))	('glioblastoma', 'Disease', (54, 66))
100044	26858939	Moreover, glioblastoma with hypomethylated Sat2 also harbored copy number alterations of adjacent euchromatic sequences, specifically near the pericentromeric region of chromosome 1.	('glioblastoma', 'Disease', (10, 22))	('Sat2', 'Gene', (43, 47))	('alterations', 'Reg', (74, 85))	('copy number', 'Var', (62, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (10, 22))	('hypomethylated', 'Var', (28, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))	('harbored', 'Reg', (53, 61))
100045	26858939	These data suggest that one consequence of hypomethylated repetitive sequences in glioblastoma is predisposition to chromosomal breakage and copy number alteration.	('chromosomal breakage', 'CPA', (116, 136))	('glioblastoma', 'Disease', (82, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('hypomethylated repetitive sequences', 'Var', (43, 78))	('copy number alteration', 'CPA', (141, 163))	('predisposition to chromosomal breakage', 'Phenotype', 'HP:0040012', (98, 136))
100046	26858939	Although the full consequences of genomic hypomethylation are unknown, murine models of defective imprinting provide evidence for a causal role of DNA methylation alteration in tumorigenesis.	('murine', 'Species', '10090', (71, 77))	('DNA', 'Gene', (147, 150))	('methylation alteration', 'Var', (151, 173))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('alteration', 'Var', (163, 173))
100048	26858939	Hypermethylation of CpG islands in the promoter regions of tumor-suppressor genes is a major event in the origin of many cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
100051	26858939	Promoter hypermethylation has been demonstrated to regulate the oncogenic and proliferation-promoting transforming growth factor (TGF)-beta signaling pathway in aggressive, highly proliferative glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (194, 207))	('TGF', 'Gene', '7040', (130, 133))	('TGF', 'Gene', (130, 133))	('glioblastomas', 'Disease', (194, 207))	('glioblastoma', 'Phenotype', 'HP:0012174', (194, 206))	('regulate', 'Reg', (51, 59))	('glioblastomas', 'Phenotype', 'HP:0012174', (194, 207))	('oncogenic', 'CPA', (64, 73))	('Promoter hypermethylation', 'Var', (0, 25))
100054	26858939	However, epigenetic silencing of PDGF-B can override the increased proliferative effects of TGF-beta signaling.	('PDGF-B', 'Gene', (33, 39))	('proliferative', 'CPA', (67, 80))	('TGF-beta', 'Gene', '7040', (92, 100))	('PDGF-B', 'Gene', '5155', (33, 39))	('override', 'PosReg', (44, 52))	('epigenetic silencing', 'Var', (9, 29))	('TGF-beta', 'Gene', (92, 100))
100055	26858939	Specifically, PDGF-B promoter hypermethylation prevents PDGF-B transcriptional activation by TGF-beta-induced Smad proteins.	('transcriptional', 'MPA', (63, 78))	('PDGF-B', 'Gene', (14, 20))	('PDGF-B', 'Gene', (56, 62))	('TGF-beta', 'Gene', '7040', (93, 101))	('PDGF-B', 'Gene', '5155', (14, 20))	('TGF-beta', 'Gene', (93, 101))	('PDGF-B', 'Gene', '5155', (56, 62))	('prevents', 'NegReg', (47, 55))	('activation', 'PosReg', (79, 89))	('hypermethylation', 'Var', (30, 46))
100056	26858939	The oncogenic effect of the TGF-beta pathway is, therefore, blocked by epigenetic alteration of one of its targets.	('TGF-beta', 'Gene', (28, 36))	('blocked', 'NegReg', (60, 67))	('epigenetic alteration', 'Var', (71, 92))	('oncogenic effect', 'CPA', (4, 20))	('TGF-beta', 'Gene', '7040', (28, 36))
100057	26858939	Genes involved in invasion and metastasis can also be affected by promoter hypermethylation in glioblastoma.	('affected', 'Reg', (54, 62))	('promoter hypermethylation', 'Var', (66, 91))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))
100058	26858939	Approximately 87% of glioblastoma exhibit CpG hypermethylation of the protocadherin-gamma subfamily A11 (PCDH-gamma-A11) gene, which is thought to be important in invasion of cancer cells into normal brain parenchyma.	('PCDH-gamma-A11', 'Gene', (105, 119))	('protocadherin-gamma subfamily A11', 'Gene', '56105', (70, 103))	('protocadherin-gamma subfamily A11', 'Gene', (70, 103))	('glioblastoma', 'Disease', (21, 33))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('PCDH-gamma-A11', 'Gene', '56105', (105, 119))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('hypermethylation', 'Var', (46, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
100059	26858939	The hypermethylation of promoter can also modulate sensitivity to drugs and radiotherapy in glioblastoma.	('sensitivity to drugs', 'MPA', (51, 71))	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('modulate', 'Reg', (42, 50))	('hypermethylation', 'Var', (4, 20))
100061	26858939	This suggests that epigenetic profiling might be one way to categorize glioblastomas and to rationally apply patient-specific therapy.	('patient', 'Species', '9606', (109, 116))	('glioblastomas', 'Disease', 'MESH:D005909', (71, 84))	('glioblastomas', 'Disease', (71, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('epigenetic', 'Var', (19, 29))	('glioblastomas', 'Phenotype', 'HP:0012174', (71, 84))
100067	26858939	Large-scale sequencing of protein-coding genes in glioblastoma revealed mutations in many genes involved in epigenetic regulation, including HDACs, HDAC2 and HDAC9, histone demethylases, JMD1A and JMD1B, histone methyltransferases, SET7, SETD7, MLL, MLL4, and methyl-CpG binding domain protein1 (MBD1).	('MBD1', 'Gene', '4152', (296, 300))	('HDAC2', 'Gene', '3066', (148, 153))	('HDAC2', 'Gene', (148, 153))	('methyl-CpG binding domain protein1', 'Gene', (260, 294))	('mutations', 'Var', (72, 81))	('MLL4', 'Gene', '9757', (250, 254))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('SET7', 'Gene', (232, 236))	('methyl-CpG binding domain protein1', 'Gene', '4152', (260, 294))	('SETD7', 'Gene', '80854', (238, 243))	('MLL', 'Gene', (245, 248))	('glioblastoma', 'Disease', (50, 62))	('MLL', 'Gene', '4297', (245, 248))	('MLL4', 'Gene', (250, 254))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('MLL', 'Gene', '4297', (250, 253))	('MLL', 'Gene', (250, 253))	('MBD1', 'Gene', (296, 300))	('SETD7', 'Gene', (238, 243))	('HDAC9', 'Gene', '9734', (158, 163))	('SET7', 'Gene', '80854', (232, 236))	('HDAC9', 'Gene', (158, 163))
100069	26858939	Following the discovery of IDH1 mutation, our understanding of the biochemistry, genetics, and epigenetics as well as the prevalence and pathogenic role of this mutation has grown at a rapid rate, and a tremendous amount of work has been performed on its translational relevance in a relative short time.	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))	('IDH1', 'Gene', (27, 31))
100070	26858939	It is, henceforth, clear that IDH1 status is a major determinant of survival, and many ways have been developed to identify the IDH mutation as well as the oncometabolite 2-HG from clinical samples, using non-invasive procedures.	('2-HG', 'Chemical', 'MESH:C019417', (171, 175))	('IDH', 'Gene', (128, 131))	('IDH1', 'Gene', (30, 34))	('IDH', 'Gene', '3417', (128, 131))	('IDH', 'Gene', (30, 33))	('clinical samples', 'Species', '191496', (181, 197))	('mutation', 'Var', (132, 140))	('IDH', 'Gene', '3417', (30, 33))	('IDH1', 'Gene', '3417', (30, 34))
100072	26525348	Targeted Therapy for MAPK Alterations in Pediatric Gliomas Although the mitogen-activated protein kinase (MAPK) pathway helps promote normal cell development, the pathway is known to contribute to the initiation and growth of many types of cancers.	('Gliomas', 'Disease', (51, 58))	('MAPK', 'Gene', (106, 110))	('MAPK', 'Gene', (21, 25))	('MAPK', 'Gene', '5595;5594;5595', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('MAPK', 'Gene', '5595;5594;5595', (21, 25))	('promote', 'PosReg', (126, 133))	('normal cell development', 'CPA', (134, 157))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('Glioma', 'Phenotype', 'HP:0009733', (51, 57))	('Gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('Gliomas', 'Disease', 'MESH:D005910', (51, 58))	('Alterations', 'Var', (26, 37))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('contribute', 'Reg', (183, 193))
100073	26525348	Tumorigenesis can result from mutations in a number of the pathway's key proteins, including but not limited to RAS, any one of the three RAF kinases, or MEK1/2.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RAF', 'Gene', '22882', (138, 141))	('RAF', 'Gene', (138, 141))	('Tumorigenesis', 'CPA', (0, 13))	('mutations', 'Var', (30, 39))	('MEK1/2', 'Gene', '5604;5605', (154, 160))	('result from', 'Reg', (18, 29))	('MEK1/2', 'Gene', (154, 160))
100075	26525348	We first describe the biology of gliomas and oncogenic mutations in the MAPK pathway and then summarize notable pre-clinical data and clinical trials for these targeted therapies.	('mutations', 'Var', (55, 64))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('MAPK', 'Gene', '5595;5594;5595', (72, 76))	('MAPK', 'Gene', (72, 76))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
100089	26525348	Patients with neurofibromatosis type 1 (NF-1), an autosomal dominant inherited genetic syndrome caused by the deletion/inactivation of NF1-a gene that codes for neurofibromin1 - a negative regulator of the RAS/mTOR pathway, are predisposed to developing many types of benign and malignant neural tumors.	('mTOR', 'Gene', (210, 214))	('malignant neural tumors', 'Phenotype', 'HP:0100697', (279, 302))	('neurofibromin1', 'Gene', (161, 175))	('neurofibromatosis type 1', 'Gene', (14, 38))	('mTOR', 'Gene', '2475', (210, 214))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (14, 31))	('genetic syndrome', 'Disease', (79, 95))	('Patients', 'Species', '9606', (0, 8))	('NF1-a', 'Gene', '4784', (135, 140))	('caused by', 'Reg', (96, 105))	('NF1-a', 'Gene', (135, 140))	('genetic syndrome', 'Disease', 'MESH:D030342', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('neurofibromatosis type 1', 'Gene', '4763', (14, 38))	('malignant neural tumors', 'Disease', (279, 302))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('NF-1', 'Gene', '4763', (40, 44))	('neurofibromin1', 'Gene', '4763', (161, 175))	('malignant neural tumors', 'Disease', 'MESH:C536149', (279, 302))	('NF-1', 'Gene', (40, 44))	('deletion/inactivation', 'Var', (110, 131))
100094	26525348	showed that approximately 25% of sporadic pediatric glioblastomas contain inactivating NF1 mutations.	('NF1', 'Gene', '4763', (87, 90))	('inactivating', 'Var', (74, 86))	('mutations', 'Var', (91, 100))	('glioblastomas', 'Phenotype', 'HP:0012174', (52, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (52, 65))	('glioblastomas', 'Disease', (52, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('NF1', 'Gene', (87, 90))
100098	26525348	Many mutated BRAF proteins exist, but specifically the oncogenic BRAF fusions and BRAFV600E caused by a missense mutation may prove to be the most prevalent and targetable in pediatric glioma.	('pediatric glioma', 'Disease', (175, 191))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', '673', (13, 17))	('caused by', 'Reg', (92, 101))	('missense mutation', 'Var', (104, 121))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('BRAF', 'Gene', '673', (65, 69))	('BRAFV600E', 'Mutation', 'rs113488022', (82, 91))	('BRAF', 'Gene', (65, 69))	('pediatric glioma', 'Disease', 'MESH:D005910', (175, 191))
100099	26525348	BRAF fusions, occurring in 66% of pilocytic astrocytomas, were demonstrated to arise from the fusion between KIAA1549 and BRAF as a result of a tandem duplication of ~2Mb at 7q34.	('pilocytic astrocytomas', 'Disease', (34, 56))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (34, 56))	('AA', 'Phenotype', 'HP:0009592', (111, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (44, 55))	('tandem duplication of ~2Mb', 'Var', (144, 170))	('arise from', 'Reg', (79, 89))	('result of', 'Reg', (132, 141))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (122, 126))	('BRAF', 'Gene', '673', (0, 4))	('fusion', 'Var', (94, 100))	('BRAF', 'Gene', (0, 4))	('KIAA1549', 'Gene', (109, 117))	('KIAA1549', 'Gene', '57670', (109, 117))
100101	26525348	Among them is a report that pediatric glioma-associated KIAA1549:BRAF fusions may regulate neuroglial cell growth via the mTOR pathway, depending on cell-type.	('pediatric glioma', 'Disease', 'MESH:D005910', (28, 44))	('regulate', 'Reg', (82, 90))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('pediatric glioma', 'Disease', (28, 44))	('BRAF', 'Gene', '673', (65, 69))	('KIAA1549', 'Gene', (56, 64))	('AA', 'Phenotype', 'HP:0009592', (58, 60))	('mTOR', 'Gene', (122, 126))	('KIAA1549', 'Gene', '57670', (56, 64))	('mTOR', 'Gene', '2475', (122, 126))	('BRAF', 'Gene', (65, 69))	('fusions', 'Var', (70, 77))	('neuroglial cell growth', 'CPA', (91, 113))
100105	26525348	However, the expression of KIAA1549:BRAF fusion results in MEK-dependent tuberin inactivation and Rheb-directed TORC1/S6K-mediated p27 phosphorylation and degradation.	('Rheb', 'Gene', (98, 102))	('TORC1', 'Gene', '23373', (112, 117))	('tuberin', 'Gene', '7249', (73, 80))	('degradation', 'MPA', (155, 166))	('tuberin', 'Gene', (73, 80))	('KIAA1549', 'Gene', '57670', (27, 35))	('MEK', 'Gene', '5609', (59, 62))	('phosphorylation', 'MPA', (135, 150))	('BRAF', 'Gene', '673', (36, 40))	('inactivation', 'NegReg', (81, 93))	('AA', 'Phenotype', 'HP:0009592', (29, 31))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', (59, 62))	('KIAA1549', 'Gene', (27, 35))	('fusion', 'Var', (41, 47))	('p27', 'Gene', '3429', (131, 134))	('Rheb', 'Gene', '6009', (98, 102))	('TORC1', 'Gene', (112, 117))	('p27', 'Gene', (131, 134))
100107	26525348	On the other hand, these driving mutations with their divergent pathways stress the importance of developing targeted therapies catered toward specific mutations in the MAPK pathway itself or toward the pathways leading to or from the MAPK pathway.	('mutations', 'Var', (152, 161))	('mutations', 'Var', (33, 42))	('MAPK', 'Gene', '5595;5594;5595', (169, 173))	('MAPK', 'Gene', (235, 239))	('MAPK', 'Gene', (169, 173))	('MAPK', 'Gene', '5595;5594;5595', (235, 239))
100109	26525348	BRAFV600E is one of the most common oncogenic mutations in human cancers, found in approximately 50% of metastatic melanomas, 10% of colon cancer and papillary thyroid cancers.	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('thyroid cancer', 'Phenotype', 'HP:0002890', (160, 174))	('colon cancer', 'Disease', (133, 145))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('melanomas', 'Disease', (115, 124))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (150, 175))	('papillary thyroid cancers', 'Disease', (150, 175))	('BRAFV600E', 'Var', (0, 9))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (150, 174))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('human', 'Species', '9606', (59, 64))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))
100110	26525348	Curiously, BRAFV600E mutant gliomas are most frequently seen in pediatric cases and can be observed in 10% to 75% of all gliomas, varying between the tumor subtypes.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('BRAFV600E', 'Var', (11, 20))	('BRAFV600E', 'Mutation', 'rs113488022', (11, 20))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Disease', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
100111	26525348	For instance, it has been reported that the BRAFV600E mutation is observed in less than 10% of pilocytic astrocytoma and as high as 75% of gangliogliomas.	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('pilocytic astrocytoma', 'Disease', (95, 116))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (95, 116))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('BRAFV600E', 'Var', (44, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
100114	26525348	Part of the enthusiasm surrounding BRAFV600E stems from the success of clinical trials using vemurafenib, a small molecule inhibitor targeting BRAFV600E, for treating melanoma with the BRAFV600E mutation.	('BRAFV600E', 'Mutation', 'rs113488022', (143, 152))	('BRAFV600E', 'Mutation', 'rs113488022', (35, 44))	('BRAFV600E', 'Gene', (143, 152))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('vemurafenib', 'Chemical', 'MESH:D000077484', (93, 104))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('BRAFV600E', 'Var', (185, 194))	('BRAFV600E', 'Mutation', 'rs113488022', (185, 194))
100116	26525348	reported that vemurafenib was associated with a relative reduction of 74% in the risk of either death or disease progression as compared with dacarbazine alone.	('vemurafenib', 'Var', (14, 25))	('reduction', 'NegReg', (57, 66))	('vemurafenib', 'Chemical', 'MESH:D000077484', (14, 25))	('disease progression', 'CPA', (105, 124))	('death', 'Disease', 'MESH:D003643', (96, 101))	('death', 'Disease', (96, 101))	('dacarbazine', 'Chemical', 'MESH:D003606', (142, 153))
100119	26525348	used knockdown studies to conclude that BRAFV600E mutated papillary thyroid carcinoma, is susceptible to selective BRAFV600E inhibitors.	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (58, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('BRAFV600E', 'Mutation', 'rs113488022', (115, 124))	('mutated', 'Var', (50, 57))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (68, 85))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('BRAFV600E mutated', 'Var', (40, 57))	('papillary thyroid carcinoma', 'Disease', (58, 85))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (58, 85))
100122	26525348	Using vemurafenib to target colon cancer patients with the same BRAFV600E mutation has shown poor efficacy, which may be due to rapid feedback activation of EGFR.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('EGFR', 'Gene', (157, 161))	('colon cancer', 'Disease', (28, 40))	('vemurafenib', 'Chemical', 'MESH:D000077484', (6, 17))	('patients', 'Species', '9606', (41, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('activation', 'PosReg', (143, 153))	('EGFR', 'Gene', '1956', (157, 161))	('BRAFV600E', 'Var', (64, 73))	('BRAFV600E', 'Mutation', 'rs113488022', (64, 73))
100125	26525348	A recent clinical trial demonstrated that vemurafenib is only partially effective for patients with advanced papillary thyroid cancer harboring the BRAFV600E mutation.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRAFV600E', 'Var', (148, 157))	('papillary thyroid cancer', 'Disease', (109, 133))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (109, 133))	('BRAFV600E', 'Mutation', 'rs113488022', (148, 157))	('vemurafenib', 'Chemical', 'MESH:D000077484', (42, 53))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (109, 133))	('thyroid cancer', 'Phenotype', 'HP:0002890', (119, 133))	('patients', 'Species', '9606', (86, 94))
100132	26525348	Similarly, a retrospective case study of four adult brain tumor patients with BRAFV600E mutated pleomorphic xanthoastrocytoma (PXA) reported 1 progressive disease response, two stable disease responses, and 1 partial response.	('brain tumor', 'Phenotype', 'HP:0030692', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('patients', 'Species', '9606', (64, 72))	('BRAFV600E mutated', 'Var', (78, 95))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('brain tumor', 'Disease', (52, 63))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (96, 125))	('brain tumor', 'Disease', 'MESH:D001932', (52, 63))	('PXA', 'Chemical', '-', (127, 130))	('pleomorphic xanthoastrocytoma', 'Disease', (96, 125))
100133	26525348	As this was a small series of patients, it remains unclear how BRAFV600E mutated PXA and other brain tumors will respond to vemurafenib in the long-term; they may have relatively durable response like melanoma or only transient responses like thyroid and colorectal cancer cells.	('BRAFV600E', 'Mutation', 'rs113488022', (63, 72))	('thyroid', 'Disease', 'MESH:D013959', (243, 250))	('colorectal cancer', 'Disease', 'MESH:D015179', (255, 272))	('brain tumors', 'Phenotype', 'HP:0030692', (95, 107))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('PXA', 'Disease', (81, 84))	('brain tumors', 'Disease', 'MESH:D001932', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('brain tumor', 'Phenotype', 'HP:0030692', (95, 106))	('patients', 'Species', '9606', (30, 38))	('colorectal cancer', 'Disease', (255, 272))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('brain tumors', 'Disease', (95, 107))	('BRAFV600E mutated', 'Var', (63, 80))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma', 'Disease', (201, 209))	('thyroid', 'Disease', (243, 250))	('colorectal cancer', 'Phenotype', 'HP:0003003', (255, 272))	('vemurafenib', 'Chemical', 'MESH:D000077484', (124, 135))	('PXA', 'Chemical', '-', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
100136	26525348	While there will likely be more mutations discovered that drive MAPK activation, the genetic novelty of BRAF mutations, among other proteins in the MAPK pathway, clearly warrant further exploration.	('MAPK', 'Gene', (148, 152))	('mutations', 'Var', (32, 41))	('MAPK', 'Gene', '5595;5594;5595', (148, 152))	('BRAF', 'Gene', '673', (104, 108))	('MAPK', 'Gene', '5595;5594;5595', (64, 68))	('mutations', 'Var', (109, 118))	('BRAF', 'Gene', (104, 108))	('MAPK', 'Gene', (64, 68))	('activation', 'PosReg', (69, 79))
100138	26525348	This research revealed new BRAF-activating mutations and recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar pediatric low grade gliomas.	('FGFR1', 'Gene', (91, 96))	('gliomas', 'Disease', (173, 180))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('FGFR1', 'Gene', '2260', (91, 96))	('NTRK2', 'Gene', (116, 121))	('BRAF', 'Gene', '673', (27, 31))	('mutations', 'Var', (43, 52))	('PTPN11', 'Gene', '5781', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('BRAF', 'Gene', (27, 31))	('activating', 'PosReg', (67, 77))	('NTRK2', 'Gene', '4915', (116, 121))	('PTPN11', 'Gene', (101, 107))
100139	26525348	Overexpression of mutant SHP-2 alone did not elevate levels of phosphorylated ERK in vitro, but the two FGFR1 mutants, either alone or in combination with mutant PTPN11, did lead to upregulation of phosphorlylated ERK.	('mutants', 'Var', (110, 117))	('ERK', 'Gene', '5594', (214, 217))	('SHP-2', 'Gene', (25, 30))	('ERK', 'Gene', '5594', (78, 81))	('SHP-2', 'Gene', '5781', (25, 30))	('ERK', 'Gene', (214, 217))	('ERK', 'Gene', (78, 81))	('PTPN11', 'Gene', '5781', (162, 168))	('upregulation', 'PosReg', (182, 194))	('PTPN11', 'Gene', (162, 168))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (104, 109))
100142	26525348	Aside from the FGFR1 and PTPN11 mutations, each case usually only possessed one pathway alteration.	('FGFR1', 'Gene', '2260', (15, 20))	('PTPN11', 'Gene', '5781', (25, 31))	('PTPN11', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('FGFR1', 'Gene', (15, 20))
100147	26525348	Approximately 50% of the cases of Noonan syndrome (NS), an autosomal dominant, dysmorphic congenital disorder, are associated with mutations of the PTPN11 gene leading to RAS/MAPK pathway activation.	('Noonan syndrome', 'Disease', (34, 49))	('mutations', 'Var', (131, 140))	('MAPK', 'Gene', '5595;5594;5595', (175, 179))	('dysmorphic congenital disorder', 'Disease', (79, 109))	('MAPK', 'Gene', (175, 179))	('PTPN11', 'Gene', '5781', (148, 154))	('Noonan syndrome', 'Disease', 'MESH:D009634', (34, 49))	('associated', 'Reg', (115, 125))	('NS', 'Disease', 'MESH:D009404', (51, 53))	('activation', 'PosReg', (188, 198))	('dysmorphic congenital disorder', 'Disease', 'MESH:D000013', (79, 109))	('PTPN11', 'Gene', (148, 154))
100150	26525348	This report not only describes a novel mutation not previously reported but also implies that the patient's mutation may represent a more powerful activating mutation given the rare association of these mutations with solid tumors.	('solid tumors', 'Disease', (218, 230))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('solid tumors', 'Disease', 'MESH:D009369', (218, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('mutation', 'Var', (108, 116))	('mutations', 'Var', (203, 212))
100151	26525348	used whole-genome, transcriptome, and targeted high-throughput sequencing of pediatric low-grade tumors to discover a few genetic alterations including the KIAA1549-BRAF fusion, new arrangements and amplifications of MYB, and recurrent intragenic duplications of the region of FGFR1.	('FGFR1', 'Gene', (277, 282))	('KIAA1549-BRAF', 'Disease', 'None', (156, 169))	('MYB', 'Gene', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('duplications', 'Var', (247, 259))	('FGFR1', 'Gene', '2260', (277, 282))	('AA', 'Phenotype', 'HP:0009592', (158, 160))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('KIAA1549-BRAF', 'Disease', (156, 169))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('fusion', 'Var', (170, 176))	('MYB', 'Gene', '4602', (217, 220))
100152	26525348	are so powerful that it suggests that, "despite the mutational heterogeneity among different tumors, genetic alterations in LGGs commonly lead to activation of the MAPK-ERK and PI3K pathways".	('ERK', 'Gene', '5594', (169, 172))	('activation', 'PosReg', (146, 156))	('ERK', 'Gene', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MAPK', 'Gene', (164, 168))	('MAPK', 'Gene', '5595;5594;5595', (164, 168))	('genetic alterations', 'Var', (101, 120))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('lead to', 'Reg', (138, 145))	('LGGs', 'Gene', (124, 128))
100156	26525348	For example, attempts to target mutated, upregulated epidermal growth factor receptor (EGFR), the most common genetic aberration associated with malignant glioma and an upstream component of the MAPK pathway, has been largely unsuccessful due to both inherent and acquired resistance.	('epidermal growth factor receptor', 'Gene', '1956', (53, 85))	('EGFR', 'Gene', '1956', (87, 91))	('MAPK', 'Gene', '5595;5594;5595', (195, 199))	('malignant glioma', 'Disease', (145, 161))	('MAPK', 'Gene', (195, 199))	('malignant glioma', 'Disease', 'MESH:D005910', (145, 161))	('EGFR', 'Gene', (87, 91))	('mutated', 'Var', (32, 39))	('upregulated', 'PosReg', (41, 52))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('epidermal growth factor receptor', 'Gene', (53, 85))
100157	26525348	Possible resistance mechanisms to EGFR tyrosine kinase inhibitors include the acquisition of secondary EGFR point mutations, co-activation and/or amplification of other RTKs, or up-regulation of drug efflux pumps.	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', (103, 107))	('drug efflux pumps', 'MPA', (195, 212))	('point mutations', 'Var', (108, 123))	('up-regulation', 'PosReg', (178, 191))	('EGFR', 'Gene', '1956', (34, 38))
100160	26525348	AZD6244 is a selective and ATP-uncompetitive inhibitor of the MAPK pathway.	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('MAPK', 'Gene', '5595;5594;5595', (62, 66))	('MAPK', 'Gene', (62, 66))	('AZD6244', 'Var', (0, 7))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))
100162	26525348	In vitro data on a panel of tumor cell lines showed that cell lines with BRAF or RAS mutations were more likely to be sensitive to AZD6244.	('BRAF', 'Gene', '673', (73, 77))	('tumor', 'Disease', (28, 33))	('sensitive to', 'MPA', (118, 130))	('AZD6244', 'Chemical', 'MESH:C517975', (131, 138))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('RAS', 'Gene', (81, 84))	('BRAF', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
100163	26525348	In vivo data corroborated these findings and suggested that AZD6244 could inhibit proliferation and induce apoptosis and differentiation in the pediatric BRAFV600E mutant glioma xenograft BT-40.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('differentiation', 'CPA', (121, 136))	('BRAFV600E', 'Gene', (154, 163))	('AZD6244', 'Var', (60, 67))	('inhibit', 'NegReg', (74, 81))	('induce', 'PosReg', (100, 106))	('AZD6244', 'Chemical', 'MESH:C517975', (60, 67))	('glioma', 'Disease', (171, 177))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))	('proliferation', 'CPA', (82, 95))	('apoptosis', 'CPA', (107, 116))
100166	26525348	Mice with orthotopic xenografts created from injected AM-38, a BRAFV600E glioblastoma cell line, showed reduced intracranial tumor growth when treated with PLX4720, but wild-type BRAF intracranial tumors treated with PLX4720 had no survival advantage or delay in tumor growth.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('BRAFV600E', 'Mutation', 'rs113488022', (63, 72))	('PLX4720', 'Var', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('intracranial tumor', 'Disease', (112, 130))	('intracranial tumor', 'Disease', 'MESH:D001932', (184, 202))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('BRAF intracranial tumors', 'Disease', 'MESH:D001932', (179, 203))	('intracranial tumor', 'Disease', 'MESH:D001932', (112, 130))	('reduced', 'NegReg', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('AM-38', 'Chemical', '-', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('glioblastoma', 'Disease', (73, 85))	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (125, 130))	('BRAF intracranial tumors', 'Disease', (179, 203))	('tumor', 'Disease', (197, 202))
100167	26525348	Their results indicate a 10% incidence of activating BRAFV600E among pediatric malignant astrocytomas and support the use of BRAFV600E specific inhibitors for patients with the BRAFV600E mutation.	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('activating', 'MPA', (42, 52))	('astrocytomas', 'Disease', 'MESH:D001254', (89, 101))	('BRAFV600E', 'Mutation', 'rs113488022', (125, 134))	('BRAFV600E', 'Var', (53, 62))	('BRAFV600E', 'Mutation', 'rs113488022', (53, 62))	('astrocytomas', 'Disease', (89, 101))	('BRAFV600E', 'Mutation', 'rs113488022', (177, 186))	('patients', 'Species', '9606', (159, 167))
100169	26525348	AZD6244 first entered the clinical trial landscape as a MEK 1/2 inhibitor in two trials.	('MEK 1/2', 'Gene', (56, 63))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))	('AZD6244', 'Var', (0, 7))	('MEK 1/2', 'Gene', '5604;5605', (56, 63))
100170	26525348	One study compared AZD6244 in combination with docetaxel versus docetaxel alone in KRAS-mutated non small cell lung cancer (NSCLC) patients.	('KRAS', 'Gene', (83, 87))	('patients', 'Species', '9606', (131, 139))	('small cell lung cancer', 'Disease', 'MESH:D055752', (100, 122))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('KRAS', 'Gene', '3845', (83, 87))	('AZD6244', 'Var', (19, 26))	('NSCLC', 'Disease', (124, 129))	('small cell lung cancer', 'Disease', (100, 122))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('AZD6244', 'Chemical', 'MESH:C517975', (19, 26))	('docetaxel', 'Chemical', 'MESH:D000077143', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('docetaxel', 'Chemical', 'MESH:D000077143', (64, 73))
100171	26525348	The other trial is sponsored by the National Cancer Institute and is studying the safety and efficacy of AZD6244 for treating patients with mutated BRAF cancers.	('BRAF cancers', 'Disease', (148, 160))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('AZD6244', 'Chemical', 'MESH:C517975', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('BRAF cancers', 'Disease', 'MESH:D009369', (148, 160))	('patients', 'Species', '9606', (126, 134))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('mutated', 'Var', (140, 147))
100175	26525348	Aside from selumetinib, other ongoing clinical trials of BRAFV600E mutant cancers include a study involving vemurafenib and a study involving combination therapy of dabrafenib and trametinib.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('vemurafenib', 'Chemical', 'MESH:D000077484', (108, 119))	('BRAFV600E', 'Var', (57, 66))	('BRAFV600E', 'Mutation', 'rs113488022', (57, 66))	('trametinib', 'Chemical', 'MESH:C560077', (180, 190))	('dabrafenib', 'Chemical', 'MESH:C561627', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('selumetinib', 'Chemical', 'MESH:C517975', (11, 22))
100177	26525348	The latter trial's goal is to determine the overall response rate of orally administered dabrafenib and trametinib in subjects with rare BRAFV600E mutated cancers.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('dabrafenib', 'Chemical', 'MESH:C561627', (89, 99))	('BRAFV600E mutated', 'Var', (137, 154))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('trametinib', 'Chemical', 'MESH:C560077', (104, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (137, 146))	('cancers', 'Disease', (155, 162))
100181	26525348	Patients under 18 years of age with relapsed or refractory BRAFV600E mutation in HGGs, LGGs, Langerhans cell histiocytosis, and other solid tumors were eligible for this study.	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('solid tumors', 'Disease', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HGGs', 'Gene', (81, 85))	('Langerhans cell histiocytosis', 'MPA', (93, 122))	('Patients', 'Species', '9606', (0, 8))	('solid tumors', 'Disease', 'MESH:D009369', (134, 146))	('histiocytosis', 'Phenotype', 'HP:0100727', (109, 122))	('BRAFV600E', 'Var', (59, 68))
100184	26525348	In addition to being relatively well-tolerated with manageable toxicity, dabrafenib appears to be effective for treating BRAFV600E mutated brain tumors.	('BRAFV600E mutated', 'Var', (121, 138))	('brain tumors', 'Disease', 'MESH:D001932', (139, 151))	('brain tumors', 'Phenotype', 'HP:0030692', (139, 151))	('dabrafenib', 'Chemical', 'MESH:C561627', (73, 83))	('BRAFV600E', 'Mutation', 'rs113488022', (121, 130))	('brain tumor', 'Phenotype', 'HP:0030692', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('brain tumors', 'Disease', (139, 151))	('toxicity', 'Disease', 'MESH:D064420', (63, 71))	('toxicity', 'Disease', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))
100185	26525348	As a whole, clinical trials of targeted therapy for MAPK alterations have been promising, but a phase II study of children with recurrent or progressive low-grade astrocytomas yielded unexpected results.	('children', 'Species', '9606', (114, 122))	('MAPK', 'Gene', (52, 56))	('alterations', 'Var', (57, 68))	('astrocytomas', 'Disease', 'MESH:D001254', (163, 175))	('MAPK', 'Gene', '5595;5594;5595', (52, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (163, 174))	('astrocytomas', 'Disease', (163, 175))
100189	26525348	Current scientific research is only beginning to understand MAPK alterations, their effects on tumorigenesis, and how to treat tumors through their targetable mutations.	('MAPK', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('alterations', 'Var', (65, 76))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('MAPK', 'Gene', '5595;5594;5595', (60, 64))	('tumor', 'Disease', (95, 100))
100196	32313423	Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas The emergence of new omics approaches, such as genomic algorithms to identify tumor mutations and molecular modeling tools to predict the three-dimensional structure of proteins, has facilitated the understanding of the dynamic mechanisms involved in the pathogenesis of low-grade gliomas including oligodendrogliomas and astrocytomas.	('TP53', 'Gene', '7157', (42, 46))	('gliomas', 'Disease', (434, 441))	('IDH1', 'Gene', (26, 30))	('gliomas', 'Disease', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (434, 440))	('Gliomas', 'Disease', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (405, 412))	('tumor', 'Disease', (202, 207))	('gliomas', 'Disease', 'MESH:D005910', (434, 441))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('IDH1', 'Gene', '3417', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('gliomas', 'Phenotype', 'HP:0009733', (434, 441))	('TP53', 'Gene', (42, 46))	('Mutations', 'Var', (47, 56))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('Gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Disease', (405, 412))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('glioma', 'Phenotype', 'HP:0009733', (405, 411))	('IDH2', 'Gene', (32, 36))	('IDH2', 'Gene', '3418', (32, 36))	('Oligodendrogliomas and Astrocytomas', 'Disease', 'MESH:D009837', (88, 123))	('oligodendrogliomas and astrocytomas', 'Disease', 'MESH:D009837', (423, 458))	('gliomas', 'Disease', 'MESH:D005910', (405, 412))	('Gliomas', 'Phenotype', 'HP:0009733', (70, 77))
100197	32313423	In this study, we targeted known mutations involved in low-grade gliomas, starting with the sequencing of genomic regions encompassing exon 4 of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) and the four exons (5-6 and 7-8) of TP53 from 32 samples, followed by computational analysis to study the impact of these mutations on the structure and function of 3 proteins IDH1, IDH2, and p53.	('IDH1', 'Gene', '3417', (393, 397))	('mutations', 'Var', (33, 42))	('isocitrate', 'Chemical', 'MESH:C034219', (145, 155))	('IDH2', 'Gene', (211, 215))	('IDH2', 'Gene', '3418', (211, 215))	('isocitrate', 'Chemical', 'MESH:C034219', (183, 193))	('TP53', 'Gene', '7157', (253, 257))	('isocitrate dehydrogenase 1', 'Gene', '3417', (145, 171))	('isocitrate dehydrogenase 1', 'Gene', (145, 171))	('gliomas', 'Disease', (65, 72))	('IDH1', 'Gene', (173, 177))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('p53', 'Gene', '7157', (409, 412))	('IDH2', 'Gene', (399, 403))	('IDH1', 'Gene', (393, 397))	('IDH2', 'Gene', '3418', (399, 403))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH1', 'Gene', '3417', (173, 177))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))	('TP53', 'Gene', (253, 257))	('p53', 'Gene', (409, 412))
100198	32313423	We obtain a mutation that has an effect on the catalytic site of the protein IDH1 as R132H and on the catalytic site of the protein IDH2 as R172M.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('R172M', 'Mutation', 'rs121913503', (140, 145))	('R172M', 'Var', (140, 145))	('IDH2', 'Gene', '3418', (132, 136))	('effect', 'Reg', (33, 39))	('IDH1', 'Gene', (77, 81))	('IDH1', 'Gene', '3417', (77, 81))	('catalytic', 'MPA', (47, 56))	('R132H', 'Var', (85, 90))	('IDH2', 'Gene', (132, 136))
100199	32313423	Other mutations at p53 have been identified as K305N, which is a pathogenic mutation; R175 H, which is a benign mutation; and R158G, which disrupts the structural conformation of the tumor suppressor protein.	('structural conformation', 'MPA', (152, 175))	('R175 H', 'Var', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('R175 H', 'Mutation', 'rs28934578', (86, 92))	('R158G', 'Var', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('tumor', 'Disease', (183, 188))	('R158G', 'Mutation', 'rs770374782', (126, 131))	('K305N', 'Mutation', 'rs200274944', (47, 52))	('disrupts', 'NegReg', (139, 147))	('K305N', 'Var', (47, 52))
100200	32313423	In low-grade gliomas, mutations in IDH1, IDH2, and TP53 may be the key to tumor progression because they have an effect on the function of the protein such as mutations R132H in IDH1 and R172M in IDH2, which change the function of the enzyme alpha-ketoglutarate, or R158G in TP53, which affects the structure of the generated protein, thus their importance in understanding gliomagenesis and for more accurate diagnosis complementary to the anatomical pathology tests.	('IDH1', 'Gene', (35, 39))	('TP53', 'Gene', (275, 279))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('structure', 'MPA', (299, 308))	('IDH2', 'Gene', (196, 200))	('R158G', 'Mutation', 'rs770374782', (266, 271))	('tumor', 'Disease', (74, 79))	('R132H', 'Mutation', 'rs121913500', (169, 174))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('IDH2', 'Gene', '3418', (196, 200))	('function', 'MPA', (127, 135))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('IDH1', 'Gene', '3417', (178, 182))	('TP53', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (242, 261))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Disease', (374, 380))	('mutations R132H', 'Var', (159, 174))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('TP53', 'Gene', '7157', (275, 279))	('glioma', 'Disease', 'MESH:D005910', (374, 380))	('R158G', 'Var', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('R132H', 'Var', (169, 174))	('IDH2', 'Gene', (41, 45))	('R172M', 'Var', (187, 192))	('mutations', 'Var', (22, 31))	('effect', 'Reg', (113, 119))	('R172M', 'Mutation', 'rs121913503', (187, 192))	('IDH2', 'Gene', '3418', (41, 45))	('TP53', 'Gene', '7157', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (374, 380))	('affects', 'Reg', (287, 294))	('gliomas', 'Disease', (13, 20))	('IDH1', 'Gene', (178, 182))	('glioma', 'Disease', (13, 19))
100204	32313423	World Health Organization's updated classification of central nervous system tumors in 2016 insists that the standard diagnostic evaluation of low-grade gliomas should now include a molecular assessment of the genes involved, like the mutations of isocitrate dehydrogenases (IDHs) IDH1 and IDH2 and p53 protein.	('protein', 'Protein', (303, 310))	('central nervous system tumors', 'Disease', (54, 83))	('IDH1', 'Gene', '3417', (281, 285))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (54, 83))	('nervous system tumors', 'Phenotype', 'HP:0004375', (62, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('IDH', 'Gene', '3417', (281, 284))	('gliomas', 'Disease', (153, 160))	('IDH2', 'Gene', (290, 294))	('isocitrate', 'Chemical', 'MESH:C034219', (248, 258))	('IDH2', 'Gene', '3418', (290, 294))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('IDH', 'Gene', (275, 278))	('p53', 'Gene', '7157', (299, 302))	('central nervous system tumors', 'Disease', 'MESH:D016543', (54, 83))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('mutations', 'Var', (235, 244))	('IDH', 'Gene', (290, 293))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('p53', 'Gene', (299, 302))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('IDH', 'Gene', '3417', (275, 278))	('IDH1', 'Gene', (281, 285))	('IDH', 'Gene', (281, 284))	('IDH', 'Gene', '3417', (290, 293))
100207	32313423	Patients with low-grade gliomas including astrocytomas and oligodendrogliomas are characterized by mutations in the active site of IDH1 at position R132 and IDH2 at position R172.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH1', 'Gene', (131, 135))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (42, 77))	('IDH1', 'Gene', '3417', (131, 135))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH2', 'Gene', (157, 161))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (99, 108))	('gliomas', 'Disease', (70, 77))	('IDH2', 'Gene', '3418', (157, 161))	('gliomas', 'Disease', (24, 31))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
100211	32313423	Mutations of p53 in certain residues such as R158G can disrupt the structural and functional properties of the protein to varying degrees and affect the prognosis of patients.	('R158G', 'Mutation', 'rs770374782', (45, 50))	('prognosis', 'CPA', (153, 162))	('affect', 'Reg', (142, 148))	('p53', 'Gene', '7157', (13, 16))	('disrupt', 'NegReg', (55, 62))	('p53', 'Gene', (13, 16))	('R158G', 'Var', (45, 50))	('patients', 'Species', '9606', (166, 174))
100212	32313423	This study aims to identify mutations in the biomarkers that are the most implicated in low-grade gliomas:IDH1, IDH2, TP53:and study the effect of these mutations on the function and structure of the proteins.	('IDH2', 'Gene', (112, 116))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('TP53', 'Gene', '7157', (118, 122))	('IDH1', 'Gene', (106, 110))	('TP53', 'Gene', (118, 122))	('gliomas', 'Disease', (98, 105))	('IDH2', 'Gene', '3418', (112, 116))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('IDH1', 'Gene', '3417', (106, 110))	('mutations', 'Var', (28, 37))
100227	32313423	To identify IDH1, IDH2, and TP53 mutations, the genomic regions encompassing exon 4 of IDH1 and IDH2 and the four exons (5-6 and 7-8) of TP53 were designed by Primer3 (PCR primer design tool version 2.0).	('IDH2', 'Gene', '3418', (96, 100))	('TP53', 'Gene', '7157', (28, 32))	('IDH2', 'Gene', '3418', (18, 22))	('IDH1', 'Gene', (12, 16))	('IDH1', 'Gene', '3417', (87, 91))	('TP53', 'Gene', (28, 32))	('IDH2', 'Gene', (18, 22))	('mutations', 'Var', (33, 42))	('IDH1', 'Gene', '3417', (12, 16))	('TP53', 'Gene', '7157', (137, 141))	('IDH2', 'Gene', (96, 100))	('IDH1', 'Gene', (87, 91))	('TP53', 'Gene', (137, 141))
100232	32313423	To understand the effects of mutations found on the structure and function of the protein, we used PolyPhen-2 Version 2.0.23 to predict the functional significance of substitution and Iterative Threading Assembly Refinement (I-TASSER) server version 5.1 for automated protein structure prediction to model protein structures for specific translated mutant exon sequences for all the mutations: R132H in IDH1, R172M in IDH2, and R158G, R175H, and K305N in TP53.	('PolyPhen-2', 'Chemical', '-', (99, 109))	('R158G', 'Var', (428, 433))	('R172M', 'Mutation', 'rs121913503', (409, 414))	('R172M', 'Var', (409, 414))	('IDH2', 'Gene', (418, 422))	('K305N', 'Var', (446, 451))	('IDH1', 'Gene', (403, 407))	('R132H', 'Mutation', 'rs121913500', (394, 399))	('R158G', 'Mutation', 'rs770374782', (428, 433))	('IDH1', 'Gene', '3417', (403, 407))	('IDH2', 'Gene', '3418', (418, 422))	('TP53', 'Gene', '7157', (455, 459))	('TP53', 'Gene', (455, 459))	('R175H', 'Mutation', 'rs28934578', (435, 440))	('K305N', 'Mutation', 'rs200274944', (446, 451))	('R175H', 'Var', (435, 440))	('R132H', 'Var', (394, 399))
100233	32313423	An R132H mutation of the IDH1 gene was detected in 11 out of 32 samples, including 9 astrocytomas and 2 oligodendrogliomas (Table 1).	('oligodendrogliomas', 'Disease', (104, 122))	('R132H', 'Var', (3, 8))	('astrocytomas', 'Disease', 'MESH:D001254', (85, 97))	('R132H', 'Mutation', 'rs121913500', (3, 8))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('astrocytomas', 'Disease', (85, 97))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (104, 122))	('detected', 'Reg', (39, 47))	('IDH1', 'Gene', (25, 29))	('IDH1', 'Gene', '3417', (25, 29))
100234	32313423	The R172M mutation in IDH2 was detected in 1 oligodendroglioma, and the R158G, R175H, and K305N mutations of the TP53 gene were identified in 5 astrocytomas.	('astrocytomas', 'Disease', (144, 156))	('identified', 'Reg', (128, 138))	('IDH2', 'Gene', (22, 26))	('IDH2', 'Gene', '3418', (22, 26))	('TP53', 'Gene', (113, 117))	('R158G', 'Mutation', 'rs770374782', (72, 77))	('R172M', 'Mutation', 'rs121913503', (4, 9))	('R172M', 'Var', (4, 9))	('astrocytomas', 'Disease', 'MESH:D001254', (144, 156))	('K305N', 'Mutation', 'rs200274944', (90, 95))	('oligodendroglioma', 'Disease', 'MESH:D009837', (45, 62))	('K305N', 'Var', (90, 95))	('R175H', 'Mutation', 'rs28934578', (79, 84))	('oligodendroglioma', 'Disease', (45, 62))	('detected', 'Reg', (31, 39))	('R175H', 'Var', (79, 84))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('TP53', 'Gene', '7157', (113, 117))	('R158G', 'Var', (72, 77))
100235	32313423	Table 1 shows the impact of amino acid substitutions on the structure and function of 3 proteins predicted by PolyPhen-2 (Figure 1).	('substitutions', 'Var', (39, 52))	('function', 'MPA', (74, 82))	('PolyPhen-2', 'Chemical', '-', (110, 120))
100239	32313423	All the IDH1 R132H, IDH2 R172M, and TP53 K305N, R158G, and R175H mutations present a score more than 0.5, so these variants are predicted to be damaging; however, R175H in p53 is a benign mutation.	('R172M', 'Mutation', 'rs121913503', (25, 30))	('TP53', 'Gene', (36, 40))	('R175H', 'Mutation', 'rs28934578', (59, 64))	('R132H', 'Var', (13, 18))	('R175H', 'Var', (59, 64))	('IDH1', 'Gene', (8, 12))	('R175H', 'Mutation', 'rs28934578', (163, 168))	('R175H', 'Var', (163, 168))	('IDH2', 'Gene', (20, 24))	('R158G', 'Mutation', 'rs770374782', (48, 53))	('IDH2', 'Gene', '3418', (20, 24))	('p53', 'Gene', '7157', (172, 175))	('TP53', 'Gene', '7157', (36, 40))	('IDH1', 'Gene', '3417', (8, 12))	('p53', 'Gene', (172, 175))	('R132H', 'Mutation', 'rs121913500', (13, 18))	('K305N', 'Mutation', 'rs200274944', (41, 46))	('K305N', 'Var', (41, 46))	('R158G', 'Var', (48, 53))
100243	32313423	The IDH1 R132H and p53 R158G mutations are found in the strand portion, and the IDH2 R172M, R175H, and K305N mutations are found in the coil position.	('IDH1', 'Gene', '3417', (4, 8))	('R172M', 'Mutation', 'rs121913503', (85, 90))	('R172M', 'Var', (85, 90))	('K305N', 'Mutation', 'rs200274944', (103, 108))	('R158G', 'Mutation', 'rs770374782', (23, 28))	('IDH2', 'Gene', '3418', (80, 84))	('K305N', 'Var', (103, 108))	('R175H', 'Mutation', 'rs28934578', (92, 97))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('IDH1', 'Gene', (4, 8))	('R175H', 'Var', (92, 97))	('IDH2', 'Gene', (80, 84))
100253	32313423	Moreover, several studies were highlighted by the computational approach of the impact of mutations in IDH1 like I147S, V444A, and D375Y and in IDH2 like N439D and R140G; using the same mechanism by which we carried out the sequencing of IDH1, IDH2 and TP53 genes, we were able to identify a few different amino acid substitutions in the IDH1, IDH2, and p53 proteins, such as IDH1 R132, IDH2 R173M, and p53 R175H, R158G, and K305N.	('R140G', 'Mutation', 'rs267606870', (164, 169))	('IDH1', 'Gene', '3417', (376, 380))	('IDH2', 'Gene', (387, 391))	('IDH2', 'Gene', (244, 248))	('IDH2', 'Gene', '3418', (387, 391))	('TP53', 'Gene', (253, 257))	('IDH2', 'Gene', '3418', (244, 248))	('K305N', 'Mutation', 'rs200274944', (425, 430))	('IDH1', 'Gene', (103, 107))	('K305N', 'Var', (425, 430))	('R158G', 'Mutation', 'rs770374782', (414, 419))	('IDH1', 'Gene', (238, 242))	('p53', 'Gene', '7157', (403, 406))	('TP53', 'Gene', '7157', (253, 257))	('IDH1', 'Gene', (338, 342))	('N439D', 'Mutation', 'rs1222149957', (154, 159))	('IDH1', 'Gene', '3417', (103, 107))	('p53', 'Gene', '7157', (354, 357))	('p53', 'Gene', (403, 406))	('IDH1', 'Gene', '3417', (238, 242))	('R175H', 'Mutation', 'rs28934578', (407, 412))	('R173M', 'Var', (392, 397))	('R132', 'Var', (381, 385))	('R158G', 'Var', (414, 419))	('IDH2', 'Gene', (344, 348))	('IDH1', 'Gene', (376, 380))	('p53', 'Gene', (354, 357))	('IDH1', 'Gene', '3417', (338, 342))	('D375Y', 'Mutation', 'rs267606759', (131, 136))	('IDH2', 'Gene', '3418', (344, 348))	('V444A', 'Mutation', 'rs121434360', (120, 125))	('IDH2', 'Gene', (144, 148))	('R173M', 'Mutation', 'p.R173M', (392, 397))	('IDH2', 'Gene', '3418', (144, 148))	('I147S', 'Mutation', 'rs121434361', (113, 118))
100255	32313423	Thirumal Kumar et al reveal that the drug therapeutics for D-2-hydroxyglutarate dehydrogenase are very limited; therefore, understanding the nature of molecular structure caused by these mutations will serve as platform for the development of novel targets for new drug therapy for D-2-hydroxyglutaric aciduria.	('aciduria', 'Phenotype', 'HP:0012072', (302, 310))	('mutations', 'Var', (187, 196))	('2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0032278', (284, 310))	('D-2-hydroxyglutarate dehydrogenase', 'Gene', (59, 93))	('D-2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0012321', (282, 310))	('D-2-hydroxyglutarate dehydrogenase', 'Gene', '728294', (59, 93))
100256	32313423	Concerning the mutation of p53 R158G (Figure 3C), arginine substitution on glycine at position 158 of p53 affects the structural conformation of the protein and may prevent DNA binding.	('R158G', 'Mutation', 'rs770374782', (31, 36))	('p53', 'Gene', '7157', (27, 30))	('p53', 'Gene', '7157', (102, 105))	('prevent', 'NegReg', (165, 172))	('structural conformation of the protein', 'MPA', (118, 156))	('glycine', 'Chemical', 'MESH:D005998', (75, 82))	('affects', 'Reg', (106, 113))	('DNA binding', 'Interaction', (173, 184))	('arginine substitution', 'Var', (50, 71))	('p53', 'Gene', (102, 105))	('R158G', 'Var', (31, 36))	('arginine', 'Chemical', 'MESH:D001120', (50, 58))	('p53', 'Gene', (27, 30))
100258	32313423	Anasuya Pal et al investigated the involvement of TP53 mutations in breast cancer and found that most of the TP53 point mutations occur in the DNA binding domain and can be classified as DNA contact or structural mutations, such as R248W, and 2 structural mutants Y234C and H179R are resistant to apoptosis.	('TP53', 'Gene', (50, 54))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('Y234C', 'Var', (264, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', '7157', (109, 113))	('Y234C', 'Mutation', 'rs587780073', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('R248W', 'Mutation', 'rs121912651', (232, 237))	('H179R', 'Mutation', 'rs1057519991', (274, 279))	('point mutations', 'Var', (114, 129))	('H179R', 'Var', (274, 279))	('resistant to apoptosis', 'CPA', (284, 306))	('TP53', 'Gene', (109, 113))	('R248W', 'Var', (232, 237))
100259	32313423	In our study, most of these mutations (IDH1 R132, IDH2 R173M, and p53 R175H, R158G, and K305N) have been identified in grade II and III glioma samples, suggesting a possible synergistic role in gliomagenesis.	('R175H', 'Mutation', 'rs28934578', (70, 75))	('glioma', 'Disease', (194, 200))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('R158G', 'Var', (77, 82))	('IDH1', 'Gene', (39, 43))	('R173M', 'Var', (55, 60))	('glioma', 'Disease', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('IDH2', 'Gene', (50, 54))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('IDH2', 'Gene', '3418', (50, 54))	('K305N', 'Mutation', 'rs200274944', (88, 93))	('IDH1', 'Gene', '3417', (39, 43))	('R173M', 'Mutation', 'p.R173M', (55, 60))	('K305N', 'Var', (88, 93))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('p53', 'Gene', '7157', (66, 69))	('R158G', 'Mutation', 'rs770374782', (77, 82))	('p53', 'Gene', (66, 69))
100260	32313423	However, Borger et al have identified for the first time a high frequency of mutations in the IDH1 and IDH2 genes in cholangiocarcinomas specifically of intrahepatic origin, which indicates that IDH1 and IDH2 are involved in other types of cancer.	('IDH2', 'Gene', (204, 208))	('IDH1', 'Gene', (94, 98))	('IDH2', 'Gene', '3418', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (240, 246))	('IDH1', 'Gene', '3417', (94, 98))	('IDH2', 'Gene', '3418', (204, 208))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (117, 136))	('IDH1', 'Gene', (195, 199))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('IDH1', 'Gene', '3417', (195, 199))	('IDH2', 'Gene', (103, 107))	('cholangiocarcinomas', 'Disease', (117, 136))
100261	32313423	Computational analysis showed that the mutations of IDH1 and IDH2 were probably harmful as well as the 2 mutations of the p53 R158G and K305N; on the contrary, the substitution R175H is a benign mutation (Figure 1).	('IDH1', 'Gene', '3417', (52, 56))	('K305N', 'Var', (136, 141))	('p53', 'Gene', '7157', (122, 125))	('IDH2', 'Gene', (61, 65))	('mutations', 'Var', (39, 48))	('R175H', 'Mutation', 'rs28934578', (177, 182))	('R158G', 'Mutation', 'rs770374782', (126, 131))	('IDH2', 'Gene', '3418', (61, 65))	('K305N', 'Mutation', 'rs200274944', (136, 141))	('IDH1', 'Gene', (52, 56))	('p53', 'Gene', (122, 125))
100263	32313423	Early effects of poor prognosis of p53 hotspot mutations have been demonstrated in low-grade astrocytomas and oligodendrogliomas.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('mutations', 'Var', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (93, 128))
100264	32313423	The structural analysis of these p53 R158G mutants revealed their possible influence on tumor progression by disrupting the structure of the protein, especially as this mutation occurs in a very dense zone in the protein, as it was demonstrated using ConSurf, also used by Thirumal Kumar et al to calculate the protein conservation score.	('disrupting', 'NegReg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('R158G', 'Mutation', 'rs770374782', (37, 42))	('influence', 'Reg', (75, 84))	('R158G mutants', 'Var', (37, 50))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mutants', 'Var', (43, 50))	('tumor', 'Disease', (88, 93))	('structure of the protein', 'MPA', (124, 148))
100265	32313423	This type of mutation that stabilizes the DNA binding structure is called "structural mutants"; it affects the overall architecture of the DNA binding surface and modifies the conformation of the protein, unlike the wild-type p53 protein that acts as a tumor suppressor due to its DNA binding activity.	('p53', 'Gene', '7157', (226, 229))	('modifies', 'Reg', (163, 171))	('protein', 'Protein', (196, 203))	('architecture', 'MPA', (119, 131))	('affects', 'Reg', (99, 106))	('conformation', 'MPA', (176, 188))	('mutation', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('p53', 'Gene', (226, 229))
100266	32313423	Finally, although we demonstrate detection of known IDH1, IDH2, and p53 mutations, limitations of this study include the difficult manipulation due to the shelf life of the samples included in the FFPE.	('mutations', 'Var', (72, 81))	('IDH2', 'Gene', '3418', (58, 62))	('IDH1', 'Gene', '3417', (52, 56))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', (52, 56))
100267	32313423	Furthermore, the spectrum of biomarkers studied must be broadened in future studies to include the TERT promoter mutations and 1p/19q co-deletion to provide further value to the study and its attempt to understand gliomagenesis.	('TERT', 'Gene', (99, 103))	('glioma', 'Disease', (214, 220))	('TERT', 'Gene', '7015', (99, 103))	('mutations', 'Var', (113, 122))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))
100270	32313423	Through computational analysis, we were able to study the pathogenicity of the IDH1, IDH2, and TP53 mutations and model the proteins generated in 3D, which allowed us to better understand gliomagenesis.	('mutations', 'Var', (100, 109))	('IDH1', 'Gene', '3417', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('IDH2', 'Gene', (85, 89))	('glioma', 'Disease', (188, 194))	('IDH1', 'Gene', (79, 83))	('IDH2', 'Gene', '3418', (85, 89))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
100280	28845038	Indeed, the new classification separates astrocytoma and oligodendroglioma solely based on the presence or absence of 1p/19q codeletion.	('oligodendroglioma', 'Disease', 'MESH:D009837', (57, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('astrocytoma', 'Disease', (41, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('oligodendroglioma', 'Disease', (57, 74))	('1p/19q codeletion', 'Var', (118, 135))	('astrocytoma', 'Disease', 'MESH:D001254', (41, 52))
100292	28845038	Moreover, in patients with tumoral IDH1 R132H mutation, both PFS and OS were improved by the addition of PCV (PFS HR 0.32, P < 0.001; OS HR 0.42, P = 0.02).	('OS HR', 'Disease', 'MESH:C567932', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumoral IDH1', 'Disease', 'MESH:D009369', (27, 39))	('tumoral IDH1', 'Disease', (27, 39))	('OS', 'Gene', '17451', (69, 71))	('patients', 'Species', '9606', (13, 21))	('PFS', 'Disease', (61, 64))	('OS', 'Gene', '17451', (134, 136))	('R132H', 'Var', (40, 45))	('PFS HR', 'Disease', 'MESH:D001919', (110, 116))	('OS HR', 'Disease', (134, 139))	('PFS HR', 'Disease', (110, 116))	('improved', 'PosReg', (77, 85))	('R132H', 'Mutation', 'rs121913500', (40, 45))
100293	28845038	Treatment effect was not evaluable in patients without IDH1 mutation.	('mutation', 'Var', (60, 68))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', (55, 59))	('patients', 'Species', '9606', (38, 46))
100306	28845038	Surprisingly, promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene was associated with better PFS not only in chemotherapy arms but also in RT arm.	('O6-methylguanine-DNA methyltransferase', 'Gene', (42, 80))	('promoter methylation', 'Var', (14, 34))	('better', 'PosReg', (113, 119))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (42, 80))	('MGMT', 'Gene', (82, 86))	('MGMT', 'Gene', '4255', (82, 86))	('PFS', 'Disease', (120, 123))
100309	28845038	In both studies, the initial reports (median follow-up: EORTC 60 m, RTOG 5.1 y) suggested improvement of PFS but not OS by the addition of PCV for the entire cohort; patients with 1p/19q codeleted tumors showed significantly better outcomes (PFS/OS) than those with non-codeleted tumors regardless of treatment arms.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors regardless', 'Disease', (280, 297))	('1p/19q', 'Var', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('OS', 'Gene', '17451', (246, 248))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('EORTC', 'Chemical', '-', (56, 61))	('tumors regardless', 'Disease', 'MESH:D009369', (280, 297))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('tumors', 'Disease', (280, 286))	('tumors', 'Disease', (197, 203))	('better', 'PosReg', (225, 231))	('OS', 'Gene', '17451', (117, 119))	('patients', 'Species', '9606', (166, 174))	('tumors', 'Disease', 'MESH:D009369', (280, 286))
100318	28845038	As a result, not only patients with codeleted, mutated tumors but also those with non-codeleted, mutated tumors lived longer after PCV + RT than RT alone, suggesting that IDH mutations may also be predictive for benefit from chemotherapy (codeleted mutated tumor: PCV + RT 14.7 y vs RT 6.8 y, HR 0.49, P = 0.01; non-codeleted mutated tumor: PCV + RT 5.5 y vs RT 3.3 y, HR 0.56, P < 0.05).	('tumors', 'Disease', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('IDH', 'Gene', '3417', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (175, 184))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('patients', 'Species', '9606', (22, 30))	('tumors', 'Disease', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (334, 339))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('IDH', 'Gene', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
100319	28845038	However, the analyses within the EORTC study cohort did not show evidence of a predictive value of IDH mutations.	('mutations', 'Var', (103, 112))	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', (99, 102))	('EORTC', 'Chemical', '-', (33, 38))
100329	28845038	Thus, together with the correlation of the 1p/19q codeletion to chemotherapeutic response, the evidence-based standard treatment for oligodendroglioma, IDH-mutant and 1p/19q-codeleted is considered to be RT + PCV (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH', 'Gene', (152, 155))	('1p/19q-codeleted', 'Var', (167, 183))	('RT + PCV', 'Chemical', '-', (204, 212))	('IDH', 'Gene', '3417', (152, 155))	('oligodendroglioma', 'Disease', (133, 150))	('oligodendroglioma', 'Disease', 'MESH:D009837', (133, 150))
100335	28845038	Many neuro-oncologists may prefer chemotherapy alone as an initial treatment for 1p/19q-codeleted gliomas to avoid the risk of late RT-induced neurocognitive decline and to reserve a therapy for the time of relapse.	('neurocognitive decline', 'Disease', 'MESH:D060825', (143, 165))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('1p/19q-codeleted', 'Var', (81, 97))	('neurocognitive decline', 'Phenotype', 'HP:0001268', (143, 165))	('neurocognitive decline', 'Disease', (143, 165))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))
100339	28845038	Moreover, in patients with tumoral IDH1 R132H mutation, both PFS and OS were improved by the addition of PCV.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumoral IDH1', 'Disease', 'MESH:D009369', (27, 39))	('tumoral IDH1', 'Disease', (27, 39))	('OS', 'Gene', '17451', (69, 71))	('patients', 'Species', '9606', (13, 21))	('PFS', 'Disease', (61, 64))	('R132H', 'Var', (40, 45))	('improved', 'PosReg', (77, 85))	('R132H', 'Mutation', 'rs121913500', (40, 45))
100349	28845038	It should be noted that EORTC 22033-26033 as well as previous comprehensive studies suggest that the majority of diffuse astrocytomas without IDH mutations are aggressive tumors whose biological and molecular characteristics resemble glioblastoma without IDH mutations.	('IDH', 'Gene', (255, 258))	('aggressive tumors', 'Disease', 'MESH:D001523', (160, 177))	('mutations', 'Var', (146, 155))	('IDH', 'Gene', '3417', (255, 258))	('IDH', 'Gene', (142, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (121, 132))	('aggressive tumors', 'Disease', (160, 177))	('glioblastoma', 'Disease', (234, 246))	('astrocytomas', 'Disease', 'MESH:D001254', (121, 133))	('IDH', 'Gene', '3417', (142, 145))	('EORTC', 'Chemical', '-', (24, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (234, 246))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (234, 246))	('astrocytomas', 'Disease', (121, 133))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
100351	28845038	Most importantly, the results of RTOG 9402 and EORTC 26951 suggested that the administration of chemotherapy in the initial treatment is critical for those tumors, and the evidence-based standard treatment for anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted is PCV + RT (or RT + PCV) (Table 2).	('IDH', 'Gene', (240, 243))	('EORTC', 'Chemical', '-', (47, 52))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (210, 238))	('IDH', 'Gene', '3417', (240, 243))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('RT + PCV', 'Chemical', '-', (288, 296))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('anaplastic oligodendroglioma', 'Disease', (210, 238))	('1p/19q-codeleted', 'Var', (255, 271))	('tumors', 'Disease', (156, 162))
100358	28845038	Importantly, the first interim analysis recently reported has shown that adjuvant TMZ was significantly associated with improved OS in the multivariate analysis, and, therefore, the optimal treatment for anaplastic astrocytoma with IDH mutation may be RT followed by adjuvant TMZ or Stupp regimen (Table 2).	('mutation', 'Var', (236, 244))	('Stupp', 'Chemical', '-', (283, 288))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (204, 226))	('TMZ', 'Chemical', 'MESH:D000077204', (276, 279))	('anaplastic astrocytoma', 'Disease', (204, 226))	('IDH', 'Gene', (232, 235))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('OS', 'Gene', '17451', (129, 131))	('IDH', 'Gene', '3417', (232, 235))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))
100371	33070553	Mutant IDH1 Enhances Temozolomide Sensitivity via Regulation of the ATM/CHK2 Pathway in Glioma Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas.	('Isocitrate dehydrogenase', 'Gene', (95, 119))	('Temozolomide Sensitivity', 'MPA', (21, 45))	('genetic abnormalities', 'Disease', 'MESH:D030342', (159, 180))	('Glioma', 'Disease', 'MESH:D005910', (88, 94))	('IDH', 'Gene', (7, 10))	('genetic abnormalities', 'Disease', (159, 180))	('glioblastomas', 'Phenotype', 'HP:0012174', (216, 229))	('Enhances', 'PosReg', (12, 20))	('gliomas', 'Disease', (194, 201))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('ATM', 'Gene', '472', (68, 71))	('CHK2', 'Gene', (72, 76))	('Glioma', 'Phenotype', 'HP:0009733', (88, 94))	('IDH', 'Gene', '3417', (7, 10))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('IDH', 'Gene', (123, 126))	('Mutant', 'Var', (0, 6))	('glioblastomas', 'Disease', (216, 229))	('Glioma', 'Disease', (88, 94))	('CHK2', 'Gene', '11200', (72, 76))	('mutations', 'Var', (129, 138))	('ATM', 'Gene', (68, 71))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('Isocitrate dehydrogenase', 'Gene', '3417', (95, 119))	('glioblastomas', 'Disease', 'MESH:D005909', (216, 229))	('Temozolomide', 'Chemical', 'MESH:D000077204', (21, 33))	('IDH', 'Gene', '3417', (123, 126))
100372	33070553	Glioma patients with these mutations had better clinical outcomes.	('mutations', 'Var', (27, 36))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('patients', 'Species', '9606', (7, 15))
100373	33070553	However, the effect of IDH1 mutation on drug sensitivity is still under debate.	('IDH', 'Gene', (23, 26))	('mutation', 'Var', (28, 36))	('drug sensitivity', 'Phenotype', 'HP:0020174', (40, 56))	('IDH', 'Gene', '3417', (23, 26))
100378	33070553	In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation.	('nude mice', 'Species', '10090', (8, 17))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))	('mutation', 'Var', (66, 74))
100380	33070553	We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type.	('TMZ', 'Chemical', 'MESH:D000077204', (14, 17))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH', 'Gene', (77, 80))	('inhibited', 'NegReg', (18, 27))	('IDH', 'Gene', '3417', (77, 80))	('glioma', 'Disease', (28, 34))	('mutant', 'Var', (82, 88))
100382	33070553	TMZ significantly induced more DNA damage (quantification of gammaH2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV+propidium iodide- cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas.	('propidium iodide', 'Chemical', 'MESH:D011419', (166, 182))	('gliomas', 'Disease', (250, 257))	('IDH', 'Gene', (238, 241))	('IDH', 'Gene', '3417', (193, 196))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (250, 257))	('gliomas', 'Disease', (280, 287))	('IDH', 'Gene', '3417', (238, 241))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('mutation', 'Var', (90, 98))	('IDH', 'Gene', (85, 88))	('gliomas', 'Disease', 'MESH:D005910', (280, 287))	('gammaH2AX', 'Chemical', '-', (61, 70))	('gliomas', 'Phenotype', 'HP:0009733', (250, 257))	('glioma', 'Phenotype', 'HP:0009733', (280, 286))	('DNA damage', 'MPA', (31, 41))	('mutation', 'Var', (198, 206))	('IDH', 'Gene', '3417', (85, 88))	('IDH', 'Gene', (193, 196))	('gliomas', 'Phenotype', 'HP:0009733', (280, 287))	('apoptosis', 'CPA', (128, 137))	('mutant', 'Var', (243, 249))
100383	33070553	The ATM-associated DNA repair signal was impaired in IDH1 mutant cells.	('mutant', 'Var', (58, 64))	('ATM', 'Gene', '472', (4, 7))	('ATM', 'Gene', (4, 7))	('impaired', 'NegReg', (41, 49))	('IDH', 'Gene', (53, 56))	('IDH', 'Gene', '3417', (53, 56))
100384	33070553	Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy.	('ATM', 'Gene', (15, 18))	('Inhibiting', 'NegReg', (0, 10))	('sensitized', 'Reg', (65, 75))	('checkpoint kinase 2', 'Gene', (19, 38))	('glioma', 'Disease', (88, 94))	('IDH', 'Gene', (76, 79))	('ATM', 'Gene', '472', (15, 18))	('IDH', 'Gene', '3417', (76, 79))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('mutant', 'Var', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('checkpoint kinase 2', 'Gene', '11200', (19, 38))
100385	33070553	We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('IDH', 'Gene', (14, 17))	('mutation', 'Var', (19, 27))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('IDH', 'Gene', '3417', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
100386	33070553	Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment.	('IDH', 'Gene', (41, 44))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH', 'Gene', '3417', (41, 44))	('TMZ', 'Chemical', 'MESH:D000077204', (78, 81))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('mutation', 'Var', (46, 54))	('sensitive to TMZ', 'MPA', (65, 81))	('gliomas', 'Disease', (28, 35))
100387	33070553	These results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.	('ATM', 'Gene', '472', (59, 62))	('IDH', 'Gene', '3417', (106, 109))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('mutant', 'Var', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (51, 54))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('ATM', 'Gene', (59, 62))	('IDH', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('enhances', 'PosReg', (73, 81))
100397	33070553	Research indicates that mutant IDH1 directly converts alpha-KG to (R)-2HG.	('mutant', 'Var', (24, 30))	('IDH', 'Gene', '3417', (31, 34))	('IDH', 'Gene', (31, 34))	('alpha-KG', 'Chemical', 'MESH:D007656', (54, 62))
100398	33070553	IDH1 mutations occurred frequently in low-grade gliomas and in most secondary glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (78, 91))	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('occurred', 'Reg', (15, 23))	('glioblastomas', 'Disease', (78, 91))	('IDH', 'Gene', '3417', (0, 3))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('mutations', 'Var', (5, 14))	('glioblastomas', 'Phenotype', 'HP:0012174', (78, 91))	('gliomas', 'Disease', (48, 55))
100399	33070553	Clinically, IDH1 mutations were associated with longer overall survival.	('overall survival', 'MPA', (55, 71))	('longer', 'PosReg', (48, 54))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('mutations', 'Var', (17, 26))
100401	33070553	Further analysis indicated that patients with IDH1 mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation were more sensitive to TMZ treatment in secondary glioblastoma versus IDH1 wild type and MGMT promoter demethylation.	('MGMT', 'Gene', (220, 224))	('MGMT', 'Gene', (104, 108))	('patients', 'Species', '9606', (32, 40))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (64, 102))	('glioblastoma versus IDH1', 'Disease', (181, 205))	('IDH', 'Gene', (201, 204))	('IDH', 'Gene', (46, 49))	('glioblastoma versus IDH1', 'Disease', 'MESH:D005909', (181, 205))	('IDH', 'Gene', '3417', (201, 204))	('TMZ', 'Chemical', 'MESH:D000077204', (154, 157))	('IDH', 'Gene', '3417', (46, 49))	('mutation', 'Var', (51, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (181, 193))	('O6-methylguanine-DNA methyltransferase', 'Gene', (64, 102))	('MGMT', 'Gene', '4255', (220, 224))	('sensitive', 'MPA', (141, 150))	('MGMT', 'Gene', '4255', (104, 108))
100409	33070553	A lower dose of TMZ was effective to induce cytotoxic damage in IDH1-R132H mutant cells.	('IDH', 'Gene', (64, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (16, 19))	('cytotoxic damage', 'Disease', 'MESH:D064420', (44, 60))	('mutant', 'Var', (75, 81))	('R132H', 'Mutation', 'rs776635794', (69, 74))	('IDH', 'Gene', '3417', (64, 67))	('cytotoxic damage', 'Disease', (44, 60))
100410	33070553	The expression of gammaH2AX in IDH1-R132H mutant group was higher than wild-type group suggesting that TMZ induced more DNA damage in IDH1 mutant gliomas.	('TMZ', 'Chemical', 'MESH:D000077204', (103, 106))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (134, 137))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Disease', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('IDH', 'Gene', '3417', (31, 34))	('R132H', 'Mutation', 'rs776635794', (36, 41))	('mutant', 'Var', (139, 145))	('DNA damage', 'MPA', (120, 130))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('gammaH2AX', 'Chemical', '-', (18, 27))	('IDH', 'Gene', (134, 137))
100411	33070553	To detect the annexin V/propidium iodide (PI) staining by flow cytometry we demonstrated that IDH1 mutation enhanced TMZ induced apoptosis.	('TMZ', 'MPA', (117, 120))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('annexin V', 'Gene', (14, 23))	('apoptosis', 'CPA', (129, 138))	('IDH', 'Gene', (94, 97))	('mutation', 'Var', (99, 107))	('IDH', 'Gene', '3417', (94, 97))	('enhanced', 'PosReg', (108, 116))	('propidium iodide', 'Chemical', 'MESH:D011419', (24, 40))	('annexin V', 'Gene', '308', (14, 23))
100414	33070553	Taken together, our findings demonstrate that IDH1 mutations enhance TMZ sensitivity via regulating ATM/CHK2 pathway in glioma and suggest a combination therapeutic method in clinic.	('enhance', 'PosReg', (61, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('mutations', 'Var', (51, 60))	('ATM', 'Gene', '472', (100, 103))	('regulating', 'Reg', (89, 99))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('TMZ sensitivity', 'MPA', (69, 84))	('IDH', 'Gene', (46, 49))	('CHK2', 'Gene', (104, 108))	('IDH', 'Gene', '3417', (46, 49))	('glioma', 'Disease', (120, 126))	('ATM', 'Gene', (100, 103))	('CHK2', 'Gene', '11200', (104, 108))
100446	33070553	The result demonstrated that IDH1 mutant cells were more sensitive to TMZ versus wild type (Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (70, 73))	('sensitive to TMZ', 'MPA', (57, 73))	('IDH', 'Gene', (29, 32))	('more', 'PosReg', (52, 56))	('IDH', 'Gene', '3417', (29, 32))	('mutant', 'Var', (34, 40))
100447	33070553	Moreover, the proliferation rate of IDH1 mutant cells was slower than that of wild-type cells especially in 72- and 96-hours' time points.	('slower', 'NegReg', (58, 64))	('IDH', 'Gene', '3417', (36, 39))	('mutant', 'Var', (41, 47))	('IDH', 'Gene', (36, 39))
100452	33070553	Quantification of gammaH2AX in wild-type cells and IDH1 mutant cells treated with TMZ (Fig.	('IDH', 'Gene', (51, 54))	('mutant', 'Var', (56, 62))	('IDH', 'Gene', '3417', (51, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('gammaH2AX', 'Protein', (18, 27))	('gammaH2AX', 'Chemical', '-', (18, 27))
100453	33070553	In addition, the western blot analysis showed that the expression of gammaH2AX in IDH1-R132H mutant group was more prominent than that in the wild-type group (Fig.	('IDH', 'Gene', '3417', (82, 85))	('prominent', 'PosReg', (115, 124))	('expression', 'MPA', (55, 65))	('R132H', 'Mutation', 'rs776635794', (87, 92))	('IDH', 'Gene', (82, 85))	('gammaH2AX', 'Chemical', '-', (69, 78))	('gammaH2AX', 'Var', (69, 78))
100454	33070553	Thus, TMZ induced more DNA damage in IDH1 mutant cells compared with wild-type glioma cells.	('mutant', 'Var', (42, 48))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('DNA damage', 'MPA', (23, 33))	('IDH', 'Gene', (37, 40))	('TMZ', 'Chemical', 'MESH:D000077204', (6, 9))	('IDH', 'Gene', '3417', (37, 40))
100457	33070553	Both annexinV+PI+ and annexinV+PI- labeled cells were more abundant in IDH1-R132H mutant cells (Fig.	('more', 'PosReg', (54, 58))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (71, 74))	('R132H', 'Mutation', 'rs776635794', (76, 81))	('mutant', 'Var', (82, 88))
100459	33070553	The expression of anti-apoptotic protein Bcl-2 was reduced in IDH1 mutant cells compared to wild-type cells (Fig.	('Bcl-2', 'Gene', (41, 46))	('reduced', 'NegReg', (51, 58))	('Bcl-2', 'Gene', '596', (41, 46))	('IDH', 'Gene', '3417', (62, 65))	('mutant', 'Var', (67, 73))	('IDH', 'Gene', (62, 65))
100468	33070553	We found that ATM inhibitor combined with TMZ induced more apoptosis than TMZ alone group in IDH1-R132H mutant glioma cells.	('glioma', 'Disease', (111, 117))	('ATM', 'Gene', '472', (14, 17))	('R132H', 'Mutation', 'rs776635794', (98, 103))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('mutant', 'Var', (104, 110))	('IDH', 'Gene', (93, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('apoptosis', 'CPA', (59, 68))	('IDH', 'Gene', '3417', (93, 96))	('ATM', 'Gene', (14, 17))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))
100469	33070553	The antitumor effect of combination therapy was more significant than that of single-drug therapy in wild-type groups compared to IDH1 mutant groups.	('IDH', 'Gene', '3417', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mutant', 'Var', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('IDH', 'Gene', (130, 133))
100470	33070553	This may be IDH1 mutations inhibited the activation of ATM more significant than wild type.	('ATM', 'Gene', '472', (55, 58))	('activation', 'MPA', (41, 51))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('ATM', 'Gene', (55, 58))	('inhibited', 'NegReg', (27, 36))	('mutations', 'Var', (17, 26))
100471	33070553	Moreover, whether the ATM inhibitor was added or not, TMZ induced more apoptosis in IDH1-R132H mutant cells than wild-type cells (Fig.	('ATM', 'Gene', (22, 25))	('apoptosis', 'CPA', (71, 80))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('R132H', 'Mutation', 'rs776635794', (89, 94))	('IDH', 'Gene', '3417', (84, 87))	('ATM', 'Gene', '472', (22, 25))	('mutant', 'Var', (95, 101))	('IDH', 'Gene', (84, 87))
100472	33070553	Moreover, combination of ATM inhibitor and TMZ inhibited cell proliferation more significantly in IDH1 mutant glioma cells (Fig.	('inhibited', 'NegReg', (47, 56))	('glioma', 'Disease', (110, 116))	('mutant', 'Var', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('ATM', 'Gene', (25, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', '3417', (98, 101))	('cell proliferation', 'CPA', (57, 75))	('ATM', 'Gene', '472', (25, 28))
100474	33070553	IDH1 mutant cells and wild-type glioma cells were subcutaneously injected into the back flanks of mice, and the tumorigenesis and tumor size were recorded.	('IDH', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('glioma', 'Disease', (32, 38))	('IDH', 'Gene', '3417', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutant', 'Var', (5, 11))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (130, 135))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('mice', 'Species', '10090', (98, 102))
100476	33070553	The results showed that the size and weight of IDH1 mutant gliomas were smaller than that of wild type (Fig.	('IDH', 'Gene', '3417', (47, 50))	('mutant', 'Var', (52, 58))	('smaller', 'NegReg', (72, 79))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Disease', (59, 66))	('IDH', 'Gene', (47, 50))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
100477	33070553	The results showed that IDH1 mutation had a certain inhibitory effect on tumor growth in vivo.	('mutation', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('IDH', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('IDH', 'Gene', '3417', (24, 27))	('inhibitory effect', 'NegReg', (52, 69))	('tumor', 'Disease', (73, 78))
100478	33070553	The expression of Ki67 in IDH1 mutation group was lower than that in wild type (Fig.	('lower', 'NegReg', (50, 55))	('mutation', 'Var', (31, 39))	('expression', 'MPA', (4, 14))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (26, 29))
100479	33070553	The results of immunohistochemistry showed that the score of wild-type Ki67 was significantly higher than that of IDH1 mutant group (Fig.	('IDH', 'Gene', '3417', (114, 117))	('IDH', 'Gene', (114, 117))	('Ki67', 'Var', (71, 75))	('higher', 'PosReg', (94, 100))
100480	33070553	In conclusion, IDH1 mutation can inhibit tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('inhibit', 'NegReg', (33, 40))	('mutation', 'Var', (20, 28))	('IDH', 'Gene', (15, 18))	('IDH', 'Gene', '3417', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
100481	33070553	To further study the effect of TMZ on IDH1 mutant glioma in vivo, we constructed subcutaneous tumor model in mice.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('IDH', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Disease', (50, 56))	('tumor', 'Disease', (94, 99))	('IDH', 'Gene', '3417', (38, 41))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (81, 99))	('mutant', 'Var', (43, 49))	('mice', 'Species', '10090', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (31, 34))
100485	33070553	We found that IDH1 mutant group was more sensitive to TMZ, and the tumor size and weight were significantly inhibited in this group (Fig.	('IDH', 'Gene', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('IDH', 'Gene', '3417', (14, 17))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutant', 'Var', (19, 25))	('tumor', 'Disease', (67, 72))	('sensitive', 'MPA', (41, 50))	('inhibited', 'NegReg', (108, 117))	('more', 'PosReg', (36, 40))
100487	33070553	It is suggested that IDH1 mutation is more sensitive to TMZ, and chemotherapy might perform more antitumor effects.	('IDH', 'Gene', (21, 24))	('TMZ', 'Chemical', 'MESH:D000077204', (56, 59))	('mutation', 'Var', (26, 34))	('IDH', 'Gene', '3417', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
100490	33070553	Genomic analysis showed that mutations of IDH1 accounted for a large proportion of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (42, 45))	('mutations', 'Var', (29, 38))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('accounted', 'Reg', (47, 56))
100491	33070553	Researches demonstrate that about 60%-80% low-grade gliomas and most secondary glioblastomas have a mutation and most of those IDH1 mutations are replacing the arginine residue with histidine (IDH1-R132H).	('IDH', 'Gene', (127, 130))	('gliomas', 'Disease', (52, 59))	('arginine', 'Chemical', 'MESH:D001120', (160, 168))	('IDH', 'Gene', '3417', (127, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('arginine', 'MPA', (160, 168))	('R132H', 'Mutation', 'rs776635794', (198, 203))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH', 'Gene', (193, 196))	('mutations', 'Var', (132, 141))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioblastomas', 'Disease', 'MESH:D005909', (79, 92))	('IDH', 'Gene', '3417', (193, 196))	('histidine', 'Chemical', 'MESH:D006639', (182, 191))	('glioblastomas', 'Disease', (79, 92))	('replacing', 'Reg', (146, 155))
100492	33070553	Tumors with IDH gene mutation have specific genetic and clinical characteristics, our previous studies identified IDH mutation with low ATRX expression were accompanied by longer progression time in glioma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('ATRX', 'Gene', (136, 140))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('IDH', 'Gene', (114, 117))	('ATRX', 'Gene', '546', (136, 140))	('longer', 'PosReg', (172, 178))	('Tumors', 'Disease', (0, 6))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (114, 117))	('mutation', 'Var', (118, 126))	('expression', 'MPA', (141, 151))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('IDH', 'Gene', '3417', (12, 15))	('glioma', 'Disease', (199, 205))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
100494	33070553	Studies of the role of IDH mutation on drug or radiation sensitivity were controversial.	('mutation', 'Var', (27, 35))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (23, 26))
100495	33070553	One kind of studies demonstrated that introduction of mutant IDH1 reduced TMZ resistance.	('reduced', 'NegReg', (66, 73))	('IDH', 'Gene', '3417', (61, 64))	('TMZ resistance', 'MPA', (74, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('mutant', 'Var', (54, 60))	('IDH', 'Gene', (61, 64))
100496	33070553	IDH1 mutation impaired PARP1-mediated DNA repair signal in glioma.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (59, 65))	('IDH', 'Gene', '3417', (0, 3))	('PARP1', 'Gene', '142', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('PARP1', 'Gene', (23, 28))	('mutation', 'Var', (5, 13))	('impaired', 'NegReg', (14, 22))
100497	33070553	showed that IDH1 mutation in acute myeloid leukemia impaired DNA repair and reduced hematopoietic stem cells.	('DNA repair', 'MPA', (61, 71))	('hematopoietic stem cells', 'CPA', (84, 108))	('mutation', 'Var', (17, 25))	('acute myeloid leukemia impaired', 'Disease', 'MESH:D015470', (29, 60))	('acute myeloid leukemia impaired', 'Disease', (29, 60))	('reduced', 'NegReg', (76, 83))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (29, 51))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (35, 51))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))
100498	33070553	Patients with oligodendroglioma tumors that occurred IDH mutation benefit from alkylating-agent chemotherapy with radiotherapy.	('mutation', 'Var', (57, 65))	('oligodendroglioma tumors', 'Disease', (14, 38))	('benefit', 'PosReg', (66, 73))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('IDH', 'Gene', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('IDH', 'Gene', '3417', (53, 56))	('oligodendroglioma tumors', 'Disease', 'MESH:D009837', (14, 38))
100499	33070553	However, some studies also demonstrated that mutant IDH1 expression increased TMZ resistance due to enhance the RAD51-mediated homologous recombination.	('mutant', 'Var', (45, 51))	('TMZ resistance', 'MPA', (78, 92))	('enhance', 'PosReg', (100, 107))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('TMZ', 'Chemical', 'MESH:D000077204', (78, 81))	('RAD51', 'Gene', (112, 117))	('increased', 'PosReg', (68, 77))	('RAD51', 'Gene', '5888', (112, 117))
100500	33070553	A clinical research also suggested that IDH1 mutation conferred resistance to TMZ.	('IDH', 'Gene', (40, 43))	('mutation', 'Var', (45, 53))	('resistance', 'MPA', (64, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (78, 81))	('IDH', 'Gene', '3417', (40, 43))
100503	33070553	Therefore, the molecular characteristics of IDH1 mutant cells in response to TMZ need to be further investigated and the development of more effective treatment is still an important priority for patients with glioma.	('mutant', 'Var', (49, 55))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('patients', 'Species', '9606', (196, 204))	('TMZ', 'Chemical', 'MESH:D000077204', (77, 80))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))	('glioma', 'Disease', (210, 216))
100506	33070553	O6 methylguanine mispairs with thymine and is recognized by the mismatch repair.	('mispairs', 'Reg', (17, 25))	('O6 methylguanine', 'Chemical', 'MESH:C008449', (0, 16))	('thymine', 'MPA', (31, 38))	('thymine', 'Chemical', 'MESH:D013941', (31, 38))	('O6 methylguanine', 'Var', (0, 16))
100508	33070553	DSBs finally trigger apoptosis, necrosis, and autophagy.	('DSBs', 'Chemical', 'MESH:C007563', (0, 4))	('DSBs', 'Var', (0, 4))	('trigger', 'Reg', (13, 20))	('autophagy', 'CPA', (46, 55))	('necrosis', 'Disease', (32, 40))	('apoptosis', 'CPA', (21, 30))	('necrosis', 'Disease', 'MESH:D009336', (32, 40))
100509	33070553	DNA damage repair involves a protein network, which can make appropriate sense and response to DNA damage, and the interference of this network can promote the occurrence of tumor.	('tumor', 'Disease', (174, 179))	('interference', 'Var', (115, 127))	('occurrence', 'CPA', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('promote', 'PosReg', (148, 155))
100512	33070553	Whether TMZ mediated DNA damage affects ATM signal pathway in IDH1 mutation of glioma was under debate.	('glioma', 'Disease', (79, 85))	('mutation', 'Var', (67, 75))	('IDH', 'Gene', '3417', (62, 65))	('ATM', 'Gene', (40, 43))	('TMZ', 'Chemical', 'MESH:D000077204', (8, 11))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('ATM', 'Gene', '472', (40, 43))	('IDH', 'Gene', (62, 65))
100514	33070553	Compared with the wild-type group, the glioma cell proliferation in the IDH1 mutant group was significantly inhibited by TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (121, 124))	('glioma', 'Disease', (39, 45))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('mutant', 'Var', (77, 83))	('inhibited', 'NegReg', (108, 117))
100517	33070553	We confirmed that IDH1 mutations elevated cell apoptosis induced by TMZ, as Annexin V-positive cells were increased in IDH1-R132H mutant group.	('IDH', 'Gene', '3417', (119, 122))	('elevated', 'PosReg', (33, 41))	('IDH', 'Gene', (18, 21))	('IDH', 'Gene', '3417', (18, 21))	('mutations', 'Var', (23, 32))	('cell apoptosis', 'CPA', (42, 56))	('Annexin V', 'Gene', (76, 85))	('Annexin V', 'Gene', '308', (76, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (68, 71))	('increased', 'PosReg', (106, 115))	('IDH', 'Gene', (119, 122))	('R132H', 'Mutation', 'rs776635794', (124, 129))
100519	33070553	Due to these molecular mechanisms, IDH1 mutant gliomas are sensitive to TMZ therapy.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH', 'Gene', (35, 38))	('TMZ', 'Chemical', 'MESH:D000077204', (72, 75))	('IDH', 'Gene', '3417', (35, 38))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('mutant', 'Var', (40, 46))
100521	33070553	Taken together, our findings demonstrate that IDH1 mutations enhance TMZ sensitivity via regulating ATM/CHK2 pathway in glioma.	('enhance', 'PosReg', (61, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('mutations', 'Var', (51, 60))	('ATM', 'Gene', '472', (100, 103))	('regulating', 'Reg', (89, 99))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('TMZ sensitivity', 'MPA', (69, 84))	('IDH', 'Gene', (46, 49))	('CHK2', 'Gene', (104, 108))	('IDH', 'Gene', '3417', (46, 49))	('glioma', 'Disease', (120, 126))	('ATM', 'Gene', (100, 103))	('CHK2', 'Gene', '11200', (104, 108))
100522	33070553	We provided the preclinical evidence that combination of TMZ and ATM inhibitor enhanced the antitumor effect in IDH1 mutant gliomas.	('ATM', 'Gene', '472', (65, 68))	('gliomas', 'Disease', (124, 131))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutant', 'Var', (117, 123))	('tumor', 'Disease', (96, 101))	('enhanced', 'PosReg', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('TMZ', 'Chemical', 'MESH:D000077204', (57, 60))	('IDH', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('ATM', 'Gene', (65, 68))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))	('IDH', 'Gene', '3417', (112, 115))
100527	33707455	We apply ImageCCA to the GTEx v6 data, and find image features that capture population variation in thyroid and in colon tissues associated with genetic variants (image morphology QTLs, or imQTLs), suggesting that genetic variation regulates population variation in tissue morphological traits.	('associated', 'Reg', (129, 139))	('regulates', 'Reg', (232, 241))	('CCA', 'Chemical', '-', (14, 17))	('QTLs', 'Disease', 'None', (191, 195))	('QTLs', 'Disease', 'None', (180, 184))	('QTLs', 'Disease', (191, 195))	('QTLs', 'Disease', (180, 184))	('variants', 'Var', (153, 161))
100576	33707455	These results suggest that this component may reflect technical covariates, such as the time between sample extraction and processing or the proportion of necrotic tissue, where genes involved in RNA decay are correlated with image features that show the morphological effects of time on the tissue sample.	('genes', 'Var', (178, 183))	('necrotic', 'Disease', (155, 163))	('necrotic', 'Disease', 'MESH:D009336', (155, 163))
100588	33707455	The genes that are non-zero in this component are highly enriched for respiratory electron transport chain, ATP synthesis coupled electron transport, and small molecule metabolic process (all three p <= 2.2 x 10-16), catalytic activity (p <= 2.9 x 10-12), oxidoreductase activity (p <= 3.2 x 10-10), and endoplasmic reticulum part (p <= 2.2 x 10-16).	('catalytic', 'MPA', (217, 226))	('ATP synthesis coupled electron transport', 'MPA', (108, 148))	('small molecule metabolic process', 'MPA', (154, 186))	('oxidoreductase', 'Gene', '8630', (256, 270))	('respiratory electron transport chain', 'MPA', (70, 106))	('genes', 'Var', (4, 9))	('ATP', 'Chemical', 'MESH:D000255', (108, 111))	('oxidoreductase', 'Gene', (256, 270))
100609	33707455	A cis-eQTL for lactate dehydrogenase D (LDHD), rs8059637, is associated with image feature 799 (FDR <= 0.1) in transverse colon samples (Fig.	('LDHD', 'Gene', '197257', (40, 44))	('rs8059637', 'Var', (47, 56))	('lactate dehydrogenase D', 'Gene', (15, 38))	('lactate dehydrogenase D', 'Gene', '197257', (15, 38))	('associated', 'Reg', (61, 71))	('LDHD', 'Gene', (40, 44))	('rs8059637', 'Mutation', 'rs8059637', (47, 56))
100614	33707455	We also found an association between a cis-eQTL for death-associated protein 3 (DAP3), rs4601579, and histological image feature 820 in thyroid tissue (FDR <= 0.1; Supplementary Fig.	('rs4601579', 'Mutation', 'rs4601579', (87, 96))	('death-associated protein 3', 'Gene', (52, 78))	('association', 'Interaction', (17, 28))	('DAP3', 'Gene', (80, 84))	('death-associated protein 3', 'Gene', '7818', (52, 78))	('rs4601579', 'Var', (87, 96))	('DAP3', 'Gene', '7818', (80, 84))
100620	33707455	Applying the ImageCCA framework to these data, and interpreting the components, we were able to find genes known to influence cellular morphology, including the extracellular matrix and the cell wall, and involved in tissue-specific morphology, including neuronal, testis, and muscle tissue.	('cellular morphology', 'CPA', (126, 145))	('influence', 'Reg', (116, 125))	('CCA', 'Chemical', '-', (18, 21))	('involved', 'Reg', (205, 213))	('genes', 'Var', (101, 106))
100657	31240524	Lack of B and T cell reactivity towards IDH1R132H in blood and tumor tissue from LGG patients Mutations in the isocitrate dehydrogenase-1 gene (IDH1) occur at high frequency in grade II-III gliomas (LGGs).	('tumor', 'Disease', (63, 68))	('II-III gliomas', 'Disease', 'MESH:D005910', (183, 197))	('IDH1', 'Gene', (40, 44))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('IDH1', 'Gene', '3417', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('IDH1', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('II-III gliomas', 'Disease', (183, 197))	('Mutations', 'Var', (94, 103))	('IDH1', 'Gene', '3417', (144, 148))
100658	31240524	IDH1 mutations are somatic, missense and heterozygous affecting codon 132 in the catalytic pocket of the enzyme.	('l', 'Chemical', '-', (85, 86))	('codon 132 in the catalytic pocket', 'MPA', (64, 97))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('affecting', 'Reg', (54, 63))	('IDH1', 'Gene', '3417', (0, 4))
100659	31240524	In LGG, most mutations (90%) result in an arginine to histidine substitution (IDH1R132H) providing a neo-epitope that is expressed in all tumor cells.	('neo-epitope', 'MPA', (101, 112))	('histidine', 'Chemical', 'MESH:D006639', (54, 63))	('result in', 'Reg', (29, 38))	('l', 'Chemical', '-', (33, 34))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('l', 'Chemical', '-', (136, 137))	('l', 'Chemical', '-', (135, 136))	('l', 'Chemical', '-', (147, 148))	('arginine', 'Chemical', 'MESH:D001120', (42, 50))	('mutations', 'Var', (13, 22))	('l', 'Chemical', '-', (146, 147))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
100660	31240524	To assess the immunogenic nature of this epitope, and its potential use to develop T cell treatments, we measured IDH1R132H-specific B and T cell reactivity in blood and tumor tissue of LGG patients.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('l', 'Chemical', '-', (88, 89))	('patients', 'Species', '9606', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('l', 'Chemical', '-', (161, 162))	('tumor', 'Disease', (170, 175))	('l', 'Chemical', '-', (144, 145))	('l', 'Chemical', '-', (87, 88))	('l', 'Chemical', '-', (143, 144))	('l', 'Chemical', '-', (79, 80))	('l', 'Chemical', '-', (66, 67))	('T cell', 'CPA', (139, 145))	('IDH1R132H-specific', 'Var', (114, 132))
100661	31240524	Sera from IDH1R132H-mutated LGG patients (n = 27) were assayed for the presence of a neo-specific antibody response using ELISA.	('IDH1R132H-mutated', 'Var', (10, 27))	('LGG', 'Disease', (28, 31))	('patients', 'Species', '9606', (32, 40))
100663	31240524	In some assays, frequencies of CD4 T cells specific for mutated peptide presented by HLA-DR were enriched prior to T cell monitoring assays.	('HLA', 'Gene', '3123', (85, 88))	('CD4', 'Gene', (31, 34))	('CD4', 'Gene', '920', (31, 34))	('mutated', 'Var', (56, 63))	('HLA', 'Gene', (85, 88))
100664	31240524	Despite high sensitivity of our assay, we failed to detect IDH1R132H-specific IgG in sera of LGG patients.	('IgG', 'Disease', (78, 81))	('LGG', 'Disease', (93, 96))	('IDH1R132H-specific', 'Var', (59, 77))	('l', 'Chemical', '-', (45, 46))	('patients', 'Species', '9606', (97, 105))
100667	31240524	The absence of both humoral and cellular responses in blood and tumors of LGG patients indicates that IDH1R132H is not sufficiently immunogenic and devaluates its further therapeutic exploitation, at least in the majority of LGG patients.	('l', 'Chemical', '-', (37, 38))	('tumors', 'Disease', (64, 70))	('l', 'Chemical', '-', (152, 153))	('l', 'Chemical', '-', (186, 187))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('patients', 'Species', '9606', (229, 237))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('IDH1R132H', 'Var', (102, 111))	('l', 'Chemical', '-', (26, 27))	('patients', 'Species', '9606', (78, 86))	('l', 'Chemical', '-', (34, 35))	('l', 'Chemical', '-', (129, 130))	('LGG', 'Disease', (225, 228))	('l', 'Chemical', '-', (200, 201))	('devaluates', 'NegReg', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('l', 'Chemical', '-', (35, 36))	('l', 'Chemical', '-', (55, 56))
100671	31240524	Approximately 80% of grade II and III tumors harbor driver mutations in isocitrate dehydrogenase (IDH) 1 or 2 genes and are classified as diffuse low-grade gliomas (LGG).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('l', 'Chemical', '-', (157, 158))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (59, 68))	('l', 'Chemical', '-', (11, 12))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (72, 104))	('l', 'Chemical', '-', (146, 147))	('l', 'Chemical', '-', (125, 126))
100680	31240524	These antigens arise from tumor-specific mutations that alter amino acid coding sequences, and hence are not present in any healthy tissues.	('mutations', 'Var', (41, 50))	('l', 'Chemical', '-', (57, 58))	('amino acid coding sequences', 'MPA', (62, 89))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('l', 'Chemical', '-', (127, 128))	('alter', 'Reg', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
100681	31240524	Different studies have already focused on the therapeutic targeting of neoantigens derived from hallmark glioma mutations, for instance the epidermal growth factor receptor (EGFRvIII), histone H3 (H3.3K27M) and isocitrate dehydrogenase 1 (IDH1R132H).	('l', 'Chemical', '-', (148, 149))	('epidermal growth factor receptor', 'Gene', (140, 172))	('hallmark glioma', 'Disease', 'MESH:D005910', (96, 111))	('l', 'Chemical', '-', (98, 99))	('epidermal growth factor receptor', 'Gene', '1956', (140, 172))	('isocitrate dehydrogenase 1 ', 'Gene', '3417', (211, 238))	('l', 'Chemical', '-', (106, 107))	('l', 'Chemical', '-', (99, 100))	('l', 'Chemical', '-', (24, 25))	('H3.3K27M', 'Var', (197, 205))	('isocitrate dehydrogenase 1 ', 'Gene', (211, 238))	('hallmark glioma', 'Disease', (96, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
100682	31240524	The IDH1R132H mutation accounts for the vast majority (~ 90%) of all mutations in IDH1 and results in an arginine to histidine amino acid substitution at codon 132 of this gene.	('mutations', 'Var', (69, 78))	('IDH1', 'Gene', '3417', (4, 8))	('l', 'Chemical', '-', (95, 96))	('l', 'Chemical', '-', (67, 68))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', (4, 8))	('arginine to', 'Var', (105, 116))	('IDH1', 'Gene', '3417', (82, 86))	('l', 'Chemical', '-', (66, 67))	('results in an', 'Reg', (91, 104))	('arginine to histidine amino acid substitution at codon 132', 'Mutation', 'rs121913500', (105, 163))
100684	31240524	In fact, it has previously been established that IDH1R132H can be presented by HLA-DR, and a spontaneous humoral as well as CD4 T cell response may occur in a subset of glioma patients.	('l', 'Chemical', '-', (37, 38))	('l', 'Chemical', '-', (118, 119))	('l', 'Chemical', '-', (132, 133))	('patients', 'Species', '9606', (176, 184))	('glioma', 'Disease', (169, 175))	('CD4', 'Gene', (124, 127))	('l', 'Chemical', '-', (24, 25))	('l', 'Chemical', '-', (133, 134))	('CD4', 'Gene', '920', (124, 127))	('l', 'Chemical', '-', (119, 120))	('l', 'Chemical', '-', (111, 112))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('HLA', 'Gene', '3123', (79, 82))	('HLA', 'Gene', (79, 82))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('l', 'Chemical', '-', (170, 171))	('IDH1R132H', 'Var', (49, 58))
100687	31240524	Patients with IDH1R132H-mutated grade II and III glioma were diagnosed at Erasmus University Medical Center (Rotterdam, The Netherlands).	('l', 'Chemical', '-', (50, 51))	('l', 'Chemical', '-', (130, 131))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('l', 'Chemical', '-', (99, 100))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1R132H-mutated', 'Var', (14, 31))	('grade II', 'Disease', (32, 40))	('glioma', 'Disease', (49, 55))
100692	31240524	In case of unknown IDH1 mutation status, we performed sanger sequencing on DNA isolated from FFPE tumor tissue samples as described previously.	('FFPE tumor', 'Disease', (93, 103))	('l', 'Chemical', '-', (82, 83))	('IDH1', 'Gene', (19, 23))	('l', 'Chemical', '-', (140, 141))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH1', 'Gene', '3417', (19, 23))	('FFPE tumor', 'Disease', 'MESH:D009369', (93, 103))	('mutation', 'Var', (24, 32))	('l', 'Chemical', '-', (115, 116))
100708	31240524	HeLa cells stably expressing DRA1*01:01 and DRB1*01:01 (DR1 + HeLa) or stably expressing DRA1*01:01 and DRB1*04:01 (DR4 + HeLa) (kind gift from prof. Fred Falkenburg, LUMC, The Netherlands) were irradiated and added to 96 well tissue culture treated plates (Sigma-Aldrich, 0.05 x 105/well) together with autologous patient PBMC (0.4 x 105/well) and 17.5 microM or no peptide in IMDM supplemented with 10 ng/mL IL-7 (200 microL/well).	('l', 'Chemical', '-', (15, 16))	('l', 'Chemical', '-', (183, 184))	('l', 'Chemical', '-', (157, 158))	('l', 'Chemical', '-', (308, 309))	('l', 'Chemical', '-', (387, 388))	('DRB1', 'Gene', '3123', (44, 48))	('HeLa', 'CellLine', 'CVCL:0030', (122, 126))	('l', 'Chemical', '-', (7, 8))	('l', 'Chemical', '-', (236, 237))	('DR1', 'Gene', '1810', (56, 59))	('DR1', 'Gene', (56, 59))	('DR4', 'Gene', (116, 119))	('DRB1', 'Gene', (44, 48))	('l', 'Chemical', '-', (251, 252))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('l', 'Chemical', '-', (225, 226))	('DRB1', 'Gene', '3123', (104, 108))	('patient', 'Species', '9606', (315, 322))	('DRA1', 'Var', (29, 33))	('l', 'Chemical', '-', (75, 76))	('HeLa', 'CellLine', 'CVCL:0030', (62, 66))	('DRB1', 'Gene', (104, 108))	('l', 'Chemical', '-', (265, 266))	('DR4', 'Gene', '3126', (116, 119))	('l', 'Chemical', '-', (342, 343))	('l', 'Chemical', '-', (287, 288))	('l', 'Chemical', '-', (429, 430))	('l', 'Chemical', '-', (430, 431))	('l', 'Chemical', '-', (224, 225))	('l', 'Chemical', '-', (286, 287))	('l', 'Chemical', '-', (341, 342))	('l', 'Chemical', '-', (8, 9))
100728	31240524	However, in 3 out of 27 samples (patients 6, 15 and 19), we observed an increased antibody signal towards IDH1R132H peptide (Fig.	('increased', 'PosReg', (72, 81))	('patients', 'Species', '9606', (33, 41))	('IDH1R132H', 'Var', (106, 115))	('l', 'Chemical', '-', (28, 29))	('antibody signal', 'MPA', (82, 97))	('l', 'Chemical', '-', (96, 97))	('increased antibody', 'Phenotype', 'HP:0010702', (72, 90))
100731	31240524	These findings argue that no IDH1R132H-specific antibodies are present in serum of 27 IDH1R132H-mutant LGG patients.	('LGG', 'Disease', (103, 106))	('patients', 'Species', '9606', (107, 115))	('IDH1R132H-mutant', 'Var', (86, 102))
100733	31240524	For this, PBMCs, that contain a mixture of antigen presenting cells and effector T cells, were derived from 30 LGG patients and loaded with IDH1R132H peptide or control peptides, and after a short-term stimulation, T cells were assessed for up-regulated surface expression of CD137 and production of IFN-gamma, both measures of TCR-mediated activation.	('l', 'Chemical', '-', (207, 208))	('IDH1R132H', 'Var', (140, 149))	('l', 'Chemical', '-', (64, 65))	('production', 'MPA', (286, 296))	('TCR', 'Gene', (328, 331))	('l', 'Chemical', '-', (86, 87))	('IFN-gamma', 'Gene', '3458', (300, 309))	('IFN-gamma', 'Gene', (300, 309))	('l', 'Chemical', '-', (85, 86))	('l', 'Chemical', '-', (219, 220))	('l', 'Chemical', '-', (220, 221))	('patients', 'Species', '9606', (115, 123))	('l', 'Chemical', '-', (248, 249))	('surface expression', 'MPA', (254, 272))	('up-regulated', 'PosReg', (241, 253))	('TCR', 'Gene', '6962', (328, 331))	('CD137', 'Gene', (276, 281))	('CD137', 'Gene', '3604', (276, 281))	('l', 'Chemical', '-', (167, 168))	('l', 'Chemical', '-', (65, 66))	('l', 'Chemical', '-', (128, 129))
100734	31240524	As the used IDH1R132H peptide has been reported to be promiscuous with respect to MHC class II, particularly HLA-DR alleles, no pre-selection of LGG patients was performed based on HLA alleles.	('l', 'Chemical', '-', (187, 188))	('l', 'Chemical', '-', (118, 119))	('patients', 'Species', '9606', (149, 157))	('HLA', 'Gene', '3123', (109, 112))	('l', 'Chemical', '-', (106, 107))	('l', 'Chemical', '-', (120, 121))	('l', 'Chemical', '-', (134, 135))	('HLA', 'Gene', (109, 112))	('l', 'Chemical', '-', (103, 104))	('MHC', 'Gene', (82, 85))	('l', 'Chemical', '-', (189, 190))	('HLA', 'Gene', '3123', (181, 184))	('HLA', 'Gene', (181, 184))	('l', 'Chemical', '-', (87, 88))	('MHC', 'Gene', '3107', (82, 85))	('l', 'Chemical', '-', (117, 118))	('l', 'Chemical', '-', (186, 187))	('IDH1R132H', 'Var', (12, 21))
100735	31240524	None of 30 patient PBMC samples stimulated with IDH1R132H peptide showed an increased frequency of CD4 T cells expressing CD137 compared to non-mutated peptide (Fig.	('l', 'Chemical', '-', (37, 38))	('CD4', 'Gene', '920', (99, 102))	('IDH1R132H peptide', 'Var', (48, 65))	('patient', 'Species', '9606', (11, 18))	('l', 'Chemical', '-', (28, 29))	('l', 'Chemical', '-', (107, 108))	('CD4', 'Gene', (99, 102))	('CD137', 'Gene', '3604', (122, 127))	('l', 'Chemical', '-', (108, 109))	('CD137', 'Gene', (122, 127))
100737	31240524	No increased frequency of CD137-positive CD8 T cells was observed in mutant peptide stimulation conditions either (data not shown).	('l', 'Chemical', '-', (50, 51))	('mutant', 'Var', (69, 75))	('l', 'Chemical', '-', (89, 90))	('CD8', 'Gene', (41, 44))	('CD8', 'Gene', '925', (41, 44))	('CD137', 'Gene', (26, 31))	('CD137', 'Gene', '3604', (26, 31))	('l', 'Chemical', '-', (49, 50))
100738	31240524	With respect to IFN-gamma, measured in supernatants from the same samples, again no enhanced responses were observed in IDH1 mutant versus wildtype peptide stimulations (Fig.	('mutant', 'Var', (125, 131))	('l', 'Chemical', '-', (161, 162))	('IDH1', 'Gene', (120, 124))	('IFN-gamma', 'Gene', '3458', (16, 25))	('IFN-gamma', 'Gene', (16, 25))	('IDH1', 'Gene', '3417', (120, 124))	('l', 'Chemical', '-', (70, 71))	('l', 'Chemical', '-', (141, 142))
100743	31240524	In the current study, we have co-cultured patient PBMC with HeLa cells stably expressing HLA-DR1 or DR4, two alleles that were described to facilitate IDH1R132H peptide-specific T cell responses, and loaded with IDH1R132H peptide (Fig.	('l', 'Chemical', '-', (183, 184))	('patient', 'Species', '9606', (42, 49))	('l', 'Chemical', '-', (182, 183))	('DR4', 'Gene', (100, 103))	('l', 'Chemical', '-', (110, 111))	('T cell responses', 'CPA', (178, 194))	('HLA', 'Gene', '3123', (89, 92))	('l', 'Chemical', '-', (67, 68))	('DR1', 'Gene', '1810', (93, 96))	('DR4', 'Gene', '3126', (100, 103))	('l', 'Chemical', '-', (75, 76))	('DR1', 'Gene', (93, 96))	('l', 'Chemical', '-', (68, 69))	('l', 'Chemical', '-', (35, 36))	('l', 'Chemical', '-', (200, 201))	('HeLa', 'CellLine', 'CVCL:0030', (60, 64))	('HLA', 'Gene', (89, 92))	('l', 'Chemical', '-', (113, 114))	('l', 'Chemical', '-', (144, 145))	('IDH1R132H', 'Var', (151, 160))	('l', 'Chemical', '-', (111, 112))	('facilitate', 'PosReg', (140, 150))
100745	31240524	Collectively, when using PBMC from LGG patients who harbor the IDH1 mutant, whether or not pre-enriched for T cell reactivity against mutant IDH1 peptide, we did not observe IDH1R132H-specific CD4 T cell responses.	('l', 'Chemical', '-', (201, 202))	('IDH1', 'Gene', (141, 145))	('IDH1', 'Gene', '3417', (63, 67))	('l', 'Chemical', '-', (2, 3))	('patients', 'Species', '9606', (39, 47))	('l', 'Chemical', '-', (112, 113))	('IDH1', 'Gene', '3417', (141, 145))	('CD4', 'Gene', (193, 196))	('l', 'Chemical', '-', (113, 114))	('l', 'Chemical', '-', (10, 11))	('l', 'Chemical', '-', (3, 4))	('IDH1', 'Gene', (174, 178))	('l', 'Chemical', '-', (202, 203))	('CD4', 'Gene', '920', (193, 196))	('IDH1', 'Gene', '3417', (174, 178))	('IDH1', 'Gene', (63, 67))	('mutant', 'Var', (134, 140))	('mutant', 'Var', (68, 74))
100747	31240524	TILs were polyclonally expanded from fresh resection material derived from 10 LGGs (with IDH1 mutation) and were subsequently stimulated with IDH1R132H peptide loaded, irradiated autologous PBMCs.	('l', 'Chemical', '-', (131, 132))	('l', 'Chemical', '-', (15, 16))	('l', 'Chemical', '-', (183, 184))	('l', 'Chemical', '-', (19, 20))	('IDH1', 'Gene', '3417', (142, 146))	('l', 'Chemical', '-', (12, 13))	('l', 'Chemical', '-', (60, 61))	('l', 'Chemical', '-', (160, 161))	('l', 'Chemical', '-', (20, 21))	('l', 'Chemical', '-', (123, 124))	('IDH1', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))	('IDH1', 'Gene', (142, 146))	('IDH1', 'Gene', '3417', (89, 93))
100749	31240524	In this study, we focused on detecting the presence of IDH1R132H-specific T and B cell reactivity in IDH1R132H-mutant LGG patients.	('patients', 'Species', '9606', (122, 130))	('LGG', 'Disease', (118, 121))	('T and', 'CPA', (74, 79))	('IDH1R132H-mutant', 'Var', (101, 117))	('IDH1R132H-specific', 'Var', (55, 73))
100750	31240524	Detection of immune reactivity against this mutated peptide would warrant and at the same time facilitate the development of immunotherapy towards IDH1R132H+ gliomas.	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('l', 'Chemical', '-', (63, 64))	('l', 'Chemical', '-', (99, 100))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('gliomas', 'Disease', (158, 165))	('IDH1R132H+', 'Var', (147, 157))	('l', 'Chemical', '-', (159, 160))	('l', 'Chemical', '-', (114, 115))
100751	31240524	Using various readouts for B and T cell responses, and using sera (n = 27 patients), PBMC (n = 30) as well as TILs (n = 10), we showed that immune cell populations with reactivity towards mutant IDH1 are not present in the LGG patient samples studied here.	('l', 'Chemical', '-', (37, 38))	('patient', 'Species', '9606', (74, 81))	('l', 'Chemical', '-', (156, 157))	('l', 'Chemical', '-', (105, 106))	('l', 'Chemical', '-', (150, 151))	('l', 'Chemical', '-', (239, 240))	('patients', 'Species', '9606', (74, 82))	('l', 'Chemical', '-', (38, 39))	('IDH1', 'Gene', (195, 199))	('patient', 'Species', '9606', (227, 234))	('IDH1', 'Gene', '3417', (195, 199))	('l', 'Chemical', '-', (104, 105))	('l', 'Chemical', '-', (149, 150))	('mutant', 'Var', (188, 194))
100754	31240524	First, levels of IDH1R132H-specific antibodies or frequencies of IDH1R132H-specific CD4 T cells may be below the detection thresholds of assays.	('l', 'Chemical', '-', (93, 94))	('l', 'Chemical', '-', (92, 93))	('l', 'Chemical', '-', (130, 131))	('l', 'Chemical', '-', (105, 106))	('CD4', 'Gene', (84, 87))	('IDH1R132H-specific', 'Var', (17, 35))	('l', 'Chemical', '-', (7, 8))	('l', 'Chemical', '-', (11, 12))	('IDH1R132H-specific', 'Var', (65, 83))	('CD4', 'Gene', '920', (84, 87))
100755	31240524	For instance, among TILs from (multiple and pooled) IDH1R132H-mutant tumors, the frequency of IDH1R132H-specific CD4 T cells was less than 2% (of CD4+ T cells) after vaccinating mice with mutant peptides.	('l', 'Chemical', '-', (47, 48))	('l', 'Chemical', '-', (37, 38))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('CD4', 'Gene', '920', (146, 149))	('l', 'Chemical', '-', (155, 156))	('IDH1R132H-mutant', 'Gene', (52, 68))	('CD4', 'Gene', '920', (113, 116))	('l', 'Chemical', '-', (156, 157))	('mice', 'Species', '10090', (178, 182))	('l', 'Chemical', '-', (122, 123))	('CD4', 'Gene', (146, 149))	('tumors', 'Disease', (69, 75))	('l', 'Chemical', '-', (121, 122))	('CD4', 'Gene', (113, 116))	('IDH1R132H-specific', 'Var', (94, 112))	('l', 'Chemical', '-', (33, 34))	('l', 'Chemical', '-', (129, 130))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
100758	31240524	Along this line, suppression of anti-tumor T cell immunity by the oncometabolite d-2-hydroxyglutarate has also recently been described in LGG, which may further limit local activation of IDH1R132H-specific CD4 T cells.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('l', 'Chemical', '-', (214, 215))	('CD4', 'Gene', (206, 209))	('l', 'Chemical', '-', (215, 216))	('l', 'Chemical', '-', (47, 48))	('l', 'Chemical', '-', (117, 118))	('l', 'Chemical', '-', (93, 94))	('limit', 'NegReg', (161, 166))	('d-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (81, 101))	('l', 'Chemical', '-', (171, 172))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('d-2-hydroxyglutarate', 'Var', (81, 101))	('l', 'Chemical', '-', (107, 108))	('l', 'Chemical', '-', (76, 77))	('l', 'Chemical', '-', (161, 162))	('l', 'Chemical', '-', (11, 12))	('l', 'Chemical', '-', (1, 2))	('CD4', 'Gene', '920', (206, 209))	('l', 'Chemical', '-', (167, 168))	('tumor', 'Disease', (37, 42))	('l', 'Chemical', '-', (48, 49))	('suppression', 'NegReg', (17, 28))
100759	31240524	A tentative low frequency of IDH1R132H-specific CD4 T cells was addressed by pre-enrichment of these cells by co-culturing PBMC of IDH1R132H-mutant patients with HeLa cells presenting IDH1R132H.	('HeLa', 'CellLine', 'CVCL:0030', (162, 166))	('patients', 'Species', '9606', (148, 156))	('l', 'Chemical', '-', (57, 58))	('l', 'Chemical', '-', (170, 171))	('l', 'Chemical', '-', (169, 170))	('CD4', 'Gene', (48, 51))	('l', 'Chemical', '-', (12, 13))	('l', 'Chemical', '-', (104, 105))	('CD4', 'Gene', '920', (48, 51))	('IDH1R132H-mutant', 'Var', (131, 147))	('l', 'Chemical', '-', (103, 104))	('l', 'Chemical', '-', (56, 57))	('l', 'Chemical', '-', (115, 116))
100761	31240524	Although the occurrence of very low frequencies of IDH1R132H-specific T cells cannot be dismissed, and these could be targeted with enrichment protocols using more professional antigen-presenting cells, optimal pMHC bindings or in vivo vaccinations with IDH1R132H, our data do suggest that the immunogenicity of IDH1R132H is low.	('l', 'Chemical', '-', (198, 199))	('l', 'Chemical', '-', (1, 2))	('l', 'Chemical', '-', (74, 75))	('IDH1R132H', 'Var', (312, 321))	('l', 'Chemical', '-', (32, 33))	('MHC', 'Gene', '3107', (212, 215))	('l', 'Chemical', '-', (112, 113))	('l', 'Chemical', '-', (325, 326))	('l', 'Chemical', '-', (150, 151))	('l', 'Chemical', '-', (75, 76))	('l', 'Chemical', '-', (175, 176))	('l', 'Chemical', '-', (209, 210))	('l', 'Chemical', '-', (199, 200))	('MHC', 'Gene', (212, 215))
100776	30808578	Among the most important new markers, particularly for adult low-grade (grade II) gliomas (LGGs), are mutations in the genes encoding isocitrate dehydrogenase isoforms 1 and 2 (IDH1/2), where patients with LGGs (and also HGGs) bearing IDH mutants show longer survival compared to patients having tumors with wild-type status.	('longer', 'PosReg', (252, 258))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('isocitrate dehydrogenase isoforms 1 and 2', 'Gene', '3417;3418', (134, 175))	('IDH', 'Gene', '3417', (177, 180))	('mutations', 'Var', (102, 111))	('gliomas', 'Disease', (82, 89))	('patients', 'Species', '9606', (280, 288))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('patients', 'Species', '9606', (192, 200))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('mutants', 'Var', (239, 246))	('IDH1/2', 'Gene', '3417;3418', (177, 183))	('IDH', 'Gene', (235, 238))	('LGGs', 'Disease', (206, 210))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH1/2', 'Gene', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('IDH', 'Gene', (177, 180))	('tumors', 'Disease', (296, 302))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('IDH', 'Gene', '3417', (235, 238))
100777	30808578	The cellular biochemical/metabolic consequences of such mutations are complicated, and how this relates to the prolonged survival in gliomas is unclear.	('mutations', 'Var', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))
100778	30808578	Nonetheless, the wild-type IDH status often yields a more HGG-like prognosis, ie, low-grade tumors with a natural history more like high-grade tumors, but there is broad heterogeneity of overall survival within that LGG class.	('IDH', 'Gene', (27, 30))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('yields', 'Reg', (44, 50))	('HGG-like', 'Disease', (58, 66))	('IDH', 'Gene', '3417', (27, 30))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('wild-type', 'Var', (17, 26))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
100782	30808578	The 13 subunits and some 30 polypeptides comprising the enzyme complex form a veritable "alphabet soup" of nomenclature, with differential subunit expression defining subcellular localization and tissue specificity; dysregulation of expression and localization are frequently seen in cancers.	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('expression', 'MPA', (233, 243))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('dysregulation', 'Var', (216, 229))	('seen', 'Reg', (276, 280))	('cancers', 'Disease', (284, 291))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))
100785	30808578	This prompted genetic experiments in a Drosophila larvae model (which certainly shows unique potential for screening of genetic interactions and drug treatments); those were followed by intracranial xenograft studies in mice, all demonstrating that V1 subunit differences have in vivo relevance for tumor growth and invasiveness.	('Drosophila', 'Species', '7227', (39, 49))	('invasiveness', 'CPA', (316, 328))	('tumor', 'Disease', (299, 304))	('mice', 'Species', '10090', (220, 224))	('differences', 'Var', (260, 271))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))
100786	30808578	The authors extended the V-ATPase subunit expression studies across gliomas and into LGGs with wild-type or mutated IDH1/2 to develop possible patterns of expression correlating with tumor grade, IDH mutation status, and other differentially-expressed genes.	('IDH', 'Gene', (116, 119))	('mutated', 'Var', (108, 115))	('IDH', 'Gene', '3417', (116, 119))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH', 'Gene', '3417', (196, 199))	('V-ATPase', 'Gene', '41550', (25, 33))	('V-ATPase', 'Gene', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('IDH1/2', 'Gene', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('tumor', 'Disease', (183, 188))	('IDH1/2', 'Gene', '3417;3418', (116, 122))	('IDH', 'Gene', (196, 199))
100787	30808578	They evaluated three datasets (TCGA, Gravendeel, and an in-house cohort), and in the end, determined that expression levels of three V-ATPase subunits (ATP6V1G2, ATPV0A1, and ATPV1C1-and probably upregulation of ATPV1G1 [Uniprot designations]) could implicate more HGG-like outcomes for patients with LGGs that were wild-type for IDH.	('V-ATPase', 'Gene', (133, 141))	('implicate', 'Reg', (250, 259))	('IDH', 'Gene', (330, 333))	('IDH', 'Gene', '3417', (330, 333))	('ATP', 'Chemical', 'MESH:D000255', (175, 178))	('ATP', 'Chemical', 'MESH:D000255', (212, 215))	('patients', 'Species', '9606', (287, 295))	('LGGs', 'Disease', (301, 305))	('HGG-like outcomes', 'Disease', (265, 282))	('ATP', 'Chemical', 'MESH:D000255', (135, 138))	('ATP6V1G2', 'Gene', '534', (152, 160))	('ATP', 'Chemical', 'MESH:D000255', (162, 165))	('ATP', 'Chemical', 'MESH:D000255', (152, 155))	('ATP6V1G2', 'Gene', (152, 160))	('ATPV1C1-and', 'Var', (175, 186))	('V-ATPase', 'Gene', '41550', (133, 141))
100829	28845308	High-resolution whole-brain structural scans were acquired for all patients as reference for the resting-state maps (3D T1-weighted sequence: TR/TE = 8.40/3.80 ms, flip angle = 8 degrees, slice orientation = sagittal, 1 x 1 x 1 mm voxel size, with varying FOV (158 x 254 x 254 in 48 patients; 175 x 240 x 240 in 27 patients; 175 x 288 x 288 in 4 patients, and 160 x 240 x 240 in 1 patient)).	('175 x 240 x 240', 'Var', (293, 308))	('175 x 288 x 288', 'Var', (325, 340))	('patient', 'Species', '9606', (315, 322))	('patient', 'Species', '9606', (346, 353))	('patients', 'Species', '9606', (67, 75))	('patients', 'Species', '9606', (283, 291))	('160 x 240 x 240', 'Var', (360, 375))	('patients', 'Species', '9606', (346, 354))	('patient', 'Species', '9606', (381, 388))	('patients', 'Species', '9606', (315, 323))	('patient', 'Species', '9606', (283, 290))	('patient', 'Species', '9606', (67, 74))
100856	28845308	The hemisphere contralateral to the lesion of LGG patients is thus characterized by lower segregation and higher integration compared to that of HGG patients.	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (50, 58))	('higher', 'PosReg', (106, 112))	('segregation', 'MPA', (90, 101))	('LGG', 'Disease', (46, 49))	('integration', 'MPA', (113, 124))	('lower', 'NegReg', (84, 89))	('lesion', 'Var', (36, 42))
100889	28845308	We conclude that the hemisphere contralateral to the lesion of LGG patients is characterized by lower segregation and higher integration compared to that of HGG patients.	('higher', 'PosReg', (118, 124))	('patients', 'Species', '9606', (67, 75))	('segregation', 'MPA', (102, 113))	('LGG', 'Disease', (63, 66))	('integration', 'MPA', (125, 136))	('lower', 'NegReg', (96, 101))	('patients', 'Species', '9606', (161, 169))	('lesion', 'Var', (53, 59))
100897	28401060	In recent years, alterations in histone acetylation have provided novel opportunities to explore new pharmacological targeting, with histone deacetylase (HDAC) overexpression reported in high-grade, late-stage proliferative tumors.	('acetylation', 'MPA', (40, 51))	('overexpression', 'PosReg', (160, 174))	('proliferative tumors', 'Disease', (210, 230))	('proliferative tumors', 'Disease', 'MESH:D001948', (210, 230))	('histone deacetylase', 'Gene', (133, 152))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('alterations', 'Var', (17, 28))	('HDAC', 'Gene', (154, 158))	('histone deacetylase', 'Gene', '9734', (133, 152))	('HDAC', 'Gene', '9734', (154, 158))
100906	28401060	A classic epigenetic modification in adult glioblastoma is DNA hypermethylation of the enzyme O-6-methylguanine-DNA methyltransferase, which suppresses its normal function to remove alkyl groups from DNA.	('hypermethylation', 'Var', (63, 79))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (94, 133))	('adult glioblastoma', 'Disease', (37, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('DNA hypermethylation', 'Var', (59, 79))	('adult glioblastoma', 'Disease', 'MESH:D005909', (37, 55))	('function', 'MPA', (163, 171))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (94, 133))	('remove alkyl groups', 'MPA', (175, 194))
100913	28401060	In particular, the N-terminal tails of histones contain lysine (K) and arginine (R) residues that can undergo posttranslational modifications including acetylation, methylation, ubiquitylation, and sumoylation, as well as serines that can be phosphorylated.	('methylation', 'MPA', (165, 176))	('acetylation', 'MPA', (152, 163))	('sumoylation', 'MPA', (198, 209))	('arginine', 'Chemical', 'MESH:D001120', (71, 79))	('histones', 'Protein', (39, 47))	('serines', 'Chemical', 'MESH:D012694', (222, 229))	('ubiquitylation', 'MPA', (178, 192))	('lysine', 'Var', (56, 62))	('arginine', 'Protein', (71, 79))	('lysine', 'Chemical', 'MESH:D008239', (56, 62))
100914	28401060	were the first to report recurrent mutations of a regulatory histone, H3F3A, in humans by exome sequencing of pediatric glioblastomas (see Figure 1).	('glioblastomas', 'Phenotype', 'HP:0012174', (120, 133))	('pediatric glioblastomas', 'Disease', (110, 133))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (110, 133))	('H3F3A', 'Gene', '3020', (70, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('H3F3A', 'Gene', (70, 75))	('humans', 'Species', '9606', (80, 86))	('mutations', 'Var', (35, 44))
100916	28401060	Mutations in H3F3A involve two critical single-point mutations in the histone tail at lysine (K) 27 (K27M) and glycine (G) 34 (G34R/V), both of which are involved with key regulatory posttranscriptional modifications.	('G34R', 'Var', (127, 131))	('H3F3A', 'Gene', '3020', (13, 18))	('lysine', 'Chemical', 'MESH:D008239', (86, 92))	('K27M', 'Var', (101, 105))	('H3F3A', 'Gene', (13, 18))	('glycine', 'Chemical', 'MESH:D005998', (111, 118))	('Mutations', 'Var', (0, 9))	('G34R', 'SUBSTITUTION', 'None', (127, 131))	('K27M', 'Mutation', 'p.K27M', (101, 105))
100917	28401060	As well as being reported in pediatric HGGs, H3.3 mutation are also reported in other childhood cancers such as chondroblastomas and giant cell tumors of the bone.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('giant cell tumors', 'Phenotype', 'HP:0011847', (133, 150))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('tumors of the bone', 'Phenotype', 'HP:0010622', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('H3.3', 'Gene', '3021', (45, 49))	('giant cell tumors of the bone', 'Disease', (133, 162))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('giant cell tumors of the bone', 'Disease', 'MESH:D018212', (133, 162))	('chondroblastomas', 'Disease', (112, 128))	('chondroblastomas', 'Disease', 'MESH:D002804', (112, 128))	('H3.3', 'Gene', (45, 49))	('reported', 'Reg', (68, 76))	('cancers', 'Disease', (96, 103))	('mutation', 'Var', (50, 58))
100918	28401060	K27 is a critical residue in all seven histone 3 variants, and it can be posttranslationally methylated or acetylated.	('K27', 'Gene', (0, 3))	('histone 3', 'Protein', (39, 48))	('K27', 'Gene', '342574', (0, 3))	('variants', 'Var', (49, 57))
100919	28401060	Acetylation may induce active transcription, while monomethylation, dimethylation or trimethylation of K27, catalyzed by the histone methyltransferase enhancer of zeste homologue 2 (EZH2), are repressive marks associated with gene silencing.	('monomethylation', 'Var', (51, 66))	('Acetylation', 'Var', (0, 11))	('enhancer of zeste homologue 2', 'Gene', (151, 180))	('EZH2', 'Gene', (182, 186))	('EZH2', 'Gene', '2146', (182, 186))	('dimethylation', 'Var', (68, 81))	('K27', 'Gene', '342574', (103, 106))	('trimethylation', 'Var', (85, 99))	('enhancer of zeste homologue 2', 'Gene', '2146', (151, 180))	('induce', 'Reg', (16, 22))	('active transcription', 'MPA', (23, 43))	('K27', 'Gene', (103, 106))
100920	28401060	The K27M mutation in certain cases results in decreased dimethylation and trimethylation of H3K27 and is associated with transcriptional activation; however, there are alternative mechanisms by which the K27M increases trimethylation, thus silencing tumor suppressor gene expression.	('transcriptional', 'MPA', (121, 136))	('K27M', 'Mutation', 'p.K27M', (204, 208))	('expression', 'MPA', (272, 282))	('trimethylation', 'MPA', (74, 88))	('K27M', 'Var', (204, 208))	('dimethylation', 'MPA', (56, 69))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('H3K27', 'Gene', (92, 97))	('trimethylation', 'MPA', (219, 233))	('H3K27', 'Gene', '126961', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('decreased', 'NegReg', (46, 55))	('silencing', 'NegReg', (240, 249))	('K27M', 'Var', (4, 8))	('tumor', 'Disease', (250, 255))	('increases', 'PosReg', (209, 218))
100921	28401060	Similarly, the G34R/V mutation results in redistribution of H3K36 methylation and altered gene transcription, including upregulation of the MYCN (V-Myc avian myelocytomatosis viral oncogene neuroblastoma-Derived Homolog) oncogene.	('V-Myc avian myelocytomatosis viral oncogene neuroblastoma', 'Disease', 'MESH:D009447', (146, 203))	('MYCN', 'Gene', (140, 144))	('H3', 'Gene', '126961', (60, 62))	('methylation', 'MPA', (66, 77))	('gene transcription', 'MPA', (90, 108))	('neuroblastoma', 'Phenotype', 'HP:0003006', (190, 203))	('G34R', 'SUBSTITUTION', 'None', (15, 19))	('upregulation', 'PosReg', (120, 132))	('G34R', 'Var', (15, 19))	('altered', 'Reg', (82, 89))	('redistribution', 'PosReg', (42, 56))
100922	28401060	Importantly, H3F3A mutations have been reported to have 100% specificity for pediatric HGGs, with no evidence of the mutations in pediatric low-grade gliomas, embryonal tumors, or ependymomas.	('pediatric HGGs', 'Disease', (77, 91))	('H3F3A', 'Gene', '3020', (13, 18))	('embryonal tumors', 'Phenotype', 'HP:0002898', (159, 175))	('H3F3A', 'Gene', (13, 18))	('embryonal tumors', 'Disease', (159, 175))	('mutations', 'Var', (19, 28))	('gliomas', 'Disease', (150, 157))	('embryonal tumors', 'Disease', 'MESH:D009373', (159, 175))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('ependymomas', 'Disease', 'MESH:D004806', (180, 191))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ependymomas', 'Disease', (180, 191))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
100924	28401060	Moreover, K27M and G34R/V mutations are associated with differing age and tumor location in childhood HGGs.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('childhood HGGs', 'Disease', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('K27M', 'Mutation', 'p.K27M', (10, 14))	('G34R', 'SUBSTITUTION', 'None', (19, 23))	('tumor', 'Disease', (74, 79))	('G34R', 'Var', (19, 23))	('K27M', 'Var', (10, 14))	('associated', 'Reg', (40, 50))
100925	28401060	K27M histone H3.3 mutations occur more commonly in younger children (median age 10.5 years, range 5-23 years) and are present in 70-80% of midline brainstem and thalamic glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('histone H3.3', 'Gene', '3021', (5, 17))	('histone H3.3', 'Gene', (5, 17))	('present', 'Reg', (118, 125))	('K27M', 'Var', (0, 4))	('children', 'Species', '9606', (59, 67))	('midline brainstem and thalamic glioblastoma', 'Disease', 'MESH:D005909', (139, 182))	('mutations', 'Var', (18, 27))
100926	28401060	G34R/V histone H3.3 mutations have been shown to occur more frequently in older children (median age 18 years, range 9-42 years) and are observed almost exclusively in hemispheric gliomas.	('G34R', 'SUBSTITUTION', 'None', (0, 4))	('histone H3.3', 'Gene', (7, 19))	('G34R', 'Var', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('children', 'Species', '9606', (80, 88))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('observed', 'Reg', (137, 145))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('histone H3.3', 'Gene', '3021', (7, 19))	('mutations', 'Var', (20, 29))
100927	28401060	The K27M histone H3.3 mutation is associated with a shorter clinical survival [0.73 years (+-0.48)] (p = 0.0008) compared with patients lacking the mutation [4.59 years (+-5.55)].	('clinical', 'MPA', (60, 68))	('histone H3.3', 'Gene', '3021', (9, 21))	('histone H3.3', 'Gene', (9, 21))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('shorter', 'NegReg', (52, 59))	('patients', 'Species', '9606', (127, 135))	('K27M', 'Var', (4, 8))
100929	28401060	The PRC2 complex has histone methyltransferase activity and silences gene expression by dimethylating or trimethylating H3K27 through its enzymatic subunits, enhancer of zeste homolog 1 and 2 (EZH1 and EZH2).	('PRC2', 'Gene', (4, 8))	('dimethylating', 'MPA', (88, 101))	('EZH2', 'Gene', '2146', (202, 206))	('EZH1', 'Gene', '2145', (193, 197))	('EZH2', 'Gene', (202, 206))	('histone methyltransferase', 'Enzyme', (21, 46))	('trimethylating', 'Var', (105, 119))	('gene expression', 'MPA', (69, 84))	('EZH1', 'Gene', (193, 197))	('activity', 'MPA', (47, 55))	('H3K27', 'Gene', (120, 125))	('H3K27', 'Gene', '126961', (120, 125))	('silences', 'NegReg', (60, 68))
100930	28401060	reported that PRC2 is inhibited by aberrant binding of mutant K27M to EZH2.	('binding', 'Interaction', (44, 51))	('inhibited', 'NegReg', (22, 31))	('mutant K27M', 'Var', (55, 66))	('K27M', 'Mutation', 'p.K27M', (62, 66))	('EZH2', 'Gene', '2146', (70, 74))	('EZH2', 'Gene', (70, 74))	('K27M', 'Var', (62, 66))
100931	28401060	Moreover, K27M alters the enzymatic activity of EZH2, the catalytic subunit of PRC2, which establishes H3K27 methylation, thereby leading to a global reduction of H3K27 methylation and the loss of gene repression (see Figure 1).	('alters', 'Reg', (15, 21))	('H3K27', 'Gene', (103, 108))	('H3K27', 'Gene', '126961', (103, 108))	('H3K27', 'Gene', '126961', (163, 168))	('EZH2', 'Gene', '2146', (48, 52))	('methylation', 'MPA', (169, 180))	('K27M', 'Mutation', 'p.K27M', (10, 14))	('H3K27', 'Gene', (163, 168))	('EZH2', 'Gene', (48, 52))	('gene repression', 'MPA', (197, 212))	('reduction', 'NegReg', (150, 159))	('enzymatic activity', 'MPA', (26, 44))	('methylation', 'MPA', (109, 120))	('K27M', 'Var', (10, 14))	('loss', 'NegReg', (189, 193))
100933	28401060	Subsequently, although mutant K27M results in a global reduction of H3K27 methylation in HGGs, Chan et al.	('reduction', 'NegReg', (55, 64))	('K27M', 'Mutation', 'p.K27M', (30, 34))	('K27M', 'Var', (30, 34))	('mutant K27M', 'Var', (23, 34))	('methylation', 'MPA', (74, 85))	('H3K27', 'Gene', (68, 73))	('H3K27', 'Gene', '126961', (68, 73))
100940	28401060	Although still occurring in pediatric gliomas with mutations in the histone tail of H3.3, the mutation is G34R/V as opposed to K27M.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('G34R', 'Var', (106, 110))	('mutations', 'Var', (51, 60))	('H3.3', 'Gene', '3021', (84, 88))	('K27M', 'Mutation', 'p.K27M', (127, 131))	('H3.3', 'Gene', (84, 88))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('pediatric gliomas', 'Disease', 'MESH:D005910', (28, 45))	('pediatric gliomas', 'Disease', (28, 45))	('G34R', 'SUBSTITUTION', 'None', (106, 110))
100942	28401060	They showed that decreased methylation of H3K36 has been shown to occur through loss of function mutations in the H3K36 methyltransferase SET domain-containing 2.	('mutations', 'Var', (97, 106))	('decreased', 'NegReg', (17, 26))	('methylation', 'MPA', (27, 38))	('H3', 'Gene', '126961', (42, 44))	('loss of function', 'NegReg', (80, 96))	('H3', 'Gene', '126961', (114, 116))
100944	28401060	In addition, the G34R/V mutation was shown to upregulate MYCN, with increased RNA polymerase II binding and transcriptional upregulation at the gene locus, through the differential genomic binding of methylated H3K36 to specific gene loci (see Figure 1).	('upregulation', 'PosReg', (124, 136))	('transcriptional', 'MPA', (108, 123))	('G34R', 'Var', (17, 21))	('upregulate', 'PosReg', (46, 56))	('MYCN', 'Disease', (57, 61))	('binding', 'Interaction', (96, 103))	('binding', 'Interaction', (189, 196))	('RNA polymerase', 'Protein', (78, 92))	('G34R', 'SUBSTITUTION', 'None', (17, 21))	('increased', 'PosReg', (68, 77))	('H3', 'Gene', '126961', (211, 213))
100947	28401060	These insights provide opportunities for novel ways to target specific genetic and epigenetic aberrations in H3.3 G34R/V mutated pediatric HGGs.	('genetic aberrations', 'Disease', 'MESH:D030342', (86, 105))	('H3.3', 'Gene', (109, 113))	('genetic aberrations', 'Disease', (86, 105))	('G34R', 'SUBSTITUTION', 'None', (114, 118))	('G34R', 'Var', (114, 118))	('H3.3', 'Gene', '3021', (109, 113))
100948	28401060	G34R/V mutations occurring in hemispheric pediatric HGG, frequently display mutations in TP53, ATRX (alpha-thalassemia/mental retardation syndrome X-linked), and DAXX (death domain-associated protein), unlike the K27M mutated HGGs.	('G34R', 'SUBSTITUTION', 'None', (0, 4))	('ATRX', 'Gene', (95, 99))	('TP53', 'Gene', '7157', (89, 93))	('G34R', 'Var', (0, 4))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (76, 85))	('DAXX', 'Gene', '1616', (162, 166))	('K27M', 'Mutation', 'p.K27M', (213, 217))	('ATRX', 'Gene', '546', (95, 99))	('mental retardation', 'Phenotype', 'HP:0001249', (119, 137))	('DAXX', 'Gene', (162, 166))	('alpha-thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (101, 155))	('mutations', 'Var', (7, 16))
100949	28401060	reported 100% of patients with H3.3 mutated G34R/V glioblastoma and who had mutations in ATRX and DAXX, which encode two subunits required for H3.3 incorporation at centromeres and telomeres.	('DAXX', 'Gene', (98, 102))	('mutations', 'Var', (76, 85))	('H3.3', 'Gene', (31, 35))	('H3.3', 'Gene', '3021', (143, 147))	('ATRX', 'Gene', (89, 93))	('G34R', 'Var', (44, 48))	('H3.3', 'Gene', (143, 147))	('V glioblastoma', 'Disease', 'MESH:D005909', (49, 63))	('patients', 'Species', '9606', (17, 25))	('ATRX', 'Gene', '546', (89, 93))	('DAXX', 'Gene', '1616', (98, 102))	('G34R', 'SUBSTITUTION', 'None', (44, 48))	('H3.3', 'Gene', '3021', (31, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('V glioblastoma', 'Disease', (49, 63))
100950	28401060	further investigated mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway in pediatric glioblastoma.	('DAXX', 'Gene', '1616', (48, 52))	('ATRX', 'Gene', '546', (43, 47))	('pediatric glioblastoma', 'Disease', (85, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('H3.3', 'Gene', '3021', (38, 42))	('DAXX', 'Gene', (48, 52))	('investigated', 'Reg', (8, 20))	('H3.3', 'Gene', (38, 42))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (85, 107))	('ATRX', 'Gene', (43, 47))	('mutations', 'Var', (21, 30))
100952	28401060	The combinatorial methylation loss of these histones was associated with H3F3A-ATRX mutations, with 60% of K27M cases and 75% of G34R mutant cases displaying ATRX loss.	('K27M', 'Var', (107, 111))	('ATRX', 'Gene', (158, 162))	('associated', 'Reg', (57, 67))	('methylation', 'MPA', (18, 29))	('mutations', 'Var', (84, 93))	('ATRX', 'Gene', (79, 83))	('ATRX', 'Gene', '546', (158, 162))	('K27M', 'Mutation', 'p.K27M', (107, 111))	('G34R', 'Mutation', 'rs1057519902', (129, 133))	('H3F3A', 'Gene', '3020', (73, 78))	('ATRX', 'Gene', '546', (79, 83))	('loss', 'NegReg', (30, 34))	('G34R', 'Var', (129, 133))	('H3F3A', 'Gene', (73, 78))
100953	28401060	H3F3A/ATRX-DAXX/TP53 mutations are strongly associated with alternative lengthening of telomeres, a telomerase-independent telomere maintenance mechanism that could allow unlimited cellular proliferation in pediatric glioblastoma.	('mutations', 'Var', (21, 30))	('pediatric glioblastoma', 'Disease', (207, 229))	('DAXX', 'Gene', '1616', (11, 15))	('H3F3A', 'Gene', '3020', (0, 5))	('ATRX', 'Gene', (6, 10))	('H3F3A', 'Gene', (0, 5))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (207, 229))	('DAXX', 'Gene', (11, 15))	('ATRX', 'Gene', '546', (6, 10))	('TP53', 'Gene', '7157', (16, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('TP53', 'Gene', (16, 20))	('associated with', 'Reg', (44, 59))
100954	28401060	A high proportion of low-grade gliomas and secondary glioblastomas have been shown to harbor mutations in isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) (see Figure 1).	('IDH2', 'Gene', (145, 149))	('IDH1', 'Gene', '3417', (140, 144))	('glioblastomas', 'Phenotype', 'HP:0012174', (53, 66))	('mutations', 'Var', (93, 102))	('glioblastomas', 'Disease', 'MESH:D005909', (53, 66))	('glioblastomas', 'Disease', (53, 66))	('IDH2', 'Gene', '3418', (145, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH1', 'Gene', (140, 144))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
100957	28401060	The mutation of IDH1 results in loss of normal enzymatic function and leads to the abnormal production of 2-hydroxyglutarate (2-HG).	('loss', 'NegReg', (32, 36))	('mutation', 'Var', (4, 12))	('leads to', 'Reg', (70, 78))	('IDH1', 'Gene', (16, 20))	('IDH1', 'Gene', '3417', (16, 20))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (106, 124))	('normal enzymatic function', 'MPA', (40, 65))
100959	28401060	Although IDH1 mutations are relatively uncommon in pediatric glioblastoma, single amino acid substitutions of arginine result in gain of function mutations in IDH1 [commonly arginine to histidine (R132H)] and occur frequently in young adults with secondary glioblastoma, which has progressed from lower grade neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (309, 318))	('IDH1', 'Gene', (9, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (257, 269))	('arginine to', 'Var', (174, 185))	('histidine', 'Chemical', 'MESH:D006639', (186, 195))	('gain of function', 'PosReg', (129, 145))	('IDH1', 'Gene', (159, 163))	('neoplasms', 'Disease', (309, 318))	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', (257, 269))	('IDH1', 'Gene', '3417', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (257, 269))	('pediatric glioblastoma', 'Disease', (51, 73))	('arginine', 'Chemical', 'MESH:D001120', (174, 182))	('IDH1', 'Gene', '3417', (159, 163))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('neoplasms', 'Phenotype', 'HP:0002664', (309, 318))	('R132H', 'Mutation', 'rs121913500', (197, 202))	('mutations', 'Var', (146, 155))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (51, 73))
100960	28401060	IDH1 mutational status has been shown to be a positive prognosticator for survival in patients with glioblastoma.	('IDH1', 'Gene', '3417', (0, 4))	('glioblastoma', 'Disease', (100, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('mutational status', 'Var', (5, 22))	('IDH1', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('patients', 'Species', '9606', (86, 94))
100962	28401060	2-HG inhibits histone demethylases and is associated with a distinct G-CIMP, specifically increasing methylation of H3K27 and H3K36, which has been associated with a block in cell differentiation (see Figure 1).	('H3', 'Gene', '126961', (126, 128))	('G-CIMP', 'Chemical', '-', (69, 75))	('methylation', 'MPA', (101, 112))	('G-CIMP', 'Disease', (69, 75))	('2-HG', 'Var', (0, 4))	('H3K27', 'Gene', (116, 121))	('H3K27', 'Gene', '126961', (116, 121))	('inhibits', 'NegReg', (5, 13))	('histone', 'Protein', (14, 21))	('increasing', 'PosReg', (90, 100))	('H3', 'Gene', '126961', (116, 118))
100963	28401060	Furthermore, the IDH1 mutations promoting methylation are associated with mutations in TP53.	('TP53', 'Gene', '7157', (87, 91))	('methylation', 'MPA', (42, 53))	('mutations', 'Var', (74, 83))	('TP53', 'Gene', (87, 91))	('IDH1', 'Gene', (17, 21))	('promoting', 'PosReg', (32, 41))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', '3417', (17, 21))
100965	28401060	The importance of identifying IDH1 mutation status is important for prognosis in this subgroup, with the opportunity to explore 2-HG inhibition and the potential to prevent the transformation of a low-grade malignancy to a HGG.	('IDH1', 'Gene', (30, 34))	('malignancy', 'Disease', 'MESH:D009369', (207, 217))	('2-HG', 'Protein', (128, 132))	('mutation', 'Var', (35, 43))	('malignancy', 'Disease', (207, 217))	('IDH1', 'Gene', '3417', (30, 34))
100966	28401060	has provided a possible explanation for the paucity of H3.3 mutations in adult glioblastoma, by mutation-independent abnormalities in histone biology.	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('adult glioblastoma', 'Disease', (73, 91))	('adult glioblastoma', 'Disease', 'MESH:D005909', (73, 91))	('H3.3', 'Gene', '3021', (55, 59))	('histone', 'MPA', (134, 141))	('mutations', 'Var', (60, 69))	('H3.3', 'Gene', (55, 59))
100971	28401060	Overexpression of MLL5 in glioblastoma primary cultures led to decreased H3.3, while knockdown of MLL5 led to increased H3.3 protein, showing a direct role for MLL5 in repressing H3.3.	('MLL5', 'Gene', (160, 164))	('glioblastoma', 'Disease', (26, 38))	('increased', 'PosReg', (110, 119))	('decreased', 'NegReg', (63, 72))	('MLL5', 'Gene', '55904', (18, 22))	('H3.3', 'Gene', '3021', (120, 124))	('H3.3', 'Gene', '3021', (179, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('MLL5', 'Gene', (98, 102))	('H3.3', 'Gene', (120, 124))	('MLL5', 'Gene', '55904', (160, 164))	('H3.3', 'Gene', '3021', (73, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('knockdown', 'Var', (85, 94))	('MLL5', 'Gene', (18, 22))	('H3.3', 'Gene', (179, 183))	('MLL5', 'Gene', '55904', (98, 102))	('H3.3', 'Gene', (73, 77))
100976	28401060	Epigenetic modifications of histone proteins occur through IDH1 mutation and induction of the G-CIMP phenotype.	('IDH1', 'Gene', '3417', (59, 63))	('mutation', 'Var', (64, 72))	('Epigenetic modifications', 'MPA', (0, 24))	('G-CIMP', 'Chemical', '-', (94, 100))	('occur', 'Reg', (45, 50))	('G-CIMP', 'Disease', (94, 100))	('induction', 'Reg', (77, 86))	('IDH1', 'Gene', (59, 63))	('histone proteins', 'Protein', (28, 44))
100982	28401060	This provides a mechanism by which patients with mutated IDH1 have a better survival compared to those with wild-type IDH1.	('mutated', 'Var', (49, 56))	('IDH1', 'Gene', (118, 122))	('survival', 'MPA', (76, 84))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (118, 122))	('better', 'PosReg', (69, 75))	('IDH1', 'Gene', '3417', (57, 61))	('patients', 'Species', '9606', (35, 43))
100993	28401060	The Cancer Genome Atlas used genome-wide sequencing of 284 glioblastoma samples to identify somatic mutations in genes involved with histone modifications and identified somatic mutations in HDAC2.	('mutations', 'Var', (100, 109))	('HDAC2', 'Gene', (191, 196))	('HDAC2', 'Gene', '3066', (191, 196))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('glioblastoma', 'Disease', (59, 71))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('Cancer Genome Atlas', 'Disease', (4, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('mutations', 'Var', (178, 187))
100996	28401060	In contrast, HDAC I overexpression has been reported in high-grade, late-stage proliferative tumors, supporting the rationale for the use of HDAC inhibitors in promoting the re-expression of silenced tumor suppressor genes in glioblastoma, as well as a more open chromatin structure facilitating access for DNA damaging agents.	('inhibitors', 'Var', (146, 156))	('glioblastoma', 'Disease', 'MESH:D005909', (226, 238))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('re-expression', 'MPA', (174, 187))	('glioblastoma', 'Disease', (226, 238))	('proliferative tumors', 'Disease', 'MESH:D001948', (79, 99))	('tumor', 'Disease', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('HDAC', 'Gene', '9734', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('HDAC', 'Gene', '9734', (141, 145))	('promoting', 'PosReg', (160, 169))	('HDAC', 'Gene', (13, 17))	('proliferative tumors', 'Disease', (79, 99))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('HDAC', 'Gene', (141, 145))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
101048	28401060	With increasing knowledge of oncogenic epigenetic changes underlying HGGs, such as the H3.3 K27M mutation, targeting to reverse these changes has been explored, although to date the field is far less advanced than HDAC inhibition.	('K27M mutation', 'Var', (92, 105))	('HDAC', 'Gene', (214, 218))	('H3.3', 'Gene', '3021', (87, 91))	('HDAC', 'Gene', '9734', (214, 218))	('K27M', 'Mutation', 'p.K27M', (92, 96))	('H3.3', 'Gene', (87, 91))
101053	28401060	With the knowledge of H3.3 mutations and subsequent aberrant histone methylation, a recent study by Grasso et al.	('mutations', 'Var', (27, 36))	('H3.3', 'Gene', '3021', (22, 26))	('histone methylation', 'MPA', (61, 80))	('H3.3', 'Gene', (22, 26))	('aberrant', 'Var', (52, 60))
101056	28401060	Western blot analyses of cells expressing the H3.3 K27M mutation showed that following panobinostat treatment, there was an increase in H3 acetylation and H3K27 methylation, suggesting there is a partial rescue of the H3.3 K27M-induced global hypomethylator phenotype CHOP.	('methylation', 'MPA', (161, 172))	('increase', 'PosReg', (124, 132))	('H3.3', 'Gene', (46, 50))	('panobinostat', 'Chemical', 'MESH:D000077767', (87, 99))	('H3K27', 'Gene', (155, 160))	('H3.3', 'Gene', (218, 222))	('K27M', 'Mutation', 'p.K27M', (51, 55))	('H3K27', 'Gene', '126961', (155, 160))	('H3', 'Gene', '126961', (136, 138))	('K27M', 'Mutation', 'p.K27M', (223, 227))	('H3', 'Gene', '126961', (155, 157))	('global hypomethylator', 'MPA', (236, 257))	('mutation', 'Var', (56, 64))	('H3.3', 'Gene', '3021', (46, 50))	('H3', 'Gene', '126961', (218, 220))	('H3', 'Gene', '126961', (46, 48))	('H3.3', 'Gene', '3021', (218, 222))
101058	28401060	As well as targeting HDAC inhibition, EZH2 inhibition provides an alternative mechanism to prevent aberrant histone methylation of target genes, which may promote cell differentiation and prevent cell proliferation in several tissues.	('HDAC', 'Gene', '9734', (21, 25))	('inhibition', 'Var', (43, 53))	('cell proliferation in several tissues', 'CPA', (196, 233))	('cell differentiation', 'CPA', (163, 183))	('prevent', 'NegReg', (188, 195))	('EZH2', 'Gene', '2146', (38, 42))	('EZH2', 'Gene', (38, 42))	('promote', 'PosReg', (155, 162))	('histone', 'Protein', (108, 115))	('HDAC', 'Gene', (21, 25))
101060	28401060	By using pharmacological inhibition of EZH2, the aggressiveness of rhabdomyosarcoma is less with a more differentiated phenotype.	('pharmacological inhibition', 'Var', (9, 35))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (67, 83))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))	('aggressiveness of rhabdomyosarcoma', 'Disease', (49, 83))	('aggressiveness of rhabdomyosarcoma', 'Disease', 'MESH:D012208', (49, 83))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))
101061	28401060	This provides further treatment options for rhabdomyosarcoma by using EZH2 inhibitors as adjuvant therapy, thus with a likely possibility of increasing the effectiveness of current conventional treatment.	('inhibitors', 'Var', (75, 85))	('rhabdomyosarcoma', 'Disease', (44, 60))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (44, 60))	('EZH2', 'Gene', '2146', (70, 74))	('increasing', 'PosReg', (141, 151))	('EZH2', 'Gene', (70, 74))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (44, 60))
101063	28401060	Phase I pediatric and phase II adult clinical trials are underway to investigate the efficacy of EZH2 inhibitors in hematological malignancies, as well as genetically defined solid tumors, including mesothelioma and malignant rhabdoid tumors ( identifier: NCT 02601937 and NCT 02601950).	('malignant rhabdoid tumors', 'Disease', (216, 241))	('hematological malignancies', 'Disease', (116, 142))	('NCT 02601950', 'Var', (273, 285))	('hematological malignancies', 'Disease', 'MESH:D019337', (116, 142))	('mesothelioma', 'Disease', (199, 211))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('solid tumors', 'Disease', (175, 187))	('EZH2', 'Gene', '2146', (97, 101))	('inhibitors', 'Var', (102, 112))	('hematological malignancies', 'Phenotype', 'HP:0004377', (116, 142))	('mesothelioma', 'Disease', 'MESH:D008654', (199, 211))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (216, 241))	('solid tumors', 'Disease', 'MESH:D009369', (175, 187))	('EZH2', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
101064	28401060	Although this review has focused predominantly on aberrations in histone H3K27 methylation, aberrations in methylation and acetylation of other histone proteins may provide positive or negative prognostic indicators for patients with glioma.	('methylation', 'MPA', (79, 90))	('negative', 'NegReg', (185, 193))	('H3K27', 'Gene', (73, 78))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('acetylation', 'MPA', (123, 134))	('H3K27', 'Gene', '126961', (73, 78))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('methylation', 'MPA', (107, 118))	('patients', 'Species', '9606', (220, 228))	('aberrations', 'Var', (92, 103))	('glioma', 'Disease', (234, 240))
101069	28401060	This study highlights the potential prognostic impact of epigenetic changes in patients with HGG.	('epigenetic changes', 'Var', (57, 75))	('patients', 'Species', '9606', (79, 87))	('HGG', 'Disease', (93, 96))
101071	28401060	Finally, the targeting of genetic mutations in combination with epigenetic aberrations may increase the likelihood of successfully treating adult and pediatric HGG.	('genetic aberrations', 'Disease', (67, 86))	('genetic mutations', 'Var', (26, 43))	('genetic aberrations', 'Disease', 'MESH:D030342', (67, 86))
101073	28401060	ACVR1 mutations were found to cosegregate with histone H3.1 K27M mutated DIPG.	('K27M', 'Mutation', 'p.K27M', (60, 64))	('DIPG', 'Chemical', '-', (73, 77))	('histone H3.1', 'Gene', '8350', (47, 59))	('ACVR1', 'Gene', (0, 5))	('K27M mutated', 'Var', (60, 72))	('ACVR1', 'Gene', '90', (0, 5))	('mutations', 'Var', (6, 15))	('histone H3.1', 'Gene', (47, 59))
101074	28401060	Previously, in patients with the autosomal dominant congenital childhood developmental disorder fibrodysplasia ossificans progressiva, identical ACVR1 mutations have been shown to constitutively activate the bone morphogenic protein (BMP)-dependent transforming growth factor-beta pathway.	('ACVR1', 'Gene', '90', (145, 150))	('BMP', 'Gene', (234, 237))	('patients', 'Species', '9606', (15, 23))	('activate', 'PosReg', (195, 203))	('autosomal dominant congenital childhood developmental disorder fibrodysplasia', 'Disease', 'MESH:D001848', (33, 110))	('childhood developmental disorder', 'Phenotype', 'HP:0000729', (63, 95))	('ACVR1', 'Gene', (145, 150))	('BMP', 'Gene', '649', (234, 237))	('mutations', 'Var', (151, 160))	('developmental disorder', 'Phenotype', 'HP:0001263', (73, 95))
101077	28401060	The discovery of aberrant histone modifications propagating gliomagenesis has allowed the exploration of HDAC inhibitors and histone demethylase inhibitors in an attempt to combat an aggressive brain tumor.	('propagating', 'Reg', (48, 59))	('brain tumor', 'Disease', (194, 205))	('aberrant', 'Var', (17, 25))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('brain tumor', 'Disease', 'MESH:D001932', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('brain tumor', 'Phenotype', 'HP:0030692', (194, 205))	('HDAC', 'Gene', (105, 109))	('glioma', 'Disease', (60, 66))	('HDAC', 'Gene', '9734', (105, 109))	('aggressive brain', 'Phenotype', 'HP:0000718', (183, 199))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
101078	28401060	Current limitations of epigenetic targeting remain a challenge; in particular, the mechanism of HDAC inhibitors and their effect on cellular signaling pathways remains to be elucidated, and the effects of broadly altering functional epigenetic changes is unpredictable.	('HDAC', 'Gene', '9734', (96, 100))	('inhibitors', 'Var', (101, 111))	('cellular signaling pathways', 'Pathway', (132, 159))	('HDAC', 'Gene', (96, 100))
101083	28401060	Targeting multiple epigenetic and genetic aberrations will likely be the key to succeeding in treating HGGs, and future clinical trials are needed to further explore combination therapies, alongside novel techniques to improve the penetration of the blood-brain barrier.	('HGGs', 'Disease', (103, 107))	('epigenetic', 'Var', (19, 29))	('genetic aberrations', 'Disease', 'MESH:D030342', (34, 53))	('genetic aberrations', 'Disease', (34, 53))
101199	27248706	First, a recent study on glioma showed that the distinct tumor microtubes can serve as routes for brain invasion, proliferation, and interconnection over long distances, providing anatomical evidence that the alteration of the posterior DMN reflects the interruption of the anterior DMN.	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('alteration', 'Var', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('glioma', 'Disease', (25, 31))
101211	31615936	Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse free and metastasis free survival in high-grade chondrosarcoma Chondrosarcomas are the second most common primary malignant bone tumors.	('Chondrosarcomas', 'Disease', 'MESH:D002813', (146, 161))	('Chondrosarcomas', 'Phenotype', 'HP:0006765', (146, 161))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('longer', 'PosReg', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('metastasis free', 'CPA', (92, 107))	('association', 'Interaction', (29, 40))	('chondrosarcoma', 'Disease', 'MESH:D002813', (131, 145))	('IDH1', 'Gene', (44, 48))	('chondrosarcoma', 'Disease', (131, 145))	('malignant bone tumors', 'Disease', (197, 218))	('IDH2', 'Gene', (49, 53))	('bone tumors', 'Phenotype', 'HP:0010622', (207, 218))	('mutation', 'Var', (54, 62))	('IDH2', 'Gene', '3418', (49, 53))	('malignant bone tumors', 'Disease', 'MESH:D009369', (197, 218))	('Chondrosarcomas', 'Disease', (146, 161))	('IDH1', 'Gene', '3417', (44, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (131, 145))
101213	31615936	IDH1 and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas.	('IDH2', 'Gene', (9, 13))	('chondrosarcomas', 'Disease', (88, 103))	('central chondrosarcoma', 'Disease', (80, 102))	('IDH2', 'Gene', '3418', (9, 13))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (88, 103))	('central chondrosarcoma', 'Disease', 'MESH:D002813', (80, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', (0, 4))	('chondrosarcomas', 'Disease', 'MESH:D002813', (88, 103))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (88, 102))	('IDH1', 'Gene', '3417', (0, 4))
101216	31615936	Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse free and metastasis free survival in high-grade chondrosarcomas.	('metastasis free survival', 'CPA', (178, 202))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (217, 231))	('relapse free', 'CPA', (161, 173))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (217, 232))	('IDH2', 'Gene', (108, 112))	('IDH1', 'Gene', (103, 107))	('mutation', 'Var', (113, 121))	('IDH2', 'Gene', '3418', (108, 112))	('longer', 'PosReg', (154, 160))	('chondrosarcomas', 'Disease', 'MESH:D002813', (217, 232))	('IDH', 'Gene', (103, 106))	('IDH', 'Gene', (47, 50))	('IDH1', 'Gene', '3417', (103, 107))	('IDH', 'Gene', (108, 111))	('chondrosarcomas', 'Disease', (217, 232))	('IDH', 'Gene', '3417', (103, 106))	('patient', 'Species', '9606', (75, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (224, 232))	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', '3417', (108, 111))
101217	31615936	Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas.	('chondrosarcomas', 'Disease', (186, 201))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (186, 200))	('TERT', 'Gene', (26, 30))	('ATRX', 'Gene', '546', (54, 58))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (186, 201))	('TERT', 'Gene', '7015', (26, 30))	('high-grade', 'Disease', (154, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('amplification', 'Var', (36, 49))	('TERT', 'Gene', (104, 108))	('mutation', 'Var', (59, 67))	('TERT', 'Gene', '7015', (104, 108))	('chondrosarcomas', 'Disease', 'MESH:D002813', (186, 201))	('ATRX', 'Gene', (54, 58))
101218	31615936	These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation, and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression.	('IDH2', 'Gene', '3418', (63, 67))	('IDH1', 'Gene', '3417', (58, 62))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (191, 205))	('mutation', 'Var', (68, 76))	('CDKN2A/2B', 'Gene', '1029', (87, 96))	('IDH2', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (109, 113))	('chondrosarcoma', 'Disease', 'MESH:D002813', (191, 205))	('CDKN2A/2B', 'Gene', (87, 96))	('association', 'Interaction', (146, 157))	('chondrosarcoma', 'Disease', (191, 205))	('telomere genes', 'Gene', (23, 37))	('mutation', 'Var', (114, 122))	('TP53', 'Gene', (109, 113))	('IDH1', 'Gene', (58, 62))	('deletion', 'Var', (97, 105))
101220	31615936	IDH1/IDH2 mutations are associated with longer relapse free and metastasis free survival in high-grade chondrosarcomas and they tend to co-occur with TERT mutations, and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.	('TERT', 'Gene', (150, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('TP53', 'Gene', (189, 193))	('CDKN2A/2B', 'Gene', (175, 184))	('TERT', 'Gene', '7015', (150, 154))	('IDH1', 'Gene', (0, 4))	('chondrosarcomas', 'Disease', (103, 118))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (232, 246))	('IDH2', 'Gene', (5, 9))	('co-occur', 'Reg', (136, 144))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (232, 247))	('IDH2', 'Gene', '3418', (5, 9))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (103, 117))	('chondrosarcomas', 'Disease', 'MESH:D002813', (232, 247))	('metastasis free survival', 'CPA', (64, 88))	('IDH1', 'Gene', '3417', (0, 4))	('TP53', 'Gene', '7157', (189, 193))	('relapse free', 'CPA', (47, 59))	('chondrosarcomas', 'Disease', (232, 247))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (103, 118))	('longer', 'PosReg', (40, 46))	('CDKN2A/2B', 'Gene', '1029', (175, 184))	('chondrosarcomas', 'Disease', 'MESH:D002813', (103, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (239, 247))	('mutations', 'Var', (10, 19))
101233	31615936	About 50% of enchondromas and central chondrosarcomas possess IDH1 or IDH2 mutations.	('chondrosarcomas possess IDH1', 'Disease', (38, 66))	('enchondromas', 'Phenotype', 'HP:0030038', (13, 25))	('IDH2', 'Gene', '3418', (70, 74))	('enchondromas', 'Disease', 'MESH:D002812', (13, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (38, 52))	('enchondroma', 'Phenotype', 'HP:0030038', (13, 24))	('chondrosarcomas possess IDH1', 'Disease', 'MESH:D002813', (38, 66))	('mutations', 'Var', (75, 84))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (38, 53))	('central chondrosarcoma', 'Disease', (30, 52))	('enchondromas', 'Disease', (13, 25))	('IDH2', 'Gene', (70, 74))	('central chondrosarcoma', 'Disease', 'MESH:D002813', (30, 52))
101235	31615936	Unlike glioblastomas, published literature has been controversial regarding the association between IDH1/IDH2 mutation and overall survival in chondrosarcoma patients.	('chondrosarcoma', 'Disease', (143, 157))	('glioblastomas', 'Disease', (7, 20))	('chondrosarcoma', 'Disease', 'MESH:D002813', (143, 157))	('IDH2', 'Gene', (105, 109))	('IDH1', 'Gene', '3417', (100, 104))	('IDH2', 'Gene', '3418', (105, 109))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (143, 157))	('association', 'Interaction', (80, 91))	('glioblastomas', 'Phenotype', 'HP:0012174', (7, 20))	('mutation', 'Var', (110, 118))	('IDH1', 'Gene', (100, 104))	('patients', 'Species', '9606', (158, 166))	('glioblastomas', 'Disease', 'MESH:D005909', (7, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (7, 19))
101236	31615936	While no association was found between IDH1/IDH2 mutation and OS in cartilaginous neoplasms in earlier studies, a recent study has proposed chondrosarcoma patients with IDH1/IDH2 mutation have significantly shorter OS than the patients without mutation.	('IDH1', 'Gene', (169, 173))	('mutation', 'Var', (179, 187))	('IDH2', 'Gene', (174, 178))	('patients', 'Species', '9606', (155, 163))	('IDH2', 'Gene', '3418', (174, 178))	('cartilaginous neoplasms', 'Disease', 'MESH:D015831', (68, 91))	('IDH2', 'Gene', (44, 48))	('neoplasms', 'Phenotype', 'HP:0002664', (82, 91))	('IDH1', 'Gene', (39, 43))	('IDH1', 'Gene', '3417', (169, 173))	('IDH2', 'Gene', '3418', (44, 48))	('chondrosarcoma', 'Disease', 'MESH:D002813', (140, 154))	('neoplasm', 'Phenotype', 'HP:0002664', (82, 90))	('cartilaginous neoplasms', 'Disease', (68, 91))	('patients', 'Species', '9606', (227, 235))	('chondrosarcoma', 'Disease', (140, 154))	('IDH1', 'Gene', '3417', (39, 43))	('shorter', 'NegReg', (207, 214))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (140, 154))
101242	31615936	Although no association was discovered between IDH mutation status and patient's overall survival, IDH1/IDH2 mutations were found to be associated with longer relapse free survival (RFS) and metastasis free survival (MFS) in high-grade chondrosarcomas.	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', (104, 107))	('patient', 'Species', '9606', (71, 78))	('IDH1', 'Gene', '3417', (99, 103))	('chondrosarcomas', 'Disease', (236, 251))	('IDH', 'Gene', '3417', (104, 107))	('metastasis free survival', 'CPA', (191, 215))	('sarcomas', 'Phenotype', 'HP:0100242', (243, 251))	('IDH', 'Gene', (47, 50))	('mutations', 'Var', (109, 118))	('IDH2', 'Gene', (104, 108))	('IDH', 'Gene', (99, 102))	('longer', 'PosReg', (152, 158))	('IDH2', 'Gene', '3418', (104, 108))	('relapse free survival', 'CPA', (159, 180))	('IDH', 'Gene', '3417', (47, 50))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (236, 250))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (236, 251))	('IDH1', 'Gene', (99, 103))	('chondrosarcomas', 'Disease', 'MESH:D002813', (236, 251))
101243	31615936	We also identified, for the first time, TERT gene amplifications and ATRX mutations in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas.	('TERT', 'Gene', '7015', (40, 44))	('TERT', 'Gene', (99, 103))	('ATRX', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('TERT', 'Gene', '7015', (99, 103))	('chondrosarcomas', 'Disease', 'MESH:D002813', (181, 196))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (181, 195))	('chondrosarcomas', 'Disease', (181, 196))	('ATRX', 'Gene', '546', (69, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('TERT', 'Gene', (40, 44))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (181, 196))
101244	31615936	These genetic abnormalities, involved in the telomere dysfunction, tend to be concurrent with IDH1/IDH2 mutations, and with CDKN2A/2B deletion or TP53 mutation.	('IDH1', 'Gene', (94, 98))	('mutations', 'Var', (104, 113))	('TP53', 'Gene', '7157', (146, 150))	('IDH2', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (94, 98))	('genetic abnormalities', 'Disease', 'MESH:D030342', (6, 27))	('mutation', 'Var', (151, 159))	('TP53', 'Gene', (146, 150))	('genetic abnormalities', 'Disease', (6, 27))	('CDKN2A/2B', 'Gene', '1029', (124, 133))	('deletion', 'Var', (134, 142))	('IDH2', 'Gene', '3418', (99, 103))	('CDKN2A/2B', 'Gene', (124, 133))
101255	31615936	Among 89 cases, hotspot mutation regions in exon 4 of IDH1 (codon 132) and IDH2 (codon 140 and 172) were genotyped using Sequenom-based mass spectrometry in 53 cases initially, then the mutation-positive cases were also confirmed using Sanger sequencing.	('IDH1', 'Gene', (54, 58))	('IDH2', 'Gene', (75, 79))	('codon', 'Var', (81, 86))	('IDH1', 'Gene', '3417', (54, 58))	('IDH2', 'Gene', '3418', (75, 79))
101256	31615936	Mutation profile analyses of the 54 tumors were performed on MSK-IMPACT platform, a validated custom hybridization capture-based assay, which is capable of detecting somatic mutations, small insertions and deletions, copy number alterations and selected structural rearrangements.	('copy number alterations', 'Var', (217, 240))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('deletions', 'Var', (206, 215))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
101260	31615936	Survival analyses based on IDH1 or IDH2 mutations were performed using Graphpad Prism 7.01.	('IDH2', 'Gene', '3418', (35, 39))	('mutations', 'Var', (40, 49))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('IDH2', 'Gene', (35, 39))
101272	31615936	IDH1 or IDH2 hot-spot mutations (IDH1 R132 and IDH2 R172) were identified in 46% (41/89) of chondrosarcomas (Table 1).	('chondrosarcomas', 'Disease', 'MESH:D002813', (92, 107))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (92, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('IDH2', 'Gene', (8, 12))	('IDH2', 'Gene', (47, 51))	('chondrosarcomas', 'Disease', (92, 107))	('IDH1', 'Gene', (33, 37))	('IDH2', 'Gene', '3418', (8, 12))	('IDH1', 'Gene', '3417', (33, 37))	('R172', 'Var', (52, 56))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (92, 107))	('IDH2', 'Gene', '3418', (47, 51))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
101273	31615936	Of these, 73% (30/41) were IDH1 (R132C: 8, R132G: 10, R132H: 5, R132I: 1, R132L: 4, R132S: 2) and 27% (11/41) were IDH2 (R172G: 1, R172M: 3, R172S: 7).	('R172G', 'Mutation', 'rs1057519906', (121, 126))	('R132L', 'Var', (74, 79))	('R132H', 'Var', (54, 59))	('R132C', 'Mutation', 'rs121913499', (33, 38))	('R132I', 'Var', (64, 69))	('R132L', 'Mutation', 'rs121913500', (74, 79))	('R132G', 'Mutation', 'rs121913499', (43, 48))	('IDH2', 'Gene', (115, 119))	('R132G', 'Var', (43, 48))	('IDH2', 'Gene', '3418', (115, 119))	('R132C:', 'Var', (33, 39))	('R132S', 'Var', (84, 89))	('R172M', 'Var', (131, 136))	('R172M', 'Mutation', 'rs121913503', (131, 136))	('IDH1', 'Gene', (27, 31))	('R172S', 'Mutation', 'rs1057519736', (141, 146))	('R132H', 'Mutation', 'rs121913500', (54, 59))	('R132S', 'Mutation', 'rs121913499', (84, 89))	('R132I', 'Mutation', 'p.R132I', (64, 69))	('R172S', 'Var', (141, 146))	('IDH1', 'Gene', '3417', (27, 31))
101274	31615936	No hotspot mutations at IDH2 R140 residue were identified.	('IDH2', 'Gene', (24, 28))	('IDH2', 'Gene', '3418', (24, 28))	('R140 residue', 'Var', (29, 41))
101276	31615936	Except for one skull base chondrosarcoma in a patient with Ollier disease, no IDH1 or IDH2 mutations were identified in chondrosarcomas arising from skull base, spine or sternum.	('IDH2', 'Gene', (86, 90))	('patient', 'Species', '9606', (46, 53))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (26, 40))	('chondrosarcomas', 'Disease', 'MESH:D002813', (120, 135))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (120, 135))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (120, 134))	('IDH2', 'Gene', '3418', (86, 90))	('IDH1', 'Gene', (78, 82))	('chondrosarcomas', 'Disease', (120, 135))	('IDH1', 'Gene', '3417', (78, 82))	('mutations', 'Var', (91, 100))	('chondrosarcoma', 'Disease', 'MESH:D002813', (26, 40))	('Ollier disease', 'Phenotype', 'HP:0500045', (59, 73))	('chondrosarcoma', 'Disease', (120, 134))	('chondrosarcoma', 'Disease', 'MESH:D002813', (120, 134))	('chondrosarcoma', 'Disease', (26, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))
101277	31615936	No statistically significant associations were found between the types of IDH1/IDH2 amino acid change and tumor grade, size, anatomic location or patient age (data not shown).	('IDH2', 'Gene', '3418', (79, 83))	('IDH1', 'Gene', (74, 78))	('amino acid change', 'Var', (84, 101))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('IDH2', 'Gene', (79, 83))	('IDH1', 'Gene', '3417', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patient', 'Species', '9606', (146, 153))	('tumor', 'Disease', (106, 111))
101281	31615936	However, there was no statistically significant difference in the OS between IDH1/IDH2 mutant and wild-type chondrosarcomas independent of grade (p = 0.845, median: IDH1/IDH2 mutant: > 263 months, cannot be further defined since less than 50% of patients died of disease, wild-type: 226 months, Figure 1B, Table 2).	('chondrosarcoma', 'Phenotype', 'HP:0006765', (108, 122))	('IDH2', 'Gene', (170, 174))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (108, 123))	('died of disease', 'Disease', 'MESH:D003643', (255, 270))	('patients', 'Species', '9606', (246, 254))	('IDH2', 'Gene', (82, 86))	('IDH2', 'Gene', '3418', (170, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('IDH1', 'Gene', (77, 81))	('mutant', 'Var', (87, 93))	('chondrosarcomas', 'Disease', 'MESH:D002813', (108, 123))	('IDH1', 'Gene', (165, 169))	('IDH2', 'Gene', '3418', (82, 86))	('IDH1', 'Gene', '3417', (77, 81))	('died of disease', 'Disease', (255, 270))	('IDH1', 'Gene', '3417', (165, 169))	('chondrosarcomas', 'Disease', (108, 123))
101282	31615936	No statistically significant difference in the OS was found between IDH1/IDH2 mutant and wild-type chondrosarcomas in each of the grade groups either (low grade, high grade and dedifferentiated, Figure 1C) Next, we analyzed if IDH1/IDH2 mutation has an impact on the RFS time (measured by time to relapse (TTR): the time from surgical resection to local relapse or, the time from the initial diagnosis to the appearance of distant metastasis, whichever comes first) and the metastasis free survival (MFS) (measured by time to metastasis, TTM, the time from the initial diagnosis to the appearance of distant metastasis).	('chondrosarcomas', 'Disease', (99, 114))	('metastasis free survival', 'CPA', (474, 498))	('IDH2', 'Gene', (232, 236))	('IDH1', 'Gene', '3417', (227, 231))	('impact', 'Reg', (253, 259))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (99, 113))	('IDH1', 'Gene', (68, 72))	('mutation', 'Var', (237, 245))	('IDH2', 'Gene', '3418', (232, 236))	('IDH2', 'Gene', (73, 77))	('IDH1', 'Gene', '3417', (68, 72))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (99, 114))	('distant metastasis', 'CPA', (423, 441))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))	('IDH1', 'Gene', (227, 231))	('chondrosarcomas', 'Disease', 'MESH:D002813', (99, 114))	('IDH2', 'Gene', '3418', (73, 77))
101283	31615936	The Kaplan-Meier RFS curves showed appreciable difference between IDH1/IDH2 mutant and wild-type groups altogether independent of grade (overall TTR medians: mutant: 120 months, wild-type: 25 months) (Figure 2A, Table 2) although the p value is borderline (p=0.063).	('IDH1', 'Gene', '3417', (66, 70))	('IDH2', 'Gene', (71, 75))	('mutant', 'Var', (76, 82))	('IDH2', 'Gene', '3418', (71, 75))	('mutant', 'Var', (158, 164))	('IDH1', 'Gene', (66, 70))
101284	31615936	For high-grade chondrosarcoma, however, TTR is significantly longer for IDH1/IDH2 mutant than wild-type group (TTR medians for high-grade: 45 vs 13 months, HR=3.5, p=0.003).	('IDH1', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (72, 76))	('IDH2', 'Gene', (77, 81))	('chondrosarcoma', 'Disease', 'MESH:D002813', (15, 29))	('chondrosarcoma', 'Disease', (15, 29))	('IDH2', 'Gene', '3418', (77, 81))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (15, 29))	('mutant', 'Var', (82, 88))
101285	31615936	No significant difference in RFS between IDH1/IDH2 mutant and wild-type groups was found in either low-grade (p=0.258, median: undefined) or dedifferentiated chondrosarcomas (p=0.775, median: 4 vs 5.5 months).	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('IDH2', 'Gene', (46, 50))	('chondrosarcomas', 'Disease', 'MESH:D002813', (158, 173))	('mutant', 'Var', (51, 57))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (158, 172))	('chondrosarcomas', 'Disease', (158, 173))	('IDH2', 'Gene', '3418', (46, 50))	('low-grade', 'Disease', (99, 108))	('IDH1', 'Gene', (41, 45))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (158, 173))	('IDH1', 'Gene', '3417', (41, 45))
101286	31615936	As far as MFS analysis, TTM is significantly longer for IDH1/IDH2 mutant than wild-type group in high-grade chondrosarcoma (TTM medians for high-grade: 50 months vs 19 months, HR=2.6, p=0.013).	('mutant', 'Var', (66, 72))	('chondrosarcoma', 'Disease', (108, 122))	('chondrosarcoma', 'Disease', 'MESH:D002813', (108, 122))	('IDH1', 'Gene', '3417', (56, 60))	('IDH2', 'Gene', (61, 65))	('IDH2', 'Gene', '3418', (61, 65))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (108, 122))	('IDH1', 'Gene', (56, 60))
101287	31615936	However, no statistically significant difference in TTM between IDH1/IDH2 mutant and wild-type groups was found in either low-grade (p=0.433) or dedifferentiated chondrosarcomas (p=0.751, Figure 2 and Table 2).	('IDH2', 'Gene', '3418', (69, 73))	('IDH2', 'Gene', (69, 73))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (162, 177))	('IDH1', 'Gene', (64, 68))	('low-grade', 'Disease', (122, 131))	('IDH1', 'Gene', '3417', (64, 68))	('chondrosarcomas', 'Disease', 'MESH:D002813', (162, 177))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (162, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('mutant', 'Var', (74, 80))	('chondrosarcomas', 'Disease', (162, 177))
101288	31615936	The overall percentages of metastasis in high-grade chondrosarcomas are 50% and 72% for IDH1/IDH2 mutant and wild-type groups, respectively.	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('IDH2', 'Gene', '3418', (93, 97))	('IDH1', 'Gene', (88, 92))	('metastasis', 'CPA', (27, 37))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (52, 67))	('chondrosarcomas', 'Disease', 'MESH:D002813', (52, 67))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (52, 66))	('IDH1', 'Gene', '3417', (88, 92))	('chondrosarcomas', 'Disease', (52, 67))	('mutant', 'Var', (98, 104))	('IDH2', 'Gene', (93, 97))
101291	31615936	IDH1/IDH2 mutations were present in 54% (7/13) of dedifferentiated chondrosarcomas (Table 2).	('chondrosarcoma', 'Phenotype', 'HP:0006765', (67, 81))	('IDH2', 'Gene', (5, 9))	('present', 'Reg', (25, 32))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (67, 82))	('IDH2', 'Gene', '3418', (5, 9))	('chondrosarcomas', 'Disease', 'MESH:D002813', (67, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('chondrosarcomas', 'Disease', (67, 82))	('IDH1', 'Gene', '3417', (0, 4))
101302	31615936	The most common recurrent genomic alterations (greater than 20%) are IDH1/IDH2 hotspot mutations (24/54, 44%), CDKN2A and/or CDKN2B homozygous or heterozygous deletions (18/54, 30%), and TP53 mutations or deletions (11/54, 20%) (Figure 3).	('deletions', 'Var', (205, 214))	('IDH1', 'Gene', (69, 73))	('IDH2', 'Gene', (74, 78))	('CDKN2B', 'Gene', '1030', (125, 131))	('IDH1', 'Gene', '3417', (69, 73))	('TP53', 'Gene', '7157', (187, 191))	('CDKN2A', 'Gene', '1029', (111, 117))	('IDH2', 'Gene', '3418', (74, 78))	('TP53', 'Gene', (187, 191))	('CDKN2A', 'Gene', (111, 117))	('deletions', 'Var', (159, 168))	('CDKN2B', 'Gene', (125, 131))	('mutations', 'Var', (192, 201))	('mutations', 'Var', (87, 96))
101303	31615936	The genetic findings that distinguish grade I chondrosarcoma from higher grade chondrosarcomas are as follows, 1) lower mutation load, 0-2 events/case; 2) rare or no CNA; 3) not associated with CDKN2A/2B deletion; 4) not associated with TP53 mutation.	('chondrosarcoma', 'Disease', 'MESH:D002813', (79, 93))	('TP53', 'Gene', '7157', (237, 241))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (79, 94))	('CDKN2A/2B', 'Gene', (194, 203))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (46, 60))	('deletion', 'Var', (204, 212))	('chondrosarcoma', 'Disease', (79, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('TP53', 'Gene', (237, 241))	('mutation load', 'MPA', (120, 133))	('chondrosarcomas', 'Disease', 'MESH:D002813', (79, 94))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (79, 93))	('chondrosarcoma', 'Disease', (46, 60))	('lower', 'NegReg', (114, 119))	('chondrosarcoma', 'Disease', 'MESH:D002813', (46, 60))	('chondrosarcomas', 'Disease', (79, 94))	('CDKN2A/2B', 'Gene', '1029', (194, 203))
101304	31615936	Only 3 of 12 low grade chondrosarcomas were informative for TERT and ATRX alterations, thus precluding further assessment of these alterations in these tumors.	('chondrosarcomas', 'Disease', 'MESH:D002813', (23, 38))	('ATRX', 'Gene', '546', (69, 73))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('TERT', 'Gene', '7015', (60, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('chondrosarcomas', 'Disease', (23, 38))	('ATRX', 'Gene', (69, 73))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (23, 38))	('alterations', 'Var', (74, 85))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('TERT', 'Gene', (60, 64))
101305	31615936	In the epigenetic regulation and chromatin remodeling pathways, IDH1/IDH2 hotspot mutations are the most common genomic alterations.	('IDH2', 'Gene', '3418', (69, 73))	('IDH1', 'Gene', (64, 68))	('common', 'Reg', (105, 111))	('mutations', 'Var', (82, 91))	('IDH1', 'Gene', '3417', (64, 68))	('IDH2', 'Gene', (69, 73))
101306	31615936	Other genomic alterations in this pathway include missense mutations, deletions or rearrangement in DNMT1, EED and KMT2C as well as those events that only occurred once (such as alterations in ARID1A, ARID1B, CARM1, CENPA, EP300, EZH2, H3F3B, KDM5A, KDM2D, PBRM1, SMARCA4, SMARCB1, TET2 and WHSC1L1).	('DNMT1', 'Gene', '1786', (100, 105))	('missense mutations', 'Var', (50, 68))	('rearrangement', 'Var', (83, 96))	('PBRM1', 'Gene', (257, 262))	('SMARCA4', 'Gene', (264, 271))	('WHSC1L1', 'Gene', '54904', (291, 298))	('EED', 'Gene', (107, 110))	('alterations', 'Var', (178, 189))	('ARID1A', 'Gene', (193, 199))	('KDM5A', 'Gene', (243, 248))	('KDM5A', 'Gene', '5927', (243, 248))	('WHSC1L1', 'Gene', (291, 298))	('TET2', 'Gene', (282, 286))	('CARM1', 'Gene', '10498', (209, 214))	('EZH2', 'Gene', (230, 234))	('EZH2', 'Gene', '2146', (230, 234))	('SMARCB1', 'Gene', '6598', (273, 280))	('KMT2C', 'Gene', '58508', (115, 120))	('SMARCB1', 'Gene', (273, 280))	('ARID1A', 'Gene', '8289', (193, 199))	('CARM1', 'Gene', (209, 214))	('DNMT1', 'Gene', (100, 105))	('EP300', 'Gene', '2033', (223, 228))	('EED', 'Gene', '8726', (107, 110))	('SMARCA4', 'Gene', '6597', (264, 271))	('TET2', 'Gene', '54790', (282, 286))	('CENPA', 'Gene', (216, 221))	('H3F3B', 'Gene', '3021', (236, 241))	('H3F3B', 'Gene', (236, 241))	('CENPA', 'Gene', '1058', (216, 221))	('ARID1B', 'Gene', (201, 207))	('EP300', 'Gene', (223, 228))	('PBRM1', 'Gene', '55193', (257, 262))	('deletions', 'Var', (70, 79))	('ARID1B', 'Gene', '57492', (201, 207))	('KMT2C', 'Gene', (115, 120))
101307	31615936	Regarding genes involved in cell cycle control, CDKN2A/2B deletion is the most common genomic alteration.	('CDKN2A/2B', 'Gene', '1029', (48, 57))	('common', 'Reg', (79, 85))	('CDKN2A/2B', 'Gene', (48, 57))	('deletion', 'Var', (58, 66))
101312	31615936	Six cases (6/32, 19%) harbored genomic alterations in TERT or ATRX, which are involved in telomere regulation (Figure 4).	('genomic alterations', 'Var', (31, 50))	('TERT', 'Gene', '7015', (54, 58))	('ATRX', 'Gene', (62, 66))	('ATRX', 'Gene', '546', (62, 66))	('TERT', 'Gene', (54, 58))
101313	31615936	These include three cases of TERT 5' promoter hotspot mutation (g.1295228C>T, g.1295250C>T), one case of focal high-amplitude TERT amplification, one case of ATRX frame-shift deletion and one case of ATRX missense point mutation.	('TERT', 'Gene', '7015', (29, 33))	('ATRX', 'Gene', (158, 162))	('TERT', 'Gene', (126, 130))	('g.1295250C>T', 'Mutation', 'g.1295250C>T', (78, 90))	('g.1295228C>T', 'Mutation', 'g.1295228C>T', (64, 76))	('ATRX', 'Gene', '546', (158, 162))	('g.1295228C>T', 'Var', (64, 76))	('TERT', 'Gene', '7015', (126, 130))	('ATRX', 'Gene', (200, 204))	('ATRX', 'Gene', '546', (200, 204))	('TERT', 'Gene', (29, 33))	('g.1295250C>T', 'Var', (78, 90))
101316	31615936	Four cases of TERT alterations and one case of ATRX frame-shift mutation co-occur with IDH1/IDH2 mutation, and with CDKN2A/2B deletion or TP53 mutation (Figure 3, 4).	('ATRX', 'Gene', (47, 51))	('TP53', 'Gene', '7157', (138, 142))	('IDH2', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (87, 91))	('CDKN2A/2B', 'Gene', (116, 125))	('ATRX', 'Gene', '546', (47, 51))	('TP53', 'Gene', (138, 142))	('TERT', 'Gene', (14, 18))	('TERT', 'Gene', '7015', (14, 18))	('IDH2', 'Gene', '3418', (92, 96))	('deletion', 'Var', (126, 134))	('mutation', 'Var', (97, 105))	('IDH1', 'Gene', (87, 91))	('CDKN2A/2B', 'Gene', '1029', (116, 125))
101317	31615936	The single case of ATRX missense mutation is wild-type for IDH1/IDH2.	('IDH1', 'Gene', '3417', (59, 63))	('missense mutation', 'Var', (24, 41))	('ATRX', 'Gene', '546', (19, 23))	('IDH2', 'Gene', (64, 68))	('ATRX', 'Gene', (19, 23))	('IDH2', 'Gene', '3418', (64, 68))	('IDH1', 'Gene', (59, 63))
101318	31615936	The co-occurrence of IDH1/IDH2 mutation with TERT/ATRX alterations is statistically significant (p=0.02, note: this p value is not statistically significant after correction for indiscriminating multiple testing by Bonferonni method), which suggests a possible cooperation of telomere dysfunction with IDH1/IDH2 mutation, and with CDKN2A/2B deletion or TP53 mutation in chondrosarcoma progression.	('TERT', 'Gene', (45, 49))	('TERT', 'Gene', '7015', (45, 49))	('CDKN2A/2B', 'Gene', '1029', (331, 340))	('IDH2', 'Gene', (307, 311))	('TP53', 'Gene', (353, 357))	('IDH1', 'Gene', (302, 306))	('deletion', 'Var', (341, 349))	('mutation', 'Var', (312, 320))	('IDH2', 'Gene', '3418', (307, 311))	('IDH1', 'Gene', (21, 25))	('mutation', 'Var', (358, 366))	('CDKN2A/2B', 'Gene', (331, 340))	('ATRX', 'Gene', (50, 54))	('chondrosarcoma', 'Disease', (370, 384))	('chondrosarcoma', 'Disease', 'MESH:D002813', (370, 384))	('ATRX', 'Gene', '546', (50, 54))	('IDH1', 'Gene', '3417', (302, 306))	('mutation', 'Var', (31, 39))	('TP53', 'Gene', '7157', (353, 357))	('IDH1', 'Gene', '3417', (21, 25))	('IDH2', 'Gene', (26, 30))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (370, 384))	('IDH2', 'Gene', '3418', (26, 30))
101319	31615936	IDH1 and IDH2 mutations are prevalent in enchondroma and central chondrosarcoma as well as in Ollier disease and Maffucci syndrome.	('IDH2', 'Gene', (9, 13))	('Ollier disease', 'Disease', (94, 108))	('IDH2', 'Gene', '3418', (9, 13))	('enchondroma and central chondrosarcoma', 'Disease', 'MESH:D002812', (41, 79))	('enchondroma', 'Phenotype', 'HP:0030038', (41, 52))	('Maffucci syndrome', 'Disease', (113, 130))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (113, 130))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (65, 79))	('Ollier disease', 'Phenotype', 'HP:0500045', (94, 108))	('IDH1', 'Gene', (0, 4))	('prevalent', 'Reg', (28, 37))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', '3417', (0, 4))
101320	31615936	In the current study, IDH1 or IDH2 mutations were identified in 46.2% of 89 chondrosarcomas, which is consistent with prior studies.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (76, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('IDH2', 'Gene', (30, 34))	('chondrosarcomas', 'Disease', 'MESH:D002813', (76, 91))	('IDH1', 'Gene', (22, 26))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (76, 90))	('IDH2', 'Gene', '3418', (30, 34))	('chondrosarcomas', 'Disease', (76, 91))	('IDH1', 'Gene', '3417', (22, 26))	('identified', 'Reg', (50, 60))	('mutations', 'Var', (35, 44))
101321	31615936	Amino acid substitutions were only found at residues R132 in IDH1 and R172 in IDH2, but not at R140 in IDH2.	('IDH2', 'Gene', '3418', (103, 107))	('IDH2', 'Gene', (78, 82))	('IDH1', 'Gene', (61, 65))	('IDH2', 'Gene', '3418', (78, 82))	('R172', 'Var', (70, 74))	('IDH1', 'Gene', '3417', (61, 65))	('IDH2', 'Gene', (103, 107))
101322	31615936	The ratio of IDH1 to IDH2 mutation is 30:11, which is slightly higher than previously reported.	('mutation', 'Var', (26, 34))	('IDH1', 'Gene', (13, 17))	('IDH2', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (21, 25))
101323	31615936	As far as tumor location, femur has the highest IDH1/IDH2 mutation percentage (77.3%) in our cohort.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('IDH2', 'Gene', (53, 57))	('tumor', 'Disease', (10, 15))	('IDH1', 'Gene', '3417', (48, 52))	('mutation', 'Var', (58, 66))	('IDH2', 'Gene', '3418', (53, 57))	('IDH1', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
101326	31615936	IDH1 or IDH2 mutations were equally distributed among low-grade, high-grade and dedifferentiated chondrosarcomas suggesting IDH1 and IDH2 mutations occur as an early event during tumorigenesis similar to glioblastoma and acute myelogenous leukemia.	('glioblastoma', 'Disease', 'MESH:D005909', (204, 216))	('IDH2', 'Gene', (8, 12))	('IDH2', 'Gene', (133, 137))	('IDH2', 'Gene', '3418', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('IDH2', 'Gene', '3418', (133, 137))	('IDH1', 'Gene', (0, 4))	('glioblastoma', 'Disease', (204, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (221, 247))	('IDH1', 'Gene', (124, 128))	('IDH1', 'Gene', '3417', (0, 4))	('tumor', 'Disease', (179, 184))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (97, 111))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (97, 112))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (227, 247))	('chondrosarcomas', 'Disease', 'MESH:D002813', (97, 112))	('acute myelogenous leukemia', 'Disease', (221, 247))	('mutations', 'Var', (138, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('IDH1', 'Gene', '3417', (124, 128))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (221, 247))	('chondrosarcomas', 'Disease', (97, 112))	('leukemia', 'Phenotype', 'HP:0001909', (239, 247))
101327	31615936	Although IDH1 and IDH2 mutation has been associated with better OS in glioma patients, only one out of three studies have shown an association in chondrosarcoma patients.	('IDH2', 'Gene', '3418', (18, 22))	('better OS', 'Disease', (57, 66))	('glioma', 'Disease', (70, 76))	('IDH1', 'Gene', (9, 13))	('mutation', 'Var', (23, 31))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('chondrosarcoma', 'Disease', (146, 160))	('IDH1', 'Gene', '3417', (9, 13))	('chondrosarcoma', 'Disease', 'MESH:D002813', (146, 160))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (161, 169))	('IDH2', 'Gene', (18, 22))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (146, 160))
101328	31615936	In the current study, we found that IDH1/IDH2 mutation is not associated with the OS either with or without tumor grade stratification, which is consistent with two previously published studies.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('IDH1', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', (108, 113))	('IDH2', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (36, 40))	('mutation', 'Var', (46, 54))	('IDH2', 'Gene', '3418', (41, 45))
101329	31615936	In contrast a recent study by Lugowska et al, proposed that IDH1/IDH2 mutations are predictors of shorter survival in chondrosarcomas.	('IDH2', 'Gene', '3418', (65, 69))	('mutations', 'Var', (70, 79))	('IDH1', 'Gene', (60, 64))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (118, 133))	('chondrosarcomas', 'Disease', 'MESH:D002813', (118, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('IDH2', 'Gene', (65, 69))	('chondrosarcomas', 'Disease', (118, 133))	('IDH1', 'Gene', '3417', (60, 64))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (118, 132))	('shorter', 'NegReg', (98, 105))
101333	31615936	We further evaluated RFS and MFS (measured by TTR and TTM) which are more disease specific and may better reflect the differences in the biological behaviors of IDH mutant and wild-type chondrosarcomas.	('chondrosarcomas', 'Disease', (186, 201))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (186, 200))	('IDH', 'Gene', '3417', (161, 164))	('mutant', 'Var', (165, 171))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (186, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('chondrosarcomas', 'Disease', 'MESH:D002813', (186, 201))	('IDH', 'Gene', (161, 164))
101334	31615936	In our study, we found that IDH1/IDH2 mutation is strongly associated with longer RFS and MFS in high-grade chondrosarcomas.	('MFS', 'MPA', (90, 93))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (108, 123))	('IDH2', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (28, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('associated', 'Reg', (59, 69))	('IDH2', 'Gene', '3418', (33, 37))	('chondrosarcomas', 'Disease', 'MESH:D002813', (108, 123))	('mutation', 'Var', (38, 46))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (108, 122))	('chondrosarcomas', 'Disease', (108, 123))	('IDH1', 'Gene', (28, 32))
101335	31615936	There were no statistically significant differences in RFS and MFS between IDH1/IDH2 mutant and wild-type low-grade or dedifferentiated chondrosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (136, 150))	('RFS', 'MPA', (55, 58))	('chondrosarcomas', 'Disease', (136, 151))	('IDH2', 'Gene', '3418', (80, 84))	('IDH1', 'Gene', (75, 79))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (136, 151))	('chondrosarcomas', 'Disease', 'MESH:D002813', (136, 151))	('IDH1', 'Gene', '3417', (75, 79))	('mutant', 'Var', (85, 91))	('MFS', 'MPA', (63, 66))	('IDH2', 'Gene', (80, 84))
101336	31615936	As most low-grade chondrosarcomas did not recur or metastasize in our cohort (only one case developed local recurrence and metastasis) and dedifferentiated chondrosarcomas progressed rapidly, a statistical difference could not be identified in these two cohorts between IDH1/IDH2 mutant and wild-type chondrosarcomas.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (156, 170))	('chondrosarcomas', 'Disease', (301, 316))	('IDH1', 'Gene', (270, 274))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (156, 171))	('mutant', 'Var', (280, 286))	('IDH2', 'Gene', (275, 279))	('chondrosarcomas', 'Disease', 'MESH:D002813', (156, 171))	('IDH2', 'Gene', '3418', (275, 279))	('sarcomas', 'Phenotype', 'HP:0100242', (308, 316))	('IDH1', 'Gene', '3417', (270, 274))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (18, 32))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (301, 315))	('chondrosarcomas', 'Disease', (156, 171))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (18, 33))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (301, 316))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('chondrosarcomas', 'Disease', 'MESH:D002813', (18, 33))	('chondrosarcomas', 'Disease', 'MESH:D002813', (301, 316))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('chondrosarcomas', 'Disease', (18, 33))
101337	31615936	Biochemically, IDH1 and IDH2 active site mutations result in neomorphic enzyme activity, which causes the accumulation of 2-hydroxyglutarate (2-HG) at supraphysiological levels within cells.	('mutations', 'Var', (41, 50))	('activity', 'MPA', (79, 87))	('IDH1', 'Gene', (15, 19))	('neomorphic', 'MPA', (61, 71))	('IDH1', 'Gene', '3417', (15, 19))	('2-HG', 'Chemical', 'MESH:C019417', (142, 146))	('IDH2', 'Gene', (24, 28))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (122, 140))	('IDH2', 'Gene', '3418', (24, 28))	('result in', 'Reg', (51, 60))
101339	31615936	Although the oncogenic effect of IDH1/IDH2 mutation is well illustrated, the mechanism underlying the association of IDH1/IDH2 mutation with better OS in glioblastoma is largely unclear, except for that overexpression of IDH1 has been shown to cause decreased proliferation in established glioma cell lines.	('glioma', 'Disease', (289, 295))	('IDH1', 'Gene', (221, 225))	('better', 'Disease', (141, 147))	('IDH1', 'Gene', '3417', (117, 121))	('mutation', 'Var', (127, 135))	('IDH1', 'Gene', (33, 37))	('glioblastoma', 'Disease', (154, 166))	('IDH2', 'Gene', (122, 126))	('IDH1', 'Gene', '3417', (221, 225))	('glioma', 'Disease', 'MESH:D005910', (289, 295))	('IDH2', 'Gene', (38, 42))	('IDH1', 'Gene', '3417', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('IDH2', 'Gene', '3418', (122, 126))	('IDH2', 'Gene', '3418', (38, 42))	('IDH1', 'Gene', (117, 121))
101341	31615936	Additional functional studies are needed to understand the biological role of IDH1/IDH2 mutations in prolonging RFS and MFS in grade II and III chondrosarcomas.	('III chondrosarcomas', 'Disease', (140, 159))	('III chondrosarcomas', 'Disease', 'MESH:D002813', (140, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('IDH2', 'Gene', '3418', (83, 87))	('IDH1', 'Gene', (78, 82))	('grade II', 'Disease', (127, 135))	('mutations', 'Var', (88, 97))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (144, 158))	('IDH1', 'Gene', '3417', (78, 82))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (144, 159))	('IDH2', 'Gene', (83, 87))	('MFS', 'MPA', (120, 123))
101344	31615936	As low-grade chondrosarcomas showed lower mutation load, very few or no CNA, absence of CDKN2A/2B deletion and TP53 mutation, these genomic findings could serve as adjunct markers to histological grading in morphologically challenging cases.	('lower', 'NegReg', (36, 41))	('CDKN2A/2B', 'Gene', (88, 97))	('absence', 'NegReg', (77, 84))	('chondrosarcomas', 'Disease', 'MESH:D002813', (13, 28))	('TP53', 'Gene', '7157', (111, 115))	('mutation', 'Var', (116, 124))	('chondrosarcomas', 'Disease', (13, 28))	('deletion', 'Var', (98, 106))	('TP53', 'Gene', (111, 115))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (13, 27))	('mutation load', 'MPA', (42, 55))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (13, 28))	('CNA', 'MPA', (72, 75))	('CDKN2A/2B', 'Gene', '1029', (88, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
101346	31615936	Prior studies have also demonstrated that CDKN2A deletion and TP53 mutation are associated with high-grade and dedifferentiated chondrosarcomas but not with low-grade chondrosarcomas.	('TP53', 'Gene', '7157', (62, 66))	('mutation', 'Var', (67, 75))	('chondrosarcomas', 'Disease', 'MESH:D002813', (167, 182))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (128, 143))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (167, 181))	('TP53', 'Gene', (62, 66))	('chondrosarcomas', 'Disease', (167, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('CDKN2A', 'Gene', (42, 48))	('associated', 'Reg', (80, 90))	('chondrosarcomas', 'Disease', 'MESH:D002813', (128, 143))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (167, 182))	('deletion', 'Var', (49, 57))	('CDKN2A', 'Gene', '1029', (42, 48))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (128, 142))	('chondrosarcomas', 'Disease', (128, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))
101347	31615936	Similar finding in astrocytoma has shown that CDKN2A deletion was strongly associated with poorer overall survival after adjustment for IDH mutation, sex, and age.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('CDKN2A', 'Gene', (46, 52))	('deletion', 'Var', (53, 61))	('CDKN2A', 'Gene', '1029', (46, 52))	('astrocytoma', 'Disease', 'MESH:D001254', (19, 30))	('astrocytoma', 'Disease', (19, 30))	('overall survival', 'MPA', (98, 114))	('poorer', 'NegReg', (91, 97))
101350	31615936	None of the low-grade chondrosarcomas tested, albeit a small number (3 cases), showed these alterations, which is consistent with the recent study that suggests TERT promoter mutations may play a role in chondrosarcoma progression since its association with increased histological grade.	('chondrosarcomas', 'Disease', (22, 37))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (22, 36))	('TERT', 'Gene', (161, 165))	('role', 'Reg', (196, 200))	('chondrosarcoma', 'Disease', (204, 218))	('chondrosarcoma', 'Disease', 'MESH:D002813', (204, 218))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (22, 37))	('TERT', 'Gene', '7015', (161, 165))	('mutations', 'Var', (175, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('chondrosarcoma', 'Disease', (22, 36))	('chondrosarcoma', 'Disease', 'MESH:D002813', (22, 36))	('chondrosarcomas', 'Disease', 'MESH:D002813', (22, 37))	('play', 'Reg', (189, 193))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (204, 218))
101351	31615936	Concurrence of TERT or ATRX mutation with IDH1/IDH2 mutation, and with CDKN2A/2B deletion or TP53 mutation in a subset of high-grade chondrosarcomas suggests a possible synergy among these pathways in the progression of chondrosarcoma.	('TERT', 'Gene', '7015', (15, 19))	('IDH2', 'Gene', (47, 51))	('ATRX', 'Gene', '546', (23, 27))	('TERT', 'Gene', (15, 19))	('deletion', 'Var', (81, 89))	('TP53', 'Gene', (93, 97))	('mutation', 'Var', (28, 36))	('mutation', 'Var', (52, 60))	('IDH2', 'Gene', '3418', (47, 51))	('mutation', 'Var', (98, 106))	('chondrosarcomas', 'Disease', (133, 148))	('IDH1', 'Gene', '3417', (42, 46))	('CDKN2A/2B', 'Gene', (71, 80))	('chondrosarcomas', 'Disease', 'MESH:D002813', (133, 148))	('chondrosarcoma', 'Disease', (133, 147))	('chondrosarcoma', 'Disease', 'MESH:D002813', (133, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('chondrosarcoma', 'Disease', 'MESH:D002813', (220, 234))	('chondrosarcoma', 'Disease', (220, 234))	('TP53', 'Gene', '7157', (93, 97))	('synergy', 'Reg', (169, 176))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (133, 147))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (220, 234))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (133, 148))	('IDH1', 'Gene', (42, 46))	('ATRX', 'Gene', (23, 27))	('CDKN2A/2B', 'Gene', '1029', (71, 80))
101352	31615936	In line with our study, TERT promoter and IDH1/IDH2 mutations co-occur in 79% of oligodendrogliomas.	('mutations', 'Var', (52, 61))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (81, 99))	('IDH2', 'Gene', (47, 51))	('IDH1', 'Gene', '3417', (42, 46))	('TERT', 'Gene', (24, 28))	('oligodendrogliomas', 'Disease', (81, 99))	('TERT', 'Gene', '7015', (24, 28))	('IDH2', 'Gene', '3418', (47, 51))	('IDH1', 'Gene', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
101353	31615936	Mechanistic study performed on glioma cells show that mutant IDH1 can indirectly reactivate TERT and contribute to astrocytic immortalization and transformation.	('contribute to', 'Reg', (101, 114))	('TERT', 'Gene', (92, 96))	('TERT', 'Gene', '7015', (92, 96))	('IDH1', 'Gene', '3417', (61, 65))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('astrocytic immortalization', 'CPA', (115, 141))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH1', 'Gene', (61, 65))	('transformation', 'CPA', (146, 160))	('mutant', 'Var', (54, 60))	('glioma', 'Disease', (31, 37))
101354	31615936	Mutant IDH1 can also initiate telomeric dysfunction and alter DNA repair pathway preferences at telomeres, cooperating with ATRX loss to drive the alternative lengthening of telomere phenotype for gliomagenesis.	('IDH1', 'Gene', '3417', (7, 11))	('telomeric dysfunction', 'Disease', 'MESH:C536801', (30, 51))	('telomeric dysfunction', 'Disease', (30, 51))	('glioma', 'Disease', (197, 203))	('loss', 'NegReg', (129, 133))	('ATRX', 'Gene', (124, 128))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('alter', 'Reg', (56, 61))	('Mutant', 'Var', (0, 6))	('DNA repair pathway', 'Pathway', (62, 80))	('IDH1', 'Gene', (7, 11))	('initiate', 'Reg', (21, 29))	('ATRX', 'Gene', '546', (124, 128))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
101355	31615936	TERT promotor and IDH1/IDH2 mutation status can be used to guide glioma classification and diagnosis, categorize glioma patients into distinct survival subgroups, and direct individualized treatments for the distinct molecular subtypes.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Disease', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH2', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('TERT', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('TERT', 'Gene', '7015', (0, 4))	('glioma', 'Disease', (113, 119))	('mutation', 'Var', (28, 36))	('IDH2', 'Gene', '3418', (23, 27))	('patients', 'Species', '9606', (120, 128))	('IDH1', 'Gene', (18, 22))
101357	31615936	This is the first study to our knowledge that identified TERT amplification and ATRX mutations in chondrosarcomas in addition to TERT promoter mutations.	('chondrosarcomas', 'Disease', 'MESH:D002813', (98, 113))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (98, 112))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (129, 133))	('TERT', 'Gene', '7015', (57, 61))	('chondrosarcomas', 'Disease', (98, 113))	('mutations', 'Var', (85, 94))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (98, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('ATRX', 'Gene', (80, 84))	('TERT', 'Gene', (129, 133))	('ATRX', 'Gene', '546', (80, 84))
101358	31615936	No significant difference in OS, RFS and MFS was identified between TERT/ATRX mutant and wild-type chondrosarcomas (data not shown).	('chondrosarcomas', 'Disease', (99, 114))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (99, 113))	('ATRX', 'Gene', (73, 77))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (99, 114))	('mutant', 'Var', (78, 84))	('ATRX', 'Gene', '546', (73, 77))	('chondrosarcomas', 'Disease', 'MESH:D002813', (99, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))
101362	31615936	FGFR3 activation mutations are associated with human hypochondroplasia, achondroplasia due to growth attenuation of the cartilage while inactivating mutations are associated with skeletal overgrowth in human CATSHL syndrome.	('achondroplasia', 'Disease', 'MESH:D000130', (72, 86))	('hypochondroplasia', 'Disease', (53, 70))	('hypochondroplasia', 'Disease', 'MESH:C562937', (53, 70))	('overgrowth', 'Phenotype', 'HP:0001548', (188, 198))	('growth attenuation of the cartilage', 'CPA', (94, 129))	('achondroplasia', 'Disease', (72, 86))	('FGFR3', 'Gene', (0, 5))	('human', 'Species', '9606', (202, 207))	('associated', 'Reg', (31, 41))	('associated', 'Reg', (163, 173))	('skeletal overgrowth in human CATSHL syndrome', 'Disease', (179, 223))	('mutations', 'Var', (17, 26))	('skeletal overgrowth in human CATSHL syndrome', 'Disease', 'MESH:C537975', (179, 223))	('human', 'Species', '9606', (47, 52))	('activation', 'PosReg', (6, 16))	('inactivating mutations', 'Var', (136, 158))	('FGFR3', 'Gene', '2261', (0, 5))
101363	31615936	We found FGFR3 deletions in two cases suggesting that FGFR3 might function as a tumor suppressor in chondrosarcoma development.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('chondrosarcoma', 'Disease', 'MESH:D002813', (100, 114))	('FGFR3', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('chondrosarcoma', 'Disease', (100, 114))	('FGFR3', 'Gene', '2261', (9, 14))	('tumor', 'Disease', (80, 85))	('FGFR3', 'Gene', (9, 14))	('deletions', 'Var', (15, 24))	('FGFR3', 'Gene', '2261', (54, 59))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (100, 114))
101366	31615936	Intracytoplasmic signaling factors downstream of these cell membrane receptors such as KRAS and PTEN are also found to be occasionally mutated, which include KRAS G12A mutation and PTEN missense mutation in one case each.	('PTEN', 'Gene', '5728', (96, 100))	('PTEN', 'Gene', '5728', (181, 185))	('KRAS', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (158, 162))	('KRAS', 'Gene', '3845', (87, 91))	('missense mutation', 'Var', (186, 203))	('G12A', 'Mutation', 'rs121913529', (163, 167))	('KRAS', 'Gene', (158, 162))	('PTEN', 'Gene', (181, 185))	('PTEN', 'Gene', (96, 100))
101372	31615936	As 50% of chondrosarcomas possess IDH1/2 mutations, we sought to correlate IDH1/2 mutations to clinical outcome in 89 patients.	('mutations', 'Var', (41, 50))	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (10, 25))	('chondrosarcomas possess IDH1', 'Disease', (10, 38))	('IDH1/2', 'Gene', (75, 81))	('IDH1/2', 'Gene', (34, 40))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (10, 24))	('chondrosarcomas possess IDH1', 'Disease', 'MESH:D002813', (10, 38))	('IDH1/2', 'Gene', '3417;3418', (75, 81))	('patients', 'Species', '9606', (118, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
101373	31615936	We found IDH1/2 mutations in 46% of the patients and while overall survival was not affected in this cohort, we found IDH mutations were associated with longer relapse free survival (RFS) and metastases free survival (MFS) in high grade chondrosarcomas.	('metastases', 'Disease', 'MESH:D009362', (192, 202))	('IDH1/2', 'Gene', (9, 15))	('relapse free survival', 'CPA', (160, 181))	('chondrosarcomas', 'Disease', 'MESH:D002813', (237, 252))	('patients', 'Species', '9606', (40, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (244, 252))	('IDH', 'Gene', (118, 121))	('mutations', 'Var', (16, 25))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (237, 251))	('chondrosarcomas', 'Disease', (237, 252))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', '3417', (118, 121))	('mutations', 'Var', (122, 131))	('metastases', 'Disease', (192, 202))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('IDH', 'Gene', '3417', (9, 12))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (237, 252))	('longer', 'PosReg', (153, 159))
101374	31615936	We also found TERT gene amplification and ATRX mutation, in addition to TERT promoter mutation in a subset of high-grade chondrosarcomas.	('chondrosarcomas', 'Disease', 'MESH:D002813', (121, 136))	('mutation', 'Var', (47, 55))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (121, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('ATRX', 'Gene', (42, 46))	('TERT', 'Gene', (14, 18))	('ATRX', 'Gene', '546', (42, 46))	('chondrosarcomas', 'Disease', (121, 136))	('TERT', 'Gene', '7015', (14, 18))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (121, 135))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
101378	28104840	Among these cancer hallmarks is immune evasion, which is accomplished by neoantigen editing, defects in antigen presentation and inhibition of tumor infiltration, and/or cytotoxic activities of immune cells.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('defects', 'Var', (93, 100))	('neoantigen editing', 'Var', (73, 91))	('tumor', 'Disease', (143, 148))	('antigen presentation', 'MPA', (104, 124))	('cancer hallmarks', 'Disease', (12, 28))	('cytotoxic activities', 'CPA', (170, 190))	('inhibition', 'NegReg', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer hallmarks', 'Disease', 'MESH:D009369', (12, 28))	('immune evasion', 'Disease', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
101380	28104840	Understanding how SCNAs and mutation load affect tumor evolution, and through what mechanisms, is a key objective in cancer research.	('affect', 'Reg', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation load', 'Var', (28, 41))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
101384	28104840	First, we found that, for most tumors, there was a positive correlation between SCNA levels and the total number of mutations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SCNA levels', 'MPA', (80, 91))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (116, 125))
101385	28104840	Second, tumors harboring activating oncogenic mutations in the receptor tyrosine kinase-RAS-phosphatidylinositol 3-kinase pathway showed fewer SCNAs, a finding at odds with the hypothesis of oncogene-driven genomic instability.	('receptor tyrosine kinase', 'Gene', (63, 87))	('mutations', 'Var', (46, 55))	('receptor tyrosine kinase', 'Gene', '5979', (63, 87))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (92, 121))	('activating', 'PosReg', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('phosphatidylinositol 3-kinase', 'Gene', (92, 121))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('fewer', 'NegReg', (137, 142))	('SCNAs', 'Disease', (143, 148))
101389	28104840	The combination of the tumor SCNA score and the tumor mutational load was a better predictor of survival after immunotherapy than either biomarker alone.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutational', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
101394	28104840	A high load of tumor neoantigens (reflecting a high level of point mutations) promotes the detection of tumors by the immune system, limiting immune evasion.	('point mutations', 'Var', (61, 76))	('promotes', 'PosReg', (78, 86))	('detection', 'MPA', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('immune evasion', 'MPA', (142, 156))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', (15, 20))	('limiting', 'NegReg', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
101404	28104840	Antibody-mediated inactivation of inhibitory molecules, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), has produced durable responses in a subset (20 to 30%) of patients with advanced tumors.	('cytotoxic T lymphocyte-associated protein 4', 'Gene', (64, 107))	('patients', 'Species', '9606', (214, 222))	('cytotoxic T lymphocyte-associated protein 4', 'Gene', '1493', (64, 107))	('CTLA-4', 'Gene', '1493', (109, 115))	('tumors', 'Disease', (237, 243))	('inactivation', 'Var', (18, 30))	('programmed death-ligand 1', 'Gene', (121, 146))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('programmed death-ligand 1', 'Gene', '29126', (121, 146))	('PD-L1', 'Gene', '29126', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('responses', 'MPA', (177, 186))	('CTLA-4', 'Gene', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PD-L1', 'Gene', (148, 153))
101408	28104840	Cytolytic immune infiltrates have also been shown to correlate with the total number of mutations in certain human tumor types, although the mechanisms controlling immune infiltration are not well understood.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
101410	28104840	We have uncovered unanticipated relationships of SCNA levels with mutation number, with classes of cancer drivers, and with cell proliferation and immune infiltration signatures.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('relationships', 'Interaction', (32, 45))	('SCNA levels', 'MPA', (49, 60))	('cancer', 'Disease', (99, 105))	('mutation', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
101416	28104840	In contrast with a previous report showing that SCNAs are more abundant in tumors with a low mutation burden, we found a positive correlation between the number (n) of mutations and SCNA level (Fig.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SCNA level', 'MPA', (182, 192))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (168, 177))
101419	28104840	The distribution of the number of mutations in these tumor types is bimodal, with most of the samples bearing ~100 exonic mutations on average and the remaining samples having a ~10-fold higher number of mutations (hypermutated; fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('exonic mutations', 'Var', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
101420	28104840	The negative correlation between mutations and SCNAs in CRC and UCEC tumors was dependent on the presence of these hypermutated samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CRC', 'Disease', (56, 59))	('CRC', 'Phenotype', 'HP:0030731', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
101421	28104840	Thus, within individual cancer types, the number of mutations tends to positively correlate with the SCNA level.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('SCNA level', 'Disease', (101, 111))
101422	28104840	Next, we separated mutations in driver genes, that is, tumor suppressor genes (TSGs) or oncogenes (OGs), as predicted by TUSON Explorer, and mutations in passenger genes, that is, genes not predicted to be cancer drivers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('oncogenes', 'Gene', (88, 97))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
101425	28104840	To investigate how alterations in different classes of cancer drivers relate to aneuploidy, we analyzed the correlations between SCNA levels and mutations in sets of TSGs and OGs acting in 14 different cancer pathways (table S2B).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('aneuploidy', 'Disease', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('aneuploidy', 'Disease', 'MESH:D000782', (80, 90))	('TSGs', 'Gene', (166, 170))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('acting', 'Reg', (179, 185))	('SCNA levels', 'MPA', (129, 140))	('cancer', 'Disease', (55, 61))
101426	28104840	Mutations in only one pathway showed a negative correlation with SCNAs: the receptor tyrosine kinase (RTK) pathway, which also includes phosphatidylinositol 3-kinase (PI3K) and RAS pathway genes (Fig.	('RTK', 'Gene', '5979', (102, 105))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (136, 165))	('receptor tyrosine kinase', 'Gene', (76, 100))	('receptor tyrosine kinase', 'Gene', '5979', (76, 100))	('Mutations', 'Var', (0, 9))	('phosphatidylinositol 3-kinase', 'Gene', (136, 165))	('RTK', 'Gene', (102, 105))	('RAS pathway', 'Pathway', (177, 188))
101433	28104840	The level of pS345Chk1, a physical marker of S phase, was also increased in high aneuploidy tumors (fig.	('increased', 'PosReg', (63, 72))	('high aneuploidy tumors', 'Disease', (76, 98))	('pS345Chk1', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('high aneuploidy tumors', 'Disease', 'MESH:D000782', (76, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
101472	28104840	In CRC, lung adenocarcinoma (LUAD), and UCEC, tumors with high mutation burden showed an increased immune signature score, consistent with previous observations (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutation burden', 'Var', (63, 78))	('lung adenocarcinoma', 'Disease', (8, 27))	('increased', 'PosReg', (89, 98))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('immune signature score', 'MPA', (99, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (8, 27))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('tumors', 'Disease', (46, 52))	('CRC', 'Disease', (3, 6))	('CRC', 'Phenotype', 'HP:0030731', (3, 6))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
101473	28104840	In contrast, in all cancer types except gliomas, tumor samples with high arm/chromosome SCNA levels showed a significant decrease in the immune signature score (~50% difference on average) (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high', 'Var', (68, 72))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('immune signature score', 'MPA', (137, 159))	('cancer', 'Disease', (20, 26))	('decrease', 'NegReg', (121, 129))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
101475	28104840	Compared to mutation number, the level of SCNAs showed a stronger correlation with the cytotoxic immune signature in most of the tumor types examined, even in those where mutation number positively correlated with the SCNA level (Fig.	('cytotoxic immune signature', 'MPA', (87, 113))	('correlation', 'Interaction', (66, 77))	('SCNA level', 'MPA', (218, 228))	('correlated', 'Reg', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('mutation number', 'Var', (171, 186))
101483	28104840	We used least absolute shrinkage and selection operator (lasso) to determine the contribution of SCNA level, the total number of point mutations, TP53 mutations, patient age, patient gender, and tumor stage to both signatures.	('tumor', 'Disease', (195, 200))	('TP53', 'Gene', '7157', (146, 150))	('patient', 'Species', '9606', (175, 182))	('TP53', 'Gene', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('patient', 'Species', '9606', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mutations', 'Var', (151, 160))
101486	28104840	6A), as were mutations in TP53, a negative regulator of cell cycle entry.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', '7157', (26, 30))
101490	28104840	The total number of mutations was selected by lasso in three tumor types (CRC, LUAD, and UCEC) (Fig.	('LUAD', 'Disease', (79, 83))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CRC', 'Phenotype', 'HP:0030731', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', (61, 66))
101495	28104840	First, we assessed tumor SCNA levels and mutational load in patients who did or did not achieve long-term survival after treatment.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mutational', 'Var', (41, 51))
101500	28104840	Next, we examined survival after stratifying the patients into two equal groups (that is, upper and lower 50%) based on either the tumor SCNA level or mutational load.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutational load', 'Var', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('patients', 'Species', '9606', (49, 57))
101502	28104840	A higher number of tumor mutations correlated with better survival (HR = 0.68, P = 0.079; Fig.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('survival', 'CPA', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('better', 'PosReg', (51, 57))	('tumor', 'Disease', (19, 24))
101509	28104840	In this data set, a higher number of tumor mutations predicted better survival (HR = 0.61, P = 0.039; table S6C and fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (37, 42))	('better', 'PosReg', (63, 69))	('survival', 'CPA', (70, 78))
101510	28104840	The correlation of both high mutation number and low SCNA level with better survival may be due to the role of an antitumor immune response in predicting a better outcome even in the absence of immunotherapy, an observation that has been previously described.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('high mutation number', 'Var', (24, 44))	('SCNA level', 'MPA', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('better', 'PosReg', (69, 75))
101513	28104840	Overall, these data indicate that tumor SCNA levels and mutational load can be used together to predict patients' survival after immunotherapy.	('mutational', 'Var', (56, 66))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
101517	28104840	We uncovered relationships between the level of SCNAs and mutations in driver genes acting in specific cancer pathways that deepen our understanding of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
101518	28104840	Unexpectedly, the level of SCNAs negatively correlated with mutations in driver genes involved in the RTK pathway, such as EGFR, PIK3CA, KRAS, and BRAF.	('EGFR', 'Gene', (123, 127))	('PIK3CA', 'Gene', (129, 135))	('RTK', 'Gene', '5979', (102, 105))	('PIK3CA', 'Gene', '5290', (129, 135))	('BRAF', 'Gene', (147, 151))	('negatively', 'NegReg', (33, 43))	('BRAF', 'Gene', '673', (147, 151))	('KRAS', 'Gene', (137, 141))	('RTK', 'Gene', (102, 105))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', '3845', (137, 141))
101520	28104840	Our analysis suggests that mutated OGs (which may behave differently in vivo than in an experimental overexpression setting) may not represent a significant source of genomic instability and SCNAs in human tumors.	('mutated', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', (206, 212))	('human', 'Species', '9606', (200, 205))	('OGs', 'Protein', (35, 38))
101527	28104840	Because the number of mutations predicts patients' survival independently of the SCNA level, combining the SCNA level with the number of mutations results in a further improvement of survival prediction.	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (22, 31))	('survival', 'MPA', (183, 191))	('improvement', 'PosReg', (168, 179))
101529	28104840	Thus, one hypothesis is that protein imbalance may impair a tumor signal needed for cytotoxic immune cell infiltration.	('imbalance', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('imbalance', 'Phenotype', 'HP:0002172', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('impair', 'NegReg', (51, 57))	('protein', 'Protein', (29, 36))	('tumor', 'Disease', (60, 65))
101531	28104840	An alternative, speculative hypothesis involves the relative concentration of neoantigen peptides in high versus low aneuploidy tumors.	('aneuploidy tumors', 'Disease', 'MESH:D000782', (117, 134))	('aneuploidy tumors', 'Disease', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (101, 105))
101535	28104840	These hypotheses also predict that the role of aneuploidy in promoting cancer immune escape is dependent on the presence of neoantigens, thus mutations.	('mutations', 'Var', (142, 151))	('aneuploidy', 'Disease', 'MESH:D000782', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('aneuploidy', 'Disease', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('promoting', 'PosReg', (61, 70))
101538	28104840	Information on both point mutations and copy number changes can simultaneously be derived from sequencing performed on patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patient', 'Species', '9606', (119, 126))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('copy number changes', 'Var', (40, 59))	('point mutations', 'Var', (20, 35))
101543	28104840	To determine SCNA calls, i.e., the presence or absence of amplifications or deletions, we considered different noise thresholds in different tumor types based on tumor purity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (141, 146))	('deletions', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
101557	28104840	For the focal SCNAs (deletions or amplifications involving a region smaller than 50% of a chromosome arm), we applied GISTIC2 to the segmentation file (from all tumor samples) of the copy number data, after excluding the arm-level (and chromosome-level) copy number changes.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('deletions', 'Var', (21, 30))
101558	28104840	The focal SCNA events (amplification and deletion) resulting from GISTIC2 analysis are listed in table S1, B and C. To distinguish between arm and chromosome events, among the arm-level SCNA events, all cases where both arms of a chromosome had the same copy number change (in value and sign) were considered as chromosome SCNA events, while all the others were considered as arm SCNA events (table S1D).	('S1, B and C', 'Gene', '5707', (103, 114))	('copy number', 'Var', (254, 265))	('chromosome SCNA', 'Disease', (312, 327))
101559	28104840	We first determined in each tumor sample whether each arm, chromosome or focal region (focal events listed in table S1, B and C) was amplified, highly amplified, deleted, or highly deleted.	('tumor', 'Disease', (28, 33))	('S1, B and C', 'Gene', '5707', (116, 127))	('deleted', 'Var', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
101565	28104840	For each TSG or OG, we defined a tumor sample as mutated in that predicted driver gene if the tumor contained at least one mutation predicted to be functionally relevant.	('mutated', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (33, 38))
101566	28104840	Specifically, for each OG, recurrent mutations were defined as all the missense mutations recurring in the same position (same amino-acid residue) with a frequency of 20% among all missense mutations (in the OG) or a frequency of 5% and a minimum total absolute number of 10 mutations among all tumor samples.	('missense mutations', 'Var', (71, 89))	('missense mutations', 'Var', (181, 199))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (295, 300))
101567	28104840	S1A, for CRC, UCEC, STAD, and other tumor types, the distribution of the number of mutations across samples is bimodal, highlighting the presence of a subset of hypermutated tumors.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (174, 180))	('CRC', 'Disease', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('CRC', 'Phenotype', 'HP:0030731', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
101588	28104840	For each of these genomic regions, the frequency of amplification and deletion across samples within each tumor type was determined.	('deletion', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
101590	28104840	Both Pearson and Spearman correlation between the net frequencies of copy number changes at the focal-level versus arm-level across the 807 genomic regions are reported for each tumor type in table S5D.	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('copy number', 'Var', (69, 80))
101627	28104840	Multivariable Cox proportional hazard model was applied considering the combination of low SCNA level (bottom 50%) and immunotherapy treatment and combination of high N of mutations and immunotherapy treatment as predictors, in addition to other covariates to control for differences between the three data sets (table S6D).	('Cox', 'Gene', (14, 17))	('mutations', 'Var', (172, 181))	('SCNA level', 'MPA', (91, 101))	('Cox', 'Gene', '1351', (14, 17))
101646	26384329	Previously, most of the studies were focused on capillary permeability measuring (Ktrans) and had already showed that Ktrans could significantly differentiate brain tumor types and help gliomas grading [- ].	('Ktrans', 'Chemical', '-', (82, 88))	('brain tumor', 'Phenotype', 'HP:0030692', (159, 170))	('gliomas', 'Disease', (186, 193))	('gliomas', 'Disease', 'MESH:D005910', (186, 193))	('Ktrans', 'Var', (118, 124))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('help', 'Reg', (181, 185))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('Ktrans', 'Chemical', '-', (118, 124))	('brain tumor', 'Disease', 'MESH:D001932', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('brain tumor', 'Disease', (159, 170))
101731	26384329	According to our results: in TP, the mean values of Ktrans, Ve and iAUC in metastases were significantly higher than the corresponding value in HGG and iAUC had the highest diagnostic power.	('Ktrans', 'Var', (52, 58))	('higher', 'PosReg', (105, 111))	('Ktrans', 'Chemical', '-', (52, 58))	('metastases', 'Disease', (75, 85))	('metastases', 'Disease', 'MESH:D009362', (75, 85))
101745	25330836	Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('PDGF-B', 'Gene', '18591', (25, 31))	('brain cancer', 'Phenotype', 'HP:0030692', (227, 239))	('Glioma', 'Phenotype', 'HP:0009733', (132, 138))	('Pax3', 'Gene', (0, 4))	('Glioma', 'Phenotype', 'HP:0009733', (186, 192))	('brainstem gliomagenesis', 'Phenotype', 'HP:0010796', (40, 63))	('DIPG', 'Chemical', '-', (194, 198))	('expression', 'Var', (5, 15))	('glioma', 'Disease', (50, 56))	('pediatric brain cancer', 'Disease', (217, 239))	('brainstem glioma', 'Phenotype', 'HP:0010796', (40, 56))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('Glioma', 'Disease', (186, 192))	('glioma', 'Disease', (104, 110))	('Glioma', 'Disease', (132, 138))	('PDGF-B', 'Gene', (25, 31))	('enhances', 'PosReg', (16, 24))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('pediatric brain cancer', 'Disease', 'MESH:D001932', (217, 239))	('BSG', 'Phenotype', 'HP:0010796', (140, 143))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('Pax3', 'Gene', '18505', (0, 4))	('Brainstem Glioma', 'Phenotype', 'HP:0010796', (122, 138))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('brainstem glioma', 'Phenotype', 'HP:0010796', (94, 110))	('Glioma', 'Disease', 'MESH:D005910', (186, 192))	('Glioma', 'Disease', 'MESH:D005910', (132, 138))
101749	25330836	In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('extends', 'PosReg', (179, 186))	('Pax3', 'Gene', (9, 13))	('BSG', 'Gene', '12215', (227, 230))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('loss', 'Var', (157, 161))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('survival', 'CPA', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Pax3', 'Gene', (165, 169))	('shortening', 'NegReg', (54, 64))	('BSG', 'Gene', (227, 230))	('enhances', 'PosReg', (14, 22))	('mice', 'Species', '10090', (239, 243))	('increasing', 'PosReg', (83, 93))	('BSG', 'Phenotype', 'HP:0010796', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('glioma', 'Disease', (37, 43))	('tumor', 'Disease', (94, 99))	('grade', 'CPA', (115, 120))	('PDGF-B-driven', 'Gene', (23, 36))	('glioma', 'Disease', 'MESH:D005910', (37, 43))
101750	25330836	Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('glioma', 'Disease', (51, 57))	('BSG', 'Gene', (115, 118))	('alterations', 'Var', (191, 202))	('PDGFRA', 'Gene', (184, 190))	('BSG', 'Phenotype', 'HP:0010796', (115, 118))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('human', 'Species', '9606', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('BSG', 'Gene', '12215', (115, 118))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('cell cycle regulatory genes', 'Gene', (222, 249))	('associates', 'Reg', (168, 178))
101757	25330836	Genetic alterations commonly found in BSG include gains and/or activating mutations in platelet-derived growth factor receptor alpha (PDGFRA), amplification of genes involved in the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway or cell cycle regulation, and a K27M mutation of histone H3.3 or 3.1.	('K27M', 'Mutation', 'p.K27M', (287, 291))	('BSG', 'Gene', '12215', (38, 41))	('K27M mutation', 'Var', (287, 300))	('BSG', 'Phenotype', 'HP:0010796', (38, 41))	('activating', 'PosReg', (63, 73))	('platelet-derived growth factor receptor alpha', 'Gene', (87, 132))	('gains', 'PosReg', (50, 55))	('amplification', 'Var', (143, 156))	('histone H3.3', 'Gene', (304, 316))	('histone H3.3', 'Gene', '15078', (304, 316))	('platelet-derived growth factor receptor alpha', 'Gene', '18595', (87, 132))	('BSG', 'Gene', (38, 41))	('PDGFRA', 'Gene', (134, 140))
101758	25330836	Recently, mutations in the ACVR1 gene have been discovered in 20-32% of cases, as well as mutations in the PPM1D gene.	('discovered', 'Reg', (48, 58))	('ACVR1', 'Gene', (27, 32))	('PPM1D', 'Gene', (107, 112))	('mutations', 'Var', (10, 19))	('PPM1D', 'Gene', '53892', (107, 112))
101760	25330836	Previous work on BSG has characterized distinct subsets of the disease, including mesenchymal and oligodendroglial, N-Myc and Hedgehog, MYCN, silent, and H3-K27M or H3-K27M and wildtype.	('MYCN', 'Gene', (136, 140))	('H3-K27M', 'Var', (154, 161))	('BSG', 'Gene', '12215', (17, 20))	('K27M', 'Mutation', 'p.K27M', (157, 161))	('H3-K27M', 'Var', (165, 172))	('N-Myc', 'Gene', '18109', (116, 121))	('silent', 'Disease', (142, 148))	('N-Myc', 'Gene', (116, 121))	('K27M', 'Mutation', 'p.K27M', (168, 172))	('MYCN', 'Gene', '18109', (136, 140))	('Hedgehog', 'Disease', (126, 134))	('BSG', 'Phenotype', 'HP:0010796', (17, 20))	('BSG', 'Gene', (17, 20))	('mesenchymal', 'Disease', (82, 93))
101762	25330836	Gliomas arising in the midline of the central nervous system (including the brainstem) commonly harbor the H3.3/3.1-K27M mutation only, while gliomas that arise in the cerebral cortex may contain an alternative H3.3-G34R/V mutation.	('G34R', 'Var', (216, 220))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('K27M', 'Mutation', 'p.K27M', (116, 120))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('H3.3/3.1-K27M', 'Var', (107, 120))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('Gliomas', 'Disease', (0, 7))	('midline of the central nervous system', 'Disease', (23, 60))	('G34R', 'SUBSTITUTION', 'None', (216, 220))	('midline of the central nervous system', 'Disease', 'MESH:D002493', (23, 60))
101764	25330836	In addition, human infratentorial and supratentorial low-grade gliomas have distinct expression signatures corresponding to normal astrocytes and NSCs from their respective regions, while the expression patterns of G34R/V and K27M mutant gliomas mimic the developmental region in which they arise.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('K27M', 'Mutation', 'p.K27M', (226, 230))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('human', 'Species', '9606', (13, 18))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('gliomas', 'Disease', (238, 245))	('G34R', 'SUBSTITUTION', 'None', (215, 219))	('K27M', 'Var', (226, 230))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('G34R', 'Var', (215, 219))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
101766	25330836	Pax3 is not only necessary for the proper specification of these developing tissues, but also for cell survival as homozygous loss of Pax3 in the mouse leads to severe neural crest and neural tube defects, attributable to an induction of p53-dependent apoptosis.	('neural tube defects', 'Disease', 'MESH:D009436', (185, 204))	('neural tube defects', 'Phenotype', 'HP:0045005', (185, 204))	('mouse', 'Species', '10090', (146, 151))	('loss', 'Var', (126, 130))	('Pax3', 'Gene', (134, 138))	('neural tube defects', 'Disease', (185, 204))
101767	25330836	Ectopic expression of Pax3 is found to be pro-tumorigenic in sarcomas and neural crest-derived tumors such as melanoma and neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('neuroblastoma', 'Disease', 'MESH:D009447', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('Ectopic expression', 'Var', (0, 18))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcomas', 'Disease', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (46, 51))	('Pax3', 'Gene', (22, 26))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('neuroblastoma', 'Disease', (123, 136))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
101772	25330836	In an expression array comparing mouse BSG and CG induced by PDGF-B overexpression and Ink4a-ARF loss, we identified Pax3 as being a brainstem-specific marker.	('CG', 'Chemical', '-', (47, 49))	('loss', 'NegReg', (97, 101))	('Ink4a-ARF', 'Gene', (87, 96))	('BSG', 'Gene', (39, 42))	('PDGF-B', 'Gene', (61, 67))	('BSG', 'Phenotype', 'HP:0010796', (39, 42))	('Ink4a-ARF', 'Gene', '12578', (87, 96))	('BSG', 'Gene', '12215', (39, 42))	('mouse', 'Species', '10090', (33, 38))	('overexpression', 'Var', (68, 82))
101776	25330836	Importantly, the regional expression pattern of Pax3 is mirrored in human glioma, revealing a subset of BSG with high PAX3 expression that associates with alterations in PDGFRA and cell cycle regulatory genes and is exclusive of ACVR1 mutations.	('BSG', 'Gene', (104, 107))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('alterations', 'Var', (155, 166))	('expression', 'MPA', (123, 133))	('human', 'Species', '9606', (68, 73))	('PAX3', 'Gene', (118, 122))	('BSG', 'Gene', '12215', (104, 107))	('PDGFRA', 'Gene', (170, 176))	('glioma', 'Disease', (74, 80))	('BSG', 'Phenotype', 'HP:0010796', (104, 107))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
101829	25330836	Secondary antibodies from Li-Cor were used at 1:10,000 for IRDye800CW or 1:20,000 for IRDye680LT.	('Cor', 'Gene', (29, 32))	('IRDye800CW', 'Var', (59, 69))	('Cor', 'Gene', '108031', (29, 32))
101832	25330836	For analyses of human data, unpaired t-test was used for the age at diagnosis of PAX3-Low versus PAX3-High tumors, and Fisher's exact test was used to test for significance of the association between high Pax3 expression and genetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Pax3', 'Gene', (205, 209))	('PAX3-High tumors', 'Disease', 'MESH:D009369', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'MPA', (210, 220))	('PAX3-High tumors', 'Disease', (97, 113))	('human', 'Species', '9606', (16, 21))	('high', 'Var', (200, 204))
101856	25330836	Collectively, these data indicate that Pax3 is a brainstem-specific marker of mouse PDGF-B-driven glioma in the context of Ink4aARF-deficiency, p53-deficiency, as well as H3.3-K27M expression.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('H3.3-K27M', 'Var', (171, 180))	('PDGF-B-driven', 'Gene', (84, 97))	('glioma', 'Disease', (98, 104))	('K27M', 'Mutation', 'p.K27M', (176, 180))	('mouse', 'Species', '10090', (78, 83))	('Ink4aARF-deficiency, p53-deficiency', 'Disease', 'MESH:D007153', (123, 158))
101869	25330836	However, Pax3 inhibited basal apoptosis as evidenced by caspase 3/7 activation (Figure 4b).	('caspase 3', 'Gene', (56, 65))	('basal apoptosis', 'CPA', (24, 39))	('activation', 'PosReg', (68, 78))	('caspase 3', 'Gene', '12367', (56, 65))	('inhibited', 'NegReg', (14, 23))	('Pax3', 'Var', (9, 13))
101872	25330836	While PDGF-B overexpression alone led to asymptomatic low-grade glioma in 5 out of 20 mice, Pax3 overexpression alone did not lead to tumor formation (Figure 5a-c).	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('glioma', 'Disease', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('led to', 'Reg', (34, 40))	('PDGF-B', 'Gene', (6, 12))	('tumor', 'Disease', (134, 139))	('overexpression', 'Var', (13, 27))
101873	25330836	When compared to PDGF-B injection alone, the addition of Pax3 to PDGF-B significantly reduced survival (Figure 5a) and increased tumor penetrance to 20 out of 25 mice (p = 0.0003, Figure 5b).	('reduced', 'NegReg', (86, 93))	('PDGF-B', 'Gene', (65, 71))	('Pax3', 'Var', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mice', 'Species', '10090', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('survival', 'CPA', (94, 102))	('increased', 'PosReg', (119, 128))	('addition', 'Var', (45, 53))
101877	25330836	Therefore, in the presence of enhanced PDGF-B signaling, Pax3 is sufficient to generate aggressive high-grade BSG, a feat that PDGF-B alone cannot achieve in the brainstem.	('BSG', 'Gene', (110, 113))	('BSG', 'Phenotype', 'HP:0010796', (110, 113))	('BSG', 'Gene', '12215', (110, 113))	('Pax3', 'Var', (57, 61))
101884	25330836	Although both groups of mice succumbed to high-grade BSG, the Pax3-KO mice displayed a significant 33% increase in survival (median survival 38 days versus 28.5 days, Figure 6e).	('increase', 'PosReg', (103, 111))	('mice', 'Species', '10090', (24, 28))	('BSG', 'Gene', (53, 56))	('BSG', 'Phenotype', 'HP:0010796', (53, 56))	('mice', 'Species', '10090', (70, 74))	('BSG', 'Gene', '12215', (53, 56))	('Pax3-KO', 'Var', (62, 69))
101892	25330836	We next compared the genetic alterations occurring in PAX3-Low versus PAX3-High BSG samples from Figure 7a.	('BSG', 'Gene', (80, 83))	('BSG', 'Phenotype', 'HP:0010796', (80, 83))	('PAX3-Low', 'Var', (54, 62))	('BSG', 'Gene', '12215', (80, 83))
101893	25330836	As is shown in Figure 7c, Table 2, and Additional file 14: Table S9, high PAX3 expression significantly associated with wildtype ACVR1, PDGFRA amplification or mutation, and CDK4/6-CCND1/2/3 amplification.	('CCND1/2/3', 'Gene', '12443;12444;12445', (181, 190))	('mutation', 'Var', (160, 168))	('expression', 'MPA', (79, 89))	('PAX3', 'Gene', (74, 78))	('high PAX3', 'Gene', (69, 78))	('CDK4/6', 'Gene', (174, 180))	('associated', 'Reg', (104, 114))	('amplification', 'Var', (143, 156))	('CCND1/2/3', 'Gene', (181, 190))	('PDGFRA', 'Gene', (136, 142))	('CDK4/6', 'Gene', '12567;12571', (174, 180))
101894	25330836	In addition, PPM1D and H3.1-K27M mutations were found exclusively in PAX3-Low tumors (27% and 18%, respectively), although these relationships were not significant due to their low frequency.	('PAX3-Low tumors', 'Disease', (69, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('PPM1D', 'Gene', (13, 18))	('K27M', 'Mutation', 'p.K27M', (28, 32))	('H3.1-K27M', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PAX3-Low tumors', 'Disease', 'MESH:D009800', (69, 84))	('found', 'Reg', (48, 53))	('PPM1D', 'Gene', '53892', (13, 18))
101895	25330836	The majority of PAX3-High tumors also contained TP53 alterations (82%) and the H3.3-K27M mutation (82%).	('TP53', 'Gene', '22059', (48, 52))	('TP53', 'Gene', (48, 52))	('contained', 'Reg', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PAX3-High tumors', 'Disease', 'MESH:D009369', (16, 32))	('PAX3-High tumors', 'Disease', (16, 32))	('K27M', 'Mutation', 'p.K27M', (84, 88))	('H3.3-K27M', 'Var', (79, 88))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
101897	25330836	Collectively, these data describe a novel subset of human BSG with high Pax3 expression that are commonly characterized by increased PDGF signaling, and highlight an important regional difference between pediatric gliomas arising in the cerebral cortex (supratentorial) and the brainstem (infratentorial) (Figure 7e).	('expression', 'MPA', (77, 87))	('BSG', 'Gene', '12215', (58, 61))	('Pax3', 'Gene', (72, 76))	('high', 'Var', (67, 71))	('human', 'Species', '9606', (52, 57))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('PDGF signaling', 'MPA', (133, 147))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('gliomas', 'Disease', (214, 221))	('BSG', 'Gene', (58, 61))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('BSG', 'Phenotype', 'HP:0010796', (58, 61))
101903	25330836	As Olig2 characterizes the majority of human BSG, particularly the oligodendroglial (PDGFRA) and H3-K27M subgroups, as well as marks a candidate cell-of-origin for BSG, the expression profile of these cells has important implications for at least a subset of the human disease.	('BSG', 'Gene', '12215', (45, 48))	('BSG', 'Phenotype', 'HP:0010796', (45, 48))	('K27M', 'Mutation', 'p.K27M', (100, 104))	('H3-K27M', 'Var', (97, 104))	('BSG', 'Gene', (164, 167))	('BSG', 'Phenotype', 'HP:0010796', (164, 167))	('human', 'Species', '9606', (263, 268))	('BSG', 'Gene', (45, 48))	('human', 'Species', '9606', (39, 44))	('BSG', 'Gene', '12215', (164, 167))
101904	25330836	It has not been previously reported that gliomas induced with the same genetic alterations in different regions of the mouse brain have distinct gene expression.	('mouse', 'Species', '10090', (119, 124))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('genetic alterations', 'Var', (71, 90))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))
101909	25330836	Importantly, we find regional expression of Pax3 in mouse PDGF-B-driven glioma in the context of Ink4aARF-loss, p53-loss, and overexpression of H3.3-K27M that is mirrored in human glioma.	('glioma', 'Disease', (72, 78))	('human', 'Species', '9606', (174, 179))	('PDGF-B-driven', 'Gene', (58, 71))	('overexpression', 'PosReg', (126, 140))	('mouse', 'Species', '10090', (52, 57))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('Ink4aARF', 'Gene', '12578', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('Pax3', 'Gene', (44, 48))	('H3.3-K27M', 'Var', (144, 153))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('K27M', 'Mutation', 'p.K27M', (149, 153))	('p53-loss', 'Var', (112, 120))	('Ink4aARF', 'Gene', (97, 105))	('glioma', 'Disease', (180, 186))
101913	25330836	Collectively, these data suggest that PAX3-High tumors may be part of the oligodendroglial and the H3-K27M subgroups previously described to harbor PDGFRA alterations.	('PAX3-High tumors', 'Disease', 'MESH:D009369', (38, 54))	('alterations', 'Var', (155, 166))	('K27M', 'Mutation', 'p.K27M', (102, 106))	('PAX3-High tumors', 'Disease', (38, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PDGFRA', 'Gene', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
101914	25330836	In addition, PPM1D, H3.1-K27M, and ACVR1 mutations occur only in PAX3-Low tumors.	('mutations', 'Var', (41, 50))	('K27M', 'Mutation', 'p.K27M', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PPM1D', 'Gene', (13, 18))	('occur', 'Reg', (51, 56))	('PAX3-Low tumors', 'Disease', 'MESH:D009800', (65, 80))	('H3.1-K27M', 'Var', (20, 29))	('PPM1D', 'Gene', '53892', (13, 18))	('ACVR1', 'Gene', (35, 40))	('PAX3-Low tumors', 'Disease', (65, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
101926	25330836	When combined with the pro-proliferative effects of increased PDGF signaling, a common event found in PAX3-High human BSG, ectopic Pax3 enhances gliomagenesis, increasing tumor frequency and promoting progression to a high-grade malignancy.	('glioma', 'Disease', (145, 151))	('increasing', 'PosReg', (160, 170))	('BSG', 'Phenotype', 'HP:0010796', (118, 121))	('BSG', 'Gene', (118, 121))	('malignancy', 'Disease', 'MESH:D009369', (229, 239))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Pax3', 'Gene', (131, 135))	('ectopic', 'Var', (123, 130))	('enhances', 'PosReg', (136, 144))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('BSG', 'Gene', '12215', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('promoting', 'PosReg', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('progression', 'CPA', (201, 212))	('human', 'Species', '9606', (112, 117))	('malignancy', 'Disease', (229, 239))
101928	25330836	Interestingly, in the absence of p53, Pax3 promotes the proliferation of brainstem progenitors, which may explain how deletion of Pax3 in p53-deficient BSG delays gliomagenesis in vivo.	('BSG', 'Gene', (152, 155))	('glioma', 'Disease', (163, 169))	('brainstem progenitors', 'CPA', (73, 94))	('promotes', 'PosReg', (43, 51))	('BSG', 'Phenotype', 'HP:0010796', (152, 155))	('BSG', 'Gene', '12215', (152, 155))	('proliferation', 'CPA', (56, 69))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('delays', 'NegReg', (156, 162))	('Pax3', 'Gene', (130, 134))	('deletion', 'Var', (118, 126))
101932	25330836	We find here that Pax3 increases the frequency of both low- and high-grade BSG in the context of PDGF signaling, supporting its role as an oncogene in both low- and high-grade brainstem lesions.	('BSG', 'Gene', (75, 78))	('low-', 'Disease', (55, 59))	('BSG', 'Phenotype', 'HP:0010796', (75, 78))	('Pax3', 'Var', (18, 22))	('BSG', 'Gene', '12215', (75, 78))	('increases', 'PosReg', (23, 32))
101937	25330836	The functional discrepancies could be explained by varying contexts of genetic alterations, differences between mouse and human tumor biology, or an inhibitory effect on Pax3 expression or function of the cerebral cortex stroma in mice.	('human', 'Species', '9606', (122, 127))	('alterations', 'Var', (79, 90))	('expression', 'MPA', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Pax3', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mice', 'Species', '10090', (231, 235))	('tumor', 'Disease', (128, 133))	('cerebral cortex stroma', 'Disease', (205, 227))	('mouse', 'Species', '10090', (112, 117))	('cerebral cortex stroma', 'Disease', 'MESH:D002543', (205, 227))
101940	25330836	We have identified a subset of human BSG with high PAX3 expression that associates with PDGFRA alterations and amplification of cell-cycle regulatory genes, and is exclusive of ACVR1 mutations.	('high', 'Var', (46, 50))	('associates', 'Reg', (72, 82))	('BSG', 'Gene', (37, 40))	('human', 'Species', '9606', (31, 36))	('BSG', 'Phenotype', 'HP:0010796', (37, 40))	('expression', 'MPA', (56, 66))	('amplification', 'MPA', (111, 124))	('alterations', 'Var', (95, 106))	('PDGFRA', 'Gene', (88, 94))	('PAX3', 'Gene', (51, 55))	('BSG', 'Gene', '12215', (37, 40))	('cell-cycle regulatory genes', 'Gene', (128, 155))
101942	25330836	Important complements to these studies in the future will be to investigate the function of Pax3 in human BSG cells, both in cell lines and xenografts, as well as in epigenetically-induced models to study how the presence of the H3.3-K27M mutation contributes to or alters Pax3 function.	('alters', 'Reg', (266, 272))	('BSG', 'Gene', '12215', (106, 109))	('H3.3-K27M', 'Var', (229, 238))	('K27M', 'Mutation', 'p.K27M', (234, 238))	('human', 'Species', '9606', (100, 105))	('function', 'MPA', (278, 286))	('Pax3', 'Gene', (273, 277))	('BSG', 'Phenotype', 'HP:0010796', (106, 109))	('BSG', 'Gene', (106, 109))
101947	32882327	Both low ARL9 expression and hypermethylation predicted favorable OS and PFS in LGG patients, according to the TCGA database.	('PFS', 'Disease', (73, 76))	('patients', 'Species', '9606', (84, 92))	('low', 'NegReg', (5, 8))	('ARL9', 'Gene', '132946', (9, 13))	('expression', 'MPA', (14, 24))	('hypermethylation', 'Var', (29, 45))	('ARL9', 'Gene', (9, 13))	('LGG', 'Disease', (80, 83))	('favorable', 'PosReg', (56, 65))
101948	32882327	Cox regression demonstrated that low ARL9 expression and ARL9 hypermethylation were independent biomarkers for OS.	('low', 'NegReg', (33, 36))	('hypermethylation', 'Var', (62, 78))	('expression', 'MPA', (42, 52))	('ARL9', 'Gene', (37, 41))	('ARL9', 'Gene', (57, 61))	('ARL9', 'Gene', '132946', (37, 41))	('ARL9', 'Gene', '132946', (57, 61))
101992	32882327	Then Pearson correlation analysis was exploited to identify the ARL9 CpG sites at which methylation was most strongly correlated with ARL9 mRNA expression.	('ARL9', 'Gene', (134, 138))	('methylation', 'Var', (88, 99))	('correlated', 'Reg', (118, 128))	('ARL9', 'Gene', '132946', (64, 68))	('ARL9', 'Gene', (64, 68))	('ARL9', 'Gene', '132946', (134, 138))
101993	32882327	As listed in Table S1, except for 3 CpG sites (cg09992215, cg10737307 and cg01382100), methylation of the remaining CpG sites well correlated with the expression of ARL9.	('cg10737307', 'Var', (59, 69))	('ARL9', 'Gene', (165, 169))	('cg09992215', 'Var', (47, 57))	('correlated', 'Reg', (131, 141))	('expression', 'MPA', (151, 161))	('cg10737307', 'Chemical', '-', (59, 69))	('methylation', 'MPA', (87, 98))	('cg01382100', 'Var', (74, 84))	('ARL9', 'Gene', '132946', (165, 169))
101998	32882327	As shown in Table 1 , the expression of ARL9 was closely correlated with age (P < 0.0001), histological type (P = 0.0282), family history of cancer (P = 0.0473), molecular subtype (P < 0.0001), radiotherapy (P = 0.0015), living status (P = 0.002) and ARL9 methylation (P < 0.0001).	('expression', 'MPA', (26, 36))	('ARL9', 'Gene', (251, 255))	('methylation', 'Var', (256, 267))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('correlated', 'Reg', (57, 67))	('ARL9', 'Gene', (40, 44))	('ARL9', 'Gene', '132946', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('ARL9', 'Gene', '132946', (251, 255))	('cancer', 'Disease', (141, 147))
102000	32882327	We utilized survival analyses to assess the association between ARL9 expression as well as ARL9 methylation and prognosis of patients with LGG.	('expression', 'MPA', (69, 79))	('ARL9', 'Gene', '132946', (91, 95))	('methylation', 'Var', (96, 107))	('LGG', 'Disease', (139, 142))	('ARL9', 'Gene', '132946', (64, 68))	('ARL9', 'Gene', (64, 68))	('ARL9', 'Gene', (91, 95))	('association', 'Interaction', (44, 55))	('patients', 'Species', '9606', (125, 133))
102001	32882327	S2, we discovered that patients with low ARL9 expression had an approximately a 2 fold longer OS than that with high ARL9 expression (HR = 0.4885, 95% CI = 0.3465-0.6889, P < 0.0001).	('ARL9', 'Gene', '132946', (41, 45))	('ARL9', 'Gene', '132946', (117, 121))	('low', 'Var', (37, 40))	('patients', 'Species', '9606', (23, 31))	('ARL9', 'Gene', (117, 121))	('longer', 'PosReg', (87, 93))	('ARL9', 'Gene', (41, 45))
102003	32882327	We observed that low ARL9 expression was more closely correlated with favorable OS than high ARL9 expression in LGG patients with WHO grade III (P = 0.0002) and astrocytoma (P < 0.0001).	('expression', 'MPA', (26, 36))	('astrocytoma', 'Disease', (161, 172))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('ARL9', 'Gene', (93, 97))	('patients', 'Species', '9606', (116, 124))	('ARL9', 'Gene', '132946', (93, 97))	('favorable OS', 'Disease', (70, 82))	('low', 'Var', (17, 20))	('ARL9', 'Gene', (21, 25))	('astrocytoma', 'Disease', 'MESH:D001254', (161, 172))	('ARL9', 'Gene', '132946', (21, 25))
102006	32882327	Regarding the prognostic value of ARL9 methylation, patients with ARL9 hypermethylation exhibited longer OS (HR = 0.4681, 95%CI = 0.3298-0.6645, P < 0.0001) or PFS time (HR = 0.4945, 95% CI = 0.3726-0.6561, P < 0.0001) than those with ARL9 hypomethylation (Fig.	('ARL9', 'Gene', (34, 38))	('hypermethylation', 'Var', (71, 87))	('ARL9', 'Gene', '132946', (34, 38))	('ARL9', 'Gene', '132946', (66, 70))	('ARL9', 'Gene', (66, 70))	('longer', 'PosReg', (98, 104))	('ARL9', 'Gene', '132946', (235, 239))	('ARL9', 'Gene', (235, 239))	('PFS', 'MPA', (160, 163))	('patients', 'Species', '9606', (52, 60))
102007	32882327	Subgroup analyses demonstrated that ARL9 hypermethylation was remarkably correlated with better OS or PFS than ARL9 hypomethylation in LGG patients with WHO grade II, grade III and astrocytoma.	('hypermethylation', 'Var', (41, 57))	('better', 'PosReg', (89, 95))	('astrocytoma', 'Disease', (181, 192))	('patients', 'Species', '9606', (139, 147))	('ARL9', 'Gene', '132946', (111, 115))	('PFS', 'CPA', (102, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (181, 192))	('ARL9', 'Gene', (111, 115))	('ARL9', 'Gene', '132946', (36, 40))	('ARL9', 'Gene', (36, 40))	('astrocytoma', 'Disease', 'MESH:D001254', (181, 192))
102008	32882327	Furthermore, we conducted the univariate along with multivariate Cox regression analyses to probe the independent prognostic variables of patients with LGG, and we found that both low ARL9 expression (HR = 0.52, 95% CI = 0.283-0.957, P = 0.036) and ARL9 hypermethylation (HR = 0.40, 95% CI = 0.213-0.753, P = 0.004) were independent prognostic variables for favorable OS (Table S2).	('hypermethylation', 'Var', (254, 270))	('ARL9', 'Gene', (184, 188))	('ARL9', 'Gene', '132946', (184, 188))	('expression', 'MPA', (189, 199))	('ARL9', 'Gene', '132946', (249, 253))	('favorable OS', 'Disease', (358, 370))	('ARL9', 'Gene', (249, 253))	('low', 'NegReg', (180, 183))	('patients', 'Species', '9606', (138, 146))
102009	32882327	Similarly, ARL9 hypermethylation (HR = 0.45, 95% CI = 0.278-0.728, P = 0.001) was an independent prognostic marker for favorable PFS (Table S2).	('ARL9', 'Gene', '132946', (11, 15))	('PFS', 'Disease', (129, 132))	('ARL9', 'Gene', (11, 15))	('hypermethylation', 'Var', (16, 32))
102010	32882327	First, we used nonparametric test to compare the difference in ARL9 mRNA expression in groups divided by age, gender, cancer type, WHO grade, 1p19q codel and IDH1-mutation.	('cancer', 'Disease', (118, 124))	('ARL9', 'Gene', (63, 67))	('ARL9', 'Gene', '132946', (63, 67))	('mRNA expression', 'MPA', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IDH1', 'Gene', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('IDH1', 'Gene', '3417', (158, 162))	('1p19q codel', 'Var', (142, 153))
102011	32882327	3 , ARL9 mRNA expression was remarkably different in groups stratified by WHO grade (P = 0.0061), 1p19q codeletion (P < 0.001) and IDH1-mutation (P < 0.001), indicating the close correlation of ARL9 mRNA expression with a series of significant clinical parameters.	('ARL9', 'Gene', (4, 8))	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', '3417', (131, 135))	('1p19q codeletion', 'Var', (98, 114))	('ARL9', 'Gene', (194, 198))	('ARL9', 'Gene', '132946', (194, 198))	('different', 'Reg', (40, 49))	('ARL9', 'Gene', '132946', (4, 8))
102015	32882327	To investigate the impacts of clinical parameters on the prognostic significance of ARL9, we further implemented a series of subgroup analyses according to four crucial clinical indexes, including WHO grade, 1p19q codeletion, IDH1-mutation and radiotherapy.	('1p19q codeletion', 'Var', (208, 224))	('IDH1', 'Gene', (226, 230))	('ARL9', 'Gene', (84, 88))	('ARL9', 'Gene', '132946', (84, 88))	('IDH1', 'Gene', '3417', (226, 230))
102016	32882327	As revealed by a panel of Kaplan-Meier curves, the correlation of low ARL9 expression with better OS still existed in LGG patients with WHO III (P = 0.0002) and radiotherapy (P = 0.0001), while no correlation was observed among LGG patients with WHO II (P = 0.9487), 1p19q codeletion (P = 0.1913), 1p19q non-codeletion (P = 0.2245), IDH1-wt (P = 0.5633), IDH1-mutation (P = 0.0878) and no radiotherapy (P = 0.0693).	('IDH1', 'Gene', (355, 359))	('IDH1', 'Gene', '3417', (355, 359))	('ARL9', 'Gene', '132946', (70, 74))	('patients', 'Species', '9606', (232, 240))	('IDH1', 'Gene', '3417', (333, 337))	('ARL9', 'Gene', (70, 74))	('patients', 'Species', '9606', (122, 130))	('IDH1', 'Gene', (333, 337))	('low', 'NegReg', (66, 69))	('1p19q', 'Var', (267, 272))	('1p19q non-codeletion', 'Var', (298, 318))	('expression', 'MPA', (75, 85))
102018	32882327	We employed Kaplan-Meier analysis to investigate the association between low ARL9 and OS in LGG patients (Fig.	('ARL9', 'Gene', (77, 81))	('patients', 'Species', '9606', (96, 104))	('ARL9', 'Gene', '132946', (77, 81))	('low', 'Var', (73, 76))	('LGG', 'Disease', (92, 95))
102022	32882327	As no previous studies have reported an association between low ARL9 expression and OS among patients with LGG, we only included the results generated from four different datasets in meta-analysis.	('low', 'Var', (60, 63))	('expression', 'MPA', (69, 79))	('ARL9', 'Gene', '132946', (64, 68))	('ARL9', 'Gene', (64, 68))	('patients', 'Species', '9606', (93, 101))
102027	32882327	S6) showed that ARL9 expression could predict 1-year, 3-year and 5-year OS with good predictability in LGG patients based on four datasets.	('LGG', 'Disease', (103, 106))	('ARL9', 'Gene', (16, 20))	('expression', 'Var', (21, 31))	('ARL9', 'Gene', '132946', (16, 20))	('patients', 'Species', '9606', (107, 115))
102047	32882327	Of note, ARL9 was implicated in gliogenesis and glial cell differentiation, and abnormal expression of ARL9 might lead to the occurrence and progression of glioma.	('expression', 'MPA', (89, 99))	('ARL9', 'Gene', (103, 107))	('glioma', 'Disease', (156, 162))	('ARL9', 'Gene', '132946', (103, 107))	('ARL9', 'Gene', '132946', (9, 13))	('ARL9', 'Gene', (9, 13))	('abnormal', 'Var', (80, 88))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('lead to', 'Reg', (114, 121))
102050	32882327	We found that both ARL9 expression and ARL9 methylation were closely associated with a series of significant features, including histological type and molecular type.	('methylation', 'Var', (44, 55))	('expression', 'MPA', (24, 34))	('associated', 'Reg', (69, 79))	('ARL9', 'Gene', (19, 23))	('ARL9', 'Gene', '132946', (19, 23))	('ARL9', 'Gene', '132946', (39, 43))	('ARL9', 'Gene', (39, 43))
102051	32882327	Cox regression models established the critical role of low ARL9 expression and ARL9 hypermethylation in the favorable prognosis of patients with LGG.	('ARL9', 'Gene', (59, 63))	('patients', 'Species', '9606', (131, 139))	('ARL9', 'Gene', '132946', (59, 63))	('expression', 'MPA', (64, 74))	('ARL9', 'Gene', '132946', (79, 83))	('ARL9', 'Gene', (79, 83))	('LGG', 'Disease', (145, 148))	('low', 'NegReg', (55, 58))	('hypermethylation', 'Var', (84, 100))
102058	32882327	In this study, we systematically explored the association between low ARL9 expression and survival in four public databases.	('low', 'Var', (66, 69))	('ARL9', 'Gene', (70, 74))	('expression', 'MPA', (75, 85))	('ARL9', 'Gene', '132946', (70, 74))
102059	32882327	Encouragingly, low ARL9 expression was highly relevant with more favorable OS among LGG patients than high ARL9 expression.	('low', 'Var', (15, 18))	('ARL9', 'Gene', (107, 111))	('patients', 'Species', '9606', (88, 96))	('ARL9', 'Gene', '132946', (107, 111))	('ARL9', 'Gene', (19, 23))	('ARL9', 'Gene', '132946', (19, 23))	('LGG', 'Disease', (84, 87))
102061	32882327	Finally, we adopted a meta-analysis to integrate four databases to assess the overall prognostic value of ARL9, and the pooled data of 1367 patients further proved that low ARL9 expression was truly associated with favorable OS among LGG patients.	('LGG', 'Disease', (234, 237))	('associated', 'Reg', (199, 209))	('expression', 'MPA', (178, 188))	('ARL9', 'Gene', '132946', (106, 110))	('ARL9', 'Gene', (173, 177))	('patients', 'Species', '9606', (140, 148))	('ARL9', 'Gene', '132946', (173, 177))	('ARL9', 'Gene', (106, 110))	('patients', 'Species', '9606', (238, 246))	('low', 'Var', (169, 172))
102074	32882327	Surprisingly, almost all the CpG sites except for cg09992215, cg10737307 and cg01382100, showed significant associations with ARL9 expression.	('cg09992215', 'Var', (50, 60))	('ARL9', 'Gene', (126, 130))	('associations', 'Interaction', (108, 120))	('cg10737307', 'Chemical', '-', (62, 72))	('expression', 'MPA', (131, 141))	('cg01382100', 'Var', (77, 87))	('cg10737307', 'Var', (62, 72))	('ARL9', 'Gene', '132946', (126, 130))
102076	32882327	In addition, we also investigated the prognostic significance of ARL9 DNA methylation and 10 selected CpG sites, and we found that ARL9 hypermethylation correlated well with favorable OS and PFS in patients with LGG, which was further proven by multivariate Cox regression.	('LGG', 'Disease', (212, 215))	('ARL9', 'Gene', '132946', (65, 69))	('patients', 'Species', '9606', (198, 206))	('ARL9', 'Gene', (65, 69))	('hypermethylation', 'Var', (136, 152))	('ARL9', 'Gene', (131, 135))	('ARL9', 'Gene', '132946', (131, 135))	('PFS', 'CPA', (191, 194))
102077	32882327	Taken together, ARL9 was negatively regulated by ARL9 methylation, and ARL9 methylation status might be a potent indicator of favorable OS and PFS.	('regulated', 'MPA', (36, 45))	('ARL9', 'Gene', (49, 53))	('negatively', 'NegReg', (25, 35))	('ARL9', 'Gene', '132946', (49, 53))	('methylation', 'Var', (54, 65))	('favorable OS', 'Disease', (126, 138))	('ARL9', 'Gene', (71, 75))	('ARL9', 'Gene', (16, 20))	('ARL9', 'Gene', '132946', (71, 75))	('PFS', 'Disease', (143, 146))	('ARL9', 'Gene', '132946', (16, 20))
102080	32882327	Finally, although we preliminarily explored the biological process of ARL9 in glioma through enrichment analysis, the detailed mechanism that links ARL9 expression and ARL9 methylation with LGG progression requires further biomedical experiments.	('methylation', 'Var', (173, 184))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('ARL9', 'Gene', '132946', (168, 172))	('ARL9', 'Gene', (168, 172))	('ARL9', 'Gene', '132946', (70, 74))	('ARL9', 'Gene', '132946', (148, 152))	('ARL9', 'Gene', (70, 74))	('ARL9', 'Gene', (148, 152))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
102082	32882327	Either low ARL9 expression or ARL9 hypermethylation predicts favorable prognosis in LGG patients.	('hypermethylation', 'Var', (35, 51))	('ARL9', 'Gene', (11, 15))	('ARL9', 'Gene', '132946', (11, 15))	('patients', 'Species', '9606', (88, 96))	('low', 'NegReg', (7, 10))	('LGG', 'Disease', (84, 87))	('ARL9', 'Gene', '132946', (30, 34))	('expression', 'MPA', (16, 26))	('ARL9', 'Gene', (30, 34))
102248	29209073	In most of the cancer types we analyzed (Supplementary Figure 1), omic similarity matrices are positively aligned and mRNA aligns closely with miRNA, methylation and copy number, but weakly with somatic mutation.	('copy number', 'Var', (166, 177))	('mRNA', 'MPA', (118, 122))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('miRNA', 'MPA', (143, 148))	('methylation', 'MPA', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
102261	29209073	This is not surprising since PRS consisting of common single nucleotide polymorphisms (SNPs) were identified in a genome-wide association study (GWAS) as being associated with cancer risk rather than prognosis.	('ith cancer', 'Disease', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('ith cancer', 'Disease', 'MESH:D009369', (172, 182))	('single nucleotide polymorphisms', 'Var', (54, 85))	('associated', 'Reg', (160, 170))
102266	29209073	3c) across cancer types is most apparent, followed by copy number and somatic mutation (rho = 0.719), while the correlation of C-indices between miRNA and somatic mutation (rho = -0.103) is low.	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('copy number', 'Var', (54, 65))
102282	29209073	Specifically, we compared the prognostic powers of (a) the kernel machine learning method for genome-wide aggregation of mRNA transcripts; (b) pre-specified prognostic signatures, including the metagene signatures and the ESTIMATE immune signatures developed across multiple cancer types; (c) the PAM50 breast cancer classifier or the MammaPrint signature that predicts distant metastasis for early stage breast cancer; (d) LGG subtypes defined by IDH1 mutation and co-deletion of chromosome 1p/19q; and (e) algorithmically selecting mRNA transcripts by L1 penalized Cox regression (LASSO).	('breast cancer', 'Disease', 'MESH:D001943', (405, 418))	('breast cancer', 'Disease', (405, 418))	('IDH1', 'Gene', '3417', (448, 452))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Disease', (412, 418))	('Cox', 'Gene', '1351', (567, 570))	('ran', 'Gene', (127, 130))	('ran', 'Gene', '5901', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (412, 418))	('co-deletion', 'Var', (466, 477))	('distant metastasis', 'CPA', (370, 388))	('Cox', 'Gene', (567, 570))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('mutation', 'Var', (453, 461))	('ran', 'Gene', (540, 543))	('ran', 'Gene', '5901', (540, 543))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Disease', (275, 281))	('IDH1', 'Gene', (448, 452))	('breast cancer', 'Phenotype', 'HP:0003002', (405, 418))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('cancer', 'Disease', 'MESH:D009369', (412, 418))
102284	29209073	On average, the kernel method improves C-index over the metagene and immune signatures by 0.018 and 0.052 (P = 0.14 and 1.62*10-4) respectively, across cancer types.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('improves', 'PosReg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('metagene', 'Var', (56, 64))	('C-index', 'MPA', (39, 46))
102285	29209073	There are a few exceptions in which the metagene and immune signatures perform slightly better than the kernel method, including the metagene signature in UCEC (C-index = 0.728 v.s 0.667 by the kernel machine learning method), in LUAD (C-index = 0.626 v.s 0.606), in COAD (C-index = 0.604 v.s 0.583), and in GB (C-index = 0.585 v.s 0.572), as well as the immune signature in STAD (0.594 v.s 0.571) and in GB (C-index = 0.594 v.s 0.572).	('GB', 'Phenotype', 'HP:0012174', (405, 407))	('0.594', 'Var', (381, 386))	('COAD', 'Disease', 'MESH:D029424', (267, 271))	('COAD', 'Disease', (267, 271))	('GB', 'Phenotype', 'HP:0012174', (308, 310))
102300	29209073	In contrast, external validation of clinical variables resulted in a C-index decrease from 0.703 (in TCGA LUAD) to 0.621 (in the NCI study), an overall reduction of 11.66%, which may reflect the discrepancy between the study populations (the NCI study included early stage patients) or the evaluation criteria of clinical variables between the two studies.	('patients', 'Species', '9606', (273, 281))	('decrease', 'NegReg', (77, 85))	('C-index', 'MPA', (69, 76))	('0.621', 'Var', (115, 120))	('reduction', 'NegReg', (152, 161))
102318	29209073	Among the different omics data types, mRNA expression most frequently provides the highest C-index for predicting patients' survival outcome compared to the other molecular profiles in our analysis, suggesting that the resulting expression of mutated genes may be more important for patients' survival than the underlying mutational patterns.	('patients', 'Species', '9606', (283, 291))	('mutated', 'Var', (243, 250))	('C-index', 'MPA', (91, 98))	('expression', 'MPA', (229, 239))	('patients', 'Species', '9606', (114, 122))
102382	28868186	Long-term seizure control was obtained after GKRS of two separate residual DNT components along the surgical margin (2005 and 2010).	('seizure', 'Disease', (10, 17))	('seizure', 'Disease', 'MESH:D012640', (10, 17))	('DNT', 'Chemical', '-', (75, 78))	('seizure', 'Phenotype', 'HP:0001250', (10, 17))	('GKRS', 'Var', (45, 49))
102462	28868186	DNT's molecular profile shows no mutations in IDH1/IDH2; no 1p/19q-deletions or TP53 gene mutations have thus far been reported matching the MA findings in our series, as illustrated in Table 1.	('IDH2', 'Gene', '3418', (51, 55))	('DNT', 'Chemical', '-', (0, 3))	('IDH1', 'Gene', (46, 50))	('TP53', 'Gene', '7157', (80, 84))	('mutations', 'Var', (33, 42))	('TP53', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (46, 50))	('IDH2', 'Gene', (51, 55))
102466	28868186	BRAFV600E immunostaining is strongly positive in glial nodules and usually negative in the floating neurons.	('negative', 'NegReg', (75, 83))	('glial nodules', 'CPA', (49, 62))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('positive', 'Reg', (37, 45))	('BRAFV600E', 'Var', (0, 9))
102467	28868186	In our cases, BRAF mutation did not coexist with other markers.	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', '673', (14, 18))	('mutation', 'Var', (19, 27))
102477	28868186	As pointed out by Chassoux and Daumas-Duport, MRI characteristics closely correlate with DNTs microscopic differentiation, the combination of which aids in classifying DNTs as type 1 (low signal on T1-weighted images with cystic/polycystic formations), type 2 (heterogeneous signal, nodular-structured), and type 3 (dysplastic-like, iso- to low signal on T1, poor delineation, grey-white matter blurring).	('Daumas-Duport', 'Disease', (31, 44))	('low', 'NegReg', (184, 187))	('grey-white matter blurring', 'Disease', 'MESH:D056784', (377, 403))	('dysplastic', 'Disease', (316, 326))	('Daumas-Duport', 'Disease', 'None', (31, 44))	('dysplastic', 'Disease', 'MESH:D004416', (316, 326))	('iso-', 'Var', (333, 337))	('grey-white matter blurring', 'Disease', (377, 403))	('DNTs', 'Chemical', 'MESH:C023514', (89, 93))	('DNTs', 'Chemical', 'MESH:C023514', (168, 172))
102483	28868186	Amino acid MET PET has been described to have a rather high specificity (90%) and sensitivity (89%) for DNTs, with lower uptake ratios for DNT compared to other epileptogenic brain neoplasms, which is also consistent with the findings in our first case.	('epileptogenic brain neoplasms', 'Disease', 'MESH:D001932', (161, 190))	('DNT', 'Chemical', '-', (104, 107))	('brain neoplasms', 'Phenotype', 'HP:0030692', (175, 190))	('DNTs', 'Disease', (104, 108))	('Amino acid MET PET', 'Var', (0, 18))	('lower', 'NegReg', (115, 120))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('epileptogenic brain neoplasms', 'Disease', (161, 190))	('DNT', 'Chemical', '-', (139, 142))	('uptake ratios for', 'MPA', (121, 138))	('DNTs', 'Chemical', 'MESH:C023514', (104, 108))
102541	28868186	In this material, GKRS resulted in long-lasting seizure-freedom (ES 1) in all cases, with two of them (Cases 1 and 3) remaining on prophylactic AED, with no observed GKRS-associated neurological deficits or cognitive dysfunction.	('GKRS', 'Var', (18, 22))	('seizure', 'Phenotype', 'HP:0001250', (48, 55))	('neurological deficits', 'Phenotype', 'HP:0000707', (182, 203))	('cognitive dysfunction', 'Disease', (207, 228))	('seizure-free', 'Disease', (48, 60))	('neurological deficits', 'Disease', (182, 203))	('seizure-free', 'Disease', 'MESH:D012640', (48, 60))	('neurological deficits', 'Disease', 'MESH:D009461', (182, 203))	('cognitive dysfunction', 'Disease', 'MESH:D003072', (207, 228))	('ES 1', 'Gene', '8209', (65, 69))	('ES 1', 'Gene', (65, 69))
102546	28148827	Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG).	('Mouse', 'Species', '10090', (25, 30))	('IDH1', 'Gene', '15926', (7, 11))	('IDH1', 'Gene', '15926', (86, 90))	('lead to', 'Reg', (148, 155))	('D-2', 'Gene', (194, 197))	('D-2', 'Gene', (216, 219))	('gliomas', 'Disease', (136, 143))	('Alters', 'Reg', (55, 61))	('IDH1', 'Gene', (7, 11))	('IDH1', 'Gene', (86, 90))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('Mutant', 'Var', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('Brain Tumor', 'Phenotype', 'HP:0030692', (62, 73))	('Tumor', 'Phenotype', 'HP:0002664', (68, 73))	('D-2', 'Gene', '28503', (194, 197))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('mutations', 'Var', (91, 100))	('D-2', 'Gene', '28503', (216, 219))	('Brain Tumor Progression', 'CPA', (62, 85))
102548	28148827	Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell cycle arrest as well as a decreased ability to undergo neuronal differentiation.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('reduced', 'NegReg', (69, 76))	('decreased', 'NegReg', (142, 151))	('p53-mediated', 'Protein', (98, 110))	('Idh1-R132H', 'Var', (48, 58))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('mouse', 'Species', '10090', (26, 31))	('proliferation', 'CPA', (77, 90))	('arrest', 'Disease', (122, 128))
102549	28148827	In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ).	('R132H', 'Mutation', 'rs121913500', (14, 19))	('reduced', 'NegReg', (31, 38))	('Idh1-R132H expression', 'Var', (9, 30))
102550	28148827	The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('perturbed', 'NegReg', (104, 113))	('NSCs', 'MPA', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('mutant', 'Var', (61, 67))	('Idh1-R132H', 'Var', (93, 103))	('R132H', 'Mutation', 'rs121913500', (98, 103))
102551	28148827	Additionally, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas.	('overexpressed', 'PosReg', (99, 112))	('tumor', 'Disease', (14, 19))	('Olig2', 'Gene', (113, 118))	('human', 'Species', '9606', (158, 163))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('Olig2', 'Gene', '10215', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('gliomas', 'Disease', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('Idh1', 'Gene', (54, 58))	('prolonged', 'PosReg', (71, 80))	('mutant', 'Var', (47, 53))
102552	28148827	These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell of origin for glioma; thus, altering the progression of tumorigenesis.	('mutant', 'Var', (25, 31))	('NSC microenvironment', 'MPA', (50, 70))	('glioma', 'Disease', (108, 114))	('altering', 'Reg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('Idh1', 'Gene', (32, 36))	('disrupts', 'NegReg', (37, 45))	('progression', 'CPA', (135, 146))
102553	28148827	Additionally, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.	('IDH1-mediated', 'Gene', (170, 183))	('brain tumor', 'Phenotype', 'HP:0030692', (48, 59))	('brain tumor', 'Phenotype', 'HP:0030692', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutant', 'Var', (163, 169))	('human', 'Species', '9606', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('brain tumor', 'Disease', (48, 59))	('mutant', 'Var', (36, 42))	('brain tumor', 'Disease', 'MESH:D001932', (48, 59))	('brain tumor', 'Disease', 'MESH:D001932', (184, 195))	('brain tumor', 'Disease', (184, 195))
102558	28148827	One key signature among the diffuse gliomas is the co-occurrence of IDH1 mutations with other alterations, such as TP53 mutations.	('co-occurrence', 'Reg', (51, 64))	('gliomas', 'Disease', (36, 43))	('IDH1', 'Gene', (68, 72))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('mutations', 'Var', (73, 82))
102559	28148827	The presence of these mutations in the initial biopsies of most patients with these gliomas suggests they are early events in tumorigenesis and are important drivers of malignant progression.	('patients', 'Species', '9606', (64, 72))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
102561	28148827	The most common mutation in IDH1 is a hotspot missense mutation at arginine 132 (R132), and among gliomas, it is most commonly mutated to histidine (R132H).	('arginine', 'Chemical', 'MESH:D001120', (67, 75))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('R132H', 'Var', (149, 154))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('R132H', 'Mutation', 'rs121913500', (149, 154))	('IDH1', 'Gene', (28, 32))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('histidine', 'Chemical', 'MESH:D006639', (138, 147))
102562	28148827	Those cells expressing IDH1-R132H display neomorphic enzymatic activity in the NADPH-dependent reduction of alpha-KG to D-2-hydroxyglutarate (D-2HG).	('D-2', 'Gene', '28503', (142, 145))	('NADPH', 'Chemical', 'MESH:D009249', (79, 84))	('D-2', 'Gene', (120, 123))	('R132H', 'Mutation', 'rs121913500', (28, 33))	('D-2', 'Gene', (142, 145))	('IDH1-R132H', 'Var', (23, 33))	('D-2', 'Gene', '28503', (120, 123))	('alpha-KG', 'Chemical', 'MESH:D007656', (108, 116))
102563	28148827	Consequently, low- and high-grade IDH1-R132H-expressing gliomas produce D-2HG at levels 100-fold higher than in IDH1 wildtype tumors.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('higher', 'PosReg', (97, 103))	('IDH1 wildtype tumors', 'Disease', (112, 132))	('gliomas', 'Disease', (56, 63))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('D-2', 'Gene', '28503', (72, 75))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('IDH1-R132H-expressing', 'Var', (34, 55))	('D-2', 'Gene', (72, 75))	('IDH1 wildtype tumors', 'Disease', 'MESH:D009369', (112, 132))
102564	28148827	The IDH1 mutation and elevated D-2HG levels confer a myriad of cellular effects including inhibition of alpha-KG-dependent dioxygenases, aberrant histone methylation, contribution to the glioma CpG island methylation phenotype (G-CIMP), increased trimethylation of histone H3 at lysine 9 and 27, and decreased levels of 5-hydroxymethylcytosine.	('increased', 'PosReg', (237, 246))	('glioma', 'Disease', (187, 193))	('contribution', 'Reg', (167, 179))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('D-2', 'Gene', '28503', (31, 34))	('G-CIMP', 'Chemical', '-', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('histone H3', 'Protein', (265, 275))	('histone methylation', 'MPA', (146, 165))	('alpha-KG', 'Chemical', 'MESH:D007656', (104, 112))	('mutation', 'Var', (9, 17))	('D-2', 'Gene', (31, 34))	('decreased', 'NegReg', (300, 309))	('IDH1', 'Gene', (4, 8))	('lysine', 'Chemical', 'MESH:D008239', (279, 285))	('inhibition', 'NegReg', (90, 100))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (320, 343))	('alpha-KG-dependent dioxygenases', 'Enzyme', (104, 135))	('trimethylation', 'MPA', (247, 261))	('levels of 5-hydroxymethylcytosine', 'MPA', (310, 343))	('aberrant', 'Var', (137, 145))
102565	28148827	Additionally, mutant IDH-mediated epigenetic dysregulation is thought to inhibit normal differentiation patterns and impart significant effects on metabolism.	('IDH', 'Gene', (21, 24))	('metabolism', 'CPA', (147, 157))	('IDH', 'Gene', '3417', (21, 24))	('mutant', 'Var', (14, 20))	('epigenetic dysregulation', 'Var', (34, 58))	('effects', 'Reg', (136, 143))	('normal differentiation patterns', 'CPA', (81, 112))	('inhibit', 'NegReg', (73, 80))
102566	28148827	Due to its promiscuous activity throughout a cell, mutant IDH1 likely promotes tumorigenesis via a convergence of various perturbed intracellular pathways within both the tumor cells of origin and the surrounding microenvironment.	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('mutant', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('promotes', 'PosReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (171, 176))	('IDH1', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
102567	28148827	To determine the effects of mutant IDH1 and D-2HG on the glioma cell of origin and the microenvironment, we generated a genetically faithful conditional knock-in mouse model of mutant Idh1.	('D-2', 'Gene', (44, 47))	('glioma', 'Disease', (57, 63))	('mouse', 'Species', '10090', (162, 167))	('D-2', 'Gene', '28503', (44, 47))	('mutant', 'Var', (177, 183))	('Idh1', 'Gene', (184, 188))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
102568	28148827	Together, this suggests that expression of mutant Idh1 has damaging effects on the glioma cell of origin and the microenvironment.	('glioma', 'Disease', (83, 89))	('expression', 'Var', (29, 39))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('mutant', 'Var', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('Idh1', 'Gene', (50, 54))
102569	28148827	Guided by the genetic signature of human gliomas, we used a mouse glioma model driven by Tp53 deficiency to show that expression of mutant Idh1 leads to distinct molecular and histological features, and alters the course of tumor progression by slowing tumor growth and prolonging survival.	('slowing tumor', 'Disease', (245, 258))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('human', 'Species', '9606', (35, 40))	('alters', 'Reg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('glioma', 'Disease', (66, 72))	('slowing tumor', 'Disease', 'MESH:D009369', (245, 258))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('glioma', 'Disease', (41, 47))	('gliomas', 'Disease', (41, 48))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumor', 'Disease', (224, 229))	('Idh1', 'Gene', (139, 143))	('tumor', 'Disease', (253, 258))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('mouse', 'Species', '10090', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('survival', 'CPA', (281, 289))	('mutant', 'Var', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('course', 'MPA', (214, 220))	('prolonging', 'PosReg', (270, 280))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))
102570	28148827	These findings provide new insight into IDH1-R132H-driven tumorigenesis, and establish a platform for future preclinical investigations focused on mutant IDH1-targeted therapy.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('IDH1-R132H-driven', 'Var', (40, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('IDH1-targeted', 'Gene', (154, 167))
102571	28148827	A targeting vector based off of the genomic sequence of the 129P2/Ola strain of mouse was generated and included a 5,426-base pair 5' homology arm encompassing exon 2 of Idh1 followed by a LoxP site, three copies of the SV40 polyadenylation signal, a neomycin-resistance gene flanked with FRT sites, another LoxP site, and a 2,416-base pair 3' homology arm encompassing exon 3 of Idh1 and the R132H mutation.	('R132H', 'Var', (393, 398))	('R132H', 'Mutation', 'rs121913500', (393, 398))	('Idh1', 'Gene', (380, 384))	('mouse', 'Species', '10090', (80, 85))
102574	28148827	hGFAP-Cre, Nestin-CreERT2, and Tp53fl/fl animals were generously provided by Dr.	('hGFAP', 'Gene', (0, 5))	('Nestin', 'Gene', (11, 17))	('hGFAP', 'Gene', '2670', (0, 5))	('Tp53fl/fl', 'Var', (31, 40))	('Nestin', 'Gene', '10763', (11, 17))
102585	28148827	The Q1/Q3 (m/z) transitions monitored: 363/147 (D-2-HG) and 367/151 (L/D-2-HG-d4).	('363/147', 'Var', (39, 46))	('D-2', 'Gene', '28503', (48, 51))	('367/151', 'Var', (60, 67))	('D-2', 'Gene', '28503', (71, 74))	('D-2', 'Gene', (48, 51))	('D-2', 'Gene', (71, 74))
102586	28148827	A set of calibrator samples in NeuroCult NSC base media was prepared by adding appropriate amounts of pure D-2-HG at the following concentration levels: 0, 0.032, 0.16, 0.8, 4, and 20 mug/m.	('0.16', 'Var', (163, 167))	('0.032', 'Var', (156, 161))	('D-2', 'Gene', '28503', (107, 110))	('D-2', 'Gene', (107, 110))
102606	28148827	Antibodies included: beta(III)Tubulin 1:1000 Covance-MMS-435P), CD31 1:100 (Abcam-ab28364), IDH1-R132H 1:100 (Dianova-H09), Ki67 1:100 (BD Pharm-550609), Olig2 1:500 (Abcam-ab136253), Sox2 1:100 (StemCell Technologies-60055).	(' 1:100', 'Gene', (37, 43))	(' 1:100', 'Gene', '3417', (68, 74))	('Olig2', 'Gene', (154, 159))	('Olig2', 'Gene', '10215', (154, 159))	('R132H', 'Var', (97, 102))	(' 1:100', 'Gene', '3417', (128, 134))	(' 1:100', 'Gene', '3417', (37, 43))	(' 1:100', 'Gene', (188, 194))	(' 1:100', 'Gene', (68, 74))	(' 1:100', 'Gene', (102, 108))	('R132H', 'SUBSTITUTION', 'None', (97, 102))	(' 1:100', 'Gene', '3417', (188, 194))	(' 1:100', 'Gene', '3417', (102, 108))	(' 1:100', 'Gene', (128, 134))
102611	28148827	A mutant Idh1 conditional knock-in model was generated via a targeting vector containing a stop cassette flanked by LoxP sites (LSL) and the IDH1-R132H mutation (referred to as Idh1LSL:R132H) (Fig.	('R132H', 'Mutation', 'rs121913500', (185, 190))	('IDH1-R132H', 'Var', (141, 151))	('Idh1', 'Gene', (9, 13))	('R132H', 'Mutation', 'rs121913500', (146, 151))
102612	28148827	Homologous recombination into the endogenous mouse Idh1 locus results in a mutant Idh1 allele with a CGA to CAC substitution in exon 3, encoding the arginine to histidine substitution and resembling the cancer-specific IDH1-R132H mutation.	('substitution', 'Var', (112, 124))	('mouse', 'Species', '10090', (45, 50))	('R132H', 'Mutation', 'rs121913500', (224, 229))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('histidine', 'Chemical', 'MESH:D006639', (161, 170))	('mutant', 'Var', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('results in', 'Reg', (62, 72))	('arginine', 'Chemical', 'MESH:D001120', (149, 157))	('Idh1', 'Gene', (82, 86))
102614	28148827	Sixty-two crosses between Idh1LSL:132H/WT heterozygous animals generated a total of 292 offspring, with 113 wildtype (Idh1WT/WT) and 179 heterozygous (Idh1LSL:R132H/WT) animals.	('Idh1LSL:132H/WT', 'Var', (26, 41))	('R132H/W', 'Mutation', 'rs121913500', (159, 166))	('crosses', 'Var', (10, 17))
102616	28148827	To validate the faithfulness of the mutant Idh1 allele, NSCs were isolated from embryonic day 14.5 (E14.5) heterozygous mutant Idh1 conditional knock-in embryos (Idh1LSL:R132H/WT) and Idh1 wildtype embryos (Idh1WT/WT).	('mutant', 'Var', (120, 126))	('R132H/W', 'Mutation', 'rs121913500', (170, 177))	('Idh1', 'Gene', (127, 131))
102617	28148827	Transient expression of Cre-recombinase led to production of D-2HG which was detected in the supernatant of mutant lines at a level 100-fold higher than in wildtype cells, suggesting D-2HG was produced at pathologically relevant levels (Fig.	('D-2', 'Gene', '28503', (183, 186))	('D-2', 'Gene', (61, 64))	('mutant', 'Var', (108, 114))	('D-2', 'Gene', '28503', (61, 64))	('higher', 'PosReg', (141, 147))	('D-2', 'Gene', (183, 186))
102618	28148827	Considering the effects of mutant IDH1 are likely cell context-dependent, we sought to determine the effects of mutant Idh1 in NSCs, a candidate cell of origin for gliomas.	('Idh1', 'Gene', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('mutant', 'Var', (27, 33))	('mutant', 'Var', (112, 118))	('gliomas', 'Disease', (164, 171))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('NSCs', 'Disease', (127, 131))
102619	28148827	Idh1LSL:R132H/WT NSCs displayed a nearly 4-fold reduction in proliferative capacity compared to wildtype NSC lines or ad-GFP-transduced control samples (Fig.	('reduction', 'NegReg', (48, 57))	('R132H/WT', 'Var', (8, 16))	('proliferative capacity', 'CPA', (61, 83))	('R132H/W', 'Mutation', 'rs121913500', (8, 15))
102620	28148827	This suggested that the proliferative defects in the Idh1LSL:R132H/WT ad-Cre infected NSCs were not resultant of the generalized effects of Cre-recombinase or adenoviral transduction, and instead were mediated by expression of mutant Idh1 (Fig.	('R132H/W', 'Mutation', 'rs121913500', (61, 68))	('infected NSCs', 'Disease', 'MESH:D007239', (77, 90))	('mutant', 'Var', (227, 233))	('mediated by', 'Reg', (201, 212))	('Idh1', 'Gene', (234, 238))	('infected NSCs', 'Disease', (77, 90))	('R132H/WT', 'Var', (61, 69))
102624	28148827	Additionally, microarray analysis was performed on three independent Idh1LSL:R132H/WT cell lines that were transduced with ad-GFP (control) or ad-Cre (Gene Expression Omnibus Accession number: GSE88828).	('ad-Cre', 'Var', (143, 149))	('R132H/W', 'Mutation', 'rs121913500', (77, 84))	('ad-GFP', 'Var', (123, 129))
102625	28148827	To further determine the role of p53 activation, NSCs were isolated from E14.5 embryos of the following two genotypes: Idh1LSL:R132H/WT; Tp53fl/fl and Tp53fl/fl, which have Tp53 conditionally deleted.	('R132H/W', 'Mutation', 'rs121913500', (127, 134))	('R132H/WT; Tp53fl/fl', 'Var', (127, 146))	('Tp53fl/fl', 'Var', (151, 160))	('Tp53', 'Gene', (173, 177))	('Tp53fl/fl', 'Var', (137, 146))
102626	28148827	Mutations were induced in vitro via ad-Cre transduction and this was accompanied by loss of p53 expression and production of D-2HG in mutant IDH1 expressing NSCs (Supplementary Fig.	('IDH1', 'Gene', (141, 145))	('D-2', 'Gene', '28503', (125, 128))	('loss', 'NegReg', (84, 88))	('expression', 'MPA', (96, 106))	('p53', 'Gene', (92, 95))	('D-2', 'Gene', (125, 128))	('mutant', 'Var', (134, 140))
102628	28148827	This data also supports the possibility that deletion of TP53 is a cooperating alteration in mutant IDH1-driven tumorigenesis.	('IDH1-driven', 'Gene', (100, 111))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('deletion', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutant', 'Var', (93, 99))	('IDH1-driven', 'Reg', (100, 111))	('tumor', 'Disease', (112, 117))	('TP53', 'Gene', (57, 61))
102629	28148827	We analyzed The Cancer Genome Atlas' (TCGA) study on diffuse lower-grade gliomas and found that while 15% of IDH1 wildtype tumors have mutations in TP53, approximately 62% of IDH1 mutant gliomas harbor a mutation in TP53.	('mutation', 'Var', (204, 212))	('gliomas', 'Disease', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('TP53', 'Gene', (148, 152))	('IDH1', 'Gene', (175, 179))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('mutations', 'Var', (135, 144))	('harbor', 'Reg', (195, 201))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('gliomas', 'Disease', (73, 80))	('TP53', 'Gene', (216, 220))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('mutant', 'Var', (180, 186))	('IDH1 wildtype tumors', 'Disease', 'MESH:D009369', (109, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH1 wildtype tumors', 'Disease', (109, 129))
102630	28148827	This finding suggests that while TP53 mutations promote low-grade gliomas, it is likely that it plays an even more important role in promoting IDH1-mutated low-grade gliomas (Fig.	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('gliomas', 'Disease', (166, 173))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('TP53', 'Gene', (33, 37))	('promoting', 'PosReg', (133, 142))	('mutations', 'Var', (38, 47))	('promote', 'PosReg', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))
102631	28148827	Mutant Idh1 was expressed in the mouse brain under the control of different brain-specific promoters of varying expression to assess its effects on cells of the brain in vivo.	('Mutant', 'Var', (0, 6))	('Idh1', 'Gene', (7, 11))	('mouse', 'Species', '10090', (33, 38))
102634	28148827	In order to assess the in vivo effects of mutant Idh1 when it is broadly expressed in the CNS, hGFAP-Cre mice were crossed to Idh1LSL:R132H/WT animals.	('mutant', 'Var', (42, 48))	('hGFAP', 'Gene', '2670', (95, 100))	('Idh1', 'Gene', (49, 53))	('hGFAP', 'Gene', (95, 100))	('mice', 'Species', '10090', (105, 109))	('R132H/W', 'Mutation', 'rs121913500', (134, 141))
102635	28148827	As expected, Idh1-R132H expression was detected in the brains of E15.5 animals bearing the Idh1-R132H mutation (hGFAP-Cre; Idh1LSL:R132H/WT), but not in wildtype controls (hGFAP-Cre; Idh1WT/WT) (Fig.	('hGFAP', 'Gene', '2670', (112, 117))	('hGFAP', 'Gene', (172, 177))	('R132H', 'Mutation', 'rs121913500', (18, 23))	('R132H', 'Mutation', 'rs121913500', (96, 101))	('R132H', 'Mutation', 'rs121913500', (131, 136))	('hGFAP', 'Gene', '2670', (172, 177))	('R132H/W', 'Mutation', 'rs121913500', (131, 138))	('hGFAP', 'Gene', (112, 117))	('Idh1-R132H mutation', 'Var', (91, 110))
102636	28148827	Additionally, D-2HG was detected in the brains of mutant animals at a level 200-fold higher than in control animals (Fig.	('D-2', 'Gene', '28503', (14, 17))	('D-2', 'Gene', (14, 17))	('mutant', 'Var', (50, 56))	('higher', 'PosReg', (85, 91))
102638	28148827	To investigate the early effects of mutant Idh1 on CNS cells, brains from postnatal day 3 (P3) hGFAP-Cre; Idh1LSL:R132H/WT and hGFAP-Cre; Idh1WT/WT animals were harvested.	('hGFAP', 'Gene', (127, 132))	('hGFAP', 'Gene', '2670', (95, 100))	('Idh1', 'Gene', (43, 47))	('hGFAP', 'Gene', '2670', (127, 132))	('mutant', 'Var', (36, 42))	('R132H/W', 'Mutation', 'rs121913500', (114, 121))	('hGFAP', 'Gene', (95, 100))	('R132H/WT', 'Var', (114, 122))
102639	28148827	hGFAP-Cre; Idh1LSL:R132H/WT brains were visibly different from the control brains with greater than 80% displaying foci of hemorrhagic lesions (16/17) throughout the cortex which were absent from control animals (0/20) (Fig.	('hGFAP', 'Gene', (0, 5))	('R132H/W', 'Mutation', 'rs121913500', (19, 26))	('hGFAP', 'Gene', '2670', (0, 5))	('hemorrhagic lesions', 'Disease', 'MESH:D006470', (123, 142))	('R132H/WT', 'Var', (19, 27))	('hemorrhagic lesions', 'Disease', (123, 142))
102642	28148827	Interestingly, vessels among mutant brains tended to be thicker and stained more intensely with CD31 (Fig.	('thicker', 'PosReg', (56, 63))	('CD31', 'Gene', '5175', (96, 100))	('mutant', 'Var', (29, 35))	('CD31', 'Gene', (96, 100))	('more intensely', 'PosReg', (76, 90))	('stained', 'MPA', (68, 75))
102645	28148827	To assess mutant Idh1's effects on the NSC population, the NSC marker Sox2 was used.	('Idh1', 'Gene', (17, 21))	('mutant', 'Var', (10, 16))	('NSC', 'Disease', (39, 42))	('Sox2', 'Gene', (70, 74))	('Sox2', 'Gene', '6657', (70, 74))
102646	28148827	hGFAP-Cre; Idh1WT/WT animals displayed a tightly organized SVZ with a structured layering rich with Sox2-positive cells; in contrast, the hGFAP-Cre; Idh1LSL:R132H/WT animals displayed a perturbed SVZ and a dispersal of NSCs emanating outward from the SVZ (Fig.	('hGFAP', 'Gene', (0, 5))	('hGFAP', 'Gene', (138, 143))	('hGFAP', 'Gene', '2670', (0, 5))	('Sox2', 'Gene', (100, 104))	('R132H/W', 'Mutation', 'rs121913500', (157, 164))	('SVZ', 'MPA', (196, 199))	('hGFAP', 'Gene', '2670', (138, 143))	('R132H/WT', 'Var', (157, 165))	('Sox2', 'Gene', '6657', (100, 104))
102647	28148827	However, when the NSCs of the SVZ were quantified and normalized to the overall number of cells in this region, there was a statistically significant increase in the number of ectopic Sox2 positively stained cells in the mutant brains (Fig.	('mutant', 'Var', (221, 227))	('Sox2', 'Gene', (184, 188))	('Sox2', 'Gene', '6657', (184, 188))	('increase', 'PosReg', (150, 158))
102648	28148827	To this end, Idh1LSL:R132H/WT NSCs were isolated from E14.5 embryos and expression of mutant Idh1 was induced in vitro via ad-Cre transduction.	('mutant', 'Var', (86, 92))	('Idh1', 'Gene', (93, 97))	('R132H/W', 'Mutation', 'rs121913500', (21, 28))
102649	28148827	Collectively, these experiments suggest that mutant Idh1 likely affects NSCs both directly, as observed through defective differentiation, and indirectly, as observed through a disorganization of the microenvironment, two components with implications in tumor initiation and development.	('differentiation', 'CPA', (122, 137))	('tumor initiation', 'Disease', 'MESH:D009369', (254, 270))	('mutant', 'Var', (45, 51))	('defective', 'NegReg', (112, 121))	('affects', 'Reg', (64, 71))	('tumor initiation', 'Disease', (254, 270))	('Idh1', 'Gene', (52, 56))	('NSCs', 'Disease', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
102650	28148827	This data also corroborates a previous study investigating the role of mutant IDH1 on embryoid body induced human neural stem cells which showed that IDH1-R132H impaired the ability of these cells to differentiate, specifically into the astrocytic and neuronal lineage.	('IDH1', 'Gene', (78, 82))	('R132H', 'Mutation', 'rs121913500', (155, 160))	('IDH1-R132H', 'Var', (150, 160))	('human', 'Species', '9606', (108, 113))	('mutant', 'Var', (71, 77))	('impaired', 'NegReg', (161, 169))
102651	28148827	To determine the effects of prolonged expression of mutant Idh1 on the developing brain and assess the potential for mutant IDH1-mediated gliomagenesis, hGFAP-Cre; Idh1WT/WT and hGFAP-Cre; Idh1LSL:R132H/WT animals were aged.	('IDH1-mediated', 'Gene', (124, 137))	('glioma', 'Disease', (138, 144))	('mutant', 'Var', (52, 58))	('mutant', 'Var', (117, 123))	('hGFAP', 'Gene', '2670', (178, 183))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('hGFAP', 'Gene', (153, 158))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('hGFAP', 'Gene', '2670', (153, 158))	('R132H/W', 'Mutation', 'rs121913500', (197, 204))	('hGFAP', 'Gene', (178, 183))
102653	28148827	By 89 days, all hGFAP-Cre; Idh1LSL:R132H/WT animals displayed the phenotypes of head doming, squinted eyes, hunched posture, and gradual immobilization, in addition to episodes of seizure and failure to thrive (Fig.	('seizure', 'Phenotype', 'HP:0001250', (180, 187))	('squinted', 'Phenotype', 'HP:0000486', (93, 101))	('hGFAP', 'Gene', (16, 21))	('head doming', 'CPA', (80, 91))	('R132H/W', 'Mutation', 'rs121913500', (35, 42))	('failure to thrive', 'Phenotype', 'HP:0001508', (192, 209))	('seizure', 'Disease', (180, 187))	('seizure', 'Disease', 'MESH:D012640', (180, 187))	('hunched posture', 'CPA', (108, 123))	('R132H/WT', 'Var', (35, 43))	('hGFAP', 'Gene', '2670', (16, 21))
102655	28148827	An analysis of serial sections of hydrocephalic hGFAP-Cre; Idh1LSL:R132H/WT brains revealed several instances of aqueductal stenosis and an overall loss of cellularity in mutant brains.	('cellularity', 'MPA', (156, 167))	('loss', 'NegReg', (148, 152))	('hGFAP', 'Gene', (48, 53))	('aqueductal stenosis', 'Disease', 'MESH:D006849', (113, 132))	('hGFAP', 'Gene', '2670', (48, 53))	('aqueductal stenosis', 'Disease', (113, 132))	('mutant', 'Var', (171, 177))	('aqueductal stenosis', 'Phenotype', 'HP:0002410', (113, 132))	('R132H/W', 'Mutation', 'rs121913500', (67, 74))
102656	28148827	The phenotypic differences observed in this hGFAP-Cre; Idh1LSL:R132H/WT model with those in the literature suggest that the timing of mutant Idh1 induction is imperative.	('hGFAP', 'Gene', '2670', (44, 49))	('Idh1', 'Gene', (141, 145))	('R132H/W', 'Mutation', 'rs121913500', (63, 70))	('hGFAP', 'Gene', (44, 49))	('mutant', 'Var', (134, 140))
102657	28148827	Whereas a previously described Nestin-Cre system induced mutant Idh1 at E10.5, our hGFAP-Cre system induced it at E13.5.	('Nestin', 'Gene', (31, 37))	('hGFAP', 'Gene', (83, 88))	('hGFAP', 'Gene', '2670', (83, 88))	('mutant', 'Var', (57, 63))	('Nestin', 'Gene', '10763', (31, 37))	('Idh1', 'Gene', (64, 68))
102658	28148827	While there was severe hemorrhage present in the former model, there were small hemorrhagic foci present in the latter model, suggesting that the severity of the mutant Idh1 phenotypes are dependent on the extent of induction.	('hemorrhage', 'Disease', 'MESH:D006470', (23, 33))	('mutant', 'Var', (162, 168))	('hemorrhagic foci', 'Disease', (80, 96))	('Idh1', 'Gene', (169, 173))	('hemorrhagic foci', 'Disease', 'MESH:D006470', (80, 96))	('hemorrhage', 'Disease', (23, 33))
102660	28148827	Nestin-CreERT2 was utilized to achieve spatio-temporal control over mutant Idh1 expression in the NSC population following administration of tamoxifen.	('Nestin', 'Gene', (0, 6))	('Idh1', 'Gene', (75, 79))	('tamoxifen', 'Chemical', 'MESH:D013629', (141, 150))	('Nestin', 'Gene', '10763', (0, 6))	('mutant', 'Var', (68, 74))
102663	28148827	This system permits the controlled and restricted expression of mutant Idh1 in the candidate cell of origin for glioma and allows for the prolonged and specific expression of mutant Idh1 in the NSCs specifically, allowing us to ask whether mutant Idh1 is capable of promoting tumorigenesis.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('Idh1', 'Gene', (182, 186))	('mutant', 'Var', (240, 246))	('glioma', 'Disease', (112, 118))	('tumor', 'Disease', (276, 281))	('promoting', 'PosReg', (266, 275))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('mutant', 'Var', (175, 181))	('mutant', 'Var', (64, 70))	('Idh1', 'Gene', (71, 75))	('Idh1', 'Gene', (247, 251))
102664	28148827	Both Nestin-CreERT2; Idh1WT/WT and Nestin-CreERT2, Idh1LSL:R132H/WT animals were generated and tamoxifen was administered at E18.5.	('Nestin', 'Gene', (35, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (95, 104))	('R132H/W', 'Mutation', 'rs121913500', (59, 66))	('Nestin', 'Gene', '10763', (5, 11))	('Nestin', 'Gene', (5, 11))	('R132H/WT', 'Var', (59, 67))	('Nestin', 'Gene', '10763', (35, 41))
102665	28148827	We next considered the effects of mutant Idh1 in the context of tumor biology and tumor progression.	('tumor', 'Disease', (64, 69))	('Idh1', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutant', 'Var', (34, 40))
102666	28148827	2a, 4b and 4d), conditionally deleted Tp53 animals were crossed into the mutant Idh1 conditional knock-in animals, leading to a compound genetic mouse model harboring the most common mutations found among the low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('mouse', 'Species', '10090', (145, 150))	('mutant', 'Var', (73, 79))	('Idh1', 'Gene', (80, 84))	('gliomas', 'Disease', (219, 226))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))
102667	28148827	Two genotypes, Nestin-CreERT2; Tp53fl/fl and Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl were administered tamoxifen at E18.5 to assess the impact of mutant Idh1 on brain tumorigenesis.	('Nestin', 'Gene', (45, 51))	('Idh1', 'Gene', (157, 161))	('Nestin', 'Gene', '10763', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('brain tumor', 'Disease', (165, 176))	('Tp53fl/fl', 'Var', (79, 88))	('brain tumor', 'Disease', 'MESH:D001932', (165, 176))	('Nestin', 'Gene', '10763', (45, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (107, 116))	('Nestin', 'Gene', (15, 21))	('R132H/W', 'Mutation', 'rs121913500', (69, 76))	('brain tumor', 'Phenotype', 'HP:0030692', (165, 176))	('mutant', 'Var', (150, 156))	('R132H/WT', 'Var', (69, 77))
102669	28148827	Among animals that harbored both the Idh1-R132H mutation and Tp53 deletion (Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl), the penetrance was reduced to 15% (4/26).	('R132H', 'Mutation', 'rs121913500', (42, 47))	('penetrance', 'MPA', (126, 136))	('reduced', 'NegReg', (141, 148))	('Nestin', 'Gene', (76, 82))	('Idh1-R132H', 'Gene', (37, 47))	('R132H', 'Mutation', 'rs121913500', (100, 105))	('R132H/W', 'Mutation', 'rs121913500', (100, 107))	('Tp53fl/fl', 'Var', (110, 119))	('Nestin', 'Gene', '10763', (76, 82))	('Tp53', 'Gene', (61, 65))
102670	28148827	An IDH1-R132H-specific antibody was tested on tumor-bearing brains from Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl and Nestin-CreERT2; Tp53fl/fl animals (Fig.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Nestin', 'Gene', (72, 78))	('R132H', 'Mutation', 'rs121913500', (96, 101))	('tumor', 'Disease', (46, 51))	('R132H/W', 'Mutation', 'rs121913500', (96, 103))	('Nestin', 'Gene', '10763', (120, 126))	('R132H', 'Mutation', 'rs121913500', (8, 13))	('Nestin', 'Gene', '10763', (72, 78))	('R132H/WT', 'Var', (96, 104))	('Nestin', 'Gene', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
102671	28148827	Tumors that developed in Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl animals stained positively with the IDH1-R132H antibody.	('Nestin', 'Gene', (25, 31))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tp53fl/fl', 'Var', (59, 68))	('R132H', 'Mutation', 'rs121913500', (49, 54))	('R132H/W', 'Mutation', 'rs121913500', (49, 56))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('R132H', 'Mutation', 'rs121913500', (110, 115))	('stained', 'Reg', (77, 84))	('Nestin', 'Gene', '10763', (25, 31))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('R132H/WT', 'Var', (49, 57))
102672	28148827	This was in contrast to those tumors that developed in animals of the genotype Nestin-CreERT2; Tp53fl/fl, which showed a lack of IDH1-R132H staining, suggesting that tumors were initiated from cells with mutations in both genes (Fig.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Nestin', 'Gene', (79, 85))	('mutations', 'Var', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('Nestin', 'Gene', '10763', (79, 85))	('R132H', 'Mutation', 'rs121913500', (134, 139))
102673	28148827	While the overall tumor penetrance was low, several histological observations include that Idh1 mutant tumors tended to be sarcomatoid in nature, with more perivascular infiltration into surrounding brain parenchyma rather than single-cell infiltration.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutant', 'Var', (96, 102))	('tumor', 'Disease', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('sarcomatoid', 'Disease', 'MESH:C538614', (123, 134))	('more', 'PosReg', (151, 155))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('sarcomatoid', 'Disease', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Idh1', 'Gene', (91, 95))
102675	28148827	Pseudopalisading necrosis was present in several of the Idh1 mutant tumors.	('necrosis', 'Disease', (17, 25))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('necrosis', 'Disease', 'MESH:D009336', (17, 25))	('Idh1', 'Gene', (56, 60))	('mutant', 'Var', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('present', 'Reg', (30, 37))
102676	28148827	Additionally, there was a prevalence of giant cells among the Idh1 mutant tumors (Fig.	('prevalence', 'Reg', (26, 36))	('Idh1', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('giant cells', 'CPA', (40, 51))	('mutant', 'Var', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
102680	28148827	Additionally, 100% of the tumor cells in the Idh1 mutant cases stained positively for Olig2, in contrast to 20% to 60% of the tumor cells in the Idh1 wildtype tumors (Fig.	('Idh1', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Olig2', 'Gene', (86, 91))	('tumors', 'Disease', (159, 165))	('Olig2', 'Gene', '10215', (86, 91))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('mutant', 'Var', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('stained positively', 'Reg', (63, 81))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (126, 131))
102681	28148827	Among human diffuse glioma samples, those harboring IDH1 mutations display an elevated expression of Olig2 compared to wildtype samples, suggesting a cooperation between mutant IDH1 and Olig2 expression in promoting tumorigenesis (Fig.	('tumor', 'Disease', (216, 221))	('human', 'Species', '9606', (6, 11))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('promoting', 'PosReg', (206, 215))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('IDH1', 'Gene', (177, 181))	('elevated', 'PosReg', (78, 86))	('Olig2', 'Gene', (101, 106))	('mutations', 'Var', (57, 66))	('Olig2', 'Gene', (186, 191))	('expression', 'MPA', (87, 97))	('Olig2', 'Gene', '10215', (101, 106))	('mutant', 'Var', (170, 176))	('glioma', 'Disease', (20, 26))	('Olig2', 'Gene', '10215', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('IDH1', 'Gene', (52, 56))
102683	28148827	When comparing overall survival of experimental animals, mutant Idh1 is shown to confer a prolonged survival among Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl tumor-bearing animals compared to Nestin-CreERT2; Tp53fl/fl tumor-bearing animals (Fig.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Nestin', 'Gene', '10763', (193, 199))	('tumor', 'Disease', (219, 224))	('Nestin', 'Gene', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('R132H/WT', 'Var', (139, 147))	('survival', 'CPA', (100, 108))	('Nestin', 'Gene', (193, 199))	('tumor', 'Disease', (159, 164))	('mutant', 'Var', (57, 63))	('prolonged', 'PosReg', (90, 99))	('Nestin', 'Gene', '10763', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('Idh1', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('R132H/W', 'Mutation', 'rs121913500', (139, 146))
102684	28148827	Though the median survival was unable to be determined due to a low number of affected animals in the Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl cohort, the average time for onset of symptoms was 233 days compared to 274 days for the Nestin-CreERT2; Tp53fl/fl versus Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl animals, respectively.	('Nestin', 'Gene', (268, 274))	('R132H/W', 'Mutation', 'rs121913500', (292, 299))	('Nestin', 'Gene', '10763', (235, 241))	('R132H/W', 'Mutation', 'rs121913500', (126, 133))	('Nestin', 'Gene', '10763', (102, 108))	('R132H/WT', 'Var', (126, 134))	('Nestin', 'Gene', (235, 241))	('Nestin', 'Gene', '10763', (268, 274))	('Nestin', 'Gene', (102, 108))
102685	28148827	The survival trend corroborates the clinical data, which shows a prolonged survival among brain tumor patients with mutations in IDH1 compared to patients with wildtype IDH1 tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('IDH1', 'Gene', (129, 133))	('wildtype IDH1 tumors', 'Disease', 'MESH:D009369', (160, 180))	('patients', 'Species', '9606', (102, 110))	('wildtype IDH1 tumors', 'Disease', (160, 180))	('prolonged', 'PosReg', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutations', 'Var', (116, 125))	('brain tumor', 'Disease', (90, 101))	('brain tumor', 'Disease', 'MESH:D001932', (90, 101))	('patients', 'Species', '9606', (146, 154))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('brain tumor', 'Phenotype', 'HP:0030692', (90, 101))
102686	28148827	For instance, among patients with Grade III anaplastic astrocytoma, survival was 65 months for those with IDH1 mutations compared to 20 months for those with wildtype IDH1 tumors.	('wildtype IDH1 tumors', 'Disease', 'MESH:D009369', (158, 178))	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('astrocytoma', 'Disease', 'MESH:D001254', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('astrocytoma', 'Disease', (55, 66))	('IDH1', 'Gene', (106, 110))	('wildtype IDH1 tumors', 'Disease', (158, 178))	('patients', 'Species', '9606', (20, 28))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))
102689	28148827	Tumor cultures were derived from animals of the genotype Nestin-CreERT2; Tp53fl/fl and Nestin-CreERT2; Idh1LSL:R132H/WT; Tp53fl/fl.	('Nestin', 'Gene', '10763', (87, 93))	('Nestin', 'Gene', '10763', (57, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('R132H/WT', 'Var', (111, 119))	('Nestin', 'Gene', (87, 93))	('Nestin', 'Gene', (57, 63))	('Tp53fl/fl', 'Var', (121, 130))	('R132H/W', 'Mutation', 'rs121913500', (111, 118))
102690	28148827	S3b) and D-2HG was elevated in the mutant IDH1-expressing brain tumor line (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('IDH1-expressing', 'Gene', (42, 57))	('brain tumor', 'Phenotype', 'HP:0030692', (58, 69))	('brain tumor', 'Disease', (58, 69))	('D-2', 'Gene', '28503', (9, 12))	('mutant', 'Var', (35, 41))	('elevated', 'PosReg', (19, 27))	('brain tumor', 'Disease', 'MESH:D001932', (58, 69))	('D-2', 'Gene', (9, 12))
102692	28148827	Mutant IDH1 has been shown to promote G-CIMP.	('promote', 'PosReg', (30, 37))	('G-CIMP', 'Disease', (38, 44))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('G-CIMP', 'Chemical', '-', (38, 44))
102693	28148827	To determine whether mutant IDH1 confers the expected hypermethylation phenotype, global methylation was assessed in cell lines derived from tumor-bearing animals.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mutant', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('hypermethylation', 'MPA', (54, 70))	('tumor', 'Disease', (141, 146))	('IDH1', 'Gene', (28, 32))
102694	28148827	An increase in global methylation in the mutant IDH1-expressing brain tumor cell line was observed (Figure 6d).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('brain tumor', 'Disease', (64, 75))	('mutant', 'Var', (41, 47))	('brain tumor', 'Disease', 'MESH:D001932', (64, 75))	('IDH1-expressing', 'Gene', (48, 63))	('brain tumor', 'Phenotype', 'HP:0030692', (64, 75))	('global methylation', 'MPA', (15, 33))	('increase', 'PosReg', (3, 11))
102696	28148827	Combined, these data suggest that the tumors derived from our genetic model recapitulate many of the features of mutant IDH1 gliomas, including expression of Olig2, a prolonged survival among mutant IDH1 patients, elevated global DNA methylation, and hypermethylation of the Bcat1 gene.	('survival', 'CPA', (177, 185))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('hypermethylation', 'MPA', (251, 267))	('mutant', 'Var', (113, 119))	('IDH1', 'Gene', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('patients', 'Species', '9606', (204, 212))	('mutant', 'Var', (192, 198))	('tumors', 'Disease', (38, 44))	('Bcat1', 'Gene', (275, 280))	('IDH1 gliomas', 'Disease', (120, 132))	('Bcat1', 'Gene', '586', (275, 280))	('Olig2', 'Gene', (158, 163))	('global DNA methylation', 'MPA', (223, 245))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (120, 132))	('elevated', 'PosReg', (214, 222))	('Olig2', 'Gene', '10215', (158, 163))
102697	28148827	Despite the prevalence of the IDH1 mutation among gliomas, its effects on the NSC population (which are a candidate cell of origin for glioma), the microenvironment from which gliomas arise, or how this mutation affects the course of tumor development are incompletely understood.	('tumor', 'Disease', (234, 239))	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('affects', 'Reg', (212, 219))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('glioma', 'Disease', (176, 182))	('gliomas', 'Disease', (50, 57))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('glioma', 'Disease', (135, 141))	('gliomas', 'Disease', (176, 183))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('IDH1', 'Gene', (30, 34))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (176, 183))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))
102698	28148827	We address these three aspects using conditional mutant Idh1 in vitro and in vivo mouse models.	('mouse', 'Species', '10090', (82, 87))	('conditional mutant', 'Var', (37, 55))	('Idh1', 'Gene', (56, 60))
102699	28148827	Considering the large body of evidence implicating the NSC as the cell of origin for glioma, our studies have focused on the effects of mutant IDH1 on the NSC in vitro and in vivo.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('effects', 'Reg', (125, 132))	('IDH1', 'Gene', (143, 147))	('glioma', 'Disease', (85, 91))	('mutant', 'Var', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
102700	28148827	We show that mutant Idh1 attenuates proliferation of NSCs, suggesting that mutant Idh1 acts as an oncogenic insult to which cells respond by undergoing cell-cycle arrest.	('mutant', 'Var', (13, 19))	('attenuates', 'NegReg', (25, 35))	('arrest', 'Disease', 'MESH:D006323', (163, 169))	('Idh1', 'Gene', (20, 24))	('NSCs', 'CPA', (53, 57))	('arrest', 'Disease', (163, 169))	('mutant', 'Var', (75, 81))	('proliferation', 'CPA', (36, 49))	('Idh1', 'Gene', (82, 86))
102701	28148827	This in vitro growth reduction as a result of mutant Idh1 corroborates both of our in vivo models: the first which shows that the Idh1 mutation reduces proliferation in the SVZ of the lateral ventricle among hGFAP-Cre; Idh1LSL:R132H/WT animals, and the second model which shows a failure of mutant Idh1 to impart a tumorigenic phenotype among Nestin-CreERT2; Idh1LSL:R132H/WT animals.	('lateral ventricle', 'Phenotype', 'HP:0006956', (184, 201))	('reduces', 'NegReg', (144, 151))	('R132H/W', 'Mutation', 'rs121913500', (367, 374))	('Nestin', 'Gene', '10763', (343, 349))	('hGFAP', 'Gene', '2670', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('R132H/W', 'Mutation', 'rs121913500', (227, 234))	('tumor', 'Disease', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('hGFAP', 'Gene', (208, 213))	('mutant', 'Var', (291, 297))	('mutation', 'Var', (135, 143))	('Nestin', 'Gene', (343, 349))	('proliferation in the SVZ of the lateral ventricle', 'CPA', (152, 201))	('Idh1', 'Gene', (130, 134))
102703	28148827	Most importantly, deletion of Tp53 rescues the proliferative defect attributed to mutant Idh1, suggesting the potential cooperative effects between Idh1 and Tp53 mutations, and explaining the co-occurring nature of these mutations among glioma patients.	('Tp53', 'Gene', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('Idh1', 'Gene', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('rescues', 'PosReg', (35, 42))	('glioma', 'Disease', (237, 243))	('patients', 'Species', '9606', (244, 252))	('deletion', 'Var', (18, 26))	('proliferative defect', 'MPA', (47, 67))	('mutant', 'Var', (82, 88))
102704	28148827	Mutant IDH1's effects on cellular behavior are cell context-dependent, reducing proliferation in some cases, and increasing proliferation and promoting tumorigenesis in other cases.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('reducing', 'NegReg', (71, 79))	('promoting', 'PosReg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('increasing', 'PosReg', (113, 123))	('proliferation', 'CPA', (124, 137))	('proliferation', 'CPA', (80, 93))	('tumor', 'Disease', (152, 157))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))
102705	28148827	discovered that immortalized human astrocytes infected with mutant IDH1 display a proliferative advantage and an enhanced ability for colony formation.	('IDH1', 'Gene', (67, 71))	('proliferative advantage', 'CPA', (82, 105))	('colony formation', 'CPA', (134, 150))	('human', 'Species', '9606', (29, 34))	('mutant', 'Var', (60, 66))	('enhanced', 'PosReg', (113, 121))
102707	28148827	shows that mutant IDH1 decreases the proliferation of the established glioma cell line U87 and a human embryonic kidney (HEK) cell line, both of which have TP53 intact.	('mutant', 'Var', (11, 17))	('glioma', 'Disease', (70, 76))	('HEK', 'CellLine', 'CVCL:M624', (121, 124))	('embryonic kidney', 'Disease', (103, 119))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('human', 'Species', '9606', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('U87', 'CellLine', 'CVCL:0022', (87, 90))	('proliferation', 'CPA', (37, 50))	('embryonic kidney', 'Disease', 'MESH:D007674', (103, 119))	('decreases', 'NegReg', (23, 32))	('IDH1', 'Gene', (18, 22))
102709	28148827	This is especially true for the IDH1 mutation, as one main feature of mutant IDH1 is the generation of the neometabolite D-2HG, which can be secreted into the extracellular compartment.	('D-2', 'Gene', '28503', (121, 124))	('mutant', 'Var', (70, 76))	('IDH1', 'Gene', (77, 81))	('neometabolite', 'Chemical', '-', (107, 120))	('D-2', 'Gene', (121, 124))
102710	28148827	The broadly expressed hGFAP-Cre promoter, which has been used previously to successfully generate glioma models, was used to drive mutant Idh1 expression in the brain.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('mutant', 'Var', (131, 137))	('Idh1', 'Gene', (138, 142))	('glioma', 'Disease', (98, 104))	('hGFAP', 'Gene', (22, 27))	('hGFAP', 'Gene', '2670', (22, 27))
102711	28148827	Perinatal hGFAP-Cre; Idh1LSL:R132H/WT animals presented with areas of hemorrhagic foci throughout the cortex, a phenotype reminiscent of a model utilizing a Nestin-Cre driver that showed severe hemorrhage and perinatal lethality.	('R132H/W', 'Mutation', 'rs121913500', (29, 36))	('hGFAP', 'Gene', (10, 15))	('R132H/WT', 'Var', (29, 37))	('hGFAP', 'Gene', '2670', (10, 15))	('hemorrhagic foci', 'Disease', (70, 86))	('hemorrhagic foci', 'Disease', 'MESH:D006470', (70, 86))	('hemorrhage', 'Disease', (194, 204))	('hemorrhage', 'Disease', 'MESH:D006470', (194, 204))	('Nestin', 'Gene', '10763', (157, 163))	('Nestin', 'Gene', (157, 163))
102712	28148827	This phenotypic variation can likely be explained by the timing and extent of mutant Idh1 induction; while Cre-recombinase begins to be expressed at E10.5 in the Nestin-Cre system, it begins at E13.5 in the hGFAP-Cre system.	('Nestin', 'Gene', '10763', (162, 168))	('E10.5', 'Var', (149, 154))	('Idh1', 'Gene', (85, 89))	('Nestin', 'Gene', (162, 168))	('hGFAP', 'Gene', (207, 212))	('hGFAP', 'Gene', '2670', (207, 212))	('mutant', 'Var', (78, 84))
102713	28148827	At P3, hGFAP-Cre; Idh1LSL:R132H/WT animals displayed reduced cortical thickness, loss of cellularity, and a disrupted SVZ, as indicated through a dispersal of Sox2-positive NSCs emanating outwards from the SVZ of the lateral ventricles.	('R132H/W', 'Mutation', 'rs121913500', (26, 33))	('cellularity', 'CPA', (89, 100))	('hGFAP', 'Gene', (7, 12))	('Sox2', 'Gene', '6657', (159, 163))	('cortical thickness', 'CPA', (61, 79))	('lateral ventricles', 'Phenotype', 'HP:0006956', (217, 235))	('Sox2', 'Gene', (159, 163))	('reduced', 'NegReg', (53, 60))	('hGFAP', 'Gene', '2670', (7, 12))	('lateral ventricle', 'Phenotype', 'HP:0006956', (217, 234))	('R132H/WT', 'Var', (26, 34))	('loss', 'NegReg', (81, 85))
102714	28148827	While further studies are needed to reveal the mechanism behind mutant Idh1's effects on the microenvironment, we speculate that the effects are at least partially mediated by D-2HG.	('D-2', 'Gene', (176, 179))	('D-2', 'Gene', '28503', (176, 179))	('microenvironment', 'MPA', (93, 109))	('effects', 'Reg', (78, 85))	('mutant', 'Var', (64, 70))	('Idh1', 'Gene', (71, 75))
102715	28148827	There is an interesting pathological similarity between hGFAP-Cre; Idh1LSL:R132H/WT animals and patients with D-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by systemic elevation of D-2HG.	('D-2', 'Gene', '28503', (110, 113))	('hGFAP', 'Gene', (56, 61))	('D-2', 'Gene', '28503', (205, 208))	('R132H/WT', 'Var', (75, 83))	('neurometabolic disorder', 'Disease', (142, 165))	('neurometabolic disorder', 'Disease', 'MESH:D030342', (142, 165))	('patients', 'Species', '9606', (96, 104))	('hGFAP', 'Gene', '2670', (56, 61))	('D-2', 'Gene', (110, 113))	('D-2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0012321', (110, 138))	('aciduria', 'Phenotype', 'HP:0012072', (130, 138))	('R132H/W', 'Mutation', 'rs121913500', (75, 82))	('D-2', 'Gene', (205, 208))
102718	28148827	The genetic data confers an unambiguous causal role of mutant IDH1 in gliomagenesis.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('mutant', 'Var', (55, 61))	('IDH1', 'Gene', (62, 66))
102719	28148827	Paradoxically, glioma patients with mutations in IDH1 tend to have a better survival clinically.	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (36, 45))	('glioma', 'Disease', (15, 21))	('better', 'PosReg', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('survival', 'CPA', (76, 84))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('IDH1', 'Gene', (49, 53))
102720	28148827	Together, this suggests that the IDH1 mutation is an effective promoter for clinically less aggressive gliomas.	('aggressive gliomas', 'Disease', 'MESH:D005910', (92, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('IDH1', 'Gene', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('aggressive gliomas', 'Disease', (92, 110))	('mutation', 'Var', (38, 46))
102721	28148827	There are two likely underlying mechanisms for this phenomenon: (i) It is possible that the IDH1 mutation can only target and transform a unique cellular population; a population distinct from those cells that give rise to non-IDH1-mutant gliomas, and a population that intrinsically gives rise to less aggressive tumors; or (ii) While the IDH1 mutation promotes cellular transformation initially, its continuous presence in tumor cells may attenuate tumor progression and aggressiveness.	('tumor', 'Disease', (425, 430))	('tumor', 'Phenotype', 'HP:0002664', (451, 456))	('aggressiveness', 'Disease', (473, 487))	('cellular transformation', 'CPA', (363, 386))	('promotes', 'PosReg', (354, 362))	('tumor', 'Disease', (314, 319))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('tumor', 'Disease', 'MESH:D009369', (425, 430))	('aggressiveness', 'Phenotype', 'HP:0000718', (473, 487))	('mutation', 'Var', (345, 353))	('aggressiveness', 'Disease', 'MESH:D001523', (473, 487))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('IDH1', 'Gene', (340, 344))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('mutation', 'Var', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (425, 430))	('attenuate', 'NegReg', (441, 450))	('aggressive tumors', 'Disease', (303, 320))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('gliomas', 'Disease', (239, 246))	('tumor', 'Disease', (451, 456))	('aggressive tumors', 'Disease', 'MESH:D001523', (303, 320))	('tumor', 'Disease', 'MESH:D009369', (451, 456))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
102722	28148827	Our experiments using the inducible Nestin-CreERT2 model indicate that in tumors driven by Tp53 deletion, mutant Idh1 is expressed in all tumor cells, supporting the notion that the two mutations target the same population of cells that give rise to tumors.	('Nestin', 'Gene', '10763', (36, 42))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('mutant', 'Var', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('rise to tumors', 'Disease', 'MESH:D009369', (242, 256))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('Nestin', 'Gene', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Idh1', 'Gene', (113, 117))	('tumors', 'Disease', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('driven by', 'Reg', (81, 90))	('rise to tumors', 'Disease', (242, 256))	('deletion', 'Var', (96, 104))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('Tp53', 'Gene', (91, 95))	('tumors', 'Disease', (74, 80))
102723	28148827	The prolonged survival among tumor-bearing animals with both mutant Idh1 and Tp53 mutations suggests that mutant Idh1 alters tumor biology as well as the course of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (164, 169))	('mutant', 'Var', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (125, 130))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Idh1', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Tp53', 'Gene', (77, 81))	('alters', 'Reg', (118, 124))	('Idh1', 'Gene', (68, 72))
102724	28148827	Our in vivo findings, coupled with previous in vitro models, support the latter mechanism and stress an important point for consideration when devising glioma treatments on the basis of mutant IDH1 inhibition.	('IDH1', 'Gene', (193, 197))	('inhibition', 'NegReg', (198, 208))	('glioma', 'Disease', (152, 158))	('mutant', 'Var', (186, 192))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
102725	28148827	Collectively, our findings provide new insight into the effects of mutant Idh1 on a candidate cell of origin for glioma, mutant Idh1's role in disrupting the microenvironment from which gliomas arise, and mutant Idh1's effect on the course of glioma progression.	('glioma', 'Disease', (186, 192))	('mutant', 'Var', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('glioma', 'Disease', (243, 249))	('effect', 'Reg', (219, 225))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('Idh1', 'Gene', (212, 216))	('effects', 'Reg', (56, 63))	('gliomas', 'Disease', (186, 193))	('disrupting', 'NegReg', (143, 153))	('glioma', 'Disease', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('gliomas', 'Disease', 'MESH:D005910', (186, 193))	('mutant', 'Var', (205, 211))	('Idh1', 'Gene', (74, 78))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('microenvironment', 'MPA', (158, 174))	('Idh1', 'Gene', (128, 132))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('mutant', 'Var', (67, 73))
102726	28148827	Additionally, this study highlights the challenges involved in modeling mutant IDH1, including (i) the impact of broad expression of mutant IDH1 on the CNS, which hinders long-term investigations of mutant IDH1 in contributing to brain tumorigenesis; (ii) the necessity to test other cooperating genetic alterations; (iii) the unclear identity of the cells of origin that are most susceptible to mutant IDH1-mediated transformation, and (iv) the unknown contribution of cell-autonomous and non-cell-autonomous effects on gliomagenesis.	('glioma', 'Phenotype', 'HP:0009733', (521, 527))	('mutant', 'Var', (72, 78))	('IDH1-mediated', 'Gene', (403, 416))	('brain tumor', 'Disease', (230, 241))	('glioma', 'Disease', (521, 527))	('mutant', 'Var', (396, 402))	('brain tumor', 'Disease', 'MESH:D001932', (230, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('brain tumor', 'Phenotype', 'HP:0030692', (230, 241))	('glioma', 'Disease', 'MESH:D005910', (521, 527))
102727	28148827	Further studies involving alternative approaches, such as orthotopic transplantation of other candidate glioma cells of origin, will help overcome these challenges and will provide a faithful foundation for understanding mutant Idh1's role in tumorigenesis and for investigating preclinical targeted therapies.	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('mutant', 'Var', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('Idh1', 'Gene', (228, 232))	('glioma', 'Disease', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
102728	28148827	Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell of origin for gliomas.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('gliomas', 'Disease', (177, 184))	('impacts', 'Reg', (136, 143))	('mutant', 'Var', (124, 130))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('aggressive tumor', 'Disease', 'MESH:D001523', (72, 88))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('Idh1', 'Gene', (131, 135))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('mouse', 'Species', '10090', (40, 45))	('aggressive tumor', 'Disease', (72, 88))
102736	25093489	Neutralisation or knockdown of the expression of integrin beta1 inhibited IGFBP-2-induced ERK activation, cell proliferation, and cell invasion.	('cell proliferation', 'CPA', (106, 124))	('knockdown', 'Var', (18, 27))	('ERK', 'Gene', (90, 93))	('integrin beta1', 'Gene', '3688', (49, 63))	('IGFBP-2', 'Gene', '3485', (74, 81))	('rat', 'Species', '10116', (118, 121))	('inhibited', 'NegReg', (64, 73))	('integrin beta1', 'Gene', (49, 63))	('ERK', 'Gene', '5594', (90, 93))	('cell invasion', 'CPA', (130, 143))	('IGFBP-2', 'Gene', (74, 81))	('activation', 'PosReg', (94, 104))
102767	25093489	U87, U251, and SU3 cells were infected with shRNA lentiviral particles (Santa Cruz Biotechnology, Santa Cruz, CA, USA) targeting beta1-integrin (sc-35674-V) or control shRNA (sc-108080) according to the manufacturer's protocol.	('U87', 'Gene', '641648', (0, 3))	('beta1-integrin', 'Gene', '3688', (129, 143))	('U87', 'Gene', (0, 3))	('U251', 'CellLine', 'CVCL:0021', (5, 9))	('sc-35674-V', 'Var', (145, 155))	('beta1-integrin', 'Gene', (129, 143))
102795	25093489	In some cultures, cells were preincubated with 50 muM PD98059 for 16 h or 2 mug ml-1 integrin beta1-neutralising antibody for 30 min before treatment with IGFBP-2.	('PD98059', 'Chemical', 'MESH:C093973', (54, 61))	('IGFBP-2', 'Gene', (155, 162))	('integrin beta1', 'Gene', (85, 99))	('IGFBP-2', 'Gene', '3485', (155, 162))	('integrin beta1', 'Gene', '3688', (85, 99))	('PD98059', 'Var', (54, 61))	('ml-1', 'Gene', (80, 84))	('ml-1', 'Gene', '112744', (80, 84))
102814	25093489	Insulin-like growth factor binding protein-2 expression was stably upregulated in U87 cells, by transfection with the pEGFP-N1-IGFBP-2 plasmid (Figure 1B).	('Insulin-like growth factor binding protein-2', 'Gene', '3485', (0, 44))	('IGFBP-2', 'Gene', (127, 134))	('IGFBP-2', 'Gene', '3485', (127, 134))	('transfection', 'Var', (96, 108))	('expression', 'MPA', (45, 55))	('Insulin-like growth factor binding protein-2', 'Gene', (0, 44))	('U87', 'Gene', (82, 85))	('U87', 'Gene', '641648', (82, 85))	('upregulated', 'PosReg', (67, 78))
102819	25093489	Moreover, PD98059, an ERK inhibitor, had no effect on IGFBP-2 overexpression-induced invasion (Figure 1F).	('IGFBP-2', 'Gene', '3485', (54, 61))	('ERK', 'Gene', '5594', (22, 25))	('ERK', 'Gene', (22, 25))	('PD98059', 'Var', (10, 17))	('overexpression-induced', 'PosReg', (62, 84))	('PD98059', 'Chemical', 'MESH:C093973', (10, 17))	('IGFBP-2', 'Gene', (54, 61))
102824	25093489	However, the knockdown of IGFBP-2 resulted in a significant reduction of the invasion through the Matrigel in U251 cells (Supplementary Figure 1E).	('IGFBP-2', 'Gene', '3485', (26, 33))	('U251', 'CellLine', 'CVCL:0021', (110, 114))	('invasion through the Matrigel in U251 cells', 'CPA', (77, 120))	('reduction', 'NegReg', (60, 69))	('knockdown', 'Var', (13, 22))	('IGFBP-2', 'Gene', (26, 33))
102835	25093489	In addition, BrdU assay also confirmed that exogenous IGFBP-2 promoted cell proliferation and cell cycle entry (Supplementary Figure 1G).	('IGFBP-2', 'Gene', '3485', (54, 61))	('rat', 'Species', '10116', (83, 86))	('BrdU', 'Chemical', 'MESH:D001973', (13, 17))	('cell cycle entry', 'CPA', (94, 110))	('exogenous', 'Var', (44, 53))	('promoted', 'PosReg', (62, 70))	('cell proliferation', 'CPA', (71, 89))	('IGFBP-2', 'Gene', (54, 61))
102844	25093489	These results indicate that exogenous IGFBP-2 enhances the activation of ERK signaling in glioblastoma cells.	('enhances', 'PosReg', (46, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('ERK', 'Gene', '5594', (73, 76))	('ERK', 'Gene', (73, 76))	('IGFBP-2', 'Gene', (38, 45))	('activation', 'MPA', (59, 69))	('IGFBP-2', 'Gene', '3485', (38, 45))	('glioblastoma', 'Disease', (90, 102))	('exogenous', 'Var', (28, 37))
102847	25093489	These findings suggest that exogenous IGFBP-2 promotes proliferation and invasion of glioblastoma cells through ERK signaling.	('proliferation', 'CPA', (55, 68))	('IGFBP-2', 'Gene', (38, 45))	('glioblastoma', 'Disease', (85, 97))	('ERK', 'Gene', '5594', (112, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('IGFBP-2', 'Gene', '3485', (38, 45))	('ERK', 'Gene', (112, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('invasion', 'CPA', (73, 81))	('rat', 'Species', '10116', (62, 65))	('promotes', 'PosReg', (46, 54))	('exogenous', 'Var', (28, 37))
102854	25093489	Integrin beta1 knockdown resulted in a significant decrease in cell proliferation and invasion.	('Integrin beta1', 'Gene', '3688', (0, 14))	('knockdown', 'Var', (15, 24))	('rat', 'Species', '10116', (75, 78))	('Integrin beta1', 'Gene', (0, 14))	('cell proliferation', 'CPA', (63, 81))	('decrease', 'NegReg', (51, 59))	('invasion', 'CPA', (86, 94))
102855	25093489	Moreover, integrin beta1 knockdown also abrogated exogenous IGFBP-2-induced ERK activation, tumour cell proliferation, and invasion (Figures 4B-G).	('integrin beta1', 'Gene', '3688', (10, 24))	('rat', 'Species', '10116', (111, 114))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('IGFBP-2', 'Gene', '3485', (60, 67))	('tumour', 'Disease', (92, 98))	('ERK', 'Gene', (76, 79))	('invasion', 'CPA', (123, 131))	('abrogated', 'NegReg', (40, 49))	('ERK', 'Gene', '5594', (76, 79))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('integrin beta1', 'Gene', (10, 24))	('knockdown', 'Var', (25, 34))	('IGFBP-2', 'Gene', (60, 67))	('activation', 'PosReg', (80, 90))
102857	25093489	Blocking integrin beta1 function by neutralisation inhibited IGFBP-2-induced ERK activation, tumour cell proliferation, cell cycle progression, and invasion (Figures 5 and 6A).	('IGFBP-2', 'Gene', (61, 68))	('integrin beta1', 'Gene', (9, 23))	('tumour', 'Disease', (93, 99))	('IGFBP-2', 'Gene', '3485', (61, 68))	('integrin beta1', 'Gene', '3688', (9, 23))	('neutralisation', 'Var', (36, 50))	('ERK', 'Gene', '5594', (77, 80))	('activation', 'PosReg', (81, 91))	('function', 'MPA', (24, 32))	('ERK', 'Gene', (77, 80))	('rat', 'Species', '10116', (112, 115))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('cell cycle progression', 'CPA', (120, 142))	('inhibited', 'NegReg', (51, 60))	('invasion', 'CPA', (148, 156))
102859	25093489	In the previous study, plasma IGFBP-2 levels after standard postoperative radiotherapy plus chemotherapy were found to be correlated with prognosis of glioblastoma patients, indicating that exogenous IGFBP-2 may affect TMZ chemosensitivity.	('IGFBP-2', 'Gene', (30, 37))	('TMZ', 'Chemical', 'MESH:D000077204', (219, 222))	('rat', 'Species', '10116', (67, 70))	('IGFBP-2', 'Gene', '3485', (30, 37))	('exogenous', 'Var', (190, 199))	('glioblastoma', 'Disease', (151, 163))	('TMZ chemosensitivity', 'CPA', (219, 239))	('patients', 'Species', '9606', (164, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('correlated', 'Reg', (122, 132))	('affect', 'Reg', (212, 218))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('IGFBP-2', 'Gene', (200, 207))	('IGFBP-2', 'Gene', '3485', (200, 207))
102863	25093489	Nevertheless, endogenous IGFBP-2 overexpression or knockdown had no significant effect on TMZ chemosensitivity in glioblastoma cells (Supplementary Figures 4 and 5).	('overexpression', 'PosReg', (33, 47))	('TMZ chemosensitivity', 'MPA', (90, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('TMZ', 'Chemical', 'MESH:D000077204', (90, 93))	('IGFBP-2', 'Gene', (25, 32))	('IGFBP-2', 'Gene', '3485', (25, 32))	('glioblastoma', 'Disease', (114, 126))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('knockdown', 'Var', (51, 60))
102864	25093489	Taken together, these results suggest that rather than endogenous IGFBP-2, exogenous IGFBP-2 induces chemoresistance to TMZ in glioblastoma cells via the integrin beta1-ERK signaling pathway.	('IGFBP-2', 'Gene', '3485', (85, 92))	('ERK', 'Gene', '5594', (169, 172))	('ERK', 'Gene', (169, 172))	('glioblastoma', 'Disease', (127, 139))	('induces', 'PosReg', (93, 100))	('glioblastoma', 'Disease', 'MESH:D005909', (127, 139))	('IGFBP-2', 'Gene', (66, 73))	('integrin beta1', 'Gene', (154, 168))	('rat', 'Species', '10116', (43, 46))	('IGFBP-2', 'Gene', '3485', (66, 73))	('exogenous', 'Var', (75, 84))	('integrin beta1', 'Gene', '3688', (154, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('TMZ', 'Chemical', 'MESH:D000077204', (120, 123))	('chemoresistance to TMZ', 'CPA', (101, 123))	('IGFBP-2', 'Gene', (85, 92))
102868	25093489	Previous studies have identified several such factors that mediate chemosensitivity through different mechanisms, including O6-methylguanine-DNA methyltransferase promoter methylation, isocitrate dehydrogenase 1 mutation, and 1p/19q status among others.	('1p/19q status', 'Var', (226, 239))	('mutation', 'Var', (212, 220))	('rat', 'Species', '10116', (191, 194))
102888	25093489	In the present study, exogenous IGFBP-2 was found to stimulate proliferation, invasion, and chemoresistance to TMZ in an integrin beta1-dependent manner in glioblastoma cells.	('integrin beta1', 'Gene', '3688', (121, 135))	('proliferation', 'CPA', (63, 76))	('rat', 'Species', '10116', (70, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('stimulate', 'PosReg', (53, 62))	('invasion', 'CPA', (78, 86))	('TMZ', 'Chemical', 'MESH:D000077204', (111, 114))	('chemoresistance', 'CPA', (92, 107))	('exogenous', 'Var', (22, 31))	('IGFBP-2', 'Gene', '3485', (32, 39))	('IGFBP-2', 'Gene', (32, 39))	('integrin beta1', 'Gene', (121, 135))	('glioblastoma', 'Disease', (156, 168))	('glioblastoma', 'Disease', 'MESH:D005909', (156, 168))
102908	25093489	To summarise, in the present study, exogenous IGFBP-2 was shown to stimulate proliferation, invasion, and chemoresistance to TMZ via the integrin beta1-ERK pathway in glioblastoma cells.	('ERK', 'Gene', '5594', (152, 155))	('chemoresistance', 'CPA', (106, 121))	('stimulate', 'PosReg', (67, 76))	('glioblastoma', 'Disease', (167, 179))	('invasion', 'CPA', (92, 100))	('ERK', 'Gene', (152, 155))	('rat', 'Species', '10116', (84, 87))	('TMZ', 'Chemical', 'MESH:D000077204', (125, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (167, 179))	('exogenous', 'Var', (36, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))	('integrin beta1', 'Gene', (137, 151))	('IGFBP-2', 'Gene', (46, 53))	('integrin beta1', 'Gene', '3688', (137, 151))	('IGFBP-2', 'Gene', '3485', (46, 53))	('proliferation', 'CPA', (77, 90))
102910	25093489	First, they reveal a mechanism by which serum IGFBP-2 can affect the prognosis of glioblastoma patients who received postoperative standard radiotherapy plus TMZ chemotherapy.	('rat', 'Species', '10116', (124, 127))	('glioblastoma', 'Disease', (82, 94))	('patients', 'Species', '9606', (95, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('TMZ', 'Chemical', 'MESH:D000077204', (158, 161))	('IGFBP-2', 'Gene', (46, 53))	('serum', 'Var', (40, 45))	('IGFBP-2', 'Gene', '3485', (46, 53))	('affect', 'Reg', (58, 64))
102923	22867897	In addition, hydrocephalus and shunt insertion in craniopharyngioma were found to be predictive of worse neurocognitive outcome, suggesting a more aggressive natural history for those patients.	('hydrocephalus', 'Disease', 'MESH:D006849', (13, 26))	('shunt', 'Var', (31, 36))	('patients', 'Species', '9606', (184, 192))	('craniopharyngioma', 'Disease', (50, 67))	('hydrocephalus', 'Disease', (13, 26))	('craniopharyngioma', 'Phenotype', 'HP:0030062', (50, 67))	('craniopharyngioma', 'Disease', 'MESH:D003397', (50, 67))	('hydrocephalus', 'Phenotype', 'HP:0000238', (13, 26))
102974	22867897	In the domain of visual auditory learning, shunt insertion did predict lower scores at baseline in the LGG group but not 5 years after CRT.	('visual auditory learning', 'Disease', 'MESH:D007859', (17, 41))	('scores', 'MPA', (77, 83))	('visual auditory learning', 'Disease', (17, 41))	('CRT', 'Gene', '799', (135, 138))	('CRT', 'Gene', (135, 138))	('shunt insertion', 'Var', (43, 58))	('LGG', 'Chemical', '-', (103, 106))	('lower', 'NegReg', (71, 76))
102982	22867897	Among children with craniopharyngioma, shunt insertion predicted significantly lower scores at baseline on the VAL (-21.89; P<.001) test, as did female sex (-13.33; P<.01).	('VAL', 'Chemical', '-', (111, 114))	('craniopharyngioma', 'Phenotype', 'HP:0030062', (20, 37))	('craniopharyngioma', 'Disease', 'MESH:D003397', (20, 37))	('scores', 'MPA', (85, 91))	('lower', 'NegReg', (79, 84))	('craniopharyngioma', 'Disease', (20, 37))	('shunt', 'Var', (39, 44))	('children', 'Species', '9606', (6, 14))
102986	22867897	In the LGG group, shunt insertion predicted lower scores at baseline (-10.06; P<.05) on the VAL test but not on the rate of learning after treatment.	('shunt', 'Var', (18, 23))	('lower', 'NegReg', (44, 49))	('scores', 'MPA', (50, 56))	('LGG', 'Chemical', '-', (7, 10))	('VAL', 'Chemical', '-', (92, 95))
102997	22867897	Nonetheless, in another study examining a younger group of patients with ependymoma, where the ages between those who received preirradiation chemotherapy vs those who did not were less discrepant, preirradiation chemotherapy was still found to be a significant risk factor for adverse neurocognitive outcome.	('ependymoma', 'Phenotype', 'HP:0002888', (73, 83))	('ependymoma', 'Disease', (73, 83))	('ependymoma', 'Disease', 'MESH:D004806', (73, 83))	('patients', 'Species', '9606', (59, 67))	('preirradiation chemotherapy', 'Var', (198, 225))
103013	22867897	Ventriculomegaly, which may occur despite shunt insertion, may result in more chronic interruption to the encoding process beyond that associated with acute surgical changes.	('interruption', 'MPA', (86, 98))	('encoding process', 'MPA', (106, 122))	('Ventriculomegaly', 'Phenotype', 'HP:0002119', (0, 16))	('Ventriculomegaly', 'Disease', (0, 16))	('Ventriculomegaly', 'Disease', 'MESH:D006849', (0, 16))	('shunt', 'Var', (42, 47))
103048	30652536	As shown by survival curves for BRCA (Fig 2E), MESO (Fig 2F), and PAAD (Fig 2G), the OS of patients with high levels of MAP2K1 and CDK4/6 was significantly lower than the OS of patients with low levels of MAP2K1 and CDK4/6.	('PAAD', 'Disease', 'MESH:D010195', (66, 70))	('CDK4/6', 'Gene', (131, 137))	('MAP2K1', 'Gene', '5604', (205, 211))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (177, 185))	('MAP2K1', 'Gene', '5604', (120, 126))	('BRCA', 'Gene', '672', (32, 36))	('MESO', 'Disease', 'MESH:D008654', (47, 51))	('MESO', 'Disease', (47, 51))	('MAP2K1', 'Gene', (205, 211))	('MAP2K1', 'Gene', (120, 126))	('BRCA', 'Gene', (32, 36))	('PAAD', 'Disease', (66, 70))	('high levels', 'Var', (105, 116))	('lower', 'NegReg', (156, 161))
103052	30652536	As shown in Figure 3, synergistic effect was predicted for several MAPK1 combinations evidenced by short OS in the high (ie, more than the median) MAPK1-high other gene-expression group and significantly better OS within the cohort in which expression of both of these genes is low (ie, below median).	('MAPK1', 'Gene', (67, 72))	('MAPK1', 'Gene', (147, 152))	('MAPK1', 'Gene', '5594', (67, 72))	('combinations', 'Var', (73, 85))	('MAPK1', 'Gene', '5594', (147, 152))
103075	30652536	ERK inhibitors are being tested in the clinic for the treatment of tumors with aberrant MAPK pathway signaling; however, combination therapies will probably be necessary to achieve durable tumor control.	('tumor', 'Disease', (189, 194))	('MAPK pathway signaling', 'Pathway', (88, 110))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('aberrant', 'Var', (79, 87))	('ERK', 'Gene', '5594', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('ERK', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', (67, 73))
103077	30652536	ERK inhibition may also be the best way to disrupt this pathway in other RAS-driven tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ERK', 'Gene', '5594', (0, 3))	('inhibition', 'Var', (4, 14))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('ERK', 'Gene', (0, 3))
103078	30652536	Our results show that expression of multiple novel targets might synergistically affect patient survival, and inhibition of these genes may increase the efficacy of ERK inhibitors.	('patient', 'Species', '9606', (88, 95))	('efficacy', 'MPA', (153, 161))	('ERK', 'Gene', '5594', (165, 168))	('affect', 'Reg', (81, 87))	('inhibition', 'Var', (110, 120))	('patient survival', 'CPA', (88, 104))	('increase', 'PosReg', (140, 148))	('ERK', 'Gene', (165, 168))
103079	30652536	We demonstrate that expression of MAPK1 and PKN3 both have to be low to predict better OS, and PKN3 inhibition may increase efficacy of the MAPK inhibitor sorafenib.	('MAPK1', 'Gene', (34, 39))	('PKN3', 'Gene', '263803', (44, 48))	('PKN3', 'Gene', (44, 48))	('PKN3', 'Gene', (95, 99))	('sorafenib', 'Chemical', 'MESH:C471405', (155, 164))	('increase', 'PosReg', (115, 123))	('PKN3', 'Gene', '263803', (95, 99))	('inhibition', 'Var', (100, 110))	('efficacy', 'MPA', (124, 132))	('MAPK1', 'Gene', '5594', (34, 39))
103091	29168082	There were no significant differences in any of the FBB PET analyses between APOE epsilon-4 carriers and non-epsilon-4 carriers.	('carriers', 'Var', (92, 100))	('APOE', 'Gene', (77, 81))	('APOE', 'Gene', '348', (77, 81))
103100	29168082	The epsilon-4 allele is associated with decreased neuronal growth and repair and promotes beta-amyloid deposition in brain tissue.	('amyloid deposition', 'Phenotype', 'HP:0011034', (95, 113))	('decreased neuronal growth', 'Disease', (40, 65))	('promotes', 'PosReg', (81, 89))	('decreased neuronal growth', 'Disease', 'MESH:D006130', (40, 65))	('epsilon-4', 'Var', (4, 13))	('decreased neuronal growth', 'Phenotype', 'HP:0002529', (40, 65))	('beta-amyloid deposition', 'MPA', (90, 113))
103143	29168082	The results of this pilot study showed that a subset of patients with gliomas treated with conformal RT +- CHT had continued decline in attention and verbal learning abilities over an approximately nine-year period, and that the APOE epsilon-4 allele may have influenced cognitive decline.	('RT +- CHT', 'Var', (101, 110))	('patients', 'Species', '9606', (56, 64))	('APOE', 'Gene', (229, 233))	('cognitive decline', 'Disease', 'MESH:D003072', (271, 288))	('verbal learning abilities', 'Disease', 'MESH:D007859', (150, 175))	('cognitive decline', 'Phenotype', 'HP:0001268', (271, 288))	('influenced', 'Reg', (260, 270))	('decline', 'NegReg', (125, 132))	('APOE', 'Gene', '348', (229, 233))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('verbal learning abilities', 'Disease', (150, 175))	('gliomas', 'Disease', (70, 77))	('cognitive decline', 'Disease', (271, 288))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
103149	29168082	Patients who received RT showed a further decline in attention, executive function, and processing speed, suggesting that both partial and whole brain RT was associated with cognitive dysfunction several years after treatment.	('decline', 'NegReg', (42, 49))	('executive function', 'CPA', (64, 82))	('associated with', 'Reg', (158, 173))	('attention', 'MPA', (53, 62))	('partial', 'Var', (127, 134))	('cognitive dysfunction', 'Disease', 'MESH:D003072', (174, 195))	('processing speed', 'CPA', (88, 104))	('Patients', 'Species', '9606', (0, 8))	('cognitive dysfunction', 'Disease', (174, 195))
103153	29168082	Patients treated with RT +- CHT had lower scores in attention and executive functions, graphomotor speed, and memory than untreated patients.	('lower', 'NegReg', (36, 41))	('patients', 'Species', '9606', (132, 140))	('RT +- CHT', 'Var', (22, 31))	('Patients', 'Species', '9606', (0, 8))	('graphomotor speed', 'CPA', (87, 104))	('memory', 'CPA', (110, 116))
103156	29168082	The preliminary findings showed significantly worse performance over time in attention and working memory in carriers of at least one epsilon-4 allele relative to non-epsilon-4-carriers over an approximately five-year period, suggesting that the epsilon-4 allele may increase susceptibility to continued cognitive impairment in long term survivors.	('continued cognitive impairment', 'Phenotype', 'HP:0001268', (294, 324))	('epsilon-4', 'Var', (246, 255))	('continued', 'Disease', (294, 303))	('carriers', 'Var', (109, 117))	('performance', 'MPA', (52, 63))	('cognitive impairment', 'Disease', 'MESH:D003072', (304, 324))	('worse', 'NegReg', (46, 51))	('epsilon-4', 'Gene', (134, 143))	('cognitive impairment', 'Phenotype', 'HP:0100543', (304, 324))	('cognitive impairment', 'Disease', (304, 324))
103160	29168082	In our prior cross-sectional study of APOE polymorphisms and cognitive functions, we described that the APOE epsilon-4 allele and additional SNPs in the APOE gene may increase the vulnerability of brain tumor patients to cognitive dysfunction.	('brain tumor', 'Disease', 'MESH:D001932', (197, 208))	('APOE', 'Gene', '348', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('cognitive dysfunction', 'Disease', 'MESH:D003072', (221, 242))	('APOE', 'Gene', (153, 157))	('brain tumor', 'Phenotype', 'HP:0030692', (197, 208))	('cognitive dysfunction', 'Disease', (221, 242))	('APOE', 'Gene', '348', (153, 157))	('patients', 'Species', '9606', (209, 217))	('APOE', 'Gene', (104, 108))	('increase', 'PosReg', (167, 175))	('APOE', 'Gene', (38, 42))	('SNPs', 'Var', (141, 145))	('brain tumor', 'Disease', (197, 208))	('APOE', 'Gene', '348', (38, 42))
103166	29168082	The results showed no significant differences in regional SUVRs between APOE epsilon-4 carriers and non-epsilon-4-carriers.	('APOE', 'Gene', (72, 76))	('APOE', 'Gene', '348', (72, 76))	('carriers', 'Var', (87, 95))
103171	29168082	These preliminary findings suggest that RT +- CHT and the APOE epsilon-4 allele may not be strongly associated with increased beta-amyloid cortical retention in these glioma survivors, despite evidence of cognitive decline.	('APOE', 'Gene', '348', (58, 62))	('cognitive decline', 'Disease', (205, 222))	('RT +- CHT', 'Var', (40, 49))	('glioma', 'Disease', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('cognitive decline', 'Disease', 'MESH:D003072', (205, 222))	('cognitive decline', 'Phenotype', 'HP:0001268', (205, 222))	('increased', 'PosReg', (116, 125))	('beta-amyloid cortical retention', 'MPA', (126, 157))	('APOE', 'Gene', (58, 62))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
103191	28717525	Despite intense intraoperative monitoring, brain tumor surgery resection may induce or aggravate the existing cognitive deficits.	('cognitive deficits', 'Disease', (110, 128))	('resection', 'Var', (63, 72))	('brain tumor', 'Disease', 'MESH:D001932', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('brain tumor', 'Disease', (43, 54))	('aggravate', 'PosReg', (87, 96))	('cognitive deficits', 'Disease', 'MESH:D003072', (110, 128))	('brain tumor', 'Phenotype', 'HP:0030692', (43, 54))	('cognitive deficits', 'Phenotype', 'HP:0100543', (110, 128))	('induce', 'Reg', (77, 83))
103294	27659825	In a comparative study of 19 children with brain tumor, 99mTc-MIBI could delineate the tumor borders better than 201TI based on the greater signal-to-noise ratio.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('brain tumor', 'Disease', 'MESH:D001932', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('brain tumor', 'Disease', (43, 54))	('children', 'Species', '9606', (29, 37))	('tumor', 'Disease', (87, 92))	('99mTc-MIBI', 'Var', (56, 66))	('tumor', 'Disease', (49, 54))	('brain tumor', 'Phenotype', 'HP:0030692', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('-MIBI', 'Chemical', 'MESH:C055887', (61, 66))
103305	27659825	These findings suggested that variations of tracer uptake may be useful for differential diagnosis of certain tumor types.	('variations', 'Var', (30, 40))	('tracer uptake', 'MPA', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
103311	27659825	To test this, two recent pediatric studies evaluated the differentiating accuracy of amino acid PET in newly diagnosed brain lesions.	('amino acid', 'Var', (85, 95))	('brain lesions', 'Disease', 'MESH:D001927', (119, 132))	('brain lesions', 'Disease', (119, 132))
103326	27659825	Notably, rCBF values on H215O-PET did not correlate with malignancy grade.	('malignancy', 'Disease', (57, 67))	('H215O-PET', 'Var', (24, 33))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('H215O', 'Chemical', '-', (24, 29))
103334	27659825	In Cox regression, both high FDG and MET tumor-to-frontal cortex SUV ratios were associated with disease progression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('associated with', 'Reg', (81, 96))	('tumor', 'Disease', (41, 46))	('disease', 'Disease', (97, 104))	('FDG', 'Chemical', 'MESH:D019788', (29, 32))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
103379	27659825	Non-resection of such cortical regions was associated with persistent seizures post-operatively.	('Non-resection', 'Var', (0, 13))	('persistent seizures post-', 'Phenotype', 'HP:0002133', (59, 84))	('seizures', 'Disease', 'MESH:D012640', (70, 78))	('seizures', 'Disease', (70, 78))	('seizures', 'Phenotype', 'HP:0001250', (70, 78))
103409	27659825	Although most studies have been relatively small (typically including a few dozens of pediatric cases, at the most), they provided some compelling data demonstrating that amino acid PET can be useful to differentiate tumors from non-tumorous lesions, assess tumoral proliferative activity, and detect tumoral metabolic heterogeneity.	('tumor', 'Disease', (258, 263))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (233, 238))	('amino', 'Var', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('non-tumorous lesions', 'Disease', (229, 249))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('non-tumorous lesions', 'Disease', 'MESH:D000073296', (229, 249))	('tumors', 'Disease', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('detect', 'Reg', (294, 300))
103410	27659825	A complete lack or paucity of amino acid uptake may prompt the clinician to opt for watchful waiting, as these tumors are usually indolent and may not need active treatment.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('lack', 'NegReg', (11, 15))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('paucity', 'Var', (19, 26))	('amino acid uptake', 'MPA', (30, 47))
103435	26245742	In clinical studies, several different amino acid PET radiotracers, including [11C]methionine, 18F-fluoroethyl-tyrosine (FET), 18F-fluoro-Ldihydroxy-phenylalanine (FDOPA), and alpha[11C]methyl-L-tryptophan (AMT) have been tested for glioma imaging, and each of them has their unique advantages and limitations.	('[11C', 'Var', (78, 82))	('glioma', 'Disease', 'MESH:D005910', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('[11C]methionine', 'Chemical', '-', (78, 93))	('18F-fluoro-Ldihydroxy-phenylalanine', 'Chemical', '-', (127, 162))	('alpha[11C]methyl-L-tryptophan', 'Chemical', 'MESH:C020774', (176, 205))	('18F-fluoroethyl-tyrosine', 'Chemical', 'MESH:C545932', (95, 119))	('FDOPA', 'Chemical', '-', (164, 169))	('glioma', 'Disease', (233, 239))	('FET', 'Chemical', 'MESH:C545932', (121, 124))	('AMT', 'Chemical', 'MESH:C020774', (207, 210))
103536	32727476	Deep semi-supervised learning for brain tumor classification This paper addresses issues of brain tumor, glioma, classification from four modalities of Magnetic Resonance Image (MRI) scans (i.e., T1 weighted MRI, T1 weighted MRI with contrast-enhanced, T2 weighted MRI and FLAIR).	('brain tumor', 'Disease', (92, 103))	('brain tumor', 'Disease', (34, 45))	('issues of brain', 'Phenotype', 'HP:0012443', (82, 97))	('brain tumor', 'Disease', 'MESH:D001932', (92, 103))	('T2 weighted MRI', 'Var', (253, 268))	('brain tumor', 'Disease', 'MESH:D001932', (34, 45))	('glioma', 'Disease', (105, 111))	('T1 weighted', 'Var', (213, 224))	('brain tumor', 'Phenotype', 'HP:0030692', (92, 103))	('brain tumor', 'Phenotype', 'HP:0030692', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('T1 weighted MRI', 'Var', (196, 211))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
103546	32727476	Glioma subtype isocitrate dehydrogenase (IDH) mutations are observed in 12% of glioblastomas, and 70% to 80% of LGG.	('IDH', 'Gene', (41, 44))	('mutations', 'Var', (46, 55))	('IDH', 'Gene', '3417', (41, 44))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('observed', 'Reg', (60, 68))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('glioblastomas', 'Disease', 'MESH:D005909', (79, 92))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('glioblastomas', 'Disease', (79, 92))
103560	32727476	included Visually Accessible Rembrandt Images (VASARI) features for predicting IDH and TP53 mutations with SVM models.	('TP53', 'Gene', '7157', (87, 91))	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', '3417', (79, 82))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))
103562	32727476	extracted histogram, shape and texture features from preoperative MRIs, and the age information is then integrated for training a random forest classifier for the prediction of IDH mutation status and 1p/19q codeletion.	('mutation status', 'Var', (181, 196))	('IDH', 'Gene', '3417', (177, 180))	('IDH', 'Gene', (177, 180))	('1p/19q codeletion', 'Var', (201, 218))
103566	32727476	proposed to apply residual CNNs to the prediction of IDH mutation using multi-institutional MRI data from four different modalities: T1 weighted, T1 weighted with contrast enhanced, T2 weighted and FLAIR (abbreviated as T1, T1ce, T2 and FLAIR in the text below).	('mutation', 'Var', (57, 65))	('IDH', 'Gene', '3417', (53, 56))	('IDH', 'Gene', (53, 56))
103632	32727476	From our experimental results, some insights can be gained from the proposed scheme:  Limitation: The imbalance of training data (including GAN generated training data) in two different classes has caused one class with relatively lower performance, consequently, it has affected the average test performance.	('performance', 'MPA', (237, 248))	('GAN', 'Gene', '8139', (140, 143))	('affected', 'Reg', (271, 279))	('imbalance', 'Var', (102, 111))	('lower', 'NegReg', (231, 236))	('imbalance', 'Phenotype', 'HP:0002172', (102, 111))	('GAN', 'Gene', (140, 143))
103661	30474767	As there is no established "minimum clinically important difference" of the KPS after neuro-oncological surgery and a 10-point change on the upper KPS is not as meaningful to a patient as a 10-point change on the lower KPS, we adapted the previous definition for "significant change" as a decrease of >= 20 points if baseline KPS >= 80, or a decrease of >= 10 points if baseline KPS < 80.	('KPS >= 80', 'Var', (326, 335))	('patient', 'Species', '9606', (177, 184))	('decrease', 'NegReg', (342, 350))	('decrease', 'NegReg', (289, 297))
103739	28467784	In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts alpha-ketoglutarate (alpha-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG).	('glioblastoma', 'Disease', 'MESH:D005909', (259, 271))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', (144, 148))	('glioblastoma', 'Disease', (259, 271))	('glutamate', 'Chemical', 'MESH:D018698', (119, 128))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (259, 271))	('isocitrate dehydrogenase 1', 'Gene', (185, 211))	('D-2-HG', 'Chemical', 'MESH:C019417', (394, 400))	('isocitrate dehydrogenase 1', 'Gene', '3417', (185, 211))	('neomorphic activity', 'CPA', (285, 304))	('IDH1', 'Gene', '3417', (81, 85))	('IDH1', 'Gene', (213, 217))	('IDH1', 'Gene', '3417', (144, 148))	('glioma', 'Disease', (96, 102))	('glioma', 'Disease', (238, 244))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (319, 338))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('induce', 'Reg', (276, 282))	('initiate', 'PosReg', (219, 227))	('lactate', 'Chemical', 'MESH:D019344', (107, 114))	('mutations', 'Var', (172, 181))	('IDH1', 'Gene', '3417', (213, 217))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (372, 392))	('acetate', 'Chemical', 'MESH:D000085', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('alpha-KG', 'Chemical', 'MESH:D007656', (340, 348))	('glioma', 'Disease', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))
103740	28467784	We investigated the effects of IDH1 mutations (IDH1MUT) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (132, 151))	('IDH1', 'Gene', '3417', (31, 35))	('IDH1', 'Gene', (47, 51))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (36, 45))	('IDH1', 'Gene', '3417', (47, 51))	('Cancer Genome Atlas', 'Disease', (132, 151))	('IDH1', 'Gene', (31, 35))
103743	28467784	In vitro, we observed that IDH1MUT cancer cells have a higher basal respiration compared to IDH1WT cancer cells and inhibition of the IDH1MUT shifts the metabolism by decreasing oxygen consumption and increasing glycolysis.	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('oxygen consumption', 'MPA', (178, 196))	('higher', 'PosReg', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('IDH1', 'Gene', (134, 138))	('glycolysis', 'MPA', (212, 222))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('oxygen', 'Chemical', 'MESH:D010100', (178, 184))	('basal respiration', 'MPA', (62, 79))	('decreasing', 'NegReg', (167, 177))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (134, 138))	('increasing', 'PosReg', (201, 211))	('inhibition', 'Var', (116, 126))	('cancer', 'Disease', (99, 105))	('IDH1', 'Gene', '3417', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('IDH1', 'Gene', '3417', (27, 31))
103754	28467784	Recently, it was demonstrated that these characteristics are strongly associated with mutations in the metabolic enzyme isocitrate dehydrogenase (IDH).	('mutations', 'Var', (86, 95))	('IDH', 'Gene', (146, 149))	('associated', 'Reg', (70, 80))	('isocitrate dehydrogenase', 'Gene', (120, 144))	('IDH', 'Gene', '3417', (146, 149))	('isocitrate dehydrogenase', 'Gene', '3417', (120, 144))
103755	28467784	Hotspot mutations in IDH1 and, less frequently, IDH2 occur in 80% of WHO grade II-III and secondary WHO grade IV gliomas and are ancestral events in the formation of these neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (172, 181))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('neoplasms', 'Disease', (172, 181))	('IDH2', 'Gene', '3418', (48, 52))	('mutations', 'Var', (8, 17))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('IDH2', 'Gene', (48, 52))	('IDH1', 'Gene', (21, 25))	('neoplasms', 'Phenotype', 'HP:0002664', (172, 181))	('IDH1', 'Gene', '3417', (21, 25))
103756	28467784	In addition to glioma, IDH1/2 mutations (IDH1/2MUT) occur in substantial percentages in various other tumor types, such as acute myeloid leukemia (20-40%), chondrosarcoma (60%), intrahepatic cholangiocarcinoma (20%) and melanoma (5-10%).	('chondrosarcoma', 'Phenotype', 'HP:0006765', (156, 170))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (123, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('IDH1/2MUT', 'Gene', '3417', (41, 50))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (178, 209))	('IDH1/2', 'Gene', '3417;3418', (23, 29))	('IDH1/2MUT', 'Gene', (41, 50))	('intrahepatic cholangiocarcinoma', 'Disease', (178, 209))	('IDH1/2', 'Gene', (23, 29))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (191, 209))	('acute myeloid leukemia', 'Disease', (123, 145))	('chondrosarcoma', 'Disease', 'MESH:D002813', (156, 170))	('mutations', 'Var', (30, 39))	('chondrosarcoma', 'Disease', (156, 170))	('tumor', 'Disease', (102, 107))	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (129, 145))	('IDH1/2', 'Gene', '3417;3418', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('glioma', 'Disease', (15, 21))	('IDH1/2', 'Gene', (41, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (123, 145))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))
103758	28467784	The mutations lead to a neomorphic activity of the enzyme that converts alpha-KG into the oncometabolite D-2-hydroxyglutarate (D-2-HG).	('alpha-KG', 'Chemical', 'MESH:D007656', (72, 80))	('D-2-HG', 'Chemical', 'MESH:C019417', (127, 133))	('neomorphic activity', 'MPA', (24, 43))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (105, 125))	('converts', 'MPA', (63, 71))	('lead to', 'Reg', (14, 21))	('mutations', 'Var', (4, 13))
103760	28467784	IDH1/2MUT changes cellular metabolism via 4 mechanisms: 1) loss of wild-type IDH1/2 (IDH1/2WT) function that affects carbohydrate and NADP+/NADPH metabolism; 2) accumulation of D-2-HG that further restricts the activity of various enzymes such as alpha-ketoglutarate dehydrogenase (alpha-KGDH), succinate dehydrogenase (SDH) and complex IV of the mitochondrial electron transport chain, 3) epigenetic effects of D-2-HG on expression of genes involved in metabolism and 4) increased degradation of the hypoxia-response transcription factor HIF-1alpha, a major inducer of expression of genes involved in glycolysis.	('affects', 'Reg', (109, 116))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('D-2-HG', 'Var', (412, 418))	('D-2-HG', 'Chemical', 'MESH:C019417', (412, 418))	('degradation', 'MPA', (482, 493))	('cellular', 'MPA', (18, 26))	('IDH1/2MUT', 'Gene', '3417', (0, 9))	('hypoxia', 'Disease', (501, 508))	('SDH', 'Gene', (320, 323))	('IDH1/2MUT', 'Gene', (0, 9))	('IDH1/2', 'Gene', (0, 6))	('IDH1/2WT', 'Gene', '3417', (85, 93))	('alpha-KG', 'Chemical', 'MESH:D007656', (282, 290))	('IDH1/2', 'Gene', '3417;3418', (85, 91))	('IDH1/2', 'Gene', '3417;3418', (77, 83))	('succinate dehydrogenase', 'Gene', (295, 318))	('expression', 'MPA', (422, 432))	('IDH1/2', 'Gene', (85, 91))	('IDH1/2', 'Gene', (77, 83))	('increased', 'PosReg', (472, 481))	('hypoxia', 'Disease', 'MESH:D000860', (501, 508))	('restricts', 'NegReg', (197, 206))	('NADP+', 'Chemical', 'MESH:D009249', (134, 139))	('HIF-1alpha', 'Gene', '3091', (539, 549))	('activity', 'MPA', (211, 219))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (247, 266))	('succinate dehydrogenase', 'Gene', '6390', (295, 318))	('D-2-HG', 'Chemical', 'MESH:C019417', (177, 183))	('NADPH', 'Chemical', 'MESH:D009249', (140, 145))	('SDH', 'Gene', '6390', (320, 323))	('IDH1/2WT', 'Gene', (85, 93))	('HIF-1alpha', 'Gene', (539, 549))
103827	28467784	There is a scarcity of relevant models to study metabolic effects of IDH mutations in vitro.	('IDH', 'Gene', (69, 72))	('mutations', 'Var', (73, 82))	('IDH', 'Gene', '3417', (69, 72))
103828	28467784	As an alternative we used the HCT116-IDH1R132H knock in cell line and its parental counterpart to investigate whether metabolic changes in IDH1R132H gliomas were reflected in this isogenic cell line pair too.	('gliomas', 'Disease', (149, 156))	('HCT116', 'CellLine', 'CVCL:0291', (30, 36))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('IDH1R132H', 'Var', (139, 148))
103837	28467784	Taken together, we show that relative to IDH1WT cells, IDH1MUT cells are dependent on OXPHOS and inhibition of the IDH1MUT decreases the oxygen consumption leading to a glycolytic phenotype.	('inhibition', 'Var', (97, 107))	('decreases', 'NegReg', (123, 132))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', (115, 119))	('oxygen', 'Chemical', 'MESH:D010100', (137, 143))	('IDH1', 'Gene', '3417', (115, 119))	('oxygen consumption', 'MPA', (137, 155))	('IDH1', 'Gene', (41, 45))	('glycolytic phenotype', 'MPA', (169, 189))	('IDH1', 'Gene', '3417', (41, 45))	('IDH1', 'Gene', (55, 59))
103848	28467784	In line with this notion, silencing of HK2 increases oxygen consumption and decreases lactate production in glioblastoma cells.	('oxygen consumption', 'MPA', (53, 71))	('lactate production', 'MPA', (86, 104))	('decreases', 'NegReg', (76, 85))	('HK2', 'Gene', (39, 42))	('HK2', 'Gene', '3099', (39, 42))	('decreases lactate', 'Phenotype', 'HP:0030086', (76, 93))	('increases', 'PosReg', (43, 52))	('glioblastoma', 'Disease', (108, 120))	('silencing', 'Var', (26, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('lactate', 'Chemical', 'MESH:D019344', (86, 93))	('oxygen', 'Chemical', 'MESH:D010100', (53, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
103851	28467784	Our results also support previous reports that show that IDH1MUT gliomas silence LDHA expression through hypermethylation of its promoter resulting in a low LDHA/LDHB ratio compared with IDH1WT glioma or normal brain tissue.	('IDH1WT glioma', 'Disease', 'MESH:D005910', (187, 200))	('LDHA', 'Gene', '3939', (157, 161))	('IDH1WT glioma', 'Disease', (187, 200))	('silence', 'NegReg', (73, 80))	('LDHA', 'Gene', (81, 85))	('low', 'NegReg', (153, 156))	('IDH1MUT glioma', 'Disease', 'MESH:D005910', (57, 71))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('LDHA', 'Gene', (157, 161))	('gliomas', 'Disease', (65, 72))	('expression', 'MPA', (86, 96))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('LDHA', 'Gene', '3939', (81, 85))	('IDH1MUT glioma', 'Disease', (57, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('LDHB', 'Gene', (162, 166))	('hypermethylation', 'Var', (105, 121))	('LDHB', 'Gene', '3945', (162, 166))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
103861	28467784	Due to the lack of stable glioma cell cultures carrying an endogenous IDH1R132H allele, we used in vitro HCT116 colorectal carcinoma cells for functional studies.	('HCT116', 'CellLine', 'CVCL:0291', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('colorectal carcinoma', 'Disease', (112, 132))	('glioma', 'Disease', (26, 32))	('IDH1R132H', 'Var', (70, 79))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (112, 132))
103864	28467784	Previous reports have shown that HCT116 IDH1MUT cells have reduced growth rates as compared to IDH1WT cells under conditions of low oxygen tension suggesting that these are more dependent on OXPHOS.	('reduced growth rates', 'Phenotype', 'HP:0001510', (59, 79))	('reduced', 'NegReg', (59, 66))	('IDH1', 'Gene', (40, 44))	('HCT116', 'Var', (33, 39))	('low oxygen tension', 'Phenotype', 'HP:0012418', (128, 146))	('IDH1', 'Gene', '3417', (40, 44))	('growth rates', 'MPA', (67, 79))	('IDH1', 'Gene', (95, 99))	('oxygen', 'Chemical', 'MESH:D010100', (132, 138))	('IDH1', 'Gene', '3417', (95, 99))	('HCT116', 'CellLine', 'CVCL:0291', (33, 39))
103870	28467784	In line with our observations, a recent study demonstrated that IDH1MUT overexpression in astrocytes results in increased PC expression and increased fractional flux through PC, suggesting that direct oxaloacetate production from pyruvate is critical for IDH1MUT cancer cells to maintain TCA activity.	('PC', 'Gene', '5091', (174, 176))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('overexpression', 'Var', (72, 86))	('cancer', 'Disease', (263, 269))	('pyruvate', 'Chemical', 'MESH:D019289', (230, 238))	('IDH1', 'Gene', (64, 68))	('oxaloacetate', 'Chemical', 'MESH:D062907', (201, 213))	('expression', 'MPA', (125, 135))	('IDH1', 'Gene', '3417', (64, 68))	('increased', 'PosReg', (112, 121))	('IDH1', 'Gene', (255, 259))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('increased', 'PosReg', (140, 149))	('IDH1', 'Gene', '3417', (255, 259))	('PC', 'Gene', '5091', (122, 124))	('TCA', 'Chemical', 'MESH:D014233', (288, 291))
103876	28467784	did not stratify their glioblastoma cohort based on IDH1MUT status but demonstrated higher expression of ACSS2 in glioblastoma than in grade II and III glioma and high ACSS2 expression in LGG patients with poor survival as opposed to low ACSS2 expression in LGG patients with prolonged survival.	('expression', 'MPA', (91, 101))	('IDH1', 'Gene', '3417', (52, 56))	('ACSS2', 'Gene', (238, 243))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('higher', 'PosReg', (84, 90))	('ACSS2', 'Gene', '55902', (105, 110))	('glioblastoma', 'Disease', (114, 126))	('ACSS2', 'Gene', '55902', (168, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('LGG', 'Disease', (188, 191))	('ACSS2', 'Gene', '55902', (238, 243))	('expression', 'MPA', (174, 184))	('glioma', 'Disease', (152, 158))	('patients', 'Species', '9606', (192, 200))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('IDH1', 'Gene', (52, 56))	('high', 'Var', (163, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('ACSS2', 'Gene', (105, 110))	('ACSS2', 'Gene', (168, 173))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('patients', 'Species', '9606', (262, 270))	('glioblastoma', 'Disease', (23, 35))
103907	33213447	Unexpectedly, a number of alterations in basal-like breast cancer were identified that distinguished it from other subtypes, which could bring future clinical benefits.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('fits', 'Disease', 'MESH:D012640', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('alterations', 'Var', (26, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('fits', 'Disease', (163, 167))
103911	33213447	It postulates that carcinogenesis is determined by alterations in cancer regulatory genes, of which two crucial groups are tumor suppressors and oncogenes, both responsible for apoptosis and proliferation regulation being utmost importance in the model of cancer platform.	('alterations', 'Var', (51, 62))	('tumor', 'Disease', (123, 128))	('carcinogenesis', 'Disease', (19, 33))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (66, 72))
103918	33213447	GCCN3/4GGC, GCCN3/4GGG or CCCCAGGC while the binding of transcription factors' themselves is dictated by a proline-rich motif located in the activation domain (excluding AP-2delta, which lacks these critical residues).	('GGC', 'Gene', (7, 10))	('AP-2delta', 'Gene', (170, 179))	('binding', 'Interaction', (45, 52))	('GGC', 'Gene', (31, 34))	('GGC', 'Gene', '79017', (7, 10))	('GGC', 'Gene', '79017', (31, 34))	('AP-2delta', 'Gene', '83741', (170, 179))	('proline', 'Chemical', 'MESH:D011392', (107, 114))	('GCCN3/4GGG', 'Var', (12, 22))
103921	33213447	It was suggested that in the case of mutation, the loss of TF activity of AP-2 members can lead to the impairment of proliferation, differentiation and apoptosis processes, suggesting AP-2 activity may play role in development.	('impairment', 'NegReg', (103, 113))	('AP-2', 'Gene', '7020', (184, 188))	('proliferation', 'CPA', (117, 130))	('activity', 'MPA', (62, 70))	('mutation', 'Var', (37, 45))	('apoptosis processes', 'CPA', (152, 171))	('AP-2', 'Gene', '7020', (74, 78))	('AP-2', 'Gene', (184, 188))	('AP-2', 'Gene', (74, 78))	('loss', 'NegReg', (51, 55))
103925	33213447	The other case of chemoresistance (to 5-fluorouracil) was shown in colorectal cancer upregulating AP-2gamma while endometrial cancer example demonstrated that knockdown of this AP-2 member sensitizes cells to megestrol acetate via Estrogen receptor alpha (ERalpha) expression upregulation.	('AP-2', 'Gene', (98, 102))	('megestrol acetate', 'Chemical', 'MESH:D019290', (209, 226))	('upregulating', 'PosReg', (85, 97))	('AP-2', 'Gene', (177, 181))	('ERalpha', 'Gene', '2099', (256, 263))	('AP-2gamma', 'Gene', '7022', (98, 107))	('AP-2gamma', 'Gene', (98, 107))	('upregulation', 'PosReg', (276, 288))	('AP-2', 'Gene', '7020', (98, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('Estrogen receptor alpha', 'Gene', '2099', (231, 254))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('AP-2', 'Gene', '7020', (177, 181))	('Estrogen receptor alpha', 'Gene', (231, 254))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (38, 52))	('endometrial cancer', 'Phenotype', 'HP:0012114', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('sensitizes', 'Reg', (189, 199))	('knockdown', 'Var', (159, 168))	('endometrial cancer', 'Disease', (114, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('endometrial cancer', 'Disease', 'MESH:D016889', (114, 132))	('ERalpha', 'Gene', (256, 263))	('colorectal cancer', 'Disease', (67, 84))
103932	33213447	Latest data regarding contribution in cancer indicates that AP-2beta overexpression has been found to promote tumor growth in both breast and thyroid cancer and predicted poor prognosis or tumor progression, respectively.	('tumor', 'Disease', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('overexpression', 'Var', (69, 83))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('promote', 'PosReg', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (150, 156))	('AP-2beta', 'Gene', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancer', 'Disease', (38, 44))	('breast and thyroid cancer', 'Disease', 'MESH:D001943', (131, 156))	('AP-2beta', 'Gene', '7021', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
104000	33213447	Among the others, signaling pathways such as Wnt, Notch (for KIRP) or ERBB (for BRCA) were implicated in explanation which is coherent with other research.	('BRCA', 'Gene', '672', (80, 84))	('ERBB', 'Gene', '1956', (70, 74))	('BRCA', 'Gene', (80, 84))	('Notch', 'Var', (50, 55))	('ERBB', 'Gene', (70, 74))
104011	33213447	Nevertheless, the tumors could be distinguished using modules 2, 11 and 19 which included genes related to cell adhesion, regulation of cell cycle arrest and inactivation of MAPK activity.	('activity', 'MPA', (179, 187))	('arrest', 'Disease', (147, 153))	('MAPK', 'Gene', (174, 178))	('inactivation', 'Var', (158, 170))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('arrest', 'Disease', 'MESH:D006323', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
104021	33213447	The last mentioned might be supported by a threefold difference in the frequency of EGFR mutations between LUSC and LUAD during a previous pan-cancer analysis.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (143, 149))	('EGFR', 'Gene', (84, 88))
104041	31991588	However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies.	('lower', 'NegReg', (63, 68))	('higher', 'PosReg', (136, 142))	('clinical', 'Species', '191496', (9, 17))	('anti-CTLA-4 antibodies', 'Var', (36, 58))	('PD-1', 'Gene', (158, 162))	('clinical response', 'CPA', (9, 26))	('antibodies', 'Var', (48, 58))	('immunotherapy-related adverse events', 'Disease', (88, 124))	('PD-1', 'Gene', '6622', (158, 162))
104043	31991588	To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment.	('therapeutic responses', 'CPA', (198, 219))	('CD80', 'Gene', '941', (146, 150))	('anti-CTLA-4 antibodies', 'Var', (161, 183))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('interaction', 'Interaction', (108, 119))	('CD86', 'Gene', '942', (155, 159))	('CD80', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('CD86', 'Gene', (155, 159))	('tumor', 'Disease', (277, 282))	('depletion', 'NegReg', (238, 247))	('antibodies', 'Var', (173, 183))
104044	31991588	Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP).	('cytotoxicity', 'Disease', 'MESH:D064420', (138, 150))	('reduced', 'NegReg', (79, 86))	('enhanced', 'PosReg', (96, 104))	('irAE', 'MPA', (87, 91))	('antibodies', 'Var', (63, 73))	('cytotoxicity', 'Disease', (138, 150))	('anti-CTLA-4', 'Gene', (51, 62))	('anti-CTLA-4 antibodies', 'Var', (51, 73))
104049	31991588	Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (14, 43))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (14, 43))	('anti-CTLA-4', 'Var', (92, 103))	('NSCLC', 'Disease', (45, 50))	('non-small cell lung carcinoma', 'Disease', (14, 43))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (18, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
104050	31991588	Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg.	('NSCLC', 'Disease', (56, 61))	('anti-CTLA-4', 'Gene', (109, 120))	('anti-CTLA-4 antibodies', 'Var', (109, 131))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('human', 'Species', '9606', (50, 55))	('antibodies', 'Var', (121, 131))	('Treg', 'Chemical', '-', (168, 172))	('tumor', 'Disease', (160, 165))	('deplete', 'NegReg', (147, 154))
104051	31991588	Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (66, 95))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (66, 95))	('anti-CTLA-4', 'Gene', (139, 150))	('non-small cell lung carcinoma', 'Disease', (66, 95))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (70, 95))	('anti-CTLA-4', 'Var', (139, 150))
104052	31991588	Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('anti-CTLA-4', 'Var', (82, 93))	('cancers', 'Disease', (71, 78))	('anti-CTLA-4', 'Gene', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
104054	31991588	As the first immune checkpoint explored for cancer immunotherapy, CTLA-4 was validated as an immunotherapeutic target after FDA approval of Ipilimumab for human use, either as monotherapy for melanoma, or as part of combination therapy with the anti-PD-1 antibody, Nivolumab, in melanoma, renal cancer, and colorectal cancer with microsatellite instability.	('cancer', 'Disease', (318, 324))	('colorectal cancer', 'Phenotype', 'HP:0003003', (307, 324))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (140, 150))	('cancer', 'Disease', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('PD-1', 'Gene', (250, 254))	('microsatellite instability', 'Var', (330, 356))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('renal cancer', 'Disease', (289, 301))	('renal cancer', 'Phenotype', 'HP:0009726', (289, 301))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('colorectal cancer', 'Disease', 'MESH:D015179', (307, 324))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('renal cancer', 'Disease', 'MESH:D007680', (289, 301))	('colorectal cancer', 'Disease', (307, 324))	('PD-1', 'Gene', '6622', (250, 254))	('Nivolumab', 'Chemical', 'MESH:D000077594', (265, 274))	('cancer', 'Disease', (44, 50))	('human', 'Species', '9606', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanoma', 'Disease', (279, 287))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
104058	31991588	An important development in cancer immunotherapy is a re-evaluation of the mechanism by which anti-CTLA-4 antibodies induce tumor rejection.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', (124, 129))	('anti-CTLA-4', 'Var', (94, 105))	('induce', 'PosReg', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('anti-CTLA-4', 'Gene', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
104060	31991588	Second, several groups, including ours, have reported that the therapeutic effect of anti-CTLA-4 antibodies requires ADCC activity that selectively depletes regulatory T cells in the tumor microenvironment.	('depletes', 'NegReg', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('ADCC', 'Protein', (117, 121))	('anti-CTLA-4', 'Gene', (85, 96))	('anti-CTLA-4 antibodies', 'Var', (85, 107))	('tumor', 'Disease', (183, 188))	('regulatory T cells', 'MPA', (157, 175))	('antibodies', 'Var', (97, 107))
104061	31991588	These two lines of fundamental studies have inspired the development of the next generation of anti-CTLA-4 antibodies with enhanced ADCC activity or preferential activation in the tumor microenvironment.	('enhanced', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('anti-CTLA-4', 'Gene', (95, 106))	('tumor', 'Disease', (180, 185))	('activity', 'MPA', (137, 145))	('ADCC', 'Protein', (132, 136))	('anti-CTLA-4', 'Var', (95, 106))
104092	31991588	Cells were stained with fluorochrome-conjugated monoclonal antibodies against mouse CD8 (Cat# 100748, Biolegend, Cat# 45-0081-82, eBioscience), mouse CD4 (Cat# 100453, Biolegend, Cat# 100531, Biolegend), mouse CD45 (Cat# 103151, Biolegend, Cat# 47-0451-82, eBioscience), mouse Foxp3 (Cat# 48-5773-82, Thermo Fisher Scientific, Cat# 17-5773-82, eBioscience), human CTLA-4 (Cat# 369604, Biolegend), and Mouse IgG2a, kappa Isotype Ctrl CTLA-4 (Cat# 400214, Biolegend).	('mouse', 'Species', '10090', (144, 149))	('CD8', 'Gene', '925', (84, 87))	('CD45', 'Gene', '19264', (210, 214))	('mouse', 'Species', '10090', (271, 276))	('Mouse', 'Species', '10090', (401, 406))	('IgG2a', 'Gene', '668478', (407, 412))	('Cat', 'Var', (216, 219))	('IgG2a', 'Gene', (407, 412))	('mouse', 'Species', '10090', (204, 209))	('mouse', 'Species', '10090', (78, 83))	('human', 'Species', '9606', (358, 363))	('Cat# 369604', 'Var', (372, 383))	('CD8', 'Gene', (84, 87))	('CD45', 'Gene', (210, 214))
104098	31991588	We used the following formula to estimate the total ranking number for each cancer type: where the RANKADCC represents the "ADCC Features" partitioning, that was the mean value of 3 ranking numbers based on the estimated cell fraction of Treg cells, FCGR3A gene expression, and FCGR3A SNP rate for V158F.	('FCGR3A', 'Gene', '2214', (250, 256))	('Treg', 'Chemical', '-', (238, 242))	('FCGR3A', 'Gene', '2214', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FCGR3A', 'Gene', (250, 256))	('V158F', 'Mutation', 'rs396991', (298, 303))	('V158F', 'Var', (298, 303))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FCGR3A', 'Gene', (278, 284))
104105	31991588	We and others have previously reported that anti-CTLA-4 antibodies, including Ipilimumab selectively depleted Treg in the mouse tumor microenvironment but not in the spleen.	('Treg', 'CPA', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('anti-CTLA-4', 'Gene', (44, 55))	('Treg', 'Chemical', '-', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (78, 88))	('antibodies', 'Var', (56, 66))	('tumor', 'Disease', (128, 133))	('depleted', 'NegReg', (101, 109))	('mouse', 'Species', '10090', (122, 127))
104106	31991588	More recently, we reported that pH-sensitive anti-CTLA-4 antibodies are more effective in ADCC and tumor rejection, which raise the issue as to whether increasing ADCC activity jeopardizes the selectivity of the antibodies.	('antibodies', 'Var', (57, 67))	('tumor', 'Disease', (99, 104))	('ADCC', 'Disease', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('anti-CTLA-4', 'Gene', (45, 56))
104154	31991588	The increased mutation rates lead to an expanded pool of potential neo-tumor antigens that also correlate with responsiveness to Ipilimumab (Supplementary Materials Figure S2A).	('Ipilimumab', 'Chemical', 'MESH:D000074324', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutation', 'Var', (14, 22))	('tumor', 'Disease', (71, 76))
104180	31991588	Since this population also expressed the highest levels of CTLA-4 (Figure 6c), it is liely that ADCC-competent anti-CTLA-4 would be highly selective for activated Treg in NSCLC.	('NSCLC', 'Disease', (171, 176))	('Treg', 'Chemical', '-', (163, 167))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('anti-CTLA-4', 'Var', (111, 122))
104190	31991588	In addition, in a mouse model with the human FcR system, it was demonstrated that binding to FCGRIIIA is critical for optimal ADCC of Treg and tumor rejection by anti-CTLA-4 antibodies.	('tumor', 'Disease', (143, 148))	('mouse', 'Species', '10090', (18, 23))	('Treg', 'Chemical', '-', (134, 138))	('Treg', 'CPA', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('anti-CTLA-4', 'Var', (162, 173))	('human', 'Species', '9606', (39, 44))	('binding', 'Interaction', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('anti-CTLA-4', 'Gene', (162, 173))
104202	31991588	Therefore, it is likely multiple cancer types may well respond to anti-CTLA-4 therapy if appropriate antibodies are employed.	('anti-CTLA-4', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('multiple cancer', 'Disease', 'MESH:D009369', (24, 39))	('multiple cancer', 'Disease', (24, 39))
104205	31991588	Our re-analysis of scRNAseq data of tumor-infiltrating T cells in NSCLC patients suggests that selective Treg depletion is achievable with anti-CTLA-4 antibodies.	('Treg', 'Chemical', '-', (105, 109))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('depletion', 'NegReg', (110, 119))	('tumor', 'Disease', (36, 41))	('anti-CTLA-4', 'Var', (139, 150))	('patients', 'Species', '9606', (72, 80))
104206	31991588	While the high ranking suggests NSCLC as a prime candidate for new anti-CTLA-4 antibodies, it is worth considering the fact that multiple randomized trials have failed to show significant improvement in survival of patients receiving Ipilimumab in combination with chemotherapy.	('patients', 'Species', '9606', (215, 223))	('anti-CTLA-4', 'Gene', (67, 78))	('NSCLC', 'Disease', (32, 37))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (234, 244))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('anti-CTLA-4', 'Var', (67, 78))
104209	31991588	Therefore, a new generation of anti-CTLA-4 antibodies must show higher anti-tumor activity in order to achieve better outcomes.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('anti-CTLA-4', 'Var', (31, 42))	('tumor', 'Disease', (76, 81))	('anti-CTLA-4', 'Gene', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
104212	31991588	In this context, we recently showed that increasing pH sensitivity of anti-CTLA-4 antibodies improves both therapeutic effect and safety when compared directly with Ipilimumab.	('therapeutic effect', 'CPA', (107, 125))	('safety', 'CPA', (130, 136))	('antibodies', 'Var', (82, 92))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (165, 175))	('anti-CTLA-4', 'Gene', (70, 81))	('anti-CTLA-4 antibodies', 'Var', (70, 92))	('improves', 'PosReg', (93, 101))
104213	31991588	Since Treg has been implicated in pathogenesis and prognosis of multiple cancer types, it is anticipated that anti-CTLA-4 antibodies that effectively and selectively deplete Treg in tumor microenvironment would have a broad impact in cancer immunotherapy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('multiple cancer', 'Disease', (64, 79))	('tumor', 'Disease', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('antibodies', 'Var', (122, 132))	('deplete', 'NegReg', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Treg', 'Chemical', '-', (174, 178))	('multiple cancer', 'Disease', 'MESH:D009369', (64, 79))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Treg', 'Chemical', '-', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cancer', 'Disease', (234, 240))	('Treg', 'Protein', (174, 178))	('anti-CTLA-4', 'Gene', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
104214	31991588	In summary, our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies.	('anti-CTLA-4', 'Gene', (138, 149))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (65, 94))	('non-small cell lung carcinoma', 'Disease', (65, 94))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (69, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('anti-CTLA-4', 'Var', (138, 149))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (65, 94))
104222	31991588	TCGA The Cancer Genome Atlas  GSEA Gene-set Enrichment Analysis  ADCC Antibody Dependent Cell-mediated Cytotoxicity/phagocytosis  ADCP Antibody Dependent Cell-mediated Phagocytosis  NSCLC Non Small Cell Lung Cancer  TMB Tumor Mutation Burden	('Cancer Genome Atlas', 'Disease', (9, 28))	('Cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('NSCLC', 'Disease', (182, 187))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (9, 28))	('TMB', 'Chemical', '-', (216, 219))	('Tumor', 'Phenotype', 'HP:0002664', (220, 225))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('Mutation', 'Var', (226, 234))	('Cytotoxicity', 'Disease', (103, 115))	('Non Small Cell Lung Cancer  TMB Tumor', 'Disease', (188, 225))	('Lung Cancer', 'Phenotype', 'HP:0100526', (203, 214))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (192, 214))	('GSEA', 'Chemical', '-', (30, 34))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))
104223	22080945	Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2 IDH1/2 mutations occur in up to 70% of low-grade gliomas and secondary glioblastomas.	('d', 'Chemical', 'MESH:D003903', (113, 114))	('glioblastomas', 'Phenotype', 'HP:0012174', (138, 151))	('IDH1', 'Gene', '3417', (67, 71))	('gliomas', 'Disease', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('cancer', 'Disease', (8, 14))	('IDH1', 'Gene', (54, 58))	('d', 'Chemical', 'MESH:D003903', (126, 127))	('d', 'Chemical', 'MESH:D003903', (6, 7))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('IDH1/2', 'Gene', '3417;3418', (67, 73))	('mutant', 'Var', (47, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('gliomas', 'Disease', (34, 41))	('glioblastomas', 'Disease', (138, 151))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH1/2', 'Gene', (67, 73))	('d', 'Chemical', 'MESH:D003903', (133, 134))	('IDH1', 'Gene', '3417', (54, 58))	('occur', 'Reg', (84, 89))	('glioblastomas', 'Disease', 'MESH:D005909', (138, 151))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('IDH1', 'Gene', (67, 71))	('mutations', 'Var', (74, 83))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
104224	22080945	Mutation of these enzymes reduces the wildtype function of the enzyme (conversion of isocitrate to alpha-ketoglutarate) while conferring a new enzymatic function, the production of d-2-hydroxyglutarate (d-2-HG) from alpha-ketoglutarate (alpha-KG).	('alpha-KG', 'Chemical', 'MESH:D007656', (237, 245))	('d-2-hydroxyglutarate', 'Gene', (181, 201))	('d', 'Chemical', 'MESH:D003903', (181, 182))	('wildtype function', 'MPA', (38, 55))	('Mutation', 'Var', (0, 8))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (99, 118))	('d', 'Chemical', 'MESH:D003903', (203, 204))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('d-2-HG', 'Chemical', 'MESH:C019417', (203, 209))	('d-2-hydroxyglutarate', 'Gene', '1734', (181, 201))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('isocitrate', 'Chemical', 'MESH:C034219', (85, 95))	('reduces', 'NegReg', (26, 33))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (216, 235))	('d', 'Chemical', 'MESH:D003903', (170, 171))	('d', 'Chemical', 'MESH:D003903', (187, 188))	('production of', 'MPA', (167, 180))
104226	22080945	Here, we discuss the recent studies that demonstrate how IDH1/2 mutation may alter the metabolism and epigenome of gliomas, how these changes may contribute to tumor formation, and opportunities they might provide for molecular targeting.	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('gliomas', 'Disease', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('contribute', 'Reg', (146, 156))	('mutation', 'Var', (64, 72))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('d', 'Chemical', 'MESH:D003903', (179, 180))	('d', 'Chemical', 'MESH:D003903', (100, 101))	('IDH1/2', 'Gene', '3417;3418', (57, 63))	('tumor', 'Disease', (160, 165))	('IDH1/2', 'Gene', (57, 63))	('alter', 'Reg', (77, 82))	('metabolism', 'MPA', (87, 97))	('d', 'Chemical', 'MESH:D003903', (211, 212))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('epigenome', 'MPA', (102, 111))	('d', 'Chemical', 'MESH:D003903', (9, 10))
104227	22080945	Metabolomic studies of IDH1/2 mutant cells have revealed alterations in glutamine, fatty acid, and citrate synthesis pathways.	('glutamine', 'Chemical', 'MESH:D005973', (72, 81))	('IDH1/2', 'Gene', '3417;3418', (23, 29))	('d', 'Chemical', 'MESH:D003903', (92, 93))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('fatty acid', 'Chemical', 'MESH:D005227', (83, 93))	('alterations', 'Reg', (57, 68))	('IDH1/2', 'Gene', (23, 29))	('d', 'Chemical', 'MESH:D003903', (97, 98))	('glutamine', 'Pathway', (72, 81))	('citrate', 'Pathway', (99, 106))	('citrate', 'Chemical', 'MESH:D019343', (99, 106))	('fatty acid', 'Pathway', (83, 93))	('mutant', 'Var', (30, 36))	('d', 'Chemical', 'MESH:D003903', (15, 16))
104228	22080945	Additionally, d-2-HG produced by IDH1/2 mutant cells can competitively inhibit alpha-KG-dependent enzymes, including histone demethylases and DNA hydroxylases, potentially leading to a distinct epigenetic phenotype.	('d', 'Chemical', 'MESH:D003903', (88, 89))	('d', 'Chemical', 'MESH:D003903', (2, 3))	('d', 'Chemical', 'MESH:D003903', (112, 113))	('inhibit', 'NegReg', (71, 78))	('d', 'Chemical', 'MESH:D003903', (175, 176))	('d-2-HG', 'Chemical', 'MESH:C019417', (14, 20))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('histone demethylases', 'Enzyme', (117, 137))	('d', 'Chemical', 'MESH:D003903', (14, 15))	('mutant', 'Var', (40, 46))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('d', 'Chemical', 'MESH:D003903', (125, 126))	('d', 'Chemical', 'MESH:D003903', (140, 141))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('DNA hydroxylases', 'Enzyme', (142, 158))	('alpha-KG', 'Chemical', 'MESH:D007656', (79, 87))	('IDH1/2', 'Gene', '3417;3418', (33, 39))	('leading to', 'Reg', (172, 182))	('alpha-KG-dependent enzymes', 'Enzyme', (79, 105))	('d', 'Chemical', 'MESH:D003903', (148, 149))	('IDH1/2', 'Gene', (33, 39))	('d', 'Chemical', 'MESH:D003903', (185, 186))	('epigenetic phenotype', 'MPA', (194, 214))	('d', 'Chemical', 'MESH:D003903', (1, 2))
104231	22080945	Studies of IDH1/2 mutations have provided mechanistic insights into tumorigenesis and potential avenues for therapeutic intervention.	('tumor', 'Disease', (68, 73))	('d', 'Chemical', 'MESH:D003903', (40, 41))	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('d', 'Chemical', 'MESH:D003903', (3, 4))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('IDH1/2', 'Gene', (11, 17))	('d', 'Chemical', 'MESH:D003903', (84, 85))	('mutations', 'Var', (18, 27))
104232	22080945	Further study of IDH1/2 mutations might allow for improved therapeutic strategies.	('d', 'Chemical', 'MESH:D003903', (57, 58))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('IDH1/2', 'Gene', (17, 23))	('d', 'Chemical', 'MESH:D003903', (11, 12))	('mutations', 'Var', (24, 33))
104237	22080945	TP53, EGFRvIII, and PI3KCA) and led to the discovery of acquired mutations in IDH1, which were not previously known or associated with cancer.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Disease', (135, 141))	('TP53', 'Gene', (0, 4))	('d', 'Chemical', 'MESH:D003903', (43, 44))	('d', 'Chemical', 'MESH:D003903', (30, 31))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('IDH1', 'Gene', (78, 82))	('d', 'Chemical', 'MESH:D003903', (63, 64))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('IDH1', 'Gene', '3417', (78, 82))	('d', 'Chemical', 'MESH:D003903', (18, 19))	('d', 'Chemical', 'MESH:D003903', (128, 129))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('mutations', 'Var', (65, 74))	('associated', 'Reg', (119, 129))
104238	22080945	Subsequent studies discovered mutations in IDH2, the mitochondrial homolog of IDH1.	('d', 'Chemical', 'MESH:D003903', (19, 20))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('IDH2', 'Gene', (43, 47))	('IDH1', 'Gene', (78, 82))	('d', 'Chemical', 'MESH:D003903', (14, 15))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('IDH1', 'Gene', '3417', (78, 82))	('IDH2', 'Gene', '3418', (43, 47))	('mutations', 'Var', (30, 39))
104239	22080945	The role of IDH1/2 mutation in tumorigenesis and tumor maintenance is unclear, but recent findings have implicated altered metabolism, modified epigenetic states, and possible connections between the two as potential tumorigenic mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('d', 'Chemical', 'MESH:D003903', (137, 138))	('d', 'Chemical', 'MESH:D003903', (113, 114))	('metabolism', 'MPA', (123, 133))	('d', 'Chemical', 'MESH:D003903', (142, 143))	('tumor', 'Disease', (217, 222))	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('d', 'Chemical', 'MESH:D003903', (47, 48))	('d', 'Chemical', 'MESH:D003903', (165, 166))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('epigenetic states', 'MPA', (144, 161))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('IDH1/2', 'Gene', (12, 18))	('modified', 'Reg', (135, 143))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (31, 36))	('altered', 'Reg', (115, 122))	('connections', 'Interaction', (176, 187))	('d', 'Chemical', 'MESH:D003903', (121, 122))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
104245	22080945	However, relatively few mutations in genes encoding metabolic enzymes are known to contribute to oncogenesis.	('mutations', 'Var', (24, 33))	('contribute', 'Reg', (83, 93))	('d', 'Chemical', 'MESH:D003903', (47, 48))
104247	22080945	SDH and fumarate dehydrogenase mutations are associated with familial cancer syndromes and lead to enzymatic inactivation with subsequent accumulation of their substrates, succinate and fumarate.	('accumulation', 'PosReg', (138, 150))	('d', 'Chemical', 'MESH:D003903', (89, 90))	('d', 'Chemical', 'MESH:D003903', (17, 18))	('enzymatic', 'MPA', (99, 108))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('fumarate', 'MPA', (186, 194))	('SDH', 'Gene', '6390', (0, 3))	('d', 'Chemical', 'MESH:D003903', (6, 7))	('d', 'Chemical', 'MESH:D003903', (94, 95))	('mutations', 'Var', (31, 40))	('d', 'Chemical', 'MESH:D003903', (54, 55))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SDH', 'Gene', (0, 3))	('associated', 'Reg', (45, 55))	('d', 'Chemical', 'MESH:D003903', (21, 22))	('fumarate', 'Chemical', 'MESH:D005650', (186, 194))	('familial cancer syndromes', 'Disease', (61, 86))	('succinate', 'Chemical', 'MESH:D019802', (172, 181))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (61, 86))	('fumarate', 'Chemical', 'MESH:D005650', (8, 16))	('succinate', 'MPA', (172, 181))	('substrates', 'MPA', (160, 170))	('d', 'Chemical', 'MESH:D003903', (184, 185))
104250	22080945	Inhibition of PHD2 in the presence of sufficient oxygen leads to increased HIF-1alpha and promotes tumorigenesis through increased glycolysis and angiogenesis.	('d', 'Chemical', 'MESH:D003903', (88, 89))	('HIF-1alpha', 'Gene', '3091', (75, 85))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('d', 'Chemical', 'MESH:D003903', (144, 145))	('PHD2', 'Gene', (14, 18))	('d', 'Chemical', 'MESH:D003903', (73, 74))	('tumor', 'Disease', (99, 104))	('HIF-1alpha', 'Gene', (75, 85))	('PHD2', 'Gene', '54583', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('glycolysis', 'MPA', (131, 141))	('increased', 'PosReg', (65, 74))	('increased', 'PosReg', (121, 130))	('d', 'Chemical', 'MESH:D003903', (59, 60))	('Inhibition', 'Var', (0, 10))	('promotes', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('oxygen', 'Chemical', 'MESH:D010100', (49, 55))	('angiogenesis', 'CPA', (146, 158))
104251	22080945	IDH1 mutations occur in up to 12% of all GBMs.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
104253	22080945	Mutations in IDH1/2 occur in up to 70% of low-grade gliomas and secondary GBMs.	('gliomas', 'Disease', (52, 59))	('occur', 'Reg', (20, 25))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('secondary GBMs', 'Disease', (64, 78))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('d', 'Chemical', 'MESH:D003903', (62, 63))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('d', 'Chemical', 'MESH:D003903', (69, 70))
104254	22080945	IDH1 and IDH2 mutations occur in 16% of acute myelogenous leukemias (AMLs) and up to 33% in AMLs with normal karyotypes, 56% of central and periosteal cartilaginous tumors, and 40% of gliomatosis cerebri cases.	('d', 'Chemical', 'MESH:D003903', (175, 176))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('IDH1', 'Gene', (0, 4))	('gliomatosis cerebri', 'Disease', 'MESH:D018302', (184, 203))	('acute myelogenous leukemias', 'Disease', (40, 67))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('d', 'Chemical', 'MESH:D003903', (7, 8))	('mutations', 'Var', (14, 23))	('cartilaginous tumors', 'Disease', (151, 171))	('IDH1', 'Gene', '3417', (0, 4))	('d', 'Chemical', 'MESH:D003903', (77, 78))	('gliomatosis cerebri', 'Disease', (184, 203))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (151, 171))	('d', 'Chemical', 'MESH:D003903', (138, 139))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('AMLs', 'Phenotype', 'HP:0004808', (69, 73))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('leukemias', 'Phenotype', 'HP:0001909', (58, 67))	('AMLs', 'Phenotype', 'HP:0004808', (92, 96))	('IDH2', 'Gene', (9, 13))	('AML', 'Disease', (69, 72))	('AML', 'Disease', 'MESH:D015470', (92, 95))	('IDH2', 'Gene', '3418', (9, 13))	('myelogenous leukemias', 'Phenotype', 'HP:0012324', (46, 67))	('acute myelogenous leukemias', 'Disease', 'MESH:D015470', (40, 67))	('AML', 'Disease', (92, 95))	('acute myelogenous leukemias', 'Phenotype', 'HP:0004808', (40, 67))
104256	22080945	IDH1/2 mutation may result in decreased prognosis for AML and increased prognosis for both low-grade gliomas (65 months for mutant IDH1/2 versus 38 months for wildtype) and secondary GBMs (31 months for mutant IDH1/2 versus 15 months for wildtype).	('gliomas', 'Disease', (101, 108))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('secondary GBMs', 'Disease', (173, 187))	('IDH1/2', 'Gene', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('IDH1/2', 'Gene', '3417;3418', (131, 137))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH1/2', 'Gene', (131, 137))	('AML', 'Disease', 'MESH:D015470', (54, 57))	('d', 'Chemical', 'MESH:D003903', (30, 31))	('IDH1/2', 'Gene', '3417;3418', (210, 216))	('d', 'Chemical', 'MESH:D003903', (171, 172))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('AML', 'Disease', (54, 57))	('IDH1/2', 'Gene', (210, 216))	('d', 'Chemical', 'MESH:D003903', (162, 163))	('decreased', 'NegReg', (30, 39))	('d', 'Chemical', 'MESH:D003903', (98, 99))	('d', 'Chemical', 'MESH:D003903', (60, 61))	('mutant', 'Var', (124, 130))	('d', 'Chemical', 'MESH:D003903', (178, 179))	('d', 'Chemical', 'MESH:D003903', (241, 242))	('mutation', 'Var', (7, 15))
104257	22080945	However, IDH1/2 mutant tumors may be recognized earlier than IDH1/2 wildtype tumors, resulting in an apparent, rather than real, association with increased survival.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('IDH1/2', 'Gene', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('d', 'Chemical', 'MESH:D003903', (46, 47))	('survival', 'MPA', (156, 164))	('d', 'Chemical', 'MESH:D003903', (71, 72))	('increased', 'PosReg', (146, 155))	('d', 'Chemical', 'MESH:D003903', (154, 155))	('IDH1/2', 'Gene', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutant', 'Var', (16, 22))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('IDH1/2', 'Gene', '3417;3418', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
104258	22080945	IDH1 mutations occur at a single amino acid residue, R132, whereas IDH2 mutations occur at two residues, R140 or R172 (the functional equivalent of R132 in IDH1).	('IDH1', 'Gene', (156, 160))	('IDH2', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (156, 160))	('d', 'Chemical', 'MESH:D003903', (99, 100))	('mutations', 'Var', (5, 14))	('d', 'Chemical', 'MESH:D003903', (42, 43))	('IDH2', 'Gene', '3418', (67, 71))	('d', 'Chemical', 'MESH:D003903', (48, 49))	('R132', 'Var', (53, 57))	('IDH1', 'Gene', (0, 4))	('R140', 'Var', (105, 109))	('R172', 'Var', (113, 117))	('IDH1', 'Gene', '3417', (0, 4))
104259	22080945	The most common mutation is the R132H IDH1 mutation.	('R132H', 'Mutation', 'rs121913500', (32, 37))	('R132H', 'Var', (32, 37))	('IDH1', 'Gene', '3417', (38, 42))	('IDH1', 'Gene', (38, 42))
104260	22080945	IDH1/2 mutations result in two enzymatic changes: decreased wildtype IDH function (oxidative decarboxylation of isocitrate to alpha-KG with simultaneous reduction of NADP+) and gain of a new enzymatic capability [reduction of alpha-KG to d-2-hydroxyglutarate (d-2-HG)] with simultaneous oxidation of NADPH (Fig.	('d', 'Chemical', 'MESH:D003903', (50, 51))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('d', 'Chemical', 'MESH:D003903', (175, 176))	('d', 'Chemical', 'MESH:D003903', (63, 64))	('d-2-hydroxyglutarate', 'Gene', (238, 258))	('alpha-KG', 'Chemical', 'MESH:D007656', (226, 234))	('IDH1/2', 'Gene', (0, 6))	('isocitrate', 'Chemical', 'MESH:C034219', (112, 122))	('d', 'Chemical', 'MESH:D003903', (238, 239))	('IDH', 'Gene', (0, 3))	('d', 'Chemical', 'MESH:D003903', (215, 216))	('d', 'Chemical', 'MESH:D003903', (244, 245))	('gain', 'PosReg', (177, 181))	('d', 'Chemical', 'MESH:D003903', (86, 87))	('NADP+', 'Chemical', 'MESH:D009249', (166, 171))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('d-2-hydroxyglutarate', 'Gene', '1734', (238, 258))	('mutations', 'Var', (7, 16))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (0, 3))	('d', 'Chemical', 'MESH:D003903', (260, 261))	('NADPH', 'Chemical', 'MESH:D009249', (300, 305))	('d', 'Chemical', 'MESH:D003903', (155, 156))	('d', 'Chemical', 'MESH:D003903', (290, 291))	('IDH', 'Gene', '3417', (69, 72))	('decreased', 'NegReg', (50, 59))	('d', 'Chemical', 'MESH:D003903', (58, 59))	('alpha-KG', 'Chemical', 'MESH:D007656', (126, 134))	('d-2-HG', 'Chemical', 'MESH:C019417', (260, 266))
104261	22080945	Changes in the active site of mutant IDH1/2 enzymes prime the enzyme to produce d-2-HG by increasing its affinity for alpha-KG and shifting the conformation of the enzyme to favor an intermediate transition state.	('produce d-2-HG', 'MPA', (72, 86))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('IDH1/2', 'Gene', (37, 43))	('affinity', 'MPA', (105, 113))	('d', 'Chemical', 'MESH:D003903', (190, 191))	('d-2-HG', 'Chemical', 'MESH:C019417', (80, 86))	('alpha-KG', 'Protein', (118, 126))	('d', 'Chemical', 'MESH:D003903', (75, 76))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('prime', 'PosReg', (52, 57))	('shifting', 'Reg', (131, 139))	('IDH1/2', 'Gene', '3417;3418', (37, 43))	('increasing', 'PosReg', (90, 100))	('mutant', 'Var', (30, 36))	('alpha-KG', 'Chemical', 'MESH:D007656', (118, 126))	('conformation', 'MPA', (144, 156))
104262	22080945	d-2-HG accumulation is a biochemical hallmark of IDH1/2 mutant tumors.	('d-2-HG', 'Chemical', 'MESH:C019417', (0, 6))	('d-2-HG accumulation', 'MPA', (0, 19))	('mutant', 'Var', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('IDH1/2', 'Gene', (49, 55))
104265	22080945	Interestingly, d-2-HG and its stereoisomer l-2-hydroxyglutarate (l-2-HG) accumulate in certain metabolic disorders, d-2 or l-2 hydroxyglutaric aciduria (d-2 or l-2-HGA), respectively.	('d', 'Chemical', 'MESH:D003903', (153, 154))	('d', 'Chemical', 'MESH:D003903', (105, 106))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('d', 'Chemical', 'MESH:D003903', (15, 16))	('l-2', 'Var', (123, 126))	('l-2-hydroxyglutarate', 'Chemical', '-', (43, 63))	('d', 'Chemical', 'MESH:D003903', (110, 111))	('d-2-HG', 'Var', (15, 21))	('l-2-HG', 'Chemical', '-', (65, 71))	('d', 'Chemical', 'MESH:D003903', (116, 117))	('d-2', 'Var', (116, 119))	('l-2-HG', 'Chemical', '-', (160, 166))	('d', 'Chemical', 'MESH:D003903', (146, 147))	('metabolic disorders', 'MPA', (95, 114))	('accumulate', 'PosReg', (73, 83))	('d-2-HG', 'Chemical', 'MESH:C019417', (15, 21))	('aciduria', 'Phenotype', 'HP:0012072', (143, 151))
104266	22080945	l-2-HGA results from inactivation of l-2-hydroxyglutaric dehydrogenase, whereas d-2-HGA results from inactivation of d-2-hydroxyglutarate dehydrogenase or IDH2 mutations.	('mutations', 'Var', (160, 169))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('d-2-hydroxyglutarate dehydrogenase', 'Gene', '728294', (117, 151))	('d', 'Chemical', 'MESH:D003903', (142, 143))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('d', 'Chemical', 'MESH:D003903', (117, 118))	('IDH2', 'Gene', (155, 159))	('IDH2', 'Gene', '3418', (155, 159))	('d-2-HG', 'Chemical', 'MESH:C019417', (80, 86))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('d', 'Chemical', 'MESH:D003903', (138, 139))	('l-2-HGA', 'Disease', (0, 7))	('inactivation', 'NegReg', (21, 33))	('d-2-hydroxyglutarate dehydrogenase', 'Gene', (117, 151))	('l-2-HG', 'Chemical', '-', (0, 6))	('d', 'Chemical', 'MESH:D003903', (43, 44))	('d', 'Chemical', 'MESH:D003903', (123, 124))	('inactivation', 'NegReg', (101, 113))	('l-2-hydroxyglutaric', 'MPA', (37, 56))
104267	22080945	IDH2 mutations found in d-2-HGA are identical to those documented in gliomas or AML.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('d', 'Chemical', 'MESH:D003903', (19, 20))	('gliomas', 'Disease', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('d', 'Chemical', 'MESH:D003903', (37, 38))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('mutations', 'Var', (5, 14))	('AML', 'Disease', (80, 83))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH2', 'Gene', (0, 4))	('d-2-HG', 'Chemical', 'MESH:C019417', (24, 30))	('d-2-HGA', 'Var', (24, 31))	('IDH2', 'Gene', '3418', (0, 4))	('AML', 'Disease', 'MESH:D015470', (80, 83))
104270	22080945	IDH1/2 mutations are significant driver mutations in glioma development as evidenced by computational analyses using Cancer-Specific High-Throughput Analysis of Somatic Mutations (CHASM).	('d', 'Chemical', 'MESH:D003903', (33, 34))	('d', 'Chemical', 'MESH:D003903', (78, 79))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('d', 'Chemical', 'MESH:D003903', (60, 61))	('glioma', 'Disease', (53, 59))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
104271	22080945	Additionally, IDH1/2 mutations occur first in grade II gliomas and their frequency does not increase with tumor grade, suggesting that these mutations are critical for initial tumor development.	('d', 'Chemical', 'MESH:D003903', (2, 3))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('d', 'Chemical', 'MESH:D003903', (65, 66))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('tumor', 'Disease', (106, 111))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('tumor', 'Disease', (176, 181))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('d', 'Chemical', 'MESH:D003903', (182, 183))	('II gliomas', 'Disease', (52, 62))	('IDH1/2', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('initial tumor', 'Disease', 'MESH:D009369', (168, 181))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('d', 'Chemical', 'MESH:D003903', (115, 116))	('II gliomas', 'Disease', 'MESH:D005910', (52, 62))	('mutations', 'Var', (21, 30))	('initial tumor', 'Disease', (168, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('d', 'Chemical', 'MESH:D003903', (1, 2))
104272	22080945	How IDH1/2 mutation contributes to the development of cancer is currently under investigation.	('d', 'Chemical', 'MESH:D003903', (39, 40))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('contributes', 'Reg', (20, 31))	('cancer', 'Disease', (54, 60))	('IDH1/2', 'Gene', (4, 10))	('mutation', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('d', 'Chemical', 'MESH:D003903', (76, 77))
104273	22080945	Initially, studies suggested that IDH1/2 mutations contribute to tumorigenesis through stabilization of HIF-1alpha, similar to SDH and fumarate dehydrogenase mutations.	('mutations', 'Var', (41, 50))	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('d', 'Chemical', 'MESH:D003903', (148, 149))	('tumor', 'Disease', (65, 70))	('SDH', 'Gene', (127, 130))	('HIF-1alpha', 'Gene', (104, 114))	('IDH1/2', 'Gene', (34, 40))	('d', 'Chemical', 'MESH:D003903', (133, 134))	('d', 'Chemical', 'MESH:D003903', (144, 145))	('d', 'Chemical', 'MESH:D003903', (14, 15))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('d', 'Chemical', 'MESH:D003903', (27, 28))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('stabilization', 'MPA', (87, 100))	('fumarate', 'Chemical', 'MESH:D005650', (135, 143))	('SDH', 'Gene', '6390', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
104274	22080945	The authors suggested alpha-KG levels were significantly decreased in IDH1/2 mutant cells, leading to inactivation of PHD2 and stabilization of HIF-1alpha.	('inactivation', 'NegReg', (102, 114))	('PHD2', 'Gene', '54583', (118, 122))	('alpha-KG levels', 'MPA', (22, 37))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('PHD2', 'Gene', (118, 122))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('IDH1/2', 'Gene', '3417;3418', (70, 76))	('alpha-KG', 'Chemical', 'MESH:D007656', (22, 30))	('HIF-1alpha', 'Gene', '3091', (144, 154))	('d', 'Chemical', 'MESH:D003903', (125, 126))	('stabilization', 'MPA', (127, 140))	('d', 'Chemical', 'MESH:D003903', (65, 66))	('mutant', 'Var', (77, 83))	('IDH1/2', 'Gene', (70, 76))	('decreased', 'NegReg', (57, 66))	('d', 'Chemical', 'MESH:D003903', (94, 95))	('HIF-1alpha', 'Gene', (144, 154))
104275	22080945	However, subsequent studies have found that alpha-KG levels are not significantly altered in IDH1/2 mutant cells, despite increased cellular demand for d-2-HG production.	('d', 'Chemical', 'MESH:D003903', (88, 89))	('d', 'Chemical', 'MESH:D003903', (152, 153))	('IDH1/2', 'Gene', (93, 99))	('d', 'Chemical', 'MESH:D003903', (23, 24))	('d', 'Chemical', 'MESH:D003903', (37, 38))	('d', 'Chemical', 'MESH:D003903', (130, 131))	('mutant', 'Var', (100, 106))	('alpha-KG', 'Chemical', 'MESH:D007656', (44, 52))	('cellular demand for d-2-HG production', 'MPA', (132, 169))	('d-2-HG', 'Chemical', 'MESH:C019417', (152, 158))	('IDH1/2', 'Gene', '3417;3418', (93, 99))	('d', 'Chemical', 'MESH:D003903', (162, 163))	('increased', 'PosReg', (122, 131))	('d', 'Chemical', 'MESH:D003903', (146, 147))	('d', 'Chemical', 'MESH:D003903', (141, 142))	('d', 'Chemical', 'MESH:D003903', (114, 115))
104276	22080945	Additionally, studies in AML and glioma with IDH1/2 mutations did not detect increased stabilization of HIF-1alpha.	('mutations', 'Var', (52, 61))	('d', 'Chemical', 'MESH:D003903', (2, 3))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('glioma', 'Disease', (33, 39))	('HIF-1alpha', 'Gene', (104, 114))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('d', 'Chemical', 'MESH:D003903', (17, 18))	('d', 'Chemical', 'MESH:D003903', (62, 63))	('IDH1/2', 'Gene', (45, 51))	('AML', 'Disease', 'MESH:D015470', (25, 28))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('AML', 'Disease', (25, 28))	('d', 'Chemical', 'MESH:D003903', (1, 2))
104278	22080945	In cells harboring IDH1/2 mutations, intracellular d-2-HG levels can reach up to 10mM.	('intracellular d-2-HG levels', 'MPA', (37, 64))	('d-2-HG', 'Chemical', 'MESH:C019417', (51, 57))	('IDH1/2', 'Gene', (19, 25))	('mutations', 'Var', (26, 35))	('IDH1/2', 'Gene', '3417;3418', (19, 25))
104279	22080945	d-2-HG and alpha-KG are similar in structure, and recent studies have shown that d-2-HG serves as competitive inhibitor of enzymes that utilize alpha-KG as a co-factor.	('d', 'Chemical', 'MESH:D003903', (9, 10))	('d-2-HG', 'Chemical', 'MESH:C019417', (0, 6))	('d', 'Chemical', 'MESH:D003903', (60, 61))	('d', 'Chemical', 'MESH:D003903', (0, 1))	('d', 'Chemical', 'MESH:D003903', (81, 82))	('d', 'Chemical', 'MESH:D003903', (48, 49))	('alpha-KG', 'Chemical', 'MESH:D007656', (144, 152))	('d-2-HG', 'Chemical', 'MESH:C019417', (81, 87))	('alpha-KG', 'Chemical', 'MESH:D007656', (11, 19))	('enzymes', 'Enzyme', (123, 130))	('d-2-HG', 'Var', (81, 87))
104282	22080945	High intracellular levels of d-2-HG in IDH1/2 mutant tumors are likely sufficient for potent enzymatic inhibition and suggest a possible mechanism by which IDH1/2 mutations contribute to tumorigenesis.	('contribute', 'Reg', (173, 183))	('IDH1/2', 'Gene', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH1/2', 'Gene', '3417;3418', (156, 162))	('tumors', 'Disease', (53, 59))	('d', 'Chemical', 'MESH:D003903', (29, 30))	('IDH1/2', 'Gene', (156, 162))	('d', 'Chemical', 'MESH:D003903', (116, 117))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mutant', 'Var', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (163, 172))	('d-2-HG', 'Chemical', 'MESH:C019417', (29, 35))	('tumor', 'Disease', (53, 58))	('IDH1/2', 'Gene', '3417;3418', (39, 45))
104283	22080945	Interestingly, mutant IDH1/2 cases in AML have a characteristic hypermethylated phenotype which may result from inhibition of TET2 by d-2-HG.	('AML', 'Disease', (38, 41))	('result from', 'Reg', (100, 111))	('d', 'Chemical', 'MESH:D003903', (78, 79))	('IDH1/2', 'Gene', (22, 28))	('d', 'Chemical', 'MESH:D003903', (134, 135))	('inhibition', 'NegReg', (112, 122))	('d-2-HG', 'Chemical', 'MESH:C019417', (134, 140))	('TET2', 'Gene', '54790', (126, 130))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('mutant', 'Var', (15, 21))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('TET2', 'Gene', (126, 130))	('hypermethylated', 'MPA', (64, 79))
104284	22080945	TET2 catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine and is mutated in approximately 24% of secondary AMLs.	('TET2', 'Gene', (0, 4))	('d', 'Chemical', 'MESH:D003903', (88, 89))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (51, 74))	('d', 'Chemical', 'MESH:D003903', (77, 78))	('AML', 'Disease', (124, 127))	('methylcytosine', 'Chemical', '-', (33, 47))	('d', 'Chemical', 'MESH:D003903', (119, 120))	('conversion', 'MPA', (19, 29))	('TET2', 'Gene', '54790', (0, 4))	('mutated', 'Var', (82, 89))	('methylcytosine to 5-hydroxymethylcytosine', 'MPA', (33, 74))	('AML', 'Disease', 'MESH:D015470', (124, 127))	('AMLs', 'Phenotype', 'HP:0004808', (124, 128))	('methylcytosine', 'Chemical', '-', (60, 74))	('d', 'Chemical', 'MESH:D003903', (55, 56))
104285	22080945	TET2 mutations result in a hypermethylated phenotype similar to that seen in mutant IDH1/2 AMLs, although the two mutations are mutually exclusive.	('TET2', 'Gene', (0, 4))	('IDH1/2', 'Gene', (84, 90))	('result in', 'Reg', (15, 24))	('AML', 'Disease', 'MESH:D015470', (91, 94))	('AMLs', 'Phenotype', 'HP:0004808', (91, 95))	('mutations', 'Var', (5, 14))	('AML', 'Disease', (91, 94))	('hypermethylated phenotype', 'MPA', (27, 52))	('TET2', 'Gene', '54790', (0, 4))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('IDH1/2', 'Gene', '3417;3418', (84, 90))	('mutant', 'Var', (77, 83))
104286	22080945	Differentially methylated genes in IDH1 mutant gliomas include processes known to contribute to tumor progression as well as several metabolic pathways (Table 1).	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH1', 'Gene', (35, 39))	('include', 'Reg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('d', 'Chemical', 'MESH:D003903', (60, 61))	('IDH1', 'Gene', '3417', (35, 39))	('tumor', 'Disease', (96, 101))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('gliomas', 'Disease', (47, 54))	('Differentially methylated', 'Var', (0, 25))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('mutant', 'Var', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
104287	22080945	In gliomas, a hypermethylated phenotype has also been identified, the glioma-CpG island methylator phenotype (G-CIMP) which correlates tightly with IDH1 mutations.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('IDH1', 'Gene', '3417', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('mutations', 'Var', (153, 162))	('G-CIMP', 'Chemical', '-', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('d', 'Chemical', 'MESH:D003903', (63, 64))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('glioma', 'Disease', (3, 9))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('d', 'Chemical', 'MESH:D003903', (86, 87))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('IDH1', 'Gene', (148, 152))
104288	22080945	Although 78% of G-CIMP positive tumors possess an IDH1 mutation, no causative link between IDH1/2 mutations and this phenotype has been directly studied.	('IDH1', 'Gene', (50, 54))	('d', 'Chemical', 'MESH:D003903', (148, 149))	('d', 'Chemical', 'MESH:D003903', (136, 137))	('IDH1/2', 'Gene', (91, 97))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('G-CIMP', 'Chemical', '-', (16, 22))	('d', 'Chemical', 'MESH:D003903', (151, 152))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('IDH1', 'Gene', '3417', (91, 95))	('mutation', 'Var', (55, 63))	('tumors', 'Disease', (32, 38))	('d', 'Chemical', 'MESH:D003903', (110, 111))	('IDH1/2', 'Gene', '3417;3418', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
104289	22080945	Transcriptional analysis of aberrantly methylated genes in G-CIMP tumors by Noushmehr et al.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('G-CIMP', 'Chemical', '-', (59, 65))	('aberrantly methylated genes', 'Var', (28, 55))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('d', 'Chemical', 'MESH:D003903', (48, 49))
104292	22080945	Although the mechanisms for these changes are not yet known, d-2-HG produced by IDH1/2 mutations may alter the epigenetic profile and thereby alter the expression of metabolic and other genes that promote tumor formation and growth.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('d', 'Chemical', 'MESH:D003903', (223, 224))	('mutations', 'Var', (87, 96))	('d', 'Chemical', 'MESH:D003903', (71, 72))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('alter', 'Reg', (142, 147))	('promote', 'PosReg', (197, 204))	('epigenetic profile', 'MPA', (111, 129))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('alter', 'Reg', (101, 106))	('expression of', 'MPA', (152, 165))	('d', 'Chemical', 'MESH:D003903', (132, 133))	('d', 'Chemical', 'MESH:D003903', (75, 76))	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('d', 'Chemical', 'MESH:D003903', (178, 179))	('tumor', 'Disease', (205, 210))	('metabolic', 'Gene', (166, 175))	('d-2-HG', 'Chemical', 'MESH:C019417', (61, 67))	('IDH1/2', 'Gene', (80, 86))
104293	22080945	Metabolic changes have been confirmed by metabolomics studies on IDH1/2 mutant cells.	('d', 'Chemical', 'MESH:D003903', (36, 37))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('mutant', 'Var', (72, 78))	('IDH1/2', 'Gene', '3417;3418', (65, 71))	('IDH1/2', 'Gene', (65, 71))
104294	22080945	indentified changes resulting from expression of mutant IDH1/2 or treatment with d-2-HG (1).	('d', 'Chemical', 'MESH:D003903', (2, 3))	('mutant', 'Var', (49, 55))	('d', 'Chemical', 'MESH:D003903', (81, 82))	('d', 'Chemical', 'MESH:D003903', (10, 11))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('d-2-HG', 'Chemical', 'MESH:C019417', (81, 87))	('IDH1/2', 'Gene', (56, 62))
104295	22080945	Some metabolic alterations were found under both conditions; however, approximately half of the observed changes in IDH1/2 mutant expressing cells could not be replicated by treatment with exogenous d-2-HG.	('d', 'Chemical', 'MESH:D003903', (169, 170))	('d', 'Chemical', 'MESH:D003903', (36, 37))	('d', 'Chemical', 'MESH:D003903', (40, 41))	('IDH1/2', 'Gene', (116, 122))	('d', 'Chemical', 'MESH:D003903', (199, 200))	('metabolic', 'MPA', (5, 14))	('d', 'Chemical', 'MESH:D003903', (151, 152))	('d', 'Chemical', 'MESH:D003903', (52, 53))	('d', 'Chemical', 'MESH:D003903', (103, 104))	('d-2-HG', 'Chemical', 'MESH:C019417', (199, 205))	('mutant', 'Var', (123, 129))	('IDH1/2', 'Gene', '3417;3418', (116, 122))
104297	22080945	Therefore, these changes are a direct result of the enzymatic activity of IDH1/2 mutant enzymes.	('IDH1/2', 'Gene', (74, 80))	('IDH1/2', 'Gene', '3417;3418', (74, 80))	('mutant', 'Var', (81, 87))	('d', 'Chemical', 'MESH:D003903', (31, 32))
104298	22080945	One such metabolic alteration is the reduction of the neuropeptide N-acetyl-aspartyl glutamate (NAAG) and its precursor N-acetylated aspartic acid (NAA) in IDH1/2 mutant cells and tumors by up to 50-fold.	('reduction', 'NegReg', (37, 46))	('N-acetylated aspartic acid', 'Chemical', '-', (120, 146))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('d', 'Chemical', 'MESH:D003903', (104, 105))	('NAA', 'Chemical', '-', (96, 99))	('N-acetyl-aspartyl glutamate', 'Chemical', 'MESH:C027172', (67, 94))	('d', 'Chemical', 'MESH:D003903', (39, 40))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('tumors', 'Disease', (180, 186))	('IDH1/2', 'Gene', '3417;3418', (156, 162))	('IDH1/2', 'Gene', (156, 162))	('NAAG', 'Chemical', 'MESH:C027172', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('d', 'Chemical', 'MESH:D003903', (131, 132))	('NAA', 'Chemical', '-', (148, 151))	('mutant', 'Var', (163, 169))	('d', 'Chemical', 'MESH:D003903', (178, 179))	('d', 'Chemical', 'MESH:D003903', (202, 203))	('d', 'Chemical', 'MESH:D003903', (145, 146))
104302	22080945	Mutant IDH1/2 produce d-2-HG from glutamine-derived alpha-KG, resulting in increased flux through this pathway.	('alpha-KG', 'Chemical', 'MESH:D007656', (52, 60))	('d', 'Chemical', 'MESH:D003903', (50, 51))	('d', 'Chemical', 'MESH:D003903', (22, 23))	('d', 'Chemical', 'MESH:D003903', (44, 45))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('d-2-HG', 'MPA', (22, 28))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('d-2-HG', 'Chemical', 'MESH:C019417', (22, 28))	('d', 'Chemical', 'MESH:D003903', (17, 18))	('Mutant', 'Var', (0, 6))	('IDH1/2', 'Gene', (7, 13))	('flux', 'MPA', (85, 89))	('increased', 'PosReg', (75, 84))	('glutamine', 'Chemical', 'MESH:D005973', (34, 43))
104303	22080945	Therefore, cells expressing mutant IDH1/2 may be more dependent upon this pathway for growth and survival.	('mutant', 'Var', (28, 34))	('d', 'Chemical', 'MESH:D003903', (54, 55))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('d', 'Chemical', 'MESH:D003903', (59, 60))	('IDH1/2', 'Gene', (35, 41))
104304	22080945	Interestingly, inhibition of alpha-KG synthesis from glutamine led to a 15-20% decrease in growth for cells expressing mutant IDH1.	('inhibition', 'NegReg', (15, 25))	('IDH1', 'Gene', '3417', (126, 130))	('alpha-KG', 'Chemical', 'MESH:D007656', (29, 37))	('growth', 'MPA', (91, 97))	('decrease', 'NegReg', (79, 87))	('glutamine', 'Chemical', 'MESH:D005973', (53, 62))	('alpha-KG', 'Protein', (29, 37))	('d', 'Chemical', 'MESH:D003903', (79, 80))	('IDH1', 'Gene', (126, 130))	('d', 'Chemical', 'MESH:D003903', (65, 66))	('mutant', 'Var', (119, 125))
104306	22080945	Glutaminase inhibition lowered glutamate and alpha-KG levels in IDH1 wildtype and mutant cells, but d-2-HG levels were not reduced, indicating the presence of a compensatory mechanism.	('d-2-HG', 'Chemical', 'MESH:C019417', (100, 106))	('lowered glutamate', 'Phenotype', 'HP:0500150', (23, 40))	('IDH1', 'Gene', (64, 68))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('d', 'Chemical', 'MESH:D003903', (72, 73))	('inhibition lowered', 'NegReg', (12, 30))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('mutant', 'Var', (82, 88))	('d', 'Chemical', 'MESH:D003903', (134, 135))	('glutamate', 'Chemical', 'MESH:D018698', (31, 40))	('IDH1', 'Gene', '3417', (64, 68))	('d', 'Chemical', 'MESH:D003903', (125, 126))	('d', 'Chemical', 'MESH:D003903', (29, 30))	('Glutaminase', 'Protein', (0, 11))	('alpha-KG levels', 'MPA', (45, 60))	('d', 'Chemical', 'MESH:D003903', (100, 101))	('glutamate', 'MPA', (31, 40))	('d', 'Chemical', 'MESH:D003903', (43, 44))	('alpha-KG', 'Chemical', 'MESH:D007656', (45, 53))
104307	22080945	Changes in the other metabolites following BPTES treatment supported this hypothesis including increases in glycolytic intermediates and decreased levels of TCA cycle intermediates which were seen in both wildtype and mutant IDH1-expressing cells.	('d', 'Chemical', 'MESH:D003903', (208, 209))	('IDH1', 'Gene', (225, 229))	('d', 'Chemical', 'MESH:D003903', (67, 68))	('TCA', 'Chemical', 'MESH:D014238', (157, 160))	('BPTES', 'Chemical', '-', (43, 48))	('glycolytic intermediates', 'MPA', (108, 132))	('d', 'Chemical', 'MESH:D003903', (137, 138))	('d', 'Chemical', 'MESH:D003903', (126, 127))	('d', 'Chemical', 'MESH:D003903', (174, 175))	('IDH1', 'Gene', '3417', (225, 229))	('d', 'Chemical', 'MESH:D003903', (216, 217))	('mutant', 'Var', (218, 224))	('d', 'Chemical', 'MESH:D003903', (135, 136))	('decreased', 'NegReg', (137, 146))	('levels of TCA cycle intermediates', 'MPA', (147, 180))	('d', 'Chemical', 'MESH:D003903', (90, 91))	('d', 'Chemical', 'MESH:D003903', (145, 146))	('increases', 'PosReg', (95, 104))
104309	22080945	Therefore, metabolic inhibition has been shown as a potential approach for selective targeting of IDH1/2 mutant tumors.	('IDH1/2', 'Gene', '3417;3418', (98, 104))	('tumors', 'Disease', (112, 118))	('IDH1/2', 'Gene', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutant', 'Var', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
104311	22080945	Changes in fatty acid metabolism may also result from IDH1/2 mutant expression.	('mutant expression', 'Var', (61, 78))	('IDH1/2', 'Gene', (54, 60))	('result', 'Reg', (42, 48))	('fatty acid', 'Chemical', 'MESH:D005227', (11, 21))	('fatty acid metabolism', 'MPA', (11, 32))	('IDH1/2', 'Gene', '3417;3418', (54, 60))	('Changes', 'Reg', (0, 7))
104312	22080945	Mutant IDH1-expressing cells exhibit decreased levels of citrate compared with wildtype-expressing IDH1 cells, coupled with increases in acetyl-CoA and triglyceride and phospholipid precursors.	('triglyceride', 'Chemical', 'MESH:D014280', (152, 164))	('d', 'Chemical', 'MESH:D003903', (167, 168))	('acetyl-CoA', 'MPA', (137, 147))	('increases', 'PosReg', (124, 133))	('d', 'Chemical', 'MESH:D003903', (72, 73))	('IDH1', 'Gene', '3417', (99, 103))	('d', 'Chemical', 'MESH:D003903', (150, 151))	('d', 'Chemical', 'MESH:D003903', (117, 118))	('d', 'Chemical', 'MESH:D003903', (180, 181))	('IDH1', 'Gene', (7, 11))	('d', 'Chemical', 'MESH:D003903', (37, 38))	('levels of citrate', 'MPA', (47, 64))	('d', 'Chemical', 'MESH:D003903', (45, 46))	('Mutant', 'Var', (0, 6))	('d', 'Chemical', 'MESH:D003903', (162, 163))	('decreased', 'NegReg', (37, 46))	('phospholipid', 'Chemical', 'MESH:D010743', (169, 181))	('IDH1', 'Gene', '3417', (7, 11))	('d', 'Chemical', 'MESH:D003903', (82, 83))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (137, 147))	('IDH1', 'Gene', (99, 103))	('citrate', 'Chemical', 'MESH:D019343', (57, 64))
104313	22080945	The combination of decreased citrate and increased lipid precursors may indicate that IDH1 mutant expressing cells shuttle citrate out of the TCA cycle to produce lipids required for cell growth.	('d', 'Chemical', 'MESH:D003903', (177, 178))	('d', 'Chemical', 'MESH:D003903', (167, 168))	('decreased citrate', 'Phenotype', 'HP:0012405', (19, 36))	('shuttle citrate out', 'MPA', (115, 134))	('lipid', 'Chemical', 'MESH:D008055', (163, 168))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('decreased', 'NegReg', (19, 28))	('d', 'Chemical', 'MESH:D003903', (39, 40))	('lipids', 'Chemical', 'MESH:D008055', (163, 169))	('d', 'Chemical', 'MESH:D003903', (158, 159))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('citrate', 'Chemical', 'MESH:D019343', (29, 36))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('citrate', 'Chemical', 'MESH:D019343', (123, 130))	('IDH1', 'Gene', (86, 90))	('d', 'Chemical', 'MESH:D003903', (74, 75))	('d', 'Chemical', 'MESH:D003903', (19, 20))	('IDH1', 'Gene', '3417', (86, 90))	('produce lipids required for cell growth', 'MPA', (155, 194))	('d', 'Chemical', 'MESH:D003903', (27, 28))	('citrate', 'MPA', (29, 36))	('increased lipid', 'Phenotype', 'HP:0003077', (41, 56))	('TCA', 'Chemical', 'MESH:D014238', (142, 145))	('mutant', 'Var', (91, 97))
104314	22080945	Increases in fatty acid/lipid synthesis are a common characteristic of many cancers, including gliomas, and it is possible IDH1/2 mutation may contribute to this phenotype.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('Increases', 'PosReg', (0, 9))	('fatty acid/lipid synthesis', 'MPA', (13, 39))	('mutation', 'Var', (130, 138))	('IDH1/2', 'Gene', '3417;3418', (123, 129))	('d', 'Chemical', 'MESH:D003903', (22, 23))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('lipid', 'Chemical', 'MESH:D008055', (24, 29))	('IDH1/2', 'Gene', (123, 129))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('gliomas', 'Disease', (95, 102))	('d', 'Chemical', 'MESH:D003903', (106, 107))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('contribute', 'Reg', (143, 153))	('d', 'Chemical', 'MESH:D003903', (90, 91))	('fatty acid', 'Chemical', 'MESH:D005227', (13, 23))
104315	22080945	In addition, mutant IDH1 may lead to decreased fatty acid oxidation in two ways: reducing available cofactors for peroxisomal beta-oxidation and by decreasing carnitine biosynthesis for mitochondrial fatty acid transport.	('IDH1', 'Gene', '3417', (20, 24))	('d', 'Chemical', 'MESH:D003903', (56, 57))	('available cofactors for peroxisomal beta-oxidation', 'MPA', (90, 140))	('reducing', 'NegReg', (81, 89))	('decreasing', 'NegReg', (148, 158))	('decreasing carnitine', 'Phenotype', 'HP:0003234', (148, 168))	('d', 'Chemical', 'MESH:D003903', (32, 33))	('fatty acid', 'Chemical', 'MESH:D005227', (200, 210))	('d', 'Chemical', 'MESH:D003903', (134, 135))	('d', 'Chemical', 'MESH:D003903', (143, 144))	('decreased fatty acid', 'Phenotype', 'HP:0040299', (37, 57))	('fatty acid oxidation', 'MPA', (47, 67))	('d', 'Chemical', 'MESH:D003903', (37, 38))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('carnitine', 'Chemical', 'MESH:D002331', (159, 168))	('d', 'Chemical', 'MESH:D003903', (4, 5))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('fatty acid', 'Chemical', 'MESH:D005227', (47, 57))	('d', 'Chemical', 'MESH:D003903', (45, 46))	('IDH1', 'Gene', (20, 24))	('decreased', 'NegReg', (37, 46))	('mutant', 'Var', (13, 19))	('d', 'Chemical', 'MESH:D003903', (194, 195))	('d', 'Chemical', 'MESH:D003903', (148, 149))	('d', 'Chemical', 'MESH:D003903', (5, 6))	('d', 'Chemical', 'MESH:D003903', (209, 210))
104318	22080945	Mutant IDH1 has decreased the ability to produce NADPH and alpha-KG, suggesting that mutation of IDH1 may lead to decreased levels of these substrates within peroxisomes and potentially decreased rates of fatty acid oxidation.	('IDH1', 'Gene', (97, 101))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('rates of fatty acid oxidation', 'MPA', (196, 225))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('mutation', 'Var', (85, 93))	('decreased', 'NegReg', (114, 123))	('alpha-KG', 'Chemical', 'MESH:D007656', (59, 67))	('d', 'Chemical', 'MESH:D003903', (16, 17))	('d', 'Chemical', 'MESH:D003903', (214, 215))	('IDH1', 'Gene', '3417', (97, 101))	('levels of these substrates within peroxisomes', 'MPA', (124, 169))	('NADPH', 'Chemical', 'MESH:D009249', (49, 54))	('IDH1', 'Gene', (7, 11))	('d', 'Chemical', 'MESH:D003903', (109, 110))	('d', 'Chemical', 'MESH:D003903', (219, 220))	('d', 'Chemical', 'MESH:D003903', (172, 173))	('Mutant', 'Var', (0, 6))	('d', 'Chemical', 'MESH:D003903', (186, 187))	('d', 'Chemical', 'MESH:D003903', (194, 195))	('IDH1', 'Gene', '3417', (7, 11))	('d', 'Chemical', 'MESH:D003903', (44, 45))	('d', 'Chemical', 'MESH:D003903', (122, 123))	('fatty acid', 'Chemical', 'MESH:D005227', (205, 215))	('decreased', 'NegReg', (186, 195))	('d', 'Chemical', 'MESH:D003903', (114, 115))
104320	22080945	demonstrated that high levels of d-2-HG can inhibit gamma-butyrobetaine hydroxylase 1, the last enzymatic step in carnitine biosynthesis.	('d', 'Chemical', 'MESH:D003903', (74, 75))	('d', 'Chemical', 'MESH:D003903', (33, 34))	('gamma-butyrobetaine hydroxylase 1', 'Gene', '8424', (52, 85))	('gamma-butyrobetaine hydroxylase 1', 'Gene', (52, 85))	('carnitine', 'Chemical', 'MESH:D002331', (114, 123))	('inhibit', 'NegReg', (44, 51))	('d', 'Chemical', 'MESH:D003903', (0, 1))	('d-2-HG', 'Chemical', 'MESH:C019417', (33, 39))	('d-2-HG', 'Var', (33, 39))	('d', 'Chemical', 'MESH:D003903', (11, 12))
104322	22080945	Consistent with this finding, levels of propionylcarnitine (a carnitine ester which sustains endogenous carnitine pools) were decreased in IDH1/2 mutant and d-2-HG-treated cells.	('IDH1/2', 'Gene', (139, 145))	('decreased', 'NegReg', (126, 135))	('d-2-HG', 'Chemical', 'MESH:C019417', (157, 163))	('carnitine', 'Chemical', 'MESH:D002331', (104, 113))	('d', 'Chemical', 'MESH:D003903', (155, 156))	('carnitine', 'Chemical', 'MESH:D002331', (49, 58))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('d', 'Chemical', 'MESH:D003903', (134, 135))	('carnitine ester', 'Chemical', '-', (62, 77))	('d', 'Chemical', 'MESH:D003903', (157, 158))	('d', 'Chemical', 'MESH:D003903', (126, 127))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('mutant', 'Var', (146, 152))	('IDH1/2', 'Gene', '3417;3418', (139, 145))	('propionylcarnitine', 'Chemical', 'MESH:C003223', (40, 58))	('levels of propionylcarnitine', 'MPA', (30, 58))	('d', 'Chemical', 'MESH:D003903', (170, 171))	('carnitine', 'Chemical', 'MESH:D002331', (62, 71))
104323	22080945	Therefore, IDH1/2 mutations may contribute to tumorigenesis by priming cells for growth by increasing fatty acid synthesis and reducing oxidation of certain fatty acids.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('d', 'Chemical', 'MESH:D003903', (111, 112))	('d', 'Chemical', 'MESH:D003903', (166, 167))	('reducing', 'NegReg', (127, 135))	('fatty acid synthesis', 'MPA', (102, 122))	('d', 'Chemical', 'MESH:D003903', (125, 126))	('increasing', 'PosReg', (91, 101))	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('tumor', 'Disease', (46, 51))	('IDH1/2', 'Gene', (11, 17))	('fatty acids', 'Chemical', 'MESH:D005227', (157, 168))	('d', 'Chemical', 'MESH:D003903', (139, 140))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('contribute', 'Reg', (32, 42))	('oxidation of certain fatty acids', 'MPA', (136, 168))	('fatty acid', 'Chemical', 'MESH:D005227', (157, 167))	('fatty acid', 'Chemical', 'MESH:D005227', (102, 112))	('mutations', 'Var', (18, 27))
104324	22080945	The discovery of the IDH1/2 mutation has profound implications for the understanding and treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('IDH1/2', 'Gene', '3417;3418', (21, 27))	('d', 'Chemical', 'MESH:D003903', (4, 5))	('implications', 'Reg', (50, 62))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mutation', 'Var', (28, 36))	('d', 'Chemical', 'MESH:D003903', (48, 49))	('IDH1/2', 'Gene', (21, 27))	('d', 'Chemical', 'MESH:D003903', (87, 88))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('d', 'Chemical', 'MESH:D003903', (73, 74))
104325	22080945	Elevated d-2-HG levels are characteristic of IDH1/2 mutant tumors and could serve as a biomarker to identify IDH1/2 mutational status or monitor tumor growth or treatment efficacy.	('tumor', 'Disease', (59, 64))	('Elevated', 'PosReg', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('IDH1/2', 'Gene', '3417;3418', (109, 115))	('IDH1/2', 'Gene', (109, 115))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('d-2-HG', 'Chemical', 'MESH:C019417', (9, 15))	('tumor', 'Disease', (145, 150))	('d', 'Chemical', 'MESH:D003903', (7, 8))	('IDH1/2', 'Gene', (45, 51))	('d', 'Chemical', 'MESH:D003903', (101, 102))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('d-2-HG levels', 'MPA', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('d', 'Chemical', 'MESH:D003903', (74, 75))	('mutant', 'Var', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('d', 'Chemical', 'MESH:D003903', (68, 69))	('tumors', 'Disease', (59, 65))	('d', 'Chemical', 'MESH:D003903', (9, 10))
104326	22080945	Studies in AML have shown that d-2-HG can be detected in serum, and increased d-2-HG levels correlate with IDH1/2 mutational status.	('d', 'Chemical', 'MESH:D003903', (78, 79))	('d-2-HG', 'Chemical', 'MESH:C019417', (31, 37))	('d-2-HG levels', 'MPA', (78, 91))	('IDH1/2', 'Gene', '3417;3418', (107, 113))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('mutational status', 'Var', (114, 131))	('d', 'Chemical', 'MESH:D003903', (3, 4))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('d', 'Chemical', 'MESH:D003903', (52, 53))	('IDH1/2', 'Gene', (107, 113))	('d-2-HG', 'Chemical', 'MESH:C019417', (78, 84))	('d', 'Chemical', 'MESH:D003903', (45, 46))	('AML', 'Disease', 'MESH:D015470', (11, 14))	('increased', 'PosReg', (68, 77))	('AML', 'Disease', (11, 14))	('d', 'Chemical', 'MESH:D003903', (76, 77))
104330	22080945	Additionally, it is unknown whether changes in methylation status in IDH1/2 mutant cells are reversible by disrupting mutant protein function.	('d', 'Chemical', 'MESH:D003903', (2, 3))	('function', 'MPA', (133, 141))	('mutant', 'Var', (76, 82))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('protein', 'Protein', (125, 132))	('mutant', 'Var', (118, 124))	('disrupting', 'NegReg', (107, 117))	('d', 'Chemical', 'MESH:D003903', (107, 108))	('d', 'Chemical', 'MESH:D003903', (1, 2))	('IDH1/2', 'Gene', (69, 75))
104331	22080945	The distinct metabolic alterations resulting from IDH1/2 mutations reveal a potential opportunity for therapeutic intervention.	('IDH1/2', 'Gene', (50, 56))	('metabolic alterations', 'MPA', (13, 34))	('d', 'Chemical', 'MESH:D003903', (4, 5))	('mutations', 'Var', (57, 66))	('IDH1/2', 'Gene', '3417;3418', (50, 56))
104332	22080945	Therefore, targeting unique metabolic pathways with IDH1/2 mutant tumors may be an alternative strategy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutant', 'Var', (59, 65))	('IDH1/2', 'Gene', '3417;3418', (52, 58))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('IDH1/2', 'Gene', (52, 58))
104333	22080945	One potential strategy for the treatment of IDH1/2 mutant tumors is inhibition of alpha-KG synthesis from glutamine.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('alpha-KG synthesis from glutamine', 'MPA', (82, 115))	('mutant', 'Var', (51, 57))	('IDH1/2', 'Gene', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('alpha-KG', 'Chemical', 'MESH:D007656', (82, 90))	('inhibition', 'NegReg', (68, 78))	('glutamine', 'Chemical', 'MESH:D005973', (106, 115))	('IDH1/2', 'Gene', '3417;3418', (44, 50))
104334	22080945	Studies from our group have demonstrated that inhibition of this pathway can specifically slow the growth of mutant IDH1-expressing cells.	('d', 'Chemical', 'MESH:D003903', (39, 40))	('inhibition', 'Var', (46, 56))	('growth', 'MPA', (99, 105))	('IDH1', 'Gene', (116, 120))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('d', 'Chemical', 'MESH:D003903', (3, 4))	('mutant', 'Var', (109, 115))	('IDH1', 'Gene', '3417', (116, 120))	('slow', 'NegReg', (90, 94))
104337	22080945	IDH1/2 mutations are central to the development of a particular subset of gliomas, and further studies could identify targeted treatments for individuals with these mutations.	('d', 'Chemical', 'MESH:D003903', (36, 37))	('d', 'Chemical', 'MESH:D003903', (148, 149))	('d', 'Chemical', 'MESH:D003903', (98, 99))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('d', 'Chemical', 'MESH:D003903', (110, 111))	('gliomas', 'Disease', (74, 81))	('d', 'Chemical', 'MESH:D003903', (144, 145))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('d', 'Chemical', 'MESH:D003903', (107, 108))	('IDH1/2', 'Gene', (0, 6))	('d', 'Chemical', 'MESH:D003903', (125, 126))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('mutations', 'Var', (7, 16))
104338	22080945	Epigenetic and metabolic alterations in IDH1/2 mutant cells provide clues to the mechanism by which these mutations lead to tumor development and/or maintenance; however, the relative contribution of these changes to each process is currently unknown.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('d', 'Chemical', 'MESH:D003903', (130, 131))	('IDH1/2', 'Gene', (40, 46))	('tumor', 'Disease', (124, 129))	('lead to', 'Reg', (116, 123))	('d', 'Chemical', 'MESH:D003903', (119, 120))	('d', 'Chemical', 'MESH:D003903', (144, 145))	('d', 'Chemical', 'MESH:D003903', (13, 14))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('metabolic', 'CPA', (15, 24))	('mutations', 'Var', (106, 115))	('d', 'Chemical', 'MESH:D003903', (65, 66))	('maintenance', 'CPA', (149, 160))	('mutant', 'Var', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
104339	22080945	To our knowledge, cell lines and animal models derived from a tumor with a naturally occurring IDH1/2 mutation have not been established.	('d', 'Chemical', 'MESH:D003903', (53, 54))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('IDH1/2', 'Gene', (95, 101))	('d', 'Chemical', 'MESH:D003903', (47, 48))	('mutation', 'Var', (102, 110))	('tumor', 'Disease', (62, 67))	('d', 'Chemical', 'MESH:D003903', (13, 14))	('d', 'Chemical', 'MESH:D003903', (42, 43))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('d', 'Chemical', 'MESH:D003903', (135, 136))	('IDH1/2', 'Gene', '3417;3418', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
104340	22080945	The literature and our experience suggest that IDH1/2 mutant tumors are resistant to cell culture establishment using standard protocols.	('IDH1/2', 'Gene', '3417;3418', (47, 53))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('d', 'Chemical', 'MESH:D003903', (122, 123))	('IDH1/2', 'Gene', (47, 53))	('d', 'Chemical', 'MESH:D003903', (17, 18))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutant', 'Var', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('d', 'Chemical', 'MESH:D003903', (125, 126))
104341	22080945	Therefore, studies of IDH1/2 mutations have been conducted in genetic and metabolic backgrounds which have not developed in concert with an IDH1/2 mutation.	('IDH1/2', 'Gene', '3417;3418', (140, 146))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('IDH1/2', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))	('d', 'Chemical', 'MESH:D003903', (119, 120))	('IDH1/2', 'Gene', (140, 146))	('d', 'Chemical', 'MESH:D003903', (14, 15))	('d', 'Chemical', 'MESH:D003903', (52, 53))	('d', 'Chemical', 'MESH:D003903', (111, 112))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('d', 'Chemical', 'MESH:D003903', (72, 73))	('d', 'Chemical', 'MESH:D003903', (93, 94))
104342	22080945	Although these efforts have yielded useful insights, cell culture systems and animal tumor models derived from tumors with naturally occurring IDH1/2 mutations need to be developed to better understand the role of mutant IDH1/2 in tumorigenesis and tumor maintenance.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('IDH1/2', 'Gene', '3417;3418', (143, 149))	('tumors', 'Disease', (111, 117))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('d', 'Chemical', 'MESH:D003903', (247, 248))	('IDH1/2', 'Gene', (143, 149))	('IDH1/2', 'Gene', '3417;3418', (221, 227))	('d', 'Chemical', 'MESH:D003903', (104, 105))	('IDH1/2', 'Gene', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('d', 'Chemical', 'MESH:D003903', (32, 33))	('mutant', 'Var', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (231, 236))	('mutations', 'Var', (150, 159))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('d', 'Chemical', 'MESH:D003903', (179, 180))	('d', 'Chemical', 'MESH:D003903', (171, 172))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (111, 116))	('d', 'Chemical', 'MESH:D003903', (76, 77))	('d', 'Chemical', 'MESH:D003903', (163, 164))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('d', 'Chemical', 'MESH:D003903', (98, 99))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('d', 'Chemical', 'MESH:D003903', (200, 201))	('d', 'Chemical', 'MESH:D003903', (193, 194))
104344	22080945	IDH1/2 mutations occur frequently and early in the development of low-grade gliomas and secondary GBM.	('d', 'Chemical', 'MESH:D003903', (36, 37))	('gliomas', 'Disease', (76, 83))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('secondary GBM', 'Disease', (88, 101))	('d', 'Chemical', 'MESH:D003903', (86, 87))	('d', 'Chemical', 'MESH:D003903', (51, 52))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('IDH1/2', 'Gene', (0, 6))	('d', 'Chemical', 'MESH:D003903', (73, 74))	('mutations', 'Var', (7, 16))
104345	22080945	IDH1/2 mutations produce high levels of d-2-HG, which can inhibit alpha-KG-dependent enzymes potentially leading to genome-wide epigenetic alterations and altered cellular metabolism.	('d', 'Chemical', 'MESH:D003903', (153, 154))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('leading to', 'Reg', (105, 115))	('IDH1/2', 'Gene', (0, 6))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('d', 'Chemical', 'MESH:D003903', (40, 41))	('epigenetic alterations', 'MPA', (128, 150))	('d', 'Chemical', 'MESH:D003903', (125, 126))	('mutations', 'Var', (7, 16))	('alpha-KG', 'Chemical', 'MESH:D007656', (66, 74))	('altered', 'Reg', (155, 162))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('alpha-KG-dependent enzymes', 'Enzyme', (66, 92))	('cellular metabolism', 'MPA', (163, 182))	('d-2-HG', 'Chemical', 'MESH:C019417', (40, 46))	('inhibit', 'NegReg', (58, 65))	('d', 'Chemical', 'MESH:D003903', (108, 109))	('d', 'Chemical', 'MESH:D003903', (161, 162))	('d', 'Chemical', 'MESH:D003903', (75, 76))
104346	22080945	Mutant IDH1/2 enzymatic activity leads to metabolic alterations including changes in glutamine, N-acetylated amino acid, and fatty acid metabolism.	('glutamine', 'MPA', (85, 94))	('d', 'Chemical', 'MESH:D003903', (107, 108))	('d', 'Chemical', 'MESH:D003903', (36, 37))	('fatty acid', 'Chemical', 'MESH:D005227', (125, 135))	('glutamine', 'Chemical', 'MESH:D005973', (85, 94))	('d', 'Chemical', 'MESH:D003903', (69, 70))	('d', 'Chemical', 'MESH:D003903', (118, 119))	('changes', 'Reg', (74, 81))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('d', 'Chemical', 'MESH:D003903', (134, 135))	('d', 'Chemical', 'MESH:D003903', (123, 124))	('metabolic alterations', 'MPA', (42, 63))	('IDH1/2', 'Gene', (7, 13))	('Mutant', 'Var', (0, 6))	('fatty acid metabolism', 'MPA', (125, 146))	('N-acetylated amino acid', 'Chemical', '-', (96, 119))	('N-acetylated amino acid', 'MPA', (96, 119))
104347	22080945	Targeting the altered metabolism in IDH1/2 mutant gliomas may be a useful therapeutic strategy.	('IDH1/2', 'Gene', (36, 42))	('altered', 'Reg', (14, 21))	('gliomas', 'Disease', (50, 57))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('metabolism', 'MPA', (22, 32))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('mutant', 'Var', (43, 49))	('IDH1/2', 'Gene', '3417;3418', (36, 42))
104358	25574225	In conclusion, HMGB1 positivity and protein expression levels are of significant clinical and prognostic value in human gliomas.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('protein expression levels', 'MPA', (36, 61))	('positivity', 'Var', (21, 31))	('human', 'Species', '9606', (114, 119))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('HMGB1', 'Gene', '3146', (15, 20))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))	('HMGB1', 'Gene', (15, 20))
104413	25574225	In a model that included the presence or absence of HMGB1 expression, pathological grade (LGG versus HGG), gender and age, pathological grade (P=0.037) and HMGB1 expression (P=0.021) were significantly associated with reduced survival times, whereas age and gender were not.	('HMGB1', 'Gene', (156, 161))	('HMGB1', 'Gene', '3146', (156, 161))	('presence', 'Var', (29, 37))	('absence', 'NegReg', (41, 48))	('HMGB1', 'Gene', (52, 57))	('HMGB1', 'Gene', '3146', (52, 57))	('LGG', 'Chemical', '-', (90, 93))	('reduced', 'NegReg', (218, 225))	('survival times', 'CPA', (226, 240))
104435	25574225	As a broad-spectrum tumor marker, the abnormal expression of HMGB1 contributes to the occurrence and development of numerous types of tumor.	('HMGB1', 'Gene', (61, 66))	('abnormal', 'Var', (38, 46))	('HMGB1', 'Gene', '3146', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('contributes to', 'Reg', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', (134, 139))	('development', 'CPA', (101, 112))
104460	33287106	Specifically, diffuse gliomas isocitrate dehydrogenase (IDH) wildtype are characterized by the worst prognosis, oligodendrogliomas, IDH mutant, and 1p/19q co-deleted, by the best while diffuse astrocytoma IDH mutant by an intermediate prognosis.	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('gliomas', 'Disease', (123, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (193, 204))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('mutant', 'Var', (136, 142))	('IDH', 'Gene', (56, 59))	('oligodendrogliomas', 'Disease', (112, 130))	('IDH', 'Gene', (205, 208))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('IDH', 'Gene', (132, 135))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', '3417', (205, 208))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('astrocytoma IDH', 'Disease', 'MESH:D001254', (193, 208))	('gliomas', 'Disease', (22, 29))	('astrocytoma IDH', 'Disease', (193, 208))	('IDH', 'Gene', '3417', (132, 135))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (112, 130))
104464	33287106	Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression, and DNA methylation profiling, showed, in the progressed sample, the activation of the MYC and RTK-RAS-PI3K pathways and upregulation of genes involved in the cell cycle transition, such as FOXM1 and E2F2, and the epigenetic silencing of genes related to Polycomb repressive complex 2.	('MYC', 'Gene', '4609', (183, 186))	('FOXM1', 'Gene', (286, 291))	('epigenetic', 'Var', (310, 320))	('E2F2', 'Gene', '1870', (296, 300))	('MYC', 'Gene', (183, 186))	('E2F2', 'Gene', (296, 300))	('activation', 'PosReg', (165, 175))	('upregulation', 'PosReg', (217, 229))	('FOXM1', 'Gene', '2305', (286, 291))
104465	33287106	However, increasing evidence shows that cancer progression is driven, not only by genetic alterations, but also by the crosstalk established by tumor cells and the surrounding microenvironment.	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('genetic alterations', 'Var', (82, 101))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
104506	33287106	Moreover, all GASC exosomes expressed high levels of the surface markers CD105, SSEA4, CD44, CD29, and CD20 and low levels of CD56, CD25, CD49E, ROR1, HLA-ABC, MCSP, and CD133.	('CD56', 'Gene', (126, 130))	('CD105', 'Var', (73, 78))	('CD29', 'Gene', '3688', (93, 97))	('ROR1', 'Gene', '4919', (145, 149))	('CD56', 'Gene', '4684', (126, 130))	('CD49E', 'Gene', '3678', (138, 143))	('CD25', 'Gene', '3559', (132, 136))	('CD44', 'Gene', '960', (87, 91))	('MCSP', 'Gene', '1464', (160, 164))	('CD44', 'Gene', (87, 91))	('CD29', 'Gene', (93, 97))	('MCSP', 'Gene', (160, 164))	('CD20', 'Gene', (103, 107))	('CD49E', 'Gene', (138, 143))	('ROR1', 'Gene', (145, 149))	('CD20', 'Gene', '54474', (103, 107))	('CD133', 'Gene', (170, 175))	('CD133', 'Gene', '8842', (170, 175))	('CD25', 'Gene', (132, 136))
104514	33287106	Therefore, among the EXO_BAD miRNAs involved in the KEGG pathways of "Glioma" (Table 4) and "Proteoglycans in cancer" (Table 5), we distinguished miRNAs dysregulated also in EXO_GOOD (i.e., EXO-SHARED miRNAs) and miRNAs selectively modulated in EXO_BAD (i.e., BAD-SPECIFIC miRNAs).	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('dysregulated', 'Var', (153, 165))	('Glioma', 'Disease', 'MESH:D005910', (70, 76))	('Glioma', 'Phenotype', 'HP:0009733', (70, 76))	('Glioma', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
104519	33287106	In fact, considering the 33 genes of the "Glioma" pathway modulated by upregulated miRNAs, six were exclusively targeted by BAD-SPECIFIC miRNAs, while the remaining were targets of either EXO-SHARED (n = 12) or both EXO-SHARED and BAD-SPECIFIC (n = 15) miRNAs (Figure 6).	('Glioma', 'Disease', 'MESH:D005910', (42, 48))	('Glioma', 'Phenotype', 'HP:0009733', (42, 48))	('Glioma', 'Disease', (42, 48))	('miRNAs', 'Var', (83, 89))	('upregulated', 'PosReg', (71, 82))
104527	33287106	The bidirectional crosstalk between tumor cells and TME contributes to tumor development and progression by promoting tumor cell proliferation, invasion, and angiogenesis; reprogramming of energy metabolism, and suppressing cell death and immune response, well-known hallmarks of cancer.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('suppressing', 'NegReg', (212, 223))	('cancer', 'Disease', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Disease', (36, 41))	('death', 'Disease', (229, 234))	('promoting', 'PosReg', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('invasion', 'CPA', (144, 152))	('angiogenesis', 'CPA', (158, 170))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (71, 76))	('death', 'Disease', 'MESH:D003643', (229, 234))	('reprogramming', 'Var', (172, 185))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (118, 123))
104537	33287106	This latter exerts a tumor suppressive function by inhibiting proliferation and malignancy of glioblastoma cells by targeting both NRAS and KRAS and by modulating microglia activation through TLR7.	('KRAS', 'Gene', '3845', (140, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('targeting', 'Var', (116, 125))	('proliferation', 'CPA', (62, 75))	('malignancy of glioblastoma', 'Disease', (80, 106))	('tumor', 'Disease', (21, 26))	('NRAS', 'Gene', (131, 135))	('microglia activation', 'CPA', (163, 183))	('TLR7', 'Gene', (192, 196))	('NRAS', 'Gene', '4893', (131, 135))	('inhibiting', 'NegReg', (51, 61))	('malignancy of glioblastoma', 'Disease', 'MESH:D005909', (80, 106))	('modulating', 'Reg', (152, 162))	('TLR7', 'Gene', '51284', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('KRAS', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
104541	33287106	Looking instead to the two miRNAs specifically enriched in EXO_GOOD, miR-320c has been shown to exert a tumor suppressive function in glioma, by acting through the modulation of either RAF1/MAPK pathway or E2F2, a key transcription factor involved in the regulation of the G1/S phase.	('E2F2', 'Gene', '1870', (206, 210))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('miR-320c', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('modulation', 'Reg', (164, 174))	('RAF1', 'Gene', (185, 189))	('RAF1', 'Gene', '5894', (185, 189))	('E2F2', 'Gene', (206, 210))	('glioma', 'Disease', (134, 140))	('miR-320c', 'Chemical', '-', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
104542	33287106	reported that miR-320c could increase radiosensitivity of glioma cell by inhibiting SIRT1 through FOXM1 modulation.	('radiosensitivity', 'CPA', (38, 54))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (29, 54))	('SIRT1', 'Gene', (84, 89))	('miR-320c', 'Var', (14, 22))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('FOXM1', 'Gene', (98, 103))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('increase', 'PosReg', (29, 37))	('FOXM1', 'Gene', '2305', (98, 103))	('inhibiting', 'NegReg', (73, 83))	('glioma', 'Disease', (58, 64))	('miR-320c', 'Chemical', '-', (14, 22))	('SIRT1', 'Gene', '23411', (84, 89))
104544	33287106	Regarding the miRNAs selectively upregulated in GASC_BAD, an oncogenic role, in glioma, has been described for miR-223-3p, miR-10b-5p, and miR-182-5p, while miR-338-3p, miR-204-5p, and miR-126-3p were described as oncosuppressive.	('glioma', 'Disease', (80, 86))	('upregulated', 'PosReg', (33, 44))	('GASC_BAD', 'Disease', (48, 56))	('miR-223', 'Gene', '407008', (111, 118))	('miR-126-3p', 'Gene', '100302148', (185, 195))	('miR-126-3p', 'Gene', (185, 195))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('miR-182-5p', 'Gene', '100302183', (139, 149))	('miR-182-5p', 'Gene', (139, 149))	('miR-223', 'Gene', (111, 118))	('miR-10b-5p', 'Var', (123, 133))
104550	33287106	Upregulated miRNAs were instead modulating KEGG pathways associated with different cancers, including glioma, chronic myeloid leukemia, prostate carcinoma, non-small cell carcinoma, renal cell carcinoma, and pancreatic carcinoma.	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('miRNAs', 'Var', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (110, 134))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (110, 134))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (118, 134))	('Upregulated', 'PosReg', (0, 11))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('pancreatic carcinoma', 'Disease', (208, 228))	('modulating', 'Reg', (32, 42))	('prostate carcinoma', 'Disease', 'MESH:D011471', (136, 154))	('non-small cell carcinoma', 'Disease', (156, 180))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (136, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('renal cell carcinoma', 'Disease', (182, 202))	('chronic myeloid leukemia', 'Disease', (110, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (208, 228))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (156, 180))	('glioma', 'Disease', (102, 108))	('KEGG pathways', 'Pathway', (43, 56))	('prostate carcinoma', 'Disease', (136, 154))	('cancers', 'Disease', (83, 90))
104552	33287106	Therefore, to get insights into the mechanisms by which EXO_BAD could exert a stronger tumor-supporting function, we focused our attention on two KEGG pathways shared by all the four exosome-related signatures: "Glioma" and "Proteoglycan in cancer".	('stronger', 'PosReg', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Disease', (87, 92))	('Glioma', 'Disease', 'MESH:D005910', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('Glioma', 'Phenotype', 'HP:0009733', (212, 218))	('Glioma', 'Disease', (212, 218))	('cancer', 'Disease', (241, 247))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('EXO_BAD', 'Var', (56, 63))
104557	33287106	Concurrently, three BAD-SPECIFIC miRNAs (miR-29b-3p, miR-34a-5p, and miR-497-5p) were downregulated in both "Glioma" and "Proteoglycans in cancer" pathways, and one, miR-582-3p, exclusively in the "Proteoglycans in cancer" pathway.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('miR-29b-3p', 'Var', (41, 51))	('Glioma', 'Phenotype', 'HP:0009733', (109, 115))	('Glioma', 'Disease', (109, 115))	('miR-34a', 'Gene', '407040', (53, 60))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('miR-34a', 'Gene', (53, 60))	('downregulated', 'NegReg', (86, 99))	('miR-497', 'Gene', (69, 76))	('miR-497', 'Gene', '574456', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Glioma', 'Disease', 'MESH:D005910', (109, 115))	('cancer', 'Disease', (139, 145))
104594	32942567	Cultured GASCs are spindle-shaped, adherent in culture, can be subcultured many times, and express the mesenchymal surface markers CD73, CD90, and CD105.	('CD105', 'Var', (147, 152))	('CD90', 'Gene', '7070', (137, 141))	('CD73', 'Gene', '4907', (131, 135))	('CD90', 'Gene', (137, 141))	('CD73', 'Gene', (131, 135))
104602	32942567	They are typically diploid and do not harbor the genetic alterations commonly seen in GSCs, such as losses of chromosome 10 or gains of chromosome 7, suggesting that GASCs are probably recruited to the tumor from a source other than GSCs.	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('losses', 'Var', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', (202, 207))
104626	32942567	demonstrated that MSC/GB crosstalk differed between two established GB cell lines, U87 and U373, with MSCs inhibiting invasion by U87 cells but enhancing that by U373 cells.	('enhancing', 'PosReg', (144, 153))	('MSCs', 'Var', (102, 106))	('U373', 'CellLine', 'CVCL:2219', (91, 95))	('inhibiting', 'NegReg', (107, 117))	('invasion', 'CPA', (118, 126))	('U373', 'CellLine', 'CVCL:2219', (162, 166))
104628	32942567	The deletion of both chromosome 1p and 19q, O-methylguanine DNA methyltransferase (MGMT) promoter methylation, and mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes are the principal prognostic factors for gliomas identified to date.	('O-methylguanine DNA methyltransferase', 'Gene', '4255', (44, 81))	('MGMT', 'Gene', '4255', (83, 87))	('mutations', 'Var', (115, 124))	('MGMT', 'Gene', (83, 87))	('O-methylguanine DNA methyltransferase', 'Gene', (44, 81))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (132, 170))	('gliomas', 'Disease', 'MESH:D005910', (218, 225))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('gliomas', 'Disease', (218, 225))	('deletion', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))
104639	32942567	They found that the GB patients from whom they were able to isolate GASCs had poorer survival than those from whom no GASCs were isolated.	('patients', 'Species', '9606', (23, 31))	('survival', 'CPA', (85, 93))	('poorer', 'NegReg', (78, 84))	('isolate', 'Var', (60, 67))
104641	32942567	They found that the percentage of GASCs in gliomas was variable between tumors and that patients with high percentages of GASCs in their tumors (fresh or cultured) had a poorer OS than those with a low percentage of these cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('patients', 'Species', '9606', (88, 96))	('GASCs', 'Var', (122, 127))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
104781	31468690	Our study showed that the expression of CTH increased the H2S level, resulting in the activation of NF-kappaB-mediated IL-1beta signaling to instigate cell invasion by sulfhydration on cysteine-38 of the NF-kappaB p65 subunit.	('NF-kappaB', 'Gene', (204, 213))	('cysteine', 'Chemical', 'MESH:D003545', (185, 193))	('H2S', 'Gene', (58, 61))	('CTH', 'Gene', (40, 43))	('expression', 'Var', (26, 36))	('IL-1beta', 'Gene', (119, 127))	('IL-1beta', 'Gene', '3553', (119, 127))	('cell invasion', 'CPA', (151, 164))	('NF-kappaB', 'Gene', '4790', (100, 109))	('NF-kappaB', 'Gene', '4790', (204, 213))	('H2S', 'Gene', '110798', (58, 61))	('increased', 'PosReg', (44, 53))	('activation', 'PosReg', (86, 96))	('sulfhydration on cysteine-38', 'MPA', (168, 196))	('NF-kappaB', 'Gene', (100, 109))
104782	31468690	The orthotopic implantation study showed that knockdown of CTH in PC3 cells resulted in the suppression of primary tumor growth and lower incidence of lymph node and bone metastasis, while overexpression of CTH in DU145 cells promoted primary tumor growth and increased incidence of lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('incidence', 'CPA', (138, 147))	('knockdown', 'Var', (46, 55))	('increased incidence of lymph node', 'Phenotype', 'HP:0032536', (260, 293))	('PC', 'Phenotype', 'HP:0012125', (66, 68))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('promoted', 'PosReg', (226, 234))	('CTH', 'Gene', (59, 62))	('suppression', 'NegReg', (92, 103))	('lower incidence of lymph node', 'Phenotype', 'HP:0002732', (132, 161))	('lower', 'NegReg', (132, 137))	('increased', 'PosReg', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Disease', (243, 248))
104793	31468690	The expression of CTH and its enzymatic gaseous product, hydrogen sulfide (H2S), was increased in PC3-B2 and PC3-B3 cells, as compared with PC3-T2 and PC3-T3 cells (Fig 1C and D).	('PC', 'Phenotype', 'HP:0012125', (98, 100))	('PC', 'Phenotype', 'HP:0012125', (140, 142))	('PC', 'Phenotype', 'HP:0012125', (109, 111))	('PC', 'Phenotype', 'HP:0012125', (151, 153))	('PC3-B2', 'Var', (98, 104))	('H2S', 'Gene', '110798', (75, 78))	('expression', 'MPA', (4, 14))	('H2S', 'Gene', (75, 78))	('increased', 'PosReg', (85, 94))	('hydrogen sulfide', 'MPA', (57, 73))	('CTH', 'Gene', (18, 21))	('hydrogen sulfide', 'Chemical', 'MESH:D006862', (57, 73))
104795	31468690	Our data indicated that PC3-B2 and PC3-B3 exhibited higher metastatic potential than PC3-T2 and PC3-T3 cells (Fig 1E and F, Appendix Fig S1), indicating that PC3-B2 and PC3-B3 cells gained increased migratory ability to disseminate to distant organs such as paraaortic lymph nodes and bone marrow and grew into micro- or macrometastatic tumors, whereas PC3-T2 and PC3-T3 cells had much less ability to do so.	('metastatic potential', 'CPA', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('PC', 'Phenotype', 'HP:0012125', (85, 87))	('PC', 'Phenotype', 'HP:0012125', (158, 160))	('PC3-B2', 'Var', (158, 164))	('PC', 'Phenotype', 'HP:0012125', (96, 98))	('macrometastatic tumors', 'Disease', 'MESH:D009369', (321, 343))	('micro-', 'CPA', (311, 317))	('migratory ability', 'CPA', (199, 216))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('grew', 'CPA', (301, 305))	('PC3-B3', 'Var', (169, 175))	('macrometastatic tumors', 'Disease', (321, 343))	('higher', 'PosReg', (52, 58))	('PC', 'Phenotype', 'HP:0012125', (24, 26))	('PC', 'Phenotype', 'HP:0012125', (35, 37))	('increased', 'PosReg', (189, 198))
104799	31468690	Both total GSH levels and the glutathione disulfide (GSSG)/GSH ratio remained unchanged in PC3-B2 and PC3-B3 cells, as compared with PC3-T2 and PC3-T3 cells (Fig EV1E and F), suggesting that redox homeostasis is not affected in bone-metastatic PC3 cells.	('PC3-B2', 'Var', (91, 97))	('GSH', 'Chemical', 'MESH:D005978', (11, 14))	('GSH', 'Chemical', 'MESH:D005978', (59, 62))	('glutathione disulfide', 'Chemical', 'MESH:D019803', (30, 51))	('PC', 'Phenotype', 'HP:0012125', (102, 104))	('PC', 'Phenotype', 'HP:0012125', (133, 135))	('PC', 'Phenotype', 'HP:0012125', (144, 146))	('PC', 'Phenotype', 'HP:0012125', (244, 246))	('GSSG', 'Chemical', 'MESH:D019803', (53, 57))	('glutathione disulfide', 'MPA', (30, 51))	('GSH levels', 'MPA', (11, 21))	('PC', 'Phenotype', 'HP:0012125', (91, 93))
104805	31468690	Concordantly, the association between CTH expression and poor survival was also observed in pancreatic adenocarcinoma (PAAD) and lower grade glioma (LGG) from the TCGA RNA-seq datasets (Fig EV1G and H), implying that CTH may play a crucial role during cancer progression in various cancer types.	('pancreatic adenocarcinoma', 'Disease', (92, 117))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('PAAD', 'Phenotype', 'HP:0006725', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('poor', 'NegReg', (57, 61))	('cancer', 'Disease', (252, 258))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (92, 117))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('expression', 'Var', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('CTH', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (282, 288))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (92, 117))	('glioma', 'Disease', (141, 147))
104809	31468690	Several polymorphic mutations on CTH are found in patients with cystathioninuria, and mutation on Q240E exhibits ~70-fold decrease in its kinetic activity 37.	('Q240E', 'Mutation', 'p.Q240E', (98, 103))	('kinetic activity 37', 'MPA', (138, 157))	('cystathioninuria', 'Phenotype', 'HP:0003153', (64, 80))	('CTH', 'Gene', (33, 36))	('cystathioninuria', 'Disease', (64, 80))	('patients', 'Species', '9606', (50, 58))	('Q240E', 'Var', (98, 103))	('decrease', 'NegReg', (122, 130))	('cystathioninuria', 'Disease', 'MESH:C535408', (64, 80))	('mutation', 'Var', (86, 94))
104810	31468690	Due to the fact that enzymatic activity of CTH is not completely abolished in this Q240E mutant, there existed residual invasion promoting ability in the cells expressing this mutant.	('Q240E', 'Mutation', 'p.Q240E', (83, 88))	('Q240E', 'Var', (83, 88))	('invasion promoting ability', 'CPA', (120, 146))
104811	31468690	In the future, we will try to identify proteins interacting with this CTHQ240E mutant to decipher the unknown mechanism of how CTH promotes cell migration.	('Q240E', 'Mutation', 'p.Q240E', (73, 78))	('CTHQ240E', 'Var', (70, 78))	('cell migration', 'CPA', (140, 154))
104814	31468690	Among them, IL-1beta, one of the pro-inflammatory cytokines, was significantly inhibited in PC3 cells with CTH knockdown (Fig 3A).	('PC', 'Phenotype', 'HP:0012125', (92, 94))	('IL-1beta', 'Gene', (12, 20))	('knockdown', 'Var', (111, 120))	('IL-1beta', 'Gene', '3553', (12, 20))	('inhibited', 'NegReg', (79, 88))	('CTH', 'Gene', (107, 110))
104816	31468690	By adding human recombinant IL-1beta to the culture medium, the reduced expression of IL-1beta mRNA by CTH knockdown was restored (Fig 3A).	('knockdown', 'Var', (107, 116))	('CTH', 'Gene', (103, 106))	('human', 'Species', '9606', (10, 15))	('expression', 'MPA', (72, 82))	('IL-1beta', 'Gene', (28, 36))	('reduced', 'NegReg', (64, 71))	('IL-1beta', 'Gene', (86, 94))	('IL-1beta', 'Gene', '3553', (28, 36))	('IL-1beta', 'Gene', '3553', (86, 94))
104817	31468690	Secreted IL-1beta protein in the culture medium was reduced in PC3 cells with CTH knockdown (Fig 3B).	('IL-1beta', 'Gene', (9, 17))	('reduced', 'NegReg', (52, 59))	('IL-1beta', 'Gene', '3553', (9, 17))	('CTH', 'Gene', (78, 81))	('knockdown', 'Var', (82, 91))	('PC', 'Phenotype', 'HP:0012125', (63, 65))
104818	31468690	More importantly, decreased cell invasion in PC3 cells with CTH knockdown was restored by treatment with recombinant IL-1beta (Fig 3C), suggesting that the decreased cell invasion by CTH knockdown was likely due to blockage of the IL-1beta production.	('IL-1beta', 'Gene', '3553', (117, 125))	('IL-1beta', 'Gene', '3553', (231, 239))	('knockdown', 'Var', (187, 196))	('cell invasion', 'CPA', (28, 41))	('PC', 'Phenotype', 'HP:0012125', (45, 47))	('cell invasion', 'CPA', (166, 179))	('men', 'Species', '9606', (95, 98))	('decreased', 'NegReg', (156, 165))	('IL-1beta', 'Gene', (117, 125))	('CTH', 'Gene', (183, 186))	('IL-1beta', 'Gene', (231, 239))
104826	31468690	We found that both VEGF mRNA expression and MMP-13 mRNA expression were significantly inhibited in PC3 cells with CTH knockdown, and treatment of IL-1beta partially restored these reductions (Fig 3F and G), indicating the possible involvement of VEGF and MMP-13 in CTH-mediated signaling pathways.	('IL-1beta', 'Gene', (146, 154))	('IL-1beta', 'Gene', '3553', (146, 154))	('PC', 'Phenotype', 'HP:0012125', (99, 101))	('knockdown', 'Var', (118, 127))	('MMP-13', 'Gene', (255, 261))	('men', 'Species', '9606', (138, 141))	('men', 'Species', '9606', (238, 241))	('VEGF', 'Gene', (19, 23))	('VEGF', 'Gene', (246, 250))	('mRNA expression', 'MPA', (24, 39))	('MMP-13', 'Gene', '4322', (44, 50))	('inhibited', 'NegReg', (86, 95))	('CTH', 'Gene', (114, 117))	('mRNA expression', 'MPA', (51, 66))	('VEGF', 'Gene', '7422', (19, 23))	('MMP-13', 'Gene', (44, 50))	('VEGF', 'Gene', '7422', (246, 250))	('MMP-13', 'Gene', '4322', (255, 261))
104828	31468690	In contrast to the rapid production of H2S by NaHS, GYY4137 serves as a slow-releasing donor of H2S 42.	('GYY4137', 'Chemical', 'MESH:C529376', (52, 59))	('H2S', 'Gene', (96, 99))	('NaHS', 'Chemical', 'MESH:D012964', (46, 50))	('H2S', 'Gene', '110798', (39, 42))	('H2S', 'Gene', (39, 42))	('H2S', 'Gene', '110798', (96, 99))	('GYY4137', 'Var', (52, 59))	('donor', 'Species', '9606', (87, 92))
104830	31468690	Treatment with GYY4137 (1-10 muM) also significantly increased cell invasion in PC3 cells (Fig EV4B).	('muM', 'Gene', (29, 32))	('GYY4137', 'Var', (15, 22))	('GYY4137', 'Chemical', 'MESH:C529376', (15, 22))	('PC', 'Phenotype', 'HP:0012125', (80, 82))	('increased', 'PosReg', (53, 62))	('muM', 'Gene', '56925', (29, 32))	('men', 'Species', '9606', (5, 8))	('cell invasion in PC3 cells', 'CPA', (63, 89))
104833	31468690	We further determined that reduced cell invasion by CTH knockdown in PC3 cells was abrogated in the presence of NaHS (Fig 4B), confirming that the CTH promotion of cell invasion was largely through H2S production.	('cell invasion', 'CPA', (164, 177))	('cell invasion', 'CPA', (35, 48))	('H2S', 'Gene', '110798', (198, 201))	('PC', 'Phenotype', 'HP:0012125', (69, 71))	('NaHS', 'Chemical', 'MESH:D012964', (112, 116))	('knockdown', 'Var', (56, 65))	('H2S', 'Gene', (198, 201))
104838	31468690	Moreover, serum-induced p65 nuclear translocation was reduced by CTH knockdown, and this reduction was restored in the presence of NaHS in PC3 cells (Appendix Fig S2).	('p65', 'Protein', (24, 27))	('CTH', 'Protein', (65, 68))	('NaHS', 'Chemical', 'MESH:D012964', (131, 135))	('reduced', 'NegReg', (54, 61))	('PC', 'Phenotype', 'HP:0012125', (139, 141))	('knockdown', 'Var', (69, 78))
104839	31468690	Treatment of NF-kappaB-specific inhibitors, SN50 and QNZ, attenuated NaHS and GYY4137-induced cell invasion (Figs 4D and EV4F), confirming our hypothesis that H2S-mediated cell invasion was due to NF-kappaB activation and its subsequent signaling pathways.	('NaHS', 'Chemical', 'MESH:D012964', (69, 73))	('attenuated', 'NegReg', (58, 68))	('activation', 'PosReg', (207, 217))	('NF-kappaB', 'Gene', (197, 206))	('cell invasion', 'CPA', (172, 185))	('H2S', 'Gene', (159, 162))	('SN50', 'Var', (44, 48))	('GYY4137-induced', 'Var', (78, 93))	('GYY4137', 'Chemical', 'MESH:C529376', (78, 85))	('NF-kappaB', 'Gene', '4790', (13, 22))	('H2S', 'Gene', '110798', (159, 162))	('NaHS', 'Gene', (69, 73))	('NF-kappaB', 'Gene', (13, 22))	('men', 'Species', '9606', (5, 8))	('NF-kappaB', 'Gene', '4790', (197, 206))
104842	31468690	Meanwhile, consistent with previous the observation that H2S mediated gene expression was due to coactivator ribosomal protein S3 (RPS3) 34, knockdown of RPS3 suppressed the expression levels of H2S-induced genes, including IL-1beta, MMP-13, and VEGF (Fig EV4G).	('knockdown', 'Var', (141, 150))	('H2S', 'Gene', (57, 60))	('H2S', 'Gene', '110798', (57, 60))	('suppressed', 'NegReg', (159, 169))	('expression levels', 'MPA', (174, 191))	('IL-1beta', 'Gene', '3553', (224, 232))	('ribosomal protein S3', 'Gene', (109, 129))	('RPS3', 'Gene', '6188', (131, 135))	('MMP-13', 'Gene', '4322', (234, 240))	('H2S', 'Gene', (195, 198))	('RPS3', 'Gene', (131, 135))	('IL-1beta', 'Gene', (224, 232))	('RPS3', 'Gene', '6188', (154, 158))	('RPS3', 'Gene', (154, 158))	('H2S', 'Gene', '110798', (195, 198))	('VEGF', 'Gene', '7422', (246, 250))	('ribosomal protein S3', 'Gene', '6188', (109, 129))	('MMP-13', 'Gene', (234, 240))	('VEGF', 'Gene', (246, 250))
104844	31468690	To determine whether sulfhydration of the NF-kappaB p65 subunit on cysteine 38 34 is required for CTH/H2S-mediated cell invasion, we established PC3 cell lines with CRISPR/Cas9-mediated knockout (KO) of p65 followed by re-expression of p65wild-type or p65C38S mutant by transient transfection (Fig 4G).	('p65wild-type', 'Var', (236, 248))	('H2S', 'Gene', (102, 105))	('NF-kappaB', 'Gene', '4790', (42, 51))	('cysteine', 'Chemical', 'MESH:D003545', (67, 75))	('p65', 'Gene', (203, 206))	('H2S', 'Gene', '110798', (102, 105))	('PC', 'Phenotype', 'HP:0012125', (145, 147))	('NF-kappaB', 'Gene', (42, 51))	('p65C38S', 'Var', (252, 259))
104845	31468690	We then confirmed that sulfhydration of p65 was abolished in p65C38S mutant in the presence of NaHS (Fig EV4H).	('abolished', 'NegReg', (48, 57))	('NaHS', 'Chemical', 'MESH:D012964', (95, 99))	('sulfhydration', 'MPA', (23, 36))	('p65C38S', 'Var', (61, 68))	('p65', 'Protein', (40, 43))
104846	31468690	Depletion of p65 attenuated NaHS-induced cell invasion (Fig 4H), indicating that H2S-mediated cell invasion was due to NF-kappaB activation.	('NaHS', 'Chemical', 'MESH:D012964', (28, 32))	('attenuated', 'NegReg', (17, 27))	('NF-kappaB', 'Gene', '4790', (119, 128))	('p65', 'Gene', (13, 16))	('H2S', 'Gene', '110798', (81, 84))	('activation', 'PosReg', (129, 139))	('NF-kappaB', 'Gene', (119, 128))	('Depletion', 'Var', (0, 9))	('H2S', 'Gene', (81, 84))	('NaHS-induced cell invasion', 'CPA', (28, 54))
104847	31468690	Moreover, re-expression of p65wild-type, but not p65C38S mutant, restored invasion abilities (Fig 4H), suggesting the sulfhydration site on cysteine 38 was required for p65-mediated cell invasion.	('cysteine', 'Chemical', 'MESH:D003545', (140, 148))	('restored', 'PosReg', (65, 73))	('p65wild-type', 'Var', (27, 39))	('invasion abilities', 'CPA', (74, 92))
104850	31468690	To examine whether p65 sulfhydration on cysteine 38 was involved in the progression of prostate cancer metastasis, we transiently transfected p65wild-type or p65C38S mutant in p65 KO PC3 cells, and then, those cells were inoculated into the mice via tail-vein injection.	('p65C38S', 'Var', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mice', 'Species', '10090', (241, 245))	('prostate cancer metastasis', 'Disease', (87, 113))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('PC', 'Phenotype', 'HP:0012125', (183, 185))	('cysteine', 'Chemical', 'MESH:D003545', (40, 48))	('prostate cancer metastasis', 'Disease', 'MESH:D011471', (87, 113))	('p65wild-type', 'Var', (142, 154))
104851	31468690	The p65 KO PC3 cells with the p65C38S mutant re-expression showed decreased number of lung-metastatic nodules (Fig 4I and J) and reduced percentage of lung-metastatic area (Fig 4I and K), as compared to the p65wild-type re-expression group, suggesting that p65 sulfhydration could be directly involved in the promotion of cancer metastasis.	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('lung-metastatic nodules', 'CPA', (86, 109))	('cancer', 'Disease', (322, 328))	('decreased', 'NegReg', (66, 75))	('PC', 'Phenotype', 'HP:0012125', (11, 13))	('C38S', 'Mutation', 'p.C38S', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('reduced', 'NegReg', (129, 136))	('lung-metastatic area', 'CPA', (151, 171))	('p65C38S', 'Var', (30, 37))
104858	31468690	Metastases in paraaortic lymph nodes were observed in 80% of mice in the shCon group compared with only 40% in the shCTH group (Fig 5D).	('mice', 'Species', '10090', (61, 65))	('Metastases', 'Disease', (0, 10))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))	('shCon', 'Var', (73, 78))
104862	31468690	As expected, the expression levels of CTH in the orthotopically implanted tumors were reduced in the shCTH groups, as compared with the shCon group (Fig 5F).	('reduced', 'NegReg', (86, 93))	('expression levels', 'MPA', (17, 34))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CTH', 'Protein', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('shCTH', 'Var', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
104864	31468690	DU145 line was originally derived from brain, and not bone, metastasis 43, and the expression level of CTH was much lower in DU145 cells, as compared to other prostate cancer lines (Fig EV1C).	('lower', 'NegReg', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('expression level', 'MPA', (83, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (159, 174))	('prostate cancer', 'Phenotype', 'HP:0012125', (159, 174))	('CTH', 'Protein', (103, 106))	('DU145', 'Var', (125, 130))	('prostate cancer', 'Disease', (159, 174))
104870	31468690	To investigate whether CTH knockdown affects angiogenesis and lymphangiogenesis, we examined the expression of corresponding endothelial cell markers using respective antibodies, anti-cluster of differentiation 31 (CD31), and anti-lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), in primary orthotopic tumors with immunohistochemical analysis.	('knockdown', 'Var', (27, 36))	('CD31', 'Gene', (215, 219))	('CTH', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('affects', 'Reg', (37, 44))	('orthotopic tumors', 'Disease', 'MESH:D009369', (303, 320))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('orthotopic tumors', 'Disease', (303, 320))	('LYVE-1', 'Gene', '10894', (283, 289))	('LYVE-1', 'Gene', (283, 289))
104872	31468690	In tumors with CTH knockdown, the numbers of vessel-like structures revealed by CD31 or LYVE-1 antibody staining were significantly reduced, as compared with the shCon group (Fig 5G and H).	('CTH', 'Gene', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('knockdown', 'Var', (19, 28))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('reduced', 'NegReg', (132, 139))	('LYVE-1', 'Gene', '10894', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('CD31', 'Protein', (80, 84))	('LYVE-1', 'Gene', (88, 94))
104884	31468690	In contrast, the expression of CTHQ240E, the mutant form of CTH with lower enzymatic activity 37, induced only cell migration, but not cell invasion (Fig EV2F), suggesting that the enzyme activity of CTH promoted cell invasion mainly through its derivative product, H2S, mediated signaling pathways.	('CTHQ240E', 'Var', (31, 39))	('cell invasion', 'CPA', (213, 226))	('CTH', 'Gene', (60, 63))	('induced', 'Reg', (98, 105))	('cell migration', 'CPA', (111, 125))	('H2S', 'Gene', '110798', (266, 269))	('H2S', 'Gene', (266, 269))	('promoted', 'PosReg', (204, 212))
104885	31468690	NF-kappaB activation requires translocation of NF-kappaB subunits, p65 and p50, from the cytosol to the nucleus 48, 49.	('p50', 'Gene', (75, 78))	('NF-kappaB', 'Gene', '4790', (0, 9))	('translocation', 'MPA', (30, 43))	('p50', 'Gene', '4790', (75, 78))	('NF-kappaB', 'Gene', (47, 56))	('NF-kappaB', 'Gene', (0, 9))	('p65', 'Var', (67, 70))	('activation', 'PosReg', (10, 20))	('NF-kappaB', 'Gene', '4790', (47, 56))
104899	31468690	Here, we observed that lymphangiogenesis was significantly reduced in CTH knockdown tumors (Fig 5H).	('CTH', 'Gene', (70, 73))	('reduced', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('knockdown', 'Var', (74, 83))	('lymphangiogenesis', 'CPA', (23, 40))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
104900	31468690	Simultaneously, we observed lower incidence of paraaortic lymph node metastases in mice bearing tumors with CTH knockdown (Fig 5D), implying that reduced lymphangiogenesis by CTH knockdown may result in reduced lymph node metastasis.	('paraaortic lymph node metastases', 'Disease', (47, 79))	('lymph node metastasis', 'CPA', (211, 232))	('reduced lymph node', 'Phenotype', 'HP:0002732', (203, 221))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lower', 'NegReg', (28, 33))	('reduced', 'NegReg', (203, 210))	('tumors', 'Disease', (96, 102))	('reduced', 'NegReg', (146, 153))	('paraaortic lymph node metastases', 'Disease', 'MESH:D009362', (47, 79))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mice', 'Species', '10090', (83, 87))	('CTH', 'Gene', (175, 178))	('knockdown', 'Var', (112, 121))	('knockdown', 'Var', (179, 188))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('lymphangiogenesis', 'CPA', (154, 171))	('CTH', 'Gene', (108, 111))
104915	31468690	The H2S donors, NaHS (for fast release) or GYY4137 (for slow release), were purchased from Sigma-Aldrich.	('GYY4137', 'Var', (43, 50))	('H2S', 'Gene', (4, 7))	('donor', 'Species', '9606', (8, 13))	('GYY4137', 'Chemical', 'MESH:C529376', (43, 50))	('NaHS', 'Chemical', 'MESH:D012964', (16, 20))	('H2S', 'Gene', '110798', (4, 7))
104957	31468690	For the tail-vein injection experiment, 1 x 106 PC3 cells with p65 knockout were transiently re-expressed p65wild-type or p65C38S and inoculated into the bloodstream via tail-vein injection.	('p65C38S', 'Var', (122, 129))	('PC', 'Phenotype', 'HP:0012125', (48, 50))	('p65wild-type', 'Var', (106, 118))	('p65', 'Gene', (63, 66))	('men', 'Species', '9606', (34, 37))
105001	29065666	Generally, calcification inside oligo tumor turns out hypointensity on T2-weighted and isointensity on T1-weighted precontrast MRI.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('hypointensity', 'Var', (54, 67))	('calcification', 'Disease', (11, 24))	('isointensity', 'Var', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('calcification', 'Disease', 'MESH:D002114', (11, 24))
105132	23765250	In summary, our data show that the ALT and ATRX protein alterations are common in both pediatric and adult high-grade astrocytomas, often with associated PDGFRA gene amplification.	('ATRX', 'Gene', (43, 47))	('alterations', 'Var', (56, 67))	('ATRX', 'Gene', '546', (43, 47))	('astrocytomas', 'Disease', 'MESH:D001254', (118, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('PDGFRA', 'Gene', (154, 160))	('astrocytomas', 'Disease', (118, 130))	('ALT', 'Protein', (35, 38))	('PDGFRA', 'Gene', '5156', (154, 160))
105138	23765250	Mutations that inactivate these genes are common in human pancreatic neuroendocrine tumors and central nervous system tumors.	('central nervous system tumors', 'Phenotype', 'HP:0100006', (95, 124))	('pancreatic neuroendocrine tumors and central nervous system tumors', 'Disease', 'MESH:D018358', (58, 124))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('human', 'Species', '9606', (52, 57))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (69, 90))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('common', 'Reg', (42, 48))	('nervous system tumors', 'Phenotype', 'HP:0004375', (103, 124))
105140	23765250	ALT can lead to immortalization of cells and carcinogenesis and is not seen in normal cells.	('ALT', 'Var', (0, 3))	('immortalization of cells', 'CPA', (16, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('carcinogenesis', 'Disease', (45, 59))	('lead to', 'Reg', (8, 15))
105142	23765250	A majority of diffuse low-grade and anaplastic adult astrocytomas, as well as secondary forms of glioblastoma, harbor mutations in the genes encoding isocitrate dehydrogenase IDH1 and IDH2.	('IDH2', 'Gene', (184, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('astrocytomas', 'Disease', (53, 65))	('citrate', 'Chemical', 'MESH:D019343', (153, 160))	('mutations', 'Var', (118, 127))	('IDH1', 'Gene', (175, 179))	('adult astrocytomas', 'Phenotype', 'HP:0009592', (47, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (53, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (53, 64))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
105143	23765250	IDH mutations and ATRX gene alterations often appear together in these astrocytomas.	('IDH', 'Gene', (0, 3))	('alterations', 'Var', (28, 39))	('astrocytomas', 'Disease', (71, 83))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('ATRX', 'Gene', (18, 22))	('appear', 'Reg', (46, 52))	('ATRX', 'Gene', '546', (18, 22))	('mutations', 'Var', (4, 13))	('astrocytomas', 'Disease', 'MESH:D001254', (71, 83))
105144	23765250	In addition, high-grade astrocytomas that lack ATRX expression and are ALT-positive often have mutations in the IDH genes.	('ATRX', 'Gene', (47, 51))	('astrocytomas', 'Disease', 'MESH:D001254', (24, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('ATRX', 'Gene', '546', (47, 51))	('mutations', 'Var', (95, 104))	('IDH', 'Gene', (112, 115))	('astrocytomas', 'Disease', (24, 36))
105145	23765250	However, in contrast to adult central nervous system tumors, IDH mutations are exceptionally rare in pediatric high-grade astrocytomas.	('central nervous system tumors', 'Phenotype', 'HP:0100006', (30, 59))	('adult central nervous system tumors', 'Disease', 'MESH:D016543', (24, 59))	('astrocytomas', 'Disease', 'MESH:D001254', (122, 134))	('nervous system tumors', 'Phenotype', 'HP:0004375', (38, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('astrocytomas', 'Disease', (122, 134))	('adult central nervous system tumors', 'Disease', (24, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('IDH', 'Gene', (61, 64))	('mutations', 'Var', (65, 74))
105146	23765250	Amplification of the platelet-derived growth factor receptor alpha (PDGFRA) gene occurs in significant subsets of pediatric and adult high-grade astrocytomas.	('astrocytomas', 'Disease', (145, 157))	('occurs', 'Reg', (81, 87))	('PDGFRA', 'Gene', (68, 74))	('Amplification', 'Var', (0, 13))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('astrocytomas', 'Disease', 'MESH:D001254', (145, 157))	('PDGFRA', 'Gene', '5156', (68, 74))
105147	23765250	As ALT and ATRX mutations are also common in high-grade astrocytomas, particularly in pediatric and young adult populations, we wanted to investigate the association of PDGFRA amplification with alterations in ALT/ATRX in adult and pediatric gliomas.	('alterations', 'Var', (195, 206))	('common', 'Reg', (35, 41))	('ATRX', 'Gene', '546', (214, 218))	('gliomas', 'Disease', 'MESH:D005910', (242, 249))	('gliomas', 'Phenotype', 'HP:0009733', (242, 249))	('ALT', 'Gene', (3, 6))	('gliomas', 'Disease', (242, 249))	('ATRX', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('PDGFRA', 'Gene', (169, 175))	('astrocytomas', 'Disease', 'MESH:D001254', (56, 68))	('ATRX', 'Gene', '546', (11, 15))	('PDGFRA', 'Gene', '5156', (169, 175))	('astrocytoma', 'Phenotype', 'HP:0009592', (56, 67))	('ATRX', 'Gene', (214, 218))	('astrocytomas', 'Disease', (56, 68))
105149	23765250	Our findings suggest a significant association between ALT positivity and loss of ATRX in both adult and pediatric high-grade astrocytomas and a correlation between ALT and PDGFRA status.	('astrocytomas', 'Disease', 'MESH:D001254', (126, 138))	('ATRX', 'Gene', (82, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('positivity', 'Var', (59, 69))	('ATRX', 'Gene', '546', (82, 86))	('astrocytomas', 'Disease', (126, 138))	('loss', 'NegReg', (74, 78))	('PDGFRA', 'Gene', (173, 179))	('ALT', 'Gene', (55, 58))	('PDGFRA', 'Gene', '5156', (173, 179))	('correlation', 'Reg', (145, 156))
105184	23765250	Thus, loss of ATRX staining was significantly associated with ALT in pediatric high-grade astrocytomas (P<0.0001).	('astrocytomas', 'Disease', (90, 102))	('loss', 'Var', (6, 10))	('ATRX', 'Gene', (14, 18))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('ATRX', 'Gene', '546', (14, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('associated', 'Reg', (46, 56))	('ALT', 'Disease', (62, 65))
105186	23765250	Telomere-specific FISH analysis in adult high-grade astrocytomas identified ALT positivity in 24 of 91 cases (26.4%; Table 1).	('ALT', 'MPA', (76, 79))	('astrocytomas', 'Disease', 'MESH:D001254', (52, 64))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('positivity', 'Var', (80, 90))	('astrocytomas', 'Disease', (52, 64))
105192	23765250	The associations between ALT positivity and ATRX loss in high-grade astrocytomas remained statistically significant with sub-stratification into adult anaplastic astrocytoma and glioblastoma subsets (P<0.0001; Table 4).	('ATRX', 'Gene', (44, 48))	('loss', 'NegReg', (49, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('ATRX', 'Gene', '546', (44, 48))	('astrocytoma', 'Disease', 'MESH:D001254', (162, 173))	('astrocytomas', 'Disease', (68, 80))	('glioblastoma', 'Disease', (178, 190))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('ALT', 'Gene', (25, 28))	('astrocytoma', 'Disease', (162, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('astrocytoma', 'Disease', 'MESH:D001254', (68, 79))	('astrocytoma', 'Phenotype', 'HP:0009592', (162, 173))	('positivity', 'Var', (29, 39))	('astrocytoma', 'Disease', (68, 79))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))
105194	23765250	In all, 26 of 72 adult high-grade astrocytomas (26.1%) stained positive for the IDH1 mutant, whereas 72.7% (8/11) of adult low-grade WHO grade II astrocytomas were IDH1 mutant (Table 5).	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('IDH1', 'Gene', (80, 84))	('II astrocytomas', 'Disease', 'MESH:D001254', (143, 158))	('astrocytomas', 'Disease', 'MESH:D001254', (34, 46))	('II astrocytomas', 'Disease', (143, 158))	('astrocytomas', 'Disease', 'MESH:D001254', (146, 158))	('astrocytoma', 'Phenotype', 'HP:0009592', (146, 157))	('astrocytomas', 'Disease', (34, 46))	('mutant', 'Var', (85, 91))	('astrocytomas', 'Disease', (146, 158))	('stained positive', 'Reg', (55, 71))
105197	23765250	In adult high-grade astrocytomas, 50% (9/18) of ALT-positive cases harbored PDGFRA amplification, which was significantly higher than the 26% (14/54) amplification rate seen in ALT-negative tumors (P = 0.031).	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('astrocytomas', 'Disease', 'MESH:D001254', (20, 32))	('higher', 'PosReg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('ALT-positive', 'Gene', (48, 60))	('PDGFRA', 'Gene', '5156', (76, 82))	('PDGFRA', 'Gene', (76, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (20, 31))	('astrocytomas', 'Disease', (20, 32))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('amplification', 'Var', (83, 96))
105207	23765250	Our data suggest that the ALT phenotype is highly associated with ATRX loss in high-grade astrocytomas of both age groups (P<0.0001), supporting the model in which loss of ATRX function impairs the heterochromatic state of telomeres, perhaps because of reduced levels of histone H3.3 incorporation; this subsequently leads to telomere destabilization and increased homologous recombination, thus facilitating the development of ALT.	('astrocytomas', 'Disease', (90, 102))	('increased', 'PosReg', (355, 364))	('ALT', 'Disease', (26, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('telomere destabilization', 'MPA', (326, 350))	('ATRX', 'Gene', (172, 176))	('leads to', 'Reg', (317, 325))	('incorporation', 'MPA', (284, 297))	('homologous recombination', 'MPA', (365, 389))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('ATRX', 'Gene', '546', (172, 176))	('impairs', 'NegReg', (186, 193))	('loss', 'Var', (164, 168))	('ALT', 'Disease', (428, 431))	('ATRX', 'Gene', (66, 70))	('reduced', 'NegReg', (253, 260))	('ATRX', 'Gene', '546', (66, 70))	('heterochromatic state of telomeres', 'MPA', (198, 232))	('loss', 'NegReg', (71, 75))
105213	23765250	Most patients whose tumors were characterized by the protein complex of G34 or K27 mutant histone H3.3 and ATRX clustered in the adolescent and young adult populations.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('patients', 'Species', '9606', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('histone H3.3', 'Protein', (90, 102))	('ATRX', 'Gene', (107, 111))	('K27 mutant', 'Var', (79, 89))	('ATRX', 'Gene', '546', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('G34', 'Var', (72, 75))
105216	23765250	Amplification of the PDGFRA gene is also present in a significant subset of pediatric and adult high-grade astrocytomas.	('PDGFRA', 'Gene', (21, 27))	('Amplification', 'Var', (0, 13))	('PDGFRA', 'Gene', '5156', (21, 27))	('astrocytomas', 'Disease', 'MESH:D001254', (107, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('astrocytomas', 'Disease', (107, 119))
105217	23765250	Of interest, our study identified a significant association between PDGFRA amplification and ALT positivity in both adult and pediatric high-grade astrocytomas (P = 0.03).	('PDGFRA', 'Gene', (68, 74))	('astrocytomas', 'Disease', 'MESH:D001254', (147, 159))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('amplification', 'Var', (75, 88))	('astrocytomas', 'Disease', (147, 159))	('positivity', 'Var', (97, 107))	('ALT', 'Gene', (93, 96))	('PDGFRA', 'Gene', '5156', (68, 74))
105221	23765250	For example, some missense ATRX mutations would not be detected by routine immunohistochemistry.	('ATRX', 'Gene', '546', (27, 31))	('ATRX', 'Gene', (27, 31))	('missense', 'Var', (18, 26))
105222	23765250	ALT may also occur because of mutations of other genes, such as DAXX, although this appears to be rare in gliomas.	('mutations', 'Var', (30, 39))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('ALT', 'Disease', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))
105226	23765250	Finally, our study found potential interactions between ALT/ATRX and other genetic alterations such as PDGFRA amplification, which should be explored further in the development of individualized treatment strategies.	('PDGFRA', 'Gene', (103, 109))	('amplification', 'Var', (110, 123))	('interactions', 'Interaction', (35, 47))	('PDGFRA', 'Gene', '5156', (103, 109))	('ATRX', 'Gene', '546', (60, 64))	('ATRX', 'Gene', (60, 64))
105296	28498803	Phage enrichment (i.e., bio-selection) was performed on solid-phase coated cytosolic proteins isolated from NCH644 and NCH421K GBM stem-like cell lines.	('men', 'Species', '9606', (12, 15))	('NCH421K', 'Var', (119, 126))	('NCH644', 'Gene', (108, 114))
105366	25392408	We identified three clusters, where Cluster 2 was enriched with IDH1 and IDH2 wild-type samples and the other two clusters were enriched for IDH1 or IDH2 mutants.	('IDH1', 'Gene', (141, 145))	('IDH2', 'Gene', (149, 153))	('IDH1', 'Gene', '3417', (141, 145))	('IDH1', 'Gene', (64, 68))	('IDH2', 'Gene', '3418', (149, 153))	('IDH1', 'Gene', '3417', (64, 68))	('IDH2', 'Gene', (73, 77))	('mutants', 'Var', (154, 161))	('IDH2', 'Gene', '3418', (73, 77))
105368	25392408	Unlike the LGG cohort, the GBM cohort harbors mutations in IDH1 but not in IDH2.	('IDH1', 'Gene', '3417', (59, 63))	('mutations', 'Var', (46, 55))	('IDH2', 'Gene', (75, 79))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('IDH2', 'Gene', '3418', (75, 79))	('IDH1', 'Gene', (59, 63))
105467	25163530	Nine characteristic metabolites were directly connected to the GFAP and MMP-9 pathway network, including Val, Glu, GSH, Tyr, Phe, Leu, Ace, GPC and Cr.	('Val', 'Chemical', 'MESH:D014633', (105, 108))	('Leu', 'Var', (130, 133))	('Ace', 'Gene', (135, 138))	('GSH', 'MPA', (115, 118))	('Glu', 'Chemical', 'MESH:D018698', (110, 113))	('Val', 'MPA', (105, 108))	('Tyr', 'MPA', (120, 123))	('Cr', 'Chemical', 'MESH:D003401', (148, 150))	('Leu', 'Chemical', 'MESH:D007930', (130, 133))	('GPC', 'Chemical', 'MESH:D005997', (140, 143))	('Phe', 'Chemical', 'MESH:D010649', (125, 128))	('GSH', 'Chemical', 'MESH:D005978', (115, 118))	('Phe', 'MPA', (125, 128))	('GPC', 'MPA', (140, 143))	('GFAP', 'Gene', (63, 67))	('Ace', 'Gene', '1636', (135, 138))	('Tyr', 'Chemical', 'MESH:D014443', (120, 123))	('Glu', 'MPA', (110, 113))	('GFAP', 'Gene', '2670', (63, 67))	('MMP-9', 'Gene', '4318', (72, 77))	('MMP-9', 'Gene', (72, 77))
105470	25163530	The altered amino acids in the tumor are mostly involved in TCA cycle anaplerosis  and protein biosynthesis .	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('TCA cycle', 'Disease', (60, 69))	('amino acids', 'MPA', (12, 23))	('altered', 'Var', (4, 11))	('tumor', 'Disease', (31, 36))	('involved', 'Reg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('TCA', 'Chemical', 'MESH:D014233', (60, 63))
105471	25163530	It has been reported that Phe, Tyr, Leu and Val are involved in anaplerosis, which enter the TCA cycle by being converted into fumarate and succinyl CoA, respectively .	('Tyr', 'Chemical', 'MESH:D014443', (31, 34))	('Phe', 'Var', (26, 29))	('fumarate', 'Chemical', 'MESH:D005650', (127, 135))	('Val', 'Var', (44, 47))	('Tyr', 'Var', (31, 34))	('anaplerosis', 'Disease', (64, 75))	('Leu', 'Var', (36, 39))	('succinyl CoA', 'Chemical', 'MESH:C012046', (140, 152))	('Leu', 'Chemical', 'MESH:D007930', (36, 39))	('TCA', 'Chemical', 'MESH:D014233', (93, 96))	('Val', 'Chemical', 'MESH:D014633', (44, 47))	('involved', 'Reg', (52, 60))	('Phe', 'Chemical', 'MESH:D010649', (26, 29))
105473	25163530	Even though, the level of Phe was decreased, the amino acids including Val, Gln, Tyr, Leu were generally up- regulated in the high group, suggesting that more active TCA cycle anaplerotic flux might occur during malignant transformation of glioma cells.	('decreased', 'NegReg', (34, 43))	('malignant transformation of glioma', 'Phenotype', 'HP:0012174', (212, 246))	('more', 'PosReg', (154, 158))	('up- regulated', 'PosReg', (105, 118))	('Val', 'Chemical', 'MESH:D014633', (71, 74))	('Tyr', 'Chemical', 'MESH:D014443', (81, 84))	('glioma', 'Disease', (240, 246))	('Leu', 'Var', (86, 89))	('Val', 'MPA', (71, 74))	('level', 'MPA', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('TCA cycle anaplerotic flux', 'MPA', (166, 192))	('TCA', 'Chemical', 'MESH:D014233', (166, 169))	('Leu', 'Chemical', 'MESH:D007930', (86, 89))	('Gln', 'Chemical', 'MESH:D005973', (76, 79))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('Gln', 'MPA', (76, 79))	('Phe', 'Chemical', 'MESH:D010649', (26, 29))	('Tyr', 'MPA', (81, 84))	('Phe', 'MPA', (26, 29))
105527	25163530	Then 50 mul of D2O containing 1.5 M KH2PO4 and 0.1% sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 (TSP) was added.	('TSP', 'Gene', (100, 103))	('KH2PO4', 'Var', (36, 42))	('D2O', 'Chemical', 'MESH:D017666', (15, 18))	('KH2PO4', 'Chemical', '-', (36, 42))	('sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4', 'Chemical', '-', (52, 98))	('TSP', 'Gene', '83592', (100, 103))
105563	18398462	In efforts to identify crucial cellular and molecular targets for glioma treatment, recent studies have indicated that all grades of gliomas contain putative tumor stem cells, which can be CD133+ or CD133- .	('glioma', 'Disease', (66, 72))	('tumor', 'Disease', (158, 163))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('CD133-', 'Var', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('glioma', 'Disease', (133, 139))	('CD133+', 'Var', (189, 195))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Disease', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
105564	18398462	Particularly, CD133+ putative GBM stem cells were capable of xenograft GBM initiation where the CD133- GBM cells from the same patients failed to do so.	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('patients', 'Species', '9606', (127, 135))	('xenograft GBM initiation', 'CPA', (61, 85))	('CD133+', 'Var', (14, 20))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))
105612	18398462	As in low-grade glioma cells, high-grade glioma cells analyzed in this study maintained the expression profiles for PDGFRalpha, A2B5, O4 and CD44 ( Table 1 and Figure 3).	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Disease', (16, 22))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('glioma', 'Disease', (41, 47))	('A2B5', 'Gene', (128, 132))	('CD44', 'Var', (141, 145))	('expression', 'MPA', (92, 102))	('PDGFRalpha', 'Gene', (116, 126))
105621	18398462	As shown in Figure 4, a small population of CD45-, but CD133+ cells can be detected in low-grade glioma specimens.	('glioma', 'Disease', (97, 103))	('CD45', 'Gene', (44, 48))	('CD133+', 'Var', (55, 61))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('CD45', 'Gene', '5788', (44, 48))
105623	18398462	This indicates that CD133+ cells, if present in low-grade gliomas, are predominantly derived from newly formed blood vessel endothelial cells, and not from the glioma cells.	('CD133+', 'Var', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Disease', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glioma', 'Disease', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
105624	18398462	In GBM specimens, the majority of CD133+ cells were of glioma origin, although CD31+CD133+ cells (ranging from 0.5 to 10% of the total living cells, n = 9) were also found.	('glioma', 'Disease', (55, 61))	('CD31', 'Gene', '5175', (79, 83))	('CD133+ cells', 'Var', (34, 46))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('CD31', 'Gene', (79, 83))
105626	18398462	In contrast to the high level A2B5 and O4 expression, the frequency of O1+ cells were significantly diminished in all low-grade and the majority of GBM specimens analyzed (Table 1 and Figure 5).	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('O1+', 'Var', (71, 74))	('diminished', 'NegReg', (100, 110))	('A2B5 and O4', 'Gene', '28894', (30, 41))
105627	18398462	The expression of GFAP and these oligodendrocyte progenitor surface markers suggests that along the oligodendrocyte lineage differentiation hierarchy, A2B5+/PDGFRalpha+ glioma cells were compromised in differentiation downstream of A2B5/O4, but upstream of the O1 stage.	('A2B5+/PDGFRalpha+', 'Var', (151, 168))	('glioma', 'Disease', (169, 175))	('differentiation', 'CPA', (202, 217))	('compromised', 'NegReg', (187, 198))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('A2B5/O4', 'Var', (232, 239))
105646	18398462	Our data show that nearly all low-grade glioma cells from the analyzed cases concomitantly express multiple cell surface markers for glial progenitor cells, such as PDGFRalpha, A2B5, O4, and CD44.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('PDGFRalpha', 'Gene', (165, 175))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('A2B5', 'Var', (177, 181))	('CD44', 'Gene', (191, 195))
105658	18398462	The aforementioned A2B5+O4-PDGFRalpha- GRPs and A2B5+O4-PDGFRalpha-CD44+ ARPs may also exist.	('A2B5+O4-PDGFRalpha-CD44+', 'Var', (48, 72))	('ARP', 'Gene', (73, 76))	('ARP', 'Gene', '7873', (73, 76))
105665	18398462	This CD44 expression does not necessarily contradict the oligodendrocyte lineage commitment of A2B5+PDGFRalpha+O4+ glioma cells which exhibited a concomitant GFAP expression, because a misexpression of CD44 can result in expansion of oligodendrocyte progenitor cells with impaired maturation and concomitant gain of GFAP expression.	('expansion', 'PosReg', (221, 230))	('GFAP expression', 'MPA', (316, 331))	('glioma', 'Disease', (115, 121))	('expansion of oligodendrocyte', 'Phenotype', 'HP:0100709', (221, 249))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('CD44', 'Gene', (202, 206))	('rat', 'Species', '10116', (285, 288))	('gain', 'PosReg', (308, 312))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('misexpression', 'Var', (185, 198))
105666	18398462	However, it cannot be excluded that A2B5+CD44+GFAP+ glioma cells without detectable PDGFRalpha and O4 expression (e.g.	('glioma', 'Disease', (52, 58))	('A2B5+CD44+GFAP+', 'Var', (36, 51))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (52, 58))
105688	31507631	The Cancer-Associated Genetic Variant Rs3903072 Modulates Immune Cells in the Tumor Microenvironment Genome-wide association studies (GWAS) have hitherto identified several germline variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('Rs3903072', 'Mutation', 'Rs3903072', (38, 47))	('cancer', 'Disease', (207, 213))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Modulates', 'Reg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('associated', 'Reg', (191, 201))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Rs3903072', 'Var', (38, 47))	('Tumor', 'Phenotype', 'HP:0002664', (78, 83))
105691	31507631	This paper presents evidence that the breast-cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor-infiltrating lymphocytes.	('breast-cancer', 'Disease', (38, 51))	('rs3903072', 'Var', (71, 80))	('CTSW', 'Gene', '1521', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('regulate', 'Reg', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CTSW', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('breast-cancer', 'Disease', 'MESH:D001943', (38, 51))	('rs3903072', 'Mutation', 'rs3903072', (71, 80))	('tumor', 'Disease', (120, 125))	('expression', 'MPA', (98, 108))
105693	31507631	Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3' end of CTSW through three-dimensional chromatin interaction.	('CTSW', 'Gene', '1521', (127, 131))	('variant', 'Var', (50, 57))	('GWAS-linked', 'Gene', (63, 74))	('CTSW', 'Gene', (127, 131))	('enhancer', 'PosReg', (75, 83))
105694	31507631	Our work thus poses the possibility that a cancer-associated genetic variant could regulate a gene not only in the cell of cancer origin but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('variant', 'Var', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('affecting', 'Reg', (276, 285))	('genetic variant', 'Var', (61, 76))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (308, 314))	('cancer', 'Disease', (123, 129))	('regulate', 'Reg', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('immune surveillance', 'MPA', (210, 229))	('gene', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('modulating', 'Reg', (195, 205))
105696	31507631	The cancer-associated genetic variants discovered by GWAS, however, are not necessarily causative themselves but may be in linkage disequilibrium (LD) with other functional variants.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('variants', 'Var', (30, 38))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))
105697	31507631	Since most GWAS variants are located in noncoding regions, previous functional characterization studies have focused on the gene regulatory function of these linked variants in cancer cells themselves and in matched normal counterparts.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('variants', 'Var', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('variants', 'Var', (16, 24))
105698	31507631	For example, usage of breast cancer epigenome facilitated the discovery of a GWAS-linked functional variant that disrupts a binding site of FOXA1, which is a critical pioneer factor in estrogen receptor-positive (ER+) breast cancers; similarly, another study identified a functional diabetes-associated variant using the epigenomic information in adipose-derived mesenchymal stem cells.	('binding', 'Interaction', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancers', 'Disease', 'MESH:D001943', (218, 232))	('breast cancers', 'Disease', (218, 232))	('diabetes', 'Disease', 'MESH:D003920', (283, 291))	('variant', 'Var', (303, 310))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('FOXA1', 'Gene', '3169', (140, 145))	('breast cancers', 'Phenotype', 'HP:0003002', (218, 232))	('FOXA1', 'Gene', (140, 145))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('breast cancer', 'Disease', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('diabetes', 'Disease', (283, 291))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('variant', 'Var', (100, 107))	('disrupts', 'NegReg', (113, 121))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
105699	31507631	Although new insights have resulted from these investigations, a provocative question that has not yet been examined is whether select cancer-associated germline variants could also be functional in cell types other than the cell of cancer origin, such as endothelial cells and immune cells, within the heterogeneous tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', (233, 239))	('variants', 'Var', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
105700	31507631	For example, in tumor-infiltrating lymphocytes (TIL), genetic variants regulating cytotoxicity-controlling genes may impact TIL's ability to eliminate cancerous cells, thereby functioning as cryptic modulators of cancer susceptibility that have escaped our attention to date.	('genetic variants', 'Var', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('ability', 'MPA', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cytotoxicity', 'Disease', (82, 94))	('cancerous', 'Disease', 'MESH:D009369', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('impact', 'Reg', (117, 123))	('cancer', 'Disease', (151, 157))	('tumor', 'Disease', (16, 21))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('cancerous', 'Disease', (151, 160))
105701	31507631	Since cancer initiation not only involves the acquisition of mutations in normal cells but also depends on the efficiency of immune surveillance against abnormal cells, it is important to identify cancer-associated germline variants that may contribute to cancer susceptibility through modulating immune cells.	('contribute', 'Reg', (242, 252))	('variants', 'Var', (224, 232))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('modulating', 'Reg', (286, 296))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('immune cells', 'CPA', (297, 309))	('cancer', 'Disease', (6, 12))
105702	31507631	We have previously introduced a systematic computational framework for studying regulatory functions of noncoding GWAS variants associated with ER+ breast cancer by employing epigenomic information from breast cancer cell lines and normal mammary epithelial cells.	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', (203, 216))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('breast cancer', 'Disease', (148, 161))	('associated', 'Reg', (128, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('GWAS', 'Gene', (114, 118))	('variants', 'Var', (119, 127))
105703	31507631	By incorporating additional data in immune cells, we here apply this approach to present evidence for the possibility that a breast cancer GWAS variant may influence immune cells in the microenvironment of tumor or its precursor.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('immune', 'CPA', (166, 172))	('breast cancer', 'Disease', (125, 138))	('variant', 'Var', (144, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('influence', 'Reg', (156, 165))	('GWAS', 'Gene', (139, 143))
105704	31507631	We demonstrate that the breast-cancer-associated single nucleotide polymorphisms (SNP), rs3903072, targets the gene CTSW uniquely in TILs.	('breast-cancer', 'Disease', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CTSW', 'Gene', '1521', (116, 120))	('single nucleotide polymorphisms', 'Var', (49, 80))	('targets', 'Reg', (99, 106))	('breast-cancer', 'Disease', 'MESH:D001943', (24, 37))	('rs3903072', 'Mutation', 'rs3903072', (88, 97))	('CTSW', 'Gene', (116, 120))	('rs3903072', 'Var', (88, 97))
105705	31507631	CTSW encodes a cysteine proteinase highly specific to natural killer (NK) cells and T cells and is potentially involved in regulating their cytotoxity; consistently, CTSW expression negatively correlates with both the risk allele at rs3903072 and the survival probability in breast cancer.	('expression', 'MPA', (171, 181))	('negatively', 'NegReg', (182, 192))	('CTSW', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('rs3903072', 'Mutation', 'rs3903072', (233, 242))	('cytotoxity', 'Disease', 'MESH:D064420', (140, 150))	('rs3903072', 'Var', (233, 242))	('cytotoxity', 'Disease', (140, 150))	('CTSW', 'Gene', (166, 170))	('CTSW', 'Gene', '1521', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('breast cancer', 'Disease', (275, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('CTSW', 'Gene', '1521', (166, 170))
105706	31507631	We propose an intergenic regulatory variant, in high LD with rs3903072, as a predicted functional SNP, which falls in a putative regulatory element (PRE) physically interacting with the 3' of CTSW.	('rs3903072', 'Var', (61, 70))	('CTSW', 'Gene', '1521', (192, 196))	('falls', 'Phenotype', 'HP:0002527', (109, 114))	('falls', 'NegReg', (109, 114))	('CTSW', 'Gene', (192, 196))	('rs3903072', 'Mutation', 'rs3903072', (61, 70))
105708	31507631	A list of ER+ breast-cancer-associated variants were first obtained from and the NHGRI-EBI GWAS catalog.	('breast-cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast-cancer', 'Disease', (14, 27))	('variants', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))
105710	31507631	We ranked the ER+ breast cancer GWAS SNPs based on the number of proximal immunoinflammatory GWAS SNPs and found rs3903072 to be the top SNP ( Supplementary Methods ).	('rs3903072', 'Mutation', 'rs3903072', (113, 122))	('breast cancer GWAS SNP', 'Disease', (18, 40))	('rs3903072', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer GWAS SNP', 'Disease', 'MESH:D001943', (18, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))
105719	31507631	For this ER+ breast cancer analysis, we constructed a multivariate linear model for each gene within the 3-Mb region centered at rs3903072, regressing the gene expression levels against the genotypes at the GWAS SNP rs3903072 as well as the gene CN ( Supplementary Methods ).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('rs3903072', 'Mutation', 'rs3903072', (216, 225))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('rs3903072', 'Mutation', 'rs3903072', (129, 138))	('rs3903072', 'Var', (129, 138))
105722	31507631	For these eQTL analyses using BRCA, UCEC, HNSC, LGG, and GTEx data, linear regression models between CTSW expression and the genotype status at rs3903072 were constructed ( Supplementary Methods ).	('rs3903072', 'Mutation', 'rs3903072', (144, 153))	('BRCA', 'Gene', (30, 34))	('CTSW', 'Gene', (101, 105))	('rs3903072', 'Var', (144, 153))	('CTSW', 'Gene', '1521', (101, 105))	('BRCA', 'Gene', '672', (30, 34))
105730	31507631	We first selected all common (minor allele frequency, MAF >= 0.05) SNPs from 1000 Genomes Project Phase 3 in high LD (r 2 >= 0.8, EUR population) with rs3903072.	('MAF', 'Gene', (54, 57))	('MAF', 'Gene', '4094', (54, 57))	('rs3903072', 'Mutation', 'rs3903072', (151, 160))	('rs3903072', 'Var', (151, 160))
105736	31507631	Processed wiggle tracks and peaks were downloaded and presented when available in hg19 [Jurkat H3K4me1 ChIP-seq track from GSE119439; TBX21 ChIP-seq pooled wiggle track and peaks in GM12878 from ENCODE ENCFF193RDB and ENCFF869HSY].	('GM12878', 'Gene', (182, 189))	('TBX21', 'Gene', (134, 139))	('GM12878', 'Chemical', '-', (182, 189))	('ENCFF869HSY]', 'Var', (218, 230))	('ENCFF869HSY', 'CellLine', 'CVCL:B032', (218, 229))	('Jurkat', 'CellLine', 'CVCL:0065', (88, 94))	('TBX21', 'Gene', '30009', (134, 139))	('ENCFF193', 'CellLine', 'CVCL:5130', (202, 210))
105738	31507631	We hypothesized that the proximity of a genetic variant associated with cancer to those associated with immunoinflammatory traits might indicate pleiotropy of nearby genes or regulatory variants.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('variant', 'Var', (48, 55))	('cancer', 'Disease', (72, 78))
105739	31507631	In this regard, we examined the NHGRI-EBI GWAS Catalog and identified rs3903072 as the top breastcancer-associated variant having the highest density of proximal variants within 100 kb associated with immunoinflammatory traits ( Supplementary Methods ;  Supplementary Figure 1 ;  Supplementary Table 1 ).	('associated', 'Reg', (185, 195))	('cancer', 'Disease', (97, 103))	('variant', 'Var', (115, 122))	('rs3903072', 'Mutation', 'rs3903072', (70, 79))	('variants', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
105740	31507631	The SNP rs3903072 has been found to be associated with ER+ breast cancer in multiple GWAS studies, and lies in close physical distance, but with weak genetic linkage ( Supplementary Table 2 ), to multiple variants associated with immunoinflammatory diseases:such as rs118086960 with psoriasis (an autoimmune disease), rs77779142 with rosacea symptom (an inflammatory skin condition), rs2231884 with inflammatory bowel disease, and rs568617 with psoriasis and Crohn's disease (an inflammatory bowel disease) ( Figure 1A ;  Supplementary Table 1 ).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rs568617', 'Mutation', 'rs568617', (431, 439))	('associated', 'Reg', (39, 49))	('rs3903072', 'Mutation', 'rs3903072', (8, 17))	('rosacea', 'Disease', (334, 341))	('rosacea', 'Phenotype', 'HP:0001041', (334, 341))	('rs118086960', 'Var', (266, 277))	('skin condition', 'Phenotype', 'HP:0000951', (367, 381))	('rs3903072', 'Var', (8, 17))	('rs118086960', 'Mutation', 'rs118086960', (266, 277))	("Crohn's disease", 'Phenotype', 'HP:0100280', (459, 474))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('psoriasis', 'Phenotype', 'HP:0003765', (445, 454))	("Crohn's disease", 'Disease', 'MESH:D003424', (459, 474))	("Crohn's disease", 'Disease', (459, 474))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (479, 505))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (479, 505))	('inflammatory bowel disease', 'Disease', (479, 505))	('autoimmune disease', 'Disease', (297, 315))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('psoriasis', 'Disease', 'MESH:D011565', (445, 454))	('rs2231884', 'Var', (384, 393))	('breast cancer', 'Disease', (59, 72))	('autoimmune disease', 'Disease', 'MESH:D001327', (297, 315))	('psoriasis', 'Disease', (445, 454))	('rs568617', 'Var', (431, 439))	('psoriasis', 'Phenotype', 'HP:0003765', (283, 292))	('rosacea', 'Disease', 'MESH:D012393', (334, 341))	('rs2231884', 'Mutation', 'rs2231884', (384, 393))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (399, 425))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (399, 425))	('inflammatory bowel disease', 'Disease', (399, 425))	('inflammatory skin', 'Phenotype', 'HP:0011123', (354, 371))	('psoriasis', 'Disease', 'MESH:D011565', (283, 292))	('autoimmune disease', 'Phenotype', 'HP:0002960', (297, 315))	('psoriasis', 'Disease', (283, 292))	('rs77779142', 'Mutation', 'rs77779142', (318, 328))	('rs77779142', 'Var', (318, 328))
105741	31507631	A direct link between this noncoding SNP rs3903072 and its regulatory function in mammary epithelial cells is currently unknown; similarly, it remains uncharacterized how and why the aforementioned SNPs in the region affect diverse immunoinflammatory traits.	('affect', 'Reg', (217, 223))	('rs3903072', 'Mutation', 'rs3903072', (41, 50))	('rs3903072', 'Var', (41, 50))	('immunoinflammatory', 'CPA', (232, 250))
105742	31507631	Discovering the target genes of rs3903072 thus represents a major step towards identifying a potential regulatory mechanism common to both breast cancer susceptibility and immunoinflammatory traits.	('rs3903072', 'Var', (32, 41))	('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))	('rs3903072', 'Mutation', 'rs3903072', (32, 41))
105744	31507631	Using ER+ breast tumor RNA sequencing (RNA-seq) and genotyping data from the BRCA dataset of TCGA, we identified several significant eQTL genes in cis for rs3903072, including CTSW, FIBP, MUS81, and EIF1AD (genotype p-values of a linear model adjusting for gene copy number: p= 3.52 x 10-5, p = 3.22 x 10-5, p = 1.24 x 10-4, p = 3.28 x 10-3, respectively ( Figure 1B ); a complete list of eQTL genes in  Supplementary Table 3 ), confirming the results previously reported.	('FIBP', 'Gene', (182, 186))	('breast tumor', 'Disease', (10, 22))	('EIF1AD', 'Gene', '84285', (199, 205))	('MUS81', 'Gene', (188, 193))	('FIBP', 'Gene', '9158', (182, 186))	('EIF1AD', 'Gene', (199, 205))	('CTSW', 'Gene', (176, 180))	('MUS81', 'Gene', '80198', (188, 193))	('rs3903072', 'Mutation', 'rs3903072', (155, 164))	('breast tumor', 'Phenotype', 'HP:0100013', (10, 22))	('eQTL', 'Gene', (133, 137))	('BRCA', 'Gene', '672', (77, 81))	('CTSW', 'Gene', '1521', (176, 180))	('rs3903072', 'Var', (155, 164))	('breast tumor', 'Disease', 'MESH:D001943', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRCA', 'Gene', (77, 81))
105750	31507631	Further eQTL analysis confirmed a similar negative correlation between CTSW expression level and the rs3903072 risk genotype in UCEC and HNSC, as well as in LGG, a cancer type not shown in the THPA survival analysis webpage (linear model between expression and rs3903072 genotype; UCEC: p = 1.52 x 10-3; HNSC: p = 5.45 x 10-3; LGG: p = 7.09 x 10-3;  Supplementary Figure 2 ).	('THPA', 'Chemical', '-', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('rs3903072', 'Mutation', 'rs3903072', (261, 270))	('rs3903072', 'Mutation', 'rs3903072', (101, 110))	('negative', 'NegReg', (42, 50))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs3903072', 'Var', (101, 110))	('CTSW', 'Gene', (71, 75))	('CTSW', 'Gene', '1521', (71, 75))
105751	31507631	Together, these results demonstrate that CTSW likely has an important biological function in cancer and that the breast cancer risk allele rs3903072-G is significantly associated with decreased expression of CTSW.	('CTSW', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('CTSW', 'Gene', '1521', (41, 45))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs3903072', 'Mutation', 'rs3903072', (139, 148))	('decreased', 'NegReg', (184, 193))	('CTSW', 'Gene', (208, 212))	('expression', 'MPA', (194, 204))	('CTSW', 'Gene', '1521', (208, 212))	('rs3903072-G', 'Var', (139, 150))
105761	31507631	We thus hypothesized that the breast-cancer-associated GWAS variant rs3903072 may regulate CTSW in immune cells within the tumor microenvironment, independent of the other eQTL genes that could potentially be regulated separately in breast cancer cells.	('rs3903072', 'Mutation', 'rs3903072', (68, 77))	('tumor', 'Disease', (123, 128))	('regulate', 'Reg', (82, 90))	('CTSW', 'Gene', '1521', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('rs3903072', 'Var', (68, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('GWAS', 'Gene', (55, 59))	('breast-cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Disease', (233, 246))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('CTSW', 'Gene', (91, 95))	('breast-cancer', 'Disease', (30, 43))
105766	31507631	Even though we do not exclude the possibility that other eQTL genes may also have important functions in TILs or breast cancer cells, the tissue specificity and the correlation structure of CTSW expression strongly suggest its significant modulation in tumor-infiltrating immune cells by the GWAS SNP rs3903072 itself or a linked genetic variant.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs3903072', 'Var', (301, 310))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('modulation', 'Reg', (239, 249))	('breast cancer', 'Disease', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('CTSW', 'Gene', (190, 194))	('tumor', 'Disease', (253, 258))	('CTSW', 'Gene', '1521', (190, 194))	('rs3903072', 'Mutation', 'rs3903072', (301, 310))
105767	31507631	As the GWAS SNP rs3903072 itself did not reside in an open chromatin region in immune cells ( Figure 3A ), we next searched for putative regulatory variants that could directly control CTSW expression.	('CTSW', 'Gene', '1521', (185, 189))	('rs3903072', 'Mutation', 'rs3903072', (16, 25))	('CTSW', 'Gene', (185, 189))	('rs3903072', 'Var', (16, 25))
105768	31507631	We first found the SNP rs658524 to be located at the center of a DHS peak in CTSW promoter among several lymphocyte cell lines ( Supplementary Figure 6 ).	('CTSW', 'Gene', '1521', (77, 81))	('rs658524', 'Mutation', 'rs658524', (23, 31))	('CTSW', 'Gene', (77, 81))	('DHS', 'Chemical', '-', (65, 68))	('rs658524', 'Var', (23, 31))
105770	31507631	Namely, the GWAS SNP rs77779142, associated with Rosacea symptoms, was in tight LD with the CTSW promoter SNP rs658524 (r 2 = 0.78 with rs658524; r 2 = 0.17 with rs3903072; 1000 Genomes Phase 3 EUR population), despite being closer to the breast cancer GWAS SNP rs3903072 than to rs658524 in genomic distance (16.6 kb to rs3903072 vs. 47.6 kb to rs658524).	('rs658524', 'Mutation', 'rs658524', (280, 288))	('rs3903072', 'Mutation', 'rs3903072', (262, 271))	('CTSW', 'Gene', (92, 96))	('Rosacea symptoms', 'Disease', 'MESH:D012393', (49, 65))	('Rosacea symptoms', 'Disease', (49, 65))	('breast cancer GWAS SNP', 'Disease', 'MESH:D001943', (239, 261))	('rs658524', 'Mutation', 'rs658524', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('breast cancer GWAS SNP', 'Disease', (239, 261))	('rs658524', 'Mutation', 'rs658524', (110, 118))	('rs77779142', 'Mutation', 'rs77779142', (21, 31))	('rs3903072', 'Mutation', 'rs3903072', (162, 171))	('rs77779142', 'Var', (21, 31))	('Rosacea', 'Phenotype', 'HP:0001041', (49, 56))	('rs3903072', 'Mutation', 'rs3903072', (321, 330))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('rs3903072', 'Var', (321, 330))	('rs658524', 'Mutation', 'rs658524', (346, 354))	('associated', 'Reg', (33, 43))	('CTSW', 'Gene', '1521', (92, 96))
105771	31507631	Another GWAS SNP rs568617, associated with Psoriasis and Crohn's disease, resided in intron of the gene FIBP next to CTSW and was in high LD with the CTSW promoter SNP rs658524 (r 2 = 0.99 to rs658524; r 2 = 0.19 to rs3903072;  Figure 1A ).	('Psoriasis', 'Phenotype', 'HP:0003765', (43, 52))	('CTSW', 'Gene', (117, 121))	('rs658524', 'Mutation', 'rs658524', (192, 200))	('rs568617', 'Mutation', 'rs568617', (17, 25))	('FIBP', 'Gene', '9158', (104, 108))	('Psoriasis', 'Disease', (43, 52))	('Psoriasis', 'Disease', 'MESH:D011565', (43, 52))	('rs658524', 'Mutation', 'rs658524', (168, 176))	('FIBP', 'Gene', (104, 108))	('rs568617', 'Var', (17, 25))	('rs3903072', 'Mutation', 'rs3903072', (216, 225))	('CTSW', 'Gene', '1521', (150, 154))	('rs3903072', 'Var', (216, 225))	('associated', 'Reg', (27, 37))	("Crohn's disease", 'Phenotype', 'HP:0100280', (57, 72))	("Crohn's disease", 'Disease', 'MESH:D003424', (57, 72))	("Crohn's disease", 'Disease', (57, 72))	('CTSW', 'Gene', '1521', (117, 121))	('CTSW', 'Gene', (150, 154))
105772	31507631	On the other hand, the promoter SNP rs658524 was strongly correlated with CTSW expression, according to our eQTL analysis in TCGA (linear model between expression and rs658524 genotype; BRCA: p = 1.02 x 10-17; UCEC: p = 1.50 x 10-11; HNSC: p = 1.32 x 10-12; LGG: p = 1.43 x 10-6;  Supplementary Figure 7A ) and GTEx (mammary tissue: p = 2.19 x 10-11; whole blood: p = 8.48 x 10-5;  Supplementary Figure 7B ), consistent with eQTL results from other immune cell studies.	('CTSW', 'Gene', '1521', (74, 78))	('rs658524', 'Var', (167, 175))	('rs658524', 'Mutation', 'rs658524', (36, 44))	('rs658524', 'Mutation', 'rs658524', (167, 175))	('BRCA', 'Gene', (186, 190))	('CTSW', 'Gene', (74, 78))	('BRCA', 'Gene', '672', (186, 190))	('rs658524', 'Var', (36, 44))	('correlated', 'Reg', (58, 68))
105773	31507631	We here note that rs658524-A also showed partial association with breast cancer risk, since the haplotypes carrying the rs658524-A allele were found to be largely biased towards the GWAS risk allele rs3903072-G compared to the alternative allele rs3903072-T, despite the balanced MAF of rs3903072 (rs3903072 MAF = 0.46; 188 haplotypes with rs658524-A-rs3903072-G and 3 haplotypes with rs658524-A-rs3903072-T among the 1,006 haplotypes from the 1000 Genomes Project Phase 3 EUR population;  Supplementary Figure 6B ).	('rs3903072', 'Mutation', 'rs3903072', (199, 208))	('rs658524-A-rs3903072-G', 'Var', (340, 362))	('rs3903072', 'Mutation', 'rs3903072', (396, 405))	('rs3903072', 'Mutation', 'rs3903072', (246, 255))	('rs658524', 'Mutation', 'rs658524', (18, 26))	('MAF', 'Gene', (308, 311))	('rs3903072-G', 'Var', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rs658524', 'Mutation', 'rs658524', (120, 128))	('MAF', 'Gene', '4094', (308, 311))	('rs658524-A', 'Var', (120, 130))	('rs658524', 'Mutation', 'rs658524', (340, 348))	('rs658524-A-rs3903072-T', 'Var', (385, 407))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('rs3903072', 'Mutation', 'rs3903072', (298, 307))	('MAF', 'Gene', (280, 283))	('rs658524-A', 'Var', (18, 28))	('rs3903072', 'Mutation', 'rs3903072', (351, 360))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('rs658524', 'Mutation', 'rs658524', (385, 393))	('rs3903072', 'Mutation', 'rs3903072', (287, 296))	('MAF', 'Gene', '4094', (280, 283))
105774	31507631	In fact, rs658524 was in weak LD with rs3903072 (low r 2 = 0.186, but high D' = 0.966), with the GWAS risk SNP having a much higher allele frequency than the risk promoter SNP (rs3903072-G frequency: 0.54; rs658524-A frequency: 0.19; 1000 Genomes Project Phase 3, EUR).	('rs3903072', 'Mutation', 'rs3903072', (38, 47))	('rs658524', 'Mutation', 'rs658524', (9, 17))	('rs3903072', 'Var', (38, 47))	('rs658524', 'Mutation', 'rs658524', (206, 214))	('rs3903072', 'Mutation', 'rs3903072', (177, 186))	('rs3903072-G', 'Var', (177, 188))	('rs658524', 'Var', (9, 17))
105775	31507631	However, the CTSW promoter SNP rs658524 itself did not entirely explain either the GWAS association or the CTSW regulation in this region.	('CTSW', 'Gene', '1521', (13, 17))	('rs658524', 'Var', (31, 39))	('CTSW', 'Gene', (107, 111))	('CTSW', 'Gene', '1521', (107, 111))	('rs658524', 'Mutation', 'rs658524', (31, 39))	('CTSW', 'Gene', (13, 17))
105777	31507631	The top SNP linked to rs658524 was rs12225345 (r 2 = 0.84), which was only moderately associated with breast cancer (p = 1.13 x 10-6), separated from the top GWAS signal cluster represented by rs3903072 (p = 2.25 x 10-12).	('rs658524', 'Var', (22, 30))	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('rs12225345', 'Var', (35, 45))	('rs12225345', 'Mutation', 'rs12225345', (35, 45))	('associated', 'Reg', (86, 96))	('rs658524', 'Mutation', 'rs658524', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rs3903072', 'Mutation', 'rs3903072', (193, 202))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
105778	31507631	Furthermore, a conditional eQTL analysis showed that, within the group of TCGA patients carrying the homozygous genotype rs658524-G/G, the rs3903072 risk allele still displayed a residual negative effect on CTSW expression (Welch t-test, two-sided, p = 6.0 x 10-4; GTEx whole blood data;  Supplementary Figure 8 ).	('negative', 'NegReg', (188, 196))	('CTSW', 'Gene', (207, 211))	('rs658524-G/G', 'Var', (121, 133))	('rs3903072', 'Mutation', 'rs3903072', (139, 148))	('patients', 'Species', '9606', (79, 87))	('CTSW', 'Gene', '1521', (207, 211))	('rs3903072', 'Var', (139, 148))	('rs658524', 'Mutation', 'rs658524', (121, 129))
105779	31507631	Thus, although the CTSW promoter SNP was in high D' with the breast cancer GWAS SNP rs3903072, it did not solely explain the breast cancer risk in 11q13.1, and other functional SNPs likely influenced the expression of CTSW.	('rs3903072', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer GWAS SNP', 'Disease', 'MESH:D001943', (61, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CTSW', 'Gene', (218, 222))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer GWAS SNP', 'Disease', (61, 83))	('CTSW', 'Gene', (19, 23))	('CTSW', 'Gene', '1521', (218, 222))	('breast cancer', 'Disease', (125, 138))	('rs3903072', 'Mutation', 'rs3903072', (84, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('CTSW', 'Gene', '1521', (19, 23))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
105780	31507631	Given that the GWAS SNP rs3903072 was located 64 kb away from CTSW promoter, we tested whether some putative functional SNPs tightly linked to rs3903072 could affect distal enhancer activities modulating CTSW expression.	('rs3903072', 'Mutation', 'rs3903072', (24, 33))	('CTSW', 'Gene', (62, 66))	('affect', 'Reg', (159, 165))	('rs3903072', 'Mutation', 'rs3903072', (143, 152))	('rs3903072', 'Var', (24, 33))	('CTSW', 'Gene', (204, 208))	('rs3903072', 'Var', (143, 152))	('CTSW', 'Gene', '1521', (62, 66))	('tested', 'Reg', (80, 86))	('modulating', 'Reg', (193, 203))	('CTSW', 'Gene', '1521', (204, 208))	('distal enhancer activities', 'MPA', (166, 192))
105781	31507631	We thus examined all common (MAF >= 0.05) SNPs from 1000 Genomes Project Phase 3 EUR population in high LD (r 2 >= 0.8) with the GWAS SNP rs3903072 and prioritized the potential functional ones using epigenetic information.	('SNP', 'Var', (134, 137))	('MAF', 'Gene', (29, 32))	('MAF', 'Gene', '4094', (29, 32))	('rs3903072', 'Mutation', 'rs3903072', (138, 147))	('rs3903072', 'Var', (138, 147))
105782	31507631	In detail, by overlapping the 30 high LD SNPs with DHS of lymphocyte cell lines ( Supplementary Table 5 ), we identified three SNP-containing PREs): PRE1 located 3 kb away from rs3903072, PRE2 at SNX32 promoter, and PRE3 at EFEMP2 promoter ( Supplementary Figure 9 ).	('EFEMP2', 'Gene', (224, 230))	('EFEMP2', 'Gene', '30008', (224, 230))	('rs3903072', 'Mutation', 'rs3903072', (177, 186))	('SNX32', 'Gene', (196, 201))	('DHS', 'Chemical', '-', (51, 54))	('SNX32', 'Gene', '254122', (196, 201))	('rs3903072', 'Var', (177, 186))
105787	31507631	Consistent with the ChIA-PET data, NK cells were found to have the highest predicted contact count for the pair of rs3903072-PRE1 and CTSW in all five models ( Supplementary Figure 10 ), in contrast to vHMEC, which had the lowest predicted contact counts.	('rs3903072-PRE1', 'Var', (115, 129))	('CTSW', 'Gene', '1521', (134, 138))	('rs3903072', 'Mutation', 'rs3903072', (115, 124))	('CTSW', 'Gene', (134, 138))	('contact count', 'MPA', (85, 98))
105789	31507631	Among the prioritized SNPs residing in the three PREs, we identified rs11227311 in PRE1 as a putative functional SNP (r 2 = 0.89 with rs3903072, 1000 Genomes Phase 3, EUR).	('PRE1', 'Gene', (83, 87))	('rs3903072', 'Var', (134, 143))	('rs11227311', 'Var', (69, 79))	('rs11227311', 'Mutation', 'rs11227311', (69, 79))	('rs3903072', 'Mutation', 'rs3903072', (134, 143))
105790	31507631	More precisely, it not only overlapped a DHS in NK cells, B cells, and type 2 T helper cells (ENCODE accession number: ENCFF933OXV, ENCFF772OPR, ENCFF001WTS, and ENCFF001WTQ) but also H3K4me1 modification and the ChIA-PET region interacting with CTSW 3' end in Jurkat ( Figure 3A ;  Supplementary Figure 9 ).	('Jurkat', 'CellLine', 'CVCL:0065', (261, 267))	('H3K4me1', 'Var', (184, 191))	('DHS', 'Chemical', '-', (41, 44))	('CTSW', 'Gene', (246, 250))	('ENCFF001WTS', 'Var', (145, 156))	('ENCFF772OPR', 'Var', (132, 143))	('CTSW', 'Gene', '1521', (246, 250))
105791	31507631	To identify candidate TFs in PRE1 potentially affected by rs11227311, we scanned the short sequences around the SNP for TF motifs, using the program FIMO (version 4.12.0) and position weight matrices (PWM) collected from multiple motif databases (Materials and Methods).	('rs11227311', 'Var', (58, 68))	('affected', 'Reg', (46, 54))	('rs11227311', 'Mutation', 'rs11227311', (58, 68))
105792	31507631	Using our previously described method for measuring the significance of motif disruption by a SNP, based on simulating null mutations on the PWMs, we identified a list of candidate TF motifs disrupted by rs11227311, including the TEAD family, TCF family, NR3C1, POU2F1, and ETV5 ( Figure 3B ;  Supplementary Figure 9 ; p-values from neutral mutation simulation: p = 0.0074, p = 0.0086, p = 0.002, p = 0.013, p = 0.045, respectively; Methods).	('rs11227311', 'Mutation', 'rs11227311', (204, 214))	('ETV5', 'Gene', '2119', (274, 278))	('motif disruption', 'Disease', 'MESH:D019958', (72, 88))	('TEAD', 'Gene', '8463', (230, 234))	('NR3C1', 'Gene', (255, 260))	('POU2F1', 'Gene', (262, 268))	('POU2F1', 'Gene', '5451', (262, 268))	('rs11227311', 'Var', (204, 214))	('ETV5', 'Gene', (274, 278))	('motif disruption', 'Disease', (72, 88))	('TCF', 'Gene', (243, 246))	('NR3C1', 'Gene', '2908', (255, 260))	('TCF', 'Gene', '6932', (243, 246))	('TEAD', 'Gene', (230, 234))	('disrupted', 'Reg', (191, 200))
105795	31507631	Although it was difficult to validate which TF can directly bind the PRE1 SNP due to insufficient ChIP-seq data in T/NK cells, we found the PRE1 candidate SNP rs11227311 to be located within a weak TCF3 ChIP-seq peak in Kasumi1 acute myeloid leukemia cell line [GEO GSE43834 ] ( Figure 3B ; Materials and Methods).	('acute myeloid leukemia', 'Disease', (228, 250))	('rs11227311', 'Var', (159, 169))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (234, 250))	('TCF3', 'Gene', '6929', (198, 202))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (228, 250))	('leukemia', 'Phenotype', 'HP:0001909', (242, 250))	('rs11227311', 'Mutation', 'rs11227311', (159, 169))	('TCF3', 'Gene', (198, 202))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (228, 250))
105796	31507631	Examination of other ChIP-seq data in ENCODE for TFs in lymphocytes also showed that the SNP rs11227311 is at the center of a strong TBX21 ChIP-seq peak in GM12878 (ENCSR739IHN;  Figure 3B ).	('rs11227311', 'Mutation', 'rs11227311', (93, 103))	('TBX21', 'Gene', (133, 138))	('TBX21', 'Gene', '30009', (133, 138))	('rs11227311', 'Var', (93, 103))	('GM12878', 'Chemical', '-', (156, 163))
105799	31507631	In this paper, we performed functional characterization of breast cancer-associated GWAS variants and proposed the idea that a noncoding cancer GWAS SNP may regulate gene expression in immune cells within the tumor microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('variants', 'Var', (89, 97))	('tumor', 'Disease', (209, 214))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('regulate', 'Reg', (157, 165))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('gene expression', 'MPA', (166, 181))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cancer', 'Disease', (66, 72))
105800	31507631	Figure 4  summarizes our hypothesis that the GWAS-linked SNP rs11227311 may directly affect TF binding affinity at the distal enhancer and regulate CTSW expression in cytotoxic lymphocytes, thereby affecting their ability to eliminate abnormal cells.	('regulate', 'Reg', (139, 147))	('rs11227311', 'Mutation', 'rs11227311', (61, 71))	('ability', 'MPA', (214, 221))	('binding affinity', 'Interaction', (95, 111))	('CTSW', 'Gene', (148, 152))	('CTSW', 'Gene', '1521', (148, 152))	('expression', 'MPA', (153, 163))	('eliminate', 'CPA', (225, 234))	('affect', 'Reg', (85, 91))	('rs11227311', 'Var', (61, 71))	('affecting', 'Reg', (198, 207))
105805	31507631	We presented evidence that a breast-cancer-associated variant may regulate the expression level of an NK/T cell-specific gene, not in breast cancer cells but in immune cells infiltrating the tumor microenvironment.	('breast-cancer', 'Disease', 'MESH:D001943', (29, 42))	('breast cancer', 'Disease', (134, 147))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('variant', 'Var', (54, 61))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('breast-cancer', 'Disease', (29, 42))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('NK/T cell-specific gene', 'Gene', (102, 125))	('regulate', 'Reg', (66, 74))	('expression level', 'MPA', (79, 95))
105820	22933885	The genetic alterations in tumour cells, together with clinical and histolpathological properties, may all define the most appropriate therapy and predict the outcome of the treatment.	('genetic alterations', 'Var', (4, 23))	('tumour', 'Disease', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))
105841	22933885	However, a chromosomal alteration has been reported, which is the most common lesion found in oligodendroglial tumours and involves a deletion at chromosomal loci 1p and 19q.	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('deletion', 'Var', (134, 142))	('oligodendroglial tumours', 'Disease', (94, 118))	('oligodendroglial tumours', 'Disease', 'MESH:D009369', (94, 118))
105842	22933885	A combined loss of 1p and 19q identifies a group of good prognosis tumours and has been reported, depending on the literature, in the range of 50% to 90% or 60% to 70% of oligodendrogliomas of any grade.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (171, 189))	('loss', 'Var', (11, 15))	('oligodendrogliomas', 'Disease', (171, 189))	('good prognosis tumours', 'Disease', 'MESH:D009369', (52, 74))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('good prognosis tumours', 'Disease', (52, 74))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
105848	22933885	The resection decreases the tumour mass effect on the brain with concomitant neurological consequences and reduces the tumour load during radiotherapy, which is the next and often the following form of the treatment in grade 3 tumours.	('decreases', 'NegReg', (14, 23))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('reduces', 'NegReg', (107, 114))	('tumour', 'Disease', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('tumour', 'Disease', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (227, 234))	('tumour', 'Disease', (227, 233))	('resection', 'Var', (4, 13))	('tumours', 'Disease', 'MESH:D009369', (227, 234))	('tumours', 'Disease', (227, 234))
105869	22933885	Mutations in p53 gene are described in 10% to 15% of tumours without 1p and 19q loss.	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('described', 'Reg', (26, 35))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('p53', 'Gene', '7157', (13, 16))
105871	22933885	Response rate or efficacy of the chemotherapy treatment was observed only in 33% of patients with p53 mutation and intact 1p and 19q chromosomes, as opposed to tumours with intact p53 gene and 1p and 19q or only 1p mutation, where the response rate was 100%.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('patients', 'Species', '9606', (84, 92))	('mutation', 'Var', (102, 110))	('p53', 'Gene', (180, 183))	('p53', 'Gene', '7157', (180, 183))	('tumours', 'Disease', (160, 167))	('p53', 'Gene', (98, 101))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('p53', 'Gene', '7157', (98, 101))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
105890	22933885	In many tumours, including gliomas, alterations in DNA may be found, such as methylation of the promoter region and their genes.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('methylation', 'Var', (77, 88))	('tumours', 'Disease', (8, 15))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('gliomas', 'Disease', (27, 34))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
105891	22933885	As MGMT is one of the key factors in resistance to chemotherapy, hypermethylation inhibits the repair mechanism due to a lower level of the active enzyme.	('repair mechanism', 'CPA', (95, 111))	('MGMT', 'Gene', (3, 7))	('MGMT', 'Gene', '4255', (3, 7))	('hypermethylation', 'Var', (65, 81))	('level', 'MPA', (127, 132))	('lower', 'NegReg', (121, 126))	('active enzyme', 'MPA', (140, 153))	('inhibits', 'NegReg', (82, 90))
105892	22933885	MGMT methylation rates in oligodendrogliomas range from 25% to 85% and were reported to be strongly associated with 1p and 19q loss.	('MGMT', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('associated', 'Reg', (100, 110))	('oligodendrogliomas', 'Disease', (26, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('MGMT', 'Gene', '4255', (0, 4))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (26, 44))
105893	22933885	However, the response rate to chemotherapy and time to progression of oligodendrogliomas were not observed to be in correlation with the degree of MGMT methylation, as is the case with glioblastoma, where promoter methylation correlated with response to the alkylating agent treatment and survival.	('oligodendrogliomas', 'Disease', (70, 88))	('glioblastoma', 'Disease', (185, 197))	('promoter', 'MPA', (205, 213))	('glioblastoma', 'Disease', 'MESH:D005909', (185, 197))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (70, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (185, 197))	('MGMT', 'Gene', '4255', (147, 151))	('MGMT', 'Gene', (147, 151))	('methylation', 'Var', (152, 163))	('correlated', 'Reg', (226, 236))
105903	17925012	Clonal mutations in primary human glial tumors: evidence in support of the mutator hypothesis A verifiable consequence of the mutator hypothesis is that even low grade neoplasms would accumulate a large number of mutations that do not influence the tumor phenotype (clonal mutations).	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('neoplasms', 'Disease', 'MESH:D009369', (168, 177))	('human', 'Species', '9606', (28, 33))	('neoplasms', 'Disease', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('glial tumors', 'Disease', 'MESH:D005910', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('glial tumors', 'Disease', (34, 46))	('tumor', 'Disease', (249, 254))	('mutations', 'Var', (213, 222))	('tumor', 'Disease', (40, 45))	('neoplasms', 'Phenotype', 'HP:0002664', (168, 177))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
105913	17925012	If mutations occur at a critical point in the coding region of gene(s) involved in the maintenance of cellular control on proliferation, DNA repair and differentiation, it might lead to development of a cancerous cell.	('cancerous', 'Disease', 'MESH:D009369', (203, 212))	('lead to', 'Reg', (178, 185))	('mutations', 'Var', (3, 12))	('cancerous', 'Disease', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
105914	17925012	Loeb proposed the mutator hypothesis, which stated that cancer cells would accumulate a large number of mutations without influencing the phenotype of a cell.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
105917	17925012	The mutator hypothesis was based on the observations of numerous mutations in different types of tumors, which could not be explained by the mutation rates of normal somatic cells.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutations', 'Var', (65, 74))
105930	17925012	These include, amongst others, p53 mutations, EGF receptor gene amplification, changes in the p21 gene, and consistent alterations in loci on chromosome 10 and in the 17p13.3 locus.	('p53', 'Gene', (31, 34))	('changes', 'Reg', (79, 86))	('EGF receptor', 'Gene', (46, 58))	('p53', 'Gene', '7157', (31, 34))	('p21', 'Gene', (94, 97))	('EGF receptor', 'Gene', '1956', (46, 58))	('p21', 'Gene', '644914', (94, 97))	('alterations', 'Reg', (119, 130))	('amplification', 'PosReg', (64, 77))	('mutations', 'Var', (35, 44))
105934	17925012	Moreover, colorectal cancers with a high frequency of point mutations displayed a comparatively stable karyotype.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('point mutations', 'Var', (54, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('colorectal cancers', 'Disease', 'MESH:D015179', (10, 28))	('colorectal cancers', 'Disease', (10, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))
105966	17925012	If a band was visible in RAPD pattern of normal (leucocyte) DNA but not the tumor (referred as ' loss of band'), it meant mutation at the 3' end of at least one primer binding site on both the alleles (that is alteration at 2 sites).	('mutation', 'Var', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('meant', 'Reg', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
105967	17925012	The minimum change required for every new band in a tumor DNA, compared to its corresponding leucocyte DNA (referred to as 'gain' in this paper) would be one mutation, which generates a perfect match, creating a primer binding site.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mutation', 'Var', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('primer', 'MPA', (212, 218))
105975	17925012	This is based on experiments (discussed below), where in a number of different tumor-primer combinations, an altered band was hybridized to the same RAPD profile, did not hybridize to any other band.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('combinations', 'Var', (92, 104))	('tumor', 'Disease', (79, 84))
105982	17925012	Five altered bands (80/35/127B, RE06/125B, 80/35/195T, RE05/195B and 70/09/173T) chosen randomly were tested for homology to other bands in the RAPD profiles (both tumor and corresponding normal DNA) from which they were amplified.	('tumor', 'Disease', (164, 169))	('80/35/195T', 'Var', (43, 53))	('RE06/125B', 'Var', (32, 41))	('80/35/127B', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('70/09/173T', 'Var', (69, 79))	('RE05/195B', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
106007	17925012	Genomic instability in the form of chromosome instability, aneuploidy, LOH, microsatellite repeat alterations are seen in almost all types of neoplastic and preneoplastic cells.	('aneuploidy', 'Disease', (59, 69))	('LOH', 'Disease', (71, 74))	('chromosome instability', 'CPA', (35, 57))	('aneuploidy', 'Disease', 'MESH:D000782', (59, 69))	('microsatellite repeat alterations', 'Var', (76, 109))	('chromosome instability', 'Phenotype', 'HP:0040012', (35, 57))
106008	17925012	All these mutations have different implications in the tumor development and progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('progression', 'CPA', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (10, 19))	('implications', 'Reg', (35, 47))
106010	17925012	Ninomiya et al have found chromosomal instability and LOH to play role in the development of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Disease', (93, 104))	('chromosomal instability', 'Phenotype', 'HP:0040012', (26, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('chromosomal instability', 'Var', (26, 49))	('LOH', 'Var', (54, 57))
106011	17925012	Goel et al have characterized the role of chromosomal and microsatellite instability in the progression of colon cancer.	('microsatellite instability', 'Var', (58, 84))	('colon cancer', 'Disease', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('chromosomal', 'Var', (42, 53))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))
106012	17925012	In other systems, if one restricts to microsatellite repeat alterations, there has been some evidence linking genomic instability to tumor progression.	('microsatellite repeat alterations', 'Var', (38, 71))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
106015	17925012	A mutator phenotype might be a liability to an aggressive rapidly dividing clone arising during tumor progression as extensive mutations might adversely affect the growth properties of these cells.	('growth properties', 'CPA', (164, 181))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('affect', 'Reg', (153, 159))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutator', 'Var', (2, 9))
106016	17925012	For example, in colorectal tumors increased frequency of point mutations is associated with a stable karyotype, which is less likely to be associated with progression.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('colorectal tumors', 'Disease', 'MESH:D015179', (16, 33))	('colorectal tumors', 'Disease', (16, 33))	('point mutations', 'Var', (57, 72))
106019	17925012	They resolved PCR product on PAGE with a higher resolution for band sizes up to 1 kb and observed that altered bands in tumors were identical to the closest normal band except for deletions in repeats like poly A, dinucleotides like CT and CA or trinucleotide repeats.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('trinucleotide repeats', 'Var', (246, 267))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('poly A', 'Var', (206, 212))	('trinucleotide', 'Chemical', '-', (246, 259))	('deletions', 'Var', (180, 189))
106021	17925012	Jackson and Loeb estimated ~100,000 genome wide alterations in cancers in the form of base substitutions, deletions, chromosomal translocations, and gene amplifications, and these mutations are found to accumulate as tumors progress.	('base substitutions', 'Var', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('deletions', 'Var', (106, 115))	('alterations', 'Var', (48, 59))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
106022	17925012	They proposed that the genomic instability caused by these alterations result from a mutator phenotype, which occurs early during tumor development and predisposes the tumor cell to the accumulation of further mutations.	('alterations', 'Var', (59, 70))	('tumor', 'Disease', (168, 173))	('genomic', 'MPA', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (130, 135))	('result', 'Reg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
106036	17925012	Tomlinson et al proposed that normal mutation rate is sufficient to explain a large number of mutations in tumors if the number of cell divisions during normal development is taken into account.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutations', 'Var', (94, 103))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
106038	17925012	Most of the published work till date on the extent of mutations in tumors is on colon carcinogenesis.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (80, 100))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('colon carcinogenesis', 'Disease', (80, 100))
106045	17925012	Agarose gel has a lower resolution range than PAGE, and while they have been extensively used in RAPD analysis, they do not resolve changes of few base pairs caused by microsatellite expansion and contraction.	('Agarose', 'Chemical', 'MESH:D012685', (0, 7))	('contraction', 'Var', (197, 208))	('microsatellite expansion', 'Var', (168, 192))
106046	17925012	Our observation of a higher number of genetic changes in tumors of lower grade could be a consequence of an increased mutation rate in early tumorigenesis due to acquisition of a mutator phenotype.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutator', 'Var', (179, 186))	('tumor', 'Disease', (141, 146))	('genetic', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutation', 'Var', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
106047	17925012	The higher number of mutations could also be a reflection of the longer time taken by a low grade tumor to clinically manifest, compared to a higher grade tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (21, 30))
106060	17925012	The alterations detected were non coding sequences, not common among tumors, and indicate that they are not selected for specific locus.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('alterations', 'Var', (4, 15))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
106063	17925012	This is in line with the mutator hypothesis - that, those mutations/genetic alterations that do not have a significant phenotypic correlation are likely to be more frequent in low grade tumors.	('low', 'Disease', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (186, 192))	('frequent', 'Reg', (164, 172))	('mutations/genetic', 'Var', (58, 75))
106076	31883050	Overall survival was better for patients with high income or high education, but income- and education-related survival differences were not significant after adjustment for age and comorbidity.	('men', 'Species', '9606', (165, 168))	('patients', 'Species', '9606', (32, 40))	('high education', 'Var', (61, 75))	('high income', 'Var', (46, 57))	('better', 'PosReg', (21, 27))	('Overall survival', 'MPA', (0, 16))
106085	31883050	The SNOMED codes used were: 94003, 94203, 94113, 94103 for astrocytoma, 93823 for oligoastrocytoma and 94503 for oligodendroglioma (for oligoastrocytoma WHO grade II and oligoastrocytoma grade III the SNOMED code is the same 93823).	('94503', 'Var', (103, 108))	('astrocytoma', 'Disease', (175, 186))	('astrocytoma', 'Disease', 'MESH:D001254', (141, 152))	('astrocytoma', 'Disease', 'MESH:D001254', (87, 98))	('astrocytoma', 'Disease', (141, 152))	('oligoastrocytoma', 'Disease', (136, 152))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('93823', 'Var', (72, 77))	('astrocytoma', 'Disease', (87, 98))	('oligodendroglioma', 'Disease', (113, 130))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (170, 186))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (82, 98))	('astrocytoma', 'Disease', 'MESH:D001254', (59, 70))	('astrocytoma', 'Disease', (59, 70))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('astrocytoma', 'Phenotype', 'HP:0009592', (141, 152))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('oligoastrocytoma', 'Disease', (170, 186))	('94103', 'Var', (49, 54))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (136, 152))	('oligoastrocytoma', 'Disease', (82, 98))	('94113', 'Var', (42, 47))	('oligodendroglioma', 'Disease', 'MESH:D009837', (113, 130))	('astrocytoma', 'Disease', 'MESH:D001254', (175, 186))
106098	31883050	The conditions removed from the index due to possible association with diagnosis of LGG were: G40; epilepsy, G41; status epilepticus, R56; convulsions, R47; dysphasia/aphasia and C70-72; Malignant tumor in central nervous system.	('status epilepticus', 'Disease', (114, 132))	('C70-72', 'Var', (179, 185))	('convulsions', 'Disease', (139, 150))	('aphasia', 'Phenotype', 'HP:0002381', (167, 174))	('Malignant tumor in central nervous system', 'Phenotype', 'HP:0100836', (187, 228))	('epilepsy', 'Disease', 'MESH:D004827', (99, 107))	('convulsions', 'Disease', 'MESH:D012640', (139, 150))	('R47', 'Var', (152, 155))	('Malignant tumor', 'Disease', 'MESH:D009369', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Malignant tumor', 'Disease', (187, 202))	('status epilepticus', 'Phenotype', 'HP:0002133', (114, 132))	('epilepsy', 'Phenotype', 'HP:0001250', (99, 107))	('epilepsy', 'Disease', (99, 107))	('dysphasia/aphasia', 'Disease', 'MESH:D001037', (157, 174))	('dysphasia/aphasia', 'Disease', (157, 174))	('G41', 'Var', (109, 112))	('status epilepticus', 'Disease', 'MESH:D013226', (114, 132))	('G40', 'Var', (94, 97))	('dysphasia', 'Phenotype', 'HP:0002357', (157, 166))	('tumor in central nervous system', 'Phenotype', 'HP:0100006', (197, 228))	('R56', 'Var', (134, 137))
106123	31883050	However, the longer waiting times for patients with low education compared that of patients with high education were present and consistently found within each separate region.	('low education', 'Phenotype', 'HP:0001249', (52, 65))	('longer', 'PosReg', (13, 19))	('low education', 'Var', (52, 65))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (83, 91))
106157	30705404	Research into the mechanisms related to the regulation of oncogenes and tumor suppresser genes has primarily focused on genomic mutations, copy number variation, and transcription dysregulation.	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('copy number variation', 'Var', (139, 160))
106158	30705404	By copy number alteration alone, 66%, 70%, and 59% of the GBM patient samples contain changes in core components of RB, TP53, and RTK pathways, respectively.	('RTK pathways', 'Pathway', (130, 142))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('patient', 'Species', '9606', (62, 69))	('changes', 'Reg', (86, 93))	('TP53', 'Gene', '7157', (120, 124))	('alteration', 'Var', (15, 25))	('TP53', 'Gene', (120, 124))	('GBM', 'Disease', (58, 61))
106159	30705404	Further, it was reported that cancer cell lines are significantly enriched in mRNA containing shortened 3'-UTRs relative to non-transformed cells.	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	("shortened 3'-UTRs", 'Var', (94, 111))
106162	30705404	Complicating this relatively straightforward model are observations from multiple groups demonstrating that 3'-UTR shortening does not obligatorily result in increased protein levels and that tumors, as opposed to cell lines, are not always prone to shorten 3'-UTRs with a bias toward oncogenes.	('shorten', 'Var', (250, 257))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('protein levels', 'MPA', (168, 182))	('increased', 'PosReg', (158, 167))
106173	30705404	This model is supported by previous data showing that knockdown of Nudt21 results in the use of proximal PASs (pPAS) resulting in the global shortening of 3'-UTRs.	('Nudt21', 'Gene', (67, 73))	('PAS', 'Gene', (112, 115))	("3'-UTRs", 'MPA', (155, 162))	('knockdown', 'Var', (54, 63))	('shortening', 'NegReg', (141, 151))	('PAS', 'Gene', '249157', (105, 108))	('PAS', 'Gene', '249157', (112, 115))	('PAS', 'Gene', (105, 108))
106174	30705404	In our previous work, we demonstrated that depletion of Nudt21 not only causes increased pPAS usage but also increases cell proliferation and enhances GBM cell tumorigenicity.	('increased', 'PosReg', (79, 88))	('cell proliferation', 'CPA', (119, 137))	('depletion', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('PAS', 'Gene', '249157', (90, 93))	('GBM', 'Phenotype', 'HP:0012174', (151, 154))	('PAS', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Nudt21', 'Gene', (56, 62))	('usage', 'MPA', (94, 99))	('increases', 'PosReg', (109, 118))	('tumor', 'Disease', (160, 165))	('enhances', 'PosReg', (142, 150))
106178	30705404	Using Poly(A)-Click-Seq, we conducted a genome-wide APA analysis in GBM cells with Nudt21 knockdown (KD) in order to identify novel downstream target genes of Nudt21 as potential biomarkers for predicting prognosis of GBM patients.	('knockdown', 'Var', (90, 99))	('Poly(A)', 'Chemical', 'MESH:D011061', (6, 13))	('GBM', 'Phenotype', 'HP:0012174', (218, 221))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('patients', 'Species', '9606', (222, 230))	('Nudt21', 'Gene', (83, 89))	('GBM', 'Disease', (218, 221))
106180	30705404	Using this information, we find that the combination of Nudt21 and Pak1 expression is a strong prognostic indicator of GBM patient survival.	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('patient', 'Species', '9606', (123, 130))	('combination', 'Var', (41, 52))	('Pak1', 'Gene', (67, 71))	('Nudt21', 'Gene', (56, 62))	('GBM', 'Disease', (119, 122))
106196	30705404	Consistent with structural studies, we found that CFIm25 pulls down both CFIm59 and CFIm68 equally in both cells and that depletion of CFIm25 in cell lysates removed almost all CFIm59 and CFIm68 (Fig.	('CFIm25', 'Gene', (50, 56))	('CFIm59', 'Gene', '79869', (73, 79))	('depletion', 'Var', (122, 131))	('CFIm59', 'Gene', '79869', (177, 183))	('CFIm68', 'Gene', '11052', (84, 90))	('CFIm68', 'Gene', (188, 194))	('CFIm68', 'Gene', (84, 90))	('CFIm25', 'Gene', '11051', (135, 141))	('removed', 'NegReg', (158, 165))	('CFIm25', 'Gene', '11051', (50, 56))	('CFIm68', 'Gene', '11052', (188, 194))	('CFIm59', 'Gene', (73, 79))	('CFIm25', 'Gene', (135, 141))	('CFIm59', 'Gene', (177, 183))
106203	30705404	To achieve this, we performed pairwise two yeast hybrid assays using each subunit of the CFIm complex fused to the Gal4-activation domain tested against Nudt21 fused to the Gal4 DNA binding domain.	('CFIm', 'Gene', (89, 93))	('yeast', 'Species', '4932', (43, 48))	('binding', 'Interaction', (182, 189))	('fused', 'Var', (102, 107))	('CFIm', 'Gene', '11052', (89, 93))	('Nudt21', 'Gene', (153, 159))
106207	30705404	To that end, we knocked down each one of CFIm subunits with siRNA in both LN229 and U251 cells and determined protein level of each CFIm subunit by western blotting.	('CFIm', 'Gene', '11052', (132, 136))	('knocked', 'Var', (16, 23))	('CFIm', 'Gene', (132, 136))	('LN229', 'CellLine', 'CVCL:0393', (74, 79))	('U251', 'CellLine', 'CVCL:0021', (84, 88))	('CFIm', 'Gene', '11052', (41, 45))	('CFIm', 'Gene', (41, 45))
106218	30705404	We first inspected PAC-seq data for Vma21, which is a previously established target of Nudt21-regulated APA, and found that the Vma21 3'-UTR was shortened in all three Nudt21 KD cells compared to the three control cells (Fig.	("3'-UTR", 'CPA', (134, 140))	('Nudt21 KD', 'Var', (168, 177))	('Vma21', 'Gene', (36, 41))	('Vma21', 'Gene', '203547', (128, 133))	('PAC', 'Phenotype', 'HP:0006699', (19, 22))	('Vma21', 'Gene', '203547', (36, 41))	('shortened', 'NegReg', (145, 154))	('Vma21', 'Gene', (128, 133))
106221	30705404	We observed that PAC-seq could accurately identify 5/6 annotated PASs and more importantly, we observed that Nudt21 KD does not change the overall usage of those PASs relative to control (Fig.	('Nudt21 KD', 'Var', (109, 118))	('PAC', 'Phenotype', 'HP:0006699', (17, 20))	('PAS', 'Gene', '249157', (65, 68))	('PAS', 'Gene', (65, 68))	('PAS', 'Gene', '249157', (162, 165))	('PAS', 'Gene', (162, 165))
106222	30705404	Taken together, these results indicate that the PAC-seq data generated from knockdown is highly congruent with previously defined PAS databases and that the Nudt21 KD does not cause a "general" phenotype of 3'-UTR shortening but rather that there is a specific subset of genes regulated by Nudt21.	('PAS', 'Gene', '249157', (130, 133))	('PAS', 'Gene', (130, 133))	('knockdown', 'Var', (76, 85))	('Nudt21', 'Gene', (290, 296))	('PAC', 'Phenotype', 'HP:0006699', (48, 51))	('cause', 'Reg', (176, 181))	("3'-UTR shortening", 'MPA', (207, 224))	('Nudt21 KD', 'Var', (157, 166))
106230	30705404	Importantly, Nudt21 KD resulted in a significant shift from the preferred usage of the most distal PAS in control-treated cells towards the most proximal PAS.	('PAS', 'Gene', '249157', (154, 157))	('PAS', 'Gene', (154, 157))	('Nudt21 KD', 'Var', (13, 22))	('shift', 'Reg', (49, 54))	('PAS', 'Gene', '249157', (99, 102))	('PAS', 'Gene', (99, 102))
106231	30705404	In the case of Pak2, a similar result was also observed except that the shiftoccurred in the middle of the 3'-UTR upon Nudt21 KD and most miRNA binding sites were remained.	('Pak2', 'Gene', '5062', (15, 19))	('Pak2', 'Gene', (15, 19))	('Nudt21 KD', 'Var', (119, 128))
106241	30705404	We reasoned that the low level of expression and the lack of a translational increase upon Nudt21 KD is because Pak2 is subject to 3'-UTR repression that is not alleviated after 3'-UTR shortening induced by Nudt21 KD.	('Pak2', 'Gene', '5062', (112, 116))	('Nudt21 KD', 'Var', (91, 100))	('Pak2', 'Gene', (112, 116))
106243	30705404	In contrast, we observed that PAK1 protein levels present in LN229 cells were significantly increased upon Nudt21 KD (Fig.	('PAK1', 'Gene', '5058', (30, 34))	('PAK1', 'Gene', (30, 34))	('Nudt21 KD', 'Var', (107, 116))	('increased', 'PosReg', (92, 101))	('LN229', 'CellLine', 'CVCL:0393', (61, 66))
106245	30705404	Further, given the lack of any increase in PAK2 levels in response to Nudt21 KD, we chose to focus our analysis on Pak1.	('PAK2', 'Gene', (43, 47))	('Nudt21 KD', 'Var', (70, 79))	('PAK2', 'Gene', '5062', (43, 47))
106246	30705404	Using soft agar assay, we found that depletion of Nudt21 significantly promoted LN229 and U251 anchorage-independent growth ability, as shown by increased colony numbers, while depletion of Pak1 reduces colony formation.	('depletion', 'Var', (37, 46))	('promoted', 'PosReg', (71, 79))	('LN229', 'CellLine', 'CVCL:0393', (80, 85))	('increased', 'PosReg', (145, 154))	('U251', 'CellLine', 'CVCL:0021', (90, 94))	('agar', 'Chemical', 'MESH:D000362', (11, 15))	('colony numbers', 'CPA', (155, 169))	('Nudt21', 'Gene', (50, 56))
106247	30705404	Similarly, we observed increased cell migration in LN229 and U251 cells when Nudt21 is knocked down whereas depletion of Pak1 reduces the number of migration cells.	('Nudt21', 'Gene', (77, 83))	('LN229', 'CellLine', 'CVCL:0393', (51, 56))	('knocked down', 'Var', (87, 99))	('increased', 'PosReg', (23, 32))	('cell migration', 'CPA', (33, 47))	('U251', 'CellLine', 'CVCL:0021', (61, 65))
106249	30705404	In the TCGA exon array GBM cohort, we found that high expression of Pak1 was correlated with poor overall survival among GBM patients (n = 348, p = 0.0233) (Fig.	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('Pak1', 'Gene', (68, 72))	('high', 'Var', (49, 53))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('overall survival', 'MPA', (98, 114))	('poor', 'NegReg', (93, 97))	('patients', 'Species', '9606', (125, 133))
106254	30705404	These data suggest that both Pak1 and its upstream regulator, Nudt21, serve as a biomarker for predicting prognosis of GBM patients and combination of Nudt21 and Pak1 expression improves its prediction value in prognosis of GBM patients.	('GBM', 'Disease', (224, 227))	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('patients', 'Species', '9606', (228, 236))	('Pak1', 'Gene', (162, 166))	('Nudt21', 'Gene', (151, 157))	('improves', 'PosReg', (178, 186))	('patients', 'Species', '9606', (123, 131))	('GBM', 'Phenotype', 'HP:0012174', (224, 227))	('combination', 'Var', (136, 147))
106256	30705404	To date, our understanding of GBM tumorigenesis has focused largely on genomic mutations, copy number alteration, and transcription dysregulation, however, post-transcriptional and translational mechanisms of GBM progression remain underappreciated.	('copy number alteration', 'Var', (90, 112))	('GBM tumor', 'Disease', (30, 39))	('GBM', 'Phenotype', 'HP:0012174', (209, 212))	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('GBM tumor', 'Disease', 'MESH:D005910', (30, 39))	('mutations', 'Var', (79, 88))
106270	30705404	Others have shown that knockdown of Nudt21 or CFIm68, but not CFIm59, leads to significant 3'-UTR shortening suggesting that the two heterotetramers are not functionally equivalent.	("3'-UTR shortening", 'MPA', (91, 108))	('CFIm68', 'Gene', (46, 52))	('knockdown', 'Var', (23, 32))	('CFIm68', 'Gene', '11052', (46, 52))	('CFIm59', 'Gene', (62, 68))	('CFIm59', 'Gene', '79869', (62, 68))	('Nudt21', 'Gene', (36, 42))
106281	30705404	In this study, we used a recently developed tool, called PAC-seq, to detect and quantify APA events that change in response to Nudt21 KD in GBM cells that may reflect the targets of Nudt21 that change APA in response to its downregulation in GBM patients.	('Nudt21 KD', 'Var', (127, 136))	('patients', 'Species', '9606', (246, 254))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('change', 'Reg', (105, 111))	('APA', 'MPA', (89, 92))	('PAC', 'Phenotype', 'HP:0006699', (57, 60))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))
106286	30705404	Moreover, phosphorylation of PAK1 can promote migration/invasion in GBM and is associated with shorter survival.	('associated', 'Reg', (79, 89))	('phosphorylation', 'Var', (10, 25))	('PAK1', 'Gene', '5058', (29, 33))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('migration/invasion', 'CPA', (46, 64))	('promote', 'PosReg', (38, 45))	('shorter', 'NegReg', (95, 102))	('PAK1', 'Gene', (29, 33))
106339	29664032	The most common genetic alterations in GB include loss of heterozygosity on chromosome 10 (LOH 10), mutations in p53, amplification and rearrangements of epidermal growth factor receptor (EGFR) gene, murine double minute 2 (MDM2) amplification, phosphatase and tensin (PTEN) homology mutations, tumour suppressor genes p16INK4a/p14ARF loss and retinoblastoma gene mutations.	('PTEN', 'Gene', (269, 273))	('p53', 'Gene', (113, 116))	('epidermal', 'Gene', (154, 163))	('retinoblastoma', 'Disease', 'MESH:D012175', (344, 358))	('loss', 'NegReg', (50, 54))	('MDM2', 'Gene', (224, 228))	('GB', 'Phenotype', 'HP:0012174', (39, 41))	('mutations', 'Var', (364, 373))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))	('tumour', 'Disease', 'MESH:D009369', (295, 301))	('tumour', 'Disease', (295, 301))	('loss', 'NegReg', (335, 339))	('EGFR', 'Gene', (188, 192))	('p16INK4a', 'Gene', '12578', (319, 327))	('retinoblastoma', 'Phenotype', 'HP:0009919', (344, 358))	('murine double minute 2', 'Gene', (200, 222))	('mutations', 'Var', (100, 109))	('retinoblastoma', 'Disease', (344, 358))	('p16INK4a', 'Gene', (319, 327))	('amplification', 'Gene', (118, 131))	('murine double minute 2', 'Gene', '17246', (200, 222))	('rearrangements', 'Var', (136, 150))
106345	29664032	extensive areas of necrosis seen in isocitrate dehydrogenase (IDH)-wild type is primary GB and IDH mutant type with limited areas of necrosis is secondary GB.	('necrosis', 'Disease', 'MESH:D009336', (133, 141))	('necrosis', 'Disease', 'MESH:D009336', (19, 27))	('IDH', 'Gene', '3417', (62, 65))	('GB', 'Phenotype', 'HP:0012174', (155, 157))	('necrosis', 'Disease', (19, 27))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', (95, 98))	('necrosis', 'Disease', (133, 141))	('mutant', 'Var', (99, 105))	('IDH', 'Gene', (62, 65))	('GB', 'Phenotype', 'HP:0012174', (88, 90))
106347	29664032	GBs with oligodendroglioma component are frequently secondary neoplasms with higher frequency of IDH-1 mutations and had a lower frequency of PTEN mutations.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('mutations', 'Var', (103, 112))	('GBs', 'Disease', (0, 3))	('neoplasms', 'Disease', 'MESH:D009369', (62, 71))	('GB', 'Phenotype', 'HP:0012174', (0, 2))	('neoplasms', 'Disease', (62, 71))	('oligodendroglioma', 'Disease', (9, 26))	('IDH-1', 'Gene', '3417', (97, 102))	('IDH-1', 'Gene', (97, 102))	('oligodendroglioma', 'Disease', 'MESH:D009837', (9, 26))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))
106349	29664032	p53 mutations are also noted in precursor low-grade lesions (59%) and anaplastic astrocytomas (53%).	('p53', 'Gene', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (81, 92))	('anaplastic astrocytomas', 'Disease', (70, 93))	('mutations', 'Var', (4, 13))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (70, 93))
106351	29664032	In secondary GBs in which mutations in the TP53 gene are more common than in primary lesions, p53 may be mutated in more than 65 per cent of the cases.	('GB', 'Phenotype', 'HP:0012174', (13, 15))	('mutations', 'Var', (26, 35))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('common', 'Reg', (62, 68))	('secondary GBs', 'Disease', (3, 16))
106352	29664032	EGFR mutations are tumour-specific and provide promising target for therapy.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('EGFR', 'Gene', (0, 4))	('tumour', 'Disease', (19, 25))	('mutations', 'Var', (5, 14))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
106354	29664032	High protein levels of EGFR occur in about 90 per cent of astrocytic tumours, suggesting that alterations in transcription and translation of these genes may also participate in tumorigenesis.	('alterations', 'Var', (94, 105))	('astrocytic tumours', 'Disease', 'MESH:D001254', (58, 76))	('participate', 'Reg', (163, 174))	('translation', 'MPA', (127, 138))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumorigenesis', 'CPA', (178, 191))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('astrocytic tumours', 'Disease', (58, 76))	('EGFR', 'Gene', (23, 27))	('transcription', 'MPA', (109, 122))
106355	29664032	Specifically, EGFR is amplified in 40 per cent, overexpressed in 60 per cent and mutated in 20-30 per cent of the patients.	('mutated', 'Var', (81, 88))	('EGFR', 'Gene', (14, 18))	('overexpressed', 'PosReg', (48, 61))	('patients', 'Species', '9606', (114, 122))
106356	29664032	Amplifications and rearrangements of EGFR are highly indicative of high-grade gliomas, with a worse prognosis than estimated from just histopathological grading.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('indicative', 'Reg', (53, 63))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('Amplifications', 'Var', (0, 14))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('rearrangements', 'Var', (19, 33))	('EGFR', 'Gene', (37, 41))
106357	29664032	This fact has prompted the investigation of EGFR inhibitors aiming to promote apoptosis of cancer cells and increasing tumour sensitivity to possible adjuvant therapies.	('EGFR', 'Gene', (44, 48))	('apoptosis', 'CPA', (78, 87))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('increasing', 'PosReg', (108, 118))	('tumour', 'Disease', (119, 125))	('promote', 'PosReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('inhibitors', 'Var', (49, 59))
106367	29664032	For IHC, representative paraffin blocks were selected based on hematoxylin and eosin (H & E)-stained slides and IHC was done for the markers p53 and EGFR according to the procedure provided in the kit (Biogenex, India).	('paraffin', 'Chemical', 'MESH:D010232', (24, 32))	('and', 'Gene', (145, 148))	('hematoxylin', 'Chemical', 'MESH:D006416', (63, 74))	('markers', 'Var', (133, 140))	('eosin', 'Chemical', 'MESH:D004801', (79, 84))	('H & E', 'Chemical', 'MESH:D006371', (86, 91))
106382	29664032	Thomas et al reported that the glioma cell line SKMG-3 had an unusual genotype in which p53 gene mutation coexisted with an amplified EGFR gene.	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('p53', 'Gene', (88, 91))	('mutation', 'Var', (97, 105))	('SKMG-3', 'CellLine', 'CVCL:8576', (48, 54))	('glioma', 'Disease', (31, 37))
106385	29664032	GB with wild-type IDH is classified as primary GB, while GB with mutant IDH is classified as secondary GB and GB not otherwise specified, a diagnosis that is reserved for those tumours for which full IDH valuation cannot be performed.	('GB', 'Phenotype', 'HP:0012174', (47, 49))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('IDH', 'Gene', (18, 21))	('tumours', 'Disease', (177, 184))	('GB', 'Phenotype', 'HP:0012174', (0, 2))	('GB', 'Phenotype', 'HP:0012174', (103, 105))	('mutant', 'Var', (65, 71))	('GB', 'Phenotype', 'HP:0012174', (110, 112))	('IDH', 'Gene', '3417', (18, 21))	('IDH', 'Gene', (200, 203))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', '3417', (200, 203))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('GB', 'Phenotype', 'HP:0012174', (57, 59))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))
106390	29664032	The usage of other important biological markers such as IDH-1 mutation and altered expression of MDM2 would have yielded better molecular results.	('IDH-1', 'Gene', '3417', (56, 61))	('IDH-1', 'Gene', (56, 61))	('altered', 'Reg', (75, 82))	('mutation', 'Var', (62, 70))	('expression', 'MPA', (83, 93))	('MDM2', 'Gene', (97, 101))
106392	29664032	Though the IHC expression of p53 and EGFR could not classify GB in majority of the cases, variable expression of these markers suggests further studies to include IDH mutation and may be able to provide preliminary information regarding prognosis as expression of p53 and EGFR carries worse prognosis even without evaluating IDH mutation.	('EGFR', 'Gene', (272, 276))	('IDH', 'Gene', (163, 166))	('IDH', 'Gene', (325, 328))	('IDH', 'Gene', '3417', (163, 166))	('GB', 'Phenotype', 'HP:0012174', (61, 63))	('p53', 'Var', (264, 267))	('IDH', 'Gene', '3417', (325, 328))
106393	25204415	The landscape of kinase fusions in cancer Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells.	('deregulation', 'MPA', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Human', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('rat', 'Species', '10116', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('key pathways', 'Pathway', (127, 139))	('cancer', 'Disease', (48, 54))	('alterations', 'Var', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (143, 149))	('cancer', 'Disease', (35, 41))	('fusions', 'Var', (24, 31))
106397	25204415	Kinases activated by gene fusions represent potentially important targets for the development of cancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gene fusions', 'Var', (21, 33))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
106399	25204415	Kinases activated by gene fusions represent an important class of oncogenes associated with both hematopoietic malignancies and solid tumours.	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('hematopoietic malignancies and solid tumours', 'Disease', 'MESH:D019337', (97, 141))	('associated', 'Reg', (76, 86))	('gene fusions', 'Var', (21, 33))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
106400	25204415	They are produced by translocations or other chromosomal rearrangements, and their protein products often represent ideal targets for the development of cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('translocations', 'Var', (21, 35))	('cancer', 'Disease', (153, 159))
106404	25204415	While such studies have helped to identify numerous point mutations and small insertion/deletions in genes driving tumorigenesis, our understanding of the landscape of gene fusions in solid tumours is incomplete.	('solid tumours', 'Disease', 'MESH:D009369', (184, 197))	('insertion/deletions', 'Var', (78, 97))	('solid tumours', 'Disease', (184, 197))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))
106407	25204415	We identify several novel and recurrent fusions involving kinases that very likely play a role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('role', 'Reg', (90, 94))	('fusions', 'Var', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('play', 'Reg', (83, 87))	('kinases', 'Enzyme', (58, 65))
106409	25204415	We then focused our detailed analysis exclusively on recurrent (n>=2 across all cancer types), putatively functional kinase fusions (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('kinase fusions', 'Var', (117, 131))	('fusions', 'Var', (124, 131))	('cancer', 'Disease', (80, 86))
106411	25204415	First, as has been observed for point mutations, the proportion of samples harbouring kinase fusions was markedly different between cancer types, reflecting differences in the aetiology of these tumours.	('kinase fusions', 'Var', (86, 100))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('different', 'Reg', (114, 123))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
106412	25204415	For instance, sarcoma samples showed the highest frequency of kinase fusions (0.57 fusions per sample), consistent with the current understanding that a large fraction of sarcomas harbour specific translocations, but only 12% of those were recurrent kinase fusions (Supplementary Fig.	('sarcoma', 'Disease', (14, 21))	('sarcomas', 'Disease', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('translocations', 'Var', (197, 211))	('kinase', 'Var', (62, 68))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcoma', 'Disease', (171, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
106414	25204415	Conversely, some cancer types, for example, clear cell and chromophobe renal cell carcinoma, showed a very low frequency of kinase fusions with no instances of recurrence (Supplementary Fig.	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 91))	('clear cell', 'Disease', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('cancer', 'Disease', (17, 23))	('chromophobe renal cell carcinoma', 'Disease', (59, 91))	('kinase fusions', 'Var', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
106415	25204415	Overall, we detected recurrent kinase fusions in 3.0% of the samples, and all cancers except clear cell and chromophobe renal cell carcinoma harboured recurrent kinase fusions (0-12.9% of samples per cancer type, median=2.1%).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('detected', 'Reg', (12, 20))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('clear cell', 'Disease', (93, 103))	('chromophobe renal cell carcinoma', 'Disease', (108, 140))	('kinase fusions', 'Var', (31, 45))	('cancer', 'Disease', (200, 206))
106417	25204415	Interestingly, we identified new tumour types harbouring such fusions and discovered several novel fusion partners for these kinases.	('tumour type', 'Disease', (33, 44))	('tumour type', 'Disease', 'MESH:D009369', (33, 44))	('fusion', 'Interaction', (99, 105))	('fusions', 'Var', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))
106419	25204415	Third, we identified several novel and recurrent kinase fusions that very likely play a role in cancer, such as those involving the MET proto-oncogene and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('role', 'Reg', (88, 92))	('play', 'Reg', (81, 85))	('PIK3CA', 'Gene', (155, 161))	('MET', 'Gene', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('PIK3CA', 'Gene', '5290', (155, 161))	('kinase fusions', 'Var', (49, 63))
106420	25204415	Our analysis also uncovered novel, recurrent fusions in kinases with no known tumorigenic genomic alterations (that is, feline Gardner-Rasheed sarcoma viral oncogene homologue, FGR and protein kinase N1, PKN1), potentially resulting in active and oncogenic fusion proteins.	('protein kinase N1', 'Gene', '5585', (185, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('PKN1', 'Gene', (204, 208))	('kinases', 'Enzyme', (56, 63))	('Gardner-Rasheed sarcoma viral', 'Disease', (127, 156))	('Gardner-Rasheed sarcoma viral', 'Disease', 'MESH:D005736', (127, 156))	('oncogenic', 'MPA', (247, 256))	('rat', 'Species', '10116', (102, 105))	('active', 'MPA', (236, 242))	('fusion', 'Interaction', (257, 263))	('FGR', 'Gene', (177, 180))	('FGR', 'Gene', '2268', (177, 180))	('fusions', 'Var', (45, 52))	('protein kinase N1', 'Gene', (185, 202))	('PKN1', 'Gene', '5585', (204, 208))
106421	25204415	Finally, we discovered a recurrent fusion in sarcoma encoding the non-catalytic portion of TRIO kinase, which resulted in the upregulation of the transcription of telomerase reverse transcriptase (TERT) in those tumours.	('TERT', 'Gene', (197, 201))	('sarcoma', 'Disease', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('TRIO', 'Gene', (91, 95))	('TRIO', 'Gene', '7204', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('telomerase reverse transcriptase', 'Gene', (163, 195))	('TERT', 'Gene', '7015', (197, 201))	('telomerase reverse transcriptase', 'Gene', '7015', (163, 195))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('transcription', 'MPA', (146, 159))	('fusion', 'Var', (35, 41))	('tumours', 'Disease', (212, 219))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('upregulation', 'PosReg', (126, 138))
106423	25204415	Consistent with previous studies, we detected EML4-ALK fusions in ~1% (5/513) of lung adenocarcinoma samples, multiple ALK fusions, including a single STRN-ALK fusion, in thyroid cancer (3/498) and one in papillary renal carcinoma.	('EML4', 'Gene', '27436', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ALK', 'Gene', '238', (156, 159))	('papillary renal carcinoma', 'Disease', (205, 230))	('STRN', 'Gene', '6801', (151, 155))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))	('ALK', 'Gene', (156, 159))	('ALK', 'Gene', '238', (51, 54))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (205, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('lung adenocarcinoma', 'Disease', (81, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('ALK', 'Gene', (51, 54))	('fusions', 'Var', (123, 130))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('ALK', 'Gene', '238', (119, 122))	('STRN', 'Gene', (151, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (205, 230))	('ALK', 'Gene', (119, 122))	('renal carcinoma', 'Phenotype', 'HP:0005584', (215, 230))	('thyroid cancer', 'Disease', (171, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('EML4', 'Gene', (46, 50))
106424	25204415	We also found several novel ALK fusion events, including a TPM1-ALK fusion in bladder cancer, a SMEK2-ALK fusion in rectal adenocarcinoma and a GTF2IRD1-ALK fusion in thyroid cancer (Fig.	('ALK', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (116, 137))	('ALK', 'Gene', '238', (28, 31))	('fusion', 'Var', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('thyroid cancer', 'Disease', (167, 181))	('ALK', 'Gene', (28, 31))	('GTF2IRD1', 'Gene', '9569', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('GTF2IRD1', 'Gene', (144, 152))	('bladder cancer', 'Disease', (78, 92))	('ALK', 'Gene', '238', (153, 156))	('SMEK2', 'Gene', '57223', (96, 101))	('ALK', 'Gene', '238', (64, 67))	('thyroid cancer', 'Disease', 'MESH:D013964', (167, 181))	('SMEK2', 'Gene', (96, 101))	('rectal adenocarcinoma', 'Disease', (116, 137))	('ALK', 'Gene', (153, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('ALK', 'Gene', (64, 67))	('thyroid cancer', 'Phenotype', 'HP:0002890', (167, 181))	('ALK', 'Gene', '238', (102, 105))
106426	25204415	We also identified multiple c-ros oncogene 1 (ROS1) fusions, including ROS1 fusions in 8/513 lung adenocarcinomas, all of which have been previously described.	('c-ros oncogene 1', 'Gene', '6098', (28, 44))	('ROS1', 'Gene', '6098', (71, 75))	('lung adenocarcinomas', 'Disease', (93, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('fusions', 'Var', (76, 83))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (93, 113))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (93, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('ROS1', 'Gene', (46, 50))	('c-ros oncogene 1', 'Gene', (28, 44))	('ROS1', 'Gene', '6098', (46, 50))	('ROS1', 'Gene', (71, 75))	('fusions', 'Var', (52, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
106429	25204415	RET proto-oncogene fusions have been identified previously in both lung adenocarcinoma and thyroid cancer.	('RET', 'Gene', '5979', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('fusions', 'Var', (19, 26))	('thyroid cancer', 'Phenotype', 'HP:0002890', (91, 105))	('thyroid cancer', 'Disease', (91, 105))	('RET', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('identified', 'Reg', (37, 47))	('thyroid cancer', 'Disease', 'MESH:D013964', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
106430	25204415	Consistent with these studies, we observed recurrent CCDC6-RET fusions in thyroid cancer but also identified several RET fusions with novel partners, including AKAP13, FKBP15, SPECC1L and TBL1XR1 (Fig.	('FKBP15', 'Gene', '23307', (168, 174))	('SPECC1L', 'Gene', (176, 183))	('RET', 'Gene', (59, 62))	('AKAP13', 'Gene', (160, 166))	('SPECC1L', 'Gene', '23384', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('thyroid cancer', 'Disease', (74, 88))	('TBL1XR1', 'Gene', '79718', (188, 195))	('RET', 'Gene', '5979', (117, 120))	('TBL1XR1', 'Gene', (188, 195))	('thyroid cancer', 'Disease', 'MESH:D013964', (74, 88))	('RET', 'Gene', '5979', (59, 62))	('CCDC6', 'Gene', (53, 58))	('FKBP15', 'Gene', (168, 174))	('AKAP13', 'Gene', '11214', (160, 166))	('CCDC6', 'Gene', '8030', (53, 58))	('thyroid cancer', 'Phenotype', 'HP:0002890', (74, 88))	('RET', 'Gene', (117, 120))	('fusions', 'Var', (63, 70))
106432	25204415	In addition, we detected previously identified RET fusions in new tumour indications, including a single CCDC6-RET fusion in colon adenocarcinoma and a single ERC1-RET fusion in breast cancer.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (125, 145))	('fusion', 'Var', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('CCDC6', 'Gene', (105, 110))	('RET', 'Gene', '5979', (111, 114))	('CCDC6', 'Gene', '8030', (105, 110))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('RET', 'Gene', '5979', (47, 50))	('RET', 'Gene', '5979', (164, 167))	('colon adenocarcinoma', 'Disease', (125, 145))	('ERC1', 'Gene', '23085', (159, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('RET', 'Gene', (111, 114))	('ERC1', 'Gene', (159, 163))	('RET', 'Gene', (164, 167))	('RET', 'Gene', (47, 50))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))
106434	25204415	BRAF (v-raf murine sarcoma viral oncogene homologue B) fusions have also been described previously in multiple cancer types, including prostate cancer, melanoma, radiation-induced thyroid cancer and pediatric low-grade gliomas.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (144, 150))	('thyroid cancer', 'Disease', 'MESH:D013964', (180, 194))	('sarcoma viral', 'Disease', 'MESH:D001102', (19, 32))	('BRAF', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('sarcoma viral', 'Disease', (19, 32))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('thyroid cancer', 'Phenotype', 'HP:0002890', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('v-raf', 'Gene', '110157', (6, 11))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('murine', 'Species', '10090', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('cancer', 'Disease', (188, 194))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('prostate cancer', 'Disease', (135, 150))	('thyroid cancer', 'Disease', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('v-raf', 'Gene', (6, 11))	('described', 'Reg', (78, 87))	('gliomas', 'Disease', (219, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('fusions', 'Var', (55, 62))
106435	25204415	Consistent with these studies, we identified a broad range of cancer types harbouring BRAF fusions, including prostate, melanoma and thyroid.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (91, 98))	('BRAF', 'Var', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('prostate', 'Disease', (110, 118))	('thyroid', 'Disease', (133, 140))
106437	25204415	Interestingly, the BRAF fusions in melanoma are exclusive of other known oncogenic events such as BRAF and NRAS mutations.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('BRAF', 'Disease', (98, 102))	('BRAF', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (107, 111))	('mutations', 'Var', (112, 121))	('NRAS', 'Gene', (107, 111))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('fusions', 'Var', (24, 31))
106441	25204415	However, these fusions all remove at least the first eight exons of BRAF, which has previously been shown to promote BRAF dimerization, independent of activated RAS (rat sarcoma viral oncogene homologues) or other mechanisms of BRAF dimerization.	('promote', 'PosReg', (109, 116))	('rat', 'Species', '10116', (166, 169))	('sarcoma viral', 'Disease', 'MESH:D001102', (170, 183))	('fusions', 'Var', (15, 22))	('BRAF dimerization', 'MPA', (117, 134))	('BRAF', 'Gene', (68, 72))	('remove', 'NegReg', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma viral', 'Disease', (170, 183))
106442	25204415	Consistent with previous studies, we also found recurrent RAF1 (also known as CRAF) fusions in various tumour types (Fig.	('tumour type', 'Disease', 'MESH:D009369', (103, 114))	('fusions', 'Var', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour type', 'Disease', (103, 114))	('CRAF', 'Gene', (78, 82))	('RAF1', 'Gene', '5894', (58, 62))	('RAF1', 'Gene', (58, 62))	('CRAF', 'Gene', '5894', (78, 82))
106443	25204415	In addition to known tumour occurrences (four fusions in melanoma, two fusions in prostate adenocarcinoma), we identified AGGF1-RAF1 fusions in seven papillary thyroid carcinoma samples (1.4%).	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('fusions', 'Var', (133, 140))	('tumour', 'Disease', (21, 27))	('AGGF1', 'Gene', (122, 127))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (150, 177))	('prostate adenocarcinoma', 'Disease', (82, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('papillary thyroid carcinoma', 'Disease', (150, 177))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (150, 177))	('RAF1', 'Gene', '5894', (128, 132))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (82, 105))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('RAF1', 'Gene', (128, 132))	('AGGF1', 'Gene', '55109', (122, 127))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (160, 177))
106446	25204415	AGGF1-RAF1 fusions appear not to be limited to thyroid cancers, as we also found a single AGGF1-RAF1 fusion in prostate cancer.	('fusion', 'Var', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('thyroid cancers', 'Disease', (47, 62))	('prostate cancer', 'Disease', (111, 126))	('AGGF1', 'Gene', '55109', (0, 5))	('thyroid cancers', 'Disease', 'MESH:D013964', (47, 62))	('AGGF1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RAF1', 'Gene', '5894', (6, 10))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('RAF1', 'Gene', (96, 100))	('RAF1', 'Gene', '5894', (96, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (47, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('AGGF1', 'Gene', '55109', (90, 95))	('RAF1', 'Gene', (6, 10))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('AGGF1', 'Gene', (0, 5))
106447	25204415	We observed a broad distribution of the fibroblast growth factor receptors FGFR1, FGFR2 and FGFR3 fusions:in particular FGFR3-TACC3 fusions:across eight of the 20 tumour types analysed (Fig.	('tumour type', 'Disease', 'MESH:D009369', (163, 174))	('TACC3', 'Gene', (126, 131))	('fusions', 'Var', (132, 139))	('FGFR3', 'Gene', (92, 97))	('FGFR1', 'Gene', (75, 80))	('FGFR3', 'Gene', (120, 125))	('fusions', 'Var', (98, 105))	('FGFR3', 'Gene', '2261', (92, 97))	('FGFR1', 'Gene', '2260', (75, 80))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('FGFR2', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (82, 87))	('tumour type', 'Disease', (163, 174))	('TACC3', 'Gene', '10460', (126, 131))	('FGFR3', 'Gene', '2261', (120, 125))
106449	25204415	We also detected a single FGFR3-TACC3 fusion in a novel indication, papillary renal carcinoma, and a novel FGFR3-ELAVL3 fusion in low-grade glioma (Supplementary Fig.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('ELAVL3', 'Gene', (113, 119))	('FGFR3', 'Gene', (26, 31))	('fusion', 'Var', (38, 44))	('FGFR3', 'Gene', '2261', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('ELAVL3', 'Gene', '1995', (113, 119))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (68, 93))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (68, 93))	('renal carcinoma', 'Phenotype', 'HP:0005584', (78, 93))	('FGFR3', 'Gene', (107, 112))	('glioma', 'Disease', (140, 146))	('TACC3', 'Gene', '10460', (32, 37))	('FGFR3', 'Gene', '2261', (26, 31))	('papillary renal carcinoma', 'Disease', (68, 93))	('TACC3', 'Gene', (32, 37))
106450	25204415	Similar to RET and NTRK1-3 (see below), fusions involving FGFR1-3 provide a therapeutic opportunity for current and future FGFR inhibitors in multiple patient subpopulations.	('RET', 'Gene', '5979', (11, 14))	('NTRK1', 'Gene', '4914', (19, 24))	('fusions', 'Var', (40, 47))	('patient', 'Species', '9606', (151, 158))	('RET', 'Gene', (11, 14))	('FGFR1', 'Gene', (58, 63))	('NTRK1', 'Gene', (19, 24))	('FGFR1', 'Gene', '2260', (58, 63))
106451	25204415	Recurrent fusions involving members of the NTRK family have been identified previously in congenital fibrosarcoma, human secretory breast carcinoma and papillary thyroid cancer, which represent clinical indications for which currently available non-kinase-targeted treatment options are usually adequate.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (152, 176))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (101, 113))	('congenital fibrosarcoma', 'Disease', (90, 113))	('congenital fibrosarcoma', 'Disease', 'MESH:D005354', (90, 113))	('thyroid cancer', 'Phenotype', 'HP:0002890', (162, 176))	('identified', 'Reg', (65, 75))	('breast carcinoma and papillary thyroid cancer', 'Disease', 'MESH:D000077273', (131, 176))	('breast carcinoma', 'Phenotype', 'HP:0003002', (131, 147))	('NTRK', 'Gene', (43, 47))	('human', 'Species', '9606', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('fusions', 'Var', (10, 17))
106452	25204415	However, recurrent NTRK1 and NTRK2 fusions have also been recently identified in diseases which represent significant unmet medical needs, including glioblastoma, cholangiocarcinoma and pediatric high-grade glioma.	('glioblastoma', 'Disease', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('NTRK1', 'Gene', '4914', (19, 24))	('fusions', 'Var', (35, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioma', 'Disease', (207, 213))	('cholangiocarcinoma', 'Disease', (163, 181))	('NTRK2', 'Gene', '4915', (29, 34))	('NTRK1', 'Gene', (19, 24))	('identified', 'Reg', (67, 77))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))	('NTRK2', 'Gene', (29, 34))
106453	25204415	Consistent with previous studies, we observed recurrent NTRK1 and NTRK3 fusions in papillary thyroid cancer and glioblastoma, but also identified a number of novel NTRK2 fusions in head and neck squamous cell carcinoma (PAN3-NTRK2), low-grade glioma (AFAP1-NTRK2) and lung adenocarcinoma (TRIM24-NTRK2) (Fig.	('lung adenocarcinoma', 'Disease', (268, 287))	('NTRK2', 'Gene', '4915', (225, 230))	('AFAP1', 'Gene', '60312', (251, 256))	('glioma', 'Disease', (243, 249))	('TRIM24', 'Gene', '8805', (289, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (83, 107))	('NTRK2', 'Gene', '4915', (257, 262))	('NTRK2', 'Gene', '4915', (296, 301))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('NTRK2', 'Gene', (164, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (268, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('AFAP1', 'Gene', (251, 256))	('neck squamous cell carcinoma', 'Disease', (190, 218))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (83, 107))	('NTRK2', 'Gene', (225, 230))	('NTRK1', 'Gene', '4914', (56, 61))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (190, 218))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (268, 287))	('PAN3', 'Gene', (220, 224))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('thyroid cancer', 'Phenotype', 'HP:0002890', (93, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('fusions', 'Var', (170, 177))	('NTRK1', 'Gene', (56, 61))	('NTRK2', 'Gene', (257, 262))	('NTRK2', 'Gene', (296, 301))	('fusions', 'Var', (72, 79))	('PAN3', 'Gene', '255967', (220, 224))	('NTRK3', 'Gene', '4916', (66, 71))	('TRIM24', 'Gene', (289, 295))	('glioblastoma', 'Disease', (112, 124))	('NTRK3', 'Gene', (66, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('papillary thyroid cancer', 'Disease', (83, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('NTRK2', 'Gene', '4915', (164, 169))
106455	25204415	Across all tumour types analysed, NTRK1-3 fusions were observed at low frequency in 9 of the 20 cancer types analysed, providing a therapeutic opportunity for the use of pan-NTRK inhibitors in multiple patient populations.	('NTRK1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('patient', 'Species', '9606', (202, 209))	('tumour type', 'Disease', (11, 22))	('NTRK1', 'Gene', '4914', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumour type', 'Disease', 'MESH:D009369', (11, 22))	('fusions', 'Var', (42, 49))	('cancer', 'Disease', (96, 102))
106456	25204415	Protein kinase C fusions have recently been described in papillary glioneuronal tumours and benign fibrous histiocytoma.	('Protein', 'Protein', (0, 7))	('benign fibrous histiocytoma', 'Disease', (92, 119))	('papillary glioneuronal tumours', 'Phenotype', 'HP:0025170', (57, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('fusions', 'Var', (17, 24))	('papillary glioneuronal tumours', 'Disease', 'MESH:D000077273', (57, 87))	('papillary glioneuronal tumours', 'Disease', (57, 87))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('described', 'Reg', (44, 53))	('histiocytoma', 'Phenotype', 'HP:0012315', (107, 119))
106457	25204415	We found two new occurrences of PRKCA (protein kinase C, alpha) fusions in lung squamous cell carcinoma and three PRKCB (protein kinase C, beta) fusions in lung squamous cell carcinoma, lung adenocarcinoma and low-grade glioma (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('lung squamous cell carcinoma', 'Disease', (156, 184))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('PRKCA', 'Gene', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('lung adenocarcinoma', 'Disease', (186, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('PRKCB', 'Gene', (114, 119))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (186, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (186, 205))	('protein kinase C, alpha', 'Gene', '5578', (39, 62))	('PRKCA', 'Gene', '5578', (32, 37))	('fusions', 'Var', (64, 71))	('PRKCB', 'Gene', '5579', (114, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 184))	('glioma', 'Disease', (220, 226))
106461	25204415	In both cases, however, N-terminal truncation of PRKCA removes the autoinhibitory pseudosubstrate segment, possibly leading to a constitutively activated kinase in the absence of a functional fusion partner.	('PRKCA', 'Gene', (49, 54))	('autoinhibitory pseudosubstrate segment', 'MPA', (67, 105))	('N-terminal truncation', 'Var', (24, 45))	('leading to', 'Reg', (116, 126))	('removes', 'NegReg', (55, 62))	('PRKCA', 'Gene', '5578', (49, 54))	('constitutively activated kinase', 'MPA', (129, 160))	('rat', 'Species', '10116', (93, 96))
106463	25204415	These data suggest that PRKCA fusions are potential oncogenic events in lung squamous cell carcinoma, leading to overexpression as well as constitutive activation of PRKCA.	('PRKCA', 'Gene', '5578', (166, 171))	('activation', 'PosReg', (152, 162))	('PRKCA', 'Gene', (166, 171))	('overexpression', 'PosReg', (113, 127))	('fusions', 'Var', (30, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 100))	('PRKCA', 'Gene', '5578', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung squamous cell carcinoma', 'Disease', (72, 100))	('PRKCA', 'Gene', (24, 29))
106464	25204415	In the same fashion, PRKCB fusions truncate the N-terminal part of the protein containing the autoinhibitory domain and are predicted to activate this kinase (Supplementary Fig.	('PRKCB', 'Gene', (21, 26))	('PRKCB', 'Gene', '5579', (21, 26))	('truncate', 'NegReg', (35, 43))	('fusions', 'Var', (27, 34))	('activate', 'PosReg', (137, 145))
106467	25204415	Anecdotally, a transforming TPR-MET fusion was previously generated in vitro via carcinogen-induced chromosomal rearrangement fusing the dimerization domain of TPR to the kinase domain of the MET receptor tyrosine kinase.	('TPR', 'Gene', '7175', (160, 163))	('fusing', 'Var', (126, 132))	('TPR', 'Gene', (28, 31))	('TPR', 'Gene', '7175', (28, 31))	('dimerization', 'MPA', (137, 149))	('rat', 'Species', '10116', (62, 65))	('TPR', 'Gene', (160, 163))
106472	25204415	We also identified single MET fusions in four other cancers: low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma and thyroid carcinoma.	('cancers', 'Disease', (52, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (129, 146))	('hepatocellular carcinoma', 'Disease', (79, 103))	('lung adenocarcinoma', 'Disease', (105, 124))	('thyroid carcinoma', 'Disease', (129, 146))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('glioma', 'Disease', (71, 77))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (129, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('single MET fusions', 'Var', (19, 37))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
106475	25204415	Mutations and, to a lesser extent, increased copy numbers in another prevalent oncogene, PIK3CA, have been characterized in diverse cancers.	('cancers', 'Disease', (132, 139))	('increased', 'PosReg', (35, 44))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Mutations', 'Var', (0, 9))	('copy numbers', 'Var', (45, 57))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
106476	25204415	While activating missense mutations in PIK3CA have been described as frequently as 50% in endometrial cancers, 30% in breast invasive carcinomas and 20% in colorectal as well as head and neck cancers, this gene has not been implicated in activating fusion events.	('missense mutations', 'Var', (17, 35))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('neck cancers', 'Disease', (187, 199))	('head and neck cancers', 'Phenotype', 'HP:0012288', (178, 199))	('neck cancers', 'Disease', 'MESH:D006258', (187, 199))	('endometrial cancers', 'Disease', 'MESH:D016889', (90, 109))	('endometrial cancers', 'Disease', (90, 109))	('colorectal', 'Disease', 'MESH:D015179', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('PIK3CA', 'Gene', '5290', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('breast invasive carcinomas', 'Disease', (118, 144))	('activating', 'PosReg', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('PIK3CA', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal', 'Disease', (156, 166))	('breast invasive carcinomas', 'Disease', 'MESH:D018270', (118, 144))
106477	25204415	We found two TBL1XR1-PIK3CA fusions in 1,072 breast cancer samples, and a single occurrence of the same gene fusion in prostate adenocarcinoma (1/335).	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TBL1XR1', 'Gene', '79718', (13, 20))	('PIK3CA', 'Gene', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('TBL1XR1', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('PIK3CA', 'Gene', '5290', (21, 27))	('fusions', 'Var', (28, 35))	('prostate adenocarcinoma', 'Disease', (119, 142))
106480	25204415	Indeed, in all samples where we detected PIK3CA translocations, and where PIK3CA was not amplified, PIK3CA mRNA expression levels were the highest within the respective tumour types (Fig.	('translocations', 'Var', (48, 62))	('highest', 'Reg', (139, 146))	('tumour type', 'Disease', 'MESH:D009369', (169, 180))	('PIK3CA', 'Gene', '5290', (74, 80))	('PIK3CA', 'Gene', (41, 47))	('PIK3CA', 'Gene', (100, 106))	('mRNA expression levels', 'MPA', (107, 129))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('PIK3CA', 'Gene', '5290', (41, 47))	('PIK3CA', 'Gene', '5290', (100, 106))	('tumour type', 'Disease', (169, 180))	('PIK3CA', 'Gene', (74, 80))
106482	25204415	These results strongly suggest that PIK3CA overexpression is driven by its fusion partner, and that PIK3CA promoter fusions are an additional oncogenic mechanism to be considered for expanding the use of targeted therapies such as PI3K, AKT or mTOR inhibitors.	('AKT', 'Gene', (237, 240))	('mTOR', 'Gene', (244, 248))	('PIK3CA', 'Gene', '5290', (36, 42))	('overexpression', 'PosReg', (43, 57))	('PIK3CA', 'Gene', (100, 106))	('fusions', 'Var', (116, 123))	('AKT', 'Gene', '207', (237, 240))	('PIK3CA', 'Gene', '5290', (100, 106))	('PIK3CA', 'Gene', (36, 42))	('mTOR', 'Gene', '2475', (244, 248))
106483	25204415	In addition to fusions involving known oncogenes, we found several novel and recurrent fusions involving kinases that have not been previously directly linked to cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('fusions', 'Var', (87, 94))	('cancer', 'Disease', (162, 168))	('kinases', 'Enzyme', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
106485	25204415	Here, we show for the first time that genetic events can lead to FGR overexpression in primary tumour samples.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('overexpression', 'MPA', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('lead to', 'Reg', (57, 64))	('tumour', 'Disease', (95, 101))	('FGR', 'Gene', (65, 68))	('FGR', 'Gene', '2268', (65, 68))	('genetic events', 'Var', (38, 52))
106487	25204415	The WASF2 and FGR genes are located very proximally on the short arm of chromosome 1, and the fusion presumably results from a tandem repeat that puts their coding regions in close proximity (Supplementary Fig.	('results from', 'Reg', (112, 124))	('tandem repeat', 'Var', (127, 140))	('WASF2', 'Gene', '10163', (4, 9))	('FGR', 'Gene', (14, 17))	('FGR', 'Gene', '2268', (14, 17))	('short arm', 'Phenotype', 'HP:0009824', (59, 68))	('WASF2', 'Gene', (4, 9))
106489	25204415	In all three cases, FGR mRNA expression in the samples harbouring a fusion was among the highest compared with all other tumours of that tissue type (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('fusion', 'Var', (68, 74))	('highest', 'Reg', (89, 96))	('FGR', 'Gene', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('FGR', 'Gene', '2268', (20, 23))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))
106491	25204415	Collectively, these data highlight a previously undocumented mechanism of genetic deregulation of a Src family member.	('genetic deregulation', 'Var', (74, 94))	('Src', 'Gene', '6714', (100, 103))	('Src', 'Gene', (100, 103))
106493	25204415	We detected fusions of PKN1 in samples of squamous cell carcinoma of the lung and hepatocellular carcinoma (Fig.	('squamous cell carcinoma of the lung and hepatocellular carcinoma', 'Disease', 'MESH:D002294', (42, 106))	('PKN1', 'Gene', '5585', (23, 27))	('fusions', 'Var', (12, 19))	('PKN1', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('detected', 'Reg', (3, 11))
106500	25204415	Overall, 3.0% of tumour samples contained a likely oncogenic, recurrent kinase fusion (2.1% excluding thyroid cancer).	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('thyroid cancer', 'Disease', (102, 116))	('tumour', 'Disease', (17, 23))	('kinase fusion', 'Var', (72, 85))
106501	25204415	The observed striking differences in the frequencies of kinase fusions across solid tumours are consistent with previous data on the relative contributions of diverse types of genetic aberrations to tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Disease', (84, 90))	('solid tumours', 'Disease', 'MESH:D009369', (78, 91))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('solid tumours', 'Disease', (78, 91))	('tumour', 'Disease', (199, 205))	('rat', 'Species', '10116', (188, 191))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('kinase', 'Var', (56, 62))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
106503	25204415	Other tumour types such as melanoma carry predominantly somatic point mutations.	('somatic point mutations', 'Var', (56, 79))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour type', 'Disease', (6, 17))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumour type', 'Disease', 'MESH:D009369', (6, 17))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
106504	25204415	Consistent with these observations, our data suggest that certain cancers are heavily driven by kinase rearrangements.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('driven by', 'Reg', (86, 95))	('cancers', 'Disease', (66, 73))	('kinase rearrangements', 'Var', (96, 117))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
106507	25204415	In stark contrast, clear cell and chromophobe renal cell carcinoma have the lowest frequencies of kinase fusions, none of which were recurrent in our analysis of this data set (Supplementary Fig.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (46, 66))	('clear cell', 'Disease', (19, 29))	('chromophobe renal cell carcinoma', 'Disease', (34, 66))	('kinase', 'Var', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 66))
106509	25204415	Our study also revealed new cancer types harbouring known fusions (for example, BRAF fusion in rectal adenocarcinoma, FGFR3 fusion in prostate adenocarcinoma, RET fusions in colon adenocarcinoma and invasive breast carcinoma, EGFR-SEPT14 in low-grade glioma, and so on).	('fusion', 'Var', (85, 91))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (95, 116))	('RET', 'Gene', '5979', (159, 162))	('SEPT14', 'Gene', '346288', (231, 237))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('colon adenocarcinoma', 'Disease', (174, 194))	('fusion', 'Var', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FGFR3', 'Gene', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('FGFR3', 'Gene', '2261', (118, 123))	('RET', 'Gene', (159, 162))	('prostate adenocarcinoma', 'Disease', (134, 157))	('EGFR', 'Gene', '1956', (226, 230))	('rectal adenocarcinoma', 'Disease', (95, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (199, 224))	('breast carcinoma', 'Phenotype', 'HP:0003002', (208, 224))	('SEPT14', 'Gene', (231, 237))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (174, 194))	('cancer', 'Disease', (28, 34))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('invasive breast carcinoma', 'Disease', (199, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('glioma', 'Disease', (251, 257))	('EGFR', 'Gene', (226, 230))
106514	25204415	For example, we found six cancer types with a single fusion in a gene of the NTRK family, but altogether, we detected a total of 23 NTRK1, NTRK2 and NTRK3 fusions across nine tumour types.	('NTRK2', 'Gene', (139, 144))	('NTRK1', 'Gene', '4914', (132, 137))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('NTRK3', 'Gene', '4916', (149, 154))	('NTRK2', 'Gene', '4915', (139, 144))	('NTRK', 'Gene', (77, 81))	('tumour type', 'Disease', (175, 186))	('NTRK1', 'Gene', (132, 137))	('tumour type', 'Disease', 'MESH:D009369', (175, 186))	('NTRK3', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('fusions', 'Var', (155, 162))
106515	25204415	NTRK fusions therefore represent a low frequency, pan-cancer event that nevertheless may account for a significant fraction of patients who could benefit from a pan-NTRK inhibitor.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('fusions', 'Var', (5, 12))	('cancer', 'Disease', (54, 60))	('patients', 'Species', '9606', (127, 135))	('NTRK', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
106517	25204415	In particular, we found recurrent fusions of MET and PIK3CA that are both bona fide oncogenes commonly activated by gene amplification or point mutations.	('fusions', 'Var', (34, 41))	('PIK3CA', 'Gene', (53, 59))	('MET', 'Gene', (45, 48))	('PIK3CA', 'Gene', '5290', (53, 59))
106518	25204415	In contrast, TBL1XR1-PIK3CA fusions likely drive increased PIK3CA mRNA expression by juxtaposing the promoter region of the partner gene to the 5' end of the intact PIK3CA coding sequence.	('TBL1XR1', 'Gene', '79718', (13, 20))	('PIK3CA', 'Gene', (165, 171))	('increased', 'PosReg', (49, 58))	('PIK3CA', 'Gene', (21, 27))	('TBL1XR1', 'Gene', (13, 20))	('PIK3CA', 'Gene', (59, 65))	('mRNA expression', 'MPA', (66, 81))	('PIK3CA', 'Gene', '5290', (165, 171))	('PIK3CA', 'Gene', '5290', (21, 27))	('fusions', 'Var', (28, 35))	('PIK3CA', 'Gene', '5290', (59, 65))
106520	25204415	We also observed fusions in some Ser/Thr kinases (for example, PRKCA, PKN1), where deletion of their regulatory N-terminal domain putatively leads to constitutive activation by de-repression of the kinase activity.	('Ser/Thr kinases', 'Enzyme', (33, 48))	('PKN1', 'Gene', (70, 74))	('activity', 'MPA', (205, 213))	('PRKCA', 'Gene', '5578', (63, 68))	('PKN1', 'Gene', '5585', (70, 74))	('deletion', 'Var', (83, 91))	('PRKCA', 'Gene', (63, 68))	('de-repression', 'NegReg', (177, 190))	('constitutive activation', 'MPA', (150, 173))
106525	25204415	However, the majority of singleton gene fusions in this set are predicted to be passenger events, occurring as a consequence of chromothripsis or genomic instability.	('chromothripsis', 'Disease', 'MESH:D000072837', (128, 142))	('singleton gene fusions', 'Var', (25, 47))	('chromothripsis', 'Disease', (128, 142))
106527	25204415	Although not the focus of this study, we describe here such an example: a recurrent fusion in two dedifferentiated liposarcoma samples (2/38; 5%) encoding the non-kinase portion of TRIO, which results in upregulation of its fusion partner TERT (Fig.	('TERT', 'Gene', (239, 243))	('liposarcoma', 'Disease', (115, 126))	('TRIO', 'Gene', (181, 185))	('TRIO', 'Gene', '7204', (181, 185))	('liposarcoma', 'Disease', 'MESH:D008080', (115, 126))	('TERT', 'Gene', '7015', (239, 243))	('upregulation', 'PosReg', (204, 216))	('liposarcoma', 'Phenotype', 'HP:0012034', (115, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('fusion', 'Var', (84, 90))
106528	25204415	Telomerase activity is a hallmark of many cancers, and two other genetic mechanisms of TERT reactivation have been described recently; both somatic mutations in the promoter of the TERT gene and DNA copy number gains of TERT were shown to activate its transcription.	('mutations in', 'Var', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('TERT', 'Gene', (181, 185))	('hallmark of many cancers', 'Disease', (25, 49))	('TERT', 'Gene', (220, 224))	('TERT', 'Gene', (87, 91))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (25, 49))	('TERT', 'Gene', '7015', (220, 224))	('TERT', 'Gene', '7015', (181, 185))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('TERT', 'Gene', '7015', (87, 91))	('transcription', 'MPA', (252, 265))	('activate', 'PosReg', (239, 247))
106540	25204415	This step relied on the analysis of a large number of samples to filter out highly recurrent fusions that were detected at improbable frequencies within a cancer type: for instance, fusions detected in >95% of samples, or fusions where both gene partners are themselves involved in >1 fusions in >25% of samples, were flagged as putative false positives.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('fusions', 'Var', (222, 229))	('fusions', 'Var', (182, 189))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
106549	33637673	This led to the hypothesis that aberrant activation of vertebrate MYB could also cause cancer.	('cause', 'Reg', (81, 86))	('cancer', 'Disease', (87, 93))	('vertebrate MYB', 'Protein', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('activation', 'PosReg', (41, 51))	('aberrant', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
106550	33637673	Despite more than three decades have elapsed since the isolation of v-myb, only recently investigators were able to detect MYB genes rearrangements and mutations, smoking gun evidence of the involvement of MYB family members in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mutations', 'Var', (152, 161))	('v-myb', 'Gene', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('human', 'Species', '9606', (228, 233))	('MYB', 'Gene', (123, 126))	('v-myb', 'Gene', '4602', (68, 73))
106574	33637673	Disruption of MYB causes embryonic lethality due to the failure of foetal hepatic haematopoiesis.	('foetal hepatic haematopoiesis', 'Disease', (67, 96))	('MYB', 'Gene', (14, 17))	('foetal hepatic haematopoiesis', 'Disease', 'MESH:D056486', (67, 96))	('embryonic lethality', 'Disease', 'MESH:D020964', (25, 44))	('embryonic lethality', 'Disease', (25, 44))	('Disruption', 'Var', (0, 10))
106579	33637673	Genetic mutations and augmented expression of MYB have been firstly noted in leukaemic cells, and only relatively recently in solid cancers.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('MYB', 'Gene', (46, 49))	('Genetic mutations', 'Var', (0, 17))	('expression', 'MPA', (32, 42))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('augmented', 'PosReg', (22, 31))
106581	33637673	The first recurrent genomic rearrangements of the MYB locus were evidenced in acute T cell leukaemia, in which MYB overexpression is caused by gene duplication or translocation, juxtaposing strong enhancers from other genomic locations.	('acute T cell leukaemia', 'Disease', (78, 100))	('MYB', 'Gene', (111, 114))	('caused by', 'Reg', (133, 142))	('translocation', 'Var', (163, 176))	('acute T cell leukaemia', 'Disease', 'MESH:D054218', (78, 100))	('gene duplication', 'Var', (143, 159))	('overexpression', 'PosReg', (115, 129))
106583	33637673	MYB gene amplification and overexpression have been observed in acute myeloid leukaemia (AML), non-Hodgkin lymphoma, colorectal cancer, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (95, 115))	('AML', 'Disease', (89, 92))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (70, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (64, 87))	('overexpression', 'PosReg', (27, 41))	('MYB', 'Gene', (0, 3))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('amplification', 'Var', (9, 22))	('breast cancer', 'Disease', (140, 153))	('colorectal cancer', 'Disease', (117, 134))	('acute myeloid leukaemia', 'Disease', (64, 87))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (99, 115))	('non-Hodgkin lymphoma', 'Disease', (95, 115))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (95, 115))	('lymphoma', 'Phenotype', 'HP:0002665', (107, 115))
106585	33637673	MYB genomic alterations have been detected in multiple forms of human cancer, suggesting a causative role.	('MYB', 'Gene', (0, 3))	('detected', 'Reg', (34, 42))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('genomic alterations', 'Var', (4, 23))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
106586	33637673	In a cluster of acute lymphoblastic leukaemia (ALL) patients, mutations of the TAL1 enhancer create ex-novo MYB-binding sites.	('acute lymphoblastic leukaemia', 'Disease', (16, 45))	('TAL1', 'Gene', (79, 83))	('MYB-binding', 'Protein', (108, 119))	('acute lymphoblastic leukaemia', 'Disease', 'MESH:D054198', (16, 45))	('TAL1', 'Gene', '6886', (79, 83))	('mutations', 'Var', (62, 71))	('patients', 'Species', '9606', (52, 60))
106589	33637673	Thus, MYB duplications may be leukaemogenic in a subset of T-ALL patients.	('MYB', 'Gene', (6, 9))	('leukaemogenic', 'Disease', (30, 43))	('duplications', 'Var', (10, 22))	('patients', 'Species', '9606', (65, 73))	('T-ALL', 'Disease', (59, 64))
106592	33637673	Mice transgenically expressing the MYB-GATA1 fusion develop myelodysplasia and leukaemia when endogenous, wild-type GATA1 expression is concurrently downregulated.	('myelodysplasia', 'Phenotype', 'HP:0002863', (60, 74))	('myelodysplasia and leukaemia', 'Disease', 'MESH:C565370', (60, 88))	('fusion', 'Var', (45, 51))	('MYB-GATA1', 'Gene', (35, 44))	('downregulated', 'NegReg', (149, 162))	('Mice', 'Species', '10090', (0, 4))	('develop', 'Reg', (52, 59))
106593	33637673	Ducassou and co-workers showed that the fusion promotes not only haematopoietic progenitor cell self-renewal, but also induces a bias toward granulocytic differentiation, consequently to sensitisation towards NGF- and IL-33-induced differentiation.	('fusion', 'Var', (40, 46))	('IL-33', 'Gene', '90865', (218, 223))	('promotes', 'PosReg', (47, 55))	('sensitisation', 'Reg', (187, 200))	('granulocytic differentiation', 'CPA', (141, 169))	('IL-33', 'Gene', (218, 223))
106595	33637673	In vivo experiments using NSG mice led to conclusive evidence that basophilic differentiation is a direct consequence of MYB-GATA1 expression, rather than loss of endogenous GATA1.	('expression', 'Var', (131, 141))	('MYB-GATA1', 'Gene', (121, 130))	('mice', 'Species', '10090', (30, 34))	('basophilic differentiation', 'CPA', (67, 93))
106599	33637673	There are only a few cases reporting fusion of EWSR1 in leukaemia, whereas it is common in soft tissue sarcoma.	('EWSR1', 'Gene', '2130', (47, 52))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (91, 110))	('sarcoma', 'Disease', (103, 110))	('leukaemia', 'Disease', (56, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('EWSR1', 'Gene', (47, 52))	('fusion', 'Var', (37, 43))	('leukaemia', 'Disease', 'MESH:D007938', (56, 65))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
106601	33637673	Therefore, it seems reasonable to speculate that the EWSR1-MYB fusion could lead to dysregulated MYB transcriptional activity.	('MYB', 'Protein', (97, 100))	('EWSR1', 'Gene', (53, 58))	('fusion', 'Var', (63, 69))	('EWSR1', 'Gene', '2130', (53, 58))	('dysregulated', 'MPA', (84, 96))	('lead to', 'Reg', (76, 83))
106605	33637673	AML is a heterogeneous disease, often characterised by the presence of gene fusions or recurrent mutations in a set of driver genes.	('mutations', 'Var', (97, 106))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('gene fusions', 'Var', (71, 83))	('AML', 'Disease', (0, 3))
106625	33637673	NOD-scid mice engrafted with leukaemia cells treated with the peptide showed significant reduction of cancer burden, which was caused by mitochondrial apoptosis.	('leukaemia', 'Disease', 'MESH:D007938', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('reduction of cancer', 'Disease', 'MESH:D007680', (89, 108))	('peptide', 'Var', (62, 69))	('leukaemia', 'Disease', (29, 38))	('reduction of cancer', 'Disease', (89, 108))	('mice', 'Species', '10090', (9, 13))
106626	33637673	Furthermore, ChIP analysis revealed a marked loss of the epigenetic mark H3K27ac on super-enhancers regulated by acetylation driven by p300:CBP, and consequent reduced expression of key MYB-regulated genes such as MYC and BCL2.	('BCL2', 'Gene', (222, 226))	('CBP', 'Gene', '1387', (140, 143))	('expression', 'MPA', (168, 178))	('p300', 'Gene', '2033', (135, 139))	('MYC', 'Gene', '4609', (214, 217))	('acetylation', 'MPA', (113, 124))	('H3K27ac', 'Var', (73, 80))	('reduced', 'NegReg', (160, 167))	('BCL2', 'Gene', '596', (222, 226))	('p300', 'Gene', (135, 139))	('loss', 'NegReg', (45, 49))	('MYC', 'Gene', (214, 217))	('CBP', 'Gene', (140, 143))
106627	33637673	PLGGs typically present gene fusions, especially related to component of the MAPK pathway, such as BRAF.	('gene fusions', 'Var', (24, 36))	('PLGGs', 'Gene', (0, 5))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('MAPK pathway', 'Pathway', (77, 89))
106628	33637673	MYB rearrangements have been recently discovered in the context of whole-genome sequencing (WGS) and/or RNA-sequencing (RNA-seq) of 249 samples of PLGGs, leading to the identification of recurrent MYB-QKI fusions in angiocentric gliomas.	('QKI', 'Gene', '9444', (201, 204))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (216, 236))	('fusions', 'Var', (205, 212))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('angiocentric gliomas', 'Disease', (216, 236))	('gliomas', 'Phenotype', 'HP:0009733', (229, 236))	('QKI', 'Gene', (201, 204))
106632	33637673	Thirdly, hemizygous loss of QKI expression caused by the rearrangement of its locus contributes to oncogenesis since it functions as a tumour-suppressor gene.	('oncogenesis', 'CPA', (99, 110))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('QKI', 'Gene', (28, 31))	('loss', 'NegReg', (20, 24))	('rearrangement', 'Var', (57, 70))	('QKI', 'Gene', '9444', (28, 31))	('tumour', 'Disease', (135, 141))
106637	33637673	MYB overexpression in colon cancer is a consequence of mutations in intron 1 regulatory sequence.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (55, 64))	('MYB', 'Protein', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('overexpression', 'PosReg', (4, 18))	('colon cancer', 'Disease', (22, 34))
106645	33637673	MYB alterations have been also observed in pancreatic cancer, where it has been shown to interact with genes required for proliferation, survival and metastasis.	('MYB', 'Gene', (0, 3))	('alterations', 'Var', (4, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('interact', 'Reg', (89, 97))	('observed', 'Reg', (31, 39))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))
106649	33637673	Gonda and colleagues reported for the first time that inhibition of MYB expression severely impairs the proliferation of ER+, but not ER-, breast cancer cell lines.	('inhibition', 'Var', (54, 64))	('impairs', 'NegReg', (92, 99))	('ER', 'Gene', '2069', (121, 123))	('proliferation', 'CPA', (104, 117))	('ER', 'Gene', '2069', (134, 136))	('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))	('MYB', 'Protein', (68, 71))
106656	33637673	CDK9 inhibitors also impaired cell proliferation and cell cycle progression, inducing arrest at both the G1/S and G2/M phases of the cell cycle.	('CDK9', 'Gene', '1025', (0, 4))	('inducing', 'Reg', (77, 85))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('cell proliferation', 'CPA', (30, 48))	('arrest', 'Disease', (86, 92))	('inhibitors', 'Var', (5, 15))	('cell cycle progression', 'CPA', (53, 75))	('impaired', 'NegReg', (21, 29))	('CDK9', 'Gene', (0, 4))	('G2/M phases of the cell cycle', 'CPA', (114, 143))
106661	33637673	After silencing MYB in an ER+ve breast cancer cell line refractory to tamoxifen therapy, the authors of the study observed that the EMT markers vimentin, ZEB1, and ZEB2 were downregulated, further supporting the hypothesis that MYB is involved in EMT and drug resistance in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('ER', 'Gene', '2069', (26, 28))	('ZEB1', 'Gene', '6935', (154, 158))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('silencing', 'Var', (6, 15))	('breast cancer', 'Disease', (32, 45))	('MYB', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('ZEB2', 'Gene', (164, 168))	('vimentin', 'Gene', '7431', (144, 152))	('tamoxifen', 'Chemical', 'MESH:D013629', (70, 79))	('vimentin', 'Gene', (144, 152))	('downregulated', 'NegReg', (174, 187))	('drug resistance', 'Phenotype', 'HP:0020174', (255, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('ZEB2', 'Gene', '9839', (164, 168))	('ZEB1', 'Gene', (154, 158))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('breast cancer', 'Disease', (274, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
106665	33637673	ACC is characterised by the presence of the MYB-NFIB fusion gene in 30-86% of cases, depending on the study.	('fusion', 'Var', (53, 59))	('NFIB', 'Gene', (48, 52))	('ACC', 'Disease', (0, 3))	('NFIB', 'Gene', '4781', (48, 52))
106667	33637673	Another consequence of the chromosomal translocations detected in ACC and other gland tumours is, in some cases, loss of genetic material.	('genetic material', 'MPA', (121, 137))	('ACC', 'Disease', (66, 69))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('loss', 'NegReg', (113, 117))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('chromosomal translocations', 'Var', (27, 53))
106668	33637673	In this regard, Mitani and colleagues theorised that two genetic events drive ACC pathogenesis: one involves the generation of fusion genes resulting from reciprocal translocation between chromosome 6q and 9p or other partners, and the other event constitutes a loss of genetic material, denoting the presence of one or more tumour suppressor genes.	('fusion genes', 'Var', (127, 139))	('tumour', 'Disease', 'MESH:D009369', (325, 331))	('tumour', 'Disease', (325, 331))	('ACC', 'Disease', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))
106670	33637673	Over half of ACC cases present chromosome 6 deletions, suggesting an important selection for these alterations in the molecular aetiology of these neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (147, 155))	('neoplasms', 'Disease', 'MESH:D009369', (147, 156))	('neoplasms', 'Disease', (147, 156))	('deletions', 'Var', (44, 53))	('ACC', 'Disease', (13, 16))	('neoplasms', 'Phenotype', 'HP:0002664', (147, 156))
106681	33637673	Unsurprisingly, MYB expression was elevated in MYB-NFIB fusion positive ACCs, probably caused by loss of the negative regulatory sequence at the 3' untranslated region of MYB.	('NFIB', 'Gene', '4781', (51, 55))	('loss', 'NegReg', (97, 101))	('negative regulatory sequence', 'MPA', (109, 137))	('expression', 'MPA', (20, 30))	('fusion', 'Var', (56, 62))	('MYB', 'Protein', (16, 19))	('elevated', 'PosReg', (35, 43))	('NFIB', 'Gene', (51, 55))
106683	33637673	Thus, MYB overexpression is a frequent consequence of the MYB-NFIB fusion in glandular tumours, but can also occur via other mechanisms.	('NFIB', 'Gene', (62, 66))	('tumours', 'Disease', (87, 94))	('NFIB', 'Gene', '4781', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('overexpression', 'PosReg', (10, 24))	('MYB', 'MPA', (6, 9))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('fusion', 'Var', (67, 73))
106695	33637673	In an effort to identify new MYB target genes in ACC, our group has generated retroviral vectors expressing wild-type MYB or two MYB-NFIB variants derived from ACC patients.	('patients', 'Species', '9606', (164, 172))	('NFIB', 'Gene', (133, 137))	('variants', 'Var', (138, 146))	('NFIB', 'Gene', '4781', (133, 137))
106707	33637673	MYBL1 rearrangements are a hallmark of low-grade gliomas (LGGs), the commonest paediatric CNS neoplasm, arising in children and adolescents.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('CNS neoplasm', 'Phenotype', 'HP:0100006', (90, 102))	('rearrangements', 'Var', (6, 20))	('children', 'Species', '9606', (115, 123))	('neoplasm', 'Disease', (94, 102))	('MYBL1', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('neoplasm', 'Disease', 'MESH:D009369', (94, 102))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
106708	33637673	These studies have identified activation of the MAPK/ERK pathway caused by the duplication of the tyrosine kinase domain (TKD) of the FGFR1 gene and frequent rearrangements of the MYB family members MYB and MYBL1 in diffuse cerebral LGGs.	('cerebral LGGs', 'Disease', (224, 237))	('MYB', 'Gene', (199, 202))	('MYBL1', 'Gene', (207, 212))	('rearrangements', 'Var', (158, 172))	('FGFR1', 'Gene', (134, 139))	('activation', 'PosReg', (30, 40))	('ERK', 'Gene', '2048', (53, 56))	('cerebral LGGs', 'Disease', 'MESH:D002544', (224, 237))	('FGFR1', 'Gene', '2260', (134, 139))	('ERK', 'Gene', (53, 56))	('diffuse', 'Disease', (216, 223))	('duplication', 'Var', (79, 90))
106709	33637673	8q13.1 gain was observed as a significant recurrent event in diffuse astrocytoma grade IIs.	('astrocytoma', 'Disease', 'MESH:D001254', (69, 80))	('astrocytoma', 'Disease', (69, 80))	('8q13.1', 'Var', (0, 6))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('grade IIs', 'Disease', (81, 90))
106710	33637673	This leads to a duplication of MYBL1 and truncation of its C-terminal NRD, resulting in anchorage-independent growth of NIH-3T3 cells and tumour formation in nude mice.	('duplication', 'Var', (16, 27))	('anchorage-independent growth', 'CPA', (88, 116))	('NIH-3T3', 'CellLine', 'CVCL:0594', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('truncation', 'MPA', (41, 51))	('nude mice', 'Species', '10090', (158, 167))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('leads to', 'Reg', (5, 13))	('MYBL1', 'Gene', (31, 36))	('tumour', 'Disease', (138, 144))
106712	33637673	Although these alterations are rare, sequencing analysis of uncommon low-grade neuro-epithelial tumours revealed that these pathogenic mutations occur at a high frequency (78%) in this cohort.	('neuro-epithelial tumours', 'Disease', (79, 103))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('mutations', 'Var', (135, 144))	('neuro-epithelial tumours', 'Disease', 'MESH:D002277', (79, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))
106713	33637673	Patients with isomorphic diffuse glioma or astrocytoma can harbour copy number alterations of MYBL1 or MYB (13 out of 25 samples, 52%), as assessed with RNA sequencing.	('MYBL1', 'Gene', (94, 99))	('astrocytoma', 'Disease', (43, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('MYB', 'Gene', (103, 106))	('glioma', 'Disease', (33, 39))	('Patients', 'Species', '9606', (0, 8))	('astrocytoma', 'Disease', 'MESH:D001254', (43, 54))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('copy number alterations', 'Var', (67, 90))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
106717	33637673	Indeed, tumours with MYB and MYBL1 translocations display overlapping gene expression profiles and clinical outcome, suggesting that the related MYB proteins are interchangeable oncogenic drivers in ACC.	('translocations', 'Var', (35, 49))	('MYBL1', 'Gene', (29, 34))	('tumours', 'Disease', (8, 15))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('MYB', 'Gene', (21, 24))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
106720	33637673	RNA and WGS unveiled that these cancers could harbour MYBL1 rearrangements, including those between MYBL1-ACTN1 and MYBL1-NFIB.	('rearrangements', 'Var', (60, 74))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('ACTN1', 'Gene', '87', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('harbour', 'Reg', (46, 53))	('MYBL1', 'Gene', (54, 59))	('ACTN1', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('NFIB', 'Gene', '4781', (122, 126))	('NFIB', 'Gene', (122, 126))
106752	33637673	20q13 amplification or copy gains are common in breast cancer and are usually associated with poor prognosis.	('copy gains', 'Var', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('20q13 amplification', 'Var', (0, 19))
106753	33637673	Notably, a MYBL2 germline polymorphism causing the Serine-to-Glycine amino acid change S427G is correlated to a high risk of basal-like breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('S427G', 'Var', (87, 92))	('MYBL2', 'Gene', (11, 16))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('S427G', 'Mutation', 'rs2070235', (87, 92))	('breast cancer', 'Disease', (136, 149))	('correlated to', 'Reg', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('Glycine amino acid', 'Chemical', 'MESH:D005998', (61, 79))	('Serine-to-Glycine amino acid', 'MPA', (51, 79))	('Serine', 'Chemical', 'MESH:D012694', (51, 57))
106760	33637673	Another neoplasia characterised by deregulation of MYBL2 is non-small-cell lung cancer (NSCLC).	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (60, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('neoplasia', 'Disease', (8, 17))	('deregulation', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('MYBL2', 'Gene', (51, 56))	('neoplasia', 'Phenotype', 'HP:0002664', (8, 17))	('NSCLC', 'Disease', (88, 93))	('neoplasia', 'Disease', 'MESH:D009369', (8, 17))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('non-small-cell lung cancer', 'Disease', (60, 86))
106764	33637673	A significant correlation between high NCAPH expression and poor prognosis was confirmed, suggesting that targeting the MYBL2-regulated gene could be of potential therapeutic value in this setting.	('high', 'Var', (34, 38))	('MYBL2-regulated gene', 'Gene', (120, 140))	('NCAPH', 'Gene', (39, 44))	('NCAPH', 'Gene', '23397', (39, 44))
106767	33637673	The strong correlation between overexpression of MYBL2 and downregulation of the miR-30 cluster suggests that the micro-RNAs antagonise the expression of MYBL2, or that the latter suppresses miRNAs expression in AML.	('miRNAs expression', 'MPA', (191, 208))	('MYBL2', 'Gene', (154, 159))	('expression', 'MPA', (140, 150))	('suppresses', 'NegReg', (180, 190))	('miR-30 cluster', 'Gene', (81, 95))	('AML', 'Disease', 'MESH:D015470', (212, 215))	('downregulation', 'NegReg', (59, 73))	('antagonise', 'NegReg', (125, 135))	('micro-RNAs', 'Var', (114, 124))	('AML', 'Disease', (212, 215))
106775	33637673	The ever-expanding number of studies reporting deregulation of MYB family members in the pathogenesis of human cancers is instigating researchers to find new and more efficient methods to target these transcription factors.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('MYB', 'Gene', (63, 66))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('human', 'Species', '9606', (105, 110))	('deregulation', 'Var', (47, 59))
106794	33478100	Recent efforts to understand the genetics of GBM have improved our knowledge of the molecular events leading to gliomagenesis and mutations; amplifications or deletions of genes such as IDH1, NF1, PTEN, P53, RB1, PDGFRA or EGFR have been identified.	('PDGFRA', 'Gene', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('IDH1', 'Gene', (186, 190))	('gliomagenesis', 'Disease', (112, 125))	('IDH1', 'Gene', '3417', (186, 190))	('EGFR', 'Gene', (223, 227))	('NF1', 'Gene', (192, 195))	('P53', 'Gene', (203, 206))	('RB1', 'Gene', (208, 211))	('PTEN', 'Gene', (197, 201))	('PTEN', 'Gene', '5728', (197, 201))	('P53', 'Gene', '7157', (203, 206))	('RB1', 'Gene', '5925', (208, 211))	('deletions', 'Var', (159, 168))	('gliomagenesis', 'Disease', 'None', (112, 125))
106832	33478100	Under controlled conditions such mitotic errors will activate the spindle assembly checkpoint (SAC) resulting in an extended mitotic arrest, and if the error cannot be resolved, the default response is death in mitosis.	('spindle', 'CPA', (66, 73))	('errors', 'Var', (41, 47))	('mitotic arrest', 'Disease', (125, 139))	('death', 'Disease', 'MESH:D003643', (202, 207))	('death', 'Disease', (202, 207))	('mitotic arrest', 'Disease', 'MESH:D006323', (125, 139))	('activate', 'PosReg', (53, 61))
106850	33478100	Phosphorylation of Y572 in PDGFRA and/or Y579 in PDGFRB creates binding sites for SRC family kinases (SFKs) including SRC, FYN and YES as well as STAT5 and we found phosphorylation (i.e.	('binding', 'Interaction', (64, 71))	('SRC', 'Gene', '6714', (118, 121))	('Y579', 'Var', (41, 45))	('SRC', 'Gene', (118, 121))	('PDGFRB', 'Gene', '5159', (49, 55))	('STAT5', 'Gene', (146, 151))	('PDGFRA', 'Gene', (27, 33))	('FYN', 'Gene', (123, 126))	('PDGFRB', 'Gene', (49, 55))	('Y572', 'Var', (19, 23))	('SRC', 'Gene', '6714', (82, 85))	('SRC', 'Gene', (82, 85))	('FYN', 'Gene', '2534', (123, 126))	('STAT5', 'Gene', '6776', (146, 151))
106854	33478100	Moreover, STAT5B can drive tumour progression in a PDGFB-driven glioma model and this involves increased BCL2L1 expression.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('PDGFB-driven', 'Gene', (51, 63))	('STAT5B', 'Var', (10, 16))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('glioma', 'Disease', (64, 70))	('BCL2L1 expression', 'MPA', (105, 122))	('tumour', 'Disease', (27, 33))	('increased', 'PosReg', (95, 104))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
106860	33478100	Inactivation of BCL2L1 and MCL1 during prolonged mitosis has been considered the priming event in mitotic death signalling.	('BCL2L1', 'Gene', (16, 22))	('death', 'Disease', 'MESH:D003643', (106, 111))	('death', 'Disease', (106, 111))	('MCL1', 'Gene', (27, 31))	('Inactivation', 'Var', (0, 12))
106865	33478100	Moreover, the DEXA-induced growth effect was also abolished by the MCL1 inhibitor S63845 and the pan BCL2 family inhibitor navitoclax, which also inhibits BCL2L1 (Figure 3K).	('S63845', 'Var', (82, 88))	('DEXA', 'Chemical', 'MESH:D003907', (14, 18))	('BCL2', 'Gene', '596', (101, 105))	('BCL2', 'Gene', '596', (155, 159))	('inhibits', 'NegReg', (146, 154))	('abolished', 'NegReg', (50, 59))	('BCL2', 'Gene', (101, 105))	('BCL2', 'Gene', (155, 159))	('S63845', 'Chemical', 'MESH:C000614727', (82, 88))	('navitoclax', 'Chemical', 'MESH:C528561', (123, 133))
106872	33478100	In these "phospho-SFK high" tumours 66% also expressed high PDGFRA or PDGFRB or both (Figure 4F), supporting a scenario in which PDGFR signalling contributes to SRC/SFK activation in high-grade gliomas.	('PDGFRB', 'Gene', '5159', (70, 76))	('activation', 'PosReg', (169, 179))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('PDGFRB', 'Gene', (70, 76))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('gliomas', 'Disease', (194, 201))	('SRC', 'Gene', '6714', (161, 164))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('SRC', 'Gene', (161, 164))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('high', 'Var', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('PDGFRA', 'Gene', (60, 66))	('tumours', 'Disease', (28, 35))
106876	33478100	Accordingly, the radioprotection capacity of DEXA varied with radio-protective effects seen in T98G, SF188 and LN229 cells but an inhibitory effect in A172 cells, in which DEXA strongly down-regulated mitosis and cell division related genes (Figure 5A,B).	('DEXA', 'Chemical', 'MESH:D003907', (172, 176))	('mitosis', 'CPA', (201, 208))	('T98G', 'CellLine', 'CVCL:0556', (95, 99))	('cell', 'Gene', (213, 217))	('SF188', 'CellLine', 'CVCL:6948', (101, 106))	('LN229', 'CellLine', 'CVCL:0393', (111, 116))	('down-regulated', 'NegReg', (186, 200))	('T98G', 'Var', (95, 99))	('DEXA', 'Chemical', 'MESH:D003907', (45, 49))
106913	33478100	In summary, we identified a mechanism in which DEXA compromises the SAC by reducing the amount of relevant players such as PLK1, MPS1, BUB1 and CENPF, and concomitantly promotes PDGFR signalling, which contributes to survival (see Figure 7I).	('reducing', 'NegReg', (75, 83))	('promotes', 'PosReg', (169, 177))	('MPS1', 'Gene', '7272', (129, 133))	('MPS1', 'Gene', (129, 133))	('DEXA', 'Var', (47, 51))	('CENPF', 'Gene', (144, 149))	('PDGFR signalling', 'MPA', (178, 194))	('amount of relevant players', 'MPA', (88, 114))	('BUB1', 'Gene', '699', (135, 139))	('BUB1', 'Gene', (135, 139))	('PLK1', 'Gene', (123, 127))	('CENPF', 'Gene', '1063', (144, 149))	('DEXA', 'Chemical', 'MESH:D003907', (47, 51))	('PLK1', 'Gene', '5347', (123, 127))
106931	33478100	PDGFR inhibition in GBM cell lines universally triggers a G2/M arrest and in a PDGFRA/PDGFA driven glioblastoma mouse model chronic activation of PDGFRA facilitates microtubule dynamics during mitosis, suggesting a role for PDGFR in driving GBM cells towards mitosis.	('glioblastoma', 'Disease', (99, 111))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('activation', 'PosReg', (132, 142))	('microtubule dynamics', 'MPA', (165, 185))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('PDGFA', 'Gene', '18590', (86, 91))	('mouse', 'Species', '10090', (112, 117))	('triggers', 'Reg', (47, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('facilitates', 'PosReg', (153, 164))	('arrest', 'Disease', (63, 69))	('PDGFR', 'Gene', (0, 5))	('PDGFRA', 'Gene', (146, 152))	('inhibition', 'Var', (6, 16))	('PDGFA', 'Gene', (86, 91))
106941	33478100	Nevertheless, our data imply that in GBM the presence of DEXA impacts on the efficacy of sunitinib, and this factor, which was not considered in previous trials, might have added an unpredicted variability to respective study outcomes.	('efficacy', 'MPA', (77, 85))	('impacts', 'Reg', (62, 69))	('DEXA', 'Chemical', 'MESH:D003907', (57, 61))	('presence', 'Var', (45, 53))	('sunitinib', 'Chemical', 'MESH:D000077210', (89, 98))
106947	33478100	GBM cell lines were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (cat#11995065, Gibco), HMC3 cells in DMEM/F12 (cat#10565018, Gibco), and MCF-10A cells in mammary epithelial cell basal medium (MEBM) (cat#CC-3151, Lonza).	('cat#11995065', 'Var', (75, 87))	('DMEM', 'Chemical', '-', (111, 115))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (32, 66))	('HMC3', 'CellLine', 'CVCL:0003', (97, 101))	('DMEM', 'Chemical', '-', (68, 72))	('cat#10565018', 'Var', (121, 133))	('MCF-10A', 'CellLine', 'CVCL:0598', (147, 154))
106951	33478100	Dexamethasone (cat#D4920), temozolomide (cat#T2577), human PDGF-BB (cat#P3201) and LPS (cat# L5293) were from Sigma/Merck (Madrid, Spain).	('cat#D4920', 'Var', (15, 24))	('PDGF-BB', 'Gene', (59, 66))	('temozolomide', 'Chemical', 'MESH:D000077204', (27, 39))	('cat# L5293', 'Var', (88, 98))	('L5293', 'CellLine', 'CVCL:0462', (93, 98))	('human', 'Species', '9606', (53, 58))	('Dexamethasone', 'Chemical', 'MESH:D003907', (0, 13))	('cat#P3201', 'Var', (68, 77))	('cat#T2577', 'Var', (41, 50))
106952	33478100	IFNgamma (cat#300-02) was from Peprotech (London, UK) and reversine (cat#ab120921) from abcam (Cambridge, UK).	('reversine', 'Chemical', 'MESH:C484369', (58, 67))	('cat#ab120921', 'Var', (69, 81))	('IFNgamma', 'Gene', (0, 8))	('IFNgamma', 'Gene', '3458', (0, 8))
106953	33478100	FDA approved drug library (cat# L1300), Ponatinib (cat#S1490), Sunitinib (cat#S7781), Dasatinib (cat# S1021), Venetoclax/ABT-199 (cat# S8048), S63845 (cat# S8383), Vincristine (cat#S1241) and Taxol (cat#S1150) were from Selleckchem (Newmarket, UK).	('S63845', 'Chemical', 'MESH:C000614727', (143, 149))	('cat# S1021', 'Var', (97, 107))	('Dasatinib', 'Chemical', 'MESH:D000069439', (86, 95))	('ABT', 'Chemical', 'MESH:C002502', (121, 124))	('Ponatinib', 'Chemical', 'MESH:C545373', (40, 49))	('Taxol', 'Chemical', 'MESH:D017239', (192, 197))	('cat#S1490', 'Var', (51, 60))	('cat# S8048', 'Var', (130, 140))	('Vincristine', 'Chemical', 'MESH:D014750', (164, 175))	('Sunitinib', 'Chemical', 'MESH:D000077210', (63, 72))	('cat#S1241', 'Var', (177, 186))	('cat#S7781', 'Var', (74, 83))	('Venetoclax', 'Chemical', 'MESH:C579720', (110, 120))	('S63845 (cat# S8383', 'Var', (143, 161))	('cat#S1150', 'Var', (199, 208))
106973	33478100	Primary antibodies were for: phospho-SRC (Tyr419) (#44-660G, Invitrogen, 1:500), PDGFR-alpha (Rb-9027, ThermoFisher, 1:200), and PDGFR-beta (#DPABH-01589; Creative Diagnostics, 1:500).	('PDGFR-beta', 'Gene', '5156', (129, 139))	('PDGFR-beta', 'Gene', (129, 139))	('SRC', 'Gene', '6714', (37, 40))	('PDGFR-alpha', 'Gene', (81, 92))	('SRC', 'Gene', (37, 40))	('Tyr419', 'Chemical', '-', (42, 48))	('#44-660G', 'Var', (51, 59))	('PDGFR-alpha', 'Gene', '5156', (81, 92))
106974	33478100	Primary antibodies were: PDGFRalpha (cat# 3174S), PDGFRbeta (cat# 3169S), p-PDGFRalpha (Y849)/beta(Y857) (cat# 3170T), p-PDGFbeta (Y740) (cat# 3168), p-SRC (Y416) (cat# 2101) and p-STAT5 (cat# 4322T) from Cell Signaling; p-PDGFRalpha (Tyr572)/PDGFRbeta (Tyr579) (cat# bs-5554R) from Bioss Inc and beta-Actin (cat# A5441) from Sigma.	('STAT5', 'Gene', (181, 186))	('cat# bs-5554R', 'Var', (263, 276))	('SRC', 'Gene', '6714', (152, 155))	('PDGFRbeta', 'Gene', '5159', (50, 59))	('SRC', 'Gene', (152, 155))	('PDGFRbeta', 'Gene', '5159', (243, 252))	('PDGFRalpha', 'Gene', (25, 35))	('PDGFRalpha', 'Gene', (223, 233))	('PDGFRalpha', 'Gene', '5156', (76, 86))	('PDGFRbeta', 'Gene', (50, 59))	('PDGFRalpha', 'Gene', (76, 86))	('PDGFRbeta', 'Gene', (243, 252))	('STAT5', 'Gene', '6776', (181, 186))	('PDGFbeta', 'Gene', '5154', (121, 129))	('cat#', 'Var', (188, 192))	('PDGFbeta', 'Gene', (121, 129))	('PDGFRalpha', 'Gene', '5156', (25, 35))	('PDGFRalpha', 'Gene', '5156', (223, 233))
106996	32006950	Other problems that affect the interpretation and accuracy of DTI include false continuities, crossing fibers, fiber truncation, and edema "noise."	('edema', 'Disease', 'MESH:D004487', (133, 138))	('edema', 'Phenotype', 'HP:0000969', (133, 138))	('false continuities', 'Var', (74, 92))	('edema', 'Disease', (133, 138))	('crossing fibers', 'CPA', (94, 109))
107004	32006950	Damage to it is associated with deficits in object recognition, including prosopagnosia.	('deficits', 'Disease', (32, 40))	('deficits', 'Disease', 'MESH:D009461', (32, 40))	('Damage', 'Var', (0, 6))	('object recognition', 'CPA', (44, 62))	('prosopagnosia', 'Disease', (74, 87))	('prosopagnosia', 'Phenotype', 'HP:0010528', (74, 87))
107016	32006950	found strong concordance such that DTI reduced the number of stimulations needed to safely confirm a tract, thereby decreasing patient fatigue and the likelihood of disruptive seizures.	('seizure', 'Phenotype', 'HP:0001250', (176, 183))	('DTI', 'Var', (35, 38))	('patient', 'Species', '9606', (127, 134))	('fatigue', 'Disease', 'MESH:D005221', (135, 142))	('disruptive seizures', 'Disease', (165, 184))	('decreasing', 'NegReg', (116, 126))	('disruptive seizures', 'Disease', 'MESH:D012640', (165, 184))	('fatigue', 'Disease', (135, 142))	('reduced', 'NegReg', (39, 46))	('fatigue', 'Phenotype', 'HP:0012378', (135, 142))	('seizures', 'Phenotype', 'HP:0001250', (176, 184))
107020	32006950	An early randomized controlled trial of the use of tractography for glioma showed clear benefits in increasing overall survival, extent of resection, and 6-month Karnofsky Performance Scale (KPS) scores in the DTI-aided high-grade glioma (HGG) group.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('overall survival', 'CPA', (111, 127))	('benefits', 'PosReg', (88, 96))	('DTI-aided', 'Var', (210, 219))	('glioma', 'Disease', (231, 237))	('increasing', 'PosReg', (100, 110))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (231, 237))
107022	32006950	Overall rates of gross-total resection (GTR) in the DTI group (118 cases, 72% GTR) were significantly higher than in the control group that underwent standard neuronavigation (120 cases, 51.7% GTR, p = 0.002).	('GTR', 'Chemical', '-', (193, 196))	('DTI', 'Var', (52, 55))	('higher', 'PosReg', (102, 108))	('gross-total resection', 'CPA', (17, 38))	('GTR', 'Chemical', '-', (40, 43))	('GTR', 'Chemical', '-', (78, 81))
107066	28693197	Recent developments in predictive biomarkers of pediatric glioma The presence of certain cancer-related genetic and epigenetic alterations in the tumor affects patient response to specific cancer therapies.	('affects', 'Reg', (152, 159))	('presence', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('patient', 'Species', '9606', (160, 167))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('epigenetic alterations', 'Var', (116, 138))	('tumor', 'Disease', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('genetic', 'Var', (104, 111))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('glioma', 'Disease', (58, 64))	('response', 'MPA', (168, 176))	('cancer', 'Disease', (189, 195))
107072	28693197	In addition to heritable risk variants, other factors with a proposed link to gliomas include, for example, ionizing radiation associated with increased risk and allergic conditions associated with reduced risk of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('allergic conditions', 'Disease', 'MESH:D004342', (162, 181))	('allergic conditions', 'Disease', (162, 181))	('ionizing radiation', 'Var', (108, 126))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('gliomas', 'Disease', (214, 221))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('reduced', 'NegReg', (198, 205))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))
107082	28693197	Certain molecular alterations are frequently seen in specific glioma subtypes and grades, and thus, they may further aid in the classification of tumors.	('seen', 'Reg', (45, 49))	('alterations', 'Var', (18, 29))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('aid', 'Reg', (117, 120))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('glioma subtypes', 'Disease', 'MESH:D005910', (62, 77))	('tumors', 'Disease', (146, 152))	('glioma subtypes', 'Disease', (62, 77))
107083	28693197	Example of these alterations include codeletion of 1p/19q in oligodendroglial tumors, IDH1 mutation in diffuse grade II-III gliomas and secondary glioblastomas, and loss of heterozygosity (LOH) of chromosome 10q, EGFR amplification, TP53 mutations, p16INK4a (CDKN2A) deletions, and PTEN mutations in glioblastomas.	('mutation', 'Var', (91, 99))	('deletions', 'Var', (267, 276))	('CDKN2A', 'Gene', '1029', (259, 265))	('mutations', 'Var', (287, 296))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (146, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (300, 312))	('EGFR', 'Gene', '1956', (213, 217))	('PTEN', 'Gene', (282, 286))	('glioblastomas', 'Disease', (300, 313))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (238, 247))	('amplification', 'Var', (218, 231))	('loss of heterozygosity', 'Var', (165, 187))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioblastomas', 'Disease', 'MESH:D005909', (300, 313))	('II-III gliomas', 'Disease', 'MESH:D005910', (117, 131))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('IDH1', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (282, 286))	('oligodendroglial tumors', 'Disease', (61, 84))	('p16INK4a', 'Gene', (249, 257))	('glioblastomas', 'Disease', (146, 159))	('TP53', 'Gene', (233, 237))	('CDKN2A', 'Gene', (259, 265))	('glioblastomas', 'Disease', 'MESH:D005909', (146, 159))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (61, 84))	('EGFR', 'Gene', (213, 217))	('IDH1', 'Gene', '3417', (86, 90))	('II-III gliomas', 'Disease', (117, 131))	('p16INK4a', 'Gene', '1029', (249, 257))	('glioblastomas', 'Phenotype', 'HP:0012174', (300, 313))	('TP53', 'Gene', '7157', (233, 237))
107084	28693197	In addition to contributing to the pathogenesis of gliomas, many of these molecular alterations have prognostic significance for prediction of the outcome of patients.	('gliomas', 'Disease', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('alterations', 'Var', (84, 95))	('contributing', 'Reg', (15, 27))	('patients', 'Species', '9606', (158, 166))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
107085	28693197	For example, codeletion of 1p/19q and IDH1 mutations have been associated with favorable prognosis, whereas LOH 10q and PTEN mutations have been linked to poor prognosis.	('IDH1', 'Gene', '3417', (38, 42))	('mutations', 'Var', (43, 52))	('PTEN', 'Gene', (120, 124))	('IDH1', 'Gene', (38, 42))	('PTEN', 'Gene', '5728', (120, 124))	('codeletion', 'Var', (13, 23))
107092	28693197	In patients diagnosed with anaplastic oligodendroglial tumors, the codeletion of 1p/19q has been associated with better survival when the patients are treated with radiotherapy and combination chemotherapy of alkylating agents procarbazine and lomustine (CCNU) together with microtubule inhibitor vincristine (PCV) compared with radiotherapy alone.	('patients', 'Species', '9606', (138, 146))	('better', 'PosReg', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lomustine', 'Chemical', 'MESH:D008130', (244, 253))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (3, 11))	('codeletion', 'Var', (67, 77))	('anaplastic oligodendroglial tumors', 'Disease', (27, 61))	('procarbazine', 'Chemical', 'MESH:D011344', (227, 239))	('1p/19q', 'Var', (81, 87))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (27, 61))	('CCNU', 'Chemical', 'MESH:D008130', (255, 259))	('vincristine', 'Chemical', 'MESH:D014750', (297, 308))
107093	28693197	The predictive significance of codeleted 1p/19q has also been indicated in low-grade gliomas, which show a good response to temozolomide chemotherapy.	('gliomas', 'Disease', (85, 92))	('temozolomide', 'Chemical', 'MESH:D000077204', (124, 136))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('codeleted 1p/19q', 'Var', (31, 47))
107095	28693197	Hypermethylation of the promoter region of the MGMT gene located at 10q26 leads to reduced MGMT expression and DNA repair activity, affecting the sensitivity of MGMT-methylated gliomas to alkylating agents.	('DNA repair activity', 'MPA', (111, 130))	('reduced', 'NegReg', (83, 90))	('gliomas', 'Disease', (177, 184))	('Hypermethylation', 'Var', (0, 16))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('sensitivity', 'MPA', (146, 157))	('MGMT', 'Gene', (47, 51))	('MGMT', 'Gene', '4255', (47, 51))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', (161, 165))	('affecting', 'Reg', (132, 141))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('MGMT', 'Gene', '4255', (91, 95))	('MGMT', 'Gene', '4255', (161, 165))
107096	28693197	MGMT hypermethylation has been associated with improved survival in glioblastomas treated with combined temozolomide and radiotherapy compared with radiotherapy alone.	('improved', 'PosReg', (47, 55))	('MGMT', 'Gene', (0, 4))	('survival', 'MPA', (56, 64))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('temozolomide', 'Chemical', 'MESH:D000077204', (104, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (68, 81))	('hypermethylation', 'Var', (5, 21))	('glioblastomas', 'Disease', (68, 81))	('MGMT', 'Gene', '4255', (0, 4))
107101	28693197	These studies suggested that MGMT hypermethylation predicts a favorable response to temozolomide treatment in elderly glioblastoma patients, whereas unmethylated MGMT seemed to predict lack of survival benefit from alkylating agent chemotherapy.	('patients', 'Species', '9606', (131, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('hypermethylation', 'Var', (34, 50))	('MGMT', 'Gene', '4255', (162, 166))	('MGMT', 'Gene', (162, 166))	('response to temozolomide treatment', 'MPA', (72, 106))	('MGMT', 'Gene', '4255', (29, 33))	('MGMT', 'Gene', (29, 33))	('glioblastoma', 'Disease', (118, 130))	('temozolomide', 'Chemical', 'MESH:D000077204', (84, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))
107104	28693197	Resistance to temozolomide often emerges also in patients with hypermethylated MGMT promoter and a good primary response to temozolomide.	('Resistance', 'MPA', (0, 10))	('MGMT', 'Gene', (79, 83))	('temozolomide', 'Chemical', 'MESH:D000077204', (14, 26))	('temozolomide', 'Chemical', 'MESH:D000077204', (124, 136))	('patients', 'Species', '9606', (49, 57))	('emerges', 'Reg', (33, 40))	('hypermethylated', 'Var', (63, 78))	('MGMT', 'Gene', '4255', (79, 83))
107105	28693197	Although the underlying mechanism for this resistance is not yet established, increased MGMT activity and DNA mismatch repair deficiency have been suggested.	('deficiency', 'Var', (126, 136))	('DNA mismatch repair', 'Gene', (106, 125))	('MGMT', 'Gene', (88, 92))	('increased', 'PosReg', (78, 87))	('MGMT', 'Gene', '4255', (88, 92))
107106	28693197	Hypermethylation of the MGMT promoter has been reported to occur in approximately 50% of astrocytomas (including glioblastomas) and in approximately 70% of oligodendroglial tumors.	('MGMT', 'Gene', '4255', (24, 28))	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('occur', 'Reg', (59, 64))	('glioblastomas', 'Phenotype', 'HP:0012174', (113, 126))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (156, 179))	('astrocytomas', 'Disease', 'MESH:D001254', (89, 101))	('oligodendroglial tumors', 'Disease', (156, 179))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('Hypermethylation', 'Var', (0, 16))	('glioblastomas', 'Disease', 'MESH:D005909', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('astrocytomas', 'Disease', (89, 101))	('glioblastomas', 'Disease', (113, 126))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('MGMT', 'Gene', (24, 28))
107107	28693197	Studies in recent past have shown the value of MGMT hypermethylation in the prediction of favorable prognosis in various glioma subtypes.	('hypermethylation', 'Var', (52, 68))	('glioma subtypes', 'Disease', (121, 136))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma subtypes', 'Disease', 'MESH:D005910', (121, 136))	('MGMT', 'Gene', (47, 51))	('MGMT', 'Gene', '4255', (47, 51))
107108	28693197	The MGMT methylation status has also been suggested to be useful in distinguishing pseudoprogression from real progression of cancer, as MGMT hypermethylation is significantly associated with pseudoprogression.	('MGMT', 'Gene', '4255', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hypermethylation', 'Var', (142, 158))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('pseudoprogression', 'Disease', (192, 209))	('MGMT', 'Gene', (4, 8))	('MGMT', 'Gene', (137, 141))	('associated with', 'Reg', (176, 191))	('MGMT', 'Gene', '4255', (137, 141))	('pseudoprogression', 'Disease', (83, 100))
107109	28693197	Moreover, the presence of MGMT hypermethylation is significantly associated with IDH1 mutation and 1p/19q codeletion.	('IDH1', 'Gene', '3417', (81, 85))	('associated', 'Reg', (65, 75))	('1p/19q codeletion', 'Disease', (99, 116))	('IDH1', 'Gene', (81, 85))	('MGMT', 'Gene', (26, 30))	('mutation', 'Var', (86, 94))	('MGMT', 'Gene', '4255', (26, 30))
107110	28693197	Interestingly, a recent report showed that the assessment of both MGMT methylation and IDH1 mutation status in glioblastoma patients provides a better prediction of survival than either status alone.	('MGMT', 'Gene', (66, 70))	('mutation', 'Var', (92, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('IDH1', 'Gene', '3417', (87, 91))	('MGMT', 'Gene', '4255', (66, 70))	('IDH1', 'Gene', (87, 91))	('survival', 'MPA', (165, 173))	('glioblastoma', 'Disease', (111, 123))	('patients', 'Species', '9606', (124, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))
107111	28693197	The longest survival was observed in patients carrying MGMT methylation and IDH1 mutation, whereas patients with unmethylated MGMT and unmutated IDH1 had the shortest survival.	('IDH1', 'Gene', (76, 80))	('MGMT', 'Gene', '4255', (55, 59))	('MGMT', 'Gene', (55, 59))	('IDH1', 'Gene', (145, 149))	('patients', 'Species', '9606', (37, 45))	('mutation', 'Var', (81, 89))	('IDH1', 'Gene', '3417', (145, 149))	('IDH1', 'Gene', '3417', (76, 80))	('patients', 'Species', '9606', (99, 107))	('MGMT', 'Gene', (126, 130))	('MGMT', 'Gene', '4255', (126, 130))
107112	28693197	Furthermore, IDH1 mutation status is suggested to affect how MGMT-methylated high-grade gliomas benefit from alkylating agent chemotherapy, since MGMT hypermethylation is associated with a better survival in IDH1-negative but not IDH1-positive patients treated with chemotherapy.	('MGMT', 'Gene', '4255', (146, 150))	('IDH1', 'Gene', (208, 212))	('MGMT', 'Gene', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('gliomas', 'Disease', (88, 95))	('better', 'PosReg', (189, 195))	('IDH1', 'Gene', (13, 17))	('IDH1', 'Gene', '3417', (208, 212))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('IDH1', 'Gene', (230, 234))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (244, 252))	('IDH1', 'Gene', '3417', (13, 17))	('MGMT', 'Gene', (61, 65))	('MGMT', 'Gene', '4255', (61, 65))	('IDH1', 'Gene', '3417', (230, 234))
107113	28693197	IDH1 mutations.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (0, 4))
107115	28693197	IDH1 mutations are early alterations in gliomagenesis, suggested to occur before TP53 mutations and codeletion of 1p/19q.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('IDH1', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (0, 4))
107116	28693197	The mutations in IDH1 are detected in 64-100% of diffuse grade II-III gliomas, and secondary glioblastomas, but only in 5-7% of primary glioblastomas.	('glioblastomas', 'Disease', (93, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('II-III gliomas', 'Disease', 'MESH:D005910', (63, 77))	('glioblastomas', 'Phenotype', 'HP:0012174', (136, 149))	('glioblastomas', 'Disease', 'MESH:D005909', (93, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (136, 149))	('glioblastomas', 'Phenotype', 'HP:0012174', (93, 106))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1', 'Gene', (17, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('II-III gliomas', 'Disease', (63, 77))	('glioblastomas', 'Disease', (136, 149))	('mutations', 'Var', (4, 13))	('IDH1', 'Gene', '3417', (17, 21))	('detected', 'Reg', (26, 34))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
107117	28693197	The majority of mutations in IDH1 affect the arginine amino acid at codon 132, which is substituted with histidine (R132H) in the most common type of mutations.	('IDH1', 'Gene', (29, 33))	('histidine', 'Chemical', 'MESH:D006639', (105, 114))	('mutations', 'Var', (16, 25))	('IDH1', 'Gene', '3417', (29, 33))	('R132H', 'Chemical', '-', (116, 121))	('arginine amino acid', 'MPA', (45, 64))	('arginine amino acid', 'Chemical', '-', (45, 64))	('affect', 'Reg', (34, 40))
107118	28693197	Mutations in IDH2 gene (at 15q26.1) encoding the mitochondrial isocitrate dehydrogenase 2 (NADP+) enzyme are also observed in gliomas, but at a lower frequency (approximately 3%).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('IDH2', 'Gene', (13, 17))	('isocitrate', 'Chemical', 'MESH:C034219', (63, 73))	('Mutations', 'Var', (0, 9))	('IDH2', 'Gene', '3418', (13, 17))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('observed', 'Reg', (114, 122))
107119	28693197	IDH1 and 2 enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate, but when mutated, they begin to produce the oncometabolite 2-hydroxyglutarate, the accumulation of which is suggested to eventually lead to cancer-promoting alterations such as genome-wide histone and DNA methylation changes.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('mutated', 'Var', (90, 97))	('cancer', 'Disease', (221, 227))	('IDH1 and 2', 'Gene', '3417;3418', (0, 10))	('changes', 'Reg', (298, 305))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (60, 79))	('lead to', 'Reg', (213, 220))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('histone', 'MPA', (270, 277))	('isocitrate', 'Chemical', 'MESH:C034219', (46, 56))	('DNA methylation', 'MPA', (282, 297))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (140, 158))
107120	28693197	The predictive value of IDH1/2 mutations remains to be clarified; some studies have reported no impact of IDH1 mutations on response to temozolomide in low-grade astrocytomas or PCV chemotherapy in anaplastic oligodendrogliomas, whereas others have shown an improved response to temozolomide chemotherapy in IDH-mutant low-grade gliomas and secondary glioblastomas or a benefit from PCV chemotherapy in anaplastic oligodendroglial tumors.	('temozolomide', 'Chemical', 'MESH:D000077204', (279, 291))	('gliomas', 'Disease', (329, 336))	('IDH1', 'Gene', (24, 28))	('astrocytomas', 'Disease', 'MESH:D001254', (162, 174))	('astrocytoma', 'Phenotype', 'HP:0009592', (162, 173))	('IDH1', 'Gene', '3417', (106, 110))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('mutations', 'Var', (111, 120))	('anaplastic oligodendroglial tumors', 'Disease', (403, 437))	('IDH', 'Gene', '3417', (106, 109))	('temozolomide', 'Chemical', 'MESH:D000077204', (136, 148))	('IDH', 'Gene', (24, 27))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('gliomas', 'Disease', 'MESH:D005910', (329, 336))	('glioblastomas', 'Phenotype', 'HP:0012174', (351, 364))	('IDH', 'Gene', (308, 311))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (403, 437))	('glioma', 'Phenotype', 'HP:0009733', (329, 335))	('IDH1', 'Gene', '3417', (24, 28))	('IDH', 'Gene', '3417', (24, 27))	('gliomas', 'Phenotype', 'HP:0009733', (329, 336))	('astrocytomas', 'Disease', (162, 174))	('tumors', 'Phenotype', 'HP:0002664', (431, 437))	('glioblastomas', 'Disease', (351, 364))	('glioblastoma', 'Phenotype', 'HP:0012174', (351, 363))	('IDH', 'Gene', '3417', (308, 311))	('improved', 'PosReg', (258, 266))	('response', 'MPA', (267, 275))	('IDH', 'Gene', (106, 109))	('IDH1', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (431, 436))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (198, 227))	('glioblastomas', 'Disease', 'MESH:D005909', (351, 364))	('anaplastic oligodendrogliomas', 'Disease', (198, 227))	('gliomas', 'Disease', (220, 227))
107121	28693197	Recently, promising results have been obtained by a selective R132H-IDH1 inhibitor, which appears to impair growth and promote differentiation of glioma cells harboring the IDH1 mutation.	('R132H', 'Chemical', '-', (62, 67))	('promote', 'PosReg', (119, 126))	('mutation', 'Var', (178, 186))	('IDH1', 'Gene', (173, 177))	('growth', 'CPA', (108, 114))	('IDH1', 'Gene', (68, 72))	('glioma', 'Disease', (146, 152))	('IDH1', 'Gene', '3417', (173, 177))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('IDH1', 'Gene', '3417', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('impair', 'NegReg', (101, 107))	('differentiation', 'CPA', (127, 142))
107130	28693197	Anaplastic oligodendroglial tumors harboring 1p/19q codeletion and elderly (>65-70 years) patients with glioblastomas harboring MGMT promoter hypermethylation can be treated by surgery and chemotherapy with or without radiotherapy.	('1p/19q codeletion', 'Var', (45, 62))	('MGMT', 'Gene', '4255', (128, 132))	('MGMT', 'Gene', (128, 132))	('Anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (0, 34))	('Anaplastic oligodendroglial tumors', 'Disease', (0, 34))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('promoter hypermethylation', 'Var', (133, 158))	('glioblastomas', 'Phenotype', 'HP:0012174', (104, 117))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('glioblastomas', 'Disease', 'MESH:D005909', (104, 117))	('glioblastomas', 'Disease', (104, 117))
107170	32413034	For each of the available MRI contrasts (T1, T1Gd, T2 y FLAIR), glioma grades (LGG and HGG) and datasets in the database (BRATS 2013, TCIA and CBICA), two reference volumes were chosen: one with the lowest mean intensity and the another with the highest.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('T1', 'Var', (41, 43))	('T1Gd', 'Var', (45, 49))	('T2', 'Gene', '292', (51, 53))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
107224	31667475	CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup (P = .004).	('associated', 'Reg', (94, 104))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
107225	31667475	Other frequent copy number changes included mesenchymal-epithelial transition (MET) (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification.	('mesenchymal-epithelial transition', 'CPA', (44, 77))	('PDGFRA', 'Gene', (107, 113))	('EGFR', 'Gene', '1956', (141, 145))	('CCND2', 'Gene', (92, 97))	('PDGFRA', 'Gene', '5156', (107, 113))	('copy number changes', 'Var', (15, 34))	('EGFR', 'Gene', (141, 145))	('CDK4', 'Gene', (123, 127))	('amplification', 'Var', (154, 167))	('CCND2', 'Gene', '894', (92, 97))	('CDK4', 'Gene', '1019', (123, 127))
107226	31667475	Glioma-CpG island methylator phenotype-low, CDKN2A deletion, and MET amplification are negative prognostic markers in IDH-mutant glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (129, 142))	('CDKN2A', 'Gene', (44, 50))	('glioblastomas', 'Disease', (129, 142))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('deletion', 'Var', (51, 59))
107228	31667475	showed that 11/13 (84.6%) of secondary glioblastomas carried IDH mutations whereas such alterations were only observed in 6/123 (4.9%) of primary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (39, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('primary glioblastomas', 'Disease', (138, 159))	('glioblastomas', 'Phenotype', 'HP:0012174', (146, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('mutations', 'Var', (65, 74))	('secondary glioblastomas', 'Disease', (29, 52))	('IDH', 'Gene', (61, 64))	('primary glioblastomas', 'Disease', 'MESH:D005909', (138, 159))
107235	31667475	Probes were excluded if they targeted the sex chromosomes, contained single-nucleotide polymorphisms, or mapped to multiple locations in the human genome.	('targeted', 'Reg', (29, 37))	('human', 'Species', '9606', (141, 146))	('single-nucleotide polymorphisms', 'Var', (69, 100))
107242	31667475	Genome-wide DNA methylation analysis revealed that IDH-mutant glioblastomas (both primary and secondary) formed a group distinct from other IDH-mutant gliomas (Grades II-III).	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('II-III', 'Chemical', 'MESH:C105002', (167, 173))	('glioblastomas', 'Phenotype', 'HP:0012174', (62, 75))	('IDH-mutant', 'Var', (51, 61))	('glioblastomas', 'Disease', (62, 75))
107243	31667475	demonstrated that IDH-mutant astrocytic tumors (Grades II-IV) is not uniform in terms of histological and genetic parameters.	('astrocytic tumors', 'Disease', (29, 46))	('IDH-mutant', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('astrocytic tumors', 'Disease', 'MESH:D001254', (29, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
107246	31667475	CDKN2A is located on chromosome 9p21, and it encodes for two different proteins, p16INK4a and p14ARF.CDKN2A negatively controls cell cycle, and CDKN2A abnormality leads to cellular proliferation and dysregulation of proapoptotic pathways.CDKN2A deletion has been described in adult and pediatric low-grade and high-grade gliomas, with frequencies ranging from 20% to 57%.	('deletion', 'Var', (245, 253))	('p14ARF', 'Gene', '1029', (94, 100))	('gliomas', 'Phenotype', 'HP:0009733', (321, 328))	('p16INK4a', 'Gene', (81, 89))	('pathways.CDKN2A', 'Gene', (229, 244))	('p16INK4a', 'Gene', '1029', (81, 89))	('p14ARF', 'Gene', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (321, 327))
107247	31667475	Loss of CDKN2A is associated with poor outcomes in pediatric and adult low-grade and malignant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('malignant gliomas', 'Disease', (85, 102))	('CDKN2A', 'Gene', (8, 14))	('malignant gliomas', 'Disease', 'MESH:D005910', (85, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('Loss', 'Var', (0, 4))
107250	31667475	Recurrent PTPRZ1-MET fusion transcript resulting in an increase in migratory activity has also been described in 15% of secondary glioblastomas.	('secondary glioblastomas', 'Disease', (120, 143))	('increase', 'PosReg', (55, 63))	('PTPRZ1', 'Gene', (10, 16))	('glioblastomas', 'Phenotype', 'HP:0012174', (130, 143))	('migratory activity', 'CPA', (67, 85))	('fusion transcript', 'Var', (21, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('PTPRZ1', 'Gene', '5803', (10, 16))
107251	31667475	These data suggest MET amplification is a poor prognostic marker, and co-occurrence of CDKN2A deletion and MET amplification further enhance the aggressiveness of glioblastoma.	('enhance', 'PosReg', (133, 140))	('deletion', 'Var', (94, 102))	('aggressiveness of glioblastoma', 'Disease', 'MESH:D005909', (145, 175))	('MET amplification', 'Var', (107, 124))	('aggressiveness of glioblastoma', 'Disease', (145, 175))	('aggressiveness', 'Phenotype', 'HP:0000718', (145, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('CDKN2A', 'Gene', (87, 93))
107270	30173409	In contrast, RAS/RAF pathway alterations are rare in adult LGG, which is typified by IDH1/2 and ATRX mutations/alterations, a high incidence of malignant transformation, and a more guarded prognosis.	('IDH', 'Gene', '3417', (85, 88))	('LGG', 'Disease', (59, 62))	('ATRX', 'Gene', (96, 100))	('alterations', 'Var', (29, 40))	('ATRX', 'Gene', '546', (96, 100))	('IDH', 'Gene', (85, 88))	('RAF', 'Gene', '22882', (17, 20))	('mutations/alterations', 'Var', (101, 122))	('RAF', 'Gene', (17, 20))
107310	30173409	Patients with midline-chiasmatic patients were 9.69 times more likely to die than those with non-midline-chiasmatic tumors (Table 2).	('midline-chiasmatic patients', 'Var', (14, 41))	('patients', 'Species', '9606', (33, 41))	('non-midline-chiasmatic tumors', 'Disease', 'MESH:D007029', (93, 122))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('non-midline-chiasmatic tumors', 'Disease', (93, 122))
107351	24265780	The ratio of ISS area to tumor area was also significantly higher for the high-grade group (1.27+-0.79) than that for the low-grade group (0.81+-0.40) (P<0.05).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('high-grade', 'Var', (74, 84))	('ISS', 'Chemical', '-', (13, 16))	('higher', 'PosReg', (59, 65))	('ISS area', 'CPA', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
107508	19434461	Our data further suggest that inhibition of IDO might be detrimental in low grade tumors, by removing a mechanism potentially leading to decreased cellular proliferation.	('IDO', 'Gene', '3620', (44, 47))	('tumors', 'Disease', (82, 88))	('inhibition', 'Var', (30, 40))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('IDO', 'Gene', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cellular proliferation', 'CPA', (147, 169))	('decreased', 'NegReg', (137, 146))
107526	19434461	On the other hand, some studies suggest that induction of IDO may hinder tumor survival, suggesting that tryptophan depletion mediated by IDO may inhibit tumor cell proliferation.	('inhibit', 'NegReg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('IDO', 'Gene', '3620', (58, 61))	('tryptophan depletion', 'MPA', (105, 125))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('hinder', 'NegReg', (66, 72))	('induction', 'Var', (45, 54))	('IDO', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (73, 78))	('IDO', 'Gene', '3620', (138, 141))	('tryptophan', 'Chemical', 'MESH:D014364', (105, 115))	('IDO', 'Gene', (138, 141))	('tumor', 'Disease', (154, 159))
107540	19434461	It has been reported that endothelial cells can express IDO, and expression of IDO in tumor endothelial cells benefited survival of patients with renal cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('benefited', 'PosReg', (110, 119))	('renal cell carcinoma', 'Disease', (146, 166))	('patients', 'Species', '9606', (132, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('tumor', 'Disease', (86, 91))	('survival', 'CPA', (120, 128))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (146, 166))	('IDO', 'Gene', '3620', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('IDO', 'Gene', '3620', (56, 59))	('IDO', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('expression', 'Var', (65, 75))	('IDO', 'Gene', (56, 59))
107555	33863293	High expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and ocular melanomas (UVM) (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('High expression', 'Var', (0, 15))	('LUSC', 'Disease', (100, 104))	('ocular melanomas', 'Phenotype', 'HP:0025534', (131, 147))	('prostate cancer', 'Disease', (229, 244))	('LGG', 'Disease', (199, 202))	('ocular melanomas', 'Disease', 'MESH:D008545', (131, 147))	('LGG', 'Disease', (73, 76))	('GMFG', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('GBM', 'Disease', (46, 49))	('ocular melanomas', 'Disease', (131, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('LUSC', 'Phenotype', 'HP:0030359', (100, 104))
107556	33863293	In contrast, high expression of GMFG was associated with better OS in skin cutaneous melanoma (SKCM) (HR = 0.59, P < 0.001) and thymoma (THYM) (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003).	('THYM', 'Phenotype', 'HP:0100522', (137, 141))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 93))	('GMFG', 'Gene', (32, 36))	('bile duct cancer', 'Phenotype', 'HP:0030153', (193, 209))	('high expression', 'Var', (13, 28))	('bile duct cancer', 'Disease', (193, 209))	('thymoma', 'Phenotype', 'HP:0100522', (128, 135))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('skin cutaneous melanoma', 'Disease', (70, 93))	('thymoma', 'Disease', 'MESH:D013945', (128, 135))	('bile duct cancer', 'Disease', 'MESH:D001650', (193, 209))	('thymoma', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('CHOL', 'Disease', (211, 215))	('CHOL', 'Disease', 'None', (211, 215))
107558	33863293	Our study preliminarily identified that GMFG may cause different survivals for different cancers through modulating tumor progression, immune response status and tissue-specific tumor microenvironment (TME).	('iron', 'Chemical', 'MESH:D007501', (192, 196))	('immune response', 'CPA', (135, 150))	('tumor', 'Disease', (178, 183))	('GMFG', 'Var', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('survivals', 'Disease', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', (116, 121))	('modulating', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
107564	33863293	These two studies demonstrated that GMFG could promote the migration and proliferation of ovarian and colorectal cancer cells, and the high expression of GMFG was related to poor survival outcome for ovarian cancer patients.	('ovarian', 'Disease', 'MESH:D010049', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('related', 'Reg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('high', 'Var', (135, 139))	('ovarian', 'Disease', (90, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('migration', 'CPA', (59, 68))	('ovarian cancer', 'Disease', (200, 214))	('colorectal cancer', 'Disease', (102, 119))	('promote', 'PosReg', (47, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('ovarian', 'Disease', (200, 207))	('patients', 'Species', '9606', (215, 223))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('proliferation', 'CPA', (73, 86))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))
107582	33863293	1c, high expression of GMFG was correlated with early pathological stage in bladder cancer (BLCA) (P = 0.016), LUAD (P = 0.015), skin cutaneous melanoma (SKCM) (P = 0.006) and thyroid cancer (THCA) (P = 0.01), but was linked with advanced pathological stage in stomach cancer (STAD) (P = 0.028).	('skin cutaneous melanoma', 'Disease', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('high expression', 'Var', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('thyroid cancer', 'Disease', (176, 190))	('stomach cancer', 'Disease', 'MESH:D013274', (261, 275))	('stomach cancer', 'Phenotype', 'HP:0012126', (261, 275))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('THCA', 'Phenotype', 'HP:0002890', (192, 196))	('thyroid cancer', 'Disease', 'MESH:D013964', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('correlated', 'Reg', (32, 42))	('GMFG', 'Gene', (23, 27))	('LUAD', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('thyroid cancer', 'Phenotype', 'HP:0002890', (176, 190))	('stomach cancer', 'Disease', (261, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 152))	('BLCA', 'Phenotype', 'HP:0009725', (92, 96))
107583	33863293	For survival outcome, high expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and UVM (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('high expression', 'Var', (22, 37))	('prostate cancer', 'Disease', (232, 247))	('LGG', 'Disease', (202, 205))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('GBM', 'Disease', (68, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LGG', 'Disease', (95, 98))	('GMFG', 'Gene', (41, 45))	('UVM', 'Disease', (153, 156))	('LUSC', 'Disease', (122, 126))
107584	33863293	In contrast, high expression of GMFG was associated with better OS in SKCM (HR = 0.59, P < 0.001) and THYM (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003) (Fig.	('bile duct cancer', 'Disease', 'MESH:D001650', (157, 173))	('CHOL', 'Disease', 'None', (175, 179))	('THYM', 'Phenotype', 'HP:0100522', (102, 106))	('SKCM', 'Disease', (70, 74))	('CHOL', 'Disease', (175, 179))	('GMFG', 'Gene', (32, 36))	('high expression', 'Var', (13, 28))	('THYM', 'Disease', (102, 106))	('bile duct cancer', 'Phenotype', 'HP:0030153', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bile duct cancer', 'Disease', (157, 173))
107590	33863293	We also summarized the top 10 most significant items of GO/KEGG pathways for each individual cancer (Supplementary file 1-4: Table S1-S4), and we found that GMFG was notably associated with the biological process of immune response in most cancers, so we decided to analyze the correlation between GMFG and its immunomodulators co-expression genes.	('cancer', 'Disease', (93, 99))	('associated with', 'Reg', (174, 189))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GMFG', 'Var', (157, 161))	('cancers', 'Disease', (240, 247))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('cancer', 'Disease', (240, 246))	('cancers', 'Disease', 'MESH:D009369', (240, 247))
107592	33863293	As for co-stimulators, GMFG was highly associated with CD80 and CD28 in most cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('CD28', 'Gene', (64, 68))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('GMFG', 'Var', (23, 27))	('cancers', 'Disease', (77, 84))	('CD28', 'Gene', '940', (64, 68))	('CD80', 'Gene', (55, 59))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CD80', 'Gene', '941', (55, 59))
107602	33863293	In addition, high expression of GMFG was associated with early pathological stage in four cancers (BLCA, LUAD, SKCM, and THCA), but was correlated with advanced pathological stage in STAD.	('cancers', 'Disease', (90, 97))	('associated', 'Reg', (41, 51))	('SKCM', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('high', 'Var', (13, 17))	('BLCA', 'Phenotype', 'HP:0009725', (99, 103))	('GMFG', 'Gene', (32, 36))	('LUAD', 'Disease', (105, 109))	('THCA', 'Phenotype', 'HP:0002890', (121, 125))	('correlated', 'Reg', (136, 146))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
107603	33863293	Moreover, the associations of GMFG expression with OS and DFS were also investigated, and high expression of GMFG predicted worse OS in four cancers (GBM, LGG, LUSC, and UVM), and worse DFS for LGG and PRAD, but was associated with better OS in SKCM and THYM, better DFS in CHOL.	('better OS', 'Disease', (232, 241))	('PRAD', 'Disease', (202, 206))	('LUSC', 'Phenotype', 'HP:0030359', (160, 164))	('high expression', 'Var', (90, 105))	('SKCM', 'Disease', (245, 249))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('CHOL', 'Disease', 'None', (274, 278))	('cancers', 'Disease', (141, 148))	('LGG', 'Disease', (155, 158))	('THYM', 'Phenotype', 'HP:0100522', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('GMFG', 'Gene', (109, 113))	('CHOL', 'Disease', (274, 278))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('worse OS', 'Disease', (124, 132))	('LUSC', 'Disease', (160, 164))	('LGG', 'Disease', (194, 197))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('THYM', 'Disease', (254, 258))
107611	33863293	Taken together, that GMFG enhances both the cancer progression and the immune defense, and patients' survival outcome may depend on the balance between the speed of cancer development and the ability of immune system against cancer tissues.	('immune defense', 'CPA', (71, 85))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GMFG', 'Var', (21, 25))	('enhances', 'PosReg', (26, 34))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
107614	33863293	Recent studies reported that GMFG regulates monocyte migration by modulating ITGB1, and functions as a negative regulator of Toll-like receptor 4 (TLR4) signaling through facilitating TLR4 endocytic trafficking in macrophages.	('ITGB1', 'Gene', (77, 82))	('GMFG', 'Var', (29, 33))	('TLR4', 'Gene', (147, 151))	('TLR4', 'Gene', '7099', (184, 188))	('modulating', 'Reg', (66, 76))	('regulates', 'Reg', (34, 43))	('facilitating', 'PosReg', (171, 183))	('ITGB1', 'Gene', '3688', (77, 82))	('TLR4', 'Gene', (184, 188))	('Toll-like receptor 4', 'Gene', '7099', (125, 145))	('TLR4', 'Gene', '7099', (147, 151))	('Toll-like receptor 4', 'Gene', (125, 145))	('monocyte migration', 'CPA', (44, 62))
107642	27898674	Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue.	('Iron', 'Chemical', 'MESH:D007501', (121, 125))	('Gliomas', 'Disease', 'MESH:D005910', (113, 120))	('Gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('Iron', 'Chemical', 'MESH:D007501', (19, 23))	('Gliomas', 'Disease', (113, 120))	('Iron Regulatory Gene Signature', 'Gene', (19, 49))	('Decreased', 'NegReg', (70, 79))	('Aberrations', 'Var', (0, 11))
107643	27898674	Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology.	('play', 'Reg', (76, 80))	('dysregulation', 'Var', (30, 43))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('iron regulatory proteins', 'Protein', (47, 71))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('iron', 'Chemical', 'MESH:D007501', (47, 51))
107649	27898674	The potential association between dysregulated iron metabolism and cancer progression has recently come to prominence in translational oncology research.	('dysregulated', 'Var', (34, 46))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('iron', 'Chemical', 'MESH:D007501', (47, 51))	('oncology', 'Phenotype', 'HP:0002664', (135, 143))
107653	27898674	Recent studies have shown that when physiologic iron metabolism is disrupted, oxidative stress can drive mutagenesis and accelerate tumor progression.	('oxidative stress', 'Phenotype', 'HP:0025464', (78, 94))	('drive', 'Reg', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('disrupted', 'Var', (67, 76))	('iron', 'Chemical', 'MESH:D007501', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('accelerate', 'PosReg', (121, 131))	('tumor', 'Disease', (132, 137))	('oxidative stress', 'MPA', (78, 94))	('mutagenesis', 'CPA', (105, 116))
107660	27898674	Variant forms of the gene encoding HFE, a key iron uptake mediator, are present with increased frequency in high-grade gliomas (glioblastoma, WHO grade IV).	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('HFE', 'Gene', '3077', (35, 38))	('gliomas', 'Disease', (119, 126))	('iron', 'Chemical', 'MESH:D007501', (46, 50))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('HFE', 'Gene', (35, 38))	('Variant', 'Var', (0, 7))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
107661	27898674	These findings appear to be clinically-significant, as one HFE variant appears to confer resistance to standard adjuvant glioma therapy (temozolomide + radiation).	('variant', 'Var', (63, 70))	('temozolomide', 'Chemical', 'MESH:D000077204', (137, 149))	('HFE variant', 'CellLine', 'CVCL:7204', (59, 70))	('adjuvant glioma', 'Disease', 'MESH:D005910', (112, 127))	('adjuvant glioma', 'Disease', (112, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('resistance', 'MPA', (89, 99))
107662	27898674	Similarly, polymorphisms in HFE have been shown to correlate with decreased survival in several forms of brain tumors, including both glioblastoma and metastatic brain tumors.	('HFE', 'Gene', (28, 31))	('brain tumors', 'Disease', (162, 174))	('brain tumors', 'Disease', 'MESH:D001932', (105, 117))	('brain tumors', 'Phenotype', 'HP:0030692', (105, 117))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('survival', 'MPA', (76, 84))	('glioblastoma', 'Disease', (134, 146))	('brain tumors', 'Disease', (105, 117))	('decreased', 'NegReg', (66, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (134, 146))	('brain tumors', 'Phenotype', 'HP:0030692', (162, 174))	('HFE', 'Gene', '3077', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('polymorphisms', 'Var', (11, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('brain tumors', 'Disease', 'MESH:D001932', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
107677	27898674	Our analysis focuses specifically on identifying aberrant expression in these 61 iron metabolism genes that are associated with changes in overall survival.	('iron', 'Chemical', 'MESH:D007501', (81, 85))	('expression', 'MPA', (58, 68))	('overall survival', 'MPA', (139, 155))	('aberrant', 'Var', (49, 57))	('associated', 'Reg', (112, 122))	('changes', 'Reg', (128, 135))
107713	27898674	Subsequent iterations from HFE produced, in general, lower survival results ending a median survival difference of 54.03 months after all eight genes were selected.	('HFE', 'Gene', '3077', (27, 30))	('iterations', 'Var', (11, 21))	('HFE', 'Gene', (27, 30))	('survival', 'MPA', (59, 67))	('lower', 'NegReg', (53, 58))
107714	27898674	While smaller gene sets produced larger differences in survival, Fig 4B shows that percentages of patients with such aberrations grow considerably when selecting more genes, beginning with 7.6% of uncensored patients with an aberration of HFE, and ending with 26.9% of patients with at least one aberration in the eight gene set.	('HFE', 'Gene', '3077', (239, 242))	('patients', 'Species', '9606', (208, 216))	('HFE', 'Gene', (239, 242))	('patients', 'Species', '9606', (98, 106))	('aberration', 'Var', (225, 235))	('patients', 'Species', '9606', (269, 277))
107718	27898674	Following Ohgaki and Kleihues, who found mutations of IDH1 as a "decisive genetic signpost" between the two glioma types, samples were separated based on the gene's mutation.	('mutations', 'Var', (41, 50))	('IDH1', 'Gene', (54, 58))	('glioma', 'Disease', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1', 'Gene', '3417', (54, 58))
107719	27898674	As secondary GBMs are relatively rare, (~10% of GBMs per the literature and 5.5% [6 of 240 tumors] with IDH1 mutations in the TCGA data), we were unable to make any meaningful regression models with this heavily restricted subgroup.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('IDH1', 'Gene', '3417', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations', 'Var', (109, 118))	('IDH1', 'Gene', (104, 108))
107720	27898674	We also performed the same analyses on LGGs conditioned on patients with IDH1 mutations, producing similar results.	('IDH1', 'Gene', (73, 77))	('patients', 'Species', '9606', (59, 67))	('IDH1', 'Gene', '3417', (73, 77))	('mutations', 'Var', (78, 87))
107721	27898674	Specifically, for patients with IDH1 mutations, we observed an average lifespan of 42.2 months for those with aberrations in the restricted eight-gene set, and 56.7 months without such aberrations.	('IDH1', 'Gene', (32, 36))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (18, 26))	('IDH1', 'Gene', '3417', (32, 36))
107722	27898674	Patients with no IDH1 mutations had a median lifetime of 18.6 months for those with aberrations in the 8-gene set, and 32.5 without such aberrations.	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (17, 21))	('aberrations in', 'Var', (84, 98))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', '3417', (17, 21))
107724	27898674	The present study shows that aberration in a set of eight iron-regulating genes is associated with decreased survival in patients with LGG.	('decreased', 'NegReg', (99, 108))	('iron', 'Chemical', 'MESH:D007501', (58, 62))	('survival', 'MPA', (109, 117))	('LGG', 'Disease', (135, 138))	('aberration', 'Var', (29, 39))	('iron-regulating genes', 'Gene', (58, 79))	('patients', 'Species', '9606', (121, 129))
107736	27898674	Furthermore, STEAP3 is associated with impaired exosome secretion, a process which has been implicated in antitumor immunity.	('impaired', 'NegReg', (39, 47))	('STEAP3', 'Var', (13, 19))	('exosome secretion', 'MPA', (48, 65))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
107740	27898674	It has been shown to increase oxidative stress, and its disruption by siRNA knockdown significantly induced apoptosis in prostate cancer, and inhibited proliferation, colony formation, and growth.	('prostate cancer', 'Disease', 'MESH:D011471', (121, 136))	('oxidative stress', 'MPA', (30, 46))	('growth', 'CPA', (189, 195))	('proliferation', 'CPA', (152, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('oxidative stress', 'Phenotype', 'HP:0025464', (30, 46))	('increase oxidative stress', 'Phenotype', 'HP:0025464', (21, 46))	('colony formation', 'CPA', (167, 183))	('prostate cancer', 'Disease', (121, 136))	('induced', 'Reg', (100, 107))	('disruption', 'Var', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('inhibited', 'NegReg', (142, 151))	('siRNA', 'Gene', (70, 75))	('increase', 'PosReg', (21, 29))	('apoptosis', 'CPA', (108, 117))
107743	27898674	Knockouts suffer from iron deficiency anemia, so it appears that its function is necessary for homeostatic levels of iron storage.	('anemia', 'Phenotype', 'HP:0001903', (38, 44))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (22, 44))	('iron deficiency anemia', 'Disease', (22, 44))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('Knockouts', 'Var', (0, 9))	('suffer from', 'Reg', (10, 21))	('iron', 'Chemical', 'MESH:D007501', (22, 26))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (22, 44))
107744	27898674	Others have found that variant forms of TMPRSS6 were associated with increased risk of childhood ALL in males, so it may be common to multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TMPRSS6', 'Gene', (40, 47))	('variant', 'Var', (23, 30))	('associated', 'Reg', (53, 63))	('cancer', 'Disease', (143, 149))	('childhood ALL', 'Disease', (87, 100))	('TMPRSS6', 'Gene', '164656', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
107748	27898674	First, the proteins derived from these two genes are known to interact, and disruption in function of either affects survival of patients with breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('affects', 'Reg', (109, 116))	('breast cancer', 'Disease', (143, 156))	('patients', 'Species', '9606', (129, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('disruption', 'Var', (76, 86))	('survival', 'CPA', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
107749	27898674	Second, the highly polymorphic nature of HFE means that disruptions in normal HFE function are extremely common, and these findings support their clinical relevance in at least one cancer type.	('function', 'MPA', (82, 90))	('HFE', 'Gene', '3077', (78, 81))	('disruptions', 'Var', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('HFE', 'Gene', '3077', (41, 44))	('HFE', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('HFE', 'Gene', (41, 44))	('cancer', 'Disease', (181, 187))
107751	27898674	In the US population, the two most common polymorphisms in HFE, H63D and C282Y, are seen in approximately 15% and 7% of the population, respectively.	('C282Y', 'Mutation', 'rs1800562', (73, 78))	('H63D', 'SUBSTITUTION', 'None', (64, 68))	('H63D', 'Var', (64, 68))	('HFE', 'Gene', '3077', (59, 62))	('C282Y', 'Var', (73, 78))	('HFE', 'Gene', (59, 62))
107770	27898674	It is not clear why iron-regulating gene function fails to differentiate long- and short-term survivors in glioblastoma multiforme, especially considering the evidence that polymorphisms in a single iron-regulatory gene, HFE, may decrease survival in GBM.	('glioblastoma multiforme', 'Disease', (107, 130))	('survival', 'CPA', (239, 247))	('iron', 'Chemical', 'MESH:D007501', (20, 24))	('iron', 'Chemical', 'MESH:D007501', (199, 203))	('HFE', 'Gene', (221, 224))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (107, 130))	('decrease', 'NegReg', (230, 238))	('HFE', 'Gene', '3077', (221, 224))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('polymorphisms', 'Var', (173, 186))
107774	27898674	Iron regulatory genes may provide useful prognostic and predictive information in one subtype, but given the relatively small proportions of patients with IDH1 mutations, the present dataset did not provide a sufficient sample size to ascertain statistically meaningful conclusions.	('IDH1', 'Gene', (155, 159))	('mutations', 'Var', (160, 169))	('IDH1', 'Gene', '3417', (155, 159))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('patients', 'Species', '9606', (141, 149))
107775	27898674	In addition, since TFRC and ferritin changes appear to be associated with cancer stem cell populations, it may be more appropriate to apply these methods to gene sets designed to interrogate stem cell character rather than iron aberrance alone in GBM.	('associated', 'Reg', (58, 68))	('iron', 'Chemical', 'MESH:D007501', (223, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('changes', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TFRC', 'Gene', '7037', (19, 23))	('cancer', 'Disease', (74, 80))	('ferritin', 'Protein', (28, 36))	('TFRC', 'Gene', (19, 23))
107787	27686946	Primary clinical endpoint was progression-free survival (PFS), correlative analyses included molecular markers (1p/19q co-deletion, MGMT methylation status, IDH1+2 mutations).	('1p/19q co-deletion', 'Var', (112, 130))	('MGMT', 'Gene', '4255', (132, 136))	('MGMT', 'Gene', (132, 136))	('IDH1+2', 'Gene', (157, 163))	('IDH1+2', 'Gene', '3417;3418', (157, 163))	('mutations', 'Var', (164, 173))
107795	27686946	Known favorable molecular prognostic factors comprise co-deletion of chromosome 1p/19q, and more recently mutation of isocitrate dehydrogenase 1 or 2 (IDH1/2) that was discovered to be present in most LGG (>80%).	('co-deletion', 'Var', (54, 65))	('IDH1/2', 'Gene', '3417;3418', (151, 157))	('mutation', 'Var', (106, 114))	('IDH1/2', 'Gene', (151, 157))
107797	27686946	We searched PubMed between June 1993 and April 2016 using the search terms, "randomized" "low grade glioma" "chemotherapy" "radiotherapy" and identified a total of only 4 conclusive trials, including reports on delaying treatment initiation, or the optimal dose of radiotherapy (EORTC 22844; EORTC 22845/MRC BR04; NCCTG/RTOG/ECOG; RTOG9802).	('glioma', 'Disease', (100, 106))	('MRC', 'CellLine', 'CVCL:0440', (304, 307))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('EORTC 22845/MRC BR04', 'Var', (292, 312))	('CTG', 'Chemical', '-', (316, 319))	('EORTC 22844', 'Var', (279, 290))
107801	27686946	Patients with an IDH mutation without co-deletion of 1p/19q, displayed a significantly longer PFS when treated with RT, while patients with wild type IDH belong to different categories of glioma often with a much more aggressive course.	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('IDH', 'Gene', '3417', (17, 20))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('mutation', 'Var', (21, 29))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', (150, 153))	('PFS', 'MPA', (94, 97))	('patients', 'Species', '9606', (126, 134))	('glioma', 'Disease', (188, 194))	('longer', 'PosReg', (87, 93))	('IDH', 'Gene', '3417', (150, 153))	('IDH', 'Gene', (17, 20))
107804	27686946	Most patients with a low-grade glioma without mutation of IDH1/2 fare substantially worse under either single modality treatment.	('IDH1/2', 'Gene', '3417;3418', (58, 64))	('patients', 'Species', '9606', (5, 13))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH1/2', 'Gene', (58, 64))	('mutation', 'Var', (46, 54))	('glioma', 'Disease', (31, 37))
107813	27686946	More recently, molecular characteristics particularly co-deletion of chromosomal arms 1p/19q (codel) that are associated with oligodendroglial histology and mutations of isocitrate dehydrogenase (IDH) 1 or 2 genes (IDHmt) have been associated with a more favorable prognosis and better response to both chemotherapy and radiation.	('oligodendroglial', 'Disease', (126, 142))	('IDH', 'Gene', '3417', (196, 199))	('IDH', 'Gene', '3417', (215, 218))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (170, 202))	('mutations', 'Var', (157, 166))	('associated', 'Reg', (110, 120))	('arms 1p', 'Gene', (81, 88))	('IDH', 'Gene', (215, 218))	('arms 1p', 'Gene', '3075', (81, 88))	('associated', 'Reg', (232, 242))	('co-deletion', 'Var', (54, 65))	('oligodendroglial', 'Disease', 'None', (126, 142))	('IDH', 'Gene', (196, 199))
107832	27686946	Patients randomized to the experimental arm were to receive TMZ (Temodal , Temodar , Merck & Co, White House Station, NJ) in a dose-dense schedule of 75 mg/m2 per day for 21 days, repeated every 28 days for up to 12 cycles, or until tumor progression or unacceptable toxicity.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('TMZ', 'Var', (60, 63))	('tumor', 'Disease', (233, 238))	('TMZ', 'Chemical', 'MESH:D000077204', (60, 63))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('toxicity', 'Disease', 'MESH:D064420', (267, 275))	('toxicity', 'Disease', (267, 275))
107833	27686946	Antibiotic prophylaxis against opportunistic Pneumocystis jiroveci infections was recommended for lymphocyte counts < 500/mm3.	('< 500/mm3', 'Var', (116, 125))	('Pneumocystis jiroveci infections', 'Phenotype', 'HP:0020102', (45, 77))	('opportunistic Pneumocystis jiroveci infections', 'Disease', 'MESH:D009894', (31, 77))	('opportunistic Pneumocystis jiroveci infections', 'Disease', (31, 77))
107837	27686946	Deletion of chromosomal arms 1p and 19q was tested by microsatellite markers or using FISH as described.	('arms 1p', 'Gene', (24, 31))	('microsatellite', 'Var', (54, 68))	('arms 1p', 'Gene', '3075', (24, 31))	('Deletion', 'Var', (0, 8))
107838	27686946	The mutation status of IDH1 and 2 was determined by immunohistochemistry for the most common mutation IDH1-R132H, complemented by DNA sequencing of negative cases.	('IDH1 and 2', 'Gene', '3417;3418', (23, 33))	('R132H', 'Var', (107, 112))	('R132H', 'SUBSTITUTION', 'None', (107, 112))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', (102, 106))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', '3417', (102, 106))
107842	27686946	The IDH1/2 mutations in glioma have been published in 2009 and were included subsequently.	('mutations', 'Var', (11, 20))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('IDH1/2', 'Gene', (4, 10))	('glioma', 'Disease', (24, 30))
107872	27686946	IDH1 or 2 mutations were detected in 327/392 (83%) of the tumors, of which 30 (9.4%) had IDH1 mutations other than the common IDH1-R132H, and 9 (2.8%) were identified in IDH2.	('IDH2', 'Gene', (170, 174))	('IDH1', 'Gene', '3417', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (94, 103))	('tumors', 'Disease', (58, 64))	('R132H', 'Var', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('IDH2', 'Gene', '3418', (170, 174))	('IDH1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('IDH1', 'Gene', '3417', (89, 93))	('IDH1', 'Gene', (126, 130))	('R132H', 'SUBSTITUTION', 'None', (131, 136))	('IDH1', 'Gene', (89, 93))	('IDH1', 'Gene', '3417', (0, 4))
107873	27686946	Co-deletions of 1p/19q (codel) were identified in 117/357 tumors (33%) and the MGMT promoter was methylated in 135/150 tumors (90%).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MGMT', 'Gene', (79, 83))	('1p/19q', 'Gene', (16, 22))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('Co-deletions', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('MGMT', 'Gene', '4255', (79, 83))
107878	27686946	The MGMT promoter status was methylated in all IDHmt/codel (45/45), most but not all (86%, 62/72) of the IDHmt/non-codel, and in 56% (5/9) of the IDHwt cases (table 3).	('MGMT', 'Gene', '4255', (4, 8))	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', (146, 149))	('IDH', 'Gene', '3417', (146, 149))	('IDH', 'Gene', (105, 108))	('methylated', 'Var', (29, 39))	('IDH', 'Gene', '3417', (105, 108))	('MGMT', 'Gene', (4, 8))	('IDH', 'Gene', (47, 50))
107888	27686946	IDH mutations that were discovered after trial implementation are characteristic for LGG and are present in over 80%.	('mutations', 'Var', (4, 13))	('LGG', 'Disease', (85, 88))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))
107948	27786240	For a finite U, its intuitionistic fuzzy set A is, where epsilon is a constant within an interval [0,1], and muA(u), nuA(u) and piA(u) denote the membership degree, non-membership degree and hesitation degree, respectively.	('nuA', 'Gene', '23224', (117, 120))	('nuA', 'Gene', (117, 120))	('piA', 'Gene', '253260', (128, 131))	('muA', 'Var', (109, 112))	('piA', 'Gene', (128, 131))
107954	27786240	The chain of the NLFI is, where U(k) and X(k) denote the input data and output data, and Psi(k), Gamma(k) and Phi(k) denote the fuzzification, hyperbolization, and defuzzification operations.	('defuzzification operations', 'Disease', (164, 190))	('defuzzification operations', 'Disease', 'MESH:D056987', (164, 190))	('Psi(k', 'Var', (89, 94))
108054	22371319	Dose modifications were implemented for unacceptable toxicity defined as grade 4 neutropenia, grade >= 3 thrombocytopenia, grade >= 3 non-hematologic toxicity not attributable to underlying disease, concurrent medication or co-morbid event, or any toxicity requiring > two weeks to resolve to grade 1 or re-treatment criteria.	('neutropenia', 'Disease', 'MESH:D009503', (81, 92))	('neutropenia', 'Phenotype', 'HP:0001875', (81, 92))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('grade >= 3', 'Var', (123, 133))	('toxicity', 'Disease', (150, 158))	('toxicity', 'Disease', 'MESH:D064420', (248, 256))	('thrombocytopenia', 'Disease', 'MESH:D013921', (105, 121))	('toxicity', 'Disease', (248, 256))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (105, 121))	('neutropenia', 'Disease', (81, 92))	('non-hematologic', 'MPA', (134, 149))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('toxicity', 'Disease', (53, 61))	('thrombocytopenia', 'Disease', (105, 121))
108081	22371319	More recently biologic factors have been linked with outcome including histology, co-deletion of chromosomes 1p19q, methylation of methylguanine methyltransferase, and IDH1/2 mutation.	('methylation', 'MPA', (116, 127))	('IDH1/2', 'Gene', '3417;3418', (168, 174))	('mutation', 'Var', (175, 183))	('IDH1/2', 'Gene', (168, 174))	('co-deletion', 'Var', (82, 93))
108086	22371319	Several important findings also implicate PDGFR signaling in LGG physiology including that exogenous PDGF induces astrocytoma proliferation and that PDGFR activation has been linked with transformation of neural stem/progenitor cells into glial tumors In addition, PDGF dominant-negative mutants can revert the transformed phenotype of human astrocytoma cells.	('glial tumors', 'Disease', (239, 251))	('astrocytoma', 'Disease', (342, 353))	('PDGF', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('PDGF', 'Gene', (265, 269))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('PDGF', 'Gene', '5154', (101, 105))	('PDGF', 'Gene', '5154', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('dominant-negative mutants', 'Var', (270, 295))	('astrocytoma proliferation', 'Disease', 'MESH:D001254', (114, 139))	('astrocytoma proliferation', 'Disease', (114, 139))	('PDGFR', 'Gene', (149, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (342, 353))	('astrocytoma', 'Disease', 'MESH:D001254', (114, 125))	('PDGF', 'Gene', (101, 105))	('PDGFR', 'Gene', '5159', (149, 154))	('PDGF', 'Gene', '5154', (42, 46))	('astrocytoma', 'Disease', (114, 125))	('PDGF', 'Gene', (149, 153))	('PDGF', 'Gene', '5154', (265, 269))	('glial tumors', 'Disease', 'MESH:D005910', (239, 251))	('astrocytoma', 'Disease', 'MESH:D001254', (342, 353))	('PDGFR', 'Gene', (42, 47))	('PDGFR', 'Gene', '5159', (42, 47))	('human', 'Species', '9606', (336, 341))
108106	22371319	Unfortunately, due to lack of archival tumor material, we were unable to assess whether PDGF/PDGFR expression or genetic abnormalities such as chromosome 1p/19q or IDH 1/2 mutations correlated with outcome.	('mutations', 'Var', (172, 181))	('archival tumor', 'Disease', 'MESH:D009369', (30, 44))	('IDH 1/2', 'Gene', (164, 171))	('PDGFR', 'Gene', '5159', (93, 98))	('PDGF', 'Gene', (88, 92))	('genetic abnormalities', 'Disease', (113, 134))	('IDH 1/2', 'Gene', '3417;3418', (164, 171))	('archival tumor', 'Disease', (30, 44))	('PDGF', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PDGF', 'Gene', '5154', (93, 97))	('correlated', 'Reg', (182, 192))	('genetic abnormalities', 'Disease', 'MESH:D030342', (113, 134))	('PDGFR', 'Gene', (93, 98))	('PDGF', 'Gene', '5154', (88, 92))
108118	34006227	In the univariate analysis, elder, high-grade tumor, high sCTLA-4 levels and high Ki-67 index were significantly associated with shorter PFS.	('high sCTLA-4 levels', 'MPA', (53, 72))	('high-grade', 'Var', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('sCTLA-4', 'Chemical', '-', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
108131	34006227	Analysis of human T cells in vitro has shown that sCTLA-4 secretion can increase during immune responses and has powerful inhibitory function, as isoform-specific blockade of sCTLA-4 significantly increases antigen-driven proliferation and cytokine secretion.	('sCTLA-4', 'Chemical', '-', (50, 57))	('blockade', 'Var', (163, 171))	('cytokine secretion', 'MPA', (240, 258))	('secretion', 'MPA', (58, 67))	('sCTLA-4', 'Chemical', '-', (175, 182))	('increases', 'PosReg', (197, 206))	('human', 'Species', '9606', (12, 17))	('antigen-driven proliferation', 'CPA', (207, 235))	('sCTLA-4', 'Gene', (175, 182))
108137	34006227	In peripheral blood mononuclear cell responses, the blockade of sCTLA-4 activates the proliferation of CD4+ and CD8+ T cells and promotes increased cytokine secretion, which enhances antitumor effects.	('activates', 'PosReg', (72, 81))	('CD8', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('promotes increased', 'PosReg', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CD4', 'Gene', (103, 106))	('proliferation', 'CPA', (86, 99))	('enhances', 'PosReg', (174, 182))	('sCTLA-4', 'Chemical', '-', (64, 71))	('CD4', 'Gene', '920', (103, 106))	('tumor', 'Disease', (187, 192))	('CD8', 'Gene', '925', (112, 115))	('sCTLA-4', 'Gene', (64, 71))	('cytokine secretion', 'MPA', (148, 166))	('increased cytokine', 'Phenotype', 'HP:0031407', (138, 156))	('blockade', 'Var', (52, 60))
108232	33290989	Our study attempted to identify hub genes related to isocitrate dehydrogenase (IDH) mutation in glioma and develop a prognostic model for IDH-mutant glioma patients.	('patients', 'Species', '9606', (156, 164))	('glioma', 'Disease', (149, 155))	('IDH', 'Gene', (138, 141))	('IDH', 'Gene', (79, 82))	('hub', 'Gene', (32, 35))	('isocitrate dehydrogenase', 'Gene', (53, 77))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', '3417', (138, 141))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('isocitrate dehydrogenase', 'Gene', '3417', (53, 77))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('hub', 'Gene', '1993', (32, 35))	('glioma', 'Disease', (96, 102))	('mutation', 'Var', (84, 92))
108239	33290989	Collectively, this study provided novel insights into the molecular mechanism of IDH mutation in glioma, and constructed a prognostic model which can be effective for predicting prognosis of glioma patients with IDH-mutation, which might promote the development of IDH target agents in glioma therapies and contribute to accurate prognostication and management in IDH-mutant glioma patients.	('patients', 'Species', '9606', (198, 206))	('IDH', 'Gene', '3417', (265, 268))	('mutation', 'Var', (85, 93))	('IDH', 'Gene', '3417', (81, 84))	('glioma', 'Disease', (375, 381))	('glioma', 'Disease', 'MESH:D005910', (375, 381))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('IDH', 'Gene', (212, 215))	('glioma', 'Disease', (286, 292))	('IDH', 'Gene', (364, 367))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (286, 292))	('glioma', 'Phenotype', 'HP:0009733', (375, 381))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('patients', 'Species', '9606', (382, 390))	('IDH', 'Gene', (265, 268))	('IDH', 'Gene', '3417', (212, 215))	('IDH', 'Gene', '3417', (364, 367))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('IDH', 'Gene', (81, 84))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
108246	33290989	Isocitrate dehydrogenase (IDH) mutation is widely used as a molecular biomarker in glioma, which has been paid a strong clinical attention.	('glioma', 'Disease', (83, 89))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('mutation', 'Var', (31, 39))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('IDH', 'Gene', (26, 29))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH', 'Gene', '3417', (26, 29))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
108247	33290989	Several studies found that IDH mutations are also linked to other cancers, including acute myeloid leukemia and cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (31, 40))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (85, 107))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('IDH', 'Gene', '3417', (27, 30))	('cholangiocarcinoma', 'Disease', (112, 130))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('linked', 'Reg', (50, 56))	('acute myeloid leukemia', 'Disease', (85, 107))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (85, 107))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (91, 107))
108248	33290989	However, significant diagnostic and prognostic relevance of IDH mutation has been only proven in glioma.	('mutation', 'Var', (64, 72))	('glioma', 'Disease', (97, 103))	('IDH', 'Gene', (60, 63))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH', 'Gene', '3417', (60, 63))
108250	33290989	IDH mutation mostly occurs in lower grade glioma (LGG) and about 5% of primary glioblastomas (GBM), but absent in the other primary brain tumors.	('brain tumors', 'Disease', (132, 144))	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('occurs', 'Reg', (20, 26))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('brain tumors', 'Phenotype', 'HP:0030692', (132, 144))	('glioblastomas', 'Disease', 'MESH:D005909', (79, 92))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('glioblastomas', 'Disease', (79, 92))	('glioma', 'Disease', (42, 48))	('brain tumors', 'Disease', 'MESH:D001932', (132, 144))
108251	33290989	Therefore, we speculated that the genes associated with the IDH mutation might be used as potential biomarkers for glioma diagnosis.	('glioma', 'Disease', (115, 121))	('mutation', 'Var', (64, 72))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('IDH', 'Gene', (60, 63))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('IDH', 'Gene', '3417', (60, 63))
108252	33290989	In recent years, more and more studies on the core genes and mechanisms that regulate IDH mutations in gliomas have emerged (Y.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('IDH', 'Gene', (86, 89))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('mutations', 'Var', (90, 99))	('IDH', 'Gene', '3417', (86, 89))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))
108253	33290989	indicated that, in glioma, MEGF10 is markedly correlated with IDH mutation.	('MEGF10', 'Gene', (27, 33))	('IDH', 'Gene', '3417', (62, 65))	('MEGF10', 'Gene', '84466', (27, 33))	('correlated', 'Reg', (46, 56))	('glioma', 'Disease', (19, 25))	('mutation', 'Var', (66, 74))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('IDH', 'Gene', (62, 65))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
108263	33290989	The results of this study indicated two novel subtypes of IDH mutation with distinct molecular and clinical characteristics and provided a robust model for predicting the prognosis of IDH-mutant glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('IDH', 'Gene', '3417', (58, 61))	('IDH', 'Gene', (184, 187))	('patients', 'Species', '9606', (202, 210))	('mutation', 'Var', (62, 70))	('glioma', 'Disease', (195, 201))	('IDH', 'Gene', '3417', (184, 187))	('IDH', 'Gene', (58, 61))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
108273	33290989	Based on the comparison of gene expression profile, the R package "CancerSubtypes" was applied to conduct consensus clustering for determining subgroups of IDH mutant glioma.	('glioma', 'Disease', (167, 173))	('IDH', 'Gene', (156, 159))	('mutant', 'Var', (160, 166))	('IDH', 'Gene', '3417', (156, 159))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
108282	33290989	Ten subnetwork genes displaying high MM, high GS and high weight, which included GPX8, CCDC109B, IGFBP2, LINC00152, LOC541471, METTL7B, S100A4, EMP3, CLIC1, and TAGLN2, were screened as the hub genes (Fig.	('CCDC109B', 'Gene', (87, 95))	('IGFBP2', 'Gene', '3485', (97, 103))	('GPX8', 'Gene', (81, 85))	('METTL7B', 'Gene', '196410', (127, 134))	('CLIC1', 'Gene', '1192', (150, 155))	('TAGLN2', 'Gene', '8407', (161, 167))	('LINC00152', 'Gene', (105, 114))	('hub', 'Gene', (190, 193))	('IGFBP2', 'Gene', (97, 103))	('S100A4', 'Gene', '6275', (136, 142))	('METTL7B', 'Gene', (127, 134))	('hub', 'Gene', '1993', (190, 193))	('EMP3', 'Gene', (144, 148))	('GPX8', 'Gene', '493869', (81, 85))	('CCDC109B', 'Gene', '55013', (87, 95))	('GS', 'Disease', 'MESH:D011125', (46, 48))	('CLIC1', 'Gene', (150, 155))	('LOC541471', 'Var', (116, 125))	('LINC00152', 'Gene', '112597', (105, 114))	('S100A4', 'Gene', (136, 142))	('TAGLN2', 'Gene', (161, 167))	('EMP3', 'Gene', '2014', (144, 148))
108285	33290989	Meanwhile, we found that the expressions of these hub genes were also markedly different between cases with and without IDH mutation in both LGG and GBM (Figure S3 and S4).	('expressions', 'MPA', (29, 40))	('IDH', 'Gene', '3417', (120, 123))	('different', 'Reg', (79, 88))	('hub', 'Gene', (50, 53))	('mutation', 'Var', (124, 132))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('IDH', 'Gene', (120, 123))	('hub', 'Gene', '1993', (50, 53))
108293	33290989	3D), suggesting that the patients of cluster1 had significantly poorer prognosis in comparison with those of cluster2.	('cluster1', 'Var', (37, 45))	('poorer', 'NegReg', (64, 70))	('patients', 'Species', '9606', (25, 33))
108295	33290989	These results suggested that the two subtypes based on the IDH mutation may provide guidance for clinicians on personalized treatments and diagnoses by identifying differences in prognosis for each epigenetic subtype.	('differences', 'Reg', (164, 175))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', '3417', (59, 62))	('mutation', 'Var', (63, 71))
108316	33290989	IDH mutation occurs in the majority of LGG (WHO grade II/III), but in only 5% -apparently - primary glioblastomas (WHO grade IV) (GBM).	('IDH', 'Gene', (0, 3))	('glioblastomas', 'Disease', (100, 113))	('IDH', 'Gene', '3417', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('mutation', 'Var', (4, 12))	('glioblastomas', 'Phenotype', 'HP:0012174', (100, 113))	('glioblastomas', 'Disease', 'MESH:D005909', (100, 113))	('LGG', 'Disease', (39, 42))
108320	33290989	After filtering GS and MM value, a total of ten hub genes (GPX8, CCDC109B, IGFBP2, LINC00152, LOC541471, METTL7B, S100A4, EMP3, CLIC1, and TAGLN2) were obtained and all of them were significant in distinguishing IDH status in glioma.	('GPX8', 'Gene', '493869', (59, 63))	('METTL7B', 'Gene', (105, 112))	('CLIC1', 'Gene', '1192', (128, 133))	('glioma', 'Disease', (226, 232))	('EMP3', 'Gene', (122, 126))	('CCDC109B', 'Gene', '55013', (65, 73))	('S100A4', 'Gene', '6275', (114, 120))	('LINC00152', 'Gene', '112597', (83, 92))	('hub', 'Gene', (48, 51))	('glioma', 'Disease', 'MESH:D005910', (226, 232))	('GS', 'Disease', 'MESH:D011125', (16, 18))	('TAGLN2', 'Gene', (139, 145))	('hub', 'Gene', '1993', (48, 51))	('IDH', 'Gene', (212, 215))	('CLIC1', 'Gene', (128, 133))	('LOC541471', 'Var', (94, 103))	('EMP3', 'Gene', '2014', (122, 126))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('IGFBP2', 'Gene', '3485', (75, 81))	('GPX8', 'Gene', (59, 63))	('S100A4', 'Gene', (114, 120))	('CCDC109B', 'Gene', (65, 73))	('IDH', 'Gene', '3417', (212, 215))	('LINC00152', 'Gene', (83, 92))	('TAGLN2', 'Gene', '8407', (139, 145))	('IGFBP2', 'Gene', (75, 81))	('METTL7B', 'Gene', '196410', (105, 112))
108328	33290989	As known, IDH1 mutation has been linked with a better prognosis in glioma patients.	('mutation', 'Var', (15, 23))	('IDH1', 'Gene', '3417', (10, 14))	('glioma', 'Disease', (67, 73))	('patients', 'Species', '9606', (74, 82))	('IDH1', 'Gene', (10, 14))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
108332	33290989	A recent study conducted by Yuan and his co-workers proved that the expression of IGFBP2 was related to the occurrence of IDH1 mutation.	('mutation', 'Var', (127, 135))	('IDH1', 'Gene', (122, 126))	('IGFBP2', 'Gene', '3485', (82, 88))	('IDH1', 'Gene', '3417', (122, 126))	('related', 'Reg', (93, 100))	('IGFBP2', 'Gene', (82, 88))
108335	33290989	indicated that hypermethylation of EMP3 was strongly associated with IDH mutation.	('IDH', 'Gene', (69, 72))	('EMP3', 'Gene', (35, 39))	('IDH', 'Gene', '3417', (69, 72))	('hypermethylation', 'Var', (15, 31))	('associated', 'Reg', (53, 63))	('EMP3', 'Gene', '2014', (35, 39))
108343	33290989	Increasing studies suggested that IDH mutation is closely related to glutathione metabolism.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('glutathione metabolism', 'MPA', (69, 91))	('related', 'Reg', (58, 65))	('glutathione', 'Chemical', 'MESH:D005978', (69, 80))	('mutation', 'Var', (38, 46))
108352	33290989	indicated that TP53 mutations are indicators of bad prognosis in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TP53', 'Gene', (15, 19))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('mutations', 'Var', (20, 29))
108372	33290989	We speculated that although the expressions of hub genes were closely related to whether glioma patients are accompanied by IDH mutations, they might not relate to the different phenotypes under IDH mutation.	('IDH', 'Gene', (195, 198))	('hub', 'Gene', '1993', (47, 50))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('IDH', 'Gene', (124, 127))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('mutations', 'Var', (128, 137))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', '3417', (124, 127))	('hub', 'Gene', (47, 50))	('glioma', 'Disease', (89, 95))	('patients', 'Species', '9606', (96, 104))
108385	33290989	Although there is no hub gene in the 31 genes that made up the signature, the predictive model composed of the signature was capable of predicting the prognosis of patients with IDH mutations in glioma.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('IDH', 'Gene', '3417', (178, 181))	('hub', 'Gene', '1993', (21, 24))	('mutations', 'Var', (182, 191))	('glioma', 'Disease', (195, 201))	('hub', 'Gene', (21, 24))	('patients', 'Species', '9606', (164, 172))	('IDH', 'Gene', (178, 181))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
108392	32272491	The Use of MEK Inhibitors in Neurofibromatosis Type 1-Associated Tumors and Management of Toxicities Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)-associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas.	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('glioma', 'Phenotype', 'HP:0009733', (333, 339))	('neurofibromatosis type 1', 'Gene', '4763', (248, 272))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (345, 368))	('gliomas', 'Phenotype', 'HP:0009733', (333, 340))	('neurofibromas', 'Phenotype', 'HP:0001067', (355, 368))	('MEK', 'Gene', '5609', (154, 157))	('neurofibromas', 'Disease', 'MESH:D009455', (355, 368))	('MEK', 'Gene', '5609', (11, 14))	('Toxicities', 'Disease', (90, 100))	('Toxicities', 'Disease', 'MESH:D064420', (90, 100))	('NF1', 'Gene', '4763', (274, 277))	('patients', 'Species', '9606', (234, 242))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('MEK', 'Gene', (154, 157))	('MEK', 'Gene', (11, 14))	('inhibitors', 'Var', (140, 150))	('NF1', 'Gene', (274, 277))	('neurofibromatosis type 1', 'Gene', (248, 272))	('gliomas', 'Disease', (333, 340))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('neurofibromas', 'Disease', (355, 368))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (248, 265))	('benefit', 'PosReg', (222, 229))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (29, 46))	('tumors', 'Disease', (290, 296))	('Tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Neurofibromatosis Type 1-Associated Tumors', 'Disease', 'MESH:C537392', (29, 71))	('gliomas', 'Disease', 'MESH:D005910', (333, 340))	('Tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Neurofibromatosis Type 1-Associated Tumors', 'Disease', (29, 71))
108395	32272491	In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side-effect management, as well as monitoring guidelines.	('MEK', 'Gene', (126, 129))	('inhibitors', 'Var', (130, 140))	('MEK', 'Gene', '5609', (126, 129))	('Tumor', 'Phenotype', 'HP:0002664', (71, 76))	('NF1', 'Gene', '4763', (144, 147))	('NF1', 'Gene', (144, 147))	('Children', 'Species', '9606', (60, 68))
108398	32272491	With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low-grade gliomas.	('neurofibromas', 'Disease', 'MESH:D009455', (159, 172))	('neurofibromas', 'Phenotype', 'HP:0001067', (159, 172))	('gliomas', 'Disease', (187, 194))	('inhibitors', 'Var', (129, 139))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (149, 172))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('MEK', 'Gene', (49, 52))	('MEK', 'Gene', '5609', (49, 52))	('NF1', 'Gene', (89, 92))	('MEK', 'Gene', (125, 128))	('NF1', 'Gene', '4763', (89, 92))	('MEK', 'Gene', '5609', (125, 128))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('neurofibromas', 'Disease', (159, 172))	('patients', 'Species', '9606', (93, 101))
108400	32272491	Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1-related tumors.	('MEK', 'Gene', (192, 195))	('MEK', 'Gene', '5609', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('NF1', 'Gene', (211, 214))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('NF1', 'Gene', '4763', (211, 214))	('Tumor', 'Phenotype', 'HP:0002664', (72, 77))	('NF1', 'Gene', (122, 125))	('NF1', 'Gene', '4763', (122, 125))	('Children', 'Species', '9606', (61, 69))	('changes', 'Var', (12, 19))
108410	32272491	Loss of functional neurofibromin results in activation of the classic RAS-MAPK signaling cascade, cell proliferation, and subsequent tumor formation.	('cell proliferation', 'CPA', (98, 116))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('classic RAS-MAPK signaling cascade', 'Pathway', (62, 96))	('activation', 'PosReg', (44, 54))	('neurofibromin', 'Gene', '4763', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('Loss', 'Var', (0, 4))	('neurofibromin', 'Gene', (19, 32))
108413	32272491	Overactivation of the RAS-MAPK signaling cascade has been implicated in the development of a number of malignancies; perhaps the most well known is melanoma.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('RAS-MAPK signaling cascade', 'Pathway', (22, 48))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('implicated', 'Reg', (58, 68))	('malignancies', 'Disease', (103, 115))	('Overactivation', 'Var', (0, 14))
108414	32272491	In melanoma, inhibition of the signaling pathway components RAF and MEK results in improved response rates and overall survival in comparison with conventional chemotherapy or BRAF inhibitors alone 3, 4, 5, 6.	('improved', 'PosReg', (83, 91))	('MEK', 'Gene', '5609', (68, 71))	('overall survival', 'CPA', (111, 127))	('inhibition', 'Var', (13, 23))	('RAF', 'Gene', '22882', (177, 180))	('RAF', 'Gene', (177, 180))	('RAF', 'Gene', '22882', (60, 63))	('RAF', 'Gene', (60, 63))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('response rates', 'CPA', (92, 106))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('MEK', 'Gene', (68, 71))
108438	32272491	PNs are also associated with a risk of malignant transformation to malignant peripheral nerve sheath tumors, the leading cause of mortality in NF1 25, 26, 27.	('PNs', 'Phenotype', 'HP:0009732', (0, 3))	('mortality', 'Disease', 'MESH:D003643', (130, 139))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (67, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mortality', 'Disease', (130, 139))	('NF1', 'Gene', (143, 146))	('PNs', 'Var', (0, 3))	('malignant transformation', 'CPA', (39, 63))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (67, 107))	('NF1', 'Gene', '4763', (143, 146))	('malignant peripheral nerve sheath tumors', 'Disease', (67, 107))
108441	32272491	demonstrated that inhibition of MEK with the oral inhibitor selumetinib in pediatric NF1-associated PNs resulted in >20% volumetric tumor shrinkage in 70% of patients 30.	('PNs', 'Phenotype', 'HP:0009732', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NF1', 'Gene', (85, 88))	('NF1', 'Gene', '4763', (85, 88))	('tumor', 'Disease', (132, 137))	('selumetinib', 'Chemical', 'MESH:C517975', (60, 71))	('inhibition', 'Var', (18, 28))	('MEK', 'Gene', (32, 35))	('patients', 'Species', '9606', (158, 166))	('MEK', 'Gene', '5609', (32, 35))
108539	32272491	Therefore, MEK inhibition may represent a novel medical therapy in a disease population with previously limited therapy options.	('MEK', 'Gene', (11, 14))	('MEK', 'Gene', '5609', (11, 14))	('inhibition', 'Var', (15, 25))
108571	30388617	Knockdown of MALAT1 was shown to inhibit cell migration, but not proliferation, in glioblastoma cell lines LN-229, LN-18, and LN-428.	('proliferation', 'CPA', (65, 78))	('MALAT1', 'Gene', (13, 19))	('Knockdown', 'Var', (0, 9))	('cell migration', 'CPA', (41, 55))	('inhibit', 'NegReg', (33, 40))	('LN-229', 'CellLine', 'CVCL:0393', (107, 113))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('MALAT1', 'Gene', '378938', (13, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
108572	30388617	reported the different results in human glioma cell lines U87 and U251 that knockdown of MALAT1 promotes cell proliferation and invasion, whereas overexpression of MALAT1 induces reductions in cell proliferation and invasion in vitro and tumorigenicity in both subcutaneous and intracranial human glioma xenograft models.	('human', 'Species', '9606', (34, 39))	('MALAT1', 'Gene', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('glioma', 'Disease', (297, 303))	('reductions', 'NegReg', (179, 189))	('glioma', 'Disease', 'MESH:D005910', (297, 303))	('MALAT1', 'Gene', '378938', (89, 95))	('cell proliferation', 'CPA', (193, 211))	('cell proliferation', 'CPA', (105, 123))	('knockdown', 'Var', (76, 85))	('U251', 'CellLine', 'CVCL:0021', (66, 70))	('invasion', 'CPA', (216, 224))	('glioma', 'Phenotype', 'HP:0009733', (297, 303))	('invasion', 'CPA', (128, 136))	('MALAT1', 'Gene', (164, 170))	('promotes', 'PosReg', (96, 104))	('glioma', 'Disease', (40, 46))	('tumor', 'Disease', (238, 243))	('MALAT1', 'Gene', '378938', (164, 170))	('human', 'Species', '9606', (291, 296))	('U87', 'CellLine', 'CVCL:0022', (58, 61))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
108583	30388617	Knockdown of HOTAIR can also increase permeability of the blood-tumor barrier (BTB) by reducing tight junction-related proteins in glioma microvascular endothelial cells via the miR-148b-3p/USF1 pathway, facilitating the delivery of antineoplastic drugs.	('glioma', 'Disease', (131, 137))	('facilitating', 'PosReg', (204, 216))	('USF1', 'Gene', '7391', (190, 194))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('permeability', 'MPA', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('blood-tumor', 'Disease', 'MESH:D009383', (58, 69))	('increase', 'PosReg', (29, 37))	('reducing', 'NegReg', (87, 95))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('USF1', 'Gene', (190, 194))	('blood-tumor', 'Disease', (58, 69))	('miR-148b', 'Gene', '442892', (178, 186))	('tight junction-related proteins', 'MPA', (96, 127))	('miR-148b', 'Gene', (178, 186))	('HOTAIR', 'Gene', '100124700', (13, 19))	('delivery', 'MPA', (221, 229))	('Knockdown', 'Var', (0, 9))	('HOTAIR', 'Gene', (13, 19))
108587	30388617	In this study, the authors showed that the antisense lncRNA of FOXM1, FOXM1-AS, facilitates nuclear interaction of ALKBH5 and FOXM1 pre-mRNA and that FOXM1-AS is critical for GSC tumorigenesis through the FOXM1 axis in vitro and in a mouse intracranial xenograft model.	('ALKBH5', 'Gene', (115, 121))	('FOXM1-AS', 'Gene', (70, 78))	('mouse', 'Species', '10090', (234, 239))	('GSC', 'Disease', (175, 178))	('FOXM1-AS', 'Var', (150, 158))	('facilitates', 'PosReg', (80, 91))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('FOXM1', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('FOXM1', 'Gene', (63, 68))	('nuclear interaction', 'MPA', (92, 111))	('tumor', 'Disease', (179, 184))
108604	30388617	GAS5 increases the expression of tumor suppressor Bcl-2-modifying factor (bmf) and Plexin C1, and it plays the anti-oncogenic role in glioma cells by directly targeting miR-222.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('expression', 'MPA', (19, 29))	('miR-222', 'Gene', (169, 176))	('anti-oncogenic role', 'CPA', (111, 130))	('Bcl-2-modifying factor', 'Gene', (50, 72))	('Plexin C1', 'Gene', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Plexin C1', 'Gene', '10154', (83, 92))	('increases', 'PosReg', (5, 14))	('GAS5', 'Var', (0, 4))	('glioma', 'Disease', (134, 140))	('tumor', 'Disease', (33, 38))	('Bcl-2-modifying factor', 'Gene', '90427', (50, 72))	('targeting', 'Reg', (159, 168))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
108609	30388617	They found that high levels of GAS5 were associated with decreased likelihood of death, recurrence, and progression in GBM patients, and they concluded that GAS5 level could serve as a reciprocal prognostic predictor of survival and disease progression in GBM patients.	('GAS5', 'MPA', (31, 35))	('recurrence', 'CPA', (88, 98))	('decreased likelihood of death', 'Disease', (57, 86))	('decreased likelihood of death', 'Disease', 'MESH:D003643', (57, 86))	('high', 'Var', (16, 20))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (260, 268))
108612	30388617	Overexpression of H19 promotes invasion, angiogenesis, and stemness of GBM cells in vitro, and it is associated with increased tumor growth in the murine xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('promotes', 'PosReg', (22, 30))	('increased', 'PosReg', (117, 126))	('tumor', 'Disease', (127, 132))	('H19', 'Gene', (18, 21))	('stemness of', 'CPA', (59, 70))	('invasion', 'CPA', (31, 39))	('angiogenesis', 'CPA', (41, 53))	('Overexpression', 'Var', (0, 14))	('murine', 'Species', '10090', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
108616	30388617	Targeting H19 may overcome TMZ resistance in glioma by suppressing the EMT via the Wnt/beta-catenin pathway.	('beta-catenin', 'Gene', (87, 99))	('H19', 'Gene', (10, 13))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('EMT', 'CPA', (71, 74))	('beta-catenin', 'Gene', '1499', (87, 99))	('suppressing', 'NegReg', (55, 66))	('TMZ', 'Chemical', 'MESH:D000077204', (27, 30))	('Targeting', 'Var', (0, 9))	('glioma', 'Disease', (45, 51))
108619	30388617	Knockdown of XIST exerts a glioma-suppressive function by inhibiting cell proliferation, migration, and invasion and tumor angiogenesis and inducing apoptosis; the in vivo studies also showed that knockdown of XIST suppresses tumor growth and prolongs the survival of tumor-bearing nude mice.	('survival', 'CPA', (256, 264))	('XIST', 'Gene', (13, 17))	('knockdown', 'Var', (197, 206))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('glioma', 'Disease', (27, 33))	('apoptosis', 'CPA', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('inhibiting', 'NegReg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('XIST', 'Gene', (210, 214))	('invasion', 'CPA', (104, 112))	('suppresses', 'NegReg', (215, 225))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('nude mice', 'Species', '10090', (282, 291))	('inducing', 'Reg', (140, 148))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (268, 273))	('prolongs', 'PosReg', (243, 251))	('cell proliferation', 'CPA', (69, 87))	('migration', 'CPA', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (226, 231))
108621	30388617	The inhibition of XIST can also increase blood-tumor barrier permeability, facilitating the delivery of antitumor drugs to a brain tumor.	('delivery', 'MPA', (92, 100))	('tumor', 'Disease', (108, 113))	('inhibition', 'Var', (4, 14))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('facilitating', 'PosReg', (75, 87))	('blood-tumor', 'Disease', 'MESH:D009383', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('XIST', 'Gene', (18, 22))	('tumor', 'Disease', (47, 52))	('brain tumor', 'Phenotype', 'HP:0030692', (125, 136))	('increase', 'PosReg', (32, 40))	('blood-tumor', 'Disease', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('brain tumor', 'Disease', (125, 136))	('brain tumor', 'Disease', 'MESH:D001932', (125, 136))
108628	30388617	In the in vivo studies, knockdown of CRNDE was demonstrated to delay the tumor formation and lead to tumor regression in tumor-bearing nude mice.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('nude mice', 'Species', '10090', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('delay', 'NegReg', (63, 68))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (73, 78))	('lead to', 'Reg', (93, 100))	('knockdown', 'Var', (24, 33))	('CRNDE', 'Protein', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
108641	30388617	In addition, in a subcutaneous xenograft mouse model, the in vivo study showed that tumors with knockdown of HCP5 and overexpression of miR-139 had the lowest volume and weight and the corresponding tumor-bearing mice had the longest survival time.	('tumor', 'Disease', (199, 204))	('knockdown', 'Var', (96, 105))	('miR-139', 'Gene', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('overexpression', 'PosReg', (118, 132))	('HCP5', 'Gene', '10866', (109, 113))	('HCP5', 'Gene', (109, 113))	('mice', 'Species', '10090', (213, 217))	('mouse', 'Species', '10090', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-139', 'Gene', '387157', (136, 143))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('lowest', 'NegReg', (152, 158))
108648	30388617	The in vivo study in a subcutaneous xenograft mouse model also showed that overexpression of RAMP2-AS1 significantly suppresses tumor growth.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mouse', 'Species', '10090', (46, 51))	('suppresses', 'NegReg', (117, 127))	('RAMP2-AS1', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
108684	30388617	analyzing HOTAIR level in serum samples from 106 GBM patients showed that a high level of HOTAIR in patient's serum is associated with increased likelihood of death (adjusted HR = 2.04, 95% confidence interval [CI] = 1.08-9.76), recurrence, and progression (adjusted HR = 1.82, 95% CI = 1.04-6.17).	('progression', 'CPA', (245, 256))	('HOTAIR', 'Gene', (90, 96))	('HOTAIR', 'Gene', '100124700', (90, 96))	('HOTAIR', 'Gene', '100124700', (10, 16))	('patients', 'Species', '9606', (53, 61))	('recurrence', 'CPA', (229, 239))	('patient', 'Species', '9606', (100, 107))	('death', 'Disease', 'MESH:D003643', (159, 164))	('HOTAIR', 'Gene', (10, 16))	('high', 'Var', (76, 80))	('death', 'Disease', (159, 164))	('patient', 'Species', '9606', (53, 60))
108693	30388617	Then, the authors used the Kaplan-Meier method to analyze progression-free survival for patients in the high-expression and low-expression groups, and they found that a high level of H19 is significantly associated with a poor progression-free survival rate (p = 0.022).	('high level', 'Var', (169, 179))	('poor', 'NegReg', (222, 226))	('patients', 'Species', '9606', (88, 96))	('H19', 'Protein', (183, 186))	('progression-free survival rate', 'CPA', (227, 257))
108695	30388617	The Kaplan-Meier overall survival curves showed that the survival time of glioma patients with high XIST levels is shorter than that in patients with low XIST levels (p = 0.0007).	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('patients', 'Species', '9606', (81, 89))	('shorter', 'NegReg', (115, 122))	('glioma', 'Disease', (74, 80))	('patients', 'Species', '9606', (136, 144))	('high XIST levels', 'Var', (95, 111))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('survival time', 'CPA', (57, 70))
108696	30388617	By using a multivariate Cox proportional hazard model, they found that high XIST expression is of high risk (HR = 2.037, 95% CI = 1.083-3.831).	('high XIST', 'Var', (71, 80))	('Cox', 'Gene', (24, 27))	('Cox', 'Gene', '1351', (24, 27))
108699	30388617	By univariate Cox regression analysis, they found that the overall survival rate is significantly lower in patients with CASC2c high expression (p = 0.008); by multivariate Cox proportional hazard regression analysis, they found that a high expression of CASC2c in astrocytoma is an independent prognostic factor of overall survival (HR = 1.98, 95% CI = 1.94-2.26).	('CASC2', 'Gene', (121, 126))	('CASC2', 'Gene', '255082', (255, 260))	('CASC2', 'Gene', '255082', (121, 126))	('astrocytoma', 'Disease', 'MESH:D001254', (265, 276))	('high', 'Var', (236, 240))	('astrocytoma', 'Disease', (265, 276))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (265, 276))	('Cox', 'Gene', '1351', (173, 176))	('Cox', 'Gene', (173, 176))	('overall', 'Disease', (316, 323))	('CASC2', 'Gene', (255, 260))	('patients', 'Species', '9606', (107, 115))	('lower', 'NegReg', (98, 103))
108702	30388617	They showed that a high level of GAS5 is associated with decreased likelihood of death (adjusted HR = 0.44, 95% CI = 0.18-0.99), recurrence, and progression (adjusted HR = 0.46, 95% CI = 0.16-0.98).	('decreased likelihood of death', 'Disease', (57, 86))	('decreased likelihood of death', 'Disease', 'MESH:D003643', (57, 86))	('recurrence', 'CPA', (129, 139))	('high level', 'Var', (19, 29))	('progression', 'CPA', (145, 156))	('GAS5', 'Protein', (33, 37))
108715	30388617	In the phenotype of viability, MALAT1, HOTAIR, HOXA11-AS, XIST, CRNDE, NEAT1, and HCP5 are shown to inhibit cell apoptosis, whereas GAS5, HOTTIP, and CASC2a are found to promote apoptosis.	('HOXA11-AS', 'Gene', (47, 56))	('NEAT1', 'Gene', (71, 76))	('CRNDE', 'Var', (64, 69))	('inhibit', 'NegReg', (100, 107))	('HOTAIR', 'Gene', (39, 45))	('MALAT1', 'Gene', (31, 37))	('HCP5', 'Gene', '10866', (82, 86))	('HCP5', 'Gene', (82, 86))	('CASC2', 'Gene', (150, 155))	('HOTAIR', 'Gene', '100124700', (39, 45))	('NEAT1', 'Gene', '283131', (71, 76))	('CASC2', 'Gene', '255082', (150, 155))	('MALAT1', 'Gene', '378938', (31, 37))	('cell apoptosis', 'CPA', (108, 122))	('HOXA11-AS', 'Gene', '221883', (47, 56))
108716	30388617	H19, XIST, and linc-POU3F3 are found to promote angiogenesis, which is crucial for glioma tumorigenesis and survival.	('glioma', 'Disease', (83, 89))	('promote', 'PosReg', (40, 47))	('H19', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('linc-POU3F3', 'Gene', (15, 26))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('linc-POU3F3', 'Gene', '100506421', (15, 26))	('angiogenesis', 'CPA', (48, 60))
108728	32444979	They are characterized by a mutation in the isocitrate dehydrogenase (IDH) enzyme and include astrocytomas and oligodendrogliomas.	('isocitrate dehydrogenase', 'Gene', (44, 68))	('IDH', 'Gene', (70, 73))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('isocitrate dehydrogenase', 'Gene', '3417', (44, 68))	('IDH', 'Gene', '3417', (70, 73))	('mutation', 'Var', (28, 36))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (94, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
108730	32444979	Advanced studies on the cellular level have an advanced understanding of the metabolic effects induced by IDH mutations, offering opportunities for specific targeted therapies that may improve patient outcomes.	('patient', 'Species', '9606', (193, 200))	('mutations', 'Var', (110, 119))	('IDH', 'Gene', (106, 109))	('IDH', 'Gene', '3417', (106, 109))
108737	32444979	Furthermore, in this classification, the molecular phenotype trumps the histopathological one and depends primarily on the isocitrate dehydrogenase (IDH) enzyme mutation status.	('IDH', 'Gene', (149, 152))	('mutation', 'Var', (161, 169))	('IDH', 'Gene', '3417', (149, 152))	('isocitrate dehydrogenase', 'Gene', (123, 147))	('isocitrate dehydrogenase', 'Gene', '3417', (123, 147))
108740	32444979	Interestingly, the incidence of IDH1 and IDH2 mutations is elevated in gliomas.	('mutations', 'Var', (46, 55))	('gliomas', 'Disease', (71, 78))	('IDH1', 'Gene', (32, 36))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('IDH1', 'Gene', '3417', (32, 36))	('IDH2', 'Gene', (41, 45))	('elevated', 'PosReg', (59, 67))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH2', 'Gene', '3418', (41, 45))
108742	32444979	Ninety-five percent of IDH mutations are found in the IDH1 isoform, with the most common mutation type consisting of a point mutation involving the arginine amino acid at codon 132, transforming it to histidine (R132H) in 92.7%, and less commonly to cysteine (R132C) in 3.6%, serine (R132S) in 1.8%, and glycine (R132G) in 0.9%.	('mutations', 'Var', (27, 36))	('glycine', 'Chemical', 'MESH:D005998', (304, 311))	('point mutation', 'Var', (119, 133))	('R132H', 'SUBSTITUTION', 'None', (212, 217))	('histidine', 'Chemical', 'MESH:D006639', (201, 210))	('IDH1', 'Gene', (54, 58))	('R132G', 'Mutation', 'rs121913499', (313, 318))	('IDH', 'Gene', (54, 57))	('IDH', 'Gene', (23, 26))	('R132C', 'Mutation', 'rs121913499', (260, 265))	('IDH1', 'Gene', '3417', (54, 58))	('R132S', 'Var', (284, 289))	('IDH', 'Gene', '3417', (54, 57))	('arginine amino acid', 'Chemical', '-', (148, 167))	('IDH', 'Gene', '3417', (23, 26))	('R132S', 'SUBSTITUTION', 'None', (284, 289))	('cysteine', 'Chemical', 'MESH:D003545', (250, 258))	('serine', 'Chemical', 'MESH:D012694', (276, 282))	('R132H', 'Var', (212, 217))
108743	32444979	The presence of IDH mutation in the vast majority of glioma cells and its higher prevalence in WHO grade II and III gliomas suggest that it is involved in the early steps of gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('glioma', 'Disease', (53, 59))	('involved', 'Reg', (143, 151))	('mutation', 'Var', (20, 28))	('glioma', 'Disease', (116, 122))	('IDH', 'Gene', (16, 19))	('III gliomas', 'Disease', 'MESH:D005910', (112, 123))	('glioma', 'Disease', (174, 180))	('IDH', 'Gene', '3417', (16, 19))	('III gliomas', 'Disease', (112, 123))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
108745	32444979	The first two pathways consist of an IDH mutation followed by either a mutation of the tumor suppressor gene TP53 and loss of transcriptional factor ATRX to differentiate into an astrocytoma, or loss of heterozygosity of chromosomes 1p and 19q (1p/19q codel) to form an oligodendroglioma.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (179, 190))	('form', 'Reg', (262, 266))	('ATRX', 'Gene', (149, 153))	('ATRX', 'Gene', '546', (149, 153))	('loss of heterozygosity', 'Var', (195, 217))	('TP53', 'Gene', '7157', (109, 113))	('mutation', 'Var', (41, 49))	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('astrocytoma', 'Disease', 'MESH:D001254', (179, 190))	('oligodendroglioma', 'Disease', 'MESH:D009837', (270, 287))	('astrocytoma', 'Disease', (179, 190))	('tumor', 'Disease', (87, 92))	('oligodendroglioma', 'Disease', (270, 287))	('IDH', 'Gene', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (109, 113))	('IDH', 'Gene', '3417', (37, 40))
108747	32444979	Further molecular studies identified mutations in TERT (telomerase reverse transcriptase), FUBP1 (far upstream element-binding protein 1), and CIC (capicua transcriptional repressor) in oligodendrogliomas.	('oligodendrogliomas', 'Disease', (186, 204))	('FUBP1', 'Gene', (91, 96))	('TERT', 'Gene', '7015', (50, 54))	('far upstream element-binding protein 1', 'Gene', '8880', (98, 136))	('gliomas', 'Phenotype', 'HP:0009733', (197, 204))	('far upstream element-binding protein 1', 'Gene', (98, 136))	('telomerase reverse transcriptase', 'Gene', (56, 88))	('CIC (capicua transcriptional repressor', 'Gene', '23152', (143, 181))	('mutations', 'Var', (37, 46))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (186, 204))	('FUBP1', 'Gene', '8880', (91, 96))	('telomerase reverse transcriptase', 'Gene', '7015', (56, 88))	('TERT', 'Gene', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
108748	32444979	Tumor evolution studies have demonstrated that the development of an IDH mutation precedes the acquisition of other associated genetic events, such as TP53 mutation, suggesting it is an early, driver mutation.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', (151, 155))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (69, 72))	('mutation', 'Var', (73, 81))	('TP53', 'Gene', '7157', (151, 155))
108749	32444979	An integrative genomic analysis, performed on 293 glioma patients by the Cancer Genome Atlas Network, showed that patients with oligodendrogliomas (IDH-mutant, 1p/19q codel) had a better overall survival (OS) than those with astrocytomas , which was consistent with other reports.	('glioma', 'Disease', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (128, 146))	('astrocytomas', 'Disease', 'MESH:D001254', (225, 237))	('astrocytoma', 'Phenotype', 'HP:0009592', (225, 236))	('glioma', 'Disease', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('patients', 'Species', '9606', (114, 122))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('1p/19q codel', 'Var', (160, 172))	('overall survival', 'MPA', (187, 203))	('oligodendrogliomas', 'Disease', (128, 146))	('IDH', 'Gene', (148, 151))	('Cancer', 'Disease', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('astrocytomas', 'Disease', (225, 237))	('patients', 'Species', '9606', (57, 65))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('IDH', 'Gene', '3417', (148, 151))	('better', 'PosReg', (180, 186))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))
108763	32444979	Other imaging modalities were developed to increase the imaging diagnostic accuracy, the most relevant of which is magnetic resonance spectroscopy (MRS) that detects peaks of 2-hydroxyglutarate (2-HG), a product of a redox reaction catalyzed by a mutant IDH .	('mutant', 'Var', (247, 253))	('IDH', 'Gene', (254, 257))	('2-HG', 'Chemical', 'MESH:C019417', (195, 199))	('IDH', 'Gene', '3417', (254, 257))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (175, 193))
108768	32444979	More recent studies have reported that homozygous loss of chromosome 9p21 with loss of CDKN2A, a common phenomenon in higher WHO grade gliomas, is also associated with a worse outcome in IDH-mutant astrocytomas and oligodendrogliomas.	('loss', 'NegReg', (79, 83))	('CDKN2A', 'Gene', '1029', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('IDH', 'Gene', (187, 190))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('astrocytoma', 'Phenotype', 'HP:0009592', (198, 209))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('IDH', 'Gene', '3417', (187, 190))	('homozygous loss', 'Var', (39, 54))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', (226, 233))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (198, 233))	('CDKN2A', 'Gene', (87, 93))
108790	32444979	Additional results presented at the American Society for Radiation Oncology (ASTRO) meeting in 2019 also showed that median OS following combination therapy was longer in IDH-mutant, 1p/19q codel oligodendrogliomas.	('Oncology', 'Phenotype', 'HP:0002664', (67, 75))	('IDH', 'Gene', '3417', (171, 174))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (196, 214))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('longer', 'PosReg', (161, 167))	('oligodendrogliomas', 'Disease', (196, 214))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('1p/19q codel', 'Var', (183, 195))	('IDH', 'Gene', (171, 174))
108792	32444979	Although no difference in survival was observed between the two treatment arms in the entire population, a long-term follow-up revealed that combination therapy was associated with a better OS in patients with tumors with 1p/19q co-deletion .	('1p/19q co-deletion', 'Var', (222, 240))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('patients', 'Species', '9606', (196, 204))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('better', 'PosReg', (183, 189))
108794	32444979	Molecular profiling further revealed a trend towards benefit specifically for patients with tumors with 1p/19q co-deletion .	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('1p/19q co-deletion', 'Var', (104, 122))	('benefit', 'PosReg', (53, 60))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
108810	32444979	IDH mutation is not specific to gliomas and has been found in other malignancies, namely acute myeloid leukemia, cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndromes.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (95, 111))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (153, 178))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('mutation', 'Var', (4, 12))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (89, 111))	('IDH', 'Gene', (0, 3))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (89, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (113, 131))	('chondrosarcoma', 'Disease', (133, 147))	('chondrosarcoma', 'Disease', 'MESH:D002813', (133, 147))	('cholangiocarcinoma', 'Disease', (113, 131))	('gliomas', 'Disease', (32, 39))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (113, 131))	('IDH', 'Gene', '3417', (0, 3))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (153, 178))	('myelodysplastic syndromes', 'Disease', (153, 178))	('found', 'Reg', (53, 58))	('malignancies', 'Disease', (68, 80))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (133, 147))	('acute myeloid leukemia', 'Disease', (89, 111))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
108816	32444979	On the other hand, IDH mutation and elevated 2-HG levels inhibit certain anti-apoptotic proteins and DNA repair enzymes and reduce the intracellular glutathione level, leading to a lower threshold for apoptosis with enhanced sensitivity to alkylating agents and to radiation through reactive oxygen species.	('DNA', 'MPA', (101, 104))	('anti-apoptotic proteins', 'Pathway', (73, 96))	('mutation', 'Var', (23, 31))	('intracellular glutathione level', 'MPA', (135, 166))	('enhanced', 'PosReg', (216, 224))	('lower', 'NegReg', (181, 186))	('2-HG', 'Chemical', 'MESH:C019417', (45, 49))	('oxygen', 'Chemical', 'MESH:D010100', (292, 298))	('inhibit', 'NegReg', (57, 64))	('glutathione', 'Chemical', 'MESH:D005978', (149, 160))	('alkylating', 'Chemical', '-', (240, 250))	('reduce the intracellular glutathione level', 'Phenotype', 'HP:0003343', (124, 166))	('IDH', 'Gene', (19, 22))	('sensitivity', 'MPA', (225, 236))	('IDH', 'Gene', '3417', (19, 22))	('reduce', 'NegReg', (124, 130))
108819	32444979	Inhibitors of the mutant IDH enzyme specifically target the production of 2-HG, but not of alpha-KG, and have been approved in the treatment of acute myeloid leukemia (AML).	('production', 'MPA', (60, 70))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('alpha-KG', 'Chemical', 'MESH:D007656', (91, 99))	('AML', 'Phenotype', 'HP:0004808', (168, 171))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('mutant', 'Var', (18, 24))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (144, 166))	('2-HG', 'MPA', (74, 78))	('AML', 'Disease', 'MESH:D015470', (168, 171))	('acute myeloid leukemia', 'Disease', (144, 166))	('target', 'Reg', (49, 55))	('2-HG', 'Chemical', 'MESH:C019417', (74, 78))	('AML', 'Disease', (168, 171))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (144, 166))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (150, 166))
108821	32444979	Ivosidenib has been shown to have a strong selectivity to mutant IDH1 and led to reduced blood levels of 2-HG when it was used in a phase I study for treatment IDH-mutant solid tumors, including 66 recurrent or progressive gliomas.	('mutant', 'Var', (58, 64))	('gliomas', 'Disease', 'MESH:D005910', (223, 230))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', (160, 163))	('reduced', 'NegReg', (81, 88))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('IDH1', 'Gene', '3417', (65, 69))	('tumors', 'Disease', (177, 183))	('gliomas', 'Phenotype', 'HP:0009733', (223, 230))	('IDH', 'Gene', '3417', (65, 68))	('2-HG', 'Chemical', 'MESH:C019417', (105, 109))	('IDH', 'Gene', '3417', (160, 163))	('blood levels of 2-HG', 'MPA', (89, 109))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('gliomas', 'Disease', (223, 230))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('IDH1', 'Gene', (65, 69))
108833	32444979	Another IDH1-mutant inhibitor, DS-1001b, previously studied in chondrosarcoma, is currently being evaluated in LGG in a phase I clinical trial (NCT03030066).	('chondrosarcoma', 'Disease', 'MESH:D002813', (63, 77))	('IDH1', 'Gene', (8, 12))	('chondrosarcoma', 'Disease', (63, 77))	('IDH1', 'Gene', '3417', (8, 12))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (63, 77))	('DS-1001b', 'Var', (31, 39))
108836	32444979	As IDH mutation leads to reduced cellular capacity for double-stranded DNA breaks repair through interference with alpha-KG-dependent alkB homolog (ALKBH) and other DNA repair enzymes, the cells become reliant on alternative end-joining for DNA repair, a mechanism shared by BRCA1/BRCA2-deficient breast cancer cells.	('ALKBH', 'Gene', '8846', (148, 153))	('alkB', 'Gene', '8846', (134, 138))	('reduced', 'NegReg', (25, 32))	('IDH', 'Gene', '3417', (3, 6))	('BRCA1', 'Gene', '672', (275, 280))	('alpha-KG', 'Chemical', 'MESH:D007656', (115, 123))	('BRCA2-deficient breast cancer', 'Disease', 'MESH:D001943', (281, 310))	('BRCA1', 'Gene', (275, 280))	('deficient breast', 'Phenotype', 'HP:0003187', (287, 303))	('mutation', 'Var', (7, 15))	('double-stranded DNA breaks repair', 'MPA', (55, 88))	('ALKBH', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('alkB', 'Gene', (134, 138))	('interference', 'NegReg', (97, 109))	('BRCA2-deficient breast cancer', 'Disease', (281, 310))	('IDH', 'Gene', (3, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (297, 310))
108838	32444979	Indeed, preclinical studies have shown that IDH mutant glioma cells are sensitive to PARPi and that PARPi increase the sensitivity of GBM to TMZ.	('glioma', 'Disease', (55, 61))	('mutant', 'Var', (48, 54))	('PARP', 'Gene', (85, 89))	('TMZ', 'Chemical', '-', (141, 144))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('PARP', 'Gene', (100, 104))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('PARP', 'Gene', '142', (85, 89))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH', 'Gene', (44, 47))	('increase', 'PosReg', (106, 114))	('sensitive', 'MPA', (72, 81))	('PARP', 'Gene', '142', (100, 104))	('IDH', 'Gene', '3417', (44, 47))	('sensitivity', 'MPA', (119, 130))
108839	32444979	Several ongoing phase I and II studies are using Olaparib alone or in combination with radiation and chemotherapy in the treatment of recurrent IDH-mutant and high-grade gliomas (NCT03561870, NCT03212742, NCT01390571).	('IDH', 'Gene', (144, 147))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('IDH', 'Gene', '3417', (144, 147))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('gliomas', 'Disease', (170, 177))	('NCT03561870', 'Var', (179, 190))	('Olaparib', 'Chemical', 'MESH:C531550', (49, 57))	('NCT03212742', 'Var', (192, 203))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))
108843	32444979	In preclinical models, demethylation of the CTCF domain led to the restoration of the insulation process, thereby preventing the upregulation of PDGFRA.	('CTCF', 'Gene', '10664', (44, 48))	('demethylation', 'Var', (23, 36))	('insulation process', 'MPA', (86, 104))	('preventing', 'NegReg', (114, 124))	('restoration', 'MPA', (67, 78))	('PDGFRA', 'Gene', (145, 151))	('upregulation', 'PosReg', (129, 141))	('PDGFRA', 'Gene', '5156', (145, 151))	('CTCF', 'Gene', (44, 48))
108848	32444979	In preclinical models, inhibition of glutaminase renders the IDH-mutant cells more sensitive to oxidative stress and, when combined with radiation, leads to cell death.	('IDH', 'Gene', '3417', (61, 64))	('more', 'PosReg', (78, 82))	('sensitive to oxidative stress', 'MPA', (83, 112))	('inhibition', 'Var', (23, 33))	('glutaminase', 'Gene', (37, 48))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('death', 'Disease', 'MESH:D003643', (162, 167))	('leads to', 'Reg', (148, 156))	('death', 'Disease', (162, 167))	('glutaminase', 'Gene', '2744', (37, 48))	('IDH', 'Gene', (61, 64))
108851	32444979	One strategy involves an IDH1 R132H-specific vaccine.	('IDH1', 'Gene', (25, 29))	('R132H', 'Var', (30, 35))	('IDH1', 'Gene', '3417', (25, 29))	('R132H', 'SUBSTITUTION', 'None', (30, 35))
108853	32444979	NOA-16 was a phase I clinical trial (NCT02454634) that evaluated safety and immunogenicity of an IDH1 R132H peptide vaccine administered to 32 patients with newly diagnosed grade III and grade IV IDH-mutant gliomas during the adjuvant temozolomide phase of treatment.	('IDH1', 'Gene', (97, 101))	('gliomas', 'Disease', (207, 214))	('IDH', 'Gene', '3417', (196, 199))	('IDH', 'Gene', (97, 100))	('gliomas', 'Disease', 'MESH:D005910', (207, 214))	('IDH1', 'Gene', '3417', (97, 101))	('R132H', 'SUBSTITUTION', 'None', (102, 107))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('patients', 'Species', '9606', (143, 151))	('IDH', 'Gene', '3417', (97, 100))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('R132H', 'Var', (102, 107))	('temozolomide', 'Chemical', 'MESH:D000077204', (235, 247))	('IDH', 'Gene', (196, 199))
108859	32444979	A major challenge to employing any immunotherapy approach in IDH-mutant gliomas is recent evidence that 2-HG produced by the mutant IDH enzyme creates an immunosuppressive tumor microenvironment.	('2-HG', 'MPA', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('IDH', 'Gene', '3417', (61, 64))	('mutant', 'Var', (125, 131))	('tumor', 'Disease', (172, 177))	('2-HG', 'Chemical', 'MESH:C019417', (104, 108))	('IDH', 'Gene', (132, 135))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('IDH', 'Gene', '3417', (132, 135))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('IDH', 'Gene', (61, 64))	('gliomas', 'Disease', (72, 79))
108862	32444979	LGG consist of IDH-mutant WHO grade II and III gliomas, which can be further subcategorized into IDH-mutant, 1p/19 codeleted gliomas or oligodendrogliomas, and IDH-mutant, 1p/19q retained, p53-mutant, ATRX-mutant gliomas, or astrocytomas.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (136, 154))	('gliomas', 'Disease', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('IDH', 'Gene', (97, 100))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('IDH', 'Gene', (160, 163))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Disease', (147, 154))	('astrocytomas', 'Disease', 'MESH:D001254', (225, 237))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('astrocytoma', 'Phenotype', 'HP:0009592', (225, 236))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('III gliomas', 'Disease', 'MESH:D005910', (43, 54))	('IDH', 'Gene', '3417', (97, 100))	('oligodendrogliomas', 'Disease', (136, 154))	('IDH', 'Gene', (15, 18))	('ATRX', 'Gene', (201, 205))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('IDH', 'Gene', '3417', (160, 163))	('ATRX', 'Gene', '546', (201, 205))	('p53', 'Gene', '7157', (189, 192))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('gliomas', 'Disease', (213, 220))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('III gliomas', 'Disease', (43, 54))	('IDH', 'Gene', '3417', (15, 18))	('astrocytomas', 'Disease', (225, 237))	('p53', 'Gene', (189, 192))	('1p/19q retained', 'Var', (172, 187))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))
108870	32444979	Finally, given that CDKN2A mutations have been linked to a worse prognosis and a high likelihood of malignant progression, CDK4/6 inhibitors, which are currently used in breast cancer and have been studied in glioblastoma, can also be of interest in the treatment of patients with IDH-mutant gliomas.	('mutations', 'Var', (27, 36))	('CDK4/6', 'Gene', '1019;1021', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('CDKN2A', 'Gene', '1029', (20, 26))	('gliomas', 'Phenotype', 'HP:0009733', (292, 299))	('IDH', 'Gene', '3417', (281, 284))	('patients', 'Species', '9606', (267, 275))	('glioblastoma', 'Disease', 'MESH:D005909', (209, 221))	('linked', 'Reg', (47, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('glioblastoma', 'Disease', (209, 221))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (209, 221))	('CDK4/6', 'Gene', (123, 129))	('breast cancer', 'Disease', (170, 183))	('gliomas', 'Disease', (292, 299))	('CDKN2A', 'Gene', (20, 26))	('gliomas', 'Disease', 'MESH:D005910', (292, 299))	('IDH', 'Gene', (281, 284))
108881	31877896	The extent of surgical resection (EOR) and the molecular classification of LGGs based on IDH mutation and 1p/19q chromosome deletion have recently been shown to have prognostic significance.	('LGGs', 'Disease', (75, 79))	('mutation', 'Var', (93, 101))	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', (89, 92))
108895	31877896	DeltaVT2T1 is considered an index of tumor infiltration.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('DeltaVT2T1', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
108897	31877896	The distribution of LGGs according to the 2016 WHO classification of brain tumors was diffuse astrocytomas, IDH-mutant (astrocytomas IDHmt), oligodendrogliomas, IDH-mutant, and 1p/19q-codeleted (oligodendrogliomas), and diffuse astrocytoma, IDH-wildtype (astrocytomas IDHwt) in 56.8%, 32.0%, and 11.2%, of cases, respectively.	('IDH', 'Gene', '3417', (241, 244))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('IDH', 'Gene', '3417', (161, 164))	('astrocytoma', 'Phenotype', 'HP:0009592', (255, 266))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (141, 159))	('IDH', 'Gene', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (195, 213))	('IDH', 'Gene', (108, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('IDH', 'Gene', (268, 271))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('1p/19q-codeleted', 'Var', (177, 193))	('astrocytoma', 'Phenotype', 'HP:0009592', (228, 239))	('brain tumors', 'Phenotype', 'HP:0030692', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('diffuse', 'Disease', (86, 93))	('brain tumors', 'Disease', 'MESH:D001932', (69, 81))	('oligodendrogliomas', 'Disease', (141, 159))	('IDH', 'Gene', (241, 244))	('IDH', 'Gene', '3417', (133, 136))	('IDH', 'Gene', '3417', (108, 111))	('oligodendrogliomas', 'Disease', (195, 213))	('IDH', 'Gene', '3417', (268, 271))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('IDH', 'Gene', (161, 164))	('brain tumors', 'Disease', (69, 81))
108900	31877896	Among IDH mutated cases, 88.1% and 11.9% of LGGs presented mutations in IDH1 and IDH2 genes, respectively.	('IDH', 'Gene', (6, 9))	('IDH1', 'Gene', (72, 76))	('IDH', 'Gene', '3417', (6, 9))	('IDH1', 'Gene', '3417', (72, 76))	('IDH2', 'Gene', (81, 85))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('LGGs', 'Disease', (44, 48))	('mutations', 'Var', (59, 68))	('IDH', 'Gene', (81, 84))	('IDH2', 'Gene', '3418', (81, 85))	('IDH', 'Gene', '3417', (81, 84))
108901	31877896	R132H was the most frequent IDH mutation (76.1% of LGG).	('R132H', 'Mutation', 'rs121913500', (0, 5))	('IDH', 'Gene', (28, 31))	('LGG', 'Disease', (51, 54))	('IDH', 'Gene', '3417', (28, 31))	('R132H', 'Var', (0, 5))
108919	31877896	Factors identified as significantly associated with OS at univariate analysis (p < 0.05) were (Table 3): age, KPS, the pre-operative tumor volume, the infiltrative growth index DeltaVT2T1, both EOR and the post-operative tumor volume, the expression of Ki67, the presence of mutated IDH1 or IDH2 genes, the 1p/19q co-deletion, the tumor molecular class, and the methylation status of the MGMT promoter.	('OS', 'Gene', '17451', (52, 54))	('mutated', 'Var', (275, 282))	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('DeltaVT2T1', 'Gene', (177, 187))	('IDH2', 'Gene', (291, 295))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('IDH1', 'Gene', (283, 287))	('tumor', 'Disease', (331, 336))	('IDH2', 'Gene', '3418', (291, 295))	('tumor', 'Disease', (133, 138))	('IDH1', 'Gene', '3417', (283, 287))	('MGMT', 'Gene', (388, 392))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('MGMT', 'Gene', '4255', (388, 392))
108922	31877896	As shown in Table 3, tumor site, both pre-operative and post-operative tumor volumes, DeltaVT2T1, EOR, Ki67 expression, IDH1/2 gene mutation, 1p/19q co-deletion, molecular class, and methylation status of the MGMT promoter were associated with PFS at Cox univariate analysis.	('PFS', 'Disease', (244, 247))	('Cox', 'Gene', '1351', (251, 254))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('Cox', 'Gene', (251, 254))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('IDH1/2', 'Gene', (120, 126))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('1p/19q co-deletion', 'Var', (142, 160))	('MGMT', 'Gene', (209, 213))	('associated', 'Reg', (228, 238))	('mutation', 'Var', (132, 140))	('MGMT', 'Gene', '4255', (209, 213))	('DeltaVT2T1', 'Gene', (86, 96))
108940	31877896	In particular, 83.3% of patients with Ki67 <=5% were able to survive beyond 5 years (mOS 88.5 months).	('mOS', 'Gene', (85, 88))	('patients', 'Species', '9606', (24, 32))	('Ki67 <=5%', 'Var', (38, 47))	('mOS', 'Gene', '17451', (85, 88))
108946	31877896	In astrocytoma IDHmt, a Ki67% <=4% further improved the prognosis.	('astrocytoma', 'Phenotype', 'HP:0009592', (3, 14))	('Ki67% <=4%', 'Var', (24, 34))	('IDH', 'Gene', (15, 18))	('improved', 'PosReg', (43, 51))	('IDH', 'Gene', '3417', (15, 18))
108968	31877896	In these cases, EOR was the major predictor of outcome: if it was <=86%, it predicted death within 10 years with a PPV of 90%, while if it was >86%, combined with a low proliferation index (Ki67 <=4%), it predicted long survival with a PPV of 64.7% (Figure 5).	('<=86', 'Var', (66, 70))	('death', 'Disease', 'MESH:D003643', (86, 91))	('long survival', 'CPA', (215, 228))	('death', 'Disease', (86, 91))
108983	31877896	We were also able to confirm the prognostic role of the DeltaVT2T1 index, which is indicative of tumor infiltration.	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('DeltaVT2T1', 'Var', (56, 66))
108993	31877896	In IDHwt, age and Ki67, but not EOR, were the major predictors of outcome; IDHwt patients with a Ki67 of >6% did not survive more than three years, while only those with an age of <28 years and Ki67 of <=2% survived more than 5 years.	('IDH', 'Gene', '3417', (3, 6))	('patients', 'Species', '9606', (81, 89))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('Ki67', 'Var', (97, 101))	('IDH', 'Gene', (3, 6))
109004	31877896	For each patient, the following data had to be available: age, gender, Karnofsky performace status (KPS), molecular classification according to WHO 2016, Ki67 expression, pre-and post-operative tumor volume, extent of resection (EOR), and preoperative infiltration index expressed by the DeltaVT2T1 value, as evaluated by magnetic resonance imaging (MRI, see below).	('DeltaVT2T1', 'Var', (288, 298))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('patient', 'Species', '9606', (9, 16))
109007	31877896	Histological examination, immunohistochemistry (IHC) for Ki67, p53, and ATRX (Supplementary Figure S3), evaluation of 1p/19q co-deletion by FISH and assessment of IDH1/2 gene mutations, and of the methylation status of the MGMT promoter were performed as in.	('MGMT', 'Gene', (223, 227))	('ATRX', 'Gene', '546', (72, 76))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('MGMT', 'Gene', '4255', (223, 227))	('ATRX', 'Gene', (72, 76))	('mutations', 'Var', (175, 184))	('IDH1/2', 'Gene', (163, 169))
109029	29666413	When texture analysis and SVM were utilized, the grading accuracy achieved by DKI biomarkers was 78.1% (sensitivity 0.77, specificity 0.79, AUC 0.79); the prediction accuracy for IDH mutation reached 83.8% (sensitivity 0.96, specificity 0.55, AUC 0.87).	('IDH', 'Gene', '3417', (179, 182))	('IDH', 'Gene', (179, 182))	('mutation', 'Var', (183, 191))
109042	29666413	In light of the 2016 update of the WHO brain tumor classification that stipulates an integrated, 'layered' diagnosis based on histological and molecular features, isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations play a key role in the classification of gliomas.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('brain tumor', 'Disease', (39, 50))	('IDH1', 'Gene', (197, 201))	('brain tumor', 'Disease', 'MESH:D001932', (39, 50))	('gliomas', 'Phenotype', 'HP:0009733', (263, 270))	('gliomas', 'Disease', (263, 270))	('brain tumor', 'Phenotype', 'HP:0030692', (39, 50))	('gliomas', 'Disease', 'MESH:D005910', (263, 270))	('IDH2', 'Gene', (206, 210))	('mutations', 'Var', (212, 221))	('IDH1', 'Gene', '3417', (197, 201))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('IDH2', 'Gene', '3418', (206, 210))
109045	29666413	According to the new biomarker-driven WHO classification, a proportion of these tumours, in particular those without IDH mutation and 1p/19q co-deletion, probably have represented IDH wild-type glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (194, 207))	('1p/19q co-deletion', 'Var', (134, 152))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('glioblastomas', 'Disease', (194, 207))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', (180, 183))	('IDH', 'Gene', '3417', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('IDH', 'Gene', '3417', (180, 183))	('glioblastomas', 'Phenotype', 'HP:0012174', (194, 207))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))
109046	29666413	but essentially highlight that (i) the methodology for obtaining DWI parameters in tumor plays a crucial role given the spatial heterogeneity and (ii) the ADC might be not the most appropriate parameter to gauge any altered diffusion properties related to the IDH mutation, and DKI should be employed to improve the diagnostic accuracy.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('IDH', 'Gene', (260, 263))	('mutation', 'Var', (264, 272))	('IDH', 'Gene', '3417', (260, 263))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
109059	29666413	DKI first-order statistics biomarkers (mean, median, standard deviation, kurtosis, 5th and 95th percentile) were entered SVM analysis to test the diagnostic performance of prediction of IDH mutation using a LOOCV to avoid over-fitting.	('mutation', 'Var', (190, 198))	('kurtosis', 'Disease', (73, 81))	('kurtosis', 'Disease', 'None', (73, 81))	('IDH', 'Gene', (186, 189))	('IDH', 'Gene', '3417', (186, 189))
109070	29666413	The IDH wild-type tumors in their study were predominantly GBMs (15 out of 16), whereas in our study the IDH wild-type tumours did not demonstrate GBM features, though some of them (most likely captured early during the natural history of tumour development) had EGFR amplification and TERT mutation, which are molecular hallmarks of GBMs.	('IDH', 'Gene', '3417', (4, 7))	('tumors', 'Disease', (18, 24))	('IDH', 'Gene', '3417', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumours', 'Disease', (119, 126))	('EGFR', 'Gene', (263, 267))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('IDH', 'Gene', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('tumour', 'Disease', (239, 245))	('EGFR', 'Gene', '1956', (263, 267))	('tumour', 'Disease', (119, 125))	('IDH', 'Gene', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('TERT', 'Gene', (286, 290))	('TERT', 'Gene', '7015', (286, 290))	('amplification', 'Var', (268, 281))
109081	29666413	Our study has also demonstrated the superiority of using texture features for determination of IDH mutation status, given the same number of biomarkers (e.g., we selected 4 biomarkers in our study), the AUC value of using texture biomarkers has improved by 49% (0.88 vs 0.59) compared with that of using first-order statistical biomarkers.	('mutation', 'Var', (99, 107))	('improved', 'PosReg', (245, 253))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('AUC', 'MPA', (203, 206))
109095	29666413	Tumour diagnosis was based on histological examinations of surgical specimens, aided by immunohistochemical testing for known biomarkers (ATRX, IDH1 R132H) and molecular tests for rarer IDH 1 and all IDH mutations, 1p/19q co-deletion and TERT promoter mutations (see details in the Histopathology section).	('TERT', 'Gene', '7015', (238, 242))	('IDH 1', 'Gene', (186, 191))	('IDH', 'Gene', (144, 147))	('IDH', 'Gene', '3417', (144, 147))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (204, 213))	('IDH', 'Gene', (200, 203))	('ATRX', 'Gene', (138, 142))	('IDH 1', 'Gene', '3417', (186, 191))	('R132H', 'Mutation', 'rs121913500', (149, 154))	('IDH', 'Gene', (186, 189))	('IDH1', 'Gene', (144, 148))	('IDH', 'Gene', '3417', (200, 203))	('ATRX', 'Gene', '546', (138, 142))	('IDH', 'Gene', '3417', (186, 189))	('IDH1', 'Gene', '3417', (144, 148))	('TERT', 'Gene', (238, 242))	('1p/19q', 'Gene', (215, 221))
109105	29666413	Subsequently, all IDH R132H immuno-negative tumors underwent further characterization by Sanger sequencing of the established tumor-associated mutations of IDH1, IDH2, histone H3F3A, TERT promoter and BRAF genes.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('IDH', 'Gene', (18, 21))	('IDH', 'Gene', '3417', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (44, 49))	('IDH', 'Gene', '3417', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('IDH2', 'Gene', (162, 166))	('mutations', 'Var', (143, 152))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('IDH1', 'Gene', (156, 160))	('IDH2', 'Gene', '3418', (162, 166))	('IDH', 'Gene', (156, 159))	('TERT', 'Gene', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('R132H', 'Mutation', 'rs121913500', (22, 27))	('TERT', 'Gene', '7015', (183, 187))	('BRAF', 'Gene', '673', (201, 205))	('tumor', 'Disease', (126, 131))	('tumors', 'Disease', (44, 50))	('BRAF', 'Gene', (201, 205))	('IDH', 'Gene', (162, 165))	('IDH1', 'Gene', '3417', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('IDH', 'Gene', '3417', (156, 159))
109106	29666413	A qPCR based copy number assay was used to determine 1p/19q status, EGFR amplification and 10q loss.	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (68, 72))	('1p/19q status', 'Var', (53, 66))	('amplification', 'Var', (73, 86))
109122	27922697	PD-1 is expressed on activated T cells, and ligation of PD-1 by tumour-associated PD-L1 induces apoptosis or downregulation of effector cytotoxic T lymphocytes (CTL), resulting in an escape from T-cell mediated immune surveillance.	('induces', 'Reg', (88, 95))	('downregulation', 'NegReg', (109, 123))	('PD-L1', 'Gene', (82, 87))	('PD-1', 'Gene', (0, 4))	('ligation', 'Var', (44, 52))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('PD-1', 'Gene', '5133', (0, 4))	('tumour', 'Disease', (64, 70))	('apoptosis', 'CPA', (96, 105))	('PD-1', 'Gene', (56, 60))	('escape', 'MPA', (183, 189))	('PD-1', 'Gene', '5133', (56, 60))	('T-cell mediated immune surveillance', 'MPA', (195, 230))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
109200	27922697	Here, we demonstrated that PD-L1 expression in 3 OSCC cell lines was significantly upregulated compared to that in normal cells; thus, PD-L1 may play a greater role in immunotolerance in the cancer microenvironment than PD-L2 does.	('PD-L1', 'Var', (135, 140))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('upregulated', 'PosReg', (83, 94))	('expression', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('PD-L1', 'Gene', (27, 32))	('PD-L2', 'Gene', (220, 225))	('PD-L2', 'Gene', '80380', (220, 225))
109271	25009229	The density of CD3- (p=0.852), CD20- (p=0.472) and CD68-positive cells (p=0.645) or Ki67-positive cells in neocortex (p=0.852) or in white matter (p=0.772) had no significant influence.	('white matter', 'Disease', (133, 145))	('CD20', 'Gene', '54474', (31, 35))	('white matter', 'Disease', 'MESH:D056784', (133, 145))	('CD20', 'Gene', (31, 35))	('CD3-', 'Protein', (15, 19))	('CD68', 'Gene', '968', (51, 55))	('CD68', 'Gene', (51, 55))	('Ki67-positive', 'Var', (84, 97))
109305	25009229	These differences in neuronal expression site should reduce KCC2 functionality in peritumoral neurons.	('reduce', 'NegReg', (53, 59))	('KCC2', 'Gene', '57468', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('differences', 'Var', (6, 17))	('KCC2', 'Gene', (60, 64))	('functionality', 'MPA', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
109356	25009229	Blockade of NKCC1 reduces tumor growth in animal models.	('NKCC1', 'Gene', (12, 17))	('Blockade', 'Var', (0, 8))	('NKCC1', 'Gene', '6558', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
109383	25009229	The following antibodies were used: anti CD3 (Ventana); anti CD20 L26 1/1000 (Dako); anti CD68 KP1 1/1000 (Dako); anti KCC2 1/2000 (gift from Kai Kaila); anti Ki67 1/50 (Dako); anti NeuN 1/500 (Chemicon).	('KCC2', 'Gene', '57468', (119, 123))	('NeuN', 'Gene', (182, 186))	('CD20', 'Gene', '54474', (61, 65))	('CD20', 'Gene', (61, 65))	('CD68', 'Gene', (90, 94))	('NeuN', 'Gene', '146713', (182, 186))	('CD68', 'Gene', '968', (90, 94))	('KCC2', 'Gene', (119, 123))	('anti CD3', 'Var', (36, 44))	('anti Ki67', 'Var', (154, 163))
109413	32932560	Codeletion of 1p/19q is another genetic modification that is associated with a favorable prognosis and treatment response and is commonly found in oligodendroglial tumors.	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('Codeletion of 1p/19q', 'Var', (0, 20))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (147, 170))	('found', 'Reg', (138, 143))	('oligodendroglial tumors', 'Disease', (147, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
109432	32932560	First, a comparison of the imaging features between the IDHmut group and IDHwt group was performed, and subsequently, a comparison of the imaging features between IDH-mutant, 1p/19q-codeleted (IDHmut1p/19qdel) and IDH-mutant, 1p/19q-nondeleted (IDHmut1p/19qnondel) was performed.	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', (193, 196))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', (163, 166))	('IDH', 'Gene', (245, 248))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', '3417', (193, 196))	('IDH', 'Gene', '3417', (163, 166))	('IDH', 'Gene', (214, 217))	('IDH', 'Gene', '3417', (245, 248))	('1p/19q-codeleted', 'Var', (175, 191))	('IDH', 'Gene', '3417', (214, 217))
109447	32932560	The univariable logistic regression analysis revealed significant associations between IDH mutation and T2 volume and between IDH mutation and ADC_mean value.	('T2 volume', 'MPA', (104, 113))	('mutation', 'Var', (91, 99))	('IDH', 'Gene', '3417', (126, 129))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (87, 90))	('ADC_mean value', 'MPA', (143, 157))	('IDH', 'Gene', (126, 129))
109448	32932560	Moreover, among the IDHmut tumors, 1p/19q codeletion demonstrated associations with CBV_mean values and ADC_mean, ADC_5, ADC_10, and ADC_15 values (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ADC_mean', 'Gene', (104, 112))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('associations', 'Interaction', (66, 78))	('ADC_5', 'Gene', (114, 119))	('1p/19q codeletion', 'Var', (35, 52))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('CBV_mean values', 'Gene', (84, 99))
109449	32932560	The multivariable regression analysis using the results from the univariable regression analysis revealed associations between IDH mutation and ADC_mean as well as 1p/19q codeletion and CBV_mean (Table 4).	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('1p/19q codeletion', 'Var', (164, 181))	('ADC_mean', 'Gene', (144, 152))	('associations', 'Interaction', (106, 118))	('mutation', 'Var', (131, 139))
109450	32932560	From the multivariable analysis, the prediction models for the IDH mutation and 1p/19q codeletion using the quantitative imaging parameters were acquired.	('mutation', 'Var', (67, 75))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (63, 66))
109451	32932560	The diagnostic performance of the prediction model showed accuracy, sensitivity and specificity values of 66.7%, 66.7%, and 72.7%, respectively, for the IDH mutation and of 66.7%, 100.0%, and 50.0%, respectively, for 1p19q codeletion using the validation dataset.	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', '3417', (153, 156))	('mutation', 'Var', (157, 165))
109467	32932560	We found significant associations between the quantitative and qualitative imaging features of G3 gliomas according to the presence of an IDH mutation and 1p/19q codeletion, which were included in the most recent WHO guidelines for glioma classification.	('IDH', 'Gene', (138, 141))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Disease', (232, 238))	('IDH', 'Gene', '3417', (138, 141))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('glioma', 'Disease', (98, 104))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('mutation', 'Var', (142, 150))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))
109471	32932560	Furthermore, regression analysis revealed significant associations between IDH mutation and ADC values, suggesting the potential role of this particular imaging feature in prediction of IDH mutation status in G3 gliomas.	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('mutation', 'Var', (79, 87))	('IDH', 'Gene', (186, 189))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (186, 189))	('ADC values', 'MPA', (92, 102))	('IDH', 'Gene', '3417', (75, 78))	('gliomas', 'Disease', (212, 219))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))
109472	32932560	However, the G3 gliomas included in our study did not show a significant difference in the proportions of tumors with contrast-enhancing portions according to the presence of the IDH mutation, inconsistent with findings by Leu et al..	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (179, 182))	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('gliomas', 'Disease', (16, 23))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutation', 'Var', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))
109479	32932560	Additionally, the regression analysis showed a significant association with the CBV value and the presence of a 1p/19q codeletion in IDHmut G3 gliomas.	('IDH', 'Gene', '3417', (133, 136))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('IDH', 'Gene', (133, 136))	('gliomas', 'Disease', (143, 150))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('presence', 'Var', (98, 106))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('1p/19q codeletion', 'Var', (112, 129))
109559	30636391	Cellular pleomorphism and microvascular proliferation were the most reliable indicators of WHO grade III ependymomas compared to mitosis or necrosis patterns.	('Cellular pleomorphism', 'Var', (0, 21))	('microvascular proliferation', 'CPA', (26, 53))	('ependymoma', 'Phenotype', 'HP:0002888', (105, 115))	('mitosis or necrosis', 'Disease', 'MESH:D009336', (129, 148))	('mitosis or necrosis', 'Disease', (129, 148))	('ependymomas', 'Disease', 'MESH:D004806', (105, 116))	('ependymomas', 'Disease', (105, 116))
109766	26690880	Evidence for molecular crosstalk between ciliary factors and regulators of the cell cycle raises the possibility dysregulation of ciliogenesis may contribute to tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('dysregulation', 'Var', (113, 126))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('contribute', 'Reg', (147, 157))	('tumour', 'Disease', (161, 167))
109779	26690880	The human genes comprising this signature are orthologs of over 80 genes identified as FOXJ1 targets in xenopus and zebrafish by overexpression and deletion/silencing approaches.	('deletion/silencing', 'Var', (148, 166))	('human', 'Species', '9606', (4, 9))	('xenopus', 'Species', '8355', (104, 111))	('FOXJ1', 'Gene', (87, 92))	('zebrafish', 'Species', '7955', (116, 125))
109808	26690880	The expression of FOXJ1 and the ciliogenesis program varied widely with some tumours expressing high levels of mRNA for FOXJ1, RFX2 and the ciliogenesis program while others had low levels of mRNA for these genes (Figure 4A, 4B).	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (77, 84))	('FOXJ1', 'Gene', (120, 125))	('ciliogenesis program', 'CPA', (140, 160))	('RFX2', 'Gene', (127, 131))	('FOXJ1', 'Gene', (18, 23))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('mRNA', 'Var', (111, 115))
109822	26690880	(Pearson r = 0.56 and Pearson r = 0.64, p < 0.0001, Figure S12A and B, Tables S6 and S7) suggesting that MYB may be involved in positively regulating FOXJ1 expression in ependymoma.	('positively', 'PosReg', (128, 138))	('ependymoma', 'Phenotype', 'HP:0002888', (170, 180))	('ependymoma', 'Disease', 'MESH:D004806', (170, 180))	('S12A', 'SUBSTITUTION', 'None', (59, 63))	('ependymoma', 'Disease', (170, 180))	('S12A', 'Var', (59, 63))	('FOXJ1', 'Gene', (150, 155))	('expression', 'MPA', (156, 166))
109829	26690880	We found that ependymomas with high FOXJ1 expression were less likely to recur (HR = 0.82, 95% CI = 0.70 to 0.96; p = 0.012; Table S8, S9).	('ependymomas', 'Disease', 'MESH:D004806', (14, 25))	('FOXJ1', 'Gene', (36, 41))	('ependymomas', 'Disease', (14, 25))	('recur', 'Disease', (73, 78))	('high', 'Var', (31, 35))	('ependymoma', 'Phenotype', 'HP:0002888', (14, 24))	('less', 'NegReg', (58, 62))
109839	26690880	These tumours arise following Cre-mediated inactivation of p53, RB and PTEN.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('tumours', 'Disease', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('PTEN', 'Gene', (71, 75))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('PTEN', 'Gene', '5728', (71, 75))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('RB', 'Disease', 'MESH:D012175', (64, 66))	('inactivation', 'Var', (43, 55))
109841	26690880	Using publicly available expression profiling data from humans with choroid plexus tumours, we also noted a strong correlation between the levels of FOXJ1 mRNA and the expression of the FOXJ1 ciliogenesis program (Figure S15A; Pearson r = 0.89, p < 0.0001; Table S11).	('S15A', 'Var', (221, 225))	('mRNA', 'MPA', (155, 159))	('FOXJ1', 'Gene', (149, 154))	('S15A', 'SUBSTITUTION', 'None', (221, 225))	('expression', 'MPA', (168, 178))	('FOXJ1', 'Gene', (186, 191))	('choroid plexus tumours', 'Disease', (68, 90))	('choroid plexus tumours', 'Disease', 'MESH:D020288', (68, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('humans', 'Species', '9606', (56, 62))
109842	26690880	Moreover, similar to our immunohistochemistry results, mRNA levels of FOXJ1, RFX2 and the ciliogenesis program were all abundant in choroid plexus papilloma but were significantly reduced in choroid plexus carcinoma (Figure 6C - E, S15B; p < 0.05; Table S11).	('S15B', 'Var', (232, 236))	('papilloma', 'Phenotype', 'HP:0012740', (147, 156))	('mRNA levels', 'MPA', (55, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('choroid plexus carcinoma', 'Disease', (191, 215))	('reduced', 'NegReg', (180, 187))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (132, 156))	('S15B', 'SUBSTITUTION', 'None', (232, 236))	('RFX2', 'Gene', (77, 81))	('choroid plexus papilloma', 'Disease', (132, 156))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (191, 215))	('choroid plexus papilloma', 'Disease', 'MESH:D020288', (132, 156))	('ciliogenesis program', 'CPA', (90, 110))	('FOXJ1', 'Gene', (70, 75))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (191, 215))
109852	26690880	For example, gene set enrichment analysis (Table S3) identified a dysregulation of Wingless-Type (WNT) and Hedgehog signaling pathways in ependymoma, both pathways that are essential for establishing appropriate polarity.	('ependymoma', 'Disease', 'MESH:D004806', (138, 148))	('ependymoma', 'Disease', (138, 148))	('Hedgehog signaling pathways', 'Pathway', (107, 134))	('dysregulation', 'Var', (66, 79))	('ependymoma', 'Phenotype', 'HP:0002888', (138, 148))
109862	26690880	Such a dependency creates vulnerabilities in the centrosome cycle that could be explored as a treatment strategy and further supports the dysregulation of centrosome biology as an important driver of malignancy in ependymoma.	('vulnerabilities', 'MPA', (26, 41))	('malignancy in ependymoma', 'Disease', 'MESH:D004806', (200, 224))	('ependymoma', 'Phenotype', 'HP:0002888', (214, 224))	('malignancy in ependymoma', 'Disease', (200, 224))	('dysregulation', 'Var', (138, 151))	('dependency', 'Var', (7, 17))
109969	33923337	Additionally, SEER analysis performed by Adams H. showed that gross total resection is independently associated with improved OS in GBM patients.	('GBM', 'Disease', (132, 135))	('patients', 'Species', '9606', (136, 144))	('improved', 'PosReg', (117, 125))	('gross total resection', 'Var', (62, 83))
109970	33923337	Additionally, in our study, the patients who had R0 resection tended to have better OS and PFS compared to those with R1/R2 surgery (p = 0.005 and p = 0.04, respectively).	('better', 'PosReg', (77, 83))	('PFS', 'CPA', (91, 94))	('patients', 'Species', '9606', (32, 40))	('R0 resection', 'Var', (49, 61))
109981	33923337	The decision about the therapeutic agent used should be made with caution in patients with grade III tumors, because long administration of temozolomide may lead to mutations in MMR genes and, subsequently, mutations in pathways leading to progression from grade III to grade IV.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('temozolomide', 'Chemical', 'MESH:D000077204', (140, 152))	('pathways', 'Pathway', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('grade III', 'Disease', (257, 266))	('lead to', 'Reg', (157, 164))	('MMR genes', 'Gene', (178, 187))	('leading to', 'Reg', (229, 239))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (77, 85))	('III tumors', 'Disease', 'MESH:D009369', (97, 107))	('mutations', 'Var', (165, 174))	('III tumors', 'Disease', (97, 107))
110012	33442944	Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome.	('tumour', 'Disease', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('high scoring', 'Var', (101, 113))
110015	33442944	Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('affect', 'Reg', (49, 55))	('affecting', 'Reg', (78, 87))	('tumour', 'Disease', (88, 94))	('glioma', 'Disease', (56, 62))	('clock', 'Gene', '9575', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('Dysregulated', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('clock', 'Gene', (23, 28))	('cell cycle', 'CPA', (116, 126))
110017	33442944	Dysregulated circadian clock genes were associated with glioma grades and the IDH status.	('IDH', 'Gene', '3417', (78, 81))	('glioma', 'Disease', (56, 62))	('clock', 'Gene', '9575', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('Dysregulated', 'Var', (0, 12))	('clock', 'Gene', (23, 28))	('IDH', 'Gene', (78, 81))	('associated', 'Reg', (40, 50))
110019	33442944	The GO and GSEA enrichment analysis suggested dysregulated circadian clock genes can affect glioma through interfering cell cycle and influencing immunocytes infltration.	('GSEA', 'Chemical', '-', (11, 15))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('clock', 'Gene', (69, 74))	('interfering', 'NegReg', (107, 118))	('glioma', 'Disease', (92, 98))	('dysregulated', 'Var', (46, 58))	('clock', 'Gene', '9575', (69, 74))	('immunocytes infltration', 'CPA', (146, 169))	('affect', 'Reg', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('influencing', 'Reg', (134, 145))	('cell cycle', 'CPA', (119, 129))
110022	33442944	2  Clinically, apart from the histologic subtype, other biomarkers including IDH status, 1p19q status and MGMT methylation status are used to predict patient survival and personalize therapy.	('patient', 'Species', '9606', (150, 157))	('1p19q status', 'Var', (89, 101))	('IDH', 'Gene', (77, 80))	('MGMT', 'Gene', '4255', (106, 110))	('MGMT', 'Gene', (106, 110))	('IDH', 'Gene', '3417', (77, 80))
110023	33442944	Lower grade glioma (LGG), IDH mutation, MGMT methylation and 1p19q codeletion are associated with better survival.	('glioma', 'Disease', (12, 18))	('MGMT', 'Gene', '4255', (40, 44))	('1p19q codeletion', 'Var', (61, 77))	('MGMT', 'Gene', (40, 44))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (26, 29))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
110042	33442944	By silencing TIMELESS not only dysregulated CCG expression but also arrested cell cycle at the G0/G1 phase.	('dysregulated', 'Var', (31, 43))	('silencing', 'Var', (3, 12))	('arrest', 'Disease', (68, 74))	('expression', 'MPA', (48, 58))	('CCG', 'Chemical', '-', (44, 47))	('TIMELESS', 'Gene', (13, 21))	('cell cycle at the G0/G1 phase', 'CPA', (77, 106))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('CCG', 'Gene', (44, 47))	('TIMELESS', 'Gene', '8914', (13, 21))
110043	33442944	Therefore, abnormal CCGs expression suppressed tumour cell proliferation according to CCK8 assay and colony-forming assay.	('suppressed', 'NegReg', (36, 46))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('abnormal', 'Var', (11, 19))	('tumour', 'Disease', (47, 53))	('CCGs', 'Chemical', '-', (20, 24))	('CCGs', 'Gene', (20, 24))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
110044	33442944	In general, abnormal CCG expression affects tumour prognosis through influencing tumour immune landscape and tumour cell proliferation.	('CCG', 'Gene', (21, 24))	('affects', 'Reg', (36, 43))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('influencing', 'Reg', (69, 80))	('tumour', 'Disease', (44, 50))	('tumour', 'Disease', (109, 115))	('tumour', 'Disease', (81, 87))	('abnormal', 'Var', (12, 20))	('CCG', 'Chemical', '-', (21, 24))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
110058	33442944	Genetic variation information in glioma, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), was downloaded from the TCGA database.	('single nucleotide polymorphisms', 'Var', (51, 82))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Disease', (33, 39))
110067	33442944	Agonists of NR1D1 and NR1D2, SR9009 (Cat# HY-16988) and SR9011 (Cat# HY-16989), were purchased from MedChemExpress (Shanghai, China).	('SR9009', 'Var', (29, 35))	('SR9011', 'Chemical', 'MESH:C572450', (56, 62))	('NR1D2', 'Gene', '9975', (22, 27))	('SR9011', 'Var', (56, 62))	('NR1D2', 'Gene', (22, 27))	('NR1D1', 'Gene', '9572', (12, 17))	('SR9009', 'Chemical', 'MESH:C572451', (29, 35))	('NR1D1', 'Gene', (12, 17))
110080	33442944	As illustrated, samples carried with mutated RORB, ARNTL, PER1 and TIMELESS only on account of 1% of all samples from the TCGA dataset (Figure 1E).	('ARNTL', 'Gene', (51, 56))	('ARNTL', 'Gene', '406', (51, 56))	('RORB', 'Gene', '6096', (45, 49))	('TIMELESS', 'Gene', (67, 75))	('TIMELESS', 'Gene', '8914', (67, 75))	('RORB', 'Gene', (45, 49))	('mutated', 'Var', (37, 44))
110084	33442944	Then, DNA methylation of CCGs was analysed in all samples, IDH wild-type glioma, and IDH mutate glioma (Figures 1I-K and S3G-L).	('IDH', 'Gene', '3417', (85, 88))	('glioma', 'Disease', (73, 79))	('IDH', 'Gene', (59, 62))	('mutate', 'Var', (89, 95))	('IDH', 'Gene', '3417', (59, 62))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('CCGs', 'Chemical', '-', (25, 29))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH', 'Gene', (85, 88))	('glioma', 'Disease', (96, 102))
110085	33442944	Negative correlation between the methylation status of core CCGs and gene expression was noticed.	('Negative', 'NegReg', (0, 8))	('CCGs', 'Chemical', '-', (60, 64))	('methylation status', 'Var', (33, 51))	('gene expression', 'MPA', (69, 84))
110092	33442944	Subgroup survival analysis based on IDH status, 1p19q status, MGMT status and radiotherapy was also conducted, and patients with a higher riskScore exhibited worse survival outcomes in the TCGA and validation datasets (Figures 2G,L, S6K,L, and S7).	('MGMT', 'Gene', (62, 66))	('patients', 'Species', '9606', (115, 123))	('MGMT', 'Gene', '4255', (62, 66))	('IDH', 'Gene', (36, 39))	('1p19q', 'Var', (48, 53))	('IDH', 'Gene', '3417', (36, 39))	('S6K,L', 'Mutation', 'p.S6K,L', (233, 238))
110094	33442944	High riskScore samples were high-grade glioma, IDH wild-type glioma, 1p19q non-codel glioma, MGMT unmethylated glioma, aggressive glioma (classical and mesenchymal) and worse treatment outcome glioma in the training and validation cohort (Figures S8 and S9).	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('MGMT', 'Gene', (93, 97))	('glioma', 'Disease', (130, 136))	('non-codel', 'Var', (75, 84))	('1p19q non-codel', 'Var', (69, 84))	('aggressive glioma', 'Disease', (119, 136))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (193, 199))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('IDH', 'Gene', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma', 'Disease', (111, 117))	('MGMT', 'Gene', '4255', (93, 97))	('glioma', 'Disease', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('IDH', 'Gene', '3417', (47, 50))	('aggressive glioma', 'Disease', 'MESH:D005910', (119, 136))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
110101	33442944	A higher degree of TP53 (46% vs 39%), IDH1 (89% vs 32%) and ATRX (33% vs 21%) mutations was observed in low-risk compared to high-risk groups.	('IDH1', 'Gene', '3417', (38, 42))	('ATRX', 'Gene', '546', (60, 64))	('mutations', 'Var', (78, 87))	('TP53', 'Gene', '7157', (19, 23))	('IDH1', 'Gene', (38, 42))	('TP53', 'Gene', (19, 23))	('ATRX', 'Gene', (60, 64))
110104	33442944	Meanwhile, deletion of regions including 9p21.3 (CDKN2A) and 1p36.23 (ERRFI1) was detected in the high-risk group (Figure 4D), and 2q37.3 (hsa-mir-3133) and 11p15.5 (hsa-mir-4298) were common deletion regions in the low-risk group (Figure 4E).	('CDKN2A', 'Gene', '1029', (49, 55))	('hsa', 'Gene', '213', (166, 169))	('mir-3133', 'Gene', (143, 151))	('hsa', 'Gene', (166, 169))	('mir-4298', 'Gene', '100423021', (170, 178))	('hsa', 'Gene', (139, 142))	('hsa', 'Gene', '213', (139, 142))	('2q37.3', 'Var', (131, 137))	('ERRFI1', 'Gene', '54206', (70, 76))	('deletion', 'Var', (11, 19))	('mir-4298', 'Gene', (170, 178))	('ERRFI1', 'Gene', (70, 76))	('mir-3133', 'Gene', '100422942', (143, 151))	('CDKN2A', 'Gene', (49, 55))
110111	33442944	In the TCGA dataset, GO and KEGG enrichment analysis based on GSVA analysis (Figures 6A, and S11A) and GSEA analysis (Figure 6B) suggested that CCGs modulate cell cycle and immune infiltration.	('GSEA', 'Chemical', '-', (103, 107))	('modulate', 'Reg', (149, 157))	('cell cycle', 'CPA', (158, 168))	('immune infiltration', 'CPA', (173, 192))	('CCGs', 'Chemical', '-', (144, 148))	('S11A', 'Var', (93, 97))	('CCGs', 'Var', (144, 148))	('S11A', 'SUBSTITUTION', 'None', (93, 97))
110116	33442944	Similar correlation with T cell-mediated immunity (Figure S12A) and cell cycle DNA replication (Figure S12B) was also verified in CGGA1 and CGGA2 datasets.	('cell cycle', 'CPA', (68, 78))	('S12B', 'Var', (103, 107))	('S12A', 'SUBSTITUTION', 'None', (58, 62))	('S12B', 'SUBSTITUTION', 'None', (103, 107))	('S12A', 'Var', (58, 62))
110121	33442944	Anti-tumour immunocytes including T cells, cytotoxic T cells, NK cells, macrophages and immunosuppressive cells including Th2 cells, apoptotic dendritic cells, immature dendritic cells were enriched in high riskScore group (Figures 7F and S13C,D).	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('tumour', 'Disease', (5, 11))	('S13C', 'Var', (239, 243))	('S13C', 'SUBSTITUTION', 'None', (239, 243))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
110126	33442944	By silencing TIMELESS expression can alter the expression of CLOCK and PERs implying circadian rhythm was interrupted (Figure 8B).	('CLOCK', 'Gene', (61, 66))	('silencing', 'Var', (3, 12))	('alter', 'Reg', (37, 42))	('expression', 'MPA', (47, 57))	('CLOCK', 'Gene', '9575', (61, 66))	('TIMELESS', 'Gene', (13, 21))	('TIMELESS', 'Gene', '8914', (13, 21))	('PERs', 'MPA', (71, 75))
110130	33442944	42 ,  43  In this work, T98G showed sensitivity to SR9009 and SR9011 implying interrupted circadian rhythm affected cells proliferation; in the meantime, U251 proliferation was also inhibited by SR9009 and SR9011 (Figure 8E and S14D).	('SR9011', 'Chemical', 'MESH:C572450', (62, 68))	('U251 proliferation', 'CPA', (154, 172))	('SR9009', 'Chemical', 'MESH:C572451', (195, 201))	('SR9011', 'Chemical', 'MESH:C572450', (206, 212))	('cells proliferation', 'CPA', (116, 135))	('SR9011', 'Var', (206, 212))	('S14D', 'Mutation', 'p.S14D', (228, 232))	('SR9009', 'Chemical', 'MESH:C572451', (51, 57))	('inhibited', 'NegReg', (182, 191))	('SR9009', 'Var', (195, 201))
110133	33442944	10 ,  11 ,  12 ,  13  Dysregulated CCG expression was associated with glioma progression 19 ,  44 ,  45  and glioma stem cells.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('glioma', 'Disease', (70, 76))	('CCG', 'Gene', (35, 38))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Disease', (109, 115))	('Dysregulated', 'Var', (22, 34))	('associated', 'Reg', (54, 64))	('CCG', 'Chemical', '-', (35, 38))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
110139	33442944	Notably, previous study supported nystatin was associated with the ratio of immunosuppressive myeloid cells 47  and deoxypodophyllotoxin can inhibit glioma progression.	('glioma', 'Disease', (149, 155))	('deoxypodophyllotoxin', 'Var', (116, 136))	('nystatin', 'Chemical', 'MESH:D009761', (34, 42))	('deoxypodophyllotoxin', 'Chemical', 'MESH:C014451', (116, 136))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('inhibit', 'NegReg', (141, 148))
110141	33442944	The maintenance of circadian rhythm depends on the interaction between TIMELESS and PERs and interrupting the expression of them cause disordered circadian.	('disordered circadian', 'MPA', (135, 155))	('cause', 'Reg', (129, 134))	('TIMELESS', 'Gene', (71, 79))	('interrupting', 'Var', (93, 105))	('expression', 'MPA', (110, 120))	('TIMELESS', 'Gene', '8914', (71, 79))
110147	33442944	Together, disordered CCGs can promote tumour progression by interfering normal cell cycle.	('promote', 'PosReg', (30, 37))	('normal cell cycle', 'CPA', (72, 89))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('CCGs', 'Chemical', '-', (21, 25))	('tumour', 'Disease', (38, 44))	('interfering', 'NegReg', (60, 71))	('CCGs', 'Protein', (21, 25))	('disordered', 'Var', (10, 20))
110153	33442944	65 ,  66 ,  67   In summary, we proved CCGs expression is associated with glioma patient's survival outcome by influencing tumour immune landscape and cell proliferation.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('patient', 'Species', '9606', (81, 88))	('associated', 'Reg', (58, 68))	('CCGs', 'Gene', (39, 43))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('expression', 'Var', (44, 54))	('CCGs', 'Chemical', '-', (39, 43))	('cell proliferation', 'CPA', (151, 169))	('tumour', 'Disease', (123, 129))	('glioma', 'Disease', (74, 80))	('influencing', 'Reg', (111, 122))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
110207	32160398	These results indicated that the patients in the RRCR group would exhibit a stronger response to checkpoint blockade immunotherapy than patient in the other groups.	('patient', 'Species', '9606', (136, 143))	('response', 'MPA', (85, 93))	('patients', 'Species', '9606', (33, 41))	('patient', 'Species', '9606', (33, 40))	('RRCR', 'Var', (49, 53))	('stronger', 'PosReg', (76, 84))
110209	32160398	Prior to this, a radiotherapy sensitivity indicator called RSI has been validated in a variety of cancers 16, 38, 39, 40, 41 and has recently been further developed.42, 43 However, the predictive power of RSI is lower than Rscore in TCGA or CGGA LGG data sets.	('lower', 'NegReg', (212, 217))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('RSI', 'Var', (205, 208))
110216	32160398	An in silico analysis based on tumour mutational burden (TMB), tumour inflammation signature (TIS) and expression of inhibitory receptors (IRs) predicted that patients in the RRCR group would show a stronger response to checkpoint blockade immunotherapy than patients in the other groups.	('tumour inflammation', 'Disease', (63, 82))	('RRCR', 'Var', (175, 179))	('response', 'MPA', (208, 216))	('patients', 'Species', '9606', (259, 267))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('stronger', 'PosReg', (199, 207))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour inflammation', 'Disease', 'MESH:D007249', (63, 82))	('patients', 'Species', '9606', (159, 167))	('tumour', 'Disease', (31, 37))	('TMB', 'Chemical', '-', (57, 60))	('tumour', 'Disease', (63, 69))
110222	31964418	Dysregulated IAPs have been reported to contribute to tumor progression and chemoresistance in various cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('IAP', 'Gene', '84061', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('contribute', 'Reg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IAP', 'Gene', (13, 16))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Disease', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('chemoresistance', 'CPA', (76, 91))	('cancers', 'Disease', (103, 110))
110287	31964418	We also found that BIRC5, BIRC6 and XIAP were heavily involved in cell cycle related pathways such as M/G1 transition, G1/S transition, G2/M checkpoints, and DNA replication.	('DNA replication', 'CPA', (158, 173))	('G2/M checkpoints', 'CPA', (136, 152))	('BIRC5', 'Gene', '332', (19, 24))	('involved', 'Reg', (54, 62))	('BIRC5', 'Gene', (19, 24))	('XIAP', 'Gene', (36, 40))	('G1/S transition', 'CPA', (119, 134))	('cell', 'Pathway', (66, 70))	('M/G1', 'SUBSTITUTION', 'None', (102, 106))	('BIRC6', 'Gene', '57448', (26, 31))	('XIAP', 'Gene', '331', (36, 40))	('M/G1', 'Var', (102, 106))	('BIRC6', 'Gene', (26, 31))
110302	31964418	For example, BIRC5 was significantly anti-correlated with miR-101, miR-664a, miR-29c, miR-30a, miR-125 and miR-139 expression in over 40% of the cancers.	('cancers', 'Disease', (145, 152))	('miR-664a', 'Gene', '100302234', (67, 75))	('miR-30a', 'Gene', '407029', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('miR-664a', 'Gene', (67, 75))	('miR-29c', 'Gene', (77, 84))	('miR-29c', 'Gene', '407026', (77, 84))	('miR-125', 'Gene', (95, 102))	('miR-30a', 'Gene', (86, 93))	('anti-correlated', 'NegReg', (37, 52))	('miR-139', 'Gene', '406931', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR-139', 'Gene', (107, 114))	('expression', 'MPA', (115, 125))	('BIRC5', 'Gene', '332', (13, 18))	('BIRC5', 'Gene', (13, 18))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('miR-101', 'Var', (58, 65))
110307	31964418	Evasion of apoptosis through dysregulated IAPs might led to uncontrolled cell growth and poor prognosis.	('IAP', 'Gene', (42, 45))	('uncontrolled cell growth', 'CPA', (60, 84))	('led', 'Reg', (53, 56))	('Evasion', 'MPA', (0, 7))	('dysregulated', 'Var', (29, 41))	('IAP', 'Gene', '84061', (42, 45))	('apoptosis', 'CPA', (11, 20))
110356	31964418	The demonstrated complexities of IAPs expression provided vast possibilities for apoptosis regulation and potential mechanisms of oncogenesis resulting from aberrant expression of IAPs.	('IAP', 'Gene', '84061', (33, 36))	('IAP', 'Gene', (180, 183))	('aberrant expression', 'Var', (157, 176))	('apoptosis', 'CPA', (81, 90))	('IAP', 'Gene', (33, 36))	('IAP', 'Gene', '84061', (180, 183))
110397	31964418	This study is supported by The National Natural Science Foundation of China 31501054, 81301092, 31301118, 81900431, Peking Unicersity International Hospital Research Grant No.	('31301118', 'Var', (96, 104))	('81900431', 'Var', (106, 114))	('C', 'Chemical', 'MESH:D002244', (70, 71))
110441	29902076	EGFR is the receptor for epidermal growth factor, and amplification/overexpression of the EGFR locus is found in about 42% of primary glioblastoma multiformes (GBM).	('primary glioblastoma', 'Disease', (126, 146))	('amplification/overexpression', 'Var', (54, 82))	('EGFR', 'Gene', (0, 4))	('primary glioblastoma', 'Disease', 'MESH:D005909', (126, 146))	('EGFR', 'Gene', '1956', (90, 94))	('glioblastoma multiforme', 'Disease', (134, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('EGFR', 'Gene', (90, 94))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (134, 157))	('EGFR', 'Gene', '1956', (0, 4))
110442	29902076	EGFR amplification in histologically pure anaplastic oligodendroglioma (ODG) is indicative of GBM.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('ODG', 'Disease', 'MESH:D009837', (72, 75))	('ODG', 'Disease', (72, 75))	('oligodendroglioma', 'Disease', (53, 70))	('EGFR', 'Gene', '1956', (0, 4))	('oligodendroglioma', 'Disease', 'MESH:D009837', (53, 70))
110443	29902076	The classic subtype has a strong association with astrocytic signature with EGFR amplification.	('amplification', 'Var', (81, 94))	('EGFR', 'Gene', '1956', (76, 80))	('astrocytic signature', 'Disease', (50, 70))	('EGFR', 'Gene', (76, 80))
110449	29902076	EGFR amplification/ overexpression/ mutation is related to angiogenesis, with a resultant increase in cerebral blood volume (CBV), cerebral blood flow (CBF), plasma volume and contrast transfer coefficient in MR perfusion.	('cerebral blood flow', 'MPA', (131, 150))	('EGFR', 'Gene', (0, 4))	('increase', 'PosReg', (90, 98))	('C', 'Chemical', 'MESH:D002244', (125, 126))	('overexpression/', 'PosReg', (20, 35))	('contrast transfer coefficient', 'MPA', (176, 205))	('cerebral blood volume', 'MPA', (102, 123))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('amplification/', 'Var', (5, 19))	('angiogenesis', 'CPA', (59, 71))	('plasma volume', 'MPA', (158, 171))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (36, 44))
110450	29902076	Metabolite changes such as reduced N-acetyl-aspartate (NAA) levels, lower creatine (Cr) and lower myoinositol (MI) in high-grade gliomas (HGG) and increased lactate proportionally with volumes of necrosis lesion, and restricted water diffusion are also related to EGFR amplification/ overexpression/ mutation.	('reduced', 'NegReg', (27, 34))	('creatine', 'Chemical', 'MESH:D003401', (74, 82))	('Cr', 'Chemical', 'MESH:D003401', (84, 86))	('N-acetyl-aspartate', 'MPA', (35, 53))	('lower', 'NegReg', (68, 73))	('reduced N-acetyl-aspartate', 'Phenotype', 'HP:0012708', (27, 53))	('EGFR', 'Gene', (264, 268))	('gliomas', 'Disease', (129, 136))	('lactate', 'Chemical', 'MESH:D019344', (157, 164))	('necrosis lesion', 'Disease', 'MESH:D009336', (196, 211))	('restricted water diffusion', 'MPA', (217, 243))	('MI', 'Chemical', 'MESH:D007294', (111, 113))	('increased', 'PosReg', (147, 156))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('myoinositol', 'Chemical', 'MESH:D007294', (98, 109))	('lactate', 'MPA', (157, 164))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('N-acetyl-aspartate', 'Chemical', 'None', (35, 53))	('amplification/', 'Var', (269, 283))	('EGFR', 'Gene', '1956', (264, 268))	('NAA', 'Chemical', 'None', (55, 58))	('necrosis lesion', 'Disease', (196, 211))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('myoinositol', 'MPA', (98, 109))	('lower', 'NegReg', (92, 97))
110455	29902076	Hypermethylated MGMT tumours tend to have mixed-nodular enhancement, non-temporal lobe lesions, and often show radiation or treatment-induced pseudo-progression.	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('Hypermethylated', 'Var', (0, 15))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('non-temporal lobe lesions', 'CPA', (69, 94))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('MGMT', 'Gene', (16, 20))	('MGMT', 'Gene', '4255', (16, 20))	('tumours', 'Disease', (21, 28))	('mixed-nodular enhancement', 'MPA', (42, 67))
110461	29902076	Mutations in IDH1 are frequently seen in diffuse LGG and secondary GBM.	('seen', 'Reg', (33, 37))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH1', 'Gene', (13, 17))
110462	29902076	IDH1 mutations are also one of the genetic features related to the proneural subtype of GBM that carry better clinical prognosis in terms of overall survival and progression-free survival, and bear favourable overall survival in diffuse astrocytomas and anaplastic astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (237, 248))	('astrocytoma', 'Disease', (237, 248))	('astrocytoma', 'Disease', 'MESH:D001254', (265, 276))	('astrocytoma', 'Phenotype', 'HP:0009592', (237, 248))	('astrocytoma', 'Disease', (265, 276))	('mutations', 'Var', (5, 14))	('astrocytomas', 'Disease', 'MESH:D001254', (237, 249))	('astrocytoma', 'Phenotype', 'HP:0009592', (265, 276))	('IDH1', 'Gene', (0, 4))	('astrocytomas', 'Disease', (237, 249))	('IDH1', 'Gene', '3417', (0, 4))
110463	29902076	GBM with IDH1 mutations tend to be in the left frontal lobe, larger at diagnosis, may be multifocal, have a high prevalence of non-enhancing tumours, cystic and diffuse components, greater frequency of contact with brain ventricles with less necrosis detection and extent of oedema, less frequent vascular abnormalities, increased oligodendroglial morphology and also metabolite changes (Figure 4).	('IDH1', 'Gene', (9, 13))	('metabolite changes', 'MPA', (368, 386))	('oedema', 'Phenotype', 'HP:0000969', (275, 281))	('oligodendroglial morphology', 'CPA', (331, 358))	('greater', 'PosReg', (181, 188))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (297, 319))	('IDH1', 'Gene', '3417', (9, 13))	('oedema', 'Disease', 'MESH:D004487', (275, 281))	('increased', 'PosReg', (321, 330))	('vascular abnormalities', 'Disease', (297, 319))	('vascular abnormalities', 'Disease', 'MESH:C564415', (297, 319))	('necrosis', 'Disease', 'MESH:D009336', (242, 250))	('mutations', 'Var', (14, 23))	('tumours', 'Disease', (141, 148))	('necrosis', 'Disease', (242, 250))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('oedema', 'Disease', (275, 281))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('increased oligodendroglial morphology', 'Phenotype', 'HP:0100709', (321, 358))
110464	29902076	Glioblastomas without IDH1 mutations showed larger volumes of contrast enhancement seen in T1W + C. The conversion to alpha-ketoglutarate by IDH1 gene is observable using MRS as the elevation of 2-hydroxyglutarate (2HG) co-detected at 2.25ppm and 4.02 ppm that reflect changes in tumour cellularity.	('mutations', 'Var', (27, 36))	('contrast', 'MPA', (62, 70))	('enhancement', 'PosReg', (71, 82))	('C', 'Chemical', 'MESH:D002244', (97, 98))	('tumour', 'Phenotype', 'HP:0002664', (280, 286))	('tumour', 'Disease', 'MESH:D009369', (280, 286))	('IDH1', 'Gene', (141, 145))	('MRS', 'Gene', (171, 174))	('alpha-ketoglutarate', 'Chemical', 'MESH:C029743', (118, 137))	('tumour', 'Disease', (280, 286))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('IDH1', 'Gene', (22, 26))	('Glioblastomas', 'Disease', (0, 13))	('MRS', 'Gene', '8011', (171, 174))	('IDH1', 'Gene', '3417', (141, 145))	('2HG', 'Chemical', 'MESH:C019417', (215, 218))	('IDH1', 'Gene', '3417', (22, 26))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (195, 213))
110465	29902076	The combined loss of 1p and 19q chromosome arms is uncommon in glioma and is considered the earliest genetic hallmark of ODG, whereby it is seen in 50-70% of the neoplasms.	('neoplasms', 'Disease', (162, 171))	('ODG', 'Disease', 'MESH:D009837', (121, 124))	('ODG', 'Disease', (121, 124))	('neoplasms', 'Disease', 'MESH:D009369', (162, 171))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('neoplasms', 'Phenotype', 'HP:0002664', (162, 171))	('loss', 'Var', (13, 17))	('glioma', 'Disease', (63, 69))
110467	29902076	In conventional MRI studies, ODG with 1p/19q loss is more likely to have indistinct borders on T1W images, mixed-signal intensities on T1W and T2W, paramagnetic susceptibility effect, calcification and infiltrative growth patterns (Figure 5).	('1p/19q', 'Var', (38, 44))	('calcification', 'Disease', 'MESH:D002114', (184, 197))	('T1W', 'MPA', (135, 138))	('calcification', 'Disease', (184, 197))	('ODG', 'Disease', 'MESH:D009837', (29, 32))	('ODG', 'Disease', (29, 32))	('loss', 'NegReg', (45, 49))	('infiltrative growth patterns', 'CPA', (202, 230))	('T2W', 'MPA', (143, 146))	('mixed-signal intensities', 'MPA', (107, 131))
110469	29902076	The increased ADC values in ODG and 1p/19q codeleted mixed oligoastrocytomas (OA) were associated with the fraction of the tumour cells (relative number of tumour cells per total cells) and degree of axonal disruption in tumour subregions.	('tumour', 'Disease', (221, 227))	('ODG', 'Disease', 'MESH:D009837', (28, 31))	('OA', 'Disease', 'MESH:D001254', (78, 80))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('increased', 'PosReg', (4, 13))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('tumour', 'Disease', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Disease', (123, 129))	('1p/19q', 'Var', (36, 42))	('ADC', 'MPA', (14, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (64, 75))	('axonal disruption in tumour', 'Disease', 'MESH:D019958', (200, 227))	('oligoastrocytomas', 'Disease', (59, 76))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (59, 76))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('ODG', 'Disease', (28, 31))	('axonal disruption in tumour', 'Disease', (200, 227))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('tumour', 'Disease', 'MESH:D009369', (221, 227))
110471	29902076	TP53 mutations are mainly found in astrocytomas and are associated with poor survival.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('astrocytomas', 'Disease', 'MESH:D001254', (35, 47))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (56, 66))	('found', 'Reg', (26, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (35, 46))	('astrocytomas', 'Disease', (35, 47))
110472	29902076	High incidence of IDH1 mutations are seen in TP53 mutations in early gliomagenesis of LGG.	('TP53', 'Gene', (45, 49))	('gliomagenesis', 'Disease', 'None', (69, 82))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', '3417', (18, 22))	('gliomagenesis', 'Disease', (69, 82))	('mutations', 'Var', (23, 32))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH1', 'Gene', (18, 22))	('TP53', 'Gene', '7157', (45, 49))
110473	29902076	GBMs with TP53 mutations were reported to be smaller in size compared to the wild type, presented as areas that were hyperintense on T2W FLAIR images.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', '7157', (10, 14))
110483	29902076	Overexpression of VEGF has been linked to ODG progression and associated with contrast-enhancing tumours, hypoxia, angiogenesis, and oedema in GBM.	('angiogenesis', 'CPA', (115, 127))	('tumours', 'Disease', 'MESH:D009369', (97, 104))	('tumours', 'Disease', (97, 104))	('associated', 'Reg', (62, 72))	('ODG', 'Disease', (42, 45))	('ODG', 'Disease', 'MESH:D009837', (42, 45))	('oedema', 'Disease', 'MESH:D004487', (133, 139))	('VEGF', 'Gene', '7422', (18, 22))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('oedema', 'Phenotype', 'HP:0000969', (133, 139))	('oedema', 'Disease', (133, 139))	('linked', 'Reg', (32, 38))	('Overexpression', 'Var', (0, 14))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('VEGF', 'Gene', (18, 22))
110491	29902076	CDKN2A deletions were reported at 42.6% in necrotic tumour of GBM patients.	('CDKN2A', 'Gene', '1029', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('deletions', 'Var', (7, 16))	('necrotic tumour', 'Disease', (43, 58))	('CDKN2A', 'Gene', (0, 6))	('necrotic tumour', 'Disease', 'MESH:D009369', (43, 58))	('patients', 'Species', '9606', (66, 74))
110492	29902076	The classic subtype of GBM also has a strong association with CDKN2A deletion (92%).	('CDKN2A', 'Gene', '1029', (62, 68))	('CDKN2A', 'Gene', (62, 68))	('deletion', 'Var', (69, 77))
110494	29902076	Overexpression of this gene has been implicated as an indicator of malignancy and poor prognosis in glioma.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('malignancy', 'Disease', 'MESH:D009369', (67, 77))	('Overexpression', 'Var', (0, 14))	('malignancy', 'Disease', (67, 77))
110499	29902076	Genomic heterogeneity can cause treatment resistance and highly heterogeneous tumours have a higher tendency for tumour progression.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('cause', 'Reg', (26, 31))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('treatment resistance', 'CPA', (32, 52))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumour', 'Disease', (78, 84))	('tumours', 'Disease', (78, 85))	('tumour', 'Disease', (113, 119))	('Genomic heterogeneity', 'Var', (0, 21))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
110500	29902076	Activated oncogenic signalling pathway via genetic mutations in EGFR/P13K/Akt and Ras/RAF/MEK pathways are major drivers for tumorigenesis.	('RAF', 'Gene', '22882', (86, 89))	('RAF', 'Gene', (86, 89))	('P13K', 'Var', (69, 73))	('genetic mutations', 'Var', (43, 60))	('MEK', 'Gene', (90, 93))	('MEK', 'Gene', '5609', (90, 93))	('P13K', 'SUBSTITUTION', 'None', (69, 73))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))
110506	29902076	Current research indicates: EGFR amplification/overexpression are associated with contrast enhancement in GBM, increase in perfusion metric, metabolite changes, and restricted water diffusion.	('GBM', 'Disease', (106, 109))	('amplification/overexpression', 'Var', (33, 61))	('increase', 'PosReg', (111, 119))	('EGFR', 'Gene', '1956', (28, 32))	('amplification/overexpression', 'PosReg', (33, 61))	('perfusion metric', 'MPA', (123, 139))	('metabolite changes', 'MPA', (141, 159))	('EGFR', 'Gene', (28, 32))	('enhancement', 'PosReg', (91, 102))	('restricted water diffusion', 'MPA', (165, 191))	('contrast', 'MPA', (82, 90))	('C', 'Chemical', 'MESH:D002244', (0, 1))
110508	29902076	Hypermethylated MGMT tumours showed mixed-nodular enhancement, non-temporal lobe lesions, and often show radiation or treatment-induced pseudo-progression.	('mixed-nodular enhancement', 'MPA', (36, 61))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('Hypermethylated', 'Var', (0, 15))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('non-temporal lobe lesions', 'CPA', (63, 88))	('radiation', 'CPA', (105, 114))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('MGMT', 'Gene', (16, 20))	('MGMT', 'Gene', '4255', (16, 20))	('tumours', 'Disease', (21, 28))
110510	29902076	Astrocytomas and ODG that harbour IDH1 mutation exhibit more favourable prognosis and response to chemotherapy compared to the wild types.	('IDH1', 'Gene', '3417', (34, 38))	('ODG', 'Disease', 'MESH:D009837', (17, 20))	('ODG', 'Disease', (17, 20))	('mutation', 'Var', (39, 47))	('IDH1', 'Gene', (34, 38))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('Astrocytomas', 'Disease', (0, 12))
110512	29902076	GBM with IDH1 mutations are larger at diagnosis, may be multifocal with left frontal lobe predominance, may be non-enhancing, have cystic and diffuse components, have a greater frequency of contact with brain ventricles, infrequent vascular abnormalities, less extent of necrosis and oedema.	('IDH1', 'Gene', (9, 13))	('oedema', 'Phenotype', 'HP:0000969', (284, 290))	('greater', 'PosReg', (169, 176))	('IDH1', 'Gene', '3417', (9, 13))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (232, 254))	('vascular abnormalities', 'Disease', (232, 254))	('vascular abnormalities', 'Disease', 'MESH:C564415', (232, 254))	('mutations', 'Var', (14, 23))	('necrosis and oedema', 'Disease', 'MESH:D004487', (271, 290))
110516	29902076	Genetic changes lead to metabolic reprogramming of the biosynthesis of glucose, glutamine, lipids, protein, DNA, and RNA for rapid growth and cell division of the tumour.	('glutamine', 'Chemical', 'MESH:C578860', (80, 89))	('lead to', 'Reg', (16, 23))	('changes', 'Var', (8, 15))	('glucose', 'Chemical', 'MESH:D005947', (71, 78))	('biosynthesis of glucose', 'MPA', (55, 78))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('glutamine', 'MPA', (80, 89))	('DNA', 'MPA', (108, 111))	('metabolic reprogramming', 'CPA', (24, 47))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('cell division', 'CPA', (142, 155))	('tumour', 'Disease', (163, 169))	('lipids', 'MPA', (91, 97))
110533	33591634	Prognostic accuracy was proved by time-dependent ROC analysis, with AUC 0.9, 0.93, and 0.876 at the survival time of 2-, 3-, and 5-year, respectively, which was superior to the AUC of the isocitrate dehydrogenase (IDH) mutation.	('isocitrate dehydrogenase', 'Gene', (188, 212))	('0.876', 'Var', (87, 92))	('isocitrate dehydrogenase', 'Gene', '3417', (188, 212))	('IDH', 'Gene', (214, 217))	('IDH', 'Gene', '3417', (214, 217))
110543	33591634	IDH mutation is a recognized prognostic biomarker for LGG patients.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('patients', 'Species', '9606', (58, 66))	('LGG', 'Disease', (54, 57))
110544	33591634	Patients with IDH1 or IDH2 mutation tend to have superior survival than others.	('IDH2', 'Gene', (22, 26))	('survival', 'CPA', (58, 66))	('mutation', 'Var', (27, 35))	('Patients', 'Species', '9606', (0, 8))	('IDH2', 'Gene', '3418', (22, 26))	('IDH1', 'Gene', (14, 18))	('superior', 'PosReg', (49, 57))	('IDH1', 'Gene', '3417', (14, 18))
110545	33591634	5  However, approximately 80%-90% of LGG patients harbor IDH1 and less than 1% harbor IDH2 mutations, which means that only a fraction of patients with poor or good prognosis can be identified based on IDH mutation status.	('IDH2', 'Gene', (86, 90))	('IDH', 'Gene', (202, 205))	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (57, 60))	('IDH', 'Gene', '3417', (202, 205))	('IDH', 'Gene', '3417', (86, 89))	('IDH2', 'Gene', '3418', (86, 90))	('IDH1', 'Gene', (57, 61))	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (91, 100))	('IDH1', 'Gene', '3417', (57, 61))	('LGG', 'Disease', (37, 40))	('IDH', 'Gene', (57, 60))	('patients', 'Species', '9606', (138, 146))
110558	33591634	Clinical parameters included age, gender, IDH mutation status, histopathological types, and overall survival (Table 1).	('IDH', 'Gene', '3417', (42, 45))	('IDH', 'Gene', (42, 45))	('mutation', 'Var', (46, 54))
110574	33591634	We derived a 24 ARGs signatures to calculate the predict index for each patient based on the expression levels of the 24 genes weighted by their regression coefficients: predict index = (-0.16347996*expression level of BAG1) + (0.31938936*expression level of LRRK2) + (0.09780923*expression level of ITGA3) + (0.05410868*expression level of DIRAS3) + (0.74255987*expression level of FGF7) + (-0.18145619*expression level of KCNK3) + (-0.03412787*expression level of BNIP3) + (0.06458334*expression level of CAPN1) + (0.06828578*expression level of DLC1) + (0.13859764*expression level of NFE2L2) + (-0.31072756*expression level of PTK6) + (-0.01122885*expression level of ACBD5) + (0.03437062*expression level of HIST1H3D) + (-0.89303388*expression level of SAR1A) + (0.30253164*expression level of SMURF1) + (0.00364621*expression level of HIST1H3H) + (-0.18239344*expression level of RNF185) + (0.02510785*expression level of ANXA5) + (-0.03842213*expression level of PEA15) + (-0.10924460*expression level of RRAGA) + (-0.10734054*expression level of NRG3) + (0.34811122*expression level of ERBB2) + (0.07805519*expression level of TP73) + (0.03900696*expression level of RBM18).	('ITGA3', 'Gene', (300, 305))	('HIST1H3D', 'Gene', (713, 721))	('BNIP3', 'Gene', (466, 471))	('0.34811122*', 'Var', (1063, 1074))	('RNF185', 'Gene', '91445', (886, 892))	('patient', 'Species', '9606', (72, 79))	('ANXA5', 'Gene', (928, 933))	('TP73', 'Gene', (1135, 1139))	('PEA15', 'Gene', '8682', (970, 975))	('CAPN1', 'Gene', (507, 512))	('PEA15', 'Gene', (970, 975))	('ERBB2', 'Gene', (1094, 1099))	('SMURF1', 'Gene', '57154', (799, 805))	('BNIP3', 'Gene', '664', (466, 471))	('KCNK3', 'Gene', '3777', (424, 429))	('DIRAS3', 'Gene', '9077', (341, 347))	('RNF185', 'Gene', (886, 892))	('NRG3', 'Gene', (1054, 1058))	('LRRK2', 'Gene', (259, 264))	('ARGs', 'Chemical', '-', (16, 20))	('ERBB2', 'Gene', '2064', (1094, 1099))	('DLC1', 'Gene', '10395', (548, 552))	('FGF7', 'Gene', (383, 387))	('HIST1H3D', 'Gene', '8351', (713, 721))	('DLC1', 'Gene', (548, 552))	('DIRAS3', 'Gene', (341, 347))	('0.07805519*', 'Var', (1104, 1115))	('PTK6', 'Gene', '5753', (631, 635))	('ANXA5', 'Gene', '308', (928, 933))	('HIST1H3H', 'Gene', (841, 849))	('RBM18', 'Gene', (1175, 1180))	('ITGA3', 'Gene', '3675', (300, 305))	('NFE2L2', 'Gene', '4780', (588, 594))	('RRAGA', 'Gene', '10670', (1012, 1017))	('BAG1', 'Gene', '573', (219, 223))	('RBM18', 'Gene', '92400', (1175, 1180))	('ACBD5', 'Gene', '91452', (672, 677))	('SMURF1', 'Gene', (799, 805))	('FGF7', 'Gene', '2252', (383, 387))	('ACBD5', 'Gene', (672, 677))	('CAPN1', 'Gene', '823', (507, 512))	('RRAGA', 'Gene', (1012, 1017))	('KCNK3', 'Gene', (424, 429))	('SAR1A', 'Gene', '56681', (758, 763))	('PTK6', 'Gene', (631, 635))	('HIST1H3H', 'Gene', '8357', (841, 849))	('TP73', 'Gene', '7161', (1135, 1139))	('NRG3', 'Gene', '10718', (1054, 1058))	('BAG1', 'Gene', (219, 223))	('SAR1A', 'Gene', (758, 763))	('NFE2L2', 'Gene', (588, 594))	('LRRK2', 'Gene', '120892', (259, 264))
110579	33591634	In TCGA training set, the AUC was 0.9, 0.93, and 0.876 at the survival time of 2, 3, and 5 years, respectively, which was better than the AUC of IDH mutation status (Figures 2C).	('IDH', 'Gene', (145, 148))	('0.876', 'Var', (49, 54))	('IDH', 'Gene', '3417', (145, 148))
110586	33591634	ROC analysis was used to investigate the prognostic or predictive accuracy of the signatures, which suggested that AUC was 0.881, 0.835, and 0.711, respectively, at 2-, 3-, and 5-year survival time, while the IDH mutation status AUC was less than 0.7 at 2, 3, and 5 years.	('IDH', 'Gene', '3417', (209, 212))	('AUC', 'Var', (115, 118))	('0.881', 'Var', (123, 128))	('0.711', 'Var', (141, 146))	('0.835', 'Var', (130, 135))	('IDH', 'Gene', (209, 212))
110588	33591634	Furthermore, predict index and IDH1 mutation showed significant prognostic value with p < 0.001 in training, test and validation sets.	('IDH1', 'Gene', '3417', (31, 35))	('mutation', 'Var', (36, 44))	('IDH1', 'Gene', (31, 35))
110593	33591634	IDH mutation and histological types were correlated with predict index, significantly, both in TCGA and CGGA cohorts (p < 0.001).	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('predict index', 'MPA', (57, 70))	('mutation', 'Var', (4, 12))
110596	33591634	Most oligodendroglioma and oligoastrocytoma carried IDH mutation with low-predict index, while most IDH wild type correspondence with high-predict index both in the TCGA and CGGA cohorts (Figure 6C,D).	('IDH', 'Gene', (100, 103))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (27, 43))	('IDH', 'Gene', '3417', (100, 103))	('IDH', 'Gene', (52, 55))	('oligoastrocytoma', 'Disease', (27, 43))	('oligodendroglioma', 'Disease', (5, 22))	('IDH', 'Gene', '3417', (52, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (32, 43))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('mutation', 'Var', (56, 64))	('oligodendroglioma', 'Disease', 'MESH:D009837', (5, 22))
110599	33591634	In TCGA cohort patients with oligoastrocytoma, astrocytoma, oligodendroglioma as well as IDH wild or mutation, showed significantly different outcomes between low-risk and high-risk groups (Figure 7A-E), while in CGGA cohort patients just with oligoastrocytoma, astrocytoma, and IDH mutation showed significantly different outcomes.	('patients', 'Species', '9606', (15, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('IDH', 'Gene', (279, 282))	('astrocytoma', 'Disease', 'MESH:D001254', (262, 273))	('astrocytoma', 'Disease', (262, 273))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (244, 260))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (29, 45))	('astrocytoma', 'Disease', 'MESH:D001254', (47, 58))	('astrocytoma', 'Disease', (47, 58))	('IDH', 'Gene', '3417', (89, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (249, 260))	('IDH', 'Gene', '3417', (279, 282))	('oligoastrocytoma', 'Disease', (244, 260))	('different', 'Reg', (132, 141))	('astrocytoma', 'Disease', 'MESH:D001254', (34, 45))	('astrocytoma', 'Disease', (34, 45))	('oligoastrocytoma', 'Disease', (29, 45))	('patients', 'Species', '9606', (225, 233))	('astrocytoma', 'Phenotype', 'HP:0009592', (262, 273))	('astrocytoma', 'Disease', 'MESH:D001254', (249, 260))	('oligodendroglioma', 'Disease', 'MESH:D009837', (60, 77))	('astrocytoma', 'Disease', (249, 260))	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('oligodendroglioma', 'Disease', (60, 77))	('IDH', 'Gene', (89, 92))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('mutation', 'Var', (101, 109))	('TCGA', 'Gene', (3, 7))
110626	32226530	Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer Rationale: Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy.	('Copy Number', 'Var', (0, 11))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DNA', 'MPA', (120, 123))	('Loss', 'NegReg', (112, 116))	('tumor', 'Disease', (151, 156))	('Cancer', 'Disease', (94, 100))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
110628	32226530	This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome.	('DDR genes', 'Gene', (75, 84))	('occurs', 'Reg', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('copy number amplification', 'Var', (46, 71))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('patient', 'Species', '9606', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
110632	32226530	Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors.	('global mutation load', 'MPA', (60, 80))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('amplification', 'Var', (26, 39))	('DDR', 'Gene', (17, 20))	('increased', 'PosReg', (145, 154))	('Tumors', 'Disease', (0, 6))	('decreased', 'NegReg', (50, 59))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
110636	32226530	Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response.	('correlations', 'Interaction', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('copy number amplification', 'Var', (182, 207))	('patient', 'Species', '9606', (277, 284))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('DDR drug resistance', 'MPA', (212, 231))	('DDR', 'Gene', (173, 176))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
110638	32226530	Tumors with DNA damage repair (DDR) deficiency demonstrate sensitivity to genome-instability targeting chemotherapies through "synthetic lethality".	('DDR', 'Gene', (31, 34))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('deficiency', 'Var', (36, 46))
110641	32226530	This led to the FDA's consecutive approval of olaparib (2014), rucaparib (2016), niraparib (2017), and talazoparib (2018), for the treatment of advanced ovarian cancer and metastatic breast cancer patients with germline BRCA mutation.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('patients', 'Species', '9606', (197, 205))	('BRCA', 'Gene', (220, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('advanced ovarian cancer', 'Disease', (144, 167))	('talazoparib', 'Chemical', 'MESH:C586365', (103, 114))	('niraparib', 'Chemical', 'MESH:C545685', (81, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('rucaparib', 'Chemical', 'MESH:C531549', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('olaparib', 'Chemical', 'MESH:C531550', (46, 54))	('advanced ovarian cancer', 'Disease', 'MESH:D010051', (144, 167))	('breast cancer', 'Disease', (183, 196))	('germline', 'Var', (211, 219))	('BRCA', 'Gene', '672', (220, 224))
110643	32226530	Despite the previously well-established connections between DDR loss-of-function and cancer development and treatment, how frequently the gain-of-function alterations in DDR pathways occur in cancer, and to what extent they affect the DNA damage repair clinical outcome and even drug response remain elusive.	('affect', 'Reg', (224, 230))	('alterations', 'Var', (155, 166))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gain-of-function', 'PosReg', (138, 154))	('DDR', 'Gene', (170, 173))	('DNA damage repair', 'MPA', (235, 252))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('loss-of-function', 'NegReg', (64, 80))
110644	32226530	In this study, we aimed to characterize the landscape of copy number amplification across nine DDR pathways in cancer by integrating the multi-dimensional genomic data from primary cancer samples and cancer cell lines across 32 cancer types.	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('copy number amplification', 'Var', (57, 82))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
110645	32226530	By further integrating the DDR gene data with tumor mutation burden, mutation signature, clinical treatment information and cancer cell line pharmacogenomics data, we sought to determine the DDR gene amplifications' impacts on the tumor genome instability, patient prognosis and drug responses.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('patient', 'Species', '9606', (257, 264))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', (231, 236))	('amplifications', 'Var', (200, 214))	('impacts', 'Reg', (216, 223))	('DDR', 'Gene', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
110647	32226530	The copy number segmentation data (SCNA score) were obtained from the Circular Binary Segmentation (CBS) algorithm, and the GISTIC (Genomic Identification of Significant Targets in Cancer) calls comprising -2 (deletion), -1 (loss), 0 (diploid), 1 (gain), and 2 (amplification) were made using GISTIC2.0.	('Circular Binary Segmentation (CBS) algorithm', 'Disease', 'MESH:C537538', (70, 114))	('loss', 'NegReg', (225, 229))	('gain', 'PosReg', (248, 252))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Cancer', 'Disease', (181, 187))	('deletion', 'Var', (210, 218))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))
110649	32226530	Genes with over 5% of samples harboring GISTIC call = -2 or 2 in more than two cancer types were defined as recurrently copy number deleted or amplified.	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('GISTIC call = -2', 'Var', (40, 56))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
110651	32226530	Gene Set Enrichment Analysis (GSEA) was performed to further interpret the association between DDR gene amplification and mRNA overexpression (see Supplementary Methods).	('mRNA overexpression', 'MPA', (122, 141))	('GSEA', 'Chemical', '-', (30, 34))	('DDR', 'Gene', (95, 98))	('amplification', 'Var', (104, 117))
110653	32226530	GSEA analysis was performed on the gene list ranked by the correlation between the gene copy number and mutation burden to determine whether DDR pathways are enriched in the top genes whose copy number gain/amplification could decrease genome instability.	('genome instability', 'MPA', (236, 254))	('decrease', 'NegReg', (227, 235))	('gain/amplification', 'PosReg', (202, 220))	('GSEA', 'Chemical', '-', (0, 4))	('copy number', 'Var', (190, 201))
110656	32226530	Overall survival rates were estimated by Kaplan-Meier curves between patients with or without specific gene copy number amplification/gain (CNAmp; GISTIC calls = 1 and 2) versus others and compared in the specific cancer types using a Cox regression model stratified by the DDR gene SNCA score.	('gene copy number amplification/gain', 'Var', (103, 138))	('SNCA', 'Gene', '6622', (283, 287))	('cancer', 'Disease', (214, 220))	('CNAmp', 'Chemical', '-', (140, 145))	('SNCA', 'Gene', (283, 287))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
110669	32226530	Intriguingly, we observed recurrent DDR gene copy number amplifications/gains (CNAmps) among the 10,489 TCGA cancer samples across 32 tumor types (Figure 1A, 1B, Table S1, and Figure S1A).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('copy number amplifications/gains', 'Var', (45, 77))	('DDR gene', 'Gene', (36, 44))	('cancer', 'Disease', (109, 115))	('CNAmp', 'Chemical', '-', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (134, 139))
110678	32226530	The overexpression of all 13 of the recurrently amplified DDR genes was significantly driven by copy number amplification in the cancer cell lines (Figure S1C and Tables S2 and S3).	('copy number amplification', 'Var', (96, 121))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('DDR genes', 'Gene', (58, 67))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('overexpression', 'PosReg', (4, 18))
110679	32226530	With the observation of significantly recurrent overexpression and amplification of DDR genes in both primary tumors and cancer cell lines, we wondered if CNAmp and overexpression of DDR genes would increase the DDR function in tumor cells.	('primary tumors', 'Disease', 'MESH:D009369', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('amplification', 'Var', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('DDR function', 'MPA', (212, 224))	('tumor', 'Disease', (228, 233))	('overexpression', 'PosReg', (48, 62))	('CNAmp', 'Chemical', '-', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('increase', 'PosReg', (199, 207))	('cancer', 'Disease', (121, 127))	('primary tumors', 'Disease', (102, 116))	('DDR genes', 'Gene', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
110681	32226530	This analysis revealed that tumors harboring CNAmp of 11 individual DDR genes (4 of which are recurrently amplified among multiple cancer types, UBE2T, PARP1, PRKDC, and RAD52) exhibited significantly reduced mutation burden versus those without CNAmp of these 11 DDR genes (Figure 2A), suggesting that the amplification of DDR genes might lead to an increased DDR function in those tumors.	('CNAmp', 'Var', (45, 50))	('RAD52', 'Gene', '5893', (170, 175))	('reduced', 'NegReg', (201, 208))	('mutation burden', 'MPA', (209, 224))	('tumors', 'Disease', 'MESH:D009369', (383, 389))	('PRKDC', 'Gene', '5591', (159, 164))	('PARP1', 'Gene', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('multiple cancer', 'Disease', (122, 137))	('PRKDC', 'Gene', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CNAmp', 'Chemical', '-', (246, 251))	('increased', 'PosReg', (351, 360))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (383, 389))	('UBE2T', 'Gene', (145, 150))	('DDR function', 'MPA', (361, 373))	('PARP1', 'Gene', '142', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('DDR genes', 'Gene', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('RAD52', 'Gene', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('UBE2T', 'Gene', '29089', (145, 150))	('CNAmp', 'Chemical', '-', (45, 50))	('tumors', 'Disease', (383, 389))	('multiple cancer', 'Disease', 'MESH:D009369', (122, 137))	('amplification', 'Var', (307, 320))
110684	32226530	Its loss-of-function mutations have been established to cause a hyper-mutator phenotype in multiple cancer types.	('multiple cancer', 'Disease', (91, 106))	('loss-of-function', 'NegReg', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('multiple cancer', 'Disease', 'MESH:D009369', (91, 106))	('hyper-mutator phenotype', 'MPA', (64, 87))	('mutations', 'Var', (21, 30))
110687	32226530	When considering all the 21 previously defined mutation signatures, including smoking-, UVB exposure-, and POLE deficiency-induced mutation signatures, we observed that tumors with DDR gene amplification have a significantly lower incidence of the aforementioned DNA damage (Figure 2D-H and Figure S2B).	('gene amplification', 'Var', (185, 203))	('DDR', 'Gene', (181, 184))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Figure 2D-H', 'Disease', 'MESH:D004062', (275, 286))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('lower', 'NegReg', (225, 230))	('Figure 2D-H', 'Disease', (275, 286))	('tumors', 'Disease', (169, 175))
110689	32226530	Tumors bearing amplification of FA pathway genes (FANCB, FANCC and FANCM in LGG and UBE2T in GBM) and HDR genes (ATM, CHECK1, MRE11A in GBM and GEN1 in skin cutaneous melanoma [SKCM]) showed significantly reduced temozolomide-induced signature score (Figure 2G), indicating the critical role of DSB-associated recombinational repair in attenuating alkylating agent-induced genome lesions.	('FANCB', 'Gene', '2187', (50, 55))	('ATM', 'Gene', (113, 116))	('FANCC', 'Gene', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 175))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MRE11A', 'Gene', (126, 132))	('FA', 'Phenotype', 'HP:0001994', (57, 59))	('GEN1', 'Gene', '348654', (144, 148))	('UBE2T', 'Gene', (84, 89))	('FA', 'Phenotype', 'HP:0001994', (50, 52))	('skin cutaneous melanoma', 'Disease', (152, 175))	('Tumors', 'Disease', (0, 6))	('FA', 'Phenotype', 'HP:0001994', (32, 34))	('UBE2T', 'Gene', '29089', (84, 89))	('FANCB', 'Gene', (50, 55))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('temozolomide', 'Chemical', 'MESH:D000077204', (213, 225))	('temozolomide-induced signature score', 'MPA', (213, 249))	('reduced', 'NegReg', (205, 212))	('FANCM', 'Gene', '57697', (67, 72))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('ATM', 'Gene', '472', (113, 116))	('FANCM', 'Gene', (67, 72))	('MRE11A', 'Gene', '4361', (126, 132))	('FANCC', 'Gene', '2176', (57, 62))	('amplification', 'Var', (15, 28))	('FA pathway genes', 'Gene', (32, 48))	('HDR genes', 'Gene', (102, 111))	('FA', 'Phenotype', 'HP:0001994', (67, 69))	('GEN1', 'Gene', (144, 148))
110690	32226530	These observations suggest that the CNAmp of DDR genes would restore the DDR function in tumor cells, thus alleviating the genome lesions and maintaining genome stability in the tumor.	('tumor', 'Disease', (178, 183))	('alleviating', 'NegReg', (107, 118))	('CNAmp', 'Chemical', '-', (36, 41))	('restore', 'PosReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('DDR genes', 'Gene', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('genome lesions', 'MPA', (123, 137))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('genome', 'MPA', (154, 160))	('DDR function', 'MPA', (73, 85))	('CNAmp', 'Var', (36, 41))	('tumor', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
110694	32226530	Amplification of the PMS2 gene is frequently found in glioblastoma multiforme (GBM, 454 [79.5%] of 571), lower grade glioma (LGG, 134 [22.4%] of 510), HNSC (205 [39.7%] of 517) and OV (132 [23.5%] of 562).	('PMS2', 'Gene', (21, 25))	('Amplification', 'Var', (0, 13))	('glioblastoma multiforme', 'Disease', (54, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('PMS2', 'Gene', '5395', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('HNSC', 'Phenotype', 'HP:0012288', (151, 155))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (54, 77))	('glioma', 'Disease', (117, 123))	('found', 'Reg', (45, 50))	('HNSC', 'Disease', (151, 155))
110695	32226530	Those patients with PMS2 gene amplification have significantly shorter survival compared to non-CNAmp patients in each cancer type (GBM, HR = 1.53, 95% CI 1.22 to 1.92, P = 1.98x10-4; LGG, HR = 2.32, 95% CI 1.69 to 3.19, P = 2.33x10-7; HNSC, HR = 1.58, 95% CI 1.24 to 2.02, P = 2.22x10-4; OV, HR = 1.42, 95% CI 1.12 to 1.79, P = 3.48x10-3) (Figure 3B).	('PMS2', 'Gene', (20, 24))	('PMS2', 'Gene', '5395', (20, 24))	('gene amplification', 'Var', (25, 43))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('shorter', 'NegReg', (63, 70))	('HNSC', 'Phenotype', 'HP:0012288', (236, 240))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (6, 14))	('CNAmp', 'Chemical', '-', (96, 101))	('survival', 'MPA', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
110697	32226530	Poor survival was observed in patients with POLM amplification in multiple cancer types (HNSC: CNAmp frequency = 36.4% [188 of 517], HR = 1.40, 95% CI 1.09 to 1.81, P = 9.17x10-3; LGG: CNAmp frequency = 23.5% [120 of 510], HR = 2.47, 95% CI 1.78 to 3.44, P = 6.83x10-3; and LUAD: CNAmp frequency = 51.9% [265 of 511], HR = 1.52, 95% CI 1.15 to 2.03, P = 3.83x10-3) (Figure 3C).	('amplification', 'Var', (49, 62))	('CNAmp', 'Chemical', '-', (280, 285))	('POLM', 'Gene', '27434', (44, 48))	('CNAmp', 'Chemical', '-', (95, 100))	('CNAmp', 'Chemical', '-', (185, 190))	('multiple cancer', 'Disease', (66, 81))	('patients', 'Species', '9606', (30, 38))	('HNSC', 'Phenotype', 'HP:0012288', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('POLM', 'Gene', (44, 48))	('multiple cancer', 'Disease', 'MESH:D009369', (66, 81))
110698	32226530	PRKDC amplification also significantly correlated with poor patient survival in multiple cancer types (sarcoma [SARC]: CNAmp frequency = 35.2% [89 of 253], HR = 2.15, 95% CI 1.46 to 3.18, P = 1.12x10-4; uterine corpus endometrial carcinoma [UCEC]: CNAmp frequency = 31.5% [165 of 523], HR = 1.72, 95% CI 1.21 to 2.44, P = 2.50x10-3) (Figure 3D).	('patient', 'Species', '9606', (60, 67))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (218, 239))	('multiple cancer', 'Disease', 'MESH:D009369', (80, 95))	('PRKDC', 'Gene', (0, 5))	('sarcoma', 'Disease', (103, 110))	('CNAmp', 'Chemical', '-', (119, 124))	('CNAmp', 'Chemical', '-', (248, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('amplification', 'Var', (6, 19))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (218, 239))	('PRKDC', 'Gene', '5591', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('multiple cancer', 'Disease', (80, 95))	('poor', 'NegReg', (55, 59))	('endometrial carcinoma', 'Disease', (218, 239))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
110700	32226530	The observation of significant positive correlations between DDR gene CNAmp and reduced tumor mutation burden, mechanism specific mutation signatures, and poor patient survival lead to our hypothesis that CNAmp of these DDR genes may cause poor patient survival by augmenting DDR function and consequently chemotherapy resistance in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('augmenting', 'PosReg', (265, 275))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('DDR function', 'MPA', (276, 288))	('DDR genes', 'Gene', (220, 229))	('patient', 'Species', '9606', (160, 167))	('tumor', 'Disease', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('chemotherapy resistance', 'CPA', (306, 329))	('CNAmp', 'Chemical', '-', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CNAmp', 'Var', (205, 210))	('tumor', 'Disease', (88, 93))	('CNAmp', 'Chemical', '-', (205, 210))	('patient', 'Species', '9606', (245, 252))
110703	32226530	Moreover, NBN CNAmp is most prominently correlated with poor overall survival in OV patients (HR = 1.36, 95% CI 1.13 to 1.64, P = 9.62x10-4) (Figure 4A).	('poor', 'NegReg', (56, 60))	('NBN CNAmp', 'Var', (10, 19))	('patients', 'Species', '9606', (84, 92))	('CNAmp', 'Chemical', '-', (14, 19))	('overall survival', 'MPA', (61, 77))
110707	32226530	Since platinum-based drugs and PARP inhibitors have been extensively used as the DSB-targeting chemotherapy of ovarian cancer, we performed a correlation analysis between NBN copy number alterations and the drug treatment response to cisplatin and PARPis across 505 cancer cell lines from the GDSC database.	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('ovarian cancer', 'Disease', (111, 125))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('PARP', 'Gene', '142', (31, 35))	('PARP', 'Gene', '142', (248, 252))	('copy', 'Var', (175, 179))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('alterations', 'Var', (187, 198))	('PARP', 'Gene', (248, 252))	('cancer', 'Disease', (119, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('PARP', 'Gene', (31, 35))	('platinum', 'Chemical', 'MESH:D010984', (6, 14))	('NBN', 'Gene', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
110708	32226530	This analysis revealed that NBN copy number is highly correlated with cellular viability responses to cisplatin treatment (rho = 0.25, P = 1.60x10-3), which is the most commonly used chemotherapy for OV patients.	('copy number', 'Var', (32, 43))	('NBN', 'Gene', (28, 31))	('patients', 'Species', '9606', (203, 211))	('correlated', 'Reg', (54, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))
110709	32226530	Moreover, the cancer cell lines with NBN amplification showed significantly increased resistance to PARP inhibitors olaparib and veliparib (Figure 4C).	('cancer', 'Disease', (14, 20))	('olaparib', 'MPA', (116, 124))	('veliparib', 'MPA', (129, 138))	('increased', 'PosReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PARP', 'Gene', (100, 104))	('resistance to', 'MPA', (86, 99))	('veliparib', 'Chemical', 'MESH:C521013', (129, 138))	('amplification', 'Var', (41, 54))	('NBN', 'Gene', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('PARP', 'Gene', '142', (100, 104))	('olaparib', 'Chemical', 'MESH:C531550', (116, 124))
110712	32226530	Consistently, NBN depletion significantly sensitized these cancer cells to cisplatin or olaparib treatment (Figure 4K-N and Figure S3D).	('sensitized', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('depletion', 'Var', (18, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('olaparib', 'Chemical', 'MESH:C531550', (88, 96))
110715	32226530	Our analysis also found a strong association between NBN amplification and AZD7762 (inhibitor for ATM substrate CHECK1/2) resistance (Figure 4C).	('AZD7762', 'Gene', (75, 82))	('AZD7762', 'Chemical', 'MESH:C532363', (75, 82))	('ATM', 'Gene', (98, 101))	('amplification', 'Var', (57, 70))	('resistance', 'MPA', (122, 132))	('ATM', 'Gene', '472', (98, 101))	('NBN', 'Gene', (53, 56))
110722	32226530	In this regard, we further integrated the copy number alterations data across 505 cancer cell lines and their responses to 37 genome-instability targeting drugs (i.e., 23 DNA-damaging drugs and 14 cell cycle/TP53 targeting agents) in GDSC.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('copy number alterations', 'Var', (42, 65))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))	('genome-instability', 'MPA', (126, 144))
110724	32226530	Among the 468 significant associations, 430 (92%) significant positive correlations indicated that DDR gene CNAmp lead to drug resistance (Table S4), suggesting that the CNAmp of DDR genes might induce a resistant phenotype to chemotherapy targeting genome-instability.	('induce', 'Reg', (195, 201))	('DDR', 'Gene', (99, 102))	('drug resistance', 'Phenotype', 'HP:0020174', (122, 137))	('DDR', 'Gene', (179, 182))	('CNAmp', 'Var', (170, 175))	('resistant phenotype', 'MPA', (204, 223))	('drug resistance', 'MPA', (122, 137))	('CNAmp', 'Chemical', '-', (108, 113))	('CNAmp', 'Chemical', '-', (170, 175))	('lead to', 'Reg', (114, 121))
110726	32226530	On the pathway level, the cancer cell lines with CNAmp of DDR genes across the BER (5 out of 10 genes), FA (3 out of 8 genes) and HDR (7 out of 21 genes) pathways exhibited significantly higher IC50s to camptothecin (P < 0.05).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('DDR', 'Gene', (58, 61))	('camptothecin', 'Chemical', 'MESH:D002166', (203, 215))	('CNAmp', 'Var', (49, 54))	('FA', 'Phenotype', 'HP:0001994', (104, 106))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('CNAmp', 'Chemical', '-', (49, 54))	('50s', 'Species', '1214577', (196, 199))	('IC50s to camptothecin', 'MPA', (194, 215))	('higher', 'PosReg', (187, 193))
110730	32226530	Six (29% of 21) HDR genes (NBN, GEN1, BARD1, RAD50, BRCA1, and BRIP1) showed significant positive correlations between the gene copy number alterations and cell line responses to veliparib and olaparib treatments respectively (P < 0.05) (Table S4).	('BRIP1', 'Gene', '83990', (63, 68))	('GEN1', 'Gene', '348654', (32, 36))	('BRCA1', 'Gene', '672', (52, 57))	('gene copy number alterations', 'Var', (123, 151))	('veliparib', 'Chemical', 'MESH:C521013', (179, 188))	('RAD50', 'Gene', (45, 50))	('GEN1', 'Gene', (32, 36))	('BRCA1', 'Gene', (52, 57))	('BARD1', 'Gene', '580', (38, 43))	('RAD50', 'Gene', '10111', (45, 50))	('cell line responses', 'CPA', (156, 175))	('olaparib', 'Chemical', 'MESH:C531550', (193, 201))	('HDR genes', 'Gene', (16, 25))	('BARD1', 'Gene', (38, 43))	('BRIP1', 'Gene', (63, 68))
110732	32226530	In the current study, by integrating multi-dimensional genomics and clinical data in cancer patients and cancer cell lines, we demonstrated that DNA damage repair (DDR) genes' copy number amplification/gain (CNAmp) and overexpression not only recurrently occur across 32 cancer types, but also lead to elevated DNA repair capacity and increased chemotherapy resistance.	('CNAmp', 'Chemical', '-', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('increased', 'PosReg', (335, 344))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('amplification/gain', 'PosReg', (188, 206))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (85, 91))	('overexpression', 'PosReg', (219, 233))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('chemotherapy resistance', 'CPA', (345, 368))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (271, 277))	('DNA repair capacity', 'MPA', (311, 330))	('elevated', 'PosReg', (302, 310))	('copy number', 'Var', (176, 187))
110734	32226530	DDR pathway deficiencies have been well-established as drug-actionable targets for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DDR pathway', 'Pathway', (0, 11))	('deficiencies', 'Var', (12, 24))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
110736	32226530	Previous studies reported that the restoration of homology-dependent recombination (HDR) function by somatic reversion of germline BRCA1/2 mutations confers platinum and PARPi resistance in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('ovarian cancer', 'Disease', (190, 204))	('mutations', 'Var', (139, 148))	('PARP', 'Gene', '142', (170, 174))	('platinum', 'CPA', (157, 165))	('BRCA1', 'Gene', '672', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('platinum', 'Chemical', 'MESH:D010984', (157, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('BRCA1', 'Gene', (131, 136))	('homology-dependent', 'MPA', (50, 68))	('PARP', 'Gene', (170, 174))
110739	32226530	Since the genome instability has been intensively reported as a prognosis marker for the cancer patient, we further adjusted the survival analysis using the genome instability data and confirmed that the strong connection between DDR gene amplification and poor patient survival still stood (data not shown).	('DDR', 'Gene', (230, 233))	('amplification', 'Var', (239, 252))	('patient', 'Species', '9606', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('patient', 'Species', '9606', (262, 269))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
110797	31821741	In univariate analyses, low BMI (underweight) was inversely associated (OR 0.36; 95% CI 0.21-0.62) to the risk of glioma compared to normal weight.	('BMI', 'MPA', (28, 31))	('glioma', 'Disease', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('low BMI', 'Phenotype', 'HP:0045082', (24, 31))	('low', 'Var', (24, 27))
110836	31821741	In glioma patients, TGF-beta has been shown to be upregulated and to take part importantly in glioma initiation and proliferation.38 Other mechanisms that could explain how alterations of the microbiota can affect the brain involve activation of the vagus nerve,39 neuroimmune pathways,40 microbial metabolites,41 and microbial-derived neurotransmitters.42 For example, microbiota-derived short-chain fatty acids control microglia maturation and function.41  In solid tumors other than malignant glioma, increasing evidence suggests meaningful associations between alterations of the intestinal microbiota and colorectal carcinoma,43, 44, 45, 46 hepatocellular carcinoma,47, 48 and breast cancer,49 among others.	('colorectal carcinoma', 'Disease', (610, 630))	('TGF-beta', 'Gene', '7039', (20, 28))	('glioma', 'Disease', (496, 502))	('solid tumors', 'Disease', 'MESH:D009369', (462, 474))	('associations', 'Interaction', (544, 556))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (610, 630))	('tumors', 'Phenotype', 'HP:0002664', (468, 474))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Disease', (3, 9))	('glioma', 'Disease', 'MESH:D005910', (496, 502))	('breast cancer', 'Disease', 'MESH:D001943', (682, 695))	('TGF-beta', 'Gene', (20, 28))	('breast cancer', 'Disease', (682, 695))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (496, 502))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (646, 670))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('alterations', 'Var', (565, 576))	('cancer', 'Phenotype', 'HP:0002664', (689, 695))	('patients', 'Species', '9606', (10, 18))	('glioma initiation', 'Disease', (94, 111))	('glioma initiation', 'Disease', 'MESH:D005910', (94, 111))	('solid tumors', 'Disease', (462, 474))	('hepatocellular carcinoma', 'Disease', (646, 670))	('glioma', 'Disease', (94, 100))	('malignant glioma', 'Disease', (486, 502))	('malignant glioma', 'Disease', 'MESH:D005910', (486, 502))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (468, 473))	('fatty acids', 'Chemical', 'MESH:D005227', (401, 412))
110850	31821741	Cohort II showed no association with a slightly increased hazard ratio.24  In a cohort of male US veterans with 192 out of 4383 glioma cases (4.38%) exposed to allergy/atopy, there was a nonsignificant correlation between allergy with latency >2 years and risk of brain tumors.16 A statistically significant trend of decreasing risk of brain cancer was observed with longer latency of allergy.16 Another cohort study based on the Swedish population which investigated the risk of various cancers including brain cancer observed no significant association with regard to the risk of brain tumors.23 Another cohort study in Taiwan found an increased risk of brain tumors after history of allergic rhinitis or asthma.60  Three meta-analyses which included most of the case-control studies cited above also found an inverse relation between allergy and glioma.18, 20, 21  Three other studies based on prospective cohorts found inverse associations of increased61, 62 or borderline63 pre-diagnostic serum IgE levels and the risk of glioma and thus provide further evidence for the involvement of the immune system.	('allergy', 'Disease', 'MESH:D004342', (385, 392))	('allergy', 'Disease', 'MESH:D004342', (837, 844))	('tumor', 'Phenotype', 'HP:0002664', (588, 593))	('brain tumors', 'Disease', 'MESH:D001932', (264, 276))	('allergy', 'Disease', (385, 392))	('brain cancer', 'Disease', 'MESH:D001932', (506, 518))	('allergy', 'Disease', (837, 844))	('brain tumors', 'Phenotype', 'HP:0030692', (264, 276))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('glioma', 'Disease', (1027, 1033))	('allergy', 'Phenotype', 'HP:0012393', (837, 844))	('allergy', 'Phenotype', 'HP:0012393', (385, 392))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('IgE', 'Gene', (1000, 1003))	('glioma', 'Disease', 'MESH:D005910', (1027, 1033))	('brain tumors', 'Disease', (582, 594))	('allergy', 'Disease', 'MESH:D004342', (160, 167))	('brain tumors', 'Phenotype', 'HP:0030692', (582, 594))	('borderline63', 'Var', (966, 978))	('glioma', 'Phenotype', 'HP:0009733', (849, 855))	('brain cancer', 'Phenotype', 'HP:0030692', (336, 348))	('cancers', 'Disease', 'MESH:D009369', (488, 495))	('IgE', 'Gene', '3497', (1000, 1003))	('brain tumors', 'Disease', (264, 276))	('increased61', 'Var', (947, 958))	('inverse', 'NegReg', (923, 930))	('brain cancer', 'Disease', 'MESH:D001932', (336, 348))	('glioma', 'Phenotype', 'HP:0009733', (1027, 1033))	('brain cancer', 'Disease', (506, 518))	('glioma', 'Disease', (849, 855))	('glioma', 'Disease', (128, 134))	('asthma', 'Disease', 'MESH:D001249', (707, 713))	('allergy', 'Disease', (160, 167))	('allergic rhinitis', 'Disease', 'MESH:D012220', (686, 703))	('brain tumors', 'Disease', 'MESH:D001932', (656, 668))	('tumors', 'Phenotype', 'HP:0002664', (662, 668))	('allergic rhinitis', 'Disease', (686, 703))	('brain tumors', 'Phenotype', 'HP:0030692', (656, 668))	('allergy', 'Phenotype', 'HP:0012393', (160, 167))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('asthma', 'Phenotype', 'HP:0002099', (707, 713))	('rhinitis', 'Phenotype', 'HP:0012384', (695, 703))	('glioma', 'Disease', 'MESH:D005910', (849, 855))	('allergy', 'Disease', 'MESH:D004342', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (662, 667))	('asthma', 'Disease', (707, 713))	('cancer', 'Phenotype', 'HP:0002664', (488, 494))	('cancer', 'Phenotype', 'HP:0002664', (512, 518))	('tumors', 'Phenotype', 'HP:0002664', (588, 594))	('allergic rhinitis', 'Phenotype', 'HP:0003193', (686, 703))	('allergy', 'Phenotype', 'HP:0012393', (222, 229))	('allergy', 'Disease', (222, 229))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (488, 495))	('brain tumors', 'Disease', (656, 668))	('brain cancer', 'Disease', (336, 348))	('cancers', 'Disease', (488, 495))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('brain tumors', 'Disease', 'MESH:D001932', (582, 594))	('brain cancer', 'Phenotype', 'HP:0030692', (506, 518))
110876	31372513	This is due to the fact that BL23 EPS induces gut microbial dysbiosis, while LGG EPS promotes microbial homeostasis.	('dysbiosis', 'Disease', (60, 69))	('EPS', 'Chemical', '-', (81, 84))	('microbial homeostasis', 'MPA', (94, 115))	('dysbiosis', 'Disease', 'MESH:D064806', (60, 69))	('promotes', 'PosReg', (85, 93))	('induces', 'Reg', (38, 45))	('EPS', 'Var', (34, 37))	('EPS', 'Chemical', '-', (34, 37))	('BL23', 'Species', '543734', (29, 33))	('LGG', 'Species', '568703', (77, 80))	('BL23', 'Gene', (29, 33))
110891	31372513	Deletion of intestinal HIF1alpha has been shown to worsen gut dysbiosis in response to alcohol exposure and exacerbate alcoholic liver disease.	('dysbiosis', 'Disease', (62, 71))	('exacerbate', 'PosReg', (108, 118))	('dysbiosis', 'Disease', 'MESH:D064806', (62, 71))	('alcohol', 'Chemical', 'MESH:D000438', (119, 126))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (119, 142))	('alcoholic liver disease', 'Disease', (119, 142))	('liver disease', 'Phenotype', 'HP:0001392', (129, 142))	('HIF1alpha', 'Gene', '797150', (23, 32))	('worsen', 'NegReg', (51, 57))	('alcohol', 'Chemical', 'MESH:D000438', (87, 94))	('HIF1alpha', 'Gene', (23, 32))	('response to alcohol exposure', 'MPA', (75, 103))	('Deletion', 'Var', (0, 8))
110897	31372513	However, apart from the well-reported benefits, dysregulated fermentation of some prebiotic polysaccharides (fibers) was reported to induce microbial dysbiosis and hepatic inflammation and liver cancer in mice, implying risks associated with their application.	('dysregulated fermentation', 'Var', (48, 73))	('liver cancer', 'Phenotype', 'HP:0002896', (189, 201))	('induce', 'PosReg', (133, 139))	('liver cancer', 'Disease', 'MESH:D006528', (189, 201))	('polysaccharides', 'Chemical', 'MESH:D011134', (92, 107))	('liver cancer', 'Disease', (189, 201))	('mice', 'Species', '10090', (205, 209))	('hepatic inflammation', 'Phenotype', 'HP:0012115', (164, 184))	('microbial', 'CPA', (140, 149))	('dysbiosis and hepatic inflammation', 'Disease', 'MESH:D064806', (150, 184))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
110906	31372513	Intriguingly, although oral administration of both LGG EPS and BL23 EPS ameliorated hepatic steatosis in high-fat diet-fed zebrafish, BL23 EPS induced liver inflammation and injury.	('liver inflammation and injury', 'Disease', 'MESH:D007249', (151, 180))	('zebrafish', 'Species', '7955', (123, 132))	('EPS', 'Chemical', '-', (139, 142))	('EPS', 'Chemical', '-', (68, 71))	('EPS ameliorated hepatic steatosis', 'Disease', 'MESH:D005234', (68, 101))	('BL23', 'Species', '543734', (134, 138))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (84, 101))	('EPS ameliorated hepatic steatosis', 'Disease', (68, 101))	('LGG', 'Species', '568703', (51, 54))	('BL23', 'Species', '543734', (63, 67))	('induced', 'Reg', (143, 150))	('EPS', 'Chemical', '-', (55, 58))	('BL23', 'Gene', (63, 67))	('steatosis', 'Phenotype', 'HP:0001397', (92, 101))	('liver inflammation', 'Phenotype', 'HP:0012115', (151, 169))	('BL23 EPS', 'Var', (134, 142))
110907	31372513	Moreover, the liver injury effect by BL23 EPS was attributable to dysbiosis of the intestinal microbiota, while LGG EPS improved the intestinal homeostasis.	('improved', 'PosReg', (120, 128))	('BL23', 'Species', '543734', (37, 41))	('LGG', 'Species', '568703', (112, 115))	('EPS', 'Chemical', '-', (116, 119))	('dysbiosis', 'Disease', (66, 75))	('EPS', 'Chemical', '-', (42, 45))	('dysbiosis', 'Disease', 'MESH:D064806', (66, 75))	('intestinal homeostasis', 'MPA', (133, 155))	('BL23 EPS', 'Var', (37, 45))	('liver injury', 'Disease', 'MESH:D056486', (14, 26))	('liver injury', 'Disease', (14, 26))
110921	31372513	Moreover, lipid droplets accumulation and triacylglyceride levels were significantly reduced by LGG EPS and BL23 EPS at the two doses compared with the high-fat diet group (Fig.	('triacylglyceride', 'Chemical', '-', (42, 58))	('EPS', 'Chemical', '-', (113, 116))	('triacylglyceride levels', 'MPA', (42, 65))	('lipid', 'Chemical', 'MESH:D008055', (10, 15))	('EPS', 'Chemical', '-', (100, 103))	('lipid droplets accumulation', 'MPA', (10, 37))	('LGG', 'Species', '568703', (96, 99))	('BL23', 'Species', '543734', (108, 112))	('LGG', 'Var', (96, 99))	('BL23', 'Var', (108, 112))	('reduced', 'NegReg', (85, 92))
110923	31372513	Similarly, LGG EPS and BL23 EPS decreased lipid droplet accumulation in liver of zebrafish larvae compared with the high-fat diet group (Fig.	('zebrafish', 'Species', '7955', (81, 90))	('BL23', 'Species', '543734', (23, 27))	('lipid droplet accumulation in', 'MPA', (42, 71))	('BL23', 'Gene', (23, 27))	('lipid', 'Chemical', 'MESH:D008055', (42, 47))	('LGG', 'Species', '568703', (11, 14))	('LGG', 'Var', (11, 14))	('EPS', 'Chemical', '-', (28, 31))	('decreased', 'NegReg', (32, 41))	('EPS', 'Chemical', '-', (15, 18))
110924	31372513	Consistent with the observed phenotypes, LGG EPS and BL23 EPS reverted the high-fat diet-associated expression of genes involved in lipogenesis and energy expenditure, to levels comparable to the control diet group (Fig.	('BL23', 'Species', '543734', (53, 57))	('BL23', 'Gene', (53, 57))	('high-fat diet-associated expression of genes', 'MPA', (75, 119))	('LGG EPS', 'Var', (41, 48))	('LGG', 'Species', '568703', (41, 44))	('EPS', 'Chemical', '-', (58, 61))	('EPS', 'Var', (58, 61))	('EPS', 'Chemical', '-', (45, 48))	('EPS', 'Var', (45, 48))	('reverted', 'NegReg', (62, 70))
110929	31372513	Moreover, BL23 EPS led to hepatocyte apoptosis, as shown by TUNEL staining and the expression of pro-apoptotic and anti-apoptotic factors (Fig.	('hepatocyte apoptosis', 'CPA', (26, 46))	('BL23', 'Gene', (10, 14))	('BL23', 'Species', '543734', (10, 14))	('led to', 'Reg', (19, 25))	('EPS', 'Chemical', '-', (15, 18))	('EPS', 'Var', (15, 18))
110930	31372513	Together, these results indicate that although both EPS's ameliorated hepatic steatosis in zebrafish fed a high-fat diet, BL23 EPS led to liver inflammation and injury, while LGG EPS showed liver protective effect.	("EPS's ameliorated hepatic steatosis", 'Disease', 'MESH:D005234', (52, 87))	('BL23', 'Species', '543734', (122, 126))	('liver inflammation and injury', 'Disease', 'MESH:D007249', (138, 167))	('BL23', 'Var', (122, 126))	('led to', 'Reg', (131, 137))	('zebrafish', 'Species', '7955', (91, 100))	('LGG', 'Species', '568703', (175, 178))	('EPS', 'Chemical', '-', (127, 130))	('steatosis', 'Phenotype', 'HP:0001397', (78, 87))	('EPS', 'Chemical', '-', (179, 182))	('EPS', 'Chemical', '-', (52, 55))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (70, 87))	("EPS's ameliorated hepatic steatosis", 'Disease', (52, 87))	('liver inflammation', 'Phenotype', 'HP:0012115', (138, 156))
110934	31372513	4b), indicating that the liver injury by BL23 EPS was not induced by the EPS per se.	('BL23 EPS', 'Var', (41, 49))	('BL23', 'Species', '543734', (41, 45))	('liver injury', 'Disease', (25, 37))	('EPS', 'Chemical', '-', (73, 76))	('liver injury', 'Disease', 'MESH:D056486', (25, 37))	('EPS', 'Chemical', '-', (46, 49))
110937	31372513	We observed that BL23 EPS, but not LGG EPS, led to intestinal bacterial outgrowth (Fig.	('EPS', 'Chemical', '-', (39, 42))	('EPS', 'Var', (22, 25))	('BL23', 'Species', '543734', (17, 21))	('intestinal bacterial outgrowth', 'CPA', (51, 81))	('led', 'Reg', (44, 47))	('LGG', 'Species', '568703', (35, 38))	('EPS', 'Chemical', '-', (22, 25))	('BL23 EPS', 'Var', (17, 25))
110949	31372513	Consistent with the liver injury phenotype, the microbiota transfer results showed that LGG EPS microbiota can reduce inflammation, while BL23 EPS microbiota enhanced inflammation in the colonized zebrafish (Fig.	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('LGG', 'Species', '568703', (88, 91))	('EPS', 'Chemical', '-', (92, 95))	('enhanced', 'PosReg', (158, 166))	('inflammation', 'Disease', (118, 130))	('EPS', 'Chemical', '-', (143, 146))	('BL23', 'Species', '543734', (138, 142))	('inflammation', 'Disease', 'MESH:D007249', (167, 179))	('BL23', 'Var', (138, 142))	('liver injury', 'Disease', (20, 32))	('zebrafish', 'Species', '7955', (197, 206))	('liver injury', 'Disease', 'MESH:D056486', (20, 32))	('reduce', 'NegReg', (111, 117))	('inflammation', 'Disease', (167, 179))
110951	31372513	We observed that the Plesiomonas strain led to significantly enhanced inflammation compared with the Cetobacterium strain (Fig.	('inflammation', 'Disease', (70, 82))	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('enhanced', 'PosReg', (61, 69))	('Plesiomonas', 'Var', (21, 32))
110960	31372513	This suggests that the LPS translocated from intestinal lumen contributed to the liver injury effect of BL23 EPS.	('EPS', 'Chemical', '-', (109, 112))	('BL23', 'Species', '543734', (104, 108))	('liver injury', 'Disease', (81, 93))	('BL23', 'Var', (104, 108))	('liver injury', 'Disease', 'MESH:D056486', (81, 93))
110961	31372513	Consistently, we observed that the LPS level in the serum and liver of BL23 EPS-fed zebrafish was significantly higher than in high-fat diet fish (Fig.	('BL23', 'Species', '543734', (71, 75))	('higher', 'PosReg', (112, 118))	('BL23', 'Var', (71, 75))	('LPS level', 'MPA', (35, 44))	('zebrafish', 'Species', '7955', (84, 93))	('EPS', 'Chemical', '-', (76, 79))
110963	31372513	The results above indicated that the BL23 EPS-altered microbiota, which featured enrichment of Proteobacteria and reduction of Fusobacteria, contributed to liver inflammation and injury.	('BL23', 'Species', '543734', (37, 41))	('contributed', 'Reg', (141, 152))	('BL23', 'Var', (37, 41))	('reduction', 'NegReg', (114, 123))	('liver inflammation', 'Phenotype', 'HP:0012115', (156, 174))	('EPS', 'Chemical', '-', (42, 45))	('liver inflammation and injury', 'Disease', 'MESH:D007249', (156, 185))	('enrichment', 'PosReg', (81, 91))	('Fusobacteria', 'MPA', (127, 139))	('Proteobacteria', 'MPA', (95, 109))
110969	31372513	Additionally, the monosaccharide combination of both EPS's led to bacterial overgrowth, similar to what was observed with BL23 EPS.	('EPS', 'Chemical', '-', (53, 56))	('BL23', 'Species', '543734', (122, 126))	('monosaccharide', 'Var', (18, 32))	('EPS', 'Chemical', '-', (127, 130))	('monosaccharide', 'Chemical', 'MESH:D009005', (18, 32))	('overgrowth', 'Phenotype', 'HP:0001548', (76, 86))	('bacterial overgrowth', 'CPA', (66, 86))
110975	31372513	We further found LGG EPS significantly induced the expression of genes related to antimicrobial peptides (AMPs) compared with either the high-fat diet or BL23 EPS groups.	('BL23', 'Species', '543734', (154, 158))	('expression of genes', 'MPA', (51, 70))	('LGG', 'Var', (17, 20))	('EPS', 'Chemical', '-', (21, 24))	('LGG', 'Species', '568703', (17, 20))	('EPS', 'Chemical', '-', (159, 162))	('induced', 'PosReg', (39, 46))	('AMPs', 'Chemical', '-', (106, 110))
111004	31372513	The expression of TLR4ba was decreased by treating germ-free zebrafish with an in vivo antisense TLR4ba morpholino or with a control morpholino.	('expression', 'MPA', (4, 14))	('TLR4ba', 'Gene', (18, 24))	('TLR4ba', 'Gene', (97, 103))	('TLR4ba', 'Gene', '403131', (18, 24))	('TLR4ba', 'Gene', '403131', (97, 103))	('decreased', 'NegReg', (29, 38))	('antisense', 'Var', (87, 96))	('zebrafish', 'Species', '7955', (61, 70))
111005	31372513	Figure 8b shows a substantial reduction in TLR4 expression with vivo antisense morpholino oligomers.	('expression', 'MPA', (48, 58))	('TLR4', 'Gene', (43, 47))	('TLR4', 'Gene', '7099', (43, 47))	('reduction', 'NegReg', (30, 39))	('antisense', 'Var', (69, 78))
111006	31372513	Knocking down TLR4ba inhibited the induction of Hif1alphaa and Hif1alphab by LGG EPS (Fig.	('EPS', 'Chemical', '-', (81, 84))	('LGG EPS', 'MPA', (77, 84))	('TLR4ba', 'Gene', (14, 20))	('LGG', 'Species', '568703', (77, 80))	('TLR4ba', 'Gene', '403131', (14, 20))	('inhibited', 'NegReg', (21, 30))	('Knocking', 'Var', (0, 8))
111014	31372513	Both BL23 EPS and LGG EPS increased the acetate and propionate in the intestinal content compared with the high-fat diet group (Fig.	('BL23', 'Var', (5, 9))	('acetate', 'Chemical', 'MESH:D000085', (40, 47))	('EPS', 'Chemical', '-', (10, 13))	('propionate', 'Chemical', 'MESH:D011422', (52, 62))	('LGG', 'Species', '568703', (18, 21))	('increased', 'PosReg', (26, 35))	('EPS', 'Chemical', '-', (22, 25))	('BL23', 'Species', '543734', (5, 9))
111015	31372513	However, the butyrate and isobutyrate levels were only increased by LGG EPS, with a reduction seen in the BL23 EPS group compared with the high-fat diet group (Fig.	('EPS', 'Chemical', '-', (72, 75))	('LGG', 'Var', (68, 71))	('BL23', 'Species', '543734', (106, 110))	('LGG', 'Species', '568703', (68, 71))	('increased', 'PosReg', (55, 64))	('isobutyrate', 'Chemical', 'MESH:D058610', (26, 37))	('butyrate', 'Chemical', 'MESH:D002087', (29, 37))	('butyrate', 'Chemical', 'MESH:D002087', (13, 21))	('EPS', 'Chemical', '-', (111, 114))
111031	31372513	The liver inflammation and injury in the BL23-EPS group resembles that of other liver diseases, such as alcoholic liver disease and NASH, except that steatosis was reversed by the EPS treatment.	('steatosis', 'Disease', (150, 159))	('steatosis', 'Disease', 'MESH:D005234', (150, 159))	('liver inflammation and injury', 'Disease', 'MESH:D007249', (4, 33))	('BL23-EPS', 'Var', (41, 49))	('liver disease', 'Phenotype', 'HP:0001392', (114, 127))	('liver disease', 'Phenotype', 'HP:0001392', (80, 93))	('NASH', 'Disease', (132, 136))	('BL23', 'Species', '543734', (41, 45))	('liver diseases', 'Disease', (80, 94))	('liver inflammation', 'Phenotype', 'HP:0012115', (4, 22))	('liver diseases', 'Disease', 'MESH:D008107', (80, 94))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (104, 127))	('liver diseases', 'Phenotype', 'HP:0001392', (80, 94))	('steatosis', 'Phenotype', 'HP:0001397', (150, 159))	('EPS', 'Chemical', '-', (180, 183))	('alcoholic liver disease', 'Disease', (104, 127))	('EPS', 'Chemical', '-', (46, 49))
111040	31372513	BL23-EPS improved hepatic steatosis but induced inflammation, which are seemingly contrasting effects.	('EPS', 'Chemical', '-', (5, 8))	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('BL23-EPS', 'Var', (0, 8))	('inflammation', 'Disease', (48, 60))	('induced', 'Reg', (40, 47))	('hepatic steatosis', 'Disease', 'MESH:D005234', (18, 35))	('BL23', 'Species', '543734', (0, 4))	('improved', 'PosReg', (9, 17))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (18, 35))	('steatosis', 'Phenotype', 'HP:0001397', (26, 35))	('hepatic steatosis', 'Disease', (18, 35))
111051	31372513	Previous studies have shown that the ERK (extracellular-signal-regulated kinase) p44/42 MAPK (ERK1/2) and classical diacylglycerol-sensitive forms of protein kinase C (PKC) are involved in the activation of HIF-1 by non-hypoxic stimuli.	('ERK1/2', 'Gene', (94, 100))	('ERK1/2', 'Gene', '399480;360144', (94, 100))	('diacylglycerol', 'Chemical', 'MESH:D004075', (116, 130))	('p44/42', 'Var', (81, 87))	('HIF-1', 'Gene', (207, 212))	('ERK', 'Enzyme', (37, 40))	('involved', 'Reg', (177, 185))
111058	31372513	Moreover, a previous study indicated that AMPs are the direct factor downstream of inflammasome signaling maintaining the homeostasis of the intestinal microbiota, and an aberrant AMP program by upstream inflammasome deficiency leads to microbial dysbiosis.	('aberrant', 'Var', (171, 179))	('AMPs', 'Chemical', '-', (42, 46))	('homeostasis', 'MPA', (122, 133))	('inflammasome deficiency leads to microbial dysbiosis', 'Disease', 'MESH:D064806', (204, 256))	('AMP', 'Chemical', '-', (42, 45))	('AMP', 'Chemical', '-', (180, 183))
111074	31372513	Interestingly, our results showed that the LGG EPS can inhibit the NFkappaB pathway, which may account for its anti-inflammatory effect.	('LGG', 'Species', '568703', (43, 46))	('LGG', 'Var', (43, 46))	('EPS', 'Chemical', '-', (47, 50))	('NFkappaB pathway', 'Pathway', (67, 83))	('inhibit', 'NegReg', (55, 62))
111169	26729052	It was found that MMP-2 expression was significantly associated with high-WHO grade gliomas (n = 24, OR = 6.54, CI = 4.98-8.60; I 2 = 0 %, P = 0.911) and poor overall survival (OS), while it did not correlate to age (n = 2, OR = 0.78, CI = 0.35-1.74; I 2 = 0 %, P = 0.621) and gender (n = 2, OR = 1.15, CI = 0.51-2.62; I 2 = 0 %, P = 0.995).	('overall survival', 'CPA', (159, 175))	('MMP-2', 'Gene', (18, 23))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('associated', 'Reg', (53, 63))	('poor', 'NegReg', (154, 158))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('expression', 'Var', (24, 34))	('MMP-2', 'Gene', '4313', (18, 23))
111185	26729052	Some studies reported that high TIMP-2 expression was associated with high-grade gliomas, but some studies gave the contrary results, and others even showed that TIMP-2 expression was not correlated with the WHO grade of gliomas.	('expression', 'MPA', (39, 49))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('gliomas', 'Disease', (221, 228))	('gliomas', 'Disease', 'MESH:D005910', (221, 228))	('TIMP-2', 'Gene', '7077', (162, 168))	('TIMP-2', 'Gene', '7077', (32, 38))	('gliomas', 'Phenotype', 'HP:0009733', (221, 228))	('high', 'Var', (27, 31))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('associated', 'Reg', (54, 64))	('TIMP-2', 'Gene', (162, 168))	('TIMP-2', 'Gene', (32, 38))
111195	26729052	The effects of MMP-2 or TIMP-2 expression on pathological grade, age, and gender were considered as statistically significant if the corresponding 95 % CI for each pooled OR did not overlap 1, and an observed OR >1 indicated that gliomas of high-WHO grade were associated with high MMP-2 or TIMP-2 expression.	('TIMP-2', 'Gene', (291, 297))	('high', 'Var', (277, 281))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('MMP-2', 'Gene', '4313', (15, 20))	('MMP-2', 'Gene', (282, 287))	('TIMP-2', 'Gene', (24, 30))	('TIMP-2', 'Gene', '7077', (291, 297))	('TIMP-2', 'Gene', '7077', (24, 30))	('gliomas', 'Disease', 'MESH:D005910', (230, 237))	('MMP-2', 'Gene', (15, 20))	('gliomas', 'Disease', (230, 237))	('MMP-2', 'Gene', '4313', (282, 287))
111202	26729052	The association of MMP-2 expression with overall survival (OS) was reported in one study, and the results showed that high MMP-2 expression was significantly associated with poor OS, while the exact data were not reported.	('high', 'Var', (118, 122))	('MMP-2', 'Gene', (123, 128))	('expression', 'MPA', (129, 139))	('MMP-2', 'Gene', '4313', (19, 24))	('MMP-2', 'Gene', (19, 24))	('MMP-2', 'Gene', '4313', (123, 128))	('overall survival', 'MPA', (41, 57))	('poor', 'Disease', (174, 178))
111218	26729052	There were also evidences that high MMP-2 expression was associated with poor OS in patients with gliomas.	('patients', 'Species', '9606', (84, 92))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('expression', 'MPA', (42, 52))	('poor OS', 'Disease', (73, 80))	('MMP-2', 'Gene', '4313', (36, 41))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('high', 'Var', (31, 35))	('MMP-2', 'Gene', (36, 41))
111227	26729052	In summary, our meta-analysis concluded that high MMP-2 expression was associated with high-grade gliomas, and there was no correlation between TIMP-2 expression and the WHO grade of gliomas.	('gliomas', 'Disease', (183, 190))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('TIMP-2', 'Gene', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('MMP-2', 'Gene', '4313', (50, 55))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('expression', 'MPA', (56, 66))	('gliomas', 'Disease', (98, 105))	('high', 'Var', (45, 49))	('TIMP-2', 'Gene', '7077', (144, 150))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('MMP-2', 'Gene', (50, 55))	('associated', 'Reg', (71, 81))
111234	32722247	Since the majority of changes was found in directions that might actually impair PpIX accumulation in WHO grade IV gliomas, additional studies are needed to analyze the corresponding factors of the heme biosynthesis also on protein level.	('PpIX', 'Chemical', 'MESH:C028025', (81, 85))	('impair', 'NegReg', (74, 80))	('heme', 'Chemical', 'MESH:D006418', (198, 202))	('changes', 'Var', (22, 29))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('PpIX accumulation', 'MPA', (81, 98))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('IV gliomas', 'Disease', (112, 122))	('IV gliomas', 'Disease', 'MESH:D005910', (112, 122))
111253	32722247	Due to multiple enzymes and transporters being involved in the metabolization of 5-ALA, a variety of alterations in mRNA expression could potentially result in increased intracellular PpIX accumulation.	('5-ALA', 'Chemical', 'MESH:C000614854', (81, 86))	('intracellular PpIX accumulation', 'MPA', (170, 201))	('alterations', 'Var', (101, 112))	('increased', 'PosReg', (160, 169))	('mRNA expression', 'MPA', (116, 131))	('PpIX', 'Chemical', 'MESH:C028025', (184, 188))
111291	32722247	Surprisingly, most statistically significant alterations in mRNA gene expression were observed in a direction that, if passed on to the protein level accordingly, should actually result in lower levels of intracellular PpIX in WHO grade IV gliomas.	('IV gliomas', 'Disease', 'MESH:D005910', (237, 247))	('alterations', 'Var', (45, 56))	('lower', 'NegReg', (189, 194))	('mRNA gene', 'Gene', (60, 69))	('PpIX', 'Chemical', 'MESH:C028025', (219, 223))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('levels of intracellular PpIX', 'MPA', (195, 223))	('gliomas', 'Phenotype', 'HP:0009733', (240, 247))	('IV gliomas', 'Disease', (237, 247))
111331	32722247	Future studies analyzing heme biosynthesis in the context of 5-ALA should thus specifically consider molecular tumor markers like 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (130, 148))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('5-ALA', 'Chemical', 'MESH:C000614854', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('heme', 'Chemical', 'MESH:D006418', (25, 29))
111351	32559177	Simplified Perfusion Fraction from Diffusion-weighted Imaging in Preoperative Prediction of IDH1 Mutation in WHO Grade II-III Gliomas: Comparison with Dynamic Contrast-enhanced and Intravoxel Incoherent Motion MRI Effect of isocitr ate dehydrogenase 1 (IDH1) mutation in neovascularization might be linked with tissue perfusion in gliomas.	('linked', 'Reg', (299, 305))	('gliomas', 'Disease', 'MESH:D005910', (331, 338))	('gliomas', 'Phenotype', 'HP:0009733', (331, 338))	('gliomas', 'Disease', (331, 338))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', (253, 257))	('II-III Gliomas', 'Disease', 'MESH:D005910', (119, 133))	('IDH1', 'Gene', '3417', (92, 96))	('Gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('IDH1', 'Gene', '3417', (253, 257))	('glioma', 'Phenotype', 'HP:0009733', (331, 337))	('II-III Gliomas', 'Disease', (119, 133))	('mutation', 'Var', (259, 267))
111353	32559177	Additionally, by comparing accuracy with dynamic contrast-enhanced (DCE) and full IVIM MRI, we tried to find the optimal imaging markers to predict IDH1 mutation status.	('IDH1', 'Gene', '3417', (148, 152))	('DCE', 'Gene', '1718', (68, 71))	('DCE', 'Gene', (68, 71))	('mutation', 'Var', (153, 161))	('IDH1', 'Gene', (148, 152))
111355	32559177	All parameters were compared between the IDH1 mutant and wild-type LGGs using the Mann-Whitney U test, including the DCE MRI-derived Ktrans, ve and vp, the conventional apparen t diffusion coefficient (ADC0,1000), IVIM-de rived perfusion fraction (f), diffusion coefficient (D) and pseudo-diffusion coefficient (D*), SPF.	('DCE', 'Gene', '1718', (117, 120))	('DCE', 'Gene', (117, 120))	('pseudo-diffusion', 'MPA', (282, 298))	('mutant', 'Var', (46, 52))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('Ktrans', 'Chemical', '-', (133, 139))
111358	32559177	DWI, DCE and IVIM MRI may noninvasively help discriminate IDH1 mutation statuses in LGGs.	('IDH1', 'Gene', '3417', (58, 62))	('DCE', 'Gene', '1718', (5, 8))	('mutation', 'Var', (63, 71))	('LGGs', 'Disease', (84, 88))	('DCE', 'Gene', (5, 8))	('IDH1', 'Gene', (58, 62))
111362	32559177	The 2016 revised fourth edition of the World Health Organization (WHO) classification of tumors of the central nervous system defines a large subset of gliomas based on molecular alterations, among which mutation of isocitrate dehydrogenase (IDH1) has shown to be the most important, for this mutation is thought to be a predictor of early steps in gliomag enesis.	('mutation', 'Var', (204, 212))	('glioma', 'Disease', 'MESH:D005910', (349, 355))	('tumors', 'Disease', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (349, 355))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('IDH1', 'Gene', (242, 246))	('glioma', 'Disease', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('IDH1', 'Gene', '3417', (242, 246))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (89, 125))	('glioma', 'Disease', (349, 355))	('mutation', 'Var', (293, 301))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
111363	32559177	It has been shown that 70%-90% of LGGs- carry IDH1 mutations, and that IDH1 mutant glioma have a survival benefit associated with the maximal surgical resection, and the use of radiation and chemical therapy.	('glioma', 'Disease', (83, 89))	('benefit', 'PosReg', (106, 113))	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', (46, 50))	('mutant', 'Var', (76, 82))	('IDH1', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (46, 50))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('survival', 'CPA', (97, 105))	('IDH1', 'Gene', '3417', (71, 75))
111364	32559177	Hence, assessing grade II and III gliomas by genetic alteration, which might be helpful for patient prognosis and clinical treatment, is now a common clinical practice.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('patient', 'Species', '9606', (92, 99))	('III gliomas', 'Disease', 'MESH:D005910', (30, 41))	('men', 'Species', '9606', (128, 131))	('grade', 'Disease', (17, 22))	('genetic alteration', 'Var', (45, 63))	('III gliomas', 'Disease', (30, 41))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
111373	32559177	The purpose of our study, therefore, was to determine the association of the three b-value DWI-derived simplified perfusion fraction (SPF) with tumor perfusion and to compare the performance with DC E and IVIM MRI-derived parameters in the preoperative prediction of IDH1 mutation status in LGGs using surgical and histopathological findings as a standard of reference.	('tumor', 'Disease', (144, 149))	('DC E', 'Chemical', '-', (196, 200))	('IDH1', 'Gene', (267, 271))	('IDH1', 'Gene', '3417', (267, 271))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mutation', 'Var', (272, 280))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('LGGs', 'Disease', (291, 295))
111389	32559177	The b-value scheme was chosen following previous recommendations which indicated that the effects of diffusion and microcapillary perfusion are both reflected within low b-values (b < 200 s/mm2), while for higher b-values (b > 200 s/mm2), a large proportion of measured signal in each imaging voxel was caused by tissue diffusion.	('tissue diffusion', 'CPA', (313, 329))	('b > 200 s/mm2', 'Var', (223, 236))	('signal', 'MPA', (270, 276))	('b < 200 s/mm2', 'Var', (180, 193))	('men', 'Species', '9606', (54, 57))	('low', 'NegReg', (166, 169))	('caused by', 'Reg', (303, 312))	('b-values', 'MPA', (170, 178))
111395	32559177	The unpaired t-test and Mann-Whitney U test were used to determine the difference in DWI, DCE and IVIM MRI parameters between WHO grade II and III gliomas, as well as between IDH1 mutant and wild-type gliomas, according to the data normality (Kolmogorov-Smirnov test).	('DCE', 'Gene', '1718', (90, 93))	('gliomas', 'Disease', (201, 208))	('DCE', 'Gene', (90, 93))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('mutant', 'Var', (180, 186))	('III gliomas', 'Disease', 'MESH:D005910', (143, 154))	('IDH1', 'Gene', (175, 179))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Disease', (147, 154))	('III gliomas', 'Disease', (143, 154))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('IDH1', 'Gene', '3417', (175, 179))
111401	32559177	Representative cases of IDH1 mutant and wild-type LGGs are shown in Figures 2 and 3.	('IDH1', 'Gene', '3417', (24, 28))	('mutant', 'Var', (29, 35))	('IDH1', 'Gene', (24, 28))
111402	32559177	The mean values +- standard deviations of DCE MRI and DWI-derived parameters for the IDH1 mutant and wild-type tumors in the whole LGGs group, are summarized in Table 3.	('DCE', 'Gene', '1718', (42, 45))	('DCE', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutant', 'Var', (90, 96))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('IDH1', 'Gene', (85, 89))	('IDH1', 'Gene', '3417', (85, 89))
111404	32559177	In the WHO grade II subgroup, vp and SPF differed significantly between IDH1 mutant and wild-type tumors (P = 0.018 and P = 0.049, respectively), whereas in the WHO grade III subgroup, only f showed a significant difference (P = 0.014).	('tumors', 'Disease', (98, 104))	('IDH1', 'Gene', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('SPF', 'MPA', (37, 40))	('differed', 'Reg', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('IDH1', 'Gene', '3417', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutant', 'Var', (77, 83))
111405	32559177	For differentiation between IDH1 mutant and wild-type LGGs, the ROC curve analysis showed that among all parameters, SPF gave the highest AUC value (0.86), followed by f (0.81) and ADC (0.80), though no significant difference in AUC values was found (P > 0.05).	('AUC value', 'MPA', (138, 147))	('mutant', 'Var', (33, 39))	('IDH1', 'Gene', '3417', (28, 32))	('IDH1', 'Gene', (28, 32))
111406	32559177	The optimal SPF threshold for IDH1 mutation discrimination was 14.5%, with a sensitivity and specificity of 94.4% and 75.0%, respectively.	('IDH1', 'Gene', (30, 34))	('IDH1', 'Gene', '3417', (30, 34))	('mutation', 'Var', (35, 43))
111408	32559177	Our results showed that diffusion and perfusion metrics exhibited substantial differences between WHO grade II and III gliomas, as well as between IDH1 mutant and wild-type LGGs.	('III gliomas', 'Disease', 'MESH:D005910', (115, 126))	('differences', 'Reg', (78, 89))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('III gliomas', 'Disease', (115, 126))	('mutant', 'Var', (152, 158))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('IDH1', 'Gene', (147, 151))	('IDH1', 'Gene', '3417', (147, 151))
111409	32559177	Among all parameters, the simplified DWI-derived perfusion fraction showed higher efficacy in IDH1 mutation detection, indicating that this recently developed three-b-value DWI approach may serve as a surrogate method for LGGs molecular diagnosis.	('detection', 'Reg', (108, 117))	('IDH1', 'Gene', (94, 98))	('higher', 'PosReg', (75, 81))	('IDH1', 'Gene', '3417', (94, 98))	('mutation', 'Var', (99, 107))
111418	32559177	Over the last decade, studies have shown that gliomas with IDH mutation are less aggressive and more sensitive to chemotherapy, contributing to a longer overall survival.	('IDH', 'Gene', (59, 62))	('overall survival', 'MPA', (153, 169))	('IDH', 'Gene', '3417', (59, 62))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('mutation', 'Var', (63, 71))	('longer', 'PosReg', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
111421	32559177	In this study, DWI, DCE, and IVIM MRI-derived perfusion parameters all showed significant differences between IDH1 mutant and wild-type LGGs.	('IDH1', 'Gene', '3417', (110, 114))	('mutant', 'Var', (115, 121))	('differences', 'Reg', (90, 101))	('IDH1', 'Gene', (110, 114))	('DCE', 'Gene', '1718', (20, 23))	('DCE', 'Gene', (20, 23))
111425	32559177	suggested that IDH1 mutation is associated with decreased invasiveness and reduced angiogenesis via downregulation of the Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', '1499', (126, 138))	('decreased invasiveness', 'Disease', 'MESH:D009361', (48, 70))	('IDH1', 'Gene', (15, 19))	('mutation', 'Var', (20, 28))	('IDH1', 'Gene', '3417', (15, 19))	('reduced', 'NegReg', (75, 82))	('decreased invasiveness', 'Disease', (48, 70))	('downregulation', 'NegReg', (100, 114))	('angiogenesis', 'CPA', (83, 95))	('beta-catenin', 'Gene', (126, 138))
111426	32559177	Furthermore, the accumulation of 2-hydroxyglutarate, an oncometabolite produced upon IDH1 mutation, has been shown to affect hypoxia-inducible factor (HIF) levels and the HIF response and may, consequently, reduce hypoxia-induced neovascularization.	('hypoxia', 'Disease', (125, 132))	('reduce', 'NegReg', (207, 213))	('hypoxia', 'Disease', (214, 221))	('HIF response', 'MPA', (171, 183))	('affect', 'Reg', (118, 124))	('accumulation', 'PosReg', (17, 29))	('hypoxia', 'Disease', 'MESH:D000860', (214, 221))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (33, 51))	('IDH1', 'Gene', (85, 89))	('hypoxia', 'Disease', 'MESH:D000860', (125, 132))	('mutation', 'Var', (90, 98))	('IDH1', 'Gene', '3417', (85, 89))
111427	32559177	According to our ROC curve analysis, the simplified DWI-derived perfusion fraction showed a superior diagnostic accuracy as a predictor for IDH1 mutation in LGGs compared to the full IVIM-derived f. This result suggests that the three-b-value simplified DWI approach could save substantial scanning time compared with the full IVIM approach, with no loss of diagnostic efficiency.	('IDH1', 'Gene', '3417', (140, 144))	('IDH1', 'Gene', (140, 144))	('mutation', 'Var', (145, 153))
111430	32559177	When WHO grade II and III gliomas were analyzed separately, we found SPF exhibited a statistically significant difference in assessing IDH1 mutation status of WHO grade II tumors, whereas f helped assess WHO grade III tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('II tumors', 'Disease', (169, 178))	('III gliomas', 'Disease', 'MESH:D005910', (22, 33))	('II tumors', 'Disease', 'MESH:D009369', (169, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('IDH1', 'Gene', (135, 139))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('II tumors', 'Disease', 'MESH:D009369', (215, 224))	('III gliomas', 'Disease', (22, 33))	('IDH1', 'Gene', '3417', (135, 139))	('III tumors', 'Disease', 'MESH:D009369', (214, 224))	('mutation status', 'Var', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('III tumors', 'Disease', (214, 224))
111431	32559177	Besides perfusion, diffusion parameters like ADC0,1000 were also predictive of IDH1 mutation in LGGs, with a lower diffusion coefficient found in IDH1 wild-type tumors.	('IDH1', 'Gene', (146, 150))	('IDH1', 'Gene', '3417', (79, 83))	('LGGs', 'Disease', (96, 100))	('tumors', 'Disease', (161, 167))	('IDH1', 'Gene', '3417', (146, 150))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('IDH1', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
111433	32559177	Therefore, we may have underestimated some associations, such as the association between perfusion-related metrics and IDH1 mutation status, in WHO grade III gliomas.	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('mutation status', 'Var', (124, 139))	('III gliomas', 'Disease', 'MESH:D005910', (154, 165))	('IDH1', 'Gene', (119, 123))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('IDH1', 'Gene', '3417', (119, 123))	('III gliomas', 'Disease', (154, 165))
111437	32559177	In conclusion, DWI, DCE, and IVIM MRI can be used as quantitative perfusion methods in preoperative IDH1 mutation prediction in LGGs.	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (100, 104))	('LGGs', 'Disease', (128, 132))	('IDH1', 'Gene', (100, 104))	('DCE', 'Gene', '1718', (20, 23))	('DCE', 'Gene', (20, 23))
111444	32418115	High cytoplasmic TrxR expression was significantly associated with adverse overall survival (OS) in adult glioblastoma (P = 0.027) and paediatric low-grade glioma (LGG) patients (P = 0.012).	('patients', 'Species', '9606', (169, 177))	('Trx', 'Gene', (17, 20))	('glioma', 'Disease', (156, 162))	('glioblastoma', 'Disease', (106, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('adverse', 'NegReg', (67, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('overall survival', 'MPA', (75, 91))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('High cytoplasmic', 'Var', (0, 16))	('Trx', 'Gene', '7295', (17, 20))
111446	32418115	For patients with high-grade gliomas, both high cytoplasmic TrxR and Trx expression were associated with poor OS (P = 0.002 and P = 0.007, respectively).	('high cytoplasmic', 'Var', (43, 59))	('Trx', 'Gene', '7295', (69, 72))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('Trx', 'Gene', (69, 72))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('expression', 'MPA', (73, 83))	('Trx', 'Gene', '7295', (60, 63))	('patients', 'Species', '9606', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('Trx', 'Gene', (60, 63))
111492	32418115	Primary antibodies against Trx (1:2000, Abcam), TrxR (1:150, Abcam) and TxNIP (1:1000, Abcam) were incubated on tissue overnight at 4  C, with antibody specificity initially confirmed by Western blotting (Supplementary Fig.	('Trx', 'Gene', '7295', (27, 30))	('Trx', 'Gene', '7295', (48, 51))	('TxNIP', 'Gene', (72, 77))	('Trx', 'Gene', (27, 30))	('Trx', 'Gene', (48, 51))	('TxNIP', 'Gene', '10628', (72, 77))	('1:150', 'Var', (54, 59))
111507	32418115	In rim samples high cytoplasmic TrxR expression was significantly associated with adverse overall survival (P = 0.027) whereas nuclear TrxR expression was not (P = 0.462) (Fig.	('high', 'Var', (15, 19))	('overall', 'MPA', (90, 97))	('Trx', 'Gene', '7295', (135, 138))	('Trx', 'Gene', '7295', (32, 35))	('Trx', 'Gene', (32, 35))	('Trx', 'Gene', (135, 138))	('adverse', 'NegReg', (82, 89))
111512	32418115	In the paediatric LGGs, high cytoplasmic TrxR was associated with supratentorial tumours (chi2 = 10.384, df = 1, P = 0.002) and the presence of tumour recurrence (chi2 = 10.231, df = 1, P = 0.004), whereas high nuclear TrxR expression was associated with the absence of tumour recurrence (chi2 = 9.850, df = 1, P = 0.001).	('Trx', 'Gene', '7295', (219, 222))	('Trx', 'Gene', '7295', (41, 44))	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('Trx', 'Gene', (219, 222))	('Trx', 'Gene', (41, 44))	('high cytoplasmic', 'Var', (24, 40))	('tumour', 'Disease', (270, 276))	('tumour', 'Disease', (81, 87))	('tumours', 'Disease', (81, 88))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
111515	32418115	Kaplan-Meier survival analysis showed that high expression of cytoplasmic TrxR was significantly associated with poor overall survival (P = 0.012) (Fig.	('overall survival', 'MPA', (118, 134))	('high', 'Var', (43, 47))	('poor', 'NegReg', (113, 117))	('Trx', 'Gene', '7295', (74, 77))	('Trx', 'Gene', (74, 77))
111516	32418115	3a) whereas high TrxR expression in the nucleus was associated with improved overall survival (P = 0.031) (Fig.	('Trx', 'Gene', (17, 20))	('high', 'Var', (12, 16))	('improved', 'PosReg', (68, 76))	('overall survival', 'MPA', (77, 93))	('Trx', 'Gene', '7295', (17, 20))	('expression', 'MPA', (22, 32))
111518	32418115	In addition, high TxNIP expression was also associated with improved overall survival (P = 0.018) (Fig.	('overall survival', 'MPA', (69, 85))	('TxNIP', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('TxNIP', 'Gene', '10628', (18, 23))	('improved', 'PosReg', (60, 68))
111520	32418115	In the paediatric HGGs, anaplastic oligodendroglioma was significantly associated with high cytoplasmic Trx expression whilst GBM with low expression (chi2 = 9.785, df = 2, P = 0.008).	('Trx', 'Gene', '7295', (104, 107))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (24, 52))	('Trx', 'Gene', (104, 107))	('high', 'Var', (87, 91))	('expression', 'MPA', (108, 118))	('anaplastic oligodendroglioma', 'Disease', (24, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
111523	32418115	Univariate survival analysis showed that high expression of both cytoplasmic TrxR and Trx was significantly associated with adverse overall survival (P = 0.002 and P = 0.007, respectively) (Fig.	('Trx', 'Gene', '7295', (86, 89))	('Trx', 'Gene', (86, 89))	('high expression', 'Var', (41, 56))	('associated', 'Reg', (108, 118))	('Trx', 'Gene', '7295', (77, 80))	('Trx', 'Gene', (77, 80))
111529	32418115	As with the other cohorts patients with high cytoplasmic TrxR expression had significantly shorter overall survival compared with low expression (P = 0.013) (Fig.	('Trx', 'Gene', (57, 60))	('overall survival', 'MPA', (99, 115))	('patients', 'Species', '9606', (26, 34))	('Trx', 'Gene', '7295', (57, 60))	('shorter', 'NegReg', (91, 98))	('high cytoplasmic', 'Var', (40, 56))
111530	32418115	High Trx expression within cytoplasm and nucleus were both associated with adverse overall survival (P = 0.033 and P = 0.007, respectively) (Fig.	('High', 'Var', (0, 4))	('overall', 'MPA', (83, 90))	('adverse', 'NegReg', (75, 82))	('expression', 'MPA', (9, 19))	('Trx', 'Gene', '7295', (5, 8))	('Trx', 'Gene', (5, 8))
111560	32418115	Current survival data demonstrate that high cytoplasmic TrxR expression is significantly associated with adverse overall survival in adult GBMs (rim area) (P = 0.027).	('high cytoplasmic', 'Var', (39, 55))	('Trx', 'Gene', '7295', (56, 59))	('Trx', 'Gene', (56, 59))	('adverse', 'NegReg', (105, 112))	('overall survival', 'CPA', (113, 129))
111576	32418115	On the contrary, significant associations were seen in the current study, results showing that high cytoplasmic TrxR expression was significantly associated with tumour recurrence and adverse overall survival (P = 0.012), and with high nuclear TrxR expression associated with lower risk of recurrence and improved overall survival (P = 0.031).	('tumour', 'Disease', (162, 168))	('Trx', 'Gene', '7295', (244, 247))	('expression', 'MPA', (117, 127))	('high', 'Var', (95, 99))	('Trx', 'Gene', (244, 247))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('overall', 'MPA', (314, 321))	('Trx', 'Gene', '7295', (112, 115))	('associated', 'Reg', (146, 156))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('improved', 'PosReg', (305, 313))	('Trx', 'Gene', (112, 115))
111580	32418115	Another study investigating 85 oligodendrogliomas showed that high Trx expression was associated with poor prognosis in univariate analysis (P = 0.0343) and remained significant in multivariate analysis (P = 0.009).	('expression', 'MPA', (71, 81))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (31, 49))	('Trx', 'Gene', '7295', (67, 70))	('Trx', 'Gene', (67, 70))	('oligodendrogliomas', 'Disease', (31, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('high', 'Var', (62, 66))
111585	32418115	Apart from Trx, high TxNIP expression was also a prognostic factor for better overall survival in this cohort, which is consistent with a study conducted in locally advanced breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('TxNIP', 'Gene', (21, 26))	('high', 'Var', (16, 20))	('TxNIP', 'Gene', '10628', (21, 26))	('Trx', 'Gene', (11, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('overall survival', 'MPA', (78, 94))	('patients', 'Species', '9606', (188, 196))	('better', 'PosReg', (71, 77))	('Trx', 'Gene', '7295', (11, 14))
111588	32418115	In primary human gastric cancers, high levels of Trx expression also correlated with shorter patient survival.	('shorter', 'NegReg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Trx', 'Gene', '7295', (49, 52))	('gastric cancers', 'Disease', 'MESH:D013274', (17, 32))	('human', 'Species', '9606', (11, 16))	('gastric cancers', 'Disease', (17, 32))	('Trx', 'Gene', (49, 52))	('gastric cancers', 'Phenotype', 'HP:0012126', (17, 32))	('patient survival', 'CPA', (93, 109))	('high', 'Var', (34, 38))	('patient', 'Species', '9606', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('expression', 'MPA', (53, 63))
111589	32418115	Consistent with these findings, the current study shows that cytoplasmic Trx expression associates with poor prognosis in HGGs.	('HGGs', 'Disease', (122, 126))	('Trx', 'Gene', (73, 76))	('Trx', 'Gene', '7295', (73, 76))	('cytoplasmic', 'Var', (61, 72))
111622	30400878	Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types.	('cancer', 'Disease', (131, 137))	('epigenomic', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('transcriptomic alterations', 'MPA', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('contribute', 'Reg', (45, 55))	('CDG', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CDG', 'Chemical', '-', (31, 34))	('mutations', 'Var', (35, 44))
111623	30400878	Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CDG', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('CDG', 'Chemical', '-', (68, 71))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
111629	30400878	Cancer arises through accumulation of somatically acquired genetic and epigenetic aberrations that lead to malignant transformation.	('epigenetic aberrations', 'Var', (71, 93))	('lead to', 'Reg', (99, 106))	('malignant transformation', 'CPA', (107, 131))	('genetic', 'Var', (59, 66))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
111630	30400878	Comprehensive characterization of somatic mutations in cancer genomes using next-generation sequencing technology has led to discoveries of cancer driver genes (CDGs) in human cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('CDGs', 'Chemical', '-', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (55, 61))
111631	30400878	Specifically, genome-wide change of DNA methylation was observed in patients with mutations in epigenetic regulators, affecting both the global levels of 5-methyl-cytosine (5mC) and the precise DNA methylation patterns in diverse regulatory sequences across the genome.	('affecting', 'Reg', (118, 127))	('5mC', 'Chemical', 'MESH:D044503', (173, 176))	('5-methyl-cytosine', 'Chemical', 'MESH:D044503', (154, 171))	('patients', 'Species', '9606', (68, 76))	('mutations', 'Var', (82, 91))	('DNA methylation patterns', 'MPA', (194, 218))	('change', 'Reg', (26, 32))
111632	30400878	A recent study investigated associations between driver gene mutations and DNA methylation alterations across many cancer types, and identified associations between mutated driver genes and site-specific methylation changes as well as some genome-wide trends in specific cancer types.	('associations', 'Interaction', (144, 156))	('cancer', 'Disease', (115, 121))	('associations', 'Interaction', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('DNA', 'Gene', (75, 78))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
111634	30400878	However, it remains largely unknown how the CDG mutations contribute to changes in cancer cell epigenomes on a pan-cancer level.	('cancer', 'Disease', (115, 121))	('CDG', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CDG', 'Chemical', '-', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('changes', 'Reg', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (83, 89))
111635	30400878	A better understanding of the connections between CDGs and altered cancer cell epigenomes is an important goal, particularly since mutations in epigenetic regulators could be novel targets for anti-cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CDGs', 'Chemical', '-', (50, 54))
111637	30400878	An integrative analysis of DNA methylation data and gene expression data of various cancer types identified pan-cancer hypo- and hyper-methylated genes that are predictive of transcription as well as methylation-driven subgroups with clinical implications.	('hypo-', 'Var', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('hyper-methylated', 'Var', (129, 145))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
111639	30400878	Here we aim to improve our understanding of the connections between CDGs and altered cancer cell epigenomes and altered cancer cell transcriptome on pan-cancer level, and how these connections contribute to the known association between cancer epigenome and transcriptome.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('CDGs', 'Chemical', '-', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CDGs', 'Var', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
111640	30400878	We used somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project to identify CDGs that, when mutated, have strong associations with genome-wide methylation or expression changes across cancer types, which we refer as methylation driver genes (MDGs) or expression driver genes (EDGs).	('CDGs', 'Chemical', '-', (143, 147))	('expression changes', 'MPA', (225, 243))	('mutated', 'Var', (159, 166))	('methylation', 'MPA', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('CDGs', 'Gene', (143, 147))	('MDG', 'Gene', (309, 312))	('associations', 'Interaction', (180, 192))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('EDG', 'Chemical', '-', (343, 346))	('MDG', 'Gene', '4350', (309, 312))	('Cancer Genome Atlas', 'Disease', (96, 115))	('cancer', 'Disease', (74, 80))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (96, 115))	('cancer', 'Disease', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
111643	30400878	This finding shows that dysregulation of chromatin regulators is potentially an important mechanism that induces global change of DNA methylation and gene expression in tumor development.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('DNA methylation', 'MPA', (130, 145))	('gene expression', 'MPA', (150, 165))	('dysregulation', 'Var', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))
111646	30400878	We then corrected for the type I/II probe bias using the BMIQ algorithm  We obtained level 2 somatic mutation data of the above-mentioned 20 tumor types from Broad Institute TCGA Genome Data Analysis Center Firehose and selected candidate CDGs using the MutSIG algorithm that tests how frequently a gene is mutated in a tumor type comparing to the background mutation rate.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('mutated', 'Var', (307, 314))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (320, 325))	('CDGs', 'Chemical', '-', (239, 243))
111651	30400878	To conduct pan-cancer analysis associating mutation and methylation/expression, within a tumor type, we selected CDGs that have mutations in at least 5 samples with matched methylation data or expression data in order to have not-too-sparse numbers in the mutated group.	('CDGs', 'Gene', (113, 117))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CDGs', 'Chemical', '-', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
111658	30400878	For the 422 CDGs, the number of tumor types in which a CDG is mutated in at least five samples varies from 1 to 14 (Additional file 2: Table S2), where TP53 and PTEN were mutated in 14 tumor types.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('TP53', 'Gene', '7157', (152, 156))	('CDG i', 'Chemical', '-', (55, 60))	('mutated', 'Var', (171, 178))	('CDGs', 'Chemical', '-', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TP53', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PTEN', 'Gene', (161, 165))	('tumor', 'Disease', (32, 37))	('PTEN', 'Gene', '5728', (161, 165))
111661	30400878	We then determine the hyper- or hypo-methylation status per CpG site by the mutation status of CDG i using the nonparametric Wilcoxon test.	('mutation', 'Var', (76, 84))	('CDG i', 'Gene', (95, 100))	('CDG i', 'Chemical', '-', (95, 100))	('hyper-', 'MPA', (22, 28))
111664	30400878	To determine if mutation status of CDG i is significantly associated with genome-wide methylation changes in cancer type k, we calculate the p-value pi,k, which is the probability of observing the number of differentially (hyper- or hypo-) methylated sites  or more that are associated with the mutation status of CDG i in cancer type k under the null hypothesis that the mutation status of CDG i is not associated with genome-wide methylation changes.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('mutation', 'Var', (16, 24))	('cancer', 'Disease', (323, 329))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CDG i', 'Chemical', '-', (391, 396))	('mutation', 'Var', (295, 303))	('cancer', 'Disease', (109, 115))	('CDG i', 'Chemical', '-', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('CDG i', 'Chemical', '-', (314, 319))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CDG i', 'Gene', (314, 319))
111675	30400878	We classify the effect of CDG i on genome-wide methylation in tumor type k as: To calculate the p-value, pi, testing if CDG i is significantly associated with genome-wide methylation changes across multiple cancer types, we compare , the observed total number of differentially methylated sites associated with CDG i summed over Ai cancer types, to B resampled values generated from the "methylation null pool" where we set B=one million.	('differentially', 'Var', (263, 277))	('CDG i', 'Chemical', '-', (311, 316))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Disease', (207, 213))	('CDG i', 'Gene', (311, 316))	('tumor', 'Disease', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('cancer', 'Disease', (332, 338))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('CDG i', 'Chemical', '-', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('CDG i', 'Chemical', '-', (26, 31))
111685	30400878	We first tested whether mutations in a CDG are significantly associated with changes in genome-wide methylation patterns in one cancer type.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('changes', 'Reg', (77, 84))	('genome-wide methylation patterns', 'MPA', (88, 120))	('CDG', 'Gene', (39, 42))	('CDG', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (24, 33))	('associated', 'Reg', (61, 71))	('cancer', 'Disease', (128, 134))
111687	30400878	We then used the number of genome-wide differentially methylated sites as the test statistic to measure degree of genome-wide methylation changes associated with the mutation status of a CDG for one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('CDG', 'Chemical', '-', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('CDG', 'Gene', (187, 190))	('mutation', 'Var', (166, 174))
111688	30400878	To assess the significance of the genome-wide methylation changes by a CDG in one cancer type, we first generated an empirical null distribution with numbers of genome-wide differentially methylated sites by mutations of non-CDGs and then calculated the p-value pi,k for CDG i in cancer type k by comparing the number of genome-wide differentially methylated sites by the mutation of CDG i in cancer type k with the empirical null distribution.	('cancer', 'Disease', (393, 399))	('CDG i', 'Chemical', '-', (384, 389))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (280, 286))	('CDG i', 'Chemical', '-', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CDG i', 'Gene', (384, 389))	('mutation', 'Var', (372, 380))	('CDGs', 'Chemical', '-', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('CDG i', 'Chemical', '-', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (393, 399))
111689	30400878	We then classify the effect of CDG i in tumor type k as hyper-methylated if pi,k<0.05 and the number of genome-wide hyper-methylated sites is greater than that of hypo-methylated sites or hypo-methylated if pi,k<0.05 and the number of genome-wide hypo-methylated sites is greater than that of hyper-methylated sites.	('k<0.05', 'Var', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('CDG i', 'Chemical', '-', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CDG i', 'Gene', (31, 36))
111696	30400878	For the complete list of CDGs whose mutation states were significantly associated with genome-wide methylation changes within each cancer type (gene i with pi,k<0.05 in the cancer type k), see Additional file 5: Table S4.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CDGs', 'Chemical', '-', (25, 29))	('cancer', 'Disease', (173, 179))	('mutation', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CDGs', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('methylation changes', 'MPA', (99, 118))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('associated', 'Reg', (71, 81))
111698	30400878	They used Principal Component Analysis (PCA) to identify driver genes whose mutations are associated with the top five PCs within each cancer.	('cancer', 'Disease', (135, 141))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
111699	30400878	The 32 MDGs were mutated with different frequencies in each cancer types (Additional file 6: Figure S1) and the mutation status of the 32 MDGs is associated with different genome-wide number of hyper- and hypo-methylated sites (Fig.	('mutation', 'Var', (112, 120))	('MDG', 'Gene', (7, 10))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MDG', 'Gene', '4350', (7, 10))	('MDG', 'Gene', (138, 141))	('cancer', 'Disease', (60, 66))	('MDG', 'Gene', '4350', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
111702	30400878	In CESC, LUSC, PAAD, and SARC tumor types, genome-wide methylation patterns were not significantly affected by mutations of any of the identified 32 MDGs, potentially due to small sample sizes or fewer number of CDGs.	('mutations', 'Var', (111, 120))	('SARC tumor', 'Disease', (25, 35))	('CDGs', 'Chemical', '-', (212, 216))	('SARC tumor', 'Phenotype', 'HP:0100242', (25, 35))	('MDG', 'Gene', (149, 152))	('SARC tumor', 'Disease', 'MESH:D009369', (25, 35))	('MDG', 'Gene', '4350', (149, 152))	('LUSC', 'Disease', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('methylation patterns', 'MPA', (55, 75))	('CESC', 'Disease', (3, 7))
111703	30400878	TP53 mutations are associated with significant genome-wide methylation changes in 8 out of the 15 tumor types in which it was mutated in more than 5 samples (Table 1).	('TP53', 'Gene', '7157', (0, 4))	('methylation changes', 'MPA', (59, 78))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('15 tumor', 'Disease', (95, 103))	('15 tumor', 'Disease', 'MESH:C567447', (95, 103))
111704	30400878	Among these 8 tumor types, more CpG sites were hypo-methylated in all but LGG.	('hypo-methylated', 'Var', (47, 62))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
111705	30400878	Instead, in LGG, TP53 mutations are associated with more hyper-methylated CpG sites.	('hyper-methylated', 'MPA', (57, 73))	('mutations', 'Var', (22, 31))	('more', 'PosReg', (52, 56))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
111706	30400878	However, almost all LGG tumors with TP53 mutations also have IDH1 mutations (Additional file 6: Figure S1), which are known to lead to hyper-methylation in LGG.	('mutations', 'Var', (41, 50))	('LGG tumors', 'Disease', (20, 30))	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('LGG tumors', 'Disease', 'MESH:D009369', (20, 30))	('IDH1', 'Gene', '3417', (61, 65))	('TP53', 'Gene', '7157', (36, 40))	('IDH1', 'Gene', (61, 65))	('TP53', 'Gene', (36, 40))	('hyper-methylation', 'MPA', (135, 152))
111708	30400878	Given the prominent role of IDH1 in LGG, we stratified LGG tumor samples by the IDH1 mutation status and further examined the effect of the other 31 MDGs within the IDH1 mutation stratum and the IDH1 wild-type stratum and found that TP53 mutations are now significantly associated with more hypo-methylation genome-wide in each stratum (Additional file 3: Text S1).	('LGG tumor', 'Disease', 'MESH:D009369', (55, 64))	('IDH1', 'Gene', '3417', (28, 32))	('hypo-methylation', 'MPA', (291, 307))	('IDH1', 'Gene', '3417', (195, 199))	('associated', 'Reg', (270, 280))	('IDH1', 'Gene', (80, 84))	('mutations', 'Var', (238, 247))	('IDH1', 'Gene', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('more', 'PosReg', (286, 290))	('TP53', 'Gene', (233, 237))	('IDH1', 'Gene', '3417', (80, 84))	('MDG', 'Gene', (149, 152))	('IDH1', 'Gene', (195, 199))	('IDH1', 'Gene', '3417', (165, 169))	('IDH1', 'Gene', (28, 32))	('MDG', 'Gene', '4350', (149, 152))	('LGG tumor', 'Disease', (55, 64))	('TP53', 'Gene', '7157', (233, 237))
111709	30400878	Similar stratified analyses were conducted in all other tumor types whose genome-wide methylation patterns were significantly associated with mutations of the identified MDGs.	('mutations', 'Var', (142, 151))	('associated', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('MDG', 'Gene', (170, 173))	('MDG', 'Gene', '4350', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
111712	30400878	To test this hypothesis, we examined whether mutations of these 24 MDGs are associated with the expression changes of known epigenomic regulator genes across the 20 tumor types, where we used the exon level RNA-Seq data of the 20 tumor tissue types from TCGA.	('tumor', 'Disease', (230, 235))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('expression', 'MPA', (96, 106))	('associated', 'Reg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('MDG', 'Gene', (67, 70))	('MDG', 'Gene', '4350', (67, 70))	('tumor', 'Disease', (165, 170))
111717	30400878	For each of these 12 genes, we first identified genome-wide target genes whose expression levels were dysregulated by the mutation status commonly across tumor types.	('expression', 'MPA', (79, 89))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
111724	30400878	For example, TP53 mutations are associated with upregulated KDM1A expression levels across all tumor types whose genome-wide methylation patterns are also significantly associated with TP53 mutations.	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', (185, 189))	('expression levels', 'MPA', (66, 83))	('mutations', 'Var', (190, 199))	('KDM1A', 'Gene', '23028', (60, 65))	('TP53', 'Gene', '7157', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('KDM1A', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('upregulated', 'PosReg', (48, 59))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', (95, 100))	('mutations', 'Var', (18, 27))
111725	30400878	KDM1A is known to physically interact with TP53 and it demethylates histone lysine residues 9 of histone 3, which in turn leads to extensive hypo-methylation in that region.	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('hypo-methylation', 'MPA', (141, 157))	('leads to', 'Reg', (122, 130))	('TP53', 'Gene', '7157', (43, 47))	('KDM1A', 'Gene', '23028', (0, 5))	('demethylates', 'Var', (55, 67))	('KDM1A', 'Gene', (0, 5))	('TP53', 'Gene', (43, 47))
111726	30400878	This analysis suggests that KDM1A may play a role in the association between TP53 mutations and genome-wide hypo-methylation changes across tumor types.	('KDM1A', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (82, 91))	('KDM1A', 'Gene', '23028', (28, 33))	('association', 'Interaction', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Disease', (140, 145))
111732	30400878	We found only a small fraction of genes in list B whose expression and methylation levels are both associated with the mutation status of the MDGs (Table 2), which suggests that the differential expression of these target genes may be directly associated with mutations of these MDGs instead of being indirectly associated through changes in their methylation patterns.	('expression', 'MPA', (195, 205))	('MDG', 'Gene', (279, 282))	('MDG', 'Gene', '4350', (279, 282))	('associated', 'Reg', (244, 254))	('MDG', 'Gene', (142, 145))	('expression', 'MPA', (56, 66))	('MDG', 'Gene', '4350', (142, 145))	('mutations', 'Var', (260, 269))	('associated', 'Reg', (99, 109))
111733	30400878	We further investigated mutation status of genes in list B to examine if the mutations affect their expression or methylation levels directly and found that the majority of genes in list B were rarely mutated across tumor types (Additional file 8: Table S6).	('tumor', 'Disease', (216, 221))	('affect', 'Reg', (87, 93))	('list B', 'Gene', (182, 188))	('expression', 'MPA', (100, 110))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('methylation levels', 'MPA', (114, 132))
111734	30400878	Although CIC was not included in the above analyses since it was mutated only in LGG, due to its important role in LGG tumors, we examined how CIC regulates expressions of target genes and found that chromatin remodeling genes in list A were significantly enriched among dysregulated target genes, in both full LGG tumor samples and in stratified samples by IDH1 mutation status (Additional file 9: Table S7).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('LGG tumor', 'Disease', 'MESH:D009369', (115, 124))	('CIC', 'Gene', '23152', (9, 12))	('mutation', 'Var', (363, 371))	('LGG tumor', 'Disease', (311, 320))	('IDH1', 'Gene', '3417', (358, 362))	('LGG tumors', 'Disease', (115, 125))	('CIC', 'Gene', (9, 12))	('LGG tumor', 'Disease', 'MESH:D009369', (311, 320))	('CIC', 'Gene', '23152', (143, 146))	('LGG tumors', 'Disease', 'MESH:D009369', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('CIC', 'Gene', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('IDH1', 'Gene', (358, 362))
111737	30400878	The mutation status of these 29 EDGs is associated with different genome-wide number of up- and down-regulated genes (Fig.	('EDG', 'Chemical', '-', (32, 35))	('down-regulated', 'NegReg', (96, 110))	('up-', 'PosReg', (88, 91))	('mutation', 'Var', (4, 12))
111738	30400878	For the complete list of CDGs whose mutation states were significantly associated with genome-wide expression changes within each cancer type, see Additional file 10: Table S8.	('CDGs', 'Chemical', '-', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('mutation', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (71, 81))
111740	30400878	To understand this high rate of overlap, within each cancer type, we examined the overlap between CDGs that are significantly associated with genome-wide methylation changes and CDGs that are significantly associated with genome-wide expression changes, and found they overlap highly.	('associated', 'Reg', (126, 136))	('CDGs', 'Disease', (98, 102))	('cancer', 'Disease', (53, 59))	('methylation changes', 'Var', (154, 173))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CDGs', 'Chemical', '-', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CDGs', 'Chemical', '-', (98, 102))
111743	30400878	A specific example of a target gene that is hypo-methylated and up-regulated by the mutation of TP53 is HSF1 gene.	('TP53', 'Gene', (96, 100))	('HSF1', 'Gene', (104, 108))	('HSF1', 'Gene', '3297', (104, 108))	('up-regulated', 'PosReg', (64, 76))	('TP53', 'Gene', '7157', (96, 100))	('mutation', 'Var', (84, 92))
111744	30400878	It is hypo-methylated and up-regulated by TP53 mutations across 9 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TP53', 'Gene', '7157', (42, 46))	('tumor', 'Disease', (66, 71))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('up-regulated', 'PosReg', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
111746	30400878	For each CDG, for every pair of tumor types in which it is mutated in more than five samples, we tested using a hypergeometric distribution if the number of overlapping target genes that are differentially methylated by the mutation of the CDG is larger than expected.	('tested', 'Reg', (97, 103))	('CDG', 'Chemical', '-', (240, 243))	('CDG', 'Chemical', '-', (9, 12))	('CDG i', 'Chemical', '-', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutation', 'Var', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CDG', 'Gene', (240, 243))	('tumor', 'Disease', (32, 37))
111750	30400878	Our findings on how CDG mutations contribute to pan-cancer-associated epigenomic alterations and transcriptomic alterations suggest that there are potentially three mechanisms (Fig.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('contribute', 'Reg', (34, 44))	('CDG', 'Gene', (20, 23))	('epigenomic alterations', 'MPA', (70, 92))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (24, 33))	('CDG', 'Chemical', '-', (20, 23))
111751	30400878	We conducted a pan-cancer analysis to identify CDGs whose somatic mutations are associated with genome-wide methylation/expression changes across multiple cancer types.	('mutations', 'Var', (66, 75))	('methylation/expression', 'MPA', (108, 130))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('CDGs', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (19, 25))	('CDGs', 'Chemical', '-', (47, 51))	('associated', 'Reg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
111752	30400878	We used a straightforward method to compare methylation/expression levels between mutated and non-mutated groups of each CDG.	('methylation/expression', 'MPA', (44, 66))	('mutated', 'Var', (82, 89))	('CDG', 'Chemical', '-', (121, 124))
111764	30400878	To identify TERT-independent TL regulation, they associated somatic alterations of 196 telomere-associated genes to TL ratio between matching tumor and normal samples and found alterations of ATRX, IDH1, TP53, BCOR, and RB1 were significantly associated with relative TL elongation under FDR<0.05.	('RB1', 'Gene', (220, 223))	('associated with', 'Reg', (243, 258))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('relative TL elongation', 'CPA', (259, 281))	('BCOR', 'Gene', '54880', (210, 214))	('RB1', 'Gene', '5925', (220, 223))	('ATRX', 'Gene', (192, 196))	('TERT', 'Gene', '7015', (12, 16))	('tumor', 'Disease', (142, 147))	('alterations', 'Var', (177, 188))	('IDH1', 'Gene', (198, 202))	('ATRX', 'Gene', '546', (192, 196))	('TP53', 'Gene', '7157', (204, 208))	('IDH1', 'Gene', '3417', (198, 202))	('BCOR', 'Gene', (210, 214))	('TP53', 'Gene', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TERT', 'Gene', (12, 16))
111766	30400878	In a recent review by Feinberg et al., an epigenetic functional classification system was introduced that classifies epigenetic genes into three categories 1) "epigenetic mediators", which correspond to tumor progenitor genes that are targets of epigenetic modification; 2) "epigenetic modifiers", which modify DNA methylation or chromatin structure; and 3) "epigenetic modulators", which influence activities of epigenetic modifiers to destabilize epigenetic states.	('DNA', 'MPA', (311, 314))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('epigenetic states', 'MPA', (449, 466))	('modifiers', 'Var', (286, 295))	('modulators', 'Var', (370, 380))	('modify', 'Reg', (304, 310))	('activities', 'MPA', (399, 409))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('influence', 'Reg', (389, 398))
111768	30400878	Further analysis that examined whether mutations of 12 MDGs out of these 24 MDGs are associated with the expression of known epigenetic modifiers across cancer types supports our mechanistic hypothesis that some of these MDGs are the ones that regulate expression of chromatin regulators.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('expression', 'MPA', (253, 263))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (39, 48))	('MDG', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MDG', 'Gene', (76, 79))	('regulate', 'Reg', (244, 252))	('MDG', 'Gene', '4350', (55, 58))	('MDG', 'Gene', '4350', (76, 79))	('MDG', 'Gene', '4350', (221, 224))	('MDG', 'Gene', (221, 224))	('associated', 'Reg', (85, 95))
111771	30400878	BRAF mutation is known to be tightly associated with a CpG island methylator phenotype (CIMP) and alteration of SWI/SNF chromatin remodeling pathway.	('SWI/SNF chromatin remodeling pathway', 'Pathway', (112, 148))	('BRAF', 'Gene', '673', (0, 4))	('alteration', 'Reg', (98, 108))	('associated', 'Reg', (37, 47))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
111783	30400878	Note that CIC mutations are associated with hyper-methylation in LGG both among IDH1 wild-type tumors and IDH1 mutated tumors.	('CIC', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (14, 23))	('IDH1', 'Gene', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', (119, 125))	('hyper-methylation', 'MPA', (44, 61))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('IDH1', 'Gene', '3417', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('IDH1', 'Gene', (106, 110))	('CIC', 'Gene', '23152', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IDH1', 'Gene', '3417', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (95, 101))	('LGG', 'Gene', (65, 68))
111784	30400878	Further studies are needed to investigate if the observed clinical and biological impact of CIC mutations in LGG is through hyper-methylation of the epigenome.	('LGG', 'Gene', (109, 112))	('mutations', 'Var', (96, 105))	('CIC', 'Gene', (92, 95))	('CIC', 'Gene', '23152', (92, 95))
111785	30400878	In this study, we identified CDGs whose somatic mutations are associated with pan-cancer genome-wide methylation/expression changes by using a simple and straightforward method to compare methylation or expression levels between mutated and non-mutated groups of each CDG.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CDG', 'Chemical', '-', (268, 271))	('associated', 'Reg', (62, 72))	('expression', 'MPA', (203, 213))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CDG', 'Chemical', '-', (29, 32))	('CDGs', 'Chemical', '-', (29, 33))	('mutations', 'Var', (48, 57))
111787	30400878	Our pan-cancer analysis examining connections between somatic mutation and DNA methylation/gene expression identified CDGs (32 MDGs and 29 EDGs) whose somatic mutations are associated with genome-wide methylation/expression changes across multiple cancer types.	('cancer', 'Disease', (248, 254))	('MDG', 'Gene', (127, 130))	('cancer', 'Disease', (8, 14))	('MDG', 'Gene', '4350', (127, 130))	('mutations', 'Var', (159, 168))	('EDG', 'Chemical', '-', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('CDGs', 'Chemical', '-', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
111790	30400878	These findings highlight that the dysregulation of chromatin regulation is an important mechanism that amplifies the impact of mutations in CDGs by global methylation and gene expression changes.	('CDGs', 'Chemical', '-', (140, 144))	('dysregulation', 'Var', (34, 47))	('gene expression', 'MPA', (171, 186))	('CDGs', 'Gene', (140, 144))	('mutations', 'Var', (127, 136))	('changes', 'Reg', (187, 194))
111837	27134530	11C-MET PET reportedly shows a higher sensitivity similar to that of 18F-FDG PET, for the detection of primary lesions in patients with PCNSL.	('18F-FDG', 'Chemical', '-', (69, 76))	('11C', 'Chemical', 'MESH:C000615233', (0, 3))	('PCNSL', 'Phenotype', 'HP:0030069', (136, 141))	('11C-MET', 'Var', (0, 7))	('PCNSL', 'Chemical', '-', (136, 141))	('patients', 'Species', '9606', (122, 130))	('primary lesions', 'Disease', (103, 118))
111838	27134530	However, some cases of PCNSL are more clearly detected using 11C-Met PET and contrast-enhanced MRI than using 18F-FDG PET (Fig.	('11C-Met', 'Chemical', '-', (61, 68))	('PCNSL', 'Disease', (23, 28))	('PCNSL', 'Phenotype', 'HP:0030069', (23, 28))	('11C-Met PET', 'Var', (61, 72))	('18F-FDG', 'Chemical', '-', (110, 117))	('PCNSL', 'Chemical', '-', (23, 28))
111840	27134530	In patients with CNS germinoma, the tumor-contouring ability of 11C-Met PET for some malignant tumors is higher than that of 18F-FDG PET.	('18F-FDG', 'Chemical', '-', (125, 132))	('11C-Met', 'Chemical', '-', (64, 71))	('CNS germinoma', 'Disease', 'MESH:D018237', (17, 30))	('higher', 'PosReg', (105, 111))	('CNS germinoma', 'Disease', (17, 30))	('malignant tumors', 'Disease', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('malignant tumors', 'Disease', 'MESH:D018198', (85, 101))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (36, 41))	('germinoma', 'Phenotype', 'HP:0100620', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('11C-Met PET', 'Var', (64, 75))	('tumor', 'Disease', (95, 100))
112051	26295306	Gene knockdowns of EZH2 and HMMR already revealed that these two genes are essential for survival of GSCs and thus very promising new molecular targets for treatment of GBM.	('HMMR', 'Gene', '3161', (28, 32))	('knockdowns', 'Var', (5, 15))	('HMMR', 'Gene', (28, 32))	('EZH2', 'Gene', '2146', (19, 23))	('EZH2', 'Gene', (19, 23))
112052	26295306	We are currently working on gene knockdowns of several genes from the presented list and have recently shown that targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo.	('targeting', 'Var', (114, 123))	('attenuates', 'NegReg', (203, 213))	('TOPK', 'Gene', '55872', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('decreases growth', 'Phenotype', 'HP:0001510', (133, 149))	('glioma', 'Disease', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PBK', 'Gene', '55872', (124, 127))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('tumor', 'Disease', (214, 219))	('TOPK', 'Gene', (128, 132))	('PBK', 'Gene', (124, 127))	('decreases', 'NegReg', (133, 142))
112070	26295306	For expression analysis of FNDC3B we also used Taqman Probes: Hs00384650_m1 and Hs00981550 (Applied Biosystems).	('FNDC3B', 'Gene', (27, 33))	('Hs00384650_m1', 'Var', (62, 75))	('FNDC3B', 'Gene', '64778', (27, 33))	('Hs00981550', 'Var', (80, 90))
112090	26295306	The following sets of microarrays were downloaded from the GEO database, quantile normalized and used for this analysis: NSC and GSC cultures and GBM tissues from: H91, H95, H80, NFCs, T65, T08, TC3, TC4, T96, T11 and T59 (encompassed in the GEO sets GSE60705, GSE53800 and GSE41467) in addition to iPS, neurons, iPS-derived neurons, astrocytes, fibroblasts, NSCs, NFCs, breast cancer cells (BCC, cancer stem cells and cell lines), leucocytes, brain tissue, GBM, ESCs, gliomas cell lines and many additional sets of GSCs [encompassed in the GEO sets GSE41468, GSE34987, GSE36426 (GSCs), GSE42133, GSE43364, GSE43452, GSE43903, GSE47515, GSE42265, GSE32658, GSE37077, GSE41565 and GSE36102].	('glioma', 'Phenotype', 'HP:0009733', (469, 475))	('breast cancer', 'Phenotype', 'HP:0003002', (371, 384))	('TC4', 'Gene', '221547', (200, 203))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('gliomas', 'Phenotype', 'HP:0009733', (469, 476))	('breast cancer', 'Disease', 'MESH:D001943', (371, 384))	('cancer', 'Disease', (397, 403))	('breast cancer', 'Disease', (371, 384))	('TC4', 'Gene', (200, 203))	('GSE42265', 'Var', (637, 645))	('GSE32658', 'Var', (647, 655))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('GSE37077', 'Var', (657, 665))	('NFCs', 'Chemical', '-', (365, 369))	('gliomas', 'Disease', (469, 476))	('cancer', 'Disease', (378, 384))	('GSE41565', 'Var', (667, 675))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('H91', 'CellLine', 'CVCL:2H63', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('GSE36102]', 'Var', (680, 689))	('gliomas', 'Disease', 'MESH:D005910', (469, 476))	('NFCs', 'Chemical', '-', (179, 183))	('H95', 'CellLine', 'CVCL:J820', (169, 172))
112091	26295306	NSC cultures from patients: H91, H95, H80 were represented by samples from HPC, SVZ, WM and GM and were grown either as spheres or in AD1% medium.	('H95', 'CellLine', 'CVCL:J820', (33, 36))	('H95', 'Var', (33, 36))	('H91', 'CellLine', 'CVCL:2H63', (28, 31))	('HPC', 'Disease', 'MESH:C537262', (75, 78))	('patients', 'Species', '9606', (18, 26))	('H80', 'Var', (38, 41))	('HPC', 'Disease', (75, 78))	('H91', 'Var', (28, 31))
112137	21992729	At a median follow-up of 28 months, the median survival was 14.6 months with RT plus TMZ versus 12.1 months with RT alone, rendering the hazard ratio for death 0.63 in the combined modality group.	('TMZ', 'Var', (85, 88))	('death', 'Disease', (154, 159))	('TMZ', 'Chemical', 'MESH:D000077204', (85, 88))	('death', 'Disease', 'MESH:D003643', (154, 159))
112139	21992729	In this trial, patients whose tumor had a methylated methylguanine methyltransferase (MGMT) gene promoter had improved survival (mOS 21.7 vs 12.7 months, OS at 2 years 46 vs 13.8%) relative to those with an unmethylated MGMT promoter, and the methylation status was the strongest predictor for outcome and benefit from TMZ chemotherapy.	('MGMT', 'Gene', (220, 224))	('patients', 'Species', '9606', (15, 23))	('MGMT', 'Gene', (86, 90))	('methylated', 'Var', (42, 52))	('MGMT', 'Gene', '4255', (86, 90))	('improved', 'PosReg', (110, 118))	('methylguanine methyltransferase', 'Gene', '4255', (53, 84))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('methylguanine methyltransferase', 'Gene', (53, 84))	('OS', 'Chemical', 'MESH:D009992', (130, 132))	('survival', 'MPA', (119, 127))	('TMZ', 'Chemical', 'MESH:D000077204', (319, 322))	('OS', 'Chemical', 'MESH:D009992', (154, 156))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('MGMT', 'Gene', '4255', (220, 224))
112141	21992729	Optimizing the adjuvant chemotherapy regimen is now one potential strategy to improve patient outcomes, specifically in patients with unmethylated MGMT promoter.	('patient', 'Species', '9606', (120, 127))	('patient', 'Species', '9606', (86, 93))	('patients', 'Species', '9606', (120, 128))	('MGMT', 'Gene', (147, 151))	('unmethylated', 'Var', (134, 146))	('MGMT', 'Gene', '4255', (147, 151))
112148	21992729	Cairncross and colleagues demonstrated that alterations of the chromosome arms 1p and 19q, in particular the loss of heterozygosity, confer chemotherapeutic sensitivity and prolong OS in grade III (anaplastic) AO treated with PCV.	('confer', 'PosReg', (133, 139))	('OS', 'Chemical', 'MESH:D009992', (181, 183))	('prolong', 'PosReg', (173, 180))	('arms 1p', 'Gene', '3075', (74, 81))	('loss', 'Var', (109, 113))	('heterozygosity', 'Var', (117, 131))	('alterations', 'Var', (44, 55))	('arms 1p', 'Gene', (74, 81))
112156	21992729	Tumors lacking 1p loss, but having a TP53 gene mutation, responded to chemotherapy but recurred quickly.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutation', 'Var', (47, 55))	('responded to chemotherapy', 'MPA', (57, 82))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
112158	21992729	Within the subset of patients with AO who have the 1p/19q codeletion, those with polysomy of chromosomes 1 and 19 were found to have an earlier recurrence than those without polysomy.	('1p/19q codeletion', 'Var', (51, 68))	('patients', 'Species', '9606', (21, 29))	('polysomy', 'Var', (81, 89))
112161	21992729	All patients with codeletion of 1p/19q and/or MGMT-promoter methylation were free from progression at 6 months.	('MGMT', 'Gene', (46, 50))	('MGMT', 'Gene', '4255', (46, 50))	('codeletion of 1p/19q', 'Var', (18, 38))	('patients', 'Species', '9606', (4, 12))
112162	21992729	EORTC is currently conducting CATNON, a Phase III intergroup trial on concurrent and adjuvant TMZ chemotherapy in patients with non-1p/19q deleted anaplastic glioma.	('TMZ', 'Chemical', 'MESH:D000077204', (94, 97))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('EORTC', 'Chemical', '-', (0, 5))	('glioma', 'Disease', (158, 164))	('patients', 'Species', '9606', (114, 122))	('non-1p/19q deleted', 'Var', (128, 146))
112164	21992729	In addition, an intergroup trial by RTOG, EORTC and NCCTG is conducting the CODEL trial, wherein patients with 1p/19q codeleted WHO Grade III malignant gliomas will be randomized to one of three arms following maximum safe resection: RT, primary TMZ or RT and TMZ.	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('1p/19q', 'Var', (111, 117))	('malignant gliomas', 'Disease', (142, 159))	('TMZ', 'Chemical', 'MESH:D000077204', (246, 249))	('TMZ', 'Chemical', 'MESH:D000077204', (260, 263))	('malignant gliomas', 'Disease', 'MESH:D005910', (142, 159))	('EORTC', 'Chemical', '-', (42, 47))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('primary TMZ', 'Disease', (238, 249))	('patients', 'Species', '9606', (97, 105))
112171	21992729	However, when used in combination with ionizing radiation the EGFR inhibitors have been shown to augment the antiproliferative and proapoptotic activity by ionizing radiation in several human cancer cell lines, as well as in mice bearing human colon cancer xenografts, as demonstrated by Bianco and colleagues.	('inhibitors', 'Var', (67, 77))	('colon cancer', 'Disease', (244, 256))	('EGFR', 'Gene', '1956', (62, 66))	('human', 'Species', '9606', (238, 243))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('EGFR', 'Gene', (62, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (244, 256))	('proapoptotic', 'CPA', (131, 143))	('cancer', 'Disease', (192, 198))	('augment', 'PosReg', (97, 104))	('human', 'Species', '9606', (186, 191))	('mice', 'Species', '10090', (225, 229))	('antiproliferative', 'CPA', (109, 126))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('colon cancer', 'Disease', 'MESH:D015179', (244, 256))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
112178	21992729	Markers such as EGFR variant III (EGFRvIII), phosphatase and tensin homolog (PTEN) expression, and phospho-Akt (P-Akt), have been reported to predict the treatment response and can potentially be used to identify the patients that will derive survival benefit from the addition of EGFR inhibitor.	('Akt', 'Gene', (107, 110))	('EGFR', 'Gene', (34, 38))	('predict', 'Reg', (142, 149))	('Akt', 'Gene', (114, 117))	('EGFR', 'Gene', '1956', (34, 38))	('treatment response', 'CPA', (154, 172))	('PTEN', 'Gene', (77, 81))	('variant', 'Var', (21, 28))	('EGFR', 'Gene', '1956', (16, 20))	('PTEN', 'Gene', '5728', (77, 81))	('Akt', 'Gene', '207', (114, 117))	('patients', 'Species', '9606', (217, 225))	('Akt', 'Gene', '207', (107, 110))	('EGFR', 'Gene', '1956', (281, 285))	('EGFR', 'Gene', (16, 20))	('EGFR', 'Gene', (281, 285))
112179	21992729	Specifically, coexpression of EGFRvIII and the tumor-suppressor protein PTEN was associated with a significant clinical response to EGFR TKI.	('clinical response', 'MPA', (111, 128))	('EGFR', 'Gene', (30, 34))	('EGFR', 'Gene', '1956', (132, 136))	('PTEN', 'Gene', (72, 76))	('PTEN', 'Gene', '5728', (72, 76))	('EGFR', 'Gene', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('coexpression', 'Var', (14, 26))	('EGFR', 'Gene', '1956', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('associated', 'Reg', (81, 91))	('tumor', 'Disease', (47, 52))
112181	21992729	However, at least one other study did not corroborate the finding that the presence of EGFRvIII and intact PTEN predicts response to therapy with EGFR inhibitors.	('PTEN', 'Gene', (107, 111))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', '1956', (146, 150))	('PTEN', 'Gene', '5728', (107, 111))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', (146, 150))	('predicts', 'Reg', (112, 120))	('presence', 'Var', (75, 83))	('response', 'MPA', (121, 129))
112195	21992729	In this trial, as well, both PFS (13.4 vs 3.4 months) and OS (23.2 months vs 13.1 months) were improved if MGMT promoter was methylated.	('PFS', 'CPA', (29, 32))	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('improved', 'PosReg', (95, 103))	('methylated', 'Var', (125, 135))	('OS', 'Chemical', 'MESH:D009992', (58, 60))
112199	21992729	Of note, only 29% of patients in this series had MGMT promoter methylated, as compared with 43% in the EORTC study by Stupp.	('MGMT', 'Gene', '4255', (49, 53))	('MGMT', 'Gene', (49, 53))	('patients', 'Species', '9606', (21, 29))	('methylated', 'Var', (63, 73))	('EORTC', 'Chemical', '-', (103, 108))
112271	21992729	Patients with methylated MGMT promoter have a better prognosis.	('MGMT', 'Gene', (25, 29))	('MGMT', 'Gene', '4255', (25, 29))	('methylated', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))
112272	21992729	Optimizing adjuvant systemic therapy regimen is a potential strategy to improve outcomes in patients with unmethylated MGMT promoter.	('MGMT', 'Gene', (119, 123))	('MGMT', 'Gene', '4255', (119, 123))	('unmethylated', 'Var', (106, 118))	('patients', 'Species', '9606', (92, 100))
112388	31379707	With the progress of genetics and molecular biology, an increasing number of molecular biomarkers were discovered in glioma, for instance, IDH mutation, MGMT methylation, TERT promoter mutation, EGFR and P53.	('P53', 'Gene', (204, 207))	('P53', 'Gene', '7157', (204, 207))	('EGFR', 'Gene', (195, 199))	('TERT', 'Gene', (171, 175))	('MGMT', 'Gene', (153, 157))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('mutation', 'Var', (143, 151))	('TERT', 'Gene', '7015', (171, 175))	('MGMT', 'Gene', '4255', (153, 157))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('IDH', 'Gene', (139, 142))	('glioma', 'Disease', (117, 123))	('EGFR', 'Gene', '1956', (195, 199))	('IDH', 'Gene', '3417', (139, 142))
112389	31379707	As is known to all, IDH1/2 mutation and MGMT promoter methylation are two important biomarkers in glioma.	('IDH1', 'Gene', '3417', (20, 24))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('mutation', 'Var', (27, 35))	('glioma', 'Disease', (98, 104))	('IDH1', 'Gene', (20, 24))
112390	31379707	IDH mutation mainly exists in low grade glioma and secondary GBM, and associates with prognosis and GBM subtype.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('IDH', 'Gene', (0, 3))	('associates', 'Reg', (70, 80))	('IDH', 'Gene', '3417', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('secondary GBM', 'Disease', (51, 64))	('mutation', 'Var', (4, 12))	('glioma', 'Disease', (40, 46))	('exists', 'Reg', (20, 26))	('GBM', 'Phenotype', 'HP:0012174', (100, 103))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
112420	31379707	The risk-score formula was constructed as follows: risk score = (0.5536 x expression level of DES) + (-0.7340 x expression level of RANBP17) + (0.0995 x expression level of CLEC5A) + (0.2810 x expression level of HOXC11) + (0.0566 x expression level of POSTN).	('CLEC5A', 'Gene', (173, 179))	('HOXC11', 'Gene', '3227', (213, 219))	('0.5536', 'Var', (65, 71))	('POSTN', 'Gene', '10631', (253, 258))	('POSTN', 'Gene', (253, 258))	('DES', 'Gene', '1674', (94, 97))	('RANBP17', 'Gene', (132, 139))	('HOXC11', 'Gene', (213, 219))	('DES', 'Gene', (94, 97))	('-0.7340', 'Var', (102, 109))	('RANBP17', 'Gene', '64901', (132, 139))	('CLEC5A', 'Gene', '23601', (173, 179))	('0.2810', 'Var', (184, 190))	('0.0995', 'Var', (144, 150))
112428	31379707	This result was in accordance with the conclusion that IDH1 mutant in glioma was related to better patient prognosis.	('patient', 'Species', '9606', (99, 106))	('glioma', 'Disease', (70, 76))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('mutant', 'Var', (60, 66))	('better', 'PosReg', (92, 98))
112429	31379707	For MGMT promoter, the risk scores decreased in patients with methylated status (P < 0.01, Figure 3C), though the average risk scores between the two groups didn't differ largely.	('MGMT', 'Gene', '4255', (4, 8))	('decreased', 'NegReg', (35, 44))	('methylated status', 'Var', (62, 79))	('patients', 'Species', '9606', (48, 56))	('MGMT', 'Gene', (4, 8))
112431	31379707	There was no significant statistical difference between high-risk group and low-risk group in GBM patients with IDH1 mutant (Figure 3D).	('mutant', 'Var', (117, 123))	('IDH1', 'Gene', (112, 116))	('patients', 'Species', '9606', (98, 106))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('IDH1', 'Gene', '3417', (112, 116))
112457	31379707	For instance, DES encodes the intermediate filament protein desmin, which is expressed in cardiac, skeletal, and smooth muscle cells, and its mutations can cause isolated cardiomyopathies and cardiac conduction diseases.	('cause', 'Reg', (156, 161))	('mutations', 'Var', (142, 151))	('cardiac conduction diseases', 'Disease', (192, 219))	('DES', 'Gene', '1674', (14, 17))	('desmin', 'Gene', '1674', (60, 66))	('DES', 'Gene', (14, 17))	('cardiomyopathies', 'Phenotype', 'HP:0001638', (171, 187))	('cardiac conduction diseases', 'Disease', 'MESH:D000075224', (192, 219))	('cardiomyopathies', 'Disease', (171, 187))	('cardiac conduction', 'Phenotype', 'HP:0011675', (192, 210))	('cardiomyopathies', 'Disease', 'MESH:D009202', (171, 187))	('desmin', 'Gene', (60, 66))
112461	31379707	RANBP17 is upregulated in dilated cardiomyopathy and ischemic cardiomyopathy samples, and may regulate the transport of different cargos in specific cardiomyopathies through enhancing the transcriptional activation of the EA2 transcription factors E12 and E47.	('cardiomyopathies', 'Disease', 'MESH:D009202', (149, 165))	('RANBP17', 'Gene', '64901', (0, 7))	('EA2', 'Gene', (222, 225))	('ischemic cardiomyopathy', 'Disease', (53, 76))	('transcriptional activation', 'MPA', (188, 214))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (26, 48))	('transport of different cargos', 'MPA', (107, 136))	('EA2', 'Gene', '773', (222, 225))	('cardiomyopathies', 'Disease', (149, 165))	('regulate', 'Reg', (94, 102))	('ischemic cardiomyopathy', 'Disease', 'MESH:D009202', (53, 76))	('enhancing', 'PosReg', (174, 183))	('upregulated', 'PosReg', (11, 22))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (34, 48))	('RANBP17', 'Gene', (0, 7))	('dilated cardiomyopathy', 'Disease', (26, 48))	('E12', 'Var', (248, 251))	('cardiomyopathies', 'Phenotype', 'HP:0001638', (149, 165))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (26, 48))	('E47', 'Var', (256, 259))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (62, 76))
112486	28083869	Under this framework, each pg is drawn from a theoretically infinite number of realizations thetah from Beta(a, b), with corresponding probability weights pih:   where deltathetah is a point mass at thetah.	('deltathetah', 'Var', (168, 179))	('pih', 'Gene', (155, 158))	('pih', 'Gene', '5177', (155, 158))
112503	28083869	Methylation is thought to play a significant role in LGG pathogenesis and GBM pathogenesis, but the differences between the two tumor classes have not been well-characterized on a genome-wide scale.	('GBM', 'Disease', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('LGG', 'Disease', (53, 56))	('tumor', 'Disease', (128, 133))
112516	28083869	Figure 3 shows the genomic location and posterior probability of group equality for the nine CpG sites in BST2, as well as group histograms and posterior densities for methylation at three sites.	('BST2', 'Gene', '684', (106, 110))	('BST2', 'Gene', (106, 110))	('CpG', 'Var', (93, 96))
112551	28206648	MiR-21-5p and miR-30a-3p produce many isomiRs in most of the analyzed cancers.	('MiR-21-5p', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-30a-3p', 'Var', (14, 24))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('MiR-21-5p', 'Chemical', '-', (0, 9))	('cancers', 'Disease', (70, 77))	('miR-30a-3p', 'Chemical', '-', (14, 24))
112552	28206648	Ovarian cancer (OV) in the case of miR-21-5p and LAML in the case of miR-30a-3p are striking exceptions to this observation.	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('miR-21-5p', 'Chemical', '-', (35, 44))	('Ovarian cancer', 'Disease', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('miR-30a-3p', 'Var', (69, 79))	('OV', 'Phenotype', 'HP:0100615', (16, 18))	('miR-30a-3p', 'Chemical', '-', (69, 79))	('miR-21-5p', 'Var', (35, 44))
112560	28206648	On the contrary, isomiRs of miR-10a-5p and the mir-200 family are largely absent from LGG and present in 71-93% of the other cancers (Figure 1B).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('mir-200', 'Gene', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('LGG', 'Disease', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('present', 'Reg', (94, 101))	('miR-10a-5p', 'Var', (28, 38))
112562	28206648	the miR-215-5p arm is specific to colon adenocarcinoma (COAD) (Supplementary Table S3) as are the isomiRs it produces (Supplementary Tables S3 and 4).	('COAD', 'Disease', 'MESH:D029424', (56, 60))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (34, 54))	('miR-215-5p', 'Var', (4, 14))	('COAD', 'Disease', (56, 60))	('colon adenocarcinoma', 'Disease', (34, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
112636	22157620	BRAF Alterations in Primary Glial and Glioneuronal Neoplasms of the Central Nervous System With Identification of 2 Novel KIAA1549:BRAF Fusion Variants Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors.	('tumors', 'Disease', (304, 310))	('BRAF', 'Gene', '673', (0, 4))	('CNS tumor', 'Phenotype', 'HP:0100006', (300, 309))	('BRAF', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('alterations', 'Var', (200, 211))	('ERK', 'Gene', '5594', (263, 266))	('Neoplasms', 'Phenotype', 'HP:0002664', (51, 60))	('Neoplasms of the Central Nervous', 'Disease', 'MESH:D016543', (51, 83))	('Neoplasms of the Central Nervous', 'Disease', (51, 83))	('KIAA1549', 'Gene', '57670', (122, 130))	('Glial and Glioneuronal Neoplasms of the Central Nervous', 'Phenotype', 'HP:0025170', (28, 83))	('ERK', 'Gene', (263, 266))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('activation', 'PosReg', (276, 286))	('KIAA1549', 'Gene', (122, 130))	('Neoplasms of the Central Nervous', 'Phenotype', 'HP:0100006', (51, 83))	('Variants', 'Var', (143, 151))
112638	22157620	Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma.	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (211, 233))	('KIAA1549', 'Gene', '57670', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('gliomas', 'Disease', (171, 178))	('pilomyxoid astrocytoma', 'Disease', (362, 384))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (244, 273))	('astrocytomas', 'Disease', (262, 274))	('astrocytomas', 'Disease', (293, 305))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('KIAA1549', 'Gene', (45, 53))	('tumors', 'Disease', (79, 85))	('astrocytomas', 'Disease', (124, 136))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('fusions', 'Var', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('pleomorphic xanthoastrocytoma', 'Disease', (244, 273))	('neuroepithelial tumors', 'Disease', (211, 233))	('astrocytoma', 'Phenotype', 'HP:0009592', (373, 384))	('pilocytic astrocytomas', 'Disease', (114, 136))	('tumors', 'Disease', (227, 233))	('pilomyxoid astrocytoma', 'Disease', 'MESH:D001254', (362, 384))	('astrocytomas', 'Disease', 'MESH:D001254', (262, 274))	('astrocytomas', 'Disease', 'MESH:D001254', (293, 305))	('astrocytoma', 'Phenotype', 'HP:0009592', (262, 273))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('astrocytoma', 'Phenotype', 'HP:0009592', (293, 304))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (211, 233))	('astrocytomas', 'Disease', 'MESH:D001254', (124, 136))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (114, 136))	('glioneuronal/neuroepithelial tumors', 'Phenotype', 'HP:0025170', (198, 233))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
112642	22157620	KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('optic pathway', 'Disease', (83, 96))	('BRAF', 'Gene', (9, 13))	('KIAA1549', 'Gene', '57670', (0, 8))	('infratentorial', 'Disease', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('KIAA1549', 'Gene', (0, 8))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('fusions', 'Var', (14, 21))	('BRAF', 'Gene', '673', (9, 13))
112643	22157620	We did not identify significantly improved progression-free survival in tumors with fusions.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('fusions', 'Var', (84, 91))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
112644	22157620	In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (138, 157))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('fusions', 'Var', (26, 33))	('pilocytic astrocytomas', 'Disease', (49, 71))	('glioneuronal tumors', 'Disease', (138, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (138, 157))	('BRAF', 'Gene', '673', (21, 25))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (49, 71))	('BRAF', 'Gene', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('KIAA1549', 'Gene', '57670', (12, 20))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('KIAA1549', 'Gene', (12, 20))
112650	22157620	Recently, independent high-resolution genomic studies have identified a tandem duplication of BRAF at 7q34 that leads to various KIAA1549:BRAF gene exon fusions in the majority (53%-72%) of PA.	('tandem duplication', 'Var', (72, 90))	('KIAA1549', 'Gene', (129, 137))	('BRAF', 'Gene', (94, 98))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', '673', (94, 98))	('BRAF', 'Gene', (138, 142))	('leads to', 'Reg', (112, 120))	('KIAA1549', 'Gene', '57670', (129, 137))
112651	22157620	In low-grade gliomas arising in patientswith neurofibromatosis type 1 (NF-1), genetic inactivation of NF1 results in K-RAS hyperactivation.	('patients', 'Species', '9606', (32, 40))	('K-RAS', 'Gene', '3845', (117, 122))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('genetic inactivation', 'Var', (78, 98))	('K-RAS', 'Gene', (117, 122))	('neurofibromatosis type 1', 'Gene', (45, 69))	('NF1', 'Gene', (102, 105))	('neurofibromatosis type 1', 'Gene', '4763', (45, 69))	('NF1', 'Gene', '4763', (102, 105))	('gliomas', 'Disease', (13, 20))	('NF-1', 'Gene', '4763', (71, 75))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('hyperactivation', 'PosReg', (123, 138))	('NF-1', 'Gene', (71, 75))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (45, 62))
112655	22157620	These genetic alterations, which are commonly seen in low-grade gliomas, invariably result in MAPK/ERK pathway activation.	('activation', 'PosReg', (111, 121))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('genetic alterations', 'Var', (6, 25))
112657	22157620	Here, we evaluated the clinical and pathologic relevance of BRAF alterations in a multi-institutional cohort of low-grade glioma and glioneuronal tumors.	('alterations', 'Var', (65, 76))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (133, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('glioma', 'Disease', (122, 128))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (133, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioneuronal tumors', 'Disease', (133, 152))
112672	22157620	Screening for mutations in BRAF exons 11 and 15 was performed by PCR in a 50-microL reaction containing 10 ng of DNA solution, 5microL of 10x PCR buffer containing 15 mmol/L MgCl2 (Qiagen), 0.2 mmol/L dNTPs (New England Biolabs, Ipswitch, MA), 1 U of Taq DNA polymerase (Qiagen), and 0.1 micromol/L of both forward and reverse primers.	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('dNTPs', 'Chemical', 'MESH:D010278', (201, 206))	('mutations', 'Var', (14, 23))	('MgCl2', 'Chemical', 'MESH:D015636', (174, 179))
112677	22157620	The distribution of molecular BRAF alterations in the total of 106 tumors is shown in Figure 1.	('alterations', 'Var', (35, 46))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
112678	22157620	BRAF alterations included KIAA1549:BRAF fusions in 51 (48%) and BRAF exon 15 (BRAFV600E) point mutations in 8 (8%).	('BRAF', 'Gene', (35, 39))	('KIAA1549', 'Gene', '57670', (26, 34))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', '673', (64, 68))	('point mutations', 'Var', (89, 104))	('fusions', 'Var', (40, 47))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', (78, 82))	('KIAA1549', 'Gene', (26, 34))	('BRAF', 'Gene', '673', (0, 4))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (35, 39))
112682	22157620	By comparison, no KIAA1549:BRAF fusions were identified in the 5 high-grade astrocytomas, 4 medulloblastomas, 2 ependymomas, or 1 dysembryoplastic neuroectodermal tumor tested.	('dysembryoplastic neuroectodermal tumor', 'Disease', (130, 168))	('ependymomas', 'Disease', 'MESH:D004806', (112, 123))	('astrocytomas', 'Disease', (76, 88))	('fusions', 'Var', (32, 39))	('medulloblastomas', 'Disease', (92, 108))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (147, 168))	('ependymomas', 'Disease', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', '673', (27, 31))	('KIAA1549', 'Gene', (18, 26))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('KIAA1549', 'Gene', '57670', (18, 26))	('BRAF', 'Gene', (27, 31))	('astrocytomas', 'Disease', 'MESH:D001254', (76, 88))	('dysembryoplastic neuroectodermal tumor', 'Disease', 'MESH:D017599', (130, 168))	('medulloblastomas', 'Disease', 'MESH:D008527', (92, 108))
112683	22157620	A single anaplastic astrocytoma had a BRAFV600E mutation.	('astrocytoma', 'Disease', 'MESH:D001254', (20, 31))	('BRAFV600E', 'Var', (38, 47))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('astrocytoma', 'Disease', (20, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (20, 31))
112689	22157620	Conversely, BRAFV600E mutations were identified in a total of 8 tumors, 6 in non-PA tumors, and 2 in PA; this difference was statistically significant (p = 0.005).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('non-PA tumors', 'Disease', 'MESH:D011471', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('non-PA tumors', 'Disease', (77, 90))	('BRAFV600E', 'Mutation', 'rs113488022', (12, 21))	('identified', 'Reg', (37, 47))	('mutations', 'Var', (22, 31))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('BRAFV600E', 'Gene', (12, 21))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
112693	22157620	In addition, 2 PCR products of approximately 210 and 800 bp in size were identified in 3 patients and in 1 patient, respectively; these resulted in KIAA1549:BRAF fusions with novel breakpoints involving 1-15/11-18 and 1-17/10-18 exons (Fig.	('fusions', 'Var', (162, 169))	('patient', 'Species', '9606', (89, 96))	('resulted in', 'Reg', (136, 147))	('BRAF', 'Gene', '673', (157, 161))	('patients', 'Species', '9606', (89, 97))	('BRAF', 'Gene', (157, 161))	('KIAA1549', 'Gene', (148, 156))	('KIAA1549', 'Gene', '57670', (148, 156))	('patient', 'Species', '9606', (107, 114))
112699	22157620	Progression-free survival was less in patients who had a subtotal resection versus patients with a gross total resection (p = 0.0001; Fig.	('less', 'NegReg', (30, 34))	('Progression-free survival', 'CPA', (0, 25))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (83, 91))	('subtotal', 'Var', (57, 65))
112702	22157620	There was a nonsignificant trend toward longer PFS in patients with KIAA1549:BRAF fusions (p = 0.15; Fig.	('PFS', 'MPA', (47, 50))	('KIAA1549', 'Gene', (68, 76))	('KIAA1549', 'Gene', '57670', (68, 76))	('BRAF', 'Gene', '673', (77, 81))	('patients', 'Species', '9606', (54, 62))	('BRAF', 'Gene', (77, 81))	('fusions', 'Var', (82, 89))
112704	22157620	We also found no differences in PFS in a comparison of PA tumors with non-PA tumors or BRAF alteration subtypes (fusion vs point mutation vs lack of fusion) (p > 0.05).	('PA tumors', 'Disease', 'MESH:D011471', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('point mutation', 'Var', (123, 137))	('BRAF', 'Gene', '673', (87, 91))	('PA tumors', 'Disease', (55, 64))	('fusion', 'Var', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('non-PA tumors', 'Disease', 'MESH:D011471', (70, 83))	('BRAF', 'Gene', (87, 91))	('PA tumors', 'Disease', 'MESH:D011471', (55, 64))	('non-PA tumors', 'Disease', (70, 83))
112709	22157620	Modern high-resolution genomic studies have provided detailed insight into the molecular genetics of these neoplasms, and there is now a general consensus that MAPK pathway activation is a fundamental feature of many, if not all, low-grade pediatric gliomas, mediated in most instances by activation of RAF family members through rearrangements and/or point mutations.	('activation', 'PosReg', (289, 299))	('RAF', 'Gene', '22882', (303, 306))	('activation', 'PosReg', (173, 183))	('gliomas', 'Disease', (250, 257))	('RAF', 'Gene', (303, 306))	('neoplasms', 'Disease', (107, 116))	('neoplasms', 'Disease', 'MESH:D009369', (107, 116))	('gliomas', 'Disease', 'MESH:D005910', (250, 257))	('neoplasm', 'Phenotype', 'HP:0002664', (107, 115))	('rearrangements', 'Var', (330, 344))	('MAPK pathway', 'Pathway', (160, 172))	('gliomas', 'Phenotype', 'HP:0009733', (250, 257))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('neoplasms', 'Phenotype', 'HP:0002664', (107, 116))	('point mutations', 'Var', (352, 367))
112712	22157620	Frequency of KIAA1549:BRAF fusion in low-grade glioma/PA varies in the literature, ranging from 60% to 73%, although the prevalence may exceed 90% in cerebellar PA. A novel aspect of our study is the discovery of 2 new KIAA1549:BRAF fusion variants.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('BRAF', 'Gene', '673', (228, 232))	('KIAA1549', 'Gene', (13, 21))	('KIAA1549', 'Gene', '57670', (13, 21))	('KIAA1549', 'Gene', (219, 227))	('BRAF', 'Gene', (228, 232))	('KIAA1549', 'Gene', '57670', (219, 227))	('BRAF', 'Gene', '673', (22, 26))	('glioma', 'Disease', (47, 53))	('fusion', 'Var', (27, 33))	('BRAF', 'Gene', (22, 26))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
112714	22157620	The new sequence-verified variants we identify have breakpoints involving exons 1-15/11-18 and 1-17/10-18 and add to the growing list of possible KIAA1549:BRAF fusions.	('BRAF', 'Gene', (155, 159))	('KIAA1549', 'Gene', (146, 154))	('KIAA1549', 'Gene', '57670', (146, 154))	('BRAF', 'Gene', '673', (155, 159))	('variants', 'Var', (26, 34))
112718	22157620	One possible explanation is that having appropriate levels of the fusion is important for tumorigenesis, but excess levels of mutant BRAF protein products may interfere with tumorigenesis and/or progression.	('tumor', 'Disease', (174, 179))	('interfere', 'NegReg', (159, 168))	('BRAF', 'Gene', '673', (133, 137))	('protein', 'Protein', (138, 145))	('tumor', 'Disease', (90, 95))	('progression', 'CPA', (195, 206))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('BRAF', 'Gene', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutant', 'Var', (126, 132))
112726	22157620	Whether specific KIAA1549:BRAF rearrangements have biologic significance is unclear.	('BRAF', 'Gene', '673', (26, 30))	('KIAA1549', 'Gene', (17, 25))	('KIAA1549', 'Gene', '57670', (17, 25))	('rearrangements', 'Var', (31, 45))	('BRAF', 'Gene', (26, 30))
112727	22157620	Why KIAA1549:BRAF fusions occur at a higher frequency at specific anatomic locations (optic pathway/cerebellum) and in association with PA histology is unclear.	('fusions', 'Var', (18, 25))	('BRAF', 'Gene', '673', (13, 17))	('KIAA1549', 'Gene', (4, 12))	('KIAA1549', 'Gene', '57670', (4, 12))	('BRAF', 'Gene', (13, 17))
112728	22157620	In a previous publication focusing on anaplastic subsets of PA, BRAF duplication was identified by FISH in approximately 60% of cerebellar tumors but in none of the extracerebellar examples.	('BRAF', 'Gene', '673', (64, 68))	('cerebellar tumors', 'Disease', 'MESH:D002528', (128, 145))	('BRAF', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cerebellar tumors', 'Disease', (128, 145))	('duplication', 'Var', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
112731	22157620	These findings suggest that BRAF alterations are tumorigenic when they occur in specific precursors, but these alterations in alternative precursors may not result in tumors because of the lack of a proper environment or the mechanism of oncogene-induced senescence.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('BRAF', 'Gene', '673', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('alterations', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('BRAF', 'Gene', (28, 32))	('tumors', 'Disease', (167, 173))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
112734	22157620	Hawkins et al recently focused on the role of KIAA1549:BRAF fusions in a "clinically relevant" subgroup of pediatric low-grade astrocytoma patients.	('astrocytoma', 'Disease', 'MESH:D001254', (127, 138))	('astrocytoma', 'Disease', (127, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (127, 138))	('patients', 'Species', '9606', (139, 147))	('fusions', 'Var', (60, 67))	('KIAA1549', 'Gene', (46, 54))	('BRAF', 'Gene', '673', (55, 59))	('KIAA1549', 'Gene', '57670', (46, 54))	('BRAF', 'Gene', (55, 59))
112735	22157620	They defined this group as non-NF-1 patients with noncerebellar tumor location and subtotal resection and found that fusions were significantly associated with better outcome in their cohort of 70 patients.	('fusions', 'Var', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patients', 'Species', '9606', (197, 205))	('patients', 'Species', '9606', (36, 44))	('NF-1', 'Gene', '4763', (31, 35))	('NF-1', 'Gene', (31, 35))	('noncerebellar tumor', 'Disease', (50, 69))	('better', 'PosReg', (160, 166))	('noncerebellar tumor', 'Disease', 'MESH:D009369', (50, 69))
112737	22157620	In summary, the results of our study are largely in keeping with previously published reports identifying BRAF alterations as a frequent event in pediatric low-grade glioma/neuroepithelial tumors, in particular tumors with PA histology, and those involving the cerebellum and optic pathways.	('neuroepithelial tumors', 'Disease', (173, 195))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (173, 195))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (173, 195))	('BRAF', 'Gene', '673', (106, 110))	('alterations', 'Var', (111, 122))	('glioma', 'Disease', (166, 172))	('particular tumors', 'Disease', (200, 217))	('particular tumors', 'Disease', 'MESH:D009369', (200, 217))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('BRAF', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
112738	22157620	We report 2 novel KIAA1549:BRAF fusion breakpoints, which add to a growing literature suggesting that these rearrangements are highly heterogeneous.	('BRAF', 'Gene', '673', (27, 31))	('KIAA1549', 'Gene', (18, 26))	('KIAA1549', 'Gene', '57670', (18, 26))	('BRAF', 'Gene', (27, 31))	('fusion', 'Var', (32, 38))
112739	22157620	In contrast to the study of Hawkins et al, we found no association between KIAA1549:BRAF fusions and clinical outcome in either our cohort as a whole or the "clinically relevant" subset, with our analysis limited by a smaller number of patients.	('KIAA1549', 'Gene', '57670', (75, 83))	('BRAF', 'Gene', '673', (84, 88))	('KIAA1549', 'Gene', (75, 83))	('patients', 'Species', '9606', (236, 244))	('BRAF', 'Gene', (84, 88))	('fusions', 'Var', (89, 96))
112740	22157620	Future studies should expand on these observations and continue to define the heterogeneous genetic and biologic features of pediatric low-grade gliomas and the role of BRAF alterations in the pathogenesis and clinical behavior of these tumors.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('alterations', 'Var', (174, 185))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('gliomas', 'Disease', (145, 152))
112770	20425038	The University of California, San Francisco (UCSF) group recently introduced a new LGG scoring system that uses a four-point scoring system to predict OS and PFS, assigning one point each for age greater than 50 years, Karnofsky performance score (KPS) <=80, maximum tumor diameter greater than 4 cm, and eloquent involvement of the tumor (Table 1) .	('tumor', 'Disease', (333, 338))	('OS', 'Chemical', '-', (151, 153))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('<=80', 'Var', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('men', 'Species', '9606', (321, 324))	('tumor', 'Disease', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))
112783	20425038	Recent reports have dramatically altered our conceptual framework of LGG molecular genetics, suggesting that isocitrate dehydrogenase (IDH) mutations are an early event in LGG pathogenesis.	('LGG', 'Disease', (172, 175))	('isocitrate dehydrogenase', 'Gene', (109, 133))	('isocitrate dehydrogenase', 'Gene', '3417', (109, 133))	('IDH', 'Gene', (135, 138))	('IDH', 'Gene', '3417', (135, 138))	('mutations', 'Var', (140, 149))
112785	20425038	Previously, it was recognized that most LGGs harbored one of two mutually exclusive genetic changes: TP53 mutations in most low-grade astrocytomas and deletions of chromosomes 1p and 19q in most pure low-grade oligodendrogliomas (Table 2).	('astrocytomas', 'Disease', 'MESH:D001254', (134, 146))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('TP53', 'Gene', '7157', (101, 105))	('gliomas', 'Phenotype', 'HP:0009733', (221, 228))	('astrocytomas', 'Disease', (134, 146))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (210, 228))	('deletions', 'Var', (151, 160))	('TP53', 'Gene', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('mutations', 'Var', (106, 115))	('oligodendrogliomas', 'Disease', (210, 228))
112786	20425038	Low-grade mixed gliomas tend to have either TP53 mutation or 1p/19q codeletion.	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('gliomas', 'Disease', (16, 23))	('TP53', 'Gene', '7157', (44, 48))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('1p/19q codeletion', 'Var', (61, 78))	('TP53', 'Gene', (44, 48))
112787	20425038	Recent studies, however, have demonstrated IDH1 mutations in 59% to 90% of grade II astrocytomas, 68% to 85% of grade II oligodendrogliomas, and 50% to 83% of grade II oligoastrocytomas (Table 2) .	('II astrocytomas', 'Disease', (81, 96))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('IDH1', 'Gene', (43, 47))	('II oligoastrocytomas', 'Disease', 'MESH:D001254', (165, 185))	('IDH1', 'Gene', '3417', (43, 47))	('II oligodendrogliomas', 'Disease', (118, 139))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('II oligoastrocytomas', 'Disease', (165, 185))	('astrocytoma', 'Phenotype', 'HP:0009592', (84, 95))	('II oligodendrogliomas', 'Disease', 'MESH:D009837', (118, 139))	('mutations', 'Var', (48, 57))	('II astrocytomas', 'Disease', 'MESH:D001254', (81, 96))
112788	20425038	The fact that IDH1 mutations are seen in similar frequencies in tumors with TP53 mutation and 1p/19q deletion suggests these mutations may precede other genetic alterations .	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('TP53', 'Gene', '7157', (76, 80))	('mutation', 'Var', (81, 89))	('1p/19q deletion', 'Var', (94, 109))	('mutations', 'Var', (19, 28))	('TP53', 'Gene', (76, 80))	('IDH1', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('IDH1', 'Gene', '3417', (14, 18))
112789	20425038	This is supported further by serial biopsies of LGGs showing that when IDH1 mutations occur, they always precede and never follow TP53 mutation or loss of heterozygosity of 1p/19q.	('mutations', 'Var', (76, 85))	('IDH1', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (71, 75))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))
112790	20425038	Moreover, large-scale genetic sequencing of 105 glioblastomas identified IDH1 mutations in almost all secondary glioblastomas but in only 7% of primary (de novo) glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('glioblastomas', 'Phenotype', 'HP:0012174', (112, 125))	('glioblastomas', 'Disease', (162, 175))	('IDH1', 'Gene', '3417', (73, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (112, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('mutations', 'Var', (78, 87))	('glioblastomas', 'Phenotype', 'HP:0012174', (48, 61))	('glioblastomas', 'Disease', (112, 125))	('glioblastomas', 'Phenotype', 'HP:0012174', (162, 175))	('glioblastomas', 'Disease', 'MESH:D005909', (48, 61))	('IDH1', 'Gene', (73, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (162, 175))	('glioblastomas', 'Disease', (48, 61))
112791	20425038	IDH mutations in gliomas have some remarkable features.	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('gliomas', 'Disease', (17, 24))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('mutations', 'Var', (4, 13))
112792	20425038	First, every IDH1 mutation occurs in codon 132, which normally codes for an arginine in the enzyme's active site.	('arginine', 'MPA', (76, 84))	('codes', 'Reg', (63, 68))	('IDH1', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', '3417', (13, 17))	('arginine', 'Chemical', 'MESH:D001120', (76, 84))
112793	20425038	All produce amino acid substitutions, which in more than 90% is a histidine, resulting in decreased catalytic activity .	('catalytic activity', 'MPA', (100, 118))	('histidine', 'Chemical', 'MESH:D006639', (66, 75))	('substitutions', 'Var', (23, 36))	('decreased', 'NegReg', (90, 99))
112795	20425038	Rare IDH2 mutations also were recognized recently in gliomas, especially oligodendrogliomas .	('oligodendrogliomas', 'Disease', (73, 91))	('IDH2', 'Gene', (5, 9))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('IDH2', 'Gene', '3418', (5, 9))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (73, 91))	('mutations', 'Var', (10, 19))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
112796	20425038	All IDH2 mutations are point mutations at codon 172 in the enzyme's active site, a position representing the precise analogue of R132 in IDH1.	('IDH2', 'Gene', '3418', (4, 8))	('mutations', 'Var', (9, 18))	('IDH1', 'Gene', (137, 141))	('IDH2', 'Gene', (4, 8))	('IDH1', 'Gene', '3417', (137, 141))
112797	20425038	IDH mutations are exceedingly rare in pediatric gliomas, nonglioma brain tumors, and other cancers.	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('brain tumors', 'Phenotype', 'HP:0030692', (67, 79))	('cancers', 'Disease', (91, 98))	('IDH', 'Gene', '3417', (0, 3))	('brain tumor', 'Phenotype', 'HP:0030692', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (4, 13))	('nonglioma brain tumors', 'Disease', 'MESH:D001932', (57, 79))	('nonglioma brain tumors', 'Disease', (57, 79))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('gliomas', 'Disease', (48, 55))
112798	20425038	The mechanisms by which IDH mutations predispose to gliomagenesis remain mysterious.	('IDH', 'Gene', (24, 27))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH', 'Gene', '3417', (24, 27))	('glioma', 'Disease', (52, 58))	('predispose', 'Reg', (38, 48))	('mutations', 'Var', (28, 37))
112801	20425038	Recent reports highlight the importance of the MAPK pathway in pilocytic astrocytomas, with many of these tumors manifesting tandem duplication of 7q, resulting in a fusion gene incorporating the kinase domain of the BRAF oncogene with constitutive BRAF activity.	('BRAF', 'Gene', '673', (249, 253))	('tandem duplication', 'Var', (125, 143))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('fusion gene', 'Var', (166, 177))	('BRAF', 'Gene', (249, 253))	('pilocytic astrocytomas', 'Disease', (63, 85))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (63, 85))	('BRAF', 'Gene', '673', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BRAF', 'Gene', (217, 221))
112802	20425038	However, the 7q34 duplication is not seen in grade II astrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))	('II astrocytomas', 'Disease', (51, 66))	('7q34 duplication', 'Var', (13, 29))	('II astrocytomas', 'Disease', 'MESH:D001254', (51, 66))
112805	20425038	However, most LGGs epigenetically silence PTEN via hypermethylation.	('epigenetically', 'Var', (19, 33))	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('hypermethylation', 'Var', (51, 67))
112807	20425038	To what extent molecular markers such as 1p/19q codeletion status, IDH mutational status, and the presence or absence of MGMT promotor hypermethylation, which is a prognostic factor in glioblastoma outcome, predict responsiveness to specific therapies or overall prognosis remains uncertain.	('MGMT', 'Gene', '4255', (121, 125))	('MGMT', 'Gene', (121, 125))	('predict', 'Reg', (207, 214))	('glioblastoma', 'Disease', (185, 197))	('glioblastoma', 'Disease', 'MESH:D005909', (185, 197))	('IDH', 'Gene', (67, 70))	('hypermethylation', 'Var', (135, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (185, 197))	('IDH', 'Gene', '3417', (67, 70))
112808	20425038	The presence of 1p/19q deletion seems to portend a better prognosis in LGG, although its favorable impact is weaker than in grade III gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('LGG', 'Disease', (71, 74))	('1p/19q deletion', 'Var', (16, 31))	('II gliomas', 'Disease', (131, 141))	('II gliomas', 'Disease', 'MESH:D005910', (131, 141))
112810	20425038	Similarly, in univariate analyses, IDH1 mutations conferred improved OS in low-grade and anaplastic gliomas as well as in glioblastomas, but it remains unclear whether mutational status retains prognostic significance when other prognostic markers are incorporated into multivariate models.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('IDH1', 'Gene', (35, 39))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('glioblastomas', 'Phenotype', 'HP:0012174', (122, 135))	('OS', 'Chemical', '-', (69, 71))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('low-grade', 'Disease', (75, 84))	('glioblastomas', 'Disease', (122, 135))	('glioblastomas', 'Disease', 'MESH:D005909', (122, 135))	('mutations', 'Var', (40, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (122, 134))	('improved', 'PosReg', (60, 68))	('gliomas', 'Disease', (100, 107))
112817	20425038	On multivariate analysis, extent of resection (EOR) was significantly associated with improved OS but not PFS.	('extent', 'Var', (26, 32))	('improved', 'PosReg', (86, 94))	('OS', 'Chemical', '-', (95, 97))
112820	20425038	similarly found that gross total resection (GTR; based on independent radiologist interpretation) was independently associated with improved OS and PFS compared with subtotal resection (5-year OS: 95% vs 70%, P = 0.017; median time to progression: 7 vs 3.5 years, P = 0.043).	('OS', 'Chemical', '-', (141, 143))	('gross total resection', 'Var', (21, 42))	('improved', 'PosReg', (132, 140))	('OS', 'Chemical', '-', (193, 195))	('PFS', 'CPA', (148, 151))
112883	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))
112890	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
112891	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
112925	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('CGB', 'Gene', (61, 64))	('cancer', 'Disease', (113, 119))	('reducing', 'NegReg', (104, 112))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
112951	30006355	Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations.	('BRAF', 'Gene', (107, 111))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (8, 12))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('BRAFV600E', 'Mutation', 'rs113488022', (75, 84))	('BRAF', 'Gene', '673', (107, 111))	('mutations', 'Var', (18, 27))
112952	30006355	Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4-ALK fusion, also present at recurrence.	('mutation', 'Var', (113, 121))	('tumor', 'Disease', (202, 207))	('ATRX', 'Gene', '546', (139, 143))	('TP53', 'Gene', (108, 112))	('EML4', 'Gene', (220, 224))	('TP53', 'Gene', '7157', (108, 112))	('deletion', 'Var', (144, 152))	('ALK', 'Gene', '238', (225, 228))	('EML4', 'Gene', '27436', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('ATRX', 'Gene', (139, 143))	('ALK', 'Gene', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
112953	30006355	DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations.	('DIG/DIA', 'Disease', (0, 7))	('DIG', 'Chemical', '-', (0, 3))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('DIA', 'Chemical', '-', (4, 7))	('mutations', 'Var', (73, 82))
112955	30006355	In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations.	('BRAF', 'Gene', '673', (29, 33))	('wild-type', 'Var', (19, 28))	('malignant progression', 'CPA', (35, 56))	('BRAF', 'Gene', (29, 33))
112956	30006355	DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAFV600E or BRAFV600D mutations.	('DIG/DIA', 'Disease', (0, 7))	('BRAFV600E', 'Var', (83, 92))	('DIG', 'Chemical', '-', (0, 3))	('BRAFV600E', 'Mutation', 'rs113488022', (83, 92))	('DIA', 'Chemical', '-', (4, 7))	('BRAFV600D mutations', 'Var', (96, 115))
112981	30006355	Hypermethylated alleles in the P14ARF gene were seen in one case.	('P14ARF', 'Gene', (31, 37))	('Hypermethylated', 'Var', (0, 15))	('P14ARF', 'Gene', '1029', (31, 37))
112982	30006355	Lonnrot and colleagues, identified MYCN amplifications in 2 cases and EGFR amplifications in 3 cases.	('EGFR', 'Gene', '1956', (70, 74))	('MYCN', 'Gene', (35, 39))	('EGFR', 'Gene', (70, 74))	('MYCN', 'Gene', '4613', (35, 39))	('amplifications', 'Var', (40, 54))
112987	30006355	UW-OncoPlex assay version 5, a targeted, massively parallel gene sequencing assay that detects mutations in 262 cancer-related genes (http://tests.labmed.washington.edu/UW-OncoPlex, last accessed May 5, 2017), was performed as described previously.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', (112, 118))
112997	30006355	Within the other five tumors, we discovered 2 (20%) BRAFV600E mutations, 2 (20%) BRAFV600D mutations, and one EML4-ALK fusion (Table 1A).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('ALK', 'Gene', (115, 118))	('BRAFV600E', 'Mutation', 'rs113488022', (52, 61))	('BRAFV600E mutations', 'Var', (52, 71))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('EML4', 'Gene', (110, 114))	('ALK', 'Gene', '238', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('EML4', 'Gene', '27436', (110, 114))	('tumors', 'Disease', (22, 28))	('mutations', 'Var', (62, 71))	('BRAFV600D', 'Var', (81, 90))
113003	30006355	Targeted DNA exome sequencing in the remaining 6 cases revealed two V600E and one V600D mutations (Table 1B).	('V600E', 'Var', (68, 73))	('V600D', 'Mutation', 'rs121913377', (82, 87))	('V600D', 'Var', (82, 87))	('V600E', 'Mutation', 'rs113488022', (68, 73))
113008	30006355	Four were the canonical V600E valine-to-glutamic acid; interestingly, 3 of 4 were found in histologically diagnosed DIAs.	('V600E', 'Var', (24, 29))	('DIAs', 'Chemical', 'MESH:C076868', (116, 120))	('valine', 'Chemical', 'MESH:D014633', (30, 36))	('DIAs', 'Disease', (116, 120))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('glutamic acid', 'Chemical', 'MESH:D018698', (40, 53))
113009	30006355	The other 3 were exceptionally rare V600D valine-to-aspartic acid point mutations, which account for less than 1% of all V600 BRAF mutations (http://cancer.sanger.ac.uk, last accessed January 8, 2018; refs.).	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('aspartic acid', 'Chemical', 'MESH:D001224', (52, 65))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('V600D valine-to-aspartic acid', 'Var', (36, 65))	('valine', 'Chemical', 'MESH:D014633', (42, 48))	('V600D', 'Mutation', 'rs121913377', (36, 41))	('V600', 'Var', (121, 125))
113011	30006355	BRAF mutations were thus discovered in 4 of 12 (25%) DIGs, but in 3 of 4 (75%) DIAs.	('DIAs', 'Disease', (79, 83))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('DIGs', 'Disease', (53, 57))	('BRAF', 'Gene', (0, 4))	('DIAs', 'Chemical', 'MESH:C076868', (79, 83))	('DIGs', 'Chemical', '-', (53, 57))
113012	30006355	None of the patients harboring BRAF mutations experienced recurrence.	('BRAF', 'Gene', '673', (31, 35))	('patients', 'Species', '9606', (12, 20))	('mutations', 'Var', (36, 45))	('BRAF', 'Gene', (31, 35))
113013	30006355	Prior to our study, eight instances of BRAF mutations had been described in DIG/DIA, seven V600E substitutions, and one V600D.	('BRAF', 'Gene', '673', (39, 43))	('V600E substitutions', 'Var', (91, 110))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('BRAF', 'Gene', (39, 43))	('DIG/DIA', 'Disease', (76, 83))	('DIG', 'Chemical', '-', (76, 79))	('mutations', 'Var', (44, 53))	('DIA', 'Chemical', '-', (80, 83))	('V600D', 'Mutation', 'rs121913377', (120, 125))
113019	30006355	As a screen for BRAFV600E mutations, VE1 staining accurately identified these mutations in only 67%-75% of DIG; moreover, it does not appear to detect other BRAFV600 mutations, including the V600D mutation.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('V600D', 'Var', (191, 196))	('DIG', 'Chemical', '-', (107, 110))	('BRAF', 'Gene', '673', (157, 161))	('mutations', 'Var', (26, 35))	('BRAF', 'Gene', (157, 161))	('BRAFV600E', 'Mutation', 'rs113488022', (16, 25))	('V600D', 'Mutation', 'rs121913377', (191, 196))
113020	30006355	BRAF mutations have been sparsely seen among adult low-grade glial-neuronal tumors.	('neuronal tumors', 'Phenotype', 'HP:0025170', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('glial-neuronal tumors', 'Disease', 'MESH:D009410', (61, 82))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('BRAF', 'Gene', (0, 4))	('glial-neuronal tumors', 'Disease', (61, 82))
113021	30006355	TCGA low-grade glioma (LGG) analysis revealed only two BRAF mutations among 283 patients, including one V600E mutation and one D594G mutation, while the UCSF LGG analysis included one V600E mutation in 23 patients.	('V600E', 'Mutation', 'rs113488022', (184, 189))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (80, 88))	('D594G', 'Mutation', 'rs121913338', (127, 132))	('BRAF', 'Gene', (55, 59))	('glioma', 'Disease', (15, 21))	('D594G', 'Var', (127, 132))	('BRAF', 'Gene', '673', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('V600E mutation', 'Var', (104, 118))
113022	30006355	Certain typically pediatric tumors are far more likely to show BRAF alterations; however, BRAFV600E mutations have been found in an estimated 66% of pleomorphic xanthoastrocytomas (PXA; ref.	('BRAF', 'Gene', (90, 94))	('mutations', 'Var', (100, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (167, 178))	('PXA', 'Chemical', '-', (181, 184))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('BRAFV600E', 'Mutation', 'rs113488022', (90, 99))	('found', 'Reg', (120, 125))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (149, 179))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', '673', (90, 94))	('BRAF', 'Gene', (63, 67))	('pleomorphic xanthoastrocytomas', 'Disease', (149, 179))
113025	30006355	Bergthold and colleagues, found that BRAFV600E mutations clustered among supratentorial pediatric LGG, a group comprised primarily of gangliogliomas, diffuse astrocytoma, DNET, and a small proportion of pilocytic astrocytomas, also demonstrating that this cluster was significantly enriched for a significant number of gene sets that together suggested a neuronal signature.	('BRAFV600E', 'Gene', (37, 46))	('astrocytoma', 'Disease', (213, 224))	('astrocytoma', 'Disease', 'MESH:D001254', (213, 224))	('supratentorial pediatric LGG', 'Disease', (73, 101))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (203, 225))	('astrocytoma', 'Phenotype', 'HP:0009592', (213, 224))	('gangliogliomas', 'Disease', (134, 148))	('gangliogliomas', 'Disease', 'MESH:D018303', (134, 148))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('mutations', 'Var', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))	('astrocytoma', 'Disease', 'MESH:D001254', (158, 169))	('astrocytoma', 'Disease', (158, 169))	('pilocytic astrocytomas', 'Disease', (203, 225))	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))
113027	30006355	The effect of these two types of BRAF mutations on RAS/MAPK function is thought to be equivalent; however, implications for treatment and diagnostic options are potentially confounding.	('mutations', 'Var', (38, 47))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (33, 37))
113028	30006355	While a small number of targeted molecular therapies have demonstrated efficacy in tumors harboring V600E and V600K mutations, V600D mutations have not been specifically evaluated in a clinical setting.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('V600K', 'Var', (110, 115))	('V600D', 'Mutation', 'rs121913377', (127, 132))	('V600E', 'Var', (100, 105))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('V600K', 'Mutation', 'rs121913227', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('V600E', 'Mutation', 'rs113488022', (100, 105))
113029	30006355	However, preclinical studies suggest that BRAFV600D mutations are likely to be sensitive to vemurafenib and dabrafenib, and as alternative proven options are lacking, BRAF inhibitors are likely to play an important role in the management of patients with V600D mutations, even in infants.	('V600D', 'Var', (255, 260))	('dabrafenib', 'Chemical', 'MESH:C561627', (108, 118))	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('V600D', 'Mutation', 'rs121913377', (255, 260))	('infants', 'Species', '9606', (280, 287))	('V600D', 'Mutation', 'rs121913377', (46, 51))	('BRAF', 'Gene', (42, 46))	('patients', 'Species', '9606', (241, 249))	('vemurafenib', 'Chemical', 'MESH:D000077484', (92, 103))
113030	30006355	To further examine the relationship between BRAFV600-mutant and wild-type DIG/DIA and other pediatric glioneuronal tumors, including other entities that harbor BRAFV600E mutations, we performed a global DNA methylation analysis using Illumina Infinium (850k) arrays.	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('DIA', 'Chemical', '-', (78, 81))	('BRAF', 'Gene', '673', (44, 48))	('glioneuronal tumors', 'Disease', (102, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (170, 179))	('BRAF', 'Gene', (44, 48))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (102, 121))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (102, 121))	('BRAFV600E', 'Mutation', 'rs113488022', (160, 169))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('DIG/DIA', 'Disease', (74, 81))	('DIG', 'Chemical', '-', (74, 77))	('neuronal tumors', 'Phenotype', 'HP:0025170', (106, 121))
113031	30006355	This analysis included 9 primary DIG/DIA from SCH, 6 primary DIG/DIA from the HD series, and reference samples of other entities collected in HD (11 GG BRAFV600E mutant, 12 PXA BRAFV600E mutant, 7 PA BRAFV600E mutant, and 12 PA with other MAPK pathway alterations).	('BRAFV600E mutant', 'Var', (152, 168))	('HD', 'Disease', 'MESH:D006816', (142, 144))	('DIG', 'Chemical', '-', (33, 36))	('PA', 'Chemical', 'MESH:D011478', (197, 199))	('BRAFV600E', 'Var', (200, 209))	('DIA', 'Chemical', '-', (65, 68))	('BRAFV600E', 'Mutation', 'rs113488022', (152, 161))	('BRAFV600E', 'Mutation', 'rs113488022', (200, 209))	('PXA', 'Chemical', '-', (173, 176))	('PA', 'Chemical', 'MESH:D011478', (225, 227))	('BRAFV600E mutant', 'Var', (177, 193))	('HD', 'Disease', 'MESH:D006816', (78, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (177, 186))	('DIG', 'Chemical', '-', (61, 64))	('DIA', 'Chemical', '-', (37, 40))
113032	30006355	DIG/DIA clearly formed a distinct molecular group regardless of BRAF mutation status (Fig.	('BRAF', 'Gene', '673', (64, 68))	('DIG', 'Chemical', '-', (0, 3))	('BRAF', 'Gene', (64, 68))	('DIA', 'Chemical', '-', (4, 7))	('mutation', 'Var', (69, 77))
113037	30006355	Koelsche and colleagues, found BRAFV600E mutations in 41 of 71 (58%) of gangliogliomas, further localizing the mutant BRAFV600E protein product predominantly to the neuronal compartments within these tumors using VE1 IHC, indicating that BRAF mutations occur in cells that have the capacity to differentiate into ganglionic cells.	('mutations', 'Var', (41, 50))	('BRAF', 'Gene', '673', (238, 242))	('BRAF', 'Gene', '673', (118, 122))	('BRAFV600E', 'Mutation', 'rs113488022', (31, 40))	('BRAF', 'Gene', (238, 242))	('mutant', 'Var', (111, 117))	('BRAF', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('BRAFV600E', 'Mutation', 'rs113488022', (118, 127))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('gangliogliomas', 'Disease', (72, 86))	('tumors', 'Disease', (200, 206))	('gangliogliomas', 'Disease', 'MESH:D018303', (72, 86))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
113038	30006355	A positive association has been found between VE1 positivity and synaptophysin-positive clusters, while a separate study made the similar observation of colocalization of BRAFV600E mutation with the neuronal markers synaptophysin and NeuN.	('NeuN', 'Gene', (234, 238))	('VE1', 'Gene', (46, 49))	('BRAFV600E', 'Gene', (171, 180))	('NeuN', 'Gene', '146713', (234, 238))	('synaptophysin', 'Gene', (65, 78))	('synaptophysin', 'Gene', (216, 229))	('synaptophysin', 'Gene', '6855', (216, 229))	('BRAFV600E', 'Mutation', 'rs113488022', (171, 180))	('positivity', 'Var', (50, 60))	('synaptophysin', 'Gene', '6855', (65, 78))
113041	30006355	Case-by-case correlation between the BRAF mutation allele frequency and ganglion cell content would provide crucial understanding of the derivation of this tumor.	('BRAF', 'Gene', '673', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('BRAF', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutation', 'Var', (42, 50))	('tumor', 'Disease', (156, 161))
113044	30006355	3A) presented at 4 months of age with a DIG negative for somatic variants on sequencing of the native tumor, underwent subtotal resection (STR) and received carboplatin and vincristine according to the Children's Oncology Group (COG) 9952 protocol for growth of the residual tumor almost immediately after surgery.	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('carboplatin', 'Chemical', 'MESH:D016190', (157, 168))	('variants', 'Var', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Oncology', 'Phenotype', 'HP:0002664', (213, 221))	('vincristine', 'Chemical', 'MESH:D014750', (173, 184))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('DIG', 'Chemical', '-', (40, 43))	('tumor', 'Disease', (102, 107))	('Children', 'Species', '9606', (202, 210))
113045	30006355	The tumor further progressed 2 years later, at which time she again underwent STR, and sequencing of this sample showed a new frameshift insertion affecting TP53.	('tumor', 'Disease', (4, 9))	('TP53', 'Gene', (157, 161))	('frameshift insertion', 'Var', (126, 146))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', '7157', (157, 161))
113046	30006355	The patient then underwent gross total resection for tumor progression 1 year later, and sequencing of this tumor held the same TP53 mutation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mutation', 'Var', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TP53', 'Gene', '7157', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TP53', 'Gene', (128, 132))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
113047	30006355	Somatic TP53 gene mutations are some of the most frequently observed in human cancers, including malignant CNS tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('observed', 'Reg', (60, 68))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('human', 'Species', '9606', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('cancers', 'Disease', (78, 85))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('malignant CNS tumors', 'Disease', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('malignant CNS tumors', 'Disease', 'MESH:D009369', (97, 117))	('mutations', 'Var', (18, 27))
113049	30006355	3B), who presented at 7 months of age with a DIA negative for somatic variants on sequencing of the native tumor, underwent STR.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('variants', 'Var', (70, 78))	('DIA', 'Chemical', '-', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
113052	30006355	Sequencing of this tumor showed a frameshift deletion affecting ATRX, as well as a nonsynonymous single-nucleotide substitution in BCORL1.	('ATRX', 'Gene', (64, 68))	('ATRX', 'Gene', '546', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('BCORL1', 'Gene', '63035', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('frameshift deletion', 'Var', (34, 53))	('tumor', 'Disease', (19, 24))	('BCORL1', 'Gene', (131, 137))
113054	30006355	The ATRX gene is a core component of a chromatin remodeling complex active in telomere function, the alteration of which results in alternative lengthening of telomeres, a presumed precursor to genomic instability, and a recognized contributor to gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('alteration', 'Var', (101, 111))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('ATRX', 'Gene', (4, 8))	('telomeres', 'Protein', (159, 168))	('ATRX', 'Gene', '546', (4, 8))	('results in', 'Reg', (121, 131))	('glioma', 'Disease', (247, 253))
113055	30006355	The additional finding of a BCORL1 point mutation is of uncertain significance.	('BCORL1', 'Gene', (28, 34))	('point mutation', 'Var', (35, 49))	('BCORL1', 'Gene', '63035', (28, 34))
113056	30006355	Both ATRX and BCORL1 are on the X chromosome, and BCOR and BCORL1 alterations are known to be involved in acute myelogenous leukemia.	('BCOR', 'Gene', (50, 54))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (106, 132))	('ATRX', 'Gene', (5, 9))	('alterations', 'Var', (66, 77))	('acute myelogenous leukemia', 'Disease', (106, 132))	('ATRX', 'Gene', '546', (5, 9))	('BCORL1', 'Gene', '63035', (14, 20))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('BCORL1', 'Gene', (14, 20))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (106, 132))	('BCOR', 'Gene', '54880', (14, 18))	('BCORL1', 'Gene', '63035', (59, 65))	('BCORL1', 'Gene', (59, 65))	('involved', 'Reg', (94, 102))	('BCOR', 'Gene', (14, 18))	('BCOR', 'Gene', '54880', (59, 63))	('BCOR', 'Gene', '54880', (50, 54))	('BCOR', 'Gene', (59, 63))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (112, 132))
113058	30006355	While 1 case of concurrent ATRX and BCOR mutations was discovered in a pediatric malignant glioma, ATRX has not been consistently described to coincide with BCOR (L1) specifically.	('mutations', 'Var', (41, 50))	('ATRX', 'Gene', (99, 103))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('BCOR', 'Gene', (36, 40))	('ATRX', 'Gene', (27, 31))	('BCOR (L1', 'Gene', '63035', (157, 165))	('ATRX', 'Gene', '546', (99, 103))	('ATRX', 'Gene', '546', (27, 31))	('malignant glioma', 'Disease', (81, 97))	('BCOR', 'Gene', '54880', (36, 40))	('malignant glioma', 'Disease', 'MESH:D005910', (81, 97))	('BCOR', 'Gene', (157, 161))	('BCOR', 'Gene', '54880', (157, 161))
113068	30006355	We have identified a subset of DIG/DIAs harboring BRAF mutations with approximately a 43.8% frequency.	('DIAs', 'Chemical', 'MESH:C076868', (35, 39))	('DIG/DIAs', 'Disease', (31, 39))	('BRAF', 'Gene', (50, 54))	('mutations', 'Var', (55, 64))	('DIG', 'Chemical', '-', (31, 34))	('BRAF', 'Gene', '673', (50, 54))
113069	30006355	While BRAFV600D mutations have, to this point, proven exceedingly rare in primary CNS tumors, our cohorts revealed 3 among only 16 total DIG/DIAs.	('DIAs', 'Chemical', 'MESH:C076868', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CNS tumors', 'Disease', 'MESH:D016543', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('BRAFV600D mutations', 'Var', (6, 25))	('CNS tumors', 'Disease', (82, 92))	('DIG', 'Chemical', '-', (137, 140))
113070	30006355	No other oncogenic mutation was consistently identified in the wild-type or mutant BRAF DIG/DIAs.	('DIAs', 'Chemical', 'MESH:C076868', (92, 96))	('mutant', 'Var', (76, 82))	('BRAF', 'Gene', '673', (83, 87))	('DIG', 'Chemical', '-', (88, 91))	('BRAF', 'Gene', (83, 87))
113071	30006355	BRAFV600E mutations were seen in 3 of the 4 DIAs, whereas the BRAFV600D mutations were all found in DIGs, perhaps suggesting a tendency for the former to arise in cells of astrocytic, rather than neuronal, lineage.	('BRAFV600E mutations', 'Var', (0, 19))	('DIGs', 'Chemical', '-', (100, 104))	('DIAs', 'Chemical', 'MESH:C076868', (44, 48))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('mutations', 'Var', (10, 19))
113074	30006355	Each incidence of malignant transformation was driven by an identifiable genetic aberration other than a BRAF mutation.	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (105, 109))	('malignant transformation', 'CPA', (18, 42))	('mutation', 'Var', (110, 118))
113078	30006355	Our findings in this regard serve to highlight the need to test all DIG/DIA for BRAF and other gene mutations including gene fusions, which might allow for the use of targeted molecular therapies, or dictate the need for chemotherapy or radiation in refractory or recurrent cases.	('mutations', 'Var', (100, 109))	('DIG', 'Chemical', '-', (68, 71))	('BRAF', 'Gene', (80, 84))	('dictate', 'Reg', (200, 207))	('DIA', 'Chemical', '-', (72, 75))	('BRAF', 'Gene', '673', (80, 84))
113086	31418054	Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001).	('18F-Fluciclovine', 'Var', (31, 47))	('higher', 'PosReg', (19, 25))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (31, 47))	('Image contrast', 'MPA', (0, 14))	('11C-Methionine', 'Chemical', '-', (60, 74))
113090	31418054	A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.	('faster', 'PosReg', (96, 102))	('11C-Methionine', 'Var', (72, 86))	('11C-Methionine', 'Chemical', '-', (72, 86))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (116, 132))	('brain uptake', 'MPA', (56, 68))
113098	31418054	Also, with 18F-FDG, the appearance of tumor-associated inflammation can mimic that of tumor progression, but this is much less of a problem for amino acids.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('18F-FDG', 'Var', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('18F-FDG', 'Chemical', 'MESH:D019788', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('inflammation', 'Disease', (55, 67))
113101	31418054	The diagnostic accuracies of current amino acid PET tracers (11C-Methionine and 18F-FET), however, remain suboptimal and the need for further improvement in neuro-imaging approaches persists.	('11C-Methionine', 'Chemical', '-', (61, 75))	('PET', 'Species', '9606', (48, 51))	('11C-Methionine', 'Var', (61, 75))	('18F-FET', 'Chemical', 'MESH:C117289', (80, 87))	('18F-FET', 'MPA', (80, 87))
113177	31418054	Both ratio values were significantly higher with 18F-Fluciclovine (p < 0.0001) (Fig.	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (49, 65))	('18F-Fluciclovine', 'Var', (49, 65))	('higher', 'PosReg', (37, 43))
113183	31418054	The overlap between 18F-Fluciclovine and MRI volumes was significantly higher than the overlap between 11C-Methionine and MRI volumes (p = 0.04).	('higher', 'PosReg', (71, 77))	('18F-Fluciclovine', 'Var', (20, 36))	('11C-Methionine', 'Chemical', '-', (103, 117))	('overlap', 'MPA', (4, 11))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (20, 36))
113223	31418054	This difference in background was a major factor driving the difference in tumor contrast between 18F-Fluciclovine and 11C-Methionine, as reflected by their tumor-to-normal brain ratios.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('18F-Fluciclovine', 'Var', (98, 114))	('tumor', 'Disease', (75, 80))	('11C-Methionine', 'Chemical', '-', (119, 133))
113225	31418054	Because of this difference in contrast, 18F-Fluciclovine tumor volumes were easier to delineate and this too may account for 18F-Fluciclovine's higher correlation and overlap with conventional imaging-derived volumes, compared to that for 11C-Methionine PET.	('11C-Methionine', 'Chemical', '-', (239, 253))	('correlation', 'MPA', (151, 162))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (125, 141))	('PET', 'Species', '9606', (254, 257))	('18F-Fluciclovine', 'Var', (125, 141))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (40, 56))	('higher', 'PosReg', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
113229	31418054	To the extent that 18F-Fluciclovine's transport is hampered by an intact BBB (and conversely enhanced by a disrupted BBB), this may pose significant challenges when interpreting a Fluciclovine study.	('transport', 'MPA', (38, 47))	('18F-Fluciclovine', 'Chemical', 'MESH:C117460', (19, 35))	('hampered', 'NegReg', (51, 59))	('Fluciclovine', 'Chemical', 'MESH:C117460', (180, 192))	('18F-Fluciclovine', 'Var', (19, 35))	('enhanced', 'PosReg', (93, 101))	('Fluciclovine', 'Chemical', 'MESH:C117460', (23, 35))
113258	32268875	Knockdown of circKIF4A inhibited the colony formation ability, migration and invasion, and promoted the apoptosis of glioma cells by regulating miR-139-3p.	('glioma', 'Disease', (117, 123))	('promoted', 'PosReg', (91, 99))	('colony formation ability', 'CPA', (37, 61))	('inhibited', 'NegReg', (23, 32))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('regulating', 'Reg', (133, 143))	('invasion', 'CPA', (77, 85))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('miR-139-3p', 'Var', (144, 154))	('apoptosis', 'CPA', (104, 113))	('circKIF4A', 'Gene', (13, 22))	('migration', 'CPA', (63, 72))
113259	32268875	Knockdown of circKIF4A inhibited Wnt/beta-catenin signaling pathway and proliferation-related signal via miR-139-3p.	('Wnt', 'Gene', '7474;22418', (33, 36))	('inhibited', 'NegReg', (23, 32))	('Wnt', 'Gene', (33, 36))	('proliferation-related signal', 'CPA', (72, 100))	('miR-139-3p', 'Var', (105, 115))	('circKIF4A', 'Gene', (13, 22))
113260	32268875	Furthermore, knockdown of circKIF4A or overexpression of miR-139 suppressed the ability of sphere formation of GICs and inhibitd Wnt/beta-catenin signaling pathway and proliferation-related signal in GICs.	('miR-139', 'Gene', (57, 64))	('overexpression', 'PosReg', (39, 53))	('Wnt', 'Gene', '7474;22418', (129, 132))	('Wnt', 'Gene', (129, 132))	('sphere formation', 'CPA', (91, 107))	('miR-139', 'Gene', '406931', (57, 64))	('inhibitd', 'NegReg', (120, 128))	('suppressed', 'NegReg', (65, 75))	('circKIF4A', 'Gene', (26, 35))	('proliferation-related', 'CPA', (168, 189))	('knockdown', 'Var', (13, 22))
113262	32268875	circKIF4A was overexpressed in glioma, and knockdown of circKIF4A suppressed glioma progression via miR-139-3p/Wnt5a axis.	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('circKIF4A', 'Gene', (56, 65))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('knockdown', 'Var', (43, 52))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Disease', (77, 83))	('suppressed', 'NegReg', (66, 76))	('glioma', 'Disease', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
113274	32268875	Abnormal expression of the Wnt/beta-catenin signaling was reported to cause the cell proliferation and inhibit the cell apoptosis in glioma, thereby promoting the progression of glioma (He et al.).	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('Wnt', 'Gene', '7474;22418', (27, 30))	('Wnt', 'Gene', (27, 30))	('promoting', 'PosReg', (149, 158))	('cell proliferation', 'CPA', (80, 98))	('glioma', 'Disease', (133, 139))	('Abnormal', 'Var', (0, 8))	('cause', 'PosReg', (70, 75))	('cell apoptosis', 'CPA', (115, 129))	('glioma', 'Disease', (178, 184))	('inhibit', 'NegReg', (103, 110))
113276	32268875	Wnt5a is one of the important members of the Wnt family, and more and more studies have shown that changes in Wnt5a expression are closely related to the progression of glioma.	('expression', 'MPA', (116, 126))	('related', 'Reg', (139, 146))	('glioma', 'Disease', (169, 175))	('changes', 'Var', (99, 106))	('Wnt', 'Gene', '7474;22418', (0, 3))	('Wnt', 'Gene', '7474;22418', (45, 48))	('Wnt', 'Gene', (0, 3))	('Wnt', 'Gene', (45, 48))	('Wnt', 'Gene', '7474;22418', (110, 113))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('Wnt', 'Gene', (110, 113))
113278	32268875	confirmed that Wnt5a could improve the invasion of glioma cells, and knocking down Wnt5a inhibited the intracranial invasion of glioma and increase the survival rate of mice (Binda et al.).	('knocking down', 'Var', (69, 82))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', (128, 134))	('inhibited', 'NegReg', (89, 98))	('survival rate of mice', 'CPA', (152, 173))	('improve', 'PosReg', (27, 34))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('increase', 'PosReg', (139, 147))	('Wnt5a', 'Gene', (83, 88))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('mice', 'Species', '10090', (169, 173))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))
113286	32268875	miR-139-3p has been reported to be low expression in multiple cancers such as colorectal cancer, head and neck cancer, and hepatocellular carcinoma, which may act as a tumor suppressor (Kanaan et al.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('miR-139-3p', 'Var', (0, 10))	('as c', 'Gene', '29108', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('expression', 'MPA', (39, 49))	('as c', 'Gene', (75, 79))	('cancers', 'Disease', (62, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('colorectal cancer', 'Disease', (78, 95))	('tumor', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('hepatocellular carcinoma', 'Disease', (123, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('low', 'NegReg', (35, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('head and neck cancer', 'Disease', 'MESH:D006258', (97, 117))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
113287	32268875	found that miR-139-3p targeting MMP11 to inhibit the invasion and migration of bladder cancer cells.	('miR-139-3p', 'Var', (11, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('MMP11', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('inhibit', 'NegReg', (41, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('bladder cancer', 'Disease', (79, 93))	('MMP11', 'Gene', '4320', (32, 37))
113289	32268875	confirmed that miR-139-3p can inhibit HPV-16 proteins and revive key tumor suppressor proteins p53, p16, and p21, thereby inhibiting proliferation and migration in HPV-16 positive cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibiting', 'NegReg', (122, 132))	('tumor', 'Disease', (69, 74))	('inhibit', 'NegReg', (30, 37))	('miR-139-3p', 'Var', (15, 25))	('HPV-16 proteins', 'Protein', (38, 53))	('p16', 'Gene', (100, 103))	('HPV-16', 'Species', '333760', (38, 44))	('HPV-16', 'Species', '333760', (164, 170))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('p21', 'Gene', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('p21', 'Gene', '644914', (109, 112))	('p16', 'Gene', '1029', (100, 103))
113290	32268875	Studies have shown that miR-139-3p expression level was reduced in glioma specimens, and overexpression of miR-139-3p inhibited the migration, invasion and proliferation of glioma cells (Tian et al.).	('inhibited', 'NegReg', (118, 127))	('miR-139-3p expression level', 'MPA', (24, 51))	('miR-139-3p', 'Var', (107, 117))	('glioma', 'Disease', (173, 179))	('glioma', 'Disease', (67, 73))	('reduced', 'NegReg', (56, 63))	('invasion', 'CPA', (143, 151))	('overexpression', 'PosReg', (89, 103))	('migration', 'CPA', (132, 141))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
113291	32268875	However, little research has been done on the molecular mechanism by which miR-139-3p regulates the development of glioma, which requires further research.	('glioma', 'Disease', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('miR-139-3p', 'Var', (75, 85))	('regulates', 'Reg', (86, 95))
113292	32268875	Therefore, the interaction of circKIF4A, miR-139-3p and Wnt5a in glioma is worthy of our comprehensive investigation.	('miR-139-3p', 'Var', (41, 51))	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))
113293	32268875	In this study, we found that circKIF4A and Wnt5a were over-expressed, and miR-139-3p was down-expressed in glioma cell lines and tissues.	('Wnt5a', 'Gene', (43, 48))	('down-expressed', 'NegReg', (89, 103))	('circKIF4A', 'Gene', (29, 38))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('over-expressed', 'PosReg', (54, 68))	('miR-139-3p', 'Var', (74, 84))	('glioma', 'Disease', (107, 113))
113301	32268875	NHAs cells were cultured in astrocyte growth medium with 5% FBS, ascorbic acid, rhEGF, insulin, L-glutamine and GA-1000.	('GA-1000', 'Chemical', '-', (112, 119))	('L-glutamine', 'Var', (96, 107))	('EGF', 'Gene', (82, 85))	('L-glutamine', 'Chemical', 'MESH:D005973', (96, 107))	('ascorbic acid', 'Chemical', 'MESH:D001205', (65, 78))	('EGF', 'Gene', '1950', (82, 85))
113313	32268875	Blocked the membranes at room temperature with 5% non-fat milk for 2 h. Then, the membranes were incubated in specific primary antibodies including Wnt5a (1:1000, ab229200, Abcam, USA), GSK-3beta (ab93926,1:500, Abcam, USA), beta-catenin (1:2000, ab6302, Abcam, USA), p-beta-catenin (1:500, ab27798, Abcam, USA), c-Myc (1:1000, ab32072, Abcam, USA), cyclinD1(1:1000, ab40754, Abcam, USA), Bcl2 (1:800, ab32124, Abcam, USA), Bax (1:1000, ab32503, Abcam, USA), and GAPDH (1:5000; ab181602, Abcam, USA) at 4  C overnight.	('c-Myc', 'Gene', '4609', (313, 318))	('1:5000;', 'Var', (470, 477))	('GAPDH', 'Gene', '2597', (463, 468))	('GAPDH', 'Gene', (463, 468))	('Bax', 'Gene', (424, 427))	('c-Myc', 'Gene', (313, 318))	('GSK-3beta', 'Gene', '2931', (186, 195))	('GSK-3beta', 'Gene', (186, 195))	('Bcl2', 'Gene', (389, 393))	('Bax', 'Gene', '581', (424, 427))	('cyclinD1', 'Gene', (350, 358))	('Bcl2', 'Gene', '596', (389, 393))	('cyclinD1', 'Gene', '595', (350, 358))
113335	32268875	To investigate the roles of circKIF4A, miR-139-3p and Wnt5a in glioma, we first detected the expression of circKIF4A, miR-139-3p and Wnt5a in 32 pairs of glioma and adjacent normal tissues.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('circKIF4A', 'Gene', (107, 116))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Disease', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('miR-139-3p', 'Var', (118, 128))	('glioma', 'Disease', (63, 69))
113342	32268875	These results suggested that abnormal expression of circKIF4A, miR-139-3p and Wnt5a may be involved in glioma progression.	('involved', 'Reg', (91, 99))	('circKIF4A', 'Gene', (52, 61))	('expression', 'MPA', (38, 48))	('miR-139-3p', 'Var', (63, 73))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('glioma', 'Disease', (103, 109))	('Wnt5a', 'Gene', (78, 83))
113344	32268875	To explore the regulatory relationship between circKIF4A, miR-139-3p and Wnt5a, the expressions of circKIF4A, miR-139-3p and Wnt5a were examined in A172 and LN229 cell lines which knocking down the circKIF4A.	('knocking', 'Var', (180, 188))	('circKIF4A', 'Gene', (198, 207))	('LN229', 'CellLine', 'CVCL:0393', (157, 162))
113347	32268875	All the above results indicated that circKIF4A regulates Wnt5a expression by targeting miR-139-3p in glioma cells.	('targeting', 'Reg', (77, 86))	('Wnt5a', 'Gene', (57, 62))	('regulates', 'Reg', (47, 56))	('glioma', 'Disease', (101, 107))	('miR-139-3p', 'Var', (87, 97))	('expression', 'MPA', (63, 73))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
113349	32268875	The colony formation assay showed that circKIF4A knockdown or miR-139-3p mimics inhibited the colony formation in A172 and LN229 cells (Fig.	('LN229', 'CellLine', 'CVCL:0393', (123, 128))	('inhibited', 'NegReg', (80, 89))	('colony formation in', 'CPA', (94, 113))	('miR-139-3p', 'Var', (62, 72))
113350	32268875	At the same time, the flow cytometry assay showed that circKIF4A knockdown or miR-139-3p mimics dramatically promoted the apoptosis of glioma cells (Fig.	('glioma', 'Disease', (135, 141))	('promoted', 'PosReg', (109, 117))	('circKIF4A', 'Gene', (55, 64))	('apoptosis', 'CPA', (122, 131))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('miR-139-3p', 'Var', (78, 88))
113351	32268875	To investigate the role of circKIF4A in regulating miR-139-3p on gliomas, a series of rescue experiments were performed.	('gliomas', 'Disease', (65, 72))	('miR-139-3p', 'Var', (51, 61))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
113353	32268875	Wound-healing assays showed that circKIF4A knockdown or miR-139-3p mimics inhibited the cell migration in A172 and LN229, as evidenced by the narrow wound gap at 0 h and 24 h compared with the control groups.	('miR-139-3p mimics', 'Var', (56, 73))	('inhibited', 'NegReg', (74, 83))	('LN229', 'CellLine', 'CVCL:0393', (115, 120))	('cell migration in', 'CPA', (88, 105))
113354	32268875	Transwell invasion assays also showed that invasion numbers of A172 and LN229 cells were markedly decreased after sh-circKIF4A or miR-139-3p mimics transfected.	('sh-circKIF4A', 'Var', (114, 126))	('miR-139-3p mimics transfected', 'Var', (130, 159))	('LN229', 'CellLine', 'CVCL:0393', (72, 77))	('decreased', 'NegReg', (98, 107))
113355	32268875	These results suggested that knockdown of circKIF4A inhibits cell migration and invasion of glioma cells through regulating miR-139-3p.	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('knockdown', 'Var', (29, 38))	('regulating', 'Reg', (113, 123))	('glioma', 'Disease', (92, 98))	('inhibits', 'NegReg', (52, 60))	('cell migration', 'CPA', (61, 75))	('miR-139-3p', 'MPA', (124, 134))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('circKIF4A', 'Gene', (42, 51))
113356	32268875	To further investigate the molecular mechanisms of circKIF4A and miR-139-3p in glioma cells, the activities of Wnt/beta-catenin signaling pathway were detected in A172 and LN229 cells.	('glioma', 'Disease', (79, 85))	('LN229', 'CellLine', 'CVCL:0393', (172, 177))	('miR-139-3p', 'Var', (65, 75))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('activities', 'MPA', (97, 107))	('Wnt', 'Gene', '7474;22418', (111, 114))	('Wnt', 'Gene', (111, 114))
113357	32268875	circKIF4A knockdown or miR-139-3p mimics inhibited the expression of Wnt5a and beta-catenin, and promoted the expression of GSK-3beta and p-beta-catenin (Fig.	('GSK-3beta', 'Gene', '2931', (124, 133))	('GSK-3beta', 'Gene', (124, 133))	('p-beta-catenin', 'Protein', (138, 152))	('expression', 'MPA', (55, 65))	('expression', 'MPA', (110, 120))	('inhibited', 'NegReg', (41, 50))	('Wnt5a', 'Protein', (69, 74))	('beta-catenin', 'Protein', (79, 91))	('miR-139-3p', 'Var', (23, 33))	('promoted', 'PosReg', (97, 105))
113361	32268875	These results suggested that knockdown of circKIF4A suppresses cell proliferation, apoptosis, migration and invasion of glioma cells through regulating miR-139-3p to inactivate Wnt/beta-catenin signaling pathway.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('inactivate', 'NegReg', (166, 176))	('knockdown', 'Var', (29, 38))	('Wnt', 'Gene', '7474;22418', (177, 180))	('regulating', 'Reg', (141, 151))	('migration', 'CPA', (94, 103))	('Wnt', 'Gene', (177, 180))	('cell proliferation', 'CPA', (63, 81))	('glioma', 'Disease', (120, 126))	('apoptosis', 'CPA', (83, 92))	('miR-139-3p', 'MPA', (152, 162))	('invasion', 'CPA', (108, 116))	('suppresses', 'NegReg', (52, 62))	('circKIF4A', 'Gene', (42, 51))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
113363	32268875	In addition, knockdown of circKIF4A or overexpression of miR-139-3p could promote the expression of GSK-3beta, p-beta-catenin and the pro-apoptotic protein Bax, and inhibit Wnt5a, beta-catenin and the proliferation-related proteins CyclinD1, c-Myc, and Bcl-2 expression.	('GSK-3beta', 'Gene', '2931', (100, 109))	('promote', 'PosReg', (74, 81))	('c-Myc', 'Gene', '4609', (242, 247))	('p-beta-catenin', 'Protein', (111, 125))	('circKIF4A', 'Gene', (26, 35))	('Bcl-2', 'Gene', '596', (253, 258))	('knockdown', 'Var', (13, 22))	('GSK-3beta', 'Gene', (100, 109))	('beta-catenin', 'Protein', (180, 192))	('Wnt5a', 'MPA', (173, 178))	('CyclinD1', 'Gene', '595', (232, 240))	('inhibit', 'NegReg', (165, 172))	('CyclinD1', 'Gene', (232, 240))	('expression', 'MPA', (86, 96))	('Bax', 'Gene', (156, 159))	('Bcl-2', 'Gene', (253, 258))	('Bax', 'Gene', '581', (156, 159))	('miR-139-3p', 'Var', (57, 67))	('c-Myc', 'Gene', (242, 247))
113364	32268875	To investigate the impact of circKIF4A on glioma tumorigenesis in vivo, A172 and LN229 cells of stably expressing sh-circKIF4A were injected into nude mice.	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (42, 62))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('sh-circKIF4A', 'Var', (114, 126))	('glioma tumorigenesis', 'Disease', (42, 62))	('LN229', 'CellLine', 'CVCL:0393', (81, 86))	('nude mice', 'Species', '10090', (146, 155))
113366	32268875	7a-c, circKIF4A knockdown decreased the tumor volume and weight compared with negative control.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('knockdown', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('decreased', 'NegReg', (26, 35))	('circKIF4A', 'Gene', (6, 15))
113367	32268875	Moreover, the expression of miR-139-3p was up-regulated and Wnt5a was down-regulated in tumor tissues from sh-circKIF4A group, compared with that in sh-NC group (Fig.	('Wnt5a', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('sh-circKIF4A', 'Var', (107, 119))	('down-regulated', 'NegReg', (70, 84))	('expression', 'MPA', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('up-regulated', 'PosReg', (43, 55))	('tumor', 'Disease', (88, 93))	('miR-139-3p', 'Gene', (28, 38))
113368	32268875	The immunohistochemical results showed that circKIF4A silencing significantly inhibited the expression of Ki-67 and Wnt5a compared with sh-NC group (Fig.	('Wnt5a', 'Gene', (116, 121))	('inhibited', 'NegReg', (78, 87))	('silencing', 'Var', (54, 63))	('Ki-67', 'Gene', '17345', (106, 111))	('circKIF4A', 'Gene', (44, 53))	('Ki-67', 'Gene', (106, 111))	('expression', 'MPA', (92, 102))
113377	32268875	Our results indicated that circKIF4A expression was dramatically increased while miR-139-3p was decreased in glioma tissues and cell lines.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('circKIF4A', 'Gene', (27, 36))	('increased', 'PosReg', (65, 74))	('decreased', 'NegReg', (96, 105))	('glioma', 'Disease', (109, 115))	('expression', 'MPA', (37, 47))	('miR-139-3p', 'Var', (81, 91))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
113379	32268875	circKIF4A inhibition could decrease Wnt5a expression by sponging miR-139, which repressed Wnt/beta-cetanin signaling pathway.	('Wnt', 'Gene', '7474;22418', (36, 39))	('Wnt', 'Gene', (36, 39))	('decrease', 'NegReg', (27, 35))	('beta-cetanin', 'Chemical', '-', (94, 106))	('miR-139', 'Gene', (65, 72))	('Wnt', 'Gene', '7474;22418', (90, 93))	('miR-139', 'Gene', '406931', (65, 72))	('inhibition', 'Var', (10, 20))	('Wnt', 'Gene', (90, 93))
113380	32268875	Furthermore, circKIF4A knockdown impaired the self-renewal of GICs and suppressed glioma cells tumorigenesis in nude mice.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('self-renewal of GICs', 'CPA', (46, 66))	('impaired', 'NegReg', (33, 41))	('knockdown', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('nude mice', 'Species', '10090', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('glioma', 'Disease', (82, 88))	('circKIF4A', 'Gene', (13, 22))	('tumor', 'Disease', (95, 100))	('suppressed', 'NegReg', (71, 81))
113381	32268875	Therefore, we conclude that circKIF4A maybe a carcinogenic circRNA in glioma progression.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('carcinogenic', 'Disease', 'MESH:D063646', (46, 58))	('carcinogenic', 'Disease', (46, 58))	('circKIF4A', 'Var', (28, 37))
113384	32268875	found that circ_0001946 acted as a competing endogenous RNA to modulating miR-671-5p and CDR1, and reduced proliferation, migration, invasion and increased apoptosis in GBM cells (Li and Diao).	('miR-671', 'Gene', '768213', (74, 81))	('invasion', 'CPA', (133, 141))	('CDR1', 'Gene', '1038', (89, 93))	('circ_0001946', 'Var', (11, 23))	('proliferation', 'CPA', (107, 120))	('increased', 'PosReg', (146, 155))	('miR-671', 'Gene', (74, 81))	('modulating', 'Reg', (63, 73))	('CDR1', 'Gene', (89, 93))	('Di', 'Disease', 'MESH:D003643', (187, 189))	('migration', 'CPA', (122, 131))	('reduced', 'NegReg', (99, 106))	('apoptosis', 'CPA', (156, 165))
113388	32268875	Our study confirms that circKIF4A was up-regulated in gliomas, and knockdown of circKIF4A inhibits glioma cell proliferation, migration, invasion and xenograft growth in vivo.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('migration', 'CPA', (126, 135))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('circKIF4A', 'Gene', (80, 89))	('knockdown', 'Var', (67, 76))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('inhibits', 'NegReg', (90, 98))	('glioma', 'Disease', (54, 60))	('glioma', 'Disease', (99, 105))	('circKIF4A', 'Gene', (24, 33))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('up-regulated', 'PosReg', (38, 50))
113389	32268875	These results fully demonstrated that circKIF4A plays a key role in glioma tumorigenesis and can promote the development of glioma.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('development', 'CPA', (109, 120))	('glioma', 'Disease', (124, 130))	('glioma tumorigenesis', 'Disease', (68, 88))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (68, 88))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('glioma', 'Disease', (68, 74))	('circKIF4A', 'Var', (38, 47))	('promote', 'PosReg', (97, 104))
113391	32268875	Dysregulation of certain miRNAs could contribute to the pathogenesis of various tumors.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Dysregulation', 'Var', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('contribute', 'Reg', (38, 48))	('miRNAs', 'Protein', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
113392	32268875	Previous studies demonstrated that miR-139-3p plays critical role in tumor progression.	('miR-139-3p', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
113393	32268875	showed that miR-139-3p inhibited tumor growth and metastasis in hepatocellular carcinoma by down-regulating ANXA2R expression (Zou et al.).	('inhibited', 'NegReg', (23, 32))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (64, 88))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('down-regulating', 'NegReg', (92, 107))	('expression', 'MPA', (115, 125))	('miR-139-3p', 'Var', (12, 22))	('tumor', 'Disease', (33, 38))	('ANXA2R', 'Gene', '389289', (108, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (64, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('hepatocellular carcinoma', 'Disease', (64, 88))	('ANXA2R', 'Gene', (108, 114))
113394	32268875	suggested that miR-139-3p can inhibit cervical cancer cell migration invasion and proliferation by targeting NOB1 (Huang et al.).	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('targeting', 'Reg', (99, 108))	('inhibit', 'NegReg', (30, 37))	('cancer', 'Disease', (47, 53))	('miR-139-3p', 'Var', (15, 25))	('NOB1', 'Gene', '28987', (109, 113))	('NOB1', 'Gene', (109, 113))	('proliferation', 'CPA', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
113395	32268875	showed that lncRNA-TP73-AS1 targets miR-139-3p to promote retinoblastoma cell proliferation (Xia et al.).	('promote', 'PosReg', (50, 57))	('retinoblastoma', 'Phenotype', 'HP:0009919', (58, 72))	('retinoblastoma', 'Disease', 'MESH:D012175', (58, 72))	('TP73', 'Gene', '7161', (19, 23))	('TP73', 'Gene', (19, 23))	('miR-139-3p', 'Var', (36, 46))	('retinoblastoma', 'Disease', (58, 72))	('AS1', 'Gene', '5729', (24, 27))	('AS1', 'Gene', (24, 27))
113396	32268875	According to recent reports, the expression of miR-139-3p in human glioma samples was markedly lower than that in normal brain tissues, and miR-139-3p inhibited proliferation, migration and invasion of glioma cells (Tian et al.	('lower', 'NegReg', (95, 100))	('invasion', 'CPA', (190, 198))	('migration', 'CPA', (176, 185))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('inhibited', 'NegReg', (151, 160))	('expression', 'MPA', (33, 43))	('glioma', 'Disease', (202, 208))	('miR-139-3p', 'Var', (140, 150))	('human', 'Species', '9606', (61, 66))	('proliferation', 'CPA', (161, 174))
113397	32268875	However, there is limited research on the molecular mechanism of miR-139-3p regulation of glioma development.	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('miR-139-3p', 'Var', (65, 75))
113398	32268875	In this study, we confirmed that the level of miR-139-3p was decreased in glioma cell lines and tissues.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Disease', (74, 80))	('miR-139-3p', 'Var', (46, 56))	('decreased', 'NegReg', (61, 70))	('level', 'MPA', (37, 42))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
113400	32268875	The expression of miR-139-3p and circKIF4A was negatively correlated in glioma specimen.	('glioma', 'Disease', (72, 78))	('circKIF4A', 'Gene', (33, 42))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('expression', 'MPA', (4, 14))	('miR-139-3p', 'Var', (18, 28))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('negatively', 'NegReg', (47, 57))
113401	32268875	Furthermore, dual-luciferase reporter assay suggested that circKIF4A interacts directly with miR-139-3p in A172 and LN229 glioma cells.	('interacts', 'Interaction', (69, 78))	('glioma', 'Disease', (122, 128))	('miR-139-3p', 'Var', (93, 103))	('LN229', 'CellLine', 'CVCL:0393', (116, 121))	('circKIF4A', 'Gene', (59, 68))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
113403	32268875	Our study found a negative correlation between miR-139-3p and Wnt5a levels in glioma samples.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('Wnt5a levels', 'MPA', (62, 74))	('negative', 'NegReg', (18, 26))	('glioma', 'Disease', (78, 84))	('miR-139-3p', 'Var', (47, 57))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
113404	32268875	Subsequently, it was proved that Wnt5a was the target gene of miR-139-3p in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('miR-139-3p', 'Var', (62, 72))
113407	32268875	For example, Wnt5a was found to be associated with decreased overall survival in patients with glioblastoma (Zeng et al.	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('Wnt5a', 'Var', (13, 18))	('patients', 'Species', '9606', (81, 89))	('decreased', 'NegReg', (51, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('overall survival', 'MPA', (61, 77))
113417	32268875	Therefore, this study indicated that circKIF4A acts as a ceRNA to active Wnt5a/beta-catenin signaling pathway mediated glioma progression by depressing miR-139-3p expression.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('miR-139-3p expression', 'MPA', (152, 173))	('depressing', 'NegReg', (141, 151))	('glioma', 'Disease', (119, 125))	('circKIF4A', 'Var', (37, 46))
113425	32268875	The circKIF4A gene knockdown decreased the colony formation ability, migration and invasion of glioma cells, and reduced tumor growth in vivo.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('colony formation ability', 'CPA', (43, 67))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', (121, 126))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('decreased', 'NegReg', (29, 38))	('reduced', 'NegReg', (113, 120))	('circKIF4A gene', 'Gene', (4, 18))
113502	31315883	In order to demonstrate the potential of our computational framework for real-time accurate detection and volumetric visualization of cancerous and non-cancerous brain tissue, two unlabeled high-resolution OCT volumes (5x2x2.5 mm3; 256x2048x2048 pixels) from a non-cancerous and a glioma-infiltrated brain region were blindly processed with our trained computational framework.	('cancerous', 'Disease', 'MESH:D009369', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancerous', 'Disease', 'MESH:D009369', (265, 274))	('non-cancerous', 'Disease', 'MESH:D009369', (261, 274))	('non-cancerous', 'Disease', 'MESH:D009369', (148, 161))	('cancerous brain', 'Phenotype', 'HP:0030692', (152, 167))	('glioma-infiltrated brain', 'Disease', 'MESH:C564230', (281, 305))	('non-cancerous', 'Disease', (261, 274))	('non-cancerous', 'Disease', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancerous', 'Disease', 'MESH:D009369', (134, 143))	('cancerous', 'Disease', (265, 274))	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('cancerous', 'Disease', (152, 161))	('non-cancerous brain', 'Disease', (148, 167))	('glioma-infiltrated brain', 'Disease', (281, 305))	('non-cancerous brain', 'Disease', 'MESH:D001932', (148, 167))	('256x2048x2048', 'Var', (232, 245))	('cancerous', 'Disease', (134, 143))
113539	30590044	Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators.	('tumor', 'Disease', (192, 197))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cytotoxicity', 'Disease', (143, 155))	('Mutations', 'Var', (0, 9))	('Hypoxic Signaling in Cancer', 'Disease', 'MESH:C566796', (95, 122))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Innate Immunity Pathway', 'Pathway', (16, 39))	('Hypoxic Signaling in Cancer', 'Disease', (95, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
113541	30590044	We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types.	('associated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('changes', 'Reg', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('overall survival', 'MPA', (144, 160))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (180, 186))	('complement genes', 'Gene', (55, 71))
113542	30590044	Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('colorectal cancer', 'Disease', (168, 185))	('hypoxia', 'Disease', (157, 164))	('patients', 'Species', '9606', (34, 42))	('crosstalk', 'Reg', (124, 133))	('mutations', 'Var', (59, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))
113543	30590044	The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55.	('mutations', 'Var', (131, 140))	('complement', 'Gene', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increased', 'PosReg', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('hypoxia', 'Disease', 'MESH:D000860', (233, 240))	('hypoxic tumor', 'Disease', 'MESH:D009369', (146, 159))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cytotoxicity', 'Disease', (203, 215))	('hypoxia', 'Disease', (233, 240))	('hypoxic signaling', 'MPA', (69, 86))	('cytotoxicity', 'Disease', 'MESH:D064420', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CD55', 'Gene', (284, 288))	('hypoxic tumor', 'Disease', (146, 159))
113545	30590044	Mutations in the complement system are prevalent across cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('prevalent', 'Reg', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Mutations', 'Var', (0, 9))	('complement system', 'Gene', (17, 34))
113546	30590044	find that colorectal cancers with complement component mutations are associated with increased hypoxic signaling and poor overall survival outcomes.	('increased hypoxic', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('colorectal cancers', 'Disease', 'MESH:D015179', (10, 28))	('mutations', 'Var', (55, 64))	('colorectal cancers', 'Disease', (10, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('increased hypoxic', 'Disease', 'MESH:D000860', (85, 102))
113548	30590044	Since uncontrolled activation of the complement system is associated with cell lysis/cytotoxicity and can result in normal tissue toxicity, the pathway is tightly controlled by membrane-bound regulators such as CD35 (complement receptor type 1), CD46 (membrane cofactor protein), CD55 (complement decay accelerating factor), and CD59 (protectin).	('complement receptor type 1', 'Gene', (217, 243))	('complement decay accelerating factor', 'Gene', '1604', (286, 322))	('membrane cofactor protein', 'Gene', (252, 277))	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('toxicity', 'Disease', (130, 138))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('result', 'Reg', (106, 112))	('cytotoxicity', 'Disease', (85, 97))	('CD35', 'Gene', '1378', (211, 215))	('complement decay accelerating factor', 'Gene', (286, 322))	('CD46', 'Gene', '4179', (246, 250))	('CD46', 'Gene', (246, 250))	('complement receptor type 1', 'Gene', '1378', (217, 243))	('CD55', 'Var', (280, 284))	('membrane cofactor protein', 'Gene', '4179', (252, 277))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('CD35', 'Gene', (211, 215))
113553	30590044	The existence of complement mutations across cancer types could provide additional evidence to support a role for complement in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('complement', 'Gene', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (28, 37))
113555	30590044	As the complement system is a complex set of over 50 proteins converging on functional networks, interrogation of mutations across cancer types and within the whole pathway is likely to yield the most insights about the relevance of any potential alterations.	('cancer', 'Disease', (131, 137))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('rat', 'Species', '10116', (251, 254))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
113557	30590044	Exome sequencing efforts, including TCGA datasets, have also recently proved useful in finding patient-specific tumor-derived antigens (neoantigens) arising as a consequence of tumor-specific mutations.	('mutations', 'Var', (192, 201))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (177, 182))
113560	30590044	Our analysis of pathways expressed in patients with complement mutations associated with poor prognostic outcomes reveals crosstalk between the complement system and hypoxia.	('mutations', 'Var', (63, 72))	('crosstalk', 'Reg', (122, 131))	('associated', 'Reg', (73, 83))	('patients', 'Species', '9606', (38, 46))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('hypoxia', 'Disease', (166, 173))
113569	30590044	Importantly, those tumors with dysregulated complement through either protein or genetic alterations are associated with the worse prognostic outcome, highlighting the clinical relevance of these findings.	('dysregulated', 'Var', (31, 43))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('genetic alterations', 'Var', (81, 100))	('clinical', 'Species', '191496', (168, 176))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('rat', 'Species', '10116', (93, 96))
113570	30590044	Using TCGA, we found that mutations and copy number alterations (CNAs) in complement system genes occurred in all tumor types queried (Figure 1A).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('mutations', 'Var', (26, 35))	('complement system genes', 'Gene', (74, 97))	('occurred', 'Reg', (98, 106))	('copy number alterations', 'Var', (40, 63))
113574	30590044	Furthermore, methylation changes of 40 complement genes are also significantly correlated with mRNA expression changes (correlation coefficients ranging from :0.5562 to 0.3180), suggesting that methylation and CNA could alter complement pathway activation through mechanisms independent of alterations in protein structure.	('methylation', 'Var', (194, 205))	('rat', 'Species', '10116', (294, 297))	('mRNA', 'MPA', (95, 99))	('activation', 'MPA', (245, 255))	('alter', 'Reg', (220, 225))	('complement pathway', 'Pathway', (226, 244))
113576	30590044	KS test analysis revealed that mutations in complement system genes, as a group, occurred at a rate above background in 8 of the cancers analyzed (Figure 1B; Table S1C).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('rat', 'Species', '10116', (95, 98))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('complement system genes', 'Gene', (44, 67))	('occurred', 'Reg', (81, 89))	('KS', 'Chemical', '-', (0, 2))
113577	30590044	A pan-cancer meta-analysis of the KS test results maintained significance even without melanoma, which had an individually high rate of complement mutations (Figure 1C; Table S1C).	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('KS', 'Chemical', '-', (34, 36))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('rat', 'Species', '10116', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
113580	30590044	Interestingly, we found that, across a number of cancer types, several complement mutations scored as significant (Figure 1D; Table S1D).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (82, 91))	('significant', 'Reg', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('complement', 'Gene', (71, 81))	('cancer', 'Disease', (49, 55))
113581	30590044	Given the rising interest in the role of T cell-mediated responses mounted to tumor-derived antigens, we asked whether any of the mutations predicted to be drivers by MutSig2CV analysis could also give rise to neoantigens with sufficiently strong predicted binding affinities (<500 nM) by NetMHCpan.	('binding', 'Interaction', (257, 264))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('give rise', 'Reg', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NetMHCpan', 'Chemical', '-', (289, 298))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', (78, 83))	('neoantigens', 'MPA', (210, 221))
113582	30590044	To assess the relevance of the predicted binding affinities for complement mutation-derived neoantigens in comparison with frequently mutated cancer drivers, we analyzed an equivalent number of peptides derived from mutations in three driver genes in colorectal cancer as assessed by MutSig2CV (APC, TP53, and ARID1A).	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('APC', 'Disease', 'MESH:D011125', (295, 298))	('TP53', 'Gene', '7157', (300, 304))	('colorectal cancer', 'Phenotype', 'HP:0003003', (251, 268))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('APC', 'Disease', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('TP53', 'Gene', (300, 304))	('ARID1A', 'Gene', '8289', (310, 316))	('colorectal cancer', 'Disease', (251, 268))	('ARID1A', 'Gene', (310, 316))	('mutations', 'Var', (216, 225))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('colorectal cancer', 'Disease', 'MESH:D015179', (251, 268))	('cancer', 'Disease', (142, 148))
113585	30590044	Given the prevalence of complement mutation-derived neoantigens with high binding affinities, we asked whether any of the complement mutations predicted to be drivers would also be expected to result in changes in immune infiltrates.	('rat', 'Species', '10116', (227, 230))	('immune infiltrates', 'MPA', (214, 232))	('mutations', 'Var', (133, 142))	('changes', 'Reg', (203, 210))	('binding', 'Interaction', (74, 81))
113586	30590044	Interestingly, several of these mutations were associated with significant increased cytolytic activity, CD8+ T cells, and cytotoxic lymphocyte infiltration (Figures S1C-S1I).	('CD8', 'Gene', (105, 108))	('CD8', 'Gene', '925', (105, 108))	('cytolytic activity', 'CPA', (85, 103))	('rat', 'Species', '10116', (150, 153))	('cytotoxic lymphocyte infiltration', 'CPA', (123, 156))	('mutations', 'Var', (32, 41))	('increased', 'PosReg', (75, 84))
113589	30590044	This analysis confirmed that complement mutations occur at a global level, with 79.7% of datasets analyzed (including 34 different cancer types) containing at least one complement network and several datasets containing more than one mutated complement network (Figure 2A; Table S2A).	('cancer', 'Disease', (131, 137))	('containing', 'Reg', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
113590	30590044	These data support the hypothesis that mutations in complement genes may be cooperative in nature, with genes working within functional networks.	('rat', 'Species', '10116', (81, 84))	('complement genes', 'Gene', (52, 68))	('mutations', 'Var', (39, 48))
113591	30590044	We hypothesized that grouping mutations into subsets based on known gene function, and then performing downstream analysis, could provide information about the functional relevance of these mutations and their possible cooperation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mutations', 'Var', (190, 199))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('mutations', 'Var', (30, 39))	('rat', 'Species', '10116', (224, 227))	('cancer', 'Disease', (234, 240))
113593	30590044	Interestingly, when performing these analyses, we found that several groups of mutations and CNAs were associated with changes in overall survival outcome across different cancer types (Figures 2B-2G; Tables S2C-S2N).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('changes', 'Reg', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('overall survival', 'MPA', (130, 146))	('cancer', 'Disease', (172, 178))	('CNAs', 'Gene', (93, 97))	('mutations', 'Var', (79, 88))
113594	30590044	The association between component mutations in colorectal cancer and poor overall survival outcome is noteworthy (Figures 2B and2C).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('mutations', 'Var', (34, 43))
113595	30590044	In addition, there is a strong association between poor overall survival and amplifications in components in skin cutaneous melanoma (SKCM) and deletions in regulators in LGG (Figures 2D-2G).	('skin cutaneous melanoma', 'Disease', (109, 132))	('amplifications', 'Var', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('overall survival', 'MPA', (56, 72))	('deletions', 'Var', (144, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('LGG', 'Gene', (171, 174))	('poor', 'NegReg', (51, 55))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (109, 132))
113598	30590044	Similarly to what we had observed from our multivariate analysis, we found that multiple complement gene mutations and CNA were significantly associated with poor overall survival outcomes (e.g., mutations in components in COADREAD, p value = 0.00273).	('poor', 'NegReg', (158, 162))	('complement gene', 'Gene', (89, 104))	('mutations', 'Var', (105, 114))	('associated', 'Reg', (142, 152))	('COADREAD', 'Disease', 'None', (223, 231))	('CNA', 'Gene', (119, 122))	('COADREAD', 'Disease', (223, 231))	('mutations', 'Var', (196, 205))
113601	30590044	These analyses showed significant correlations with overall survival for certain groups of genes (e.g., protease and receptor mutations, q < 0.05), as well as for individual genes (e.g., mutations and deletions in C1QA, p < 0.05), even when performing stage, age, and cancer-type corrections (Tables S2O-S2T).	('C1QA', 'Gene', (214, 218))	('cancer-type', 'Disease', 'MESH:D009369', (268, 279))	('C1QA', 'Gene', '712', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer-type', 'Disease', (268, 279))	('mutations', 'Var', (187, 196))	('mutations', 'Var', (126, 135))	('deletions', 'Var', (201, 210))	('correlations', 'Reg', (34, 46))
113602	30590044	Overall, these analyses demonstrate that certain complement mutations and CNAs (either analyzed at the individual gene level or in gene subsets) are associated with changes in overall survival, both in specific cancer types as well as when analyzed at the pan-cancer level.	('CNAs', 'Gene', (74, 78))	('overall survival', 'MPA', (176, 192))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (211, 217))	('complement', 'Gene', (49, 59))	('cancer', 'Disease', (260, 266))	('changes', 'Reg', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('rat', 'Species', '10116', (31, 34))
113607	30590044	Overall, hypoxia gene sets as a whole were enriched in patients with complement mutations (p value = 0.0005, GSEA-squared), with two of the four additional hypoxia signatures nominally enriched (p < 0.05) in these two groups of patients (Figures S2C and S2D; Tables S3A, S3D, and S3E).	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', (9, 16))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (228, 236))	('GSEA', 'Chemical', '-', (109, 113))	('patients', 'Species', '9606', (55, 63))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
113609	30590044	We then refined the analysis by asking whether hypoxia signatures were also enriched specifically in patients with component mutations in colorectal cancer, where a strong association between these mutations and poor overall survival had been observed.	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (101, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia', 'Disease', (47, 54))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
113610	30590044	Overall, hypoxia signatures as a whole were enriched in patients with component mutations (p value = 0.0008, GSEA-squared) with four of five signatures being nominally enriched (p < 0.05) (Figures 3B-3E; Tables S3B-S3E and S3G-S3I).	('patients', 'Species', '9606', (56, 64))	('hypoxia', 'Disease', (9, 16))	('mutations', 'Var', (80, 89))	('GSEA', 'Chemical', '-', (109, 113))	('S3G-S3I', 'Var', (223, 230))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
113612	30590044	To assess the specificity of the association between hypoxia and complement mutations in colorectal cancer, we asked whether component mutations were also associated with hypoxia signatures in SKCM, another cancer type where this group of mutations was associated with poor outcome.	('hypoxia', 'Disease', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Disease', (207, 213))	('SKCM', 'Disease', (193, 197))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('associated', 'Reg', (155, 165))	('colorectal cancer', 'Disease', (89, 106))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('hypoxia', 'Disease', (171, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
113613	30590044	Interestingly, no significant association was found between component mutations in SKCM and hypoxia signatures in this group (Figure S2G; Table S3J).	('hypoxia', 'Disease', 'MESH:D000860', (92, 99))	('SKCM', 'Gene', (83, 87))	('mutations', 'Var', (70, 79))	('hypoxia', 'Disease', (92, 99))
113614	30590044	To extend these analyses, we also asked whether hypoxia signatures would be enriched in patients with mutations in a different group of complement genes, the regulators, also associated with poor overall survival in LGG, and once again observed no significant association (Figure S2H; Table S3K).	('LGG', 'Disease', (216, 219))	('poor', 'NegReg', (191, 195))	('associated with', 'Reg', (175, 190))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (102, 111))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('hypoxia', 'Disease', (48, 55))
113615	30590044	These data suggest certain specificity in the association between component mutations and hypoxia in colorectal cancer, and therefore we decided to focus on colorectal cancer for our subsequent experiments.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('mutations', 'Var', (76, 85))	('colorectal cancer', 'Disease', (157, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('association', 'Interaction', (46, 57))	('hypoxia', 'Disease', (90, 97))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
113616	30590044	Furthermore, these data suggest that colorectal cancer patients with component mutations have tumors associated with high expression of hypoxia signatures, and therefore may have more hypoxic tumors, providing one potential explanation for the poor overall survival observed in this patient population.	('hypoxia', 'Disease', (136, 143))	('tumors', 'Disease', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('hypoxic tumors', 'Disease', (184, 198))	('mutations', 'Var', (79, 88))	('hypoxia', 'Disease', 'MESH:D000860', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (283, 290))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('colorectal cancer', 'Disease', (37, 54))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('hypoxic tumors', 'Disease', 'MESH:D009369', (184, 198))
113620	30590044	Notably, the murine colorectal cancer cells tested, CT26, have a mutation in central complement component C3 (pV254I).	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('complement component C3', 'Disease', (85, 108))	('complement component C3', 'Disease', 'MESH:C565169', (85, 108))	('colorectal cancer', 'Disease', (20, 37))	('CT26', 'CellLine', 'CVCL:7254', (52, 56))	('murine', 'Species', '10090', (13, 19))	('mutation', 'Var', (65, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('pV254I', 'Gene', (110, 116))
113621	30590044	The human colorectal cancer cells tested, HCT116 also harbor a C3 mutation, but in this case the C3 mutation is silent, and therefore should not alter amino acid sequence.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('HCT116', 'CellLine', 'CVCL:0291', (42, 48))	('colorectal cancer', 'Disease', (10, 27))	('mutation', 'Var', (66, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
113623	30590044	On one hand, complement component mutations are highly associated with hypoxia signatures and therefore hypoxia-induced gene expression changes.	('hypoxia', 'Disease', (71, 78))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))	('associated', 'Reg', (55, 65))	('complement component', 'Gene', (13, 33))	('expression', 'MPA', (125, 135))	('hypoxia', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('mutations', 'Var', (34, 43))
113624	30590044	On the other, we note that hypoxia itself can also regulate the terminal consequence of complement system activation by making cancer cells (including those with complement component mutations) more resistant to CMC.	('resistant', 'CPA', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (183, 192))	('CMC', 'Chemical', '-', (212, 215))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('hypoxia', 'Disease', (27, 34))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('cancer', 'Disease', (127, 133))
113629	30590044	We asked whether increased mRNA levels of either of these regulators was associated with a hypoxia signature (same as was used in Figure 3A) and found that there was a positive and significant correlation between CD55 mRNA expression and the hypoxia signature tested in colorectal cancer TCGA patient samples (Figure 4B).	('hypoxia', 'Disease', (242, 249))	('increased', 'PosReg', (17, 26))	('hypoxia', 'Disease', 'MESH:D000860', (242, 249))	('colorectal cancer', 'Disease', (270, 287))	('hypoxia', 'Disease', (91, 98))	('CD55', 'Var', (213, 217))	('patient', 'Species', '9606', (293, 300))	('colorectal cancer', 'Disease', 'MESH:D015179', (270, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('colorectal cancer', 'Phenotype', 'HP:0003003', (270, 287))	('mRNA levels', 'MPA', (27, 38))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
113634	30590044	Notably, CD55 mRNA expression in colorectal cancer correlates with poor patient prognosis (Figure 4C).	('CD55 mRNA', 'Var', (9, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('patient', 'Species', '9606', (72, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('colorectal cancer', 'Disease', (33, 50))
113640	30590044	These data suggested that both HIF1alpha and HIF2alpha contribute to the regulation of CD55 under hypoxic conditions (Figures S3G and S3H).	('hypoxic conditions', 'Disease', 'MESH:D009135', (98, 116))	('regulation', 'MPA', (73, 83))	('CD55', 'Gene', (87, 91))	('hypoxic conditions', 'Disease', (98, 116))	('S3H', 'Var', (134, 137))
113641	30590044	Since the greatest decrease in CD55 expression was observed following depletion of the dimerization HIFa partner, HIF1beta, these data indicate that the hypoxia-inducible expression of CD55 is likely dependent on both HIF1alpha and HIF2alpha (since loss of HIF1beta leads to loss of HIF1alpha- and HIF2alpha-dependent transcriptional activation).	('decrease', 'NegReg', (19, 27))	('CD55', 'Gene', (185, 189))	('HIF1beta', 'Gene', '405', (114, 122))	('HIF1beta', 'Gene', '405', (257, 265))	('CD55', 'Gene', (31, 35))	('loss', 'Var', (249, 253))	('hypoxia', 'Disease', 'MESH:D000860', (153, 160))	('hypoxia', 'Disease', (153, 160))	('HIF1beta', 'Gene', (257, 265))	('expression', 'MPA', (36, 46))	('HIF1beta', 'Gene', (114, 122))
113652	30590044	Pathway-level mutational analysis revealed that complement pathway mutations are widespread across many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('complement pathway', 'Pathway', (48, 66))	('mutations', 'Var', (67, 76))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
113653	30590044	Additionally, KS test analysis revealed that mutations in complement genes, as a group, occur at a rate above background in a number of the cancers analyzed.	('mutations', 'Var', (45, 54))	('rat', 'Species', '10116', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('occur', 'Reg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('KS', 'Chemical', '-', (14, 16))	('complement genes', 'Gene', (58, 74))
113655	30590044	This is due to the fact that specific groups of mutations in these cancer types could still be clinically significant if not analyzed as a block.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('clinical', 'Species', '191496', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (48, 57))
113656	30590044	Indeed, analysis of immune infiltration differences between patients with and without CD55 mutations (one of the mutations giving rise to neoantigens) correlates with altered immune infiltrates including increased cytotoxic T cell responses.	('cytotoxic T cell responses', 'CPA', (214, 240))	('patients', 'Species', '9606', (60, 68))	('increased', 'PosReg', (204, 213))	('CD55', 'Gene', (86, 90))	('rat', 'Species', '10116', (33, 36))	('mutations', 'Var', (91, 100))	('rat', 'Species', '10116', (188, 191))	('altered', 'Reg', (167, 174))
113660	30590044	A closer look at the CD55 mutations identified in colorectal cancer suggests that these mutations occur across different short consensus repeat (SCR) domains, suggesting that they are likely to be loss of function.	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('CD55', 'Gene', (21, 25))	('short consensus repeat', 'Disease', 'MESH:D000647', (121, 143))	('short consensus repeat', 'Disease', (121, 143))	('mutations', 'Var', (26, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', (50, 67))
113661	30590044	However, to our knowledge, none of the CD55 mutations we report here overlap with variants identified in other diseases such as Cromer Inab phenotype (lack of all Cromer complex blood group antigens) or even those variants that have been associated with lung cancer or gastric cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('gastric cancer', 'Disease', (269, 283))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('lung cancer', 'Disease', (254, 265))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mutations', 'Var', (44, 53))	('variants', 'Var', (214, 222))	('associated', 'Reg', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('CD55', 'Gene', (39, 43))
113662	30590044	Interestingly, showed that missense mutation L205F (present in a colon adenocarcinoma patient) results in 50% reduced CD55 function compared to wild-type CD55.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (65, 85))	('reduced', 'NegReg', (110, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('L205F', 'Mutation', 'p.L205F', (45, 50))	('patient', 'Species', '9606', (86, 93))	('CD55', 'Protein', (118, 122))	('L205F', 'Var', (45, 50))	('colon adenocarcinoma', 'Disease', (65, 85))
113663	30590044	We note, however, that CD55 mutations are not associated with changes in overall survival in colorectal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('CD55', 'Gene', (23, 27))	('colorectal cancer', 'Disease', (93, 110))	('mutations', 'Var', (28, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('patients', 'Species', '9606', (111, 119))
113664	30590044	In contrast, we report that high CD55 mRNA expression is significantly associated with decreased disease-free survival in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('decreased', 'NegReg', (87, 96))	('colorectal cancer', 'Disease', (122, 139))	('CD55', 'Protein', (33, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('disease-free survival', 'CPA', (97, 118))	('high', 'Var', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
113683	30590044	However, while apoptosis programs may also be triggered in hypoxic tumors (especially in a p53 wild-type tumor), it is common for tumors to evade such apoptosis through mechanisms including p53 mutations.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('hypoxic tumors', 'Disease', (59, 73))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('p53', 'Gene', '7157', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (105, 110))	('apoptosis programs', 'CPA', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p53', 'Gene', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', (130, 136))	('mutations', 'Var', (194, 203))	('p53', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('hypoxic tumors', 'Disease', 'MESH:D009369', (59, 73))	('evade', 'NegReg', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
113717	30590044	To determine the enrichment of complement mutations in each TCGA cancer, a modified Kolmogorov-Smirnov (KS) test using the method of GSEA (kt.test2; https://github.com/franapoli/signed-ks-test) was performed on "mutation ranks."	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('GSEA', 'Chemical', '-', (133, 137))	('cancer', 'Disease', (65, 71))	('mutations', 'Var', (42, 51))	('KS', 'Chemical', '-', (104, 106))
113738	30590044	The list of variants predicted as "cancer drivers" by Mutsig2CV was used for neoantigen prediction (following removal of synonymous mutations), Genes, mutations, neoantigens and predicted binding affinities (IC50) are shown in Tables S1E-S1I).	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variants', 'Var', (12, 20))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))
113739	30590044	The term neoantigen refers to tumor specific DNA alterations that give rise to novel peptide sequences, usually entirely absent from the normal human genome.	('alterations', 'Var', (49, 60))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('rat', 'Species', '10116', (53, 56))	('give rise to', 'Reg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
113740	30590044	The list of variants and the list of HLA alleles was fed into the NetMHCpan (v3) via topiary tool (https://github.com/openvax/topiary) to calculate predicted binding affinities of predicted true neoantigens.	('variants', 'Var', (12, 20))	('NetMHCpan', 'Chemical', '-', (66, 75))	('binding', 'Interaction', (158, 165))
113764	30590044	An additional covariate of mutational load which is the sum of all non-silent mutations in a cancer sample was used (variable: corrected.for.load.wal.pval; Tables S2C, S2E, S2G, S2I, S2K, and S2M) to control for genomic instability and as a proxy for MSI.	('S2K', 'Var', (183, 186))	('S2M', 'Var', (192, 195))	('cancer', 'Disease', (93, 99))	('MSI', 'Disease', 'None', (251, 254))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('MSI', 'Disease', (251, 254))	('S2I', 'Var', (178, 181))	('S2M', 'Mutation', 'p.S2M', (192, 195))	('S2E', 'Var', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('S2G', 'Var', (173, 176))
113765	30590044	These data represent Benjamani Hochberg corrected Log q-values of the model including age, stage, gender, and in the cases of COADREAD, ESCA, STAD and UCEC also mutational load correction.	('COADREAD', 'Disease', 'None', (126, 134))	('ESCA', 'Disease', (136, 140))	('mutational load correction', 'Var', (161, 187))	('COADREAD', 'Disease', (126, 134))
113771	30590044	Complement mutations occur at a significantly higher rate than background mutations Complement component mutations are associated with poor overall survival Tumors with complement component mutations harbor increased hypoxic signaling Hypoxic colorectal cancer cells are resistant to complement-mediated cytotoxicity	('Hypoxic colorectal cancer', 'Disease', (235, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('complement component', 'Gene', (169, 189))	('cytotoxicity', 'Disease', (304, 316))	('mutations', 'Var', (190, 199))	('Hypoxic colorectal cancer', 'Disease', 'MESH:D015179', (235, 260))	('increased hypoxic', 'Disease', 'MESH:D000860', (207, 224))	('Tumors', 'Disease', (157, 163))	('Tumors', 'Disease', 'MESH:D009369', (157, 163))	('Tumors', 'Phenotype', 'HP:0002664', (157, 163))	('rat', 'Species', '10116', (53, 56))	('increased hypoxic', 'Disease', (207, 224))	('cytotoxicity', 'Disease', 'MESH:D064420', (304, 316))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('Tumor', 'Phenotype', 'HP:0002664', (157, 162))
113775	29741274	LGGs in the cerebral hemispheres resulted in significantly fewer neurologic impairments, compared with that of other locations at baseline (P < 0.001) and at last follow-up (P < 0.001).	('neurologic impairments', 'Disease', 'MESH:D009422', (65, 87))	('LGGs', 'Var', (0, 4))	('neurologic impairments', 'Phenotype', 'HP:0000707', (65, 87))	('fewer', 'NegReg', (59, 64))	('neurologic impairments', 'Disease', (65, 87))
113835	29741274	The proportion of patients whose MRS scores worsened over time did not differ by PSI among the site groups (P >= 0.67) except for PF tumors, in which short PSIs were marginally associated with worsening MRS (P = 0.053).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('PF tumors', 'Disease', 'MESH:D009369', (130, 139))	('MRS', 'Disease', 'MESH:D008556', (203, 206))	('short PSIs', 'Var', (150, 160))	('MRS', 'Disease', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('patients', 'Species', '9606', (18, 26))	('MRS', 'Disease', 'MESH:D008556', (33, 36))	('MRS', 'Disease', (203, 206))	('PF tumors', 'Disease', (130, 139))
113846	29741274	Long PSIs of brainstem LGG were associated with increased ear and vestibular dysfunction at last follow-up (25.0% long PSI versus 0.0% short PSI; P = 0.039).	('increased', 'PosReg', (48, 57))	('Long PSIs', 'Var', (0, 9))	('vestibular dysfunction', 'Disease', 'MESH:D000160', (66, 88))	('vestibular dysfunction', 'Disease', (66, 88))	('vestibular dysfunction', 'Phenotype', 'HP:0001751', (66, 88))
113850	29741274	Optic pathway and midline tumors with long PSIs had significantly worsened dysmetria over time (P = 0.007).	('dysmetria', 'Disease', (75, 84))	('dysmetria', 'Phenotype', 'HP:0001310', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('dysmetria', 'Disease', 'MESH:D002524', (75, 84))	('long PSIs', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('midline tumors', 'Disease', (18, 32))	('worsened', 'NegReg', (66, 74))	('midline tumors', 'Disease', 'MESH:D009369', (18, 32))
113862	29741274	For all patients, we found that long PSIs were associated with a higher incidence of long-term ataxia and dysmetria, and long PSIs were associated with ear and vestibular dysfunction specifically in patients with brainstem LGG.	('associated', 'Reg', (136, 146))	('long PSIs', 'Var', (121, 130))	('vestibular dysfunction', 'Phenotype', 'HP:0001751', (160, 182))	('dysmetria', 'Phenotype', 'HP:0001310', (106, 115))	('vestibular dysfunction', 'Disease', (160, 182))	('patients', 'Species', '9606', (199, 207))	('vestibular dysfunction', 'Disease', 'MESH:D000160', (160, 182))	('ataxia and dysmetria', 'Disease', 'MESH:D002524', (95, 115))	('ataxia', 'Phenotype', 'HP:0001251', (95, 101))	('patients', 'Species', '9606', (8, 16))
113931	30463249	Moreover, the authors found that the images produced by lioUS have few artefacts, better definition, and a more accurate visualization of the residual tumor compared with cioUS.	('lioUS', 'Var', (56, 61))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))
113948	30463249	With regards to the prognosis of patients undergoing surgery for brain gliomas, it has been demonstrated that IOUS improves the prevalence of GTR and significantly increases 1- and 2-year overall survival.	('1- and', 'CPA', (174, 180))	('increases', 'PosReg', (164, 173))	('patients', 'Species', '9606', (33, 41))	('IOUS', 'Var', (110, 114))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('overall survival', 'CPA', (188, 204))	('brain gliomas', 'Disease', 'MESH:C564230', (65, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('brain gliomas', 'Disease', (65, 78))	('GTR', 'MPA', (142, 145))	('improves', 'PosReg', (115, 123))
113977	29625051	Transcriptional and epigenetic dysregulation of cancer cells frequently leads to oncogenic de-differentiation and acquisition of stemness features by altering core signaling pathways that regulate the phenotypes of normal stem cells.	('altering', 'Reg', (150, 158))	('core signaling pathways', 'Pathway', (159, 182))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epigenetic dysregulation', 'Var', (20, 44))	('acquisition', 'CPA', (114, 125))	('stemness features', 'CPA', (129, 146))	('oncogenic de-differentiation', 'CPA', (81, 109))	('cancer', 'Disease', (48, 54))	('leads to', 'Reg', (72, 80))	('dysregulation', 'Var', (31, 44))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
114017	29625051	This result could arise from a high frequency of IDH1/2 mutations and resulting DNA hypermethylation.	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('DNA hypermethylation', 'MPA', (80, 100))	('mutations', 'Var', (56, 65))	('IDH1/2', 'Gene', (49, 55))
114020	29625051	BRCA samples with high mRNAsi were more likely to be ER-negative, and enriched for FAT3 and TP53 mutations.	('mutations', 'Var', (97, 106))	('BRCA', 'Gene', (0, 4))	('FAT3', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('FAT3', 'Gene', '120114', (83, 87))	('BRCA', 'Gene', '672', (0, 4))
114029	29625051	High mRNAsi was associated with higher expression of miR-181c-3p, miR-22-3p, and miR-30b-3p (Figure 3B, right bottom).	('miR-22-3p', 'Gene', '407008', (66, 75))	('higher', 'PosReg', (32, 38))	('miR-30b-3p', 'Var', (81, 91))	('miR-181c-3p', 'Var', (53, 64))	('mRNAsi', 'MPA', (5, 11))	('expression', 'MPA', (39, 49))	('miR-22-3p', 'Gene', (66, 75))
114030	29625051	We found a strong association between high mDNAsi, high pathologic grade and recently published molecular subtypes of glioma (Figure 3C).	('glioma', 'Disease', (118, 124))	('high', 'Var', (38, 42))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('mole', 'Phenotype', 'HP:0003764', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
114031	29625051	mDNAsi was low in less aggressive gliomas that are characterized by codel and G-CIMP-high features and was highest in highly aggressive GBMs characterized by IDH mutations (G-CIMP-low) and poor clinical outcome.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH', 'Gene', '3417', (158, 161))	('mutations', 'Var', (162, 171))	('aggressive gliomas', 'Disease', 'MESH:D005910', (23, 41))	('less', 'Disease', (18, 22))	('G-CIMP', 'Chemical', '-', (173, 179))	('low', 'NegReg', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('aggressive gliomas', 'Disease', (23, 41))	('G-CIMP', 'Chemical', '-', (78, 84))	('IDH', 'Gene', (158, 161))	('highest', 'Reg', (107, 114))
114032	29625051	Also, high mDNAsi is strongly associated with more aggressive classical and mesenchymal subtypes of GBM, suggesting that it can stratify tumors with distinct clinical outcomes.	('associated', 'Reg', (30, 40))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('GBM', 'Disease', (100, 103))	('high', 'Var', (6, 10))	('mDNAsi', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
114033	29625051	We also found that high mDNAsi was associated with mutations in NF1 and EGFR and infrequent mutations in IDH1, TP53, CIC, and ATRX (Figure 3C, left), with higher expression of ANNEXIN-A1 protein and lower expression of ANNEXIN-A7, and with expression of the miR-200 family (Figure 3C, right bottom).	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (72, 76))	('ATRX', 'Gene', (126, 130))	('mDNAsi', 'Disease', (24, 30))	('NF1', 'Gene', (64, 67))	('IDH1', 'Gene', '3417', (105, 109))	('ATRX', 'Gene', '546', (126, 130))	('ANNEXIN-A7', 'Gene', '310', (219, 229))	('TP53', 'Gene', '7157', (111, 115))	('CIC', 'Gene', (117, 120))	('ANNEXIN-A7', 'Gene', (219, 229))	('higher', 'PosReg', (155, 161))	('ANNEXIN-A1', 'Gene', (176, 186))	('lower', 'NegReg', (199, 204))	('EGFR', 'Gene', (72, 76))	('expression', 'MPA', (205, 215))	('ANNEXIN-A1', 'Gene', '301', (176, 186))	('IDH1', 'Gene', (105, 109))	('TP53', 'Gene', (111, 115))	('expression', 'MPA', (162, 172))	('NF1', 'Gene', '4763', (64, 67))
114036	29625051	IDH1 mutations are known to reduce cell differentiation, and high values of the mRNAsi in a subset of IDH mutant gliomas might capture this phenomenon.	('IDH', 'Gene', '3417', (102, 105))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (106, 112))	('mRNAsi', 'MPA', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('cell differentiation', 'CPA', (35, 55))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', (113, 120))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('reduce', 'NegReg', (28, 34))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('IDH1', 'Gene', (0, 4))	('IDH', 'Gene', (102, 105))	('IDH1', 'Gene', '3417', (0, 4))
114039	29625051	The most salient associations of mRNAsi and mDNAsi are presented in Figure 4, while the following results of the comprehensive analyses are shown in the supplementary material: associations with mutations (Figure S3), associations with miRNA expression and protein abundance (Figure S4), associations with the tumor grading and clinical outcome (Figure S5).	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('miRNA expression', 'MPA', (236, 252))	('tumor', 'Disease', (310, 315))	('mutations', 'Var', (195, 204))	('protein abundance', 'MPA', (257, 274))	('associations', 'Interaction', (218, 230))	('associations', 'Interaction', (288, 300))	('associations', 'Interaction', (177, 189))
114040	29625051	We found a strong association between mDNAsi and known molecular subtypes, somatic mutations in SETD2 and TP53 genes, and with tobacco smoking status in LUAD (Figures 4A and S3).	('mutations', 'Var', (83, 92))	('tobacco', 'Species', '4097', (127, 134))	('mDNAsi', 'Disease', (38, 44))	('SETD2', 'Gene', '29072', (96, 101))	('mole', 'Phenotype', 'HP:0003764', (55, 59))	('SETD2', 'Gene', (96, 101))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
114047	29625051	Analyses of HNSC samples revealed that high indices are correlated with NSD1 mutation, E-cadherin protein expression, miR-200-3p, and previously identified classical molecular subtypes (Figure 4B).	('NSD1', 'Gene', '64324', (72, 76))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('mole', 'Phenotype', 'HP:0003764', (166, 170))	('mutation', 'Var', (77, 85))	('miR-200-3p', 'Var', (118, 128))	('expression', 'MPA', (106, 116))	('NSD1', 'Gene', (72, 76))
114048	29625051	NSD1 mutation was recently linked in HNSC tumors to blockade of cellular differentiation and promotion of oncogenesis.	('cellular differentiation', 'CPA', (64, 88))	('NSD1', 'Gene', (0, 4))	('linked', 'Reg', (27, 33))	('promotion', 'PosReg', (93, 102))	('oncogenesis', 'CPA', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HNSC tumors', 'Disease', 'MESH:D009369', (37, 48))	('blockade', 'NegReg', (52, 60))	('mutation', 'Var', (5, 13))	('NSD1', 'Gene', '64324', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HNSC tumors', 'Disease', (37, 48))
114057	29625051	Detailed analyses of ACC samples revealed an association between high mRNAsi and defined molecular subtypes, clinical stage, and mutations in PRKAR1A and TP53 genes (Figure 4D).	('TP53', 'Gene', (154, 158))	('ACC', 'Gene', (21, 24))	('PRKAR1A', 'Gene', '5573', (142, 149))	('mutations', 'Var', (129, 138))	('ACC', 'Gene', '31', (21, 24))	('mole', 'Phenotype', 'HP:0003764', (89, 93))	('PRKAR1A', 'Gene', (142, 149))	('TP53', 'Gene', '7157', (154, 158))
114064	29625051	Roughly 80% of LGG tumors carry an IDH1/2 mutation and, as demonstrated by our group and others, tconfers a genome-wide hypermethylator phenotype (G-CIMP).	('G-CIMP', 'Chemical', '-', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LGG tumors', 'Disease', (15, 25))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('mutation', 'Var', (42, 50))	('hypermethylator', 'MPA', (120, 135))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('LGG tumors', 'Disease', 'MESH:D009369', (15, 25))	('IDH1/2', 'Gene', (35, 41))
114067	29625051	Compared to G-CIMP-high tumors, G-CIMP-low tumors are known to be more proliferative, express cell-cycle-related genes, and have various stem cell-like genomic features.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('G-CIMP-low', 'Var', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('G-CIMP', 'Chemical', '-', (12, 18))	('proliferative', 'CPA', (71, 84))	('G-CIMP', 'Chemical', '-', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('more', 'PosReg', (66, 70))	('cell-cycle-related', 'Gene', (94, 112))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
114101	29625051	According to our analysis, pyrvinium and puromycin could inhibit stemness in LUAD.	('puromycin', 'Chemical', 'MESH:D011691', (41, 50))	('pyrvinium', 'Var', (27, 36))	('pyrvinium', 'Chemical', 'MESH:C024631', (27, 36))	('inhibit', 'NegReg', (57, 64))	('stemness', 'CPA', (65, 73))	('LUAD', 'Disease', (77, 81))
114122	29625051	High mRNAsi was associated with basal breast carcinomas but also Her2 and lumB subtypes that are more aggressive than the hormone-dependent lumA group.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('associated', 'Reg', (16, 26))	('Her2', 'Gene', '2064', (65, 69))	('lumA', 'Gene', (140, 144))	('breast carcinomas', 'Disease', 'MESH:D001943', (38, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('breast carcinomas', 'Disease', (38, 55))	('High mRNAsi', 'Var', (0, 11))	('breast carcinomas', 'Phenotype', 'HP:0003002', (38, 55))	('lumB', 'Disease', (74, 78))	('Her2', 'Gene', (65, 69))	('lumA', 'Gene', '79188', (140, 144))
114123	29625051	In contrast, high mDNAsi was strongly associated with high-grade glioblastomas, poor overall and progression-free survival.	('mDNAsi', 'Gene', (18, 24))	('poor', 'NegReg', (80, 84))	('associated', 'Reg', (38, 48))	('high', 'Var', (13, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
114125	29625051	Dedifferentiated cells can arise from different sources: from long-lived stem or progenitor cells that accumulate mutations in oncogenic pathways, or via dedifferentiation from non-stem cancer cells that convert to CSCs through deregulation of developmental and/or non-developmental pathways.	('deregulation', 'Reg', (228, 240))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('oncogenic pathways', 'Pathway', (127, 145))	('developmental and/or', 'Pathway', (244, 264))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
114131	29625051	Cancer cells in many primary solid tumors are basically epithelial regardless of their degrees of dedifferentiation, but some cells in such contexts could acquire mesenchymal characteristics, either by accumulating additional mutations or by undergoing epigenetic changes shaped by the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('solid tumors', 'Disease', (29, 41))	('epigenetic changes', 'Var', (253, 271))	('undergoing', 'Reg', (242, 252))	('mutations', 'Var', (226, 235))	('acquire', 'PosReg', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('accumulating', 'PosReg', (202, 214))	('mesenchymal characteristics', 'CPA', (163, 190))
114171	29625051	Additionally, we downloaded independent, non-TCGA datasets of gliomas [ (GSE36245, GSE36278) and (GSE30339)] and BRCA samples (GSE59000) and applied our metrics to measure the stemness in the validation data.	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('GSE59000', 'Var', (127, 135))	('BRCA', 'Gene', '672', (113, 117))	('GSE30339)]', 'Var', (98, 108))	('gliomas', 'Disease', (62, 69))	('BRCA', 'Gene', (113, 117))	('GSE36278', 'Var', (83, 91))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
114175	29625051	To eliminate somatic tissue-specific probes, we removed probes that were consistently methylated (standard deviation beta value > 0.05) in non-tumor adult tissues available through TCGA.	('non-tumor', 'Disease', 'MESH:D009369', (139, 148))	('methylated', 'Var', (86, 96))	('non-tumor', 'Disease', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
114343	22723849	However, to date, only the IDH1 mutation and G-CIMP signature have been validated to predict prognosis across various studies.	('G-CIMP', 'Chemical', '-', (45, 51))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))	('IDH1', 'Gene', (27, 31))
114344	22723849	Beyond their involvement in a variety of biological processes, miRNAs have also been found to participate in processes involved in the molecular pathology of cancer.	('participate', 'Reg', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('miRNAs', 'Var', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
114405	22723849	The U87 and U251 cells transfected with miR-196b mimics showed increased cell proliferation rates compared to those of mock-transfected cells (Figure 4A).	('increased', 'PosReg', (63, 72))	('mimics', 'Var', (49, 55))	('U251', 'CellLine', 'CVCL:0021', (12, 16))	('miR-196b', 'Gene', (40, 48))	('U87', 'Gene', (4, 7))	('miR-196b', 'Gene', '442920', (40, 48))	('cell proliferation rates', 'CPA', (73, 97))	('U87', 'Gene', '641648', (4, 7))
114410	22723849	It has been reported that aberrant miRNA expression patterns highly correlate with progression and prognosis in various cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('aberrant', 'Var', (26, 34))	('correlate', 'Reg', (68, 77))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('miRNA expression patterns', 'MPA', (35, 60))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
114436	22723849	We also show that miR-196b is tightly associated with cell cycle progression and that ectopic expression in GBM cells could increase proliferation significantly.	('ectopic expression', 'Var', (86, 104))	('increase', 'PosReg', (124, 132))	('miR-196b', 'Gene', (18, 26))	('associated', 'Reg', (38, 48))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('miR-196b', 'Gene', '442920', (18, 26))	('proliferation', 'CPA', (133, 146))	('cell cycle progression', 'CPA', (54, 76))
114445	33479027	The cSCC CD8+ T-cell population contained a higher proportion of CD69+/CD103+ TRMs than that in non-lesional skin and blood.	('CD8', 'Gene', '925', (9, 12))	('CD8', 'Gene', (9, 12))	('CD69+/CD103+ TRMs', 'Var', (65, 82))
114446	33479027	These cSCC CD69+/CD103+ TRMs exhibited increased IL-10 production, and higher CD39, CTLA-4 and PD-1 expression compared with CD103- TRMs in the tumor.	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', (144, 149))	('CD39', 'Gene', (78, 82))	('CD69+/CD103+', 'Var', (11, 23))	('PD-1', 'Gene', (95, 99))	('increased IL-10 production', 'Phenotype', 'HP:0030783', (39, 65))	('CTLA-4', 'Gene', (84, 90))	('expression', 'MPA', (100, 110))	('increased', 'PosReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('IL-10 production', 'MPA', (49, 65))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
114447	33479027	CD103+ cells were more frequent in P-M than P-NM cSCCs.	('P-M', 'Disease', (35, 38))	('CD103+ cells', 'Var', (0, 12))	('cSCCs', 'Chemical', '-', (49, 54))
114449	33479027	Immunofluorescence microscopy showed that the majority of CD103 was present on CD8+ T cells and that CD8+CD103+ cells were significantly more frequent in P-M than P-NM cSCCs.	('CD8', 'Gene', '925', (101, 104))	('P-M', 'Var', (154, 157))	('CD8', 'Gene', (79, 82))	('CD103', 'Gene', (58, 63))	('CD8', 'Gene', '925', (79, 82))	('cSCCs', 'Chemical', '-', (168, 173))	('CD8', 'Gene', (101, 104))
114452	33479027	In genetically susceptible individuals, including those with variant MC1R genotype and/or fair skin, exposure to ultraviolet radiation induces alterations in cancer driver genes within keratinocytes, which enable the development of skin cancers and precancerous skin lesions.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('MC1R', 'Gene', '4157', (69, 73))	('skin cancers', 'Disease', (232, 244))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('skin cancers', 'Disease', 'MESH:D012878', (232, 244))	('MC1R', 'Gene', (69, 73))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (237, 243))	('skin cancer', 'Phenotype', 'HP:0008069', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('enable', 'PosReg', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('fair skin', 'Phenotype', 'HP:0007513', (90, 99))	('cancer', 'Disease', (252, 258))	('precancerous skin lesions', 'Disease', 'MESH:D011230', (249, 274))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('precancerous skin lesions', 'Disease', (249, 274))	('variant', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('alterations', 'Reg', (143, 154))	('skin cancers', 'Phenotype', 'HP:0008069', (232, 244))
114453	33479027	Dysfunctional cutaneous immunity is also a well-known risk factor for keratinocyte skin cancer, especially cutaneous squamous cell carcinoma (cSCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('cutaneous squamous cell carcinoma', 'Disease', (107, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('skin cancer', 'Disease', (83, 94))	('skin cancer', 'Phenotype', 'HP:0008069', (83, 94))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (107, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 140))	('skin cancer', 'Disease', 'MESH:D012878', (83, 94))	('Dysfunctional', 'Var', (0, 13))
114501	33479027	CD69-CD103- T cells accounted for significantly lower proportions of the CD3+ population in cSCC and NS compared with blood (mean 44.2% and 35.7% vs 77.4%, respectively: p<0.0001 for both comparisons, n=36 tumors, figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('lower', 'NegReg', (48, 53))	('CD69-CD103- T cells', 'Var', (0, 19))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('cSCC', 'Disease', (92, 96))	('tumors', 'Disease', (206, 212))
114502	33479027	The percentage of CD3+ T cells that were CD69+CD103+ TRMs was also higher in cSCCs and NS than blood (mean 9.1% and 11.4% vs 0.3%, respectively, p<0.0001, n=36 tumors, figure 3B).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('higher', 'PosReg', (67, 73))	('CD69+CD103+ TRMs', 'Var', (41, 57))	('cSCCs', 'Disease', (77, 82))	('cSCCs', 'Chemical', '-', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
114504	33479027	While greater numbers of CD69+CD103+ TRMs were present in the CD4+FOXP3- population (mean 7.9%, figure 3D), and in the total CD4+ population (mean 7.0%, figure 3E) than in the Treg group, CD69+CD103+ TRMs were present in greater amounts in the CD8+ population (mean 24.1%, figure 3F).	('CD69+CD103+ TRMs', 'Var', (25, 41))	('CD8', 'Gene', (244, 247))	('CD8', 'Gene', '925', (244, 247))
114505	33479027	Significantly higher percentages of tumor-infiltrating CD103+ T cells were CD8+ (mean 62.0%, figure 3G) than CD4+ (mean 34.8%, p<0.0001), CD4+FOXP3+ (mean 1.4%, p<0.0001) and CD4+FOXP3- (33.0%, p=0.0009).	('CD103+', 'Var', (55, 61))	('CD8', 'Gene', '925', (75, 78))	('CD4+FOXP3+', 'Var', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', (36, 41))	('higher', 'PosReg', (14, 20))
114506	33479027	Although CD103+ TRMs accounted for similar percentages of the total lymphocyte and CD3+ T-cell populations in cSCC and NS, the percentage of CD4 T cells that were CD103+ TRMs was lower in cSCC than NS (p=0.0007, figure 3E, H, I), whereas, by contrast, cSCCs contained higher percentages of CD8 T cells that were CD103+ TRMs than NS (p=0.0039, figure 3F and I).	('CD8', 'Gene', (290, 293))	('lower', 'NegReg', (179, 184))	('CD8', 'Gene', '925', (290, 293))	('cSCCs', 'Chemical', '-', (252, 257))	('cSCC', 'Disease', (188, 192))	('CD103+ TRMs', 'Var', (163, 174))
114508	33479027	These CD103+ TRMs were predominantly located in the peritumoral stromal areas, although there were smaller frequencies that were present in the tumor nests, where the vast majority of CD8 T cells expressed CD103 (figure 4B).	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CD103', 'Var', (206, 211))	('tumor', 'Disease', (56, 61))	('CD8', 'Gene', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CD103+', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD8', 'Gene', '925', (184, 187))
114510	33479027	In the cSCC CD8 T-cell population, CD103+ TRMs produced similar amounts of IFNgamma, TNFalpha and IL-2 compared with CD69- T cells and CD103- TRMs (figure 5A).	('CD8', 'Gene', '925', (12, 15))	('TNFalpha', 'Gene', (85, 93))	('IFNgamma', 'Gene', (75, 83))	('TNFalpha', 'Gene', '7124', (85, 93))	('IFNgamma', 'Gene', '3458', (75, 83))	('IL-2', 'Gene', '3558', (98, 102))	('CD103+ TRMs', 'Var', (35, 46))	('CD8', 'Gene', (12, 15))	('IL-2', 'Gene', (98, 102))
114512	33479027	While IL-10 production was detected in a relatively small proportion of the CD8+CD103+ cells, it suggested a possible upregulation of an immunosuppressive phenotype by tumor-infiltrating CD103+ TRM, therefore expression of the inhibitory markers CD39, CTLA-4 and PD-1 was investigated.	('CD103+', 'Var', (187, 193))	('tumor', 'Disease', (168, 173))	('upregulation', 'PosReg', (118, 130))	('immunosuppressive phenotype', 'MPA', (137, 164))	('CD8', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CD8', 'Gene', '925', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
114514	33479027	Analysis of the tumor-infiltrating CD4+ T-cell population showed that CD4+CD103+ TRMs expressed IFNgamma in higher frequencies than CD69- T cells, and TNFalpha in greater percentages than CD69- T cells and CD103- TRMs, but there were no significant differences between the CD4+CD103+ TRMs and the other T-cell subsets in the expression of IL-2 (online supplemental figure 5A-C).	('TNFalpha', 'Gene', (151, 159))	('IL-2', 'Gene', '3558', (339, 343))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('IL-2', 'Gene', (339, 343))	('CD4+CD103+', 'Var', (70, 80))	('TNFalpha', 'Gene', '7124', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('IFNgamma', 'Gene', (96, 104))	('tumor', 'Disease', (16, 21))	('IFNgamma', 'Gene', '3458', (96, 104))
114515	33479027	Although more of the CD4+CD103+ TRMs expressed IL-10, this did not reach statistical significance (n=10 tumors), but there was a significantly higher proportion of CD4+CD103+ TRMs than CD69- T cells and CD103- TRMs expressing CD39 (online supplemental figure 5DE).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CD4+CD103+', 'Var', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
114516	33479027	These results suggest that CD103+ TRMs, which are predominantly within the cSCC CD8 T-cell population, display a regulatory phenotype.	('CD103+', 'Var', (27, 33))	('CD8', 'Gene', (80, 83))	('CD8', 'Gene', '925', (80, 83))
114517	33479027	Consistent with this, immunofluorescence microscopy confirmed CD103+ immune cells in cSCC also expressed CD39 (n=5 tumors, figure 5B and online supplemental figure 6).	('CD39', 'Var', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('cSCC', 'Disease', (85, 89))
114522	33479027	CD103 was expressed on immune cells infiltrating the cSCC stroma (figure 6A), and P-M cSCCs contained significantly increased percentages of CD103+ cells in the immune infiltrate compared with P-NM cSCCs (median 12.1% vs 6.9%, respectively, p<0.0001, figure 6B).	('cSCCs', 'Chemical', '-', (86, 91))	('CD103+ cells', 'Var', (141, 153))	('cSCCs', 'Chemical', '-', (198, 203))	('P-M', 'Var', (82, 85))	('increased', 'PosReg', (116, 125))
114523	33479027	cSCCs were then characterized into two groups based on CD103 expression:CD103 low (below median expression; CD103 expressed by <9.24% of immune infiltrate, n=41 tumors) and CD103 high (above median expression; CD103 expressed by >=9.25% of immune infiltrate, n=41 tumors).	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('low', 'NegReg', (78, 81))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('CD103', 'Gene', (72, 77))	('CD103', 'Var', (173, 178))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cSCCs', 'Chemical', '-', (0, 5))
114525	33479027	To investigate the association between CD103 expression and survival in other cancer types, TCGA data were analyzed using TIMER2.0, demonstrating that high (greater than median) expression of ITGAE (encoding CD103) was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, renal cell carcinoma, kidney chromophobe cancer and lower grade glioma, figure 6D, whereas two cancer types showed the opposite association (high ITGAE expression was associated with increased survival in cervical/endocervical cancer and pancreatic adenocarcinoma).	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (528, 534))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (539, 564))	('cancer', 'Disease', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('breast carcinoma', 'Phenotype', 'HP:0003002', (283, 299))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('breast carcinoma', 'Disease', (283, 299))	('renal cell carcinoma, kidney chromophobe cancer', 'Disease', 'MESH:C538614', (301, 348))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('carcinoma', 'Phenotype', 'HP:0030731', (555, 564))	('expression', 'Var', (178, 188))	('glioma', 'Disease', (365, 371))	('pancreatic adenocarcinoma', 'Disease', (539, 564))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Disease', (396, 402))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (301, 321))	('cancer', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('increased', 'PosReg', (484, 493))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('breast carcinoma', 'Disease', 'MESH:D001943', (283, 299))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('cutaneous melanoma', 'Disease', (263, 281))	('survival', 'MPA', (243, 251))	('cancer', 'Disease', (528, 534))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (263, 281))	('reduced', 'NegReg', (235, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('glioma', 'Phenotype', 'HP:0009733', (365, 371))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (263, 281))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (539, 564))
114529	33479027	There was no significant difference in CD8-CD103+ cell frequencies between P-M and P-NM cSCCs (2.0% vs 2.3% of immune infiltrate respectively, p=0.59, figure 6G).	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('P-M', 'Var', (75, 78))	('P-NM', 'Var', (83, 87))	('cSCCs', 'Chemical', '-', (88, 93))
114541	33479027	Non-recirculating TRMs express CD69 and include CD103- TRM and CD103+ TRM subgroups, which have potent effector functions, whereas recirculating T cells in skin include TCMs and TMMs.	('TMMs', 'Disease', 'None', (178, 182))	('TMMs', 'Disease', (178, 182))	('CD69', 'Var', (31, 35))	('CD103+', 'Var', (63, 69))
114544	33479027	Many tumor-infiltrating memory T cells expressed the TRM marker CD69, and TRMs were subcategorized as CD103+ or CD103-.	('CD69', 'Gene', (64, 68))	('tumor-infiltrating memory T', 'Disease', (5, 32))	('tumor-infiltrating memory T', 'Disease', 'MESH:D017254', (5, 32))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CD103-', 'Var', (112, 118))	('CD103+', 'Var', (102, 108))
114553	33479027	Extracellular ATP also activates the purinergic receptor P2Rx7, which is required for the generation and functionality of long-lived CD103+ TRMs in tissues.	('activates', 'PosReg', (23, 32))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('CD103+', 'Var', (133, 139))	('P2Rx7', 'Gene', (57, 62))	('P2Rx7', 'Gene', '5027', (57, 62))
114557	33479027	Related to this, CD103+ TRM cells have been reported to have higher expression of inhibitory receptors such as CTLA4, Tim-3 and PD-1, as well as CD39.	('expression', 'MPA', (68, 78))	('higher', 'PosReg', (61, 67))	('Tim-3', 'Gene', (118, 123))	('PD-1', 'Gene', (128, 132))	('CD103+', 'Var', (17, 23))	('CTLA4', 'Gene', (111, 116))	('CD39', 'Gene', (145, 149))	('Tim-3', 'Gene', '84868', (118, 123))
114558	33479027	Likewise, CD103+CD39+ tumor-infiltrating CD8 T cells have been shown to be enriched for tumor-reactive cells and display exhausted gene signatures.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('CD103+CD39+', 'Var', (10, 21))	('gene signatures', 'MPA', (131, 146))	('CD8', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CD8', 'Gene', '925', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (88, 93))
114559	33479027	This suggests that the role of CD103 on tumor-infiltrating T cells in cancer may be more complex than previously thought, and that tumor-reactive CD103+ TRMs may boost or inhibit the antitumor immune response.	('boost', 'PosReg', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CD103+', 'Var', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', (187, 192))	('inhibit', 'NegReg', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
114560	33479027	Indeed, we showed that CD103+ TRMs are associated with poorer clinical outcomes in cSCC, which is in contrast to some studies on other types of cancer.	('cSCC', 'Disease', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CD103+ TRMs', 'Var', (23, 34))	('poorer', 'NegReg', (55, 61))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
114562	33479027	CD103+ TRMs have also been described as protective or conveying better prognosis in other tumor types, including oropharyngeal, head and neck, lung, breast and ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('better', 'PosReg', (64, 70))	('ovarian cancers', 'Phenotype', 'HP:0100615', (160, 175))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (149, 175))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('CD103+ TRMs', 'Var', (0, 11))	('oropharyngeal', 'Disease', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('lung', 'Disease', (143, 147))
114565	33479027	In addition, Gabriely and colleagues also demonstrated that high CD103 expression was associated with shorter survival in patients with glioma and glioblastoma.	('shorter', 'NegReg', (102, 109))	('expression', 'MPA', (71, 81))	('survival', 'MPA', (110, 118))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioblastoma', 'Disease', (147, 159))	('high', 'Var', (60, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('CD103', 'Gene', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('patients', 'Species', '9606', (122, 130))	('glioma', 'Disease', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
114568	33479027	Further evidence for the association between CD103 and poorer clinical outcome in cancer was demonstrated in TCGA data showing high ITGAE expression was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, kidney chromophobe cancer, renal cell carcinoma, lower grade glioma and adrenocortical carcinoma.	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('high', 'Var', (127, 131))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (307, 331))	('reduced', 'NegReg', (169, 176))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (254, 260))	('breast carcinoma', 'Disease', 'MESH:D001943', (217, 233))	('adrenocortical carcinoma', 'Disease', (307, 331))	('glioma', 'Disease', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (262, 282))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('cutaneous melanoma', 'Disease', (197, 215))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (197, 215))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (197, 215))	('breast carcinoma', 'Phenotype', 'HP:0003002', (217, 233))	('kidney chromophobe cancer', 'Disease', 'MESH:D007680', (235, 260))	('breast carcinoma', 'Disease', (217, 233))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('renal cell carcinoma', 'Disease', (262, 282))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (262, 282))	('kidney chromophobe cancer', 'Disease', (235, 260))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (307, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('CD103', 'Gene', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
114569	33479027	Based on the associations of CD103+ TRMs with metastases and survival in different types of cancer, it remains unclear how CD103+ TRMs influences outcome in different cancers and whether the pathogenic role of CD103+ TRMs in diverse cancer types is tumor or organ-dependent, or differs between primary and metastatic tumors in some cancer types.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('CD103+', 'Gene', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('tumor', 'Disease', (249, 254))	('influences', 'Reg', (135, 145))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('CD103+', 'Var', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', (167, 174))	('tumors', 'Disease', (317, 323))	('CD103+', 'Var', (210, 216))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('cancer', 'Disease', (332, 338))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('associations', 'Interaction', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('metastases', 'Disease', (46, 56))	('cancer', 'Disease', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (167, 174))
114573	33479027	CD4+CD103+ TRMs in cSCC were able to produce IFNgamma and TNFalpha (and also upregulated CD39 and PD-1, online supplemental figure 5), so it is possible that their reduction/suppression by Tregs is another mechanism for decreased immune surveillance in cSCC.	('PD-1', 'Gene', (98, 102))	('TNFalpha', 'Gene', (58, 66))	('upregulated', 'PosReg', (77, 88))	('CD39', 'Gene', (89, 93))	('CD4+CD103+', 'Var', (0, 10))	('decreased immune surveillance', 'Phenotype', 'HP:0002721', (220, 249))	('TNFalpha', 'Gene', '7124', (58, 66))	('Tregs', 'Chemical', '-', (189, 194))	('IFNgamma', 'Gene', (45, 53))	('IFNgamma', 'Gene', '3458', (45, 53))
114598	31632393	In addition, temozolomide, a DNA alkylating agent, is only effective against tumors that have epigenetically silenced the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), which occurs in ~45% of all glioblastomas.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (215, 228))	('MGMT', 'Gene', '4255', (180, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (215, 227))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (140, 178))	('MGMT', 'Gene', (180, 184))	('glioblastomas', 'Disease', 'MESH:D005909', (215, 228))	('temozolomide', 'Chemical', 'MESH:C047246', (13, 25))	('glioblastomas', 'Disease', (215, 228))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('O6-methylguanine-DNA-methyltransferase', 'Gene', (140, 178))	('epigenetically silenced', 'Var', (94, 117))
114601	31632393	Genetically, astrocytomas tend to possess TP53 and ATRX mutations whereas oligodendrogliomas are characterized by mutations in the TERT promoter and co-deletion of the 1p and 19q chromosomal arms.	('TP53', 'Gene', '7157', (42, 46))	('mutations', 'Var', (56, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (13, 25))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (74, 92))	('mutations', 'Var', (114, 123))	('ATRX', 'Gene', (51, 55))	('TP53', 'Gene', (42, 46))	('oligodendrogliomas', 'Disease', (74, 92))	('astrocytomas', 'Disease', (13, 25))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('ATRX', 'Gene', '546', (51, 55))	('TERT', 'Gene', (131, 135))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('TERT', 'Gene', '7015', (131, 135))
114604	31632393	The salient genomic feature that largely distinguishes LGG from glioblastoma is the mutational status of the two genes encoding the isoforms of isocitrate dehydrogenase (IDH1/2); ~80% of LGG harbor IDH mutations, compared to only ~5% of glioblastomas.	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('IDH1/2', 'Gene', (170, 176))	('IDH', 'Gene', '3417', (170, 173))	('isocitrate', 'Chemical', 'MESH:D007523', (144, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('IDH', 'Gene', '3417', (198, 201))	('glioblastomas', 'Phenotype', 'HP:0012174', (237, 250))	('glioblastoma', 'Disease', (237, 249))	('LGG', 'Disease', (187, 190))	('IDH', 'Gene', (170, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (237, 249))	('glioblastomas', 'Disease', 'MESH:D005909', (237, 250))	('IDH', 'Gene', (198, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('IDH1/2', 'Gene', '3417;3418', (170, 176))	('glioblastomas', 'Disease', (237, 250))	('mutations', 'Var', (202, 211))
114605	31632393	Interestingly, IDH mutations are an independent prognostic factor in gliomas and are associated with increased survival in all types, including glioblastoma.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('increased', 'PosReg', (101, 110))	('mutations', 'Var', (19, 28))	('glioblastoma', 'Disease', (144, 156))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('IDH', 'Gene', (15, 18))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('IDH', 'Gene', '3417', (15, 18))
114606	31632393	The most common IDH alteration observed in gliomas is a missense mutation in IDH1 that replaces an arginine residue at position 132 with a histidine residue.	('arginine residue', 'MPA', (99, 115))	('missense mutation', 'Var', (56, 73))	('IDH', 'Gene', (16, 19))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('IDH', 'Gene', (77, 80))	('gliomas', 'Disease', (43, 50))	('IDH', 'Gene', '3417', (16, 19))	('IDH', 'Gene', '3417', (77, 80))	('arginine residue at position 132 with a histidine', 'Mutation', 'p.H132R', (99, 148))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
114607	31632393	While wild-type IDH converts isocitrate to alpha-ketoglutarate, the neomorphic enzyme generated by the R132H mutation no longer fulfills this function and instead uses alpha-ketoglutarate as a substrate to catalyze large amounts of the oncometabolite 2-hydroxyglutarate (2-HG), a hallmark feature of LGG.	('R132H', 'Var', (103, 108))	('2-HG', 'Chemical', 'MESH:C019417', (271, 275))	('R132H', 'Mutation', 'p.R132H', (103, 108))	('IDH', 'Gene', (16, 19))	('isocitrate', 'MPA', (29, 39))	('IDH', 'Gene', '3417', (16, 19))	('alpha-ketoglutarate', 'Chemical', 'MESH:C029743', (168, 187))	('alpha-ketoglutarate', 'Chemical', 'MESH:C029743', (43, 62))	('isocitrate', 'Chemical', 'MESH:D007523', (29, 39))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (251, 269))
114608	31632393	While it is understood how IDH1 mutations directly shape the phenotypic and epigenetic landscape of glioma cells through 2-HG by significantly altering the methylome of glioma cells and directly causing the glioma CpG island methylator phenotype (G-CIMP), a strong positive prognostic indicator in glioma and glioblastoma, it is relatively less clear how these alterations shape the surrounding TME.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma cells', 'Disease', (169, 181))	('glioma', 'Disease', (298, 304))	('glioma', 'Disease', 'MESH:D005910', (298, 304))	('glioma', 'Disease', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('mutations', 'Var', (32, 41))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma cells', 'Disease', 'MESH:D005910', (169, 181))	('glioma cells', 'Disease', (100, 112))	('causing', 'Reg', (195, 202))	('glioma', 'Phenotype', 'HP:0009733', (298, 304))	('glioma', 'Disease', (207, 213))	('methylome', 'MPA', (156, 165))	('2-HG', 'Chemical', 'MESH:C019417', (121, 125))	('glioblastoma', 'Disease', 'MESH:D005909', (309, 321))	('IDH1', 'Gene', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('altering', 'Reg', (143, 151))	('glioma cells', 'Disease', 'MESH:D005910', (100, 112))	('glioblastoma', 'Disease', (309, 321))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioblastoma', 'Phenotype', 'HP:0012174', (309, 321))
114609	31632393	Naturally, it is highly probable that the unique epigenetic landscape of IDHmut glioma cells alters the expression of key components of the signaling pathways which regulate tumor-microenvironment crosstalk.	('tumor', 'Disease', (174, 179))	('IDHmut glioma', 'Disease', 'MESH:D005910', (73, 86))	('epigenetic', 'Var', (49, 59))	('alters', 'Reg', (93, 99))	('glioma cells', 'Disease', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('expression', 'MPA', (104, 114))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('glioma cells', 'Disease', 'MESH:D005910', (80, 92))	('IDHmut glioma', 'Disease', (73, 86))
114613	31632393	This effect strongly impacted adaptive anti-tumor immunity, as combination therapy of a mutant IDH1 inhibitor (BAY1436032) with PD-1 inhibition significantly extended overall survival of glioma-bearing mice.	('impacted', 'Reg', (21, 29))	('BAY1436032', 'Var', (111, 121))	('mice', 'Species', '10090', (202, 206))	('glioma', 'Disease', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('IDH1', 'Gene', (95, 99))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('extended', 'PosReg', (158, 166))	('overall survival', 'CPA', (167, 183))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('BAY1436032', 'Chemical', 'MESH:C434003', (111, 121))	('combination', 'Interaction', (63, 74))	('tumor', 'Disease', (44, 49))
114614	31632393	Similarly, in RCAS/tva models of glioma, it has been shown that IDH1 mutations are associated with reduced neutrophil chemotaxis and anti-tumor immunity.	('mutations', 'Var', (69, 78))	('glioma', 'Disease', (33, 39))	('tumor', 'Disease', (138, 143))	('IDH1', 'Gene', (64, 68))	('neutrophil chemotaxis', 'CPA', (107, 128))	('neutrophil chemotaxis', 'Phenotype', 'HP:0040238', (107, 128))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('reduced', 'NegReg', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
114630	31632393	This indicates that the differences in ECM composition are partially regulated by IDH mutational status in gliomas.	('IDH', 'Gene', '3417', (82, 85))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('ECM composition', 'MPA', (39, 54))	('mutational status', 'Var', (86, 103))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('regulated', 'Reg', (69, 78))	('IDH', 'Gene', (82, 85))
114633	31632393	Originally, glioblastoma was divided into 4 molecular subtypes based on bulk gene expression data: proneural (PN) characterized by aberrations in platelet-derived growth factor A (PDGFRA), TP53, and increased phosphoinositide 3-kinase (PI3K) signaling; classical (CL) characterized by epidermal growth factor receptor (EGFR) gain and phosphatase and tensin homolog (PTEN) loss underscored by chromosome 7 amplification and chromosome 10 loss, respectively; mesenchymal (MES) characterized by neurofibromin 1 (NF-1) loss and/or mutation; and neural which did not possess any characteristic genomic features (Figure 1).	('EGFR', 'Gene', '1956', (319, 323))	('PDGFRA', 'Gene', (180, 186))	('TP53', 'Gene', (189, 193))	('PDGFRA', 'Gene', '5156', (180, 186))	('epidermal growth factor receptor', 'Gene', (285, 317))	('epidermal growth factor receptor', 'Gene', '1956', (285, 317))	('glioblastoma', 'Disease', (12, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('mutation', 'Var', (527, 535))	('phosphoinositide 3-kinase', 'Gene', '5293', (209, 234))	('TP53', 'Gene', '7157', (189, 193))	('EGFR', 'Gene', (319, 323))	('neurofibromin 1 (NF-1', 'Gene', '4763', (492, 513))	('loss', 'NegReg', (437, 441))	('phosphoinositide 3-kinase', 'Gene', (209, 234))	('PTEN', 'Gene', (366, 370))	('gain', 'PosReg', (325, 329))	('loss', 'NegReg', (515, 519))	('loss', 'NegReg', (372, 376))	('PTEN', 'Gene', '5728', (366, 370))	('glioblastoma', 'Disease', 'MESH:D005909', (12, 24))
114637	31632393	Consequently, IDH mutations in glioblastoma are considered a hallmark of the PN signature.	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('mutations', 'Var', (18, 27))
114663	31632393	In addition, PD-1 positive lymphocytes are enriched in MES tumors possessing NF1 and RB1 mutations, and depleted in CL tumors that possess EGFR amplification events and PTEN deletions.	('MES', 'Disease', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('NF1', 'Gene', (77, 80))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('PTEN', 'Gene', (169, 173))	('NF1', 'Gene', '4763', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('PTEN', 'Gene', '5728', (169, 173))	('EGFR', 'Gene', '1956', (139, 143))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (89, 98))	('EGFR', 'Gene', (139, 143))	('RB1', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RB1', 'Gene', '5925', (85, 88))
114667	31632393	For example, NF-1 deficiency in IDH-wild type glioma cells results in increased recruitment of macrophages.	('NF-1', 'Gene', (13, 17))	('increased', 'PosReg', (70, 79))	('glioma cells', 'Disease', (46, 58))	('recruitment of macrophages', 'MPA', (80, 106))	('NF-1', 'Gene', '4763', (13, 17))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('deficiency', 'Var', (18, 28))	('glioma cells', 'Disease', 'MESH:D005910', (46, 58))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
114681	31632393	Interestingly, studies have proposed differences in vascular features and/or angiogenic factors according to IDH mutational status.	('differences', 'Reg', (37, 48))	('IDH', 'Gene', (109, 112))	('angiogenic factors', 'CPA', (77, 95))	('mutational status', 'Var', (113, 130))	('vascular features', 'CPA', (52, 69))	('IDH', 'Gene', '3417', (109, 112))
114682	31632393	For example, in highly vascularized glioblastoma, it has been shown that IDH1 mutations are associated with lower expression of VEGF and improved overall survival.	('VEGF', 'Gene', (128, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('overall survival', 'CPA', (146, 162))	('mutations', 'Var', (78, 87))	('VEGF', 'Gene', '7422', (128, 132))	('lower', 'NegReg', (108, 113))	('expression', 'MPA', (114, 124))	('IDH1', 'Gene', (73, 77))	('improved', 'PosReg', (137, 145))	('glioblastoma', 'Disease', (36, 48))
114684	31632393	Finally, 2-HG levels have been associated with reduced healthy brain vasculature and increased vascular hyperplasia.	('healthy brain vasculature', 'CPA', (55, 80))	('2-HG levels', 'Var', (9, 20))	('increased', 'PosReg', (85, 94))	('vascular hyperplasia', 'Disease', (95, 115))	('2-HG', 'Chemical', 'MESH:C019417', (9, 13))	('vascular hyperplasia', 'Disease', 'MESH:D006965', (95, 115))	('reduced', 'NegReg', (47, 54))
114733	31632393	To date, it is only known that the histone methyltransferase MLL1 is induced by hypoxia in glioblastoma cells and that loss of MLL1 reduces the expression of HIF transcripts and HIF targets.	('MLL1', 'Gene', '4297', (127, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('MLL1', 'Gene', '4297', (61, 65))	('expression', 'MPA', (144, 154))	('hypoxia', 'Disease', 'MESH:D000860', (80, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('reduces', 'NegReg', (132, 139))	('MLL1', 'Gene', (127, 131))	('MLL1', 'Gene', (61, 65))	('glioblastoma', 'Disease', (91, 103))	('loss', 'Var', (119, 123))	('hypoxia', 'Disease', (80, 87))
114759	31632393	Activated plasmin releases membrane-bound FasL, which then acts as a paracrine death signal on cancer cells, and cleaves L1CAM, an important receptor for vascular co-option, and thus cancer cell survival.	('L1CAM', 'Gene', (121, 126))	('cleaves', 'Var', (113, 120))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('plasmin', 'Gene', '5340', (10, 17))	('FasL', 'Gene', (42, 46))	('cancer', 'Disease', (95, 101))	('L1CAM', 'Gene', '3897', (121, 126))	('FasL', 'Gene', '356', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('plasmin', 'Gene', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
114770	31632393	One proposed mechanism by which astrocytes modulate the molecular landscape of brain metastases is through the delivery of micro-RNAs packaged in extracellular vesicles.	('micro-RNAs', 'Var', (123, 133))	('brain metastases', 'Disease', (79, 95))	('brain metastases', 'Disease', 'MESH:D009362', (79, 95))	('modulate', 'Reg', (43, 51))
114774	31632393	The CL molecular subtype of glioblastoma is strongly associated with an astrocytic signature, and amplified or hyperactive EGFR is a hallmark feature of glioblastoma cells with an astrocyte-like signature.	('EGFR', 'Gene', (123, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('astrocytic signature', 'MPA', (72, 92))	('glioblastoma', 'Disease', (28, 40))	('amplified', 'Var', (98, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('associated', 'Reg', (53, 63))	('hyperactive', 'Disease', (111, 122))	('EGFR', 'Gene', '1956', (123, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('hyperactive', 'Disease', 'MESH:D006948', (111, 122))	('glioblastoma', 'Disease', (153, 165))
114781	31632393	ALK-translocation or amplification is a major driver of some lung cancers as well as neuroblastomas.	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('neuroblastomas', 'Phenotype', 'HP:0003006', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancers', 'Disease', 'MESH:D008175', (61, 73))	('lung cancers', 'Phenotype', 'HP:0100526', (61, 73))	('neuroblastomas', 'Disease', 'MESH:D009447', (85, 99))	('neuroblastoma', 'Phenotype', 'HP:0003006', (85, 98))	('ALK', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('amplification', 'Var', (21, 34))	('lung cancers', 'Disease', (61, 73))	('neuroblastomas', 'Disease', (85, 99))	('ALK', 'Gene', '238', (0, 3))
114782	31632393	Finally, classical (CL) glioblastoma, characterized by high-level EGFR amplification events, not only shares a common oncogenic alteration with Her2+ breast cancer brain metastases, but also with EGFR-amplified lung cancer brain metastases.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('Her2', 'Gene', (144, 148))	('classical', 'Disease', (9, 18))	('EGFR', 'Gene', '1956', (196, 200))	('brain metastases', 'Disease', 'MESH:D009362', (223, 239))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('brain metastases', 'Disease', (223, 239))	('EGFR', 'Gene', (66, 70))	('breast cancer', 'Disease', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('lung cancer', 'Disease', (211, 222))	('amplification events', 'Var', (71, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (24, 36))	('EGFR', 'Gene', (196, 200))	('brain metastases', 'Disease', 'MESH:D009362', (164, 180))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('brain metastases', 'Disease', (164, 180))	('EGFR', 'Gene', '1956', (66, 70))	('glioblastoma', 'Disease', (24, 36))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (24, 36))	('Her2', 'Gene', '2064', (144, 148))
114788	31632393	For example, they found that mutations in STK11 and VHL are associated with a reduced macrophage signature, that loss of p53 is associated with a decrease in cytotoxic lymphocytes, and that mutations in BRAF are associated with an increase in co-stimulatory molecules across all cancer types.	('p53', 'Gene', '7157', (121, 124))	('VHL', 'Disease', (52, 55))	('cancer', 'Disease', (279, 285))	('co-stimulatory molecules', 'MPA', (243, 267))	('p53', 'Gene', (121, 124))	('mutations', 'Var', (190, 199))	('STK11', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cytotoxic lymphocytes', 'CPA', (158, 179))	('decrease', 'NegReg', (146, 154))	('mutations', 'Var', (29, 38))	('BRAF', 'Gene', '673', (203, 207))	('loss', 'Var', (113, 117))	('VHL', 'Disease', 'MESH:D006623', (52, 55))	('STK11', 'Gene', '6794', (42, 47))	('reduced', 'NegReg', (78, 85))	('BRAF', 'Gene', (203, 207))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('increase', 'PosReg', (231, 239))
114798	31632393	Further, responsive tumors were enriched in MAPK pathway alterations whereas unresponsive tumors were enriched in loss-of-function PTEN mutations and concomitantly increased PI3K-Akt signaling.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('PTEN', 'Gene', (131, 135))	('PTEN', 'Gene', '5728', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('alterations', 'Var', (57, 68))	('tumors', 'Disease', (90, 96))	('loss-of-function', 'NegReg', (114, 130))	('MAPK pathway', 'Pathway', (44, 56))	('mutations', 'Var', (136, 145))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('PI3K-Akt signaling', 'Pathway', (174, 192))	('increased', 'PosReg', (164, 173))
114810	31632393	For example, leveraging the high prevalence of macrophages in glioblastoma, macrophage reprogramming through blockade of CSF-1R has been highly effective in pre-clinical models.	('blockade', 'Var', (109, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('glioblastoma', 'Disease', (62, 74))	('CSF-1R', 'Gene', '1436', (121, 127))	('CSF-1R', 'Gene', (121, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('macrophage reprogramming', 'CPA', (76, 100))
114824	30667110	This system distinguishes different subtypes of low- and of high-grade glioma based on mutations in isocitrate dehydrogenase 1 (IDH1), and codeletion of the short arm of chromosome 1 and the long arm of chromosome 19 (1q/19p) (Sanson et al., 2009).	('IDH1', 'Gene', '3417', (128, 132))	('isocitrate dehydrogenase 1', 'Gene', (100, 126))	('glioma', 'Disease', (71, 77))	('short arm', 'Phenotype', 'HP:0009824', (157, 166))	('low-', 'Disease', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('mutations', 'Var', (87, 96))	('IDH1', 'Gene', (128, 132))	('isocitrate dehydrogenase 1', 'Gene', '3417', (100, 126))
114831	30667110	Therefore, in clinical as well as fundamental experimental settings, high GFAP expression is believed to mark more differentiated, less malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('GFAP', 'Gene', (74, 78))	('malignant tumors', 'Disease', (136, 152))	('malignant tumors', 'Disease', 'MESH:D018198', (136, 152))	('GFAP', 'Gene', '2670', (74, 78))	('high', 'Var', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))
114857	30667110	These lower molecular weight GFAP fragments have been detected in brain extracts of Alexander disease patients, a rare nervous system disorder caused by GFAP mutations (M.-H. Chen, Hagemann, Quinlan, Messing, & Perng, 2013; Lin, Messing, & Perng, 2017).	('GFAP', 'Gene', (153, 157))	('caused', 'Reg', (143, 149))	('nervous system disorder', 'Disease', (119, 142))	('GFAP', 'Gene', (29, 33))	('Alexander disease', 'Disease', 'MESH:D038261', (84, 101))	('nervous system disorder', 'Phenotype', 'HP:0000707', (119, 142))	('patients', 'Species', '9606', (102, 110))	('GFAP', 'Gene', '2670', (29, 33))	('nervous system disorder', 'Disease', 'MESH:D009421', (119, 142))	('GFAP', 'Gene', '2670', (153, 157))	('mutations', 'Var', (158, 167))	('Alexander disease', 'Disease', (84, 101))
114864	30667110	(1978) describe GFAP immunoreactivity in all grade I and II astrocytomas, the presence of GFAP negative areas in grade III, and show that four out of 17 grade IV astrocytomas are GFAP negative.	('II astrocytomas', 'Disease', (57, 72))	('astrocytomas', 'Disease', (60, 72))	('astrocytomas', 'Disease', 'MESH:D001254', (60, 72))	('GFAP', 'Gene', (16, 20))	('GFAP', 'Gene', '2670', (90, 94))	('immunoreactivity', 'Var', (21, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('GFAP', 'Gene', (179, 183))	('IV astrocytoma', 'Disease', 'MESH:D005909', (159, 173))	('GFAP', 'Gene', '2670', (179, 183))	('astrocytomas', 'Disease', 'MESH:D001254', (162, 174))	('astrocytoma', 'Phenotype', 'HP:0009592', (162, 173))	('GFAP', 'Gene', '2670', (16, 20))	('astrocytomas', 'Disease', (162, 174))	('II astrocytomas', 'Disease', 'MESH:D001254', (57, 72))	('GFAP', 'Gene', (90, 94))	('IV astrocytoma', 'Disease', (159, 173))
114879	30667110	However, patients with the grade IV subtype that correlates with high GFAP expression as identified by Motomura et al.	('patients', 'Species', '9606', (9, 17))	('GFAP', 'Gene', '2670', (70, 74))	('high', 'Var', (65, 69))	('GFAP', 'Gene', (70, 74))
114909	30667110	Although most studies report to be able to discriminate between these two cell types, and distinctions in the morphology of reactive and neoplastic astrocytes have been clearly described (Yoshii et al., 1992), quantification of process-rich GFAP positive areas might lead to an overestimation of GFAP levels in neoplastic cells.	('neoplastic astrocytes', 'Phenotype', 'HP:0009592', (137, 158))	('GFAP', 'Gene', '2670', (296, 300))	('lead to', 'Reg', (267, 274))	('quantification', 'Var', (210, 224))	('GFAP', 'Gene', '2670', (241, 245))	('overestimation', 'MPA', (278, 292))	('GFAP', 'Gene', (296, 300))	('GFAP', 'Gene', (241, 245))
114942	30667110	We recently showed that quantification of the relative level of GFAPdelta to GFAPalpha, the GFAPdelta/GFAPalpha ratio, using RNA sequencing data obtained from the cancer genome atlas (TCGA) indeed indicates that low- and high-grade astrocytoma express different combinations of GFAP variants.	('low-', 'Disease', (212, 216))	('GFAP', 'Gene', '2670', (278, 282))	('GFAP', 'Gene', (77, 81))	('GFAP', 'Gene', (64, 68))	('GFAP', 'Gene', (92, 96))	('GFAP', 'Gene', (102, 106))	('astrocytoma', 'Disease', 'MESH:D001254', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('GFAP', 'Gene', '2670', (102, 106))	('GFAP', 'Gene', '2670', (92, 96))	('astrocytoma', 'Disease', (232, 243))	('GFAP', 'Gene', '2670', (64, 68))	('GFAP', 'Gene', '2670', (77, 81))	('astrocytoma', 'Phenotype', 'HP:0009592', (232, 243))	('cancer genome atlas', 'Disease', 'MESH:D009369', (163, 182))	('variants', 'Var', (283, 291))	('GFAP', 'Gene', (278, 282))	('cancer genome atlas', 'Disease', (163, 182))
114964	30667110	Interestingly, one study has isolated GFAP expressing cells from blood of grade IV astrocytoma patients and showed that they contain astrocytoma specific mutations, indicating that GFAP positive glioma cells can leave the tumor and enter the bloodstream (Muller et al., 2014).	('GFAP', 'Gene', '2670', (38, 42))	('IV astrocytoma', 'Disease', 'MESH:D005909', (80, 94))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('astrocytoma', 'Disease', 'MESH:D001254', (133, 144))	('astrocytoma', 'Disease', (133, 144))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('IV astrocytoma', 'Disease', (80, 94))	('astrocytoma', 'Disease', 'MESH:D001254', (83, 94))	('astrocytoma', 'Disease', (83, 94))	('tumor', 'Disease', (222, 227))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('patients', 'Species', '9606', (95, 103))	('GFAP', 'Gene', (181, 185))	('GFAP', 'Gene', (38, 42))	('glioma', 'Disease', (195, 201))	('mutations', 'Var', (154, 163))	('glioma', 'Disease', 'MESH:D005910', (195, 201))	('GFAP', 'Gene', '2670', (181, 185))
114969	30667110	However, in current literature, a significant correlation is not consistently reproduced mainly caused by intra- and inter-tumor heterogeneity of GFAP positive cell localization, morphology, function, and expression of GFAP variants.	('GFAP', 'Gene', '2670', (219, 223))	('tumor', 'Disease', (123, 128))	('variants', 'Var', (224, 232))	('GFAP', 'Gene', '2670', (146, 150))	('GFAP', 'Gene', (219, 223))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('GFAP', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
114970	30667110	Different types of evidence support the presence of a specialized GFAP intermediate filament network composed of different GFAP variants (splice isoforms, posttranslational modifications, degradation products) in astrocytoma cell subpopulations.	('astrocytoma', 'Disease', (213, 224))	('GFAP', 'Gene', '2670', (66, 70))	('astrocytoma', 'Phenotype', 'HP:0009592', (213, 224))	('GFAP', 'Gene', (123, 127))	('GFAP', 'Gene', '2670', (123, 127))	('variants', 'Var', (128, 136))	('GFAP', 'Gene', (66, 70))	('astrocytoma', 'Disease', 'MESH:D001254', (213, 224))
114971	30667110	As these variants, as shown for GFAPdelta, differentially correlate to the malignancy of the tumor, the current use of commercial GFAP antibodies that recognize all isoforms most likely masks a consistent correlation of GFAP to astrocytoma malignancy grade.	('malignancy of the tumor', 'Disease', (75, 98))	('malignancy of the tumor', 'Disease', 'MESH:D018198', (75, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('masks', 'NegReg', (186, 191))	('GFAP', 'Gene', (130, 134))	('astrocytoma malignancy', 'Disease', 'MESH:D020339', (228, 250))	('GFAP', 'Gene', (220, 224))	('GFAP', 'Gene', '2670', (32, 36))	('GFAP', 'Gene', '2670', (220, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (228, 239))	('correlate', 'Reg', (58, 67))	('GFAP', 'Gene', '2670', (130, 134))	('variants', 'Var', (9, 17))	('astrocytoma malignancy', 'Disease', (228, 250))	('GFAP', 'Gene', (32, 36))
114972	30667110	Discrimination between GFAP variants, as we show here for GFAPdelta and GFAPalpha, helps to identify different types of GFAP positive cells that could improve the assessment of astrocytoma differentiation and malignancy.	('malignancy', 'Disease', (209, 219))	('GFAP', 'Gene', '2670', (58, 62))	('GFAP', 'Gene', (120, 124))	('variants', 'Var', (28, 36))	('GFAP', 'Gene', (23, 27))	('GFAP', 'Gene', '2670', (72, 76))	('astrocytoma', 'Disease', 'MESH:D001254', (177, 188))	('improve', 'PosReg', (151, 158))	('GFAP', 'Gene', (58, 62))	('astrocytoma', 'Disease', (177, 188))	('GFAP', 'Gene', '2670', (23, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (177, 188))	('GFAP', 'Gene', '2670', (120, 124))	('GFAP', 'Gene', (72, 76))	('malignancy', 'Disease', 'MESH:D009369', (209, 219))
114979	30667110	Therefore, future studies need to focus on further identifying the GFAP positive cell population and make use of the possibility to discriminate between GFAP variants that could be fruitful to diagnosis and to the understanding of the molecular basis of glioma.	('GFAP', 'Gene', (153, 157))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('variants', 'Var', (158, 166))	('GFAP', 'Gene', (67, 71))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('GFAP', 'Gene', '2670', (67, 71))	('GFAP', 'Gene', '2670', (153, 157))	('glioma', 'Disease', (254, 260))
114980	30102398	FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs).	('CRs', 'Chemical', '-', (193, 196))	('cancer hallmark', 'Disease', (140, 155))	('cancer hallmark', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Epigenetic alterations', 'Var', (98, 120))
114981	30102398	However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers.	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('CR', 'Chemical', '-', (45, 47))	('cancer', 'Disease', (64, 70))	('deregulation', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
114992	30102398	DNA methylators and histone modifiers can code and decode various modifications on cytosine and histone residues and are usually further divided into readers, writers, and erasers.	('modifications', 'Var', (66, 79))	('cytosine', 'MPA', (83, 91))	('cytosine', 'Chemical', 'MESH:D003596', (83, 91))	('histone', 'Protein', (96, 103))
114995	30102398	Chromatin remodelers are a special type of CRs that can disrupt the contact between nucleosomes and DNA, shuffle nucleosomes around, replace them or remove them from the chromatin, and cause abnormal epigenetic modifications.	('contact', 'Interaction', (68, 75))	('epigenetic modifications', 'MPA', (200, 224))	('cause', 'Reg', (185, 190))	('replace', 'Reg', (133, 140))	('disrupt', 'NegReg', (56, 63))	('CRs', 'Chemical', '-', (43, 46))	('shuffle', 'Var', (105, 112))	('remove', 'NegReg', (149, 155))
114996	30102398	The alteration of epigenetic marks is a prevalent feature in cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('epigenetic marks', 'Var', (18, 34))
114998	30102398	For example, it is widely accepted that mutations can perturb CR functions.	('CR functions', 'CPA', (62, 74))	('mutations', 'Var', (40, 49))	('perturb', 'NegReg', (54, 61))	('CR', 'Chemical', '-', (62, 64))
114999	30102398	have found that genetic alteration of DNMT3A (a DNA methylation transferase) can induce genome-wide alterations of DNA methylation and gene expression.	('genetic alteration', 'Var', (16, 34))	('gene expression', 'MPA', (135, 150))	('alterations', 'Reg', (100, 111))	('DNMT3A', 'Gene', (38, 44))	('DNMT3A', 'Gene', '1788', (38, 44))	('DNA methylation', 'MPA', (115, 130))
115000	30102398	Moreover, patients with DNMT3A mutations have poor prognosis compared with those without such mutations.	('DNMT3A', 'Gene', (24, 30))	('DNMT3A', 'Gene', '1788', (24, 30))	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (10, 18))
115003	30102398	They found that dysregulation of these CRs results in structural abnormalities in chromatins and epigenetic alterations of numerous cancer-associated genes, which finally lead to increased tumor volume, extracapsular extension, and metastases in prostate cancer patients.	('numerous cancer', 'Disease', 'MESH:D009369', (123, 138))	('structural abnormalities', 'Disease', (54, 78))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('increased', 'PosReg', (179, 188))	('structural abnormalities', 'Disease', 'MESH:C566527', (54, 78))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('metastases in prostate cancer', 'Disease', 'MESH:D009362', (232, 261))	('chromatins', 'Protein', (82, 92))	('metastases in prostate cancer', 'Disease', (232, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('numerous cancer', 'Disease', (123, 138))	('epigenetic alterations', 'Var', (97, 119))	('extracapsular extension', 'CPA', (203, 226))	('dysregulation', 'Var', (16, 29))	('tumor', 'Disease', (189, 194))	('CRs', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('patients', 'Species', '9606', (262, 270))
115034	30102398	To evaluate the global regulatory effect of a given CR on the DNA hypermethylation (or hypomethylation) in a specific cancer type, we computed the significance of Pearson correlation (P value) between CR expression and aberrant hypermethylation (or hypomethylation) of tumor samples.	('CR', 'Chemical', '-', (52, 54))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('aberrant', 'Var', (219, 227))	('tumor', 'Disease', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CR', 'Chemical', '-', (201, 203))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
115110	30102398	Mutation frequency and centrality in PPIN were found to be the top two recurrent features (Figure 2I), which were involved in 25 and 29 cancer types, respectively.	('Mutation frequency', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('PPIN', 'Gene', (37, 41))	('cancer', 'Disease', (136, 142))	('involved', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
115121	30102398	Moreover, we found that DNA methylation readers and histone modification writers were the most common functional CRs across all 33 cancer types (Figure 3A).	('cancer', 'Disease', (131, 137))	('DNA methylation readers', 'Var', (24, 47))	('histone modification writers', 'Var', (52, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CRs', 'Chemical', '-', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
115124	30102398	Moreover, histone modification readers and writers as well as chromatin remodelers played important roles across cancer types compared with DNA methylation erasers and histone modification erasers (Figure 3B, bottom).	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('histone', 'Var', (10, 17))	('cancer', 'Disease', (113, 119))	('played', 'Reg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
115130	30102398	Functional enrichment analysis showed that DNA methylators, histone modifiers and chromatin remodelers were all enriched in at least one cancer hallmark, especially in the hallmark 'genome instability and mutation', highlighting the extent of genome alternations in cancer (Supplementary Figure S8 and Supplementary Table S5).	("mutation'", 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('Supplementary Figure S8', 'Disease', (274, 297))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer hallmark', 'Disease', (137, 152))	('cancer', 'Disease', (137, 143))	('cancer hallmark', 'Disease', 'MESH:D009369', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Supplementary Figure S8', 'Disease', 'MESH:D017034', (274, 297))
115132	30102398	Functional histone modifiers in almost all cancer types were enriched in the functions 'evading apoptosis', 'genome instability and mutation', 'insensitivity to antigrowth signals', and 'self-sufficiency in growth signals'.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	("'evading", 'Disease', (87, 95))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (192, 213))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	("mutation'", 'Var', (132, 141))
115144	30102398	For example, we found that PHF19, a writer for H3K36me3 as a component of polycomb repressive complex 2 (PRC2), was prioritized as a breast invasive carcinoma (BRCA) related CR in our analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('H3K36me3', 'Var', (47, 55))	('PHF19', 'Gene', '26147', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (160, 164))	('PHF19', 'Gene', (27, 32))	('BRCA', 'Gene', '672', (160, 164))	('BRCA', 'Gene', (160, 164))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (133, 158))	('CR', 'Chemical', '-', (174, 176))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (133, 158))	('breast invasive carcinoma', 'Disease', (133, 158))
115147	30102398	Moreover, the genome-wide H3K36me3 marks showed an obvious increase in cancer.	('H3K36me3 marks', 'Var', (26, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('increase', 'PosReg', (59, 67))
115162	30102398	Among these CRs, 14 were up-regulated in cancer, and 1 was down-regulated (Supplementary Figure S11A).	('up-regulated', 'PosReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CRs', 'Chemical', '-', (12, 15))	('S11A', 'Var', (96, 100))	('down-regulated', 'NegReg', (59, 73))	('S11A', 'SUBSTITUTION', 'None', (96, 100))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
115163	30102398	Interestingly, 11 of these 15 CRs showed consistent deregulation across cancer types compared with the corresponding adjacent normal samples (Supplementary Figure S11B).	('deregulation', 'MPA', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CRs', 'Chemical', '-', (30, 33))	('S11B', 'Var', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('S11B', 'SUBSTITUTION', 'None', (163, 167))	('cancer', 'Disease', (72, 78))
115170	30102398	For cancer-specific CRs, we found that these CRs included 36% of the DNA methylation erasers and 35% of the histone modification erasers.	('CRs', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('histone modification', 'MPA', (108, 128))	('methylation', 'Var', (73, 84))	('DNA', 'MPA', (69, 72))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('CRs', 'Chemical', '-', (45, 48))
115178	30102398	KMT2C showed a higher mutation frequency in KIRP patients, whereas the aberrant regulation of miRNAs and its regulation of DNA methylation over open sea regions were additional features in KICH patients.	('mutation', 'Var', (22, 30))	('KICH', 'Disease', (189, 193))	('patients', 'Species', '9606', (194, 202))	('DNA methylation', 'MPA', (123, 138))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('KICH', 'Disease', 'None', (189, 193))	('patients', 'Species', '9606', (49, 57))
115184	30102398	We found that common CRs in cancer had higher values for all seven features compared with specific CRs, especially in four functional features (all P < 0.05, Wilcoxon rank-sum test), including mutation frequency, differential expression, degree in PPIN, and regulation of genome hypermethylation (Figure 5C, top, and Supplementary Table S8).	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation frequency', 'Var', (193, 211))	('CRs', 'Chemical', '-', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRs', 'Chemical', '-', (21, 24))	('PPIN', 'Protein', (248, 252))	('cancer', 'Disease', (28, 34))	('differential expression', 'MPA', (213, 236))
115210	30102398	Patients in subtype 1 of ACC showed the highest mutation frequency of TP53 and CGI methylation, while patients in subtype 3 showed high mutation of KDM6B and the lowest open sea methylation.	('TP53', 'Gene', '7157', (70, 74))	('patients', 'Species', '9606', (102, 110))	('KDM6B', 'Gene', '23135', (148, 153))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (70, 74))	('mutation', 'Var', (48, 56))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('KDM6B', 'Gene', (148, 153))	('methylation', 'Var', (83, 94))	('CGI', 'Protein', (79, 82))
115235	30102398	Analysis of the functional features revealed recurrent multi-omics effects of functional CRs across 33 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('effects', 'Reg', (67, 74))	('CRs', 'Chemical', '-', (89, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('functional', 'Var', (78, 88))
115240	30102398	By comparison between common, specific and mixed CRs as well as DNA methylators, histone modifiers and chromatin remodelers, we found that DNA methylation readers as well as histone modification readers and writers were with more common CRs, suggesting that these three categories of CRs tend to be aberrant across cancer types.	('methylation', 'Var', (143, 154))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Disease', (315, 321))	('CRs', 'Chemical', '-', (284, 287))	('DNA', 'Var', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('CRs', 'Chemical', '-', (237, 240))	('CRs', 'Chemical', '-', (49, 52))
115241	30102398	We also found that DNA methylation erasers and histone modification erasers tend to be dysregulated in specific cancer type.	('DNA', 'MPA', (19, 22))	('histone modification', 'MPA', (47, 67))	('methylation', 'Var', (23, 34))	('erasers', 'NegReg', (68, 75))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
115247	30102398	Moreover, we found that DNA methylators and histone modifiers can induce the development of cancer by regulation of DNA methylation and histone modifications, such as DNMT1, DNMT3A and PHF19.	('PHF19', 'Gene', '26147', (185, 190))	('histone', 'Protein', (136, 143))	('cancer', 'Disease', (92, 98))	('development of', 'CPA', (77, 91))	('PHF19', 'Gene', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('DNMT3A', 'Gene', (174, 180))	('DNMT3A', 'Gene', '1788', (174, 180))	('DNMT1', 'Gene', (167, 172))	('induce', 'PosReg', (66, 72))	('DNA', 'MPA', (116, 119))	('DNMT1', 'Gene', '1786', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('modifications', 'Var', (144, 157))
115310	33063446	The recurrent score significantly increased in 1p/19q non-codeletion tumors in the validation database (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('1p/19q non-codeletion', 'Var', (47, 68))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('increased', 'PosReg', (34, 43))
115340	31554817	Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome.	('ALK', 'Gene', (15, 18))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('Alterations', 'Var', (0, 11))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('tumors', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('children', 'Species', '9606', (151, 159))	('gliomas', 'Disease', (72, 79))	('Infant', 'Species', '9606', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('gliomas', 'Disease', (87, 94))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('ALK', 'Gene', '238', (15, 18))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))
115343	31554817	Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively.	('gliomas harbor RAS', 'Disease', (15, 33))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('mutations', 'Var', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('gliomas harbor RAS', 'Disease', 'MESH:D005910', (15, 33))
115366	31554817	RAS/MAPK activating alterations were the most common events (56/118, 47.5%) and primarily consisted of KIAA1549-BRAF fusions (28/118, 23.7%) and BRAFV600E mutations (21/118, 17.8%) (Fig.	('alte', 'Gene', '9189', (20, 24))	('RAS/MAPK', 'Gene', (0, 8))	('BRAFV600E mutations', 'Var', (145, 164))	('BRAFV600E', 'Mutation', 'rs113488022', (145, 154))	('alte', 'Gene', (20, 24))	('KIAA1549-BRAF', 'Var', (103, 116))
115367	31554817	Additional RAS/MAPK pathway alterations, such as FGFR1 fusions (FGFR1-TACC1, n = 3), FGFR1-tyrosine kinase duplications ((TKD), n = 2), RAF1 fusion (PML-RAF1, n = 1), and MYBL1 gain (n = 1) were also observed.	('PML', 'Gene', (149, 152))	('tyrosine kinase', 'Gene', (91, 106))	('RAS/MAPK pathway', 'Pathway', (11, 27))	('alte', 'Gene', '9189', (28, 32))	('TACC1', 'Gene', '6867', (70, 75))	('MYBL1', 'Gene', (171, 176))	('RAF1', 'Gene', (136, 140))	('fusion', 'Var', (141, 147))	('(PML', 'Gene', '5371', (148, 152))	('gain', 'PosReg', (177, 181))	('duplications', 'Var', (107, 119))	('FGFR1', 'Gene', (49, 54))	('tyrosine kinase', 'Gene', '7294', (91, 106))	('TACC1', 'Gene', (70, 75))	('alte', 'Gene', (28, 32))	('fusions', 'Var', (55, 62))
115375	31554817	Truncation of the extracellular ligand-binding domain with retention of the intracellular tyrosine kinase domain in the RTK-fusions identified suggests these are activating events (Fig.	('Truncation', 'Var', (0, 10))	('tyrosine kinase', 'Gene', '7294', (90, 105))	('tyrosine kinase', 'Gene', (90, 105))
115394	31554817	Group 3 tumors consisted primarily of optic pathway hypothalamic glioma (OPHG) (31/39, 79.5%) and RAS/MAPK-activation was almost exclusively due to BRAF alterations (Fig.	('alte', 'Gene', (153, 157))	('hypothalamic glioma', 'Disease', 'MESH:D005910', (52, 71))	('hypothalamic glioma', 'Phenotype', 'HP:0025037', (52, 71))	('alte', 'Gene', '9189', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('BRAF', 'Var', (148, 152))	('hypothalamic glioma', 'Disease', (52, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
115395	31554817	Importantly, despite half of all OPHGs in this study being driven by BRAFV600E, no non-OPHG group 3 tumors harbored this mutation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BRAFV600E', 'Var', (69, 78))	('BRAFV600E', 'Mutation', 'rs113488022', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors harbor', 'Disease', 'MESH:C537062', (100, 113))	('tumors harbor', 'Disease', (100, 113))
115404	31554817	Group 1 tumors are enriched for ALK/ROS1/NTRK/MET fusions, alterations analogous to those detected in adult carcinomas such as non-small cell lung cancer and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (8, 14))	('alte', 'Gene', '9189', (59, 63))	('carcinomas', 'Disease', (108, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (127, 153))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('colorectal cancer', 'Disease', (158, 175))	('fusions', 'Var', (50, 57))	('ALK', 'Gene', '238', (32, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('non-small cell lung cancer', 'Disease', (127, 153))	('ALK', 'Gene', (32, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('carcinomas', 'Disease', 'MESH:D002277', (108, 118))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('alte', 'Gene', (59, 63))
115407	31554817	With the exception of NTRK fusions, which were previously shown to be enriched in non-brainstem infant HGG, these alterations have been rarely reported in gliomas and this study provides a comprehensive explanation for the isolated case reports of ALK and ROS1 fusions in pediatric glial tumors.	('ROS1', 'Gene', (256, 260))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('alte', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('ALK', 'Gene', '238', (248, 251))	('infant', 'Species', '9606', (96, 102))	('non-brainstem infant HGG', 'Disease', (82, 106))	('fusions', 'Var', (261, 268))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('alte', 'Gene', '9189', (114, 118))	('glial tumors', 'Disease', 'MESH:D004194', (282, 294))	('glial tumors', 'Disease', (282, 294))	('ALK', 'Gene', (248, 251))	('gliomas', 'Disease', (155, 162))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
115426	31554817	Given the multiple progressions typically observed with conventional chemotherapy and the encouraging results of targeted BRAF/MEK inhibitors in pLGG, these patients should be prioritized for targeted therapies early after initial diagnosis.	('patients', 'Species', '9606', (157, 165))	('pLGG', 'Disease', (145, 149))	('inhibitors', 'Var', (131, 141))	('BRAF/MEK', 'Gene', (122, 130))
115516	29117388	Schwannian cell lineage markers S100/Sox10: often lost in malignant transformation; CD34 fibroblastic framework: often lost in high-grade MPNST; Ki67 greater than 10%: suggests malignancy; p16/CDKN2A loss: a step in transition from plexiform neurofibroma to MPNST, occasionally observed in histologically defined neurofibroma; H3K27me3: variably observed loss in MPNST; TP53: extensive positivity suggests high-grade MPNST.	('neurofibroma', 'Disease', (242, 254))	('Ki67', 'Chemical', '-', (145, 149))	('Sox10', 'Gene', '6663', (37, 42))	('TP53', 'Gene', (370, 374))	('neurofibroma', 'Disease', (313, 325))	('CD34', 'Gene', '947', (84, 88))	('CDKN2A', 'Gene', (193, 199))	('S100', 'Gene', (32, 36))	('S100', 'Gene', '6271', (32, 36))	('neurofibroma', 'Disease', 'MESH:D009455', (242, 254))	('CDKN2A', 'Gene', '1029', (193, 199))	('neurofibroma', 'Phenotype', 'HP:0001067', (242, 254))	('malignancy', 'Disease', 'MESH:D009369', (177, 187))	('TP53', 'Gene', '7157', (370, 374))	('neurofibroma', 'Phenotype', 'HP:0001067', (313, 325))	('CD34', 'Gene', (84, 88))	('neurofibroma', 'Disease', 'MESH:D009455', (313, 325))	('Sox10', 'Gene', (37, 42))	('p16', 'Gene', (189, 192))	('plexiform neurofibroma', 'Phenotype', 'HP:0009732', (232, 254))	('malignancy', 'Disease', (177, 187))	('H3K27me3', 'Var', (327, 335))	('p16', 'Gene', '1029', (189, 192))
115537	29117388	Zebrafish Nf1 mutants develop fish MPNST when crossed to other mutations and may be useful for preclinical drug screening.	('fish MPNST', 'MPA', (30, 40))	('mutants', 'Var', (14, 21))	('Nf1', 'Gene', (10, 13))	('develop', 'PosReg', (22, 29))	('Zebrafish', 'Species', '7955', (0, 9))
115539	29117388	Genetically engineered mouse models (GEMMs) harboring mutations in Nf1 and Trp53 develop MPNSTs with concomitant changes in the microenvironment and are currently being routinely used in preclinical drug testing.	('changes', 'Reg', (113, 120))	('Trp53', 'Gene', '22059', (75, 80))	('mutations', 'Var', (54, 63))	('MPNSTs', 'CPA', (89, 95))	('Nf1', 'Gene', (67, 70))	('mouse', 'Species', '10090', (23, 28))	('Trp53', 'Gene', (75, 80))
115567	29054837	Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways Heterozygous mutations in NADP-dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin.	('phospholipid', 'MPA', (58, 70))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('IDH', 'Gene', '3418', (178, 181))	('IDH', 'Gene', (31, 34))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('NADP-dependent', 'Gene', (136, 150))	('energy', 'MPA', (72, 78))	('NADP', 'Chemical', 'MESH:D009249', (136, 140))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('gliomas', 'Disease', (42, 49))	('affects', 'Reg', (50, 57))	('oxidative stress', 'Phenotype', 'HP:0025464', (84, 100))	('mutations', 'Var', (123, 132))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('isocitrate', 'Chemical', 'MESH:C034219', (151, 161))	('phospholipid', 'Chemical', 'MESH:D010743', (58, 70))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('IDH', 'Gene', (178, 181))	('IDH', 'Gene', '3418', (31, 34))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (220, 227))
115571	29054837	Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation.	('differences', 'Reg', (29, 40))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('phospholipid composition', 'MPA', (48, 72))	('IDH1', 'Gene', (98, 102))	('phospholipid', 'Chemical', 'MESH:D010743', (48, 60))	('mutation', 'Var', (103, 111))	('IDH1', 'Gene', '3417', (98, 102))
115573	29054837	Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand.	('D2HG', 'Var', (51, 55))	('central carbon metabolism', 'MPA', (117, 142))	('carbon', 'Chemical', 'MESH:D002244', (125, 131))
115579	29054837	The identification of heterozygous point mutations in the genes encoding for isocitrate dehydrogenase (IDH) 1 and 2 has been a breakthrough in the understanding of possible causes of glioma genesis (Parsons et al, 2008).	('glioma genesis', 'Disease', 'MESH:D005910', (183, 197))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (77, 115))	('glioma genesis', 'Disease', (183, 197))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('heterozygous point mutations', 'Var', (22, 50))
115580	29054837	IDH mutations are present in the vast majority of lower grade gliomas and define a subtype with a favorable prognosis (Hartmann et al, 2009; Yan et al, 2009).	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3418', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('mutations', 'Var', (4, 13))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
115585	29054837	The cancer-associated mutation of IDH (IDHm) has gained a neomorphic activity whereby alphaKG is converted to D-2-hydroxyglutarate (D2HG) while oxidizing NADPH.	('IDH', 'Gene', (34, 37))	('mutation', 'Var', (22, 30))	('neomorphic activity', 'MPA', (58, 77))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (110, 130))	('IDHm', 'Gene', '3418', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('IDHm', 'Gene', (39, 43))	('IDH', 'Gene', '3418', (39, 42))	('oxidizing', 'MPA', (144, 153))	('converted', 'MPA', (97, 106))	('IDH', 'Gene', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('IDH', 'Gene', '3418', (34, 37))	('NADPH', 'Chemical', 'MESH:D009249', (154, 159))
115588	29054837	Glioma cells carrying an endogenous IDH mutation are notoriously difficult to grow in culture or to expand in vivo in rodent models, and if so, they grow very slowly.	('mutation', 'Var', (40, 48))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH', 'Gene', (36, 39))	('IDH', 'Gene', '3418', (36, 39))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('grow', 'CPA', (149, 153))	('slowly', 'NegReg', (159, 165))
115590	29054837	While glioblastoma (GBM) cell lines engineered to overexpress the mutant enzyme have served as useful models for metabolic profiling (Reitman et al, 2011; Mohrenz et al, 2013; Ohka et al, 2014; Shi et al, 2014), this set up harbors some limitations: The mutation is introduced out of the appropriate genetic background, the stoichiometric balance of the mutant versus wild-type form (IDHwt) is disrupted, and the specificities of the brain microenvironment, likely to impact cellular metabolism, are not maintained.	('mutant', 'Var', (66, 72))	('stoichiometric', 'MPA', (324, 338))	('glioblastoma', 'Disease', (6, 18))	('disrupted', 'Reg', (394, 403))	('GBM', 'Phenotype', 'HP:0012174', (20, 23))	('mutant', 'Var', (354, 360))	('mutation', 'Var', (254, 262))	('glioblastoma', 'Disease', 'MESH:D005909', (6, 18))	('IDH', 'Gene', (384, 387))	('IDH', 'Gene', '3418', (384, 387))	('glioblastoma', 'Phenotype', 'HP:0012174', (6, 18))
115591	29054837	In an attempt to shed light on the mechanistic link between IDH mutations and oncometabolic adaptations, we profiled the in vivo metabolic content of patient-derived glioma xenografts and clinical glioma samples with or without the IDH mutation.	('mutation', 'Var', (236, 244))	('patient', 'Species', '9606', (150, 157))	('glioma', 'Disease', (166, 172))	('glioma', 'Disease', (197, 203))	('IDH', 'Gene', (232, 235))	('IDH', 'Gene', (60, 63))	('IDH', 'Gene', '3418', (232, 235))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('IDH', 'Gene', '3418', (60, 63))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('clinical', 'Species', '191496', (188, 196))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
115594	29054837	In comparison, PDXs of lower grade diffuse gliomas carrying the IDH mutation have long been difficult to establish, and no cell culture models of these glioma subtypes exist.	('glioma subtype', 'Disease', 'MESH:D005910', (152, 166))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('mutation', 'Var', (68, 76))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('glioma subtype', 'Disease', (152, 166))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('IDH', 'Gene', '3418', (64, 67))	('IDH', 'Gene', (64, 67))
115600	29054837	IDHwt PDXs (P3, T434, P8) were GBM-derived, while IDHm PDXs contained two lower grade gliomas (LGG: E478, T186) and one glioblastoma (T394) (see diagnostic details in Table 1).	('T186', 'Var', (106, 110))	('IDHm', 'Gene', '3418', (50, 54))	('IDH', 'Gene', (0, 3))	('LGG', 'Var', (95, 98))	('IDHm', 'Gene', (50, 54))	('IDH', 'Gene', '3418', (0, 3))	('glioblastoma', 'Disease', (120, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('P3', 'Var', (12, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('IDH', 'Gene', (50, 53))	('IDH', 'Gene', '3418', (50, 53))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
115609	29054837	Several higher mass metabolites (e.g., m/z 778.47; m/z 807.53) were accumulated in IDHm gliomas, with much lower detection in IDHwt tumors (Fig 1B and C; MSI images in Fig EV1B).	('EV1B', 'Chemical', '-', (172, 176))	('IDHm gliomas', 'Disease', (83, 95))	('IDHm gliomas', 'Disease', 'MESH:D005910', (83, 95))	('m/z 778.47', 'Var', (39, 49))	('IDHwt tumors', 'Disease', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('m/z 807.53', 'Var', (51, 61))	('IDHwt tumors', 'Disease', 'MESH:D009369', (126, 138))
115611	29054837	Interestingly, two putative phospholipids (m/z ratio of 778.51 and m/z 821.53) appeared specifically enriched in lower grade IDHm PDX compared to GBMs (Fig 1C; m/z 778.51 more than 1,000-fold increase, Table EV2), thus correlating with grade rather than IDH status.	('IDH', 'Gene', (254, 257))	('IDH', 'Gene', '3418', (254, 257))	('lower', 'NegReg', (113, 118))	('m/z 778.51', 'Var', (160, 170))	('IDH', 'Gene', (125, 128))	('IDH', 'Gene', '3418', (125, 128))	('m/z 821.53', 'Var', (67, 77))	('EV2', 'Gene', '147138', (208, 211))	('IDHm', 'Gene', '3418', (125, 129))	('EV2', 'Gene', (208, 211))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))	('IDHm', 'Gene', (125, 129))	('phospholipids', 'Chemical', 'MESH:D010743', (28, 41))
115619	29054837	This correlated with the generally lower proliferation index of IDHm xenografts (e.g., MIB index based on Ki67 staining was 21.8 +- 3% for E478 and 54.7 +- 2% for P3 PDX) and the slower tumor development in mice (Table 1), which is also in agreement with the better prognosis of IDHm glioma patients observed in the clinic.	('glioma', 'Phenotype', 'HP:0009733', (284, 290))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('IDHm', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('IDHm', 'Gene', '3418', (64, 68))	('proliferation index', 'CPA', (41, 60))	('E478', 'Var', (139, 143))	('tumor', 'Disease', (186, 191))	('patients', 'Species', '9606', (291, 299))	('mice', 'Species', '10090', (207, 211))	('lower', 'NegReg', (35, 40))	('IDHm glioma', 'Disease', (279, 290))	('slower', 'NegReg', (179, 185))	('IDHm glioma', 'Disease', 'MESH:D005910', (279, 290))	('IDHm', 'Gene', '3418', (279, 283))	('IDHm', 'Gene', (279, 283))
115627	29054837	To gain a better understanding of the flux of glucose carbons in IDHm gliomas, 13C6-glucose was injected in two PDXs (E478 and P3) 20 min before sacrifice (Fig 3B-D).	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('E478', 'Var', (118, 122))	('13C6-glucose', 'Chemical', '-', (79, 91))	('glucose', 'Chemical', 'MESH:D005947', (84, 91))	('glucose', 'Chemical', 'MESH:D005947', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('carbons', 'Chemical', 'MESH:D002244', (54, 61))	('IDHm gliomas', 'Disease', 'MESH:D005910', (65, 77))	('IDHm gliomas', 'Disease', (65, 77))
115630	29054837	This was in sharp contrast to IDHwt tumors and contralateral brain regions, where a significant fraction of 13C2 isotopologues were present in both alphaKG and D2HG (Fig 3C and D).	('13C2', 'Chemical', '-', (108, 112))	('IDHwt tumors', 'Disease', (30, 42))	('D2HG', 'Var', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('IDHwt tumors', 'Disease', 'MESH:D009369', (30, 42))
115634	29054837	In an attempt to address this, we traced 13C5-glutamine in IDHm and IDHwt PDXs.	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', '3418', (59, 62))	('13C5-glutamine', 'Var', (41, 55))	('IDHm', 'Gene', '3418', (59, 63))	('13C5-glutamine', 'Chemical', '-', (41, 55))	('IDHm', 'Gene', (59, 63))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3418', (68, 71))
115657	29054837	Comparable GSH levels between mutant and wild-type gliomas were also found in the clinical specimen (Fig EV4).	('gliomas', 'Disease', (51, 58))	('GSH', 'MPA', (11, 14))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('EV4', 'Chemical', '-', (105, 108))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('clinical', 'Species', '191496', (82, 90))	('mutant', 'Var', (30, 36))	('GSH', 'Chemical', '-', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
115660	29054837	Although we were not able to directly measure cysteine (neither by MSI nor by LC-MS), we found lower levels of the cysteine precursor metabolite cystathionine in IDHm gliomas by MSI (Fig 5B), suggesting high turnover.	('lower', 'NegReg', (95, 100))	('IDHm gliomas', 'Disease', (162, 174))	('IDHm gliomas', 'Disease', 'MESH:D005910', (162, 174))	('cystathionine', 'Chemical', 'MESH:D003540', (145, 158))	('cysteine', 'Chemical', 'MESH:D003545', (115, 123))	('cysteine', 'Chemical', 'MESH:D003545', (46, 54))	('MSI', 'Var', (178, 181))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))
115668	29054837	Taken together, our data indicate that IDH mutation imposes a shortage of the reducing equivalents required to maintain a balanced redox state and may rely on cysteine availability for incorporation in GSH to ensure antioxidant functions.	('GSH', 'Chemical', '-', (202, 205))	('shortage', 'NegReg', (62, 70))	('cysteine', 'Chemical', 'MESH:D003545', (159, 167))	('rely', 'Reg', (151, 155))	('mutation', 'Var', (43, 51))	('antioxidant functions', 'MPA', (216, 237))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', '3418', (39, 42))	('cysteine', 'MPA', (159, 167))
115669	29054837	In this context, high CBS expression may represent a marker of oxidative stress and increased reliance on the transsulfuration pathway for cysteine generation.	('expression', 'MPA', (26, 36))	('CBS', 'Gene', (22, 25))	('high', 'Var', (17, 21))	('cysteine', 'Chemical', 'MESH:D003545', (139, 147))	('oxidative stress', 'Phenotype', 'HP:0025464', (63, 79))	('CBS', 'Gene', '875', (22, 25))
115671	29054837	Despite considerable insight in the epigenetic alterations resulting from the gain-of-function mutation in IDH1 or IDH2, the metabolic consequences of the mutant enzyme, whether D2HD-dependent or not, are still poorly understood, in part due to the difficulties in establishing IDH-mutant gliomas in culture and/or in vivo as xenografts.	('gliomas', 'Disease', 'MESH:D005910', (289, 296))	('IDH1', 'Gene', (107, 111))	('gliomas', 'Phenotype', 'HP:0009733', (289, 296))	('IDH2', 'Gene', (115, 119))	('gliomas', 'Disease', (289, 296))	('gain-of-function', 'PosReg', (78, 94))	('IDH', 'Gene', (278, 281))	('IDH1', 'Gene', '3417', (107, 111))	('IDH', 'Gene', '3418', (278, 281))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', '3418', (107, 110))	('IDH', 'Gene', '3418', (115, 118))	('IDH2', 'Gene', '3418', (115, 119))	('IDH', 'Gene', (115, 118))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('mutation', 'Var', (95, 103))
115672	29054837	Here, we applied in situ metabolic profiling and LC-MS on brain sections of glioma PDX and human glioma samples with and without the IDH1 mutation for large-scale unbiased metabolic profiling of these tumors.	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('IDH1', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutation', 'Var', (138, 146))	('tumors', 'Disease', (201, 207))	('IDH1', 'Gene', '3417', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('human', 'Species', '9606', (91, 96))
115679	29054837	The exact mechanism through which mutant IDH affects lipid synthesis requires further insight, avenues lie in limited citrate availability for TCA cycle and fatty acid synthesis, and the inability of mutant IDH1 to engage in reductive carboxylation for citrate production (Grassian et al, 2014).	('IDH1', 'Gene', (207, 211))	('IDH', 'Gene', (41, 44))	('lipid synthesis', 'MPA', (53, 68))	('TCA cycle', 'MPA', (143, 152))	('limited', 'NegReg', (110, 117))	('citrate', 'Chemical', 'MESH:D019343', (118, 125))	('mutant', 'Var', (200, 206))	('IDH', 'Gene', (207, 210))	('citrate', 'Chemical', 'MESH:D019343', (253, 260))	('affects', 'Reg', (45, 52))	('IDH1', 'Gene', '3417', (207, 211))	('citrate availability', 'MPA', (118, 138))	('IDH', 'Gene', '3418', (41, 44))	('TCA', 'Chemical', 'MESH:D014233', (143, 146))	('reductive carboxylation for citrate production', 'MPA', (225, 271))	('IDH', 'Gene', '3418', (207, 210))	('fatty acid', 'Chemical', 'MESH:D005227', (157, 167))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('mutant', 'Var', (34, 40))
115682	29054837	Interestingly, recent data showed a direct inhibitory effect of D2HG on pyruvate dehydrogenase (PDH) (Izquierdo-Garcia et al, 2015) and ATP synthase activity (Fu et al, 2015).	('pyruvate dehydrogenase', 'Gene', '54704', (72, 94))	('inhibitory', 'NegReg', (43, 53))	('Izquierdo-Garcia', 'Disease', 'MESH:C536767', (102, 118))	('pyruvate dehydrogenase', 'Gene', (72, 94))	('ATP', 'Chemical', 'MESH:D000255', (136, 139))	('PDH', 'Gene', (96, 99))	('Izquierdo-Garcia', 'Disease', (102, 118))	('D2HG', 'Var', (64, 68))	('ATP synthase activity', 'MPA', (136, 157))	('PDH', 'Gene', '54704', (96, 99))
115683	29054837	Reduced glycolysis is also in line with the reported silencing of lactate dehydrogenase A through promoter hypermethylation in IDH1m tumors (Chesnelong et al, 2014).	('glycolysis', 'MPA', (8, 18))	('lactate dehydrogenase A', 'Gene', '3939', (66, 89))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('silencing', 'NegReg', (53, 62))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('IDH1', 'Gene', (127, 131))	('promoter hypermethylation', 'Var', (98, 123))	('IDH1', 'Gene', '3417', (127, 131))	('lactate dehydrogenase A', 'Gene', (66, 89))
115684	29054837	Thus, the reduced energy potential may be the combined result of limited IDHwt function and of overproduction of D2HG by the mutant enzyme directly affecting metabolic enzyme activity and gene expression.	('energy potential', 'MPA', (18, 34))	('reduced', 'NegReg', (10, 17))	('mutant', 'Var', (125, 131))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3418', (73, 76))	('overproduction', 'PosReg', (95, 109))	('affecting', 'Reg', (148, 157))	('metabolic enzyme activity', 'MPA', (158, 183))
115686	29054837	This is in sharp contrast with the results obtained in IDHwt glioma and normal brain, where under the same experimental conditions both alphaKG and D2HG are, at least in part, derived from glucose.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glucose', 'Chemical', 'MESH:D005947', (189, 196))	('D2HG', 'Var', (148, 152))	('IDHwt glioma', 'Disease', 'MESH:D005910', (55, 67))	('IDHwt glioma', 'Disease', (55, 67))
115694	29054837	Transcriptional silencing or chemical inhibition of glutaminase, the enzyme converting glutamine to glutamate, led to reduced cell proliferation in IDHm cells in vitro (Seltzer et al, 2010; Emadi et al, 2014).	('glutaminase', 'Protein', (52, 63))	('IDHm', 'Gene', '3418', (148, 152))	('chemical inhibition', 'Var', (29, 48))	('reduced', 'NegReg', (118, 125))	('glutamate', 'Chemical', 'MESH:D018698', (100, 109))	('IDHm', 'Gene', (148, 152))	('glutamine', 'Chemical', 'MESH:D005973', (87, 96))	('Transcriptional', 'Var', (0, 15))
115695	29054837	However, this is not supported by our in vivo data since in both IDHwt and IDHm tumors, the cataplerotic activity of glutamine synthetase (GS), as opposed to the anaplerotic activity of glutaminase, was detectable (13C2 glutamine in Fig 3C).	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3418', (65, 68))	('GS', 'Disease', 'MESH:D011125', (139, 141))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('glutamine synthetase', 'Gene', (117, 137))	('cataplerotic activity', 'MPA', (92, 113))	('IDHm tumors', 'Disease', (75, 86))	('IDH', 'Gene', '3418', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDHm tumors', 'Disease', 'MESH:D009369', (75, 86))	('glutamine synthetase', 'Gene', '2752', (117, 137))	('IDH', 'Gene', (75, 78))	('13C2 glutamine', 'Var', (215, 229))	('13C2 glutamine', 'Chemical', '-', (215, 229))
115705	29054837	Here, we identify CBS not only as a novel prognostic marker for 1p/19q co-deleted IDHm gliomas (ODG subtype), but also as a potential target to tilt the balance toward high-oxidative stress in IDHm gliomas.	('IDHm gliomas', 'Disease', 'MESH:D005910', (193, 205))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('IDHm gliomas', 'Disease', (193, 205))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('IDHm gliomas', 'Disease', 'MESH:D005910', (82, 94))	('IDHm gliomas', 'Disease', (82, 94))	('CBS', 'Gene', '875', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('1p/19q co-deleted', 'Var', (64, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (173, 189))	('CBS', 'Gene', (18, 21))	('-oxidative stress', 'Phenotype', 'HP:0025464', (172, 189))
115706	29054837	In conclusion, the present study provides important insight into the metabolism of IDHm and IDHwt gliomas and points to hitherto unrecognized metabolic vulnerabilities imposed by the activity of mutant IDH.	('IDH', 'Gene', (202, 205))	('IDH', 'Gene', '3418', (202, 205))	('IDHwt gliomas', 'Disease', (92, 105))	('IDH', 'Gene', '3418', (92, 95))	('IDH', 'Gene', (83, 86))	('IDH', 'Gene', '3418', (83, 86))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (92, 105))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('IDHm', 'Gene', '3418', (83, 87))	('IDH', 'Gene', (92, 95))	('IDHm', 'Gene', (83, 87))	('mutant', 'Var', (195, 201))
115710	29054837	IDH1 status, 1p/19q co-deletion, hypermethylation status, and grade are indicated in Table EV6.	('IDH1', 'Gene', (0, 4))	('hypermethylation status', 'Var', (33, 56))	('EV6', 'Chemical', '-', (91, 94))	('IDH1', 'Gene', '3417', (0, 4))
115712	29054837	Patient-derived glioma xenografts (PDX) were generated in NOD/Scid mice (male or female, at least 2 months of age) as previously described (Golebiewska et al, 2013; Navis et al, 2013; Sanzey et al, 2015; Bougnaud et al, 2016) from 3 IDHwt gliomas (P3, P8, and T434) and 3 IDHm gliomas (E478, T186, and T394).	('E478', 'Var', (286, 290))	('T434', 'Var', (260, 264))	('T186', 'Var', (292, 296))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (233, 246))	('IDHwt gliomas', 'Disease', (233, 246))	('gliomas', 'Phenotype', 'HP:0009733', (277, 284))	('IDHm gliomas', 'Disease', (272, 284))	('T394', 'Var', (302, 306))	('mice', 'Species', '10090', (67, 71))	('glioma', 'Disease', (16, 22))	('glioma', 'Disease', (277, 283))	('glioma', 'Disease', (239, 245))	('IDHm gliomas', 'Disease', 'MESH:D005910', (272, 284))	('glioma', 'Disease', 'MESH:D005910', (277, 283))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('P3', 'Var', (248, 250))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('Patient', 'Species', '9606', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
115731	29054837	Overall, the TEC values were comparable for the different regions (mutant or wild-type tumor, contralateral brain, and control brain), indicating that for the majority of compounds, the quantification is not likely to be affected by strong tissue effects (Table EV5).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('mutant', 'Var', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
115736	29054837	For all MS data shown, P-values are based on unpaired two-tailed t-test of mean abundances of metabolites between PDX with and without IDH1 mutation.	('IDH1', 'Gene', (135, 139))	('mutation', 'Var', (140, 148))	('IDH1', 'Gene', '3417', (135, 139))
115737	29054837	U-13C6-Glucose (13C6-Glc) or U-13C5 glutamine (13C5-Gln) tracer from Cambridge Isotope Laboratories (CIL, USA, Andover, MA) was dissolved in saline solution (0.9% NaCl) and administered by a single bolus injection in the tail vein to ensure doses of 1 mg/g for the 13C6-Glc or 0.15 mg/g for 13C5-Gln.	('13C6-Glc', 'Chemical', '-', (265, 273))	('glutamine', 'Chemical', 'MESH:D005973', (36, 45))	('U-13C5', 'Chemical', '-', (29, 35))	('saline', 'Chemical', 'MESH:D012965', (141, 147))	('13C5-Gln', 'Chemical', '-', (47, 55))	('U-13C5', 'Var', (29, 35))	('Isotope Laboratories', 'Disease', (79, 99))	('13C5-Gln', 'Chemical', '-', (291, 299))	('U-13C6-Glucose', 'Chemical', '-', (0, 14))	('Isotope Laboratories', 'Disease', 'MESH:D007757', (79, 99))	('13C6-Glc', 'Chemical', '-', (16, 24))	('NaCl', 'Chemical', 'MESH:D012965', (163, 167))
115751	29054837	Point mutations in the enzyme isocitrate dehydrogenase (IDH) are thought to be a driver for a major subset of gliomas, leading to the generation of the oncometabolite D2HG and subsequent abnormalities in gene expression.	('isocitrate', 'Chemical', 'MESH:C034219', (30, 40))	('D2HG', 'MPA', (167, 171))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('abnormalities', 'Reg', (187, 200))	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3418', (56, 59))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('gene expression', 'MPA', (204, 219))	('Point mutations', 'Var', (0, 15))
115753	29054837	The present study uncovers a mutant IDH-specific metabolic landscape which is clinically relevant and highlights novel metabolic vulnerabilities in IDH-mutant gliomas that may be therapeutically exploited.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', '3418', (148, 151))	('mutant', 'Var', (29, 35))	('IDH', 'Gene', (36, 39))	('IDH', 'Gene', '3418', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('clinical', 'Species', '191496', (78, 86))
115773	27329594	Studies showed TEL2/CLK2 orthologs increased the telomere length in Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae.	('TEL2', 'Gene', (15, 19))	('increased', 'PosReg', (35, 44))	('yeast', 'Species', '4932', (107, 112))	('telomere length', 'CPA', (49, 64))	('TEL2', 'Gene', '9894', (15, 19))	('Saccharomyces cerevisiae', 'Species', '4932', (113, 137))	('orthologs', 'Var', (25, 34))	('Caenorhabditis elegans', 'Species', '6239', (68, 90))
115786	27329594	The median survival interval in the high- and low-TELO2 expressions level was 59 weeks and 113 weeks, respectively.	('TELO2', 'Gene', (50, 55))	('TELO2', 'Gene', '9894', (50, 55))	('high-', 'Var', (36, 41))
115787	27329594	These data demonstrate that high TELO2 mRNA expression correlates with shorter survival in human high-grade gliomas, supporting the hypothesis of TELO2 belongs to oncogene.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('TELO2', 'Gene', (146, 151))	('TELO2', 'Gene', (33, 38))	('gliomas', 'Disease', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('mRNA expression', 'MPA', (39, 54))	('TELO2', 'Gene', '9894', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('TELO2', 'Gene', '9894', (33, 38))	('high', 'Var', (28, 32))	('shorter', 'NegReg', (71, 78))	('human', 'Species', '9606', (91, 96))
115793	27329594	We further validate the level of TELO2 mRNA expression in human normal brain and three glioma cell lines, LN229, GBM8401, and U118MG through wet lab approach using q-RT PCR.	('TELO2', 'Gene', (33, 38))	('glioma', 'Disease', (87, 93))	('human', 'Species', '9606', (58, 63))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('TELO2', 'Gene', '9894', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('LN229', 'CellLine', 'CVCL:0393', (106, 111))	('U118MG', 'Var', (126, 132))
115795	27329594	Moreover, TELO2 was also statistically higher in human GBM8401 and U118MG glioma cell line than in normal brain (P < 0.01, P < 0.005, respectively).	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('higher', 'PosReg', (39, 45))	('TELO2', 'Gene', '9894', (10, 15))	('GBM8401', 'Var', (55, 62))	('human', 'Species', '9606', (49, 54))	('glioma', 'Disease', (74, 80))	('TELO2', 'Gene', (10, 15))	('U118MG', 'Var', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
115800	27329594	Finally, the protein production of TELO2 and mTOR in human normal brain and four glioma cell lines, LN229, U87MG, GBM8401, and U118MG through wet lab approach using Western blotting (Figure 5A).	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('U87MG', 'Var', (107, 112))	('LN229', 'CellLine', 'CVCL:0393', (100, 105))	('U118MG', 'Var', (127, 133))	('mTOR', 'MPA', (45, 49))	('TELO2', 'Gene', '9894', (35, 40))	('glioma', 'Disease', (81, 87))	('human', 'Species', '9606', (53, 58))	('protein production', 'MPA', (13, 31))	('U87MG', 'CellLine', 'CVCL:0022', (107, 112))	('TELO2', 'Gene', (35, 40))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
115801	27329594	The protein level of TELO2 significantly increased correlates with the mTOR expression in human glioma cell lines including U118MG, GBM8401, U87MG, and LN229 as compared with normal brain tissue (Figure 5B and 5C).	('protein level', 'MPA', (4, 17))	('increased', 'PosReg', (41, 50))	('U87MG', 'Var', (141, 146))	('TELO2', 'Gene', '9894', (21, 26))	('mTOR expression', 'MPA', (71, 86))	('correlates', 'MPA', (51, 61))	('GBM8401', 'Var', (132, 139))	('LN229', 'CellLine', 'CVCL:0393', (152, 157))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('human', 'Species', '9606', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('TELO2', 'Gene', (21, 26))	('U118MG', 'Var', (124, 130))	('glioma', 'Disease', (96, 102))	('U87MG', 'CellLine', 'CVCL:0022', (141, 146))
115815	27329594	mTOR incorporates oncogenic signaling from some growth factor receptors via PI3K, to modulate nutrient status and cellular energy, to stimulate downstream targets that promote tumor growth and suppress glioma cell invasion.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('stimulate', 'PosReg', (134, 143))	('suppress', 'NegReg', (193, 201))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('tumor', 'Disease', (176, 181))	('promote', 'PosReg', (168, 175))	('PI3K', 'Var', (76, 80))	('glioma', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
115830	27329594	Further study of downstream targets (pS6k, 4EBP1, pp70S6k) in signaling pathways activated in glioma cell lines would be another one interesting study in the future.	('pS6k', 'Gene', (37, 41))	('glioma', 'Disease', (94, 100))	('4EBP1', 'Gene', '1978', (43, 48))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('pp70S6k', 'Var', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('4EBP1', 'Gene', (43, 48))	('pS6k', 'Gene', '6198', (37, 41))
115857	27329594	Two datasets (GDS1815 / 209528_s_at / TELO2 and GDS1962 / 34260_s_at / TELO2) gather from the GEO profiles were analyzed.	('TELO2', 'Gene', (71, 76))	('TELO2', 'Gene', '9894', (38, 43))	('GDS1962 / 34260_s_at', 'Var', (48, 68))	('TELO2', 'Gene', (38, 43))	('TELO2', 'Gene', '9894', (71, 76))
115881	20399149	TCGA also reaffirmed genetic alterations in TP53, PTEN, EGFR, RB1 NF1, ERBB2, PIK3R1, and PIK3CA mutations and detected an increased frequency of NF1 mutations in GBM patients.	('PIK3R1', 'Gene', (78, 84))	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', '1956', (56, 60))	('alterations', 'Var', (29, 40))	('TP53', 'Gene', (44, 48))	('RB1', 'Gene', '5925', (62, 65))	('ERBB2', 'Gene', (71, 76))	('PTEN', 'Gene', (50, 54))	('RB1', 'Gene', (62, 65))	('PIK3CA', 'Gene', (90, 96))	('mutations', 'Var', (150, 159))	('NF1', 'Gene', '4763', (66, 69))	('PIK3R1', 'Gene', '5295', (78, 84))	('ERBB2', 'Gene', '2064', (71, 76))	('NF1', 'Gene', '4763', (146, 149))	('PTEN', 'Gene', '5728', (50, 54))	('EGFR', 'Gene', (56, 60))	('NF1', 'Gene', (66, 69))	('TP53', 'Gene', '7157', (44, 48))	('NF1', 'Gene', (146, 149))	('GBM', 'Disease', (163, 166))	('patients', 'Species', '9606', (167, 175))	('PIK3CA', 'Gene', '5290', (90, 96))
115882	20399149	Recent DNA sequencing analyses of primary GBM tumors using a more comprehensive approach also identified novel somatic mutations in isocitrate dehydrogenase 1 (IDH1) that occur in 12% of all GBM patients.	('isocitrate dehydrogenase 1', 'Gene', (132, 158))	('GBM tumors', 'Disease', (42, 52))	('isocitrate dehydrogenase 1', 'Gene', '3417', (132, 158))	('GBM tumors', 'Disease', 'MESH:D005910', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('IDH1', 'Gene', (160, 164))	('IDH1', 'Gene', '3417', (160, 164))	('GBM', 'Disease', (191, 194))	('patients', 'Species', '9606', (195, 203))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (119, 128))	('occur', 'Reg', (171, 176))
115883	20399149	IDH1 mutations have only been detected at the arginine residue in codon 132, with the most common change being the R132H mutation, which results in a novel gain of enzyme function in directly catalyzing alpha-ketoglutarate to R(-)-2-hydroxyglutarate.	('enzyme function', 'MPA', (164, 179))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (226, 249))	('R132H', 'Var', (115, 120))	('gain', 'PosReg', (156, 160))	('R132H', 'Mutation', 'rs121913500', (115, 120))	('IDH1', 'Gene', (0, 4))	('arginine', 'Chemical', 'MESH:D001120', (46, 54))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (203, 222))	('IDH1', 'Gene', '3417', (0, 4))
115884	20399149	IDH1 mutations are enriched in secondary GBM cases, younger individuals and coincident with increased patient survival.	('patient', 'Species', '9606', (102, 109))	('secondary GBM cases', 'Disease', (31, 50))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
115885	20399149	Higher IDH1 mutation rates are seen in grade II and III astrocytomas and oligodendrogliomas, suggesting that IDH1 mutations generally occur in the progressive form of glioma, rather than in de novo GBM.	('oligodendrogliomas', 'Disease', (73, 91))	('IDH1', 'Gene', '3417', (7, 11))	('occur', 'Reg', (134, 139))	('mutations', 'Var', (114, 123))	('glioma', 'Disease', (84, 90))	('IDH1', 'Gene', (109, 113))	('glioma', 'Disease', (167, 173))	('astrocytomas', 'Disease', 'MESH:D001254', (56, 68))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('IDH1', 'Gene', '3417', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (73, 91))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('astrocytomas', 'Disease', (56, 68))	('IDH1', 'Gene', (7, 11))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
115886	20399149	Mutations in the related IDH2 gene are of lower frequency and generally non-overlapping with tumors containing IDH1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1', 'Gene', '3417', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (116, 125))	('IDH2', 'Gene', (25, 29))	('tumors', 'Disease', (93, 99))	('IDH1', 'Gene', (111, 115))	('IDH2', 'Gene', '3418', (25, 29))
115887	20399149	Cancer-specific DNA methylation changes are hallmarks of human cancers, in which global DNA hypomethylation is often seen concomitantly with hypermethylation of CpG islands (reviewed in).	('human cancers', 'Disease', 'MESH:D009369', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('human cancers', 'Disease', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('changes', 'Var', (32, 39))
115888	20399149	CpG island hypermethylation events have also been shown to serve as biomarkers in human cancers, for early detection in blood and other bodily fluids, for prognosis or prediction of response to therapy and to monitor cancer recurrence.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('hypermethylation', 'Var', (11, 27))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('human cancers', 'Disease', 'MESH:D009369', (82, 95))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human cancers', 'Disease', (82, 95))	('CpG', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
115889	20399149	A CpG island methylator phenotype (CIMP) was first characterized in human colorectal cancer by Toyota and colleagues as cancer-specific CpG island hypermethylation of a subset of genes in a subset of tumors.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('hypermethylation', 'Var', (147, 163))	('human', 'Species', '9606', (68, 73))	('CIMP', 'Chemical', '-', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('cancer', 'Disease', (120, 126))	('genes', 'Gene', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colorectal cancer', 'Disease', (74, 91))
115891	20399149	Colorectal CIMP is characterized by tumors in the proximal colon, a tight association with BRAF mutations, and microsatellite instability caused by MLH1 promoter hypermethylation and transcriptional silencing.	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('BRAF', 'Gene', '673', (91, 95))	('hypermethylation', 'Var', (162, 178))	('BRAF', 'Gene', (91, 95))	('microsatellite', 'MPA', (111, 125))	('transcriptional silencing', 'Var', (183, 208))	('CIMP', 'Chemical', '-', (11, 15))	('Colorectal', 'Disease', (0, 10))	('MLH1', 'Gene', '4292', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MLH1', 'Gene', (148, 152))	('Colorectal CIMP', 'Phenotype', 'HP:0200063', (0, 15))	('tumors', 'Disease', (36, 42))	('association', 'Interaction', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (96, 105))	('Colorectal', 'Disease', 'MESH:D015179', (0, 10))
115892	20399149	DNA methylation alterations have been widely reported in human gliomas, and there have been several reports of promoter-associated CpG island hypermethylation in human GBM and other glioma subtypes.	('glioma subtypes', 'Disease', (182, 197))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('human', 'Species', '9606', (57, 62))	('hypermethylation', 'Var', (142, 158))	('glioma subtypes', 'Disease', 'MESH:D005910', (182, 197))	('alterations', 'Var', (16, 27))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('human', 'Species', '9606', (162, 167))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('human gliomas', 'Disease', (57, 70))	('human gliomas', 'Disease', 'MESH:D005910', (57, 70))	('methylation alterations', 'Var', (4, 27))
115894	20399149	Hypermethylation of the MGMT promoter-associated CpG island has been shown in a large percentage of GBM patients.	('MGMT', 'Gene', '4255', (24, 28))	('CpG island', 'Gene', (49, 59))	('GBM', 'Disease', (100, 103))	('shown', 'Reg', (69, 74))	('Hypermethylation', 'Var', (0, 16))	('patients', 'Species', '9606', (104, 112))	('MGMT', 'Gene', (24, 28))
115900	20399149	CIMP in colorectal cancer is characterized by correlated cancer-specific CpG island hypermethylation of a subset of genes in a subset of tumors, and not just a stochastic increase in the frequency of generic CpG island methylation across the genome.	('tumors', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('CpG island hypermethylation', 'Var', (73, 100))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', (19, 25))	('colorectal cancer', 'Disease', 'MESH:D015179', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CIMP', 'Chemical', '-', (0, 4))	('hypermethylation', 'Var', (84, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (8, 25))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('colorectal cancer', 'Disease', (8, 25))
115916	20399149	We observed significantly better survival for proneural G-CIMP-positive patients (median survival of 150 weeks) than proneural G-CIMP-negative patients (median survival of 42 weeks) or all other non-proneural GBM patients (median survivals of 54 weeks).	('proneural G-CIMP-positive', 'Var', (46, 71))	('G-CIMP', 'Chemical', '-', (56, 62))	('patients', 'Species', '9606', (72, 80))	('survival', 'MPA', (33, 41))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (213, 221))	('G-CIMP', 'Chemical', '-', (127, 133))	('better', 'PosReg', (26, 32))
115918	20399149	Nine genes were found to have somatic mutations that were significantly associated with proneural G-CIMP-positive tumors (Figure S3A, Table S2).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('associated', 'Reg', (72, 82))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (38, 47))	('G-CIMP', 'Chemical', '-', (98, 104))
115919	20399149	IDH1 somatic mutations, recently identified primarily in secondary GBM tumors, were found to be very tightly associated with G-CIMP in our data set (Table 1), with 18 IDH1 mutations primarily observed in 23 (78%) G-CIMP-positive tumors, and 184 G-CIMP-negative tumors were IDH1-wildtype (p< 2.2x10-16).	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('GBM tumors', 'Disease', 'MESH:D005910', (67, 77))	('IDH1', 'Gene', (167, 171))	('IDH1', 'Gene', '3417', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('IDH1', 'Gene', (0, 4))	('G-CIMP', 'Chemical', '-', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('G-CIMP', 'Chemical', '-', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('G-CIMP', 'Chemical', '-', (245, 251))	('IDH1', 'Gene', '3417', (167, 171))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (229, 235))	('IDH1', 'Gene', '3417', (0, 4))	('associated', 'Reg', (109, 119))	('G-CIMP', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('mutations', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('mutations', 'Var', (172, 181))	('G-CIMP-positive', 'Disease', (213, 228))	('IDH1', 'Gene', (273, 277))	('GBM tumors', 'Disease', (67, 77))	('observed', 'Reg', (192, 200))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
115921	20399149	However, the five discordant cases of G-CIMP-positive, IDH1-wildtype tumors are significantly younger at the time of diagnosis compared to patients with G-CIMP-negative, IDH1-wildtype (median ages of 37 and 59 years respectively; p<0.008).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('IDH1-wildtype tumors', 'Disease', 'MESH:D009369', (55, 75))	('G-CIMP', 'Chemical', '-', (38, 44))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', (170, 174))	('patients', 'Species', '9606', (139, 147))	('IDH1', 'Gene', '3417', (170, 174))	('G-CIMP', 'Chemical', '-', (153, 159))	('IDH1-wildtype tumors', 'Disease', (55, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('G-CIMP-positive', 'Var', (38, 53))	('IDH1', 'Gene', (55, 59))
115923	20399149	We did not observe any IDH2 mutations in the TCGA data set.	('IDH2', 'Gene', (23, 27))	('IDH2', 'Gene', '3418', (23, 27))	('mutations', 'Var', (28, 37))
115924	20399149	Tumors displaying both G-CIMP-positive and IDH1 mutation occurred at low frequency in primary GBM, but were enriched in the set of 16 recurrent (treated) tumors, and to an even greater degree in the set of four secondary GBM (Table 1).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('primary GBM', 'Disease', (86, 97))	('IDH1', 'Gene', (43, 47))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutation', 'Var', (48, 56))	('G-CIMP', 'Chemical', '-', (23, 29))	('IDH1', 'Gene', '3417', (43, 47))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
115925	20399149	We also identified examples of germline mutations (nine genes) and loss of heterozygosity (six genes) that were significantly associated with proneural G-CIMP-positive tumors (Figure S3B-C, Table S2).	('associated', 'Reg', (126, 136))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('G-CIMP', 'Chemical', '-', (152, 158))	('loss of heterozygosity', 'Var', (67, 89))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
115927	20399149	We identified significant copy number differences in 2,875 genes between proneural G-CIMP-positive and G-CIMP-negative tumors (Figure 3A, Table S3).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('G-CIMP', 'Chemical', '-', (83, 89))	('copy number differences', 'Var', (26, 49))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('G-CIMP', 'Chemical', '-', (103, 109))
115930	20399149	Accompanying the gains at chromosome 10p in proneural G-CIMP-positive tumors, we also detected deletions of the same chromosome arm in G-CIMP-negative tumors (Figure 3C).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('deletions', 'Var', (95, 104))	('G-CIMP', 'Chemical', '-', (135, 141))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('G-CIMP', 'Chemical', '-', (54, 60))	('gains', 'PosReg', (17, 22))
115932	20399149	These findings point to G-CIMP-positive tumors as having a distinct profile of copy number variation when compared to G-CIMP-negative tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('G-CIMP', 'Chemical', '-', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('G-CIMP', 'Chemical', '-', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('G-CIMP-positive', 'Var', (24, 39))	('tumors', 'Disease', (40, 46))
115934	20399149	Among 3,153 CpG sites that were differentially methylated between proneural G-CIMP positive and proneural G-CIMP-negative tumors, 3,098 (98%) were hypermethylated (Figure 4A).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('G-CIMP', 'Chemical', '-', (76, 82))	('hypermethylated', 'Var', (147, 162))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('G-CIMP', 'Chemical', '-', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
115940	20399149	Integration of the normalized gene expression and DNA methylation gene lists identified a total of 300 genes with both significant DNA hypermethylation and gene expression changes in G-CIMP-positive tumors compared to G-CIMP-negative tumors within the proneural subset.	('G-CIMP-positive', 'Var', (183, 198))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('G-CIMP', 'Chemical', '-', (183, 189))	('G-CIMP', 'Chemical', '-', (218, 224))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('changes', 'Reg', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
115941	20399149	Of these, 263 were significantly down-regulated and hypermethylated within proneural G-CIMP-positive tumors (Figure 4C, lower right quadrant).	('hypermethylated', 'Var', (52, 67))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('G-CIMP', 'Chemical', '-', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('down-regulated', 'NegReg', (33, 47))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
115947	20399149	In this combined dataset, the expression of the 263-gene set was significantly associated with patient outcome (Figure S5G).	('expression', 'MPA', (30, 40))	('patient', 'Species', '9606', (95, 102))	('263-gene set', 'Var', (48, 60))	('patient', 'Disease', (95, 102))	('associated with', 'Reg', (79, 94))
115948	20399149	Together, these findings suggest that G-CIMP-positive GBMs tumors have epigenetically-related gene expression differences which are more consistent with low-grade gliomas as well as high grade tumors with favorable prognosis.	('gliomas', 'Disease', (163, 170))	('epigenetically-related gene expression differences', 'MPA', (71, 121))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('GBMs tumors', 'Disease', 'MESH:D009369', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('GBMs tumors', 'Disease', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('G-CIMP-positive', 'Var', (38, 53))	('G-CIMP', 'Chemical', '-', (38, 44))
115952	20399149	A sample was considered G-CIMP positive if at least six genes displayed a combination of DOCK5 DNA hypomethylation and/or hypermethylation of the remaining genes in the panel.	('hypomethylation', 'Var', (99, 114))	('DOCK5', 'Gene', (89, 94))	('DOCK5', 'Gene', '80005', (89, 94))	('hypermethylation', 'Var', (122, 138))	('G-CIMP', 'Chemical', '-', (24, 30))
115964	20399149	Together, these findings show that G-CIMP is a prevalent molecular signature in low grade gliomas and confers improved survival in these tumors.	('gliomas', 'Disease', (90, 97))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('G-CIMP', 'Var', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('G-CIMP', 'Chemical', '-', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('improved', 'PosReg', (110, 118))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('survival', 'MPA', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
115972	20399149	G-CIMP-positive samples were associated with secondary or recurrent (treated) tumors and tightly associated with IDH1 mutation.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('secondary or recurrent', 'CPA', (45, 67))	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation', 'Var', (118, 126))	('associated', 'Reg', (29, 39))	('associated', 'Reg', (97, 107))	('G-CIMP', 'Chemical', '-', (0, 6))
115973	20399149	G-CIMP tumors also showed a relative lack of copy number variation commonly observed in GBM, including EGFR amplification, chromosome 7 gain and chromosome 10 loss.	('chromosome', 'Var', (145, 155))	('amplification', 'Var', (108, 121))	('EGFR', 'Gene', '1956', (103, 107))	('chromosome 7', 'Gene', (123, 135))	('EGFR', 'Gene', (103, 107))	('tumors', 'Disease', (7, 13))	('loss', 'NegReg', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('GBM', 'Disease', (88, 91))	('lack', 'NegReg', (37, 41))	('gain', 'PosReg', (136, 140))	('G-CIMP', 'Chemical', '-', (0, 6))
115974	20399149	Interestingly, G-CIMP tumors displayed copy-number alterations which were also shown in gliomas with IDH1 mutations in a recent report.	('IDH1', 'Gene', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('IDH1', 'Gene', '3417', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('gliomas', 'Disease', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('G-CIMP', 'Chemical', '-', (15, 21))	('mutations', 'Var', (106, 115))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('copy-number alterations', 'Var', (39, 62))	('tumors', 'Disease', (22, 28))
115977	20399149	Interestingly, of the five discordant cases of G-CIMP-positive, IDH1-wildtype tumors, two patients survived more than five years after diagnosis, suggesting that G-CIMP-positive status may confer favorable outcome independent of IDH1 mutation status.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('IDH1', 'Gene', (229, 233))	('G-CIMP-positive', 'Var', (162, 177))	('IDH1', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (229, 233))	('G-CIMP', 'Chemical', '-', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH1', 'Gene', '3417', (64, 68))	('G-CIMP', 'Chemical', '-', (47, 53))	('IDH1-wildtype tumors', 'Disease', 'MESH:D009369', (64, 84))	('patients', 'Species', '9606', (90, 98))	('IDH1-wildtype tumors', 'Disease', (64, 84))
115981	20399149	G-CIMP is highly associated with IDH1 mutation across all glioma tumor grades, and the prevalence of both decreases with increasing tumor grade.	('glioma tumor', 'Disease', 'MESH:D005910', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (65, 70))	('associated', 'Reg', (17, 27))	('IDH1', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1', 'Gene', '3417', (33, 37))	('tumor', 'Disease', (132, 137))	('mutation', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('glioma tumor', 'Disease', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('G-CIMP', 'Chemical', '-', (0, 6))
115985	20399149	In the non-TCGA independent validation set examined in this study, an IDH1 mutation was detected in 40/43 (93%) low- and intermediate-grade gliomas, but only 7/57 (13%) of primary GBMs.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('low- and', 'Disease', (112, 120))	('mutation', 'Var', (75, 83))	('IDH1', 'Gene', '3417', (70, 74))	('detected', 'Reg', (88, 96))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))	('IDH1', 'Gene', (70, 74))
115991	20399149	According to this model, a lack of methylation of these genes in G-CIMP-negative tumors would result in a relative increase in expression of these genes, which in turn would promote tumor progression and/or lack of response to currently available treatment modalities.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (182, 187))	('lack', 'NegReg', (27, 31))	('expression', 'MPA', (127, 137))	('promote', 'PosReg', (174, 181))	('G-CIMP', 'Chemical', '-', (65, 71))	('increase', 'PosReg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('lack', 'NegReg', (207, 211))	('methylation', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
115993	20399149	RBP1 and G0S2 are the two genes showing the strongest evidence for epigenetic silencing in G-CIMP tumors.	('G0S2', 'Gene', (9, 13))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('RBP1', 'Gene', '5947', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('epigenetic silencing', 'Var', (67, 87))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('G-CIMP', 'Chemical', '-', (91, 97))	('G0S2', 'Gene', '50486', (9, 13))	('RBP1', 'Gene', (0, 4))
115998	20399149	Interestingly, studies in breast cancer cells have shown that silencing of RBP1 plays an important role in RA signaling by lowering all-trans-retinoic acid production and loss of RAR levels and activity mediated by de-repression of PI3K/Akt signaling pathway, leading to loss of cell differentiation and tumor progression .	('breast cancer', 'Disease', (26, 39))	('RAR', 'Gene', (179, 182))	('de-repression', 'NegReg', (215, 228))	('cell differentiation', 'CPA', (279, 299))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Akt', 'Gene', '207', (237, 240))	('tumor', 'Disease', (304, 309))	('all-trans-retinoic acid production', 'MPA', (132, 166))	('loss', 'NegReg', (171, 175))	('RBP1', 'Gene', '5947', (75, 79))	('RBP1', 'Gene', (75, 79))	('silencing', 'Var', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('RA', 'Chemical', 'MESH:D014212', (107, 109))	('loss', 'NegReg', (271, 275))	('lowering', 'NegReg', (123, 131))	('RA', 'Chemical', 'MESH:D014212', (179, 181))	('RAR', 'Gene', '5914', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('RA signaling', 'MPA', (107, 119))	('activity', 'MPA', (194, 202))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('Akt', 'Gene', (237, 240))
116000	20399149	Thus, dissecting the gene expression and DNA methylation alterations of G-CIMP tumors among lower grade gliomas will be helpful to better understand the roles of a mutant IDH1 and G-CIMP DNA methylation on tumor grade and patient survival.	('G-CIMP', 'Chemical', '-', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('G-CIMP', 'Chemical', '-', (180, 186))	('tumors', 'Disease', (79, 85))	('gliomas', 'Disease', (104, 111))	('tumor', 'Disease', (79, 84))	('patient', 'Species', '9606', (222, 229))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('IDH1', 'Gene', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('mutant', 'Var', (164, 170))	('tumor', 'Disease', (206, 211))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('IDH1', 'Gene', '3417', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
116004	20399149	Oncogene-induced senescence by mutant BRAF is known to be mediated by IGFBP7.	('mutant', 'Var', (31, 37))	('IGFBP7', 'Gene', (70, 76))	('Oncogene-induced senescence', 'CPA', (0, 27))	('BRAF', 'Gene', '673', (38, 42))	('mediated', 'Reg', (58, 66))	('BRAF', 'Gene', (38, 42))	('IGFBP7', 'Gene', '3490', (70, 76))
116005	20399149	Hence, CIMP-mediated inactivation of IGFBP7 provides a suitable environment for the acquisition of BRAF mutation.	('inactivation', 'Var', (21, 33))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('IGFBP7', 'Gene', (37, 43))	('mutation', 'Var', (104, 112))	('CIMP', 'Chemical', '-', (7, 11))	('IGFBP7', 'Gene', '3490', (37, 43))
116006	20399149	The tight concordance of G-CIMP status with IDH1 mutation in GBM tumors is very reminiscent of colorectal CIMP, in which DNA hypermethylation is strongly associated with BRAF mutation.	('BRAF', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('IDH1', 'Gene', (44, 48))	('colorectal CIMP', 'Disease', (95, 110))	('mutation', 'Var', (49, 57))	('CIMP', 'Chemical', '-', (106, 110))	('IDH1', 'Gene', '3417', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('GBM tumors', 'Disease', (61, 71))	('CIMP', 'Chemical', '-', (27, 31))	('GBM tumors', 'Disease', 'MESH:D005910', (61, 71))	('colorectal CIMP', 'Phenotype', 'HP:0200063', (95, 110))	('associated', 'Reg', (154, 164))	('BRAF', 'Gene', '673', (170, 174))	('G-CIMP', 'Chemical', '-', (25, 31))
116007	20399149	We hypothesize that the transcriptional silencing of as yet unknown G-CIMP targets may provide an advantageous environment for the acquisition of IDH1 mutation.	('IDH1', 'Gene', (146, 150))	('IDH1', 'Gene', '3417', (146, 150))	('mutation', 'Var', (151, 159))	('silencing', 'NegReg', (40, 49))	('G-CIMP', 'Chemical', '-', (68, 74))
116015	20399149	One sample (TCGA-06-0178) with a confirmed IDH1 mutation was removed from our analyses, since it became clear that an incorrect tissue type had been shipped for the DNA methylation analysis.	('mutation', 'Var', (48, 56))	('IDH1', 'Gene', '3417', (43, 47))	('IDH1', 'Gene', (43, 47))
116023	20399149	Using TCGA data, we identified a subset of GBM tumors with characteristic promoter DNA methylation alterations, referred to as a glioma CpG Island Methylator Phenotype (G-CIMP).	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('methylation alterations', 'Var', (87, 110))	('promoter DNA', 'Gene', (74, 86))	('G-CIMP', 'Chemical', '-', (169, 175))	('GBM tumors', 'Disease', (43, 53))	('alterations', 'Var', (99, 110))	('GBM tumors', 'Disease', 'MESH:D005910', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('glioma', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
116024	20399149	G-CIMP tumors have distinct molecular features, including a high frequency of IDH1 mutation and characteristic copy-number alterations.	('IDH1', 'Gene', (78, 82))	('tumors', 'Disease', (7, 13))	('G-CIMP', 'Disease', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('mutation', 'Var', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('IDH1', 'Gene', '3417', (78, 82))	('copy-number', 'MPA', (111, 122))	('G-CIMP', 'Chemical', '-', (0, 6))
116027	20399149	Identification of a CpG island methylator phenotype (G-CIMP) in gliomas G-CIMP is tightly associated with IDH1 mutation G-CIMP patients are younger at diagnosis and display improved survival G-CIMP is more prevalent among low- and intermediate-grade gliomas	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('G-CIMP', 'Chemical', '-', (72, 78))	('gliomas', 'Disease', (250, 257))	('G-CIMP', 'Chemical', '-', (53, 59))	('gliomas', 'Disease', 'MESH:D005910', (250, 257))	('gliomas', 'Phenotype', 'HP:0009733', (250, 257))	('G-CIMP', 'Chemical', '-', (191, 197))	('gliomas', 'Disease', (64, 71))	('IDH1', 'Gene', (106, 110))	('patients', 'Species', '9606', (127, 135))	('improved', 'PosReg', (173, 181))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('mutation', 'Var', (111, 119))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('IDH1', 'Gene', '3417', (106, 110))	('G-CIMP', 'Chemical', '-', (120, 126))	('survival', 'MPA', (182, 190))
116056	33392065	The following biomarkers were recorded: 1) IDH1 (isocitrate dehydrogenase 1), 2) 1p19q, 3) TP53, 4) ATRX, and 5) Ki67.	('1p19q', 'Var', (81, 86))	('TP53', 'Gene', (91, 95))	('ATRX', 'Gene', (100, 104))	('IDH1', 'Gene', (43, 47))	('ATRX', 'Gene', '546', (100, 104))	('IDH1', 'Gene', '3417', (43, 47))	('TP53', 'Gene', '7157', (91, 95))	('Ki67', 'Var', (113, 117))
116057	33392065	IDH1 and 1p19q codeletion and alpha thalassemia/mental retardation syndrome X-linked (ATRX) status were scored as positive or negative.	('ATRX', 'Gene', '546', (86, 90))	('1p19q codeletion', 'Var', (9, 25))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (36, 84))	('ATRX', 'Gene', (86, 90))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (36, 84))	('IDH1', 'Gene', (0, 4))	('mental retardation', 'Phenotype', 'HP:0001249', (48, 66))	('IDH1', 'Gene', '3417', (0, 4))
116084	33392065	Using this approach, WHO grade, molecular diagnosis, location, cortical involvement, multicentric, uniformity, margin enhance, 1p19q codeletion, and biomarker synergy (IDH+/ATRX-/TP53-) were independent prediction factors ( Table 2 ).	('TP53', 'Gene', (179, 183))	('IDH', 'Gene', '3417', (168, 171))	('ATRX', 'Gene', '546', (173, 177))	('1p19q codeletion', 'Var', (127, 143))	('ATRX', 'Gene', (173, 177))	('TP53', 'Gene', '7157', (179, 183))	('IDH', 'Gene', (168, 171))
116104	33392065	1p19q codeletion, where parts of oligodendroglial tumors exhibited a loss of heterozygosity in the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q).	('oligodendroglial tumors', 'Disease', (33, 56))	('loss', 'NegReg', (69, 73))	('1p19q', 'Var', (0, 5))	('short arm', 'Phenotype', 'HP:0009824', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (33, 56))
116105	33392065	1p19q codeletions in gliomas became a valuable biomarker of TMZ and PCV chemotherapy effectiveness and were associated with a better OS.	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('TMZ', 'Chemical', 'MESH:D000077204', (60, 63))	('1p19q codeletions', 'Var', (0, 17))	('gliomas', 'Disease', (21, 28))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
116106	33392065	For astrocytic tumors, which do not typically exhibit 1p19q codeletions, mutations in the alpha thalassemia/mental retardation (ATRX) gene could help to maintain telomere length.	('astrocytic tumors', 'Disease', 'MESH:D001254', (4, 21))	('mental retardation', 'Disease', (108, 126))	('help', 'Reg', (145, 149))	('mental retardation', 'Disease', 'MESH:D008607', (108, 126))	('mental retardation', 'Phenotype', 'HP:0001249', (108, 126))	('maintain', 'Reg', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('thalassemia', 'Disease', (96, 107))	('telomere length', 'MPA', (162, 177))	('ATRX', 'Gene', (128, 132))	('thalassemia', 'Disease', 'MESH:D013789', (96, 107))	('ATRX', 'Gene', '546', (128, 132))	('astrocytic tumors', 'Disease', (4, 21))	('mutations', 'Var', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
116107	33392065	TP53 is a key DNA damage repair molecule whose molecular mutation is associated with astrocytic histology and thus increases microglia infiltration.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (69, 79))	('increases', 'PosReg', (115, 124))	('microglia infiltration', 'CPA', (125, 147))	('astrocytic histology', 'Disease', (85, 105))	('molecular mutation', 'Var', (47, 65))
116124	33392065	IDH and ATRX mutations, 1p19q codeletions, and TP53 mutations are early events in gliomagenesis, and the tumor behavior of lower-grade gliomas can be predicted depending on these key molecules.	('ATRX', 'Gene', '546', (8, 12))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('IDH', 'Gene', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('TP53', 'Gene', '7157', (47, 51))	('glioma', 'Disease', (82, 88))	('tumor', 'Disease', (105, 110))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Disease', (135, 141))	('IDH', 'Gene', '3417', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('mutations', 'Var', (13, 22))	('mutations', 'Var', (52, 61))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('gliomas', 'Disease', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('1p19q', 'Gene', (24, 29))	('ATRX', 'Gene', (8, 12))	('TP53', 'Gene', (47, 51))
116227	32564774	In view of the importance of VEGFA in the angiogenesis pathway and to better understand its role in GBM, we selected one representative cell line of each subgroup, U87 as high, U373 as medium, and LN229 as low expression.	('LN229', 'Var', (197, 202))	('U373', 'Var', (177, 181))	('LN229', 'CellLine', 'CVCL:0393', (197, 202))	('GBM', 'Phenotype', 'HP:0012174', (100, 103))	('U87', 'Var', (164, 167))
116234	32564774	3a, the branch reduction number was only significant when U87 and U373-Spe-CM were used (P < 0.05).	('U373-Spe-CM', 'Var', (66, 77))	('branch reduction number', 'Disease', (8, 31))	('branch reduction number', 'Disease', 'MESH:D007674', (8, 31))	('U87', 'Var', (58, 61))
116236	32564774	These data demonstrate that U87 and U373-Spe-CM can efficiently reduce HBMEC tube formation.	('U373-Spe-CM', 'Var', (36, 47))	('reduce', 'NegReg', (64, 70))	('HBMEC tube formation', 'CPA', (71, 91))	('HBMEC', 'CellLine', 'CVCL:0307', (71, 76))	('U87', 'Var', (28, 31))
116237	32564774	After 3 h, the number of HBMECs that moved through the membrane with U87-C-CM was 6.7-fold higher than the number of cells incubated with U87-Spe-CM (P < 0.01).	('U87-C-CM', 'Var', (69, 77))	('HBMECs', 'CellLine', 'CVCL:0307', (25, 31))	('higher', 'PosReg', (91, 97))
116241	32564774	No changes in cell migration were observed in the wells incubated with LN229-CM (Fig.	('cell migration', 'CPA', (14, 28))	('LN229-CM', 'Var', (71, 79))	('LN229', 'CellLine', 'CVCL:0393', (71, 76))
116242	32564774	Consistent with these observations, we noticed a marked decrease in the HBMEC migration activity using U87 and U373-Spe-CM by the xCELLigence Real Time Cell Analyzer (Fig.	('U373-Spe-CM', 'Var', (111, 122))	('decrease', 'NegReg', (56, 64))	('HBMEC migration activity', 'CPA', (72, 96))	('HBMEC', 'CellLine', 'CVCL:0307', (72, 77))
116243	32564774	Importantly, we found that Spe-CM causes the disruption of the autocrine VEGF/VEGFR2 signaling loop as shown in the dramatic decrease of VEGFR2 expression (Additional file 1: Figure S6).	('VEGFR2', 'Gene', (78, 84))	('VEGFR2', 'Gene', (137, 143))	('VEGF', 'Gene', '7422', (137, 141))	('VEGFR2', 'Gene', '3791', (78, 84))	('expression', 'MPA', (144, 154))	('disruption', 'MPA', (45, 55))	('VEGF', 'Gene', (78, 82))	('VEGF', 'Gene', (137, 141))	('VEGF', 'Gene', '7422', (73, 77))	('decrease', 'NegReg', (125, 133))	('VEGFR2', 'Gene', '3791', (137, 143))	('Spe-CM', 'Var', (27, 33))	('VEGF', 'Gene', '7422', (78, 82))	('VEGF', 'Gene', (73, 77))
116245	32564774	Once we confirmed that CM from U87 and U373 treated with Spe of bevacizumab is sufficient to switch off the angiogenesis in vitro, we wondered whether the pathway would be limited in vivo.	('switch off', 'NegReg', (93, 103))	('bevacizumab', 'Chemical', 'MESH:D000068258', (64, 75))	('U373', 'Var', (39, 43))	('angiogenesis', 'CPA', (108, 120))
116249	32564774	Furthermore, the c-CM from U87 Spe and U373 SD and Spe, but not from LN229, presented a sustained decrease in neovascularization (Fig.	('LN229', 'CellLine', 'CVCL:0393', (69, 74))	('decrease', 'NegReg', (98, 106))	('U373 SD', 'Var', (39, 46))	('neovascularization', 'CPA', (110, 128))	('U87 Spe', 'Var', (27, 34))
116251	32564774	Analysis of angiogenesis-related factors (VEGFA, VEGFB, and VEGFR2) in Matrigel plugs obtained from c-CM-U87 and c-CM-U373 evidenced a high decrease in expression after the addition of the Spe of bevacizumab.	('c-CM-U87', 'Var', (100, 108))	('c-CM-U373', 'Var', (113, 122))	('VEGFR2', 'Gene', (60, 66))	('decrease', 'NegReg', (140, 148))	('VEGFB', 'Gene', '7423', (49, 54))	('bevacizumab', 'Chemical', 'MESH:D000068258', (196, 207))	('VEGFR2', 'Gene', '3791', (60, 66))	('VEGFB', 'Gene', (49, 54))	('expression', 'MPA', (152, 162))	('VEGFA', 'Gene', (42, 47))
116297	32564774	However, the median OS of patients with high VEGFA treated with bevacizumab increased in 8.5 months (Additional file 1: Figure S11C), and no effect was observed in patients with low VEGFA expression (Additional file 1: Figure S11B).	('S11B', 'SUBSTITUTION', 'None', (226, 230))	('S11B', 'Var', (226, 230))	('increased', 'PosReg', (76, 85))	('S11C', 'SUBSTITUTION', 'None', (127, 131))	('patients', 'Species', '9606', (26, 34))	('bevacizumab', 'Chemical', 'MESH:D000068258', (64, 75))	('S11C', 'Var', (127, 131))	('patients', 'Species', '9606', (164, 172))
116312	28232861	Cancer is a complex genetic disease spanning multiple molecular events such as point mutations, structural variations, translocations and activation of epigenetic and transcriptional signatures and networks.	('structural variations', 'Var', (96, 117))	('ran', 'Gene', (120, 123))	('ran', 'Gene', (168, 171))	('genetic disease', 'Disease', (20, 35))	('ran', 'Gene', '5901', (120, 123))	('ran', 'Gene', '5901', (168, 171))	('genetic disease', 'Disease', 'MESH:D030342', (20, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('point mutations', 'Var', (79, 94))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('activation', 'PosReg', (138, 148))
116315	28232861	For example, although we know that the majority of the most aggressive form of brain tumors such as glioma harbor the mutation of a single gene (IDH), the mechanistic explanation of the activation of its characteristic epigenetic and transcriptional signatures are still far to be well characterized.	('glioma', 'Disease', (100, 106))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('brain tumors', 'Disease', 'MESH:D001932', (79, 91))	('brain tumors', 'Phenotype', 'HP:0030692', (79, 91))	('mutation', 'Var', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ran', 'Gene', (235, 238))	('brain tumors', 'Disease', (79, 91))	('ran', 'Gene', '5901', (235, 238))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
116317	28232861	The Cancer Genome Atlas (TCGA): The TCGA consortium, which is a National Institute of Health (NIH) initiative, makes publicly available molecular and clinical information for more than 30 types of human cancers including exome (variant analysis), single nucleotide polymorphism (SNP), DNA methylation, transcriptome (mRNA), microRNA (miRNA) and proteome.	('single nucleotide polymorphism', 'Var', (247, 277))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('ran', 'Gene', (303, 306))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('DNA', 'MPA', (285, 288))	('ran', 'Gene', '5901', (303, 306))	('Cancer Genome Atlas', 'Disease', (4, 23))	('human', 'Species', '9606', (197, 202))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
116327	28232861	The next steps describes how one could use TCGAbiolinks & RTCGAToolbox to download clinical, genomics, transcriptomics, epigenomics data, as well as subtype information and GISTIC results (i.e., identified genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth).	('drive', 'Disease', (269, 274))	('that', 'PosReg', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('somatic copy-number', 'Var', (224, 243))	('ran', 'Gene', (104, 107))	('ran', 'Gene', '5901', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (275, 281))
116338	28232861	Annotated VCF files often have variants reported on multiple transcripts whereas the protected MAF (*protected.maf) only reports the most critically affected one and the Somatic MAFs (*somatic.maf) are further processed to remove low quality and potential germline variants.	('MAF', 'Gene', '4094', (178, 181))	('variants', 'Var', (31, 39))	('ran', 'Gene', (62, 65))	('ran', 'Gene', '5901', (62, 65))	('MAF', 'Gene', (178, 181))	('MAF', 'Gene', '4094', (95, 98))	('maf', 'Gene', '4094', (111, 114))	('maf', 'Gene', '4094', (193, 196))	('reported', 'Reg', (40, 48))	('maf', 'Gene', (111, 114))	('maf', 'Gene', (193, 196))	('MAF', 'Gene', (95, 98))
116341	28232861	The following arguments allows users to select the version and tumor type of interest:   These arguments can be used to select the data type to download: RNAseq_Gene, Clinic, miRNASeq_Gene, ccRNAseq2_Gene_Norm, CNA_SNP, CNV_SNP, CNA_Seq, CNA_CGH, Methylation, Mutation, mRNA_Array, miRNA_Array, and RPPA.	('Mutation', 'Var', (260, 268))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
116342	28232861	Using RTCGAToolbox to get the GISTIC results  Copy number variations (CNVs) have a critical role in cancer development and progression.	('Copy number variations', 'Var', (46, 68))	('progression', 'CPA', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
116343	28232861	A chromosomal segment can be deleted or amplified as a result of genomic rearrangements, such as deletions, duplications, insertions and translocations.	('insertions', 'Var', (122, 132))	('ran', 'Gene', (138, 141))	('ran', 'Gene', '5901', (138, 141))	('deletions', 'Var', (97, 106))	('duplications', 'Var', (108, 120))	('ran', 'Gene', (77, 80))	('ran', 'Gene', '5901', (77, 80))
116353	28232861	Recurrent CNV identification in cancer with GAIA  Recurrent amplifications and deletions were identified for both LGG ( Figure 1a) and GBM ( Figure 1b), and represented in chromosomal overview plots by a statistical score (- log 10 corrected p-value for amplifications and log 10 corrected p-value for deletions).	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('deletions', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
116360	28232861	We used circlize CRAN package to represent significant CNV (resulting from GAIA analysis) and recurrent mutations (selecting curated genetic variations retrieved from TCGA that are identified in at least two tumor samples) in LGG.	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (208, 213))
116370	28232861	These islands are normally found in sites of transcription initiation and their methylation can lead to gene silencing .	('methylation', 'Var', (80, 91))	('lead to', 'Reg', (96, 103))	('ran', 'Gene', (46, 49))	('ran', 'Gene', '5901', (46, 49))	('gene', 'MPA', (104, 108))
116371	28232861	Thus, the investigation of the DNA methylation is crucial to understanding regulatory gene networks in cancer as the DNA methylation represses transcription .	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('DNA', 'Var', (117, 120))	('ran', 'Gene', (144, 147))	('ran', 'Gene', '5901', (144, 147))	('methylation', 'Var', (121, 132))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('represses', 'NegReg', (133, 142))
116382	28232861	The user may be interested in looking for unique signatures in the regions defined by 'differentially methylated' to identify candidate transcription factors that could bind to these elements affected by the accumulation or absence of DNA methylation.	('ran', 'Gene', (137, 140))	('ran', 'Gene', '5901', (137, 140))	('absence', 'NegReg', (224, 231))	('DNA methylation', 'Var', (235, 250))
116387	28232861	However, these regions are associated neither with transcribed regions nor Polycomb repression as the H3K36me3 and H3K27me3 heatmaps does not show an enrichment nearby the position 0, and the average profile also does not show a peak at position 0.	('ran', 'Gene', (52, 55))	('ran', 'Gene', '5901', (52, 55))	('H3K27me3', 'Var', (115, 123))	('H3K36me3', 'Var', (102, 110))
116428	25471132	Extrachromosomal driver mutations in glioblastoma and low grade glioma Alteration of the number of copies of Double Minutes (DMs) with oncogenic EGFR mutations in response to tyrosine kinase inhibitors (TKIs) is a novel adaptive mechanism of glioblastoma.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('response', 'MPA', (163, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (242, 254))	('glioblastoma', 'Disease', 'MESH:D005909', (37, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('EGFR', 'Gene', '1956', (145, 149))	('glioblastoma', 'Disease', 'MESH:D005909', (242, 254))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('EGFR', 'Gene', (145, 149))	('DM', 'Disease', 'MESH:D009223', (125, 127))	('mutations', 'Var', (150, 159))	('glioma', 'Disease', (64, 70))	('mutations', 'Var', (24, 33))	('glioblastoma', 'Disease', (242, 254))	('glioblastoma', 'Disease', (37, 49))
116431	25471132	These mutations together with DMs are lost by cancer cells in culture.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (6, 15))	('DM', 'Disease', 'MESH:D009223', (30, 32))
116432	25471132	We confirm the extrachromosomal origin of such mutations by showing that wild type and mutated DMs may coexist in the same tumor.	('DM', 'Disease', 'MESH:D009223', (95, 97))	('tumor', 'Disease', (123, 128))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
116436	25471132	One form of genomic instability which makes tumors susceptible to acquiring point mutations is often referred to as the mutator phenotype .	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Disease', (44, 50))	('point mutations', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
116437	25471132	It is expected that the probability of acquisition of gain-of-function mutations in oncogenes is considerably lower than the probability of acquisition of loss-of-function mutations in tumor suppressor genes, because the first occur in a few critical sites, while the second occur anywhere in the coding sequence of the gene.	('tumor', 'Disease', (185, 190))	('gain-of-function', 'PosReg', (54, 70))	('oncogenes', 'Gene', (84, 93))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
116438	25471132	RTKs like EGFR, PDGFRA)  which may increase the probability of acquisition of gain-of-function mutations .	('EGFR', 'Gene', '1956', (10, 14))	('gain-of-function', 'PosReg', (78, 94))	('EGFR', 'Gene', (10, 14))	('PDGFRA', 'Gene', '5156', (16, 22))	('mutations', 'Var', (95, 104))	('PDGFRA', 'Gene', (16, 22))
116446	25471132	Therefore the mutation load in DMs is expected to be higher than that in chromosomal DNA because the repair of DNA damage by NHEJ results in acquisition of point mutations and small indels and the DNA damage repair mechanism is less efficient in the micronuclei compared to the nucleus .	('DM', 'Disease', 'MESH:D009223', (31, 33))	('acquisition', 'PosReg', (141, 152))	('point mutations', 'Var', (156, 171))	('NHEJ', 'Gene', (125, 129))
116447	25471132	It is also expected that the mutational load in the regions amplified as DMs may be considerably higher than in chromosomal non-amplified DNA as this kind of amplification may reach 100s of copies per cell or more .	('mutational', 'Var', (29, 39))	('higher', 'PosReg', (97, 103))	('DM', 'Disease', 'MESH:D009223', (73, 75))
116456	25471132	Notably, one individual had four mutations associated with FAs in the primary tumor which were lost in the spheres (GBM IV-34) (Figure 1).	('primary tumor', 'Disease', (70, 83))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('primary tumor', 'Disease', 'MESH:D009369', (70, 83))	('associated', 'Reg', (43, 53))	('FAs', 'Disease', (59, 62))
116457	25471132	One of these mutations, PDGFRA N659K (COSM22415), was within a 5.1Mb amplification (chr4:52.86-57.98Mb) while the other three: MARS p.G888E, DDIT3 p.P11S and DDIT3 p.S31L were within an amplification of 1.5Mb on chromosome 12 (chr12:57.86-59.31Mb).	('PDGFRA', 'Gene', '5156', (24, 30))	('DDIT3', 'Gene', '1649', (158, 163))	('PDGFRA', 'Gene', (24, 30))	('DDIT3', 'Gene', (141, 146))	('N659K', 'Mutation', 'rs1057519700', (31, 36))	('chr12:57.86-59.31', 'STRUCTURAL_ABNORMALITY', 'None', (227, 244))	('p.P11S', 'Mutation', 'p.P11S', (147, 153))	('DDIT3', 'Gene', '1649', (141, 146))	('p.G888E', 'Mutation', 'rs757725212', (132, 139))	('p.S31L', 'Mutation', 'p.S31L', (164, 170))	('p.G888E', 'Var', (132, 139))	('p.P11S', 'Var', (147, 153))	('DDIT3', 'Gene', (158, 163))	('COSM22415', 'Chemical', '-', (38, 47))	('chr4:52.86-57.98', 'STRUCTURAL_ABNORMALITY', 'None', (84, 100))
116458	25471132	The fraction of reads supporting these mutations was close to 100% in the primary tumor sample (86%, 97%, 99% and 100% respectively).	('primary tumor', 'Disease', 'MESH:D009369', (74, 87))	('primary tumor', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutations', 'Var', (39, 48))
116462	25471132	In both tumors the EGFR (p.A289V and p.S227Y) mutations and focal amplifications were present in the primary tissues and gliomaspheres at passage 0, however they were completely lost at later passages (Table 1).	('p.S227Y', 'Var', (37, 44))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('EGFR', 'Gene', '1956', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('p.S227Y', 'Mutation', 'p.S227Y', (37, 44))	('EGFR', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('p.A289V', 'Var', (25, 32))	('p.A289V', 'Mutation', 'rs149840192', (25, 32))
116465	25471132	This cell line is of particular interest as amplified EGFR copies harbor the in-frame deletion of exons 2 to 7 coding for the extracellular ligand (EGFRvIII).	('to 7', 'Species', '1214577', (106, 110))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))	('deletion', 'Var', (86, 94))
116471	25471132	The EGFR p.C326S (COSM1600351) mutation was within the focally amplified region and was identified in 36% of reads of the primary tumor but was lost in the spheres.	('p.C326S', 'Var', (9, 16))	('primary tumor', 'Disease', 'MESH:D009369', (122, 135))	('EGFR', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('p.C326S', 'Mutation', 'p.C326S', (9, 16))	('primary tumor', 'Disease', (122, 135))	('EGFR', 'Gene', '1956', (4, 8))
116472	25471132	On the other hand if mutations occur after the formation of DMs and therefore are of extrachromosomal origin, their absence in the spheres could be explained by the loss of DMs from the tumor cells (Figure 3a upper panel).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('DM', 'Disease', 'MESH:D009223', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('loss', 'NegReg', (165, 169))	('DM', 'Disease', 'MESH:D009223', (173, 175))	('mutations', 'Var', (21, 30))
116474	25471132	In order to validate this hypothesis we reanalyzed the DNA sequencing data from GBM primary tumors from the TCGA study with FAs and point mutations in EGFR, focusing on samples where EGFR mutations were present in less than 90% of reads (Figure 3b).	('EGFR', 'Gene', (151, 155))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('primary tumors', 'Disease', (84, 98))	('point mutations', 'Var', (132, 147))	('primary tumors', 'Disease', 'MESH:D009369', (84, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('EGFR', 'Gene', '1956', (151, 155))
116477	25471132	In the 7 remaining TCGA GBM tumors we detected 9 EGFR mutations showing a level of amplification of more than 36 copies per cell.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('GBM tumors', 'Disease', (24, 34))	('GBM tumors', 'Disease', 'MESH:D005910', (24, 34))
116479	25471132	Therefore, these data confirm the existence of GBM tumors in which the mutated and wild type DM copies coexist and therefore support the scenario where the DMs are first formed and the mutation subsequently occurred in one of the DM copies.	('DM', 'Disease', 'MESH:D009223', (156, 158))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('DM', 'Disease', 'MESH:D009223', (230, 232))	('mutated', 'Var', (71, 78))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('GBM tumors', 'Disease', (47, 57))	('GBM tumors', 'Disease', 'MESH:D005910', (47, 57))	('DM', 'Disease', 'MESH:D009223', (93, 95))
116483	25471132	In total we have identified 1129 somatic mutations across all tumor types which map within regions of FAs and comprise 0.58% of all studied mutations.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
116484	25471132	We found a positive correlation between mutation rates and extent of FAs across all tumor types (P=0.002, R=0.75).	('mutation', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
116485	25471132	In each tumor type the mutation rates within FAs were higher than outside, with an average increase of 3.67 fold +- 2.68.	('higher', 'PosReg', (54, 60))	('mutation', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))
116486	25471132	The most important increase of mutation rates within FAs were observed in brain tumors: low grade gliomas (LGG; 9 fold) and glioblastomas (GBM; 8 fold) (Figure 4).	('glioblastomas', 'Disease', (124, 137))	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutation', 'Var', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('increase', 'PosReg', (19, 27))	('brain tumors', 'Disease', (74, 86))	('gliomas', 'Disease', (98, 105))	('glioblastomas', 'Phenotype', 'HP:0012174', (124, 137))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('glioblastomas', 'Disease', 'MESH:D005909', (124, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
116489	25471132	The probability of fixation of "oncogenic" driver mutations in FAs as compared to the total number of mutations increased in almost all tumor types with the most pronounced effect in LGG (4 fold) and GBM (6 fold).	('FAs', 'Disease', (63, 66))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
116491	25471132	When all tumors were analyzed, 212 genes revealed a significant enrichment of mutations in focally amplified regions (p <0.05).	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
116495	25471132	The strongest enrichment of mutations in FAs was observed in EGFR in GBM, low grade glioma, head and neck squamous cell carcinoma, lung and uterine cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('GBM', 'Disease', (69, 72))	('lung', 'Disease', 'MESH:D008171', (131, 135))	('glioma', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (92, 129))	('lung', 'Disease', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('neck squamous cell carcinoma', 'Disease', (101, 129))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (101, 129))	('EGFR', 'Gene', '1956', (61, 65))	('uterine cancer', 'Phenotype', 'HP:0010784', (140, 154))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('mutations', 'Var', (28, 37))	('EGFR', 'Gene', (61, 65))
116496	25471132	PDGFRA mutations were enriched in FAs in GBM, low grade glioma and lung cancer; and KIT mutations in lung cancer.	('glioma', 'Disease', (56, 62))	('PDGFRA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('PDGFRA', 'Gene', '5156', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Disease', (101, 112))	('GBM', 'Disease', (41, 44))	('FAs', 'Disease', (34, 37))
116497	25471132	Similar co-localizations were observed for NOTCH3 mutations in ovarian and breast cancers; CCNE1 mutations in uterine cancer; BCL11A mutations in lung cancer and WHSC1L1 mutations in head and neck squamous cell carcinoma and lung cancer (Supplementary Figure 4).	('mutations', 'Var', (97, 106))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancer', 'Disease', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (63, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('BCL11A', 'Gene', '53335', (126, 132))	('WHSC1L1', 'Gene', '54904', (162, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('NOTCH3', 'Gene', '4854', (43, 49))	('neck squamous cell carcinoma and lung cancer', 'Disease', 'MESH:D002294', (192, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('WHSC1L1', 'Gene', (162, 169))	('mutations', 'Var', (133, 142))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (230, 236))	('breast cancers', 'Phenotype', 'HP:0003002', (75, 89))	('NOTCH3', 'Gene', (43, 49))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (183, 220))	('cancer', 'Disease', (118, 124))	('CCNE1', 'Gene', (91, 96))	('uterine cancer', 'Phenotype', 'HP:0010784', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Disease', (225, 236))	('BCL11A', 'Gene', (126, 132))	('CCNE1', 'Gene', '898', (91, 96))	('mutations', 'Var', (50, 59))	('mutations', 'Var', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
116498	25471132	The most remarkable effect was observed in EGFR where the percentage of mutations in FA in all tumors increased from 39% (all mutations) to 65% (putative driver mutations) followed by PDGFRA (from 17 to 50% in LGG) and ERBB2 (from 7 to 11% in all tumors).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('mutations', 'Var', (72, 81))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('PDGFRA', 'Gene', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('ERBB2', 'Gene', (219, 224))	('PDGFRA', 'Gene', '5156', (184, 190))	('EGFR', 'Gene', '1956', (43, 47))	('ERBB2', 'Gene', '2064', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('EGFR', 'Gene', (43, 47))	('tumors', 'Disease', (95, 101))
116500	25471132	In this work we demonstrate the existence of a non-random association of focal amplifications and likely driver mutations in tumors.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('mutations', 'Var', (112, 121))	('focal amplifications', 'Var', (73, 93))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))
116501	25471132	In addition we propose a mechanism for acquisition of gain-of-function driver mutations in oncogenes mediated by the higher mutation load observed in DMs.	('oncogenes', 'Gene', (91, 100))	('gain-of-function', 'PosReg', (54, 70))	('DM', 'Disease', 'MESH:D009223', (150, 152))	('mutations', 'Var', (78, 87))
116503	25471132	DM origin of such mutations was confirmed by revealing the GBM tumors where wild type and mutated DM copies coexist (Figure 3a upper panel).	('GBM tumors', 'Disease', (59, 69))	('GBM tumors', 'Disease', 'MESH:D005910', (59, 69))	('DM', 'Disease', 'MESH:D009223', (98, 100))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('DM', 'Disease', 'MESH:D009223', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutations', 'Var', (18, 27))
116507	25471132	After cell division the cell with the highest number of DMs harboring the driver mutation will have a proliferative advantage.	('proliferative advantage', 'CPA', (102, 125))	('mutation', 'Var', (81, 89))	('DM', 'Disease', 'MESH:D009223', (56, 58))
116509	25471132	An important consequence of this model is that, in the case of changes of environmental conditions, the number of DMs could be modulated and even reduced to zero resulting in the complete loss of ALEMs.	('ALEMs', 'MPA', (196, 201))	('changes', 'Var', (63, 70))	('loss', 'NegReg', (188, 192))	('DM', 'Disease', 'MESH:D009223', (114, 116))
116511	25471132	By studying a large number of tumors from publicly available data (TCGA consortium) we have detected co-localization of mutations with amplifications in tumors known to harbor DMs such as GBM, LGG and LUSC.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('LUSC', 'Disease', (201, 205))	('DM', 'Disease', 'MESH:D009223', (176, 178))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('LGG', 'Disease', (193, 196))	('amplifications', 'Var', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Disease', (153, 159))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('GBM', 'Disease', (188, 191))
116514	25471132	Remarkably, our model explains the observations made by Nathanson et al., 2014, where the extrachromosomal EGFRvIII mutation disappeared in response to Tyrosine-Kinase Inhibitors (TKIs).	('EGFR', 'Gene', '1956', (107, 111))	('mutation', 'Var', (116, 124))	('response to', 'MPA', (140, 151))	('EGFR', 'Gene', (107, 111))	('disappeared', 'NegReg', (125, 136))
116517	25471132	According to our model amplification of EGFR which is not a strong oncogenic event per se may increase the mutation load and enhance the probability of acquisition of the driver mutations in EGFR.	('increase', 'PosReg', (94, 102))	('amplification', 'Var', (23, 36))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('EGFR', 'Gene', '1956', (40, 44))	('acquisition', 'MPA', (152, 163))	('enhance', 'PosReg', (125, 132))	('EGFR', 'Gene', (40, 44))	('mutations', 'Var', (178, 187))	('mutation load', 'MPA', (107, 120))
116519	25471132	They result from a mutagenic process which is based on the increased mutational load of DMs that include proliferation-promoting genes such as tyrosine-kinases receptors leading to an increased adaptive potential of the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('DM', 'Disease', 'MESH:D009223', (88, 90))	('mutational', 'Var', (69, 79))	('tumor', 'Disease', (220, 225))	('increased', 'PosReg', (184, 193))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
116532	25471132	Genes amplifications were investigated by FISH analysis using the LSI EGFR Spectrum Orange/CEP7 Spectrum Green probe (Vysis, Abbott Laboratories, Illinois, USA) and the BAC probe RP11-231c18 directed against PDGFRA (chr4:55,127,335-55,259,498; hg19, spectrum green) and the control probe dj963K6 (4qter, spectrum red).	('chr4:55,127,335-55,259,498', 'STRUCTURAL_ABNORMALITY', 'None', (216, 242))	('RP11-231c18', 'Var', (179, 190))	('spectrum green', 'Chemical', '-', (250, 264))	('EGFR', 'Gene', '1956', (70, 74))	('Spectrum', 'Chemical', '-', (75, 83))	('PDGFRA', 'Gene', (208, 214))	('EGFR', 'Gene', (70, 74))	('PDGFRA', 'Gene', '5156', (208, 214))	('Spectrum', 'Chemical', '-', (96, 104))
116536	32732999	Identification of relevant genetic alterations in cancer using topological data analysis Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('lead to', 'Reg', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (164, 173))	('tumors', 'Disease', (218, 224))
116537	32732999	While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutations', 'Var', (16, 25))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))
116538	32732999	Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression.	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Disease', (113, 119))	('changes', 'Reg', (165, 172))	('expression', 'MPA', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', (75, 80))
116539	32732999	We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (190, 209))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cancer', 'Disease', (95, 101))	('ADAMTS12', 'Gene', (178, 186))	('lung adenocarcinoma', 'Disease', (190, 209))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (190, 209))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('inactivating mutations', 'Var', (130, 152))
116542	32732999	Rare cancer mutations are often missed using recurrence-based statistical approaches, but are usually accompanied by changes in expression.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (5, 11))	('changes', 'Reg', (117, 124))	('expression', 'MPA', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
116545	32732999	Large-scale cross-sectional cancer molecular studies, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium, enable this identification by systematically compiling genetic alterations across many tumors.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('genetic', 'Var', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('Cancer', 'Disease', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Cancer', 'Disease', (115, 121))	('cancer', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (115, 121))
116548	32732999	These studies have also revealed that most cancer mutations occur at low frequencies (<10% of samples), including potentially actionable therapeutic targets.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
116549	32732999	The identification of low-prevalence cancer-associated mutations using recurrence-based methods is challenging because of the large number of samples needed to achieve statistical power and the inherent complexity in modeling the background mutation rates.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (55, 64))
116551	32732999	It is estimated that for the current size of ongoing cross-sectional studies (typically consisting of less than 1000 patients) only cancer-associated mutations that occur at intermediate or high frequencies (>15%) are fully accessible to recurrence-based methods.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (150, 159))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
116552	32732999	This is consistent with the observation that patients in these studies often completely lack mutations in known cancer-associated genes.	('mutations', 'Var', (93, 102))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (45, 53))	('lack', 'NegReg', (88, 92))
116555	32732999	If a mutation is accompanied by consistent changes in copy number, gene expression, and/or methylation, it is possible to leverage these changes to relate the mutation event to cancer progression.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('copy number', 'MPA', (54, 65))	('gene expression', 'MPA', (67, 82))	('changes', 'Reg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('methylation', 'MPA', (91, 102))	('mutation', 'Var', (5, 13))
116556	32732999	Several studies have utilized changes in the copy number, expression, or methylation of the mutated gene (cis-effects) to identify novel cancer-associated mutations.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (155, 164))	('expression', 'MPA', (58, 68))	('changes', 'Reg', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))
116557	32732999	However, the identification of cancer-associated mutations based on changes in genes other than the mutated gene (trans-effects) is more challenging and usually requires providing information about known gene-gene relationships to reduce the number of false positives.	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mutations', 'Var', (49, 58))
116558	32732999	DriverNet, OncoIMPACT, CaMoDi, and Xseq utilize trans-effects in gene expression to identify cancer-associated mutations.	('mutations', 'Var', (111, 120))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
116559	32732999	Current approaches for the identification of cancer-associated mutations using expression data are sensitive to several confounding effects.	('mutations', 'Var', (63, 72))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
116575	32732999	We hypothesized that if a mutated gene appears localized in the expression space, it is associated with consistent global expression patterns across a subset of tumors, and is therefore a candidate driver of tumor progression (Fig.	('expression', 'MPA', (122, 132))	('tumors', 'Disease', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mutated gene', 'Var', (26, 38))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
116576	32732999	On the other hand, if mutations of a gene are clonally expanded as a result of being in the same genome as a positively-selected mutation, but are not cancer-related, they will appear randomly scattered in the expression subspace (Fig.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutation', 'Var', (129, 137))	('cancer', 'Disease', (151, 157))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
116579	32732999	Based on this analysis, we subsampled mutations in two hypermutated tumors (nmut > 102.5) that were present in the LGG cohort.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutations', 'Var', (38, 47))
116582	32732999	In particular, some of the most significant genes according to our approach, like FUBP1, NOTCH1, PTEN, EGFR, and NF1, were mutated in less than 10% of the patients within that tumor type (Fig.	('EGFR', 'Gene', '1956', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('FUBP1', 'Gene', (82, 87))	('PTEN', 'Gene', (97, 101))	('PTEN', 'Gene', '5728', (97, 101))	('EGFR', 'Gene', (103, 107))	('tumor', 'Disease', (176, 181))	('NF1', 'Gene', (113, 116))	('NOTCH1', 'Gene', '4851', (89, 95))	('NOTCH1', 'Gene', (89, 95))	('NF1', 'Gene', '4763', (113, 116))	('FUBP1', 'Gene', '8880', (82, 87))	('patients', 'Species', '9606', (155, 163))	('mutated', 'Var', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
116587	32732999	These tumors harbored frequent deletions of the chromosome arm 19q, in addition to molecular alterations characteristic of astrocytic gliomas, such as TP53 and ATRX mutations (Fisher's exact test p-value < 0.01, Supplementary Fig.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('ATRX', 'Gene', '546', (160, 164))	('TP53', 'Gene', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('deletions', 'Var', (31, 40))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('TP53', 'Gene', '7157', (151, 155))	('ATRX', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (165, 174))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (123, 141))	('astrocytic gliomas', 'Disease', (123, 141))
116594	32732999	Some of the most significant cancer genes identified by MutSig2CV based on recurrence, such as PIK3R1 (mutated in 4% of the tumors), were not selected by our expression-based approach, highlighting the independence of recurrence- and expression-based approaches.	('PIK3R1', 'Gene', (95, 101))	('cancer', 'Disease', (29, 35))	('MutSig2CV', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('PIK3R1', 'Gene', '5295', (95, 101))
116611	32732999	Elusive genes included NOTCH2 mutations in breast invasive carcinoma (mutated in 2% of the tumors), which have been recently reported by manual inspection; inactivating mutations of the tumor-suppressor genes KMT2A (also known as MLL1) and CUX1 in head and neck squamous cell carcinoma (each present in 1% of the tumors); inactivating mutations of the tumor-suppressor gene ADAMTS12 in lung adenocarcinoma (present in 4% of the tumors); mutations in the kinase domain of CHEK2 in thyroid carcinoma (present in 1% of the tumors), which have been associated with increased susceptibility to this cancer type; inactivating mutations of the putative tumor-suppressor gene USP9X in thyroid carcinoma (present in 1% of the tumors), which codes for a deubiquitinase regulating the TGFbeta and hippo signaling pathways; and inactivating mutations of ATRX in pheochromocytoma and paraganglioma (present in 2% of the tumors).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (717, 723))	('tumor', 'Disease', (313, 318))	('tumors', 'Disease', 'MESH:D009369', (907, 913))	('lung adenocarcinoma', 'Disease', (386, 405))	('KMT2A', 'Gene', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Disease', (91, 96))	('CUX1', 'Gene', (240, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (396, 405))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (480, 497))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (520, 526))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (386, 405))	('cancer', 'Disease', (594, 600))	('CHEK2', 'Gene', '11200', (471, 476))	('tumors', 'Disease', (91, 97))	('NOTCH2', 'Gene', '4853', (23, 29))	('tumors', 'Disease', (907, 913))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (850, 866))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (520, 525))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('CUX1', 'Gene', '1523', (240, 244))	('NOTCH2', 'Gene', (23, 29))	('hippo signaling pathways', 'Pathway', (786, 810))	('MLL1', 'Gene', (230, 234))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (520, 525))	('CHEK2', 'Gene', (471, 476))	('mutations', 'Var', (437, 446))	('tumor', 'Disease', (352, 357))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (677, 694))	('tumor', 'Disease', 'MESH:D009369', (907, 912))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (594, 600))	('glioma', 'Phenotype', 'HP:0009733', (878, 884))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('KMT2A', 'Gene', '4297', (209, 214))	('inactivating mutations', 'Var', (816, 838))	('carcinoma', 'Phenotype', 'HP:0030731', (488, 497))	('USP9X', 'Gene', '8239', (668, 673))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (257, 285))	('tumors', 'Disease', (313, 319))	('TGFbeta', 'Gene', '7039', (774, 781))	('tumor', 'Phenotype', 'HP:0002664', (428, 433))	('tumor', 'Disease', (717, 722))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (262, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('tumor', 'Disease', (646, 651))	('tumor', 'Disease', 'MESH:D009369', (717, 722))	('tumor', 'Disease', (907, 912))	('thyroid carcinoma', 'Disease', (480, 497))	('tumors', 'Disease', 'MESH:D009369', (428, 434))	('tumor', 'Disease', 'MESH:D009369', (646, 651))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (386, 405))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('neck squamous cell carcinoma', 'Disease', (257, 285))	('TGFbeta', 'Gene', (774, 781))	('carcinoma', 'Phenotype', 'HP:0030731', (685, 694))	('cancer', 'Disease', 'MESH:D009369', (594, 600))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (43, 68))	('tumors', 'Phenotype', 'HP:0002664', (428, 434))	('MLL1', 'Gene', '4297', (230, 234))	('tumors', 'Disease', (428, 434))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (43, 68))	('inactivating mutations', 'Var', (607, 629))	('tumors', 'Disease', 'MESH:D009369', (717, 723))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (850, 884))	('paraganglioma', 'Phenotype', 'HP:0002668', (871, 884))	('thyroid carcinoma', 'Disease', (677, 694))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (520, 526))	('tumor', 'Disease', (428, 433))	('ATRX', 'Gene', (842, 846))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (480, 497))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('breast invasive carcinoma', 'Disease', (43, 68))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (677, 694))	('tumors', 'Phenotype', 'HP:0002664', (717, 723))	('ATRX', 'Gene', '546', (842, 846))	('tumor', 'Disease', 'MESH:D009369', (428, 433))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumors', 'Disease', 'MESH:D009369', (520, 526))	('USP9X', 'Gene', (668, 673))
116615	32732999	Using TCGA survival data we found that, among the previously unreported cancer-associated genes, inactivating mutations of ADAMTS12 were associated with poor survival (Fig.	('associated', 'Reg', (137, 147))	('inactivating mutations', 'Var', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ADAMTS12', 'Gene', (123, 131))	('poor survival', 'CPA', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
116620	32732999	Consistent with the suggested antitumorgenic properties of ADAMTS12, we observed that LUAD patients with chromosome 5p amplification and unaltered ADAMTS12 gene have better overall survival than those without chromosome 5p amplification (Fig.	('patients', 'Species', '9606', (91, 99))	('tumor', 'Disease', (34, 39))	('chromosome', 'Var', (105, 115))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('overall survival', 'CPA', (173, 189))	('ADAMTS12', 'Gene', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('better', 'PosReg', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
116621	32732999	To the contrary, patients with chromosome 5p amplification and truncating mutations in ADAMTS12 have a reduced survival with respect to patients that harbor the amplification without mutations in ADAMTS12 (Fig.	('chromosome', 'Var', (31, 41))	('survival', 'MPA', (111, 119))	('reduced', 'NegReg', (103, 110))	('truncating mutations', 'Var', (63, 83))	('ADAMTS12', 'Gene', (196, 204))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (17, 25))	('ADAMTS12', 'Gene', (87, 95))
116622	32732999	To validate ADAMTS12 inactivation as a driver of progression in lung carcinoma, we investigated the effect of silencing ADAMTS12 in the lung carcinoma cell line LL/2-luc-M38 using a shRNA plasmid.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('inactivation', 'Var', (21, 33))	('silencing', 'Var', (110, 119))	('lung carcinoma', 'Disease', 'MESH:D008175', (136, 150))	('lung carcinoma', 'Disease', (136, 150))	('lung carcinoma', 'Disease', (64, 78))	('lung carcinoma', 'Disease', 'MESH:D008175', (64, 78))	('ADAMTS12', 'Gene', (120, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
116630	32732999	To identify which somatic mutations are relevant to the progression of tumors, most genomic analyses focus on the recurrence of mutations and define candidate cancer-associated genes as those mutated at a higher frequency than expected under a modeled local neutral mutation rate.	('cancer', 'Disease', (159, 165))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
116632	32732999	Here, we have adopted an alternative definition for candidate cancer-associated gene based on the assumption that mutations in these genes are accompanied by consistent global expression patterns in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (114, 123))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
116633	32732999	Remarkably, these two fundamentally different definitions are in practice highly consistent with each other, as we find that most mutations occurring at a high frequency compared to the local neutral mutation rate are associated with consistent global mRNA expression patterns in the tumor.	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('mRNA expression patterns', 'MPA', (252, 276))	('tumor', 'Disease', (284, 289))
116635	32732999	One example of such elusive cancer-associated mutations are truncating mutations of the PEST domain of NOTCH2 occurring in breast invasive carcinoma.	('NOTCH2', 'Gene', (103, 109))	('mutations', 'Var', (46, 55))	('truncating mutations', 'Var', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (123, 148))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('NOTCH2', 'Gene', '4853', (103, 109))	('cancer', 'Disease', (28, 34))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (123, 148))	('breast invasive carcinoma', 'Disease', (123, 148))
116642	32732999	These results are consistent with the observation that patients of lung adenocarcinoma with tumors harboring truncating mutations of ADAMTS12 have poor survival.	('truncating mutations', 'Var', (109, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('ADAMTS12', 'Gene', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('patients', 'Species', '9606', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
116651	32732999	The score C(g) is therefore a sum over the edges of the network, where the contribution of each edge is proportional to the product of the fraction of tumors that harbor the mutated gene in each of the two nodes connected by the edge.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutated gene', 'Var', (174, 186))
116683	32732999	Sections were incubated with anti-ADAMTS12 (H-142, Santa Cruz Biotechnologies, 1 h at 37  C; 1:50 dilution) or with anti-Ki-67 (ab66155, Abcam, o/n at 4  C; 1:4000 dilution) primary antibodies.	('Ki-67', 'Gene', '17345', (121, 126))	('Ki-67', 'Gene', (121, 126))	('anti-ADAMTS12', 'Var', (29, 42))
116692	32461966	hsCRP was significantly related to slower psychomotor speed in high-grade glioma patients (rho = 0.30, p < 0.05).	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('slower psychomotor', 'Disease', (35, 53))	('high-grade glioma', 'Disease', (63, 80))	('psychomotor speed', 'Phenotype', 'HP:0025356', (42, 59))	('hsCRP', 'Var', (0, 5))	('slower psychomotor', 'Disease', 'MESH:D011596', (35, 53))
116693	32461966	In meningioma sample, NT-proBNP correlated with decreased psychomotor speed (rho = 0.38, p < 0.01), mental flexibility (rho = 0.33, p < 0.01), worse cumulative learning (rho = -0.27, p < 0.05), and delayed recall (rho = 0.30, p < 0.01).	('worse', 'NegReg', (143, 148))	('NT-proBNP', 'Var', (22, 31))	('psychomotor speed', 'Phenotype', 'HP:0025356', (58, 75))	('meningioma', 'Disease', (3, 13))	('delayed recall', 'CPA', (198, 212))	('mental flexibility', 'CPA', (100, 118))	('meningioma', 'Phenotype', 'HP:0002858', (3, 13))	('decreased psychomotor speed', 'Disease', 'MESH:D011596', (48, 75))	('decreased psychomotor speed', 'Disease', (48, 75))
116716	32461966	Similarly, in a sample of stroke patient levels, NT-proBNP at admission was associated with worse cognitive functioning in univariate analysis, but the relationship became nonsignificant when the model was adjusted for age, stroke type, and other clinical variables.	('stroke', 'Disease', (26, 32))	('NT-proBNP', 'Var', (49, 58))	('stroke', 'Disease', 'MESH:D020521', (26, 32))	('stroke', 'Phenotype', 'HP:0001297', (224, 230))	('worse cognitive functioning', 'Phenotype', 'HP:0001268', (92, 119))	('stroke', 'Phenotype', 'HP:0001297', (26, 32))	('stroke', 'Disease', (224, 230))	('cognitive functioning', 'CPA', (98, 119))	('worse', 'NegReg', (92, 97))	('stroke', 'Disease', 'MESH:D020521', (224, 230))
116718	32461966	The heart interplays with other organs and deterioration of cardiac function inevitably leads to other organ dysfunction, including the decreased function of the brain.	('deterioration', 'Var', (43, 56))	('deterioration of cardiac function', 'Phenotype', 'HP:0001635', (43, 76))	('organ dysfunction', 'Disease', (103, 120))	('function', 'MPA', (146, 154))	('leads to', 'Reg', (88, 96))	('organ dysfunction', 'Disease', 'MESH:D009102', (103, 120))	('decreased', 'NegReg', (136, 145))
116722	32461966	in a sample of 108 BT patients found no association between increase in NT-proBNP and cardiac dysfunction; levels of NT-proBNP were directly associated with cerebral damage.	('cardiac dysfunction', 'Disease', (86, 105))	('cerebral damage', 'Disease', (157, 172))	('levels', 'Var', (107, 113))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (86, 105))	('cerebral damage', 'Disease', 'MESH:D000070625', (157, 172))	('associated with', 'Reg', (141, 156))
116723	32461966	Previous research showed that inflammation is associated with decreased hippocampal volume, impaired endothelial function of brain vasculature, neurodegeneration, and impaired neurogenesis, dysregulation of frontal neural pathways or may have indirect impact on cognitive functioning via vascular factors.	('neurodegeneration', 'Disease', 'MESH:D019636', (144, 161))	('endothelial', 'MPA', (101, 112))	('decreased', 'NegReg', (62, 71))	('impaired neurogenesis', 'Disease', 'MESH:D001750', (167, 188))	('decreased hippocampal volume', 'Phenotype', 'HP:0025517', (62, 90))	('impaired', 'NegReg', (92, 100))	('impaired neurogenesis', 'Disease', (167, 188))	('neurodegeneration', 'Phenotype', 'HP:0002180', (144, 161))	('hippocampal volume', 'CPA', (72, 90))	('dysregulation', 'Var', (190, 203))	('neurodegeneration', 'Disease', (144, 161))	('frontal neural pathways', 'Pathway', (207, 230))
116727	32224866	mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in lower grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('IDH1', 'Gene', (57, 61))	('Isocitrate dehydrogenase', 'Gene', '3417', (77, 101))	('Rac1', 'Gene', (7, 11))	('Glioma', 'Disease', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('IDH', 'Gene', (57, 60))	('Isocitrate dehydrogenase', 'Gene', (77, 101))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('IDH', 'Gene', (103, 106))	('Aggressiveness', 'Phenotype', 'HP:0000718', (39, 53))	('Cancer Aggressiveness', 'Disease', 'MESH:D009369', (32, 53))	('mTORC2', 'Gene', (0, 6))	('IDH1', 'Gene', '3417', (57, 61))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))	('IDH', 'Gene', '3417', (57, 60))	('Rac1', 'Gene', '5879', (7, 11))	('IDH', 'Gene', '3417', (103, 106))	('Glioma', 'Disease', 'MESH:D005910', (70, 76))	('mTORC2', 'Gene', '74343', (0, 6))	('genetic abnormalities', 'Disease', 'MESH:D030342', (129, 150))	('Cancer Aggressiveness', 'Disease', (32, 53))	('genetic abnormalities', 'Disease', (129, 150))	('mutations', 'Var', (108, 117))	('gliomas', 'Disease', (166, 173))	('Predisposes', 'Reg', (20, 31))	('Glioma', 'Phenotype', 'HP:0009733', (70, 76))
116728	32224866	The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('dioxygenases', 'Enzyme', (117, 129))	('IDH', 'Gene', (34, 37))	('neomorphic enzyme', 'Enzyme', (4, 21))	('dysfunction', 'MPA', (102, 113))	('mutants', 'Var', (38, 45))	('activity', 'MPA', (22, 30))	('IDH', 'Gene', '3417', (34, 37))	('oxygen', 'Chemical', 'MESH:D010100', (119, 125))	('epigenetic', 'MPA', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('leads to', 'Reg', (46, 54))	('metabolic reprogramming', 'CPA', (135, 158))
116729	32224866	However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness.	('regulate', 'Reg', (50, 58))	('mutants', 'Var', (42, 49))	('aggressiveness', 'Disease', 'MESH:D001523', (117, 131))	('IDH', 'Gene', (38, 41))	('aggressiveness', 'Disease', (117, 131))	('IDH', 'Gene', '3417', (38, 41))	('aggressiveness', 'Phenotype', 'HP:0000718', (117, 131))	('oncogenic transformation', 'CPA', (88, 112))
116733	32224866	Mutations in isocitrate dehydrogenase1/2 (IDH1/2) are common genetic defects in grade II/III diffusive astrocytoma and oligodendroglioma.	('IDH1/2', 'Gene', '3417;3418', (42, 48))	('oligodendroglioma', 'Disease', 'MESH:D009837', (119, 136))	('astrocytoma', 'Disease', 'MESH:D001254', (103, 114))	('astrocytoma', 'Disease', (103, 114))	('Mutations', 'Var', (0, 9))	('IDH1/2', 'Gene', (42, 48))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('oligodendroglioma', 'Disease', (119, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
116734	32224866	Cancer-associated IDH mutations commonly locate in an arginine residue at the center of the catalytic domain (IDH1 R132, IDH2 R140, and R172).	('arginine', 'Chemical', 'MESH:D001120', (54, 62))	('R140', 'Var', (126, 130))	('IDH', 'Gene', (110, 113))	('R172', 'Var', (136, 140))	('R132', 'Var', (115, 119))	('IDH', 'Gene', (18, 21))	('IDH2', 'Gene', '3418', (121, 125))	('IDH', 'Gene', (121, 124))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', '3417', (18, 21))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('IDH', 'Gene', '3417', (121, 124))	('mutations', 'Var', (22, 31))	('locate', 'Reg', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('IDH2', 'Gene', (121, 125))
116735	32224866	Pathogenic IDH mutations catalyze alpha-ketoglutarate (alpha-KG) into D-2-hydroxyglutarate (D-2-HG), an oncometabolite closely related to the deactivation of alpha-KG-dependent dioxygenases.	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('D-2-HG', 'Chemical', 'MESH:C019417', (92, 98))	('Pathogenic', 'Reg', (0, 10))	('mutations', 'Var', (15, 24))	('D-2-hydroxyglutarate', 'Gene', '28503', (70, 90))	('oxygen', 'Chemical', 'MESH:D010100', (179, 185))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (34, 53))	('alpha-KG', 'Chemical', 'MESH:D007656', (158, 166))	('alpha-KG', 'Chemical', 'MESH:D007656', (55, 63))	('D-2-hydroxyglutarate', 'Gene', (70, 90))
116736	32224866	For example, D-2-HG affects the catalytic function of DNA/histone demethylases, leading to the genome-wide hypermethylation and cancer stemness.	('D-2-HG', 'Var', (13, 19))	('cancer stemness', 'Disease', (128, 143))	('D-2-HG', 'Chemical', 'MESH:C019417', (13, 19))	('DNA/histone demethylases', 'Enzyme', (54, 78))	('genome-wide hypermethylation', 'MPA', (95, 123))	('cancer stemness', 'Disease', 'MESH:D009369', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('affects', 'Reg', (20, 27))	('catalytic function', 'MPA', (32, 50))	('leading to', 'Reg', (80, 90))
116737	32224866	Moreover, IDH mutants disrupt the homeostasis of the Krebs cycle by depleting carbon-based metabolites, resulting in metabolic reprogramming and Warburg-like metabolism.	('IDH', 'Gene', (10, 13))	('carbon', 'Chemical', 'MESH:D002244', (78, 84))	('mutants', 'Var', (14, 21))	('IDH', 'Gene', '3417', (10, 13))	('Warburg-like metabolism', 'CPA', (145, 168))	('disrupt', 'Reg', (22, 29))	('homeostasis', 'MPA', (34, 45))	('resulting in', 'Reg', (104, 116))	('metabolic reprogramming', 'CPA', (117, 140))	('depleting', 'NegReg', (68, 77))	('carbon-based metabolites', 'MPA', (78, 102))	('Krebs', 'Chemical', '-', (53, 58))
116738	32224866	Despite the increasing awareness of the molecular mechanisms of IDH mutations on cancer metabolism and transformation, it remains elusive as to how metabolic deficient cancers, such as IDH1-mutated glioma, acquire an aggressive phenotype during oncogenic transformation.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('IDH', 'Gene', '3417', (64, 67))	('IDH', 'Gene', (185, 188))	('metabolic deficient cancers', 'Disease', (148, 175))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('glioma', 'Disease', (198, 204))	('IDH', 'Gene', '3417', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('metabolic deficient cancers', 'Disease', 'MESH:D009369', (148, 175))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('cancer', 'Disease', (168, 174))	('mutations', 'Var', (68, 77))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('IDH', 'Gene', (64, 67))
116751	32224866	IDH1 mutation was confirmed by immunoblotting, Sanger sequencing, and D-2-HG assay.	('IDH1', 'Gene', (0, 4))	('D-2-HG', 'Chemical', 'MESH:C019417', (70, 76))	('mutation', 'Var', (5, 13))
116752	32224866	This trend was consistently recorded in both pathogenic IDH1 mutants R132C and R132H.	('R132H', 'SUBSTITUTION', 'None', (79, 84))	('R132C', 'Var', (69, 74))	('R132C', 'Mutation', 'rs121913499', (69, 74))	('recorded', 'Reg', (28, 36))	('R132H', 'Var', (79, 84))	('IDH1', 'Gene', (56, 60))
116754	32224866	The distinctive mRNA expression pattern suggests altered cellular motility in cancer cells with IDH1 mutation.	('altered', 'Reg', (49, 56))	('cellular motility', 'CPA', (57, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutation', 'Var', (101, 109))	('IDH1', 'Gene', (96, 100))
116755	32224866	This phenomenon was also confirmed in U251 cells with doxycycline-inducible IDH1 R132H expression (Figure S2A).	('IDH1', 'Gene', (76, 80))	('R132H', 'SUBSTITUTION', 'None', (81, 86))	('R132H', 'Var', (81, 86))	('doxycycline', 'Chemical', 'MESH:D004318', (54, 65))
116758	32224866	It has been suggested that IDH mutant reprograms metabolic pathways by producing D-2-HG.	('reprograms', 'Reg', (38, 48))	('IDH', 'Gene', (27, 30))	('mutant', 'Var', (31, 37))	('metabolic pathways', 'Pathway', (49, 67))	('D-2-HG', 'MPA', (81, 87))	('D-2-HG', 'Chemical', 'MESH:C019417', (81, 87))	('IDH', 'Gene', '3417', (27, 30))
116762	32224866	Similarly, IDH1R132H U251 xenografts showed more dextran uptake as compared with IDH1 wild type counterparts in nude mice (Figure 2D).	('more', 'PosReg', (44, 48))	('dextran uptake', 'MPA', (49, 63))	('nude mice', 'Species', '10090', (112, 121))	('IDH1R132H', 'Var', (11, 20))	('dextran', 'Chemical', 'MESH:D003911', (49, 56))
116765	32224866	Moreover, electron microscopy showed the enhancement of endocytosis in IDH1-mutated cells, evidenced by an increase in quantity (2.27-fold for IDH1R132C; 2.61-fold for IDH1R132H) and diameter (76.2 nm for IDH1WT; 109.2 nm for IDH1R132C; 105.4 nm for IDH1R132H) of the endocytic vesicles in U251 cells with IDH1 mutation (Figure 2H,I).	('IDH1', 'Gene', (306, 310))	('endocytosis', 'MPA', (56, 67))	('increase', 'PosReg', (107, 115))	('R132C', 'Mutation', 'rs121913499', (230, 235))	('mutation', 'Var', (311, 319))	('R132C', 'Mutation', 'rs121913499', (147, 152))	('quantity', 'MPA', (119, 127))	('enhancement', 'PosReg', (41, 52))
116768	32224866	Our results showed that TS603 cells with IDH1R132H mutant exhibited stronger expression of endosomal markers, as well as dextran uptake compared with IDH1WT GSC923 cells (Figure S3A,B).	('dextran', 'Chemical', 'MESH:D003911', (121, 128))	('expression', 'MPA', (77, 87))	('stronger', 'PosReg', (68, 76))	('dextran uptake', 'MPA', (121, 135))	('IDH1R132H', 'Var', (41, 50))	('endosomal markers', 'MPA', (91, 108))
116770	32224866	Phase-contrast microscopy and phalloidin labeling showed the condensed F-actin framework in the cutting-edge of the lamellipodia region, indicating a reorganization of the cytoskeleton in the IDH1-mutated cells, which might be mediated by small GTPase activation (Figure 3B).	('phalloidin', 'Chemical', 'MESH:D010590', (30, 40))	('reorganization', 'Reg', (150, 164))	('GTP', 'Chemical', 'MESH:D006160', (245, 248))	('IDH1-mutated', 'Var', (192, 204))
116775	32224866	Results showed that the active form of Rac1, but not Cdc42, was selectively accumulated in IDH1-mutated cells (Figure 3E,F).	('Cdc42', 'Gene', '998', (53, 58))	('active', 'MPA', (24, 30))	('Rac1', 'Gene', (39, 43))	('accumulated', 'PosReg', (76, 87))	('Rac1', 'Gene', '5879', (39, 43))	('Cdc42', 'Gene', (53, 58))	('IDH1-mutated', 'Var', (91, 103))
116783	32224866	We stratified these tumor specimens by their IDH1 mutation status and focused on the DEGs.	('DEGs', 'Gene', '8560', (85, 89))	('mutation', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH1', 'Gene', (45, 49))	('DEGs', 'Gene', (85, 89))	('tumor', 'Disease', (20, 25))
116785	32224866	Importantly, we identified that IDH1 mutation status correlates with remarkably higher expression of Rictor in both patient samples and transduced U251 cells (Figure 4B).	('Rictor', 'Gene', '253260', (101, 107))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('patient', 'Species', '9606', (116, 123))	('Rictor', 'Gene', (101, 107))	('expression', 'MPA', (87, 97))	('higher', 'PosReg', (80, 86))
116786	32224866	Additionally, the upregulation of Rictor in IDH1-mutated U251 cells and BTICs correlated with enhanced mTORC2 downstream, such as phosphorylation of Ak strain transforming (Akt) and Protein kinase C alpha (PKCalpha), whereas the mTORC1 downstream, such as ribosomal protein S6 kinase beta-1 (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) phosphorylation, were not altered with IDH1 mutation (Figure S4A,B).	('IDH1', 'Gene', (413, 417))	('upregulation', 'PosReg', (18, 30))	('Rictor', 'Gene', '253260', (34, 40))	('mTORC2', 'Gene', (103, 109))	('4EBP1', 'Gene', '1978', (367, 372))	('ribosomal protein S6 kinase beta-1', 'Gene', (256, 290))	('p70S6K', 'Gene', (292, 298))	('BTIC', 'Chemical', '-', (72, 76))	('mTORC2', 'Gene', '74343', (103, 109))	('eukaryotic translation initiation factor 4E-binding protein 1', 'Gene', '1978', (304, 365))	('ribosomal protein S6 kinase beta-1', 'Gene', '6195', (256, 290))	('Rictor', 'Gene', (34, 40))	('enhanced', 'PosReg', (94, 102))	('Protein kinase C alpha', 'Gene', '5578', (182, 204))	('PKCalpha', 'Gene', '5578', (206, 214))	('4EBP1', 'Gene', (367, 372))	('phosphorylation', 'MPA', (130, 145))	('mutation', 'Var', (418, 426))	('mTORC1', 'Gene', (229, 235))	('Protein kinase C alpha', 'Gene', (182, 204))	('p70S6K', 'Gene', '6198', (292, 298))	('PKCalpha', 'Gene', (206, 214))	('mTORC1', 'Gene', '382056', (229, 235))
116788	32224866	mTORC1 downstream, such as p70S6K and 4EBP1, was minimally affected by genetic silencing of Rictor, whereas mTORC2 downstream signaling, such as Akt, Pkcalpha, and Rac1, was found to be suppressed in IDH1-mutated cells (Figure 4C, Figure S3E, and Figure S4C).	('Pkcalpha', 'Gene', (150, 158))	('mTORC2', 'Gene', '74343', (108, 114))	('mTORC1', 'Gene', '382056', (0, 6))	('Pkcalpha', 'Gene', '5578', (150, 158))	('Rictor', 'Gene', (92, 98))	('Rac1', 'Gene', '5879', (164, 168))	('Rictor', 'Gene', '253260', (92, 98))	('p70S6K', 'Gene', (27, 33))	('genetic silencing', 'Var', (71, 88))	('Rac1', 'Gene', (164, 168))	('p70S6K', 'Gene', '6198', (27, 33))	('4EBP1', 'Gene', '1978', (38, 43))	('mTORC1', 'Gene', (0, 6))	('suppressed', 'NegReg', (186, 196))	('4EBP1', 'Gene', (38, 43))	('mTORC2', 'Gene', (108, 114))
116789	32224866	By mediating Rac1 phosphorylation, Rictor is key to the cytoskeleton reorganization and food-seeking pattern in IDH1-mutated cells.	('Rictor', 'Gene', '253260', (35, 41))	('Rictor', 'Gene', (35, 41))	('Rac1', 'Gene', (13, 17))	('Rac1', 'Gene', '5879', (13, 17))	('mediating', 'Reg', (3, 12))	('IDH1-mutated', 'Var', (112, 124))
116791	32224866	Moreover, the invasive capability of IDH1-mutated BTIC cells was significantly impaired by Rac1 or Rictor knockdown (Figure S2E).	('invasive capability of', 'CPA', (14, 36))	('Rac1', 'Gene', (91, 95))	('Rac1', 'Gene', '5879', (91, 95))	('Rictor', 'Gene', '253260', (99, 105))	('Rictor', 'Gene', (99, 105))	('knockdown', 'Var', (106, 115))	('BTIC', 'Chemical', '-', (50, 54))	('impaired', 'NegReg', (79, 87))
116792	32224866	These results suggested that the Rictor/Rac1 pathway is vital for the enhanced cellular motility pattern associated with IDH1 mutation.	('IDH1', 'Gene', (121, 125))	('Rac1', 'Gene', (40, 44))	('Rictor', 'Gene', '253260', (33, 39))	('Rictor', 'Gene', (33, 39))	('mutation', 'Var', (126, 134))	('enhanced', 'PosReg', (70, 78))	('cellular motility pattern', 'CPA', (79, 104))	('Rac1', 'Gene', '5879', (40, 44))
116795	32224866	Moreover, Rac1 and Rictor suppression led to cell viability decrease in IDH1-mutated U251 cells and BTIC TS603, but not in IDH1 wild type U251 cells and BTIC GSC923 (Figure S3D), which indicates that targeting of the mTORC2/Rac1 pathway might be a potential therapeutic approach for cancers with IDH1 mutations.	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('Rac1', 'Gene', '5879', (224, 228))	('Rac1', 'Gene', '5879', (10, 14))	('mTORC2', 'Gene', '74343', (217, 223))	('BTIC', 'Chemical', '-', (153, 157))	('decrease', 'NegReg', (60, 68))	('Rictor', 'Gene', '253260', (19, 25))	('mutations', 'Var', (301, 310))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('cancers', 'Disease', (283, 290))	('BTIC', 'Chemical', '-', (100, 104))	('Rac1', 'Gene', (224, 228))	('Rac1', 'Gene', (10, 14))	('IDH1-mutated', 'Gene', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('cell viability', 'CPA', (45, 59))	('suppression', 'NegReg', (26, 37))	('Rictor', 'Gene', (19, 25))	('mTORC2', 'Gene', (217, 223))	('IDH1', 'Gene', (296, 300))
116800	32224866	mTOR inhibitor omipalisib, which potently suppresses both mTORC1 and two activities, showed suppression of cell proliferation in both IDH1 wild type and mutated cells (Figure 6A,B), which indicated that mTOR signaling plays essential roles in both glioma molecular subtypes.	('glioma', 'Disease', (248, 254))	('mTOR', 'Gene', (58, 62))	('mTORC1', 'Gene', '382056', (58, 64))	('mutated', 'Var', (153, 160))	('cell proliferation', 'CPA', (107, 125))	('suppresses', 'NegReg', (42, 52))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('suppression', 'NegReg', (92, 103))	('mTOR', 'Gene', '2475', (58, 62))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('omipalisib', 'Chemical', 'MESH:C561454', (15, 25))	('mTORC1', 'Gene', (58, 64))	('mTOR', 'Gene', '2475', (0, 4))	('mTOR', 'Gene', (203, 207))	('mTOR', 'Gene', (0, 4))	('mTOR', 'Gene', '2475', (203, 207))
116802	32224866	Consistently, results showed that Rac1 inhibition by EHT-1864 led to suppression in cells with IDH1 mutations, whereas total mTOR inhibition by omipalisib showed potent suppression in both IDH1 wild type and mutant cells (Figure 6C-G).	('mutations', 'Var', (100, 109))	('suppression', 'NegReg', (69, 80))	('mTOR', 'Gene', '2475', (125, 129))	('EHT-1864', 'Chemical', 'MESH:C506907', (53, 61))	('mTOR', 'Gene', (125, 129))	('omipalisib', 'Chemical', 'MESH:C561454', (144, 154))	('Rac1', 'Gene', '5879', (34, 38))	('EHT-1864', 'Gene', (53, 61))	('IDH1', 'Gene', (95, 99))	('Rac1', 'Gene', (34, 38))
116804	32224866	Pathogenic IDH1 variants (R132C, R132H) were generated by using the Quikchange lightning mutagenesis kit (Agilent, Santa Clara, CA, USA).	('R132C', 'Var', (26, 31))	('R132C', 'Mutation', 'rs121913499', (26, 31))	('Pathogenic', 'Reg', (0, 10))	('R132H', 'Var', (33, 38))	('R132H', 'SUBSTITUTION', 'None', (33, 38))	('IDH1', 'Gene', (11, 15))
116807	32224866	IDH1/2 coding transfer plasmids were co-transfected with pMD2.G (Addgene 12259, Watertown, MA, USA) and psPAX2 (Addgene 12260, Watertown, MA, USA) using lipofectamine 3000 according to the manufacturer's protocol (Invitrogen, Carlsbad, CA, USA).	('Addgene 12260', 'Var', (112, 125))	('IDH1/2', 'Gene', (0, 6))	('lipofectamine', 'Chemical', 'MESH:C086724', (153, 166))	('IDH1/2', 'Gene', '3417;3418', (0, 6))
116810	32224866	IDH1 mutation transduced U251 cells, and doxycycline-induced IDH1 mutation U251 cells were generated by lentivirus infection.	('lentivirus infection', 'Disease', 'MESH:D016180', (104, 124))	('IDH1', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('IDH1', 'Gene', (0, 4))	('lentivirus infection', 'Disease', (104, 124))	('mutation', 'Var', (5, 13))	('doxycycline', 'Chemical', 'MESH:D004318', (41, 52))
116823	32224866	IPA core analysis was performed to assess the affected pathways and functions by IDH mutations.	('mutations', 'Var', (85, 94))	('IDH', 'Gene', '3417', (81, 84))	('IDH', 'Gene', (81, 84))
116877	32224866	The present study revealed that pathogenic IDH1 mutation contributes to cancer aggressiveness via prompting cellular food-seeking, motility, chemotaxis, and endocytosis, which resulted from the augmented mTORC2/Rac1 pathway and concomitant cytoskeleton mobilization.	('cellular food-seeking', 'CPA', (108, 129))	('mTORC2', 'Gene', (204, 210))	('mTORC2', 'Gene', '74343', (204, 210))	('Rac1', 'Gene', (211, 215))	('chemotaxis', 'CPA', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('motility', 'CPA', (131, 139))	('IDH1', 'Gene', (43, 47))	('cancer aggressiveness', 'Disease', (72, 93))	('endocytosis', 'MPA', (157, 168))	('mutation', 'Var', (48, 56))	('augmented', 'PosReg', (194, 203))	('aggressiveness', 'Phenotype', 'HP:0000718', (79, 93))	('prompting', 'PosReg', (98, 107))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (72, 93))	('Rac1', 'Gene', '5879', (211, 215))
116879	32224866	Mutations in IDH1/2 have been identified in multiple types of human malignancies, such as lower grade glioma, secondary glioblastoma, acute myeloid leukemia, chondrosarcoma, and cholangiocarcinoma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('acute myeloid leukemia', 'Disease', (134, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (178, 196))	('chondrosarcoma', 'Disease', (158, 172))	('chondrosarcoma', 'Disease', 'MESH:D002813', (158, 172))	('cholangiocarcinoma', 'Disease', (178, 196))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (178, 196))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('human', 'Species', '9606', (62, 67))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (158, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('identified', 'Reg', (30, 40))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))	('malignancies', 'Disease', (68, 80))	('glioblastoma', 'Disease', (120, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('glioma', 'Disease', (102, 108))
116883	32224866	Pathogenic mutations in IDH1 lead to neomorphic changes in the enzyme activity, which allow the enzyme to utilize alpha-KG, leading to D-2-HG production.	('D-2-HG production', 'MPA', (135, 152))	('mutations', 'Var', (11, 20))	('leading to', 'Reg', (124, 134))	('enzyme activity', 'MPA', (63, 78))	('IDH1', 'Gene', (24, 28))	('changes', 'Reg', (48, 55))	('alpha-KG', 'Chemical', 'MESH:D007656', (114, 122))	('D-2-HG', 'Chemical', 'MESH:C019417', (135, 141))
116884	32224866	The variant of R132C and R132H are frequently identified in IDH-mutated malignancies, and R132C variant catalyzes D-2-HG production more efficiently.	('IDH', 'Gene', '3417', (60, 63))	('D-2-HG', 'Chemical', 'MESH:C019417', (114, 120))	('D-2-HG production', 'MPA', (114, 131))	('R132H', 'Var', (25, 30))	('R132H', 'SUBSTITUTION', 'None', (25, 30))	('IDH', 'Gene', (60, 63))	('R132C', 'Var', (90, 95))	('R132C', 'Mutation', 'rs121913499', (90, 95))	('R132C', 'Mutation', 'rs121913499', (15, 20))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('malignancies', 'Disease', (72, 84))	('R132C', 'Var', (15, 20))	('catalyzes', 'MPA', (104, 113))
116885	32224866	Several pioneering findings suggested that the changes in IDH1 catalytic function result in substantial changes in cellular metabolisms, such as the depletion of carbon hydrate metabolites from the Krebs cycle, Warburg-like metabolism, and utilization of alternative metabolites.	('Krebs', 'Chemical', '-', (198, 203))	('cellular metabolisms', 'MPA', (115, 135))	('depletion of carbon hydrate metabolites', 'MPA', (149, 188))	('carbon hydrate', 'Chemical', '-', (162, 176))	('catalytic function', 'MPA', (63, 81))	('changes', 'Var', (47, 54))	('Warburg-like metabolism', 'MPA', (211, 234))	('changes', 'Reg', (104, 111))	('IDH1', 'Gene', (58, 62))	('utilization of', 'MPA', (240, 254))
116889	32224866	Overexpression of BMP4 is related to the invasion and migration of melanoma cells and ovarian cancer cells.	('BMP4', 'Gene', '652', (18, 22))	('related', 'Reg', (26, 33))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('invasion', 'CPA', (41, 49))	('migration', 'CPA', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('BMP4', 'Gene', (18, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('Overexpression', 'Var', (0, 14))	('melanoma cells and ovarian cancer', 'Disease', 'MESH:D008545', (67, 100))
116890	32224866	As another example, CHI3L1, which encodes chitinase 3-like 1, was up-regulated by 38.20-fold in cells harboring IDH1 mutants.	('up-regulated', 'PosReg', (66, 78))	('CHI3L1', 'Gene', (20, 26))	('mutants', 'Var', (117, 124))	('IDH1', 'Gene', (112, 116))	('chitinase 3-like 1', 'Gene', '1116', (42, 60))	('chitinase 3-like 1', 'Gene', (42, 60))	('CHI3L1', 'Gene', '1116', (20, 26))
116895	32224866	Overall, we discovered that the acquisition of cancer-associated IDH1 mutant is associated with a distinctive transcriptional pattern, which may contribute to the unique food-seeking pattern.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutant', 'Var', (70, 76))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('IDH1', 'Gene', (65, 69))
116897	32224866	Consistently, we showed up-regulation of Rictor in IDH1 the mutant-transduced model and patient-derived cells, which potentiates the activity of mTORC2.	('mutant-transduced', 'Var', (60, 77))	('mTORC2', 'Gene', '74343', (145, 151))	('patient', 'Species', '9606', (88, 95))	('IDH1', 'Gene', (51, 55))	('potentiates', 'PosReg', (117, 128))	('activity', 'MPA', (133, 141))	('Rictor', 'Gene', '253260', (41, 47))	('mTORC2', 'Gene', (145, 151))	('up-regulation', 'PosReg', (24, 37))	('Rictor', 'Gene', (41, 47))
116898	32224866	These findings suggested a significant correlation between IDH1 mutant enzyme and Rictor/mTORC2 mobilization.	('mTORC2', 'Gene', (89, 95))	('Rictor', 'Gene', '253260', (82, 88))	('mTORC2', 'Gene', '74343', (89, 95))	('Rictor', 'Gene', (82, 88))	('IDH1', 'Gene', (59, 63))	('mutant', 'Var', (64, 70))
116899	32224866	However, the molecular mechanism of how the IDH1 mutant enzyme activated mTORC2 activity remains elusive.	('mTORC2', 'Gene', '74343', (73, 79))	('mTORC2', 'Gene', (73, 79))	('mutant', 'Var', (49, 55))	('IDH1', 'Gene', (44, 48))	('activated', 'PosReg', (63, 72))
116900	32224866	One possible explanation is that the IDH1-distinctive hypermethylation phenotype may enable some of the key regulatory elements in the mTORC2 complex.	('mTORC2', 'Gene', '74343', (135, 141))	('hypermethylation', 'Var', (54, 70))	('enable', 'PosReg', (85, 91))	('mTORC2', 'Gene', (135, 141))	('regulatory', 'MPA', (108, 118))
116902	32224866	Moreover, the IDH1-mutant depletes metabolites from the TCA cycle, which may also activate endocytosis pathways such as mTORC2.	('activate', 'PosReg', (82, 90))	('TCA', 'Chemical', 'MESH:D014238', (56, 59))	('endocytosis', 'MPA', (91, 102))	('mTORC2', 'Gene', (120, 126))	('mTORC2', 'Gene', '74343', (120, 126))	('IDH1-mutant', 'Var', (14, 25))	('depletes metabolites', 'MPA', (26, 46))	('IDH1-mutant', 'Gene', (14, 25))
116903	32224866	More effort is necessary to reveal the link between IDH1 mutation and the mTOR pathway.	('mTOR', 'Gene', '2475', (74, 78))	('mutation', 'Var', (57, 65))	('IDH1', 'Gene', (52, 56))	('mTOR', 'Gene', (74, 78))
116906	32224866	It is likely that in the context of the IDH mutant, the Krebs cycle metabolites are depleted in the form of D-2-hydroxyglutarate.	('depleted', 'NegReg', (84, 92))	('Krebs cycle', 'Enzyme', (56, 67))	('D-2-hydroxyglutarate', 'Gene', '28503', (108, 128))	('IDH', 'Gene', (40, 43))	('Krebs', 'Chemical', '-', (56, 61))	('IDH', 'Gene', '3417', (40, 43))	('mutant', 'Var', (44, 50))	('D-2-hydroxyglutarate', 'Gene', (108, 128))
116925	33069100	High nuclear ENO-1/ MBP-1 expression was associated with improved overall survival in epithelial ovarian cancer (EOC).	('overall survival', 'MPA', (66, 82))	('epithelial ovarian cancer', 'Disease', (86, 111))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (86, 111))	('MBP-1', 'Gene', '2023', (20, 25))	('MBP-1', 'Gene', (20, 25))	('High nuclear', 'Var', (0, 12))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('improved', 'PosReg', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EOC', 'Phenotype', 'HP:0025318', (113, 116))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (86, 111))
116937	33069100	High nuclear Enolase-1/ MBP-1 expression was associated with improved overall survival (88.6 vs. 33.1 months, median; p = 0.013).	('improved', 'PosReg', (61, 69))	('Enolase-1', 'Gene', '2023', (13, 22))	('overall survival', 'MPA', (70, 86))	('High', 'Var', (0, 4))	('MBP-1', 'Gene', '2023', (24, 29))	('MBP-1', 'Gene', (24, 29))	('Enolase-1', 'Gene', (13, 22))
116965	33069100	Unspecific color responses were avoided by blocking the endogenous peroxidase with 3% H2O2 in methanol, followed by rehydrating it in 70%, then 50% ethanol.	('ethanol', 'Chemical', 'MESH:D000431', (148, 155))	('H2O2', 'Chemical', 'MESH:D006861', (86, 90))	('H2O2', 'Var', (86, 90))	('methanol', 'Chemical', 'MESH:D000432', (94, 102))	('ethanol', 'Chemical', 'MESH:D000431', (95, 102))	('endogenous peroxidase', 'Enzyme', (56, 77))	('blocking', 'NegReg', (43, 51))
116980	33069100	A negative correlation was observed between high nuclear ENO-1/ MBP-1 staining and grading (p<0.001; Cc= -0.318).	('negative', 'NegReg', (2, 10))	('high nuclear', 'Var', (44, 56))	('MBP-1', 'Gene', '2023', (64, 69))	('MBP-1', 'Gene', (64, 69))	('grading', 'CPA', (83, 90))
116987	33069100	Nuclear ENO-1/ MBP-1 expression was significantly associated with a longer OS in the whole cohort (Fig.	('associated with', 'Reg', (50, 65))	('longer OS', 'Disease', (68, 77))	('expression', 'Var', (21, 31))	('MBP-1', 'Gene', '2023', (15, 20))	('MBP-1', 'Gene', (15, 20))
116998	33069100	Alternative splicing of the ENO1 gene results in a 36 kDa nuclear isoform, called myc promoter-binding protein 1 (MBP-1).	('myc promoter-binding protein 1', 'Gene', '2023', (82, 112))	('ENO1', 'Gene', (28, 32))	('myc promoter-binding protein 1', 'Gene', (82, 112))	('results in', 'Reg', (38, 48))	('Alternative splicing', 'Var', (0, 20))	('MBP-1', 'Gene', '2023', (114, 119))	('MBP-1', 'Gene', (114, 119))	('ENO1', 'Gene', '2023', (28, 32))
117001	33069100	Indeed studies in gastric, prostate and breast cancer revealed that elevated levels of MBP-1 reduce proliferation, migration and invasion in respective cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('invasion', 'CPA', (129, 137))	('proliferation', 'CPA', (100, 113))	('cancer', 'Disease', (47, 53))	('MBP-1', 'Gene', '2023', (87, 92))	('gastric', 'Disease', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MBP-1', 'Gene', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('reduce', 'NegReg', (93, 99))	('levels', 'Var', (77, 83))
117040	31953672	In addition, DSC has been shown to reflect differences in angiogenic pathways between isocitrate dehydrogenase (IDH) mutant and wild type gliomas and to help predict patient survival and response to anti-angiogenic therapy (bevacizumab).	('DSC', 'Disease', (13, 16))	('gliomas', 'Disease', (138, 145))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('differences', 'Reg', (43, 54))	('mutant', 'Var', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('IDH', 'Gene', '3417', (112, 115))	('angiogenic', 'CPA', (58, 68))	('isocitrate dehydrogenase', 'Gene', (86, 110))	('bevacizumab', 'Chemical', 'MESH:D000068258', (224, 235))	('patient', 'Species', '9606', (166, 173))	('IDH', 'Gene', (112, 115))	('isocitrate dehydrogenase', 'Gene', '3417', (86, 110))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))
117054	31953672	Next, PET data were reconstructed using the OP-OSEM algorithm (3 iterations and 24 subsets) with the Siemens off-line reconstruction e7 tool, in a matrix size of 344x344x109 voxels (2.4 x 2.4 x 2.0 mm3 voxel size) for the mCT and 344x344x127 voxels (2.1 x 2.1 x 2.0 mm3 voxel size) for the mMR, and a post-reconstruction Gaussian filter of 3.0 mm kernel size.	('344x344x127', 'Var', (230, 241))	('344x344x109', 'Var', (162, 173))	('mMR', 'Gene', '50771', (290, 293))	('mMR', 'Gene', (290, 293))
117068	31953672	In total, our cohort comprised 46 patients (Table 1): 31 patients were diagnosed with an IDH wild type WHO grade IV glioblastoma, 12 patients with an IDH mutant, 1p/19q codeleted oligodendroglioma (WHO grade II/III) and 3 patients with an IDH mutant, 1p/19q intact astrocytoma (WHO grade III).	('oligodendroglioma', 'Disease', (179, 196))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (133, 141))	('astrocytoma', 'Phenotype', 'HP:0009592', (265, 276))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', (239, 242))	('IDH', 'Gene', '3417', (89, 92))	('glioblastoma', 'Disease', (116, 128))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('IDH', 'Gene', '3417', (150, 153))	('IDH', 'Gene', '3417', (239, 242))	('astrocytoma', 'Disease', 'MESH:D001254', (265, 276))	('astrocytoma', 'Disease', (265, 276))	('1p/19q', 'Var', (162, 168))	('patients', 'Species', '9606', (34, 42))	('oligodendroglioma', 'Disease', 'MESH:D009837', (179, 196))	('patients', 'Species', '9606', (57, 65))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('IDH', 'Gene', (89, 92))
117069	31953672	Given that IDH status separates gliomas into two biologically distinct diseases, we grouped IDH mutant tumors into "lower-grade gliomas" (LGG), as opposed to the IDH wild type glioblastomas (GB), for the subsequent analyses.	('glioblastomas', 'Disease', 'MESH:D005909', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('IDH', 'Gene', '3417', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('tumors', 'Disease', (103, 109))	('IDH', 'Gene', '3417', (162, 165))	('mutant', 'Var', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('GB', 'Phenotype', 'HP:0012174', (191, 193))	('glioblastomas', 'Phenotype', 'HP:0012174', (176, 189))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Disease', (32, 39))	('IDH', 'Gene', (92, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('IDH', 'Gene', (11, 14))	('glioblastomas', 'Disease', (176, 189))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('IDH', 'Gene', (162, 165))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('IDH', 'Gene', '3417', (92, 95))
117074	31953672	In the FHT in GB, the APTw-positive relative volume was also higher than both FET and CBV, albeit to a lower extent.	('FET', 'Chemical', 'MESH:C117289', (78, 81))	('FHT', 'Var', (7, 10))	('higher', 'PosReg', (61, 67))	('GB', 'Phenotype', 'HP:0012174', (14, 16))
117096	31953672	Across both entities and regions studied, we find that the overlap between APTw/CBV is relevantly lower than between APTw/FET, indicating a potential synergistic value of combining APTw and CBV information.	('APTw/CBV', 'Var', (75, 83))	('FET', 'Chemical', 'MESH:C117289', (122, 125))	('lower', 'NegReg', (98, 103))	('overlap', 'Interaction', (59, 66))
117112	31953672	Both in IDH wild-type glioblastomas and IDH mutant lower-grade gliomas, we observed relevant overlap between tumor areas defined by different imaging modalities, strongest for APTw and FET in contrast-enhancing parts of glioblastomas, but also in the FLAIR-hyperintense region of lower-grade gliomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (22, 35))	('IDH', 'Gene', (8, 11))	('FET', 'Chemical', 'MESH:C117289', (185, 188))	('glioma', 'Phenotype', 'HP:0009733', (292, 298))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH', 'Gene', (40, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (220, 232))	('glioblastomas', 'Disease', (220, 233))	('gliomas', 'Phenotype', 'HP:0009733', (292, 299))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('IDH', 'Gene', '3417', (8, 11))	('glioblastomas', 'Disease', (22, 35))	('glioblastomas', 'Disease', 'MESH:D005909', (220, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IDH', 'Gene', '3417', (40, 43))	('glioblastomas', 'Disease', 'MESH:D005909', (22, 35))	('gliomas', 'Disease', (292, 299))	('gliomas', 'Disease', (63, 70))	('glioblastomas', 'Phenotype', 'HP:0012174', (220, 233))	('gliomas', 'Disease', 'MESH:D005910', (292, 299))	('mutant', 'Var', (44, 50))	('tumor', 'Disease', (109, 114))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
117115	24714777	Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas.	('gliomas', 'Disease', (93, 100))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', '3417', (82, 85))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('occur', 'Reg', (147, 152))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('mutations', 'Var', (29, 38))	('Isocitrate dehydrogenase', 'Gene', '3417', (101, 125))	('mutations', 'Var', (137, 146))	('associated', 'Reg', (43, 53))	('gliomas', 'Disease', (181, 188))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH', 'Gene', (82, 85))	('Isocitrate dehydrogenase', 'Gene', (101, 125))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
117117	24714777	We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('IDH1-mutant', 'Gene', (63, 74))	('tumor', 'Disease', (27, 32))	('glioma', 'Disease', (75, 81))	('IDH1-mutant', 'Var', (63, 74))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
117118	24714777	Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))
117121	24714777	All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation.	('mutant', 'Var', (26, 32))	('IDH1', 'Gene', (33, 37))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (57, 75))
117122	24714777	All xenograft-producing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET or N-MYC.	('TP53', 'Gene', (100, 104))	('PIK3CA', 'Gene', (172, 178))	('MET', 'Gene', (207, 210))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('mutations', 'Var', (60, 69))	('N-MYC', 'Gene', (214, 219))	('oligodendroglioma', 'Disease', 'MESH:D009837', (78, 95))	('TP53', 'Gene', '7157', (100, 104))	('N-MYC', 'Gene', '4613', (214, 219))	('PIK3CA', 'Gene', '5290', (172, 178))	('activating', 'Reg', (148, 158))	('oligodendroglioma', 'Disease', (78, 95))	('astrocytoma', 'Disease', 'MESH:D001254', (106, 117))	('gliomas', 'Disease', (24, 31))	('astrocytoma', 'Disease', (106, 117))	('PDGFRA', 'Gene', '5156', (199, 205))	('PDGFRA', 'Gene', (199, 205))	('CIC', 'Gene', (73, 76))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('amplification', 'Var', (182, 195))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
117123	24714777	Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P=.0007).	('detected', 'Reg', (38, 46))	('TP53', 'Gene', '7157', (18, 22))	('IDH1', 'Gene', (5, 9))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
117124	24714777	Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT or PTEN mutation or PDGFRA, MET or N-MYC amplification.	('PDGFRA', 'Gene', '5156', (151, 157))	('PDGFRA', 'Gene', (151, 157))	('PIK3CA', 'Gene', '5290', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('alterations', 'Reg', (22, 33))	('patients', 'Species', '9606', (93, 101))	('PTEN', 'Gene', '5728', (134, 138))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('mutation', 'Var', (139, 147))	('MET', 'Var', (159, 162))	('KRAS', 'Gene', '3845', (121, 125))	('N-MYC', 'Gene', (166, 171))	('AKT', 'Gene', '207', (127, 130))	('N-MYC', 'Gene', '4613', (166, 171))	('KRAS', 'Gene', (121, 125))	('PIK3CA', 'Gene', (113, 119))	('IDH-mutant', 'Gene', (75, 85))	('glioma', 'Disease', (86, 92))	('cancer', 'Disease', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('PTEN', 'Gene', (134, 138))	('AKT', 'Gene', (127, 130))
117125	24714777	IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations while IDH/TP53 tumors correlated with PDGFRA/MET amplification.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('KRAS', 'Gene', '3845', (50, 54))	('tumors', 'Disease', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PIK3CA', 'Gene', (43, 49))	('KRAS', 'Gene', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', (75, 79))	('tumors', 'Disease', (15, 21))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('PIK3CA', 'Gene', '5290', (43, 49))	('PDGFRA', 'Gene', (103, 109))	('PDGFRA', 'Gene', '5156', (103, 109))	('associated', 'Reg', (27, 37))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDH/CIC', 'Disease', (0, 7))	('TP53', 'Gene', '7157', (75, 79))
117126	24714777	A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('IDH-mutant', 'Gene', (12, 22))	('gliomas', 'Disease', (23, 30))	('mutations', 'Var', (36, 45))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('patients', 'Species', '9606', (100, 108))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))
117128	24714777	Shortly after the discovery of recurrent mutations in the isocitrate dehydrogenase (IDH1) and IDH2 genes it was recognized that IDH-mutant diffuse gliomas have a clinical phenotype distinct from IDH-wildtype gliomas.	('mutations', 'Var', (41, 50))	('IDH-wildtype gliomas', 'Disease', 'MESH:D005910', (195, 215))	('IDH2', 'Gene', '3418', (94, 98))	('IDH1', 'Gene', (84, 88))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('gliomas', 'Disease', (208, 215))	('isocitrate dehydrogenase', 'Gene', (58, 82))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('IDH-wildtype gliomas', 'Disease', (195, 215))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Disease', (147, 154))	('isocitrate dehydrogenase', 'Gene', '3417', (58, 82))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('IDH-mutant', 'Gene', (128, 138))	('IDH2', 'Gene', (94, 98))
117129	24714777	More recently, two major genetic subtypes of IDH-mutant glioma have been identified: one genetic lineage is defined by TP53 and alpha thalassemia/mental retardation syndrome x-linked (ATRX) mutations and strong correlation with astrocytic histology, and a second lineage is characterized by concurrent mutations in homolog of Drosophila capicua (CIC), Far Upstream Element Binding Protein (FUBP1) and the telomerase reverse transcriptase (TERT) promoter as well as tight association with 1p/19q codeletion and oligodendroglioma histopathology.	('capicua', 'Gene', (337, 344))	('oligodendroglioma', 'Disease', (510, 527))	('TP53', 'Gene', '7157', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (521, 527))	('mutations', 'Var', (302, 311))	('mutations', 'Var', (190, 199))	('glioma', 'Disease', (56, 62))	('Drosophila', 'Species', '7227', (326, 336))	('FUBP1', 'Gene', (390, 395))	('mental retardation', 'Phenotype', 'HP:0001249', (146, 164))	('TERT', 'Gene', (439, 443))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('TERT', 'Gene', '7015', (439, 443))	('capicua', 'Gene', '53560', (337, 344))	('TP53', 'Gene', (119, 123))	('alpha thalassemia/mental retardation syndrome x-linked', 'Gene', '43080', (128, 182))	('FUBP1', 'Gene', '8880', (390, 395))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioma', 'Disease', (521, 527))	('oligodendroglioma', 'Disease', 'MESH:D009837', (510, 527))	('glioma', 'Disease', 'MESH:D005910', (521, 527))
117130	24714777	Notably, the genomic alterations that frequently occur in the more common IDH-wildtype primary glioblastoma (GBM, WHO Grade IV), including EGFR gene amplification and rearrangement, PTEN mutation and CDKN2A-CDKN2B deletion, are rare in IDH-mutant gliomas.	('PTEN', 'Gene', (182, 186))	('CDKN2B', 'Gene', (207, 213))	('deletion', 'Var', (214, 222))	('gliomas', 'Disease', 'MESH:D005910', (247, 254))	('CDKN2A', 'Gene', '1029', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('primary glioblastoma', 'Disease', 'MESH:D005909', (87, 107))	('CDKN2B', 'Gene', '1030', (207, 213))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('EGFR', 'Gene', '1956', (139, 143))	('primary glioblastoma', 'Disease', (87, 107))	('gliomas', 'Disease', (247, 254))	('EGFR', 'Gene', (139, 143))	('mutation', 'Var', (187, 195))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))	('CDKN2A', 'Gene', (200, 206))	('rearrangement', 'Var', (167, 180))	('PTEN', 'Gene', '5728', (182, 186))
117131	24714777	Thus, IDH-mutant gliomas are thought to arise via a molecular pathway that is distinct from primary GBM.	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('IDH-mutant', 'Var', (6, 16))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('gliomas', 'Disease', (17, 24))
117132	24714777	Although IDH-mutant diffuse gliomas carry a relatively better prognosis, most ultimately transform to a more malignant phenotype and become lethal.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('transform', 'Reg', (89, 98))	('IDH-mutant', 'Var', (9, 19))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
117134	24714777	IDH1/2 mutation and widespread hypermethylation of CpG islands (CpG island hypermethylator phenotype or CIMP) are the earliest known events in glioma development, preceding the "lineage-defining" acquisition of TP53 mutation in astrocytomas or 1p/19q co-deletion in oligodendrogliomas.	('astrocytomas', 'Disease', (228, 240))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('oligodendrogliomas', 'Disease', (266, 284))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('TP53', 'Gene', '7157', (211, 215))	('glioma', 'Disease', (277, 283))	('astrocytoma', 'Phenotype', 'HP:0009592', (228, 239))	('gliomas', 'Phenotype', 'HP:0009733', (277, 284))	('mutation', 'Var', (7, 15))	('TP53', 'Gene', (211, 215))	('glioma', 'Disease', (143, 149))	('CIMP', 'Chemical', '-', (104, 108))	('astrocytomas', 'Disease', 'MESH:D001254', (228, 240))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (277, 283))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (266, 284))
117135	24714777	Mutant IDH1/2 represents a "trunk" mutation in the molecular evolutionary tree of gliomas since it is ubiquitously present throughout the tumor cell mass and retained on progression from low- to high-grade with few exceptions.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumor', 'Disease', (138, 143))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('IDH1/2', 'Gene', (7, 13))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
117138	24714777	One limitation in the study of IDH-mutant glioma has been the scarcity of experimental models harboring endogenous IDH1/2 mutation.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('mutation', 'Var', (122, 130))	('IDH1/2', 'Gene', (115, 121))	('glioma', 'Disease', (42, 48))
117141	24714777	Herein, we hypothesized that additional "tertiary" genetic alterations, which have been noted to occur in IDH-mutant gliomas, could be the drivers of the progressive malignant phenotype of IDH-mutant gliomas.	('tert', 'Gene', '7015', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('gliomas', 'Disease', (200, 207))	('IDH-mutant', 'Var', (106, 116))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tert', 'Gene', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('IDH-mutant', 'Gene', (106, 116))
117142	24714777	We therefore tested 20 consecutive IDH-mutant glioma specimens from patients undergoing surgery at our institution for the ability to establish intracerebral xenografts in mice.	('glioma', 'Disease', (46, 52))	('mice', 'Species', '10090', (172, 176))	('patients', 'Species', '9606', (68, 76))	('tested', 'Reg', (13, 19))	('IDH-mutant', 'Var', (35, 45))	('IDH-mutant', 'Gene', (35, 45))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
117143	24714777	We performed a comparative genetic analysis of all primary tumor specimens using a CLIA-certified molecular panel and discovered that the IDH-mutant gliomas that successfully established orthotopic xenografts (8 tumors) were enriched with additional tertiary oncogenic genetic alterations, including PIK3CA mutation and amplification of the PDGFRA, MET, and N-MYC genes.	('tumor', 'Disease', (59, 64))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('MET', 'Gene', (349, 352))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('PIK3CA', 'Gene', '5290', (300, 306))	('N-MYC', 'Gene', (358, 363))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('amplification', 'Var', (320, 333))	('N-MYC', 'Gene', '4613', (358, 363))	('tumors', 'Disease', (212, 218))	('tumor', 'Disease', (212, 217))	('gliomas', 'Disease', (149, 156))	('PDGFRA', 'Gene', (341, 347))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tert', 'Gene', (250, 254))	('PDGFRA', 'Gene', '5156', (341, 347))	('PIK3CA', 'Gene', (300, 306))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('IDH-mutant', 'Var', (138, 148))	('tert', 'Gene', '7015', (250, 254))	('mutation', 'Var', (307, 315))
117147	24714777	From September 2011 to October 2012, we prospectively accrued 20 consecutive untreated (9 patients) and previously treated (11 patients) IDH-mutant glioma patients undergoing resection at the Massachusetts General Hospital (MGH).	('glioma', 'Disease', (148, 154))	('IDH-mutant', 'Var', (137, 147))	('patients', 'Species', '9606', (127, 135))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (90, 98))
117158	24714777	Primary antibodies used for IHC were anti-IDH1 R132H (Dianova, 1: 100), Ki-67 (MIB-1, Dako, 1: 150), anti-CD31 (BD Pharmingen, 1: 150) and anti-nestin (Santa Cruz, 1: 400).	('MIB-1', 'Gene', (79, 84))	('Ki-67', 'Var', (72, 77))	('CD31', 'Gene', (106, 110))	('MIB-1', 'Gene', '57534', (79, 84))	('CD31', 'Gene', '5175', (106, 110))	('R132H', 'Mutation', 'rs121913500', (47, 52))	('anti-nestin', 'Var', (139, 150))	('anti-IDH1 R132H', 'Var', (37, 52))
117161	24714777	Fluorescence in situ hybridization (FISH) assays for the EGFR, MET and PDGFRA genes were performed using BAC probes CTD-2113A18 (7p EGFR locus), CTB-13N12 (7q MET locus), CEP7 (centromere 7 control), RP11-58C6 (4q PDGFRA locus) and CEP4 (centromere 4 control) (Abbott) as described.	('EGFR', 'Gene', '1956', (132, 136))	('RP11', 'Gene', (200, 204))	('CTB-13N12', 'Var', (145, 154))	('CTD-2113A18', 'Var', (116, 127))	('EGFR', 'Gene', (132, 136))	('CEP4', 'Gene', (232, 236))	('PDGFRA', 'Gene', (214, 220))	('CEP7', 'Gene', (171, 175))	('EGFR', 'Gene', '1956', (57, 61))	('PDGFRA', 'Gene', (71, 77))	('PDGFRA', 'Gene', '5156', (214, 220))	('RP11', 'Gene', '26121', (200, 204))	('PDGFRA', 'Gene', '5156', (71, 77))	('EGFR', 'Gene', (57, 61))
117169	24714777	To knock down N-myc expression, lentivirus vectors carrying shRNA for N-MYC (Sigma, pLKO.1) were packaged using ScreenFect (Wako)-mediated co-transfection of vector and packaging plasmid DNAs to 293T cells.	('293T', 'CellLine', 'CVCL:0063', (195, 199))	('N-myc', 'Gene', (14, 19))	('N-MYC', 'Gene', (70, 75))	('knock', 'Var', (3, 8))	('N-myc', 'Gene', '4613', (14, 19))	('N-MYC', 'Gene', '4613', (70, 75))
117171	24714777	We studied the potential of 20 serially collected patient IDH1-mutant glioma specimens to form xenograft after stereotactic implantation in immunocompromised mouse brains.	('glioma', 'Disease', (70, 76))	('mouse', 'Species', '10090', (158, 163))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1-mutant', 'Var', (58, 69))	('patient', 'Species', '9606', (50, 57))	('IDH1-mutant', 'Gene', (58, 69))
117173	24714777	All 20 gliomas in our study had IDH1 mutations, which occur far more frequently than IDH2 mutations in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('IDH1', 'Gene', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('mutations', 'Var', (37, 46))	('IDH2', 'Gene', (85, 89))	('gliomas', 'Disease', (7, 14))	('gliomas', 'Disease', 'MESH:D005910', (7, 14))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))	('IDH2', 'Gene', '3418', (85, 89))
117177	24714777	All xenografts harbored endogenous IDH1 R132H mutation and retained the mutant allele upon serial passage in vitro or serial transplantation in orthotopic xenograft (Supplementary Figs.	('R132H', 'Var', (40, 45))	('IDH1', 'Gene', (35, 39))	('R132H', 'Mutation', 'rs121913500', (40, 45))
117183	24714777	All 8 xenograft-forming tumors and 10 of 12 non-xenograft-forming tumors harbored the IDH1 R132H variant, which accounts for ~90% of the IDH1 mutations in gliomas, and the remaining two non-xenograft-forming gliomas harbored IDH1 R132C.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('R132C', 'Mutation', 'rs121913499', (230, 235))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('mutations', 'Var', (142, 151))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('R132H', 'Var', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('IDH1', 'Gene', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('gliomas', 'Disease', (208, 215))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('IDH1', 'Gene', (137, 141))	('tumors', 'Disease', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('R132H', 'Mutation', 'rs121913500', (91, 96))	('gliomas', 'Disease', (155, 162))
117184	24714777	Interestingly, one glioma xenograft (MGG79) was homozygous for IDH1 R132H mutation and the corresponding orthotopic xenograft produced high-levels of 2HG (Supplementary Fig.	('R132H', 'Mutation', 'rs121913500', (68, 73))	('R132H mutation', 'Var', (68, 82))	('glioma xenograft', 'Disease', 'MESH:D005910', (19, 35))	('glioma xenograft', 'Disease', (19, 35))	('IDH1', 'Gene', (63, 67))	('2HG', 'MPA', (150, 153))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
117186	24714777	We specifically assessed for "tertiary" genetic alterations, which we defined as non-lineage mutations, since lineage-associated mutations (astrocytic ATRX/TP53 mutations or oligodendroglial CIC/TERT mutations and 1p/19q codeletion) occur in virtually all low-grade IDH-mutant gliomas.	('oligodendroglial CIC', 'Disease', (174, 194))	('occur', 'Reg', (233, 238))	('TERT', 'Gene', (195, 199))	('TP53', 'Gene', '7157', (156, 160))	('oligodendroglial CIC', 'Disease', 'None', (174, 194))	('tert', 'Gene', (30, 34))	('TP53', 'Gene', (156, 160))	('gliomas', 'Disease', 'MESH:D005910', (277, 284))	('gliomas', 'Disease', (277, 284))	('TERT', 'Gene', '7015', (195, 199))	('gliomas', 'Phenotype', 'HP:0009733', (277, 284))	('1p/19q codeletion', 'Var', (214, 231))	('tert', 'Gene', '7015', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))
117188	24714777	The detected tertiary alterations included hotspot activating mutations in PIK3CA (2/6) and high-level focal amplifications in the PDGFRA (2/6) and MET (1/6) genes (Table 1).	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('tert', 'Gene', (13, 17))	('PDGFRA', 'Gene', (131, 137))	('MET (1/6', 'Gene', '3004', (148, 156))	('PDGFRA', 'Gene', '5156', (131, 137))	('activating', 'PosReg', (51, 61))	('tert', 'Gene', '7015', (13, 17))	('mutations', 'Var', (62, 71))
117194	24714777	2A), suggesting these mutations play a role in the tumor initiating capability of IDH1-mutant gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('play', 'Reg', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('IDH1-mutant', 'Var', (82, 93))	('role', 'Reg', (39, 43))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('IDH1-mutant', 'Gene', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
117197	24714777	We observed more potent inhibition of MGG108 than MGG152 cells (IC50 = 7.5 muM for MGG108 vs. 20.1 muM for MGG152), indicating PIK3CA mutation functions as a driver of proliferation in MGG108 cells (Fig.	('MGG108', 'Chemical', '-', (83, 89))	('mutation', 'Var', (134, 142))	('PIK3CA', 'Gene', (127, 133))	('PIK3CA', 'Gene', '5290', (127, 133))	('MGG108', 'Chemical', '-', (38, 44))	('MGG108', 'Chemical', '-', (185, 191))
117199	24714777	As expected, MGG152 was significantly more sensitive to JQ1 in cell viability assays relative to MGG108, which lacks N-MYC or C-MYC amplification (IC50 = 0.04 muM for MGG152 vs. 2.08 muM for MGG108) (Fig.	('C-MYC', 'Gene', (126, 131))	('MGG108', 'Chemical', '-', (97, 103))	('MGG108', 'Chemical', '-', (191, 197))	('N-MYC', 'Gene', (117, 122))	('MGG152', 'Var', (167, 173))	('C-MYC', 'Gene', '4609', (126, 131))	('N-MYC', 'Gene', '4613', (117, 122))
117202	24714777	We found that sunitinib was more potent against a line with high-level PDGFRA amplification (MGG117) than those without (MGG108 and MGG119), while crizotinib was most effective in a line harboring MET amplification (MGG132) (Supplementary Fig.	('sunitinib', 'Chemical', 'MESH:D000077210', (14, 23))	('PDGFRA', 'Gene', (71, 77))	('crizotinib', 'Chemical', 'MESH:D000077547', (147, 157))	('PDGFRA', 'Gene', '5156', (71, 77))	('MGG132', 'Var', (216, 222))	('MGG108', 'Chemical', '-', (121, 127))
117203	24714777	These data suggest that tertiary alterations are oncogenic drivers in IDH-mutant glioma xenografts.	('tert', 'Gene', '7015', (24, 28))	('glioma xenograft', 'Disease', (81, 97))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma xenograft', 'Disease', 'MESH:D005910', (81, 97))	('IDH-mutant', 'Var', (70, 80))	('tert', 'Gene', (24, 28))
117214	24714777	PIK3CA and KRAS mutations were most often detected in tumors with at least a component of oligodendroglioma histology (7 of 9 PIK3CA mutant and 3 of 4 KRAS mutant tumors).	('oligodendroglioma', 'Disease', 'MESH:D009837', (90, 107))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))	('oligodendroglioma', 'Disease', (90, 107))	('PIK3CA', 'Gene', '5290', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('PIK3CA', 'Gene', '5290', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('tumors', 'Disease', (54, 60))	('detected', 'Reg', (42, 50))	('KRAS', 'Gene', (11, 15))	('KRAS', 'Gene', '3845', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('mutant', 'Var', (133, 139))	('KRAS', 'Gene', (151, 155))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('PIK3CA', 'Gene', (126, 132))	('PIK3CA', 'Gene', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (163, 169))
117216	24714777	When specific oncogenes were compared by IDH genetic lineage rather than histopathology (within the set of tumors with tertiary mutations and confirmed lineage mutations), we identified significant associations between 1p/19q codeleted tumors and intracellular signaling pathway gene mutations (KRAS or PIK3CA, P = .002) and between receptor tyrosine kinase amplification (PDGFRA or MET) and non-1p/19q codeleted (TP53 mutant) tumors (P = .029).	('PDGFRA', 'Gene', '5156', (373, 379))	('PDGFRA', 'Gene', (373, 379))	('tert', 'Gene', (119, 123))	('TP53', 'Gene', '7157', (414, 418))	('tert', 'Gene', '7015', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (427, 433))	('PIK3CA', 'Gene', '5290', (303, 309))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (284, 293))	('intracellular', 'Gene', (247, 260))	('tumor', 'Phenotype', 'HP:0002664', (427, 432))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('tumors', 'Disease', (427, 433))	('KRAS', 'Gene', '3845', (295, 299))	('receptor tyrosine kinase', 'Gene', '5979', (333, 357))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('KRAS', 'Gene', (295, 299))	('TP53', 'Gene', (414, 418))	('PIK3CA', 'Gene', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('receptor tyrosine kinase', 'Gene', (333, 357))	('tumors', 'Disease', 'MESH:D009369', (427, 433))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
117218	24714777	For two patients with PDGFRA amplification and one patient with focal MET amplification, we confirmed these alterations were present in the progressive but not in the initial tumor specimens (Fig.	('tumor', 'Disease', (175, 180))	('amplification', 'Var', (29, 42))	('patient', 'Species', '9606', (51, 58))	('PDGFRA', 'Gene', '5156', (22, 28))	('patient', 'Species', '9606', (8, 15))	('PDGFRA', 'Gene', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (8, 16))
117219	24714777	In 2 of 3 PIK3CA mutant patients, the PIK3CA mutations were present only in the progressive tumor (Fig.	('PIK3CA', 'Gene', '5290', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('PIK3CA', 'Gene', (10, 16))	('PIK3CA', 'Gene', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PIK3CA', 'Gene', '5290', (38, 44))	('patients', 'Species', '9606', (24, 32))	('mutant', 'Var', (17, 23))
117220	24714777	The third patient (Patient 6 in Table 2) had PIK3CA E545G mutation in both the diagnostic and progressive tumor specimens.	('E545G', 'Var', (52, 57))	('E545G', 'Mutation', 'rs121913274', (52, 57))	('patient', 'Species', '9606', (10, 17))	('Patient', 'Species', '9606', (19, 26))	('PIK3CA', 'Gene', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('PIK3CA', 'Gene', '5290', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
117221	24714777	This patient was treated with 12 cycles of temozolomide and progressed just 24.6 months after diagnosis, a relatively rapid time to progression for low-grade oligodendrogliomas with 1p/19q codeletion.	('1p/19q codeletion', 'Var', (182, 199))	('patient', 'Species', '9606', (5, 12))	('temozolomide', 'Chemical', 'MESH:D000077204', (43, 55))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (158, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('oligodendrogliomas', 'Disease', (158, 176))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))
117224	24714777	These tertiary alterations are associated with more malignant tumors in patients and increased tumor-forming ability in mice.	('malignant tumors', 'Disease', 'MESH:D018198', (52, 68))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('more', 'PosReg', (47, 51))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (62, 67))	('alterations', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tert', 'Gene', (6, 10))	('increased', 'PosReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('malignant tumors', 'Disease', (52, 68))	('tert', 'Gene', '7015', (6, 10))	('tumor', 'Disease', (95, 100))	('patients', 'Species', '9606', (72, 80))
117225	24714777	Importantly, these tertiary alterations represent potential therapeutic targets for patients with IDH-mutant gliomas who are most in need of treatment.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('tert', 'Gene', (19, 23))	('patients', 'Species', '9606', (84, 92))	('tert', 'Gene', '7015', (19, 23))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('IDH-mutant', 'Var', (98, 108))
117228	24714777	Our findings are consistent with prior reports; recurrent PIK3CA mutations have been detected in a subset of IDH-mutant, 1p/19q codeleted anaplastic oligodendrogliomas and two recent reports observed enrichment of PDGFRA amplification in IDH-mutant versus IDH-wildtype primary GBM.	('oligodendrogliomas', 'Disease', (149, 167))	('amplification', 'Var', (221, 234))	('IDH-mutant', 'Disease', (109, 119))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('PIK3CA', 'Gene', (58, 64))	('PDGFRA', 'Gene', (214, 220))	('PIK3CA', 'Gene', '5290', (58, 64))	('PDGFRA', 'Gene', '5156', (214, 220))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (149, 167))	('detected', 'Reg', (85, 93))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('mutations', 'Var', (65, 74))
117231	24714777	Together with these reports, our data suggests IDH-mutant gliomas may undergo a sequenced genetic evolution analogous to IDH2-mutant acute myeloid leukemia, where stepwise acquisition of distinct classes of mutations results in more aggressive disease.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (139, 155))	('IDH-mutant', 'Var', (47, 57))	('more', 'PosReg', (228, 232))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (133, 155))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('IDH2', 'Gene', '3418', (121, 125))	('acute myeloid leukemia', 'Disease', (133, 155))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('aggressive disease', 'Disease', 'MESH:D001523', (233, 251))	('results in', 'Reg', (217, 227))	('gliomas', 'Disease', (58, 65))	('aggressive disease', 'Disease', (233, 251))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (133, 155))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('IDH2', 'Gene', (121, 125))
117232	24714777	The mechanisms by which IDH-mutant gliomas acquire tertiary mutations are largely unknown.	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('IDH-mutant', 'Var', (24, 34))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('tert', 'Gene', (51, 55))	('gliomas', 'Disease', (35, 42))	('tert', 'Gene', '7015', (51, 55))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))
117234	24714777	All of the hypermutated gliomas in their dataset harbored driver mutations, many in the PI3K/mTOR signaling pathway.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('harbored', 'Reg', (49, 57))	('gliomas', 'Disease', (24, 31))	('mutations', 'Var', (65, 74))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
117236	24714777	Five of our 10 chemotherapy-treated patients had PI3K/mTOR pathway mutations in their tumors, and interestingly one tumor had activating mutations in 3 oncogenes (PIK3CA, AKT and KRAS), suggesting it may be hypermutated.	('KRAS', 'Gene', '3845', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PIK3CA', 'Gene', (163, 169))	('KRAS', 'Gene', (179, 183))	('activating', 'PosReg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (116, 121))	('patients', 'Species', '9606', (36, 44))	('tumors', 'Disease', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('AKT', 'Gene', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('mTOR', 'Gene', (54, 58))	('PIK3CA', 'Gene', '5290', (163, 169))	('tumor', 'Disease', (86, 91))	('mutations', 'Var', (67, 76))	('mTOR', 'Gene', '2475', (54, 58))	('AKT', 'Gene', '207', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
117244	24714777	However, these mutations were detected in datasets consisting mostly of IDH-wildtype gliomas that evolve along a distinct molecular pathway.	('mutations', 'Var', (15, 24))	('IDH-wildtype gliomas', 'Disease', 'MESH:D005910', (72, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('IDH-wildtype gliomas', 'Disease', (72, 92))
117248	24714777	Outcomes for this subgroup are poor relative to the 1p/19q codeleted subtype possibly due to the uncertain efficacy of chemotherapy in these tumors given their lack of 1p/19q codeletion.	('1p/19q codeletion', 'Var', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))
117249	24714777	We detected recurrent mutations in KRAS, which have been reported to be rare in glial tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('glial tumors', 'Disease', (80, 92))	('KRAS', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('KRAS', 'Gene', '3845', (35, 39))	('glial tumors', 'Disease', 'MESH:D005910', (80, 92))	('mutations', 'Var', (22, 31))
117250	24714777	Recent clinical data suggest that cancers driven by KRAS mutation may be sensitive to MEK inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutation', 'Var', (57, 65))	('KRAS', 'Gene', (52, 56))	('MEK', 'Gene', (86, 89))	('KRAS', 'Gene', '3845', (52, 56))	('MEK', 'Gene', '5609', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
117252	24714777	Analogously, a recent study reported that Myc pathway inhibition potently reduces viability of acute myeloid leukemia cells driven by mutant IDH2.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (95, 117))	('acute myeloid leukemia', 'Disease', (95, 117))	('IDH2', 'Gene', '3418', (141, 145))	('inhibition', 'NegReg', (54, 64))	('Myc', 'Gene', '4609', (42, 45))	('Myc', 'Gene', (42, 45))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (95, 117))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('reduces', 'NegReg', (74, 81))	('viability', 'CPA', (82, 91))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (101, 117))	('mutant', 'Var', (134, 140))	('IDH2', 'Gene', (141, 145))
117253	24714777	Finally, development of anticancer agents in IDH-mutant gliomas has been limited by the scarcity of biologically accurate preclinical models that are serviceable for testing therapeutics.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH-mutant', 'Var', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
117254	24714777	We have established a panel of endogenous IDH-mutant intracerebral glioma xenografts that represent a powerful platform for studying IDH-mutant tumor biology and for answering fundamental questions regarding treatment of IDH-mutant gliomas.	('tumor', 'Disease', (144, 149))	('gliomas', 'Disease', (232, 239))	('IDH-mutant', 'Var', (42, 52))	('gliomas', 'Disease', 'MESH:D005910', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('gliomas', 'Phenotype', 'HP:0009733', (232, 239))	('glioma xenograft', 'Disease', 'MESH:D005910', (67, 83))	('glioma xenograft', 'Disease', (67, 83))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('intracerebral glioma', 'Disease', 'MESH:D005910', (53, 73))	('IDH-mutant', 'Gene', (42, 52))	('intracerebral glioma', 'Disease', (53, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))
117255	24714777	Future work utilizing these orthotopic xenografts may help determine the optimal therapeutic strategy for IDH-mutant gliomas, which may involve inhibition of mutant IDH1, inhibition of tertiary genetic alterations, alteration of metabolic or epigenetic pathways, or a combination thereof.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('metabolic or epigenetic pathways', 'Pathway', (229, 261))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('inhibition', 'NegReg', (144, 154))	('alteration', 'Reg', (215, 225))	('IDH1', 'Gene', (165, 169))	('tert', 'Gene', (185, 189))	('IDH-mutant', 'Gene', (106, 116))	('mutant', 'Var', (158, 164))	('tert', 'Gene', '7015', (185, 189))
117256	24714777	Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes identify gliomas with a better prognosis.	('IDH2', 'Gene', '3418', (65, 69))	('gliomas', 'Disease', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('isocitrate dehydrogenase 1', 'Gene', (27, 53))	('IDH2', 'Gene', (65, 69))	('isocitrate dehydrogenase 1', 'Gene', '3417', (27, 53))	('mutations', 'Var', (10, 19))	('IDH1', 'Gene', (55, 59))
117258	24714777	Here, we find that a subset of IDH-mutant gliomas acquire mutations in cancer driver genes when they recur.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
117260	24714777	Moreover, IDH-mutant gliomas with driver mutations preferentially establish orthotopic xenograft tumors in mouse brain and are sensitive to targeted inhibition of the mutant gene product.	('mutations', 'Var', (41, 50))	('preferentially establish', 'PosReg', (51, 75))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('tumors', 'Disease', (97, 103))	('gliomas', 'Disease', (21, 28))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
117261	24714777	Identification of targetable recurrent driver mutations provides novel therapeutic possibilities for the IDH-mutant glioma patients who are most in need of new treatments.	('mutations', 'Var', (46, 55))	('glioma', 'Disease', (116, 122))	('patients', 'Species', '9606', (123, 131))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
117268	23771511	Regions with rCBVmax corresponded with hotspot regions in all tumors, regions with MDmin corresponded with hotspot regions in 20/23 tumors.	('rCBV', 'Chemical', '-', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('rCBVmax', 'Var', (13, 20))	('hotspot', 'MPA', (39, 46))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
117320	23771511	Microsatellite analysis confirmed the presence of LOH 1p/19q in 9/11 tumors (82 %) with an oligodendroglial component.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('oligodendroglial component', 'Disease', (91, 117))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('LOH 1p/19q', 'Var', (50, 60))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('oligodendroglial component', 'Disease', 'MESH:C562869', (91, 117))
117341	23771511	The mean MDmin for oligodendroglial tumors harboring LOH 1p/19q (n = 9) was lower than for those with intact 1p/19q (n = 2), but the difference was not significant (P = 0.81).	('MDmin', 'MPA', (9, 14))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (19, 42))	('oligodendroglial tumors', 'Disease', (19, 42))	('LOH 1p/19q', 'Var', (53, 63))	('lower', 'NegReg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
117344	23771511	We found that regions with rCBVmax corresponded with hotspot regions on PET in all tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('rCBV', 'Chemical', '-', (27, 31))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('rCBVmax', 'Var', (27, 34))
117363	23771511	The evaluation of rCBV in oligodendrogliomas is further complicated by the fact that tumors with co-deletions of chromosome 1p/19q show generally higher rCBVmax than non-deleted oligodendrogliomas.	('higher', 'PosReg', (146, 152))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (178, 196))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('oligodendrogliomas', 'Disease', (26, 44))	('rCBVmax', 'MPA', (153, 160))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (26, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('rCBV', 'Chemical', '-', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('oligodendrogliomas', 'Disease', (178, 196))	('co-deletions', 'Var', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('chromosome 1p/19q', 'Gene', (113, 130))	('rCBV', 'Chemical', '-', (153, 157))	('tumors', 'Disease', (85, 91))
117385	33543003	Likewise, ECM remodeling via metalloproteinases and impaired or ectopic interaction with ECM receptors such as CD44 are reportedly major Pan-Cancer drivers of dissemination and resistance to therapy.	('CD44', 'Gene', (111, 115))	('ectopic', 'Var', (64, 71))	('metalloproteinases', 'Enzyme', (29, 47))	('Pan-Cancer', 'Disease', (137, 147))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CD44', 'Gene', '960', (111, 115))	('Pan-Cancer', 'Disease', 'MESH:D009369', (137, 147))
117386	33543003	On the other hand, understanding and manipulating the peritumoral matrisome composition shows promising therapeutic potential.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('manipulating', 'Var', (37, 49))
117429	33543003	The master regulators identified were typically hub proteins (such as TP53 and P300), governing large networks of TFs as expected, and the number of drivers in a cancer type correlated linearly with the number of TFs they controlled (Suppl Fig.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('TP53', 'Gene', '7157', (70, 74))	('TF', 'Gene', '2152', (213, 215))	('P300', 'Var', (79, 83))	('TP53', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('TF', 'Gene', '2152', (114, 116))
117436	33543003	In general, pathway activation by mutations (at least two cancer-specific master regulators carrying oncogenic mutations in the same pathway) was infrequent, though in some tumors (BLCA, COAD, LUAD, READ and UCEC) it accounted for the majority of active pathways.	('COAD', 'Disease', 'MESH:D029424', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('COAD', 'Disease', (187, 191))	('LUAD', 'Disease', (193, 197))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (58, 64))	('READ', 'Disease', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (34, 43))
117485	33543003	Pan-Cancer drivers were filtered so that, for each cancer, their frequency of mutation in the tumor of interest was > average frequency of mutation of the same driver in the whole Pan-Cancer cohort.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Pan-Cancer', 'Disease', 'MESH:D009369', (180, 190))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (94, 99))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Pan-Cancer', 'Disease', (0, 10))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Pan-Cancer', 'Disease', (180, 190))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Pan-Cancer', 'Disease', 'MESH:D009369', (0, 10))
117486	33543003	Cancer-specific drivers were filtered so that their frequency of mutation in the tumor of interest was >5%, well above the lower limit of intermediate-frequency drivers and the Pan-Cancer frequency of mutation in drivers (4.16%).	('Pan-Cancer', 'Disease', (177, 187))	('Pan-Cancer', 'Disease', 'MESH:D009369', (177, 187))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutation', 'Var', (65, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
117512	33372594	For example, colon cancer cells that are deficient in p53, one of the most important tumor suppressors, activate the mevalonate pathway to adapt to the lack of oxygen and nutrients.	('tumor', 'Disease', (85, 90))	('mevalonate pathway', 'Pathway', (117, 135))	('adapt', 'MPA', (139, 144))	('colon cancer', 'Phenotype', 'HP:0003003', (13, 25))	('colon cancer', 'Disease', 'MESH:D015179', (13, 25))	('activate', 'PosReg', (104, 112))	('p53', 'Gene', (54, 57))	('mevalonate', 'Chemical', 'MESH:D008798', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colon cancer', 'Disease', (13, 25))	('p53', 'Gene', '7157', (54, 57))	('deficient', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('oxygen', 'Chemical', 'MESH:D010100', (160, 166))
117539	33372594	Of the 29 metabolic pathways tested in the 33 cancer types, the OS analyses affirmed statistical significance for 166 cancer-pathway combinations post permutation and multiple test correction (Supplementary Table S3), and the DSS analyses affirmed 170 similarly (Supplementary Table S4).	('combinations', 'Var', (133, 145))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DSS', 'Gene', (226, 229))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('DSS', 'Gene', '5376', (226, 229))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('metabolic pathways', 'Pathway', (10, 28))
117545	33372594	Pyruvate can directly induce the Warburg effect and it has been suggested to be a cancer therapeutic target.	('Pyruvate', 'Chemical', 'MESH:D019289', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Warburg effect', 'CPA', (33, 47))	('Pyruvate', 'Var', (0, 8))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('induce', 'Reg', (22, 28))
117573	33372594	Of all possible 493 (49x17) cancer-pathway combinations, 328 (66%) showed significantly different expression post multiple test adjustment, signaling significant expression alteration between tumor and normal samples for the metabolic pathways tested.	('tumor', 'Disease', (192, 197))	('combinations', 'Var', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('alteration', 'Reg', (173, 183))	('expression', 'MPA', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('different', 'Reg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('expression', 'MPA', (98, 108))
117574	33372594	Of these 328 dysregulated cancer-pathway combinations, 126 had higher expression in tumor samples and 202 had higher expression in normal samples (Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('expression', 'MPA', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('combinations', 'Var', (41, 53))	('tumor', 'Disease', (84, 89))	('expression', 'MPA', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('higher', 'PosReg', (63, 69))
117588	33372594	Overall, 166 and 170 cancer-pathway combinations were found to be significantly associated with survival for OS and DSS respectively.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('DSS', 'Gene', (116, 119))	('associated with', 'Reg', (80, 95))	('DSS', 'Gene', '5376', (116, 119))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('combinations', 'Var', (36, 48))
117597	33372594	Interruption of folate metabolism pathway may produce substantial toxic effect on cell division process, the key to tumorigenesis.	('tumor', 'Disease', (116, 121))	('Interruption', 'Var', (0, 12))	('cell division process', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('folate', 'Enzyme', (16, 22))	('folate', 'Chemical', 'MESH:D005492', (16, 22))
117598	33372594	Inhibition of folate metabolism pathway has been used in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('folate', 'Chemical', 'MESH:D005492', (14, 20))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('folate metabolism pathway', 'Pathway', (14, 39))
117627	33372594	YG was supported by Cancer Center Support Grant from National Cancer Institute (P30CA118100).	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cancer', 'Disease', (62, 68))	('Cancer', 'Disease', (20, 26))	('P30CA118100', 'Var', (80, 91))	('Cancer', 'Disease', 'MESH:D009369', (20, 26))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))
117650	32066399	HLA molecules are well-known for their major roles in the modulation of human immune system, and aberrant expression of HLA molecules has been indicated in multiple types of human cancers, such as breast cancer, prostate cancer and non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (232, 258))	('aberrant', 'Var', (97, 105))	('indicated', 'Reg', (143, 152))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('non-small cell lung cancer', 'Disease', (232, 258))	('human', 'Species', '9606', (72, 77))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('breast cancer', 'Disease', (197, 210))	('human', 'Species', '9606', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (232, 258))	('prostate cancer', 'Disease', 'MESH:D011471', (212, 227))	('prostate cancer', 'Phenotype', 'HP:0012125', (212, 227))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', (180, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (236, 258))	('prostate cancer', 'Disease', (212, 227))
117662	32066399	Subsequently, the pathological diagnosis of each enrolled patient was re-evaluated by an experienced neuropathologist according to the 2016 WHO classification, data of isocitrate dehydrogenase (IDH) mutation status (detected by pyrosequencing, 233 patients available) and 1p19q co-deletion status (detected by fluorescence, 236 patients available) were reviewed.	('patient', 'Species', '9606', (328, 335))	('patient', 'Species', '9606', (58, 65))	('patients', 'Species', '9606', (328, 336))	('mutation', 'Var', (199, 207))	('isocitrate dehydrogenase', 'Gene', (168, 192))	('IDH', 'Gene', (194, 197))	('isocitrate dehydrogenase', 'Gene', '3417', (168, 192))	('patient', 'Species', '9606', (248, 255))	('patients', 'Species', '9606', (248, 256))	('IDH', 'Gene', '3417', (194, 197))
117702	32066399	The identification of tumor-specific genetic alterations, such as IDH mutation, 1p19q co-deletion, telomerase reverse transcriptase promoter mutation, etc.	('IDH', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('IDH', 'Gene', '3417', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('1p19q co-deletion', 'Var', (80, 97))
117706	32066399	Aberrant expression of HLA-E has been identified in various human malignancies, such as breast cancer, gastric cancer, rectal cancer, and colorectal cancer.	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('HLA-E', 'Gene', '3133', (23, 28))	('rectal cancer', 'Phenotype', 'HP:0100743', (142, 155))	('malignancies', 'Disease', (66, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rectal cancer', 'Disease', (119, 132))	('rectal cancer', 'Phenotype', 'HP:0100743', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('identified', 'Reg', (38, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('rectal cancer', 'Disease', 'MESH:D012004', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('rectal cancer', 'Disease', 'MESH:D012004', (119, 132))	('colorectal cancer', 'Disease', (138, 155))	('HLA-E', 'Gene', (23, 28))	('gastric cancer', 'Disease', (103, 117))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('human', 'Species', '9606', (60, 65))
117716	32066399	IDH1 mutation has been identified to be one of most important molecular pathological alterations in glioma, but HLA-E showed little association with it.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('HLA-E', 'Gene', (112, 117))	('HLA-E', 'Gene', '3133', (112, 117))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
117719	32066399	For instance, expression of HLA-E has been reported to resulted in a worse relapse-free period for patients with breast cancer.	('HLA-E', 'Gene', '3133', (28, 33))	('expression', 'Var', (14, 24))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HLA-E', 'Gene', (28, 33))	('breast cancer', 'Disease', (113, 126))	('worse', 'NegReg', (69, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('patients', 'Species', '9606', (99, 107))	('relapse-free period', 'CPA', (75, 94))
117744	31842801	Among these genes, ZAP70, CD3E, CD3G, CD3D, and CD247 were part of the TCR 'signal-triggering module'; (3) High expression of the PIGs involved in the TCR signaling pathway was associated with improved OS in 5 cancer types (breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), and sarcoma (SARC)), but was associated with decreased OS in brain lower-grade glioma (LGG).	('BRCA', 'Gene', '672', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (331, 368))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TCR', 'Gene', '6962', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('lung adenocarcinoma', 'Disease', (377, 396))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (331, 368))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (224, 249))	('BRCA', 'Gene', (251, 255))	('TCR', 'Gene', (71, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (258, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (387, 396))	('sarcoma', 'Disease', 'MESH:D012509', (409, 416))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('glioma', 'Disease', (484, 490))	('TCR', 'Gene', (151, 154))	('sarcoma', 'Disease', (409, 416))	('decreased', 'NegReg', (450, 459))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (377, 396))	('glioma', 'Disease', 'MESH:D005910', (484, 490))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (377, 396))	('PIGs', 'Species', '9823', (130, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('glioma', 'Phenotype', 'HP:0009733', (484, 490))	('breast invasive carcinoma', 'Disease', (224, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (409, 416))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('improved', 'PosReg', (193, 201))	('High expression', 'Var', (107, 122))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (224, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancer', 'Disease', (210, 216))	('TCR', 'Gene', '6962', (71, 74))
117756	31842801	In addition, pembrolizumab was associated with a significantly longer OS for platinum-refractory advanced urothelial carcinoma than standard therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('urothelial carcinoma', 'Disease', (106, 126))	('pembrolizumab', 'Var', (13, 26))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (106, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))
117803	31842801	Eleven genes (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were identified as participating in the TCR signaling pathway (Fig.	('TCR', 'Gene', (128, 131))	('CD247', 'Var', (62, 67))	('ICOS', 'Gene', (33, 37))	('PTPRC', 'Gene', '100522631', (21, 26))	('PTPRC', 'Gene', (21, 26))	('ICOS', 'Gene', '733597', (33, 37))	('GRAP2', 'Gene', '100516438', (81, 86))	('GRAP2', 'Gene', (81, 86))	('participating', 'Reg', (107, 120))	('CD3G', 'Gene', (45, 49))	('CD40LG', 'Gene', '397231', (69, 75))	('CD40LG', 'Gene', (69, 75))	('ITK', 'Gene', (57, 60))	('ZAP70', 'Var', (14, 19))	('TCR', 'Gene', '6962', (128, 131))	('CD3D', 'Gene', (51, 55))	('ITK', 'Gene', '100523474', (57, 60))	('CD3E', 'Gene', (39, 43))
117805	31842801	ZAP70, CD3E, CD3G, CD3D, and CD247 were classified into a 'TCR signal triggering module' by Acuto et al., which was crucial to the successful initiation of T cell activation.	('CD3E', 'Var', (7, 11))	('CD3G', 'Var', (13, 17))	('CD3D', 'Var', (19, 23))	('ZAP70', 'Var', (0, 5))	('TCR', 'Gene', '6962', (59, 62))	('CD247', 'Var', (29, 34))	('TCR', 'Gene', (59, 62))
117808	31842801	Second, 6 (LCK, ZAP70, CD3E, CD3G, CD3D, and CD247) out of 11 PIGs played crucial roles in activating T cell activation.	('CD3D', 'Var', (35, 39))	('activating T cell activation', 'MPA', (91, 119))	('PIGs', 'Species', '9823', (62, 66))	('CD247', 'Var', (45, 50))
117819	31842801	High-level expression of the PIGs participating in the TCR signaling pathway was associated with improved OS in 5 cancer types (BRCA, CESC, HNSC, LUAD, and SARC), but with decreased OS in LGG.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('HNSC', 'Disease', (140, 144))	('cancer', 'Disease', (114, 120))	('BRCA', 'Gene', (128, 132))	('improved', 'PosReg', (97, 105))	('LUAD', 'Disease', (146, 150))	('BRCA', 'Gene', '672', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TCR', 'Gene', '6962', (55, 58))	('CESC', 'Disease', (134, 138))	('PIGs', 'Species', '9823', (29, 33))	('High-level expression', 'Var', (0, 21))	('TCR', 'Gene', (55, 58))
117838	31842801	Eleven PIGs (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were mainly shared by the 6 cancer types (BRCA, CESC, HNSC, LUAD, SARC, and LGG) involved in the TCR signaling pathway.	('CD40LG', 'Gene', '397231', (68, 74))	('CD3D', 'Var', (50, 54))	('ITK', 'Gene', '100523474', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PIGs', 'Species', '9823', (7, 11))	('ZAP70', 'Var', (13, 18))	('CD40LG', 'Gene', (68, 74))	('TCR', 'Gene', (184, 187))	('PTPRC', 'Gene', '100522631', (20, 25))	('BRCA', 'Gene', '672', (129, 133))	('ICOS', 'Gene', (32, 36))	('GRAP2', 'Gene', (80, 85))	('BRCA', 'Gene', (129, 133))	('CD3G', 'Var', (44, 48))	('PTPRC', 'Gene', (20, 25))	('cancer', 'Disease', (115, 121))	('ITK', 'Gene', (56, 59))	('ICOS', 'Gene', '733597', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CD247', 'Var', (61, 66))	('GRAP2', 'Gene', '100516438', (80, 85))	('TCR', 'Gene', '6962', (184, 187))
117839	31842801	Six genes (ZAP70, LCK, CD3E, CD3G, CD3D, and CD247) played a key role in triggering the TCR signaling pathway.	('CD3D', 'Gene', (35, 39))	('CD3G', 'Gene', (29, 33))	('LCK', 'Gene', (18, 21))	('CD247', 'Gene', (45, 50))	('TCR', 'Gene', (88, 91))	('ZAP70', 'Var', (11, 16))	('triggering', 'Reg', (73, 83))	('TCR', 'Gene', '6962', (88, 91))	('CD3E', 'Gene', (23, 27))
117845	31842801	In this study, there was no significant difference between the OS in patients with high expression of CTLA4 and PD1 and that of patients with low expression of CTLA4 and PD1 in most cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CTLA4', 'Gene', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('high expression', 'Var', (83, 98))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (128, 136))	('PD1', 'Gene', (112, 115))
117847	31842801	High expression of 11 PIGs was associated with good prognosis in BRCA, CESC, HNSC, LUAD, and SARC but poor prognosis in LGG.	('High expression', 'Var', (0, 15))	('LUAD', 'Disease', (83, 87))	('BRCA', 'Gene', (65, 69))	('CESC', 'Disease', (71, 75))	('SARC but', 'Disease', (93, 101))	('BRCA', 'Gene', '672', (65, 69))	('PIGs', 'Species', '9823', (22, 26))	('HNSC', 'Disease', (77, 81))
117852	31842801	Among them, CD45 can modulate LCK activation or inactivation by the dephosphorylation of Tyr505 of LCK or the dephosphorylation of Tyr394 of LCK.	('CD45', 'Var', (12, 16))	('Tyr505', 'Var', (89, 95))	('LCK', 'Protein', (141, 144))	('inactivation', 'NegReg', (48, 60))	('Tyr394', 'Chemical', '-', (131, 137))	('dephosphorylation', 'MPA', (110, 127))	('Tyr505', 'Chemical', '-', (89, 95))	('activation', 'PosReg', (34, 44))	('LCK', 'Protein', (99, 102))	('LCK', 'Protein', (30, 33))	('modulate', 'Reg', (21, 29))	('dephosphorylation', 'MPA', (68, 85))
117872	31870275	However, detection of isocitrate dehydrogenase (IDH) mutation and chromosome1p/19q codeletion, biomarkers to classify gliomas, is time- and cost-intensive and diagnostic discordance remains an issue.	('isocitrate dehydrogenase', 'Gene', (22, 46))	('IDH', 'Gene', (48, 51))	('mutation', 'Var', (53, 61))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('isocitrate dehydrogenase', 'Gene', '3417', (22, 46))	('IDH', 'Gene', '3417', (48, 51))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
117875	31870275	By characterizing genome-wide A-to-I RNA editing signatures of 638 gliomas, we found that tumors without IDH mutation exhibited higher total editing level compared with those carrying it (Kolmogorov-Smirnov test, p < 0.0001).	('editing level', 'MPA', (141, 154))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('gliomas', 'Disease', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('IDH', 'Gene', (105, 108))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH', 'Gene', '3417', (105, 108))	('higher', 'PosReg', (128, 134))	('mutation', 'Var', (109, 117))
117877	31870275	The area under the receiver operating characteristic curve (AUC) of SVM in predicting IDH mutation and 1p/19q codeletion were 0.989 and 0.990, respectively.	('IDH', 'Gene', '3417', (86, 89))	('IDH', 'Gene', (86, 89))	('1p/19q codeletion', 'Var', (103, 120))
117878	31870275	After performing feature selection, AUCs of SVM and AdaBoost in predicting IDH mutation were higher than that of random forest (0.985 and 0.983 vs. 0.977; DeLong test, p < 0.05), but AUCs of the three algorithms in predicting 1p/19q codeletion were similar (0.976-0.982).	('IDH', 'Gene', '3417', (75, 78))	('mutation', 'Var', (79, 87))	('IDH', 'Gene', (75, 78))
117886	31870275	In 2016, the World Health Organization (WHO) changed its classification of diffuse gliomas by considering the presence/absence of isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('mutation', 'Var', (161, 169))	('isocitrate dehydrogenase', 'Gene', (130, 154))	('IDH', 'Gene', (156, 159))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('isocitrate dehydrogenase', 'Gene', '3417', (130, 154))	('IDH', 'Gene', '3417', (156, 159))
117887	31870275	A large subset of adult diffuse gliomas now falls into one of the following categories: IDH mutation with 1p/19q codeletion (oligodendroglioma), IDH mutation without 1p/19q codeletion (most grades II and III astrocytoma), and IDH wildtype (most glioblastoma).	('falls', 'Phenotype', 'HP:0002527', (44, 49))	('glioblastoma', 'Disease', (245, 257))	('IDH', 'Gene', '3417', (226, 229))	('mutation', 'Var', (92, 100))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('IDH', 'Gene', '3417', (145, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (245, 257))	('IDH', 'Gene', (88, 91))	('1p/19q codeletion', 'Var', (106, 123))	('III astrocytoma', 'Disease', 'MESH:D001254', (204, 219))	('IDH', 'Gene', '3417', (88, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (208, 219))	('gliomas', 'Disease', (32, 39))	('III astrocytoma', 'Disease', (204, 219))	('oligodendroglioma', 'Disease', 'MESH:D009837', (125, 142))	('IDH', 'Gene', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (245, 257))	('IDH', 'Gene', (145, 148))	('oligodendroglioma', 'Disease', (125, 142))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
117888	31870275	Some studies have found that LGG patients with IDH mutation had prolonged overall survival (OS) compared with those carrying wildtype IDH.	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', '3417', (134, 137))	('prolonged', 'PosReg', (64, 73))	('patients', 'Species', '9606', (33, 41))	('overall survival', 'MPA', (74, 90))	('mutation', 'Var', (51, 59))	('LGG', 'Disease', (29, 32))	('IDH', 'Gene', (47, 50))	('IDH', 'Gene', (134, 137))
117889	31870275	Also, GBM and anaplastic astrocytoma patients who had IDH mutation exhibited improved progression-free survival and OS compared with those without IDH mutation.	('GBM', 'Disease', (6, 9))	('IDH', 'Gene', '3417', (147, 150))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('patients', 'Species', '9606', (37, 45))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (14, 36))	('mutation', 'Var', (58, 66))	('progression-free survival', 'CPA', (86, 111))	('IDH', 'Gene', (54, 57))	('IDH', 'Gene', '3417', (54, 57))	('IDH', 'Gene', (147, 150))	('anaplastic astrocytoma', 'Disease', (14, 36))	('improved', 'PosReg', (77, 85))
117890	31870275	Furthermore, patients with both IDH mutation and 1p/19q codeletion had increased OS compared with those with only IDH mutation.	('1p/19q codeletion', 'Var', (49, 66))	('IDH', 'Gene', (114, 117))	('patients', 'Species', '9606', (13, 21))	('IDH', 'Gene', '3417', (114, 117))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('increased', 'PosReg', (71, 80))
117892	31870275	For example, immunohistochemistry (IHC) is a common method to detect IDH mutation and requires antibodies to recognize mutations.	('IDH', 'Gene', (69, 72))	('mutation', 'Var', (73, 81))	('IDH', 'Gene', '3417', (69, 72))
117893	31870275	However, IHC fails to detect less common IDH mutations and the concordance rate between IHC and Sanger sequencing was estimated to range 88 to 99%.	('IDH', 'Gene', '3417', (41, 44))	('IDH', 'Gene', (41, 44))	('mutations', 'Var', (45, 54))
117894	31870275	Taken together, a single method which provides standardized, accurate and objective prediction of IDH mutation and 1p/19q codeletion is warranted.	('mutation', 'Var', (102, 110))	('IDH', 'Gene', '3417', (98, 101))	('IDH', 'Gene', (98, 101))
117898	31870275	IDH mutant gliomas were clustered into three groups: (1) presence of 1p/19q codeletion; (2) absence of 1p/19q codeletion and low global DNA methylation; and (3) absence of 1p/19q codeletion and high global DNA methylation.	('IDH', 'Gene', (0, 3))	('global DNA methylation', 'MPA', (129, 151))	('1p/19q codeletion', 'Var', (69, 86))	('1p/19q codeletion', 'Var', (103, 120))	('global DNA methylation', 'MPA', (199, 221))	('mutant', 'Var', (4, 10))	('absence', 'NegReg', (92, 99))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('absence', 'NegReg', (161, 168))	('presence', 'Reg', (57, 65))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('low', 'NegReg', (125, 128))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
117899	31870275	However, the authors did not develop a method capable of predicting IDH mutation and 1p/19q codeletion, which limits the clinical utility of DNA methylation.	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', (68, 71))	('1p/19q codeletion', 'Var', (85, 102))
117903	31870275	RNA-Seq data can be used to identify events that could cause tumor development and progression, including single nucleotide variation, gene expression alteration, alternative isoforms, gene fusion, and RNA editing events.	('RNA', 'MPA', (202, 205))	('single nucleotide variation', 'Var', (106, 133))	('gene', 'MPA', (135, 139))	('gene fusion', 'Var', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('alteration', 'Var', (151, 161))	('cause', 'Reg', (55, 60))	('tumor', 'Disease', (61, 66))
117908	31870275	reported a negative correlation between the editing level of miR-376a-5p and glioma tumor volume.	('miR-376a-5p', 'Var', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('glioma tumor', 'Disease', (77, 89))	('editing', 'MPA', (44, 51))	('negative', 'NegReg', (11, 19))	('glioma tumor', 'Disease', 'MESH:D005910', (77, 89))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('miR-376a-5p', 'Chemical', '-', (61, 72))
117909	31870275	The authors found that reduced editing of miR-376a-5p was associated with more aggressive glioblastoma and poor prognosis.	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('miR-376a-5p', 'Chemical', '-', (42, 53))	('aggressive glioblastoma', 'Disease', (79, 102))	('reduced', 'NegReg', (23, 30))	('editing', 'MPA', (31, 38))	('miR-376a-5p', 'Var', (42, 53))	('aggressive glioblastoma', 'Disease', 'MESH:D005909', (79, 102))
117917	31870275	Samples were classified into three groups based on the status of IDH mutation and 1p/19q codeletion (Table 1): (1) IDH wt: samples without IDH mutation; (2) IDH mut-codel: samples with both IDH mutation and 1p/19q codeletion; and (3) IDH mut-non-codel: samples with only IDH mutation (no 1p/19q codeletion).	('IDH', 'Gene', (234, 237))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (271, 274))	('IDH', 'Gene', '3417', (157, 160))	('IDH', 'Gene', '3417', (234, 237))	('IDH', 'Gene', '3417', (65, 68))	('1p/19q codeletion', 'Var', (207, 224))	('IDH', 'Gene', (190, 193))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (190, 193))	('IDH', 'Gene', '3417', (139, 142))	('IDH', 'Gene', (271, 274))	('IDH', 'Gene', (157, 160))
117926	31870275	Next, we developed models to classify gliomas by predicting the status of IDH mutation and 1p/19q codeletion.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('mutation', 'Var', (78, 86))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH', 'Gene', (74, 77))	('IDH', 'Gene', '3417', (74, 77))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
117932	31870275	Figure 3a reveals sites more heavily edited in IDH wildtype (especially GBM) samples as well as sites more heavily edited in IDH mutant samples.	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', (125, 128))	('IDH', 'Gene', '3417', (125, 128))	('IDH', 'Gene', (47, 50))	('mutant', 'Var', (129, 135))
117935	31870275	For 1p/19q codeletion (124 sites), enrichment in ncRNA_intronic (p = 0.02) and depletion in UTR3 (p = 0.01) and intronic (p = 0.01) were detected.	('ncRNA', 'Gene', '54719', (49, 54))	('UTR3', 'Protein', (92, 96))	('1p/19q codeletion', 'Var', (4, 21))	('ncRNA', 'Gene', (49, 54))	('depletion', 'MPA', (79, 88))
117938	31870275	However, only nine of the 413 samples with IDH mutation belong to GBM.	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', (43, 46))	('mutation', 'Var', (47, 55))
117940	31870275	Using editing signatures of less than 200 sites, our models achieved high accuracy of predicting IDH mutation and 1p/19q codeletion.	('IDH', 'Gene', (97, 100))	('mutation', 'Var', (101, 109))	('1p/19q codeletion', 'Var', (114, 131))	('IDH', 'Gene', '3417', (97, 100))
117943	31870275	For example, chr6:159679878 (one of the sites used to predict 1p/19q codeletion) has prognostic value for LGG patients.	('patients', 'Species', '9606', (110, 118))	('LGG', 'Disease', (106, 109))	('chr6:159679878', 'Var', (13, 27))
117944	31870275	Patients with higher level of editing at chr6:159,679,878 have worse OS and progression free interval than those with lower editing (log-rank test: p < 0.0001; Fig.	('Patients', 'Species', '9606', (0, 8))	('editing', 'Var', (30, 37))	('progression free interval', 'CPA', (76, 101))	('worse', 'NegReg', (63, 68))
117958	31870275	We selected tumors that have both RNA-Seq bam files and annotation of IDH mutation and 1p/19q codeletion available, resulting in 638 samples (496 LGG and 142 GBM).	('mutation', 'Var', (74, 82))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
117961	31870275	Because DNA changes could result in misidentification of RNA editing events, we downloaded somatic mutation data from GDC and germline variant data from the TCGA Pan-Cancer analysis project and GDC legacy archive.	('Cancer', 'Disease', 'MESH:D009369', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('result', 'Reg', (26, 32))	('Cancer', 'Disease', (166, 172))	('changes', 'Var', (12, 19))
117963	31870275	Three supervised learning algorithms including support vector machines (SVM), random forest (RF) and AdaBoost (AB) were used in this study to predict the status of IDH mutation and 1p/19q codeletion.	('1p/19q codeletion', 'Var', (181, 198))	('IDH', 'Gene', '3417', (164, 167))	('learning algorithms', 'Disease', 'MESH:D007859', (17, 36))	('learning algorithms', 'Disease', (17, 36))	('mutation', 'Var', (168, 176))	('IDH', 'Gene', (164, 167))
117970	29069756	In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma.	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('glioma', 'Disease', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('human', 'Species', '9606', (27, 32))	('P4HB', 'Gene', (131, 135))	('correlated', 'Reg', (140, 150))	('aberrant expression', 'Var', (108, 127))	('angiogenic', 'CPA', (185, 195))	('glioma', 'Disease', (209, 215))	('malignancy', 'Disease', 'MESH:D009369', (167, 177))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('malignancy', 'Disease', (167, 177))
117973	29069756	Since tumor invasion and Vascularisation are typical hallmarks in malignant glioma, our findings uncover a promising anti-glioma mechanism through P4HB-mediated retardation of MAPK signal transduction.	('malignant glioma', 'Disease', 'MESH:D005910', (66, 82))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Disease', (76, 82))	('MAPK signal transduction', 'Pathway', (176, 200))	('glioma', 'Disease', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('P4HB-mediated', 'Var', (147, 160))	('retardation', 'Disease', (161, 172))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('retardation', 'Disease', 'MESH:D008607', (161, 172))	('tumor', 'Disease', (6, 11))	('malignant glioma', 'Disease', (66, 82))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
117979	29069756	Therefore, perturbation of ER homeostasis could have critical roles in Tumourigenesis, and targeting ER chaperones represents a novel direction for developing anti-tumor therapy.	('Tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (164, 169))	('ER homeostasis', 'MPA', (27, 41))	('Tumourigenesis', 'CPA', (71, 85))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('perturbation', 'Var', (11, 23))
117981	29069756	Elevated levels of P4HB may confer tolerance against extracellular stresses such as hypoxia and ischemia.	('hypoxia', 'Disease', (84, 91))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('ischemia', 'Disease', (96, 104))	('P4HB', 'Var', (19, 23))	('ischemia', 'Disease', 'MESH:D007511', (96, 104))	('tolerance', 'MPA', (35, 44))
117985	29069756	Our work provided novel findings that aberrant expression of P4HB promotes tumour invasion, angiogenesis and growth via the MAPK signaling pathways.	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('angiogenesis', 'CPA', (92, 104))	('aberrant expression', 'Var', (38, 57))	('tumour', 'Disease', (75, 81))	('P4HB', 'Gene', (61, 65))	('growth', 'CPA', (109, 115))	('promotes', 'PosReg', (66, 74))	('MAPK signaling pathways', 'Pathway', (124, 147))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
117988	29069756	Levels of intensity varied among different cancer grades, in that P4HB was detectable in 30/48 (62.5%) high-grade, but only 5/16 (31.2%) in low-grade gliomas.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('P4HB', 'Var', (66, 70))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('detectable', 'Reg', (75, 85))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
117989	29069756	Only 12.6% of low-grade glioma cases demonstrated more than 25% of P4HB-stained cells, which was around 30% relative to high-grade glioma (47.9% cases), suggesting that P4HB expression was correlated with glioma malignancy grades (Figure 1A).	('glioma', 'Disease', (131, 137))	('correlated', 'Reg', (189, 199))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma malignancy', 'Disease', 'MESH:D005910', (205, 222))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('glioma', 'Disease', (205, 211))	('glioma malignancy', 'Disease', (205, 222))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('P4HB', 'Var', (169, 173))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('glioma', 'Disease', (24, 30))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
117992	29069756	Microvessels (arterioles, venules, and capillaries) densities and VEGF staining intensities were significantly stronger in high-grade (high P4HB expression) when compared to the low-grade glioma (low P4HB expression) (Figure 2A).	('VEGF', 'Gene', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('VEGF', 'Gene', '7422', (66, 70))	('stronger', 'PosReg', (111, 119))	('glioma', 'Disease', (188, 194))	('high P4HB expression', 'Var', (135, 155))
117994	29069756	In low-grade glioma with low P4HB expression, microvessels were predominantly pericyte-liked with a capillary phenotype, whereas in high-grade glioma there was hypervascularity with enlarged, branched and disorganized vessel structures.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('microvessels', 'CPA', (46, 58))	('P4HB', 'Gene', (29, 33))	('low', 'Var', (25, 28))	('glioma', 'Disease', (143, 149))	('glioma', 'Disease', (13, 19))
117995	29069756	Microvessel density (MVD) correlated positively with P4HB in both low-grade (p = 0.003) and high-grade gliomas (p = 0.0001) (Figure 2B).	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('positively', 'PosReg', (37, 47))	('Microvessel', 'MPA', (0, 11))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('P4HB', 'Var', (53, 57))
118000	29069756	Figure 5A illustrates that GBM cells with P4HB over-expression were successfully established in D54, U87 and U251 cells (D54-P4HB, U87-P4HB and U251-P4HB).	('over-expression', 'PosReg', (47, 62))	('U87', 'Gene', (131, 134))	('U87', 'Gene', (101, 104))	('P4HB', 'Gene', (42, 46))	('U251-P4HB', 'Var', (144, 153))	('U87', 'Gene', '641648', (131, 134))	('U87', 'Gene', '641648', (101, 104))
118002	29069756	A similar trend was observed on matrigel invasion assay, with U87-P4HB and U251-P4HB cells showing greater invasion ability at 24 hours when compared to their respective vector controls (p < 0.001) (Figure 5D).	('U251-P4HB', 'Var', (75, 84))	('U87', 'Gene', (62, 65))	('invasion ability', 'CPA', (107, 123))	('greater', 'PosReg', (99, 106))	('U87', 'Gene', '641648', (62, 65))	('matrigel invasion assay', 'CPA', (32, 55))
118004	29069756	Suppression of MAPK activities by using U0126, at 0, 1, 5, 10 muM for 2 hours in P4HB over-expressing U87 and U251 cells (U87 P4HB and U251 P4HB) was found to reduce VEGF expression without affecting P4HB level (Figure 5G).	('muM', 'Gene', '56925', (62, 65))	('U87', 'Gene', '641648', (122, 125))	('VEGF', 'Gene', (166, 170))	('U0126', 'Var', (40, 45))	('muM', 'Gene', (62, 65))	('MAPK', 'Enzyme', (15, 19))	('VEGF', 'Gene', '7422', (166, 170))	('U87', 'Gene', (102, 105))	('U87', 'Gene', (122, 125))	('Suppression', 'NegReg', (0, 11))	('U0126', 'Chemical', 'MESH:C113580', (40, 45))	('U87', 'Gene', '641648', (102, 105))	('reduce', 'NegReg', (159, 165))	('activities', 'MPA', (20, 30))	('P4HB', 'Gene', (81, 85))
118005	29069756	The invasive and angiogenic abilities of U87 P4HB and U251 P4HB cells were affected phenotypically after the reduction of MAPK activity (Figure 5H and 5I).	('U87', 'Gene', '641648', (41, 44))	('MAPK', 'Protein', (122, 126))	('affected', 'Reg', (75, 83))	('reduction', 'NegReg', (109, 118))	('U87', 'Gene', (41, 44))	('activity', 'MPA', (127, 135))	('U251 P4HB', 'Var', (54, 63))
118007	29069756	At 14 day post-implantation, stable P4HB cells (U87 P4HB-1, U87 P4HB-2 and U251 P4HB) exhibited significantly greater exponential growth when compared with vector control (U87 Vec-Ctrl and U251 Vec-Ctrl) (p < 0.05) (Figure 6B).	('U87', 'Gene', '641648', (172, 175))	('U87', 'Gene', '641648', (48, 51))	('U251 P4HB', 'Var', (75, 84))	('greater', 'PosReg', (110, 117))	('U87', 'Gene', (60, 63))	('U87', 'Gene', '641648', (60, 63))	('U87', 'Gene', (172, 175))	('exponential growth', 'CPA', (118, 136))	('U87', 'Gene', (48, 51))
118017	29069756	A conditional heterozygous deletion of GRP78 may reduce tumour angiogenesis and metastatic growth in tumor endothelial cells but not in normal tissue.	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('GRP78', 'Gene', (39, 44))	('deletion', 'Var', (27, 35))	('GRP78', 'Gene', '3309', (39, 44))	('reduce', 'NegReg', (49, 55))	('tumour', 'Disease', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
118021	29069756	As such, it is conceivable, though unproven, that high P4HB expression in brain tumours may also exert impact on disease progression and clinical outcome.	('P4HB', 'Protein', (55, 59))	('expression', 'MPA', (60, 70))	('brain tumours', 'Disease', 'MESH:D001932', (74, 87))	('brain tumours', 'Phenotype', 'HP:0030692', (74, 87))	('brain tumours', 'Disease', (74, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('impact', 'Reg', (103, 109))	('disease progression', 'CPA', (113, 132))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('high', 'Var', (50, 54))
118026	29069756	Abnormalities in MAPK signaling play a critical role in the development and progression of cancer.	('Abnormalities', 'Var', (0, 13))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MAPK signaling', 'Pathway', (17, 31))
118031	29069756	Conversely, inhibiting MAPK pathway with U0126 abrogated the induction of VEGF, tumor invasion and angiogenesis, without alterations in P4HB protein levels.	('VEGF', 'Gene', '7422', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('U0126', 'Chemical', 'MESH:C113580', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('VEGF', 'Gene', (74, 78))	('angiogenesis', 'CPA', (99, 111))	('tumor', 'Disease', (80, 85))	('MAPK pathway', 'Pathway', (23, 35))	('abrogated', 'NegReg', (47, 56))	('U0126', 'Var', (41, 46))	('inhibiting', 'NegReg', (12, 22))
118048	29069756	Briefly, after blocking with 5% non-fat milk in TBS-T (20 mM Tris, 137 mM NaCl, 0.1% Tween-20, pH 7.6), the membrane was probed with one of the following primary antibodies (at 1:1000 dilution) at 4 C overnight: rabbit monoclonal antibodies against P4HB, total p44/42 MAP kinase (Erk 1/2) (total MAPK), phosphor-p44/42 MAP kinase (Erk1/2) (Thr202/Tyr204) (pMAPK), and VEGF (all from Cell Signaling Technology Inc.).	('TBS-T', 'Disease', (48, 53))	('VEGF', 'Gene', (368, 372))	('Erk 1/2', 'Gene', '5595;5594', (280, 287))	('Erk 1/2', 'Gene', (280, 287))	('VEGF', 'Gene', '7422', (368, 372))	('P4HB', 'Gene', (249, 253))	('Erk1/2', 'Gene', '5595;5594', (331, 337))	('TBS-T', 'Disease', 'MESH:D001260', (48, 53))	('Thr202/Tyr204', 'Var', (340, 353))	('rabbit', 'Species', '9986', (212, 218))	('Erk1/2', 'Gene', (331, 337))
118062	29069756	MAPK inhibition was achieved by U0126, a small molecule inhibitor (Cell signaling Technology Inc).	('inhibition', 'NegReg', (5, 15))	('MAPK', 'MPA', (0, 4))	('U0126', 'Var', (32, 37))	('U0126', 'Chemical', 'MESH:C113580', (32, 37))
118067	29069756	1 x 106 GBM cells in 5muL of PBS (U87-Vec-Ctrl, P4HB-1 and P4HB-2; U251-Vec-Ctrl, P4HB) were slowly deposited (1muL/min) in the right striatum at a depth of -3.5 mm from dura with a 10-muL syringe (26-gauge needle; Hamilton Co., Reno, NV, USA).	('PBS', 'Chemical', 'MESH:D007854', (29, 32))	('P4HB-2; U251-Vec-Ctrl', 'Var', (59, 80))	('U251-Vec-Ctrl', 'Var', (67, 80))	('U87', 'Gene', (34, 37))	('U87', 'Gene', '641648', (34, 37))	('P4HB-1', 'Var', (48, 54))
118069	29069756	This study is the first to describe the oncogenic effects of P4HB in glioma and the mechanistic linking of P4HB-mediated MAPK activation in glioma progression, invasion and angiogenesis.	('glioma', 'Disease', (69, 75))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('invasion', 'CPA', (160, 168))	('angiogenesis', 'CPA', (173, 185))	('activation', 'PosReg', (126, 136))	('P4HB-mediated', 'Var', (107, 120))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('MAPK', 'Gene', (121, 125))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('glioma', 'Disease', (140, 146))	('P4HB', 'Var', (61, 65))
118070	29069756	It provides new knowledge on the significance of chaperone proteins dysregulation in malignant glioma both clinically and at a molecular level.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('dysregulation', 'Var', (68, 81))	('malignant glioma', 'Disease', 'MESH:D005910', (85, 101))	('malignant glioma', 'Disease', (85, 101))
118071	29069756	These findings supplement our previous finding that inhibition of P4HB may resensitise chemoresistant GBM to TMZ.	('chemoresistant GBM', 'Disease', (87, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (109, 112))	('inhibition', 'Var', (52, 62))	('P4HB', 'Protein', (66, 70))
118072	29069756	P4HB may be further exploited as a potential predictive marker for GBM prognosis and an alternative therapeutic approach for GBM and possibility in other cancers.	('P4HB', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('GBM', 'Disease', (67, 70))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
118073	29069756	Future studies will help to delineation the whole picture of P4HB dependent MAPK signaling together with their molecular interactions in glioma malignancy.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('glioma malignancy', 'Disease', 'MESH:D005910', (137, 154))	('glioma malignancy', 'Disease', (137, 154))	('P4HB', 'Var', (61, 65))	('MAPK signaling', 'MPA', (76, 90))
118075	27877908	An immuno-wall microdevice exhibits rapid and sensitive detection of IDH1-R132H mutation specific to grade II and III gliomas World Health Organization grade II and III gliomas most frequently occur in the central nervous system (CNS) in adults.	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('IDH1', 'Gene', '3417', (69, 73))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Disease', (118, 125))	('III gliomas', 'Disease', 'MESH:D005910', (114, 125))	('III gliomas', 'Disease', (114, 125))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('R132H', 'Var', (74, 79))	('III gliomas', 'Disease', 'MESH:D005910', (165, 176))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('R132H', 'SUBSTITUTION', 'None', (74, 79))	('IDH1', 'Gene', (69, 73))	('III gliomas', 'Disease', (165, 176))
118078	27877908	Approximately 69-80% of grade II and III gliomas harbor mutations in the isocitrate dehydrogenase 1 gene (IDH1), of which 83-90% are found to be the IDH1-R132H mutation.	('mutations', 'Var', (56, 65))	('R132H', 'SUBSTITUTION', 'None', (154, 159))	('IDH1', 'Gene', (149, 153))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('III gliomas', 'Disease', 'MESH:D005910', (37, 48))	('IDH1', 'Gene', '3417', (149, 153))	('isocitrate', 'Chemical', 'MESH:C034219', (73, 83))	('grade II', 'Disease', (24, 32))	('IDH1', 'Gene', (106, 110))	('R132H', 'Var', (154, 159))	('III gliomas', 'Disease', (37, 48))	('IDH1', 'Gene', '3417', (106, 110))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))
118079	27877908	Detection of the IDH1-R132H mutation should help in the differential diagnosis of grade II and III gliomas from other types of CNS tumors and help determine the boundary between the tumor and normal brain tissue.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('III gliomas', 'Disease', 'MESH:D005910', (95, 106))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('grade II', 'Disease', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (131, 136))	('IDH1', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('CNS tumors', 'Disease', 'MESH:D009369', (127, 137))	('R132H', 'Var', (22, 27))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('III gliomas', 'Disease', (95, 106))	('CNS tumors', 'Disease', (127, 137))	('IDH1', 'Gene', '3417', (17, 21))	('R132H', 'SUBSTITUTION', 'None', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
118080	27877908	In this study, we established a highly sensitive antibody-based device, referred to as the immuno-wall, to detect the IDH1-R132H mutation in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('IDH1', 'Gene', (118, 122))	('R132H', 'SUBSTITUTION', 'None', (123, 128))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('IDH1', 'Gene', '3417', (118, 122))	('gliomas', 'Disease', (141, 148))	('R132H', 'Var', (123, 128))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
118083	27877908	Our results suggested that 10% content of the IDH1-R132H mutation in a sample of 0.33 mul volume, with 500 ng protein, or from 500 cells is theoretically sufficient for the analysis.	('IDH1', 'Gene', (46, 50))	('R132H', 'Var', (51, 56))	('R132H', 'SUBSTITUTION', 'None', (51, 56))	('IDH1', 'Gene', '3417', (46, 50))
118084	27877908	The immuno-wall device will enable the rapid and highly sensitive detection of the IDH1-R132H mutation in routine clinical practice.	('clinical', 'Species', '191496', (114, 122))	('IDH1', 'Gene', '3417', (83, 87))	('R132H', 'Var', (88, 93))	('R132H', 'SUBSTITUTION', 'None', (88, 93))	('IDH1', 'Gene', (83, 87))
118090	27877908	Recent comprehensive genetic studies in large cohorts of LGGs revealed that the isocitrate dehydrogenase 1 (IDH1) mutation was found in 69-80% of these gliomas.	('IDH1', 'Gene', '3417', (108, 112))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('isocitrate', 'Chemical', 'MESH:C034219', (80, 90))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('mutation', 'Var', (114, 122))	('found', 'Reg', (127, 132))	('IDH1', 'Gene', (108, 112))
118091	27877908	The most significant of the IDH1 mutations in LGGs substitutes the amino acid residue 132 from arginine to histidine (R132H), accounting for 83-90% of IDH1 mutations.	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (156, 165))	('132 from arginine to histidine', 'Mutation', 'rs121913500', (86, 116))	('mutations', 'Var', (33, 42))	('R132H', 'Var', (118, 123))	('IDH1', 'Gene', (151, 155))	('R132H', 'SUBSTITUTION', 'None', (118, 123))	('IDH1', 'Gene', '3417', (151, 155))	('IDH1', 'Gene', (28, 32))
118092	27877908	While the wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate and produces alpha-ketoglutarate (alpha-KG) in the tricarboxylic acid cycle, the mutant IDH1 converts alpha-KG further into 2-hydroxyglutarate, which, as an oncogenic metabolite, plays several crucial roles in the initiation of glioma.	('IDH1', 'Gene', '3417', (20, 24))	('initiation of glioma', 'Disease', 'MESH:D005910', (293, 313))	('initiation of glioma', 'Disease', (293, 313))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (130, 148))	('isocitrate', 'Chemical', 'MESH:C034219', (68, 78))	('alpha-KG', 'Chemical', 'MESH:D007656', (113, 121))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (92, 111))	('IDH1', 'Gene', (167, 171))	('mutant', 'Var', (160, 166))	('alpha-KG', 'Chemical', 'MESH:D007656', (181, 189))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('IDH1', 'Gene', '3417', (167, 171))	('IDH1', 'Gene', (20, 24))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (203, 221))
118093	27877908	More importantly, the IDH1 mutation is rarely found in other CNS tumors, and regardless of their locations (i.e.	('CNS tumors', 'Disease', (61, 71))	('CNS tumors', 'Disease', 'MESH:D009369', (61, 71))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('IDH1', 'Gene', '3417', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
118094	27877908	in the tumor core or in the margin), and every tumor cell in an LGG harboring the mutation of IDH1 expresses the mutated IDH1.	('IDH1', 'Gene', (121, 125))	('IDH1', 'Gene', (94, 98))	('tumor', 'Disease', (7, 12))	('mutation', 'Var', (82, 90))	('IDH1', 'Gene', '3417', (121, 125))	('IDH1', 'Gene', '3417', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutated', 'Var', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
118095	27877908	These facts suggest that detection of the IDH1 mutation would enable clinicians to distinguish LGGs from other CNS tumors and to better delineate the ambiguous tumor margin from the normal brain.	('CNS tumors', 'Disease', (111, 121))	('CNS tumors', 'Disease', 'MESH:D009369', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IDH1', 'Gene', '3417', (42, 46))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('IDH1', 'Gene', (42, 46))	('LGGs', 'Disease', (95, 99))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
118096	27877908	The IDH1 mutation is a potential biomarker; however, the only means of detecting this mutation in routine clinical practice thus far are direct sequencing and immunohistochemistry with anti-IDHR132H antibody, both of which are time-consuming and labor-intensive.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', (4, 8))	('clinical', 'Species', '191496', (106, 114))
118099	27877908	In this study, we developed a novel immuno-wall device to detect the IDH1-R132H mutation in glioma.	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('IDH1', 'Gene', '3417', (69, 73))	('glioma', 'Disease', (92, 98))	('R132H', 'Var', (74, 79))	('R132H', 'SUBSTITUTION', 'None', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('IDH1', 'Gene', (69, 73))
118100	27877908	We found high sensitivity for IDH1-R132H even in small amounts of tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('R132H', 'Var', (35, 40))	('tumor', 'Disease', (66, 71))	('sensitivity', 'MPA', (14, 25))	('IDH1', 'Gene', (30, 34))	('R132H', 'SUBSTITUTION', 'None', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('IDH1', 'Gene', '3417', (30, 34))
118103	27877908	U87 and immortalized normal human astrocytoma (NHA), expressing either mutated IDH1 (U87-IDH1-R132H, NHA-IDH1-R132H, respectively) or wild-type IDH1 (U87-wtIDH1, NHA-wtIDH1, respectively) were kindly donated by Dr Russell O. Pieper of the University of California, San Francisco, CA, USA.	('U87', 'Gene', '641648', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('R132H', 'Var', (110, 115))	('R132H', 'Var', (94, 99))	('IDH1', 'Gene', '3417', (105, 109))	('IDH1', 'Gene', (144, 148))	('IDH1', 'Gene', (89, 93))	('U87', 'Gene', '641648', (85, 88))	('IDH1', 'Gene', (168, 172))	('IDH1', 'Gene', (79, 83))	('U87', 'Gene', (150, 153))	('R132H', 'SUBSTITUTION', 'None', (110, 115))	('R132H', 'SUBSTITUTION', 'None', (94, 99))	('U87', 'Gene', (0, 3))	('astrocytoma', 'Disease', 'MESH:D001254', (34, 45))	('IDH1', 'Gene', '3417', (144, 148))	('astrocytoma', 'Disease', (34, 45))	('IDH1', 'Gene', '3417', (89, 93))	('IDH1', 'Gene', '3417', (79, 83))	('IDH1', 'Gene', '3417', (168, 172))	('IDH1', 'Gene', (156, 160))	('U87', 'Gene', (85, 88))	('human', 'Species', '9606', (28, 33))	('IDH1', 'Gene', (105, 109))	('IDH1', 'Gene', '3417', (156, 160))	('mutated', 'Var', (71, 78))	('U87', 'Gene', '641648', (150, 153))
118117	27877908	A biotinylated anti-R132H mutated IDH1 antibody (HMab-2), an anti-wild-type IDH1 antibody (RcMab-1), and a fluorescent DyLight650-conjugated goat anti-rat IgG antibody (Abcam, Cambridge, UK) were used to label R132H mutated IDH1.	('IDH1', 'Gene', (76, 80))	('IDH1', 'Gene', '3417', (34, 38))	('R132H', 'SUBSTITUTION', 'None', (20, 25))	('IDH1', 'Gene', '3417', (224, 228))	('IgG antibody', 'Phenotype', 'HP:0003237', (155, 167))	('R132H', 'Var', (210, 215))	('HMab-2', 'Chemical', '-', (49, 55))	('IDH1', 'Gene', '3417', (76, 80))	('R132H', 'SUBSTITUTION', 'None', (210, 215))	('IDH1', 'Gene', (224, 228))	('goat', 'Species', '9925', (141, 145))	('rat', 'Species', '10116', (151, 154))	('IDH1', 'Gene', (34, 38))	('biotin', 'Chemical', 'MESH:D001710', (2, 8))	('R132H', 'Var', (20, 25))
118132	27877908	On the basis of our previous study which detected a mutation in lung cancer (manuscript in preparation), we found that 1.5 mul of cell lysate at a concentration of 1.0 mg ml-1 was sufficient for conducting an immuno-wall assay.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rat', 'Species', '10116', (154, 157))	('ml-1', 'Gene', (171, 175))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('ml-1', 'Gene', '51761', (171, 175))	('mutation', 'Var', (52, 60))	('rat', 'Species', '10116', (96, 99))
118133	27877908	The cell lysate extracted from U87-IDH1-R132H, at a protein concentration of 0.5-2.5 mg ml-1, yielded a positive fluorescence intensity along the immuno-wall (Figure S1).	('rat', 'Species', '10116', (67, 70))	('ml-1', 'Gene', '51761', (88, 92))	('ml-1', 'Gene', (88, 92))	('positive', 'PosReg', (104, 112))	('R132H', 'Var', (40, 45))	('R132H', 'SUBSTITUTION', 'None', (40, 45))
118134	27877908	Thus, our device detected IDH1-R132H in as little as 0.5 mg ml-1 of protein lysates.	('ml-1', 'Gene', '51761', (60, 64))	('ml-1', 'Gene', (60, 64))	('R132H', 'Var', (31, 36))	('IDH1', 'Gene', (26, 30))	('R132H', 'SUBSTITUTION', 'None', (31, 36))	('detected', 'Reg', (17, 25))	('IDH1', 'Gene', '3417', (26, 30))
118135	27877908	Western blotting confirmed that the anti-IDH1-R132H antibody, HMab-2, was specific to the lysate from NHA-IDH1-R132H and U87-IDH1-R132H cells, whereas the anti-IDH1 antibody, RcMab-1, recognized both wild-type and mutant IDH1 in NHA and U87 cells (Figure 2(A)).	('IDH1', 'Gene', (160, 164))	('R132H', 'SUBSTITUTION', 'None', (46, 51))	('R132H', 'SUBSTITUTION', 'None', (111, 116))	('IDH1', 'Gene', '3417', (106, 110))	('IDH1', 'Gene', '3417', (41, 45))	('U87', 'Gene', (121, 124))	('IDH1', 'Gene', (221, 225))	('mutant', 'Var', (214, 220))	('IDH1', 'Gene', '3417', (160, 164))	('U87', 'Gene', (237, 240))	('R132H', 'Var', (130, 135))	('IDH1', 'Gene', (125, 129))	('HMab-2', 'Chemical', '-', (62, 68))	('IDH1', 'Gene', '3417', (221, 225))	('R132H', 'SUBSTITUTION', 'None', (130, 135))	('R132H', 'Var', (111, 116))	('IDH1', 'Gene', '3417', (125, 129))	('R132H', 'Var', (46, 51))	('U87', 'Gene', '641648', (121, 124))	('IDH1', 'Gene', (106, 110))	('IDH1', 'Gene', (41, 45))	('U87', 'Gene', '641648', (237, 240))
118136	27877908	In the immuno-wall assay, at the highest protein concentration (3.0 mg ml-1), U87 and NHA cells expressing wild-type IDH1 did not show fluorescence while both types of cells expressing IDH1-R132H displayed strong fluorescence.	('IDH1', 'Gene', '3417', (185, 189))	('rat', 'Species', '10116', (56, 59))	('fluorescence', 'MPA', (213, 225))	('ml-1', 'Gene', '51761', (71, 75))	('IDH1', 'Gene', '3417', (117, 121))	('ml-1', 'Gene', (71, 75))	('R132H', 'Var', (190, 195))	('U87', 'Gene', (78, 81))	('U87', 'Gene', '641648', (78, 81))	('R132H', 'SUBSTITUTION', 'None', (190, 195))	('IDH1', 'Gene', (185, 189))	('IDH1', 'Gene', (117, 121))
118137	27877908	The mean fluorescence intensity was significantly different between cells expressing wild-type IDH1 and IDH1-R132H (Figure 2(B)).	('IDH1', 'Gene', '3417', (104, 108))	('R132H', 'SUBSTITUTION', 'None', (109, 114))	('different', 'Reg', (50, 59))	('IDH1', 'Gene', (95, 99))	('R132H', 'Var', (109, 114))	('fluorescence intensity', 'MPA', (9, 31))	('IDH1', 'Gene', '3417', (95, 99))	('IDH1', 'Gene', (104, 108))
118138	27877908	Next, in order to determine the detection limit of the ratio of mutated IDH1/wild-type IDH1, we mixed 3.0 mg ml-1 cell lysate from mutant cells with the same concentration of wild-type cell lysate in various ratios.	('IDH1', 'Gene', (72, 76))	('ml-1', 'Gene', '51761', (109, 113))	('ml-1', 'Gene', (109, 113))	('rat', 'Species', '10116', (208, 211))	('IDH1', 'Gene', '3417', (87, 91))	('mutant', 'Var', (131, 137))	('IDH1', 'Gene', '3417', (72, 76))	('mutated', 'Var', (64, 71))	('rat', 'Species', '10116', (165, 168))	('IDH1', 'Gene', (87, 91))	('rat', 'Species', '10116', (55, 58))
118139	27877908	When mutated IDH1 comprised more than 10% of the cell lysate, strong fluorescence was observed.	('IDH1', 'Gene', '3417', (13, 17))	('fluorescence', 'MPA', (69, 81))	('mutated', 'Var', (5, 12))	('IDH1', 'Gene', (13, 17))
118140	27877908	The results indicate that the device can detect the IDH1-R132H mutation if the sample contains more than 10% of mutated IDH1.	('detect', 'Reg', (41, 47))	('IDH1', 'Gene', '3417', (52, 56))	('R132H', 'Var', (57, 62))	('IDH1', 'Gene', (120, 124))	('IDH1', 'Gene', '3417', (120, 124))	('IDH1', 'Gene', (52, 56))	('R132H', 'SUBSTITUTION', 'None', (57, 62))
118141	27877908	However, because the data shown here were determined using artificial cell lines overexpressing mutated or wild-type IDH1, further studies are needed to explore the detection threshold in clinical samples.	('mutated', 'Var', (96, 103))	('clinical samples', 'Species', '191496', (188, 204))	('IDH1', 'Gene', '3417', (117, 121))	('IDH1', 'Gene', (117, 121))
118144	27877908	The DNA sequencing showed that all four LGGs harbored the IDH1-R132H mutation.	('R132H', 'Var', (63, 68))	('IDH1', 'Gene', '3417', (58, 62))	('IDH1', 'Gene', (58, 62))	('R132H', 'SUBSTITUTION', 'None', (63, 68))
118147	27877908	All four LGGs containing the IDH1-R132H mutation as determined by DNA sequencing displayed positive intensity in the immuno-wall assay.	('positive', 'PosReg', (91, 99))	('IDH1', 'Gene', (29, 33))	('R132H', 'SUBSTITUTION', 'None', (34, 39))	('IDH1', 'Gene', '3417', (29, 33))	('R132H', 'Var', (34, 39))
118148	27877908	Next, we evaluated the mutant allele frequencies (MAFs) by pyrosequencing the LGG samples exhibiting the IDH1-R132H mutation (Table 1).	('IDH1', 'Gene', (105, 109))	('R132H', 'Var', (110, 115))	('IDH1', 'Gene', '3417', (105, 109))	('R132H', 'SUBSTITUTION', 'None', (110, 115))	('MAF', 'Gene', '4094', (50, 53))	('MAF', 'Gene', (50, 53))
118150	27877908	Our immuno-wall assay for IDH1-R132H detected as low as 10% of MAF (Figure 4).	('R132H', 'Var', (31, 36))	('IDH1', 'Gene', (26, 30))	('MAF', 'Gene', '4094', (63, 66))	('MAF', 'Gene', (63, 66))	('R132H', 'SUBSTITUTION', 'None', (31, 36))	('IDH1', 'Gene', '3417', (26, 30))
118152	27877908	As the immuno-wall was able to detect mutated cells with an MAF as low as 10%, we sought to utilize the device to estimate the gross tumor margin.	('MAF', 'Gene', '4094', (60, 63))	('MAF', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('mutated cells', 'Var', (38, 51))
118159	27877908	In this study, we established a highly sensitive antibody-based device to detect the IDH1-R132H mutation in glioma.	('glioma', 'Disease', (108, 114))	('R132H', 'Var', (90, 95))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('R132H', 'SUBSTITUTION', 'None', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1', 'Gene', (85, 89))	('IDH1', 'Gene', '3417', (85, 89))
118161	27877908	Our immuno-wall device detected the IDH1 mutation within 15 min with substantially high sensitivity.	('mutation', 'Var', (41, 49))	('detected', 'Reg', (23, 31))	('IDH1', 'Gene', '3417', (36, 40))	('IDH1', 'Gene', (36, 40))
118170	27877908	The rapid detection of IDH1 mutation may also assist in determining the extent of tumor removal.	('assist', 'Reg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('IDH1', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IDH1', 'Gene', '3417', (23, 27))	('tumor', 'Disease', (82, 87))
118173	27877908	In this study, we evaluated a representative LGG case in which IDH1-R132H was detected at the center of the tumor concurrent with wild-type IDH1 at the margin.	('IDH1', 'Gene', '3417', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('IDH1', 'Gene', '3417', (63, 67))	('R132H', 'SUBSTITUTION', 'None', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('IDH1', 'Gene', (140, 144))	('IDH1', 'Gene', (63, 67))	('R132H', 'Var', (68, 73))
118176	27877908	In this study, we demonstrated that our immuno-wall assay could detect mutated IDH1 in a tissue lysate containing 10% IDH1 mutant allele at a protein concentration of 1.0-1.5 mg ml-1 (Figure S2).	('IDH1', 'Gene', '3417', (79, 83))	('IDH1', 'Gene', (118, 122))	('mutated', 'Var', (71, 78))	('IDH1', 'Gene', '3417', (118, 122))	('rat', 'Species', '10116', (157, 160))	('rat', 'Species', '10116', (25, 28))	('ml-1', 'Gene', '51761', (178, 182))	('ml-1', 'Gene', (178, 182))	('IDH1', 'Gene', (79, 83))	('detect', 'Reg', (64, 70))	('mutant', 'Var', (123, 129))
118181	27877908	Some challenges remain before this diagnostic tool can be applied clinically, but our immuno-wall assay may lead to rapid and highly sensitive detection of the IDH1-R132H mutation preoperatively and intra-operatively.	('R132H', 'SUBSTITUTION', 'None', (165, 170))	('rat', 'Species', '10116', (208, 211))	('IDH1', 'Gene', (160, 164))	('rat', 'Species', '10116', (186, 189))	('clinical', 'Species', '191496', (66, 74))	('IDH1', 'Gene', '3417', (160, 164))	('R132H', 'Var', (165, 170))
118221	33976246	As previously described, higher levels of preoperative  T2T1 MRI index represent the prevalence of the diffusive growing mechanism with the tendency to infiltrate the functional cortical areas and subcortical pathways, thus limiting the achievable resection.	('as', 'Gene', '112935892', (190, 192))	('As', 'Gene', '112935892', (0, 2))	('T2T1 MRI', 'Var', (56, 64))	('higher', 'PosReg', (25, 31))	('infiltrate', 'PosReg', (152, 162))	('limiting', 'NegReg', (224, 232))	('resection', 'CPA', (248, 257))
118244	33976246	Specifically, results of multivariate analysis showed that OS is independently associated with preoperative tumor growing pattern expressed by DeltaT2T1 (p = 0.004), molecular class (p = 0.028), EOR (p = 0.018) (Table 4, Fig.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('as', 'Gene', '112935892', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('DeltaT2T1', 'Var', (143, 152))	('tumor', 'Disease', (108, 113))	('as', 'Gene', '112935892', (178, 180))
118246	33976246	Figure 2 shows the OS Kaplan-Meier curves stratified according to preoperative tumor volume, DeltaT2T1, EOR, volume of residual tumor, molecular class and intraoperative protocol.	('as', 'Gene', '112935892', (147, 149))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (79, 84))	('DeltaT2T1', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
118280	33976246	Phenotypic and genotypic parameters in the diagnosis of DLGGs (mutations in the IDH1 and IDH2 genes mutations and 1p/19q co-deletion) have become of crucial importance.	('mutations', 'Var', (63, 72))	('mutations', 'Var', (100, 109))	('IDH2', 'Gene', '3418', (89, 93))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('IDH2', 'Gene', (89, 93))	('1p/19q co-deletion', 'Var', (114, 132))	('DLGGs', 'Disease', (56, 61))
118283	33976246	The median EOR was larger in Oligodendroglioma than in Diffuse Astrocytoma IDH1/2 wild-type (92% vs. 83%; p = 0.002) and tended to also be larger in Diffuse Astrocytoma IDH1/2 mutated than in Diffuse Astrocytoma IDH1/2 wild-type (87% vs. 83%; p = 0.05).	('Astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('As', 'Gene', '112935892', (200, 202))	('IDH1/2', 'Gene', '3417;3418', (212, 218))	('Astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('IDH1/2', 'Gene', (212, 218))	('IDH1/2', 'Gene', '3417;3418', (75, 81))	('EOR', 'MPA', (11, 14))	('larger', 'PosReg', (139, 145))	('IDH1/2', 'Gene', (75, 81))	('as', 'Gene', '112935892', (16, 18))	('Astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('IDH1/2', 'Gene', '3417;3418', (169, 175))	('As', 'Gene', '112935892', (63, 65))	('Oligodendroglioma', 'Disease', 'MESH:D009837', (29, 46))	('IDH1/2', 'Gene', (169, 175))	('mutated', 'Var', (176, 183))	('larger', 'PosReg', (19, 25))	('Oligodendroglioma', 'Disease', (29, 46))	('As', 'Gene', '112935892', (157, 159))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
118286	33976246	Interestingly, 3 and 5 years estimated OS in patients with an EOR of 100% was higher in patients belonging to molecular class of Diffuse Astrocytoma IDH1/2 mutated and Oligodendroglioma.	('Astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('Oligodendroglioma', 'Disease', (168, 185))	('higher', 'PosReg', (78, 84))	('patients', 'Species', '9606', (88, 96))	('as', 'Gene', '112935892', (75, 77))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('IDH1/2', 'Gene', '3417;3418', (149, 155))	('mutated', 'Var', (156, 163))	('Oligodendroglioma', 'Disease', 'MESH:D009837', (168, 185))	('as', 'Gene', '112935892', (122, 124))	('patients', 'Species', '9606', (45, 53))	('As', 'Gene', '112935892', (137, 139))	('IDH1/2', 'Gene', (149, 155))
118287	33976246	Otherwise, considering the 10 years estimated OS, the percentage was similar amongst Diffuse Astrocytoma IDH1/2 mutated and Oligodendroglioma, and greater for Diffuse Astrocytoma IDH1/2 wild-type.	('as', 'Gene', '112935892', (66, 68))	('IDH1/2', 'Gene', '3417;3418', (179, 185))	('Oligodendroglioma', 'Disease', (124, 141))	('Astrocytoma', 'Phenotype', 'HP:0009592', (167, 178))	('IDH1/2', 'Gene', (105, 111))	('As', 'Gene', '112935892', (93, 95))	('As', 'Gene', '112935892', (167, 169))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('Oligodendroglioma', 'Disease', 'MESH:D009837', (124, 141))	('mutated', 'Var', (112, 119))	('Astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('IDH1/2', 'Gene', (179, 185))	('IDH1/2', 'Gene', '3417;3418', (105, 111))
118294	33976246	Although intraoperative mapping of brain areas was shown to promote greater extent of resection and reduce functional deficits, this was shown only recently for some non-invasive techniques.	('promote', 'PosReg', (60, 67))	('as', 'Gene', '112935892', (48, 50))	('resection', 'Var', (86, 95))	('functional', 'MPA', (107, 117))	('as', 'Gene', '112935892', (173, 175))	('as', 'Gene', '112935892', (44, 46))	('as', 'Gene', '112935892', (134, 136))	('reduce', 'NegReg', (100, 106))
118305	32547876	Moreover, hyper-methylation of four methylation sites indicated better OS (P < 0.05), and three of them also shown statistical significantly association with better RFS, except for SERPINA5 cg15509705 (P = 0.0762).	('better', 'PosReg', (64, 70))	('RFS', 'MPA', (165, 168))	('SERPINA5', 'Gene', '5104', (181, 189))	('association', 'Interaction', (141, 152))	('cg15509705', 'Var', (190, 200))	('SERPINA5', 'Gene', (181, 189))	('hyper-methylation', 'Var', (10, 27))
118306	32547876	Taken together, these findings indicated that the gene expression and methylation of SERPINA5 and TIMP1 may serve as prognostic predictors in LGGs and may help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.	('tumors', 'Disease', (199, 205))	('LGGs', 'Disease', (142, 146))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('TIMP1', 'Gene', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('SERPINA5', 'Gene', '5104', (85, 93))	('methylation', 'Var', (70, 81))	('TIMP1', 'Gene', '7076', (98, 103))	('SERPINA5', 'Gene', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('help', 'Reg', (155, 159))
118315	32547876	analyzed transcriptome-wide data of primary tumor samples identified eight transcriptionally different groups (five isocitrate dehydrogenase (IDH)1/2 mutant, three IDH1/2 wild type).	('IDH', 'Gene', '3417', (164, 167))	('IDH', 'Gene', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('IDH', 'Gene', '3417', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('IDH1', 'Gene', (164, 168))	('mutant', 'Var', (150, 156))	('IDH', 'Gene', (164, 167))	('tumor', 'Disease', (44, 49))	('IDH1', 'Gene', '3417', (164, 168))
118316	32547876	Recently, studies have revealed that IDH mutations disrupt histone demethylation and suggest a better survival rate.	('histone demethylation', 'MPA', (59, 80))	('mutations', 'Var', (41, 50))	('survival rate', 'CPA', (102, 115))	('disrupt', 'NegReg', (51, 58))	('IDH', 'Gene', (37, 40))	('better', 'PosReg', (95, 101))	('IDH', 'Gene', '3417', (37, 40))
118317	32547876	In particular, IDH mutation and 1p/19q deletion are used as biomarkers to classify gliomas in the 2016 WHO classification of central nervous system tumors.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('central nervous system tumors', 'Disease', (125, 154))	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('nervous system tumors', 'Phenotype', 'HP:0004375', (133, 154))	('IDH', 'Gene', (15, 18))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (125, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('IDH', 'Gene', '3417', (15, 18))	('central nervous system tumors', 'Disease', 'MESH:D016543', (125, 154))
118322	32547876	These evidences suggested that alteration of DNA methylation can be exploited for functional characterizations and diagnosis of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('alteration', 'Var', (31, 41))
118324	32547876	We found that the gene expression and methylation of SERPINA5 and TIMP1 can function as prognostic predictors in LGGs, which might help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.	('tumors', 'Disease', (175, 181))	('SERPINA5', 'Gene', '5104', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('TIMP1', 'Gene', '7076', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('methylation', 'Var', (38, 49))	('SERPINA5', 'Gene', (53, 61))	('LGGs', 'Disease', (113, 117))	('TIMP1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
118337	32547876	Of the 37 methylation sites, 4 differential methylation sites (SERPINA5 cg15509705; TIMP1 cg27151711; TIMP1 cg16523424; TIMP1 cg04791822) were identified (Table S2).	('cg27151711', 'Var', (90, 100))	('TIMP1', 'Gene', (84, 89))	('TIMP1', 'Gene', (102, 107))	('SERPINA5', 'Gene', '5104', (63, 71))	('cg15509705', 'Var', (72, 82))	('TIMP1', 'Gene', (120, 125))	('TIMP1', 'Gene', '7076', (84, 89))	('cg27151711', 'Chemical', '-', (90, 100))	('TIMP1', 'Gene', '7076', (120, 125))	('TIMP1', 'Gene', '7076', (102, 107))	('SERPINA5', 'Gene', (63, 71))	('cg16523424', 'Var', (108, 118))
118348	32547876	TIMP1 high expression group exhibited poor survival as compared to low expression group (HR = 8.656, 95% CI [2.578-29.060], P = 0.014).	('TIMP1', 'Gene', (0, 5))	('high expression', 'Var', (6, 21))	('poor', 'NegReg', (38, 42))	('TIMP1', 'Gene', '7076', (0, 5))	('survival', 'CPA', (43, 51))
118350	32547876	6A-6D, hyper-methylation of 4 methylation sites indicated better OS (SERPINA5 cg15509705: HR = 1.66, 95% CI [1.101-2.501], P < 0.0001; TIMP1 cg27151711: HR = 5.375, 95% CI [2.435-11.87], P < 0.0001; TIMP1 cg16523424: HR = 3.978, 95% CI [2.245-7.049], P <0.0001; TIMP1 cg04791822: HR = 7.284, 95% CI [2.458-21.59], P <0.0001).	('TIMP1', 'Gene', '7076', (262, 267))	('cg15509705', 'Var', (78, 88))	('TIMP1', 'Gene', '7076', (135, 140))	('SERPINA5', 'Gene', '5104', (69, 77))	('cg27151711', 'Chemical', '-', (141, 151))	('TIMP1', 'Gene', (199, 204))	('TIMP1', 'Gene', (262, 267))	('TIMP1', 'Gene', '7076', (199, 204))	('TIMP1', 'Gene', (135, 140))	('SERPINA5', 'Gene', (69, 77))
118351	32547876	In addition, except for SERPINA5 cg15509705 (HR = 1.411, 95% CI [0.967-2.058], P = 0.0762, Fig.	('cg15509705', 'Var', (33, 43))	('SERPINA5', 'Gene', '5104', (24, 32))	('SERPINA5', 'Gene', (24, 32))
118361	32547876	Previous studies indicated that the dysregulation of SERPINA5 has been implicated in migration, invasion and metastasis in hepatocellular carcinoma, ovarian and prostate cancers.	('dysregulation', 'Var', (36, 49))	('SERPINA5', 'Gene', '5104', (53, 61))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('hepatocellular carcinoma, ovarian and prostate cancers', 'Disease', 'MESH:D011471', (123, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('implicated', 'Reg', (71, 81))	('SERPINA5', 'Gene', (53, 61))	('prostate cancers', 'Phenotype', 'HP:0012125', (161, 177))	('invasion', 'CPA', (96, 104))	('metastasis', 'CPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('migration', 'CPA', (85, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))
118364	32547876	More recently, researchers have found that the high methylation degree of CpG sites significantly correlated with lower SERPINA5 expression levels and two distinct CpG sites of the SERPINA5 promoter were hypermethylated in normal epithelial prostate cells, benign hyperplasic cells and low-invasive malignant LNCaP cells, whereas essentially unmethylated in aggressive DU-145 and PC-3 cell line.	('SERPINA5', 'Gene', '5104', (181, 189))	('SERPINA5', 'Gene', '5104', (120, 128))	('high methylation', 'Var', (47, 63))	('SERPINA5', 'Gene', (120, 128))	('lower', 'NegReg', (114, 119))	('LNCaP', 'CellLine', 'CVCL:0395', (309, 314))	('DU-145', 'CellLine', 'CVCL:0105', (369, 375))	('PC-3', 'CellLine', 'CVCL:0035', (380, 384))	('SERPINA5', 'Gene', (181, 189))	('hypermethylated', 'Var', (204, 219))
118365	32547876	In addition, SERPINA5 has been identified to be more highly methylated in HR-, basal-like, or p53 mutant breast cancer than HR+, luminal A, or p53 wild-type breast cancers, and gene signature composed of SERPINA5 and 3 other genes can predict the prognosis of patients with stage I LUAD.	('breast cancers', 'Disease', 'MESH:D001943', (157, 171))	('breast cancers', 'Disease', (157, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('predict', 'Reg', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('p53', 'Gene', '7157', (143, 146))	('mutant', 'Var', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('stage I LUAD', 'Disease', (274, 286))	('p53', 'Gene', '7157', (94, 97))	('SERPINA5', 'Gene', '5104', (13, 21))	('patients', 'Species', '9606', (260, 268))	('p53', 'Gene', (143, 146))	('SERPINA5', 'Gene', '5104', (204, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('p53', 'Gene', (94, 97))	('methylated', 'MPA', (60, 70))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('SERPINA5', 'Gene', (13, 21))	('more highly', 'PosReg', (48, 59))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('SERPINA5', 'Gene', (204, 212))
118366	32547876	These evidences suggested that methylation of SERPINA5 may be used to indicate the malignancy of some tumors and to predict the prognosis of patients.	('indicate', 'Reg', (70, 78))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('SERPINA5', 'Gene', (46, 54))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('methylation', 'Var', (31, 42))	('malignancy', 'Disease', (83, 93))	('SERPINA5', 'Gene', '5104', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('patients', 'Species', '9606', (141, 149))
118367	32547876	In this study, our results also shown that hyper-methylation of SERPINA5 was statistical significantly association with lower expression and better prognosis in LGGs.	('SERPINA5', 'Gene', '5104', (64, 72))	('lower', 'NegReg', (120, 125))	('expression', 'MPA', (126, 136))	('SERPINA5', 'Gene', (64, 72))	('better', 'PosReg', (141, 147))	('hyper-methylation', 'Var', (43, 60))	('LGGs', 'Disease', (161, 165))
118373	32547876	The overall relationship of high TIMP1 expression with poor cancer outcome has been demonstrated in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('TIMP1', 'Gene', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('TIMP1', 'Gene', '7076', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('cancer', 'Disease', (60, 66))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gliomas', 'Disease', (100, 107))
118374	32547876	Consistent with previous studies, our results shown that TIMP1 high expression was also independent poor predictor for OS.	('high expression', 'Var', (63, 78))	('TIMP1', 'Gene', (57, 62))	('TIMP1', 'Gene', '7076', (57, 62))
118375	32547876	Additionally, we also found that methylation of TIMP1 were highly negatively correlated with its gene expression and hyper-methylation of TIMP1 indicated better OS and RFS.	('TIMP1', 'Gene', '7076', (48, 53))	('negatively', 'NegReg', (66, 76))	('TIMP1', 'Gene', '7076', (138, 143))	('better', 'PosReg', (154, 160))	('methylation', 'MPA', (33, 44))	('TIMP1', 'Gene', (48, 53))	('TIMP1', 'Gene', (138, 143))	('RFS', 'CPA', (168, 171))	('gene expression', 'MPA', (97, 112))	('hyper-methylation', 'Var', (117, 134))
118380	32547876	Previous evidences indicated that dysregulation of F-box protein-mediated ubiquitylation has been implicated in cancer and other diseases.	('cancer', 'Disease', (112, 118))	('dysregulation', 'Var', (34, 47))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('implicated', 'Reg', (98, 108))	('F-box protein-mediated', 'Protein', (51, 73))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
118382	32547876	Moreover, our results shown that hyper-methylation of FBXO17 was statistical significantly association with lower expression and better prognosis in LGGs (Fig.	('better', 'PosReg', (129, 135))	('FBXO17', 'Gene', (54, 60))	('hyper-methylation', 'Var', (33, 50))	('LGGs', 'Disease', (149, 153))	('lower', 'NegReg', (108, 113))	('expression', 'MPA', (114, 124))	('FBXO17', 'Gene', '115290', (54, 60))
118385	32547876	IDH1/2 mutations are clearly important prognostic markers in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('mutations', 'Var', (7, 16))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
118386	32547876	In LGGs, patients with IDH1/2 mutation have better prognosis than patients with IDH wild-type.	('LGGs', 'Disease', (3, 7))	('patients', 'Species', '9606', (9, 17))	('mutation', 'Var', (30, 38))	('IDH1', 'Gene', (23, 27))	('IDH', 'Gene', (80, 83))	('IDH1', 'Gene', '3417', (23, 27))	('IDH', 'Gene', '3417', (80, 83))	('IDH', 'Gene', (23, 26))	('patients', 'Species', '9606', (66, 74))	('IDH', 'Gene', '3417', (23, 26))
118387	32547876	In anaplastic oligodendroglial tumors, IDH1 mutation are prognostic for overall survival but not predictive for outcome to PCV chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutation', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('IDH1', 'Gene', (39, 43))	('prognostic', 'Reg', (57, 67))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (3, 37))	('anaplastic oligodendroglial tumors', 'Disease', (3, 37))	('IDH1', 'Gene', '3417', (39, 43))
118390	32547876	In this study, we identified SERPINA5 and TIMP1 as prognostic predict markers in LGGs, and the methylation of these genes is correlated with the survival of LGG patients.	('TIMP1', 'Gene', '7076', (42, 47))	('methylation', 'Var', (95, 106))	('SERPINA5', 'Gene', (29, 37))	('correlated with', 'Reg', (125, 140))	('patients', 'Species', '9606', (161, 169))	('TIMP1', 'Gene', (42, 47))	('SERPINA5', 'Gene', '5104', (29, 37))	('LGGs', 'Disease', (81, 85))	('LGG', 'Disease', (157, 160))
118392	32547876	In addition, the present study firstly revealed that SERPINA5 hypo-methylation was negatively correlated with its expression, and both hypo-methylation and high expression of SERPINA5 predict poor survival in LGGs.	('SERPINA5', 'Gene', '5104', (53, 61))	('SERPINA5', 'Gene', '5104', (175, 183))	('negatively', 'NegReg', (83, 93))	('hypo-methylation', 'Var', (62, 78))	('SERPINA5', 'Gene', (53, 61))	('poor survival', 'CPA', (192, 205))	('hypo-methylation', 'Var', (135, 151))	('expression', 'MPA', (114, 124))	('SERPINA5', 'Gene', (175, 183))	('LGGs', 'Disease', (209, 213))
118441	30541578	With more data from children treated with PBT, the proton beam model policy adopted by the American Society of Radiation Oncology in 2017 supports PBT in children with solid neoplasms, and it is now an option for many Children's Oncology Group (COG) protocols.	('Oncology', 'Phenotype', 'HP:0002664', (229, 237))	('solid neoplasms', 'Disease', (168, 183))	('solid neoplasms', 'Disease', 'MESH:D018250', (168, 183))	('neoplasms', 'Phenotype', 'HP:0002664', (174, 183))	('COG', 'Chemical', '-', (245, 248))	('Children', 'Species', '9606', (218, 226))	('Oncology', 'Phenotype', 'HP:0002664', (121, 129))	('PBT', 'Var', (147, 150))	('children', 'Species', '9606', (20, 28))	('children', 'Species', '9606', (154, 162))
118446	30541578	There were no late toxicities of the heart, lungs, and digestive tract side effects, and no second primary tumor occurred, which was significantly better than that of photon therapy; the notable finding was that the intelligence quotient (IQ) of patients using PBT decreased slower than that using photon therapy.	('PBT', 'Var', (261, 264))	('intelligence quotient', 'Phenotype', 'HP:0001249', (216, 237))	('toxicities', 'Disease', 'MESH:D064420', (19, 29))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('patients', 'Species', '9606', (246, 254))	('decreased', 'NegReg', (265, 274))	('intelligence quotient', 'MPA', (216, 237))	('toxicities', 'Disease', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('IQ', 'Phenotype', 'HP:0001249', (239, 241))
118460	30541578	first showed the improved long-term health-related quality of life (HRQoL) outcomes of children with brain tumors treated with PBT compared to photon RT.	('improved', 'PosReg', (17, 25))	('children', 'Species', '9606', (87, 95))	('brain tumors', 'Phenotype', 'HP:0030692', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('brain tumors', 'Disease', (101, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('PBT', 'Var', (127, 130))	('brain tumors', 'Disease', 'MESH:D001932', (101, 113))
118466	30541578	At a median follow-up of 13.1 years in the photon therapy group and 6.9 years in the PBT group, the cumulative incidence of second malignancies (radiation-induced or in-field) at 10 years was significantly higher in photon therapy group than that in PBT group (14% vs. 0%; P = 0.015).	('malignancies', 'Disease', (131, 143))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))	('photon therapy', 'Var', (216, 230))	('higher', 'PosReg', (206, 212))
118487	30541578	However, PBT can increase the tumor dose and can better protect normal tissues.	('PBT', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('increase', 'PosReg', (17, 25))	('tumor', 'Disease', (30, 35))
118489	30541578	The patients with low-grade chondrosarcoma usually have a better long-term survival than those with chordoma in PBT and can even achieve a curable effect.	('chordoma', 'Disease', 'MESH:D002817', (100, 108))	('chondrosarcoma', 'Disease', (28, 42))	('low-grade', 'Var', (18, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('chordoma', 'Phenotype', 'HP:0010762', (100, 108))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (28, 42))	('chordoma', 'Disease', (100, 108))	('patients', 'Species', '9606', (4, 12))	('chondrosarcoma', 'Disease', 'MESH:D002813', (28, 42))
118496	30541578	The estimated 10-year OS rates of the PBT group reached 60%, which was significantly higher than that of conventional photon therapy (21%) and SRT (40%).	('higher', 'PosReg', (85, 91))	('OS', 'Chemical', '-', (22, 24))	('PBT', 'Var', (38, 41))
118523	30541578	In a retrospective case-control study, IMPT-treated NPC patients (n = 10) had significantly lower rates of gastrostomy tube insertion compared to IMRT-treated patients (n = 20) (20% vs. 65%, P = 0.02).	('IMPT-treated', 'Var', (39, 51))	('patients', 'Species', '9606', (56, 64))	('NPC', 'Phenotype', 'HP:0100630', (52, 55))	('NPC', 'Disease', 'MESH:D052556', (52, 55))	('NPC', 'Disease', (52, 55))	('IMRT', 'Chemical', '-', (146, 150))	('IMPT', 'Chemical', '-', (39, 43))	('gastrostomy', 'Disease', (107, 118))	('patients', 'Species', '9606', (159, 167))	('lower', 'NegReg', (92, 97))
118542	30541578	In a retrospective study that enrolled 336 patients with large choroidal melanomas, the rates of visual acuity retention at 10 years were 8.7% for >= 20/200 and 22.4% for at least counting fingers; neovascular glaucoma was found in 25.3% patients.	('choroidal melanomas', 'Disease', (63, 82))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('neovascular glaucoma', 'Disease', 'MESH:D015355', (198, 218))	('patients', 'Species', '9606', (43, 51))	('choroidal melanomas', 'Disease', 'MESH:D008545', (63, 82))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (63, 81))	('>= 20/200', 'Var', (147, 156))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (63, 82))	('glaucoma', 'Phenotype', 'HP:0000501', (210, 218))	('neovascular glaucoma', 'Disease', (198, 218))	('patients', 'Species', '9606', (238, 246))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
118620	30541578	Recently, one notable study at MD Anderson was reported that grade 4 lymphopenia during chemo-radiotherapy for EC was associated with poor overall and disease-specific survival outcomes, and OS in this group was significantly worse than the grade 0-2 group, with a median OS 2.8 vs. 5.0 years (P = 0.027).	('OS', 'Chemical', '-', (272, 274))	('lymphopenia', 'Phenotype', 'HP:0001888', (69, 80))	('lymphopenia', 'Disease', 'MESH:D008231', (69, 80))	('OS', 'Chemical', '-', (191, 193))	('grade 4', 'Var', (61, 68))	('poor', 'NegReg', (134, 138))	('lymphopenia', 'Disease', (69, 80))
118621	30541578	The important finding in the study was that PBT could reduce the low dose area, and then resulted in less lymphopenia risk.	('less', 'NegReg', (101, 105))	('lymphopenia', 'Disease', 'MESH:D008231', (106, 117))	('reduce', 'NegReg', (54, 60))	('PBT', 'Var', (44, 47))	('lymphopenia', 'Disease', (106, 117))	('low dose area', 'MPA', (65, 78))	('lymphopenia', 'Phenotype', 'HP:0001888', (106, 117))
118652	30541578	evaluated long-term outcomes with a focus on sexual health for young patients treated with PSPT in a dose of 76-82 Gy (2 Gy/F) or 70-72.5 Gy (2.5 Gy/F).	('patients', 'Species', '9606', (69, 77))	('70-72.5 Gy', 'Var', (130, 140))	('PSPT', 'Gene', (91, 95))
118702	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))
118703	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
118705	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('expression', 'MPA', (165, 175))	('cancer', 'Disease', (47, 53))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
118707	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
118709	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
118710	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
118711	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
118712	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('associated', 'Reg', (113, 123))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('short', 'NegReg', (129, 134))
118714	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('expression', 'MPA', (48, 58))	('associated', 'Reg', (27, 37))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
118716	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('rat', 'Species', '10116', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (129, 141))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('affects', 'Reg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('mutations', 'Var', (6, 15))
118718	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('177-338aa', 'Var', (174, 183))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
118720	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('cancer', 'Disease', (397, 403))	('activation', 'PosReg', (146, 156))	('proliferation', 'CPA', (292, 305))	('promote', 'PosReg', (284, 291))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('EGFR', 'Gene', (96, 100))	('dimerization', 'Var', (33, 45))	('survival', 'CPA', (319, 327))	('metastasis', 'CPA', (441, 451))	('growth', 'CPA', (307, 313))	('activates', 'PosReg', (218, 227))	('contribute', 'Reg', (353, 363))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('autophosphorylation', 'MPA', (161, 180))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('rat', 'Species', '10116', (299, 302))
118722	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
118724	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
118727	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('lung adenocarcinoma', 'Disease', (105, 124))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
118729	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
118732	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
118736	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))	('indels', 'Var', (33, 39))
118746	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('alterations', 'Var', (30, 41))	('EGFR', 'Gene', (25, 29))	('rat', 'Species', '10116', (34, 37))
118747	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
118748	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
118749	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
118751	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
118753	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
118754	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('located', 'Reg', (71, 78))	('Furin', 'Gene', (86, 91))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
118755	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
118756	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
118757	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
118758	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
118759	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
118760	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Var', (159, 164))	('G598A', 'Var', (100, 105))	('G598V', 'Var', (82, 87))
118761	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
118763	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('L858R', 'Var', (170, 175))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
118767	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
118769	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ESCA', 'Disease', (92, 96))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('BLCA', 'Disease', (161, 165))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('rat', 'Species', '10116', (78, 81))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('HNSC', 'Disease', (106, 110))	('STAD', 'Disease', (119, 123))
118771	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('EGFR amplification', 'MPA', (93, 111))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
118772	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (141, 144))	('alterations', 'Var', (55, 66))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (155, 158))	('patient', 'Species', '9606', (80, 87))
118773	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('DFS', 'CPA', (114, 117))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median', 'MPA', (100, 106))
118774	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('shortened', 'NegReg', (115, 124))	('patients', 'Species', '9606', (125, 133))
118775	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
118776	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('LUAD', 'Disease', (34, 38))	('short survival', 'MPA', (79, 93))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
118778	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutation', 'Var', (287, 295))	('cancers', 'Disease', (128, 135))	('increased', 'PosReg', (337, 346))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('EGFR', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (33, 39))	('EGFR expression', 'MPA', (347, 362))	('tumors', 'Disease', (232, 238))
118798	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))
118799	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
118802	32067422	For both cancer types, the CpGs with significant associations were mostly located in the gene body, where higher CpG methylation was associated with a better outcome.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('higher', 'PosReg', (106, 112))	('methylation', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CpG', 'MPA', (113, 116))
118804	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))
118807	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('EGFR', 'Gene', (30, 34))	('alterations', 'Var', (35, 46))	('alteration', 'Var', (122, 132))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
118809	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
118810	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
118811	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
118812	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('prolonged', 'PosReg', (150, 159))	('NSCLC', 'Disease', (87, 92))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
118814	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('EGFR', 'Gene', (19, 23))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
118815	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
118817	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (160, 165))
118818	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))
118819	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('amplification', 'Var', (5, 18))	('patient', 'Species', '9606', (74, 81))	('EGFR', 'Gene', (42, 46))	('short patient survival', 'CPA', (68, 90))
118820	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
118821	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))
118822	32067422	However, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('high', 'Var', (9, 13))
118824	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
118829	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('cancer', 'Disease', (152, 158))	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
118830	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
118831	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))
118859	31921517	The risk score = (0.4470 x expression level of WEE1) + (-0.1530 x expression level of CRTAC1) + (-0.3723 x expression level of SEMA4G).	('expression level', 'MPA', (66, 82))	('SEMA4G', 'Gene', (127, 133))	('CRTAC1', 'Gene', '55118', (86, 92))	('CRTAC1', 'Gene', (86, 92))	('WEE1', 'Gene', (47, 51))	('SEMA4G', 'Gene', '57715', (127, 133))	('WEE1', 'Gene', '7465', (47, 51))	('0.4470', 'Var', (18, 24))
118861	31921517	Kaplan-Meier curves were performed to estimate and compare the survival for TCGA LGGs patients with a high score or a low score.	('high score', 'Var', (102, 112))	('TCGA', 'Gene', (76, 80))	('patients', 'Species', '9606', (86, 94))
118863	31921517	Univariate and multivariate Cox hazard regression analysis were conducted for the potential prognostic factors such as age group (younger vs. old), gender (male vs. female), pathologic grade (G2 vs. G3), radiation therapy (Yes vs. No), molecular therapy (Yes vs. No) and risk score (High vs. Low).	('N', 'Chemical', 'MESH:D009584', (231, 232))	('N', 'Chemical', 'MESH:D009584', (263, 264))	('G2 vs.', 'Var', (192, 198))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))
118886	31921517	Multivariate Cox proportional hazard regression demonstrated that age group (HR = 0.274, p = 2.21E-09), pathologic grade (HR = 2.49, p = 0.00011) and risk score (HR = 0.198, p < 0.000000000168) were independent prognostic factors in the training set, while pathologic grade (HR = 3.799, p = 0.00000151), 1p19q status (HR = 4.566, p = 0.0000388), radiation therapy (HR = 0.524, p = 0.046), and risk score (HR = 0.415, p = 0.000653) were independent prognostic factors in validation dataset (Table 2).	('1p19q status', 'Var', (304, 316))	('Cox', 'Gene', '1351', (13, 16))	('Cox', 'Gene', (13, 16))
118897	31921517	Prognostic factors for the low-grade glioma that are well known include IDH mutations, 1p/19q co-deficiency, ATRX mutation, TERT promoter mutations, CIC loss, FUBP1 loss and PTEN loss and the above prognostic marker contribute to clinicians to understand the mechanism of low-grade gliomas.	('glioma', 'Disease', 'MESH:D005910', (282, 288))	('ATRX', 'Gene', '546', (109, 113))	('PTEN', 'Gene', (174, 178))	('TERT', 'Gene', (124, 128))	('mutation', 'Var', (114, 122))	('loss', 'NegReg', (179, 183))	('TERT', 'Gene', '7015', (124, 128))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('PTEN', 'Gene', '5728', (174, 178))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('IDH', 'Gene', (72, 75))	('loss', 'NegReg', (165, 169))	('FUBP1', 'Gene', (159, 164))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('1p/19q co-deficiency', 'Gene', (87, 107))	('CIC loss', 'Disease', (149, 157))	('IDH', 'Gene', '3417', (72, 75))	('CIC loss', 'Disease', 'MESH:D016388', (149, 157))	('mutations', 'Var', (76, 85))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('glioma', 'Disease', (37, 43))	('FUBP1', 'Gene', '8880', (159, 164))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('ATRX', 'Gene', (109, 113))	('glioma', 'Disease', (282, 288))
118903	31921517	For the BP category, chromosome segregation was the most enrichment and research has proven that chromosome instability contributes to the development of genetic heterogeneity in tumors and allows the outgrowth of tumorigenic cells with advantageous karyotypes.	('outgrowth', 'CPA', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('chromosome', 'Var', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('genetic heterogeneity', 'MPA', (154, 175))	('tumor', 'Disease', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('chromosome instability', 'Phenotype', 'HP:0040012', (97, 119))	('tumor', 'Disease', (179, 184))
118909	31921517	Moreover, patients with high WEE1 expression had poor survival than did patients with low WEE1 expression in grade III gliomas.	('WEE1', 'Gene', (90, 94))	('WEE1', 'Gene', '7465', (90, 94))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('WEE1', 'Gene', (29, 33))	('WEE1', 'Gene', '7465', (29, 33))	('expression', 'Var', (34, 44))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('high', 'Var', (24, 28))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('poor', 'NegReg', (49, 53))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (72, 80))
118911	31921517	Previous study found that inhibition of CRTAC1 reduces ultraviolet B irradiation induced-apoptosis through P38 mitogen-activated protein kinase and jun Amino-Terminal kinase pathway.	('Amino', 'Chemical', 'MESH:D000596', (152, 157))	('reduces', 'NegReg', (47, 54))	('P38 mitogen-activated protein kinase', 'Gene', '1432', (107, 143))	('inhibition', 'Var', (26, 36))	('jun Amino-Terminal kinase pathway', 'Pathway', (148, 181))	('CRTAC1', 'Gene', (40, 46))	('P38 mitogen-activated protein kinase', 'Gene', (107, 143))	('CRTAC1', 'Gene', '55118', (40, 46))
118913	31921517	To some extent, this is consistent with our finding that CRTAC1 high expression prolongs survival time in LGG patients.	('LGG', 'Disease', (106, 109))	('high expression', 'Var', (64, 79))	('prolongs', 'PosReg', (80, 88))	('survival time', 'CPA', (89, 102))	('CRTAC1', 'Gene', (57, 63))	('CRTAC1', 'Gene', '55118', (57, 63))	('patients', 'Species', '9606', (110, 118))
118918	31921517	Our study demonstrated that SEMA4G was significantly down-regulated in grade III patients compared to grade II and the high-expression of SEMA4G was associated with a good prognosis in LGG patients.	('SEMA4G', 'Gene', (28, 34))	('LGG', 'Disease', (185, 188))	('patients', 'Species', '9606', (81, 89))	('SEMA4G', 'Gene', (138, 144))	('high-expression', 'Var', (119, 134))	('associated', 'Reg', (149, 159))	('SEMA4G', 'Gene', '57715', (28, 34))	('patients', 'Species', '9606', (189, 197))	('SEMA4G', 'Gene', '57715', (138, 144))	('down-regulated', 'NegReg', (53, 67))
118928	31797609	Mutations in normal cells are usually repaired or result in apoptosis, whereas in cancer cells mutations accumulate, leading to uncontrolled growth and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('result in', 'Reg', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Mutations', 'Var', (0, 9))	('uncontrolled growth', 'MPA', (128, 147))	('leading to', 'Reg', (117, 127))
118929	31797609	Tumors contain around 2-5 driver mutations that cause and accelerate cancer, and about 10-200 passenger mutations which are byproducts of thwarted DNA repair mechanisms.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('accelerate', 'PosReg', (58, 68))	('mutations', 'Var', (33, 42))	('cause', 'Reg', (48, 53))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
118930	31797609	Driver mutations define some characteristics of the tumor and may offer therapeutic targets, yet identifying them amid the myriad of passengers remains a challenge.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (7, 16))
118931	31797609	The Cancer Genome Atlas (TCGA) is a publicly accessible dataset of cancer samples cataloguing mutations, mRNA, miRNA, DNA methylation, copy number variation, and protein expression for roughly 11,000 patients across 33 cancer types.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (94, 103))	('miRNA', 'MPA', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (219, 225))
118933	31797609	One subtype harbored mutations in BRAF and the other subtype in RAS genes such as KRAS, NRAS, or HRAS.	('HRAS', 'Gene', '3265', (97, 101))	('NRAS', 'Gene', (88, 92))	('HRAS', 'Gene', (97, 101))	('BRAF', 'Gene', '673', (34, 38))	('NRAS', 'Gene', '4893', (88, 92))	('KRAS', 'Gene', (82, 86))	('BRAF', 'Gene', (34, 38))	('KRAS', 'Gene', '3845', (82, 86))	('mutations', 'Var', (21, 30))
118939	31797609	These data included batch-corrected and normalized gene expression data, as well as single nucleotide variant (SNV) calls determined from the TCGA's MC3 consensus analysis, and gene-associated copy number data from GISTIC2.	('single nucleotide variant', 'Var', (84, 109))	('MC3', 'Gene', (149, 152))	('MC3', 'Gene', '4159', (149, 152))
118940	31797609	Isocitrate Dehydrogenase 1 (IDH1) is one of three IDH enzymes, which when mutated causes hypermethylation and subsequent altered gene expression in gliomas.	('IDH', 'Gene', (28, 31))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('IDH1', 'Gene', '3417', (28, 32))	('causes', 'Reg', (82, 88))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('IDH', 'Gene', '3417', (28, 31))	('altered', 'Reg', (121, 128))	('Isocitrate Dehydrogenase 1', 'Gene', (0, 26))	('IDH', 'Gene', '3417', (50, 53))	('hypermethylation', 'MPA', (89, 105))	('mutated', 'Var', (74, 81))	('IDH', 'Gene', (50, 53))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (0, 26))	('IDH1', 'Gene', (28, 32))
118941	31797609	In order to test LURE's ability to discover known "catch" events, we created a test set of bait and catch events using IDH1 missense mutations in the TCGA Lower Grade Glioma (LGG) samples.	('Glioma', 'Phenotype', 'HP:0009733', (167, 173))	('Glioma', 'Disease', (167, 173))	('IDH1', 'Gene', (119, 123))	('IDH1', 'Gene', '3417', (119, 123))	('missense mutations', 'Var', (124, 142))	('Glioma', 'Disease', 'MESH:D005910', (167, 173))
118942	31797609	Of the 210 LGG samples with an IDH1 missense mutation, we created an initial bait with 150 samples and three sets of 20 samples as potential catch events.	('missense mutation', 'Var', (36, 53))	('IDH1', 'Gene', '3417', (31, 35))	('IDH1', 'Gene', (31, 35))
118943	31797609	LURE identified all three of the held-out events in the Catch Cover, as well as the IDH2 missense mutation event.	('IDH2', 'Gene', (84, 88))	('IDH2', 'Gene', '3418', (84, 88))	('missense mutation', 'Var', (89, 106))
118944	31797609	IDH2 is another IDH isozyme, and a mutation in IDH2 has the same oncogenic effect as an IDH1 mutation (Supp.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (47, 50))	('IDH2', 'Gene', (47, 51))	('IDH1', 'Gene', (88, 92))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', (88, 91))	('IDH2', 'Gene', (0, 4))	('IDH', 'Gene', '3417', (16, 19))	('mutation', 'Var', (35, 43))	('IDH2', 'Gene', '3418', (47, 51))	('IDH1', 'Gene', '3417', (88, 92))	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', (47, 50))	('IDH2', 'Gene', '3418', (0, 4))
118946	31797609	Missense mutations in SF3B1 lead to aberrant splicing and a unique gene expression signature.	('SF3B1', 'Gene', '23451', (22, 27))	('Missense mutations', 'Var', (0, 18))	('SF3B1', 'Gene', (22, 27))	('lead to', 'Reg', (28, 35))
118948	31797609	Of the 80 UVM samples, 18 samples have missense mutations in SF3B1.	('UVM', 'Phenotype', 'HP:0007716', (10, 13))	('SF3B1', 'Gene', (61, 66))	('missense mutations', 'Var', (39, 57))	('SF3B1', 'Gene', '23451', (61, 66))
118949	31797609	We created an initial bait using 8 of these SF3B1 mutant samples and left out the remaining two sets of 5 samples for discovery.	('SF3B1', 'Gene', (44, 49))	('mutant', 'Var', (50, 56))	('SF3B1', 'Gene', '23451', (44, 49))
118950	31797609	LURE re-discovered both withheld sets correctly, collecting all of the SF3B1 missense events in the Catch Cover (Supp.	('missense', 'Var', (77, 85))	('SF3B1', 'Gene', (71, 76))	('SF3B1', 'Gene', '23451', (71, 76))
118956	31797609	Among the high-confidence results with a final classifier PR AUC > 0.8, 14 of 59 bait-catch associations were between events involving the same gene, such as TP53 truncating, splice site, and missense mutations, in various tumor types (Fig.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('splice site', 'Var', (175, 186))	('missense mutations', 'Var', (192, 210))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('truncating', 'Var', (163, 173))
118958	31797609	In addition, we identified gene fusion event partners in BRAF and RET that associated with a BRAF missense mutation in THCA.	('BRAF', 'Gene', (93, 97))	('THCA', 'Phenotype', 'HP:0002890', (119, 123))	('BRAF', 'Gene', '673', (57, 61))	('RET', 'Gene', '5979', (66, 69))	('THCA', 'Disease', (119, 123))	('BRAF', 'Gene', '673', (93, 97))	('BRAF', 'Gene', (57, 61))	('RET', 'Gene', (66, 69))	('associated', 'Reg', (75, 85))	('THCA', 'Disease', 'MESH:D013964', (119, 123))	('missense mutation', 'Var', (98, 115))
118960	31797609	In particular, four canonical pathway-oriented findings emerge: EGFR signaling, TP53/TP63/SMAD4, PI3K, and MAPK/RKT (Fig.	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('PI3K', 'Var', (97, 101))	('TP63', 'Gene', '8626', (85, 89))	('SMAD4', 'Gene', '4089', (90, 95))	('MAPK/RKT', 'Pathway', (107, 115))	('EGFR', 'Gene', '1956', (64, 68))	('TP63', 'Gene', (85, 89))	('EGFR', 'Gene', (64, 68))	('SMAD4', 'Gene', (90, 95))
118963	31797609	These LURE associations for PTEN reveal crosstalk between pathways and provide further evidence that alterations in PTEN influence EGFR signaling and beta-catenin signaling.	('crosstalk', 'Reg', (40, 49))	('PTEN', 'Gene', (28, 32))	('beta-catenin', 'Gene', '1499', (150, 162))	('PTEN', 'Gene', '5728', (28, 32))	('alterations', 'Var', (101, 112))	('PTEN', 'Gene', '5728', (116, 120))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('PTEN', 'Gene', (116, 120))	('influence', 'Reg', (121, 130))	('beta-catenin', 'Gene', (150, 162))
118965	31797609	For example, alpha-thalassemia mental retardation X-linked (ATRX), a gene recurrently mutated in LGG, only has an oncogenic effect with a loss-of-function mutation:either a truncating mutation or copy number loss:whereas a missense mutation may not have an oncogenic effect.	('oncogenic effect', 'CPA', (114, 130))	('LGG', 'Gene', (97, 100))	('ATRX', 'Gene', (60, 64))	('truncating mutation', 'Var', (173, 192))	('ATRX', 'Gene', '546', (60, 64))	('loss-of-function', 'NegReg', (138, 154))	('alpha-thalassemia mental retardation X-linked', 'Disease', 'MESH:C538258', (13, 58))	('copy number loss', 'Var', (196, 212))	('mental retardation', 'Phenotype', 'HP:0001249', (31, 49))	('alpha-thalassemia mental retardation X-linked', 'Disease', (13, 58))
118969	31797609	ALT-positive (ALT+) samples lengthen telomeres through homologous recombination, mediated by loss-of-function mutations in the ATRX and DAXX genes.	('lengthen telomeres', 'Phenotype', 'HP:0031413', (28, 46))	('mutations', 'Var', (110, 119))	('ATRX', 'Gene', (127, 131))	('DAXX', 'Gene', (136, 140))	('homologous recombination', 'CPA', (55, 79))	('ATRX', 'Gene', '546', (127, 131))	('lengthen', 'PosReg', (28, 36))	('loss-of-function', 'NegReg', (93, 109))	('DAXX', 'Gene', '1616', (136, 140))	('telomeres', 'CPA', (37, 46))
118970	31797609	Approximately 80% of tumors with ALT harbor mutations in ATRX or DAXX, leaving 20% with no known driver.	('DAXX', 'Gene', '1616', (65, 69))	('ATRX', 'Gene', '546', (57, 61))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('ALT', 'Disease', (33, 36))	('DAXX', 'Gene', (65, 69))	('mutations', 'Var', (44, 53))	('ATRX', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
118971	31797609	Using LURE, we sought to identify new driver mutations of the ALT pathway using gene expression signatures of samples harboring ATRX loss-of-function mutations.	('ATRX', 'Gene', '546', (128, 132))	('loss-of-function', 'NegReg', (133, 149))	('mutations', 'Var', (150, 159))	('ATRX', 'Gene', (128, 132))
118974	31797609	Since TP53 is commonly mutated in ALT+ samples and TP53 mutations are not known to be sufficient to cause ALT, we excluded TP53 events from the possible catches in order to identify novel ALT drivers.	('TP53', 'Gene', '7157', (6, 10))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (6, 10))	('TP53', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (123, 127))
118975	31797609	Using ATRX truncating mutations as bait, LURE identified four associated mutations in sarcomas (Fig.	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('ATRX', 'Gene', (6, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('sarcomas', 'Disease', (86, 94))	('ATRX', 'Gene', '546', (6, 10))	('mutations', 'Var', (73, 82))
118976	31797609	While we expect ATRX truncating mutations to associate with an ATRX copy number deletion, the deletions found in RB1 and SP100 are novel.	('SP100', 'Gene', (121, 126))	('ATRX', 'Gene', (63, 67))	('ATRX', 'Gene', '546', (16, 20))	('RB1', 'Gene', (113, 116))	('mutations', 'Var', (32, 41))	('ATRX', 'Gene', '546', (63, 67))	('RB1', 'Gene', '5925', (113, 116))	('ATRX', 'Gene', (16, 20))
118977	31797609	We suggest that the expression signature LURE identified in this analysis is classifying ALT+ TMM samples, and that the associated alterations are possibly driving the TMM.	('TMM', 'Chemical', 'MESH:C068303', (168, 171))	('TMM', 'Disease', (168, 171))	('alterations', 'Var', (131, 142))	('TMM', 'Chemical', 'MESH:C068303', (94, 97))	('ALT+ TMM', 'Disease', (89, 97))
118978	31797609	Previous work has associated RB1 alterations with long telomeres in the absence of TERT mutations and ATRX inactivation.	('long telomeres', 'MPA', (50, 64))	('ATRX', 'Gene', (102, 106))	('ATRX', 'Gene', '546', (102, 106))	('RB1', 'Gene', (29, 32))	('alterations', 'Var', (33, 44))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))	('RB1', 'Gene', '5925', (29, 32))
118979	31797609	In addition, mouse models have revealed that the knock-out of Rb-family proteins causes elongated telomeres.	('mouse', 'Species', '10090', (13, 18))	('knock-out', 'Var', (49, 58))	('elongated telomeres', 'CPA', (88, 107))	('Rb-family proteins', 'Protein', (62, 80))	('Rb', 'Chemical', 'MESH:D012413', (62, 64))
118980	31797609	We therefore suggest that an SP100 deletion may lead to unhindered ALT TMM activity.	('unhindered', 'MPA', (56, 66))	('SP100', 'Gene', (29, 34))	('deletion', 'Var', (35, 43))	('lead to', 'Reg', (48, 55))	('TMM', 'Chemical', 'MESH:C068303', (71, 74))
118981	31797609	In LGG, again using ATRX truncating mutations as bait, LURE found similar results identifying associations with other ATRX alterations such as ATRX deletions, splice site mutations, and missense mutations (Supp.	('ATRX', 'Gene', (143, 147))	('ATRX', 'Gene', '546', (118, 122))	('ATRX', 'Gene', (20, 24))	('associations', 'Interaction', (94, 106))	('ATRX', 'Gene', '546', (143, 147))	('deletions', 'Var', (148, 157))	('ATRX', 'Gene', '546', (20, 24))	('missense mutations', 'Var', (186, 204))	('splice site mutations', 'Var', (159, 180))	('ATRX', 'Gene', (118, 122))
118982	31797609	While ATRX missense mutations are not generally thought to be ALT drivers, we found that ATRX missense mutations were in fact associated with truncating mutations, suggesting a loss of function role for some of these missense mutations.	('associated', 'Reg', (126, 136))	('ATRX', 'Gene', (89, 93))	('ATRX', 'Gene', (6, 10))	('truncating mutations', 'MPA', (142, 162))	('ATRX', 'Gene', '546', (89, 93))	('ATRX', 'Gene', '546', (6, 10))	('missense mutations', 'Var', (94, 112))
118983	31797609	Oncogenic mutations of the HRAS, NRAS, or KRAS genes are frequently found in human tumors, altering the control of cellular proliferation, differentiation, and survival.	('survival', 'CPA', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('NRAS', 'Gene', (33, 37))	('HRAS', 'Gene', (27, 31))	('tumors', 'Disease', (83, 89))	('NRAS', 'Gene', '4893', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('control', 'MPA', (104, 111))	('HRAS', 'Gene', '3265', (27, 31))	('differentiation', 'CPA', (139, 154))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (10, 19))	('altering', 'Reg', (91, 99))	('human', 'Species', '9606', (77, 82))
118984	31797609	Oncogenic mutations in a number of other upstream or downstream components of the MAPK/RTK signaling pathway, including membrane receptor tyrosine kinases (RTKs) and cytosolic kinases, have been recently detected in a variety of cancer types.	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('detected', 'Reg', (204, 212))	('tyrosine', 'Chemical', 'None', (138, 146))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
118985	31797609	Oncogenic RAS mutations and other mutation events within the MAPK/RTK signaling pathway are often mutually exclusive, indicating that the deregulation of Ras-dependent signaling is essential for tumorigenesis.	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (195, 200))	('RAS', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
118986	31797609	Previous studies have shown that tumor samples harboring Ras protein mutations have a unique gene expression signature, and Ras-dependent samples can be more accurately defined by this signature than by mutation status alone.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('Ras', 'Gene', (57, 60))	('gene expression signature', 'MPA', (93, 118))
118988	31797609	One interesting association found by LURE in Head and Neck Squamous Cell Carcinomas (HNSC) is between HRAS missense mutations and focal deletions of the 2q23.3 locus (Fig.	('HRAS', 'Gene', (102, 106))	('Carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('Squamous Cell Carcinomas', 'Phenotype', 'HP:0002860', (59, 83))	('2q23.3', 'Gene', (153, 159))	('missense mutations', 'Var', (107, 125))	('HRAS', 'Gene', '3265', (102, 106))	('Neck Squamous Cell Carcinomas', 'Disease', (54, 83))	('Carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('Neck Squamous Cell Carcinomas', 'Disease', 'MESH:C535575', (54, 83))
118989	31797609	The samples were almost mutually exclusive for these events, with only one sample having both a 2q23.3 deletion and an HRAS alteration and no samples having alterations in either KRAS or NRAS.	('KRAS', 'Gene', '3845', (179, 183))	('NRAS', 'Gene', (187, 191))	('2q23.3', 'Gene', (96, 102))	('NRAS', 'Gene', '4893', (187, 191))	('HRAS', 'Gene', '3265', (119, 123))	('KRAS', 'Gene', (179, 183))	('alteration', 'Var', (124, 134))	('HRAS', 'Gene', (119, 123))	('deletion', 'Var', (103, 111))
118991	31797609	We suggest that in the absence of an HRAS mutation, MAPK signaling may be activated by a deletion of the 2q23.3 locus in HNSC.	('activated', 'PosReg', (74, 83))	('HRAS', 'Gene', '3265', (37, 41))	('deletion', 'Var', (89, 97))	('2q23.3', 'Gene', (105, 111))	('MAPK signaling', 'MPA', (52, 66))	('HRAS', 'Gene', (37, 41))
119000	31797609	For example, LURE found that deletions in 2q23.3 in head-and-neck cancers are strongly associated with RTK signaling.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('associated', 'Reg', (87, 97))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('RTK signaling', 'MPA', (103, 116))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('deletions', 'Var', (29, 38))	('2q23.3', 'Gene', (42, 48))
119009	29325141	Human cancers are complex diseases involving multiple genetic and epigenetic changes in the genome.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', (6, 13))	('epigenetic', 'Var', (66, 76))
119012	29325141	Gene regulatory network perturbations have been demonstrated to contribute to the development and progression of cancer, however, the molecular determinants of the gene regulatory network perturbations remains a fundamental challenge in cancer.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('contribute', 'Reg', (64, 74))	('cancer', 'Disease', (113, 119))	('perturbations', 'Var', (24, 37))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
119112	29325141	These results indicate that identification of lncRNA mediated transcriptional perturbation increased our understanding of the role of lncRNAs in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('perturbation', 'Var', (78, 90))	('increased', 'PosReg', (91, 100))
119117	29325141	We observed that the pan-cancer lncRNA modulator RP3-402G11.28 can mediated the regulation between NFKB1 and HDAC7, and lncRNA high expression can regulate the expression of HDAC7 (Figure 5D).	('pan-cancer', 'Disease', 'MESH:C537931', (21, 31))	('expression', 'MPA', (160, 170))	('NFKB1', 'Gene', (99, 104))	('HDAC7', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('HDAC7', 'Gene', (174, 179))	('regulation', 'MPA', (80, 90))	('regulate', 'Reg', (147, 155))	('pan-cancer', 'Disease', (21, 31))	('HDAC7', 'Gene', '51564', (109, 114))	('RP3-402G11.28', 'Var', (49, 62))	('NFKB1', 'Gene', '4790', (99, 104))	('HDAC7', 'Gene', '51564', (174, 179))
119120	29325141	Moreover, alterations of cell cycle regulators have been implicated in human cancer, including CDK6 (53).	('alterations', 'Var', (10, 21))	('CDK6', 'Gene', (95, 99))	('implicated', 'Reg', (57, 67))	('cancer', 'Disease', (77, 83))	('CDK6', 'Gene', '1021', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cell cycle regulators', 'Gene', (25, 46))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (71, 76))
119121	29325141	Here, we found that pan-cancer lncRNA modulator RP11-490M8.1 could regulate the expression of CDK6 (Figure 5F).	('regulate', 'Reg', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pan-cancer', 'Disease', (20, 30))	('RP11-490M8.1', 'Var', (48, 60))	('expression', 'MPA', (80, 90))	('pan-cancer', 'Disease', 'MESH:C537931', (20, 30))	('CDK6', 'Gene', (94, 98))	('CDK6', 'Gene', '1021', (94, 98))
119122	29325141	PD0332991 had been demonstrated to be an orally active, highly selective inhibitor of CDK6 by blocking retinoblastoma (Rb) phosphorylation (54).	('retinoblastoma', 'Disease', 'MESH:D012175', (103, 117))	('retinoblastoma', 'Disease', (103, 117))	('Rb', 'Phenotype', 'HP:0009919', (119, 121))	('blocking', 'NegReg', (94, 102))	('retinoblastoma', 'Phenotype', 'HP:0009919', (103, 117))	('PD0332991', 'Chemical', 'MESH:C500026', (0, 9))	('CDK6', 'Gene', (86, 90))	('CDK6', 'Gene', '1021', (86, 90))	('PD0332991', 'Var', (0, 9))
119123	29325141	These results indicated that PD0332991 might regulate the expression of CDK6 synergistically with lncRNA RP11-490M8.1.	('expression', 'MPA', (58, 68))	('PD0332991', 'Chemical', 'MESH:C500026', (29, 38))	('regulate', 'Reg', (45, 53))	('PD0332991', 'Var', (29, 38))	('CDK6', 'Gene', (72, 76))	('CDK6', 'Gene', '1021', (72, 76))
119168	29325141	National Program on Key Basic Research Project (973 Program) [2014CB910504]; Creative Research Groups of the National Natural Science Foundation of China [81421063]; National High Technology Research and Development Program of China (863 Program) [2014AA021102]; National Natural Science Foundation of China [91439117, 61473106, 31571331, 61502126, 61603116]; NCI Transition Career Development Award [1K22CA214765-01]; China Postdoctoral Science Foundation [2016T90309, 2015M571436, 2016M591544, LBH-Z14134, LBH-Z16142]; Natural Science Foundation of Heilongjiang Province [QC2015020]; Weihan Yu Youth Science Fund Project of Harbin Medical University, University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province [UNPYSCT-2016189, UNPYSCT-2017060]; Harbin Special Funds of Innovative Talents on Science and Technology Research Project [2015RAQXJ091, 2017RAQXJ164]; Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant [RP160021 to N.S.	('LBH', 'Gene', '81606', (496, 499))	('Cancer', 'Phenotype', 'HP:0002664', (898, 904))	('LBH', 'Gene', (508, 511))	('[RP160021', 'Var', (979, 988))	('LBH', 'Gene', (496, 499))	('LBH', 'Gene', '81606', (508, 511))	('Cancer', 'Disease', (898, 904))	('Cancer', 'Disease', 'MESH:D009369', (898, 904))
119192	18976072	In another EORTC study of patients with LGG comparing low- versus high-dose radiation therapy, the 5-year patient survival rate was ~ 78% for tumors <= 3 cm, 58% for tumors > 3 to <= 5 cm, and 44% for tumors > 5 to <= 10 cm.	('patient', 'Species', '9606', (26, 33))	('<= 3 cm', 'Var', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('patient', 'Species', '9606', (106, 113))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('EORTC', 'Chemical', '-', (11, 16))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
119194	18976072	A subset analysis from that study found that patients whose tumors had codeletion of chromosomes 1p and 19q, and/or the 1;19 translocation, had significantly better survival rates.	('better', 'PosReg', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('survival rates', 'CPA', (165, 179))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('patients', 'Species', '9606', (45, 53))	('chromosomes 1p', 'Var', (85, 99))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('codeletion', 'Var', (71, 81))	('tumors', 'Disease', (60, 66))
119234	18976072	If all 3 favorable prognostic factors were present (< 1 cm residual tumor, tumor diameter < 4 cm, and oligodendroglioma histological type), the 2- and 5-year PFS rates were 100 and 70%, respectively (Fig.	('tumor', 'Disease', (68, 73))	('oligodendroglioma', 'Disease', 'MESH:D009837', (102, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('< 1', 'Var', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('oligodendroglioma', 'Disease', (102, 119))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (75, 80))
119307	33752729	Specifically, the mutation in the KDM5C gene has a significant impact on tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('KDM5C', 'Gene', (34, 39))	('mutation', 'Var', (18, 26))	('impact', 'Reg', (63, 69))	('KDM5C', 'Gene', '8242', (34, 39))
119326	33752729	In orchidectomized rodent males, T or DHT increases spine dendritic density.	('DHT', 'Chemical', 'MESH:D013196', (38, 41))	('spine dendritic density', 'CPA', (52, 75))	('increases', 'PosReg', (42, 51))	('T or DHT', 'Var', (33, 41))
119337	33752729	The dysregulation of the MAPK pathway is a frequent mechanism involved in the over-proliferation of many cancer types such as astrocytomas.	('MAPK pathway', 'Pathway', (25, 37))	('astrocytomas', 'Disease', 'MESH:D001254', (126, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('cancer', 'Disease', (105, 111))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('astrocytomas', 'Disease', (126, 138))	('involved', 'Reg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (90, 93))
119351	33752729	The differences in the dosage of X-linked genes have been associated with the sex-specific genetic architecture of some diseases, such as dyskeratosis congenita, and severe combined immunodeficiency syndromes.	('differences', 'Var', (4, 15))	('associated', 'Reg', (58, 68))	('dyskeratosis congenita', 'Disease', (138, 160))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (138, 160))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (173, 198))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (166, 198))	('combined immunodeficiency syndromes', 'Disease', (173, 208))	('immunodeficiency', 'Phenotype', 'HP:0002721', (182, 198))	('combined immunodeficiency syndromes', 'Disease', 'MESH:D016511', (173, 208))
119353	33752729	These authors suggest that mutations in TSGs that escape X-inactivation have a significant influence on a male predominance of cancer, or in other words, that biallelic expression of EXITS genes confers a protection status against cancer in women.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('biallelic expression', 'Var', (159, 179))	('influence', 'Reg', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('women', 'Species', '9606', (241, 246))	('TSGs', 'Gene', (40, 44))
119424	33752729	P4 also promoted the migration and invasion of U251 and U87 human glioblastoma-derived cell lines, and when RU486 or oligonucleotide antisense against PR were used together with P4, the effect of P4 was blocked.	('P4', 'Chemical', 'MESH:C015586', (0, 2))	('P4', 'Chemical', 'MESH:C015586', (178, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('P4', 'Chemical', 'MESH:C015586', (196, 198))	('U87', 'Gene', (56, 59))	('U87', 'Gene', '641648', (56, 59))	('oligonucleotide', 'Chemical', 'MESH:D009841', (117, 132))	('RU486', 'Var', (108, 113))	('RU486', 'Chemical', 'MESH:D015735', (108, 113))	('glioblastoma', 'Disease', (66, 78))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('U251', 'CellLine', 'CVCL:0021', (47, 51))	('rat', 'Species', '10116', (24, 27))	('migration', 'CPA', (21, 30))	('promoted', 'PosReg', (8, 16))	('human', 'Species', '9606', (60, 65))
119438	33752729	Besides, DHP increased the migration of glioblastoma cells.	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('DHP', 'Var', (9, 12))	('DHP', 'Chemical', 'MESH:D043582', (9, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('rat', 'Species', '10116', (30, 33))	('increased', 'PosReg', (13, 22))	('glioblastoma', 'Disease', (40, 52))
119443	33752729	Chek and cols found that a 43-year-old male with glioblastoma multiforme exclusively treated with RU486 showed a significant improvement of quality of life since the patient improved speech and movement of his hands after 2 weeks of starting the treatment with RU486.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (49, 72))	('improvement', 'PosReg', (125, 136))	('improved', 'PosReg', (174, 182))	('speech', 'MPA', (183, 189))	('RU486', 'Chemical', 'MESH:D015735', (261, 266))	('men', 'Species', '9606', (132, 135))	('glioblastoma multiforme', 'Disease', (49, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('RU486', 'Var', (98, 103))	('men', 'Species', '9606', (198, 201))	('patient', 'Species', '9606', (166, 173))	('RU486', 'Chemical', 'MESH:D015735', (98, 103))	('quality', 'MPA', (140, 147))	('men', 'Species', '9606', (251, 254))
119471	33752729	However, several studies have reported the significance of exogenous female gonadal steroid hormones, such as the administered as contraceptives or hormone replacement therapies, and the risk of developing a glioblastoma.	('glioblastoma', 'Disease', (208, 220))	('glioblastoma', 'Disease', 'MESH:D005909', (208, 220))	('men', 'Species', '9606', (163, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))	('exogenous', 'Var', (59, 68))	('steroid', 'Chemical', 'MESH:D013256', (84, 91))
119483	33752729	Gonzalez-Arenas and cols found that tibolone, a selective tissue estrogenic activity regulator, commonly used in the treatment of menopausal symptoms, increased the proliferation of U251 and U87 derived glioblastoma cells lines, and this effect was blocked by ERs or PRs antagonists, ICI 182, 780, and RU 486.	('increased', 'PosReg', (151, 160))	('U87', 'Gene', (191, 194))	('U251', 'CellLine', 'CVCL:0021', (182, 186))	('tibolone', 'Chemical', 'MESH:C027385', (36, 44))	('ER', 'Gene', '2099', (260, 262))	('U87', 'Gene', '641648', (191, 194))	('glioblastoma', 'Disease', (203, 215))	('rat', 'Species', '10116', (172, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (203, 215))	('glioblastoma', 'Phenotype', 'HP:0012174', (203, 215))	('proliferation', 'CPA', (165, 178))	('men', 'Species', '9606', (130, 133))	('men', 'Species', '9606', (122, 125))	('tibolone', 'Var', (36, 44))
119494	33752729	These authors also detected the AR in eight human GBM cell lines: A172, LN-18, LN-229, M059, T-98G, U87-MG, U118-MG, and U138-MG.	('human', 'Species', '9606', (44, 49))	('U87', 'Gene', '641648', (100, 103))	('U138', 'Chemical', '-', (121, 125))	('U138-MG', 'Var', (121, 128))	('AR', 'Gene', '367', (32, 34))	('T-98G', 'Mutation', 'c.-98T>G', (93, 98))	('U118', 'Chemical', '-', (108, 112))	('U118-MG', 'Var', (108, 115))	('LN-229', 'CellLine', 'CVCL:0393', (79, 85))	('U87', 'Gene', (100, 103))
119495	33752729	In this study, the authors discovered that DHT antagonized the cell growth induced by TGFbeta and increased the apoptosis rate.	('TGFbeta', 'Gene', '7039', (86, 93))	('DHT', 'Var', (43, 46))	('apoptosis rate', 'CPA', (112, 126))	('DHT', 'Chemical', 'MESH:D013196', (43, 46))	('TGFbeta', 'Gene', (86, 93))	('increased', 'PosReg', (98, 107))	('rat', 'Species', '10116', (122, 125))	('antagonized', 'NegReg', (47, 58))	('cell growth', 'CPA', (63, 74))
119519	33752729	Once the role of gonadal steroid hormones and their receptor in glioblastoma progression and prevalence have been completely demonstrated, new options for glioblastoma therapy could be incorporated, for example, agonists or antagonists of gonadal steroid hormones receptors, enzyme inhibitors, the gonadal steroid hormones themselves in concentrations effective to suppress tumor growth, and their genes and protein targets.	('rat', 'Species', '10116', (344, 347))	('antagonists', 'Var', (224, 235))	('glioblastoma', 'Disease', (64, 76))	('steroid', 'Chemical', 'MESH:D013256', (247, 254))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('rat', 'Species', '10116', (132, 135))	('tumor', 'Disease', (374, 379))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('glioblastoma', 'Disease', (155, 167))	('steroid', 'Chemical', 'MESH:D013256', (25, 32))	('rat', 'Species', '10116', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('steroid', 'Chemical', 'MESH:D013256', (306, 313))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
119528	32164609	TMB was higher for the group of mutant genes that are frequently mutated in glioblastomas (GBMs) and lower for the group of mutant genes that are frequently mutated in lower-grade gliomas (LGGs).	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('GBMs', 'Disease', (91, 95))	('glioblastomas', 'Disease', (76, 89))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('TMB', 'Chemical', '-', (0, 3))	('GBMs', 'Disease', 'MESH:D005909', (91, 95))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('lower', 'NegReg', (101, 106))	('mutant', 'Var', (32, 38))	('GBMs', 'Phenotype', 'HP:0012174', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioblastomas', 'Phenotype', 'HP:0012174', (76, 89))	('TMB', 'MPA', (0, 3))	('higher', 'PosReg', (8, 14))	('glioblastomas', 'Disease', 'MESH:D005909', (76, 89))
119530	32164609	TMB was associated with grade, age, subtype and mutations affecting genomic structure.	('TMB', 'Chemical', '-', (0, 3))	('TMB', 'Disease', (0, 3))	('associated', 'Reg', (8, 18))	('mutations', 'Var', (48, 57))
119533	32164609	TMB was higher in the mismatch repair (MMR) gene mutant group than in the wild-type group, but the MMR pathway was enriched in the TMBHigh group of gliomas without mutations in classical MMR genes.	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('mutant', 'Var', (49, 55))	('TMB', 'Chemical', '-', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('TMB', 'Chemical', '-', (131, 134))	('TMBHigh', 'Chemical', '-', (131, 138))	('TMB', 'MPA', (0, 3))	('higher', 'PosReg', (8, 14))
119539	32164609	Tumor mutational burden (or tumor mutational load) is a potential biomarker of immune checkpoint inhibitors in many cancer types, as neoantigens are generated by somatic tumor mutations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (176, 185))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
119562	32164609	The following covariates were used in Cox regression analysis (univariate and multivariable): TMB group, sex, WHO grade, histology, IDH status and chromosome 1p/19q codeletion.	('IDH status', 'Disease', 'MESH:D013226', (132, 142))	('IDH status', 'Disease', (132, 142))	('Cox', 'Gene', '1351', (38, 41))	('chromosome 1p/19q codeletion', 'Var', (147, 175))	('Cox', 'Gene', (38, 41))	('TMB', 'Chemical', '-', (94, 97))
119565	32164609	To study the value of TMB in glioma, we first analyzed the types and distributions of nonsynonymous mutations (Supplementary Table 1).	('glioma', 'Disease', (29, 35))	('nonsynonymous mutations', 'Var', (86, 109))	('TMB', 'Chemical', '-', (22, 25))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
119566	32164609	As previously reported, the mutation frequencies of IDH1 were higher in LGG than in GBM, and the mutation rates of PTEN and EGFR were higher in GBM than in LGG.	('IDH1', 'Gene', '3417', (52, 56))	('EGFR', 'Gene', '1956', (124, 128))	('PTEN', 'Gene', (115, 119))	('higher', 'PosReg', (134, 140))	('PTEN', 'Gene', '5728', (115, 119))	('mutation rates', 'MPA', (97, 111))	('EGFR', 'Gene', (124, 128))	('LGG', 'Disease', (72, 75))	('mutation', 'Var', (28, 36))	('IDH1', 'Gene', (52, 56))	('higher', 'Reg', (62, 68))
119568	32164609	Tumors with elevated TMB are enriched for mutations in PTEN or EGFR.	('EGFR', 'Gene', '1956', (63, 67))	('PTEN', 'Gene', '5728', (55, 59))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMB', 'Chemical', '-', (21, 24))	('EGFR', 'Gene', (63, 67))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TMB', 'MPA', (21, 24))	('mutations', 'Var', (42, 51))	('PTEN', 'Gene', (55, 59))
119569	32164609	Consistently, IDH mutations were primarily found in tumors with low TMB (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('IDH', 'Gene', (14, 17))	('mutations', 'Var', (18, 27))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('IDH', 'Gene', '3417', (14, 17))	('found', 'Reg', (43, 48))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('TMB', 'Chemical', '-', (68, 71))	('low TMB', 'Var', (64, 71))
119571	32164609	With correction for multiple hypotheses, we found that TMB was higher in the PTEN mutant group than in the PTEN wild-type group but lower in the IDH1 mutant group than in the IDH1 wild-type group (Table 1).	('PTEN', 'Gene', (107, 111))	('TMB', 'MPA', (55, 58))	('IDH1', 'Gene', (145, 149))	('PTEN', 'Gene', '5728', (107, 111))	('IDH1', 'Gene', '3417', (145, 149))	('TMB', 'Chemical', '-', (55, 58))	('IDH1', 'Gene', (175, 179))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('lower', 'NegReg', (132, 137))	('higher', 'PosReg', (63, 69))	('mutant', 'Var', (150, 156))	('IDH1', 'Gene', '3417', (175, 179))	('mutant', 'Var', (82, 88))
119577	32164609	Overall survival was decreased in patients with a high TMB compared to those with a low TMB (hazard ratio 3.91, 95% confidence interval 3.33-5.70; p < 0.001, log-rank; Fig.	('decreased', 'NegReg', (21, 30))	('TMB', 'Chemical', '-', (55, 58))	('patients', 'Species', '9606', (34, 42))	('Overall survival', 'CPA', (0, 16))	('TMB', 'Chemical', '-', (88, 91))	('high', 'Var', (50, 54))
119582	32164609	In the univariate analysis, age, grade, histology, IDH status, chromosome 1p/19q codeletion and TMB were statistically significantly associated with overall survival (p < 0.01) (Table 1, Supplementary Table 3).	('TMB', 'Chemical', '-', (96, 99))	('overall', 'MPA', (149, 156))	('chromosome 1p/19q codeletion', 'Var', (63, 91))	('IDH status', 'Disease', 'MESH:D013226', (51, 61))	('IDH status', 'Disease', (51, 61))	('TMB', 'Disease', (96, 99))	('associated', 'Reg', (133, 143))
119583	32164609	In the multivariable analysis, grade, chromosome 1p/19q codeletion and TMB were independently associated with overall survival (Table 2).	('overall survival', 'MPA', (110, 126))	('TMB', 'Disease', (71, 74))	('chromosome 1p/19q codeletion', 'Var', (38, 66))	('associated', 'Reg', (94, 104))	('TMB', 'Chemical', '-', (71, 74))
119593	32164609	In contrast, the transcriptional programs of adenylate cyclase activity and synaptic transmission were enriched in the TMBLow group (Fig.	('TMBLow', 'Chemical', '-', (119, 125))	('synaptic transmission', 'MPA', (76, 97))	('TMBLow', 'Var', (119, 125))
119600	32164609	Only 3.6% of glioma patients harbored MMR gene mutations (32 of 897 glioma patients).	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('patients', 'Species', '9606', (75, 83))	('MMR gene', 'Gene', (38, 46))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (20, 28))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', (13, 19))
119601	32164609	TMB was elevated in patients exhibiting MLH1, MSH2, MSH6, PMS2, POLD1 or POLE gene mutations (Fig.	('elevated', 'PosReg', (8, 16))	('mutations', 'Var', (83, 92))	('MSH6', 'Gene', (52, 56))	('PMS2', 'Gene', (58, 62))	('TMB', 'Chemical', '-', (0, 3))	('POLE gene', 'Gene', (73, 82))	('MSH6', 'Gene', '2956', (52, 56))	('MSH2', 'Gene', (46, 50))	('POLD1', 'Gene', '5424', (64, 69))	('PMS2', 'Gene', '5395', (58, 62))	('patients', 'Species', '9606', (20, 28))	('POLD1', 'Gene', (64, 69))	('TMB', 'MPA', (0, 3))	('MSH2', 'Gene', '4436', (46, 50))	('MLH1', 'Gene', '4292', (40, 44))	('MLH1', 'Gene', (40, 44))
119616	32164609	For most genes, TMB was elevated in the individual gene mutant group compared to the individual gene wild-type group.	('elevated', 'PosReg', (24, 32))	('mutant', 'Var', (56, 62))	('TMB', 'Chemical', '-', (16, 19))	('TMB', 'MPA', (16, 19))
119617	32164609	For example, TMB was higher in the PTEN mutant group than in the PTEN wild-type group.	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (65, 69))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))	('higher', 'PosReg', (21, 27))	('TMB', 'MPA', (13, 16))	('mutant', 'Var', (40, 46))	('TMB', 'Chemical', '-', (13, 16))
119618	32164609	It is reasonable as TMB is an aggregate of mutations that result in protein alterations.	('TMB', 'Chemical', '-', (20, 23))	('mutations', 'Var', (43, 52))	('result in', 'Reg', (58, 67))	('protein alterations', 'MPA', (68, 87))
119619	32164609	However, for genes that were mutated in lower-grade glioma, such as IDH1, TMB was lower in the IDH1 mutant group than in the IDH1 wild-type group.	('IDH1', 'Gene', '3417', (95, 99))	('mutant', 'Var', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('IDH1', 'Gene', '3417', (125, 129))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH1', 'Gene', (68, 72))	('TMB', 'MPA', (74, 77))	('IDH1', 'Gene', (95, 99))	('IDH1', 'Gene', '3417', (68, 72))	('TMB', 'Chemical', '-', (74, 77))	('glioma', 'Disease', (52, 58))	('IDH1', 'Gene', (125, 129))	('lower', 'NegReg', (82, 87))
119623	32164609	As reported in pan-cancer studies, the correlation between TMB and T cell immunity was moderate, and TMB was elevated in the MMR gene mutant group.	('MMR', 'Gene', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('TMB', 'MPA', (101, 104))	('elevated', 'PosReg', (109, 117))	('TMB', 'Chemical', '-', (59, 62))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('TMB', 'Chemical', '-', (101, 104))	('mutant', 'Var', (134, 140))
119632	32164609	The mutational load calculated by exome sequencing is associated with the tumor grade and age of patients.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mutational load', 'Var', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('associated', 'Reg', (54, 64))	('patients', 'Species', '9606', (97, 105))
119640	32164609	With immune checkpoint inhibitor treatment, the tumor size of glioblastomas with hypermutation was significantly reduced.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('tumor', 'Disease', (48, 53))	('hypermutation', 'Var', (81, 94))	('glioblastomas', 'Phenotype', 'HP:0012174', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('glioblastomas', 'Disease', 'MESH:D005909', (62, 75))	('reduced', 'NegReg', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('glioblastomas', 'Disease', (62, 75))
119646	32164609	TMB is associated with shorter overall survival in glioma patients.	('glioma', 'Disease', (51, 57))	('TMB', 'Chemical', '-', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('TMB', 'Var', (0, 3))	('patients', 'Species', '9606', (58, 66))	('overall survival', 'MPA', (31, 47))	('shorter', 'NegReg', (23, 30))
119648	32164609	TMB was higher in the MMR gene mutant group, but the MMR pathway was enriched in the TMBHigh group.	('TMBHigh', 'Chemical', '-', (85, 92))	('MMR gene', 'Gene', (22, 30))	('mutant', 'Var', (31, 37))	('TMB', 'Chemical', '-', (0, 3))	('TMB', 'MPA', (0, 3))	('higher', 'PosReg', (8, 14))	('TMB', 'Chemical', '-', (85, 88))
119729	30297783	In contrast, the clustering pattern based on raw RPPA data and mRNA expression data have not such prognostic power (Supplementary Figs S7 and S8): the top three BRCA clusters using RPPA data in terms of sample sizes, C15 (n = 555), C8 (n = 96), and C7 (n = 68) had 5-year survival rates (95% confidence interval) of 0.81 (0.74-0.87), 0.72 (0.58-0.88), and 0.83 (0.66-1), respectively with p-value of 0.2679, and the top three BRCA clusters using mRNA expression data, C14 (n = 548), C9 (n = 111), C3 (n = 57) had 5-year survival rates (95% confidence interval) of 0.80 (0.73-0.88), 0.74 (0.61-0.90), and 0.91 (0.80-1), respectively with p-value of 0.0862 (Supplementary Fig.	('BRCA', 'Gene', (426, 430))	('BRCA', 'Gene', (161, 165))	('C15', 'Gene', (217, 220))	('BRCA', 'Phenotype', 'HP:0003002', (161, 165))	('C15', 'Gene', '51316', (217, 220))	('BRCA', 'Phenotype', 'HP:0003002', (426, 430))	('C14', 'Var', (468, 471))	('BRCA', 'Gene', '672', (161, 165))	('BRCA', 'Gene', '672', (426, 430))
119740	30297783	APC was the second most commonly mutated gene, and was mostly located in CORE samples in C4 (82%) with EP > 0.9 (Fig.	('APC', 'Disease', 'MESH:D011125', (0, 3))	('APC', 'Disease', (0, 3))	('EP > 0.9', 'Var', (103, 111))
119741	30297783	More importantly, the PBRM1 gene was reported as a novel target for KIRC and, in our study, the mutations were found in KIRC and THCA samples in C8 (60%), compared to no mutations in KIRC and THCA samples in C5 (Fig.	('THCA', 'Phenotype', 'HP:0002890', (129, 133))	('THCA', 'Phenotype', 'HP:0002890', (192, 196))	('PBRM1', 'Gene', (22, 27))	('PBRM1', 'Gene', '55193', (22, 27))	('mutations', 'Var', (96, 105))
119773	30297783	There were 21 pathways across cancer types for which only the PRECISE score was predictive of survival times: for example, patients with KIRC, SKCM, and PCPG for the apoptosis pathway.	('apoptosis pathway', 'Pathway', (166, 183))	('PCPG', 'Var', (153, 157))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('patients', 'Species', '9606', (123, 131))	('KIRC', 'Var', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
119798	30297783	The mesenchymal tumor types, low-grade gliomas and glioblastoma multiforme tend to have higher PRECISE EMT scores as compared to epithelial-type tumors such as ovarian, lung and stomach adenocarcinomas, which shows PRECISE preserves and accentuates the actual biological mechanism of these pathways in relevant tumor types.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('epithelial-type tumors', 'Disease', 'MESH:D002277', (129, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (311, 316))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (4, 21))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('glioblastoma multiforme', 'Disease', (51, 74))	('epithelial-type tumors', 'Disease', (129, 151))	('tumor', 'Disease', (16, 21))	('ovarian', 'Disease', (160, 167))	('mesenchymal tumor', 'Disease', (4, 21))	('ovarian', 'Disease', 'MESH:D010051', (160, 167))	('stomach adenocarcinomas', 'Disease', (178, 201))	('higher', 'PosReg', (88, 94))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (51, 74))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('low-grade', 'Var', (29, 38))	('gliomas', 'Disease', (39, 46))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (178, 201))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
119851	27057217	In summary, the results of this study suggest that in situations where a preoperative grading of tumor is required Tc-99m GHA can be used in tumor grading and its use should be encouraged.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Tc-99', 'Chemical', '-', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (97, 102))	('Tc-99m', 'Var', (115, 121))
119948	27057217	These shortcomings heralded the use of newer Tc-99m labeled radiopharmaceuticals in brain scanning, the most prominent of these being Tc-99m DTPA and Tc-99m GHA.	('Tc-99', 'Chemical', '-', (150, 155))	('Tc-99m', 'Var', (150, 156))	('Tc-99', 'Chemical', '-', (134, 139))	('Tc-99m', 'Var', (134, 140))	('Tc-99', 'Chemical', '-', (45, 50))	('DTPA', 'Chemical', '-', (141, 145))
119958	27057217	They described that the only shortcoming of Tc-99m GHA SPECT had been its low sensitivity in detecting posterior fossa tumors as studied.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('Tc-99', 'Chemical', '-', (44, 49))	('Tc-99m', 'Var', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('fossa tumors', 'Disease', (113, 125))	('fossa tumors', 'Disease', 'MESH:D015192', (113, 125))
119959	27057217	Tc-99m GHA shows intense physiological uptake in nasal mucosa, and large intracranial venous sinuses also retain a significant amount of radioactivity.	('intracranial venous sinuses', 'Disease', (73, 100))	('Tc-99m', 'Var', (0, 6))	('Tc-99', 'Chemical', '-', (0, 5))	('intracranial venous sinuses', 'Disease', 'MESH:D012852', (73, 100))	('radioactivity', 'MPA', (137, 150))
119964	27057217	observed the Tc-99m GHA SPECT has a high specificity for neoplastic tissues as compared to nonneoplastic lesion determining its sensitivity and specificity being 97.62% and 100%, respectively.	('nonneoplastic lesion', 'Disease', 'MESH:D004194', (91, 111))	('Tc-99', 'Chemical', '-', (13, 18))	('Tc-99m', 'Var', (13, 19))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (57, 74))	('nonneoplastic lesion', 'Disease', (91, 111))
119968	27057217	performed to compare the performance of Tc-99m GHA SPECT and F-18 FDG PET-CT for detection of tumor recurrence in patients of glioma they found that Tc-99m GHA had a sensitivity, specificity and accuracy of 85%, 97% and 89% respectively whereas those for F-18 FDG PET-Ct were 70%, 97% and 80% respectively.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('F-18', 'Gene', (255, 259))	('Tc-99', 'Chemical', '-', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('F-18', 'Gene', '10046', (61, 65))	('Tc-99m GHA', 'Var', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('F-18', 'Gene', '10046', (255, 259))	('Tc-99', 'Chemical', '-', (40, 45))	('tumor', 'Disease', (94, 99))	('man', 'Species', '9606', (31, 34))	('glioma', 'Disease', (126, 132))	('patients', 'Species', '9606', (114, 122))	('F-18', 'Gene', (61, 65))
119969	27057217	On histopathological subgroup analysis, Tc-99m GHA SPECT performed better than F-18 FDG PET-CT in all grades except for Grade II gliomas, where both were equally effective.	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('II gliomas', 'Disease', (126, 136))	('F-18', 'Gene', (79, 83))	('Tc-99m', 'Var', (40, 46))	('F-18', 'Gene', '10046', (79, 83))	('Tc-99', 'Chemical', '-', (40, 45))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('II gliomas', 'Disease', 'MESH:D005910', (126, 136))
119972	27057217	Sensitivity, specificity, and accuracy were 86.4%, 62.5%, and 80% for Tc-99m GHA SPECT-CT and 100%, 87.5%, and 96% for F-18 FDOPA PET-CT, respectively.	('F-18', 'Gene', '10046', (119, 123))	('Tc-99', 'Chemical', '-', (70, 75))	('Tc-99m', 'Var', (70, 76))	('FDOPA', 'Chemical', 'MESH:C043437', (124, 129))	('F-18', 'Gene', (119, 123))
119975	27057217	showed the F-18 FDOPA PET-CT was more reliable than F-18 FDG PET-CT or N-13 ammonia PET-CT in evaluating brain tumors, thereby putting Tc-99m GHA in the same league of radiotracers even though it is more economical and widely available than the other PET radiotracers.	('brain tumors', 'Disease', 'MESH:D001932', (105, 117))	('brain tumors', 'Phenotype', 'HP:0030692', (105, 117))	('Tc-99', 'Chemical', '-', (135, 140))	('FDOPA', 'Chemical', 'MESH:C043437', (16, 21))	('F-18', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('F-18', 'Gene', (11, 15))	('brain tumors', 'Disease', (105, 117))	('N-13 ammonia', 'Chemical', '-', (71, 83))	('brain tumor', 'Phenotype', 'HP:0030692', (105, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('F-18', 'Gene', '10046', (11, 15))	('F-18', 'Gene', '10046', (52, 56))	('Tc-99m', 'Var', (135, 141))
119985	27057217	Interestingly, it was noted that some low-grade tumors such as vestibular schwannoma (case 7 of master table) showed an intense uptake of Tc-99m GHA (Tmax/N = 4.82) however T/N ratios fell within the range of low-grade tumors (T/N = 1.74).	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('uptake', 'MPA', (128, 134))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('vestibular schwannoma', 'Disease', 'MESH:D009464', (63, 84))	('tumors', 'Disease', (48, 54))	('vestibular schwannoma', 'Disease', (63, 84))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('schwannoma', 'Phenotype', 'HP:0100008', (74, 84))	('Tc-99', 'Chemical', '-', (138, 143))	('Tc-99m', 'Var', (138, 144))	('vestibular schwannoma', 'Phenotype', 'HP:0009588', (63, 84))
119998	20001799	Similar to genetic mutations, alterations in epigenetic regulation can lead to uncontrolled cell division, tumor initiation and growth, invasiveness and metastasis.	('lead to', 'Reg', (71, 78))	('invasiveness', 'Disease', 'MESH:D009362', (136, 148))	('invasiveness', 'Disease', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor initiation', 'Disease', 'MESH:D009369', (107, 123))	('metastasis', 'CPA', (153, 163))	('growth', 'CPA', (128, 134))	('alterations', 'Var', (30, 41))	('tumor initiation', 'Disease', (107, 123))	('uncontrolled cell division', 'CPA', (79, 105))	('epigenetic', 'Var', (45, 55))
120000	20001799	Understanding epigenetic dysregulation in brain cancers has provided new tools for prognostication, as well as suggesting new approaches to therapy.	('brain cancers', 'Disease', 'MESH:D001932', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('brain cancers', 'Disease', (42, 55))	('epigenetic dysregulation', 'Var', (14, 38))	('brain cancer', 'Phenotype', 'HP:0030692', (42, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
120003	20001799	The discovery of altered epigenetic profiles in human neoplasia has led to new integrative models in which both genetic and epigenetic mechanisms contribute to and interact in cancer, and perhaps many other common human diseases.	('contribute', 'Reg', (146, 156))	('neoplasia', 'Disease', (54, 63))	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('neoplasia', 'Phenotype', 'HP:0002664', (54, 63))	('interact', 'Reg', (164, 172))	('neoplasia', 'Disease', 'MESH:D009369', (54, 63))	('human', 'Species', '9606', (214, 219))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('epigenetic', 'Var', (25, 35))
120004	20001799	Owing to their reversible nature, epigenetic alterations are being targeted for reversal by therapeutic agents in cancer clinical trials.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('epigenetic alterations', 'Var', (34, 56))	('cancer', 'Disease', (114, 120))
120011	20001799	Recent structural analysis in mice has demonstrated that DNMT3A and DNMT3L can form a complex that has two active sites and can bind DNA.	('bind', 'Interaction', (128, 132))	('mice', 'Species', '10090', (30, 34))	('DNMT3A', 'Var', (57, 63))	('DNA', 'Protein', (133, 136))	('DNMT3L', 'Var', (68, 74))
120018	20001799	Loss of TET1 and its family member TET2 are associated with malignancies, and a TET1 fusion to the histone methyltransferase MLL has been described in acute myeloid leukemia.	('fusion', 'Var', (85, 91))	('TET2', 'Gene', '54790', (35, 39))	('acute myeloid leukemia', 'Disease', (151, 173))	('TET1', 'Gene', '80312', (80, 84))	('TET1', 'Gene', '80312', (8, 12))	('described', 'Reg', (138, 147))	('leukemia', 'Phenotype', 'HP:0001909', (165, 173))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (157, 173))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (151, 173))	('TET1', 'Gene', (80, 84))	('TET2', 'Gene', (35, 39))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (151, 173))	('TET1', 'Gene', (8, 12))	('MLL', 'Gene', '4297', (125, 128))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('MLL', 'Gene', (125, 128))	('Loss', 'Var', (0, 4))	('associated', 'Reg', (44, 54))	('malignancies', 'Disease', (60, 72))
120019	20001799	While modification of DNA by CpG methylation generally leads to gene silencing, post-translational modifications of histone proteins including acetylation, methylation, phosphorylation, ubiquitination or sumoylation can lead to either gene activation or repression, depending on which specific amino acid residue is modified.	('activation', 'PosReg', (240, 250))	('modifications', 'Var', (99, 112))	('gene', 'MPA', (235, 239))	('gene', 'MPA', (64, 68))	('ubiquitination', 'Disease', 'MESH:C563003', (186, 200))	('modification', 'Var', (6, 18))	('acetylation', 'MPA', (143, 154))	('ubiquitination', 'Disease', (186, 200))	('methylation', 'MPA', (156, 167))	('lead to', 'Reg', (220, 227))	('sumoylation', 'MPA', (204, 215))	('silencing', 'NegReg', (69, 78))	('repression', 'MPA', (254, 264))	('phosphorylation', 'MPA', (169, 184))
120022	20001799	Mono-, di- and tri-methylation on histone H3 at lysine 4 (H3K4) is associated with transcriptional activation, while the di- and tri-methylation on histone H3 at lysine 9 (H3K9me2 and H3K9me3) is indicative of transcriptional inhibition.	('transcriptional', 'MPA', (83, 98))	('histone H3', 'Gene', '260423', (148, 158))	('histone H3', 'Gene', (148, 158))	('histone H3', 'Gene', '260423', (34, 44))	('Mono-', 'Var', (0, 5))	('lysine', 'Chemical', 'MESH:D008239', (162, 168))	('tri-methylation', 'Var', (15, 30))	('activation', 'PosReg', (99, 109))	('histone H3', 'Gene', (34, 44))	('di-', 'Var', (7, 10))	('lysine', 'Chemical', 'MESH:D008239', (48, 54))
120025	20001799	H3K27me3 in cancer cells can recruit DNA methyltransferases to gene promoters, potentially leading to de novo methylation and gene silencing (Figure 1C).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('leading to', 'Reg', (91, 101))	('methylation', 'MPA', (110, 121))	('DNA methyltransferase', 'Gene', '1786', (37, 58))	('recruit', 'PosReg', (29, 36))	('H3K27me3', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('DNA methyltransferase', 'Gene', (37, 58))	('gene', 'MPA', (126, 130))
120026	20001799	However, a subset of inactive genes marked by H3K27me3 in cancer cells do not undergo de novo methylation (Figure 1D).	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('H3K27me3', 'Var', (46, 54))
120028	20001799	MiRNAs have the capacity to fine-tune gene-expression programs and cell function through cell-type-specific and temporal regulation of their expression, which itself can be deregulated through epigenetic mechanisms in brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (218, 230))	('brain tumors', 'Phenotype', 'HP:0030692', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('epigenetic', 'Var', (193, 203))	('brain tumors', 'Disease', (218, 230))	('expression', 'MPA', (141, 151))	('gene-expression', 'MPA', (38, 53))
120031	20001799	Conditional removal of DNMT1 in mouse CNS precursor cells leads to global demethylation and perinatal death from a defect in neural control of respiration.	('global demethylation', 'MPA', (67, 87))	('DNMT1', 'Gene', (23, 28))	('leads to', 'Reg', (58, 66))	('defect', 'NegReg', (115, 121))	('defect in neural control of respiration', 'Phenotype', 'HP:0002493', (115, 154))	('removal', 'Var', (12, 19))	('mouse', 'Species', '10090', (32, 37))	('neural control of respiration', 'MPA', (125, 154))
120035	20001799	Mutations in methyl CpG binding protein 2 (MECP2) are known to cause Rett syndrome, a developmental disease associated with mental retardation.	('mental retardation', 'Disease', (124, 142))	('MECP2', 'Gene', '4204', (43, 48))	('methyl CpG binding protein 2', 'Gene', '4204', (13, 41))	('methyl CpG binding protein 2', 'Gene', (13, 41))	('Rett syndrome', 'Disease', (69, 82))	('mental retardation', 'Phenotype', 'HP:0001249', (124, 142))	('mental retardation', 'Disease', 'MESH:D008607', (124, 142))	('cause', 'Reg', (63, 68))	('Rett syndrome', 'Disease', 'MESH:D015518', (69, 82))	('Mutations', 'Var', (0, 9))	('MECP2', 'Gene', (43, 48))	('developmental disease', 'Disease', 'MESH:D001848', (86, 107))	('developmental disease', 'Disease', (86, 107))
120036	20001799	Mice with generalized or CNS-specific deletions of Mecp2 have virtually indistinguishable phenotypes, suggesting the function of MeCP2 is primarily related to development of the CNS.	('Mecp2', 'Gene', (51, 56))	('Mecp2', 'Gene', '17257', (51, 56))	('Mice', 'Species', '10090', (0, 4))	('deletions', 'Var', (38, 47))
120037	20001799	In one of these mouse models, point mutations in Mecp2 lead to increased histone H3 acetylation in the cerebellum and cortex.	('point mutations', 'Var', (30, 45))	('increased', 'PosReg', (63, 72))	('Mecp2', 'Gene', '17257', (49, 54))	('Mecp2', 'Gene', (49, 54))	('mouse', 'Species', '10090', (16, 21))	('histone H3', 'Gene', '260423', (73, 83))	('histone H3', 'Gene', (73, 83))
120039	20001799	The CREB-binding protein (CBP) exhibits HAT activity, and mutations of CBP underlie at least 50% of cases of Rubinstein-Taybi syndrome, a mental retardation disorder that also carries a risk of cancer, including medulloblastoma and glioma.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (194, 200))	('a mental retardation disorder', 'Disease', 'MESH:D038901', (136, 165))	('mental retardation', 'Phenotype', 'HP:0001249', (138, 156))	('CREB-binding protein', 'Gene', '1387', (4, 24))	('medulloblastoma', 'Phenotype', 'HP:0002885', (212, 227))	('medulloblastoma and glioma', 'Disease', 'MESH:D008527', (212, 238))	('Rubinstein-Taybi syndrome', 'Disease', (109, 134))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('CBP', 'Gene', (26, 29))	('CBP', 'Gene', (71, 74))	('Rubinstein-Taybi syndrome', 'Disease', 'MESH:D012415', (109, 134))	('CBP', 'Gene', '1387', (26, 29))	('CBP', 'Gene', '1387', (71, 74))	('CREB-binding protein', 'Gene', (4, 24))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('a mental retardation disorder', 'Disease', (136, 165))
120045	20001799	Hypomethylation of genomic DNA has been found in many different cancers, including GBMs, where up to 80% exhibit demethylation compared with normal brain.	('DNA', 'Gene', (27, 30))	('Hypomethylation', 'Var', (0, 15))	('GBMs', 'Disease', (83, 87))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('found', 'Reg', (40, 45))	('demethylation', 'MPA', (113, 126))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
120052	20001799	Many different pathways are affected by hypermethylation-related gene silencing in gliomas, including cell-cycle regulation, apoptosis, DNA repair, angiogenesis, drug resistance and invasion.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('cell-cycle regulation', 'CPA', (102, 123))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('DNA repair', 'CPA', (136, 146))	('silencing', 'NegReg', (70, 79))	('gliomas', 'Disease', (83, 90))	('hypermethylation-related', 'Var', (40, 64))	('drug resistance', 'CPA', (162, 177))	('affected', 'Reg', (28, 36))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('drug resistance', 'Phenotype', 'HP:0020174', (162, 177))	('apoptosis', 'CPA', (125, 134))	('invasion', 'CPA', (182, 190))	('angiogenesis', 'CPA', (148, 160))
120053	20001799	For example, the tumor suppressor genes PTEN and RB are known to undergo DNA hypermethylation-induced silencing in GBM cell lines and hypermethylation in primary tumors.	('primary tumors', 'Disease', (154, 168))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (17, 22))	('PTEN', 'Gene', (40, 44))	('primary tumors', 'Disease', 'MESH:D009369', (154, 168))	('tumor', 'Disease', (162, 167))	('PTEN', 'Gene', '5728', (40, 44))	('silencing', 'NegReg', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('hypermethylation', 'Var', (134, 150))
120054	20001799	PDCD4, a tumor suppressor that can suppress expression of target genes, is itself silenced in many cancers including gliomas through methylation of the 5' CpG island.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('expression of', 'MPA', (44, 57))	('PDCD4', 'Gene', (0, 5))	('methylation', 'Var', (133, 144))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('PDCD4', 'Gene', '27250', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancers', 'Disease', (99, 106))	('tumor', 'Disease', (9, 14))	('silenced', 'NegReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('suppress', 'NegReg', (35, 43))
120058	20001799	Hypermethylation of the promoter of the DNA repair protein ERCC1 may have a role in the development of resistance to cisplatin in gliomas, since the levels of ERCC1 mRNA are associated with sensitivity to cisplatin in glioma samples and hypermethylation of ERCC1 in glioma cell lines and primary gliomas may confer resistance through suppression of ERCC1 mRNA and protein.	('ERCC1', 'Gene', (59, 64))	('suppression', 'NegReg', (334, 345))	('ERCC1', 'Gene', '2067', (257, 262))	('glioma', 'Disease', (218, 224))	('glioma', 'Disease', (266, 272))	('glioma', 'Disease', (130, 136))	('gliomas', 'Disease', (130, 137))	('resistance', 'MPA', (315, 325))	('sensitivity to cisplatin', 'MPA', (190, 214))	('gliomas', 'Disease', (296, 303))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('glioma', 'Disease', 'MESH:D005910', (266, 272))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('hypermethylation', 'Var', (237, 253))	('glioma', 'Disease', (296, 302))	('associated', 'Reg', (174, 184))	('primary gliomas', 'Disease', 'MESH:D005910', (288, 303))	('ERCC1', 'Gene', (257, 262))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('ERCC1', 'Gene', '2067', (159, 164))	('mRNA and', 'MPA', (355, 363))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('gliomas', 'Disease', 'MESH:D005910', (296, 303))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (266, 272))	('ERCC1', 'Gene', '2067', (349, 354))	('primary gliomas', 'Disease', (288, 303))	('protein', 'Protein', (364, 371))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('ERCC1', 'Gene', (159, 164))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (205, 214))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('gliomas', 'Phenotype', 'HP:0009733', (296, 303))	('DNA repair protein', 'Gene', '442459', (40, 58))	('ERCC1', 'Gene', (349, 354))	('ERCC1', 'Gene', '2067', (59, 64))	('DNA repair protein', 'Gene', (40, 58))
120061	20001799	Many of these genes were chosen for investigation using a candidate gene approach, but it remains possible that a subset of glioma genes might be inactivated primarily by methylation, and thus, only through methylation screening could such genes be identified.	('glioma', 'Disease', (124, 130))	('methylation', 'Var', (171, 182))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('inactivated', 'NegReg', (146, 157))	('glioma', 'Disease', 'MESH:D005910', (124, 130))
120065	20001799	In this study, HOXA11, CD81, PR KCDBP, TES, MEST, TNFRSF10A and FZD9 were hypermethylated in more than 50% of the samples.	('MEST', 'Gene', (44, 48))	('MEST', 'Gene', '4232', (44, 48))	('FZD9', 'Gene', '8326', (64, 68))	('PR KCDBP', 'Gene', '112464', (29, 37))	('TNFRSF10A', 'Gene', (50, 59))	('hypermethylated', 'Var', (74, 89))	('FZD9', 'Gene', (64, 68))	('CD81', 'Gene', (23, 27))	('TES', 'Gene', (39, 42))	('TES', 'Gene', '26136', (39, 42))	('HOXA11', 'Gene', '3207', (15, 21))	('CD81', 'Gene', '975', (23, 27))	('TNFRSF10A', 'Gene', '8797', (50, 59))	('HOXA11', 'Gene', (15, 21))	('PR KCDBP', 'Gene', (29, 37))
120066	20001799	An integrated genomic and epigenomic approach using copy-number analysis and DNA-methylation scanning identified both SLC5A8 and WNK2 methylation in primary human gliomas.	('gliomas', 'Disease', (163, 170))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('methylation', 'Var', (134, 145))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('SLC5A8', 'Gene', (118, 124))	('WNK2', 'Gene', (129, 133))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('SLC5A8', 'Gene', '160728', (118, 124))	('WNK2', 'Gene', '65268', (129, 133))	('human', 'Species', '9606', (157, 162))
120067	20001799	Methylation of SLC5A8 is correlated with decreased expression, while re-expression of exogenous SLC5A8 led to inhibition of colony formation in vitro.	('inhibition', 'NegReg', (110, 120))	('SLC5A8', 'Gene', (96, 102))	('Methylation', 'Var', (0, 11))	('decreased', 'NegReg', (41, 50))	('SLC5A8', 'Gene', '160728', (96, 102))	('colony formation in vitro', 'CPA', (124, 149))	('SLC5A8', 'Gene', (15, 21))	('expression', 'MPA', (51, 61))	('SLC5A8', 'Gene', '160728', (15, 21))
120072	20001799	On a pathway level, WNK2 epigenetic silencing may synergize with genetic amplification of EGFR, a potent oncogene in gliomas, as WNK2 suppresses the activity of MEK1 through the Rho-GTPase pathway mechanism, and reduces EGFR signaling.	('gliomas', 'Disease', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('Rho-GTPase pathway', 'Pathway', (178, 196))	('WNK2', 'Gene', '65268', (20, 24))	('WNK2', 'Gene', '65268', (129, 133))	('EGFR', 'Gene', '1956', (220, 224))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('MEK1', 'Gene', '5604', (161, 165))	('EGFR', 'Gene', (90, 94))	('WNK2', 'Gene', (20, 24))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('suppresses', 'NegReg', (134, 144))	('activity', 'MPA', (149, 157))	('WNK2', 'Gene', (129, 133))	('epigenetic silencing', 'Var', (25, 45))	('reduces', 'NegReg', (212, 219))	('EGFR', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (90, 94))	('MEK1', 'Gene', (161, 165))
120073	20001799	These studies underscore the importance of integrative genetic and epigenetic screens to discover novel mutations or alterations, and how they give rise to brain cancers.	('alterations', 'Var', (117, 128))	('mutations', 'Var', (104, 113))	('brain cancers', 'Disease', 'MESH:D001932', (156, 169))	('brain cancers', 'Disease', (156, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('give rise', 'Reg', (143, 152))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('brain cancer', 'Phenotype', 'HP:0030692', (156, 168))
120074	20001799	Hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter is associated with increased sensitivity to combined chemo- and radio-therapy.	('Hypermethylation', 'Var', (0, 16))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (24, 62))	('MGMT', 'Gene', (64, 68))	('increased', 'PosReg', (98, 107))	('sensitivity', 'MPA', (108, 119))	('MGMT', 'Gene', '4255', (64, 68))	('O6-methylguanine-DNA-methyltransferase', 'Gene', (24, 62))
120077	20001799	While high levels of MGMT are correlated with resistance to alkylating agents in glioma cell lines and xenografts, promoter hypermethylation of MGMT is associated with increased patient survival when coupled with radiation and treatment with temozolomide.	('patient survival', 'CPA', (178, 194))	('increased', 'PosReg', (168, 177))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('promoter hypermethylation', 'Var', (115, 140))	('patient', 'Species', '9606', (178, 185))	('glioma', 'Disease', (81, 87))	('temozolomide', 'Chemical', 'MESH:D000077204', (242, 254))	('MGMT', 'Gene', '4255', (21, 25))	('MGMT', 'Gene', '4255', (144, 148))	('MGMT', 'Gene', (21, 25))	('MGMT', 'Gene', (144, 148))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
120079	20001799	Recurrent GBMs with methylated MGMT exhibited a high incidence of G-C to A-T transition mutations at non-CpG sites (81%), also seen in mismatch repair genes (MMR), similar to those reported for p53.	('methylated', 'Var', (20, 30))	('MGMT', 'Gene', '4255', (31, 35))	('MGMT', 'Gene', (31, 35))	('mutations', 'Var', (88, 97))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('G-C to A-T transition', 'Gene', (66, 87))
120108	20001799	Hypermethylation and gene silencing of HIC1 is commonly found in medulloblastomas of all stages and pathology, and treatment with 5-aza can reactivate HIC1.	('HIC1', 'Gene', '3090', (39, 43))	('HIC1', 'Gene', (151, 155))	('Hypermethylation', 'Var', (0, 16))	('HIC1', 'Gene', '3090', (151, 155))	('medulloblastomas', 'Disease', 'MESH:D008527', (65, 81))	('medulloblastomas', 'Disease', (65, 81))	('medulloblastoma', 'Phenotype', 'HP:0002885', (65, 80))	('HIC1', 'Gene', (39, 43))	('gene', 'MPA', (21, 25))	('5-aza', 'Chemical', 'MESH:D001374', (130, 135))	('found', 'Reg', (56, 61))
120111	20001799	The hypermethylation leads to reduced SPINT2 expression, which is reversible by treatment with 5-aza.	('expression', 'MPA', (45, 55))	('reduced', 'NegReg', (30, 37))	('SPINT2', 'Gene', '10653', (38, 44))	('SPINT2', 'Gene', (38, 44))	('5-aza', 'Chemical', 'MESH:D001374', (95, 100))	('hypermethylation', 'Var', (4, 20))
120115	20001799	The hypermethylation of S100A6 is associated with the aggressive large cell/anaplastic morphophenotype.	('associated', 'Reg', (34, 44))	('S100', 'Gene', (24, 28))	('aggressive large cell/anaplastic', 'Disease', (54, 86))	('S100', 'Gene', '6271', (24, 28))	('hypermethylation', 'Var', (4, 20))
120116	20001799	MCJ, a member of the DNAJ protein family, is silenced via promoter methylation in medulloblastomas.	('medulloblastomas', 'Disease', 'MESH:D008527', (82, 98))	('promoter methylation', 'Var', (58, 78))	('medulloblastomas', 'Disease', (82, 98))	('medulloblastoma', 'Phenotype', 'HP:0002885', (82, 97))	('MCJ', 'Gene', (0, 3))	('MCJ', 'Gene', '29103', (0, 3))	('silenced', 'NegReg', (45, 53))
120118	20001799	Furthermore, epigenetic loss of MCJ expression can result from biallelic promoter methylation or methylation on one allele combined with genetic loss of the other allele.	('MCJ', 'Gene', '29103', (32, 35))	('loss', 'NegReg', (145, 149))	('result', 'Reg', (51, 57))	('epigenetic', 'Var', (13, 23))	('biallelic', 'Var', (63, 72))	('MCJ', 'Gene', (32, 35))	('expression', 'MPA', (36, 46))	('methylation', 'Var', (97, 108))
120119	20001799	Other genes such as DIKKOPF-1 and COL1A2 are also silenced via DNA methylation in medulloblastomas.	('DIKKOPF-1', 'Gene', (20, 29))	('medulloblastomas', 'Disease', 'MESH:D008527', (82, 98))	('medulloblastomas', 'Disease', (82, 98))	('medulloblastoma', 'Phenotype', 'HP:0002885', (82, 97))	('silenced', 'NegReg', (50, 58))	('COL1A2', 'Gene', (34, 40))	('COL1A2', 'Gene', '1278', (34, 40))	('DNA methylation', 'Var', (63, 78))
120123	20001799	The genetic alteration of such epigenetic-modifying genes leads to a global loss of H3K9me2, and might also result in a genome-wide redistribution or global loss of other histone methylation at specific lysine residues.	('loss', 'NegReg', (76, 80))	('lysine', 'Chemical', 'MESH:D008239', (203, 209))	('genetic alteration', 'Var', (4, 22))	('redistribution', 'MPA', (132, 146))	('H3K9me2', 'Protein', (84, 91))	('loss', 'NegReg', (157, 161))
120124	20001799	Thus, alteration of multiple epigenetic mechanisms, either directly through epigenetic 'mutations' or indirectly through genetic alterations of genes encoding epigenetic modifying enzymes, contributes to the formation of medulloblastomas.	('epigenetic', 'Var', (76, 86))	('medulloblastomas', 'Disease', (221, 237))	('medulloblastoma', 'Phenotype', 'HP:0002885', (221, 236))	('medulloblastomas', 'Disease', 'MESH:D008527', (221, 237))	('contributes', 'Reg', (189, 200))	('alteration', 'Var', (6, 16))
120125	20001799	Despite the identification of a large number of epigenetic alterations in brain tumors, very little progress has been made in finding marks with prognostic value.	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('brain tumors', 'Disease', (74, 86))	('epigenetic alterations', 'Var', (48, 70))
120126	20001799	The most well studied epigenetic mark for prognosis of treatment for gliomas is the methylation status of MGMT.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('methylation status', 'Var', (84, 102))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('MGMT', 'Gene', '4255', (106, 110))	('MGMT', 'Gene', (106, 110))
120127	20001799	Hypermethylation of the MGMT promoter region, when sufficiently dense, leads to MGMT silencing in gliomas, lymphomas, breast cancer, prostate cancer and retinoblastoma.	('Hypermethylation', 'Var', (0, 16))	('silencing', 'NegReg', (85, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('MGMT', 'Gene', '4255', (24, 28))	('lymphomas', 'Disease', 'MESH:D008223', (107, 116))	('retinoblastoma', 'Disease', 'MESH:D012175', (153, 167))	('MGMT', 'Gene', '4255', (80, 84))	('gliomas', 'Disease', (98, 105))	('lymphomas', 'Phenotype', 'HP:0002665', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('retinoblastoma', 'Phenotype', 'HP:0009919', (153, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))	('MGMT', 'Gene', (24, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('lymphomas', 'Disease', (107, 116))	('retinoblastoma', 'Disease', (153, 167))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('prostate cancer', 'Disease', (133, 148))	('MGMT', 'Gene', (80, 84))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('lymphoma', 'Phenotype', 'HP:0002665', (107, 115))
120128	20001799	Hypermethylation of the MGMT promoter region along with radiation and treatment with temozolomide, is associated with longer survival of patients with GBMs and those low-grade gliomas treated with temozolomide only.	('MGMT', 'Gene', '4255', (24, 28))	('gliomas', 'Disease', 'MESH:D005910', (176, 183))	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('gliomas', 'Disease', (176, 183))	('GBMs', 'Disease', (151, 155))	('Hypermethylation', 'Var', (0, 16))	('temozolomide', 'Chemical', 'MESH:D000077204', (85, 97))	('patients', 'Species', '9606', (137, 145))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('temozolomide', 'Chemical', 'MESH:D000077204', (197, 209))	('longer', 'PosReg', (118, 124))	('MGMT', 'Gene', (24, 28))
120132	20001799	In contrast to GBM, hypermethylation of MGMT occurs later in progressive oligodendrogliomas, suggesting that its prognostic effect in oligodendrogliomas might be different than for GBMs and low-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('gliomas', 'Disease', (84, 91))	('MGMT', 'Gene', '4255', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (73, 91))	('gliomas', 'Disease', (145, 152))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (134, 152))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('oligodendrogliomas', 'Disease', (73, 91))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Disease', (200, 207))	('MGMT', 'Gene', (40, 44))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('oligodendrogliomas', 'Disease', (134, 152))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('hypermethylation', 'Var', (20, 36))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))
120141	20001799	A mechanism by which promoter hypermethylation of TMS1/ASC associates with long-term survival requires further investigation.	('TMS1', 'Gene', '29108', (50, 54))	('ASC', 'Gene', (55, 58))	('ASC', 'Gene', '29108', (55, 58))	('associates with', 'Reg', (59, 74))	('promoter hypermethylation', 'Var', (21, 46))	('TMS1', 'Gene', (50, 54))
120142	20001799	A fourth epigenetic mark with a potential prognostic significance was recently identified in a retrospective study of 27 GBMs, which found methylation of the tumor suppressor p15 promoter in 37% of the samples.	('tumor', 'Disease', (158, 163))	('p15', 'Gene', (175, 178))	('p15', 'Gene', '1030', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('methylation', 'Var', (139, 150))
120144	20001799	Patients with methylation of p15 had a significant shorter overall survival (16.9 vs 23.8 months).	('p15', 'Gene', '1030', (29, 32))	('shorter', 'NegReg', (51, 58))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (14, 25))	('overall survival', 'MPA', (59, 75))	('p15', 'Gene', (29, 32))
120145	20001799	With the knowledge that many loci exhibit epigenetic alterations in brain cancers, it is no surprise that therapies that can reverse these changes are being pursued.	('brain cancers', 'Disease', 'MESH:D001932', (68, 81))	('brain cancers', 'Disease', (68, 81))	('brain cancer', 'Phenotype', 'HP:0030692', (68, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('epigenetic alterations', 'Var', (42, 64))
120147	20001799	Theoretically, modulation of DNA methylation could provide therapeutic benefit by reversing hypermethylation and restoring expression of silenced genes in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('reversing', 'Reg', (82, 91))	('expression', 'MPA', (123, 133))	('modulation', 'Var', (15, 25))	('hypermethylation', 'MPA', (92, 108))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('restoring', 'PosReg', (113, 122))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
120155	20001799	Inhibition of HDACs could also provide a therapeutic benefit alone, or in combination with temozolomide.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (14, 18))	('Inhibition', 'Var', (0, 10))	('temozolomide', 'Chemical', 'MESH:D000077204', (91, 103))
120161	20001799	One speculation is that HDAC inhibition results in increased acetylation in promoters and activates critical growth regulating or apoptotic genes.	('HDAC', 'Gene', '9734', (24, 28))	('activates', 'PosReg', (90, 99))	('acetylation in promoters', 'MPA', (61, 85))	('apoptotic genes', 'Gene', (130, 145))	('increased', 'PosReg', (51, 60))	('inhibition', 'Var', (29, 39))	('critical growth regulating', 'Gene', (100, 126))	('HDAC', 'Gene', (24, 28))
120178	20001799	Another HDACi not yet in clinical trials is pivaloyloxymethyl butyrate (AN-9), a derivative of butyrate.	('butyrate', 'Chemical', 'MESH:D002087', (62, 70))	('AN-9', 'Chemical', 'MESH:C070441', (72, 76))	('pivaloyloxymethyl', 'Var', (44, 61))	('butyrate', 'Chemical', 'MESH:D002087', (95, 103))	('pivaloyloxymethyl butyrate', 'Chemical', 'MESH:C070441', (44, 70))	('HDAC', 'Gene', (8, 12))	('HDAC', 'Gene', '9734', (8, 12))
120187	20001799	As previously discussed, epigenome-wide screens have been employed to detect cancer-specific changes in DNA methylation, histone modifications and miRNA expression, typically by microarray approaches.	('histone modifications', 'MPA', (121, 142))	('DNA', 'Protein', (104, 107))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('miRNA expression', 'MPA', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('methylation', 'Var', (108, 119))	('changes', 'Reg', (93, 100))
120191	20001799	Thus, there are many possibilities for uncovering new epigenetic alterations with prognostic value in human brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('epigenetic alterations', 'Var', (54, 76))	('brain tumors', 'Phenotype', 'HP:0030692', (108, 120))	('brain tumors', 'Disease', 'MESH:D001932', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('brain tumors', 'Disease', (108, 120))	('human', 'Species', '9606', (102, 107))
120199	20001799	This combined approach of altering DNA methylation and histone acetylation, which results in synergistic effects in vitro at lower doses, might reduce toxicity and increase efficacy sufficiently to promote clinical trials in brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (225, 237))	('brain tumors', 'Phenotype', 'HP:0030692', (225, 237))	('toxicity', 'Disease', 'MESH:D064420', (151, 159))	('brain tumors', 'Disease', (225, 237))	('altering', 'Reg', (26, 34))	('methylation', 'Var', (39, 50))	('efficacy', 'MPA', (173, 181))	('toxicity', 'Disease', (151, 159))	('DNA', 'Protein', (35, 38))	('reduce', 'NegReg', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('acetylation', 'MPA', (63, 74))	('histone', 'Protein', (55, 62))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('increase', 'PosReg', (164, 172))
120202	20001799	Papers of special note have been highlighted as:   of interest    of considerable interest Genome-wide scans and candidate approaches have identified genes that exhibit promoter hyper- and hypo-methylation in gliomas compared with normal brain.	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('hypo-methylation', 'Var', (189, 205))	('gliomas', 'Phenotype', 'HP:0009733', (209, 216))	('gliomas', 'Disease', (209, 216))	('promoter', 'MPA', (169, 177))	('gliomas', 'Disease', 'MESH:D005910', (209, 216))
120206	20001799	Promoter region methylation of MGMT is a associated with a longer survival of patients with GBMs and low-grade gliomas treated with temozolomide and radiation.	('GBMs', 'Disease', (92, 96))	('gliomas', 'Disease', (111, 118))	('MGMT', 'Gene', '4255', (31, 35))	('MGMT', 'Gene', (31, 35))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('patients', 'Species', '9606', (78, 86))	('longer', 'PosReg', (59, 65))	('survival', 'CPA', (66, 74))	('temozolomide', 'Chemical', 'MESH:D000077204', (132, 144))	('methylation', 'Var', (16, 27))
120236	30263090	This benefit was accrued most significantly by patients with tumors harboring 1p/19q codeletion and IDH1 mutation.	('tumors', 'Disease', (61, 67))	('mutation', 'Var', (105, 113))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('IDH1', 'Gene', '3417', (100, 104))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('IDH1', 'Gene', (100, 104))	('1p/19q codeletion', 'Var', (78, 95))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
120238	30263090	In patients with LGG with an unfavorable natural history, such as with intact 1p/19q and wild-type IDH1, RT/TMZ plus adjuvant TMZ may be the best option.	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('LGG', 'Disease', (17, 20))	('LGG', 'Chemical', '-', (17, 20))	('intact 1p/19q', 'Var', (71, 84))	('patients', 'Species', '9606', (3, 11))	('IDH1', 'Gene', (99, 103))	('TMZ', 'Chemical', 'MESH:D000077204', (126, 129))	('IDH1', 'Gene', '3417', (99, 103))
120248	30263090	According to the 2016 WHO classification system, grade II oligodendroglioma is now defined by an isocitrate dehydrogenase (IDH) mutation with whole-arm codeletion of chromosomal arms 1p and 19q, whereas IDH mutation combined with intact 1p and 19q chromosomal status is classified as IDH-mutant astrocytoma.	('IDH', 'Gene', '3417', (123, 126))	('IDH', 'Gene', (203, 206))	('isocitrate dehydrogenase', 'Gene', (97, 121))	('astrocytoma', 'Disease', (295, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (295, 306))	('IDH', 'Gene', '3417', (203, 206))	('isocitrate dehydrogenase', 'Gene', '3417', (97, 121))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('II oligodendroglioma', 'Disease', 'MESH:D009837', (55, 75))	('IDH', 'Gene', (284, 287))	('IDH', 'Gene', (123, 126))	('mutation', 'Var', (128, 136))	('IDH', 'Gene', '3417', (284, 287))	('II oligodendroglioma', 'Disease', (55, 75))	('astrocytoma', 'Disease', 'MESH:D001254', (295, 306))
120250	30263090	While histological grade continues to be a factor in treatment consideration, the prognoses of patients with these tumors has been shown to correlate more closely with molecular alterations than with grade.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (95, 103))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('molecular alterations', 'Var', (168, 189))
120265	30263090	IDH1 R132H mutations were detected in 35 of 57 patients (61%) in the group that received radiation therapy alone and in 36 of 56 (64%) in the group that received radiation therapy plus chemotherapy.	('patients', 'Species', '9606', (47, 55))	('R132H', 'Var', (5, 10))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
120267	30263090	OS was reported as 61.2 and 157.2 median months for patients with wild-type and mutant IDH1, respectively.	('IDH1', 'Gene', (87, 91))	('patients', 'Species', '9606', (52, 60))	('IDH1', 'Gene', '3417', (87, 91))	('mutant', 'Var', (80, 86))
120289	30263090	In terms of IDH1, median PFS and OS were 134.4 and 43.2 months for patients with mutant IDH1, respectively, and 21.6 and 7.2 months for patients with wild-type IDH1, respectively.	('IDH1', 'Gene', (12, 16))	('patients', 'Species', '9606', (67, 75))	('IDH1', 'Gene', (88, 92))	('IDH1', 'Gene', (160, 164))	('IDH1', 'Gene', '3417', (160, 164))	('patients', 'Species', '9606', (136, 144))	('IDH1', 'Gene', '3417', (12, 16))	('mutant', 'Var', (81, 87))	('IDH1', 'Gene', '3417', (88, 92))
120304	30263090	The benefit of chemotherapy in this patient group was found to be more frequent and durable responses in patients with histologically classified oligodendroglioma, particularly in those with combined 1p/19q loss, compared with those with an astrocytoma.	('patient', 'Species', '9606', (105, 112))	('astrocytoma', 'Disease', 'MESH:D001254', (241, 252))	('patients', 'Species', '9606', (105, 113))	('loss', 'NegReg', (207, 211))	('astrocytoma', 'Disease', (241, 252))	('oligodendroglioma', 'Disease', (145, 162))	('astrocytoma', 'Phenotype', 'HP:0009592', (241, 252))	('oligodendroglioma', 'Disease', 'MESH:D009837', (145, 162))	('combined 1p/19q', 'Var', (191, 206))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('patient', 'Species', '9606', (36, 43))
120308	30263090	These trials identified three candidate predictive markers for benefit from adjuvant PCV: IDH mutations, CpG island methylated phenotype, and MGMT promoter methylation.	('MGMT', 'Gene', '4255', (142, 146))	('IDH', 'Gene', (90, 93))	('MGMT', 'Gene', (142, 146))	('mutations', 'Var', (94, 103))	('IDH', 'Gene', '3417', (90, 93))
120314	30263090	These data offer compelling reason to recommend treatment with radiation followed by adjuvant PCV in patients with an IDH mutant, 1p19q-codeleted tumour.	('patients', 'Species', '9606', (101, 109))	('tumour', 'Disease', (146, 152))	('IDH', 'Gene', (118, 121))	('1p19q-codeleted', 'Var', (130, 145))	('IDH', 'Gene', '3417', (118, 121))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
120325	30263090	Our understanding of the role of TMZ compared to PCV in the treatment of patients with lower-grade glioma will be informed by the CODEL (ALLIANCE-N0577-CODEL) trial, which has reopened as a two-arm comparison of radiation therapy with adjuvant PCV vs. radiation therapy with concurrent and adjuvant TMZ in patients with 1p/19q-codeleted anaplastic (Grade III) oligodendroglioma; whether these findings will be generalizable to patients with Grade II codeleted tumors is unclear.	('oligodendroglioma', 'Disease', (360, 377))	('patients', 'Species', '9606', (427, 435))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('oligodendroglioma', 'Disease', 'MESH:D009837', (360, 377))	('glioma', 'Disease', 'MESH:D005910', (371, 377))	('glioma', 'Phenotype', 'HP:0009733', (371, 377))	('tumors', 'Disease', (460, 466))	('tumors', 'Phenotype', 'HP:0002664', (460, 466))	('TMZ', 'Chemical', 'MESH:D000077204', (33, 36))	('tumors', 'Disease', 'MESH:D009369', (460, 466))	('glioma', 'Disease', (99, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (299, 302))	('glioma', 'Disease', (371, 377))	('patients', 'Species', '9606', (306, 314))	('tumor', 'Phenotype', 'HP:0002664', (460, 465))	('patients', 'Species', '9606', (73, 81))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('1p/19q-codeleted', 'Var', (320, 336))
120336	30263090	For example, these studies all predate the recognition of the intermediate risk LGG represented by tumors harboring an IDH mutation, but lacking 1p and 19q codeletion, and harboring instead deletion of ATRX.	('IDH', 'Gene', '3417', (119, 122))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('ATRX', 'Gene', (202, 206))	('mutation', 'Var', (123, 131))	('deletion', 'Var', (190, 198))	('ATRX', 'Gene', '546', (202, 206))	('LGG', 'Disease', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('IDH', 'Gene', (119, 122))	('LGG', 'Chemical', '-', (80, 83))	('tumors', 'Disease', (99, 105))
120338	30263090	Conversely, in Figure 3, patients included within the IDH mutant subgroup may include patients with both lower-risk IDH mutant, 1p and 19q co-deleted tumours, as well as patients with intermediate IDH mutant, 1p and 19 intact, ATRX-deleted tumors.	('mutant', 'Var', (58, 64))	('IDH', 'Gene', '3417', (116, 119))	('tumors', 'Disease', (240, 246))	('mutant', 'Var', (120, 126))	('patients', 'Species', '9606', (86, 94))	('tumours', 'Disease', (150, 157))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('ATRX', 'Gene', (227, 231))	('IDH', 'Gene', (54, 57))	('IDH', 'Gene', (197, 200))	('ATRX', 'Gene', '546', (227, 231))	('patients', 'Species', '9606', (170, 178))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('patients', 'Species', '9606', (25, 33))	('IDH', 'Gene', '3417', (197, 200))	('IDH', 'Gene', '3417', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('IDH', 'Gene', (116, 119))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))
120339	30263090	For now, the data suggest that for patients harboring a tumor with an unfavorable natural history, such as those with intact 1p/19q and wild-type IDH1, TMZ and RT may be the best option.	('IDH1', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TMZ', 'Chemical', 'MESH:D000077204', (152, 155))	('IDH1', 'Gene', '3417', (146, 150))	('intact 1p/19q', 'Var', (118, 131))	('tumor', 'Disease', (56, 61))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
120346	30263090	In patients harboring a tumor with an unfavorable natural history, such as those with intact 1p/19q and wild-type IDH1, RT/TMZ plus adjuvant TMZ may be the best option.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('TMZ', 'Chemical', 'MESH:D000077204', (141, 144))	('IDH1', 'Gene', (114, 118))	('intact 1p/19q', 'Var', (86, 99))	('tumor', 'Disease', (24, 29))	('TMZ', 'Chemical', 'MESH:D000077204', (123, 126))	('IDH1', 'Gene', '3417', (114, 118))	('patients', 'Species', '9606', (3, 11))	('1p/19q', 'Var', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
120351	27160082	Tri-methylation on lysine 4 of histone H3 (H3K4me3) is an activating epigenetic mark that is enriched at promoter and promotes expression.	('expression', 'MPA', (127, 137))	('promotes', 'PosReg', (118, 126))	('Tri-methylation', 'Var', (0, 15))	('lysine', 'Chemical', 'MESH:D008239', (19, 25))
120353	27160082	Using The Cancer Genome Atlas (TCGA) data, we inferred the homeobox-regulated genes' expression is higher in 548 GBM cases than in 27 lower grade glioma cases giving that OLIG2 expression can be a reference.	('expression', 'MPA', (85, 95))	('OLIG2', 'Gene', (171, 176))	('GBM', 'Var', (113, 116))	('higher', 'PosReg', (99, 105))	('glioma', 'Disease', (146, 152))	('OLIG2', 'Gene', '10215', (171, 176))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	("homeobox-regulated genes'", 'Gene', (59, 84))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))
120357	27160082	The first three subgroups are associated with mutations IDH1 (R132H), H3F3A (K27) and H3F3A (G34); and the subgroups RTK I and II are associated with platelet-derived growth factor receptor (PDGFRA) and epidermal growth factor receptor (EGFR) amplifications respectively and both with CDKN2A deletion.	('CDKN2A', 'Gene', '1029', (285, 291))	('K27', 'Gene', (77, 80))	('IDH1', 'Gene', (56, 60))	('associated', 'Reg', (134, 144))	('EGFR', 'Gene', '1956', (237, 241))	('mutations', 'Var', (46, 55))	('H3F3A', 'Gene', '3020', (86, 91))	('H3F3A', 'Gene', '3020', (70, 75))	('deletion', 'Var', (292, 300))	('associated', 'Reg', (30, 40))	('epidermal growth factor receptor', 'Gene', (203, 235))	('R132H', 'Mutation', 'rs121913500', (62, 67))	('IDH1', 'Gene', '3417', (56, 60))	('H3F3A', 'Gene', (86, 91))	('H3F3A', 'Gene', (70, 75))	('CDKN2A', 'Gene', (285, 291))	('epidermal growth factor receptor', 'Gene', '1956', (203, 235))	('K27', 'Gene', '342574', (77, 80))	('amplifications', 'Var', (243, 257))	('EGFR', 'Gene', (237, 241))	('PDGFRA', 'Gene', '5156', (191, 197))	('PDGFRA', 'Gene', (191, 197))
120363	27160082	Recently, the combinatorial loss of both H3K4me3 and H3K27me3 was identified in majority of paediatric GBMs with the mutations in H3.3-ATRX-DAXX pathway.	('H3K4me3', 'Protein', (41, 48))	('mutations', 'Var', (117, 126))	('ATRX', 'Gene', '546', (135, 139))	('DAXX', 'Gene', (140, 144))	('ATRX', 'Gene', (135, 139))	('K27', 'Gene', '342574', (55, 58))	('K27', 'Gene', (55, 58))	('DAXX', 'Gene', '1616', (140, 144))	('loss', 'NegReg', (28, 32))
120364	27160082	In primary GBM, it was found that the recurrent hypomethylation of TERT, which encodes telomerase reverse transcriptase, and oncogenes GLI3 and TP73, resulting in increases of H3K4me3 and transcription.	('TP73', 'Gene', (144, 148))	('transcription', 'MPA', (188, 201))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('H3K4me3', 'Protein', (176, 183))	('hypomethylation', 'Var', (48, 63))	('GLI3', 'Gene', '2737', (135, 139))	('increases', 'PosReg', (163, 172))	('GLI3', 'Gene', (135, 139))	('TP73', 'Gene', '7161', (144, 148))
120370	27160082	The homeobox proteins connect to cancer-related pathways and the cadherin proteins function in cell-cell adhesion, suggesting that the alteration in H3K4me3 is closely associated with GBM formation and migration.	('function', 'Reg', (83, 91))	('associated', 'Reg', (168, 178))	('migration', 'CPA', (202, 211))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('homeobox proteins', 'Protein', (4, 21))	('H3K4me3', 'Protein', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('GBM formation', 'CPA', (184, 197))	('alteration', 'Var', (135, 145))
120372	27160082	Immunohistochemistry indicated GFAP+, OLIG2+, EMA+, VIM+, NEU-N+ and CD34+.	('CD34+', 'Var', (69, 74))	('VIM', 'Gene', (52, 55))	('GFAP', 'Gene', '2670', (31, 35))	('OLIG2', 'Gene', (38, 43))	('VIM', 'Gene', '7431', (52, 55))	('NEU-N+', 'Var', (58, 64))	('OLIG2', 'Gene', '10215', (38, 43))	('GFAP', 'Gene', (31, 35))
120382	27160082	We identified the H3K4me3 peaks with tool MACS, resulting 17424 and 20482 peaks for GBM and control respectively, with a decrease in 3058 in GBM (Figure 1B).	('MACS', 'Gene', (42, 46))	('H3K4me3', 'Protein', (18, 25))	('3058', 'Var', (133, 137))	('MACS', 'Gene', '54453', (42, 46))	('decrease', 'NegReg', (121, 129))
120386	27160082	Enrichment analysis suggested that the 252 H3K4me3-gained genes are enriched in 'homeobox' term and the 1278 H3K4me3-lost genes are enriched in terms of 'glycoprotein', 'intrinsic to membrane', 'signal peptide' and 'cadherin' (Figure 2A and Supplementary Figure S3B).	("'homeobox' term", 'Disease', (80, 95))	('H3K4me3-gained', 'Var', (43, 57))	('Supplementary Figure S3', 'Disease', (241, 264))	('Supplementary Figure S3', 'Disease', 'MESH:D017034', (241, 264))
120407	27160082	In the IDH subgroup, the mutant IDH1 gene shows high expression.	('IDH', 'Gene', (7, 10))	('mutant', 'Var', (25, 31))	('IDH', 'Gene', '3417', (7, 10))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('expression', 'MPA', (53, 63))
120414	27160082	Moreover, the other homeobox genes, from HOXA2 to HOXA13, are methylated on H3K4 in GBM.	('HOXA13', 'Gene', '3209', (50, 56))	('HOXA2', 'Gene', (41, 46))	('methylated', 'Var', (62, 72))	('HOXA2', 'Gene', '3199', (41, 46))	('HOXA13', 'Gene', (50, 56))	('homeobox genes', 'Gene', (20, 34))	('H3K4', 'Protein', (76, 80))
120480	26084803	Patients who undergo gross total resection for high-grade and low-grade brain cancers have a 200% and 160% increase in median survival, respectively, as compared to those who only undergo subtotal resection.	('low-grade', 'Var', (62, 71))	('median survival', 'MPA', (119, 134))	('increase', 'PosReg', (107, 115))	('brain cancers', 'Disease', 'MESH:D001932', (72, 85))	('brain cancers', 'Disease', (72, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('Patients', 'Species', '9606', (0, 8))	('high-grade', 'Var', (47, 57))	('brain cancer', 'Phenotype', 'HP:0030692', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
120481	26084803	Patients who incur surgery-related deficits, however, have a 25% decreased median survival than patients without deficits, regardless of extent of resection.	('median survival', 'MPA', (75, 90))	('deficits', 'Var', (35, 43))	('decreased', 'NegReg', (65, 74))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (96, 104))
120646	33176066	Here, DAA used a corrected P-value (FDR <= 0.05) as the cutoff for significance, as well as log-fold change (logFC) >= 1 (+-5%) or <= -1 (+-5%) for up- or downregulated proteins, respectively.	('<= -1', 'Var', (131, 136))	('DAA', 'Chemical', '-', (6, 9))	('up-', 'PosReg', (148, 151))	('proteins', 'Protein', (169, 177))	('downregulated', 'NegReg', (155, 168))
120694	33176066	Specifically, DAA was applied to the following group comparisons: (a) all pairwise subtype combinations (i.e., luminal vs. Her2, luminal vs. TNBC, and Her2 vs. TNBC); (b) ER+ versus ER-, (c) PgR+ versus PgR-, (d) high Her2 (3+/2+) versus low Her2 (1+/0), (e) high (3+/2+) versus low (1+/0) TIL status, and (f) high-grade tumors (i.e., GR3) versus low-grade tumors (GR2/1).	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('PgR', 'Gene', (191, 194))	('Her2', 'Gene', (151, 155))	('PgR', 'Gene', '5241', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('TNBC', 'Chemical', '-', (141, 145))	('ER', 'Gene', '2099', (182, 184))	('tumors', 'Disease', (357, 363))	('Her2', 'Gene', '2064', (123, 127))	('luminal', 'Chemical', 'MESH:D010634', (129, 136))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('PgR', 'Gene', '5241', (191, 194))	('GR3', 'Gene', (335, 338))	('Her2', 'Gene', (123, 127))	('tumors', 'Disease', 'MESH:D009369', (357, 363))	('Her2', 'Gene', '2064', (242, 246))	('high (3+/2+', 'Var', (259, 270))	('Her2', 'Gene', '2064', (218, 222))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('DAA', 'Chemical', '-', (14, 17))	('GR3', 'Gene', '10507', (335, 338))	('tumors', 'Disease', (321, 327))	('ER', 'Gene', '2099', (171, 173))	('PgR', 'Gene', (203, 206))	('Her2', 'Gene', (218, 222))	('TNBC', 'Chemical', '-', (160, 164))	('Her2', 'Gene', (242, 246))	('luminal', 'Chemical', 'MESH:D010634', (111, 118))	('Her2', 'Gene', '2064', (151, 155))	('tumors', 'Disease', 'MESH:D009369', (321, 327))
120755	33176066	SETD1A has been shown to be involved in the regulation of mitotic gene expression, and the knockdown of this gene leads to cellular senescence [72].	('SETD1A', 'Gene', '9739', (0, 6))	('SETD1A', 'Gene', (0, 6))	('cellular senescence', 'CPA', (123, 142))	('knockdown', 'Var', (91, 100))	('leads to', 'Reg', (114, 122))	('mitotic gene', 'Gene', (58, 70))
120794	33176066	In the case of ARG3, NAT1, and THTPA, there was a good correlation between the level of protein in TIF and all IHC scores, supported by the distinct probability peaks in Fig.	('THTPA', 'Gene', '79178', (31, 36))	('ARG3', 'Var', (15, 19))	('ARG3', 'Chemical', '-', (15, 19))	('THTPA', 'Gene', (31, 36))	('NAT1', 'Gene', (21, 25))	('NAT1', 'Gene', '9', (21, 25))
120805	33176066	The AUCs of the individual proteins ranged from 0.74 to 0.91, with SEC23B and PIPI4K2B having the lowest and highest specificity/sensitivity values, respectively, for classification of Her2 versus TNBC subtypes.	('lowest', 'NegReg', (98, 104))	('PIPI4K2B', 'Var', (78, 86))	('TNBC', 'Chemical', '-', (197, 201))	('SEC23B', 'Gene', (67, 73))	('SEC23B', 'Gene', '10483', (67, 73))	('Her2', 'Gene', (185, 189))	('Her2', 'Gene', '2064', (185, 189))
120831	33176066	Amplification of the 22q arm of chromosome 13, the position of CELSR1, is also frequently observed in DCIS [99].	('Amplification', 'Var', (0, 13))	('DCIS [', 'Disease', (102, 108))	('CELSR1', 'Gene', '9620', (63, 69))	('CELSR1', 'Gene', (63, 69))	('observed', 'Reg', (90, 98))
120832	33176066	In our IHC analysis, CELSR1 positivity was mainly associated with the cytoplasmic compartment, as expected for primary breast carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('breast carcinomas', 'Disease', 'MESH:D001943', (119, 136))	('breast carcinomas', 'Disease', (119, 136))	('positivity', 'Var', (28, 38))	('breast carcinomas', 'Phenotype', 'HP:0003002', (119, 136))	('CELSR1', 'Gene', '9620', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('associated', 'Reg', (50, 60))	('CELSR1', 'Gene', (21, 27))
120833	33176066	Moreover, CELSR1 positivity strongly correlated with less aggressive luminal type tumors.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('positivity', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('aggressive luminal type tumors', 'Disease', (58, 88))	('CELSR1', 'Gene', '9620', (10, 16))	('CELSR1', 'Gene', (10, 16))	('aggressive luminal type tumors', 'Disease', 'MESH:D001523', (58, 88))
120835	33176066	Three proteins, MIEN1, PIP412B, SEC23B, were upregulated in tumor/TIF samples of the Her2-enriched subtype compared to the levels detected in the luminal (MIEN1) and TNBC (MIEN1, PIP412B, and SEC23B) subtypes (Fig.	('TNBC', 'Chemical', '-', (166, 170))	('PIP412B', 'Var', (23, 30))	('upregulated', 'PosReg', (45, 56))	('tumor', 'Disease', (60, 65))	('MIEN1', 'Gene', '84299', (155, 160))	('MIEN1', 'Gene', '84299', (172, 177))	('MIEN1', 'Gene', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('luminal', 'Chemical', 'MESH:D010634', (146, 153))	('MIEN1', 'Gene', (155, 160))	('Her2', 'Gene', '2064', (85, 89))	('Her2', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('SEC23B', 'Gene', (192, 198))	('SEC23B', 'Gene', '10483', (192, 198))	('MIEN1', 'Gene', '84299', (16, 21))	('SEC23B', 'Gene', (32, 38))	('SEC23B', 'Gene', '10483', (32, 38))	('MIEN1', 'Gene', (16, 21))
120843	33176066	Thus, MIEN1 is a component of the breast tumor secretome in Her2-positive patients, and targeting MIEN1 in the bloodstream may represent a promising approach to prevent breast tumor metastasis, especially for Her2-enriched cancers.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MIEN1', 'Gene', (6, 11))	('breast tumor', 'Disease', 'MESH:D001943', (169, 181))	('breast tumor', 'Phenotype', 'HP:0100013', (34, 46))	('breast tumor', 'Phenotype', 'HP:0100013', (169, 181))	('targeting', 'Var', (88, 97))	('breast tumor', 'Disease', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Her2', 'Gene', '2064', (60, 64))	('MIEN1', 'Gene', '84299', (98, 103))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancers', 'Disease', (223, 230))	('MIEN1', 'Gene', (98, 103))	('Her2', 'Gene', (60, 64))	('breast tumor metastasis', 'Disease', 'MESH:D001943', (169, 192))	('patients', 'Species', '9606', (74, 82))	('Her2', 'Gene', '2064', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast tumor metastasis', 'Disease', (169, 192))	('prevent', 'NegReg', (161, 168))	('Her2', 'Gene', (209, 213))	('breast tumor', 'Disease', 'MESH:D001943', (34, 46))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('MIEN1', 'Gene', '84299', (6, 11))
120964	23592309	Voxel-based analysis of 201Tl SPECT for grading and diagnostic accuracy of gliomas: comparison with ROI analysis The aim of this retrospective study was to assess the utility of a voxel-based analysis (VBA) method for 201Tl SPECT in glioma, compared to conventional ROI analysis.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('glioma', 'Disease', 'MESH:D005910', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('201Tl', 'Chemical', 'MESH:C000615114', (218, 223))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('glioma', 'Disease', (75, 81))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('201Tl', 'Var', (218, 223))	('201Tl', 'Chemical', 'MESH:C000615114', (24, 29))	('glioma', 'Disease', (233, 239))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
121033	22568967	This was repeated for two other published signatures and the performance of LDA equations was evaluated on an independent test set, which contained status of IDH1 mutation, EGFR amplification, MGMT methylation and gene VEGF expression, among other clinical and molecular information.	('VEGF', 'Gene', (219, 223))	('MGMT', 'Gene', (193, 197))	('MGMT', 'Gene', '4255', (193, 197))	('VEGF', 'Gene', '7422', (219, 223))	('EGFR', 'Gene', '1956', (173, 177))	('IDH1', 'Gene', (158, 162))	('EGFR', 'Gene', (173, 177))	('mutation', 'Var', (163, 171))	('IDH1', 'Gene', '3417', (158, 162))
121034	22568967	The high survival group predicted by equations based on our local and one of the published signatures contained a significantly higher percentage of cases displaying IDH1 mutation and non-amplification of EGFR.	('IDH1', 'Gene', (166, 170))	('mutation', 'Var', (171, 179))	('IDH1', 'Gene', '3417', (166, 170))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))	('non-amplification', 'Var', (184, 201))
121035	22568967	In contrast, only the equation based on the published signature showed in the poor survival group a significant high percentage of cases displaying a hypothesised methylation of MGMT gene promoter and overexpression of gene VEGF.	('overexpression', 'PosReg', (201, 215))	('MGMT', 'Gene', '4255', (178, 182))	('VEGF', 'Gene', '7422', (224, 228))	('VEGF', 'Gene', (224, 228))	('methylation', 'Var', (163, 174))	('MGMT', 'Gene', (178, 182))
121043	22568967	Moreover, Gb cases showing mutation of a specific locus of IDH1 and non-amplification of EGFR gene have been related to a better prognosis.	('IDH1', 'Gene', '3417', (59, 63))	('EGFR', 'Gene', (89, 93))	('Gb', 'Phenotype', 'HP:0012174', (10, 12))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (59, 63))	('EGFR', 'Gene', '1956', (89, 93))	('non-amplification', 'Var', (68, 85))
121045	22568967	The differential status of IDH1 mutation and EGFR amplification found between groups stratified by our local signature-based equation (LocSBE) and Colman signature-based equation (ColSBE), suggests that the two groups of Gbs identified here may correspond to the classical primary and secondary Gbs.	('EGFR', 'Gene', (45, 49))	('Gb', 'Phenotype', 'HP:0012174', (221, 223))	('Gb', 'Phenotype', 'HP:0012174', (295, 297))	('EGFR', 'Gene', '1956', (45, 49))	('IDH1', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))
121046	22568967	However, only ColSBE provided two groups that displayed a significant survival difference, as well as a differential percentage of cases showing both expected methylation of gene MGMT promoter and overexpression of gene VEGF.	('overexpression', 'PosReg', (197, 211))	('VEGF', 'Gene', '7422', (220, 224))	('methylation', 'Var', (159, 170))	('MGMT', 'Gene', (179, 183))	('VEGF', 'Gene', (220, 224))	('MGMT', 'Gene', '4255', (179, 183))
121057	22568967	Among available data sets containing Gbs, uniquely this one provides a large number of cases (n=73) with survival and KPS data, as well as status of both IDH1 mutation and EGFR amplification.	('EGFR', 'Gene', '1956', (172, 176))	('EGFR', 'Gene', (172, 176))	('Gb', 'Phenotype', 'HP:0012174', (37, 39))	('mutation', 'Var', (159, 167))	('IDH1', 'Gene', (154, 158))	('IDH1', 'Gene', '3417', (154, 158))
121060	22568967	However, we also fitted a Cox's proportional hazards model in Gravendeel's data set for the variables IDH1 and EGFR status, LOH of chromosomes 1p and 19q, age, gender, administration of chemotherapy and radiotherapy, surgery type, and KPS.	('EGFR', 'Gene', '1956', (111, 115))	('IDH1', 'Gene', (102, 106))	('EGFR', 'Gene', (111, 115))	('LOH', 'Var', (124, 127))	('IDH1', 'Gene', '3417', (102, 106))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
121065	22568967	The difference between the percentage of cases showing both IDH1 mutation and non-amplification of EGFR in each Gb subtype was assessed using Pearson's chi2-test and considered significant for a P-value under 0.05.	('EGFR', 'Gene', (99, 103))	('IDH1', 'Gene', (60, 64))	('Gb', 'Phenotype', 'HP:0012174', (112, 114))	('mutation', 'Var', (65, 73))	('IDH1', 'Gene', '3417', (60, 64))	('EGFR', 'Gene', '1956', (99, 103))
121082	22568967	We assigned the class group to cases from Gravendeel's data set using Equations 1, 2, 3 and evaluated in each Gb group the percentage of individuals simultaneously showing IDH1 mutation and non-amplification of EGFR.	('mutation', 'Var', (177, 185))	('IDH1', 'Gene', '3417', (172, 176))	('Gb', 'Phenotype', 'HP:0012174', (110, 112))	('EGFR', 'Gene', '1956', (211, 215))	('showing', 'Reg', (164, 171))	('non-amplification', 'Var', (190, 207))	('EGFR', 'Gene', (211, 215))	('IDH1', 'Gene', (172, 176))
121084	22568967	As previous work reported that secondary Gbs are characterised by a higher accumulation of IDH1 mutation, the use of LocSBE and ColSBE seems to distinguish these two subtypes.	('Gb', 'Phenotype', 'HP:0012174', (41, 43))	('secondary Gbs', 'Disease', (31, 44))	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))	('IDH1', 'Gene', '3417', (91, 95))
121087	22568967	Similarly, the hazard ratio increased almost three times (or 275%) for those patients not displaying IDH1 mutation and almost halved (down to 55.8%) for those ones showing EGFR amplification.	('IDH1', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (172, 176))	('IDH1', 'Gene', '3417', (101, 105))	('EGFR', 'Gene', (172, 176))	('mutation', 'Var', (106, 114))	('patients', 'Species', '9606', (77, 85))
121088	22568967	Patients simultaneously harbouring IDH1 mutation and EGFR non-amplification further reduced the probability of death down to a 25.5%.	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('non-amplification', 'Var', (58, 75))	('IDH1', 'Gene', '3417', (35, 39))	('reduced', 'NegReg', (84, 91))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('death', 'Disease', 'MESH:D003643', (111, 116))	('death', 'Disease', (111, 116))
121089	22568967	In front of this result, we tested whether those patients simultaneously harbouring IDH1 mutation, non-amplification of EGFR and classified as GLE by ColSBE displayed a lower probability of death than the rest of patients.	('non-amplification', 'Var', (99, 116))	('mutation', 'Var', (89, 97))	('IDH1', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (84, 88))	('tested', 'Reg', (28, 34))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (49, 57))	('EGFR', 'Gene', '1956', (120, 124))	('lower', 'NegReg', (169, 174))	('death', 'Disease', 'MESH:D003643', (190, 195))	('death', 'Disease', (190, 195))	('GLE', 'Chemical', '-', (143, 146))	('EGFR', 'Gene', (120, 124))
121114	22568967	The GLE assigned by LocSBE and ColSBE displayed a significant higher percentage of Gbs harbouring both IDH1 mutation and non-amplification of EGFR than GHE.	('IDH1', 'Gene', '3417', (103, 107))	('GHE', 'Chemical', '-', (152, 155))	('Gb', 'Phenotype', 'HP:0012174', (83, 85))	('EGFR', 'Gene', '1956', (142, 146))	('non-amplification', 'Var', (121, 138))	('EGFR', 'Gene', (142, 146))	('GLE', 'Chemical', '-', (4, 7))	('mutation', 'Var', (108, 116))	('IDH1', 'Gene', (103, 107))
121115	22568967	In fact, the percentage of cases showing IDH1 mutation in primary Gbs described by Yan and collaborators (6%) was similar to the percentage of GHE cases detected by ColSBE in Gravendeel's data set, which displayed both IDH1 mutation and non-amplification of EGFR (6.5%).	('EGFR', 'Gene', '1956', (258, 262))	('Gb', 'Phenotype', 'HP:0012174', (66, 68))	('IDH1', 'Gene', '3417', (219, 223))	('EGFR', 'Gene', (258, 262))	('GHE', 'Chemical', '-', (143, 146))	('IDH1', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('IDH1', 'Gene', (219, 223))	('IDH1', 'Gene', '3417', (41, 45))
121116	22568967	This value is also similar to the percentage of primary Gbs showing IDH1 mutation, as described by Lai and collaborators.	('mutation', 'Var', (73, 81))	('Gb', 'Phenotype', 'HP:0012174', (56, 58))	('IDH1', 'Gene', '3417', (68, 72))	('IDH1', 'Gene', (68, 72))
121117	22568967	Moreover, the percentage of cases showing such alteration in GLE cases (44.4%) approached the percentage of proneural cases with IDH1 mutated (30%), as described by.	('mutated', 'Var', (134, 141))	('GLE', 'Chemical', '-', (61, 64))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', (129, 133))
121118	22568967	Considering that only proneural and neural cases showed IDH1 mutation in their work and that GLE based on ColSBE showed a predominant percentage of proneural cases, GLE-classified cases are expected to display a better prognosis than GHE ones.	('GLE', 'Chemical', '-', (93, 96))	('GLE', 'Chemical', '-', (165, 168))	('mutation', 'Var', (61, 69))	('IDH1', 'Gene', '3417', (56, 60))	('GHE', 'Chemical', '-', (234, 237))	('proneural', 'Disease', (148, 157))	('IDH1', 'Gene', (56, 60))
121147	33194684	Concerning surgery, gross total, subtotal, and partial resection are defined by no residual tumor volume, residue <=10 and >=10 cm3 on flair-weighted MRI, respectively.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('<=10', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
121159	33194684	The main biomolecular variables KI67 index, 1p19q codeletion, and IDH mutation were also recovered if available.	('IDH', 'Gene', '3417', (66, 69))	('IDH', 'Gene', (66, 69))	('1p19q', 'Var', (44, 49))
121190	33194684	The IDH status was obtained for 175 (51.6%) patients of which 139 had an IDH mutation.	('patients', 'Species', '9606', (44, 52))	('IDH', 'Gene', '3417', (4, 7))	('mutation', 'Var', (77, 85))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', (4, 7))
121191	33194684	The 1p19q codeletion status was obtained for 182 (53.6%) patients of which 64 had an 1p19q codeleted glioma.	('1p19q', 'Var', (85, 90))	('patients', 'Species', '9606', (57, 65))	('glioma', 'Disease', (101, 107))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
121192	33194684	The estimated Kaplan-Meier OS was 18.6 years (95% CI: 13- not reached) for patients IDH mutated, 16.5 years (95% CI: 15.7- not reached) for patients 1p19q codeleted, 9.3 years (95% CI: 8.3- not reached) for patients with IDH mutation and without 1p19q codeletion and 15.9 years (95% CI: 11- not reached) for patients without IDH mutation nor 1p19q codeletion.	('patients', 'Species', '9606', (207, 215))	('1p19q', 'Var', (149, 154))	('patients', 'Species', '9606', (308, 316))	('patients', 'Species', '9606', (75, 83))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', (221, 224))	('IDH', 'Gene', (325, 328))	('patients', 'Species', '9606', (140, 148))	('IDH', 'Gene', (84, 87))	('IDH', 'Gene', '3417', (221, 224))	('IDH', 'Gene', '3417', (325, 328))
121204	33194684	This result is coherent because KPS alteration is essentially related to either comorbidities or a marked tumoral evolution with functional connectivity infiltration.	('alteration', 'Var', (36, 46))	('tumoral', 'Disease', (106, 113))	('tumoral', 'Disease', 'MESH:D009369', (106, 113))	('related', 'Reg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('KPS', 'Gene', (32, 35))
121207	33194684	Although age is considered as a strong prognostic factor in many studies, we did not find significant difference in OS between three age classes (<34, 35-60 and >60).	('age', 'Gene', (133, 136))	('age', 'Gene', '5973', (9, 12))	('<34', 'Var', (146, 149))	('age', 'Gene', '5973', (133, 136))	('age', 'Gene', (9, 12))
121221	33194684	Nevertheless, several studies show that the association PCV+RT has a significant toxicity.	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('PCV+RT', 'Var', (56, 62))	('toxicity', 'Disease', (81, 89))
121235	32208352	Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations.	('epigenetic', 'MPA', (193, 203))	('mutations', 'Var', (114, 123))	('glioma', 'Disease', (156, 162))	('gliomas', 'Disease', (156, 163))	('IDH1', 'Gene', (26, 30))	('Regulate', 'Reg', (42, 50))	('Glioma', 'Phenotype', 'HP:0009733', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('IDH1', 'Gene', '3417', (10, 14))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('Mutant', 'Var', (19, 25))	('IDH', 'Gene', (109, 112))	('Glioma', 'Disease', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('IDH1', 'Gene', '3417', (26, 30))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('Expression', 'MPA', (62, 72))	('Podoplanin', 'Gene', (51, 61))	('Podoplanin', 'Gene', '10630', (51, 61))	('Glioma', 'Disease', 'MESH:D005910', (76, 82))	('IDH1', 'Gene', (10, 14))
121237	32208352	In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed.	('IDH-mutated', 'Gene', (80, 91))	('IDH-mutated', 'Var', (80, 91))	('podoplanin', 'Gene', '10630', (43, 53))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('podoplanin', 'Gene', (43, 53))	('IDH-wild-type', 'Gene', (96, 109))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('IDH-wild-type', 'Gene', '3417', (96, 109))
121238	32208352	Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells.	('IDH1', 'Gene', (107, 111))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('mutant', 'Var', (100, 106))	('Pdpn', 'Gene', (162, 166))	('promoted', 'PosReg', (41, 49))	('expression', 'MPA', (72, 82))	('Pdpn', 'Gene', (86, 90))	('suppressed', 'NegReg', (151, 161))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (116, 136))	('transcription', 'MPA', (54, 67))	('expression', 'MPA', (167, 177))
121240	32208352	In the last decade, isocitrate dehydrogenase (IDH) mutations have been believed to be the most important genetic alteration in glioma.	('isocitrate', 'Chemical', 'MESH:C034219', (20, 30))	('mutations', 'Var', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('IDH', 'Gene', (46, 49))	('glioma', 'Disease', (127, 133))
121241	32208352	IDH mutations exist in approximately 80% of lower-grade gliomas (LGGs, grade II-III), 85% of secondary glioblastomas (GBMs, grade IV), but only in 5% of primary GBMs.	('IDH', 'Gene', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioblastomas', 'Phenotype', 'HP:0012174', (103, 116))	('mutations', 'Var', (4, 13))	('lower-grade gliomas', 'Disease', (44, 63))	('glioblastomas', 'Disease', 'MESH:D005909', (103, 116))	('glioblastomas', 'Disease', (103, 116))
121242	32208352	The mutation equips IDH1 with a neomorphic enzyme activity, resulting in a reduction of alpha-KG into D-2-hydroxyglutarate (D-2-HG).	('2-HG', 'Chemical', 'MESH:C019417', (126, 130))	('mutation', 'Var', (4, 12))	('alpha-KG', 'Chemical', '-', (88, 96))	('reduction', 'NegReg', (75, 84))	('IDH1', 'Gene', (20, 24))	('D-2-HG', 'Chemical', 'MESH:C019417', (124, 130))
121243	32208352	IDH mutations cause a global hypermethylated phenotype and gene silencing in glioma, including pyruvate carboxylase, F3, and related vascular genes, which contribute to the malignancy progression of gliomas.	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('hypermethylated phenotype', 'MPA', (29, 54))	('glioma', 'Gene', (77, 83))	('malignancy', 'Disease', 'MESH:D009369', (173, 183))	('malignancy', 'Disease', (173, 183))	('mutations', 'Var', (4, 13))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (199, 206))	('gene', 'MPA', (59, 63))	('contribute', 'Reg', (155, 165))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
121246	32208352	In primary GBM, wild-type IDH1 was proved to increase the intracellular levels of alpha-KG, NADPH, and lipid biosynthesis and decrease the ROS level and histone methylation in primary GBM, which contribute to the aggressive clinical courses.	('ROS', 'Chemical', '-', (139, 142))	('NADPH', 'MPA', (92, 97))	('intracellular levels of alpha-KG', 'MPA', (58, 90))	('IDH1', 'Var', (26, 30))	('wild-type', 'Var', (16, 25))	('decrease', 'NegReg', (126, 134))	('lipid biosynthesis', 'MPA', (103, 121))	('histone methylation', 'MPA', (153, 172))	('ROS level', 'MPA', (139, 148))	('increase', 'PosReg', (45, 53))
121251	32208352	In this study, the roles of wild-type and mutant IDH1 in regulating Pdpn expression were extensively investigated, which might be helpful to understand the malignancy of glioma.	('mutant', 'Var', (42, 48))	('malignancy of glioma', 'Phenotype', 'HP:0012174', (156, 176))	('malignancy of glioma', 'Disease', 'MESH:D005910', (156, 176))	('expression', 'MPA', (73, 83))	('malignancy of glioma', 'Disease', (156, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('Pdpn', 'Gene', (68, 72))	('IDH1', 'Gene', (49, 53))
121255	32208352	Idh1LSL-R132Q/+ mice were mated with Gfap-Cre mice to establish Idh1LSL-R132Q/+ Gfap-Cre (Idh1-KI) mice and the corresponding control Idh1+/+ Gfap-Cre (Idh1-WT) mice.	('R132Q', 'SUBSTITUTION', 'None', (72, 77))	('R132Q', 'Var', (8, 13))	('R132Q', 'Var', (72, 77))	('R132Q', 'SUBSTITUTION', 'None', (8, 13))
121266	32208352	The primary antibodies included mouse anti-human IDH1 (R132H) (MAB-0733, MXB Biotech), rabbit anti-human IDH1 (8137, Cell Signaling Technology), and mouse anti-human Pdpn (D2-40, MXB Biotech).	('MXB', 'Gene', (179, 182))	('R132H', 'Var', (55, 60))	('MXB', 'Gene', (73, 76))	('rabbit', 'Species', '9986', (87, 93))	('MXB', 'Gene', '4600', (73, 76))	('R132H', 'Mutation', 'rs121913500', (55, 60))	('human', 'Species', '9606', (160, 165))	('human', 'Species', '9606', (99, 104))	('MXB', 'Gene', '4600', (179, 182))	('human', 'Species', '9606', (43, 48))
121269	32208352	The pGL3-Pdpn promoter constructs were co-transfected with 400 ng of pcDNA3.1-IDH1-WT or pcDNA3.1-IDH1-R132H into 293T cells to investigate the effects of wild-type and mutant IDH1 on Pdpn transcription.	('R132H', 'Var', (103, 108))	('mutant', 'Var', (169, 175))	('R132H', 'SUBSTITUTION', 'None', (103, 108))	('IDH1', 'Gene', (176, 180))
121274	32208352	To express the wild-type and mutant IDH1 in U87 and U251 cells, the wild-type IDH1 and mutant IDH1 (R132H) were subcloned into the pLenti-C-Myc-DDK-IRES-Puro vector (Origene) and pRRLSIN-cPPT-CMV-IRES-Hygro vector (Eureka Biotech, China), respectively, and the lentiviruses were generated and purified as previously described.	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', (36, 40))	('R132H', 'Var', (100, 105))	('mutant', 'Var', (29, 35))	('R132H', 'SUBSTITUTION', 'None', (100, 105))	('mutant', 'Var', (87, 93))
121279	32208352	The primary antibodies used in this study are as follows: mouse anti-human Pdpn (D2-40, MXB Biotech, 1:100), golden Syrian hamster anti-mouse Pdpn (8.1.1, EBioscience, 1:1000), mouse anti-human IDH1 (R132H) (MAB-0733, MXB Biotech, 1:1000), goat anti-human IDH1 (sc-49996, Santa Cruz, 1:1000), mouse anti-human beta-tubulin (KM9003T, Sungene Biotech, 1:1000), and mouse anti-human beta-actin (KM9001, Sungene Biotech, 1:1000).	('Syrian hamster', 'Species', '10036', (116, 130))	('beta-actin', 'Gene', '728378', (380, 390))	('beta-actin', 'Gene', (380, 390))	('R132H', 'Var', (200, 205))	('R132H', 'SUBSTITUTION', 'None', (200, 205))	('goat', 'Species', '9925', (240, 244))
121282	32208352	Consistent with these results, the immunohistochemical staining also showed that Pdpn was greatly reduced in astrocytoma (A), anaplastic astrocytoma (AA), and GBM with mutant IDH (IDH-MU) compared to the same subtypes with wild-type IDH (IDH-WT) (Figure 1B).	('IDH-WT', 'Gene', '3417', (238, 244))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('mutant', 'Var', (168, 174))	('anaplastic astrocytoma', 'Disease', (126, 148))	('AA', 'Phenotype', 'HP:0009592', (150, 152))	('IDH-WT', 'Gene', (238, 244))	('reduced', 'NegReg', (98, 105))	('astrocytoma', 'Disease', (109, 120))	('IDH', 'Gene', (175, 178))	('Pdpn', 'Gene', (81, 85))
121283	32208352	In addition, qPCR and immunoblotting showed that Pdpn expression was notably higher in GBM compared with LGG but was suppressed by IDH mutations in all astrocytic tumors, including A, AA, and GBM (Figure 1, D and E).	('expression', 'MPA', (54, 64))	('astrocytic tumors', 'Disease', (152, 169))	('GBM', 'Disease', (87, 90))	('higher', 'PosReg', (77, 83))	('Pdpn', 'Gene', (49, 53))	('mutations', 'Var', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('astrocytic tumors', 'Disease', 'MESH:D001254', (152, 169))	('suppressed', 'NegReg', (117, 127))	('IDH', 'Gene', (131, 134))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('AA', 'Phenotype', 'HP:0009592', (184, 186))
121286	32208352	To investigate the reduced Pdpn expression in IDH-mutated glioma, the mutant IDH1 (R132H) was overexpressed into U87 and U251 cells with or without overexpressing wild-type IDH1.	('R132H', 'Var', (83, 88))	('mutant', 'Var', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('R132H', 'SUBSTITUTION', 'None', (83, 88))	('IDH1', 'Gene', (77, 81))	('overexpressed', 'PosReg', (94, 107))
121288	32208352	In U251 glioma cells, the wild-type IDH1 overexpression vastly demethylated the CpG islands in the Pdpn promoter, while mutant IDH1 (R132H) expression restored the hypermethylation of the Pdpn promoter (Figure 6B).	('CpG islands', 'MPA', (80, 91))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('restored', 'PosReg', (151, 159))	('IDH1', 'Gene', (127, 131))	('R132H', 'SUBSTITUTION', 'None', (133, 138))	('R132H', 'Var', (133, 138))	('hypermethylation', 'MPA', (164, 180))	('mutant', 'Var', (120, 126))	('demethylated', 'NegReg', (63, 75))
121289	32208352	Therefore, we demonstrated that the alpha-KG levels in IDH-mutated glioma were lower than those in IDH-wild-type glioma (Figure 6C), and the knockin of mutant IDH1 (R132H) consistently reduced the intracellular alpha-KG levels in the mice primary glia cell (Figure 6D).	('IDH-mutated', 'Var', (55, 66))	('R132H', 'SUBSTITUTION', 'None', (165, 170))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH1', 'Gene', (159, 163))	('lower', 'NegReg', (79, 84))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('intracellular alpha-KG levels', 'MPA', (197, 226))	('alpha-KG levels', 'MPA', (36, 51))	('R132H', 'Var', (165, 170))	('reduced', 'NegReg', (185, 192))
121297	32208352	Comparing with IDH wild-type glioma, the expressions of PD-L1, transgelin-2 (TAGLN2), and branched-chain amino acid transaminase 1 (BACT1) were also significantly reduced in IDH mutated glioma, which were primarily due to the promoters hypermethylation.	('glioma', 'Disease', (186, 192))	('IDH mutated', 'Var', (174, 185))	('branched-chain amino acid transaminase 1', 'Gene', '586', (90, 130))	('PD-L1', 'Gene', '29126', (56, 61))	('branched-chain amino acid transaminase 1', 'Gene', (90, 130))	('BACT1', 'Gene', '586', (132, 137))	('reduced', 'NegReg', (163, 170))	('expressions', 'MPA', (41, 52))	('BACT1', 'Gene', (132, 137))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('transgelin-2', 'Gene', (63, 75))	('TAGLN2', 'Gene', '8407', (77, 83))	('transgelin-2', 'Gene', '8407', (63, 75))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('TAGLN2', 'Gene', (77, 83))	('PD-L1', 'Gene', (56, 61))
121338	28618012	The stable isotopes most widely utilized in brain cancer studies include 13C-glucose, 13C-glutamine, and 13C-acetate.	('brain cancer', 'Phenotype', 'HP:0030692', (44, 56))	('13C-acetate', 'Chemical', '-', (105, 116))	('13C-glutamine', 'Chemical', '-', (86, 99))	('brain cancer', 'Disease', (44, 56))	('13C-glutamine', 'Var', (86, 99))	('13C-acetate', 'Var', (105, 116))	('13C-glucose', 'Var', (73, 84))	('13C-glucose', 'Chemical', '-', (73, 84))	('brain cancer', 'Disease', 'MESH:D001932', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
121364	28618012	For example, the 5-carbon compound glutamate can be present in 6 different isomers (m, m+1, m+2, m+3, m+4, m+5) with 32 different positional isotopomers.	('glutamate', 'Protein', (35, 44))	('m+3', 'Var', (97, 100))	('glutamate', 'Chemical', 'MESH:D018698', (35, 44))	('m+4', 'Var', (102, 105))	('m+2', 'Var', (92, 95))	('carbon', 'Chemical', 'MESH:D002244', (19, 25))
121394	28618012	D-2-hydroxyglutaric acid (D-2-HG) is an important oncometabolite and well-recognized diagnostic marker of IDH mutations in several cancers including low grade gliomas.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('IDH', 'Gene', '3417', (106, 109))	('mutations', 'Var', (110, 119))	('gliomas', 'Disease', (159, 166))	('cancers', 'Disease', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('D-2-hydroxyglutaric acid', 'Chemical', '-', (0, 24))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('IDH', 'Gene', (106, 109))
121404	28618012	used ristocetin A glycopeptide antibiotic silica gel bonded chiral column combined with mass spectrometry in MRM mode to detect D-2HG and L-2HG.	('ristocetin A', 'Chemical', 'MESH:C016719', (5, 17))	('2H', 'Chemical', 'MESH:D003903', (130, 132))	('silica gel', 'Chemical', 'MESH:D058428', (42, 52))	('2H', 'Chemical', 'MESH:D003903', (140, 142))	('glycopeptide', 'Chemical', 'MESH:D006020', (18, 30))	('L-2HG', 'Var', (138, 143))	('D-2HG', 'Var', (128, 133))
121422	28618012	Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) have been identified in LGGs and in secondary glioblastoma, and result in a NADPH-dependent reduction of alpha-ketoglutarate to D-2-HG.	('NADPH', 'Chemical', 'MESH:D009249', (144, 149))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (173, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('IDH1', 'Gene', '3417', (62, 66))	('Mutations', 'Var', (0, 9))	('LGGs', 'Disease', (92, 96))	('alpha-ketoglutarate to D-2-HG', 'MPA', (173, 202))	('glioblastoma', 'Disease', (114, 126))	('isocitrate dehydrogenase', 'Gene', (34, 58))	('IDH1', 'Gene', (62, 66))	('isocitrate dehydrogenase', 'Gene', '3417', (34, 58))
121423	28618012	IDH mutations associated with an elevated level of D-2-HG contribute to tumour formation and malignant progression in gliomas, however, a high level of D-2-HG is also a predictor of longer survival and good response to temozolomide (TMZ) in LGGs.	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('TMZ', 'Chemical', 'MESH:D000077204', (233, 236))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('IDH', 'Gene', '3417', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('longer', 'PosReg', (182, 188))	('temozolomide', 'Chemical', 'MESH:D000077204', (219, 231))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('mutations', 'Var', (4, 13))	('D-2-HG', 'Var', (152, 158))	('tumour', 'Disease', (72, 78))	('high', 'Var', (138, 142))	('malignant progression', 'CPA', (93, 114))
121426	28618012	Kallenberg and colleagues reported that MI level was significantly higher in patients with GBM compared to patients with LGGs and control subjects.	('higher', 'PosReg', (67, 73))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (107, 115))	('GBM', 'Var', (91, 94))	('MI level', 'MPA', (40, 48))
121432	28618012	Recently, Moren and colleagues performed metabolic profiling on tumour tissue and serum samples from glioma patients and were able to identify a metabolic signature of GBM compared to oligodendrogliomas (, Table 1).	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('GBM', 'Var', (168, 171))	('glioma', 'Disease', (101, 107))	('metabolic', 'MPA', (145, 154))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('glioma', 'Disease', (195, 201))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (184, 202))	('patients', 'Species', '9606', (108, 116))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('glioma', 'Disease', 'MESH:D005910', (195, 201))	('oligodendrogliomas', 'Disease', (184, 202))
121443	28618012	Gln metabolizes to alpha-ketoglutarate and provides energy through substrate level phosphorylation in the tricarboxylic acid (TCA) cycle, thereby acting as metabolic fuel.	('substrate level phosphorylation', 'MPA', (67, 98))	('rat', 'Species', '10116', (72, 75))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (106, 124))	('TCA', 'Chemical', 'MESH:D014233', (126, 129))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (19, 38))	('energy', 'MPA', (52, 58))	('Gln', 'Var', (0, 3))	('rat', 'Species', '10116', (34, 37))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))
121574	27820599	Tissue mechanics promote IDH1-dependent HIF1alpha-tenascin C feedback to regulate glioblastoma aggression Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1).	('isocitrate dehydrogenase 1', 'Gene', (228, 254))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('isocitrate dehydrogenase 1', 'Gene', '3417', (228, 254))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('IDH1', 'Gene', (256, 260))	('tenascin C', 'Gene', '3371', (50, 60))	('IDH1', 'Gene', '3417', (25, 29))	('overall', 'MPA', (116, 123))	('glioma brain tumours', 'Disease', (151, 171))	('mutations', 'Var', (191, 200))	('Increased', 'PosReg', (106, 115))	('tenascin C', 'Gene', (50, 60))	('IDH1', 'Gene', '3417', (256, 260))	('brain tumours', 'Phenotype', 'HP:0030692', (158, 171))	('glioblastoma aggression', 'Disease', (82, 105))	('HIF1alpha', 'Gene', '3091', (40, 49))	('aggression', 'Phenotype', 'HP:0000718', (95, 105))	('glioma brain tumours', 'Disease', 'MESH:C564230', (151, 171))	('patients', 'Species', '9606', (137, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('HIF1alpha', 'Gene', (40, 49))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('brain tumour', 'Phenotype', 'HP:0030692', (158, 170))	('IDH1', 'Gene', (25, 29))	('glioblastoma aggression', 'Disease', 'MESH:D005909', (82, 105))
121577	27820599	Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1alpha-dependent TNC expression to decrease ECM stiffness and mechanosignalling.	('HIF1alpha-dependent TNC expression', 'MPA', (123, 157))	('glioma aggression', 'Disease', (93, 110))	('glioma aggression', 'Disease', 'MESH:D005910', (93, 110))	('IDH1', 'Gene', (78, 82))	('decrease', 'NegReg', (161, 169))	('mechanosignalling', 'CPA', (188, 205))	('restricts', 'NegReg', (83, 92))	('mutant', 'Var', (71, 77))	('ECM', 'MPA', (170, 173))	('reducing', 'NegReg', (114, 122))	('aggression', 'Phenotype', 'HP:0000718', (100, 110))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
121583	27820599	Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) characterize the majority of LGGs and a small percentage of GBMs, and define subtypes that associate with better responses to radiation treatment and an improved prognosis compared with gliomas with wild-type (WT) IDH.	('IDH', 'Gene', (279, 282))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('LGGs', 'Disease', (94, 98))	('IDH', 'Gene', '3417', (279, 282))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (60, 63))	('gliomas', 'Disease', 'MESH:D005910', (251, 258))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('gliomas', 'Disease', (251, 258))	('IDH', 'Gene', '3417', (60, 63))	('better', 'PosReg', (171, 177))
121584	27820599	Oncogenic IDH mutations divert metabolic flux resulting in high levels of (R)-2-hydroxyglutarate, an onco-metabolite implicated in hypoxia-inducible factor 1 alpha (HIF1alpha) stability, epigenetic modifications and extracellular matrix (ECM) remodelling.	('divert', 'Reg', (24, 30))	('IDH', 'Gene', (10, 13))	('metabolic flux', 'MPA', (31, 45))	('hypoxia-inducible factor 1 alpha', 'Gene', (131, 163))	('IDH', 'Gene', '3417', (10, 13))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (74, 96))	('mutations', 'Var', (14, 23))	('hypoxia-inducible factor 1 alpha', 'Gene', '3091', (131, 163))
121593	27820599	Mutations in IDH genes characterize the majority of LGGs and a small percentage of GBMs.	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', '3417', (13, 16))	('Mutations', 'Var', (0, 9))	('LGGs', 'Disease', (52, 56))
121595	27820599	To this end, the R132H IDH1 GBM samples exhibited mechanical characteristics more concordant with the LGG samples (Fig.1d,e).	('R132H', 'Mutation', 'rs121913500', (17, 22))	('R132H', 'Var', (17, 22))	('IDH1', 'Gene', (23, 27))
121596	27820599	R132H IDH1 GBM samples also had lower pFAK and pMLC2 levels, reflecting reduced mechanosignalling (Fig.	('reduced', 'NegReg', (72, 79))	('R132H', 'Mutation', 'rs121913500', (0, 5))	('FAK', 'Gene', '5747', (39, 42))	('FAK', 'Gene', (39, 42))	('MLC2', 'Gene', (48, 52))	('mechanosignalling', 'MPA', (80, 97))	('IDH1', 'Gene', (6, 10))	('MLC2', 'Gene', '4633', (48, 52))	('R132H', 'Var', (0, 5))	('lower', 'NegReg', (32, 37))
121597	27820599	These data demonstrate that ECM stiffness correlates with glioma aggression and that IDH1 mutational status associates with a softer ECM, regardless of histological grade.	('glioma aggression', 'Disease', (58, 75))	('glioma aggression', 'Disease', 'MESH:D005910', (58, 75))	('mutational status', 'Var', (90, 107))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1', 'Gene', (85, 89))	('softer ECM', 'MPA', (126, 136))	('aggression', 'Phenotype', 'HP:0000718', (65, 75))
121600	27820599	Indeed, a survey of the ECM status of the softer ECMs in the IDH1-mutant human GBM biopsies revealed a reduction in the levels of TNC (Fig.	('IDH1-mutant', 'Var', (61, 72))	('human', 'Species', '9606', (73, 78))	('IDH1-mutant', 'Gene', (61, 72))	('levels', 'MPA', (120, 126))	('reduction', 'NegReg', (103, 112))
121601	27820599	Further, bioinformatics analysis of publicly available messenger RNA expression data revealed a significant correlation between IDH1 mutational status and TNC expression in LGG tumours, with stratification of LGG patients by TNC upregulation revealing reduced patient survival (Fig.	('patient', 'Species', '9606', (260, 267))	('patient survival', 'CPA', (260, 276))	('LGG tumours', 'Disease', 'MESH:D009369', (173, 184))	('patient', 'Species', '9606', (213, 220))	('upregulation', 'PosReg', (229, 241))	('TNC', 'Gene', (155, 158))	('LGG tumours', 'Disease', (173, 184))	('reduced', 'NegReg', (252, 259))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (213, 221))	('mutational', 'Var', (133, 143))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('IDH1', 'Gene', (128, 132))
121602	27820599	Similarly, IDH1 mutational status correlated significantly with TNC mRNA expression in GBM tumours (Fig.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('mutational', 'Var', (16, 26))	('GBM tumours', 'Disease', 'MESH:D005910', (87, 98))	('TNC mRNA expression', 'MPA', (64, 83))	('GBM tumours', 'Disease', (87, 98))	('correlated', 'Reg', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('IDH1', 'Gene', (11, 15))
121604	27820599	Consistent with a relationship between IDH1 mutational status, ECM stiffness and glioma aggression, ectopic expression of the R132H IDH1 mutation significantly improved the survival of nude mice bearing xenografts derived from either primary GBM cells or the U87 cell line (Fig.	('aggression', 'Phenotype', 'HP:0000718', (88, 98))	('IDH1', 'Gene', (132, 136))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma aggression', 'Disease', 'MESH:D005910', (81, 98))	('R132H', 'Mutation', 'rs121913500', (126, 131))	('nude mice', 'Species', '10090', (185, 194))	('improved', 'PosReg', (160, 168))	('R132H', 'Var', (126, 131))	('U87', 'CellLine', 'CVCL:0022', (259, 262))	('survival', 'CPA', (173, 181))	('glioma aggression', 'Disease', (81, 98))
121606	27820599	In both the primary and U87 xenograft models, we noted that the softer IDH1-mutant-expressing GBM tumours had low to negligible TNC expression (Fig.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('GBM tumours', 'Disease', 'MESH:D005910', (94, 105))	('TNC expression', 'MPA', (128, 142))	('U87', 'CellLine', 'CVCL:0022', (24, 27))	('IDH1-mutant-expressing', 'Var', (71, 93))	('GBM tumours', 'Disease', (94, 105))	('IDH1-mutant-expressing', 'Gene', (71, 93))
121607	27820599	To experimentally test the role of TNC in ECM stiffness and glioma aggression, we knocked down TNC in primary GBM cells (WT IDH1, Supplementary Fig.	('aggression', 'Phenotype', 'HP:0000718', (67, 77))	('knocked', 'Var', (82, 89))	('glioma aggression', 'Disease', 'MESH:D005910', (60, 77))	('glioma aggression', 'Disease', (60, 77))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('TNC', 'Gene', (95, 98))
121611	27820599	These findings demonstrate that TNC can impact glioma aggression by increasing ECM stiffness and suggest a molecular role for IDH1 mutational status in perturbing this relationship.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('ECM stiffness', 'MPA', (79, 92))	('aggression', 'Phenotype', 'HP:0000718', (54, 64))	('mutational', 'Var', (131, 141))	('impact', 'Reg', (40, 46))	('increasing', 'PosReg', (68, 78))	('IDH1', 'Gene', (126, 130))	('glioma aggression', 'Disease', (47, 64))	('glioma aggression', 'Disease', 'MESH:D005910', (47, 64))	('TNC', 'Var', (32, 35))
121614	27820599	A bioinformatics analysis revealed a strong correlation between TNC mRNA upregulation and expression of hypoxia-induced genes in both WT and R132H IDH1 patient GBMs (Fig.	('TNC', 'Gene', (64, 67))	('R132H', 'Var', (141, 146))	('R132H', 'Mutation', 'rs121913500', (141, 146))	('expression', 'MPA', (90, 100))	('hypoxia', 'Disease', (104, 111))	('IDH1', 'Gene', (147, 151))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('patient', 'Species', '9606', (152, 159))	('upregulation', 'PosReg', (73, 85))
121615	27820599	3a), and expression of carbonic anhydrase 9 (CA9), a HIF1alpha-target gene, was reduced in R132H tumours (Fig.	('tumours', 'Disease', (97, 104))	('CA9', 'Gene', (45, 48))	('reduced', 'NegReg', (80, 87))	('carbonic anhydrase 9', 'Gene', (23, 43))	('CA9', 'Gene', '768', (45, 48))	('carbonic anhydrase 9', 'Gene', '768', (23, 43))	('expression', 'MPA', (9, 19))	('R132H', 'Var', (91, 96))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('R132H', 'Mutation', 'rs121913500', (91, 96))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
121618	27820599	shRNA-mediated knockdown of HIF1alpha reduced hypoxia-dependent induction of TNC (SupplementaryFig.3c-f).	('hypoxia', 'Disease', (46, 53))	('hypoxia', 'Disease', 'MESH:D000860', (46, 53))	('knockdown', 'Var', (15, 24))	('reduced', 'NegReg', (38, 45))	('HIF1alpha', 'Gene', (28, 37))	('TNC', 'MPA', (77, 80))
121623	27820599	The presence of the IDH1 mutation could enhance GBM patient survival by increasing the production of the onco-metabolite (R)-2-hydroxyglutarate, which can induce genome-wide methylation alterations and alter cellular redox state to promote cellular transformation.	('promote', 'PosReg', (232, 239))	('methylation alterations', 'MPA', (174, 197))	('mutation', 'Var', (25, 33))	('cellular redox state', 'MPA', (208, 228))	('production of', 'MPA', (87, 100))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (121, 143))	('presence', 'Var', (4, 12))	('induce', 'Reg', (155, 161))	('alter', 'Reg', (202, 207))	('patient', 'Species', '9606', (52, 59))	('enhance', 'PosReg', (40, 47))	('increasing', 'PosReg', (72, 82))	('IDH1', 'Gene', (20, 24))	('cellular transformation', 'CPA', (240, 263))
121625	27820599	Analysis of WT and R132H IDH1 GBM xenografts revealed that R132H IDH1 tumours had low to barely detectable nuclear HIF1alpha (and TNC) despite evident necrosis (asterisks) and hypoxia (Fig.	('R132H', 'Mutation', 'rs121913500', (59, 64))	('IDH1 tumours', 'Disease', 'MESH:D009369', (65, 77))	('hypoxia', 'Disease', (176, 183))	('hypoxia', 'Disease', 'MESH:D000860', (176, 183))	('IDH1 tumours', 'Disease', (65, 77))	('necrosis', 'Disease', 'MESH:D009336', (151, 159))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('low', 'NegReg', (82, 85))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('HIF1alpha', 'Protein', (115, 124))	('necrosis', 'Disease', (151, 159))	('R132H', 'Var', (59, 64))
121626	27820599	4b) suggesting a profound dysregulation of the hypoxic response in xenograft tumours expressing the R132H IDH1 mutation.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('hypoxic response', 'MPA', (47, 63))	('xenograft tumours', 'Disease', (67, 84))	('R132H', 'Var', (100, 105))	('xenograft tumours', 'Disease', 'MESH:D009369', (67, 84))	('R132H', 'Mutation', 'rs121913500', (100, 105))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
121627	27820599	Experimentally, we observed a lack of upregulation of either HIF1alpha or TNC in R132H IDH1 GBM cells cultured in vitro under hypoxia, a finding that was recapitulated with experimental models endogenously expressing R132H IDH1 (Fig.	('R132H', 'Mutation', 'rs121913500', (217, 222))	('HIF1alpha', 'Protein', (61, 70))	('hypoxia', 'Disease', (126, 133))	('hypoxia', 'Disease', 'MESH:D000860', (126, 133))	('upregulation', 'PosReg', (38, 50))	('R132H', 'Var', (81, 86))	('TNC', 'Gene', (74, 77))	('R132H', 'Mutation', 'rs121913500', (81, 86))
121629	27820599	Importantly, survival was decreased in mice bearing orthotopic R132H IDH1 GBM tumours expressing the constitutively active HIF1alpha (CA-HIF) compared with vector-only tumours (Fig.	('R132H', 'Var', (63, 68))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('survival', 'CPA', (13, 21))	('IDH1 GBM tumours', 'Disease', (69, 85))	('R132H', 'Mutation', 'rs121913500', (63, 68))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('vector-only tumours', 'Disease', 'MESH:D000079426', (156, 175))	('decreased', 'NegReg', (26, 35))	('IDH1 GBM tumours', 'Disease', 'MESH:D005910', (69, 85))	('vector-only tumours', 'Disease', (156, 175))	('mice', 'Species', '10090', (39, 43))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
121631	27820599	These data suggest that the R132H IDH1 mutation blunts hypoxia sensing to reduce HIF1alpha-dependent TNC expression, and provide a potential explanation for why patients bearing tumours with mutations in IDH experience improved survival.	('bearing tumours', 'Disease', (170, 185))	('blunts hypoxia', 'Disease', 'MESH:D000860', (48, 62))	('survival', 'CPA', (228, 236))	('R132H', 'Var', (28, 33))	('improved', 'PosReg', (219, 227))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('reduce', 'NegReg', (74, 80))	('R132H', 'Mutation', 'rs121913500', (28, 33))	('mutations', 'Var', (191, 200))	('IDH', 'Gene', (204, 207))	('patients', 'Species', '9606', (161, 169))	('blunts hypoxia', 'Disease', (48, 62))	('bearing tumours', 'Disease', 'MESH:C565129', (170, 185))	('IDH', 'Gene', '3417', (204, 207))	('HIF1alpha-dependent TNC expression', 'MPA', (81, 115))
121632	27820599	While IDH mutations may confer prolonged survival in glioma patients suffering from gliomas, IDH-mutation-bearing gliomas still frequently recur despite surgical resection and treatment.	('gliomas', 'Disease', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('gliomas', 'Disease', (114, 121))	('glioma', 'Disease', (114, 120))	('patients', 'Species', '9606', (60, 68))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('IDH', 'Gene', (6, 9))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('IDH', 'Gene', (93, 96))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', (84, 90))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('IDH', 'Gene', '3417', (6, 9))	('IDH', 'Gene', '3417', (93, 96))	('mutations', 'Var', (10, 19))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
121637	27820599	Indeed, mechanical analysis of patient-matched IDH1-mutant GBM pairs, at initial diagnosis (primary tumour) and at recurrence (secondary tumour excised after treatment with gamma radiation and temozolomide chemotherapy), revealed a remarkable increase in the stiffness of the associated ECMs in the secondary IDH1-mutant GBMs (Fig.	('primary tumour', 'Disease', (92, 106))	('IDH1-mutant', 'Var', (47, 58))	('primary tumour', 'Disease', 'MESH:D009369', (92, 106))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', (137, 143))	('stiffness', 'MPA', (259, 268))	('patient', 'Species', '9606', (31, 38))	('increase', 'PosReg', (243, 251))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('temozolomide', 'Chemical', 'MESH:D000077204', (193, 205))	('tumour', 'Disease', (100, 106))	('IDH1-mutant', 'Gene', (309, 320))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
121639	27820599	As such, we explored whether we could increase the aggression of R132H IDH1 GBM cells by enhancing mechanosignalling through plating the cells on a stiff substrate.	('aggression', 'Disease', 'MESH:D001523', (51, 61))	('increase', 'PosReg', (38, 46))	('R132H', 'Mutation', 'rs121913500', (65, 70))	('enhancing', 'PosReg', (89, 98))	('aggression', 'Disease', (51, 61))	('mechanosignalling', 'MPA', (99, 116))	('IDH1', 'Gene', (71, 75))	('aggression', 'Phenotype', 'HP:0000718', (51, 61))	('R132H', 'Var', (65, 70))
121641	27820599	We compared their characteristic cell spreading behaviour and found that R132H IDH1 cells spread better on stiff substrates (Fig.	('R132H', 'Var', (73, 78))	('spread', 'CPA', (90, 96))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('better', 'PosReg', (97, 103))	('IDH1', 'Gene', (79, 83))
121642	27820599	When R132H IDH1 cells were subjected to hypoxia, they showed a robust upregulation of HIF1A, TNC and Glut1 expression (Fig.	('hypoxia', 'Disease', (40, 47))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('upregulation', 'PosReg', (70, 82))	('Glut1', 'Gene', (101, 106))	('expression', 'MPA', (107, 117))	('R132H', 'Var', (5, 10))	('HIF1A', 'Gene', (86, 91))	('HIF1A', 'Gene', '3091', (86, 91))	('TNC', 'Gene', (93, 96))	('Glut1', 'Gene', '6513', (101, 106))	('R132H', 'Mutation', 'rs121913500', (5, 10))
121644	27820599	These findings indicate that a stiffened ECM overrides the blunted hypoxia sensing conferred by expression of the mutant R132H IDH1.	('mutant R132H', 'Var', (114, 126))	('hypoxia', 'Disease', (67, 74))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('R132H', 'Var', (121, 126))	('R132H', 'Mutation', 'rs121913500', (121, 126))	('overrides', 'PosReg', (45, 54))
121645	27820599	To directly assess whether enhancing mechanosignalling could override the blunted hypoxia sensing conferred by the R132H IDH1 gene, we ectopically expressed an auto-clustering beta1 integrin mutant (V737N) in the R132H IDH1 cells to recapitulate downstream stiffness-dependent mechanosignalling through elevation of FAK signalling.	('beta1 integrin', 'Gene', '3688', (176, 190))	('V737N', 'Var', (199, 204))	('R132H', 'Mutation', 'rs121913500', (213, 218))	('beta1 integrin', 'Gene', (176, 190))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('R132H', 'Mutation', 'rs121913500', (115, 120))	('V737N', 'Mutation', 'p.V737N', (199, 204))	('FAK', 'Gene', (316, 319))	('FAK', 'Gene', '5747', (316, 319))	('elevation', 'PosReg', (303, 312))
121646	27820599	We found that R132H IDH1 GBM cells expressing the auto-clustering V737N mutated beta1 integrin spread similarly on the soft and stiff substrates (Fig.	('beta1 integrin', 'Gene', '3688', (80, 94))	('R132H', 'Mutation', 'rs121913500', (14, 19))	('beta1 integrin', 'Gene', (80, 94))	('V737N', 'Mutation', 'p.V737N', (66, 71))	('V737N mutated', 'Var', (66, 79))
121647	27820599	Consistent with cell spreading, V737N R132H IDH1 GBM cells responded to hypoxia largely independently of the underlying substrate stiffness with robust increases in HIF1alpha, TNC and Glut1 expression levels on both soft and stiff substrates (Fig.	('V737N R132H', 'Var', (32, 43))	('V737N', 'Mutation', 'p.V737N', (32, 37))	('Glut1', 'Gene', (184, 189))	('increases', 'PosReg', (152, 161))	('R132H', 'Mutation', 'rs121913500', (38, 43))	('IDH1', 'Gene', (44, 48))	('TNC', 'MPA', (176, 179))	('HIF1alpha', 'Protein', (165, 174))	('expression levels', 'MPA', (190, 207))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('Glut1', 'Gene', '6513', (184, 189))
121648	27820599	These data indicate that ECM stiffness can induce HIF1alpha and suggest that the relationship between IDH1 mutation and hypoxia sensing through HIF1alpha may be largely dependent on the stiffness of the ECM micro environment of the tissue.	('HIF1alpha', 'Gene', (144, 153))	('HIF1alpha', 'MPA', (50, 59))	('hypoxia', 'Disease', (120, 127))	('IDH1', 'Gene', (102, 106))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('induce', 'Reg', (43, 49))	('mutation', 'Var', (107, 115))
121649	27820599	We performed xenograft injections of R132H IDH1 cells expressing either WT or V737N beta1 integrin to test whether enhancing cellular mechanosignalling in mutant GBMs would increase tumour aggression and, if so, whether this increase would be associated with elevated HIF1alpha and TNC expression.	('cellular mechanosignalling', 'CPA', (125, 151))	('beta1 integrin', 'Gene', '3688', (84, 98))	('elevated', 'PosReg', (259, 267))	('tumour aggression', 'Disease', 'MESH:D001523', (182, 199))	('V737N', 'Mutation', 'p.V737N', (78, 83))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour aggression', 'Disease', (182, 199))	('mutant', 'Var', (155, 161))	('TNC expression', 'Protein', (282, 296))	('increase', 'PosReg', (173, 181))	('enhancing', 'PosReg', (115, 124))	('beta1 integrin', 'Gene', (84, 98))	('aggression', 'Phenotype', 'HP:0000718', (189, 199))	('R132H', 'Mutation', 'rs121913500', (37, 42))	('HIF1alpha', 'Protein', (268, 277))	('V737N', 'Var', (78, 83))
121650	27820599	Survival was decreased in mice bearing the V737N beta1 tumours compared with WT beta1 tumours (Fig.	('beta1', 'Gene', (49, 54))	('beta1', 'Gene', (80, 85))	('V737N', 'Mutation', 'p.V737N', (43, 48))	('WT beta1 tumours', 'Disease', 'MESH:C536751', (77, 93))	('WT beta1 tumours', 'Disease', (77, 93))	('beta1', 'Gene', '15129', (49, 54))	('tumours', 'Disease', (86, 93))	('tumours', 'Disease', (55, 62))	('beta1', 'Gene', '15129', (80, 85))	('Survival', 'CPA', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', 'MESH:D009369', (55, 62))	('mice', 'Species', '10090', (26, 30))	('decreased', 'NegReg', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('V737N', 'Var', (43, 48))
121651	27820599	Tumours derived from R132H IDH1 GBM cells expressing the V737N integrin demonstrated increased mechanosignalling (Fig.	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('R132H', 'Mutation', 'rs121913500', (21, 26))	('mechanosignalling', 'CPA', (95, 112))	('V737N', 'Mutation', 'p.V737N', (57, 62))	('increased', 'PosReg', (85, 94))	('V737N', 'Var', (57, 62))
121652	27820599	In contrast, R132H IDH1 GBM tumours expressing WT beta1 integrin had low to negligible HIF1alpha and TNC protein expression, despite pronounced hypoxia (Fig.	('R132H', 'Var', (13, 18))	('expression', 'MPA', (113, 123))	('R132H', 'Mutation', 'rs121913500', (13, 18))	('IDH1 GBM tumours', 'Disease', 'MESH:D005910', (19, 35))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('beta1 integrin', 'Gene', '3688', (50, 64))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('hypoxia', 'Disease', (144, 151))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('IDH1 GBM tumours', 'Disease', (19, 35))	('low', 'NegReg', (69, 72))	('TNC protein', 'Protein', (101, 112))	('HIF1alpha', 'Protein', (87, 96))	('beta1 integrin', 'Gene', (50, 64))
121653	27820599	Interestingly, V737N tumours were substantially stiffer than control tumours (Fig.	('tumours', 'Disease', (69, 76))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('V737N', 'Var', (15, 20))	('tumours', 'Disease', (21, 28))	('V737N', 'SUBSTITUTION', 'None', (15, 20))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
121654	27820599	These findings further link GBM aggression to tissue mechanics, and suggest that elevated mechanosignalling can bypass the protective activity imparted by the R132H IDH1 to promote tumour aggression.	('GBM aggression', 'Disease', (28, 42))	('protective activity', 'MPA', (123, 142))	('tumour aggression', 'Disease', 'MESH:D001523', (181, 198))	('aggression', 'Phenotype', 'HP:0000718', (32, 42))	('bypass', 'NegReg', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('R132H', 'Var', (159, 164))	('tumour aggression', 'Disease', (181, 198))	('aggression', 'Phenotype', 'HP:0000718', (188, 198))	('elevated', 'PosReg', (81, 89))	('GBM aggression', 'Disease', 'MESH:D005910', (28, 42))	('mechanosignalling', 'MPA', (90, 107))	('R132H', 'Mutation', 'rs121913500', (159, 164))	('IDH1', 'Gene', (165, 169))	('promote', 'PosReg', (173, 180))
121657	27820599	Consistent with the hypothesis that tissue mechanics may induce HIF1alpha and TNC in GBMs expressing the mutant IDH1 by reducing levels of miR-203, reporter assays using the wild-type and mutated 3'UTR consensus sites confirmed that miR-203 interacts with and inhibits HIF1alpha transcription at three out of three predicted sites and TNC at one of two predicted sites (Fig.	('inhibits', 'NegReg', (260, 268))	('reducing', 'NegReg', (120, 128))	('miR-203', 'Gene', '406986', (139, 146))	('IDH1', 'Gene', (112, 116))	('miR-203', 'Gene', (139, 146))	('HIF1alpha', 'Gene', (269, 278))	('transcription', 'MPA', (279, 292))	('induce', 'PosReg', (57, 63))	('levels', 'MPA', (129, 135))	('miR-203', 'Gene', '406986', (233, 240))	('miR-203', 'Gene', (233, 240))	('TNC', 'MPA', (335, 338))	('mutant', 'Var', (105, 111))	('interacts', 'Interaction', (241, 250))
121658	27820599	Experimentally, we tested whether antagomiR-mediated knockdown of miR-203 could elevate HIF1alpha and TNC levels in R132H IDH1 GBM cells grown in culture (on a soft ECM where miR-203 levels are elevated) and in vivo (Supplementary Fig.	('HIF1alpha', 'Protein', (88, 97))	('R132H', 'Mutation', 'rs121913500', (116, 121))	('miR', 'Gene', (40, 43))	('knockdown', 'Var', (53, 62))	('miR', 'Gene', '29116', (40, 43))	('miR', 'Gene', (66, 69))	('miR', 'Gene', (175, 178))	('TNC levels', 'MPA', (102, 112))	('miR', 'Gene', '29116', (175, 178))	('miR-203', 'Gene', '406986', (175, 182))	('miR-203', 'Gene', (66, 73))	('miR-203', 'Gene', (175, 182))	('elevate', 'PosReg', (80, 87))	('miR', 'Gene', '29116', (66, 69))	('miR-203', 'Gene', '406986', (66, 73))
121659	27820599	Consistent with a mechanistic interaction, we observed elevated HIF1alpha and TNC levels in R132H IDH1 GBM cells with reduced miR-203 (ant-203) compared with vector controls (Supplementary Fig.	('HIF1alpha', 'MPA', (64, 73))	('reduced', 'NegReg', (118, 125))	('TNC levels', 'MPA', (78, 88))	('miR-203', 'Gene', (126, 133))	('R132H', 'Var', (92, 97))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('elevated', 'PosReg', (55, 63))	('miR-203', 'Gene', '406986', (126, 133))
121660	27820599	Importantly, orthotopically injected R132H IDH1 tumours with reduced miR-203 exhibited decreased survival (Fig.	('miR-203', 'Gene', '406986', (69, 76))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('decreased', 'NegReg', (87, 96))	('R132H', 'Var', (37, 42))	('survival', 'CPA', (97, 105))	('IDH1 tumours', 'Disease', (43, 55))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('R132H', 'Mutation', 'rs121913500', (37, 42))	('IDH1 tumours', 'Disease', 'MESH:D009369', (43, 55))	('reduced', 'NegReg', (61, 68))	('miR-203', 'Gene', (69, 76))
121662	27820599	Taken together, these data suggest that tumour therapy may contribute to the development of more aggressive IDH1-mutant GBMs by increasing ECM stiffness and reducing miR-203 expression (Fig.	('GBMs', 'Disease', (120, 124))	('miR-203', 'Gene', '406986', (166, 173))	('reducing', 'NegReg', (157, 165))	('IDH1-mutant', 'Gene', (108, 119))	('miR-203', 'Gene', (166, 173))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('expression', 'MPA', (174, 184))	('tumour', 'Disease', (40, 46))	('ECM stiffness', 'MPA', (139, 152))	('increasing', 'PosReg', (128, 138))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('IDH1-mutant', 'Var', (108, 119))
121665	27820599	Our studies highlight the cellular plasticity and sensitivity of R132H IDH1 GBM cells to ECM stiffness and oxygen tension.	('IDH1', 'Gene', (71, 75))	('oxygen', 'Chemical', 'MESH:D010100', (107, 113))	('R132H', 'Mutation', 'rs121913500', (65, 70))	('R132H', 'Var', (65, 70))
121666	27820599	In all likelihood, mutations in IDH1 will exert a myriad of context-dependent effects to varying consequence depending on the origin of the tumour, the stage of the disease, the oxygen tension within the tumour and the duration of the disease.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour', 'Disease', (204, 210))	('oxygen', 'Chemical', 'MESH:D010100', (178, 184))	('IDH1', 'Gene', (32, 36))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (19, 28))	('tumour', 'Disease', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
121667	27820599	Gain-of-function IDH mutations often induce a CpG island methylator phenotype (G-CIMP) that is associated with improved outcome.	('IDH', 'Gene', '3417', (17, 20))	('CpG island methylator phenotype', 'MPA', (46, 77))	('Gain-of-function', 'PosReg', (0, 16))	('IDH', 'Gene', (17, 20))	('mutations', 'Var', (21, 30))
121668	27820599	IDH mutations are most prevalent in LGG, which, as a result of being less proliferative and diffusely infiltrative, may be less hypoxic than higher-grade GBMs.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('prevalent', 'Reg', (23, 32))	('LGG', 'Disease', (36, 39))	('mutations', 'Var', (4, 13))
121669	27820599	Therefore, LGGs frequently have a relatively long disease course where the long-term effect of IDH mutations (global DNA hypermethylation) is likely to dominate LGG pathobiology.	('LGG', 'Disease', (161, 164))	('LGGs', 'Disease', (11, 15))	('mutations', 'Var', (99, 108))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))
121670	27820599	Our work presents an example of one mechanism, outside of the sustained effects imparted by hypermethylation, whereby expression of the mutant IDH1 can compromise HIF1alpha induction in response to hypoxia to modify the ECM and alter tissue mechanics and tumour aggression.	('ECM', 'MPA', (220, 223))	('HIF1alpha', 'Protein', (163, 172))	('alter', 'Reg', (228, 233))	('induction', 'MPA', (173, 182))	('hypoxia', 'Disease', (198, 205))	('hypoxia', 'Disease', 'MESH:D000860', (198, 205))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('IDH1', 'Gene', (143, 147))	('tumour aggression', 'Disease', 'MESH:D001523', (255, 272))	('aggression', 'Phenotype', 'HP:0000718', (262, 272))	('modify', 'Reg', (209, 215))	('tumour aggression', 'Disease', (255, 272))	('mutant', 'Var', (136, 142))	('tissue mechanics', 'CPA', (234, 250))	('compromise', 'NegReg', (152, 162))
121701	27820599	5'-DIG labelled probes targeting miR-203 (Exiqon 35029-01), U6 small nuclear RNA (positive control, Exiqon 99002-01) or Scramble-miR (negative control, Exiqon 99004-01) were diluted to 40 nM in hybridization buffer.	('miR', 'Gene', (33, 36))	('miR', 'Gene', (129, 132))	('miR-203', 'Gene', (33, 40))	('miR', 'Gene', '29116', (33, 36))	('miR-203', 'Gene', '406986', (33, 40))	('miR', 'Gene', '29116', (129, 132))	('Exiqon 35029-01', 'Var', (42, 57))
121765	30899427	However, there was no clear picture that the effect size was associated with the standard error of the SMD to suggest publication bias (Egger test, P-value = 0.17, 0.72, 0.24 for rTBF, rTBFmean and rTBFmax, respectively).	('SMD', 'Disease', (103, 106))	('TBF', 'Chemical', '-', (180, 183))	('TBF', 'Chemical', '-', (186, 189))	('rTBFmax', 'Var', (198, 205))	('TBFmax', 'Chemical', '-', (199, 205))	('TBFmean', 'Chemical', '-', (186, 193))	('SMD', 'Disease', 'MESH:C537501', (103, 106))	('TBF', 'Chemical', '-', (199, 202))
121797	30899427	also reported that rTBFmax provided higher sensitivity and specificity than rTBFmean.	('higher', 'PosReg', (36, 42))	('specificity', 'MPA', (59, 70))	('rTBFmax', 'Var', (19, 26))	('TBFmax', 'Chemical', '-', (20, 26))	('TBFmean', 'Chemical', '-', (77, 84))	('sensitivity', 'MPA', (43, 54))
121804	30899427	The 2016 WHO classification of brain tumours puts more emphasis on the genetic and molecular subtyping of gliomas by stratifying them according to the isocitrate-dehydrogenase-(IDH) and 1p/19q mutation status or co-deletion, respectively.	('isocitrate-dehydrogenase-(IDH) and 1p', 'Gene', '3417', (151, 188))	('brain tumours', 'Disease', 'MESH:D001932', (31, 44))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('brain tumours', 'Phenotype', 'HP:0030692', (31, 44))	('brain tumours', 'Disease', (31, 44))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('brain tumour', 'Phenotype', 'HP:0030692', (31, 43))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('co-deletion', 'Var', (212, 223))
121869	27688706	Methylation of sites that are in the promoters of genes can affect their expression and lead to their silencing, a feature found in a number of human cancers.	('silencing', 'MPA', (102, 111))	('human', 'Species', '9606', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('Methylation', 'Var', (0, 11))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('expression', 'MPA', (73, 83))	('affect', 'Reg', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
121870	27688706	Methylation is believed to be closely related to gene expression, and DNA methylation sites have been increasingly found to be related to the processes of cancer.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('related', 'Reg', (127, 134))	('sites', 'Var', (86, 91))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
121871	27688706	Methylation biomarkers have also been associated with the response of a patient to particular treatment of cancer as shown in some clinical studies.	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Methylation', 'Var', (0, 11))	('patient', 'Species', '9606', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
121904	27688706	The possibility of manipulating receptor tyrosine kinase signaling in order to prevent cancer or enhance cancer therapy was explored previously.	('cancer', 'Disease', (87, 93))	('manipulating', 'Var', (19, 31))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('receptor tyrosine kinase', 'Gene', (32, 56))	('receptor tyrosine kinase', 'Gene', '5979', (32, 56))	('enhance', 'PosReg', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
122029	27061921	A phase II study of sorafenib in progressive LGG showed unexpected acceleration of tumor growth in both NF1 and BRAF fusion LGG, with the only response in a BRAF wild-type LGG; likely related to paradoxical ERK activation.	('sorafenib', 'Chemical', 'MESH:D000077157', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('BRAF', 'Gene', (112, 116))	('fusion', 'Var', (117, 123))	('acceleration', 'PosReg', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('NF1', 'Gene', '4763', (104, 107))	('NF1', 'Gene', (104, 107))
122103	26367871	Second, the ROC curve demonstrates that the AQoCE approach predicts the grade of gliomas by combining Cho/NAA, Cho/Cr and LL/Cr in the tumoral area with good performance.	('tumoral', 'Disease', 'MESH:D009369', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('Cho', 'Chemical', 'MESH:D002794', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Cho/NAA', 'Var', (102, 109))	('AQoCE', 'Chemical', '-', (44, 49))	('Cr', 'Chemical', 'MESH:D003401', (125, 127))	('NAA', 'Chemical', 'MESH:C000179', (106, 109))	('Cho', 'Chemical', 'MESH:D002794', (102, 105))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('Cr', 'Chemical', 'MESH:D003401', (115, 117))	('gliomas', 'Disease', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('LL', 'Chemical', 'MESH:C038361', (122, 124))	('tumoral', 'Disease', (135, 142))
122133	23459421	Herein the biologic and practical aspects of four key molecular biomarkers in gliomas are discussed, including two that have been known for some time (1p/19q codeletion and EGFR amplification) as well as two whose relevance was discovered via advanced whole-genome assays (IDH1/2 mutations and BRAF alterations).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH1/2', 'Gene', (273, 279))	('mutations', 'Var', (280, 289))	('EGFR', 'Gene', '1956', (173, 177))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('EGFR', 'Gene', (173, 177))	('IDH1/2', 'Gene', '3417;3418', (273, 279))
122148	23459421	The presence of calcifications should not be used as a discriminator between astrocytomas and oligodendrogliomas; likewise, the absence of "chickenwire" capillaries and "fried egg" artifact do not rule out an oligodendroglioma.	('absence', 'Var', (128, 135))	('oligodendroglioma', 'Disease', 'MESH:D009837', (209, 226))	('oligodendroglioma', 'Disease', (209, 226))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('oligodendroglioma', 'Disease', (94, 111))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('oligodendroglioma', 'Disease', 'MESH:D009837', (94, 111))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (77, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (77, 88))
122150	23459421	The presence of mitoses in a glioma raises the WHO grade to III, though the exact number of mitoses required per microscopic area has never been firmly established.	('glioma', 'Disease', (29, 35))	('mitoses', 'Var', (16, 23))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('presence', 'Var', (4, 12))
122163	23459421	Instead, discussion is focused on four high-yield genetic biomarkers: Two that have been known to exist for a long time: 1p/19q codeletion EGFR amplification Two that were discovered only recently as the result of whole genome assays and sophisticated bioinformatics: IDH1/2 mutation BRAF fusion/mutation Careful use of both "old" and "new" biomarkers greatly enhances the practice of surgical neuropathology (Table 1).	('mutation BRAF', 'Var', (275, 288))	('BRAF', 'Var', (284, 288))	('IDH1/2', 'Gene', '3417;3418', (268, 274))	('EGFR', 'Gene', '1956', (139, 143))	('enhances', 'PosReg', (360, 368))	('EGFR', 'Gene', (139, 143))	('IDH1/2', 'Gene', (268, 274))
122166	23459421	For example, numerous studies have shown that oligodendrogliomas with 1p/19q codeletion show improved response to adjuvant radiochemotherapy and longer survival, with the survival difference being much stronger in grade III anaplastic oligodendrogliomas than in grade II oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (246, 253))	('oligodendrogliomas', 'Disease', (235, 253))	('II oligodendrogliomas', 'Disease', (268, 289))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (271, 289))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('oligodendrogliomas', 'Disease', (271, 289))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (46, 64))	('improved', 'PosReg', (93, 101))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (224, 253))	('anaplastic oligodendrogliomas', 'Disease', (224, 253))	('response', 'MPA', (102, 110))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (235, 253))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('1p/19q codeletion', 'Var', (70, 87))	('oligodendrogliomas', 'Disease', (46, 64))	('stronger', 'PosReg', (202, 210))	('II oligodendrogliomas', 'Disease', 'MESH:D009837', (268, 289))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
122167	23459421	Interestingly, though, the codeletion may impart such a survival difference only if the tumor is treated with adjuvant therapy:i.e.	('tumor', 'Disease', (88, 93))	('codeletion', 'Var', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
122170	23459421	Yet even in gliomas that contain both oligodendroglial and astrocytic features (so-called "oligoastrocytomas"), those with the codeletion tend to behave more like oligodendrogliomas, whereas strong nuclear p53 staining is more suggestive of astrocytic differentiation.	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('oligodendrogliomas', 'Disease', (163, 181))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (91, 108))	('codeletion', 'Var', (127, 137))	('gliomas', 'Disease', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (163, 181))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('gliomas', 'Disease', (174, 181))	('oligodendroglial and astrocytic', 'Disease', 'MESH:D001254', (38, 69))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('oligoastrocytomas', 'Disease', (91, 108))
122171	23459421	However, this author's experience suggests that histologically unequivocal GBMs should not be reclassified based solely on the presence of 1p/19q codeletion, because those tumors will still behave like GBMs and, through extensive genomic instability, produce false-positive results (manuscript under review).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', (172, 178))	('GBMs', 'Disease', (75, 79))	('1p/19q codeletion', 'Var', (139, 156))
122173	23459421	However, some case reports have suggested an overlap between oligodendrogliomas and neurocytomas since 1p/19q codeletion is occasionally seen in rare oligo-like tumors that also show unequivocal signs of neurocytic differentiation.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (61, 79))	('neurocytoma', 'Phenotype', 'HP:0030064', (84, 95))	('1p/19q codeletion', 'Var', (103, 120))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('neurocytomas', 'Disease', (84, 96))	('oligodendrogliomas', 'Disease', (61, 79))	('neurocytomas', 'Disease', 'MESH:D018306', (84, 96))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('seen', 'Reg', (137, 141))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))
122175	23459421	In particular, it has been demonstrated that all gliomas with true whole-arm 1p/19q codeletion should also have IDH1/2 mutations.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))	('IDH1/2', 'Gene', '3417;3418', (112, 118))	('IDH1/2', 'Gene', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('arm 1p', 'Gene', (73, 79))	('mutations', 'Var', (119, 128))	('gliomas', 'Disease', (49, 56))	('arm 1p', 'Gene', '9622', (73, 79))
122177	23459421	Coexistence of EGFR amplification and 1p/19q codeletion is extremely rare, to the point where such cases are probably just false-positive for true whole-arm codeletion.	('amplification', 'Var', (20, 33))	('1p/19q', 'Var', (38, 44))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))
122178	23459421	1p/19q codeletion is about half as frequent in oligodendrogliomas arising in temporal lobe tumors versus those in the frontal, parietal, or occipital lobes, and has been reported to be especially uncommon in tumors from the insula, though the latter assertion has been disputed.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('occipital lobes', 'Disease', 'MESH:D004828', (140, 155))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (47, 65))	('temporal lobe tumors', 'Disease', 'MESH:C538521', (77, 97))	('insula', 'Disease', 'None', (224, 230))	('1p/19q codeletion', 'Var', (0, 17))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('oligodendrogliomas', 'Disease', (47, 65))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('insula', 'Disease', (224, 230))	('tumors', 'Disease', (91, 97))	('temporal lobe tumors', 'Disease', (77, 97))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('frequent', 'Reg', (35, 43))	('occipital lobes', 'Disease', (140, 155))
122179	23459421	All these observations are applicable only to the adult patient population, since pediatric oligodendrogliomas rarely have 1p/19q codeletion and, even when apparent codeletion is found, it is not clear whether it has any prognostic value in this context.	('1p/19q codeletion', 'Var', (123, 140))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('oligodendrogliomas', 'Disease', (92, 110))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('patient', 'Species', '9606', (56, 63))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (92, 110))
122180	23459421	There are many ways to test for 1p/19q codeletion in routine clinical samples; two of the most common are fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR)-based microsatellite loss of heterozygosity (LOH).	('clinical samples', 'Species', '191496', (61, 77))	('microsatellite', 'Var', (190, 204))	('loss of heterozygosity', 'NegReg', (205, 227))
122184	23459421	And FISH is well-suited to detecting polysomy of chromosomes 1 and 19, which has been shown to correlate with shorter progression-free survival in anaplastic oligodendrogliomas that have relative 1p/19q codeletion.	('anaplastic oligodendrogliomas', 'Disease', (147, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('shorter', 'NegReg', (110, 117))	('polysomy', 'Var', (37, 45))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('1p/19q codeletion', 'Var', (196, 213))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (147, 176))
122185	23459421	Because the goal is to find relative deletions of 1p and 19q, and tissue sections need to be 4-6 microns thick for FISH to work even though nuclei are usually greater than 6 microns in diameter, it follows that partial loss of some tumor nuclei, including their DNA, is inevitable.	('deletions', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('loss', 'NegReg', (219, 223))
122186	23459421	Some incorporate 1p/1q and 19q/19p signal ratios into the analysis, whereas others base it solely on the percent of tumor cells showing deletion of 1p and 19q signals relative to 1q and 19p signals.	('1p and', 'Gene', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('deletion', 'Var', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
122188	23459421	Even if optimal probes and interpretation criteria were known, 1p/19q FISH would still be unreliable for proving a glioma in the case of a biopsy where only scattered atypical cells are present, as "dilution" with nonneoplastic nuclei would render the data unreliable.	('1p/19q FISH', 'Var', (63, 74))	('glioma', 'Disease', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))
122189	23459421	If using percent of tumor nuclei with relative deletion, at least 40% should show relative loss of both 1p36 and 19q13.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('deletion', 'Var', (47, 55))	('loss', 'NegReg', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('1p36', 'Protein', (104, 108))	('19q13', 'Protein', (113, 118))	('tumor', 'Disease', (20, 25))
122196	23459421	From a clinical perspective there is no targeted therapy for 1p/19q-codeleted gliomas to date:that is, no particular chemotherapy or course of radiation has proven to be specifically more effective in 1p/19q-codeleted gliomas, just that such tumors respond better to any adjuvant therapy compared to their 1p/19q-intact brethren.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('1p/19q-codeleted', 'Var', (201, 217))	('clinical', 'Species', '191496', (7, 15))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('gliomas', 'Disease', 'MESH:D005910', (218, 225))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('gliomas', 'Disease', (218, 225))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))
122199	23459421	Amplification of the epidermal growth factor receptor (EGFR) gene on 7p12 has been known to occur in gliomas since the 1980s, preceding even 1p/19q codeletion as a recognized phenomenon in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('EGFR', 'Gene', '1956', (55, 59))	('Amplification', 'Var', (0, 13))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('gliomas', 'Disease', (101, 108))	('epidermal growth factor receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('epidermal growth factor receptor', 'Gene', '1956', (21, 53))	('p12', 'Gene', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('gliomas', 'Disease', (189, 196))	('p12', 'Gene', '56655', (70, 73))
122200	23459421	From a diagnostic standpoint EGFR amplification occurs in about 40% of all GBMs, specifically primary GBMs but not secondary GBMs.	('GBMs', 'Disease', (75, 79))	('occurs', 'Reg', (48, 54))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('amplification', 'Var', (34, 47))	('primary GBMs', 'Disease', (94, 106))
122201	23459421	Amplification is more common in patients 40 years or older, and is only very rarely seen in pediatric high-grade gliomas.	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (32, 40))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('common', 'Reg', (22, 28))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))
122202	23459421	Nearly half of all GBMs with EGFR amplification (and less than 10% without amplification) contain a truncated variant of the gene, encoding a protein that lacks the extracellular domain and is therefore constitutively active (EGFRvIII).	('extracellular domain', 'MPA', (165, 185))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (226, 230))	('EGFR', 'Gene', (29, 33))	('lacks', 'NegReg', (155, 160))	('EGFR', 'Gene', '1956', (226, 230))	('variant', 'Var', (110, 117))
122203	23459421	Because the majority of gliomas with EGFR amplification are histologically GBMs, in cases where the tissue biopsy is not fully representative of the actual tumor, detecting amplification is usually tantamount to a diagnosis of GBM.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('actual tumor', 'Disease', (149, 161))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('EGFR', 'Gene', '1956', (37, 41))	('amplification', 'Var', (42, 55))	('EGFR', 'Gene', (37, 41))	('gliomas', 'Disease', (24, 31))	('actual tumor', 'Disease', 'MESH:D009369', (149, 161))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
122204	23459421	Yet around 15 to 25% of grade III anaplastic astrocytomas also show EGFR amplification, and while some studies suggest such tumors will behave more like GBMs, others do not.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('astrocytomas', 'Disease', 'MESH:D001254', (45, 57))	('astrocytoma', 'Phenotype', 'HP:0009592', (45, 56))	('EGFR', 'Gene', '1956', (68, 72))	('tumors', 'Disease', (124, 130))	('astrocytomas', 'Disease', (45, 57))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('EGFR', 'Gene', (68, 72))	('amplification', 'Var', (73, 86))
122205	23459421	Thus, it is not entirely clear whether EGFR amplification in an otherwise grade III glioma always represents an undersampled GBM.	('I glioma', 'Disease', (82, 90))	('amplification', 'Var', (44, 57))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('I glioma', 'Disease', 'MESH:D005910', (82, 90))
122207	23459421	Another feature of EGFR amplification is its tight association with astrocytic gliomas:to wit, tumors that look like oligodendrogliomas but have EGFR amplification lack 1p/19q codeletion and are extremely aggressive, meriting the term "small cell GBM" instead of oligodendroglioma.	('lack', 'NegReg', (164, 168))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('1p/19q codeletion', 'MPA', (169, 186))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('EGFR', 'Gene', (19, 23))	('oligodendroglioma', 'Disease', 'MESH:D009837', (263, 280))	('tumors', 'Disease', (95, 101))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (117, 135))	('EGFR', 'Gene', (145, 149))	('oligodendroglioma', 'Disease', (263, 280))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (68, 86))	('astrocytic gliomas', 'Disease', (68, 86))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('EGFR', 'Gene', '1956', (19, 23))	('oligodendroglioma', 'Disease', 'MESH:D009837', (117, 134))	('oligodendrogliomas', 'Disease', (117, 135))	('oligodendroglioma', 'Disease', (117, 134))	('EGFR', 'Gene', '1956', (145, 149))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('amplification', 'Var', (150, 163))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
122208	23459421	Parenthetically, EGFR amplification and p53 mutation are also nearly mutually exclusive in gliomas, although rare cases of dual amplification and mutation have been documented.	('mutation', 'Var', (44, 52))	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('p53', 'Gene', (40, 43))	('amplification', 'Var', (22, 35))	('p53', 'Gene', '7157', (40, 43))	('EGFR', 'Gene', '1956', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('EGFR', 'Gene', (17, 21))
122218	23459421	Worth noting are the occasional cases of GBM that show only scattered cells with EGFR amplification yet, by both histology and CEP7 hyperploidy, clearly contain many neoplastic cells (Figure 2).	('amplification', 'Var', (86, 99))	('contain', 'Reg', (153, 160))	('neoplastic cells', 'CPA', (166, 182))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
122224	23459421	Results have been mixed thus far, not only because of the heterogeneous nature of receptor tyrosine kinase amplification, but also in part because alterations in other downstream proteins can thwart EGFR inhibition (e.g.	('EGFR', 'Gene', (199, 203))	('EGFR', 'Gene', '1956', (199, 203))	('thwart', 'NegReg', (192, 198))	('alterations', 'Var', (147, 158))
122228	23459421	One of the most recent and exciting events in neuro-oncology has been the discovery of mutations in isocitrate dehydrogenase types 1 and 2 (IDH1/2) in gliomas, found via whole-genome sequencing in GBMs.	('IDH1/2', 'Gene', '3417;3418', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('isocitrate', 'Chemical', 'MESH:C034219', (100, 110))	('mutations', 'Var', (87, 96))	('IDH1/2', 'Gene', (140, 146))	('oncology', 'Phenotype', 'HP:0002664', (52, 60))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
122231	23459421	First, IDH1 or IDH2 mutations are present in about 80% of astrocytomas and oligodendrogliomas, and in 15% of GBMs (practically all of which are secondary GBMs).	('IDH1', 'Gene', '3417', (7, 11))	('IDH2', 'Gene', (15, 19))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('present', 'Reg', (34, 41))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (58, 93))	('IDH1', 'Gene', (7, 11))	('IDH2', 'Gene', '3418', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('GBMs', 'Disease', (109, 113))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('mutations', 'Var', (20, 29))
122232	23459421	Second, they are always point mutations, restricted to the arginine codons encoding isocitrate binding sites for both enzymes (R132 in IDH1 and R172 in IDH2, with very rare R100, R49, and G97 mutations in IDH1).	('IDH1', 'Gene', (205, 209))	('R100', 'Var', (173, 177))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', '3417', (205, 209))	('IDH2', 'Gene', '3418', (152, 156))	('R172', 'Var', (144, 148))	('IDH2', 'Gene', (152, 156))	('IDH1', 'Gene', '3417', (135, 139))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('isocitrate', 'Chemical', 'MESH:C034219', (84, 94))	('R132', 'Var', (127, 131))	('R49', 'Var', (179, 182))	('G97', 'Var', (188, 191))
122234	23459421	Fourth, the similarly high rate of IDH1/2 mutation in both astrocytic and oligodendroglial tumors, and its tight association with TP53 mutations in the former and 1p/19q codeletion in the latter, suggests that it is an early step in gliomagenesis, perhaps in a glial cell precursor (Figure 3).	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('glioma', 'Disease', 'MESH:D005910', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (74, 97))	('oligodendroglial tumors', 'Disease', (74, 97))	('mutations', 'Var', (135, 144))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', '7157', (130, 134))	('astrocytic', 'Disease', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('glioma', 'Disease', (233, 239))	('TP53', 'Gene', (130, 134))	('IDH1/2', 'Gene', (35, 41))
122235	23459421	Fifth, these mutations appear to be relatively specific to gliomas versus most other solid neoplasms, though about half of all cartilaginous tumors, some intrahepatic cholangiocarcinomas, a minority of melanomas and thyroid carcinomas, and very rare prostate and colon cancers also contain IDH1/2 mutations.	('gliomas versus most other solid neoplasms', 'Disease', 'MESH:D005910', (59, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('contain', 'Reg', (282, 289))	('gliomas versus most other solid neoplasms', 'Disease', (59, 100))	('colon cancers', 'Phenotype', 'HP:0003003', (263, 276))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (216, 234))	('melanomas', 'Disease', 'MESH:D008545', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('neoplasms', 'Phenotype', 'HP:0002664', (91, 100))	('melanomas', 'Disease', (202, 211))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('colon cancers', 'Disease', 'MESH:D015179', (263, 276))	('cartilaginous tumors', 'Disease', (127, 147))	('IDH1/2', 'Gene', '3417;3418', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('colon cancers', 'Disease', (263, 276))	('IDH1/2', 'Gene', (290, 296))	('intrahepatic cholangiocarcinomas', 'Disease', (154, 186))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (127, 147))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('mutations', 'Var', (13, 22))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('prostate', 'Disease', (250, 258))	('mutations', 'Var', (297, 306))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (216, 234))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (154, 186))	('thyroid carcinomas', 'Disease', (216, 234))
122236	23459421	Finally, high-grade gliomas that harbor IDH1/2 mutations are less aggressive than their grade-matched wild-type counterparts.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('aggressive', 'CPA', (66, 76))	('IDH1/2', 'Gene', (40, 46))	('mutations', 'Var', (47, 56))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('less', 'NegReg', (61, 65))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
122237	23459421	In fact, IDH1/2 mutation status may be the most powerful independent molecular prognostic marker identified to date in high-grade gliomas, though whether it is the most powerful marker has been disputed.	('IDH1/2', 'Gene', (9, 15))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('mutation status', 'Var', (16, 31))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
122238	23459421	One study even showed that grade IV GBMs with IDH1/2 mutations fared better than grade III anaplastic astrocytomas without the mutation, and that this mutation, preferentially occurring in younger adults, accounts for the well-known correlation of younger patient age with longer survival.	('IDH1/2', 'Gene', (46, 52))	('astrocytomas', 'Disease', 'MESH:D001254', (102, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('mutations', 'Var', (53, 62))	('astrocytomas', 'Disease', (102, 114))	('IDH1/2', 'Gene', '3417;3418', (46, 52))	('patient', 'Species', '9606', (256, 263))
122239	23459421	In contrast, 15 to 30% of acute myeloid leukemias have IDH1/2 mutations, with either no effect or an adverse effect on prognosis.	('mutations', 'Var', (62, 71))	('myeloid leukemias', 'Disease', (32, 49))	('leukemias', 'Phenotype', 'HP:0001909', (40, 49))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (32, 49))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (26, 49))	('IDH1/2', 'Gene', '3417;3418', (55, 61))	('myeloid leukemias', 'Disease', 'MESH:D007951', (32, 49))	('IDH1/2', 'Gene', (55, 61))
122240	23459421	IDH1/2 mutations are practically always heterozygous, meaning that there is always one wild-type allele in the tumor.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
122241	23459421	Likewise, mutation of both IDH1 and IDH2 in the same tumor is exceedingly rare.	('IDH2', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('IDH2', 'Gene', '3418', (36, 40))	('mutation', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH1', 'Gene', (27, 31))	('tumor', 'Disease', (53, 58))	('IDH1', 'Gene', '3417', (27, 31))
122242	23459421	These findings indicate a dominant gain-of-function, which was proven when studies showed that mutant IDH1 enzyme no longer performs its regular function, but instead converts alpha-ketoglutarate to D-2-hydroxyglutarate (D-2-HG), which is normally present in only trace amounts but is greatly increased in mutant gliomas.	('gliomas', 'Disease', (313, 320))	('D-2-HG', 'Chemical', 'MESH:C019417', (221, 227))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (199, 219))	('gliomas', 'Disease', 'MESH:D005910', (313, 320))	('mutant', 'Var', (306, 312))	('converts', 'MPA', (167, 175))	('increased', 'PosReg', (293, 302))	('IDH1', 'Gene', (102, 106))	('glioma', 'Phenotype', 'HP:0009733', (313, 319))	('gain-of-function', 'PosReg', (35, 51))	('mutant', 'Var', (95, 101))	('IDH1', 'Gene', '3417', (102, 106))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (176, 195))	('gliomas', 'Phenotype', 'HP:0009733', (313, 320))
122243	23459421	While the full consequences of D-2-HG are still being characterized (and beyond the scope of this discussion), one noteworthy effect appears to be promotion of a hypermethylator profile by competitively inhibiting alpha-ketoglutarate-dependent demethylases.	('alpha-ketoglutarate-dependent demethylases', 'Enzyme', (214, 256))	('promotion', 'PosReg', (147, 156))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (214, 233))	('inhibiting', 'NegReg', (203, 213))	('D-2-HG', 'Var', (31, 37))	('D-2-HG', 'Chemical', 'MESH:C019417', (31, 37))	('hypermethylator profile', 'MPA', (162, 185))
122244	23459421	Interestingly, there exist very rare organic acidurias that usually contain defects in D- or L-2-HG dehydrogenase, with consequent elevation of D-2-HG or L-2-HG, respectively.	('L-2-HG dehydrogenase', 'Gene', (93, 113))	('aciduria', 'Phenotype', 'HP:0012072', (45, 53))	('D-2-HG', 'MPA', (144, 150))	('defects', 'Var', (76, 83))	('L-2-HG', 'MPA', (154, 160))	('D-2-HG', 'Chemical', 'MESH:C019417', (144, 150))	('organic acidurias', 'Chemical', '-', (37, 54))	('L-2-HG dehydrogenase', 'Gene', '28913', (93, 113))	('organic acidurias', 'Disease', (37, 54))	('elevation', 'PosReg', (131, 140))	('organic acidurias', 'Phenotype', 'HP:0001992', (37, 54))
122246	23459421	Even more provocative was the finding that D-2-HG aciduria is sometimes caused by a germline IDH2 mutation at R140, with the same biochemical result as the R172 mutation, yet to date no D-2-HG aciduria patients have been diagnosed with any kind of cancer other than chondromatosis.	('cancer', 'Disease', (248, 254))	('D-2-HG', 'Chemical', 'MESH:C019417', (43, 49))	('IDH2', 'Gene', '3418', (93, 97))	('aciduria', 'Disease', 'MESH:C537358', (193, 201))	('mutation at R140', 'Var', (98, 114))	('aciduria', 'Disease', 'MESH:C537358', (50, 58))	('chondromatosis', 'Disease', 'MESH:D018210', (266, 280))	('aciduria', 'Disease', (193, 201))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('aciduria', 'Phenotype', 'HP:0012072', (193, 201))	('aciduria', 'Disease', (50, 58))	('aciduria', 'Phenotype', 'HP:0012072', (50, 58))	('chondromatosis', 'Disease', (266, 280))	('D-2-HG', 'Chemical', 'MESH:C019417', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('caused by', 'Reg', (72, 81))	('IDH2', 'Gene', (93, 97))
122248	23459421	The role of IDH1/2 mutations and D-2-HG in gliomas will obviously be the subject of intense investigation for quite some time, but testing for the mutation has immediate practical relevance in surgical neuropathology.	('IDH1/2', 'Gene', (12, 18))	('mutations', 'Var', (19, 28))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('D-2-HG', 'Chemical', 'MESH:C019417', (33, 39))
122250	23459421	It has been proposed to help distinguish between a diffusely infiltrative glioma and a PA, the latter being negative for IDH1/2 mutations but usually positive for BRAF mutations or rearrangements (see below).	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('positive', 'Reg', (150, 158))	('mutations', 'Var', (128, 137))	('IDH1/2', 'Gene', '3417;3418', (121, 127))	('glioma', 'Disease', (74, 80))	('diffusely', 'Disease', (51, 60))	('IDH1/2', 'Gene', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('mutations', 'Var', (168, 177))	('rearrangements', 'Var', (181, 195))
122251	23459421	However, since IDH1/2 mutations are rare in diffuse gliomas from preadolescent patients, and the rate of BRAF fusions in PAs to declines with patient age, the utility of dual IDH/BRAF testing to differentiate the two is unclear.	('gliomas', 'Disease', (52, 59))	('IDH', 'Gene', '3417', (175, 178))	('PAs to declines', 'Disease', 'MESH:D060825', (121, 136))	('PAs to declines', 'Disease', (121, 136))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH1/2', 'Gene', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH', 'Gene', (15, 18))	('patient', 'Species', '9606', (79, 86))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (79, 87))	('patient', 'Species', '9606', (142, 149))	('IDH', 'Gene', '3417', (15, 18))	('IDH', 'Gene', (175, 178))	('IDH1/2', 'Gene', '3417;3418', (15, 21))
122252	23459421	Another topic of ambiguity is the prognostic power of IDH1/2 mutations in grade II gliomas; some have shown the mutations to be favorable markers, but others have not.	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('II gliomas', 'Disease', 'MESH:D005910', (80, 90))	('IDH1/2', 'Gene', (54, 60))	('mutations', 'Var', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('II gliomas', 'Disease', (80, 90))	('IDH1/2', 'Gene', '3417;3418', (54, 60))
122254	23459421	If so, inclusion of such cases in survival analyses of wild-type grade II gliomas would mask the prognostic effects of IDH1/2 mutations in true diffusely infiltrative grade II gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('IDH1/2', 'Gene', '3417;3418', (119, 125))	('II gliomas', 'Disease', 'MESH:D005910', (173, 183))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('grade', 'Disease', (65, 70))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('II gliomas', 'Disease', 'MESH:D005910', (71, 81))	('IDH1/2', 'Gene', (119, 125))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('mutations', 'Var', (126, 135))	('II gliomas', 'Disease', (173, 183))	('II gliomas', 'Disease', (71, 81))
122255	23459421	The gold standard for IDH1/2 mutation testing is obviously PCR amplification and sequencing of the tumor, which is quite feasible in routine FFPE tissues.	('mutation', 'Var', (29, 37))	('tumor', 'Disease', (99, 104))	('IDH1/2', 'Gene', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PCR amplification', 'Var', (59, 76))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('IDH1/2', 'Gene', '3417;3418', (22, 28))
122257	23459421	However, the development of an R132H-specific IDH1 mutant antibody has already rendered upfront PCR/sequencing unnecessary, to be used only if the immunostain is negative or equivocal.	('R132H-specific', 'Var', (31, 45))	('IDH1', 'Gene', (46, 50))	('R132H', 'Mutation', 'rs121913500', (31, 36))	('IDH1', 'Gene', '3417', (46, 50))
122258	23459421	This is because about 95% of all IDH1/2 mutations are in IDH1, and among those over 90% are arginine-to-histidine R132H, making an R132H-specific antibody an excellent screening test.	('arginine', 'Chemical', 'MESH:D001120', (92, 100))	('IDH1/2', 'Gene', (33, 39))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', (57, 61))	('R132H', 'Mutation', 'rs121913500', (114, 119))	('R132H', 'Mutation', 'rs121913500', (131, 136))	('mutations', 'Var', (40, 49))	('arginine-to-histidine', 'Var', (92, 113))	('IDH1', 'Gene', '3417', (33, 37))	('IDH1', 'Gene', '3417', (57, 61))	('IDH1/2', 'Gene', '3417;3418', (33, 39))	('histidine', 'Chemical', 'MESH:D006639', (104, 113))
122261	23459421	Sometimes staining heterogeneity is seen, where some areas are nicely positive while other areas of obvious tumor are negative; such cases are still always positive for the R132H IDH1 mutation on sequencing.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('obvious tumor', 'Disease', 'MESH:D009369', (100, 113))	('R132H', 'Var', (173, 178))	('IDH1', 'Gene', (179, 183))	('positive', 'Reg', (156, 164))	('obvious tumor', 'Disease', (100, 113))	('R132H', 'Mutation', 'rs121913500', (173, 178))	('IDH1', 'Gene', '3417', (179, 183))
122262	23459421	The practical aspects of screening all gliomas and suspected gliomas via R132H IDH1 antibodies are obvious: Faster turnaround time Lower cost Ability to detect just a few scattered positive cells that even the most sensitive PCR tests would miss Thus, upfront R132H IDH1 immunostaining is now done routinely on all our gliomas, including suboptimal biopsies suspected of harboring glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (381, 387))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Disease', (61, 68))	('R132H', 'Var', (260, 265))	('IDH1', 'Gene', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('gliomas', 'Disease', (319, 326))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('glioma', 'Disease', (319, 325))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('IDH1', 'Gene', '3417', (79, 83))	('glioma', 'Disease', 'MESH:D005910', (319, 325))	('glioma', 'Disease', (39, 45))	('IDH1', 'Gene', (266, 270))	('gliomas', 'Disease', 'MESH:D005910', (319, 326))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Disease', (381, 387))	('R132H', 'Mutation', 'rs121913500', (260, 265))	('glioma', 'Phenotype', 'HP:0009733', (319, 325))	('glioma', 'Disease', 'MESH:D005910', (381, 387))	('glioma', 'Disease', (61, 67))	('IDH1', 'Gene', '3417', (266, 270))	('gliomas', 'Disease', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (319, 326))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
122263	23459421	Any case that is immunonegative or equivocal is reflex-tested for less common IDH1 and IDH2 mutations by RT-PCR/FMCA.	('IDH1', 'Gene', (78, 82))	('mutations', 'Var', (92, 101))	('IDH1', 'Gene', '3417', (78, 82))	('IDH2', 'Gene', (87, 91))	('IDH2', 'Gene', '3418', (87, 91))
122265	23459421	Testing for IDH1/2 mutations is therefore advisable on all infiltrative gliomas or suspected gliomas, especially in patients approximately age 14 years and up.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH1/2', 'Gene', (12, 18))	('patients', 'Species', '9606', (116, 124))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('mutations', 'Var', (19, 28))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
122267	23459421	Conventional comparative genomic hybridization showed no large cytogenetic abnormalities in most of these tumors, but array comparative genomic hybridization identified a biologically active, low-level copy number gain of the BRAF gene on 7q34 in a significant proportion of PAs.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('copy number', 'Var', (202, 213))	('BRAF', 'Gene', (226, 230))	('PAs', 'Disease', (275, 278))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('gain', 'PosReg', (214, 218))
122270	23459421	In PAs the BRAF copy gain is due to a tandem duplication producing a KIAA1549:BRAF fusion protein with loss of the Ras-binding domain on BRAF, though a minority of cases can involve RAF1 fusion with SRGAP or FAM131B.	('FAM131B', 'Gene', '9715', (208, 215))	('RAF1', 'Gene', '5894', (182, 186))	('KIAA1549', 'Gene', '57670', (69, 77))	('PAs the BRAF copy gain', 'Disease', (3, 25))	('KIAA1549', 'Gene', (69, 77))	('tandem duplication', 'Var', (38, 56))	('PAs the BRAF copy gain', 'Disease', 'MESH:D015430', (3, 25))	('RAF1', 'Gene', (182, 186))	('FAM131B', 'Gene', (208, 215))	('loss', 'NegReg', (103, 107))	('Ras-binding domain', 'MPA', (115, 133))
122273	23459421	In fact, loss of p16 in PAs may correlate with higher risk of aggressive behavior.	('p16', 'Gene', (17, 20))	('aggressive behavior', 'Disease', (62, 81))	('loss', 'Var', (9, 13))	('aggressive behavior', 'Disease', 'MESH:D001523', (62, 81))	('p16', 'Gene', '1029', (17, 20))	('aggressive behavior', 'Phenotype', 'HP:0000718', (62, 81))
122280	23459421	Another BRAF alteration is the constitutively active V600E point mutation, previously known to be important in melanomas, colonic adenocarcinomas, and papillary thyroid carcinomas.	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (151, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('papillary thyroid carcinomas', 'Disease', (151, 179))	('V600E', 'Var', (53, 58))	('melanomas', 'Disease', (111, 120))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (161, 179))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (122, 145))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (151, 179))	('colonic adenocarcinomas', 'Disease', (122, 145))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
122282	23459421	In both children and adults about 10% of PAs have the mutation (but only 2% of cerebellar tumors).	('mutation', 'Var', (54, 62))	('children', 'Species', '9606', (8, 16))	('PAs', 'Disease', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cerebellar tumors', 'Disease', (79, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cerebellar tumors', 'Disease', 'MESH:D002528', (79, 96))
122284	23459421	Although present in tumors with PA-like morphology, V600E is more common in other tumors in the PA differential, including 25% of pediatric and adult gangliogliomas and 80% of pleomorphic xanthoastrocytomas.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (82, 88))	('common', 'Reg', (66, 72))	('gangliogliomas', 'Disease', (150, 164))	('gangliogliomas', 'Disease', 'MESH:D018303', (150, 164))	('V600E', 'Var', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (176, 206))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('pleomorphic xanthoastrocytomas', 'Disease', (176, 206))	('V600E', 'Mutation', 'rs113488022', (52, 57))	('astrocytoma', 'Phenotype', 'HP:0009592', (194, 205))
122286	23459421	Less than 10% of NF1-associated PAs contain a BRAF fusion or mutation, but such cases do occur.	('mutation', 'Var', (61, 69))	('NF1', 'Gene', (17, 20))	('NF1', 'Gene', '4763', (17, 20))	('BRAF', 'CPA', (46, 50))	('PAs', 'Disease', (32, 35))
122287	23459421	From a diagnostics standpoint the presence of a BRAF fusion is therefore most suggestive of a low-grade glioma, especially a PA, but whether it can be used to definitively prove PA is still unclear.	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Disease', (104, 110))	('presence', 'Var', (34, 42))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))
122288	23459421	In contrast, detecting a V600E mutation is more associated with other tumors in the PA differential, but again cannot be used to definitively prove one type of tumor versus another.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('associated', 'Reg', (48, 58))	('tumor', 'Disease', (70, 75))	('V600E', 'Var', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('V600E', 'Mutation', 'rs113488022', (25, 30))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
122289	23459421	From an outcome-based perspective, recent work showed that supratentorial low-grade pediatric gliomas with BRAF fusion usually behave as typical grade I PAs regardless of what they look like under the microscope or whether they are completely resected, whereas PAs without BRAF fusion are more likely to behave like grade II diffuse astrocytomas.	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('astrocytoma', 'Phenotype', 'HP:0009592', (333, 344))	('pediatric gliomas', 'Disease', (84, 101))	('astrocytomas', 'Disease', (333, 345))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('pediatric gliomas', 'Disease', 'MESH:D005910', (84, 101))	('astrocytomas', 'Disease', 'MESH:D001254', (333, 345))	('fusion', 'Var', (112, 118))
122292	23459421	Nevertheless, while there is not yet a consensus on the prognostic impact of BRAF fusion in gliomas, as of now it appears to be at least a neutral biomarker, and perhaps even a favorable marker in certain contexts.	('fusion', 'Var', (82, 88))	('BRAF', 'Gene', (77, 81))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
122293	23459421	In contrast, data on BRAF V600E mutations and outcome are very sparse.	('V600E', 'Var', (26, 31))	('BRAF', 'Gene', (21, 25))	('V600E', 'Mutation', 'rs113488022', (26, 31))
122294	23459421	Our recent work comparing both types of BRAF alterations in the same cohort of pediatric low-grade gliomas suggested that there is a trend toward divergence in prognosis:i.e.	('alterations', 'Var', (45, 56))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
122295	23459421	BRAF fusions tend to be associated with longer PFS, while BRAF V600E mutations suggest shorter PFS.	('V600E', 'Mutation', 'rs113488022', (63, 68))	('fusions', 'Var', (5, 12))	('BRAF', 'Gene', (58, 62))	('V600E mutations', 'Var', (63, 78))
122298	23459421	Likewise, comparable anti V600E clinical trials in low grade pediatric gliomas are still in progress, but if animal model data and experience with melanomas is any indication, such therapies are worth pursuing.	('clinical', 'Species', '191496', (32, 40))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('melanomas', 'Disease', (147, 156))	('pediatric gliomas', 'Disease', (61, 78))	('anti V600E', 'Var', (21, 31))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('melanomas', 'Disease', 'MESH:D008545', (147, 156))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('pediatric gliomas', 'Disease', 'MESH:D005910', (61, 78))
122302	23459421	Naturally the standard way to detect BRAF V600E point mutation is via PCR and sequencing, but recently the same group that developed the aforementioned R132H IDH1-specific antibody has produced a V600E BRAF-specific antibody.	('R132H', 'Var', (152, 157))	('V600E', 'Var', (196, 201))	('R132H', 'Mutation', 'rs121913500', (152, 157))	('V600E point mutation', 'Var', (42, 62))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('V600E', 'Mutation', 'rs113488022', (196, 201))	('IDH1', 'Gene', (158, 162))	('IDH1', 'Gene', '3417', (158, 162))
122303	23459421	In summary, testing for BRAF fusion and mutation is recommended in cases where the differential is between a PA and one of its mimickers, especially if there is concern that the tumor could be a grade II-IV diffusely infiltrative glioma.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (178, 183))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('glioma', 'Disease', (230, 236))
122304	23459421	The presence of the fusion or point mutation, however, might not unequivocally diagnose one type of tumor versus another, and is less useful in non-pediatric patients.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('fusion', 'Var', (20, 26))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('patients', 'Species', '9606', (158, 166))	('point mutation', 'Var', (30, 44))
122308	23459421	But in certain circumstances, testing for 1p/19q codeletion, EGFR amplification, IDH1/2 mutations, and/or BRAF alterations can help refine the patient's diagnosis and prognosis (Table 1, Figure 6).	('amplification', 'Var', (66, 79))	('patient', 'Species', '9606', (143, 150))	('1p/19q codeletion', 'Var', (42, 59))	('alterations', 'Var', (111, 122))	('mutations', 'Var', (88, 97))	('IDH1/2', 'Gene', (81, 87))	('BRAF', 'Gene', (106, 110))	('refine', 'Reg', (132, 138))	('IDH1/2', 'Gene', '3417;3418', (81, 87))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
122309	23459421	Yet based on the rates of EGFR amplification and IDH1/2 mutations in the adult population, as well as the frequencies of grades II-IV gliomas, tumor cells can now be detected in about 60% of suboptimally-biopsied diffusely infiltrative gliomas, even in cases where the diagnosis of glioma cannot be made based on light microscopy alone.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma', 'Disease', 'MESH:D005910', (282, 288))	('gliomas', 'Disease', 'MESH:D005910', (236, 243))	('glioma', 'Disease', (282, 288))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mutations', 'Var', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('II-IV gliomas', 'Disease', (128, 141))	('gliomas', 'Phenotype', 'HP:0009733', (236, 243))	('EGFR', 'Gene', (26, 30))	('gliomas', 'Disease', (134, 141))	('EGFR', 'Gene', '1956', (26, 30))	('glioma', 'Disease', (134, 140))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('tumor', 'Disease', (143, 148))	('gliomas', 'Disease', (236, 243))	('II-IV gliomas', 'Disease', 'MESH:D005910', (128, 141))	('glioma', 'Disease', (236, 242))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('glioma', 'Disease', 'MESH:D005910', (236, 242))	('IDH1/2', 'Gene', (49, 55))
122317	33353229	Copy number alteration (CNA) is a cytogenetic hallmark of cancer pathophysiology.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Copy number alteration', 'Var', (0, 22))
122321	33353229	For this reason, the identification of the copy number aberration has been a key issue in cancer research.	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('copy number aberration', 'Var', (43, 65))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
122362	33353229	The mutation and inactivation of p53 is related to the proliferation and progression of glioma, invasion, and anti-apoptotic activity.	('inactivation', 'Var', (17, 29))	('related', 'Reg', (40, 47))	('glioma', 'Disease', (88, 94))	('mutation', 'Var', (4, 12))	('p53', 'Gene', (33, 36))	('invasion', 'CPA', (96, 104))	('p53', 'Gene', '7157', (33, 36))	('progression', 'CPA', (73, 84))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('anti-apoptotic activity', 'CPA', (110, 133))
122363	33353229	It is possible that copy number alterations in p53-related pathways disrupt the CNAs-GE relationship in the favorable group of LGG.	('copy number alterations', 'Var', (20, 43))	('CNAs-GE relationship', 'Disease', (80, 100))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('disrupt', 'NegReg', (68, 75))
122367	33353229	In the pathway, p53 regulates caspase 10, which is associated with apoptotic signaling in glioblastoma, and capase 10 induced cellular death in response to the chemotherapeutic agent, which has a possibility of prolonged survival.	('cellular', 'CPA', (126, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('caspase 10', 'Gene', (30, 40))	('p53', 'Gene', (16, 19))	('capase 10', 'Var', (108, 117))	('regulates', 'Reg', (20, 29))	('associated', 'Reg', (51, 61))	('p53', 'Gene', '7157', (16, 19))	('caspase 10', 'Gene', '843', (30, 40))	('death', 'Disease', 'MESH:D003643', (135, 140))	('glioblastoma', 'Disease', (90, 102))	('death', 'Disease', (135, 140))	('induced', 'Reg', (118, 125))
122372	33353229	EFGR gene amplification and overexpression can be observed in approximately 40% of glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('amplification', 'Var', (10, 23))	('glioblastoma', 'Disease', (83, 95))	('overexpression', 'PosReg', (28, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('EFGR gene', 'Gene', (0, 9))
122377	33353229	Moreover, the variant of the methylenetetrahydrofolate reductase was shown to be significantly associated with patient survival.	('patient survival', 'CPA', (111, 127))	('patient', 'Species', '9606', (111, 118))	('methylenetetrahydrofolate reductase', 'Gene', (29, 64))	('associated', 'Reg', (95, 105))	('variant', 'Var', (14, 21))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (29, 64))
122380	31861486	Overexpression of PSAT1 Gene is a Favorable Prognostic Marker in Lower-Grade Gliomas and Predicts a Favorable Outcome in Patients with IDH1 Mutations and Chromosome 1p19q Codeletion Patients with lower-grade gliomas (LGGs) have highly diverse clinical outcomes.	('Patients', 'Species', '9606', (121, 129))	('Glioma', 'Phenotype', 'HP:0009733', (77, 83))	('Gliomas', 'Disease', 'MESH:D005910', (77, 84))	('IDH1', 'Gene', (135, 139))	('Gliomas', 'Disease', (77, 84))	('Gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('gliomas', 'Disease', (208, 215))	('IDH1', 'Gene', '3417', (135, 139))	('Mutations', 'Var', (140, 149))	('PSAT1', 'Gene', '29968', (18, 23))	('PSAT1', 'Gene', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('Patients', 'Species', '9606', (182, 190))
122387	31861486	Our results demonstrated that PSAT1 overexpression is a favorable prognostic marker of LGGs and significantly correlated with patient age <=40, and a lower WHO histological grade, as well as mutations in IDH1, TP53 and ATRX, but not with chromosome 1p19q codeletions.	('LGGs', 'Disease', (87, 91))	('IDH1', 'Gene', (204, 208))	('TP53', 'Gene', (210, 214))	('correlated', 'Reg', (110, 120))	('overexpression', 'PosReg', (36, 50))	('PSAT1', 'Gene', (30, 35))	('ATRX', 'Gene', (219, 223))	('mutations', 'Var', (191, 200))	('IDH1', 'Gene', '3417', (204, 208))	('PSAT1', 'Gene', '29968', (30, 35))	('patient', 'Species', '9606', (126, 133))	('ATRX', 'Gene', '546', (219, 223))	('TP53', 'Gene', '7157', (210, 214))
122388	31861486	More importantly, LGG patients with isocitrate dehydrogenase 1 (IDH1) mutations, chromosome 1p19q codeletions, and PSAT1 overexpression may have the best overall survival (five-year survival rate: 100%).	('PSAT1', 'Gene', (115, 120))	('mutations', 'Var', (70, 79))	('isocitrate dehydrogenase 1', 'Gene', (36, 62))	('IDH1', 'Gene', (64, 68))	('patients', 'Species', '9606', (22, 30))	('LGG', 'Disease', (18, 21))	('isocitrate dehydrogenase 1', 'Gene', '3417', (36, 62))	('IDH1', 'Gene', '3417', (64, 68))	('PSAT1', 'Gene', '29968', (115, 120))
122389	31861486	Finally, we observed a coordinated biological reaction between IDH1 mutations and PSAT1 overexpression, and suggested overexpression of PSAT1 might enhance the function of mutant IDH1 to promote a favorable outcome in LGG patients.	('promote', 'PosReg', (187, 194))	('mutant', 'Var', (172, 178))	('IDH1', 'Gene', '3417', (63, 67))	('LGG', 'Disease', (218, 221))	('PSAT1', 'Gene', (82, 87))	('patients', 'Species', '9606', (222, 230))	('PSAT1', 'Gene', '29968', (82, 87))	('PSAT1', 'Gene', '29968', (136, 141))	('PSAT1', 'Gene', (136, 141))	('IDH1', 'Gene', (179, 183))	('enhance', 'PosReg', (148, 155))	('mutations', 'Var', (68, 77))	('IDH1', 'Gene', '3417', (179, 183))	('function', 'MPA', (160, 168))	('IDH1', 'Gene', (63, 67))
122397	31861486	Although IDH1 mutations and chromosome 1p/19q codeletions have been identified as favorable prognostic biomarkers of LGGs, a new biomarker is still needed that could further predict the outcomes of LGG patients with IDH1 mutations and chromosome 1p/19q codeletion.	('mutations', 'Var', (221, 230))	('LGGs', 'Disease', (117, 121))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('patients', 'Species', '9606', (202, 210))	('IDH1', 'Gene', '3417', (216, 220))	('IDH1', 'Gene', (216, 220))	('LGG', 'Disease', (198, 201))	('mutations', 'Var', (14, 23))
122418	31861486	More importantly, our results also demonstrated that LGG patients with IDH1 mutations, chromosome 1p/19q codeletion and overexpression of PSAT1 could have the best overall survival of all patients.	('chromosome', 'Var', (87, 97))	('mutations', 'Var', (76, 85))	('overexpression', 'PosReg', (120, 134))	('patients', 'Species', '9606', (57, 65))	('IDH1', 'Gene', (71, 75))	('patients', 'Species', '9606', (188, 196))	('IDH1', 'Gene', '3417', (71, 75))	('PSAT1', 'Gene', (138, 143))	('PSAT1', 'Gene', '29968', (138, 143))
122433	31861486	Patients with a high expression of PSAT1 had significantly better overall survival (OS) (median survival: 8.767 years; five-year survival rate: 71.1%) than those with a low expression of PSAT1 (median survival: 5.247 years; five-year survival rate: 53.1%) (Figure 1C).	('high expression', 'Var', (16, 31))	('overall survival', 'MPA', (66, 82))	('PSAT1', 'Gene', '29968', (187, 192))	('PSAT1', 'Gene', (187, 192))	('better', 'PosReg', (59, 65))	('Patients', 'Species', '9606', (0, 8))	('PSAT1', 'Gene', '29968', (35, 40))	('PSAT1', 'Gene', (35, 40))
122436	31861486	The 2016 WHO classification of tumors of the CNS suggests the use of IDH1 mutation status and chromosome 1p19q codeletion status to predict the prognosis of LGG patients.	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('IDH1', 'Gene', '3417', (69, 73))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors of the CNS', 'Phenotype', 'HP:0100006', (31, 48))	('patients', 'Species', '9606', (161, 169))	('IDH1', 'Gene', (69, 73))	('LGG', 'Disease', (157, 160))
122437	31861486	According to the guidelines of the 2016 WHO classification of CNS tumors, patients in the TCGA LGG cohort (n = 520) were classified into three groups for further analyses, including IDH1 wild-type, IDH1 mutations with 1p19q codeletion, and IDH1 mutations without 1p19q codeletion (Figure 2A).	('IDH1', 'Gene', '3417', (240, 244))	('IDH1', 'Gene', '3417', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (245, 254))	('1p19q codeletion', 'Var', (218, 234))	('patients', 'Species', '9606', (74, 82))	('IDH1', 'Gene', (198, 202))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CNS tumors', 'Disease', 'MESH:D016543', (62, 72))	('IDH1', 'Gene', '3417', (198, 202))	('IDH1', 'Gene', (240, 244))	('IDH1', 'Gene', (182, 186))	('mutations', 'Var', (203, 212))	('CNS tumors', 'Disease', (62, 72))
122438	31861486	PSAT1 appeared to be highly expressed in the group that had mutations in IDH1 without 1p19q codeletion.	('IDH1', 'Gene', '3417', (73, 77))	('PSAT1', 'Gene', '29968', (0, 5))	('PSAT1', 'Gene', (0, 5))	('IDH1', 'Gene', (73, 77))	('mutations', 'Var', (60, 69))
122439	31861486	Consistent with previously published literature, mutations in TP53 and ATRX, as well as low expression of the TERT gene, were also enriched in the IDH1 mutations without 1p19q codeletion group (Figure 2A).	('TP53', 'Gene', '7157', (62, 66))	('mutations', 'Var', (49, 58))	('mutations', 'Var', (152, 161))	('IDH1', 'Gene', '3417', (147, 151))	('ATRX', 'Gene', '546', (71, 75))	('TP53', 'Gene', (62, 66))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('IDH1', 'Gene', (147, 151))	('ATRX', 'Gene', (71, 75))	('expression', 'MPA', (92, 102))
122440	31861486	The expression levels of PSAT1 were significantly higher in the group of LGGs with IDH1 mutations, with 1p19q noncodeletion, with ATRX mutations, with TP53 mutations, with wild-type CIC, and with wild-type FUBP1 (Figure 2B).	('expression levels', 'MPA', (4, 21))	('higher', 'PosReg', (50, 56))	('FUBP1', 'Gene', '8880', (206, 211))	('ATRX', 'Gene', (130, 134))	('TP53', 'Gene', (151, 155))	('IDH1', 'Gene', '3417', (83, 87))	('PSAT1', 'Gene', '29968', (25, 30))	('ATRX', 'Gene', '546', (130, 134))	('mutations', 'Var', (88, 97))	('mutations', 'Var', (135, 144))	('CIC', 'Gene', '23152', (182, 185))	('FUBP1', 'Gene', (206, 211))	('TP53', 'Gene', '7157', (151, 155))	('CIC', 'Gene', (182, 185))	('PSAT1', 'Gene', (25, 30))	('IDH1', 'Gene', (83, 87))
122441	31861486	When LGG patients were classified into three groups according to the IDH1 mutation status and chromosome 1p19q codeletion status, the expression levels of PSAT1 were significantly higher in the group of LGGs with IDH1 mutations without chromosome 1p19q codeletion (Figure 2C).	('patients', 'Species', '9606', (9, 17))	('PSAT1', 'Gene', '29968', (155, 160))	('IDH1', 'Gene', (69, 73))	('IDH1', 'Gene', '3417', (213, 217))	('IDH1', 'Gene', '3417', (69, 73))	('PSAT1', 'Gene', (155, 160))	('mutations', 'Var', (218, 227))	('higher', 'PosReg', (180, 186))	('IDH1', 'Gene', (213, 217))	('expression levels', 'MPA', (134, 151))
122443	31861486	IDH1 mutations are known to be a favorable prognostic marker of LGGs and more enriched in grade II gliomas compared to grade III gliomas.	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('gliomas', 'Disease', (129, 136))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('LGGs', 'Disease', (64, 68))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('IDH1', 'Gene', '3417', (0, 4))
122446	31861486	Our results confirmed that the overexpression of the PSAT1 gene correlates with mutations in IDH1, ATRX and TP53, a lower WHO grade of LGGs, as well as wild-type CIC and wild-type FUBP1, but not with chromosome 1p19q codeletion.	('lower', 'NegReg', (116, 121))	('IDH1', 'Gene', (93, 97))	('ATRX', 'Gene', (99, 103))	('PSAT1', 'Gene', (53, 58))	('mutations', 'Var', (80, 89))	('IDH1', 'Gene', '3417', (93, 97))	('TP53', 'Gene', (108, 112))	('CIC', 'Gene', (162, 165))	('PSAT1', 'Gene', '29968', (53, 58))	('FUBP1', 'Gene', '8880', (180, 185))	('TP53', 'Gene', '7157', (108, 112))	('ATRX', 'Gene', '546', (99, 103))	('FUBP1', 'Gene', (180, 185))	('overexpression', 'PosReg', (31, 45))	('CIC', 'Gene', '23152', (162, 165))
122447	31861486	In addition, overexpression of PSAT1, as well as mutations in ATRX and TP53, and low expression of TERT are enriched in IDH1-mutant LGGs without 1p19q codeletion.	('expression', 'MPA', (85, 95))	('PSAT1', 'Gene', (31, 36))	('TERT', 'Gene', (99, 103))	('mutations', 'Var', (49, 58))	('LGGs', 'Disease', (132, 136))	('TERT', 'Gene', '7015', (99, 103))	('ATRX', 'Gene', (62, 66))	('IDH1', 'Gene', (120, 124))	('overexpression', 'PosReg', (13, 27))	('TP53', 'Gene', '7157', (71, 75))	('IDH1', 'Gene', '3417', (120, 124))	('TP53', 'Gene', (71, 75))	('ATRX', 'Gene', '546', (62, 66))	('PSAT1', 'Gene', '29968', (31, 36))
122448	31861486	IDH1 mutation status and chromosome 1p19q codeletion status are the most important markers in LGGs.	('IDH1', 'Gene', (0, 4))	('LGGs', 'Disease', (94, 98))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
122449	31861486	When LGG patients in the TCGA dataset (n = 520) were classified into two groups according to IDH1 mutation status, the group with IDH1 mutations (n = 404) had better OS (median survival: 8.186 years; five-year survival rate: 69.3%) than the group of IDH1 wild-type (n = 116) (median survival: 2.123 years; five-year survival rate: 32.9%) (Figure S3A).	('IDH1', 'Gene', (93, 97))	('patients', 'Species', '9606', (9, 17))	('IDH1', 'Gene', '3417', (93, 97))	('mutations', 'Var', (135, 144))	('IDH1', 'Gene', (130, 134))	('IDH1', 'Gene', (250, 254))	('better', 'PosReg', (159, 165))	('IDH1', 'Gene', '3417', (130, 134))	('IDH1', 'Gene', '3417', (250, 254))
122450	31861486	When LGG patients were classified into four groups according to IDH1 mutation status and PSAT1 expression status, high expression of PSAT1 was shown to be a significantly favorable prognostic marker in IDH1-mutant LGGs, but not in IDH1 wild-type LGGs (Figure 3A).	('patients', 'Species', '9606', (9, 17))	('IDH1', 'Gene', (231, 235))	('high', 'Var', (114, 118))	('PSAT1', 'Gene', '29968', (133, 138))	('PSAT1', 'Gene', (133, 138))	('IDH1', 'Gene', (64, 68))	('PSAT1', 'Gene', '29968', (89, 94))	('LGGs', 'Disease', (214, 218))	('PSAT1', 'Gene', (89, 94))	('favorable', 'PosReg', (171, 180))	('IDH1', 'Gene', (202, 206))	('IDH1', 'Gene', '3417', (231, 235))	('IDH1', 'Gene', '3417', (64, 68))	('IDH1', 'Gene', '3417', (202, 206))
122451	31861486	When LGG patients were classified into four groups according to chromosome 1p19q codeletion status and PSAT1 expression status, high expression of PSAT1 was shown to be a significantly favorable prognostic marker both in 1p19q codeleted and 1p19q not-codeleted LGGs (Figure 3B).	('patients', 'Species', '9606', (9, 17))	('1p19q', 'Var', (241, 246))	('1p19q codeleted', 'Var', (221, 236))	('favorable', 'PosReg', (185, 194))	('PSAT1', 'Gene', '29968', (147, 152))	('PSAT1', 'Gene', (147, 152))	('PSAT1', 'Gene', (103, 108))	('high expression', 'Var', (128, 143))	('PSAT1', 'Gene', '29968', (103, 108))
122452	31861486	When LGG patients were classified into three groups (IDH1 wild-type, IDH1 mutations with 1p19q codeletion, and IDH1 mutations without 1p19q codeletion) according to the guideline of the 2016 WHO classification of CNS tumors, the group of IDH1 wild-type (n = 116) had the worst OS (median survival: 2.123 years; five-year survival rate: 32.9%), and the group with IDH1 mutations and chromosome 1p19q codeletion (n = 155) had the best OS (median survival: 12.863 years; five-year survival rate: 78.2%) (Figure 3C).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('IDH1', 'Gene', (69, 73))	('mutations', 'Var', (368, 377))	('IDH1', 'Gene', '3417', (69, 73))	('IDH1', 'Gene', (238, 242))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('chromosome 1p19q codeletion', 'Var', (382, 409))	('IDH1', 'Gene', (53, 57))	('mutations', 'Var', (74, 83))	('IDH1', 'Gene', (363, 367))	('IDH1', 'Gene', '3417', (238, 242))	('IDH1', 'Gene', '3417', (111, 115))	('CNS tumors', 'Disease', 'MESH:D016543', (213, 223))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', '3417', (363, 367))	('CNS tumors', 'Disease', (213, 223))	('IDH1', 'Gene', (111, 115))
122453	31861486	To provide a more accurate prognosis prediction of LGGs, the expression status of the PSAT1 gene was incorporated with IDH1 mutation status and chromosome 1p19q codeletion status to stratify LGG patients into six subgroups (Figure 3D).	('LGGs', 'Disease', (51, 55))	('IDH1', 'Gene', (119, 123))	('patients', 'Species', '9606', (195, 203))	('LGG', 'Disease', (191, 194))	('mutation', 'Var', (124, 132))	('IDH1', 'Gene', '3417', (119, 123))	('PSAT1', 'Gene', (86, 91))	('PSAT1', 'Gene', '29968', (86, 91))
122454	31861486	When PSAT1 expression was incorporated, LGG patients with IDH1 mutations and chromosome 1p19q codeletion (n = 155) were significantly stratified into two clinically distinct subgroups depending on PSAT1 expression (p = 0.004628).	('mutations', 'Var', (63, 72))	('IDH1', 'Gene', '3417', (58, 62))	('patients', 'Species', '9606', (44, 52))	('PSAT1', 'Gene', (5, 10))	('PSAT1', 'Gene', '29968', (197, 202))	('PSAT1', 'Gene', '29968', (5, 10))	('PSAT1', 'Gene', (197, 202))	('IDH1', 'Gene', (58, 62))
122455	31861486	LGG patients with IDH1 mutations, chromosome 1p19q codeletion, and a high expression of PSAT1 (n = 66) had significantly better OS (median survival: 12.863 years; five-year survival rate: 100%) than those with a low expression of PSAT1 (n = 89) (median survival: 7.964 years; five-year survival rate: 67.0%).	('PSAT1', 'Gene', '29968', (88, 93))	('IDH1', 'Gene', '3417', (18, 22))	('PSAT1', 'Gene', (88, 93))	('better', 'PosReg', (121, 127))	('PSAT1', 'Gene', '29968', (230, 235))	('PSAT1', 'Gene', (230, 235))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (4, 12))	('IDH1', 'Gene', (18, 22))
122456	31861486	In addition, by incorporating PSAT1 expression, LGG patients with IDH1 mutations but not chromosome 1p19q codeletion (n = 249) were stratified into two distinct subgroups significantly (p = 0.033793).	('IDH1', 'Gene', '3417', (66, 70))	('LGG', 'Disease', (48, 51))	('PSAT1', 'Gene', (30, 35))	('PSAT1', 'Gene', '29968', (30, 35))	('mutations', 'Var', (71, 80))	('IDH1', 'Gene', (66, 70))	('patients', 'Species', '9606', (52, 60))
122457	31861486	LGG patients with IDH1 mutations and a high expression of PSAT1, but not chromosome 1p19q codeletion (n = 154) had significantly better OS (median survival: 8.186 years; five-year survival rate: 70.5%) than those with a low expression of PSAT1 (n = 95) (median survival: 5.296 years; five-year survival rate: 59.1%) (Figure 3D).	('better', 'PosReg', (129, 135))	('PSAT1', 'Gene', '29968', (238, 243))	('PSAT1', 'Gene', (238, 243))	('IDH1', 'Gene', '3417', (18, 22))	('mutations', 'Var', (23, 32))	('PSAT1', 'Gene', '29968', (58, 63))	('patients', 'Species', '9606', (4, 12))	('PSAT1', 'Gene', (58, 63))	('IDH1', 'Gene', (18, 22))
122459	31861486	Since the group with IDH1 mutations and a high expression of PSAT1, but not chromosome 1p19q codeletion (n = 154), had better OS (median survival: 8.186 years; five-year survival rate: 70.5%) than the group with IDH1 mutations, chromosome 1p19q codeletion and a low expression of PSAT1 (n = 89) (median survival: 7.964 years; five-year survival rate: 67.0%) (Figure 3D), we then tried to set up a new algorithm by incorporating PSAT1 expression with IDH1 mutation status (Figure 3E).	('PSAT1', 'Gene', (428, 433))	('PSAT1', 'Gene', '29968', (428, 433))	('PSAT1', 'Gene', (280, 285))	('PSAT1', 'Gene', '29968', (61, 66))	('PSAT1', 'Gene', (61, 66))	('PSAT1', 'Gene', '29968', (280, 285))	('mutations', 'Var', (26, 35))	('IDH1', 'Gene', (212, 216))	('IDH1', 'Gene', (450, 454))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (212, 216))	('IDH1', 'Gene', '3417', (450, 454))	('IDH1', 'Gene', '3417', (21, 25))
122460	31861486	PSAT1 expression significantly (p = 0.005027) separated LGG patients with IDH1 mutations into more distinct subgroups (Figure 3A) compared to chromosome 1p19q codeletion status (p = 0.044243) (Figure 3C).	('IDH1', 'Gene', (74, 78))	('patients', 'Species', '9606', (60, 68))	('PSAT1', 'Gene', '29968', (0, 5))	('LGG', 'Disease', (56, 59))	('PSAT1', 'Gene', (0, 5))	('IDH1', 'Gene', '3417', (74, 78))	('mutations', 'Var', (79, 88))
122461	31861486	Based on our results, we suggest a new algorithm for classifying LGG patients into more clinically relevant subgroups depending on IDH1 mutation status, the expression status of PSAT1 and chromosome 1p19q codeletion status (Figure 3E).	('IDH1', 'Gene', (131, 135))	('LGG', 'Disease', (65, 68))	('mutation', 'Var', (136, 144))	('IDH1', 'Gene', '3417', (131, 135))	('PSAT1', 'Gene', (178, 183))	('PSAT1', 'Gene', '29968', (178, 183))	('patients', 'Species', '9606', (69, 77))
122463	31861486	Although PSAT1 expression was relatively lower in LGGs with 1p19q codeletion, the stratification of combining IDH1 mutations, chromosome 1p19q codeletion and PSAT1 overexpression predicted the best OS in the TCGA LGG patients (median survival: 12.863 years; five-year survival rate: 100.0%; adjusted Hazard Ratio = 0.118) (Figure 3D,E).	('PSAT1', 'Gene', (9, 14))	('IDH1', 'Gene', '3417', (110, 114))	('mutations', 'Var', (115, 124))	('lower', 'NegReg', (41, 46))	('PSAT1', 'Gene', (158, 163))	('expression', 'MPA', (15, 25))	('PSAT1', 'Gene', '29968', (158, 163))	('patients', 'Species', '9606', (217, 225))	('IDH1', 'Gene', (110, 114))	('TCGA LGG', 'Disease', (208, 216))	('PSAT1', 'Gene', '29968', (9, 14))
122465	31861486	In our results, the expression levels of PSAT1 were also significantly higher in grade II and III gliomas with IDH1 mutations than in those of IDH1 wild-type (Figure 4A), and significantly higher in grade II gliomas than in grade III gliomas (Figure 4B).	('higher', 'PosReg', (71, 77))	('grade II', 'Disease', (81, 89))	('IDH1', 'Gene', (143, 147))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('IDH1', 'Gene', (111, 115))	('gliomas', 'Disease', (234, 241))	('gliomas', 'Disease', (98, 105))	('higher', 'PosReg', (189, 195))	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('IDH1', 'Gene', '3417', (143, 147))	('expression levels', 'MPA', (20, 37))	('IDH1', 'Gene', '3417', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('gliomas', 'Disease', (208, 215))	('mutations', 'Var', (116, 125))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('PSAT1', 'Gene', '29968', (41, 46))	('PSAT1', 'Gene', (41, 46))
122466	31861486	However, the expression levels of PSAT1 were not significantly distinct between 1p19q codeleted and 1p19q not-codeleted LGGs (Figure 4C).	('PSAT1', 'Gene', '29968', (34, 39))	('1p19q', 'Var', (100, 105))	('PSAT1', 'Gene', (34, 39))	('1p19q codeleted', 'Var', (80, 95))
122467	31861486	When LGG patients were classified into three groups (IDH1 wild-type, IDH1 mutations with 1p19q codeletion and IDH1 mutations without 1p19q codeletion) according to the guideline of the 2016 WHO classification of CNS tumors, the expression levels of PSAT1 were highest in the LGG group with IDH1 mutations but not chromosome 1p19q codeletion.	('CNS tumors', 'Disease', 'MESH:D016543', (212, 222))	('mutations', 'Var', (295, 304))	('IDH1', 'Gene', (110, 114))	('expression levels', 'MPA', (228, 245))	('IDH1', 'Gene', (69, 73))	('IDH1', 'Gene', '3417', (110, 114))	('PSAT1', 'Gene', '29968', (249, 254))	('LGG', 'Disease', (275, 278))	('PSAT1', 'Gene', (249, 254))	('IDH1', 'Gene', (53, 57))	('IDH1', 'Gene', (290, 294))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CNS tumors', 'Disease', (212, 222))	('patients', 'Species', '9606', (9, 17))	('highest', 'Reg', (260, 267))	('IDH1', 'Gene', '3417', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', '3417', (290, 294))
122469	31861486	When LGG patients in the CGGA dataset were classified into 4 groups according to the WHO grade and IDH1 mutation status, the expression levels of PSAT1 were highest in the group of grade II gliomas with IDH1 mutations, which was supposed to be the group with the best prognosis in LGGs (Figure 4E).	('PSAT1', 'Gene', '29968', (146, 151))	('patients', 'Species', '9606', (9, 17))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('highest', 'Reg', (157, 164))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('gliomas', 'Disease', (190, 197))	('mutations', 'Var', (208, 217))	('IDH1', 'Gene', '3417', (99, 103))	('expression levels', 'MPA', (125, 142))	('IDH1', 'Gene', (99, 103))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('IDH1', 'Gene', (203, 207))	('PSAT1', 'Gene', (146, 151))	('IDH1', 'Gene', '3417', (203, 207))
122470	31861486	The prognostic significance of IDH1 mutation status and 1p19q codeletion status in LGGs in the CGGA dataset were shown to be highly significant (Figure S3B).	('LGGs', 'Disease', (83, 87))	('IDH1', 'Gene', '3417', (31, 35))	('1p19q', 'Var', (56, 61))	('mutation status', 'Var', (36, 51))	('significant', 'Reg', (132, 143))	('IDH1', 'Gene', (31, 35))
122471	31861486	When LGG patients in the CGGA dataset were classified into two groups according to PSAT1 expression for survival analysis, patients with a high expression of PSAT1 were shown to have significantly (p = 0.004216) better OS (median survival: 5.679 years; five-year survival rate: 54.3%; adjusted HR = 0.629) than those with a low expression of PSAT1 (median survival: 3.652 years; five-year survival rate: 40.0%) (Figure 4F).	('high expression', 'Var', (139, 154))	('patients', 'Species', '9606', (9, 17))	('PSAT1', 'Gene', '29968', (342, 347))	('better', 'PosReg', (212, 218))	('PSAT1', 'Gene', (342, 347))	('patients', 'Species', '9606', (123, 131))	('PSAT1', 'Gene', (158, 163))	('PSAT1', 'Gene', '29968', (158, 163))	('PSAT1', 'Gene', (83, 88))	('PSAT1', 'Gene', '29968', (83, 88))
122472	31861486	When LGG patients were classified into three groups according to the guideline of the 2016 WHO classification of CNS tumors, patients with IDH1 mutations and 1p19q codeletion had the best OS (median survival: 6.879 years; five-year survival rate: 77.3%; adjusted HR = 0.221), but those with wild-type IDH1 had the worst OS (median survival: 2.003 years; five-year survival rate: 34.1%) (Figure 4G).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('IDH1', 'Gene', (139, 143))	('CNS tumors', 'Disease', 'MESH:D016543', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('IDH1', 'Gene', (301, 305))	('1p19q', 'Var', (158, 163))	('CNS tumors', 'Disease', (113, 123))	('IDH1', 'Gene', '3417', (139, 143))	('IDH1', 'Gene', '3417', (301, 305))	('mutations', 'Var', (144, 153))	('patients', 'Species', '9606', (125, 133))
122473	31861486	When LGG patients in the CGGA dataset were classified into 6 groups according to IDH1 mutation status, 1p19q codeletion status and the expression status of PSAT1, the group with IDH1 mutations, 1p19q codeletion and a high expression of PSAT1 had the best OS (median survival: 6.879 years; five-year survival rate: 93.9%; adjusted HR = 0.189), but the group with wild-type IDH1 and a high expression of PSAT1 had the worst OS (median survival: 1.836 years; five-year survival rate: 30.3%; adjusted HR = 2.009) (Figure 4H).	('patients', 'Species', '9606', (9, 17))	('IDH1', 'Gene', '3417', (178, 182))	('mutations', 'Var', (183, 192))	('PSAT1', 'Gene', '29968', (402, 407))	('IDH1', 'Gene', '3417', (372, 376))	('PSAT1', 'Gene', '29968', (156, 161))	('PSAT1', 'Gene', (236, 241))	('PSAT1', 'Gene', (156, 161))	('PSAT1', 'Gene', '29968', (236, 241))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', (178, 182))	('1p19q', 'Var', (194, 199))	('IDH1', 'Gene', '3417', (81, 85))	('IDH1', 'Gene', (372, 376))	('PSAT1', 'Gene', (402, 407))
122474	31861486	Overexpression of PSAT1 was shown to be a significantly favorable prognostic marker in IDH1-mutant LGGs with 1p19q codeletion (p = 0.006988) as well as in IDH1-mutant LGGs without 1p19q codeletion (p = 0.008510) in the CGGA cohort (Figure 4H).	('IDH1', 'Gene', (155, 159))	('IDH1', 'Gene', '3417', (87, 91))	('1p19q codeletion', 'Var', (109, 125))	('IDH1', 'Gene', '3417', (155, 159))	('PSAT1', 'Gene', (18, 23))	('IDH1', 'Gene', (87, 91))	('PSAT1', 'Gene', '29968', (18, 23))
122475	31861486	Our results confirmed that overexpression of the PSAT1 gene correlates with IDH1 mutations, a lower tumor grade, and a better outcome in LGGs in the CGGA dataset.	('IDH1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('IDH1', 'Gene', '3417', (76, 80))	('lower', 'NegReg', (94, 99))	('mutations', 'Var', (81, 90))	('overexpression', 'PosReg', (27, 41))	('PSAT1', 'Gene', '29968', (49, 54))	('LGGs', 'Disease', (137, 141))	('PSAT1', 'Gene', (49, 54))
122476	31861486	Furthermore, LGG patients with IDH1 mutations, 1p19q codeletion and overexpression of PSAT1 had the best prognosis of all patients.	('IDH1', 'Gene', '3417', (31, 35))	('1p19q codeletion', 'Var', (47, 63))	('mutations', 'Var', (36, 45))	('overexpression', 'PosReg', (68, 82))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (17, 25))	('PSAT1', 'Gene', (86, 91))	('PSAT1', 'Gene', '29968', (86, 91))	('IDH1', 'Gene', (31, 35))
122480	31861486	In addition, overexpression of the PSAT1 gene is significantly correlated with alive patient status, patient age <= 40, a lower WHO histological grade, IDH1 mutations, TP53 mutations, ATRX mutations, wild-type FUBP1, low expression of TERT and chromosome 1p19q noncodeletion, but not with wild-type CIC (Table 2).	('IDH1', 'Gene', (152, 156))	('overexpression', 'PosReg', (13, 27))	('FUBP1', 'Gene', (210, 215))	('TERT', 'Gene', (235, 239))	('TERT', 'Gene', '7015', (235, 239))	('TP53', 'Gene', '7157', (168, 172))	('CIC', 'Gene', (299, 302))	('IDH1', 'Gene', '3417', (152, 156))	('mutations', 'Var', (157, 166))	('mutations', 'Var', (189, 198))	('patient', 'Species', '9606', (85, 92))	('FUBP1', 'Gene', '8880', (210, 215))	('mutations', 'Var', (173, 182))	('ATRX', 'Gene', (184, 188))	('patient', 'Species', '9606', (101, 108))	('CIC', 'Gene', '23152', (299, 302))	('PSAT1', 'Gene', '29968', (35, 40))	('PSAT1', 'Gene', (35, 40))	('ATRX', 'Gene', '546', (184, 188))	('TP53', 'Gene', (168, 172))
122481	31861486	The correlations of PSAT1 overexpression with IDH1 mutations, a lower WHO grade and a favorable outcome of LGG patients were also validated in the CGGA dataset (Figure 4A,B,F) and the REMBRANT cohort (Figure S4).	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', (46, 50))	('WHO grade', 'CPA', (70, 79))	('overexpression', 'PosReg', (26, 40))	('lower', 'NegReg', (64, 69))	('IDH1', 'Gene', '3417', (46, 50))	('PSAT1', 'Gene', '29968', (20, 25))	('PSAT1', 'Gene', (20, 25))	('patients', 'Species', '9606', (111, 119))
122485	31861486	And the high promoter methylation status of the PSAT1 gene was shown to be a significantly favorable prognostic marker in the TCGA LGG cohort (Figure S5J).	('PSAT1', 'Gene', '29968', (48, 53))	('high', 'Var', (8, 12))	('PSAT1', 'Gene', (48, 53))	('TCGA LGG', 'Disease', (126, 134))
122486	31861486	Although the 2016 WHO classification of CNS tumors suggested using IDH1 mutation status and chromosome 1p19q codeletion status to stratify LGG patients into clinically distinct subgroups, this classification still remains limited in prognosis predictions.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('CNS tumors', 'Disease', 'MESH:D016543', (40, 50))	('IDH1', 'Gene', (67, 71))	('patients', 'Species', '9606', (143, 151))	('CNS tumors', 'Disease', (40, 50))	('IDH1', 'Gene', '3417', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('LGG', 'Disease', (139, 142))	('mutation', 'Var', (72, 80))
122487	31861486	For example, even though IDH1 mutations and chromosome 1p19q codeletions are both favorable prognostic markers, some LGG patients with those favorable prognostic markers still died rapidly.	('LGG', 'Disease', (117, 120))	('mutations', 'Var', (30, 39))	('IDH1', 'Gene', (25, 29))	('patients', 'Species', '9606', (121, 129))	('IDH1', 'Gene', '3417', (25, 29))
122489	31861486	In this study, we demonstrated that in LGG patients with IDH1 mutations and chromosome 1p19q codeletions, those with PSAT1 overexpression may have significantly (p = 0.004628) better OS (median survival: 12.863 years; five-year survival rate: 100%) than those with low PSAT1 expression (median survival: 7.964 years; five-year survival rate: 67.0%) (Figure 3D).	('PSAT1', 'Gene', '29968', (269, 274))	('PSAT1', 'Gene', (269, 274))	('patients', 'Species', '9606', (43, 51))	('IDH1', 'Gene', (57, 61))	('better', 'PosReg', (176, 182))	('IDH1', 'Gene', '3417', (57, 61))	('PSAT1', 'Gene', '29968', (117, 122))	('PSAT1', 'Gene', (117, 122))	('mutations', 'Var', (62, 71))
122493	31861486	However, a recent study suggested that a high level of PSAT1 protein could be a favorable prognostic marker for regorafenib-induced GBM suppression.	('regorafenib', 'Chemical', 'MESH:C559147', (112, 123))	('high', 'Var', (41, 45))	('GBM', 'Disease', (132, 135))	('GBM', 'Disease', 'MESH:D005909', (132, 135))	('protein', 'Protein', (61, 68))	('PSAT1', 'Gene', '29968', (55, 60))	('PSAT1', 'Gene', (55, 60))
122497	31861486	When IDH1 is mutated, there will be loss of its normal enzymatic function, the production of alpha-KG.	('production of', 'MPA', (79, 92))	('IDH1', 'Gene', (5, 9))	('loss', 'NegReg', (36, 40))	('normal enzymatic function', 'MPA', (48, 73))	('IDH1', 'Gene', '3417', (5, 9))	('mutated', 'Var', (13, 20))	('alpha-KG', 'Chemical', 'MESH:D007656', (93, 101))
122499	31861486	The mutation in the IDH1 gene was first described in cancers by Sjoblom et al.	('IDH1', 'Gene', '3417', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IDH1', 'Gene', (20, 24))
122500	31861486	and further identified to have clinical impact on GBM by Parsons et al.. To date, IDH1 mutations have been identified in a number of cancer types, especially in gliomas and acute myelogenous leukemia (AML).	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('AML', 'Disease', (201, 204))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (173, 199))	('GBM', 'Disease', (50, 53))	('IDH1', 'Gene', '3417', (82, 86))	('acute myelogenous leukemia', 'Disease', (173, 199))	('mutations', 'Var', (87, 96))	('GBM', 'Disease', 'MESH:D005909', (50, 53))	('gliomas', 'Disease', (161, 168))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (179, 199))	('cancer', 'Disease', (133, 139))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (173, 199))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('identified', 'Reg', (107, 117))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('IDH1', 'Gene', (82, 86))	('leukemia', 'Phenotype', 'HP:0001909', (191, 199))	('AML', 'Disease', 'MESH:D015470', (201, 204))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))
122501	31861486	IDH1 mutation is the most well-known prognostic biomarker of LGGs.	('IDH1', 'Gene', (0, 4))	('LGGs', 'Disease', (61, 65))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
122502	31861486	LGG patients with IDH1 mutations will have a better prognosis and therapeutic response than those with wild-type IDH1.	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', '3417', (113, 117))	('mutations', 'Var', (23, 32))	('therapeutic response', 'CPA', (66, 86))	('patients', 'Species', '9606', (4, 12))	('IDH1', 'Gene', (18, 22))
122503	31861486	Mutations in the IDH1 gene are commonly present in more than 70% of LGGs and secondary glioblastomas, which is consistent with our data (404/520 = 77.7%) (Figure 2B and Figure 3A).	('glioblastomas', 'Phenotype', 'HP:0012174', (87, 100))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (17, 21))	('glioblastomas', 'Disease', 'MESH:D005909', (87, 100))	('present', 'Reg', (40, 47))	('IDH1', 'Gene', '3417', (17, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('glioblastomas', 'Disease', (87, 100))
122504	31861486	However, the definite mechanism by which IDH1 mutations promote a favorable outcome in patients with LGGs is still not well elucidated.	('mutations', 'Var', (46, 55))	('LGGs', 'Disease', (101, 105))	('IDH1', 'Gene', (41, 45))	('promote', 'PosReg', (56, 63))	('patients', 'Species', '9606', (87, 95))	('IDH1', 'Gene', '3417', (41, 45))
122505	31861486	In our results, we observed a strong and significant correlation between IDH1 mutations and high expression of the PSAT1 gene (Figure 2B and Figure 4A) (Table 2).	('PSAT1', 'Gene', (115, 120))	('IDH1', 'Gene', '3417', (73, 77))	('mutations', 'Var', (78, 87))	('high expression', 'MPA', (92, 107))	('IDH1', 'Gene', (73, 77))	('PSAT1', 'Gene', '29968', (115, 120))
122507	31861486	Based on our findings, we hypothesized that there might be a strong connection between IDH1 mutations and PSAT1 overexpression to promote a favorable outcome of LGG patients.	('LGG', 'Disease', (161, 164))	('promote', 'PosReg', (130, 137))	('IDH1', 'Gene', '3417', (87, 91))	('overexpression', 'PosReg', (112, 126))	('PSAT1', 'Gene', (106, 111))	('mutations', 'Var', (92, 101))	('PSAT1', 'Gene', '29968', (106, 111))	('patients', 'Species', '9606', (165, 173))	('IDH1', 'Gene', (87, 91))
122510	31861486	Conversely, mutant IDH1 converts alpha-KG to R-2-hydroxyglutarate (R-2HG) (Figure 5B).	('alpha-KG', 'Chemical', 'MESH:D007656', (33, 41))	('IDH1', 'Gene', (19, 23))	('mutant', 'Var', (12, 18))	('IDH1', 'Gene', '3417', (19, 23))	('R-2-hydroxyglutarate', 'Chemical', '-', (45, 65))
122511	31861486	This finding is compatible with our hypothesis that overexpression of the PSAT1 gene increases the production of alpha-KG which could be the substrate for mutant IDH1 to convert NADPH to NADP+ and gain R-2HG (Figure 5B).	('production of', 'MPA', (99, 112))	('PSAT1', 'Gene', (74, 79))	('convert', 'Reg', (170, 177))	('NADPH', 'Chemical', 'MESH:D009249', (178, 183))	('IDH1', 'Gene', '3417', (162, 166))	('PSAT1', 'Gene', '29968', (74, 79))	('alpha-KG', 'Chemical', 'MESH:D007656', (113, 121))	('mutant', 'Var', (155, 161))	('alpha-KG', 'Protein', (113, 121))	('NADPH', 'MPA', (178, 183))	('gain', 'PosReg', (197, 201))	('NADP+', 'Chemical', 'MESH:D009249', (187, 192))	('R-2HG', 'CPA', (202, 207))	('increases', 'PosReg', (85, 94))	('IDH1', 'Gene', (162, 166))
122513	31861486	In this study, we observed a strong and significant correlation between IDH1 mutations and high expression of PSAT1.	('PSAT1', 'Gene', '29968', (110, 115))	('PSAT1', 'Gene', (110, 115))	('IDH1', 'Gene', (72, 76))	('high expression', 'MPA', (91, 106))	('IDH1', 'Gene', '3417', (72, 76))	('mutations', 'Var', (77, 86))
122515	31861486	From the literature review, we noticed there might be a coordinated biological reaction between IDH1 mutations and a high expression of PSAT1.	('IDH1', 'Gene', '3417', (96, 100))	('mutations', 'Var', (101, 110))	('PSAT1', 'Gene', '29968', (136, 141))	('PSAT1', 'Gene', (136, 141))	('IDH1', 'Gene', (96, 100))
122516	31861486	Our results suggested that overexpression of the PSAT1 gene contributes to a favorable outcome in patients with LGGs, which is probably related to therapeutic resistance induced by IDH1 mutations, and overexpression of PSAT1 promote alpha-KG synthesis, which could enhance the function of mutant IDH1.	('function', 'MPA', (277, 285))	('mutations', 'Var', (186, 195))	('alpha-KG synthesis', 'MPA', (233, 251))	('enhance', 'PosReg', (265, 272))	('IDH1', 'Gene', '3417', (296, 300))	('PSAT1', 'Gene', (49, 54))	('mutant', 'Var', (289, 295))	('patients', 'Species', '9606', (98, 106))	('alpha-KG', 'Chemical', 'MESH:D007656', (233, 241))	('IDH1', 'Gene', (181, 185))	('PSAT1', 'Gene', '29968', (219, 224))	('PSAT1', 'Gene', (219, 224))	('IDH1', 'Gene', (296, 300))	('PSAT1', 'Gene', '29968', (49, 54))	('LGGs', 'Disease', (112, 116))	('promote', 'PosReg', (225, 232))	('IDH1', 'Gene', '3417', (181, 185))
122518	31861486	And overexpression of PSAT1 could be incorporated with IDH1 mutations and chromosome 1p19q codeletion to classify LGG patients and predict those with the best overall survival.	('IDH1', 'Gene', '3417', (55, 59))	('LGG', 'Disease', (114, 117))	('PSAT1', 'Gene', '29968', (22, 27))	('PSAT1', 'Gene', (22, 27))	('mutations', 'Var', (60, 69))	('patients', 'Species', '9606', (118, 126))	('IDH1', 'Gene', (55, 59))
122519	31861486	Our results also suggested the coordinated biological reaction between IDH1 mutations and overexpression of PSAT1, which may contribute to a favorable outcome in patients with LGGs.	('patients', 'Species', '9606', (162, 170))	('PSAT1', 'Gene', '29968', (108, 113))	('mutations', 'Var', (76, 85))	('LGGs', 'Disease', (176, 180))	('IDH1', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (71, 75))	('overexpression', 'PosReg', (90, 104))	('PSAT1', 'Gene', (108, 113))
122524	31861486	The clinical information and gene expression profiles of LGG patients in the CGGA dataset (n = 318), including IDH1 mutation status, chromosome 1p19q codeletion status, the WHO histological grade, expression levels of PSAT1, overall survival time, and survival status were collected from the CGGA website  (Table S2).	('PSAT1', 'Gene', '29968', (218, 223))	('PSAT1', 'Gene', (218, 223))	('mutation', 'Var', (116, 124))	('IDH1', 'Gene', '3417', (111, 115))	('patients', 'Species', '9606', (61, 69))	('IDH1', 'Gene', (111, 115))
122530	31861486	Our findings suggest that overexpression of the PSAT1 gene severs as a favorable prognostic marker of LGGs, which could assist the limitation of IDH1 mutations and chromosome 1p19q codeletion in the prognostication of LGGs clinically.	('IDH1', 'Gene', (145, 149))	('overexpression', 'PosReg', (26, 40))	('IDH1', 'Gene', '3417', (145, 149))	('mutations', 'Var', (150, 159))	('PSAT1', 'Gene', (48, 53))	('LGGs', 'Disease', (218, 222))	('LGGs', 'Disease', (102, 106))	('PSAT1', 'Gene', '29968', (48, 53))
122610	29071540	MEK inhibitors block signalling of the MAPK pathway downstream of RAF, thereby thought to circumvent the problems encountered in first generation BRAF inhibitors.	('RAF', 'Gene', '22882', (147, 150))	('BRAF', 'Gene', (146, 150))	('RAF', 'Gene', (66, 69))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('block', 'NegReg', (15, 20))	('MAPK pathway', 'Pathway', (39, 51))	('inhibitors', 'Var', (4, 14))	('BRAF', 'Gene', '673', (146, 150))	('signalling', 'MPA', (21, 31))	('RAF', 'Gene', (147, 150))	('RAF', 'Gene', '22882', (66, 69))
122634	27385209	In gliomas with major genomic lesions unrelated to RTK pathway, high RMPA signature was associated with short survival.	('high', 'Var', (64, 68))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('short survival', 'MPA', (104, 118))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))	('RMPA', 'Chemical', '-', (69, 73))
122645	27385209	EGFR, PDGFRA, FGFR1, FGFR2, FGFR4 and MET are frequently amplified, mutated, or fused in high-grade gliomas or in secondary GBMs.	('FGFR4', 'Gene', (28, 33))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('FGFR2', 'Gene', (21, 26))	('fused', 'Reg', (80, 85))	('PDGFRA', 'Gene', (6, 12))	('EGFR', 'Gene', (0, 4))	('FGFR2', 'Gene', '2263', (21, 26))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('PDGFRA', 'Gene', '5156', (6, 12))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('FGFR1', 'Gene', (14, 19))	('MET', 'Gene', (38, 41))	('FGFR1', 'Gene', '2260', (14, 19))	('mutated', 'Var', (68, 75))	('EGFR', 'Gene', '1956', (0, 4))	('gliomas', 'Disease', (100, 107))	('FGFR4', 'Gene', '2264', (28, 33))
122646	27385209	Co-activation of multiple RTKs, and mosaic amplification of EGFR and PDGFRA have been observed in a small subset of GBMs.	('mosaic amplification', 'Var', (36, 56))	('PDGFRA', 'Gene', (69, 75))	('PDGFRA', 'Gene', '5156', (69, 75))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (60, 64))
122648	27385209	Along the RAS-RAF-MEK-MAPK cascade, somatic mutations which inactivate or delete NF1, the RAS-GTPase inhibitor, are found in about 10% of the GBMs.	('RAF', 'Gene', (14, 17))	('RAF', 'Gene', '22882', (14, 17))	('NF1', 'Gene', (81, 84))	('MEK', 'Gene', (18, 21))	('NF1', 'Gene', '4763', (81, 84))	('mutations', 'Var', (44, 53))	('MEK', 'Gene', '5609', (18, 21))	('delete', 'Var', (74, 80))	('inactivate', 'Var', (60, 70))
122650	27385209	Both of these alterations can result in activation of the RAS-RAF-MEK-MAPK cascade.	('alterations', 'Var', (14, 25))	('RAF', 'Gene', (62, 65))	('MEK', 'Gene', (66, 69))	('MEK', 'Gene', '5609', (66, 69))	('activation', 'PosReg', (40, 50))	('RAF', 'Gene', '22882', (62, 65))
122651	27385209	In the PI3K-AKT pathway, mutations, including deletions, in PTEN, and amplification or activating mutations in the catalytic component p110alpha or regulatory component p85alpha of PI3K, occur in GBMs in a mutually exclusively manner.	('p85alpha', 'Gene', (169, 177))	('p110alpha', 'Gene', '5290', (135, 144))	('p85alpha', 'Gene', '5295', (169, 177))	('p110alpha', 'Gene', (135, 144))	('PI3K-AKT pathway', 'Pathway', (7, 23))	('PTEN', 'Gene', (60, 64))	('activating', 'PosReg', (87, 97))	('PTEN', 'Gene', '5728', (60, 64))	('deletions', 'Var', (46, 55))
122670	27385209	The two RMPA subtypes were associated with distinct prognoses, harbored unique sets of somatic copy number alterations (SCNA) in RTK-related genes, and contained different extents of angiogenic activities and infiltrating immune cells.	('RMPA', 'Chemical', '-', (8, 12))	('associated', 'Reg', (27, 37))	('RTK-related genes', 'Gene', (129, 146))	('copy number alterations', 'Var', (95, 118))
122672	27385209	Among the top 100 probe sets most closely correlated to SPRY1 (212558_at), 48 common probe sets encoding 26 genes also closely co-expressed with SPRY2 (204011_at) and SPRY4 (221489_s_at) were defined as the SPRY-module (SPRY-M).	('SPRY1', 'Gene', '10252', (56, 61))	('SPRY1', 'Gene', (56, 61))	('SPRY2', 'Gene', (145, 150))	('SPRY4', 'Gene', '81848', (167, 172))	('SPRY2', 'Gene', '10253', (145, 150))	('204011_at', 'Var', (152, 161))	('SPRY4', 'Gene', (167, 172))
122673	27385209	Similarly, the top 100 most closely co-expressed probe sets to NF1 (212678-at) and PTEN (225363-at), corresponding to 85 and 79 genes respectively, were defined as the NF1-M and PTEN-M (Supplementary Table S1).	('PTEN', 'Gene', (178, 182))	('PTEN', 'Gene', '5728', (83, 87))	('PTEN', 'Gene', '5728', (178, 182))	('NF1', 'Gene', '4763', (63, 66))	('PTEN-M', 'Gene', (178, 184))	('PTEN-M', 'Gene', '5728', (178, 184))	('NF1', 'Gene', (168, 171))	('NF1', 'Gene', '4763', (168, 171))	('212678-at', 'Var', (68, 77))	('225363-at', 'Var', (89, 98))	('NF1', 'Gene', (63, 66))	('PTEN', 'Gene', (83, 87))
122683	27385209	In all data sets analyzed, patients with the RMPAlow subtype were associated with a highly significantly longer survival compared to the patients with the RMPAhigh subtype (Figure 1 and Supplementary Figure S2).	('longer', 'PosReg', (105, 111))	('RMPA', 'Chemical', '-', (155, 159))	('patients', 'Species', '9606', (137, 145))	('Supplementary Figure S2', 'Disease', (186, 209))	('Supplementary Figure S2', 'Disease', 'MESH:D017034', (186, 209))	('patients', 'Species', '9606', (27, 35))	('survival', 'MPA', (112, 120))	('RMPAlow', 'Var', (45, 52))	('RMPA', 'Chemical', '-', (45, 49))
122685	27385209	Using morphological criteria for diagnosis, patients with high-grade gliomas are often associated with poor survival compared with patients with low-grade gliomas, but there is considerable heterogeneity in the survival time of both high and low grade gliomas.	('patients', 'Species', '9606', (131, 139))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('patients', 'Species', '9606', (44, 52))	('gliomas', 'Disease', 'MESH:D005910', (252, 259))	('gliomas', 'Phenotype', 'HP:0009733', (252, 259))	('gliomas', 'Disease', (252, 259))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('poor', 'NegReg', (103, 107))	('gliomas', 'Disease', (155, 162))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))	('high-grade', 'Var', (58, 68))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
122688	27385209	Weak and region-dependent staining of p-ERK and p-AKT was observed in the RMPAlow gliomas, whereas RMPAhigh gliomas showed wide-spread and more intense staining of p-ERK and p-AKT, irrespective of their morphological diagnosis.	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (99, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('p-AKT', 'Protein', (174, 179))	('RMPAlow gliomas', 'Disease', (74, 89))	('RMPAhigh gliomas', 'Disease', (99, 115))	('RMPAlow gliomas', 'Disease', 'MESH:D005910', (74, 89))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('p-ERK', 'Var', (38, 43))	('p-ERK', 'Protein', (164, 169))
122698	27385209	To search for genomic alterations potentially causal for the RMPAhigh signature, we analyzed the SCNA and mutations in the RTKs/RTK ligands, and in the key members of the RAS-RAF-MEK-MAPK cascade and the PI3K-AKT pathway in the TCGA mRNA-seq database (Supplementary Table S6).	('RAF', 'Gene', '22882', (175, 178))	('RTKs/RTK', 'Gene', (123, 131))	('MEK', 'Gene', (179, 182))	('MEK', 'Gene', '5609', (179, 182))	('RMPA', 'Chemical', '-', (61, 65))	('mutations', 'Var', (106, 115))	('RAF', 'Gene', (175, 178))	('PI3K-AKT pathway', 'Pathway', (204, 220))
122700	27385209	Among the 166 RMPAhigh gliomas, 88 harbored focal amplification of EGFR, and 35 of these EGFR amplifications also harbored mutations in EGFR; an additional 7 RMPAhigh gliomas harbored EGFR mutations without detectable focal amplification (Supplementary Table S6).	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (158, 174))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (14, 30))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('EGFR', 'Gene', (67, 71))	('RMPAhigh gliomas', 'Disease', (158, 174))	('RMPAhigh gliomas', 'Disease', (14, 30))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('EGFR', 'Gene', (184, 188))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('mutations', 'Var', (189, 198))	('EGFR', 'Gene', (136, 140))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (67, 71))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('EGFR', 'Gene', '1956', (184, 188))	('harbored', 'Reg', (114, 122))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', '1956', (89, 93))	('mutations', 'Var', (123, 132))
122701	27385209	Compared with those RMPAhigh gliomas without EGFR alterations, RMPAhigh gliomas with EGFR alterations showed higher EGFR expression (Supplementary Figure S4).	('alterations', 'Var', (90, 101))	('EGFR', 'Gene', (85, 89))	('RMPAhigh gliomas', 'Disease', (20, 36))	('RMPAhigh gliomas', 'Disease', (63, 79))	('EGFR', 'Gene', (45, 49))	('higher', 'PosReg', (109, 115))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('expression', 'MPA', (121, 131))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (20, 36))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (63, 79))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('EGFR', 'Gene', '1956', (45, 49))
122702	27385209	However, unsupervised principle component analysis of the global transcriptome data showed similar transcriptomic profiles between the RMPAhigh gliomas with or without EGFR alterations (Supplementary Figure S5).	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (135, 151))	('EGFR', 'Gene', '1956', (168, 172))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('EGFR', 'Gene', (168, 172))	('alterations', 'Var', (173, 184))	('RMPAhigh gliomas', 'Disease', (135, 151))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))
122704	27385209	Amplifications and mutations of PDGFRA, KIT and KDR were found in 8-15% of RMPAhigh gliomas, followed by EPHB3 (7.7%), FGFR1 (5.9%), FGFR3 (5.9%) and MET (4.1%) (Supplementary Table S6).	('FGFR3', 'Gene', (133, 138))	('EPHB3', 'Gene', (105, 110))	('KDR', 'Gene', (48, 51))	('FGFR1', 'Gene', (119, 124))	('found', 'Reg', (57, 62))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (75, 91))	('mutations', 'Var', (19, 28))	('EPHB3', 'Gene', '2049', (105, 110))	('KIT', 'Gene', (40, 43))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('FGFR1', 'Gene', '2260', (119, 124))	('PDGFRA', 'Gene', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('FGFR3', 'Gene', '2261', (133, 138))	('PDGFRA', 'Gene', '5156', (32, 38))	('RMPAhigh gliomas', 'Disease', (75, 91))	('KDR', 'Gene', '3791', (48, 51))
122706	27385209	Losses and mutations of NF1 and PTEN, as well as amplification and mutation of PIK3CA were preferentially found in the RMPAhigh gliomas.	('mutations', 'Var', (11, 20))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('mutation', 'Var', (67, 75))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (119, 135))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('found', 'Reg', (106, 111))	('PIK3CA', 'Gene', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('RMPAhigh gliomas', 'Disease', (119, 135))	('NF1', 'Gene', (24, 27))	('PIK3CA', 'Gene', '5290', (79, 85))	('NF1', 'Gene', '4763', (24, 27))
122708	27385209	A tendency towards mutual exclusivity between the loss or mutation of NF1 and amplification or mutation of EGFR was observed using Fisher's exact tests (Supplementary Table S7), indicating that both types of alteration may be sufficient to activate the RAS-RAF-MEK-MAPK cascade in RMPAhigh gliomas.	('RAF', 'Gene', (257, 260))	('glioma', 'Phenotype', 'HP:0009733', (290, 296))	('NF1', 'Gene', '4763', (70, 73))	('EGFR', 'Gene', '1956', (107, 111))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (281, 297))	('loss', 'NegReg', (50, 54))	('activate', 'PosReg', (240, 248))	('MEK', 'Gene', (261, 264))	('EGFR', 'Gene', (107, 111))	('MEK', 'Gene', '5609', (261, 264))	('mutation', 'Var', (58, 66))	('gliomas', 'Phenotype', 'HP:0009733', (290, 297))	('RMPAhigh gliomas', 'Disease', (281, 297))	('RAF', 'Gene', '22882', (257, 260))	('NF1', 'Gene', (70, 73))	('alteration', 'Var', (208, 218))
122709	27385209	Co-occurrence between amplification of EPHB3 and alterations in PIK3CA (both at chromosome 3q26-3q27), and amplifications in PDGFRA, KIT and KDR (all at 4q12) were also found in a subset of RMPAhigh gliomas (Supplementary Table S7), due to their localization in the common amplicons (Supplementary Figure S6).	('EPHB3', 'Gene', (39, 44))	('PIK3CA', 'Gene', (64, 70))	('alterations', 'Var', (49, 60))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('found', 'Reg', (169, 174))	('KDR', 'Gene', (141, 144))	('PDGFRA', 'Gene', '5156', (125, 131))	('PDGFRA', 'Gene', (125, 131))	('PIK3CA', 'Gene', '5290', (64, 70))	('RMPAhigh gliomas', 'Disease', (190, 206))	('amplification', 'Var', (22, 35))	('KIT', 'Gene', (133, 136))	('EPHB3', 'Gene', '2049', (39, 44))	('KDR', 'Gene', '3791', (141, 144))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (190, 206))
122713	27385209	The amplifications of BRAF, EPHB4, FGF23 and INSRR were associated with gene-dosage related changes in expression (Supplementary Table S6).	('expression', 'MPA', (103, 113))	('INSRR', 'Gene', (45, 50))	('amplifications', 'Var', (4, 18))	('BRAF', 'Gene', '673', (22, 26))	('FGF23', 'Gene', '8074', (35, 40))	('BRAF', 'Gene', (22, 26))	('EPHB4', 'Gene', '2050', (28, 33))	('INSRR', 'Gene', '3645', (45, 50))	('EPHB4', 'Gene', (28, 33))	('FGF23', 'Gene', (35, 40))
122719	27385209	Thus, recurrent loss of chromosomal regions and frequent mutations in PTEN and NF1 strongly contributed to the weak expression and functional loss of NF1-M and PTEN-M in the RMPAhigh glioma subtype.	('expression', 'MPA', (116, 126))	('PTEN-M', 'Gene', (160, 166))	('glioma subtype', 'Disease', 'MESH:D005910', (183, 197))	('loss', 'NegReg', (142, 146))	('weak', 'NegReg', (111, 115))	('NF1', 'Gene', (150, 153))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', (160, 164))	('PTEN', 'Gene', '5728', (70, 74))	('glioma subtype', 'Disease', (183, 197))	('PTEN', 'Gene', '5728', (160, 164))	('NF1', 'Gene', '4763', (150, 153))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('NF1', 'Gene', '4763', (79, 82))	('mutations', 'Var', (57, 66))	('NF1', 'Gene', (79, 82))	('RMPA', 'Chemical', '-', (174, 178))	('PTEN-M', 'Gene', '5728', (160, 166))
122723	27385209	In addition, the vast majority of the gliomas with IDH1 mutation were found in the RMPAlow subtype.	('IDH1', 'Gene', '3417', (51, 55))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('RMPAlow', 'Disease', (83, 90))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))	('gliomas', 'Disease', (38, 45))	('found', 'Reg', (70, 75))	('RMPA', 'Chemical', '-', (83, 87))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
122727	27385209	Mutual exclusivity was found between the alterations in EGFR and NF1, co-occurrences of SCNAs in RTK-signaling genes were due to their location in the common amplicons.	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (65, 68))	('alterations', 'Var', (41, 52))
122728	27385209	Further, recurrent genomic losses in the members in PTEN-M and NF1-M directly caused their weak expression in the RMPAhigh gliomas.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('genomic losses', 'Var', (19, 33))	('RMPAhigh gliomas', 'Disease', (114, 130))	('expression', 'MPA', (96, 106))	('PTEN-M', 'Gene', (52, 58))	('PTEN-M', 'Gene', '5728', (52, 58))	('RMPAhigh gliomas', 'Disease', 'MESH:D005910', (114, 130))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('weak', 'NegReg', (91, 95))	('NF1', 'Gene', (63, 66))	('NF1', 'Gene', '4763', (63, 66))
122739	27385209	Though the cohort size was limited, patients with gliomas of RMPAhigh signature were associated with poor survival compared with patients with RMPAlow gliomas (Supplementary Figure S8).	('poor', 'NegReg', (101, 105))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (129, 137))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Disease', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('RMPA', 'Chemical', '-', (61, 65))	('RMPAlow gliomas', 'Disease', (143, 158))	('RMPA', 'Chemical', '-', (143, 147))	('gliomas', 'Disease', (151, 158))	('RMPAhigh', 'Var', (61, 69))	('survival', 'MPA', (106, 114))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('RMPAlow gliomas', 'Disease', 'MESH:D005910', (143, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
122740	27385209	Cells from these RMPAhigh or RMPAlow gliomas were co-stained with APC-conjugated mAb against CD45 (for labeling infiltrating immune cells) or CD105 (for labeling immature proliferating vessel endothelial cells), and one of the PE-conjugated mAb for RTK.	('CD45', 'Gene', (93, 97))	('RMPA', 'Chemical', '-', (29, 33))	('CD105', 'Var', (142, 147))	('RMPAlow gliomas', 'Disease', (29, 44))	('RMPAlow gliomas', 'Disease', 'MESH:D005910', (29, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('CD45', 'Gene', '5788', (93, 97))	('RMPA', 'Chemical', '-', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
122754	27385209	IDH1 mutation and co-deletion of chromosome 1p19q, but not the alterations in RTK pathway genes, are the predominant form of somatic genomic alterations in PM gliomas.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('co-deletion', 'Var', (18, 29))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
122764	27385209	Due to an amplicon at chromosome 7q, about 9% of the RMPAlow gliomas harbored amplifications of MET, EPHA1, EPHB4, EPHB6, and BRAF.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('EPHA1', 'Gene', (101, 106))	('amplifications', 'Var', (78, 92))	('EPHB6', 'Gene', (115, 120))	('RMPAlow gliomas', 'Disease', (53, 68))	('EPHB6', 'Gene', '2051', (115, 120))	('MET', 'Gene', (96, 99))	('RMPAlow gliomas', 'Disease', 'MESH:D005910', (53, 68))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('EPHA1', 'Gene', '2041', (101, 106))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('EPHB4', 'Gene', '2050', (108, 113))	('EPHB4', 'Gene', (108, 113))
122785	27385209	Using Pearson correlation coefficient analysis in glioma gene expression database GSE4290 including the transcriptome data from 157 adult diffuse gliomas WHO grades II-IV and 23 epileptic brain samples, we first identified the top 100 most correlated probe sets to SPRY1 (212558_at), SPRY2 (204011_at) or SPRY4 (221489_s_at).	('SPRY1', 'Gene', (265, 270))	('epileptic', 'Disease', 'MESH:D004827', (178, 187))	('gliomas', 'Disease', (146, 153))	('epileptic', 'Disease', (178, 187))	('glioma', 'Disease', (146, 152))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('SPRY4', 'Gene', (305, 310))	('204011_at', 'Var', (291, 300))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('GSE4290', 'Chemical', '-', (82, 89))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('SPRY2', 'Gene', '10253', (284, 289))	('SPRY1', 'Gene', '10252', (265, 270))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('SPRY4', 'Gene', '81848', (305, 310))	('SPRY2', 'Gene', (284, 289))
122786	27385209	Similarly, the top 100 most closely co-expressed probe sets to NF1 (212678-at) and PTEN (225363-at), corresponding to 85 and 79 genes, respectively, were identified as NF1-M and PTEN-M (Supplementary Table S1).	('PTEN', 'Gene', (178, 182))	('PTEN', 'Gene', '5728', (83, 87))	('PTEN', 'Gene', '5728', (178, 182))	('NF1', 'Gene', '4763', (63, 66))	('PTEN-M', 'Gene', (178, 184))	('PTEN-M', 'Gene', '5728', (178, 184))	('NF1', 'Gene', (168, 171))	('NF1', 'Gene', '4763', (168, 171))	('212678-at', 'Var', (68, 77))	('225363-at', 'Var', (89, 98))	('NF1', 'Gene', (63, 66))	('PTEN', 'Gene', (83, 87))
122797	27385209	Alexa Fluor  555 conjugated goat anti-rabbit IgG (Life Sciences) was used in detecting anti-p-ERK and anti-p-AKT, Alexa Fluor  647 conjugated Goat anti-Mouse IgG (life) was used in detecting anti-CD31 and anti-CD68.	('rabbit', 'Species', '9986', (38, 44))	('Alexa Fluor  555', 'Chemical', 'MESH:C000608607', (0, 16))	('anti-p-ERK', 'Var', (87, 97))	('anti-CD68', 'Var', (205, 214))	('goat', 'Species', '9925', (28, 32))	('anti-CD31', 'Var', (191, 200))	('Goat', 'Species', '9925', (142, 146))	('Alexa Fluor  647', 'Chemical', 'MESH:C569686', (114, 130))	('Mouse', 'Species', '10090', (152, 157))
122810	27385209	About 5x105 cells were then stained with allophycocyanin (APC)-conjugated anti-CD45 (clone H130, Biolegend), or anti-CD105 (clone 43A3, Biolegend) monoclonal antibodies (mAb) in combination with a phycoerythrin (PE)-conjugated mAb against one of the RTKs including PDGFRA (clone 16A1, Biolegend), EGFR (clone AY13, Biolegend), EPHA2 (clone 371805, R&D), EPHB4 (clone 395810, R&D), MET (clone 95106, R&D), ERBB2 (clone Neu 24.7, BD), PLXNB2 (clone 537223, R&D), VEGFR1 (clone 49560, R&D), KDR (clone 89106, R&D), NRP1 (clone12C2, Biolegend), at saturating concentrations or the isotype-matched control mAbs at 4 C for 15 minutes.	('VEGFR1', 'Gene', '2321', (461, 467))	('EPHA2', 'Gene', '1969', (327, 332))	('VEGFR1', 'Gene', (461, 467))	('PLXNB2', 'Gene', (433, 439))	('ERBB2', 'Gene', (405, 410))	('EGFR', 'Gene', (297, 301))	('&D', 'Var', (483, 485))	('KDR', 'Gene', (488, 491))	('ERBB2', 'Gene', '2064', (405, 410))	('EGFR', 'Gene', (462, 466))	('EPHB4', 'Gene', (354, 359))	('CD45', 'Gene', (79, 83))	('PDGFRA', 'Gene', '5156', (265, 271))	('PDGFRA', 'Gene', (265, 271))	('CD45', 'Gene', '5788', (79, 83))	('EGFR', 'Gene', '1956', (297, 301))	('EPHA2', 'Gene', (327, 332))	('KDR', 'Gene', '3791', (488, 491))	('PLXNB2', 'Gene', '23654', (433, 439))	('EGFR', 'Gene', '1956', (462, 466))	('NRP1', 'Gene', '8829', (512, 516))	('NRP1', 'Gene', (512, 516))	('EPHB4', 'Gene', '2050', (354, 359))
122822	27121858	Patients with high CHI3L1 expression had a shorter overall survival (p < 0.001).	('expression', 'MPA', (26, 36))	('CHI3L1', 'Gene', '1116', (19, 25))	('high', 'Var', (14, 18))	('overall survival', 'MPA', (51, 67))	('Patients', 'Species', '9606', (0, 8))	('CHI3L1', 'Gene', (19, 25))	('shorter', 'NegReg', (43, 50))
122922	27121858	Recent discoveries found that CHI3L1 acts on glioblastoma-stem like cells (GSCs) to drive the formation of tumour vascularization and targeting CHI3L1 may compliment conventional anti-angiogenic therapies to provide a substantial clinical benefit to patients with GBM.	('CHI3L1', 'Gene', (144, 150))	('CHI3L1', 'Gene', '1116', (30, 36))	('targeting', 'Var', (134, 143))	('patients', 'Species', '9606', (250, 258))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('CHI3L1', 'Gene', '1116', (144, 150))	('glioblastoma', 'Disease', (45, 57))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', (107, 113))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('CHI3L1', 'Gene', (30, 36))
122925	25956465	Metabolic consequences of oncogenic IDH mutations Specific point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in a variety of cancers, including acute myeloid leukemia (AML), low-grade gliomas, and chondrosarcomas.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (174, 190))	('IDH', 'Gene', (121, 124))	('AML', 'Disease', 'MESH:D015470', (192, 195))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('IDH', 'Gene', (112, 115))	('AML', 'Disease', (192, 195))	('AML', 'Phenotype', 'HP:0004808', (192, 195))	('chondrosarcomas', 'Disease', (221, 236))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (168, 190))	('leukemia', 'Phenotype', 'HP:0001909', (182, 190))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (168, 190))	('point mutations', 'Var', (59, 74))	('mutations', 'Var', (40, 49))	('IDH', 'Gene', '3417', (121, 124))	('IDH', 'Gene', '3417', (112, 115))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancers', 'Disease', (149, 156))	('occur', 'Reg', (127, 132))	('gliomas', 'Disease', (208, 215))	('IDH', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (221, 235))	('isocitrate dehydrogenase 1', 'Gene', (78, 104))	('isocitrate dehydrogenase 1', 'Gene', '3417', (78, 104))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (221, 236))	('acute myeloid leukemia', 'Disease', (168, 190))	('IDH', 'Gene', '3417', (36, 39))	('chondrosarcomas', 'Disease', 'MESH:D002813', (221, 236))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
122926	25956465	These mutations inactivate wild-type enzymatic activity and convey neomorphic function to produce D-2-hydroxyglutarate (D-2HG), which accumulates at millimolar levels within tumors.	('D-2-', 'Gene', '1734', (98, 102))	('inactivate', 'NegReg', (16, 26))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('D-2', 'Gene', (120, 123))	('D-2', 'Gene', (98, 101))	('D-2-', 'Gene', (98, 102))	('D-2', 'Gene', '1734', (98, 101))	('D-2', 'Gene', '1734', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutations', 'Var', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('wild-type', 'MPA', (27, 36))
122928	25956465	Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors.	('neomorphic', 'CPA', (18, 28))	('mutant', 'Var', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('IDH2', 'Gene', (57, 61))	('blood tumors', 'Disease', (125, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('blood tumors', 'Disease', 'MESH:D009383', (125, 137))	('solid', 'Disease', (115, 120))	('IDH1', 'Gene', (48, 52))	('blood tumors', 'Phenotype', 'HP:0004377', (125, 137))
122929	25956465	As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism.	('IDH2', 'Gene', (12, 16))	('impact', 'Reg', (109, 115))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (50, 68))	('mutations', 'Var', (82, 91))	('TCA', 'Chemical', 'MESH:D014233', (70, 73))	('IDH1', 'Gene', (3, 7))	('intermediary metabolism', 'MPA', (119, 142))
122930	25956465	The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future.	('IDH', 'Gene', (144, 147))	('mutations', 'Var', (148, 157))	('IDH', 'Gene', '3417', (144, 147))	('wild-type metabolic activity', 'MPA', (17, 45))	('loss', 'NegReg', (4, 8))
122931	25956465	Here we review how IDH1 and IDH2 mutations influence cellular metabolism, epigenetics, and other biochemical functions, discussing these changes in the context of current efforts to therapeutically target cancers bearing these mutations.	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('influence', 'Reg', (43, 52))	('epigenetics', 'MPA', (74, 85))	('cancers', 'Disease', (205, 212))	('IDH1', 'Gene', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('mutations', 'Var', (33, 42))	('cellular metabolism', 'MPA', (53, 72))	('IDH2', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('pig', 'Species', '9823', (75, 78))
122932	25956465	Mutations in oncogenes and tumor suppressors facilitate the rapid growth of cancer cells and their survival in response to environmental stress.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('rapid growth', 'CPA', (60, 72))	('tumor', 'Disease', (27, 32))	('facilitate', 'PosReg', (45, 55))	('survival', 'CPA', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Mutations', 'Var', (0, 9))	('oncogenes', 'Gene', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
122938	25956465	Homozygous loss-of-function mutations in fumarate hydratase (FH) or one of the five subunits comprising the succinate dehydrogenase (SDH) complex can lead to the development of specific cancers, representing the first time that metabolic enzymes were classified as bonafide tumor suppressors.	('SDH', 'Gene', (133, 136))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('fumarate hydratase', 'Gene', '2271', (41, 59))	('succinate dehydrogenase', 'Gene', '6390', (108, 131))	('loss-of-function', 'NegReg', (11, 27))	('FH', 'Gene', '2271', (61, 63))	('succinate dehydrogenase', 'Gene', (108, 131))	('fumarate hydratase', 'Gene', (41, 59))	('SDH', 'Gene', '6390', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('mutations', 'Var', (28, 37))
122939	25956465	More recently, mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) have been discovered in various cancers.	('IDH2', 'Gene', (68, 72))	('mutations', 'Var', (15, 24))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('isocitrate dehydrogenase 1', 'Gene', (28, 54))	('cancers', 'Disease', (106, 113))	('isocitrate dehydrogenase 1', 'Gene', '3417', (28, 54))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('IDH1', 'Gene', (62, 66))	('discovered', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
122941	25956465	Finally, the metabolic and epigenetic consequences of mutant IDH1 and IDH2 are discussed in the context of current efforts to therapeutically target cancers harboring these mutations.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('pig', 'Species', '9823', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('IDH1', 'Gene', (61, 65))	('mutant', 'Var', (54, 60))	('IDH2', 'Gene', (70, 74))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
122942	25956465	Mutation of IDH1 and IDH2 were initially identified through exome sequencing of colon tumor and glioblastoma multiforme (GBM).	('colon tumor', 'Disease', 'MESH:D015179', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('identified', 'Reg', (41, 51))	('colon tumor', 'Phenotype', 'HP:0100273', (80, 91))	('IDH1', 'Gene', (12, 16))	('Mutation', 'Var', (0, 8))	('colon tumor', 'Disease', (80, 91))	('IDH2', 'Gene', (21, 25))	('glioblastoma multiforme', 'Disease', (96, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (96, 119))
122943	25956465	Since these discoveries, IDH mutations have been observed in several other tumor types, including acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma.	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (98, 120))	('IDH', 'Gene', (25, 28))	('chondrosarcoma', 'Disease', 'MESH:D002813', (128, 142))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 179))	('chondrosarcoma', 'Disease', (128, 142))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('intrahepatic cholangiocarcinoma', 'Disease', (148, 179))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('AML', 'Disease', (122, 125))	('tumor', 'Disease', (75, 80))	('IDH', 'Gene', '3417', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (128, 142))	('acute myeloid leukemia', 'Disease', (98, 120))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (104, 120))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (98, 120))	('observed', 'Reg', (49, 57))
122944	25956465	These mutations are somatically acquired and occur on distinct arginine residues of IDH1 (R132) and IDH2 (R172 or R140).	('R132', 'Var', (90, 94))	('IDH1', 'Gene', (84, 88))	('arginine', 'Chemical', 'MESH:D001120', (63, 71))	('occur', 'Reg', (45, 50))	('IDH2', 'Gene', (100, 104))	('R172 or R140', 'Var', (106, 118))
122945	25956465	Interestingly, IDH1 mutations occur at much higher incidences than IDH2 mutations in low grade gliomas, cholangiocarcinoma, and chondrosarcoma; however, IDH1 and IDH2 mutations occur at similar rates in AML.	('AML', 'Phenotype', 'HP:0004808', (203, 206))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH1', 'Gene', (15, 19))	('cholangiocarcinoma', 'Disease', (104, 122))	('chondrosarcoma', 'Disease', 'MESH:D002813', (128, 142))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('chondrosarcoma', 'Disease', (128, 142))	('gliomas', 'Disease', (95, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('AML', 'Disease', 'MESH:D015470', (203, 206))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (128, 142))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('mutations', 'Var', (20, 29))	('AML', 'Disease', (203, 206))
122946	25956465	Due to the frequency of observation in low grade gliomas, IDH mutations are thought to play a significant role in early tumorigenesis and precede other oncogenic mutations.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('IDH', 'Gene', '3417', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH', 'Gene', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('gliomas', 'Disease', (49, 56))	('mutations', 'Var', (62, 71))	('tumor', 'Disease', (120, 125))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
122947	25956465	In contrast to SDH and FH mutants, which exhibit traditional homozygous loss-of-function mutations, IDH mutants retain one wild-type allele and rarely exhibit loss of heterozygosity.	('IDH', 'Gene', (100, 103))	('mutants', 'Var', (104, 111))	('IDH', 'Gene', '3417', (100, 103))	('SDH', 'Gene', '6390', (15, 18))	('mutations', 'Var', (89, 98))	('loss-of-function', 'NegReg', (72, 88))	('FH', 'Gene', '2271', (23, 25))	('SDH', 'Gene', (15, 18))
122948	25956465	Subsequently, an analysis of the x-ray structure of mutant IDH1 in conjunction with metabolomics profiling demonstrated that (D)-2-hydroxyglutarate (D- or R-2HG) was produced by mutant IDH1 and accumulated at high levels in mutant tumors, confirming a gain-of-function mechanism.	('mutant', 'Var', (178, 184))	('IDH1', 'Gene', (185, 189))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('mutant', 'Var', (52, 58))	('(D)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (125, 147))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('IDH1', 'Gene', (59, 63))	('tumors', 'Disease', (231, 237))
122949	25956465	Similar production of D-2HG was demonstrated in cells and tumors harboring IDH2 mutations.	('D-2', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('mutations', 'Var', (80, 89))	('D-2', 'Gene', '1734', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('IDH2', 'Gene', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (58, 64))
122951	25956465	However, the mutant IDH enzyme loses oxidative activity and instead reduces alpha-ketoglutarate (aKG, also known as 2-oxoglutarate) to D-2HG, consuming one molecule of NADPH in the process (Figure 1).	('mutant', 'Var', (13, 19))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (116, 130))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (76, 95))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('oxidative activity', 'MPA', (37, 55))	('D-2', 'Gene', '1734', (135, 138))	('alpha-ketoglutarate', 'MPA', (76, 95))	('loses', 'NegReg', (31, 36))	('NADPH', 'Gene', (168, 173))	('NADPH', 'Gene', '1666', (168, 173))	('reduces alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (68, 95))	('D-2', 'Gene', (135, 138))	('reduces', 'NegReg', (68, 75))
122953	25956465	Deficiency in L2HGDH or D2HGDH due to homozygous loss-of-function mutation causes patients to develop 2HG aciduria characterized by an accumulation of either enantiomer in body fluids.	('D2HGDH', 'Gene', (24, 30))	('patients', 'Species', '9606', (82, 90))	('D2HGDH', 'Gene', '728294', (24, 30))	('develop', 'PosReg', (94, 101))	('L2HGDH', 'Gene', (14, 20))	('loss-of-function', 'NegReg', (49, 65))	('Deficiency', 'Disease', 'MESH:D007153', (0, 10))	('2HG aciduria', 'MPA', (102, 114))	('accumulation', 'PosReg', (135, 147))	('mutation', 'Var', (66, 74))	('Deficiency', 'Disease', (0, 10))	('L2HGDH', 'Gene', '79944', (14, 20))	('aciduria', 'Phenotype', 'HP:0012072', (106, 114))
122954	25956465	About 50% of patients with D-2HG aciduria have autosomal recessive mutations in D2HGDH; however, the majority of patients with normal D-2HGDH enzyme but high D-2HG harbored mutations in IDH2 (either R140Q or R140G).	('patients', 'Species', '9606', (13, 21))	('D-2', 'Gene', (27, 30))	('D-2', 'Gene', '1734', (134, 137))	('D-2HGDH', 'Gene', (134, 141))	('autosomal recessive', 'Disease', (47, 66))	('D-2', 'Gene', '1734', (27, 30))	('R140G', 'Mutation', 'rs267606870', (208, 213))	('IDH2', 'Gene', (186, 190))	('D-2', 'Gene', (158, 161))	('R140G', 'Var', (208, 213))	('patients', 'Species', '9606', (113, 121))	('D2HGDH', 'Gene', (80, 86))	('R140Q', 'Mutation', 'rs121913502', (199, 204))	('D-2HGDH', 'Gene', '728294', (134, 141))	('D-2', 'Gene', (134, 137))	('harbored', 'Reg', (164, 172))	('D-2', 'Gene', '1734', (158, 161))	('aciduria', 'Phenotype', 'HP:0012072', (33, 41))	('D2HGDH', 'Gene', '728294', (80, 86))
122958	25956465	Thus, D-2HG accumulation from mutant IDH may not be sufficient to drive malignancy and may require additional oncogenic mutations.	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('malignancy', 'Disease', (72, 82))	('D-2', 'Gene', (6, 9))	('IDH', 'Gene', (37, 40))	('mutant', 'Var', (30, 36))	('D-2', 'Gene', '1734', (6, 9))	('IDH', 'Gene', '3417', (37, 40))
122959	25956465	Indeed, IDH mutations observed in low-grade gliomas frequently precede 1p/19q co-deletion and/or TP53 mutation which give rise to either oligoastrocytomas/oligodendrogliomas or low grade astrocytomas, respectively.	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('TP53', 'Gene', '7157', (97, 101))	('IDH', 'Gene', (8, 11))	('gliomas', 'Disease', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('astrocytomas', 'Disease', (142, 154))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('give rise to', 'Reg', (117, 129))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('IDH', 'Gene', '3417', (8, 11))	('astrocytomas', 'Disease', (187, 199))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('oligoastrocytomas/oligodendrogliomas', 'Disease', 'MESH:D001254', (137, 173))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('TP53', 'Gene', (97, 101))	('astrocytomas', 'Disease', 'MESH:D001254', (142, 154))	('1p/19q', 'Gene', (71, 77))	('gliomas', 'Disease', (166, 173))	('mutation', 'Var', (102, 110))	('mutations', 'Var', (12, 21))	('astrocytomas', 'Disease', 'MESH:D001254', (187, 199))	('oligoastrocytomas/oligodendrogliomas', 'Disease', (137, 173))
122960	25956465	These tumors follow distinct transformation programs with 1p/19q co-deleted tumors commonly activating PI3K/Akt or Ras and p53 mutant tumors amplifying receptor tyrosine kinases (i.e., MET and PDGFR).	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('PDGFR', 'Gene', (193, 198))	('PDGFR', 'Gene', '5159', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('receptor tyrosine kinases', 'MPA', (152, 177))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumors', 'Disease', (134, 140))	('Akt', 'Gene', (108, 111))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('amplifying', 'PosReg', (141, 151))	('Akt', 'Gene', '207', (108, 111))	('activating', 'PosReg', (92, 102))	('mutant', 'Var', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', (76, 82))	('p53', 'Gene', '7157', (123, 126))	('Ras', 'Pathway', (115, 118))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('p53', 'Gene', (123, 126))
122961	25956465	Further transformation of IDH mutant low-grade gliomas into secondary glioblastomas requires EGFR amplification, PTEN loss, and/or additional genetic alterations.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastomas', 'Disease', (70, 83))	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', (93, 97))	('loss', 'NegReg', (118, 122))	('gliomas', 'Disease', (47, 54))	('PTEN', 'Gene', (113, 117))	('amplification', 'Var', (98, 111))	('IDH', 'Gene', (26, 29))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('PTEN', 'Gene', '5728', (113, 117))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('IDH', 'Gene', '3417', (26, 29))	('mutant', 'Var', (30, 36))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))
122962	25956465	Sequencing of IDH1 and IDH2 in AML patients indicated that these mutations occurred in a subset of tumors that were distinct from those harboring loss-of-function TET2 mutations, suggesting that D-2HG accumulation disrupts the function of TET2 or another aKG-dependent dioxygenase.	('TET2', 'Gene', '54790', (239, 243))	('D-2', 'Gene', (195, 198))	('aKG-dependent dioxygenase', 'Enzyme', (255, 280))	('disrupts', 'NegReg', (214, 222))	('mutations', 'Var', (168, 177))	('TET2', 'Gene', (163, 167))	('AML', 'Disease', 'MESH:D015470', (31, 34))	('patients', 'Species', '9606', (35, 43))	('D-2', 'Gene', '1734', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('AML', 'Disease', (31, 34))	('AML', 'Phenotype', 'HP:0004808', (31, 34))	('TET2', 'Gene', (239, 243))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('TET2', 'Gene', '54790', (163, 167))	('function', 'MPA', (227, 235))	('oxygen', 'Chemical', 'MESH:D010100', (271, 277))	('mutations', 'Var', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
122964	25956465	As such, D-2HG acts in a manner similar to the succinate and fumarate that accumulate in the context of SDH and FH mutant tumors, respectively.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('SDH', 'Gene', '6390', (104, 107))	('fumarate', 'Chemical', 'MESH:D005650', (61, 69))	('mutant', 'Var', (115, 121))	('D-2', 'Gene', '1734', (9, 12))	('SDH', 'Gene', (104, 107))	('succinate', 'Chemical', 'MESH:D019802', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('FH', 'Gene', '2271', (112, 114))	('accumulate', 'PosReg', (75, 85))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('D-2', 'Gene', (9, 12))
122965	25956465	Indeed, D-2HG accumulation resulting from mutant IDH expression has been observed to promote DNA and/or histone hypermethylation phenotypes.	('D-2', 'Gene', '1734', (8, 11))	('mutant', 'Var', (42, 48))	('IDH', 'Gene', (49, 52))	('promote', 'PosReg', (85, 92))	('DNA', 'MPA', (93, 96))	('IDH', 'Gene', '3417', (49, 52))	('histone hypermethylation phenotypes', 'MPA', (104, 139))	('D-2', 'Gene', (8, 11))	('N', 'Chemical', 'MESH:D009584', (94, 95))
122966	25956465	At least in the context of SDH mutant cells, this inhibitory effect on dioxygenase activity can be ameliorated by addition of cell-permeable aKG analogs.	('mutant', 'Var', (31, 37))	('activity', 'MPA', (83, 91))	('dioxygenase', 'Enzyme', (71, 82))	('SDH', 'Gene', (27, 30))	('oxygen', 'Chemical', 'MESH:D010100', (73, 79))	('SDH', 'Gene', '6390', (27, 30))
122967	25956465	In addition, histone hypermethylation associated with IDH1 mutant expression in U87 glioma cells was reversed by octyl-aKG addition.	('IDH1', 'Gene', (54, 58))	('glioma', 'Disease', (84, 90))	('mutant', 'Var', (59, 65))	('U87', 'CellLine', 'CVCL:0022', (80, 83))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('histone hypermethylation', 'MPA', (13, 37))
122969	25956465	On the other hand, other studies have observed increases in HIF1a levels in IDH1 mutant U87 cells or in brain-specific Nestin-IDH1R132H/wT transgenic mouse embryos.	('IDH1', 'Gene', (76, 80))	('HIF1a', 'Gene', (60, 65))	('HIF1a', 'Gene', '3091', (60, 65))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('mutant', 'Var', (81, 87))	('increases', 'PosReg', (47, 56))	('U87', 'CellLine', 'CVCL:0022', (88, 91))	('mouse', 'Species', '10090', (150, 155))
122971	25956465	Overall, the role of IDH mutants and 2HG on HIF1a stabilization is complex and can be influenced by cell type, tissue, and the local microenvironment.	('IDH', 'Gene', (21, 24))	('mutants', 'Var', (25, 32))	('IDH', 'Gene', '3417', (21, 24))	('HIF1a', 'Gene', (44, 49))	('HIF1a', 'Gene', '3091', (44, 49))	('influenced', 'Reg', (86, 96))
122972	25956465	The epigenetic dysregulation caused by aKG antagonism has been proposed to be one mechanism through which D-2HG contributes to tumorigenesis in mutant IDH tumors (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH tumors', 'Disease', 'MESH:D009369', (151, 161))	('epigenetic dysregulation', 'MPA', (4, 28))	('antagonism', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('contributes', 'Reg', (112, 123))	('tumor', 'Disease', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('IDH tumors', 'Disease', (151, 161))	('tumor', 'Disease', (155, 160))	('D-2', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('D-2', 'Gene', '1734', (106, 109))	('mutant', 'Var', (144, 150))	('pig', 'Species', '9823', (5, 8))
122974	25956465	As this family of enzymes catalyzes a wide variety of reactions and includes protein- and DNA-modifying enzymes as well as metabolic enzymes (reviewed by), additional insights are needed to determine the mechanistic drivers of tumorigenesis downstream of mutant IDH.	('IDH', 'Gene', (262, 265))	('mutant', 'Var', (255, 261))	('tumor', 'Disease', (227, 232))	('IDH', 'Gene', '3417', (262, 265))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
122976	25956465	Structural studies of IDH1 suggest that its IDH1 follows a self-regulation feedback mechanism whereby isocitrate binds directly to Arg132, inducing a conformational change that allows the Asp279 residue to interact with Ca2+ cofactor and participate in catalysis.	('interact', 'Interaction', (206, 214))	('participate', 'Reg', (238, 249))	('conformational change', 'MPA', (150, 171))	('isocitrate', 'Chemical', 'MESH:C034219', (102, 112))	('Ca2+', 'Chemical', 'MESH:D000069285', (220, 224))	('catalysis', 'MPA', (253, 262))	('Arg132', 'Gene', (131, 137))	('Arg132', 'Chemical', '-', (131, 137))	('Asp279', 'Chemical', '-', (188, 194))	('inducing', 'Reg', (139, 147))	('Asp279', 'Var', (188, 194))
122978	25956465	Arg132 directly interacts with isocitrate, and amino acid substitutions from any of the mutations observed in gliomas prevented isocitrate from binding.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('interacts', 'Interaction', (16, 25))	('binding', 'Interaction', (144, 151))	('isocitrate', 'Chemical', 'MESH:C034219', (128, 138))	('isocitrate', 'Chemical', 'MESH:C034219', (31, 41))	('isocitrate', 'MPA', (128, 138))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('Arg132', 'Chemical', '-', (0, 6))	('amino acid substitutions', 'Var', (47, 71))	('Arg132', 'Var', (0, 6))	('prevented', 'NegReg', (118, 127))
122979	25956465	Thus, IDH1 mutants become insensitive to physiological isocitrate levels and exhibit a >80% decreased capacity to carry out the oxidative reaction.	('mutants', 'Var', (11, 18))	('oxidative reaction', 'MPA', (128, 146))	('IDH1', 'Gene', (6, 10))	('carry out', 'MPA', (114, 123))	('isocitrate', 'Chemical', 'MESH:C034219', (55, 65))	('decreased', 'NegReg', (92, 101))
122981	25956465	IDH1 mutants exhibit a sequential kinetic mechanism whereby NADPH first binds, reductively trapping aKG into D-2HG before allowing it to undergo carboxylation to form ICT.	('D-2', 'Gene', (109, 112))	('NADPH', 'Gene', '1666', (60, 65))	('binds', 'Interaction', (72, 77))	('IDH1', 'Gene', (0, 4))	('D-2', 'Gene', '1734', (109, 112))	('mutants', 'Var', (5, 12))	('reductively trapping', 'MPA', (79, 99))	('ICT', 'Chemical', 'MESH:C565846', (167, 170))	('carboxylation', 'MPA', (145, 158))	('NADPH', 'Gene', (60, 65))
122982	25956465	IDH1-R132 variants (H, C, G, S, L) exhibit significantly different kinetic parameters for aKG and, consequently, produce different levels of D-2HG in cells expressing IDH1-R132.	('D-2', 'Gene', '1734', (141, 144))	('levels', 'MPA', (131, 137))	('aKG', 'MPA', (90, 93))	('variants', 'Var', (10, 18))	('produce', 'Reg', (113, 120))	('D-2', 'Gene', (141, 144))	('IDH1-R132', 'Gene', (0, 9))	('different', 'Reg', (57, 66))
122983	25956465	These mechanistic insights offer an explanation as to why D-2HG is preferentially produced by mutant IDH1 enzymes.	('IDH1', 'Gene', (101, 105))	('D-2', 'Gene', (58, 61))	('preferentially', 'PosReg', (67, 81))	('mutant', 'Var', (94, 100))	('D-2', 'Gene', '1734', (58, 61))
122984	25956465	In addition to the IDH1-R132 and IDH2-R172 and R140Q mutants, other IDH mutation sites have been predicted and/or demonstrated to exhibit neomorphic activity, including IDH1-R100, IDH1-Y179, and IDH1-G97.	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', (195, 198))	('R140Q', 'Mutation', 'rs121913502', (47, 52))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', (180, 183))	('IDH', 'Gene', (169, 172))	('neomorphic activity', 'CPA', (138, 157))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', (33, 36))	('R140Q', 'Var', (47, 52))	('IDH', 'Gene', '3417', (169, 172))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3417', (33, 36))
122985	25956465	IDH1-Y179 and IDH1-G97 mutants exhibited lower Km values for isocitrate (i.e., improved binding); suggesting that neomorphic function is not reliant on an impaired utilization of isocitrate.	('IDH1-G97 mutants', 'Var', (14, 30))	('isocitrate', 'Chemical', 'MESH:C034219', (179, 189))	('improved', 'PosReg', (79, 87))	('IDH1-Y179', 'Var', (0, 9))	('lower', 'NegReg', (41, 46))	('Km values for isocitrate', 'MPA', (47, 71))	('isocitrate', 'Chemical', 'MESH:C034219', (61, 71))	('binding', 'Interaction', (88, 95))
122986	25956465	Ultimately, the changes in wild-type and neomorphic function of IDH1 and IDH2 described above influence cell signaling, epigenetics, and enzyme activity to directly and indirectly drive metabolic reprogramming within tumors (Figure 2).	('changes', 'Var', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('enzyme', 'Enzyme', (137, 143))	('IDH1', 'Gene', (64, 68))	('epigenetics', 'MPA', (120, 131))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('cell signaling', 'MPA', (104, 118))	('drive', 'Reg', (180, 185))	('pig', 'Species', '9823', (121, 124))	('metabolic reprogramming', 'CPA', (186, 209))	('IDH2', 'Gene', (73, 77))	('neomorphic', 'MPA', (41, 51))	('influence', 'Reg', (94, 103))
122990	25956465	While hyperactivation of PI3K/Akt signaling contributes to the aggressiveness of gliomas, U87 glioma cells expressing IDH1-R132H exhibited decreased Akt levels at both the mRNA and protein level.	('hyperactivation', 'PosReg', (6, 21))	('R132H', 'Mutation', 'rs121913500', (123, 128))	('Akt', 'Gene', (149, 152))	('IDH1-R132H', 'Var', (118, 128))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('Akt', 'Gene', (30, 33))	('Akt', 'Gene', '207', (149, 152))	('Akt', 'Gene', '207', (30, 33))	('glioma', 'Disease', (81, 87))	('aggressiveness of gliomas', 'Disease', (63, 88))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('aggressiveness of gliomas', 'Disease', 'MESH:D005910', (63, 88))	('aggressiveness', 'Phenotype', 'HP:0000718', (63, 77))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', (94, 100))	('U87', 'CellLine', 'CVCL:0022', (90, 93))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('decreased', 'NegReg', (139, 148))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))
122991	25956465	Furthermore, expression of mutant IDH1 in LN-319 glioblastoma cells caused a decrease in Akt phosphorylation, suggesting that mutant tumors may exhibit less of a glycolytic metabolic phenotype compared to IDH1 wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('mutant', 'Var', (27, 33))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('decrease', 'NegReg', (77, 85))	('Akt', 'Gene', '207', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (220, 226))	('LN-319 glioblastoma cells', 'Disease', (42, 67))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('LN-319 glioblastoma cells', 'Disease', 'MESH:D005909', (42, 67))	('Akt', 'Gene', (89, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('IDH1', 'Gene', (34, 38))	('glycolytic metabolic', 'MPA', (162, 182))	('mutant', 'Var', (126, 132))
122992	25956465	Importantly, the majority of tumors harboring both IDH mutations and 1p/19q co-deletion exhibit activation of PI3K/Akt; thus, the role of Akt on glucose metabolism in mutant IDH tumors may also rely on external factors (i.e.	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('IDH', 'Gene', '3417', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('mutant', 'Var', (167, 173))	('IDH', 'Gene', (174, 177))	('IDH tumors', 'Disease', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (29, 35))	('IDH tumors', 'Disease', 'MESH:D009369', (174, 184))	('activation', 'PosReg', (96, 106))	('IDH', 'Gene', '3417', (174, 177))	('glucose', 'Chemical', 'MESH:D005947', (145, 152))	('Akt', 'Gene', (138, 141))	('mutations', 'Var', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('Akt', 'Gene', (115, 118))	('Akt', 'Gene', '207', (138, 141))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Akt', 'Gene', '207', (115, 118))	('IDH', 'Gene', (51, 54))	('tumors', 'Disease', (178, 184))
122995	25956465	One recent study observed that IDH mutant gliomas and tumor-derived brain tumor stem cells silence LDHA expression through promoter hypermethylation.	('LDHA', 'Gene', (99, 103))	('brain tumor', 'Disease', 'MESH:D001932', (68, 79))	('brain tumor', 'Disease', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutant', 'Var', (35, 41))	('tumor', 'Disease', (74, 79))	('IDH', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('promoter', 'MPA', (123, 131))	('gliomas', 'Disease', (42, 49))	('LDHA', 'Gene', '3939', (99, 103))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH', 'Gene', '3417', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('silence', 'NegReg', (91, 98))	('brain tumor', 'Phenotype', 'HP:0030692', (68, 79))	('tumor', 'Disease', (54, 59))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))
122996	25956465	In addition, one study identified that AML patients with IDH1 or IDH2 mutant tumors exhibited lower LDH activity compared to wild-type IDH1 or IDH2 tumors, suggesting a common phenotype between IDH mutants mediated by aKG/2HG.	('IDH', 'Gene', (65, 68))	('IDH2 tumors', 'Disease', (143, 154))	('IDH', 'Gene', (57, 60))	('IDH', 'Gene', '3417', (194, 197))	('IDH', 'Gene', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('IDH', 'Gene', '3417', (65, 68))	('IDH', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', (77, 83))	('IDH', 'Gene', '3417', (57, 60))	('IDH', 'Gene', '3417', (143, 146))	('AML', 'Disease', 'MESH:D015470', (39, 42))	('patients', 'Species', '9606', (43, 51))	('mutant', 'Var', (70, 76))	('LDH', 'Gene', (100, 103))	('AML', 'Disease', (39, 42))	('IDH', 'Gene', '3417', (135, 138))	('AML', 'Phenotype', 'HP:0004808', (39, 42))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('LDH', 'Gene', '3945', (100, 103))	('IDH2 tumors', 'Disease', 'MESH:D009369', (143, 154))	('lower', 'NegReg', (94, 99))	('IDH', 'Gene', (194, 197))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
122997	25956465	An analysis of gene expression in IDH1 mutant and IDH1 wild-type glioma samples demonstrated that factor inhibiting HIF-1 (FIH-1/HIFAN) was upregulated in IDH1 mutant tumors.	('IDH1', 'Gene', (155, 159))	('factor inhibiting HIF-1', 'Gene', (98, 121))	('glioma', 'Disease', (65, 71))	('FIH-1', 'Gene', '55662', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('upregulated', 'PosReg', (140, 151))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('FIH-1', 'Gene', (123, 128))	('mutant', 'Var', (160, 166))	('factor inhibiting HIF-1', 'Gene', '55662', (98, 121))	('mutant', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('IDH1', 'Gene', (34, 38))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
122998	25956465	FIH-1 inhibits the activity of HIF1a by preventing its transactivation in an aKG-dependent manner, and HIF1a levels are known to be decreased in IDH1 mutant gliomas, enhancing tumorigenesis.	('IDH1', 'Gene', (145, 149))	('FIH-1', 'Gene', '55662', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('enhancing', 'PosReg', (166, 175))	('HIF1a', 'Gene', (31, 36))	('inhibits', 'NegReg', (6, 14))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('tumor', 'Disease', (176, 181))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('mutant', 'Var', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('transactivation in an aKG-dependent', 'MPA', (55, 90))	('HIF1a', 'Gene', '3091', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('FIH-1', 'Gene', (0, 5))	('HIF1a', 'Gene', '3091', (31, 36))	('HIF1a', 'Gene', (103, 108))	('activity', 'MPA', (19, 27))	('gliomas', 'Disease', (157, 164))	('decreased', 'NegReg', (132, 141))	('preventing', 'NegReg', (40, 50))
123000	25956465	Putatively as a consequence of HIF1a suppression, IDH1 mutant gliomas expressed high levels of LDHB relative to LDHA as compared to IDH1 wild-type gliomas or normal brain tissue.	('LDHA', 'Gene', '3939', (112, 116))	('IDH1', 'Gene', (50, 54))	('LDHB', 'Gene', (95, 99))	('LDHB', 'Gene', '3945', (95, 99))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('HIF1a', 'Gene', (31, 36))	('HIF1a', 'Gene', '3091', (31, 36))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('mutant', 'Var', (55, 61))	('suppression', 'NegReg', (37, 48))	('gliomas', 'Disease', (147, 154))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('LDHA', 'Gene', (112, 116))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
123001	25956465	Acting as the final step in converting glucose to lactate, LDHA silencing may act to mitigate aerobic glycolysis.	('mitigate', 'NegReg', (85, 93))	('LDHA', 'Gene', (59, 63))	('aerobic glycolysis', 'MPA', (94, 112))	('LDHA', 'Gene', '3939', (59, 63))	('lactate', 'Chemical', 'MESH:D019344', (50, 57))	('glucose', 'Chemical', 'MESH:D005947', (39, 46))	('silencing', 'Var', (64, 73))
123005	25956465	Thus, alteration of HIF1a expression in mutant IDH cells and tumors may influence PDH activity and lead to changes in flux of glucose-derived pyruvate into the mitochondria.	('changes', 'Reg', (107, 114))	('tumors', 'Disease', (61, 67))	('IDH', 'Gene', '3417', (47, 50))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('PDH', 'Gene', (82, 85))	('activity', 'MPA', (86, 94))	('HIF1a', 'Gene', (20, 25))	('derived pyruvate', 'Chemical', '-', (134, 150))	('PDH', 'Gene', '54704', (82, 85))	('glucose', 'Chemical', 'MESH:D005947', (126, 133))	('alteration', 'Var', (6, 16))	('influence', 'Reg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutant', 'Var', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('IDH', 'Gene', (47, 50))	('HIF1a', 'Gene', '3091', (20, 25))
123009	25956465	One recent study demonstrated that IDH mutant overexpression in astrocytes results in an increased fractional flux through pyruvate carboxylase and an increase in PC expression, suggesting this pathway is critical for IDH mutant cells to maintain TCA activity.	('pyruvate carboxylase', 'Gene', '5091', (123, 143))	('overexpression', 'PosReg', (46, 60))	('PC expression', 'MPA', (163, 176))	('IDH', 'Gene', (35, 38))	('pyruvate carboxylase', 'Gene', (123, 143))	('TCA', 'Chemical', 'MESH:D014233', (247, 250))	('increase', 'PosReg', (151, 159))	('IDH', 'Gene', '3417', (35, 38))	('mutant', 'Var', (39, 45))	('IDH', 'Gene', (218, 221))	('increased', 'PosReg', (89, 98))	('IDH', 'Gene', '3417', (218, 221))
123010	25956465	Consistent with this observation, we observed increased pyruvate cycling through malic enzymes and PC in HCT116 cells harboring heterozygous IDH1 mutations.	('HCT116', 'CellLine', 'CVCL:0291', (105, 111))	('IDH1', 'Gene', (141, 145))	('mutations', 'Var', (146, 155))	('increased', 'PosReg', (46, 55))	('malic', 'Enzyme', (81, 86))	('pyruvate', 'Chemical', 'MESH:D019289', (56, 64))	('pyruvate cycling', 'MPA', (56, 72))	('increased pyruvate', 'Phenotype', 'HP:0003542', (46, 64))
123015	25956465	These pathways are highly active in most cancer cells as a result of oncogenic mutations or limited glucose oxidation.	('glucose oxidation', 'Disease', 'MESH:D004194', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('glucose oxidation', 'Disease', (100, 117))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('limited', 'NegReg', (92, 99))	('mutations', 'Var', (79, 88))
123017	25956465	Not surprisingly, much of the D-2HG produced by mutant IDH1 and IDH2 in cells is derived from glutamine.	('D-2', 'Gene', (30, 33))	('mutant', 'Var', (48, 54))	('glutamine', 'Chemical', 'MESH:D005973', (94, 103))	('IDH2', 'Gene', (64, 68))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('D-2', 'Gene', '1734', (30, 33))	('IDH1', 'Gene', (55, 59))
123018	25956465	Due to its clinical prevalence and the availability of cell models more studies have focused on the impact of mutant IDH1 on TCA metabolism compared to mutant IDH2.	('TCA', 'Chemical', 'MESH:D014233', (125, 128))	('mutant', 'Var', (110, 116))	('IDH1', 'Gene', (117, 121))	('TCA metabolism', 'MPA', (125, 139))
123019	25956465	Beyond aKG generation, flux through both glutaminolytic and reductive carboxylation pathways are significantly impacted by IDH mutations.	('IDH', 'Gene', (123, 126))	('impacted', 'Reg', (111, 119))	('glutaminolytic', 'Pathway', (41, 55))	('flux', 'MPA', (23, 27))	('mutations', 'Var', (127, 136))	('reductive', 'Pathway', (60, 69))	('IDH', 'Gene', '3417', (123, 126))
123022	25956465	recently observed that gliomas harboring IDH1 mutations overexpressed glutamate dehydrogenase 1 and 2 (GLUD1 and GLUD2), and orthotopic growth of mutant glioma lines were sensitive to GLUD1 or GLUD2 knockdown.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('GLUD1', 'Gene', (184, 189))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('glutamate dehydrogenase 1 and 2', 'Gene', '2746;2747', (70, 101))	('GLUD1', 'Gene', (103, 108))	('GLUD2', 'Gene', (193, 198))	('GLUD2', 'Gene', '2747', (193, 198))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('mutations', 'Var', (46, 55))	('GLUD2', 'Gene', (113, 118))	('glioma', 'Disease', (153, 159))	('GLUD2', 'Gene', '2747', (113, 118))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('overexpressed', 'PosReg', (56, 69))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('GLUD1', 'Gene', '2746', (184, 189))	('gliomas', 'Disease', (23, 30))	('glioma', 'Disease', (23, 29))	('IDH1', 'Gene', (41, 45))	('GLUD1', 'Gene', '2746', (103, 108))
123023	25956465	We observed a similar increase in the dependence of IDH1 mutant cells on glutaminolysis in our analysis of a panel of HCT116 cells, providing evidence that these changes arise due to a direct impact on metabolism rather than indirectly through cell lineage-specific mechanisms.	('glutaminolysis', 'MPA', (73, 87))	('increase', 'PosReg', (22, 30))	('mutant', 'Var', (57, 63))	('impact', 'Reg', (192, 198))	('dependence', 'MPA', (38, 48))	('HCT116', 'CellLine', 'CVCL:0291', (118, 124))	('IDH1', 'Gene', (52, 56))	('metabolism', 'MPA', (202, 212))
123024	25956465	Notably, this dependence on oxidative glutamine metabolism was exacerbated by culture under hypoxia, such that mutant IDH1 cells exhibited decreased growth and increased respiration under hypoxia.	('hypoxia', 'Disease', (92, 99))	('mutant', 'Var', (111, 117))	('increased', 'PosReg', (160, 169))	('IDH1', 'Gene', (118, 122))	('hypoxia', 'Disease', (188, 195))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('hypoxia', 'Disease', 'MESH:D000860', (92, 99))	('respiration', 'MPA', (170, 181))	('decreased growth', 'Phenotype', 'HP:0001510', (139, 155))	('decreased', 'NegReg', (139, 148))	('glutamine', 'Chemical', 'MESH:D005973', (38, 47))	('growth', 'MPA', (149, 155))
123027	25956465	Given the demonstrated role of IDH1 in this reaction, mutant IDH1 cells exhibit a strong defect in the conversion of glutamine to isocitrate, citrate, and acetyl-CoA under various conditions.	('glutamine', 'Chemical', 'MESH:D005973', (117, 126))	('citrate', 'Chemical', 'MESH:D019343', (142, 149))	('conversion of glutamine to isocitrate', 'MPA', (103, 140))	('citrate', 'MPA', (142, 149))	('IDH1', 'Gene', (61, 65))	('isocitrate', 'Chemical', 'MESH:C034219', (130, 140))	('acetyl-CoA', 'MPA', (155, 165))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (155, 165))	('mutant', 'Var', (54, 60))	('citrate', 'Chemical', 'MESH:D019343', (133, 140))	('defect', 'NegReg', (89, 95))
123028	25956465	Indeed, the extent that heterozygous mutant IDH HCT116 cells and IDH1-R132C HT1080 fibrosarcoma cells activate this pathway under hypoxia was compromised when compared to cells with IDH2 mutations or wild-type IDH.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (83, 95))	('activate', 'PosReg', (102, 110))	('hypoxia', 'Disease', (130, 137))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (182, 185))	('IDH', 'Gene', '3417', (210, 213))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('IDH', 'Gene', '3417', (65, 68))	('mutant', 'Var', (37, 43))	('R132C', 'Var', (70, 75))	('HCT116', 'CellLine', 'CVCL:0291', (48, 54))	('R132C', 'SUBSTITUTION', 'None', (70, 75))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (210, 213))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', (182, 185))
123032	25956465	As noted above, we observed increased sensitivity to ETC/respiration inhibitors and changes in oxygen consumption rates in IDH1 mutant HCT116 cells under hypoxia.	('increased', 'PosReg', (28, 37))	('oxygen', 'Chemical', 'MESH:D010100', (95, 101))	('changes', 'Reg', (84, 91))	('sensitivity', 'MPA', (38, 49))	('hypoxia', 'Disease', (154, 161))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('IDH1', 'Gene', (123, 127))	('mutant', 'Var', (128, 134))	('oxygen consumption rates', 'MPA', (95, 119))	('HCT116', 'CellLine', 'CVCL:0291', (135, 141))
123033	25956465	and other studies have demonstrated that D-2HG produced by mutant IDH inhibits complex IV (also known as cytochrome c oxidase, COX) of the ETC.	('IDH', 'Gene', (66, 69))	('IDH', 'Gene', '3417', (66, 69))	('mutant', 'Var', (59, 65))	('D-2', 'Gene', (41, 44))	('inhibits', 'NegReg', (70, 78))	('D-2', 'Gene', '1734', (41, 44))
123034	25956465	This mechanism induced mutant IDH leukemia cell lines (patient-derived and engineered) to become sensitive to Bcl-2 inhibitors, initially identified as a target in a shRNA screen.	('induced', 'Reg', (15, 22))	('leukemia', 'Phenotype', 'HP:0001909', (34, 42))	('N', 'Chemical', 'MESH:D009584', (169, 170))	('Bcl-2', 'Gene', (110, 115))	('IDH leukemia', 'Disease', 'MESH:D007938', (30, 42))	('Bcl-2', 'Gene', '596', (110, 115))	('IDH leukemia', 'Disease', (30, 42))	('patient', 'Species', '9606', (55, 62))	('sensitive', 'MPA', (97, 106))	('mutant', 'Var', (23, 29))
123036	25956465	Interestingly, N-acetylated amino acids including N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) were significantly decreased in human glioma cells expressing IDH1-R132H.	('N', 'Chemical', 'MESH:D009584', (109, 110))	('N-acetyl-aspartyl-glutamate', 'Chemical', 'MESH:C027172', (50, 77))	('N-acetyl-aspartyl-glutamate', 'MPA', (50, 77))	('N-acetyl-aspartate', 'MPA', (89, 107))	('acetylated amino acids', 'Chemical', '-', (17, 39))	('decreased', 'NegReg', (133, 142))	('IDH1-R132H', 'Var', (176, 186))	('R132H', 'Mutation', 'rs121913500', (181, 186))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('glioma', 'Disease', (152, 158))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('N-acetylated amino acids', 'MPA', (15, 39))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('NAAG', 'Chemical', 'MESH:C027172', (79, 83))	('NAA', 'Chemical', 'MESH:C000179', (79, 82))	('human', 'Species', '9606', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('NAA', 'Chemical', 'MESH:C000179', (109, 112))	('N-acetyl-aspartate', 'Chemical', 'MESH:C000179', (89, 107))
123037	25956465	These results suggest that mutant IDH tumors may exhibit perturbed acetyl-CoA metabolism, potentially due to changes in pathway fluxes fueling acetyl-CoA pools.	('acetyl-CoA', 'Chemical', 'MESH:D000105', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('changes', 'Reg', (109, 116))	('IDH tumors', 'Disease', (34, 44))	('mutant', 'Var', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('acetyl-CoA pools', 'MPA', (143, 159))	('perturbed', 'Reg', (57, 66))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (143, 153))	('acetyl-CoA metabolism', 'MPA', (67, 88))	('IDH tumors', 'Disease', 'MESH:D009369', (34, 44))	('pathway fluxes', 'MPA', (120, 134))
123038	25956465	In addition to differences in acetyl-CoA metabolism, IDH mutant tumors exhibited a significantly altered phospholipid profile compared to wild-type IDH tumors.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('altered', 'Reg', (97, 104))	('mutant', 'Var', (57, 63))	('tumors', 'Disease', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (30, 40))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('phospholipid profile', 'MPA', (105, 125))	('phospholipid', 'Chemical', 'MESH:D010743', (105, 117))	('differences', 'Reg', (15, 26))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('acetyl-CoA metabolism', 'MPA', (30, 51))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', (53, 56))	('IDH tumors', 'Disease', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('IDH tumors', 'Disease', 'MESH:D009369', (148, 158))	('IDH', 'Gene', '3417', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('IDH', 'Gene', '3417', (53, 56))
123039	25956465	Specifically, pools of the phospholipid metabolites phosphoethanolamine and glycerophosphocholine were significantly perturbed in mutant IDH versus wild-type IDH tumors.	('glycerophosphocholine', 'Chemical', 'MESH:D005997', (76, 97))	('IDH', 'Gene', '3417', (158, 161))	('IDH tumors', 'Disease', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('IDH', 'Gene', '3417', (137, 140))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (52, 71))	('IDH', 'Gene', (158, 161))	('phospholipid', 'Chemical', 'MESH:D010743', (27, 39))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('IDH tumors', 'Disease', 'MESH:D009369', (158, 168))	('mutant', 'Var', (130, 136))	('glycerophosphocholine', 'MPA', (76, 97))	('perturbed', 'Reg', (117, 126))	('IDH', 'Gene', (137, 140))
123040	25956465	Several of the oncogenic signaling pathways altered in IDH mutant tumors also impact fatty acid synthesis and uptake.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('uptake', 'MPA', (110, 116))	('fatty acid synthesis', 'MPA', (85, 105))	('IDH', 'Gene', (55, 58))	('mutant', 'Var', (59, 65))	('tumors', 'Disease', (66, 72))	('impact', 'Reg', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('IDH', 'Gene', '3417', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('oncogenic signaling pathways', 'Pathway', (15, 43))	('fatty acid', 'Chemical', 'MESH:D005227', (85, 95))
123045	25956465	Generally, cells expressing IDH2-R172 accumulate more or similar amounts of D-2HG than those with mutant IDH1, though IDH2-R140Q mutants produce the least.	('IDH2-R172', 'Var', (28, 37))	('D-2', 'Gene', '1734', (76, 79))	('IDH2-R140Q', 'Var', (118, 128))	('R140Q', 'Mutation', 'rs121913502', (123, 128))	('D-2', 'Gene', (76, 79))
123046	25956465	In vitro enzyme studies and ectopic expression of mutants has indicated that differences in gene expression and compartment localization/conditions may influence the differential D-2HG production by IDH1-R132 mutants versus IDH2-R172 mutants.	('D-2', 'Gene', '1734', (179, 182))	('D-2', 'Gene', (179, 182))	('mutants', 'Var', (209, 216))	('IDH1-R132', 'Gene', (199, 208))	('influence', 'Reg', (152, 161))
123047	25956465	In addition to effects on D-2HG accumulation, some evidence indicates that the intermediary metabolism of cells with mutant IDH1 versus IDH2 differs as well.	('D-2', 'Gene', (26, 29))	('intermediary metabolism', 'MPA', (79, 102))	('mutant', 'Var', (117, 123))	('D-2', 'Gene', '1734', (26, 29))	('IDH1', 'Gene', (124, 128))	('differs', 'Reg', (141, 148))
123049	25956465	In contrast, the profile of glucose and glutamine-driven TCA metabolism in cells with either IDH2-R172 or IDH2-R140Q mutations was similar to that of parental cells cultured normally or in the presence of exogenous D-2HG.	('TCA', 'Chemical', 'MESH:D014233', (57, 60))	('IDH2-R140Q mutations', 'Var', (106, 126))	('D-2', 'Gene', '1734', (215, 218))	('IDH2-R172', 'Var', (93, 102))	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('R140Q', 'Mutation', 'rs121913502', (111, 116))	('D-2', 'Gene', (215, 218))	('glucose', 'Chemical', 'MESH:D005947', (28, 35))
123052	25956465	In the context of analyzing flux changes in heterozygous IDH mutant tumors versus those with WT IDH1 and IDH2 it is important to consider that a heterozygous mixture of homo- and heterodimers will exist within cells.	('IDH', 'Gene', '3417', (57, 60))	('tumors', 'Disease', (68, 74))	('IDH', 'Gene', '3417', (96, 99))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('IDH', 'Gene', (105, 108))	('mutant', 'Var', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('IDH', 'Gene', (57, 60))	('IDH', 'Gene', '3417', (105, 108))	('IDH', 'Gene', (96, 99))
123053	25956465	Notably, the binding affinity of IDH1-R132 and IDH1-WT monomers was not significantly different, suggesting that a diversity of homo- and hetero- IDH1 dimers exists in IDH1 mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mutant', 'Var', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (180, 186))	('IDH1', 'Gene', (168, 172))
123054	25956465	In contrast, IDH2-R172 weakly binds IDH2-WT, indicating that there is a greater enrichment of WT-WT homodimers in mutant IDH2 tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mutant', 'Var', (114, 120))	('IDH2 tumors', 'Disease', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('IDH2 tumors', 'Disease', 'MESH:D009369', (121, 132))
123056	25956465	Despite the observed in vitro differences in metabolism and growth, HCT116 cells containing either IDH1 or IDH2 mutations panel grew significantly slower as xenografts when compared to parental cells.	('grew', 'CPA', (128, 132))	('HCT116', 'CellLine', 'CVCL:0291', (68, 74))	('mutations', 'Var', (112, 121))	('slower', 'NegReg', (147, 153))	('IDH1', 'Gene', (99, 103))	('IDH2', 'Gene', (107, 111))
123057	25956465	These findings highlight the importance of microenvironment on metabolism and the impact of IDH mutations as well as the need for better cell/tumor models.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('IDH', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('IDH', 'Gene', '3417', (92, 95))	('mutations', 'Var', (96, 105))
123058	25956465	Beyond glucose, glutamine, and acetyl-CoA metabolism, aKG and 2HG can influence a number of other metabolic pathways.	('aKG', 'Var', (54, 57))	('glucose', 'MPA', (7, 14))	('acetyl-CoA metabolism', 'MPA', (31, 52))	('glutamine', 'Chemical', 'MESH:D005973', (16, 25))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (31, 41))	('influence', 'Reg', (70, 79))	('glucose', 'Chemical', 'MESH:D005947', (7, 14))	('glutamine', 'MPA', (16, 25))
123060	25956465	For example, the activity of several proline and lysine hydroxylases are perturbed in the context of IDH mutations, leading to compromised collagen maturation and impacts on extracellular matrix (ECM) processing.	('extracellular', 'MPA', (174, 187))	('compromised', 'NegReg', (127, 138))	('IDH', 'Gene', '3417', (101, 104))	('collagen maturation', 'CPA', (139, 158))	('IDH', 'Gene', (101, 104))	('mutations', 'Var', (105, 114))	('perturbed', 'Reg', (73, 82))	('activity', 'MPA', (17, 25))	('impacts', 'Reg', (163, 170))
123061	25956465	Notably, a significant impact on ECM was observed in an IDH mutant knock-in model.	('impact', 'Reg', (23, 29))	('IDH', 'Gene', (56, 59))	('mutant', 'Var', (60, 66))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('IDH', 'Gene', '3417', (56, 59))	('ECM', 'MPA', (33, 36))
123064	25956465	Notably, BCAT1 expression is high in glioblastoma and suppressed by ectopic mutant IDH1 overexpression, suggesting that aKG or D-2HG levels influence branched chain amino acid (BCAA) metabolism.	('BCAT1', 'Gene', (9, 14))	('ectopic mutant', 'Var', (68, 82))	('suppressed', 'NegReg', (54, 64))	('overexpression', 'PosReg', (88, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (37, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('high', 'Reg', (29, 33))	('BCAT1', 'Gene', '586', (9, 14))	('influence', 'Reg', (140, 149))	('D-2', 'Gene', (127, 130))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('expression', 'MPA', (15, 25))	('D-2', 'Gene', '1734', (127, 130))	('branched chain amino acid', 'Chemical', 'MESH:D000597', (150, 175))	('BCAA', 'Chemical', 'MESH:D000597', (177, 181))	('IDH1', 'Gene', (83, 87))	('glioblastoma', 'Disease', (37, 49))
123065	25956465	The activities of aspartate aminotransaminase (AST) and glutamate dehydrogenase (GDH), enzymes that utilize aKG as a substrate, were decreased in IDH1 mutant U87 cells due to changes in expression (AST) or posttranslational modifications (GDH).	('GDH', 'Gene', (81, 84))	('GDH', 'Gene', '2746', (239, 242))	('changes', 'Reg', (175, 182))	('U87', 'CellLine', 'CVCL:0022', (158, 161))	('activities', 'MPA', (4, 14))	('AST', 'Gene', '26503', (198, 201))	('GDH', 'Gene', (239, 242))	('AST', 'Gene', '26503', (47, 50))	('glutamate dehydrogenase', 'Gene', (56, 79))	('glutamate dehydrogenase', 'Gene', '2746', (56, 79))	('decreased', 'NegReg', (133, 142))	('mutant', 'Var', (151, 157))	('aspartate aminotransaminase', 'Gene', '26503', (18, 45))	('AST', 'Gene', (47, 50))	('AST', 'Gene', (198, 201))	('aspartate aminotransaminase', 'Gene', (18, 45))	('IDH1', 'Gene', (146, 150))	('GDH', 'Gene', '2746', (81, 84))	('expression', 'MPA', (186, 196))
123066	25956465	More focused, functional characterization of these pathways may highlight additional metabolic perturbations in IDH mutant tumors.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('IDH', 'Gene', (112, 115))	('mutant', 'Var', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('IDH', 'Gene', '3417', (112, 115))
123074	25956465	Mutation in either IDH1 or IDH2 deactivates the NADPH-production capacity of these enzymes; thus, mutant IDH cells may need to reroute flux through compensatory NADP+-dependent enzymes or suffer a decrease in available NADPH.	('IDH', 'Gene', (27, 30))	('NADP+', 'Chemical', 'MESH:D009249', (161, 166))	('IDH', 'Gene', '3417', (27, 30))	('NADPH', 'Gene', (48, 53))	('Mutation', 'Var', (0, 8))	('NADPH', 'Gene', (219, 224))	('NADPH', 'Gene', '1666', (219, 224))	('NADPH', 'Gene', '1666', (48, 53))	('IDH', 'Gene', (105, 108))	('IDH', 'Gene', (19, 22))	('reroute flux', 'MPA', (127, 139))	('IDH', 'Gene', '3417', (105, 108))	('IDH', 'Gene', '3417', (19, 22))	('mutant', 'Var', (98, 104))	('decrease', 'NegReg', (197, 205))	('deactivates', 'NegReg', (32, 43))
123078	25956465	In fact, one study of clonally selected cells overexpressing wild-type or IDH1-R132H glioma cells indicated that NADPH levels were decreased relative to wild-type IDH1 cells.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('R132H', 'Mutation', 'rs121913500', (79, 84))	('NADPH', 'Gene', '1666', (113, 118))	('decreased', 'NegReg', (131, 140))	('IDH1-R132H', 'Var', (74, 84))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('NADPH', 'Gene', (113, 118))
123079	25956465	Consequently, ROS and GSH levels were increased and decreased, respectively, in cells expressing mutant IDH1.	('ROS', 'MPA', (14, 17))	('GSH levels', 'MPA', (22, 32))	('decreased', 'NegReg', (52, 61))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('mutant', 'Var', (97, 103))	('GSH', 'Chemical', '-', (22, 25))	('IDH1', 'Gene', (104, 108))	('increased', 'PosReg', (38, 47))
123080	25956465	Furthermore, mutant IDH1 cells exhibited increased sensitivity to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP), which can induce oxidative stress in tumor cells.	('mutant', 'Var', (13, 19))	('oxidative', 'MPA', (143, 152))	('increased', 'PosReg', (41, 50))	('oxidative stress', 'Phenotype', 'HP:0025464', (143, 159))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('sensitivity', 'MPA', (51, 62))	('cis-diamminedichloroplatinum', 'Chemical', 'MESH:D002945', (89, 117))	('temozolomide', 'Chemical', 'MESH:D000077204', (66, 78))	('tumor', 'Disease', (163, 168))	('IDH1', 'Gene', (20, 24))	('CDDP', 'Chemical', 'MESH:D002945', (119, 123))	('induce', 'Reg', (136, 142))
123081	25956465	These data provide some indication that oncogenic IDH1 perturbs NADPH homeostasis; however, the extent that these findings correlate with survival and treatment responsiveness remains unclear.	('NADPH', 'Gene', (64, 69))	('IDH1', 'Gene', (50, 54))	('oncogenic', 'Var', (40, 49))	('NADPH', 'Gene', '1666', (64, 69))	('perturbs', 'Reg', (55, 63))
123082	25956465	Ultimately, additional molecular studies are required to elucidate whether this increased sensitivity to oxidative stress is due to an inability to compensate metabolically or because of orthogonal effects of the mutation on cell physiology/epigenetics.	('sensitivity', 'MPA', (90, 101))	('oxidative stress', 'Phenotype', 'HP:0025464', (105, 121))	('mutation', 'Var', (213, 221))	('pig', 'Species', '9823', (242, 245))
123083	25956465	An in vivo knock-in model of IDH1-R132H exhibited increased NADP+/NADPH ratio, decreased GSH, and decreased ascorbate in whole brains, consistent with a decrease in NADPH production and redox control capacity.	('GSH', 'MPA', (89, 92))	('NADP+', 'Chemical', 'MESH:D009249', (60, 65))	('NADPH', 'Gene', (165, 170))	('R132H', 'Mutation', 'rs121913500', (34, 39))	('decreased', 'NegReg', (79, 88))	('IDH1-R132H', 'Var', (29, 39))	('ascorbate', 'Chemical', 'MESH:D001205', (108, 117))	('NADPH', 'Gene', '1666', (165, 170))	('ascorbate', 'MPA', (108, 117))	('increased', 'PosReg', (50, 59))	('NADPH', 'Gene', (66, 71))	('NADPH', 'Gene', '1666', (66, 71))	('GSH', 'Chemical', '-', (89, 92))	('decreased', 'NegReg', (98, 107))	('decrease', 'NegReg', (153, 161))
123084	25956465	However, intracellular ROS levels in total brains of IDH1-R132H knock-in mice were significantly reduced relative to IDH1-WT knock-in brains.	('R132H', 'Mutation', 'rs121913500', (58, 63))	('mice', 'Species', '10090', (73, 77))	('intracellular ROS levels', 'MPA', (9, 33))	('IDH1-R132H', 'Var', (53, 63))	('reduced', 'NegReg', (97, 104))	('ROS', 'Chemical', 'MESH:D017382', (23, 26))
123085	25956465	Inhibition of IDH1-R132H may increase total ROS levels and, along with reduced NADPH and GSH levels, increase oxidative stress in these tumors and lead to cell death.	('tumors', 'Disease', (136, 142))	('oxidative stress', 'Phenotype', 'HP:0025464', (110, 126))	('IDH1-R132H', 'Gene', (14, 24))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('increase', 'PosReg', (101, 109))	('increase', 'PosReg', (29, 37))	('lead to', 'Reg', (147, 154))	('reduced', 'NegReg', (71, 78))	('increase oxidative stress', 'Phenotype', 'HP:0025464', (101, 126))	('NADPH', 'Gene', (79, 84))	('NADPH', 'Gene', '1666', (79, 84))	('Inhibition', 'Var', (0, 10))	('ROS levels', 'MPA', (44, 54))	('GSH', 'Chemical', '-', (89, 92))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('oxidative stress', 'MPA', (110, 126))	('increase total ROS levels', 'Phenotype', 'HP:0025464', (29, 54))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('cell death', 'CPA', (155, 165))
123088	25956465	Mutation of mtDNA has been observed to contribute to tumorigenicity in several cancer types; to this end, mutant IDH2 cells in particular may exhibit compromised mitochondrial NADPH homeostasis, which may lead to increased mtDNA mutation and mitochondrial dysfunction.	('mtDNA', 'Gene', (223, 228))	('N', 'Chemical', 'MESH:D009584', (226, 227))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (242, 267))	('mitochondrial dysfunction', 'Disease', (242, 267))	('compromised', 'NegReg', (150, 161))	('mutant', 'Var', (106, 112))	('increased', 'PosReg', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NADPH', 'Gene', (176, 181))	('NADPH', 'Gene', '1666', (176, 181))	('N', 'Chemical', 'MESH:D009584', (176, 177))	('cancer', 'Disease', (79, 85))	('IDH2', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutation', 'MPA', (229, 237))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (242, 267))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
123089	25956465	Given the distinct, gain-of-function activity caused by IDH mutations, several efforts have identified selective pharmacological agents that target mutant IDH1 and IDH2 enzymes.	('IDH', 'Gene', '3417', (164, 167))	('IDH', 'Gene', (155, 158))	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3417', (155, 158))	('IDH', 'Gene', '3417', (56, 59))	('activity', 'MPA', (37, 45))	('gain-of-function', 'PosReg', (20, 36))	('mutations', 'Var', (60, 69))	('IDH', 'Gene', (164, 167))
123090	25956465	One of the first compounds (AGI-5198) to be discovered specifically inhibited IDH1-R132H and IDH1-R132C mutant enzymes, reduced 2HG levels in glioma cells, and impaired growth of IDH1 mutant but not IDH1 WT glioma xenografts.	('growth', 'CPA', (169, 175))	('IDH1-R132H', 'Gene', (78, 88))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('mutant', 'Var', (104, 110))	('enzymes', 'Enzyme', (111, 118))	('inhibited', 'NegReg', (68, 77))	('WT glioma', 'Disease', (204, 213))	('reduced', 'NegReg', (120, 127))	('impaired', 'NegReg', (160, 168))	('glioma', 'Disease', (207, 213))	('IDH1', 'Gene', (179, 183))	('2HG levels', 'MPA', (128, 138))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('R132C', 'Mutation', 'rs121913499', (98, 103))	('IDH1-R132C mutant', 'Var', (93, 110))	('glioma', 'Disease', (142, 148))	('R132H', 'Mutation', 'rs121913500', (83, 88))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('WT glioma', 'Disease', 'MESH:D005910', (204, 213))
123091	25956465	AGI-5198 suppression of 2HG levels did not completely ameliorate the DNA hypermethylation phenotype in mutant IDH1 glioma cells, suggesting that mutant IDH1-mediated epigenetic dysregulation is not easily reversed.	('glioma', 'Disease', (115, 121))	('pig', 'Species', '9823', (167, 170))	('mutant', 'Var', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('IDH1', 'Gene', (110, 114))
123092	25956465	Since AGI-5198 was discovered, several other inhibitors have been identified that reduce D-2HG production in both in vitro and in vivo models.	('D-2', 'Gene', (89, 92))	('reduce', 'NegReg', (82, 88))	('D-2', 'Gene', '1734', (89, 92))	('inhibitors', 'Var', (45, 55))
123093	25956465	Shortly after the discovery of AGI-5198, medicinal chemistry optimization yielded the first inhibitor of IDH2-R140Q (AGI-6780) that reversed the hematopoietic differentiation induced by IDH2-R140Q in TF-1 erythroleukemia cells.	('reversed', 'PosReg', (132, 140))	('leukemia', 'Phenotype', 'HP:0001909', (212, 220))	('IDH2-R140Q', 'Var', (186, 196))	('R140Q', 'Mutation', 'rs121913502', (191, 196))	('erythroleukemia', 'Disease', (205, 220))	('hematopoietic differentiation', 'CPA', (145, 174))	('erythroleukemia', 'Disease', 'MESH:D004915', (205, 220))	('R140Q', 'Mutation', 'rs121913502', (110, 115))
123094	25956465	Several additional inhibitors of the IDH2-R172K and IDH2-R140Q, the two highest frequency IDH2 mutations, have recently been discovered, including IDH2-C100 and AG-221, a derivative of AGI-6780, which both exhibit efficacy in cell and in vivo models (Patent WO 2013102431).	('IDH2-R172K', 'Var', (37, 47))	('R140Q', 'Mutation', 'rs121913502', (57, 62))	('R172K', 'Mutation', 'rs121913503', (42, 47))	('IDH2-C100', 'Disease', (147, 156))	('IDH2-C100', 'Disease', 'None', (147, 156))	('mutations', 'Var', (95, 104))	('IDH2', 'Gene', (90, 94))	('IDH2-R140Q', 'Var', (52, 62))
123095	25956465	In aggressive IDH2 mutant primary AML xenografts models, AG-221 treatment reduced 2HG levels >90%, reversed histone and DNA hypermethylation, and conferred significant survival benefits to mice.	('survival benefits', 'CPA', (168, 185))	('mice', 'Species', '10090', (189, 193))	('DNA hypermethylation', 'MPA', (120, 140))	('reversed', 'NegReg', (99, 107))	('2HG levels', 'MPA', (82, 92))	('mutant', 'Var', (19, 25))	('IDH2', 'Gene', (14, 18))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('AG-221', 'Gene', (57, 63))	('reduced', 'NegReg', (74, 81))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('AML', 'Disease', (34, 37))
123097	25956465	As we continue to gain a better appreciation of the response of solid and blood tumors to these inhibitors, alternative approaches worth investigating are combinatorial treatments that target the metabolic deficiencies in IDH mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('IDH', 'Gene', '3417', (222, 225))	('mutant', 'Var', (226, 232))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('blood tumors', 'Phenotype', 'HP:0004377', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('metabolic deficiencies', 'Disease', 'MESH:D008659', (196, 218))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('metabolic deficiencies', 'Disease', (196, 218))	('blood tumors', 'Disease', (74, 86))	('blood tumors', 'Disease', 'MESH:D009383', (74, 86))	('IDH', 'Gene', (222, 225))
123098	25956465	While resistance to changes the epigenetic state of IDH mutant cells may emerge, these tumors are unlikely to regain the wild-type IDH1 or IDH2 activity that was originally lost to mutation.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutant', 'Var', (56, 62))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (131, 134))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('IDH', 'Gene', '3417', (139, 142))	('IDH', 'Gene', (139, 142))	('tumors', 'Disease', (87, 93))	('pig', 'Species', '9823', (33, 36))	('activity', 'MPA', (144, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
123099	25956465	The discovery, functional characterization, and clinical development of therapies surrounding oncogenic IDH mutations highlight the great potential impact of advanced scientific technologies on medicine.	('IDH', 'Gene', '3417', (104, 107))	('IDH', 'Gene', (104, 107))	('mutations', 'Var', (108, 117))
123100	25956465	In order to fully exploit the metabolic and physiological defects of IDH mutant tumors additional studies are required to identify and target such biochemical pathways in cellular and preclinical models.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH', 'Gene', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDH', 'Gene', '3417', (69, 72))	('mutant', 'Var', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
123101	25956465	Improved biological models are still required, since patient-derived IDH mutant tumor cells grow slowly, ectopic expression of mutant enzymes is unstable and ineffective at producing high D-2HG levels, and isogenic, engineered cell lines lack appropriate biological context.	('mutant', 'Var', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('slowly', 'NegReg', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH', 'Gene', (69, 72))	('D-2', 'Gene', (188, 191))	('ineffective', 'NegReg', (158, 169))	('tumor', 'Disease', (80, 85))	('mutant', 'Var', (73, 79))	('IDH', 'Gene', '3417', (69, 72))	('D-2', 'Gene', '1734', (188, 191))	('patient', 'Species', '9606', (53, 60))
123102	25956465	Ultimately, molecular level analyses of how IDH mutations impact the metabolism, epigenetics, and oncogenic development of tumors will lead to additional insights into the pathogenesis of other transforming events (e.g.	('pig', 'Species', '9823', (82, 85))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('metabolism', 'MPA', (69, 79))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('impact', 'Reg', (58, 64))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))	('mutations', 'Var', (48, 57))
123138	30977933	Even considering just the group of diffuse gliomas, a wide range of molecular alterations is relevant for their proper classification and treatment: IDH1/2, ATRX, TP53, TERT promoter and histone H3-coding genes mutations, 1p/19q chromosomal arms codeletion, EGFR alterations and MGMT promoter methylation 16, 17.	('EGFR', 'Gene', '1956', (258, 262))	('MGMT', 'Gene', (279, 283))	('TERT', 'Gene', '7015', (169, 173))	('ATRX', 'Gene', (157, 161))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('MGMT', 'Gene', '4255', (279, 283))	('EGFR', 'Gene', (258, 262))	('TP53', 'Gene', '7157', (163, 167))	('mutations', 'Var', (211, 220))	('ATRX', 'Gene', '546', (157, 161))	('IDH1/2', 'Gene', '3417;3418', (149, 155))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('TP53', 'Gene', (163, 167))	('gliomas', 'Disease', (43, 50))	('alterations', 'Var', (263, 274))	('TERT', 'Gene', (169, 173))	('IDH1/2', 'Gene', (149, 155))
123141	30977933	Analysis of the circulating cfNA shed by tumour cells allows detection of gene alterations, including mutations or fusions, changes in methylation profile, copy number variations and to quantify tumour burden; moreover, overall cfDNA (i.e.	('fusions', 'Var', (115, 122))	('copy number', 'Var', (156, 167))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('tumour', 'Disease', (195, 201))	('mutations', 'Var', (102, 111))	('methylation profile', 'MPA', (135, 154))	('tumour', 'Disease', (41, 47))	('changes', 'Reg', (124, 131))	('cfDNA', 'Disease', (228, 233))
123143	30977933	evaluated the detection of IDH1 mutations in plasma cfDNA of patients with histologically proven glioma with known tumour IDH-status:7 sensitivity and specificity were 60% and 100%, respectively (Table 1).	('glioma', 'Disease', (97, 103))	('patients', 'Species', '9606', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumour IDH-status', 'Disease', 'MESH:D009369', (115, 132))	('mutations', 'Var', (32, 41))	('IDH1', 'Gene', (27, 31))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('tumour IDH-status', 'Disease', (115, 132))	('IDH1', 'Gene', '3417', (27, 31))
123148	30977933	who identified EGFR amplification and a TP53 mutation in glioblastoma patients (Table 1) 1, 2.	('patients', 'Species', '9606', (70, 78))	('glioblastoma', 'Disease', (57, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('TP53', 'Gene', '7157', (40, 44))	('EGFR', 'Gene', '1956', (15, 19))	('mutation', 'Var', (45, 53))	('EGFR', 'Gene', (15, 19))	('TP53', 'Gene', (40, 44))	('amplification', 'Var', (20, 33))
123149	30977933	further showed that CSF-derived cfDNA analysis detects mutations of both primary and secondary brain tumours 20.	('mutations', 'Var', (55, 64))	('secondary brain tumours', 'Disease', (85, 108))	('detects', 'Reg', (47, 54))	('secondary brain tumours', 'Disease', 'MESH:D001932', (85, 108))	('brain tumours', 'Phenotype', 'HP:0030692', (95, 108))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
123159	30977933	Conversely, the presence of ctDNA was associated with tumour progression, a higher tumour burden, tumour spread in the ventricular system/subarachnoid space and a shorter survival time since CSF collection.	('tumour', 'Disease', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('subarachnoid space', 'Phenotype', 'HP:0012704', (138, 156))	('tumour', 'Disease', (54, 60))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('shorter', 'NegReg', (163, 170))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('presence', 'Var', (16, 24))	('higher', 'PosReg', (76, 82))	('ctDNA', 'Gene', (28, 33))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
123164	30977933	EGFR alterations are another relevant molecular hallmark as EGFR amplification and/or EGFRvIII variant are present in many glioblastomas 25, 26 and have been targeted in many clinical trials employing a wide range of strategies (i.e.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (86, 90))	('variant', 'Var', (95, 102))	('glioblastomas', 'Phenotype', 'HP:0012174', (123, 136))	('EGFR', 'Gene', '1956', (0, 4))	('glioblastomas', 'Disease', 'MESH:D005909', (123, 136))	('EGFR', 'Gene', (86, 90))	('alterations', 'Var', (5, 16))	('EGFR', 'Gene', '1956', (60, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('glioblastomas', 'Disease', (123, 136))	('EGFR', 'Gene', (60, 64))
123167	30977933	Also, detection of mutations affecting histone H3 genes in a case series of paediatric brain tumours showed high sensitivity and specificity: 87.5% and 100% respectively 32.	('brain tumours', 'Phenotype', 'HP:0030692', (87, 100))	('brain tumours', 'Disease', 'MESH:D001932', (87, 100))	('brain tumours', 'Disease', (87, 100))	('mutations', 'Var', (19, 28))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('histone H3 genes', 'Gene', (39, 55))
123168	30977933	This finding is especially relevant as the H3 K27M mutation characterizes, although not exclusively, a subgroup of highly malignant midline diffuse gliomas, usually occurring in children.	('midline diffuse gliomas', 'Disease', (132, 155))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('midline diffuse gliomas', 'Disease', 'MESH:D005910', (132, 155))	('highly', 'Disease', (115, 121))	('H3 K27M', 'Var', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('K27M', 'Mutation', 'p.K27M', (46, 50))	('children', 'Species', '9606', (178, 186))
123172	30977933	Sensitivity reached 96.3% (36/37) when considering only patients with a detectable mutation in the tumour tissue sample, while in 83% (31/37), it was possible to achieve the same results as tissue analysis by liquid biopsy.	('patients', 'Species', '9606', (56, 64))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('mutation', 'Var', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
123176	30977933	focused on midline gliomas and evaluated H3 K27M mutations and typical partner alterations in cfDNA by droplet digital PCR 34.	('midline gliomas', 'Disease', 'MESH:D005910', (11, 26))	('K27M', 'Mutation', 'p.K27M', (44, 48))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('H3 K27M mutations', 'Var', (41, 58))	('midline gliomas', 'Disease', (11, 26))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
123180	30977933	For instance, the H3 K27M mutation, which was initially considered as a potential pathognomonic alteration of malignant diffuse brainstem glioma, has been reported in a wider range of tumours 35.	('H3 K27M', 'Var', (18, 25))	('glioma', 'Disease', (138, 144))	('K27M', 'Mutation', 'p.K27M', (21, 25))	('tumours', 'Disease', 'MESH:D009369', (184, 191))	('reported', 'Reg', (155, 163))	('tumours', 'Disease', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('brainstem glioma', 'Phenotype', 'HP:0010796', (128, 144))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))
123182	30977933	demonstrated the possibility of detecting MYD88 mutations, a common alteration of primary central nervous system lymphomas (PCNSL) (Table 1) 37.	('lymphomas', 'Phenotype', 'HP:0002665', (113, 122))	('MYD88', 'Gene', (42, 47))	('primary central nervous system lymphomas', 'Phenotype', 'HP:0030069', (82, 122))	('central nervous system lymphomas', 'Disease', 'MESH:D002493', (90, 122))	('central nervous system lymphomas', 'Disease', (90, 122))	('MYD88', 'Gene', '4615', (42, 47))	('mutations', 'Var', (48, 57))
123183	30977933	Epigenetic alterations are also relevant biomarkers in primary brain tumours.	('Epigenetic alterations', 'Var', (0, 22))	('brain tumours', 'Disease', 'MESH:D001932', (63, 76))	('brain tumours', 'Disease', (63, 76))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('brain tumours', 'Phenotype', 'HP:0030692', (63, 76))
123192	30977933	However, blood CTCs were successfully detected in a series of 33 glioblastomas using a combination of markers (SOX2, Tubulin beta-3, EGFR, A2B5 and c-MET) with a sensitivity (defined as the rate of patients with at least one positive sample) of 13/33 (39%) 57.	('SOX2', 'Gene', '6657', (111, 115))	('c-MET', 'Gene', (148, 153))	('patients', 'Species', '9606', (198, 206))	('SOX2', 'Gene', (111, 115))	('Tubulin beta-3', 'Gene', '10381', (117, 131))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('A2B5', 'Var', (139, 143))	('c-MET', 'Gene', '4233', (148, 153))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('EGFR', 'Gene', '1956', (133, 137))	('glioblastomas', 'Disease', (65, 78))	('Tubulin beta-3', 'Gene', (117, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('EGFR', 'Gene', (133, 137))
123216	30977933	detected IDH1 mutations in CSF-derived EVs of patients with IDH-mutant gliomas using highly sensitive techniques; conversely, serum-derived EVs of the same patients were negative 68.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (46, 54))	('IDH1', 'Gene', (9, 13))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('IDH1', 'Gene', '3417', (9, 13))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', (60, 63))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH', 'Gene', '3417', (9, 12))	('IDH', 'Gene', '3417', (60, 63))	('mutations', 'Var', (14, 23))
123236	30977933	Within the possible practical applications of liquid biopsy in this setting, CSF testing in patients with CNS involvement by NSCLC seems one of the most promising, mirroring the already widespread practice of blood-based testing to promptly detect emerging resistance-associated mutations in extra-CNS NSCLC.	('mutations', 'Var', (279, 288))	('NSCLC', 'Disease', (302, 307))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (302, 307))	('resistance-associated', 'Reg', (257, 278))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))
123237	30977933	As recently shown by Nanjo et al., the specific detection of the EGFR T790M mutation in CSF cfDNA was associated with clinical efficacy of treatment with osimertinib, a third-generation EGFR tyrosine kinase inhibitor developed to overcome T790M-induced resistance 100.	('T790M', 'Var', (70, 75))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('T790M', 'Mutation', 'rs121434569', (239, 244))	('EGFR', 'Gene', '1956', (186, 190))	('EGFR', 'Gene', (186, 190))	('T790M', 'Mutation', 'rs121434569', (70, 75))
123249	30977933	Conversely, resection and histological examination will probably remain the cornerstone diagnostic approach if feasible, considered its therapeutic relevance and the risk of diagnostic pitfalls due to overlapping molecular features even between significantly different tumour entities [for example, a pilocytic astrocytoma (grade I) can rarely harbour the H3 K27M mutation which is characteristic of diffuse midline gliomas (grade IV)].	('astrocytoma', 'Phenotype', 'HP:0009592', (311, 322))	('glioma', 'Phenotype', 'HP:0009733', (416, 422))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('midline gliomas', 'Disease', (408, 423))	('H3 K27M', 'Var', (356, 363))	('midline gliomas', 'Disease', 'MESH:D005910', (408, 423))	('astrocytoma', 'Disease', 'MESH:D001254', (311, 322))	('K27M', 'Mutation', 'p.K27M', (359, 363))	('gliomas', 'Phenotype', 'HP:0009733', (416, 423))	('astrocytoma', 'Disease', (311, 322))	('tumour', 'Disease', (269, 275))
123258	31564237	Prediction of IDH Status Through MRI Features and Enlightened Reflection on the Delineation of Target Volume in Low-Grade Gliomas Isocitrate dehydrogenase mutational status defines distinct biologic behavior and clinical outcomes in low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('IDH', 'Gene', (14, 17))	('mutational', 'Var', (155, 165))	('Isocitrate dehydrogenase', 'Gene', (130, 154))	('IDH', 'Gene', '3417', (14, 17))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))	('Gliomas', 'Disease', 'MESH:D005910', (122, 129))	('Gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('gliomas', 'Disease', (243, 250))	('Gliomas', 'Disease', (122, 129))	('Isocitrate dehydrogenase', 'Gene', '3417', (130, 154))
123261	31564237	Isocitrate dehydrogenase mutation was related to more frequency of cortical involvement compared to isocitrate dehydrogenase-wild-type group (34/46 vs 6/24, P = .0001).	('isocitrate dehydrogenase', 'Gene', '3417', (100, 124))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('mutation', 'Var', (25, 33))	('isocitrate dehydrogenase', 'Gene', (100, 124))	('cortical involvement', 'CPA', (67, 87))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
123271	31564237	Isocitrate dehydrogenase mutation signifies less aggressive biologic behavior and better clinical outcomes, while the wild-type group behaves more like higher grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('mutation', 'Var', (25, 33))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('gliomas', 'Disease', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
123276	31564237	Previous studies have attempted to predict IDH1/2 mutation with different MRI including conventional MRI (cMRI), advanced MRI such as diffusion and perfusion imaging, and molecular imaging using various nuclear medicine tracers.	('IDH1', 'Gene', '3417', (43, 47))	('IDH1', 'Gene', (43, 47))	('mutation', 'Var', (50, 58))
123278	31564237	A retrospective single institution study was performed on 78 patients with pathologically proven WHO LGG with a presurgery MRI and molecular data on IDH to evaluate the predictive roles of MRI features in IDH mutational status and their potential impact on the determination of clinical target volume in radiotherapy.	('IDH', 'Gene', (149, 152))	('patients', 'Species', '9606', (61, 69))	('IDH', 'Gene', (205, 208))	('IDH', 'Gene', '3417', (149, 152))	('IDH', 'Gene', '3417', (205, 208))	('mutational', 'Var', (209, 219))
123281	31564237	All tissue samples were tested for IDH mutation, O-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q deletions if possible.	('1p/19q deletions', 'Var', (127, 143))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))	('MGMT', 'Gene', (88, 92))	('tested', 'Reg', (24, 30))	('O-methylguanine-DNA methyltransferase', 'Gene', '4255', (49, 86))	('MGMT', 'Gene', '4255', (88, 92))	('O-methylguanine-DNA methyltransferase', 'Gene', (49, 86))
123283	31564237	Patients were divided into 2 groups based on the presence of IDH mutation.	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (65, 73))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))
123288	31564237	Isocitrate dehydrogenase 1/2 alterations in the hotspot codons R132 and R172 were also simultaneously assessed using bidirectional cycle sequencing of polymerase chain reaction-amplified fragments with the standard Sanger method.	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('alterations', 'Var', (29, 40))
123290	31564237	Telomerase reverse transcriptase (TERT) promoter mutations were analyzed by direct DNA sequencing.	('TERT', 'Gene', (34, 38))	('TERT', 'Gene', '7015', (34, 38))	('mutations', 'Var', (49, 58))
123304	31564237	Isocitrate dehydrogenase mutation was related to more frequency of cortical involvement compared to IDH-WT group (34/46 vs 6/24, P = .0001).	('IDH', 'Gene', (100, 103))	('IDH', 'Gene', '3417', (100, 103))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('mutation', 'Var', (25, 33))	('cortical involvement', 'CPA', (67, 87))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
123312	31564237	Isocitrate dehydrogenase mutation is an early step in gliomagenesis, which occurs in 70% to 90% of grade II gliomas.	('II gliomas', 'Disease', (105, 115))	('gliomagenesis', 'Disease', (54, 67))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('mutation', 'Var', (25, 33))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('II gliomas', 'Disease', 'MESH:D005910', (105, 115))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('gliomagenesis', 'Disease', 'None', (54, 67))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
123313	31564237	Isocitrate dehydrogenase mutation is regarded as predictive markers of better SEN and prolonged survival.	('better', 'PosReg', (71, 77))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('mutation', 'Var', (25, 33))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
123322	31564237	As previously reported, IDH mutation was strongly positively associated with MGMT methylation.	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', '3417', (24, 27))	('mutation', 'Var', (28, 36))	('MGMT', 'Gene', '4255', (77, 81))	('MGMT', 'Gene', (77, 81))	('associated', 'Reg', (61, 71))
123325	31564237	Isocitrate dehydrogenase mutation is regarded as a founder biochemical event in tumorigenesis that triggers methylation of genomic segments covering, among others, the MGMT gene.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MGMT', 'Gene', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutation', 'Var', (25, 33))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('methylation', 'MPA', (108, 119))	('tumor', 'Disease', (80, 85))	('triggers', 'Reg', (99, 107))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('MGMT', 'Gene', '4255', (168, 172))
123326	31564237	During the course of gliomagenesis, IDH mutation and MGMT methylation are considered to be early events, followed by the acquisition of either TP53 mutation or 1p19qloh.	('TP53', 'Gene', (143, 147))	('gliomagenesis', 'Disease', 'None', (21, 34))	('TP53', 'Gene', '7157', (143, 147))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('IDH', 'Gene', (36, 39))	('1p19qloh', 'Var', (160, 168))	('MGMT', 'Gene', (53, 57))	('gliomagenesis', 'Disease', (21, 34))	('MGMT', 'Gene', '4255', (53, 57))	('IDH', 'Gene', '3417', (36, 39))
123339	31564237	Nodular or ring-like enhancement is association with blood-brain barrier breakdown and angiogenesis, which is frequently observed in high-grade glioma.	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('blood-brain barrier breakdown', 'CPA', (53, 82))	('glioma', 'Disease', (144, 150))	('Nodular', 'Var', (0, 7))	('angiogenesis', 'CPA', (87, 99))
123343	31564237	Significant concordance between the gadolinium enhancement in MRI and IDH-WT was found in our study (16/24 vs 8/46, P < .0001), consistent with previous finding but contradictory to the theory that IDH1 mutation may facilitate angiogenesis by inhibiting aKG-dependent dioxygenases.	('aKG-dependent dioxygenases', 'Enzyme', (254, 280))	('inhibiting', 'NegReg', (243, 253))	('facilitate', 'PosReg', (216, 226))	('IDH', 'Gene', (70, 73))	('IDH1', 'Gene', (198, 202))	('gadolinium', 'MPA', (36, 46))	('mutation', 'Var', (203, 211))	('IDH', 'Gene', '3417', (70, 73))	('IDH1', 'Gene', '3417', (198, 202))	('IDH', 'Gene', (198, 201))	('angiogenesis', 'CPA', (227, 239))	('IDH', 'Gene', '3417', (198, 201))	('gadolinium', 'Chemical', 'MESH:D005682', (36, 46))
123363	31564237	Recently,11C-MET and18F-FET PET were proved to allow a better delineation of tumor margins and improve targeting of biopsy and radiotherapy, suggesting the application of biological tumor volume defined by SUV value in radiotherapy of gliomas.	('tumor', 'Disease', (182, 187))	('and18F-FET PET', 'Var', (17, 31))	('gliomas', 'Disease', (235, 242))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gliomas', 'Disease', 'MESH:D005910', (235, 242))	('gliomas', 'Phenotype', 'HP:0009733', (235, 242))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('11C-MET', 'Chemical', 'MESH:C098756', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (77, 82))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
123364	31564237	However, a meta-analysis comparing the diagnostic ACC of different imaging technique to delineate diffuse gliomas reported that for LGGs, the area under the hsROC curve was higher for MRS (0.781) than T2/FLAIR (0.774), followed by PET-MET (0.668) and PET-FET (0.649).	('PET-MET', 'Chemical', 'MESH:C098756', (231, 238))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('0.781', 'Var', (189, 194))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('higher', 'PosReg', (173, 179))
123383	30613474	Data generated through various genome-wide molecular profiling tools (e.g., mRNA levels, gene copy number, CpG methylation, mutation profile) led to the molecular classifications of tumors.	('mRNA levels', 'MPA', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('led to', 'Reg', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('mutation', 'Var', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
123391	30613474	The authors then divided each of the glioma cohort across RS median (below the median is low risk or LR, while above the median is high risk or HR), and by employing GSEA (Gene Set Enrichment Analysis), they demonstrated that the Gene Ontology (GO) Bioprocess gene sets M13664 (Immune System Process; with 334 member genes) and M1987 (Immune Response; with 237 member genes) exhibit a high Normalized Enrichment Score (NES).	('M13664', 'Var', (270, 276))	('glioma', 'Disease', (37, 43))	('GSEA', 'Chemical', '-', (166, 170))	('RS', 'Chemical', '-', (58, 60))	('M1987', 'Var', (328, 333))	('ES', 'Chemical', 'MESH:D004540', (420, 422))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
123414	30613474	Ongoing clinical trials of these drugs against glioma include: NCT02311920 (phase I; ipilimumab and/or nivolumab in combination with temozolomide against newly diagnosed GBM or gliosarcoma), NCT02337491 (phase II; pembrolizumab with or without bevacizumab against recurrent GBM), NCT02017717 (phase III; effectiveness and safety of nivolumab compared to bevacizumab and of nivolumab with or without ipilimumab in GBM) [see, or clinicaltrials.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('gliosarcoma', 'Disease', (177, 188))	('NCT02311920', 'Var', (63, 74))	('pembrolizumab', 'Chemical', 'MESH:C582435', (214, 227))	('glioma', 'Disease', (47, 53))	('ipilimumab', 'Chemical', 'MESH:D000074324', (399, 409))	('gliosarcoma', 'Disease', 'MESH:D018316', (177, 188))	('NCT02337491', 'Var', (191, 202))	('ipilimumab', 'Chemical', 'MESH:D000074324', (85, 95))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('temozolomide', 'Chemical', 'MESH:D000077204', (133, 145))
123429	33718432	Epigenetic regulation is essential for cellular homeostasis and its dysregulation is associated with a variety of cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('dysregulation', 'Var', (68, 81))	('Epigenetic regulation', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('associated', 'Reg', (85, 95))
123437	33718432	In this study, we utilized RNA-seq data or RNA microarray data for 1,125 gliomas from the CGGA (n = 307), TCGA (n = 598) and GSE16011 (n = 250) datasets, and matched copy number variation (CNV; n = 598) and single nucleotide polymorphism (SNP; n = 583) data from the TCGA dataset.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('single nucleotide polymorphism', 'Var', (207, 237))	('gliomas', 'Disease', (73, 80))
123440	33718432	Tumor mutation burden (TMB) was also calculated for samples with mutation data in the TCGA dataset and we found TMB showed a positive correlation with our risk score, which may mean that DNA repair system is highly impaired in gliomas with higher risk score and dysregulation of lysine acetylation may lead to malignant progression in glioma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('gliomas', 'Disease', (227, 234))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('glioma', 'Disease', (335, 341))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('glioma', 'Disease', 'MESH:D005910', (335, 341))	('malignant progression', 'CPA', (310, 331))	('impaired', 'NegReg', (215, 223))	('dysregulation', 'Var', (262, 275))	('lead to', 'Reg', (302, 309))	('TMB', 'Chemical', '-', (112, 115))	('lysine', 'Chemical', 'MESH:D008239', (279, 285))	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('glioma', 'Phenotype', 'HP:0009733', (335, 341))	('lysine acetylation', 'MPA', (279, 297))	('DNA repair', 'MPA', (187, 197))	('TMB', 'Chemical', '-', (23, 26))	('glioma', 'Disease', (227, 233))
123441	33718432	Overall, mRNA expressions and genome alterations of LARs were significant associated with the clinical outcomes of glioma patients and our study provides a method to perform clinical applications of them.	('glioma', 'Disease', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('LAR', 'Gene', (52, 55))	('mRNA expressions', 'MPA', (9, 25))	('genome alterations', 'Var', (30, 48))	('patients', 'Species', '9606', (122, 130))	('LAR', 'Gene', '5792', (52, 55))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('associated', 'Reg', (74, 84))
123449	33718432	GSEA software (http://software.broadinstitute.org/gsea/index.jsp) was used to investigate the enriched tumor hallmarks in the LA3 subgroup compared with those in the LA1/2 subgroups.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor hallmarks', 'Disease', (103, 118))	('tumor hallmarks', 'Disease', 'MESH:D009369', (103, 118))	('LA3', 'Var', (126, 129))	('GSEA', 'Chemical', '-', (0, 4))
123458	33718432	Given the crucial biological roles of each LAR, we systematically analyzed the correlation between LAR mRNA expression levels and clinicopathological characteristics (including WHO grades, IDH mutation status, and 1p/19q codeletion status) in gliomas.	('LAR', 'Gene', '5792', (43, 46))	('LAR', 'Gene', '5792', (99, 102))	('IDH', 'Gene', (189, 192))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('IDH', 'Gene', '3417', (189, 192))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('gliomas', 'Disease', (243, 250))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))	('mutation', 'Var', (193, 201))	('LAR', 'Gene', (43, 46))	('LAR', 'Gene', (99, 102))
123468	33718432	We also evaluated the mRNA expression of the 33 LARs according to 1p/19q codeletion status in LGGs with mutated IDH.	('mutated', 'Var', (104, 111))	('LAR', 'Gene', '5792', (48, 51))	('LAR', 'Gene', (48, 51))	('IDH', 'Gene', (112, 115))	('IDH', 'Gene', '3417', (112, 115))
123469	33718432	We found that HDAC1/2/3/4/5/6/10/11, as well as KAT1/2A/2B/7, SIRT2/3/4/5/7, LEF1, TCF1, ESCO1/2 were closely associated with 1p/19q codeletion status in LGGs with mutated IDH (Figure 1G).	('SIRT2/3/4/5/7', 'Gene', (62, 75))	('IDH', 'Gene', (172, 175))	('LEF1', 'Gene', '51176', (77, 81))	('KAT1/2A/2B/7', 'Gene', (48, 60))	('IDH', 'Gene', '3417', (172, 175))	('ESCO1/2', 'Gene', (89, 96))	('TCF1', 'Gene', (83, 87))	('SIRT2/3/4/5/7', 'Gene', '22933;23410;23409;23408;51547', (62, 75))	('1p/19q codeletion status', 'Var', (126, 150))	('LEF1', 'Gene', (77, 81))	('HDAC1/2/3/4/5/6/10/11', 'Gene', (14, 35))	('associated', 'Reg', (110, 120))	('KAT1/2A/2B/7', 'Gene', '8520;2648;8850;11143', (48, 60))	('ESCO1/2', 'Gene', '114799;157570', (89, 96))	('mutated', 'Var', (164, 171))	('TCF1', 'Gene', '6927', (83, 87))	('HDAC1/2/3/4/5/6/10/11', 'Gene', '3065;3066', (14, 35))
123474	33718432	Subsequently, we evaluated the differences in clinicopathological features and expression levels among the three clusters (LA1, LA2, and LA3) (Figure 2F), and found that, compared with the other two groups, LA3 was significantly related to increased age at diagnosis (p < 0.001), higher WHO grade (p < 0.001), fewer IDH mutations (p < 0.001), and fewer 1p/19q codeletions (p < 0.001) (Supplementary Table S3).	('increased', 'PosReg', (240, 249))	('fewer', 'NegReg', (347, 352))	('1p/19q', 'MPA', (353, 359))	('IDH', 'Gene', (316, 319))	('higher', 'PosReg', (280, 286))	('fewer', 'NegReg', (310, 315))	('LA3', 'Var', (207, 210))	('IDH', 'Gene', '3417', (316, 319))	('WHO grade', 'CPA', (287, 296))
123475	33718432	In contrast, the other two subgroups correlated with younger age at diagnosis, lower WHO grade, more IDH mutations, and more 1p/19q codeletions.	('lower', 'NegReg', (79, 84))	('1p/19q codeletions', 'Var', (125, 143))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (101, 104))	('WHO', 'MPA', (85, 88))
123495	33718432	The high-risk subgroup was highly associated with older age, higher WHO grade, wild-type IDH, and non-codeletion of 1p/19q, and OS time decreased with the risk score increasing.	('IDH', 'Gene', (89, 92))	('non-codeletion', 'Var', (98, 112))	('OS time', 'CPA', (128, 135))	('IDH', 'Gene', '3417', (89, 92))	('decreased', 'NegReg', (136, 145))
123505	33718432	We found that 36 (6.17%) of the 583 samples contained mutations in genes coding for the LARs, in which KAT6B (8/583) and CREBBP (5/583) were the most frequently mutated genes.	('CREBBP', 'Gene', '1387', (121, 127))	('contained', 'Reg', (44, 53))	('mutations', 'Var', (54, 63))	('CREBBP', 'Gene', (121, 127))	('KAT6B', 'Gene', (103, 108))	('LAR', 'Gene', (88, 91))	('LAR', 'Gene', '5792', (88, 91))	('KAT6B', 'Gene', '23522', (103, 108))
123506	33718432	Within the eight mutations found in KAT6B, six were present in oligodendrogliomas and six of the samples were in the low-risk subgroup.	('KAT6B', 'Gene', (36, 41))	('present', 'Reg', (52, 59))	('KAT6B', 'Gene', '23522', (36, 41))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (63, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('mutations', 'Var', (17, 26))	('oligodendrogliomas', 'Disease', (63, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
123507	33718432	All the mutations in CREBBP were in samples from high-risk patients, and comprised two glioblastomas and three astrocytomas.	('CREBBP', 'Gene', '1387', (21, 27))	('mutations', 'Var', (8, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (87, 100))	('glioblastomas', 'Disease', (87, 100))	('patients', 'Species', '9606', (59, 67))	('CREBBP', 'Gene', (21, 27))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('glioblastomas', 'Disease', 'MESH:D005909', (87, 100))	('comprised', 'Reg', (73, 82))	('astrocytomas', 'Disease', (111, 123))
123508	33718432	In the waterfall plot depicting the 30 most frequently mutated genes in gliomas (Supplementary Figure S6A), we noticed that glioma patients with a high-risk score often carried a higher frequency of gene mutations.	('patients', 'Species', '9606', (131, 139))	('glioma', 'Disease', (72, 78))	('glioma', 'Disease', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('gene mutations', 'Var', (199, 213))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
123517	33718432	Codeletion of these genes is frequently observed in oligodendrogliomas, and is highly associated with improved responses to radiochemotherapy and longer survival than diffuse gliomas without these alterations.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('Codeletion', 'Var', (0, 10))	('responses to radiochemotherapy', 'MPA', (111, 141))	('observed', 'Reg', (40, 48))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (52, 70))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Disease', (175, 182))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('oligodendrogliomas', 'Disease', (52, 70))	('improved', 'PosReg', (102, 110))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
123518	33718432	Although Kaplan-Meier curves revealed that copy number deletions of HDAC1 and SIRT2 are related to a better prognosis, we could not determine whether 1p/19q codeletions resulted in differential OS.	('SIRT2', 'Gene', (78, 83))	('copy number deletions', 'Var', (43, 64))	('HDAC1', 'Gene', (68, 73))	('SIRT2', 'Gene', '22933', (78, 83))	('HDAC1', 'Gene', '3065', (68, 73))
123520	33718432	We found that, for both genes, copy number deletions were associated with lower mRNA expression, and in gliomas without HDAC1 or SIRT2 copy number variations, patients with lower HDAC1 expression or higher SIRT2 expression showed better clinical prognosis.	('expression', 'MPA', (185, 195))	('HDAC1', 'Gene', '3065', (120, 125))	('lower', 'NegReg', (74, 79))	('SIRT2', 'Gene', (206, 211))	('SIRT2', 'Gene', '22933', (206, 211))	('HDAC1', 'Gene', (179, 184))	('mRNA expression', 'MPA', (80, 95))	('gliomas', 'Disease', (104, 111))	('SIRT2', 'Gene', (129, 134))	('HDAC1', 'Gene', '3065', (179, 184))	('SIRT2', 'Gene', '22933', (129, 134))	('patients', 'Species', '9606', (159, 167))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('HDAC1', 'Gene', (120, 125))	('expression', 'MPA', (212, 222))	('higher', 'PosReg', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('lower', 'NegReg', (173, 178))	('copy number deletions', 'Var', (31, 52))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
123521	33718432	These results indicated that HDAC1 may be one of the oncogenes lost in gliomas with 1p deletion, while SIRT2, as a protective factor, is lost with 19q codeletions in glioma patients.	('HDAC1', 'Gene', (29, 34))	('gliomas', 'Disease', (71, 78))	('patients', 'Species', '9606', (173, 181))	('SIRT2', 'Gene', '22933', (103, 108))	('glioma', 'Disease', (71, 77))	('glioma', 'Disease', (166, 172))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('HDAC1', 'Gene', '3065', (29, 34))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('1p deletion', 'Var', (84, 95))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('SIRT2', 'Gene', (103, 108))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
123522	33718432	The EP300 is located on chromosome 22q, and deletion of this gene is also common in gliomas.	('EP300', 'Gene', '2033', (4, 9))	('EP300', 'Gene', (4, 9))	('gliomas', 'Disease', (84, 91))	('deletion', 'Var', (44, 52))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('common', 'Reg', (74, 80))
123525	33718432	We found that copy number deletions of EP300 were associated with lower EP300 mRNA expression levels, and reduced expression of EP300 in gliomas without EP300 CNVs was related to a worse clinical prognosis (Figure 7D).	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('EP300', 'Gene', '2033', (39, 44))	('EP300', 'Gene', (39, 44))	('copy number deletions', 'Var', (14, 35))	('lower', 'NegReg', (66, 71))	('gliomas', 'Disease', (137, 144))	('EP300', 'Gene', (72, 77))	('EP300', 'Gene', '2033', (72, 77))	('EP300', 'Gene', '2033', (153, 158))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('expression', 'MPA', (114, 124))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('EP300', 'Gene', (153, 158))	('EP300', 'Gene', (128, 133))	('EP300', 'Gene', '2033', (128, 133))	('reduced', 'NegReg', (106, 113))
123527	33718432	The CNVs for the other four LARs-KAT6B (10q), SIRT1(10q), HDAC10 (22q), and HDAC9 (7q)-were highly associated with the risk signature and may be affected in chromosomal alterations such as 10q-, 22q- and 7+ in gliomas.	('SIRT1', 'Gene', (46, 51))	('gliomas', 'Disease', (210, 217))	('KAT6B', 'Gene', (33, 38))	('HDAC9', 'Gene', (76, 81))	('HDAC9', 'Gene', '9734', (76, 81))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('HDAC10', 'Gene', '83933', (58, 64))	('LAR', 'Gene', '5792', (28, 31))	('KAT6B', 'Gene', '23522', (33, 38))	('LAR', 'Gene', (28, 31))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('22q-', 'Var', (195, 199))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))	('10q-', 'Var', (189, 193))	('HDAC10', 'Gene', (58, 64))	('SIRT1', 'Gene', '23411', (46, 51))	('associated', 'Reg', (99, 109))	('affected', 'Reg', (145, 153))
123531	33718432	We further identified three subgroups (LA1/2/3) of gliomas by consensus clustering of 26 OS-related LARs, and confirmed that LA3 was the most malignant subtype with the poorest prognosis.	('gliomas', 'Disease', (51, 58))	('LAR', 'Gene', (100, 103))	('LA3', 'Var', (125, 128))	('LAR', 'Gene', '5792', (100, 103))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
123543	33718432	The TMB is associated with neoantigen abundance and increased immunogenicity, and is used to quantitatively assess mutations carried by tumor cells, which was usually used to predict the response to immunotherapy in cancer patients It is defined as the total number of somatic gene coding errors, base substitutions, gene insertions, or deletion errors that are detected per million bases.	('TMB', 'Chemical', '-', (4, 7))	('base substitutions', 'Var', (297, 315))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('deletion errors', 'Var', (337, 352))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('gene insertions', 'Var', (317, 332))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Disease', (136, 141))
123544	33718432	In recent years, several studies have demonstrated that dysregulation of lysine acetylation may result in errors during DNA damage repair.	('lysine acetylation', 'MPA', (73, 91))	('lysine', 'Chemical', 'MESH:D008239', (73, 79))	('DNA damage repair', 'MPA', (120, 137))	('dysregulation', 'Var', (56, 69))	('result', 'Reg', (96, 102))
123546	33718432	Based on these observations, we speculate that dysregulation of lysine acetylation of both histone and non-histone proteins may play a pivotal role in impairing the DNA damage repair response, which would then lead to hypermutations and an increased neoantigen load, leading to malignant progression of tumors.	('increased', 'PosReg', (240, 249))	('neoantigen load', 'MPA', (250, 265))	('impairing', 'NegReg', (151, 160))	('leading to', 'Reg', (267, 277))	('dysregulation', 'Var', (47, 60))	('DNA damage repair', 'MPA', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('lysine acetylation', 'MPA', (64, 82))	('lysine', 'Chemical', 'MESH:D008239', (64, 70))	('lead to', 'Reg', (210, 217))	('tumors', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('hypermutations', 'MPA', (218, 232))
123549	33718432	We further found that specific chromosomal alterations in gliomas were highly related to the CNVs of several LARs.	('chromosomal alterations', 'Var', (31, 54))	('related', 'Reg', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('LAR', 'Gene', (109, 112))	('CNVs', 'Disease', (93, 97))	('LAR', 'Gene', '5792', (109, 112))
123563	30061525	In 2008, a multi-group collaboration found that IDH1 mutations occurred in 12% of glioblastomas, and subsequent researchers observed IDH1 mutations in 50-80% of LGGs and secondary GBM.	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('IDH1', 'Gene', '3417', (48, 52))	('glioblastomas', 'Disease', 'MESH:D005909', (82, 95))	('mutations', 'Var', (53, 62))	('IDH1', 'Gene', (133, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('glioblastomas', 'Disease', (82, 95))	('IDH1', 'Gene', '3417', (133, 137))	('IDH1', 'Gene', (48, 52))	('occurred', 'Reg', (63, 71))	('mutations', 'Var', (138, 147))
123568	30061525	However, when IDH is mutated, the isocitrate will be converted to 2-hydroxyglutarate, which can inhibit the activity of man alpha-ketoglutarate-dependent dioxygenases, including, but are not limited, to histone demethylases.	('isocitrate', 'Chemical', 'MESH:C034219', (34, 44))	('IDH', 'Gene', (14, 17))	('activity', 'MPA', (108, 116))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (66, 84))	('oxygen', 'Chemical', 'MESH:D010100', (156, 162))	('IDH', 'Gene', '3417', (14, 17))	('man', 'Species', '9606', (120, 123))	('man alpha-ketoglutarate-dependent dioxygenases', 'Enzyme', (120, 166))	('inhibit', 'NegReg', (96, 103))	('mutated', 'Var', (21, 28))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (124, 143))
123569	30061525	Several lines of research however, have shown that IDH1 mutations were early events in the development of gliomas and had a different impact on gliomas.	('IDH1', 'Gene', '3417', (51, 55))	('mutations', 'Var', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('IDH1', 'Gene', (51, 55))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))
123570	30061525	Previous studies demonstrated that IDH1 mutations frequently occurred in grade II and III gliomas and secondary GBM glioblastoma, but rarely in primary GBM; whereas IDH2 mutations occur in fewer than 3% of glial tumors.	('gliomas', 'Disease', (90, 97))	('IDH1', 'Gene', (35, 39))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('glioblastoma', 'Disease', (116, 128))	('IDH1', 'Gene', '3417', (35, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('glial tumors', 'Disease', 'MESH:D005910', (206, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('IDH2', 'Gene', (165, 169))	('glial tumors', 'Disease', (206, 218))	('mutations', 'Var', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('occurred', 'Reg', (61, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('grade II', 'Disease', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('IDH2', 'Gene', '3418', (165, 169))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
123573	30061525	pointed out that IDH1 mutation could be a molecular signature and predictive factor of secondary glioblastomas, which may serve as biomarkers for assessing tumor progression and treatment.	('glioblastomas', 'Disease', (97, 110))	('mutation', 'Var', (22, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('IDH1', 'Gene', (17, 21))	('glioblastomas', 'Phenotype', 'HP:0012174', (97, 110))	('tumor', 'Disease', (156, 161))	('IDH1', 'Gene', '3417', (17, 21))	('glioblastomas', 'Disease', 'MESH:D005909', (97, 110))
123574	30061525	Among all molecular alteration types in gliomas, IDH genotype is the most important, as patients with the IDH gene mutation have significantly longer survival time than patients of IDH wild-type, which is independent of WHO grade.	('IDH', 'Gene', (181, 184))	('IDH', 'Gene', '3417', (106, 109))	('patients', 'Species', '9606', (169, 177))	('survival time', 'CPA', (150, 163))	('IDH', 'Gene', (49, 52))	('IDH', 'Gene', '3417', (181, 184))	('patients', 'Species', '9606', (88, 96))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('longer', 'PosReg', (143, 149))	('IDH', 'Gene', '3417', (49, 52))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('mutation', 'Var', (115, 123))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('IDH', 'Gene', (106, 109))
123582	30061525	conduct a radiomics model using texture features and visually accessible Rembrandt images (VASARI) annotations features to predict IDH1 mutations and found that the texture feature achieved a higher accuracy than with the VASARI features.	('IDH1', 'Gene', '3417', (131, 135))	('mutations', 'Var', (136, 145))	('IDH1', 'Gene', (131, 135))
123599	30061525	This dataset contains 33 cancers with various data types, including gene expression profiling, copy number variation profiling, single nucleotide polymorphism (SNP) genotyping, and so on.	('copy number', 'Var', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('single nucleotide polymorphism', 'Var', (128, 158))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
123657	29643764	Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas.	('PDL-1', 'Gene', '29126', (216, 221))	('mutations', 'Var', (166, 175))	('gliomas', 'Disease', (236, 243))	('gliomas', 'Disease', 'MESH:D005910', (236, 243))	('PDL-1', 'Gene', (216, 221))	('IDH1', 'Gene', (161, 165))	('gliomas', 'Phenotype', 'HP:0009733', (236, 243))	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('IDH1', 'Gene', '3417', (161, 165))
123661	29643764	We also found that quantitative levels of IDH1 mutant proteins were positively associated with recurrence-free survival (RFS).	('associated', 'Reg', (79, 89))	('recurrence-free survival', 'CPA', (95, 119))	('IDH1', 'Gene', '3417', (42, 46))	('proteins', 'Protein', (54, 62))	('IDH1', 'Gene', (42, 46))	('mutant', 'Var', (47, 53))
123662	29643764	A key product of the IDH1 mutation (2-hydroxyglutarate) was found to transiently increase DNA methylation and suppress PD-L1 expression.	('suppress', 'NegReg', (110, 118))	('mutation', 'Var', (26, 34))	('PD-L1', 'Gene', (119, 124))	('expression', 'MPA', (125, 135))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (36, 54))	('DNA methylation', 'MPA', (90, 105))	('IDH1', 'Gene', (21, 25))	('increase', 'PosReg', (81, 89))	('PD-L1', 'Gene', '29126', (119, 124))	('IDH1', 'Gene', '3417', (21, 25))
123663	29643764	Conclusions: IDH1 mutations impact the immune landscape of gliomas by affecting immune infiltrations and manipulating checkpoint ligand PD-L1 expression.	('gliomas', 'Disease', (59, 66))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('PD-L1', 'Gene', (136, 141))	('IDH1', 'Gene', (13, 17))	('impact', 'Reg', (28, 34))	('immune infiltrations', 'CPA', (80, 100))	('immune landscape', 'MPA', (39, 55))	('affecting', 'Reg', (70, 79))	('IDH1', 'Gene', '3417', (13, 17))	('PD-L1', 'Gene', '29126', (136, 141))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('mutations', 'Var', (18, 27))
123669	29643764	Mounting evidence indicates that tumor-associated mutations represent key factors that affect immunogenicity in tumors.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('affect', 'Reg', (87, 93))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (112, 117))	('immunogenicity', 'MPA', (94, 108))	('tumors', 'Disease', (112, 118))
123671	29643764	Approximately 90% of the mutations occur in the IDH1 gene (Yan et al.,).	('IDH1', 'Gene', (48, 52))	('mutations', 'Var', (25, 34))	('IDH1', 'Gene', '3417', (48, 52))
123672	29643764	There is evidence to support the notion that IDH1 mutations may be associated with glioma susceptibility (Amary et al.,; Pansuriya et al.,).	('glioma', 'Disease', (83, 89))	('IDH1', 'Gene', '3417', (45, 49))	('mutations', 'Var', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('associated', 'Reg', (67, 77))	('IDH1', 'Gene', (45, 49))
123674	29643764	Although IDH1 mutations that encode tumor-specific epitopes can be immunologically exploited, the tumor microenvironment, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) (Almand et al.,; Dieckmann et al.,; Chen and Mellman,; Zhou et al.,), may suppress antitumor immunity and play a critical role in cancer development and progression.	('IDH1', 'Gene', (9, 13))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('IDH1', 'Gene', '3417', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (372, 378))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('suppress', 'NegReg', (316, 324))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cancer', 'Disease', 'MESH:D009369', (372, 378))
123675	29643764	Thus far, few reports have been published on the association between IDH gene mutations and tumor immune cell infiltration, such as CD8+ T cells (Kohanbash et al.,), macrophages, and CD4+ T, B, and dendritic cells (Amankulor et al.,), as well as the connections between mutations and immune-checkpoint molecules (Berghoff et al.,; Hodges et al.,).	('IDH', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CD4', 'Gene', (183, 186))	('mutations', 'Var', (78, 87))	('association', 'Interaction', (49, 60))	('IDH', 'Gene', '3417', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CD4', 'Gene', '920', (183, 186))	('tumor', 'Disease', (92, 97))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))
123676	29643764	In this study, we provide more evidence to support the finding that the regulation of PD-L1 also known as cluster of differentiation 274 (CD274) glioma expression is directly associated with tumor IDH1 mutation status.	('associated', 'Reg', (175, 185))	('glioma', 'Disease', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('PD-L1', 'Gene', '29126', (86, 91))	('IDH1', 'Gene', (197, 201))	('mutation', 'Var', (202, 210))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('IDH1', 'Gene', '3417', (197, 201))	('expression', 'MPA', (152, 162))	('PD-L1', 'Gene', (86, 91))
123677	29643764	The global immune landscapes of the IDH1 wildtype and mutant tumors were found to be significantly different.	('different', 'Reg', (99, 108))	('tumors', 'Disease', (61, 67))	('IDH1', 'Gene', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('IDH1', 'Gene', '3417', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutant', 'Var', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
123692	29643764	To quantify the protein levels of mutant IDH1, as well as the PD-L1 expression, all captured 20X magnification fields of IHC were imported to Image-Pro Premier 9.1 to measure each image's integrated optical density (IOD).	('PD-L1', 'Gene', '29126', (62, 67))	('integrated optical density', 'MPA', (188, 214))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('PD-L1', 'Gene', (62, 67))	('mutant', 'Var', (34, 40))
123699	29643764	DNA sequencing was performed to validate the accuracy of IDH1 mutation detection using an anti-IDH1 monoclonal antibody.	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', (95, 99))	('mutation', 'Var', (62, 70))	('IDH1', 'Gene', '3417', (57, 61))	('IDH1', 'Gene', '3417', (95, 99))
123705	29643764	PD-L1 methylation status was determined by the methylation-specific (Ms) PCR and pyrosequencing, using the following primers for sequence amplification: for cg15837913: sense, 5'-GGTAGAATATTAGGGATTTTGAGTATTT-3'; anti-sense, 5'-CAACAACAAA CCCATATAACTTTAAT-3'.	('PD-L1', 'Gene', (0, 5))	('sense', 'Var', (169, 174))	('PD-L1', 'Gene', '29126', (0, 5))
123712	29643764	Mounting evidence suggests that LGG progression is highly associated with IDH1 mutations and their related genetic abnormalities, such as TP53 mutation or total 1p/19q loss (Ichimura et al.,; Suzuki et al.,).	('loss', 'NegReg', (168, 172))	('TP53', 'Gene', '7157', (138, 142))	('associated', 'Reg', (58, 68))	('IDH1', 'Gene', (74, 78))	('TP53', 'Gene', (138, 142))	('mutation', 'Var', (143, 151))	('genetic abnormalities', 'Disease', (107, 128))	('genetic abnormalities', 'Disease', 'MESH:D030342', (107, 128))	('IDH1', 'Gene', '3417', (74, 78))	('mutations', 'Var', (79, 88))	('LGG progression', 'Disease', (32, 47))
123723	29643764	The mutation status of the IDH1 gene was shown to correlate with outcomes in patients with gliomas using mostly unpaired patient samples.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('mutation', 'Var', (4, 12))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('patients', 'Species', '9606', (77, 85))	('IDH1', 'Gene', (27, 31))	('patient', 'Species', '9606', (121, 128))	('patient', 'Species', '9606', (77, 84))	('IDH1', 'Gene', '3417', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
123724	29643764	We found a similar trend in this study using patients' paired samples; specifically, IDH1 mutation status was strongly correlated with patients' prolonged RFS (Figures S2A,B).	('patients', 'Species', '9606', (135, 143))	('RFS', 'MPA', (155, 158))	('patients', 'Species', '9606', (45, 53))	('correlated', 'Reg', (119, 129))	('IDH1', 'Gene', (85, 89))	('prolonged', 'PosReg', (145, 154))	('IDH1', 'Gene', '3417', (85, 89))	('mutation status', 'Var', (90, 105))
123725	29643764	Interestingly, we also found that quantitatively, the increased level of the mutant IDH1 protein (Figures S3 A,B) was positively associated with prolonged RFS, not OS (Figures 3A,B) in all three groups (Figures 3C,D).	('level', 'MPA', (64, 69))	('IDH1', 'Gene', (84, 88))	('RFS', 'Disease', (155, 158))	('increased', 'PosReg', (54, 63))	('IDH1', 'Gene', '3417', (84, 88))	('mutant', 'Var', (77, 83))	('protein', 'Protein', (89, 96))
123733	29643764	Since tumor-associated DNA methylation is a key epigenetic alteration that manipulates gene expression patterns which, in turn, can aid in tumor progression (Das and Singal,; Ehrlich,), we evaluated the DNA methylation profile of PD-L1 in primary LGGs and GBMs using normal brain tissues as controls to determine if there are glioma-specific DNA hyper- or hypo-methylation resulting in gene expression modulation.	('gene expression', 'MPA', (386, 401))	('hypo-methylation', 'Var', (356, 372))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('glioma', 'Disease', 'MESH:D005910', (326, 332))	('GBM', 'Phenotype', 'HP:0012174', (256, 259))	('manipulates', 'Reg', (75, 86))	('hyper-', 'Var', (346, 352))	('glioma', 'Phenotype', 'HP:0009733', (326, 332))	('PD-L1', 'Gene', (230, 235))	('aid', 'Reg', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('glioma', 'Disease', (326, 332))	('PD-L1', 'Gene', '29126', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
123735	29643764	In the datasets, 5 probes within CpG islands were used to detect DNA methylations for PD-L1.	('methylations', 'Var', (69, 81))	('PD-L1', 'Gene', (86, 91))	('PD-L1', 'Gene', '29126', (86, 91))
123736	29643764	Using normal brain tissues as controls, two of the probes within the PD-L1 promoter, cg15837913 and cg19724470, were found to be significantly different between normal brains and tumors, and the status of methylation also differed between IDH1-mutant and wildtype tumors (Figures 5A-C).	('PD-L1', 'Gene', '29126', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('differed', 'Reg', (222, 230))	('wildtype tumors', 'Disease', (255, 270))	('cg15837913', 'Var', (85, 95))	('different', 'Reg', (143, 152))	('tumors', 'Disease', (179, 185))	('IDH1', 'Gene', (239, 243))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('cg19724470', 'Var', (100, 110))	('wildtype tumors', 'Disease', 'MESH:D009369', (255, 270))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('IDH1', 'Gene', '3417', (239, 243))	('PD-L1', 'Gene', (69, 74))
123737	29643764	Since mutations in the IDH1 gene results in the production of 2HG (Dang et al.,), we tested the DNA methylation status of PD-L1 of an IDH1 wildtype GBM line U87 when 2HG (0, 3, or 6 mM) was added daily to the cell culture, based on previously published report (Bralten et al.,).	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('results in', 'Reg', (33, 43))	('tested', 'Reg', (85, 91))	('IDH1', 'Gene', (23, 27))	('PD-L1', 'Gene', (122, 127))	('IDH1', 'Gene', (134, 138))	('U87', 'Gene', (157, 160))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', '3417', (134, 138))	('PD-L1', 'Gene', '29126', (122, 127))	('mutations', 'Var', (6, 15))	('U87', 'Gene', '641648', (157, 160))
123739	29643764	These data imply that IDH1 mutations are directly involved in regulating PD-L1 expression in gliomas.	('mutations', 'Var', (27, 36))	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('expression', 'MPA', (79, 89))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('PD-L1', 'Gene', '29126', (73, 78))	('IDH1', 'Gene', (22, 26))	('regulating', 'Reg', (62, 72))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH1', 'Gene', '3417', (22, 26))	('PD-L1', 'Gene', (73, 78))
123740	29643764	Since genetic alterations in tumors constitute a major source of tumor-specific antigens that can mediate immunological recognition, cancer immunotherapy can be developed to provide unique and precise tumor-specific therapy (Rosenberg et al.,; Restifo et al.,).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancer', 'Disease', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('genetic alterations', 'Var', (6, 25))
123745	29643764	Coincidentally, we found that primary tumors with IDH1 mutations generally have lower levels of immune infiltrates compared with IDH1 wildtype tumors, including GBMs, which showed significantly greater numbers of immunosuppressive tumor-infiltrating cells, such as Tregs and TAMs.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('primary tumors', 'Disease', 'MESH:D009369', (30, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('immunosuppressive tumor', 'Disease', (213, 236))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1 wildtype tumors', 'Disease', 'MESH:D009369', (129, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('levels of immune infiltrates', 'MPA', (86, 114))	('IDH1 wildtype tumors', 'Disease', (129, 149))	('mutations', 'Var', (55, 64))	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (213, 236))	('lower', 'NegReg', (80, 85))	('primary tumors', 'Disease', (30, 44))	('IDH1', 'Gene', (50, 54))	('IDH1', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))
123747	29643764	This prediction was later partly confirmed by the most recent reports that IDH mutations suppress STAT1 and CD8+ T cell accumulation and downregulate leukocyte chemotaxis in gliomas (Amankulor et al.,; Kohanbash et al.,).	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('downregulate', 'NegReg', (137, 149))	('CD8', 'Gene', '925', (108, 111))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('leukocyte chemotaxis', 'MPA', (150, 170))	('CD8', 'Gene', (108, 111))	('gliomas', 'Disease', (174, 181))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('suppress', 'NegReg', (89, 97))	('STAT1', 'Gene', (98, 103))	('STAT1', 'Gene', '6772', (98, 103))	('mutations', 'Var', (79, 88))
123748	29643764	Additionally, no difference was found in the overall tumor mutation load between IDH1 wildtype and mutant tumors (Hodges et al.,), suggesting that more underlying mechanisms are involved in generating the differential immune landscape.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('IDH1', 'Gene', '3417', (81, 85))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('IDH1', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (53, 58))	('mutant', 'Var', (99, 105))	('tumor', 'Disease', (106, 111))
123750	29643764	Importantly, we found that the key immunoregulatory genes of PD-1 ligands, PD-L1 and PDCD1LG2 (PD-L2) (Keir et al.,), were tightly associated with IDH1 mutations in these pLGGs and pGBMs (the PDCD1LG2 results are not shown in this report).	('PDCD1LG2', 'Gene', '80380', (85, 93))	('PDCD1LG2', 'Gene', (192, 200))	('mutations', 'Var', (152, 161))	('PD-1', 'Gene', (61, 65))	('PDCD1LG2', 'Gene', (85, 93))	('PD-L1', 'Gene', (75, 80))	('PD-1', 'Gene', '5133', (61, 65))	('IDH1', 'Gene', '3417', (147, 151))	('GBM', 'Phenotype', 'HP:0012174', (182, 185))	('associated', 'Reg', (131, 141))	('PD-L2', 'Gene', (95, 100))	('PD-L2', 'Gene', '80380', (95, 100))	('PD-L1', 'Gene', '29126', (75, 80))	('IDH1', 'Gene', (147, 151))	('PDCD1LG2', 'Gene', '80380', (192, 200))
123755	29643764	We then specifically focused on evaluating the potential consequence of the IDH1 mutation and its impact on the immune landscape in gliomas.	('IDH1', 'Gene', (76, 80))	('focused', 'Reg', (21, 28))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('mutation', 'Var', (81, 89))	('impact', 'Reg', (98, 104))	('IDH1', 'Gene', '3417', (76, 80))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
123756	29643764	We found that a quantity of IDH1-mutant protein expressed in tumors was positively associated with RFS, but not with OS in all tested patients, suggesting that certain factors can transiently control tumor growth as a result of the IDH1 mutation.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumors', 'Disease', (61, 67))	('RFS', 'Disease', (99, 102))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('IDH1', 'Gene', '3417', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('IDH1', 'Gene', (232, 236))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutation', 'Var', (237, 245))	('associated', 'Reg', (83, 93))	('IDH1', 'Gene', '3417', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('protein', 'Protein', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('IDH1', 'Gene', (28, 32))
123757	29643764	Previous research has shown that IDH1 mutations result in the production of the oncometabolite 2HG, and the accumulation of this product in vivo contributes to the formation and malignant progression of gliomas (Dang et al.,).	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('IDH1', 'Gene', (33, 37))	('accumulation', 'PosReg', (108, 120))	('IDH1', 'Gene', '3417', (33, 37))	('malignant progression', 'CPA', (178, 199))	('contributes', 'Reg', (145, 156))	('production', 'MPA', (62, 72))	('2HG', 'MPA', (95, 98))	('mutations', 'Var', (38, 47))	('gliomas', 'Disease', (203, 210))	('result in', 'Reg', (48, 57))
123760	29643764	Nevertheless, our results suggest that epigenetic alterations in gliomas caused by the IDH1 mutation could be one of the mechanisms of action underlying the distinct immunological features between IDH1-mutant and wildtype tumors.	('gliomas', 'Disease', (65, 72))	('mutation', 'Var', (92, 100))	('IDH1', 'Gene', '3417', (87, 91))	('epigenetic alterations', 'Var', (39, 61))	('IDH1', 'Gene', (197, 201))	('wildtype tumors', 'Disease', 'MESH:D009369', (213, 228))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('caused', 'Reg', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('IDH1', 'Gene', '3417', (197, 201))	('IDH1', 'Gene', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('wildtype tumors', 'Disease', (213, 228))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
123761	29643764	The impact of IDH mutations in gliomas was found to apparently sensitize the tumors to radio/chemotherapy, as no differences were found in the progression-free survival between IDH-mutant and IDH-WT gliomas if patients were not given radio/chemotherapy from the time of surgery to the time of disease progression (Hartmann et al.,; Ahmadi et al.,).	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH', 'Gene', '3417', (177, 180))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('IDH', 'Gene', '3417', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (210, 218))	('sensitize', 'Reg', (63, 72))	('tumors', 'Disease', (77, 83))	('IDH', 'Gene', (14, 17))	('IDH-WT gliomas', 'Disease', (192, 206))	('gliomas', 'Disease', (199, 206))	('IDH', 'Gene', (192, 195))	('IDH-WT gliomas', 'Disease', 'MESH:D005910', (192, 206))	('gliomas', 'Disease', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('IDH', 'Gene', '3417', (14, 17))	('IDH', 'Gene', (177, 180))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))	('mutations', 'Var', (18, 27))
123770	28785028	Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression.	('patients', 'Species', '9606', (105, 113))	('shorter', 'NegReg', (185, 192))	('expression', 'Var', (156, 166))	('cysteine-rich protein 61', 'Gene', '3491', (124, 148))	('high', 'Var', (119, 123))	('overall survival', 'CPA', (80, 96))	('OS', 'Chemical', '-', (98, 100))	('cysteine-rich protein 61', 'Gene', (124, 148))	('CCN1', 'Gene', (150, 154))	('patients', 'Species', '9606', (206, 214))	('CCN1', 'Gene', '3491', (150, 154))	('CCN1', 'Gene', (224, 228))	('CCN1', 'Gene', '3491', (224, 228))	('progression-free survival', 'CPA', (44, 69))
123772	28785028	Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma.	('CCN1', 'Gene', '3491', (148, 152))	('CCN1', 'Gene', (91, 95))	('PIK3R1Met326Ile', 'Var', (50, 65))	('glioblastoma', 'Disease', (196, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (196, 208))	('frequent', 'Reg', (75, 83))	('high expression', 'Var', (96, 111))	('CCN1', 'Gene', '3491', (91, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('CCN1', 'Gene', (148, 152))
123774	28785028	Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.	('correlated', 'Reg', (49, 59))	('expression', 'MPA', (70, 80))	('CCN1', 'Gene', (65, 69))	('PIK3R1Met326Ile', 'Var', (10, 25))	('glioblastoma', 'Disease', (103, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('CCN1', 'Gene', '3491', (65, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
123779	28785028	Somatic mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) have also been found in glioma, and glioblastoma patients with wild-type IDH had a poorer prognosis than those with mutant IDH.	('IDH', 'Gene', '3417', (68, 71))	('glioblastoma', 'Disease', (109, 121))	('IDH', 'Gene', '3417', (196, 199))	('glioma', 'Disease', (97, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('IDH', 'Gene', (146, 149))	('found', 'Reg', (88, 93))	('mutations', 'Var', (8, 17))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('patients', 'Species', '9606', (122, 130))	('IDH', 'Gene', '3417', (146, 149))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', (196, 199))
123786	28785028	With respect to glioblastoma, PIK3R1 mutations represent one of the most common genetic aberrations, and the phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently targeted signaling pathways for therapeutic strategies.	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('mutations', 'Var', (37, 46))	('phosphoinositide 3-kinase', 'Gene', '5295', (109, 134))	('glioblastoma', 'Disease', (16, 28))	('phosphoinositide 3-kinase', 'Gene', (109, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))	('PIK3R1', 'Gene', (30, 36))
123787	28785028	Some germline mutations are known to participate in different types of familial glioma.	('germline mutations', 'Var', (5, 23))	('participate', 'Reg', (37, 48))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('familial glioma', 'Disease', 'MESH:D005910', (71, 86))	('familial glioma', 'Disease', (71, 86))
123788	28785028	Germline mutations in p53 may give rise to Li-Fraumeni syndrome, germline mutations in the mismatch DNA repair genes MLH1 and PMS2 are implicated in Turcot syndrome, and individuals with germline mutations in the NF1 or NF2 gene are susceptible to neurofibromatosis, which progresses to glioma.	('Germline mutations', 'Var', (0, 18))	('neurofibromatosis', 'Disease', 'MESH:C537392', (248, 265))	('PMS2', 'Gene', (126, 130))	('NF1', 'Gene', (213, 216))	('susceptible', 'Reg', (233, 244))	('neurofibromatosis', 'Disease', (248, 265))	('MLH1', 'Gene', (117, 121))	('glioma', 'Disease', (287, 293))	('NF2', 'Gene', '4771', (220, 223))	('p53', 'Gene', '7157', (22, 25))	('Turcot syndrome', 'Disease', (149, 164))	('glioma', 'Disease', 'MESH:D005910', (287, 293))	('MLH1', 'Gene', '4292', (117, 121))	('implicated', 'Reg', (135, 145))	('NF2', 'Gene', (220, 223))	('give rise to', 'Reg', (30, 42))	('PMS2', 'Gene', '5395', (126, 130))	('p53', 'Gene', (22, 25))	('Li-Fraumeni syndrome', 'Disease', (43, 63))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (248, 265))	('Turcot syndrome', 'Disease', 'MESH:C536928', (149, 164))	('mutations', 'Var', (74, 83))	('NF1', 'Gene', '4763', (213, 216))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (43, 63))
123791	28785028	The results demonstrated that a germline mutation in PIK3R1 (p85alpha, the regulatory subunit of PI3K) occurred at a higher rate in patients with high CCN1 expression.	('occurred', 'Reg', (103, 111))	('germline mutation', 'Var', (32, 49))	('CCN1', 'Gene', '3491', (151, 155))	('p85alpha', 'Gene', (61, 69))	('CCN1', 'Gene', (151, 155))	('p85alpha', 'Gene', '5295', (61, 69))	('expression', 'MPA', (156, 166))	('PIK3R1', 'Gene', (53, 59))	('patients', 'Species', '9606', (132, 140))
123797	28785028	The genetic alterations related to CCN1 expression were investigated using a HaloPlex Cancer Research Panel, which targets Catalogue of Somatic Mutations in Cancer (COSMIC) mutations within 47 genes known to be associated with cancer.	('HaloPlex Cancer', 'Disease', (77, 92))	('CCN1', 'Gene', '3491', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Cancer', 'Disease', (157, 163))	('HaloPlex Cancer', 'Disease', 'MESH:D009369', (77, 92))	('mutations', 'Var', (173, 182))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('Cancer', 'Disease', 'MESH:D009369', (157, 163))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('OS', 'Chemical', '-', (166, 168))	('Cancer', 'Disease', 'MESH:D009369', (86, 92))	('Cancer', 'Disease', (86, 92))	('cancer', 'Disease', (227, 233))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associated', 'Reg', (211, 221))	('CCN1', 'Gene', (35, 39))
123801	28785028	In contrast, the number of specific PIK3R1 mutations (chromosome 5, 67588148 G- > A, Met326Ile) tended to be higher in the CCN1 high expression group (4/7 cases, 57.1%) compared with the CCN1 low expression group (1/7 cases, 14.3%) (p = 0.266, Fisher's exact test) (Table 1).	('CCN1', 'Gene', (187, 191))	('CCN1', 'Gene', '3491', (187, 191))	('higher', 'PosReg', (109, 115))	('67588148 G- > A', 'Mutation', 'rs3730089', (68, 83))	('CCN1', 'Gene', (123, 127))	('CCN1', 'Gene', '3491', (123, 127))	('mutations', 'Var', (43, 52))	('Met326Ile', 'Mutation', 'rs3730089', (85, 94))	('high', 'Var', (128, 132))	('PIK3R1', 'Gene', (36, 42))	('Met326Ile', 'Var', (85, 94))
123809	28785028	The frequency of PIK3R1Met326Ile in glioblastoma was significantly higher in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) (p = 0.036, Fisher's exact test) (Fig.	('higher', 'PosReg', (67, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('CCN1', 'Gene', (81, 85))	('glioblastoma', 'Disease', (36, 48))	('CCN1', 'Gene', '3491', (81, 85))	('PIK3R1Met326Ile', 'Var', (17, 32))	('high expression', 'Var', (86, 101))	('CCN1', 'Gene', (138, 142))	('CCN1', 'Gene', '3491', (138, 142))
123811	28785028	In lower grade glioma, the CCN1 high expression group tended to have a high frequency of PIK3R1Met326Ile, but it was not statistically significant (Table 3 and Supplementary Table S1; astrocytoma, p = 0.2488; oligodendroglioma, p = 0.3158, Fisher's exact test).	('high expression', 'PosReg', (32, 47))	('oligodendroglioma', 'Disease', 'MESH:D009837', (209, 226))	('PIK3R1Met326Ile', 'Var', (89, 104))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('astrocytoma', 'Disease', 'MESH:D001254', (184, 195))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('CCN1', 'Gene', (27, 31))	('astrocytoma', 'Disease', (184, 195))	('glioma', 'Disease', (15, 21))	('Met326Ile', 'Mutation', 'rs3730089', (95, 104))	('CCN1', 'Gene', '3491', (27, 31))	('glioma', 'Disease', (220, 226))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (184, 195))	('oligodendroglioma', 'Disease', (209, 226))
123813	28785028	The survival curves were compared using a log-rank test based on age, sex, surgical status, CCN1 expression and PIK3R1 mutational status.	('mutational', 'Var', (119, 129))	('CCN1', 'Gene', '3491', (92, 96))	('PIK3R1', 'Gene', (112, 118))	('CCN1', 'Gene', (92, 96))
123814	28785028	The results showed that gross total resection, high CCN1 expression and PIK3R1Met326Ile (Fig.	('CCN1', 'Gene', '3491', (52, 56))	('high', 'Var', (47, 51))	('Met326Ile', 'Mutation', 'rs3730089', (78, 87))	('CCN1', 'Gene', (52, 56))	('PIK3R1Met326Ile', 'Var', (72, 87))
123815	28785028	Furthermore, gross total resection, high CCN1 expression and PIK3R1Met326Ile (Fig.	('PIK3R1Met326Ile', 'Var', (61, 76))	('CCN1', 'Gene', (41, 45))	('Met326Ile', 'Mutation', 'rs3730089', (67, 76))	('CCN1', 'Gene', '3491', (41, 45))	('high', 'Var', (36, 40))
123817	28785028	In multivariate analysis, high CCN1 was a prognostic factor for PFS [hazard ratio (HR) = 2.109 (1.105-4.025), p = 0.0236] and OS [HR = 2.488 (1.298-4.769), p = 0.0060], while the PIK3R1Met326Ile mutation was a prognostic factor for OS [HR = 2.089 (1.020-4.277), p = 0.0439] (Table 5).	('PIK3R1Met326Ile', 'Gene', (179, 194))	('high', 'Var', (26, 30))	('OS', 'Chemical', '-', (232, 234))	('PFS', 'Disease', (64, 67))	('OS', 'Chemical', '-', (126, 128))	('CCN1', 'Gene', (31, 35))	('CCN1', 'Gene', '3491', (31, 35))
123824	28785028	Plasmids expressing CCN1, wild-type PIK3R1, mutant PIK3R1, or a combination of these plasmids were transfected into U87MG glioma cells, which carry low CCN1 expression, no PIK3R1 somatic mutations and PIK3R1Met326Ile germline mutation (Fig.	('PIK3R1', 'Gene', (172, 178))	('expression', 'MPA', (157, 167))	('CCN1', 'Gene', '3491', (152, 156))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('U87MG', 'CellLine', 'CVCL:0022', (116, 121))	('glioma', 'Disease', (122, 128))	('PIK3R1', 'Gene', (51, 57))	('CCN1', 'Gene', (20, 24))	('CCN1', 'Gene', '3491', (20, 24))	('mutant', 'Var', (44, 50))	('CCN1', 'Gene', (152, 156))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('low', 'NegReg', (148, 151))	('PIK3R1Met326Ile', 'Var', (201, 216))
123825	28785028	Western blot analysis confirmed that overexpression vectors induced detectable levels of CCN1, PIK3R1 and PIK3R1 mutant (Fig.	('PIK3R1', 'Gene', (95, 101))	('PIK3R1', 'Gene', (106, 112))	('CCN1', 'Gene', (89, 93))	('CCN1', 'Gene', '3491', (89, 93))	('mutant', 'Var', (113, 119))
123826	28785028	WST-1 assay showed that overexpression of CCN1, PIK3R1 or PIK3R1 mutant had no effect on cell proliferation (Fig.	('PIK3R1', 'Gene', (58, 64))	('cell proliferation', 'CPA', (89, 107))	('PIK3R1', 'Gene', (48, 54))	('mutant', 'Var', (65, 71))	('CCN1', 'Gene', (42, 46))	('CCN1', 'Gene', '3491', (42, 46))
123827	28785028	In contrast, invasion assays showed that CCN1 and PIK3R1 mutant both significantly increased cell invasion compared to the control (Fig.	('increased', 'PosReg', (83, 92))	('cell invasion', 'CPA', (93, 106))	('CCN1', 'Gene', (41, 45))	('mutant', 'Var', (57, 63))	('CCN1', 'Gene', '3491', (41, 45))	('PIK3R1', 'Gene', (50, 56))
123828	28785028	Furthermore, the combination of CCN1 together with wild-type PIK3R1, and CCN1 with PIK3R1 mutant showed enhanced cell motility; however, there was no difference between these groups.	('CCN1', 'Gene', (32, 36))	('CCN1', 'Gene', '3491', (32, 36))	('cell motility', 'CPA', (113, 126))	('mutant', 'Var', (90, 96))	('enhanced', 'PosReg', (104, 112))	('combination', 'Interaction', (17, 28))	('PIK3R1', 'Gene', (83, 89))	('CCN1', 'Gene', (73, 77))	('CCN1', 'Gene', '3491', (73, 77))
123829	28785028	In this study, high expression of CCN1 was related to cCCN1 expression and highly germline mutation of PIK3R1Met326Ile, and PIK3R1Met326Ile was found to be a prognostic factor in glioblastoma patients.	('expression', 'MPA', (60, 70))	('PIK3R1Met326Ile', 'Gene', (103, 118))	('glioblastoma', 'Disease', (179, 191))	('related', 'Reg', (43, 50))	('patients', 'Species', '9606', (192, 200))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('Met326Ile', 'Mutation', 'rs3730089', (109, 118))	('CCN1', 'Gene', (34, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('Met326Ile', 'Mutation', 'rs3730089', (130, 139))	('CCN1', 'Gene', '3491', (34, 38))	('CCN1', 'Gene', (55, 59))	('CCN1', 'Gene', '3491', (55, 59))	('PIK3R1Met326Ile', 'Var', (124, 139))
123835	28785028	Reports suggest that activation of PI3K signaling with overexpression of Akt or loss of PTEN leads to gliomagenesis, while Bai et al.	('overexpression', 'PosReg', (55, 69))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('PI3K signaling', 'Pathway', (35, 49))	('loss', 'Var', (80, 84))	('PTEN', 'Gene', (88, 92))	('leads to', 'Reg', (93, 101))	('PTEN', 'Gene', '5728', (88, 92))	('activation', 'PosReg', (21, 31))	('glioma', 'Disease', (102, 108))	('Akt', 'Protein', (73, 76))
123838	28785028	found that several types of somatic mutation in the iSH2 domain of PIK3R1 promoted gliomagenesis.	('glioma', 'Disease', (83, 89))	('promoted', 'PosReg', (74, 82))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('PIK3R1', 'Gene', (67, 73))	('mutation', 'Var', (36, 44))
123840	28785028	showed that individuals carrying one or two copies of the 326Ile variant had a 47% increased risk of colon cancer compared with Met/Met.	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('colon cancer', 'Disease', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('326Ile', 'Var', (58, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))
123845	28785028	However, in gastric cancer, PIK3R1Met326Ile was associated with increased p85alpha expression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Met326Ile', 'Mutation', 'rs3730089', (34, 43))	('p85alpha', 'Gene', (74, 82))	('gastric cancer', 'Disease', (12, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (12, 26))	('p85alpha', 'Gene', '5295', (74, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (12, 26))	('expression', 'MPA', (83, 93))	('PIK3R1Met326Ile', 'Var', (28, 43))	('increased', 'PosReg', (64, 73))
123851	28785028	Recently, clinical trials have been conducted to identify therapeutic targets for cancers based on specific genetic alterations, and our results may be highly relevant to these trials.	('genetic alterations', 'Var', (108, 127))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
123856	28785028	In conclusion, high expression of CCN1 by immunohistochemical staining was significantly correlated with cCCN1 on western blotting, and the PIK3R1Met326Ile germline mutation existed at a high rate in the CCN1 high expression group.	('CCN1', 'Gene', (204, 208))	('CCN1', 'Gene', '3491', (204, 208))	('CCN1', 'Gene', (106, 110))	('PIK3R1Met326Ile', 'Var', (140, 155))	('CCN1', 'Gene', '3491', (106, 110))	('CCN1', 'Gene', (34, 38))	('CCN1', 'Gene', '3491', (34, 38))	('correlated', 'Reg', (89, 99))
123862	28785028	Slices were incubated with primary antibodies (anti-CYR61, 1:100, Novus Biologicals, Littleton, CO, USA; anti-PIK3R1, 1:100, Sigma-Aldrich, St Louis, MO, USA).	('CYR61', 'Gene', '3491', (52, 57))	('anti-PIK3R1', 'Var', (105, 116))	('CYR61', 'Gene', (52, 57))
123926	26638183	Notably, childhood and adult brain tumors are distinguished by unique mutations with precise neuroanatomical and age-dependent associations, highlighting changing selective pressures driving gliomagenesis in different developmental contexts.	('mutations', 'Var', (70, 79))	('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))	('glioma', 'Disease', (191, 197))	('brain tumor', 'Phenotype', 'HP:0030692', (29, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))
123932	26638183	In this regard, sporadic PAs most commonly develop in the cerebellum, whereas those in children with NF1 predominate in the optic pathways (optic nerve, chiasm, tracks, and radiations).	('radiations', 'Disease', (173, 183))	('sporadic PAs', 'Disease', (16, 28))	('children', 'Species', '9606', (87, 95))	('develop', 'Reg', (43, 50))	('NF1', 'Var', (101, 104))	('sporadic PAs', 'Disease', 'MESH:D011471', (16, 28))	('radiations', 'Disease', 'MESH:D004194', (173, 183))
123941	26638183	Molecular analyses have shown that PAs arising in children with NF1 harbor bi-allelic inactivation of the NF1 tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('children', 'Species', '9606', (50, 58))	('NF1', 'Gene', (106, 109))	('PAs', 'Disease', (35, 38))	('bi-allelic inactivation', 'Var', (75, 98))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
123942	26638183	As such, patients with NF1 are born with one mutated copy of the NF1 gene (germline NF1 gene mutation) and develop tumors following somatic (acquired) loss of the remaining NF1 allele in the appropriate cell type (neuroglial progenitor cell).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('NF1', 'Var', (23, 26))	('tumors', 'Disease', (115, 121))	('develop', 'PosReg', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('NF1', 'Gene', (65, 68))	('loss', 'NegReg', (151, 155))
123943	26638183	Whole genome sequencing of NF1-PA tumors demonstrated the presence of non-neoplastic cells (microglia) harboring only the germline NF1 gene mutation and tumor cells with alterations affecting both NF1 alleles (germline NF1 gene mutation and somatically-acquired NF1 gene mutation).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NF1', 'Gene', (131, 134))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('NF1', 'Gene', (197, 200))	('NF1-PA tumors', 'Disease', 'MESH:C537392', (27, 40))	('NF1-PA tumors', 'Disease', (27, 40))	('mutation', 'Var', (140, 148))	('alterations', 'Var', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('rat', 'Species', '10116', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('NF1', 'Gene', (219, 222))	('NF1', 'Gene', (262, 265))	('rat', 'Species', '10116', (48, 51))
123945	26638183	However, rare cases of NF1-PAs have been reported containing other potential cooperating genetic changes, including the common BRAF rearrangement (see below) and hemizygous loss of the PTEN tumor suppressor gene.	('hemizygous loss of the PTEN tumor', 'Disease', 'MESH:D006223', (162, 195))	('changes', 'Var', (97, 104))	('NF1-PAs', 'Disease', 'MESH:C537392', (23, 30))	('NF1-PAs', 'Disease', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('rat', 'Species', '10116', (82, 85))	('hemizygous loss of the PTEN tumor', 'Disease', (162, 195))	('rearrangement', 'Var', (132, 145))
123946	26638183	In contrast, NF1 gene mutations are rare in sporadic PAs, where genomic rearrangement in many tumors results in the generation of a fusion transcript in which the kinase domain of the BRAF gene is fused to a gene of unknown function (KIAA1549).	('BRAF', 'Gene', (184, 188))	('sporadic PAs', 'Disease', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('results in', 'Reg', (101, 111))	('NF1', 'Gene', (13, 16))	('sporadic PAs', 'Disease', 'MESH:D011471', (44, 56))	('tumors', 'Disease', (94, 100))	('mutations', 'Var', (22, 31))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('rat', 'Species', '10116', (120, 123))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('fused', 'Interaction', (197, 202))
123947	26638183	These fusion BRAF alterations create a BRAF molecule lacking the regulatory amino terminal domain, leading to deregulated (increased) BRAF activation of the downstream MEK signaling cascade.	('alterations', 'Var', (18, 29))	('MEK', 'Gene', (168, 171))	('MEK', 'Gene', '5609', (168, 171))	('activation', 'PosReg', (139, 149))	('rat', 'Species', '10116', (22, 25))	('deregulated', 'MPA', (110, 121))
123949	26638183	Further genomic studies revealed the presence of other potential driver mutations in sporadic PA, including mutations in the KRAS, FGFR1, PTPN11, and NTRK2 genes.	('FGFR1', 'Gene', '2260', (131, 136))	('NTRK2', 'Gene', (150, 155))	('KRAS', 'Gene', (125, 129))	('mutations', 'Var', (108, 117))	('KRAS', 'Gene', '3845', (125, 129))	('sporadic', 'Disease', (85, 93))	('PTPN11', 'Gene', '5781', (138, 144))	('NTRK2', 'Gene', '4915', (150, 155))	('PTPN11', 'Gene', (138, 144))	('FGFR1', 'Gene', (131, 136))
123950	26638183	KRAS and PTPN11 mutations are rare, occurring in ~2% of tumors sequenced.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutations', 'Var', (16, 25))	('PTPN11', 'Gene', '5781', (9, 15))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('PTPN11', 'Gene', (9, 15))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
123952	26638183	However, ~5% of sporadic PAs harbored mutations in the fibroblast growth factor receptor (FGFR1; residues K655, K656, N546, T568), which potentially leads to constitutive activation of this receptor tyrosine kinase protein.	('sporadic PAs', 'Disease', (16, 28))	('N546', 'Var', (118, 122))	('K656', 'Var', (112, 116))	('constitutive', 'MPA', (158, 170))	('sporadic PAs', 'Disease', 'MESH:D011471', (16, 28))	('activation', 'PosReg', (171, 181))	('receptor tyrosine kinase', 'Gene', (190, 214))	('T568', 'Var', (124, 128))	('receptor tyrosine kinase', 'Gene', '5979', (190, 214))	('mutations', 'Var', (38, 47))	('FGFR1', 'Gene', (90, 95))	('FGFR1', 'Gene', '2260', (90, 95))
123954	26638183	In this respect, the NF1 protein, neurofibromin, functions to inactivate RAS by accelerating its conversion from its active GTP-bound to an inactive GDP-bound state, while activating mutations in the PTPN11 gene increase the conversion of GDP-bound to GTP-bound RAS.	('rat', 'Species', '10116', (86, 89))	('conversion', 'MPA', (225, 235))	('conversion', 'MPA', (97, 107))	('PTPN11', 'Gene', '5781', (200, 206))	('neurofibromin', 'Gene', (34, 47))	('GTP', 'Chemical', 'MESH:D006160', (124, 127))	('GDP', 'Chemical', 'MESH:D006153', (149, 152))	('PTPN11', 'Gene', (200, 206))	('inactivate', 'NegReg', (62, 72))	('RAS', 'Protein', (73, 76))	('increase', 'PosReg', (212, 220))	('accelerating', 'PosReg', (80, 92))	('GTP', 'Chemical', 'MESH:D006160', (252, 255))	('activating mutations', 'Var', (172, 192))	('GDP', 'Chemical', 'MESH:D006153', (239, 242))	('neurofibromin', 'Gene', '4763', (34, 47))
123964	26638183	A mutation in one of three genes characterizes approximately two thirds of pediatric DAs: MYB, BRAF, and FGFR1.	('MYB', 'Gene', '4602', (90, 93))	('mutation', 'Var', (2, 10))	('FGFR1', 'Gene', (105, 110))	('MYB', 'Gene', (90, 93))	('FGFR1', 'Gene', '2260', (105, 110))
123966	26638183	About 25% of pediatric DAs harbor a BRAFV600E mutation, whereas alterations of the FGFR1 gene characterize a lower proportion of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('FGFR1', 'Gene', (83, 88))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('rat', 'Species', '10116', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('BRAFV600E', 'Var', (36, 45))	('BRAFV600E', 'Mutation', 'rs113488022', (36, 45))	('FGFR1', 'Gene', '2260', (83, 88))
123967	26638183	FGFR1 contains a duplication of the tyrosine kinase domain in some tumors, and a FGFR1-TACC1 fusion occurs in others.	('TACC1', 'Gene', '6867', (87, 92))	('FGFR1', 'Gene', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('duplication', 'Var', (17, 28))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', '2260', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('TACC1', 'Gene', (87, 92))	('tumors', 'Disease', (67, 73))
123968	26638183	In striking contrast, diffuse LGGs in adults harbor an entirely different set of mutations: an IDH1 mutation occurs in most adult LGGs and is accompanied by an ATRX or TP53 mutation in many astrocytomas.	('astrocytomas', 'Disease', (190, 202))	('ATRX', 'Gene', '546', (160, 164))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('mutation', 'Var', (100, 108))	('IDH1', 'Gene', (95, 99))	('astrocytomas', 'Disease', 'MESH:D001254', (190, 202))	('ATRX', 'Gene', (160, 164))	('IDH1', 'Gene', '3417', (95, 99))	('astrocytoma', 'Phenotype', 'HP:0009592', (190, 201))
123969	26638183	An IDH2 mutation occurs in place of an IDH1 mutation in rare adult-type diffuse gliomas, while in diffuse oligodendrogliomas, IDH1/2 mutation is accompanied by co-deletion of chromosomes 1p and 19q and often a CIC gene mutation.	('IDH1/2', 'Gene', '3417;3418', (126, 132))	('gliomas', 'Disease', (117, 124))	('oligodendrogliomas', 'Disease', (106, 124))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mutation', 'Var', (219, 227))	('IDH1/2', 'Gene', (126, 132))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('IDH1', 'Gene', (39, 43))	('IDH1', 'Gene', (126, 130))	('mutation', 'Var', (8, 16))	('CIC', 'Gene', (210, 213))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('IDH1', 'Gene', '3417', (39, 43))	('IDH2', 'Gene', (3, 7))	('IDH2', 'Gene', '3418', (3, 7))	('IDH1', 'Gene', '3417', (126, 130))	('mutation', 'Var', (133, 141))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (106, 124))	('gliomas', 'Disease', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('CIC', 'Gene', '23152', (210, 213))
123979	26638183	In this regard, the expression of an oncogenic KRAS allele in GFAP+ neuroglial progenitor cells results in the formation of an infiltrative intermediate-grade glioma arising from the subventricular zone (SVZ).	('glioma', 'Disease', (159, 165))	('expression', 'Var', (20, 30))	('rat', 'Species', '10116', (133, 136))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('KRAS', 'Gene', (47, 51))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('KRAS', 'Gene', '3845', (47, 51))	('results in', 'Reg', (96, 106))
123982	26638183	In addition, transgenic mice harboring an oncogenic HRAS mutation in neuroglial progenitor cells developed high-grade gliomas.	('mutation', 'Var', (57, 65))	('HRAS', 'Gene', '15461', (52, 56))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('HRAS', 'Gene', (52, 56))	('transgenic mice', 'Species', '10090', (13, 28))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
123984	26638183	Early work focused on BRAF gene alterations has demonstrated that oncogenic BRAFV600E expression in neuroglial progenitor cells alone is not sufficient to generate gliomas, but does result in high-grade tumors when coupled with Cdkn2a loss.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('Cdkn2a', 'Gene', (228, 234))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('Cdkn2a', 'Gene', '1029', (228, 234))	('rat', 'Species', '10116', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('BRAFV600E', 'Var', (76, 85))	('loss', 'NegReg', (235, 239))	('BRAFV600E', 'Mutation', 'rs113488022', (76, 85))	('BRAF', 'Gene', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))	('result in', 'Reg', (182, 191))	('rat', 'Species', '10116', (55, 58))	('rat', 'Species', '10116', (159, 162))
123985	26638183	However, the introduction of the kinase domain of an oncogenic BRAFV600 molecule into nestin+ neuroglial progenitor cells within the cerebral hemispheres is sufficient to produce low-grade gliomas with features of pilocytic astrocytoma.	('pilocytic astrocytoma', 'Disease', (214, 235))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('BRAFV600', 'Gene', (63, 71))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('astrocytoma', 'Phenotype', 'HP:0009592', (224, 235))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (214, 235))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('produce', 'Reg', (171, 178))	('introduction', 'Var', (13, 25))	('gliomas', 'Disease', (189, 196))
123990	26638183	Mice harboring a germline inactivating mutation in the Nf1 gene coupled with somatic Nf1 gene inactivation in neuroglial progenitors develop low-grade gliomas of the optic nerve and chiasm by 3 months of age.	('gliomas of the optic nerve', 'Disease', (151, 177))	('germline', 'Var', (17, 25))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('Nf1', 'Gene', (55, 58))	('gliomas of the optic nerve', 'Disease', 'MESH:D020339', (151, 177))	('Mice', 'Species', '10090', (0, 4))	('inactivation', 'Var', (94, 106))	('Nf1', 'Gene', (85, 88))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
123992	26638183	Moreover, since these tumors arise in the optic pathway, the resulting conditional Nf1 mutant mice develop optic nerve dysfunction, retinal ganglion cell (RGC) loss, retinal nerve fiber layer thinning, and reduced visual acuity.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('thinning', 'NegReg', (192, 200))	('reduced', 'NegReg', (206, 213))	('visual acuity', 'CPA', (214, 227))	('retinal nerve fiber layer', 'CPA', (166, 191))	('loss', 'NegReg', (160, 164))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutant', 'Var', (87, 93))	('Nf1', 'Gene', (83, 86))	('mice', 'Species', '10090', (94, 98))	('reduced visual acuity', 'Phenotype', 'HP:0007663', (206, 227))	('develop', 'PosReg', (99, 106))	('tumors', 'Disease', (22, 28))	('optic nerve dysfunction', 'Disease', (107, 130))	('optic nerve dysfunction', 'Disease', 'MESH:D009901', (107, 130))
123994	26638183	Seminal work in GEM strains in which multiple tumor suppressor genes are simultaneously deleted resulted in the generation of a number of models of adult high-grade glioma, and suggested that high-grade glioma (glioblastoma) formation can be driven by the introduction of mutations in cells from multiple differentiation states and diverse brain regions.	('mutations', 'Var', (272, 281))	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Disease', (203, 209))	('glioblastoma', 'Disease', (211, 223))	('glioblastoma', 'Disease', 'MESH:D005909', (211, 223))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('rat', 'Species', '10116', (116, 119))	('deleted', 'Var', (88, 95))	('glioma', 'Disease', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
123995	26638183	In one model of glioblastoma, combined deletion of Nf1 and Tp53 was induced in neural stem cells, however tumors developed from oligodendrocyte progenitor cells that were descendants of the mutated stem cells.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('Tp53', 'Gene', (59, 63))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('deletion', 'Var', (39, 47))	('Nf1', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
123996	26638183	Thus tumor cell of origin may be difficult to pinpoint precisely, however inducing mutations in a range of cell types can result in models of adult glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('mutations', 'Var', (83, 92))	('adult glioblastoma', 'Disease', (142, 160))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('result in', 'Reg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('adult glioblastoma', 'Disease', 'MESH:D005909', (142, 160))	('tumor', 'Disease', (5, 10))
123997	26638183	In striking contrast, there appears to be exquisite selectivity in both the specific cell type and the region of the central nervous system when single low-grade glioma-associated mutations are involved.	('glioma', 'Disease', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('mutations', 'Var', (180, 189))	('glioma', 'Disease', 'MESH:D005910', (162, 168))
123999	26638183	Moreover, this sporadic PA-associated mutation has brain region-specific effects, such that cerebellar and brainstem NSCs exhibit increased proliferation, whereas those from the cortex or lateral ventricle subventricular zone (lv-SVZ) do not.	('NSC', 'Disease', (117, 120))	('cerebellar', 'CPA', (92, 102))	('lateral ventricle', 'Phenotype', 'HP:0006956', (188, 205))	('NSC', 'Disease', 'OMIM:617394', (117, 120))	('PA-associated', 'Disease', (24, 37))	('rat', 'Species', '10116', (147, 150))	('mutation', 'Var', (38, 46))	('increased', 'PosReg', (130, 139))
124003	26638183	Whereas Nf1 loss in neuroglial progenitor cells alone is not sufficient for optic glioma formation, neuroglial progenitor Nf1 gene inactivation in mice heterozygous for a germline Nf1 gene mutation results in tumor development.	('mice', 'Species', '10090', (147, 151))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumor', 'Disease', (209, 214))	('Nf1', 'Gene', (122, 125))	('optic glioma', 'Disease', (76, 88))	('results in', 'Reg', (198, 208))	('inactivation', 'NegReg', (131, 143))	('mutation', 'Var', (189, 197))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('Nf1', 'Gene', (180, 183))	('optic glioma', 'Disease', 'MESH:D020339', (76, 88))	('optic glioma', 'Phenotype', 'HP:0009734', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
124007	26638183	Formal demonstration for a requirement for microglia in Nf1 mouse optic glioma development and maintenance derives from both genetic (Cx3cr1 mutant and CD11b-TK mice) and pharmacological (minocycline, JNK inhibition) silencing experiments in which impaired microglial function is sufficient to delay optic glioma formation and inhibit established tumor proliferation.	('inhibit', 'NegReg', (327, 334))	('CD11b', 'Gene', (152, 157))	('delay optic glioma', 'Disease', (294, 312))	('optic glioma', 'Disease', 'MESH:D020339', (66, 78))	('Cx3cr1', 'Gene', '13051', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('optic glioma', 'Phenotype', 'HP:0009734', (66, 78))	('glioma', 'Phenotype', 'HP:0009733', (306, 312))	('minocycline', 'Chemical', 'MESH:D008911', (188, 199))	('silencing', 'NegReg', (217, 226))	('rat', 'Species', '10116', (14, 17))	('mice', 'Species', '10090', (161, 165))	('mutant', 'Var', (141, 147))	('optic glioma', 'Disease', 'MESH:D020339', (300, 312))	('Cx3cr1', 'Gene', (134, 140))	('mouse', 'Species', '10090', (60, 65))	('JNK', 'Gene', (201, 204))	('tumor', 'Disease', (347, 352))	('delay optic glioma', 'Disease', 'MESH:D020339', (294, 312))	('optic glioma', 'Phenotype', 'HP:0009734', (300, 312))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('CD11b', 'Gene', '16409', (152, 157))	('impaired', 'Var', (248, 256))	('JNK', 'Gene', '26419', (201, 204))	('rat', 'Species', '10116', (360, 363))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('optic glioma', 'Disease', (66, 78))
124009	26638183	), employing advanced RNA-sequencing methods to discover those essential microglia-produced growth factors and cytokines (gliomagens) have led to the identification of a limited number of gliomagens whose silencing has a profound effect on Nf1 murine optic glioma maintenance.	('optic glioma', 'Phenotype', 'HP:0009734', (251, 263))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('optic glioma', 'Disease', 'MESH:D020339', (251, 263))	('glioma', 'Disease', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('optic glioma', 'Disease', (251, 263))	('silencing', 'Var', (205, 214))	('glioma', 'Disease', (188, 194))	('glioma', 'Disease', (257, 263))	('murine', 'Species', '10090', (244, 250))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
124013	26638183	This apparent sexual dimorphism is also observed in Nf1 mutant mice, such that only female Nf1+/-GFAP CKO mice exhibit visual acuity loss as a result of greater RGC death, despite nearly identical optic glioma volumes in male and female mice.	('optic glioma', 'Disease', (197, 209))	('visual acuity loss', 'Disease', (119, 137))	('mice', 'Species', '10090', (106, 110))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('Nf1+/-GFAP', 'Var', (91, 101))	('visual acuity loss', 'Phenotype', 'HP:0000572', (119, 137))	('mice', 'Species', '10090', (63, 67))	('greater', 'PosReg', (153, 160))	('visual acuity loss', 'Disease', 'MESH:D014786', (119, 137))	('mice', 'Species', '10090', (237, 241))	('optic glioma', 'Phenotype', 'HP:0009734', (197, 209))	('optic glioma', 'Disease', 'MESH:D020339', (197, 209))	('RGC death', 'CPA', (161, 170))
124015	26638183	Using mice heterozygous for a germline mutation in the Nf1 and p53 genes (NPCis mice), Reilly and colleagues have demonstrated striking strain-dependent effects on gliomagenesis.	('p53', 'Gene', (63, 66))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('Nf1', 'Gene', (55, 58))	('mice', 'Species', '10090', (6, 10))	('effects', 'Reg', (153, 160))	('germline mutation', 'Var', (30, 47))	('mice', 'Species', '10090', (80, 84))	('glioma', 'Disease', (164, 170))	('rat', 'Species', '10116', (121, 124))
124018	26638183	Analogously, single nucleotide polymorphisms in the adenylate cyclase 8 (ADCY8) gene correlate with glioma risk in a sex-specific manner in children with NF1.	('glioma', 'Disease', (100, 106))	('adenylate cyclase 8', 'Gene', (52, 71))	('ADCY8', 'Gene', (73, 78))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('ADCY8', 'Gene', '114', (73, 78))	('adenylate cyclase 8', 'Gene', '114', (52, 71))	('children', 'Species', '9606', (140, 148))	('single nucleotide polymorphisms', 'Var', (13, 44))
124023	26638183	High-grade diffuse gliomas (HGGs, grades III and IV) are distinguished from the low-grade diffuse gliomas by defined histological criteria detailed in the WHO classification of nervous system tumors, including brisk mitotic activity and nuclear pleiomorphism in grades III and IV glial neoplasms, and with the addition of microvascular proliferation and necrosis in the grade IV tumors, also known as glioblastoma.	('tumors', 'Disease', (192, 198))	('glioblastoma', 'Disease', 'MESH:D005909', (401, 413))	('brisk', 'Var', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('nuclear pleiomorphism', 'CPA', (237, 258))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('glioblastoma', 'Disease', (401, 413))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('gliomas', 'Disease', (19, 26))	('necrosis', 'Disease', 'MESH:D009336', (354, 362))	('gliomas', 'Disease', (98, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (401, 413))	('tumors', 'Disease', (379, 385))	('glial neoplasms', 'Disease', (280, 295))	('necrosis', 'Disease', (354, 362))	('nervous system tumors', 'Disease', (177, 198))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('tumors', 'Disease', 'MESH:D009369', (379, 385))	('neoplasms', 'Phenotype', 'HP:0002664', (286, 295))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('microvascular proliferation', 'CPA', (322, 349))	('glial neoplasms', 'Disease', 'MESH:D005910', (280, 295))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('nervous system tumors', 'Phenotype', 'HP:0004375', (177, 198))	('rat', 'Species', '10116', (343, 346))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('nervous system tumors', 'Disease', 'MESH:D009423', (177, 198))
124030	26638183	Clear connections with neural development are strongly demonstrated by the markedly different location spectrum of high-grade gliomas across different age groups, and the intriguing specificity of recurrent mutations in particular subgroups (Figure 4).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('mutations', 'Var', (207, 216))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('rat', 'Species', '10116', (62, 65))	('gliomas', 'Disease', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))
124034	26638183	DIPGs carry the worse prognosis of all pediatric HGGs, with a 2-year survival of less than 10%.	('DIPGs', 'Var', (0, 5))	('DIPGs', 'Chemical', 'MESH:C060938', (0, 5))	('pediatric HGGs', 'Disease', (39, 53))
124036	26638183	The identification of a recurrent hotspot mutation in histone H3 encoding a substitution of lysine 27 with methionine (K27M) in nearly 80% of DIPGs provided conclusive evidence that the molecular pathogenesis of DIPGs is distinct from cortical HGGs in children or adults.	('K27M', 'Mutation', 'p.K27M', (119, 123))	('DIPGs', 'Chemical', 'MESH:C060938', (142, 147))	('DIPGs', 'Disease', (212, 217))	('K27M', 'Var', (119, 123))	('children', 'Species', '9606', (252, 260))	('DIPGs', 'Disease', (142, 147))	('DIPGs', 'Chemical', 'MESH:C060938', (212, 217))	('lysine 27 with methionine', 'Mutation', 'p.K27M', (92, 117))
124037	26638183	Among 16 genes encoding 3 different isoforms of histone H3, the mutations are found in mutually exclusive patterns with 75% of H3 mutations targeting H3F3A, one of two genes encoding the H3.3 isoform, and 25% of mutations targeting HIST1H3B, or rarely HIST1H3C, two of 10 genes encoding the H3.1 isoform.	('HIST1H3C', 'Gene', '8352', (252, 260))	('H3F3A', 'Gene', (150, 155))	('HIST1H3C', 'Gene', (252, 260))	('targeting', 'Reg', (140, 149))	('mutations', 'Var', (130, 139))	('H3F3A', 'Gene', '3020', (150, 155))	('HIST1H3B', 'Gene', (232, 240))	('HIST1H3B', 'Gene', '8358', (232, 240))
124038	26638183	H3 K27M mutations were also identified in non-brainstem HGGs arising in midline structures such as thalamic tumors as well as less common cerebellar or spinal cord HGGs.	('identified', 'Reg', (28, 38))	('non-brainstem HGGs', 'Disease', (42, 60))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('thalamic tumors', 'Disease', (99, 114))	('K27M', 'Mutation', 'p.K27M', (3, 7))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('H3 K27M mutations', 'Var', (0, 17))	('thalamic tumors', 'Disease', 'MESH:D013786', (99, 114))
124039	26638183	Strikingly, an alternate mutation was identified in H3F3A in cortical HGGs mostly arising in adolescents and young adults; a glycine 34 substitution with either arginine or valine (G34R/V).	('G34R', 'SUBSTITUTION', 'None', (181, 185))	('G34R', 'Var', (181, 185))	('H3F3A', 'Gene', '3020', (52, 57))	('H3F3A', 'Gene', (52, 57))	('glycine 34 substitution with either arginine or valine', 'Mutation', 'rs1057519902', (125, 179))
124040	26638183	A number of other tumor types contain recurrent mutations in enzymes that catalyze or remove post-translational modifications of histone H3, however, many of these enzymes may also regulate other proteins, therefore the precise connection between cancer and histone H3 regulation was not entirely clear.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Disease', (18, 23))	('histone', 'Protein', (129, 136))	('cancer', 'Disease', (247, 253))	('regulate', 'Reg', (181, 189))	('post-translational modifications', 'MPA', (93, 125))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('proteins', 'Protein', (196, 204))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
124041	26638183	Direct mutation of histone H3 in pediatric HGG, including DIPG, was the first identification of histone mutation in human cancer, making an unambiguous connection between histone regulation and oncogenesis.	('DIPG', 'Chemical', '-', (58, 62))	('Direct mutation', 'Var', (0, 15))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('human', 'Species', '9606', (116, 121))
124042	26638183	In this regard, the H3 K27M mutant protein comprises only 5-15% of the total histone H3 in a tumor cell; however, the expression of this mutant causes a dramatic and dominant loss of lysine 27 trimethylation (H3K27me3) on the wild-type H3 co-expressed from the histone H3 gene family in these tumors.	('lysine 27 trimethylation', 'MPA', (183, 207))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('loss', 'NegReg', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('lysine', 'Chemical', 'MESH:D008239', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('tumor', 'Disease', (293, 298))	('tumors', 'Disease', (293, 299))	('mutant', 'Var', (137, 143))	('K27M', 'Mutation', 'p.K27M', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
124043	26638183	This post-translational modification is associated with transcriptionally-silent chromatin, and in tumors or cell lines containing K27M mutation, a low level of residual H3K27me3 is detected, where its distribution in the genome marks a different subset of genes than in tumors without the K27M mutation.	('K27M mutation', 'Var', (131, 144))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('K27M', 'Mutation', 'p.K27M', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('H3K27me3', 'Protein', (170, 178))	('K27M', 'Mutation', 'p.K27M', (290, 294))	('tumors', 'Disease', (99, 105))
124044	26638183	There is no clear dominant mechanism of action associated with G34R/V mutations, although elevated MYCN expression is noted in some of these tumors, perhaps due to altered localization of H3K36me3 chromatin marks.	('elevated', 'PosReg', (90, 98))	('G34R', 'SUBSTITUTION', 'None', (63, 67))	('MYCN', 'Gene', '4613', (99, 103))	('localization', 'MPA', (172, 184))	('G34R', 'Var', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('H3K36me3', 'Protein', (188, 196))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('expression', 'MPA', (104, 114))	('MYCN', 'Gene', (99, 103))
124045	26638183	Tumors carrying histone H3 K27M or G34R/V mutations were each associated with characteristic global DNA methylation signatures.	('histone H3', 'Protein', (16, 26))	('K27M', 'Mutation', 'p.K27M', (27, 31))	('G34R', 'SUBSTITUTION', 'None', (35, 39))	('Tumors', 'Disease', (0, 6))	('global DNA methylation', 'MPA', (93, 115))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('G34R', 'Var', (35, 39))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
124046	26638183	These differential methylation signatures as well as their associated gene expression signatures in tumors with K27M relative to those harboring the G34R/V mutation highlighted genes associated with hindbrain versus cortical development respectively, consistent with the developmental origins of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('K27M', 'Mutation', 'p.K27M', (112, 116))	('hindbrain', 'CPA', (199, 208))	('tumors', 'Disease', (300, 306))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('G34R', 'SUBSTITUTION', 'None', (149, 153))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('K27M', 'Var', (112, 116))	('G34R', 'Var', (149, 153))	('associated', 'Reg', (183, 193))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))
124048	26638183	The age distribution of cortical glioblastomas with H3F3A G34R/V mutation, from late adolescence into early adulthood, overlaps with adult secondary glioblastomas with IDH1 R132H mutation, which occur over a broader age range from late adolescence into adulthood with a mean age of 33-45.	('glioblastomas', 'Phenotype', 'HP:0012174', (33, 46))	('IDH1', 'Gene', '3417', (168, 172))	('glioblastomas', 'Phenotype', 'HP:0012174', (149, 162))	('G34R', 'SUBSTITUTION', 'None', (58, 62))	('R132H', 'Mutation', 'rs121913500', (173, 178))	('glioblastomas', 'Disease', (149, 162))	('glioblastomas', 'Disease', 'MESH:D005909', (33, 46))	('glioblastomas', 'Disease', (33, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('cortical glioblastomas', 'Disease', 'MESH:D005909', (24, 46))	('G34R', 'Var', (58, 62))	('H3F3A', 'Gene', '3020', (52, 57))	('H3F3A', 'Gene', (52, 57))	('cortical glioblastomas', 'Disease', (24, 46))	('IDH1', 'Gene', (168, 172))	('glioblastomas', 'Disease', 'MESH:D005909', (149, 162))
124049	26638183	H3F3A G34R/V and IDH1 R132H mutations are mutually exclusive, and there are a number of biological and molecular features that distinguish tumors with these mutations.	('G34R', 'SUBSTITUTION', 'None', (6, 10))	('G34R', 'Var', (6, 10))	('H3F3A', 'Gene', '3020', (0, 5))	('H3F3A', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('IDH1', 'Gene', (17, 21))	('tumors', 'Disease', (139, 145))	('R132H', 'Var', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('IDH1', 'Gene', '3417', (17, 21))	('R132H', 'Mutation', 'rs121913500', (22, 27))
124050	26638183	Glioblastomas with IDH1 mutation most frequently arise in the frontal lobe, while those with H3F3A G34R/V predominantly arise in the other lobes of the cerebral cortex, implying different developmental origins.	('G34R', 'Var', (99, 103))	('IDH1', 'Gene', (19, 23))	('H3F3A', 'Gene', '3020', (93, 98))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('Glioblastomas', 'Disease', (0, 13))	('IDH1', 'Gene', '3417', (19, 23))	('arise', 'Reg', (49, 54))	('mutation', 'Var', (24, 32))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('H3F3A', 'Gene', (93, 98))	('G34R', 'SUBSTITUTION', 'None', (99, 103))
124051	26638183	IDH1 mutations are the molecular hallmark of secondary glioblastomas, which arise from the malignant transformation of a lower grade astrocytoma, while H3F3A G34R/V mutant glioblastomas, like the vast majority of pediatric glioblastomas, arise as primary or de novo malignancies without evidence of a precursor lower-grade lesion.	('glioblastomas', 'Phenotype', 'HP:0012174', (172, 185))	('glioblastoma', 'Phenotype', 'HP:0012174', (223, 235))	('glioblastomas', 'Disease', 'MESH:D005909', (223, 236))	('astrocytoma', 'Disease', 'MESH:D001254', (133, 144))	('IDH1', 'Gene', (0, 4))	('H3F3A', 'Gene', (152, 157))	('astrocytoma', 'Disease', (133, 144))	('G34R', 'SUBSTITUTION', 'None', (158, 162))	('glioblastomas', 'Disease', (55, 68))	('G34R', 'Var', (158, 162))	('glioblastomas', 'Disease', 'MESH:D005909', (55, 68))	('glioblastomas', 'Disease', (172, 185))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (213, 236))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))	('IDH1', 'Gene', '3417', (0, 4))	('mutations', 'Var', (5, 14))	('glioblastomas', 'Phenotype', 'HP:0012174', (223, 236))	('glioblastomas', 'Disease', 'MESH:D005909', (172, 185))	('malignancies', 'Disease', 'MESH:D009369', (266, 278))	('pediatric glioblastomas', 'Disease', (213, 236))	('mutant', 'Var', (165, 171))	('malignancies', 'Disease', (266, 278))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('H3F3A', 'Gene', '3020', (152, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))	('glioblastomas', 'Phenotype', 'HP:0012174', (55, 68))	('glioblastomas', 'Disease', (223, 236))
124052	26638183	On a molecular level, the IDH1 R132H mutation results in catalysis of alpha-ketoglutarate to R-2-hydroxyglutarate (R-2HG).	('R-2-hydroxyglutarate', 'Chemical', '-', (93, 113))	('catalysis', 'MPA', (57, 66))	('results in', 'Reg', (46, 56))	('R132H', 'Var', (31, 36))	('R132H', 'Mutation', 'rs121913500', (31, 36))	('IDH1', 'Gene', (26, 30))	('IDH1', 'Gene', '3417', (26, 30))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (70, 89))
124054	26638183	IDH1 mutant tumors are associated with a global DNA hypermethylation signature known as the glioma-CpG island methylator phenotype (G-CIMP), in contrast to the relatively global hypomethylation signatures associated with histone H3 mutant tumors.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('G-CIMP', 'Chemical', '-', (132, 138))	('DNA hypermethylation', 'MPA', (48, 68))	('glioma', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutant', 'Var', (5, 11))	('tumors', 'Disease', (12, 18))	('IDH1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('IDH1', 'Gene', '3417', (0, 4))
124057	26638183	ACVR1 mutations almost always co-occur with HIST1H3B K27M, encoding mutant histone H3.1, which is also associated with younger age.	('K27M', 'Mutation', 'p.K27M', (53, 57))	('histone H3.1', 'Gene', '8352', (75, 87))	('associated', 'Reg', (103, 113))	('ACVR1', 'Gene', (0, 5))	('co-occur', 'Reg', (30, 38))	('K27M', 'Var', (53, 57))	('ACVR1', 'Gene', '90', (0, 5))	('HIST1H3B', 'Gene', (44, 52))	('HIST1H3B', 'Gene', '8358', (44, 52))	('mutations', 'Var', (6, 15))	('histone H3.1', 'Gene', (75, 87))
124058	26638183	Although H3.1 K27M mutations are also found in thalamic HGGs, ACVR1 mutation has only been identified in DIPG.	('DIPG', 'Chemical', '-', (105, 109))	('K27M', 'Mutation', 'p.K27M', (14, 18))	('ACVR1', 'Gene', (62, 67))	('H3.1', 'Var', (9, 13))	('ACVR1', 'Gene', '90', (62, 67))
124059	26638183	Several of the identical missense substitutions found as somatic mutations in DIPG occur as heterozygous germline alterations in patients who inherit the disease fibrodysplasia ossificans progressiva (FOP), which is a disorder of abnormal cell fate in which different cell types inappropriately differentiate into osteoblasts and form ectopic bony lesions at sites of inflammation.	('inflammation', 'Disease', (368, 380))	('rat', 'Species', '10116', (118, 121))	('form', 'Reg', (330, 334))	('patients', 'Species', '9606', (129, 137))	('fibrodysplasia', 'Disease', 'MESH:D009221', (162, 176))	('DIPG', 'Chemical', '-', (78, 82))	('mutations', 'Var', (65, 74))	('osteoblasts', 'CPA', (314, 325))	('missense substitutions', 'Var', (25, 47))	('inflammation', 'Disease', 'MESH:D007249', (368, 380))	('DIPG', 'Gene', (78, 82))	('fibrodysplasia', 'Disease', (162, 176))
124062	26638183	Although activation of BMP signaling through ACVR1 mutation may contribute to DIPG formation, BMP treatment induces differentiation and inhibits tumorigenesis in medulloblastoma.	('BMP', 'Gene', (94, 97))	('mutation', 'Var', (51, 59))	('BMP', 'Gene', (23, 26))	('activation', 'PosReg', (9, 19))	('induces', 'Reg', (108, 115))	('tumor', 'Disease', (145, 150))	('ACVR1', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('medulloblastoma', 'Phenotype', 'HP:0002885', (162, 177))	('ACVR1', 'Gene', '90', (45, 50))	('medulloblastoma', 'Disease', 'MESH:D008527', (162, 177))	('BMP', 'Gene', '649', (94, 97))	('differentiation', 'MPA', (116, 131))	('medulloblastoma', 'Disease', (162, 177))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('contribute', 'Reg', (64, 74))	('DIPG', 'Chemical', '-', (78, 82))	('BMP', 'Gene', '649', (23, 26))	('inhibits', 'NegReg', (136, 144))
124064	26638183	Pediatric HGGs also contain mutations in pathways that are common to many tumor types.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('pathways', 'Pathway', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (28, 37))	('HGGs', 'Disease', (10, 14))
124067	26638183	The TP53 checkpoint is compromised through TP53 mutations in more than half of pediatric HGG, whereas mutually-exclusive mutations in PPM1D, a TP53 target gene involved in DNA damage response, are found in an additional 10-20% of DIPGs and midline HGGs.	('TP53', 'Gene', (143, 147))	('mutations', 'Var', (121, 130))	('TP53', 'Gene', (4, 8))	('PPM1D', 'Gene', (134, 139))	('midline HGGs', 'Disease', (240, 252))	('DIPGs', 'Chemical', 'MESH:C060938', (230, 235))	('PPM1D', 'Gene', '8493', (134, 139))	('TP53', 'Gene', '7157', (143, 147))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('midline HGGs', 'Disease', 'MESH:D009436', (240, 252))	('mutations', 'Var', (48, 57))	('TP53', 'Gene', '7157', (4, 8))
124069	26638183	The importance of this cell cycle regulator is underscored by the observation that approximately one quarter of non-brainstem HGGs harbor homozygous CDKN2A deletion, which encodes the CDK4/6 inhibitor (INK4A) as well as the p19ARF protein, which controls p53 function through MDM2.	('INK4A', 'Gene', (202, 207))	('CDK4/6', 'Gene', (184, 190))	('MDM2', 'Gene', (276, 280))	('CDKN2A', 'Gene', '1029', (149, 155))	('p19ARF', 'Gene', (224, 230))	('MDM2', 'Gene', '4193', (276, 280))	('CDK4/6', 'Gene', '1019;1021', (184, 190))	('INK4A', 'Gene', '1029', (202, 207))	('CDKN2A', 'Gene', (149, 155))	('p19ARF', 'Gene', '1029', (224, 230))	('deletion', 'Var', (156, 164))
124072	26638183	The most frequent RTK alterations are focal amplifications and/or activating mutations of PDGFRA, which are found in approximately 30% of tumors.	('RTK', 'Gene', (18, 21))	('focal amplifications', 'Var', (38, 58))	('rat', 'Species', '10116', (26, 29))	('PDGFRA', 'Gene', (90, 96))	('PDGFRA', 'Gene', '5156', (90, 96))	('activating', 'PosReg', (66, 76))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('RTK', 'Gene', '5979', (18, 21))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
124073	26638183	Downstream mutations in PIK3CA or PIK3R1, encoding the catalytic and regulatory subunits of PI3-kinase (PI3K), respectively, occur in 10-25% of pediatric HGGs regardless of location.	('PIK3R1', 'Gene', (34, 40))	('mutations', 'Var', (11, 20))	('PI3-kinase', 'Gene', '5295', (92, 102))	('PI3-kinase', 'Gene', (92, 102))	('PIK3CA', 'Gene', (24, 30))	('occur', 'Reg', (125, 130))	('PIK3CA', 'Gene', '5290', (24, 30))	('PIK3R1', 'Gene', '5295', (34, 40))
124074	26638183	However, it is not clear whether complete loss of NF1 gene expression and function is observed in these tumors characterized by NF1 gene mutation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutation', 'Var', (137, 145))	('NF1', 'Gene', (50, 53))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('NF1', 'Gene', (128, 131))
124075	26638183	FGFR1 activating mutations are found predominantly in thalamic HGGs, but not in other locations.	('activating', 'PosReg', (6, 16))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('thalamic HGGs', 'Disease', (54, 67))	('mutations', 'Var', (17, 26))
124076	26638183	Approximately 10% of cortical pediatric HGGs contain BRAFV600E mutations, but these mutations have not been reported in DIPG.	('BRAFV600E', 'Mutation', 'rs113488022', (53, 62))	('BRAFV600E', 'Var', (53, 62))	('cortical', 'Disease', (21, 29))	('DIPG', 'Chemical', '-', (120, 124))
124078	26638183	Structural variants generating activating fusions of the NTRK family of neurotrophin receptors are also found in ~5% of brainstem and non-brainstem pediatric HGGs, with an increased incidence among HGGs arising in children younger than three years of age.	('variants', 'Var', (11, 19))	('NTRK', 'Gene', (57, 61))	('children', 'Species', '9606', (214, 222))	('activating', 'PosReg', (31, 41))	('HGGs', 'Disease', (158, 162))	('rat', 'Species', '10116', (24, 27))	('NTRK', 'Gene', '4915', (57, 61))
124080	26638183	It is intriguing that NTRK fusion genes in the context of few other genetic alterations are found in both low-grade and high-grade gliomas, but with different prognoses.	('gliomas', 'Disease', (131, 138))	('fusion genes', 'Var', (27, 39))	('found', 'Reg', (92, 97))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('rat', 'Species', '10116', (80, 83))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('low-grade', 'Disease', (106, 115))	('NTRK', 'Gene', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('NTRK', 'Gene', '4915', (22, 26))
124083	26638183	Using combinations of loss of function mutations of Tp53, Rb, Pten or Nf1, there is strong evidence that high-grade gliomas can arise from neural stem and/or progenitor cells in the subventricular zone, as well as outside of proliferative niches, most likely from either astrocyte or oligodendrocyte progenitor cells.	('rat', 'Species', '10116', (232, 235))	('Tp53', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('Nf1', 'Gene', (70, 73))	('gliomas', 'Disease', (116, 123))	('Pten', 'Gene', '5728', (62, 66))	('Pten', 'Gene', (62, 66))	('loss of function', 'NegReg', (22, 38))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
124085	26638183	However, the PI3K pathway is typically activated by mutations other than PTEN in childhood HGGs, and many of the mouse models introduced the mutations in adult mice, therefore these models likely have greatest relevance to adult glioblastoma.	('mutations', 'Var', (52, 61))	('PTEN', 'Gene', (73, 77))	('adult glioblastoma', 'Disease', 'MESH:D005909', (223, 241))	('activated', 'PosReg', (39, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (229, 241))	('PI3K pathway', 'Pathway', (13, 25))	('mice', 'Species', '10090', (160, 164))	('adult glioblastoma', 'Disease', (223, 241))	('PTEN', 'Gene', '19211', (73, 77))	('mouse', 'Species', '10090', (113, 118))
124086	26638183	Modeling the oncogenic effects of these mutations may therefore require a more in-depth consideration of relevant developmental setting than is needed for cancer mutations that occur commonly in many different tumor types, such as Tp53.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('rat', 'Species', '10116', (95, 98))	('tumor', 'Disease', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (155, 161))	('Tp53', 'Disease', (231, 235))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
124090	26638183	These mutations would be expected to deregulate the same pathways as disrupted by PDGFRA and Tp53 mutations, which are common in human DIPG.	('PDGFRA', 'Gene', (82, 88))	('DIPG', 'Chemical', '-', (135, 139))	('Tp53', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('human', 'Species', '9606', (129, 134))	('deregulate', 'Reg', (37, 47))	('mutations', 'Var', (6, 15))	('PDGFRA', 'Gene', '5156', (82, 88))
124091	26638183	Retroviral expression of H3.3 K27M in p53-deficient neural progenitor cells induced proliferation of the surrounding cells in the neonatal mouse brainstem, without glioma formation or a cell-autonomous increase of proliferation in the cells expressing the mutant H3.3.	('glioma', 'Disease', (164, 170))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('rat', 'Species', '10116', (221, 224))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('rat', 'Species', '10116', (91, 94))	('K27M', 'Mutation', 'p.K27M', (30, 34))	('H3.3', 'Gene', (263, 267))	('mouse', 'Species', '10090', (139, 144))	('proliferation', 'CPA', (214, 227))	('proliferation', 'CPA', (84, 97))	('H3.3 K27M', 'Var', (25, 34))	('induced', 'Reg', (76, 83))
124093	26638183	Although these model systems were not ideal to evaluate mutant H3.3-driven glioma formation, they revealed an intimate interaction between H3.3 mutant cells and the surrounding microenvironment that may be relevant to tumorigenesis.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('H3.3', 'Gene', (139, 143))	('mutant', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('glioma', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('mutant', 'Var', (144, 150))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
124099	26638183	Expression of H3.3 K27M accelerated proliferation of neural progenitor cells derived from human embryonic stem cells, but not of undifferentiated embryonic stem cells or differentiated astrocytes.	('rat', 'Species', '10116', (43, 46))	('rat', 'Species', '10116', (30, 33))	('human', 'Species', '9606', (90, 95))	('accelerated', 'PosReg', (24, 35))	('proliferation', 'CPA', (36, 49))	('K27M', 'Mutation', 'p.K27M', (19, 23))	('H3.3 K27M', 'Var', (14, 23))
124100	26638183	Combined expression of H3.3 K27M with a mutant PDGFRalpha and dominant negative Tp53 increased cell migration, inhibited differentiation of neural progenitor cells into astrocytes, and demonstrated infiltrative growth in the pons when implanted into immunodeficient mice.	('immunodeficient', 'Disease', (250, 265))	('rat', 'Species', '10116', (103, 106))	('H3.3 K27M', 'Var', (23, 32))	('infiltrative', 'PosReg', (198, 210))	('rat', 'Species', '10116', (204, 207))	('rat', 'Species', '10116', (192, 195))	('Tp53', 'Gene', (80, 84))	('K27M', 'Mutation', 'p.K27M', (28, 32))	('increased', 'PosReg', (85, 94))	('inhibited', 'NegReg', (111, 120))	('mutant', 'Var', (40, 46))	('immunodeficient', 'Disease', 'MESH:D007153', (250, 265))	('PDGFRalpha', 'Gene', (47, 57))	('cell migration', 'CPA', (95, 109))	('mice', 'Species', '10090', (266, 270))
124101	26638183	Given the general association of BMP signaling with differentiation and cell fate decisions, it seems highly likely that ACVR1 mutations, which are limited to the youngest of DIPG patients, contributes to gliomagenesis by influencing cell differentiation within the developing pons.	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('BMP', 'Gene', '649', (33, 36))	('glioma', 'Disease', (205, 211))	('ACVR1', 'Gene', (121, 126))	('DIPG', 'Chemical', '-', (175, 179))	('ACVR1', 'Gene', '90', (121, 126))	('BMP', 'Gene', (33, 36))	('cell differentiation within the developing pons', 'CPA', (234, 281))	('mutations', 'Var', (127, 136))	('contributes', 'Reg', (190, 201))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('patients', 'Species', '9606', (180, 188))	('influencing', 'Reg', (222, 233))
124103	26638183	In pediatric glioma, cell-intrinsic factors that distinguish these childhood brain tumors from their adult counterparts include not only the specific genetic mutations that drive gliomagenesis and maintain tumor growth, but also the putative cell of origin.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('tumor', 'Disease', (83, 88))	('brain tumors', 'Disease', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('glioma', 'Disease', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('pediatric glioma', 'Disease', 'MESH:D005910', (3, 19))	('mutations', 'Var', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('pediatric glioma', 'Disease', (3, 19))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('brain tumor', 'Phenotype', 'HP:0030692', (77, 88))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('tumor', 'Disease', (206, 211))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))	('glioma', 'Disease', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
124104	26638183	Multiple studies in murine models of adult high-grade glioma have revealed that the cell of origin may be less important, since these malignancies have been generated by introducing mutations in neurons, oligodendrocyte precursor cells, astrocytes, and neural stem cells with the same driver genetic alterations.	('malignancies', 'Disease', 'MESH:D009369', (134, 146))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('rat', 'Species', '10116', (304, 307))	('malignancies', 'Disease', (134, 146))	('murine', 'Species', '10090', (20, 26))	('glioma', 'Disease', (54, 60))	('rat', 'Species', '10116', (161, 164))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('mutations', 'Var', (182, 191))
124107	26638183	In this manner, the signature PA KIAA1549:BRAF fusion gene has little effect on astrocyte growth, but increases the proliferation of neural stem cells from the cerebellum as opposed to the cortex.	('BRAF fusion', 'Gene', (42, 53))	('rat', 'Species', '10116', (123, 126))	('proliferation', 'CPA', (116, 129))	('gene', 'Var', (54, 58))	('increases', 'PosReg', (102, 111))
124110	26638183	While the majority of these studies have focused on high-grade gliomas that model adult glioblastoma, there is emerging evidence that silencing microglia function may disrupt critical cellular relationships with the tumor ecosystem to profoundly impair glioma growth (Solga A & Gutmann DH, unpublished observations).	('disrupt', 'NegReg', (167, 174))	('tumor', 'Disease', (216, 221))	('gliomas', 'Disease', (63, 70))	('adult glioblastoma', 'Disease', 'MESH:D005909', (82, 100))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('silencing', 'Var', (134, 143))	('glioma growth', 'Disease', (253, 266))	('microglia', 'Protein', (144, 153))	('impair', 'NegReg', (246, 252))	('adult glioblastoma', 'Disease', (82, 100))	('glioma growth', 'Disease', 'MESH:D005910', (253, 266))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
124115	26638183	Finally, the influence of background genomics has not been fully investigated, but represents an essential element that dictate how mutations impact on preneoplastic cells and how non-neoplastic stromal cells respond to an evolving glioma.	('impact', 'Reg', (142, 148))	('glioma', 'Disease', (232, 238))	('mutations', 'Var', (132, 141))	('dictate', 'Reg', (120, 127))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))
124117	26638183	While less is known about these genomic modifiers in humans, early studies in children with NF1 have revealed several potential single nucleotide polymorphisms which influence optic glioma formation.	('humans', 'Species', '9606', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('optic glioma', 'Phenotype', 'HP:0009734', (176, 188))	('NF1', 'Gene', (92, 95))	('single nucleotide polymorphisms', 'Var', (128, 159))	('children', 'Species', '9606', (78, 86))	('optic glioma', 'Disease', 'MESH:D020339', (176, 188))	('influence', 'Reg', (166, 175))	('optic glioma', 'Disease', (176, 188))
124118	26638183	The mechanisms underlying these effects are currently unknown, but could reflect the impact of specific NF1 gene mutations on neurofibromin expression and function in the context of NF1-associated tumors or sporadic gliomas harboring other genetic changes.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('neurofibromin', 'Gene', (126, 139))	('expression', 'MPA', (140, 150))	('sporadic gliomas', 'Disease', (207, 223))	('impact', 'Reg', (85, 91))	('sporadic gliomas', 'Disease', 'MESH:D005910', (207, 223))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('function', 'MPA', (155, 163))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('neurofibromin', 'Gene', '4763', (126, 139))	('NF1', 'Gene', (104, 107))
124136	24911025	Moreover, inter- and intra-pathologist variability may also lead to an inaccurate tumor evaluation.	('variability', 'Var', (39, 50))	('lead', 'Reg', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
124186	24911025	Tumors with mTBF<=182 ml/100 g/min were referred as low-perfused gliomas (n = 8), whereas tumors with mTBF>182 ml/100 g/min were classified as high-perfused gliomas (n = 10).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('mTBF', 'Var', (12, 16))	('TBF', 'Chemical', '-', (103, 106))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('Tumors', 'Disease', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('TBF', 'Chemical', '-', (13, 16))	('gliomas', 'Disease', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumors', 'Disease', (90, 96))	('gliomas', 'Disease', (157, 164))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
124197	24911025	In order to exclude any bias due to the extent of surgery, we re-conducted the Kaplan-Meier curve analysis including only patients with total tumor resection (n = 12); among them 7 low-perfused and 5 high-perfused gliomas.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('gliomas', 'Disease', (214, 221))	('patients', 'Species', '9606', (122, 130))	('low-perfused', 'Var', (181, 193))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
124198	24911025	Despite the lower sample size, the comparison revealed again significantly (P = 0.0046) longer EFS for patients with low-perfused gliomas (average mTBF: 866.1+-92.5 days (95% CI: 684.9-1001 days)) compared to patients with high-perfused gliomas (average mTBF: 261.3+-65.4 days (95% CI: 133.0-389.1 days)) ( Fig.5 ).	('TBF', 'Chemical', '-', (255, 258))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('EFS', 'MPA', (95, 98))	('TBF', 'Chemical', '-', (148, 151))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('patients', 'Species', '9606', (209, 217))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('gliomas', 'Disease', (237, 244))	('patients', 'Species', '9606', (103, 111))	('longer', 'PosReg', (88, 94))	('low-perfused', 'Var', (117, 129))
124208	24911025	Although multivariate Cox proportional-hazard regression revealed that tumor histopathology and mTBF did not act as independent prognostic factors in our study, there was, similar to previously published data, a tendency for mTBF to be superior in the prognosis of EFS compared to tumor histopathology.	('TBF', 'Chemical', '-', (97, 100))	('EFS', 'Disease', (265, 268))	('TBF', 'Chemical', '-', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('superior', 'PosReg', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (71, 76))	('mTBF', 'Var', (225, 229))	('tumor', 'Disease', (281, 286))
124217	24911025	Despite the lower sample size, significantly longer EFS for patients with low-perfused gliomas compared to patients with high-perfused gliomas was observed.	('EFS', 'MPA', (52, 55))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('patients', 'Species', '9606', (60, 68))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('low-perfused', 'Var', (74, 86))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('longer', 'PosReg', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('patients', 'Species', '9606', (107, 115))	('gliomas', 'Disease', (87, 94))
124236	32869484	Because of bioinformatics study on gliomas, the WHO added molecular markers, such as IDH mutation status, chromosome 1p or 19q codeletion (1p/19q codel) status, into the glioma diagnostic guideline to improve the diagnosis and treatment accuracy.	('IDH', 'Gene', '3417', (85, 88))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('glioma', 'Disease', (170, 176))	('mutation', 'Var', (89, 97))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('IDH', 'Gene', (85, 88))	('gliomas', 'Disease', (35, 42))	('improve', 'PosReg', (201, 208))	('glioma', 'Disease', (35, 41))
124251	32869484	LGG tumour purity also correlated with molecular signatures such as IDH mutation, chromosome 1p/19q codeletion, chromosome 7 gain and 10 loss and the 4 LGG subtypes, classical, proneural, neural and mesenchymal subtypes (Figure 1G).	('IDH', 'Gene', '3417', (68, 71))	('chromosome 7', 'Gene', (112, 124))	('LGG tumour', 'Disease', 'MESH:D009369', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('gain', 'PosReg', (125, 129))	('loss', 'NegReg', (137, 141))	('chromosome', 'Var', (82, 92))	('LGG tumour', 'Disease', (0, 10))	('IDH', 'Gene', (68, 71))	('neural', 'CPA', (188, 194))	('mutation', 'Var', (72, 80))
124252	32869484	The prognosis benefit mutation like IDH mutation and chromosome 1p19q codel were prone to exist in high-purity group which could explain partially the better prognosis of high-purity group (Figure 1F).	('chromosome 1p19q codel', 'Var', (53, 75))	('IDH', 'Gene', '3417', (36, 39))	('IDH', 'Gene', (36, 39))
124253	32869484	Additionally, we also observed more classical driver mutations of glioma like chromosome 7 gain and 10 loss and mutation of TP53, EGFR and ATRX in low-purity group which indicated the malignant potential of these tumours of low-purity group (Figure 1D,1H).	('glioma', 'Disease', (66, 72))	('chromosome 7', 'Gene', (78, 90))	('EGFR', 'Gene', '1956', (130, 134))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('TP53', 'Gene', '7157', (124, 128))	('mutation', 'Var', (112, 120))	('ATRX', 'Gene', '546', (139, 143))	('EGFR', 'Gene', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (213, 220))	('TP53', 'Gene', (124, 128))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('tumours', 'Disease', 'MESH:D009369', (213, 220))	('tumours', 'Disease', (213, 220))	('ATRX', 'Gene', (139, 143))	('gain', 'PosReg', (91, 95))	('loss', 'NegReg', (103, 107))
124259	32869484	To validate risk score prediction power, we risk score into multiCox regression with gender, grade, IDH mutation, 1p19q codeletion and MGMT promoter methylation and the HR of risk score was 1.03 with FDR equalling 0.048.	('IDH', 'Gene', (100, 103))	('MGMT', 'Gene', (135, 139))	('IDH', 'Gene', '3417', (100, 103))	('MGMT', 'Gene', '4255', (135, 139))	('mutation', 'Var', (104, 112))	('1p19q codeletion', 'Var', (114, 130))
124265	32023222	High values of PDI signature/ risk score and cluster 1 in gliomas were associated with malignant clinicopathological characteristics and poor prognosis.	('High', 'Var', (0, 4))	('PDI', 'Gene', (15, 18))	('PDI', 'Gene', '5034', (15, 18))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('cluster 1', 'Gene', (45, 54))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('associated', 'Reg', (71, 81))
124266	32023222	Analysis of the distinctive genomic alterations in gliomas revealed that many cases having high PDI signature and risk score were associated with genomic aberrations of driver oncogenes.	('gliomas', 'Disease', (51, 58))	('genomic aberrations', 'Var', (146, 165))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('PDI', 'Gene', '5034', (96, 99))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('PDI', 'Gene', (96, 99))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('associated', 'Reg', (130, 140))
124288	32023222	Inhibition of PDIA1 was shown to decrease the resistance to temozolomide (TMZ) in malignant glioma.	('decrease', 'NegReg', (33, 41))	('PDIA1', 'Gene', (14, 19))	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('malignant glioma', 'Disease', (82, 98))	('malignant glioma', 'Disease', 'MESH:D005910', (82, 98))	('Inhibition', 'Var', (0, 10))	('PDIA1', 'Gene', '5034', (14, 19))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('resistance to temozolomide', 'MPA', (46, 72))	('temozolomide', 'Chemical', 'MESH:D000077204', (60, 72))
124289	32023222	suggested that PDIA5 knockdown in GBM cells significantly suppressed the growth and migration of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PDIA5', 'Gene', (15, 20))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('suppressed', 'NegReg', (58, 68))	('PDIA5', 'Gene', '10954', (15, 20))	('tumor', 'Disease', (97, 102))	('knockdown', 'Var', (21, 30))
124302	32023222	In the TCGA LGGGBM cohort, the mRNA expression of P4HB, PDIA3, PDIA4, PDIA5, PDIA6, ERP27, ERP29, ERP44, TMX1, TMX3, TMX4, TXNDC5, TXNDC12, AGR3, and DNAJC10 in gliomas with mutant IDH were lower in comparison to those in gliomas with wild-type IDH.	('GBM', 'Phenotype', 'HP:0012174', (15, 18))	('ERP29', 'Gene', (91, 96))	('TMX3', 'Gene', '54495', (111, 115))	('ERP44', 'Gene', (98, 103))	('PDIA4', 'Gene', (63, 68))	('PDIA6', 'Gene', '10130', (77, 82))	('TMX1', 'Gene', '81542', (105, 109))	('PDIA3', 'Gene', '2923', (56, 61))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('PDIA6', 'Gene', (77, 82))	('DNAJC10', 'Gene', (150, 157))	('AGR3', 'Gene', '155465', (140, 144))	('P4HB', 'Gene', '5034', (50, 54))	('TMX1', 'Gene', (105, 109))	('TXNDC5', 'Gene', (123, 129))	('IDH', 'Gene', (245, 248))	('TMX4', 'Gene', '56255', (117, 121))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('gliomas', 'Disease', (161, 168))	('ERP44', 'Gene', '23071', (98, 103))	('mutant', 'Var', (174, 180))	('PDIA4', 'Gene', '9601', (63, 68))	('PDIA5', 'Gene', (70, 75))	('TMX3', 'Gene', (111, 115))	('IDH', 'Gene', (181, 184))	('ERP27', 'Gene', (84, 89))	('DNAJC10', 'Gene', '54431', (150, 157))	('TXNDC12', 'Gene', '51060', (131, 138))	('P4HB', 'Gene', (50, 54))	('IDH', 'Gene', '3417', (245, 248))	('lower', 'NegReg', (190, 195))	('mRNA expression', 'MPA', (31, 46))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('TXNDC5', 'Gene', '81567', (123, 129))	('ERP27', 'Gene', '121506', (84, 89))	('ERP29', 'Gene', '10961', (91, 96))	('PDIA5', 'Gene', '10954', (70, 75))	('TMX4', 'Gene', (117, 121))	('IDH', 'Gene', '3417', (181, 184))	('AGR3', 'Gene', (140, 144))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('gliomas', 'Disease', (222, 229))	('PDIA3', 'Gene', (56, 61))	('TXNDC12', 'Gene', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
124303	32023222	The mRNA expression of PDIA2, CASQ1, and CASQ2 was higher in the mutant IDH group (Figure 1C).	('CASQ2', 'Gene', (41, 46))	('PDIA2', 'Gene', (23, 28))	('mutant', 'Var', (65, 71))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('mRNA expression', 'MPA', (4, 19))	('CASQ1', 'Gene', '844', (30, 35))	('CASQ2', 'Gene', '845', (41, 46))	('higher', 'PosReg', (51, 57))	('PDIA2', 'Gene', '64714', (23, 28))	('CASQ1', 'Gene', (30, 35))
124305	32023222	Unlike previous findings, within the CGGA LGGGBM cohort, TMX2 was up-regulated in gliomas with mutant IDH and the expression of TMX4 in the two groups was not statistically significant (Figure 1H).	('IDH', 'Gene', '3417', (102, 105))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('up-regulated', 'PosReg', (66, 78))	('TMX2', 'Gene', (57, 61))	('TMX4', 'Gene', (128, 132))	('TMX2', 'Gene', '51075', (57, 61))	('TMX4', 'Gene', '56255', (128, 132))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('mutant', 'Var', (95, 101))	('IDH', 'Gene', (102, 105))
124307	32023222	Further, PDIA2, TMX2, and CASQ1 were down-regulated in LGG with mutant IDH and 1p19q noncodeletion, and PDIA5, PDILT, ERP27, TMX1, TXNDC12, AGR3, and DNAJC10 were up-regulated in both TCGA and CGGA (Figure 1E, Supplementary Figure 1C).	('IDH', 'Gene', (71, 74))	('CASQ1', 'Gene', '844', (26, 31))	('DNAJC10', 'Gene', (150, 157))	('CASQ1', 'Gene', (26, 31))	('PDILT', 'Gene', '204474', (111, 116))	('AGR3', 'Gene', '155465', (140, 144))	('PDIA5', 'Gene', (104, 109))	('up-regulated', 'PosReg', (163, 175))	('TMX2', 'Gene', (16, 20))	('IDH', 'Gene', '3417', (71, 74))	('mutant', 'Var', (64, 70))	('down-regulated', 'NegReg', (37, 51))	('PDIA5', 'Gene', '10954', (104, 109))	('ERP27', 'Gene', (118, 123))	('DNAJC10', 'Gene', '54431', (150, 157))	('PDIA2', 'Gene', '64714', (9, 14))	('TXNDC12', 'Gene', '51060', (131, 138))	('ERP27', 'Gene', '121506', (118, 123))	('TMX1', 'Gene', '81542', (125, 129))	('PDIA2', 'Gene', (9, 14))	('PDILT', 'Gene', (111, 116))	('AGR3', 'Gene', (140, 144))	('TMX2', 'Gene', '51075', (16, 20))	('TMX1', 'Gene', (125, 129))	('TXNDC12', 'Gene', (131, 138))
124308	32023222	There was no significant difference in the mRNA level of other members of the PDI gene family in the low-grade gliomas with mutant IDH (1p19q codeletion vs. 1p19q noncodeletion) in TCGA or CGGA (Figure 1E, Supplementary Figure 1C).	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('1p19q codeletion', 'Var', (136, 152))	('mutant', 'Var', (124, 130))	('PDI', 'Gene', '5034', (78, 81))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('IDH', 'Gene', (131, 134))	('PDI', 'Gene', (78, 81))	('IDH', 'Gene', '3417', (131, 134))
124313	32023222	The value of PDI signature in patients separated by subtype, MGMT promoter status, 1p19q codel status, IDH status, gender, age, grade, and cancer (LGG vs. GBM).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('IDH', 'Gene', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('1p19q', 'Var', (83, 88))	('PDI', 'Gene', (13, 16))	('IDH', 'Gene', '3417', (103, 106))	('PDI', 'Gene', '5034', (13, 16))	('patients', 'Species', '9606', (30, 38))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('MGMT', 'Gene', '4255', (61, 65))	('MGMT', 'Gene', (61, 65))	('cancer', 'Disease', (139, 145))
124314	32023222	In the TCGA LGGGBM cohort there were significant differences between the patients separated by subtype (CL+ME vs. NE+PN), MGMT promoter status, 1p19q codel status, IDH status, age, grade, cancer (LGG vs. GBM), but not by gender (Figure 2C-2J).	('CL+ME', 'Chemical', '-', (104, 109))	('GBM', 'Phenotype', 'HP:0012174', (15, 18))	('IDH', 'Gene', '3417', (164, 167))	('GBM', 'Phenotype', 'HP:0012174', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('MGMT', 'Gene', '4255', (122, 126))	('1p19q codel', 'Var', (144, 155))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('differences', 'Reg', (49, 60))	('MGMT', 'Gene', (122, 126))	('patients', 'Species', '9606', (73, 81))	('IDH', 'Gene', (164, 167))
124316	32023222	Further, there were statistical differences observed in the groups divided by subtype (CL+ME vs. NE+PN), 1p19q codel status, IDH status in TCGA LGG and/or GBM cohort.	('IDH', 'Gene', (125, 128))	('1p19q codel status', 'Var', (105, 123))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('IDH', 'Gene', '3417', (125, 128))	('CL+ME', 'Chemical', '-', (87, 92))
124320	32023222	Furthermore, as validated in the CGGA datasets, patients in the low-value group exhibited longer OS than those in the the high-value group (Supplementary Figure 2J-2L).	('longer', 'PosReg', (90, 96))	('patients', 'Species', '9606', (48, 56))	('OS', 'Chemical', '-', (97, 99))	('low-value', 'Var', (64, 73))
124321	32023222	These findings indicated a significant association between PDI signature and clinical features and the high value of PDI signature was associated with poor prognosis.	('PDI', 'Gene', '5034', (117, 120))	('high value', 'Var', (103, 113))	('PDI', 'Gene', (59, 62))	('PDI', 'Gene', '5034', (59, 62))	('PDI', 'Gene', (117, 120))
124322	32023222	High mutation frequency in IDH1, TP53, and ATRX were associated with low PDI signature in gliomas (IDH1, 89% vs. 17%; TP53, 48% vs. 31%; ATRX, 32% vs. 15%), whereas TTN, MUC16, and PIK3CA were associated with high PDI signature (TTN, 10% vs. 24%; MUC16, 8% vs. 13%; PIK3CA, 5% vs. 11%) (Figure 3A-3B).	('TP53', 'Gene', '7157', (33, 37))	('PIK3CA', 'Gene', (181, 187))	('PDI', 'Gene', (214, 217))	('TP53', 'Gene', (118, 122))	('IDH1', 'Gene', '3417', (99, 103))	('PIK3CA', 'Gene', (266, 272))	('gliomas', 'Disease', (90, 97))	('TTN', 'Gene', '7273', (229, 232))	('MUC16', 'Gene', (170, 175))	('MUC16', 'Gene', '94025', (247, 252))	('TTN', 'Gene', '7273', (165, 168))	('TTN', 'Gene', (229, 232))	('ATRX', 'Gene', (43, 47))	('ATRX', 'Gene', (137, 141))	('PDI', 'Gene', '5034', (73, 76))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('ATRX', 'Gene', '546', (43, 47))	('TTN', 'Gene', (165, 168))	('ATRX', 'Gene', '546', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('TP53', 'Gene', '7157', (118, 122))	('PIK3CA', 'Gene', '5290', (181, 187))	('low', 'NegReg', (69, 72))	('IDH1', 'Gene', (27, 31))	('TP53', 'Gene', (33, 37))	('High mutation frequency', 'Var', (0, 23))	('MUC16', 'Gene', (247, 252))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('PDI', 'Gene', (73, 76))	('PIK3CA', 'Gene', '5290', (266, 272))	('PDI', 'Gene', '5034', (214, 217))	('IDH1', 'Gene', (99, 103))	('MUC16', 'Gene', '94025', (170, 175))	('IDH1', 'Gene', '3417', (27, 31))
124323	32023222	The mutation frequency of CIC in the low PDI signature group reached 20% (Figure 3A) while the mutations in PTEN, EGFR, NF1, and RYR2 were enriched in the cases with high PDI signature, of which all their frequencies were more than 10% (Figure 3B).	('PTEN', 'Gene', (108, 112))	('RYR2', 'Gene', (129, 133))	('CIC', 'Gene', '23152', (26, 29))	('PTEN', 'Gene', '5728', (108, 112))	('mutation', 'Var', (4, 12))	('EGFR', 'Gene', '1956', (114, 118))	('NF1', 'Gene', (120, 123))	('PDI', 'Gene', '5034', (171, 174))	('CIC', 'Gene', (26, 29))	('PDI', 'Gene', '5034', (41, 44))	('PDI', 'Gene', (171, 174))	('NF1', 'Gene', '4763', (120, 123))	('PDI', 'Gene', (41, 44))	('mutations', 'Var', (95, 104))	('EGFR', 'Gene', (114, 118))	('RYR2', 'Gene', '6262', (129, 133))
124330	32023222	As shown in Figure 4A-4B, cluster 1 was related to the status of MGMT promoter unmethylated, 1p19q noncodel, IDH wildtype, higher grade, and GBM.	('MGMT', 'Gene', (65, 69))	('MGMT', 'Gene', '4255', (65, 69))	('GBM', 'Phenotype', 'HP:0012174', (141, 144))	('IDH', 'Gene', (109, 112))	('1p19q noncodel', 'Var', (93, 107))	('IDH', 'Gene', '3417', (109, 112))
124337	32023222	The higher risk score was related to the subtype (CL+ME vs. NE+PN), MGMT promoter unmethylated, 1p19q noncodel, IDH wildtype, age>=45, and GBM groups (Figure 6C-6F, 6H, 6J, 6E).	('CL+ME', 'Var', (50, 55))	('CL+ME', 'Chemical', '-', (50, 55))	('MGMT', 'Gene', '4255', (68, 72))	('1p19q noncodel', 'Var', (96, 110))	('unmethylated', 'Var', (82, 94))	('MGMT', 'Gene', (68, 72))	('IDH', 'Gene', (112, 115))	('IDH', 'Gene', '3417', (112, 115))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
124339	32023222	There were statistical differences in the LGG/GBM patients classified by subtype (CL+ME vs. NE+PN), 1p19q codel status, IDH status, but not by MGMT promoter status in the TCGA GBM cohort (Supplementary Figure 3F-3K).	('IDH', 'Gene', '3417', (120, 123))	('patients', 'Species', '9606', (50, 58))	('LGG/GBM', 'Disease', (42, 49))	('CL+ME', 'Chemical', '-', (82, 87))	('1p19q', 'Var', (100, 105))	('MGMT', 'Gene', (143, 147))	('MGMT', 'Gene', '4255', (143, 147))	('GBM', 'Phenotype', 'HP:0012174', (176, 179))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('IDH', 'Gene', (120, 123))
124344	32023222	The frequency of IDH1, TP53, and ATRX mutations was significantly higher in gliomas with low risk score than those with high risk score (IDH1, 87% vs. 8%; TP53, 38% vs. 30%; ATRX, 24% vs. 10%), while the mutation frequency of TTN, PIK3CA, and MUC16 was significantly lower (TTN, 8% vs. 24%; PIK3CA, 6% vs. 11%; MUC16, 3% vs. 15%).	('MUC16', 'Gene', '94025', (243, 248))	('ATRX', 'Gene', (174, 178))	('ATRX', 'Gene', '546', (174, 178))	('IDH1', 'Gene', '3417', (17, 21))	('IDH1', 'Gene', '3417', (137, 141))	('MUC16', 'Gene', '94025', (311, 316))	('gliomas', 'Disease', (76, 83))	('PIK3CA', 'Gene', '5290', (231, 237))	('TP53', 'Gene', (155, 159))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('TP53', 'Gene', '7157', (23, 27))	('mutations', 'Var', (38, 47))	('MUC16', 'Gene', (243, 248))	('TTN', 'Gene', '7273', (274, 277))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('PIK3CA', 'Gene', '5290', (291, 297))	('MUC16', 'Gene', (311, 316))	('TTN', 'Gene', '7273', (226, 229))	('higher', 'PosReg', (66, 72))	('ATRX', 'Gene', (33, 37))	('TTN', 'Gene', (274, 277))	('PIK3CA', 'Gene', (231, 237))	('TP53', 'Gene', '7157', (155, 159))	('ATRX', 'Gene', '546', (33, 37))	('TTN', 'Gene', (226, 229))	('IDH1', 'Gene', (137, 141))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('IDH1', 'Gene', (17, 21))	('TP53', 'Gene', (23, 27))	('PIK3CA', 'Gene', (291, 297))
124345	32023222	Mutations of CIC (28%), FUBP1 (16%), and NOTCH1(12%) in low risk score group and, EGFR (30%), PTEN (25%), NF1 (13%), RYR2 (12%), and RB1 (11%) in high risk score group were identified (Figure 7A, 7B).	('FUBP1', 'Gene', '8880', (24, 29))	('EGFR', 'Gene', (82, 86))	('RB1', 'Gene', '5925', (133, 136))	('PTEN', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (94, 98))	('RYR2', 'Gene', '6262', (117, 121))	('CIC', 'Gene', '23152', (13, 16))	('NF1', 'Gene', (106, 109))	('Mutations', 'Var', (0, 9))	('FUBP1', 'Gene', (24, 29))	('RB1', 'Gene', (133, 136))	('NOTCH1', 'Gene', (41, 47))	('NF1', 'Gene', '4763', (106, 109))	('NOTCH1', 'Gene', '4851', (41, 47))	('EGFR', 'Gene', '1956', (82, 86))	('CIC', 'Gene', (13, 16))	('RYR2', 'Gene', (117, 121))
124346	32023222	The incidence of the amplification of Chr 7 together with a deletion of Chr 10 increased with an increase in the value of risk score in gliomas, while the codeletion of 1p/19q decreased (Figure 7C).	('increase', 'PosReg', (97, 105))	('deletion', 'Var', (60, 68))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('gliomas', 'Disease', (136, 143))	('value of risk score', 'MPA', (113, 132))	('amplification', 'Var', (21, 34))	('Chr 10', 'Gene', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
124347	32023222	GISTIC 2.0 analysis identified several significant regions of amplification harboring multiple oncogenes in gliomas with a high-risk score, including 1q32.1 (PIK3C2B), 4q12 (PDGFRA), 7p11 2 (EGFR), and 12q14 1(CDK4).	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('7p11 2', 'Var', (183, 189))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('EGFR', 'Gene', '1956', (191, 195))	('PIK3C2B', 'Gene', (158, 165))	('4q12', 'Var', (168, 172))	('EGFR', 'Gene', (191, 195))	('12q14 1', 'Var', (202, 209))	('1q32.1', 'Var', (150, 156))	('PIK3C2B', 'Gene', '5287', (158, 165))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('CDK4', 'Gene', (210, 214))	('PDGFRA', 'Gene', (174, 180))	('CDK4', 'Gene', '1019', (210, 214))	('PDGFRA', 'Gene', '5156', (174, 180))
124348	32023222	Focal deletion peaks were detected in the group with a high-risk score, such as 9p21 2 (TUSC1), 9p21 3 (CDKN2A, CDKN2B), 10q23 31 (PTEN, FAS), and 10q26 3 (BNIP3).	('CDKN2A', 'Gene', '1029', (104, 110))	('BNIP3', 'Gene', (156, 161))	('10q23 31', 'Var', (121, 129))	('9p21 3', 'Var', (96, 102))	('PTEN', 'Gene', (131, 135))	('CDKN2B', 'Gene', (112, 118))	('9p21 2', 'Var', (80, 86))	('PTEN', 'Gene', '5728', (131, 135))	('BNIP3', 'Gene', '664', (156, 161))	('10q26 3', 'Var', (147, 154))	('TUSC1', 'Gene', (88, 93))	('CDKN2B', 'Gene', '1030', (112, 118))	('TUSC1', 'Gene', '286319', (88, 93))	('CDKN2A', 'Gene', (104, 110))	('FAS', 'Chemical', 'MESH:C038178', (137, 140))
124349	32023222	Additionally, there were significant genomic regions of amplification (8q23 3, 8q24 21, 11q23 3, 19q13 3) and deletion (1p12, 4q35 2, 14q24 3, 18q23, 19q13 43) observed only in gliomas with low-risk scores (Figure 7E).	('gliomas', 'Disease', (177, 184))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('amplification', 'PosReg', (56, 69))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('8q23 3', 'Var', (71, 77))	('1p12', 'Var', (120, 124))
124354	32023222	The risk score was the best indicator in predicting 3-year survival, subtype (CL+ME/NE+PN), MGMT status, 1p19q codel status and IDH status.	('IDH', 'Gene', (128, 131))	('CL+ME', 'Chemical', '-', (78, 83))	('1p19q codel status', 'Var', (105, 123))	('MGMT', 'Gene', '4255', (92, 96))	('IDH', 'Gene', '3417', (128, 131))	('MGMT', 'Gene', (92, 96))
124358	32023222	Risk score (TCGA p = 0 0198, HR = 1 66; CGGA p = 0 0072, HR = 1 56) and 1p19q (TCGA p = 0 0392, HR = 1 84; CGGA p = 2 35E-05, HR = 3 27) were independent prognostic indicators for OS time.	('1p19q', 'Var', (72, 77))	('OS time', 'Disease', (180, 187))	('OS', 'Chemical', '-', (180, 182))
124360	32023222	Through Cox regression analyses, risk score, WHO grade, IDH, 1p19q, and age were identified as independent factors in predicting DSS, while risk score and IDH were identified as significant prognostic factors of PFI (Supplementary Table 1).	('1p19q', 'Var', (61, 66))	('DSS', 'Chemical', '-', (129, 132))	('DSS', 'Disease', (129, 132))	('IDH', 'Gene', (155, 158))	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3417', (155, 158))	('IDH', 'Gene', '3417', (56, 59))	('Cox', 'Gene', '1351', (8, 11))	('Cox', 'Gene', (8, 11))
124378	32023222	reported that the inhibition of PDIA6 transduced EGFR signaling via activating and inducing ADAM17 enhanced U87MG cell migration and invasion.	('U87MG', 'CellLine', 'CVCL:0022', (108, 113))	('EGFR', 'Gene', '1956', (49, 53))	('ADAM17', 'Gene', '6868', (92, 98))	('PDIA6', 'Gene', '10130', (32, 37))	('invasion', 'CPA', (133, 141))	('inducing', 'Reg', (83, 91))	('enhanced', 'PosReg', (99, 107))	('EGFR', 'Gene', (49, 53))	('activating', 'PosReg', (68, 78))	('ADAM17', 'Gene', (92, 98))	('PDIA6', 'Gene', (32, 37))	('inhibition', 'Var', (18, 28))	('U87MG cell migration', 'CPA', (108, 128))
124396	32023222	Gastric cancer patients having high expression of PDIA3 had a favorable prognosis and this was associated with the involvement of PDIA3 in antigen processing and formation of a complex with MCH class I which induced an immune response.	('complex', 'Interaction', (177, 184))	('Gastric cancer', 'Disease', (0, 14))	('PDIA3', 'Gene', '2923', (130, 135))	('patients', 'Species', '9606', (15, 23))	('PDIA3', 'Gene', (130, 135))	('involvement', 'Reg', (115, 126))	('PDIA3', 'Gene', (50, 55))	('Gastric cancer', 'Disease', 'MESH:D013274', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('high expression', 'Var', (31, 46))	('PDIA3', 'Gene', '2923', (50, 55))	('antigen processing', 'MPA', (139, 157))
124403	32023222	BAP2 and analogs play key roles in inducing ER stress, decreasing DNA repair proteins' expression, inhibiting cell migration and growth in GBM via binding to His256 in the b domain of PDI.	('binding', 'Interaction', (147, 154))	('DNA repair proteins', 'Protein', (66, 85))	('inducing', 'Reg', (35, 43))	('inhibiting', 'NegReg', (99, 109))	('BAP2', 'Gene', (0, 4))	('PDI', 'Gene', (184, 187))	('PDI', 'Gene', '5034', (184, 187))	('cell migration', 'CPA', (110, 124))	('ER stress', 'MPA', (44, 53))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))	('expression', 'MPA', (87, 97))	('BAP2', 'Gene', '10458', (0, 4))	('decreasing', 'NegReg', (55, 65))	('His256', 'Var', (158, 164))	('His256', 'Chemical', '-', (158, 164))
124428	32023222	ROC and the area under the curve (AUC) were used to compare the prediction performance of PDI signature, risk score, clustering and grade in several aspects, including 3-year OS, subtype (CL+ME, NE+PN), MGMT status (methylated, unmethylated), 1p19q codel status (codel, noncodel), and IDH status (wildtype, mutant).	('PDI', 'Gene', (90, 93))	('OS', 'Chemical', '-', (175, 177))	('MGMT', 'Gene', '4255', (203, 207))	('IDH', 'Gene', (285, 288))	('1p19q', 'Var', (243, 248))	('IDH', 'Gene', '3417', (285, 288))	('CL+ME', 'Chemical', '-', (188, 193))	('PDI', 'Gene', '5034', (90, 93))	('MGMT', 'Gene', (203, 207))
124439	31824866	Development and Validation of an IDH1-Associated Immune Prognostic Signature for Diffuse Lower-Grade Glioma A mutation in the isocitrate dehydrogenase 1 (IDH1) gene is the most common mutation in diffuse lower-grade gliomas (LGGs), and it is significantly related to the prognosis of LGGs.	('Glioma', 'Disease', 'MESH:D005910', (101, 107))	('Glioma', 'Disease', (101, 107))	('IDH1', 'Gene', (33, 37))	('related', 'Reg', (256, 263))	('isocitrate dehydrogenase 1', 'Gene', (126, 152))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('isocitrate dehydrogenase 1', 'Gene', '3417', (126, 152))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('IDH1', 'Gene', '3417', (33, 37))	('IDH1', 'Gene', (154, 158))	('LGGs', 'Disease', (284, 288))	('gliomas', 'Disease', 'MESH:D005910', (216, 223))	('IDH1', 'Gene', '3417', (154, 158))	('gliomas', 'Disease', (216, 223))	('mutation in', 'Var', (110, 121))	('Glioma', 'Phenotype', 'HP:0009733', (101, 107))
124444	31824866	A total of 41 immune prognostic genes were identified based on the IDH1 mutation status.	('IDH1', 'Gene', '3417', (67, 71))	('IDH1', 'Gene', (67, 71))	('mutation', 'Var', (72, 80))
124459	31824866	Based on the molecular profiles of gliomas, the mutation in the isocitrate dehydrogenase 1 (IDH1) gene has been identified to facilitate patient stratification and predict prognosis, along with other molecular markers including the 1p/19q co-deletion, methylguanine methyltransferase (MGMT) promoter methylation, tumor protein (TP) 53, and telomerase reverse transcriptase (TERT) promoters.	('patient', 'Species', '9606', (137, 144))	('telomerase reverse transcriptase', 'Gene', '7015', (340, 372))	('gliomas', 'Disease', (35, 42))	('tumor protein (TP) 53', 'Gene', '7157', (313, 334))	('MGMT', 'Gene', '4255', (285, 289))	('methylguanine methyltransferase', 'Gene', '4255', (252, 283))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('IDH1', 'Gene', (92, 96))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('mutation', 'Var', (48, 56))	('tumor protein (TP) 53', 'Gene', (313, 334))	('facilitate', 'PosReg', (126, 136))	('telomerase reverse transcriptase', 'Gene', (340, 372))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('MGMT', 'Gene', (285, 289))	('TERT', 'Gene', (374, 378))	('isocitrate dehydrogenase 1', 'Gene', '3417', (64, 90))	('isocitrate dehydrogenase 1', 'Gene', (64, 90))	('IDH1', 'Gene', '3417', (92, 96))	('methylguanine methyltransferase', 'Gene', (252, 283))	('TERT', 'Gene', '7015', (374, 378))
124462	31824866	More notably, research increasingly suggests that the IDH1 mutation conferred an immunologically quiescent phenotype.	('IDH1', 'Gene', (54, 58))	('mutation', 'Var', (59, 67))	('IDH1', 'Gene', '3417', (54, 58))	('conferred', 'Reg', (68, 77))	('immunologically quiescent phenotype', 'MPA', (81, 116))
124463	31824866	reported that the immunological tumor microenvironment was associated with IDH mutation status in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('associated', 'Reg', (59, 69))	('immunological tumor', 'Disease', 'MESH:D007154', (18, 37))	('iron', 'Chemical', 'MESH:D007501', (46, 50))	('gliomas', 'Disease', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('IDH', 'Gene', (75, 78))	('immunological tumor', 'Disease', (18, 37))	('IDH', 'Gene', '3417', (75, 78))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('mutation status', 'Var', (79, 94))
124466	31824866	Hence, we performed a comprehensive analysis to further explore the relationship between IDH1 mutation status and the immune response based on RNA sequencing (RNA-seq) data.	('IDH1', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))	('IDH1', 'Gene', '3417', (89, 93))
124468	31824866	We systematically analyzed the influence of the IDH1 mutation on the immune microenvironment, and developed an immune prognostic signature (IPS) based on four IDH1-associated immune genes to classify patients into subgroups with distinct prognosis and immunophenotypes.	('patients', 'Species', '9606', (200, 208))	('IDH1', 'Gene', (159, 163))	('mutation', 'Var', (53, 61))	('IDH1', 'Gene', '3417', (48, 52))	('IDH1', 'Gene', '3417', (159, 163))	('iron', 'Chemical', 'MESH:D007501', (84, 88))	('IDH1', 'Gene', (48, 52))
124482	31824866	In LGGs, the IDH1 mutation is the most common type of mutation (Figure 1A).	('IDH1', 'Gene', '3417', (13, 17))	('mutation', 'Var', (18, 26))	('common', 'Reg', (39, 45))	('IDH1', 'Gene', (13, 17))
124492	31824866	Consistent with the findings in the TCGA database, patients with high-risk scores had significantly worse OS than those with low-risk scores (Figure 3G).	('patients', 'Species', '9606', (51, 59))	('worse', 'NegReg', (100, 105))	('high-risk scores', 'Var', (65, 81))
124494	31824866	The IDH1 mutation is a stable marker for better prognosis in LGG.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', (4, 8))	('LGG', 'Disease', (61, 64))
124509	31824866	To examine whether the IPS was an independent prognostic factor for LGG patients, we first applied univariate Cox analysis and found that the IPS was significantly associated with OS [Hazard ratio (HR): 6.346, 95% confidence interval (CI): 5.436-9.078, P < 0.001; Figure 8A].	('associated', 'Reg', (164, 174))	('Cox', 'Gene', '1351', (110, 113))	('Cox', 'Gene', (110, 113))	('IPS', 'Var', (142, 145))	('patients', 'Species', '9606', (72, 80))
124514	31824866	The discovery of IDH mutations in gliomas as compared to their IDH wildtype counterparts, plays a crucial part in the understanding of glioma biology.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('mutations', 'Var', (21, 30))	('IDH', 'Gene', '3417', (17, 20))	('glioma', 'Disease', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', '3417', (63, 66))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Disease', (34, 40))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('IDH', 'Gene', (17, 20))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
124515	31824866	Mounting evidence reveals that the immunological tumor microenvironment of the gliomas differs based on their IDH1 mutation.	('gliomas', 'Disease', (79, 86))	('IDH1', 'Gene', '3417', (110, 114))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('iron', 'Chemical', 'MESH:D007501', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('immunological tumor', 'Disease', 'MESH:D007154', (35, 54))	('immunological tumor', 'Disease', (35, 54))	('mutation', 'Var', (115, 123))	('IDH1', 'Gene', (110, 114))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
124516	31824866	However, the mechanism governing the association of IDH1 mutation with the immune microenvironment is yet to be studied.	('mutation', 'Var', (57, 65))	('IDH1', 'Gene', '3417', (52, 56))	('IDH1', 'Gene', (52, 56))	('iron', 'Chemical', 'MESH:D007501', (90, 94))
124517	31824866	In the current study, the role of IDH1 mutations in the regulation of immune phenotype in LGGs was comprehensively studied.	('LGGs', 'Disease', (90, 94))	('IDH1', 'Gene', (34, 38))	('IDH1', 'Gene', '3417', (34, 38))	('mutations', 'Var', (39, 48))
124519	31824866	The prognostic value of this four-gene IPS was also independent of the known strong prognostic factors, like IDH1 mutation, age, and tumor grade.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('IDH1', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('IDH1', 'Gene', '3417', (109, 113))	('tumor', 'Disease', (133, 138))	('mutation', 'Var', (114, 122))
124527	31824866	Previous studies have also demonstrated a relationship between HFE genotype and increased frequency of cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genotype', 'Var', (67, 75))	('HFE', 'Gene', '3077', (63, 66))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HFE', 'Gene', (63, 66))
124530	31824866	demonstrated that high expression of VAV3 was related to poor survival in glioblastomas, whereas its effect on LGG prognosis was not identified previously.	('VAV3', 'Gene', '10451', (37, 41))	('glioblastomas', 'Disease', 'MESH:D005909', (74, 87))	('poor', 'NegReg', (57, 61))	('glioblastomas', 'Disease', (74, 87))	('high', 'Var', (18, 22))	('VAV3', 'Gene', (37, 41))	('glioblastomas', 'Phenotype', 'HP:0012174', (74, 87))
124542	31824866	It also provides a novel way to elucidate the mechanism of the IDH1 mutation on prognosis from an immunological perspective.	('mutation', 'Var', (68, 76))	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (63, 67))
124579	25301723	Furthermore, we generated RIP1-Tag2 mice knocked-out for tenascin-C (TNC; ref.	('tenascin-C', 'Gene', (57, 67))	('knocked-out', 'Var', (41, 52))	('mice', 'Species', '10090', (36, 40))
124580	25301723	We compared the number of angiogenic islets and the relative proportion of non-angiogenic and angiogenic islets from control and TNC-depleted RIP1-Tag2 mice on tissue sections, which revealed a significant decrease in the absence of TNC (Fig.	('TNC', 'Gene', (233, 236))	('mice', 'Species', '10090', (152, 156))	('decrease', 'NegReg', (206, 214))	('absence', 'Var', (222, 229))
124596	25301723	Finally, we analyzed GBM from two independent cohorts and found that high AngioMatrix expression significantly correlated with shortened patient survival (Fig.	('patient', 'Species', '9606', (137, 144))	('AngioMatrix', 'Protein', (74, 85))	('shortened', 'NegReg', (127, 136))	('expression', 'MPA', (86, 96))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('high', 'Var', (69, 73))	('patient survival', 'CPA', (137, 153))
124635	33837625	Herein, we identified fatty acid binding protein 5 (FABP5) as one of the most enriched genes in malignant LGGs and elevated FABP5 revealed severe outcomes in LGGs.	('malignant LGGs', 'Disease', (96, 110))	('FABP5', 'Gene', (52, 57))	('FABP5', 'Gene', '2171', (52, 57))	('fatty acid binding protein 5', 'Gene', (22, 50))	('elevated', 'Var', (115, 123))	('FABP5', 'Gene', (124, 129))	('FABP5', 'Gene', '2171', (124, 129))	('fatty acid binding protein 5', 'Gene', '2171', (22, 50))	('malignant LGGs', 'Disease', 'MESH:D009369', (96, 110))	('LGGs', 'Disease', (158, 162))
124636	33837625	Functionally, lentiviral suppression of FABP5 reduced malignant characters including proliferation, cloning formation, immigration, invasion and TMZ resistance, contrarily, the malignancies of LGGs were enhanced by exogenous overexpression of FABP5.	('suppression', 'NegReg', (25, 36))	('FABP5', 'Gene', (243, 248))	('TMZ resistance', 'CPA', (145, 159))	('cloning formation', 'CPA', (100, 117))	('TMZ', 'Chemical', 'MESH:D000077204', (145, 148))	('malignancies of LGGs', 'Disease', 'MESH:D009369', (177, 197))	('FABP5', 'Gene', '2171', (243, 248))	('immigration', 'CPA', (119, 130))	('lentiviral', 'Var', (14, 24))	('malignancies of LGGs', 'Disease', (177, 197))	('enhanced', 'PosReg', (203, 211))	('FABP5', 'Gene', '2171', (40, 45))	('reduced', 'NegReg', (46, 53))	('malignant characters', 'CPA', (54, 74))	('FABP5', 'Gene', (40, 45))
124645	33837625	6 ,  7  Evidence strongly suggests that mutations in isocitrate dehydrogenase (IDH) 1 and IDH2 could be found in more than 70% of LGGs and predict a more favourable prognosis, contrarily, patients with IDH wild-type LGGs show significantly dismal outcomes.	('IDH', 'Gene', (202, 205))	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', (90, 93))	('IDH', 'Gene', '3417', (202, 205))	('IDH2', 'Gene', '3418', (90, 94))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (53, 85))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', '3417', (90, 93))	('predict', 'Reg', (139, 146))	('patients', 'Species', '9606', (188, 196))	('mutations', 'Var', (40, 49))	('LGGs', 'Disease', (130, 134))	('IDH2', 'Gene', (90, 94))
124646	33837625	6  Moreover, Reuss et al 8  demonstrate that the majority of IDH wild-type LGGs show extremely severe survival and should be identified as unrecognized GBMs, indicating that IDH mutation might be responsible for malignant subtype transition in LGGs.	('IDH', 'Gene', '3417', (174, 177))	('IDH', 'Gene', '3417', (61, 64))	('mutation', 'Var', (178, 186))	('responsible', 'Reg', (196, 207))	('IDH', 'Gene', (174, 177))	('IDH', 'Gene', (61, 64))
124647	33837625	Following the detection of IDH mutations in LGGs, combined deletion of chromosome arms 1p and 19q (1p/19q co-deletion), which are frequently observed in oligodendrogliomas, are found to be correlated with prolonged survival in LGGs.	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (31, 40))	('oligodendrogliomas', 'Disease', (153, 171))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('IDH', 'Gene', '3417', (27, 30))	('LGGs', 'Disease', (227, 231))	('arms 1p', 'Gene', (82, 89))	('arms 1p', 'Gene', '3075', (82, 89))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (153, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('prolonged', 'PosReg', (205, 214))
124648	33837625	9  Researchers find that LGGs with IDH mutation and 1p/19q co-deletion are more sensitive to radio treatment and chemotherapy and reveal more favourable survival when compared to LGGs without these alterations.	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))	('1p/19q co-deletion', 'Var', (52, 70))	('favourable', 'PosReg', (142, 152))	('survival', 'CPA', (153, 161))	('sensitive', 'MPA', (80, 89))
124649	33837625	10  Comparatively, patients with IDH wild-type and 1p/19q intact LGGs present a significantly decreased median survival time of 1.7 years, which is similar to GBM patients.	('1p/19q intact', 'Var', (51, 64))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (19, 27))	('decreased', 'NegReg', (94, 103))	('IDH', 'Gene', (33, 36))	('median survival', 'MPA', (104, 119))	('IDH', 'Gene', '3417', (33, 36))
124652	33837625	LGGs with EGFR amplification, TERT promoter mutation or H3F3A mutation exhibit more severe prognosis despite the genetic background of wild-type IDH.	('EGFR', 'Gene', '1956', (10, 14))	('amplification', 'Var', (15, 28))	('TERT', 'Gene', (30, 34))	('EGFR', 'Gene', (10, 14))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('H3F3A', 'Gene', '3020', (56, 61))	('TERT', 'Gene', '7015', (30, 34))	('mutation', 'Var', (62, 70))	('H3F3A', 'Gene', (56, 61))
124653	33837625	14  Additionally, a long-term randomized clinical trial also indicates that benefit of procarbazine, lomustine, vincristine (PCV) chemotherapy on LGGs is not limited to the 1p/19q co-deleted cases while the survival of patients with 1p/19q non co-deletion is markedly prolonged by PCV treatment.	('vincristine', 'Chemical', 'MESH:D014750', (112, 123))	('prolonged', 'PosReg', (268, 277))	('1p/19q', 'Var', (173, 179))	('lomustine', 'Chemical', 'MESH:D008130', (101, 110))	('patients', 'Species', '9606', (219, 227))	('procarbazine', 'Chemical', 'MESH:D011344', (87, 99))
124657	33837625	Functionally, lentiviral suppression of FABP5 reduced malignant characters including proliferation, cloning formation, immigration and invasion, contrarily, the malignancies of LGGs particularly chemotherapy resistance to temozolomide (TMZ) was markedly enhanced by exogenous overexpression of FABP5.	('suppression', 'NegReg', (25, 36))	('FABP5', 'Gene', (294, 299))	('cloning formation', 'CPA', (100, 117))	('FABP5', 'Gene', '2171', (294, 299))	('invasion', 'CPA', (135, 143))	('lentiviral', 'Var', (14, 24))	('overexpression', 'PosReg', (276, 290))	('TMZ', 'Chemical', 'MESH:D000077204', (236, 239))	('enhanced', 'PosReg', (254, 262))	('exogenous', 'Var', (266, 275))	('FABP5', 'Gene', '2171', (40, 45))	('malignancies of LGGs', 'Disease', 'MESH:D009369', (161, 181))	('reduced', 'NegReg', (46, 53))	('malignant characters', 'CPA', (54, 74))	('malignancies of LGGs', 'Disease', (161, 181))	('FABP5', 'Gene', (40, 45))	('temozolomide', 'Chemical', 'MESH:D000077204', (222, 234))	('chemotherapy resistance to temozolomide', 'MPA', (195, 234))
124700	33837625	Additionally, Kaplan-Meier analysis was performed among the three subgroups and the results indicated that LGGs patients with IDH wild-type and 1p/19q non co-deletion had the most severe overall survivals while patients with IDH mutation and 1p/19q co-deletion exhibited prolonged survivals, which was consistent with the WHO classification (Figure 1B).	('patients', 'Species', '9606', (211, 219))	('IDH', 'Gene', '3417', (126, 129))	('1p/19q non co-deletion', 'Var', (144, 166))	('IDH', 'Gene', (225, 228))	('patients', 'Species', '9606', (112, 120))	('IDH', 'Gene', '3417', (225, 228))	('IDH', 'Gene', (126, 129))
124705	33837625	To further investigate the expression of FABP5 in LGGs, qRT-PCR analysis was performed by using LGG samples (0864, 3247, 0708, 1789, 7419, 6567 and 7624) compared with non-tumour samples deriving from the matched para-cancerous tissues (7419 and 7624).	('para-cancerous', 'Disease', (213, 227))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('0864', 'Var', (109, 113))	('FABP5', 'Gene', '2171', (41, 46))	('FABP5', 'Gene', (41, 46))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('para-cancerous', 'Disease', 'MESH:D009369', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
124711	33837625	Additionally, FABP5 was highly expressed in IDHWT and 1p/19qNon co-del LGGs, which was considered as the most lethal subtype of LGGs (Figure 2B).	('FABP5', 'Gene', '2171', (14, 19))	('FABP5', 'Gene', (14, 19))	('1p/19qNon', 'Var', (54, 63))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))
124717	33837625	The data indicated that FABP5 were likely to be enriched in IDHWT and 1p/19qNon co-del LGGs compared to other two subgroups (IDHWT and 1p/19qNon co-del samples accounted for 44.44% in FABP5High samples and accounted for 23.08% in FABP5Low samples) (Figure 2F).	('FABP5', 'Gene', (230, 235))	('FABP5', 'Gene', '2171', (230, 235))	('FABP5', 'Gene', (24, 29))	('FABP5', 'Gene', '2171', (24, 29))	('IDH', 'Gene', (125, 128))	('IDH', 'Gene', (60, 63))	('FABP5', 'Gene', (184, 189))	('1p/19qNon co-del', 'Var', (70, 86))	('FABP5', 'Gene', '2171', (184, 189))	('IDH', 'Gene', '3417', (125, 128))	('IDH', 'Gene', '3417', (60, 63))
124722	33837625	Consistent with other previous studies, IDHWT and 1p/19qNon-co-del samples showed more severe outcomes compared with samples exhibiting other molecular subtypes (Figure 3A).	('IDH', 'Gene', '3417', (40, 43))	('IDH', 'Gene', (40, 43))	('1p/19qNon-co-del', 'Var', (50, 66))
124725	33837625	The results demonstrated that elevated FABP5 combined with either IDH wild-type or 1p/19q non co-deletion indicated poor prognosis in LGG patients (Figure 3E,F), which is consistent with the results from CGGA dataset (Figure 3G,H).	('IDH', 'Gene', (66, 69))	('LGG', 'Disease', (134, 137))	('IDH', 'Gene', '3417', (66, 69))	('1p/19q non co-deletion', 'Var', (83, 105))	('elevated', 'PosReg', (30, 38))	('FABP5', 'Gene', '2171', (39, 44))	('FABP5', 'Gene', (39, 44))	('patients', 'Species', '9606', (138, 146))
124730	33837625	qRT-PCR and western blotting analysis confirmed that FABP5 expression was markedly decreased in FABP5 knock-down 0708 cells and 7419 cells (Figure 4C,D and Figure S1C).	('knock-down', 'Var', (102, 112))	('FABP5', 'Gene', (96, 101))	('FABP5', 'Gene', '2171', (96, 101))	('decreased', 'NegReg', (83, 92))	('FABP5', 'Gene', '2171', (53, 58))	('expression', 'MPA', (59, 69))	('FABP5', 'Gene', (53, 58))
124737	33837625	The result showed that elevated FABP5 significantly enhanced the proliferation and TMZ resistance of 0708 and 7419 cells (Figure 5E,F).	('proliferation', 'CPA', (65, 78))	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('enhanced', 'PosReg', (52, 60))	('elevated', 'Var', (23, 31))	('FABP5', 'Gene', '2171', (32, 37))	('TMZ resistance', 'CPA', (83, 97))	('FABP5', 'Gene', (32, 37))
124746	33837625	Furthermore, qRT-PCR results verified that mesenchymal-related biomarkers were remarkably elevated by FABP5 overexpression; however, epithelial phenotype was significantly reduced (Figure 6D).	('reduced', 'NegReg', (172, 179))	('elevated', 'PosReg', (90, 98))	('FABP5', 'Gene', '2171', (102, 107))	('epithelial phenotype', 'CPA', (133, 153))	('overexpression', 'Var', (108, 122))	('mesenchymal-related', 'CPA', (43, 62))	('FABP5', 'Gene', (102, 107))
124752	33837625	To further validate bioinformatics results and elucidate the effects of FABP5 on regulation of NF-kappaB signalling, lentiviral suppression of FABP5 followed with or without TNFalpha treatment was performed in 0708 LGG cells.	('NF-kappaB', 'Gene', '4790', (95, 104))	('suppression', 'Var', (128, 139))	('FABP5', 'Gene', (143, 148))	('TNFalpha', 'Gene', '7124', (174, 182))	('FABP5', 'Gene', '2171', (143, 148))	('FABP5', 'Gene', (72, 77))	('NF-kappaB', 'Gene', (95, 104))	('FABP5', 'Gene', '2171', (72, 77))	('TNFalpha', 'Gene', (174, 182))
124753	33837625	In vitro cell growth assays indicated that FABP5 silencing significantly reduced cell proliferation of LGG cells while the cell growth kinetics was partially rescued by the treatment of TNFalpha (Figure 8B).	('silencing', 'Var', (49, 58))	('cell proliferation of LGG cells', 'CPA', (81, 112))	('reduced', 'NegReg', (73, 80))	('TNFalpha', 'Gene', (186, 194))	('FABP5', 'Gene', '2171', (43, 48))	('FABP5', 'Gene', (43, 48))	('TNFalpha', 'Gene', '7124', (186, 194))
124754	33837625	Similarly, as expected, the ability for colony formation, invasion and migration were also decreased by FABP5 knock-down and subsequent TNFalpha treatment exhibited apparent rescue effects against FABP5 silencing (Figure 8C-E and Figure S1G-I).	('TNFalpha', 'Gene', '7124', (136, 144))	('FABP5', 'Gene', (104, 109))	('FABP5', 'Gene', '2171', (104, 109))	('FABP5', 'Gene', '2171', (197, 202))	('knock-down', 'Var', (110, 120))	('decreased', 'NegReg', (91, 100))	('FABP5', 'Gene', (197, 202))	('TNFalpha', 'Gene', (136, 144))
124755	33837625	In addition, qRT-PCR analysis showed that FABP5 knock-down reduced the expression of a wide range of mesenchymal biomarkers; however, TNFalpha could partially reverse the inhibition effects (Figure 8F).	('TNFalpha', 'Gene', (134, 142))	('reduced', 'NegReg', (59, 66))	('FABP5', 'Gene', (42, 47))	('FABP5', 'Gene', '2171', (42, 47))	('knock-down', 'Var', (48, 58))	('TNFalpha', 'Gene', '7124', (134, 142))	('expression of a wide range of mesenchymal biomarkers', 'MPA', (71, 123))
124756	33837625	As shown in Figure 8G and Figure S1J, western blot analysis showed that FABP5 knock-down significantly decreased expression of IKKalpha, particularly, reduced the phosphorylation level of IKKalpha thus reduced NF-kappaB expression through increased releasing of IKbeta.	('reduced', 'NegReg', (202, 209))	('IKbeta', 'Protein', (262, 268))	('expression', 'MPA', (113, 123))	('reduced', 'NegReg', (151, 158))	('releasing', 'MPA', (249, 258))	('knock-down', 'Var', (78, 88))	('expression', 'MPA', (220, 230))	('FABP5', 'Gene', (72, 77))	('decreased', 'NegReg', (103, 112))	('FABP5', 'Gene', '2171', (72, 77))	('NF-kappaB', 'Gene', '4790', (210, 219))	('increased', 'PosReg', (239, 248))	('IKKalpha', 'Gene', '1147', (188, 196))	('IKKalpha', 'Gene', '1147', (127, 135))	('IKKalpha', 'Gene', (188, 196))	('IKKalpha', 'Gene', (127, 135))	('NF-kappaB', 'Gene', (210, 219))	('phosphorylation level', 'MPA', (163, 184))
124760	33837625	20  Numerous studies demonstrate that IDH mutations induce aberrant DNA histone and methylation thus lead to glioma CpG-island methylator phenotype (G-CIMP), which is considered to be correlated with distinct biological and clinical characters in LGGs.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH', 'Gene', (38, 41))	('DNA', 'MPA', (68, 71))	('aberrant', 'Var', (59, 67))	('glioma', 'Disease', 'MESH:D005910', (109, 115))	('IDH', 'Gene', '3417', (38, 41))	('glioma', 'Disease', (109, 115))	('methylation', 'MPA', (84, 95))	('mutations', 'Var', (42, 51))	('lead to', 'Reg', (101, 108))
124761	33837625	21 ,  22  Mutant IDH in LGGs acquire a neomorphic enzymatic activity which leads to conversion of alpha-ketoglutarate (alpha-KG) to D-2-hydroxyglutarate (D-2-HG), thus suppresses alpha-KG-dependent dioxygenases in LGGs.	('conversion', 'MPA', (84, 94))	('IDH', 'Gene', '3417', (17, 20))	('alpha-KG-dependent', 'MPA', (179, 197))	('D-2-HG', 'Chemical', 'MESH:C019417', (154, 160))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (132, 152))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (98, 117))	('suppresses', 'NegReg', (168, 178))	('Mutant', 'Var', (10, 16))	('IDH', 'Gene', (17, 20))
124780	33837625	Mechanism study reveals that FABP5 silencing reduces intracellular fatty acid (FA) levels then suppressed NF-kappaB signalling that leads to reduction of the downstream target genes in breast cancer cells.	('NF-kappaB', 'Gene', '4790', (106, 115))	('suppressed', 'NegReg', (95, 105))	('silencing', 'Var', (35, 44))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('fatty acid', 'Chemical', 'MESH:D005227', (67, 77))	('reduces', 'NegReg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('NF-kappaB', 'Gene', (106, 115))	('breast cancer', 'Disease', (185, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('FABP5', 'Gene', (29, 34))	('FABP5', 'Gene', '2171', (29, 34))	('reduction', 'NegReg', (141, 150))
124791	31159557	Three observers used three different methods to define the regions of interest: (i) circles at maximum perfusion and minimum apparent diffusion coefficient; (ii) freeform 2D encompassing the tumor at largest cross-section only; (iii) freeform 3D on all cross-sections.	('apparent diffusion coefficient', 'MPA', (125, 155))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('minimum', 'NegReg', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('perfusion', 'MPA', (103, 112))	('tumor', 'Disease', (191, 196))	('freeform', 'Var', (162, 170))
124793	31159557	For 2D and 3D methods, histogram analysis yielded additional statistics: the minimum and maximum 5% and 10% pixel values of the tumor (min5%, min10%, max5%, max10%).	('min10%', 'Var', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
124826	31159557	For PWI, both freeform 2D and 3D methods yielded significant differences between low- and high-grade gliomas when comparing the mean, max5%, or max10% of either TTP (P <= 0.015) or rCBV (P <= 0.001), as documented in Table 2.	('TTP', 'Gene', (161, 164))	('TTP', 'Gene', '7538', (161, 164))	('low-', 'Disease', (81, 85))	('differences', 'Reg', (61, 72))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('men', 'Species', '9606', (207, 210))	('max10', 'Var', (144, 149))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
124855	31151164	Detection and Correlation of Single and Concomitant TP53, PTEN, and CDKN2A Alterations in Gliomas Gliomas are the most frequent primary tumors of central nervous system and represent a heterogeneous group of tumors that originates from the glial cells.	('tumors', 'Disease', (136, 142))	('CDKN2A', 'Gene', (68, 74))	('Gliomas', 'Disease', 'MESH:D005910', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('Gliomas', 'Disease', 'MESH:D005910', (98, 105))	('TP53', 'Gene', (52, 56))	('CDKN2A', 'Gene', '1029', (68, 74))	('Glioma', 'Phenotype', 'HP:0009733', (90, 96))	('tumors of central nervous system', 'Disease', (136, 168))	('Gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('Alterations', 'Var', (75, 86))	('PTEN', 'Gene', (58, 62))	('Glioma', 'Phenotype', 'HP:0009733', (98, 104))	('Gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('Gliomas', 'Disease', (90, 97))	('PTEN', 'Gene', '5728', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors of central nervous system', 'Phenotype', 'HP:0100006', (136, 168))	('TP53', 'Gene', '7157', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('Gliomas', 'Disease', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumors of central nervous system', 'Disease', 'MESH:D016543', (136, 168))
124857	31151164	Though genetic alterations in these genes play a significant role in tumorigenesis, few studies are available regarding the incidence and relation of concomitant TP53, PTEN, and CDKN2A alterations in gliomas.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('alterations', 'Var', (185, 196))	('PTEN', 'Gene', (168, 172))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('gliomas', 'Disease', (200, 207))	('tumor', 'Disease', (69, 74))	('TP53', 'Gene', (162, 166))	('TP53', 'Gene', '7157', (162, 166))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('CDKN2A', 'Gene', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('CDKN2A', 'Gene', '1029', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
124858	31151164	The purpose of this study was to evaluate the occurrence of mutation and deletion in these genes, through single-strand conformational polymorphism, array-comparative genomic hybridization, and fluorescence in situ hybridization techniques, in 69 gliomas samples.	('mutation', 'Var', (60, 68))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('gliomas', 'Disease', (247, 254))	('gliomas', 'Disease', 'MESH:D005910', (247, 254))	('deletion', 'Var', (73, 81))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))
124859	31151164	Molecular results demonstrated a significant higher prevalence of TP53, PTEN, and CDKN2A alterations in astrocytoma than other tumor subtypes, and heterozygous deletion was the most frequent event.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('astrocytoma', 'Disease', 'MESH:D001254', (104, 115))	('PTEN', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('tumor', 'Disease', (127, 132))	('CDKN2A', 'Gene', (82, 88))	('astrocytoma', 'Disease', (104, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('CDKN2A', 'Gene', '1029', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('higher', 'PosReg', (45, 51))	('alterations', 'Var', (89, 100))
124860	31151164	In addition, a significant association was observed between TP53 and CDKN2A alterations (p = 0.0424), which tend to coexist in low grade astrocytomas (5/46 cases (10.9%)), suggesting that they are early events in development of these tumors, and PTEN and CDKN2A deletions (p = 0.0022), which occurred concomitantly in 9/50 (18%) patients, with CDKN2A changes preceding PTEN deletions, present preferably in high-grade gliomas.	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('gliomas', 'Disease', 'MESH:D005910', (418, 425))	('TP53', 'Gene', (60, 64))	('CDKN2A', 'Gene', (344, 350))	('astrocytomas', 'Disease', 'MESH:D001254', (137, 149))	('CDKN2A', 'Gene', '1029', (69, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('glioma', 'Phenotype', 'HP:0009733', (418, 424))	('CDKN2A', 'Gene', (255, 261))	('gliomas', 'Phenotype', 'HP:0009733', (418, 425))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CDKN2A', 'Gene', '1029', (344, 350))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('TP53', 'Gene', '7157', (60, 64))	('patients', 'Species', '9606', (329, 337))	('CDKN2A', 'Gene', '1029', (255, 261))	('changes', 'Var', (351, 358))	('astrocytomas', 'Disease', (137, 149))	('tumors', 'Disease', (234, 240))	('gliomas', 'Disease', (418, 425))	('CDKN2A', 'Gene', (69, 75))
124871	31151164	It has been showed that mutations and/or deletions of tumor suppressor genes are critical events behind the pathogenesis of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deletions', 'Var', (41, 50))	('mutations', 'Var', (24, 33))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
124875	31151164	TP53 mutational status (exons 4-11) was determined in 48 cases, while 65 were successfully analyzed for TP53 deletion evaluation and 44 for both analyses.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (0, 4))	('deletion', 'Var', (109, 117))	('TP53', 'Gene', (104, 108))
124876	31151164	Of 48 gliomas samples analyzed, PCR-SSCP revealed aberrantly migrated bands in 6 (12.5%) (Table 2).	('aberrantly', 'Var', (50, 60))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('gliomas', 'Disease', (6, 13))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))
124877	31151164	TP53 mutation was more prevalent in male patients (66.7%) and the mean age of patients with mutation was 44.2 years, higher than wild-type TP53 patients (35.5).	('higher', 'PosReg', (117, 123))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (92, 100))	('patients', 'Species', '9606', (78, 86))	('TP53', 'Gene', '7157', (139, 143))	('prevalent', 'Reg', (23, 32))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (144, 152))	('TP53', 'Gene', (139, 143))	('mutation', 'Var', (5, 13))
124880	31151164	In addition, WHO grades II and IV showed highest frequency of TP53 mutations in the study, since 33.3% (2/6) of the changes were identified in each one of them.	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
124885	31151164	The sample presented the genotype in heterozygous, Arg/Pro (G/C) and Pro/Leu (C/T), respectively (Figure 2).	('Arg/Pro (G/C', 'Var', (51, 63))	('Pro', 'Chemical', 'MESH:D011392', (55, 58))	('Arg', 'Chemical', 'MESH:D001120', (51, 54))	('Leu', 'Chemical', 'MESH:D007930', (73, 76))	('Pro/Leu (C/T', 'Var', (69, 81))	('Pro', 'Chemical', 'MESH:D011392', (69, 72))
124886	31151164	Analysis of TP53 deletion was performed in 65 of the cases, 18 of which were analyzed by array-comparative genomic hybridization (aCGH) alone, 23 by interphase fluorescence in situ hybridization (iFISH), and 24 by both methods.	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('deletion', 'Var', (17, 25))
124887	31151164	Figure 3 illustrate TP53 deletion identified by array-CGH and confirmed by iFISH.	('deletion', 'Var', (25, 33))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
124888	31151164	There was a general agreement between aCGH and FISH methodologies, with concordance for detection of TP53 deletion of 91.7%.	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', (101, 105))	('deletion', 'Var', (106, 114))
124889	31151164	In two cases, TP53 deletion was identified by iFISH, but not by aCGH.	('TP53', 'Gene', '7157', (14, 18))	('deletion', 'Var', (19, 27))	('TP53', 'Gene', (14, 18))
124890	31151164	TP53 deletion was slightly more prevalent in female patients (52.6%) and the mean age of patients harboring this alteration (39.7 years) was higher than those with no deletion (35.5 years).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (52, 60))
124891	31151164	The frequency of TP53 deletion was significantly higher in astrocytomas (15/49 cases, 30.6%) when compared to other histological groups (p = 0.0048).	('astrocytomas', 'Disease', 'MESH:D001254', (59, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('deletion', 'Var', (22, 30))	('astrocytomas', 'Disease', (59, 71))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))	('higher', 'Reg', (49, 55))
124892	31151164	Further, the highest frequency of TP53 deletion was identified in high-grade gliomas (HGG) (WHO grade III and IV) when compared to low-grade gliomas (LGG) (WHO grade I and II) (13/37 cases, 35.1% vs. 6/28 cases, 21.4% respectively); however, no association was observed between the presence of this alteration and WHO grading groups (p = 0.3535).	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('TP53', 'Gene', (34, 38))	('gliomas', 'Disease', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('deletion', 'Var', (39, 47))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('gliomas', 'Disease', (141, 148))	('TP53', 'Gene', '7157', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
124893	31151164	Table 3 summarizes the frequency of TP53 deletion for each histologic subtype and WHO grading groups.	('deletion', 'Var', (41, 49))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
124894	31151164	The occurrence of concomitant allelic deletion and mutation in TP53 gene were analyzed in a total of 44 samples, and it was observed that in the 4 samples that harbored TP53 mutations, 2 of them (50%) also presented TP53 heterozygous deletion.	('TP53', 'Gene', (216, 220))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (169, 173))	('TP53', 'Gene', '7157', (216, 220))	('TP53', 'Gene', (169, 173))	('mutations', 'Var', (174, 183))
124896	31151164	PTEN deletion was more prevalent in male patients (69.6%) and the mean age of patients harboring this alteration (50.5 years) was significantly higher than those with no deletion (28.3 years; p = 0.0002) (Figure 5).	('deletion', 'Var', (5, 13))	('patients', 'Species', '9606', (78, 86))	('higher', 'PosReg', (144, 150))	('patients', 'Species', '9606', (41, 49))	('PTEN', 'Gene', (0, 4))
124897	31151164	Astrocytomas demonstrated a significantly higher frequency of PTEN deletion (20/46 cases, 43.5%) than other histological groups (p <= 0.0001).	('PTEN', 'Gene', (62, 66))	('deletion', 'Var', (67, 75))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('Astrocytomas', 'Disease', (0, 12))
124898	31151164	A total of 63 samples were evaluated for CDKN2A deletion, of which 36 were analyzed only by aCGH, 21 by iFISH, and 6 by both methods.	('deletion', 'Var', (48, 56))	('CDKN2A', 'Gene', '1029', (41, 47))	('CDKN2A', 'Gene', (41, 47))
124899	31151164	Figure 6 illustrate CDKN2A deletion identified by array-CGH and confirmed by iFISH.	('deletion', 'Var', (27, 35))	('CDKN2A', 'Gene', '1029', (20, 26))	('CDKN2A', 'Gene', (20, 26))
124901	31151164	Of the 63 cases analyzed, CDKN2A deletion was identified in 28 cases (44.4%).	('deletion', 'Var', (33, 41))	('CDKN2A', 'Gene', '1029', (26, 32))	('CDKN2A', 'Gene', (26, 32))
124902	31151164	CDKN2A deletion was more prevalent in male patients (71.4%) and the mean age of patients harboring heterozygous deletion (45.5 years) and homozygous deletions (42.6 years) were significantly higher than those with no deletion (29.2 years; p = 0.0091 and p = 0.0089, respectively) (Figure 7).	('prevalent', 'Reg', (25, 34))	('higher', 'PosReg', (191, 197))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (43, 51))	('CDKN2A', 'Gene', (0, 6))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))
124904	31151164	Table 5 summarizes the frequency of CDKN2A deletion for each histologic subtype and WHO grading groups.	('deletion', 'Var', (43, 51))	('CDKN2A', 'Gene', '1029', (36, 42))	('CDKN2A', 'Gene', (36, 42))
124906	31151164	TP53 alteration (mutation or deletion), PTEN, and CDKN2A deletion occurred together in seven samples, 6/46 (13%) astrocytomas, and 1/4 (25%) oligodendrogliomas.	('TP53', 'Gene', '7157', (0, 4))	('CDKN2A', 'Gene', (50, 56))	('TP53', 'Gene', (0, 4))	('occurred', 'Reg', (66, 74))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('deletion', 'Var', (57, 65))	('PTEN', 'Gene', (40, 44))	('astrocytomas', 'Disease', (113, 125))	('CDKN2A', 'Gene', '1029', (50, 56))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (141, 159))	('alteration', 'Reg', (5, 15))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('oligodendrogliomas', 'Disease', (141, 159))	('astrocytomas', 'Disease', 'MESH:D001254', (113, 125))
124908	31151164	Considering cases with alterations in only two genes, a significant association was observed between TP53 and CDKN2A alterations (p = 0.0424) and between PTEN and CDKN2A deletions (p = 0.0022), but not between TP53 and PTEN alterations (p = 0.5879).	('alterations', 'Var', (117, 128))	('CDKN2A', 'Gene', (110, 116))	('CDKN2A', 'Gene', '1029', (163, 169))	('TP53', 'Gene', (210, 214))	('CDKN2A', 'Gene', '1029', (110, 116))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', (101, 105))	('deletions', 'Var', (170, 179))	('CDKN2A', 'Gene', (163, 169))	('PTEN', 'Gene', (154, 158))	('TP53', 'Gene', '7157', (210, 214))
124910	31151164	Co-alterations of TP53 and PTEN genes were present in only HGG (2.8%), and combined PTEN and CDKN2A alterations were observed predominantly in HGG (22.2%) when compared to LGG (3.8%).	('CDKN2A', 'Gene', (93, 99))	('TP53', 'Gene', '7157', (18, 22))	('CDKN2A', 'Gene', '1029', (93, 99))	('TP53', 'Gene', (18, 22))	('PTEN', 'Gene', (84, 88))	('HGG', 'Disease', (143, 146))	('PTEN genes', 'Gene', (27, 37))	('alterations', 'Var', (100, 111))
124911	31151164	Additionally, co-alteration in TP53 and CDKN2A genes were also more frequently observed in HGG, however, with a frequency similar to the one observed in LGG (8.3% vs. 7.7%).	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('CDKN2A', 'Gene', (40, 46))	('HGG', 'Disease', (91, 94))	('CDKN2A', 'Gene', '1029', (40, 46))	('observed', 'Reg', (79, 87))	('co-alteration', 'Var', (14, 27))
124912	31151164	Further, a higher frequency of concurrent TP53, PTEN, and CDKN2A alterations was observed in gliomas of higher malignancy grade (16.7%).	('PTEN', 'Gene', (48, 52))	('alterations', 'Var', (65, 76))	('TP53', 'Gene', '7157', (42, 46))	('gliomas of higher malignancy', 'Disease', 'MESH:D005910', (93, 121))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('TP53', 'Gene', (42, 46))	('gliomas of higher malignancy', 'Disease', (93, 121))	('CDKN2A', 'Gene', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('CDKN2A', 'Gene', '1029', (58, 64))
124914	31151164	Large-scale cytogenetic and molecular studies have detected many recurrent genetic and epigenetic abnormalities associated with different subtypes of glial tumors, and it has become clear that these markers are useful in identifying more uniform gliomas subgroups.	('glial tumors', 'Disease', 'MESH:D005910', (150, 162))	('epigenetic abnormalities', 'Var', (87, 111))	('gliomas', 'Disease', 'MESH:D005910', (246, 253))	('gliomas', 'Phenotype', 'HP:0009733', (246, 253))	('gliomas', 'Disease', (246, 253))	('glial tumors', 'Disease', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('genetic', 'Var', (75, 82))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
124915	31151164	Like in other types of cancers, initiation and progression of gliomas are a consequence of sequential genetic alterations, such as point mutations, epigenetic changes, copy number alterations, and chromosomal rearrangements, affecting genes that are essential to maintaining cellular homeostasis.	('point', 'Disease', (131, 136))	('copy number alterations', 'Var', (168, 191))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('chromosomal rearrangements', 'Var', (197, 223))	('gliomas', 'Disease', (62, 69))	('epigenetic changes', 'Var', (148, 166))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
124916	31151164	Therefore, the focus of this investigation was to analyze the influence of independently and combined alterations in TP53, PTEN, and CDKN2A tumor suppressor genes in the gliomagenesis, evaluating a possible association of our findings with clinical variable of the patients.	('glioma', 'Disease', (170, 176))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CDKN2A', 'Gene', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('patients', 'Species', '9606', (265, 273))	('PTEN', 'Gene', (123, 127))	('CDKN2A', 'Gene', '1029', (133, 139))	('alterations', 'Var', (102, 113))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('tumor', 'Disease', (140, 145))
124917	31151164	Genetic alterations in TP53, PTEN, and CDKN2A genes are important molecular markers, being commonly observed in gliomas.	('Genetic alterations', 'Var', (0, 19))	('CDKN2A', 'Gene', (39, 45))	('PTEN', 'Gene', (29, 33))	('CDKN2A', 'Gene', '1029', (39, 45))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('observed', 'Reg', (100, 108))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
124918	31151164	Loss of function of their respective proteins, which are inactivated directly by mutations and allelic deletions or indirectly by alterations of genes that interact with their protein product, is a common characteristic in a majority of human cancers, resulting in escape from the tumor-suppressor process.	('human', 'Species', '9606', (237, 242))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('escape', 'CPA', (265, 271))	('Loss of function', 'NegReg', (0, 16))	('proteins', 'Protein', (37, 45))	('alterations', 'Var', (130, 141))	('cancers', 'Disease', (243, 250))	('mutations', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('tumor', 'Disease', (281, 286))
124919	31151164	In our study, TP53 abnormalities (mutation and/or deletion) occurred in 23/69 (33.3%) samples, with a significant prevalence of both gene mutation (p = 0.0016) and allelic loss (p = 0.0048) in astrocytomas, when compared to the other histological groups, confirming previous reports.	('astrocytomas', 'Disease', (193, 205))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('deletion', 'Var', (50, 58))	('allelic', 'Var', (164, 171))	('gene mutation', 'Var', (133, 146))	('abnormalities', 'Var', (19, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (193, 205))	('astrocytoma', 'Phenotype', 'HP:0009592', (193, 204))
124920	31151164	TP53 deletions were more frequent than mutations and were detected in 19/65 cases (29.2%) and 6/48 cases (12.5%), respectively, confirming the data of previous publications demonstrating higher incidence of TP53 deletion than gene mutation in cancer.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (207, 211))	('deletion', 'Var', (212, 220))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('TP53', 'Gene', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('deletions', 'Var', (5, 14))
124921	31151164	In addition, no significant association (p = 0.2530) between presence of mutation and deletion of TP53 was found in the 44 samples in which both analyses were allowed.	('mutation', 'Var', (73, 81))	('TP53', 'Gene', '7157', (98, 102))	('deletion', 'Var', (86, 94))	('TP53', 'Gene', (98, 102))
124922	31151164	Since most TP53 mutations (~90%) identified in gliomas are concentrated in mutational hotspots regions (exons 5-9), studies have limited their mutational analysis to this portion of the gene.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))
124923	31151164	This fact has caused some bias in the literature, because mutations located outside these classic hotspots have already been identified, especially in primary glioblastoma.	('glioblastoma', 'Disease', (159, 171))	('mutations', 'Var', (58, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))
124924	31151164	In our study, we found that 5 of 8 (62.5%) mutations in TP53 gene were localized into hotspot region, confirming the prevalence of mutations described in literature in this region; however, 3 mutations (37.5%) were present in exons 4, 10, and 11, thus showing the need for studying all exons of TP53 gene in gliomas.	('TP53', 'Gene', '7157', (56, 60))	('gliomas', 'Disease', (308, 315))	('glioma', 'Phenotype', 'HP:0009733', (308, 314))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (43, 52))	('gliomas', 'Disease', 'MESH:D005910', (308, 315))	('gliomas', 'Phenotype', 'HP:0009733', (308, 315))	('TP53', 'Gene', '7157', (295, 299))	('TP53', 'Gene', (295, 299))
124925	31151164	On the other hand, although some reports have identified low frequency of PTEN mutations in HGG, which is consistent with our results, since no mutation was identified in 34 tumors, a mutational rate in up to ~60% in high-grade astrocytomas has been detected in most of the previous studies.	('astrocytomas', 'Disease', (228, 240))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('HGG', 'Gene', (92, 95))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (228, 239))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('astrocytomas', 'Disease', 'MESH:D001254', (228, 240))	('mutations', 'Var', (79, 88))
124927	31151164	Further, other genetic events may be associated with inactivation of the PTEN protein and consequent participation in the process of malignant progression of gliomas.	('PTEN protein', 'Protein', (73, 85))	('participation', 'Reg', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('associated', 'Reg', (37, 47))	('gliomas', 'Disease', (158, 165))	('inactivation', 'Var', (53, 65))
124928	31151164	PTEN deletions also have been reported in up to 88.1% of anaplastic astrocytomas, from 0% to 50% in oligodendrogliomas/oligoastrocytomas and rarely in LGG.	('reported', 'Reg', (30, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('astrocytomas', 'Disease', (68, 80))	('astrocytomas', 'Disease', 'MESH:D001254', (124, 136))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('oligodendrogliomas/oligoastrocytomas', 'Disease', 'MESH:D001254', (100, 136))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('astrocytomas', 'Disease', (124, 136))	('oligodendrogliomas/oligoastrocytomas', 'Disease', (100, 136))	('PTEN', 'Gene', (0, 4))	('deletions', 'Var', (5, 14))
124929	31151164	Consistent with these studies, we found the presence of PTEN deletion in 23 cases from 62 (37.1%), with a significantly higher prevalence detected in astrocytomas (p <= 0.0001).	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('astrocytomas', 'Disease', 'MESH:D001254', (150, 162))	('PTEN', 'Gene', (56, 60))	('deletion', 'Var', (61, 69))	('astrocytomas', 'Disease', (150, 162))
124930	31151164	Although most investigations show a higher frequency of PTEN mutation when compared to allelic loss, Pollack et al.	('PTEN', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('Pollack', 'Species', '185739', (101, 108))
124933	31151164	Our findings are consistent with literature, since we report CDKN2A deletions in 28 from 63 cases (44.4%), with significantly higher frequency of both heterozygous and homozygous deletion in astrocytomas (p <= 0.0001 and p = 0.006 respectively).	('astrocytomas', 'Disease', (191, 203))	('deletions', 'Var', (68, 77))	('CDKN2A', 'Gene', (61, 67))	('higher', 'PosReg', (126, 132))	('CDKN2A', 'Gene', '1029', (61, 67))	('astrocytomas', 'Disease', 'MESH:D001254', (191, 203))	('astrocytoma', 'Phenotype', 'HP:0009592', (191, 202))
124934	31151164	Previous publications have shown that TP53 heterozygous deletion occur more frequently than homozygous deletion in cancer.	('cancer', 'Disease', (115, 121))	('TP53', 'Gene', (38, 42))	('heterozygous deletion', 'Var', (43, 64))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('TP53', 'Gene', '7157', (38, 42))
124942	31151164	showed in a series of 18 biopsies of prostate cancer that two cases with a heterozygous PTEN deletion detected by FISH presented decreased expression of PTEN protein.	('PTEN protein', 'Protein', (153, 165))	('prostate cancer', 'Disease', (37, 52))	('PTEN', 'Gene', (88, 92))	('deletion', 'Var', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (139, 149))	('prostate cancer', 'Disease', 'MESH:D011471', (37, 52))	('decreased', 'NegReg', (129, 138))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))
124943	31151164	Overall, it has been reported that TP53 genetic alterations are early events in gliomagenesis, while genetic changes affecting PTEN have been identified mainly in HGG, considered to be involved in malignant glioma progression.	('glioma', 'Disease', (80, 86))	('HGG', 'Disease', (163, 166))	('malignant glioma', 'Disease', (197, 213))	('malignant glioma', 'Disease', 'MESH:D005910', (197, 213))	('glioma', 'Disease', (207, 213))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('genetic alterations', 'Var', (40, 59))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('PTEN', 'Gene', (127, 131))	('glioma', 'Disease', 'MESH:D005910', (207, 213))
124944	31151164	Our data are in concordance previous studies, since we found no statistically significant difference between the presence of TP53 mutation/deletion and grade of malignancy (p = 0.9985 and p = 0.3535, respectively), while a significantly higher frequency of PTEN deletion in HGG was identified (55.6%) (p = 0.05).	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('TP53', 'Gene', '7157', (125, 129))	('malignancy', 'Disease', (161, 171))	('TP53', 'Gene', (125, 129))	('mutation/deletion', 'Var', (130, 147))	('deletion', 'Var', (262, 270))	('PTEN', 'Gene', (257, 261))
124945	31151164	In addition, although the majority of investigations have shown that CDKN2A deletions are more frequently identified in HGG when compared to LGG, suggesting a role for CDKN2A pathway in malignant progression, no significant association was observed between the presence of CDKN2A losses and WHO grading groups (p = 0.1901) in our study, suggesting that this is an early event in initiation and progression of gliomas.	('CDKN2A', 'Gene', '1029', (69, 75))	('CDKN2A', 'Gene', (273, 279))	('gliomas', 'Phenotype', 'HP:0009733', (409, 416))	('gliomas', 'Disease', 'MESH:D005910', (409, 416))	('CDKN2A', 'Gene', '1029', (273, 279))	('glioma', 'Phenotype', 'HP:0009733', (409, 415))	('CDKN2A', 'Gene', (168, 174))	('gliomas', 'Disease', (409, 416))	('HGG', 'Disease', (120, 123))	('deletions', 'Var', (76, 85))	('CDKN2A', 'Gene', (69, 75))	('CDKN2A', 'Gene', '1029', (168, 174))
124946	31151164	Our results are supported by Reis et al., who reported no significant differences when the frequency of CKN2A deletion was compared between low- and high-grade tumors (44.7% x 50.8%; p = 0.6, respectively), and also by Purkait et al., who found lower frequency of CDKN2A deletion in grade-II tumors (27.3%) when compared to grade-III tumors (30%), although the difference was not statistically significant.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('CDKN2A', 'Gene', '1029', (264, 270))	('tumors', 'Disease', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('tumors', 'Disease', (334, 340))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('deletion', 'Var', (271, 279))	('deletion', 'Var', (110, 118))	('CKN2A', 'Gene', (104, 109))	('tumors', 'Disease', (160, 166))	('CDKN2A', 'Gene', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
124948	31151164	While PTEN alterations (mutation and deletion) were detected predominantly in HGG (346/1310 cases, 26.4%) when compared to LGG (29/847 cases, 3.4%), the frequency of TP53 alterations was similar in these two groups (LGG (350/847 cases, 41.3% against HGG (426/1310 cases, 32.5%)), supporting our experimental data.	('alterations', 'Var', (11, 22))	('deletion', 'Var', (37, 45))	('TP53', 'Gene', '7157', (166, 170))	('HGG', 'Disease', (78, 81))	('TP53', 'Gene', (166, 170))	('PTEN', 'Gene', (6, 10))
124949	31151164	On the other hand, concerning CDKN2A deletion, we found a different situation, since this alteration was found mainly in HGG (426/2114 cases, 53.9%), while in LGG was identified in 8.9% (67/750) of samples, suggesting that this is a late event in progression of gliomas and is involved in tumor malignancy.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('gliomas', 'Disease', 'MESH:D005910', (262, 269))	('gliomas', 'Phenotype', 'HP:0009733', (262, 269))	('gliomas', 'Disease', (262, 269))	('deletion', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('CDKN2A', 'Gene', (30, 36))	('tumor', 'Disease', (289, 294))	('CDKN2A', 'Gene', '1029', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('malignancy', 'Disease', 'MESH:D009369', (295, 305))	('malignancy', 'Disease', (295, 305))	('HGG', 'Disease', (121, 124))
124950	31151164	However, as previously mentioned, published data on CDKN2A deletion in gliomas are still conflicting, and further studies are needed to clarify the timing of changes in this gene in the progression of glial tumors.	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('CDKN2A', 'Gene', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glial tumors', 'Disease', 'MESH:D005910', (201, 213))	('deletion', 'Var', (59, 67))	('CDKN2A', 'Gene', '1029', (52, 58))	('glial tumors', 'Disease', (201, 213))
124951	31151164	It is also important to report that, according to the TCGA dataset, TP53, PTEN, and CDKN2A alterations (mutation and deletion) are more prevalent in gliomas derived from astrocytic lineage, which confirms our results, since we found a significant association of these genes alterations with astrocytomas.	('gliomas', 'Disease', (149, 156))	('CDKN2A', 'Gene', (84, 90))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('CDKN2A', 'Gene', '1029', (84, 90))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('astrocytomas', 'Disease', (291, 303))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('PTEN', 'Gene', (74, 78))	('prevalent', 'Reg', (136, 145))	('alterations', 'Var', (91, 102))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('astrocytomas', 'Disease', 'MESH:D001254', (291, 303))	('astrocytoma', 'Phenotype', 'HP:0009592', (291, 302))
124952	31151164	Most of our glioma samples harbored alterations in at least one gene (40/62 cases, 64.5%).	('glioma', 'Disease', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('alterations', 'Var', (36, 47))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
124953	31151164	The most frequent aberrations detected were concomitant deletion of PTEN and CKDN2A genes (9/40 cases, 22.5%), followed by simultaneous alterations in all three genes (7/40 cases, 17.5%), individual changes in TP53, PTEN, and CDKN2A (6/40 cases each, 15%), co-alteration of TP53 and CKDN2A (5/40 cases, 12.5%), and co-alteration of TP53 and PTEN genes (1/40 cases, 2.5%).	('deletion', 'Var', (56, 64))	('PTEN', 'Gene', (341, 345))	('TP53', 'Gene', (210, 214))	('CKDN2A', 'Gene', (77, 83))	('PTEN', 'Gene', (68, 72))	('CDKN2A', 'Gene', (226, 232))	('TP53', 'Gene', '7157', (274, 278))	('alterations', 'Reg', (136, 147))	('TP53', 'Gene', '7157', (332, 336))	('CDKN2A', 'Gene', '1029', (226, 232))	('TP53', 'Gene', (274, 278))	('TP53', 'Gene', '7157', (210, 214))	('TP53', 'Gene', (332, 336))
124955	31151164	In addition, among these 27 samples that showed alterations, it was observed a higher frequency of co-alteration in PTEN and CDKN2A genes (29.6%), followed by alterations of all three genes (18.5%), co-alteration in TP53 and CDKN2A (14.8%), and concomitant deletion of TP53 and PTEN genes (3.7%).	('TP53', 'Gene', (216, 220))	('alterations', 'Var', (159, 170))	('CDKN2A', 'Gene', (225, 231))	('TP53', 'Gene', '7157', (269, 273))	('CDKN2A', 'Gene', '1029', (225, 231))	('deletion', 'Var', (257, 265))	('TP53', 'Gene', (269, 273))	('CDKN2A', 'Gene', (125, 131))	('TP53', 'Gene', '7157', (216, 220))	('PTEN', 'Gene', (116, 120))	('CDKN2A', 'Gene', '1029', (125, 131))	('PTEN', 'Gene', (278, 282))
124956	31151164	Overall, a strong association was noted for the co-occurrence of PTEN and CDKN2A deletions (p = 0.0022).	('PTEN', 'Gene', (65, 69))	('CDKN2A', 'Gene', '1029', (74, 80))	('deletions', 'Var', (81, 90))	('CDKN2A', 'Gene', (74, 80))
124959	31151164	These findings are similar to other studies that found an association for the co-occurrence of PTEN and CDKN2A deletions and/or TP53 and CDKN2A alterations in gliomas, while concomitants TP53 and PTEN alterations were less frequent.	('CDKN2A', 'Gene', '1029', (104, 110))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', '7157', (187, 191))	('TP53', 'Gene', (128, 132))	('CDKN2A', 'Gene', (137, 143))	('TP53', 'Gene', (187, 191))	('PTEN', 'Gene', (95, 99))	('CDKN2A', 'Gene', '1029', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('deletions', 'Var', (111, 120))	('alterations', 'Var', (144, 155))	('CDKN2A', 'Gene', (104, 110))
124961	31151164	Although it was observed that co-occurrence of PTEN and CDKN2A losses (both heterozygous and homozygous deletion) were detected in higher frequency in HGG, LGG showed a frequency of individual CDKN2A deletion similar to that observed in more aggressive tumors, while the presence of individual PTEN deletion was significantly higher in more aggressive tumors, suggesting that allelic loss of CDKN2A is a prior event to PTEN alterations.	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('CDKN2A', 'Gene', (392, 398))	('deletion', 'Var', (200, 208))	('aggressive tumors', 'Disease', 'MESH:D001523', (242, 259))	('CDKN2A', 'Gene', (193, 199))	('aggressive tumors', 'Disease', (341, 358))	('CDKN2A', 'Gene', '1029', (392, 398))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('CDKN2A', 'Gene', '1029', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('aggressive tumors', 'Disease', (242, 259))	('PTEN', 'Gene', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('CDKN2A', 'Gene', (56, 62))	('aggressive tumors', 'Disease', 'MESH:D001523', (341, 358))	('CDKN2A', 'Gene', '1029', (56, 62))	('losses', 'NegReg', (63, 69))
124962	31151164	Although much have been reported on the presence of genetic alterations in TP53, PTEN, and CDKN2A genes in several tumor types, few studies have focused on the analysis of the incidence of co-alterations of these three genes, through different types of mechanisms which lead to loss of protein function, such as mutations and deletions, in a single sample of gliomas.	('loss', 'NegReg', (278, 282))	('deletions', 'Var', (326, 335))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CDKN2A', 'Gene', (91, 97))	('gliomas', 'Phenotype', 'HP:0009733', (359, 366))	('gliomas', 'Disease', (359, 366))	('tumor', 'Disease', (115, 120))	('protein', 'Protein', (286, 293))	('gliomas', 'Disease', 'MESH:D005910', (359, 366))	('CDKN2A', 'Gene', '1029', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (359, 365))	('PTEN', 'Gene', (81, 85))	('mutations', 'Var', (312, 321))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
124963	31151164	Our results demonstrated the presence of simultaneous alterations of these genes and association with different clinical-pathological variables of the patients, evidencing its importance in the development and progression of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (225, 232))	('gliomas', 'Disease', (225, 232))	('gliomas', 'Disease', 'MESH:D005910', (225, 232))	('patients', 'Species', '9606', (151, 159))	('alterations', 'Var', (54, 65))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('association', 'Interaction', (85, 96))
124965	31151164	Further, our findings indicate that TP53 changes and CDKN2A deletions tend to coexist in LGG, suggesting that they are early events in progression of these tumors, as well as CDKN2A and PTEN deletions, since a significant association was observed, with CDKN2A changes preceding PTEN deletions, that are involved with malignant progression of gliomas.	('deletions', 'Var', (283, 292))	('changes', 'Var', (260, 267))	('CDKN2A', 'Gene', '1029', (53, 59))	('CDKN2A', 'Gene', '1029', (253, 259))	('gliomas', 'Phenotype', 'HP:0009733', (342, 349))	('TP53', 'Gene', (36, 40))	('deletions', 'Var', (60, 69))	('CDKN2A', 'Gene', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('TP53', 'Gene', '7157', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('CDKN2A', 'Gene', '1029', (175, 181))	('gliomas', 'Disease', (342, 349))	('tumors', 'Disease', (156, 162))	('PTEN', 'Gene', (278, 282))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('CDKN2A', 'Gene', (53, 59))	('CDKN2A', 'Gene', (253, 259))	('gliomas', 'Disease', 'MESH:D005910', (342, 349))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('LGG', 'Disease', (89, 92))
124979	31151164	Fragmented DNAs were labeled with Cy3 (reference DNA) and Cy5 (test samples) fluorescent dUTP, respectively.	('Cy3', 'Var', (34, 37))	('Cy5', 'Var', (58, 61))	('Cy5', 'Chemical', 'MESH:C085321', (58, 61))	('Cy3', 'Chemical', '-', (34, 37))	('dUTP', 'Chemical', 'MESH:C027078', (89, 93))
124992	28423669	Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('arrested', 'NegReg', (54, 62))	('TALNEC2', 'Gene', (13, 20))	('cells in the G1\\S phase of the cell cycle', 'CPA', (67, 108))	('cell proliferation', 'CPA', (31, 49))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('inhibited', 'NegReg', (21, 30))	('Silencing', 'Var', (0, 9))	('TALNEC2', 'Chemical', '-', (13, 20))
124993	28423669	In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts.	('decreased', 'NegReg', (34, 43))	('increased', 'PosReg', (101, 110))	('survival', 'CPA', (165, 173))	('prolonged', 'PosReg', (155, 164))	('sensitivity', 'MPA', (111, 122))	('TALNEC2', 'Chemical', '-', (26, 33))	('mice', 'Species', '10090', (177, 181))	('TALNEC2', 'Gene', (26, 33))	('silencing', 'Var', (13, 22))
125017	28423669	To activate the endogenous E2Fs we employed the E7 HPV16 protein, which disrupts the pRB/E2F complexes.	('pRB', 'Gene', (85, 88))	('complexes', 'Interaction', (93, 102))	('pRB', 'Gene', '5925', (85, 88))	('E7 HPV16', 'Var', (48, 56))	('HPV16', 'Species', '333760', (51, 56))
125019	28423669	These results indicate that in addition to being regulated by ectopic E2F1, TALNEC2 was also regulated by the endogenous E2Fs.	('E2F1', 'Gene', '1869', (70, 74))	('E2F1', 'Gene', (70, 74))	('TALNEC2', 'Chemical', '-', (76, 83))	('ectopic', 'Var', (62, 69))	('TALNEC2', 'Gene', (76, 83))	('regulated', 'Reg', (93, 102))
125020	28423669	Furthermore, TALNEC2 RNA levels increased in response to activation of ectopic E2F1, even in the presence of CHX, indicating that de novo protein synthesis was not required for E2F1-mediated upregulation of TALNEC2 and suggesting that it is a direct E2F1 target (Supplementary Figure 1A).	('E2F1', 'Gene', (79, 83))	('ectopic', 'Var', (71, 78))	('TALNEC2 RNA levels', 'MPA', (13, 31))	('activation', 'PosReg', (57, 67))	('TALNEC2', 'Chemical', '-', (207, 214))	('E2F1', 'Gene', '1869', (177, 181))	('E2F1', 'Gene', '1869', (250, 254))	('E2F1', 'Gene', (177, 181))	('E2F1', 'Gene', (250, 254))	('increased', 'PosReg', (32, 41))	('E2F1', 'Gene', '1869', (79, 83))	('TALNEC2', 'Chemical', '-', (13, 20))
125028	28423669	TALNEC2 RNA was enriched in the cytoplasm of these cells, similar to the cytoplasmic control transcripts (GAPDH and tubulin), as opposed to the nuclear control (the lncRNA MALAT1).	('GAPDH', 'Gene', (106, 111))	('MALAT1', 'Gene', (172, 178))	('TALNEC2', 'Var', (0, 7))	('MALAT1', 'Gene', '378938', (172, 178))	('GAPDH', 'Gene', '2597', (106, 111))	('TALNEC2', 'Chemical', '-', (0, 7))
125030	28423669	Silencing of TALNEC2 in MCF-7 breast cancer cells by two specific siRNAs (Figure 2A) resulted in a significant increase in the number of cells in the G1 phase of the cell cycle and a concomitant reduction in the number of cells in S phase suggesting that TALNEC2 may have a role in G1 exit (Figures 2B, 2C).	('TALNEC2', 'Chemical', '-', (255, 262))	('increase', 'PosReg', (111, 119))	('TALNEC2', 'Gene', (13, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('reduction', 'NegReg', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (24, 43))	('MCF-7 breast cancer', 'Disease', (24, 43))	('Silencing', 'Var', (0, 9))	('TALNEC2', 'Chemical', '-', (13, 20))
125034	28423669	Hydroxyurea-treated cells were arrested in G1 and silencing of TALNEC2 enhanced this arrest.	('enhanced', 'PosReg', (71, 79))	('Hydroxyurea', 'Chemical', 'MESH:D006918', (0, 11))	('TALNEC2', 'Chemical', '-', (63, 70))	('TALNEC2', 'Gene', (63, 70))	('silencing', 'Var', (50, 59))
125037	28423669	These results indicate that silencing TALNEC2 inhibited G1 exit and cell-cycle progression.	('TALNEC2', 'Chemical', '-', (38, 45))	('G1 exit', 'CPA', (56, 63))	('TALNEC2', 'Gene', (38, 45))	('cell-cycle progression', 'CPA', (68, 90))	('silencing', 'Var', (28, 37))	('inhibited', 'NegReg', (46, 55))
125041	28423669	Silencing of TALNEC2 inhibited the growth of MCF-7 cells by up to 66% (Figures 3B, Supplementary Figures 6B, 6D), and this inhibition was not associated with increased cell death.	('TALNEC2', 'Gene', (13, 20))	('death', 'Disease', 'MESH:D003643', (173, 178))	('growth', 'CPA', (35, 41))	('MCF-7', 'CellLine', 'CVCL:0031', (45, 50))	('inhibited', 'NegReg', (21, 30))	('TALNEC2', 'Chemical', '-', (13, 20))	('Silencing', 'Var', (0, 9))	('death', 'Disease', (173, 178))
125042	28423669	Silencing of TALNEC2 in glioma cell lines U87 and A172 (Figure 3C) also decreased cell proliferation, which started after 24 h of silencing (Figures 3D, Supplementary Figure 6E).	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('U87', 'Gene', '641648', (42, 45))	('TALNEC2', 'Gene', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('cell proliferation', 'CPA', (82, 100))	('decreased', 'NegReg', (72, 81))	('silencing', 'Var', (130, 139))	('glioma', 'Disease', (24, 30))	('Silencing', 'Var', (0, 9))	('TALNEC2', 'Chemical', '-', (13, 20))	('U87', 'Gene', (42, 45))
125050	28423669	The GCMIP-low group harbors an IDH mutation but demonstrates an aggressive phenotype.	('IDH', 'Gene', '3417', (31, 34))	('IDH', 'Gene', (31, 34))	('mutation', 'Var', (35, 43))
125053	28423669	We also observed that the LGm6-GBM class had higher mean expression of TALNEC2 than the PA-like group (t-test, P=0.0427).	('expression', 'MPA', (57, 67))	('LGm6-GBM', 'Var', (26, 34))	('TALNEC2', 'Chemical', '-', (71, 78))	('TALNEC2', 'Protein', (71, 78))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('PA', 'Chemical', 'MESH:D011478', (88, 90))	('higher', 'PosReg', (45, 51))
125063	28423669	In addition, deregulation of non-coding RNA expression has been also implicated in patient prognosis.	('patient', 'Species', '9606', (83, 90))	('deregulation', 'Var', (13, 25))	('implicated', 'Reg', (69, 79))	('non-coding RNA expression', 'Protein', (29, 54))
125070	28423669	We found that silencing of TALNEC2 in the HF2355 and HF2414 GSCs (Figure 5A) decreased the self-renewal (Figure 5B) and the frequency of sphere formation (Supplementary Figure 8).	('self-renewal', 'CPA', (91, 103))	('silencing', 'Var', (14, 23))	('TALNEC2', 'Chemical', '-', (27, 34))	('HF2414', 'Gene', (53, 59))	('TALNEC2', 'Gene', (27, 34))	('sphere formation', 'CPA', (137, 153))	('HF2355', 'CellLine', 'CVCL:L945', (42, 48))	('HF2414', 'CellLine', 'CVCL:AR02', (53, 59))	('decreased', 'NegReg', (77, 86))
125071	28423669	In addition, silencing of TALNEC2 decreased the expression of the stemness markers Nanog, SOX2 and Oct4 (Figure 5C, 5E), and the expression of the mesenchymal markers CTGF, fibronectin and YKL40 in the GSCs (Figure 5D, 5E).	('decreased', 'NegReg', (34, 43))	('TALNEC2', 'Chemical', '-', (26, 33))	('TALNEC2', 'Gene', (26, 33))	('Oct4', 'Gene', (99, 103))	('expression', 'MPA', (129, 139))	('SOX2', 'Gene', '6657', (90, 94))	('expression', 'MPA', (48, 58))	('fibronectin', 'Gene', (173, 184))	('SOX2', 'Gene', (90, 94))	('CTGF', 'Gene', '1490', (167, 171))	('Nanog', 'Gene', '79923', (83, 88))	('silencing', 'Var', (13, 22))	('YKL40', 'Gene', '1116', (189, 194))	('Nanog', 'Gene', (83, 88))	('CTGF', 'Gene', (167, 171))	('fibronectin', 'Gene', '2335', (173, 184))	('Oct4', 'Gene', '5460', (99, 103))	('YKL40', 'Gene', (189, 194))	('stemness', 'CPA', (66, 74))
125073	28423669	In accordance with the effect of TALNEC2 on the expression of mesenchymal markers and with its increased expression in the mesenchymal GBM subtype, we found that silencing of TALNEC2 inhibited the migration of GSCs as indicated by transwell migration assays (Figure 5F).	('migration of GSCs', 'CPA', (197, 214))	('silencing', 'Var', (162, 171))	('TALNEC2', 'Gene', (175, 182))	('GBM', 'Phenotype', 'HP:0012174', (135, 138))	('TALNEC2', 'Chemical', '-', (33, 40))	('inhibited', 'NegReg', (183, 192))	('TALNEC2', 'Chemical', '-', (175, 182))
125074	28423669	We found that silencing of TALNEC2 not only decreased the self-renewal of the GSCs but also increased their sensitivity to gamma-radiation.	('silencing', 'Var', (14, 23))	('TALNEC2', 'Chemical', '-', (27, 34))	('TALNEC2', 'Gene', (27, 34))	('increased their sensitivity to gamma-radiation', 'Phenotype', 'HP:0011133', (92, 138))	('sensitivity to gamma-radiation', 'MPA', (108, 138))	('self-renewal of the GSCs', 'CPA', (58, 82))	('increased', 'PosReg', (92, 101))	('decreased', 'NegReg', (44, 53))
125079	28423669	As presented in Figure 5I, silencing of TALNEC2 prolonged mouse median survival by 12 days (P<0.0001).	('mouse', 'Species', '10090', (58, 63))	('silencing', 'Var', (27, 36))	('prolonged', 'PosReg', (48, 57))	('TALNEC2', 'Chemical', '-', (40, 47))	('TALNEC2', 'Gene', (40, 47))
125081	28423669	We found that silencing of TALNEC2 in U87 cells resulted in an increased expression of miRNAs associated with tumor suppression (e.g., let-7b, miR-7, miR-124, miR-137, miR-129-3p, miR-142-3p, miR-205, miR-376c, miR-492, miR-562 and miR-3144) and in a decrease in the expression of miRNAs associated with tumor promotion (e.g., miR-9, miR-21 miR-33b, miR-155, miR-191, miR-525-3p, and miR-767-3p).	('miR', 'Gene', '220972', (211, 214))	('TALNEC2', 'Chemical', '-', (27, 34))	('miR-7', 'Gene', '10859', (384, 389))	('miR-155', 'Gene', (350, 357))	('miR-492', 'Gene', (211, 218))	('miR-155', 'Gene', '406947', (350, 357))	('miR-492', 'Gene', '574449', (211, 218))	('silencing', 'Var', (14, 23))	('U87', 'Gene', '641648', (38, 41))	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', (232, 235))	('miR', 'Gene', '220972', (150, 153))	('miR-767', 'Gene', (384, 391))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (159, 162))	('miR-205', 'Gene', '406988', (192, 199))	('suppression', 'NegReg', (116, 127))	('miR', 'Gene', (327, 330))	('increased', 'PosReg', (63, 72))	('miR-525', 'Gene', (368, 375))	('miR-21', 'Gene', (334, 340))	('miR', 'Gene', (350, 353))	('miR', 'Gene', '220972', (220, 223))	('decrease', 'NegReg', (251, 259))	('miR', 'Gene', '220972', (201, 204))	('miR', 'Gene', (180, 183))	('miR-7', 'Gene', (143, 148))	('miR', 'Gene', (384, 387))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (368, 371))	('miR', 'Gene', (281, 284))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('miR-191', 'Gene', '406966', (359, 366))	('miR', 'Gene', (334, 337))	('miR-191', 'Gene', (359, 366))	('let-7b', 'Gene', (135, 141))	('miR', 'Gene', (359, 362))	('expression', 'MPA', (267, 277))	('miR', 'Gene', '220972', (341, 344))	('miR-129-3p', 'Gene', (168, 178))	('miR', 'Gene', (143, 146))	('miR-3144', 'Gene', '100422951', (232, 240))	('miR-562', 'Gene', '693147', (220, 227))	('miR-33b', 'Gene', (341, 348))	('TALNEC2', 'Gene', (27, 34))	('miR-376c', 'Gene', (201, 209))	('miR', 'Gene', '220972', (232, 235))	('miR', 'Gene', (211, 214))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('expression', 'MPA', (73, 83))	('miR', 'Gene', '220972', (159, 162))	('let-7b', 'Gene', '406884', (135, 141))	('miR', 'Gene', '220972', (327, 330))	('miR', 'Gene', (192, 195))	('miR-7', 'Gene', '10859', (143, 148))	('miR', 'Gene', '220972', (350, 353))	('miR-376c', 'Gene', '442913', (201, 209))	('miR-7', 'Gene', (384, 389))	('U87', 'Gene', (38, 41))	('miR', 'Gene', (150, 153))	('miR-137', 'Gene', (159, 166))	('tumor', 'Disease', (110, 115))	('miR-33b', 'Gene', '693120', (341, 348))	('miR-129-3p', 'Gene', '100302220', (168, 178))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (87, 90))	('miR', 'Gene', (341, 344))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('miR', 'Gene', '220972', (384, 387))	('miR-205', 'Gene', (192, 199))	('miR', 'Gene', (220, 223))	('miR-525', 'Gene', '574470', (368, 375))	('miR', 'Gene', '220972', (368, 371))	('miR-3144', 'Gene', (232, 240))	('tumor', 'Disease', (304, 309))	('miR-562', 'Gene', (220, 227))	('miR', 'Gene', '220972', (281, 284))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('miR', 'Gene', '220972', (334, 337))	('miR', 'Gene', (201, 204))	('miR', 'Gene', '220972', (359, 362))	('miR-21', 'Gene', '406991', (334, 340))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (168, 171))	('miR-767', 'Gene', '768215', (384, 391))	('miR-137', 'Gene', '406928', (159, 166))
125095	28423669	Long-noncoding RNAs are emerging as important regulators of various biological processes including cell-cycle progression and tumorigenesis.	('Long-noncoding', 'Var', (0, 14))	('cell-cycle', 'CPA', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
125099	28423669	Our data indicate that consistently with a possible role in G1/S transition, the RNA levels of TALNEC2 increased as synchronized cells move through late G1 and early S. Importantly, its silencing, in a number of cancer cells lines, resulted in a significant increase in the number of cells in the G1 phase and a concomitant reduction in the number of cells in the S phase.	('cells in the G1 phase', 'CPA', (284, 305))	('reduction', 'NegReg', (324, 333))	('increase', 'PosReg', (258, 266))	('silencing', 'Var', (186, 195))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('TALNEC2', 'Chemical', '-', (95, 102))	('TALNEC2', 'Gene', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
125100	28423669	Furthermore, upon silencing of TALNEC2, fewer cells were released from an arrest at the G1/S transition point and proceeded into S phase.	('silencing', 'Var', (18, 27))	('fewer', 'NegReg', (40, 45))	('TALNEC2', 'Chemical', '-', (31, 38))	('TALNEC2', 'Gene', (31, 38))
125101	28423669	In agreement with these effects on cell cycle distribution, silencing of TALNEC2 also inhibited cell proliferation.	('TALNEC2', 'Chemical', '-', (73, 80))	('TALNEC2', 'Gene', (73, 80))	('cell proliferation', 'CPA', (96, 114))	('silencing', 'Var', (60, 69))	('inhibited', 'NegReg', (86, 95))
125106	28423669	Non-coding RNAs (including both miRNAs and lncRNAs) have been recently implicated as important regulators of various tumorigenic processes including GBM.	('miR', 'Gene', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Non-coding', 'Var', (0, 10))	('tumor', 'Disease', (117, 122))	('GBM', 'Disease', (149, 152))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('miR', 'Gene', '220972', (32, 35))
125111	28423669	Expression of the tumor suppressor lncRNA MEG3 is markedly decreased in glioma tissues and its ectopic expression inhibits proliferation and promotes apoptosis in human glioma cell lines.	('apoptosis', 'CPA', (150, 159))	('promotes', 'PosReg', (141, 149))	('MEG3', 'Gene', '55384', (42, 46))	('glioma', 'Disease', (169, 175))	('tumor', 'Disease', (18, 23))	('ectopic', 'Var', (95, 102))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('glioma', 'Disease', (72, 78))	('Expression', 'MPA', (0, 10))	('inhibits', 'NegReg', (114, 122))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('proliferation', 'CPA', (123, 136))	('decreased', 'NegReg', (59, 68))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('human', 'Species', '9606', (163, 168))	('MEG3', 'Gene', (42, 46))
125117	28423669	Importantly, we found that TALNEC2, in addition to being highly expressed in GSCs compared to NSCs and astrocytes, also regulated the stemness of these cells and that silencing of this lncRNA significantly decreased the self-renewal and stemness characteristics of the GSCs.	('TALNEC2', 'Chemical', '-', (27, 34))	('stemness characteristics of the GSCs', 'CPA', (237, 273))	('decreased', 'NegReg', (206, 215))	('self-renewal', 'CPA', (220, 232))	('silencing', 'Var', (167, 176))	('stemness of these cells', 'CPA', (134, 157))
125119	28423669	We found that TLANEC2 regulated the mesenchymal transformation of GSCs and that silencing of TALNEC2 decreased both the migration and expression of mesenchymal markers in these cells.	('mesenchymal transformation of GSCs', 'CPA', (36, 70))	('silencing', 'Var', (80, 89))	('expression', 'MPA', (134, 144))	('TALNEC2', 'Chemical', '-', (93, 100))	('decreased', 'NegReg', (101, 110))	('TALNEC2', 'Gene', (93, 100))	('migration', 'CPA', (120, 129))
125122	28423669	Altogether, our results indicate that silencing of TALNEC2 inhibited the proneural-to-mesenchymal transit of GSCs and the TCGA analysis of increased expression of TALNEC2 in the mesenchymal subtype of GBM further supports a role of TALNEC2 in this pathway.	('TALNEC2', 'Chemical', '-', (51, 58))	('TALNEC2', 'Gene', (51, 58))	('TALNEC2', 'Chemical', '-', (163, 170))	('proneural-to-mesenchymal transit of GSCs', 'CPA', (73, 113))	('increased', 'PosReg', (139, 148))	('inhibited', 'NegReg', (59, 68))	('TALNEC2', 'Chemical', '-', (232, 239))	('GBM', 'Phenotype', 'HP:0012174', (201, 204))	('silencing', 'Var', (38, 47))
125123	28423669	We found that in parallel to the inhibition of the stemness and mesenchymal transformation of GSCs, silencing of TALNEC2 also enhanced the sensitivity of the cells to gamma-irradiation.	('silencing', 'Var', (100, 109))	('enhanced', 'PosReg', (126, 134))	('stemness', 'CPA', (51, 59))	('TALNEC2', 'Chemical', '-', (113, 120))	('sensitivity', 'MPA', (139, 150))	('TALNEC2', 'Gene', (113, 120))
125126	28423669	We found that silencing of TALNEC2 expression in these GSCs significantly increased the mean survival of the xenograft-bearing mice.	('silencing', 'Var', (14, 23))	('mean survival', 'CPA', (88, 101))	('TALNEC2', 'Chemical', '-', (27, 34))	('mice', 'Species', '10090', (127, 131))	('TALNEC2', 'Gene', (27, 34))	('increased', 'PosReg', (74, 83))
125127	28423669	These findings further demonstrate that TALNEC2 silencing decreased the tumorigenic potential of GSCs in vivo, together with the decreased expression of TALNEC2 in long-term survival GBM patients, suggest that inhibiting this pathway may improve GBM patient prognosis.	('patients', 'Species', '9606', (187, 195))	('silencing', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('decreased', 'NegReg', (58, 67))	('TALNEC2', 'Chemical', '-', (153, 160))	('GBM', 'Disease', (246, 249))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TALNEC2', 'Chemical', '-', (40, 47))	('patient', 'Species', '9606', (250, 257))	('improve', 'PosReg', (238, 245))	('GBM', 'Phenotype', 'HP:0012174', (246, 249))	('patient', 'Species', '9606', (187, 194))	('TALNEC2', 'Gene', (40, 47))	('GBM', 'Phenotype', 'HP:0012174', (183, 186))
125128	28423669	Since normal neural cells express significantly lower levels of TALNEC2, silencing of TALNEC2 in GSCs which decreases their self-renewal and mesenchymal transformation can be employed as a novel therapeutic approach to abrogate the oncogenic potential of GSCs with no damage to normal cells in the brain.	('silencing', 'Var', (73, 82))	('TALNEC2', 'Chemical', '-', (86, 93))	('TALNEC2', 'Gene', (86, 93))	('decreases', 'NegReg', (108, 117))	('TALNEC2', 'Chemical', '-', (64, 71))	('abrogate', 'NegReg', (219, 227))	('oncogenic potential', 'CPA', (232, 251))
125130	28423669	We performed microarray analysis of miRNA expression of glioma cells silenced for TALNEC2 and found that silencing of TALNEC2 increased the expression of several tumor suppressor miRNAs such as miR-137, miR-124, miR-205, miR-7 and miR-492, whereas it decreased the expression of some oncomiRs such as miR-21, miR-155, miR-33b and miR-191.	('miR-191', 'Gene', '406966', (330, 337))	('miR-7', 'Gene', (221, 226))	('tumor', 'Disease', (162, 167))	('miR', 'Gene', '220972', (203, 206))	('miR-191', 'Gene', (330, 337))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (212, 215))	('expression', 'MPA', (265, 275))	('miR', 'Gene', (330, 333))	('miR-155', 'Gene', (309, 316))	('miR-205', 'Gene', '406988', (212, 219))	('TALNEC2', 'Chemical', '-', (82, 89))	('miR', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('miR', 'Gene', '220972', (194, 197))	('miR', 'Gene', '220972', (288, 291))	('miR-155', 'Gene', '406947', (309, 316))	('miR', 'Gene', (203, 206))	('miR-7', 'Gene', '10859', (221, 226))	('miR', 'Gene', (179, 182))	('miR', 'Gene', (194, 197))	('miR', 'Gene', '220972', (231, 234))	('glioma', 'Disease', (56, 62))	('miR', 'Gene', '220972', (301, 304))	('miR', 'Gene', '220972', (318, 321))	('miR', 'Gene', (288, 291))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('TALNEC2', 'Chemical', '-', (118, 125))	('TALNEC2', 'Gene', (118, 125))	('miR-205', 'Gene', (212, 219))	('miR-21', 'Gene', '406991', (301, 307))	('miR', 'Gene', '220972', (309, 312))	('miR-33b', 'Gene', '693120', (318, 325))	('miR-137', 'Gene', (194, 201))	('miR-492', 'Gene', (231, 238))	('miR', 'Gene', (301, 304))	('miR', 'Gene', '220972', (221, 224))	('miR-492', 'Gene', '574449', (231, 238))	('miR-137', 'Gene', '406928', (194, 201))	('miR', 'Gene', (231, 234))	('miR', 'Gene', (318, 321))	('expression', 'MPA', (140, 150))	('miR-33b', 'Gene', (318, 325))	('decreased', 'NegReg', (251, 260))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('miR', 'Gene', '220972', (212, 215))	('miR', 'Gene', '220972', (330, 333))	('miR', 'Gene', (309, 312))	('silencing', 'Var', (105, 114))	('miR-21', 'Gene', (301, 307))	('miR', 'Gene', '220972', (36, 39))	('increased', 'PosReg', (126, 135))	('miR', 'Gene', (221, 224))
125179	33062411	Global RNA editome landscape discovers reduced RNA editing in glioma: loss of editing of gamma-amino butyric acid receptor alpha subunit 3 (GABRA3) favors glioma migration and invasion Gliomas are the most common and lethal type of intracranial tumors.	('favors', 'PosReg', (148, 154))	('glioma migration', 'Disease', 'MESH:D005910', (155, 171))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('editing', 'Var', (78, 85))	('intracranial tumors', 'Disease', (232, 251))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('Gliomas', 'Disease', 'MESH:D005910', (185, 192))	('intracranial tumors', 'Disease', 'MESH:D001932', (232, 251))	('glioma migration', 'Disease', (155, 171))	('Glioma', 'Phenotype', 'HP:0009733', (185, 191))	('GABRA3', 'Gene', (140, 146))	('Gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('glioma', 'Disease', (62, 68))	('loss of editing', 'Var', (70, 85))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('Gliomas', 'Disease', (185, 192))	('glioma', 'Disease', (155, 161))
125185	33062411	More specifically, we found Gamma-aminobutyric acid type A receptor alpha3 (GABRA3) to be edited (c.1026 A-to-G; pI343M) in 73% (editing ratio 0.8) of control samples compared to LGG (28.96%; 0.47) and GBM (5.2%; 0.53) samples.	('GABRA3', 'Gene', (76, 82))	('c.1026 A-to-G; pI343M', 'Var', (98, 119))	('GBM', 'Phenotype', 'HP:0012174', (202, 205))	('Gamma-aminobutyric acid', 'Chemical', 'MESH:D005680', (28, 51))	('pI343M', 'Var', (113, 119))	('GABRA3', 'Chemical', '-', (76, 82))	('Gamma-aminobutyric acid type A receptor', 'Protein', (28, 67))
125189	33062411	Further, exogenously expressed edited GABRA3 inhibited migration and invasion of glioma cells efficiently but not the unedited GABRA3.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('GABRA3', 'Chemical', '-', (38, 44))	('edited', 'Var', (31, 37))	('GABRA3', 'Chemical', '-', (127, 133))	('glioma', 'Disease', (81, 87))	('inhibited', 'NegReg', (45, 54))	('GABRA3', 'Gene', (38, 44))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
125197	33062411	RNA editing increases proteomic diversity in cancer.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('increases', 'PosReg', (12, 21))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('proteomic diversity', 'MPA', (22, 41))	('cancer', 'Disease', (45, 51))	('RNA editing', 'Var', (0, 11))
125198	33062411	In mammals, especially in humans, the most common type of editing changes include A-to-I and C-to-U base modifications.	('A-to-I', 'Var', (82, 88))	('humans', 'Species', '9606', (26, 32))	('editing changes', 'Var', (58, 73))	('C-to-U base modifications', 'Var', (93, 118))	('changes', 'Var', (66, 73))
125205	33062411	Also, it was observed that restoration of the defective editing activity was able to inhibit proliferation of brain tumor cells.	('brain tumor', 'Phenotype', 'HP:0030692', (110, 121))	('inhibit', 'NegReg', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('brain tumor', 'Disease', (110, 121))	('brain tumor', 'Disease', 'MESH:D001932', (110, 121))	('defective editing', 'Var', (46, 63))	('editing', 'Var', (56, 63))
125208	33062411	Increased editing of AZIN1 transcript resulting in amino acid substitution was observed in HCC and the above change was seen to confer enhanced tumorigenicity.	('AZIN1', 'Gene', (21, 26))	('tumor', 'Disease', (144, 149))	('amino acid substitution', 'Var', (51, 74))	('HCC', 'Disease', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('Increased', 'PosReg', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('enhanced', 'PosReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('editing', 'MPA', (10, 17))	('AZIN1', 'Gene', '51582', (21, 26))
125214	33062411	Pathway analysis of differentially edited genes was performed to find out cellular processes regulated by editing in glioma.	('editing', 'Var', (106, 113))	('glioma', 'Disease', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (117, 123))
125215	33062411	Under-editing of glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) has been reported to play a role in glioma aggressive phenotype.	('glioma aggressive', 'Disease', 'MESH:D005910', (111, 128))	('role', 'Reg', (103, 107))	('GRIA2', 'Gene', '2891', (68, 73))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('Under-editing', 'Var', (0, 13))	('glutamate ionotropic receptor AMPA type subunit 2', 'Gene', (17, 66))	('play', 'Reg', (96, 100))	('glutamate ionotropic receptor AMPA type subunit 2', 'Gene', '2891', (17, 66))	('glioma aggressive', 'Disease', (111, 128))	('GRIA2', 'Gene', (68, 73))
125216	33062411	Here, we further studied the effect of missense RNA editing in gamma-amino butyric acid receptor alpha subunit 3 (GABRA3), a gene involved in neuronal signaling in the brain.	('GABRA3', 'Chemical', '-', (114, 120))	('GABRA3', 'Gene', (114, 120))	('missense RNA editing', 'Var', (39, 59))
125217	33062411	Experimental investigation revealed that loss of editing in this gene in glioma leads to a more aggressive tumor phenotype.	('glioma', 'Disease', (73, 79))	('aggressive tumor', 'Disease', 'MESH:D001523', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('more', 'PosReg', (91, 95))	('aggressive tumor', 'Disease', (96, 112))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('editing', 'Var', (49, 56))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('loss of editing', 'Var', (41, 56))
125228	33062411	Antibodies used include anti-GABRA3 (HPA000839-100UL; Sigma-Aldrich, St. Louis, MO, USA), DDK (#TA-50011; Origene, Rockville, MD, USA), Actin (#A3854; Sigma-Aldrich, St. Louis, MO, USA).	('#TA-50011;', 'Var', (95, 105))	('#A3854;', 'Var', (143, 150))	('GABRA3', 'Chemical', '-', (29, 35))	('HPA000839-100UL', 'Var', (37, 52))
125250	33062411	Hence, the variants were compared with corresponding whole exome sequencing data only in TCGA glioma samples to eliminate individual-specific genetic changes.	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('variants', 'Var', (11, 19))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Disease', (94, 100))
125255	33062411	We found majority of editing events were ADAR specific changes (A-to-I that is, A-to-G or T-to-C) followed by APOBEC specific changes (C-to-U that is, C-to-T or G-to-A) in control brain samples (Fig.	('C-to-T', 'Var', (151, 157))	('G-to-A', 'Var', (161, 167))	('ADAR', 'Gene', (41, 45))	('T-to-C', 'Var', (90, 96))	('ADAR', 'Gene', '103', (41, 45))
125262	33062411	A-to-I RNA editing, the most prevalent editing event found in our data, is carried out by the ADAR family of enzymes.	('ADAR', 'Gene', '103', (94, 98))	('ADAR', 'Gene', (94, 98))	('A-to-I RNA', 'Var', (0, 10))
125270	33062411	We also carried out Gene Ontology (GO) analysis to find pathways that get regulated by editing to understand further the role of RNA editing in gliomagenesis.	('editing', 'Var', (87, 94))	('glioma', 'Disease', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Disease', 'MESH:D005910', (144, 150))
125272	33062411	To identify proteins that are importantly regulated by editing in glioma, we identified genes from the above 14 pathways that get commonly altered in all the five datasets (Fig.	('glioma', 'Disease', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('editing', 'Var', (55, 62))	('glioma', 'Disease', 'MESH:D005910', (66, 72))
125288	33062411	Consequently, the protein levels of GABRA3 were found to be reduced in unedited GABRA3 overexpressing cells compared to those expressing the edited form (Fig.	('GABRA3', 'Chemical', '-', (36, 42))	('GABRA3', 'Gene', (80, 86))	('protein levels', 'MPA', (18, 32))	('reduced', 'NegReg', (60, 67))	('overexpressing', 'Var', (87, 101))	('GABRA3', 'Chemical', '-', (80, 86))
125292	33062411	A-to-I changes are the most common type of RNA editing events in mammals, especially in humans.	('changes', 'Var', (7, 14))	('A-to-I changes', 'Var', (0, 14))	('humans', 'Species', '9606', (88, 94))
125296	33062411	We also observed that majority of editing events are ADAR specific changes (A-to-I that is, A-to-G or T-to-C) followed by APOBEC specific changes (C-to-U that is, C-to-T or G-to-A) similar to previously reported studies.	('C-to-T', 'Var', (163, 169))	('T-to-C', 'Var', (102, 108))	('ADAR', 'Gene', '103', (53, 57))	('ADAR', 'Gene', (53, 57))
125309	33062411	From literature, we see that GABRA3 editing increases during brain development in rats with a simultaneous decrease in the expression.	('rats', 'Species', '10116', (82, 86))	('expression', 'MPA', (123, 133))	('increases', 'PosReg', (44, 53))	('decrease', 'NegReg', (107, 115))	('GABRA3', 'Var', (29, 35))	('GABRA3', 'Chemical', '-', (29, 35))
125310	33062411	However, in our study, we reveal that loss of editing in GABRA3 led to reduced gene expression levels in LGG and GBM samples from both TCGA and CGGA datasets.	('editing', 'Var', (46, 53))	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('GABRA3', 'Gene', (57, 63))	('gene expression levels', 'MPA', (79, 101))	('reduced', 'NegReg', (71, 78))	('loss', 'NegReg', (38, 42))	('GABRA3', 'Chemical', '-', (57, 63))
125311	33062411	Moreover, experimental studies revealed that loss of editing leads to reduced levels of GABRA3 RNA and protein accompanied by a more migratory and invasive phenotype of the glioma cell lines.	('reduced', 'NegReg', (70, 77))	('editing', 'Var', (53, 60))	('glioma', 'Disease', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('more', 'PosReg', (128, 132))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('loss', 'Var', (45, 49))	('GABRA3', 'Chemical', '-', (88, 94))
125312	33062411	This opposing regulation of GABRA3 by editing could be cell type-specific and development-specific.	('editing', 'Var', (38, 45))	('GABRA3', 'Chemical', '-', (28, 34))	('GABRA3', 'Gene', (28, 34))
125315	33062411	But during early developmental stages, the effect of GABRA3 editing is probably specific to the neuronal population due to the requirement of a switch of GABA response from excitatory to inhibitory post-synaptic potentials (Ben-Ari et al., Nat.	('GABRA3', 'Chemical', '-', (53, 59))	('GABA', 'Chemical', 'MESH:D005680', (154, 158))	('editing', 'Var', (60, 67))	('Nat', 'Gene', '6046', (240, 243))	('GABRA3', 'Gene', (53, 59))	('Nat', 'Gene', (240, 243))	('GABA response', 'MPA', (154, 167))
125316	33062411	In a recent study, it is shown that loss of editing in GABRA3 leads to invasive phenotype in breast cancer.	('GABRA3', 'Gene', (55, 61))	('editing', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('loss of editing', 'Var', (36, 51))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('GABRA3', 'Chemical', '-', (55, 61))
125317	33062411	In this study, we reveal the tumor suppressive nature of editing of GABRA3 in glioma which stresses on the requirement for the gene to be edited in normal scenario.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('GABRA3', 'Chemical', '-', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('editing', 'Var', (57, 64))	('tumor', 'Disease', (29, 34))	('glioma', 'Disease', (78, 84))	('GABRA3', 'Gene', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
125322	33062411	Thus, GABRA3 editing in glioma may lead to decrease in the protein which might be responsible for the aggressive tumor phenotype but this requires further validation in future.	('aggressive tumor', 'Disease', 'MESH:D001523', (102, 118))	('decrease', 'NegReg', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('aggressive tumor', 'Disease', (102, 118))	('protein', 'MPA', (59, 66))	('editing', 'Var', (13, 20))	('GABRA3', 'Chemical', '-', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Disease', (24, 30))	('GABRA3', 'Gene', (6, 12))
125324	33062411	Furthermore, the effect of loss of editing of GABRA3 during glioma progression highlights the importance of RNA editing for the maintenance of tissue homeostasis.	('GABRA3', 'Chemical', '-', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('GABRA3', 'Gene', (46, 52))	('glioma', 'Disease', (60, 66))	('editing', 'Var', (35, 42))	('loss', 'NegReg', (27, 31))
125343	28469392	High-throughput methods have been used to discover radiation-related miRNAs, and alterations in the levels of these miRNAs have been shown to modulate the radiosensitivity of several malignances, including glioblastoma, laryngeal carcinoma, and lung cancer.	('lung cancer', 'Disease', (245, 256))	('modulate', 'Reg', (142, 150))	('radiosensitivity', 'CPA', (155, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('glioblastoma', 'Disease', (206, 218))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('miR', 'Gene', '220972', (116, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('miR', 'Gene', (116, 119))	('glioblastoma', 'Disease', 'MESH:D005909', (206, 218))	('laryngeal carcinoma', 'Disease', (220, 239))	('alterations', 'Var', (81, 92))	('miR', 'Gene', (69, 72))	('miR', 'Gene', '220972', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (220, 239))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (220, 239))
125380	28469392	It could be that miRNAs are associated with the development of therapeutic resistance, and aberrant miRNA expression was implicated in cancer progression as well as radioresistance and chemoresistance in brain tumor.	('chemoresistance', 'CPA', (185, 200))	('cancer', 'Disease', (135, 141))	('brain tumor', 'Phenotype', 'HP:0030692', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('associated', 'Reg', (28, 38))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('radioresistance', 'CPA', (165, 180))	('brain tumor', 'Disease', (204, 215))	('aberrant', 'Var', (91, 99))	('implicated', 'Reg', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('brain tumor', 'Disease', 'MESH:D001932', (204, 215))
125418	30558313	Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (43, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (32, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mixed', 'Reg', (21, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (68, 82))	('neuroblastomas', 'Disease', 'MESH:D009447', (68, 82))	('pancreatic neuroendocrine tumors', 'Disease', (32, 64))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 64))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (43, 63))	('neuroblastomas', 'Disease', (68, 82))	('PPGLs', 'Var', (15, 20))
125425	30558313	Similarly, PPGLs are separated into 4 groups named after their molecular characteristics: pseudohypoxia related to succinate dehydrogenase or VHL/EPAS1 disturbances, wnt-altered and kinase-signaling pathways.	('pseudohypoxia', 'Disease', 'None', (90, 103))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('EPAS1', 'Gene', '2034', (146, 151))	('VHL', 'Disease', (142, 145))	('EPAS1', 'Gene', (146, 151))	('disturbances', 'Var', (152, 164))	('pseudohypoxia', 'Disease', (90, 103))
125465	30558313	Results showed a separation into two clusters, one consisting of low and high grade gliomas and a second including NBL, PNET, and PPGL (Figure 4, Supplementary Figures S10A-C and S11A-C).	('NBL', 'Phenotype', 'HP:0003006', (115, 118))	('S11A', 'Var', (179, 183))	('S10A', 'Var', (168, 172))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('S11A', 'SUBSTITUTION', 'None', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('S10A', 'SUBSTITUTION', 'None', (168, 172))
125483	30558313	This includes presence of both telomerase activation and alternative lengthening of telomeres due to ATRX or DAXX truncation as well as somatic or germline driver mutations in MEN1.	('telomerase', 'Enzyme', (31, 41))	('mutations', 'Var', (163, 172))	('DAXX', 'Gene', '1616', (109, 113))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('activation', 'PosReg', (42, 52))	('ATRX', 'Gene', (101, 105))	('DAXX', 'Gene', (109, 113))	('ATRX', 'Gene', '546', (101, 105))
125583	31686437	In terms of patients with diffuse astrocytoma, IDH-mutant and oligodendroglioma (IDH-mutant and 1p19q codeletion), standard brain radiotherapy and adjuvant PCV (procarbazine+lomustine+vincristine) combination chemotherapy should be considered primarily for the high-risk group while observation with regular follow up should be considered for the low-risk group.	('patients', 'Species', '9606', (12, 20))	('IDH', 'Gene', '3417', (47, 50))	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('oligodendroglioma', 'Disease', (62, 79))	('diffuse astrocytoma', 'Disease', (26, 45))	('IDH', 'Gene', '3417', (81, 84))	('1p19q', 'Var', (96, 101))	('procarbazine+lomustine+vincristine', 'Chemical', 'MESH:D008130', (161, 195))	('oligodendroglioma', 'Disease', 'MESH:D009837', (62, 79))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (26, 45))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', (47, 50))
125596	31686437	Major shifts in pathologic diagnosis of WHO grade II glioma included the use of molecular definitions for isocitrate dehydrogenase (IDH)-mutant astrocytomas, oligodendroglioma (IDH-mutant, 1p19q codeleted) and IDH-wildtype astrocytomas, resulting in the elimination of oligoastrocytoma as an integrated diagnosis.	('IDH', 'Gene', '3417', (210, 213))	('oligoastrocytoma', 'Disease', (269, 285))	('astrocytomas', 'Disease', (144, 156))	('IDH', 'Gene', '3417', (177, 180))	('astrocytomas', 'Disease', (223, 235))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('astrocytoma', 'Phenotype', 'HP:0009592', (223, 234))	('isocitrate dehydrogenase', 'Gene', '3417', (106, 130))	('grade II glioma', 'Disease', 'MESH:D005910', (44, 59))	('grade II glioma', 'Disease', (44, 59))	('-mutant', 'Var', (136, 143))	('astrocytomas', 'Disease', 'MESH:D001254', (144, 156))	('oligodendroglioma', 'Disease', 'MESH:D009837', (158, 175))	('IDH', 'Gene', (132, 135))	('astrocytomas', 'Disease', 'MESH:D001254', (223, 235))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('oligodendroglioma', 'Disease', (158, 175))	('IDH', 'Gene', (210, 213))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (269, 285))	('IDH', 'Gene', (177, 180))	('isocitrate dehydrogenase', 'Gene', (106, 130))	('IDH', 'Gene', '3417', (132, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (274, 285))
125618	31686437	Besides the importance of histopathological diagnosis of grade II glioma based on morphological features, codeletion of 1p19q testing and IDH1/2 mutation testing are also essential parts in the molecular diagnosis for grade II glioma.	('grade II glioma', 'Disease', 'MESH:D005910', (218, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('grade II glioma', 'Disease', (218, 233))	('IDH1/2', 'Gene', '3417;3418', (138, 144))	('grade II glioma', 'Disease', 'MESH:D005910', (57, 72))	('grade II glioma', 'Disease', (57, 72))	('IDH1/2', 'Gene', (138, 144))	('mutation', 'Var', (145, 153))
125619	31686437	ATP-dependent helicase (ATRX) mutation test is also required for workup of grade II gliomas.	('II gliomas', 'Disease', (81, 91))	('mutation', 'Var', (30, 38))	('ATRX', 'Gene', (24, 28))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('II gliomas', 'Disease', 'MESH:D005910', (81, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('grade II glioma', 'Disease', 'MESH:D005910', (75, 90))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('ATRX', 'Gene', '546', (24, 28))	('grade II glioma', 'Disease', (75, 90))
125623	31686437	The tumor is considered to have molecular features of glioblastoma if it has one or more of the following findings: 1) EGFR amplification, 2) combined whole chromosome 7 gain and whole chromosome 10 loss, and 3) TERT promoter mutation.	('tumor', 'Disease', (4, 9))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('TERT', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (212, 216))	('gain', 'PosReg', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('EGFR', 'Gene', '1956', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('amplification', 'Var', (124, 137))	('loss', 'NegReg', (199, 203))	('EGFR', 'Gene', (119, 123))	('glioblastoma', 'Disease', (54, 66))
125678	31686437	For patients with IDH1 mutants, there is evidence suggesting that a supra-marginal resection is the most appropriate.	('mutants', 'Var', (23, 30))	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', (18, 22))	('patients', 'Species', '9606', (4, 12))
125686	31686437	Although there are no identified targeted agents with demonstrate efficacy in WHO grade II cerebral glioma, the panel encourages molecular testing of tumors such as performing next generation sequencing because if a driver mutation is detected, it may be reasonable to treat the patient with a targeted therapy on a compassionate use basis.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cerebral glioma', 'Disease', 'MESH:D005910', (91, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('cerebral glioma', 'Disease', (91, 106))	('mutation', 'Var', (223, 231))	('patient', 'Species', '9606', (279, 286))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))
125688	31686437	IDH1 and IDH2 mutation testing is an essential part for workup of WHO grade II glioma.	('IDH2', 'Gene', (9, 13))	('grade II glioma', 'Disease', 'MESH:D005910', (70, 85))	('grade II glioma', 'Disease', (70, 85))	('IDH2', 'Gene', '3418', (9, 13))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('mutation', 'Var', (14, 22))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
125692	31686437	ATRX mutation test and MGMT gene promoter methylation test are also helpful for workup of WHO grade II gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('ATRX', 'Gene', (0, 4))	('grade II glioma', 'Disease', 'MESH:D005910', (94, 109))	('II gliomas', 'Disease', (100, 110))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('MGMT', 'Gene', '4255', (23, 27))	('grade II glioma', 'Disease', (94, 109))	('MGMT', 'Gene', (23, 27))	('ATRX', 'Gene', '546', (0, 4))	('mutation', 'Var', (5, 13))	('II gliomas', 'Disease', 'MESH:D005910', (100, 110))
125728	31686437	The 2016 Blue Book on CNS tumors states that the presence of an astrocytic "component" is compatible with the diagnosis of oligodendroglioma if it shows 1p19q codeletion and IDH mutation.	('1p19q codeletion', 'Var', (153, 169))	('CNS tumors', 'Disease', 'MESH:D016543', (22, 32))	('IDH', 'Gene', '3417', (174, 177))	('CNS tumor', 'Phenotype', 'HP:0100006', (22, 31))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('oligodendroglioma', 'Disease', 'MESH:D009837', (123, 140))	('CNS tumors', 'Disease', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('IDH', 'Gene', (174, 177))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('oligodendroglioma', 'Disease', (123, 140))
125729	31686437	This implies that only oligodendrogliomas and mixed oligodendroglioma-astrocytoma tumors need to be analyzed for 1p19q codeletion, whereas histologically pure astrocytomas do not.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('1p19q codeletion', 'Var', (113, 129))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('oligodendrogliomas', 'Disease', (23, 41))	('oligodendroglioma-astrocytoma tumors', 'Disease', 'MESH:D009837', (52, 88))	('astrocytomas', 'Disease', 'MESH:D001254', (159, 171))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('astrocytoma', 'Phenotype', 'HP:0009592', (159, 170))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('astrocytomas', 'Disease', (159, 171))	('oligodendroglioma-astrocytoma tumors', 'Disease', (52, 88))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (23, 41))
125730	31686437	On the other hand, according to the 2016 CNS WHO review article published in Acta Neuropathologica, a diffuse glioma that is histologically astrocytic but has 1p19q codeletion and IDH mutation necessitates a diagnosis of oligodendroglioma.	('glioma', 'Disease', (110, 116))	('glioma', 'Disease', (232, 238))	('IDH', 'Gene', (180, 183))	('oligodendroglioma', 'Disease', (221, 238))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('Acta Neuropathologica', 'Disease', 'None', (77, 98))	('oligodendroglioma', 'Disease', 'MESH:D009837', (221, 238))	('IDH', 'Gene', '3417', (180, 183))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('1p19q codeletion', 'Var', (159, 175))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('Acta Neuropathologica', 'Disease', (77, 98))
125775	21394775	Alterations in Gly levels are implicated in several diseases of the central nervous system.	('implicated', 'Reg', (30, 40))	('Gly', 'Chemical', 'MESH:D005998', (15, 18))	('Alterations', 'Var', (0, 11))	('Gly levels', 'MPA', (15, 25))
125805	21394775	Published metabolite T2 and T1 values were used; T2 = 150, 250, and 200 ms for Cr, NAA, and other metabolites, respectively, and T1 = 1.2 for mI, Glu and Gln, and 1.5 for other metabolites.	('mI', 'Chemical', 'MESH:D007294', (142, 144))	('Gln', 'Var', (154, 157))	('Glu', 'Chemical', 'MESH:D018698', (146, 149))	('NAA', 'Chemical', 'MESH:C000179', (83, 86))	('Gln', 'Chemical', 'MESH:D005973', (154, 157))	('Glu', 'Var', (146, 149))	('Cr', 'Chemical', '-', (79, 81))
125807	21394775	Figure 1 displays numerically-calculated PRESS spectra of mI (brown, thin) and mI+Gly (blue, thick) vs. the first and second subecho times TE1 and TE2 between 50 - 110 ms, for a concentration ratio of [mI]/[Gly] = 5.	('Gly', 'Chemical', 'MESH:D005998', (207, 210))	('TE2', 'Gene', '8260', (147, 150))	('Gly', 'Chemical', 'MESH:D005998', (82, 85))	('TE2', 'Gene', (147, 150))	('mI', 'Chemical', 'MESH:D007294', (58, 60))	('mI+Gly', 'Var', (79, 85))	('mI', 'Chemical', 'MESH:D007294', (202, 204))	('mI', 'Chemical', 'MESH:D007294', (79, 81))
125809	21394775	For TE1 and TE2 in 50 - 70 ms, the maximum amplitude of the mI multiplet appeared at the Gly ~3.55 ppm resonance, making it difficult to resolve Gly from the mI background signal.	('TE2', 'Gene', (12, 15))	('Gly', 'Chemical', 'MESH:D005998', (89, 92))	('Gly', 'MPA', (89, 92))	('mI', 'Chemical', 'MESH:D007294', (60, 62))	('mI', 'Chemical', 'MESH:D007294', (158, 160))	('TE1', 'Var', (4, 7))	('Gly', 'Chemical', 'MESH:D005998', (145, 148))	('TE2', 'Gene', '8260', (12, 15))
125818	21394775	For phantom-2, which contained Gly at [mI]/[Gly] = 5, Gly was not readily detectable in a STEAM spectrum due to the large mI signal.	('Gly', 'Chemical', 'MESH:D005998', (54, 57))	('Gly at [mI]/[', 'Var', (31, 44))	('mI', 'Chemical', 'MESH:D007294', (39, 41))	('Gly', 'Chemical', 'MESH:D005998', (44, 47))	('mI signal', 'MPA', (122, 131))	('mI', 'Chemical', 'MESH:D007294', (122, 124))	('Gly', 'Chemical', 'MESH:D005998', (31, 34))
125978	19708033	Although patients with glioblastoma multiforme and high-grade AST both had median survivals of4 months, their survival curves were different (log-rank test, P = .002; results not shown).	('patients', 'Species', '9606', (9, 17))	('high-grade', 'Var', (51, 61))	('glioblastoma multiforme', 'Disease', (23, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (23, 46))	('AST', 'Phenotype', 'HP:0009592', (62, 65))
125987	19708033	For example, a population study of patients of all ages found a median survival of 5.6 years in patients with low-grade AST and 11.6 years in patients with low-grade OLI, compared with 0.75 years and 4.75 years, respectively, in patients in the current study aged >=65 years.	('patients', 'Species', '9606', (229, 237))	('age', 'Gene', (259, 262))	('low-grade AST', 'Var', (110, 123))	('low-grade', 'Var', (156, 165))	('age', 'Gene', '5973', (259, 262))	('age', 'Gene', (51, 54))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (35, 43))	('AST', 'Phenotype', 'HP:0009592', (120, 123))	('patients', 'Species', '9606', (142, 150))	('age', 'Gene', '5973', (51, 54))
126012	19708033	Conservative management with more aggressive treatment at the time of disease recurrence or progression may be indicated for some patients, especially those with low-grade OLI who, even in this age group, demonstrated a median survival approaching 5 years.	('age', 'Gene', (194, 197))	('age', 'Gene', '5973', (16, 19))	('low-grade', 'Var', (162, 171))	('age', 'Gene', '5973', (194, 197))	('patients', 'Species', '9606', (130, 138))	('age', 'Gene', (16, 19))
126116	31693978	In 15 patients with lesions involving the left-sided language-eloquent brain areas (MTG, STG, IFG, angular gyrus), Krieg and colleagues performed bilateral repetitive navigated transcranial magnetic stimulation language mapping by measuring the error rate of an object-naming task for left and right hemisphere stimulation.	('STG', 'Gene', (89, 92))	('error', 'MPA', (245, 250))	('lesions', 'Var', (20, 27))	('STG', 'Gene', '29113', (89, 92))	('patients', 'Species', '9606', (6, 14))
126264	27835585	KLF4 knockdown attenuated glioma cells invasion and growth.	('knockdown', 'Var', (5, 14))	('attenuated', 'NegReg', (15, 25))	('KLF4', 'Gene', (0, 4))	('glioma', 'Disease', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
126286	27835585	Furthermore, for the analysis of overall survival (OS), glioma patients group with low FOXO1 protein level had significantly poorer OS than the patients group with high FOXO1 protein level (Figure 2B).	('low', 'Var', (83, 86))	('glioma', 'Disease', (56, 62))	('poorer', 'NegReg', (125, 131))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (63, 71))	('FOXO1', 'Gene', (87, 92))
126290	27835585	We firstly detected FOXO1 protein level in a series of human glioma cell lines and found that FOXO1 protein was relatively lowly expressed in the A172, U87MG, U118MG and U251MG glioma cell lines, compared with endogenous control beta-Actin (Figure 3A).	('U251MG', 'Var', (170, 176))	('lowly', 'NegReg', (123, 128))	('U118MG', 'CellLine', 'CVCL:0633', (159, 165))	('U87MG', 'CellLine', 'CVCL:0022', (152, 157))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('expressed', 'MPA', (129, 138))	('glioma', 'Disease', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('FOXO1', 'Gene', (94, 99))	('U251MG', 'CellLine', 'CVCL:0021', (170, 176))	('U87MG', 'Var', (152, 157))	('protein', 'Protein', (100, 107))	('human', 'Species', '9606', (55, 60))	('U118MG', 'Var', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioma', 'Disease', (61, 67))	('beta-Actin', 'Gene', (229, 239))	('beta-Actin', 'Gene', '728378', (229, 239))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
126293	27835585	As shown, FOXO1 overexpression significantly inhibited the invasive potential of U87MG and U251MG cells (Figure 3C).	('U251MG', 'CellLine', 'CVCL:0021', (91, 97))	('U251MG', 'Var', (91, 97))	('overexpression', 'PosReg', (16, 30))	('invasive potential', 'CPA', (59, 77))	('U87MG', 'CellLine', 'CVCL:0022', (81, 86))	('FOXO1', 'Gene', (10, 15))	('inhibited', 'NegReg', (45, 54))
126294	27835585	Moreover, ectopic FOXO1 expression markedly inhibited U87MG and U251MG cells proliferation in vitro (Figure 3D).	('inhibited', 'NegReg', (44, 53))	('U87MG', 'CellLine', 'CVCL:0022', (54, 59))	('U251MG', 'CellLine', 'CVCL:0021', (64, 70))	('FOXO1', 'Gene', (18, 23))	('ectopic', 'Var', (10, 17))
126296	27835585	We injected subcutaneously into the oxter of athymic mice with FOXO1 overexpressing U87MG and U251MG cell lines and their related control cell lines.	('U87MG', 'CellLine', 'CVCL:0022', (84, 89))	('overexpressing', 'PosReg', (69, 83))	('U87MG', 'Var', (84, 89))	('FOXO1', 'Gene', (63, 68))	('U251MG', 'Var', (94, 100))	('U251MG', 'CellLine', 'CVCL:0021', (94, 100))	('mice', 'Species', '10090', (53, 57))
126298	27835585	Tumors induced by FOXO1 overexpression cells were significantly smaller and lighter than tumors induced by control cells (Figure 3E).	('tumors', 'Disease', (89, 95))	('lighter', 'NegReg', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('Tumors', 'Disease', (0, 6))	('FOXO1', 'Gene', (18, 23))	('smaller', 'NegReg', (64, 71))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('overexpression', 'Var', (24, 38))
126306	27835585	Furthermore, for the analysis of overall survival (OS), glioma patients group with high KLF4 protein level had significantly worse OS than the patients group with low KLF4 protein level (Figure 4G).	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('patients', 'Species', '9606', (143, 151))	('high KLF4', 'Var', (83, 92))	('patients', 'Species', '9606', (63, 71))
126308	27835585	To examine the role of KLF4 in regulating FOXO1 expression, we firstly used shRNAs to knockdown KLF4 expression in U87MG and U251MG cells (Figure 5A).	('knockdown', 'Var', (86, 95))	('FOXO1', 'Gene', (42, 47))	('KLF4', 'Gene', (96, 100))	('U251MG', 'CellLine', 'CVCL:0021', (125, 131))	('U87MG', 'CellLine', 'CVCL:0022', (115, 120))
126310	27835585	Then, Chromatin immunoprecipitation-qPCR (ChIP-qPCR) assay further confirmed that KLF4 protein was exactly recruited to the two binding sites in the putative FOXO1 promoter in U87MG and U251MG cell lines and that KLF4 knockdown resulted into decrease of the binding level (Figure 5B).	('knockdown', 'Var', (218, 227))	('FOXO1', 'Gene', (158, 163))	('binding level', 'MPA', (258, 271))	('U251MG', 'CellLine', 'CVCL:0021', (186, 192))	('U87MG', 'CellLine', 'CVCL:0022', (176, 181))	('recruited', 'PosReg', (107, 116))	('decrease', 'NegReg', (242, 250))
126312	27835585	Experimental results indicated an increase of the wild-type FOXO1 promoter luciferase activity was observed in U87MG and U251MG cell lines after KLF4 knockdown, but without significant change on the binding sites mutant-type (Figure 5C).	('U87MG', 'CellLine', 'CVCL:0022', (111, 116))	('activity', 'MPA', (86, 94))	('knockdown', 'Var', (150, 159))	('U251MG', 'CellLine', 'CVCL:0021', (121, 127))	('FOXO1 promoter', 'Gene', (60, 74))	('increase', 'PosReg', (34, 42))
126316	27835585	As shown, KLF4 knockdown significantly inhibited the invasive potential of U87MG and U251MG cells (Figure 6A).	('inhibited', 'NegReg', (39, 48))	('knockdown', 'Var', (15, 24))	('U251MG', 'CellLine', 'CVCL:0021', (85, 91))	('KLF4', 'Gene', (10, 14))	('U87MG', 'CellLine', 'CVCL:0022', (75, 80))	('invasive potential', 'CPA', (53, 71))
126317	27835585	Moreover, KLF4 knockdown markedly inhibited U87MG and U251MG cells proliferation in vitro (Figure 6B).	('knockdown', 'Var', (15, 24))	('U251MG', 'CellLine', 'CVCL:0021', (54, 60))	('KLF4', 'Gene', (10, 14))	('inhibited', 'NegReg', (34, 43))	('U87MG', 'CellLine', 'CVCL:0022', (44, 49))
126319	27835585	We injected subcutaneously into the oxter of athymic mice with KLF4 knockdowned U87MG and U251MG cell lines and their related control cell lines.	('U87MG', 'CellLine', 'CVCL:0022', (80, 85))	('KLF4', 'Gene', (63, 67))	('U251MG', 'CellLine', 'CVCL:0021', (90, 96))	('mice', 'Species', '10090', (53, 57))	('knockdowned', 'Var', (68, 79))
126320	27835585	Tumors induced by KLF4 knockdowned cells were significantly smaller and lighter than tumors induced by control cells (Figure 6C).	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('lighter', 'NegReg', (72, 79))	('KLF4', 'Gene', (18, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('smaller', 'NegReg', (60, 67))	('knockdowned', 'Var', (23, 34))	('tumors', 'Disease', (85, 91))
126326	27835585	Our results showed that ectopic FOXO1 expression inhibited glioma cells invasive potential and inhibited glioma cells growth in vitro and in vivo.	('glioma', 'Disease', (59, 65))	('FOXO1', 'Gene', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('inhibited', 'NegReg', (95, 104))	('glioma', 'Disease', (105, 111))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('invasive potential', 'CPA', (72, 90))	('ectopic', 'Var', (24, 31))	('inhibited', 'NegReg', (49, 58))	('glioma', 'Disease', 'MESH:D005910', (105, 111))
126334	27835585	KLF4 knockdown up-regulated FOXO1 expression at both mRNA and protein levels in glioma cells.	('glioma', 'Disease', (80, 86))	('expression', 'MPA', (34, 44))	('knockdown', 'Var', (5, 14))	('FOXO1', 'Gene', (28, 33))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('up-regulated', 'PosReg', (15, 27))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
126353	27835585	Human glioma cell lines A172, U87MG, U118MG and U251MG were obtained from and maintained as recommended by the American Type Culture Collection (ATCC, Manassas, VA, USA).	('Human', 'Species', '9606', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('U87MG', 'CellLine', 'CVCL:0022', (30, 35))	('U251MG', 'Var', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('U251MG', 'CellLine', 'CVCL:0021', (48, 54))	('U87MG', 'Var', (30, 35))	('U118MG', 'Var', (37, 43))	('glioma', 'Disease', (6, 12))	('U118MG', 'CellLine', 'CVCL:0633', (37, 43))
126405	28049410	Each tumor folder includes a set of directories, each for a specific experiment type, containing the publicly available TCGA data of that experiment type for that tumor converted in BED format, and accordingly named, i.e., cnv, dnamethylation, dnaseq, mirnaseq, rnaseq, rnaseqv2.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (163, 168))	('dnamethylation', 'Var', (228, 242))	('tumor', 'Disease', (5, 10))
126419	28049410	This query applies on RNA-seq, DNA-methylation and DNA-seq data of TCGA Head and Neck Squamous Cell Carcinoma (HNSC) patients to find the DNA somatic mutations occurring within the first 2000 bp2 outside of the genes that are both expressed and methylated in at least one of these patients, and extracts these mutations of the top three patients with the highest number of such somatic mutations.	('Neck Squamous Cell Carcinoma', 'Disease', (81, 109))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('patients', 'Species', '9606', (281, 289))	('HNSC', 'Disease', (111, 115))	('HNSC', 'Disease', 'None', (111, 115))	('mutations', 'Var', (150, 159))	('Carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('patients', 'Species', '9606', (117, 125))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (81, 109))	('patients', 'Species', '9606', (337, 345))
126421	28049410	The second JOIN operator applies on this single sample data set and on the entire HNSC DNA-seq data set, and in each sample of the latter one it finds the DNA somatic mutations occurring within the first 2000 bp upstream or downstream of any of the expressed methylated genes extracted.	('HNSC', 'Disease', (82, 86))	('HNSC', 'Disease', 'None', (82, 86))	('mutations', 'Var', (167, 176))
126425	28049410	Leveraging on GMQL and TCGA data in BED format, this last example query shows how to easily combine heterogeneous datasets to answer complex biomedical questions, such as to select DNA somatic mutations potentially relevant in altering the regulation of gene expression, which is generally repressed by DNA methylation.	('mutations', 'Var', (193, 202))	('regulation', 'MPA', (240, 250))	('altering', 'Reg', (227, 235))	('GMQL', 'Chemical', '-', (14, 18))
126433	28049410	API Application program interface BED Browser extensible data BRCA Breast invasive carcinoma CNV Copy number variation CSV Comma separated value DNA Deoxyribonucleic acid FTP File transfer protocol GDC Genomic data commons GTF Gene transfer format GMQL GenoMetric query language GUI Graphical user interface HGNC HUGO gene nomenclature committee HNSC Head and neck squamous cell carcinoma HTTP Hyper text transfer protocol HUGO Human genome organisation ICGC International cancer genome consortium ID Identifier KIRC Kidney renal clear cell carcinoma LGG Lower grade glioma LUAD Lung adenocarcinoma miRNA microRNA NCBI National Center for Biotechnology Information REST REpresentational State transfer RNA Ribonucleic acid RPKM Reads per kilo base per million mapped reads SAM Sequence alignment/map TCGA The Cancer Genome Atlas UCSC University of California at Santa Cruz URL Uniform resource locator UUID Universally unique identifier VCF Variant call format XML eXtensible markup language	('glioma', 'Disease', (567, 573))	('neck squamous cell carcinoma', 'Disease', (360, 388))	('Kidney renal clear cell carcinoma', 'Disease', (517, 550))	('BRCA', 'Gene', '672', (62, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (365, 388))	('carcinoma', 'Phenotype', 'HP:0030731', (589, 598))	('glioma', 'Disease', 'MESH:D005910', (567, 573))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (360, 388))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (579, 598))	('carcinoma', 'Phenotype', 'HP:0030731', (541, 550))	('LUAD', 'Phenotype', 'HP:0030078', (574, 578))	('Human', 'Species', '9606', (428, 433))	('HUGO', 'Gene', '22862', (313, 317))	('HUGO', 'Gene', (423, 427))	('adenocarcinoma', 'Disease', (584, 598))	('Variant', 'Var', (941, 948))	('glioma', 'Phenotype', 'HP:0009733', (567, 573))	('cancer', 'Disease', 'MESH:D009369', (473, 479))	('BRCA', 'Gene', (62, 66))	('GMQL', 'Chemical', '-', (248, 252))	('HUGO', 'Gene', '22862', (423, 427))	('Breast invasive carcinoma', 'Disease', (67, 92))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (517, 550))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('adenocarcinoma', 'Disease', 'MESH:D000230', (584, 598))	('GDC', 'Chemical', '-', (198, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('Cancer', 'Phenotype', 'HP:0002664', (809, 815))	('HNSC', 'Disease', 'None', (346, 350))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (67, 92))	('BRCA', 'Phenotype', 'HP:0003002', (62, 66))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (67, 92))	('cancer', 'Disease', (473, 479))	('GTF', 'Chemical', '-', (223, 226))	('HNSC', 'Disease', (346, 350))	('cancer', 'Phenotype', 'HP:0002664', (473, 479))	('HUGO', 'Gene', (313, 317))
126443	32677981	Furthermore, we found that knockdown FTL dramatically repressed EMT and reduced migration and invasion of glioma by regulating AKT/GSK3beta/ beta-catenin signaling both in vitro and in vivo.	('reduced', 'NegReg', (72, 79))	('knockdown', 'Var', (27, 36))	('regulating', 'Reg', (116, 126))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('GSK3beta', 'Gene', (131, 139))	('GSK3beta', 'Gene', '2931', (131, 139))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('migration', 'CPA', (80, 89))	('repressed', 'NegReg', (54, 63))	('beta-catenin', 'Gene', (141, 153))	('FTL', 'Gene', (37, 40))	('invasion of', 'CPA', (94, 105))	('AKT', 'Gene', '207', (127, 130))	('beta-catenin', 'Gene', '1499', (141, 153))	('glioma', 'Disease', (106, 112))	('EMT', 'CPA', (64, 67))	('AKT', 'Gene', (127, 130))
126456	32677981	Hypoxia microenvironment promotes glioma cells aggressive phenotype by upregulating hypoxia-inducible factor (HIF) family.HIF1A is highly expressed in glioblastoma and significantly correlated with IDH1/2 mutation.	('hypoxia', 'Disease', (84, 91))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('HIF1A', 'Gene', (122, 127))	('HIF1A', 'Gene', '3091', (122, 127))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('Hypoxia', 'Disease', (0, 7))	('glioma cells aggressive', 'Disease', 'MESH:D005910', (34, 57))	('glioblastoma', 'Disease', (151, 163))	('IDH1', 'Gene', (198, 202))	('glioma cells aggressive', 'Disease', (34, 57))	('IDH1', 'Gene', '3417', (198, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('iron', 'Chemical', 'MESH:D007501', (16, 20))	('correlated', 'Reg', (182, 192))	('mutation', 'Var', (205, 213))
126488	32677981	U251 and U87 cells were transfected with Lentivirus for 72 h and treated with puromycin(4 mug/ml) for 7 days.The specific small interfering RNA (siRNA) for FTL (siG143101050 18-1-5),HIF1A(siG0811494537-1-5), CTNNB1(siB08220115 751-1-5), HIF2A (siG170217101514-1-5) and scramble siRNAs were purchased from RiboBio (Guangzhou, China).	('U251', 'CellLine', 'CVCL:0021', (0, 4))	('siG143101050', 'Var', (161, 173))	('HIF2A', 'Gene', '2034', (237, 242))	('CTNNB1', 'Gene', '1499', (208, 214))	('siG170217101514-1-5', 'Var', (244, 263))	('HIF1A', 'Gene', (182, 187))	('HIF1A', 'Gene', '3091', (182, 187))	('puromycin', 'Chemical', 'MESH:D011691', (78, 87))	('CTNNB1', 'Gene', (208, 214))	('HIF2A', 'Gene', (237, 242))
126548	32677981	Hypoxic area in glioma tissues always presented with more necrosis and microvascular proliferation (Mvp).	('microvascular proliferation', 'CPA', (71, 98))	('more', 'PosReg', (53, 57))	('necrosis', 'Disease', (58, 66))	('glioma', 'Disease', (16, 22))	('necrosis', 'Disease', 'MESH:D009336', (58, 66))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('Hypoxic', 'Var', (0, 7))	('glioma', 'Disease', 'MESH:D005910', (16, 22))
126557	32677981	To further determine the mechanism by which hypoxia induced FTL expression, we treated U87 and U251 cells with cobalt chloride (CoCl2,400 mM) for 24 h.The results showed that inhibition HIF1A degradation dramatically promoted the expression of FTL in glioma cells (Fig.	('FTL', 'Gene', (244, 247))	('U251', 'CellLine', 'CVCL:0021', (95, 99))	('cobalt chloride', 'Chemical', 'MESH:C018021', (111, 126))	('hypoxia', 'Disease', (44, 51))	('inhibition', 'Var', (175, 185))	('hypoxia', 'Disease', 'MESH:D000860', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('expression', 'MPA', (230, 240))	('HIF1A', 'Gene', (186, 191))	('promoted', 'PosReg', (217, 225))	('HIF1A', 'Gene', '3091', (186, 191))	('glioma', 'Disease', (251, 257))	('CoCl2', 'Chemical', 'MESH:C018021', (128, 133))
126559	32677981	2g-i).IF staining also confirmed that knockdown HIF1A in glioma cells decreased FTL expression (Figure S2C).	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('glioma', 'Disease', (57, 63))	('HIF1A', 'Gene', (48, 53))	('decreased', 'NegReg', (70, 79))	('HIF1A', 'Gene', '3091', (48, 53))	('FTL expression', 'MPA', (80, 94))	('knockdown', 'Var', (38, 47))	('glioma', 'Disease', 'MESH:D005910', (57, 63))
126562	32677981	FTL promoter activity was increased in response to hypoxia and knockdown HIF1A in U87 and U251 cells inhibited hypoxia induced FTL promoter activity (Fig.	('hypoxia', 'Disease', (111, 118))	('inhibited', 'NegReg', (101, 110))	('U251', 'CellLine', 'CVCL:0021', (90, 94))	('HIF1A', 'Gene', '3091', (73, 78))	('hypoxia', 'Disease', 'MESH:D000860', (111, 118))	('FTL promoter activity', 'MPA', (0, 21))	('increased', 'PosReg', (26, 35))	('hypoxia', 'Disease', (51, 58))	('hypoxia', 'Disease', 'MESH:D000860', (51, 58))	('HIF1A', 'Gene', (73, 78))	('FTL', 'Gene', (127, 130))	('knockdown', 'Var', (63, 72))
126563	32677981	Then we constructed mutant luciferase plasmid with ablation of HREs on FTL promoter by changing 5'-GCGTG-3' to 5'-GCTCT-3'.Our results showed that transfection of mutant-FTL-luc in U87 and U251 cells could dramatically abrogate hypoxia-mediated FTL induction when compared with cells that were transfected with wildtype FTL-Luc (Fig.	('hypoxia', 'Disease', (228, 235))	('hypoxia', 'Disease', 'MESH:D000860', (228, 235))	('U251', 'CellLine', 'CVCL:0021', (189, 193))	('mutant-FTL-luc', 'Var', (163, 177))	('abrogate', 'NegReg', (219, 227))
126570	32677981	Knockdown FTL obviously altered the morphology of U87 and U251 cells, namely from spindle shape to round shield with less pseudopods (Fig.	('spindle shape', 'CPA', (82, 95))	('round shield', 'CPA', (99, 111))	('altered', 'Reg', (24, 31))	('Knockdown', 'Var', (0, 9))	('U251', 'CellLine', 'CVCL:0021', (58, 62))	('FTL', 'Gene', (10, 13))
126571	32677981	Knocking down FTL inhibited the migration and invasion of U87 and U251 cells (Fig.	('Knocking down', 'Var', (0, 13))	('U251', 'CellLine', 'CVCL:0021', (66, 70))	('FTL', 'Gene', (14, 17))	('inhibited', 'NegReg', (18, 27))
126573	32677981	Results of western blot showed that knockdown FTL significantly reduced the expression of vimentin and snail1, but increased E-cadherin expression (Fig.	('vimentin', 'Gene', '7431', (90, 98))	('E-cadherin', 'Gene', '999', (125, 135))	('increased', 'PosReg', (115, 124))	('vimentin', 'Gene', (90, 98))	('FTL', 'Gene', (46, 49))	('snail1', 'Gene', (103, 109))	('knockdown', 'Var', (36, 45))	('expression', 'MPA', (76, 86))	('snail1', 'Gene', '6615', (103, 109))	('reduced', 'NegReg', (64, 71))	('E-cadherin', 'Gene', (125, 135))
126575	32677981	Immunofluorescence (IF) staining was then performed to verified our findings and the results showed knockdown FTL obviously altered expression of EMT related proteins of vimentin, snail1 in glioma cells (Figure S3G).	('knockdown', 'Var', (100, 109))	('vimentin', 'Gene', '7431', (170, 178))	('glioma', 'Disease', (190, 196))	('altered', 'Reg', (124, 131))	('vimentin', 'Gene', (170, 178))	('snail1', 'Gene', (180, 186))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('snail1', 'Gene', '6615', (180, 186))	('expression', 'MPA', (132, 142))	('FTL', 'Gene', (110, 113))
126578	32677981	Inhibition of HIF1A obviously enhanced the invasion of glioma cells, while hypoxia-enhanced invasion of glioma cells was blocked by knocking down FTL expression (Fig.	('glioma', 'Disease', (55, 61))	('hypoxia', 'Disease', (75, 82))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('enhanced', 'PosReg', (30, 38))	('HIF1A', 'Gene', (14, 19))	('FTL expression', 'Gene', (146, 160))	('knocking down', 'Var', (132, 145))	('HIF1A', 'Gene', '3091', (14, 19))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('Inhibition', 'Var', (0, 10))	('glioma', 'Disease', (104, 110))
126579	32677981	3i-j).What's more, silencing FTL significantly reduced the expression of hypoxia-enhanced EMT markers, such as snial1 and vimentin (Fig.	('silencing', 'Var', (19, 28))	('expression', 'MPA', (59, 69))	('FTL', 'Gene', (29, 32))	('hypoxia', 'Disease', (73, 80))	('hypoxia', 'Disease', 'MESH:D000860', (73, 80))	('vimentin', 'Gene', '7431', (122, 130))	('reduced', 'NegReg', (47, 54))	('vimentin', 'Gene', (122, 130))
126581	32677981	Then we used IHC to detect expression of EMT markers and the results showed that inhibition of FTL significantly reduced expression of snail1 and vimentin in vivo (Fig.	('vimentin', 'Gene', '7431', (146, 154))	('inhibition', 'Var', (81, 91))	('vimentin', 'Gene', (146, 154))	('expression', 'MPA', (121, 131))	('FTL', 'Gene', (95, 98))	('snail1', 'Gene', (135, 141))	('reduced', 'NegReg', (113, 120))	('snail1', 'Gene', '6615', (135, 141))
126584	32677981	In our validation cohort, we performed IHC staining and we found patients in high FTL expression group had higher level of beta-catenin when compared with patients in lower FTL expression group (Figure S4B-C).What's more, in glioma tissues with high FTL expression, the accumulation of beta-catenin in the nucleus was more common than in low FTL expression glioma tissues.	('beta-catenin', 'Gene', '1499', (123, 135))	('beta-catenin', 'Gene', (123, 135))	('beta-catenin', 'Gene', (286, 298))	('glioma', 'Disease', 'MESH:D005910', (357, 363))	('glioma', 'Phenotype', 'HP:0009733', (357, 363))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('glioma', 'Disease', (225, 231))	('patients', 'Species', '9606', (155, 163))	('beta-catenin', 'Gene', '1499', (286, 298))	('patients', 'Species', '9606', (65, 73))	('high FTL expression', 'Var', (245, 264))	('accumulation', 'PosReg', (270, 282))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioma', 'Disease', (357, 363))
126586	32677981	We found that knockdown FTL reduced the expression of beta-catenin, while overexpression FTL increase the expression of beta-catenin (Fig.	('expression', 'MPA', (40, 50))	('FTL', 'Gene', (24, 27))	('beta-catenin', 'Gene', '1499', (120, 132))	('reduced', 'NegReg', (28, 35))	('expression', 'MPA', (106, 116))	('beta-catenin', 'Gene', '1499', (54, 66))	('beta-catenin', 'Gene', (54, 66))	('knockdown', 'Var', (14, 23))	('beta-catenin', 'Gene', (120, 132))
126591	32677981	Then we performed WB to detect the expression of AKT,p-AKT,GSK3beta, p-GSK3beta and our results showed that knocking down FTL significantly inhibited the expression of p-AKT (ser473) and p-GSK3beta(ser9),but the expression of total AKT and GSK3beta had no significant change (Fig.	('ser473', 'Chemical', '-', (175, 181))	('AKT', 'Gene', '207', (232, 235))	('ser9', 'Chemical', '-', (198, 202))	('AKT', 'Gene', (55, 58))	('AKT', 'Gene', '207', (170, 173))	('inhibited', 'NegReg', (140, 149))	('GSK3beta', 'Gene', '2931', (71, 79))	('AKT', 'Gene', '207', (49, 52))	('GSK3beta', 'Gene', '2931', (189, 197))	('GSK3beta', 'Gene', (240, 248))	('AKT', 'Gene', '207', (55, 58))	('GSK3beta', 'Gene', '2931', (59, 67))	('ser473', 'Var', (175, 181))	('GSK3beta', 'Gene', (59, 67))	('AKT', 'Gene', (232, 235))	('GSK3beta', 'Gene', (71, 79))	('AKT', 'Gene', (170, 173))	('GSK3beta', 'Gene', (189, 197))	('GSK3beta', 'Gene', '2931', (240, 248))	('AKT', 'Gene', (49, 52))	('knocking down', 'Var', (108, 121))	('FTL', 'Gene', (122, 125))	('expression', 'MPA', (154, 164))
126596	32677981	We found that both IM-12 and beta-catenin plasmid could reversed the effects of FTL knockdown on cell invasion in U87 and U251 cells (Fig.	('IM-12', 'Chemical', '-', (19, 24))	('FTL', 'Gene', (80, 83))	('knockdown', 'Var', (84, 93))	('cell invasion', 'CPA', (97, 110))	('beta-catenin', 'Gene', (29, 41))	('beta-catenin', 'Gene', '1499', (29, 41))	('U251', 'CellLine', 'CVCL:0021', (122, 126))
126600	32677981	First, we used the CCK-8 assay to detect the survival rate of U87 and U251 cells treated with different concentrations of TMZ and the results showed that inhibition of FTL enhanced the efficacy of TMZ and decreased cell survival rate (Fig.	('inhibition', 'Var', (154, 164))	('enhanced', 'PosReg', (172, 180))	('U251', 'CellLine', 'CVCL:0021', (70, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (197, 200))	('efficacy', 'MPA', (185, 193))	('decreased', 'NegReg', (205, 214))	('FTL', 'Gene', (168, 171))	('TMZ', 'Chemical', 'MESH:D000077204', (122, 125))	('cell survival rate', 'CPA', (215, 233))
126607	32677981	Six nude mice were randomly divided into two groups and received two cycles of intraperitoneal injection of TMZ (50 mg/kg/day,5 day/cycle).FTL stable knockdown U87 cells generated smaller tumors than the cells expressing NC-shRNA under TMZ treatment (Figure S5F).	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('TMZ', 'Chemical', 'MESH:D000077204', (236, 239))	('knockdown', 'Var', (150, 159))	('smaller', 'NegReg', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('nude mice', 'Species', '10090', (4, 13))
126608	32677981	The growth of implanted tumors in mice injected with FTL-shRNA U87 cells were much lower than cells transfected with NC-shRNA (Figure S5G-H).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mice', 'Species', '10090', (34, 38))	('FTL-shRNA', 'Var', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('lower', 'NegReg', (83, 88))
126609	32677981	Furthermore, results of IHC staining also revealed that knockdown FTL in U87 cell significantly reduced the MGMT expression and increased cleaved-caspase3 expression (Figure S5I).	('caspase3', 'Gene', (146, 154))	('MGMT', 'Gene', (108, 112))	('MGMT', 'Gene', '4255', (108, 112))	('increased', 'PosReg', (128, 137))	('caspase3', 'Gene', '836', (146, 154))	('FTL', 'Gene', (66, 69))	('knockdown', 'Var', (56, 65))	('reduced', 'NegReg', (96, 103))
126616	32677981	Consistent with this findings, in LGG patients who expressed high FTL had shorter survival time than those expressed low FTL if they treated with TMZ at any time, whereas FTL expression wasn't significantly associated with survival time of patients who were treated with IR alone (Fig.	('shorter', 'NegReg', (74, 81))	('survival time', 'CPA', (82, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (146, 149))	('high FTL', 'Var', (61, 69))	('patients', 'Species', '9606', (240, 248))	('patients', 'Species', '9606', (38, 46))
126622	32677981	Furthermore, in LGG with high MGMT promoter methylation, FTL expression identified distinct survival groups.	('MGMT', 'Gene', (30, 34))	('high', 'Var', (25, 29))	('FTL', 'Gene', (57, 60))	('MGMT', 'Gene', '4255', (30, 34))
126624	32677981	Our data showed that patients with methylated MGMT who had high FTL expression presented similar prognosis with patients with unmethylated MGMT.	('expression', 'MPA', (68, 78))	('MGMT', 'Gene', (46, 50))	('MGMT', 'Gene', (139, 143))	('MGMT', 'Gene', '4255', (46, 50))	('patients', 'Species', '9606', (112, 120))	('MGMT', 'Gene', '4255', (139, 143))	('patients', 'Species', '9606', (21, 29))	('high', 'Var', (59, 63))	('FTL', 'Gene', (64, 67))
126643	32677981	Also, knocking down FTL dramatically altered glioma cell to blunt morphology and reduced the migration and invasion of glioma cells, as well as alter expression of snail and E-cadherin.	('expression', 'MPA', (150, 160))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('altered', 'Reg', (37, 44))	('snail', 'Gene', '6615', (164, 169))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('alter', 'Reg', (144, 149))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', (45, 51))	('E-cadherin', 'Gene', (174, 184))	('glioma', 'Disease', (119, 125))	('E-cadherin', 'Gene', '999', (174, 184))	('reduced', 'NegReg', (81, 88))	('snail', 'Gene', (164, 169))	('FTL', 'Gene', (20, 23))	('knocking down', 'Var', (6, 19))
126648	32677981	The nuclear accumulation of beta-catenin correlated with WHO grades and cytoplasmic- nuclear beta-catenin was an independent prognostic factors in glioma.FTL positively correlated with beta-catenin and the nuclear accumulation of beta-catenin was more common in glioma tissues with high FTL expression.	('beta-catenin', 'Gene', '1499', (185, 197))	('common', 'Reg', (252, 258))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('FTL', 'Gene', (287, 290))	('beta-catenin', 'Gene', (230, 242))	('glioma', 'Disease', (147, 153))	('beta-catenin', 'Gene', '1499', (230, 242))	('correlated', 'Reg', (169, 179))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('beta-catenin', 'Gene', (93, 105))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('beta-catenin', 'Gene', '1499', (93, 105))	('high', 'Var', (282, 286))	('nuclear accumulation', 'MPA', (206, 226))	('glioma', 'Disease', (262, 268))	('beta-catenin', 'Gene', (28, 40))	('beta-catenin', 'Gene', '1499', (28, 40))	('glioma', 'Disease', 'MESH:D005910', (262, 268))	('beta-catenin', 'Gene', (185, 197))
126650	32677981	We found that knocking down FTL in glioma cells dramatically reduced nucleus accumulation of beta-catenin and dramatical decrease of activity of beta-catenin signaling detected by Luciferase reporter system.	('FTL', 'Gene', (28, 31))	('beta-catenin', 'Gene', (93, 105))	('knocking down', 'Var', (14, 27))	('nucleus accumulation of', 'MPA', (69, 92))	('beta-catenin', 'Gene', (145, 157))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('beta-catenin', 'Gene', '1499', (93, 105))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('decrease', 'NegReg', (121, 129))	('beta-catenin', 'Gene', '1499', (145, 157))	('reduced', 'NegReg', (61, 68))	('glioma', 'Disease', (35, 41))
126652	32677981	In our study, inhibition of FTL inactivated AKT by phosphorylation (ser473) and decrease of the phosphorylation level of GSK3beta (ser9).	('FTL', 'Gene', (28, 31))	('GSK3beta', 'Gene', (121, 129))	('ser473', 'Chemical', '-', (68, 74))	('GSK3beta', 'Gene', '2931', (121, 129))	('AKT', 'Gene', '207', (44, 47))	('phosphorylation level', 'MPA', (96, 117))	('phosphorylation', 'MPA', (51, 66))	('AKT', 'Gene', (44, 47))	('inhibition', 'Var', (14, 24))	('ser9', 'Chemical', '-', (131, 135))	('decrease', 'NegReg', (80, 88))
126660	32677981	We found that hypoxia enhanced the invasion of glioma cells, while inhibition FTL in glioma cells could mostly eliminate hypoxia-promoted invasion.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('inhibition', 'Var', (67, 77))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('glioma', 'Disease', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', (85, 91))	('invasion', 'CPA', (35, 43))	('hypoxia', 'Disease', (14, 21))	('hypoxia', 'Disease', 'MESH:D000860', (14, 21))	('FTL', 'Gene', (78, 81))	('hypoxia', 'Disease', 'MESH:D000860', (121, 128))	('hypoxia', 'Disease', (121, 128))	('enhanced', 'PosReg', (22, 30))
126668	32677981	Consistent with these findings, we found thatknocking down FTL significantly inhibited the proliferation and increased apoptosis of glioma cells treated with TMZ(400 muM).	('glioma', 'Disease', (132, 138))	('inhibited', 'NegReg', (77, 86))	('apoptosis', 'CPA', (119, 128))	('muM', 'Gene', '56925', (166, 169))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('TMZ', 'Chemical', 'MESH:D000077204', (158, 161))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('proliferation', 'CPA', (91, 104))	('thatknocking down', 'Var', (41, 58))	('increased', 'PosReg', (109, 118))	('muM', 'Gene', (166, 169))	('FTL', 'Gene', (59, 62))
126670	32677981	Together, FTL could enhanced TMZ resistance and decreased the cytotoxic effect of TMZ therapy on glioma cells.	('enhanced', 'PosReg', (20, 28))	('glioma', 'Disease', (97, 103))	('TMZ', 'MPA', (29, 32))	('decreased', 'NegReg', (48, 57))	('cytotoxic effect', 'CPA', (62, 78))	('FTL', 'Var', (10, 13))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (29, 32))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
126687	29368212	The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033 The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('IDH', 'Gene', '3417', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('glioma', 'Disease', (162, 168))	('mutant', 'Var', (65, 71))	('DDR genes', 'Gene', (21, 30))	('glioma', 'Disease', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('IDH', 'Gene', (61, 64))	('patients', 'Species', '9606', (138, 146))
126690	29368212	Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG.	('tested', 'Reg', (8, 14))	('mutant', 'Var', (157, 163))	('EORTC', 'Chemical', '-', (126, 131))	('IDH', 'Gene', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('IDH', 'Gene', '3417', (201, 204))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('patients', 'Species', '9606', (114, 122))
126691	29368212	The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4.	('CpGs', 'Var', (33, 37))	('MLH3', 'Gene', '27030', (139, 143))	('MGMT', 'Gene', (133, 137))	('PFS', 'Disease', (85, 88))	('SMC4', 'Gene', '10051', (156, 160))	('MGMT', 'Gene', '4255', (133, 137))	('DDR genes', 'Gene', (46, 55))	('SMC4', 'Gene', (156, 160))	('MLH3', 'Gene', (139, 143))
126697	29368212	The prognosis of patients varies greatly depending on clinical factors (tumor size, patient's age) and the molecular subtype, oligodendroglioma: mutant for isocitrate dehydrogenase 1 or 2 (IDH1 or 2; IDHmt) with co-deletion of the chromosomal arms 1p and 19q (codel); or astrocytoma: with (IDHmt), or without IDH mutation (IDH wild type).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutant', 'Var', (145, 151))	('patient', 'Species', '9606', (17, 24))	('IDH', 'Gene', (200, 203))	('IDH', 'Gene', (309, 312))	('astrocytoma', 'Phenotype', 'HP:0009592', (271, 282))	('IDH', 'Gene', '3417', (200, 203))	('IDH1', 'Gene', (189, 193))	('IDH', 'Gene', (189, 192))	('oligodendroglioma', 'Disease', 'MESH:D009837', (126, 143))	('tumor', 'Disease', (72, 77))	('IDH', 'Gene', (323, 326))	('IDH', 'Gene', '3417', (309, 312))	('patients', 'Species', '9606', (17, 25))	('IDH', 'Gene', (290, 293))	('oligodendroglioma', 'Disease', (126, 143))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('patient', 'Species', '9606', (84, 91))	('astrocytoma', 'Disease', 'MESH:D001254', (271, 282))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('IDH1', 'Gene', '3417', (189, 193))	('astrocytoma', 'Disease', (271, 282))	('IDH', 'Gene', '3417', (189, 192))	('IDH', 'Gene', '3417', (323, 326))	('IDH', 'Gene', '3417', (290, 293))
126707	29368212	The majority of low-grade glioma harbor an IDH1 or 2 mutation, which is associated with a glioma CpG island methylator phenotype (G-CIMP).	('glioma', 'Disease', (90, 96))	('mutation', 'Var', (53, 61))	('associated', 'Reg', (72, 82))	('IDH1', 'Gene', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('G-CIMP', 'Chemical', '-', (130, 136))	('glioma', 'Disease', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1', 'Gene', '3417', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
126708	29368212	This implies that a large number of genes are epigenetically inactivated by promoter methylation, impacting cancer-relevant pathways and potentially modulating treatment response.	('impacting', 'Reg', (98, 107))	('treatment response', 'CPA', (160, 178))	('promoter methylation', 'Var', (76, 96))	('modulating', 'Reg', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
126715	29368212	The trial design of EORTC 22033 comprised a 2-step process: first, patients were registered and tumor tissue was submitted for central pathology review and determination of the deletion status of chromosome 1p (stratification factor).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (67, 75))	('deletion', 'Var', (177, 185))	('tumor', 'Disease', (96, 101))	('EORTC', 'Chemical', '-', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
126721	29368212	A three Gaussian mixture model based on M values was used to establish the DNA methylation status of probes in non-tumoral brain tissue (NTB) in order to remove methylated and hemi-methylated probes.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('remove', 'NegReg', (154, 160))	('tumor', 'Disease', (115, 120))	('hemi-methylated', 'Var', (176, 191))	('methylated', 'MPA', (161, 171))	('tumoral brain tissue', 'Phenotype', 'HP:0030692', (115, 135))	('tumoral brain', 'Phenotype', 'HP:0030692', (115, 128))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
126723	29368212	The list of DDR genes was adopted from Pearl et al.. A list of 167235 CpGs was detected in promoter regions and 101981 CpGs were considered as unmethylated in non-tumoral brain tissue.	('101981', 'Var', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumoral brain tissue', 'Phenotype', 'HP:0030692', (163, 183))	('tumor', 'Disease', (163, 168))	('tumoral brain', 'Phenotype', 'HP:0030692', (163, 176))
126725	29368212	In brief, the M values of the methylation probes cg12434587 and cg12981137 were used as input into the logistic regression model (MGMT-STP27).	('MGMT-STP27', 'Gene', '4255', (130, 140))	('cg12434587', 'Var', (49, 59))	('MGMT-STP27', 'Gene', (130, 140))	('cg12981137', 'Var', (64, 74))
126738	29368212	Classification of the samples into WHO subgroups based on the methylation data identified 40 (30.3%) G-CIMP 1p/19q codel ('oligodendroglioma'), 80 (60.6%) G-CIMP 1p/19q non-codel ('astrocytoma, IDHmt'), and 12 (9.1%) non-CIMP ('astrocytoma, IDHwt') tumors.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('IDH', 'Gene', '3417', (241, 244))	("'oligodendroglioma'", 'Disease', 'MESH:D009837', (122, 141))	('astrocytoma', 'Disease', 'MESH:D001254', (228, 239))	('astrocytoma', 'Disease', (228, 239))	('IDH', 'Gene', '3417', (194, 197))	('astrocytoma', 'Disease', 'MESH:D001254', (181, 192))	('astrocytoma', 'Disease', (181, 192))	('non-codel', 'Var', (169, 178))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('G-CIMP 1p/19q codel', 'Var', (101, 120))	('G-CIMP', 'Chemical', '-', (155, 161))	('G-CIMP 1p/19q non-codel', 'Var', (155, 178))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('G-CIMP', 'Chemical', '-', (101, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (228, 239))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('IDH', 'Gene', (241, 244))	('astrocytoma', 'Phenotype', 'HP:0009592', (181, 192))	("'oligodendroglioma'", 'Disease', (122, 141))	('IDH', 'Gene', (194, 197))	('tumors', 'Disease', (249, 255))
126739	29368212	There were less biopsy-only patients in our cohort, as expected, and the association of the 1p/19q codeletion status and PFS was different.	('patients', 'Species', '9606', (28, 36))	('1p/19q codeletion status', 'Var', (92, 116))	('PFS', 'Disease', (121, 124))
126741	29368212	Where both were available, G-CIMP and IDH1/2 mutation information agree almost perfectly, 100% for TCGA-1 and TCGA-2, 97.56% for EORTC 22033, and 97.42% for AGlioma.	('AGlioma', 'Disease', (157, 164))	('TCGA-1', 'Gene', (99, 105))	('EORTC', 'Chemical', '-', (129, 134))	('EORTC 22033', 'Var', (129, 140))	('AGlioma', 'Disease', 'None', (157, 164))	('G-CIMP', 'Chemical', '-', (27, 33))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('IDH1/2', 'Gene', (38, 44))	('TCGA-2', 'Gene', (110, 116))
126755	29368212	The functional probeset included MGMT that is of known relevance for DNA repair associated with TMZ treatment-induced lesions, and the putative mismatch repair (MMR) gene MLH3.	('TMZ', 'Chemical', 'MESH:D000077204', (96, 99))	('MLH3', 'Gene', '27030', (171, 175))	('MLH3', 'Gene', (171, 175))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (33, 37))	('lesions', 'Var', (118, 125))
126756	29368212	POLE4, or homologous recombination (HR), e.g.	('POLE4', 'Gene', '56655', (0, 5))	('POLE4', 'Gene', (0, 5))	('homologous recombination', 'Var', (10, 34))
126767	29368212	The top up-regulated DDR gene in IDHmt codeleted tumors was hTERT, whose activating promoter mutations are known to be correlated with overexpression and 1p/19q codeletion (supplementary Table S3, Online Resource 3).	('hTERT', 'Gene', (60, 65))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('up-regulated', 'PosReg', (8, 20))	('IDH', 'Gene', '3417', (33, 36))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('IDH', 'Gene', (33, 36))	('S3, Online Resource 3', 'Gene', '6188', (193, 214))	('DDR gene', 'Gene', (21, 29))
126789	29368212	Here we set out to investigate whether epigenetic inactivation of DDR genes affected the patients' benefit (PFS, time lapse from initial surgery to treatment failure upon randomization to RT or TMZ therapy) from genotoxic treatment with either RT or TMZ in EORTC 22033.	('TMZ', 'Chemical', 'MESH:D000077204', (194, 197))	('TMZ', 'Chemical', 'MESH:D000077204', (250, 253))	('DDR genes', 'Gene', (66, 75))	('patients', 'Species', '9606', (89, 97))	('EORTC', 'Chemical', '-', (257, 262))	('epigenetic inactivation', 'Var', (39, 62))	('affected', 'Reg', (76, 84))
126798	29368212	This is in agreement with the clinical observation of a worse PFS of IDHmt non-codeleted patients when treated with TMZ, while there was no difference when treated with radiotherapy.	('IDH', 'Gene', (69, 72))	('PFS', 'MPA', (62, 65))	('IDH', 'Gene', '3417', (69, 72))	('TMZ', 'Var', (116, 119))	('patients', 'Species', '9606', (89, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (116, 119))
126800	29368212	In IDHmt LGG the MGMT methylation score summarizes methylation of two MGMT alleles, while GBM harbor frequent loss of one allele (> 80%; CHR 10q26), and the methylation of the retained allele informs on inactivation of the MGMT gene.	('MGMT', 'Gene', (223, 227))	('loss', 'NegReg', (110, 114))	('IDH', 'Gene', '3417', (3, 6))	('MGMT', 'Gene', '4255', (223, 227))	('MGMT', 'Gene', (70, 74))	('inactivation', 'NegReg', (203, 215))	('methylation', 'MPA', (51, 62))	('MGMT', 'Gene', '4255', (70, 74))	('methylation', 'Var', (157, 168))	('MGMT', 'Gene', '4255', (17, 21))	('MGMT', 'Gene', (17, 21))	('IDH', 'Gene', (3, 6))
126801	29368212	Thus, a high MGMT methylation score increases the probability of inactivating both MGMT alleles.	('MGMT', 'Gene', '4255', (83, 87))	('MGMT', 'Gene', (83, 87))	('methylation', 'Var', (18, 29))	('MGMT', 'Gene', (13, 17))	('MGMT', 'Gene', '4255', (13, 17))
126802	29368212	Methylation of three CpGs in the MLH3 promoter appear predictive for benefit from RT.	('MLH3', 'Gene', (33, 37))	('Methylation', 'Var', (0, 11))	('MLH3', 'Gene', '27030', (33, 37))	('benefit', 'PosReg', (69, 76))
126804	29368212	Germline mutations in MLH3 have been associated with the Lynch syndrome, although not fulfilling the Amsterdam I criteria, and with an unclear clinical role.	('Germline mutations', 'Var', (0, 18))	('MLH3', 'Gene', (22, 26))	('Lynch syndrome', 'Disease', (57, 71))	('associated', 'Reg', (37, 47))	('Lynch syndrome', 'Disease', 'MESH:D003123', (57, 71))	('MLH3', 'Gene', '27030', (22, 26))
126805	29368212	Frequent MLH3 methylation in IDHmt LGG has been reported previously; MLH3 may be involved in other cancer-relevant processes.	('involved', 'Reg', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('methylation', 'Var', (14, 25))	('MLH3', 'Gene', (69, 73))	('IDH', 'Gene', (29, 32))	('MLH3', 'Gene', '27030', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('IDH', 'Gene', '3417', (29, 32))	('MLH3', 'Gene', '27030', (9, 13))	('MLH3', 'Gene', (9, 13))
126808	29368212	Genes encoding members of the cohesion complex are targeted by deletion or mutation in 16% of LGG/GBM, suggestive of a glioma genesis relevant role of the pathway.	('LGG/GBM', 'Gene', (94, 101))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('mutation', 'Var', (75, 83))	('glioma', 'Disease', (119, 125))	('deletion', 'Var', (63, 71))
126811	29368212	In breast cancer inactivation of BRCA1 and/or 2 by promoter methylation is currently considered for treatment with the same PARP inhibitor in a trial (clinicaltrial.gov, NCT03205761).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('PARP', 'Gene', '1302', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('PARP', 'Gene', (124, 128))	('BRCA1', 'Gene', '672', (33, 38))	('BRCA1', 'Gene', (33, 38))	('inactivation', 'NegReg', (17, 29))	('promoter methylation', 'Var', (51, 71))
126813	29368212	Along the same lines, PARP inhibitors may be useful for LGG patients with promoter methylation of MLH3, or XRCC1 that when defective have been reported to render cells sensitive to PARP inhibition, and are therefore discussed as being potentially amenable to PARP inhibitor treatments.	('PARP', 'Gene', (22, 26))	('MLH3', 'Gene', '27030', (98, 102))	('XRCC1', 'Gene', '7515', (107, 112))	('PARP', 'Gene', '1302', (181, 185))	('PARP', 'Gene', (181, 185))	('MLH3', 'Gene', (98, 102))	('patients', 'Species', '9606', (60, 68))	('LGG', 'Disease', (56, 59))	('XRCC1', 'Gene', (107, 112))	('PARP', 'Gene', '1302', (259, 263))	('promoter methylation', 'Var', (74, 94))	('sensitive', 'MPA', (168, 177))	('PARP', 'Gene', (259, 263))	('PARP', 'Gene', '1302', (22, 26))
126817	29368212	The current efforts to promote the HM-450K methylation platform (or the more recent version, EPIC) as a diagnostic tool for classification of brain tumors, will make the here identified markers potentially evaluable in routine diagnostics and may allow validation of the presented results.	('brain tumors', 'Disease', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('HM-450K', 'Var', (35, 42))	('brain tumors', 'Phenotype', 'HP:0030692', (142, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('brain tumors', 'Disease', 'MESH:D001932', (142, 154))
126821	29368212	We have focused our investigations to epigenetically silenced DDR genes, since promoter methylation seems to be quite stable in tumors and may not easily change under treatment.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('DDR genes', 'Gene', (62, 71))	('epigenetically silenced', 'Var', (38, 61))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
126822	29368212	While mutations in DDR genes are exceedingly rare in chemo-naive LGG, with the exception of TERTp and ATRX, there are other mechanisms attenuating relevant DNA repair systems.	('ATRX', 'Gene', (102, 106))	('TERTp', 'Gene', '7015', (92, 97))	('attenuating', 'NegReg', (135, 146))	('ATRX', 'Gene', '546', (102, 106))	('TERTp', 'Gene', (92, 97))	('DDR genes', 'Gene', (19, 28))	('mutations', 'Var', (6, 15))	('DNA repair systems', 'MPA', (156, 174))
126824	29368212	2HG, produced by the neomorphic function of the IDH1 and 2 mutants is accumulated to high concentrations in the respective tumors and may confer sensitivity to alkylating agent chemotherapy and protracted natural history.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('mutants', 'Var', (59, 66))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('IDH1 and 2', 'Gene', '3417;3418', (48, 58))	('sensitivity', 'MPA', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
126860	26294301	alanine in meningiomas, taurine in medulloblastomas) or in pyogenic abscesses as byproducts of fermentation (e.g.	('abscesses', 'Phenotype', 'HP:0025615', (68, 77))	('medulloblastomas', 'Disease', 'MESH:D008527', (35, 51))	('taurine', 'Chemical', 'MESH:D013654', (24, 31))	('taurine', 'MPA', (24, 31))	('alanine', 'Var', (0, 7))	('meningiomas', 'Phenotype', 'HP:0002858', (11, 22))	('medulloblastomas', 'Disease', (35, 51))	('meningiomas', 'Disease', (11, 22))	('pyogenic abscesses', 'Disease', (59, 77))	('meningiomas', 'Disease', 'MESH:D008577', (11, 22))	('alanine', 'Chemical', 'MESH:D000409', (0, 7))
126872	26294301	Dynamic susceptibility-contrast (DSC) T2- and/or T2*-weighted MR perfusion is similarly obtained during first-pass rapid IV bolus of gadolinium-contrast, resulting in a first-pass drop in MR signal that can characterize vessel density (macro-vessel and/or micro-vessel, depending on the precise sequence employed) in the form of relative CBV measured within a lesion of interest.	('gadolinium', 'Chemical', 'MESH:D005682', (133, 143))	('T2*-weighted', 'Var', (49, 61))	('T2-', 'Var', (38, 41))	('MR signal', 'MPA', (188, 197))	('drop', 'NegReg', (180, 184))
126875	26294301	T1 DCE images are typically higher resolution with fewer magnetic susceptibility artifacts than are T2/T2* DSC images, and while MR signal intensity does not scale linearly with gadolinium contrast concentration, this scaling problem is worse for T2/T2* DSC imaging than for T1 DCE.	('gadolinium', 'Chemical', 'MESH:D005682', (178, 188))	('fewer', 'NegReg', (51, 56))	('higher', 'PosReg', (28, 34))	('T1 DCE', 'Var', (0, 6))	('magnetic susceptibility artifacts', 'MPA', (57, 90))
126971	26294301	In a more recent prospective study of glioma patients (14 WHO grade IV, 9 grade II or III) who underwent both FMISO PET and FDG PET exams, FMISO PET showed an improved ability to distinguish GBM from lower grades as compared with FDG.	('FDG', 'Chemical', 'MESH:D019788', (124, 127))	('improved', 'PosReg', (159, 167))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('FMISO', 'Var', (139, 144))	('GBM', 'Disease', (191, 194))	('patients', 'Species', '9606', (45, 53))	('glioma', 'Disease', (38, 44))	('FDG', 'Chemical', 'MESH:D019788', (230, 233))
126990	26294301	For example, different markers for cellular proliferation (low ADC, elevated Cho, increased 18F-fluorothymidine) and tumor vascularity (elevated perfusion by DCE, DSC and ASL) have been shown to identify similar areas for surgical sampling in a variety of high- and low-grade gliomas.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('ASL', 'Disease', (171, 174))	('Cho', 'Chemical', 'MESH:D002794', (77, 80))	('tumor', 'Disease', (117, 122))	('gliomas', 'Disease', (276, 283))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('gliomas', 'Disease', 'MESH:D005910', (276, 283))	('ASL', 'Disease', 'MESH:D056807', (171, 174))	('elevated', 'PosReg', (68, 76))	('low', 'Var', (59, 62))	('increased', 'PosReg', (82, 91))	('Cho', 'MPA', (77, 80))	('ADC', 'MPA', (63, 66))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('18F-fluorothymidine', 'Chemical', '-', (92, 111))
127001	25785246	This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway.	('RAS', 'Gene', (57, 60))	('RAF', 'Gene', '22882', (65, 68))	('RAF', 'Gene', (65, 68))	('mutation', 'Var', (26, 34))	('occurs through', 'Reg', (11, 25))
127003	25785246	Initially reported as a point mutation (V600E) in the majority of metastatic melanomas, other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer, colon carcinomas, hairy cell leukemia, and more recently in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (272, 279))	('melanomas', 'Disease', (77, 86))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (230, 249))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('V600E', 'Var', (40, 45))	('reported', 'Reg', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (186, 210))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (186, 210))	('thyroid cancer', 'Phenotype', 'HP:0002890', (196, 210))	('gliomas', 'Disease', (272, 279))	('hairy cell leukemia', 'Disease', (230, 249))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('colon carcinomas', 'Disease', (212, 228))	('colon carcinomas', 'Disease', 'MESH:D015179', (212, 228))	('gliomas', 'Disease', 'MESH:D005910', (272, 279))	('alterations', 'Var', (94, 105))	('BRAF', 'Gene', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('human', 'Species', '9606', (162, 167))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('leukemia', 'Phenotype', 'HP:0001909', (241, 249))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('papillary thyroid cancer', 'Disease', (186, 210))
127004	25785246	The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('MEK', 'Gene', (264, 267))	('inhibition', 'NegReg', (250, 260))	('mutations', 'Var', (32, 41))	('MAPK pathway', 'Pathway', (175, 187))	('inhibition', 'NegReg', (217, 227))	('BRAF', 'Protein', (212, 216))	('BRAF', 'Gene', (49, 53))	('affect', 'Reg', (164, 170))
127011	25785246	PAs of the optic tract are common in the hereditary syndrome neurofibromatosis type 1 and are commonly associated with defect in the NF1 gene.	('PAs of the optic tract', 'Disease', (0, 22))	('associated', 'Reg', (103, 113))	('NF1', 'Gene', (133, 136))	('hereditary syndrome neurofibromatosis type', 'Disease', 'MESH:C537392', (41, 83))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (61, 78))	('NF1', 'Gene', '4763', (133, 136))	('hereditary syndrome neurofibromatosis type', 'Disease', (41, 83))	('defect', 'Var', (119, 125))	('common', 'Reg', (27, 33))
127021	25785246	Mutations in the GNAQ gene are thought to lead to constitutive activation of the MAPK pathway, independent of BRAF.	('GNAQ', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('MAPK pathway', 'Pathway', (81, 93))	('activation', 'PosReg', (63, 73))	('GNAQ', 'Gene', '2776', (17, 21))
127022	25785246	Characterization of mutant proteins has revealed a mutation hotspot resulting in a valine to glutamate substitution at position 600, often referred to as BRAF V600E in a range of tumor types.	('V600E', 'Mutation', 'rs113488022', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('valine to glutamate substitution at position 600', 'Mutation', 'rs113488022', (83, 131))	('mutant', 'Var', (20, 26))	('valine', 'MPA', (83, 89))	('tumor', 'Disease', (179, 184))
127024	25785246	The oncogenic V600E mutation lies within the activation segment disrupting the auto-inhibitory mechanism and converting BRAF into its active form thus allowing constitutive activation of the MAPK pathway.	('BRAF', 'MPA', (120, 124))	('V600E', 'Var', (14, 19))	('converting', 'Reg', (109, 119))	('activation', 'PosReg', (173, 183))	('MAPK pathway', 'Pathway', (191, 203))	('disrupting', 'NegReg', (64, 74))	('allowing', 'Reg', (151, 159))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('auto-inhibitory mechanism', 'MPA', (79, 104))
127025	25785246	demonstrated that overexpression of the mutant BRAF V600E kinase domain alone induced tumor formation with clinical and histological features of PAs whereas the full length V600E mutant protein which still contained the autoregulatory domain did not give rise to tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('V600E', 'Mutation', 'rs113488022', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Disease', (86, 91))	('BRAF', 'Gene', (47, 51))	('induced', 'Reg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Disease', (263, 268))	('PAs', 'Disease', (145, 148))	('mutant', 'Var', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('V600E', 'Mutation', 'rs113488022', (52, 57))
127026	25785246	In inkk4a/ARF-deficient mice, the full length BRAF V600E could induce tumorigenesis but these more closely resembled high-grade astrocytomas.	('astrocytomas', 'Disease', (128, 140))	('BRAF', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', (70, 75))	('V600E', 'Var', (51, 56))	('ARF-deficient', 'Disease', 'MESH:D058186', (10, 23))	('ARF-deficient', 'Disease', (10, 23))	('induce', 'PosReg', (63, 69))	('astrocytomas', 'Disease', 'MESH:D001254', (128, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
127029	25785246	With loss of ARF and the RAF1 mutation, mice developed lesions similar to glioblastoma, yet without ARF loss, small hyperplastic lesions developed which may represent tumors more similar to PAs.	('glioblastoma', 'Disease', (74, 86))	('ARF loss', 'Disease', (100, 108))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('mutation', 'Var', (30, 38))	('loss of ARF', 'Disease', 'MESH:D015431', (5, 16))	('RAF1', 'Gene', (25, 29))	('loss of ARF', 'Disease', (5, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('ARF loss', 'Disease', 'MESH:D015431', (100, 108))	('small hyperplastic lesions', 'Disease', 'MESH:D051437', (110, 136))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mice', 'Species', '10090', (40, 44))	('small hyperplastic lesions', 'Disease', (110, 136))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
127030	25785246	reported that the presence of BRAF V600E alone was insufficient for gliomagenesis and a concomitant homozygous deletion of CDKN2A (which encodes P14ARF and P16INK4A) was required for the development of astrocytomas from neural progenitor cells (Figure 1).	('insufficient for gliomagenesis', 'Disease', (51, 81))	('astrocytomas', 'Disease', 'MESH:D001254', (202, 214))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('P16INK4A', 'Gene', '1029', (156, 164))	('V600E', 'Var', (35, 40))	('P14ARF', 'Gene', (145, 151))	('insufficient for gliomagenesis', 'Disease', 'MESH:D000309', (51, 81))	('astrocytoma', 'Phenotype', 'HP:0009592', (202, 213))	('astrocytomas', 'Disease', (202, 214))	('CDKN2A', 'Gene', (123, 129))	('CDKN2A', 'Gene', '1029', (123, 129))	('P14ARF', 'Gene', '1029', (145, 151))	('V600E', 'Mutation', 'rs113488022', (35, 40))	('deletion', 'Var', (111, 119))	('P16INK4A', 'Gene', (156, 164))
127031	25785246	It was demonstrated that expression of BRAFV600E may cause transformation when combined with loss of CDKN2A in human neural progenitor cells and the resultant tumors displayed the histology of malignant astrocytomas.	('cause', 'Reg', (53, 58))	('CDKN2A', 'Gene', (101, 107))	('malignant astrocytomas', 'Disease', 'MESH:D020339', (193, 215))	('loss', 'NegReg', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('human', 'Species', '9606', (111, 116))	('CDKN2A', 'Gene', '1029', (101, 107))	('tumors', 'Disease', (159, 165))	('displayed', 'Reg', (166, 175))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('astrocytoma', 'Phenotype', 'HP:0009592', (203, 214))	('transformation', 'Disease', (59, 73))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('BRAFV600E', 'Var', (39, 48))	('malignant astrocytomas', 'Disease', (193, 215))
127032	25785246	Outwith the glioma biology field, it has been proposed that the BRAF V600E mutation may be responsible for the induction of growth arrest and senescence in melanocytic naevi, in a process termed "oncogene-induced senescence" whereby melanocytic naevi can remain in growth arrest for a lifetime.	('growth arrest', 'Disease', 'MESH:D006323', (265, 278))	('V600E', 'Var', (69, 74))	('growth arrest', 'Phenotype', 'HP:0001510', (124, 137))	('senescence', 'CPA', (142, 152))	('growth arrest', 'Phenotype', 'HP:0001510', (265, 278))	('glioma', 'Disease', (12, 18))	('BRAF', 'Gene', (64, 68))	('naevi', 'Phenotype', 'HP:0003764', (168, 173))	('melanocytic naevi', 'Phenotype', 'HP:0000995', (233, 250))	('growth arrest', 'Disease', 'MESH:D006323', (124, 137))	('naevi', 'Phenotype', 'HP:0003764', (245, 250))	('growth arrest', 'Disease', (124, 137))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('growth arrest', 'Disease', (265, 278))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('melanocytic naevi', 'Phenotype', 'HP:0000995', (156, 173))
127036	25785246	The KIAA1549:BRAF fusion has been reported in a range of PAs (59-90%) and so it is increasingly used as a diagnostic marker for PAs, where neuropathological distinction from malignant glioma can be difficult.	('reported', 'Reg', (34, 42))	('PAs', 'Disease', (57, 60))	('malignant glioma', 'Disease', (174, 190))	('PAs', 'Disease', (128, 131))	('fusion', 'Var', (18, 24))	('malignant glioma', 'Disease', 'MESH:D005910', (174, 190))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('AA', 'Phenotype', 'HP:0009592', (6, 8))
127045	25785246	In another cohort study of over 1,300 CNS tumors, 66.7% of PXAs, 18% of GGs, and 9% of extra-cerebellar PAs harbored the BRAF V600E mutation.	('PXAs', 'Chemical', '-', (59, 63))	('BRAF V600E', 'Var', (121, 131))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('V600E', 'Mutation', 'rs113488022', (126, 131))	('PXAs', 'Disease', (59, 63))	('cerebellar PAs', 'Disease', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cerebellar PAs', 'Disease', 'MESH:D002528', (93, 107))
127046	25785246	Further mutations have been found in the BRAF gene in gliomas including a 3bp insertion at codon 598 which mimics the V600E mutation.	('V600E', 'Mutation', 'rs113488022', (118, 123))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('V600E', 'Var', (118, 123))	('BRAF', 'Gene', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
127047	25785246	Further findings indicate that aberrations of MYB and MYBL1 may help distinguish LGGs from PAs as these aberrations were found in 68% of diffuse astrocytomas but 0% pilocytic tumors.	('astrocytomas', 'Disease', (145, 157))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('aberrations', 'Var', (31, 42))	('found', 'Reg', (121, 126))	('pilocytic tumors', 'Disease', 'MESH:D001254', (165, 181))	('MYB', 'Gene', '4602', (46, 49))	('MYBL1', 'Gene', (54, 59))	('MYB', 'Gene', '4602', (54, 57))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('MYB', 'Gene', (46, 49))	('MYBL1', 'Gene', '4603', (54, 59))	('astrocytomas', 'Disease', 'MESH:D001254', (145, 157))	('MYB', 'Gene', (54, 57))	('LGGs', 'Disease', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('pilocytic tumors', 'Disease', (165, 181))	('PAs', 'Disease', (91, 94))
127048	25785246	The BRAF V600E mutant and the KIAA1549:BRAF fusion are generally mutually exclusive with only a few cases reported with both the fusion and the V600E mutation.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (144, 149))	('AA', 'Phenotype', 'HP:0009592', (32, 34))	('V600E', 'Var', (9, 14))	('V600E', 'Mutation', 'rs113488022', (144, 149))	('BRAF', 'Gene', (4, 8))
127049	25785246	In summary, although currently assessment of the BRAF fusion is of most diagnostic use in posterior fossa PAs, and the BRAF V600E mutation is more prevalent in PXAs, both of these alterations have been described to varying degrees in other pediatric LGGs including DA.	('V600E', 'Mutation', 'rs113488022', (124, 129))	('fossa PAs', 'Disease', (100, 109))	('fossa PAs', 'Disease', 'MESH:D015192', (100, 109))	('V600E', 'Var', (124, 129))	('BRAF', 'Gene', (119, 123))	('PXAs', 'Chemical', '-', (160, 164))	('PXAs', 'Disease', (160, 164))	('prevalent', 'Reg', (147, 156))
127052	25785246	The overall findings were that the 5-year progression-free survival (PFS) was 61% in BRAF fusion positive tumors compared to 18% in fusion negative tumors (with PFS defined as greater than 25% increase in tumor volume on consecutive MRI scans).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', (148, 153))	('BRAF', 'Gene', (85, 89))	('fusion positive', 'Var', (90, 105))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (106, 111))
127054	25785246	also report the presence of BRAF rearrangements as a positive prognostic marker in a cohort of LGGs including PAs, GGs, PMAs, PXAs, diffuse astrocytomas, oligodendrogliomas (ODGs), subependymal giant cell astrocytomas (SGCAs), dysembryoplastic neuroepithelial tumors, and LGGs not otherwise specified.	('astrocytomas', 'Disease', 'MESH:D001254', (140, 152))	('PXAs', 'Chemical', '-', (126, 130))	('GGs', 'Disease', (115, 118))	('subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (181, 216))	('oligodendrogliomas', 'Disease', (154, 172))	('PAs', 'Disease', (110, 113))	('astrocytomas', 'Disease', (205, 217))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('subependymal giant cell astrocytomas', 'Phenotype', 'HP:0009718', (181, 217))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('subependymal giant cell astrocytomas', 'Disease', 'MESH:D001254', (181, 217))	('PXAs', 'Disease', (126, 130))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (227, 266))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (244, 266))	('SGCA', 'Gene', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('PMAs', 'Disease', (120, 124))	('astrocytomas', 'Disease', (140, 152))	('SGCAs', 'Phenotype', 'HP:0009718', (219, 224))	('BRAF', 'Gene', (28, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (205, 217))	('astrocytoma', 'Phenotype', 'HP:0009592', (205, 216))	('SGCA', 'Gene', '6442', (219, 223))	('astrocytoma', 'Phenotype', 'HP:0009592', (140, 151))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (154, 172))	('rearrangements', 'Var', (33, 47))	('dysembryoplastic neuroepithelial tumors', 'Disease', (227, 266))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (244, 265))	('subependymal giant cell astrocytomas', 'Disease', (181, 217))
127055	25785246	BRAF rearrangement was found to be associated with longer PFS and decreased risk of death, only one fusion positive patient died within the 20-year follow-up period.	('PFS', 'MPA', (58, 61))	('patient', 'Species', '9606', (116, 123))	('rearrangement', 'Var', (5, 18))	('BRAF', 'Gene', (0, 4))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))
127056	25785246	In a small cohort of PAs, the presence of the BRAF V600E mutation has been reported to be significantly associated with both diffusely infiltrating architecture and increased risk of progression in LGGs.	('BRAF', 'Gene', (46, 50))	('V600E', 'Var', (51, 56))	('associated', 'Reg', (104, 114))	('LGGs', 'Disease', (198, 202))	('V600E', 'Mutation', 'rs113488022', (51, 56))
127057	25785246	The association with location is less controversial with mounting evidence that the BRAF V600E mutation is more common in supratentorial PAs and the KIAA1549:BRAF fusion being more common in posterior fossa PAs.	('supratentorial PAs', 'Disease', (122, 140))	('BRAF', 'Gene', (84, 88))	('fossa PAs', 'Disease', 'MESH:D015192', (201, 210))	('common', 'Reg', (112, 118))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('AA', 'Phenotype', 'HP:0009592', (151, 153))	('V600E', 'Var', (89, 94))	('fossa PAs', 'Disease', (201, 210))
127058	25785246	looking specifically at supratentorial LGGs found that midline tumors which are usually unresectable were more likely to harbor the KIAA1549:BRAF fusion (65% cases) compared to only 11% of lobar tumors which were found to be BRAF fusion positive.	('midline tumors', 'Disease', 'MESH:D009369', (55, 69))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('AA', 'Phenotype', 'HP:0009592', (134, 136))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('KIAA1549', 'Var', (132, 140))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('midline tumors', 'Disease', (55, 69))
127059	25785246	In this study, it was also found that BRAF fusion positive tumors had better 5-year PFS irrespective of tumor histotype or location with 5-year PFS of 65% in fusion positive PAs compared to 17% for fusion negative tumors.	('fusion positive', 'Var', (43, 58))	('fusion positive', 'Var', (158, 173))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('PFS', 'MPA', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
127064	25785246	report the discovery of a selective inhibitor PLX4720 of BRAF V600E whose cytotoxic effects are specific to mutant cells only.	('BRAF V600E', 'Var', (57, 67))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('PLX4720', 'Chemical', 'MESH:C528407', (46, 53))	('PLX4720', 'Var', (46, 53))
127065	25785246	This PLX4720 drug induced cell cycle arrest and apoptosis in V600E mutant cell lines derived from colon carcinoma, and melanoma cells and yet had minimal effects in other cancer cell lines which did not possess the V600E mutant, including RAS-mutant colon carcinoma cells, large cell lung cancer cells, and metastatic melanoma.	('colon carcinoma', 'Disease', (98, 113))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('melanoma', 'Disease', (318, 326))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('melanoma', 'Disease', (119, 127))	('PLX4720', 'Chemical', 'MESH:C528407', (5, 12))	('arrest', 'Disease', (37, 43))	('V600E', 'Var', (215, 220))	('lung cancer', 'Disease', (284, 295))	('colon carcinoma', 'Disease', 'MESH:D015179', (98, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (26, 43))	('V600E', 'Var', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('large cell lung cancer', 'Phenotype', 'HP:0030360', (273, 295))	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('cancer', 'Disease', (171, 177))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('lung cancer', 'Disease', 'MESH:D008175', (284, 295))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colon carcinoma', 'Disease', (250, 265))	('apoptosis', 'CPA', (48, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (284, 295))	('V600E', 'Mutation', 'rs113488022', (215, 220))	('PLX4720', 'Gene', (5, 12))	('colon carcinoma', 'Disease', 'MESH:D015179', (250, 265))	('cancer', 'Disease', (289, 295))
127066	25785246	Moreover, a dose of 20 mg/kg PLX4720 was given orally for 14 days to mice with colorectal carcinoma xenografts which harbored the V600E mutation, achieving tumor regression below palpable levels in four of nine mice.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (79, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PLX4720', 'Chemical', 'MESH:C528407', (29, 36))	('V600E', 'Mutation', 'rs113488022', (130, 135))	('mice', 'Species', '10090', (211, 215))	('tumor', 'Disease', (156, 161))	('V600E', 'Var', (130, 135))	('colorectal carcinoma', 'Disease', (79, 99))
127067	25785246	demonstrated that BRAF mutant cells, unlike their wild-type relatives, are dependent on MEK signaling for growth and survival and therefore BRAF V600E mutant cells had enhanced sensitivity to MEK inhibitors compared to wild-type BRAF cells and NRAS mutant cells.	('V600E', 'Mutation', 'rs113488022', (145, 150))	('NRAS', 'Gene', '4893', (244, 248))	('mutant', 'Var', (151, 157))	('V600E mutant', 'Var', (145, 157))	('enhanced', 'PosReg', (168, 176))	('BRAF', 'Gene', (140, 144))	('sensitivity', 'MPA', (177, 188))	('NRAS', 'Gene', (244, 248))
127068	25785246	Furthermore, daily treatment with the MEK inhibitor PD0325901 in BRAF V600E mice xenografts showed complete suppression of growth, whereas wild-type xenografts were insensitive to MEK inhibition.	('growth', 'MPA', (123, 129))	('suppression', 'NegReg', (108, 119))	('mice', 'Species', '10090', (76, 80))	('PD0325901', 'Var', (52, 61))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (65, 69))	('PD0325901', 'Chemical', 'MESH:C506614', (52, 61))
127070	25785246	report significantly increased survival in mice transplanted with human V600E mutated astrocytoma cells when treated with the first generation BRAF inhibitor vemurafenib (PLX4720).	('mice', 'Species', '10090', (43, 47))	('increased', 'PosReg', (21, 30))	('astrocytoma', 'Disease', 'MESH:D001254', (86, 97))	('survival', 'CPA', (31, 39))	('astrocytoma', 'Disease', (86, 97))	('human', 'Species', '9606', (66, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('PLX4720', 'Chemical', 'MESH:C528407', (171, 178))	('V600E mutated', 'Var', (72, 85))	('vemurafenib', 'Chemical', 'MESH:D000077484', (158, 169))	('V600E', 'Mutation', 'rs113488022', (72, 77))
127071	25785246	In these intracranial astrocytoma models, the overall tumor size was decreased with BRAF inhibitor treatment, whereas no response was observed when administered with the wild-type BRAF control treatment.	('treatment', 'Var', (99, 108))	('decreased', 'NegReg', (69, 78))	('BRAF', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('intracranial astrocytoma', 'Disease', (9, 33))	('inhibitor treatment', 'Var', (89, 108))	('tumor', 'Disease', (54, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (22, 33))	('intracranial astrocytoma', 'Disease', 'MESH:D001254', (9, 33))
127072	25785246	demonstrated efficacy of the BRAFV600E inhibitor PLX4720 in reducing tumor growth and increasing survival in the BRAFV600E mouse model, whilst being ineffective in the wild-type xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PLX4720', 'Gene', (49, 56))	('mouse', 'Species', '10090', (123, 128))	('tumor', 'Disease', (69, 74))	('PLX4720', 'Chemical', 'MESH:C528407', (49, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('survival', 'CPA', (97, 105))	('increasing', 'PosReg', (86, 96))	('BRAFV600E', 'Var', (113, 122))	('BRAFV600E', 'Mutation', 'rs113488022', (113, 122))	('reducing', 'NegReg', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
127074	25785246	When the MEK inhibitor AZD6244 was tested against PA xenograft models, complete regression was observed in the BRAF V600E mutant xenograft whereas tumor progression was observed in wild-type BRAF xenografts.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('regression', 'NegReg', (80, 90))	('V600E', 'Mutation', 'rs113488022', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('AZD6244', 'Chemical', 'MESH:C517975', (23, 30))	('V600E', 'Var', (116, 121))	('BRAF', 'Gene', (111, 115))
127075	25785246	further report the use of MEK inhibitors (AZD6244 or PD0325901) in NF1-deficient GBM cell lines with resultant growth inhibition in a subset of cells (both agents) and in vivo in nude mouse xenograft models (PD03125901).	('NF1-deficient', 'Disease', (67, 80))	('AZD6244', 'Chemical', 'MESH:C517975', (42, 49))	('PD0325901', 'Var', (53, 62))	('NF1-deficient', 'Disease', 'MESH:C537392', (67, 80))	('PD0325901', 'Chemical', 'MESH:C506614', (53, 62))	('mouse', 'Species', '10090', (184, 189))	('growth', 'MPA', (111, 117))	('AZD6244', 'Var', (42, 49))	('MEK', 'Gene', (26, 29))
127077	25785246	Paradoxical activation, whereby the BRAF inhibitor activates the MAPK pathway, has been described in cells with wild-type BRAF treated with a first generation BRAF inhibitor and appears to be caused by transactivation of RAF dimers to initiate ERK signaling.	('MAPK pathway', 'Pathway', (65, 77))	('activates', 'PosReg', (51, 60))	('ERK', 'Gene', (244, 247))	('activation', 'PosReg', (12, 22))	('inhibitor', 'Var', (41, 50))	('RAF', 'Gene', '22882', (221, 224))	('RAF', 'Gene', '22882', (160, 163))	('RAF', 'Gene', (221, 224))	('RAF', 'Gene', (160, 163))	('RAF', 'Gene', '22882', (37, 40))	('RAF', 'Gene', '22882', (123, 126))	('RAF', 'Gene', (123, 126))	('RAF', 'Gene', (37, 40))	('ERK', 'Gene', '5594', (244, 247))
127078	25785246	have called for careful patient selection in RAF inhibitor trials due to the finding of paradoxical activation of the MAPK pathway in V600E negative cells through RAF1 priming.	('RAF', 'Gene', '22882', (45, 48))	('RAF', 'Gene', (45, 48))	('MAPK pathway', 'Pathway', (118, 130))	('RAF', 'Gene', '22882', (163, 166))	('V600E negative', 'Var', (134, 148))	('patient', 'Species', '9606', (24, 31))	('RAF', 'Gene', (163, 166))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('activation', 'PosReg', (100, 110))
127079	25785246	Much of the clinical research into agents such as BRAF or MEK inhibitors has been performed on V600E positive metastatic melanomas in adults.	('melanomas', 'Disease', 'MESH:D008545', (121, 130))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('melanomas', 'Disease', (121, 130))	('V600E positive', 'Var', (95, 109))
127084	25785246	A phase III clinical trial of vemurafenib compared to the standard therapy dacarbazine in previously untreated metastatic melanoma with known BRAF V600E mutation demonstrated an increase in overall survival of 20%, and a reduction of 63% in the risk of death in the vemurafenib group.	('death', 'Disease', (253, 258))	('V600E', 'Var', (147, 152))	('reduction', 'NegReg', (221, 230))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('dacarbazine', 'Chemical', 'MESH:D003606', (75, 86))	('vemurafenib', 'Chemical', 'MESH:D000077484', (266, 277))	('overall', 'MPA', (190, 197))	('increase', 'PosReg', (178, 186))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('vemurafenib', 'Chemical', 'MESH:D000077484', (30, 41))	('BRAF', 'Gene', (142, 146))	('death', 'Disease', 'MESH:D003643', (253, 258))
127093	25785246	RAF1 mutations lead to increased homodimerization and heterodimerization with BRAF following exposure to the RAF inhibitor PLX4032.	('RAF', 'Gene', '22882', (0, 3))	('RAF', 'Gene', '22882', (79, 82))	('RAF', 'Gene', (0, 3))	('RAF', 'Gene', (79, 82))	('heterodimerization', 'MPA', (54, 72))	('mutations', 'Var', (5, 14))	('PLX4032', 'Chemical', 'MESH:D000077484', (123, 130))	('RAF', 'Gene', (109, 112))	('increased', 'PosReg', (23, 32))	('RAF', 'Gene', '22882', (109, 112))	('homodimerization', 'MPA', (33, 49))
127095	25785246	report novel MEK 1 mutations arising as a consequence of treatment of metastatic melanoma with the MEK inhibitor AZD6244.	('MEK 1', 'Gene', (13, 18))	('mutations', 'Var', (19, 28))	('MEK 1', 'Gene', '5604', (13, 18))	('AZD6244', 'Chemical', 'MESH:C517975', (113, 120))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
127096	25785246	MEK mutations were found either in the allosteric drug binding site or in one of the function domains and were shown to cause pharmacological resistance to both AZD6244 and cross resistance to the BRAF inhibitor PLX4720.	('MEK', 'Gene', (0, 3))	('cause', 'Reg', (120, 125))	('pharmacological resistance', 'MPA', (126, 152))	('cross resistance', 'MPA', (173, 189))	('mutations', 'Var', (4, 13))	('PLX4720', 'Chemical', 'MESH:C528407', (212, 219))	('AZD6244', 'Chemical', 'MESH:C517975', (161, 168))
127097	25785246	Other MEK1 mutations have been described as a mechanism conferring resistance in metastatic melanoma from a patient with an initial near-complete response to PLX4032 with subsequent relapse in week 16 of treatment leading to rapid disease progression and death.	('mutations', 'Var', (11, 20))	('PLX4032', 'Chemical', 'MESH:D000077484', (158, 165))	('MEK1', 'Gene', '5604', (6, 10))	('death', 'Disease', 'MESH:D003643', (255, 260))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('patient', 'Species', '9606', (108, 115))	('MEK1', 'Gene', (6, 10))	('death', 'Disease', (255, 260))
127100	25785246	Combined therapy using both a BRAF inhibitor (PLX4720) and a MEK inhibitor (AZD6244) has demonstrated the ability to overcome resistance to MEK inhibition in metastatic melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('PLX4720', 'Var', (46, 53))	('melanoma', 'Disease', (169, 177))	('PLX4720', 'Chemical', 'MESH:C528407', (46, 53))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('AZD6244', 'Chemical', 'MESH:C517975', (76, 83))
127101	25785246	demonstrated the ability to induce complete regression of V600E positive xenograft metastatic melanomas through combining CRM1 and BRAF inhibition.	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('V600E positive', 'Var', (58, 72))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('V600E', 'Mutation', 'rs113488022', (58, 63))	('CRM1', 'Gene', '7514', (122, 126))	('CRM1', 'Gene', (122, 126))	('melanomas', 'Disease', (94, 103))
127103	25785246	Flexible switching between RAF isoforms as a mechanism of resistance to RAF inhibitors may be overcome through co-targeting of MEK and IGF1R or PI3K in BRAF inhibitor-resistant melanoma cells (BRAF inhibitor-SB-590885).	('RAF', 'Gene', (27, 30))	('IGF1R', 'Gene', '3480', (135, 140))	('MEK', 'Gene', (127, 130))	('PI3K', 'Var', (144, 148))	('RAF', 'Gene', (72, 75))	('RAF', 'Gene', '22882', (72, 75))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('RAF', 'Gene', '22882', (194, 197))	('RAF', 'Gene', '22882', (153, 156))	('RAF', 'Gene', (194, 197))	('RAF', 'Gene', (153, 156))	('RAF', 'Gene', '22882', (27, 30))	('SB-590885', 'Chemical', 'MESH:C508204', (208, 217))	('IGF1R', 'Gene', (135, 140))
127105	25785246	demonstrated the increased efficacy of dual therapy combining the BRAF V600E inhibitor PLX4720 and the CDK4/6 inhibitor PD0332991 in human GBM xenograft models compared to either agent as a monotherapy.	('PLX4720', 'Chemical', 'MESH:C528407', (87, 94))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('CDK4/6', 'Gene', '1019;1021', (103, 109))	('PD0332991', 'Chemical', 'MESH:C500026', (120, 129))	('CDK4/6', 'Gene', (103, 109))	('human', 'Species', '9606', (133, 138))	('PLX4720', 'Var', (87, 94))
127107	25785246	In clinical cohorts, the timing and order of combination therapy has been found to impact on outcome, with prolonged survival being seen in patients receiving MEK inhibitors before BRAF inhibitors compared to the reverse sequence of drug administration.	('prolonged', 'PosReg', (107, 116))	('MEK', 'Gene', (159, 162))	('patients', 'Species', '9606', (140, 148))	('impact', 'Reg', (83, 89))	('inhibitors', 'Var', (163, 173))
127111	25785246	Although the BRAF V600E mutation is more prevalent in PXAs, it has been described to varying degrees in other pediatric LGGs and is of less diagnostic use.	('V600E', 'Var', (18, 23))	('PXAs', 'Disease', (54, 58))	('BRAF', 'Gene', (13, 17))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('PXAs', 'Chemical', '-', (54, 58))
127112	25785246	In terms of prognosis, the KIAA1549 BRAF fusion has been described as an independent positive prognostic biomarker in low-grade pediatric gliomas, irrespective of tumor type.	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('pediatric gliomas', 'Disease', 'MESH:D005910', (128, 145))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('tumor', 'Disease', (163, 168))	('AA', 'Phenotype', 'HP:0009592', (29, 31))	('KIAA1549', 'Var', (27, 35))	('pediatric gliomas', 'Disease', (128, 145))
127113	25785246	As more targeted molecular therapies become available, there will be increased pressure for testing for both the BRAF V600E and the KIAA1549 BRAF fusion in order to predict treatment options in pediatric LGGs.	('V600E', 'Mutation', 'rs113488022', (118, 123))	('AA', 'Phenotype', 'HP:0009592', (134, 136))	('LGGs', 'Disease', (204, 208))	('V600E', 'Var', (118, 123))	('BRAF', 'Var', (113, 117))
127114	25785246	However, it will be important to learn from lessons from therapeutic targeting of BRAF in metastatic melanoma, whereby targeting one pathway may induce resistance through upregulation of other pathways.	('resistance', 'MPA', (152, 162))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('targeting', 'Var', (119, 128))	('induce', 'PosReg', (145, 151))	('upregulation', 'PosReg', (171, 183))
127119	23998913	The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis.	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (137, 165))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('due', 'Reg', (170, 173))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (177, 186))	('blood cancers', 'Disease', (90, 103))	('blood cancers', 'Phenotype', 'HP:0001909', (90, 103))	('blood cancers', 'Disease', 'MESH:D009369', (90, 103))	('neoplastic haematopoiesis', 'Disease', 'MESH:D009369', (273, 298))	('myeloproliferative neoplasms', 'Disease', (137, 165))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (137, 165))	('neoplastic haematopoiesis', 'Disease', (273, 298))	('cancer', 'Disease', (96, 102))	('neoplasms', 'Phenotype', 'HP:0002664', (156, 165))
127154	23998913	Cancer initiation after in vivo injection, aberrant/blocked differentiation and genetic alterations are common features of both GCSCs and leukaemia stem cells.	('leukaemia', 'Disease', (138, 147))	('GCSC', 'Chemical', '-', (128, 132))	('genetic', 'CPA', (80, 87))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('leukaemia', 'Disease', 'MESH:D007938', (138, 147))	('aberrant/blocked', 'Var', (43, 59))
127157	23998913	One underlying hypothesis is that transformation of NSCs or non-committed NPCs would generate high-grade gliomas, while low-grade gliomas are generated when lineage-committed progenitors (e.g.	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('generate', 'Reg', (85, 93))	('transformation', 'Var', (34, 48))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
127163	23998913	Inhibition of EGFR will alleviate the differentiation block induced by ID3, but will promote invasiveness.	('differentiation block', 'CPA', (38, 59))	('EGFR', 'Gene', '1956', (14, 18))	('invasiveness', 'CPA', (93, 105))	('EGFR', 'Gene', (14, 18))	('promote', 'PosReg', (85, 92))	('alleviate', 'NegReg', (24, 33))	('ID3', 'Gene', (71, 74))	('Inhibition', 'Var', (0, 10))	('ID3', 'Gene', '3399', (71, 74))
127165	23998913	A recent study using gene expression analysis further subdivided GBMs in several subtypes characterized by abnormalities in PDGFR-alpha, isocitrate dehydrogenase 1 (IDH1), EGFR and NF1.	('EGFR', 'Gene', '1956', (172, 176))	('abnormalities', 'Var', (107, 120))	('EGFR', 'Gene', (172, 176))	('isocitrate dehydrogenase 1', 'Gene', (137, 163))	('IDH1', 'Gene', (165, 169))	('PDGFR-alpha', 'Gene', '5156', (124, 135))	('isocitrate dehydrogenase 1', 'Gene', '3417', (137, 163))	('NF1', 'Gene', (181, 184))	('IDH1', 'Gene', '3417', (165, 169))	('NF1', 'Gene', '4763', (181, 184))	('PDGFR-alpha', 'Gene', (124, 135))
127174	23998913	The major challenges are to actually elucidate the heterogeneity in leukaemia-initiating cells and to somehow be able to isolate, study and target HSCs that carry mutations such as BCR-ABL, as they apparently behave quite similarly to their normal counterparts in several assays.	('mutations', 'Var', (163, 172))	('leukaemia', 'Disease', 'MESH:D007938', (68, 77))	('BCR-ABL', 'Gene', (181, 188))	('BCR-ABL', 'Gene', '25', (181, 188))	('leukaemia', 'Disease', (68, 77))
127175	23998913	Recently, the interleukin (IL) receptor-associated protein 1 (IRAP1) was detected specifically on BCR-ABL mutated, but not on normal HSCs, and also was detected in stem and progenitor cells of AML patients, thus opening the path to use it for specific detection of cancer-initiating cells and targeted treatment.	('AP1', 'Gene', (64, 67))	('patients', 'Species', '9606', (197, 205))	('men', 'Species', '9606', (307, 310))	('AML', 'Phenotype', 'HP:0004808', (193, 196))	('BCR-ABL', 'Gene', (98, 105))	('BCR-ABL', 'Gene', '25', (98, 105))	('AML', 'Disease', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('AP1', 'Gene', '3726', (64, 67))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('AML', 'Disease', 'MESH:D015470', (193, 196))	('mutated', 'Var', (106, 113))
127180	23998913	Furthermore, while in chronic myeloid cancers, such as BCR-ABL-negative MPNs, the main molecular basis is represented by mutations in Janus kinase 2 (JAK2) or cytokine receptors leading to constitutive JAK-signal transducer and activator of transcription (STAT) signalling, in secondary leukaemia and in the more severe MPN, many more mutations, especially in epigenetic regulators and genes coding for transcription factors, have been identified.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mutations', 'Var', (121, 130))	('leukaemia', 'Disease', 'MESH:D007938', (287, 296))	('JAK2', 'Gene', '3717', (150, 154))	('chronic myeloid cancers', 'Phenotype', 'HP:0005506', (22, 45))	('chronic myeloid cancers', 'Disease', (22, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('BCR-ABL', 'Gene', '25', (55, 62))	('Janus kinase 2', 'Gene', (134, 148))	('JAK2', 'Gene', (150, 154))	('leukaemia', 'Disease', (287, 296))	('leading to', 'Reg', (178, 188))	('Janus kinase 2', 'Gene', '3717', (134, 148))	('chronic myeloid cancers', 'Disease', 'MESH:D015464', (22, 45))	('MPN', 'Phenotype', 'HP:0005547', (320, 323))	('MPN', 'Phenotype', 'HP:0005547', (72, 75))	('BCR-ABL', 'Gene', (55, 62))
127181	23998913	Furthermore, in myelodysplastic conditions, differentiation programmes are blocked, but proliferation of early committed progenitors is enhanced, while they also derive from a mutated or modified HSC.	('enhanced', 'PosReg', (136, 144))	('myelodysplastic conditions', 'Disease', (16, 42))	('mutated', 'Var', (176, 183))	('early committed progenitors', 'CPA', (105, 132))	('myelodysplastic conditions', 'Phenotype', 'HP:0002863', (16, 42))	('myelodysplastic conditions', 'Disease', 'MESH:D009190', (16, 42))	('proliferation', 'CPA', (88, 101))
127183	23998913	First, HSCs acquire a significant number of mutations before any driver leukaemia is acquired (~5-10/year).	('HSCs', 'Disease', (7, 11))	('leukaemia', 'Disease', 'MESH:D007938', (72, 81))	('mutations', 'Var', (44, 53))	('leukaemia', 'Disease', (72, 81))
127185	23998913	Once driver mutations occur for leukaemia, then all these previous mutations are captured and carried by the clone as it expands.	('mutations', 'Var', (12, 21))	('leukaemia', 'Disease', 'MESH:D007938', (32, 41))	('leukaemia', 'Disease', (32, 41))
127186	23998913	It remains to be determined whether stem cells in the CNS might also acquire mutations over the years, and whether known drivers for glioma cooperate with those to induce progression to high-grade gliomas.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('gliomas', 'Phenotype', 'HP:0009733', (197, 204))	('gliomas', 'Disease', (197, 204))	('glioma', 'Disease', (197, 203))	('gliomas', 'Disease', 'MESH:D005910', (197, 204))	('mutations', 'Var', (77, 86))	('glioma', 'Disease', (133, 139))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
127200	23998913	It is generally considered that cancer stem cells might acquire mutations that propel immortality, self-renewal and variable differentiation blocks in their progenitors.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('self-renewal', 'CPA', (99, 111))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (64, 73))
127207	23998913	Studies that have compared benign astrocytoma, low-grade glioma and high-grade glioma (glioblastoma multiforme) have highlighted potentially important genetic events associated with glioma progression, such as methylation of DNA methylase 1 (DNAMT1), methyl guanine methyl transferase (MGMT) and EGFR promoters, chromosomal losses and gains, IDH1 mutations in low-grade astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', (342, 346))	('astrocytoma', 'Disease', 'MESH:D001254', (370, 381))	('glioblastoma multiforme', 'Disease', (87, 110))	('astrocytoma', 'Disease', (370, 381))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (87, 110))	('glioma', 'Disease', (57, 63))	('EGFR', 'Gene', (296, 300))	('DNAMT1', 'Gene', (242, 248))	('IDH1', 'Gene', '3417', (342, 346))	('astrocytoma', 'Disease', 'MESH:D001254', (34, 45))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('astrocytoma', 'Disease', (34, 45))	('mutations', 'Var', (347, 356))	('glioma', 'Disease', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('astrocytoma', 'Phenotype', 'HP:0009592', (370, 381))	('glioma', 'Disease', (79, 85))	('EGFR', 'Gene', '1956', (296, 300))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('gains', 'PosReg', (335, 340))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))
127211	23998913	Similar to cancer stem cells isolated from glioblastomas, stem cells of low-grade gliomas are more resistant to chemotherapeutics than their differentiated daughter cells.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('glioblastomas', 'Disease', 'MESH:D005909', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('low-grade', 'Var', (72, 81))	('glioblastomas', 'Disease', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('gliomas', 'Disease', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('cancer', 'Disease', (11, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (43, 56))
127213	23998913	Defects in the niche have recently been shown to induce in humans dysplastic features and neoplastic transformation.	('neoplastic transformation', 'CPA', (90, 115))	('dysplastic', 'Disease', 'MESH:D004416', (66, 76))	('induce', 'Reg', (49, 55))	('dysplastic', 'Disease', (66, 76))	('Defects', 'Var', (0, 7))	('humans', 'Species', '9606', (59, 65))
127216	23998913	A similar type of observation has been made in human MPNs where endothelial cells in certain vessels were found to carry the JAK2 V617F mutation, especially in patients with Budd-Chiari syndrome and portal vein thrombosis and thus to be derived from the MPN stem cell.	('MPN', 'Phenotype', 'HP:0005547', (53, 56))	('V617F', 'Var', (130, 135))	('patients', 'Species', '9606', (160, 168))	('portal vein thrombosis', 'Phenotype', 'HP:0030242', (199, 221))	('Budd-Chiari syndrome', 'Disease', 'MESH:D006502', (174, 194))	('vein thrombosis', 'Phenotype', 'HP:0004936', (206, 221))	('Budd-Chiari syndrome', 'Disease', (174, 194))	('vein thrombosis', 'Disease', (206, 221))	('MPN', 'Phenotype', 'HP:0005547', (254, 257))	('V617F', 'SUBSTITUTION', 'None', (130, 135))	('JAK2', 'Gene', '3717', (125, 129))	('human', 'Species', '9606', (47, 52))	('Budd-Chiari syndrome', 'Phenotype', 'HP:0002639', (174, 194))	('vein thrombosis', 'Disease', 'MESH:D020246', (206, 221))	('JAK2', 'Gene', (125, 129))
127250	23998913	Although CD133 positivity was correlated with poor clinical prognosis in brain tumours, the use of CD133 as a unique glioma stem-cell marker is not sufficient to mark the entire self-renewing tumour cell reservoir.	('brain tumours', 'Disease', 'MESH:D001932', (73, 86))	('CD133', 'Gene', (9, 14))	('brain tumours', 'Phenotype', 'HP:0030692', (73, 86))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('CD133', 'Gene', '8842', (9, 14))	('brain tumour', 'Phenotype', 'HP:0030692', (73, 85))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('brain tumours', 'Disease', (73, 86))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumour', 'Disease', (192, 198))	('glioma', 'Disease', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('positivity', 'Var', (15, 25))	('CD133', 'Gene', (99, 104))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))	('CD133', 'Gene', '8842', (99, 104))
127261	23998913	Overall nestin/CD133 positivity was associated with a poor prognosis and better correlated with clinical course and survival than the histological grading.	('nestin', 'Gene', (8, 14))	('positivity', 'Var', (21, 31))	('CD133', 'Gene', (15, 20))	('CD133', 'Gene', '8842', (15, 20))	('nestin', 'Gene', '10763', (8, 14))
127280	23998913	The loss of proliferation ability and tumourigenicity of glioblastoma stem cells was recently demonstrated in vivo after SOX2 silencing.	('SOX2', 'Gene', (121, 125))	('glioblastoma', 'Disease', (57, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('SOX2', 'Gene', '6657', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('loss', 'NegReg', (4, 8))	('tumour', 'Disease', (38, 44))	('proliferation ability', 'CPA', (12, 33))	('silencing', 'Var', (126, 135))
127298	23998913	Malignant gliomas, particularly GBM, frequently display amplification of EGFR, specific activating mutations in EGFR and, to a lesser extent PDGFR amplification.	('EGFR', 'Gene', (112, 116))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('PDGFR', 'Gene', (141, 146))	('Malignant gliomas', 'Disease', 'MESH:D005910', (0, 17))	('EGFR', 'Gene', '1956', (73, 77))	('PDGFR', 'Gene', '5159', (141, 146))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (99, 108))	('activating', 'PosReg', (88, 98))	('amplification', 'MPA', (56, 69))	('EGFR', 'Gene', '1956', (112, 116))	('Malignant gliomas', 'Disease', (0, 17))
127305	23998913	It is interesting that in cells expressing certain EGFR mutants, levels of Erk1,2 MAP-kinase activity are quite low, presumably because of induction of MAP-kinase phosphatases, which would prevent excessive MAP-kinase activation, which could have differentiation or anti-proliferative effects.	('levels', 'MPA', (65, 71))	('EGFR', 'Gene', (51, 55))	('mutants', 'Var', (56, 63))	('low', 'NegReg', (112, 115))	('Erk', 'Gene', (75, 78))	('MAP-kinase activation', 'MPA', (207, 228))	('Erk', 'Gene', '5594', (75, 78))	('EGFR', 'Gene', '1956', (51, 55))
127309	23998913	Based on results obtained in other cancers, pan type I PI3K inhibitors (covering the alpha, beta, delta and gamma p110 isoforms) will likely be effective, in contrast to isoform-specific inhibitors.	('other cancers', 'Disease', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('PI3K', 'Var', (55, 59))	('other cancers', 'Disease', 'MESH:D009369', (29, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))
127313	23998913	Not only EGFR gene amplification is the most common alteration in high-grade glioma, but also 50% of the EGFR amplified tumours express a constitutively active form of EGFR, which is required for glioma growth.	('EGFR', 'Gene', '1956', (168, 172))	('glioma growth', 'Disease', (196, 209))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('EGFR', 'Gene', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('amplification', 'Var', (19, 32))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('EGFR', 'Gene', (9, 13))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('EGFR', 'Gene', (168, 172))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('EGFR', 'Gene', '1956', (105, 109))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('glioma growth', 'Disease', 'MESH:D005910', (196, 209))	('amplified', 'Var', (110, 119))	('EGFR', 'Gene', '1956', (9, 13))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', (196, 202))	('glioma', 'Disease', 'MESH:D005910', (77, 83))
127317	23998913	Epidermal growth factor receptor is overexpressed and/or mutated in many carcinomas, including lung, breast, colon, head and neck, prostate and ovarian, but not in haematological disorders.	('colon', 'Disease', (109, 114))	('prostate', 'Disease', (131, 139))	('ovarian', 'Disease', (144, 151))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('haematological disorders', 'Disease', 'MESH:D006402', (164, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinomas', 'Disease', (73, 83))	('carcinomas', 'Disease', 'MESH:D002277', (73, 83))	('haematological disorders', 'Disease', (164, 188))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('overexpressed', 'PosReg', (36, 49))	('breast', 'Disease', (101, 107))	('mutated', 'Var', (57, 64))	('lung', 'Disease', (95, 99))
127318	23998913	Nevertheless, some mutations are specific for glioblastoma.	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('mutations', 'Var', (19, 28))
127320	23998913	The genetic alterations found throughout the tumour bulk in gliomas, such as loss of p53 and PTEN, result in significant resistance to therapy in all cell types.	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('resistance to therapy', 'CPA', (121, 142))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('loss', 'Var', (77, 81))	('tumour', 'Disease', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
127321	23998913	PTEN and p53 are shown to negatively regulate NSC self-renewal, and their deficiency leads to a significant decrease in the level of apoptosis in neurospheres.	('deficiency', 'Var', (74, 84))	('regulate', 'Reg', (37, 45))	('level of apoptosis', 'MPA', (124, 142))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('NSC self-renewal', 'CPA', (46, 62))	('negatively', 'NegReg', (26, 36))	('decrease', 'NegReg', (108, 116))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
127323	23998913	The inhibition of Akt with pharmacological inhibitors disrupts neurosphere formation, induces apoptosis, reduces migration and invasion in vitro and significantly delays intracranial tumour formation.	('intracranial tumour', 'Disease', 'MESH:D001932', (170, 189))	('induces', 'Reg', (86, 93))	('inhibition', 'Var', (4, 14))	('intracranial tumour', 'Disease', (170, 189))	('delays', 'NegReg', (163, 169))	('neurosphere formation', 'CPA', (63, 84))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('reduces', 'NegReg', (105, 112))	('apoptosis', 'CPA', (94, 103))	('disrupts', 'NegReg', (54, 62))	('Akt', 'Protein', (18, 21))
127325	23998913	The precise reasons for failure are unknown, but pathological RTK signalling might be a late event promoting survival and proliferation in glioma, while the initiating event remains unknown.	('failure', 'Disease', 'MESH:D017093', (24, 31))	('glioma', 'Disease', (139, 145))	('failure', 'Disease', (24, 31))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('pathological', 'Var', (49, 61))	('proliferation', 'CPA', (122, 135))	('promoting', 'PosReg', (99, 108))	('survival', 'CPA', (109, 117))
127328	23998913	The PI3K pathway is constitutively active in AML, either by overexpression, namely of the p110 PI3K delta, other catalytic subunits or activating mutations.	('AML', 'Phenotype', 'HP:0004808', (45, 48))	('overexpression', 'PosReg', (60, 74))	('AML', 'Disease', 'MESH:D015470', (45, 48))	('p110 PI3K', 'Var', (90, 99))	('PI3K pathway', 'Pathway', (4, 16))	('AML', 'Disease', (45, 48))
127331	23998913	Overexpression of PDGFRA is present in human low-grade gliomas and further enhanced by gene amplification in a subset of high-grade glioblastoma, whereas PDGF-B induces angiogenesis characteristic for secondary glioblastoma.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('enhanced', 'PosReg', (75, 83))	('gene amplification', 'Var', (87, 105))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Disease', (211, 223))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('angiogenesis', 'CPA', (169, 181))	('human', 'Species', '9606', (39, 44))	('PDGF-B', 'Gene', (154, 160))	('PDGF-B', 'Gene', '5155', (154, 160))	('gliomas', 'Disease', (55, 62))	('induces', 'Reg', (161, 168))	('PDGFRA', 'Gene', '5156', (18, 24))	('PDGFRA', 'Gene', (18, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (211, 223))
127340	23998913	In contrast, imatinib is quite effective in haematopoietic malignancies associated with translocations or mutations in PDGFR, while hydroxyurea is a standard treatment for MPNs.	('men', 'Species', '9606', (163, 166))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('hydroxyurea', 'Chemical', 'MESH:D006918', (132, 143))	('MPN', 'Phenotype', 'HP:0005547', (172, 175))	('associated', 'Reg', (72, 82))	('translocations', 'Var', (88, 102))	('PDGFR', 'Gene', (119, 124))	('malignancies', 'Disease', (59, 71))	('mutations', 'Var', (106, 115))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('PDGFR', 'Gene', '5159', (119, 124))
127345	23998913	Increased Notch activity promotes tumour growth, whereas Notch pathway blockade inhibits proliferation and/or survival.	('proliferation', 'CPA', (89, 102))	('Notch', 'Gene', (57, 62))	('tumour growth', 'Disease', (34, 47))	('Notch', 'Gene', '4851;4853', (10, 15))	('blockade', 'Var', (71, 79))	('Notch', 'Gene', (10, 15))	('promotes', 'PosReg', (25, 33))	('tumour growth', 'Disease', 'MESH:D006130', (34, 47))	('inhibits', 'NegReg', (80, 88))	('survival', 'CPA', (110, 118))	('Notch', 'Gene', '4851;4853', (57, 62))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
127361	23998913	Furthermore, high TGF-beta signalling via Smad proteins is considered of poor prognosis in glioblastoma and can induce proliferation, provided that the PDGF-B gene can be induced by demethylation.	('proliferation', 'MPA', (119, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('high', 'Var', (13, 17))	('TGF-beta', 'Gene', (18, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('PDGF-B', 'Gene', (152, 158))	('PDGF-B', 'Gene', '5155', (152, 158))	('TGF-beta', 'Gene', '7040', (18, 26))	('glioblastoma', 'Disease', (91, 103))	('induce', 'PosReg', (112, 118))
127362	23998913	Of great therapeutic interest, inhibitors of TGF-beta receptors target cancer stem cells located in perivascular niches.	('TGF-beta', 'Gene', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('target', 'Reg', (64, 70))	('perivascular niches', 'Phenotype', 'HP:0012520', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('perivascular niche', 'Phenotype', 'HP:0012520', (100, 118))	('inhibitors', 'Var', (31, 41))	('TGF-beta', 'Gene', '7040', (45, 53))
127364	23998913	How these ID proteins maintain the cancer stem-cell phenotype is not known, but the response of GCSCs to TGF-beta receptor inhibitors by reducing ID1, ID3 proteins and cell surface CD44 is very important as such markers appear to be functionally linked to the cancer-initiating phenotype of GCSCs.	('ID1', 'Gene', '3397', (146, 149))	('reducing', 'NegReg', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('ID1', 'Gene', (146, 149))	('ID3', 'Gene', '3399', (151, 154))	('CD44', 'Gene', '960', (181, 185))	('TGF-beta', 'Gene', '7040', (105, 113))	('inhibitors', 'Var', (123, 133))	('cancer', 'Disease', (260, 266))	('TGF-beta', 'Gene', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CD44', 'Gene', (181, 185))	('GCSC', 'Chemical', '-', (291, 295))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('ID3', 'Gene', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('GCSC', 'Chemical', '-', (96, 100))	('cancer', 'Disease', (35, 41))
127373	23998913	Epigenetic silencing of BMPR1B in a subset of gliomas leads to astroglial differentiation block.	('BMPR1B', 'Gene', (24, 30))	('astroglial differentiation block', 'CPA', (63, 95))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('Epigenetic silencing', 'Var', (0, 20))	('leads to', 'Reg', (54, 62))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('BMPR1B', 'Gene', '658', (24, 30))
127376	23998913	Inhibition of Hedgehog-Gli signalling suppresses self-renewal and proliferation, while increasing apoptosis.	('Gli', 'Gene', '2735', (23, 26))	('apoptosis', 'CPA', (98, 107))	('self-renewal', 'CPA', (49, 61))	('Gli', 'Gene', (23, 26))	('Inhibition', 'Var', (0, 10))	('suppresses', 'NegReg', (38, 48))	('increasing', 'PosReg', (87, 97))
127387	23998913	Inhibition of STAT3 with specific inhibitors disrupts proliferation and maintenance of GCSCs.	('STAT3', 'Gene', (14, 19))	('GCSC', 'Chemical', '-', (87, 91))	('disrupts', 'NegReg', (45, 53))	('maintenance', 'CPA', (72, 83))	('Inhibition', 'Var', (0, 10))	('proliferation', 'CPA', (54, 67))	('STAT3', 'Gene', '6774', (14, 19))	('GCSCs', 'CPA', (87, 92))
127399	23998913	Interleukin-13Ralpha2 was also shown to activate MAP-kinase signalling in intestinal cells from inflammatory bowel disease patients.	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (96, 122))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (96, 122))	('patients', 'Species', '9606', (123, 131))	('inflammatory bowel disease', 'Disease', (96, 122))	('MAP-kinase signalling', 'MPA', (49, 70))	('Interleukin-13Ralpha2', 'Var', (0, 21))	('activate', 'PosReg', (40, 48))
127402	23998913	Especially in patients who harbour EGFR overexpression and presence of the constitutively active delta-EGFR, STAT5b was shown to induce BclXL expression and survival of GBM cells.	('EGFR', 'Gene', '1956', (103, 107))	('survival', 'CPA', (157, 165))	('induce', 'PosReg', (129, 135))	('BclXL', 'Gene', '598', (136, 141))	('STAT5b', 'Gene', (109, 115))	('overexpression', 'PosReg', (40, 54))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('STAT5b', 'Gene', '6777', (109, 115))	('BclXL', 'Gene', (136, 141))	('patients', 'Species', '9606', (14, 22))	('presence', 'Var', (59, 67))
127403	23998913	In contrast, in haematopoietic cancers, especially human MPNs that do not harbour BCR-ABL or PDGFR translocations, the JAK2 V617F unique acquired mutation is prevalent, followed by mutations in Tpo receptor and negative regulators such as Cbl.	('Tpo', 'Gene', (194, 197))	('JAK2', 'Gene', '3717', (119, 123))	('PDGFR', 'Gene', '5159', (93, 98))	('haematopoietic cancers', 'Disease', (16, 38))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('V617F', 'SUBSTITUTION', 'None', (124, 129))	('MPN', 'Phenotype', 'HP:0005547', (57, 60))	('JAK2', 'Gene', (119, 123))	('BCR-ABL', 'Gene', (82, 89))	('BCR-ABL', 'Gene', '25', (82, 89))	('haematopoietic cancers', 'Disease', 'MESH:D009369', (16, 38))	('human', 'Species', '9606', (51, 56))	('V617F', 'Var', (124, 129))	('Cbl', 'Gene', (239, 242))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('Cbl', 'Gene', '867', (239, 242))	('PDGFR', 'Gene', (93, 98))	('Tpo', 'Gene', '7066', (194, 197))
127404	23998913	These mutations are associated with constitutive activation of STAT5 and STAT3 Other mutations in JAKs, especially V617F homologous JAK1 mutations, are associated with T-adult acute lymphoblastoid leukaemia (T-ALL).	('JAK1', 'Gene', '3716', (132, 136))	('STAT5', 'Gene', (63, 68))	('V617F', 'SUBSTITUTION', 'None', (115, 120))	('JAKs', 'Gene', (98, 102))	('T-adult acute lymphoblastoid leukaemia (T-ALL)', 'Disease', 'MESH:D054218', (168, 214))	('STAT3', 'Gene', (73, 78))	('JAKs', 'Gene', '3716;3717;16452;3718', (98, 102))	('mutations', 'Var', (137, 146))	('lymphoblastoid leukaemia', 'Phenotype', 'HP:0005526', (182, 206))	('mutations', 'Var', (85, 94))	('acute lymphoblastoid leukaemia', 'Phenotype', 'HP:0006721', (176, 206))	('V617F', 'Var', (115, 120))	('associated', 'Reg', (152, 162))	('STAT5', 'Gene', '6776', (63, 68))	('mutations', 'Var', (6, 15))	('JAK1', 'Gene', (132, 136))	('STAT3', 'Gene', '6774', (73, 78))
127409	23998913	Mutations that affect amino acid residue 132 of IDH1 were found in ~70% of WHO grade II and grade III astrocytomas and oligodendrogliomas and in the secondary glioblastomas developed from these tumours.	('glioblastomas', 'Disease', (159, 172))	('tumours', 'Disease', (194, 201))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('IDH1', 'Gene', (48, 52))	('found', 'Reg', (58, 63))	('glioblastomas', 'Disease', 'MESH:D005909', (159, 172))	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (119, 137))	('tumours', 'Disease', 'MESH:D009369', (194, 201))	('astrocytomas', 'Disease', (102, 114))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('IDH1', 'Gene', '3417', (48, 52))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('oligodendrogliomas', 'Disease', (119, 137))	('glioblastomas', 'Phenotype', 'HP:0012174', (159, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))	('astrocytomas', 'Disease', 'MESH:D001254', (102, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))
127410	23998913	Isocitrate dehydrogenase 1 mutations might be an early event with more frequent detections in low-grade gliomas.	('mutations', 'Var', (27, 36))	('gliomas', 'Disease', (104, 111))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
127411	23998913	Tumours negative for IDH1 mutations frequently exhibited mutations at the analogous amino acid (R172) of the IDH2.	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('IDH2', 'Gene', (109, 113))	('R172', 'Var', (96, 100))	('mutations at', 'Var', (57, 69))	('IDH2', 'Gene', '3418', (109, 113))	('IDH1', 'Gene', (21, 25))	('exhibited', 'Reg', (47, 56))	('IDH1', 'Gene', '3417', (21, 25))
127412	23998913	Isocitrate dehydrogenase mutated tumours had a better outcome than those with wild-type IDH genes.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumours', 'Disease', (33, 40))	('IDH', 'Gene', (88, 91))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('IDH', 'Gene', '3417', (88, 91))	('mutated', 'Var', (25, 32))
127413	23998913	However, this is not the case when, for example, IDH1 mutation is associated with expression of PDGFR alpha, which predicts shorter survival.	('mutation', 'Var', (54, 62))	('IDH1', 'Gene', '3417', (49, 53))	('PDGFR alpha', 'Gene', (96, 107))	('associated', 'Reg', (66, 76))	('shorter', 'NegReg', (124, 131))	('IDH1', 'Gene', (49, 53))	('PDGFR alpha', 'Gene', '5156', (96, 107))
127414	23998913	The mutations are changing the function of IDH enzymes, from rendering isocitrate to alpha-ketoglutarate; the mutant IDH proteins catalyse the production of D-2-hydroxyglutarate from alpha-ketoglutarate (alpha-KG).	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (183, 202))	('IDH', 'Gene', '3417', (43, 46))	('proteins', 'Protein', (121, 129))	('IDH', 'Gene', (117, 120))	('alpha-KG', 'Chemical', 'MESH:D007656', (204, 212))	('mutant', 'Var', (110, 116))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (85, 104))	('IDH', 'Gene', '3417', (117, 120))	('isocitrate', 'Chemical', 'MESH:C034219', (71, 81))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', (43, 46))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (157, 177))
127415	23998913	The product D-2-hydroxyglutarate inhibits competitively alpha-KG-dependent enzymes such as TET (Ten Eleven Translocation) hydroxylases and demethylases.	('alpha-KG', 'Chemical', 'MESH:D007656', (56, 64))	('alpha-KG-dependent enzymes', 'Enzyme', (56, 82))	('D-2-hydroxyglutarate', 'Var', (12, 32))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (12, 32))	('inhibits', 'NegReg', (33, 41))	('demethylases', 'Enzyme', (139, 151))	('TET', 'Chemical', '-', (91, 94))
127416	23998913	In AML, IDH1/2 mutations are also detected and they do correlate with better outcome.	('mutations', 'Var', (15, 24))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('IDH1/2', 'Gene', '3417;3418', (8, 14))	('AML', 'Disease', (3, 6))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('IDH1/2', 'Gene', (8, 14))
127417	23998913	Although most low-grade gliomas carry IDH1/2 mutations, some do not, and for those, it was recently found that TET2 miscoding mutations were not detected, but 14% of the cases had methylation of the TET2 promoter.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('mutations', 'Var', (45, 54))	('TET2', 'Gene', (199, 203))	('TET2', 'Gene', (111, 115))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH1/2', 'Gene', (38, 44))	('methylation', 'MPA', (180, 191))	('TET2', 'Gene', '54790', (199, 203))	('gliomas', 'Disease', (24, 31))	('TET2', 'Gene', '54790', (111, 115))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
127418	23998913	None of the IDH1/2 mutated gliomas had methylation of the TET2 promoter.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('TET2', 'Gene', (58, 62))	('IDH1/2', 'Gene', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('methylation', 'MPA', (39, 50))	('mutated', 'Var', (19, 26))	('IDH1/2', 'Gene', '3417;3418', (12, 18))	('TET2', 'Gene', '54790', (58, 62))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('gliomas', 'Disease', (27, 34))
127419	23998913	Thus, like in haematological malignancies, absence of TET2 expression appears to be mutually exclusive with IDH1/2 mutations, and this makes sense as the product of mutated IDH1/2 is an inhibitor of TET2.	('mutated', 'Var', (165, 172))	('IDH1/2', 'Gene', (173, 179))	('TET2', 'Gene', (199, 203))	('mutations', 'Var', (115, 124))	('haematological malignancies', 'Disease', 'MESH:D019337', (14, 41))	('absence', 'NegReg', (43, 50))	('TET2', 'Gene', '54790', (54, 58))	('haematological malignancies', 'Disease', (14, 41))	('TET2', 'Gene', (54, 58))	('expression', 'MPA', (59, 69))	('IDH1/2', 'Gene', '3417;3418', (108, 114))	('TET2', 'Gene', '54790', (199, 203))	('IDH1/2', 'Gene', '3417;3418', (173, 179))	('IDH1/2', 'Gene', (108, 114))
127421	23998913	Ten-Eleven-Translocation 2 mutations are an independent positive prognostic factor in myelodysplastic syndromes.	('mutations', 'Var', (27, 36))	('Ten-Eleven-Translocation 2', 'Gene', (0, 26))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (86, 111))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (86, 111))	('myelodysplastic syndromes', 'Disease', (86, 111))
127423	23998913	Overall, it is tempting to speculate that, like in the haematopoietic system, absence of TET2 activity, either by IDH1/2 mutations or by promoter methylation, promotes self-renewal of tumour-initiating cells for low-grade diffuse gliomas.	('TET2', 'Gene', (89, 93))	('IDH1/2', 'Gene', (114, 120))	('absence', 'NegReg', (78, 85))	('mutations', 'Var', (121, 130))	('gliomas', 'Disease', (230, 237))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('promotes', 'PosReg', (159, 167))	('self-renewal', 'CPA', (168, 180))	('activity', 'MPA', (94, 102))	('IDH1/2', 'Gene', '3417;3418', (114, 120))	('TET2', 'Gene', '54790', (89, 93))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('gliomas', 'Disease', 'MESH:D005910', (230, 237))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('tumour', 'Disease', (184, 190))
127424	23998913	Recurrent mutations affecting two critical amino acids (K27 and G34) of histone H3.3 are found in approximately one-third of paediatric GBM, thus emphasizing the connection between chromatin remodelling, structure and glioblastoma.	('K27', 'Var', (56, 59))	('histone H3.3', 'Gene', (72, 84))	('glioblastoma', 'Disease', (218, 230))	('glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('G34', 'Var', (64, 67))	('histone H3.3', 'Gene', '3020', (72, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('mutations', 'Var', (10, 19))
127425	23998913	The histone H3.3 variant is normally enriched in chromatin regions of high turnover such as telomeres and is associated with chaperone proteins such as DAXX (death-domain associated protein) and ATRX (alpha-thalassaemia/mental retardation syndrome X-linked), which themselves are mutated in 31% of paediatric GBM and in several cancers including pancreatic neuroendocrine tumours and AML.	('cancers', 'Phenotype', 'HP:0002664', (328, 335))	('cancers', 'Disease', (328, 335))	('variant', 'Var', (17, 24))	('mental retardation', 'Phenotype', 'HP:0001249', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('thalassaemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (207, 256))	('ATRX', 'Gene', (195, 199))	('paediatric GBM', 'Disease', (298, 312))	('ATRX', 'Gene', '546', (195, 199))	('pancreatic neuroendocrine tumours', 'Disease', 'MESH:D010190', (346, 379))	('histone H3.3', 'Gene', (4, 16))	('cancers', 'Disease', 'MESH:D009369', (328, 335))	('mutated', 'Var', (280, 287))	('pancreatic neuroendocrine tumours', 'Disease', (346, 379))	('DAXX', 'Gene', (152, 156))	('tumours', 'Phenotype', 'HP:0002664', (372, 379))	('histone H3.3', 'Gene', '3020', (4, 16))	('AML', 'Disease', 'MESH:D015470', (384, 387))	('DAXX', 'Gene', '1616', (152, 156))	('tumour', 'Phenotype', 'HP:0002664', (372, 378))	('AML', 'Phenotype', 'HP:0004808', (384, 387))	('thalassaemia/mental retardation syndrome X-linked', 'Disease', (207, 256))	('AML', 'Disease', (384, 387))
127426	23998913	Such mutations define epigenetic subgroups of GBM with distinct global methylation patterns and are mutually exclusive with IDH1 mutations.	('IDH1', 'Gene', '3417', (124, 128))	('IDH1', 'Gene', (124, 128))	('global methylation', 'MPA', (64, 82))	('mutations', 'Var', (5, 14))
127427	23998913	Of great interest, the different H3.3 mutations give rise to GBM in separate anatomic compartments, with differential regulation of transcription factors.	('men', 'Species', '9606', (93, 96))	('H3.3', 'Gene', (33, 37))	('give rise to', 'Reg', (48, 60))	('mutations', 'Var', (38, 47))	('GBM', 'Disease', (61, 64))
127428	23998913	Overall TET2 and IDH1/2 mutations are being mainly described in haematopoietic and brain cancers, but recently, it was shown that 5-hydroxymethylcytosine depletion was detected in those and other cancers such as squamous cell lung cancer, in the absence of TET2 and IDH mutations.	('brain cancers', 'Disease', 'MESH:D001932', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('mutations', 'Var', (24, 33))	('TET2', 'Gene', (257, 261))	('other cancers', 'Disease', 'MESH:D009369', (190, 203))	('other cancers', 'Disease', (190, 203))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('TET2', 'Gene', '54790', (8, 12))	('IDH', 'Gene', '3417', (17, 20))	('5-hydroxymethylcytosine depletion', 'MPA', (130, 163))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('squamous cell lung cancer', 'Disease', (212, 237))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('IDH', 'Gene', (266, 269))	('TET2', 'Gene', '54790', (257, 261))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (130, 153))	('detected', 'Reg', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('brain cancers', 'Disease', (83, 96))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (212, 237))	('TET2', 'Gene', (8, 12))	('IDH1/2', 'Gene', (17, 23))	('IDH', 'Gene', '3417', (266, 269))	('IDH', 'Gene', (17, 20))
127441	21968943	A Phase II Study of O6-Benzylguanine and Temozolomide in Pediatric Patients with Recurrent or Progressive High Grade Gliomas and Brainstem Gliomas: A Pediatric Brain Tumor Consortium Study To estimate the sustained (>=8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide  (TMZ).	('O6-Benzylguanine', 'Chemical', 'MESH:C064976', (20, 36))	('Patients', 'Species', '9606', (67, 75))	('Tumor', 'Phenotype', 'HP:0002664', (166, 171))	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (409, 425))	('temozolomide', 'Chemical', 'MESH:D000077204', (437, 449))	('Gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('Gliomas and Brainstem Gliomas', 'Disease', 'MESH:D005910', (117, 146))	('gliomas', 'Disease', (352, 359))	('gliomas', 'Disease', (314, 321))	('TMZ', 'Chemical', 'MESH:D000077204', (452, 455))	('glioma', 'Phenotype', 'HP:0009733', (314, 320))	('Temozolomide', 'Chemical', 'MESH:D000077204', (41, 53))	('gliomas', 'Disease', 'MESH:D005910', (352, 359))	('Gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Brainstem Gliomas', 'Phenotype', 'HP:0010796', (129, 146))	('O6BG', 'Chemical', 'MESH:C064976', (427, 431))	('O6-benzylguanine', 'Var', (409, 425))	('gliomas', 'Disease', 'MESH:D005910', (314, 321))	('Brain Tumor', 'Phenotype', 'HP:0030692', (160, 171))	('glioma', 'Phenotype', 'HP:0009733', (352, 358))	('patients', 'Species', '9606', (264, 272))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (342, 359))	('BSG', 'Chemical', '-', (361, 364))	('gliomas', 'Phenotype', 'HP:0009733', (352, 359))	('gliomas', 'Phenotype', 'HP:0009733', (314, 321))
127444	21968943	The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms.	('toxicities', 'Disease', (63, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('O6BG', 'Chemical', 'MESH:C064976', (19, 23))	('toxicities', 'Disease', 'MESH:D064420', (63, 73))	('myelosuppression and gastrointestinal symptoms', 'Disease', 'MESH:D012817', (79, 125))	('O6BG', 'Var', (19, 23))
127448	21968943	The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.	('HGG', 'Disease', (138, 141))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('O6BG', 'Chemical', 'MESH:C064976', (19, 23))	('patients', 'Species', '9606', (99, 107))	('BSG', 'Disease', (146, 149))	('BSG', 'Chemical', '-', (146, 149))	('O6BG', 'Var', (19, 23))
127456	21968943	Although the O6-methylguanine adducts represent less than 10% of the methylation events, these lesions are primarily responsible for TMZ-mediated cytotoxicity by triggering the mismatch repair pathway and apoptosis.	('apoptosis', 'CPA', (205, 214))	('mismatch repair pathway', 'Pathway', (177, 200))	('O6-methylguanine', 'Var', (13, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (146, 158))	('triggering', 'Reg', (162, 172))	('TMZ', 'Chemical', 'MESH:D000077204', (133, 136))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (13, 29))	('responsible', 'Reg', (117, 128))	('cytotoxicity', 'Disease', (146, 158))
127458	21968943	It is a single turnover protein that specifically recognizes and removes the methyl adduct from the O6-position of guanine, thus restoring DNA but inactivating itself in the process.MGMT promoter methylation, which leads to lower MGMT protein expression, is associated with better clinical outcomes in adults and children with high-grade gliomas.	('gliomas', 'Disease', (338, 345))	('MGMT', 'Gene', '4255', (230, 234))	('MGMT', 'Gene', (182, 186))	('children', 'Species', '9606', (313, 321))	('gliomas', 'Disease', 'MESH:D005910', (338, 345))	('MGMT', 'Gene', '4255', (182, 186))	('expression', 'MPA', (243, 253))	('methylation', 'Var', (196, 207))	('lower', 'NegReg', (224, 229))	('guanine', 'Chemical', 'MESH:D006147', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (338, 345))	('glioma', 'Phenotype', 'HP:0009733', (338, 344))	('MGMT', 'Gene', (230, 234))	('better', 'PosReg', (274, 280))
127460	21968943	In preclinical studies, O6BG potentiates TMZ antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('O6BG', 'Var', (24, 28))	('potentiates', 'PosReg', (29, 40))	('tumor', 'Disease', (49, 54))	('O6BG', 'Chemical', 'MESH:C064976', (24, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (41, 44))
127463	21968943	We hypothesized that the efficacy of TMZ would be enhanced when given with O6BG to children with high-grade and brainstem gliomas.	('O6BG', 'Var', (75, 79))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('O6BG', 'Chemical', 'MESH:C064976', (75, 79))	('TMZ', 'Chemical', 'MESH:D000077204', (37, 40))	('efficacy', 'MPA', (25, 33))	('gliomas', 'Disease', (122, 129))	('enhanced', 'PosReg', (50, 58))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (112, 129))	('children', 'Species', '9606', (83, 91))
127466	21968943	Eligible patients were required to have bidimensionally measurable disease on radiographic studies; no more than two recurrences/progression; a Karnofsky or Lansky performance score >=60; recovered from the toxic effects (to grade < 2 using CTCAE v.3.0) of prior therapy; received their last dose of known myelosuppressive chemotherapy or biologic therapy >=3 weeks prior to registration (>=6 weeks for nitrosourea), and nonmyelosuppressive agent >=7 days prior to registration; received their last fraction of radiation >=12 weeks prior to registration; adequate hematologic function (ANC>1500/mm3, Hb >8 gm/dl, ALC >=500/mm3, platelets >=100,000/mm3); an age-adjusted normal serum creatinine or a creatinine clearance >60 mL/min/1.73m2; SGOT and SGPT up to 2.5 times the upper limit of normal; and total bilirubin up to 1.5 times the upper limit of normal.	('ANC>1500/mm3', 'Var', (586, 598))	('patients', 'Species', '9606', (9, 17))	('min/1', 'Gene', '966', (727, 732))	('SGOT', 'MPA', (739, 743))	('SGPT', 'MPA', (748, 752))	('ALC', 'Gene', (613, 616))	('nitrosourea', 'Chemical', 'MESH:D009607', (403, 414))	('ALC', 'Gene', '55821', (613, 616))	('min/1', 'Gene', (727, 732))	('serum creatinine', 'MPA', (677, 693))	('creatinine clearance', 'MPA', (699, 719))
127470	21968943	The primary endpoint of this study was estimation of the confirmed, sustained (>=8 weeks) objective response rate (complete response + partial response) in children with HGG and BSG treated with the combination of O6BG and TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (223, 226))	('children', 'Species', '9606', (156, 164))	('O6BG', 'Chemical', 'MESH:C064976', (214, 218))	('BSG', 'Chemical', '-', (178, 181))	('HGG', 'Disease', (170, 173))	('BSG', 'Disease', (178, 181))	('O6BG', 'Var', (214, 218))
127483	21968943	The TMZ dose was also reduced for patients with any grade 4 toxicity or dose-related intolerable grade 3 toxicity at least possibly related to the combination of O6BG and TMZ.	('toxicity', 'Disease', (60, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (171, 174))	('O6BG', 'Var', (162, 166))	('patients', 'Species', '9606', (34, 42))	('reduced', 'NegReg', (22, 29))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (4, 7))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('toxicity', 'Disease', (105, 113))	('O6BG', 'Chemical', 'MESH:C064976', (162, 166))
127488	21968943	Patients who completed fewer than two courses of therapy were considered evaluable if they experienced disease progression or died from any cause after receiving any O6BG and TMZ.	('experienced', 'Reg', (91, 102))	('Patients', 'Species', '9606', (0, 8))	('O6BG', 'Var', (166, 170))	('TMZ', 'Chemical', 'MESH:D000077204', (175, 178))	('O6BG', 'Chemical', 'MESH:C064976', (166, 170))
127521	21968943	In the Phase II trial of TMZ plus O6BG in adults with TMZ-resistant glioma, objective response rates based on MacDonald criteria were 3% for patients with glioblastoma multiforme and 16% for patients with anaplastic gliomas, but the median progression-free survival was less than 8 weeks.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('O6BG', 'Var', (34, 38))	('patients', 'Species', '9606', (191, 199))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (155, 178))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (205, 223))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('patients', 'Species', '9606', (141, 149))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('anaplastic gliomas', 'Disease', (205, 223))	('glioblastoma multiforme', 'Disease', (155, 178))	('O6BG', 'Chemical', 'MESH:C064976', (34, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('glioma', 'Disease', (68, 74))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('TMZ', 'Chemical', 'MESH:D000077204', (25, 28))	('glioma', 'Disease', (216, 222))
127523	21968943	A Phase II study of O6BG administered with BCNU to patients with nitrosourea-resistant recurrent and progressive malignant glioma also did not show any significant benefit.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('BCNU', 'Chemical', 'MESH:D002330', (43, 47))	('progressive malignant glioma', 'Phenotype', 'HP:0012174', (101, 129))	('nitrosourea', 'Chemical', 'MESH:D009607', (65, 76))	('malignant glioma', 'Disease', (113, 129))	('O6BG', 'Var', (20, 24))	('malignant glioma', 'Disease', 'MESH:D005910', (113, 129))	('patients', 'Species', '9606', (51, 59))	('O6BG', 'Chemical', 'MESH:C064976', (20, 24))
127524	21968943	Prior studies have demonstrated both significant potentiation of alkylating agents in vitro when administered with O6BG and a correlation between MGMT expression and outcome for patients with high grade gliomas treated with TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (224, 227))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('O6BG', 'Chemical', 'MESH:C064976', (115, 119))	('alkylating agents', 'MPA', (65, 82))	('MGMT', 'Gene', '4255', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('MGMT', 'Gene', (146, 150))	('patients', 'Species', '9606', (178, 186))	('potentiation', 'PosReg', (49, 61))	('O6BG', 'Var', (115, 119))	('gliomas', 'Disease', (203, 210))
127526	21968943	The lack of potentiation of TMZ activity when administered with O6BG may be due to a number of factors.	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('O6BG', 'Chemical', 'MESH:C064976', (64, 68))	('TMZ activity', 'MPA', (28, 40))	('O6BG', 'Var', (64, 68))	('potentiation', 'MPA', (12, 24))
127530	21968943	MGMT expression within the tumor may not be effectively depleted: O6BG and its metabolites do not penetrate well across the intact blood:brain barrier, although studies in adults showed that 100 mg/m2 O6BG effectively reduced MGMT levels to <10 fmol/mg protein in brain tumors.	('MGMT', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('O6BG', 'Var', (201, 205))	('brain tumors', 'Disease', 'MESH:D001932', (264, 276))	('brain tumors', 'Phenotype', 'HP:0030692', (264, 276))	('MGMT', 'Gene', '4255', (0, 4))	('MGMT', 'Gene', '4255', (226, 230))	('reduced', 'NegReg', (218, 225))	('O6BG', 'Chemical', 'MESH:C064976', (66, 70))	('MGMT', 'Gene', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('O6BG', 'Chemical', 'MESH:C064976', (201, 205))	('tumor', 'Disease', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('brain tumors', 'Disease', (264, 276))
127533	21968943	Several approaches may be used to try to enhance the activity of O6BG with TMZ.	('enhance', 'PosReg', (41, 48))	('O6BG', 'Var', (65, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))	('activity', 'MPA', (53, 61))	('O6BG', 'Chemical', 'MESH:C064976', (65, 69))
127538	21968943	In summary, this study of O6BG and TMZ, administered on a daily x 5 schedule every 28 days to children with high-grade gliomas and brainstem gliomas, did not appear to significantly improve the activity of temozolomide alone.	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('temozolomide', 'Chemical', 'MESH:D000077204', (206, 218))	('O6BG', 'Chemical', 'MESH:C064976', (26, 30))	('improve', 'PosReg', (182, 189))	('children', 'Species', '9606', (94, 102))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (131, 148))	('gliomas', 'Disease', (119, 126))	('activity', 'MPA', (194, 202))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('gliomas', 'Disease', (141, 148))	('O6BG', 'Var', (26, 30))
127547	32493417	In this set, one case was found to harbor a CREBBP-GOLGA6L2 fusion and one case a CREBBP-SRRM2 fusion.	('fusion', 'Var', (60, 66))	('SRRM2', 'Gene', (89, 94))	('SRRM2', 'Gene', '23524', (89, 94))	('GOLGA6L2', 'Gene', '283685', (51, 59))	('CREBBP', 'Gene', (44, 50))	('GOLGA6L2', 'Gene', (51, 59))	('CREBBP', 'Gene', (82, 88))	('CREBBP', 'Gene', '1387', (44, 50))	('CREBBP', 'Gene', '1387', (82, 88))
127551	32493417	Fusion transcripts are increasingly recognized as important oncogenic drivers in tumors of the central nervous system (CNS).	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (81, 117))	('Fusion transcripts', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (81, 117))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors of the central nervous system', 'Disease', (81, 117))
127552	32493417	These include KIAA1549-BRAF, typically resulting from tandem duplication and characteristic of pilocytic astrocytoma, C11orf95-RELA in supratentorial ependymoma, and FGFR-TACC (e.g.	('supratentorial ependymoma', 'Disease', (135, 160))	('BRAF', 'Gene', '673', (23, 27))	('pilocytic astrocytoma', 'Disease', (95, 116))	('RELA', 'Gene', (127, 131))	('RELA', 'Gene', '5970', (127, 131))	('KIAA1549', 'Gene', (14, 22))	('BRAF', 'Gene', (23, 27))	('C11orf95', 'Gene', (118, 126))	('KIAA1549', 'Gene', '57670', (14, 22))	('ependymoma', 'Phenotype', 'HP:0002888', (150, 160))	('tandem duplication', 'Var', (54, 72))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (95, 116))	('supratentorial ependymoma', 'Disease', 'MESH:D004806', (135, 160))	('resulting from', 'Reg', (39, 53))	('C11orf95', 'Gene', '65998', (118, 126))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
127554	32493417	Recurrent fusion transcripts have additionally been identified in pediatric infiltrating gliomas, including those involving the MYB and MYBL1 loci.	('identified', 'Reg', (52, 62))	('MYB', 'Gene', (128, 131))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('MYBL1', 'Gene', (136, 141))	('fusion', 'Var', (10, 16))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('MYBL1', 'Gene', '4603', (136, 141))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('MYB', 'Gene', '4602', (136, 139))	('MYB', 'Gene', '4602', (128, 131))	('MYB', 'Gene', (136, 139))
127557	32493417	These tumors, termed "high grade neuroepithelial tumor with BCOR alteration" (HGNET-BCOR), are characterized in most cases by an internal tandem duplication involving exon 15 of the gene.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('BCOR', 'Gene', (84, 88))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (33, 54))	('BCOR', 'Gene', (60, 64))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (33, 54))	('BCOR', 'Gene', '54880', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BCOR', 'Gene', '54880', (60, 64))	('neuroepithelial tumor', 'Disease', (33, 54))	('internal tandem duplication', 'Var', (129, 156))
127558	32493417	Fusion transcripts involving the BCOR gene have also been described in a diversity of tumors extrinsic to the CNS including clear cell sarcoma of the kidney, ossifying fibromyxoid tumors, acute promyelocytic leukemia, endometrial stromal sarcoma (ESS), adult non-uterine sarcoma, and a subset of small blue round cell sarcomas .	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (124, 156))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('sarcoma', 'Disease', (135, 142))	('BCOR', 'Gene', '54880', (33, 37))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (188, 216))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (135, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcomas', 'Disease', (318, 326))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('BCOR', 'Gene', (33, 37))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', (180, 186))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (135, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (158, 186))	('ossifying fibromyxoid tumors', 'Disease', (158, 186))	('described', 'Reg', (58, 67))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (218, 245))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (263, 278))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('sarcoma', 'Disease', 'MESH:D012509', (271, 278))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (188, 216))	('sarcoma', 'Disease', 'MESH:D012509', (238, 245))	('sarcoma of the kidney', 'Disease', (135, 156))	('sarcoma', 'Disease', (271, 278))	('sarcoma', 'Disease', 'MESH:D012509', (318, 325))	('sarcoma', 'Disease', (238, 245))	('sarcomas', 'Disease', 'MESH:D012509', (318, 326))	('acute promyelocytic leukemia', 'Disease', (188, 216))	('Fusion transcripts', 'Var', (0, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (318, 326))	('sarcoma', 'Disease', (318, 325))	('leukemia', 'Phenotype', 'HP:0001909', (208, 216))	('endometrial stromal sarcoma', 'Disease', (218, 245))
127587	32493417	A targeted next generation sequencing panel (Oncomine v3) revealed truncating mutations in NF1 and ARID1A.	('truncating mutations', 'Var', (67, 87))	('ARID1A', 'Gene', (99, 105))	('NF1', 'Gene', (91, 94))	('NF1', 'Gene', '4763', (91, 94))	('ARID1A', 'Gene', '8289', (99, 105))
127590	32493417	In addition, targeted PCR followed by Sanger sequencing and immunohistochemistry was conducted to rule out mutations of H3F3A at codons 27 and 34.	('H3F3A', 'Gene', (120, 125))	('mutations', 'Var', (107, 116))	('H3F3A', 'Gene', '3020', (120, 125))
127591	32493417	If current recommendations for the adult setting were to be applied, the presence of TERT promoter mutation in combination with an absence of IDH1/IDH2 mutation would be compatible with a diagnosis of diffuse astrocytic glioma, with molecular features of glioblastoma, WHO grade IV.	('presence', 'Var', (73, 81))	('TERT', 'Gene', (85, 89))	('IDH1', 'Gene', '3417', (142, 146))	('glioblastoma', 'Disease', (255, 267))	('TERT', 'Gene', '7015', (85, 89))	('IDH1', 'Gene', (142, 146))	('mutation', 'Var', (99, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (255, 267))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('IDH2', 'Gene', (147, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (255, 267))	('astrocytic glioma', 'Disease', 'MESH:D001254', (209, 226))	('IDH2', 'Gene', '3418', (147, 151))	('astrocytic glioma', 'Disease', (209, 226))
127608	32493417	Furthermore, we compared the BCOR-CREBBP fusion product in the present case to that of previously reported chimeric transcripts involving BCOR rearrangements with CREBBP or EP300 in ESS and pediatric gliomas.	('BCOR', 'Gene', (138, 142))	('rearrangements', 'Var', (143, 157))	('CREBBP', 'Gene', '1387', (163, 169))	('gliomas', 'Disease', (200, 207))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('CREBBP', 'Gene', (34, 40))	('BCOR', 'Gene', (29, 33))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('BCOR', 'Gene', '54880', (138, 142))	('EP300', 'Gene', (173, 178))	('BCOR', 'Gene', '54880', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('ESS', 'Disease', (182, 185))	('CREBBP', 'Gene', '1387', (34, 40))	('CREBBP', 'Gene', (163, 169))	('EP300', 'Gene', '2033', (173, 178))
127609	32493417	The previously reported events include BCOR-CREBBP and CREBBP-BCOR fusions in ESS, and EP300-BCOR fusions in 3 cases of pediatric glioma.	('BCOR', 'Gene', (93, 97))	('CREBBP', 'Gene', (44, 50))	('BCOR', 'Gene', '54880', (62, 66))	('glioma', 'Disease', (130, 136))	('BCOR', 'Gene', '54880', (93, 97))	('fusions', 'Var', (98, 105))	('CREBBP-BCOR', 'Gene', (55, 66))	('BCOR', 'Gene', (39, 43))	('EP300', 'Gene', (87, 92))	('EP300', 'Gene', '2033', (87, 92))	('BCOR', 'Gene', '54880', (39, 43))	('CREBBP', 'Gene', '1387', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('CREBBP', 'Gene', '1387', (44, 50))	('CREBBP-BCOR', 'Gene', '1387;54880', (55, 66))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('CREBBP', 'Gene', (55, 61))	('BCOR', 'Gene', (62, 66))
127610	32493417	The extent of the BCOR segment of the chimeric transcripts was variable among the reported cases (Supplementary Fig.	('BCOR', 'Gene', (18, 22))	('chimeric', 'Var', (38, 46))	('BCOR', 'Gene', '54880', (18, 22))
127616	32493417	Gene fusions have been described in a diversity of CNS tumors similar to other tumor families, including hematopoietic neoplasms and sarcomas.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CNS tumors', 'Disease', (51, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('hematopoietic neoplasms', 'Disease', (105, 128))	('sarcomas', 'Disease', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Gene fusions', 'Var', (0, 12))	('CNS tumors', 'Disease', 'MESH:D016543', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('tumor', 'Disease', (79, 84))	('CNS tumor', 'Phenotype', 'HP:0100006', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (55, 60))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (105, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('described', 'Reg', (23, 32))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (105, 128))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
127617	32493417	For example, a tandem duplication event linking BRAF to a nearby gene, KIAA1549, is a recurrent event seen in a majority of pilocytic astrocytomas and represents the predominant neoplastic driver in such cases.	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('KIAA1549', 'Gene', (71, 79))	('KIAA1549', 'Gene', '57670', (71, 79))	('tandem duplication event', 'Var', (15, 39))	('pilocytic astrocytomas', 'Disease', (124, 146))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (124, 146))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
127618	32493417	For example, those infiltrating gliomas with FGFR-TACC fusions may present with other oncogenic alterations including CDKN2A loss, CDK4 amplification, MDM2 amplification and/or TERT promoter mutations.	('CDKN2A', 'Gene', (118, 124))	('TERT', 'Gene', (177, 181))	('CDK4', 'Gene', (131, 135))	('amplification', 'Var', (156, 169))	('loss', 'NegReg', (125, 129))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('TERT', 'Gene', '7015', (177, 181))	('CDK4', 'Gene', '1019', (131, 135))	('CDKN2A', 'Gene', '1029', (118, 124))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('MDM2', 'Gene', '4193', (151, 155))	('MDM2', 'Gene', (151, 155))	('FGFR-TACC', 'Gene', (45, 54))	('present', 'Reg', (67, 74))	('amplification', 'Var', (136, 149))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('fusions', 'Var', (55, 62))
127622	32493417	Recent in vivo studies suggest that the PUFD domain is essential for a tumor suppressor function of BCOR and that loss of BCOR promotes leukemogenesis.	('promotes', 'PosReg', (127, 135))	('BCOR', 'Gene', '54880', (100, 104))	('BCOR', 'Gene', '54880', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('loss', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('BCOR', 'Gene', (122, 126))	('tumor', 'Disease', (71, 76))	('BCOR', 'Gene', (100, 104))	('leukemogenesis', 'Disease', (136, 150))
127623	32493417	Moreover, next-generation sequencing studies have revealed various BCOR alterations in a broad range of neoplastic diseases.	('alterations', 'Var', (72, 83))	('neoplastic diseases', 'Disease', 'MESH:D009386', (104, 123))	('neoplastic diseases', 'Disease', (104, 123))	('BCOR', 'Gene', (67, 71))	('BCOR', 'Gene', '54880', (67, 71))
127624	32493417	In CNS tumors, loss of function BCOR mutations (e.g., nonsense, frameshift, splice sites and deletions) have been described in medulloblastoma, high-grade pediatric gliomas and astroblastomas.	('medulloblastoma', 'Disease', 'MESH:D008527', (127, 142))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('medulloblastoma', 'Phenotype', 'HP:0002885', (127, 142))	('BCOR', 'Gene', '54880', (32, 36))	('medulloblastoma', 'Disease', (127, 142))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('BCOR', 'Gene', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('astroblastomas', 'Disease', (177, 191))	('CNS tumors', 'Disease', 'MESH:D016543', (3, 13))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('splice sites', 'Var', (76, 88))	('CNS tumor', 'Phenotype', 'HP:0100006', (3, 12))	('frameshift', 'Var', (64, 74))	('loss of function', 'NegReg', (15, 31))	('astroblastomas', 'Disease', 'MESH:D018302', (177, 191))	('nonsense', 'Var', (54, 62))	('deletions', 'Var', (93, 102))	('gliomas', 'Disease', (165, 172))	('CNS tumors', 'Disease', (3, 13))
127626	32493417	Moreover, since the BCOR gene is located on the X-chromosome, the BCOR gene in the index case is present as only one allele and the fusion event would lead to a complete loss of putative tumor-suppressor activity mediated by the PUFD.	('BCOR', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('BCOR', 'Gene', '54880', (20, 24))	('BCOR', 'Gene', '54880', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('loss', 'NegReg', (170, 174))	('tumor', 'Disease', (187, 192))	('fusion', 'Var', (132, 138))	('BCOR', 'Gene', (20, 24))
127634	32493417	In cancer, CREBBP/EP300 is targeted by both mutations and structural alterations.	('CREBBP', 'Gene', '1387', (11, 17))	('EP300', 'Gene', (18, 23))	('EP300', 'Gene', '2033', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('CREBBP', 'Gene', (11, 17))	('structural alterations', 'Var', (58, 80))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
127637	32493417	Given that the CREBBP component of the fusion transcript in our case retains only exon 31 and consequently lacks most of the functional domains, loss of CREBBP through this gene fusion potentially promotes gliomagenesis.	('CREBBP', 'Gene', (15, 21))	('exon 31', 'MPA', (82, 89))	('CREBBP', 'Gene', '1387', (153, 159))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('lacks', 'NegReg', (107, 112))	('glioma', 'Disease', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('loss', 'Var', (145, 149))	('CREBBP', 'Gene', '1387', (15, 21))	('functional domains', 'MPA', (125, 143))	('promotes', 'PosReg', (197, 205))	('CREBBP', 'Gene', (153, 159))
127641	32493417	While the pathogenic impact of most reported gene fusions is gain-of-function, such as constitutive kinase activation and abnormal activity of transcriptional factors, fusions resulting in loss of function of tumor suppressors have been identified as well.	('tumor', 'Disease', (209, 214))	('gain-of-function', 'PosReg', (61, 77))	('transcriptional', 'Protein', (143, 158))	('loss of function', 'NegReg', (189, 205))	('activity', 'MPA', (131, 139))	('fusions', 'Var', (50, 57))	('constitutive', 'MPA', (87, 99))	('fusions', 'Var', (168, 175))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('activation', 'PosReg', (107, 117))
127642	32493417	The APC-COMMD10 fusion in colorectal cancer is one example wherein fusion-mediated truncation leads to a loss-of-function of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('truncation', 'Var', (83, 93))	('colorectal cancer', 'Disease', (26, 43))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('APC', 'Disease', 'MESH:D011125', (4, 7))	('APC', 'Disease', (4, 7))	('tumor', 'Disease', (125, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('COMMD10', 'Gene', '51397', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('COMMD10', 'Gene', (8, 15))	('fusion', 'Var', (16, 22))	('loss-of-function', 'NegReg', (105, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))
127643	32493417	suggested that the lack of functional domains in APC resulting from the APC-COMMD10 gene fusion can lead to tumorigenesis where loss of APC is known to be a critical event in the development of colon cancer.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('fusion', 'Var', (89, 95))	('colon cancer', 'Disease', 'MESH:D015179', (194, 206))	('COMMD10', 'Gene', '51397', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('APC', 'Disease', 'MESH:D011125', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('tumor', 'Disease', (108, 113))	('colon cancer', 'Disease', (194, 206))	('APC', 'Disease', (136, 139))	('lead to', 'Reg', (100, 107))	('APC', 'Disease', (49, 52))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (194, 206))	('COMMD10', 'Gene', (76, 83))	('APC', 'Disease', (72, 75))
127646	32493417	A fusion involving CREBBP with BCORL1 has been described in ossifying fibromyxoid tumors, with a similar breakpoint region to that seen in our case, though with a distinct predicted fusion transcript that preserves the HAT domain of CREBBP.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('BCORL1', 'Gene', '63035', (31, 37))	('CREBBP', 'Gene', (19, 25))	('CREBBP', 'Gene', '1387', (233, 239))	('HAT domain', 'MPA', (219, 229))	('CREBBP', 'Gene', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BCORL1', 'Gene', (31, 37))	('described', 'Reg', (47, 56))	('CREBBP', 'Gene', '1387', (19, 25))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (60, 88))	('ossifying fibromyxoid tumors', 'Disease', (60, 88))	('fusion', 'Var', (2, 8))
127654	32493417	Given that CNS tumors with previously reported BCOR alterations, such as BCOR ex15 ITD, EP300-BCOR fusions, and loss-of-function mutations predominantly arise in pediatric or young adult patients, expanding analysis to larger cohorts enriched in pediatric patients would be warranted and may increase the chances of detecting further events involving CREBBP and/or BCOR.	('BCOR', 'Gene', '54880', (73, 77))	('ex15 ITD', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CREBBP', 'Gene', (351, 357))	('BCOR', 'Gene', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('patients', 'Species', '9606', (187, 195))	('CNS tumors', 'Disease', 'MESH:D016543', (11, 21))	('BCOR', 'Gene', '54880', (365, 369))	('BCOR', 'Gene', '54880', (47, 51))	('EP300', 'Gene', '2033', (88, 93))	('loss-of-function', 'NegReg', (112, 128))	('CREBBP', 'Gene', '1387', (351, 357))	('BCOR', 'Gene', (365, 369))	('BCOR', 'Gene', '54880', (94, 98))	('BCOR', 'Gene', (47, 51))	('CNS tumor', 'Phenotype', 'HP:0100006', (11, 20))	('EP300', 'Gene', (88, 93))	('BCOR', 'Gene', (94, 98))	('mutations', 'Var', (129, 138))	('patients', 'Species', '9606', (256, 264))	('CNS tumors', 'Disease', (11, 21))
127672	31547109	Evidence-based data demonstrated good diagnostic performance of PET with different tracers in detecting brain tumors, in particular, radiolabelled amino acid tracers showed the highest diagnostic performance values.	('brain tumors', 'Phenotype', 'HP:0030692', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('brain tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('brain tumors', 'Disease', 'MESH:D001932', (104, 116))	('radiolabelled', 'Var', (133, 146))	('brain tumor', 'Phenotype', 'HP:0030692', (104, 115))
127686	31547109	18F-FET is taken up into neoplastic cells due to their increased amino acid uptake through an L-type amino acid transport system, and it is not incorporated into proteins.	('18F-FET', 'Chemical', 'MESH:C528727', (0, 7))	('increased', 'PosReg', (55, 64))	('amino acid uptake', 'MPA', (65, 82))	('18F-FET', 'Var', (0, 7))
127695	31547109	A comprehensive computer literature search of the Cochrane library and PubMed/Medline databases was performed to find published meta-analyses on the diagnostic performance or prognostic value of PET or hybrid PET/CT or PET/MRI in patients with brain tumors.	('brain tumor', 'Phenotype', 'HP:0030692', (244, 255))	('PET', 'Var', (195, 198))	('PET/MRI', 'Gene', '78996', (219, 226))	('PET/MRI', 'Gene', (219, 226))	('patients', 'Species', '9606', (230, 238))	('brain tumors', 'Disease', 'MESH:D001932', (244, 256))	('brain tumors', 'Phenotype', 'HP:0030692', (244, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('brain tumors', 'Disease', (244, 256))
127696	31547109	Meta-analyses investigating the diagnostic performance or prognostic value of PET or PET/CT or PET/MRI with different tracers in brain tumors were eligible for inclusion.	('PET/MRI', 'Gene', (95, 102))	('brain tumors', 'Disease', 'MESH:D001932', (129, 141))	('PET', 'Var', (78, 81))	('brain tumors', 'Phenotype', 'HP:0030692', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PET/MRI', 'Gene', '78996', (95, 102))	('brain tumors', 'Disease', (129, 141))	('brain tumor', 'Phenotype', 'HP:0030692', (129, 140))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
127700	31547109	A meta-analysis including patients with suspicious primary brain tumors showed that 18F-FDG PET or PET/CT has a moderate sensitivity and specificity for differentiating brain tumors from non-tumor lesions.	('18F-FDG', 'Chemical', 'MESH:D019788', (84, 91))	('brain tumor', 'Phenotype', 'HP:0030692', (169, 180))	('18F-FDG PET', 'Var', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('brain tumors', 'Disease', (59, 71))	('brain tumors', 'Disease', 'MESH:D001932', (169, 181))	('brain tumors', 'Phenotype', 'HP:0030692', (169, 181))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (175, 180))	('brain tumors', 'Disease', (169, 181))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('patients', 'Species', '9606', (26, 34))	('brain tumors', 'Disease', 'MESH:D001932', (59, 71))	('brain tumors', 'Phenotype', 'HP:0030692', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('brain tumor', 'Phenotype', 'HP:0030692', (59, 70))
127702	31547109	Another meta-analysis also demonstrated that 18F-FDG PET or PET/CT have a moderate diagnostic performance in distinguishing between tumoral and non-tumoral lesions in the brain, lower than amino acid PET.	('18F-FDG', 'Var', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('non-tumoral lesions', 'Disease', (144, 163))	('non-tumoral lesions', 'Disease', 'MESH:D001932', (144, 163))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('18F-FDG', 'Chemical', 'MESH:D019788', (45, 52))	('tumoral', 'Disease', (132, 139))	('tumoral', 'Disease', 'MESH:D009369', (132, 139))	('tumoral', 'Disease', (148, 155))	('tumoral', 'Disease', 'MESH:D009369', (148, 155))
127707	31547109	In a head-to-head comparative meta-analysis, the diagnostic performance of 18F-FET PET or PET/CT in distinguishing between tumoral and non-tumoral lesions in the brain was found to be significantly higher compared to that of 18F-FDG PET or PET/CT performed in the same patients.	('tumoral', 'Disease', (139, 146))	('tumoral', 'Disease', 'MESH:D009369', (139, 146))	('18F-FDG', 'Chemical', 'MESH:D019788', (225, 232))	('tumoral', 'Disease', (123, 130))	('tumoral', 'Disease', 'MESH:D009369', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('non-tumoral lesions', 'Disease', (135, 154))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('18F-FET', 'Var', (75, 82))	('18F-FET', 'Chemical', 'MESH:C528727', (75, 82))	('non-tumoral lesions', 'Disease', 'MESH:D001932', (135, 154))	('patients', 'Species', '9606', (269, 277))	('higher', 'PosReg', (198, 204))
127715	31547109	A recent meta-analysis demonstrated a lower sensitivity of 18F-FDG PET or PET/CT in differentiating between high-grade and low-grade gliomas compared to radiolabelled amino acid PET (11C-methionine and 18F-FET) but with higher specificity.	('18F-FDG', 'Var', (59, 66))	('18F-FET', 'Chemical', 'MESH:C528727', (202, 209))	('lower', 'NegReg', (38, 43))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('18F-FDG', 'Chemical', 'MESH:D019788', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('high-grade', 'Disease', (108, 118))	('11C-methionine', 'Chemical', 'MESH:C086242', (183, 197))
127716	31547109	11C-methionine PET or PET/CT had a moderate diagnostic accuracy in differentiating between high-grade and low-grade gliomas, according to data provided by a recent meta-analysis (pooled sensitivity and specificity of 80% and 72%, respectively).	('high-grade', 'Disease', (91, 101))	('11C-methionine', 'Chemical', 'MESH:C086242', (0, 14))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('11C-methionine PET', 'Var', (0, 18))
127717	31547109	Another meta-analysis demonstrated that 11C-methionine PET or PET/CT has a higher sensitivity compared to 18F-FDG PET or PET/CT in differentiating between high-grade and low-grade gliomas but with lower specificity; diagnostic performance values were similar to those of 18F-FET PET or PET/CT in this setting.	('11C-methionine', 'Var', (40, 54))	('18F-FET', 'Chemical', 'MESH:C528727', (271, 278))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('11C-methionine', 'Chemical', 'MESH:C086242', (40, 54))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('18F-FDG', 'Chemical', 'MESH:D019788', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('high-grade', 'Disease', (155, 165))
127721	31547109	For differentiating high-grade from low-grade gliomas, 18F-FDOPA PET or PET/CT showed a pooled sensitivity of 88% and a pooled specificity of 73%.	('18F-FDOPA', 'Chemical', 'MESH:C043437', (55, 64))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('high-grade', 'Disease', (20, 30))	('gliomas', 'Disease', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('18F-FDOPA', 'Var', (55, 64))
127723	31547109	A recent evidence-based article suggested that radiolabelled amino acid PET may ameliorate the delineation of high-grade gliomas compared to standard MRI.	('radiolabelled amino acid', 'Var', (47, 71))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('ameliorate', 'PosReg', (80, 90))
127726	31547109	showed that the diagnostic performance of 18F-FDG PET or PET/CT in detecting recurrent brain tumors was lower compared to that of radiolabelled amino acid PET or PET/CT.	('brain tumors', 'Disease', (87, 99))	('18F-FDG', 'Var', (42, 49))	('brain tumor', 'Phenotype', 'HP:0030692', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('lower', 'NegReg', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('18F-FDG', 'Chemical', 'MESH:D019788', (42, 49))	('brain tumors', 'Disease', 'MESH:D001932', (87, 99))	('brain tumors', 'Phenotype', 'HP:0030692', (87, 99))
127729	31547109	reported a moderate sensitivity (70%) but a good specificity (88%) of 18F-FDG PET or PET/CT in detecting recurrent glioma; however, the diagnostic accuracy was lower compared to that of 11C-methionine PET or PET/CT and magnetic resonance spectroscopy in this setting.	('11C-methionine', 'Chemical', 'MESH:C086242', (186, 200))	('18F-FDG', 'Var', (70, 77))	('glioma', 'Disease', (115, 121))	('18F-FDG', 'Chemical', 'MESH:D019788', (70, 77))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('lower', 'NegReg', (160, 165))
127730	31547109	Another meta-analysis demonstrated that the diagnostic performance of 18F-FDG PET or PET/CT in detecting recurrent glioma is not optimal, in particular if compared with other available neuroimaging methods.	('glioma', 'Disease', (115, 121))	('18F-FDG', 'Chemical', 'MESH:D019788', (70, 77))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('18F-FDG PET', 'Var', (70, 81))
127731	31547109	11C-methionine PET or PET/CT demonstrated good diagnostic performance in detecting brain tumor recurrence (pooled sensitivity and specificity of 92% and 87%, respectively), with higher values compared to 18F-FDG PET or PET/CT.	('brain tumor', 'Phenotype', 'HP:0030692', (83, 94))	('11C-methionine', 'Chemical', 'MESH:C086242', (0, 14))	('higher', 'PosReg', (178, 184))	('brain tumor', 'Disease', 'MESH:D001932', (83, 94))	('brain tumor', 'Disease', (83, 94))	('18F-FDG', 'Chemical', 'MESH:D019788', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('11C-methionine PET', 'Var', (0, 18))
127732	31547109	For high-grade gliomas, pooled sensitivity and specificity of 11C-methionine PET or PET/CT in detecting glioma recurrence were 70% and 93%, respectively.	('11C-methionine PET', 'Var', (62, 80))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('glioma', 'Disease', (15, 21))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('11C-methionine', 'Chemical', 'MESH:C086242', (62, 76))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('PET/CT', 'Var', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('glioma', 'Disease', (104, 110))
127733	31547109	Compared to dynamic susceptibility contrast-enhanced MRI, 11C-methionine PET or PET/CT demonstrated comparable pooled sensitivity and specificity in detecting glioma recurrence, with pooled values of 87% and 81.3%, respectively.	('glioma', 'Disease', (159, 165))	('11C-methionine PET', 'Var', (58, 76))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('PET/CT', 'Var', (80, 86))	('11C-methionine', 'Chemical', 'MESH:C086242', (58, 72))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))
127734	31547109	who demonstrated that the diagnostic performance of 11C-methionine PET or PET/CT in detecting glioma recurrence was similar to that of magnetic resonance spectroscopy.	('11C-methionine PET', 'Var', (52, 70))	('PET/CT', 'Var', (74, 80))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('11C-methionine', 'Chemical', 'MESH:C086242', (52, 66))
127738	31547109	The good diagnostic performance of 18F-FET PET or PET/CT in this setting was also confirmed by Furuse et al., who reported increased diagnostic performance of 18F-FET PET or PET/CT compared to 18F-FDG and 11C-methionine PET or PET/CT.	('increased', 'PosReg', (123, 132))	('PET/CT', 'Var', (174, 180))	('11C-methionine', 'Chemical', 'MESH:C086242', (205, 219))	('18F-FET PET', 'Var', (159, 170))	('18F-FET', 'Chemical', 'MESH:C528727', (35, 42))	('18F-FET', 'Chemical', 'MESH:C528727', (159, 166))	('18F-FDG', 'Chemical', 'MESH:D019788', (193, 200))	('diagnostic performance', 'MPA', (133, 155))
127739	31547109	found that amino acid PET or PET/CT, including 18F-FET PET, has a good diagnostic performance in differentiating residual or recurrent brain tumors from treatment-related changes (pseudoprogression) in patients with high-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('gliomas', 'Disease', (227, 234))	('18F-FET', 'Chemical', 'MESH:C528727', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('18F-FET PET', 'Var', (47, 58))	('brain tumors', 'Disease', (135, 147))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('brain tumor', 'Phenotype', 'HP:0030692', (135, 146))	('patients', 'Species', '9606', (202, 210))	('amino acid PET', 'Var', (11, 25))	('brain tumors', 'Phenotype', 'HP:0030692', (135, 147))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('brain tumors', 'Disease', 'MESH:D001932', (135, 147))
127746	31547109	A meta-analysis demonstrated that the pooled sensitivity and specificity of 18F-FDG PET or PET/CT in detecting brain metastases in patients with lung cancer were 21% and 100%, respectively.	('patients', 'Species', '9606', (131, 139))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('metastases', 'Disease', (117, 127))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('18F-FDG PET', 'Var', (76, 87))	('18F-FDG', 'Chemical', 'MESH:D019788', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
127748	31547109	18F-FDG PET and PET/CT showed considerable accuracy in identifying PCNSL among various brain lesions in immunocompetent patients (pooled sensitivity and specificity of 88% and 86%, respectively), therefore, 18F-FDG PET/CT could be a valuable diagnostic imaging method in this setting.	('PCNSL', 'Disease', 'MESH:D016543', (67, 72))	('18F-FDG', 'Var', (207, 214))	('PCNSL', 'Disease', (67, 72))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('patients', 'Species', '9606', (120, 128))	('brain lesions', 'Disease', (87, 100))	('brain lesions', 'Disease', 'MESH:D001927', (87, 100))	('18F-FDG', 'Chemical', 'MESH:D019788', (207, 214))
127751	31547109	A recent meta-analysis demonstrated that increased TBR at 18F-FDG PET, 11C-methionine PET and 18F-FET PET could indicate poor overall survival (pooled hazard ratios were 3.05 for 18F-FDG PET, 1.59 for 11C-methionine PET, and 1.15 for 18F-FET PET).	('overall survival', 'CPA', (126, 142))	('11C-methionine', 'Chemical', 'MESH:C086242', (201, 215))	('increased', 'PosReg', (41, 50))	('11C-methionine', 'Chemical', 'MESH:C086242', (71, 85))	('18F-FET', 'Chemical', 'MESH:C528727', (234, 241))	('18F-FDG', 'Chemical', 'MESH:D019788', (58, 65))	('18F-FET', 'Chemical', 'MESH:C528727', (94, 101))	('18F-FDG', 'Chemical', 'MESH:D019788', (179, 186))	('18F-FDG PET', 'Var', (58, 69))	('TBR', 'CPA', (51, 54))	('18F-FDG PET', 'Var', (179, 190))	('11C-methionine PET', 'Var', (71, 89))	('poor', 'NegReg', (121, 125))
127775	31547109	To this end, some cost-effectiveness analyses on the use of amino acid PET or PET/CT in brain tumors are already available, demonstrating that the combination of amino acid PET and MRI may be cost-effective for target selection in patients with suspicious glioma, for the surgical plan in patients with high-grade glioma, and for the evaluation of patients with suspicious recurrent high-grade glioma or brain metastasis.	('patients', 'Species', '9606', (348, 356))	('glioma', 'Disease', (314, 320))	('glioma', 'Disease', 'MESH:D005910', (394, 400))	('glioma', 'Disease', 'MESH:D005910', (314, 320))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('brain tumors', 'Disease', 'MESH:D001932', (88, 100))	('brain tumors', 'Phenotype', 'HP:0030692', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Phenotype', 'HP:0009733', (394, 400))	('brain tumor', 'Phenotype', 'HP:0030692', (88, 99))	('glioma', 'Disease', (256, 262))	('glioma', 'Phenotype', 'HP:0009733', (314, 320))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('patients', 'Species', '9606', (289, 297))	('amino', 'Var', (162, 167))	('brain tumors', 'Disease', (88, 100))	('brain metastasis', 'CPA', (404, 420))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('patients', 'Species', '9606', (231, 239))	('glioma', 'Disease', (394, 400))
127785	33173989	Furthermore, analysis using data from The Cancer Genome Atlas database confirmed the molecular mechanism and biological significance of dysregulation of TPTEP1 in glioma progression.	('glioma', 'Disease', (163, 169))	('dysregulation', 'Var', (136, 149))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('TPTEP1', 'Gene', '387590', (153, 159))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('TPTEP1', 'Gene', (153, 159))
127795	33173989	Furthermore, nano complex targeting metastasis associated lung adenocarcinoma transcript 1 may lower the stemness of GBM cells and improve the sensitivity of GBM cells to the current first-line therapy of GBM.	('sensitivity', 'MPA', (143, 154))	('lower', 'NegReg', (95, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (58, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('stemness of GBM cells', 'CPA', (105, 126))	('nano', 'Var', (13, 17))	('improve', 'PosReg', (131, 138))	('lung adenocarcinoma', 'Disease', (58, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (58, 77))
127864	33173989	Consistently, Kaplan-Meier analysis revealed that patients with glioma who had high TPTEP1 expression levels had a prolonged overall survival time compared with those who had low TPTEP1 expression levels (P<0.001, log-rank test).	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('expression', 'MPA', (91, 101))	('TPTEP1', 'Gene', '387590', (179, 185))	('patients', 'Species', '9606', (50, 58))	('TPTEP1', 'Gene', '387590', (84, 90))	('TPTEP1', 'Gene', (179, 185))	('prolonged', 'PosReg', (115, 124))	('glioma', 'Disease', (64, 70))	('high', 'Var', (79, 83))	('overall survival time', 'CPA', (125, 146))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('TPTEP1', 'Gene', (84, 90))
127865	33173989	In addition, patients with glioma with high TPTEP1 expression levels had a prolonged progression-free survival time compared with those with low TPTEP1 expression levels (P=0.004; Fig.	('glioma', 'Disease', (27, 33))	('high', 'Var', (39, 43))	('prolonged', 'PosReg', (75, 84))	('TPTEP1', 'Gene', '387590', (145, 151))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('TPTEP1', 'Gene', (44, 50))	('patients', 'Species', '9606', (13, 21))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('progression-free survival time', 'CPA', (85, 115))	('expression', 'MPA', (51, 61))	('TPTEP1', 'Gene', '387590', (44, 50))	('TPTEP1', 'Gene', (145, 151))
127870	33173989	TPTEP1 knockdown augmented cells stemness and radioresistance in SHG44 (Fig.	('TPTEP1', 'Gene', '387590', (0, 6))	('augmented', 'PosReg', (17, 26))	('cells stemness', 'CPA', (27, 41))	('TPTEP1', 'Gene', (0, 6))	('SHG44', 'Gene', (65, 70))	('knockdown', 'Var', (7, 16))	('radioresistance', 'CPA', (46, 61))
127871	33173989	In addition, TPTEP1 knockdown promoted cells stemness and expression of radioresistance-associated genes, including OCT4, ALDH1 and gamma-H2AX (Fig.	('cells stemness', 'CPA', (39, 53))	('ALDH1', 'Gene', '216', (122, 127))	('TPTEP1', 'Gene', '387590', (13, 19))	('H2AX', 'Gene', (138, 142))	('expression', 'MPA', (58, 68))	('TPTEP1', 'Gene', (13, 19))	('promoted', 'PosReg', (30, 38))	('OCT4', 'Gene', '5460', (116, 120))	('radioresistance-associated genes', 'Gene', (72, 104))	('ALDH1', 'Gene', (122, 127))	('knockdown', 'Var', (20, 29))	('OCT4', 'Gene', (116, 120))	('H2AX', 'Gene', '3014', (138, 142))
127880	33173989	A dual-luciferase reporter assay was performed to determine whether TPTEP1 is targeted by miR-106a-5p, and luciferase activities were downregulated by miR-106a-5p overexpression and upregulated by miR-106a-5p knockdown in SHG44 and U251 cells treated with WT TPTEP1.	('miR-106a-5p', 'Var', (197, 208))	('TPTEP1', 'Gene', (259, 265))	('downregulated', 'NegReg', (134, 147))	('TPTEP1', 'Gene', '387590', (259, 265))	('miR-106a-5p', 'Chemical', '-', (197, 208))	('upregulated', 'PosReg', (182, 193))	('U251', 'CellLine', 'CVCL:0021', (232, 236))	('TPTEP1', 'Gene', (68, 74))	('TPTEP1', 'Gene', '387590', (68, 74))	('activities', 'MPA', (118, 128))	('miR-106a-5p', 'Var', (151, 162))	('miR-106a-5p', 'Chemical', '-', (151, 162))	('luciferase', 'Enzyme', (107, 117))	('overexpression', 'PosReg', (163, 177))	('miR-106a-5p', 'Chemical', '-', (90, 101))
127881	33173989	In glioma cells transfected with Mut TPTEP1 harboring mutations in the miR-106a-5p binding sequence inside TPTEP1, these impacts on luciferase activities were abrogated (Fig.	('TPTEP1', 'Gene', (37, 43))	('luciferase', 'Enzyme', (132, 142))	('activities', 'MPA', (143, 153))	('TPTEP1', 'Gene', '387590', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('abrogated', 'NegReg', (159, 168))	('mutations', 'Var', (54, 63))	('miR-106a-5p', 'Chemical', '-', (71, 82))	('TPTEP1', 'Gene', '387590', (37, 43))	('TPTEP1', 'Gene', (107, 113))	('glioma', 'Disease', (3, 9))
127882	33173989	RT-qPCR analysis demonstrated that depletion of miR-106a-5p promoted the expression levels of TPTEP1, while upregulation of miR-106a-5p inhibited the expression levels of TPTEP1 (Fig.	('miR-106a-5p', 'Chemical', '-', (124, 135))	('miR-106a-5p', 'Chemical', '-', (48, 59))	('TPTEP1', 'Gene', '387590', (94, 100))	('TPTEP1', 'Gene', (171, 177))	('promoted', 'PosReg', (60, 68))	('inhibited', 'NegReg', (136, 145))	('expression levels', 'MPA', (73, 90))	('upregulation', 'PosReg', (108, 120))	('TPTEP1', 'Gene', (94, 100))	('TPTEP1', 'Gene', '387590', (171, 177))	('expression levels', 'MPA', (150, 167))	('miR-106a-5p', 'Var', (48, 59))	('miR-106a-5p', 'Var', (124, 135))
127884	33173989	TPTEP1 knockdown elevated miR-106a-5p expression levels, and TPTEP1 overexpression induced the opposite effect (Fig.	('TPTEP1', 'Gene', '387590', (0, 6))	('TPTEP1', 'Gene', (61, 67))	('miR-106a-5p', 'Chemical', '-', (26, 37))	('TPTEP1', 'Gene', (0, 6))	('TPTEP1', 'Gene', '387590', (61, 67))	('elevated', 'PosReg', (17, 25))	('knockdown', 'Var', (7, 16))	('miR-106a-5p expression levels', 'MPA', (26, 55))
127885	33173989	Furthermore, TPTEP1 and miR-106a-5p were demonstrated to interact with RNA-induced silencing complexes (RISC)-related Ago2 by RNA immunoprecipitation assays (Fig.	('TPTEP1', 'Gene', '387590', (13, 19))	('TPTEP1', 'Gene', (13, 19))	('interact', 'Interaction', (57, 65))	('miR-106a-5p', 'Var', (24, 35))	('miR-106a-5p', 'Chemical', '-', (24, 35))
127887	33173989	A previous study identified MAPK14 as the target of miR-106a-5p in the modulation of cell differentiation.	('cell differentiation', 'CPA', (85, 105))	('miR-106a-5p', 'Chemical', '-', (52, 63))	('MAPK14', 'Gene', (28, 34))	('MAPK14', 'Gene', '1432', (28, 34))	('miR-106a-5p', 'Var', (52, 63))
127889	33173989	The results demonstrated that overexpression of miR-106-5p decreased MAPK14 and phosphorylated-MAPK14 expression levels, and miR-106-5p knockdown elevated MAPK14 expression levels (Fig.	('miR-106', 'Gene', (48, 55))	('MAPK14', 'Gene', '1432', (95, 101))	('miR-106', 'Gene', (125, 132))	('decreased', 'NegReg', (59, 68))	('miR-106', 'Gene', '406899', (48, 55))	('expression levels', 'MPA', (162, 179))	('miR-106', 'Gene', '406899', (125, 132))	('MAPK14', 'Gene', (155, 161))	('MAPK14', 'Gene', (69, 75))	('knockdown', 'Var', (136, 145))	('MAPK14', 'Gene', '1432', (155, 161))	('MAPK14', 'Gene', '1432', (69, 75))	('expression levels', 'MPA', (102, 119))	('elevated', 'PosReg', (146, 154))	('MAPK14', 'Gene', (95, 101))
127890	33173989	In addition, the luciferase activities were downregulated by miR-106-5p overexpression and were upregulated by miR-106-5p knockdown in SHG44 and U251 cells treated with WT MAPK14 3'UTR reporter vector (Fig.	('activities', 'MPA', (28, 38))	('downregulated', 'NegReg', (44, 57))	('miR-106', 'Gene', (111, 118))	('miR-106', 'Gene', '406899', (61, 68))	('MAPK14', 'Gene', (172, 178))	('miR-106', 'Gene', '406899', (111, 118))	('knockdown', 'Var', (122, 131))	('MAPK14', 'Gene', '1432', (172, 178))	('miR-106', 'Gene', (61, 68))	('upregulated', 'PosReg', (96, 107))	('luciferase', 'Enzyme', (17, 27))	('U251', 'CellLine', 'CVCL:0021', (145, 149))	('overexpression', 'PosReg', (72, 86))
127894	33173989	Consistently, TPTEP1 overexpression upregulated MAPK14 and phosphorylated-MAPK14 expression levels in miR-106a-5p-overexpressed SHG44 cells, while TPTEP1 knockdown downregulated MAPK14 and phosphorylated-MAPK14 expression levels in miR-106a-5p-depleted U251 cells, which suggests that TPTEP1 restores MAPK14 expression regulated by miR-106a-5p (Fig.	('MAPK14', 'Gene', '1432', (301, 307))	('MAPK14', 'Gene', (204, 210))	('miR-106a-5p', 'Chemical', '-', (102, 113))	('miR-106a-5p', 'Chemical', '-', (332, 343))	('expression', 'MPA', (81, 91))	('MAPK14', 'Gene', '1432', (204, 210))	('upregulated', 'PosReg', (36, 47))	('TPTEP1', 'Gene', '387590', (285, 291))	('miR-106a-5p', 'Var', (332, 343))	('TPTEP1', 'Gene', (285, 291))	('TPTEP1', 'Gene', '387590', (14, 20))	('MAPK14', 'Gene', (178, 184))	('miR-106a-5p', 'Chemical', '-', (232, 243))	('MAPK14', 'Gene', '1432', (178, 184))	('TPTEP1', 'Gene', (14, 20))	('U251', 'CellLine', 'CVCL:0021', (253, 257))	('TPTEP1', 'Gene', '387590', (147, 153))	('expression', 'MPA', (308, 318))	('MAPK14', 'Gene', (74, 80))	('MAPK14', 'Gene', '1432', (74, 80))	('downregulated', 'NegReg', (164, 177))	('MAPK14', 'Gene', (48, 54))	('TPTEP1', 'Gene', (147, 153))	('MAPK14', 'Gene', '1432', (48, 54))	('MAPK14', 'Gene', (301, 307))
127895	33173989	Notably, the depletion of miR-106a-5p inhibited glioma cell stemness and radioresistance, while downregulation of TPTEP1 or MAPK14 enhanced glioma cell stemness and radioresistance in miR-106a-5p-silenced U251.	('glioma cell stemness', 'Disease', (48, 68))	('glioma cell stemness', 'Disease', 'MESH:D005910', (48, 68))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('miR-106a-5p', 'Var', (26, 37))	('TPTEP1', 'Gene', '387590', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('miR-106a-5p', 'Chemical', '-', (184, 195))	('miR-106a-5p', 'Chemical', '-', (26, 37))	('inhibited', 'NegReg', (38, 47))	('U251', 'CellLine', 'CVCL:0021', (205, 209))	('downregulation', 'NegReg', (96, 110))	('MAPK14', 'Gene', (124, 130))	('glioma cell stemness', 'Disease', 'MESH:D005910', (140, 160))	('depletion', 'MPA', (13, 22))	('enhanced', 'PosReg', (131, 139))	('MAPK14', 'Gene', '1432', (124, 130))	('glioma cell stemness', 'Disease', (140, 160))	('TPTEP1', 'Gene', (114, 120))
127896	33173989	However, the upregulation of TPTEP1 or MAPK14 reversed glioma cell stemness and radioresistance modulated by miR-106a-5p overexpression in SHG44, which indicates that TPTEP1 or MAPK14 may attenuate the stimulated impacts of miR-106a-5p on glioma cell stemness and radioresistance.	('TPTEP1', 'Gene', (167, 173))	('miR-106a-5p', 'Chemical', '-', (109, 120))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('radioresistance', 'CPA', (80, 95))	('attenuate', 'NegReg', (188, 197))	('miR-106a-5p', 'Var', (109, 120))	('TPTEP1', 'Gene', '387590', (29, 35))	('glioma cell stemness', 'Disease', 'MESH:D005910', (239, 259))	('glioma cell stemness', 'Disease', (239, 259))	('upregulation', 'PosReg', (13, 25))	('TPTEP1', 'Gene', (29, 35))	('glioma cell stemness', 'Disease', 'MESH:D005910', (55, 75))	('glioma cell stemness', 'Disease', (55, 75))	('MAPK14', 'Gene', (177, 183))	('miR-106a-5p', 'Chemical', '-', (224, 235))	('MAPK14', 'Gene', '1432', (177, 183))	('TPTEP1', 'Gene', '387590', (167, 173))	('MAPK14', 'Gene', (39, 45))	('MAPK14', 'Gene', '1432', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
127897	33173989	Furthermore, overexpression of TPTEP1 was demonstrated to suppress cells stemness and radioresistance, and depletion of MAPK14 in TPTEP1-overexpressed U251 cells augmented cell stemness and radioresistance.	('cells stemness', 'CPA', (67, 81))	('U251', 'CellLine', 'CVCL:0021', (151, 155))	('TPTEP1', 'Gene', (130, 136))	('TPTEP1', 'Gene', '387590', (31, 37))	('MAPK14', 'Gene', (120, 126))	('MAPK14', 'Gene', '1432', (120, 126))	('augmented', 'PosReg', (162, 171))	('TPTEP1', 'Gene', (31, 37))	('TPTEP1', 'Gene', '387590', (130, 136))	('cell stemness', 'CPA', (172, 185))	('depletion', 'Var', (107, 116))	('suppress', 'NegReg', (58, 66))
127901	33173989	miR-106a-5p expression levels were also demonstrated to be negatively associated with MAPK14 expression levels in glioma tissues (P=0.001, kappa=-0.253) (Fig.	('negatively', 'NegReg', (59, 69))	('glioma', 'Disease', (114, 120))	('expression levels', 'MPA', (93, 110))	('MAPK14', 'Gene', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('miR-106a-5p', 'Var', (0, 11))	('MAPK14', 'Gene', '1432', (86, 92))	('expression', 'MPA', (12, 22))	('miR-106a-5p', 'Chemical', '-', (0, 11))
127919	33173989	The results of the present study confirmed that miRNA-106a-5p serves as an oncogene by augmenting TPTEP1-mediated stemness and radioresistance of glioma.	('miRNA-106a-5p', 'Var', (48, 61))	('glioma', 'Disease', (146, 152))	('augmenting', 'NegReg', (87, 97))	('TPTEP1', 'Gene', (98, 104))	('radioresistance', 'CPA', (127, 142))	('miRNA-106a-5p', 'Chemical', '-', (48, 61))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('TPTEP1', 'Gene', '387590', (98, 104))
127920	33173989	Previous studies have demonstrated the stimulating effects of TPTEP1 and the inhibitory effect of miRNA-106a-5p on cancer cell apoptosis.	('inhibitory', 'NegReg', (77, 87))	('cancer', 'Disease', (115, 121))	('miRNA-106a-5p', 'Chemical', '-', (98, 111))	('TPTEP1', 'Gene', '387590', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TPTEP1', 'Gene', (62, 68))	('miRNA-106a-5p', 'Var', (98, 111))	('stimulating effects', 'PosReg', (39, 58))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
127926	33173989	In addition, MAPK14 was verified as a target gene of miR-106a-5p, and cooperated with miR-106a-5p and TPTEP1 to regulate glioma progression.	('miR-106a-5p', 'Var', (53, 64))	('MAPK14', 'Gene', (13, 19))	('miR-106a-5p', 'Chemical', '-', (53, 64))	('regulate', 'Reg', (112, 120))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('TPTEP1', 'Gene', (102, 108))	('MAPK14', 'Gene', '1432', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('TPTEP1', 'Gene', '387590', (102, 108))	('miR-106a-5p', 'Chemical', '-', (86, 97))	('glioma', 'Disease', (121, 127))
127927	33173989	The rescue experiments and association analysis in tissues further confirmed the modulation of the TPTEP1/miR-106a-5p/MAPK14 axis in glioma progression.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('TPTEP1', 'Gene', (99, 105))	('TPTEP1', 'Gene', '387590', (99, 105))	('glioma', 'Disease', (133, 139))	('MAPK14', 'Gene', (118, 124))	('miR-106a-5p', 'Chemical', '-', (106, 117))	('modulation', 'Var', (81, 91))	('MAPK14', 'Gene', '1432', (118, 124))
127931	33173989	TPTEP1 and miR-106a-5p formed a reciprocal regulatory circuit to facilitate P38 MAPK signaling activation in glioma.	('TPTEP1', 'Gene', '387590', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('facilitate', 'PosReg', (65, 75))	('activation', 'PosReg', (95, 105))	('glioma', 'Disease', (109, 115))	('TPTEP1', 'Gene', (0, 6))	('miR-106a-5p', 'Var', (11, 22))	('P38', 'Gene', (76, 79))	('P38', 'Gene', '1432', (76, 79))	('miR-106a-5p', 'Chemical', '-', (11, 22))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
127939	32651364	Silencing AVIL nearly eradicated glioblastoma cells in culture, and dramatically inhibited in vivo xenografts in mice, but had no effect on normal control cells.	('AVIL', 'Gene', (10, 14))	('glioblastoma', 'Disease', (33, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('mice', 'Species', '10090', (113, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('inhibited', 'NegReg', (81, 90))	('eradicated', 'NegReg', (22, 32))	('Silencing', 'Var', (0, 9))
127941	32651364	AVIL regulates the cytoskeleton through modulating F-actin, while mutants disrupting F-actin binding are defective in its tumorigenic capabilities.	('regulates', 'Reg', (5, 14))	('mutants', 'Var', (66, 73))	('disrupting', 'NegReg', (74, 84))	('F-actin', 'MPA', (51, 58))	('defective', 'NegReg', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('binding', 'Interaction', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('modulating', 'Reg', (40, 50))	('tumor', 'Disease', (122, 127))	('cytoskeleton', 'MPA', (19, 31))
127950	32651364	Even though large sets of genome and transcriptome data are available to facilitate the identification of driver mutations in cancer, true signals are often buried in a large number of passenger events.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
127951	32651364	In contrast to adult cancers, pediatric tumors tend to have fewer point mutations and structural changes.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('structural changes', 'CPA', (86, 104))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('point mutations', 'Var', (66, 81))	('cancers', 'Disease', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
127953	32651364	Suspecting that other tumors may also dysregulate AVIL expression, we examined AVIL in adult cancers and found its critical role in the tumorigenesis of GBM.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Disease', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (22, 27))	('dysregulate', 'Var', (38, 49))	('tumors', 'Disease', (22, 28))	('tumor', 'Disease', (136, 141))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
127959	32651364	Previously, we identified a gene fusion in alveolar rhabdomyosarcoma, a pediatric cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (43, 68))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (52, 68))	('alveolar rhabdomyosarcoma', 'Disease', (43, 68))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('gene fusion', 'Var', (28, 39))	('cancer', 'Disease', (82, 88))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (43, 68))	('fusion in alveolar', 'Phenotype', 'HP:0009754', (33, 51))
127976	32651364	Here we subdivided the TCGA samples into GBMs with IDH-wild type, GBMs with IDH-mutant, Lower-grade glioma (LGG) with IDH-wild type, LGG with mutant IDH and 1p/19q codeletion, and LGG with IDH mutant without 1p/19q codeletion.	('glioma', 'Disease', (100, 106))	('IDH', 'Gene', (189, 192))	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', (149, 152))	('IDH and 1p/19', 'Gene', '3417', (149, 162))	('IDH', 'Gene', '3417', (189, 192))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (51, 54))	('IDH', 'Gene', '3417', (149, 152))	('mutant', 'Var', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', '3417', (118, 121))
127977	32651364	Consistent with REMBRANT data, GBMs with or without IDH mutation have high level of AVIL expression.	('mutation', 'Var', (56, 64))	('AVIL expression', 'MPA', (84, 99))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))
127982	32651364	These results further suggest that in addition to the 15-18% of cases that have copy number gain, a higher percentage of glioblastomas may use post-transcriptional/translational mechanisms to up-regulate AVIL expression.	('glioblastomas', 'Disease', (121, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('copy number gain', 'Var', (80, 96))	('up-regulate', 'PosReg', (192, 203))	('AVIL', 'Protein', (204, 208))	('glioblastomas', 'Phenotype', 'HP:0012174', (121, 134))	('glioblastomas', 'Disease', 'MESH:D005909', (121, 134))
127987	32651364	Because IDH1 mutation status has proven to be a more important prognostic factor than histologic grade, we then compared AVIL IHC scores between IDH1 (R132) mutant and wild-type tumors, with the observer blinded to IDH1 status.	('IDH1', 'Gene', (145, 149))	('mutant', 'Var', (157, 163))	('IDH1', 'Gene', (215, 219))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('IDH1', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('IDH1', 'Gene', '3417', (145, 149))	('IDH1', 'Gene', '3417', (215, 219))	('IDH1', 'Gene', '3417', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
128000	32651364	We also measured the effect of silencing AVIL on the migratory ability and invasiveness of A172 and U251 cells.	('silencing', 'Var', (31, 40))	('invasiveness', 'CPA', (75, 87))	('U251', 'CellLine', 'CVCL:0021', (100, 104))	('migratory ability', 'CPA', (53, 70))
128001	32651364	To confirm whether AVIL plays an important role in tumorigenesis in vivo, we tested the effect of silencing AVIL in tumor initiation with a widely used U251 intracranial xenograft model.	('AVIL', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tested', 'Reg', (77, 83))	('tumor', 'Disease', (51, 56))	('silencing', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('U251', 'CellLine', 'CVCL:0021', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
128013	32651364	Consistently, we found that silencing AVIL in two GSCs, GSC11 and GSC627, resulted in dramatic reduction of cell proliferation, while no obvious difference was observed in the neural stem cell culture (Fig.	('reduction', 'NegReg', (95, 104))	('cell proliferation', 'CPA', (108, 126))	('GSCs', 'Chemical', '-', (50, 54))	('silencing', 'Var', (28, 37))	('AVIL', 'Protein', (38, 42))	('GSC627', 'Gene', (66, 72))
128020	32651364	To examine the potential connection and collaborative effect of AVIL with these three pathways, we performed a modified oncogene cooperativity assay, where we introduced alone the EGFR vIII mutant, shRNA targeting TP53, or shRNA targeting RB, or in combination with AVIL overexpression.	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('mutant', 'Var', (190, 196))	('TP53', 'Gene', '7157', (214, 218))	('TP53', 'Gene', (214, 218))
128027	32651364	On the other hand, we found no significant changes of AVIL expression when we introduced EGFR mutant, shTP53 or shRB into these astrocytes (Supplementary Fig.	('introduced', 'Reg', (78, 88))	('EGFR', 'Gene', (89, 93))	('TP53', 'Gene', (104, 108))	('TP53', 'Gene', '7157', (104, 108))	('mutant', 'Var', (94, 100))	('EGFR', 'Gene', '1956', (89, 93))	('AVIL', 'MPA', (54, 58))
128032	32651364	We expressed Myc-tagged AVIL, either wild-type or mutants, in glioblastoma cells in which endogenous AVIL was silenced and performed co-immunoprecipitation with anti-Myc antibody to assess the interaction between actin and AVIL mutants.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('AVIL', 'Gene', (24, 28))	('AVIL', 'Gene', (223, 227))	('Myc', 'Gene', (13, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('mutants', 'Var', (228, 235))	('interaction', 'Interaction', (193, 204))	('glioblastoma', 'Disease', (62, 74))	('Myc', 'Gene', '4609', (166, 169))	('mutants', 'Var', (50, 57))	('Myc', 'Gene', (166, 169))	('Myc', 'Gene', '4609', (13, 16))
128033	32651364	We then chose two mutants (AVIL K808C and AVIL F819C) that yielded the lowest amount of actin in the co-immunoprecipitation experiment and are also highly conserved for further studies.	('actin', 'MPA', (88, 93))	('K808C', 'SUBSTITUTION', 'None', (32, 37))	('lowest', 'NegReg', (71, 77))	('AVIL F819C', 'Var', (42, 52))	('K808C', 'Var', (32, 37))	('F819C', 'Mutation', 'p.F819C', (47, 52))
128039	32651364	16) Consistently, using proteasome inhibitor MG132, the effect of AVIL silencing on FOXM1 was fully abolished (Fig.	('silencing', 'Var', (71, 80))	('abolished', 'NegReg', (100, 109))	('FOXM1', 'Gene', (84, 89))	('MG132', 'Chemical', 'MESH:C072553', (45, 50))
128040	32651364	Among the genes that were inversely regulated by AVIL silencing vs. overexpressing, LIN28B caught our attention.	('AVIL silencing', 'Var', (49, 63))	('LIN28B', 'Gene', (84, 90))	('LIN28B', 'Gene', '389421', (84, 90))
128044	32651364	Indeed, we found that silencing AVIL or FOXM1 resulted in reduced LIN28B expression, whereas overexpressing AVIL or FOXM1 enhanced LIN28 expression (Fig.	('enhanced', 'PosReg', (122, 130))	('expression', 'MPA', (137, 147))	('LIN28B', 'Gene', '389421', (66, 72))	('AVIL', 'Gene', (32, 36))	('LIN28', 'Gene', (66, 71))	('LIN28', 'Gene', '79727', (66, 71))	('LIN28B', 'Gene', (66, 72))	('silencing', 'Var', (22, 31))	('LIN28', 'Gene', (131, 136))	('FOXM1', 'Gene', (40, 45))	('expression', 'MPA', (73, 83))	('FOXM1', 'Gene', (116, 121))	('LIN28', 'Gene', '79727', (131, 136))	('reduced', 'NegReg', (58, 65))
128047	32651364	Consistently, AVIL mutants defective in F-actin binding also failed to induce LIN28B to the same extent as the wild-type AVIL (Fig.	('failed', 'NegReg', (61, 67))	('LIN28B', 'Gene', (78, 84))	('mutants', 'Var', (19, 26))	('induce', 'Reg', (71, 77))	('LIN28B', 'Gene', '389421', (78, 84))	('F-actin', 'Protein', (40, 47))
128048	32651364	Clinically, high LIN28B expression correlates with poor prognosis in patients with GBMs (Fig.	('LIN28B', 'Gene', '389421', (17, 23))	('high', 'Var', (12, 16))	('expression', 'MPA', (24, 34))	('GBMs', 'Disease', (83, 87))	('LIN28B', 'Gene', (17, 23))	('patients', 'Species', '9606', (69, 77))
128052	32651364	Indeed, we observed that silencing AVIL induced all of the members of let-7 that are expressed (let7-f, let7-g, and mir-98 are not expressed in U87 cells) (Fig.	('silencing', 'Var', (25, 34))	('mir-98', 'Gene', '407054', (116, 122))	('U87', 'CellLine', 'CVCL:0022', (144, 147))	('let7-g', 'Gene', '406890', (104, 110))	('mir-98', 'Gene', (116, 122))	('let7-g', 'Gene', (104, 110))	('let-7', 'Gene', (70, 75))
128060	32651364	Silencing AVIL induced GBM cell death in vitro, and prevented/reduced GBM xenograft formation and growth in animal models.	('growth in animal models', 'CPA', (98, 121))	('AVIL', 'Gene', (10, 14))	('death', 'Disease', (32, 37))	('prevented/reduced', 'NegReg', (52, 69))	('Silencing', 'Var', (0, 9))	('death', 'Disease', 'MESH:D003643', (32, 37))	('GBM cell', 'CPA', (23, 31))
128062	32651364	Tumor cells use multiple "tricks" to dysregulate some oncogenes, which at the same time give credence to the genes as key players in tumorigenesis and malignancy.	('oncogenes', 'Gene', (54, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('malignancy', 'Disease', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('dysregulate', 'Var', (37, 48))
128064	32651364	It is amplified by copy number gain in some glioblastomas, and upregulated at the transcriptional/translational level in other GBMs.	('copy number', 'Var', (19, 30))	('glioblastomas', 'Phenotype', 'HP:0012174', (44, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('gain', 'PosReg', (31, 35))	('glioblastomas', 'Disease', 'MESH:D005909', (44, 57))	('upregulated', 'PosReg', (63, 74))	('glioblastomas', 'Disease', (44, 57))
128068	32651364	It can form NPM-ALK fusions in ~60% of anaplastic large-cell lymphomas (ALCLs), or EML-ALK in a subset of non-small-cell lung cancers; additionally, it can have gain-of-function point mutations in neuroblastomas, and copy number gain in several tumor types.	('ALK', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('lymphomas', 'Disease', 'MESH:D008223', (61, 70))	('lung cancers', 'Disease', 'MESH:D008175', (121, 133))	('lymphomas', 'Phenotype', 'HP:0002665', (61, 70))	('neuroblastomas', 'Phenotype', 'HP:0003006', (197, 211))	('point mutations', 'Var', (178, 193))	('lung cancers', 'Disease', (121, 133))	('neuroblastomas', 'Disease', (197, 211))	('lung cancers', 'Phenotype', 'HP:0100526', (121, 133))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('neuroblastomas', 'Disease', 'MESH:D009447', (197, 211))	('gain-of-function', 'PosReg', (161, 177))	('lymphomas', 'Disease', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('ALK', 'Gene', '238', (16, 19))	('gain', 'PosReg', (229, 233))	('tumor', 'Disease', (245, 250))	('ALK', 'Gene', (16, 19))	('ALK', 'Gene', '238', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('copy number', 'Var', (217, 228))	('NPM', 'Gene', (12, 15))	('NPM', 'Gene', '4869', (12, 15))	('anaplastic large-cell lymphomas', 'Phenotype', 'HP:0012193', (39, 70))
128070	32651364	Considering gene fusions often result in aberrant expression of one of the proto-oncogenes, our strategy was to start from a gene fusion in pediatric cancer, then extend to adult tumors including GBM.	('expression', 'MPA', (50, 60))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('gene fusions', 'Var', (12, 24))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('result in', 'Reg', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
128074	32651364	Recently, AVIL mutants were found to be involved in the alteration PLCE1 action, and contribute to the Steroid-resistant nephrotic syndrome.	('AVIL', 'Gene', (10, 14))	('Steroid-resistant', 'MPA', (103, 120))	('nephrotic syndrome', 'Disease', (121, 139))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (121, 139))	('alteration', 'Reg', (56, 66))	('PLCE1', 'Gene', (67, 72))	('contribute', 'Reg', (85, 95))	('Steroid', 'Chemical', 'MESH:D013256', (103, 110))	('mutants', 'Var', (15, 22))	('PLCE1', 'Gene', '51196', (67, 72))	('Steroid-resistant nephrotic syndrome', 'Phenotype', 'HP:0012588', (103, 139))	('nephrotic syndrome', 'Disease', 'MESH:D009404', (121, 139))	('action', 'MPA', (73, 79))	('involved', 'Reg', (40, 48))
128081	32651364	In addition, we showed that AVIL functions upstream of FOXM1, which in turn regulates LIN28B transcription, and that AVIL mutants, which are defective in F-actin binding failed to rescue reduced LIN28B caused by AVIL silencing.	('mutants', 'Var', (122, 129))	('LIN28B', 'Gene', '389421', (86, 92))	('LIN28B', 'Gene', (86, 92))	('transcription', 'MPA', (93, 106))	('LIN28B', 'Gene', (195, 201))	('reduced', 'NegReg', (187, 194))	('regulates', 'Reg', (76, 85))	('LIN28B', 'Gene', '389421', (195, 201))	('silencing', 'NegReg', (217, 226))
128181	31999549	and TCGA studies were examined with respect to their representation in each of the clusters identified by nNMF and are shown in Table 1. nNMF C1 that was made by Proneural is characterized by TP53-mutations, classical subtype enriched C2 is characterized by EFGR-mutations and PTEN-mutations, and the cluster C3 enriched by Mesenchymal is characterized by NF1-mutations.	('TP53', 'Gene', '7157', (192, 196))	('PTEN', 'Gene', (277, 281))	('PTEN', 'Gene', '5728', (277, 281))	('NF1', 'Gene', (356, 359))	('NF1', 'Gene', '4763', (356, 359))	('EFGR-mutations', 'Var', (258, 272))	('TP53', 'Gene', (192, 196))
128183	31999549	nNMF-C1 is almost entirely made up of mutant IDH with non-codeletion, nNMF-C2 is enriched with IDH wild type, and nNMF-C3 is highly enriched with mutant IDH with codeletion (Table 2).	('mutant', 'Var', (38, 44))	('nNMF-C3', 'Disease', 'MESH:C565169', (114, 121))	('nNMF-C3', 'Disease', (114, 121))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', '3417', (45, 48))	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('nNMF-C2', 'Disease', (70, 77))	('IDH', 'Gene', '3417', (153, 156))	('nNMF-C2', 'Disease', 'OMIM:217000', (70, 77))
128186	31999549	Consistent with TCGA study results, the survival outcome was most favorable for the patients having IDH mutation and 1p/19q codeletion (nNMF-C3).	('IDH', 'Gene', (100, 103))	('1p/19q codeletion', 'Var', (117, 134))	('patients', 'Species', '9606', (84, 92))	('nNMF-C3', 'Disease', 'MESH:C565169', (136, 143))	('IDH', 'Gene', '3417', (100, 103))	('nNMF-C3', 'Disease', (136, 143))
128192	31999549	nNMF-C1 that was enriched by the Basal and Mesenchymal is characterized by mutations in CDKN2A and TP53 genes, Basal enriched nNMF-C2 is characterized by CDKN2A, FAT1, CASP8, NOTCH1 and HRAS mutations.	('CDKN2A', 'Gene', (88, 94))	('TP53', 'Gene', (99, 103))	('FAT1', 'Gene', (162, 166))	('CDKN2A', 'Gene', '1029', (88, 94))	('NOTCH1', 'Gene', '4851', (175, 181))	('CDKN2A', 'Gene', (154, 160))	('CASP8', 'Gene', (168, 173))	('HRAS', 'Gene', '3265', (186, 190))	('CASP8', 'Gene', '841', (168, 173))	('NOTCH1', 'Gene', (175, 181))	('FAT1', 'Gene', '2195', (162, 166))	('CDKN2A', 'Gene', '1029', (154, 160))	('nNMF-C2', 'Disease', (126, 133))	('mutations', 'Var', (75, 84))	('HRAS', 'Gene', (186, 190))	('TP53', 'Gene', '7157', (99, 103))	('nNMF-C2', 'Disease', 'OMIM:217000', (126, 133))
128193	31999549	nNMF-C3 which is enriched with Atypical subtype is characterized by mutations in PIK3CA, KMT2D and NSD1 genes, and nNMF-C4 which is enriched by Mesenchymal subtype is characterized by TP53 and NOTCH1 mutations.	('nNMF-C4', 'Gene', (115, 122))	('PIK3CA', 'Gene', (81, 87))	('NOTCH1', 'Gene', (193, 199))	('PIK3CA', 'Gene', '5290', (81, 87))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('KMT2D', 'Gene', (89, 94))	('KMT2D', 'Gene', '8085', (89, 94))	('NSD1', 'Gene', '64324', (99, 103))	('nNMF-C3', 'Disease', (0, 7))	('nNMF-C3', 'Disease', 'MESH:C565169', (0, 7))	('mutations', 'Var', (68, 77))	('NOTCH1', 'Gene', '4851', (193, 199))	('NSD1', 'Gene', (99, 103))
128210	31291988	The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo.	('ATG4C', 'Gene', (114, 119))	('silencing', 'Var', (104, 113))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('TMZ', 'Chemical', 'MESH:D000077204', (62, 65))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('si', 'Chemical', 'MESH:D012825', (104, 106))
128212	31291988	The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 x 10- 7).	('overall survival', 'MPA', (11, 27))	('expression', 'MPA', (68, 78))	('OS', 'Chemical', '-', (29, 31))	('ATG4C', 'Protein', (62, 67))	('reduced', 'NegReg', (97, 104))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('patients', 'Species', '9606', (41, 49))	('higher', 'Var', (55, 61))	('si', 'Chemical', 'MESH:D012825', (83, 85))
128215	31291988	ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation.	('suppressed', 'NegReg', (16, 26))	('autophagy', 'CPA', (27, 36))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('ROS', 'Protein', (69, 72))	('depletion', 'Var', (6, 15))	('ATG4C', 'Gene', (0, 5))	('apoptosis', 'CPA', (51, 60))	('triggered', 'PosReg', (41, 50))
128216	31291988	Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('suppressed', 'NegReg', (19, 29))	('TMZ-activated autophagy', 'CPA', (30, 53))	('Depletion', 'Var', (0, 9))	('TMZ', 'Chemical', 'MESH:D000077204', (30, 33))	('promoted', 'PosReg', (58, 66))	('ATG4C', 'Gene', (13, 18))	('glioma', 'Disease', (82, 88))	('sensitivity', 'CPA', (67, 78))
128217	31291988	Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice.	('glioma', 'Disease', (55, 61))	('suppressed', 'NegReg', (30, 40))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('growth', 'MPA', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('knockdown', 'Var', (20, 29))	('ATG4C', 'Gene', (14, 19))	('nude mice', 'Species', '10090', (76, 85))
128218	31291988	ATG4C is a potential prognostic predictor for glioma patient.	('ATG4C', 'Var', (0, 5))	('glioma', 'Disease', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('patient', 'Species', '9606', (53, 60))
128226	31291988	Several molecular biomarkers, such as IDH mutation, 1p/19q co-deletion and MGMT promoter methylation, are shown to predict prognosis and/or drug responses for gliomas.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('IDH', 'Gene', (38, 41))	('predict', 'Reg', (115, 122))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('1p/19q co-deletion', 'Var', (52, 70))	('IDH', 'Gene', '3417', (38, 41))	('mutation', 'Var', (42, 50))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('MGMT', 'Gene', '4255', (75, 79))	('MGMT', 'Gene', (75, 79))
128230	31291988	Additionally, recent studies have suggested that TMZ-induced autophagy sustained the survival of glioblastoma cells, thereby contributing to drug resistance and recurrence.	('recurrence', 'MPA', (161, 171))	('TMZ', 'Chemical', 'MESH:D000077204', (49, 52))	('TMZ-induced', 'Var', (49, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('survival', 'CPA', (85, 93))	('contributing', 'Reg', (125, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (141, 156))	('sustained', 'PosReg', (71, 80))	('drug resistance', 'MPA', (141, 156))	('autophagy', 'CPA', (61, 70))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
128237	31291988	In this study, we tried to determine whether interference with ATG4C can affect autophagy activity and TMZ sensitivity in glioma cell lines, as well as its role in disease progression of glioma both in vitro and in vivo.	('TMZ', 'Chemical', 'MESH:D000077204', (103, 106))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('affect', 'Reg', (73, 79))	('autophagy activity', 'CPA', (80, 98))	('glioma', 'Disease', (187, 193))	('glioma', 'Disease', (122, 128))	('TMZ sensitivity', 'CPA', (103, 118))	('interference', 'Var', (45, 57))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('ATG4C', 'Gene', (63, 68))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('si', 'Chemical', 'MESH:D012825', (179, 181))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
128253	31291988	After seeded in 6-well plates for 24 h, cells were infected with ATG4C sh-RNA (sh-ATG4C) or negative control sh-RNA (sh-NC) at a multiplicity of infection (MOI) of 10 in the Opti-MEM medium.	('sh-RNA', 'Gene', (71, 77))	('ATG4C', 'Var', (65, 70))	('infection', 'Disease', (145, 154))	('Opti-MEM medium', 'Chemical', '-', (174, 189))	('infection', 'Disease', 'MESH:D007239', (145, 154))
128262	31291988	Blots were blocked in TBST buffer containing 5% (m/v) nonfat milk at room temperature for 2 h and then incubated at 4  C overnight with primary antibodies as follows: GAPDH (Protein Tech), ATG4C (Abcam), LC3 (Cell Signaling Technology), P62 (Cell Signaling Technology), p21 (Ab clonal), p53 (AB clonal), Cyclin E (Cell Signaling Technology), Bcl-2 (Protein Tech), BAX (Protein Tech) and PARP (Protein Tech).	('PARP', 'Gene', (387, 391))	('Tech', 'Gene', '57449', (401, 405))	('Tech', 'Gene', '57449', (377, 381))	('Tech', 'Gene', (377, 381))	('Tech', 'Gene', (401, 405))	('Tech', 'Gene', '57449', (257, 261))	('Tech', 'Gene', (257, 261))	('p21', 'Gene', (270, 273))	('GAPDH', 'Gene', '2597', (167, 172))	('p53', 'Gene', '7157', (287, 290))	('Cyclin', 'Gene', '5111', (304, 310))	('Tech', 'Gene', '57449', (329, 333))	('Tech', 'Gene', (329, 333))	('Tech', 'Gene', '57449', (224, 228))	('Tech', 'Gene', (224, 228))	('p53', 'Gene', (287, 290))	('GAPDH', 'Gene', (167, 172))	('P62', 'Gene', '23636', (237, 240))	('BAX', 'Gene', (364, 367))	('Tech', 'Gene', '57449', (357, 361))	('Tech', 'Gene', (357, 361))	('p21', 'Gene', '1026', (270, 273))	('Bcl-2', 'Gene', (342, 347))	('LC3', 'Var', (204, 207))	('BAX', 'Gene', '581', (364, 367))	('TBST buffer', 'Chemical', '-', (22, 33))	('PARP', 'Gene', '1302', (387, 391))	('Cyclin', 'Gene', (304, 310))	('Bcl-2', 'Gene', '596', (342, 347))	('Tech', 'Gene', '57449', (182, 186))	('Tech', 'Gene', (182, 186))	('P62', 'Gene', (237, 240))
128303	31291988	The results showed that mRNA expression of ATG3 (HR = 0.63, 95% CI: 0.40-0.99, p = 0.05), ATG4C (HR = 1.54, 95% CI: 1.16-2.01, p = 3 x 10- 3) and ATG5 (HR = 0.61, 95% CI: 0.43-0.86, p = 5 x 10- 3) were independent OS prognostic factors in gliomas patients (Table 2).	('ATG5', 'Gene', '9474', (146, 150))	('ATG3', 'Gene', '64422', (43, 47))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('OS', 'Chemical', '-', (214, 216))	('gliomas', 'Disease', (239, 246))	('patients', 'Species', '9606', (247, 255))	('ATG5', 'Gene', (146, 150))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('mRNA expression', 'MPA', (24, 39))	('ATG4C', 'Var', (90, 95))	('ATG3', 'Gene', (43, 47))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
128305	31291988	We observed that only ATG4C mRNA expression was significantly associated with OS in LGG patients (Fig.	('ATG4C mRNA expression', 'Var', (22, 43))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('LGG patients', 'Disease', (84, 96))	('associated', 'Reg', (62, 72))	('patients', 'Species', '9606', (88, 96))	('OS', 'Chemical', '-', (78, 80))	('si', 'Chemical', 'MESH:D012825', (48, 50))
128306	31291988	Moreover, the median relapse-free survival (RFS) time of LGG patients with low ATG4C mRNA expression was significantly longer than those with high expression (Fig.	('LGG', 'Disease', (57, 60))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('low', 'Var', (75, 78))	('longer', 'PosReg', (119, 125))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('patients', 'Species', '9606', (61, 69))	('ATG4C', 'Gene', (79, 84))	('relapse-free survival', 'CPA', (21, 42))	('si', 'Chemical', 'MESH:D012825', (96, 98))
128317	31291988	Results from colony-formation assay also showed that knockdown of ATG4C by si-RNA transfection reduced the number of colonies remarkably (Fig.	('knockdown', 'Var', (53, 62))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('ATG4C', 'Gene', (66, 71))	('reduced', 'NegReg', (95, 102))
128318	31291988	The impaired proliferation of glioma cell by si-ATG4C might be a result, at least in part, from unorganized cell cycle.	('si-ATG4C', 'Var', (45, 53))	('impaired', 'NegReg', (4, 12))	('glioma', 'Disease', (30, 36))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
128319	31291988	For this reason, we analyzed the cell cycle distribution of glioma cells after ATG4C silencing.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('analyzed', 'Reg', (20, 28))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('glioma', 'Disease', (60, 66))	('ATG4C', 'Gene', (79, 84))	('silencing', 'Var', (85, 94))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
128321	31291988	Meanwhile, knockdown of ATG4C increased the protein expression of p21 and p53 while decreased the expression of Cyclin E (Fig.	('p21', 'Gene', (66, 69))	('p21', 'Gene', '1026', (66, 69))	('Cyclin', 'Gene', '5111', (112, 118))	('Cyclin', 'Gene', (112, 118))	('p53', 'Gene', (74, 77))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('ATG4C', 'Gene', (24, 29))	('p53', 'Gene', '7157', (74, 77))	('increased', 'PosReg', (30, 39))	('decreased', 'NegReg', (84, 93))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('knockdown', 'Var', (11, 20))	('protein expression', 'MPA', (44, 62))	('expression', 'MPA', (98, 108))
128325	31291988	Intriguingly, we found that both of LC3-II and P62 protein levels were obviously increased in cells treated with si-ATG4C (Fig.	('P62', 'Gene', '23636', (47, 50))	('LC3-II', 'MPA', (36, 42))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('P62', 'Gene', (47, 50))	('si-ATG4C', 'Var', (113, 121))	('increased', 'PosReg', (81, 90))
128326	31291988	Our results showed that, in the presence of BafA1, knockdown of ATG4C reduced the protein expression of LC3-II remarkably, which suggested impaired autophagic flux (Fig.	('protein expression', 'MPA', (82, 100))	('reduced', 'NegReg', (70, 77))	('autophagic flux', 'CPA', (148, 163))	('LC3-II', 'Protein', (104, 110))	('impaired', 'NegReg', (139, 147))	('ATG4C', 'Gene', (64, 69))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('knockdown', 'Var', (51, 60))
128330	31291988	The effect of ATG4C on apoptosis was investigated in T98G using Annexin V-FITC/PI and Hoechst 33342 staining.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('Annexin V', 'Gene', '308', (64, 73))	('Annexin V', 'Gene', (64, 73))	('T98G', 'Var', (53, 57))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (86, 99))	('V-FITC', 'Chemical', '-', (72, 78))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('T98G', 'CellLine', 'CVCL:0556', (53, 57))
128331	31291988	5a and b, knockdown of ATG4C significantly promoted apoptosis in T98G cells.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('promoted', 'PosReg', (43, 51))	('ATG4C', 'Gene', (23, 28))	('T98G', 'CellLine', 'CVCL:0556', (65, 69))	('apoptosis', 'CPA', (52, 61))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('knockdown', 'Var', (10, 19))
128332	31291988	And ATG4C depletion-induced apoptosis was further enhanced by starvation, a known factor for autophagy stimulation.	('apoptosis', 'CPA', (28, 37))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('ATG4C', 'Gene', (4, 9))	('enhanced', 'PosReg', (50, 58))	('depletion-induced', 'Var', (10, 27))
128333	31291988	Western blot analysis showed that ATG4C ablation remarkably increased the expression of pro-apoptosis proteins BAX and cleaved-PARP, while reduced the expression of the anti-apoptosis protein Bcl-2 (Fig.	('expression', 'MPA', (74, 84))	('Bcl-2', 'Gene', '596', (192, 197))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('ablation', 'Var', (40, 48))	('PARP', 'Gene', (127, 131))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('expression', 'MPA', (151, 161))	('ATG4C', 'Gene', (34, 39))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('reduced', 'NegReg', (139, 146))	('BAX', 'Gene', '581', (111, 114))	('BAX', 'Gene', (111, 114))	('PARP', 'Gene', '1302', (127, 131))	('increased', 'PosReg', (60, 69))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('Bcl-2', 'Gene', (192, 197))
128334	31291988	Consistently, ATG4C ablation significantly increased the activity of caspase-3/6/9 (Fig.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('caspase-3/6/9', 'Gene', (69, 82))	('caspase-3/6/9', 'Gene', '836', (69, 82))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('activity', 'MPA', (57, 65))	('increased', 'PosReg', (43, 52))	('ablation', 'Var', (20, 28))	('ATG4C', 'Gene', (14, 19))
128337	31291988	5e, ATG4C ablation increased the level of ROS remarkably in a time-dependent manner in T98G cells.	('ROS', 'MPA', (42, 45))	('T98G', 'CellLine', 'CVCL:0556', (87, 91))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('increased', 'PosReg', (19, 28))	('ablation', 'Var', (10, 18))	('ATG4C', 'Gene', (4, 9))
128341	31291988	To validate the effect of TMZ in activating autophagy in glioma cells, U87-MG and T98G cells were treated with series concentrations of TMZ (12.5, 25, and 50 muM for U87-MG cells, and 200, 400, 800, 1600 muM for T98G cells).	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('T98G', 'CellLine', 'CVCL:0556', (82, 86))	('T98G', 'CellLine', 'CVCL:0556', (212, 216))	('glioma', 'Disease', (57, 63))	('U87-MG', 'CellLine', 'CVCL:0022', (71, 77))	('TMZ', 'Chemical', 'MESH:D000077204', (26, 29))	('activating', 'MPA', (33, 43))	('U87-MG', 'CellLine', 'CVCL:0022', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('TMZ', 'Chemical', 'MESH:D000077204', (136, 139))	('12.5', 'Var', (141, 145))
128342	31291988	Western blot analysis showed that TMZ increased the LC3-II/LC3-I ratio and LC3-II protein levels in a concentration-dependent manner in both cells (Fig.	('si', 'Chemical', 'MESH:D012825', (18, 20))	('LC3-II/LC3-I ratio', 'MPA', (52, 70))	('TMZ', 'Var', (34, 37))	('LC3-II protein levels', 'MPA', (75, 96))	('increased', 'PosReg', (38, 47))	('TMZ', 'Chemical', 'MESH:D000077204', (34, 37))
128349	31291988	6f, ATG4C ablation also decreased the IC50 of TMZ in both U87MG and T98G cells obviously (Fig.	('T98G', 'CellLine', 'CVCL:0556', (68, 72))	('IC50 of TMZ', 'MPA', (38, 49))	('decreased', 'NegReg', (24, 33))	('TMZ', 'Chemical', 'MESH:D000077204', (46, 49))	('U87MG', 'CellLine', 'CVCL:0022', (58, 63))	('ablation', 'Var', (10, 18))
128352	31291988	Additionally, the tumors from mice injected with ATG4C depleted U87-MG cells was significantly smaller than those in control group (Fig.	('smaller', 'NegReg', (95, 102))	('U87-MG', 'CellLine', 'CVCL:0022', (64, 70))	('mice', 'Species', '10090', (30, 34))	('U87-MG', 'Var', (64, 70))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
128353	31291988	Moreover, ATG4C knockdown also remarkably impaired the proliferation of primary glioblastoma cells (Additionaly file 4: Figure S4).	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('proliferation', 'CPA', (55, 68))	('knockdown', 'Var', (16, 25))	('ATG4C', 'Gene', (10, 15))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('impaired', 'NegReg', (42, 50))
128355	31291988	7d, the expression of Ki67, LC3 and ATG4C were decreased significantly in tumor tissues from sh-ATG4C group.	('si', 'Chemical', 'MESH:D012825', (14, 16))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('LC3', 'Gene', (28, 31))	('ATG4C', 'Gene', (36, 41))	('Ki67', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('sh-ATG4C', 'Var', (93, 101))	('tumor', 'Disease', (74, 79))	('expression', 'MPA', (8, 18))	('Ki67', 'Gene', '17345', (22, 26))	('decreased', 'NegReg', (47, 56))
128356	31291988	In this study, we identified that the mRNA level of ATG4C was associated with worse prognosis in glioma patients.	('mRNA level', 'MPA', (38, 48))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('glioma', 'Disease', (97, 103))	('ATG4C', 'Var', (52, 57))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('patients', 'Species', '9606', (104, 112))
128366	31291988	We demonstrated that knockdown ATG4C remarkably suppressed the proliferation of glioma cell lines by inducing cell cycle arrest at G1 phase.	('glioma', 'Disease', (80, 86))	('ATG4C', 'Gene', (31, 36))	('proliferation', 'CPA', (63, 76))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (110, 127))	('cell cycle arrest at G1 phase', 'CPA', (110, 139))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('suppressed', 'NegReg', (48, 58))	('inducing', 'Reg', (101, 109))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('knockdown', 'Var', (21, 30))
128369	31291988	In our current works, we observed that knockdown ATG4C induced a decrease in Cyclin E and an increase in P21 and P53 expression, which indicate obvious cell cycle arrest caused by ATG4C ablation.	('Cyclin', 'Gene', '5111', (77, 83))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (152, 169))	('increase', 'PosReg', (93, 101))	('P53', 'Gene', (113, 116))	('knockdown', 'Var', (39, 48))	('expression', 'MPA', (117, 127))	('P53', 'Gene', '7157', (113, 116))	('P21', 'Gene', (105, 108))	('Cyclin', 'Gene', (77, 83))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('decrease', 'NegReg', (65, 73))	('cell cycle', 'CPA', (152, 162))	('ATG4C', 'Gene', (49, 54))	('P21', 'Gene', '1026', (105, 108))
128370	31291988	Additionally, we observed that knockdown ATG4C could restrain the proliferation of primarily cultured glioblastoma cells from patients (Additional file 3: Figure S3).	('glioblastoma', 'Disease', (102, 114))	('proliferation', 'CPA', (66, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('restrain', 'NegReg', (53, 61))	('patients', 'Species', '9606', (126, 134))	('ATG4C', 'Gene', (41, 46))	('knockdown', 'Var', (31, 40))
128371	31291988	A large body of evidence suggests that inhibition of the activity of other ATG4 family members, including ATG4A, ATG4B and ATG4D, could suppress tumor progression and enhance chemosensitivity or the efficacy of radiotherapy.	('enhance', 'PosReg', (167, 174))	('inhibition', 'Var', (39, 49))	('chemosensitivity', 'CPA', (175, 191))	('si', 'Chemical', 'MESH:D012825', (183, 185))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ATG4D', 'Gene', '84971', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ATG4D', 'Gene', (123, 128))	('ATG4B', 'Gene', '23192', (113, 118))	('ATG4', 'Gene', (75, 79))	('tumor', 'Disease', (145, 150))	('ATG4A', 'Gene', (106, 111))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('activity', 'MPA', (57, 65))	('suppress', 'NegReg', (136, 144))	('ATG4A', 'Gene', '115201', (106, 111))	('ATG4B', 'Gene', (113, 118))	('efficacy of radiotherapy', 'CPA', (199, 223))
128375	31291988	Previous researches suggested that the miR-376 mediated ATG4C silencing could suppress autophagy in breast cancer cells and hepatocarcinoma cells.	('ATG4C', 'Gene', (56, 61))	('hepatocarcinoma', 'Disease', (124, 139))	('autophagy in', 'CPA', (87, 99))	('hepatocarcinoma', 'Disease', 'None', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('miR-376', 'Chemical', '-', (39, 46))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('suppress', 'NegReg', (78, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('miR-376', 'Var', (39, 46))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('silencing', 'NegReg', (62, 71))
128376	31291988	In the current work, we observed that LC3-II expression was significantly reduced in the presence of BafA1 in sh-ATG4C cells, indicating impaired autophagic flux.	('autophagic flux', 'CPA', (146, 161))	('BafA1', 'Gene', (101, 106))	('LC3-II', 'Protein', (38, 44))	('impaired', 'NegReg', (137, 145))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('expression', 'MPA', (45, 55))	('reduced', 'NegReg', (74, 81))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('presence', 'Var', (89, 97))
128378	31291988	However, we observed concomitantly increased protein expression of LC3-II and P62 in glioma cells transfected with si-ATG4C.	('P62', 'Gene', '23636', (78, 81))	('increased', 'PosReg', (35, 44))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('protein expression', 'MPA', (45, 63))	('si-ATG4C', 'Var', (115, 123))	('glioma', 'Disease', (85, 91))	('P62', 'Gene', (78, 81))	('LC3-II', 'Protein', (67, 73))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
128379	31291988	According to the functions of ATG4 family members in LC3 processing, ATG4C is putative to cleavage of pro-LC3 and delipidation of LC 3 II from the membrane of the autophagsome through the cysteine peptidase activity.	('ATG4C', 'Var', (69, 74))	('delipidation', 'MPA', (114, 126))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('cleavage', 'MPA', (90, 98))
128386	31291988	Consistent with the in vivo findings, knockdown ATG4C restrained the proliferation of glioma with significantly decreased tumor volumes and weights.	('glioma', 'Disease', (86, 92))	('proliferation', 'CPA', (69, 82))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('restrained', 'NegReg', (54, 64))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('decreased', 'NegReg', (112, 121))	('ATG4C', 'Gene', (48, 53))	('knockdown', 'Var', (38, 47))	('tumor', 'Disease', (122, 127))
128387	31291988	In tumor tissues of mice xenograft, the expression of both Ki67 and LC3 proteins were decreased in the sh-ATG4C group.	('expression', 'MPA', (40, 50))	('tumor', 'Disease', (3, 8))	('Ki67', 'Gene', '17345', (59, 63))	('LC3 proteins', 'Protein', (68, 80))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('mice', 'Species', '10090', (20, 24))	('sh-ATG4C', 'Var', (103, 111))	('decreased', 'NegReg', (86, 95))	('Ki67', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
128388	31291988	These results indicated that ATG4C ablation may impaired the proliferation of glioma through suppressing autophagy in vivo.	('impaired', 'NegReg', (48, 56))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('ATG4C', 'Gene', (29, 34))	('glioma', 'Disease', (78, 84))	('autophagy', 'CPA', (105, 114))	('suppressing', 'NegReg', (93, 104))	('proliferation', 'CPA', (61, 74))	('ablation', 'Var', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('si', 'Chemical', 'MESH:D012825', (100, 102))
128391	31291988	O6-MeG lead to DNA mispairs during DNA replication, and that results in DNA double strand breaks through futile cycles of mismatch repair system.	('lead to', 'Reg', (7, 14))	('O6-MeG', 'Var', (0, 6))	('results in', 'Reg', (61, 71))	('mispairs', 'Var', (19, 27))	('O6-MeG', 'Chemical', 'MESH:C008449', (0, 6))
128393	31291988	In our study, we observed for the first time that ATG4C is involved in TMZ-induced autophagy, and depletion of ATG4C significantly increased the sensitivity of U87-MG and T98G cells to TMZ, which are thought to be TMZ sensitivity and resistance cells, respectively.	('TMZ', 'Chemical', 'MESH:D000077204', (185, 188))	('depletion', 'Var', (98, 107))	('increased', 'PosReg', (131, 140))	('T98G', 'CellLine', 'CVCL:0556', (171, 175))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('si', 'Chemical', 'MESH:D012825', (236, 238))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('sensitivity', 'MPA', (145, 156))	('TMZ', 'Chemical', 'MESH:D000077204', (214, 217))	('U87-MG', 'CellLine', 'CVCL:0022', (160, 166))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('ATG4C', 'Gene', (111, 116))
128398	31291988	Additionally, ATG4C ablation could promote TMZ cytotoxicity to glioma cells by inhibiting autophagy.	('cytotoxicity', 'Disease', 'MESH:D064420', (47, 59))	('autophagy', 'CPA', (90, 99))	('inhibiting', 'NegReg', (79, 89))	('cytotoxicity', 'Disease', (47, 59))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('promote', 'PosReg', (35, 42))	('ablation', 'Var', (20, 28))	('ATG4C', 'Gene', (14, 19))	('glioma', 'Disease', (63, 69))
128422	27250577	Four different positron-emitting isotopes (carbon-11 [11C], nitrogen-13 [13N], oxygen-15 [15O], and fluorine-18 [18F]) are mainly produced in a cyclotron.	('oxygen-15 [15O]', 'Var', (79, 94))	('carbon-11 [11C]', 'Var', (43, 58))	('nitrogen', 'Chemical', 'MESH:D009584', (60, 68))	('oxygen', 'Chemical', 'MESH:D010100', (79, 85))	('fluorine', 'Chemical', 'MESH:D005461', (100, 108))	('11C', 'Chemical', 'MESH:C000615233', (54, 57))	('carbon', 'Chemical', 'MESH:D002244', (43, 49))	('13N', 'Chemical', 'MESH:C000615247', (73, 76))
128427	27250577	Intravenously injected [18F]FDG enters the cells by the same glucose transporters (GLUTs) as glucose.	('[18F]FDG', 'Var', (23, 31))	('glucose', 'Chemical', 'MESH:D005947', (93, 100))	('GLUT', 'Gene', '6513', (83, 87))	('glucose transporters', 'MPA', (61, 81))	('glucose', 'Chemical', 'MESH:D005947', (61, 68))	('GLUT', 'Gene', (83, 87))
128434	27250577	Thus, the decreased sensitivity of lesion detection of [18F]FDG PET is a major limitation for assessing gliomas.	('gliomas', 'Disease', (104, 111))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('[18F]FDG', 'Var', (55, 63))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
128438	27250577	[11C]MET is one of the essential amino acids and is used for evaluating protein synthesis and cell proliferation in gliomas.	('[11C]MET', 'Var', (0, 8))	('essential amino acids', 'Chemical', 'MESH:D000601', (23, 44))	('11C', 'Chemical', 'MESH:C000615233', (1, 4))	('gliomas', 'Disease', (116, 123))	('cell proliferation', 'CPA', (94, 112))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
128445	27250577	To have a longer half-life of positron emitters, [18F]FET and [18F]FDOPA were developed.	('[18F]', 'Var', (49, 54))	('FDOPA', 'Chemical', 'MESH:C043437', (67, 72))	('[18F]', 'Var', (62, 67))
128447	27250577	Although [18F]FET and [18F]FDOPA can delineate tumor extent and provide excellent tumor-to-background contrast, they have some disadvantages.	('[18F]FET', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('[18F]', 'Var', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('FDOPA', 'Chemical', 'MESH:C043437', (27, 32))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (47, 52))
128452	27250577	Previous studies have shown that the accumulation of anti-[18F]FACBC was high in gliomas and low in normal tissues and inflammatory regions.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('anti-[18F]FACBC', 'Var', (53, 68))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))
128453	27250577	We expected that anti-[18F]FACBC PET may be useful for the diagnosis of low and high-grade gliomas.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('anti-[', 'Var', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
128456	27250577	Because, [18F]FLT accumulation in normal brain tissue is very low, it provides excellent tumor-to-background contrast.	('[18F]FLT', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
128458	27250577	Because of [18F]FLT leakage in radiation necrosis and disruption of the blood-brain barrier (BBB), [18F]FLT accumulation can increase, which may make it difficult to differentiate from metabolically active tumors.	('[18F]FLT', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('radiation necrosis', 'Disease', 'MESH:D004194', (31, 49))	('radiation necrosis', 'Disease', (31, 49))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('increase', 'PosReg', (125, 133))	('active tumors', 'Disease', 'MESH:D009369', (199, 212))	('active tumors', 'Disease', (199, 212))
128473	27250577	Figure 1 shows representative cases of [18F]FDG, [11C]MET, [18F]FLT, and [18F]FMISO PET studies in diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (120, 142))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('[11C]MET', 'Var', (49, 57))	('astrocytoma', 'Disease', 'MESH:D001254', (107, 118))	('glioblastoma', 'Disease', (148, 160))	('astrocytoma', 'Disease', (107, 118))	('astrocytoma', 'Disease', 'MESH:D001254', (131, 142))	('11C', 'Chemical', 'MESH:C000615233', (50, 53))	('anaplastic astrocytoma', 'Disease', (120, 142))	('astrocytoma', 'Disease', (131, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (148, 160))	('[18F]FLT', 'Var', (59, 67))	('[18F]FMISO', 'Var', (73, 83))	('[18F]FDG', 'Var', (39, 47))
128480	27250577	Previously, combined modalities of [11C]MET and MRI have been shown to significantly enhance the accuracy for the identification of active tumors relative to that of [18F]FDG.	('[11C]MET', 'Var', (35, 43))	('active tumors', 'Disease', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('11C', 'Chemical', 'MESH:C000615233', (36, 39))	('enhance', 'PosReg', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('active tumors', 'Disease', 'MESH:D009369', (132, 145))
128481	27250577	Particularly in low-grade gliomas, [11C]MET is better suited for biopsy targeted lesions than is [18F]FDG.	('[11C]MET', 'Var', (35, 43))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('11C', 'Chemical', 'MESH:C000615233', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
128486	27250577	Therefore, [18F]FDG, [11C]MET, and [18F]FET, as well as [18F]FLT, which can identify regions of tumors with increased proliferation rates, could be implemented for combined PET/MRI guidance in high-grade gliomas.	('[11C]MET', 'Var', (21, 29))	('[18F]FET', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('tumors', 'Disease', (96, 102))	('gliomas', 'Disease', (204, 211))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('[18F]FDG', 'Var', (11, 19))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('11C', 'Chemical', 'MESH:C000615233', (22, 25))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))
128495	27250577	For glioma patients treated with chemotherapy, [11C]MET and [18F]FET PET may improve response assessment.	('improve', 'PosReg', (77, 84))	('[18F]FET PET', 'Var', (60, 72))	('11C', 'Chemical', 'MESH:C000615233', (48, 51))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('response assessment', 'MPA', (85, 104))	('patients', 'Species', '9606', (11, 19))	('[11C]MET', 'Var', (47, 55))	('glioma', 'Disease', (4, 10))
128502	27250577	However, [18F]FLT is significantly dependent on BBB permeability and is mainly restricted to contrast-enhancing tumor lesions.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('[18F]FLT', 'Var', (9, 17))
128503	27250577	Compared with the MRI-based RANO criteria, [18F]FET and [18F]FDOPA PET are useful for determining antiangiogenic treatment failure with bevacizumab earlier and have been used to predict a favorable outcome for responders to bevacizumab.	('FDOPA', 'Chemical', 'MESH:C043437', (61, 66))	('[18F]', 'Var', (56, 61))	('bevacizumab', 'Chemical', 'MESH:D000068258', (136, 147))	('antiangiogenic treatment', 'MPA', (98, 122))	('[18F]', 'Var', (43, 48))	('bevacizumab', 'Chemical', 'MESH:D000068258', (224, 235))
128509	27250577	A recent study showed an association between volume-based tumor measurements and patient prognosis because [11C]MET uptake reflected tumor expansion more accurately than did MRI (Figs.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patient', 'Species', '9606', (81, 88))	('11C', 'Chemical', 'MESH:C000615233', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('[11C]MET', 'Var', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (133, 138))
128513	27250577	The proliferative volume of [18F]FLT appears to be more predictive than tumor volume on MRI for overall survival.	('tumor', 'Disease', (72, 77))	('[18F]FLT', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
128519	27250577	[18F]FET PET may be useful for this indication within the short time frame of the first 12 weeks after radio-chemotherapy with temozolomide because the sensitivity and specificity of [18F]FET have been found to be >90% for differentiating pseudoprogression from tumor recurrence in glioblastoma patients.	('glioblastoma', 'Phenotype', 'HP:0012174', (282, 294))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('temozolomide', 'Chemical', 'MESH:D000077204', (127, 139))	('pseudoprogression', 'Disease', (239, 256))	('tumor', 'Disease', (262, 267))	('patients', 'Species', '9606', (295, 303))	('[18F]', 'Var', (183, 188))	('glioblastoma', 'Disease', (282, 294))	('glioblastoma', 'Disease', 'MESH:D005909', (282, 294))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
128522	27250577	It is important that [18F]FET and [18F]FDOPA may facilitate the diagnosis of pseudoprogression following radio-chemotherapy for malignant glioma.	('malignant glioma', 'Disease', (128, 144))	('malignant glioma', 'Disease', 'MESH:D005910', (128, 144))	('FDOPA', 'Chemical', 'MESH:C043437', (39, 44))	('facilitate', 'PosReg', (49, 59))	('pseudoprogression', 'Disease', (77, 94))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('[18F]FET', 'Var', (21, 29))	('[18F]', 'Var', (34, 39))
128599	21949886	The tv-a transgenic mice have been cross-bred with mice carrying targeted deletions of tumor suppressor genes (Ink4a-/-; Arf-/-) frequently deleted in human glioma.	('deletions', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mice', 'Species', '10090', (51, 55))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('human', 'Species', '9606', (151, 156))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Disease', (87, 92))	('transgenic mice', 'Species', '10090', (9, 24))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('glioma', 'Disease', (157, 163))	('Ink4a-/-; Arf', 'Gene', '12578', (111, 124))	('Ink4a-/-; Arf', 'Gene', (111, 124))
128605	21949886	We have investigated whether MCs have a role in glioma and show for the first time that both mouse and human gliomas accommodate MCs.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('human', 'Species', '9606', (103, 108))	('mouse', 'Species', '10090', (93, 98))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('MCs', 'Var', (129, 132))	('glioma', 'Disease', (109, 115))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('glioma', 'Disease', (48, 54))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
128611	21949886	As shown in Figure 1, MCs were present in gliomas of both Ntv-a and Gtv-a transgenes, and both in Arf-/- and Ink4-/- animals.	('transgenes', 'Var', (74, 84))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('Gtv-a', 'Gene', (68, 73))	('Gtv-a', 'Chemical', '-', (68, 73))	('Ntv-a', 'Gene', (58, 63))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
128631	21949886	Indeed, we were able to identify proliferating MCs in both Ntv-a- and Gtv-a Arf-/- mouse gliomas as compared with non-tumor tissue (Figure 3A), with an average of 7% and 4% of proliferative MCs, respectively (Figure 3B).	('rat', 'Species', '10116', (183, 186))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('mouse', 'Species', '10090', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('rat', 'Species', '10116', (40, 43))	('non-tumor', 'Disease', (114, 123))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('Ntv-a-', 'Var', (59, 65))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('non-tumor', 'Disease', 'MESH:D009369', (114, 123))	('Gtv-a', 'Chemical', '-', (70, 75))
128638	21949886	We analyzed gliomas for expression of CXCL12 and CXCR4 and found abundant expression of CXCL12 in both Ntv-a- and Gtv-a Arf-/- gliomas (Figure 4; left panel) and there was also a clear expression of CXCR4 in the same samples (Figure 4; middle panel).	('expression', 'MPA', (74, 84))	('CXCL12', 'MPA', (88, 94))	('gliomas', 'Disease', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('Ntv-a-', 'Var', (103, 109))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('Gtv-a', 'Chemical', '-', (114, 119))
128645	21949886	Specific blockade of CXCL12 decreased MC migration by circa 32% and 20% as compared to migration towards glioma cell-conditioned medium or glioma cell-conditioned medium supplemented with non-specific IgG, respectively (Figure 6A).	('rat', 'Species', '10116', (90, 93))	('decreased', 'NegReg', (28, 37))	('glioma', 'Disease', (139, 145))	('glioma', 'Disease', (105, 111))	('rat', 'Species', '10116', (44, 47))	('MC migration', 'CPA', (38, 50))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('blockade', 'Var', (9, 17))
128683	21949886	In the in vitro migration assay CXCL12 neutralization in glioma-conditioned medium led to a significant decrease of MC migration.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('CXCL12 neutralization', 'Var', (32, 53))	('glioma', 'Disease', (57, 63))	('MC migration', 'CPA', (116, 128))	('rat', 'Species', '10116', (19, 22))	('decrease', 'NegReg', (104, 112))	('rat', 'Species', '10116', (122, 125))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('decrease of MC', 'Phenotype', 'HP:0025066', (104, 118))
128684	21949886	Similarly, blocking of its receptor, CXCR4, resulted in reduced migration of MCs further, strengthening the notion that a CXCL12/CXCR4 axis plays an active role in MC recruitment to the tumor site.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('migration of MCs further', 'CPA', (64, 88))	('rat', 'Species', '10116', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('reduced', 'NegReg', (56, 63))	('tumor', 'Disease', (186, 191))	('blocking', 'Var', (11, 19))
128687	21949886	Despite being expressed by glioma cells at a higher level, CXCL12 is additionally expressed by endothelial cells further increasing its chemotactic potential.	('glioma', 'Disease', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('chemotactic potential', 'MPA', (136, 157))	('increasing', 'PosReg', (121, 131))	('CXCL12', 'Var', (59, 65))
128690	21949886	One favored possibility would be that MCs promote the tumor angiogenesis in gliomas, a notion that is well in line with a proposed function of MCs in various other types of tumor settings.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('MCs', 'Var', (38, 41))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('promote', 'PosReg', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
128693	21949886	In the animal studies animals had free access to food and water and they were housed and treated following the conditions approved by Uppsala Ethical Committee on Animal Experiments, which also approved the experimental protocol (approval C32/3 from 19.03.2003 and C246/10 from 29.09.2010).	('C246/10', 'Var', (265, 272))	('water', 'Chemical', 'MESH:D014867', (58, 63))	('C32', 'Gene', '75458', (239, 242))	('C32', 'Gene', (239, 242))
128822	25772366	Leveraging a neurofibromatosis-1 (Nf1) genetically-engineered mouse LGG model, we report the isolation of CD133+ multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts.	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('mouse', 'Species', '10090', (62, 67))	('parent tumor', 'Disease', 'MESH:D063129', (230, 242))	('CD133+', 'Var', (106, 112))	('neurofibromatosis-1', 'Gene', (13, 32))	('glioma-like lesions', 'Disease', (180, 199))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('parent tumor', 'Disease', (230, 242))	('generate', 'Reg', (171, 179))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Disease', (136, 142))	('neurofibromatosis-1', 'Gene', '18015', (13, 32))	('glioma-like lesions', 'Disease', 'MESH:D005910', (180, 199))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('glioma', 'Disease', (180, 186))
128843	25772366	To determine whether CSCs could be generated from low-grade glioma-bearing mice, single cells were dissociated from the optic nerves/chiasm of Nf1flox/flox (wild-type), Nf1+/-, and Nf1+/-GFAPCKO mice at 3 months of age, and maintained in defined media.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('mice', 'Species', '10090', (75, 79))	('mice', 'Species', '10090', (195, 199))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('glioma', 'Disease', (60, 66))	('Nf1flox/flox', 'Var', (143, 155))	('GFAP', 'Gene', '14580', (187, 191))	('Nf1+/-', 'Var', (169, 175))	('GFAP', 'Gene', (187, 191))
128846	25772366	In contrast, cells from Nf1flox/flox (WT) and Nf1+/- mice took nearly 3 weeks to form smaller clusters, which could not be maintained by serial passaging due to loss of proliferation and self-renewal ability.	('Nf1+/-', 'Var', (46, 52))	('self-renewal ability', 'CPA', (187, 207))	('Nf1flox/flox', 'Var', (24, 36))	('loss', 'NegReg', (161, 165))	('mice', 'Species', '10090', (53, 57))
128850	25772366	In addition, other GSC markers identified in glioblastoma GSCs, including A2B5, CD15 and CD49f, were expressed in o-GSCs, but not in Nf1-/- TVZ NSCs (Figure 1D, E).	('glioblastoma GSCs', 'Disease', 'MESH:D005909', (45, 62))	('glioblastoma GSCs', 'Disease', (45, 62))	('CD15', 'Gene', '14345', (80, 84))	('o-GSCs', 'Disease', (114, 120))	('CD49f', 'Gene', '16403', (89, 94))	('CD49f', 'Gene', (89, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('A2B5', 'Var', (74, 78))	('CD15', 'Gene', (80, 84))
128854	25772366	Nf1+/- mice were chosen to provide a more faithful genetic background, since these tumors arise in patients with a germline NF1 gene mutation.	('NF1', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutation', 'Var', (133, 141))	('tumors', 'Disease', (83, 89))	('mice', 'Species', '10090', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
128872	25772366	While we observed no change in total tuberin expression, there was increased hamartin expression in both Nf1-/- TVZ NSCs and o-GSCs, and a decrease in phosphorylation-mediated tuberin inactivation (Ser939 and Thr1462), excluding tuberin/hamartin-mediated mTOR activation as the mechanism underlying the increased mTOR activity in o-GSCs (Figure S5A).	('mTOR', 'Gene', (313, 317))	('tuberin', 'Gene', '22084', (176, 183))	('Ser939', 'Chemical', '-', (198, 204))	('hamartin', 'Gene', '64930', (237, 245))	('hamartin', 'Gene', (237, 245))	('mTOR', 'Gene', (255, 259))	('hamartin', 'Gene', '64930', (77, 85))	('hamartin', 'Gene', (77, 85))	('Nf1-/-', 'Var', (105, 111))	('tuberin', 'Gene', (176, 183))	('Thr1462', 'Chemical', '-', (209, 216))	('tuberin', 'Gene', '22084', (229, 236))	('increased', 'PosReg', (67, 76))	('decrease', 'NegReg', (139, 147))	('mTOR', 'Gene', '56717', (313, 317))	('expression', 'MPA', (86, 96))	('tuberin', 'Gene', (229, 236))	('tuberin', 'Gene', '22084', (37, 44))	('mTOR', 'Gene', '56717', (255, 259))	('tuberin', 'Gene', (37, 44))
128877	25772366	Moreover, PD901 did not inhibit ERK-Thr202/Tyr204 phosphorylation as a result of aberrant MEK activation (phospho-MEK-Ser217/221; Figure 5D).	('PD901', 'Chemical', 'MESH:C506614', (10, 15))	('phospho-MEK-Ser217/221', 'Var', (106, 128))	('MEK', 'Protein', (90, 93))	('Ser217', 'Chemical', '-', (118, 124))	('Thr202', 'Chemical', '-', (36, 42))	('Tyr204', 'Chemical', '-', (43, 49))	('activation', 'PosReg', (94, 104))
128878	25772366	In KRAS mutant human tumors, reactivation of CRAF creates a MEK-CRAF complex, which increases MEK/ERK phosphorylation after PD901 treatment.	('KRAS', 'Gene', '3845', (3, 7))	('tumors', 'Disease', (21, 27))	('MEK/ERK phosphorylation', 'MPA', (94, 117))	('mutant', 'Var', (8, 14))	('PD901', 'Chemical', 'MESH:C506614', (124, 129))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('increases', 'PosReg', (84, 93))	('human', 'Species', '9606', (15, 20))	('KRAS', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
128891	25772366	Cleavage of one initiator caspase (caspase-12, but not caspase-9) as well as the caspase-6, caspase-3, and poly (ADP-ribose) polymerase (PARP) downstream effectors, was observed in o-GSCs after Abcg1 shRNA-mediated knockdown (Figure 7G-H).	('caspase-3', 'Gene', '12367', (92, 101))	('PARP', 'Gene', (137, 141))	('poly (ADP-ribose) polymerase', 'Gene', (107, 135))	('caspase-9', 'Gene', (55, 64))	('PARP', 'Gene', '11545', (137, 141))	('observed', 'Reg', (169, 177))	('caspase-6', 'Gene', '12368', (81, 90))	('poly (ADP-ribose) polymerase', 'Gene', '11545', (107, 135))	('caspase-3', 'Gene', (92, 101))	('caspase-12', 'Gene', (35, 45))	('knockdown', 'Var', (215, 224))	('caspase-9', 'Gene', '12371', (55, 64))	('caspase-6', 'Gene', (81, 90))	('Cleavage', 'MPA', (0, 8))	('caspase-12', 'Gene', '12364', (35, 45))
128892	25772366	Finally, to determine whether ER stress was responsible for Abcg1 knockdown-induced cell death, the expression of BiP and CHOP, two markers of ER stress were examined.	('CHOP', 'Gene', '13198', (122, 126))	('knockdown-induced', 'Var', (66, 83))	('Abcg1', 'Gene', (60, 65))	('BiP', 'Gene', '14828', (114, 117))	('CHOP', 'Gene', (122, 126))	('BiP', 'Gene', (114, 117))
128893	25772366	Abcg1 knockdown increased BiP and CHOP expression by 2 to 2.5-fold and 4.5 to 7-fold, respectively, relative to controls (Figure 7I).	('BiP', 'Gene', (26, 29))	('to 7', 'Species', '1214577', (75, 79))	('CHOP', 'Gene', '13198', (34, 38))	('Abcg1', 'Gene', (0, 5))	('increased', 'PosReg', (16, 25))	('CHOP', 'Gene', (34, 38))	('BiP', 'Gene', '14828', (26, 29))	('knockdown', 'Var', (6, 15))
128895	25772366	Moreover, BiP, CHOP, cleaved caspase-3, and cleaved PARP expression in Abcg1 knockdown o-GSCs were reduced to control levels (Figure 7J) following 4-phenyl butyric acid (PBA) treatment, a treatment capable of blocking ER stress.	('PBA', 'Chemical', 'MESH:C075773', (170, 173))	('BiP', 'Gene', '14828', (10, 13))	('4-phenyl butyric acid', 'Chemical', 'MESH:C075773', (147, 168))	('caspase-3', 'Gene', (29, 38))	('cleaved', 'MPA', (44, 51))	('CHOP', 'Gene', (15, 19))	('Abcg1', 'Gene', (71, 76))	('knockdown', 'Var', (77, 86))	('BiP', 'Gene', (10, 13))	('PARP', 'Gene', (52, 56))	('PARP', 'Gene', '11545', (52, 56))	('CHOP', 'Gene', '13198', (15, 19))	('reduced', 'NegReg', (99, 106))	('caspase-3', 'Gene', '12367', (29, 38))
128899	25772366	Moreover, non-neoplastic stromal cells (e.g., microglia) are important for both mouse Nf1 optic glioma development and maintenance, such that disruption of their function delays optic gliomagenesis and reduces tumor proliferation.	('optic glioma', 'Phenotype', 'HP:0009734', (178, 190))	('disruption', 'Var', (142, 152))	('delays optic gliomagenesis', 'Disease', (171, 197))	('optic glioma', 'Disease', 'MESH:D020339', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('reduces', 'NegReg', (202, 209))	('optic glioma', 'Disease', (90, 102))	('tumor', 'Disease', (210, 215))	('delays optic gliomagenesis', 'Disease', 'MESH:D009901', (171, 197))	('mouse', 'Species', '10090', (80, 85))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('optic glioma', 'Phenotype', 'HP:0009734', (90, 102))	('optic glioma', 'Disease', 'MESH:D020339', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
128905	25772366	First, we demonstrate that o-GSCs form glioma-like lesions following injection into the brainstems of Nf1+/- mice, a region where gliomas form in children with NF1 who harbor a germline NF1 gene mutation.	('glioma-like lesions', 'Disease', 'MESH:D005910', (39, 58))	('NF1', 'Gene', (186, 189))	('children', 'Species', '9606', (146, 154))	('glioma-like lesions', 'Disease', (39, 58))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('mutation', 'Var', (195, 203))	('mice', 'Species', '10090', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
128922	25772366	In this report, we demonstrate that Abcg1 knockdown increased ER stress protein expression and apoptosis, which could be rescued by PBA treatment.	('PBA', 'Chemical', 'MESH:C075773', (132, 135))	('increased', 'PosReg', (52, 61))	('apoptosis', 'CPA', (95, 104))	('Abcg1', 'Gene', (36, 41))	('ER stress protein expression', 'MPA', (62, 90))	('knockdown', 'Var', (42, 51))
128925	25772366	While the precise mechanism responsible for ABCG1-mediated suppression of ER stress remains to be elucidated, its potential importance to glioma biology is underscored by preliminary studies demonstrating that high ABCG1 expression correlated with shorter overall survival in patients with glioblastoma of the mesenchymal subtype (Jingqin Luo, unpublished results).	('patients', 'Species', '9606', (276, 284))	('glioma', 'Disease', (138, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (290, 302))	('ER stress', 'MPA', (74, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (290, 302))	('overall survival', 'MPA', (256, 272))	('shorter', 'NegReg', (248, 255))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('ABCG1', 'Gene', (215, 220))	('high', 'Var', (210, 214))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('ABCG1-mediated', 'Gene', (44, 58))	('glioblastoma', 'Disease', (290, 302))
128929	25772366	Optic chiasm was microdissected from 3-month-old Nf1flox/flox, Nf1+/- and Nf1+/-GFAPCKO mice to generate primary optic nerve neurospheres.	('GFAP', 'Gene', (80, 84))	('Nf1+/-', 'Var', (63, 69))	('Nf1flox/flox', 'Var', (49, 61))	('GFAP', 'Gene', '14580', (80, 84))	('mice', 'Species', '10090', (88, 92))
128931	25772366	Wild-type and Nf1-/- NSCs were generated from Nf1flox/flox mouse brains following infection with Ad5-LacZ and Ad5-Cre adenovirus (University of Iowa Gene Transfer Core, Iowa City, IA), respectively.	('Ad5-LacZ', 'Var', (97, 105))	('Ad5-Cre', 'Var', (110, 117))	('mouse', 'Species', '10090', (59, 64))
128947	33761371	Mutations in CIC improve the prognosis of patients in the high IMriskScore group.	('improve', 'PosReg', (17, 24))	('CIC', 'Gene', '23152', (13, 16))	('Mutations', 'Var', (0, 9))	('prognosis', 'MPA', (29, 38))	('patients', 'Species', '9606', (42, 50))	('CIC', 'Gene', (13, 16))
128953	33761371	Mutations in CIC significantly improved the prognosis of patients in the high IMriskScore group.	('improved', 'PosReg', (31, 39))	('prognosis', 'MPA', (44, 53))	('patients', 'Species', '9606', (57, 65))	('CIC', 'Gene', '23152', (13, 16))	('Mutations', 'Var', (0, 9))	('CIC', 'Gene', (13, 16))
128955	33761371	Moreover, IMriskScore is an independent risk factor that can be used clinically to predict LGG patient outcomes.	('IMriskScore', 'Var', (10, 21))	('LGG', 'Disease', (91, 94))	('patient', 'Species', '9606', (95, 102))
128999	33761371	LncRNAs aberrant expression may affect cell proliferation, tumor progression, or metastasis, therefore we have hypothesized that the expression of lncRNAs may be potentially associated with MRI radiomics.	('aberrant expression', 'Var', (8, 27))	('associated', 'Reg', (174, 184))	('tumor', 'Disease', (59, 64))	('LncRNAs', 'Gene', (0, 7))	('affect', 'Reg', (32, 38))	('metastasis', 'CPA', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cell proliferation', 'CPA', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
129006	33761371	These findings show that IMriskScore is an independent prognostic factor for LGG patients (Table 2).	('LGG', 'Disease', (77, 80))	('patients', 'Species', '9606', (81, 89))	('IMriskScore', 'Var', (25, 36))
129017	33761371	In neuro-oncology, the exceptional disease control demonstrated by IDH1 inhibitors was presented at the ASCO 2020 meeting, where a clinical phase II study of the IDH1 inhibitor FT-2102, in combination with azacitidine, in patients with recurrent or progressive gliomas with IDH1 mutations, achieved a 47% disease control rate and a median progression-free survival of 8.3 months.	('gliomas', 'Disease', 'MESH:D005910', (261, 268))	('oncology', 'Phenotype', 'HP:0002664', (9, 17))	('mutations', 'Var', (279, 288))	('azacitidine', 'Chemical', 'MESH:D001374', (206, 217))	('IDH1', 'Gene', '3417', (162, 166))	('IDH1', 'Gene', (67, 71))	('patients', 'Species', '9606', (222, 230))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('IDH1', 'Gene', (274, 278))	('IDH1', 'Gene', '3417', (67, 71))	('IDH1', 'Gene', '3417', (274, 278))	('FT-2102', 'Chemical', '-', (177, 184))	('disease control', 'CPA', (305, 320))	('gliomas', 'Phenotype', 'HP:0009733', (261, 268))	('gliomas', 'Disease', (261, 268))	('IDH1', 'Gene', (162, 166))
129019	33761371	In addition, high expression of IDH1 was significantly correlated with IMriskScore (p < 0.05) (Fig.	('correlated', 'Reg', (55, 65))	('high', 'Var', (13, 17))	('IMriskScore', 'Disease', (71, 82))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))
129027	33761371	A lower proportion of SMCs was found in the low IMriskScore group compared with the high IMriskScore group.	('SMCs', 'Disease', 'None', (22, 26))	('SMCs', 'Disease', (22, 26))	('low IMriskScore', 'Var', (44, 59))
129031	33761371	Expression of UBQLN4 in the high IMriskScore group was significantly lower compared with expression level in the low IMriskScore group (Fig.	('UBQLN4', 'Gene', '56893', (14, 20))	('Expression', 'MPA', (0, 10))	('UBQLN4', 'Gene', (14, 20))	('lower', 'NegReg', (69, 74))	('high IMriskScore', 'Var', (28, 44))
129032	33761371	A significant lower mutation frequency of Capicua (CIC) and NOTCH1 was observed in the low-IMriskScores group compared with the high-risk group.	('CIC', 'Gene', (51, 54))	('Capicua', 'Gene', '23152', (42, 49))	('NOTCH1', 'Gene', '4851', (60, 66))	('lower', 'NegReg', (14, 19))	('mutation', 'Var', (20, 28))	('NOTCH1', 'Gene', (60, 66))	('CIC', 'Gene', '23152', (51, 54))	('Capicua', 'Gene', (42, 49))	('low-IMriskScores', 'Disease', (87, 103))
129033	33761371	Survival analysis show that CIC mutations are associated with a better prognosis, whereas NOTCH1 mutations do not have a significant effect on prognosis compared with CIC mutations (Fig.	('CIC', 'Gene', (28, 31))	('CIC', 'Gene', '23152', (167, 170))	('mutations', 'Var', (32, 41))	('CIC', 'Gene', '23152', (28, 31))	('NOTCH1', 'Gene', '4851', (90, 96))	('NOTCH1', 'Gene', (90, 96))	('CIC', 'Gene', (167, 170))
129034	33761371	In summary, IMriskScores are significantly associated with LGG gene instability, whereas CIC mutations in high-risk patients are associated with a better prognosis.	('LGG', 'Disease', (59, 62))	('patients', 'Species', '9606', (116, 124))	('CIC', 'Gene', '23152', (89, 92))	('instability', 'MPA', (68, 79))	('CIC', 'Gene', (89, 92))	('associated', 'Reg', (43, 53))	('IMriskScores', 'Var', (12, 24))
129035	33761371	This implies that mutations in the CIC gene correlate with the IMriskScore and may be an important risk marker for glioma prognosis.	('CIC', 'Gene', (35, 38))	('glioma', 'Disease', (115, 121))	('IMriskScore', 'Disease', (63, 74))	('correlate', 'Reg', (44, 53))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('CIC', 'Gene', '23152', (35, 38))	('mutations', 'Var', (18, 27))
129050	33761371	The IMriskScore was shown to be significantly correlated with prognosis, CIC mutations, and immunotherapy efficacy in LGG patients and showed that MRI radiomics-based prediction models can accurately predict IMriskScore in patients with LGG.	('CIC', 'Gene', '23152', (73, 76))	('LGG', 'Disease', (237, 240))	('CIC', 'Gene', (73, 76))	('correlated', 'Reg', (46, 56))	('patients', 'Species', '9606', (122, 130))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (223, 231))
129058	33761371	Previous studies report that GABAAR is associated with clinical features correlated with poor prognosis in LGG patients (including seizures, memory impairment, hallucinations and anxiety).	('memory impairment', 'Disease', 'MESH:D008569', (141, 158))	('seizures', 'Phenotype', 'HP:0001250', (131, 139))	('anxiety', 'Disease', (179, 186))	('anxiety', 'Phenotype', 'HP:0000739', (179, 186))	('seizure', 'Phenotype', 'HP:0001250', (131, 138))	('hallucinations', 'Phenotype', 'HP:0000738', (160, 174))	('memory impairment', 'Disease', (141, 158))	('LGG', 'Disease', (107, 110))	('patients', 'Species', '9606', (111, 119))	('hallucinations', 'Disease', (160, 174))	('anxiety', 'Disease', 'MESH:D001007', (179, 186))	('GABAAR', 'Var', (29, 35))	('hallucinations', 'Disease', 'MESH:D006212', (160, 174))	('seizures', 'Disease', 'MESH:D012640', (131, 139))	('memory impairment', 'Phenotype', 'HP:0002354', (141, 158))	('seizures', 'Disease', (131, 139))
129074	33761371	The absence of CIC promotes helper T cell differentiation and immune response.	('promotes', 'PosReg', (19, 27))	('CIC', 'Gene', '23152', (15, 18))	('helper T cell differentiation', 'CPA', (28, 57))	('CIC', 'Gene', (15, 18))	('immune response', 'CPA', (62, 77))	('absence', 'Var', (4, 11))
129075	33761371	Therefore, a high IMriskScore score may be an indicator of good prognosis in patients with CIC mutations.	('patients', 'Species', '9606', (77, 85))	('CIC', 'Gene', '23152', (91, 94))	('CIC', 'Gene', (91, 94))	('mutations', 'Var', (95, 104))
129076	33761371	We propose for the first time that CIC mutations are an important prognostic factor in LGG and may be associated with efficacy of immunotherapy.	('CIC', 'Gene', (35, 38))	('associated', 'Reg', (102, 112))	('LGG', 'Disease', (87, 90))	('mutations', 'Var', (39, 48))	('CIC', 'Gene', '23152', (35, 38))
129077	33761371	A high IMriskScore may suggest a poor prognosis for CIC wild-type patients, whereas a high IMriskScore may suggest a positive prognosis for CIC mutant patients.	('CIC', 'Gene', (52, 55))	('CIC', 'Gene', (140, 143))	('patients', 'Species', '9606', (151, 159))	('CIC', 'Gene', '23152', (140, 143))	('mutant', 'Var', (144, 150))	('CIC', 'Gene', '23152', (52, 55))	('patients', 'Species', '9606', (66, 74))
129078	33761371	This implies that the use of CIC's targeted agents for patients with high IMriskScore may significantly improve the prognosis of patients.	('CIC', 'Gene', '23152', (29, 32))	('patients', 'Species', '9606', (129, 137))	('IMriskScore', 'Gene', (74, 85))	('prognosis', 'CPA', (116, 125))	('improve', 'PosReg', (104, 111))	('CIC', 'Gene', (29, 32))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (55, 63))
129080	33761371	In diffuse low-grade gliomas, MRI radiomics models have been shown to predict IDH mutations and tumor aggressiveness.	('predict', 'Reg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor aggressiveness', 'Disease', (96, 116))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('aggressiveness', 'Phenotype', 'HP:0000718', (102, 116))	('mutations', 'Var', (82, 91))	('gliomas', 'Disease', (21, 28))	('IDH', 'Gene', (78, 81))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (96, 116))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('IDH', 'Gene', '3417', (78, 81))
129089	33761371	High-frequency mutant CIC, an immunosuppressive gene, showed a high mutation frequency in the low IMriskScore group.	('mutant', 'Var', (15, 21))	('low IMriskScore', 'Disease', (94, 109))	('CIC', 'Gene', '23152', (22, 25))	('CIC', 'Gene', (22, 25))
129090	33761371	CIC mutation is significantly correlated with a good outcome of patients in the high IMriskScore group.	('CIC', 'Gene', '23152', (0, 3))	('patients', 'Species', '9606', (64, 72))	('CIC', 'Gene', (0, 3))	('mutation', 'Var', (4, 12))
129092	33761371	In addition, further clinical studies are needed to explore the combined effect of IMriskScore and CIC mutations on efficacy of immunotherapy and prognosis of LGG patients.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (163, 171))	('CIC', 'Gene', '23152', (99, 102))	('LGG', 'Disease', (159, 162))	('CIC', 'Gene', (99, 102))	('IMriskScore', 'Gene', (83, 94))
129095	33761371	Mutations in the high-frequency mutant gene CIC are associated with IMriskScore and significantly affect the prognosis of LGG patients.	('LGG', 'Disease', (122, 125))	('CIC', 'Gene', '23152', (44, 47))	('associated', 'Reg', (52, 62))	('Mutations', 'Var', (0, 9))	('CIC', 'Gene', (44, 47))	('IMriskScore', 'Disease', (68, 79))	('patients', 'Species', '9606', (126, 134))	('affect', 'Reg', (98, 104))
129144	33679809	DNA methylation is a form of DNA chemical modification, and as an essential regulator of gene transcription, can be carcinogenic.	('carcinogenic', 'Disease', (116, 128))	('carcinogenic', 'Disease', 'MESH:D063646', (116, 128))	('methylation', 'Var', (4, 15))
129167	33679809	Kaplan-Meier survival analysis also demonstrated that among patients with CESC (Figure 3D; p = 0.021), DLBC (Figure 3E; p = 0.009), LUAD (Figure 3H; p = 0.020), THCA (Figure 3I; p = 0.013), and SKCM (Figure 3G, p = 0.029), those with high levels of TREM2 had longer survival times, while in patients with LGG (Figure 3B; P = 0.003), LIHC (Figure 3C; p = 0.006), and KIRC (Figure 3F; p = 0.014), high TREM2 expression was associated with poor OS.	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('patients', 'Species', '9606', (60, 68))	('THCA', 'Phenotype', 'HP:0002890', (161, 165))	('high', 'Var', (395, 399))	('patients', 'Species', '9606', (291, 299))	('longer', 'PosReg', (259, 265))	('survival times', 'CPA', (266, 280))	('poor OS', 'Disease', (437, 444))	('expression', 'MPA', (406, 416))	('TREM2', 'Gene', (400, 405))
129172	33679809	KM analysis showed that individuals with in CESC (Figure 5B; p = 0.001) and DLBC (Figure 5E; p = 0.003) and high levels of TREM2 expression had longer survival times, while patients with LGG (Figure 5C; p = 0.005) and PRAD (Figure 5D; p < 0.001) and high TREM2 expression had poor PFI.	('survival times', 'CPA', (151, 165))	('patients', 'Species', '9606', (173, 181))	('longer', 'PosReg', (144, 150))	('expression', 'MPA', (261, 271))	('high', 'Var', (108, 112))	('TREM2', 'Gene', (123, 128))	('TREM2', 'Gene', (255, 260))
129202	33679809	TREM2 methylation level was a protective factor in patients with mesothelioma, uveal melanoma, and liver cancer, in terms of OS (Figure 12B).	('methylation level', 'Var', (6, 23))	('liver cancer', 'Disease', (99, 111))	('mesothelioma', 'Disease', (65, 77))	('TREM2', 'Gene', (0, 5))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('patients', 'Species', '9606', (51, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('liver cancer', 'Phenotype', 'HP:0002896', (99, 111))	('liver cancer', 'Disease', 'MESH:D006528', (99, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
129212	33679809	The results demonstrate that TREM2 expression is positively associated with several immune cell-related pathways, including B, CD4 T, and CD8 T cells, and immune factor-related pathways such as TNF, cell migration, and synaptic pruning.	('cell migration', 'CPA', (199, 213))	('immune cell-related pathways', 'Pathway', (84, 112))	('TREM2', 'Gene', (29, 34))	('CD4', 'Gene', '920', (127, 130))	('synaptic pruning', 'CPA', (219, 235))	('associated', 'Reg', (60, 70))	('CD8', 'Gene', (138, 141))	('TNF', 'Gene', (194, 197))	('CD8', 'Gene', '925', (138, 141))	('TNF', 'Gene', '7124', (194, 197))	('CD4', 'Gene', (127, 130))	('expression', 'Var', (35, 45))
129221	33679809	Similarly, TREM2 expression was previously reported as associated with shorter survival time in patients with gastric cancer.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('survival time', 'CPA', (79, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Var', (17, 27))	('TREM2', 'Gene', (11, 16))	('patients', 'Species', '9606', (96, 104))	('shorter', 'NegReg', (71, 78))
129224	33679809	In contrast, high TREM2 expression is associated with good prognosis in patients with CESC, LUAD, and THCA.	('CESC', 'Disease', (86, 90))	('THCA', 'Phenotype', 'HP:0002890', (102, 106))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('THCA', 'Disease', (102, 106))	('LUAD', 'Disease', (92, 96))	('TREM2', 'Gene', (18, 23))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('patients', 'Species', '9606', (72, 80))
129236	33679809	High-frequency MSI in colorectal cancer is an independent predictor of clinical characteristics and prognosis.	('colorectal cancer', 'Disease', (22, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('High-frequency MSI', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))
129248	33679809	These results all indicate that expression of TREM2 is closely related to immune infiltration of tumor cells, affects patient prognosis, and proposes new targets for the development of immunosuppressants.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('patient prognosis', 'CPA', (118, 135))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'Var', (32, 42))	('tumor', 'Disease', (97, 102))	('affects', 'Reg', (110, 117))	('related', 'Reg', (63, 70))	('patient', 'Species', '9606', (118, 125))	('TREM2', 'Gene', (46, 51))
129277	31930277	Grade I to IV assignment as a malignancy ruler was kept and mutations in IDH1 and histone H3 (H3K27M) were included, as well as the 1p/19q-codeletion (Table 1).	('malignancy', 'Disease', (30, 40))	('IDH1', 'Gene', '3417', (73, 77))	('malignancy', 'Disease', 'MESH:D009369', (30, 40))	('IDH1', 'Gene', (73, 77))	('mutations', 'Var', (60, 69))	('H3K27M', 'Gene', (94, 100))
129281	31930277	Despite the typical heterogeneity, LGG harbor alterations in the BRAF gene that commonly lead to the loss of its regulatory N-terminal region.	('loss', 'NegReg', (101, 105))	('alterations', 'Var', (46, 57))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', (65, 69))	('regulatory N-terminal region', 'MPA', (113, 141))
129282	31930277	Other genetic abnormalities are also described, but in all cases, the defects frequently lead to constitutive activation of the MAP (mitogen-activated protein) kinase pathway.	('activation', 'PosReg', (110, 120))	('lead to', 'Reg', (89, 96))	('genetic abnormalities', 'Disease', 'MESH:D030342', (6, 27))	('genetic abnormalities', 'Disease', (6, 27))	('constitutive', 'MPA', (97, 109))	('defects', 'Var', (70, 77))
129283	31930277	Besides BRAF mutations, translocations involving tyrosine kinase receptors have been likewise documented.	('mutations', 'Var', (13, 22))	('BRAF', 'Gene', (8, 12))	('BRAF', 'Gene', '673', (8, 12))	('tyrosine', 'Protein', (49, 57))
129285	31930277	Furthermore, mutations in fibroblast growth factor receptor 1 (FGFR1) are the second most common point mutation in LGG, after BRAF V600E.	('V600E', 'Mutation', 'rs113488022', (131, 136))	('common', 'Reg', (90, 96))	('fibroblast growth factor receptor 1', 'Gene', (26, 61))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('mutations', 'Var', (13, 22))	('fibroblast growth factor receptor 1', 'Gene', '2260', (26, 61))
129299	31930277	Methylation of the MGMT promoter reduces protein expression, thus impairing the repair capacity of TMZ-induced damage, boosting the response to treatment.	('impairing', 'NegReg', (66, 75))	('repair', 'MPA', (80, 86))	('Methylation', 'Var', (0, 11))	('protein expression', 'MPA', (41, 59))	('boosting', 'PosReg', (119, 127))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('TMZ', 'Chemical', 'MESH:D000077204', (99, 102))	('response to treatment', 'MPA', (132, 153))	('reduces', 'NegReg', (33, 40))
129300	31930277	In a randomized phase III clinical trial with a set of 206 GBM patients, Stupp and colleagues observed that 45% of patients presented methylations in the MGMT promoter.	('patients', 'Species', '9606', (115, 123))	('methylations', 'Var', (134, 146))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('patients', 'Species', '9606', (63, 71))	('MGMT', 'Gene', (154, 158))	('MGMT', 'Gene', '4255', (154, 158))
129303	31930277	MGMT methylation could also be found in patient serum and strongly correlated with its presence in the tumor tissues, suggesting that detection in blood samples could represent a reliable tool to predict response to TMZ treatment.	('MGMT', 'Gene', (0, 4))	('patient', 'Species', '9606', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('methylation', 'Var', (5, 16))	('tumor', 'Disease', (103, 108))	('TMZ', 'Chemical', 'MESH:D000077204', (216, 219))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('MGMT', 'Gene', '4255', (0, 4))
129304	31930277	MGMT methylation also disclosed its relevance as biomarker for other types of malignancies, including breast, colorectal, prostate, cervical, gastric  and lung  cancers.	('breast', 'Disease', (102, 108))	('colorectal', 'Disease', (110, 120))	('MGMT', 'Gene', (0, 4))	('lung  cancers', 'Disease', (155, 168))	('methylation', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('malignancies', 'Disease', (78, 90))	('lung  cancers', 'Disease', 'MESH:D008175', (155, 168))	('gastric', 'Disease', (142, 149))	('prostate', 'Disease', (122, 130))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cervical', 'Disease', (132, 140))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('lung  cancers', 'Phenotype', 'HP:0100526', (155, 168))	('MGMT', 'Gene', '4255', (0, 4))
129325	31930277	Additionally, the use of inhibitors targeting RAD51 and mitotic kinases in tumor-derived cell cultures promoted a decrease in the viability of G3 cells.	('viability', 'CPA', (130, 139))	('RAD51', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('inhibitors', 'Var', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('decrease', 'NegReg', (114, 122))	('tumor', 'Disease', (75, 80))
129331	31930277	Several studies have demonstrated that activation of DDR-DNA repair system works as an oncogene-induced barrier against tumor establishment, and mutations or alterations that lead to loss of function or downregulation could represent a trigger for gliomagenesis.	('glioma', 'Disease', (248, 254))	('mutations', 'Var', (145, 154))	('loss of function', 'NegReg', (183, 199))	('downregulation', 'NegReg', (203, 217))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('alterations', 'Var', (158, 169))	('DDR', 'Chemical', '-', (53, 56))	('tumor', 'Disease', (120, 125))
129333	31930277	Using a similar model, Squatrito and colleagues showed that components of the DDR pathway are frequently altered in gliomas and loss of ATM or its downstream targets accelerates tumor formation.	('DDR', 'Chemical', '-', (78, 81))	('tumor', 'Disease', (178, 183))	('loss', 'Var', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('DDR pathway', 'Pathway', (78, 89))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('ATM', 'Gene', (136, 139))	('gliomas', 'Disease', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('altered', 'Reg', (105, 112))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('ATM', 'Gene', '472', (136, 139))	('accelerates', 'PosReg', (166, 177))
129334	31930277	Loss of ATRX, a protein required for non-homologous end joining (NHEJ), was also reported to promote GBM growth in an animal model.	('GBM growth', 'CPA', (101, 111))	('ATRX', 'Gene', '546', (8, 12))	('promote', 'PosReg', (93, 100))	('ATRX', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))
129335	31930277	A study conducted within the Brazilian population showed that patients carrying the Thr241Met polymorphism in the XRCC3 gene presented an increased risk of tumor development, suggesting that its malfunction contributes to astrocytoma and glioblastoma susceptibility.	('XRCC3', 'Gene', (114, 119))	('XRCC3', 'Gene', '7517', (114, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('Thr241Met', 'Var', (84, 93))	('astrocytoma', 'Phenotype', 'HP:0009592', (222, 233))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('astrocytoma', 'Disease', 'MESH:D001254', (222, 233))	('Thr241Met', 'SUBSTITUTION', 'None', (84, 93))	('patients', 'Species', '9606', (62, 70))	('malfunction', 'MPA', (195, 206))	('tumor', 'Disease', (156, 161))	('glioblastoma', 'Disease', (238, 250))	('glioblastoma', 'Disease', 'MESH:D005909', (238, 250))	('astrocytoma', 'Disease', (222, 233))
129336	31930277	XRCC3 encodes a protein involved in HR repair, and this polymorphism can potentially affect the enzyme function as well as its interaction with other repair proteins.	('polymorphism', 'Var', (56, 68))	('XRCC3', 'Gene', (0, 5))	('XRCC3', 'Gene', '7517', (0, 5))	('function', 'MPA', (103, 111))	('enzyme', 'Enzyme', (96, 102))	('affect', 'Reg', (85, 91))	('interaction', 'Interaction', (127, 138))
129337	31930277	Additionally, a nonsynonymous single nucleotide polymorphism (SNP) in the EXO1 gene was found to be potentially associated with GBM susceptibility.	('EXO1', 'Gene', (74, 78))	('GBM', 'Disease', (128, 131))	('nonsynonymous single nucleotide polymorphism', 'Var', (16, 60))	('EXO1', 'Gene', '9156', (74, 78))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('associated', 'Reg', (112, 122))
129346	31930277	Silencing of EXO1 in T98G cells led to faster restoration of DNA injury induced by ionizing radiation (IR), suggesting that the absence of EXO1 possibly directs the DSB repair to the faster and error-prone NHEJ pathway.	('EXO1', 'Gene', (13, 17))	('absence', 'Var', (128, 135))	('restoration', 'MPA', (46, 57))	('directs', 'Reg', (153, 160))	('T98G', 'CellLine', 'CVCL:0556', (21, 25))	('DSB', 'Chemical', '-', (165, 168))	('EXO1', 'Gene', '9156', (139, 143))	('DNA injury induced by ionizing radiation', 'MPA', (61, 101))	('faster', 'PosReg', (39, 45))	('EXO1', 'Gene', '9156', (13, 17))	('Silencing', 'Var', (0, 9))	('EXO1', 'Gene', (139, 143))
129349	31930277	Additionally, NEIL3 knockdown was associated with a higher percentage of DNA damage and cell death after IR.	('NEIL3', 'Gene', '55247', (14, 19))	('NEIL3', 'Gene', (14, 19))	('DNA damage', 'CPA', (73, 83))	('knockdown', 'Var', (20, 29))	('cell death', 'CPA', (88, 98))
129360	31930277	However, some patients did not present any clinical improvement after TMZ administration, even when MGMT levels are reduced, indicating that methylated MGMT promoter uniquely does not mean a successful treatment.	('MGMT', 'Gene', '4255', (100, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (70, 73))	('MGMT', 'Gene', (152, 156))	('MGMT', 'Gene', '4255', (152, 156))	('methylated', 'Var', (141, 151))	('patients', 'Species', '9606', (14, 22))	('MGMT', 'Gene', (100, 104))
129364	31930277	It was also shown that the disruption of Ape1  or DNA polymerase beta activity sensitizes cells to TMZ.	('DNA polymerase beta', 'Gene', '5423', (50, 69))	('activity', 'MPA', (70, 78))	('DNA polymerase beta', 'Gene', (50, 69))	('disruption', 'Var', (27, 37))	('Ape1', 'Gene', '328', (41, 45))	('TMZ', 'Chemical', 'MESH:D000077204', (99, 102))	('sensitizes', 'Reg', (79, 89))	('Ape1', 'Gene', (41, 45))
129366	31930277	MMR machinery defects have also been associated with TMZ resistance.	('defects', 'Var', (14, 21))	('TMZ resistance', 'Disease', (53, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (53, 56))	('associated', 'Reg', (37, 47))	('MMR machinery', 'Gene', (0, 13))
129367	31930277	The MMR pathway acts primarily during replication, recognizing and correcting insertions, deletions and base misincorporations, such as the mismatch between a TMZ-induced O6-methylguanine (O6-MeG) and thymidine.	('TMZ', 'Chemical', 'MESH:D000077204', (159, 162))	('insertions', 'Var', (78, 88))	('mismatch', 'Var', (140, 148))	('thymidine', 'Chemical', 'MESH:D013936', (201, 210))	('MMR pathway', 'Pathway', (4, 15))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (171, 187))	('O6-MeG', 'Chemical', 'MESH:C008449', (189, 195))	('deletions', 'Var', (90, 99))
129372	31930277	Additionally, clinical data showed the presence of MSH6 mutations in GBM specimens after TMZ therapy but not in pre-treatment samples, suggesting that these changes results from CT and may contribute to recurrence.	('mutations', 'Var', (56, 65))	('results from', 'Reg', (165, 177))	('MSH6', 'Gene', '2956', (51, 55))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('TMZ', 'Chemical', 'MESH:D000077204', (89, 92))	('MSH6', 'Gene', (51, 55))
129377	31930277	Although TMZ does not cause DSB directly, O6-MeG can lead to futile repair cycles, stalling replication forks and inducing DSBs subsequently.	('lead to', 'Reg', (53, 60))	('DSB', 'Chemical', '-', (123, 126))	('replication', 'MPA', (92, 103))	('O6-MeG', 'Var', (42, 48))	('TMZ', 'Chemical', 'MESH:D000077204', (9, 12))	('stalling', 'NegReg', (83, 91))	('inducing', 'Reg', (114, 122))	('DSB', 'Chemical', '-', (28, 31))	('O6-MeG', 'Chemical', 'MESH:C008449', (42, 48))	('DSBs', 'Chemical', 'MESH:C007563', (123, 127))	('DSBs', 'MPA', (123, 127))
129379	31930277	It has been demonstrated that mutation or knockdown of ATM or ATR kinases, which are sensors of DSB occurrence, sensitizes cells to TMZ.	('ATM', 'Gene', '472', (55, 58))	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('mutation', 'Var', (30, 38))	('DSB', 'Chemical', '-', (96, 99))	('sensitizes', 'Reg', (112, 122))	('ATR', 'Gene', '545', (62, 65))	('ATR', 'Gene', (62, 65))	('ATM', 'Gene', (55, 58))	('knockdown', 'Var', (42, 51))
129380	31930277	Moreover, the pharmacological inhibition or knockdown of downstream proteins in the HR pathway, such as BRCA2, RAD51, and CHK2, also increased sensitivity to treatment.	('BRCA2', 'Gene', (104, 109))	('sensitivity to treatment', 'MPA', (143, 167))	('CHK2', 'Gene', (122, 126))	('RAD51', 'Gene', (111, 116))	('HR pathway', 'Pathway', (84, 94))	('BRCA2', 'Gene', '675', (104, 109))	('pharmacological', 'Var', (14, 29))	('CHK2', 'Gene', '11200', (122, 126))	('knockdown', 'Var', (44, 53))	('increased', 'PosReg', (133, 142))
129381	31930277	Furthermore, GBM cells treated with other alkylating agents were more sensitive after inhibition of MRE11, a component of MRN complex that recognizes DNA lesions and recruits ATM kinase.	('MRE11', 'Gene', (100, 105))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))	('ATM', 'Gene', '472', (175, 178))	('ATM', 'Gene', (175, 178))	('inhibition', 'Var', (86, 96))	('sensitive', 'MPA', (70, 79))	('MRE11', 'Gene', '4361', (100, 105))
129382	31930277	In contrast, some reports suggest that ATM/ATR activation is required to induce cell death after the MMR futile cycle is established and that MRE11 knockdown decreases sensitivity to TMZ.	('decreases', 'NegReg', (158, 167))	('ATR', 'Gene', '545', (43, 46))	('ATR', 'Gene', (43, 46))	('sensitivity to TMZ', 'MPA', (168, 186))	('MRE11', 'Gene', (142, 147))	('TMZ', 'Chemical', 'MESH:D000077204', (183, 186))	('ATM', 'Gene', (39, 42))	('cell death', 'CPA', (80, 90))	('ATM', 'Gene', '472', (39, 42))	('MRE11', 'Gene', '4361', (142, 147))	('knockdown', 'Var', (148, 157))
129388	31930277	PARP1 is rapidly activated by strand breaks and signals the presence of DNA lesions by attaching ADP-ribose units to chromatin proteins, leading to the recruitment of the downstream targets.	('strand breaks', 'Var', (30, 43))	('recruitment', 'MPA', (152, 163))	('activated', 'PosReg', (17, 26))	('PARP1', 'Gene', '142', (0, 5))	('ADP-ribose', 'Chemical', 'MESH:D000246', (97, 107))	('PARP1', 'Gene', (0, 5))
129393	31930277	Additionally, inhibition of PARP1 intensifies SSBs occurrence, which are converted to DSBs during replication.	('SSBs', 'Disease', (46, 50))	('PARP1', 'Gene', (28, 33))	('intensifies', 'PosReg', (34, 45))	('DSBs', 'Chemical', 'MESH:C007563', (86, 90))	('occurrence', 'MPA', (51, 61))	('inhibition', 'Var', (14, 24))	('PARP1', 'Gene', '142', (28, 33))
129394	31930277	This effect is greater in BRCA1/2 defective cells because missed DSBs restoration is secondly impaired and cell death is activated.	('DSBs', 'Chemical', 'MESH:C007563', (65, 69))	('defective', 'Var', (34, 43))	('impaired', 'NegReg', (94, 102))	('BRCA1/2', 'Gene', (26, 33))	('missed DSBs', 'Disease', (58, 69))	('BRCA1/2', 'Gene', '672;675', (26, 33))
129396	31930277	Although mutations in BRCA genes are rare in GBM, PTEN mutations similarly impair HR and are found in one-third of cases, enabling the exploration of PARPi synthetic lethality also for GBM.	('mutations', 'Var', (55, 64))	('PTEN', 'Gene', (50, 54))	('GBM', 'Phenotype', 'HP:0012174', (185, 188))	('PTEN', 'Gene', '5728', (50, 54))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('BRCA', 'Gene', '672', (22, 26))	('impair', 'NegReg', (75, 81))	('BRCA', 'Gene', (22, 26))
129398	31930277	So far, the inhibition of constitutively active DDR and repair proteins, a common alteration in GBM, shows great potential to improve treatment effectiveness.	('inhibition', 'Var', (12, 22))	('improve', 'PosReg', (126, 133))	('treatment effectiveness', 'CPA', (134, 157))	('DDR', 'Protein', (48, 51))	('DDR', 'Chemical', '-', (48, 51))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))
129403	31930277	In addition, inhibition of RAD51 in glioma stem cells reduced IR-induced foci formation and DSB repair, diminishing CSC population .	('RAD51', 'Gene', (27, 32))	('DSB', 'Chemical', '-', (92, 95))	('diminishing', 'NegReg', (104, 115))	('inhibition', 'Var', (13, 23))	('glioma', 'Disease', (36, 42))	('reduced', 'NegReg', (54, 61))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('DSB repair', 'CPA', (92, 102))	('IR-induced foci formation', 'CPA', (62, 87))	('CSC population', 'CPA', (116, 130))
129409	31930277	The knockdown of a 292-gene cluster reduced cell growth of U87 cells when combined with a sublethal dose of TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('292-gene', 'Gene', (19, 27))	('cell growth of U87 cells', 'CPA', (44, 68))	('U87', 'CellLine', 'CVCL:0022', (59, 62))	('reduced', 'NegReg', (36, 43))	('knockdown', 'Var', (4, 13))
129421	31930277	Additionally, patients usually present lymphopenia as GBM induces sequestration of T-cells in the bone marrow, reducing their amount at the tumor site and in lymphoid organs; and the blood-brain barrier blocks and/or effluxes antibodies and other large molecules.	('antibodies', 'Protein', (226, 236))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('GBM', 'Var', (54, 57))	('lymphopenia', 'Phenotype', 'HP:0001888', (39, 50))	('lymphopenia', 'Disease', (39, 50))	('sequestration', 'MPA', (66, 79))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('amount at the', 'MPA', (126, 139))	('reducing', 'NegReg', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('effluxes', 'MPA', (217, 225))	('patients', 'Species', '9606', (14, 22))	('lymphopenia', 'Disease', 'MESH:D008231', (39, 50))	('tumor', 'Disease', (140, 145))
129423	31930277	Moreover, a recently identified hypermutated GBM subtype, harboring mutations in the exonuclease domain of the polymerase epsilon gene (POLE) and/or biallelic MMR deficiency (bMMRD), respond better to immunotherapies such as immune checkpoint inhibition and neoantigen loads.	('MMR deficiency', 'Disease', (159, 173))	('bMMRD', 'Disease', (175, 180))	('respond', 'MPA', (183, 190))	('mutations in', 'Var', (68, 80))	('bMMRD', 'Disease', 'None', (175, 180))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('MMR deficiency', 'Disease', 'MESH:C536928', (159, 173))	('POLE', 'Gene', (136, 140))	('better', 'PosReg', (191, 197))
129424	31930277	Furthermore, the hypermutated phenotype could also cause the arising of key mutations that provide new tumor competencies, opening the possibility to exploit their synthetic lethality potential and improve treatment response through a combination of radio-chemo-immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('improve', 'PosReg', (198, 205))	('mutations', 'Var', (76, 85))	('hypermutated', 'Var', (17, 29))	('tumor competencies', 'Disease', 'MESH:D009369', (103, 121))	('cause', 'Reg', (51, 56))	('tumor competencies', 'Disease', (103, 121))	('treatment response', 'CPA', (206, 224))
129426	31930277	It was observed that TTF could suppress invasion and migration of U87 and U373 GBM cell lines, and angiogenesis in endothelial cell lines by downregulation of PI3K/AKT/NF-kB pathway.	('AKT', 'Gene', (164, 167))	('U87', 'CellLine', 'CVCL:0022', (66, 69))	('angiogenesis', 'CPA', (99, 111))	('TTF', 'Var', (21, 24))	('AKT', 'Gene', '207', (164, 167))	('downregulation', 'NegReg', (141, 155))	('GBM', 'Phenotype', 'HP:0012174', (79, 82))	('suppress', 'NegReg', (31, 39))
129427	31930277	Impairing of epithelial to mesenchymal transition (EMT) was also observed after TTF, which promoted both increased E-cadherin and diminished vimentin expression.	('vimentin', 'Gene', '7431', (141, 149))	('diminished', 'NegReg', (130, 140))	('vimentin', 'Gene', (141, 149))	('epithelial to mesenchymal transition', 'CPA', (13, 49))	('increased', 'PosReg', (105, 114))	('TTF', 'Var', (80, 83))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))
129428	31930277	Additionally, patients treated with TTF presented enhanced overall survival when compared to those who received conventional therapy only.	('enhanced', 'PosReg', (50, 58))	('patients', 'Species', '9606', (14, 22))	('TTF', 'Var', (36, 39))	('overall survival', 'CPA', (59, 75))
129432	31930277	Secondly, PDT increases the success of tumor ablation by eliminating its roots while normal brain tissue is spared due to a preferable accumulation of PSs in tumor cells, improving progression-free and overall survival of patients.	('tumor', 'Disease', (158, 163))	('roots', 'MPA', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PSs', 'MPA', (151, 154))	('PDT', 'Var', (10, 13))	('patients', 'Species', '9606', (222, 230))	('improving', 'PosReg', (171, 180))	('eliminating', 'NegReg', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('progression-free', 'CPA', (181, 197))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('accumulation', 'PosReg', (135, 147))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('overall survival', 'CPA', (202, 218))
129438	30709931	Landscape of germline and somatic mitochondrial DNA mutations in pediatric malignancies Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies.	('mutations', 'Var', (52, 61))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('malignancies', 'Disease', (75, 87))	('malignancies', 'Disease', (179, 191))	('mitochondrial DNA', 'Gene', (34, 51))
129440	30709931	We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at 4 statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET.	('MT-ND4', 'Gene', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MT-ND4', 'Gene', '4538', (157, 163))	('COX3', 'Gene', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('MT-ND5', 'Gene', '4540', (169, 175))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (78, 87))	('COX3', 'Gene', '4514', (151, 155))	('mutations', 'Var', (24, 33))	('mtDNA', 'Gene', (18, 23))	('loss-of-function', 'NegReg', (61, 77))	('MT-ND5', 'Gene', (169, 175))
129441	30709931	A skewed ratio (4.83) of non-synonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified based on Monte Carlo simulations in the tumors.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mtDNA', 'Gene', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('dN', 'Chemical', '-', (59, 61))	('dS', 'Chemical', 'MESH:D003903', (62, 64))
129443	30709931	mtDNA mutations varied by cancer type and mtDNA haplogroup.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mtDNA', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
129444	30709931	Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('role', 'Reg', (76, 80))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('mtDNA', 'Gene', (53, 58))	('cancers', 'Disease', (129, 136))	('mutations', 'Var', (59, 68))
129448	30709931	Many aspects of mitochondrial biology are important in cancer, including mitochondrial biogenesis and turnover, fission and fusion dynamics, oxidative stress, metabolism, bioenergetics, signaling, and variation in mitochondrial DNA (mtDNA) sequence and abundance.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('variation', 'Var', (201, 210))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('cancer', 'Disease', (55, 61))
129451	30709931	At least 8.5% of pediatric cancer patients have germline mutations in cancer predisposition genes.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Disease', (27, 33))	('germline mutations', 'Var', (48, 66))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))
129454	30709931	Epigenetic factors, such as chromatin remodeling and histone modifications, also appear to play a more critical role in pediatric compared to adult cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pediatric', 'Disease', (120, 129))	('adult cancers', 'Disease', (142, 155))	('histone modifications', 'Var', (53, 74))	('adult cancers', 'Disease', 'MESH:D009369', (142, 155))
129456	30709931	The importance of mtDNA mutations in cancer has been less well recognized, despite several large-scale studies showing significant numbers of mtDNA mutations in a variety of adult tumors.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (148, 157))	('mtDNA', 'Gene', (142, 147))	('adult tumors', 'Disease', (174, 186))	('cancer', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('adult tumors', 'Disease', 'MESH:C538052', (174, 186))
129457	30709931	These mtDNA mutations, to a large extent, have been dismissed as passenger events during tumorigenesis.	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mtDNA', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
129458	30709931	mtDNA mutations have been reported in a few pediatric cancer subtypes, e.g.	('reported', 'Reg', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('mtDNA', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (6, 15))
129459	30709931	medulloblastoma, glioma, acute myelogenous leukemia (AML), and neuroblastoma, but little is known regarding the spectrum of mtDNA mutations across pediatric malignancies and its contribution to tumorigenesis.	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (31, 51))	('medulloblastoma', 'Disease', 'MESH:D008527', (0, 15))	('medulloblastoma', 'Phenotype', 'HP:0002885', (0, 15))	('tumor', 'Disease', (194, 199))	('medulloblastoma', 'Disease', (0, 15))	('neuroblastoma', 'Disease', (63, 76))	('neuroblastoma', 'Phenotype', 'HP:0003006', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('neuroblastoma', 'Disease', 'MESH:D009447', (63, 76))	('glioma', 'Disease', (17, 23))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (25, 51))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('mtDNA', 'Gene', (124, 129))	('acute myelogenous leukemia', 'Disease', (25, 51))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('malignancies', 'Disease', (157, 169))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('AML', 'Disease', 'MESH:D015470', (53, 56))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (25, 51))	('AML', 'Disease', (53, 56))	('mutations', 'Var', (130, 139))	('AML', 'Phenotype', 'HP:0004808', (53, 56))
129469	30709931	All tumor-only mtDNA mutations are listed in Supplementary Table 1.	('tumor', 'Disease', (4, 9))	('mtDNA', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (21, 30))
129473	30709931	Since there are 12 classes of possible point substitutions (SC1, ..., SC12), the probability of observing substitution SCx leading to a synonymous mutation in a set of observed mutations can be defined as  where P(syn SCx) is the frequency at which the substitution class SCx leads to a synonymous mutation and P(SCx) is the frequency of this substitution class in the data, i.e., mutational signature.	('SCx', 'Gene', (272, 275))	('SCx', 'Gene', '642658', (218, 221))	('SCx', 'Gene', '642658', (119, 122))	('SCx', 'Gene', (313, 316))	('SCx', 'Gene', '642658', (272, 275))	('substitution', 'Var', (106, 118))	('SCx', 'Gene', (218, 221))	('leads to', 'Reg', (276, 284))	('SCx', 'Gene', (119, 122))	('SCx', 'Gene', '642658', (313, 316))	('synonymous mutation', 'MPA', (287, 306))
129475	30709931	For both pediatric and adult tumor-only mtDNA mutations, we created one million simulated datasets with the number of mutations and the mutational signature identical to the original empirical dataset, but with randomly assigned positions.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('mtDNA', 'Gene', (40, 45))
129480	30709931	All adult cancer mutations are included in Supplementary Table 3.	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))
129487	30709931	For comparison with adult cancers, we reanalyzed mtDNA genome mutations previously reported in 2,202 adult cancers.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('adult cancers', 'Disease', 'MESH:D009369', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('adult cancers', 'Disease', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('adult cancers', 'Disease', 'MESH:D009369', (20, 33))	('mtDNA genome', 'Gene', (49, 61))	('mutations', 'Var', (62, 71))	('adult cancers', 'Disease', (101, 114))
129490	30709931	Three hundred and ninety-one tumor-only mtDNA mutations were detected in 284 (45.7%) of the 616 remaining cancers (Supplementary Table 1).	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('tumor', 'Disease', (29, 34))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('mtDNA', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
129491	30709931	The mean number of tumor-only mtDNA mutations seen across all subtypes was 0.63 +- 0.84, ranging from a significantly lower number of 0.36 mtDNA mutations per tumor in low-grade gliomas (LGG) compared to other subtypes (p = 0.017, Mann-Whitney rank test) to 1.15 mtDNA mutations per tumor in adrenocortical carcinomas (ACC) (Fig.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('mutations', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ACC', 'Phenotype', 'HP:0006744', (319, 322))	('tumor', 'Disease', (19, 24))	('gliomas', 'Disease', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (292, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('adrenocortical carcinomas', 'Disease', (292, 317))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (159, 164))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (292, 317))	('mutations', 'Var', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (307, 317))	('tumor', 'Disease', (283, 288))	('lower', 'NegReg', (118, 123))
129492	30709931	Nearly all tumor-only mtDNA mutations (99.2%) were present in a heteroplasmic state, with levels ranging from 2.5% to almost 100% (near-homoplasmy), but significantly skewed toward low-level heteroplasmy (skewness = 2.38, Pearson's kurtosis = 5.23), with the average heteroplasmy at 17.7% (Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('mtDNA', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('mutations', 'Var', (28, 37))
129494	30709931	In total, we identified 158 missense, 71 rRNA, 45 LoF, 43 D-loop, 36 synonymous, and 35 tRNA tumor-only mtDNA mutations with varied heteroplasmy levels (Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('missense', 'Var', (28, 36))	('LoF', 'NegReg', (50, 53))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
129497	30709931	However, the majority (68.4%) of pediatric, tumor-only mtDNA mutations were detected at heteroplasmy levels below 10% with a median heteroplasmy of 7.2% (Fig.	('mtDNA', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
129498	30709931	2a), while the distribution of adult tumor-only mtDNA mutations was more uniform across all heteroplasmy levels (Fig.	('mtDNA', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
129499	30709931	We did not observe significant difference in heteroplasmy levels of different classes of tumor-only mtDNA mutations, in either pediatric cancers (Supplementary Figure 1a) or adult cancers (Supplementary Figure 1b).	('heteroplasmy levels', 'MPA', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mtDNA', 'Gene', (100, 105))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('adult cancers', 'Disease', (174, 187))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('adult cancers', 'Disease', 'MESH:D009369', (174, 187))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
129500	30709931	We observed a significant number of missense and LoF mutations at high heteroplasmy in both pediatric and adult cancers, as well as low heteroplasmy tumor-only mtDNA mutations.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('adult cancers', 'Disease', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (53, 62))	('adult cancers', 'Disease', 'MESH:D009369', (106, 119))	('tumor', 'Disease', (149, 154))	('missense', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('LoF', 'NegReg', (49, 52))
129502	30709931	Reanalysis of data from Corces et al revealed that tumor cells from the same patient harbored frameshift variants which, while rare in the bulk population, were nearly homoplasmic within some cells and absent in others.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('frameshift variants', 'Var', (94, 113))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
129503	30709931	This intra-tumor variability, while apparent at single-cell level, was obscured in bulk samples; due to averaging of VAF, these mutations appear to have low heteroplasmy (Supplementary Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('low', 'NegReg', (153, 156))	('mutations', 'Var', (128, 137))	('intra-tumor', 'Disease', 'MESH:D009369', (5, 16))	('intra-tumor', 'Disease', (5, 16))	('heteroplasmy', 'MPA', (157, 169))	('AF', 'Disease', 'MESH:D001281', (118, 120))
129504	30709931	These results support our hypothesis that LoF mtDNA mutations can arise in distinct or individual tumor cells.	('mutations', 'Var', (52, 61))	('mtDNA', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
129505	30709931	Low observed heteroplasmy of mtDNA mutations in tumors can thus result from individual cells harboring different mtDNA mutations, suggesting that LoF mtDNA mutations in individual tumor cells may in fact have a functional role in tumor development or progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (156, 165))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (180, 185))	('mtDNA', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mtDNA', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mtDNA', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (35, 44))
129506	30709931	The composition of heteroplasmic mtDNA variants in matched normal blood from pediatric cancer patients and in our non-cancer pediatric control samples was dramatically different from the observed pediatric tumor-only mtDNA mutations.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (94, 102))	('different', 'Reg', (168, 177))	('tumor', 'Disease', (206, 211))	('mtDNA', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('variants', 'Var', (39, 47))
129507	30709931	A chi-square test showed that the composition of the tumor-only mtDNA mutations was significantly different from that of the heteroplasmic mtDNA variants in non-cancer control samples (p-value < 2.2e-16).	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mtDNA', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', (161, 167))	('different', 'Reg', (98, 107))
129508	30709931	Specifically, 51.6% of all tumor-only mtDNA mutations were either missense or LoF, which is significantly higher than 6.2% found in the non-cancer control samples (Z-score = 16.4, p < 0.001, Z-test).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('missense', 'Var', (66, 74))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('LoF', 'NegReg', (78, 81))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('mtDNA', 'Gene', (38, 43))
129509	30709931	In both the matched normal and non-cancer control datasets and in direct contrast to tumor-only mtDNA mutations, the most frequent heteroplasmic variants were within the D-loop region (43.8% in matched normal and 41.5% in non-cancer), followed by synonymous variants with uneven heteroplasmy levels (Fig.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variants', 'Var', (145, 153))	('cancer', 'Disease', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
129510	30709931	Nearly 85% of all heteroplasmic variants in both datasets were known to be benign, haplogroup-defining markers (Supplementary Tables 9 & 10), which demonstrated evidence of intensive purifying selection against deleterious variants in non-cancer cells.	('cancer', 'Disease', (239, 245))	('variants', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
129511	30709931	Missense variants were largely confined to low heteroplasmy levels and only two LoF variants were detected at very low heteroplasmy in matched normal tissues: m.12384T>TC, an MT-ND5 frameshift variant in a hyperdiploid B-cell leukemia patient at 4.8% heteroplasmy, and m.14527A>AC, an MT-ND6 frameshift variant, in an ependymoma patient at 3.1% heteroplasmy.	('patient', 'Species', '9606', (235, 242))	('m.14527A>AC', 'Var', (269, 280))	('patient', 'Species', '9606', (329, 336))	('MT-ND5', 'Gene', (175, 181))	('hyperdiploid B-cell leukemia', 'Disease', (206, 234))	('ependymoma', 'Phenotype', 'HP:0002888', (318, 328))	('leukemia', 'Phenotype', 'HP:0001909', (226, 234))	('ependymoma', 'Disease', (318, 328))	('MT-ND5', 'Gene', '4540', (175, 181))	('m.12384T>TC', 'Mutation', 'm.12384T>TC', (159, 170))	('ependymoma', 'Disease', 'MESH:D004806', (318, 328))	('MT-ND6', 'Gene', '4541', (285, 291))	('MT-ND6', 'Gene', (285, 291))	('m.14527A>AC', 'Mutation', 'm.14527A>AC', (269, 280))	('hyperdiploid B-cell leukemia', 'Disease', 'MESH:D015448', (206, 234))	('m.12384T>TC', 'Var', (159, 170))
129512	30709931	Interestingly, four pediatric cancer patients harbored homoplasmic variants (ependymoma, m.14484T>C; Ewing sarcoma, m.1555A>G; hyperdiploid B-cell acute lymphoblastic leukemia (ALL), m.14484T>C; and neuroblastoma, m.11778G>A) in their matched tumor and normal samples that are causal of Leber's Hereditary Optic Neuropathy (LHON) and hearing loss.	('m.14484T>C', 'Mutation', 'm.14484T>C', (89, 99))	('m.1555A>G', 'Var', (116, 125))	('hyperdiploid B-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (127, 175))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('m.14484T>C', 'Mutation', 'm.14484T>C', (183, 193))	('ependymoma', 'Disease', (77, 87))	('neuroblastoma', 'Disease', (199, 212))	('tumor', 'Disease', (243, 248))	('neuroblastoma', 'Phenotype', 'HP:0003006', (199, 212))	('patients', 'Species', '9606', (37, 45))	('hearing loss', 'Disease', 'MESH:D034381', (334, 346))	('ependymoma', 'Phenotype', 'HP:0002888', (77, 87))	('m.11778G>A', 'Mutation', 'm.11778G>A', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('neuroblastoma', 'Disease', 'MESH:D009447', (199, 212))	('Optic Neuropathy', 'Phenotype', 'HP:0001138', (306, 322))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (147, 175))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('Neuropathy', 'Phenotype', 'HP:0009830', (312, 322))	('cancer', 'Disease', (30, 36))	('ependymoma', 'Disease', 'MESH:D004806', (77, 87))	('hearing loss', 'Disease', (334, 346))	('m.11778G>A', 'Var', (214, 224))	('hyperdiploid B-cell acute lymphoblastic leukemia', 'Disease', (127, 175))	('m.1555A>G', 'Mutation', 'm.1555A>G', (116, 125))	('m.14484T>C', 'Var', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (153, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('hearing loss', 'Phenotype', 'HP:0000365', (334, 346))	("Leber's Hereditary Optic Neuropathy", 'Disease', (287, 322))	('m.14484T>C', 'Var', (183, 193))	('ALL', 'Phenotype', 'HP:0006721', (177, 180))	('Ewing sarcoma', 'Disease', (101, 114))	("Leber's Hereditary Optic Neuropathy", 'Disease', 'MESH:D029242', (287, 322))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
129513	30709931	Three cancer patients' matched tumor and normal samples had heteroplasmic mtDNA variants known to cause classic mitochondrial diseases: ACC, m.3243A>G (5.0%); B-cell ALL, m.9185T>C (4.9%); neuroblastoma, m.8363G>A (53.4%) (Supplementary Table 11).	('patients', 'Species', '9606', (13, 21))	('m.3243A>G', 'Mutation', 'm.3243A>G', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mitochondrial diseases', 'Disease', (112, 134))	('m.8363G>A', 'Var', (204, 213))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (112, 134))	('m.8363G>A', 'Mutation', 'm.8363G>A', (204, 213))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('ALL', 'Phenotype', 'HP:0006721', (166, 169))	('neuroblastoma', 'Disease', (189, 202))	('m.9185T>C', 'Var', (171, 180))	('neuroblastoma', 'Phenotype', 'HP:0003006', (189, 202))	('mtDNA', 'Gene', (74, 79))	('neuroblastoma', 'Disease', 'MESH:D009447', (189, 202))	('cancer', 'Disease', (6, 12))	('m.9185T>C', 'Mutation', 'm.9185T>C', (171, 180))	('cause', 'Reg', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('m.3243A>G', 'Var', (141, 150))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
129514	30709931	Compared to the low prevalence rate (1 in 5000) of mitochondrial disorders in the general population, these results are suggestive of increased cancer risk associated with known pathogenic mtDNA variants, contrary to an earlier report.	('variants', 'Var', (195, 203))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (51, 74))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('mitochondrial disorders', 'Disease', (51, 74))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
129515	30709931	Clinical data for these patients were not available due to the de-identified nature of this dataset, so it is unclear whether these patients suffered from symptomatic mitochondrial disorders associated with these mtDNA variants.	('mitochondrial disorders', 'Disease', (167, 190))	('variants', 'Var', (219, 227))	('suffered', 'Reg', (141, 149))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (132, 140))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (167, 190))
129517	30709931	For statistical power, we focused on macro-haplogroups with at least 20 patients: A (20), B (20), H (207), J (47), K (30), L (102), T (43) and U (57).	('U (57', 'Var', (143, 148))	('patients', 'Species', '9606', (72, 80))	('B (20', 'Var', (90, 95))	('J (47', 'Var', (107, 112))	('H (207', 'Var', (98, 104))	('T (43', 'Var', (132, 137))	('K (30', 'Var', (115, 120))	('L (102', 'Var', (123, 129))
129519	30709931	However, we observed that the number of tumor-only mtDNA mutations per sample differed significantly between the two largest macro-haplogroups: 0.66 for H, which is mostly Eurasian-specific, and 0.47 for L, which is mostly African-specific (p = 0.03, Kruskal-Wallis test).	('mtDNA', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('0.47', 'Var', (195, 199))
129523	30709931	We observed a highly skewed dN/dS ratio (4.83) of non-synonymous mutations (including missense, stop-gain and stop-loss) versus synonymous tumor-only mutations in pediatric cancers.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('stop-loss', 'Var', (110, 119))	('cancers', 'Disease', (173, 180))	('dN', 'Chemical', '-', (28, 30))	('missense', 'Var', (86, 94))	('synonymous tumor', 'Disease', 'MESH:D009369', (128, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('dS', 'Chemical', 'MESH:D003903', (31, 33))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('synonymous tumor', 'Disease', (128, 144))	('stop-gain', 'Disease', (96, 105))
129524	30709931	If we include the LoF mutations in the non-synonymous category, the dN/dS ratio was even higher (5.64).	('dN', 'Chemical', '-', (68, 70))	('dS', 'Chemical', 'MESH:D003903', (71, 73))	('dN/dS ratio', 'MPA', (68, 79))	('higher', 'PosReg', (89, 95))	('mutations', 'Var', (22, 31))
129525	30709931	Interestingly, the dN/dS ratio was higher for the tumor-only mtDNA mutations between 0.1 and 0.5 heteroplasmy (7.3) than at less than 0.1 heteroplasmy (5.2), although this is not statistically significant.	('dS', 'Chemical', 'MESH:D003903', (22, 24))	('dN/dS ratio', 'MPA', (19, 30))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mtDNA', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('higher', 'PosReg', (35, 41))	('tumor', 'Disease', (50, 55))	('dN', 'Chemical', '-', (19, 21))
129528	30709931	Using the mutational signature shown for tumor-only mtDNA mutations in this study, we calculated an expected dN/dS ratio of 3.11 (Supplementary Table 2), which is significantly lower than the observed ratios of 4.83 (Z = 3.28, p = 5.19x10-4) (Fig.	('dN', 'Chemical', '-', (109, 111))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('dS', 'Chemical', 'MESH:D003903', (112, 114))	('mtDNA', 'Gene', (52, 57))	('tumor', 'Disease', (41, 46))	('dN/dS ratio', 'MPA', (109, 120))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
129530	30709931	Similarly, a lower dN/dS ratio of 0.93 was observed in the heteroplasmic mtDNA variants found in control samples with no history of cancer.	('cancer', 'Disease', (132, 138))	('lower', 'NegReg', (13, 18))	('mtDNA', 'Gene', (73, 78))	('dS', 'Chemical', 'MESH:D003903', (22, 24))	('dN/dS ratio', 'MPA', (19, 30))	('variants', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('dN', 'Chemical', '-', (19, 21))
129532	30709931	Combined, these analyses provide strong statistical evidence that non-synonymous tumor-only mtDNA mutations are under positive selection, hence enriched in tumors, but subjected to strong purifying selection, thus diminished, in non-tumor tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mtDNA', 'Gene', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('synonymous tumor', 'Disease', 'MESH:D009369', (70, 86))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumors', 'Disease', (156, 162))	('tumor', 'Disease', (81, 86))	('synonymous tumor', 'Disease', (70, 86))
129533	30709931	We performed a similar analysis using only high-quality tumor-only mtDNA mutations found in adult cancers from the Ju et al.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('adult cancers', 'Disease', (92, 105))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (73, 82))	('adult cancers', 'Disease', 'MESH:D009369', (92, 105))	('mtDNA', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
129535	30709931	This indicates that the tumor-only mtDNA mutations in adult cancer are likely under similar strong positive selection.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mtDNA', 'Gene', (35, 40))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
129536	30709931	Loss-of-function mutations are the most striking group of mtDNA mutations in tumor vs. control comparisons.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', (77, 82))	('mutations', 'Var', (17, 26))	('mtDNA', 'Gene', (58, 63))
129537	30709931	We identified a total of 45 tumor-only mtDNA LoF (frameshift and nonsense) mutations, with heteroplasmy ranging from 2.5% to 73% (Table 2, Supplementary Table 1).	('LoF', 'NegReg', (45, 48))	('tumor', 'Disease', (28, 33))	('mtDNA', 'Gene', (39, 44))	('frameshift', 'Var', (50, 60))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
129538	30709931	Similarly, LoF mutations were frequently observed in Ewing sarcomas (EWS) (11.4%) and osteosarcomas (OS) (13.5%).	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('EWS', 'Gene', '2130', (69, 72))	('EWS', 'Gene', (69, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('Ewing sarcomas', 'Disease', (53, 67))	('mutations', 'Var', (15, 24))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (53, 67))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('osteosarcomas', 'Disease', (86, 99))	('osteosarcomas', 'Phenotype', 'HP:0002669', (86, 99))	('osteosarcomas', 'Disease', 'MESH:D012516', (86, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('LoF', 'NegReg', (11, 14))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (53, 67))	('EWS', 'Phenotype', 'HP:0012254', (69, 72))
129539	30709931	Combined, these three cancer subtypes had significantly more LoF mutations compared to other subtypes (p = 2.41x10-4).	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('LoF', 'NegReg', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (65, 74))
129540	30709931	For example, we observed LoF mutations in only 2 of 45 neuroblastoma samples (4.4%), and in 5 of 157 CNS tumors combined (3.2%).	('neuroblastoma', 'Disease', (55, 68))	('CNS tumors', 'Disease', (101, 111))	('mutations', 'Var', (29, 38))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('LoF', 'NegReg', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('neuroblastoma', 'Disease', 'MESH:D009447', (55, 68))	('CNS tumors', 'Disease', 'MESH:D016543', (101, 111))
129541	30709931	In hematologic malignancies, 19 of 302 (6.3%) B-ALL and 2 out of 20 (10%) acute myeloid leukemia (AML) cases harbored a LoF mutation in the cancer sample.	('malignancies', 'Disease', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('acute myeloid leukemia', 'Disease', (74, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('AML', 'Disease', 'MESH:D015470', (98, 101))	('cancer', 'Disease', (140, 146))	('LoF', 'NegReg', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (74, 96))	('B-ALL and 2', 'Gene', '28907', (46, 57))	('mutation', 'Var', (124, 132))	('malignancies', 'Disease', 'MESH:D009369', (15, 27))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (74, 96))	('ALL', 'Phenotype', 'HP:0006721', (48, 51))	('AML', 'Disease', (98, 101))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))
129543	30709931	The majority of LoF mutations were within the mitochondrial complex I genes, particularly, with the most (11) in MT-ND5.	('LoF', 'NegReg', (16, 19))	('MT-ND5', 'Gene', (113, 119))	('mutations', 'Var', (20, 29))	('MT-ND5', 'Gene', '4540', (113, 119))
129544	30709931	We observed three recurrent tumor-only LoF mutations, including m.12417C>CA in MT-ND5 in four cases (ependymoma, Ewing sarcoma, ETV6-RUNX1 B-ALL, Ph-positive ALL), m.10191TC>T in MT-ND3 in two cases (B-ALL and high-grade glioma (HGG)), and m.9531A>AC in MT-CO3 in two cases (OS and Ph-positive ALL).	('tumor', 'Disease', (28, 33))	('MT-ND5', 'Gene', '4540', (79, 85))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('m.9531A>AC', 'Var', (240, 250))	('MT-ND5', 'Gene', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('OS', 'Phenotype', 'HP:0002669', (275, 277))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('m.10191TC>T', 'Var', (164, 175))	('ALL', 'Phenotype', 'HP:0006721', (294, 297))	('ALL', 'Phenotype', 'HP:0006721', (158, 161))	('ependymoma', 'Disease', (101, 111))	('ALL', 'Phenotype', 'HP:0006721', (141, 144))	('ETV6', 'Gene', '2120', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('m.9531A>AC', 'Mutation', 'm.9531A>AC', (240, 250))	('Ewing sarcoma', 'Disease', (113, 126))	('MT-ND3', 'Gene', (179, 185))	('ependymoma', 'Phenotype', 'HP:0002888', (101, 111))	('m.10191TC>T', 'Mutation', 'm.10191TC>T', (164, 175))	('LoF', 'NegReg', (39, 42))	('MT-ND3', 'Gene', '4537', (179, 185))	('m.12417C>CA', 'Var', (64, 75))	('MT-CO3', 'Gene', (254, 260))	('m.12417C>CA', 'Mutation', 'm.12417C>CA', (64, 75))	('glioma', 'Disease', (221, 227))	('ETV6', 'Gene', (128, 132))	('RUNX1', 'Gene', (133, 138))	('ependymoma', 'Disease', 'MESH:D004806', (101, 111))	('MT-CO3', 'Gene', '4514', (254, 260))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('ALL', 'Phenotype', 'HP:0006721', (202, 205))	('RUNX1', 'Gene', '861', (133, 138))
129545	30709931	To further explore possible mutational hotspots, we conducted a meta-analysis of pediatric tumor-only mutations, in combination with previously published tumor-only mtDNA mutations from 2,202 primarily adult cancers (Supplementary Table 3).	('adult cancers', 'Disease', 'MESH:D009369', (202, 215))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('adult cancers', 'Disease', (202, 215))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (154, 159))
129546	30709931	Four windows (9445-9544, 10960-11059, 11768-11867, 12374-12473) within MT-ND4, MT-ND5 and MT-CO3 genes exhibited a substantial and significant enrichment of frameshift indels (p = 5.9x10-3 to 1.8x10-28, Bonferroni correction, Supplementary Table 15), indicating the presence of mutational hotspots (Fig 5a).	('MT-CO3', 'Gene', (90, 96))	('MT-ND5', 'Gene', '4540', (79, 85))	('MT-ND4', 'Gene', '4538', (71, 77))	('MT-ND4', 'Gene', (71, 77))	('MT-ND5', 'Gene', (79, 85))	('MT-CO3', 'Gene', '4514', (90, 96))	('frameshift indels', 'Var', (157, 174))
129547	30709931	After restricting the analysis to 20 long homopolymers within coding regions, hotspots in MT-ND4 (polyA 11032-11038 and polyC 11867-11872) and MT-ND5 (polyA 12418-12425) remained significant (p = 3.1x10-3 - 9.2x10-11, Bonferroni correction, Supplementary Table 16).	('MT-ND4', 'Gene', '4538', (90, 96))	('MT-ND4', 'Gene', (90, 96))	('polyA 12418-12425', 'Var', (151, 168))	('polyC 11867-11872', 'Var', (120, 137))	('MT-ND5', 'Gene', (143, 149))	('polyA 11032-11038', 'Var', (98, 115))	('MT-ND5', 'Gene', '4540', (143, 149))
129548	30709931	We used the same approach to test for clustering of probable pathogenic tumor-only tRNA mutations (as defined by predicted MitoTIP score >= 16.25).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('pathogenic', 'Reg', (61, 71))	('mutations', 'Var', (88, 97))	('tRNA', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
129549	30709931	One 20bp window located in MT-TM (TRNM), encoding the mitochondrial tRNA for methionine, was significantly enriched for pathogenic mutations (p = 2.361x10-5, Bonferroni correction, Supplementary Table 17).	('mutations', 'Var', (131, 140))	('methionine', 'Chemical', 'MESH:D008715', (77, 87))	('TRNM', 'Gene', '4569', (34, 38))	('TRNM', 'Gene', (34, 38))	('MT-TM', 'Gene', '4569', (27, 32))	('MT-TM', 'Gene', (27, 32))	('pathogenic', 'Reg', (120, 130))
129550	30709931	Identification of a MT-TM mutational hotspot is novel and may lead to important insights into tumor pathogenesis, since the mitochondrial tRNA genes are hotspots for pathogenic mutations that also cause mitochondrial disorders.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MT-TM', 'Gene', '4569', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (177, 186))	('mitochondrial disorders', 'Disease', (203, 226))	('MT-TM', 'Gene', (20, 25))	('tumor', 'Disease', (94, 99))	('mitochondrial tRNA', 'Gene', (124, 142))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (203, 226))	('cause', 'Reg', (197, 202))
129552	30709931	We observed a statistically significant enrichment of highly pathogenic variants in the MT-TM gene in adult samples (p = 2.78x10-4, Welch's t-test) compared to all other tRNA genes (Supplementary Figure 4d), which is in agreement with the presence of a hotspot for pathogenic mutations in this gene in both pediatric and adult cancers.	('MT-TM', 'Gene', '4569', (88, 93))	('MT-TM', 'Gene', (88, 93))	('adult cancers', 'Disease', (321, 334))	('pathogenic', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('variants', 'Var', (72, 80))	('adult cancers', 'Disease', 'MESH:D009369', (321, 334))	('cancers', 'Phenotype', 'HP:0002664', (327, 334))
129554	30709931	Fifteen to 29 tumor-only mtDNA mutations per sample were found in 5 mtDNA-hypermutated samples (Supplementary Table 18).	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mtDNA', 'Gene', (25, 30))
129556	30709931	We observed a strong correlation between the number of missense mutations in the nuclear genome and the number of mutations in the mitochondrial genome (Pearson correlation coefficient = 0.43, p = 1.33x10-7), suggesting potentially common mechanisms underlying the increased number of nuclear and mtDNA tumor-only mutations.	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('missense mutations', 'Var', (55, 73))	('tumor', 'Disease', (303, 308))
129559	30709931	We have demonstrated the spectrum of the mtDNA mutations that are both shared by and unique to individual pediatric cancer subtypes.	('mtDNA', 'Gene', (41, 46))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
129560	30709931	While different pediatric cancer subtypes showed different mean numbers of tumor-only mtDNA mutations, the types of mtDNA mutations seen also varied among different subtypes.	('mtDNA', 'Gene', (86, 91))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
129561	30709931	For example, LGGs had the fewest number of tumor-only mtDNA mutations, lacked any LoF mutations, and any mtDNA mutations present in these tumors occurred at very low heteroplasmy levels.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mtDNA', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
129562	30709931	In contrast, a total of six LoF mutations were identified in 5 of 20 (25%) ACC samples, which is significantly higher than in any other subtype of pediatric malignancy.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('malignancy', 'Disease', (157, 167))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('ACC', 'Disease', (75, 78))	('mutations', 'Var', (32, 41))	('LoF', 'NegReg', (28, 31))
129563	30709931	15-70% of ACCs and the vast majority of osteosarcomas have inactivating TP53 alterations.	('osteosarcomas', 'Disease', (40, 53))	('osteosarcomas', 'Phenotype', 'HP:0002669', (40, 53))	('osteosarcomas', 'Disease', 'MESH:D012516', (40, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('TP53', 'Gene', '7157', (72, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('TP53', 'Gene', (72, 76))	('alterations', 'Var', (77, 88))	('ACCs', 'Disease', (10, 14))	('ACC', 'Phenotype', 'HP:0006744', (10, 13))	('inactivating', 'Var', (59, 71))
129564	30709931	previously reported that MT-ND5 somatic mutations down regulate mitochondrial electron transport chain complex I enzyme activity and increase reactive oxygen species, also epigenetically upregulate nuclear anti-apoptotic genes in p53 deficient cells.	('MT-ND5', 'Gene', '4540', (25, 31))	('upregulate', 'PosReg', (187, 197))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (142, 165))	('MT-ND5', 'Gene', (25, 31))	('p53', 'Gene', '7157', (230, 233))	('mutations', 'Var', (40, 49))	('reactive oxygen species', 'MPA', (142, 165))	('epigenetically', 'Var', (172, 186))	('down regulate', 'NegReg', (50, 63))	('increase', 'PosReg', (133, 141))	('activity', 'MPA', (120, 128))	('p53', 'Gene', (230, 233))	('nuclear anti-apoptotic genes', 'Gene', (198, 226))
129565	30709931	Based on this finding we initially postulated that a link between TP53 mutations and complex I activity could explain why LoF mutations in ACC and OS were observed at such high frequency relative to the rest of the pediatric tumors studied.	('TP53', 'Gene', '7157', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('TP53', 'Gene', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('mutations', 'Var', (71, 80))	('activity', 'MPA', (95, 103))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('mutations', 'Var', (126, 135))	('OS', 'Phenotype', 'HP:0002669', (147, 149))	('tumors', 'Disease', (225, 231))
129566	30709931	However, only 2 of the 20 ACC tumors in our dataset had a nuclear TP53 mutation.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', '7157', (66, 70))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
129567	30709931	Similarly, while CPCs also harbor TP53 mutations, no LoF mutations were observed in the four CPC samples that we studied.	('CPC', 'Phenotype', 'HP:0030392', (17, 20))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('CPC', 'Phenotype', 'HP:0030392', (93, 96))	('TP53', 'Gene', '7157', (34, 38))
129570	30709931	both observed a skewed dN/dS ratio (indicating an increase in non-synonymous tumor-only mtDNA mutations compared to synonymous mtDNA mutations) in adult cancers.	('dN', 'Chemical', '-', (23, 25))	('dS', 'Chemical', 'MESH:D003903', (26, 28))	('mutations', 'Var', (94, 103))	('synonymous tumor', 'Disease', 'MESH:D009369', (66, 82))	('adult cancers', 'Disease', (147, 160))	('mtDNA', 'Gene', (88, 93))	('increase', 'PosReg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('adult cancers', 'Disease', 'MESH:D009369', (147, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('synonymous tumor', 'Disease', (66, 82))
129572	30709931	Sequencing and analyzing the mtDNA genome in a large number of children without cancer provided further support for this conclusion.	('Sequencing', 'Var', (0, 10))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('children', 'Species', '9606', (63, 71))
129573	30709931	Our analysis clearly demonstrated that non-synonymous or deleterious mtDNA mutations were under strong negative selection in normal cells, but under strong positive selection in tumor cells.	('tumor', 'Disease', (178, 183))	('non-synonymous', 'Var', (39, 53))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mtDNA', 'Gene', (69, 74))
129574	30709931	Thus, we have demonstrated for the first time that the highly skewed dN/dS ratio of tumor-only mtDNA mutations is a strong indicator that mtDNA mutations have broad contributions to tumor development not only in pediatric cancers but also in adult cancers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('adult cancers', 'Disease', 'MESH:D009369', (242, 255))	('mtDNA', 'Gene', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('mutations', 'Var', (144, 153))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('cancers', 'Disease', (248, 255))	('adult cancers', 'Disease', (242, 255))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mtDNA', 'Gene', (138, 143))	('mutations', 'Var', (101, 110))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('contributions', 'Reg', (165, 178))	('dN', 'Chemical', '-', (69, 71))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (84, 89))	('dS', 'Chemical', 'MESH:D003903', (72, 74))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
129575	30709931	We postulate that a significant fraction of the observed non-synonymous or deleterious mtDNA mutations provide the tumor cells with a significant selective advantage.	('mtDNA', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', (115, 120))	('non-synonymous', 'Var', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
129576	30709931	While LoF tumor-only mtDNA mutations in a variety of cancers have previously been reported, including several recurrent mutations, we discovered clustering of LoF mtDNA mutations in MT-CO3, MT-ND4, and MT-ND5, predominantly in the Complex I (ND) subunit genes (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('mutations', 'Var', (169, 178))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mtDNA', 'Gene', (163, 168))	('LoF tumor', 'Disease', 'MESH:D009369', (6, 15))	('MT-ND4', 'Gene', (190, 196))	('LoF tumor', 'Disease', (6, 15))	('MT-ND4', 'Gene', '4538', (190, 196))	('MT-ND5', 'Gene', (202, 208))	('MT-CO3', 'Gene', '4514', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MT-CO3', 'Gene', (182, 188))	('MT-ND5', 'Gene', '4540', (202, 208))	('LoF', 'NegReg', (159, 162))
129577	30709931	Rather, these hotspot mtDNA mutations were shared by diverse childhood and adult cancers as demonstrated by our meta-analysis.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('adult cancers', 'Disease', (75, 88))	('adult cancers', 'Disease', 'MESH:D009369', (75, 88))	('mtDNA', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (28, 37))
129578	30709931	While the observed LoF mutations were spread across all 13 mtDNA protein-coding genes, the existence of hotspots of LoF mtDNA mutations in childhood and adult cancers indicates that defects in specific mitochondrial genes, function, and related pathways such as mitochondrial apoptosis may play a more important role than previously appreciated for tumorigenesis of childhood and adult cancers.	('adult cancers', 'Disease', (153, 166))	('cancers', 'Phenotype', 'HP:0002664', (386, 393))	('adult cancers', 'Disease', 'MESH:D009369', (153, 166))	('adult cancers', 'Disease', (380, 393))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('mutations', 'Var', (23, 32))	('function', 'MPA', (223, 231))	('mtDNA', 'Gene', (120, 125))	('adult cancers', 'Disease', 'MESH:D009369', (380, 393))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('LoF', 'NegReg', (116, 119))	('mutations', 'Var', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('mitochondrial genes', 'Gene', (202, 221))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('defects', 'Var', (182, 189))	('tumor', 'Disease', (349, 354))
129579	30709931	This is supported by the high predicted pathogenicity scores of tumor-only mutations in some of the mtDNA genes.	('tumor', 'Disease', (64, 69))	('mtDNA', 'Gene', (100, 105))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
129580	30709931	The importance of individual LoF mtDNA mutations to tumor development, especially those occurring within complex I genes, is supported by previous studies.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mtDNA', 'Gene', (33, 38))	('LoF', 'NegReg', (29, 32))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
129581	30709931	experimentally demonstrated that mitochondrial complex I dysfunction, caused by a heteroplasmic nonsense MT-ND5 mutation, promoted tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('MT-ND5', 'Gene', (105, 111))	('mutation', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('promoted', 'PosReg', (122, 130))	('tumor', 'Disease', (131, 136))	('MT-ND5', 'Gene', '4540', (105, 111))	('caused by', 'Reg', (70, 79))
129582	30709931	This result is similar to that reported by Ishikawa et al., who demonstrated complex I deficiencies caused by a MT-ND6 frameshift mutation contributed to tumor progression and metastasis.	('metastasis', 'CPA', (176, 186))	('I deficiencies', 'Disease', (85, 99))	('I deficiencies', 'Disease', 'MESH:C537728', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('frameshift mutation', 'Var', (119, 138))	('MT-ND6', 'Gene', '4541', (112, 118))	('MT-ND6', 'Gene', (112, 118))	('tumor', 'Disease', (154, 159))
129583	30709931	Recently, Gopal et al reported that LoF mutations in the complex I genes lead to rewiring of glutathione metabolism in renal oncocytoma and are early genetic events that contribute to tumor formation.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('rewiring of glutathione metabolism', 'MPA', (81, 115))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('LoF', 'NegReg', (36, 39))	('renal oncocytoma', 'Disease', 'MESH:C537750', (119, 135))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (184, 189))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (119, 135))	('renal oncocytoma', 'Disease', (119, 135))	('glutathione', 'Chemical', 'MESH:D005978', (93, 104))	('complex I', 'Gene', (57, 66))
129584	30709931	Notably, 13 and 8 of these 45 LoF mutations that we found were above 15% and 40% heteroplasmy, respectively, with the highest observed at 73% in a neuroblastoma tumor (Supplementary Table 1).	('neuroblastoma tumor', 'Disease', (147, 166))	('LoF', 'NegReg', (30, 33))	('heteroplasmy', 'MPA', (81, 93))	('neuroblastoma tumor', 'Disease', 'MESH:D009447', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutations', 'Var', (34, 43))	('neuroblastoma', 'Phenotype', 'HP:0003006', (147, 160))
129585	30709931	High heteroplasmy levels support a contributing role for a mtDNA mutation in tumorigenesis, consistent with the Park et al study demonstrating that a LoF MT-ND5 mutation promoted tumorigenesis at high-level heteroplasmy but not at homoplasmy.	('MT-ND5', 'Gene', (154, 160))	('mutation', 'Var', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('LoF', 'NegReg', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MT-ND5', 'Gene', '4540', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (77, 82))	('promoted', 'PosReg', (170, 178))	('tumor', 'Disease', (179, 184))
129586	30709931	Conversely, tumor heterogeneity may lead to skewed lower heteroplasmy levels observed for other LoF mutations, as we illustrated in the single-cell ATACseq data from two acute myeloid leukemia patients.	('mutations', 'Var', (100, 109))	('acute myeloid leukemia', 'Disease', (170, 192))	('patients', 'Species', '9606', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (170, 192))	('heteroplasmy levels', 'MPA', (57, 76))	('lower', 'NegReg', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (170, 192))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (176, 192))	('tumor', 'Disease', (12, 17))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))
129587	30709931	We have demonstrated clustering of tumor-only mtDNA mutations in the MT-TM gene encoding the tRNA for methionine (Fig.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('methionine', 'Chemical', 'MESH:D008715', (102, 112))	('tumor', 'Disease', (35, 40))	('MT-TM', 'Gene', '4569', (69, 74))	('MT-TM', 'Gene', (69, 74))
129588	30709931	A heteroplasmic pathogenic MT-TM mutation was first reported in a patient with splenic lymphoma, with deficient mitochondrial respiratory chain enzyme activities and Complex IV COX2 subunit expression.	('splenic lymphoma', 'Disease', (79, 95))	('COX2', 'Gene', (177, 181))	('mutation', 'Var', (33, 41))	('splenic lymphoma', 'Disease', 'MESH:D013158', (79, 95))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('deficient mitochondrial respiratory', 'Disease', (102, 137))	('activities', 'MPA', (151, 161))	('pathogenic', 'Reg', (16, 26))	('COX2', 'Gene', '4513', (177, 181))	('MT-TM', 'Gene', '4569', (27, 32))	('patient', 'Species', '9606', (66, 73))	('MT-TM', 'Gene', (27, 32))	('deficient mitochondrial respiratory', 'Disease', 'MESH:D012131', (102, 137))
129590	30709931	Of note, the 22 mitochondrial tRNA genes are also hotspots for pathogenic mutations that cause classical mitochondrial disorders.	('mitochondrial tRNA genes', 'Gene', (16, 40))	('mutations', 'Var', (74, 83))	('mitochondrial disorders', 'Disease', (105, 128))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (105, 128))
129591	30709931	Mitochondrial haplogroups, as defined by common fixed (homoplasmic) mtDNA polymorphisms, have long been found to be associated with varied risks for diverse cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('polymorphisms', 'Var', (74, 87))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('mtDNA', 'Gene', (68, 73))	('associated', 'Reg', (116, 126))
129592	30709931	For example, the mtDNA haplogroup M7B2 was found to be a risk factor for leukemia, while haplogroup U was found to increase the risk for both renal and prostate cancers.	('mtDNA', 'Var', (17, 22))	('renal and prostate cancers', 'Disease', 'MESH:D011471', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('increase', 'PosReg', (115, 123))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('M7B2', 'Var', (34, 38))	('leukemia', 'Disease', (73, 81))	('prostate cancers', 'Phenotype', 'HP:0012125', (152, 168))
129594	30709931	However, we observed significantly fewer tumor-only mtDNA mutations occurring in patients belonging to the L (African) macro-haplogroup compared to the H (Eurasian macro-haplogroup).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (58, 67))	('fewer', 'NegReg', (35, 40))	('mtDNA', 'Gene', (52, 57))	('tumor', 'Disease', (41, 46))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
129596	30709931	There is significant mitochondrial heterogeneity in different cells and microenvironments which, while highlighting the tumor extraordinary metabolic plasticity during tumorigenesis, makes it extremely challenging to select a single representative or appropriate assay to assess the functional significance of the candidate mtDNA mutation.	('tumor', 'Disease', (168, 173))	('mtDNA', 'Gene', (324, 329))	('mutation', 'Var', (330, 338))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (120, 125))
129597	30709931	A thorough characterization of the likely functional significance of a mtDNA mutation would likely require a suite of assays targeting all aspects of tumorigenesis.	('mutation', 'Var', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mtDNA', 'Gene', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
129598	30709931	Determining the functional significance of tumor-only mtDNA mutations is complicated by heteroplasmy and intra-tumor heterogeneity and, in some cases, tumor percentage.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('intra-tumor', 'Disease', 'MESH:D009369', (105, 116))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (111, 116))	('intra-tumor', 'Disease', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mtDNA', 'Gene', (54, 59))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
129599	30709931	A tumor-only mtDNA mutation may be observed at low VAF from next-generation sequencing of a tumor sample.	('mutation', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('AF', 'Disease', 'MESH:D001281', (52, 54))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (2, 7))	('mtDNA', 'Gene', (13, 18))	('tumor', 'Disease', (92, 97))
129603	30709931	Similarly, our analysis of the single-cell ATACseq data from two acute myeloid leukemia patients also supports this hypothesis, since individual tumor cells had near-homoplasmy levels of some LoF mtDNA mutations that were observed at low heteroplasmy at bulk cell populations.	('mtDNA', 'Gene', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (71, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (65, 87))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('patients', 'Species', '9606', (88, 96))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (65, 87))	('LoF', 'NegReg', (192, 195))	('tumor', 'Disease', (145, 150))	('acute myeloid leukemia', 'Disease', (65, 87))	('mutations', 'Var', (202, 211))
129604	30709931	If the near homoplasmy state of LoF mutations in single cells translates to a selective disadvantage, these tumor cells are expected to be purified away, so that they would represent lower fractions of all mtDNA mutations at higher heteroplasmy levels when the bulk tumor cells are sequenced.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('LoF', 'NegReg', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('mtDNA', 'Gene', (206, 211))
129605	30709931	However, our data showed that the likely functionally deleterious tumor-only mtDNA mutations, including the LoF mutations, occurred at comparable if not higher heteroplasmy levels than the likely functionally neutral tumor-only mtDNA mutations, such as the synonymous and D-loop region mutations (Supplementary Figure 6).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (66, 71))	('mutations', 'Var', (112, 121))	('mtDNA', 'Gene', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
129606	30709931	This is true for tumor-only mtDNA mutations found in both pediatric and adult cancers.	('mtDNA', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('adult cancers', 'Disease', 'MESH:D009369', (72, 85))	('tumor', 'Disease', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('adult cancers', 'Disease', (72, 85))	('mutations', 'Var', (34, 43))
129607	30709931	Furthermore, although most of the tumor-only mtDNA mutations were seen at low heteroplasmy, the composition of these mutations across different heteroplasmy levels remained similar (Figure 2a &2b, Supplementary Figure 6), which argues that the deleterious mtDNA mutations were not selected against.	('mtDNA', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
129608	30709931	Combined with single-cell ATACseq data, we should not dismiss the likely functional significance of a tumor-only mtDNA mutation because of low heteroplasmy.	('mutation', 'Var', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mtDNA', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
129609	30709931	The most intriguing observation from this study was our novel finding that four childhood cancer patients harbored homoplasmic or heteroplasmic mtDNA germline variants that are known to cause classical mitochondrial disorders, which have not been previously linked to a cancer phenotype.	('mitochondrial disorders', 'Disease', 'MESH:D028361', (202, 225))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('variants', 'Var', (159, 167))	('mitochondrial disorders', 'Disease', (202, 225))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cause', 'Reg', (186, 191))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('mtDNA', 'Gene', (144, 149))	('patients', 'Species', '9606', (97, 105))
129612	30709931	Park et al reported that homoplasmic MT-ND5 mutations prevents tumor development.	('tumor', 'Disease', (63, 68))	('prevents', 'NegReg', (54, 62))	('MT-ND5', 'Gene', '4540', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MT-ND5', 'Gene', (37, 43))
129615	30709931	It is also intriguing that there are four pediatric cancer patients with homoplasmic pathogenic variants that cause primary mitochondrial diseases, yet, it was shown by Park et al that the homoplasmic MT-ND5 mutations prevents tumor development.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('prevents', 'NegReg', (218, 226))	('tumor', 'Disease', (227, 232))	('variants', 'Var', (96, 104))	('mutations', 'Var', (208, 217))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (124, 146))	('MT-ND5', 'Gene', '4540', (201, 207))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mitochondrial diseases', 'Disease', (124, 146))	('MT-ND5', 'Gene', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
129616	30709931	To explain this, we speculate that there is residual mitochondrial function in cells with these homoplasmic pathogenic mtDNA variants or they would cause death or miscarriage instead of mitochondrial diseases only.	('mitochondrial function', 'MPA', (53, 75))	('miscarriage', 'Disease', (163, 174))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (186, 208))	('death', 'Disease', (154, 159))	('death', 'Disease', 'MESH:D003643', (154, 159))	('miscarriage', 'Phenotype', 'HP:0005268', (163, 174))	('variants', 'Var', (125, 133))	('mitochondrial diseases', 'Disease', (186, 208))	('cause', 'Reg', (148, 153))	('mtDNA', 'Gene', (119, 124))
129617	30709931	We found five samples that were mtDNA-hypermutated, with significantly more tumor-only mtDNA mutations than other samples (15-29 vs. 0.63 +- 0.84).	('mtDNA', 'Gene', (87, 92))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
129619	30709931	It is possible that the same underlying mechanism causes somatic nuclear DNA and mtDNA mutations in cancer.	('nuclear DNA', 'Disease', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mtDNA', 'Gene', (81, 86))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('mutations', 'Var', (87, 96))
129620	30709931	These data provide further support for tumor-only mtDNA mutations contributing to diverse cancer development.	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('contributing', 'Reg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mtDNA', 'Gene', (50, 55))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
129621	30709931	In conclusion, the present study establishes the broad landscape of germline and tumor-only mtDNA genome mutations across numerous subtypes of childhood leukemias, brain tumors, and solid tumors.	('tumor', 'Disease', (188, 193))	('childhood leukemias', 'Disease', 'MESH:D007938', (143, 162))	('mtDNA genome', 'Gene', (92, 104))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mutations', 'Var', (105, 114))	('brain tumors', 'Disease', (164, 176))	('childhood leukemias', 'Disease', (143, 162))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (81, 86))	('tumors', 'Disease', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('leukemias', 'Phenotype', 'HP:0001909', (153, 162))	('brain tumors', 'Disease', 'MESH:D001932', (164, 176))	('brain tumors', 'Phenotype', 'HP:0030692', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('tumors', 'Disease', (170, 176))
129622	30709931	We utilized a highly powered public dataset, combined with additional data from pediatric controls with no history of cancer, to demonstrate that deleterious mtDNA mutations contribute significantly to the tumorigenesis of pediatric cancers.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('mtDNA', 'Gene', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('mutations', 'Var', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
129623	30709931	The highly skewed dN/dS ratio clearly indicates non-synonymous mtDNA mutations in general, rather than a few isolated mutations, provide tumor cells a selective advantage.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', (137, 142))	('advantage', 'PosReg', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('dN', 'Chemical', '-', (18, 20))	('dS', 'Chemical', 'MESH:D003903', (21, 23))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mtDNA', 'Gene', (63, 68))	('non-synonymous', 'Var', (48, 62))
129624	30709931	Our findings provide novel insights into the nature of mtDNA heteroplasmic mutations that alter normal mitochondrial electron transport chain function, and likely make substantial contributions to tumorigenesis in diverse pediatric cancers.	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('mtDNA', 'Gene', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('mitochondrial electron transport chain function', 'MPA', (103, 150))	('cancers', 'Disease', (232, 239))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('heteroplasmic', 'Var', (61, 74))	('contributions', 'Reg', (180, 193))	('tumor', 'Disease', (197, 202))	('alter', 'Reg', (90, 95))
129625	30709931	This is highlighted by the discoveries of hotspots for mtDNA LoF and likely pathogenic tRNA mutations shared between pediatric and adult cancers, which suggests that certain mitochondrial genes and pathways may play a bigger role in tumorigenesis than others.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mtDNA', 'Gene', (55, 60))	('adult cancers', 'Disease', 'MESH:D009369', (131, 144))	('tumor', 'Disease', (233, 238))	('mutations', 'Var', (92, 101))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('LoF', 'NegReg', (61, 64))	('tRNA', 'Gene', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('adult cancers', 'Disease', (131, 144))
129626	30709931	Future functional studies are required to determine the effect of specific mutations on mitochondrial function and their role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
129627	30709931	Statement of Significance: This pan-cancer mtDNA study establishes the landscape of germline and tumor mtDNA mutations and identifies hotspots of tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric malignancies.	('malignancies', 'Disease', (221, 233))	('mtDNA', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (97, 102))	('mutations', 'Var', (109, 118))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
129628	23063752	Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation The Hedgehog (Hh) pathway regulates the growth of a subset of adult gliomas and better definition of Hh-responsive subtypes could enhance the clinical utility of monitoring and targeting this pathway in patients.	('mutation', 'Var', (88, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('glioblastomas', 'Disease', (46, 59))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('growth', 'MPA', (137, 143))	('regulates', 'MPA', (123, 132))	('isocitrate dehydrogenase', 'Gene', (63, 87))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('gliomas', 'Disease', (165, 172))	('isocitrate dehydrogenase', 'Gene', '3417', (63, 87))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('patients', 'Species', '9606', (300, 308))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))
129632	23063752	Indices of an operational Hh pathway were measured in all primary cultures and xenografts derived from IDH-mutant glioma specimens, including IDH-mutant glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (153, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('glioma', 'Disease', (114, 120))	('glioblastomas', 'Disease', (153, 166))	('IDH-mutant', 'Var', (103, 113))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('IDH-mutant', 'Gene', (103, 113))	('glioblastomas', 'Phenotype', 'HP:0012174', (153, 166))
129633	23063752	In contrast, the Hh pathway was not operational in glioblastomas that lacked IDH mutation or history of antecedent lower-grade disease.	('glioblastomas', 'Disease', (51, 64))	('mutation', 'Var', (81, 89))	('IDH', 'Gene', (77, 80))	('glioblastomas', 'Phenotype', 'HP:0012174', (51, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('glioblastomas', 'Disease', 'MESH:D005909', (51, 64))
129642	23063752	A role for aberrant Hh signaling in tumorigenesis was first appreciated with the discovery of mutations in Hh signal transduction components conferring ligand-independent pathway activation in medulloblastoma and basal cell carcinoma.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (213, 233))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (213, 233))	('basal cell carcinoma', 'Disease', (213, 233))	('medulloblastoma', 'Disease', (193, 208))	('Hh signal transduction components', 'Gene', (107, 140))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('activation', 'PosReg', (179, 189))	('medulloblastoma', 'Phenotype', 'HP:0002885', (193, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('medulloblastoma', 'Disease', 'MESH:D008527', (193, 208))	('ligand-independent pathway', 'Pathway', (152, 178))	('tumor', 'Disease', (36, 41))
129653	23063752	The high frequency of IDH mutations in GII and GIII gliomas and their occurrence in patient tumor specimens prior to the acquisition of either TP53 mutation or loss of 1p/19q has been interpreted to suggest that IDHI mutations are an early event in gliomagenesis in a cell type that can give rise to astrocytic and oligodendroglial tumors.	('give rise to', 'Reg', (287, 299))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutations', 'Var', (26, 35))	('TP53', 'Gene', '7157', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('IDHI', 'Disease', (212, 216))	('gliomas', 'Disease', (52, 59))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDHI', 'Disease', 'None', (212, 216))	('IDH', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('glioma', 'Disease', (249, 255))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('oligodendroglial tumors', 'Disease', (315, 338))	('patient', 'Species', '9606', (84, 91))	('tumor', 'Disease', (332, 337))	('TP53', 'Gene', (143, 147))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (315, 338))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('tumor', 'Disease', (92, 97))	('glioma', 'Disease', (52, 58))	('mutations', 'Var', (217, 226))
129654	23063752	In this study, we sequenced IDH1 and IDH2 in glioma specimens previously annotated for Hh pathway activity and in a larger set of clinical specimens as part of an extensive survey to define the malignant glioma subtypes that manifest an operational Hh pathway.	('sequenced', 'Var', (18, 27))	('malignant glioma subtypes', 'Disease', 'MESH:D005910', (194, 219))	('IDH2', 'Gene', (37, 41))	('glioma', 'Disease', (204, 210))	('malignant glioma subtypes', 'Disease', (194, 219))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH2', 'Gene', '3418', (37, 41))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('glioma', 'Disease', (45, 51))	('IDH1', 'Gene', (28, 32))
129659	23063752	Additionally, measurements in primary brain tumors were corroborated using probes for PTCH1 (Hs00970979_m1, Life Technologies) and GAPDH (Hs99999905_m1, Life Technologies).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('GAPDH', 'Gene', '2597', (131, 136))	('PTCH1', 'Gene', (86, 91))	('GAPDH', 'Gene', (131, 136))	('Hs00970979_m1', 'Var', (93, 106))	('brain tumors', 'Disease', 'MESH:D001932', (38, 50))	('brain tumors', 'Phenotype', 'HP:0030692', (38, 50))	('brain tumor', 'Phenotype', 'HP:0030692', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Hs99999905_m1', 'Var', (138, 151))	('brain tumors', 'Disease', (38, 50))
129660	23063752	For qRT-PCR analysis of primary cell cultures and xenografted tumors, reactions were performed with TaqMan Fast Universal PCR Master Mix (Life Technologies), cDNA template, and probes (TaqMan Gene Expression Assay, Life Technologies) for hGLI1 (Hs01110766_m1), hPROM1 (Hs01009261_m1) and hGAPDH (Hs99999905_m1).	('hGLI1', 'Gene', '2735', (238, 243))	('hGAPDH', 'Gene', (288, 294))	('hPROM1', 'Gene', '8842', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('hGAPDH', 'Gene', '2597', (288, 294))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Hs01009261_m1', 'Var', (269, 282))	('Hs99999905_m1', 'Var', (296, 309))	('hGLI1', 'Gene', (238, 243))	('hPROM1', 'Gene', (261, 267))	('Hs01110766_m1', 'Var', (245, 258))
129688	23063752	Point mutations (R132H, R132G, R132S and Y183C) were introduced into the IDH1 open reading frame by PCR site-specific mutagenesis (Quick change II XL Site Directed Mutagenesis Kit, Strata gene) using pCMV6-Entry wild-type IDH1 vector (OriGene) as a cDNA template.	('R132H', 'Var', (17, 22))	('Y183C', 'Var', (41, 46))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('R132G', 'Mutation', 'rs121913499', (24, 29))	('R132S', 'Var', (31, 36))	('R132S', 'Mutation', 'rs121913499', (31, 36))	('R132G', 'Var', (24, 29))	('Y183C', 'Mutation', 'rs34599179', (41, 46))
129690	23063752	In subsequent experiments, HEK 293T cells cultured in 6-well plates were transfected with 4 lg per well of IDH1 plasmid containing wild-type sequences or point mutations (Y183C, R132H, R132S or R132G).	('R132S', 'Var', (185, 190))	('R132H', 'Mutation', 'rs121913500', (178, 183))	('R132H', 'Var', (178, 183))	('R132G', 'Var', (194, 199))	('R132S', 'Mutation', 'rs121913499', (185, 190))	('Y183C', 'Mutation', 'rs34599179', (171, 176))	('Y183C', 'Var', (171, 176))	('R132G', 'Mutation', 'rs121913499', (194, 199))	('HEK 293T', 'CellLine', 'CVCL:0063', (27, 35))
129703	23063752	Briefly, mouse embryonic fibroblasts (NIH 3T3) plated in 12-well plates were transfected (FuGene 6, Roche) with 600 ng of Gli-reporter (pGL3-8xGli-luciferase) and pCMV-LacZ, (a transfection control with a 9:1 ratio of Gli-reporter:LacZ) and 700 ng of IDH1 plasmid per well (pCMV6-Entry vector, IDH1, R132S, R132G, and Y183C).	('Gli', 'Gene', '2735', (218, 221))	('R132G', 'Var', (307, 312))	('Gli', 'Gene', '2735', (122, 125))	('Gli', 'Gene', '2735', (143, 146))	('Y183C', 'Mutation', 'rs34599179', (318, 323))	('R132S', 'Var', (300, 305))	('mouse', 'Species', '10090', (9, 14))	('Y183C', 'Var', (318, 323))	('Gli', 'Gene', (218, 221))	('R132G', 'Mutation', 'rs121913499', (307, 312))	('R132S', 'Mutation', 'rs121913499', (300, 305))	('NIH 3T3', 'CellLine', 'CVCL:0594', (38, 45))	('Gli', 'Gene', (143, 146))	('Gli', 'Gene', (122, 125))
129705	23063752	In additional experiments, NIH 3T3 cells were transfected (FuGene 6, Roche) with IDH constructs (IDH1, R132S, R132G, and Y183C) over a range of 100 -1600 ng in two fold increments, 700 ng of Gli-reporter and pCMV-LacZ (9:1 ratio of Gli-reporter:LacZ), and variable amounts of empty vector (pCMV6-Entry) to normalize the total DNA quantity in each well.	('R132S', 'Var', (103, 108))	('Y183C', 'Var', (121, 126))	('Gli', 'Gene', (232, 235))	('Gli', 'Gene', (191, 194))	('R132S', 'Mutation', 'rs121913499', (103, 108))	('Gli', 'Gene', '2735', (191, 194))	('IDH1', 'Var', (97, 101))	('R132G', 'Mutation', 'rs121913499', (110, 115))	('Gli', 'Gene', '2735', (232, 235))	('NIH 3T3', 'CellLine', 'CVCL:0594', (27, 34))	('Y183C', 'Mutation', 'rs34599179', (121, 126))	('R132G', 'Var', (110, 115))
129729	23063752	Mutations at arginine R132 of IDH1 or R172 of IDH2 were detected in 33 of 34 (97%) of GII gliomas, 19 of 28 (68%) of GIII gliomas and 4 of 49 (6.8%) glioblastomas (Fig.	('IDH2', 'Gene', (46, 50))	('GII gliomas', 'Disease', 'MESH:D005910', (86, 97))	('R172', 'Var', (38, 42))	('IDH2', 'Gene', '3418', (46, 50))	('gliomas', 'Disease', (90, 97))	('glioblastomas', 'Disease', (149, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('gliomas', 'Disease', (122, 129))	('glioblastomas', 'Disease', 'MESH:D005909', (149, 162))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('GII gliomas', 'Disease', (86, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1', 'Gene', (30, 34))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('detected', 'Reg', (56, 64))	('arginine', 'Chemical', 'MESH:D001120', (13, 21))	('glioblastomas', 'Phenotype', 'HP:0012174', (149, 162))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('Mutations at arginine R132', 'Var', (0, 26))
129730	23063752	Of the four GBM with IDH1 mutations, by histopathological and clinical data, two were diagnosed as sGBM, one as pGBM and one as recurrent GBM (recGBM) with prior resection 14 months earlier.	('mutations', 'Var', (26, 35))	('pGBM', 'Chemical', '-', (112, 116))	('IDH1', 'Gene', (21, 25))	('sGBM', 'Disease', (99, 103))
129732	23063752	The similar frequencies of GBM with elevated PTCH1 mRNA levels and IDH mutations suggest that the Hh pathway may be activated in a subset of GBM as well as GII and GIII gliomas.	('mRNA levels', 'MPA', (51, 62))	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('elevated', 'PosReg', (36, 44))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('activated', 'PosReg', (116, 125))	('IDH', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('PTCH1', 'Gene', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('Hh pathway', 'Pathway', (98, 108))
129735	23063752	Consistent with the idea that the Hh pathway may be activated in a subset of GBM characterized by IDH mutation, PTCH staining was observed only in an IDH mutant GBM and not in three other GBM that were wild-type for IDH (Fig.	('Hh pathway', 'Pathway', (34, 44))	('PTCH', 'Gene', '5727', (112, 116))	('mutation', 'Var', (102, 110))	('PTCH', 'Gene', (112, 116))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', (98, 101))	('activated', 'PosReg', (52, 61))	('mutant', 'Var', (154, 160))
129737	23063752	To assess further the operational status of the Hh pathway GIV gliomas, glioma sphere cultures were generated from IDH mutant (n=3) and IDH wild-type (n=4) GBM specimens and assayed under stem cell culture conditions.	('glioma', 'Disease', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('GIV gliomas', 'Disease', 'MESH:D005910', (59, 70))	('GIV gliomas', 'Disease', (59, 70))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('IDH', 'Gene', (115, 118))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('mutant', 'Var', (119, 125))	('glioma', 'Disease', (63, 69))
129742	23063752	Analysis of IDH sequence with respect to WHO grade and Hh signal response revealed that an operational Hh pathway could be measured in all cultures derived from IDH mutant gliomas (Fig.	('mutant', 'Var', (165, 171))	('Hh pathway', 'Pathway', (103, 113))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('measured', 'Reg', (123, 131))	('gliomas', 'Disease', (172, 179))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('IDH', 'Gene', (161, 164))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))
129744	23063752	In GIV gliomas, a responsive Hh pathway was measured only in GBM with IDH mutation or histopathological evidence of progression from a lower grade glioma (Fig.	('mutation', 'Var', (74, 82))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))	('GIV gliomas', 'Disease', (3, 14))	('glioma', 'Disease', 'MESH:D005910', (7, 13))	('IDH', 'Gene', (70, 73))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('glioma', 'Disease', (147, 153))	('GIV gliomas', 'Disease', 'MESH:D005910', (3, 14))	('glioma', 'Disease', (7, 13))
129745	23063752	Thus, in the absence of histopathological evidence to support the diagnosis of sGBM, the presence of an IDH mutation may serve as a molecular marker of Hh-responsive high grade gliomas.	('IDH', 'Gene', (104, 107))	('gliomas', 'Disease', (177, 184))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('mutation', 'Var', (108, 116))
129747	23063752	Sequence analysis of the primary cell lines that we generated from IDH mutant gliomas revealed loss of the mutation in all instances (Fig.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('mutant', 'Var', (71, 77))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('loss', 'NegReg', (95, 99))
129748	23063752	The mechanism by which IDH mutation is lost in cell culture is unknown, though it has been suggested that only viable non-tumor cells remain in culture following the elimination of IDH mutant tumor cells.	('tumor', 'Disease', (192, 197))	('IDH', 'Gene', (181, 184))	('mutant', 'Var', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (122, 127))
129751	23063752	The sequencing results, however, do not alter interpretation of the differential Hh responses measured in cell lines derived from gliomas with wild-type IDH sequences; the Hh pathway was modulated in cells cultured from IDH wild-type GIII gliomas, but not in cells cultured from IDH wild-type pGBM.	('modulated', 'Reg', (187, 196))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Disease', (239, 246))	('Hh pathway', 'Pathway', (172, 182))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('IDH', 'Var', (220, 223))	('pGBM', 'Chemical', '-', (293, 297))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
129752	23063752	We have previously reported that pharmacological inhibition of the Hh pathway in GIII glioma xenografts confers a survival advantage.	('glioma', 'Disease', (86, 92))	('pharmacological inhibition', 'Var', (33, 59))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('survival advantage', 'CPA', (114, 132))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('Hh pathway', 'Pathway', (67, 77))
129753	23063752	To gain a better appreciation of the influence of IDH mutation on Hh pathway modulation in vivo, we sequenced the tumors from three primary orthotopic glioma xenograft models that were characterized for pathway responsiveness.	('primary orthotopic glioma', 'Disease', 'MESH:D005910', (132, 157))	('mutation', 'Var', (54, 62))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('primary orthotopic glioma', 'Disease', (132, 157))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
129754	23063752	The parent tumor and engrafted tumor specimens contained an IDH1 R132H mutation for the Hh-responsive GIII oligoastrocytoma model and wild-type IDH sequences for the Hh-responsive GIII astrocytoma and Hh-unresponsive pGBM models (Table 1).	('astrocytoma', 'Disease', 'MESH:D001254', (185, 196))	('astrocytoma', 'Phenotype', 'HP:0009592', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('R132H', 'Mutation', 'rs121913500', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('astrocytoma', 'Disease', (185, 196))	('IDH1', 'Gene', (60, 64))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (31, 36))	('pGBM', 'Chemical', '-', (217, 221))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (107, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (185, 196))	('oligoastrocytoma', 'Disease', (107, 123))	('astrocytoma', 'Disease', 'MESH:D001254', (112, 123))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('R132H', 'Var', (65, 70))	('astrocytoma', 'Disease', (112, 123))
129755	23063752	The retention of IDH1 R132H mutation in the Hh-responsive GIII oligoastrocytoma xenograft provides strong evidence for an operational Hh pathway in the presence of IDH mutation.	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (63, 79))	('oligoastrocytoma', 'Disease', (63, 79))	('IDH1', 'Gene', (17, 21))	('R132H', 'Var', (22, 27))	('R132H', 'Mutation', 'rs121913500', (22, 27))
129759	23063752	CD133 positive and negative cells were isolated by fluorescence-activated cell sorting (FACS) from the IDH1 mutant GBM xenograft, two IDH wild-type GBMs (one xenograft and one tumor specimen) and an IDH1 mutant anaplastic astrocytoma specimen (positive control).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('astrocytoma', 'Phenotype', 'HP:0009592', (222, 233))	('tumor', 'Disease', (176, 181))	('mutant', 'Var', (108, 114))	('astrocytoma', 'Disease', 'MESH:D001254', (222, 233))	('astrocytoma', 'Disease', (222, 233))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('IDH1', 'Gene', (103, 107))
129760	23063752	In both IDH mutant and wild-type tumors, human Prominin-1 (hPROM1, which encodes CD133) transcript levels were greatly enriched and depleted in cells sorted for positive and negative CD133 antibody staining, respectively (Fig.	('Prominin-1', 'Gene', (47, 57))	('hPROM1', 'Gene', (59, 65))	('enriched', 'PosReg', (119, 127))	('hPROM1', 'Gene', '8842', (59, 65))	('IDH', 'Gene', (8, 11))	('human', 'Species', '9606', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('transcript levels', 'MPA', (88, 105))	('mutant', 'Var', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('depleted', 'NegReg', (132, 140))	('Prominin-1', 'Gene', '8842', (47, 57))	('tumors', 'Disease', (33, 39))
129761	23063752	Conversely, hGLI1 levels were enriched in CD133+ cells only when sorted from the IDH1 mutant GBM xenograft and analplastic astrocytoma (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('mutant', 'Var', (86, 92))	('IDH1', 'Gene', (81, 85))	('hGLI1', 'Gene', '2735', (12, 17))	('astrocytoma', 'Disease', 'MESH:D001254', (123, 134))	('hGLI1', 'Gene', (12, 17))	('astrocytoma', 'Disease', (123, 134))
129762	23063752	Taken together with sequencing results of tumors assayed for Hh signaling in vitro and in vivo, these findings fortify the utility of IDH mutation as a molecular marker to identify Hh responsive GBM.	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IDH', 'Gene', (134, 137))
129764	23063752	The production of 2 hydroxyglutarate by expression of IDH1 with mutation at R132 was confirmed with LC-MS/MS (Fig.	('mutation at R132', 'Var', (64, 80))	('2 hydroxyglutarate', 'Chemical', 'MESH:C019417', (18, 36))	('IDH1', 'Gene', (54, 58))
129766	23063752	Furthermore, the pathway response to a constant level of Shh stimulation was not enhanced or inhibited by the expression level of wild-type, polymorphic or mutant IDH1 constructs (Fig.	('Shh', 'Gene', '6469', (57, 60))	('IDH1', 'Gene', (163, 167))	('Shh', 'Gene', (57, 60))	('mutant', 'Var', (156, 162))
129767	23063752	Together, these data indicate that IDH1 mutation and 2-hydroxyglutarate levels do not impact Hh pathway response.	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('Hh pathway', 'Pathway', (93, 103))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (53, 71))
129770	23063752	Based upon an extensive survey of patient specimens, we report that the Hh pathway is operational in astrocytomas, oligodendrogliomas, and oligoastrocytomas, and in a subgroup of glioblastomas delineated by IDH1 mutation or clinical evidence for progression from a lower grade glioma.	('IDH1', 'Gene', (207, 211))	('oligodendrogliomas', 'Disease', (115, 133))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('glioblastomas', 'Phenotype', 'HP:0012174', (179, 192))	('astrocytomas', 'Disease', (144, 156))	('patient', 'Species', '9606', (34, 41))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('glioblastomas', 'Disease', (179, 192))	('astrocytomas', 'Disease', (101, 113))	('astrocytomas', 'Disease', 'MESH:D001254', (144, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (179, 192))	('glioma', 'Disease', (277, 283))	('glioma', 'Disease', (126, 132))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (115, 133))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (139, 156))	('oligoastrocytomas', 'Disease', (139, 156))	('glioma', 'Disease', 'MESH:D005910', (277, 283))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('mutation', 'Var', (212, 220))	('Hh pathway', 'Pathway', (72, 82))	('astrocytomas', 'Disease', 'MESH:D001254', (101, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))
129775	23063752	In this study, we found evidence for an operant Hh pathway in every glioma harboring an IDH mutation, demonstrating that IDH mutation may serve as a marker to identify Hh-responsive gliomas.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('mutation', 'Var', (92, 100))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('Hh pathway', 'Pathway', (48, 58))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('IDH', 'Gene', (88, 91))	('glioma', 'Disease', (182, 188))	('glioma', 'Disease', (68, 74))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('gliomas', 'Disease', (182, 189))
129776	23063752	The value of this finding is particularly evident in the case of glioblastoma where we were able to identify Hh-responsive tumors by IDH mutation from within a larger collection of unresponsive IDH wild-type GIV gliomas.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (137, 145))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('glioblastoma', 'Disease', (65, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('GIV gliomas', 'Disease', 'MESH:D005910', (208, 219))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('IDH', 'Gene', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('GIV gliomas', 'Disease', (208, 219))
129777	23063752	Sequence analysis for IDH mutations and immunohistochemistry with an IDH1 antibody specific for the most frequent mutation, R132H, represent highly specific and sensitive assays that are gaining routine use in the realms of histopathology, translational investigation and clinical trial.	('R132H', 'Mutation', 'rs121913500', (124, 129))	('R132H', 'Var', (124, 129))	('IDH', 'Gene', (22, 25))
129778	23063752	The very high frequency of IDH mutation in oligodendrogliomas, oligoastrocytomas, astrocytomas and sGBM has been interpreted to suggest that it is an early genetic alteration in a common cell of origin that is distinct from the cellular origin for pGBM.	('IDH', 'Gene', (27, 30))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('oligodendrogliomas', 'Disease', (43, 61))	('astrocytomas', 'Disease', (68, 80))	('astrocytomas', 'Disease', (82, 94))	('oligoastrocytomas', 'Disease', (63, 80))	('mutation', 'Var', (31, 39))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (63, 80))	('astrocytomas', 'Disease', 'MESH:D001254', (82, 94))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('pGBM', 'Chemical', '-', (248, 252))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (43, 61))
129780	23063752	In this context it is not surprising that some Hh responsive gliomas did not contain IDH mutations.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('mutations', 'Var', (89, 98))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))
129784	23063752	Thus while IDH mutation typifies GII gliomas, GIII gliomas and sGBM, it is not required for classifying these glioma subtypes according to histopathological or transcriptome criteria.	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('gliomas', 'Disease', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('gliomas', 'Disease', (51, 58))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('GII gliomas', 'Disease', (33, 44))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('mutation', 'Var', (15, 23))	('IDH', 'Gene', (11, 14))	('glioma', 'Disease', (110, 116))	('glioma', 'Disease', (37, 43))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('GII gliomas', 'Disease', 'MESH:D005910', (33, 44))	('glioma', 'Disease', 'MESH:D005910', (37, 43))
129785	23063752	In this regard, IDH mutation characterizes Hh responsive gliomas encompassing a spectrum of ensuing grades of malignancy.	('characterizes', 'Reg', (29, 42))	('mutation', 'Var', (20, 28))	('IDH', 'Gene', (16, 19))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('malignancy', 'Disease', (110, 120))	('gliomas', 'Disease', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
129790	21305617	This review focuses on mouse models of glioma with a special emphasis on genetically engineered models developed around key genetic glioma signature mutations in the PDGFR, EGFR and NF1 genes and pathways.	('glioma', 'Disease', (132, 138))	('mutations', 'Var', (149, 158))	('glioma', 'Disease', (39, 45))	('NF1', 'Gene', (182, 185))	('genetic glioma', 'Disease', 'MESH:D030342', (124, 138))	('mouse', 'Species', '10090', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('EGFR', 'Gene', (173, 177))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('PDGFR', 'Gene', (166, 171))	('genetic glioma', 'Disease', (124, 138))
129805	21305617	In a third report, a combination of proteomic and genomic analyses was used to subdivide tumors into three subclasses based on signal transduction pathway activation and genetic alterations.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('genetic alterations', 'Var', (170, 189))	('rat', 'Species', '10116', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
129806	21305617	In summary, the data indicate that there are three distinct glioma subtypes that show either EGFR activation associated with amplification or mutation of receptor, PDGF-pathway activation, which is associated with PDGF ligand expression at the protein level and PDGFR amplification in half of the cases, or loss of NF1 expression.	('PDGF-pathway', 'Gene', (164, 176))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('amplification', 'Var', (125, 138))	('PDGF ligand', 'Gene', (214, 225))	('activation', 'PosReg', (98, 108))	('activation', 'PosReg', (177, 187))	('EGFR', 'Gene', (93, 97))	('glioma', 'Disease', (60, 66))	('mutation', 'Var', (142, 150))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
129822	21305617	In addition, DNA repair defects in these immunocompromised host mice can limit their capacity to tolerate novel treatments, including radiation therapy.	('rat', 'Species', '10116', (101, 104))	('limit', 'NegReg', (73, 78))	('mice', 'Species', '10090', (64, 68))	('DNA', 'Gene', (13, 16))	('defects', 'Var', (24, 31))
129842	21305617	A germline alteration that is sufficient to convert normal cells to tumor in 100% of affected cells would generally be embryonically lethal and could not be maintained as a line of mice.	('tumor', 'Disease', (68, 73))	('mice', 'Species', '10090', (181, 185))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('alteration', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
129843	21305617	In the majority of human cancers, most mutations occur somatically in a single cell or small group of specific cell types, and the identity of the mutation-bearing cell is one determinant of the characteristics of the resulting tumor cells.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mutations', 'Var', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('tumor', 'Disease', (228, 233))	('cancers', 'Disease', (25, 32))	('human', 'Species', '9606', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
129851	21305617	Given the high frequency with which pRB function is impaired in human astrocytomas, a transgenic astrocytoma model was developed by tissue-specific inactivation of the Rb family proteins via the expression of SV40 T antigen, and later a fragment of the SV40 T antigen (T121), which effectively inactivates the Rb pathway, expressed under control of the GFAP promoter.	('Rb family proteins', 'Protein', (168, 186))	('human', 'Species', '9606', (64, 69))	('SV40 T antigen', 'Var', (209, 223))	('astrocytoma', 'Disease', 'MESH:D001254', (70, 81))	('pRB', 'Gene', '5925', (36, 39))	('astrocytoma', 'Disease', 'MESH:D001254', (97, 108))	('astrocytoma', 'Disease', (70, 81))	('astrocytomas', 'Disease', 'MESH:D001254', (70, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('astrocytoma', 'Disease', (97, 108))	('inactivation', 'NegReg', (148, 160))	('inactivates', 'NegReg', (294, 305))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('Rb pathway', 'Pathway', (310, 320))	('astrocytomas', 'Disease', (70, 82))	('pRB', 'Gene', (36, 39))	('transgenic', 'Species', '10090', (86, 96))
129853	21305617	Furthermore, in this model, the combination of pten inactivation induces increased tumor cell survival and invasion along with angiogenesis.	('increased', 'PosReg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('angiogenesis', 'CPA', (127, 139))	('pten', 'Gene', (47, 51))	('inactivation', 'Var', (52, 64))	('invasion', 'CPA', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
129857	21305617	Moderately elevated levels of V12Ha-ras expression leads to astrocytomas of varying grades in 95% of animals, with 50% of these mice developing astrocytomas by 3 months of age.	('astrocytomas', 'Disease', (60, 72))	('V12Ha', 'CellLine', 'CVCL:6758', (30, 35))	('astrocytomas', 'Disease', 'MESH:D001254', (144, 156))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('leads to', 'Reg', (51, 59))	('mice', 'Species', '10090', (128, 132))	('astrocytomas', 'Disease', (144, 156))	('astrocytomas', 'Disease', 'MESH:D001254', (60, 72))	('rat', 'Species', '10116', (4, 7))	('V12Ha-ras', 'Var', (30, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))
129860	21305617	The RCAS/tv-a system has been used to transfer constitutively active mutant forms of K-Ras and Akt to nestin-expressing neural progenitor cells.	('RCAS', 'Chemical', '-', (4, 8))	('mutant', 'Var', (69, 75))	('K-Ras', 'Gene', (85, 90))	('tv-a', 'Chemical', 'MESH:C050413', (9, 13))	('Akt', 'Gene', (95, 98))	('K-Ras', 'Gene', '16653', (85, 90))
129872	21305617	These three classes are distinct and show either EGFR activation associated with amplification or mutation of receptor, PDGF-pathway activation, which is mainly ligand-driven, or loss of Nf-1 expression.	('mutation', 'Var', (98, 106))	('Nf-1', 'Gene', '18015', (187, 191))	('EGFR', 'Gene', (49, 53))	('expression', 'MPA', (192, 202))	('PDGF-pathway', 'Pathway', (120, 132))	('activation', 'PosReg', (54, 64))	('amplification', 'Var', (81, 94))	('activation', 'PosReg', (133, 143))	('loss', 'NegReg', (179, 183))	('Nf-1', 'Gene', (187, 191))
129901	21305617	For example, adult GBMs commonly demonstrate amplification of EGFR and inactivation by mutation or deletion of pten.	('pten', 'Gene', (111, 115))	('rat', 'Species', '10116', (40, 43))	('EGFR', 'Gene', (62, 66))	('amplification', 'MPA', (45, 58))	('deletion', 'Var', (99, 107))	('inactivation', 'NegReg', (71, 83))	('mutation', 'Var', (87, 95))
129905	21305617	In response to the observation that human secondary gliomas commonly show mutation and/or loss of p53, often in combination with alterations in PDGF signaling, researchers engineered mouse models that contain these specific genetic alterations.	('gliomas', 'Disease', (52, 59))	('mutation', 'Var', (74, 82))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('loss', 'NegReg', (90, 94))	('rat', 'Species', '10116', (236, 239))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('rat', 'Species', '10116', (133, 136))	('mouse', 'Species', '10090', (183, 188))	('p53', 'Gene', (98, 101))	('human', 'Species', '9606', (36, 41))
129933	21305617	Perifosine, an inhibitor of Akt signaling, was also shown to have some efficacy in this model, prompting clinical trials for this agent in glioma patients.	('Perifosine', 'Chemical', 'MESH:C105905', (0, 10))	('glioma', 'Disease', (139, 145))	('efficacy', 'MPA', (71, 79))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('Perifosine', 'Var', (0, 10))	('patients', 'Species', '9606', (146, 154))
129938	21305617	In addition, the prevalence of malignant glioma in individuals harboring a germline NF1 mutation is considerably higher than the population at large.	('mutation', 'Var', (88, 96))	('NF1', 'Gene', (84, 87))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('higher', 'PosReg', (113, 119))	('malignant glioma', 'Disease', 'MESH:D005910', (31, 47))	('malignant glioma', 'Disease', (31, 47))
129940	21305617	The recent publication of TCGA data for sporadic human glioma has provided compelling support for NF1 as a potentially causal agent in glioma, as NF1 was mutated at a similar frequency to other well-known tumor suppressors such as Pten, p53, Rb, and CDKN2A.	('glioma', 'Disease', (55, 61))	('glioma', 'Disease', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('CDKN2A', 'Gene', (250, 256))	('CDKN2A', 'Gene', '1029', (250, 256))	('human', 'Species', '9606', (49, 54))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('mutated', 'Var', (154, 161))	('NF1', 'Gene', (146, 149))
129941	21305617	Indeed, subsequent studies have begun to reveal NF1 mutations in a broader spectrum of solid tumors, albeit with a lesser proportion than seen in glioma.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))	('glioma', 'Disease', (146, 152))	('solid tumors', 'Disease', (87, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('NF1', 'Gene', (48, 51))
129948	21305617	Mice harboring heterozygous loss of function mutations in cis for the NF1 and p53 tumor suppressor genes developed glioma spontaneously - the NF1 and p53 genes reside on the same human and mouse chromosomes.	('mutations', 'Var', (45, 54))	('glioma', 'Disease', (115, 121))	('human', 'Species', '9606', (179, 184))	('mouse', 'Species', '10090', (189, 194))	('loss of function', 'NegReg', (28, 44))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p53', 'Gene', (78, 81))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (82, 87))	('NF1', 'Gene', (70, 73))
129952	21305617	Some mouse strains harboring the cis NF1 and p53 mutations gave rise to tumors rarely while others had substantially increased tumor incidence.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('p53', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('increased', 'PosReg', (117, 126))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (72, 77))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('cis NF1', 'Gene', (33, 40))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mouse', 'Species', '10090', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
129955	21305617	An added feature of these models was the inclusion of germline conditional or null mutations in only one allele for each tumor suppressor (NF1 and p53).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('p53', 'Gene', (147, 150))	('null mutations', 'Var', (78, 92))	('tumor', 'Disease', (121, 126))	('germline conditional', 'Var', (54, 74))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
129958	21305617	Cells isolated from these tumors were shown to have undergone LOH for both the NF1 and p53 tumor suppressor genes, while non-tumor cells from brains of the same mice retained wild type NF1 and p53 alleles.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mice', 'Species', '10090', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('LOH', 'Var', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('NF1', 'Gene', (79, 82))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', (26, 32))
129959	21305617	These mice developed secondary glioma with manifest pathologic evidence of Grade II, Grade III and Grade IV tumors, indicating that mutation in these two tumor suppressor genes was sufficient to generate malignant glioma (Fig.	('IV tumors', 'Disease', 'MESH:D009369', (105, 114))	('mice', 'Species', '10090', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('tumor', 'Disease', (108, 113))	('rat', 'Species', '10116', (199, 202))	('tumor', 'Disease', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('glioma', 'Disease', (214, 220))	('malignant glioma', 'Disease', (204, 220))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('malignant glioma', 'Disease', 'MESH:D005910', (204, 220))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('glioma', 'Disease', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('IV tumors', 'Disease', (105, 114))	('generate', 'Reg', (195, 203))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('mutation', 'Var', (132, 140))
129968	21305617	Pten mutations are prevalent in human high-grade gliomas, but have not been observed in preceding low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('prevalent', 'Reg', (19, 28))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('Pten', 'Gene', (0, 4))	('human', 'Species', '9606', (32, 37))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
129969	21305617	It was found that inclusion of one heterozygous conditional Pten allele in the context of NF1 and p53 loss resulted in de novo high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('p53', 'Gene', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('loss', 'NegReg', (102, 106))	('inclusion', 'Var', (18, 27))	('resulted in', 'Reg', (107, 118))	('NF1', 'Gene', (90, 93))
129970	21305617	These results provided experimental evidence for the idea that Pten mutation in human glioma may be a causal mutation in transition from lower-grade to high-grade tumors and in the appearance of primary glioma.	('glioma', 'Disease', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('causal', 'Reg', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('mutation', 'Var', (68, 76))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('primary glioma', 'Disease', 'MESH:D005910', (195, 209))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('primary glioma', 'Disease', (195, 209))	('mutation', 'Reg', (109, 117))	('tumors', 'Disease', (163, 169))	('human', 'Species', '9606', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('Pten', 'Gene', (63, 67))	('glioma', 'Disease', (203, 209))
129973	21305617	Activating Cre recombinase specifically in the stem/progenitor cells of the CNS has provided evidence that loss of NF1 and p53 in these cells is sufficient to initiate glioma development.	('initiate', 'Reg', (159, 167))	('NF1', 'Gene', (115, 118))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('loss', 'Var', (107, 111))	('p53', 'Gene', (123, 126))	('glioma', 'Disease', (168, 174))
129975	21305617	Such data are most consistent with the idea that, in these NF1-based models that use mutations frequently observed in human glioma, tumors arise from stem cells and not from more differentiated cells.	('glioma', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (85, 94))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('human', 'Species', '9606', (118, 123))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
129977	21305617	Returning to earlier questions, it will be of interest to replace the NF1 mutation with PDGFR- or EGFR-activating mutations to experimentally examine whether these mutations have distinct clinical outcomes and whether the same or distinct cells in the brain are susceptible to form gliomas when sustaining each mutation.	('mutation', 'Var', (74, 82))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('PDGFR-', 'Gene', '18596', (88, 94))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('PDGFR-', 'Gene', (88, 94))	('NF1', 'Gene', (70, 73))
129983	21305617	It is one of the major oncogenic drivers of high-grade gliomas, where it has been shown to be overexpressed and mutated in over 50% of tumors.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('mutated', 'Var', (112, 119))
129985	21305617	Evidence that members of this family play crucial roles in the development of neoplastic transformation come from their high percentage of mutations in various cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('mutations', 'Var', (139, 148))	('cancers', 'Disease', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
129986	21305617	In addition to EGFR, ErbB2 (or Her2/neu) has been shown to be mutated in many neoplasms, with the most common being breast cancer.	('Her2/neu', 'Gene', (31, 39))	('common', 'Reg', (103, 109))	('breast cancer', 'Disease', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('neoplasms', 'Disease', 'MESH:D009369', (78, 87))	('ErbB2', 'Gene', (21, 26))	('Her2/neu', 'Gene', '13866', (31, 39))	('neoplasms', 'Disease', (78, 87))	('ErbB2', 'Gene', '13866', (21, 26))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('mutated', 'Var', (62, 69))
129987	21305617	The EGFRvII mutation consists of an extracellular domain deletion of 83 amino acids in the second cysteine rich region of the receptor.	('cysteine', 'Chemical', 'MESH:D003545', (98, 106))	('mutation', 'Var', (12, 20))	('EGFRvII', 'Gene', (4, 11))
129988	21305617	In ~50% of malignant glioma tumors with an EGFR gene amplification event, an intragenic deletion encompassing exons 2 to 7 of the gene locus is observed.	('malignant glioma', 'Disease', (11, 27))	('EGFR gene', 'Gene', (43, 52))	('malignant glioma', 'Disease', 'MESH:D005910', (11, 27))	('glioma tumors', 'Disease', 'MESH:D005910', (21, 34))	('deletion', 'Var', (88, 96))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('amplification event', 'Var', (53, 72))	('to 7', 'Species', '1214577', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('glioma tumors', 'Disease', (21, 34))
129992	21305617	Interestingly, EGFRvV mutant receptors are found in tumors that carry the EGFRvIII allele.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('found', 'Reg', (43, 48))	('EGFRvV', 'Gene', (15, 21))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('EGFRvIII', 'Gene', (74, 82))	('mutant', 'Var', (22, 28))
129993	21305617	Finally, a recent massive sequencing effort of the receptor from GBM tumors has uncovered several oncogenic missense point mutations in the extracellular domain of the receptor that in some cases have been shown to confer oncogenic potential.	('missense point mutations in', 'Var', (108, 135))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GBM tumors', 'Disease', 'MESH:D005910', (65, 75))	('GBM tumors', 'Disease', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('oncogenic potential', 'CPA', (222, 241))
129995	21305617	A major challenge now is to assign cancer relevance to the numerous GBM-associated genetic alterations in relevant and accurate model systems.	('genetic alterations', 'Var', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('rat', 'Species', '10116', (95, 98))	('rat', 'Species', '10116', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
130010	21305617	Interestingly, loss of Rb1 had little effect on the penetrance, latency or grade of the tumors formed.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('latency', 'CPA', (64, 71))	('Rb1', 'Gene', (23, 26))	('loss', 'Var', (15, 19))	('Rb1', 'Gene', '19645', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
130011	21305617	This is probably due to the fact that in mice, compensatory mechanisms exist between the Rb family members (p107 and p130) in tumorigenesis.	('p107', 'Var', (108, 112))	('mice', 'Species', '10090', (41, 45))	('p130', 'Var', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
130013	21305617	To address this issue, the authors performed comparative genome hybridization (CGH) on S100b-v-erbB transgene oligodendroglial tumors and demonstrated gain and loss of specific chromosomal regions that are orthologous with copy number alterations observed in human oligodendrogliomas, including deletions of chromosome 1p36.	('gain', 'PosReg', (151, 155))	('oligodendrogliomas', 'Disease', (265, 283))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('deletions', 'Var', (295, 304))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('loss', 'NegReg', (160, 164))	('rat', 'Species', '10116', (50, 53))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('S100b', 'Gene', (87, 92))	('S100b', 'Gene', '20203', (87, 92))	('rat', 'Species', '10116', (239, 242))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (265, 283))	('human', 'Species', '9606', (259, 264))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (110, 133))	('rat', 'Species', '10116', (145, 148))	('oligodendroglial tumors', 'Disease', (110, 133))
130021	21305617	Surprisingly, overexpression of either wild type EGFR or EGFRvIII variant under the glial fibrillary acidic protein (GFAP) promoter is incapable of driving tumorigenesis.	('glial fibrillary acidic protein', 'Gene', '14580', (84, 115))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('EGFRvIII', 'Gene', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glial fibrillary acidic protein', 'Gene', (84, 115))	('tumor', 'Disease', (156, 161))	('variant', 'Var', (66, 73))
130030	21305617	Insertion of foreign sequences within this locus has been demonstrated to leave the collagen 1a1 expression unperturbed and allows for efficient single integration transgenesis.	('rat', 'Species', '10116', (157, 160))	('collagen', 'MPA', (84, 92))	('Insertion', 'Var', (0, 9))	('leave', 'Reg', (74, 79))	('rat', 'Species', '10116', (65, 68))
130096	33023662	Interestingly, with the criterion that any uptake above the background should be considered abnormal, using only visual inspection provided a higher sensitivity with 18F-FDOPA, but the specificity was as poor as that with 18F-FDG.	('uptake', 'MPA', (43, 49))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (166, 175))	('sensitivity', 'MPA', (149, 160))	('18F-FDG', 'Chemical', '-', (222, 229))	('18F-FDOPA', 'Var', (166, 175))	('higher', 'PosReg', (142, 148))
130102	33023662	The authors concluded that the sensitivity with 18F-FDOPA was substantially higher compared to the other radiotracers, but the figures and p-value were not provided.	('18F-FDOPA', 'Chemical', 'MESH:C043437', (48, 57))	('sensitivity', 'MPA', (31, 42))	('18F-FDOPA', 'Var', (48, 57))	('higher', 'PosReg', (76, 82))	('radiotracer', 'Chemical', '-', (105, 116))
130158	33023662	Surprisingly, patients with the IDH mutation showed higher 18F-FDOPA T/N (1.6 vs. 1.2; p = 0.046) and T/S ratios (0.9 vs. 0.6; p = 0.024) than patients without the IDH mutation.	('18F-FDOPA T/N', 'MPA', (59, 72))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('IDH', 'Gene', '3417', (164, 167))	('T/S ratios', 'MPA', (102, 112))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('patients', 'Species', '9606', (143, 151))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('higher', 'PosReg', (52, 58))	('patients', 'Species', '9606', (14, 22))	('IDH', 'Gene', (164, 167))	('mutation', 'Var', (36, 44))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (59, 68))
130164	33023662	analyzed the correlation between the IDH mutation and the 1p/19q co-deletion with numerous static (SUVmax, SUVmean, T/S, T/N and MTV) and dynamic (time to peak and slope) PET indices.	('S', 'Chemical', 'MESH:D013455', (107, 108))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('mutation', 'Var', (41, 49))	('1p/19q', 'Gene', (58, 64))	('IDH', 'Gene', (37, 40))	('MTV', 'Chemical', '-', (129, 132))	('S', 'Chemical', 'MESH:D013455', (99, 100))	('IDH', 'Gene', '3417', (37, 40))
130166	33023662	The best index was time to peak, both for the IDH mutation (p < 0.001, AUC = 0.789) and for 1p/19q co-deletion (p = 0.034, AUC = 0.679).	('IDH', 'Gene', '3417', (46, 49))	('time to', 'MPA', (19, 26))	('IDH', 'Gene', (46, 49))	('1p/19q co-deletion', 'Var', (92, 110))
130203	33023662	For non-contrast-enhanced patients (n = 3), BTV60Gy ranged from 48 to 202 times smaller than the GTV60Gy (composed of the FLAIR MRI volume), while the resulting PTV60Gy ranged from 3.2 to 72 times smaller.	('PTV', 'Chemical', '-', (161, 164))	('BTV60Gy', 'Var', (44, 51))	('patients', 'Species', '9606', (26, 34))	('smaller', 'NegReg', (80, 87))
130205	33023662	All priority dose volume constraints for PTV60Gy (V100% >= 95% and V110% < 0.5 cc) were met in both treatment plans for all patients, and all plans met critical organs at risk constraints (according to the Radiation Therapy Oncology Group).	('V100% >', 'Var', (50, 57))	('patients', 'Species', '9606', (124, 132))	('PTV', 'Chemical', '-', (41, 44))	('met', 'Gene', '79811', (148, 151))	('met', 'Gene', (148, 151))	('Oncology', 'Phenotype', 'HP:0002664', (224, 232))	('met', 'Gene', '79811', (88, 91))	('met', 'Gene', (88, 91))	('V110%', 'Var', (67, 72))
130283	33023662	Indeed, it may show increased amino-acid uptake and high rCBV values that are not related to tumor grade but more consistently related to 1p/19q co-deletion.	('increased', 'PosReg', (20, 29))	('rCBV', 'Chemical', '-', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('related', 'Reg', (127, 134))	('amino-acid uptake', 'MPA', (30, 47))	('rCBV values', 'MPA', (57, 68))	('1p/19q co-deletion', 'Var', (138, 156))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
130361	32210512	In the first transformation layer of DTL program, in above syntax, "action" was set to "crop" and dimensions for crop rectangle were set for all images such as top: 48px, left: 64px, right: 71px and bottom: 37px.	('crop', 'Gene', (88, 92))	('crop', 'Gene', '51747', (113, 117))	('crop', 'Gene', '51747', (88, 92))	('DTL', 'Chemical', '-', (37, 40))	('crop', 'Gene', (113, 117))	('right: 71px', 'Var', (183, 194))
130449	29740523	ADCs greater than 800 are predictive of low-grade gliomas, with a sensitivity of 84.5%.	('gliomas', 'Disease', (50, 57))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('ADCs greater than 800', 'Var', (0, 21))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
130451	25981859	Inhibition of MEK Confers Hypersensitivity to X-radiation in the context of BRAF mutation in a Model of Childhood Astrocytoma Curative therapy for childhood glioma presents challenges when complete resection is not possible.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('X-radiation', 'Disease', (46, 57))	('Hypersensitivity', 'Disease', 'MESH:D004342', (26, 42))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('Hypersensitivity', 'Disease', (26, 42))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('mutation', 'Var', (81, 89))	('MEK', 'Gene', (14, 17))	('MEK', 'Gene', '5609', (14, 17))	('X-radiation', 'Disease', 'MESH:D004194', (46, 57))	('glioma', 'Disease', (157, 163))	('Astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('Hypersensitivity to X-radiation', 'Phenotype', 'HP:0011133', (26, 57))
130454	25981859	The regulation of TORC1 signaling by BRAF was examined in BT-40 (BRAF mutant) and BT-35 (BRAF wild type) xenografts, in a cell line derived from the BT-40 xenograft and two adult BRAF mutant glioblastoma cell lines.	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('mutant', 'Var', (184, 190))	('BT', 'Chemical', 'MESH:C005465', (82, 84))	('BT-40', 'Chemical', '-', (58, 63))	('BT', 'Chemical', 'MESH:C005465', (58, 60))	('glioblastoma', 'Disease', (191, 203))	('glioblastoma', 'Disease', 'MESH:D005909', (191, 203))	('BT', 'Chemical', 'MESH:C005465', (149, 151))	('BT-40', 'Chemical', '-', (149, 154))
130456	25981859	Inhibition of MEK signaling by selumetinib, suppressed TORC1 signaling only in the context of the BRAF-mutant both in vitro and in vivo.	('suppressed', 'NegReg', (44, 54))	('BRAF-mutant', 'Gene', (98, 109))	('TORC1 signaling', 'MPA', (55, 70))	('BRAF-mutant', 'Var', (98, 109))	('MEK signaling', 'Pathway', (14, 27))	('selumetinib', 'Chemical', 'MESH:C517975', (31, 42))
130457	25981859	Inhibition of MEK signaling in BT-40 cells or in xenografts lead to a complete suppression of FANCD2 and conferred hypersensitivity to XRT in BT-40 xenografts without increasing local skin toxicity.	('MEK', 'Pathway', (14, 17))	('suppression', 'NegReg', (79, 90))	('FANCD2', 'Gene', (94, 100))	('skin toxicity', 'Disease', (184, 197))	('skin toxicity', 'Disease', 'MESH:D012871', (184, 197))	('hypersensitivity', 'Disease', (115, 131))	('hypersensitivity', 'Disease', 'MESH:D004342', (115, 131))	('BT-40', 'Chemical', '-', (142, 147))	('Inhibition', 'Var', (0, 10))	('BT-40', 'Chemical', '-', (31, 36))	('local skin toxicity', 'Phenotype', 'HP:0011355', (178, 197))
130458	25981859	Selumetinib suppressed TORC1 signaling in the context of BRAF mutation.	('BRAF', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('TORC1 signaling', 'MPA', (23, 38))	('suppressed', 'NegReg', (12, 22))
130460	25981859	These data suggest the possibility of potentiating the effect of XRT selectively in tumor cells by MEK inhibition in the context of mutant BRAF or maintaining tumor control at lower doses of XRT that would decrease long-term sequelae.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('BRAF', 'Gene', (139, 143))	('MEK', 'Enzyme', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutant', 'Var', (132, 138))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (84, 89))	('potentiating', 'PosReg', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('inhibition', 'NegReg', (103, 113))
130471	25981859	Low-grade gliomas are primarily associated with activation of BRAF through a tandem duplication that results in the KIAA1549-BRAF fusion leading to constitutively activated BRAF or through an activating point mutation of BRAF (predominantly V600E), leading to activation of the MAP kinase pathway.	('BRAF', 'Gene', (221, 225))	('KIAA1549-BRAF', 'Disease', (116, 129))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('activating', 'PosReg', (192, 202))	('V600E', 'Var', (241, 246))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('MAP kinase pathway', 'Pathway', (278, 296))	('tandem duplication', 'Var', (77, 95))	('KIAA1549-BRAF', 'Disease', 'None', (116, 129))	('activation', 'PosReg', (260, 270))	('V600E', 'Mutation', 'rs113488022', (241, 246))	('gliomas', 'Disease', (10, 17))	('BRAF', 'MPA', (173, 177))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
130472	25981859	The KIAA1549-BRAF fusion is largely restricted to juvenile pilocytic astrocytoma (65- 80%) whereas BRAFV600E occurs more frequently in other LGG such as, pleomorphic xanthoastrocytomas (60%), gangliogliomas (20-40%), diffuse firbrillary astrocytomas (8%) and in approximately 10% of high grade astrocytomas.	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (154, 184))	('astrocytomas', 'Disease', (294, 306))	('astrocytomas', 'Disease', 'MESH:D001254', (172, 184))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('BRAFV600E', 'Var', (99, 108))	('pleomorphic xanthoastrocytomas', 'Disease', (154, 184))	('gangliogliomas', 'Disease', 'MESH:D018303', (192, 206))	('astrocytomas', 'Disease', (237, 249))	('astrocytomas', 'Disease', 'MESH:D001254', (294, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (294, 305))	('KIAA1549-BRAF', 'Disease', (4, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (237, 248))	('gangliogliomas', 'Disease', (192, 206))	('astrocytomas', 'Disease', (172, 184))	('BRAFV600E', 'Mutation', 'rs113488022', (99, 108))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('astrocytoma', 'Phenotype', 'HP:0009592', (172, 183))	('astrocytomas', 'Disease', 'MESH:D001254', (237, 249))	('juvenile pilocytic astrocytoma', 'Disease', (50, 80))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('KIAA1549-BRAF', 'Disease', 'None', (4, 17))	('juvenile pilocytic astrocytoma', 'Disease', 'MESH:D001254', (50, 80))
130473	25981859	Thus, activating mutation of BRAF appears to be the most common lesion in intermediate grade astrocytoma.	('BRAF', 'Gene', (29, 33))	('astrocytoma', 'Disease', 'MESH:D001254', (93, 104))	('common', 'Reg', (57, 63))	('activating mutation', 'Var', (6, 25))	('astrocytoma', 'Disease', (93, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))
130474	25981859	Homozygous deletion of the CDKN2A locus is frequent (~70%) in tumors harboring the BRAFV600E mutation.	('BRAFV600E', 'Var', (83, 92))	('BRAFV600E', 'Mutation', 'rs113488022', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CDKN2A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (27, 33))
130475	25981859	Recently, Mistry et al reported that low-grade gliomas that harbor BRAFV600E mutations and CDKN2A deletions are at a higher risk of transforming to high-grade gliomas and represent a distinct subtype of secondary high-grade gliomas in children.	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('CDKN2A', 'Gene', (91, 97))	('CDKN2A', 'Gene', '1029', (91, 97))	('gliomas', 'Disease', (47, 54))	('children', 'Species', '9606', (235, 243))	('gliomas', 'Disease', 'MESH:D005910', (224, 231))	('BRAFV600E', 'Mutation', 'rs113488022', (67, 76))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('gliomas', 'Disease', (224, 231))	('BRAFV600E', 'Gene', (67, 76))	('deletions', 'Var', (98, 107))
130476	25981859	Findings for BRAF mutation, similar to other tumors with activated BRAF (e.g.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BRAF', 'Gene', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mutation', 'Var', (18, 26))
130481	25981859	While FANCD2 deficiency is associated with hypersensitivity to drugs that cross-link DNA, bone marrow stromal cells from FANCD2 deficient mice are hypersensitive to ionizing radiation (XRT), whereas hematopoietic progenitor cells are not.	('hypersensitive', 'Disease', (147, 161))	('hypersensitivity to drugs', 'Phenotype', 'HP:0410323', (43, 68))	('FANCD2', 'Gene', (6, 12))	('FANCD2', 'Gene', (121, 127))	('deficiency', 'Var', (13, 23))	('associated', 'Reg', (27, 37))	('mice', 'Species', '10090', (138, 142))	('hypersensitivity', 'Disease', 'MESH:D004342', (43, 59))	('hypersensitivity', 'Disease', (43, 59))	('hypersensitive', 'Disease', 'MESH:D004342', (147, 161))	('deficient', 'NegReg', (128, 137))	('hypersensitive to ionizing radiation', 'Phenotype', 'HP:0011133', (147, 183))
130484	25981859	Similarly, we reported previously that knockdown of FANCD2 increased the sensitivity of rhabdomyosarcoma cells to XRT.	('FANCD2', 'Gene', (52, 58))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (88, 104))	('rhabdomyosarcoma', 'Disease', (88, 104))	('knockdown', 'Var', (39, 48))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (88, 104))	('sensitivity', 'MPA', (73, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('increased', 'PosReg', (59, 68))
130485	25981859	We also found that both rapamycin and the TOR kinase inhibitor AZD8055 caused the loss of FANCD2 both in vitro and in rhabdomyosarcoma xenografts, and enhanced XRT sensitivity.	('FANCD2', 'Gene', (90, 96))	('enhanced', 'PosReg', (151, 159))	('AZD8055', 'Var', (63, 70))	('AZD8055', 'Chemical', 'MESH:C546624', (63, 70))	('rhabdomyosarcoma xenografts', 'Disease', (118, 145))	('XRT sensitivity', 'MPA', (160, 175))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (118, 134))	('loss', 'NegReg', (82, 86))	('rapamycin', 'Chemical', 'MESH:D020123', (24, 33))	('rhabdomyosarcoma xenografts', 'Disease', 'MESH:D012208', (118, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
130486	25981859	In the course of studies with two patient derived xenografts, we noted that inhibition of MEK by selumetinib, suppressed TORC1 signaling only in the context of the BRAFV600E mutation.	('inhibition', 'NegReg', (76, 86))	('selumetinib', 'Chemical', 'MESH:C517975', (97, 108))	('TORC1 signaling', 'MPA', (121, 136))	('patient', 'Species', '9606', (34, 41))	('MEK', 'Enzyme', (90, 93))	('suppressed', 'NegReg', (110, 120))	('BRAFV600E', 'Var', (164, 173))	('BRAFV600E', 'Mutation', 'rs113488022', (164, 173))
130507	25981859	BRAFV600E regulates TORC1 signaling: We reported previously that the BRAFV600E BT-40 astrocytoma xenograft was highly sensitive to the MEK inhibitor selumetinib, whereas the BT-35 astrocytoma with wild type BRAF was intrinsically resistant to the same treatment.	('sensitive', 'MPA', (118, 127))	('BRAFV600E', 'Var', (69, 78))	('BRAFV600E', 'Mutation', 'rs113488022', (69, 78))	('selumetinib', 'Chemical', 'MESH:C517975', (149, 160))	('BT-40', 'Chemical', '-', (79, 84))	('astrocytoma', 'Disease', 'MESH:D001254', (180, 191))	('BT', 'Chemical', 'MESH:C005465', (174, 176))	('astrocytoma', 'Phenotype', 'HP:0009592', (180, 191))	('astrocytoma', 'Disease', (180, 191))	('astrocytoma', 'Disease', 'MESH:D001254', (85, 96))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('astrocytoma', 'Disease', (85, 96))	('BT', 'Chemical', 'MESH:C005465', (79, 81))	('astrocytoma', 'Phenotype', 'HP:0009592', (85, 96))
130509	25981859	However, in BT-40 xenografts, TORC1 signaling was attenuated as shown by decreased phospho-4EBP1 and phospho-S6 that was also associated with decreased total protein in BT-40 xenografts.	('TORC1 signaling', 'MPA', (30, 45))	('total protein', 'MPA', (152, 165))	('EBP1', 'Gene', (92, 96))	('decreased', 'NegReg', (73, 82))	('EBP1', 'Gene', '4790', (92, 96))	('decreased', 'NegReg', (142, 151))	('BT-40', 'Var', (12, 17))	('attenuated', 'NegReg', (50, 60))	('BT-40', 'Chemical', '-', (12, 17))	('phospho-S6', 'MPA', (101, 111))	('BT-40', 'Chemical', '-', (169, 174))
130516	25981859	In the cell line, inhibition of TORC1 was associated with feedback phosphorylation of AKT (S473).	('inhibition', 'NegReg', (18, 28))	('AKT', 'Gene', (86, 89))	('feedback phosphorylation', 'MPA', (58, 82))	('TORC1', 'Gene', (32, 37))	('S473', 'Var', (91, 95))	('AKT', 'Gene', '207', (86, 89))
130517	25981859	Inhibition of TORC1 signaling was less marked in two cell lines derived from adult glioblastoma with BRAFV600E mutations, AM38 and DBTRG-MG.	('mutations', 'Var', (111, 120))	('BRAFV600E', 'Mutation', 'rs113488022', (101, 110))	('TORC1 signaling', 'MPA', (14, 29))	('BRAFV600E', 'Gene', (101, 110))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('DBTRG-MG', 'CellLine', 'CVCL:1169', (131, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
130521	25981859	We examined whether the response to selumetinib treatment was cytostatic or cytototoxic in the three BRAF-mutant cell lines.	('selumetinib', 'Chemical', 'MESH:C517975', (36, 47))	('BRAF-mutant', 'Gene', (101, 112))	('BRAF-mutant', 'Var', (101, 112))
130525	25981859	These results further differentiate the childhood astrocytoma from the adult glioblastoma cell lines, but also support the conjecture that inhibition of TORC1 signaling by MEK inhibitors in the context of BRAF mutation is required for cell death.	('glioblastoma', 'Disease', (77, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('mutation', 'Var', (210, 218))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('astrocytoma', 'Disease', 'MESH:D001254', (50, 61))	('TORC1 signaling', 'MPA', (153, 168))	('astrocytoma', 'Disease', (50, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))
130527	25981859	We have shown previously that treatment of mice bearing rhabdomyosarcoma xenografts with the TOR kinase inhibitor, AZD8055, or rapamycin, resulted in a downregulation of the DNA damage repair protein FANCD2.	('DNA damage repair protein', 'MPA', (174, 199))	('mice', 'Species', '10090', (43, 47))	('downregulation', 'NegReg', (152, 166))	('FANCD2', 'Gene', (200, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('AZD8055', 'Chemical', 'MESH:C546624', (115, 122))	('rhabdomyosarcoma xenografts', 'Disease', (56, 83))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (56, 72))	('rapamycin', 'Chemical', 'MESH:D020123', (127, 136))	('AZD8055', 'Var', (115, 122))	('rhabdomyosarcoma xenografts', 'Disease', 'MESH:D012208', (56, 83))
130532	25981859	Inhibition of TORC1 has been associated with increased sensitivity to XRT, and it was considered that rapamycin-induced G1 arrest could contribute to the sensitizing effects.	('arrest', 'Disease', (123, 129))	('TORC1', 'Gene', (14, 19))	('increased', 'PosReg', (45, 54))	('sensitivity', 'MPA', (55, 66))	('rapamycin', 'Chemical', 'MESH:D020123', (102, 111))	('Inhibition', 'Var', (0, 10))	('arrest', 'Disease', 'MESH:D006323', (123, 129))
130533	25981859	We also showed that AZD8055 could enhance the effect of XRT, and that FANCD2 was regulated downstream of TORC1 in part by S6K1/2 activity.	('FANCD2', 'Gene', (70, 76))	('effect', 'MPA', (46, 52))	('S6K1/2', 'Gene', (122, 128))	('enhance', 'PosReg', (34, 41))	('AZD8055', 'Var', (20, 27))	('AZD8055', 'Chemical', 'MESH:C546624', (20, 27))	('S6K1/2', 'Gene', '6198;6199', (122, 128))	('XRT', 'MPA', (56, 59))
130549	25981859	Radiation resistance induced by oncogenic Ras appears to be mediated through activation of the PI3K/Akt pathway, as inhibitors of PI3K, but not rapamycin, MEK or p38 were able to selectively radiosensitize in the presence of oncogenic Ras.	('Akt', 'Gene', (100, 103))	('p38', 'Gene', (162, 165))	('activation', 'PosReg', (77, 87))	('inhibitors', 'Var', (116, 126))	('Akt', 'Gene', '207', (100, 103))	('rapamycin', 'Chemical', 'MESH:D020123', (144, 153))	('Radiation resistance', 'CPA', (0, 20))	('radiosensitize', 'NegReg', (191, 205))	('p38', 'Gene', '5594', (162, 165))
130554	25981859	In vitro, inhibition of MEK dramatically reduced clonogenic survival in BT-40c cells, derived from the xenograft, whereas it had less effect on survival in two BRAF(V600E) mutant glioblastoma lines derived from adults.	('V600E', 'Var', (165, 170))	('reduced', 'NegReg', (41, 48))	('V600E', 'SUBSTITUTION', 'None', (165, 170))	('clonogenic survival', 'CPA', (49, 68))	('glioblastoma', 'Disease', (179, 191))	('MEK', 'Gene', (24, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('BT-40', 'Chemical', '-', (72, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('inhibition', 'Var', (10, 20))
130556	25981859	In mice, conditional knockout of mTOR results in the loss of the Fanconi anemia group D2 (FANCD2) mRNA and protein expression in hematopoietic stem and progenitor cells.	('loss of the Fanconi anemia', 'Disease', 'MESH:D005199', (53, 79))	('loss of the Fanconi anemia', 'Disease', (53, 79))	('mice', 'Species', '10090', (3, 7))	('mTOR', 'Gene', (33, 37))	('knockout', 'Var', (21, 29))	('anemia', 'Phenotype', 'HP:0001903', (73, 79))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (65, 79))
130557	25981859	Consistent with these results, inhibition of TOR kinase by AZD8055 or TORC1 signaling by rapamycin resulted in a loss of FANCD2 in sarcoma xenografts or cell lines, resulting in increased sensitivity to ionizing radiation.	('inhibition', 'NegReg', (31, 41))	('FANCD2', 'Gene', (121, 127))	('TORC1 signaling', 'MPA', (70, 85))	('AZD8055', 'Var', (59, 66))	('AZD8055', 'Chemical', 'MESH:C546624', (59, 66))	('loss', 'NegReg', (113, 117))	('sarcoma xenografts', 'Disease', 'MESH:D012509', (131, 149))	('rapamycin', 'Chemical', 'MESH:D020123', (89, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('sarcoma xenografts', 'Disease', (131, 149))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (178, 221))	('sensitivity to ionizing radiation', 'MPA', (188, 221))	('increased', 'PosReg', (178, 187))
130574	25981859	Selumetinib was shown to reduce levels of vascular endothelial growth factor (VEGF) that protects endothelial cells from lethal effects of radiation, and we have shown that suppression of TORC1 signaling results in reduced tumor cell-derived VEGF, at least in some pediatric cancer lines.	('suppression', 'Var', (173, 184))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('vascular endothelial growth factor', 'Gene', (42, 76))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('TORC1', 'MPA', (188, 193))	('VEGF', 'Gene', (242, 246))	('VEGF', 'Gene', (78, 82))	('reduced', 'NegReg', (215, 222))	('vascular endothelial growth factor', 'Gene', '7422', (42, 76))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('VEGF', 'Gene', '7422', (242, 246))	('VEGF', 'Gene', '7422', (78, 82))	('cancer', 'Disease', (275, 281))
130576	25981859	One concern over combining MEK inhibition with XRT is the potential to increase normal tissue toxicity, in this case brain tissue, causing enhanced radiation-induced necrosis.	('necrosis', 'Disease', (166, 174))	('MEK', 'Enzyme', (27, 30))	('increase', 'PosReg', (71, 79))	('inhibition', 'Var', (31, 41))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('enhanced', 'PosReg', (139, 147))	('necrosis', 'Disease', 'MESH:D009336', (166, 174))	('toxicity', 'Disease', (94, 102))
130578	25981859	Conceptually, suppression of TORC1 signaling resulting in downregulation of FANCD2 should be context specific, occurring only in mutant BRAF tumor cells when MEK is inhibited.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('FANCD2', 'Gene', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('suppression', 'NegReg', (14, 25))	('tumor', 'Disease', (141, 146))	('downregulation', 'NegReg', (58, 72))	('TORC1 signaling', 'MPA', (29, 44))	('mutant', 'Var', (129, 135))
130581	25981859	As children with low-grade tumors often receive XRT either upfront (in older patients) or after recurrence, and many harbor BRAF aberrations, suppression of MEK in the context of activated BRAF may selectively sensitize tumor tissue to XRT, allowing more effective tumor control, or allowing reduced doses of XRT thus reducing radiation-induced late effects.	('more', 'PosReg', (250, 254))	('tumor', 'Disease', (220, 225))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('sensitize', 'Reg', (210, 219))	('children', 'Species', '9606', (3, 11))	('MEK', 'Gene', (157, 160))	('suppression', 'NegReg', (142, 153))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (265, 270))	('patients', 'Species', '9606', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumors', 'Disease', (27, 33))	('aberrations', 'Var', (129, 140))
130582	25981859	In addition, these data also support the use of a selumetinib as a radiosensitizer at diagnosis in the small subset of children with high-grade glioma who harbor a BRAF V600E mutations.	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('V600E', 'Mutation', 'rs113488022', (169, 174))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('V600E', 'Var', (169, 174))	('selumetinib', 'Chemical', 'MESH:C517975', (50, 61))	('children', 'Species', '9606', (119, 127))	('glioma', 'Disease', (144, 150))	('BRAF', 'Gene', (164, 168))
130595	33679596	Despite the inherent limitations associated with imaging reconstruction algorithms, DTI (Diffusion Tensor Imaging) has recently been included in the presurgical glioma workup to aid in the mapping of functional pathways and to prevent extensive damage associated with radical resection.	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('as', 'Gene', '112935892', (33, 35))	('as', 'Gene', '112935892', (252, 254))	('as', 'Gene', '112935892', (116, 118))	('DTI', 'Var', (84, 87))	('glioma', 'Disease', (161, 167))	('functional pathways', 'Pathway', (200, 219))
130687	33679596	With respect to naming abilities, a study involving 99 patients with glioma showed that noun naming deficits depended on damage to parts of the sagittal stratum (including the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus), in addition to cortical lesions.	('glioma', 'Disease', (69, 75))	('naming abilities', 'Phenotype', 'HP:0002463', (16, 32))	('naming deficits', 'Phenotype', 'HP:0002463', (93, 108))	('damage', 'Var', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('fasciculus and the inferior longitudinal fasciculus', 'Disease', 'MESH:D004204', (202, 253))	('patients', 'Species', '9606', (55, 63))	('deficits', 'NegReg', (100, 108))	('noun naming', 'MPA', (88, 99))
130733	32860002	Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors.	('TRK', 'Gene', (132, 135))	('TRK', 'Gene', (84, 87))	('NTRK1', 'Gene', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('fusions Fusions', 'Var', (136, 151))	('TRK', 'Gene', (28, 31))	('TRK', 'Gene', '4914', (181, 184))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (43, 61))	('TRK', 'Gene', '4914', (163, 166))	('NTRK3', 'Gene', '4916', (180, 185))	('TRK', 'Gene', '4914', (132, 135))	('TRK', 'Gene', (170, 173))	('TRK', 'Gene', '4914', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NTRK2', 'Gene', '4915', (169, 174))	('NTRK3', 'Gene', (180, 185))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (235, 256))	('TRK', 'Gene', '4914', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('mesenchymal neoplasms', 'Disease', (235, 256))	('mesenchymal tumors', 'Disease', (43, 61))	('neoplasm', 'Phenotype', 'HP:0002664', (247, 255))	('TRK', 'Gene', '4914', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('neoplasms', 'Phenotype', 'HP:0002664', (247, 256))	('NTRK2', 'Gene', (169, 174))	('malignant tumors', 'Disease', (287, 303))	('malignant tumors', 'Disease', 'MESH:D009369', (287, 303))	('TRK', 'Gene', (181, 184))	('TRK', 'Gene', (163, 166))	('NTRK1', 'Gene', '4914', (162, 167))	('Fusions', 'Var', (144, 151))
130746	32860002	The presence of NTRK1-3 fusions has been identified as an agnostic marker for treatment response with a selective small-molecule inhibitor of the TRK kinases (TKI) in solid tumors.	('TRK', 'Gene', (146, 149))	('TRK', 'Gene', '4914', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('TRK', 'Gene', (17, 20))	('TKI', 'Gene', (159, 162))	('TRK', 'Gene', '4914', (17, 20))	('NTRK1-3', 'Gene', (16, 23))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('NTRK1-3', 'Gene', '4914;4915;4916', (16, 23))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('fusions', 'Var', (24, 31))
130747	32860002	The ETV6-NTRK3 gene fusion has been described in sporadic solid tumors, including congenital infantile fibrosarcoma (IFS), congenital "cellular" mesoblastic nephroma, secretory breast carcinoma, and carcinoma of the salivary gland (mammary analog secretory carcinoma) in more than 90% of cases and fusion detection has been used as diagnostic confirmation.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('fusion', 'Var', (20, 26))	('ETV6', 'Gene', '2120', (4, 8))	('carcinoma', 'Disease', (257, 266))	('carcinoma', 'Disease', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma of the salivary', 'Disease', (199, 224))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (103, 115))	('tumors', 'Disease', (64, 70))	('carcinoma of the salivary', 'Disease', 'MESH:D012468', (199, 224))	('breast carcinoma', 'Disease', 'MESH:D001943', (177, 193))	('carcinoma', 'Disease', (199, 208))	('carcinoma of the salivary gland', 'Phenotype', 'HP:0100684', (199, 230))	('carcinoma', 'Disease', 'MESH:D009369', (257, 266))	('congenital infantile fibrosarcoma', 'Disease', 'MESH:D005354', (82, 115))	('sporadic', 'Disease', (49, 57))	('described', 'Reg', (36, 45))	('carcinoma', 'Disease', 'MESH:D009369', (184, 193))	('IFS', 'Chemical', '-', (117, 120))	('ETV6', 'Gene', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('nephroma', 'Disease', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('carcinoma', 'Disease', 'MESH:D009369', (199, 208))	('congenital infantile fibrosarcoma', 'Disease', (82, 115))	('breast carcinoma', 'Phenotype', 'HP:0003002', (177, 193))	('breast carcinoma', 'Disease', (177, 193))	('NTRK3', 'Gene', '4916', (9, 14))	('mesoblastic nephroma', 'Phenotype', 'HP:0100881', (145, 165))	('NTRK3', 'Gene', (9, 14))	('nephroma', 'Disease', 'MESH:D018201', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
130750	32860002	In addition, NTRK fusions were detected in other more common cancer types, such as papillary thyroid carcinoma, gastrointestinal stromal tumor (GIST), gliomas, non-small cell lung cancer (NSCLC), colorectal carcinoma (most frequently found in MSI-high carcinoma associated with MLH1 promoter hypermethylation), as well as malignant melanomas, uterine sarcomas, and pancreatic adenocarcinomas, however in less than 1% of all solid tumors overall.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (83, 110))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (430, 436))	('lung cancer', 'Disease', (175, 186))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D000230', (365, 391))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (351, 358))	('colorectal carcinoma', 'Disease', (196, 216))	('MLH1', 'Gene', '4292', (278, 282))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (365, 391))	('TRK', 'Gene', '4914', (14, 17))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (196, 216))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (112, 142))	('tumors', 'Disease', 'MESH:D009369', (430, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('pancreatic adenocarcinomas', 'Disease', (365, 391))	('malignant melanomas', 'Disease', 'MESH:D008545', (322, 341))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (112, 142))	('malignant melanomas', 'Disease', (322, 341))	('cancer', 'Disease', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (381, 390))	('NSCLC', 'Disease', (188, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('promoter hypermethylation', 'Var', (283, 308))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('gastrointestinal stromal tumor', 'Disease', (112, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gliomas', 'Disease', (151, 158))	('MSI-high carcinoma', 'Disease', 'MESH:D009369', (243, 261))	('sarcomas', 'Disease', 'MESH:D012509', (351, 359))	('MSI-high carcinoma', 'Disease', (243, 261))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (83, 110))	('tumors', 'Phenotype', 'HP:0002664', (430, 436))	('GIST', 'Phenotype', 'HP:0100723', (144, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (351, 359))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('sarcomas', 'Disease', (351, 359))	('malignant melanomas', 'Phenotype', 'HP:0002861', (322, 341))	('MLH1', 'Gene', (278, 282))	('TRK', 'Gene', (14, 17))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('papillary thyroid carcinoma', 'Disease', (83, 110))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))
130753	32860002	At the moment, RNA-based NGS screening approaches are the most reliable method to detect NTRK1-3 fusions also with unknown partners.	('NTRK1-3', 'Gene', '4914;4915;4916', (89, 96))	('NTRK1-3', 'Gene', (89, 96))	('fusions', 'Var', (97, 104))
130774	32860002	IHC positive cases with available FFPE material were sent for RNA-based analysis with Archer FusionPlex Sarcoma Panel to assess specific NTRK1, NTRK2, and NTRK3 rearrangements for the production of NTRK fusion transcripts.	('NTRK1', 'Gene', (137, 142))	('NTRK3', 'Gene', '4916', (155, 160))	('NTRK2', 'Gene', '4915', (144, 149))	('Sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Archer FusionPlex Sarcoma', 'Disease', (86, 111))	('rearrangements', 'Var', (161, 175))	('NTRK3', 'Gene', (155, 160))	('NTRK2', 'Gene', (144, 149))	('Archer FusionPlex Sarcoma', 'Disease', 'MESH:D012509', (86, 111))	('TRK', 'Gene', (199, 202))	('TRK', 'Gene', '4914', (199, 202))	('NTRK1', 'Gene', '4914', (137, 142))	('TRK', 'Gene', (145, 148))	('TRK', 'Gene', '4914', (145, 148))	('TRK', 'Gene', (138, 141))	('TRK', 'Gene', '4914', (138, 141))	('TRK', 'Gene', (156, 159))	('TRK', 'Gene', '4914', (156, 159))
130803	32860002	Staining for ALK, CD68 and CD163 were observed, whereas CD34, EMA, SMA, S100, and SOX10 were negative.	('ALK', 'Gene', (13, 16))	('SOX10', 'Gene', (82, 87))	('CD163', 'Gene', '9332', (27, 32))	('SOX10', 'Gene', '6663', (82, 87))	('SMA', 'Gene', '6606', (67, 70))	('SMA', 'Gene', (67, 70))	('CD163', 'Gene', (27, 32))	('ALK', 'Gene', '238', (13, 16))	('CD68', 'Var', (18, 22))	('S100', 'Gene', (72, 76))	('S100', 'Gene', '6271', (72, 76))
130804	32860002	Based on the unusual morphology for benign fibrous histiocytoma, the ALK expression by IHC and the fact that "epithelioid fibrous histiocytoma (EFH)" commonly demonstrate ALK fusions, NGS testing was performed and revealed IRF2BP2-NTRK1 fusion (Fig.	('NTRK1', 'Gene', '4914', (231, 236))	('IRF2BP2', 'Gene', (223, 230))	('benign fibrous histiocytoma', 'Disease', (36, 63))	('ALK', 'Gene', '238', (69, 72))	('IRF2BP2', 'Gene', '359948', (223, 230))	('fusion', 'Var', (237, 243))	('NTRK1', 'Gene', (231, 236))	('benign fibrous histiocytoma', 'Disease', 'MESH:D018219', (36, 63))	('ALK', 'Gene', (171, 174))	('fibrous histiocytoma', 'Disease', 'MESH:D018219', (43, 63))	('histiocytoma', 'Phenotype', 'HP:0012315', (130, 142))	('ALK', 'Gene', (69, 72))	('fibrous histiocytoma', 'Disease', (122, 142))	('ALK', 'Gene', '238', (171, 174))	('fibrous histiocytoma', 'Disease', 'MESH:D018219', (122, 142))	('histiocytoma', 'Phenotype', 'HP:0012315', (51, 63))
130813	32860002	Molecular analysis showed TMB3-NTRK1 fusion (Fig.	('fusion', 'Var', (37, 43))	('NTRK1', 'Gene', '4914', (31, 36))	('NTRK1', 'Gene', (31, 36))
130819	32860002	A growing body of evidence recognizes the oncogenic role of chromosomal translocations involving NTRK genes found infrequently across a wide range of solid neoplasms.	('TRK', 'Gene', (98, 101))	('neoplasms', 'Disease', 'MESH:D009369', (156, 165))	('TRK', 'Gene', '4914', (98, 101))	('neoplasms', 'Disease', (156, 165))	('neoplasm', 'Phenotype', 'HP:0002664', (156, 164))	('chromosomal translocations', 'Var', (60, 86))	('neoplasms', 'Phenotype', 'HP:0002664', (156, 165))
130824	32860002	Recently, the locally aggressive LFLNT has been described, a tumor entity habouring NTRK-fusions, with similar morphology as dermatofibrosarcoma protuberans and co-expression of CD34, S100 and pan-TRK.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('TRK', 'Gene', (197, 200))	('locally aggressive LFLNT', 'Disease', (14, 38))	('S100', 'Gene', '6271', (184, 188))	('TRK', 'Gene', '4914', (197, 200))	('TRK', 'Gene', (85, 88))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (132, 144))	('TRK', 'Gene', '4914', (85, 88))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (125, 156))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('dermatofibrosarcoma protuberans', 'Disease', (125, 156))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('S100', 'Gene', (184, 188))	('tumor', 'Disease', (61, 66))	('CD34', 'Var', (178, 182))
130832	32860002	The principal mechanism of NTRK1/2/3 gene fusions includes a fusion of the 3  region of the NTRK gene containing the NTRK kinase domain with the critical tyrosine docking site with a 5  fusion partner gene which is highly variable.	('TRK', 'Gene', (118, 121))	('tyrosine', 'Chemical', 'MESH:D014443', (154, 162))	('TRK', 'Gene', '4914', (93, 96))	('TRK', 'Gene', '4914', (118, 121))	('NTRK1/2/3', 'Gene', '4914;4915;4916', (27, 36))	('fusion', 'Interaction', (61, 67))	('NTRK1/2/3', 'Gene', (27, 36))	('TRK', 'Gene', (28, 31))	('TRK', 'Gene', (93, 96))	('fusions', 'Var', (42, 49))	('TRK', 'Gene', '4914', (28, 31))
130834	32860002	Various molecular assays can detect NTRK rearrangements.	('rearrangements', 'Var', (41, 55))	('TRK', 'Gene', (37, 40))	('TRK', 'Gene', '4914', (37, 40))
130842	32860002	Tumors harboring NTRK1 rearrangements usually show strong, diffuse cytoplasmic staining.	('NTRK1', 'Gene', (17, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('rearrangements', 'Var', (23, 37))	('NTRK1', 'Gene', '4914', (17, 22))
130843	32860002	Nuclear staining (at least focal) has been described in tumors harboring NTRK3 fusions and may be used as a surrogate of the presence of NTRK3 fusions, however, the staining in these tumors can be weak.	('NTRK3', 'Gene', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NTRK3', 'Gene', '4916', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('Nuclear staining', 'MPA', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('NTRK3', 'Gene', (73, 78))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('NTRK3', 'Gene', '4916', (137, 142))	('tumors', 'Disease', (183, 189))	('fusions', 'Var', (79, 86))
130848	32860002	False-positive staining with TRK antibodys can occur in non-NTRK fused tumors, mainly tumors with neural and smooth muscle differentiation, and some others namely: GIST, leiomyosarcoma, glioblastoma, neuroblastoma, a primitive myxoid mesenchymal tumor of infancy, synovial sarcoma, Ewing sarcoma, and fibrous hamartoma of infancy, SFT, soft tissue round cell sarcomas with YWHAE rearrangements, BCOR internal tandem duplications (ITD) and BCOR-CCNB3 fusions and clear cell sarcomas of the kidney (another BCOR family tumor) as well as ossifying fibromyxoid tumors with ZC3H7B-BCOR fusion.	('neuroblastoma', 'Disease', (200, 213))	('TRK', 'Gene', (29, 32))	('TRK', 'Gene', (61, 64))	('CCNB3', 'Gene', (444, 449))	('Ewing sarcoma', 'Disease', (282, 295))	('neuroblastoma', 'Disease', 'MESH:D009447', (200, 213))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (264, 280))	('fibrous hamartoma', 'Disease', 'MESH:D006222', (301, 318))	('leiomyosarcoma', 'Disease', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (557, 562))	('CCNB3', 'Gene', '85417', (444, 449))	('ZC3H7B', 'Gene', (569, 575))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (535, 563))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('BCOR', 'Gene', '54880', (439, 443))	('fusions', 'Var', (450, 457))	('TRK', 'Gene', '4914', (29, 32))	('YWHAE', 'Gene', (373, 378))	('tumor', 'Disease', (557, 562))	('sarcomas', 'Disease', 'MESH:D012509', (473, 481))	('TRK', 'Gene', '4914', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (557, 563))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('BCOR', 'Gene', '54880', (505, 509))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('BCOR', 'Gene', (395, 399))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (282, 295))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (282, 295))	('tumor', 'Disease', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (517, 522))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (557, 563))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', (86, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (473, 481))	('sarcomas of the kidney', 'Disease', 'MESH:D012509', (473, 495))	('glioblastoma', 'Disease', (186, 198))	('sarcomas', 'Disease', (473, 481))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (264, 280))	('sarcomas of the kidney', 'Disease', (473, 495))	('sarcoma', 'Phenotype', 'HP:0100242', (473, 480))	('sarcomas', 'Disease', 'MESH:D012509', (359, 367))	('BCOR', 'Gene', (576, 580))	('sarcomas', 'Disease', (359, 367))	('tumors', 'Phenotype', 'HP:0002664', (557, 563))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (170, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (200, 213))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (359, 366))	('synovial sarcoma', 'Disease', (264, 280))	('BCOR', 'Gene', (439, 443))	('fibrous hamartoma', 'Disease', (301, 318))	('GIST', 'Phenotype', 'HP:0100723', (164, 168))	('YWHAE', 'Gene', '7531', (373, 378))	('tumor', 'Disease', (517, 522))	('BCOR', 'Gene', '54880', (395, 399))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('fibrous hamartoma', 'Phenotype', 'HP:0100882', (301, 318))	('tumor', 'Disease', 'MESH:D009369', (517, 522))	('BCOR', 'Gene', (505, 509))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (71, 76))	('BCOR', 'Gene', '54880', (576, 580))	('hamartoma', 'Phenotype', 'HP:0010566', (309, 318))	('tumor', 'Phenotype', 'HP:0002664', (557, 562))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (359, 367))	('ZC3H7B', 'Gene', '23264', (569, 575))	('ossifying fibromyxoid tumors', 'Disease', (535, 563))
130857	32860002	To date, most of the fusions described in mesenchymal neoplasms involve NTRK1 and NTRK3 genes and include different fusion partner genes, most common being ETV6, LMNA, and TPM3.	('LMNA', 'Gene', '4000', (162, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (54, 63))	('mesenchymal neoplasms', 'Disease', (42, 63))	('NTRK1', 'Gene', (72, 77))	('TPM3', 'Gene', '7170', (172, 176))	('NTRK3', 'Gene', '4916', (82, 87))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (42, 63))	('ETV6', 'Gene', '2120', (156, 160))	('ETV6', 'Gene', (156, 160))	('fusions', 'Var', (21, 28))	('LMNA', 'Gene', (162, 166))	('NTRK1', 'Gene', '4914', (72, 77))	('neoplasm', 'Phenotype', 'HP:0002664', (54, 62))	('TPM3', 'Gene', (172, 176))	('NTRK3', 'Gene', (82, 87))
130877	32358581	Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth.	('glioma', 'Disease', (194, 200))	('Neurofibromatosis-1', 'Gene', '4763', (158, 177))	('low-grade', 'Var', (184, 193))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (158, 175))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('Neurofibromatosis-1', 'Gene', (158, 177))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('mouse', 'Species', '10090', (43, 48))	('human', 'Species', '9606', (60, 65))
130878	32358581	NF1-mutant human and mouse brain neurons elaborate midkine to activate naive CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival.	('CD8', 'Gene', (77, 80))	('induces', 'Reg', (113, 120))	('CD8', 'Gene', '925', (77, 80))	('human', 'Species', '9606', (11, 16))	('mouse', 'Species', '10090', (21, 26))	('NF1-mutant', 'Gene', (0, 10))	('NF1-mutant', 'Var', (0, 10))
130896	32358581	We demonstrate that human and mouse NF1-mutant neurons produce midkine to activate T cells, which in turn leads to increased T cell Ccl4 secretion and the priming of microglia to elaborate Ccl5 to maintain LGG cell growth.	('T cells', 'CPA', (83, 90))	('human', 'Species', '9606', (20, 25))	('T cell Ccl4 secretion', 'MPA', (125, 146))	('increased', 'PosReg', (115, 124))	('NF1-mutant', 'Gene', (36, 46))	('NF1-mutant', 'Var', (36, 46))	('elaborate Ccl5', 'MPA', (179, 193))	('increased T cell', 'Phenotype', 'HP:0100828', (115, 131))	('activate', 'PosReg', (74, 82))	('mouse', 'Species', '10090', (30, 35))	('LGG cell growth', 'CPA', (206, 221))
130922	32358581	For these studies, we leveraged both human-induced pluripotent stem cells (hiPSCs) harboring actual NF1 patient germline NF1 gene mutations, as well as Nf1-mutant mice.	('mutations', 'Var', (130, 139))	('patient', 'Species', '9606', (104, 111))	('NF1', 'Gene', (100, 103))	('human', 'Species', '9606', (37, 42))	('mice', 'Species', '10090', (163, 167))	('NF1', 'Gene', (121, 124))
130923	32358581	Human neurons were generated from isogenic hiPSCs either heterozygous (NF1-het) or homozygous (NF1-null) for two NF1 patient germline NF1 gene mutations [c.2041C>T and c.6576C>T] using established protocols.	('Human', 'Species', '9606', (0, 5))	('c.6576C>T]', 'Var', (168, 178))	('c.6576C>T', 'Mutation', 'rs758917402', (168, 177))	('NF1', 'Gene', (134, 137))	('patient', 'Species', '9606', (117, 124))	('c.2041C>T', 'Mutation', 'rs768638173', (154, 163))	('[c.2041C>T', 'Var', (153, 163))
130931	32358581	For these experiments, we stimulated CD3+ T cells with either MDK or CSF-2 at the concentrations measured in the CM of heterozygous NF1-mutant hiPSC-derived neurons (~50 ng ml-1 MDK, 200 pg ml-1, CSF-2), as seen in patients with NF1.	('CD3', 'Gene', '12503', (37, 40))	('patients', 'Species', '9606', (215, 223))	('NF1-mutant', 'Gene', (132, 142))	('NF1-mutant', 'Var', (132, 142))	('CD3', 'Gene', (37, 40))
130934	32358581	To determine whether MDK mediates hiPSC-derived neuron CM to increase T cell Ccl4 release, T cells were incubated with CM collected from control and heterozygous NF1-mutant (c.2041C>T and c.6576C>T) hiPSC-derived neurons.	('c.6576C>T', 'Mutation', 'rs758917402', (188, 197))	('T cell Ccl4 release', 'MPA', (70, 89))	('increase T cell', 'Phenotype', 'HP:0100828', (61, 76))	('c.6576C>T', 'Var', (188, 197))	('increase', 'PosReg', (61, 69))	('c.2041C>T', 'Var', (174, 183))	('c.2041C>T', 'Mutation', 'rs768638173', (174, 183))
130935	32358581	Treatment with the CM of c.2041C>T and c.6576C>T NF1-mutant hiPSC-neurons increased T cell Ccl4 production (Fig.	('NF1-mutant', 'Gene', (49, 59))	('c.6576C>T', 'Var', (39, 48))	('NF1-mutant', 'Var', (49, 59))	('c.2041C>T', 'Mutation', 'rs768638173', (25, 34))	('T cell Ccl4 production', 'MPA', (84, 106))	('increased', 'PosReg', (74, 83))	('increased T cell', 'Phenotype', 'HP:0100828', (74, 90))	('c.6576C>T', 'Mutation', 'rs758917402', (39, 48))	('c.2041C>T', 'Var', (25, 34))
130941	32358581	2a), optic nerves from Nf1+/- and Nf1 OPG mice exhibited higher levels of Mdk transcript expression (Fig.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('Nf1 OPG', 'Var', (34, 41))	('Mdk', 'Gene', '17242', (74, 77))	('Nf1+/-', 'Var', (23, 29))	('higher', 'PosReg', (57, 63))	('mice', 'Species', '10090', (42, 46))	('Mdk', 'Gene', (74, 77))
130948	32358581	Lrp1-neutralizing antibodies inhibited the ability of both MDK and hiPSC NF1-mutant neuron CM to increase T cell Ccl4 expression (Fig.	('increase T cell', 'Phenotype', 'HP:0100828', (97, 112))	('inhibited', 'NegReg', (29, 38))	('increase', 'PosReg', (97, 105))	('NF1-mutant', 'Var', (73, 83))	('Lrp1', 'Gene', (0, 4))	('Lrp1', 'Gene', '16971', (0, 4))	('T cell Ccl4 expression', 'MPA', (106, 128))	('hiPSC NF1-mutant', 'Gene', (67, 83))
130954	32358581	Importantly, Lrp1 inhibition increased phosphorylated NFAT1S54 levels and blocked the nuclear translocation of NFAT1 in the setting of MDK exposure (Fig.	('Lrp1', 'Gene', (13, 17))	('NFAT1', 'Gene', '18019', (54, 59))	('NFAT1', 'Gene', (54, 59))	('nuclear translocation', 'MPA', (86, 107))	('blocked', 'NegReg', (74, 81))	('increased', 'PosReg', (29, 38))	('Lrp1', 'Gene', '16971', (13, 17))	('NFAT1', 'Gene', '18019', (111, 116))	('phosphorylated', 'MPA', (39, 53))	('NFAT1', 'Gene', (111, 116))	('inhibition', 'Var', (18, 28))
130958	32358581	Moreover, MDK-induced T cell Ccl4 production was reduced following treatment with the FK506 and cyclosporin (calcineurin inhibitors; Fig.	('FK506', 'Var', (86, 91))	('reduced', 'NegReg', (49, 56))	('T cell Ccl4 production', 'MPA', (22, 44))	('FK506', 'Chemical', 'MESH:D016559', (86, 91))	('cyclosporin', 'Chemical', 'MESH:D016572', (96, 107))
130959	32358581	FK506 treatment also inhibited hiPSC-derived neuron CM induction of T cell Ccl4 production (Fig.	('T cell Ccl4 production', 'MPA', (68, 90))	('inhibited', 'NegReg', (21, 30))	('FK506', 'Chemical', 'MESH:D016559', (0, 5))	('FK506', 'Var', (0, 5))
130966	32358581	Similar to the optic nerves, more CD3+ T cells were observed in the meningeal space of OPG mice relative to controls (Fig.	('mice', 'Species', '10090', (91, 95))	('more', 'PosReg', (29, 33))	('CD3', 'Gene', (34, 37))	('CD3', 'Gene', '12503', (34, 37))	('OPG', 'Var', (87, 90))	('P', 'Chemical', 'MESH:D010758', (88, 89))	('S', 'Chemical', 'MESH:D013455', (0, 1))
130992	32358581	Second, because the stromal (T cells and microglia) cells in both murine and human NF1-OPG are heterozygous for a germline NF1 gene mutation, we also examined the ability of Nf1+/- T cells and microglia to interact and produce Ccl5.	('interact', 'Interaction', (206, 214))	('examined', 'Reg', (150, 158))	('NF1', 'Gene', (123, 126))	('murine', 'Species', '10090', (66, 72))	('mutation', 'Var', (132, 140))	('P', 'Chemical', 'MESH:D010758', (88, 89))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('human', 'Species', '9606', (77, 82))
130997	32358581	Based on prior studies demonstrating that Ccl5 is necessary for murine Nf1 OPG growth in vivo and operates to control glioblastoma cell growth by inhibiting apoptosis, we next sought to determine whether Ccl5 increases the survival of cancer stem cells from murine Nf1 optic gliomas (optic glioma stem cells; o-GSCs).	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('apoptosis', 'CPA', (157, 166))	('optic gliomas', 'Disease', (269, 282))	('murine', 'Species', '10090', (64, 70))	('survival', 'CPA', (223, 231))	('P', 'Chemical', 'MESH:D010758', (76, 77))	('optic gliomas', 'Phenotype', 'HP:0009734', (269, 282))	('increases', 'PosReg', (209, 218))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('optic glioma', 'Disease', (284, 296))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('optic glioma', 'Disease', 'MESH:D020339', (269, 281))	('murine', 'Species', '10090', (258, 264))	('inhibiting', 'NegReg', (146, 156))	('gliomas', 'Phenotype', 'HP:0009733', (275, 282))	('optic glioma', 'Disease', 'MESH:D020339', (284, 296))	('glioma', 'Phenotype', 'HP:0009733', (290, 296))	('optic gliomas', 'Disease', 'MESH:D020339', (269, 282))	('optic glioma', 'Phenotype', 'HP:0009734', (269, 281))	('Nf1', 'Var', (265, 268))	('optic glioma', 'Phenotype', 'HP:0009734', (284, 296))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('cancer', 'Disease', (235, 241))	('glioblastoma', 'Disease', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('o-GSCs', 'Chemical', '-', (309, 315))
131006	32358581	We have previously shown that CD44 is the CCL5 receptor on Nf1-deficient high-grade glioma cells.	('CD44', 'Var', (30, 34))	('glioma', 'Disease', (84, 90))	('Nf1-deficient', 'Gene', (59, 72))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
131008	32358581	Second, following Cd44 knockdown in o-GSCs, Ccl5 no longer inhibited o-GSC death (Fig.	('S', 'Chemical', 'MESH:D013455', (72, 73))	('death', 'Disease', (75, 80))	('o-GSCs', 'Chemical', '-', (36, 42))	('knockdown', 'Var', (23, 32))	('inhibited', 'NegReg', (59, 68))	('o-GSC', 'Chemical', '-', (36, 41))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('Cd44', 'Gene', '12505', (18, 22))	('o-GSC', 'Chemical', '-', (69, 74))	('Cd44', 'Gene', (18, 22))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('death', 'Disease', 'MESH:D003643', (75, 80))
131013	32358581	A similar correlation between high tumor CCL5 expression and reduced progression-free survival was observed in the one dataset with sufficient numbers of samples for analysis; Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('S', 'Chemical', 'MESH:D013455', (176, 177))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('progression-free survival', 'CPA', (69, 94))	('tumor', 'Disease', (35, 40))	('high', 'Var', (30, 34))	('expression', 'MPA', (46, 56))	('reduced', 'NegReg', (61, 68))	('CCL5', 'Gene', (41, 45))
131016	32358581	Moreover, we demonstrate that NF1-mutant neurons support glioma growth by producing MDK, which activates T cells to produce Ccl4, a cytokine that induces microglia to express a critical glioma growth factor (Ccl5) (Fig.	('NF1-mutant', 'Gene', (30, 40))	('NF1-mutant', 'Var', (30, 40))	('glioma growth', 'Disease', (186, 199))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('glioma growth', 'Disease', 'MESH:D005910', (186, 199))	('support', 'PosReg', (49, 56))	('glioma growth', 'Disease', 'MESH:D005910', (57, 70))	('glioma growth', 'Disease', (57, 70))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
131026	32358581	These tightly regulated interactions are not only essential for normal brain development, during which neuronal complement (C1q) expression triggers microglia-mediated synaptic pruning, but can be subverted to drive nervous system disease progression in the setting of peripheral nerve injury and neurodegenerative disorders.	('nervous system disease', 'Disease', (216, 238))	('nervous system disease', 'Phenotype', 'HP:0000707', (216, 238))	('C1q', 'Gene', (124, 127))	('C1q', 'Gene', '12259', (124, 127))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (297, 324))	('expression', 'Var', (129, 139))	('nerve injury and neurodegenerative disorders', 'Disease', 'MESH:D019636', (280, 324))	('triggers', 'Reg', (140, 148))	('microglia-mediated synaptic pruning', 'CPA', (149, 184))	('nervous system disease', 'Disease', 'MESH:D009422', (216, 238))
131028	32358581	Our finding that NF1-mutant mouse and human neurons increase their expression of MDK, which operates to activate T cells through NFAT-1 signaling, also expands the role of neurons as immune system regulators.	('NFAT-1', 'Gene', (129, 135))	('mouse', 'Species', '10090', (28, 33))	('human', 'Species', '9606', (38, 43))	('increase', 'PosReg', (52, 60))	('NF1-mutant', 'Gene', (17, 27))	('expression', 'MPA', (67, 77))	('NFAT-1', 'Gene', '4773', (129, 135))	('NF1-mutant', 'Var', (17, 27))	('MDK', 'Gene', (81, 84))
131035	32358581	For example, pediatric LGG exhibit higher levels of T cell infiltration relative to their malignant counterparts, while CD4+ and Foxp3+ T cell glioma content correlated with increased tumor progression.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('CD4+', 'Var', (120, 124))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('Foxp3', 'Gene', '20371', (129, 134))	('glioma', 'Disease', (143, 149))	('Foxp3', 'Gene', (129, 134))	('higher', 'PosReg', (35, 41))	('increased', 'PosReg', (174, 183))	('T cell infiltration', 'MPA', (52, 71))
131052	32358581	All mice, including Nf1+/- mice (neomycin sequence insertion within exon 31 of the murine Nf1 gene), Nf1flox/mut; GFAP-Cre (OPG) mice (Nf1+/- mice with somatic Nf1 gene inactivation in neuroglial progenitors at E15.5) and Nf1flox/flox mice (controls), were maintained on a strict C57BL/6 background and used in accordance with an approved Animal Studies Committee protocol at Washington University.	('neomycin', 'Chemical', 'MESH:D009355', (33, 41))	('mice', 'Species', '10090', (4, 8))	('mice', 'Species', '10090', (27, 31))	('P', 'Chemical', 'MESH:D010758', (117, 118))	('mice', 'Species', '10090', (129, 133))	('mice', 'Species', '10090', (142, 146))	('S', 'Chemical', 'MESH:D013455', (346, 347))	('P', 'Chemical', 'MESH:D010758', (125, 126))	('inactivation', 'Var', (169, 181))	('mice', 'Species', '10090', (235, 239))	('Nf1', 'Gene', (160, 163))	('murine', 'Species', '10090', (83, 89))
131059	32358581	Isogenic human iPSCs homozygous or heterozygous for the c.2041C>T or c.6513T>A NF1 patient-specific NF1 germline mutations were engineered using CRISPR/Cas9 technology by the Washington University Genome Engineering and iPSC Core Facility (GEiC).	('c.2041C>T', 'Mutation', 'rs768638173', (56, 65))	('c.6513T>A', 'Mutation', 'rs758917402', (69, 78))	('human', 'Species', '9606', (9, 14))	('NF1', 'Gene', (100, 103))	('patient', 'Species', '9606', (83, 90))	('NF1', 'Gene', (79, 82))	('c.6513T>A', 'Var', (69, 78))	('c.2041C>T', 'Var', (56, 65))
131137	31179925	Intriguingly, TERThigh cancers tend to have mutations in extracellular matrix organization genes and amplify MAPK signaling.	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('TERT', 'Gene', (14, 18))	('TERT', 'Gene', '7015', (14, 18))	('amplify', 'Reg', (101, 108))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('MAPK signaling', 'Pathway', (109, 123))	('extracellular matrix organization genes', 'Gene', (57, 96))
131150	31179925	Although TERT is actively transcribed in most human normal cells and tissues, TERT transcripts in normal cells are non-functional variants generated by alternative splicing.	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('alternative splicing', 'Var', (152, 172))	('human', 'Species', '9606', (46, 51))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
131152	31179925	These mechanisms include TERT promoter point mutations, methylation, rearrangements, DNA amplifications, transcript fusions and posttranslational modification.	('TERT', 'Gene', (25, 29))	('methylation', 'Var', (56, 67))	('TERT', 'Gene', '7015', (25, 29))	('rearrangements', 'Var', (69, 83))
131164	31179925	The MW estimator formula was as follows:where Yi Zi Wi denotes the outcome (mRNA expression level; SCNA; methylation data; miRNA expression level; SNP mutations), 1 o 0 denotes the TERTlow group or TERThigh group, and the mean matching weight was assigned to the ith subject.	('TERT', 'Gene', '7015', (198, 202))	('TERT', 'Gene', (181, 185))	('TERT', 'Gene', '7015', (181, 185))	('Yi Zi Wi', 'Var', (46, 54))	('TERT', 'Gene', (198, 202))
131171	31179925	Then, we applied the PSM model to find significant TERThigh/TERTlow -specific methylation probes at an FDR < 0.05 and a permutation test P < 0.05.	('methylation', 'Var', (78, 89))	('TERT', 'Gene', '7015', (60, 64))	('TERT', 'Gene', (51, 55))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (60, 64))
131192	31179925	Samples with 2 or more RNA-Seq quantified reads of TERT were defined as TERThigh, while those with less than 2 reads of TERT and without known ALT-related somatic alterations (ATRX or DAXX mutations, deletions or structural variants) were defined as TERTlow.	('ATRX', 'Gene', '546', (176, 180))	('DAXX', 'Gene', '1616', (184, 188))	('TERT', 'Gene', (250, 254))	('TERT', 'Gene', (120, 124))	('TERT', 'Gene', (51, 55))	('reads', 'Var', (42, 47))	('TERT', 'Gene', '7015', (250, 254))	('TERT', 'Gene', '7015', (120, 124))	('TERT', 'Gene', '7015', (51, 55))	('DAXX', 'Gene', (184, 188))	('ATRX', 'Gene', (176, 180))	('deletions', 'Var', (200, 209))	('structural', 'Var', (213, 223))	('ALT', 'Chemical', '-', (143, 146))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
131207	31179925	When examining the relationship between DNA methylation and mRNA expression, we found that TERThigh or TERTlow-specific DNA methylation was associated with TERThigh or TERTlow-specific downregulated gene expression levels in most cancer types (except for KIRC), suggesting mRNA expression regulation by DNA methylation (Additional file 5: Figure S3).	('TERT', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('downregulated', 'NegReg', (185, 198))	('TERT', 'Gene', '7015', (91, 95))	('TERT', 'Gene', (156, 160))	('gene expression levels', 'MPA', (199, 221))	('TERT', 'Gene', (168, 172))	('TERT', 'Gene', '7015', (103, 107))	('TERT', 'Gene', (103, 107))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('TERT', 'Gene', '7015', (168, 172))	('methylation', 'Var', (124, 135))	('TERT', 'Gene', '7015', (156, 160))
131233	31179925	Intriguingly, knockdown of the strong hub group gene TPX2 or EXO1 significantly reduced 50% telomerase activity in both cells (Fig.	('EXO1', 'Gene', (61, 65))	('TPX2', 'Gene', (53, 57))	('reduced', 'NegReg', (80, 87))	('hub', 'Gene', '1993', (38, 41))	('TPX2', 'Gene', '22974', (53, 57))	('telomerase activity', 'MPA', (92, 111))	('knockdown', 'Var', (14, 23))	('EXO1', 'Gene', '9156', (61, 65))	('hub', 'Gene', (38, 41))
131234	31179925	Knockdown of the median hub group gene resulted in less telomerase activity (~ 40% decrease in RAD54L knocked down HEK293T cells, Additional file 11: Figure S8D) or increased telomerase activity (RAD54L knocked down HepG2 cells in Additional file 11: Figure S8D and FOXM1 knocked down cells in Additional file 11: Figure S8E).	('RAD54L', 'Gene', (196, 202))	('telomerase activity', 'MPA', (56, 75))	('HEK293T', 'CellLine', 'CVCL:0063', (115, 122))	('RAD54L', 'Gene', '8438', (95, 101))	('FOXM1', 'Gene', (266, 271))	('RAD54L', 'Gene', '8438', (196, 202))	('hub', 'Gene', '1993', (24, 27))	('FOXM1', 'Gene', '2305', (266, 271))	('decrease', 'NegReg', (83, 91))	('HepG2', 'CellLine', 'CVCL:0027', (216, 221))	('less', 'NegReg', (51, 55))	('knocked', 'Var', (102, 109))	('RAD54L', 'Gene', (95, 101))	('telomerase activity', 'MPA', (175, 194))	('hub', 'Gene', (24, 27))	('increased', 'PosReg', (165, 174))
131236	31179925	In parallel with decreased telomerase activities, TPX2 or EXO1 knockdown reduced the viability of fibrosarcoma HTC75 cells and HepG2 cells (Fig.	('viability', 'CPA', (85, 94))	('fibrosarcoma', 'Disease', (98, 110))	('TPX2', 'Gene', (50, 54))	('EXO1', 'Gene', '9156', (58, 62))	('decreased', 'NegReg', (17, 26))	('reduced', 'NegReg', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('EXO1', 'Gene', (58, 62))	('TPX2', 'Gene', '22974', (50, 54))	('fibrosarcoma', 'Disease', 'MESH:D005354', (98, 110))	('telomerase activities', 'MPA', (27, 48))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (98, 110))	('HTC75', 'CellLine', 'CVCL:3382', (111, 116))	('HepG2', 'CellLine', 'CVCL:0027', (127, 132))	('knockdown', 'Var', (63, 72))
131252	31179925	At FDR = 0.5, we found significant TERThigh/TERTlow-specific SCNAs with 8 amplification peaks (12p13.33 in BRCA; 7p11.2 and 7q31.2 in LGG; 17q23.1 in LUAD; 8q24.21 in LIHC; 5p15.33, 12q15 and 17p11.2 in SARC) and 11 deletion peaks (8p23.2 in LIHC; 1p36.32, 2p25.3, 6p25.3, 10q23.31, 10q26.3, 13q14.2, 16q11.2, 16q23.1, 17p23.1 and Xq22.3 in SARC) (Fig.	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('LIHC', 'Disease', (242, 246))	('BRCA', 'Gene', '672', (107, 111))	('Xq22.3', 'Var', (331, 337))	('LIHC', 'Disease', (167, 171))	('BRCA', 'Gene', (107, 111))	('LIHC', 'Disease', 'None', (242, 246))	('LIHC', 'Disease', 'None', (167, 171))	('TERT', 'Gene', (35, 39))	('8p23.2', 'Var', (232, 238))	('16q11.2', 'Var', (301, 308))	('TERT', 'Gene', '7015', (35, 39))
131255	31179925	REACTOME pathway analysis showed that TERThigh-specific mutated genes were enriched in stimuli-sensing channels, cardiac conduction and extracellular matrix organization (Fig.	('cardiac conduction', 'CPA', (113, 131))	('mutated genes', 'Var', (56, 69))	('cardiac conduction', 'Phenotype', 'HP:0011675', (113, 131))	('TERT', 'Gene', (38, 42))	('TERT', 'Gene', '7015', (38, 42))	('extracellular matrix organization', 'CPA', (136, 169))
131262	31179925	Examining the TERT-associated mutation/SCNA list, we found 8 drug targets with mutations/SCNAs across cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations/SCNAs', 'Var', (79, 94))	('TERT', 'Gene', (14, 18))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('TERT', 'Gene', '7015', (14, 18))
131263	31179925	All targets are mutated or amplified in either LGG, LIHC or LUAD but not in other cancers.	('LIHC', 'Disease', (52, 56))	('LIHC', 'Disease', 'None', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('amplified', 'Var', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('mutated', 'Var', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('LUAD', 'Disease', (60, 64))	('LGG', 'Disease', (47, 50))
131267	31179925	In targeted therapy, gefitinib and erlotinib, EGFR inhibitors, were approved for the treatment of cancers with EGFR mutations or hyperactivation, including certain breast and lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast and lung cancers', 'Disease', 'MESH:D001943', (164, 187))	('erlotinib', 'Chemical', 'MESH:D000069347', (35, 44))	('gefitinib', 'Chemical', 'MESH:D000077156', (21, 30))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('EGFR', 'Gene', '1956', (111, 115))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('EGFR', 'Gene', '1956', (46, 50))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('EGFR', 'Gene', (111, 115))	('hyperactivation', 'Var', (129, 144))	('mutations', 'Var', (116, 125))	('cancers', 'Disease', (98, 105))	('EGFR', 'Gene', (46, 50))	('lung cancers', 'Phenotype', 'HP:0100526', (175, 187))
131280	31179925	Moreover, TERThigh patients tend to have mutated genes enriched in extracellular matrix organization and amplify genes in cell cycle progression-related MAPK signaling.	('mutated', 'Var', (41, 48))	('patients', 'Species', '9606', (19, 27))	('cell', 'MPA', (122, 126))	('TERT', 'Gene', (10, 14))	('TERT', 'Gene', '7015', (10, 14))	('extracellular matrix organization', 'CPA', (67, 100))
131286	31179925	These data suggest that telomere attrition and TERT activation may promote miR-17-92 cluster expression in certain cancer types.	('telomere attrition', 'Var', (24, 42))	('cancer', 'Disease', (115, 121))	('TERT', 'Gene', (47, 51))	('TERT', 'Gene', '7015', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('expression', 'MPA', (93, 103))	('miR-17-92', 'Gene', '407975', (75, 84))	('miR-17-92', 'Gene', (75, 84))	('promote', 'PosReg', (67, 74))
131296	31179925	However, anti-telomerase therapies have been shown to induce ALT in mouse and human cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('ALT', 'MPA', (61, 64))	('mouse', 'Species', '10090', (68, 73))	('cancer', 'Disease', (84, 90))	('anti-telomerase', 'Var', (9, 24))	('ALT', 'Chemical', '-', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (78, 83))	('induce', 'PosReg', (54, 60))
131299	31179925	TERT promoter mutations have recently been shown to be major drivers of TERT expression.	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (72, 76))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', '7015', (72, 76))
131304	30388142	Methylation dependent down-regulation of G0S2 leads to suppression of invasion and improved prognosis of IDH1-mutant glioma Isocitrate dehydrogenase (IDH) mutations are a prognostic factor in diffuse glioma.	('G0S2', 'Gene', '50486', (41, 45))	('prognosis', 'CPA', (92, 101))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('IDH1', 'Gene', '3417', (105, 109))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', '3417', (105, 108))	('glioma', 'Disease', (200, 206))	('Isocitrate dehydrogenase', 'Gene', '3417', (124, 148))	('suppression', 'NegReg', (55, 66))	('down-regulation', 'NegReg', (22, 37))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('G0S2', 'Gene', (41, 45))	('Isocitrate dehydrogenase', 'Gene', (124, 148))	('IDH', 'Gene', '3417', (150, 153))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('glioma', 'Disease', (117, 123))	('improved', 'PosReg', (83, 91))	('mutations', 'Var', (155, 164))	('IDH1', 'Gene', (105, 109))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('IDH', 'Gene', (105, 108))	('invasion', 'CPA', (70, 78))
131305	30388142	In a subset of IDH-mutant glioma, remodeling of the methylome results in the glioma-CpG island methylator phenotype (G-CIMP) and transcriptional reorganization.	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('glioma-CpG', 'Disease', (77, 87))	('G-CIMP', 'Chemical', '-', (117, 123))	('glioma-CpG', 'Disease', 'MESH:D005910', (77, 87))	('IDH', 'Gene', '3417', (15, 18))	('glioma', 'Disease', (26, 32))	('IDH', 'Gene', (15, 18))	('glioma', 'Disease', (77, 83))	('results in', 'Reg', (62, 72))	('transcriptional reorganization', 'CPA', (129, 159))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('remodeling', 'Var', (34, 44))
131307	30388142	We found that G0S2 expression tended to increase as the WHO grade increased, and G0S2 knockdown inhibited glioma invasion.	('expression', 'MPA', (19, 29))	('knockdown', 'Var', (86, 95))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('increase', 'PosReg', (40, 48))	('G0S2', 'Gene', (81, 85))	('G0S2', 'Gene', (14, 18))	('inhibited', 'NegReg', (96, 105))	('glioma', 'Disease', (106, 112))
131322	30388142	Genome-wide analyses have shown that novel somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 12% of all patients with GBM.	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', (92, 96))	('isocitrate dehydrogenase 1', 'Gene', '3417', (64, 90))	('GBM', 'Phenotype', 'HP:0012174', (132, 135))	('GBM', 'Disease', (132, 135))	('isocitrate dehydrogenase 1', 'Gene', (64, 90))	('IDH1', 'Gene', '3417', (92, 96))	('patients', 'Species', '9606', (118, 126))	('occur', 'Reg', (98, 103))
131323	30388142	An IDH1 mutation at the arginine residue in codon 132, most commonly the R132H mutation, promotes the direct catalysis of alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG).	('promotes', 'PosReg', (89, 97))	('R132H', 'Var', (73, 78))	('direct catalysis of alpha-ketoglutarate', 'MPA', (102, 141))	('arginine', 'Chemical', 'MESH:D001120', (24, 32))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (156, 174))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (122, 141))	('2-HG', 'Chemical', 'MESH:C019417', (176, 180))	('mutation', 'Var', (8, 16))	('IDH1', 'Gene', (3, 7))	('IDH1', 'Gene', '3417', (3, 7))
131325	30388142	IDH mutations are enriched in WHO grade II and III astrocytoma and oligodendroglioma and in secondary GBM (>75%), but are not common in primary GBM (5%).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (51, 62))	('GBM', 'Phenotype', 'HP:0012174', (144, 147))	('mutations', 'Var', (4, 13))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (51, 84))
131327	30388142	In this classification, IDH1 mutations, the codeletion status of chromosome arms 1p and 19q, and the histone 3 mutational status can be used to distinguish between biologically distinct glioma.	('glioma', 'Disease', (186, 192))	('IDH1', 'Gene', '3417', (24, 28))	('mutations', 'Var', (29, 38))	('distinguish', 'Reg', (144, 155))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('IDH1', 'Gene', (24, 28))
131328	30388142	Patients with WHO grade III anaplastic astrocytoma and GBM carrying IDH1 mutations have a significantly longer median overall survival than patients with wild-type IDH1.	('astrocytoma', 'Phenotype', 'HP:0009592', (39, 50))	('overall survival', 'MPA', (118, 134))	('IDH1', 'Gene', (68, 72))	('Patients', 'Species', '9606', (0, 8))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('longer', 'PosReg', (104, 110))	('patients', 'Species', '9606', (140, 148))	('IDH1', 'Gene', '3417', (68, 72))	('IDH1', 'Gene', (164, 168))	('IDH1', 'Gene', '3417', (164, 168))	('astrocytoma', 'Disease', 'MESH:D001254', (39, 50))	('mutations', 'Var', (73, 82))	('astrocytoma', 'Disease', (39, 50))
131329	30388142	However, the mechanism underlying the improved prognosis in patients with glioma carrying IDH1 mutations is not fully understood.	('IDH1', 'Gene', (90, 94))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('improved', 'PosReg', (38, 46))	('IDH1', 'Gene', '3417', (90, 94))	('patients', 'Species', '9606', (60, 68))	('glioma', 'Disease', (74, 80))	('mutations', 'Var', (95, 104))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
131330	30388142	Concurrent genome-wide DNA methylation and DNA promoter CpG island hypermethylation leads to transcriptional silencing in cancer.	('transcriptional', 'MPA', (93, 108))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('silencing', 'NegReg', (109, 118))	('hypermethylation', 'Var', (67, 83))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
131331	30388142	A distinct subset of glioma displaying DNA hypermethylation, i.e., glioma-CpG island methylator phenotype (G-CIMP), has a characteristic profile; it is more prevalent among lower grade glioma, strongly associated with IDH1 mutation, diagnosed at a younger age, and has a significantly better prognosis.	('G-CIMP', 'Chemical', '-', (107, 113))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('associated', 'Reg', (202, 212))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('IDH1', 'Gene', (218, 222))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('mutation', 'Var', (223, 231))	('IDH1', 'Gene', '3417', (218, 222))	('glioma-CpG', 'Disease', 'MESH:D005910', (67, 77))	('prevalent', 'Reg', (157, 166))	('glioma', 'Disease', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('glioma-CpG', 'Disease', (67, 77))	('glioma', 'Disease', (185, 191))
131333	30388142	These observations prompted us to hypothesize that the epigenetic silencing of G0S2 in G-CIMP may improve prognosis in patients with IDH1 mutations.	('improve', 'PosReg', (98, 105))	('epigenetic silencing', 'Var', (55, 75))	('G-CIMP', 'Chemical', '-', (87, 93))	('patients', 'Species', '9606', (119, 127))	('IDH1', 'Gene', (133, 137))	('prognosis', 'CPA', (106, 115))	('G0S2', 'Gene', (79, 83))	('IDH1', 'Gene', '3417', (133, 137))	('mutations', 'Var', (138, 147))
131334	30388142	In this study, we revealed the functional role of G0S2 in glioma and elucidated one explanation for the increased survival in glioma with IDH1 mutation.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('increased', 'PosReg', (104, 113))	('IDH1', 'Gene', '3417', (138, 142))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('mutation', 'Var', (143, 151))	('glioma', 'Disease', (126, 132))	('glioma', 'Disease', (58, 64))	('IDH1', 'Gene', (138, 142))	('G0S2', 'Gene', (50, 54))
131337	30388142	Total RNA was prepared using the RNeasy Mini Kit (74104; Qiagen, Hilden, Germany) or TRIzol Reagent (15596026; Invitrogen, Carlsbad, CA, USA) according to the manufacturers' instructions.	('15596026;', 'Var', (101, 110))	('74104;', 'Var', (50, 56))	('TRIzol', 'Chemical', 'MESH:C411644', (85, 91))
131353	30388142	At 2 days after siRNA transfection, U251 cells were harvested with Trypsin-EDTA (0.25%), washed with PBS, and resuspended in invasion assay buffer at 4 x 105 cells/ml.	('transfection', 'Var', (22, 34))	('PBS', 'Gene', (101, 104))	('PBS', 'Gene', '1131', (101, 104))	('U251', 'CellLine', 'CVCL:0021', (36, 40))	('EDTA', 'Chemical', 'MESH:D004492', (75, 79))
131367	30388142	Sections were incubated for 2 h at room temperature with a primary antibody against G0S2 (1:200; Novus, St. Louis, MO, USA) followed by incubation for 30 min at room temperature with Anti-rabbit IgG labeled with biotin (1:1000).	('biotin', 'Chemical', 'MESH:D001710', (212, 218))	('1:200;', 'Var', (90, 96))	('rabbit', 'Species', '9986', (188, 194))	('G0S2', 'Gene', (84, 88))
131376	30388142	Mutant IDH1 was statistically significantly related to both higher G0S2 methylation (0.749 vs. 0.366, p = 9.439e-53) and lower G0S2 expression (3.1 vs. 7.03, p = 0.000) compared to wild-type IDH1 among WHO grade II-IV gliomas (Fig 1B and 1C).	('G0S2', 'Protein', (67, 71))	('IDH1', 'Gene', (191, 195))	('IDH1', 'Gene', '3417', (7, 11))	('G0S2', 'Protein', (127, 131))	('higher', 'PosReg', (60, 66))	('methylation', 'MPA', (72, 83))	('IDH1', 'Gene', '3417', (191, 195))	('lower', 'NegReg', (121, 126))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('Mutant', 'Var', (0, 6))	('II-IV gliomas', 'Disease', 'MESH:D005910', (212, 225))	('expression', 'MPA', (132, 142))	('IDH1', 'Gene', (7, 11))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('II-IV gliomas', 'Disease', (212, 225))
131378	30388142	Interestingly, G0S2 mutations were not reported in 1102 gliomas among TCGA WHO grade II-IV gliomas (Fig 1D), supporting the notion that G0S2 is epigenetically silenced in gliomas harboring IDH1 mutations.	('II-IV gliomas', 'Disease', (85, 98))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('IDH1', 'Gene', '3417', (189, 193))	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('gliomas', 'Disease', (171, 178))	('IDH1', 'Gene', (189, 193))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('II-IV gliomas', 'Disease', 'MESH:D005910', (85, 98))	('mutations', 'Var', (20, 29))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
131382	30388142	G0S2 levels were significantly higher for wild-type IDH1 than for mutant IDH1 among WHO grade III/IV gliomas.	('IDH1', 'Gene', '3417', (52, 56))	('mutant', 'Var', (66, 72))	('IDH1', 'Gene', '3417', (73, 77))	('G0S2 levels', 'MPA', (0, 11))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IV gliomas', 'Disease', (98, 108))	('IV gliomas', 'Disease', 'MESH:D005910', (98, 108))	('higher', 'PosReg', (31, 37))	('IDH1', 'Gene', (73, 77))	('IDH1', 'Gene', (52, 56))
131384	30388142	These findings suggest that reduced expression of G0S2 contributes to better pathological features in glioma with IDH1 mutation.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('reduced', 'NegReg', (28, 35))	('mutation', 'Var', (119, 127))	('IDH1', 'Gene', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glioma', 'Disease', (102, 108))	('better', 'PosReg', (70, 76))	('IDH1', 'Gene', '3417', (114, 118))	('G0S2', 'Protein', (50, 54))	('expression', 'MPA', (36, 46))
131389	30388142	siRNA-mediated knockdown of G0S2 in the U251 malignant glioma cell line significantly suppressed cellular invasion (Fig 3B and 3C).	('knockdown', 'Var', (15, 24))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('suppressed', 'NegReg', (86, 96))	('U251', 'CellLine', 'CVCL:0021', (40, 44))	('malignant glioma', 'Disease', 'MESH:D005910', (45, 61))	('G0S2', 'Gene', (28, 32))	('malignant glioma', 'Disease', (45, 61))
131394	30388142	U87 GBM cells infected with the lentivirus encoding G0S2 shRNA in mouse brains exhibited reduced cell invasion toward surrounding normal brain tissues (Fig 4B).	('mouse', 'Species', '10090', (66, 71))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('reduced', 'NegReg', (89, 96))	('G0S2', 'Var', (52, 56))	('shRNA', 'Gene', (57, 62))
131397	30388142	Of note, the G0S2 promoter contains a CpG island, suggesting that G0S2 down-regulation in the mutant IDH1 background results from epigenetic silencing.	('IDH1', 'Gene', (101, 105))	('IDH1', 'Gene', '3417', (101, 105))	('down-regulation', 'NegReg', (71, 86))	('mutant', 'Var', (94, 100))	('epigenetic silencing', 'MPA', (130, 150))	('G0S2', 'Gene', (66, 70))
131398	30388142	To test this hypothesis, we examined whether GBM cells transfected with a mutant IDH1 plasmid (pcDNA3-Flag-IDH1-R132H, a gift from Yue Xiong, #62907; Addgene, Cambridge, MA, USA) decreased the G0S2 mRNA level, and DNA hypomethylation by TET2 overexpression could restore the G0S2 mRNA level.	('decreased', 'NegReg', (179, 188))	('G0S2 mRNA level', 'MPA', (275, 290))	('IDH1', 'Gene', (107, 111))	('IDH1', 'Gene', '3417', (81, 85))	('TET2', 'Gene', (237, 241))	('IDH1', 'Gene', '3417', (107, 111))	('G0S2 mRNA level', 'MPA', (193, 208))	('IDH1', 'Gene', (81, 85))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('R132H', 'Mutation', 'rs121913500', (112, 117))	('TET2', 'Gene', '54790', (237, 241))	('mutant', 'Var', (74, 80))	('restore', 'PosReg', (263, 270))
131399	30388142	It was reported that expression of IDH1 mutation lead to decrease in 5hmC, and that 5hmC decrease was associated with TET2 gene expression.	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('decrease', 'NegReg', (57, 65))	('TET2', 'Gene', '54790', (118, 122))	('5hmC', 'MPA', (69, 73))	('IDH1', 'Gene', '3417', (35, 39))	('decrease', 'NegReg', (89, 97))	('TET2', 'Gene', (118, 122))
131400	30388142	Actually, TET2 expression was decreased in GBM cells transfected with the mutant IDH1 plasmid (Fig 5A).	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('IDH1', 'Gene', '3417', (81, 85))	('IDH1', 'Gene', (81, 85))	('expression', 'MPA', (15, 25))	('TET2', 'Gene', '54790', (10, 14))	('mutant', 'Var', (74, 80))	('TET2', 'Gene', (10, 14))	('decreased', 'NegReg', (30, 39))
131401	30388142	Co-transfection of the mutant IDH1 plasmid with the TET2 plasmid (FH-TET2-pEF, a gift from Anjana Rao, Addgene #41710) recovered G0S2 expression (Fig 5B).	('IDH1', 'Gene', '3417', (30, 34))	('TET2', 'Gene', (52, 56))	('TET2', 'Gene', (69, 73))	('expression', 'MPA', (134, 144))	('G0S2', 'Gene', (129, 133))	('TET2', 'Gene', '54790', (52, 56))	('IDH1', 'Gene', (30, 34))	('TET2', 'Gene', '54790', (69, 73))	('recovered', 'PosReg', (119, 128))	('mutant', 'Var', (23, 29))
131402	30388142	These results suggest that IDH1 mutation represses G0S2 by DNA methylation.	('represses', 'NegReg', (41, 50))	('DNA methylation', 'MPA', (59, 74))	('G0S2', 'Gene', (51, 55))	('IDH1', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))
131403	30388142	Mutations and the overexpression of several oncogenes have been identified in glioma.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('overexpression', 'PosReg', (18, 32))	('Mutations', 'Var', (0, 9))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
131406	30388142	Excess 2-HG contributes to the progression of epigenetic alterations, including DNA methylation at promoter CpG islands, and finally increases the risk of developing glioma.	('DNA methylation', 'Var', (80, 95))	('epigenetic alterations', 'MPA', (46, 68))	('2-HG', 'Chemical', 'MESH:C019417', (7, 11))	('glioma', 'Disease', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('increases', 'PosReg', (133, 142))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))
131409	30388142	found that IDH mutations promote gliomagenesis by disrupting the chromosomal topology and allowing aberrant regulatory interactions that induce PDGFRA expression.	('chromosomal topology', 'MPA', (65, 85))	('PDGFRA', 'Gene', '5156', (144, 150))	('IDH', 'Gene', (11, 14))	('induce', 'PosReg', (137, 143))	('disrupting', 'NegReg', (50, 60))	('IDH', 'Gene', '3417', (11, 14))	('glioma', 'Disease', (33, 39))	('mutations', 'Var', (15, 24))	('expression', 'MPA', (151, 161))	('regulatory interactions', 'MPA', (108, 131))	('promote', 'PosReg', (25, 32))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('PDGFRA', 'Gene', (144, 150))
131410	30388142	Hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter-associated CpG island has been reported as a favorable prognostic indicator.	('O6-methylguanine-DNA methyltransferase', 'Gene', (24, 62))	('Hypermethylation', 'Var', (0, 16))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (24, 62))	('MGMT', 'Gene', (64, 68))	('MGMT', 'Gene', '4255', (64, 68))
131413	30388142	reported that the methylation status of the MGMT promoter also predicts the response to radiotherapy in the absence of adjuvant alkylating agents in patients with newly diagnosed GBM.	('patients', 'Species', '9606', (149, 157))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('MGMT', 'Gene', (44, 48))	('methylation', 'Var', (18, 29))	('MGMT', 'Gene', '4255', (44, 48))	('predicts', 'Reg', (63, 71))
131414	30388142	IDH mutations are associated with improved survival in patients with glioma, and are a useful prognostic marker in clinical settings.	('glioma', 'Disease', (69, 75))	('improved', 'PosReg', (34, 42))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('survival', 'MPA', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('patients', 'Species', '9606', (55, 63))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('mutations', 'Var', (4, 13))
131415	30388142	However, the mechanism underlying the improved prognosis in patients with IDH mutations has not been determined.	('IDH', 'Gene', '3417', (74, 77))	('IDH', 'Gene', (74, 77))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (78, 87))
131416	30388142	In this study, we elucidated the role of G0S2 in glioma cell invasion and identified a mechanism by which patients with glioma carrying IDH mutations and G-CIMP show better prognosis.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('patients', 'Species', '9606', (106, 114))	('G-CIMP', 'Chemical', '-', (154, 160))	('glioma', 'Disease', (120, 126))	('mutations', 'Var', (140, 149))	('G-CIMP', 'Var', (154, 160))	('better', 'PosReg', (166, 172))	('glioma', 'Disease', (49, 55))
131418	30388142	According to our analysis, survival was longer for the lower G0S2 expression group than for the higher G0S2 expression group among the patients with WHO grade II-IV gliomas and WHO grade II/III gliomas in the TCGA dataset.	('patients', 'Species', '9606', (135, 143))	('G0S2 expression', 'Var', (61, 76))	('longer', 'PosReg', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('II-IV gliomas', 'Disease', 'MESH:D005910', (159, 172))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('gliomas', 'Disease', (194, 201))	('II-IV gliomas', 'Disease', (159, 172))	('II glioma', 'Disease', 'MESH:D005910', (191, 200))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('lower', 'NegReg', (55, 60))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('gliomas', 'Disease', (165, 172))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('II glioma', 'Disease', (191, 200))
131426	30388142	In other cancers, G0S2 is correlated with cancer invasion, apotosis, and metabolism.	('cancer', 'Disease', (9, 15))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('apotosis', 'Disease', 'None', (59, 67))	('apotosis', 'Disease', (59, 67))	('cancer', 'Disease', (42, 48))	('correlated', 'Reg', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('G0S2', 'Var', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('metabolism', 'Disease', (73, 83))
131428	30388142	We demonstrated that glioma harboring mutant IDH1 epigenetically represses G0S2 expression, thereby suppressing surrounding cell invasion and resulting in a better prognosis.	('mutant', 'Var', (38, 44))	('epigenetically', 'Var', (50, 64))	('IDH1', 'Gene', '3417', (45, 49))	('represses', 'NegReg', (65, 74))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('G0S2', 'Gene', (75, 79))	('suppressing', 'NegReg', (100, 111))	('expression', 'MPA', (80, 90))	('glioma', 'Disease', (21, 27))	('IDH1', 'Gene', (45, 49))	('surrounding cell invasion', 'CPA', (112, 137))
131429	30388142	Consistent with our results, G0S2 expression was down-regulated epigenetically by DNA hypermethylation in non-small cell lung cancer cell lines.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (106, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hypermethylation', 'Var', (86, 102))	('G0S2', 'Gene', (29, 33))	('expression', 'MPA', (34, 44))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (106, 132))	('down-regulated', 'NegReg', (49, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('non-small cell lung cancer', 'Disease', (106, 132))	('DNA', 'Gene', (82, 85))	('epigenetically', 'MPA', (64, 78))
131431	30388142	G0S2 promotes apoptosis by interacting with BCL2 and by preventing the formation of protective BCL2 and BAX heterodimers.	('preventing', 'NegReg', (56, 66))	('formation', 'MPA', (71, 80))	('BCL2', 'Gene', (95, 99))	('apoptosis', 'CPA', (14, 23))	('BAX', 'Gene', (104, 107))	('BCL2', 'Gene', '596', (44, 48))	('G0S2', 'Var', (0, 4))	('BAX', 'Gene', '581', (104, 107))	('BCL2', 'Gene', '596', (95, 99))	('promotes', 'PosReg', (5, 13))	('interacting', 'Interaction', (27, 38))	('BCL2', 'Gene', (44, 48))
131434	30388142	Clearly, as the characteristics of glioma with IDH mutations are related to both the inactivation of several tumor suppressor genes and the overexpression of other genes, although it should be noted that G0S2 is not an only marker for the better prognosis of IDH mutation glioma, the epigenetic down-regulation of the G0S2 is not the only factor determining the biological characteristics of glioma, however, our results showed that epigenetic G0S2 downregulation following IDH1 mutation effectively inhibits the invasion of GBM cells both in vitro and in vivo.	('invasion of GBM cells', 'CPA', (513, 534))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('glioma', 'Disease', (272, 278))	('glioma', 'Disease', (35, 41))	('mutation', 'Var', (479, 487))	('glioma', 'Disease', (392, 398))	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (392, 398))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IDH1', 'Gene', (474, 478))	('IDH', 'Gene', (47, 50))	('IDH', 'Gene', (474, 477))	('downregulation', 'NegReg', (449, 463))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('IDH', 'Gene', (259, 262))	('glioma', 'Phenotype', 'HP:0009733', (392, 398))	('G0S2', 'Gene', (444, 448))	('IDH', 'Gene', '3417', (47, 50))	('IDH1', 'Gene', '3417', (474, 478))	('GBM', 'Phenotype', 'HP:0012174', (525, 528))	('IDH', 'Gene', '3417', (474, 477))	('inhibits', 'NegReg', (500, 508))	('epigenetic', 'Var', (433, 443))	('IDH', 'Gene', '3417', (259, 262))	('tumor', 'Disease', (109, 114))
131435	30388142	In conclusion, we identified one mechanism by which IDH mutations improve prognosis in glioma.	('mutations', 'Var', (56, 65))	('glioma', 'Disease', (87, 93))	('improve', 'PosReg', (66, 73))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('prognosis', 'MPA', (74, 83))
131444	29443896	We show that Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated FNMA.	('Dex', 'Chemical', 'MESH:D003907', (79, 82))	('CALR expression', 'MPA', (27, 42))	('suppresses', 'NegReg', (68, 78))	('Dex-mediated FNMA', 'Disease', (79, 96))	('siRNA', 'Gene', (52, 57))	('Dex', 'Chemical', 'MESH:D003907', (13, 16))	('knockdown', 'Var', (58, 67))
131453	29443896	In this study, we focus on CALR, since several studies have revealed a connection between disruption of CALR function and various malignancies including myeloproliferative disorders, osteocarcoma, ovarian and non-small cell lung cancer, breast cancer, and Glioblastoma (GBM).	('malignancies', 'Disease', (130, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (153, 181))	('Glioblastoma', 'Disease', (256, 268))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('CALR', 'Gene', (104, 108))	('breast cancer', 'Disease', (237, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (209, 235))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (153, 181))	('myeloproliferative disorders', 'Disease', (153, 181))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (213, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('disruption', 'Var', (90, 100))	('Glioblastoma', 'Disease', 'MESH:D005909', (256, 268))	('osteocarcoma, ovarian and non-small cell lung cancer', 'Disease', 'MESH:D002289', (183, 235))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Glioblastoma', 'Phenotype', 'HP:0012174', (256, 268))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
131456	29443896	Moreover, TCGA analysis for CALR expression in both GBM and low-grade gliomas (LGG) showed that of the 591 sequenced GBM samples, only three (0.5%) patients demonstrated genetic alteration of CALR.	('patients', 'Species', '9606', (148, 156))	('CALR', 'Gene', (192, 196))	('genetic alteration', 'Var', (170, 188))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
131461	29443896	Similarly, low-grade gliomas (LGG) demonstrated only 11 mutations (1.9%) in CALR in the 591 patient samples tested.	('mutations', 'Var', (56, 65))	('patient', 'Species', '9606', (92, 99))	('gliomas', 'Disease', (21, 28))	('CALR', 'Gene', (76, 80))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
131464	29443896	We explored the effects on FNMA of siRNA knockdown of CALR in Dex-treated GBM cells.	('Dex', 'Chemical', 'MESH:D003907', (62, 65))	('knockdown', 'Var', (41, 50))	('CALR', 'Gene', (54, 58))
131474	29443896	Previous studies showed that the corticosteroid receptor inhibitor, RU-486, abolishes Dex-mediated induction of FNMA in GBM cells.	('RU-486', 'Var', (68, 74))	('Dex', 'Chemical', 'MESH:D003907', (86, 89))	('FNMA', 'Disease', (112, 116))	('RU-486', 'Chemical', 'MESH:D015735', (68, 74))	('abolishes', 'NegReg', (76, 85))
131475	29443896	Here, we show that RU-486 also blocks Dex-mediated upregulation of CALR (Figure 3C).	('upregulation', 'PosReg', (51, 63))	('Dex', 'Chemical', 'MESH:D003907', (38, 41))	('CALR', 'MPA', (67, 71))	('blocks', 'NegReg', (31, 37))	('RU-486', 'Var', (19, 25))	('RU-486', 'Chemical', 'MESH:D015735', (19, 25))
131495	29443896	In both instances, altered CALR expression has been associated with correspondingly higher rate of metastases and poor overall survival.	('higher', 'PosReg', (84, 90))	('CALR', 'Protein', (27, 31))	('metastases', 'Disease', (99, 109))	('altered', 'Var', (19, 26))	('metastases', 'Disease', 'MESH:D009362', (99, 109))
131498	29443896	That amplification of the CALR gene in a small subset of patients identified in the TCGA database correlated with improved survival, also suggests that Dex-mediated up-regulation of CALR could, in principle, be beneficial.	('up-regulation', 'PosReg', (165, 178))	('amplification', 'Var', (5, 18))	('patients', 'Species', '9606', (57, 65))	('improved', 'PosReg', (114, 122))	('Dex', 'Chemical', 'MESH:D003907', (152, 155))	('survival', 'MPA', (123, 131))	('CALR gene', 'Gene', (26, 35))
131506	29443896	In wild-type fibroblasts, engagement of surface integrins induces a transient elevation in cytosolic calcium concentration.	('elevation', 'PosReg', (78, 87))	('calcium', 'Chemical', 'MESH:D002118', (101, 108))	('transient elevation in cytosolic calcium concentration', 'Phenotype', 'HP:0003575', (68, 122))	('cytosolic calcium concentration', 'MPA', (91, 122))	('surface integrins', 'Protein', (40, 57))	('engagement', 'Var', (26, 36))
131515	29443896	This is consistent with the fact that Dex not only upregulates FNMA in GBM cells, but also results in the reorganization of actin into stress fibers.	('upregulates', 'PosReg', (51, 62))	('actin into stress fibers', 'MPA', (124, 148))	('Dex', 'Var', (38, 41))	('Dex', 'Chemical', 'MESH:D003907', (38, 41))	('FNMA', 'MPA', (63, 67))	('results in', 'Reg', (91, 101))	('reorganization', 'MPA', (106, 120))
131516	29443896	We next asked whether CALR expression, significantly decreases dispersal velocity on tissue culture plastic as was observed for aggregates of Dex-treated GBM cells.	('expression', 'Var', (27, 37))	('dispersal velocity on', 'MPA', (63, 84))	('Dex', 'Chemical', 'MESH:D003907', (142, 145))	('decreases', 'NegReg', (53, 62))
131528	29443896	However, we have previously demonstrated Dex-mediated dispersal inhibition in widely-used GBM lines including, U87MG, LN229, and U118MG.	('Dex-mediated dispersal inhibition', 'MPA', (41, 74))	('U87MG', 'CellLine', 'CVCL:0022', (111, 116))	('LN229', 'CellLine', 'CVCL:0393', (118, 123))	('Dex', 'Chemical', 'MESH:D003907', (41, 44))	('U118MG', 'Var', (129, 135))
131554	29443896	Cells were later selected based on Neomycin resistance with Geneticin (G418, 600 mug/mL) for few weeks and then sorted by FACS using GFP.	('Neomycin', 'Chemical', 'MESH:D009355', (35, 43))	('G418, 600 mug/mL', 'Var', (71, 87))	('based', 'Reg', (26, 31))	('Neomycin resistance', 'MPA', (35, 54))	('G418', 'Chemical', 'MESH:C010680', (71, 75))
131622	27338365	The main molecular and genetic features of primary GBM are represented by: amplification of epidermal growth factor receptor (EGFR), deletion or mutation of homozygous cycline dependent kinase (CDK) inhibitor p16INK4A/(CDKN2A), alterations in phosphatase and tensin homolog (PTEN) on chromosome 10, and deletion in the INK4 alpha.	('CDK', 'Gene', (194, 197))	('p16INK4A', 'Gene', (209, 217))	('CDKN2A', 'Gene', '1029', (219, 225))	('p16INK4A', 'Gene', '1029', (209, 217))	('PTEN', 'Gene', '5728', (275, 279))	('EGFR', 'Gene', '1956', (126, 130))	('deletion', 'Var', (133, 141))	('mutation', 'Var', (145, 153))	('epidermal growth factor receptor', 'Gene', (92, 124))	('epidermal growth factor receptor', 'Gene', '1956', (92, 124))	('amplification', 'Reg', (75, 88))	('INK4 alpha', 'Gene', '1029', (319, 329))	('INK4 alpha', 'Gene', (319, 329))	('rat', 'Species', '10116', (232, 235))	('EGFR', 'Gene', (126, 130))	('alterations', 'Var', (228, 239))	('CDKN2A', 'Gene', (219, 225))	('PTEN', 'Gene', (275, 279))	('deletion', 'Var', (303, 311))
131623	27338365	TP53 mutations are common in secondary GBM, unlike the primary types.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('common', 'Reg', (19, 25))	('secondary GBM', 'Disease', (29, 42))
131625	27338365	Interestingly, isocitrate dehydrogenase 1 (IDH1) mutations are very frequent in secondary GBMs (>80%) and rare in primary (<5%).	('isocitrate dehydrogenase 1', 'Gene', (15, 41))	('isocitrate dehydrogenase 1', 'Gene', '3417', (15, 41))	('mutations', 'Var', (49, 58))	('frequent', 'Reg', (68, 76))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))	('secondary GBMs', 'Disease', (80, 94))
131626	27338365	IDH1 mutations are frequent (80)% in diffuse astrocytoma WHO grade 2 and anaplastic astrocytoma WHO grade 3, in the precursor lesions of secondary glioblastomas, as well as in oligodendroglial tumors.	('astrocytoma', 'Disease', 'MESH:D001254', (45, 56))	('astrocytoma', 'Disease', (45, 56))	('glioblastomas', 'Phenotype', 'HP:0012174', (147, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (45, 56))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('glioblastomas', 'Disease', 'MESH:D005909', (147, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('astrocytoma', 'Disease', 'MESH:D001254', (84, 95))	('glioblastomas', 'Disease', (147, 160))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('astrocytoma', 'Disease', (84, 95))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (176, 199))	('astrocytoma', 'Phenotype', 'HP:0009592', (84, 95))	('oligodendroglial tumors', 'Disease', (176, 199))	('IDH1', 'Gene', '3417', (0, 4))
131627	27338365	IDH2 mutations are less frequent and prevail in anaplastic oligodendrogliomas (5%) and oligoastrocytomas (6%).	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('prevail', 'Reg', (37, 44))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (48, 77))	('anaplastic oligodendrogliomas', 'Disease', (48, 77))	('mutations', 'Var', (5, 14))	('oligoastrocytomas', 'Disease', (87, 104))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (87, 104))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH2', 'Gene', (0, 4))	('IDH2', 'Gene', '3418', (0, 4))
131629	27338365	Tumors arise as the result of both hereditary and somatic mutations in oncogenes and tumor suppressor genes.	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (85, 90))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('oncogenes', 'Gene', (71, 80))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
131637	27338365	Mutations due to failed repair mechanisms are described in two tumor suppressor genes: Ras oncogene and tp53.	('tumor', 'Disease', (63, 68))	('Ras', 'Gene', (87, 90))	('tp53', 'Gene', '7157', (104, 108))	('tp53', 'Gene', (104, 108))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
131640	27338365	Its mutations induce the inactivation of p16ink-4a, the super expression of CDK4 and CDK6 and of ubiquitin ligase Mdm2 and Mdm4, alterating the cell cycle regulation.	('Mdm2', 'Gene', (114, 118))	('CDK4', 'Gene', (76, 80))	('CDK4', 'Gene', '1019', (76, 80))	('super expression', 'MPA', (56, 72))	('p16ink-4a', 'Gene', (41, 50))	('CDK6', 'Gene', (85, 89))	('inactivation', 'MPA', (25, 37))	('p16ink-4a', 'Gene', '1029', (41, 50))	('CDK6', 'Gene', '1021', (85, 89))	('rat', 'Species', '10116', (133, 136))	('Mdm2', 'Gene', '4193', (114, 118))	('cell cycle regulation', 'CPA', (144, 165))	('mutations', 'Var', (4, 13))	('Mdm4', 'Gene', '4194', (123, 127))	('Mdm4', 'Gene', (123, 127))	('alterating', 'Reg', (129, 139))
131645	27338365	The gliomagenesis is characterized by abnormalities in growth factor receptors.	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('growth factor receptors', 'Protein', (55, 78))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('abnormalities in growth', 'Phenotype', 'HP:0001507', (38, 61))	('glioma', 'Disease', (4, 10))	('abnormalities', 'Var', (38, 51))
131646	27338365	Different growth factor receptors, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), C-Kit, vascular endhotelial growth factor receptor (VEGFR), appeared mutated in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('C-Kit', 'Gene', (133, 138))	('EGFR', 'Gene', (186, 190))	('C-Kit', 'Gene', '3815', (133, 138))	('EGFR', 'Gene', '1956', (77, 81))	('vascular endhotelial growth factor receptor', 'Gene', (140, 183))	('platelet-derived growth factor receptor', 'Gene', '5159', (84, 123))	('platelet-derived growth factor receptor', 'Gene', (84, 123))	('PDGFR', 'Gene', (125, 130))	('mutated', 'Var', (202, 209))	('PDGFR', 'Gene', '5159', (125, 130))	('VEGFR', 'Gene', '3791', (185, 190))	('EGFR', 'Gene', '1956', (186, 190))	('VEGFR', 'Gene', (185, 190))	('glioma', 'Disease', (213, 219))	('epidermal growth factor receptor', 'Gene', (43, 75))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('epidermal growth factor receptor', 'Gene', '1956', (43, 75))	('vascular endhotelial growth factor receptor', 'Gene', '3791', (140, 183))	('EGFR', 'Gene', (77, 81))
131648	27338365	In GBM, several receptor tyrosine kinases (RTK genes), such as ERBB2, belonging to EGF receptor family, and MET gene, encoding hepatocyte growth factor receptor, are mutated.	('EGF', 'Gene', '1950', (83, 86))	('MET gene', 'Gene', (108, 116))	('hepatocyte growth factor receptor', 'Gene', (127, 160))	('mutated', 'Var', (166, 173))	('ERBB2', 'Gene', '2064', (63, 68))	('ERBB2', 'Gene', (63, 68))	('EGF', 'Gene', (83, 86))	('hepatocyte growth factor receptor', 'Gene', '4233', (127, 160))
131653	27338365	Mutations in IDH1 and IDH2 regard the majority of low-grade gliomas in adults, defining a subtype associated with a better prognosis.	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('IDH2', 'Gene', (22, 26))	('gliomas', 'Disease', (60, 67))	('IDH1', 'Gene', (13, 17))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
131654	27338365	Low-grade gliomas with IDH mutation and codeletion of chromosome arms 1p and 19q (1p/19q codeletion), as oligodendrogliomas, show more effective responses to radiochemotherapy, and are associated with longer survival than diffuse gliomas, which do not report the abovementioned alterations.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (105, 123))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('more', 'PosReg', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('oligodendrogliomas', 'Disease', (105, 123))	('codeletion', 'Var', (40, 50))	('IDH', 'Gene', (23, 26))	('longer', 'PosReg', (201, 207))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('gliomas', 'Disease', (230, 237))	('IDH', 'Gene', '3417', (23, 26))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))	('rat', 'Species', '10116', (282, 285))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('gliomas', 'Disease', 'MESH:D005910', (230, 237))
131656	27338365	A recent study demonstrated three types of lower-grade glioma disease characterized by the IDH and 1p/19q pattern.	('IDH', 'Gene', '3417', (91, 94))	('rat', 'Species', '10116', (22, 25))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH', 'Gene', (91, 94))	('glioma disease', 'Disease', (55, 69))	('glioma disease', 'Disease', 'MESH:D005910', (55, 69))	('1p/19q', 'Var', (99, 105))
131657	27338365	This genomic study underlined that low-grade gliomas can present an IDH mutation with a 1p/19q codeletion or a TP53 mutation, and that the majority of these tumors with wild-type IDH showed genomic and clinical similarities to primary (wild-type IDH) GBM.	('IDH', 'Gene', '3417', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (179, 182))	('TP53', 'Gene', '7157', (111, 115))	('IDH', 'Gene', '3417', (246, 249))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('TP53', 'Gene', (111, 115))	('IDH', 'Gene', (246, 249))	('mutation', 'Var', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('IDH', 'Gene', (68, 71))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
131660	27338365	Genomic analysis demonstrated that in more than 70% of patients with low or high-grade gliomas, the mutation of amino acid 132 of IDH1 occurred, and in 12% of the GBM samples.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('mutation of amino acid 132', 'Var', (100, 126))	('low', 'Disease', (69, 72))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('occurred', 'Reg', (135, 143))	('IDH1', 'Gene', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('IDH1', 'Gene', '3417', (130, 134))	('patients', 'Species', '9606', (55, 63))	('rat', 'Species', '10116', (24, 27))	('gliomas', 'Disease', (87, 94))
131661	27338365	Further studies discovered that the IDH1/2 mutations lead to the conversion, NADPH dependent, of alpha-KG to d-2-hydroxyglutarate (d-2HG), supporting their pro-oncogenic role.	('NADPH', 'Gene', (77, 82))	('NADPH', 'Gene', '50506', (77, 82))	('IDH1', 'Gene', (36, 40))	('lead to', 'Reg', (53, 60))	('alpha-KG', 'Chemical', '-', (97, 105))	('d-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (109, 129))	('mutations', 'Var', (43, 52))	('IDH1', 'Gene', '3417', (36, 40))	('conversion', 'MPA', (65, 75))
131662	27338365	Literature data reported that increased levels of d-2HG in cells caused oxidative stress in rat brains, which could potentially promote oncogenesis.	('oxidative stress', 'MPA', (72, 88))	('rat', 'Species', '10116', (92, 95))	('d-2HG', 'Var', (50, 55))	('promote', 'PosReg', (128, 135))	('rat', 'Species', '10116', (4, 7))	('oxidative stress', 'Phenotype', 'HP:0025464', (72, 88))	('oncogenesis', 'CPA', (136, 147))
131663	27338365	In patients with gliomas, IDH1/2 mutations and TP53 mutations usually coexist, even if IDH2 mutations are rare.	('mutations', 'Var', (52, 61))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('coexist', 'Reg', (70, 77))	('IDH1', 'Gene', (26, 30))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (3, 11))	('TP53', 'Gene', '7157', (47, 51))	('IDH2', 'Gene', (87, 91))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('gliomas', 'Disease', (17, 24))	('IDH1', 'Gene', '3417', (26, 30))	('TP53', 'Gene', (47, 51))	('IDH2', 'Gene', '3418', (87, 91))
131665	27338365	The H3.3 mutations are based on the amino acid substitutions at K27 or G34.	('G34', 'Var', (71, 74))	('H3.3', 'Gene', (4, 8))	('K27', 'Gene', (64, 67))	('K27', 'Gene', '342574', (64, 67))
131667	27338365	The 30%-40% of pediatric/young adult GBMs, are characterized by two particular epigenetic dysregulation mechanisms: the recurrent and mutually exclusive mutations in either H3F3A or IDH1, and the aberrant DNA methylation patterns.	('IDH1', 'Gene', '3417', (182, 186))	('mutations', 'Var', (153, 162))	('H3F3A', 'Gene', '3020', (173, 178))	('IDH1', 'Gene', (182, 186))	('H3F3A', 'Gene', (173, 178))
131668	27338365	It was been demonstrated, in thalamic and midline location GBMs and in diffuse intrinsic pontine gliomas (DIPGs), a high frequency of H3F3A K27 mutations, inferring that K27 mutant GBM represent an anatomically-defined subset.	('K27', 'Gene', '342574', (170, 173))	('K27', 'Gene', (170, 173))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('K27', 'Gene', '342574', (140, 143))	('H3F3A', 'Gene', (134, 139))	('gliomas', 'Disease', (97, 104))	('midline location GBMs', 'Disease', (42, 63))	('diffuse', 'Disease', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('rat', 'Species', '10116', (19, 22))	('K27', 'Gene', (140, 143))	('midline location GBMs', 'Disease', 'MESH:D009436', (42, 63))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('mutations', 'Var', (144, 153))	('H3F3A', 'Gene', '3020', (134, 139))
131672	27338365	The deletion of NFKBIA (encoding nuclear factor of kappa-light polypeptide gene enhancer in B-cells inhibitor-alpha), an inhibitor of the EGFR-signaling pathway, is reported to promote tumor development in GBM, which does not show mutations of EGFR.	('tumor', 'Disease', (185, 190))	('EGFR', 'Gene', '1956', (244, 248))	('promote', 'PosReg', (177, 184))	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'Gene', (244, 248))	('NFKBIA', 'Gene', (16, 22))	('EGFR', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('nuclear factor of kappa-light polypeptide gene enhancer in B-cells inhibitor-alpha', 'Gene', '4792', (33, 115))	('deletion', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('NFKBIA', 'Gene', '4792', (16, 22))
131673	27338365	Upon stimulation with a ligand such as tumor necrosis factor alpha (TNF-alpha) or lipopolysaccharide (LPS), IkappaBalpha is phosphorylated by the signalosome; this phosphorylation induces the rapid degradation of IkappaBalpha, which determines the inhibition of NF-kappaB and leads to the translocation of p50/p65 into the nucleus to activate the transcription of downstream target genes, including cytokines, which promote tumor growth and invasiveness.	('p65', 'Gene', '5970', (310, 313))	('tumor necrosis factor alpha', 'Gene', (39, 66))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (424, 429))	('degradation', 'MPA', (198, 209))	('p50', 'Gene', '8874', (306, 309))	('IkappaBalpha', 'Gene', (213, 225))	('tumor', 'Disease', 'MESH:D009369', (424, 429))	('IkappaBalpha', 'Gene', (108, 120))	('transcription', 'MPA', (347, 360))	('IkappaBalpha', 'Gene', '4792', (213, 225))	('TNF-alpha', 'Gene', '7124', (68, 77))	('translocation', 'MPA', (289, 302))	('IkappaBalpha', 'Gene', '4792', (108, 120))	('TNF-alpha', 'Gene', (68, 77))	('tumor necrosis factor alpha', 'Gene', '7124', (39, 66))	('tumor', 'Phenotype', 'HP:0002664', (424, 429))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (82, 100))	('activate', 'PosReg', (334, 342))	('tumor', 'Disease', (39, 44))	('p50', 'Gene', (306, 309))	('p65', 'Gene', (310, 313))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('invasiveness', 'CPA', (441, 453))	('promote', 'PosReg', (416, 423))	('phosphorylation', 'Var', (164, 179))
131674	27338365	Interestingly, in GBM, NFKBIA deletion and EGFR amplification are mutually exclusive, raising the possibility that the two genetic events could activate the same pathway.	('activate', 'PosReg', (144, 152))	('deletion', 'Var', (30, 38))	('EGFR', 'Gene', '1956', (43, 47))	('NFKBIA', 'Gene', (23, 29))	('EGFR', 'Gene', (43, 47))	('NFKBIA', 'Gene', '4792', (23, 29))	('amplification', 'Var', (48, 61))
131675	27338365	EGFR alterations include amplifications, mutations and deletions, even though the most common is represented by the variant III deletion of the extracellular domain (EGFR-vIII mutant).	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('variant III deletion', 'Var', (116, 136))	('vIII', 'Gene', (171, 175))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('alterations', 'Var', (5, 16))	('vIII', 'Gene', '1351', (171, 175))	('EGFR', 'Gene', '1956', (0, 4))	('deletions', 'Var', (55, 64))
131678	27338365	Frequently, mutations of ATRX are found in 67% of grade 2 astrocytomas, 73% of grade 3 astrocytomas, and in 57% of secondary GBMs, but rarely in primary GBM (4%).	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('ATRX', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('astrocytomas', 'Disease', 'MESH:D001254', (58, 70))	('astrocytomas', 'Disease', 'MESH:D001254', (87, 99))	('ATRX', 'Gene', '546', (25, 29))	('found', 'Reg', (34, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('astrocytomas', 'Disease', (58, 70))	('astrocytomas', 'Disease', (87, 99))
131683	27338365	In the presence of metal cations, such as Fe2+ and Cu+, H2O2 can be additionally reduced into OH, an extremely reactive form of ROS characterized by a strong oxidizing potential, responsible for the oxidative stress-induced cellular damage, and consequently genome instability.	('Fe2+', 'Var', (42, 46))	('H2O2', 'Chemical', 'MESH:D006861', (56, 60))	('H2O2', 'Var', (56, 60))	('ROS', 'Chemical', 'MESH:D017382', (128, 131))	('Cu+', 'Chemical', 'MESH:D003300', (51, 54))	('Cu+', 'Var', (51, 54))	('oxidative stress', 'Phenotype', 'HP:0025464', (199, 215))	('metal', 'Chemical', 'MESH:D008670', (19, 24))	('Fe2+', 'Chemical', 'MESH:C038178', (42, 46))
131685	27338365	There are several factors that influence the cell response to ROS damage, depending on the intensity and duration of the stimulus, and especially on the context of the signal.	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('damage', 'Var', (66, 72))	('ROS', 'Protein', (62, 65))	('rat', 'Species', '10116', (107, 110))
131688	27338365	ROS can modify the structure of the signaling proteins through a direct process of phosphorylation, and thus they could indirectly interfere in the signal process, including immune signaling, apoptosis, metabolism, aging, and hypoxic stress.	('metabolism', 'CPA', (203, 213))	('ROS', 'Var', (0, 3))	('modify', 'Reg', (8, 14))	('aging', 'CPA', (215, 220))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('signal process', 'MPA', (148, 162))	('phosphorylation', 'MPA', (83, 98))	('apoptosis', 'CPA', (192, 201))	('hypoxic stress', 'Disease', 'MESH:D004194', (226, 240))	('hypoxic stress', 'Disease', (226, 240))	('structure of the signaling proteins', 'MPA', (19, 54))	('interfere', 'NegReg', (131, 140))	('immune signaling', 'CPA', (174, 190))
131689	27338365	Particularly, ROS can potentiate the EGF and platelet derived growth factor (PDGF) mediated signaling pathways, in which EGF and PDGF promote the tyrosine kinase activity of their receptor and subsequently their autophosphorylation, activating the related downstream pathways, such as PI3K-AKT signaling and the mitogen activated protein kinase cascade (MAPK).	('EGF', 'Gene', '1950', (121, 124))	('promote', 'PosReg', (134, 141))	('EGF', 'Gene', (37, 40))	('tyrosine kinase activity', 'MPA', (146, 170))	('ROS', 'Var', (14, 17))	('activating', 'PosReg', (233, 243))	('MAPK', 'Gene', '5594', (354, 358))	('AKT', 'Gene', '207', (290, 293))	('mitogen activated protein kinase cascade', 'Pathway', (312, 352))	('EGF and platelet derived growth factor', 'Gene', '1950', (37, 75))	('autophosphorylation', 'MPA', (212, 231))	('MAPK', 'Gene', (354, 358))	('EGF', 'Gene', '1950', (37, 40))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('AKT', 'Gene', (290, 293))	('PDGF', 'Gene', (129, 133))	('EGF', 'Gene', (121, 124))	('potentiate', 'PosReg', (22, 32))
131692	27338365	The majority of ROS-induced mutations involves modification of guanine, causing G   T transversions.	('causing', 'Reg', (72, 79))	('ROS-induced', 'Gene', (16, 27))	('modification', 'Var', (47, 59))	('guanine', 'Protein', (63, 70))	('guanine', 'Chemical', 'MESH:D006147', (63, 70))	('G   T transversions', 'MPA', (80, 99))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('mutations', 'Var', (28, 37))
131693	27338365	Interestingly, ROS can modify both initiation and progression of cancer, especially if the mutations induced involve critical genes such as oncogenes or tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('modify', 'Reg', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('ROS', 'Var', (15, 18))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
131701	27338365	It has been reported that ROS can cause neuron and astrocyte death through apoptosis and necrosis mechanisms.	('necrosis', 'Disease', (89, 97))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('apoptosis', 'CPA', (75, 84))	('cause', 'Reg', (34, 39))	('ROS', 'Var', (26, 29))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))
131703	27338365	In a recent paper, TPA-induced invasion/migration of U87 cells was sequentially blocked by protein kinase C (PKC) inhibitor, Go6976, COX-2 inhibitor, NS398, NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI), and the ROS scavengers, superoxide dismutase (SOD) and tempol, followed by the reduction of relative signal pathway.	('relative signal pathway', 'Pathway', (310, 333))	('blocked', 'NegReg', (80, 87))	('DPI', 'Chemical', 'MESH:C007517', (212, 215))	('NADPH', 'Gene', '50506', (157, 162))	('COX-2', 'Gene', (133, 138))	('NS398', 'Chemical', 'MESH:C080955', (150, 155))	('Go6976', 'Chemical', 'MESH:C081021', (125, 131))	('NS398', 'Var', (150, 155))	('Go6976', 'Var', (125, 131))	('superoxide dismutase', 'Gene', '6647', (242, 262))	('COX-2', 'Gene', '4513', (133, 138))	('SOD', 'Gene', (264, 267))	('TPA-induced', 'Gene', (19, 30))	('diphenyleneiodonium chloride', 'Chemical', 'MESH:C007517', (182, 210))	('U87', 'Gene', '641648', (53, 56))	('SOD', 'Gene', '6647', (264, 267))	('TPA', 'Chemical', 'MESH:D013755', (19, 22))	('NADPH', 'Gene', (157, 162))	('ROS', 'Chemical', 'MESH:D017382', (226, 229))	('U87', 'Gene', (53, 56))	('rat', 'Species', '10116', (43, 46))	('invasion/migration', 'CPA', (31, 49))	('superoxide dismutase', 'Gene', (242, 262))
131712	27338365	In this interesting study, the authors revealed that knocking down Nrf2 stunted glioma cell proliferation by ATP depletion, induced 5' AMP-activated protein kinase activation and consequently inhibited the mammalian target of rapamycin (mTOR) pathway.	('glioma', 'Disease', (80, 86))	('mTOR', 'Gene', '2475', (237, 241))	('Nrf2', 'Gene', (67, 71))	('mTOR', 'Gene', (237, 241))	('Nrf2', 'Gene', '4780', (67, 71))	('rat', 'Species', '10116', (99, 102))	('mammalian target of rapamycin', 'Gene', (206, 235))	('mammalian target of rapamycin', 'Gene', '2475', (206, 235))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	("5' AMP-activated protein kinase", 'MPA', (132, 163))	('inhibited', 'NegReg', (192, 201))	('activation', 'PosReg', (164, 174))	('stunted', 'NegReg', (72, 79))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('knocking down', 'Var', (53, 66))	('induced', 'Reg', (124, 131))	('ATP', 'Chemical', 'MESH:D000255', (109, 112))
131713	27338365	It has also been indicated that Nrf2 inhibits the differentiation of glioma stem cells and its silencing may promote cellular differentiation.	('glioma', 'Disease', (69, 75))	('Nrf2', 'Gene', (32, 36))	('promote', 'PosReg', (109, 116))	('cellular differentiation', 'CPA', (117, 141))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('silencing', 'Var', (95, 104))	('Nrf2', 'Gene', '4780', (32, 36))	('inhibits', 'NegReg', (37, 45))
131720	27338365	These researchers thus suggested that the combination of a CBD treatment with the inhibition of system SLC7A11 through the use of specific modulators of ROS, might reduce glioma stem cells survival and tumor invasion.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('tumor', 'Disease', (202, 207))	('reduce', 'NegReg', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('glioma', 'Disease', (171, 177))	('inhibition', 'NegReg', (82, 92))	('CBD', 'Chemical', 'MESH:D002185', (59, 62))	('SLC7A11', 'Gene', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('ROS', 'Chemical', 'MESH:D017382', (153, 156))	('SLC7A11', 'Gene', '23657', (103, 110))	('modulators', 'Var', (139, 149))
131738	27338365	Specifically, the ROS accumulation secondary to EGFR hyper-activation requires an increased cellular dependence by PARP-1 mediated Base Excision Repair genes and it could be helpful for the development of even more effective anticancer drug combinations.	('cellular dependence', 'MPA', (92, 111))	('ROS', 'MPA', (18, 21))	('EGFR', 'Gene', '1956', (48, 52))	('accumulation', 'PosReg', (22, 34))	('PARP-1', 'Gene', (115, 121))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('PARP-1', 'Gene', '142', (115, 121))	('EGFR', 'Gene', (48, 52))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('increased', 'PosReg', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('hyper-activation', 'Var', (53, 69))
131756	27338365	In recent years, with the view to develop ROS-responsive biomaterials, a variety of ROS-responsive drug delivery systems have been designed to deliver anticancer agents to tumors such as drugs, proteins and small interfering RNAs (siRNAs).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('small interfering', 'Var', (207, 224))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
131757	27338365	H2O2 is related to apoptosis, dysregulation of cell proliferation and DNA mutations and, thus, represents a common marker for oxidative stress in carcinogenesis.	('carcinogenesis', 'Disease', (146, 160))	('apoptosis', 'CPA', (19, 28))	('related', 'Reg', (8, 15))	('oxidative stress', 'Phenotype', 'HP:0025464', (126, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('DNA mutations', 'Gene', (70, 83))	('rat', 'Species', '10116', (59, 62))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('cell proliferation', 'CPA', (47, 65))
131761	27338365	It has been shown recently that, fluorescent polymer NPs bearing pinacol-type boronic ester linkers, initiate self-immolative polymer degradation and subsequently the release of the cargo drug in the presence of higher ROS concentrations, typically present in cytoplasmatic environment tumor cells.	('pinacol-type', 'Var', (65, 77))	('release of the cargo drug', 'MPA', (167, 192))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('polymer', 'Chemical', 'MESH:D011108', (126, 133))	('ROS', 'Chemical', 'MESH:D017382', (219, 222))	('pinacol', 'Chemical', 'MESH:C000621940', (65, 72))	('polymer', 'Chemical', 'MESH:D011108', (45, 52))	('self-immolative polymer degradation', 'MPA', (110, 145))	('rat', 'Species', '10116', (230, 233))	('boronic ester', 'Chemical', '-', (78, 91))
131766	27338365	The acquisition of anticancer drug resistance includes enhanced expression of transporters that increase anticancer drugs efflux, alterations in drug metabolism, mutations in drug targets and the activation or inactivation of downstream proliferation or death signaling pathways.	('mutations', 'Var', (162, 171))	('expression', 'MPA', (64, 74))	('inactivation', 'NegReg', (210, 222))	('proliferation or death signaling pathways', 'Pathway', (237, 278))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('enhanced', 'PosReg', (55, 63))	('rat', 'Species', '10116', (244, 247))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('alterations', 'Reg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('rat', 'Species', '10116', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('increase', 'PosReg', (96, 104))	('drug resistance', 'Phenotype', 'HP:0020174', (30, 45))	('drug metabolism', 'MPA', (145, 160))
131793	27338365	It consists of guiding and delivering cytotoxic ROS directly to the solid tumor, or inactivating the antioxidative enzyme system.	('antioxidative enzyme system', 'Enzyme', (101, 128))	('solid tumor', 'Disease', (68, 79))	('inactivating', 'Var', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('solid tumor', 'Disease', 'MESH:D009369', (68, 79))	('ROS', 'Protein', (48, 51))
131796	33594759	Ferroptosis-related gene signature as a prognostic marker for lower-grade gliomas Ferroptosis is a newly discovered form of programmed cell death, which has unique biological effects on metabolism and redox biology.	('Ferroptosis', 'Var', (82, 93))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
131802	33594759	3 ,  4  Isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation are widely utilized for molecular analysis in gliomas, but are insufficient for the precise prediction of prognosis.	('Isocitrate dehydrogenase 1', 'Gene', (8, 34))	('IDH1', 'Gene', (36, 40))	('gliomas', 'Disease', (187, 194))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (74, 112))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (8, 34))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('MGMT', 'Gene', (114, 118))	('MGMT', 'Gene', '4255', (114, 118))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('O6-methylguanine-DNA methyltransferase', 'Gene', (74, 112))
131820	33594759	Univariate and multivariate Cox analyses were used to screen for prognostic factors such as grade, radiation therapy, age, gender, IDH1 status, MGMT promoter status, 1p/19q codeletion and risk score.	('IDH1', 'Gene', (131, 135))	('1p/19q codeletion', 'Var', (166, 183))	('IDH1', 'Gene', '3417', (131, 135))	('MGMT', 'Gene', '4255', (144, 148))	('MGMT', 'Gene', (144, 148))
131833	33594759	We found that the risk score was higher in older patients (age > 40 years), and in patients with grade III, IDH1 wild-type, MGMT promoter unmethylated, patients receiving radiation therapy, and in those with 1p/19q non-codeletion (P <.05, Figure 6A-F).	('higher', 'PosReg', (33, 39))	('MGMT', 'Gene', (124, 128))	('1p/19q non-codeletion', 'Var', (208, 229))	('unmethylated', 'Var', (138, 150))	('MGMT', 'Gene', '4255', (124, 128))	('IDH1', 'Gene', '3417', (108, 112))	('patients', 'Species', '9606', (152, 160))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (83, 91))	('IDH1', 'Gene', (108, 112))	('non-codeletion', 'Var', (215, 229))
131842	33594759	7  High expression of VDAC2 was associated with a longer OS and negatively correlated with glioma grades.	('High expression', 'Var', (3, 18))	('glioma', 'Disease', (91, 97))	('longer OS', 'CPA', (50, 59))	('associated', 'Reg', (32, 42))	('VDAC2', 'Gene', '7417', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('VDAC2', 'Gene', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('negatively', 'NegReg', (64, 74))
131863	33594759	Age, grade, radiation therapy, IDH1 status, 1p/19q codeletion, MGMT promoter methylation and the risk score were significantly associated with OS in the univariate Cox regression analysis.	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('associated', 'Reg', (127, 137))	('IDH1', 'Gene', '3417', (31, 35))	('1p/19q codeletion', 'Var', (44, 61))	('IDH1', 'Gene', (31, 35))
131871	32280672	More than 70% of WHO grade II/III gliomas were found to harbor isocitrate dehydrogenase (IDH) mutations which generated targetable metabolic vulnerabilities.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('mutations', 'Var', (94, 103))	('III gliomas', 'Disease', 'MESH:D005910', (30, 41))	('isocitrate', 'Chemical', 'MESH:C034219', (63, 73))	('isocitrate dehydrogenase', 'Gene', (63, 87))	('III gliomas', 'Disease', (30, 41))	('IDH', 'Gene', (89, 92))	('glioma', 'Disease', (34, 40))	('isocitrate dehydrogenase', 'Gene', '3417', (63, 87))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
131874	32280672	More than 70% of WHO grade II/III gliomas were found to harbor IDH mutations which mainly included IDH1 mutations and IDH2 mutations.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH2', 'Gene', (118, 122))	('mutations', 'Var', (104, 113))	('IDH', 'Gene', (63, 66))	('IDH2', 'Gene', '3418', (118, 122))	('mutations', 'Var', (67, 76))	('IDH1', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (99, 103))	('mutations', 'Var', (123, 132))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
131875	32280672	IDH mutations predominantly occur at arginine 132 resulting in substitutions, including R132H (most common, 88%), R132C, R132L, R132S, and R132G.	('R132G', 'Var', (139, 144))	('R132L', 'Mutation', 'p.R132L', (121, 126))	('R132L', 'Var', (121, 126))	('R132G', 'Mutation', 'p.R132G', (139, 144))	('R132S', 'Var', (128, 133))	('R132H', 'Var', (88, 93))	('R132H', 'Mutation', 'p.R132H', (88, 93))	('R132S', 'Mutation', 'p.R132S', (128, 133))	('R132C', 'Var', (114, 119))	('R132C', 'Mutation', 'p.R132C', (114, 119))	('arginine', 'Chemical', 'MESH:D001120', (37, 45))
131877	32280672	The common function of IDH1/2 active site mutations is a neomorphic enzyme activity that catalyzes the conversion of alpha-KG to R-2-hydroxyglutarate (R-2HG), while oxidizing NADPH.	('R-2-hydroxyglutarate', 'Chemical', '-', (129, 149))	('IDH1/2', 'Gene', (23, 29))	('oxidizing', 'MPA', (165, 174))	('mutations', 'Var', (42, 51))	('conversion', 'MPA', (103, 113))
131878	32280672	Patients with IDH mutant gliomas had a better outcome than those with IDH wild-type genes.	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('Patients', 'Species', '9606', (0, 8))	('IDH mutant', 'Var', (14, 24))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
131882	32280672	There was no significant difference in the oxidized ACAA2 isoenzyme ACAA1 (Figure 4), suggesting that the IDH mutation is associated with the expression of ACAA2.	('associated', 'Reg', (122, 132))	('ACAA2', 'Disease', (156, 161))	('ACAA1', 'Gene', '30', (68, 73))	('mutation', 'Var', (110, 118))	('IDH', 'Gene', (106, 109))	('ACAA1', 'Gene', (68, 73))
131886	32280672	IDHs represent key enzymes within the tricarboxylic acid (TCA) cycle, and mutations of IDHs were believed to be involved in the metabolic processes of glucose, lipid, and amino acid in both physiology and pathology procedures.	('involved', 'Reg', (112, 120))	('TCA', 'Chemical', 'MESH:D014233', (58, 61))	('mutations', 'Var', (74, 83))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (38, 56))	('IDHs', 'Gene', (87, 91))	('lipid', 'Chemical', 'MESH:D008055', (160, 165))	('glucose', 'Chemical', 'MESH:D005947', (151, 158))
131887	32280672	For gliomas, mutation at Arg132 of IDH1, and at the analogous codon Arg172 of IDH2, represents early initiating events that drive the evolution of low-grade glioma, including grade II to III astrocytoma and oligodendroglioma.	('gliomas', 'Phenotype', 'HP:0009733', (4, 11))	('IDH1', 'Gene', (35, 39))	('Arg172', 'Chemical', '-', (68, 74))	('Arg172', 'Var', (68, 74))	('IDH2', 'Gene', (78, 82))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('oligodendroglioma', 'Disease', (207, 224))	('astrocytoma', 'Disease', 'MESH:D001254', (191, 202))	('mutation at Arg132', 'Var', (13, 31))	('low-grade glioma', 'Disease', (147, 163))	('oligodendroglioma', 'Disease', 'MESH:D009837', (207, 224))	('astrocytoma', 'Disease', (191, 202))	('Arg132', 'Chemical', '-', (25, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (191, 202))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))
131888	32280672	These mutations are also detected in grade IV glioblastoma (GBM), referred to as IDH1 mutant GBM, which account for ~10% of all grade IV clinical cases but are absent in pediatric high-grade malignancies and in nonglial subtypes of brain tumors.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('brain tumors', 'Disease', 'MESH:D001932', (232, 244))	('brain tumors', 'Phenotype', 'HP:0030692', (232, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('brain tumors', 'Disease', (232, 244))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('detected', 'Reg', (25, 33))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('malignancies', 'Disease', (191, 203))	('mutations', 'Var', (6, 15))
131897	27125842	Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies Insulin-like growth factor binding protein 2 (IGFBP2) overexpression is common in high-grade glioma and is both a strong biomarker of aggressive behaviour and a well-documented prognostic factor.	('IGFBP2', 'Gene', (107, 113))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (259, 279))	('Insulin-like growth factor binding protein 2', 'Gene', (125, 169))	('IGFBP2', 'Gene', (59, 65))	('IGFBP2', 'Gene', '16008', (171, 177))	('glioma', 'Disease', (218, 224))	('Insulin-like growth factor binding protein 2', 'Gene', '16008', (125, 169))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('overexpression', 'PosReg', (179, 193))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('IGFBP2', 'Gene', '16008', (59, 65))	('IGFBP2', 'Gene', (171, 177))	('IGFBP2', 'Gene', '16008', (107, 113))	('Glioma', 'Disease', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('aberrant', 'Var', (50, 58))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))
131904	27125842	Inhibition of IGFBP2 also impaired tumour cell spread.	('IGFBP2', 'Gene', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('Inhibition', 'Var', (0, 10))	('impaired tumour', 'Disease', (26, 41))	('impaired tumour', 'Disease', 'MESH:D001523', (26, 41))
131918	27125842	Although our earlier report demonstrated that inhibition of at least one major IGFBP2-mediated pathway impairs glioma progression, direct inhibition of IGFBP2 has not yet been assessed.	('glioma', 'Disease', (111, 117))	('inhibition', 'Var', (46, 56))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('IGFBP2-mediated', 'Gene', (79, 94))	('impairs', 'NegReg', (103, 110))
131949	27125842	The antibodies used for Western blot were IGFBP2 C-18 1:500 (Santa Cruz Biotechnology #6001), pEGFRY1068 (CST #3777), EGFR (CST #4267), pSTAT3Y705 (CST #9145), STAT3 (CST #9139), Bcl-xL (CST #2764), LSD1 (CST #2184), Actin I-19 (Santa Cruz Biotechnology #1616), Tubulin 1:2000 (CST #2128), Histone H3 1:5000 (CST #4499), Histone H3K9me2 1:2000 (CST #9753), Histone H3K27me3 1:2000 (CST #9733), pAktS473 (CST # 4051), Akt (CST #9272), and GFP (BD Bioscience #632375).	('STAT3', 'Gene', (137, 142))	('Bcl-xL', 'Gene', (179, 185))	('STAT3', 'Gene', (160, 165))	('Bcl-xL', 'Gene', '12048', (179, 185))	('CST #9733', 'Var', (382, 391))	('CST #9139', 'Var', (167, 176))	('Akt', 'Gene', (395, 398))	('Akt', 'Gene', (417, 420))	('Histone H3K27me3', 'Protein', (357, 373))	('Akt', 'Gene', '11651', (395, 398))	('CST #9272', 'Var', (422, 431))	('CST # 4051', 'Var', (404, 414))	('Akt', 'Gene', '11651', (417, 420))	('CST #', 'Var', (205, 210))	('STAT3', 'Gene', '20848', (137, 142))	('EGFR', 'Gene', (95, 99))	('EGFR', 'Gene', '13649', (95, 99))	('STAT3', 'Gene', '20848', (160, 165))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', '13649', (118, 122))	('CST #2764', 'Var', (187, 196))
131995	27125842	As IGFBP2 inhibition resulted in primarily low-grade and diffuse tumours, we assessed overall tumour size and the tumour's spread from the injection site to the contralateral hemisphere as indicators of tumour cell migration and invasion capacity.	('tumour', 'Disease', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('tumour cell migration', 'Disease', (203, 224))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('tumour', 'Disease', (203, 209))	('tumours', 'Disease', (65, 72))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('inhibition', 'Var', (10, 20))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', (114, 120))	('tumour cell migration', 'Disease', 'MESH:D014085', (203, 224))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('IGFBP2', 'Gene', (3, 9))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
132002	27125842	Treatment with the IGFBP2-neutralizing antibody led to a reduction in the levels of phosphorylated (activated) EGFR and STAT3, as well as decreased expression of the STAT3 downstream target, Bcl-xL (Figure 4A).	('Bcl-xL', 'Gene', '12048', (191, 197))	('IGFBP2-neutralizing', 'Gene', (19, 38))	('decreased', 'NegReg', (138, 147))	('STAT3', 'Gene', (166, 171))	('reduction', 'NegReg', (57, 66))	('EGFR', 'Gene', '13649', (111, 115))	('STAT3', 'Gene', '20848', (120, 125))	('EGFR', 'Gene', (111, 115))	('antibody', 'Var', (39, 47))	('IGFBP2-neutralizing', 'Var', (19, 38))	('expression', 'MPA', (148, 158))	('STAT3', 'Gene', (120, 125))	('STAT3', 'Gene', '20848', (166, 171))	('Bcl-xL', 'Gene', (191, 197))
132003	27125842	Neutralization of IGFBP2 also led to decreased levels of phosphorylated Akt (Supplementary Figure 4).	('Akt', 'Gene', '11651', (72, 75))	('levels of phosphorylated', 'MPA', (47, 71))	('Akt', 'Gene', (72, 75))	('IGFBP2', 'Gene', (18, 24))	('Neutralization', 'Var', (0, 14))	('decreased', 'NegReg', (37, 46))
132010	27125842	Overexpression of IGFBP2 is one of the most consistent and significant events associated with poor prognosis, tumour progression, and tumour recurrence.	('associated', 'Reg', (78, 88))	('IGFBP2', 'Gene', (18, 24))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('poor', 'Disease', (94, 98))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Disease', (134, 140))	('Overexpression', 'Var', (0, 14))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
132019	27125842	This is consistent with observations in patients, where IGFBP2 levels are associated with poorer survival not only in GBM patients, but also among LGG patients.	('IGFBP2', 'Gene', (56, 62))	('survival', 'MPA', (97, 105))	('patients', 'Species', '9606', (40, 48))	('levels', 'Var', (63, 69))	('poorer', 'NegReg', (90, 96))	('LGG', 'Chemical', '-', (147, 150))	('patients', 'Species', '9606', (151, 159))	('GBM', 'Disease', (118, 121))	('patients', 'Species', '9606', (122, 130))
132023	27125842	These findings not only solidify the concept that IGFBP2 is a driver of tumorigenesis but also suggest there is a key window during which IGFBP2 establishes a more aggressive tumour and in which therapeutic intervention may be most effective.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('IGFBP2', 'Var', (138, 144))	('aggressive tumour', 'Disease', 'MESH:D001523', (164, 181))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('aggressive tumour', 'Disease', (164, 181))
132031	27125842	In GBM cases, TCGA protein lysate array data indicate that IGFBP2 levels are significantly decreased in G-CIMP+ cases, although the IGFBP2 promoter itself does not appear to be methylated.	('IGFBP2 levels', 'MPA', (59, 72))	('G-CIMP+', 'Chemical', '-', (104, 111))	('G-CIMP+', 'Var', (104, 111))	('decreased', 'NegReg', (91, 100))
132033	27125842	Both of these observations are consistent with earlier reports that associate IGFBP2 expression with hypomethylation and are consistent with IGFBP2 being a poor prognostic factor, as IDH mutation and G-CIMP+ confer better prognosis.	('IDH', 'Gene', (183, 186))	('G-CIMP+', 'Chemical', '-', (200, 207))	('G-CIMP+', 'Var', (200, 207))	('IGFBP2', 'Gene', (78, 84))	('hypomethylation', 'MPA', (101, 116))	('IDH', 'Gene', '15926', (183, 186))	('better', 'PosReg', (215, 221))
132035	27125842	For example, IDH mutation occurs as an early event in tumorigenesis, programming these tumours to develop and progress in a manner that may not require IGFBP2 for progression but also imparting a better overall prognosis.	('tumours', 'Disease', (87, 94))	('programming', 'Reg', (69, 80))	('IDH', 'Gene', '15926', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumor', 'Disease', (54, 59))	('IDH', 'Gene', (13, 16))	('tumours', 'Disease', 'MESH:D009369', (87, 94))
132040	27125842	We also recently demonstrated that siRNA-based inhibition of IGFBP2 and mutation of the nuclear localization signal of IGFBP2 impaired glioma cell migration and invasion, demonstrating that IGFBP2 has nuclear roles in addition to secreted activities, findings that must be considered in assessing the therapeutic impacts of IGFBP2-neutralizing antibodies.	('inhibition', 'NegReg', (47, 57))	('impaired glioma cell migration', 'Disease', 'MESH:D005910', (126, 156))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('IGFBP2', 'Gene', (61, 67))	('impaired glioma cell migration', 'Disease', (126, 156))	('IGFBP2', 'Gene', (119, 125))	('mutation', 'Var', (72, 80))
132044	27125842	Inhibition of IGFBP2 in several cancer cells and animal models sensitizes tumour cells to traditional chemotherapeutic agents such as docetaxel, 5-FU, and doxorubicin in prostate and breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (183, 196))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('docetaxel', 'Chemical', 'MESH:D000077143', (134, 143))	('5-FU', 'Chemical', 'MESH:D005472', (145, 149))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('sensitizes', 'Reg', (63, 73))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('doxorubicin', 'Chemical', 'MESH:D004317', (155, 166))	('Inhibition', 'Var', (0, 10))	('prostate', 'Disease', (170, 178))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('IGFBP2', 'Gene', (14, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
132045	27125842	IGFBP2 inhibition has also been demonstrated to sensitize some GSCs to temozolomide.	('temozolomide', 'Chemical', 'MESH:D000077204', (71, 83))	('inhibition', 'Var', (7, 17))	('sensitize', 'Reg', (48, 57))	('IGFBP2', 'Gene', (0, 6))	('GSCs', 'Disease', (63, 67))
132048	27125842	IGFBP2 inhibition resulted in fewer high-grade tumours, but we were unable to directly determine whether IGFBP2 inhibition resulted in tumour regression.	('tumour', 'Disease', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumour', 'Disease', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('inhibition', 'Var', (7, 17))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('fewer', 'NegReg', (30, 35))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('IGFBP2', 'Gene', (0, 6))
132073	32650779	Overexpression of HOTAIR has been associated with poor prognosis, invasiveness and aggressiveness of various cancer types.	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('HOTAIR', 'Gene', (18, 24))	('invasiveness and aggressiveness of various cancer', 'Disease', 'MESH:D009362', (66, 115))	('HOTAIR', 'Gene', '100124700', (18, 24))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
132074	32650779	Complex secondary structure and ability to form independent structural domains ensure the multi-acting nature of HOTAIR and it has been defined to contribute to various cellular mechanisms via different molecular interactions such as scaffolding protein complexes, decoying microRNAs, epigenetically targeting genes and enabling RNA-protein/DNA-protein interactions.	('microRNAs', 'MPA', (274, 283))	('epigenetically targeting', 'Var', (285, 309))	('enabling', 'PosReg', (320, 328))	('HOTAIR', 'Gene', (113, 119))	('RNA-protein/DNA-protein interactions', 'Interaction', (329, 365))	('contribute', 'Reg', (147, 157))	('HOTAIR', 'Gene', '100124700', (113, 119))	('genes', 'Gene', (310, 315))	('decoying', 'NegReg', (265, 273))
132111	32650779	The cells were lysed using RIPA lysis buffer containing 1 mM Na3VO2, 1 mM NaF, and 1% protease inhibitor cocktail (Roche Diagnostics, Indianapolis, IN, USA), and the lysates were subjected to Western blot analysis as described previously.	('NaF', 'Gene', '3576', (74, 77))	('NaF', 'Gene', (74, 77))	('Na3VO2', 'Chemical', '-', (61, 67))	('RIPA lysis buffer', 'Chemical', '-', (27, 44))	('Na3VO2', 'Var', (61, 67))
132147	32650779	Analysis of three independent experiments showed that average of 45% knock-down of HOTAIR (Fig.	('knock-down', 'Var', (69, 79))	('HOTAIR', 'Gene', (83, 89))	('HOTAIR', 'Gene', '100124700', (83, 89))
132175	32650779	We further confirmed the rescue of HGF-suppressed HOTAIR expression after c-Met tyrosine kinase inhibition by SU11274 in HCC cell lines HuH-7, SNU-449, MAHLAVU and SK-HEP-1.	('HCC', 'Gene', '619501', (121, 124))	('HuH-7', 'Gene', '284424', (136, 141))	('SK-HEP-1', 'CellLine', 'CVCL:0525', (164, 172))	('HuH-7', 'Gene', (136, 141))	('HOTAIR', 'Gene', (50, 56))	('HGF', 'Gene', (35, 38))	('c-Met', 'Gene', (74, 79))	('SNU-449', 'CellLine', 'CVCL:0454', (143, 150))	('HCC', 'Gene', (121, 124))	('c-Met', 'Gene', '4233', (74, 79))	('HOTAIR', 'Gene', '100124700', (50, 56))	('SU11274', 'Var', (110, 117))	('SU11274', 'Chemical', 'MESH:C478479', (110, 117))	('HGF', 'Gene', '3082', (35, 38))	('inhibition', 'NegReg', (96, 106))
132176	32650779	c-Met tyrosine kinase inhibition rescued HGF-induced HOTAIR suppression in HCC cell lines (Fig.	('inhibition', 'Var', (22, 32))	('c-Met', 'Gene', '4233', (0, 5))	('HCC', 'Gene', '619501', (75, 78))	('HOTAIR', 'Gene', (53, 59))	('HGF', 'Gene', (41, 44))	('HOTAIR', 'Gene', '100124700', (53, 59))	('HGF', 'Gene', '3082', (41, 44))	('HCC', 'Gene', (75, 78))	('c-Met', 'Gene', (0, 5))
132206	32650779	Immunofluorescent analysis of cytoskeletal organization of F-actin and Vimentin in SNU-398 MET OE clones showed that ectopic MET expression and its suppressive effect on HOTAIR expression was also resulted in thickening of F-actin stress fibrils, and increase in Vimentin expression and polarity (Supplementary Fig.	('Vimentin', 'Gene', '7431', (71, 79))	('ectopic MET expression', 'Var', (117, 139))	('SNU-398', 'CellLine', 'CVCL:0077', (83, 90))	('expression', 'MPA', (272, 282))	('polarity', 'CPA', (287, 295))	('HOTAIR', 'Gene', (170, 176))	('Vimentin', 'Gene', (263, 271))	('HOTAIR', 'Gene', '100124700', (170, 176))	('Vimentin', 'Gene', (71, 79))	('F-actin stress', 'Protein', (223, 237))	('increase', 'PosReg', (251, 259))	('Vimentin', 'Gene', '7431', (263, 271))	('thickening', 'PosReg', (209, 219))
132228	32650779	It is very important to note that inhibition of expression with siRNAs is limited mostly with cytoplasmic HOTAIR mRNA targeting and further studies should be done to address the detailed mechanism of HOTAIR action in means of molecular interactions and/or epigenetic function in HCC cells.	('HOTAIR', 'Gene', (200, 206))	('HCC', 'Gene', '619501', (279, 282))	('HOTAIR', 'Gene', '100124700', (200, 206))	('HCC', 'Gene', (279, 282))	('epigenetic function', 'Var', (256, 275))	('HOTAIR', 'Gene', (106, 112))	('HOTAIR', 'Gene', '100124700', (106, 112))
132236	32650779	HOTAIR over-expression reduced Caveolin-1 expression and activation via suppressing activation of c-Met and its downstream effector Src kinase.	('HOTAIR', 'Gene', '100124700', (0, 6))	('Src', 'Gene', '6714', (132, 135))	('Caveolin-1', 'Gene', '857', (31, 41))	('expression', 'MPA', (42, 52))	('HOTAIR', 'Gene', (0, 6))	('Caveolin-1', 'Gene', (31, 41))	('c-Met', 'Gene', (98, 103))	('over-expression', 'Var', (7, 22))	('activation', 'MPA', (84, 94))	('suppressing', 'NegReg', (72, 83))	('Src', 'Gene', (132, 135))	('reduced', 'NegReg', (23, 30))	('c-Met', 'Gene', '4233', (98, 103))	('activation', 'MPA', (57, 67))
132238	32650779	defined function of HOTAIR in epigenetic regulation of its target genes and they reported Caveolin-1 as one of the most differentially expressed genes in response to HOTAIR knock-down in foreskin fibroblasts.	('epigenetic regulation', 'MPA', (30, 51))	('HOTAIR', 'Gene', (166, 172))	('Caveolin-1', 'Gene', '857', (90, 100))	('HOTAIR', 'Gene', '100124700', (166, 172))	('HOTAIR', 'Gene', (20, 26))	('Caveolin-1', 'Gene', (90, 100))	('knock-down', 'Var', (173, 183))	('HOTAIR', 'Gene', '100124700', (20, 26))
132239	32650779	In addition to the HOTAIR OE data, we showed that HOTAIR knock-down elevated CAV1 expression in HuH-7 cells (Supplementary Fig.	('CAV1', 'Gene', (77, 81))	('expression', 'MPA', (82, 92))	('HOTAIR', 'Gene', (19, 25))	('HOTAIR', 'Gene', (50, 56))	('elevated', 'PosReg', (68, 76))	('HuH-7', 'Gene', '284424', (96, 101))	('CAV1', 'Gene', '857', (77, 81))	('HOTAIR', 'Gene', '100124700', (19, 25))	('HuH-7', 'Gene', (96, 101))	('HOTAIR', 'Gene', '100124700', (50, 56))	('knock-down', 'Var', (57, 67))
132254	32650779	As expected, by attainment of those abilities, HOTAIR over-expression increased metastatic ability of SNU-449 cells which was defined to be highly metastatic in our previous studies in zebrafish xenograft model.	('zebrafish', 'Species', '7955', (185, 194))	('increased', 'PosReg', (70, 79))	('over-expression', 'Var', (54, 69))	('SNU-449', 'CellLine', 'CVCL:0454', (102, 109))	('HOTAIR', 'Gene', (47, 53))	('HOTAIR', 'Gene', '100124700', (47, 53))	('metastatic ability', 'CPA', (80, 98))
132262	32650779	Consistent with HOTAIR over-expression data in SNU-449 cells, c-Met overexpression in SNU-398 cells increased F-actin stress fibrils and Vimentin expression and, HOTAIR knock-down induced Vimentin expression in HuH-7 cells (Supplementary Fig.	('HuH-7', 'Gene', (211, 216))	('c-Met', 'Gene', (62, 67))	('SNU-449', 'CellLine', 'CVCL:0454', (47, 54))	('HOTAIR', 'Gene', '100124700', (162, 168))	('F-actin stress fibrils', 'MPA', (110, 132))	('expression', 'MPA', (146, 156))	('Vimentin', 'Gene', '7431', (188, 196))	('increased', 'PosReg', (100, 109))	('HOTAIR', 'Gene', (162, 168))	('HOTAIR', 'Gene', '100124700', (16, 22))	('Vimentin', 'Gene', (188, 196))	('HuH-7', 'Gene', '284424', (211, 216))	('SNU-398', 'CellLine', 'CVCL:0077', (86, 93))	('c-Met', 'Gene', '4233', (62, 67))	('HOTAIR', 'Gene', (16, 22))	('knock-down', 'Var', (169, 179))	('expression', 'MPA', (197, 207))	('Vimentin', 'Gene', '7431', (137, 145))	('induced', 'Reg', (180, 187))	('Vimentin', 'Gene', (137, 145))
132275	32650779	Analysis of available data generated by siRNA knock-down of HOTAIR in an HCC cell line HepG2, (Fig.	('HCC', 'Gene', '619501', (73, 76))	('HOTAIR', 'Gene', (60, 66))	('HCC', 'Gene', (73, 76))	('HOTAIR', 'Gene', '100124700', (60, 66))	('knock-down', 'Var', (46, 56))	('HepG2', 'CellLine', 'CVCL:0027', (87, 92))
132282	32650779	Considering the complex structure and multifunctional behavior, HOTAIR might be regulating c-Met signaling through physically interacting and epigenetic or transcriptional suppression of c-Met and/or its regulators.	('c-Met', 'Gene', (187, 192))	('epigenetic or transcriptional', 'Var', (142, 171))	('HOTAIR', 'Gene', (64, 70))	('c-Met', 'Gene', (91, 96))	('c-Met', 'Gene', '4233', (187, 192))	('c-Met', 'Gene', '4233', (91, 96))	('regulating', 'Reg', (80, 90))	('HOTAIR', 'Gene', '100124700', (64, 70))	('suppression', 'NegReg', (172, 183))
132284	32650779	In conclusion, HOTAIR over-expression suppresses c-Met expression, activation and also disrupts its organization on plasma membrane by modulating Caveolin-1 expression and activation.	('expression', 'MPA', (157, 167))	('c-Met', 'Gene', (49, 54))	('over-expression', 'Var', (22, 37))	('Caveolin-1', 'Gene', '857', (146, 156))	('activation', 'MPA', (172, 182))	('c-Met', 'Gene', '4233', (49, 54))	('HOTAIR', 'Gene', (15, 21))	('modulating', 'Reg', (135, 145))	('organization on plasma membrane', 'MPA', (100, 131))	('disrupts', 'NegReg', (87, 95))	('HOTAIR', 'Gene', '100124700', (15, 21))	('suppresses', 'NegReg', (38, 48))	('Caveolin-1', 'Gene', (146, 156))	('activation', 'MPA', (67, 77))
132293	32650779	https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89377 Wu et al., 2018, performed an integrated proteomic and transcriptomic analysis to examine the overall transcriptomic changes in HepG2 cells after HOTAIR knockdown by RNA sequencing (data accessible at NCBI GEO database (Wu et al., 2018), accession GSE98091).	('HOTAIR', 'Gene', '100124700', (206, 212))	('knockdown', 'Var', (213, 222))	('HepG2', 'CellLine', 'CVCL:0027', (188, 193))	('HOTAIR', 'Gene', (206, 212))
132358	31075771	According to the guideline of the European Association for Neuro-Oncology (EANO), negative immunostaining for IDH1-R132H mutation was followed by sequencing for alternative mutations in IDH1 or IDH2 in patients who were 55 years of age or younger at diagnosis or had a history of a pre-existing lower-grade glioma.	('IDH1', 'Gene', '3417', (110, 114))	('IDH1', 'Gene', (186, 190))	('IDH2', 'Gene', (194, 198))	('glioma', 'Disease', (307, 313))	('IDH1', 'Gene', '3417', (186, 190))	('IDH2', 'Gene', '3418', (194, 198))	('mutations', 'Var', (173, 182))	('patients', 'Species', '9606', (202, 210))	('R132H', 'Mutation', 'rs121913500', (115, 120))	('glioma', 'Disease', 'MESH:D005910', (307, 313))	('Oncology', 'Phenotype', 'HP:0002664', (65, 73))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('IDH1', 'Gene', (110, 114))
132384	31075771	A significantly higher mean percentage of tumor cells (62% vs 34%, p = 0.005) and frequency of high-grade histology (p = 0.001) were found in fluorescing compared to nonfluorescing samples.	('higher', 'PosReg', (16, 22))	('fluorescing', 'Var', (142, 153))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('high-grade histology', 'CPA', (95, 115))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
132386	31075771	In the single patient with CPpIX < 0.001 mug/ml, only 1 suspected tumor region was available for analysis, and it did not contain tumor tissue according to histopathological assessment.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('< 0.001 mug/ml', 'Var', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PpIX', 'Chemical', 'MESH:C028025', (28, 32))	('men', 'Species', '9606', (180, 183))	('patient', 'Species', '9606', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CPpIX', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (130, 135))
132414	31075771	In this sense, a significantly higher percentage of tumor cells and frequency of high-grade histology were found in fluorescing compared to nonfluorescing samples.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('fluorescing', 'Var', (116, 127))	('higher', 'PosReg', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('high-grade histology', 'CPA', (81, 101))
132424	31075771	Moreover, quantitative PpIX analysis was able to markedly increase the sensitivity (58% vs 30%) for detection of tumor tissue and the NPV (59% vs 31%) compared to visible fluorescence.	('tumor', 'Disease', (113, 118))	('increase', 'PosReg', (58, 66))	('PpIX', 'Gene', (23, 27))	('analysis', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PpIX', 'Chemical', 'MESH:C028025', (23, 27))
132544	30510874	Median survival was 10 months for patients with FDG PET scores of 2 or 3 (glucose uptake>/=adjacent cortex) and 20 months for those with scores of 0 or 1 (glucose uptake</=adjacent cortex).	('glucose', 'Chemical', 'MESH:D005947', (155, 162))	('FDG', 'Chemical', 'MESH:D019788', (48, 51))	('FDG PET', 'Gene', (48, 55))	('scores', 'Var', (56, 62))	('patients', 'Species', '9606', (34, 42))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))
132575	28586047	Previous studies have determined that alteration of miRNA expression level is associated with development and prognosis of human cancers, including pancreatic, breast, non-small cell lung and ovarian cancer.	('associated', 'Reg', (78, 88))	('pancreatic', 'Disease', 'MESH:D010195', (148, 158))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (192, 206))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('pancreatic', 'Disease', (148, 158))	('human', 'Species', '9606', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('ovarian cancer', 'Disease', 'MESH:D010051', (192, 206))	('cancers', 'Disease', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('small cell lung and ovarian cancer', 'Phenotype', 'HP:0030357', (172, 206))	('breast', 'Disease', (160, 166))	('alteration', 'Var', (38, 48))	('miRNA expression level', 'MPA', (52, 74))	('non-small cell lung', 'Disease', (168, 187))	('ovarian cancer', 'Disease', (192, 206))
132588	28586047	In the Cox proportional hazard regression analysis, 3 miRNAs including has-miR-1287, has-miR-326 and has-miR-1275 were considered as risk miRNAs for cerebral LGGs prognosis (Table I).	('miR-326', 'Gene', '442900', (89, 96))	('has-miR-1275', 'Var', (101, 113))	('miR-1287', 'Gene', (75, 83))	('cerebral LGGs', 'Disease', (149, 162))	('miR-326', 'Gene', (89, 96))	('miR-1287', 'Gene', '100302133', (75, 83))
132610	28586047	Additionally, miR-326 may be a potential tumor suppressor in glioma cells, and transfection of miR-326 into glioma cells may reduce tumorigenicity.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('glioma', 'Disease', (108, 114))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('miR-326', 'Gene', '442900', (14, 21))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR-326', 'Gene', (95, 102))	('tumor', 'Disease', (132, 137))	('reduce', 'NegReg', (125, 131))	('transfection', 'Var', (79, 91))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('miR-326', 'Gene', (14, 21))	('miR-326', 'Gene', '442900', (95, 102))
132612	28586047	From the results of survival analysis, patients with high expression of miR-326 had reduced survival compared with those with low expression of it.	('patients', 'Species', '9606', (39, 47))	('miR-326', 'Gene', '442900', (72, 79))	('reduced', 'NegReg', (84, 91))	('survival', 'MPA', (92, 100))	('high expression', 'Var', (53, 68))	('miR-326', 'Gene', (72, 79))
132619	28586047	Additionally, NGF may stimulate SOS1 and activate Ras signaling to exert various functions in cell proliferation.	('SOS1', 'Gene', (32, 36))	('stimulate', 'PosReg', (22, 31))	('activate', 'PosReg', (41, 49))	('SOS1', 'Gene', '6654', (32, 36))	('NGF', 'Var', (14, 17))	('cell proliferation', 'CPA', (94, 112))	('Ras signaling', 'Pathway', (50, 63))
132653	27672334	However, recent works by Brat et al have led to a paradigm shift in the classification of gliomas by focusing on molecular markers: namely, the mutational statuses of isocitrate dehydrogenase and codeletion of 1p and 19q chromosomal arms were found to better predict the clinical behavior of these tumors compared to histological assessment alone.	('better', 'PosReg', (252, 258))	('gliomas', 'Disease', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('codeletion', 'Var', (196, 206))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('tumors', 'Disease', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('predict', 'Reg', (259, 266))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('mutational', 'Var', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
132682	27672334	The sensitivity and specificity of 5-ALA-induced fluorescence were 85% and 100%, respectively; fluorescence resulted in greater resection of the tumor in seven of nine patients (Table 1).	('greater', 'PosReg', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('resection', 'CPA', (128, 137))	('tumor', 'Disease', (145, 150))	('fluorescence', 'Var', (95, 107))	('patients', 'Species', '9606', (168, 176))	('5-ALA', 'Chemical', 'MESH:C000614854', (35, 40))
132751	27672334	Complication rate, including new neurological deficit 30 days after surgery, was 8% for the residual fluorescence group compared to 18.5% in patients without residual fluorescence; however, the difference was not significant (P=0.267).	('neurological deficit', 'Disease', (33, 53))	('neurological deficit', 'Phenotype', 'HP:0000707', (33, 53))	('residual fluorescence', 'Var', (92, 113))	('new neurological deficit', 'Phenotype', 'HP:0002344', (29, 53))	('neurological deficit', 'Disease', 'MESH:D009461', (33, 53))	('patients', 'Species', '9606', (141, 149))
132814	27672334	The strongest predictor of GTR was noneloquent localization of the tumor (OR: 0.082, P<0.01).	('noneloquent localization', 'Var', (35, 59))	('GTR', 'Chemical', '-', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('GTR', 'Disease', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
132875	27672334	For example, conjugation of EGF to 5-ALA can target EGFR + gliomas, ultimately improving their visualization and resection (Figure 4).	('conjugation', 'Var', (13, 24))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('resection', 'CPA', (113, 122))	('improving', 'PosReg', (79, 88))	('5-ALA', 'Chemical', 'MESH:C000614854', (35, 40))	('gliomas', 'Disease', (59, 66))	('visualization', 'MPA', (95, 108))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
132878	33481830	In our previous study we showed that PTENP1 methylation is present not only in tumor, but also in normal endometrium tissues of women over 45 years old.	('women', 'Species', '9606', (128, 133))	('methylation', 'Var', (44, 55))	('tumor', 'Disease', (79, 84))	('PTENP1', 'Gene', (37, 43))	('PTENP1', 'Gene', '11191', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
132883	33481830	According to our data, PTENP1 methylation elevates the level of the pseudogene sense transcript.	('level of the pseudogene sense transcript', 'MPA', (55, 95))	('methylation', 'Var', (30, 41))	('elevates', 'PosReg', (42, 50))	('PTENP1', 'Gene', (23, 29))	('PTENP1', 'Gene', '11191', (23, 29))
132885	33481830	The data obtained suggested that PTENP1 methylation is associated with age-related changes in normal and hyperplastic endometrial tissues.	('methylation', 'Var', (40, 51))	('hyperplastic endometrial tissues', 'Phenotype', 'HP:0040298', (105, 137))	('PTENP1', 'Gene', (33, 39))	('PTENP1', 'Gene', '11191', (33, 39))	('associated', 'Reg', (55, 65))
132888	33481830	The trend is the most pronounced in case of the sequences located in the promoter CGIs of the genes of transcription factors and specific receptors, reparation system genes, epigenetic regulation of genome functioning, and other genes, including those acting as tumor suppressors, as it has been demonstrated for human peripheral blood leukocytes.	('sequences', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('human', 'Species', '9606', (313, 318))	('tumor', 'Disease', (262, 267))	('epigenetic', 'Var', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
132891	33481830	In endometrial cancer, hypermethylation affects tumor suppressor genes (for example, MLH1, RASSF1A, APC, KLF4, ALDH1A2, and PCDH10), as well as genes, the products of which are involved in cell adhesion (SVEP1), differentiation (FGF12, TNFSF11, ASCL1), and embryogenesis (NODAL, TBX18).	('RASSF1A', 'Gene', '11186', (91, 98))	('TBX18', 'Gene', '9096', (279, 284))	('KLF4', 'Gene', '9314', (105, 109))	('RASSF1A', 'Gene', (91, 98))	('FGF12', 'Gene', (229, 234))	('SVEP1', 'Gene', '79987', (204, 209))	('PCDH10', 'Gene', (124, 130))	('MLH1', 'Gene', (85, 89))	('APC', 'Disease', 'MESH:D011125', (100, 103))	('APC', 'Disease', (100, 103))	('PCDH10', 'Gene', '57575', (124, 130))	('hypermethylation', 'Var', (23, 39))	('TNFSF11', 'Gene', '8600', (236, 243))	('SVEP1', 'Gene', (204, 209))	('tumor', 'Disease', (48, 53))	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('MLH1', 'Gene', '4292', (85, 89))	('FGF12', 'Gene', '2257', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TNFSF11', 'Gene', (236, 243))	('endometrial cancer', 'Disease', (3, 21))	('ASCL1', 'Gene', '429', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('KLF4', 'Gene', (105, 109))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('ALDH1A2', 'Gene', '8854', (111, 118))	('ASCL1', 'Gene', (245, 250))	('TBX18', 'Gene', (279, 284))	('ALDH1A2', 'Gene', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
132892	33481830	In addition to protein-coding genes, hypermethylation in endometrial cancer was noted in the region of some enhancer sequences, as well as in a series of miRNA genes (MIR25, MIR93, MIR99, MIR106B, MIR324, MIR3074) and lncRNAs (e.g., MEG3).	('MEG3', 'Gene', '55384', (233, 237))	('MIR99', 'Var', (181, 186))	('MIR3074', 'Gene', (205, 212))	('MIR3074', 'Gene', '100422842', (205, 212))	('endometrial cancer', 'Phenotype', 'HP:0012114', (57, 75))	('MIR106B', 'Gene', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('MIR93', 'Gene', (174, 179))	('MIR93', 'Gene', '407051', (174, 179))	('hypermethylation', 'Var', (37, 53))	('endometrial cancer', 'Disease', (57, 75))	('MIR324', 'Gene', '442898', (197, 203))	('MEG3', 'Gene', (233, 237))	('MIR106B', 'Gene', '406900', (188, 195))	('MIR25', 'Gene', '407014', (167, 172))	('endometrial cancer', 'Disease', 'MESH:D016889', (57, 75))	('MIR25', 'Gene', (167, 172))	('MIR324', 'Gene', (197, 203))
132941	33481830	According to our data, we did not find significant differences in the frequency of pseudogene methylation between samples of normal endometrium and endometrial polyps (24% and 26.6% respectively).	('endometrial polyps', 'Disease', 'MESH:D011127', (148, 166))	('endometrial polyps', 'Disease', (148, 166))	('pseudogene methylation', 'Var', (83, 105))
132944	33481830	Therefore, we decided to divide the patients into age groups and compare the frequencies of PTENP1 methylation in normal endometrium, endometrial polyps, endometrial hyperplasia and endometrial carcinoma within each of the age groups, as well as compare the age groups with each other.	('endometrial polyps', 'Disease', 'MESH:D011127', (134, 152))	('methylation', 'Var', (99, 110))	('endometrial polyps', 'Disease', (134, 152))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (182, 203))	('patients', 'Species', '9606', (36, 44))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (154, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('PTENP1', 'Gene', (92, 98))	('endometrial carcinoma', 'Disease', (182, 203))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (182, 203))	('PTENP1', 'Gene', '11191', (92, 98))	('endometrial hyperplasia', 'Disease', (154, 177))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (154, 177))
132950	33481830	PTENP1 methylation frequency in the EP patients of group III was considerably lower than in women of the same age group with NE, EH, or EC (p < 0.05).	('PTENP1', 'Gene', (0, 6))	('EH', 'Phenotype', 'HP:0040298', (129, 131))	('patients', 'Species', '9606', (39, 47))	('women', 'Species', '9606', (92, 97))	('EP', 'Gene', '2069', (36, 38))	('methylation', 'Var', (7, 18))	('lower', 'NegReg', (78, 83))	('PTENP1', 'Gene', '11191', (0, 6))
132951	33481830	In the case of normal endometrium PTENP1 methylation was detected in 3.8% of samples obtained from women of age group I, in 20.8% of samples of age group II, and in 58% of samples of age group III (Table 3, Fig 2B).	('PTENP1', 'Gene', (34, 40))	('methylation', 'Var', (41, 52))	('women', 'Species', '9606', (99, 104))	('detected', 'Reg', (57, 65))	('PTENP1', 'Gene', '11191', (34, 40))
132953	33481830	Thus, PTENP1 methylation in normal endometrium starts to be particularly pronounced in women aged 45 years or older, which can be associated with approaching or ongoing menopause.	('methylation', 'Var', (13, 24))	('pronounced', 'Reg', (73, 83))	('associated', 'Reg', (130, 140))	('ongoing menopause', 'Phenotype', 'HP:0008209', (161, 178))	('women', 'Species', '9606', (87, 92))	('PTENP1', 'Gene', (6, 12))	('PTENP1', 'Gene', '11191', (6, 12))
132955	33481830	At the same time, we did not find significant differences in the frequencies of pseudogene methylation between the age groups of patients with endometrial carcinoma and women with endometrial polyps.	('endometrial carcinoma', 'Disease', (143, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('methylation', 'Var', (91, 102))	('women', 'Species', '9606', (169, 174))	('patients', 'Species', '9606', (129, 137))	('endometrial polyps', 'Disease', 'MESH:D011127', (180, 198))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (143, 164))	('endometrial polyps', 'Disease', (180, 198))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (143, 164))	('pseudogene methylation', 'Var', (80, 102))
132958	33481830	At the same time, a comparison of NE tissue samples from women under 45 years with groups of women over 45 years old revealed statistically significant differences in the frequencies of PTENP1 methylation.	('PTENP1', 'Gene', (186, 192))	('methylation', 'Var', (193, 204))	('PTENP1', 'Gene', '11191', (186, 192))	('women', 'Species', '9606', (57, 62))	('women', 'Species', '9606', (93, 98))	('differences', 'Reg', (152, 163))
132970	33481830	Therefore, we can propose that methylation of PTENP1 may promote its' expression.	("' expression", 'MPA', (68, 80))	('promote', 'PosReg', (57, 64))	('PTENP1', 'Gene', (46, 52))	('PTENP1', 'Gene', '11191', (46, 52))	('methylation', 'Var', (31, 42))
132972	33481830	Analysis of 7 human cell lines (COLO-357, HEK-293, HeLa, HepG2, MCF-7, SKBR-3 and SKOV-3) treated with different concentrations of 5-Azacytidine revealed that inhibition of DNA methylation significantly reduces PTENP1 level in all tested cell lines.	('DNA methylation', 'Protein', (173, 188))	('SKOV-3', 'CellLine', 'CVCL:0532', (82, 88))	('HEK-293', 'CellLine', 'CVCL:0045', (42, 49))	('5-Azacytidine', 'Chemical', 'MESH:D001374', (131, 144))	('COLO', 'Species', '307630', (32, 36))	('MCF-7', 'CellLine', 'CVCL:0031', (64, 69))	('reduces', 'NegReg', (203, 210))	('human', 'Species', '9606', (14, 19))	('HepG2', 'CellLine', 'CVCL:0027', (57, 62))	('SKBR-3', 'CellLine', 'CVCL:0033', (71, 77))	('PTENP1', 'Gene', (211, 217))	('PTENP1', 'Gene', '11191', (211, 217))	('HeLa', 'CellLine', 'CVCL:0030', (51, 55))	('inhibition', 'Var', (159, 169))
132974	33481830	The level of PTEN gene expression was decreased in most cells treated with 5-Azacytidine with the exception of HEK-293 and MCF-7 cells (the level remained unchanged).	('decreased', 'NegReg', (38, 47))	('5-Azacytidine', 'Var', (75, 88))	('MCF-7', 'CellLine', 'CVCL:0031', (123, 128))	('level', 'MPA', (4, 9))	('HEK-293', 'CellLine', 'CVCL:0045', (111, 118))	('5-Azacytidine', 'Chemical', 'MESH:D001374', (75, 88))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))
132978	33481830	Altogether, our data confirm that in all 8 tested cell lines CpG methylation may promote PTENP1 expression.	('promote', 'PosReg', (81, 88))	('expression', 'MPA', (96, 106))	('methylation', 'Var', (65, 76))	('CpG methylation', 'Var', (61, 76))	('PTENP1', 'Gene', (89, 95))	('PTENP1', 'Gene', '11191', (89, 95))
132986	33481830	On the other hand, in acute myeloid leukemia and lower grade glioma patients PTENP1 hypermethylation strongly correlated with favorable prognosis (Fig 5C and 5D).	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('acute myeloid leukemia', 'Disease', (22, 44))	('correlated', 'Reg', (110, 120))	('PTENP1', 'Gene', (77, 83))	('glioma', 'Disease', (61, 67))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (28, 44))	('patients', 'Species', '9606', (68, 76))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (22, 44))	('PTENP1', 'Gene', '11191', (77, 83))	('hypermethylation', 'Var', (84, 100))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (22, 44))
132987	33481830	In contrast, in sarcoma, hypermethylation of pseudogene was found in patients with shorter survival (Fig 5B).	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('hypermethylation', 'Var', (25, 41))	('sarcoma', 'Disease', (16, 23))	('shorter', 'NegReg', (83, 90))	('pseudogene', 'Protein', (45, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('found', 'Reg', (60, 65))	('patients', 'Species', '9606', (69, 77))
132989	33481830	Data obtained in this study demonstrates that PTENP1 methylation may reflect age-related changes that occur in endometrium after the age of 45 and may indirectly indicate the approach or onset of menopause.	('indicate', 'Reg', (162, 170))	('PTENP1', 'Gene', (46, 52))	('PTENP1', 'Gene', '11191', (46, 52))	('methylation', 'Var', (53, 64))	('onset of menopause', 'Phenotype', 'HP:0008209', (187, 205))
132990	33481830	This statement may be true for normal endometrium, endometrial hyperplasia, and endometrial carcinoma, but not for endometrial polyps, since the frequency of pseudogene methylation in EP tissue does not change with age.	('EP', 'Gene', '2069', (184, 186))	('endometrial hyperplasia', 'Disease', (51, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (51, 74))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (80, 101))	('endometrial polyps', 'Disease', 'MESH:D011127', (115, 133))	('pseudogene methylation', 'Var', (158, 180))	('endometrial polyps', 'Disease', (115, 133))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (51, 74))	('endometrial carcinoma', 'Disease', (80, 101))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))
132996	33481830	In this study we showed that EP has also epigenetic peculiarities: the frequency of PTENP1 methylation in EP does not depend on patient's age.	('methylation', 'Var', (91, 102))	('PTENP1', 'Gene', (84, 90))	('EP', 'Gene', '2069', (29, 31))	('PTENP1', 'Gene', '11191', (84, 90))	('EP', 'Gene', '2069', (106, 108))	('patient', 'Species', '9606', (128, 135))
133001	33481830	Incubation of cultured cells with methylase inhibitors 5-Azacytidine or 5-Aza-2'-deoxycytidine led to a decrease in the PTENP1 expression in all 8 tested cell lines.	('5-Azacytidine', 'Chemical', 'MESH:D001374', (55, 68))	('expression', 'MPA', (127, 137))	('PTENP1', 'Gene', (120, 126))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (72, 94))	("5-Aza-2'-deoxycytidine", 'Var', (72, 94))	('decrease', 'NegReg', (104, 112))	('PTENP1', 'Gene', '11191', (120, 126))	('5-Azacytidine', 'Var', (55, 68))
133003	33481830	These results suggested that PTENP1 methylation contributes to an increase in the level of PTENP1 sense non-coding RNA as well as PTEN mRNA.	('level', 'MPA', (82, 87))	('increase', 'PosReg', (66, 74))	('PTENP1', 'Gene', (29, 35))	('PTENP1', 'Gene', '11191', (29, 35))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('PTENP1', 'Gene', (91, 97))	('PTEN', 'Gene', '5728', (91, 95))	('PTEN', 'Gene', (91, 95))	('PTENP1', 'Gene', '11191', (91, 97))	('PTEN', 'Gene', (130, 134))	('PTEN', 'Gene', '5728', (130, 134))	('methylation', 'Var', (36, 47))
133004	33481830	Interestingly, the decrease in the level of PTENP1 after treatment with 5-Azacytidine was found not only in those lines in which we detected methylation of the pseudogene promoter (HeLa, SKOV-3, HepG2 and MCF-7), but also in those lines in which we did not detect the methylation (HEK-293, COLO-357 and SKBR-3).	('5-Azacytidine', 'Chemical', 'MESH:D001374', (72, 85))	('decrease', 'NegReg', (19, 27))	('COLO', 'Species', '307630', (290, 294))	('SKBR-3', 'CellLine', 'CVCL:0033', (303, 309))	('PTENP1', 'Gene', (44, 50))	('SKOV-3', 'CellLine', 'CVCL:0532', (187, 193))	('HeLa', 'CellLine', 'CVCL:0030', (181, 185))	('methylation', 'Var', (141, 152))	('PTENP1', 'Gene', '11191', (44, 50))	('HepG2', 'CellLine', 'CVCL:0027', (195, 200))	('HEK-293', 'CellLine', 'CVCL:0045', (281, 288))	('MCF-7', 'CellLine', 'CVCL:0031', (205, 210))
133010	33481830	In addition, methylation of exons 1 and 2 also increases the level of hTERT gene expression.	('hTERT', 'Gene', '7015', (70, 75))	('methylation', 'Var', (13, 24))	('hTERT', 'Gene', (70, 75))	('increases', 'PosReg', (47, 56))	('level', 'MPA', (61, 66))
133012	33481830	When the sequences are methylated, the CTCF binding efficiency is very low.	('low', 'NegReg', (71, 74))	('CTCF', 'Gene', '10664', (39, 43))	('methylated', 'Var', (23, 33))	('CTCF', 'Gene', (39, 43))
133014	33481830	The promoter methylation could inhibit the binding of p53 (a repressor of Survivin expression) and leads to an increase in mRNA level.	('promoter methylation', 'Var', (4, 24))	('binding', 'Interaction', (43, 50))	('increase', 'PosReg', (111, 119))	('methylation', 'Var', (13, 24))	('p53', 'Gene', (54, 57))	('p53', 'Gene', '7157', (54, 57))	('inhibit', 'NegReg', (31, 38))	('mRNA level', 'MPA', (123, 133))
133016	33481830	Since PTENP1 methylation is likely to contribute to an increase in its expression level, it can be assumed that this epigenetic modification should correlate with a more favorable prognosis for patients with cancer.	('increase', 'PosReg', (55, 63))	('cancer', 'Disease', (208, 214))	('patients', 'Species', '9606', (194, 202))	('methylation', 'Var', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('expression level', 'MPA', (71, 87))	('PTENP1', 'Gene', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('PTENP1', 'Gene', '11191', (6, 12))
133018	33481830	In contrast, in sarcoma, PTENP1 methylation is correlated with a poor prognosis.	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('methylation', 'Var', (32, 43))	('sarcoma', 'Disease', (16, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('PTENP1', 'Gene', (25, 31))	('PTENP1', 'Gene', '11191', (25, 31))
133021	33481830	For example, Chengping Wu and colleagues showed that PTENP1 may serve as a sponge for miR-27a-3p to upregulate EGR1 level in cervical cancer cells.	('PTENP1', 'Gene', (53, 59))	('EGR1', 'Gene', (111, 115))	('PTENP1', 'Gene', '11191', (53, 59))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('EGR1', 'Gene', '1958', (111, 115))	('miR-27a-3p', 'Var', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('upregulate', 'PosReg', (100, 110))
133025	33481830	In our previous study we demonstrated the absence of a correlation of PTENP1 methylation with the clinical characteristics of endometrial cancer (disease stage, FIGO grade, myometrium invasion).	('endometrial cancer', 'Phenotype', 'HP:0012114', (126, 144))	('methylation', 'Var', (77, 88))	('PTENP1', 'Gene', '11191', (70, 76))	('endometrial cancer', 'Disease', 'MESH:D016889', (126, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('FIGO grade', 'Disease', (161, 171))	('endometrial cancer', 'Disease', (126, 144))	('PTENP1', 'Gene', (70, 76))
133026	33481830	Here, we found higher frequency of PTENP1 methylation in patients over 45 years with EH and EC, which did not differ from methylation of NE in women of matched age groups.	('PTENP1', 'Gene', (35, 41))	('PTENP1', 'Gene', '11191', (35, 41))	('EH', 'Phenotype', 'HP:0040298', (85, 87))	('higher', 'PosReg', (15, 21))	('patients', 'Species', '9606', (57, 65))	('women', 'Species', '9606', (143, 148))	('methylation', 'Var', (42, 53))
133027	33481830	The data obtained indicated that PTENP1 methylation is associated with age-related changes, but not with malignancy of endometrial tissue.	('methylation', 'Var', (40, 51))	('PTENP1', 'Gene', (33, 39))	('PTENP1', 'Gene', '11191', (33, 39))	('associated', 'Reg', (55, 65))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))
133028	33481830	Our data allow us to conclude that PTENP1 methylation reflects age-related changes that occur in normal and hyperplastic endometrium (but not in endometrial polyps).	('PTENP1', 'Gene', (35, 41))	('PTENP1', 'Gene', '11191', (35, 41))	('endometrial polyps', 'Disease', 'MESH:D011127', (145, 163))	('endometrial polyps', 'Disease', (145, 163))	('hyperplastic endometrium', 'Phenotype', 'HP:0040298', (108, 132))	('methylation', 'Var', (42, 53))
133030	33481830	The obtained data suggest that age-related increase in the frequency of PTENP1 methylation and elevation in the level of its' expression may serve as a protective mechanism aimed to prevent malignant transformation of endometrial tissue in women during the perimenopause, menopause, and postmenopause periods.	('PTENP1', 'Gene', '11191', (72, 78))	('women', 'Species', '9606', (240, 245))	('prevent', 'NegReg', (182, 189))	("' expression", 'MPA', (124, 136))	('malignant transformation', 'CPA', (190, 214))	('postmenopause periods', 'Phenotype', 'HP:0008209', (287, 308))	('increase', 'PosReg', (43, 51))	('methylation', 'Var', (79, 90))	('level of', 'MPA', (112, 120))	('PTENP1', 'Gene', (72, 78))
133138	33029111	The sensitivity of dabrafenib, a selective inhibitor of mutated forms of BRAF kinase for BRAF-mutated melanoma, thyroid cancer, and non-small-cell lung cancer, was found to be positively associated with PPARGC1A (correlation coefficient = 0.448, p < 0.001) and PPARGC1B (correlation coefficient = 0.377, p = 0.003).	('PPARGC1B', 'Gene', (261, 269))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('sensitivity', 'MPA', (4, 15))	('mutated', 'Var', (56, 63))	('dabrafenib', 'Chemical', 'MESH:C561627', (19, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('BRAF', 'Gene', '673', (89, 93))	('PPARGC1A', 'Gene', (203, 211))	('BRAF', 'Gene', (89, 93))	('associated', 'Interaction', (187, 197))	('BRAF', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PPARGC1A', 'Gene', '10891', (203, 211))	('thyroid cancer', 'Disease', (112, 126))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('PPARGC1B', 'Gene', '133522', (261, 269))	('thyroid cancer', 'Disease', 'MESH:D013964', (112, 126))	('thyroid cancer', 'Phenotype', 'HP:0002890', (112, 126))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('non-small-cell lung cancer', 'Disease', (132, 158))	('BRAF', 'Gene', '673', (73, 77))
133143	33029111	Statistically significant survival differences were observed between high and low PPAR-expressed patients in some types of cancers, suggesting that PPARs might become potential prognostic indicators for clinical applications.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PPAR', 'Gene', (148, 152))	('PPAR', 'Gene', '5465', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PPAR', 'Gene', (82, 86))	('cancers', 'Disease', (123, 130))	('high', 'Var', (69, 73))	('PPAR', 'Gene', '5465', (148, 152))	('patients', 'Species', '9606', (97, 105))
133196	31983026	A defining event in the development and progression of gliomas is the isocitrate dehydrogenase (IDH) mutation, which is present in 70% of low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('isocitrate dehydrogenase', 'Gene', '3417', (70, 94))	('IDH', 'Gene', '3417', (96, 99))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('mutation', 'Var', (101, 109))	('isocitrate dehydrogenase', 'Gene', (70, 94))	('IDH', 'Gene', (96, 99))
133199	31983026	Oncogenic mutations in stem cells or progenitor cells might also affect cancer cell migration and several studies have reported that the mutational status is related to the anatomical distribution pattern of low-grade glioma (LGG) subtypes in the brain.	('affect', 'Reg', (65, 71))	('glioma', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('related', 'Reg', (158, 165))	('mutations', 'Var', (10, 19))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('cancer', 'Disease', (72, 78))
133211	31983026	In summary, based on molecular markers patients were classified into three molecular groups: (i) the low-risk group being IDH mutated, 1p19q co-deleted, (ii) the intermediate-risk group being IDH mutated and 1p19q non-co-deleted, and (iii) the high-risk group being IDH wild-type.	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', '3417', (192, 195))	('patients', 'Species', '9606', (39, 47))	('1p19q non-co-deleted', 'Var', (208, 228))	('IDH', 'Gene', (266, 269))	('1p19q co-deleted', 'Var', (135, 151))	('IDH', 'Gene', '3417', (266, 269))	('IDH', 'Gene', (192, 195))
133212	31983026	These risk groups correspond to the WHO classification of (i) oligodendroglioma, IDH-mutant and 1p19q co-deleted, (ii) diffuse astrocytoma, IDH-mutant and (iii) diffuse astrocytoma, IDH wild-type.	('astrocytoma', 'Disease', (127, 138))	('IDH', 'Gene', '3417', (140, 143))	('oligodendroglioma', 'Disease', (62, 79))	('1p19q co-deleted', 'Var', (96, 112))	('IDH', 'Gene', '3417', (182, 185))	('astrocytoma', 'Phenotype', 'HP:0009592', (127, 138))	('astrocytoma', 'Disease', 'MESH:D001254', (169, 180))	('astrocytoma', 'Disease', (169, 180))	('oligodendroglioma', 'Disease', 'MESH:D009837', (62, 79))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', '3417', (81, 84))	('astrocytoma', 'Disease', 'MESH:D001254', (127, 138))	('IDH', 'Gene', (140, 143))	('IDH', 'Gene', (182, 185))
133214	31983026	Samples classified as IDH wild-type after MLPA assessment were subject to PCR and DNA sequencing for IDH1 and IDH2 mutations.	('IDH1', 'Gene', (101, 105))	('IDH2', 'Gene', '3418', (110, 114))	('mutations', 'Var', (115, 124))	('IDH', 'Gene', (110, 113))	('IDH1', 'Gene', '3417', (101, 105))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (22, 25))	('IDH2', 'Gene', (110, 114))	('IDH', 'Gene', '3417', (101, 104))
133217	31983026	If IDH R132H mutation and accompanying ATRX loss were observed, no further analyses were carried out and tumors were classified as IDH mutated, 1p19q non-co-deleted.	('tumors', 'Disease', (105, 111))	('ATRX', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('IDH', 'Gene', '3417', (3, 6))	('R132H', 'Mutation', 'rs121913500', (7, 12))	('ATRX', 'Gene', '546', (39, 43))	('IDH', 'Gene', (131, 134))	('loss', 'NegReg', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IDH', 'Gene', '3417', (131, 134))	('1p19q non-co-deleted', 'Var', (144, 164))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('IDH', 'Gene', (3, 6))
133218	31983026	Samples negative for IDHR132H mutation on immunohistochemistry were subject to PCR and DNA sequencing for other IDH1 and IDH2 mutations.	('IDHR132H', 'Var', (21, 29))	('IDH2', 'Gene', '3418', (121, 125))	('IDH1', 'Gene', (112, 116))	('IDH1', 'Gene', '3417', (112, 116))	('IDH2', 'Gene', (121, 125))
133219	31983026	In samples with IDH mutation and ATRX presence, we then carried out fluorescence in situ hybridization (FISH) to confirm the 1p19q codeletion.	('ATRX', 'Gene', '546', (33, 37))	('IDH', 'Gene', (16, 19))	('1p19q', 'Var', (125, 130))	('IDH', 'Gene', '3417', (16, 19))	('ATRX', 'Gene', (33, 37))
133220	31983026	However, in three cases there was too little additional tissue available, and we had to assume 1p19q co-deletion based only IDH and ATRX presence without FISH confirmation.	('IDH', 'Gene', (124, 127))	('1p19q', 'Var', (95, 100))	('IDH', 'Gene', '3417', (124, 127))	('ATRX', 'Gene', (132, 136))	('ATRX', 'Gene', '546', (132, 136))
133221	31983026	Also, for a selected group of IDH1 R132H-negative patients (n = 7) we were not able to do PCR and DNA sequencing for other IDH-mutations.	('patients', 'Species', '9606', (50, 58))	('R132H', 'Mutation', 'rs121913500', (35, 40))	('R132H-negative', 'Var', (35, 49))	('IDH1', 'Gene', (30, 34))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', (123, 126))	('IDH', 'Gene', '3417', (30, 33))	('IDH', 'Gene', '3417', (123, 126))	('IDH1', 'Gene', '3417', (30, 34))
133223	31983026	113 were IDH mutated, 46 were IDH wild-type, and 49 were both IDH mutated and 1p19q co-deleted (Fig.	('1p19q', 'Var', (78, 83))	('IDH', 'Gene', '3417', (62, 65))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (9, 12))	('IDH', 'Gene', '3417', (30, 33))	('IDH', 'Gene', (62, 65))
133228	31983026	Tumors with IDH mutation and 1p19q co-deletion showed similar distances from both SVZ and SGZ as the tumors with IDH mutation and no co-deletion.	('IDH', 'Gene', '3417', (113, 116))	('mutation', 'Var', (16, 24))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Tumors', 'Disease', (0, 6))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('IDH', 'Gene', (113, 116))	('1p19q co-deletion', 'Var', (29, 46))	('tumors', 'Disease', (101, 107))
133235	31983026	These findings may suggest that the stem cell origin of IDH wild-type and IDH mutated LGGs may be different.	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', (74, 77))	('mutated', 'Var', (78, 85))	('IDH', 'Gene', '3417', (74, 77))
133241	31983026	As the presence of 1p/19q co-deleted tumors is limited to a subset of tumors with IDH mutations they show the same anatomical predilection as IDH-mutated tumors in general.	('IDH', 'Gene', '3417', (82, 85))	('mutations', 'Var', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('IDH', 'Gene', (142, 145))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('IDH', 'Gene', '3417', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', (37, 43))	('IDH', 'Gene', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
133275	31983026	For 1p19q codeletion status ATRX immunohistochemistry was used as a surrogate marker in a subset of patients.	('patients', 'Species', '9606', (100, 108))	('ATRX', 'Gene', '546', (28, 32))	('ATRX', 'Gene', (28, 32))	('1p19q codeletion', 'Var', (4, 20))
133277	31983026	Loss of ATRX expression is close to being mutually exclusive to 1p/19q codeletion, but this approach might have caused a slight underclassification of 1p19q co-deleted tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('ATRX', 'Gene', '546', (8, 12))	('expression', 'MPA', (13, 23))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('1p19q', 'Var', (151, 156))	('Loss', 'NegReg', (0, 4))	('ATRX', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
133278	31983026	In addition, a small subset of tumors additional sequencing for other IDH-mutations than IDH1 R132H was not feasible.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('IDH', 'Gene', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('R132H', 'Var', (94, 99))	('R132H', 'Mutation', 'rs121913500', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('IDH', 'Gene', '3417', (70, 73))	('IDH', 'Gene', (89, 92))	('IDH1', 'Gene', (89, 93))	('IDH', 'Gene', '3417', (89, 92))	('IDH1', 'Gene', '3417', (89, 93))
133280	31983026	Although non- IDH1 R132H mutations are rare, this may have influenced our findings.	('R132H', 'Var', (19, 24))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('IDH1', 'Gene', (14, 18))	('influenced', 'Reg', (59, 69))	('IDH1', 'Gene', '3417', (14, 18))
133301	31213842	The Kaplan-Meier plot and log-rank test in our patient series showed that high LAMC1 expression was significantly associated with shorter survival, which was consistent with the TCGA database analysis.	('LAMC1', 'Gene', (79, 84))	('expression', 'MPA', (85, 95))	('patient', 'Species', '9606', (47, 54))	('high', 'Var', (74, 78))	('shorter', 'NegReg', (130, 137))
133318	31213842	The results indicated that LAMC1 expression was significantly upregulated in high-grade glioma tissues compared with low-grade glioma tissues and normal brain tissues and that high LAMC1 expression correlated with shorter overall survival (OS) time and progression-free survival (PFS), which shed light on the molecular mechanism underlying the initiation and progression of glioma.	('glioma', 'Disease', (375, 381))	('expression', 'MPA', (187, 197))	('LAMC1', 'Gene', (27, 32))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (375, 381))	('upregulated', 'PosReg', (62, 73))	('glioma', 'Phenotype', 'HP:0009733', (375, 381))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('expression', 'MPA', (33, 43))	('overall survival', 'CPA', (222, 238))	('progression-free survival', 'CPA', (253, 278))	('glioma', 'Disease', (127, 133))	('shorter', 'NegReg', (214, 221))	('LAMC1', 'Gene', (181, 186))	('high', 'Var', (176, 180))
133347	31213842	A log-rank test was employed to compare the survival between patients with GBMs with high LAMC1 expression and those with low LAMC1 expression.	('patients', 'Species', '9606', (61, 69))	('expression', 'Var', (96, 106))	('LAMC1', 'Gene', (90, 95))	('high', 'Var', (85, 89))
133359	31213842	As shown in Figure 3, glioma patients with high LAMC1 expression had apparently shorter survival times.	('patients', 'Species', '9606', (29, 37))	('LAMC1', 'Gene', (48, 53))	('high', 'Var', (43, 47))	('glioma', 'Disease', (22, 28))	('survival times', 'CPA', (88, 102))	('shorter', 'NegReg', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
133363	31213842	Chi-square test analysis indicated that high LAMC1 expression was significantly associated with glioma WHO grade (P<0.05) but not with patient sex, age, or tumor size and IDH1 mutation or MGMT promoter methylation (Table 2).	('high', 'Var', (40, 44))	('patient', 'Species', '9606', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('LAMC1', 'Gene', (45, 50))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('associated', 'Reg', (80, 90))	('IDH1', 'Gene', (171, 175))	('expression', 'MPA', (51, 61))	('MGMT', 'Gene', (188, 192))	('tumor', 'Disease', (156, 161))	('MGMT', 'Gene', '4255', (188, 192))	('IDH1', 'Gene', '3417', (171, 175))	('glioma', 'Disease', (96, 102))
133365	31213842	As shown in Figure 5, glioma patients with high LAMC1 expression (IRS >=4) had apparently shorter recurrence-free survival (RFS) and OS times.	('IRS >=4', 'Gene', (66, 73))	('patients', 'Species', '9606', (29, 37))	('LAMC1', 'Gene', (48, 53))	('high', 'Var', (43, 47))	('OS times', 'CPA', (133, 141))	('recurrence-free survival', 'CPA', (98, 122))	('shorter', 'NegReg', (90, 97))	('IRS >=4', 'Gene', '8471', (66, 73))	('glioma', 'Disease', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
133366	31213842	The differences in RFS and OS times between glioma patients with high LAMC1 expression (IRS >=4) and those with low LAMC1 expression (IRS<4) were significant (P<0.05).	('IRS<4', 'Gene', (134, 139))	('LAMC1', 'Gene', (70, 75))	('IRS<4', 'Gene', '8471', (134, 139))	('high', 'Var', (65, 69))	('IRS >=4', 'Gene', (88, 95))	('RFS', 'MPA', (19, 22))	('glioma', 'Disease', (44, 50))	('patients', 'Species', '9606', (51, 59))	('expression', 'Var', (76, 86))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('IRS >=4', 'Gene', '8471', (88, 95))
133382	31213842	They found that SNP rs10911251 near LAMC1 (1q25.3) was associated with CRC (OR 5 1.09, P 5 1.75 3 1028).	('LAMC1', 'Gene', (36, 41))	('SNP rs10911251', 'Var', (16, 30))	('CRC', 'Disease', (71, 74))	('associated', 'Reg', (55, 65))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('rs10911251', 'Mutation', 'rs10911251', (20, 30))
133386	31213842	Hiroyasu Kashima et al also found that silencing LAMC1 expression in high-grade endometrioid carcinoma cell lines in vitro did not affect cell proliferation but suppressed cell motility and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('LAMC1', 'Gene', (49, 54))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (80, 102))	('suppressed', 'NegReg', (161, 171))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (80, 102))	('silencing', 'Var', (39, 48))	('endometrioid carcinoma', 'Disease', (80, 102))
133400	25257301	Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations.	('mutations', 'Var', (147, 156))	('TP53', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('astrocytic tumors', 'Disease', (70, 87))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('astrocytic tumors', 'Disease', 'MESH:D001254', (70, 87))	('TP53', 'Gene', '7157', (160, 164))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (100, 123))	('Mutations', 'Var', (0, 9))	('ATRX', 'Gene', (183, 187))	('TP53', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ATRX', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (13, 17))	('oligodendroglial tumors', 'Disease', (100, 123))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('ATRX', 'Gene', '546', (35, 39))	('ATRX', 'Gene', '546', (183, 187))
133401	25257301	We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('astrocytomas', 'Disease', 'MESH:D001254', (164, 176))	('oligoastrocytomas', 'Disease', (159, 176))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (159, 176))	('astrocytomas', 'Disease', 'MESH:D001254', (19, 31))	('mutations', 'Var', (41, 50))	('oligoastrocytomas', 'Disease', (14, 31))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (14, 31))	('TP53', 'Gene', '7157', (54, 58))	('astrocytomas', 'Disease', (181, 193))	('ATRX', 'Gene', (76, 80))	('astrocytic tumors', 'Disease', (124, 141))	('ATRX', 'Gene', '546', (76, 80))	('astrocytic tumors', 'Disease', 'MESH:D001254', (124, 141))	('astrocytomas', 'Disease', (164, 176))	('astrocytomas', 'Disease', (19, 31))	('astrocytomas', 'Disease', 'MESH:D001254', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('TP53', 'Gene', (54, 58))
133402	25257301	p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('oligodendrogliomas', 'Disease', (138, 156))	('protein', 'Protein', (4, 11))	('mutation', 'Var', (39, 47))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('increases', 'PosReg', (78, 87))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (138, 156))	('astrocytomas and oligoastrocytomas', 'Disease', 'MESH:D001254', (91, 125))
133403	25257301	Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data.	('p.R132H', 'Mutation', 'rs121913500', (121, 128))	('mutant', 'Var', (63, 69))	('IDH1', 'Gene', (115, 119))	('IDH1', 'Gene', '3417', (56, 60))	('IDH1', 'Gene', '3417', (115, 119))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('IDH1', 'Gene', (56, 60))
133418	25257301	Mutations in isocitrate dehydrogenase 1 and 2 genes (IDH1/2) have been identified in >80% of ALGGs as well as a subset of GBMs that progressed from lower grade gliomas.	('IDH1', 'Gene', (53, 57))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('gliomas', 'Disease', (160, 167))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (53, 57))	('identified', 'Reg', (71, 81))	('ALGGs', 'Disease', (93, 98))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('isocitrate', 'Chemical', 'MESH:C034219', (13, 23))
133419	25257301	IDH1/2 mutations are the most frequent mutations detected in lower grade gliomas and those tumors associated with IDH1/2 mutation are reported to have better outcomes compared to wild type tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('IDH1', 'Gene', (114, 118))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('IDH1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('type tumors', 'Disease', 'MESH:D009369', (184, 195))	('IDH1', 'Gene', '3417', (114, 118))	('IDH1', 'Gene', '3417', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('gliomas', 'Disease', (73, 80))	('mutations', 'Var', (7, 16))	('tumors', 'Disease', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (91, 97))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('type tumors', 'Disease', (184, 195))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))
133421	25257301	Mutant IDH1/2 enzymes gain neomorphic functions that result in the production of the putative oncometabolite 2-Hydroxyglutarate (2HG) from alpha-KG; however, the precise mechanism by which IDH1/2 mutations promote tumorigenesis remains to be elucidated including other cooperating genomic events that are required for cellular transformation.	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (109, 127))	('IDH1', 'Gene', '3417', (7, 11))	('IDH1', 'Gene', '3417', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('alpha-KG', 'Chemical', 'MESH:D007656', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('neomorphic functions', 'CPA', (27, 47))	('promote', 'PosReg', (206, 213))	('gain', 'PosReg', (22, 26))	('tumor', 'Disease', (214, 219))	('IDH1', 'Gene', (189, 193))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('mutations', 'Var', (196, 205))
133422	25257301	The presence of IDH1/2 mutations in both astrocytomas and oligodendrogliomas suggests that this mutation occurs early in glioma development, most likely in a stem/progenitor cell that can give rise to both cell types.	('glioma', 'Disease', (69, 75))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (41, 76))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('IDH1', 'Gene', (16, 20))	('mutations', 'Var', (23, 32))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH1', 'Gene', '3417', (16, 20))	('glioma', 'Disease', (121, 127))
133426	25257301	Furthermore we sought to determine whether targeted sequencing might reliably and simultaneously capture known mutations with prognostic significance, identify patients who may benefit from targeted therapies and help re-envision a modern classification system for ALGGs incorporating histologic and molecular data to improve inter-observer reliability for diagnosis of these challenging tumors.	('challenging tumors', 'Disease', (376, 394))	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (160, 168))	('tumors', 'Phenotype', 'HP:0002664', (388, 394))	('challenging tumors', 'Disease', 'MESH:D009369', (376, 394))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))
133430	25257301	The most common mutations across the ALGG cohort were IDH1 and IDH2, which collectively occurred in 90% (97/108) of tumors suggesting that formation of these neomorphic metabolic enzymes represents an early event in gliomagenesis.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('IDH2', 'Gene', '3418', (63, 67))	('IDH1', 'Gene', (54, 58))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('IDH1', 'Gene', '3417', (54, 58))	('IDH2', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('glioma', 'Disease', (216, 222))
133431	25257301	Examination of lineage specific mutations showed a predominance of TP53 mutations in astrocytic (71%, 20/28) and mixed lineage (80%, 12/15) tumors (Figure 1A, Supplemental Table 1-4).	('mutations', 'Var', (72, 81))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('astrocytic', 'Disease', (85, 95))	('mixed lineage', 'CPA', (113, 126))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
133432	25257301	ATRX mutations were similarly restricted to astrocytic and mixed lineag tumors with a frequency of 54% (15/28) and 60% (9/15), respectively.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('lineag tumors', 'Disease', (65, 78))	('astrocytic', 'Disease', (44, 54))	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('ATRX', 'Gene', '546', (0, 4))	('lineag tumors', 'Disease', 'MESH:D015456', (65, 78))
133433	25257301	Interestingly, all ATRX mutations co-occurred with TP53 mutations in these tumors, suggesting that TP53 mutations preceded ATRX alterations.	('TP53', 'Gene', (99, 103))	('ATRX', 'Gene', (123, 127))	('mutations', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', (51, 55))	('ATRX', 'Gene', '546', (19, 23))	('co-occurred', 'Reg', (34, 45))	('ATRX', 'Gene', (19, 23))	('ATRX', 'Gene', '546', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', '7157', (99, 103))	('mutations', 'Var', (24, 33))	('tumors', 'Disease', (75, 81))	('TP53', 'Gene', '7157', (51, 55))
133436	25257301	Of the 44 tumors independently assigned O2 diagnoses, only one sample contained an ATRX mutation, while TP53 mutations were not detected.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutation', 'Var', (88, 96))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('tumors', 'Disease', (10, 16))	('ATRX', 'Gene', (83, 87))	('O2', 'Chemical', '-', (40, 42))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('ATRX', 'Gene', '546', (83, 87))
133437	25257301	Comparatively, in O3 tumors we found only one sample (1/21) harbored an ATRX mutation while TP53 mutations were more frequent (19%, 4/21) (Figure 1B).	('ATRX', 'Gene', '546', (72, 76))	('harbored', 'Reg', (60, 68))	('mutation', 'Var', (77, 85))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('ATRX', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
133438	25257301	These findings suggest that in oligodendroglial tumors TP53 mutations are more likely to be later events where they may function to mediate progression or resistance to therapy, while in astrocytic and mixed lineage tumors TP53 and ATRX lesions are often early genetic events along with IDH1 mutations.	('tumors', 'Disease', (48, 54))	('IDH1', 'Gene', (287, 291))	('tumors', 'Disease', (216, 222))	('TP53', 'Gene', '7157', (223, 227))	('TP53', 'Gene', '7157', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('IDH1', 'Gene', '3417', (287, 291))	('oligodendroglial tumors', 'Disease', (31, 54))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (31, 54))	('ATRX', 'Gene', (232, 236))	('TP53', 'Gene', (55, 59))	('ATRX', 'Gene', '546', (232, 236))	('TP53', 'Gene', (223, 227))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
133444	25257301	Consistent with high frequencies of wildtype ATRX in oligodendroglial tumors, ATRX protein expression was high in these tumors while astrocytic and mixed lineage tumors in which ATRX is frequently mutated (loss of function events) exhibited low protein levels.	('ATRX', 'Gene', (78, 82))	('expression', 'MPA', (91, 101))	('tumors', 'Disease', (120, 126))	('ATRX', 'Gene', '546', (78, 82))	('ATRX', 'Gene', (45, 49))	('mutated', 'Var', (197, 204))	('high', 'PosReg', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('ATRX', 'Gene', '546', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('oligodendroglial tumors', 'Disease', (53, 76))	('ATRX', 'Gene', (178, 182))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('ATRX', 'Gene', '546', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (53, 76))	('tumors', 'Disease', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
133448	25257301	Furthermore when we compared p53 levels to TP53 mutational status we found that tumors with TP53 mutations were significantly more likely to express p53 protein (Figure 2D).	('mutations', 'Var', (97, 106))	('p53', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('express', 'MPA', (141, 148))	('p53', 'Gene', '7157', (149, 152))	('more', 'PosReg', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('p53', 'Gene', (29, 32))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (43, 47))	('p53', 'Gene', '7157', (29, 32))	('TP53', 'Gene', (43, 47))
133451	25257301	As previously described our cohort of ALGGs demonstrated a high frequency of IDH1/2 mutations; however the spectrum of mutations was diverse and highlighted the need for integration of sequencing based assays into routine diagnostics.	('mutations', 'Var', (84, 93))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', (77, 81))
133452	25257301	At present, the standard method for detecting IDH1 mutations is by immunohistochemistry (IHC) using an antibody specific for the IDH1 p.R132H variant.	('mutations', 'Var', (51, 60))	('p.R132H', 'Mutation', 'rs121913500', (134, 141))	('IDH1', 'Gene', (129, 133))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('IDH1', 'Gene', '3417', (129, 133))	('p.R132H', 'Var', (134, 141))
133453	25257301	Since the OncoPanel sequencing platform includes IDH1 and IDH2, we sought to characterize the spectrum of IDH1/2 mutations given the important clinical and prognostic implications of IDH1/2 mutations in gliomas.	('IDH1', 'Gene', (183, 187))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('IDH1', 'Gene', '3417', (183, 187))	('IDH2', 'Gene', '3418', (58, 62))	('IDH1', 'Gene', '3417', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('IDH1', 'Gene', '3417', (106, 110))	('mutations', 'Var', (113, 122))	('IDH1', 'Gene', (106, 110))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', (49, 53))	('gliomas', 'Disease', (203, 210))
133454	25257301	As demonstrated in Figure 3A, 90% (97/108) of tumors in our cohort harbored either an IDH1 or IDH2 mutation.	('IDH1', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('IDH2', 'Gene', '3418', (94, 98))	('IDH1', 'Gene', '3417', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('mutation', 'Var', (99, 107))	('tumors', 'Disease', (46, 52))	('harbored', 'Reg', (67, 75))	('IDH2', 'Gene', (94, 98))
133455	25257301	When analyzed by lineage, 100% (65/65) of pure oligodendroglial tumors contained IDH1/2 mutations while 64.3% and 93.3% of astrocytic and mixed lineage tumors were positive for IDH1/2 mutations, respectively (Figure3C).	('tumors', 'Disease', (64, 70))	('IDH1', 'Gene', '3417', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('contained', 'Reg', (71, 80))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('IDH1', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (47, 70))	('mutations', 'Var', (88, 97))	('IDH1', 'Gene', (81, 85))	('oligodendroglial tumors', 'Disease', (47, 70))	('IDH1', 'Gene', '3417', (177, 181))	('tumors', 'Disease', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
133456	25257301	Interestingly IDH2 mutations were restricted to oligodendroglial tumors with a similar distribution between O2 and O3.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('IDH2', 'Gene', (14, 18))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (48, 71))	('oligodendroglial tumors', 'Disease', (48, 71))	('O2', 'Chemical', '-', (108, 110))	('IDH2', 'Gene', '3418', (14, 18))
133457	25257301	The most common mutation identified was IDH1 p.R132H, which occurred in the majority of tumors independent of lineage or grade (Figure 3C, D); however we found that over 13.9% (15/108) of tumors harbored non-IDH1 p.R132H variants or IDH2 mutations, which would not be detected by traditional IHC analysis.	('IDH2', 'Gene', '3418', (233, 237))	('p.R132H', 'Var', (213, 220))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Disease', (188, 194))	('p.R132H', 'Mutation', 'rs121913500', (45, 52))	('IDH1', 'Gene', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('IDH1', 'Gene', (208, 212))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('IDH1', 'Gene', '3417', (40, 44))	('p.R132H', 'Mutation', 'rs121913500', (213, 220))	('IDH1', 'Gene', '3417', (208, 212))	('IDH2', 'Gene', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Disease', (88, 94))
133458	25257301	Among DA2s IDH1 p.R132L or p.R132C accounted for 20% of IDH1 mutations (n=1, 1 respectively) while 11% of AA3s harbored IDH1 p.R132C or p.R132S mutations.	('p.R132S', 'Mutation', 'rs121913499', (136, 143))	('IDH1', 'Gene', '3417', (11, 15))	('p.R132C', 'Var', (27, 34))	('IDH1', 'Gene', '3417', (120, 124))	('p.R132C', 'Mutation', 'rs121913499', (27, 34))	('IDH1', 'Gene', '3417', (56, 60))	('mutations', 'Var', (61, 70))	('p.R132S', 'Var', (136, 143))	('p.R132C', 'Mutation', 'rs121913499', (125, 132))	('IDH1', 'Gene', (120, 124))	('p.R132C', 'Var', (125, 132))	('p.R132L', 'Var', (16, 23))	('p.R132L', 'Mutation', 'rs121913500', (16, 23))	('IDH1', 'Gene', (11, 15))	('IDH1', 'Gene', (56, 60))
133459	25257301	This was similar for mixed lineage tumors that presented with 13.3% (2/15) IDH1 p.R132L and p.R132C mutations.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IDH1', 'Gene', '3417', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('IDH1', 'Gene', (75, 79))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('p.R132L', 'Var', (80, 87))	('p.R132L', 'Mutation', 'rs121913500', (80, 87))	('p.R132C', 'Var', (92, 99))	('p.R132C', 'Mutation', 'rs121913499', (92, 99))
133460	25257301	Furthermore despite the high frequency of IDH1 p.R132H mutations detected in oligodendroglial tumors, we found that 13.6% (6/44) of O2s had IDH2, IDH1 p.R132G or IDH1 p.R132S mutations.	('IDH1', 'Gene', '3417', (162, 166))	('IDH1', 'Gene', '3417', (146, 150))	('p.R132H', 'Mutation', 'rs121913500', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('p.R132H', 'Var', (47, 54))	('IDH1', 'Gene', '3417', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IDH2', 'Gene', (140, 144))	('p.R132S', 'Var', (167, 174))	('IDH2', 'Gene', '3418', (140, 144))	('p.R132G', 'Mutation', 'rs121913499', (151, 158))	('oligodendroglial tumors', 'Disease', (77, 100))	('O2s', 'Chemical', '-', (132, 135))	('IDH1', 'Gene', (162, 166))	('IDH1', 'Gene', (146, 150))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (77, 100))	('p.R132S', 'Mutation', 'rs121913499', (167, 174))	('p.R132G', 'Var', (151, 158))	('IDH1', 'Gene', (42, 46))
133461	25257301	Similarly 14.3% (3/21) of O3 tumors in our cohort harbored IDH2 p.R172K or p.R172W mutations.	('p.R172W', 'Mutation', 'rs1057519906', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('p.R172K', 'Var', (64, 71))	('IDH2', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('p.R172K', 'Mutation', 'rs121913503', (64, 71))	('tumors', 'Disease', (29, 35))	('p.R172W', 'Var', (75, 82))	('IDH2', 'Gene', '3418', (59, 63))
133462	25257301	In sum, a total of 13.9% (15/108) IDH1/2 mutant tumors in our ALGG cohort would have eluded detection if relying solely on traditional IDH1 p.R132H immunohistochemistry.	('IDH1', 'Gene', '3417', (34, 38))	('mutant', 'Var', (41, 47))	('IDH1', 'Gene', (135, 139))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('IDH1', 'Gene', '3417', (135, 139))	('p.R132H', 'Mutation', 'rs121913500', (140, 147))	('IDH1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
133463	25257301	As expected IDH mutations were the most prevalent lesion in our ALGG cohort; however, 10% of tumors (11/108) were negative for IDH1/2 mutations, including three DA2s, one OA2 and seven AA3s.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('OA2', 'Gene', '474286', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('IDH1', 'Gene', (127, 131))	('negative', 'NegReg', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('mutations', 'Var', (134, 143))	('OA2', 'Gene', (171, 174))	('tumors', 'Disease', (93, 99))	('IDH1', 'Gene', '3417', (127, 131))
133465	25257301	Of the seven AA3 tumors, three contained EGFR amplification with monosomy 10 or CDKN2A/B deletion, a pattern more typical of GBM than ALGG suggesting that these tumors may in fact be more clinically aggressive than typical AA3s or under-sampled with respect to the overall features of the tumor (Figure 4).	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', (17, 23))	('tumor', 'Disease', (161, 166))	('EGFR', 'Gene', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('CDKN2A', 'Gene', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Disease', (17, 22))	('monosomy 10', 'Gene', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('EGFR', 'Gene', '1956', (41, 45))	('aggressive than typical', 'Phenotype', 'HP:0000718', (199, 222))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CDKN2A', 'Gene', '1029', (80, 86))	('amplification', 'Var', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('AA3', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
133466	25257301	The remaining four AA3s lacked EGFR amplification but were positive for EGFR mutations (p.V774M, p.G598V, p.L861Q, p.R108K, p.G449V).	('p.V774M', 'Var', (88, 95))	('EGFR', 'Gene', '1956', (31, 35))	('p.R108K', 'Var', (115, 122))	('EGFR', 'Gene', '1956', (72, 76))	('p.R108K', 'Mutation', 'rs1057519828', (115, 122))	('p.G449V', 'Mutation', 'p.G449V', (124, 131))	('p.G598V', 'Var', (97, 104))	('EGFR', 'Gene', (31, 35))	('p.L861Q', 'Mutation', 'rs121913444', (106, 113))	('positive', 'Reg', (59, 67))	('p.V774M', 'Mutation', 'rs567477136', (88, 95))	('EGFR', 'Gene', (72, 76))	('p.G598V', 'Mutation', 'rs139236063', (97, 104))	('p.G449V', 'Var', (124, 131))	('p.L861Q', 'Var', (106, 113))
133467	25257301	Similarly two DA2s harbored EGFR (p.V301del) and PTEN (p.G165R) mutations respectively, whereas the third DA2 harbored the oncogenic FGFR1 p.K656E mutation, which has recently been implicated in pediatric GBMs and pontine gliomas.	('PTEN', 'Gene', '5728', (49, 53))	('p.K656E', 'Mutation', 'rs869320694', (139, 146))	('EGFR', 'Gene', '1956', (28, 32))	('FGFR1', 'Gene', (133, 138))	('p.V301del', 'Var', (34, 43))	('FGFR1', 'Gene', '2260', (133, 138))	('p.G165R', 'Mutation', 'rs587782603', (55, 62))	('EGFR', 'Gene', (28, 32))	('p.G165R', 'Var', (55, 62))	('p.V301del', 'Mutation', 'p.301delV', (34, 43))	('implicated', 'Reg', (181, 191))	('p.K656E', 'Var', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('gliomas', 'Disease', (222, 229))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('PTEN', 'Gene', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
133468	25257301	The single IDH1/2 wildtype OA2 showed PIK3R1 p.EY451del, and a frameshift mutation (p.E76fs) in the cancer associated phosphatase PTPN11 gene.	('p.EY451del', 'Var', (45, 55))	('PIK3R1', 'Gene', (38, 44))	('p.EY451del', 'Mutation', 'p.451delEY', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PIK3R1', 'Gene', '5295', (38, 44))	('IDH1', 'Gene', '3417', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PTPN11', 'Gene', (130, 136))	('OA2', 'Gene', '474286', (27, 30))	('p.E76fs', 'Mutation', 'p.E76fsX', (84, 91))	('p.E76fs', 'Var', (84, 91))	('PTPN11', 'Gene', '5781', (130, 136))	('cancer', 'Disease', (100, 106))	('OA2', 'Gene', (27, 30))	('IDH1', 'Gene', (11, 15))
133472	25257301	Our analysis of 108 ALGGs encompassing astrocytic, mixed and oligodendroglial lineage tumors revealed that TP53 mutations were most frequent in astrocytic and mixed lineage tumors but were rarely present in oligodendroglial tumors and when present were only seen in anaplastic oligodendrogliomas, consistent with previous studies.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (112, 121))	('oligodendroglial lineage tumors', 'Disease', 'MESH:D015456', (61, 92))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (266, 295))	('anaplastic oligodendrogliomas', 'Disease', (266, 295))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('oligodendroglial tumors', 'Disease', (207, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('TP53', 'Gene', (107, 111))	('tumors', 'Disease', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (207, 230))	('oligodendroglial lineage tumors', 'Disease', (61, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (288, 294))	('mixed lineage', 'CPA', (159, 172))	('frequent', 'Reg', (132, 140))	('TP53', 'Gene', '7157', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('astrocytic', 'Disease', (144, 154))	('gliomas', 'Phenotype', 'HP:0009733', (288, 295))
133473	25257301	These findings suggest that early events in the formation of oligodendroglial tumors include IDH1/2 mutations in association with 1p/19q co-deletion, FUBP1 and CIC mutations but not TP53 mutations.	('IDH1', 'Gene', (93, 97))	('mutations', 'Var', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', '7157', (182, 186))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (61, 84))	('TP53', 'Gene', (182, 186))	('FUBP1', 'Gene', (150, 155))	('oligodendroglial tumors', 'Disease', (61, 84))	('IDH1', 'Gene', '3417', (93, 97))	('CIC', 'Gene', '23152', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CIC', 'Gene', (160, 163))	('FUBP1', 'Gene', '8880', (150, 155))
133474	25257301	When present in anaplastic oligodendrogliomas, TP53 mutations may represent a marker of progression and/or resistance to therapies, which is supported by previous studies showing that TP53 mutations in malignant gliomas are a primary mechanism leading to radio-resistance.	('mutations', 'Var', (52, 61))	('anaplastic oligodendrogliomas', 'Disease', (16, 45))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('leading', 'Reg', (244, 251))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('malignant gliomas', 'Disease', (202, 219))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('radio-resistance', 'Disease', (255, 271))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('malignant gliomas', 'Disease', 'MESH:D005910', (202, 219))	('TP53', 'Gene', '7157', (47, 51))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (16, 45))	('mutations', 'Var', (189, 198))	('TP53', 'Gene', (47, 51))
133475	25257301	Similarly, ATRX mutations were also enriched in astrocytic and mixed lineage tumors but only 2/65 oligodendroglial tumors contained ATRX mutations.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (16, 25))	('ATRX', 'Gene', (11, 15))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (98, 121))	('ATRX', 'Gene', (132, 136))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('astrocytic', 'Disease', (48, 58))	('oligodendroglial tumors', 'Disease', (98, 121))	('ATRX', 'Gene', '546', (11, 15))	('ATRX', 'Gene', '546', (132, 136))
133476	25257301	When ATRX mutations were present in astrocytic and mixed lineage gliomas, they always (100%) co-occurred with TP53 mutations.	('gliomas', 'Disease', (65, 72))	('TP53', 'Gene', '7157', (110, 114))	('astrocytic', 'Disease', (36, 46))	('TP53', 'Gene', (110, 114))	('ATRX', 'Gene', '546', (5, 9))	('ATRX', 'Gene', (5, 9))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutations', 'Var', (10, 19))	('co-occurred', 'Reg', (93, 104))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
133477	25257301	These findings suggest that (1) TP53 mutations occur prior to developing ATRX mutations in astrocytic and mixed lineage gliomas and, (2) TP53 mutations predispose a tumor to developing ATRX mutations, which may further accelerate tumorigenesis.	('TP53', 'Gene', '7157', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('mutations', 'Var', (142, 151))	('mutations', 'Var', (190, 199))	('mutations', 'Var', (78, 87))	('TP53', 'Gene', (137, 141))	('tumor', 'Disease', (230, 235))	('accelerate', 'PosReg', (219, 229))	('ATRX', 'Gene', (185, 189))	('predispose', 'Reg', (152, 162))	('ATRX', 'Gene', (73, 77))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('TP53', 'Gene', (32, 36))	('ATRX', 'Gene', '546', (185, 189))	('gliomas', 'Disease', (120, 127))	('ATRX', 'Gene', '546', (73, 77))	('tumor', 'Disease', (165, 170))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('TP53', 'Gene', '7157', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
133479	25257301	In fact, TP53 mutated tumors significantly correlated with increased protein expression, which is consistent with high protein expression in astrocytic and mixed lineage tumors.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mutated', 'Var', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TP53', 'Gene', '7157', (9, 13))	('protein expression', 'MPA', (69, 87))	('TP53', 'Gene', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('increased', 'PosReg', (59, 68))	('tumors', 'Disease', (22, 28))	('tumors', 'Disease', (170, 176))
133482	25257301	We investigated the spectrum of IDH1/2 mutations in ALGGs given their critical role as prognostic indicators for a more favorable clinical course compared to IDH wildtype gliomas.	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('IDH wildtype gliomas', 'Disease', 'MESH:D005910', (158, 178))	('IDH1', 'Gene', (32, 36))	('ALGGs', 'Gene', (52, 57))	('IDH1', 'Gene', '3417', (32, 36))	('mutations', 'Var', (39, 48))	('IDH wildtype gliomas', 'Disease', (158, 178))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))
133483	25257301	The current standard-of-care assay in clinical labs is to perform IHC for IDH1 p.R132H, the most common variant among IDH1 mutations.	('IDH1', 'Gene', (118, 122))	('IDH1', 'Gene', (74, 78))	('IDH1', 'Gene', '3417', (118, 122))	('p.R132H', 'Var', (79, 86))	('IDH1', 'Gene', '3417', (74, 78))	('p.R132H', 'Mutation', 'rs121913500', (79, 86))
133484	25257301	In our study we demonstrated that among the 97 IDH1/2 mutated ALGGs in our cohort, 17% (15/97) would not have been detected by IHC against IDH1 p.R132H.	('IDH1', 'Gene', (139, 143))	('ALGGs', 'Gene', (62, 67))	('IDH1', 'Gene', (47, 51))	('IDH1', 'Gene', '3417', (139, 143))	('mutated', 'Var', (54, 61))	('p.R132H', 'Mutation', 'rs121913500', (144, 151))	('IDH1', 'Gene', '3417', (47, 51))
133485	25257301	In fact, 10% of O2s and 20% of O3s were positive for IDH2 mutations and negative for IDH1 mutations.	('O3s', 'Chemical', 'MESH:D010126', (31, 34))	('mutations', 'Var', (58, 67))	('IDH2', 'Gene', (53, 57))	('IDH1', 'Gene', '3417', (85, 89))	('IDH2', 'Gene', '3418', (53, 57))	('IDH1', 'Gene', (85, 89))	('O2s', 'Chemical', '-', (16, 19))	('positive', 'Reg', (40, 48))
133486	25257301	Given the clinical value of identifying IDH1/2 mutated gliomas, our findings provide a compelling reason to advance IDH1 p.R132H protein negative ALGGs for exome or targeted sequencing of IDH1/2.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('p.R132H', 'Mutation', 'rs121913500', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', (188, 192))	('IDH1', 'Gene', (116, 120))	('IDH1', 'Gene', '3417', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH1', 'Gene', '3417', (188, 192))	('p.R132H', 'Var', (121, 128))	('mutated', 'Var', (47, 54))	('IDH1', 'Gene', '3417', (116, 120))
133487	25257301	Although the prevalence of IDH1/2 mutations among ALGGs was high (90%), it suggests that for the remaining 10% of IDH1/2 wildtype tumors an alternate mechanism might be attributed to gliomagenesis.	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('IDH1', 'Gene', (114, 118))	('glioma', 'Disease', (183, 189))	('type tumors', 'Disease', (125, 136))	('type tumors', 'Disease', 'MESH:D009369', (125, 136))	('IDH1', 'Gene', '3417', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('IDH1', 'Gene', (27, 31))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('IDH1', 'Gene', '3417', (27, 31))	('mutations', 'Var', (34, 43))
133488	25257301	In fact, among the seven IDH1/2 wildtype AA3s, 3 harbored polysomy 7 with EGFR amplification and monosomy 10, a pattern of genomic aberrations more consistent with GBM rather than AA3.	('polysomy 7', 'Var', (58, 68))	('harbored', 'Reg', (49, 57))	('EGFR', 'Gene', '1956', (74, 78))	('IDH1', 'Gene', (25, 29))	('EGFR', 'Gene', (74, 78))	('IDH1', 'Gene', '3417', (25, 29))
133490	25257301	The four other IDH1/2 wildtype AA3s each harbored varying EGFR mutations in combination with other gene variants (e.g.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('IDH1', 'Gene', (15, 19))	('harbored', 'Reg', (41, 49))	('EGFR', 'Gene', (58, 62))	('IDH1', 'Gene', '3417', (15, 19))
133494	25257301	Based on our data, following histopathology review, tumors classified along the ALGG spectrum including WHO Grades II and III astrocytomas, oligodendrogliomas and mixed tumors could be initially divided based on IDH1/2 mutations into mutant and wildtype groups.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('astrocytomas', 'Disease', 'MESH:D001254', (126, 138))	('IDH1', 'Gene', '3417', (212, 216))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (140, 158))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumors', 'Disease', (52, 58))	('astrocytomas', 'Disease', (126, 138))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('IDH1', 'Gene', (212, 216))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('oligodendrogliomas', 'Disease', (140, 158))	('mutations', 'Var', (219, 228))	('tumors', 'Disease', (169, 175))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
133496	25257301	As the majority of ALGGs are likely to be IDH1/2 mutated, oligodendroglial tumors can be readily identified by the presence of 1p/19q co-deletion, mutations in CIC and FUBP1, and high ATRX with low p53 protein expression.	('mutations', 'Var', (147, 156))	('low', 'NegReg', (194, 197))	('ATRX', 'Gene', '546', (184, 188))	('IDH1', 'Gene', '3417', (42, 46))	('CIC', 'Gene', '23152', (160, 163))	('FUBP1', 'Gene', (168, 173))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (58, 81))	('CIC', 'Gene', (160, 163))	('ATRX', 'Gene', (184, 188))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('IDH1', 'Gene', (42, 46))	('oligodendroglial tumors', 'Disease', (58, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('FUBP1', 'Gene', '8880', (168, 173))
133497	25257301	Astrocytomas and oligoastrocytomas would most often harbor mutations in TP53, ATRX and PTEN and show high p53 with low ATRX protein expression.	('ATRX', 'Gene', (78, 82))	('PTEN', 'Gene', (87, 91))	('p53', 'Gene', '7157', (106, 109))	('PTEN', 'Gene', '5728', (87, 91))	('oligoastrocytomas', 'Disease', (17, 34))	('ATRX', 'Gene', '546', (78, 82))	('TP53', 'Gene', '7157', (72, 76))	('Astrocytomas', 'Disease', (0, 12))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (17, 34))	('ATRX', 'Gene', '546', (119, 123))	('TP53', 'Gene', (72, 76))	('mutations', 'Var', (59, 68))	('p53', 'Gene', (106, 109))	('harbor', 'Reg', (52, 58))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('ATRX', 'Gene', (119, 123))
133499	25257301	This hypothesis is supported by the nearly identical frequencies and patterns of TP53, ATRX and PTEN mutations; however a greater number of tumors, especially oligoastrocytomas, will need to be analyzed in order to fully define the relationship between astrocytomas and mixed gliomas.	('astrocytomas', 'Disease', 'MESH:D001254', (164, 176))	('gliomas', 'Disease', 'MESH:D005910', (276, 283))	('oligoastrocytomas', 'Disease', (159, 176))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (159, 176))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('TP53', 'Gene', '7157', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('astrocytomas', 'Disease', (253, 265))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PTEN', 'Gene', (96, 100))	('mutations', 'Var', (101, 110))	('tumors', 'Disease', (140, 146))	('astrocytomas', 'Disease', (164, 176))	('astrocytomas', 'Disease', 'MESH:D001254', (253, 265))	('TP53', 'Gene', (81, 85))	('PTEN', 'Gene', '5728', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('gliomas', 'Disease', (276, 283))	('ATRX', 'Gene', (87, 91))	('ATRX', 'Gene', '546', (87, 91))
133500	25257301	Based on our findings astrocytomas and mixed tumors could be classified simply as Diffuse Glioma (IDH1/2 mutant) WHO II or Anaplastic Diffuse Glioma (IDH1/2 mutant) WHO Grade III based on traditional glioma grading criteria.	('astrocytomas', 'Disease', 'MESH:D001254', (22, 34))	('Glioma', 'Disease', 'MESH:D005910', (90, 96))	('IDH1', 'Gene', '3417', (98, 102))	('mutant', 'Var', (105, 111))	('Glioma', 'Disease', (142, 148))	('glioma', 'Disease', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('Anaplastic Diffuse Glioma', 'Disease', 'MESH:D005910', (123, 148))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('Glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('astrocytomas', 'Disease', (22, 34))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('Glioma', 'Disease', 'MESH:D005910', (142, 148))	('Glioma', 'Disease', (90, 96))	('IDH1', 'Gene', '3417', (150, 154))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Anaplastic Diffuse Glioma', 'Disease', (123, 148))	('IDH1', 'Gene', (98, 102))	('Glioma', 'Phenotype', 'HP:0009733', (142, 148))
133501	25257301	ALGGs found to lack IDH1/2 mutations need to be thoroughly re-investigated with integration of clinical, surgical and neuroimaging data to ensure adequate sampling of the patients' tumors.	('mutations', 'Var', (27, 36))	('IDH1', 'Gene', '3417', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Disease', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('patients', 'Species', '9606', (171, 179))	('IDH1', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
133502	25257301	Three of 7 AA3s in our cohort showed evidence of EGFR amplification, monosomy 10 and CDKN2A/B deletion a pattern more typical of GBM rather than ALGG.	('EGFR', 'Gene', '1956', (49, 53))	('deletion', 'Var', (94, 102))	('amplification', 'Var', (54, 67))	('EGFR', 'Gene', (49, 53))	('CDKN2A', 'Gene', (85, 91))	('CDKN2A', 'Gene', '1029', (85, 91))	('monosomy', 'Gene', (69, 77))
133504	25257301	Alternatively, IDH1/2 wildtype ALGGs that lack a genomic GBM signature should be evaluated for other potential oncogenic drivers, including mutations such as FGFR1 p.K656E, which has been identified in pediatric gliomas.	('IDH1', 'Gene', (15, 19))	('p.K656E', 'Mutation', 'rs869320694', (164, 171))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('FGFR1', 'Gene', (158, 163))	('IDH1', 'Gene', '3417', (15, 19))	('pediatric gliomas', 'Disease', 'MESH:D005910', (202, 219))	('FGFR1', 'Gene', '2260', (158, 163))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('p.K656E', 'Var', (164, 171))	('pediatric gliomas', 'Disease', (202, 219))
133506	25257301	With open clinical trials for IDH1 mutant glioma patients, determining IDH1 mutational status for ALGG patients is critical for satisfying trial entry criteria.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('mutant', 'Var', (35, 41))	('IDH1', 'Gene', (71, 75))	('IDH1', 'Gene', (30, 34))	('IDH1', 'Gene', '3417', (71, 75))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (103, 111))	('glioma', 'Disease', (42, 48))	('IDH1', 'Gene', '3417', (30, 34))
133508	25257301	Furthermore as studies have shown that IDH1/2 mutant gliomas have a favorable prognosis compared to their wildtype counterparts, excluding or controlling for these patients in GBM clinical trials will be critical when analyzing results to ensure that IDH1/2 mutant GBM patients do not confound interpretation of drug effectiveness on patient survival.	('IDH1', 'Gene', '3417', (251, 255))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('patient', 'Species', '9606', (164, 171))	('IDH1', 'Gene', (39, 43))	('gliomas', 'Disease', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('patient', 'Species', '9606', (334, 341))	('IDH1', 'Gene', (251, 255))	('mutant', 'Var', (46, 52))	('IDH1', 'Gene', '3417', (39, 43))	('patient', 'Species', '9606', (269, 276))	('patients', 'Species', '9606', (164, 172))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('patients', 'Species', '9606', (269, 277))
133517	25257301	The OncoPanel assay detects mutations in 275 different cancer genes.	('detects', 'Reg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (55, 61))
133521	25257301	The following primary antibodies were utilized: p53 (ImmunoTech #1767), ATRX (Sigma, HPA001906), IDH1(R132H) (Dianova, DIA-H05).	('ATRX', 'Gene', '546', (72, 76))	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (48, 51))	('ATRX', 'Gene', (72, 76))	('R132H', 'Var', (102, 107))	('R132H', 'SUBSTITUTION', 'None', (102, 107))
133525	33400376	Single-nucleotide variant, RNA expression matrix and corresponding clinical data of low-grade glioma came from public database.	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('Single-nucleotide variant', 'Var', (0, 25))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Disease', (94, 100))
133528	33400376	DNMT3A mutation was the most frequent among the m5C regulators in low-grade glioma.	('m5C', 'Chemical', '-', (48, 51))	('glioma', 'Disease', (76, 82))	('frequent', 'Reg', (29, 37))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('DNMT3A', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('DNMT3A', 'Gene', '1788', (0, 6))
133554	33400376	The 'maftools' package of R language was used to analyse the single-nucleotide variants (SNV) of low-grade glioma in TCGA dataset.	('single-nucleotide variants', 'Var', (61, 87))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('glioma', 'Disease', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (107, 113))
133555	33400376	Among all 506 low-grade glioma mutation samples, there were 15 samples with m5C regulator mutations, as shown in Figure 1.	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('mutations', 'Var', (90, 99))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('m5C', 'Chemical', '-', (76, 79))	('mutation', 'Var', (31, 39))	('glioma', 'Disease', (24, 30))	('m5C regulator', 'Gene', (76, 89))
133556	33400376	The main variant class of m5C regulators was missense mutation, followed by nonsense mutation and frame shift deletion.	('missense mutation', 'Var', (45, 62))	('m5C', 'Chemical', '-', (26, 29))	('nonsense mutation', 'Var', (76, 93))	('frame shift deletion', 'Var', (98, 118))
133557	33400376	C > T was the most common SNV in low-grade glioma.	('C > T', 'Var', (0, 5))	('glioma', 'Disease', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
133558	33400376	5 out of 13 m5C regulators had SNV mutations, including DNMT3A, TET2, DNMT3B, DNMT1 and NSUN5.	('DNMT3B', 'Gene', (70, 76))	('m5C', 'Chemical', '-', (12, 15))	('TET2', 'Gene', '54790', (64, 68))	('NSUN5', 'Gene', '55695', (88, 93))	('DNMT1', 'Gene', (78, 83))	('NSUN5', 'Gene', (88, 93))	('DNMT1', 'Gene', '1786', (78, 83))	('SNV', 'Gene', (31, 34))	('TET2', 'Gene', (64, 68))	('DNMT3A', 'Gene', (56, 62))	('DNMT3A', 'Gene', '1788', (56, 62))	('DNMT3B', 'Gene', '1789', (70, 76))	('mutations', 'Var', (35, 44))
133559	33400376	Besides, the mutation of DNMT3A was the most frequent.	('mutation', 'Var', (13, 21))	('DNMT3A', 'Gene', (25, 31))	('DNMT3A', 'Gene', '1788', (25, 31))	('frequent', 'Reg', (45, 53))
133586	33400376	m5C methylation is widespread in DNA and RNA modification.	('m5C', 'Chemical', '-', (0, 3))	('m5C', 'Var', (0, 3))	('DNA', 'Disease', (33, 36))
133588	33400376	m5C methylation mainly occurs in the vicinity of the start codon and the 3`UTR region of mRNAs in the transcriptome.	('occurs', 'Reg', (23, 29))	('m5C', 'Chemical', '-', (0, 3))	('m5C', 'Var', (0, 3))	('methylation', 'Var', (4, 15))
133591	33400376	We found that DNMT3A mutation was the most frequent.	('DNMT3A', 'Gene', (14, 20))	('frequent', 'Reg', (43, 51))	('DNMT3A', 'Gene', '1788', (14, 20))	('mutation', 'Var', (21, 29))
133595	33400376	For example, knockdown of TRDMT1 can change the level of HEK293 mRNA methylation and inhibit tumour cell proliferation and migration.	('HEK293', 'CellLine', 'CVCL:0045', (57, 63))	('tumour', 'Disease', (93, 99))	('level', 'MPA', (48, 53))	('TRDMT1', 'Gene', '1787', (26, 32))	('inhibit', 'NegReg', (85, 92))	('TRDMT1', 'Gene', (26, 32))	('HEK293', 'Protein', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('knockdown', 'Var', (13, 22))	('change', 'Reg', (37, 43))
133620	32033580	The co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) occursin about 60-90% of ODGs, thus making it the molecular hallmark for ODGs.	('ODGs', 'Disease', (167, 171))	('co-deletion', 'Var', (4, 15))	('short arm', 'Phenotype', 'HP:0009824', (23, 32))	('ODGs', 'Disease', 'MESH:D009837', (119, 123))	('ODGs', 'Disease', 'MESH:D009837', (167, 171))	('ODGs', 'Disease', (119, 123))
133658	32033580	The three readers assessed only conventional MR images (T1WI, T2WI, FLAIR and T1 CE), and recorded the final diagnosis using a 4-point scale (1 = definite ODG2; 2 = likely ODG2; 3 = likely ODG3; and 4 = definite ODG3).	('ODG3', 'Gene', '29893', (212, 216))	('ODG2', 'Gene', (172, 176))	('ODG2', 'Gene', '9210', (155, 159))	('ODG3', 'Gene', '29893', (189, 193))	('ODG2', 'Gene', (155, 159))	('ODG2', 'Gene', '9210', (172, 176))	('T1WI', 'Var', (56, 60))	('ODG3', 'Gene', (212, 216))	('ODG3', 'Gene', (189, 193))
133683	32033580	At last, a number of cognitive biases may adversely affect the accuracy of a radiologists report of a glioma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('biases', 'Var', (31, 37))	('glioma', 'Disease', (102, 108))	('affect', 'Reg', (52, 58))
133696	31977292	The SWI/SNF complex mutations in gynecologic cancers: molecular mechanisms and models The SWI/SNF (Mating Type SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression.	('gene expression', 'MPA', (267, 282))	('chromatin structure', 'MPA', (235, 254))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('control', 'Reg', (259, 266))	('SWI/SNF', 'Gene', (90, 97))	('modulate', 'Reg', (226, 234))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('interact', 'Interaction', (174, 182))	('Sucrose', 'Chemical', 'MESH:D013395', (118, 125))	('cancers', 'Disease', (45, 52))	('mutations', 'Var', (20, 29))
133697	31977292	Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
133698	31977292	These SWI/SNF mutations occur at different stages of tumour development and are restricted to unique histologic types of gynecologic cancer.	('SWI/SNF', 'Gene', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('occur', 'Reg', (24, 29))	('tumour', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
133699	31977292	Thus, the SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression.	('promote', 'PosReg', (91, 98))	('SWI/SNF', 'Gene', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('progression', 'CPA', (133, 144))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (18, 27))
133700	31977292	In this review, we will summarize the current knowledge of SWI/SNF mutations in gynecologic cancer development to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.	('SWI/SNF', 'Gene', (59, 66))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
133705	31977292	In addition to finding common well-studied tumor suppressors and oncogenes, genomic analysis of gynecologic cancers has identified frequent mutations of genes encoding subunits of the SWI/SNF (Mating Type SWItch/Sucrose Non-Fermentable) chromatin remodeling complex.	('died', 'Disease', 'MESH:D003643', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Sucrose', 'Chemical', 'MESH:D013395', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (140, 149))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Disease', (43, 48))	('died', 'Disease', (38, 42))	('cancers', 'Disease', (108, 115))
133706	31977292	Some mutations, such as SMARCA4/BRG1, occur as a germline event and function as a classic tumor suppressor and key driver in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (136, 158))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (125, 145))	('BRG1', 'Gene', (32, 36))	('hypercalcemic type', 'Disease', (160, 178))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutations', 'Var', (5, 14))	('carcinoma of the ovary', 'Disease', (136, 158))	('BRG1', 'Gene', '6597', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
133707	31977292	Other mutations occur either early during the transformation or as a late event during the progression of gynecologic cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('occur', 'Reg', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (6, 15))
133708	31977292	These studies suggest specific roles of mutations in the SWI/SNF complex during multiple steps of gynecologic cancer development.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (40, 49))	('roles', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('SWI/SNF', 'Gene', (57, 64))
133709	31977292	In this review, we will summarize the current knowledge of SWI/SNF mutations in gynecologic cancer development to provide insights into both molecular pathogenesis and the potential treatment implications of these disease.	('SWI/SNF', 'Gene', (59, 66))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
133719	31977292	The BAF complex displayed a strong enrichment in active enhancers (H3K27ac and H3K4me1) and primed enhancers (H3K4me1), suggestive of their key roles in enhancer regulation, whereas the PBAF complex had the strongest presence in active promoters (H3K27ac and H3K4me3).	('H3K4me3', 'Var', (259, 266))	('BAF', 'Chemical', '-', (187, 190))	('H3K4me1', 'Var', (79, 86))	('enhancers', 'PosReg', (56, 65))	('H3K27ac', 'Var', (67, 74))	('BAF', 'Chemical', '-', (4, 7))	('H3K27ac', 'Var', (247, 254))
133721	31977292	Given its pivotal role in regulating diverse pathways, it is not surprising that mutations impacting SWI/SNF function occur in a broad spectrum of cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('function', 'MPA', (109, 117))	('SWI/SNF', 'Gene', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('mutations', 'Var', (81, 90))	('occur', 'Reg', (118, 123))	('cancers', 'Disease', (147, 154))
133722	31977292	Indeed, data from The Cancer Genome Atlas (TCGA) has shown that mutations of the SWI/SNF subunits are found in about 20% of all cancers, a rate that approaches the frequency of TP53 mutations.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Cancer', 'Disease', (22, 28))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Disease', (128, 135))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', '7157', (177, 181))	('found', 'Reg', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', (177, 181))	('SWI/SNF', 'Gene', (81, 88))
133727	31977292	Mutations in the SWI/SNF complexes have been reported in multiple types of gynecologic cancers (Figure.	('cancers', 'Disease', (87, 94))	('SWI/SNF', 'Gene', (17, 24))	('reported', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
133728	31977292	These mutations, which impact different subunits of the complex, arise at different stages of tumor development and thus may play distinct roles in each tumor type.	('play', 'Reg', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mutations', 'Var', (6, 15))
133729	31977292	In contrast, the inactivating mutations of SMARCA4, SMARCB1 or ARID1A/B genes are late events in the development of endometrial cancer that may promote disease progression.	('SMARCB1', 'Gene', '6598', (52, 59))	('endometrial cancer', 'Disease', 'MESH:D016889', (116, 134))	('inactivating mutations', 'Var', (17, 39))	('SMARCB1', 'Gene', (52, 59))	('promote', 'PosReg', (144, 151))	('endometrial cancer', 'Disease', (116, 134))	('ARID1A/B', 'Gene', '8289', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('endometrial cancer', 'Phenotype', 'HP:0012114', (116, 134))	('ARID1A/B', 'Gene', (63, 71))	('SMARCA4', 'Gene', (43, 50))
133730	31977292	In this section, we will summarize the current understanding of SWI/SNF mutations in gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('mutations', 'Var', (72, 81))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SWI/SNF', 'Gene', (64, 71))
133742	31977292	We and others have discovered that, unlike most common ovarian malignancies, the genome of SCCOHT is diploid with inactivating germline and/or somatic mutations of the SMARCA4 gene as the only recurrent feature and the likely driver event in ~90% of SCCOHT tumors.	('inactivating', 'Var', (114, 126))	('SCCOHT tumors', 'Disease', (250, 263))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('SMARCA4', 'Gene', (168, 175))	('ovarian malignancies', 'Disease', 'MESH:D010049', (55, 75))	('SCCOHT tumors', 'Disease', 'MESH:D009369', (250, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('ovarian malignancies', 'Phenotype', 'HP:0100615', (55, 75))	('ovarian malignancies', 'Disease', (55, 75))	('mutations', 'Var', (151, 160))
133744	31977292	Through IHC analysis of over 3000 primary gynecologic tumors, we further demonstrated that loss of SMARCA4, either alone or together with SMARCA2, is highly sensitive and specific for the diagnosis of SCCOHT, thus providing a definitive tool for SCCOHT diagnosis.	('SMARCA4', 'Gene', (99, 106))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SMARCA2', 'Gene', (138, 145))	('SMARCA2', 'Gene', '6595', (138, 145))	('SCCOHT', 'Disease', (201, 207))	('loss', 'Var', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
133746	31977292	SCCOHTs share both histological and genetic similarities to malignant rhabdoid tumors of the kidney, soft tissues and brain, which are tumors caused by mutations in SMARCB1.	('SMARCB1', 'Gene', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mutations', 'Var', (152, 161))	('malignant rhabdoid tumors of the kidney', 'Disease', (60, 99))	('malignant rhabdoid tumors of the kidney', 'Disease', 'MESH:D018335', (60, 99))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('SMARCB1', 'Gene', '6598', (165, 172))	('caused by', 'Reg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
133758	31977292	Research from our group and others has shown that somatic mutations in the ARID1A gene, encoding an accessory subunit of the SWI/SNF chromatin remodeling complex, commonly occur in both CCOC and ENOC, resulting in complete loss of ARID1A protein expression in ~50% of CCOC and 30% of ENOC.	('mutations', 'Var', (58, 67))	('CCOC', 'Chemical', '-', (186, 190))	('ARID1A', 'Gene', (75, 81))	('occur', 'Reg', (172, 177))	('CCOC', 'Chemical', '-', (268, 272))	('ARID1A', 'Gene', (231, 237))	('loss', 'NegReg', (223, 227))
133762	31977292	Moreover, ARID1A loss is significantly associated with genetic alterations that activate the PI3K/AKT signaling pathway in CCOC, such as PTEN loss and/or gain-of-function mutations of PIK3CA gene, suggesting a cooperative role of ARID1A inactivation and PI3K/AKT activation in malignant transformation of premalignant lesions.	('PTEN loss', 'Disease', (137, 146))	('AKT', 'Gene', '207', (259, 262))	('malignant transformation of premalignant lesions', 'Disease', (277, 325))	('CCOC', 'Chemical', '-', (123, 127))	('ARID1A', 'Gene', (10, 16))	('gain-of-function', 'PosReg', (154, 170))	('AKT', 'Gene', '207', (98, 101))	('PTEN loss', 'Disease', 'MESH:D006223', (137, 146))	('AKT', 'Gene', (259, 262))	('activate', 'PosReg', (80, 88))	('PIK3CA', 'Gene', (184, 190))	('mutations', 'Var', (171, 180))	('loss', 'NegReg', (17, 21))	('CCOC', 'Disease', (123, 127))	('AKT', 'Gene', (98, 101))	('malignant transformation of premalignant lesions', 'Disease', 'MESH:D009369', (277, 325))
133765	31977292	The genomic landscapes of sporadic EECs and HGSECs have been elucidated by TCGA and ourselves, in which mutations of ARID1A occurs in about 30-50% of low grade EEC, 40-60% of high grade EEC and a much lower frequency in HGSEC and endometrial carcinosarcoma.	('mutations', 'Var', (104, 113))	('HGSEC', 'Disease', (220, 225))	('EEC', 'Chemical', '-', (160, 163))	('endometrial carcinosarcoma', 'Phenotype', 'HP:0012114', (230, 256))	('EEC', 'Phenotype', 'HP:0012114', (160, 163))	('EEC', 'Phenotype', 'HP:0012114', (186, 189))	('endometrial carcinosarcoma', 'Disease', 'MESH:D002296', (230, 256))	('EEC', 'Chemical', '-', (35, 38))	('ARID1A', 'Gene', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('low grade EEC', 'Disease', (150, 163))	('occurs', 'Reg', (124, 130))	('endometrial carcinosarcoma', 'Disease', (230, 256))	('EEC', 'Phenotype', 'HP:0012114', (35, 38))	('EEC', 'Chemical', '-', (186, 189))
133769	31977292	Mutation of ARID1A was observed in 22% (7/32) of CCEC along with protein loss, in agreement with an earlier report by Fadare et al..	('loss', 'NegReg', (73, 77))	('CCEC', 'Disease', (49, 53))	('observed', 'Reg', (23, 31))	('Mutation', 'Var', (0, 8))	('ARID1A', 'Gene', (12, 18))	('CCEC', 'Chemical', '-', (49, 53))	('protein', 'MPA', (65, 72))
133770	31977292	Thus, ARID1A mutations occurs at differential frequencies in most common types of endometrial carcinomas, with a significant enrichment in EEC.	('EEC', 'Chemical', '-', (139, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (82, 104))	('EEC', 'Phenotype', 'HP:0012114', (139, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('EEC', 'Disease', (139, 142))	('endometrial carcinomas', 'Disease', (82, 104))	('ARID1A', 'Gene', (6, 12))	('mutations', 'Var', (13, 22))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (82, 104))
133776	31977292	Patients with Lynch syndrome, one of the most prevalent hereditary cancer predisposition syndromes arising from a germline mutation in one of the four microsatellite repair genes (MLH1, MSH2, MSH6, PMS2), have a 40-60% lifetime risk of developing ECs.	('Lynch syndrome', 'Disease', (14, 28))	('MSH6', 'Gene', '2956', (192, 196))	('mutation', 'Var', (123, 131))	('arising from', 'Reg', (99, 111))	('hereditary cancer', 'Disease', 'MESH:D009369', (56, 73))	('MLH1', 'Gene', '4292', (180, 184))	('PMS2', 'Gene', '5395', (198, 202))	('hereditary cancer', 'Disease', (56, 73))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('ECs', 'Disease', (247, 250))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('MSH2', 'Gene', (186, 190))	('PMS2', 'Gene', (198, 202))	('MLH1', 'Gene', (180, 184))	('MSH6', 'Gene', (192, 196))	('MSH2', 'Gene', '4436', (186, 190))
133780	31977292	This discrepancy may be attributed to the size and origin of different Lynch syndrome kindreds that may carry distinct mutations of mismatch repair genes.	('Lynch syndrome', 'Disease', 'MESH:D003123', (71, 85))	('Lynch syndrome', 'Disease', (71, 85))	('mutations', 'Var', (119, 128))
133791	31977292	These include inactivating mutations in SMARCA4 resulting in loss of SMARCA4 protein in 30-40% of DDEC, inactivation of SMARCB1 resulting in loss of SMARCB1 protein in 2-7% of DDEC, or co-inactivation of ARID1A and ARID1B resulting in concurrent loss of ARID1A and ARID1B proteins in 28% of DDEC.	('ARID1B', 'Gene', '57492', (265, 271))	('inactivating mutations', 'Var', (14, 36))	('SMARCB1', 'Gene', (149, 156))	('ARID1B', 'Gene', (265, 271))	('ARID1B', 'Gene', '57492', (215, 221))	('loss', 'NegReg', (141, 145))	('loss', 'NegReg', (61, 65))	('SMARCA4', 'Gene', (69, 76))	('inactivation', 'Var', (104, 116))	('protein', 'Protein', (77, 84))	('ARID1B', 'Gene', (215, 221))	('co-inactivation', 'Var', (185, 200))	('SMARCB1', 'Gene', (120, 127))	('loss', 'NegReg', (246, 250))	('SMARCB1', 'Gene', '6598', (120, 127))	('SMARCA4', 'Gene', (40, 47))	('protein', 'Protein', (157, 164))	('SMARCB1', 'Gene', '6598', (149, 156))
133794	31977292	Furthermore, mutational loss of SMARCA4, SMARCB1 or ARID1A/ARID1B is often associated with loss of the expression of SMARCA2 protein, the alternative ATPase of the SWI/SNF complex, through non-genetic mechanisms.	('ATPase', 'Gene', (150, 156))	('SMARCB1', 'Gene', (41, 48))	('mutational loss', 'Var', (13, 28))	('ARID1B', 'Gene', (59, 65))	('expression', 'MPA', (103, 113))	('protein', 'Protein', (125, 132))	('ARID1B', 'Gene', '57492', (59, 65))	('SMARCA4', 'Gene', (32, 39))	('loss', 'NegReg', (91, 95))	('SMARCA2', 'Gene', (117, 124))	('SMARCA2', 'Gene', '6595', (117, 124))	('ATPase', 'Gene', '1769', (150, 156))	('SMARCB1', 'Gene', '6598', (41, 48))
133795	31977292	Such SWI/SNF mutations are also implicated in undifferentiated carcinomas of ovary, urinary tract, gastrointestinal tract and kidney, suggesting that the SWI/SNF deficiency acquired during tumor progression may be a widespread mechanism that promotes cancer dedifferentiation.	('tumor', 'Disease', (189, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('SNF deficiency', 'Phenotype', 'HP:0025457', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('implicated', 'Reg', (32, 42))	('SNF deficiency', 'Disease', 'MESH:D007153', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('undifferentiated carcinomas of ovary', 'Disease', 'MESH:D010051', (46, 82))	('undifferentiated carcinomas of ovary', 'Disease', (46, 82))	('SNF deficiency', 'Disease', (158, 172))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (251, 257))	('SWI/SNF', 'Gene', (5, 12))	('promotes', 'PosReg', (242, 250))
133804	31977292	discovered SMARCA4 mutations and/or protein loss in 5 cases of undifferentiated uterine sarcoma with a median age of diagnosis of 33 years old, close to that of SCCOHT.	('SMARCA4', 'Gene', (11, 18))	('mutations', 'Var', (19, 28))	('loss', 'NegReg', (44, 48))	('protein', 'Protein', (36, 43))	('undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (63, 95))	('undifferentiated uterine sarcoma', 'Disease', (63, 95))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (80, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
133817	31977292	studied the clinicopathologic, IHC, and molecular genetic features of 14 SMARCB1-deficient vulvar neoplasms and uncovered that the proximal-type epithelioid sarcoma was the predominant subtype with SMARCB1 deficiency, followed by myoepithelial carcinoma.	('died', 'Disease', (3, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('SMARCB1', 'Gene', (73, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (233, 253))	('SMARCB1', 'Gene', '6598', (198, 205))	('deficiency', 'Var', (206, 216))	('SMARCB1', 'Gene', (198, 205))	('SMARCB1-deficient vulvar neoplasms', 'Disease', (73, 107))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('myoepithelial carcinoma', 'Disease', (230, 253))	('vulvar neoplasms', 'Phenotype', 'HP:0030416', (91, 107))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (230, 253))	('SMARCB1-deficient vulvar neoplasms', 'Disease', 'MESH:D014846', (73, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('died', 'Disease', 'MESH:D003643', (3, 7))	('sarcoma', 'Disease', (157, 164))	('SMARCB1', 'Gene', '6598', (73, 80))
133821	31977292	Despite this, future study of a large number of cases are required to fully characterize the clinicopathologic, immunophenotypic and genomic features of these two entities and address whether SMARCB1 inactivation is the only recurrent driver event, as seen in epithelioid sarcomas at other anatomic sites.	('sarcomas', 'Phenotype', 'HP:0100242', (272, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('sarcomas', 'Disease', (272, 280))	('SMARCB1', 'Gene', '6598', (192, 199))	('SMARCB1', 'Gene', (192, 199))	('inactivation', 'Var', (200, 212))	('sarcomas', 'Disease', 'MESH:D012509', (272, 280))
133826	31977292	Supporting this, analysis of transcriptomic profiles from the ARID1A wild-type and mutant CCOC failed to identify a canonical signaling process that was distinct between wild-type and ARID1A mutant tumors.	('CCOC', 'Chemical', '-', (90, 94))	('mutant', 'Var', (83, 89))	('CCOC', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
133827	31977292	found that loss of ARID1A was significantly correlated with advanced FIGO stage and high CA125 levels and a shorter progression-free survival in 60 patients of CCOC that received platinum-based chemotherapy.	('CCOC', 'Chemical', '-', (160, 164))	('patients', 'Species', '9606', (148, 156))	('CA125', 'Gene', '94025', (89, 94))	('loss', 'Var', (11, 15))	('shorter', 'NegReg', (108, 115))	('ARID1A', 'Gene', (19, 25))	('FIGO', 'Disease', (69, 73))	('CA125', 'Gene', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (179, 187))	('progression-free survival', 'CPA', (116, 141))
133840	31977292	demonstrated that ARID1A mutations correlated with a better outcome in endometrial carcinoma.	('mutations', 'Var', (25, 34))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (71, 92))	('ARID1A', 'Gene', (18, 24))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (71, 92))	('endometrial carcinoma', 'Disease', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
133842	31977292	further investigated whether such correlation reflects the enrichment of ARID1A mutations in MSI tumor.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('ARID1A', 'Gene', (73, 79))
133843	31977292	It was unveiled that ARID1A mutation status was not significantly associated with survival in patients with MSI tumors, but was associated with a better prognosis in patients with MSS tumors, implying that ARID1A mutation status may predict patient outcome in MSS endometrial cancer.	('mutation', 'Var', (28, 36))	('MSS tumors', 'Disease', (180, 190))	('predict', 'Reg', (233, 240))	('patients', 'Species', '9606', (94, 102))	('MSI tumors', 'Disease', (108, 118))	('patient', 'Species', '9606', (94, 101))	('patient', 'Species', '9606', (166, 173))	('endometrial cancer', 'Phenotype', 'HP:0012114', (264, 282))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MSS endometrial cancer', 'Disease', 'MESH:D016889', (260, 282))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('MSI tumors', 'Disease', 'MESH:D009369', (108, 118))	('MSS endometrial cancer', 'Disease', (260, 282))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('patient', 'Species', '9606', (241, 248))	('ARID1A', 'Gene', (21, 27))	('MSS tumors', 'Disease', 'MESH:D013132', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (166, 174))
133845	31977292	Although DDEC displayed a worse outcome than grade 3 endometrial cancer, our initial comparison between 15 DDEC with intact SMARCA4/SMARCB1 and 15 DDEC with loss of SMARCA4 or SMARCB1 did not identify significant differences in disease-specific survival.	('SMARCB1', 'Gene', '6598', (176, 183))	('SMARCA4', 'Gene', (165, 172))	('SMARCB1', 'Gene', (132, 139))	('SMARCB1', 'Gene', '6598', (132, 139))	('SMARCB1', 'Gene', (176, 183))	('endometrial cancer', 'Disease', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('intact', 'Var', (117, 123))	('endometrial cancer', 'Phenotype', 'HP:0012114', (53, 71))	('loss', 'NegReg', (157, 161))	('endometrial cancer', 'Disease', 'MESH:D016889', (53, 71))
133881	31977292	Given the strong association of ARID1A loss and PIK3CA or PTEN mutations in endometriosis-associated ovarian cancer, it is plausible that such mutations may be present in this endometriosis cell line.	('mutations', 'Var', (63, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('endometriosis', 'Phenotype', 'HP:0030127', (176, 189))	('PIK3CA', 'Gene', (48, 54))	('endometriosis', 'Disease', 'MESH:D004715', (76, 89))	('loss', 'NegReg', (39, 43))	('endometriosis-associated ovarian cancer', 'Disease', 'MESH:D004715', (76, 115))	('endometriosis', 'Disease', (176, 189))	('endometriosis', 'Disease', (76, 89))	('endometriosis', 'Disease', 'MESH:D004715', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('endometriosis-associated ovarian cancer', 'Disease', (76, 115))	('ARID1A', 'Gene', (32, 38))	('endometriosis', 'Phenotype', 'HP:0030127', (76, 89))	('PTEN', 'Gene', '19211', (58, 62))	('PTEN', 'Gene', (58, 62))
133886	31977292	Since within the normal uterine environment, endometrial epithelial progenitor cells undergo terminal differentiation with a preference towards secretory cells, it is speculated that the local ovarian microenvironment of each patient, which holds distinct differentiation pressure, may determine the differentiation of ARID1A-deficient biopotential premalignant progenitor cells of endometriotic cysts and together with accumulated additional mutations or epigenetic changes to drive their malignant transformation towards either ENOC or CCOC, respectively (Figure 4).	('CCOC', 'Chemical', '-', (538, 542))	('patient', 'Species', '9606', (226, 233))	('epigenetic changes', 'Var', (456, 474))	('ARID1A-deficient', 'Gene', (319, 335))	('CCOC', 'Disease', (538, 542))	('determine', 'Reg', (286, 295))	('ENOC', 'Disease', (530, 534))	('malignant transformation', 'CPA', (490, 514))	('mutations', 'Var', (443, 452))
133888	31977292	Recently, we and others have demonstrated that TOV112D and OVK18, two ENOC cell lines, are likely DDEC cell lines derived from dedifferentiated carcinomas of the ovary based on their lack of expression of both SMARCA4 and SMARCA2 and histological reevaluation of original tumor material (Karnezis et al., manuscript in preparation).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('SMARCA2', 'Gene', (222, 229))	('SMARCA2', 'Gene', '6595', (222, 229))	('TOV112D', 'Var', (47, 54))	('SMARCA4', 'Gene', (210, 217))	('carcinomas of the ovary', 'Disease', (144, 167))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas of the ovary', 'Disease', 'MESH:D010051', (144, 167))	('OVK18', 'Gene', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
133890	31977292	As ARID1A/ARID1B-dual deficient DDEC has intact PBAF and GBAF complexes and SMARCB1-deficient DDEC has functional GBAF complex, whereas SMARCA4-deficient DDEC loses ATPase activity of all SWI/SNF complexes completely (Figure 5), it is plausible to propose that inactivation of the BAF complexes is sufficient to stall the differentiation of cancer initiating cells and drive histological dedifferentiation.	('ARID1B', 'Gene', (10, 16))	('BAF', 'Chemical', '-', (115, 118))	('stall', 'NegReg', (312, 317))	('BAF', 'Chemical', '-', (281, 284))	('ARID1B', 'Gene', '57492', (10, 16))	('BAF', 'Chemical', '-', (49, 52))	('cancer', 'Disease', (341, 347))	('SMARCB1', 'Gene', '6598', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('SMARCB1', 'Gene', (76, 83))	('SMARCA4-deficient DDEC loses', 'Disease', 'MESH:D011504', (136, 164))	('SMARCA4-deficient DDEC loses', 'Disease', (136, 164))	('GBAF', 'Chemical', '-', (114, 118))	('GBAF', 'Chemical', '-', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('histological dedifferentiation', 'CPA', (375, 405))	('activity', 'MPA', (172, 180))	('ATPase', 'Gene', (165, 171))	('inactivation', 'Var', (261, 273))	('BAF', 'Chemical', '-', (58, 61))	('drive', 'Reg', (369, 374))	('ATPase', 'Gene', '1769', (165, 171))
133894	31977292	Efforts from several teams have attempted to determine whether inactivation of ARID1A is sufficient to drive the development of ovarian cancer and whether co-existing mutations are required to synergize with ARID1A loss to promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('ovarian cancer', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('inactivation', 'Var', (63, 75))	('loss', 'NegReg', (215, 219))	('drive', 'Reg', (103, 108))	('tumor', 'Disease', (231, 236))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('ARID1A', 'Gene', (79, 85))	('ARID1A', 'Gene', (208, 214))	('promote', 'PosReg', (223, 230))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
133895	31977292	reported that adenoviral-mediated co-depletion of Pten and Arid1a in ovarian surface epithelium of the Ptenfl/fl;Arid1afl/fl mice induces ovarian hyperplasia as early as 2 months after genetic depletion, which drives the development of undifferentiated or endometrioid carcinoma of the ovary in 6/13 mice examined at 6 months and 7/9 mice at 8-9 months.	('Pten', 'Gene', (50, 54))	('Pten', 'Gene', '19211', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('mice', 'Species', '10090', (334, 338))	('ovarian hyperplasia', 'Disease', 'MESH:D006965', (138, 157))	('ovarian hyperplasia', 'Disease', (138, 157))	('undifferentiated or endometrioid carcinoma of the ovary', 'Disease', 'MESH:D010051', (236, 291))	('mice', 'Species', '10090', (125, 129))	('co-depletion', 'Var', (34, 46))	('Pten', 'Gene', (103, 107))	('Arid1afl/fl', 'Var', (113, 124))	('mice', 'Species', '10090', (300, 304))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (256, 278))	('induces', 'Reg', (130, 137))	('Arid1a', 'Gene', (59, 65))	('Pten', 'Gene', '19211', (103, 107))
133896	31977292	Noteworthy, inactivation of one or both alleles of Arid1a in ovarian surface epithelium prolonged the survival of tumor-bearing Apc/Pten-deficient mice and promoted cancer cell differentiation to more closely resemble the histology of human ovarian endometrioid cancer.	('Pten', 'Gene', '19211', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('inactivation', 'Var', (12, 24))	('Pten', 'Gene', (132, 136))	('mice', 'Species', '10090', (147, 151))	('survival', 'CPA', (102, 110))	('tumor', 'Disease', (114, 119))	('human ovarian endometrioid cancer', 'Disease', 'MESH:D016889', (235, 268))	('Apc', 'Gene', (128, 131))	('promoted', 'PosReg', (156, 164))	('cancer', 'Disease', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Apc', 'Gene', '11789', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('human ovarian endometrioid cancer', 'Disease', (235, 268))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (249, 268))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('prolonged', 'PosReg', (88, 97))	('Arid1a', 'Gene', (51, 57))
133897	31977292	found that inactivation of Arid1a and expression of Pik3ca H1047R activating mutation in ovarian surface epithelium of the Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R mice rapidly develop primary ovarian tumor with a 7.5 week latency and clear cell carcinoma-like histopathology.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('Pik3ca', 'Gene', '18706', (145, 151))	('H1047R', 'SUBSTITUTION', 'None', (152, 158))	('ovarian tumor', 'Phenotype', 'HP:0100615', (188, 201))	('primary', 'CPA', (180, 187))	('Pik3ca', 'Gene', (52, 58))	('H1047R', 'Var', (59, 65))	('Pik3ca', 'Gene', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('develop', 'PosReg', (172, 179))	('ovarian tumor', 'Disease', (188, 201))	('clear cell carcinoma', 'Disease', (230, 250))	('inactivation', 'Var', (11, 23))	('ovarian tumor', 'Disease', 'MESH:D010051', (188, 201))	('Pik3ca', 'Gene', '18706', (52, 58))	('H1047R', 'SUBSTITUTION', 'None', (59, 65))	('H1047R', 'Var', (152, 158))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (230, 250))	('mice', 'Species', '10090', (159, 163))	('Arid1a', 'Gene', (27, 33))
133898	31977292	In contrast, mice with deletion of Pten or Arid1a or activation of Pik3ca.H1047R alone did not develop ovarian lesions except that activation of Pik3ca.H1047R led to development of hyperplasia in ovarian surface epithelium.	('Pten', 'Gene', (35, 39))	('mice', 'Species', '10090', (13, 17))	('Pik3ca', 'Gene', (67, 73))	('Pten', 'Gene', '19211', (35, 39))	('Pik3ca', 'Gene', '18706', (145, 151))	('deletion', 'Var', (23, 31))	('ovarian lesions', 'Disease', 'MESH:D010049', (103, 118))	('ovarian lesions', 'Disease', (103, 118))	('Pik3ca', 'Gene', '18706', (67, 73))	('hyperplasia', 'Disease', 'MESH:D006965', (181, 192))	('ovarian lesions', 'Phenotype', 'HP:0100615', (103, 118))	('Arid1a', 'Gene', (43, 49))	('ovarian surface epithelium', 'CPA', (196, 222))	('hyperplasia', 'Disease', (181, 192))	('Pik3ca', 'Gene', (145, 151))
133904	31977292	As ARID1A is also frequently mutated in endometrial carcinomas, inactivation of Arid1a, alone or in combination with genetic mutations of other genes (such as Pten, Pik3ca), in specific mouse cre strains in which the cre expression is driven by endometrial tissue specific promoters (i.e.	('inactivation', 'Var', (64, 76))	('Arid1a', 'Gene', (80, 86))	('Pten', 'Gene', (159, 163))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (40, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Pten', 'Gene', '19211', (159, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('endometrial carcinomas', 'Disease', (40, 62))	('mouse', 'Species', '10090', (186, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (40, 62))	('Pik3ca', 'Gene', (165, 171))	('Pik3ca', 'Gene', '18706', (165, 171))
133908	31977292	These putative tissue-specific GEMMs will open the opportunity for better understanding how inactivation of ARID1A interacts with other genetic mutations as well as ovarian microenvironment to drive transformation of precursor cells through comparison of the gene expression profiles and epigenetic states of tumor cells to those of the precursor cells that can be identified by lineage tracking markers.	('inactivation', 'Var', (92, 104))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('ARID1A', 'Gene', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
133909	31977292	reported that inactivation of Smarca4 using a Wap-cre line, which activates cre expression in granulosa cells of mouse ovary and multiple lineages of mouse uterus, led to frequent development of ovarian cyst and a low incidence of endometrial cancer.	('ovarian cyst', 'Disease', 'MESH:D010048', (195, 207))	('Wap', 'Gene', (46, 49))	('ovarian cyst', 'Phenotype', 'HP:0000138', (195, 207))	('inactivation', 'Var', (14, 26))	('Smarca4', 'Gene', (30, 37))	('ovarian cyst', 'Disease', (195, 207))	('endometrial cancer', 'Disease', (231, 249))	('endometrial cancer', 'Phenotype', 'HP:0012114', (231, 249))	('Wap', 'Gene', '22373', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mouse', 'Species', '10090', (113, 118))	('led to', 'Reg', (164, 170))	('mouse', 'Species', '10090', (150, 155))	('endometrial cancer', 'Disease', 'MESH:D016889', (231, 249))	('activates', 'PosReg', (66, 75))
133911	31977292	Therefore, inactivation of Smarca4 cannot drive the transformation of ovarian granulosa cells, but has the ability to transform unknown lineage in uterus.	('transform', 'Reg', (118, 127))	('ovarian granulosa', 'Disease', (70, 87))	('ovarian granulosa', 'Disease', 'MESH:D010049', (70, 87))	('inactivation', 'Var', (11, 23))	('Smarca4', 'Gene', (27, 34))
133915	31977292	Furthermore, additional inactivation of Smarca4 or the BAF complex through dual inactivation of Arid1a/Arid1b will likely promote the development of undifferentiated cancer resembling human DDEC in GEMMs of well differentiated endometrial cancer, such as Pgr-Cre:Ptenfl/fl GEMM mice.	('undifferentiated cancer', 'Disease', 'MESH:D009369', (149, 172))	('promote', 'PosReg', (122, 129))	('Pgr', 'Gene', (255, 258))	('human', 'Species', '9606', (184, 189))	('endometrial cancer', 'Phenotype', 'HP:0012114', (227, 245))	('Smarca4', 'Gene', (40, 47))	('BAF', 'Chemical', '-', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('Arid1b', 'Gene', (103, 109))	('endometrial cancer', 'Disease', (227, 245))	('Arid1b', 'Gene', '57492', (103, 109))	('Pten', 'Gene', (263, 267))	('Pten', 'Gene', '19211', (263, 267))	('endometrial cancer', 'Disease', 'MESH:D016889', (227, 245))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('inactivation', 'Var', (24, 36))	('mice', 'Species', '10090', (278, 282))	('Pgr', 'Gene', '5241', (255, 258))	('undifferentiated cancer', 'Disease', (149, 172))
133916	31977292	These models will offer great opportunities for better understanding the context-specific tumor suppressive roles of distinct SWI/SNF mutations in gynecologic cancers.	('cancers', 'Disease', (159, 166))	('SWI/SNF', 'Gene', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('mutations', 'Var', (134, 143))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
133917	31977292	Although SWI/SNF gene mutations occur in nearly 20% of all human cancers, most SWI/SNF gene mutations are loss of function mutations, including nonsense, frameshift and large deletions, that lead to concurrent loss of their protein expression.	('human', 'Species', '9606', (59, 64))	('cancers', 'Disease', (65, 72))	('loss of function', 'NegReg', (106, 122))	('protein expression', 'MPA', (224, 242))	('SWI/SNF gene', 'Gene', (79, 91))	('large deletions', 'Var', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (92, 101))	('frameshift', 'Var', (154, 164))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('nonsense', 'Var', (144, 152))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('loss', 'NegReg', (210, 214))
133918	31977292	Consequently, many efforts have been invested to identify synthetic lethal targets that are conferred by these SWI/SNF mutations on cancer cells, which has been summarized in details in several reviews.	('cancer', 'Disease', (132, 138))	('SWI/SNF', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
133931	31977292	Mutations of several SWI/SNF subunits have been discovered in multiple gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('discovered', 'Reg', (48, 58))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('SWI/SNF', 'Gene', (21, 28))
133932	31977292	The frequency and inactivating nature of these mutations supports that the SWI/SNF complexes are bona fide tumor suppressors in gynecologic tissues, which also define unique vulnerabilities that warrants further clinical investigations.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (47, 56))	('SWI/SNF', 'Gene', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
133933	31977292	These SWI/SNF mutations may function as either the sole driver event (SCCOHT), a malignant transformation-permitting early event (CCOC/ENOC/EEC) or a late progression event (DDEC) in distinct gynecologic cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('SWI/SNF', 'Gene', (6, 13))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('CCOC', 'Chemical', '-', (130, 134))	('EEC', 'Chemical', '-', (140, 143))	('EEC', 'Phenotype', 'HP:0012114', (140, 143))	('mutations', 'Var', (14, 23))
133935	31977292	The SWI/SNF mutations appears to have a value in predicting the worse outcome of DDEC patients even though a large number of cases are required to validate its clinical utility.	('DDEC', 'Disease', (81, 85))	('mutations', 'Var', (12, 21))	('SWI/SNF', 'Gene', (4, 11))	('patients', 'Species', '9606', (86, 94))
133937	31977292	Furthermore, the pathogenic roles of the SWI/SNF mutations are far beyond being fully understood in gynecologic cancers.	('mutations', 'Var', (49, 58))	('SWI/SNF', 'Gene', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
133938	31977292	The fact that specific subunits are mutated in specific gynecologic malignancies implies that the SWI/SNF complexes function in context-specific manners.	('mutated', 'Var', (36, 43))	('malignancies', 'Disease', (68, 80))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))
133942	31977292	The understanding of SWI/SNF complex mutations and their cellular interactions will be pivotal to developing novel treatment strategies for these gynecologic malignancies, particularly those which portend poor prognoses and often only have conventional platinum-based chemotherapy as a therapeutic option.	('SWI/SNF complex', 'Gene', (21, 36))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('gynecologic', 'Disease', (146, 157))	('platinum', 'Chemical', 'MESH:D010984', (253, 261))	('malignancies', 'Disease', (158, 170))	('mutations', 'Var', (37, 46))
133948	30531922	High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mutations', 'Var', (76, 85))	('ATRX', 'Gene', (89, 93))	('alterations', 'Reg', (176, 187))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', '7157', (50, 54))	('tumors', 'Disease', (11, 17))	('PI3 kinase pathways', 'Pathway', (230, 249))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('associated', 'Reg', (94, 104))	('ATRX', 'Gene', '546', (89, 93))	('TP53', 'Gene', (50, 54))	('CDKN2A', 'Gene', (59, 65))	('CDKN2A', 'Gene', '1029', (59, 65))
133949	30531922	Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('mutations', 'Var', (33, 42))	('MAP kinase pathway', 'Pathway', (86, 104))
133955	30531922	NF1 is caused by germline mutations in the NF1 tumor suppressor gene, which encodes a GTPase-activating protein called neurofibromin that functions as a negative regulator of the RAS oncoprotein.	('neurofibromin', 'Gene', (119, 132))	('GTP', 'Chemical', 'MESH:D006160', (86, 89))	('NF1', 'Disease', (0, 3))	('NF1', 'Gene', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('germline mutations', 'Var', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('neurofibromin', 'Gene', '4763', (119, 132))	('caused by', 'Reg', (7, 16))	('tumor', 'Disease', (47, 52))
133958	30531922	Recent genome-wide sequencing studies have revealed that sporadic malignancies including sporadic gliomas (both lower grade glioma and glioblastoma, GBM) have haploinsufficient or nullizygous loss of NF1, indicating that NF1 functions as a somatic tumor suppressor in the general population.	('nullizygous loss', 'Var', (180, 196))	('haploinsufficient', 'Disease', (159, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('glioma', 'Disease', (124, 130))	('NF1', 'Gene', (200, 203))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('tumor', 'Disease', (248, 253))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('haploinsufficient', 'Disease', 'MESH:D058495', (159, 176))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('sporadic gliomas', 'Disease', (89, 105))	('glioblastoma', 'Disease', (135, 147))	('sporadic gliomas', 'Disease', 'MESH:D005910', (89, 105))
133961	30531922	NF1 patients are also prone to developing non-optic gliomas, more frequently later in life, which manifest with a spectrum of histological subtypes including high-grade gliomas.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', (169, 176))	('developing', 'PosReg', (31, 41))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('patients', 'Species', '9606', (4, 12))	('NF1', 'Var', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('optic gliomas', 'Phenotype', 'HP:0009734', (46, 59))
133962	30531922	Although the predisposition to develop central nervous system tumors in patients with NF1 is well recognized, the molecular features of gliomas occurring in patients with NF1 have remained obscure, preventing development and application of novel therapeutic approaches.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('central nervous system tumors', 'Disease', 'MESH:D016543', (39, 68))	('develop', 'PosReg', (31, 38))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('patients', 'Species', '9606', (157, 165))	('gliomas', 'Disease', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('central nervous system tumors', 'Disease', (39, 68))	('NF1', 'Var', (171, 174))	('nervous system tumors', 'Phenotype', 'HP:0004375', (47, 68))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (39, 68))	('patients', 'Species', '9606', (72, 80))
133971	30531922	Whole exome sequencing (WES) was performed for the 59 NF1-glioma samples and matched blood DNA (available from 43 patients) and was used to call germline and somatic single nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) as previously described (see also Methods and Extended Data Fig.	('Met', 'Chemical', 'MESH:C034758', (310, 313))	('single nucleotide variants', 'Var', (166, 192))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('NF1-glioma', 'Disease', (54, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('NF1-glioma', 'Disease', 'MESH:D009456', (54, 64))	('N', 'Chemical', 'MESH:D009584', (271, 272))	('patients', 'Species', '9606', (114, 122))
133979	30531922	To determine the pattern and frequency of the predisposing NF1 gene mutations in patients who developed glioma, we analyzed blood DNA by WES.	('NF1 gene', 'Gene', (59, 67))	('patients', 'Species', '9606', (81, 89))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('mutations', 'Var', (68, 77))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('glioma', 'Disease', (104, 110))
133980	30531922	We also inferred the germline status of NF1 mutations from the analysis of tumor-only samples using a recently described computational approach that models the allele frequency of genomic events under different scenarios accounting for copy number events, minor and major alleles, and clonality (Supplementary Table 3a,b).	('NF1', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
133981	30531922	We found germline mutations inactivating the NF1 gene (typically truncating and frameshift) in 51 of the 56 (91%) patients analyzed.	('frameshift', 'Var', (80, 90))	('patients', 'Species', '9606', (114, 122))	('truncating', 'MPA', (65, 75))	('NF1', 'Gene', (45, 48))
133982	30531922	The 91% NF1 germline mutation rate is within the highest frequencies previously reported in NF1 patients by several studies that have used multiple and highly sensitive assays for NF1 mutation detection (typically 83-95%).	('NF1', 'Gene', (8, 11))	('germline', 'Var', (12, 20))	('patients', 'Species', '9606', (96, 104))
133983	30531922	Among the identified NF1 germline mutations, 32 variants had previously been reported in NF1 patients (http://www.hgmd.cf.ac.uk), whereas 19 are new pathogenic variants.	('NF1', 'Gene', (21, 24))	('variants', 'Var', (48, 56))	('patients', 'Species', '9606', (93, 101))
133985	30531922	The comparative analysis of blood and glioma DNA revealed that the variant allele frequency of the constitutive NF1 gene mutations increased, resulting in loss of heterozygosity in the majority of tumors (Supplementary Table 3a,b).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('loss', 'NegReg', (155, 159))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('mutations', 'Var', (121, 130))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('heterozygosity', 'MPA', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('glioma', 'Disease', (38, 44))	('tumors', 'Disease', (197, 203))	('NF1 gene', 'Gene', (112, 120))
133986	30531922	The spectrum of NF1 mutations in patients who developed gliomas did not cluster into specific domains of the NF1 protein and the distribution of mutations was not related to patient age or tumor grade (Fig.	('NF1', 'Gene', (16, 19))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('tumor', 'Disease', (189, 194))	('patient', 'Species', '9606', (33, 40))	('gliomas', 'Disease', (56, 63))	('patients', 'Species', '9606', (33, 41))	('patient', 'Species', '9606', (174, 181))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutations', 'Var', (20, 29))
133987	30531922	These findings are in agreement with the broad distribution of germline mutations of the NF1 gene previously reported in unselected NF1 patients.	('NF1', 'Gene', (89, 92))	('germline mutations', 'Var', (63, 81))	('patients', 'Species', '9606', (136, 144))
133988	30531922	They also indicate that the probability of developing a brain tumor is not dependent on particular patterns of NF1 gene mutations in the patient's germline.	('NF1', 'Gene', (111, 114))	('brain tumor', 'Phenotype', 'HP:0030692', (56, 67))	('patient', 'Species', '9606', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (120, 129))	('brain tumor', 'Disease', (56, 67))	('brain tumor', 'Disease', 'MESH:D001932', (56, 67))
133990	30531922	This finding is consistent with previous studies that reported frequent somatic NF1 mutations in neurofibromas from NF1 patients.	('neurofibromas', 'Disease', 'MESH:D009455', (97, 110))	('NF1', 'Gene', (80, 83))	('mutations', 'Var', (84, 93))	('neurofibromas', 'Phenotype', 'HP:0001067', (97, 110))	('patients', 'Species', '9606', (120, 128))	('neurofibromas', 'Disease', (97, 110))
133993	30531922	The application of a stringent somatic mutation-calling algorithm to the cohort of NF1-glioma resulted in 1,007 high-confidence somatic mutations across 59 tumors, including 838 SNVs and 169 indels, 767 of which were predicted to carry pathogenic effects (Supplementary Table 4).	('NF1-glioma', 'Disease', (83, 93))	('indels', 'Var', (191, 197))	('NF1-glioma', 'Disease', 'MESH:D009456', (83, 93))	('N', 'Chemical', 'MESH:D009584', (179, 180))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('mutations', 'Var', (136, 145))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('SNVs', 'Var', (178, 182))	('tumors', 'Disease', (156, 162))
133995	30531922	The lowest rate of mutations in pediatric NF1-glioma is within the low range of mutation frequencies in pediatric tumors.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (19, 28))	('pediatric tumors', 'Disease', 'MESH:D063766', (104, 120))	('NF1-glioma', 'Disease', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('pediatric tumors', 'Disease', (104, 120))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('NF1-glioma', 'Disease', 'MESH:D009456', (42, 52))
133999	30531922	Statistically significant CNVs comprised gains at 5q31.3 (FGF1), 5p15.33 (TERT), 4q31.21 (IL15), and 17p13.2 (KIF1C), and losses at 9p21.3 (CDKN2A/CDKN2B; see Extended Data Figs.	('gains', 'PosReg', (41, 46))	('17p13.2', 'Var', (101, 108))	('losses', 'NegReg', (122, 128))	('IL15', 'Gene', (90, 94))	('CDKN2A', 'Gene', '1029', (140, 146))	('KIF1C', 'Gene', (110, 115))	('KIF1C', 'Gene', '10749', (110, 115))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('TERT', 'Gene', (74, 78))	('4q31.21', 'Var', (81, 88))	('FGF1', 'Gene', (58, 62))	('TERT', 'Gene', '7015', (74, 78))	('IL15', 'Gene', '3600', (90, 94))	('FGF1', 'Gene', '2246', (58, 62))	('CDKN2B', 'Gene', (147, 153))	('CDKN2A', 'Gene', (140, 146))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('5p15.33', 'Var', (65, 72))	('CDKN2B', 'Gene', '1030', (147, 153))
134001	30531922	Similarly, mutations of H3.3 histone genes, genetic lesions frequently found in sporadic pediatric gliomas, were absent in pediatric or adult NF1-gliomas.	('mutations', 'Var', (11, 20))	('pediatric gliomas', 'Disease', 'MESH:D005910', (89, 106))	('NF1-gliomas', 'Disease', 'MESH:D009456', (142, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('genetic lesions', 'Disease', (44, 59))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('pediatric gliomas', 'Disease', (89, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('H3.3', 'Gene', (24, 28))	('genetic lesions', 'Disease', 'MESH:D020022', (44, 59))	('NF1-gliomas', 'Disease', (142, 153))
134003	30531922	Sporadic gliomas frequently harbor genetic alterations that cause telomere elongation.	('genetic alterations', 'Var', (35, 54))	('Sporadic gliomas', 'Disease', 'MESH:D005910', (0, 16))	('Sporadic gliomas', 'Disease', (0, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))
134004	30531922	This process is typically carried out through mutations in the TERT gene promoter in IDH wild-type tumors.	('mutations', 'Var', (46, 55))	('IDH wild-type tumors', 'Disease', 'MESH:D009369', (85, 105))	('IDH wild-type tumors', 'Disease', (85, 105))	('TERT', 'Gene', (63, 67))	('TERT', 'Gene', '7015', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
134005	30531922	Conversely, in lower grade, sporadic gliomas of adults harboring co-occurring mutations of IDH1 and TP53, the telomerase-independent alternative lengthening of telomeres (ALT) is sustained by inactivating mutations of ATRX, a gene encoding a chromatin remodeler and epigenetic modifier protein.	('TP53', 'Gene', '7157', (100, 104))	('inactivating mutations', 'Var', (192, 214))	('sporadic gliomas', 'Disease', 'MESH:D005910', (28, 44))	('ATRX', 'Gene', '546', (218, 222))	('TP53', 'Gene', (100, 104))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('IDH1', 'Gene', (91, 95))	('mutations', 'Var', (78, 87))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('IDH1', 'Gene', '3417', (91, 95))	('ATRX', 'Gene', (218, 222))	('sporadic gliomas', 'Disease', (28, 44))
134006	30531922	In NF1-glioma, we failed to detect mutations in the TERT promoter by targeted sequencing but we found copy number gain of the TERT gene more frequently in low-grade than high-grade tumors (47% versus 12%, P = 9 x 10-3; Fig.	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('TERT', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('copy number', 'Var', (102, 113))	('gain', 'PosReg', (114, 118))	('TERT', 'Gene', (52, 56))	('TERT', 'Gene', '7015', (126, 130))	('TERT', 'Gene', '7015', (52, 56))	('NF1-glioma', 'Disease', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('NF1-glioma', 'Disease', 'MESH:D009456', (3, 13))
134007	30531922	Despite the absence of IDH1 mutations, high-grade NF1-glioma frequently harbored inactivating mutations of ATRX (9 of 24, 38%; Fig.	('IDH1', 'Gene', (23, 27))	('NF1-glioma', 'Disease', (50, 60))	('ATRX', 'Gene', (107, 111))	('harbored', 'Reg', (72, 80))	('IDH1', 'Gene', '3417', (23, 27))	('inactivating mutations', 'Var', (81, 103))	('NF1-glioma', 'Disease', 'MESH:D009456', (50, 60))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('ATRX', 'Gene', '546', (107, 111))
134009	30531922	ATRX mutations were mutually exclusive with TERT gene copy number gain and co-occurred with copy number loss of CDKN2A/CDKN2B, which was also more frequent in high-grade (58%) in comparison with low-grade tumors (19%; see Fig.	('TERT', 'Gene', (44, 48))	('loss', 'NegReg', (104, 108))	('TERT', 'Gene', '7015', (44, 48))	('CDKN2A', 'Gene', (112, 118))	('low-grade tumors', 'Disease', (195, 211))	('ATRX', 'Gene', (0, 4))	('low-grade tumors', 'Disease', 'MESH:D008228', (195, 211))	('gain', 'PosReg', (66, 70))	('copy number', 'Var', (92, 103))	('CDKN2A', 'Gene', '1029', (112, 118))	('frequent', 'Reg', (147, 155))	('mutations', 'Var', (5, 14))	('CDKN2B', 'Gene', (119, 125))	('ATRX', 'Gene', '546', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('CDKN2B', 'Gene', '1030', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))
134010	30531922	7, and Supplementary Table 7), and mutations of TP53.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (35, 44))
134011	30531922	TP53 mutations were absent in low-grade NF1-glioma (Fig.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('NF1-glioma', 'Disease', (40, 50))	('NF1-glioma', 'Disease', 'MESH:D009456', (40, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
134012	30531922	ATRX mutation emerged from a multinomial regression model, including also age and grade, as the only independent predictor of somatic mutational spectrum in protein-coding regions (P = 1.1 x 10-3) with accumulation of C T transitions in ATRX mutant NF1-glioma (Extended Data Fig.	('ATRX', 'Gene', (0, 4))	('accumulation', 'PosReg', (202, 214))	('ATRX', 'Gene', (237, 241))	('NF1-glioma', 'Disease', (249, 259))	('ATRX', 'Gene', '546', (0, 4))	('mutant', 'Var', (242, 248))	('NF1-glioma', 'Disease', 'MESH:D009456', (249, 259))	('ATRX', 'Gene', '546', (237, 241))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))
134013	30531922	In conclusion, together with TP53 mutations and CDKN2A copy number losses, ATRX mutations characterize high- but not low-grade gliomas from NF1 patients.	('ATRX', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('ATRX', 'Gene', '546', (75, 79))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('patients', 'Species', '9606', (144, 152))	('CDKN2A', 'Gene', (48, 54))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (29, 33))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('CDKN2A', 'Gene', '1029', (48, 54))	('high-', 'Disease', (103, 108))
134018	30531922	Genetic alterations of cilium/centrosome occurred in a significant fraction of NF1-gliomas but were similarly distributed in high- and low-grade NF1-gliomas (Fig.	('Genetic alterations', 'Var', (0, 19))	('NF1-gliomas', 'Disease', 'MESH:D009456', (79, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('NF1-gliomas', 'Disease', 'MESH:D009456', (145, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('occurred', 'Reg', (41, 49))	('NF1-gliomas', 'Disease', (79, 90))	('NF1-gliomas', 'Disease', (145, 156))
134021	30531922	Among the 4 fragments, 36 of 64 of the observed alterations (56%, including 29 copy number gains and 7 SNVs) were shared by all samplings, whereas 37% of alterations (24 of 64, including 5 copy number gains, 12 copy number losses, and 7 SNVs) were private to a single tumor lesion (Supplementary Fig.	('tumor lesion', 'Disease', (268, 280))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('copy number gains', 'Var', (189, 206))	('copy number losses', 'Var', (211, 229))	('tumor lesion', 'Disease', 'MESH:D001932', (268, 280))	('alterations', 'Var', (154, 165))	('N', 'Chemical', 'MESH:D009584', (238, 239))	('N', 'Chemical', 'MESH:D009584', (104, 105))
134022	30531922	Functional annotation revealed that ATRX mutations are damaging events predicted to generate truncated or inactive ATRX proteins (Fig.	('mutations', 'Var', (41, 50))	('ATRX', 'Gene', '546', (115, 119))	('ATRX', 'Gene', '546', (36, 40))	('truncated', 'MPA', (93, 102))	('ATRX', 'Gene', (115, 119))	('inactive', 'MPA', (106, 114))	('ATRX', 'Gene', (36, 40))	('proteins', 'Protein', (120, 128))
134023	30531922	In accordance with the increased frequency of high-grade tumors in older patients, we also found that ATRX mutations in NF1-gliomas primarily occurred in adults.	('occurred', 'Reg', (142, 150))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('mutations', 'Var', (107, 116))	('ATRX', 'Gene', (102, 106))	('ATRX', 'Gene', '546', (102, 106))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('NF1-gliomas', 'Disease', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('NF1-gliomas', 'Disease', 'MESH:D009456', (120, 131))	('patients', 'Species', '9606', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
134024	30531922	Conversely, ATRX mutations were rare in children as only 1 of the 22 pediatric NF1-gliomas (4.5%) harbored an ATRX mutation (Fig.	('NF1-gliomas', 'Disease', 'MESH:D009456', (79, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('ATRX', 'Gene', '546', (12, 16))	('ATRX', 'Gene', (110, 114))	('children', 'Species', '9606', (40, 48))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('ATRX', 'Gene', '546', (110, 114))	('NF1-gliomas', 'Disease', (79, 90))	('mutation', 'Var', (115, 123))	('ATRX', 'Gene', (12, 16))
134025	30531922	As ATRX mutations occurring in NF1-gliomas are predicted to severely impact ATRX protein expression, we sought to validate our sequencing findings in an independent data set of 23 NF1-gliomas (16 high-grade and 7 low-grade) using formalin-fixed, paraffin-embedded samples and ATRX immunohistochemistry.	('ATRX', 'Gene', '546', (276, 280))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('expression', 'MPA', (89, 99))	('mutations', 'Var', (8, 17))	('impact', 'Reg', (69, 75))	('formalin', 'Chemical', 'MESH:D005557', (230, 238))	('ATRX', 'Gene', (76, 80))	('NF1-gliomas', 'Disease', (31, 42))	('NF1-gliomas', 'Disease', 'MESH:D009456', (31, 42))	('ATRX', 'Gene', '546', (76, 80))	('ATRX', 'Gene', (3, 7))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('ATRX', 'Gene', '546', (3, 7))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('NF1-gliomas', 'Disease', (180, 191))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('NF1-gliomas', 'Disease', 'MESH:D009456', (180, 191))	('paraffin', 'Chemical', 'MESH:D010232', (246, 254))	('ATRX', 'Gene', (276, 280))
134028	30531922	Next, we asked whether loss of ATRX is associated with the ALT phenotype in the context of NF1-gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('NF1-gliomas', 'Disease', (91, 102))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('ATRX', 'Gene', (31, 35))	('NF1-gliomas', 'Disease', 'MESH:D009456', (91, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('associated', 'Reg', (39, 49))	('loss', 'Var', (23, 27))	('ATRX', 'Gene', '546', (31, 35))	('ALT', 'Disease', (59, 62))
134030	30531922	The C-circle assay of 21 NF1-gliomas from which genomic DNA was available showed that 10 of 10 gliomas harboring ATRX mutations scored positive for the presence of ALT-specific C-circles but only 1 of 11 (9%) tumors that retained a wild-type ATRX gene was positive for C-circles (P = 2.3 x 10-5; see Fig.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('NF1-gliomas', 'Disease', (25, 36))	('NF1-gliomas', 'Disease', 'MESH:D009456', (25, 36))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('ATRX', 'Gene', (242, 246))	('ATRX', 'Gene', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('ATRX', 'Gene', '546', (113, 117))	('ATRX', 'Gene', '546', (242, 246))	('mutations', 'Var', (118, 127))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (95, 102))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('positive', 'Reg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('ALT-specific C-circles', 'MPA', (164, 186))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))
134040	30531922	The application of ESTIMATE, a validated computational approach for the inference of the fraction of stromal/immune cells and consequently the tumor cell purity within tumor samples, showed that the low-grade/high-immune group had significantly lower tumor purity and higher immune score when compared with either the low-grade/low-immune or the high-grade groups (Fig.	('tumor', 'Disease', (251, 256))	('low-grade/high-immune', 'Var', (199, 220))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('immune score', 'MPA', (275, 287))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('lower', 'NegReg', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('higher', 'PosReg', (268, 274))
134045	30531922	Recent data showed that aberrant DNA methylation of genes expressed by immune cells regulates the extent of immune infiltration in solid tumors.	('regulates', 'Reg', (84, 93))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('aberrant', 'Var', (24, 32))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
134049	30531922	Functional gene ontology analysis of the genes corresponding to the hyper-methylated probes in the low-immune group of NFl-gliomas identified enriched immune system categories (Supplementary Fig.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('NFl-gliomas', 'Disease', 'MESH:D005910', (119, 130))	('hyper-methylated', 'Var', (68, 84))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('NFl-gliomas', 'Disease', (119, 130))
134050	30531922	We further confirmed this finding by an integrated analysis of gene expression and DNA methylation, from which a total of 68 genes enriched for immune categories emerged as significantly hyper-methylated and down-regulated in low-versus high-immune NFl-gliomas (Supplementary Fig.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('NFl-gliomas', 'Disease', 'MESH:D005910', (249, 260))	('N', 'Chemical', 'MESH:D009584', (249, 250))	('low-versus', 'Var', (226, 236))	('gliomas', 'Phenotype', 'HP:0009733', (253, 260))	('hyper-methylated', 'PosReg', (187, 203))	('NFl-gliomas', 'Disease', (249, 260))	('down-regulated', 'NegReg', (208, 222))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))
134054	30531922	To characterize the neoantigens identified in high-immune NFl-gliomas, we performed a homogenous, proximity-based assay that measures the affinity kinetics of mutant neoantigens and corresponding wild-type peptides for binding to their restricted HLA class I allele.	('NFl-gliomas', 'Disease', (58, 69))	('binding', 'Interaction', (219, 226))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('mutant', 'Var', (159, 165))	('NFl-gliomas', 'Disease', 'MESH:D005910', (58, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
134065	30531922	The subset of sporadic LGm6 gliomas in cluster l exhibited significant enrichment for low-grade histology (P = 0.02) and, albeit not reaching statistical significance, there was a trend for increased frequency of NF1 mutations in this group (Supplementary Fig.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('NF1', 'Gene', (213, 216))	('gliomas', 'Disease', (28, 35))	('mutations', 'Var', (217, 226))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('LGm6', 'Gene', (23, 27))
134068	30531922	We also found that the key alterations identified in high-grade NFl-gliomas (ATRX and TP53 mutations and CDKN2A copy number losses) were also highly recurrent in LGm6 grade III and IV tumors in the LGm6 subgroup (Fig.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('NFl-gliomas', 'Disease', 'MESH:D005910', (64, 75))	('TP53', 'Gene', '7157', (86, 90))	('CDKN2A', 'Gene', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('copy number losses', 'Var', (112, 130))	('ATRX', 'Gene', '546', (77, 81))	('tumors', 'Disease', (184, 190))	('TP53', 'Gene', (86, 90))	('CDKN2A', 'Gene', '1029', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('mutations', 'Var', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('ATRX', 'Gene', (77, 81))	('NFl-gliomas', 'Disease', (64, 75))
134069	30531922	Re-evaluation of ATRX status revealed that mutation of this gene is more frequent in this group than the other subtypes of sporadic IDH wild-type gliomas (Fig.	('ATRX', 'Gene', (17, 21))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('mutation', 'Var', (43, 51))	('ATRX', 'Gene', '546', (17, 21))	('sporadic IDH wild-type gliomas', 'Disease', (123, 153))	('sporadic IDH wild-type gliomas', 'Disease', 'MESH:D005910', (123, 153))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('frequent', 'Reg', (73, 81))
134071	30531922	Furthermore, we found that, whereas the clinical outcome of LGm6-GBM was poor regardless of the ATRX status, ATRX mutations conferred a significantly worse prognosis to the grade III LGm6 patients (P = 0.03), with a survival that was comparable to that of LGm6-GBM.	('worse', 'NegReg', (150, 155))	('mutations', 'Var', (114, 123))	('ATRX', 'Gene', '546', (109, 113))	('ATRX', 'Gene', (96, 100))	('patients', 'Species', '9606', (188, 196))	('ATRX', 'Gene', '546', (96, 100))	('ATRX', 'Gene', (109, 113))
134073	30531922	Finally, to identify the transcription factors that are causally involved as master regulators of the transcriptomic changes associated with loss of ATRX in the LGm6 group of IDH wild-type gliomas, we used the transcriptional network assembled from a TCGA-derived pan-glioma cohort and applied the regularized gradient-boosting machine (RGBM) approach, a recently developed algorithm that involves gradient-boosting machines for the inference of gene regulatory networks.	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('IDH', 'Gene', '3417', (175, 178))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('ATRX', 'Gene', '546', (149, 153))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('loss', 'Var', (141, 145))	('glioma cohort', 'Disease', 'MESH:D005910', (268, 281))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('glioma cohort', 'Disease', (268, 281))	('ATRX', 'Gene', (149, 153))	('IDH', 'Gene', (175, 178))	('gliomas', 'Disease', (189, 196))
134074	30531922	RGBM was benchmarked with synthetic data and used to identify the master regulators that direct mitochondrial metabolic reprogramming of tumors harboring the FGFR3-TACC3 gene fusions.	('TACC3', 'Gene', '10460', (164, 169))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('TACC3', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('FGFR3', 'Gene', (158, 163))	('fusions', 'Var', (175, 182))	('FGFR3', 'Gene', '2261', (158, 163))
134075	30531922	We inferred the activity of master regulators enriched in ATRX mutant samples within the LGm6 cluster of IDH wild-type gliomas by computing a score that integrates the ability of transcription factors to activate their targets in each individual tumor sample.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('mutant', 'Var', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('ATRX', 'Gene', (58, 62))	('gliomas', 'Disease', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('IDH', 'Gene', (105, 108))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('activity', 'MPA', (16, 24))	('ATRX', 'Gene', '546', (58, 62))	('tumor', 'Disease', (246, 251))	('IDH', 'Gene', '3417', (105, 108))
134076	30531922	The analysis resulted in 41 activated master regulators and 48 inhibited master regulators in the 8 ATRX mutant high-grade LGm6 samples compared with 40 ATRX wild-type gliomas (two-sided MWW-GST q < 0.01, absolute NES > 0.6, and two-sided MWW test for differential activity q <0.01; see Fig.	('ATRX', 'Gene', '546', (153, 157))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('mutant', 'Var', (105, 111))	('ATRX', 'Gene', (100, 104))	('activated', 'PosReg', (28, 37))	('ATRX', 'Gene', '546', (100, 104))	('ATRX', 'Gene', (153, 157))	('inhibited', 'NegReg', (63, 72))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('gliomas', 'Disease', (168, 175))	('N', 'Chemical', 'MESH:D009584', (214, 215))
134077	30531922	The first cluster included all ATRX mutant samples, whereas the second cluster was exclusively composed of ATRX wild-type samples (Fig.	('ATRX', 'Gene', (31, 35))	('ATRX', 'Gene', (107, 111))	('mutant', 'Var', (36, 42))	('included', 'Reg', (18, 26))	('ATRX', 'Gene', '546', (31, 35))	('ATRX', 'Gene', '546', (107, 111))
134078	30531922	This finding independently validates the 41 activated master regulators as key drivers of the hallmark features of ATRX mutant gliomas within the LGm6 group.	('ATRX', 'Gene', '546', (115, 119))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('ATRX', 'Gene', (115, 119))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('mutant', 'Var', (120, 126))
134079	30531922	The enrichment map network built from gene ontology categories and informed by the inferred targets of the 10 most active master regulators in ATRX mutant tumors shown in Fig.	('ATRX', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('mutant', 'Var', (148, 154))	('ATRX', 'Gene', '546', (143, 147))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))
134080	30531922	This is consistent with the role of the most active master regulators in ATRX mutant gliomas (MYST3, CHD2, ZMIZ1, NCOR1, NSD1) as chromatin and epigenetic modifiers.	('MYST3', 'Gene', '7994', (94, 99))	('CHD2', 'Gene', '1106', (101, 105))	('NCOR1', 'Gene', (114, 119))	('NSD1', 'Gene', (121, 125))	('MYST3', 'Gene', (94, 99))	('gliomas', 'Disease', (85, 92))	('ATRX', 'Gene', (73, 77))	('ATRX', 'Gene', '546', (73, 77))	('ZMIZ1', 'Gene', '57178', (107, 112))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('ZMIZ1', 'Gene', (107, 112))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('NCOR1', 'Gene', '9611', (114, 119))	('CHD2', 'Gene', (101, 105))	('mutant', 'Var', (78, 84))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('NSD1', 'Gene', '64324', (121, 125))
134081	30531922	The activation of a unique set of master regulators with important functions in chromatin remodeling and transcriptional coregulation as drivers of the ATRX mutant transcriptome within the IDH wild-type LGm6 cluster provides a clue to the molecular events that become deregulated and trigger global epigenomic remodeling and transcriptional changes following loss of ATRX function in brain tumors.	('IDH', 'Gene', (189, 192))	('mutant', 'Var', (157, 163))	('IDH', 'Gene', '3417', (189, 192))	('loss', 'NegReg', (359, 363))	('ATRX', 'Gene', '546', (367, 371))	('transcriptional', 'MPA', (325, 340))	('brain tumors', 'Phenotype', 'HP:0030692', (384, 396))	('brain tumor', 'Phenotype', 'HP:0030692', (384, 395))	('tumor', 'Phenotype', 'HP:0002664', (390, 395))	('brain tumors', 'Disease', 'MESH:D001932', (384, 396))	('ATRX', 'Gene', (152, 156))	('brain tumors', 'Disease', (384, 396))	('tumors', 'Phenotype', 'HP:0002664', (390, 396))	('ATRX', 'Gene', (367, 371))	('ATRX', 'Gene', '546', (152, 156))	('deregulated', 'PosReg', (268, 279))
134082	30531922	Here, we reported the landscape of genetic and epigenetic alterations of gliomas occurring in NF1 patients.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('patients', 'Species', '9606', (98, 106))	('epigenetic alterations', 'Var', (47, 69))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', (73, 80))
134083	30531922	It is important to consider that the inaccessible brain tumor location, the relatively benign behavior of brain lesions, the comorbidities, and the neurological deterioration associated with surgical intervention most frequently argue against surgery as choice of treatment for glioma patients with NF113.	('brain tumor', 'Disease', 'MESH:D001932', (50, 61))	('neurological deterioration', 'Disease', 'MESH:D009422', (148, 174))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NF113', 'Var', (299, 304))	('brain tumor', 'Phenotype', 'HP:0030692', (50, 61))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('brain lesions', 'Disease', (106, 119))	('brain lesions', 'Disease', 'MESH:D001927', (106, 119))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('neurological deterioration', 'Disease', (148, 174))	('patients', 'Species', '9606', (285, 293))	('neurological deterioration', 'Phenotype', 'HP:0002344', (148, 174))	('glioma', 'Disease', (278, 284))	('brain tumor', 'Disease', (50, 61))
134086	30531922	We found that abundant infiltrates of activated T lymphocytes and mutation-derived neoantigens characterize a subset of low-grade gliomas, whereas high-grade tumors exhibit frequent mutations of ATRX typically co-occurring with alterations of TP53 and CDKN2A.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('ATRX', 'Gene', (195, 199))	('CDKN2A', 'Gene', (252, 258))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('alterations', 'Var', (228, 239))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('CDKN2A', 'Gene', '1029', (252, 258))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('ATRX', 'Gene', '546', (195, 199))	('TP53', 'Gene', '7157', (243, 247))	('TP53', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (182, 191))
134087	30531922	We also classified gliomas occurring in the context of the NF1 syndrome within a particular methylation sub-group of sporadic gliomas, the LGm6, that recapitulates mutational and epigenetic profiles of NF1-glioma.	('NF1-glioma', 'Disease', 'MESH:D009456', (202, 212))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('sporadic gliomas', 'Disease', (117, 133))	('sporadic gliomas', 'Disease', 'MESH:D005910', (117, 133))	('gliomas', 'Disease', (126, 133))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('epigenetic', 'Var', (179, 189))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('NF1-glioma', 'Disease', (202, 212))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
134088	30531922	The discovery that ATRX mutations drive aggressiveness in NF1-glioma prompted re-evaluation of the mutational and clinical features of the sporadic glioma counterpart (LGm6), leading to a more accurate classification of the sporadic tumors that cluster into this group.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('aggressiveness', 'Disease', (40, 54))	('NF1-glioma', 'Disease', 'MESH:D009456', (58, 68))	('ATRX', 'Gene', '546', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('aggressiveness', 'Phenotype', 'HP:0000718', (40, 54))	('sporadic glioma', 'Disease', 'MESH:D005910', (139, 154))	('ATRX', 'Gene', (19, 23))	('sporadic glioma', 'Disease', (139, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('aggressiveness', 'Disease', 'MESH:D001523', (40, 54))	('sporadic tumors', 'Disease', 'MESH:D020821', (224, 239))	('mutations', 'Var', (24, 33))	('NF1-glioma', 'Disease', (58, 68))	('sporadic tumors', 'Disease', (224, 239))
134093	30531922	The only set of recurrently mutated genes in low-grade NF1-glioma are genes involved in the MAPK pathway, thus recapitulating the genetic features of sporadic pilocytic astrocytoma.	('NF1-glioma', 'Disease', (55, 65))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (159, 180))	('NF1-glioma', 'Disease', 'MESH:D009456', (55, 65))	('low-grade', 'Var', (45, 54))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('pilocytic astrocytoma', 'Disease', (159, 180))
134095	30531922	Loss of ATRX in high-grade NF1-glioma is unique when considered within the genetic contexts associated with ATRX mutations in sporadic gliomas, in which they are typically associated with mutations of H3.3 in children or IDH1 in adults.	('IDH1', 'Gene', (221, 225))	('NF1-glioma', 'Disease', 'MESH:D009456', (27, 37))	('ATRX', 'Gene', '546', (108, 112))	('ATRX', 'Gene', '546', (8, 12))	('children', 'Species', '9606', (209, 217))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('IDH1', 'Gene', '3417', (221, 225))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('mutations', 'Var', (113, 122))	('ATRX', 'Gene', (108, 112))	('sporadic gliomas', 'Disease', (126, 142))	('ATRX', 'Gene', (8, 12))	('NF1-glioma', 'Disease', (27, 37))	('sporadic gliomas', 'Disease', 'MESH:D005910', (126, 142))
134096	30531922	The inactivating mutations of the ATRX gene result in loss of a functional ATRX protein with at least two important mechanistic consequences: development of the ALT phenotype and activation of a transcriptional/chromatin remodeling gene expression signature in ATRX mutant NF1-glioma.	('ATRX', 'Gene', (75, 79))	('inactivating mutations', 'Var', (4, 26))	('ATRX', 'Gene', (34, 38))	('transcriptional/chromatin', 'MPA', (195, 220))	('ATRX', 'Gene', '546', (75, 79))	('NF1-glioma', 'Disease', (273, 283))	('mutant', 'Var', (266, 272))	('protein', 'Protein', (80, 87))	('ATRX', 'Gene', (261, 265))	('ATRX', 'Gene', '546', (34, 38))	('activation', 'PosReg', (179, 189))	('ATRX', 'Gene', '546', (261, 265))	('NF1-glioma', 'Disease', 'MESH:D009456', (273, 283))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))	('loss of a', 'NegReg', (54, 63))
134097	30531922	Previous work reported that mouse models of low-grade glioma sustained by loss of NF1 manifest specific alterations of the immune microenvironment.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('alterations', 'Reg', (104, 115))	('mouse', 'Species', '10090', (28, 33))	('NF1', 'Gene', (82, 85))	('glioma', 'Disease', (54, 60))	('loss', 'Var', (74, 78))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
134101	30531922	The reduced DNA methylation of immune genes expressed in low-grade/high-immune NF1-glioma is consistent with previous studies in which reduced methylation and increased expression of immune genes in human tumors was linked to tumor infiltration by lymphocytes characterized by demethylated and transcriptionally active genes involved in T lymphocyte functions that, on the contrary, were highly methylated and transcriptionally repressed in cancer cells.	('NF1-glioma', 'Disease', 'MESH:D009456', (79, 89))	('reduced', 'NegReg', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('expression', 'MPA', (169, 179))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('human', 'Species', '9606', (199, 204))	('cancer', 'Disease', 'MESH:D009369', (441, 447))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('NF1-glioma', 'Disease', (79, 89))	('tumors', 'Disease', (205, 211))	('demethylated', 'Var', (277, 289))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('reduced', 'NegReg', (135, 142))	('methylation', 'MPA', (143, 154))	('DNA methylation', 'MPA', (12, 27))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (441, 447))	('increased', 'PosReg', (159, 168))	('tumor', 'Disease', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (441, 447))	('tumor', 'Disease', (226, 231))
134102	30531922	Taken together, our findings suggest that the long indolent course of low-grade NF1-gliomas that rarely progress to high-grade disease may be preserved by the checks imposed by the adaptive immunity acquired by some low-grade tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('low-grade tumors', 'Disease', (216, 232))	('NF1-gliomas', 'Disease', 'MESH:D009456', (80, 91))	('low-grade', 'Var', (70, 79))	('low-grade tumors', 'Disease', 'MESH:D008228', (216, 232))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('NF1-gliomas', 'Disease', (80, 91))
134104	30531922	Prompted by the discovery that high-grade IDH wild-type gliomas in NF1 patients harbor frequent mutations of ATRX, we re-analyzed the LGm6 subgroup of sporadic tumors.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('IDH', 'Gene', (42, 45))	('NF1', 'Gene', (67, 70))	('gliomas', 'Disease', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('ATRX', 'Gene', '546', (109, 113))	('patients', 'Species', '9606', (71, 79))	('IDH', 'Gene', '3417', (42, 45))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('sporadic tumors', 'Disease', 'MESH:D020821', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('sporadic tumors', 'Disease', (151, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('ATRX', 'Gene', (109, 113))	('mutations', 'Var', (96, 105))
134106	30531922	Indeed, mutation pattern and clinical outcome of grade II-LGm6 gliomas diverge markedly from those of grade III-LGm6 tumors harboring ATRX mutations, which are more similar to LGm6-GBM.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (139, 148))	('ATRX', 'Gene', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('ATRX', 'Gene', '546', (134, 138))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
134108	30531922	As previous studies have shown that loss of ATRX increases sensitivity to DNA-damaging agents, ATRX mutations may represent a point of therapeutic intervention for high-grade NF1-gliomas and LGm6 sporadic gliomas.	('ATRX', 'Gene', (44, 48))	('ATRX', 'Gene', (95, 99))	('mutations', 'Var', (100, 109))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('ATRX', 'Gene', '546', (44, 48))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('ATRX', 'Gene', '546', (95, 99))	('increases', 'PosReg', (49, 58))	('loss', 'Var', (36, 40))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('sporadic gliomas', 'Disease', (196, 212))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('NF1-gliomas', 'Disease', (175, 186))	('sporadic gliomas', 'Disease', 'MESH:D005910', (196, 212))	('sensitivity to DNA-damaging agents', 'MPA', (59, 93))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('NF1-gliomas', 'Disease', 'MESH:D009456', (175, 186))
134117	30531922	Blood DNA was available from 43 of the 56 patients and was used for WES and NF1 germline mutation calling to confirm the clinical diagnosis, and to identify SNVs from matched tumor-normal pairs.	('tumor', 'Disease', (175, 180))	('mutation', 'Var', (89, 97))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('NF1', 'Gene', (76, 79))
134126	30531922	To reduce false positive events, all somatic variants detected by matched normal and virtual normal methods were further filtered according to the following criteria:  Somatic variants were annotated using AnnoVar algorithm, which aggregates information from genomic and protein resources (GENECODE, UniProt, dbNSFP) with cancer (COSMIC, ClinVar) and non-cancer variant databases (dbSNP, 1000 Genomes, Kaviar, Haplotype Reference Consortium, Exome Aggregation Consortium, NHLBI Exome Variant Server).	('N', 'Chemical', 'MESH:D009584', (472, 473))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('Re', 'Chemical', 'MESH:D012211', (420, 422))	('cancer', 'Disease', (322, 328))	('variants', 'Var', (45, 53))	('N', 'Chemical', 'MESH:D009584', (384, 385))	('N', 'Chemical', 'MESH:D009584', (311, 312))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('N', 'Chemical', 'MESH:D009584', (292, 293))	('Ser', 'Chemical', 'MESH:C530429', (492, 495))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('cancer', 'Disease', (355, 361))	('cancer', 'Disease', 'MESH:D009369', (355, 361))
134127	30531922	Variants reported in the non-cancer databases with a minor allele frequency >=0.05 were classified as germline polymorphisms and excluded.	('cancer', 'Disease', (29, 35))	('Variants', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
134128	30531922	Additionally, variants occurring in very large genes (for example, TTN and USH2A) and highly paralogous genes (for example, mucins and keratins) were filtered out as common sequencing artifacts.	('variants', 'Var', (14, 22))	('USH2A', 'Gene', (75, 80))	('TTN', 'Gene', (67, 70))	('TTN', 'Gene', '7273', (67, 70))	('USH2A', 'Gene', '7399', (75, 80))
134148	30531922	Samples were clustered using the hierarchical clustering algorithm based on the Ward linkage method and Euclidean distance as implemented in R. Gene ontology enrichment was computed using either: (1) MWW-GST, when a full ranked list of genes was available; or (2) Fisher's exact test, when only a list of significant genes was available (that is, down-regulated and hyper-methylated genes, lists of genes in the regulons of the top 10 ATRX mutant, and wild-type-specific master regulators).	('ATRX', 'Gene', (435, 439))	('hyper-methylated genes', 'Var', (366, 388))	('mutant', 'Var', (440, 446))	('down-regulated', 'NegReg', (347, 361))	('ATRX', 'Gene', '546', (435, 439))
134150	30531922	To identify master regulators of the gene expression signature activated in the high-grade LGm6 IDH wild-type pan-glioma ATRX mutant (8 samples) versus ATRX wild-type (40 samples) subgroup, we used the transcriptional network assembled from gene expression profiles of the IDH wild-type pan-glioma data set using the RGBM algorithm from our previous works.	('LGm6', 'Gene', (91, 95))	('IDH', 'Gene', '3417', (96, 99))	('glioma', 'Disease', (114, 120))	('ATRX', 'Gene', '546', (152, 156))	('ATRX', 'Gene', (121, 125))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Disease', (291, 297))	('IDH', 'Gene', '3417', (273, 276))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (291, 297))	('IDH', 'Gene', (273, 276))	('ATRX', 'Gene', (152, 156))	('glioma', 'Disease', 'MESH:D005910', (291, 297))	('ATRX', 'Gene', '546', (121, 125))	('mutant', 'Var', (126, 132))	('IDH', 'Gene', (96, 99))
134151	30531922	As a result, we obtained 89 master regulators, 41 of which were enriched in ATRX mutant samples (two-sided MWW-GST adjusted P < 0.01, absolute NES> 0.6, and two-sided MWW test for differential activity adjusted P < 0.01).	('N', 'Chemical', 'MESH:D009584', (143, 144))	('ATRX', 'Gene', '546', (76, 80))	('ATRX', 'Gene', (76, 80))	('mutant', 'Var', (81, 87))
134164	30531922	The correlation between mutational spectrum as response variable (C >T, C >A, C >G, T >C, T > A, and T >G) and age, grade, and ATRX mutational status as predictor variable was determined by a Dirichlet-multinomial model.	('T >C', 'Var', (84, 88))	('ATRX', 'Gene', (127, 131))	('C >G', 'Var', (78, 82))	('ATRX', 'Gene', '546', (127, 131))	('C >T', 'Var', (66, 70))	('C >A', 'Var', (72, 76))
134167	30531922	Binding affinity of mutant and corresponding wild-type peptides to the patient's germline HLA alleles was predicted using netMHCpan-4.0.	('mutant', 'Var', (20, 26))	('patient', 'Species', '9606', (71, 78))	('Binding affinity', 'Interaction', (0, 16))
134202	30531922	Sections were incubated in horseradish peroxidase-conjugated secondary antibody (Dako Envision+ System HRP Labelled Polymer ready to use anti-mouse and anti-rabbit, K4000 and K4003, respectively) for 30 min and 3,3-di-amino-benzidine (Vector) was used as substrate.	('K4003', 'Chemical', 'MESH:D011188', (175, 180))	('mouse', 'Species', '10090', (142, 147))	('K4000', 'Var', (165, 170))	('3,3-di-amino-benzidine', 'Chemical', 'MESH:D001560', (211, 233))	('horseradish', 'Species', '3704', (27, 38))	('K4003', 'Var', (175, 180))	('rabbit', 'Species', '9986', (157, 163))	('K4000', 'Chemical', 'MESH:D011188', (165, 170))
134235	31628300	Indeed, in TCGA PAAD, when we evaluated the hematoxylin and eosin (H&E) slides for the presence or absence of immune infiltrate and tertiary lymphoid structures within the tumor, samples with high immune weights showed apparent infiltration, which was absent in low immune-weighted samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TCGA PAAD', 'Chemical', 'MESH:C070654', (11, 20))	('hematoxylin', 'Chemical', 'MESH:D006416', (44, 55))	('with high immune', 'Var', (187, 203))	('tumor', 'Disease', (172, 177))	('eosin', 'Chemical', 'MESH:D004801', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
134236	31628300	In addition, high immune weights predict better overall survival in TCGA PAAD, as well as a subset of the 33 cancer types (Supplementary Fig.	('overall survival', 'MPA', (48, 64))	('high', 'Var', (13, 17))	('cancer type', 'Disease', 'MESH:D009369', (109, 120))	('better', 'PosReg', (41, 47))	('TCGA PAAD', 'Chemical', 'MESH:C070654', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('immune weights', 'MPA', (18, 32))	('TCGA PAAD', 'Disease', (68, 77))	('cancer type', 'Disease', (109, 120))
134238	31628300	Based on previous tumor subtype calls (the Moffitt schema) derived by consensus clustering using exemplar genes for these samples, we show that Moffitt Basal-like samples (n = 37) are associated with higher DECODER basal compartment weights and Moffitt Classical samples (n = 113) with higher DECODER classical compartment weights (Fig.	('tumor', 'Disease', (18, 23))	('DECODER basal compartment weights', 'MPA', (207, 240))	('Moffitt', 'Var', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('higher', 'PosReg', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
134262	31628300	Comparing with ATAC-seq clusters and iClusters, D29.13:GBM + LGG(Brain) was associated with A5:Brain, and C11:LGG(IDH1 mut) or C23:GBM/LGG(IDH1 wt), respectively.	('IDH1', 'Gene', (114, 118))	('IDH1', 'Gene', (139, 143))	('D29.13', 'Var', (48, 54))	('C11:LGG', 'Var', (106, 113))	('C23', 'Chemical', 'MESH:C038399', (127, 130))	('IDH1', 'Gene', '3417', (114, 118))	('IDH1', 'Gene', '3417', (139, 143))	('C23:GBM/LGG', 'Var', (127, 138))
134264	31628300	Similarly, D21.5:COAD + STAD + ESCA(Pan-GI) and D29.26:STAD + ESCA(Digestive) were found to be related to the pan-GI system and clusters, with D21.5:COAD + STAD + ESCA(Pan-GI) exhibiting the highest weights in colon adenocarcinoma (COAD) and stomach adenocarcinoma (STAD), and the second highest weights in esophageal carcinoma (ESCA).	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('D29.26', 'Var', (48, 54))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (242, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('stomach adenocarcinoma', 'Disease', (242, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('esophageal carcinoma', 'Disease', (307, 327))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (307, 327))	('D21.5:COAD + STAD + ESCA', 'Var', (143, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (307, 327))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (210, 230))	('D21.5', 'Var', (11, 16))	('colon adenocarcinoma', 'Disease', (210, 230))
134266	31628300	Interestingly, while D16.12:Pan-Squamous showed the second highest weights in BLCA, we found that the cancer-specific D29.24:BLCA compartment was overrepresented as well.	('cancer', 'Disease', (102, 108))	('D29.24', 'Var', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
134267	31628300	Compartments D27.24:BRCA-Basal, D20.18:BRCA-Her2 + , D28.11:BRCA-Chr8qAmp, and D27.13:BRCA-Luminal were all found to be associated with breast invasive carcinoma (BRCA) (N = 141), enabled by sample sufficiency in the data set and as expected by its known heterogeneity.	('BRCA', 'Gene', (39, 43))	('BRCA', 'Gene', '672', (20, 24))	('breast invasive carcinoma', 'Disease', (136, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (136, 161))	('BRCA', 'Gene', (20, 24))	('associated with', 'Reg', (120, 135))	('BRCA', 'Gene', '672', (86, 90))	('BRCA', 'Gene', '672', (163, 167))	('BRCA', 'Gene', (86, 90))	('D27.24', 'Var', (13, 19))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (136, 161))	('BRCA', 'Gene', (163, 167))	('BRCA', 'Gene', '672', (60, 64))	('BRCA', 'Gene', '672', (39, 43))	('D20.18', 'Var', (32, 38))	('BRCA', 'Gene', (60, 64))
134323	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('inactivated', 'NegReg', (53, 64))	('tumor', 'Disease', (16, 21))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
134324	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('histone H3', 'Protein', (99, 109))	('H3K9me3', 'Protein', (181, 188))	('hypermethylation', 'Var', (11, 27))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
134339	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
134369	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('MDA-MB468', 'Var', (177, 186))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('HER2', 'Gene', '2064', (193, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
134391	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('multiple cancer', 'Disease', (181, 196))	('altered', 'Var', (53, 60))	('expression', 'MPA', (90, 100))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('reduced', 'NegReg', (82, 89))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))	('upregulation', 'PosReg', (165, 177))
134425	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('aberrant', 'Var', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ZNFs', 'Chemical', '-', (130, 134))	('cancer', 'Disease', (107, 113))
134428	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
134429	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
134430	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
134435	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
134440	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
134498	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
134499	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
134501	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
134516	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
134517	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('ZNF', 'Gene', (188, 191))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
134528	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
134550	29467620	Silencing of miR-429 in GECs increased the expression of TJ-associated proteins and the distribution continuity.	('miR-429', 'Gene', '554210', (13, 20))	('TJ-associated proteins', 'Protein', (57, 79))	('expression', 'MPA', (43, 53))	('increased', 'PosReg', (29, 38))	('miR-429', 'Gene', (13, 20))	('distribution', 'MPA', (88, 100))	('Silencing', 'Var', (0, 9))
134553	29467620	Conversely, silencing of miR-429 increased the expression and phosphorylation levels of p70S6K, and increased phosphorylation levels of S6, while decreasing BTB permeability.	('p70S6K', 'Gene', (88, 94))	('decreasing', 'NegReg', (146, 156))	('increased', 'PosReg', (100, 109))	('p70S6K', 'Gene', '6198', (88, 94))	('miR-429', 'Gene', '554210', (25, 32))	('silencing', 'Var', (12, 21))	('BTB', 'Chemical', '-', (157, 160))	('miR-429', 'Gene', (25, 32))	('increased', 'PosReg', (33, 42))	('phosphorylation levels', 'MPA', (62, 84))	('BTB permeability', 'MPA', (157, 173))	('expression', 'MPA', (47, 57))	('phosphorylation levels', 'MPA', (110, 132))
134575	29467620	Furthermore, FTY720-induced inhibition of the PI3K/AKT/mTOR/p70S6K signaling pathway was shown to suppress migration and invasion in human glioblastoma cell lines.	('mTOR', 'Gene', (55, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (139, 151))	('mTOR', 'Gene', '2475', (55, 59))	('p70S6K', 'Gene', (60, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('AKT', 'Gene', (51, 54))	('FTY720', 'Chemical', 'MESH:D000068876', (13, 19))	('p70S6K', 'Gene', '6198', (60, 66))	('human', 'Species', '9606', (133, 138))	('suppress', 'NegReg', (98, 106))	('inhibition', 'NegReg', (28, 38))	('glioblastoma', 'Disease', (139, 151))	('AKT', 'Gene', '207', (51, 54))	('FTY720-induced', 'Var', (13, 27))
134627	29467620	TEER values and HRP flux were tested and the changes of BTB models permeability were evaluated in 0.5, 1, 2, 3, and 6 h. The results showed that there was no significant difference of TEER values in the 0.005 nM group.	('0.005 nM', 'Var', (203, 211))	('BTB', 'Chemical', '-', (56, 59))	('TEER', 'MPA', (184, 188))
134639	29467620	To further study the effect of miR-429 on BTB permeability, miR-429 plasmids of the overexpression and silencing expression, and corresponding negative control plasmids were transfected into hCMEC/D3 cells.	('silencing', 'Var', (103, 112))	('miR-429', 'Gene', (60, 67))	('overexpression', 'PosReg', (84, 98))	('miR-429', 'Gene', '554210', (31, 38))	('miR-429', 'Gene', (31, 38))	('D', 'Chemical', 'MESH:D003903', (197, 198))	('BTB', 'Chemical', '-', (42, 45))	('miR-429', 'Gene', '554210', (60, 67))
134643	29467620	After the overexpression and silencing miR-429 BTB models were successfully established, TEER values and HRP flux were performed, respectively.	('silencing', 'Var', (29, 38))	('miR-429', 'Gene', '554210', (39, 46))	('miR-429', 'Gene', (39, 46))	('BTB', 'Chemical', '-', (47, 50))
134654	29467620	Bioinformatics software Human Release TargetScan 6.22 was applied to test the potential targets of miR-429, and the results showed that there were two potential binding sites at 139-145 and 2151-2157 of occludin mRNA 3'UTR.	('2151-2157', 'Var', (190, 199))	('occludin', 'Gene', (203, 211))	('binding', 'Interaction', (161, 168))	('miR-429', 'Gene', (99, 106))	('Human', 'Species', '9606', (24, 29))	('occludin', 'Gene', '100506658', (203, 211))	('miR-429', 'Gene', '554210', (99, 106))
134662	29467620	After the establishment of p70S6K overexpression and silencing in vitro BTB models, the TEER values and HRP fluxes in BTB models were performed.	('BTB', 'Chemical', '-', (72, 75))	('BTB', 'Chemical', '-', (118, 121))	('p70S6K', 'Gene', (27, 33))	('overexpression', 'PosReg', (34, 48))	('p70S6K', 'Gene', '6198', (27, 33))	('silencing', 'Var', (53, 62))
134665	29467620	Western blot was applied to test the expressions of TJ-associated proteins (ZO-1, occludin and claudin-5) of GECs in vitro BTB models with p70S6K overexpression and silencing, respectively.	('overexpression', 'PosReg', (146, 160))	('claudin-5', 'Gene', (95, 104))	('ZO-1', 'Gene', '7082', (76, 80))	('occludin', 'Gene', '100506658', (82, 90))	('BTB', 'Chemical', '-', (123, 126))	('claudin-5', 'Gene', '7122', (95, 104))	('ZO-1', 'Gene', (76, 80))	('occludin', 'Gene', (82, 90))	('p70S6K', 'Gene', '6198', (139, 145))	('silencing', 'Var', (165, 174))	('p70S6K', 'Gene', (139, 145))
134667	29467620	The immunofluorescence was applied to detect the expressions and distribution of ZO-1, occludin and claudin-5 in vitro BTB models with p70S6K overexpression and silencing, respectively.	('occludin', 'Gene', '100506658', (87, 95))	('overexpression', 'PosReg', (142, 156))	('occludin', 'Gene', (87, 95))	('BTB', 'Chemical', '-', (119, 122))	('ZO-1', 'Gene', (81, 85))	('p70S6K', 'Gene', (135, 141))	('ZO-1', 'Gene', '7082', (81, 85))	('silencing', 'Var', (161, 170))	('claudin-5', 'Gene', (100, 109))	('claudin-5', 'Gene', '7122', (100, 109))	('p70S6K', 'Gene', '6198', (135, 141))
134669	29467620	qRT-PCR and western blot were applied to detect the expressions of p70S6K in vitro BTB models of miR-429 overexpression and silencing.	('BTB', 'Chemical', '-', (83, 86))	('p70S6K', 'Gene', '6198', (67, 73))	('miR-429', 'Gene', (97, 104))	('silencing', 'Var', (124, 133))	('miR-429', 'Gene', '554210', (97, 104))	('p70S6K', 'Gene', (67, 73))
134684	29467620	Western blot was used to detect the protein expressions of p70S6K, p-p70S6K, S6K, and p-S6K in vitro BTB models with cotransfection of miR-429 and p70S6K.	('p-S6K', 'Gene', (86, 91))	('miR-429', 'Gene', (135, 142))	('BTB', 'Chemical', '-', (101, 104))	('S6K', 'Var', (77, 80))	('p-S6K', 'Gene', '6198', (86, 91))	('p70S6K', 'Gene', (147, 153))	('p70S6K', 'Gene', '6198', (147, 153))	('p70S6K', 'Gene', (69, 75))	('p70S6K', 'Gene', '6198', (59, 65))	('miR-429', 'Gene', '554210', (135, 142))	('p70S6K', 'Gene', (59, 65))	('p70S6K', 'Gene', '6198', (69, 75))
134710	29467620	To verify whether miR-429, as a tumor-inhibiting factor, could regulate BTB permeability, we successfully established stably transfected cell lines of miR-429 overexpression and silencing, and we then built in vitro BTB models.	('BTB', 'Chemical', '-', (72, 75))	('overexpression', 'PosReg', (159, 173))	('miR-429', 'Gene', '554210', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('BTB', 'Chemical', '-', (216, 219))	('miR-429', 'Gene', '554210', (18, 25))	('miR-429', 'Gene', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('silencing', 'Var', (178, 187))	('tumor', 'Disease', (32, 37))	('miR-429', 'Gene', (18, 25))
134716	29467620	In this study, the results of qRT-PCR and western blotting showed miR-429 overexpression greatly down-regulated mRNA and protein expression of ZO-1, occludin and claudin-5; conversely, miR-429 silencing induced up-regulation of ZO-1, occludin and claudin-5.	('claudin-5', 'Gene', '7122', (162, 171))	('occludin', 'Gene', '100506658', (149, 157))	('miR-429', 'Gene', (66, 73))	('ZO-1', 'Gene', '7082', (143, 147))	('occludin', 'Gene', '100506658', (234, 242))	('down-regulated', 'NegReg', (97, 111))	('ZO-1', 'Gene', (143, 147))	('occludin', 'Gene', (149, 157))	('miR-429', 'Gene', (185, 192))	('claudin-5', 'Gene', (162, 171))	('claudin-5', 'Gene', '7122', (247, 256))	('occludin', 'Gene', (234, 242))	('miR-429', 'Gene', '554210', (66, 73))	('up-regulation', 'PosReg', (211, 224))	('ZO-1', 'Gene', '7082', (228, 232))	('ZO-1', 'Gene', (228, 232))	('miR-429', 'Gene', '554210', (185, 192))	('silencing', 'Var', (193, 202))	('claudin-5', 'Gene', (247, 256))
134720	29467620	The results showed that there was one potential binding site at 71-77 of the ZO-1 mRNA 3'UTR and there were two potential binding sites at 139-145 and 2151-2157 of the occludin mRNA 3'UTR.	('occludin', 'Gene', (168, 176))	('ZO-1', 'Gene', (77, 81))	('binding', 'Interaction', (48, 55))	('2151-2157', 'Var', (151, 160))	('ZO-1', 'Gene', '7082', (77, 81))	('occludin', 'Gene', '100506658', (168, 176))
134745	29467620	Conversely, miR-429 silencing significantly up-regulated p70S6K expression, as well as increasing phosphorylation of p70S6K.	('miR-429', 'Gene', (12, 19))	('p70S6K', 'Gene', (57, 63))	('expression', 'MPA', (64, 74))	('phosphorylation', 'MPA', (98, 113))	('p70S6K', 'Gene', '6198', (57, 63))	('p70S6K', 'Gene', (117, 123))	('up-regulated', 'PosReg', (44, 56))	('p70S6K', 'Gene', '6198', (117, 123))	('miR-429', 'Gene', '554210', (12, 19))	('increasing', 'PosReg', (87, 97))	('silencing', 'Var', (20, 29))
134756	29467620	Overexpression of miR-429 greatly down-regulated p70S6K expression, as well as the phosphorylation levels, while miR-429 silencing significantly up-regulated p70S6K expression, and increased phosphorylation levels.	('silencing', 'Var', (121, 130))	('phosphorylation levels', 'MPA', (191, 213))	('up-regulated', 'PosReg', (145, 157))	('miR-429', 'Gene', (113, 120))	('p70S6K', 'Gene', (158, 164))	('down-regulated', 'NegReg', (34, 48))	('expression', 'MPA', (165, 175))	('p70S6K', 'Gene', '6198', (158, 164))	('p70S6K', 'Gene', '6198', (49, 55))	('miR-429', 'Gene', '554210', (18, 25))	('p70S6K', 'Gene', (49, 55))	('phosphorylation levels', 'MPA', (83, 105))	('increased', 'PosReg', (181, 190))	('miR-429', 'Gene', (18, 25))	('miR-429', 'Gene', '554210', (113, 120))
134757	29467620	miR-429 knockdown increased the expression of ZO-1, occludin and claudin-5.	('increased', 'PosReg', (18, 27))	('occludin', 'Gene', '100506658', (52, 60))	('miR-429', 'Gene', '554210', (0, 7))	('occludin', 'Gene', (52, 60))	('knockdown', 'Var', (8, 17))	('ZO-1', 'Gene', '7082', (46, 50))	('claudin-5', 'Gene', (65, 74))	('miR-429', 'Gene', (0, 7))	('expression', 'MPA', (32, 42))	('claudin-5', 'Gene', '7122', (65, 74))	('ZO-1', 'Gene', (46, 50))
134770	28660218	Six consecutive patients (four male, two female), who were clinically suspected of having high- or low-grade glioma, received both FACBC-PET and MET-PET within a two-week interval.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('FACBC-PET', 'Var', (131, 140))	('MET', 'Chemical', 'MESH:C038344', (145, 148))	('patients', 'Species', '9606', (16, 24))	('FACBC', 'Chemical', '-', (131, 136))	('glioma', 'Disease', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
134772	28660218	SUVs for FACBC were lower than those for MET in the non-lesion cerebral cortex, brain stem, and cerebellar hemisphere.	('lower', 'NegReg', (20, 25))	('FACBC', 'Var', (9, 14))	('non-lesion cerebral cortex', 'Disease', 'MESH:D001927', (52, 78))	('FACBC', 'Chemical', '-', (9, 14))	('non-lesion cerebral cortex', 'Disease', (52, 78))	('MET', 'Chemical', 'MESH:C038344', (41, 44))
134774	28660218	FACBC-PET showed higher contrast than MET-PET by both visual and semi-quantitative analyses and may therefore provide better assessment for the detection of glioma.	('contrast', 'MPA', (24, 32))	('MET', 'Chemical', 'MESH:C038344', (38, 41))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('FACBC-PET', 'Var', (0, 9))	('higher', 'PosReg', (17, 23))	('glioma', 'Disease', (157, 163))	('FACBC', 'Chemical', '-', (0, 5))
134778	28660218	High MET accumulation in primary brain tumors is considered to indicate malignant status and significantly unfavorable prognosis.	('brain tumors', 'Phenotype', 'HP:0030692', (33, 45))	('High', 'Var', (0, 4))	('brain tumors', 'Disease', 'MESH:D001932', (33, 45))	('brain tumors', 'Disease', (33, 45))	('MET', 'Chemical', 'MESH:C038344', (5, 8))	('brain tumor', 'Phenotype', 'HP:0030692', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('indicate', 'Reg', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
134800	28660218	The collected tissues were stained with hematoxylin and eosin, and immunohistochemistry was performed for glial fibrillary acidic protein (GFAP), 1p and 19q copy number status, telomerase reverse transcriptase (TERT) promoter, the methylation status of the O6-methylguanine DNA methyltransferase (MGMT) promoter, Ki-67 (MIB-1), and mutant isocitrate dehydrogenase 1 protein (IDH1 R132H).	('IDH1', 'Gene', (375, 379))	('eosin', 'Chemical', 'MESH:D004801', (56, 61))	('telomerase reverse transcriptase', 'Gene', (177, 209))	('MIB-1', 'Gene', (320, 325))	('TERT', 'Gene', (211, 215))	('MIB-1', 'Gene', '57534', (320, 325))	('GFAP', 'Gene', (139, 143))	('TERT', 'Gene', '7015', (211, 215))	('MGMT', 'Gene', (297, 301))	('IDH1', 'Gene', '3417', (375, 379))	('GFAP', 'Gene', '2670', (139, 143))	('telomerase reverse transcriptase', 'Gene', '7015', (177, 209))	('O6-methylguanine DNA methyltransferase', 'Gene', (257, 295))	('glial fibrillary acidic protein', 'Gene', '2670', (106, 137))	('R132H', 'Mutation', 'rs121913500', (380, 385))	('glial fibrillary acidic protein', 'Gene', (106, 137))	('hematoxylin', 'Chemical', 'MESH:D006416', (40, 51))	('mutant', 'Var', (332, 338))	('MGMT', 'Gene', '4255', (297, 301))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (257, 295))
134806	28660218	In the oligodendroglioma case, which featured TERT mutation, IDH1 mutation, and 1p19q co-deletion, high levels of tracer uptake were found in both PET studies (Figure 4; Case 4).	('oligodendroglioma', 'Disease', (7, 24))	('TERT', 'Gene', '7015', (46, 50))	('IDH1', 'Gene', '3417', (61, 65))	('oligodendroglioma', 'Disease', 'MESH:D009837', (7, 24))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH1', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('TERT', 'Gene', (46, 50))	('1p19q', 'Var', (80, 85))
134807	28660218	FACBC has low background accumulation, while image contrast was higher with FACBC-PET than MET-PET and the tumor was clearly depicted in cases 1, 4, 5, and 6.	('FACBC-PET', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('FACBC', 'Chemical', '-', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('higher', 'PosReg', (64, 70))	('MET', 'Chemical', 'MESH:C038344', (91, 94))	('background accumulation', 'MPA', (14, 37))	('FACBC', 'Chemical', '-', (0, 5))	('image contrast', 'MPA', (45, 59))
134809	28660218	SUVs for MET in glioma were similar to SUVs for FACBC, but L/Nmean and L/Nmax were higher in FACBC-PET than MET-PET (Figure 3).	('FACBC', 'Chemical', '-', (48, 53))	('MET', 'Chemical', 'MESH:C038344', (108, 111))	('L/Nmax', 'MPA', (71, 77))	('L/Nmean', 'MPA', (59, 66))	('FACBC', 'Chemical', '-', (93, 98))	('MET', 'Chemical', 'MESH:C038344', (9, 12))	('glioma', 'Disease', (16, 22))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('higher', 'PosReg', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('FACBC-PET', 'Var', (93, 102))
134822	28660218	Case 4, a 57-year-old man, was diagnosed with Grade II, IDH mutant oligodendroglioma, featuring TERT mutation and 1p19q co-deletion (Figure 4; Case 4).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH', 'Gene', (56, 59))	('TERT', 'Gene', (96, 100))	('oligodendroglioma', 'Disease', (67, 84))	('IDH', 'Gene', '3417', (56, 59))	('TERT', 'Gene', '7015', (96, 100))	('1p19q co-deletion', 'Var', (114, 131))	('oligodendroglioma', 'Disease', 'MESH:D009837', (67, 84))	('man', 'Species', '9606', (22, 25))
134826	28660218	Though both PET approaches could detect the tumor in the left frontal lobe, FACBC-PET showed the high cellularity border more clearly than MET-PET.	('FACBC-PET', 'Var', (76, 85))	('FACBC', 'Chemical', '-', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MET', 'Chemical', 'MESH:C038344', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
134830	28660218	Once again, FACBC-PET displayed the tumor border against normal cortex more clearly than MET-PET.	('FACBC-PET', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('FACBC', 'Chemical', '-', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MET', 'Chemical', 'MESH:C038344', (89, 92))	('tumor', 'Disease', (36, 41))
134834	28660218	Our data indicated that FACBC-PET performs better than MET-PET for visual assessment in glioma.	('MET', 'Chemical', 'MESH:C038344', (55, 58))	('FACBC', 'Chemical', '-', (24, 29))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('FACBC-PET', 'Var', (24, 33))
134856	27013192	CSF1 overexpression promotes high-grade glioma formation without impacting the polarization status of glioma-associated microglia and macrophages Current therapies for high-grade gliomas extend survival only modestly.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('promotes', 'PosReg', (20, 28))	('glioma', 'Disease', (102, 108))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('CSF1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('glioma', 'Disease', (40, 46))	('CSF1', 'Gene', '12977', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('gliomas', 'Disease', (179, 186))	('overexpression', 'Var', (5, 19))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (179, 185))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))
134913	27013192	All of the GSC and glioma cell lines tested express the mRNA encoding a secreted CSF1 isoform (SEC) (Figure 1A, B).	('mRNA', 'Var', (56, 60))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('glioma', 'Disease', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
134921	27013192	Despite expressing the Ras* transgene (Supplemental Figure S1B), Ras*; Csf1op/op mice displayed a significant reduction in glioma formation, with only one glioma detected in the brains analyzed (5.56%).	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('reduction', 'NegReg', (110, 119))	('mice', 'Species', '10090', (81, 85))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('Csf1', 'Gene', '12977', (71, 75))	('Csf1', 'Gene', (71, 75))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('glioma', 'Disease', (123, 129))	('Ras', 'Var', (65, 68))	('glioma', 'Disease', (155, 161))
134926	27013192	Therefore, CSF1 deficiency does not impact time to a moribund state in Ras* mice, but significantly deters glioma formation in vivo.	('deters', 'NegReg', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('glioma', 'Disease', (107, 113))	('mice', 'Species', '10090', (76, 80))	('CSF1', 'Gene', (11, 15))	('deficiency', 'Var', (16, 26))
134931	27013192	Ras*; CSF1 OE mice had a significant reduction in time to a moribund state compared to the Ras* Control cohort (p = 0.0002) (Figure 3A).	('time to a moribund state', 'MPA', (50, 74))	('Ras*; CSF1 OE', 'Var', (0, 13))	('mice', 'Species', '10090', (14, 18))	('reduction', 'NegReg', (37, 46))
134933	27013192	Ras*; CSF1 OE mice display significantly increased high-grade glioma formation (53.57%) as compared to Ras* Control mice (19.44%) (p = 0.017).	('mice', 'Species', '10090', (116, 120))	('increased', 'PosReg', (41, 50))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('mice', 'Species', '10090', (14, 18))	('Ras*; CSF1 OE', 'Var', (0, 13))	('glioma', 'Disease', (62, 68))
134934	27013192	Low-grade gliomas were detected in 7.14% of Ras*; CSF1 OE mice and 11.11% of Ras* Control mice.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('Ras*; CSF1 OE', 'Var', (44, 57))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('mice', 'Species', '10090', (58, 62))	('mice', 'Species', '10090', (90, 94))	('detected', 'Reg', (23, 31))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
134935	27013192	In addition, the high-grade gliomas in Ras*; CSF1 OE mice were significantly larger than those from the Ras* Control cohort (p <.001) (Figure 3C).	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('Ras', 'Var', (39, 42))	('larger', 'PosReg', (77, 83))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('mice', 'Species', '10090', (53, 57))	('gliomas', 'Disease', (28, 35))
134936	27013192	To determine if CSF1 over-expression in Ras*; CSF1 OE gliomas is associated with a concomitant change in GAM density compared to Ras* Control gliomas, immunofluorescence for IBA1 (a pan microglia/macrophage marker) was performed (Supplemental Figure S3B).	('S3B', 'Gene', (250, 253))	('change', 'Reg', (95, 101))	('gliomas', 'Disease', (142, 149))	('over-expression', 'PosReg', (21, 36))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('IBA1', 'Gene', (174, 178))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('GAM', 'CPA', (105, 108))	('IBA1', 'Gene', '114737', (174, 178))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('CSF1 OE', 'Var', (46, 53))	('S3B', 'Gene', '11778', (250, 253))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
134938	27013192	GAM densities were also significantly increased in Ras*; CSF1 OE high-grade gliomas compared to microglial density in CSF1 OE normal brains lacking the Ras* transgene (p < 0.001) (Figure 3D).	('GAM densities', 'CPA', (0, 13))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Ras*; CSF1 OE', 'Var', (51, 64))	('increased', 'PosReg', (38, 47))
134940	27013192	Using this method, Ras*; CSF1 OE high-grade gliomas were also found to have increased GAMs compared to high-grade gliomas in Ras* Control mice (p< 0.03, Supplemental Figure S2C).	('Ras*; CSF1 OE', 'Var', (19, 32))	('GAMs', 'CPA', (86, 90))	('gliomas', 'Disease', (114, 121))	('increased', 'PosReg', (76, 85))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('mice', 'Species', '10090', (138, 142))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
134941	27013192	Studies of the limited number of low-grade tumors available from Ras*; CSF1 OE mice (n = 2) indicate that GAMs density appears higher in Ras*; CSF1 OE low-grade gliomas as compared to Ras* Control (n = 3) low-grade gliomas (Supplemental Figure S2D), however the number of tumors available precluded statistical analysis.	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('higher', 'PosReg', (127, 133))	('gliomas', 'Disease', (161, 168))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('gliomas', 'Disease', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('Ras*; CSF1 OE', 'Var', (137, 150))	('tumors', 'Disease', (272, 278))	('mice', 'Species', '10090', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('gliomas', 'Disease', 'MESH:D005910', (215, 222))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
134942	27013192	Therefore, CSF1 over-expression promotes the development of aggressive high-grade tumors in vivo with increased GAM density.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('over-expression', 'Var', (16, 31))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('development', 'CPA', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('promotes', 'PosReg', (32, 40))	('CSF1', 'Gene', (11, 15))
134980	27013192	Our results indicate that one mechanism by which CSF1 over-expression promotes gliomagenesis is by increasing GAM density.	('glioma', 'Disease', (79, 85))	('increasing', 'PosReg', (99, 109))	('over-expression', 'Var', (54, 69))	('GAM density', 'CPA', (110, 121))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('promotes', 'PosReg', (70, 78))	('CSF1', 'Gene', (49, 53))
134982	27013192	Our in vivo results are also consistent with previous findings that CSF1R inhibition reduces GAM numbers in GL261 glioma allografts.	('inhibition', 'Var', (74, 84))	('glioma', 'Disease', (114, 120))	('CSF1R', 'Gene', (68, 73))	('GAM numbers', 'CPA', (93, 104))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('GL261', 'CellLine', 'CVCL:Y003', (108, 113))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('reduces', 'NegReg', (85, 92))
134996	27013192	An in vivo RCAS glioma study utilizing established gliomas showed that CSF1R inhibition shrank gliomas by decreasing the expression of M2 markers such as Arg1 and Cd206 in GAMs.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('expression', 'MPA', (121, 131))	('Arg1', 'Gene', (154, 158))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (51, 58))	('Cd206', 'Gene', (163, 168))	('Cd206', 'Gene', '17533', (163, 168))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('RCAS glioma', 'Disease', (11, 22))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Disease', (95, 102))	('decreasing', 'NegReg', (106, 116))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('Arg1', 'Gene', '11846', (154, 158))	('inhibition', 'Var', (77, 87))	('CSF1R', 'Gene', (71, 76))	('RCAS glioma', 'Disease', 'MESH:D005910', (11, 22))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))
134999	27013192	Although CSF1 transgenic over-expression was found to modulate GAM density and glioma volume, it did not impact expression of M1 and M2 markers in GAMs.	('over-expression', 'PosReg', (25, 40))	('transgenic', 'Var', (14, 24))	('CSF1', 'Gene', (9, 13))	('glioma', 'Disease', (79, 85))	('modulate', 'Reg', (54, 62))	('GAM density', 'CPA', (63, 74))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))
135043	26449498	IL-8 and VEGF mRNAs analyzed with RT-qPCR were quantified by TaqMan Gene Expression Assays (Applied Biosystems, codes HS00174103m1 and HS00173626_m1), respectively, and normalized to calibrator genes GAPDH mRNA (code HS02758991_g1), RPL13A (code HS03043885_g1), 18S rRNA (code 4310893E) according to the manufacturer's instructions, with a 7900HT Fast Real Time PCR System (Applied Biosystems).	('code HS03043885_g1', 'Var', (241, 259))	('RPL13A', 'Gene', (233, 239))	('GAPDH', 'Gene', '2597', (200, 205))	('RPL13A', 'Gene', '23521', (233, 239))	('GAPDH', 'Gene', (200, 205))	('code 4310893E', 'Var', (272, 285))	('HS00173626_m1', 'Var', (135, 148))	('IL-8 and VEGF', 'Gene', '3576;7422', (0, 13))
135045	26449498	MiR-93 expression was firstly normalized to U6 snRNA (code 001973) and let-7c (code 000379).	('code 000379', 'Var', (79, 90))	('MiR-93', 'Gene', '407051', (0, 6))	('MiR-93', 'Gene', (0, 6))	('let-7c', 'Gene', (71, 77))	('let-7c', 'Gene', '406885', (71, 77))	('code 001973', 'Var', (54, 65))
135078	26449498	5a, (right side), demonstrate increase of VEGF release in cells in which down-regulation of miR-93 was forced by transfection with antagomiR-93.	('transfection', 'Var', (113, 125))	('miR-93', 'Gene', (137, 143))	('down-regulation', 'NegReg', (73, 88))	('VEGF', 'Gene', '7422', (42, 46))	('increase', 'PosReg', (30, 38))	('miR-93', 'Gene', '407051', (92, 98))	('miR-93', 'Gene', (92, 98))	('VEGF', 'Gene', (42, 46))	('miR-93', 'Gene', '407051', (137, 143))
135158	23869222	Alterations in the activity of the 26S proteasome have been associated with malignant glioma cells, although the specific defects have not been identified.	('malignant glioma', 'Disease', 'MESH:D005910', (76, 92))	('malignant glioma', 'Disease', (76, 92))	('Alterations', 'Var', (0, 11))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('26S', 'Protein', (35, 38))	('activity', 'MPA', (19, 27))	('associated', 'Reg', (60, 70))
135160	23869222	In the present study, the human Nin one binding protein (NOB1) was identified as a direct target of miR-326 and a potential oncogene in human glioma.	('Nin one binding protein', 'Gene', '28987', (32, 55))	('human', 'Species', '9606', (136, 141))	('miR-326', 'Var', (100, 107))	('glioma', 'Disease', (142, 148))	('Nin one binding protein', 'Gene', (32, 55))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('NOB1', 'Gene', (57, 61))	('human', 'Species', '9606', (26, 31))
135164	23869222	Furthermore, high levels of NOB1 were associated with unfavorable prognosis of glioma patients.	('high levels', 'Var', (13, 24))	('glioma', 'Disease', (79, 85))	('NOB1', 'Gene', (28, 32))	('associated', 'Reg', (38, 48))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('patients', 'Species', '9606', (86, 94))
135165	23869222	Taken together, these results indicate that miR-326 and NOB1 may play an important role in the development of glioma.	('glioma', 'Disease', (110, 116))	('NOB1', 'Gene', (56, 60))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('miR-326', 'Var', (44, 51))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('play', 'Reg', (65, 69))
135173	23869222	miRNAs dysregulation could drive tumorigenesis, through the roles miRNAs can adopt as tumour suppressors or oncogenes.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('drive', 'PosReg', (27, 32))	('miRNAs', 'Protein', (0, 6))	('dysregulation', 'Var', (7, 20))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', (33, 38))	('tumour', 'Disease', (86, 92))
135178	23869222	The dysregulation of miR-326 and its possible involvement in different cancers such as medulloblastoma, cholangiocarcinoma, and chronic lymphocytic leukemia have been suggested in previous studies.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('dysregulation', 'Var', (4, 17))	('involvement', 'Reg', (46, 57))	('cholangiocarcinoma', 'Disease', (104, 122))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (128, 156))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (128, 156))	('medulloblastoma', 'Phenotype', 'HP:0002885', (87, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('medulloblastoma', 'Disease', 'MESH:D008527', (87, 102))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('chronic lymphocytic leukemia', 'Disease', (128, 156))	('miR-326', 'Gene', (21, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('medulloblastoma', 'Disease', (87, 102))
135180	23869222	Furthermore, we demonstrate that miR-326 inhibits the activation of the MAPK pathway, which is one of the core pathways in glioma, and miR-326 overexpression impaired cell viability and the invasiveness of glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('inhibits', 'NegReg', (41, 49))	('MAPK pathway', 'Pathway', (72, 84))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('invasiveness of glioma', 'Disease', 'MESH:D005910', (190, 212))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('glioma', 'Disease', (206, 212))	('miR-326', 'Var', (135, 142))	('overexpression', 'PosReg', (143, 157))	('miR-326', 'Var', (33, 40))	('impaired', 'NegReg', (158, 166))	('cell viability', 'CPA', (167, 181))	('glioma', 'Disease', (123, 129))	('invasiveness of glioma', 'Disease', (190, 212))
135207	23869222	The Annexin V-FITC Apoptosis Detection kit (Calbiochem) and PI (Sigma) was used to assess the apoptotic effect of miR-326.	('miR-326', 'Var', (114, 121))	('Annexin V', 'Gene', '308', (4, 13))	('Annexin V', 'Gene', (4, 13))
135215	23869222	When the female BALB/c-nu mice were 7-8 weeks of age, each mouse was inoculated with 1.5x107 U373 cells transfected with miR-326 or miR-control or NOB1 shRNA in 0.2 mL of medium subcutaneously in the forelimb, the mouse injected mock-infected cells as control.	('mouse', 'Species', '10090', (59, 64))	('miR-326', 'Var', (121, 128))	('miR-control', 'Var', (132, 143))	('NOB1', 'Var', (147, 151))	('mouse', 'Species', '10090', (214, 219))	('U373', 'CellLine', 'CVCL:2219', (93, 97))	('mice', 'Species', '10090', (26, 30))
135231	23869222	To test this hypothesis, A172 and U373 cells were transiently transfected with miR-326 or miR-NC precursors, which miR-326 significantly repressed NOB1 expression, the intervention effects of which was similar to NOB1 RNA interference (RNAi) (Figure 2).	('miR-326', 'Var', (115, 122))	('repressed', 'NegReg', (137, 146))	('U373', 'CellLine', 'CVCL:2219', (34, 38))	('expression', 'MPA', (152, 162))	('NOB1', 'Gene', (147, 151))
135232	23869222	The growth of two glioma cell lines transfected with miR-326, miR-NC, NOB1-shRNA or untreated controls was examined using the MTT [3-(4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl -2H- tetrazolium bromide] assay.	('glioma', 'Disease', (18, 24))	('miR-NC', 'Var', (62, 68))	('miR-326', 'Var', (53, 60))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('MTT', 'Chemical', 'MESH:C070243', (126, 129))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('3-(4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl -2H- tetrazolium bromide', 'Chemical', 'MESH:C000598529', (131, 200))
135233	23869222	As shown in Figures 3A and B, ectopic expression of miR-326 significantly inhibited the growth of glioma cells compared to the negative control 3 d after infection (P<0.05),and there were no statistically significant differences in growth rate between miR-326 overexpressing cells and NOB1 shRNA infected cells.	('inhibited', 'NegReg', (74, 83))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('miR-326', 'Gene', (52, 59))	('ectopic expression', 'Var', (30, 48))	('glioma', 'Disease', (98, 104))
135235	23869222	No significant difference in BrdU incorporation was observed between cells with different treatment at 24 h. However, BrdU incorporation was decreased in A172 cells expressing miR-326 or through NOB1 shRNA treatment compared to the controls at 72 h, similar results were observed in U373 cells (Figures 3C and D).	('miR-326', 'Var', (176, 183))	('U373', 'CellLine', 'CVCL:2219', (283, 287))	('decreased', 'NegReg', (141, 150))	('BrdU incorporation', 'MPA', (118, 136))	('BrdU', 'Chemical', 'MESH:D001973', (29, 33))	('BrdU', 'Chemical', 'MESH:D001973', (118, 122))
135241	23869222	Similar to NOB1 silencing, overexpression of miR-326 caused a substantial reduction in colony formation in soft agar compared with the control cells (P<0.05; Figures 5A-D).	('miR-326', 'Var', (45, 52))	('agar', 'Chemical', 'MESH:D000362', (112, 116))	('NOB1', 'Gene', (11, 15))	('colony formation in soft agar', 'CPA', (87, 116))	('reduction', 'NegReg', (74, 83))	('silencing', 'Var', (16, 25))	('overexpression', 'PosReg', (27, 41))
135242	23869222	To further confirm the effect of increased miR-326 levels on the tumorigenesis of glioma cells in vivo, U373 cells transfected with miR-326, miR-control or NOB1 shRNA were inoculated into the flank of nude mice.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('miR-326', 'Var', (132, 139))	('U373', 'CellLine', 'CVCL:2219', (104, 108))	('glioma', 'Disease', (82, 88))	('nude mice', 'Species', '10090', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
135244	23869222	Mean tumor volume in the miR-326 group or the NOB1shRNA group was 697.02 mm3 or 745.91 mm3, whereas tumor volumes in mice treated with saline or negative control plasmid were 919.56 mm3 or 1077.27 mm3, respectively (P<0.01) after 21 d (Figure 5E).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Disease', (5, 10))	('NOB1shRNA', 'Var', (46, 55))	('saline', 'Chemical', 'MESH:D012965', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('miR-326', 'Var', (25, 32))
135245	23869222	These results demonstrated that miR-326 overexpression significantly inhibited tumor formation in human glioma cells, and suggest that miR-326 may play a critical role in the tumorigenicity of human glioma cells in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('tumor', 'Disease', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('overexpression', 'PosReg', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('miR-326', 'Gene', (32, 39))	('miR-326', 'Var', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('inhibited', 'NegReg', (69, 78))	('glioma', 'Disease', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('human', 'Species', '9606', (98, 103))	('glioma', 'Disease', (104, 110))	('human', 'Species', '9606', (193, 198))
135246	23869222	In U373 and A172 cells, the phosphorylation of three members of the MAPK pathway, p38 (T180/Y182), ERK1/2 (T202/Y204, T185/Y187), and JNK (T183/Y185, T221/Y223) increased significantly after NOB1 suppression compared to the negative control (P<0.05, Figure 6).	('T183/Y185', 'Var', (139, 148))	('p38', 'Gene', '5594', (82, 85))	('NOB1', 'Gene', (191, 195))	('T180/Y182', 'Var', (87, 96))	('p38', 'Gene', (82, 85))	('phosphorylation', 'MPA', (28, 43))	('T185/Y187', 'Var', (118, 127))	('increased', 'PosReg', (161, 170))	('JNK', 'Gene', (134, 137))	('U373', 'CellLine', 'CVCL:2219', (3, 7))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('T221/Y223', 'Var', (150, 159))	('T202/Y204', 'Var', (107, 116))	('MAPK pathway', 'Pathway', (68, 80))	('ERK1/2', 'Gene', (99, 105))	('suppression', 'NegReg', (196, 207))	('JNK', 'Gene', '5599', (134, 137))
135258	23869222	Previous studies have suggested that the dysregulation of miRNAs may play an important role in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('dysregulation', 'Var', (41, 54))	('cancer', 'Disease', (95, 101))	('miRNAs', 'Protein', (58, 64))	('play', 'Reg', (69, 73))
135260	23869222	In the present study, we focused on miR-326, which has been shown to suppress tumor growth in medulloblastoma and malignant glioma.	('malignant glioma', 'Disease', (114, 130))	('medulloblastoma', 'Disease', (94, 109))	('malignant glioma', 'Disease', 'MESH:D005910', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('medulloblastoma', 'Disease', 'MESH:D008527', (94, 109))	('miR-326', 'Var', (36, 43))	('medulloblastoma', 'Phenotype', 'HP:0002885', (94, 109))	('tumor', 'Disease', (78, 83))	('suppress', 'NegReg', (69, 77))
135262	23869222	In this study, we demonstrated that miR-326 inhibits tumorigenesis both in vitro and in vivo by blocking a novel miR-326 target, NOB1, which interacts with the 19S regulatory particle and is required for the maturation of the 26S proteasome.	('blocking', 'NegReg', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('miR-326', 'Var', (36, 43))	('NOB1', 'Gene', (129, 133))	('19S', 'Protein', (160, 163))	('miR-326', 'Gene', (113, 120))	('tumor', 'Disease', (53, 58))	('inhibits', 'NegReg', (44, 52))	('interacts', 'Interaction', (141, 150))
135263	23869222	Analysis of cell cycle distribution in human glioma cells overexpressing miR-326 showed a substantial decrease in S-phase and an increase in G1 phase populations, leading to a significant delay of proliferation in U373 and A172 glioma cells.	('U373', 'CellLine', 'CVCL:2219', (214, 218))	('S-phase', 'CPA', (114, 121))	('G1 phase populations', 'CPA', (141, 161))	('glioma', 'Disease', (228, 234))	('miR-326', 'Var', (73, 80))	('decrease', 'NegReg', (102, 110))	('delay', 'NegReg', (188, 193))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('increase', 'PosReg', (129, 137))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('proliferation', 'CPA', (197, 210))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('human', 'Species', '9606', (39, 44))	('glioma', 'Disease', (45, 51))
135264	23869222	This growth inhibitory effect was also observed by colony formation in soft agar and nude mouse xenograft assays, suggesting that miR-326 and NOB1 are critical for human glioma tumorigenesis in vitro and in vivo.	('NOB1', 'Gene', (142, 146))	('human', 'Species', '9606', (164, 169))	('glioma', 'Disease', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mouse', 'Species', '10090', (90, 95))	('miR-326', 'Var', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('agar', 'Chemical', 'MESH:D000362', (76, 80))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('tumor', 'Disease', (177, 182))
135272	23869222	These findings suggest the therapeutic potential of NOB1 inhibition for glioma.	('glioma', 'Disease', (72, 78))	('NOB1', 'Gene', (52, 56))	('inhibition', 'Var', (57, 67))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))
135277	23869222	Our results showed that silencing of NOB1 expression increased the phosphorylation of these 3 proteins, suggesting that the anti-glioma effect of NOB1 might be mediated by MAPK activation.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('phosphorylation of these 3', 'MPA', (67, 93))	('increased', 'PosReg', (53, 62))	('NOB1', 'Gene', (37, 41))	('glioma', 'Disease', (129, 135))	('silencing', 'Var', (24, 33))
135282	33364071	In patients with metastatic pancreatic cancer and germline mutations in BRCA1 or BRCA2, maintenance therapy with olaparib doubled the time to disease progression and the proportion of patients who were progression-free at 2 years, in the phase III POLO trial (Kindler et al., 2019).	('pancreatic cancer', 'Disease', (28, 45))	('BRCA1', 'Gene', '672', (72, 77))	('doubled', 'PosReg', (122, 129))	('patients', 'Species', '9606', (184, 192))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('germline mutations', 'Var', (50, 68))	('BRCA2', 'Gene', (81, 86))	('BRCA1', 'Gene', (72, 77))	('BRCA2', 'Gene', '675', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patients', 'Species', '9606', (3, 11))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('time', 'MPA', (134, 138))	('olaparib', 'Chemical', 'MESH:C531550', (113, 121))
135288	33364071	Dr. Cole continued: "Now that we have a targeted medicine that can benefit patients with BRCA mutations, it is our duty to search for this mutation to identify those who will benefit from a treatment that could extend their life."	('BRCA', 'Gene', '672', (89, 93))	('patients', 'Species', '9606', (75, 83))	('BRCA', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))
135291	33364071	Some 4% to 7% of patients with metastatic pancreatic cancer harbor a germline BRCA mutation.	('pancreatic cancer', 'Disease', (42, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('mutation', 'Var', (83, 91))	('BRCA', 'Gene', '672', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (17, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('BRCA', 'Gene', (78, 82))
135295	33364071	Of 3,315 patients with pancreatic cancer screened, 247, or 7.5%, had germline BRCA mutations, and 154 were enrolled after not experiencing disease progression during 16 weeks or more of platinum-based chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (83, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('germline', 'Var', (69, 77))	('pancreatic cancer', 'Disease', (23, 40))	('BRCA', 'Gene', '672', (78, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('BRCA', 'Gene', (78, 82))
135305	33364071	"We conclude that a strategic approach of first-line platinum-based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation," said Dr. Kindler.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('germline', 'Var', (219, 227))	('olaparib', 'Chemical', 'MESH:C531550', (105, 113))	('pancreatic cancer', 'Disease', (190, 207))	('platinum', 'Chemical', 'MESH:D010984', (53, 61))	('BRCA', 'Gene', '672', (228, 232))	('patients', 'Species', '9606', (165, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA', 'Gene', (228, 232))
135309	33364071	Olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer: Phase III POLO trial [Abstract LBA4].	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('patients', 'Species', '9606', (86, 94))	('mutation', 'Var', (116, 124))	('BRCA', 'Gene', '672', (111, 115))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('BRCA', 'Gene', (111, 115))	('platinum', 'Chemical', 'MESH:D010984', (55, 63))	('pancreatic cancer', 'Disease', (140, 157))
135311	33364071	However, many patients do not always understand trial details and the fact that benefits may only be applicable to a certain group, like this study was in patients with BRCA mutations (which only occurs in about 4% to 7% of patients).	('BRCA', 'Gene', '672', (169, 173))	('patients', 'Species', '9606', (224, 232))	('patients', 'Species', '9606', (155, 163))	('mutations', 'Var', (174, 183))	('patients', 'Species', '9606', (14, 22))	('BRCA', 'Gene', (169, 173))
135325	33364071	After the launch of the APACT trial, gemcitabine plus capecitabine and modified FOLFIRINOX demonstrated survival benefits in the adjuvant ESPAC-4 (Neoptolemos et al., 2017) and PRODIGE 24 trials (Conroy et al., 2018) and so became preferred treatments.	('modified', 'Var', (71, 79))	('survival benefits', 'CPA', (104, 121))	('ESPAC-4', 'Chemical', '-', (138, 145))	('capecitabine', 'Chemical', 'MESH:D000069287', (54, 66))	('gemcitabine', 'Chemical', 'MESH:C056507', (37, 48))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (80, 90))
135331	33364071	The most common grade >= 3 hematologic and nonhematologic toxicities were for nab-paclitaxel/gemcitabine vs gemcitabine, neutropenia (49% vs 43%) and fatigue (10% vs 3%).	('nab-paclitaxel/gemcitabine', 'Var', (78, 104))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('neutropenia', 'Phenotype', 'HP:0001875', (121, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (108, 119))	('neutropenia', 'Disease', 'MESH:D009503', (121, 132))	('nab', 'Chemical', '-', (78, 81))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('fatigue', 'Disease', 'MESH:D005221', (150, 157))	('fatigue', 'Disease', (150, 157))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('toxicities', 'Disease', (58, 68))	('neutropenia', 'Disease', (121, 132))	('fatigue', 'Phenotype', 'HP:0012378', (150, 157))
135374	33364071	This study found improved overall survival in patients in the pembrolizumab plus chemotherapy arm, regardless of PD-L1 expression, although survival rates were higher in groups with enhanced PD-L1 expression (CPS >= 1) and high PD-L1 expression (CPS > 20).	('improved', 'PosReg', (17, 25))	('patients', 'Species', '9606', (46, 54))	('higher', 'PosReg', (160, 166))	('expression', 'MPA', (234, 244))	('PD-L1', 'Gene', (113, 118))	('high', 'Var', (223, 227))	('CPS >= 1', 'Gene', '1373', (209, 217))	('overall', 'MPA', (26, 33))	('PD-L1', 'Gene', '29126', (113, 118))	('PD-L1', 'Gene', (191, 196))	('PD-L1', 'Gene', '29126', (191, 196))	('CPS', 'Chemical', '-', (209, 212))	('pembrolizumab', 'Chemical', 'MESH:C582435', (62, 75))	('PD-L1', 'Gene', (228, 233))	('enhanced', 'PosReg', (182, 190))	('PD-L1', 'Gene', '29126', (228, 233))	('CPS >= 1', 'Gene', (209, 217))	('expression', 'MPA', (197, 207))	('CPS', 'Chemical', '-', (246, 249))	('survival', 'MPA', (140, 148))
135396	33364071	Second, antibody titers of patients receiving SurVaxM produced an increase in SurVaxM.	('increase', 'PosReg', (66, 74))	('antibody', 'Var', (8, 16))	('SurVaxM', 'Chemical', '-', (46, 53))	('SurVaxM', 'MPA', (78, 85))	('patients', 'Species', '9606', (27, 35))	('SurVaxM', 'Chemical', '-', (78, 85))
135402	33364071	Arecent, updated predictive analysis of the three World Health Organization (WHO)-defined molecular subgroups based on IDH mutation status and 1p/19q codeletion status represented in the high-risk treatment arms of a phase III trial found that both IDH-mutant subgroups may derive benefit from the addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy.	('benefit', 'PosReg', (281, 288))	('IDH', 'Gene', '3417', (119, 122))	('mutation', 'Var', (123, 131))	('lomustine', 'Chemical', 'MESH:D008130', (329, 338))	('procarbazine', 'Chemical', 'MESH:D011344', (315, 327))	('IDH', 'Gene', '3417', (249, 252))	('vincristine', 'Chemical', 'MESH:D014750', (344, 355))	('IDH', 'Gene', (249, 252))	('IDH', 'Gene', (119, 122))
135407	33364071	Of these specimens, 41% were categorized as IDH-mutated, 1p/19q noncodeleted, 35% were IDH-mutated, 1p/19q codeleted, and 24% were IDH wild-type.	('1p/19q', 'Var', (100, 106))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (87, 90))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (131, 134))	('1p/19q noncodeleted', 'Var', (57, 76))	('IDH', 'Gene', '3417', (44, 47))
135411	33364071	https://doi.org/10.1200/JCO.2019.37.15_suppl.2002 Nanette Fong, RN, MSN Ronald Reagan UCLA Medical Center Since the completion of the NRG-RTOG 9802 trial, clinical practice at the UCLA Neuro-Oncology Program has changed in the treatment of low-grade IDH mutated, 1p/19q co-deleted and 1p/19q noncodeleted patients.	('Oncology', 'Phenotype', 'HP:0002664', (191, 199))	('low-grade', 'Var', (240, 249))	('Fong', 'Gene', '348751', (58, 62))	('1p/19q noncodeleted', 'Var', (285, 304))	('MSN', 'Gene', '4478', (68, 71))	('MSN', 'Gene', (68, 71))	('patients', 'Species', '9606', (305, 313))	('Fong', 'Gene', (58, 62))	('IDH', 'Gene', (250, 253))	('1p/19q co-deleted', 'Var', (263, 280))	('IDH', 'Gene', '3417', (250, 253))
135427	33364071	A weighted analysis of both patient groups, which controlled for other factors that may have led to differences between the patient groups, found that the relative risk of a severe toxicity was two-thirds lower for patients treated with proton therapy vs patients treated with photon therapy.	('patients', 'Species', '9606', (215, 223))	('proton therapy', 'Var', (237, 251))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('toxicity', 'Disease', (181, 189))	('patient', 'Species', '9606', (255, 262))	('patients', 'Species', '9606', (255, 263))	('patient', 'Species', '9606', (28, 35))	('patient', 'Species', '9606', (124, 131))	('lower', 'NegReg', (205, 210))	('patient', 'Species', '9606', (215, 222))
135437	32695826	Additionally, LUZP2 was targeted by miR-142-5p according to 2 prediction databases and 1 validated database, which was negatively related to LUZP2 mRNA expression (p < 0.001).	('LUZP2', 'Gene', (141, 146))	('mRNA expression', 'MPA', (147, 162))	('miR-142-5p', 'Chemical', '-', (36, 46))	('negatively', 'NegReg', (119, 129))	('miR-142-5p', 'Var', (36, 46))
135443	32695826	LUZP2 has been reported to be deleted in patients with Wilms' tumor-Aniridia-Genitourinary anomalies-mental Retardation (WAGR) syndrome, which is a scarce congenital anomaly syndrome consisting of Wilms' tumor, genital anomalies, aniridia, and mental retardation.	("Wilms' tumor", 'Disease', 'MESH:D009396', (197, 209))	('aniridia', 'Disease', (230, 238))	("Wilms' tumor-Aniridia-Genitourinary anomalies-mental Retardation (WAGR) syndrome", 'Disease', 'MESH:D017624', (55, 135))	('mental retardation', 'Phenotype', 'HP:0001249', (244, 262))	('LUZP2', 'Gene', (0, 5))	('genital anomalies', 'Phenotype', 'HP:0000078', (211, 228))	('-Genitourinary anomalies', 'Phenotype', 'HP:0000119', (76, 100))	('mental retardation', 'Disease', 'MESH:D008607', (244, 262))	('genital anomalies', 'Disease', 'MESH:D014564', (211, 228))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('scarce congenital anomaly syndrome', 'Disease', 'MESH:D000013', (148, 182))	('genital anomalies', 'Disease', (211, 228))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (55, 67))	('Aniridia', 'Phenotype', 'HP:0000526', (68, 76))	('aniridia', 'Disease', 'MESH:D015783', (230, 238))	('mental retardation', 'Disease', (244, 262))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (197, 209))	('-mental Retardation', 'Phenotype', 'HP:0001249', (100, 119))	('aniridia', 'Phenotype', 'HP:0000526', (230, 238))	('deleted', 'Var', (30, 37))	('scarce congenital anomaly syndrome', 'Disease', (148, 182))	("Wilms' tumor", 'Disease', 'MESH:D009396', (55, 67))	("Wilms' tumor", 'Disease', (55, 67))	("Wilms' tumor", 'Disease', (197, 209))
135444	32695826	It is reported that polymorphic variants in this gene are associated with the late-onset Alzheimer's disease and schizophrenia.	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (89, 108))	("Alzheimer's disease", 'Disease', (89, 108))	('associated', 'Reg', (58, 68))	('polymorphic variants', 'Var', (20, 40))	('schizophrenia', 'Disease', 'MESH:D012559', (113, 126))	('schizophrenia', 'Disease', (113, 126))	('schizophrenia', 'Phenotype', 'HP:0100753', (113, 126))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (89, 108))
135445	32695826	A genome-wide association study shows that rs7943454 in LUZP2 was associated with plasma NFL with suggestive levels and rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of the right middle temporal gyrus in the whole cohort.	('atrophy', 'Disease', 'MESH:D001284', (184, 191))	('associated', 'Reg', (143, 153))	('rs7943454', 'Mutation', 'rs7943454', (43, 52))	('rs7943454', 'DBSNP_MENTION', 'None', (43, 52))	('AD', 'Disease', 'MESH:D000544', (177, 179))	('LUZP2', 'Gene', (56, 61))	('AD', 'Disease', (177, 179))	('rs7943454', 'Mutation', 'rs7943454', (120, 129))	('atrophy', 'Disease', (184, 191))	('rs7943454', 'DBSNP_MENTION', 'None', (120, 129))	('associated', 'Reg', (66, 76))	('rs7943454', 'Var', (43, 52))	('rs7943454', 'Var', (120, 129))	('NFL', 'Gene', (89, 92))	('NFL', 'Gene', '4747', (89, 92))
135452	32695826	In the univariate Cox analysis in TCGA cohort, characteristics, such as age, grade, IDH1 mutant status, radiotherapy, histology, and LUZP2 expression, were associated with survival.	('mutant status', 'Var', (89, 102))	('IDH1', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (84, 88))	('expression', 'MPA', (139, 149))	('LUZP2', 'Gene', (133, 138))	('associated with', 'Reg', (156, 171))
135455	32695826	miR-5590-3p and miR-142-5p are found in the Venn diagram (Figure 5(a)).	('miR-5590-3p', 'Var', (0, 11))	('miR-5590-3p', 'Chemical', '-', (0, 11))	('miR-142-5p', 'Var', (16, 26))
135463	32695826	The role of miR-142-5p in the development of malignant tumors has been widely reported, including colorectal cancer, which can promote the progress of cancer, and gastric cancer, which can inhibit the metastasis of cancer.	('colorectal cancer', 'Disease', (98, 115))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('malignant tumors', 'Disease', (45, 61))	('malignant tumors', 'Disease', 'MESH:D009369', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('promote', 'PosReg', (127, 134))	('cancer', 'Disease', (151, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('inhibit', 'NegReg', (189, 196))	('gastric cancer', 'Disease', (163, 177))	('progress', 'CPA', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('metastasis', 'CPA', (201, 211))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('miR-142-5p', 'Var', (12, 22))
135484	24123865	We subsequently demonstrated that the PPAR-alpha agonist fenofibrate has antiangiogenic anti-tumor activity, and that the antiangiogenic effects of PPAR modulation are synergistic with COX2 inhibition and metronomic cytotoxic therapy in a preclinical model.	('PPAR-alpha', 'Gene', '5465', (38, 48))	('antiangiogenic', 'MPA', (122, 136))	('PPAR', 'Gene', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('PPAR', 'Gene', '5465', (38, 42))	('PPAR-alpha', 'Gene', (38, 48))	('modulation', 'Var', (153, 163))	('COX2', 'Gene', (185, 189))	('PPAR', 'Gene', '5465', (148, 152))	('COX2', 'Gene', '4513', (185, 189))	('PPAR', 'Gene', (38, 42))	('fenofibrate', 'Chemical', 'MESH:D011345', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
135489	24123865	Eligible patients were <=21 years with evaluable recurrent or progressive tumors for which no curative therapy remained, Karnofsky/Lansky performance status >=50, estimated life expectancy >2 months, no significant underlying organ disease, and adequate organ function, defined as serum creatinine <1.5 mg/dl, total bilirubin <=1.5 mg/dl, transaminases and alkaline phosphatase <=3 times normal, hemoglobin >=8.0 g/dl, platelets >75,000/mm3, and absolute neutrophil count >1,000/mm3.	('total bilirubin', 'MPA', (310, 325))	('organ disease', 'Disease', (226, 239))	('patients', 'Species', '9606', (9, 17))	('>=50', 'Var', (157, 161))	('alkaline phosphatase', 'MPA', (357, 377))	('platelets', 'MPA', (419, 428))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('hemoglobin', 'MPA', (396, 406))	('organ disease', 'Disease', 'MESH:D019965', (226, 239))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('serum creatinine', 'MPA', (281, 297))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
135500	24123865	Response was defined as follows: complete resolution of all demonstrable tumor, complete response (CR); >=50% decrease in the product of the two maximum perpendicular diameters relative to the baseline evaluation, partial response (PR); <50% decrease and <25% increase in product of diameters, stable disease (SD); and >=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease (PD).	('product', 'MPA', (272, 279))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('death', 'Disease', 'MESH:D003643', (446, 451))	('SD', 'Disease', 'MESH:D029461', (310, 312))	('death', 'Disease', (446, 451))	('stable disease', 'Disease', (294, 308))	('product', 'MPA', (337, 344))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('partial response', 'Var', (214, 230))	('increase', 'PosReg', (325, 333))	('complete', 'Disease', (80, 88))	('tumor', 'Disease', (73, 78))	('PD', 'Disease', 'MESH:D010300', (474, 476))	('decrease', 'NegReg', (110, 118))	('CR', 'Chemical', '-', (99, 101))	('<50', 'Var', (237, 240))	('progressive disease', 'Disease', (453, 472))
135576	24123865	The inclusion of the PPAR-alpha agonist fenofibrate was prompted by the preclinical observation that PPAR modulation acts synergistically with COX-2 inhibition and low-dose etoposide to inhibit antiangiogenesis.	('antiangiogenesis', 'CPA', (194, 210))	('PPAR-alpha', 'Gene', '5465', (21, 31))	('modulation', 'Var', (106, 116))	('PPAR', 'Gene', (101, 105))	('inhibit', 'NegReg', (186, 193))	('PPAR', 'Gene', '5465', (21, 25))	('PPAR-alpha', 'Gene', (21, 31))	('etoposide', 'Chemical', 'MESH:D005047', (173, 182))	('COX-2', 'Gene', '4513', (143, 148))	('fenofibrate', 'Chemical', 'MESH:D011345', (40, 51))	('PPAR', 'Gene', '5465', (101, 105))	('COX-2', 'Gene', (143, 148))	('PPAR', 'Gene', (21, 25))
135644	23947815	Specific primers were developed targeting: ABBA1 [NM 138383], APOD [NM 001647], ARX [NM 139058], CXCL14 [NM 004887], FOSB [NM 001114171], FOXG1 [NM 005249], GPR17 [NM 001161415], LHX2 [NM 004789], NRXN2 [NM 015080], PTGD2S [NM 000954], SDC3 [NM 014654], SNX22 [NM 024798], SPOCK1 [NM 004598], TIMP4 [NM 003256] and ZFHX4 [NM 024721].	('[NM 001114171]', 'Var', (122, 136))	('TIMP4', 'Gene', '7079', (293, 298))	('[NM 015080]', 'Var', (203, 214))	('[NM 138383]', 'Var', (49, 60))	('ABBA1', 'Gene', (43, 48))	('PTGD2S', 'Gene', '5730', (216, 222))	('PTGD2S', 'Gene', (216, 222))	('ABBA1', 'Gene', '92154', (43, 48))	('TIMP4', 'Gene', (293, 298))
135645	23947815	Beta actin (ACTB) [NM 001101], Pyruvate kinase (PKM2) [NM 002654] and Beta-2-microglobulin (B2M) [NM 004048] were used as the endogenous control genes for each tumour specimen.	('tumour', 'Disease', (160, 166))	('[NM 004048]', 'Var', (97, 108))	('[NM 002654]', 'Var', (54, 65))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('[NM 001101]', 'Var', (18, 29))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
135647	23947815	2P/N 4303859), using the value emerged by geometric mean of B2M, PKM2 and ACTB as the normalizer (Ctref).	('2P/N', 'Var', (0, 4))	('2P/N', 'SUBSTITUTION', 'None', (0, 4))	('B2M', 'Var', (60, 63))	('PKM2', 'Var', (65, 69))
135662	23947815	Mutations in this gene cause X-linked mental retardation and epilepsy.	('epilepsy', 'Phenotype', 'HP:0001250', (61, 69))	('mental retardation', 'Phenotype', 'HP:0001249', (38, 56))	('X-linked mental retardation', 'Disease', (29, 56))	('epilepsy', 'Disease', (61, 69))	('X-linked mental retardation', 'Disease', 'MESH:D038901', (29, 56))	('Mutations', 'Var', (0, 9))	('epilepsy', 'Disease', 'MESH:D004827', (61, 69))	('cause', 'Reg', (23, 28))
135666	23947815	Moreover, we did not identify significantly improved progression-free survival in tumours with gene-fusions or BRAF V600E mutation.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('gene-fusions', 'Var', (95, 107))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('V600E', 'Mutation', 'rs113488022', (116, 121))	('tumours', 'Disease', (82, 89))	('improved', 'PosReg', (44, 52))	('BRAF', 'Gene', (111, 115))
135692	27667176	Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood.	('Annexin A2', 'Gene', (29, 39))	('Glioblastoma', 'Disease', (96, 108))	('Glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('Annexin A2', 'Gene', '302', (29, 39))	('Glioblastoma', 'Disease', (83, 95))	('Glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('Glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('Epigenetic', 'Var', (49, 59))	('Glioblastomas', 'Disease', 'MESH:D005909', (96, 109))	('Glioblastomas', 'Disease', (96, 109))	('Glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))
135695	27667176	ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion.	('ANXA2', 'Gene', (0, 5))	('suppressed', 'NegReg', (64, 74))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('abrogated', 'NegReg', (116, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('knockdown', 'Var', (6, 15))
135698	27667176	Epigenetic control of Annexin A2 (ANXA2) was predicted and confirmed to determine the invasive mesenchymal subtype.	('Epigenetic', 'Var', (0, 10))	('determine', 'Reg', (72, 81))	('Annexin A2', 'Gene', (22, 32))	('Annexin A2', 'Gene', '302', (22, 32))
135700	27667176	Our method is applied to the brain cancer glioblastoma multiforme (GBM), revealing that the invasive mesenchymal subtype is driven by epigenetic modulation of the expression of Annexin A2 (ANXA2).	('brain cancer', 'Phenotype', 'HP:0030692', (29, 41))	('Annexin A2', 'Gene', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('brain cancer glioblastoma multiforme', 'Disease', 'MESH:D005909', (29, 65))	('invasive mesenchymal subtype', 'CPA', (92, 120))	('driven by', 'Reg', (124, 133))	('Annexin A2', 'Gene', '302', (177, 187))	('epigenetic modulation', 'Var', (134, 155))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('brain cancer glioblastoma multiforme', 'Disease', (29, 65))	('cancer glioblastoma multiforme', 'Phenotype', 'HP:0012174', (35, 65))
135716	27667176	In-depth analysis of two independent patient cohorts further supports that ANXA2 suppression in lower grade glioma is likely explained by methylation induced by IDH1 mutation.	('patient', 'Species', '9606', (37, 44))	('glioma', 'Disease', (108, 114))	('IDH1', 'Gene', (161, 165))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('suppression', 'NegReg', (81, 92))	('mutation', 'Var', (166, 174))	('ANXA2', 'Gene', (75, 80))	('IDH1', 'Gene', '3417', (161, 165))
135719	27667176	Our analysis and results thus support a new functional link between epigenetic regulation and mesenchymal transformation, and identifies ANXA2 as a possible therapeutic target against mesenchymal glioma.	('ANXA2', 'Gene', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('epigenetic regulation', 'Var', (68, 89))	('mesenchymal transformation', 'CPA', (94, 120))	('glioma', 'Disease', (196, 202))
135763	27667176	Firstly, we confirmed known key subtype selective mutations, including NF1 (mesenchymal) and IDH1 (proneural), as well as amplifications of PDGFRA (proneural) and EGFR amplification (classical).	('PDGFRA', 'Gene', (140, 146))	('IDH1', 'Gene', (93, 97))	('amplifications', 'Var', (122, 136))	('NF1', 'Gene', (71, 74))	('IDH1', 'Gene', '3417', (93, 97))	('NF1', 'Gene', '4763', (71, 74))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'Gene', (163, 167))	('PDGFRA', 'Gene', '5156', (140, 146))
135767	27667176	This methylation event (cg23352695) may warrant further investigation as a possible determinant of classical subtype GBM.	('classical subtype GBM', 'Disease', (99, 120))	('cg23352695', 'Chemical', '-', (24, 34))	('cg23352695', 'Var', (24, 34))
135769	27667176	Such detections are not a consequence of IDH1 mutation, since this mutational event was identified as an independent node in the model, and was thus accounted for.	('mutation', 'Var', (46, 54))	('IDH1', 'Gene', '3417', (41, 45))	('IDH1', 'Gene', (41, 45))
135773	27667176	Finally, we looked at the methylation status of the ANXA2 promoter (cg08081036) in a cohort of in-house high and low grade gliomas analyzed by methylation array and gene expression profile (Supplementary Fig.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('gliomas', 'Disease', (123, 130))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('cg08081036', 'Var', (68, 78))
135782	27667176	In accordance with this, and consistent with our network, we observed a clear association of ANXA2 methylation with survival in TCGA patients (Fig.	('methylation', 'Var', (99, 110))	('patients', 'Species', '9606', (133, 141))	('ANXA2', 'Gene', (93, 98))	('survival', 'MPA', (116, 124))	('TCGA', 'Disease', (128, 132))
135783	27667176	3b), ANXA2 methylation was significantly associated with IDH1 mutation in TCGA samples (Fig.	('IDH1', 'Gene', '3417', (57, 61))	('mutation', 'Var', (62, 70))	('associated', 'Reg', (41, 51))	('IDH1', 'Gene', (57, 61))
135785	27667176	3), with the hypomethylating agent 5'-Aza-2'-deoxycytidine (5-Aza-2-dC) alone or in combination with the histone deacetylase inhibitor Trichostatin A (TSA), because histone deacetylation has been shown to cooperate with DNA methylation to epigenetically repress transcription.	('epigenetically', 'Var', (239, 253))	('repress', 'NegReg', (254, 261))	('deoxycytidine', 'Chemical', 'MESH:D003841', (45, 58))	('transcription', 'MPA', (262, 275))	('TSA', 'Chemical', 'MESH:C012589', (151, 154))	('Trichostatin A', 'Chemical', 'MESH:C012589', (135, 149))	('5-Aza-2-dC', 'Chemical', 'MESH:D000077209', (60, 70))
135786	27667176	Our results showed increased expression of ANXA2 upon 5-Aza-2-dC treatment and a further increment with the combination of 5-Aza-2-dC and TSA, indicating that ANXA2 expression is epigenetically regulated (Fig.	('ANXA2', 'Gene', (43, 48))	('5-Aza-2-dC', 'Chemical', 'MESH:D000077209', (123, 133))	('5-Aza-2-dC', 'Var', (54, 64))	('ANXA2', 'Gene', (159, 164))	('increased', 'PosReg', (19, 28))	('TSA', 'Chemical', 'MESH:C012589', (138, 141))	('expression', 'MPA', (29, 39))	('5-Aza-2-dC', 'Chemical', 'MESH:D000077209', (54, 64))
135791	27667176	Silencing of ANXA2 led to suppression of mesenchymal marker transcripts, as measured by GSEA (Fig.	('ANXA2', 'Gene', (13, 18))	('suppression', 'NegReg', (26, 37))	('GSEA', 'Chemical', '-', (88, 92))	('Silencing', 'Var', (0, 9))	('mesenchymal', 'CPA', (41, 52))
135794	27667176	1) in which patients survival was linked to methylation events, which in turn tended to be in the promoter region of G-CIMP reported genes (Fisher test p-values 2.5   10- 25 and 2.5   10- 61 for genes directly or one network step away from the survival node, respectively).	('G-CIMP', 'Chemical', '-', (117, 123))	('patients', 'Species', '9606', (12, 20))	('methylation', 'Var', (44, 55))	('linked', 'Reg', (34, 40))
135801	27667176	ANXA2 knockdown in BTSC168 (Fig.	('knockdown', 'Var', (6, 15))	('ANXA2', 'Gene', (0, 5))	('BTSC168', 'Chemical', '-', (19, 26))
135803	27667176	Interestingly, silencing of ANXA2 in BTSC380, BTSC407, and in the GBM cell line SNB19 resulted in decreased STAT3 phosphorylation (Fig.	('SNB19', 'CellLine', 'CVCL:0535', (80, 85))	('ANXA2', 'Gene', (28, 33))	('silencing', 'Var', (15, 24))	('STAT3 phosphorylation', 'MPA', (108, 129))	('decreased', 'NegReg', (98, 107))
135805	27667176	Upon ANXA2 silencing, two primary BTSC lines (BTSC168 and BTSC407) lost their characteristic elongated shape and their dispersed distribution, tending instead to cluster together to form large spheres (Fig.	('silencing', 'Var', (11, 20))	('ANXA2', 'Protein', (5, 10))	('dispersed distribution', 'MPA', (119, 141))	('BTSC168', 'Chemical', '-', (46, 53))	('elongated', 'MPA', (93, 102))	('lost', 'NegReg', (67, 71))
135809	27667176	Applied to GBM, our model implied that a number of methylation events, independently of IDH1 mutation, contribute to a mesenchymal/proneural axis in GBM.	('IDH1', 'Gene', (88, 92))	('methylation', 'MPA', (51, 62))	('mesenchymal/proneural axis', 'CPA', (119, 145))	('IDH1', 'Gene', '3417', (88, 92))	('mutation', 'Var', (93, 101))	('contribute to', 'Reg', (103, 116))
135816	27667176	When extending the analysis to lower grade glioma (LGG) and secondary GBM, which tend to be IDH1 mutant and hypermethylated, we noted elevated ANXA2 promoter methylation and suppressed expression.	('expression', 'MPA', (185, 195))	('glioma', 'Disease', (43, 49))	('IDH1', 'Gene', (92, 96))	('suppressed', 'NegReg', (174, 184))	('mutant', 'Var', (97, 103))	('promoter methylation', 'MPA', (149, 169))	('IDH1', 'Gene', '3417', (92, 96))	('elevated', 'PosReg', (134, 142))	('ANXA2', 'Protein', (143, 148))	('hypermethylated', 'Var', (108, 123))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
135818	27667176	Together, these observations imply that ANXA2 can be suppressed by IDH1 mutation in LGG but also that IDH1-independent mechanisms can modulate ANXA2 via methylation of its promoter in GBM cells.	('ANXA2', 'MPA', (40, 45))	('IDH1', 'Gene', (67, 71))	('ANXA2', 'Gene', (143, 148))	('IDH1', 'Gene', (102, 106))	('methylation', 'MPA', (153, 164))	('IDH1', 'Gene', '3417', (67, 71))	('modulate', 'Reg', (134, 142))	('IDH1', 'Gene', '3417', (102, 106))	('mutation', 'Var', (72, 80))	('suppressed', 'NegReg', (53, 63))
135819	27667176	Although we did not observe any significant effect of ANXA2 on global DNA methylation, several G-CIMP target genes were among the genes affected by ANXA2 knockdown.	('G-CIMP', 'Chemical', '-', (95, 101))	('ANXA2', 'Gene', (148, 153))	('knockdown', 'Var', (154, 163))	('affected', 'Reg', (136, 144))
135820	27667176	Thus, it is possible that ANXA2 knockdown leads to a general shift in gene expression that effectively mimics the expression modulation normally achieved through DNA methylation in G-CIMP tumors.	('tumors', 'Disease', (188, 194))	('shift', 'Reg', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('knockdown', 'Var', (32, 41))	('gene expression', 'MPA', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('G-CIMP', 'Chemical', '-', (181, 187))	('ANXA2', 'Gene', (26, 31))
135821	27667176	Since G-CIMP tumors are associated with the most favorable patients' prognosis, we speculate that the acquisition of a G-CIMP-like gene expression signature upon ANXA2 knockdown in BTSCs might explain the connection between ANXA2 methylation and survival in our two cohorts.	('G-CIMP', 'Chemical', '-', (6, 12))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('ANXA2', 'Gene', (162, 167))	('patients', 'Species', '9606', (59, 67))	('G-CIMP', 'Chemical', '-', (119, 125))	('knockdown', 'Var', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
135822	27667176	IDH1 mutation correlates significantly with both ANXA2 methylation or expression.	('ANXA2', 'Protein', (49, 54))	('methylation', 'MPA', (55, 66))	('expression', 'MPA', (70, 80))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
135823	27667176	However, as estimated by a correlation analysis on TCGA cases, IDH1 status only explains circa 62% of the variation of ANXA2 promoter (cg08081036) methylation and 26% of the expression variation.	('methylation', 'MPA', (147, 158))	('IDH1', 'Gene', '3417', (63, 67))	('expression', 'MPA', (174, 184))	('cg08081036', 'Var', (135, 145))	('IDH1', 'Gene', (63, 67))
135824	27667176	Thus, removing IDH1 mutant cases from the analysis, a significant degree of correlation between ANXA2 expression and methylation is retained (r = - 0.21, p = 0.03).	('IDH1', 'Gene', (15, 19))	('expression', 'MPA', (102, 112))	('methylation', 'MPA', (117, 128))	('ANXA2', 'Gene', (96, 101))	('IDH1', 'Gene', '3417', (15, 19))	('mutant', 'Var', (20, 26))
135825	27667176	We further find that after removal of IDH1 mutant cases, ANXA2 expression is predictive of longer survival (Supplementary Fig.	('ANXA2', 'Gene', (57, 62))	('IDH1', 'Gene', '3417', (38, 42))	('expression', 'MPA', (63, 73))	('mutant', 'Var', (43, 49))	('IDH1', 'Gene', (38, 42))	('longer survival', 'CPA', (91, 106))
135828	27667176	3e, indicted by a "x") two patients with ANXA2 methylation but wildtype IDH1 status showed nonetheless a more favorable prognosis.	('patients', 'Species', '9606', (27, 35))	('IDH1', 'Gene', '3417', (72, 76))	('methylation', 'Var', (47, 58))	('IDH1', 'Gene', (72, 76))
135830	27667176	Together, our results therefore imply that while IDH1 mutation is a key mechanism behind ANXA2 suppression, particularly in LGG and secondary GBM, it is likely regulated by additional factors, and may have clinical promise as a prognostic complementary to IDH1 mutation, or as an indirect marker of G-CIMP cases.	('mutation', 'Var', (54, 62))	('ANXA2', 'Gene', (89, 94))	('IDH1', 'Gene', '3417', (49, 53))	('G-CIMP', 'Chemical', '-', (299, 305))	('LGG', 'Disease', (124, 127))	('IDH1', 'Gene', (256, 260))	('suppression', 'NegReg', (95, 106))	('IDH1', 'Gene', '3417', (256, 260))	('IDH1', 'Gene', (49, 53))
135835	27667176	In BTSC168 ANXA2 knockdown resulted in a more pronounced loss of the mesenchymal signature by Phillips and Verhaak compared to the other tested cell line, BTSC161 (Fig.	('ANXA2', 'Gene', (11, 16))	('mesenchymal signature by Phillips', 'CPA', (69, 102))	('BTSC168 ANXA2', 'Gene', (3, 16))	('loss', 'NegReg', (57, 61))	('knockdown', 'Var', (17, 26))	('BTSC168', 'Chemical', '-', (3, 10))
135861	33639927	These include, primarily, codeletion of chromosomal arms 1p and 19q, and the genetic status of isocitrate dehydrogenase 1 (IDH1).	('arms 1p', 'Gene', '3075', (52, 59))	('arms 1p', 'Gene', (52, 59))	('isocitrate dehydrogenase 1', 'Gene', (95, 121))	('IDH1', 'Gene', (123, 127))	('isocitrate dehydrogenase 1', 'Gene', '3417', (95, 121))	('IDH1', 'Gene', '3417', (123, 127))	('codeletion', 'Var', (26, 36))
135862	33639927	Further mutations are described for Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), tumor protein P53 (TP53), telomerase reverse transcriptase (TERT), H3 histone family member 3A (H3F3A) and histone cluster 1 H3 family member B or C (HIST1H3B/C), B-Raf proto-oncogene, serine/threonine kinase (BRAF) and KIAA1549-BRAF fusion, deletions of cyclin dependent kinase inhibitor 2A or 2B (CDKN2A/B), fusions of RELA proto-oncogene, NF-KB subunit (RELA), catenin-beta 1 (CTNNB1) referred to the group of wingless-type MMTV integration site family (WNT), or PTCH and SUFU within sonic hedgehog signaling molecule (SHH)-activated subgroup.	('sonic hedgehog', 'Gene', '6469', (606, 620))	('telomerase reverse transcriptase', 'Gene', (145, 177))	('SUFU', 'Gene', (594, 598))	('tumor protein P53', 'Gene', (119, 136))	('RELA', 'Gene', (476, 480))	('MMTV', 'Species', '11757', (546, 550))	('RELA', 'Gene', '5970', (476, 480))	('catenin-beta 1', 'Gene', '1499', (483, 497))	('histone cluster 1 H3 family member B or C', 'Gene', (226, 267))	('mental retardation', 'Phenotype', 'HP:0001249', (54, 72))	('deletions', 'Var', (361, 370))	('sonic hedgehog', 'Gene', (606, 620))	('PTCH', 'Gene', '5727', (585, 589))	('H3F3A', 'Gene', '3020', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SHH', 'Gene', '6469', (641, 644))	('thalassemia/mental retardation syndrome', 'Disease', 'MESH:C538258', (42, 81))	('TERT', 'Gene', (179, 183))	('TERT', 'Gene', '7015', (179, 183))	('histone cluster 1 H3 family member B or C', 'Gene', '8358;8352', (226, 267))	('TP53', 'Gene', (138, 142))	('telomerase reverse transcriptase', 'Gene', '7015', (145, 177))	('KIAA1549', 'Gene', '57670', (339, 347))	('HIST1H3B', 'Gene', (269, 277))	('RELA', 'Gene', (440, 444))	('HIST1H3B', 'Gene', '8358', (269, 277))	('RELA', 'Gene', '5970', (440, 444))	('thalassemia/mental retardation syndrome', 'Disease', (42, 81))	('H3 histone family member 3A', 'Gene', '3020', (186, 213))	('CDKN2A/B', 'Gene', (418, 426))	('CTNNB1', 'Gene', '1499', (499, 505))	('serine', 'Chemical', 'MESH:D012694', (304, 310))	('H3F3A', 'Gene', (215, 220))	('BRAF', 'Gene', (348, 352))	('BRAF', 'Gene', '673', (348, 352))	('KIAA1549', 'Gene', (339, 347))	('SUFU', 'Gene', '51684', (594, 598))	('SHH', 'Gene', (641, 644))	('catenin-beta 1', 'Gene', (483, 497))	('H3 histone family member 3A', 'Gene', (186, 213))	('PTCH', 'Gene', (585, 589))	('ATRX', 'Gene', (112, 116))	('TP53', 'Gene', '7157', (138, 142))	('BRAF', 'Gene', '673', (329, 333))	('ATRX', 'Gene', '546', (112, 116))	('CDKN2A/B', 'Gene', '1029;1030', (418, 426))	('BRAF', 'Gene', (329, 333))	('CTNNB1', 'Gene', (499, 505))	('fusions', 'Var', (429, 436))	('tumor protein P53', 'Gene', '7157', (119, 136))
135866	33639927	Information exists on prominent mutations within gliomas that suggests different biomarkers for specific age groups.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('mutations', 'Var', (32, 41))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
135867	33639927	Some tumors primarily occur in children, such as diffuse midline gliomas with their molecular feature of mutated H3F3A or HIST1H3B/C.	('tumors', 'Disease', (5, 11))	('H3F3A', 'Gene', '3020', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('midline gliomas', 'Disease', (57, 72))	('HIST1H3B', 'Gene', (122, 130))	('midline gliomas', 'Disease', 'MESH:D005910', (57, 72))	('HIST1H3B', 'Gene', '8358', (122, 130))	('H3F3A', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutated', 'Var', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('children', 'Species', '9606', (31, 39))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
135868	33639927	Pilocytic astrocytomas are common for pediatric but not elderly patients and frequently exhibit BRAF mutations and fusion transcripts.	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (64, 72))	('astrocytomas', 'Disease', 'MESH:D001254', (10, 22))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('astrocytomas', 'Disease', (10, 22))	('exhibit', 'Reg', (88, 95))	('fusion transcripts', 'Var', (115, 133))
135877	33639927	So far, various targets within the signaling cascades of growth factor receptors, cell cycle, angiogenesis, antitumor immune responses and epigenetic modulators have been investigated for therapy.	('tumor', 'Disease', (112, 117))	('epigenetic modulators', 'Var', (139, 160))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))
135898	33639927	For instance, H3F3A, AHNAK2, SOX1, SUSD2 and KMT2C are most frequently mutated in young age classes.	('SUSD2', 'Gene', (35, 40))	('H3F3A', 'Gene', '3020', (14, 19))	('SOX1', 'Gene', '6656', (29, 33))	('AHNAK2', 'Gene', (21, 27))	('mutated', 'Var', (71, 78))	('H3F3A', 'Gene', (14, 19))	('AHNAK2', 'Gene', '113146', (21, 27))	('SOX1', 'Gene', (29, 33))	('SUSD2', 'Gene', '56241', (35, 40))	('KMT2C', 'Gene', '58508', (45, 50))	('KMT2C', 'Gene', (45, 50))
135899	33639927	PIK3CA and TERT are upon top mutated genes within adult samples and RYR2 mutations are more frequent within older adults.	('RYR2', 'Gene', (68, 72))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('TERT', 'Gene', (11, 15))	('TERT', 'Gene', '7015', (11, 15))	('RYR2', 'Gene', '6262', (68, 72))	('mutations', 'Var', (73, 82))
135920	33639927	IDH1 is the most important gene mutation succeeding TERT within LGG classification using the traditional age classes, and remains important in updated classifiers.	('TERT', 'Gene', (52, 56))	('TERT', 'Gene', '7015', (52, 56))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (0, 4))
135922	33639927	BCORL1 is involved in tumor progression and respective mutations occur in HGGs and LGGs.	('occur', 'Reg', (65, 70))	('LGGs', 'Disease', (83, 87))	('BCORL1', 'Gene', '63035', (0, 6))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('HGGs', 'Disease', (74, 78))	('BCORL1', 'Gene', (0, 6))	('tumor', 'Disease', (22, 27))
135960	32648580	In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 70))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('BRCA', 'Gene', (30, 34))	('malignancy', 'Disease', (174, 184))	('YIF1B', 'Gene', '90522', (84, 89))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('breast invasive carcinoma', 'Disease', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('YIF1B', 'Gene', (84, 89))	('high', 'Var', (79, 83))	('expression', 'MPA', (90, 100))	('disease-free', 'MPA', (124, 136))	('liver hepatocellular carcinoma', 'Disease', (40, 70))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (3, 28))	('BRCA', 'Phenotype', 'HP:0003002', (30, 34))	('BRCA', 'Gene', '672', (30, 34))
136000	32648580	The following survival analyses, using patient data dichotomized for the median expression value in each cancer type (Figure 3), show that survival differences were all significant in OS-related cancer types, and that patients with high expression of YIF1B had worse outcomes (Figure 3).	('significant', 'Reg', (169, 180))	('patient', 'Species', '9606', (39, 46))	('YIF1B', 'Gene', (251, 256))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YIF1B', 'Gene', '90522', (251, 256))	('high expression', 'Var', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
136004	32648580	In the following survival analysis, cancer types with high YIF1B expression again exhibited a worse prognosis in comparison with the low expression groups (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('YIF1B', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('cancer', 'Disease', (36, 42))	('YIF1B', 'Gene', '90522', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
136014	32648580	Their corresponding linear regression graphs show that high YIF1B expression is linked to a possible increased infiltration level by immune cells.	('infiltration level by immune cells', 'MPA', (111, 145))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (66, 76))	('YIF1B', 'Gene', '90522', (60, 65))	('high', 'Var', (55, 59))	('YIF1B', 'Gene', (60, 65))
136024	32648580	The coefficient values would indicate that YIF1B expression positively correlates with high mutation status in COAD, BLCA and LIHC, but low mutation in THYM, LAML and ESCA (particularly THYM).	('COAD', 'Disease', 'MESH:D029424', (111, 115))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('YIF1B', 'Gene', '90522', (43, 48))	('COAD', 'Disease', (111, 115))	('high mutation status', 'Var', (87, 107))	('THYM', 'Phenotype', 'HP:0100522', (186, 190))	('YIF1B', 'Gene', (43, 48))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))
136030	32648580	Having established a correlation between YIF1B expression and the mutation indicators, TMB and MSI, further investigation of links between YIF1B expression and tumorigenesis mechanisms was warranted, in particular a relationship with MMR defects and methylation of specific tumor suppression genes.	('MMR defects', 'Disease', (234, 245))	('MMR defects', 'Disease', 'MESH:C536928', (234, 245))	('YIF1B', 'Gene', '90522', (139, 144))	('YIF1B', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TMB', 'Chemical', '-', (87, 90))	('YIF1B', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (160, 165))	('methylation', 'Var', (250, 261))	('YIF1B', 'Gene', '90522', (41, 46))
136040	32648580	In follow-on survival analysis, after dichotomizing patients according to their mean YIF1B expression value, patients in the high expression group had worse OS, which is consistent with in the results obtained using TCGA data (Supplementary Figure S1).	('YIF1B', 'Gene', (85, 90))	('patients', 'Species', '9606', (109, 117))	('YIF1B', 'Gene', '90522', (85, 90))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (52, 60))
136045	32648580	A correlation with disease progression rates was identified for LIHC and BRCA, for which patients with high YIF1B expression suffered from early recurrence of tumor.	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRCA', 'Gene', (73, 77))	('YIF1B', 'Gene', (108, 113))	('tumor', 'Disease', (159, 164))	('LIHC', 'Disease', (64, 68))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (89, 97))	('expression', 'MPA', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('YIF1B', 'Gene', '90522', (108, 113))
136047	32648580	Previous research has shown that YIF1B is involved in anterograde vesicle traffic in cells, transporting 'cargo' proteins (including the serotonin receptor HTR1A) from the endoplasmic reticulum to the cell membrane via the Golgi apparatus; such cell membrane localization being accelerated upon knocking out YIF1B in HeLa cells.	('YIF1B', 'Gene', '90522', (33, 38))	('YIF1B', 'Gene', '90522', (308, 313))	("transporting 'cargo' proteins", 'MPA', (92, 121))	('serotonin', 'Chemical', 'MESH:D012701', (137, 146))	('knocking out', 'Var', (295, 307))	('YIF1B', 'Gene', (33, 38))	('HTR1A', 'Gene', '3350', (156, 161))	('YIF1B', 'Gene', (308, 313))	('accelerated', 'PosReg', (278, 289))	('HeLa', 'CellLine', 'CVCL:0030', (317, 321))	('HTR1A', 'Gene', (156, 161))
136050	32648580	A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder.	('movement disorder', 'Phenotype', 'HP:0100022', (204, 221))	('mutations', 'Var', (93, 102))	('YIF1B', 'Gene', (87, 92))	('specific proteins', 'MPA', (130, 147))	('link', 'Reg', (2, 6))	('association', 'Interaction', (72, 83))	('epilepsy and movement disorder', 'Disease', 'MESH:D004827', (191, 221))	('encephalopathy', 'Disease', 'MESH:D001927', (175, 189))	('epilepsy', 'Phenotype', 'HP:0001250', (191, 199))	('HTR', 'Gene', '7012', (33, 36))	('encephalopathy', 'Phenotype', 'HP:0001298', (175, 189))	('encephalopathy', 'Disease', (175, 189))	('YIF1B', 'Gene', '90522', (87, 92))	('causing', 'Reg', (167, 174))	('HTR', 'Gene', (33, 36))
136065	32648580	Furthermore, COAD patients with high MSI have demonstrated better checkpoint inhibitor responses and survival in both low and high clinical stages.	('high MSI', 'Var', (32, 40))	('COAD', 'Disease', (13, 17))	('better', 'PosReg', (59, 65))	('COAD', 'Disease', 'MESH:D029424', (13, 17))	('checkpoint inhibitor responses', 'MPA', (66, 96))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (101, 109))
136077	32648580	For example, protein activity might be affected in normal or cancer cells by post-transcription modification and/or regulated proteolysis.	('regulated proteolysis', 'MPA', (116, 137))	('affected', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('post-transcription modification', 'Var', (77, 108))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activity', 'MPA', (21, 29))	('protein', 'Protein', (13, 20))
136098	31681612	With advancements in molecular biology, a number of significant genetic alterations (IDH mutation, 1p/19q codeletion, H3ys27Met, and RELA-fusion) are now associated with heterogeneous tumor histology and are clinically significant based on the revised 2016 World Health Organization (WHO) classification.	('IDH', 'Gene', '3417', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('RELA', 'Gene', (133, 137))	('RELA', 'Gene', '5970', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('1p/19q codeletion', 'Var', (99, 116))	('tumor', 'Disease', (184, 189))	('IDH', 'Gene', (85, 88))	('associated', 'Reg', (154, 164))	('H3ys27Met', 'Var', (118, 127))
136118	31681612	Similar to that with KL, DNA methylation of the LCTL promoter can silence its endogenous expression.	('silence', 'NegReg', (66, 73))	('LCTL', 'Gene', '197021', (48, 52))	('LCTL', 'Gene', (48, 52))	('endogenous expression', 'MPA', (78, 99))	('KL', 'Gene', '9365', (21, 23))	('DNA methylation', 'Var', (25, 40))
136119	31681612	After identifying that high LCTL expression might lead to glioma progression, we further investigated its potential biological role in glioma based on gene ontology (GO) analysis and observed that it is markedly involved in tumor-associated immune responses in this disease.	('lead to', 'Reg', (50, 57))	('glioma', 'Disease', (135, 141))	('high', 'Var', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma progression', 'Disease', (58, 76))	('tumor', 'Disease', (224, 229))	('LCTL', 'Gene', '197021', (28, 32))	('LCTL', 'Gene', (28, 32))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Disease', (58, 64))	('glioma progression', 'Disease', 'MESH:D005910', (58, 76))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
136153	31681612	Results indicated that high LCTL expression is not only significantly associated with poor prognosis in glioma patients (Figures 2A,B), but also in patients with high grade glioma (Figures 2C,D).	('patients', 'Species', '9606', (148, 156))	('high', 'Var', (23, 27))	('glioma', 'Disease', (173, 179))	('LCTL', 'Gene', '197021', (28, 32))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('LCTL', 'Gene', (28, 32))	('associated', 'Reg', (70, 80))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', (104, 110))	('patients', 'Species', '9606', (111, 119))
136154	31681612	Recently, increasing evidence has suggested recurrent point mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) occur in specific types of glioma.	('IDH2', 'Gene', (114, 118))	('occur', 'Reg', (120, 125))	('point mutations', 'Var', (54, 69))	('IDH1', 'Gene', (105, 109))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('IDH2', 'Gene', '3418', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('IDH1', 'Gene', '3417', (105, 109))	('isocitrate', 'Chemical', 'MESH:D007523', (73, 83))	('glioma', 'Disease', (147, 153))
136156	31681612	Further, in the latest version of the WHO Classification of Central Nervous System Tumors published in 2016, IDH mutations were adopted as a decisive marker for glioma classification.	('Tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Tumor', 'Phenotype', 'HP:0002664', (83, 88))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('mutations', 'Var', (113, 122))	('Nervous System Tumors', 'Phenotype', 'HP:0004375', (68, 89))	('Central Nervous System Tumors', 'Disease', 'MESH:D016543', (60, 89))	('IDH', 'Gene', (109, 112))	('Central Nervous System Tumors', 'Disease', (60, 89))	('glioma', 'Disease', (161, 167))	('Central Nervous System Tumors', 'Phenotype', 'HP:0100006', (60, 89))	('IDH', 'Gene', '3417', (109, 112))
136163	31681612	It is widely recognized that both genetic alterations (mutations, loss of heterozygosity, deletions, insertions, aneuploidy, etc.)	('aneuploidy', 'Disease', 'MESH:D000782', (113, 123))	('mutations', 'Var', (55, 64))	('insertions', 'Var', (101, 111))	('loss of heterozygosity', 'Var', (66, 88))	('aneuploidy', 'Disease', (113, 123))	('deletions', 'Var', (90, 99))
136166	31681612	Interestingly, after the analysis of genetic alterations by cBioPortal, we found no genetic alterations including mutations and putative copy-number alterations in LCTL in TCGA Merged Cohort of LGG and GBM (Supplementary Table S2).	('GBM', 'Disease', (202, 205))	('LCTL', 'Gene', '197021', (164, 168))	('mutations', 'Var', (114, 123))	('GBM', 'Disease', 'MESH:D005909', (202, 205))	('LCTL', 'Gene', (164, 168))
136169	31681612	The LCTL DNA methylation beta values at cg00686404 were significantly higher in the low LCTL expression group than in the high LCTL expression group (Figure 3A).	('LCTL', 'Gene', (127, 131))	('low', 'Var', (84, 87))	('LCTL', 'Gene', '197021', (4, 8))	('LCTL', 'Gene', (4, 8))	('LCTL', 'Gene', '197021', (88, 92))	('higher', 'PosReg', (70, 76))	('cg00686404', 'Var', (40, 50))	('LCTL', 'Gene', '197021', (127, 131))	('LCTL', 'Gene', (88, 92))
136170	31681612	Meanwhile, the beta values at cg00686404 were negatively correlated with LCTL mRNA expression (Pearson's r = -0.682, p < 2.2e-16; Figure 3B).	('LCTL', 'Gene', '197021', (73, 77))	('negatively', 'NegReg', (46, 56))	('LCTL', 'Gene', (73, 77))	('correlated', 'Interaction', (57, 67))	('cg00686404', 'Var', (30, 40))
136171	31681612	To further validate our previous results, we next analyzed the predictive value of LCTL promoter DNA methylation for glioma patients and found that patients with high levels had significantly better prognosis than those with low levels (Figures 3E,F, p < 0.0001).	('patients', 'Species', '9606', (148, 156))	('better', 'PosReg', (192, 198))	('LCTL', 'Gene', '197021', (83, 87))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('LCTL', 'Gene', (83, 87))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('high levels', 'Var', (162, 173))	('glioma', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))
136172	31681612	In summary, these results indicate that the expression of LCTL is likely regulated by DNA methylation of its promoter, and that this epigenetic modification might also represent a potential prognostic marker for glioma patients.	('expression', 'MPA', (44, 54))	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('LCTL', 'Gene', '197021', (58, 62))	('LCTL', 'Gene', (58, 62))	('methylation', 'Var', (90, 101))	('patients', 'Species', '9606', (219, 227))	('regulated', 'Reg', (73, 82))	('glioma', 'Disease', (212, 218))
136217	31681612	DNA methylation, the main epigenetic modification, is also involved in the pathogenesis of cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('involved', 'Reg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('DNA methylation', 'Var', (0, 15))
136222	31681612	Here, we found that the endogenous expression of LCTL is regulated by promoter DNA methylation rather than genetic alterations in glioma.	('LCTL', 'Gene', '197021', (49, 53))	('promoter DNA methylation', 'Var', (70, 94))	('glioma', 'Disease', (130, 136))	('LCTL', 'Gene', (49, 53))	('regulated by', 'Reg', (57, 69))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('endogenous expression', 'MPA', (24, 45))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
136232	31681612	Recently, accumulating evidence has demonstrated that cross-talk between EMT-associated factors and the TME might facilitate tumor immune escape.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cross-talk', 'Var', (54, 64))	('facilitate', 'PosReg', (114, 124))	('tumor', 'Disease', (125, 130))
136237	31681612	FGFR dysfunction is widely found in cancers and FGF biology is involved in many effects in a myriad of cell types, and is a key component of the tumor environment.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('FGFR', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancers', 'Disease', (36, 43))	('involved', 'Reg', (63, 71))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('FGF', 'Gene', (48, 51))	('dysfunction', 'Var', (5, 16))
136247	31681612	Our findings provide opportunities to explore novel therapeutic approaches based on the epigenetic targeting of LCTL.	('LCTL', 'Gene', '197021', (112, 116))	('LCTL', 'Gene', (112, 116))	('epigenetic targeting', 'Var', (88, 108))
136252	31044160	A high burden of tumor-specific mutant peptides (neoantigens) correlates with better survival and response to immunotherapies in selected solid tumors but how neoantigens impact clinical outcome in GBM remains unclear.	('solid tumors', 'Disease', 'MESH:D009369', (138, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (144, 149))	('better', 'PosReg', (78, 84))	('tumor', 'Disease', (17, 22))	('GBM', 'Phenotype', 'HP:0012174', (198, 201))	('impact', 'Reg', (171, 177))	('solid tumors', 'Disease', (138, 150))	('mutant', 'Var', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
136259	31044160	Recent reports have shown that nonsynonymous coding mutations may increase tumor immunogenicity.	('increase', 'PosReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('nonsynonymous coding mutations', 'Var', (31, 61))
136260	31044160	In selected tumor types such as melanoma, lung cancer, and colorectal tumors, the somatic mutational burden correlates with the probability to generate immunogenic peptides that are presented to CD8+ T cells on restricted HLA-I subtypes.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('CD8', 'Gene', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (12, 17))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('colorectal tumors', 'Disease', (59, 76))	('mutational', 'Var', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CD8', 'Gene', '925', (195, 198))	('colorectal tumors', 'Disease', 'MESH:D015179', (59, 76))	('tumor', 'Disease', (70, 75))	('lung cancer', 'Disease', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
136263	31044160	In the case of glioma higher mutational load is associated with increased tumor aggressiveness.	('mutational', 'Var', (29, 39))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (74, 94))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glioma', 'Disease', (15, 21))	('tumor aggressiveness', 'Disease', (74, 94))	('increased', 'PosReg', (64, 73))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('aggressiveness', 'Phenotype', 'HP:0000718', (80, 94))
136269	31044160	To define the importance of neoantigens in human glioma, we designed a stringent neoantigen prediction algorithm that considers the differential binding affinity of mutant and wild-type 9-mer peptides to HLA-I (neoantigen quantity model, Supplementary Fig.	('mutant', 'Var', (165, 171))	('binding', 'Interaction', (145, 152))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('human', 'Species', '9606', (43, 48))	('glioma', 'Disease', (49, 55))
136277	31044160	This analysis including 14 matched glioma neoantigens and corresponding wild-type peptides revealed that each mutant peptide bound with higher affinity to HLA-I than the wild-type counterpart, thus validating the stringency of our approach (Fig.	('higher', 'PosReg', (136, 142))	('mutant', 'Var', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('bound', 'Interaction', (125, 130))	('HLA-I', 'Protein', (155, 160))	('glioma', 'Disease', (35, 41))
136280	31044160	Recently, it has been proposed that the difference in binding affinity between any wild-type and mutant peptide (termed differential agretopicity index, DAI) is a more accurate indicator of peptide immunogenicity than the binding affinity of the mutant peptide and it has been shown that the mean DAI of all tumor peptide pairs was a predictor of survival in melanoma and non-small cell lung cancer.	('melanoma', 'Phenotype', 'HP:0002861', (359, 367))	('melanoma', 'Disease', (359, 367))	('binding', 'Interaction', (54, 61))	('melanoma', 'Disease', 'MESH:D008545', (359, 367))	('lung cancer', 'Phenotype', 'HP:0100526', (387, 398))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (372, 398))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (376, 398))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('mutant', 'Var', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (372, 398))	('tumor', 'Disease', (308, 313))	('predictor of', 'Reg', (334, 346))	('non-small cell lung cancer', 'Disease', (372, 398))
136282	31044160	In some glioma sub-types and the aggregated cohort of all gliomas, high DAI was associated with a worse clinical outcome (Supplementary Fig.	('high DAI', 'Var', (67, 75))	('glioma', 'Disease', (8, 14))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('glioma', 'Disease', 'MESH:D005910', (8, 14))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('glioma', 'Disease', (58, 64))
136296	31044160	Compared to heterozygous HLA-I carriers, homozygosity for HLA-I loci is predicted to present a smaller and less diverse repertoire of tumor-derived neoantigens to cytotoxic T lymphocytes (CTLs).	('HLA-I', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('loci', 'Var', (64, 68))	('tumor', 'Disease', (134, 139))
136312	31044160	Confirming the lack of significance of CD8+ T cell enrichment score for survival, we found a lower CD8+ T cell enrichment score in the more favorable IDH mutant when compared with IDH wild-type gliomas (Wilcoxon p-value 2.26E-16, Supplementary Fig.	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('CD8', 'Gene', (99, 102))	('CD8', 'Gene', '925', (99, 102))	('IDH', 'Gene', (180, 183))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('gliomas', 'Disease', (194, 201))	('lower', 'NegReg', (93, 98))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (150, 153))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('IDH', 'Gene', '3417', (150, 153))	('mutant', 'Var', (154, 160))
136319	31044160	Aberrant DNA methylation of genes expressed by immune cells were reported to regulate the extent of immune infiltration in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('regulate', 'Reg', (77, 85))	('solid tumors', 'Disease', (123, 135))	('Aberrant DNA methylation', 'Var', (0, 24))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
136326	31044160	We failed to find recurrent genes harboring mutations that produce neoantigens in the high-quality neoantigens/high CD8+ T cell group.	('CD8', 'Gene', '925', (116, 119))	('mutations', 'Var', (44, 53))	('CD8', 'Gene', (116, 119))
136329	31044160	In particular, we found that genetic alterations of PIK3CA, RB1 and MDM2 were present in 24-28% of GBM unable to generate high-quality neoantigens and attract CD8+ T lymphocytes but only in 0-8% of GBM with high-quality neoantigens and high CD8+ T lymphocytes (RNA-seq, p = 0.06; Agilent, p = 0.02; Supplementary Table 5).	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('GBM', 'Phenotype', 'HP:0012174', (198, 201))	('MDM2', 'Gene', '4193', (68, 72))	('MDM2', 'Gene', (68, 72))	('CD8', 'Gene', (241, 244))	('PIK3CA', 'Gene', (52, 58))	('CD8', 'Gene', (159, 162))	('CD8', 'Gene', '925', (241, 244))	('RB1', 'Gene', (60, 63))	('alterations', 'Var', (37, 48))	('PIK3CA', 'Gene', '5290', (52, 58))	('CD8', 'Gene', '925', (159, 162))	('RB1', 'Gene', '5925', (60, 63))
136335	31044160	Progression from low-grade to high-grade glioma evolves through increasing mutational burden.	('mutational burden', 'Var', (75, 92))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('glioma', 'Disease', (41, 47))
136336	31044160	Even among GBM patients, a higher number of mutations is associated with a more aggressive disease and worse survival.	('patients', 'Species', '9606', (15, 23))	('GBM', 'Phenotype', 'HP:0012174', (11, 14))	('mutations', 'Var', (44, 53))	('aggressive disease', 'Disease', 'MESH:D001523', (80, 98))	('aggressive disease', 'Disease', (80, 98))
136349	31044160	Binding affinities of mutant and corresponding wild-type 9-mer peptides, relevant to the patient's HLA-I alleles, were predicted using netMHCpan-4.0.	('netMHCpan', 'Chemical', '-', (135, 144))	('Binding affinities', 'MPA', (0, 18))	('patient', 'Species', '9606', (89, 96))	('mutant', 'Var', (22, 28))
136350	31044160	A mutant-specific binder, relevant to the restricted HLA-I allele, was referred to as neoantigen when the mutant IC50 was less than 500 nM and IC50 of the corresponding wild-type binder, relevant to all HLA-I alleles of the patient, more than 500 nM.	('less', 'NegReg', (122, 126))	('mutant', 'Var', (106, 112))	('patient', 'Species', '9606', (224, 231))
136368	31044160	The same process was used to select the genes with mutation or copy number changes specifically occurring in low-quality neoantigens and low CD8+ T cells group.	('CD8', 'Gene', (141, 144))	('copy number changes', 'Var', (63, 82))	('mutation', 'Var', (51, 59))	('CD8', 'Gene', '925', (141, 144))
136370	31044160	Wilcoxon test followed by multiple testing using the Benjamini-Hochberg method for FDR estimation were used to identify DNA probes differentially methylated between the high-quality neoantigens and high CD8+ T cell group of glioma and the low-quality neoantigens and low CD8+ T cell group of tumors.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Disease', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('CD8', 'Gene', (271, 274))	('CD8', 'Gene', '925', (271, 274))	('CD8', 'Gene', (203, 206))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('CD8', 'Gene', '925', (203, 206))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('methylated', 'Var', (146, 156))	('differentially', 'Reg', (131, 145))	('glioma', 'Disease', (224, 230))
136485	28768481	At a glance, we could confirm earlier findings that the predominant methylation and expression patterns separate perfectly by mutations in the IDH genes, rather than by histology.	('IDH', 'Gene', '3417', (143, 146))	('methylation', 'MPA', (68, 79))	('mutations', 'Var', (126, 135))	('expression', 'MPA', (84, 94))	('IDH', 'Gene', (143, 146))
136490	28768481	Since TP53 is a master regulator of cell fate, including apoptosis, disabling its expression has a direct impact on the function of downstream expression pathways.	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('disabling', 'Var', (68, 77))	('expression', 'MPA', (82, 92))	('function', 'MPA', (120, 128))	('impact', 'Reg', (106, 112))
136492	28768481	In gliomas, for instance, it has been reported that mutations in the IDH (isocitrate dehydrogenase genes 1 and 2, collectively referred to as IDH) genes result in the hyper-methylation of a number of sites.	('mutations', 'Var', (52, 61))	('hyper-methylation', 'MPA', (167, 184))	('result in', 'Reg', (153, 162))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', (142, 145))	('IDH', 'Gene', '3417', (69, 72))	('IDH', 'Gene', '3417', (142, 145))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))
136493	28768481	Characterizing the methylation patterns that differ between tumor types allows for a more accurate diagnosis and can thus inform the choice of treatment.	('methylation', 'Var', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('inform', 'Reg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
136500	28768481	They identified a different grouping that is based on mutations in the IDH1 and IDH2 genes, which allows for a more accurate classification.	('IDH2', 'Gene', '3418', (80, 84))	('mutations', 'Var', (54, 63))	('IDH1', 'Gene', (71, 75))	('IDH1', 'Gene', '3417', (71, 75))	('IDH2', 'Gene', (80, 84))
136504	28768481	Gene expression of ERBB2 is also altered and 2-fold lower in the IDH mutant samples, as shown in dark red (Fig.	('ERBB2', 'Gene', '2064', (19, 24))	('ERBB2', 'Gene', (19, 24))	('IDH', 'Gene', (65, 68))	('mutant', 'Var', (69, 75))	('IDH', 'Gene', '3417', (65, 68))	('lower', 'NegReg', (52, 57))	('altered', 'Reg', (33, 40))	('Gene expression', 'MPA', (0, 15))
136506	28768481	Here, we can visually confirm that the mutation status of IDH is the best predictor for methylation (Fig.	('methylation', 'MPA', (88, 99))	('IDH', 'Gene', '3417', (58, 61))	('IDH', 'Gene', (58, 61))	('mutation status', 'Var', (39, 54))
136508	28768481	By contrast, codeletion of chromosome arms 1p and 19q (1p/19q codeletion), reported to be associated with improved prognosis and therapy in low-grade gliomas patients, appears to have no effect on the methylation of ERBB2.	('improved', 'PosReg', (106, 114))	('ERBB2', 'Gene', (216, 221))	('ERBB2', 'Gene', '2064', (216, 221))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('methylation', 'MPA', (201, 212))	('low-grade', 'Disease', (140, 149))	('patients', 'Species', '9606', (158, 166))	('codeletion', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
136509	28768481	Likewise, neither mutations in the promoter of the TERT (Telomerase Reverse Transcriptase) gene, nor the promoter methylation status of the gene encoding for repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which has been reported to be correlated with long-term survival in glioblastoma, plays an obvious role in the methylation of this and other genes in the pathway.	('correlated with', 'Reg', (249, 264))	('glioblastoma', 'Disease', (287, 299))	('O6-methylguanine-DNA methyltransferase', 'Gene', (172, 210))	('Telomerase Reverse Transcriptase', 'Gene', '7015', (57, 89))	('TERT', 'Gene', (51, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (287, 299))	('glioblastoma', 'Phenotype', 'HP:0012174', (287, 299))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (172, 210))	('TERT', 'Gene', '7015', (51, 55))	('Telomerase Reverse Transcriptase', 'Gene', (57, 89))	('mutations', 'Var', (18, 27))
136512	28768481	There, we found that in FAS, SMO and ERBB2, the average expression level of the samples in IDH mutants is lower than the average expression level of the wild-type samples, while for DAPK1 the mutants exhibit higher expression levels.	('ERBB2', 'Gene', (37, 42))	('FAS', 'Chemical', 'MESH:C038178', (24, 27))	('lower', 'NegReg', (106, 111))	('ERBB2', 'Gene', '2064', (37, 42))	('expression', 'MPA', (129, 139))	('DAPK1', 'Gene', '1612', (182, 187))	('expression level', 'MPA', (56, 72))	('SMO', 'Gene', '6608', (29, 32))	('IDH', 'Gene', (91, 94))	('SMO', 'Gene', (29, 32))	('mutants', 'Var', (95, 102))	('DAPK1', 'Gene', (182, 187))	('IDH', 'Gene', '3417', (91, 94))
136528	28768481	After sorting the samples by methylation of CASP8 in increasing order, Additional file 2: Video S1 shows methylation and expression in the TNF signaling pathway, rendering TRADD, CASP8, CFLAR and MAP3K8 dark blue in the beginning (low methylation), and then sharply turning red when switching from showing wild type samples to IDH mutant samples.	('MAP3K8', 'Gene', (196, 202))	('TRADD', 'Gene', '8717', (172, 177))	('CASP8', 'Gene', (44, 49))	('CASP8', 'Gene', '841', (44, 49))	('CASP8', 'Gene', (179, 184))	('TRADD', 'Gene', (172, 177))	('CASP8', 'Gene', '841', (179, 184))	('IDH', 'Gene', (327, 330))	('CFLAR', 'Gene', '8837', (186, 191))	('IDH', 'Gene', '3417', (327, 330))	('TNF signaling pathway', 'Pathway', (139, 160))	('mutant', 'Var', (331, 337))	('CFLAR', 'Gene', (186, 191))	('MAP3K8', 'Gene', '1326', (196, 202))
136641	26894279	(2010) demonstrated in a group of 24 brain tumor patients that deviations of +-20% from a standard fMRI threshold (t ranging from 2.8 to 26.4 across subjects) had no significant effect on COM, number of activated voxels, or the reproducibility of the location of activated voxels.	('brain tumor', 'Disease', 'MESH:D001932', (37, 48))	('brain tumor', 'Disease', (37, 48))	('brain tumor', 'Phenotype', 'HP:0030692', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('deviations', 'Var', (63, 73))	('patients', 'Species', '9606', (49, 57))
136718	33503035	The ratios of genetic alterations in PLOD family members for LGG different from 3% to 12% for each member (PLOD1 3%; PLOD2 5%; PLOD3 15%) (Fig 3B).	('PLOD3', 'Gene', (127, 132))	('PLOD3', 'Gene', '8985', (127, 132))	('PLOD2', 'Gene', (117, 122))	('genetic alterations', 'Var', (14, 33))	('PLOD', 'Gene', '5351', (37, 41))	('PLOD', 'Gene', (117, 121))	('PLOD', 'Gene', (37, 41))	('PLOD', 'Gene', '5351', (127, 131))	('PLOD', 'Gene', (107, 111))	('PLOD2', 'Gene', '5352', (117, 122))	('PLOD', 'Gene', '5351', (117, 121))	('PLOD1', 'Gene', (107, 112))	('PLOD', 'Gene', (127, 131))	('PLOD', 'Gene', '5351', (107, 111))	('PLOD1', 'Gene', '5351', (107, 112))
136720	33503035	The genetic alteration analysis showed a significantly shorter overall and disease-free survival of patients with PLODs mutation in LGG patients.	('disease-free survival', 'CPA', (75, 96))	('mutation', 'Var', (120, 128))	('shorter', 'NegReg', (55, 62))	('patients', 'Species', '9606', (100, 108))	('LGG', 'Disease', (132, 135))	('patients', 'Species', '9606', (136, 144))	('PLOD', 'Gene', (114, 118))	('overall', 'CPA', (63, 70))	('PLOD', 'Gene', '5351', (114, 118))
136721	33503035	We speculate that detecting mutations in the PLOD gene family members will help determine the prognosis of LGG patients.	('PLOD', 'Gene', (45, 49))	('PLOD', 'Gene', '5351', (45, 49))	('LGG', 'Disease', (107, 110))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (111, 119))
136744	33503035	In breast cancer tumorigenesis, high expression of PLOD2 was positively associated with poorer prognosis.	('tumor', 'Disease', (17, 22))	('PLOD2', 'Gene', (51, 56))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('associated', 'Reg', (72, 82))	('PLOD2', 'Gene', '5352', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('high expression', 'Var', (32, 47))
136746	33503035	In addition, Li X et al, indicated that knockdown of PLOD2 in glioblastoma (GBM) can play antitumor effect under hypoxia conditions.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('hypoxia', 'Disease', (113, 120))	('knockdown', 'Var', (40, 49))	('PLOD2', 'Gene', (53, 58))	('tumor', 'Disease', (94, 99))	('glioblastoma', 'Disease', (62, 74))	('PLOD2', 'Gene', '5352', (53, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))
136778	30704458	Using per-cancer and pan-cancer settings, the model predicted both known, including EGFR inhibitors in non-small cell lung cancer and tamoxifen in ER+ breast cancer, and novel drug targets, such as vinorelbine for TTN-mutated tumors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('inhibitors', 'Var', (89, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (103, 129))	('vinorelbine', 'Chemical', 'MESH:D000077235', (198, 209))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (134, 143))	('TTN', 'Gene', '7273', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (158, 164))	('breast cancer', 'Disease', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('non-small cell lung cancer', 'Disease', (103, 129))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('TTN', 'Gene', (214, 217))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('ER', 'Gene', '2099', (147, 149))	('tumors', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (103, 129))	('cancer', 'Disease', (123, 129))	('EGFR', 'Gene', (84, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))
136782	30704458	For instance, recent reports identified mutation profiles associated with drug response both in tumor type-specific and pan-cancer manners.	('mutation', 'Var', (40, 48))	('cancer', 'Disease', (124, 130))	('drug response', 'Disease', (74, 87))	('associated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
136796	30704458	In this study, we analyzed 622 cell lines with available expression, mutation, and IC50 data and 9059 tumors with expression and mutation profiles.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('IC50', 'Gene', (83, 87))	('mutation', 'Var', (69, 77))	('expression', 'Species', '29278', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('expression', 'Species', '29278', (57, 67))
136803	30704458	We pre-trained an autoencoder on each of the TCGA mutation and expression datasets to optimize the capability to capture high-order features.	('TCGA', 'Gene', (45, 49))	('expression', 'Species', '29278', (63, 73))	('mutation', 'Var', (50, 58))
136809	30704458	For each method, top 64 principal components of mutations and gene expression were merged to predict IC50 values of all (using linear regression) or individual drugs (SVM).	('expression', 'Species', '29278', (67, 77))	('mutations', 'Var', (48, 57))	('IC50', 'MPA', (101, 105))
136823	30704458	Also, two EGFR inhibitors, afatinib and gefitinib, achieved better performance in non-small cell lung cancers (NSCLC) with mutated EGFR (P = 2.0 x 10- 7 and 6.6 x 10- 3).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (82, 109))	('afatinib', 'Chemical', 'MESH:D000077716', (27, 35))	('NSCLC', 'Disease', (111, 116))	('EGFR', 'Gene', (10, 14))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('EGFR', 'Gene', (131, 135))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('non-small cell lung cancers', 'Disease', (82, 109))	('gefitinib', 'Chemical', 'MESH:D000077156', (40, 49))	('mutated', 'Var', (123, 130))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (86, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (82, 108))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (82, 109))	('lung cancers', 'Phenotype', 'HP:0100526', (97, 109))
136828	30704458	The top three combinations were TP53 mutations in lung adenocarcinoma (LUAD; modulating response to 235 drugs), lung squamous cell carcinoma (LUSC; 228 drugs), and stomach adenocarcinoma (STAD; 224 drugs) (Table 2).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('lung squamous cell carcinoma', 'Disease', (112, 140))	('TP53', 'Gene', '7157', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('lung adenocarcinoma', 'Disease', (50, 69))	('mutations', 'Var', (37, 46))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('TP53', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('stomach adenocarcinoma', 'Disease', (164, 186))
136830	30704458	The mutation has been shown to be associated with cancer stem cells and resistance functions and thus regulates drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (112, 127))	('associated', 'Reg', (34, 44))	('regulates', 'Reg', (102, 111))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutation', 'Var', (4, 12))	('resistance functions', 'CPA', (72, 92))	('drug resistance', 'MPA', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
136834	30704458	We also identified gene mutations that sensitized tumors to a large number of drugs, such as IDH1 (138 drugs; Table 2).	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sensitized', 'Reg', (39, 49))	('tumors', 'Disease', (50, 56))	('mutations', 'Var', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
136836	30704458	Our finding agreed with the report and showed that IDH1 mutation dramatically reduced IC50 of chemotherapeutic agents, e.g., doxorubicin in LGG (DeltaIC50 = - 0.85; P = 3.6 x 10- 71; Fig.	('IC50 of', 'MPA', (86, 93))	('doxorubicin', 'MPA', (125, 136))	('reduced', 'NegReg', (78, 85))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))	('doxorubicin', 'Chemical', 'MESH:D004317', (125, 136))
136837	30704458	We also carried out a study to explore how gene mutations affect drug response in a pan-cancer setting.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene mutations', 'Var', (43, 57))	('drug response', 'MPA', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('affect', 'Reg', (58, 64))
136839	30704458	Among them, TP53 (9 sensitive and 242 resistant drugs) and TTN mutations (44 and 162) were associated with the largest numbers of resistant and sensitive drugs, respectively (Table 3).	('mutations', 'Var', (63, 72))	('TTN', 'Gene', (59, 62))	('TP53', 'Gene', '7157', (12, 16))	('TTN', 'Gene', '7273', (59, 62))	('TP53', 'Gene', (12, 16))
136840	30704458	Many of the drugs with large TP53 mutations-modulated changes in DeltaIC50 ( DeltaIC50  >= 0.7; Fig.	('changes', 'Reg', (54, 61))	('DeltaIC50', 'MPA', (65, 74))	('TP53', 'Gene', '7157', (29, 33))	('mutations-modulated', 'Var', (34, 53))	('TP53', 'Gene', (29, 33))
136850	30704458	For each drug, pan-cancer patients predicted to be very sensitive and resistant (with IC50 in bottom and top 1%, n = 91 in each group; Fig.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('IC50', 'Var', (86, 90))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
136855	30704458	On average, each sensitive tumor harbored 2.7 mutations among these genes, much higher than 0.51 observed in the resistant group (Fig.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
136864	30704458	Nine of the top 10 differentially mutated genes were enriched in the resistant group and led by TP53 mutations (mutation rate, 95.6% in resistant vs. 13.2% in sensitive patients; Fig.	('patients', 'Species', '9606', (169, 177))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', (96, 100))
136870	30704458	Furthermore, DeepDR may incorporate additional genomic mutation information, such as copy number alterations, into data matrices MTCGA and MCCLE, to enrich the complexity of tumor mutation for model training and further reduce the training MSE.	('tumor', 'Disease', (174, 179))	('copy number alterations', 'Var', (85, 108))	('CCLE', 'Chemical', '-', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
136871	30704458	In this study, by integrating genomics profiles to the predictions, we systematically investigated how single gene mutations, as well as the interplay between cancer type, mutations, and biological functions, were associated with the predicted drug response.	('cancer', 'Disease', (159, 165))	('mutations', 'Var', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('drug response', 'MPA', (244, 257))	('associated', 'Reg', (214, 224))
136890	27287018	RNA-binding proteins (RBPs) are master regulators of co- and post-transcriptional mechanisms, including RNA processing (splicing, capping, and polyadenylation), transport, decay, localization, and translation.	('RBP', 'Gene', (22, 25))	('polyadenylation', 'Var', (143, 158))	('decay', 'MPA', (172, 177))	('RBP', 'Gene', '5725', (22, 25))
136892	27287018	Mutations and alterations in RBP expression levels, which have been observed in many tumor tissues, are known to impact large gene sets and to contribute to tumor initiation and growth.	('alterations', 'Var', (14, 25))	('growth', 'CPA', (178, 184))	('tumor', 'Disease', (157, 162))	('tumor initiation', 'Disease', (157, 173))	('tumor', 'Disease', (85, 90))	('impact', 'Reg', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('RBP', 'Gene', '5725', (29, 32))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('contribute', 'Reg', (143, 153))	('expression levels', 'MPA', (33, 50))	('tumor initiation', 'Disease', 'MESH:D009369', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('RBP', 'Gene', (29, 32))
136895	27287018	Hence, RBPs play key roles in this biological context and their alteration is expected to be a major contributor to gliomagenesis.	('RBP', 'Gene', (7, 10))	('glioma', 'Disease', (116, 122))	('alteration', 'Var', (64, 74))	('RBP', 'Gene', '5725', (7, 10))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('contributor', 'Reg', (101, 112))
136898	27287018	Moreover, several genes in pathways relevant to GBM initiation and development, such as RTK, PI3K, RAS, MAPK, AKT, RB, and p53, as well as a set of additional cancer genes, displayed alterations in their splicing and expression profiles upon SNRPB knockdown.	('cancer', 'Disease', (159, 165))	('splicing', 'MPA', (204, 212))	('RTK', 'Disease', (88, 91))	('alterations', 'Reg', (183, 194))	('AKT', 'Gene', (110, 113))	('AKT', 'Gene', '207', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('SNRPB', 'Gene', (242, 247))	('p53', 'Gene', (123, 126))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('p53', 'Gene', '7157', (123, 126))	('expression profiles', 'MPA', (217, 236))	('knockdown', 'Var', (248, 257))
136919	27287018	To try to identify mechanisms responsible for the upregulation of RBPs in tumor samples, we evaluated whether the 21 selected RBPs are targeted by frequently downregulated miRNAs in GBM (tumor suppressor miRNAs).	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('RBP', 'Gene', (126, 129))	('GBM', 'Phenotype', 'HP:0012174', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('RBP', 'Gene', (66, 69))	('downregulated', 'NegReg', (158, 171))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (74, 79))	('miRNAs', 'Var', (172, 178))	('RBP', 'Gene', '5725', (126, 129))	('RBP', 'Gene', '5725', (66, 69))
136922	27287018	We also evaluated whether the 21 RBPs presented mutations and/or copy-number alterations (CNA) in GBM samples from TCGA.	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('copy-number alterations', 'Var', (65, 88))	('RBP', 'Gene', '5725', (33, 36))	('mutations', 'Var', (48, 57))	('RBP', 'Gene', (33, 36))
136924	27287018	CNA, missense mutations, and/or truncating mutations were present in 17 out of 21 evaluated RBPs, not different from randomly selected RBPs sets (p-value > 0.1; simulation with 100,000 sets of 21 randomly selected RBPs; Additional file 2: Figure S4).	('missense mutations', 'Var', (5, 23))	('RBP', 'Gene', '5725', (135, 138))	('truncating', 'MPA', (32, 42))	('CNA', 'Disease', (0, 3))	('RBP', 'Gene', '5725', (214, 217))	('RBP', 'Gene', '5725', (92, 95))	('RBP', 'Gene', (135, 138))	('RBP', 'Gene', (214, 217))	('RBP', 'Gene', (92, 95))
136926	27287018	Transient knockdowns were performed with siRNAs (median knockdown efficiency ~90 %; Additional file 1: Table S6) in U251 and U343 GBM cells and their impact on viability (MTS assay), proliferation (IncuCyte), and apoptosis (Caspase-3/7 assay) were evaluated.	('Caspase-3', 'Gene', '836', (224, 233))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('Caspase-3', 'Gene', (224, 233))	('knockdown', 'Var', (56, 65))
136930	27287018	Events were classified in five categories: exon skipping (SE), mutually exclusive exons (MXE), alternative 5' splice site (A5SS), alternative 3' splice site (A3SS), or intron retention (RI).	('intron retention', 'Disease', (168, 184))	('exon skipping', 'Var', (43, 56))	('SE', 'Disease', 'None', (58, 60))
136935	27287018	At the expression level, 8 out of 33 evaluated genes were differentially expressed: four of them were upregulated (HRAS, MET, NF1, and TP53) and four downregulated upon knockdown (AKT1, AKT2, FGFR3, PDGFRA).	('PDGFRA', 'Gene', (199, 205))	('downregulated', 'NegReg', (150, 163))	('AKT2', 'Gene', (186, 190))	('knockdown', 'Var', (169, 178))	('FGFR3', 'Gene', (192, 197))	('TP53', 'Gene', '7157', (135, 139))	('AKT1', 'Gene', '207', (180, 184))	('upregulated', 'PosReg', (102, 113))	('AKT2', 'Gene', '208', (186, 190))	('HRAS', 'Gene', '3265', (115, 119))	('NF1', 'Gene', (126, 129))	('HRAS', 'Gene', (115, 119))	('TP53', 'Gene', (135, 139))	('NF1', 'Gene', '4763', (126, 129))	('AKT1', 'Gene', (180, 184))	('FGFR3', 'Gene', '2261', (192, 197))	('PDGFRA', 'Gene', '5156', (199, 205))
136940	27287018	To explore mechanisms that could contribute to the upregulation of those RBPs, we analyzed non-synonymous mutations, CNAs, and targeting by tumor suppressor miRNAs.	('RBP', 'Gene', '5725', (73, 76))	('CNAs', 'Var', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('non-synonymous mutations', 'Var', (91, 115))	('RBP', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
136945	27287018	The impact of RBP alterations in cancer is still poorly appreciated.	('alterations', 'Var', (18, 29))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('RBP', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('RBP', 'Gene', '5725', (14, 17))
136947	27287018	We identified an interesting subset of aberrantly expressed RBPs implicated in splicing, pointing to an additional layer of alterations that could contribute to GBM development.	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('RBP', 'Gene', '5725', (60, 63))	('aberrantly expressed', 'Var', (39, 59))	('contribute', 'Reg', (147, 157))	('RBP', 'Gene', (60, 63))
136952	27287018	For instance, SF3B1, SRSF1, U2AF65, and CELF4 are often mutated in chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Disease', (67, 95))	('SRSF1', 'Gene', '6426', (21, 26))	('mutated', 'Var', (56, 63))	('SF3B1', 'Gene', (14, 19))	('U2AF65', 'Gene', (28, 34))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('CELF4', 'Gene', '56853', (40, 45))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (67, 95))	('U2AF65', 'Gene', '11338', (28, 34))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (67, 95))	('SF3B1', 'Gene', '23451', (14, 19))	('CELF4', 'Gene', (40, 45))	('SRSF1', 'Gene', (21, 26))
136953	27287018	Subsequent reports revealed that alterations in splicing factors occur in solid tumors, including neuroblastomas, pancreatic ductal adenocarcinoma, lung cancer, melanoma, colon cancer, and estrogen receptor-positive breast tumors.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (114, 146))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('occur', 'Reg', (65, 70))	('breast tumors', 'Phenotype', 'HP:0100013', (216, 229))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('colon cancer', 'Disease', 'MESH:D015179', (171, 183))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pancreatic ductal adenocarcinoma', 'Disease', (114, 146))	('splicing factors', 'MPA', (48, 64))	('lung cancer', 'Disease', (148, 159))	('colon cancer', 'Disease', (171, 183))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('solid tumors', 'Disease', (74, 86))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (114, 146))	('neuroblastomas', 'Phenotype', 'HP:0003006', (98, 112))	('alterations', 'Var', (33, 44))	('neuroblastomas', 'Disease', (98, 112))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('neuroblastomas', 'Disease', 'MESH:D009447', (98, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (171, 183))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('solid tumors', 'Disease', 'MESH:D009369', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('breast tumors', 'Disease', 'MESH:D001943', (216, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('breast tumors', 'Disease', (216, 229))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))
136958	27287018	For instance, genomic instability, a common feature in cancer, can be induced by RNA processing defects.	('genomic instability', 'CPA', (14, 33))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RNA processing', 'Protein', (81, 95))	('induced', 'Reg', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('defects', 'Var', (96, 103))
136959	27287018	One would expect that alterations in core splicing proteins, such as the ones encoded by SNRPB, could cause major disruptions in RNA processing, affecting the entire transcriptome in a global and homogeneous manner.	('RNA processing', 'MPA', (129, 143))	('cause', 'Reg', (102, 107))	('disruptions', 'Disease', (114, 125))	('alterations', 'Var', (22, 33))	('entire transcriptome', 'MPA', (159, 179))	('affecting', 'Reg', (145, 154))	('disruptions', 'Disease', 'MESH:D019958', (114, 125))	('SNRPB', 'Gene', (89, 94))
136960	27287018	In addition to its essential role in splicing, mutations in SNRPB are known to cause cerebro-costo-mandibular syndrome.	('cerebro-costo-mandibular syndrome', 'Disease', (85, 118))	('-mandibular', 'Phenotype', 'HP:0000303', (98, 109))	('mutations', 'Var', (47, 56))	('cerebro-costo-mandibular syndrome', 'Disease', 'MESH:D008336', (85, 118))	('cause', 'Reg', (79, 84))	('SNRPB', 'Gene', (60, 65))
136969	27287018	Additionally, we observed that knockdown of SNRPB altered multiple genes associated with critical genes/pathways relevant to GBM development (RTK, PI3K, MAPK, RAS, AKT, RB, and p53) and other cancer genes.	('AKT', 'Gene', (164, 167))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (192, 198))	('altered', 'Reg', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('AKT', 'Gene', '207', (164, 167))	('SNRPB', 'Gene', (44, 49))	('knockdown', 'Var', (31, 40))	('GBM', 'Phenotype', 'HP:0012174', (125, 128))
136970	27287018	Despite the need for a more detailed analysis to determine how alterations identified here affect protein function in specific ways to contribute to tumor initiation and growth, we conclude that our data suggest diverse routes by which SNRPB influences GBM development.	('alterations', 'Var', (63, 74))	('GBM', 'Phenotype', 'HP:0012174', (253, 256))	('tumor initiation', 'Disease', 'MESH:D009369', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('affect', 'Reg', (91, 97))	('GBM development', 'CPA', (253, 268))	('tumor initiation', 'Disease', (149, 165))	('influences', 'Reg', (242, 252))	('SNRPB', 'Gene', (236, 241))	('protein', 'Protein', (98, 105))
136988	27287018	A simulation with 100,000 random sets of 21 out of 1542 RBPs was performed to determine if our selected set presented enrichment for CNA and mutations.	('RBP', 'Gene', '5725', (56, 59))	('RBP', 'Gene', (56, 59))	('mutations', 'Var', (141, 150))	('CNA', 'Disease', (133, 136))
136990	27287018	A list containing frequently downregulated miRNAs in GBM (tumor suppressor miRNAs) was downloaded from Hermansen and Kristensen.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('miRNAs', 'Var', (43, 49))	('GBM', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('downregulated', 'NegReg', (29, 42))
137012	27287018	To identify splicing alterations produced by SNRPB knockdown, raw RNA-Seq reads of control and knockdown experiments were mapped against the human reference genome (hg19/GRCh37) and a reference transcriptome (GENCODE version 19) using GSNAP (version 2014-05-15).	('SNRPB', 'Gene', (45, 50))	('human', 'Species', '9606', (141, 146))	('splicing', 'MPA', (12, 20))	('knockdown', 'Var', (51, 60))
137035	25552286	A recently updated trial (RTOG 9802) comparing radiation therapy with or without procarbazine, CCNU and vincristine (PCV) reports improved progression-free as well as overall survival with addition of PCV, but ironically is infrequently used over the past decade to treat LGG.	('PCV', 'Var', (201, 204))	('LGG', 'Disease', (272, 275))	('CCNU', 'Gene', '10309', (95, 99))	('CCNU', 'Gene', (95, 99))	('procarbazine', 'Chemical', 'MESH:D011344', (81, 93))	('vincristine', 'Chemical', 'MESH:D014750', (104, 115))	('overall survival', 'CPA', (167, 183))	('progression-free', 'CPA', (139, 155))	('improved', 'PosReg', (130, 138))
137057	25552286	A number of molecular tumor markers have been associated with LGG overall survival including 1) combined deletions of chromosomes 1p and 19q 2) mutations in the Isocitrate dehydrogenase 1/2 (IDH1/2) genes and 3) methylation of the O-methylguanine-DNA methyltransferase (MGMT) gene.	('O-methylguanine-DNA methyltransferase', 'Gene', '4255', (231, 268))	('IDH1/2', 'Gene', (191, 197))	('O-methylguanine-DNA methyltransferase', 'Gene', (231, 268))	('deletions', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('MGMT', 'Gene', (270, 274))	('methylation', 'Var', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('MGMT', 'Gene', '4255', (270, 274))	('IDH1/2', 'Gene', '3417;3418', (191, 197))	('tumor', 'Disease', (22, 27))	('associated', 'Reg', (46, 56))	('mutations', 'Var', (144, 153))
137058	25552286	The high rate of p53 mutation/deletion in some gliomas as well as the belief that this change represents an early step in glioma development has led investigators to examine this alteration in association with LGG survival with inconsistent results.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Disease', (122, 128))	('glioma', 'Disease', (47, 53))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('mutation/deletion', 'Var', (21, 38))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
137059	25552286	Recent sequencing revealed mutations in two tumor suppressor genes (homolog of Drosophiliacapicua (CIC) on 19q and far-upstream binding protein 1 (FUBP1) on 1p in 38% and 14% of 21 oligo II (and 0/15 (0%) of astro II and 1/18 (6%) of mixed II).	('mutations', 'Var', (27, 36))	('FUBP1', 'Gene', '8880', (147, 152))	('CIC', 'Gene', '23152', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('far-upstream binding protein 1', 'Gene', (115, 145))	('CIC', 'Gene', (99, 102))	('FUBP1', 'Gene', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('far-upstream binding protein 1', 'Gene', '8880', (115, 145))	('astro II', 'Disease', (208, 216))	('tumor', 'Disease', (44, 49))
137060	25552286	Essentially all glioma with a CIC or FUBP1 mutation in that study also had an IDH gene mutation as well as co-deletion of 1p/19q.	('FUBP1', 'Gene', (37, 42))	('mutation', 'Var', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('CIC', 'Gene', '23152', (30, 33))	('glioma', 'Disease', (16, 22))	('FUBP1', 'Gene', '8880', (37, 42))	('CIC', 'Gene', (30, 33))	('IDH', 'Gene', (78, 81))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('mutation', 'Var', (87, 95))	('IDH', 'Gene', '3417', (78, 81))
137061	25552286	Jenkins et al found most 1p and 19q deletions in oligo II were the result of an unbalanced translocation between the whole chromosomal arms of 1p and 19q and that translocation/deletion was associated with significantly improved overall survival.	('improved', 'PosReg', (220, 228))	('deletions', 'Var', (36, 45))	('translocation/deletion', 'Var', (163, 185))	('most 1p', 'Gene', (20, 27))	('overall', 'MPA', (229, 236))	('unbalanced translocation', 'MPA', (80, 104))	('most 1p', 'Gene', '100507249', (20, 27))
137062	25552286	A recent notable finding is that mutations in the NADP+ dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in the majority of grade II (all subtypes) and III gliomas as well as secondary GBM but in only a minority of primary GBM.	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('IDH1', 'Gene', '3417', (103, 107))	('IDH2', 'Gene', (112, 116))	('occur', 'Reg', (117, 122))	('isocitrate', 'Chemical', 'MESH:C034219', (66, 76))	('mutations', 'Var', (33, 42))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('IDH2', 'Gene', '3418', (112, 116))	('grade II', 'Disease', (142, 150))	('gliomas', 'Disease', (174, 181))	('secondary GBM', 'Disease', (193, 206))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('IDH1', 'Gene', (103, 107))
137064	25552286	IDH mutations are associated with a glioma CpG island DNA hypermethylator phenotype (G-CIMP) and are associated with improved LGG survival as well as possible LGG response to treatment.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('improved', 'PosReg', (117, 125))	('glioma', 'Disease', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('mutations', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('LGG survival', 'CPA', (126, 138))
137065	25552286	Such data suggest that IDH mutations are an early step in the development of LGG.	('mutations', 'Var', (27, 36))	('LGG', 'Disease', (77, 80))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (23, 26))
137066	25552286	Methylation of MGMT (a DNA repair gene located on 10q) is a commonly observed change in LGG that predicts HGG response to treatment as well as overall survival; this change may confer chemo sensitivity in LGG by causing an altered response to TMZ (the primary agent used to treat LGG) although efforts to examine this are limited by small sample size.	('causing', 'Reg', (212, 219))	('altered', 'Reg', (223, 230))	('MGMT', 'Gene', '4255', (15, 19))	('MGMT', 'Gene', (15, 19))	('TMZ', 'Chemical', '-', (243, 246))	('response to TMZ', 'MPA', (231, 246))	('change', 'Var', (166, 172))
137067	25552286	There is evidence to suggest that a series of ordered genetic alterations occurs when progressing from LGG to HGG with TP53 mutation an early event.	('HGG', 'Disease', (110, 113))	('LGG', 'Disease', (103, 106))	('mutation', 'Var', (124, 132))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
137069	25552286	TP53 mutation is found in all LGG subtypes but is highly correlated with the proportion of tumor astrocytes.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('correlated', 'Reg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('mutation', 'Var', (5, 13))
137070	25552286	Interestingly, a recent study examined mutations in the chromatin modifier Alpha Thalassemia/Mental Retardation Syndrome X-linked (ATRX) (as well as CIC, FUBP1, and IDH1) and noted almost complete correlation between the presence of TP53 and ATRX mutations, regardless of LGG subtype.	('Mental Retardation', 'Phenotype', 'HP:0001249', (93, 111))	('ATRX', 'Gene', '546', (131, 135))	('Alpha Thalassemia/Mental Retardation Syndrome X-linked', 'Gene', '546', (75, 129))	('CIC', 'Gene', (149, 152))	('ATRX', 'Gene', '546', (242, 246))	('TP53', 'Gene', (233, 237))	('FUBP1', 'Gene', (154, 159))	('CIC', 'Gene', '23152', (149, 152))	('ATRX', 'Gene', (242, 246))	('mutations', 'Var', (39, 48))	('IDH1', 'Gene', (165, 169))	('FUBP1', 'Gene', '8880', (154, 159))	('mutations', 'Var', (247, 256))	('IDH1', 'Gene', '3417', (165, 169))	('ATRX', 'Gene', (131, 135))	('TP53', 'Gene', '7157', (233, 237))
137072	25552286	IDH1 mutation and 1p/19q deletion).	('IDH1', 'Gene', (0, 4))	('1p/19q deletion', 'Var', (18, 33))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
137075	25552286	Recently, several groups have presented results from larger case series: Using 271 LGG drawn from the Groupe Hospitalier Pitie-Salpetriere in Paris, Houillier et al tested whether TP53 mutation, 1p/19q co-deletion, MGMT promoter methylation, and IDH1 mutation predicted natural course of disease or response to treatment (alkylating agent/XRT) while controlling for extent of surgical resection.	('mutation', 'Var', (251, 259))	('IDH1', 'Gene', (246, 250))	('mutation', 'Var', (185, 193))	('TP53', 'Gene', (180, 184))	('MGMT', 'Gene', (215, 219))	('TP53', 'Gene', '7157', (180, 184))	('MGMT', 'Gene', '4255', (215, 219))	('IDH1', 'Gene', '3417', (246, 250))	('tested', 'Reg', (165, 171))	('predicted', 'Reg', (260, 269))
137077	25552286	IDH1 mutation and 1p/19q co-deletion was predictive of OS while IDH1 mutation, 1p/19q deletion and MGMT promoter methylation were each associated in univariate analyses with response to TMZ but small sample size precluded a multivariate analysis including the three markers simultaneously.	('IDH1', 'Gene', (64, 68))	('1p/19q deletion', 'Var', (79, 94))	('1p/19q', 'Var', (18, 24))	('mutation', 'Var', (69, 77))	('associated', 'Reg', (135, 145))	('IDH1', 'Gene', '3417', (64, 68))	('TMZ', 'Chemical', '-', (186, 189))	('MGMT', 'Gene', (99, 103))	('IDH1', 'Gene', (0, 4))	('MGMT', 'Gene', '4255', (99, 103))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
137080	25552286	IDH1 mutation and 1p/19q co-deletion were predictive of OS (and of PFS in persons receiving chemo/XRT at diagnosis).	('persons', 'Species', '9606', (74, 81))	('PFS', 'Disease', (67, 70))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
137083	25552286	The TCGA and others have recently defined and validated four gene-expression-based classification profiles for grade IV glioma (GBM): Proneural (notable for PDGFRA alterations, IDH1 and TP53 mutations, as well as oligodendroglioma cell type), Neural (associated with a variety of neuron markers and closest to normal brain), Classical (EGFR amplification and CDKN2A alterations) and Mesenchymal (NF1 and MET alterations).	('IDH1', 'Gene', (177, 181))	('NF1', 'Gene', '4763', (396, 399))	('Mesenchymal', 'CPA', (383, 394))	('IV glioma', 'Disease', (117, 126))	('CDKN2A', 'Gene', (359, 365))	('PDGFRA', 'Gene', (157, 163))	('EGFR', 'Gene', (336, 340))	('NF1', 'Gene', (396, 399))	('PDGFRA', 'Gene', '5156', (157, 163))	('mutations', 'Var', (191, 200))	('TP53', 'Gene', (186, 190))	('alterations', 'Var', (366, 377))	('IDH1', 'Gene', '3417', (177, 181))	('CDKN2A', 'Gene', '1029', (359, 365))	('oligodendroglioma', 'Disease', 'MESH:D009837', (213, 230))	('IV glioma', 'Disease', 'MESH:D005910', (117, 126))	('EGFR', 'Gene', '1956', (336, 340))	('oligodendroglioma', 'Disease', (213, 230))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Proneural', 'Disease', (134, 143))	('TP53', 'Gene', '7157', (186, 190))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('alterations', 'Var', (164, 175))
137091	25552286	This demonstrates that, in addition to the rare variation associated with Mendelian disorders, common genetic variation also contributes to glioma genesis.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('Mendelian disorders', 'Disease', 'MESH:D030342', (74, 93))	('glioma genesis', 'Disease', (140, 154))	('contributes', 'Reg', (125, 136))	('common genetic variation', 'Var', (95, 119))	('glioma genesis', 'Disease', 'MESH:D005910', (140, 154))	('Mendelian disorders', 'Disease', (74, 93))
137092	25552286	While rare heritable loss-of-function mutations in TP53 and p16 cause glioma-associated familial cancer syndromes, inherited SNPs near both these genes also appear to contribute to glioma genesis.	('glioma-associated familial cancer syndromes', 'Disease', (70, 113))	('p16', 'Gene', (60, 63))	('glioma genesis', 'Disease', (181, 195))	('TP53', 'Gene', (51, 55))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('loss-of-function', 'NegReg', (21, 37))	('glioma-associated familial cancer syndromes', 'Disease', 'MESH:D005910', (70, 113))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('p16', 'Gene', '1029', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('glioma genesis', 'Disease', 'MESH:D005910', (181, 195))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', '7157', (51, 55))
137093	25552286	In total, GWAS of glioma patients have identified 9 independently significant SNP associations located in 8 genes (Table 2).	('glioma', 'Disease', (18, 24))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('patients', 'Species', '9606', (25, 33))	('SNP associations', 'Var', (78, 94))
137099	25552286	In contrast, RTEL region polymorphisms were most strongly associated with grade IV but less so with grade II/III glioma risk.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('associated', 'Reg', (58, 68))	('RTEL', 'Gene', '51750', (13, 17))	('polymorphisms', 'Var', (25, 38))	('glioma', 'Disease', (113, 119))	('grade IV', 'Disease', (74, 82))	('RTEL', 'Gene', (13, 17))
137101	25552286	The CDKN2A/B region SNPs were also associated with Grade IV and grade II/III astrocytoms but not with oligo II/III.	('CDKN2A/B', 'Gene', (4, 12))	('Grade IV', 'Disease', (51, 59))	('associated', 'Reg', (35, 45))	('astrocytoms', 'Disease', (77, 88))	('SNPs', 'Var', (20, 24))	('CDKN2A/B', 'Gene', '1029;1030', (4, 12))	('grade II/III astrocytoms', 'Disease', (64, 88))
137104	25552286	A pooled analysis of the US/UK/German/French data confirmed these findings and found evidence of an additional independent association for glioma (regardless of grade) risk with rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene although interestingly this gene was not associated with survival.	('rs11979158', 'Mutation', 'rs11979158', (178, 188))	('glioma', 'Disease', (139, 145))	('rs11979158', 'Var', (178, 188))	('rs2252586', 'Mutation', 'rs2252586', (193, 202))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('EGFR', 'Gene', '1956', (236, 240))	('rs2252586', 'Var', (193, 202))	('EGFR', 'Gene', (236, 240))
137107	25552286	Jenkins et al further examine the CCDC26 (8q24) region and find strong association for a low frequency variant at 8q24.21 (rs55705857) associated with 1) oligo II/III regardless of IDH mutation status (OR=6.3, p=2.2x10-23), and 2) astro II-IV with mutated IDH1/IDH2 (OR=5.16-6.66, p=4.7x10-12 to 2.2x10-8) but not astrocytic tumors with wild type IDH1/IDH2.	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('rs55705857', 'Var', (123, 133))	('IDH1', 'Gene', (256, 260))	('associated', 'Reg', (135, 145))	('IDH', 'Gene', '3417', (352, 355))	('IDH2', 'Gene', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('IDH', 'Gene', '3417', (256, 259))	('IDH', 'Gene', (261, 264))	('IDH2', 'Gene', '3418', (261, 265))	('CCDC26', 'Gene', '137196', (34, 40))	('IDH1', 'Gene', '3417', (256, 260))	('IDH1', 'Gene', (347, 351))	('IDH', 'Gene', (181, 184))	('oligo II/III', 'Disease', (154, 166))	('CCDC26', 'Gene', (34, 40))	('IDH', 'Gene', (347, 350))	('IDH', 'Gene', '3417', (261, 264))	('rs55705857', 'Mutation', 'rs55705857', (123, 133))	('mutated', 'Var', (248, 255))	('IDH1', 'Gene', '3417', (347, 351))	('IDH2', 'Gene', (352, 356))	('astrocytic tumors', 'Disease', (314, 331))	('IDH', 'Gene', (352, 355))	('IDH', 'Gene', '3417', (181, 184))	('IDH', 'Gene', '3417', (347, 350))	('astro II-IV', 'Disease', (231, 242))	('IDH2', 'Gene', '3418', (352, 356))	('association', 'Interaction', (71, 82))	('IDH', 'Gene', (256, 259))	('astrocytic tumors', 'Disease', 'MESH:D001254', (314, 331))
137110	25552286	CCDC26 variants increase risk for oligodendroglial tumors regardless of IDH-mutation status and also for IDH-mutated astrocytoma.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CCDC26', 'Gene', (0, 6))	('astrocytoma', 'Disease', (117, 128))	('CCDC26', 'Gene', '137196', (0, 6))	('variants', 'Var', (7, 15))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('IDH', 'Gene', (105, 108))	('IDH', 'Gene', '3417', (105, 108))	('astrocytoma', 'Disease', 'MESH:D001254', (117, 128))
137111	25552286	SNPs near CDKN2B/ANRIL confer increased risk for astrocytic tumors of all grades, including glioblastomas, but are not associated with oligodendroglial tumors.	('glioblastomas', 'Phenotype', 'HP:0012174', (92, 105))	('CDKN2B', 'Gene', '1030', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('astrocytic tumors', 'Disease', 'MESH:D001254', (49, 66))	('ANRIL', 'Gene', '100048912', (17, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('SNPs', 'Var', (0, 4))	('glioblastomas', 'Disease', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('CDKN2B', 'Gene', (10, 16))	('tumors', 'Disease', (152, 158))	('ANRIL', 'Gene', (17, 22))	('astrocytic tumors', 'Disease', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumors', 'Disease', (60, 66))
137112	25552286	There are few studies of genetic polymorphism and survival after diagnosis of glioma; those that exist focus on HGG (no study includes more than 50 LGG patients) with examination of SNPs in genes involved in DNA repair, cell cycle regulation, and immune function as well as in tumor markers of note.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('glioma', 'Disease', (78, 84))	('SNPs', 'Var', (182, 186))	('tumor', 'Disease', (277, 282))	('patients', 'Species', '9606', (152, 160))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
137114	25552286	progressed from LGG) suggesting that SSBP2 germline variants and tumor expression (which were not linked to IDH mutation status) may be an important independent predictor of survival for LGG.	('germline', 'Var', (43, 51))	('tumor', 'Disease', (65, 70))	('IDH', 'Gene', (108, 111))	('SSBP2', 'Gene', (37, 42))	('IDH', 'Gene', '3417', (108, 111))	('LGG', 'Disease', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('SSBP2', 'Gene', '23635', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
137115	25552286	Dr. Bondy also examined associations with GBM survival with the 100 top-ranking glioma susceptibility polymorphisms identified from the two glioma GWAS and found that polymorphisms in the LIG4, HMGA2, BTBD2, and RTEL1 genes (all involved in the double-strand break repair pathway) were associated with GBM survival in the MDA GWAS cohort (although not confirmed in the validation set).	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('associated', 'Reg', (286, 296))	('LIG4', 'Gene', '3981', (188, 192))	('RTEL1', 'Gene', (212, 217))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('polymorphisms', 'Var', (167, 180))	('glioma GWAS', 'Disease', (140, 151))	('BTBD2', 'Gene', (201, 206))	('glioma', 'Disease', (80, 86))	('HMGA2', 'Gene', (194, 199))	('glioma GWAS', 'Disease', 'MESH:D005910', (140, 151))	('GBM survival', 'CPA', (302, 314))	('RTEL1', 'Gene', '51750', (212, 217))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('LIG4', 'Gene', (188, 192))	('BTBD2', 'Gene', '55643', (201, 206))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioma', 'Disease', (140, 146))	('HMGA2', 'Gene', '8091', (194, 199))
137116	25552286	Preliminary analyses from the UCSF/Mayo study indicate that the variant at 8q24.21 (rs55705857) associated so strongly with glioma risk appears to also be associated with survival.	('rs55705857', 'Var', (84, 94))	('glioma', 'Disease', (124, 130))	('associated', 'Reg', (96, 106))	('associated', 'Reg', (155, 165))	('Mayo', 'Species', '162683', (35, 39))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('rs55705857', 'Mutation', 'rs55705857', (84, 94))
137127	25467557	Using QLQ-C30, radiation treated patients compared to non-radiation patients reported lower physical functioning (p=0.002), role functioning (p=0.004), and more constipation problems (p<0.001).	('QLQ-C30', 'Var', (6, 13))	('constipation', 'Disease', (161, 173))	('role functioning', 'CPA', (124, 140))	('patients', 'Species', '9606', (33, 41))	('lower', 'NegReg', (86, 91))	('patients', 'Species', '9606', (68, 76))	('physical functioning', 'CPA', (92, 112))	('constipation', 'Phenotype', 'HP:0002019', (161, 173))	('constipation', 'Disease', 'MESH:D003248', (161, 173))	('non-radiation', 'Disease', 'MESH:D004194', (54, 67))	('non-radiation', 'Disease', (54, 67))
137129	25467557	Using QLQ-BN20, patients with deep tumors compared to cortical tumors reported more bladder control problems (p=0.016).	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('QLQ-BN20', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('deep tumors', 'Disease', (30, 41))	('patients', 'Species', '9606', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('bladder control problem', 'Phenotype', 'HP:0000020', (84, 107))	('bladder control', 'Phenotype', 'HP:0000020', (84, 99))	('bladder control', 'Disease', (84, 99))	('more', 'PosReg', (79, 83))	('deep tumors', 'Disease', 'MESH:D057887', (30, 41))	('cortical tumors', 'Disease', 'MESH:D016543', (54, 69))	('cortical tumors', 'Disease', (54, 69))	('bladder control problems', 'Phenotype', 'HP:0000020', (84, 108))
137176	25467557	Patients who received PORT reported more difficulty with physical (80 vs. 95, p=0.002) and role (79 vs. 94, p=0.004) functioning as wee as increased symptoms of constipation (20 vs. 4, p= 0.001) compared to those who did not receive PORT.	('constipation', 'Disease', (161, 173))	('PORT', 'Var', (22, 26))	('increased', 'PosReg', (139, 148))	('Patients', 'Species', '9606', (0, 8))	('constipation', 'Phenotype', 'HP:0002019', (161, 173))	('physical', 'CPA', (57, 65))	('constipation', 'Disease', 'MESH:D003248', (161, 173))
137234	23324827	IDH1(R132H) mutant protein immunohistochemistry was positive in all tissue components.	('IDH1', 'Gene', (0, 4))	('R132H', 'SUBSTITUTION', 'None', (5, 10))	('R132H', 'Var', (5, 10))
137235	23324827	Alterations identified in all samples included dup(1)(q21q41), del(1)(q41qter), del(2)(q31.1), del(2)(q36.3qter), del(4)(q35.1qter), dup(7)(q22.2q36.3), del(7)(q36.3qter), del(9)(p21.3pter), dup(10)(p13pter), del(10) (q26.13q26.3), dup(17) (q12qter), and copy neutral LOH(20)(p11.23p11.21).	('p11', 'Gene', '6281', (282, 285))	('p21', 'Gene', (179, 182))	('del(2)(q31.1', 'Var', (80, 92))	('dup(10', 'Var', (191, 197))	('p11', 'Gene', '6281', (276, 279))	('dup(1)(q21q41', 'Var', (47, 60))	('dup(17) (q12qter', 'Var', (232, 248))	('copy neutral LOH(20', 'Var', (255, 274))	('dup(7)(q22.2q36.3', 'Var', (133, 150))	('p21', 'Gene', '644914', (179, 182))	('del(4)(q35.1qter', 'Var', (114, 130))	('del(1)(q41qter', 'Var', (63, 77))	('p11', 'Gene', (282, 285))	('del(10) (q26.13q26.3', 'Var', (209, 229))	('del(2)(q36.3qter', 'Var', (95, 111))	('p11', 'Gene', (276, 279))	('del(7)(q36.3qter', 'Var', (153, 169))
137236	23324827	The recurrent tumor had additional alterations, including del(3)(p21.31q13.31), del(18) (q21.2qter), and a homozygous del(9)(p21.3)(CDKN2A locus) and the sarcoma component had, in addition, del(4)(p14pter), del(6)(q12qter), del(11)(q24.3qter), and del(16)(p11.2pter).	('CDKN2A', 'Gene', (132, 138))	('del(11)(q24.3qter', 'Var', (224, 241))	('tumor', 'Disease', (14, 19))	('del(6)(q12qter', 'Var', (207, 221))	('p21', 'Gene', (65, 68))	('CDKN2A', 'Gene', '1029', (132, 138))	('del(4)(p14pter', 'Var', (190, 204))	('del(18) (q21.2qter', 'Var', (80, 98))	('p21', 'Gene', '644914', (65, 68))	('p11', 'Gene', '6281', (256, 259))	('p21', 'Gene', (125, 128))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('p21', 'Gene', '644914', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('p11', 'Gene', (256, 259))
137237	23324827	In conclusion, unique copy number alterations were identified during tumor progression from a low-grade glioma to gliosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('glioma to gliosarcoma', 'Disease', 'MESH:D018316', (104, 125))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('glioma to gliosarcoma', 'Disease', (104, 125))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('copy number alterations', 'Var', (22, 45))
137247	23324827	In a small series of GS, examination of microdissected tissue from both the glial and sarcomatous components revealed PTEN mutations, TP53 mutation, p16 deletion, and amplification of MDM2 and CDK4 in both tissue components.	('MDM2', 'Gene', (184, 188))	('p16', 'Gene', '1029', (149, 152))	('CDK4', 'Gene', (193, 197))	('deletion', 'Var', (153, 161))	('mutation', 'Var', (139, 147))	('TP53', 'Gene', (134, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('amplification', 'Reg', (167, 180))	('CDK4', 'Gene', '1019', (193, 197))	('PTEN', 'Gene', '5728', (118, 122))	('sarcomatous component', 'Disease', 'MESH:D018316', (86, 107))	('sarcomatous component', 'Disease', (86, 107))	('PTEN', 'Gene', (118, 122))	('p16', 'Gene', (149, 152))	('GS', 'Disease', 'MESH:D011125', (21, 23))	('TP53', 'Gene', '7157', (134, 138))	('mutations', 'Var', (123, 132))	('MDM2', 'Gene', '4193', (184, 188))
137250	23324827	We report a case of true secondary GS arising in the absence of previous therapy in which we separately analyzed copy number alterations in the primary low-grade tumor and in the glial and sarcomatous components at the time of tumor progression.	('copy', 'Var', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('sarcomatous component', 'Disease', 'MESH:D018316', (189, 210))	('tumor', 'Disease', (227, 232))	('sarcomatous component', 'Disease', (189, 210))	('tumor', 'Disease', (162, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('GS', 'Disease', 'MESH:D011125', (35, 37))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
137254	23324827	Immunohistochemistry was performed using antibodies against glial fibrillary acidic protein (GFAP; prediluted, rabbit monoclonal; Ventana, Tucson, AZ, USA), p53 (clone BP53-11; Ventana; prediluted), Ki-67 (MIB1; Ventana; 1:1,000), and IDH1(R132H) (clone H09; Dianova; 1:50).	('p53', 'Gene', '7157', (157, 160))	('glial fibrillary acidic protein', 'Gene', '2670', (60, 91))	('GFAP', 'Gene', '2670', (93, 97))	('rabbit', 'Species', '9986', (111, 117))	('R132H', 'SUBSTITUTION', 'None', (240, 245))	('MIB1', 'Gene', '57534', (206, 210))	('BP53', 'Gene', (168, 172))	('BP53', 'Gene', '474209', (168, 172))	('MIB1', 'Gene', (206, 210))	('p53', 'Gene', (157, 160))	('R132H', 'Var', (240, 245))	('glial fibrillary acidic protein', 'Gene', (60, 91))	('GFAP', 'Gene', (93, 97))
137263	23324827	Mutant IDH1(R132H) protein was expressed in both tissue components (Fig.	('R132H', 'Var', (12, 17))	('IDH1', 'Gene', (7, 11))	('R132H', 'SUBSTITUTION', 'None', (12, 17))
137272	23324827	Genes localized to areas of deletion unique to the sarcomatous component of the tumor at histologic progression included BAI3, DDX43, SESN1, ROS1, WISP3, and MYCT1 in Chr6(q12qter) and TSC2, RAB26, AXIN1, BAIAP3, LITAF, and MAZ in Chr 16(p11.2pter).	('SESN1', 'Gene', (134, 139))	('LITAF', 'Gene', '9516', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MAZ', 'Gene', '4150', (224, 227))	('AXIN1', 'Gene', (198, 203))	('sarcomatous component of the tumor', 'Disease', (51, 85))	('WISP3', 'Gene', (147, 152))	('MYCT1', 'Gene', (158, 163))	('BAI3', 'Gene', (121, 125))	('BAIAP3', 'Gene', (205, 211))	('ROS1', 'Gene', (141, 145))	('sarcomatous component of the tumor', 'Phenotype', 'HP:0100242', (51, 85))	('WISP3', 'Gene', '8838', (147, 152))	('DDX43', 'Gene', '55510', (127, 132))	('MYCT1', 'Gene', '80177', (158, 163))	('TSC2', 'Gene', '7249', (185, 189))	('p11', 'Gene', '6281', (238, 241))	('BAI3', 'Gene', '577', (121, 125))	('SESN1', 'Gene', '27244', (134, 139))	('RAB26', 'Gene', '25837', (191, 196))	('MAZ', 'Gene', (224, 227))	('AXIN1', 'Gene', '8312', (198, 203))	('p11', 'Gene', (238, 241))	('deletion', 'Var', (28, 36))	('BAIAP3', 'Gene', '8938', (205, 211))	('RAB26', 'Gene', (191, 196))	('TSC2', 'Gene', (185, 189))	('LITAF', 'Gene', (213, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomatous component of the tumor', 'Disease', 'MESH:D018316', (51, 85))	('ROS1', 'Gene', '6098', (141, 145))	('DDX43', 'Gene', (127, 132))
137274	23324827	IDH1 and 2 mutations are early events in infiltrating gliomas, and supported the bona fide secondary GS nature of this case.	('mutations', 'Var', (11, 20))	('IDH1 and 2', 'Gene', '3417;3418', (0, 10))	('GS', 'Disease', 'MESH:D011125', (101, 103))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
137275	23324827	The deletion at Chr 3(p21.31q13.31)] is commonly found in solid tumors and is believed to harbor several known and putative tumor suppressors.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', (58, 70))	('tumor', 'Disease', (124, 129))	('p21', 'Gene', (22, 25))	('p21', 'Gene', '644914', (22, 25))	('deletion', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('solid tumors', 'Disease', 'MESH:D009369', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
137277	23324827	RASSF1A may be involved in the pathogenesis of gliomas, because it has been found to be down-regulated in gliomas by promoter methylation.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('RASSF1A', 'Gene', (0, 7))	('promoter methylation', 'Var', (117, 137))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('gliomas', 'Disease', (47, 54))	('RASSF1A', 'Gene', '11186', (0, 7))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('down-regulated', 'NegReg', (88, 102))	('involved', 'Reg', (15, 23))
137278	23324827	Epigenetic silencing of RASSF1A by promoter methylation also correlates with tumor grade in gliomas.	('RASSF1A', 'Gene', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Epigenetic silencing', 'Var', (0, 20))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('RASSF1A', 'Gene', '11186', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('tumor', 'Disease', (77, 82))	('correlates', 'Reg', (61, 71))
137279	23324827	Deregulation of RASSF1A is observed in other histologic types of central nervous system neoplasms, including primitive neuroectodermal tumors and medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (146, 161))	('neuroectodermal tumors', 'Disease', (119, 141))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (119, 141))	('medulloblastoma', 'Disease', (146, 161))	('Deregulation', 'Var', (0, 12))	('central nervous system neoplasms', 'Disease', 'MESH:D016543', (65, 97))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (109, 141))	('observed', 'Reg', (27, 35))	('central nervous system neoplasms', 'Disease', (65, 97))	('RASSF1A', 'Gene', (16, 23))	('medulloblastoma', 'Disease', 'MESH:D008527', (146, 161))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (119, 141))	('neoplasm', 'Phenotype', 'HP:0002664', (88, 96))	('RASSF1A', 'Gene', '11186', (16, 23))
137280	23324827	Although RASSF1A is typically silenced by promoter methylation in a variety of neoplasms, there are limited cases in which mutations have been identified.	('neoplasms', 'Disease', (79, 88))	('promoter methylation', 'Var', (42, 62))	('neoplasm', 'Phenotype', 'HP:0002664', (79, 87))	('neoplasms', 'Disease', 'MESH:D009369', (79, 88))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))	('RASSF1A', 'Gene', (9, 16))	('RASSF1A', 'Gene', '11186', (9, 16))
137281	23324827	Abnormalities of FOXP1 expression have been identified in several solid organ tumors and cancer cell lines, although no specific relationship is seen for gliomas.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Abnormalities', 'Var', (0, 13))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('FOXP1', 'Gene', '27086', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('cancer', 'Disease', (89, 95))	('gliomas', 'Disease', (154, 161))	('FOXP1', 'Gene', (17, 22))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('identified', 'Reg', (44, 54))	('expression', 'MPA', (23, 33))
137282	23324827	Interestingly, loss of PHLPP1(18q) has recently been found to act synergistically with loss of PTEN in glioblastoma.	('loss', 'Var', (15, 19))	('PHLPP1', 'Gene', (23, 29))	('PTEN', 'Gene', (95, 99))	('PHLPP1', 'Gene', '23239', (23, 29))	('glioblastoma', 'Disease', (103, 115))	('PTEN', 'Gene', '5728', (95, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
137284	23324827	Deletion of this gene is frequently seen with associated loss of MTAP in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('MTAP', 'Gene', '4507', (65, 69))	('glioblastoma', 'Disease', (73, 85))	('loss', 'NegReg', (57, 61))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('MTAP', 'Gene', (65, 69))	('Deletion', 'Var', (0, 8))
137285	23324827	The p16/INK4A pathway is altered in both primary and secondary GBM via both deletions/mutations and promoter methylation.	('altered', 'Reg', (25, 32))	('deletions/mutations', 'Var', (76, 95))	('INK4A', 'Gene', '1029', (8, 13))	('p16', 'Gene', '1029', (4, 7))	('p16', 'Gene', (4, 7))	('INK4A', 'Gene', (8, 13))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('promoter methylation', 'Var', (100, 120))
137286	23324827	In a study of GS by Reis et al., p16 deletion was restricted to the sarcomatous region in a GS for which both glial and sarcoma portions were analyzed separately.	('GS', 'Disease', 'MESH:D011125', (14, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('p16', 'Gene', (33, 36))	('deletion', 'Var', (37, 45))	('sarcomatous', 'Disease', 'MESH:D018316', (68, 79))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('p16', 'Gene', '1029', (33, 36))	('GS', 'Disease', 'MESH:D011125', (92, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('sarcomatous', 'Disease', (68, 79))	('sarcoma', 'Disease', (68, 75))	('sarcoma', 'Disease', (120, 127))	('sarcomatous region', 'Phenotype', 'HP:0100242', (68, 86))
137288	23324827	Loss of p16 leads to deregulation of the cell cycle, because p16 binds to CDK4, ultimately inhibiting transition to the S phase.	('inhibiting', 'NegReg', (91, 101))	('binds', 'Interaction', (65, 70))	('p16', 'Gene', '1029', (8, 11))	('cell cycle', 'CPA', (41, 51))	('p16', 'Gene', (61, 64))	('transition to the S phase', 'CPA', (102, 127))	('CDK4', 'Gene', (74, 78))	('CDK4', 'Gene', '1019', (74, 78))	('deregulation', 'MPA', (21, 33))	('p16', 'Gene', (8, 11))	('p16', 'Gene', '1029', (61, 64))	('Loss', 'Var', (0, 4))
137289	23324827	Copy number alterations unique to the sarcomatous component may be of particular interest in our case because they may reveal some of the factors associated with sequential progression.	('sarcomatous component', 'Disease', 'MESH:D018316', (38, 59))	('sarcomatous component', 'Disease', (38, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('Copy number alterations', 'Var', (0, 23))	('reveal', 'Reg', (119, 125))
137297	23324827	There are limited data indicating a relationship between TSC2 alterations and high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('TSC2', 'Gene', '7249', (57, 61))	('TSC2', 'Gene', (57, 61))	('alterations', 'Var', (62, 73))
137301	23324827	Some of the alterations in early sarcomatous transformation in this unique glioma example may also provide important biological clues about mesenchymal induction in cancer.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('sarcomatous', 'Disease', 'MESH:D018316', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('alterations', 'Var', (12, 23))	('glioma', 'Disease', (75, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomatous', 'Disease', (33, 44))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (33, 59))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
137307	23324827	In addition, several molecular alterations, for example CDKN2A deletions are more typically seen in higher-grade neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (113, 122))	('deletions', 'Var', (63, 72))	('seen', 'Reg', (92, 96))	('CDKN2A', 'Gene', (56, 62))	('neoplasm', 'Phenotype', 'HP:0002664', (113, 121))	('neoplasms', 'Disease', 'MESH:D009369', (113, 122))	('neoplasms', 'Disease', (113, 122))	('CDKN2A', 'Gene', '1029', (56, 62))
137308	23324827	IDH1(R132H) mutations occur in a small (7 %) subset of gliosarcomas, but the imaging features (lack of contrast enhancement) and pathologic characteristics, including lack of mitotic activity and very low ki67 labeling index, in a well sampled specimen are all supportive of the diagnosis despite the unusual age.	('gliosarcomas', 'Disease', 'MESH:D018316', (55, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('mutations', 'Var', (12, 21))	('R132H', 'Var', (5, 10))	('mitotic activity', 'CPA', (175, 191))	('ki67 labeling index', 'MPA', (205, 224))	('R132H', 'SUBSTITUTION', 'None', (5, 10))	('gliosarcomas', 'Disease', (55, 67))
137311	23324827	In conclusion, we report a rare case of secondary GS arising in the absence of previous radiotherapy for which we were able to identify unique copy number alterations seen during tumor progression from a low-grade glioma to GS.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('copy number alterations', 'Var', (143, 166))	('glioma', 'Disease', (214, 220))	('GS', 'Disease', 'MESH:D011125', (50, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('GS', 'Disease', 'MESH:D011125', (224, 226))	('tumor', 'Disease', (179, 184))
137313	23324827	Notably, several tumor suppressors are present in these deletions, and these molecular pathways may be important for tumor progression from low to high-grade astrocytoma and maybe from glioma to sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('important', 'Reg', (103, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (17, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('deletions', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('astrocytoma', 'Disease', 'MESH:D001254', (158, 169))	('astrocytoma', 'Disease', (158, 169))	('glioma to sarcoma', 'Disease', 'MESH:D005910', (185, 202))	('glioma to sarcoma', 'Disease', (185, 202))
137323	33579299	At last, we demonstrated that high FCER1G levels presented great immunotherapeutic response in glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('immunotherapeutic response', 'CPA', (65, 91))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', (95, 101))	('high', 'Var', (30, 34))	('FCER1G', 'Gene', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
137333	33579299	Currently, cancer immunotherapy based on immune checkpoint blockades (ICBs), notably anti-CTLA4 (cytotoxic T-lymphocyte associated protein 4), anti-PDCD1/PD-1 (programmed cell death 1), anti-CD274/PD-L1, has emerged as a revolutionary treatment for patients with advanced highly aggressive therapy-resistant tumors.	('programmed cell death 1', 'Gene', '100533201', (160, 183))	('anti-CD274/PD-L1', 'Var', (186, 202))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cytotoxic T-lymphocyte associated protein 4', 'Gene', '397286', (97, 140))	('patients', 'Species', '9606', (249, 257))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('anti-PDCD1/PD-1', 'Var', (143, 158))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cytotoxic T-lymphocyte associated protein 4', 'Gene', (97, 140))	('anti-CTLA4', 'Var', (85, 95))	('cancer', 'Disease', (11, 17))	('programmed cell death 1', 'Gene', (160, 183))	('tumors', 'Disease', (308, 314))
137368	33579299	Specifically speaking, patients with high expression level of FCER1G showed a shorter overall survival (OS), progression-free interval (PFI) and disease-specific survival (DSS) than low expression patients both in LGG and GBM cohort (Fig.	('GBM', 'Phenotype', 'HP:0012174', (222, 225))	('patients', 'Species', '9606', (197, 205))	('patients', 'Species', '9606', (23, 31))	('FCER1G', 'Gene', (62, 68))	('progression-free interval', 'CPA', (109, 134))	('disease-specific', 'MPA', (145, 161))	('high expression level', 'Var', (37, 58))	('shorter', 'NegReg', (78, 85))	('overall survival', 'MPA', (86, 102))
137385	33579299	To improve the stability of the results, a fixed effects model was employed to pool the HRs of the six cohorts, and the result also validated that patients with high level of FCER1G expression exerted shorter OS times than patients with low expression level (RR = 1.30, 95 % CI  1.24-1.38, Fig.	('FCER1G', 'Gene', (175, 181))	('patients', 'Species', '9606', (147, 155))	('shorter', 'NegReg', (201, 208))	('patients', 'Species', '9606', (223, 231))	('high level', 'Var', (161, 171))	('OS times', 'MPA', (209, 217))
137388	33579299	Through univariate analysis of clinical characteristics, we found that FCER1G was more likely to be associated with older age (P = 0.002), high malignancy (P < 0.001), GBM type (P < 0.001), post-operative relapse (P < 0.001), poorer survival (P < 0.001), IDH wild type (P < 0.001), and different therapeutic options (Radiotherapy, P = 0.047; chemotherapy, P = 0.009), however, there is no significant differences in gender (Table 1).	('IDH', 'Gene', (255, 258))	('IDH', 'Gene', '3417', (255, 258))	('GBM', 'Phenotype', 'HP:0012174', (168, 171))	('high malignancy', 'Disease', 'MESH:D009369', (139, 154))	('FCER1G', 'Var', (71, 77))	('poorer survival', 'CPA', (226, 241))	('high malignancy', 'Disease', (139, 154))
137399	33579299	The result showed that FCER1G had a closely interactions with FCGR3A, ITGB2, LYN, SYK, in which FCER1G acts as a core gene (Fig.	('FCGR3A', 'Gene', (62, 68))	('FCER1G', 'Var', (96, 102))	('SYK', 'Gene', (82, 85))	('ITGB2', 'Gene', (70, 75))	('FCGR3A', 'Gene', '2214', (62, 68))	('SYK', 'Gene', '6850', (82, 85))	('LYN', 'Gene', '4067', (77, 80))	('LYN', 'Gene', (77, 80))	('ITGB2', 'Gene', '3689', (70, 75))	('interactions', 'Interaction', (44, 56))
137413	33579299	Patients with high FCER1G expression showed high levels of the therapeutic targets PD1, PDL1 and CTLA4, which indicated a hypothetic treatment as immune checkpoint.	('high', 'Var', (14, 18))	('CTLA4', 'MPA', (97, 102))	('FCER1G', 'Gene', (19, 25))	('Patients', 'Species', '9606', (0, 8))
137414	33579299	Patients with high FCER1G expression get higher scores in the TIS signature (P < 0.001), reporting to be correlated with response to anti PDL1 checkpoint inhibitor pembrolizumab, which supporting the hypothesis (Fig.	('pembrolizumab', 'Chemical', 'MESH:C582435', (164, 177))	('FCER1G', 'Gene', (19, 25))	('TIS signature', 'MPA', (62, 75))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (41, 47))
137416	33579299	The ImmuCellAI predicted that patients with high FCER1G levels were more likely to respond to immunotherapy (81.6 %, 413/506, CGGA) than low FCER1G subgroup (52.5 %, 266/507, CGGA.	('FCER1G', 'Gene', (49, 55))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (44, 48))	('respond', 'CPA', (83, 90))
137431	33579299	Furthermore, we illustrated gene FCER1G as a novel diagnostic and therapeutic target for the first time, which stratified glioma cases into high and low FCER1G expression subgroups that demonstrated with distinct clinical outcomes.	('expression', 'MPA', (160, 170))	('FCER1G', 'Gene', (153, 159))	('high', 'Var', (140, 144))	('glioma', 'Disease', (122, 128))	('low', 'NegReg', (149, 152))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
137442	33579299	Notably, patients with high FCER1G expression showed high levels of the therapeutic targets PDL1 and CTLA4, which indicated a hypothetic treatment as immune checkpoint.	('patients', 'Species', '9606', (9, 17))	('FCER1G', 'Gene', (28, 34))	('high', 'Var', (23, 27))	('CTLA4', 'Gene', (101, 106))
137446	33579299	The possibility of immunotherapy response was predicted in patients with gliomas by ImmuCellAI, SubMap and TIDE algorithm, both of which suggested that high levels of FCER1G tended to more likely respond to immunotherapy.	('respond to immunotherapy', 'CPA', (196, 220))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('FCER1G', 'Gene', (167, 173))	('more', 'PosReg', (184, 188))	('high levels', 'Var', (152, 163))	('patients', 'Species', '9606', (59, 67))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', (73, 80))
137468	32922947	Multiple retrospective studies and large meta-analyses have demonstrated that, regardless of low- or high-grade, primary or recurrent, greater EOR can significantly prolong both progression-free survival (PFS) and overall survival (OS) of diffuse gliomas compared with partial resection or biopsy.	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('progression-free survival', 'CPA', (178, 203))	('EOR', 'Var', (143, 146))	('overall survival', 'CPA', (214, 230))	('EOR', 'Chemical', '-', (143, 146))	('gliomas', 'Disease', (247, 254))	('gliomas', 'Disease', 'MESH:D005910', (247, 254))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))	('prolong', 'PosReg', (165, 172))
137476	32922947	Studies have confirmed that, although IDH mutation occurs in the early stages of glioma formation and may affect DNA demethylation and lead to tumorigenesis, the exact mechanism remains unclear.	('lead to', 'Reg', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('DNA demethylation', 'MPA', (113, 130))	('tumor', 'Disease', (143, 148))	('IDH', 'Gene', (38, 41))	('IDH', 'Gene', '3417', (38, 41))	('glioma', 'Disease', (81, 87))	('mutation', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('affect', 'Reg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
137477	32922947	IDH mutation is often associated with p53 mutation, 1p/19q codeletion, or alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation and commonly occurs in low-grade gliomas and secondary glioblastomas (GBMs), but are rare in primary GBMs.	('mental retardation', 'Phenotype', 'HP:0001249', (92, 110))	('GBMs', 'Phenotype', 'HP:0012174', (246, 250))	('1p/19q codeletion', 'Var', (52, 69))	('mutation', 'Var', (4, 12))	('gliomas', 'Disease', (178, 185))	('IDH', 'Gene', (0, 3))	('occurs', 'Reg', (158, 164))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (80, 128))	('mutation', 'Var', (42, 50))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('glioblastomas', 'Phenotype', 'HP:0012174', (200, 213))	('associated', 'Reg', (22, 32))	('p53', 'Gene', '7157', (38, 41))	('ATRX', 'Gene', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('mutation', 'Var', (136, 144))	('IDH', 'Gene', '3417', (0, 3))	('ATRX', 'Gene', '546', (130, 134))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('glioblastomas', 'Disease', (200, 213))	('p53', 'Gene', (38, 41))	('GBMs', 'Phenotype', 'HP:0012174', (215, 219))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (80, 128))	('glioblastomas', 'Disease', 'MESH:D005909', (200, 213))
137484	32922947	Similarly, another study found that EOR affected the prognosis of patients with malignant diffuse astrocytoma (WHO grade 3/4) differently according to IDH mutation expression.	('affected', 'Reg', (40, 48))	('astrocytoma', 'Phenotype', 'HP:0009592', (98, 109))	('IDH', 'Gene', '3417', (151, 154))	('EOR', 'Chemical', '-', (36, 39))	('malignant diffuse astrocytoma', 'Disease', 'MESH:D020339', (80, 109))	('patients', 'Species', '9606', (66, 74))	('mutation', 'Var', (155, 163))	('malignant diffuse astrocytoma', 'Disease', (80, 109))	('IDH', 'Gene', (151, 154))
137485	32922947	The authors revealed that residual enhancing tissue decreases OS in those with malignant diffuse astrocytoma of IDH wild-type, while residual either enhancing or non-enhancing tissue decreases OS of malignant diffuse astrocytoma with IDH mutation.	('IDH', 'Gene', (234, 237))	('malignant diffuse astrocytoma', 'Disease', 'MESH:D020339', (79, 108))	('decreases', 'NegReg', (52, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (217, 228))	('IDH', 'Gene', '3417', (234, 237))	('malignant diffuse astrocytoma', 'Disease', (199, 228))	('malignant diffuse astrocytoma', 'Disease', (79, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('decreases', 'NegReg', (183, 192))	('IDH', 'Gene', (112, 115))	('mutation', 'Var', (238, 246))	('malignant diffuse astrocytoma', 'Disease', 'MESH:D020339', (199, 228))	('IDH', 'Gene', '3417', (112, 115))
137490	32922947	1p/19q chromosome codeletion results in the mutation of the FUBP1 and CIC genes, which promote tumorigenesis and cell proliferation.	('cell proliferation', 'CPA', (113, 131))	('CIC genes', 'Gene', (70, 79))	('results in', 'Reg', (29, 39))	('mutation', 'Var', (44, 52))	('FUBP1', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('FUBP1', 'Gene', '8880', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('promote', 'PosReg', (87, 94))	('tumor', 'Disease', (95, 100))
137491	32922947	In addition, 1p/19q chromosome codeletion can improve the treatment effect of chemotherapy drugs such as procarbazine, lomustine, and vincristine (i.e., PCV) and temozolomide (TMZ), which further results in prognostic improvement.	('procarbazine', 'Chemical', 'MESH:D011344', (105, 117))	('1p/19q chromosome codeletion', 'Var', (13, 41))	('TMZ', 'Chemical', 'MESH:D000077204', (176, 179))	('vincristine', 'Chemical', 'MESH:D014750', (134, 145))	('lomustine', 'Chemical', 'MESH:D008130', (119, 128))	('temozolomide', 'Chemical', 'MESH:D000077204', (162, 174))	('improvement', 'PosReg', (218, 229))	('treatment', 'MPA', (58, 67))	('improve', 'PosReg', (46, 53))
137492	32922947	GTR is not always recommended for diffuse gliomas with IDH mutation and 1p/19q codeletion, especially for those located in the eloquent area.	('GTR', 'Chemical', '-', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH', 'Gene', (55, 58))	('1p/19q codeletion', 'Var', (72, 89))	('IDH', 'Gene', '3417', (55, 58))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
137493	32922947	A previous study demonstrated that, in low-grade diffuse gliomas with IDH mutation and 1p/19q codeletion, GTR would not significantly prolong OS.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('mutation', 'Var', (74, 82))	('1p/19q codeletion', 'Var', (87, 104))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (70, 73))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('GTR', 'Chemical', '-', (106, 109))
137494	32922947	Compared with IDH-mutant astrocytoma, a small residue in low-grade diffuse glioma with IDH mutation and 1p/19q codeletion is acceptable for its slight impact on OS, which is in accordance with previous studies.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('IDH', 'Gene', (14, 17))	('astrocytoma', 'Disease', (25, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('IDH', 'Gene', '3417', (14, 17))	('IDH', 'Gene', (87, 90))	('1p/19q', 'Var', (104, 110))	('glioma', 'Disease', (75, 81))	('IDH', 'Gene', '3417', (87, 90))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('astrocytoma', 'Disease', 'MESH:D001254', (25, 36))
137495	32922947	suggested that EOR affects the prognosis of lower-grade diffuse gliomas with IDH mutation and 1p/19q codeletion (WHO grade 2/3), and GTR should be recommended if the tumor is located in the non-eloquent area.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('IDH', 'Gene', '3417', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('affects', 'Reg', (19, 26))	('EOR', 'Chemical', '-', (15, 18))	('tumor', 'Disease', (166, 171))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('1p/19q codeletion', 'Var', (94, 111))	('IDH', 'Gene', (77, 80))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('GTR', 'Chemical', '-', (133, 136))
137498	32922947	Regarding anaplastic gliomas with IDH mutation and 1p/19q codeletion (WHO grade 3), GTR also has no significant survival benefit compared with partial resection, which may be associated with sensitivity to postoperative chemotherapy.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('1p/19q codeletion', 'Var', (51, 68))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('gliomas', 'Disease', (21, 28))	('GTR', 'Chemical', '-', (84, 87))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
137504	32922947	MGMT promoter methylation helps to improve EOR.	('MGMT', 'Gene', (0, 4))	('EOR', 'Chemical', '-', (43, 46))	('EOR', 'MPA', (43, 46))	('methylation', 'Var', (14, 25))	('improve', 'PosReg', (35, 42))	('MGMT', 'Gene', '4255', (0, 4))
137505	32922947	In MGMT promoter methylated GBMs, intraoperative ultrasound, intraoperative MRI, and 5-aminolevulinic acid (5-ALA) fluorescence staining can more accurately determine tumor boundaries, reduce the false-negative rate, and, ultimately, improve EOR.	('false-negative', 'MPA', (196, 210))	('MGMT', 'Gene', (3, 7))	('MGMT', 'Gene', '4255', (3, 7))	('EOR', 'Chemical', '-', (242, 245))	('EOR', 'MPA', (242, 245))	('methylated', 'Var', (17, 27))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (85, 106))	('improve', 'PosReg', (234, 241))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('reduce', 'NegReg', (185, 191))	('5-ALA', 'Chemical', 'MESH:C000614854', (108, 113))	('GBMs', 'Phenotype', 'HP:0012174', (28, 32))	('tumor', 'Disease', (167, 172))
137510	32922947	found that MGMT promoter methylated was a prognostic factor for improved OS in GBMs with complete removal of enhancing tissue.	('MGMT', 'Gene', '4255', (11, 15))	('MGMT', 'Gene', (11, 15))	('methylated', 'Var', (25, 35))	('GBMs', 'Phenotype', 'HP:0012174', (79, 83))	('improved', 'PosReg', (64, 72))
137515	32922947	EGFRvIII sustainably activates the P13K/Akt pathway independent of specific receptor binding, thereby promoting GBM cell proliferation, reducing apoptosis, and increasing angiogenesis and invasiveness.	('GBM cell proliferation', 'CPA', (112, 134))	('increasing', 'PosReg', (160, 170))	('EGFR', 'Gene', (0, 4))	('reducing', 'NegReg', (136, 144))	('Akt', 'Gene', '207', (40, 43))	('Akt', 'Gene', (40, 43))	('angiogenesis', 'CPA', (171, 183))	('P13K', 'Var', (35, 39))	('activates', 'PosReg', (21, 30))	('promoting', 'PosReg', (102, 111))	('invasiveness', 'CPA', (188, 200))	('EGFR', 'Gene', '1956', (0, 4))	('apoptosis', 'CPA', (145, 154))	('P13K', 'SUBSTITUTION', 'None', (35, 39))
137524	32922947	The nanoprobe overcomes navigational bias caused by brain shift and accurately divides the borders of GBMs, which is expected to improve EOR and prognosis of GBMs with the EGFRvIII deletion mutation.	('EGFR', 'Gene', '1956', (172, 176))	('deletion mutation', 'Var', (181, 198))	('improve', 'PosReg', (129, 136))	('EGFR', 'Gene', (172, 176))	('EOR', 'Chemical', '-', (137, 140))	('GBMs', 'Phenotype', 'HP:0012174', (102, 106))	('GBMs', 'Phenotype', 'HP:0012174', (158, 162))
137528	32922947	TP53 gene mutation involves multiple regulatory factors and is believed to promote malignant progression of low-grade glioma.	('TP53', 'Gene', '7157', (0, 4))	('glioma', 'Disease', (118, 124))	('TP53', 'Gene', (0, 4))	('promote', 'PosReg', (75, 82))	('mutation', 'Var', (10, 18))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('malignant progression', 'CPA', (83, 104))
137530	32922947	Loss of ATRX can result in telomerase phenotype prolongation and subsequently induces more aggressive proliferation of tumor cells.	('tumor', 'Disease', (119, 124))	('induces', 'Reg', (78, 85))	('ATRX', 'Gene', '546', (8, 12))	('prolongation', 'Disease', (48, 60))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('telomerase phenotype', 'MPA', (27, 47))	('ATRX', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Loss', 'Var', (0, 4))	('more', 'PosReg', (86, 90))	('prolongation', 'Disease', 'MESH:D011273', (48, 60))
137531	32922947	Currently, there are no specific treatments for these two gene mutations; however, ATRX loss, TP53 gene mutation, and IDH mutation usually occur simultaneously and are mutually exclusive from 1p/19q codeletion.	('ATRX', 'Gene', (83, 87))	('IDH', 'Gene', (118, 121))	('TP53', 'Gene', '7157', (94, 98))	('loss', 'NegReg', (88, 92))	('TP53', 'Gene', (94, 98))	('IDH', 'Gene', '3417', (118, 121))	('mutation', 'Var', (104, 112))	('ATRX', 'Gene', '546', (83, 87))
137532	32922947	proposed the use of rapid immunohistochemistry to detect the expression of these two genes for further prediction of 1p/19q codeletion (accuracy = 80%) and then combined this with IDH mutation to guide surgery.	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (180, 183))	('1p/19q codeletion', 'Var', (117, 134))
137537	32922947	In addition to the molecular markers mentioned above, there are many other molecular variants associated with diffuse gliomas.	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('variants', 'Var', (85, 93))	('associated', 'Reg', (94, 104))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
137546	32922947	For diffuse gliomas with possibly IDH mutation and 1p/19q codeletion, functional protection should be highly considered when tumor is involving eloquent brain regions.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('gliomas', 'Disease', (12, 19))	('1p/19q codeletion', 'Var', (51, 68))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('tumor', 'Disease', (125, 130))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
137553	32922947	ATRX Alpha-thalassemia/mental retardation syndrome X-linked mutation EGFR Epidermal growth factor receptor EOR Extent of resection GBM Glioblastoma GTR Gross total resection IDH Isocitrate dehydrogenase MGMT O6-methylguanine-DNA methyltransferase MRI Magnetic resonance imaging OS Overall survival PFS Progression-free survival TMZ Temozolomide WHO World Health Organization Lianwang Li conducted the literature review and manuscript writing.	('mutation', 'Var', (60, 68))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (11, 59))	('Epidermal growth factor receptor', 'Gene', (74, 106))	('Glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('IDH', 'Gene', (174, 177))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (208, 246))	('MGMT', 'Gene', (203, 207))	('EGFR', 'Gene', '1956', (69, 73))	('Glioblastoma', 'Disease', (135, 147))	('Isocitrate dehydrogenase', 'Gene', '3417', (178, 202))	('Glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('IDH', 'Gene', '3417', (174, 177))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (11, 59))	('Epidermal growth factor receptor', 'Gene', '1956', (74, 106))	('Isocitrate dehydrogenase', 'Gene', (178, 202))	('O6-methylguanine-DNA methyltransferase', 'Gene', (208, 246))	('GTR', 'Chemical', '-', (148, 151))	('MGMT', 'Gene', '4255', (203, 207))	('ATRX', 'Gene', (0, 4))	('EGFR', 'Gene', (69, 73))	('mental retardation', 'Phenotype', 'HP:0001249', (23, 41))	('ATRX', 'Gene', '546', (0, 4))	('TMZ', 'Chemical', 'MESH:D000077204', (328, 331))	('Temozolomide', 'Chemical', 'MESH:D000077204', (332, 344))	('EOR', 'Chemical', '-', (107, 110))
137554	30651372	The Germline Variants rs61757955 and rs34988193 are Predictive of Survival in Lower Grade Glioma Patients Lower grade gliomas are invasive brain tumors that are difficult to completely resect neurosurgically.	('rs34988193', 'Mutation', 'rs34988193', (37, 47))	('rs61757955', 'Var', (22, 32))	('brain tumors', 'Phenotype', 'HP:0030692', (139, 151))	('invasive brain tumors', 'Disease', 'MESH:D009361', (130, 151))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('invasive brain tumors', 'Disease', (130, 151))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('rs61757955', 'Mutation', 'rs61757955', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Glioma', 'Disease', 'MESH:D005910', (90, 96))	('Glioma', 'Phenotype', 'HP:0009733', (90, 96))	('rs34988193', 'Var', (37, 47))	('Glioma', 'Disease', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
137556	30651372	Although previous studies have shown that specific germline variants increase the risk of tumor formation, no previous study has screened many germline variants to identify variants predictive of survival in glioma patients.	('patients', 'Species', '9606', (215, 223))	('glioma', 'Disease', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('variants', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
137558	30651372	We identified two germline variants that are predictive of poor patient outcomes by Cox regression, controlling for eleven covariates.	('variants', 'Var', (27, 35))	('patient', 'Species', '9606', (64, 71))	('Cox', 'Gene', (84, 87))	('Cox', 'Gene', '1351', (84, 87))
137559	30651372	rs61757955 is a germline variant found in the 3' UTR of GRB2 associated with increased KRAS signaling, CIC mutations, and 1p/19q co-deletion.	('GRB2', 'Gene', (56, 60))	('KRAS', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (87, 91))	('CIC', 'Gene', (103, 106))	('GRB2', 'Gene', '2885', (56, 60))	('rs61757955', 'Var', (0, 10))	('increased', 'PosReg', (77, 86))	('rs61757955', 'Mutation', 'rs61757955', (0, 10))	('CIC', 'Gene', '23152', (103, 106))
137560	30651372	rs34988193 is a germline variant found in the tumor suppressor gene ANKDD1a that causes an amino acid change from lysine to glutamate.	('lysine', 'Chemical', 'MESH:D008239', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('causes', 'Reg', (81, 87))	('rs34988193', 'Var', (0, 10))	('ANKDD1a', 'Gene', (68, 75))	('tumor', 'Disease', (46, 51))	('ANKDD1a', 'Gene', '348094', (68, 75))	('glutamate', 'Chemical', 'MESH:D018698', (124, 133))	('rs34988193', 'Mutation', 'rs34988193', (0, 10))	('amino acid change from lysine to glutamate', 'MPA', (91, 133))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
137561	30651372	This variant was found to be predictive of poor prognosis in two independent lower grade glioma datasets and is predicted to be within the top 0.06% of deleterious mutations across the human genome.	('human', 'Species', '9606', (185, 190))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('poor', 'NegReg', (43, 47))	('variant', 'Var', (5, 12))	('glioma', 'Disease', (89, 95))
137562	30651372	This is the first study presenting an approach to screening many germline variants to identify variants predictive of survival and our application of this methodology revealed the germline variants rs61757955 and rs34988193 as being predictive of survival in lower grade glioma patients.	('rs61757955', 'Var', (198, 208))	('rs61757955', 'Mutation', 'rs61757955', (198, 208))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('predictive', 'Reg', (233, 243))	('glioma', 'Disease', 'MESH:D005910', (271, 277))	('rs34988193', 'Mutation', 'rs34988193', (213, 223))	('patients', 'Species', '9606', (278, 286))	('glioma', 'Disease', (271, 277))	('rs34988193', 'Var', (213, 223))
137571	30651372	While studies have shown that germline mutations can increase an individual's susceptibility for specific cancers, including a recent study that identified 853 pathogenic or likely pathogenic germline variants found in 8% of 10,389 cancer patients, no study has comprehensively screened all of the germline variants in a given cancer type to discover the prognostic variants in that cancer type.	('cancer', 'Disease', (383, 389))	('cancer', 'Disease', (232, 238))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('variants', 'Var', (201, 209))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (327, 333))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('mutations', 'Var', (39, 48))	('increase', 'PosReg', (53, 61))	('susceptibility', 'MPA', (78, 92))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (383, 389))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('patients', 'Species', '9606', (239, 247))
137573	30651372	Here we present a novel methodology for identifying prognostic germline variants and report two germline variants that we have found to be associated with survival in lower grade glioma patients.	('associated with', 'Reg', (139, 154))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('variants', 'Var', (105, 113))	('glioma', 'Disease', (179, 185))	('patients', 'Species', '9606', (186, 194))
137578	30651372	Variant calling was performed on the TCGA lower grade glioma whole exome sequenced normal blood samples (WXS normal), whole-exome sequenced tumor samples (WXS tumor), and RNA sequenced tumor samples (RNA tumor) using VarDict on CGC.	('tumor', 'Disease', (185, 190))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('WXS tumor', 'Disease', 'MESH:D009369', (155, 164))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('tumor', 'Disease', (159, 164))	('glioma', 'Disease', (54, 60))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('WXS tumor', 'Disease', (155, 164))	('Variant', 'Var', (0, 7))	('tumor', 'Disease', (140, 145))
137581	30651372	We used the WXS tumor samples to insert variant calls into the WXS normal samples at positions at which a variant status was listed as unknown in the WXS normal samples.	('variant', 'Var', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('WXS tumor', 'Disease', 'MESH:D009369', (12, 21))	('WXS tumor', 'Disease', (12, 21))
137582	30651372	If the variant status was still missing in a given patient, we then used the RNA tumor sample to insert variant calls into the combined WXS variant call set, allowing us to create the combined set of variant calls.	('variant', 'Var', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('patient', 'Species', '9606', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
137583	30651372	Only variants with an allele frequency of greater than 5% in gnomAD and found in 15 or more of the TCGA lower grade glioma patients were tested for an association with survival by Cox regression.	('glioma', 'Disease', (116, 122))	('patients', 'Species', '9606', (123, 131))	('Cox', 'Gene', '1351', (180, 183))	('variants', 'Var', (5, 13))	('gnomAD', 'Gene', (61, 67))	('Cox', 'Gene', (180, 183))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
137584	30651372	Because we used the WXS tumor and RNA tumor samples to fill in missing variant calls, we evaluated whether somatic mutations were affecting the validity of our results.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('WXS tumor', 'Disease', 'MESH:D009369', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('variant', 'Var', (71, 78))	('tumor', 'Disease', (24, 29))	('WXS tumor', 'Disease', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
137585	30651372	We first determined the percentage of variants called in the WXS tumor sample that were somatic mutations.	('WXS tumor', 'Disease', 'MESH:D009369', (61, 70))	('WXS tumor', 'Disease', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('variants', 'Var', (38, 46))
137587	30651372	Since we used the RNA tumor sample to fill in missing variant calls, we evaluated whether RNA editing was having a significant impact on our analysis.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('variant', 'Var', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
137591	30651372	In order to test whether rs61757955 significantly improves the survival model consisting of the eleven covariates selected by Lasso, we compared the two ROC curves using the bootstrap method with 1000 iterations.	('improves', 'PosReg', (50, 58))	('rs61757955', 'Var', (25, 35))	('rs61757955', 'Mutation', 'rs61757955', (25, 35))
137592	30651372	We also used this bootstrapping approach to determine whether ANKDD1a expression levels, GRB2 expression levels, rs61757955, and rs34988193 together improve the survival model with respect to the eleven covariates selected by Lasso.	('improve', 'PosReg', (149, 156))	('GRB2', 'Gene', '2885', (89, 93))	('survival model', 'CPA', (161, 175))	('rs34988193', 'Mutation', 'rs34988193', (129, 139))	('rs61757955', 'Var', (113, 123))	('rs61757955', 'Mutation', 'rs61757955', (113, 123))	('expression levels', 'MPA', (94, 111))	('ANKDD1a', 'Gene', (62, 69))	('expression', 'MPA', (70, 80))	('GRB2', 'Gene', (89, 93))	('ANKDD1a', 'Gene', '348094', (62, 69))	('rs34988193', 'Var', (129, 139))
137598	30651372	Gene set enrichment analysis (GSEA) of mRNA changes associated with rs61757955 and rs34988193 was performed by dividing the patients into two groups for each variant based on whether or not they had the reference allele at the position of the variant.	('mRNA changes', 'MPA', (39, 51))	('rs61757955', 'Var', (68, 78))	('rs34988193', 'Var', (83, 93))	('rs61757955', 'Mutation', 'rs61757955', (68, 78))	('GSEA', 'Chemical', '-', (30, 34))	('patients', 'Species', '9606', (124, 132))	('rs34988193', 'Mutation', 'rs34988193', (83, 93))
137602	30651372	This led us to identify rs34988193 in ANKDD1a as a potentially deleterious variant predictive of survival.	('rs34988193', 'Mutation', 'rs34988193', (24, 34))	('ANKDD1a', 'Gene', (38, 45))	('ANKDD1a', 'Gene', '348094', (38, 45))	('rs34988193', 'Var', (24, 34))
137603	30651372	Because rs34988193 causes an amino acid change from positively charged lysine to negatively charged glutamate, we ran a BLASTp (httpps://blast.ncbi.nlm.nih.gov/Blast.cgi) search so that we could determine how many species have a protein homologous to ANKDD1a and how consistently the wild type lysine residue was conserved.	('lysine', 'Chemical', 'MESH:D008239', (71, 77))	('ANKDD1a', 'Gene', (251, 258))	('ANKDD1a', 'Gene', '348094', (251, 258))	('glutamate', 'Chemical', 'MESH:D018698', (100, 109))	('rs34988193', 'Var', (8, 18))	('lysine', 'Chemical', 'MESH:D008239', (294, 300))	('amino acid change', 'MPA', (29, 46))	('rs34988193', 'Mutation', 'rs34988193', (8, 18))
137605	30651372	We retrieved linked variants from Ensembl using the population of Utah residents with Northern and Western European ancestry which is demographically similar to the TCGA lower grade glioma patient population.	('variants', 'Var', (20, 28))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('patient', 'Species', '9606', (189, 196))	('Ensembl', 'Gene', (34, 41))	('glioma', 'Disease', (182, 188))
137606	30651372	Briefly, we used the variant caller VarDict on Cancer Genomics Cloud to identify variants from whole exome sequencing (WXS) and RNA sequencing samples in about 500 lower grade glioma patients.	('glioma', 'Disease', (176, 182))	('Cancer', 'Disease', (47, 53))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('variants', 'Var', (81, 89))	('patients', 'Species', '9606', (183, 191))
137610	30651372	We only tested variants found in 15 or more lower grade glioma TCGA patients and listed in gnomAD as having an allele frequency of greater than 5%.	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('patients', 'Species', '9606', (68, 76))	('variants', 'Var', (15, 23))
137611	30651372	Because we used sequencing data from the WXS tumor and RNA tumor samples to fill in missing calls in the WXS normal samples, we evaluated our variant calls for contributions from somatic mutations and RNA editing.	('variant', 'Var', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('WXS tumor', 'Disease', 'MESH:D009369', (41, 50))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('WXS tumor', 'Disease', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
137612	30651372	We first showed that the majority of variant calls in the tumor sample are germline variant calls.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('variant calls', 'Var', (37, 50))
137615	30651372	We therefore estimated that over 99.9% of variants called in the WXS tumor sample consisted of germline variants and that the percentage of somatic mutations in the WXS tumor sample across all patients was quite small (Figure S1).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patients', 'Species', '9606', (193, 201))	('WXS tumor', 'Disease', 'MESH:D009369', (65, 74))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('WXS tumor', 'Disease', (165, 174))	('WXS tumor', 'Disease', 'MESH:D009369', (165, 174))	('WXS tumor', 'Disease', (65, 74))	('consisted', 'Reg', (82, 91))
137616	30651372	Because somatic mutations rarely occur at the same position, we suspected that the number of somatic mutations included in our study was extremely small since we limited our analysis to variants found in 15 or more of the lower grade glioma patients and found in gnomAD with an allele frequency of greater than 5%.	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('variants', 'Var', (186, 194))	('glioma', 'Disease', (234, 240))	('patients', 'Species', '9606', (241, 249))
137621	30651372	In order to reduce the risk of identifying variants that are prognostic because they are confounded by other covariates known to be associated with survival, we used the machine learning algorithm Lasso to determine which of 17 covariates should be controlled for in our Cox regression model.	('variants', 'Var', (43, 51))	('Cox', 'Gene', '1351', (271, 274))	('Cox', 'Gene', (271, 274))
137624	30651372	We ran Cox regression on all 196,022 variants one at a time, controlling for these 11 covariates, to identify germline variants predictive of survival.	('variants', 'Var', (37, 45))	('Cox', 'Gene', '1351', (7, 10))	('Cox', 'Gene', (7, 10))
137625	30651372	rs61757955 results in a mutation in the 3' UTR of Growth Factor Receptor Bound Protein 2 (GRB2) and is associated with a poor prognosis (p=7.08E-10, hazard ratio(HR)=20.4, Figure 3B, Table 2A).	('GRB2', 'Gene', (90, 94))	('Growth Factor Receptor Bound Protein 2', 'Gene', '2885', (50, 88))	('GRB2', 'Gene', '2885', (90, 94))	('results in', 'Reg', (11, 21))	('rs61757955', 'Var', (0, 10))	('mutation in', 'Var', (24, 35))	('rs61757955', 'Mutation', 'rs61757955', (0, 10))	('Growth Factor Receptor Bound Protein 2', 'Gene', (50, 88))
137626	30651372	To determine whether rs61757955 enhances the survival model compared to the eleven clinical covariates alone, we calculated a risk score for each patient using a Cox regression model with rs61757955 and the other 11 covariates and a risk score using the 11 covariates alone.	('enhances', 'PosReg', (32, 40))	('survival model', 'CPA', (45, 59))	('rs61757955', 'Var', (188, 198))	('rs61757955', 'Var', (21, 31))	('rs61757955', 'Mutation', 'rs61757955', (21, 31))	('rs61757955', 'Mutation', 'rs61757955', (188, 198))	('Cox', 'Gene', '1351', (162, 165))	('Cox', 'Gene', (162, 165))	('patient', 'Species', '9606', (146, 153))
137628	30651372	The increased area under the curve suggests that rs61757955 enhances the survival model compared to the eleven clinical covariates alone (p=0.0489, Figure 3C).	('rs61757955', 'Var', (49, 59))	('survival model', 'CPA', (73, 87))	('rs61757955', 'Mutation', 'rs61757955', (49, 59))	('enhances', 'PosReg', (60, 68))
137629	30651372	The allele frequency of rs61757955 is close to 0% according to the 1000 Genomes Project in the Chinese population and, as expected, did not show up in the Chinese Glioma Genome Atlas.	('rs61757955', 'Var', (24, 34))	('rs61757955', 'Mutation', 'rs61757955', (24, 34))	('Glioma', 'Disease', 'MESH:D005910', (163, 169))	('Glioma', 'Phenotype', 'HP:0009733', (163, 169))	('Glioma', 'Disease', (163, 169))
137630	30651372	We also found rs28672782, a germline variant found in the intron of BRSK2, to be associated with a favorable prognosis, though the testable sample size for this variant was small and the maximum follow up for patients with this variant was only three years.	('rs28672782', 'Var', (14, 24))	('patients', 'Species', '9606', (209, 217))	('BRSK2', 'Gene', (68, 73))	('BRSK2', 'Gene', '9024', (68, 73))	('rs28672782', 'Mutation', 'rs28672782', (14, 24))
137631	30651372	In order to test whether rs61757955 in GRB2 is associated with an increased risk of other genomic abnormalities, we separated patients on the basis of this variant to see if there was a difference in the incidence of the genomic or histological variables (Table 3).	('GRB2', 'Gene', (39, 43))	('patients', 'Species', '9606', (126, 134))	('rs61757955', 'Var', (25, 35))	('rs61757955', 'Mutation', 'rs61757955', (25, 35))	('GRB2', 'Gene', '2885', (39, 43))
137633	30651372	38% of patients with this variant had CIC mutated gliomas, whereas only 16% of patients without the variant had a CIC mutation (p=0.0168, Table 3).	('CIC', 'Gene', (38, 41))	('CIC', 'Gene', (114, 117))	('gliomas', 'Disease', (50, 57))	('variant', 'Var', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('patients', 'Species', '9606', (79, 87))	('CIC', 'Gene', '23152', (38, 41))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('patients', 'Species', '9606', (7, 15))	('CIC', 'Gene', '23152', (114, 117))
137634	30651372	Although the incidence of oligodendrogliomas was elevated in patients with the variant compared to patients without the variant, consistent with reports from the literature that 1p/19q co-deletions and CIC mutations are enriched in oligodendrogliomas, this difference was not statistically significant (p=0.475).	('CIC', 'Gene', (202, 205))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (232, 250))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('co-deletions', 'Var', (185, 197))	('patients', 'Species', '9606', (61, 69))	('oligodendrogliomas', 'Disease', (26, 44))	('oligodendrogliomas', 'Disease', (232, 250))	('patients', 'Species', '9606', (99, 107))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (26, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('CIC', 'Gene', '23152', (202, 205))	('elevated', 'PosReg', (49, 57))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('variant', 'Var', (79, 86))
137635	30651372	Since rs61757955 is in a non-coding region, we also tested whether this variant is associated with differences in gene expression.	('rs61757955', 'Mutation', 'rs61757955', (6, 16))	('tested', 'Reg', (52, 58))	('gene expression', 'MPA', (114, 129))	('rs61757955', 'Var', (6, 16))
137638	30651372	We found rs61757955 to be associated with increased KRAS signaling (FDR=0.015) (Figure 3D).	('increased', 'PosReg', (42, 51))	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('rs61757955', 'Var', (9, 19))	('rs61757955', 'Mutation', 'rs61757955', (9, 19))
137639	30651372	Because we only have whole exome sequencing and RNA sequencing data from The Cancer Genome Atlas, we do not know whether the upregulation of genes in the KRAS signaling pathway and the increased incidence of CIC mutations and 1p/19q deletions are due to this variant or a linked variant in a regulatory region that we would be able to analyze with whole genome sequencing data.	('Cancer', 'Disease', (77, 83))	('KRAS', 'Gene', '3845', (154, 158))	('upregulation', 'PosReg', (125, 137))	('Cancer', 'Disease', 'MESH:D009369', (77, 83))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CIC', 'Gene', '23152', (208, 211))	('1p/19q', 'Gene', (226, 232))	('CIC', 'Gene', (208, 211))	('deletions', 'Var', (233, 242))	('KRAS', 'Gene', (154, 158))
137640	30651372	Therefore, we identified the four other variants that are genetically linked to rs61757955 in the European population, the population which is most similar to the TCGA lower grade glioma patient population (Table S3).	('rs61757955', 'Mutation', 'rs61757955', (80, 90))	('linked', 'Reg', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('patient', 'Species', '9606', (187, 194))	('rs61757955', 'Var', (80, 90))	('glioma', 'Disease', (180, 186))
137641	30651372	We found the germline variant rs34988193 in the tumor suppressor gene ANKDD1a to be associated with poor prognosis in the TCGA dataset (p=0.001, HR=1.73, FDR < 0.10, Figure 4A-B, Table 2B).	('tumor', 'Disease', (48, 53))	('rs34988193', 'Mutation', 'rs34988193', (30, 40))	('ANKDD1a', 'Gene', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ANKDD1a', 'Gene', '348094', (70, 77))	('rs34988193', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
137642	30651372	Because this variant is found in both the European and Asian populations, we were able to test whether this variant is also predictive of survival in the independent Chinese Glioma Genome Atlas (CGGA) dataset.	('Glioma', 'Disease', 'MESH:D005910', (174, 180))	('variant', 'Var', (108, 115))	('Glioma', 'Disease', (174, 180))	('Glioma', 'Phenotype', 'HP:0009733', (174, 180))
137645	30651372	The AAG to GAG codon change results in the incorporation of negatively charged glutamate instead of the wild type positively charged lysine residue in the loop between ankyrin repeats nine and ten (Figure 4D).	('GAG', 'Chemical', 'MESH:D006025', (11, 14))	('glutamate', 'Chemical', 'MESH:D018698', (79, 88))	('glutamate', 'Protein', (79, 88))	('AAG', 'Gene', (4, 7))	('change', 'Var', (21, 27))	('negatively', 'NegReg', (60, 70))	('results in', 'Reg', (28, 38))	('lysine', 'Chemical', 'MESH:D008239', (133, 139))	('AAG', 'Gene', '4350', (4, 7))	('incorporation', 'MPA', (43, 56))
137650	30651372	As a result of this analysis, we found the germline variants rs61757955 in the 3' UTR of GRB2 and rs34988193 in the protein-coding region of ANKDD1a to be predictive of survival in lower grade glioma patients.	('GRB2', 'Gene', '2885', (89, 93))	('patients', 'Species', '9606', (200, 208))	('rs34988193', 'Mutation', 'rs34988193', (98, 108))	('rs61757955', 'Var', (61, 71))	('glioma', 'Disease', (193, 199))	('rs61757955', 'Mutation', 'rs61757955', (61, 71))	('ANKDD1a', 'Gene', (141, 148))	('ANKDD1a', 'Gene', '348094', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('rs34988193', 'Var', (98, 108))	('GRB2', 'Gene', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('predictive of', 'Reg', (155, 168))
137651	30651372	We constructed a survival model consisting of the eleven clinical covariates, rs61757955, rs34988193, GRB2 expression, and ANKDD1a expression and generated a receiver operator characteristic curve by using this model to categorize patients as alive or dead after seven years of follow up.	('GRB2', 'Gene', '2885', (102, 106))	('patients', 'Species', '9606', (231, 239))	('rs61757955', 'Var', (78, 88))	('ANKDD1a', 'Gene', (123, 130))	('expression', 'MPA', (107, 117))	('GRB2', 'Gene', (102, 106))	('rs34988193', 'Var', (90, 100))	('expression', 'MPA', (131, 141))	('ANKDD1a', 'Gene', '348094', (123, 130))	('rs61757955', 'Mutation', 'rs61757955', (78, 88))	('rs34988193', 'Mutation', 'rs34988193', (90, 100))
137653	30651372	Although many studies have commented on how germline variants could enable physicians to better individualize patient care by being able to better predict how a patient might respond to chemotherapeutic treatment, most large-scale studies have focused on identifying germline variants that predispose or protect an individual to a disease.	('patient', 'Species', '9606', (161, 168))	('variants', 'Var', (276, 284))	('patient', 'Species', '9606', (110, 117))	('predispose', 'Reg', (290, 300))	('variants', 'Var', (53, 61))
137655	30651372	The germline variant rs61757955 in GRB2 is not found in the Asian population and so could not be confirmed in an independent dataset.	('rs61757955', 'Var', (21, 31))	('GRB2', 'Gene', (35, 39))	('GRB2', 'Gene', '2885', (35, 39))	('rs61757955', 'Mutation', 'rs61757955', (21, 31))
137656	30651372	In contrast, the germline variant rs34988193 in ANKDD1a is found in both the European and Asian populations, and remarkably, was found to be prognostic with very similar hazard ratios in both the TCGA and CGGA datasets.	('ANKDD1a', 'Gene', '348094', (48, 55))	('rs34988193', 'Var', (34, 44))	('rs34988193', 'Mutation', 'rs34988193', (34, 44))	('ANKDD1a', 'Gene', (48, 55))
137662	30651372	In this study, we found rs61757955 to be associated with differences in 1p/19q co-deletion status.	('1p/19q co-deletion', 'Disease', (72, 90))	('rs61757955', 'Var', (24, 34))	('associated', 'Reg', (41, 51))	('rs61757955', 'Mutation', 'rs61757955', (24, 34))
137670	30651372	Separating patients on the basis of this variant revealed that the KRAS signaling pathway is upregulated in patients with this variant.	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (108, 116))	('KRAS', 'Gene', (67, 71))	('variant', 'Var', (127, 134))	('upregulated', 'PosReg', (93, 104))	('KRAS', 'Gene', '3845', (67, 71))	('variant', 'Var', (41, 48))
137672	30651372	We also found this variant to be associated with an increased incidence of CIC mutations and 1p/19q co-deletions.	('1p/19q', 'Disease', (93, 99))	('CIC', 'Gene', '23152', (75, 78))	('variant', 'Var', (19, 26))	('CIC', 'Gene', (75, 78))
137674	30651372	Mutations in CIC are common in oligodendrogliomas and are associated with poor prognosis.	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('CIC', 'Gene', '23152', (13, 16))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (31, 49))	('Mutations', 'Var', (0, 9))	('oligodendrogliomas', 'Disease', (31, 49))	('CIC', 'Gene', (13, 16))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('common', 'Reg', (21, 27))
137675	30651372	Although patients with rs61757955 variant exhibited an elevation in the incidence of oligodendrogliomas which we expected given the increased incidence of CIC mutations and 1p/19q co-deletions, this difference was not statistically significant.	('CIC', 'Gene', (155, 158))	('patients', 'Species', '9606', (9, 17))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (85, 103))	('rs61757955', 'Var', (23, 33))	('rs61757955', 'Mutation', 'rs61757955', (23, 33))	('oligodendrogliomas', 'Disease', (85, 103))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('elevation', 'PosReg', (55, 64))	('CIC', 'Gene', '23152', (155, 158))
137676	30651372	It is possible that this germline variant or the four other germline variants that it is linked with increase a patient's risk for oligodendrogliomas with the CIC mutation and 1p/19q co-deletion.	('CIC', 'Gene', (159, 162))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('patient', 'Species', '9606', (112, 119))	('increase', 'PosReg', (101, 109))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (131, 149))	('CIC', 'Gene', '23152', (159, 162))	('1p/19q co-deletion', 'Var', (176, 194))	('oligodendrogliomas', 'Disease', (131, 149))
137677	30651372	Although it is possible that the 3' UTR of GRB2 has regulatory activity or affects GRB2 protein translation efficiency, it is also possible that one of the variants that rs61757955 is linked to regulates the KRAS signaling pathway.	('affects', 'Reg', (75, 82))	('rs61757955', 'Var', (170, 180))	('GRB2', 'Gene', '2885', (83, 87))	('rs61757955', 'Mutation', 'rs61757955', (170, 180))	('KRAS', 'Gene', (208, 212))	('regulatory activity', 'MPA', (52, 71))	('GRB2', 'Gene', (43, 47))	('GRB2', 'Gene', '2885', (43, 47))	('KRAS', 'Gene', '3845', (208, 212))	('GRB2', 'Gene', (83, 87))	('protein', 'Protein', (88, 95))	('regulates', 'Reg', (194, 203))
137678	30651372	None of the four linked variants are in the protein coding sequence of GRB2 so that if they upregulate RAS activity, like the rs61757955, they likely do so by regulating the expression of GRB2.	('expression', 'MPA', (174, 184))	('GRB2', 'Gene', (71, 75))	('upregulate', 'PosReg', (92, 102))	('GRB2', 'Gene', '2885', (71, 75))	('rs61757955', 'Var', (126, 136))	('GRB2', 'Gene', (188, 192))	('RAS', 'Protein', (103, 106))	('regulating', 'Reg', (159, 169))	('rs61757955', 'Mutation', 'rs61757955', (126, 136))	('GRB2', 'Gene', '2885', (188, 192))
137680	30651372	We will be able to apply our approach to variants in regulatory regions in the future to specifically identify these prognostic variants when whole genome sequencing data for gliomas is available.	('variants', 'Var', (128, 136))	('gliomas', 'Disease', (175, 182))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
137684	30651372	Hypermethylation of this gene is common in GBM and leads to decreased ANKDD1a expression and increased cell proliferation.	('decreased', 'NegReg', (60, 69))	('expression', 'MPA', (78, 88))	('increased', 'PosReg', (93, 102))	('Hypermethylation', 'Var', (0, 16))	('cell proliferation', 'CPA', (103, 121))	('ANKDD1a', 'Gene', (70, 77))	('ANKDD1a', 'Gene', '348094', (70, 77))
137685	30651372	We found the germline variant rs34988193, located at the end of the ninth of ten ankyrin repeat domains in this protein, to be associated with a poor prognosis in lower grade glioma patients in both the TCGA and CGGA datasets.	('associated', 'Reg', (127, 137))	('rs34988193', 'Mutation', 'rs34988193', (30, 40))	('glioma', 'Disease', (175, 181))	('patients', 'Species', '9606', (182, 190))	('rs34988193', 'Var', (30, 40))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
137688	30651372	The change from a positively to negatively charged amino acid resulting from the germline variant rs34988193 in the loop of ANKDD1a may disrupt ANKDD1a's protein interaction partners and could explain the poor prognosis associated with this variant seen in two independent datasets.	('ANKDD1a', 'Gene', '348094', (144, 151))	('rs34988193', 'Mutation', 'rs34988193', (98, 108))	('interaction', 'Interaction', (162, 173))	('ANKDD1a', 'Gene', (144, 151))	('rs34988193', 'Var', (98, 108))	('disrupt', 'NegReg', (136, 143))	('ANKDD1a', 'Gene', '348094', (124, 131))	('ANKDD1a', 'Gene', (124, 131))	('protein', 'Protein', (154, 161))
137689	30651372	Given the amino acid change, further studies involving rs34988193 in ANKDD1a could be directed towards experimentally determining whether or not this variant alters ANKDD1a's protein-protein interactions.	('protein-protein interactions', 'MPA', (175, 203))	('alters', 'Reg', (158, 164))	('rs34988193', 'Var', (55, 65))	('ANKDD1a', 'Gene', (165, 172))	('rs34988193', 'Mutation', 'rs34988193', (55, 65))	('ANKDD1a', 'Gene', '348094', (165, 172))	('ANKDD1a', 'Gene', (69, 76))	('ANKDD1a', 'Gene', '348094', (69, 76))
137690	30651372	rs61757955 in GRB2 and rs34988193 in ANKDD1a could also be used to enhance predictions made by survival models clinically, as we found that these variants are significant predictors of prognosis even after controlling for eleven covariates.	('GRB2', 'Gene', '2885', (14, 18))	('rs34988193', 'Mutation', 'rs34988193', (23, 33))	('ANKDD1a', 'Gene', (37, 44))	('ANKDD1a', 'Gene', '348094', (37, 44))	('enhance', 'PosReg', (67, 74))	('predictors', 'Reg', (171, 181))	('rs61757955', 'Var', (0, 10))	('rs61757955', 'Mutation', 'rs61757955', (0, 10))	('GRB2', 'Gene', (14, 18))	('rs34988193', 'Var', (23, 33))
137691	30651372	The prognostic effect of rs34988193 in ANKDD1a seems to be fairly reliable, as we found that this variant had a similar hazard ratio in both the TCGA and CGGA datasets.	('rs34988193', 'Var', (25, 35))	('ANKDD1a', 'Gene', (39, 46))	('ANKDD1a', 'Gene', '348094', (39, 46))	('rs34988193', 'Mutation', 'rs34988193', (25, 35))
137692	30651372	Our approach could be used in the future to identify sets of germline variants that together enhance the predictions made by survival models, though the current number of lower grade glioma sequencing samples is small relative to the large number of possible combinations of germline variants.	('glioma', 'Disease', (183, 189))	('variants', 'Var', (70, 78))	('enhance', 'PosReg', (93, 100))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))
137717	33680971	GB and LGG patients were defined per the Central Brain Tumor Registry of the United States (CBTRUS), with International Classification of Disease-Oncology (version 3) histological codes 9440/3, 9441/3, and 9442/3 for GB and 9400/3, 9410/3, 9411/3, 9420/3, 9401/3, 9450/3, 9451/3, 9460/3, and 9382/3 for LGG.	('GB', 'Phenotype', 'HP:0012174', (217, 219))	('Brain Tumor', 'Phenotype', 'HP:0030692', (49, 60))	('GB', 'Phenotype', 'HP:0012174', (0, 2))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('9400/3', 'Var', (224, 230))	('patients', 'Species', '9606', (11, 19))	('9440/3', 'Var', (186, 192))	('Classification of Disease-Oncology', 'Disease', (120, 154))	('Classification of Disease-Oncology', 'Disease', 'MESH:D008310', (120, 154))	('Oncology', 'Phenotype', 'HP:0002664', (146, 154))
137755	33680971	One study showed that this sex difference may be partially explained through increased malignant transformation susceptibly in male astrocytes with loss of p53 function when compared to female astrocytes with a loss of p53 function.	('p53', 'Gene', '7157', (219, 222))	('loss', 'NegReg', (148, 152))	('malignant transformation', 'CPA', (87, 111))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('function', 'Var', (160, 168))	('increased', 'PosReg', (77, 86))	('p53', 'Gene', (219, 222))
137776	33537074	Systematic analysis of enhancer regulatory circuit perturbation driven by copy number variations in malignant glioma Background: Enhancers are emerging regulatory regions controlling gene expression in diverse cancer types.	('malignant glioma', 'Disease', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('copy number variations', 'Var', (74, 96))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('malignant glioma', 'Disease', 'MESH:D005910', (100, 116))	('cancer', 'Disease', (210, 216))
137777	33537074	However, the functions of enhancer regulatory circuit perturbations driven by copy number variations (CNVs) in malignant glioma are unclear.	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('malignant glioma', 'Disease', 'MESH:D005910', (111, 127))	('malignant glioma', 'Disease', (111, 127))	('copy number variations', 'Var', (78, 100))
137781	33537074	In particular, the degree of perturbations for amplified enhancers was much greater accompanied by the glioma malignant progression.	('glioma malignant', 'Disease', (103, 119))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('amplified', 'Var', (47, 56))	('glioma malignant', 'Disease', 'MESH:D005910', (103, 119))
137789	33537074	Accumulating evidence suggests that perturbation of gene expression is closely associated with carcinogenesis, which might be triggered by genomic rearrangement, site-specific transcription factors, or long-range enhancer interactions.	('perturbation', 'Var', (36, 48))	('associated', 'Reg', (79, 89))	('carcinogenesis', 'Disease', (95, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))
137792	33537074	Gene CNAs may impact the activities of a variety of oncogenic or tumor-suppressive pathways.	('tumor', 'Disease', (65, 70))	('activities', 'MPA', (25, 35))	('CNAs', 'Var', (5, 9))	('oncogenic', 'Pathway', (52, 61))	('impact', 'NegReg', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
137794	33537074	Perturbations of enhancer activities are also frequently associated with oncogenes and translocations that result in aberrant gene expression in cancer.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('activities', 'MPA', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Perturbations', 'Var', (0, 13))	('associated', 'Reg', (57, 67))
137796	33537074	Gene copy number amplification can also lead to chemotherapy resistance and poor overall survival in patients with cancer.	('poor', 'NegReg', (76, 80))	('Gene copy number amplification', 'Var', (0, 30))	('cancer', 'Disease', (115, 121))	('chemotherapy resistance', 'CPA', (48, 71))	('lead to', 'Reg', (40, 47))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('overall', 'MPA', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
137812	33537074	To identify the enhancers with CNV alterations in glioma, we first downloaded 65,423 human enhancers from FANTOM5 data portal.	('alterations', 'Var', (35, 46))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('human', 'Species', '9606', (85, 90))
137817	33537074	To validate the enhancers with CNVs alteration in glioma tissues, we also obtained the CNVs of cell lines from Cancer Cell Line Encyclopedia (CCLE).	('alteration', 'Var', (36, 46))	('glioma', 'Disease', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
137820	33537074	Patients with glioma were divided into two groups depending on the presence of CNVs of an enhancer (the group with CNAs of an enhancer, and the group without CNAs).	('glioma', 'Disease', (14, 20))	('CNAs', 'Var', (115, 119))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))
137821	33537074	Moreover, we looked for genes showing higher expression in enhancer-amplified patients or lower expression in enhancer-deleted patients.	('expression', 'MPA', (96, 106))	('patients', 'Species', '9606', (78, 86))	('lower', 'NegReg', (90, 95))	('expression', 'MPA', (45, 55))	('patients', 'Species', '9606', (127, 135))	('higher', 'PosReg', (38, 44))	('enhancer-amplified', 'Var', (59, 77))
137828	33537074	The AME tool integrated in MEME Suite was used to identify TF motifs that were significantly enriched in CNV-altered enhancers compared with all enhancers provided by FANTOM5.	('CNV-altered', 'Disease', (105, 116))	('motifs', 'Var', (62, 68))	('enhancers', 'PosReg', (117, 126))	('TF', 'Gene', '2152', (59, 61))
137857	33537074	We found 226, 193, and 367 amplification peaks and 309, 249, and 317 deletion peaks in patients with grade II, grade III and grade IV glioma, respectively.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('amplification peaks', 'MPA', (27, 46))	('glioma', 'Disease', (134, 140))	('deletion', 'Var', (69, 77))	('patients', 'Species', '9606', (87, 95))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
137860	33537074	We found that a significantly overlap of the CNA-driven enhancers between the cell lines and glioma tissues (Figure S2, p < 0.001 for amplification and deletion), demonstrating the predicted amplification or deletion of enhancer regions in glioma.	('deletion', 'Var', (208, 216))	('glioma', 'Disease', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioma', 'Disease', (240, 246))
137861	33537074	Taken together, those results presented a general picture of enhancer alterations (1,641 amplified and 1,115 deleted enhancers in total) during glioma progression and suggested widespread CNAs of enhancers, complementary to other genomic elements.	('alterations', 'Var', (70, 81))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Disease', (144, 150))	('enhancer', 'PosReg', (61, 69))
137869	33537074	By contrast, 173 genes involved in 565 interactions showed lower expression in enhancer-deleted patients.	('patients', 'Species', '9606', (96, 104))	('lower', 'NegReg', (59, 64))	('expression', 'MPA', (65, 75))	('enhancer-deleted', 'Var', (79, 95))
137874	33537074	Moreover, we found significantly higher EGFR expression in patients with E1- and E2-amplified glioma (Figure S4C-D).	('higher', 'PosReg', (33, 39))	('glioma', 'Disease', (94, 100))	('E2-amplified', 'Var', (81, 93))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('expression', 'MPA', (45, 55))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (59, 67))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('E1-', 'Var', (73, 76))
137882	33537074	We found that genes regulated by enhancers were more likely to be associated with cancer (Figure 2E, p < 0.05).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('enhancers', 'Var', (33, 42))	('associated', 'Reg', (66, 76))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
137883	33537074	Together, all these results suggested that CNAs of enhancers perturbed the expression of cancer-related genes.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('CNAs', 'Var', (43, 47))	('perturbed', 'NegReg', (61, 70))	('cancer', 'Disease', (89, 95))	('expression', 'MPA', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
137887	33537074	For the amplified group, we found that genes exhibited significantly higher expression in enhancer- and gene-amplified patients than in only enhancer or only gene-amplified patients (Figure 3E).	('patients', 'Species', '9606', (173, 181))	('patients', 'Species', '9606', (119, 127))	('expression', 'MPA', (76, 86))	('enhancer-', 'Var', (90, 99))	('gene-amplified', 'Var', (104, 118))	('higher', 'PosReg', (69, 75))
137888	33537074	Moreover, both enhancer- and gene-deleted patients exhibited significantly lower expression of genes compared with enhancer- or gene-deleted patients (Figure 3F).	('gene-deleted', 'Var', (29, 41))	('lower', 'NegReg', (75, 80))	('patients', 'Species', '9606', (42, 50))	('expression of genes', 'MPA', (81, 100))	('patients', 'Species', '9606', (141, 149))
137906	33537074	Moreover, the greater slope in the amplified group suggested that SIX1 might influence the expression of MYC more strongly in patients with amplified enhancer.	('expression', 'MPA', (91, 101))	('influence', 'Reg', (77, 86))	('MYC', 'Gene', '4609', (105, 108))	('MYC', 'Gene', (105, 108))	('SIX1', 'Gene', (66, 70))	('patients', 'Species', '9606', (126, 134))	('SIX1', 'Gene', '6495', (66, 70))	('amplified', 'Var', (140, 149))
137909	33537074	Epigenetic silencing of MGMT by promoter methylation in glioma cells had been previously found.	('MGMT', 'Gene', '4255', (24, 28))	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('promoter methylation', 'Var', (32, 52))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('Epigenetic silencing', 'Var', (0, 20))	('MGMT', 'Gene', (24, 28))
137916	33537074	We first calculated the connectivity of TFs and genes in the glioma global network, and found that approximately 13.2% of TFs regulated more than 20 target genes in enhancer-amplified network and 9% in enhancer-deleted network (Figure S10A).	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('TF', 'Gene', '2152', (40, 42))	('TF', 'Gene', '2152', (122, 124))	('S10A', 'SUBSTITUTION', 'None', (235, 239))	('glioma', 'Disease', (61, 67))	('regulated', 'Reg', (126, 135))	('S10A', 'Var', (235, 239))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
137917	33537074	Moreover, approximately 26% of target genes were regulated by more than seven TFs in enhancer-amplified network and 20% in enhancer-deleted network (Figure S10B).	('S10B', 'SUBSTITUTION', 'None', (156, 160))	('regulated', 'Reg', (49, 58))	('TF', 'Gene', '2152', (78, 80))	('S10B', 'Var', (156, 160))
137944	33537074	We next used siRNA technology to knock down these target genes in U251 cell line and measure the expression of genes.	('knock', 'Var', (33, 38))	('measure', 'Reg', (85, 92))	('U251', 'CellLine', 'CVCL:0021', (66, 70))	('expression', 'MPA', (97, 107))
137946	33537074	Together, all of these results suggested that enhancer target genes significantly promote cell proliferation and migration in glioma.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('promote', 'PosReg', (82, 89))	('cell proliferation', 'CPA', (90, 108))	('genes', 'Var', (62, 67))	('migration', 'CPA', (113, 122))	('glioma', 'Disease', (126, 132))
137953	33537074	We also observed that activity alterations of enhancers perturb the regulation of genes by TFs.	('TF', 'Gene', '2152', (91, 93))	('alterations', 'Var', (31, 42))	('regulation of genes', 'MPA', (68, 87))	('perturb', 'Reg', (56, 63))	('activity', 'MPA', (22, 30))
137960	33537074	Given increasing evidence that the majority of disease-associated sequence variations are observed in enhancers, it is interesting to investigate whether these variations will alter the TFs binding.	('TF', 'Gene', '2152', (186, 188))	('variations', 'Var', (75, 85))	('binding', 'Interaction', (190, 197))	('alter', 'Reg', (176, 181))
137971	32038216	The Dice scores obtained for the validation set for whole tumor (WT :NCR/NE +ET +ED), tumor core (TC:NCR/NET +ET), and enhancing tumor (ET) are 0.90216, 0.87247, and 0.82445.	('N', 'Chemical', 'MESH:D009584', (69, 70))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (58, 63))	('NET', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('0.82445', 'Var', (166, 173))	('ED', 'Phenotype', 'HP:0000969', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('NET', 'Gene', '2004', (105, 108))	('0.90216', 'Var', (144, 151))	('0.87247', 'Var', (153, 160))	('tumor', 'Disease', (86, 91))	('ED', 'Disease', 'MESH:D004487', (81, 83))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('N', 'Chemical', 'MESH:D009584', (101, 102))
138054	32038216	The box-and-whisker plots in Figure 6 report the Dice score and Hausdroff performance of the segmentation result for the nested tumor sub-regions WT, TC, and ET for the 66 patients from BraTS 2018 validation dataset for the MPS-CNN as well as the other ten (A-J) models.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('BraTS', 'Disease', (186, 191))	('patients', 'Species', '9606', (172, 180))	('MPS-CNN', 'Var', (224, 231))	('BraTS', 'Disease', 'MESH:D001932', (186, 191))
138083	31836713	An understanding of the fundamental processes of such biological adaptation and disruption of any of the involved steps may lead to a robust treatment approach that reduces the likelihood of patient relapse.	('disruption', 'Var', (80, 90))	('lead to', 'Reg', (124, 131))	('patient', 'Species', '9606', (191, 198))	('reduces', 'NegReg', (165, 172))
138110	31836713	Yet, such additional changes create a larger step between CT and LE; similarly, for CTpan and LE or CTmvp and LE.	('LE', 'Chemical', '-', (65, 67))	('LE', 'Chemical', '-', (110, 112))	('LE', 'Chemical', '-', (94, 96))	('CTpan', 'Chemical', '-', (84, 89))	('create', 'Reg', (29, 35))	('changes', 'Var', (21, 28))	('CTmvp', 'Chemical', '-', (100, 105))
138191	29392423	BRAFV600E inhibitor therapy can potentially reverse visual and neurologic decline associated with progressive OPG.	('OPG', 'Disease', (110, 113))	('OPG', 'Phenotype', 'HP:0009734', (110, 113))	('neurologic decline', 'Phenotype', 'HP:0002344', (63, 81))	('OPG', 'Chemical', '-', (110, 113))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E inhibitor', 'Var', (0, 19))
138198	29392423	Targeted inhibition of BRAFV600E-mutant protein, an activator of the MAPK pathway, is beneficial in treating central nervous system (CNS) tumors that carry this mutation.	('central nervous system (CNS) tumors', 'Disease', 'MESH:D016543', (109, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('protein', 'Protein', (40, 47))	('BRAFV600E-mutant', 'Var', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
138206	29392423	This report demonstrates the prompt and excellent clinical and imaging response to BRAFV600E inhibition in progressive OPG and makes a case for timely biopsy of these lesions in affected children who have not responded to frontline therapy.	('inhibition', 'NegReg', (93, 103))	('BRAFV600E', 'Var', (83, 92))	('BRAFV600E', 'Mutation', 'rs113488022', (83, 92))	('OPG', 'Chemical', '-', (119, 122))	('children', 'Species', '9606', (187, 195))	('OPG', 'Phenotype', 'HP:0009734', (119, 122))
138256	29392423	Tandem duplication of the BRAF oncogene at 7q34, with subsequent fusion to the KIAA1549 gene, is the most common aberration in PA (found in ~75% of cerebellar PAs).	('cerebellar PAs', 'Disease', 'MESH:D002528', (148, 162))	('Tandem duplication', 'Var', (0, 18))	('BRAF', 'Gene', '673', (26, 30))	('KIAA1549', 'Gene', '57670', (79, 87))	('BRAF', 'Gene', (26, 30))	('KIAA1549', 'Gene', (79, 87))	('cerebellar PAs', 'Disease', (148, 162))	('common', 'Reg', (106, 112))
138258	29392423	Both aberrations result in formation of a mutant protein that constitutively activates the MAPK pathway through the RAS/RAF complex.	('mutant', 'Var', (42, 48))	('RAF', 'Gene', '673', (120, 123))	('protein', 'Protein', (49, 56))	('MAPK pathway', 'Pathway', (91, 103))	('activates', 'PosReg', (77, 86))	('result in', 'Reg', (17, 26))	('RAF', 'Gene', (120, 123))
138260	29392423	Although large clinical trials of BRAFV600E inhibitors for treatment of refractory pediatric LGG are ongoing (clinicaltrials.gov), extensive data prove the drug's utility in adult melanoma.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('inhibitors', 'Var', (44, 54))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('BRAFV600E', 'Gene', (34, 43))
138261	29392423	BRAF mutations occur in up to 60% of adult patients with melanomas, and BRAFV600E inhibitors improve the outcome and survival in those patients.	('melanomas', 'Disease', (57, 66))	('BRAF', 'Gene', (72, 76))	('outcome', 'CPA', (105, 112))	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (43, 51))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('survival', 'CPA', (117, 125))	('improve', 'PosReg', (93, 100))	('BRAF', 'Gene', '673', (72, 76))
138262	29392423	Furthermore, recent studies report profound responses to BRAF-inhibitor therapy in pediatric patients with brain tumors that express BRAFV600 mutations.	('mutations', 'Var', (142, 151))	('brain tumors', 'Disease', (107, 119))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', (133, 137))	('brain tumors', 'Phenotype', 'HP:0030692', (107, 119))	('brain tumors', 'Disease', 'MESH:D001932', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('patients', 'Species', '9606', (93, 101))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
138263	29392423	Our case series demonstrates the rapid and dramatic effect of BRAFV600E inhibitor vemurafenib in children with OPG.	('vemurafenib', 'Chemical', 'MESH:D000077484', (82, 93))	('children', 'Species', '9606', (97, 105))	('BRAFV600E', 'Var', (62, 71))	('BRAFV600E', 'Mutation', 'rs113488022', (62, 71))	('OPG', 'Disease', (111, 114))	('OPG', 'Phenotype', 'HP:0009734', (111, 114))	('OPG', 'Chemical', '-', (111, 114))
138293	29180475	Manipulating specific isoforms of Tp63 and Tp73 is an effective approach to induce regression in Tp53-deficient and mutant tumors.	('Tp73', 'Gene', (43, 47))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('Tp53-deficient', 'Disease', (97, 111))	('Tp63', 'Gene', (34, 38))	('Tp73', 'Gene', '7161', (43, 47))	('Tp53-deficient', 'Disease', 'MESH:D007153', (97, 111))	('mutant', 'Var', (116, 122))	('Tp63', 'Gene', '8626', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
138309	29180475	tumor suppressor or oncogene) using association of gene scores and survival that conforms with the predicted function.	('tumor', 'Disease', 'MESH:D009369', (0, 5))	('gene scores', 'Var', (51, 62))	('association', 'Interaction', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (0, 5))
138314	29180475	Taqman probes included: human Lef1 (Hs01547250_m1) and human GAPDH (Hs03929097_g1) as internal controls.	('human', 'Species', '9606', (24, 29))	('human', 'Species', '9606', (55, 60))	('Lef1', 'Gene', (30, 34))	('Hs01547250_m1', 'Var', (36, 49))	('GAPDH', 'Gene', '2597', (61, 66))	('Hs03929097_g1', 'Var', (68, 81))	('Lef1', 'Gene', '51176', (30, 34))	('GAPDH', 'Gene', (61, 66))
138316	29180475	For siRNA assays, 40 nM of siLef1 (SASI_Hs02_00349169 and SASI_Hs01_00151600, Sigma) was transfected into 0.5x106 cells on 6-cm dishes using Lipofectamine RNAi Max (Invitrogen).	('Lipofectamine', 'Chemical', 'MESH:C086724', (141, 154))	('Lef1', 'Gene', (29, 33))	('SASI_Hs01_00151600', 'Var', (58, 76))	('Lef1', 'Gene', '51176', (29, 33))	('SASI_Hs02_00349169', 'Var', (35, 53))
138338	29180475	2a), knockdown of DeltaNp63 decreased soft agar colony formation but not proliferation (Fig.	('decreased', 'NegReg', (28, 37))	('knockdown', 'Var', (5, 14))	('p63', 'Gene', (24, 27))	('p63', 'Gene', '8626', (24, 27))	('soft agar colony formation', 'CPA', (38, 64))
138349	29180475	Similarly to the results where DeltaNp63 was knocked down, the Lef1 knockdown reduced MCF10-CA1D and HCC95 colony formation (Fig.	('HCC95', 'CellLine', 'CVCL:5137', (101, 106))	('Lef1', 'Gene', '51176', (63, 67))	('p63', 'Gene', '8626', (37, 40))	('Lef1', 'Gene', (63, 67))	('knockdown', 'Var', (68, 77))	('reduced', 'NegReg', (78, 85))	('MCF10-CA1D', 'CellLine', 'CVCL:6683', (86, 96))	('p63', 'Gene', (37, 40))
138404	29180475	The suppressive activity of DeltaNp63 in tumor progression is consistent with previous reports indicating that DeltaNp63 serves to promote differentiation of epithelial tissues and that loss of DeltaNp63 leads to pluripotency.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('p63', 'Gene', '8626', (200, 203))	('tumor', 'Disease', (41, 46))	('p63', 'Gene', (34, 37))	('p63', 'Gene', (117, 120))	('loss', 'Var', (186, 190))	('pluripotency', 'MPA', (213, 225))	('p63', 'Gene', '8626', (34, 37))	('p63', 'Gene', (200, 203))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('p63', 'Gene', '8626', (117, 120))	('promote', 'PosReg', (131, 138))
138409	29180475	TP63 alterations have been previously implicated in many cancer and is frequently used as a diagnostic marker.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('alterations', 'Var', (5, 16))	('TP63', 'Gene', '8626', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('implicated', 'Reg', (38, 48))	('TP63', 'Gene', (0, 4))
138432	26923836	In glioma surgery, a positive outcome requires resecting the maximum amount of tumoral tissue even when it has invaded the normal parenchyma, while preserving as much of the normal adjacent tissue and its cerebral functions, including higher cognition.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('resecting', 'Var', (47, 56))	('cerebral functions', 'CPA', (205, 223))	('glioma', 'Disease', (3, 9))	('tumoral', 'Disease', (79, 86))	('tumoral', 'Disease', 'MESH:D009369', (79, 86))	('higher cognition', 'CPA', (235, 251))
138448	26923836	Alterations of the default mode network and/or its functional connectivity have been reported in several neurological conditions, including Alzheimer's disease, autism, and schizophrenia.	('reported', 'Reg', (85, 93))	('autism', 'Disease', 'MESH:D001321', (161, 167))	('schizophrenia', 'Disease', (173, 186))	('default mode network', 'Pathway', (19, 39))	('Alterations', 'Var', (0, 11))	('schizophrenia', 'Disease', 'MESH:D012559', (173, 186))	('functional', 'MPA', (51, 61))	('autism', 'Disease', (161, 167))	('schizophrenia', 'Phenotype', 'HP:0100753', (173, 186))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (140, 159))	('autism', 'Phenotype', 'HP:0000717', (161, 167))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (140, 159))	("Alzheimer's disease", 'Disease', (140, 159))
138467	26923836	studied the DMN with glioma cases using the deactivation profiles of language task datasets, and noted increased DMN connectivity in hippocampal lesions, but decreased connectivity in the VMPFC.	('decreased', 'NegReg', (158, 167))	('increased', 'PosReg', (103, 112))	('DMN', 'Chemical', '-', (113, 116))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('DMN', 'Var', (113, 116))	('glioma', 'Disease', (21, 27))	('DMN', 'Chemical', '-', (12, 15))	('connectivity', 'MPA', (168, 180))
138517	26923836	Here, we provide an example of a case of focal epilepsy with a lesion in the anterior cingulate gyrus to demonstrate evaluation by EEG-fMRI (Fig.	('epilepsy', 'Disease', (47, 55))	('focal epilepsy', 'Phenotype', 'HP:0007359', (41, 55))	('lesion', 'Var', (63, 69))	('epilepsy', 'Disease', 'MESH:D004827', (47, 55))	('epilepsy', 'Phenotype', 'HP:0001250', (47, 55))
138559	33947134	Deficient activity of coagulation inhibitors may, at least partially, be responsible for hypercoagulability in cancer patients.	('Deficient activity of coagulation', 'Phenotype', 'HP:0001928', (0, 33))	('hypercoagulability', 'Phenotype', 'HP:0100724', (89, 107))	('activity', 'MPA', (10, 18))	('coagulation', 'Protein', (22, 33))	('Deficient', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))	('hypercoagulability', 'Disease', (89, 107))	('hypercoagulability', 'Disease', 'MESH:D019851', (89, 107))
138566	33947134	Increasing degrees of tumor malignancy is associated with the expression of TFPI-2, possibly suggesting a role for TFPI-2 in maintaining the stability of the tumor environment and inhibiting the growth of neoplasms and the formation of metastases.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('TFPI-2', 'Gene', '7980', (115, 121))	('TFPI-2', 'Gene', '7980', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('neoplasms', 'Disease', 'MESH:D009369', (205, 214))	('metastases', 'Disease', 'MESH:D009362', (236, 246))	('tumor malignancy', 'Disease', 'MESH:D009369', (22, 38))	('neoplasms', 'Disease', (205, 214))	('tumor', 'Disease', (158, 163))	('TFPI-2', 'Gene', (76, 82))	('TFPI-2', 'Gene', (115, 121))	('tumor malignancy', 'Disease', (22, 38))	('metastases', 'Disease', (236, 246))	('stability', 'MPA', (141, 150))	('inhibiting', 'NegReg', (180, 190))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (22, 27))	('neoplasm', 'Phenotype', 'HP:0002664', (205, 213))	('expression', 'Var', (62, 72))
138575	33947134	It is of interest that, as with TFPI-2, silencing of the TM gene promoter is implicated in the observed downregulation of TM synthesis.	('TFPI-2', 'Gene', '7980', (32, 38))	('TM', 'Gene', '7056', (122, 124))	('TFPI-2', 'Gene', (32, 38))	('silencing', 'Var', (40, 49))	('downregulation', 'NegReg', (104, 118))	('TM', 'Gene', '7056', (57, 59))
138591	33947134	Immunohistochemical (IHC) studies were performed on G2-grade gliomas (8 astrocytomas, 5 oligodendrogliomas) and high-grade gliomas (G3-12 anaplastic astrocytomas, 4 anaplastic oligodendrogliomas; G4-11 glioblastomas), as well as control fragments of respective normal tissues, which were derived from the neoplasm-free surgical margins.	('neoplasm', 'Disease', 'MESH:D009369', (305, 313))	('gliomas', 'Disease', (187, 194))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', (123, 130))	('neoplasm', 'Disease', (305, 313))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (138, 161))	('astrocytomas', 'Disease', (72, 84))	('oligodendrogliomas', 'Disease', (176, 194))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('oligodendrogliomas', 'Disease', (88, 106))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('glioblastomas', 'Phenotype', 'HP:0012174', (202, 215))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('anaplastic astrocytomas', 'Disease', (138, 161))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('neoplasm', 'Phenotype', 'HP:0002664', (305, 313))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('G3-12', 'Var', (132, 137))	('astrocytomas', 'Disease', (149, 161))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('astrocytomas', 'Disease', 'MESH:D001254', (72, 84))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('glioblastomas', 'Disease', (202, 215))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (176, 194))	('glioblastomas', 'Disease', 'MESH:D005909', (202, 215))	('astrocytomas', 'Disease', 'MESH:D001254', (149, 161))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (88, 106))
138621	33947134	Thromboembolic complications in cancer patients may result from profiles of oncogenic driver mutations and their impact on the expression of coagulation-related genes:coagulome.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (39, 47))	('expression', 'MPA', (127, 137))	('cancer', 'Disease', (32, 38))	('impact', 'Reg', (113, 119))	('Thromboembolic complications', 'Phenotype', 'HP:0001907', (0, 28))	('profiles', 'Var', (64, 72))	('Thromboembolic complications', 'Disease', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('result from', 'Reg', (52, 63))	('Thromboembolic complications', 'Disease', 'MESH:D013923', (0, 28))
138624	33947134	The F1+2 fragment is a byproduct of the conversion of prothrombin to thrombin and is an indicator of extravascular thrombin generation in neoplasms.	('thrombin', 'Gene', (69, 77))	('thrombin', 'Gene', '2147', (69, 77))	('neoplasms', 'Disease', 'MESH:D009369', (138, 147))	('neoplasms', 'Disease', (138, 147))	('thrombin', 'Gene', (115, 123))	('neoplasm', 'Phenotype', 'HP:0002664', (138, 146))	('neoplasms', 'Phenotype', 'HP:0002664', (138, 147))	('thrombin', 'Gene', '2147', (115, 123))	('thrombin', 'Gene', (57, 65))	('thrombin', 'Gene', '2147', (57, 65))	('F1+2', 'Var', (4, 8))
138626	33947134	The presence of F1+2 in association with colon cancer cells and the endothelial cells of blood vessels supplying the tumor indicates that thrombin is generated at the sites.	('thrombin', 'Gene', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('thrombin', 'Gene', '2147', (138, 146))	('F1+2', 'Var', (16, 20))	('colon cancer', 'Phenotype', 'HP:0003003', (41, 53))	('colon cancer', 'Disease', 'MESH:D015179', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('colon cancer', 'Disease', (41, 53))
138664	33947134	In some highly aggressive cancers, deletion of the TFPI-2 gene locus on chromosome 7q results in the complete lack of TFPI-2 protein expression.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('lack', 'NegReg', (110, 114))	('TFPI-2', 'Gene', '7980', (118, 124))	('TFPI-2', 'Gene', (118, 124))	('TFPI-2', 'Gene', (51, 57))	('aggressive cancers', 'Disease', (15, 33))	('protein', 'Protein', (125, 132))	('aggressive cancers', 'Disease', 'MESH:D009369', (15, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('deletion', 'Var', (35, 43))	('TFPI-2', 'Gene', '7980', (51, 57))
138666	33947134	Interestingly, proapoptotic signaling pathways and apoptosis were observed in human glioma cell lines upon TFPI-2 restoration.	('observed', 'Reg', (66, 74))	('TFPI-2', 'Gene', (107, 113))	('restoration', 'Var', (114, 125))	('glioma', 'Disease', (84, 90))	('TFPI-2', 'Gene', '7980', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('proapoptotic signaling pathways', 'Pathway', (15, 46))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('apoptosis', 'CPA', (51, 60))	('human', 'Species', '9606', (78, 83))
138673	33947134	Clinical observations show a correlation between high levels of PAI-1 and cancer relapse and survival time in patients with gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('PAI-1', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('survival time', 'CPA', (93, 106))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('high', 'Var', (49, 53))	('PAI-1', 'Gene', '5054', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (110, 118))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
138678	33947134	In gliomas of higher-grade malignancy, there is a multidirectional failure of the anticoagulant mechanisms expressed by dysregulation in the PC system and PAI-1 deficiency.	('malignancy', 'Disease', 'MESH:D009369', (27, 37))	('PAI-1 deficiency', 'Disease', 'MESH:C537409', (155, 171))	('malignancy', 'Disease', (27, 37))	('dysregulation', 'Var', (120, 133))	('PAI-1 deficiency', 'Disease', (155, 171))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('anticoagulant mechanisms', 'MPA', (82, 106))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))
138749	32705511	Not unexpectedly, the identified genetic alterations with survival implications were more extensive in the high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('genetic alterations', 'Var', (33, 52))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
138777	31024229	Results: This approach achieves Dice similarity scores of 0.6652, 0.5880, and 0.6682 for edema, non-enhancing tumors, and enhancing tumors, respectively, in which the Dice loss is used for single-pass training.	('edema', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('edema', 'Disease', 'MESH:D004487', (89, 94))	('edema', 'Phenotype', 'HP:0000969', (89, 94))	('tumors', 'Disease', (132, 138))	('0.6682', 'Var', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
138806	31024229	The images for each patient comprise four scanning sequences: T1-weighted, T2-weighted, post-contrast T1-weighted, and FLAIR.	('T2-weighted', 'MPA', (75, 86))	('T1-weighted', 'Var', (102, 113))	('patient', 'Species', '9606', (20, 27))	('T1-weighted', 'MPA', (62, 73))
138867	31024229	We obtain final scores of 0.6652, 0.5880, and 0.6682 for edemas, non-enhancing tumors, and enhancing tumors, respectively, using the Dice loss.	('0.5880', 'Var', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('edemas', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('edemas', 'Disease', 'MESH:D004487', (57, 63))	('0.6682', 'Var', (46, 52))	('edemas', 'Phenotype', 'HP:0000969', (57, 63))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('edema', 'Phenotype', 'HP:0000969', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
138875	31024229	Table 3 indicates that the Dice similarity scores of our proposed method are 0.7043, 0.5889, and 0.7206 for edemas, non-enhancing tumors, and enhancing tumors, respectively, which are higher than those of all comparison methods for every class.	('0.5889', 'Var', (85, 91))	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('edemas', 'Disease', 'MESH:D004487', (108, 114))	('0.7206', 'Var', (97, 103))	('edemas', 'Phenotype', 'HP:0000969', (108, 114))	('edemas', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('edema', 'Phenotype', 'HP:0000969', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
138878	31024229	U-Net increases the number of up-sampling and skip connections compared with FCN, which can supplement more location information for semantic information.	('U-Net', 'Chemical', '-', (0, 5))	('up-sampling', 'PosReg', (30, 41))	('U-Net', 'Var', (0, 5))	('skip', 'CPA', (46, 50))
138888	31024229	The final results obtained by our proposed method were 0.7043 for edema, 0.5889 for non-enhancing tumors, and 0.7206 for enhancing tumors.	('edema', 'Disease', 'MESH:D004487', (66, 71))	('0.7206', 'Var', (110, 116))	('tumors', 'Disease', (98, 104))	('edema', 'Phenotype', 'HP:0000969', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('edema', 'Disease', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Disease', (131, 137))	('non-enhancing', 'MPA', (84, 97))	('0.5889', 'Var', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
138911	23456655	The CSF levels of the citric, isocitric, and lactic acids were significantly higher in grade I-III gliomas with mutant IDH than in those with wild-type IDH.	('IDH', 'Gene', '3417', (119, 122))	('citric', 'Chemical', 'MESH:D019343', (33, 39))	('lactic acids', 'Chemical', 'MESH:D019344', (45, 57))	('higher', 'PosReg', (77, 83))	('isocitric', 'Chemical', '-', (30, 39))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('IDH', 'Gene', (152, 155))	('citric', 'Chemical', 'MESH:D019343', (22, 28))	('I-III gliomas', 'Disease', (93, 106))	('CSF levels of', 'MPA', (4, 17))	('I-III gliomas', 'Disease', 'MESH:D005910', (93, 106))	('IDH', 'Gene', '3417', (152, 155))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('mutant', 'Var', (112, 118))	('IDH', 'Gene', (119, 122))	('isocitric', 'MPA', (30, 39))
138923	23456655	Recently, mutations in the isocitrate dehydrogenase (IDH) genes have been identified in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('isocitrate dehydrogenase', 'Gene', (27, 51))	('IDH', 'Gene', (53, 56))	('identified', 'Reg', (74, 84))	('isocitrate dehydrogenase', 'Gene', '3417', (27, 51))	('mutations', 'Var', (10, 19))	('IDH', 'Gene', '3417', (53, 56))
138925	23456655	Previous reports have indicated that these mutations are frequently observed in astrocytic and oligodendroglial tumors of grades II and III.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (95, 118))	('observed', 'Reg', (68, 76))	('oligodendroglial tumors', 'Disease', (95, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
138926	23456655	Because these enzymes catalyze reactions of energy metabolism, IDH mutations may alter global cellular metabolism.	('IDH', 'Gene', (63, 66))	('alter', 'Reg', (81, 86))	('global cellular metabolism', 'MPA', (87, 113))	('IDH', 'Gene', '3417', (63, 66))	('mutations', 'Var', (67, 76))
138945	23456655	To detect the IDH mutations, forward and reverse primers were designed to amplify exon 4 (codon R132) of the IDH1 gene and exon 4 (codon R172) of the IDH2 gene.	('IDH', 'Gene', (14, 17))	('codon R132', 'Var', (90, 100))	('IDH', 'Gene', '3417', (14, 17))	('IDH1', 'Gene', (109, 113))	('IDH2', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (109, 113))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', (109, 112))	('IDH', 'Gene', '3417', (150, 153))	('IDH2', 'Gene', '3418', (150, 154))	('IDH', 'Gene', '3417', (109, 112))
138952	23456655	The concentration of downstream molecules of isocitric acid in the TCA cycle, i.e., succinic acid, fumaric acid, and malic acid, were relatively lower in GBMs than in grades I-II or III gliomas (Supplementary Table S1).	('concentration', 'MPA', (4, 17))	('II gliomas', 'Disease', 'MESH:D005910', (183, 193))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('isocitric acid', 'Chemical', 'MESH:C034219', (45, 59))	('succinic acid', 'Chemical', 'MESH:D019802', (84, 97))	('TCA', 'Chemical', 'MESH:D014238', (67, 70))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('malic acid', 'Chemical', 'MESH:C030298', (117, 127))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('fumaric acid', 'Chemical', 'MESH:C032005', (99, 111))	('lower', 'NegReg', (145, 150))	('GBMs', 'Var', (154, 158))	('fumaric acid', 'MPA', (99, 111))	('succinic acid', 'MPA', (84, 97))	('II gliomas', 'Disease', (183, 193))	('malic acid', 'MPA', (117, 127))
138954	23456655	The levels of lactic acid (1.21-fold, p = 0.033) and 2-aminopimelic acid (1.87-fold, p = 0.042) were higher in GBMs than in grades I-II gliomas (Fig.	('GBMs', 'Var', (111, 115))	('levels', 'MPA', (4, 10))	('I-II gliomas', 'Disease', 'MESH:D005910', (131, 143))	('2-aminopimelic acid', 'MPA', (53, 72))	('higher', 'PosReg', (101, 107))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('lactic acid', 'Chemical', 'MESH:D019344', (14, 25))	('I-II gliomas', 'Disease', (131, 143))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('lactic acid', 'MPA', (14, 25))	('2-aminopimelic acid', 'Chemical', 'MESH:C009845', (53, 72))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
138975	23456655	However, in high-grade gliomas alone, the CSF citric and isocitric acid levels were significantly higher in gliomas with gadolinium enhancement than in those without gadolinium enhancement (citric acid: p = 0.019, isocitric acid: p = 0.019).	('gliomas', 'Disease', (108, 115))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('citric', 'Chemical', 'MESH:D019343', (60, 66))	('citric', 'Chemical', 'MESH:D019343', (217, 223))	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('citric acid', 'Chemical', 'MESH:D019343', (190, 201))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('gadolinium', 'Chemical', 'MESH:D005682', (166, 176))	('isocitric acid', 'Chemical', 'MESH:C034219', (57, 71))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('citric', 'Chemical', 'MESH:D019343', (190, 196))	('citric acid', 'Chemical', 'MESH:D019343', (60, 71))	('citric acid', 'Chemical', 'MESH:D019343', (217, 228))	('isocitric acid', 'Chemical', 'MESH:C034219', (214, 228))	('gadolinium enhancement', 'Var', (121, 143))	('citric', 'Chemical', 'MESH:D019343', (46, 52))	('gliomas', 'Disease', (23, 30))	('gadolinium', 'Chemical', 'MESH:D005682', (121, 131))	('higher', 'PosReg', (98, 104))
138977	23456655	IDH mutations are quite rare in GBMs.	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))
138980	23456655	Six glioma cases possessed a mutant IDH1 or a mutant IDH2, and 12 cases had wild-type IDH1 and IDH2 (Table 1).	('IDH1', 'Gene', (36, 40))	('IDH1', 'Gene', (86, 90))	('IDH2', 'Gene', (53, 57))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('mutant', 'Var', (29, 35))	('IDH1', 'Gene', '3417', (86, 90))	('IDH2', 'Gene', (95, 99))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('IDH2', 'Gene', '3418', (53, 57))	('mutant', 'Var', (46, 52))	('IDH1', 'Gene', '3417', (36, 40))	('IDH2', 'Gene', '3418', (95, 99))	('glioma', 'Disease', (4, 10))
138981	23456655	The levels of the following three molecules were significantly increased in gliomas with a mutant IDH compared with that observed in the wild-type IDH gliomas: citric acid (1.43-fold, p = 0.0114, Q = 0.0447), isocitric acid (1.42-fold, p = 0.0130, Q = 0.0447), and lactic acid (1.18-fold, p = 0.0312, Q = 0.0717) (Table 3; Fig.	('IDH', 'Gene', '3417', (147, 150))	('citric acid', 'Chemical', 'MESH:D019343', (160, 171))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('citric acid', 'MPA', (160, 171))	('IDH', 'Gene', '3417', (98, 101))	('IDH gliomas', 'Disease', 'MESH:D005910', (147, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('isocitric acid', 'Chemical', 'MESH:C034219', (209, 223))	('gliomas', 'Disease', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('citric acid', 'Chemical', 'MESH:D019343', (212, 223))	('lactic acid', 'MPA', (265, 276))	('isocitric acid', 'MPA', (209, 223))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('lactic acid', 'Chemical', 'MESH:D019344', (265, 276))	('gliomas', 'Disease', (151, 158))	('IDH', 'Gene', (147, 150))	('increased', 'PosReg', (63, 72))	('IDH gliomas', 'Disease', (147, 158))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('IDH', 'Gene', (98, 101))	('mutant', 'Var', (91, 97))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))
138982	23456655	In contrast, the levels of pyruvate + oxaloacetic acid was significantly decreased in gliomas with a mutant IDH compared to those with the wild-type IDH (0.62-fold, p = 0.0492, Q = 0.0847) (Table 3; Fig.	('levels of pyruvate + oxaloacetic acid', 'MPA', (17, 54))	('IDH', 'Gene', (149, 152))	('decreased', 'NegReg', (73, 82))	('IDH', 'Gene', (108, 111))	('pyruvate', 'Chemical', 'MESH:D019289', (27, 35))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('IDH', 'Gene', '3417', (149, 152))	('IDH', 'Gene', '3417', (108, 111))	('mutant', 'Var', (101, 107))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('oxaloacetic acid', 'Chemical', 'MESH:D062907', (38, 54))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
138983	23456655	In addition, in gliomas with a mutant IDH, we observed a trend towards lower succinic, fumaric, and malic acid levels, which are downstream metabolites of isocitric acid in the TCA cycle.	('mutant', 'Var', (31, 37))	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('IDH', 'Gene', (38, 41))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('gliomas', 'Disease', (16, 23))	('fumaric', 'MPA', (87, 94))	('isocitric acid', 'Chemical', 'MESH:C034219', (155, 169))	('IDH', 'Gene', '3417', (38, 41))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('succinic', 'MPA', (77, 85))	('malic acid', 'Chemical', 'MESH:C030298', (100, 110))	('malic acid levels', 'MPA', (100, 117))	('TCA', 'Chemical', 'MESH:D014238', (177, 180))	('lower', 'NegReg', (71, 76))
139000	23456655	The lactic acid level in the CSF was significantly elevated in the GBMs compared with the grades I-II gliomas.	('I-II gliomas', 'Disease', 'MESH:D005910', (97, 109))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('GBMs', 'Var', (67, 71))	('lactic acid level in the CSF', 'MPA', (4, 32))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('lactic acid', 'Chemical', 'MESH:D019344', (4, 15))	('elevated', 'PosReg', (51, 59))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))	('I-II gliomas', 'Disease', (97, 109))
139004	23456655	Interestingly, the present study demonstrated that the CSF levels of lactic acid were significantly increased in gliomas with a mutant IDH compared with wild-type IDH in only low-grade gliomas (grades I-III).	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('CSF levels of lactic acid', 'MPA', (55, 80))	('increased', 'PosReg', (100, 109))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH', 'Gene', (163, 166))	('gliomas', 'Disease', (113, 120))	('mutant', 'Var', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('IDH', 'Gene', (135, 138))	('IDH', 'Gene', '3417', (163, 166))	('lactic acid', 'Chemical', 'MESH:D019344', (69, 80))	('IDH', 'Gene', '3417', (135, 138))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('gliomas', 'Disease', (185, 192))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))
139007	23456655	Although gliomas with a mutant IDH are known to be associated with improved survival, further studies are required to determine the association between the CSF lactic acid levels and the prognosis in low-grade gliomas.	('mutant', 'Var', (24, 30))	('gliomas', 'Disease', (210, 217))	('lactic acid', 'Chemical', 'MESH:D019344', (160, 171))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('IDH', 'Gene', (31, 34))	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('IDH', 'Gene', '3417', (31, 34))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('improved', 'PosReg', (67, 75))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
139017	23456655	The CSF levels of citric and isocitric acid, which are TCA cycle metabolites, were significantly elevated in GBMs compared with grades I-II or III gliomas.	('elevated', 'PosReg', (97, 105))	('citric', 'Chemical', 'MESH:D019343', (18, 24))	('II gliomas', 'Disease', (144, 154))	('GBMs', 'Var', (109, 113))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('citric', 'Chemical', 'MESH:D019343', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('TCA', 'Chemical', 'MESH:D014238', (55, 58))	('isocitric acid', 'Chemical', 'MESH:C034219', (29, 43))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('II gliomas', 'Disease', 'MESH:D005910', (144, 154))
139025	23456655	IDH mutations were frequently observed in astrocytic and oligodendroglial tumors of grades II and III.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (57, 80))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('oligodendroglial tumors', 'Disease', (57, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('observed', 'Reg', (30, 38))	('mutations', 'Var', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
139027	23456655	reported that amino acid, choline lipid, and TCA cycle metabolite levels were altered in cells expressing IDH mutants.	('choline', 'Chemical', 'MESH:D002794', (26, 33))	('IDH', 'Gene', '3417', (106, 109))	('TCA cycle metabolite levels', 'MPA', (45, 72))	('mutants', 'Var', (110, 117))	('amino acid', 'MPA', (14, 24))	('lipid', 'Chemical', 'MESH:D008055', (34, 39))	('TCA', 'Chemical', 'MESH:D014238', (45, 48))	('altered', 'Reg', (78, 85))	('IDH', 'Gene', (106, 109))	('choline lipid', 'MPA', (26, 39))
139028	23456655	They described that the late TCA intermediates fumarate and malate were reduced in IDH mutant-expressing cells.	('TCA', 'Chemical', 'MESH:D014238', (29, 32))	('reduced', 'NegReg', (72, 79))	('mutant-expressing', 'Var', (87, 104))	('malate', 'MPA', (60, 66))	('IDH', 'Gene', (83, 86))	('fumarate', 'Chemical', 'MESH:D005650', (47, 55))	('malate', 'Chemical', 'MESH:C030298', (60, 66))	('IDH', 'Gene', '3417', (83, 86))
139030	23456655	Metabolic changes by IDH mutations are reported to be different among cell types; however, further studies are necessary.	('IDH', 'Gene', (21, 24))	('mutations', 'Var', (25, 34))	('IDH', 'Gene', '3417', (21, 24))	('Metabolic changes', 'MPA', (0, 17))
139031	23456655	We discovered that CSF concentrations of pyruvate + oxaloacetic acid were significantly lower in the gliomas with IDH mutations compared with those with a wild-type IDH.	('oxaloacetic acid', 'Chemical', 'MESH:D062907', (52, 68))	('IDH', 'Gene', (165, 168))	('gliomas', 'Disease', (101, 108))	('IDH', 'Gene', '3417', (165, 168))	('IDH', 'Gene', (114, 117))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('mutations', 'Var', (118, 127))	('pyruvate', 'Chemical', 'MESH:D019289', (41, 49))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH', 'Gene', '3417', (114, 117))	('lower', 'NegReg', (88, 93))	('CSF concentrations of pyruvate + oxaloacetic acid', 'MPA', (19, 68))
139032	23456655	In contrast, the CSF concentrations of lactic, citric, and isocitric acid were significantly higher in gliomas with IDH mutations compared with those of a wild-type IDH.	('higher', 'PosReg', (93, 99))	('IDH', 'Gene', (116, 119))	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('IDH', 'Gene', '3417', (116, 119))	('gliomas', 'Disease', (103, 110))	('IDH', 'Gene', (165, 168))	('IDH', 'Gene', '3417', (165, 168))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('isocitric acid', 'Chemical', 'MESH:C034219', (59, 73))	('lactic', 'Chemical', '-', (39, 45))	('citric', 'Chemical', 'MESH:D019343', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('mutations', 'Var', (120, 129))	('CSF concentrations of lactic', 'MPA', (17, 45))	('citric', 'Chemical', 'MESH:D019343', (62, 68))
139033	23456655	In addition, the levels of the late TCA cycle metabolites that act downstream of isocitric acid decreased in the gliomas with IDH mutations.	('levels of the', 'MPA', (17, 30))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH', 'Gene', '3417', (126, 129))	('decreased', 'NegReg', (96, 105))	('gliomas', 'Disease', (113, 120))	('TCA', 'Chemical', 'MESH:D014238', (36, 39))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('mutations', 'Var', (130, 139))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('isocitric acid', 'Chemical', 'MESH:C034219', (81, 95))	('IDH', 'Gene', (126, 129))
139035	23456655	From these data, CSF metabolite levels may reflect the metabolic changes caused by the IDH mutations in the glioma cells.	('CSF metabolite levels', 'MPA', (17, 38))	('glioma', 'Disease', (108, 114))	('IDH', 'Gene', (87, 90))	('metabolic', 'MPA', (55, 64))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('IDH', 'Gene', '3417', (87, 90))	('mutations', 'Var', (91, 100))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('reflect', 'Reg', (43, 50))
139036	23456655	Recently, biochemical studies revealed that mutant IDH1 protein gains the function to catalyze the reduction of alpha-ketoglutarate to 2-hydroxyglutarate (2-HG) in a NADPH-consuming manner.	('IDH1', 'Gene', '3417', (51, 55))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (135, 153))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (112, 131))	('NADPH', 'Chemical', 'MESH:D009249', (166, 171))	('reduction', 'MPA', (99, 108))	('protein', 'Protein', (56, 63))	('IDH1', 'Gene', (51, 55))	('mutant', 'Var', (44, 50))
139038	23456655	However, our study, which used the GCMS-QP2010 Ultra and Plus, did not detect 2-HG in the CSF of the glioma patients with the IDH mutation.	('IDH', 'Gene', '3417', (126, 129))	('mutation', 'Var', (130, 138))	('glioma', 'Disease', (101, 107))	('patients', 'Species', '9606', (108, 116))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH', 'Gene', (126, 129))
139056	23451252	The increased expression of PKM2, however, was also important, because shRNA-mediated PKM2 knockdown decreased total PKM2 and the already low levels of PK activity, but paradoxically also limited cell growth in vitro and in vivo.	('activity', 'MPA', (155, 163))	('PKM2', 'Gene', (28, 32))	('knockdown', 'Var', (91, 100))	('PKM2', 'Gene', (117, 121))	('decreased', 'NegReg', (101, 110))	('PKM2', 'Gene', '5315', (117, 121))	('PKM2', 'Gene', (86, 90))	('cell growth', 'CPA', (196, 207))	('PKM2', 'Gene', '5315', (28, 32))	('PKM2', 'Gene', '5315', (86, 90))	('limited', 'NegReg', (188, 195))
139057	23451252	These results show that pyruvate kinase M expression, but not pyruvate kinase activity, is regulated in a grade-specific manner in glioma, but that changes in both PK activity and PKM2 expression contribute to growth of GBM.	('glioma', 'Disease', (131, 137))	('growth', 'CPA', (210, 216))	('pyruvate kinase M', 'Gene', '5315', (24, 41))	('PKM2', 'Gene', '5315', (180, 184))	('pyruvate', 'Chemical', 'MESH:D019289', (62, 70))	('pyruvate', 'Chemical', 'MESH:D019289', (24, 32))	('pyruvate kinase M', 'Gene', (24, 41))	('PKM2', 'Gene', (180, 184))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('contribute', 'Reg', (196, 206))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('activity', 'MPA', (167, 175))	('changes', 'Var', (148, 155))
139087	23451252	All WHO grade IV specimens were analyzed for IDH1/2 mutations as previously described and those with a previous histological diagnosis of a lower-grade glioma in combination with IDH mutation were defined as secondary GBM (N = 17).	('mutations', 'Var', (52, 61))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (179, 182))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('IDH', 'Gene', '3417', (45, 48))	('glioma', 'Disease', (152, 158))	('IDH1/2', 'Gene', (45, 51))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
139100	23451252	After 2 weeks of G418 selection (1 mg/ml, Roche), 6 colonies were picked, expanded in G418-containing medium, and assessed for PKM1 expression by Western blot analysis.	('G418', 'Chemical', 'MESH:C010680', (17, 21))	('PKM', 'Gene', (127, 130))	('PKM', 'Gene', '5315', (127, 130))	('G418', 'Var', (17, 21))	('G418', 'Chemical', 'MESH:C010680', (86, 90))
139113	23451252	Tumor growth was monitored weekly by treating mice with D-luciferin (150 mg/kg IP, Gold-Biotechnology) and measuring bioluminescence using a Xenogen IVIS Bioluminescence imaging station (Caliper).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('D-luciferin', 'Chemical', 'MESH:C532924', (56, 67))	('mice', 'Species', '10090', (46, 50))	('D-luciferin', 'Var', (56, 67))	('measuring bioluminescence', 'MPA', (107, 132))
139146	23451252	Specifically, expression of PKM1 increased the intracellular levels of ATP (Fig 3C) and pyruvate (Fig 3D) and decreased the intracellular levels of lactate (Fig 3E), consistent with the ability of the constitutively active PKM1 isoform to convert PEP to pyruvate and to direct this pyruvate away from lactate production and toward ATP production in the mitochondria.	('lactate', 'Chemical', 'MESH:D019344', (301, 308))	('PKM', 'Gene', '5315', (28, 31))	('pyruvate', 'Chemical', 'MESH:D019289', (282, 290))	('ATP', 'Gene', '51761', (331, 334))	('ATP', 'Gene', (71, 74))	('expression', 'Var', (14, 24))	('PKM', 'Gene', (223, 226))	('pyruvate', 'Chemical', 'MESH:D019289', (88, 96))	('lactate', 'Chemical', 'MESH:D019344', (148, 155))	('intracellular levels of lactate', 'MPA', (124, 155))	('PKM', 'Gene', '5315', (223, 226))	('pyruvate', 'Chemical', 'MESH:D019289', (254, 262))	('decreased', 'NegReg', (110, 119))	('increased', 'PosReg', (33, 42))	('ATP', 'Gene', (331, 334))	('PEP', 'Chemical', 'MESH:D010728', (247, 250))	('ATP', 'Gene', '51761', (71, 74))	('PKM', 'Gene', (28, 31))	('pyruvate', 'MPA', (88, 96))
139155	23451252	PKM2, however, also has activities that allow it, even in the metabolically inactive dimeric form, to stimulate growth, and consistent with these observations, PKM2 knock-down cells proliferated more slowly in culture (Fig 4F), formed fewer and smaller colonies in soft agar (Fig 4 G-H), formed tumors that were smaller than those formed by control cells 24 days following intracranial implantation (Fig 5A), and took significantly longer to result in symptoms that necessitated sacrifice of the animals (Fig 5B).	('tumors', 'Disease', (295, 301))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('PKM2', 'Gene', (0, 4))	('PKM2', 'Gene', '5315', (0, 4))	('knock-down', 'Var', (165, 175))	('fewer', 'NegReg', (235, 240))	('formed', 'Reg', (288, 294))	('PKM2', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('proliferated', 'CPA', (182, 194))	('slowly', 'NegReg', (200, 206))	('colonies', 'CPA', (253, 261))	('PKM2', 'Gene', '5315', (160, 164))	('smaller', 'NegReg', (245, 252))
139180	23451252	A number of genetic events including c-myc over-expression, growth factor over-expression, and Ras pathway activation have been linked to the control of PKM transcript splicing, and the increased incidence of these alterations in GBM may tilt the balance of splicing toward production of the PKM2 transcript and help explain the grade-specific increases in PKM2 expression noted.	('PKM', 'Gene', '5315', (357, 360))	('PKM', 'Gene', (292, 295))	('Ras', 'Pathway', (95, 98))	('PKM', 'Gene', '5315', (292, 295))	('PKM', 'Gene', '5315', (153, 156))	('PKM2', 'Gene', '5315', (357, 361))	('PKM2', 'Gene', (292, 296))	('alterations', 'Var', (215, 226))	('splicing', 'MPA', (258, 266))	('balance', 'MPA', (247, 254))	('PKM2', 'Gene', '5315', (292, 296))	('GBM', 'Gene', (230, 233))	('PKM', 'Gene', (153, 156))	('c-myc', 'Gene', '4609', (37, 42))	('c-myc', 'Gene', (37, 42))	('PKM2', 'Gene', (357, 361))	('PKM', 'Gene', (357, 360))
139181	23451252	It's worth noting, however, that the present study examined both de novo GBM, as well as secondary GBM that arose from lower grade tumors based on their mutant IDH status.	('GBM', 'Disease', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mutant', 'Var', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('IDH', 'Gene', (160, 163))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('IDH', 'Gene', '3417', (160, 163))
139189	23451252	While the effects of PKM2 knock-down noted in the present study are consistent with the non-metabolic effects of PKM2, the accumulation of cells was not associated with a generalized slowing in cell cycle progression but rather a specific G2 arrest.	('G2 arrest', 'CPA', (239, 248))	('knock-down', 'Var', (26, 36))	('PKM2', 'Gene', (21, 25))	('PKM2', 'Gene', '5315', (21, 25))	('cell cycle progression', 'CPA', (194, 216))	('PKM2', 'Gene', (113, 117))	('PKM2', 'Gene', '5315', (113, 117))
139194	33557011	Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies Gliomas are major causes of worldwide cancer-associated deaths in children.	('children', 'Species', '9606', (164, 172))	('Gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('Glioma', 'Phenotype', 'HP:0009733', (98, 104))	('Gliomas', 'Disease', 'MESH:D005910', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('Glioma', 'Phenotype', 'HP:0009733', (11, 17))	('Gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('cancer', 'Disease', (136, 142))	('deaths', 'Disease', (154, 160))	('Gliomas', 'Disease', (98, 105))	('BRAF', 'Gene', '673', (20, 24))	('Gliomas', 'Disease', 'MESH:D005910', (11, 18))	('deaths', 'Disease', 'MESH:D003643', (154, 160))	('BRAF', 'Gene', (20, 24))	('Histone', 'Var', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Gliomas', 'Disease', (11, 18))
139201	33557011	A body of evidence demonstrates that B-Raf Proto-Oncogene or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and histone H3 mutations are valuable biomarkers for paediatric low-grade gliomas (pLGGs) and high-grade gliomas (pHGGs).	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('Sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('Sarcoma', 'Disease', (74, 81))	('mutations', 'Var', (129, 138))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('gliomas', 'Disease', (188, 195))	('gliomas', 'Disease', (219, 226))	('Sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))
139203	33557011	Although histone H3 mutations are reliable prognosis biomarkers in pHGGs, children with these mutations have a dismal prognosis.	('pHGGs', 'Disease', (67, 72))	('children', 'Species', '9606', (74, 82))	('histone H3', 'Protein', (9, 19))	('mutations', 'Var', (20, 29))
139204	33557011	The BRAF V600E mutation is seen in the majority of pLGGs (as seen in pleomorphic xanthoastrocytoma and gangliomas).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('pLGGs', 'Disease', (51, 56))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('pleomorphic xanthoastrocytoma and gangliomas', 'Disease', 'MESH:D008228', (69, 113))
139205	33557011	By contrast, the H3K27M mutation is found in the majority of paediatric diffuse intrinsic pontine glioma and other midline gliomas in pHGGs.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('midline gliomas', 'Disease', (115, 130))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('midline gliomas', 'Disease', 'MESH:D005910', (115, 130))	('H3K27M', 'Var', (17, 23))	('glioma', 'Disease', (98, 104))	('glioma', 'Disease', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('K27M', 'Mutation', 'p.K27M', (19, 23))
139206	33557011	pLGG patients with a BRAF V600E mutation often have a lower progression-free survival rate in comparison to wild-type pLGGs when treated with conventional therapies.	('patients', 'Species', '9606', (5, 13))	('pLGG', 'Disease', (0, 4))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', (21, 25))	('progression-free survival rate', 'CPA', (60, 90))	('V600E', 'Var', (26, 31))	('lower', 'NegReg', (54, 59))
139207	33557011	BRAF inhibitors (Dabrafenib and Vemurafenib), however, show higher overall survival and tumour response in BRAF V600E mutated pLGGs than conventional therapies in some studies.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('BRAF', 'Gene', (107, 111))	('V600E mutated', 'Var', (112, 125))	('tumour', 'Disease', (88, 94))	('higher', 'PosReg', (60, 66))	('V600E', 'Mutation', 'rs113488022', (112, 117))	('overall survival', 'CPA', (67, 83))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('Dabrafenib', 'Chemical', 'MESH:C561627', (17, 27))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (32, 43))
139208	33557011	To date, targeted therapy and precision medicine are promising avenues for paediatric gliomas with BRAF V600E and diffuse intrinsic pontine glioma with the H3K27M mutations.	('BRAF V600E', 'Var', (99, 109))	('glioma', 'Disease', (86, 92))	('paediatric', 'Disease', (75, 85))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('H3K27M', 'Var', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('K27M', 'Mutation', 'p.K27M', (158, 162))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('glioma', 'Disease', (140, 146))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
139210	33557011	The present review discusses the diagnostic tools and the perspective of liquid biopsies in the detection of BRAF V600E and H3K27M mutations.	('H3K27M', 'Var', (124, 130))	('K27M', 'Mutation', 'p.K27M', (126, 130))	('BRAF', 'Gene', (109, 113))	('V600E', 'Mutation', 'rs113488022', (114, 119))
139223	33557011	Since then, other genetic alterations, predominantly BRAF-KIAA1549 fusion genes, which were involved in the MAPK pathway were identified.	('KIAA1549', 'Gene', (58, 66))	('KIAA1549', 'Gene', '57670', (58, 66))	('fusion', 'Var', (67, 73))
139224	33557011	BRAF-KIAA1549 fusions are the most prevalent alterations in pLGGs, accounting for two-thirds of pLGGs, while BRAF V600E mutations only contribute to 17% of pLGGs.	('prevalent', 'Reg', (35, 44))	('pLGGs', 'Disease', (96, 101))	('V600E', 'Var', (114, 119))	('KIAA1549', 'Gene', (5, 13))	('KIAA1549', 'Gene', '57670', (5, 13))	('V600E', 'Mutation', 'rs113488022', (114, 119))
139225	33557011	pLGG patients with the BRAF V600E mutation respond poorly to both radiotherapy and chemotherapy, resulting in a lower progression-free survival (PFS) rate over five and 10 years in comparison to LGGs the of wild-type status.	('V600E', 'Var', (28, 33))	('patients', 'Species', '9606', (5, 13))	('BRAF', 'Gene', (23, 27))	('progression-free survival', 'CPA', (118, 143))	('V600E', 'Mutation', 'rs113488022', (28, 33))	('lower', 'NegReg', (112, 117))
139231	33557011	Histone H3 mutations were first discovered in pHGGs in 2012, and the histone H3K27M mutation constitutes most of the somatic mutations in diffuse midline glioma.	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('midline glioma', 'Disease', 'MESH:D005910', (146, 160))	('midline glioma', 'Disease', (146, 160))	('K27M', 'Mutation', 'p.K27M', (79, 83))	('histone H3K27M mutation', 'Var', (69, 92))
139232	33557011	Histone mutations are highly prevalent in pHGGs in comparison to other forms of malignancies.	('pHGGs', 'Disease', (42, 47))	('Histone', 'Protein', (0, 7))	('prevalent', 'Reg', (29, 38))	('mutations', 'Var', (8, 17))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('malignancies', 'Disease', (80, 92))
139234	33557011	These histone mutations cause the substitution of lysine at position 27 with methionine (K27M) on the histone tail.	('K27M', 'Mutation', 'p.K27M', (89, 93))	('cause', 'Reg', (24, 29))	('histone', 'Gene', (6, 13))	('lysine at position 27 with methionine', 'Mutation', 'p.K27M', (50, 87))	('K27M', 'Var', (89, 93))	('substitution', 'Var', (34, 46))	('mutations', 'Var', (14, 23))
139235	33557011	The tumours with the H3.3K27M mutation are more aggressive clinically than those with the H3.1K27M mutation.	('H3.3K27M', 'Var', (21, 29))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('K27M', 'Mutation', 'p.K27M', (25, 29))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('K27M', 'Mutation', 'p.K27M', (94, 98))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('aggressive clinically', 'CPA', (48, 69))	('tumours', 'Disease', (4, 11))
139236	33557011	The K27M mutation causes tumour progression by interfering with the post-translational modifications of H3.	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('causes', 'Reg', (18, 24))	('K27M', 'Var', (4, 8))	('tumour', 'Disease', (25, 31))	('interfering', 'NegReg', (47, 58))	('post-translational modifications', 'MPA', (68, 100))
139237	33557011	Besides, molecular alterations in children with pHGGs are commonly associated with histone H3 mutations, whereas IDH mutations, PTEN loss, and EGFR amplifications are commonly found in adult HGG but rarely happen in pHGGs.	('EGFR', 'Gene', (143, 147))	('IDH', 'Gene', '3417', (113, 116))	('molecular alterations', 'Var', (9, 30))	('pHGGs', 'Disease', (48, 53))	('mutations', 'Var', (94, 103))	('PTEN loss', 'Disease', 'MESH:D006223', (128, 137))	('associated', 'Reg', (67, 77))	('EGFR', 'Gene', '1956', (143, 147))	('PTEN loss', 'Disease', (128, 137))	('IDH', 'Gene', (113, 116))	('children', 'Species', '9606', (34, 42))	('histone H3', 'Protein', (83, 93))
139239	33557011	Most importantly, understanding the pathogenesis of BRAF and histone H3 mutations and the feasibility of these biomarkers to be utilised as diagnostic and prognostic tools are more crucial, because these mutations are unique alterations that are distinct from adult gliomas and constitute the highest percentage in paediatric gliomas.	('mutations', 'Var', (72, 81))	('glioma', 'Phenotype', 'HP:0009733', (326, 332))	('mutations', 'Var', (204, 213))	('gliomas', 'Disease', 'MESH:D005910', (266, 273))	('gliomas', 'Phenotype', 'HP:0009733', (266, 273))	('gliomas', 'Disease', (266, 273))	('gliomas', 'Disease', 'MESH:D005910', (326, 333))	('gliomas', 'Phenotype', 'HP:0009733', (326, 333))	('gliomas', 'Disease', (326, 333))	('BRAF', 'Gene', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (266, 272))
139243	33557011	This article reviews critically the use of BRAF V600E and H3K27M mutations as biomarkers and targeted options as well as their associated challenges in translating these biomarkers to clinical applications for paediatric gliomas.	('K27M', 'Mutation', 'p.K27M', (60, 64))	('gliomas', 'Disease', (221, 228))	('gliomas', 'Disease', 'MESH:D005910', (221, 228))	('gliomas', 'Phenotype', 'HP:0009733', (221, 228))	('BRAF', 'Gene', (43, 47))	('V600E', 'Mutation', 'rs113488022', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('H3K27M', 'Var', (58, 64))
139244	33557011	In addition, the diagnostic tools and the potential of liquid biopsy in the detection of BRAF V600E and H3K27M mutations for the diagnosis of paediatric gliomas are discussed intensively.	('K27M', 'Mutation', 'p.K27M', (106, 110))	('gliomas', 'Disease', (153, 160))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('BRAF', 'Gene', (89, 93))	('H3K27M', 'Var', (104, 110))	('paediatric', 'Disease', (142, 152))	('V600E', 'Mutation', 'rs113488022', (94, 99))
139251	33557011	The BRAF V600E mutation is a point mutation, in which valine at position 600 is replaced with glutamic acid, whereas, for the BRAF-KIAA1549 fusion, the BRAF gene fused with the KIAA1549 gene, causing the removal of the regulatory domain.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('BRAF', 'Gene', (152, 156))	('valine at position 600 is replaced with glutamic acid', 'Mutation', 'rs113488022', (54, 107))	('regulatory domain', 'MPA', (219, 236))	('V600E', 'Var', (9, 14))	('removal', 'NegReg', (204, 211))	('KIAA1549', 'Gene', '57670', (131, 139))	('KIAA1549', 'Gene', (131, 139))	('KIAA1549', 'Gene', (177, 185))	('KIAA1549', 'Gene', '57670', (177, 185))
139257	33557011	The BRAF-KIAA1549 fusions predominantly occur in pLGGs, and 70% are detected in pilocytic astrocytoma, which is usually located at the posterior fossa and cerebellum.	('fusions', 'Var', (18, 25))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (80, 101))	('pLGGs', 'Disease', (49, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('KIAA1549', 'Gene', '57670', (9, 17))	('pilocytic astrocytoma', 'Disease', (80, 101))	('KIAA1549', 'Gene', (9, 17))	('occur', 'Reg', (40, 45))
139258	33557011	BRAF alterations, especially V600E, have been studied intensively as potential diagnostic biomarkers for different types of cancers, including melanoma, colorectal cancer, papillary thyroid carcinoma and hairy cell leukaemia.	('V600E', 'Mutation', 'rs113488022', (29, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('hairy cell leukaemia', 'Disease', 'MESH:D007943', (204, 224))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (182, 199))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('colorectal cancer', 'Disease', (153, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('hairy cell leukaemia', 'Disease', (204, 224))	('V600E', 'Var', (29, 34))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (172, 199))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('papillary thyroid carcinoma', 'Disease', (172, 199))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('cancers', 'Disease', (124, 131))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (172, 199))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
139261	33557011	employed the NanoString nCounter System for detecting duplications and different configurations of BRAF-KIAA1549 fusions (97% sensitivity and 98% specificity) in 90 FFPE pLGG samples.	('KIAA1549', 'Gene', '57670', (104, 112))	('fusions', 'Var', (113, 120))	('duplications', 'Var', (54, 66))	('KIAA1549', 'Gene', (104, 112))
139263	33557011	Most recently, the BRAF V600E mutation in the FFPE samples of paediatric and adult LGGs were detected using a fully automated PCR with 100% sensitivity and specificity when compared with PCR and next-generation sequencing.	('V600E', 'Var', (24, 29))	('BRAF', 'Gene', (19, 23))	('V600E', 'Mutation', 'rs113488022', (24, 29))
139265	33557011	Liquid biopsies of circulating tumour DNA in the plasma, serum and CSF isolated from 29 CNS paediatric patients revealed the presence of the BRAF V600E mutation.	('BRAF', 'Gene', (141, 145))	('V600E', 'Var', (146, 151))	('V600E', 'Mutation', 'rs113488022', (146, 151))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (103, 111))	('tumour', 'Disease', (31, 37))
139267	33557011	To date, the prognostic value of BRAF alterations, either BRAF-KIAA1549 or BRAF V600E, in pLGGs remains questionable.	('KIAA1549', 'Gene', '57670', (63, 71))	('pLGGs', 'Disease', (90, 95))	('KIAA1549', 'Gene', (63, 71))	('BRAF V600E', 'Var', (75, 85))	('V600E', 'Mutation', 'rs113488022', (80, 85))
139268	33557011	Two independent studies supported the role of BRAF-KIAA1549 fusions as prognostic biomarkers.	('KIAA1549', 'Gene', '57670', (51, 59))	('fusions', 'Var', (60, 67))	('KIAA1549', 'Gene', (51, 59))
139270	33557011	Regardless of the patients' ages, tumour locations and pathology, the results revealed that the clinical outcomes of patients with these fusions had a five-year PFS of 61%, significantly better than those without the fusions, which was only 18%.	('PFS', 'MPA', (161, 164))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('fusions', 'Var', (137, 144))	('patients', 'Species', '9606', (18, 26))	('better', 'PosReg', (187, 193))	('patients', 'Species', '9606', (117, 125))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
139271	33557011	showed a significant improvement in PFS of all pLGGs harbouring BRAF-KIAA1549 fusions as compared to those without the fusions.	('improvement', 'PosReg', (21, 32))	('KIAA1549', 'Gene', '57670', (69, 77))	('fusions', 'Var', (78, 85))	('KIAA1549', 'Gene', (69, 77))	('PFS', 'MPA', (36, 39))
139273	33557011	Conversely, Colin and colleagues argued that the prognostic factors, including patients' ages, extent of tumour resections and tumour locations of the BRAF-KIAA1549 fusions, are significantly associated with the clinical outcomes.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('associated', 'Reg', (192, 202))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', (105, 111))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('fusions', 'Var', (165, 172))	('KIAA1549', 'Gene', '57670', (156, 164))	('patients', 'Species', '9606', (79, 87))	('tumour', 'Disease', (127, 133))	('KIAA1549', 'Gene', (156, 164))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
139275	33557011	A meta-analysis encompassing 1308 adults and paediatric gliomas from 11 studies revealed that children aged 0 to 16 years old with a BRAF V600E mutation have a favourable prognosis, with a hazard ratio of 0.51.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('V600E', 'Var', (138, 143))	('children', 'Species', '9606', (94, 102))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('BRAF', 'Gene', (133, 137))	('V600E', 'Mutation', 'rs113488022', (138, 143))
139277	33557011	demonstrated that pLGGs harbouring BRAF mutations together with CDKN2A deletion have a high chance to transform into HGG, because CDKN2A deletion might alter the clinical behaviour of the BRAF V600E mutant tumours.	('CDKN2A', 'Gene', (130, 136))	('V600E', 'Mutation', 'rs113488022', (193, 198))	('CDKN2A', 'Gene', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('deletion', 'Var', (137, 145))	('BRAF', 'Gene', (188, 192))	('CDKN2A', 'Gene', '1029', (130, 136))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('mutations', 'Var', (40, 49))	('CDKN2A', 'Gene', '1029', (64, 70))	('V600E', 'Var', (193, 198))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('clinical behaviour', 'MPA', (162, 180))	('alter', 'Reg', (152, 157))	('tumours', 'Disease', (206, 213))
139278	33557011	revealed that the five-year PFS of pLGG patients with a BRAF V600E mutation and CDKN2A deletion was low (approximately 24%), while those without the deletion had a five-year PFS of 68.7%.	('CDKN2A', 'Gene', '1029', (80, 86))	('patients', 'Species', '9606', (40, 48))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('pLGG', 'Disease', (35, 39))	('V600E', 'Var', (61, 66))	('deletion', 'Var', (87, 95))	('CDKN2A', 'Gene', (80, 86))	('BRAF', 'Gene', (56, 60))
139279	33557011	Additionally, the 10-year PFS of BRAF V600E patients with CDKN2A deletion and without the deletion were approximately 0% and 46%, respectively.	('patients', 'Species', '9606', (44, 52))	('BRAF', 'Gene', (33, 37))	('CDKN2A', 'Gene', (58, 64))	('V600E', 'Mutation', 'rs113488022', (38, 43))	('deletion', 'Var', (65, 73))	('CDKN2A', 'Gene', '1029', (58, 64))
139280	33557011	The authors claimed that BRAF V600E mutations with other associated alterations might influence the prognosis.	('BRAF', 'Gene', (25, 29))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('influence', 'Reg', (86, 95))	('V600E mutations', 'Var', (30, 45))
139281	33557011	There are still many factors that have yet to be investigated thoroughly, including confounding factors, the relationship of BRAF mutations and other associated genetic alterations, as well as BRAF alterations as an independent prognostic indicator in affecting the clinical outcomes of patients.	('affecting', 'Reg', (252, 261))	('patients', 'Species', '9606', (287, 295))	('alterations', 'Reg', (198, 209))	('mutations', 'Var', (130, 139))	('BRAF', 'Gene', (125, 129))
139284	33557011	The most common histone H3 mutation involves the substitution of lysine at position 27 with methionine (H3K27M) in variants H3.1 and H3.3, encoded by the HIST1H3B and H3F3A genes, respectively.	('K27M', 'Mutation', 'p.K27M', (106, 110))	('HIST1H3B', 'Gene', (154, 162))	('HIST1H3B', 'Gene', '8358', (154, 162))	('histone H3', 'Gene', (16, 26))	('H3.1', 'Gene', (124, 128))	('H3F3A', 'Gene', (167, 172))	('mutation', 'Var', (27, 35))	('substitution', 'Var', (49, 61))	('H3.1', 'Gene', '8352', (124, 128))	('lysine at position 27 with methionine', 'Mutation', 'p.K27M', (65, 102))	('H3F3A', 'Gene', '3020', (167, 172))
139285	33557011	In addition, other mutations also take place in histone H3.3, of which glycine 34 is replaced with valine or arginine (H3.3G34V/R), mainly involving the H3F3A gene.	('H3F3A', 'Gene', (153, 158))	('glycine 34 is replaced with valine', 'SUBSTITUTION', 'None', (71, 105))	('H3F3A', 'Gene', '3020', (153, 158))	('H3.3G34V/R', 'Var', (119, 129))	('glycine 34 is replaced with valine', 'Var', (71, 105))
139287	33557011	The H3.3 and H3.1 mutations were detected in FFPE tissues from 143 paediatric high-grade astrocytomas using immunohistochemistry, and this result was in good agreement with that determined with the pyrosequencing method.	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('H3.1', 'Gene', '8352', (13, 17))	('astrocytomas', 'Disease', 'MESH:D001254', (89, 101))	('detected', 'Reg', (33, 41))	('astrocytomas', 'Disease', (89, 101))	('H3.3', 'Gene', (4, 8))	('H3.1', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
139288	33557011	The missense H3K27M mutation is mostly found in pHGGs derived from midline locations of the brain, including the brainstem, thalamus, pons, cerebellum and spinal cord.	('missense', 'Var', (4, 12))	('H3K27M', 'Gene', (13, 19))	('K27M', 'Mutation', 'p.K27M', (15, 19))
139289	33557011	A point mutation in the histone H3 variant (H3.3 or H3.1) is commonly found in diffuse intrinsic pontine glioma.	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('H3.1', 'Gene', (52, 56))	('glioma', 'Disease', (105, 111))	('point mutation', 'Var', (2, 16))	('H3.1', 'Gene', '8352', (52, 56))	('found', 'Reg', (70, 75))	('glioma', 'Disease', 'MESH:D005910', (105, 111))
139290	33557011	reported that 78% of H3K27M mutations are detected in diffuse intrinsic pontine glioma, approximately 60% and 18% of which involve the H3F3A gene and HIST1H3B gene, respectively.	('glioma', 'Disease', (80, 86))	('HIST1H3B', 'Gene', (150, 158))	('HIST1H3B', 'Gene', '8358', (150, 158))	('H3F3A', 'Gene', '3020', (135, 140))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('involve', 'Reg', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('H3K27M', 'Gene', (21, 27))	('H3F3A', 'Gene', (135, 140))	('mutations', 'Var', (28, 37))	('K27M', 'Mutation', 'p.K27M', (23, 27))	('detected', 'Reg', (42, 50))
139291	33557011	studied 49 patients with paediatric diffuse midline glioma and discovered that 80% of the tumour carried H3K27M mutations, of which 63.6% and 15.9% of the H3F3A and HIST1H3B genes, respectively, were mutated.	('H3K27M', 'Gene', (105, 111))	('HIST1H3B', 'Gene', (165, 173))	('HIST1H3B', 'Gene', '8358', (165, 173))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('H3F3A', 'Gene', '3020', (155, 160))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (112, 121))	('K27M', 'Mutation', 'p.K27M', (107, 111))	('midline glioma', 'Disease', 'MESH:D005910', (44, 58))	('midline glioma', 'Disease', (44, 58))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('patients', 'Species', '9606', (11, 19))	('H3F3A', 'Gene', (155, 160))	('tumour', 'Disease', (90, 96))
139292	33557011	The studies demonstrated that H3F3A and HIST1H3B mutations are common in the pHGGs derived from midline locations of the brain.	('HIST1H3B', 'Gene', '8358', (40, 48))	('common', 'Reg', (63, 69))	('mutations', 'Var', (49, 58))	('H3F3A', 'Gene', (30, 35))	('H3F3A', 'Gene', '3020', (30, 35))	('HIST1H3B', 'Gene', (40, 48))
139293	33557011	These mutations are hardly found in adult malignant gliomas, thus making H3K27M a distinct biomarker for paediatric gliomas.	('H3K27M', 'Var', (73, 79))	('gliomas', 'Disease', (52, 59))	('K27M', 'Mutation', 'p.K27M', (75, 79))	('malignant gliomas', 'Disease', (42, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('malignant gliomas', 'Disease', 'MESH:D005910', (42, 59))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
139296	33557011	In another study using CSF-derived DNA from paediatric midline gliomas, H3 mutations were detected using Sanger sequencing and nested PCR targeting H3F3A, with a sensitivity and specificity of 87.5% and 100%, respectively.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('midline gliomas', 'Disease', 'MESH:D005910', (55, 70))	('H3F3A', 'Gene', '3020', (148, 153))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('mutations', 'Var', (75, 84))	('H3F3A', 'Gene', (148, 153))	('midline gliomas', 'Disease', (55, 70))
139299	33557011	Most importantly, 82.5% of the 57 CSF-circulating tumour DNA samples harboured a single tumour-specific mutation, indicating the potential of CSF-circulating tumour DNA in detecting mutations in brainstem gliomas.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (195, 212))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', (88, 94))	('tumour', 'Disease', (50, 56))	('gliomas', 'Disease', (205, 212))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('brainstem glioma', 'Phenotype', 'HP:0010796', (195, 211))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('tumour', 'Disease', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('mutations', 'Var', (182, 191))
139300	33557011	This finding was corroborated with another study that detected 88% of the CSF, and plasma-circulating tumour DNA harboured H3K27M mutations in diffuse midline glioma patients.	('midline glioma', 'Disease', (151, 165))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('H3K27M', 'Gene', (123, 129))	('tumour', 'Disease', (102, 108))	('mutations', 'Var', (130, 139))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('K27M', 'Mutation', 'p.K27M', (125, 129))	('patients', 'Species', '9606', (166, 174))	('midline glioma', 'Disease', 'MESH:D005910', (151, 165))
139303	33557011	Paediatric groups that suffer from diffuse intrinsic pontine glioma containing H3K27M mutations have a worse prognosis with a median survival of 0.73 years, as compared to those harbouring wild-type tumours: 4.59 years.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('mutations', 'Var', (86, 95))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('K27M', 'Mutation', 'p.K27M', (81, 85))	('tumours', 'Disease', (199, 206))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('glioma', 'Disease', (61, 67))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('H3K27M', 'Gene', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
139306	33557011	demonstrated that molecular alterations and clinical behaviour within H3.1K27M and H3.3K27M could affect the patients' prognoses.	('K27M', 'Mutation', 'p.K27M', (74, 78))	('H3.3K27M', 'Var', (83, 91))	('patients', 'Species', '9606', (109, 117))	('K27M', 'Mutation', 'p.K27M', (87, 91))	('H3.1K27M', 'Var', (70, 78))	('affect', 'Reg', (98, 104))
139307	33557011	Most recently, a retrospective study introduced three prognostic markers to refine diffuse midline glioma prognosis: the loss of 17p, PDGFRA amplification and a complex chromosomal profile.	('17p', 'Protein', (129, 132))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('loss', 'Var', (121, 125))	('midline glioma', 'Disease', 'MESH:D005910', (91, 105))	('midline glioma', 'Disease', (91, 105))	('PDGFRA', 'Gene', '5156', (134, 140))	('PDGFRA', 'Gene', (134, 140))
139310	33557011	The researchers demonstrated that H3K27M mutations were associated with worsen clinical outcome regardless of anatomic location, the extent of surgical resection and histopathological grading.	('mutations', 'Var', (41, 50))	('associated', 'Reg', (56, 66))	('H3K27M', 'Protein', (34, 40))	('K27M', 'Mutation', 'p.K27M', (36, 40))	('worsen', 'NegReg', (72, 78))
139311	33557011	This indicates that H3K27M mutations in paediatric diffuse midline glioma patients can be used as important prognostic biomarkers.	('mutations', 'Var', (27, 36))	('K27M', 'Mutation', 'p.K27M', (22, 26))	('patients', 'Species', '9606', (74, 82))	('H3K27M', 'Protein', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('midline glioma', 'Disease', 'MESH:D005910', (59, 73))	('midline glioma', 'Disease', (59, 73))
139313	33557011	However, these diagnostic methods cannot provide information on chromosomal mutations and rearrangements of the tumours, which is crucial in diagnosing pHGGs associated with H3 mutations.	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('associated', 'Reg', (158, 168))	('pHGGs', 'Disease', (152, 157))	('mutations', 'Var', (177, 186))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumours', 'Disease', (112, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))
139319	33557011	However, the whole-genome sequencing of liquid biopsies is gaining popularity for detecting H3 mutations in pHGGs owing to the precision of the method to determine single and multiple mutations in cancerous cells, as well as the accessibility of tumour materials in liquid biopsies.	('tumour', 'Disease', (246, 252))	('cancerous', 'Disease', (197, 206))	('pHGGs', 'Gene', (108, 113))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancerous', 'Disease', 'MESH:D009369', (197, 206))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('tumour', 'Disease', 'MESH:D009369', (246, 252))
139321	33557011	If this phenomenon is true for paediatric cancers, it could explain why liquid biopsies are not popular in pLGGs, as the circulating tumour DNA concentration in plasma could be too low for detecting BRAF V600E mutations.	('cancers', 'Disease', (42, 49))	('V600E', 'Mutation', 'rs113488022', (204, 209))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('BRAF V600E mutations', 'Var', (199, 219))
139324	33557011	Collectively, not many diagnostic and sampling methods have been developed for detecting the BRAF V600E mutation, as compared to BRAF-KIAA1549 mutations.	('BRAF', 'Gene', (93, 97))	('KIAA1549', 'Gene', (134, 142))	('KIAA1549', 'Gene', '57670', (134, 142))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('V600E', 'Var', (98, 103))
139325	33557011	Hence, the development of diagnostic assays for detecting the BRAF V600E mutation in pLGGs using liquid biopsies is the way forward.	('BRAF V600E', 'Var', (62, 72))	('V600E', 'Mutation', 'rs113488022', (67, 72))	('pLGGs', 'Gene', (85, 90))
139342	33557011	Dabrafenib is a selective BRAF V600E inhibitor with a significant clinical response in a variety of BRAF V600E adult malignancies, including melanoma, non-small cell lung cancer and anaplastic thyroid cancer.	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('anaplastic thyroid cancer', 'Disease', (182, 207))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (182, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('malignancies', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', (151, 177))	('BRAF V600E', 'Var', (100, 110))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (182, 207))	('thyroid cancer', 'Phenotype', 'HP:0002890', (193, 207))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('V600E', 'Mutation', 'rs113488022', (31, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))
139343	33557011	The drug is approved for the treatment of unresectable or metastatic BRAF V600E melanoma as a single agent or in combination with the MEK inhibitor Trametinib.	('MEK', 'Gene', (134, 137))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('Trametinib', 'Chemical', 'MESH:C560077', (148, 158))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('MEK', 'Gene', '5609', (134, 137))	('BRAF V600E', 'Var', (69, 79))
139344	33557011	The positive clinical response to Dabrafenib in these BRAF V600E adult malignancies has opened doors to several trials of the drug in paediatric gliomas, in which the initial findings demonstrated that Dabrafenib in BRAF V600-relapsed or refractory pLGGs showed an overall response rate of 41%.	('BRAF V600-relapsed', 'Var', (216, 234))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('malignancies', 'Disease', (71, 83))	('Dabrafenib', 'Chemical', 'MESH:C561627', (34, 44))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('BRAF', 'Var', (54, 58))	('Dabrafenib', 'Chemical', 'MESH:C561627', (202, 212))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('gliomas', 'Disease', (145, 152))
139350	33557011	Vemurafenib is a small molecule that acts as a competitive and selective inhibitor of the ATP-binding domain of the BRAF V600E mutation in cells.	('V600E', 'Var', (121, 126))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (116, 120))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('V600E', 'Mutation', 'rs113488022', (121, 126))
139351	33557011	The drug has been approved by the Food and Drug Administration (FDA) for treating metastatic melanomas with the same mutation.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('melanomas', 'Disease', (93, 102))	('mutation', 'Var', (117, 125))
139359	33557011	Fractionated external beam radiotherapy (doses from 54 to 60 Gy) is the standard treatment for midline gliomas with the H3K27 mutation.	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('midline gliomas', 'Disease', (95, 110))	('mutation', 'Var', (126, 134))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('midline gliomas', 'Disease', 'MESH:D005910', (95, 110))	('H3K27', 'Gene', (120, 125))
139361	33557011	The role of the chemotherapeutic agent, Temozolomide remains unclear in pHGGs with the H3K27 mutation, as these gliomas are O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('H3K27', 'Gene', (87, 92))	('Temozolomide', 'Chemical', 'MESH:D000077204', (40, 52))	('mutation', 'Var', (93, 101))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (124, 163))	('gliomas', 'Disease', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (124, 163))	('MGMT', 'Gene', (165, 169))	('MGMT', 'Gene', '4255', (165, 169))
139365	33557011	Therefore, the deregulation or mutations of HDAC may promote human malignancy.	('mutations', 'Var', (31, 40))	('malignancy', 'Disease', 'MESH:D009369', (67, 77))	('HDAC', 'Gene', (44, 48))	('deregulation', 'Var', (15, 27))	('malignancy', 'Disease', (67, 77))	('HDAC', 'Gene', '9734', (44, 48))	('human', 'Species', '9606', (61, 66))	('promote', 'PosReg', (53, 60))
139374	33557011	The drug temporarily inhibited the growth of a H3.3K27M tumour at a dosage of 10 mg/kg, three times a week, to a Nonobese diabetic/severe combined immunodeficiency (NOD-SCID) patient-derived orthotopic xenograft diffuse intrinsic pontine glioma mice model.	('immunodeficiency', 'Disease', (147, 163))	('H3.3K27M', 'Var', (47, 55))	('diabetic', 'Disease', 'MESH:D003920', (122, 130))	('diabetic', 'Disease', (122, 130))	('inhibited', 'NegReg', (21, 30))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (138, 163))	('immunodeficiency', 'Disease', 'MESH:D007153', (147, 163))	('patient', 'Species', '9606', (175, 182))	('/severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (130, 163))	('growth', 'MPA', (35, 41))	('immunodeficiency', 'Phenotype', 'HP:0002721', (147, 163))	('glioma', 'Disease', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))	('K27M', 'Mutation', 'p.K27M', (51, 55))	('mice', 'Species', '10090', (245, 249))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))
139377	33557011	Once considered a dream drug, ONC201 is a molecule that induces the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which is specific for killing tumour cells, but does not harm non-neoplastic cells.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumour necrosis', 'Disease', 'MESH:D009336', (68, 83))	('ONC201', 'Var', (30, 36))	('tumour necrosis', 'Disease', (68, 83))	('tumour', 'Disease', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('induces', 'PosReg', (56, 63))	('tumour', 'Disease', (68, 74))	('TRAIL', 'Gene', '8743', (132, 137))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('TRAIL', 'Gene', (132, 137))
139379	33557011	Its ability to antagonise DRD2 receptors lead to the activation of an integrated stress response coupled with inactivation of the Akt/ERK pathway, thus inhibiting tumour progression.	('DRD2', 'Gene', (26, 30))	('inactivation', 'NegReg', (110, 122))	('activation', 'PosReg', (53, 63))	('DRD2', 'Gene', '1813', (26, 30))	('ERK', 'Gene', (134, 137))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('Akt', 'Gene', '207', (130, 133))	('inhibiting', 'NegReg', (152, 162))	('ERK', 'Gene', '5594', (134, 137))	('antagonise', 'Var', (15, 25))	('Akt', 'Gene', (130, 133))	('integrated stress response', 'MPA', (70, 96))	('tumour', 'Disease', (163, 169))
139380	33557011	The first patient who received the drug in a phase II clinical trial (NCT02525692) was a 10-year-old girl with a diffuse intrinsic pontine glioma with the H3K27M mutation.	('girl', 'Species', '9606', (101, 105))	('K27M', 'Mutation', 'p.K27M', (157, 161))	('glioma', 'Disease', (139, 145))	('patient', 'Species', '9606', (10, 17))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('H3K27M', 'Var', (155, 161))
139384	33557011	Among the four paediatric patients with H3K27M gliomas in the study who were treated with adjuvant ONC201 after radiation therapy, two diffuse intrinsic pontine glioma patients remained progression-free for a minimum of 53 and 81 weeks, respectively.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('H3K27M', 'Var', (40, 46))	('glioma', 'Disease', (47, 53))	('gliomas', 'Disease', (47, 54))	('patients', 'Species', '9606', (26, 34))	('K27M', 'Mutation', 'p.K27M', (42, 46))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('patients', 'Species', '9606', (168, 176))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('glioma', 'Disease', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
139387	33557011	Nevertheless, the clinical outcomes and radiographic responses from this study and the drug's ability to target the H3K27 mutation specifically provide an initial or potential clinical proof-of-concept and a rationale for further clinical testing of the agent in the treatment of these gliomas.	('gliomas', 'Disease', (286, 293))	('gliomas', 'Disease', 'MESH:D005910', (286, 293))	('gliomas', 'Phenotype', 'HP:0009733', (286, 293))	('mutation', 'Var', (122, 130))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('H3K27', 'Gene', (116, 121))
139388	33557011	The chemically modified enhanced derivatives of ONC201, namely ONC206 and ONC212, are shown to be more efficacious by enhancing OTX016 (a BRBD4 antagonist) in suppressing in vitro and in vivo glioblastoma via the serine-one carbon-glycine pathway and transcription factor ATF4.	('ONC212', 'Var', (74, 80))	('serine', 'Chemical', 'MESH:D012694', (213, 219))	('ATF4', 'Gene', '468', (272, 276))	('glioblastoma', 'Disease', (192, 204))	('carbon', 'Chemical', 'MESH:D002244', (224, 230))	('glioblastoma', 'Disease', 'MESH:D005909', (192, 204))	('serine-one carbon-glycine pathway', 'Pathway', (213, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (192, 204))	('OTX016', 'Gene', (128, 134))	('suppressing', 'NegReg', (159, 170))	('glycine', 'Chemical', 'MESH:D005998', (231, 238))	('ATF4', 'Gene', (272, 276))	('enhancing', 'PosReg', (118, 127))	('ONC201', 'Gene', (48, 54))
139409	33557011	Even as BRAF inhibitors suppress BRAF monomers in BRAF V600E malignant cells, they may also cause RAF dimerisation in non-BRAF-mutated cells and the cells containing splice variants of the mutation.	('cause', 'Reg', (92, 97))	('monomers', 'MPA', (38, 46))	('RAF', 'Gene', '22882', (34, 37))	('RAF', 'Gene', '22882', (51, 54))	('RAF', 'Gene', (98, 101))	('RAF', 'Gene', (51, 54))	('V600E', 'Var', (55, 60))	('RAF', 'Gene', '22882', (9, 12))	('RAF', 'Gene', (9, 12))	('RAF', 'Gene', '22882', (123, 126))	('RAF', 'Gene', (123, 126))	('RAF', 'Gene', '22882', (98, 101))	('suppress', 'NegReg', (24, 32))	('V600E', 'Mutation', 'rs113488022', (55, 60))	('RAF', 'Gene', (34, 37))
139412	33557011	The use of BRAF/MEK inhibitor combination therapy in treating paediatric malignancies with the BRAF V600E mutation is minimal, and several clinical trials are still underway.	('V600E', 'Var', (100, 105))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('BRAF', 'Gene', (95, 99))	('MEK', 'Gene', (16, 19))	('V600E', 'Mutation', 'rs113488022', (100, 105))	('malignancies', 'Disease', (73, 85))	('MEK', 'Gene', '5609', (16, 19))
139415	33557011	A case report on a 16-year-old adolescent female with a recurrent anaplastic ganglioma positive for the BRAF V600E mutation showed a significant response to 150-mg Dabrafenib (orally, twice daily) and 2-mg Trametinib (orally, four times daily) after being intolerant to Vemurafenib.	('Trametinib', 'Chemical', 'MESH:C560077', (206, 216))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (270, 281))	('ganglioma', 'Disease', 'None', (77, 86))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('positive', 'Reg', (87, 95))	('ganglioma', 'Disease', (77, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('Dabrafenib', 'Chemical', 'MESH:C561627', (164, 174))	('BRAF', 'Gene', (104, 108))	('V600E', 'Var', (109, 114))
139427	33557011	Several clinical trials for targeted therapies aiming at specific mutations in paediatric gliomas are underway, and the future treatments for these tumours look promising.	('mutations', 'Var', (66, 75))	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('gliomas', 'Disease', (90, 97))	('tumours', 'Disease', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
139431	33557011	The in-depth understandings of the molecular mechanisms coupled with various molecular methods (FISH, real-time PCR, NanoString nCounter system and whole-genomic sequencing) that provide high sensitivity and specificity have led to the discoveries of BRAF and histone H3 mutations as biomarkers in paediatric gliomas.	('gliomas', 'Disease', (309, 316))	('gliomas', 'Disease', 'MESH:D005910', (309, 316))	('gliomas', 'Phenotype', 'HP:0009733', (309, 316))	('histone H3', 'Protein', (260, 270))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('BRAF', 'Gene', (251, 255))	('mutations', 'Var', (271, 280))
139456	31853670	But recently, high-resolution MRS technique with selective TE and different editing method is being used in glioma diagnosis to detect 2-hydroxyglutarate (2-HG), which accumulates within the gliomas having isocitrate dehydrogenase 1 and 2 (IDH 1/2) mutations.	('IDH 1/2', 'Gene', '3417;3418', (240, 247))	('glioma', 'Disease', (108, 114))	('gliomas', 'Disease', (191, 198))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (135, 153))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('IDH 1/2', 'Gene', (240, 247))	('glioma', 'Disease', (191, 197))	('mutations', 'Var', (249, 258))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('isocitrate', 'Chemical', 'MESH:D007523', (206, 216))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('2-HG', 'Chemical', 'MESH:C019417', (155, 159))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))
139460	31853670	The data of radiologic-pathologic correlation from meta-analysis of current literature demonstrates that the tumoral cellularity correlates with low T2 signal and low ADC; atypia with low ADC and high fractional anisotropy; mitotic activity with high Cho/Cr, Cho/NAA ratios, rCBV, and APT signal; the microvascular proliferation with high rCBV, volume transfer coefficient (Ktrans), volume fraction of plasma (Vp), and ITSS; and necrosis with necrotic cavity and high lactate levels on MR spectroscopy.	('volume fraction of plasma', 'MPA', (383, 408))	('necrotic cavity', 'Disease', 'MESH:D020139', (443, 458))	('ADC', 'MPA', (167, 170))	('necrosis', 'Disease', 'MESH:D009336', (429, 437))	('lactate', 'Chemical', 'MESH:D019344', (468, 475))	('Cr', 'Chemical', 'MESH:D002857', (255, 257))	('rCBV', 'Gene', (339, 343))	('necrosis', 'Disease', (429, 437))	('tumoral', 'Disease', (109, 116))	('low', 'NegReg', (184, 187))	('microvascular proliferation', 'CPA', (301, 328))	('tumoral', 'Disease', 'MESH:D009369', (109, 116))	('ADC', 'MPA', (188, 191))	('T2 signal', 'MPA', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NAA', 'Chemical', 'None', (263, 266))	('high', 'Var', (334, 338))	('mitotic activity', 'CPA', (224, 240))	('low', 'NegReg', (145, 148))	('necrotic cavity', 'Disease', (443, 458))
139478	31853670	According to the updated WHO 2016 classification, 75-80% of grade II diffusely infiltrating astrocytomas have IDH1/2 mutation and 20-25% do not.	('astrocytomas', 'Disease', 'MESH:D001254', (92, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('astrocytomas', 'Disease', (92, 104))	('IDH1/2', 'Gene', '3417;3418', (110, 116))	('mutation', 'Var', (117, 125))	('IDH1/2', 'Gene', (110, 116))
139479	31853670	An IDH1/2 mutant diffusely infiltrating astrocytoma has also had a loss of nuclear alpha-thalassemia/mental retardation syndrome X-linked expression (ATRX) status and TP53 mutations.	('mutations', 'Var', (172, 181))	('alpha-thalassemia/mental retardation syndrome X-linked expression', 'Gene', '546', (83, 148))	('astrocytoma', 'Phenotype', 'HP:0009592', (40, 51))	('ATRX', 'Gene', (150, 154))	('mutant', 'Var', (10, 16))	('IDH1/2', 'Gene', '3417;3418', (3, 9))	('mental retardation', 'Phenotype', 'HP:0001249', (101, 119))	('astrocytoma', 'Disease', 'MESH:D001254', (40, 51))	('loss', 'NegReg', (67, 71))	('ATRX', 'Gene', '546', (150, 154))	('IDH1/2', 'Gene', (3, 9))	('TP53', 'Gene', '7157', (167, 171))	('astrocytoma', 'Disease', (40, 51))	('TP53', 'Gene', (167, 171))
139481	31853670	Essentially LGG has mild nuclear atypia, moderate pleomorphism, high degree of cellular differentiation, and low MIB-1, with intrinsic capacity to progress to IDH1 mutant anaplastic astrocytoma or glioblastoma.	('astrocytoma', 'Disease', (182, 193))	('mutant', 'Var', (164, 170))	('astrocytoma', 'Disease', 'MESH:D001254', (182, 193))	('low', 'NegReg', (109, 112))	('IDH1', 'Gene', (159, 163))	('MIB-1', 'Gene', (113, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('astrocytoma', 'Phenotype', 'HP:0009592', (182, 193))	('IDH1', 'Gene', '3417', (159, 163))	('MIB-1', 'Gene', '57534', (113, 118))	('progress', 'Reg', (147, 155))	('glioblastoma', 'Disease', (197, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (197, 209))
139483	31853670	Although IDH1 mutant glioblastoma has still significantly worse outcomes than grade II and III gliomas, there are no differences in survival between IDH mutant grades II and III.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH1', 'Gene', (9, 13))	('IDH', 'Gene', (149, 152))	('glioblastoma', 'Disease', (21, 33))	('mutant', 'Var', (14, 20))	('IDH1', 'Gene', '3417', (9, 13))	('IDH', 'Gene', '3417', (149, 152))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('IDH', 'Gene', (9, 12))	('gliomas', 'Disease', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('IDH', 'Gene', '3417', (9, 12))
139485	31853670	The premise is cyclin-dependent kinase Inhibitor 2A/B homozygous deletion with combination of necrosis and copy number variation has the most relevant results for survival but the proliferation (mitotic count) has only a minor influence on survival.	('necrosis', 'Disease', (94, 102))	('necrosis', 'Disease', 'MESH:D009336', (94, 102))	('2A/B', 'Var', (49, 53))	('2A/B', 'SUBSTITUTION', 'None', (49, 53))
139488	31853670	Radiomic features extracted from the optimal texture analysis of ADC and T2 FLAIR images play an important role in the noninvasive prediction of the IDH1 mutation and loss of ATRX expression status in LGGs.	('ATRX', 'Gene', (175, 179))	('LGGs', 'Disease', (201, 205))	('IDH1', 'Gene', (149, 153))	('mutation', 'Var', (154, 162))	('expression', 'MPA', (180, 190))	('IDH1', 'Gene', '3417', (149, 153))	('ATRX', 'Gene', '546', (175, 179))	('loss', 'Var', (167, 171))
139497	31853670	3) is a slow-growing glioma with IDH1 or IDH2 mutation and codeletion of chromosomal arms 1p and 19q (1p19q-codeletion).	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('IDH1', 'Gene', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('IDH1', 'Gene', '3417', (33, 37))	('IDH2', 'Gene', (41, 45))	('glioma', 'Disease', (21, 27))	('mutation', 'Var', (46, 54))	('IDH2', 'Gene', '3418', (41, 45))
139517	27585860	In both models, p53 constrains progression to advanced adenocarcinomas.	('adenocarcinomas', 'Disease', (55, 70))	('p53', 'Var', (16, 19))	('adenocarcinomas', 'Disease', 'MESH:D000230', (55, 70))
139526	27585860	Studies in transplant models have underscored the functional importance of specific genetic variants in modulating growth dynamics of different subclones within tumours.	('growth dynamics', 'MPA', (115, 130))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('modulating', 'Reg', (104, 114))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('tumours', 'Disease', 'MESH:D009369', (161, 168))	('tumours', 'Disease', (161, 168))	('genetic variants', 'Var', (84, 100))
139527	27585860	Unfortunately, similar analyses in physiologically relevant, autochthonous cancer models during tumour progression are lacking due to technical challenges in inducing sequential mutations in subclonal populations and unambiguously tracing them at single-cell resolution.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (178, 187))	('tumour', 'Disease', (96, 102))
139528	27585860	We have previously developed autochthonous models of lung and pancreatic cancer by simultaneous Cre recombinase-mediated activation of oncogenic Kras (KrasG12D) and biallelic inactivation of p53 in cells residing in the tissues of origin.	('lung and pancreatic cancer', 'Disease', 'MESH:D010190', (53, 79))	('biallelic inactivation', 'Var', (165, 187))	('Kras', 'Gene', '16653', (145, 149))	('Kras', 'Gene', (151, 155))	('Kras', 'Gene', '16653', (151, 155))	('KrasG12D', 'Gene', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('p53', 'Gene', (191, 194))	('KrasG12D', 'Gene', '16653', (151, 159))	('activation', 'PosReg', (121, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('Kras', 'Gene', (145, 149))
139531	27585860	Furthermore, reactivation of p53 in advanced lung tumours led to selective loss of adenocarcinoma cells, consistent with a specific role of p53 mutation in regulating late-stage lung tumour progression.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('lung tumour', 'Disease', 'MESH:D008175', (178, 189))	('lung tumour', 'Disease', 'MESH:D008175', (45, 56))	('adenocarcinoma', 'Disease', (83, 97))	('lung tumours', 'Disease', (45, 57))	('p53', 'Gene', (29, 32))	('lung tumour', 'Phenotype', 'HP:0100526', (178, 189))	('lung tumour', 'Phenotype', 'HP:0100526', (45, 56))	('reactivation', 'Var', (13, 25))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('loss', 'NegReg', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('lung tumour', 'Disease', (178, 189))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('lung tumours', 'Disease', 'MESH:D008175', (45, 57))
139532	27585860	Finally, exome-sequencing analyses of murine lung adenocarcinomas derived from LSL-KrasG12D/KrasWT; p53flox/flox mice revealed no recurrent mutations beyond Kras and p53 (ref.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (45, 65))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (45, 65))	('Kras', 'Gene', (92, 96))	('Kras', 'Gene', '16653', (92, 96))	('KrasG12D', 'Gene', '16653', (83, 91))	('Kras', 'Gene', '16653', (83, 87))	('p53', 'Gene', (166, 169))	('Kras', 'Gene', (157, 161))	('Kras', 'Gene', '16653', (157, 161))	('KrasG12D', 'Gene', (83, 91))	('mutations', 'Var', (140, 149))	('murine', 'Species', '10090', (38, 44))	('mice', 'Species', '10090', (113, 117))	('Kras', 'Gene', (83, 87))	('lung adenocarcinomas', 'Disease', (45, 65))
139535	27585860	Similar to what is seen in human lung tumours, p53 mutations are primarily observed in more advanced human pancreatic lesions, including pancreatic ductal adenocarcinoma (PDAC) or precursor PanINs of high-grade histology.	('mutations', 'Var', (51, 60))	('lung tumours', 'Disease', (33, 45))	('lung tumour', 'Phenotype', 'HP:0100526', (33, 44))	('pancreatic lesions', 'Disease', (107, 125))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('human', 'Species', '9606', (27, 32))	('pancreatic ductal adenocarcinoma', 'Disease', (137, 169))	('pancreatic lesions', 'Disease', 'MESH:D010182', (107, 125))	('observed', 'Reg', (75, 83))	('lung tumours', 'Disease', 'MESH:D008175', (33, 45))	('human', 'Species', '9606', (101, 106))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (137, 169))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (137, 169))	('PDAC', 'Phenotype', 'HP:0006725', (171, 175))	('p53', 'Gene', (47, 50))	('PDAC', 'Chemical', '-', (171, 175))
139536	27585860	Moreover, p53 mutation shortens the latency and increases the frequency of PDAC formation in mouse pancreatic tumour models in which p53 is simultaneously mutated at the time of oncogenic Kras activation.	('mutated', 'Var', (155, 162))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (99, 116))	('increases', 'PosReg', (48, 57))	('mouse', 'Species', '10090', (93, 98))	('Kras', 'Gene', (188, 192))	('Kras', 'Gene', '16653', (188, 192))	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic tumour', 'Disease', 'MESH:D010190', (99, 116))	('mutation', 'Var', (14, 22))	('pancreatic tumour', 'Disease', (99, 116))	('p53', 'Gene', (133, 136))	('latency', 'MPA', (36, 43))	('shortens', 'NegReg', (23, 31))	('PDAC', 'Chemical', '-', (75, 79))	('p53', 'Gene', (10, 13))
139540	27585860	In contrast, we determine that p53 suppresses both the initiation and expansion of early pancreatic tumours, which correlates with expression of the p53 regulator p19ARF.	('pancreatic tumour', 'Phenotype', 'HP:0002894', (89, 106))	('expansion', 'CPA', (70, 79))	('pancreatic tumours', 'Disease', (89, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('p19ARF', 'Gene', (163, 169))	('pancreatic tumours', 'Disease', 'MESH:D010190', (89, 107))	('initiation', 'CPA', (55, 65))	('p53', 'Var', (31, 34))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('p19ARF', 'Gene', '12578', (163, 169))	('suppresses', 'NegReg', (35, 45))
139542	27585860	To generate sporadic p53 LOH in Kras-initiated tumors, we took advantage of mosaic analysis with double markers (MADM), which permits simultaneous fluorescence cell labelling and mutagenesis through a single Cre-mediated inter-chromosomal recombination event in mice.	('mutagenesis', 'Var', (179, 190))	('mice', 'Species', '10090', (262, 266))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('rat', 'Species', '10116', (7, 10))	('Kras-initiated tumors', 'Disease', 'MESH:D009369', (32, 53))	('Kras-initiated tumors', 'Disease', (32, 53))	('p53', 'Gene', (21, 24))
139543	27585860	MADM has been used to study the consequence of tumour suppressor gene LOH on tissue development and cancer initiation at single-cell resolution.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', (47, 53))	('LOH', 'Var', (70, 73))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
139546	27585860	Mitotic recombination and X segregation (G2-X) of the MADM cassettes is predicted to result in the generation of two genotypically and phenotypically distinct daughter cells from a colourless p53KO/WTparent cell: GFP+/tdTomato- (green) p53KO/KO and GFP-/tdTomato+ (red) p53WT/WT (Fig.	('rat', 'Species', '10116', (103, 106))	('GFP+/tdTomato-', 'Var', (213, 227))	('result in', 'Reg', (85, 94))	('cassettes', 'Var', (59, 68))	('GFP-/tdTomato+', 'Var', (249, 263))
139547	27585860	In contrast, G2-Z, G0 or G1 recombination results in the generation of GFP+/tdTomato+ (yellow) and GFP-/tdTomato- (colourless) p53KO/WT cells (Fig.	('G1 recombination', 'Var', (25, 41))	('GFP+/tdTomato+', 'Var', (71, 85))	('rat', 'Species', '10116', (61, 64))	('G2-Z', 'Var', (13, 17))	('p53KO/WT', 'Var', (127, 135))	('GFP-/tdTomato-', 'Var', (99, 113))
139549	27585860	To determine whether sporadic and sequential (following Kras mutation) p53 LOH promotes lung tumour progression, we administered lentiviral Cre via the trachea to adult K-MADM-p53 mice to induce stable Cre expression in lung epithelial cells.	('mutation', 'Var', (61, 69))	('lung tumour', 'Phenotype', 'HP:0100526', (88, 99))	('p53', 'Gene', (71, 74))	('promotes', 'PosReg', (79, 87))	('lung tumour', 'Disease', (88, 99))	('mice', 'Species', '10090', (180, 184))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('Kras', 'Gene', (56, 60))	('lung tumour', 'Disease', 'MESH:D008175', (88, 99))	('Kras', 'Gene', '16653', (56, 60))
139559	27585860	In addition, a small number of low-grade adenomas harboured rare yellow p53KO/WT cells (Fig.	('adenomas', 'Disease', (41, 49))	('yellow p53KO/WT', 'Var', (65, 80))	('adenomas', 'Disease', 'MESH:D000236', (41, 49))
139563	27585860	To further evaluate whether p53 also suppresses cell expansion in early lung tumours, we classified lung adenomas based on their green or red cell predominance in tissue sections of K-MADM-p53 mice at 10-16 weeks post infection (p.i.)	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('lung tumours', 'Disease', 'MESH:D008175', (72, 84))	('lung tumour', 'Phenotype', 'HP:0100526', (72, 83))	('suppresses', 'NegReg', (37, 47))	('red cell predominance', 'Phenotype', 'HP:0031965', (138, 159))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('lung adenomas', 'Disease', (100, 113))	('mice', 'Species', '10090', (193, 197))	('lung tumours', 'Disease', (72, 84))	('infection', 'Disease', (218, 227))	('p53', 'Var', (28, 31))	('infection', 'Disease', 'MESH:D007239', (218, 227))	('lung adenomas', 'Disease', 'MESH:D000236', (100, 113))
139566	27585860	Given the possibility for stochastic differences in individual daughter cell expansion following G2-X recombination, we did observe tumours (69 of 132) that showed green or red cell predominance.	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumours', 'Disease', (132, 139))	('red cell predominance', 'Phenotype', 'HP:0031965', (173, 194))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('G2-X', 'Var', (97, 101))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))
139567	27585860	However, the proportions of green-dominant and red-dominant tumours were not statistically different, suggesting that green p53KO/KO cells did not have a selective growth advantage at this stage (Fig.	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('p53KO/KO', 'Var', (124, 132))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
139581	27585860	Interestingly, Pdx1-Cre-K-MADM-p53 mice exhibited a median survival of ~11 weeks, falling in between that observed in Pdx1-Cre; LSL-KrasG12D/KrasWT (KC) mice harbouring homozygous p53 mutation (~6 weeks) and heterozygous p53 mutation (~16 weeks) (Fig.	('Kras', 'Gene', '16653', (141, 145))	('KrasG12D', 'Gene', '16653', (132, 140))	('p53', 'Gene', (180, 183))	('Kras', 'Gene', '16653', (132, 136))	('Pdx1', 'Gene', (118, 122))	('Pdx1', 'Gene', (15, 19))	('mice', 'Species', '10090', (35, 39))	('Pdx1', 'Gene', '18609', (15, 19))	('mice', 'Species', '10090', (153, 157))	('Pdx1', 'Gene', '18609', (118, 122))	('falling', 'Phenotype', 'HP:0002527', (82, 89))	('Kras', 'Gene', (132, 136))	('Kras', 'Gene', (141, 145))	('KrasG12D', 'Gene', (132, 140))	('mutation', 'Var', (184, 192))
139590	27585860	Overall, these findings suggest a potential tumour suppressive role of p53 throughout oncogenic Kras-mediated pancreatic tumorigenesis, contrasting with mainly late functions during lung tumour progression.	('lung tumour', 'Disease', 'MESH:D008175', (182, 193))	('tumour', 'Disease', (187, 193))	('p53', 'Var', (71, 74))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('pancreatic', 'Disease', (110, 120))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('lung tumour', 'Phenotype', 'HP:0100526', (182, 193))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('Kras', 'Gene', (96, 100))	('Kras', 'Gene', '16653', (96, 100))	('pancreatic', 'Disease', 'MESH:D010195', (110, 120))	('lung tumour', 'Disease', (182, 193))
139598	27585860	As wild-type p53 is difficult to detect by immunohistochemistry (IHC) on tissue sections with currently available antibodies, we took advantage of oncogenic Kras-driven lung and pancreatic cancer models harbouring a p53R172H mutant allele (LSL-KrasG12D; LSL-p53R172H), which demonstrate similar histologic progression to the MADM models.	('lung and pancreatic cancer', 'Disease', 'MESH:D010190', (169, 195))	('KrasG12D', 'Gene', '16653', (244, 252))	('rat', 'Species', '10116', (282, 285))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p53R172H', 'Var', (216, 224))	('Kras', 'Gene', (157, 161))	('Kras', 'Gene', (244, 248))	('KrasG12D', 'Gene', (244, 252))	('Kras', 'Gene', '16653', (157, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('Kras', 'Gene', '16653', (244, 248))
139599	27585860	In these mice, mutant p53 is stabilized, due in part to loss of feedback inhibition, and serves as a marker of endogenous p53 expression.	('loss', 'NegReg', (56, 60))	('p53', 'Gene', (22, 25))	('feedback inhibition', 'MPA', (64, 83))	('mice', 'Species', '10090', (9, 13))	('mutant', 'Var', (15, 21))
139604	27585860	As p53 mutant cells may induce p19ARF by loss of negative feedback, we verified that p19ARF expression was observed in early pancreatic tumours even in the context of wild-type p53 (Fig.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('induce', 'Reg', (24, 30))	('mutant', 'Var', (7, 13))	('p19ARF', 'Gene', '12578', (85, 91))	('p19ARF', 'Gene', (31, 37))	('pancreatic tumours', 'Disease', (125, 143))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (125, 142))	('p19ARF', 'Gene', '12578', (31, 37))	('negative feedback', 'MPA', (49, 66))	('pancreatic tumours', 'Disease', 'MESH:D010190', (125, 143))	('p19ARF', 'Gene', (85, 91))	('p53', 'Gene', (3, 6))	('loss', 'NegReg', (41, 45))
139616	27585860	Although labelled cells of the same colour were separated by an average of ~8.7 cell diameters (range 2.47-27.76, n=31 tumours), p53KO/KO cells surprisingly exhibited significantly decreased dispersal than p53WT/WT cells (7.2 versus 10.2 cell diameters, P=0.013, two-tailed paired Student's t-test).	('rat', 'Species', '10116', (52, 55))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('dispersal', 'MPA', (191, 200))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('tumours', 'Disease', (119, 126))	('p53KO/KO', 'Var', (129, 137))	('decreased', 'NegReg', (181, 190))
139621	27585860	Unlike early models that induced simultaneous cooperating mutations in large numbers of cells, MADM permits sporadic and sequential mutagenesis of oncogenes and tumour suppressor genes, more faithfully mimicking the clonal genetic evolution observed in human cancers.	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('mutagenesis', 'Var', (132, 143))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', (259, 266))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumour', 'Disease', (161, 167))	('human', 'Species', '9606', (253, 258))	('rat', 'Species', '10116', (51, 54))
139624	27585860	However, given that mutagenesis and fluorescent labelling occur through separate recombination events, decreased recombinase activity enhances the likelihood of uncoupling of these events.	('mutagenesis', 'Var', (20, 31))	('recombinase', 'Enzyme', (113, 124))	('rat', 'Species', '10116', (76, 79))	('activity', 'MPA', (125, 133))	('decreased', 'NegReg', (103, 112))	('enhances', 'PosReg', (134, 142))	('uncoupling', 'MPA', (161, 171))
139627	27585860	Genetic analyses on human cancers would suggest that p53 functions late during tumour progression, as p53 mutations are principally identified in lung adenocarcinomas and high-grade PanINs or PDAC rather than their lower-grade precursors.	('human', 'Species', '9606', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('lung adenocarcinomas', 'Disease', (146, 166))	('rat', 'Species', '10116', (197, 200))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (146, 166))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (146, 166))	('PDAC', 'Phenotype', 'HP:0006725', (192, 196))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('identified', 'Reg', (132, 142))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (106, 115))	('p53', 'Gene', (102, 105))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('PDAC', 'Chemical', '-', (192, 196))	('tumour', 'Disease', (79, 85))
139628	27585860	In contrast, p53 suppresses both the initiation and early expansion of pancreatic tumours.	('pancreatic tumours', 'Disease', 'MESH:D010190', (71, 89))	('early expansion', 'CPA', (52, 67))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('p53', 'Var', (13, 16))	('suppresses', 'NegReg', (17, 27))	('initiation', 'CPA', (37, 47))	('pancreatic tumours', 'Disease', (71, 89))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (71, 88))
139634	27585860	Indeed, mutant PIK3CAH1047R expression in the pancreas phenocopies oncogenic Kras in terms of tumour progression and p19ARF expression.	('PIK3CAH1047R', 'Gene', (15, 27))	('tumour', 'Disease', (94, 100))	('p19ARF', 'Gene', (117, 123))	('pancreas phenocopies oncogenic Kras', 'Disease', (46, 81))	('mutant', 'Var', (8, 14))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (124, 134))	('p19ARF', 'Gene', '12578', (117, 123))	('pancreas phenocopies oncogenic Kras', 'Disease', 'MESH:D000074723', (46, 81))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
139635	27585860	In addition, Cre-mediated deletion of the PI3K effector Pdk1 in Kras-initiated pancreatic tumours reduces the induction of p19ARF.	('pancreatic tumour', 'Phenotype', 'HP:0002894', (79, 96))	('Pdk1', 'Gene', (56, 60))	('p19ARF', 'Gene', '12578', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('deletion', 'Var', (26, 34))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('Kras-initiated pancreatic tumours', 'Disease', (64, 97))	('Kras-initiated pancreatic tumours', 'Disease', 'MESH:D010190', (64, 97))	('induction', 'MPA', (110, 119))	('p19ARF', 'Gene', (123, 129))	('reduces', 'NegReg', (98, 105))	('Pdk1', 'Gene', '228026', (56, 60))
139637	27585860	These include additional signalling pathways (for example, Notch), epigenetic modifiers (for example, Bmi1 (ref.))	('Notch', 'Gene', '18128', (59, 64))	('Notch', 'Gene', (59, 64))	('epigenetic modifiers', 'Var', (67, 87))	('signalling pathways', 'Pathway', (25, 44))	('Bmi1', 'Gene', '12151', (102, 106))	('Bmi1', 'Gene', (102, 106))
139645	27585860	How these truncal mutations propagate throughout a tumour remains poorly understood, although a recent computational model predicted intratumoral cell dispersion during tumour growth as a potential mechanism and is consistent with our findings.	('tumour', 'Disease', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('rat', 'Species', '10116', (136, 139))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Disease', (51, 57))	('mutations', 'Var', (18, 27))
139650	27585860	MADM11-GT (Stock #013749), MADM11-TG (Stock #013751), Pdx1-Cre (Stock #014647) and p53flox/flox (Stock #008462) mice were obtained from the Jackson Laboratory.	('Stock #008462', 'Var', (97, 110))	('rat', 'Species', '10116', (152, 155))	('Stock #014647', 'Var', (64, 77))	('Pdx1', 'Gene', (54, 58))	('Pdx1', 'Gene', '18609', (54, 58))	('Stock #013749', 'Var', (11, 24))	('mice', 'Species', '10090', (112, 116))
139651	27585860	MADM11-TG,p53WT/MADM11-TG,p53WT mice were crossed with p53KO/WT mice, which carry a p53-null allele lacking exons 2-6 (ref.).	('lacking', 'NegReg', (100, 107))	('mice', 'Species', '10090', (64, 68))	('mice', 'Species', '10090', (32, 36))	('p53WT/MADM11-TG', 'Var', (10, 25))	('exons 2-6', 'MPA', (108, 117))
139652	27585860	Intercrossing the progeny MADM11-TG,p53WT/p53KO mice permitted recombination of the p53-null mutation onto the same chromosome as the MADM cassette.	('mutation', 'Var', (93, 101))	('mice', 'Species', '10090', (48, 52))	('p53-null', 'Gene', (84, 92))
139653	27585860	These MADM11-TG,p53KO/p53WT mice were subsequently crossed to MADM11-TG,p53WT/MADM11-TG,p53WT mice, to generate MADM11-TG,p53WT/MADM11-TG,p53KO.	('mice', 'Species', '10090', (28, 32))	('p53KO', 'Var', (138, 143))	('mice', 'Species', '10090', (94, 98))	('p53WT/MADM11-TG', 'Var', (122, 137))	('rat', 'Species', '10116', (107, 110))
139655	27585860	mice to create LSL-KrasG12D/KrasWT; MADM11-TG,p53WT/MADM11-TG,p53KO breeders.	('Kras', 'Gene', (19, 23))	('Kras', 'Gene', '16653', (19, 23))	('p53WT/MADM11-TG', 'Var', (46, 61))	('KrasG12D', 'Gene', (19, 27))	('mice', 'Species', '10090', (0, 4))	('Kras', 'Gene', (28, 32))	('KrasG12D', 'Gene', '16653', (19, 27))	('Kras', 'Gene', '16653', (28, 32))
139658	27585860	KrasLA2,Rosa26-CreERT2/KrasWT; MADM11-GT,p53WT/MADM11-TG-p53KO (KrasLA2,Rosa26-CreERT2/KrasWT; MADM-p53) and KrasLA2,Rosa26-CreERT2/KrasWT; MADM (lacking p53 mutation) mice were generated in parallel crosses.	('Rosa26', 'Gene', (72, 78))	('Rosa26', 'Gene', (8, 14))	('rat', 'Species', '10116', (182, 185))	('Rosa26', 'Gene', (117, 123))	('Kras', 'Gene', (64, 68))	('Kras', 'Gene', (0, 4))	('Kras', 'Gene', (87, 91))	('Rosa26', 'Gene', '14910', (72, 78))	('Rosa26', 'Gene', '14910', (8, 14))	('Kras', 'Gene', '16653', (64, 68))	('Kras', 'Gene', (109, 113))	('Kras', 'Gene', (23, 27))	('Kras', 'Gene', '16653', (0, 4))	('Kras', 'Gene', '16653', (87, 91))	('Rosa26', 'Gene', '14910', (117, 123))	('Kras', 'Gene', (132, 136))	('Kras', 'Gene', '16653', (109, 113))	('Kras', 'Gene', '16653', (23, 27))	('mice', 'Species', '10090', (168, 172))	('mutation', 'Var', (158, 166))	('p53', 'Gene', (154, 157))	('Kras', 'Gene', '16653', (132, 136))
139664	27585860	KrasLA2,Rosa26-CreERT2/KrasWT; MADM-p53 and KrasLA2,Rosa26-CreERT2/KrasWT; MADM (lacking p53 mutation) mice at 5-10 weeks of age were injected intraperitoneally with tamoxifen (Sigma) at a dose of 9 mg per 40 g total body weight every other day for a total of three doses, to induce CreERT2-mediated recombination.	('Rosa26', 'Gene', (52, 58))	('Kras', 'Gene', (44, 48))	('Kras', 'Gene', (67, 71))	('Kras', 'Gene', '16653', (44, 48))	('Kras', 'Gene', (23, 27))	('Kras', 'Gene', '16653', (67, 71))	('Rosa26', 'Gene', (8, 14))	('Kras', 'Gene', '16653', (23, 27))	('mice', 'Species', '10090', (103, 107))	('Kras', 'Gene', (0, 4))	('p53', 'Gene', (89, 92))	('Kras', 'Gene', '16653', (0, 4))	('Rosa26', 'Gene', '14910', (52, 58))	('induce', 'Reg', (276, 282))	('mutation', 'Var', (93, 101))	('Rosa26', 'Gene', '14910', (8, 14))	('tamoxifen', 'Chemical', 'MESH:D013629', (166, 175))
139674	27585860	IHC for p53 and p19ARF was performed as previously described.	('p19ARF', 'Gene', '12578', (16, 22))	('p19ARF', 'Gene', (16, 22))	('p53', 'Var', (8, 11))
139676	27585860	Endogenous wild-type p53 was not detectable in tissue sections using this antibody; thus, p53 IHC was performed on sections from mouse tumours harbouring a p53R172H mutation exhibiting p53 protein accumulation due to loss of negative feedback.	('p53R172H', 'Var', (156, 164))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('accumulation', 'PosReg', (197, 209))	('mouse', 'Species', '10090', (129, 134))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
139697	27585860	Some of these mice also harboured heterozygous or homozygous mutations in Lep (leptin, ob) or Lepr (leptin receptor, db), although these genotypes did not have an impact on the frequency of tumour types observed.	('Lepr', 'Gene', (94, 98))	('tumour', 'Disease', (190, 196))	('Lepr', 'Gene', '16847', (94, 98))	('Lep', 'Gene', '16846', (74, 77))	('tumour', 'Disease', 'MESH:D009369', (190, 196))	('leptin', 'Gene', '16846', (79, 85))	('mice', 'Species', '10090', (14, 18))	('Lep', 'Gene', (74, 77))	('Lep', 'Gene', '16846', (94, 97))	('mutations', 'Var', (61, 70))	('leptin receptor', 'Gene', '16847', (100, 115))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('leptin', 'Gene', '16846', (100, 106))	('Lep', 'Gene', (94, 97))	('leptin', 'Gene', (100, 106))	('leptin', 'Gene', (79, 85))	('leptin receptor', 'Gene', (100, 115))
139742	26518678	In both cases, patients have mutations of the retinoblastoma tumour suppressor gene on chromosome 13q14.	('retinoblastoma', 'Phenotype', 'HP:0009919', (46, 60))	('patients', 'Species', '9606', (15, 23))	('retinoblastoma tumour', 'Disease', 'MESH:D012175', (46, 67))	('retinoblastoma tumour', 'Disease', (46, 67))	('mutations', 'Var', (29, 38))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
139783	26518678	In highly myopic patients, the globe can be elongated and the resulting chemical shift artefact can lead to asymmetric thickening of the outline of the globe mimicking the presence of a tumour while, on the contrary, retinal detachment may mask small tumours.	('tumour', 'Disease', (186, 192))	('highly myopic', 'Phenotype', 'HP:0011003', (3, 16))	('retinal detachment may mask small tumours', 'Disease', 'MESH:D012163', (217, 258))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('asymmetric thickening', 'Phenotype', 'HP:0001528', (108, 129))	('retinal detachment', 'Phenotype', 'HP:0000541', (217, 235))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('chemical shift', 'MPA', (72, 86))	('tumour', 'Disease', (251, 257))	('lead to', 'Reg', (100, 107))	('artefact', 'Var', (87, 95))	('retinal detachment may mask small tumours', 'Disease', (217, 258))	('patients', 'Species', '9606', (17, 25))	('tumour', 'Disease', 'MESH:D009369', (186, 192))
139817	26518678	Nevertheless, de Blank et al found that decreased FA of the optic radiations in patients with ONG was predictive of visual acuity loss during the following year and, therefore, suggested that DTI may be used as a non-invasive tool to prospectively identify those patients who will require therapy.	('patients', 'Species', '9606', (80, 88))	('visual acuity loss', 'Phenotype', 'HP:0000572', (116, 134))	('visual acuity loss', 'Disease', 'MESH:D014786', (116, 134))	('patients', 'Species', '9606', (263, 271))	('FA of', 'MPA', (50, 55))	('ONG', 'Var', (94, 97))	('radiations', 'Disease', 'MESH:D004194', (66, 76))	('radiations', 'Disease', (66, 76))	('decreased', 'NegReg', (40, 49))	('visual acuity loss', 'Disease', (116, 134))
139873	26518678	On MRI, dermoids typically appear hyperintense on T1W and T2W and hypointense on STIR (Fig.	('hypo', 'Disease', (66, 70))	('hypo', 'Disease', 'MESH:D052456', (66, 70))	('T1W', 'Var', (50, 53))	('T2W', 'Var', (58, 61))
139894	26518678	Thus, ADC values appear to be highly sensitive and specific in differentiating BMT from malignant tumours of the lacrimal gland.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('BMT', 'Disease', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('malignant tumours', 'Disease', 'MESH:D009369', (88, 105))	('malignant tumours', 'Disease', (88, 105))	('ADC', 'Var', (6, 9))
140053	26246470	'Cut from the same cloth': Shared microsatellite variants among cancers link to ectodermal tissues-neural tube and crest cells The pluripotent cells of the embryonic ectodermal tissues are known to be a precursor for multiple tumor types.	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('cancers', 'Disease', (64, 71))	('microsatellite variants', 'Var', (34, 57))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('link', 'Reg', (72, 76))	('tumor', 'Disease', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
140056	26246470	Therefore, we hypothesized that these variants, identified from germline DNA, are shared by cancers from tissues originating from ectodermal tissues: neural tube cells (NTC) and crest cells (NCC).	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('variants', 'Var', (38, 46))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
140058	26246470	The results of this analysis show that variant loci among the cancers with tissue origins from NTC/NCC were closely linked.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variant', 'Var', (39, 46))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('NTC/NCC', 'Disease', (95, 102))	('cancers', 'Disease', (62, 69))
140068	26246470	These simple sequences have attracted attention because expansion of tri-nucleotide repeat sequences are important contributors to over 40 different neurological disorders including Fragile X, Huntington's and Parkinson's disease.	('contributors', 'Reg', (115, 127))	('tri-nucleotide repeat sequences', 'Var', (69, 100))	('neurological disorders', 'Disease', (149, 171))	('tri-', 'Chemical', '-', (69, 73))	('neurological disorders', 'Disease', 'MESH:D009422', (149, 171))	("Fragile X, Huntington's and Parkinson's disease", 'Disease', 'MESH:D006816', (182, 229))	('expansion', 'Var', (56, 65))
140069	26246470	We have developed a microsatellite genotyping algorithm that is highly accurate (96.5%) and has been successfully used to identify breast and brain cancer-linked DNA, MST variants in addition to variants identified in response to cell stressors and aging.	('MST', 'Gene', (167, 170))	('breast and brain cancer', 'Disease', 'MESH:D001943', (131, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('brain cancer', 'Phenotype', 'HP:0030692', (142, 154))	('variants', 'Var', (171, 179))
140072	26246470	We therefore hypothesized that the identification of these cancer-specific variant loci from germline DNA would indicate a common embryonic tissue of origin and that these variant loci could serve as targets for the development of powerful combination therapeutics and foster a novel understanding in cancer etiology.	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('variant', 'Var', (75, 82))	('cancer', 'Disease', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
140076	26246470	Genotypes from loci identified from tumors with NTC/NCC lineage showed multiple shared CAML genotypes (see Table 1); the most common locus identified in MEL, GBM, LGG, and MB was in an intron of PSME (15:63040517-63040532).	('MB', 'Phenotype', 'HP:0002885', (172, 174))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('MEL', 'Phenotype', 'HP:0002861', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('15:63040517-63040532', 'Var', (201, 221))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
140090	26246470	With the reoccurrence of most cancers diagnosed at advanced stages and following chemotherapeutic and radiological treatments; and with more than 50% of somatic mutations arising prior to tumor formations in several cancers, efforts to identify cancer cell(s) of origin that are tissue-specific are intensively studied.	('tumor', 'Disease', (188, 193))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cancers', 'Disease', (216, 223))	('cancer', 'Disease', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Disease', (30, 36))	('cancers', 'Disease', (30, 37))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('mutations', 'Var', (161, 170))
140091	26246470	Genomic variants in non-coding regions of genomic material, including those in microsatellites, are accelerating the identification of cancer-promoting elements which may be additive to the effects of mutations in the coding regions of genes.	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('variants', 'Var', (8, 16))
140093	26246470	This suggests that the spectrum of CAML genotypes in MEL may be attributed to variants in embryonic ectodermal tissues which might contribute to tumors with NCC and/or NTC lineage.	('MEL', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('contribute', 'Reg', (131, 141))	('MEL', 'Phenotype', 'HP:0002861', (53, 56))	('variants', 'Var', (78, 86))
140101	26246470	Thus, modifications to NCOR1 could lead to changes in gene expression.	('modifications', 'Var', (6, 19))	('gene expression', 'MPA', (54, 69))	('NCOR1', 'Gene', (23, 28))	('lead to changes', 'Reg', (35, 50))	('NCOR1', 'Gene', '9611', (23, 28))
140102	26246470	Additionally, we discovered variants in KIF1B and TLN2 in BC and shared with NTC/NCC lineage cancers: isoform-2 of KIF1B is important for neuronal apoptosis; and TLN2 has been monitored in cerebrospinal fluid of epileptic patients and is mostly known for its contribution during plaque formation in cytoskeletal interaction with integrins.	('epileptic', 'Disease', 'MESH:D004827', (212, 221))	('cancers', 'Disease', (93, 100))	('KIF1B', 'Gene', '23095', (40, 45))	('epileptic', 'Disease', (212, 221))	('TLN2', 'Gene', '83660', (162, 166))	('TLN2', 'Gene', '83660', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('variants', 'Var', (28, 36))	('patients', 'Species', '9606', (222, 230))	('TLN2', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('KIF1B', 'Gene', (115, 120))	('TLN2', 'Gene', (50, 54))	('KIF1B', 'Gene', '23095', (115, 120))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('KIF1B', 'Gene', (40, 45))
140105	26246470	Potentially supportive of this nascent hypothesis are recent data showing modified expression and metabolic activity by GLUD1/2 in gliomas with IDH1 mutation, we identified an intronic variant in GLUD1 in our GBM CAML signature and this locus is shared with BC (although, in BC the locus is a non-signature variant).	('gliomas', 'Disease', (131, 138))	('GBM', 'Phenotype', 'HP:0012174', (209, 212))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('GLUD1', 'Gene', '2746', (120, 125))	('variant', 'Var', (185, 192))	('GLUD1', 'Gene', (120, 125))	('GLUD1/2', 'Gene', '2746;2747', (120, 127))	('GLUD1', 'Gene', '2746', (196, 201))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('expression', 'MPA', (83, 93))	('IDH1', 'Gene', (144, 148))	('GLUD1', 'Gene', (196, 201))	('mutation', 'Var', (149, 157))	('IDH1', 'Gene', '3417', (144, 148))	('GLUD1/2', 'Gene', (120, 127))
140111	26246470	As such, the biological associations to hereditary and neurological diseases and disorders among genes containing overlapping CAML genotypes in the NTC/NCC lineage cancers suggests that modification to non-coding, intronic regions are (1) sensitive to disease manifestation and, (2) differing combinations of tissue-specific CAML genotypes may contribute to diseases of NTC/NCC lineage, albeit different disease phenotypes, due to alternative splicing via non-coding variants.	('diseases', 'Disease', (358, 366))	('NTC/NCC', 'Disease', (370, 377))	('alternative splicing', 'Var', (431, 451))	('neurological diseases and disorders', 'Disease', 'MESH:D009422', (55, 90))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('contribute', 'Reg', (344, 354))
140113	26246470	This conserved variant in all NTC/NCC originating cancers suggests the possibility to identify tumors with wild-type p53 that are regulated differently due to CAML variants in PSME.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('p53', 'Gene', (117, 120))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('p53', 'Gene', '7157', (117, 120))	('variants', 'Var', (164, 172))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('PSME', 'Gene', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (95, 101))
140114	26246470	Furthermore, the identification of a variant locus in FUBP3 in all the brain cancers (GBM, LGG, and MB) supports the potential for tissue-specific CAML and disease linkage.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('brain cancer', 'Phenotype', 'HP:0030692', (71, 83))	('MB', 'Phenotype', 'HP:0002885', (100, 102))	('FUBP3', 'Gene', (54, 59))	('variant', 'Var', (37, 44))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('LGG', 'Disease', (91, 94))	('FUBP3', 'Gene', '8939', (54, 59))	('brain cancers', 'Disease', 'MESH:D001932', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('brain cancers', 'Disease', (71, 84))
140116	26246470	Interestingly, FUBP3 binds to a microsatellite repeat region at the 3'-end of FGF9 and regulates its expression.	('FGF9', 'Gene', '2254', (78, 82))	('binds', 'Interaction', (21, 26))	('FUBP3', 'Gene', (15, 20))	('FUBP3', 'Gene', '8939', (15, 20))	('FGF9', 'Gene', (78, 82))	('regulates', 'Reg', (87, 96))	('microsatellite repeat', 'Var', (32, 53))	('expression', 'MPA', (101, 111))
140118	26246470	As previously identified, mutations in FUBP1 and IDH1 are closely associated with oligodendrogliomas, and are important prognostic and molecular markers for differentiating glioma phenotypes.	('FUBP1', 'Gene', (39, 44))	('IDH1', 'Gene', '3417', (49, 53))	('glioma', 'Disease', (93, 99))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (82, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('glioma', 'Disease', (173, 179))	('associated', 'Reg', (66, 76))	('FUBP1', 'Gene', '8880', (39, 44))	('mutations', 'Var', (26, 35))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('oligodendrogliomas', 'Disease', (82, 100))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('IDH1', 'Gene', (49, 53))
140123	26246470	Similar to the analysis of 1kGP samples, glioblastoma (GBM), lower-grade glioma (LGG), medulloblastoma (MB), and melanoma (MEL) samples were analyzed for genotypes, loci with significantly different variants (non-predominant) from the consensus (predominant genotype) in one population compared with the second population were identified as significant (p-value <= 0.01).	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('glioma', 'Disease', (73, 79))	('variants', 'Var', (199, 207))	('glioblastoma', 'Disease', (41, 53))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (41, 53))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('medulloblastoma', 'Disease', 'MESH:D008527', (87, 102))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('MB', 'Phenotype', 'HP:0002885', (104, 106))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('medulloblastoma', 'Phenotype', 'HP:0002885', (87, 102))	('MEL', 'Phenotype', 'HP:0002861', (123, 126))	('medulloblastoma', 'Disease', (87, 102))
140130	26246470	Variant cancer-associated microsatellite loci appear to demonstrate disease and tissue specificity; identifying these variants from germline DNA highlights the potential for conserved cancer and tissue-specific mechanistic attributes and therapy targets in addition to understanding cancer origin.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', (283, 289))	('variants', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
140131	26246470	Locating CAML variants that are shared globally by tissues originating from ectodermal tissues (NTC and NCC: LGG, MB, GBM, and MEL) but also distinct to the central nervous system (GBM, LGG, and MB) and further unique from breast cancer (a non-nervous system tissue) strengthens the argument for cancer cells of origin being in-part intrinsic to the ecology of tumorigenesis, cancer, and the individual.	('MB', 'Phenotype', 'HP:0002885', (195, 197))	('cancer', 'Disease', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('tumor', 'Disease', (361, 366))	('breast cancer', 'Disease', (223, 236))	('GBM', 'Phenotype', 'HP:0012174', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('MB', 'Phenotype', 'HP:0002885', (114, 116))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('variants', 'Var', (14, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (296, 302))	('GBM', 'Phenotype', 'HP:0012174', (118, 121))	('MEL', 'Phenotype', 'HP:0002861', (127, 130))
140199	26032848	The results showed that high levels of Sema3C protein in glioma samples was markedly associated with a shorter overall survival (p < 0.0001).	('Sema3C', 'Gene', '10512', (39, 45))	('glioma', 'Disease', (57, 63))	('overall', 'MPA', (111, 118))	('shorter', 'NegReg', (103, 110))	('high', 'Var', (24, 28))	('Sema3C', 'Gene', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
140212	26032848	Taking into account this functional background of Sema3C, perhaps it is not surprising to witness an increasing number of studies showing that aberrant expression levels of this protein is associated with a number of cancer phenotypes.	('aberrant', 'Var', (143, 151))	('Sema3C', 'Gene', '10512', (50, 56))	('associated', 'Reg', (189, 199))	('expression levels', 'MPA', (152, 169))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('Sema3C', 'Gene', (50, 56))
140215	26032848	High Sema3C expression increased motility and invasion of prostate cancer cells, whereas in ovarian cancer high levels of Sema3C were associated with shorter patient survival.	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('High', 'Var', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('ovarian cancer', 'Disease', (92, 106))	('Sema3C', 'Gene', (122, 128))	('patient', 'Species', '9606', (158, 165))	('Sema3C', 'Gene', '10512', (5, 11))	('Sema3C', 'Gene', '10512', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Disease', (58, 73))	('motility', 'CPA', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increased', 'PosReg', (23, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('shorter', 'NegReg', (150, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))	('Sema3C', 'Gene', (5, 11))	('invasion', 'CPA', (46, 54))
140222	26032848	1) indicating that the aberrant expression of Sema3C may be strongly associated with the advancement of glioma malignancy.	('aberrant expression', 'Var', (23, 42))	('glioma malignancy', 'Disease', 'MESH:D005910', (104, 121))	('Sema3C', 'Gene', '10512', (46, 52))	('glioma malignancy', 'Disease', (104, 121))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('associated with', 'Reg', (69, 84))	('Sema3C', 'Gene', (46, 52))
140228	26032848	SEMA3C methylation frequency has been determined in 72 % of low-grade gliomas and in 56 % of glioblastomas, whereas the gene expression data placed SEMA3C among genes that were prominently downregulated in gliomas.	('glioblastomas', 'Disease', (93, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('SEMA3C', 'Gene', '10512', (0, 6))	('SEMA3C', 'Gene', (0, 6))	('downregulated', 'NegReg', (189, 202))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('glioblastomas', 'Disease', 'MESH:D005909', (93, 106))	('methylation', 'Var', (7, 18))	('glioblastomas', 'Phenotype', 'HP:0012174', (93, 106))	('SEMA3C', 'Gene', '10512', (148, 154))	('SEMA3C', 'Gene', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Disease', (206, 213))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (206, 213))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
140242	25524464	Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent Ganglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age.	('ganglioglioma', 'Disease', (40, 53))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('gliomas', 'Disease', (173, 180))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (108, 129))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('BRAFV600E mutated', 'Var', (22, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('BRAFV600E', 'Mutation', 'rs113488022', (22, 31))	('pilocytic astrocytoma', 'Disease', (108, 129))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (57, 68))
140243	25524464	Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively.	('BRAFV600E', 'Var', (58, 67))	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('KIAA1549-BRAF', 'Disease', 'None', (84, 97))	('Activation', 'PosReg', (0, 10))	('KIAA1549-BRAF', 'Disease', (84, 97))
140244	25524464	We report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery.	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('BRAFV600E mutated', 'Var', (23, 40))	('cervicomedullary', 'Gene', (41, 57))
140250	25524464	Activation of the MAP Kinase (MAPK) pathway has been shown to be the main molecular alteration present in LGG and can be caused by duplication or mutation of the BRAF gene.	('caused by', 'Reg', (121, 130))	('duplication', 'Var', (131, 142))	('LGG', 'Disease', (106, 109))	('Activation', 'PosReg', (0, 10))	('BRAF', 'Gene', '673', (162, 166))	('mutation', 'Var', (146, 154))	('BRAF', 'Gene', (162, 166))
140251	25524464	In PA the most frequent genetic alteration consists in a duplication of the 7q34 region leading to a KIAA1549-BRAF fusion protein that is constitutively active whereas in GG the BRAFV600E mutation is more frequent.	('duplication', 'Var', (57, 68))	('KIAA1549-BRAF', 'Disease', 'None', (101, 114))	('KIAA1549-BRAF', 'Disease', (101, 114))	('BRAFV600E', 'Var', (178, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (178, 187))
140252	25524464	Inhibitors of MAPK pathway have been considered as a potential target therapy for these tumours.	('MAPK pathway', 'Pathway', (14, 26))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('Inhibitors', 'Var', (0, 10))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
140254	25524464	More recently, an activity of this drug was proved also in pediatric BRAFV600E mutated malignant astrocytomas.	('activity', 'MPA', (18, 26))	('BRAFV600E', 'Mutation', 'rs113488022', (69, 78))	('astrocytomas', 'Disease', 'MESH:D001254', (97, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('BRAFV600E mutated', 'Var', (69, 86))	('astrocytomas', 'Disease', (97, 109))
140255	25524464	Herein, we report on a case of BRAFV600E mutated cervicomedullary LGG successfully treated with Vemurafenib as single agent after failure of conventional treatment.	('BRAFV600E', 'Mutation', 'rs113488022', (31, 40))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (96, 107))	('cervicomedullary LGG', 'Disease', (49, 69))	('BRAFV600E mutated', 'Var', (31, 48))
140266	25524464	Considering the progressive clinical deterioration of the patient and the absence of other effective options, molecular testing for evaluation of a target therapy was performed on the tumour tissue from the first biopsy: according to data from the literature, the KIAA-BRAF fusion gene detection and BRAFV600E testing were performed on fresh frozen (FF) tumor tissue by RT-PCR, PCR amplification and subsequent sequencing.	('KIAA-BRAF', 'Gene', (264, 273))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('KIAA-BRAF', 'Gene', '673', (264, 273))	('BRAFV600E', 'Var', (300, 309))	('patient', 'Species', '9606', (58, 65))	('BRAFV600E', 'Mutation', 'rs113488022', (300, 309))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', (354, 359))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))
140276	25524464	Based on these results, a treatment with Vemurafenib was started on compassionate use in November 2013 (240 mg, 370 mg/m2, twice a day (BID), equivalent to the minimal dose that proved active in the adult cohort).	('240', 'Var', (104, 107))	('BID', 'Gene', '637', (136, 139))	('BID', 'Gene', (136, 139))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (41, 52))
140297	25524464	Subsequent studies revealed other, less common, molecular alterations in BRAF gene driving activation of the same pathway: the most frequent is the point mutation that occurs at codon 600 (BRAFV600E), firstly associated with several non-CNS human tumors, that results in substitution of valine by glutamic acid.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('BRAF', 'Gene', '673', (189, 193))	('BRAF', 'Gene', '673', (73, 77))	('BRAFV600E', 'Mutation', 'rs113488022', (189, 198))	('tumors', 'Disease', (247, 253))	('valine', 'MPA', (287, 293))	('valine', 'Chemical', 'MESH:D014633', (287, 293))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('human', 'Species', '9606', (241, 246))	('glutamic acid', 'Chemical', 'MESH:D018698', (297, 310))	('substitution', 'Var', (271, 283))	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', (73, 77))
140298	25524464	BRAFV600E mutation appears to be particularly associated with paediatric GG where its status changes based on the anatomical location.	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('associated', 'Reg', (46, 56))	('BRAFV600E', 'Var', (0, 9))	('paediatric GG', 'Disease', (62, 75))
140300	25524464	revealed a significantly worse recurrence-free survival of BRAFV600E-mutated GG compared to negative tumors, suggesting a negative prognostic role for this mutation in GG.	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('worse', 'NegReg', (25, 30))	('recurrence-free survival', 'CPA', (31, 55))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('BRAFV600E-mutated', 'Var', (59, 76))
140306	25524464	In vitro and in vivo studies of paediatric astrocytoma cell lines expressing BRAFV600E mutation have been performed and show that target inhibition of mutated BRAF exerts an antiproliferative activity and slows tumour growth, improving survival.	('astrocytoma', 'Disease', (43, 54))	('survival', 'CPA', (236, 244))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('BRAF', 'Gene', (159, 163))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('tumour growth', 'Disease', (211, 224))	('improving', 'PosReg', (226, 235))	('inhibition', 'NegReg', (137, 147))	('antiproliferative activity', 'CPA', (174, 200))	('slows', 'NegReg', (205, 210))	('BRAFV600E', 'Mutation', 'rs113488022', (77, 86))	('astrocytoma', 'Disease', 'MESH:D001254', (43, 54))	('tumour growth', 'Disease', 'MESH:D006130', (211, 224))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('BRAF', 'Gene', '673', (159, 163))	('mutated', 'Var', (151, 158))
140307	25524464	With this strong supportive rationale, a safety and pilot efficacy clinical trial of Vemurafenib against BRAFV600E mutant recurrent or refractory LGG in children has recently started (ClinicalTrials.gov Identifier: NCT01748149).	('BRAFV600E', 'Gene', (105, 114))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (85, 96))	('mutant', 'Var', (115, 121))	('LGG', 'Disease', (146, 149))	('children', 'Species', '9606', (153, 161))	('BRAFV600E', 'Mutation', 'rs113488022', (105, 114))
140316	25524464	Most of them rely upon the alternative reactivation of the MAP kinase signaling pathway through the mutational activation of other key molecule of the pathway, such as NRAS, MEK1 or MEK2, or the occurrence of BRAF-V600E splice variants.	('activation', 'PosReg', (111, 121))	('NRAS', 'Gene', '4893', (168, 172))	('V600E', 'Mutation', 'rs113488022', (214, 219))	('MEK1', 'Gene', '5604', (174, 178))	('MEK2', 'Gene', '5605', (182, 186))	('MAP kinase signaling pathway', 'Pathway', (59, 87))	('BRAF', 'Gene', (209, 213))	('MEK1', 'Gene', (174, 178))	('MEK2', 'Gene', (182, 186))	('BRAF', 'Gene', '673', (209, 213))	('NRAS', 'Gene', (168, 172))	('mutational', 'Var', (100, 110))
140319	25524464	It is important to point out, however, that the induction of secondary cutaneous lesions and the promotion of proliferation of pre-malignant cells harboring RAS mutation in non-cutaneous tissues, reported in some adult patients, raise considerable concern, especially in the pediatric population.	('RAS', 'Gene', (157, 160))	('secondary cutaneous lesions', 'CPA', (61, 88))	('promotion', 'PosReg', (97, 106))	('mutation', 'Var', (161, 169))	('proliferation', 'CPA', (110, 123))	('patients', 'Species', '9606', (219, 227))
140330	23440878	The average APT-weighted signal was significantly higher in the lesions than in the contralateral normal-appearing brain tissue (P < 0.001).	('APT', 'Chemical', '-', (12, 15))	('lesions', 'Var', (64, 71))	('APT-weighted signal', 'MPA', (12, 31))	('higher', 'PosReg', (50, 56))
140362	23440878	The achieved signal-to-noise ratios were estimated to be about 53, 122, and 69 for images at +-3, +-3.5, and +-4 ppm, respectively, which are high enough for detecting the APT signal of 2-3% of the bulk water intensity.	('APT', 'Chemical', '-', (172, 175))	('+-3.5', 'Var', (98, 103))	('water', 'Chemical', 'MESH:D014867', (203, 208))	('+-4 ppm', 'Var', (109, 116))
140381	23440878	For gliomas with gadolinium enhancement, the tumor region consisted of areas encircled by the gadolinium enhancement as well as some adjacent areas with the T2 and FLAIR hyperintensities.	('gliomas', 'Phenotype', 'HP:0009733', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('tumor', 'Disease', (45, 50))	('gadolinium', 'Chemical', 'MESH:D005682', (17, 27))	('gadolinium', 'Chemical', 'MESH:D005682', (94, 104))	('gliomas', 'Disease', (4, 11))	('gadolinium', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('gliomas', 'Disease', 'MESH:D005910', (4, 11))
140397	23440878	The hyperintense areas on the APT-weighted image were much smaller than the abnormal areas on T2-weighted and FLAIR and appeared associated with the most solid aspects of the lesion (gadolinium-enhancing portion) and some areas nearby.	('associated', 'Reg', (129, 139))	('hyperintense areas', 'Var', (4, 22))	('smaller', 'NegReg', (59, 66))	('gadolinium', 'Chemical', 'MESH:D005682', (183, 193))	('APT', 'Chemical', '-', (30, 33))
140415	23440878	For all low-grade gliomas (n = 6), the average APT-weighted image intensities were marginally significantly higher in the region of FLAIR hyperintensity than in the contralateral brain tissue (1.09% vs. 0.51%; P = 0.046), and the contrast was small (0.51%), consistent with the fact that no marked APT-weighted hyperintensity was clearly seen on the images.	('gliomas', 'Disease', (18, 25))	('hyperintensity', 'Var', (138, 152))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('APT-weighted image intensities', 'MPA', (47, 77))	('APT', 'Chemical', '-', (47, 50))	('APT', 'Chemical', '-', (298, 301))	('higher', 'PosReg', (108, 114))
140478	19273186	For instance, low-grade serous carcinoma shows fewer molecular abnormalities by both cytogenetic analysis and single nucleotide polymorphism analysis than high-grade carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (166, 175))	('serous carcinoma', 'Disease', 'MESH:D018284', (24, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Disease', (31, 40))	('carcinoma', 'Disease', (166, 175))	('single nucleotide polymorphism', 'Var', (110, 140))	('molecular abnormalities', 'Disease', (53, 76))	('serous carcinoma', 'Disease', (24, 40))	('carcinoma', 'Disease', 'MESH:D002277', (31, 40))	('molecular abnormalities', 'Disease', 'MESH:C567116', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
140481	19273186	High-grade serous carcinoma commonly involves p53 mutations, but such mutations are rare in low-grade carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('serous carcinoma', 'Disease', (11, 27))	('serous carcinoma', 'Disease', 'MESH:D018284', (11, 27))	('mutations', 'Var', (50, 59))	('p53', 'Gene', (46, 49))	('low-grade carcinoma', 'Disease', 'MESH:D008228', (92, 111))	('involves', 'Reg', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('low-grade carcinoma', 'Disease', (92, 111))
140482	19273186	Accumulating data suggest that loss of BRCA1/2 function may predispose to the development of both sporadic and hereditary high-grade serous carcinomas.	('serous carcinomas', 'Disease', (133, 150))	('function', 'MPA', (47, 55))	('sporadic', 'Disease', (98, 106))	('loss', 'Var', (31, 35))	('BRCA1/2', 'Gene', (39, 46))	('predispose', 'Reg', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('serous carcinomas', 'Disease', 'MESH:D018284', (133, 150))	('BRCA1/2', 'Gene', '672;675', (39, 46))
140484	19273186	It has been demonstrated that cells with defective BRCA1 are hypersensitive to DNA-damaging agents, are slower to repair double-stranded DNA breaks, and show impairment in transcription-coupled repair.	('transcription-coupled repair', 'MPA', (172, 200))	('repair double-stranded DNA breaks', 'MPA', (114, 147))	('BRCA1', 'Gene', '672', (51, 56))	('defective', 'Var', (41, 50))	('hypersensitive', 'Disease', 'MESH:D004342', (61, 75))	('BRCA1', 'Gene', (51, 56))	('slower', 'NegReg', (104, 110))	('hypersensitive', 'Disease', (61, 75))
140486	19273186	We recently demonstrated that BTAK, a mitotic phase regulatory protein, is overexpressed in ovaries of women with a BRCA mutation or history of ovarian or breast cancer.	('ovarian or breast cancer', 'Disease', (144, 168))	('BTAK', 'Gene', '6790', (30, 34))	('ovaries', 'Disease', (92, 99))	('BRCA', 'Gene', '672;675', (116, 120))	('ovarian or breast cancer', 'Disease', 'MESH:D010051', (144, 168))	('ovaries', 'Disease', 'MESH:D010051', (92, 99))	('mutation', 'Var', (121, 129))	('BTAK', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('women', 'Species', '9606', (103, 108))	('BRCA', 'Gene', (116, 120))	('overexpressed', 'PosReg', (75, 88))
140489	19273186	Low-grade serous carcinoma is characterized by mutations in the KRAS or BRAF pathway, as mutations in KRAS or its downstream mediator BRAF have been detected in 68% of low-grade and 61% of low-malignant-potential (LMP) serous carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (226, 236))	('serous carcinomas', 'Disease', 'MESH:D018284', (219, 236))	('detected', 'Reg', (149, 157))	('low-malignant-potential', 'Disease', (189, 212))	('mutations', 'Var', (89, 98))	('low-grade', 'Disease', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('serous carcinoma', 'Disease', (10, 26))	('BRAF', 'Gene', '673', (72, 76))	('LMP', 'Chemical', '-', (214, 217))	('serous carcinoma', 'Disease', 'MESH:D018284', (219, 235))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (134, 138))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (134, 138))	('KRAS', 'Gene', '3845', (64, 68))	('serous carcinoma', 'Disease', 'MESH:D018284', (10, 26))	('serous carcinomas', 'Disease', (219, 236))	('KRAS', 'Gene', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', '3845', (102, 106))	('KRAS', 'Gene', (102, 106))
140496	19273186	Dab2 could sequester Grb2 from binding to SOS, and the dissociation of the Grb2/SOS complex may reduce Ras activation, which is thought to be a feedback mechanism for Ras downregulation.	('Grb2', 'Gene', (21, 25))	('SOS', 'Chemical', 'MESH:C405951', (42, 45))	('dissociation', 'Var', (55, 67))	('Dab2', 'Gene', (0, 4))	('Grb2', 'Gene', '2885', (75, 79))	('Dab2', 'Gene', '1601', (0, 4))	('activation', 'MPA', (107, 117))	('SOS', 'Chemical', 'MESH:C405951', (80, 83))	('Ras', 'Protein', (103, 106))	('Grb2', 'Gene', '2885', (21, 25))	('reduce', 'NegReg', (96, 102))	('Grb2', 'Gene', (75, 79))
140500	19273186	Alternatively, loss of Dab2 may contribute to tumor cell growth, as Dab2 transfection suppressed the expression in morphologically normal epithelium adjacent to ovarian cancer suggests that Dab2 functions as a tumor suppressor and that its expression is an early event in ovarian cancer progression.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('loss', 'Var', (15, 19))	('ovarian cancer', 'Disease', 'MESH:D010051', (272, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('Dab2', 'Gene', (190, 194))	('Dab2', 'Gene', (23, 27))	('tumor', 'Disease', (210, 215))	('ovarian cancer', 'Disease', 'MESH:D010051', (161, 175))	('suppressed', 'NegReg', (86, 96))	('ovarian cancer', 'Disease', (272, 286))	('Dab2', 'Gene', '1601', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('Dab2', 'Gene', (68, 72))	('Dab2', 'Gene', '1601', (23, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (272, 286))	('tumor', 'Disease', (46, 51))	('ovarian cancer', 'Disease', (161, 175))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('Dab2', 'Gene', '1601', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('transfection', 'Var', (73, 85))	('expression', 'MPA', (101, 111))
140505	19273186	Mutational analysis of low-grade serous carcinoma showed high frequency of KRAS and BRAF mutations, suggesting that this group of tumors develops through a dysregulated RAS-RAF signaling pathway.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('BRAF', 'Gene', '673', (84, 88))	('serous carcinoma', 'Disease', (33, 49))	('BRAF', 'Gene', (84, 88))	('RAF', 'Gene', (173, 176))	('RAF', 'Gene', '22882', (173, 176))	('serous carcinoma', 'Disease', 'MESH:D018284', (33, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('KRAS', 'Gene', (75, 79))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('RAF', 'Gene', '22882', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('RAF', 'Gene', (85, 88))	('KRAS', 'Gene', '3845', (75, 79))
140506	19273186	High-grade serous carcinoma has a high frequency of mutations in the p53 and BRCA1/2 genes, and thus these tumors most probably arise via TP53 mutations and BRCA1 or BRCA2 dysfunction.	('BRCA1', 'Gene', (77, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('BRCA2 dysfunction', 'Disease', (166, 183))	('serous carcinoma', 'Disease', (11, 27))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Gene', (138, 142))	('mutations', 'Var', (143, 152))	('serous carcinoma', 'Disease', 'MESH:D018284', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('BRCA1/2', 'Gene', (77, 84))	('BRCA1', 'Gene', '672', (157, 162))	('arise', 'Reg', (128, 133))	('mutations', 'Var', (52, 61))	('p53', 'Gene', (69, 72))	('BRCA1', 'Gene', (157, 162))	('TP53', 'Gene', '7157', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('BRCA2 dysfunction', 'Disease', 'MESH:D006331', (166, 183))	('BRCA1', 'Gene', '672', (77, 82))	('BRCA1/2', 'Gene', '672;675', (77, 84))
140517	19273186	Mutation of the beta-catenin gene is one of the most common molecular alterations in endometrioid carcinoma and thus may be a useful molecular marker.	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (85, 107))	('endometrioid carcinoma', 'Disease', (85, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Mutation', 'Var', (0, 8))	('beta-catenin', 'Gene', (16, 28))	('beta-catenin', 'Gene', '1499', (16, 28))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (85, 107))
140521	19273186	Deregulation of the cadherin/catenin complex has been implicated in the development, progression, differentiation, invasion, and metastasis of several malignancies.	('Deregulation', 'Var', (0, 12))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('implicated', 'Reg', (54, 64))	('invasion', 'CPA', (115, 123))	('metastasis', 'CPA', (129, 139))	('malignancies', 'Disease', (151, 163))	('differentiation', 'CPA', (98, 113))	('cadherin/catenin complex', 'Protein', (20, 44))
140522	19273186	Deregulation of beta-catenin may be caused by an oncogenic mutation in the beta-catenin gene (CTNNB1), mutations in the APC gene, or alterations of the Wnt signal transduction pathway.	('beta-catenin', 'Gene', '1499', (75, 87))	('mutations', 'Var', (103, 112))	('CTNNB1', 'Gene', '1499', (94, 100))	('APC', 'Disease', 'MESH:D011125', (120, 123))	('APC', 'Disease', (120, 123))	('beta-catenin', 'Gene', (16, 28))	('caused by', 'Reg', (36, 45))	('Deregulation', 'MPA', (0, 12))	('alterations', 'Reg', (133, 144))	('Wnt signal transduction pathway', 'Pathway', (152, 183))	('mutation', 'Var', (59, 67))	('beta-catenin', 'Gene', (75, 87))	('beta-catenin', 'Gene', '1499', (16, 28))	('CTNNB1', 'Gene', (94, 100))
140524	19273186	For instance, frequency of beta-catenin mutation is higher in synchronous tumors than in single ovarian carcinomas.	('ovarian carcinomas', 'Disease', 'MESH:D010051', (96, 114))	('mutation', 'Var', (40, 48))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (96, 113))	('beta-catenin', 'Gene', '1499', (27, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('synchronous tumors', 'Disease', 'MESH:D009378', (62, 80))	('ovarian carcinomas', 'Disease', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (96, 114))	('synchronous tumors', 'Disease', (62, 80))	('higher', 'Reg', (52, 58))	('beta-catenin', 'Gene', (27, 39))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
140525	19273186	Moreover, ovarian endometrioid cancers exhibit microsatellite instability and PTEN alterations less frequently than their uterine counterparts.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ovarian endometrioid cancers', 'Disease', 'MESH:D010051', (10, 38))	('PTEN', 'Gene', (78, 82))	('microsatellite', 'Var', (47, 61))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('ovarian endometrioid cancers', 'Disease', (10, 38))	('alterations', 'Reg', (83, 94))
140526	19273186	PTEN mutations are found more frequently in endometrioid carcinomas (approximately 43%) than other histologic types, indicating that they may play a role in the development of this subtype.	('play', 'Reg', (142, 146))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (44, 67))	('role', 'Reg', (149, 153))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('mutations', 'Var', (5, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('PTEN', 'Gene', (0, 4))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (44, 66))	('endometrioid carcinomas', 'Disease', (44, 67))
140534	19273186	Analyses of KRAS mutations lend molecular genetic support to this theory.	('KRAS', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('KRAS', 'Gene', '3845', (12, 16))
140535	19273186	KRAS mutations are common in mucinous ovarian tumors.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mucinous ovarian tumors', 'Disease', (29, 52))	('mutations', 'Var', (5, 14))	('mucinous ovarian tumors', 'Disease', 'MESH:D010051', (29, 52))	('common', 'Reg', (19, 25))	('mucinous ovarian tumors', 'Phenotype', 'HP:0031494', (29, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('KRAS', 'Gene', (0, 4))	('ovarian tumors', 'Phenotype', 'HP:0100615', (38, 52))	('KRAS', 'Gene', '3845', (0, 4))
140536	19273186	Interestingly, some microdissected mucinous tumors were found to have the same KRAS mutation in histologically benign, borderline, and malignant areas of the same tumor.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('KRAS', 'Gene', '3845', (79, 83))	('mucinous tumors', 'Disease', 'MESH:D002288', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('KRAS', 'Gene', (79, 83))	('mucinous tumors', 'Disease', (35, 50))	('mutation', 'Var', (84, 92))
140537	19273186	Thus, KRAS mutation may be an early event in ovarian mucinous carcinogenesis.	('KRAS', 'Gene', '3845', (6, 10))	('ovarian mucinous carcinogenesis', 'Disease', (45, 76))	('mutation', 'Var', (11, 19))	('KRAS', 'Gene', (6, 10))	('ovarian mucinous carcinogenesis', 'Disease', 'MESH:D063646', (45, 76))
140557	19273186	While p53 mutations are common in tumorigenesis and have been found in various epithelial subtypes, particularly serous ovarian carcinoma, they are conspicuously absent in OCCA, implying that other anti-apoptotic mechanisms are involved.	('p53', 'Gene', (6, 9))	('tumor', 'Disease', (34, 39))	('serous ovarian carcinoma', 'Disease', (113, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (113, 137))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (120, 137))	('absent', 'NegReg', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
140559	19273186	A high frequency of aberrant methylation that results in transcriptional silencing of TMS-1/ASC has been observed in OCCA tumors, indicating a mechanism for apoptotic escape in tumor development; this may have implications for drug resistance in OCCA as well.	('tumors', 'Disease', (122, 128))	('methylation', 'Var', (29, 40))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('ASC', 'Gene', '29108', (92, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (227, 242))	('OCCA', 'Disease', (117, 121))	('transcriptional', 'MPA', (57, 72))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('aberrant methylation', 'Var', (20, 40))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('ASC', 'Gene', (92, 95))	('TMS-1', 'Gene', '29108', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (122, 127))	('TMS-1', 'Gene', (86, 91))
140560	19273186	Mutations in the PTEN gene are common in endometrioid and clear cell ovarian cancers but not in serous or mucinous ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('serous or mucinous ovarian cancers', 'Disease', (96, 130))	('common', 'Reg', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('ovarian cancers', 'Phenotype', 'HP:0100615', (115, 130))	('clear cell ovarian cancers', 'Disease', 'MESH:D008649', (58, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('clear cell ovarian cancers', 'Disease', (58, 84))	('mucinous ovarian cancer', 'Phenotype', 'HP:0031494', (106, 129))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('Mutations', 'Var', (0, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('PTEN', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('endometrioid', 'Disease', (41, 53))	('ovarian cancers', 'Phenotype', 'HP:0100615', (69, 84))	('serous or mucinous ovarian cancers', 'Disease', 'MESH:D018297', (96, 130))
140564	19273186	The CD44-10v isoform was also absent in the contralateral, unaffected ovaries, suggesting that aberrant alternative mRNA splicing of CD44 is involved in the development and progression of OCCA.	('ovaries', 'Disease', 'MESH:D010051', (70, 77))	('aberrant alternative mRNA splicing', 'Var', (95, 129))	('CD44', 'Gene', '960', (133, 137))	('CD44', 'Gene', (133, 137))	('CD44', 'Gene', '960', (4, 8))	('ovaries', 'Disease', (70, 77))	('OCCA', 'Disease', (188, 192))	('CD44', 'Gene', (4, 8))	('involved', 'Reg', (141, 149))
140569	19273186	In experimental systems, mismatch repair-deficient cells are highly tolerant to the methylating chemotherapeutic drugs streptozocin and temozolomide, and, to a lesser extent, cisplatin and doxorubicin.	('temozolomide', 'Chemical', 'MESH:D000077204', (136, 148))	('tolerant', 'MPA', (68, 76))	('methylating', 'MPA', (84, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (189, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('streptozocin', 'Chemical', 'MESH:D013311', (119, 131))	('mismatch repair-deficient', 'Var', (25, 50))
140571	19273186	We observed high-level microsatellite instability involvement in the development of a subset of OCCAs and a strong association between alterations in hMLH1 and hMSH2 expression and microsatellite instability in these tumors.	('hMLH1', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('involvement', 'Reg', (50, 61))	('hMSH2', 'Gene', '4436', (160, 165))	('tumors', 'Disease', (217, 223))	('hMSH2', 'Gene', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('hMLH1', 'Gene', '4292', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('microsatellite instability', 'MPA', (23, 49))	('alterations', 'Var', (135, 146))	('microsatellite instability', 'MPA', (181, 207))	('expression', 'MPA', (166, 176))
140584	19273186	Dysregulation of different HOX genes leads to development of serous, endometrioid, and mucinous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('Dysregulation', 'Var', (0, 13))	('mucinous carcinomas', 'Disease', (87, 106))	('serous', 'Disease', (61, 67))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (87, 106))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (87, 105))	('leads to', 'Reg', (37, 45))	('HOX genes', 'Gene', (27, 36))	('endometrioid', 'Disease', (69, 81))
140592	19273186	Cellular senescence may act to suppress tumor formation at a young age but promote it at an older age, perhaps because abrogation of the senescence program by genetic mutations in epithelial cells provides a favorable tumor microenvironment.	('promote', 'PosReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutations', 'Var', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('suppress', 'NegReg', (31, 39))
140619	19273186	Despite our knowledge of genetic alternations in ovarian cancer, we do not understand how these genetic changes work together to transform normal ovarian surface epithelial cells into cancerous cells.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('alternations', 'Var', (33, 45))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('ovarian cancer', 'Disease', (49, 63))
140627	19273186	Mutation activation in K-ras and inactivation in PTEN or double mutational inactivation in APC and PTEN leads to development of ovarian endometrioid carcinoma, whereas concurrent inactivation of p53 and Rb leads to development of serous carcinoma from mouse ovarian surface epithelial cells.	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('mouse', 'Species', '10090', (252, 257))	('activation', 'PosReg', (9, 19))	('APC', 'Disease', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('leads to', 'Reg', (104, 112))	('serous carcinoma', 'Disease', (230, 246))	('ovarian endometrioid carcinoma', 'Disease', (128, 158))	('double mutational inactivation', 'Var', (57, 87))	('K-ras', 'Protein', (23, 28))	('ovarian endometrioid carcinoma', 'Disease', 'MESH:D016889', (128, 158))	('PTEN', 'Gene', (99, 103))	('inactivation', 'Var', (33, 45))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (136, 158))	('APC', 'Disease', 'MESH:D011125', (91, 94))	('serous carcinoma', 'Disease', 'MESH:D018284', (230, 246))	('PTEN', 'Gene', (49, 53))
140632	19273186	Rarely, cells transfected with T/t or E6/E7, after many passages in culture, produced colonies in soft agar or formed tumors in nude mice, presumably as a result of spontaneous mutation.	('formed', 'Reg', (111, 117))	('nude mice', 'Species', '10090', (128, 137))	('T/t', 'Var', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('E6/E7', 'Gene', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('E6/E7', 'Gene', '1489078', (38, 43))	('tumors', 'Disease', (118, 124))	('produced', 'Reg', (77, 85))	('colonies in soft agar', 'CPA', (86, 107))
140644	19273186	To overcome this limitation, we generated a second-generation model of immortalized, nontumorigenic cells by using retrovirus-mediated small-interfering RNA against p53 or Rb, in combination with the ectopic hTERT expression.	('p53', 'Gene', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('small-interfering RNA', 'Var', (135, 156))	('hTERT', 'Gene', '7015', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hTERT', 'Gene', (208, 213))	('tumor', 'Disease', (88, 93))
140651	30936198	BCR-NTRK2 fusion in a low-grade glioma with distinctive morphology and unexpected aggressive behavior A 52-yr-old man was found to have a 6.6-cm left frontotemporal mass.	('glioma', 'Disease', (32, 38))	('NTRK2', 'Gene', (4, 9))	('fusion', 'Var', (10, 16))	('aggressive behavior', 'Phenotype', 'HP:0000718', (82, 101))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('man', 'Species', '9606', (114, 117))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('NTRK2', 'Gene', '4915', (4, 9))	('BCR', 'Gene', (0, 3))	('BCR', 'Gene', '613', (0, 3))
140667	30936198	Ancillary testing identified the tumor tissue as negative for hotspot mutations in IDH1, IDH2, EGFR, and BRAF via sequencing and negative for co-deletion of Chromosomes 1p and 19q via fluorescence in situ hybridization (FISH).	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (70, 79))	('IDH1', 'Gene', '3417', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('BRAF', 'Gene', (105, 109))	('hotspot', 'PosReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IDH2', 'Gene', (89, 93))	('tumor', 'Disease', (33, 38))	('EGFR', 'Gene', '1956', (95, 99))	('IDH1', 'Gene', (83, 87))	('IDH2', 'Gene', '3418', (89, 93))	('EGFR', 'Gene', (95, 99))
140668	30936198	A subpopulation of cells was noted to show polysomy of 19p and 19q in the range of three to five copies (in ~39% of nuclei counted).	('polysomy', 'Var', (43, 51))	('nuc', 'Gene', (116, 119))	('nuc', 'Gene', '4924', (116, 119))
140680	30936198	Anchored multiplex PCR was performed by an internally validated protocol using the FusionPlex CTL kit (Archer AB0007) RNA-targeted component for fusion, splicing, or exon-skipping variant detection from 19 genes including NTRK1, NTRK2, NTRK3, and BRAF.	('NTRK3', 'Gene', (236, 241))	('NTRK2', 'Gene', (229, 234))	('NTRK1', 'Gene', '4914', (222, 227))	('BRAF', 'Gene', '673', (247, 251))	('NTRK2', 'Gene', '4915', (229, 234))	('BRAF', 'Gene', (247, 251))	('NTRK3', 'Gene', '4916', (236, 241))	('NTRK1', 'Gene', (222, 227))	('exon-skipping variant', 'Var', (166, 187))
140692	30936198	FISH studies were performed on nuclei from FFPE tumor sections from the same block using the DNA probes LSI 1p/1q [1p36/1q25] and LSI 19p/19q [19p13/19q13].	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('LSI 19p/19q [19p13/19q13]', 'Var', (130, 155))	('nuc', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('LSI 1p/1q [1p36/1q25]', 'Var', (104, 125))	('nuc', 'Gene', '4924', (31, 34))
140693	30936198	There were increased copies of 19p and 19q probes in the range of 3 to 5 per nucleus in 39% of cells counted, nuc ish(LSI1p,LSI1q)x2[100],(LSI19p,LSI19q)x3~5[39/100].	('nuc', 'Gene', (77, 80))	('nuc', 'Gene', '4924', (110, 113))	('LSI1p', 'Var', (118, 123))	('LSI19p', 'Var', (139, 145))	('nuc', 'Gene', '4924', (77, 80))	('nuc', 'Gene', (110, 113))
140697	30936198	An RNA fusion transcript (Chr 9:g.87359888::Chr 22:g.23524426) was detected that included exon 1 of BCR (NM_004327.3) and exon 13 of NTRK2 (NM_001018064.1) and was predicted to arise from a t(9;22)(q21;q11) rearrangement (Table 1; Fig.	('BCR', 'Gene', (100, 103))	('BCR', 'Gene', '613', (100, 103))	('NM_001018064.1', 'Var', (140, 154))	('NTRK2', 'Gene', (133, 138))	('NM_004327.3', 'Var', (105, 116))	('NTRK2', 'Gene', '4915', (133, 138))	('t(9;22)(q21;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (190, 206))
140705	30936198	NTRK2 gene rearrangements in cancer have been identified as pathogenic, tipping the homeostatic scales toward proliferation and tumorigenesis.	('cancer', 'Disease', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tipping', 'Reg', (72, 79))	('rearrangements', 'Var', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('NTRK2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('NTRK2', 'Gene', '4915', (0, 5))	('homeostatic scales', 'MPA', (84, 102))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
140706	30936198	Tumors with NTRK gene rearrangements have been shown to overexpress Trk by immunohistochemistry.	('Trk', 'Gene', '4914', (68, 71))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Trk', 'Gene', (68, 71))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('overexpress', 'PosReg', (56, 67))	('NTRK gene', 'Gene', (12, 21))	('rearrangements', 'Var', (22, 36))
140708	30936198	The BCR-NTRK2 fusion product was predicted to be activating based on the prediction of an in-frame product, the protein domains that were predicted to be retained, and by similarity with other fusions involving the BCR and NTRK2 genes.	('BCR', 'Gene', (4, 7))	('NTRK2', 'Gene', (8, 13))	('BCR', 'Gene', '613', (4, 7))	('BCR', 'Gene', (215, 218))	('activating', 'MPA', (49, 59))	('fusion', 'Var', (14, 20))	('NTRK2', 'Gene', '4915', (8, 13))	('BCR', 'Gene', '613', (215, 218))	('NTRK2', 'Gene', (223, 228))	('NTRK2', 'Gene', '4915', (223, 228))
140727	30936198	Since the conclusion of this case, larotrectinib was approved by the FDA for use in advanced solid tumors with fusions involving any of the three NTRK genes.	('fusions', 'Var', (111, 118))	('NTRK', 'Gene', (146, 150))	('solid tumors', 'Disease', (93, 105))	('larotrectinib', 'Chemical', 'MESH:C000609083', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (93, 105))
140729	30936198	But an expanded access trial and clinical trials including general primary brain neoplasms and gliomas specifically are open at this time (ClinicalTrials.gov identification numbers NCT03025360, NCT02576431, NCT02465060).	('primary brain neoplasms', 'Disease', 'MESH:D001932', (67, 90))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('brain neoplasms', 'Phenotype', 'HP:0030692', (75, 90))	('NCT02576431', 'Var', (194, 205))	('NCT02465060', 'Var', (207, 218))	('neoplasms', 'Phenotype', 'HP:0002664', (81, 90))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('NCT03025360', 'Var', (181, 192))	('gliomas', 'Disease', (95, 102))	('pan', 'Gene', (9, 12))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('primary brain neoplasms', 'Disease', (67, 90))	('pan', 'Gene', '51816', (9, 12))	('neoplasm', 'Phenotype', 'HP:0002664', (81, 89))
140745	29631562	We excluded glioblastoma-like tumors (7a10d subgroup) and derived a gene expression signature distinguishing histologically classified oligodendrogliomas with concurrent 1p/19q co-deletion and IDH mutation (1p/19q subgroup) from those with predominant IDH mutation alone (IDHme subgroup).	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('oligodendrogliomas', 'Disease', (135, 153))	('glioblastoma-like tumors', 'Disease', 'MESH:D005909', (12, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('IDH', 'Gene', (272, 275))	('IDH', 'Gene', (193, 196))	('IDH', 'Gene', '3417', (272, 275))	('IDH', 'Gene', '3417', (193, 196))	('IDH', 'Gene', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('1p/19q co-deletion', 'Var', (170, 188))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (135, 153))	('IDH', 'Gene', '3417', (252, 255))	('glioblastoma-like tumors', 'Disease', (12, 36))
140757	29631562	Three different gene expression subtypes of 1p/19q co-deleted oligodendrogliomas have recently been revealed, but the analysis of the clinical relevance of these subtypes requires additional studies.	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (62, 80))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('oligodendrogliomas', 'Disease', (62, 80))	('1p/19q co-deleted', 'Var', (44, 61))
140759	29631562	These mutations are associated with the glioma-CpG island methylator phenotype (G-CIMP) and with a better prognosis compared to IDH wild-type tumors.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('associated', 'Reg', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('G-CIMP', 'Chemical', '-', (80, 86))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (128, 131))	('glioma', 'Disease', (40, 46))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('mutations', 'Var', (6, 15))
140762	29631562	According to this new classification, oligodendrogliomas are characterized by the co-occurrence of the mutation of IDH1/2 and the 1p/19q co-deletion.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('1p/19q co-deletion', 'Var', (130, 148))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (38, 56))	('IDH1/2', 'Gene', '3417;3418', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('oligodendrogliomas', 'Disease', (38, 56))	('mutation', 'Var', (103, 111))	('IDH1/2', 'Gene', (115, 121))
140763	29631562	Notably, this class does not accommodate IDH-mutated tumors with 1p/19q wild-type that were classified as oligodendrogliomas based on histology before.	('IDH', 'Gene', (41, 44))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (106, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('IDH', 'Gene', '3417', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('oligodendrogliomas', 'Disease', (106, 124))	('1p/19q', 'Var', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))
140765	29631562	Recently, it has been shown that glioma subgroups can be defined based on IDH mutation and 1p/19q co-deletion status deriving genetic subgroups that are more reflective of disease subtypes than glioma classes defined by histology.	('mutation', 'Var', (78, 86))	('glioma', 'Disease', (194, 200))	('glioma', 'Disease', (33, 39))	('IDH', 'Gene', (74, 77))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('IDH', 'Gene', '3417', (74, 77))
140774	29631562	To further characterize molecular differences, we derived a signature of differentially expressed genes distinguishing tumors with 1p/19 co-deletion and IDH mutation from tumors that predominantly showed an IDH mutation.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('1p/19', 'Gene', (131, 136))	('mutation', 'Var', (157, 165))	('IDH', 'Gene', (207, 210))	('IDH', 'Gene', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('IDH', 'Gene', '3417', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('IDH', 'Gene', '3417', (153, 156))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
140781	29631562	These subgroups were named taking into account the following molecular properties: (i) 1p/19q - co-deletion of chromosomal arms 1p and 19q and presence of characteristic IDH1/2 mutation, (ii) IDHme - predominance of IDH1/2 mutation but no co-deletion of 1p and 19q, and (iii) 7a10d - no co-deletion of 1p and 19q, lack of IDH1/2 mutations, amplification of chromosome 7, and deletion of chromosome 10.	('IDH', 'Gene', (216, 219))	('IDH', 'Gene', '3417', (322, 325))	('deletion', 'Var', (375, 383))	('lack', 'NegReg', (314, 318))	('IDH', 'Gene', '3417', (170, 173))	('IDH1/2', 'Gene', '3417;3418', (322, 328))	('IDH', 'Gene', '3417', (192, 195))	('IDH', 'Gene', '3417', (216, 219))	('IDH1/2', 'Gene', (322, 328))	('mutation', 'Var', (177, 185))	('mutation', 'Var', (223, 231))	('IDH', 'Gene', (322, 325))	('IDH1/2', 'Gene', '3417;3418', (170, 176))	('IDH1/2', 'Gene', (170, 176))	('IDH1/2', 'Gene', '3417;3418', (216, 222))	('IDH', 'Gene', (170, 173))	('amplification', 'Var', (340, 353))	('IDH1/2', 'Gene', (216, 222))	('IDH', 'Gene', (192, 195))
140795	29631562	The largest subgroup comprised 133 tumors (68.9%) and showed the characteristic 1p/19q co-deletion as well as IDH1 or IDH2 mutations in each tumor.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('IDH1', 'Gene', '3417', (110, 114))	('IDH2', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('co-deletion', 'Var', (87, 98))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('IDH2', 'Gene', '3418', (118, 122))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('1p/19q', 'Gene', (80, 86))	('IDH1', 'Gene', (110, 114))	('mutations', 'Var', (123, 132))
140797	29631562	Since the majority of tumors in this subgroup had an IDH1/2 mutation (82%), we named this subgroup IDH mutation-enriched (IDHme).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', (122, 125))	('mutation', 'Var', (60, 68))	('IDH', 'Gene', '3417', (122, 125))	('IDH1/2', 'Gene', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('IDH', 'Gene', (53, 56))	('IDH1/2', 'Gene', '3417;3418', (53, 59))	('IDH', 'Gene', (99, 102))	('tumors', 'Disease', (22, 28))	('IDH', 'Gene', '3417', (53, 56))
140798	29631562	The third subgroup comprised 15 tumors (7.8%) that were characterized by an amplification of chromosome 7 and a deletion of chromosome 10 as typically observed in classical glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (173, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('glioblastomas', 'Disease', (173, 186))	('deletion', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('15 tumors', 'Disease', 'MESH:C567447', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('glioblastomas', 'Phenotype', 'HP:0012174', (173, 186))	('15 tumors', 'Disease', (29, 38))	('amplification', 'Var', (76, 89))
140799	29631562	Only three tumors in this subgroup had an IDH1 or IDH2 mutation (20%).	('IDH2', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('IDH1', 'Gene', '3417', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('IDH2', 'Gene', '3418', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('mutation', 'Var', (55, 63))	('IDH1', 'Gene', (42, 46))
140800	29631562	It is important to note that the 7a10d subgroup formed an own subcluster that is relatively distant to the 1p/19q and IDHme subgroups, which were both part of one larger subcluster (Fig.	('7a10d', 'Var', (33, 38))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (118, 121))
140802	29631562	Only 5% and 2% of the 1p/19q tumors showed a mutation of, respectively, TP53 and ATRX, while about two-third of the IDHme tumors had at least one of these two genes mutated.	('IDHme tumors', 'Disease', (116, 128))	('ATRX', 'Gene', (81, 85))	('TP53', 'Gene', '7157', (72, 76))	('19q tumors', 'Disease', 'MESH:C538311', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ATRX', 'Gene', '546', (81, 85))	('TP53', 'Gene', (72, 76))	('IDHme tumors', 'Disease', 'MESH:D009369', (116, 128))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('mutation', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('19q tumors', 'Disease', (25, 35))
140803	29631562	For 7a10d tumors, these numbers were 40% and 25%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('7a10d', 'Var', (4, 9))
140811	29631562	In contrast, the vast majority of tumors in the 7a10d subgroup had a negative correlation with the proneural subtype (Fig.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('proneural subtype', 'Disease', (99, 116))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('negative', 'NegReg', (69, 77))	('7a10d', 'Var', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
140813	29631562	In a similar analysis, we compared the associations of the three oligodendroglioma subgroups with the expression signature of the G-CIMP subtype driven by the mutation of IDH.	('oligodendroglioma', 'Disease', (65, 82))	('IDH', 'Gene', '3417', (171, 174))	('oligodendroglioma', 'Disease', 'MESH:D009837', (65, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('G-CIMP', 'Chemical', '-', (130, 136))	('mutation', 'Var', (159, 167))	('associations', 'Interaction', (39, 51))	('IDH', 'Gene', (171, 174))
140815	29631562	We also analyzed whether there are differences in patient survival between the three subgroups by using the clinical data available for 125 1p/19q, 34 IDHme, and 15 7a10d tumors.	('1p/19q', 'Var', (140, 146))	('IDH', 'Gene', '3417', (151, 154))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('patient', 'Species', '9606', (50, 57))	('IDH', 'Gene', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
140817	29631562	In sharp contrast, patients from 7a10d showed significantly shorter survival than patients from the 1p/19q and IDHme subgroups (Fig.	('7a10d', 'Var', (33, 38))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (82, 90))	('IDH', 'Gene', (111, 114))	('IDH', 'Gene', '3417', (111, 114))	('survival', 'MPA', (68, 76))	('shorter', 'NegReg', (60, 67))
140820	29631562	Diffuse gliomas were grouped into three major subtypes based on the IDH mutation status and the presence of the 1p/19q co-deletion in.	('IDH', 'Gene', '3417', (68, 71))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('gliomas', 'Disease', (8, 15))	('1p/19q co-deletion', 'Var', (112, 130))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('IDH', 'Gene', (68, 71))
140821	29631562	The IDHme subgroup is included in the subtype that has no 1p/19q co-deletion but an IDH mutation in.	('IDH', 'Gene', '3417', (4, 7))	('mutation in', 'Var', (88, 99))	('IDH', 'Gene', (84, 87))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', (4, 7))
140823	29631562	1) shows that tumors with an IDH mutation are more similar to each other than tumors without an IDH mutation.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('mutation', 'Var', (33, 41))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('IDH', 'Gene', '3417', (96, 99))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH', 'Gene', (29, 32))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('IDH', 'Gene', '3417', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('IDH', 'Gene', (96, 99))
140837	29631562	Generally, strong differences in chromosomal mutations, subtype characteristics, and patient survival between the 7a10d subgroup and the other two subgroups 1p/19q and IDHme (Figs.	('patient', 'Species', '9606', (85, 92))	('7a10d', 'Var', (114, 119))	('differences', 'Reg', (18, 29))
140838	29631562	1 and 2) indicate that 7a10d tumors rather resemble glioblastoma-like tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('7a10d', 'Var', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (29, 35))	('glioblastoma-like tumors', 'Disease', (52, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('glioblastoma-like tumors', 'Disease', 'MESH:D005909', (52, 76))
140842	29631562	The expression of half of the signature genes was downregulated in 1p/19q compared to IDHme, while the other half was upregulated.	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (86, 89))	('expression', 'MPA', (4, 14))	('1p/19q', 'Var', (67, 73))	('upregulated', 'PosReg', (118, 129))	('downregulated', 'NegReg', (50, 63))
140845	29631562	Looking at the annotations of the 5113 signature genes we found that the categories transcription factor/cofactor, kinase, phosphatase, signaling pathway gene, and tumor suppressor gene were significantly enriched for downregulated genes in tumors of the 1p/19q subgroup compared to that of the IDHme subgroup (P <0.05, Fig.	('downregulated', 'NegReg', (218, 231))	('tumor', 'Disease', (164, 169))	('IDH', 'Gene', '3417', (295, 298))	('tumor', 'Disease', (241, 246))	('1p/19q', 'Var', (255, 261))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('phosphatase', 'Gene', (123, 134))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('signaling pathway gene', 'Gene', (136, 158))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('IDH', 'Gene', (295, 298))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
140846	29631562	For signature genes upregulated in 1p/19q compared to IDHme only the transcription factor/cofactor category was found to be significantly enriched (P <0.1).	('1p/19q', 'Var', (35, 41))	('IDH', 'Gene', '3417', (54, 57))	('upregulated', 'PosReg', (20, 31))	('IDH', 'Gene', (54, 57))
140849	29631562	4b), the pentose phosphate pathway (generating NADPH, pentoses, and Ribose 5-phosphate, a precursor for nucleotide synthesis) and inositol phosphate pathway (generating inositol phosphates that play a role in various cellular processes including cell growth and differentiation, cell migration and apoptosis) were significantly enriched with genes downregulated in 1p/19q (P <0.05 and P <0.01, respectively).	('inositol phosphates', 'Chemical', 'MESH:D007295', (169, 188))	('Ribose 5-phosphate', 'Pathway', (68, 86))	('inositol phosphate pathway', 'Pathway', (130, 156))	('apoptosis', 'CPA', (298, 307))	('cell migration', 'CPA', (279, 293))	('1p/19q', 'Var', (365, 371))	('pentose phosphate pathway', 'Pathway', (9, 34))	('pentose phosphate', 'Chemical', 'MESH:D010428', (9, 26))	('Ribose 5-phosphate', 'Chemical', 'MESH:C031626', (68, 86))	('pentoses', 'Chemical', 'MESH:D010429', (54, 62))	('inositol phosphate', 'Chemical', 'MESH:D007295', (169, 187))	('inositol phosphate', 'Chemical', 'MESH:D007295', (130, 148))	('downregulated', 'NegReg', (348, 361))	('pentoses', 'MPA', (54, 62))	('NADPH', 'Chemical', 'MESH:D009249', (47, 52))
140853	29631562	nodes with high degree that have many connections to other nodes, may help to identify potential key regulators involved in the manifestation of differences between the 1p/19q and IDHme subgroups.	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (180, 183))	('1p/19q', 'Var', (169, 175))
140856	29631562	The expression of genes in this cluster is downregulated in 1p/19q compared to IDHme.	('downregulated', 'NegReg', (43, 56))	('IDH', 'Gene', (79, 82))	('expression of', 'MPA', (4, 17))	('IDH', 'Gene', '3417', (79, 82))	('1p/19q', 'Var', (60, 66))
140859	29631562	In contrast to the first gene cluster described above, the expression of genes in this second cluster is upregulated in 1p/19q compared to IDHme.	('upregulated', 'PosReg', (105, 116))	('expression', 'MPA', (59, 69))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (139, 142))	('1p/19q', 'Var', (120, 126))
140862	29631562	One of them is PHB (upregulated in 1p/19q compared to IDHme) that codes for prohibitin, which inhibits DNA synthesis, has been associated with breast cancer, and plays a role in regulating proliferation.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('associated with', 'Reg', (127, 142))	('proliferation', 'CPA', (189, 202))	('breast cancer', 'Disease', (143, 156))	('1p/19q', 'Var', (35, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('prohibitin', 'Gene', '5245', (76, 86))	('upregulated', 'PosReg', (20, 31))	('inhibits', 'NegReg', (94, 102))	('IDH', 'Gene', (54, 57))	('DNA synthesis', 'MPA', (103, 116))	('IDH', 'Gene', '3417', (54, 57))	('prohibitin', 'Gene', (76, 86))
140863	29631562	CREB3L1 (upregulated in 1p/19q) is thought to be involved in the protection of astrocytes from ER stress-induced cell death.	('1p/19q', 'Var', (24, 30))	('upregulated', 'PosReg', (9, 20))	('CREB3L1', 'Gene', '90993', (0, 7))	('CREB3L1', 'Gene', (0, 7))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))
140868	29631562	Further, ETV4 involved in developmental processes and oncogenesis was upregulated in 1p/19q compared to IDHme.	('ETV4', 'Gene', '2118', (9, 13))	('1p/19q', 'Var', (85, 91))	('IDH', 'Gene', (104, 107))	('IDH', 'Gene', '3417', (104, 107))	('upregulated', 'PosReg', (70, 81))	('ETV4', 'Gene', (9, 13))
140870	29631562	In more detail, they observed that differences in bulk gene expression profiles between oligodendrogliomas and astrocytomas can be primarily explained by the impact of characteristic tumor class-specific mutations (oligodendrogliomas: 1p/19q co-deletion, CIC mutations; astrocytomas: TP53 mutations) and differences in the composition of the tumor microenvironment, but not by distinct expression programs of glial lineages of malignant cells.	('astrocytomas', 'Disease', (270, 282))	('mutations', 'Var', (289, 298))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('CIC', 'Gene', '23152', (255, 258))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (215, 233))	('astrocytomas', 'Disease', (111, 123))	('oligodendrogliomas', 'Disease', (88, 106))	('TP53', 'Gene', '7157', (284, 288))	('astrocytomas', 'Disease', 'MESH:D001254', (270, 282))	('tumor', 'Disease', (342, 347))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (270, 281))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('mutations', 'Var', (204, 213))	('oligodendrogliomas', 'Disease', (215, 233))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('tumor', 'Disease', (183, 188))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('oligodendrogliomas and astrocytomas', 'Disease', 'MESH:D009837', (88, 123))	('CIC', 'Gene', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('TP53', 'Gene', (284, 288))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (88, 106))
140871	29631562	They compared oligodendrogliomas defined based on their histology and the presence of the 1p/19q co-deletion to astrocytomas defined based on their histology and the presence of mutations in TP53 or ATRX.	('astrocytoma', 'Phenotype', 'HP:0009592', (112, 123))	('astrocytomas', 'Disease', (112, 124))	('ATRX', 'Gene', (199, 203))	('TP53', 'Gene', '7157', (191, 195))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('TP53', 'Gene', (191, 195))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (14, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (112, 124))	('ATRX', 'Gene', '546', (199, 203))	('mutations', 'Var', (178, 187))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('oligodendrogliomas', 'Disease', (14, 32))
140875	29631562	4c) in 1p/19q compared to IDHme.	('1p/19q', 'Var', (7, 13))	('IDH', 'Gene', '3417', (26, 29))	('IDH', 'Gene', (26, 29))
140877	29631562	6) were downregulated in 1p/19q compared to IDHme, which might indicate potentially existing morphological differences.	('IDH', 'Gene', '3417', (44, 47))	('1p/19q', 'Var', (25, 31))	('IDH', 'Gene', (44, 47))	('downregulated', 'NegReg', (8, 21))
140879	29631562	The 1p/19q subgroup showed higher expression of genes of the oligodendrocyte-like program than the IDHme subgroup, whereas IDHme showed higher expression of genes of the astrocyte-like program.	('IDH', 'Gene', '3417', (99, 102))	('expression', 'MPA', (34, 44))	('expression', 'MPA', (143, 153))	('1p/19q', 'Var', (4, 10))	('oligodendrocyte-like program', 'CPA', (61, 89))	('higher', 'PosReg', (136, 142))	('higher', 'PosReg', (27, 33))	('IDH', 'Gene', (123, 126))	('IDH', 'Gene', (99, 102))	('IDH', 'Gene', '3417', (123, 126))
140880	29631562	Interestingly, we found a weak trend that the 1p/19q and IDHme subgroups differ in the expression of the stemness program from.	('IDH', 'Gene', '3417', (57, 60))	('expression', 'MPA', (87, 97))	('1p/19q', 'Var', (46, 52))	('IDH', 'Gene', (57, 60))	('stemness program from', 'Gene', (105, 126))
140881	29631562	This included genes involved in cytoskeleton remodeling (absolute average log-ratio for 1p/19q compared to IDHme >1; DCX,TMSB15A: upregulated in 1p/19q; FNBP1L: downregulated in 1p/19q) and MYT1L, a known key factor of neural differentiation, upregulated in 1p/19q compared to IDHme.	('upregulated', 'PosReg', (130, 141))	('TMSB15A', 'Gene', '11013', (121, 128))	('1p/19q', 'Var', (258, 264))	('IDH', 'Gene', '3417', (277, 280))	('downregulated', 'NegReg', (161, 174))	('upregulated', 'PosReg', (243, 254))	('IDH', 'Gene', (107, 110))	('TMSB15A', 'Gene', (121, 128))	('MYT1L', 'Gene', (190, 195))	('FNBP1L', 'Gene', (153, 159))	('FNBP1L', 'Gene', '54874', (153, 159))	('MYT1L', 'Gene', '23040', (190, 195))	('DCX', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (107, 110))	('DCX', 'Gene', '1641', (117, 120))	('IDH', 'Gene', (277, 280))
140885	29631562	Interestingly, all HOX genes were downregulated in 1p/19q compared to IDHme, whereas all SOX genes were upregulated in 1p/19q compared to IDHme (Fig.	('HOX genes', 'Gene', (19, 28))	('IDH', 'Gene', (138, 141))	('downregulated', 'NegReg', (34, 47))	('IDH', 'Gene', (70, 73))	('1p/19q', 'Var', (51, 57))	('IDH', 'Gene', '3417', (138, 141))	('upregulated', 'PosReg', (104, 115))	('IDH', 'Gene', '3417', (70, 73))	('SOX genes', 'Gene', (89, 98))	('1p/19q', 'Var', (119, 125))
140886	29631562	This indicates the activity of different stemness programs between 1p/19q (potentially SOX-driven) and IDHme (potentially HOX-driven) tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('stemness programs', 'CPA', (41, 58))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('IDH', 'Gene', (103, 106))	('IDH', 'Gene', '3417', (103, 106))	('1p/19q', 'Var', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
140898	29631562	We used additional information about the presence of a 1p/19q co-deletion and an IDH mutation to further characterize these subgroups.	('IDH', 'Gene', '3417', (81, 84))	('1p/19q co-deletion', 'Var', (55, 73))	('IDH', 'Gene', (81, 84))
140899	29631562	In accordance with previous findings for histologically classified oligodendrogliomas and gliomas in general, we observed a large 1p/19q subgroup characterized by concurrent 1p/19q co-deletion and IDH mutation, an intermediate IDHme subgroup of tumors that mainly show an IDH mutation but no commonly overrepresented gene copy number alterations, and a small 7a10d subgroup showing a concurrent duplication of chromosome 7 and a deletion of chromosome 10 where most tumors lacked IDH mutations.	('IDH', 'Gene', (272, 275))	('oligodendrogliomas', 'Disease', (67, 85))	('IDH', 'Gene', '3417', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('deletion', 'Var', (429, 437))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (466, 472))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('gliomas', 'Disease', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH', 'Gene', '3417', (272, 275))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (466, 471))	('IDH', 'Gene', (197, 200))	('tumors', 'Disease', (245, 251))	('tumors', 'Disease', (466, 472))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH', 'Gene', (480, 483))	('IDH', 'Gene', '3417', (197, 200))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (67, 85))	('tumors', 'Disease', 'MESH:D009369', (466, 472))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('IDH', 'Gene', (227, 230))	('1p/19q co-deletion', 'Var', (174, 192))	('gliomas', 'Disease', (78, 85))	('IDH', 'Gene', '3417', (480, 483))
140900	29631562	In addition, considering Verhaak and G-CIMP classes, the 1p/19q and the IDHme subgroup resembled each other, whereas the 7a10d subgroup strongly deviated from these two subgroups also in terms of significantly lower overall patient survival (Fig.	('patient', 'Species', '9606', (224, 231))	('G-CIMP', 'Chemical', '-', (37, 43))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (72, 75))	('lower', 'NegReg', (210, 215))	('7a10d', 'Var', (121, 126))
140904	29631562	We therefore decided to focus our further analyses on the comparison of the 1p/19q and the IDHme subgroups.	('IDH', 'Gene', '3417', (91, 94))	('IDH', 'Gene', (91, 94))	('1p/19q', 'Var', (76, 82))
140908	29631562	The strong downregulation of these pathways in the 1p/19q subgroup compared to the IDHme subgroup might be associated with a better sensitivity to treatment and prognosis of (1p/19q) oligodendrogliomas compared to other low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (230, 237))	('oligodendrogliomas', 'Disease', (183, 201))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('IDH', 'Gene', (83, 86))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('1p/19q', 'Var', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('better', 'PosReg', (125, 131))	('gliomas', 'Disease', (194, 201))	('IDH', 'Gene', '3417', (83, 86))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('downregulation', 'NegReg', (11, 25))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (183, 201))	('gliomas', 'Disease', (230, 237))	('1p/19q', 'Var', (175, 181))
140911	29631562	Since all or the vast majority of tumors of these two subgroups show IDH mutations, the globally observed expression differences are likely to be strongly influenced by the 1p/19q co-deletion.	('influenced', 'Reg', (155, 165))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('IDH', 'Gene', (69, 72))	('expression', 'MPA', (106, 116))	('IDH', 'Gene', '3417', (69, 72))	('mutations', 'Var', (73, 82))	('1p/19q co-deletion', 'Var', (173, 191))
140912	29631562	All HOX genes included in our network were downregulated and all SOX genes were upregulated in 1p/19q compared to IDHme.	('downregulated', 'NegReg', (43, 56))	('SOX genes', 'Gene', (65, 74))	('IDH', 'Gene', (114, 117))	('IDH', 'Gene', '3417', (114, 117))	('upregulated', 'PosReg', (80, 91))	('HOX genes', 'Gene', (4, 13))	('1p/19q', 'Var', (95, 101))
140921	29631562	It is likely that such signs were not present in nearly half of the 7a10d tumors (6 of 15), otherwise these tumors would have been assigned the WHO grade IV instead of grade II according to the WHO 2007 brain tumor classification system.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('7a10d', 'Var', (68, 73))	('tumors', 'Disease', (74, 80))	('brain tumor', 'Disease', (203, 214))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', (108, 114))	('brain tumor', 'Disease', 'MESH:D001932', (203, 214))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('brain tumor', 'Phenotype', 'HP:0030692', (203, 214))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
140926	29631562	This is further supported by the presence of characteristic ATRX (30 of 45 tumors) or TP53 (35 of 45 tumors) mutations in IDH-mutated tumors.	('IDH', 'Gene', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('TP53', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ATRX', 'Gene', (60, 64))	('IDH', 'Gene', '3417', (122, 125))	('tumors', 'Disease', (134, 140))	('ATRX', 'Gene', '546', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('TP53', 'Gene', '7157', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutations', 'Var', (109, 118))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
140928	29631562	In the light of the new WHO 2016 brain tumor classification system, we performed an in-depth comparison of oligodendrogliomas (IDH-mutant and 1p/19q co-deleted) represented by our 1p/19q subgroup to astrocytomas (vast majority IDH-mutant) represented by our IDHme subgroup.	('IDH', 'Gene', (127, 130))	('brain tumor', 'Disease', 'MESH:D001932', (33, 44))	('brain tumor', 'Disease', (33, 44))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (227, 230))	('IDH', 'Gene', (258, 261))	('1p/19q', 'Var', (180, 186))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('astrocytomas', 'Disease', 'MESH:D001254', (199, 211))	('astrocytoma', 'Phenotype', 'HP:0009592', (199, 210))	('IDH', 'Gene', '3417', (227, 230))	('IDH', 'Gene', '3417', (258, 261))	('brain tumor', 'Phenotype', 'HP:0030692', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (107, 125))	('astrocytomas', 'Disease', (199, 211))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('oligodendrogliomas', 'Disease', (107, 125))
140929	29631562	This is supported by our finding that the 1p/19q subgroup expressed an oligodendrocyte-like program and that the IDHme subgroup expressed an astrocyte-like program.	('IDH', 'Gene', '3417', (113, 116))	('1p/19q', 'Var', (42, 48))	('astrocyte-like program', 'CPA', (141, 163))	('IDH', 'Gene', (113, 116))	('oligodendrocyte-like program', 'CPA', (71, 99))
140941	29156677	Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway.	('gene fusions', 'Var', (230, 242))	('BRAF', 'Gene', '109880', (261, 265))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('MAPK', 'Gene', '26413;26417', (327, 331))	('activating', 'PosReg', (214, 224))	('BRAF', 'Gene', '109880', (60, 64))	('MAPK', 'Gene', (327, 331))	('BRAF', 'Gene', (261, 265))	('mTOR', 'Gene', '56717', (123, 127))	('BRAF', 'Gene', '109880', (225, 229))	('KIAA1549-BRAF', 'Disease', (252, 265))	('MAPK', 'Gene', '26413;26417', (109, 113))	('BRAF', 'Gene', (60, 64))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('MAPK', 'Gene', (109, 113))	('drive', 'PosReg', (283, 288))	('BRAF', 'Gene', (225, 229))	('KIAA1549-BRAF', 'Disease', 'None', (252, 265))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('mTOR', 'Gene', (123, 127))
140943	29156677	While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies.	('MAPK', 'Gene', (77, 81))	('MEK', 'Gene', (221, 224))	('KIAA1549-BRAF', 'Disease', 'None', (96, 109))	('MAPK', 'Gene', '26413;26417', (77, 81))	('MEK', 'Gene', '17242', (221, 224))	('MEK', 'Gene', '17242', (205, 208))	('activation', 'PosReg', (82, 92))	('KIAA1549-BRAF', 'Disease', (96, 109))	('PLX8394', 'Var', (37, 44))	('MAPK', 'Gene', (306, 310))	('MAPK', 'Gene', (145, 149))	('MEK', 'Gene', (205, 208))	('MAPK', 'Gene', '26413;26417', (306, 310))	('MAPK', 'Gene', '26413;26417', (145, 149))	('inhibit', 'NegReg', (69, 76))
140945	29156677	However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones.	('PLX8394', 'Var', (31, 38))	('increased', 'PosReg', (52, 61))	('PI3K/mTOR pathway', 'Pathway', (99, 116))	('expression', 'MPA', (66, 76))	('MEK', 'Gene', '17242', (23, 26))	('MEK', 'Gene', (23, 26))	('RTK', 'Protein', (62, 65))
140951	29156677	Subsequent studies found BRAF mutations in nearly 80% of PAs and up to 60% of pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas.	('pleomorphic xanthoastrocytomas', 'Disease', (78, 108))	('gangliogliomas', 'Disease', (120, 134))	('PAs', 'Disease', (57, 60))	('gangliogliomas', 'Disease', 'MESH:D018303', (120, 134))	('PAs', 'Disease', 'MESH:D011471', (57, 60))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (78, 108))	('mutations', 'Var', (30, 39))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('BRAF', 'Gene', (25, 29))
140957	29156677	Subsequent efforts led to FDA-approval of BRAF inhibitors (BRAFi), vemurafenib and dabrafenib, against BRAF-V600E metastatic melanoma.	('dabrafenib', 'Chemical', 'MESH:C561627', (83, 93))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('vemurafenib', 'Chemical', 'MESH:D000077484', (67, 78))	('BRAF-V600E', 'Var', (103, 113))	('V600E', 'Mutation', 'rs113488022', (108, 113))
140958	29156677	However, BRAF-targeted therapies have shown diverse clinical responses to different activating BRAF alterations in melanoma and other cancers.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('cancers', 'Disease', (134, 141))	('BRAF', 'Gene', (95, 99))	('activating', 'PosReg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (100, 111))
140959	29156677	We have previously shown that unlike BRAF-V600E, KIAA1549-BRAF fusions functions as distinct, constitutive homodimers that are resistant to first-generation RAFi, vemurafenib (research analog PLX4720) and undergo paradoxical activation in response to PLX4720.	('KIAA1549-BRAF', 'Disease', 'None', (49, 62))	('activation', 'PosReg', (225, 235))	('vemurafenib', 'Chemical', 'MESH:D000077484', (163, 174))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('KIAA1549-BRAF', 'Disease', (49, 62))	('fusions', 'Var', (63, 70))
140968	29156677	Despite several clinical trials that have begun to test targeted therapies in pediatric glioma patients with diverse mutational landscapes (clinicaltrials.gov Identifiers- NCT00782626, NCT01158651, NCT02124772, NCT01089101 and NCT01748149), there are no existing biological studies to delineate potential acquired resistance mechanisms to such therapies.	('pediatric glioma', 'Disease', (78, 94))	('patients', 'Species', '9606', (95, 103))	('NCT01089101', 'Var', (211, 222))	('pediatric glioma', 'Disease', 'MESH:D005910', (78, 94))	('NCT02124772', 'Var', (198, 209))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('NCT01158651', 'Var', (185, 196))
140972	29156677	The few available PLGG patient derived cell lines, such as BT-40 with BRAF-V600E, a modified astrocytoma cell line and Res189 with several malignant glioma mutations would not serve as representative models for studying BRAF-fusion signaling and drug sensitivity.	('ser', 'Chemical', 'MESH:D012694', (176, 179))	('glioma', 'Disease', (149, 155))	('drug sensitivity', 'Phenotype', 'HP:0020174', (246, 262))	('astrocytoma', 'Disease', 'MESH:D001254', (93, 104))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('BRAF-V600E', 'Var', (70, 80))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('astrocytoma', 'Disease', (93, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('patient', 'Species', '9606', (23, 30))
140973	29156677	We evaluated MEKi in different settings- KIAA1549-BRAF fusion variants or BRAF V600E expressed in NIH3T3 cells, an HCT-116 RAS-mutant cell line, as well as a FAM131B-BRAF fusion expressing NIH3T3 cell line generated for this study.	('KIAA1549-BRAF', 'Disease', (41, 54))	('NIH3T3', 'CellLine', 'CVCL:0594', (189, 195))	('HCT-116', 'CellLine', 'CVCL:0291', (115, 122))	('variants', 'Var', (62, 70))	('MEK', 'Gene', '17242', (13, 16))	('V600E', 'Mutation', 'rs113488022', (79, 84))	('KIAA1549-BRAF', 'Disease', 'None', (41, 54))	('BRAF V600E', 'Gene', (74, 84))	('NIH3T3', 'CellLine', 'CVCL:0594', (98, 104))	('MEK', 'Gene', (13, 16))
140977	29156677	Interestingly, we observed an inverse relationship between pMEK and pERK levels in response to selumetinib, binimetinib, and cobimetinib in the KIAA1549-BRAF, FAM131B-BRAF and HCT-116 RAS-mutant cells.	('pERK levels', 'MPA', (68, 79))	('FAM131B-BRAF', 'Var', (159, 171))	('HCT-116', 'CellLine', 'CVCL:0291', (176, 183))	('KIAA1549-BRAF', 'Disease', (144, 157))	('cobimetinib', 'Chemical', 'MESH:C574276', (125, 136))	('pMEK', 'Chemical', '-', (59, 63))	('selumetinib', 'Chemical', 'MESH:C517975', (95, 106))	('pMEK', 'MPA', (59, 63))	('ser', 'Chemical', 'MESH:D012694', (20, 23))	('KIAA1549-BRAF', 'Disease', 'None', (144, 157))	('binimetinib', 'Chemical', 'MESH:C581313', (108, 119))
140981	29156677	In order to further demonstrate trametinib in vivo efficacy, we performed flank xenograft injections of NIH3T3 cells expressing KIAA1549-BRAF and FAM131B-BRAF in NSG immuno-deficient mice and treated these mice with trametinib.	('trametinib', 'Chemical', 'MESH:C560077', (32, 42))	('FAM131B-BRAF', 'Var', (146, 158))	('KIAA1549-BRAF', 'Disease', 'None', (128, 141))	('mice', 'Species', '10090', (206, 210))	('NIH3T3', 'CellLine', 'CVCL:0594', (104, 110))	('trametinib', 'Chemical', 'MESH:C560077', (216, 226))	('mice', 'Species', '10090', (183, 187))	('KIAA1549-BRAF', 'Disease', (128, 141))
140985	29156677	Whole genome sequencing studies have identified a number of novel BRAF-fusions in PLGGs, albeit at lower frequency than either FAM131B-BRAF or KIAA1549-BRAF fusions.	('PLGGs', 'Gene', (82, 87))	('KIAA1549-BRAF', 'Disease', 'None', (143, 156))	('BRAF-fusions', 'Var', (66, 78))	('KIAA1549-BRAF', 'Disease', (143, 156))
140986	29156677	We characterized the PLGG-associated fusions, GNAI1-BRAF, MACF1-BRAF, MKRN1-BRAF, FXR1-BRAF, and CLCN6-BRAF, by stably over-expressing in NIH3T3 (Supplementary Figure 1D) and observed activation of pERK levels by these BRAF-fusions compared to vector control (Supplementary Figure 1E).	('MKRN1', 'Gene', (70, 75))	('activation', 'PosReg', (184, 194))	('ser', 'Chemical', 'MESH:D012694', (177, 180))	('NIH3T3', 'Gene', (138, 144))	('MKRN1', 'Gene', '54484', (70, 75))	('NIH3T3', 'CellLine', 'CVCL:0594', (138, 144))	('over-expressing', 'PosReg', (119, 134))	('BRAF-fusions', 'Var', (219, 231))	('pERK levels', 'MPA', (198, 209))
140991	29156677	This correlates with previous findings in BT-40 cell line where selumetinib suppressed TORC1 signaling (mTOR component), albeit in BRAF-V600E mutation background.	('TORC1', 'Gene', (87, 92))	('TORC1', 'Gene', '382056', (87, 92))	('suppressed', 'NegReg', (76, 86))	('V600E', 'Mutation', 'rs113488022', (136, 141))	('BRAF-V600E', 'Var', (131, 141))	('selumetinib', 'Chemical', 'MESH:C517975', (64, 75))
140993	29156677	Interestingly, GNAI1- and MKRN1-BRAF fusions exhibited increased sensitivity and inhibition of colony formation at lower trametinib concentrations than MACF1-, FXR1-, and CLCN6-BRAF colony formation.	('MKRN1', 'Gene', '54484', (26, 31))	('trametinib concentrations', 'MPA', (121, 146))	('increased', 'PosReg', (55, 64))	('inhibition', 'NegReg', (81, 91))	('colony formation', 'CPA', (95, 111))	('fusions', 'Var', (37, 44))	('sensitivity', 'MPA', (65, 76))	('lower', 'NegReg', (115, 120))	('trametinib', 'Chemical', 'MESH:C560077', (121, 131))	('MKRN1', 'Gene', (26, 31))
141016	29156677	Previous studies have also shown that targeting MEK drives rapid reprogramming of the kinome that ultimately underlies single-agent resistance.	('MEK', 'Gene', (48, 51))	('reprogramming', 'CPA', (65, 78))	('targeting', 'Var', (38, 47))	('MEK', 'Gene', '17242', (48, 51))
141022	29156677	Like MEKi-resistant clones, PLX8394i-resistant clones display in vitro drug-resistant colony formation (Figure 4A, Supplementary Figure 3A) as well as PLX8394-resistant in vivo flank-injected tumors (Figure 4B).	('PLX8394i-resistant', 'Var', (28, 46))	('drug-resistant colony formation', 'CPA', (71, 102))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('MEK', 'Gene', '17242', (5, 8))	('MEK', 'Gene', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
141025	29156677	We also performed targeted Sanger sequencing or RNAseq variant analysis of BRAF and MEK in each of the BRAFi- and MEKi-resistant clones and did not identify any gatekeeper or other second site suppressor mutations (data not shown).	('MEK', 'Gene', '17242', (114, 117))	('variant analysis', 'Var', (55, 71))	('MEK', 'Gene', (114, 117))	('BRAF', 'Gene', (75, 79))	('MEK', 'Gene', '17242', (84, 87))	('gatekeeper', 'Species', '111938', (161, 171))	('MEK', 'Gene', (84, 87))
141028	29156677	When incubated with everolimus as single-agent mTORi, KIAA1549-BRAF variants expressed in NIH3T3 displayed varying levels of decrease in pS6 and no effect on pERK (Figure 5A, left panel, Supplementary Figure S4A).	('pERK', 'MPA', (158, 162))	('variants', 'Var', (68, 76))	('KIAA1549-BRAF', 'Disease', 'None', (54, 67))	('NIH3T3', 'Gene', (90, 96))	('NIH3T3', 'CellLine', 'CVCL:0594', (90, 96))	('everolimus', 'Chemical', 'MESH:D000068338', (20, 30))	('pS6', 'MPA', (137, 140))	('decrease', 'NegReg', (125, 133))	('KIAA1549-BRAF', 'Disease', (54, 67))
141032	29156677	Interestingly, the addition of everolimus with trametinib, selumetinib, or binimetinib further decreased pS6 signal in both KIAA1549-BRAF and FAM131B-BRAF expressing NIH3T3 (Figure 5A, respectively, Supplementary Figure 4C).	('decreased', 'NegReg', (95, 104))	('trametinib', 'Chemical', 'MESH:C560077', (47, 57))	('everolimus', 'Chemical', 'MESH:D000068338', (31, 41))	('FAM131B-BRAF', 'Var', (142, 154))	('KIAA1549-BRAF', 'Disease', (124, 137))	('binimetinib', 'Chemical', 'MESH:C581313', (75, 86))	('NIH3T3', 'Var', (166, 172))	('pS6 signal', 'MPA', (105, 115))	('NIH3T3', 'CellLine', 'CVCL:0594', (166, 172))	('KIAA1549-BRAF', 'Disease', 'None', (124, 137))	('selumetinib', 'Chemical', 'MESH:C517975', (59, 70))
141035	29156677	Combining PLX8394 with everolimus caused reduction in pS6 signal but had minimal effect on pMEK (Supplementary Figure 4D).	('PLX8394', 'Var', (10, 17))	('pMEK', 'Chemical', '-', (91, 95))	('everolimus', 'Chemical', 'MESH:D000068338', (23, 33))	('pS6 signal', 'MPA', (54, 64))	('pMEK', 'MPA', (91, 95))	('reduction', 'NegReg', (41, 50))
141037	29156677	Similar effect of trametinib and everolimus co-treatment was observed in vivo with near total inhibition of KIAA1549-BRAF or FAM131B-BRAF driven tumor growth (Figure 5C, left and right graph respectively).	('KIAA1549-BRAF', 'Disease', 'None', (108, 121))	('inhibition', 'NegReg', (94, 104))	('FAM131B-BRAF', 'Var', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('everolimus', 'Chemical', 'MESH:D000068338', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('trametinib', 'Chemical', 'MESH:C560077', (18, 28))	('KIAA1549-BRAF', 'Disease', (108, 121))	('ser', 'Chemical', 'MESH:D012694', (63, 66))
141043	29156677	We observed similar levels of prolonged inhibition of BRAF-fusion driven tumor growth with 0.3mg/kg trametinib combined with 10mg/kg everolimus compared to 1mg/kg trametinib and 10mg/kg everolimus suggesting effectiveness of lower trametinib doses (Figure 5E).	('BRAF-fusion', 'Gene', (54, 65))	('trametinib', 'Chemical', 'MESH:C560077', (231, 241))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('0.3mg/kg', 'Var', (91, 99))	('everolimus', 'Chemical', 'MESH:D000068338', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('inhibition', 'NegReg', (40, 50))	('trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('ser', 'Chemical', 'MESH:D012694', (5, 8))	('tumor', 'Disease', (73, 78))	('everolimus', 'Chemical', 'MESH:D000068338', (133, 143))	('trametinib', 'Chemical', 'MESH:C560077', (163, 173))
141054	29156677	Our current findings with KIAA1549-BRAF and FAM131B-BRAF show robust responsiveness to clinically available MEKi such as trametinib.	('MEK', 'Gene', '17242', (108, 111))	('responsiveness', 'MPA', (69, 83))	('FAM131B-BRAF', 'Var', (44, 56))	('KIAA1549-BRAF', 'Disease', 'None', (26, 39))	('MEK', 'Gene', (108, 111))	('trametinib', 'Chemical', 'MESH:C560077', (121, 131))	('KIAA1549-BRAF', 'Disease', (26, 39))
141058	29156677	Numerous studies, largely in melanoma, have demonstrated that successful targeting of the MAPK signaling cascade is dependent on discrete, mutation-specific response to inhibitors among wild-type BRAF, BRAF-V600E and mutant-RAS tumors This is partly due to altered protein-protein interactions, RAF-heterodimerization, and kinase-substrate interactions as well as reorganization of a highly dynamic signaling network in response to targeted inhibitors.	('altered', 'Reg', (257, 264))	('interactions', 'Interaction', (340, 352))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('melanoma', 'Disease', (29, 37))	('V600E', 'Mutation', 'rs113488022', (207, 212))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('RAF-heterodimerization', 'Protein', (295, 317))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('BRAF-V600E', 'Var', (202, 212))	('MAPK', 'Gene', (90, 94))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('mutant-RAS', 'Var', (217, 227))	('MAPK', 'Gene', '26413;26417', (90, 94))	('protein-protein interactions', 'Protein', (265, 293))	('reorganization', 'Reg', (364, 378))
141059	29156677	RAF-targeted therapies such as vemurafenib and dabrafenib are approved treatments for malignant melanomas with BRAF-V600E/K mutations.	('vemurafenib', 'Chemical', 'MESH:D000077484', (31, 42))	('malignant melanomas', 'Disease', (86, 105))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('dabrafenib', 'Chemical', 'MESH:C561627', (47, 57))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('V600E', 'Var', (116, 121))	('V600E', 'SUBSTITUTION', 'None', (116, 121))	('malignant melanomas', 'Disease', 'MESH:D008545', (86, 105))	('malignant melanomas', 'Phenotype', 'HP:0002861', (86, 105))
141060	29156677	However, due to emergent resistance to single-agent RAFi in patients, combination treatments of BRAFi (dabrafenib) with MEKi (trametinib) have been developed for melanomas and are also being tested in pediatric patients with plexiform NF-1, BRAF-V600E refractory/relapsed tumors (NCT02124772).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('MEK', 'Gene', (120, 123))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('tumors', 'Disease', (272, 278))	('patients', 'Species', '9606', (211, 219))	('V600E', 'Mutation', 'rs113488022', (246, 251))	('trametinib', 'Chemical', 'MESH:C560077', (126, 136))	('patients', 'Species', '9606', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('BRAF-V600E', 'Var', (241, 251))	('melanomas', 'Disease', (162, 171))	('MEK', 'Gene', '17242', (120, 123))	('dabrafenib', 'Chemical', 'MESH:C561627', (103, 113))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))
141062	29156677	However, recent studies have highlighted important mechanistic differences in sensitivity to different MEK inhibitors based on mechanism of inhibition, mutational context, and induction of RAF-MEK complexes as seen in mutant-RAS tumors.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('MEK', 'Gene', '17242', (103, 106))	('MEK', 'Gene', '17242', (193, 196))	('induction', 'Reg', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('mutant-RAS', 'Var', (218, 228))	('MEK', 'Gene', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('MEK', 'Gene', (193, 196))	('tumors', 'Disease', (229, 235))
141063	29156677	In contrast to BRAF point mutations, BRAF gene fusions define a distinct mechanism of BRAF activation in several solid tumors across adult and pediatric patients.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (153, 161))	('activation', 'PosReg', (91, 101))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('BRAF', 'Gene', (86, 90))	('fusions', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('solid tumors', 'Disease', (113, 125))
141065	29156677	Distinct mechanisms of inhibition previously observed for cobimetinib and GDC0623 in RAS-mutant cells may in part parallel their inhibition profile against BRAF-fusions as seen in our study.	('GDC0623', 'Gene', (74, 81))	('GDC0623', 'Chemical', 'MESH:C000622437', (74, 81))	('ser', 'Chemical', 'MESH:D012694', (47, 50))	('RAS-mutant', 'Gene', (85, 95))	('RAS-mutant', 'Var', (85, 95))	('cobimetinib', 'Chemical', 'MESH:C574276', (58, 69))
141066	29156677	Selumetinib is currently undergoing clinical testing for recurrent/refractory PLGGs where patients harbor KIAA1549-BRAF or BRAF-V600E or both and phase I data has shown 8/38 sustained partial responses (NCT01089101).	('KIAA1549-BRAF', 'Disease', (106, 119))	('V600E', 'Mutation', 'rs113488022', (128, 133))	('BRAF-V600E', 'Var', (123, 133))	('KIAA1549-BRAF', 'Disease', 'None', (106, 119))	('PLGGs', 'Disease', (78, 83))	('partial responses', 'NegReg', (184, 201))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('patients', 'Species', '9606', (90, 98))
141067	29156677	However, differences in MEKi sensitivity among BRAF-fusion, RAS-mutant or BRAF-V600E mutations as well as induced MEK phosphorylation observed in our study further highlight the unique signaling context invoked by the BRAF-fusion.	('differences', 'Reg', (9, 20))	('MEK', 'Gene', '17242', (24, 27))	('BRAF-V600E', 'Gene', (74, 84))	('BRAF-fusion', 'Gene', (47, 58))	('MEK', 'Gene', '17242', (114, 117))	('MEK', 'Gene', (24, 27))	('MEK', 'Gene', (114, 117))	('mutations', 'Var', (85, 94))	('ser', 'Chemical', 'MESH:D012694', (136, 139))	('V600E', 'Mutation', 'rs113488022', (79, 84))
141072	29156677	Current strategies for BRAF-V600E melanomas that delay, but have yet to eliminate acquired resistance to BRAFi include combinatorial therapy with BRAFi and MEKi, co-targeting of the MAPK and PI3K pathways, and the combination of small molecule inhibitors with immunotherapy.	('V600E', 'Var', (28, 33))	('V600E', 'SUBSTITUTION', 'None', (28, 33))	('MEK', 'Gene', '17242', (156, 159))	('MAPK', 'Gene', (182, 186))	('MAPK', 'Gene', '26413;26417', (182, 186))	('MEK', 'Gene', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))
141074	29156677	Our in vitro and in vivo studies show that PLGG-associated KIAA1549-BRAF and FAM131B-BRAF fusions utilize the PI3K-AKT-mTOR pathway as an escape mechanism in response to BRAF/MEK inhibition.	('AKT', 'Gene', '11651', (115, 118))	('MEK', 'Gene', (175, 178))	('KIAA1549-BRAF', 'Disease', (59, 72))	('AKT', 'Gene', (115, 118))	('FAM131B-BRAF', 'Var', (77, 89))	('MEK', 'Gene', '17242', (175, 178))	('KIAA1549-BRAF', 'Disease', 'None', (59, 72))
141079	29156677	Everolimus is relatively well tolerated with long-term treatment as has been shown in the EXIST-1 study (NCT00789828), where everolimus was used to treat tuberous sclerosis patients (germ-line mutations in TSC1/2) with subependymal giant cell astrocytomas (SEGAs).	('SEGAs', 'Phenotype', 'HP:0009718', (257, 262))	('everolimus', 'Chemical', 'MESH:D000068338', (125, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (243, 254))	('patients', 'Species', '9606', (173, 181))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (154, 172))	('subependymal giant cell astrocytomas', 'Disease', 'MESH:D001254', (219, 255))	('mutations', 'Var', (193, 202))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))	('tuberous sclerosis', 'Disease', (154, 172))	('TSC1/2', 'Gene', '7248;7249', (206, 212))	('subependymal giant cell astrocytomas', 'Phenotype', 'HP:0009718', (219, 255))	('subependymal giant cell astrocytomas', 'Disease', (219, 255))	('TSC1/2', 'Gene', (206, 212))
141089	29156677	The same strategies were used for the generation of FAM131B-BRAF, MACF1-BRAF, FXR1-BRAF, MKRN130-BRAF, CLCN6-BRAF, and GNAI1-BRAF constructs/lines based on published description or independent confirmation of their genomic alterations in patient-derived samples.	('MKRN1', 'Gene', (89, 94))	('patient', 'Species', '9606', (238, 245))	('FAM131B-BRAF', 'Var', (52, 64))	('MKRN1', 'Gene', '54484', (89, 94))
141092	29156677	The ability of the BRAF mutants to transform cells was assessed by anchorage independent growth, as determined in soft agar assay (Cell Biolabs  San Diego, CA) and quantified as previously described.	('agar', 'Chemical', 'MESH:D000362', (119, 123))	('mutants', 'Var', (24, 31))	('BRAF', 'Gene', (19, 23))	('cells', 'CPA', (45, 50))	('anchorage independent growth', 'CPA', (67, 95))
141096	29156677	For MAPK and PI3K/mTOR pathway analysis, pMEK (#9154), MEK (#4694), pERK (#4370), ERK (#4695), pAKT Ser473 (#4060), pAKT Thr308 (#4056), AKT (#2920), pS6 (#2215) and S6 (#2317) antibodies from Cell Signaling were used.	('PI3K/mTOR', 'Gene', (13, 22))	('Ser473', 'Chemical', '-', (100, 106))	('#4370', 'Var', (74, 79))	('MEK', 'Gene', (55, 58))	('AKT', 'Gene', '11651', (137, 140))	('#4694', 'Var', (60, 65))	('AKT', 'Gene', '11651', (96, 99))	('#4695', 'Var', (87, 92))	('ERK', 'Gene', '26413', (69, 72))	('Thr308', 'Chemical', '-', (121, 127))	('AKT', 'Gene', (117, 120))	('#2920', 'Var', (142, 147))	('pERK', 'Gene', '13666', (68, 72))	('ERK', 'Gene', (82, 85))	('#4056', 'Var', (129, 134))	('MEK', 'Gene', '17242', (42, 45))	('#9154', 'Var', (47, 52))	('PI3K/mTOR', 'Gene', '18708;56717', (13, 22))	('#2215', 'Var', (155, 160))	('AKT', 'Gene', (137, 140))	('ERK', 'Gene', '26413', (82, 85))	('AKT', 'Gene', '11651', (117, 120))	('MEK', 'Gene', '17242', (55, 58))	('AKT', 'Gene', (96, 99))	('MEK', 'Gene', (42, 45))	('#4060', 'Var', (108, 113))	('ERK', 'Gene', (69, 72))	('pERK', 'Gene', (68, 72))
141111	29156677	NSG mice were flank injected with 1x105 cells of KIAA-BRAF and FAM131B-BRAF and treated daily with trametinib (1 mg/kg).	('KIAA-BRAF', 'Gene', (49, 58))	('mice', 'Species', '10090', (4, 8))	('trametinib', 'Chemical', 'MESH:C560077', (99, 109))	('KIAA-BRAF', 'Gene', '109880', (49, 58))	('FAM131B-BRAF', 'Var', (63, 75))
141243	25180159	We also excluded three patients whose tumours were located around the temporal basal regions that were severely influenced by distortions of DTI and one patient because of appreciable motion artefacts in MP-RAGE.	('tumours', 'Disease', (38, 45))	('patients', 'Species', '9606', (23, 31))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('patient', 'Species', '9606', (23, 30))	('DTI', 'Gene', (141, 144))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('patient', 'Species', '9606', (153, 160))	('distortions', 'Var', (126, 137))	('RAGE', 'Gene', '101669765', (207, 211))	('RAGE', 'Gene', (207, 211))
141267	25180159	Lower final radius than 2.0 could cause stepping-stone like clusters by the KM++ with k = 20, which was the maximum number in the study, partly because of overfitting.	('k = 20', 'Gene', '54474', (86, 92))	('KM++', 'Chemical', '-', (76, 80))	('stepping-stone like clusters', 'CPA', (40, 68))	('cause', 'Reg', (34, 39))	('k = 20', 'Gene', (86, 92))	('KM++', 'Var', (76, 80))
141283	25180159	ROIs were manually traced by two of the authors in the DTI space according to abnormalities on MP-RAGE, without any knowledge of the clinical or pathological data.	('RAGE', 'Gene', (98, 102))	('abnormalities', 'Var', (78, 91))	('RAGE', 'Gene', '101669765', (98, 102))
141298	25180159	The tests also showed that AUC was significantly lower for the 4-class DTcIs than for the others (p < 0.001).	('4-class', 'Var', (63, 70))	('lower', 'NegReg', (49, 54))	('DTcIs', 'Chemical', '-', (71, 76))	('AUC', 'MPA', (27, 30))
141420	21900399	Again, this is evidence of the biasing effect of high D and the invisible low densities of invading glioma cells.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('high D', 'Var', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))
141430	21900399	Specifically, we confirmed the in vivo observation that pGBMs tend to have increased expression of VEGF when compared to Grade 3 and sGBMs, as shown in Figure 6a.	('expression', 'MPA', (85, 95))	('VEGF', 'Gene', '7422', (99, 103))	('VEGF', 'Gene', (99, 103))	('increased', 'PosReg', (75, 84))	('pGBMs', 'Var', (56, 61))
141442	21900399	In summary, these patient-specific simulations are compared with patient-specific information from imaging and histology and we find that the simulations provide consistent patterns between these 5 distinct data points: overall T1Gd radius, T2 radius, tumor grade, central necrosis visible T1Gd MRI and HIF1-alpha immunohistochemistry.	('HIF1-alpha', 'Gene', (303, 313))	('necrosis', 'Disease', 'MESH:D009336', (273, 281))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('T1Gd', 'Var', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('necrosis', 'Disease', (273, 281))	('patient', 'Species', '9606', (18, 25))	('patient', 'Species', '9606', (65, 72))	('HIF1-alpha', 'Gene', '3091', (303, 313))	('tumor', 'Disease', (252, 257))
141447	21900399	This highlighted a disparity between the current in vivo grading schemes and observed tumor behavior, and suggests that malignant "progression" may be less related to acquisition of new genetic abnormalities than a natural consequence of a relatively small set of initial key molecular-genetic changes that "turn on" the glioma cells to proliferate and invade.	('glioma', 'Disease', 'MESH:D005910', (321, 327))	('genetic abnormalities', 'Disease', (186, 207))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor behavior', 'Disease', 'MESH:D001523', (86, 100))	('invade', 'CPA', (353, 359))	('proliferate', 'PosReg', (337, 348))	('changes', 'Var', (294, 301))	('glioma', 'Disease', (321, 327))	('tumor behavior', 'Disease', (86, 100))	('turn', 'Reg', (308, 312))	('genetic abnormalities', 'Disease', 'MESH:D030342', (186, 207))	('glioma', 'Phenotype', 'HP:0009733', (321, 327))
141450	21900399	A comparison of this survival map with the grade map (for the same initial size of a T2 radius of 1 cm) shows that the shortest survival times are for those in silico tumors with both high D and high rho whereas the WHO grading scheme applied to the simulated tumors would suggest only high rho is important.	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('shortest', 'NegReg', (119, 127))	('high rho', 'Var', (195, 203))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', (260, 266))	('high D', 'Var', (184, 190))
141471	21900399	Although commonly attributed to molecular-genetic factors such as the accumulation of genetic mutation, this study combines mathematical modeling with experimental and clinical data for human gliomas to suggest that changes in cell kinetics are not necessary to generate the imaging and histological features of malignant progression seen in vivo.	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('gliomas', 'Disease', (192, 199))	('human', 'Species', '9606', (186, 191))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('mutation', 'Var', (94, 102))
141495	33109195	The transcriptional processing of piRNAs includes the generation of pre-piRNAs, the modification of the 5 ' and 3' ends, and finally methylation.	('modification', 'Var', (84, 96))	('piR', 'Gene', (34, 37))	('piR', 'Gene', '8544', (72, 75))	('piR', 'Gene', (72, 75))	('methylation', 'MPA', (133, 144))	('rat', 'Species', '10116', (58, 61))	('piR', 'Gene', '8544', (34, 37))
141514	33109195	One study reported that the PIWI-piRNA complex was associated with expression of the neurotransmitter serotonin through CpG methylation of the cAMP-responsive element-binding protein 2 (CREB2) promoter.	('cAMP-responsive element-binding protein 2', 'Gene', (143, 184))	('CREB2', 'Gene', '468', (186, 191))	('piR', 'Gene', '8544', (33, 36))	('CpG', 'Var', (120, 123))	('associated', 'Reg', (51, 61))	('cAMP-responsive element-binding protein 2', 'Gene', '468', (143, 184))	('serotonin', 'Chemical', 'MESH:D012701', (102, 111))	('expression', 'MPA', (67, 77))	('CREB2', 'Gene', (186, 191))	('methylation', 'Var', (124, 135))	('piR', 'Gene', (33, 36))
141546	33109195	First the the DmHen1/Pimet piRNA methyl-transferase adds a 2'-O-methyl group to the 3' ends of piRNAs in order to allow the formation of the Piwi-piRNA complex and Piwi-piRISCs.	('piR', 'Gene', '8544', (146, 149))	('piR', 'Gene', '8544', (169, 172))	('piR', 'Gene', (27, 30))	('DmHen1/Pimet', 'Var', (14, 26))	('piR', 'Gene', '8544', (95, 98))	('piR', 'Gene', (146, 149))	('allow', 'Reg', (114, 119))	('piR', 'Gene', (169, 172))	('piR', 'Gene', '8544', (27, 30))	('piR', 'Gene', (95, 98))
141551	33109195	Moreover, germline piRNAs are lower in Drosophila mutants with reduced expression of Armi, implying that somatic components are also needed for the biogenesis of germline piRNAs.	('expression', 'MPA', (71, 81))	('lower', 'NegReg', (30, 35))	('Drosophila', 'Species', '7227', (39, 49))	('reduced', 'NegReg', (63, 70))	('piR', 'Gene', (171, 174))	('piR', 'Gene', '8544', (19, 22))	('Armi', 'Gene', '38427', (85, 89))	('piR', 'Gene', '8544', (171, 174))	('mutants', 'Var', (50, 57))	('piR', 'Gene', (19, 22))	('Armi', 'Gene', (85, 89))
141566	33109195	Lee and colleagues reported that there were plentiful piRNA detected in mouse dendritic spines, and that knockdown of piRNAs led to decreased spine density in the axons.	('piR', 'Gene', '8544', (118, 121))	('piR', 'Gene', '8544', (54, 57))	('mouse', 'Species', '10090', (72, 77))	('knockdown', 'Var', (105, 114))	('piR', 'Gene', (118, 121))	('decreased', 'NegReg', (132, 141))	('piR', 'Gene', (54, 57))	('spine density in the axons', 'CPA', (142, 168))
141567	33109195	piRNAs were shown to be present in Aplysia brain neurons, and their mutations affected the neuron function as well as brain development.	('Aplysia brain neurons', 'Disease', (35, 56))	('piR', 'Gene', (0, 3))	('affected', 'Reg', (78, 86))	('Aplysia brain neurons', 'Disease', 'MESH:D009410', (35, 56))	('brain development', 'CPA', (118, 135))	('neuron function', 'CPA', (91, 106))	('mutations', 'Var', (68, 77))	('piR', 'Gene', '8544', (0, 3))
141586	33109195	As discussed earlier, the main function of piRNAs is to regulate transposons.	('transposons', 'Var', (65, 76))	('piR', 'Gene', (43, 46))	('transposons', 'Species', '2387', (65, 76))	('piR', 'Gene', '8544', (43, 46))
141588	33109195	This may be supported by evidence indicating that inactivation of Aub or Piwi in Drosophila, inhibits the growth of lethal malignant brain tumors.	('brain tumors', 'Phenotype', 'HP:0030692', (133, 145))	('Piwi', 'Gene', (73, 77))	('Drosophila', 'Species', '7227', (81, 91))	('malignant brain tumors', 'Disease', (123, 145))	('inhibits', 'NegReg', (93, 101))	('malignant brain tumors', 'Disease', 'MESH:D001932', (123, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Aub', 'Gene', (66, 69))	('brain tumor', 'Phenotype', 'HP:0030692', (133, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('inactivation', 'Var', (50, 62))
141592	33109195	L1 retrotransposons are regulated by these piRNAs, and piRNA mutants show increased retrotransposon expression in the brain.	('piR', 'Gene', (43, 46))	('transposons', 'Species', '2387', (8, 19))	('piR', 'Gene', '8544', (43, 46))	('piR', 'Gene', (55, 58))	('increased', 'PosReg', (74, 83))	('mutants', 'Var', (61, 68))	('retrotransposon expression', 'MPA', (84, 110))	('piR', 'Gene', '8544', (55, 58))
141596	33109195	reported that variant rs147061479 in piR-598 elevated the risk of glioma by using qPCR and genome-wide expression profiling.	('piR', 'Gene', (37, 40))	('glioma', 'Disease', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('piR', 'Gene', '8544', (37, 40))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('elevated', 'PosReg', (45, 53))	('rs147061479', 'Mutation', 'rs147061479', (22, 33))	('variant rs147061479', 'Var', (14, 33))
141597	33109195	They found that rs147061479 abolished the tumor-suppressive function of piR-598, instead conferring tumor growth-promoting properties.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (42, 47))	('abolished', 'NegReg', (28, 37))	('piR', 'Gene', '8544', (72, 75))	('rs147061479', 'Var', (16, 27))	('tumor', 'Disease', (100, 105))	('piR', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('rs147061479', 'Mutation', 'rs147061479', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
141601	33109195	The microRNA miR-153 is also involved in pathogenesis of gliomas.	('microRNA miR-153', 'Var', (4, 20))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('miR-153', 'Chemical', '-', (13, 20))	('gliomas', 'Disease', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('involved', 'Reg', (29, 37))
141612	33109195	They analyzed the genetic variants in 1428 separate piRNAs and their association with glioma risk, using imputed and measured genotypes from the GliomaScan genome-wide association study (2401 controls and 1840 cases).	('glioma', 'Disease', (86, 92))	('piR', 'Gene', '8544', (52, 55))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('piR', 'Gene', (52, 55))	('rat', 'Species', '10116', (47, 50))	('association', 'Interaction', (69, 80))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('Glioma', 'Disease', 'MESH:D005910', (145, 151))	('Glioma', 'Phenotype', 'HP:0009733', (145, 151))	('Glioma', 'Disease', (145, 151))	('variants', 'Var', (26, 34))
141614	33109195	Variants in five piRNAs were found to be associated with glioma riak, and four of these showed narrow clusters of higher association signals surrounding the index variant.	('Variants', 'Var', (0, 8))	('piR', 'Gene', (17, 20))	('associated with', 'Reg', (41, 56))	('glioma riak', 'Disease', 'MESH:D005910', (57, 68))	('piR', 'Gene', '8544', (17, 20))	('glioma riak', 'Disease', (57, 68))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
141615	33109195	piR-598 functional analysis showed that wild-type piRNA transfection affected the expression of genes implicated in cell death and survival, and attenuated colony formation and glioma cell viability.	('piR', 'Gene', (0, 3))	('colony formation', 'CPA', (156, 172))	('attenuated', 'NegReg', (145, 155))	('glioma', 'Disease', (177, 183))	('piR', 'Gene', '8544', (50, 53))	('affected', 'Reg', (69, 77))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('death', 'Disease', 'MESH:D003643', (121, 126))	('transfection', 'Var', (56, 68))	('death', 'Disease', (121, 126))	('piR', 'Gene', '8544', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('expression of genes', 'MPA', (82, 101))	('piR', 'Gene', (50, 53))
141616	33109195	On the other hand, transfection with piR-598 containing the variant allele at rs147061479 increased cell proliferation.	('piR', 'Gene', (37, 40))	('increased', 'PosReg', (90, 99))	('piR', 'Gene', '8544', (37, 40))	('rs147061479', 'Var', (78, 89))	('rat', 'Species', '10116', (112, 115))	('cell proliferation', 'CPA', (100, 118))	('rs147061479', 'Mutation', 'rs147061479', (78, 89))
141617	33109195	Use of genetic association analysis has identified numerous piRNAs related to glioma risk, and follow-up functional analysis suggested that variant rs147061479 in piR-598 increased glioma risk by abolishing the tumor-inhibitory property of piR-598, and instead conferring growth-promoting properties.	('piR', 'Gene', '8544', (163, 166))	('piR', 'Gene', '8544', (60, 63))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('tumor', 'Disease', (211, 216))	('increased', 'PosReg', (171, 180))	('growth-promoting properties', 'CPA', (272, 299))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('variant rs147061479', 'Var', (140, 159))	('piR', 'Gene', (240, 243))	('U', 'Chemical', 'MESH:D014529', (0, 1))	('piR', 'Gene', '8544', (240, 243))	('rs147061479', 'Mutation', 'rs147061479', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('conferring', 'Reg', (261, 271))	('abolishing', 'NegReg', (196, 206))	('glioma', 'Disease', (181, 187))	('glioma', 'Disease', (78, 84))	('piR', 'Gene', (163, 166))	('piR', 'Gene', (60, 63))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
141620	33109195	PIWIL1 is a target for miR-154-5p, and this may explain the anti-cancer effects of miR-154-5p.	('PIWIL1', 'Gene', '9271', (0, 6))	('miR-154-5p', 'Var', (23, 33))	('miR-154-5p', 'Chemical', '-', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-154-5p', 'Chemical', '-', (23, 33))	('miR-154-5p', 'Var', (83, 93))	('PIWIL1', 'Gene', (0, 6))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
141623	33109195	Another study reported that up-regulation of miR-154-5p inhibited rapid growth and metastasis of GBM, and promoted apoptosis, while inhibition miR-154-5p expression had the opposite effects.	('miR-154-5p', 'Chemical', '-', (45, 55))	('miR-154-5p', 'Chemical', '-', (143, 153))	('promoted', 'PosReg', (106, 114))	('miR-154-5p', 'Var', (45, 55))	('metastasis of GBM', 'CPA', (83, 100))	('apoptosis', 'CPA', (115, 124))	('inhibited', 'NegReg', (56, 65))	('up-regulation', 'PosReg', (28, 41))	('rapid growth', 'CPA', (66, 78))
141628	33109195	In vitro studies showed that knock-down of PIWIL2 in glioma cells induced cell cycle arrest and promoted apoptosis.	('glioma', 'Disease', (53, 59))	('apoptosis', 'CPA', (105, 114))	('arrest', 'Disease', (85, 91))	('PIWIL2', 'Gene', '55124', (43, 49))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('promoted', 'PosReg', (96, 104))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('PIWIL2', 'Gene', (43, 49))	('knock-down', 'Var', (29, 39))
141629	33109195	In addition, silencing of PIWIL2 expression inhibited the migration of glioma cells.	('inhibited', 'NegReg', (44, 53))	('glioma', 'Disease', (71, 77))	('rat', 'Species', '10116', (61, 64))	('PIWIL2', 'Gene', '55124', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('PIWIL2', 'Gene', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('silencing', 'Var', (13, 22))
141638	33109195	Both CRNDE knock-down or miR-384 up-regulation led to a decrease in PIWIL4 in glioma.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('CRNDE', 'Gene', '643911', (5, 10))	('CRNDE', 'Gene', (5, 10))	('knock-down', 'Var', (11, 21))	('miR-384', 'Gene', (25, 32))	('up-regulation', 'PosReg', (33, 46))	('decrease', 'NegReg', (56, 64))	('glioma', 'Disease', (78, 84))	('PIWIL4', 'Gene', '143689', (68, 74))	('PIWIL4', 'Gene', (68, 74))	('miR-384', 'Gene', '494333', (25, 32))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
141645	33109195	It is well-known that there is a relationship between epigenetic modifications (such as histone alterations and DNA hypo/hyper-methylation) and the development and progression of cancer.	('epigenetic modifications', 'Var', (54, 78))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('histone', 'MPA', (88, 95))	('cancer', 'Disease', (179, 185))	('rat', 'Species', '10116', (100, 103))
141646	33109195	piRNA/PIWI complexes may be involved in tumorigenesis via abnormal DNA methylation leading to genomic silencing and an increased stem-like state.	('stem-like state', 'CPA', (129, 144))	('piR', 'Gene', (0, 3))	('abnormal', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('DNA', 'Protein', (67, 70))	('involved', 'Reg', (28, 36))	('tumor', 'Disease', (40, 45))	('piR', 'Gene', '8544', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('genomic silencing', 'MPA', (94, 111))	('increased', 'PosReg', (119, 128))
141658	33109195	Moreover, piR-DQ593109 and PIWIL1 lowered MEG3 expression, while restoration of MEG3 abrogated the post-transcriptional suppression of RUNX3 by sponging miR-330-5p.	('MEG3', 'Gene', '55384', (42, 46))	('rat', 'Species', '10116', (70, 73))	('restoration', 'Var', (65, 76))	('piR', 'Gene', (10, 13))	('PIWIL1', 'Gene', '9271', (27, 33))	('miR-330', 'Gene', (153, 160))	('RUNX3', 'Gene', (135, 140))	('miR-330', 'Gene', '442902', (153, 160))	('RUNX3', 'Gene', '864', (135, 140))	('lowered', 'NegReg', (34, 41))	('MEG3', 'Gene', '55384', (80, 84))	('PIWIL1', 'Gene', (27, 33))	('piR', 'Gene', '8544', (10, 13))	('abrogated', 'NegReg', (85, 94))	('post-transcriptional suppression', 'MPA', (99, 131))	('MEG3', 'Gene', (42, 46))	('expression', 'MPA', (47, 57))	('MEG3', 'Gene', (80, 84))
141666	33109195	Up-regulation of miR-367-3p, piR-30,188 and PIWIL3 or knockdown of OIP5-AS1 led to suppression of glioma progression.	('miR-367', 'Gene', (17, 24))	('suppression', 'NegReg', (83, 94))	('knockdown', 'Var', (54, 63))	('OIP5-AS1', 'Gene', '729082;11339;5729', (67, 75))	('PIWIL3', 'Gene', '440822', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('PIWIL3', 'Gene', (44, 50))	('OIP5-AS1', 'Gene', (67, 75))	('U', 'Chemical', 'MESH:D014529', (0, 1))	('Up-regulation', 'PosReg', (0, 13))	('piR-30', 'Chemical', '-', (29, 35))	('glioma', 'Disease', (98, 104))	('miR-367', 'Gene', '442912', (17, 24))
141680	33109195	Deregulated piRNAs have been detected in colon, gastric, lung, breast, bladder, uterine, thyroid, and kidney cancer tissues.	('thyroid', 'Disease', (89, 96))	('kidney cancer', 'Disease', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Deregulated', 'Var', (0, 11))	('bladder', 'Disease', (71, 78))	('uterine', 'Disease', (80, 87))	('piR', 'Gene', '8544', (12, 15))	('breast', 'Disease', (63, 69))	('detected', 'Reg', (29, 37))	('gastric', 'Disease', (48, 55))	('piR', 'Gene', (12, 15))	('colon', 'Disease', (41, 46))	('lung', 'Disease', (57, 61))	('kidney cancer', 'Phenotype', 'HP:0009726', (102, 115))	('kidney cancer', 'Disease', 'MESH:D007680', (102, 115))
141681	33109195	Abnormal expression of piRNAs is a signature finding with valuable prognostic or diagnostic implications for several types of cancer.	('piR', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('piR', 'Gene', '8544', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('expression', 'MPA', (9, 19))	('Abnormal', 'Var', (0, 8))
141690	32725165	The mRNA expression-based stemness index (mRNAsi) was significantly associated with the glioma histologic grade, isocitrate dehydrogenase 1 (IDH1) mutation and overall survival of glioma patients by the nonparametric test and Kaplan-Meier survival analysis.	('patients', 'Species', '9606', (187, 195))	('IDH1', 'Gene', (141, 145))	('associated', 'Reg', (68, 78))	('overall', 'CPA', (160, 167))	('mRNAsi', 'Disease', 'None', (42, 48))	('mutation', 'Var', (147, 155))	('isocitrate dehydrogenase 1', 'Gene', '3417', (113, 139))	('glioma', 'Disease', (88, 94))	('IDH1', 'Gene', '3417', (141, 145))	('isocitrate dehydrogenase 1', 'Gene', (113, 139))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('mRNA expression-based', 'MPA', (4, 25))	('mRNAsi', 'Disease', (42, 48))	('glioma', 'Disease', (180, 186))
141694	32725165	In conclusion, this bioinformatics study demonstrates the mRNAsi as a reliable index for the IDH1 mutation, histologic grade and OS of glioma patients and provides a well-applied model for predicting the OS for patients with glioma based on prognostic SRGs.	('mRNAsi', 'Disease', (58, 64))	('IDH1', 'Gene', (93, 97))	('glioma', 'Disease', (135, 141))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (211, 219))	('IDH1', 'Gene', '3417', (93, 97))	('SRGs', 'Chemical', '-', (252, 256))	('glioma', 'Disease', (225, 231))	('mRNAsi', 'Disease', 'None', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('patients', 'Species', '9606', (142, 150))	('glioma', 'Disease', 'MESH:D005910', (225, 231))
141710	32725165	Additionally, we identified the differential expressed genes (DEGs) and the association between mRNAsi and histologic grade, isocitrate dehydrogenase 1 (IDH1) mutation and OS.	('IDH1', 'Gene', (153, 157))	('mRNAsi', 'Disease', (96, 102))	('IDH1', 'Gene', '3417', (153, 157))	('association', 'Interaction', (76, 87))	('mutation', 'Var', (159, 167))	('mRNAsi', 'Disease', 'None', (96, 102))	('isocitrate dehydrogenase 1', 'Gene', '3417', (125, 151))	('isocitrate dehydrogenase 1', 'Gene', (125, 151))
141738	32725165	Furthermore, IDH1 mutations were more often detected in high mRNAsi tumors (Figure 5D, P=0.001).	('high mRNAsi tumors', 'Disease', (56, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('high mRNAsi tumors', 'Disease', 'MESH:D009369', (56, 74))	('IDH1', 'Gene', (13, 17))	('detected', 'Reg', (44, 52))	('IDH1', 'Gene', '3417', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutations', 'Var', (18, 27))
141754	32725165	Here, we found mRNAsi was a reliable index that was significantly up-regulated in high grade glioma and LGG with IDH1 mutation by bioinformatics methods.	('glioma', 'Disease', (93, 99))	('up-regulated', 'PosReg', (66, 78))	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (113, 117))	('mRNAsi', 'Disease', (15, 21))	('mutation', 'Var', (118, 126))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('mRNAsi', 'Disease', 'None', (15, 21))
141763	32725165	We found that the mRNAsi of glioma patients was significantly associated with pathological grade, IDH1 mutation and their OS.	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('associated', 'Reg', (62, 72))	('mRNAsi of glioma', 'Disease', (18, 34))	('mRNAsi of glioma', 'Disease', 'MESH:D005910', (18, 34))	('IDH1', 'Gene', (98, 102))	('patients', 'Species', '9606', (35, 43))	('mutation', 'Var', (103, 111))	('IDH1', 'Gene', '3417', (98, 102))
141767	32725165	Its mutation is supposed to be an early event in glioma formation and can promote the proliferation and colony formation of normal human astrocyte cell normal human astrocyte cells.	('promote', 'PosReg', (74, 81))	('proliferation', 'CPA', (86, 99))	('mutation', 'Var', (4, 12))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('human', 'Species', '9606', (159, 164))	('human', 'Species', '9606', (131, 136))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('colony formation', 'CPA', (104, 120))	('glioma', 'Disease', (49, 55))
141768	32725165	Additionally, the IDH-driven epigenetic changes remain the glioma cells in a less differentiated or stem-like state, rendering them vulnerable to suffering additional oncologic events, such as the mutation of tumor suppressor protein 53 (TP53).	('glioma', 'Disease', (59, 65))	('tumor suppressor protein 53', 'Gene', '7157', (209, 236))	('IDH', 'Gene', (18, 21))	('tumor suppressor protein 53', 'Gene', (209, 236))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('IDH', 'Gene', '3417', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TP53', 'Gene', '7157', (238, 242))	('TP53', 'Gene', (238, 242))	('epigenetic changes', 'Var', (29, 47))	('mutation', 'Var', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
141787	32725165	CHI3L1 can be associated with IDH status and 1p/19q co-deletion in patients with glioma.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('patients', 'Species', '9606', (67, 75))	('CHI3L1', 'Gene', (0, 6))	('associated', 'Reg', (14, 24))	('glioma', 'Disease', (81, 87))	('1p/19q co-deletion', 'Var', (45, 63))	('IDH', 'Gene', (30, 33))	('CHI3L1', 'Gene', '1116', (0, 6))	('IDH', 'Gene', '3417', (30, 33))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
141797	32725165	This bioinformatics analysis demonstrates the mRNAsi as a reliable index for the IDH1 mutation, histologic grade and OS of glioma and provides a well-applied model for predicting the OS for patients with glioma based on prognostic SRGs.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('patients', 'Species', '9606', (190, 198))	('glioma', 'Disease', (204, 210))	('mRNAsi', 'Disease', (46, 52))	('IDH1', 'Gene', (81, 85))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('glioma', 'Disease', (123, 129))	('mutation', 'Var', (86, 94))	('IDH1', 'Gene', '3417', (81, 85))	('SRGs', 'Chemical', '-', (231, 235))	('mRNAsi', 'Disease', 'None', (46, 52))
141812	32346611	demonstrate that PABPC5 increases the stability of HCG15.	('stability', 'MPA', (38, 47))	('increases', 'PosReg', (24, 33))	('HCG15', 'Gene', '414761', (51, 56))	('HCG15', 'Gene', (51, 56))	('PABPC5', 'Var', (17, 23))
141845	32346611	Studies have reported that ZNF331 methylates in the promoter region of human gastric cancer cells, which inactivates them and increases the growth and invasion capabilities of gastric cancer cells.	('increases', 'PosReg', (126, 135))	('human', 'Species', '9606', (71, 76))	('gastric cancer', 'Disease', (77, 91))	('methylates', 'Var', (34, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inactivates', 'NegReg', (105, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('ZNF331', 'Gene', '55422', (27, 33))	('gastric cancer', 'Disease', (176, 190))	('ZNF331', 'Gene', (27, 33))
141860	32346611	The results showed that knockdown of PABPC5 affected proliferation, migration, invasion, and VM in glioma cells.	('affected', 'Reg', (44, 52))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Disease', (99, 105))	('proliferation', 'CPA', (53, 66))	('invasion', 'CPA', (79, 87))	('PABPC5', 'Gene', (37, 43))	('migration', 'CPA', (68, 77))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('knockdown', 'Var', (24, 33))
141872	32346611	Next, the effect of PABPC5 knockdown on HCG15 was detected.	('PABPC5', 'Gene', (20, 26))	('HCG15', 'Gene', (40, 45))	('HCG15', 'Gene', '414761', (40, 45))	('knockdown', 'Var', (27, 36))
141873	32346611	Compared with the control group, the expression of HCG15 was not significantly different in the PABPC5 (-)-NC group; compared with the PABPC5 (-)-NC group, the expression level of HCG15was significantly reduced in PABPC5 (-) group (p < 0.01).	('HCG15', 'Gene', '414761', (180, 185))	('HCG15', 'Gene', '414761', (51, 56))	('reduced', 'NegReg', (203, 210))	('PABPC5', 'Var', (214, 220))	('expression level', 'MPA', (160, 176))	('HCG15', 'Gene', (51, 56))	('HCG15', 'Gene', (180, 185))
141875	32346611	As shown in Figure 2B, in the anti-PABPC5 group, HCG15 enrichment was significantly higher than in the anti-immunoglobulin G (IgG) group (p < 0.01 and p < 0.05).	('HCG15', 'Gene', (49, 54))	('HCG15', 'Gene', '414761', (49, 54))	('anti-PABPC5', 'Var', (30, 41))	('higher', 'PosReg', (84, 90))
141881	32346611	Compared with the PABPC5 (-) + HCG15 (+)-NC group, HCG15 (+) reversed the inhibitory effect of PABPC5 (-) on proliferation, migration, invasion, VM ability of VM and LAMC2 protein expression in PABPC5 (-) + HCG15 (+) (p < 0.01 and p < 0.05).	('HCG15', 'Gene', '414761', (31, 36))	('HCG15', 'Gene', '414761', (51, 56))	('migration', 'CPA', (124, 133))	('VM ability of', 'CPA', (145, 158))	('HCG15', 'Gene', (31, 36))	('HCG15', 'Gene', (51, 56))	('expression', 'MPA', (180, 190))	('HCG15', 'Gene', '414761', (207, 212))	('LAMC2 protein', 'Protein', (166, 179))	('proliferation', 'CPA', (109, 122))	('HCG15', 'Gene', (207, 212))	('PABPC5 (-) +', 'Var', (194, 206))	('invasion', 'CPA', (135, 143))
141892	32346611	After PABPC5 knockdown in glioma cells, compared with the control group, there was no significant statistical difference between the PABPC5 (-)-NC group.	('PABPC5', 'Gene', (6, 12))	('glioma', 'Disease', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('knockdown', 'Var', (13, 22))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
141893	32346611	Compared with the PABPC5 (-)-NC group, the expression of ZNF331 mRNA and protein was significantly increased in the PABPC5 (-) group (p < 0.01 and p < 0.05).	('mRNA and', 'MPA', (64, 72))	('ZNF331', 'Gene', '55422', (57, 63))	('ZNF331', 'Gene', (57, 63))	('increased', 'PosReg', (99, 108))	('expression', 'MPA', (43, 53))	('PABPC5 (-', 'Var', (116, 125))
141899	32346611	Compared with the control group, the PABPC5 (-)+HCG15 (-)-NC group and PABPC5 (-) + HCG15 (+)-NC group had significantly increased mRNA and protein levels of ZNF331 (p < 0.01 and p < 0.05).	('increased', 'PosReg', (121, 130))	('HCG15', 'Gene', '414761', (84, 89))	('HCG15', 'Gene', (48, 53))	('PABPC5', 'Var', (37, 43))	('ZNF331', 'Gene', '55422', (158, 164))	('ZNF331', 'Gene', (158, 164))	('HCG15', 'Gene', (84, 89))	('HCG15', 'Gene', '414761', (48, 53))
141911	32346611	We further knocked down or overexpressed STAU1 and knocked down HCG15 in glioma cells and detected changes in ZNF331 protein expression.	('glioma', 'Disease', (73, 79))	('STAU1', 'Gene', '6780', (41, 46))	('HCG15', 'Gene', (64, 69))	('changes', 'Reg', (99, 106))	('ZNF331', 'Gene', '55422', (110, 116))	('overexpressed', 'PosReg', (27, 40))	('HCG15', 'Gene', '414761', (64, 69))	('ZNF331', 'Gene', (110, 116))	('protein expression', 'MPA', (117, 135))	('knocked down', 'Var', (11, 23))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('knocked down', 'NegReg', (51, 63))	('STAU1', 'Gene', (41, 46))
141915	32346611	Furthermore, ZNF331 was knocked down or overexpressed in glioma cells, which were transfected with HCG15 (-) at the same time.	('HCG15', 'Gene', (99, 104))	('glioma', 'Disease', (57, 63))	('knocked', 'Var', (24, 31))	('HCG15', 'Gene', '414761', (99, 104))	('ZNF331', 'Gene', '55422', (13, 19))	('ZNF331', 'Gene', (13, 19))	('overexpressed', 'PosReg', (40, 53))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
141920	32346611	We predicted from the bioinformatics database (JASPAR) that ZNF331 may have potential binding sites with the promoter regions (-2,000 ~ -1,000 bp) of LAMC2 and PABPC5.	('ZNF331', 'Gene', (60, 66))	('-2,000', 'Var', (127, 133))	('binding', 'Interaction', (86, 93))	('ZNF331', 'Gene', '55422', (60, 66))
141924	32346611	ZNF331 was knocked down or overexpressed in glioma cells.	('ZNF331', 'Gene', (0, 6))	('knocked down', 'Var', (11, 23))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('ZNF331', 'Gene', '55422', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
141943	32346611	Compared with the PABPC5 (-) group, HCG15 (-) group, and ZNF331 (+) group, the number of VMs was significantly reduced in the PABPC5 (-) + HCG15 (-) + ZNF331 (+) group (p < 0.05) (Figure 6D).	('HCG15', 'Gene', '414761', (139, 144))	('ZNF331', 'Gene', '55422', (57, 63))	('reduced', 'NegReg', (111, 118))	('HCG15', 'Gene', '414761', (36, 41))	('ZNF331', 'Gene', (57, 63))	('PABPC5', 'Var', (126, 132))	('ZNF331', 'Gene', '55422', (151, 157))	('HCG15', 'Gene', (139, 144))	('ZNF331', 'Gene', (151, 157))	('HCG15', 'Gene', (36, 41))
141951	32346611	RBPs play an important role in regulating the formation of VM of tumor cells by binding to single- or double-stranded RNA.	('RBP', 'Gene', (0, 3))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('single-', 'Var', (91, 98))	('RBP', 'Gene', '57794', (0, 3))	('binding', 'Interaction', (80, 87))	('RNA', 'Protein', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
141953	32346611	Fus is highly expressed in glioma tissues and cells, and knockdown of Fus inhibits formation of glioma cell VM through the feedback regulation loop formed by circ_002136/miR-138-5p/SOX13.	('glioma', 'Disease', (27, 33))	('Fus', 'Gene', (0, 3))	('glioma tissues', 'Disease', (27, 41))	('SOX13', 'Gene', '9580', (181, 186))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('Fus', 'Gene', '2521', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('knockdown', 'Var', (57, 66))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma tissues', 'Disease', 'MESH:D005910', (27, 41))	('Fus', 'Gene', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('inhibits', 'NegReg', (74, 82))	('Fus', 'Gene', '2521', (70, 73))	('SOX13', 'Gene', (181, 186))	('glioma', 'Disease', (96, 102))
141954	32346611	This study found that PABPC5 was highly expressed in glioma tissues and cells and that knockdown of PABPC5 inhibited proliferation, migration, invasion, and VM formation of glioma cell.	('proliferation', 'CPA', (117, 130))	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', (173, 179))	('PABPC5', 'Gene', (100, 106))	('invasion', 'CPA', (143, 151))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('migration', 'CPA', (132, 141))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma tissues', 'Disease', (53, 67))	('PABPC5', 'Gene', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('inhibited', 'NegReg', (107, 116))	('glioma tissues', 'Disease', 'MESH:D005910', (53, 67))	('knockdown', 'Var', (87, 96))
141965	32346611	For example, SNHG16 and USF1 are highly expressed in glioma tissues and cells and play a role in promoting VM formation by combining miR-212-3p and miR-429.	('VM formation', 'CPA', (107, 119))	('USF1', 'Gene', '7391', (24, 28))	('SNHG16', 'Gene', '100507246', (13, 19))	('miR-212-3p', 'Var', (133, 143))	('SNHG16', 'Gene', (13, 19))	('miR-212-3p', 'Chemical', '-', (133, 143))	('promoting', 'PosReg', (97, 106))	('combining', 'Interaction', (123, 132))	('glioma tissues', 'Disease', (53, 67))	('miR-429', 'Gene', '554210', (148, 155))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('USF1', 'Gene', (24, 28))	('glioma tissues', 'Disease', 'MESH:D005910', (53, 67))	('miR-429', 'Gene', (148, 155))
141970	32346611	Furthermore, we found that the expression level of HCG15 was decreased after PABPC5 knockdown in glioma cells, whereas the nascent HCG15 was not transcribed but the half-life of HCG15 was shortened.	('HCG15', 'Gene', '414761', (131, 136))	('HCG15', 'Gene', (178, 183))	('HCG15', 'Gene', '414761', (51, 56))	('glioma', 'Disease', (97, 103))	('knockdown', 'Var', (84, 93))	('HCG15', 'Gene', '414761', (178, 183))	('HCG15', 'Gene', (51, 56))	('HCG15', 'Gene', (131, 136))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('decreased', 'NegReg', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('half-life', 'MPA', (165, 174))	('PABPC5', 'Gene', (77, 83))	('expression level', 'MPA', (31, 47))
141972	32346611	Therefore, the stability of HCG15 was changed by knockdown of PABPC5, which was not caused by HCG15 nascent RNA.	('knockdown', 'Var', (49, 58))	('changed', 'Reg', (38, 45))	('PABPC5', 'Gene', (62, 68))	('HCG15', 'Gene', '414761', (94, 99))	('HCG15', 'Gene', (28, 33))	('HCG15', 'Gene', (94, 99))	('stability', 'MPA', (15, 24))	('HCG15', 'Gene', '414761', (28, 33))
141973	32346611	When knockdown of PABPC5 was combined with knockdown of HCG15, the effect was strengthened further regarding proliferation, migration, invasion, and VM formation ability in glioma cells.	('HCG15', 'Gene', '414761', (56, 61))	('glioma', 'Disease', (173, 179))	('migration', 'CPA', (124, 133))	('HCG15', 'Gene', (56, 61))	('knockdown', 'Var', (43, 52))	('PABPC5', 'Gene', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('VM formation ability', 'CPA', (149, 169))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('proliferation', 'CPA', (109, 122))	('strengthened', 'PosReg', (78, 90))	('invasion', 'CPA', (135, 143))
141986	32346611	We found that knockdown of HCG15 significantly increased the expression level of ZNF331 mRNA and extended its half-life.	('HCG15', 'Gene', '414761', (27, 32))	('HCG15', 'Gene', (27, 32))	('half-life', 'MPA', (110, 119))	('mRNA', 'MPA', (88, 92))	('increased', 'PosReg', (47, 56))	('ZNF331', 'Gene', '55422', (81, 87))	('ZNF331', 'Gene', (81, 87))	('expression level', 'MPA', (61, 77))	('knockdown', 'Var', (14, 23))	('extended', 'PosReg', (97, 105))
141990	32346611	Therefore, we knocked down STAU1 and UPF1 in glioma cells.	('STAU1', 'Gene', '6780', (27, 32))	('UPF1', 'Gene', (37, 41))	('UPF1', 'Gene', '5976', (37, 41))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('STAU1', 'Gene', (27, 32))	('glioma', 'Disease', (45, 51))	('knocked', 'Var', (14, 21))
141993	32346611	Overexpression of STAU1 reversed knockdown of HCG15, which increased ZNF331 protein expression.	('ZNF331', 'Gene', '55422', (69, 75))	('ZNF331', 'Gene', (69, 75))	('HCG15', 'Gene', '414761', (46, 51))	('knockdown', 'Var', (33, 42))	('protein expression', 'MPA', (76, 94))	('HCG15', 'Gene', (46, 51))	('STAU1', 'Gene', (18, 23))	('increased', 'PosReg', (59, 68))	('STAU1', 'Gene', '6780', (18, 23))
141997	32346611	The lncRNA SNHG5 is highly expressed in colorectal cancer cells, and knockdown of SNHG5 blocks STAU1-mediated decay of SPATA2 mRNA and inhibits growth of colorectal cancer cells through the SMD pathway.	('SNHG5', 'Gene', '387066', (82, 87))	('colorectal cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SNHG5', 'Gene', '387066', (11, 16))	('inhibits', 'NegReg', (135, 143))	('SPATA2', 'Gene', '9825', (119, 125))	('growth', 'CPA', (144, 150))	('SNHG5', 'Gene', (82, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('SNHG5', 'Gene', (11, 16))	('SPATA2', 'Gene', (119, 125))	('blocks', 'NegReg', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('colorectal cancer', 'Disease', (40, 57))	('STAU1', 'Gene', (95, 100))	('STAU1', 'Gene', '6780', (95, 100))	('SMD', 'Gene', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('SMD', 'Gene', '6638', (190, 193))	('knockdown', 'Var', (69, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
142004	32346611	Further, the ChIP experiment was used to confirm that ZNF331 had a binding effect and binding site with the promoter region of the upstream RBP PABPC5, and knockdown of ZNF331 also increased PABPC5 mRNA and protein expression levels.	('knockdown', 'Var', (156, 165))	('RBP', 'Gene', (140, 143))	('ZNF331', 'Gene', '55422', (169, 175))	('RBP', 'Gene', '57794', (140, 143))	('binding', 'Interaction', (86, 93))	('ZNF331', 'Gene', (169, 175))	('ZNF331', 'Gene', '55422', (54, 60))	('PABPC5', 'Gene', (191, 197))	('ZNF331', 'Gene', (54, 60))	('increased', 'PosReg', (181, 190))	('binding', 'Interaction', (67, 74))
142006	32346611	Finally, in this study, knockdown of PABPC5, knockdown of HCG15, and overexpression of ZNF331 were performed alone or in combination in nude mice.	('ZNF331', 'Gene', '55422', (87, 93))	('ZNF331', 'Gene', (87, 93))	('HCG15', 'Gene', (58, 63))	('nude mice', 'Species', '10090', (136, 145))	('PABPC5', 'Gene', (37, 43))	('HCG15', 'Gene', '414761', (58, 63))	('knockdown', 'Var', (45, 54))
142007	32346611	It was confirmed that knockdown of PABPC5, knockdown of HCG15, and overexpression of ZNF331 alone could effectively inhibit the growth of transplanted tumors and prolong the survival of nude mice.	('nude mice', 'Species', '10090', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('HCG15', 'Gene', '414761', (56, 61))	('survival', 'CPA', (174, 182))	('prolong', 'PosReg', (162, 169))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('HCG15', 'Gene', (56, 61))	('knockdown', 'Var', (43, 52))	('ZNF331', 'Gene', '55422', (85, 91))	('PABPC5', 'Gene', (35, 41))	('ZNF331', 'Gene', (85, 91))	('knockdown', 'Var', (22, 31))	('inhibit', 'NegReg', (116, 123))
142008	32346611	Combined knockdown of PABPC5, knockdown of HCG15, and overexpression of ZNF331 had the best antitumor effect and the longest survival time in nude mice.	('ZNF331', 'Gene', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('nude mice', 'Species', '10090', (142, 151))	('HCG15', 'Gene', '414761', (43, 48))	('knockdown', 'Var', (30, 39))	('PABPC5', 'Gene', (22, 28))	('HCG15', 'Gene', (43, 48))	('ZNF331', 'Gene', '55422', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
142009	32346611	The potential value of PABPC5 knockdown, HCG15 knockdown, and ZNF331 overexpression alone or association was suggested.	('HCG15', 'Gene', '414761', (41, 46))	('knockdown', 'Var', (47, 56))	('HCG15', 'Gene', (41, 46))	('association', 'Interaction', (93, 104))	('ZNF331', 'Gene', '55422', (62, 68))	('ZNF331', 'Gene', (62, 68))
142011	32346611	Knockdown of PABPC5 reduced the stability of HCG15, and knockdown of HCG15 is through the SMD pathway to prevent its degradation of ZNF331 mRNA.	('prevent', 'NegReg', (105, 112))	('PABPC5', 'Gene', (13, 19))	('reduced', 'NegReg', (20, 27))	('HCG15', 'Gene', '414761', (69, 74))	('HCG15', 'Gene', '414761', (45, 50))	('SMD', 'Gene', (90, 93))	('ZNF331', 'Gene', '55422', (132, 138))	('ZNF331', 'Gene', (132, 138))	('HCG15', 'Gene', (69, 74))	('SMD', 'Gene', '6638', (90, 93))	('HCG15', 'Gene', (45, 50))	('stability', 'MPA', (32, 41))	('knockdown', 'Var', (56, 65))
142045	31806013	Single-nucleus chromatin accessibility reveals intratumoral epigenetic heterogeneity in IDH1 mutant gliomas The presence of genome-wide DNA hypermethylation is a hallmark of lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) mutations.	('IDH1', 'Gene', (88, 92))	('IDH', 'Gene', (231, 234))	('IDH', 'Gene', (88, 91))	('isocitrate dehydrogenase', 'Gene', (205, 229))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Disease', (186, 193))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('IDH1', 'Gene', '3417', (88, 92))	('IDH', 'Gene', '3417', (231, 234))	('IDH', 'Gene', '3417', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('gliomas', 'Disease', 'MESH:D005910', (186, 193))	('mutations', 'Var', (236, 245))	('isocitrate dehydrogenase', 'Gene', '3417', (205, 229))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('mutant', 'Var', (93, 99))	('gliomas', 'Disease', (100, 107))
142047	31806013	Despite the DNA hypermethylation seen in bulk tumors, intra-tumoral heterogeneity at the epigenetic level has not been thoroughly analyzed.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('intra-tumoral', 'Disease', 'MESH:D009369', (54, 67))	('intra-tumoral', 'Disease', (54, 67))	('hypermethylation', 'Var', (16, 32))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
142048	31806013	To address this question, we performed the first epigenetic profiling of single cells in a cohort of 5 gliomas with IDH1 mutation using single nucleus Assay for Transposase-Accessible Chromatin with high-throughput sequencing (snATAC-seq).	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('IDH1', 'Gene', (116, 120))	('mutation', 'Var', (121, 129))	('single nucleus', 'Phenotype', 'HP:0003687', (136, 150))	('IDH1', 'Gene', '3417', (116, 120))
142053	31806013	Isocitrate dehydrogenase 1 (IDH1), and to a lesser extent, its mitochondrial homolog, IDH2, are mutated in a majority of adult lower grade gliomas (LGGs).	('mutated', 'Var', (96, 103))	('IDH2', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (28, 32))	('gliomas', 'Disease', (139, 146))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('IDH2', 'Gene', '3418', (86, 90))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IDH1', 'Gene', (28, 32))
142055	31806013	The most common IDH1 mutation in gliomas (IDH1 R132) occurs in the catalytic domain of IDH1 and confers the ability to produce 2-hydroxyglutarate (2-HG).	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('IDH1', 'Gene', '3417', (42, 46))	('2-HG', 'Chemical', 'MESH:C019417', (147, 151))	('IDH1', 'Gene', '3417', (87, 91))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('mutation', 'Var', (21, 29))	('gliomas', 'Disease', (33, 40))	('IDH1', 'Gene', (16, 20))	('produce 2-hydroxyglutarate', 'MPA', (119, 145))	('ability', 'MPA', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('IDH1', 'Gene', '3417', (16, 20))	('IDH1', 'Gene', (42, 46))	('IDH1', 'Gene', (87, 91))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (127, 145))
142056	31806013	2-HG competitively inhibits enzymes that use alphaKG as a cofactor, such as TET family of enzymes and Jmj-C domain containing histone demethylases, leading to DNA hypermethylation, and aberrant methylation of a number of histone marks along with impaired differentiation leading to an expansion of stem/progenitor cells.	('expansion', 'PosReg', (285, 294))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('aberrant', 'Var', (185, 193))	('TET', 'Chemical', 'MESH:C010349', (76, 79))	('DNA hypermethylation', 'MPA', (159, 179))	('inhibits', 'NegReg', (19, 27))	('methylation', 'MPA', (194, 205))
142057	31806013	Gliomas with IDH mutation exhibit global DNA hypermethylation and are subdivided into two distinct molecular subgroups: IDHmut-codel (hemizygous co-deletion of chromosome arms 1p/19q) and IDHmut-noncodel (without co-deletion of 1p/19q) gliomas.	('IDH', 'Gene', '3417', (188, 191))	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', '3417', (120, 123))	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('gliomas', 'Disease', (236, 243))	('mutation', 'Var', (17, 25))	('gliomas', 'Disease', 'MESH:D005910', (236, 243))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH', 'Gene', (188, 191))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('gliomas', 'Phenotype', 'HP:0009733', (236, 243))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('global DNA hypermethylation', 'MPA', (34, 61))	('arms 1p', 'Gene', '3075', (171, 178))	('Gliomas', 'Disease', (0, 7))	('arms 1p', 'Gene', (171, 178))	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', (120, 123))
142058	31806013	While transcriptional heterogeneity at the single cell level and longitudinal alterations in the bulk epigenomes of IDH mutant gliomas have been investigated, little is known about intratumoral epigenetic heterogeneity at the single cell level.	('IDH', 'Gene', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('IDH', 'Gene', '3417', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('tumor', 'Disease', (186, 191))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('mutant', 'Var', (120, 126))
142059	31806013	To address this question, we interrogated the accessible chromatin at the individual cell level in gliomas with IDH mutation using single nucleus Assay for Transposase-Accessible Chromatin with high-throughput sequencing (snATAC-seq) on a subset of 5 patient samples.	('single nucleus', 'Phenotype', 'HP:0003687', (131, 145))	('mutation', 'Var', (116, 124))	('patient', 'Species', '9606', (251, 258))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('IDH', 'Gene', (112, 115))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('IDH', 'Gene', '3417', (112, 115))
142062	31806013	Furthermore, we identify CYTOR as a poor prognosis factor in gliomas with IDH mutation.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('mutation', 'Var', (78, 86))	('CYTOR', 'Gene', '112597', (25, 30))	('gliomas', 'Disease', (61, 68))	('IDH', 'Gene', (74, 77))	('CYTOR', 'Gene', (25, 30))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('IDH', 'Gene', '3417', (74, 77))
142063	31806013	Overall, our results point to differential accessibility of non-coding RNAs as an important source of epigenetic heterogeneity within individual tumors and between molecular subgroups.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('epigenetic', 'MPA', (102, 112))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('non-coding RNAs', 'Var', (60, 75))	('tumors', 'Disease', 'MESH:D009369', (145, 151))
142104	31806013	Gliomas with IDH mutation exhibit global DNA hypermethylation.	('IDH', 'Gene', '3417', (13, 16))	('mutation', 'Var', (17, 25))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))	('IDH', 'Gene', (13, 16))
142106	31806013	To our knowledge, our study is the first description of chromatin accessibility of gliomas with IDH mutation using single nucleus ATAC-seq.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('single nucleus', 'Phenotype', 'HP:0003687', (115, 129))	('IDH', 'Gene', '3417', (96, 99))	('mutation', 'Var', (100, 108))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH', 'Gene', (96, 99))
142117	31806013	PEA3 subfamily of ETS proteins (ETV1, ETV4, ETV5) amplify transcriptional signals when RAS/MAPK signaling pathway is active, and abolishing Ets activity leads to a block in glioma initiation.	('Ets', 'Enzyme', (140, 143))	('block', 'NegReg', (164, 169))	('PEA3', 'Gene', '2118', (0, 4))	('glioma initiation', 'Disease', 'MESH:D005910', (173, 190))	('ETV5', 'Gene', '2119', (44, 48))	('PEA3', 'Gene', (0, 4))	('ETV4', 'Gene', (38, 42))	('abolishing', 'Var', (129, 139))	('ETV4', 'Gene', '2118', (38, 42))	('ETV5', 'Gene', (44, 48))	('activity', 'MPA', (144, 152))	('amplify transcriptional signals', 'MPA', (50, 81))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('ETV1', 'Gene', (32, 36))	('ETV1', 'Gene', '2115', (32, 36))	('glioma initiation', 'Disease', (173, 190))
142125	31806013	Given that IDHmut-codel samples harbor chromosome arm deletions, we were able to infer the presence of 1p/19q deletions in a large majority of our snATAC-seq data.	('IDH', 'Gene', '3417', (11, 14))	('deletions', 'Var', (54, 63))	('IDH', 'Gene', (11, 14))	('chromosome arm', 'Gene', (39, 53))
142156	31466300	BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors BRAF mutations have been identified as targetable, oncogenic mutations in many cancers.	('Primary Brain Tumors', 'Disease', (60, 80))	('RAF', 'Gene', '22882', (34, 37))	('BRAF', 'Gene', '673', (81, 85))	('RAF', 'Gene', '22882', (1, 4))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (81, 85))	('BRAF', 'Gene', (0, 4))	('RAF', 'Gene', (82, 85))	('RAF', 'Gene', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('Primary Brain Tumors', 'Disease', 'MESH:D001932', (60, 80))	('RAF', 'Gene', (1, 4))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (86, 95))	('MEK', 'Gene', '5609', (42, 45))	('Brain Tumors', 'Phenotype', 'HP:0030692', (68, 80))	('Tumors', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('MEK', 'Gene', (42, 45))	('RAF', 'Gene', '22882', (82, 85))
142157	31466300	Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest.	('brain tumors', 'Phenotype', 'HP:0030692', (44, 56))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('mutations', 'Var', (121, 130))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('brain tumor', 'Phenotype', 'HP:0030692', (44, 55))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('primary brain tumors', 'Disease', 'MESH:D001932', (36, 56))	('primary brain tumors', 'Disease', (36, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('glioma', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('glioma', 'Disease', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
142158	31466300	In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications.	('brain tumor', 'Phenotype', 'HP:0030692', (114, 125))	('BRAF', 'Gene', (43, 47))	('fusion alterations', 'Var', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('brain tumor', 'Disease', (114, 125))	('brain tumor', 'Disease', 'MESH:D001932', (114, 125))	('mutations', 'Var', (48, 57))
142160	31466300	Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('RAF', 'Gene', '22882', (107, 110))	('RAF', 'Gene', '22882', (52, 55))	('RAF', 'Gene', (107, 110))	('MEK', 'Gene', '5609', (23, 26))	('RAF', 'Gene', (52, 55))	('RAF', 'Gene', '22882', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('RAF', 'Gene', (15, 18))	('tumor', 'Disease', (78, 83))	('RAF', 'Gene', '22882', (164, 167))	('MEK', 'Gene', (23, 26))	('RAF', 'Gene', (164, 167))	('V600 mutations', 'Var', (111, 125))
142161	31466300	While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors.	('RAF', 'Gene', '22882', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RAF', 'Gene', (24, 27))	('primary brain tumors', 'Disease', (51, 71))	('primary brain tumors', 'Disease', 'MESH:D001932', (51, 71))	('brain tumors', 'Phenotype', 'HP:0030692', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('MEK', 'Gene', (176, 179))	('RAF', 'Gene', '22882', (154, 157))	('MEK', 'Gene', '5609', (176, 179))	('RAF', 'Gene', (154, 157))	('mutations', 'Var', (28, 37))	('brain tumor', 'Phenotype', 'HP:0030692', (59, 70))
142169	31466300	Of note, in cells with the BRAF V600E mutation, the nonmutated BRAF gene still produces wild-type protein that is free to dimerize and activate downstream ERK signaling accordingly.	('ERK', 'Gene', (155, 158))	('V600E', 'Var', (32, 37))	('activate', 'PosReg', (135, 143))	('BRAF', 'Gene', (27, 31))	('V600E', 'Mutation', 'p.V600E', (32, 37))	('ERK', 'Gene', '5594', (155, 158))	('BRAF', 'Gene', (63, 67))
142170	31466300	The BRAF V600E mutation is present in approximately 60% of melanoma, 40% of non-small cell lung cancer (NSLCL), and 12% of colorectal cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('NSLCL', 'Disease', (104, 109))	('non-small cell lung cancer', 'Disease', (76, 102))	('colorectal cancer', 'Disease', (123, 140))	('V600E', 'Mutation', 'p.V600E', (9, 14))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('NSLCL', 'Phenotype', 'HP:0030358', (104, 109))	('BRAF', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (76, 102))	('NSLCL', 'Disease', 'MESH:D002289', (104, 109))	('V600E', 'Var', (9, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
142175	31466300	Currently, there are three combinations of RAF and MEK inhibitors approved by the United States Food and Drug Administration (U.S. FDA) for patients with BRAF V600E/K mutations in advanced or metastatic melanoma, NSCLC, or anaplastic thyroid cancer: vemurafenib/cobimetinib (Genentech), dabrafenib/trametinib (Novartis), and encorafenib/binimetinib (Array BioPharma).	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('dabrafenib', 'Chemical', 'MESH:C561627', (287, 297))	('RAF', 'Gene', (43, 46))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('thyroid cancer', 'Disease', (234, 248))	('NSCLC', 'Disease', (213, 218))	('encorafenib', 'Chemical', 'None', (325, 336))	('MEK', 'Gene', '5609', (51, 54))	('V600E', 'Mutation', 'p.V600E', (159, 164))	('patients', 'Species', '9606', (140, 148))	('RAF', 'Gene', '22882', (155, 158))	('thyroid cancer', 'Disease', 'MESH:D013964', (234, 248))	('MEK', 'Gene', (51, 54))	('trametinib', 'Chemical', 'MESH:C560077', (298, 308))	('vemurafenib', 'Chemical', 'MESH:C551177', (250, 261))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (223, 248))	('V600E/K mutations', 'Var', (159, 176))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('N', 'Chemical', 'MESH:D009584', (310, 311))	('binimetinib', 'Chemical', 'MESH:C581313', (337, 348))	('thyroid cancer', 'Phenotype', 'HP:0002890', (234, 248))	('cobimetinib', 'Chemical', 'MESH:C574276', (262, 273))	('RAF', 'Gene', (155, 158))	('N', 'Chemical', 'MESH:D009584', (213, 214))	('RAF', 'Gene', '22882', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
142176	31466300	The remarkable responses seen in patients with BRAF-mutated cancers have attracted attention in the field of neuro-oncology.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('patients', 'Species', '9606', (33, 41))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('BRAF-mutated', 'Var', (47, 59))	('oncology', 'Phenotype', 'HP:0002664', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
142178	31466300	Moreover, next-generation sequencing (NGS) of tumor specimens has enabled identification of other mutations in the BRAF gene in primary brain tumors, but many of these do not respond to FDA-approved RAF inhibitors and may in fact progress more rapidly.	('RAF', 'Gene', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('RAF', 'Gene', '22882', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RAF', 'Gene', '22882', (116, 119))	('progress', 'PosReg', (230, 238))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (46, 51))	('primary brain tumors', 'Disease', (128, 148))	('primary brain tumors', 'Disease', 'MESH:D001932', (128, 148))	('mutations', 'Var', (98, 107))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('brain tumors', 'Phenotype', 'HP:0030692', (136, 148))	('brain tumor', 'Phenotype', 'HP:0030692', (136, 147))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('RAF', 'Gene', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
142179	31466300	Here, we summarize the mutations in BRAF described to date in glioma and provide an overview of their functional implications for tumor biology and treatment with targeted drugs.	('BRAF', 'Gene', (36, 40))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('glioma', 'Disease', (62, 68))
142180	31466300	Over 100 unique mutations in the BRAF gene have been identified in cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('BRAF', 'Gene', (33, 37))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('identified', 'Reg', (53, 63))
142181	31466300	Through extensive work in melanoma, it is clear that these mutations lead to ERK activation via different functional mechanisms.	('ERK', 'Gene', '5594', (77, 80))	('activation', 'PosReg', (81, 91))	('ERK', 'Gene', (77, 80))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('mutations', 'Var', (59, 68))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
142183	31466300	While V600E is the most common mutation in BRAF, other mutations are being identified in glioma due to increasing use of clinical NGS.	('V600E', 'Mutation', 'p.V600E', (6, 11))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('BRAF', 'Gene', (43, 47))	('glioma', 'Disease', (89, 95))	('V600E', 'Var', (6, 11))
142184	31466300	Using cBioPortal.org, multiple patient cohorts were queried for glioma with mutations in BRAF (MSK-IMPACT Clinical Sequencing Cohort and TCGA).	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('mutations', 'Var', (76, 85))	('PA', 'Disease', 'MESH:D001254', (101, 103))	('patient', 'Species', '9606', (31, 38))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
142185	31466300	Thirty-nine gliomas with BRAF mutations were identified in cBioPortal, of which 17 (44%) had V600E mutations, eight had other known activating mutations (20%), and five had fusions conferring kinase activity (13%).	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('gliomas', 'Disease', (12, 19))	('V600E', 'Mutation', 'p.V600E', (93, 98))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('mutations', 'Var', (30, 39))	('V600E mutations', 'Var', (93, 108))
142186	31466300	Similar to other cancers, the most common mutation in the BRAF gene in glioma is the c.1799T>A mutation.	('c.1799T>A', 'Var', (85, 94))	('c.1799T>A', 'Mutation', 'c.1799T>A', (85, 94))	('glioma', 'Disease', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('BRAF', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
142188	31466300	This allows BRAF V600-mutated monomers to activate downstream MEK1/2 independent of dimerization.	('MEK1/2', 'Gene', (62, 68))	('activate', 'PosReg', (42, 50))	('BRAF', 'Var', (12, 16))	('V600-mutated', 'Var', (17, 29))	('MEK1/2', 'Gene', '5604;5605', (62, 68))
142189	31466300	Valine substitutions to several other amino acids (R, K, D) have been described, though these have not been reported in glioma.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('glioma', 'Disease', (120, 126))	('Valine substitutions', 'Var', (0, 20))	('Valine', 'Chemical', 'MESH:C521924', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
142190	31466300	V600E mutations strongly activate downstream ERK signaling, leading to suppression of upstream RAS activity through negative feedback from active ERK, resulting in low basal RAS activity in these cells.	('ERK', 'Gene', '5594', (146, 149))	('ERK', 'Gene', (45, 48))	('V600E', 'Mutation', 'p.V600E', (0, 5))	('upstream', 'MPA', (86, 94))	('activate', 'PosReg', (25, 33))	('low', 'NegReg', (164, 167))	('ERK', 'Gene', (146, 149))	('basal RAS activity', 'MPA', (168, 186))	('suppression', 'NegReg', (71, 82))	('negative feedback', 'MPA', (116, 133))	('V600E mutations', 'Var', (0, 15))	('ERK', 'Gene', '5594', (45, 48))
142191	31466300	BRAF V600E mutations have been described in a variety of adult and pediatric gliomas, including pleomorphic xanthoastrocytoma (PXA; 60-80%), ganglioglioma (20-70%), pilocytic astrocytoma (PA; 9-10%), low-grade glioma (LGG; 5-15%), pediatric glioblastoma (pGBM; 20%), and adult GBM (3%).	('mutations', 'Var', (11, 20))	('described', 'Reg', (31, 40))	('V600E mutations', 'Var', (5, 20))	('adult GBM', 'Disease', (271, 280))	('glioma', 'Disease', (148, 154))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('PA', 'Disease', 'MESH:D001254', (188, 190))	('BRAF', 'Gene', (0, 4))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (165, 186))	('glioma', 'Disease', (210, 216))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('pilocytic astrocytoma', 'Disease', (165, 186))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('PXA', 'Disease', 'MESH:D008228', (127, 130))	('pediatric gliomas', 'Disease', 'MESH:D005910', (67, 84))	('ganglioglioma', 'Disease', 'MESH:D018303', (141, 154))	('glioblastoma', 'Disease', 'MESH:D005909', (241, 253))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('PXA', 'Disease', (127, 130))	('glioblastoma', 'Disease', (241, 253))	('V600E', 'Mutation', 'p.V600E', (5, 10))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (96, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (241, 253))	('pediatric gliomas', 'Disease', (67, 84))	('glioma', 'Disease', (77, 83))	('ganglioglioma', 'Disease', (141, 154))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('pleomorphic xanthoastrocytoma', 'Disease', (96, 125))
142194	31466300	BRAF mutations are exceedingly rare in ependymomas.	('ependymomas', 'Disease', 'MESH:D004806', (39, 50))	('ependymoma', 'Phenotype', 'HP:0002888', (39, 49))	('ependymomas', 'Disease', (39, 50))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', (0, 4))
142196	31466300	A subset of non-V600E mutations in BRAF activate MEK though dimerization but without a requirement for activation by RAS.	('BRAF', 'Gene', (35, 39))	('MEK', 'Gene', (49, 52))	('MEK', 'Gene', '5609', (49, 52))	('dimerization', 'MPA', (60, 72))	('V600E', 'Mutation', 'p.V600E', (16, 21))	('non-V600E', 'Var', (12, 21))	('activate', 'PosReg', (40, 48))
142197	31466300	These class II mutations undergo constitutive, RAS-independent dimerization, leading to increased ERK activation with low RAS activity due to negative feedback.	('mutations', 'Var', (15, 24))	('ERK', 'Gene', '5594', (98, 101))	('increased', 'PosReg', (88, 97))	('activation', 'PosReg', (102, 112))	('ERK', 'Gene', (98, 101))
142198	31466300	Common class II point mutations, such as K601E/N/T, L597Q/V, and G469A/V/R, have all been identified in glioma, but their relative frequency is unknown.	('identified', 'Reg', (90, 100))	('K601E', 'Var', (41, 46))	('L597Q', 'SUBSTITUTION', 'None', (52, 57))	('G469A', 'SUBSTITUTION', 'None', (65, 70))	('L597Q', 'Var', (52, 57))	('K601E', 'SUBSTITUTION', 'None', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('G469A', 'Var', (65, 70))	('glioma', 'Disease', (104, 110))
142199	31466300	In-frame deletions removing part of the beta3-alphaC loop have been identified in glioma and other tumors, leading to a shortened alphaC helix that is constrained into the active confirmation, preventing autoinhibition and resulting in increased kinase activity.	('shortened', 'NegReg', (120, 129))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('kinase activity', 'MPA', (246, 261))	('preventing', 'NegReg', (193, 203))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('glioma', 'Disease', (82, 88))	('increased', 'PosReg', (236, 245))	('deletions', 'Var', (9, 18))	('autoinhibition', 'MPA', (204, 218))	('beta3-alphaC', 'Chemical', 'MESH:C513342', (40, 52))	('alphaC helix', 'Protein', (130, 142))	('tumors', 'Disease', (99, 105))
142201	31466300	Fusion mutations are very common in low-grade glioma, where they are found in the majority of pilocytic astrocytoma.	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (94, 115))	('glioma', 'Disease', (46, 52))	('Fusion mutations', 'Var', (0, 16))	('common', 'Reg', (26, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('pilocytic astrocytoma', 'Disease', (94, 115))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
142205	31466300	These mutations have impaired, or sometimes absent (i.e., D594G), kinase activity.	('D594G', 'Var', (58, 63))	('impaired', 'NegReg', (21, 29))	('D594G', 'Mutation', 'p.D594G', (58, 63))	('absent', 'NegReg', (44, 50))	('kinase activity', 'MPA', (66, 81))
142206	31466300	Class III mutations are dependent on RAS and upstream input from receptor tyrosine kinases (RTKs), for their activity.	('mutations', 'Var', (10, 19))	('activity', 'MPA', (109, 117))	('tyrosine', 'Chemical', 'None', (74, 82))
142207	31466300	Class III mutants bind more tightly to activated RAS than does wild-type BRAF, leading to increased activation of the wild-type binding partner (BRAF, ARAF, or CRAF) upon dimerization.	('increased activation', 'PosReg', (90, 110))	('mutants', 'Var', (10, 17))	('ARAF', 'Gene', '369', (151, 155))	('CRAF', 'Gene', (160, 164))	('ARAF', 'Gene', (151, 155))	('CRAF', 'Gene', '5894', (160, 164))
142208	31466300	These amplifiers of ERK signaling often occur in conjunction with other mutations that increase upstream RAS activity, such as RAS mutations, NF1 loss, or RTK mutations or amplification.	('loss', 'NegReg', (146, 150))	('mutations', 'Var', (131, 140))	('RAS', 'Gene', (127, 130))	('NF1', 'Gene', '4763', (142, 145))	('increase', 'PosReg', (87, 95))	('mutations', 'Var', (159, 168))	('activity', 'MPA', (109, 117))	('ERK', 'Gene', (20, 23))	('ERK', 'Gene', '5594', (20, 23))	('upstream', 'MPA', (96, 104))	('NF1', 'Gene', (142, 145))	('RTK', 'Gene', (155, 158))
142209	31466300	Several class III mutations with impaired kinase function, such as G466E/A/V or G596D/R, have been identified in glioma, as has the kinase dead mutation D594G (Table 1).	('D594G', 'Var', (153, 158))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('G596D', 'SUBSTITUTION', 'None', (80, 85))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('D594G', 'Mutation', 'p.D594G', (153, 158))	('G466E', 'SUBSTITUTION', 'None', (67, 72))	('glioma', 'Disease', (113, 119))	('G596D', 'Var', (80, 85))	('G466E', 'Var', (67, 72))	('identified', 'Reg', (99, 109))
142210	31466300	Of the four class III mutations seen in the cBioPortal dataset, two have co-occurring homozygous deletion of NF1 and one has amplification of EGFR (ERBB1).	('EGFR', 'Gene', '1956', (142, 146))	('NF1', 'Gene', (109, 112))	('EGFR', 'Gene', (142, 146))	('NF1', 'Gene', '4763', (109, 112))	('ERBB1', 'Gene', '1956', (148, 153))	('mutations', 'Var', (22, 31))	('ERBB1', 'Gene', (148, 153))	('deletion', 'Var', (97, 105))
142211	31466300	Type I RAF inhibitors are ATP-competitive small molecules that selectively bind to and inhibit all RAF monomers, not only BRAF V600E.	('ATP', 'Chemical', 'MESH:D000255', (26, 29))	('RAF', 'Gene', (7, 10))	('V600E', 'Var', (127, 132))	('V600E', 'Mutation', 'p.V600E', (127, 132))	('bind', 'Interaction', (75, 79))	('RAF', 'Gene', '22882', (123, 126))	('RAF', 'Gene', '22882', (99, 102))	('RAF', 'Gene', (123, 126))	('RAF', 'Gene', (99, 102))	('RAF', 'Gene', '22882', (7, 10))	('inhibit', 'NegReg', (87, 94))
142212	31466300	These drugs are quite effective at inhibiting ERK in cells where ERK signaling is driven by BRAF V600E, and there are three FDA-approved inhibitors in this class for some systemic cancers: vemurafenib, dabrafenib, and encorafenib.	('vemurafenib', 'Chemical', 'MESH:C551177', (189, 200))	('ERK', 'Gene', '5594', (46, 49))	('ERK', 'Gene', (65, 68))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('encorafenib', 'Chemical', 'None', (218, 229))	('ERK', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('V600E', 'Mutation', 'p.V600E', (97, 102))	('systemic cancers', 'Disease', 'MESH:D009369', (171, 187))	('inhibiting', 'NegReg', (35, 45))	('driven by', 'Reg', (82, 91))	('BRAF V600E', 'Var', (92, 102))	('ERK', 'Gene', '5594', (65, 68))	('dabrafenib', 'Chemical', 'MESH:C561627', (202, 212))	('systemic cancers', 'Disease', (171, 187))
142215	31466300	Type I RAF inhibitors lead to increased ERK signaling in cells with wild-type RAF and non-V600E mutations by facilitating the formation of RAF dimers, particularly BRAF-CRAF heterodimers.	('non-V600E mutations', 'Var', (86, 105))	('V600E', 'Mutation', 'p.V600E', (90, 95))	('RAF', 'Gene', (170, 173))	('RAF', 'Gene', (139, 142))	('increased', 'PosReg', (30, 39))	('RAF', 'Gene', '22882', (7, 10))	('mutations', 'Var', (96, 105))	('ERK', 'Gene', '5594', (40, 43))	('RAF', 'Gene', '22882', (78, 81))	('RAF', 'Gene', (7, 10))	('RAF', 'Gene', '22882', (165, 168))	('formation', 'MPA', (126, 135))	('ERK', 'Gene', (40, 43))	('CRAF', 'Gene', (169, 173))	('RAF', 'Gene', (78, 81))	('RAF', 'Gene', (165, 168))	('RAF', 'Gene', '22882', (170, 173))	('facilitating', 'PosReg', (109, 121))	('CRAF', 'Gene', '5894', (169, 173))	('RAF', 'Gene', '22882', (139, 142))
142218	31466300	For this reason, type I RAF inhibitors should only be used in tumors with BRAF V600E mutations (Table 2).	('V600E', 'Var', (79, 84))	('V600E', 'Mutation', 'p.V600E', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RAF', 'Gene', '22882', (24, 27))	('RAF', 'Gene', (24, 27))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('RAF', 'Gene', '22882', (75, 78))	('RAF', 'Gene', (75, 78))
142222	31466300	One paradox breaker, PLX8394, is effective against class I and II BRAF mutations and also disrupts dimer formation as a means to inhibit ERK signaling.	('BRAF', 'Gene', (66, 70))	('PLX8394', 'Chemical', 'MESH:C581574', (21, 28))	('inhibit', 'NegReg', (129, 136))	('mutations', 'Var', (71, 80))	('ERK', 'Gene', '5594', (137, 140))	('ERK', 'Gene', (137, 140))	('disrupts', 'NegReg', (90, 98))	('dimer formation', 'MPA', (99, 114))	('PLX8394', 'Var', (21, 28))
142226	31466300	Dimer disrupters are potentially powerful inhibitors as they can interfere with signaling through wild-type RAF as well as mutant RAF.	('RAF', 'Gene', '22882', (108, 111))	('RAF', 'Gene', (108, 111))	('signaling', 'MPA', (80, 89))	('interfere', 'NegReg', (65, 74))	('RAF', 'Gene', (130, 133))	('mutant', 'Var', (123, 129))	('RAF', 'Gene', '22882', (130, 133))
142232	31466300	MEK inhibitor monotherapy leads to nondurable responses in patients with BRAF V600E-mutated melanoma.	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('V600E', 'Mutation', 'p.V600E', (78, 83))	('patients', 'Species', '9606', (59, 67))	('BRAF V600E-mutated', 'Var', (73, 91))
142235	31466300	MEK inhibitors can also be effective against other mutations that cause hyperactive ERK signaling.	('mutations', 'Var', (51, 60))	('ERK', 'Gene', '5594', (84, 87))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('ERK', 'Gene', (84, 87))	('hyperactive', 'Disease', 'MESH:D006948', (72, 83))	('hyperactive', 'Disease', (72, 83))
142236	31466300	By virtue of the fact that MEK is downstream of RAF, MEK inhibitors have potential efficacy against tumors with RAS mutations, type I or II BRAF mutations, RTK amplification or mutations, NF1 loss, and EGFR overexpression.	('EGFR', 'Gene', (202, 206))	('mutations', 'Var', (145, 154))	('mutations', 'Var', (177, 186))	('NF1', 'Gene', '4763', (188, 191))	('MEK', 'Gene', '5609', (53, 56))	('RAF', 'Gene', '22882', (141, 144))	('MEK', 'Gene', '5609', (27, 30))	('RAF', 'Gene', '22882', (48, 51))	('NF1', 'Gene', (188, 191))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('loss', 'NegReg', (192, 196))	('EGFR', 'Gene', '1956', (202, 206))	('MEK', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('MEK', 'Gene', (27, 30))	('amplification', 'Var', (160, 173))	('RAF', 'Gene', (48, 51))	('RAF', 'Gene', (141, 144))	('tumors', 'Disease', (100, 106))	('mutations', 'Var', (116, 125))	('overexpression', 'PosReg', (207, 221))	('RTK', 'Gene', (156, 159))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('RAS', 'Gene', (112, 115))
142239	31466300	ERK inhibitors have the potential to inhibit ERK signaling driven by class I, II, and III mutations, as well as other genomic events, by virtue of their direct inhibition of this central node in signaling.	('ERK', 'Gene', (45, 48))	('mutations', 'Var', (90, 99))	('inhibit', 'NegReg', (37, 44))	('inhibition', 'NegReg', (160, 170))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', '5594', (45, 48))	('ERK', 'Gene', (0, 3))
142243	31466300	MAPK/ERK pathway mutations have been identified in approximately 95% of pilocytic astrocytoma (PA).	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('ERK', 'Gene', '5594', (5, 8))	('ERK', 'Gene', (5, 8))	('pilocytic astrocytoma', 'Disease', (72, 93))	('PA', 'Disease', 'MESH:D001254', (95, 97))	('identified', 'Reg', (37, 47))	('mutations', 'Var', (17, 26))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (72, 93))
142244	31466300	The most common mutation in PA is the KIAA1549-BRAF fusion, which occurs in approximately 60-70% of PA. Fusions between BRAF and other proteins have been identified less frequently in PA (Table 1).	('Fusions', 'Var', (104, 111))	('PA', 'Disease', 'MESH:D001254', (100, 102))	('PA', 'Disease', 'MESH:D001254', (184, 186))	('KIAA1549', 'Gene', '57670', (38, 46))	('proteins', 'Protein', (135, 143))	('KIAA1549', 'Gene', (38, 46))	('BRAF', 'Gene', (120, 124))	('PA', 'Disease', 'MESH:D001254', (28, 30))
142246	31466300	Given the high frequency of fusions in PA, type II RAF inhibitors, specifically the dimer disrupter TAK-580, are being tested in this population (Table 3).	('fusions', 'Var', (28, 35))	('RAF', 'Gene', '22882', (51, 54))	('PA', 'Disease', 'MESH:D001254', (39, 41))	('RAF', 'Gene', (51, 54))
142247	31466300	The class I BRAF V600E mutation has been identified in approximately 10% of PA and is mutually exclusive with BRAF fusions.	('PA', 'Disease', 'MESH:D001254', (76, 78))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', (12, 16))	('V600E', 'Mutation', 'p.V600E', (17, 22))
142248	31466300	BRAF V600E-mutated PA appears to be associated with an inferior prognosis compared to PA with wild-type BRAF, which may be due to the fact that class I mutations are such strong drivers of ERK signaling and correlate with the relative absence of BRAF fusions in high-grade glioma.	('V600E-mutated', 'Var', (5, 18))	('mutations', 'Var', (152, 161))	('PA', 'Disease', 'MESH:D001254', (86, 88))	('glioma', 'Disease', (273, 279))	('PA', 'Disease', 'MESH:D001254', (19, 21))	('V600E', 'Mutation', 'p.V600E', (5, 10))	('ERK', 'Gene', '5594', (189, 192))	('BRAF', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (273, 279))	('glioma', 'Phenotype', 'HP:0009733', (273, 279))	('ERK', 'Gene', (189, 192))
142251	31466300	A phase II study of selumetinib in pediatric patients with pilocytic astrocytoma containing either KIAA1549-BRAF or BRAF V600E showed a sustained response rate of 36% (9/25).	('KIAA1549', 'Gene', '57670', (99, 107))	('V600E', 'Var', (121, 126))	('KIAA1549', 'Gene', (99, 107))	('V600E', 'Mutation', 'p.V600E', (121, 126))	('pilocytic astrocytoma', 'Disease', (59, 80))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('patients', 'Species', '9606', (45, 53))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (59, 80))	('selumetinib', 'Chemical', 'MESH:C517975', (20, 31))	('BRAF', 'Var', (116, 120))
142253	31466300	Interestingly, both types of BRAF mutation were responsive to selumetinib, though the response rate may be higher in tumors with BRAF fusions rather than those with BRAF V600E mutations.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('selumetinib', 'Chemical', 'MESH:C517975', (62, 73))	('mutation', 'Var', (34, 42))	('fusions', 'Var', (134, 141))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('V600E', 'Mutation', 'p.V600E', (170, 175))	('BRAF', 'Var', (129, 133))	('higher', 'PosReg', (107, 113))	('response', 'MPA', (86, 94))
142255	31466300	While pediatric low-grade gliomas (pLGG) have relatively few mutations overall, 82% have a mutation in the ERK signaling pathway.	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (107, 110))	('mutation', 'Var', (91, 99))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
142258	31466300	Pediatric oligodendroglioma, which occur only rarely, have also been identified to harbor KIAA1549-BRAF fusions, suggesting they are different from their adult counterparts.	('Pediatric oligodendroglioma', 'Disease', (0, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('KIAA1549', 'Gene', (90, 98))	('Pediatric oligodendroglioma', 'Disease', 'MESH:D009837', (0, 27))	('KIAA1549', 'Gene', '57670', (90, 98))	('fusions', 'Var', (104, 111))
142259	31466300	Pediatric glioblastoma have BRAF mutations in approximately 10-20% of cases.	('Pediatric glioblastoma', 'Disease', (0, 22))	('Pediatric glioblastoma', 'Disease', 'MESH:D005909', (0, 22))	('mutations', 'Var', (33, 42))	('BRAF', 'Gene', (28, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
142260	31466300	In contrast to low-grade glioma, BRAF V600E in pGBM appears to confer a more indolent clinical course compared to pGBM with wild-type BRAF.	('pGBM', 'Gene', (47, 51))	('V600E', 'Mutation', 'p.V600E', (38, 43))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('BRAF V600E', 'Var', (33, 43))	('glioma', 'Disease', (25, 31))
142261	31466300	One study investigating the genetics of secondary GBM found 39% of secondary GBM contained BRAF V600E mutations, while none contained BRAF fusions or IDH1 mutations, suggesting BRAF V600E either permits or promotes malignant transformation.	('V600E', 'Mutation', 'p.V600E', (182, 187))	('V600E', 'Mutation', 'p.V600E', (96, 101))	('malignant transformation', 'CPA', (215, 239))	('promotes', 'PosReg', (206, 214))	('mutations', 'Var', (102, 111))	('BRAF V600E', 'Var', (177, 187))	('IDH1', 'Gene', (150, 154))	('secondary GBM', 'Disease', (67, 80))	('BRAF V600E', 'Gene', (91, 101))	('permits', 'PosReg', (195, 202))	('IDH1', 'Gene', '3417', (150, 154))
142267	31466300	The interim analysis of a clinical trial administering dabrafenib to children with BRAF V600-mutated relapsed or refractory LGG found a RR of 41%, with another 41% of patients maintaining stable disease for six months or longer.	('relapsed', 'Disease', (101, 109))	('dabrafenib', 'Chemical', 'MESH:C561627', (55, 65))	('patients', 'Species', '9606', (167, 175))	('V600-mutated', 'Var', (88, 100))	('BRAF', 'Gene', (83, 87))	('children', 'Species', '9606', (69, 77))
142272	31466300	BRAF V600E-mutated LGG in young adults are associated with a better clinical course than BRAF wild-type LGG.	('V600E', 'Mutation', 'p.V600E', (5, 10))	('BRAF V600E-mutated', 'Var', (0, 18))	('V600E-mutated', 'Var', (5, 18))	('LGG', 'Gene', (19, 22))
142275	31466300	The effect of BRAF V600E mutations on the clinical course of GBM in adults is unclear and has not been sufficiently studied to date, primarily given the rarity of these tumors.	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('V600E', 'Var', (19, 24))	('V600E', 'Mutation', 'p.V600E', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BRAF', 'Gene', (14, 18))	('tumors', 'Disease', (169, 175))
142276	31466300	In young adults (aged 18-35), BRAF V600E mutations are associated with improved overall survival compared with wild type.	('V600E', 'Var', (35, 40))	('V600E', 'Mutation', 'p.V600E', (35, 40))	('BRAF', 'Gene', (30, 34))	('overall', 'MPA', (80, 87))	('improved', 'PosReg', (71, 79))
142278	31466300	In a basket study of vemurafenib in adults with BRAF V600E-mutated gliomas, the response rate of adults with PXA was high (43%; 3/7) and similar to pediatric patients, but the response rate in GBM and anaplastic astrocytoma was much lower at 9% (1/11).	('astrocytoma', 'Disease', 'MESH:D001254', (212, 223))	('astrocytoma', 'Disease', (212, 223))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('astrocytoma', 'Phenotype', 'HP:0009592', (212, 223))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('gliomas', 'Disease', (67, 74))	('PXA', 'Disease', (109, 112))	('V600E', 'Mutation', 'p.V600E', (53, 58))	('BRAF V600E-mutated', 'Var', (48, 66))	('PXA', 'Disease', 'MESH:D008228', (109, 112))	('patients', 'Species', '9606', (158, 166))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('vemurafenib', 'Chemical', 'MESH:C551177', (21, 32))
142284	31466300	Pleomorphic xanthoastrocytoma (PXA) are rare but have a high rate of BRAF V600E mutations (~70%) and a low rate of fusions.	('PXA', 'Disease', 'MESH:D008228', (31, 34))	('mutations', 'Var', (80, 89))	('Pleomorphic xanthoastrocytoma', 'Disease', (0, 29))	('V600E', 'Mutation', 'p.V600E', (74, 79))	('astrocytoma', 'Phenotype', 'HP:0009592', (18, 29))	('Pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (0, 29))	('PXA', 'Disease', (31, 34))	('BRAF', 'Gene', (69, 73))
142285	31466300	BRAF V600E mutations are associated with improved overall and progression-free survival in both grade II and grade III PXA.	('improved', 'PosReg', (41, 49))	('progression-free survival', 'CPA', (62, 87))	('PXA', 'Disease', (119, 122))	('grade II', 'Disease', (96, 104))	('V600E', 'Var', (5, 10))	('PXA', 'Disease', 'MESH:D008228', (119, 122))	('V600E', 'Mutation', 'p.V600E', (5, 10))	('BRAF', 'Gene', (0, 4))
142289	31466300	BRAF V600E mutations are common in ganglioglioma, occurring in approximately 50%.	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('V600E', 'Var', (5, 10))	('V600E', 'Mutation', 'p.V600E', (5, 10))	('ganglioglioma', 'Disease', (35, 48))	('BRAF', 'Gene', (0, 4))	('ganglioglioma', 'Disease', 'MESH:D018303', (35, 48))
142291	31466300	In pediatric patients with grade I gangliogliomas, several cases have been identified with both H3 K27M and BRAF V600E mutations.	('K27M', 'Mutation', 'p.K27M', (99, 103))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('patients', 'Species', '9606', (13, 21))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gangliogliomas', 'Disease', (35, 49))	('H3 K27M', 'Var', (96, 103))	('gangliogliomas', 'Disease', 'MESH:D018303', (35, 49))	('BRAF', 'Gene', (108, 112))	('V600E', 'Mutation', 'p.V600E', (113, 118))
142292	31466300	Some of these patients were observed to have a relatively indolent disease course despite the H3 K27M mutation (40%), suggesting these tumors may not behave as aggressively as diffuse midline glioma, K3 K27M mutant.	('midline glioma', 'Disease', 'MESH:D005910', (184, 198))	('midline glioma', 'Disease', (184, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('K3 K27M', 'Var', (200, 207))	('K27M', 'Mutation', 'p.K27M', (203, 207))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('K27M', 'Mutation', 'p.K27M', (97, 101))	('patients', 'Species', '9606', (14, 22))
142306	31466300	Mechanisms of resistance to RAF inhibitor monotherapy often involve maintenance of ERK addiction through upregulation of other pathway activators, either upstream or downstream of mutant BRAF.	('RAF', 'Gene', (28, 31))	('ERK', 'Gene', (83, 86))	('upregulation', 'PosReg', (105, 117))	('RAF', 'Gene', '22882', (28, 31))	('mutant', 'Var', (180, 186))	('RAF', 'Gene', '22882', (188, 191))	('RAF', 'Gene', (188, 191))	('ERK', 'Gene', '5594', (83, 86))
142308	31466300	Emergent mutations in NRAS or loss of function mutations in NF1 can increase activation and dimerization of RAF kinases.	('RAF', 'Gene', '22882', (108, 111))	('RAF', 'Gene', (108, 111))	('loss of function', 'NegReg', (30, 46))	('mutations', 'Var', (9, 18))	('NF1', 'Gene', (60, 63))	('NRAS', 'Gene', (22, 26))	('mutations', 'Var', (47, 56))	('NF1', 'Gene', '4763', (60, 63))	('dimerization', 'MPA', (92, 104))	('increase', 'PosReg', (68, 76))	('NRAS', 'Gene', '4893', (22, 26))	('activation', 'MPA', (77, 87))
142311	31466300	The mechanism of acquired resistance to dabrafenib in one pediatric glioma was identified as a novel in cis mutation in BRAF (BRAF V600E L514V), which, upon biochemical characterization, was found to enhance dimerization, thereby decreasing sensitivity to dabrafenib.	('L514V', 'Var', (137, 142))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('L514V', 'SUBSTITUTION', 'None', (137, 142))	('pediatric glioma', 'Disease', 'MESH:D005910', (58, 74))	('V600E', 'Var', (131, 136))	('dabrafenib', 'Chemical', 'MESH:C561627', (40, 50))	('dabrafenib', 'Chemical', 'MESH:C561627', (256, 266))	('dimerization', 'MPA', (208, 220))	('decreasing', 'NegReg', (230, 240))	('sensitivity to dabrafenib', 'MPA', (241, 266))	('pediatric glioma', 'Disease', (58, 74))	('V600E', 'SUBSTITUTION', 'None', (131, 136))	('enhance', 'PosReg', (200, 207))
142313	31466300	BRAF mutations, particularly the V600E mutation and KIAA1549-BRAF fusions, are present in a significant subset of primary brain tumors.	('primary brain tumors', 'Disease', 'MESH:D001932', (114, 134))	('primary brain tumors', 'Disease', (114, 134))	('brain tumors', 'Phenotype', 'HP:0030692', (122, 134))	('V600E', 'Var', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('V600E', 'Mutation', 'p.V600E', (33, 38))	('KIAA1549', 'Gene', '57670', (52, 60))	('brain tumor', 'Phenotype', 'HP:0030692', (122, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('KIAA1549', 'Gene', (52, 60))
142315	31466300	Based on our current understanding of the mechanism by which different BRAF mutations activate ERK signaling, sensitivity to type I RAF inhibitors is mutation-dependent and limited to BRAF V600E mutant tumors.	('V600E', 'Mutation', 'p.V600E', (189, 194))	('mutations', 'Var', (76, 85))	('RAF', 'Gene', '22882', (185, 188))	('ERK', 'Gene', '5594', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('RAF', 'Gene', (185, 188))	('RAF', 'Gene', (72, 75))	('RAF', 'Gene', '22882', (132, 135))	('tumors', 'Disease', (202, 208))	('ERK', 'Gene', (95, 98))	('RAF', 'Gene', (132, 135))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('activate', 'PosReg', (86, 94))	('RAF', 'Gene', '22882', (72, 75))	('V600E', 'Var', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
142319	31466300	For class II or III mutations, including BRAF-fusions, preclinical data and data in other cancers clearly support the inefficacy of type I RAF inhibitors.	('cancers', 'Disease', (90, 97))	('RAF', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RAF', 'Gene', '22882', (42, 45))	('RAF', 'Gene', '22882', (139, 142))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('RAF', 'Gene', (139, 142))	('mutations', 'Var', (20, 29))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
142320	31466300	In tumors with these mutations, novel RAF inhibitors that prevent paradoxical activation, those that disrupt BRAF dimerization, or small molecule inhibitors targeting MEK or ERK may have potential.	('MEK', 'Gene', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('MEK', 'Gene', '5609', (167, 170))	('RAF', 'Gene', '22882', (38, 41))	('RAF', 'Gene', (110, 113))	('RAF', 'Gene', (38, 41))	('paradoxical activation', 'MPA', (66, 88))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('ERK', 'Gene', '5594', (174, 177))	('RAF', 'Gene', '22882', (110, 113))	('ERK', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('dimerization', 'MPA', (114, 126))	('mutations', 'Var', (21, 30))
142321	31466300	In patients with these mutations, RAF-targeted therapy should only be considered in the setting of a clinical trial.	('mutations', 'Var', (23, 32))	('RAF', 'Gene', '22882', (34, 37))	('patients', 'Species', '9606', (3, 11))	('RAF', 'Gene', (34, 37))
142323	31466300	Whether BRAF mutations are present in all cells in a glioma or only a subset of tumor cells remains controversial and certainly has the potential to affect tumor response to targeted therapy.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('glioma', 'Disease', (53, 59))	('affect', 'Reg', (149, 155))	('BRAF', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('mutations', 'Var', (13, 22))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
142325	31466300	In summary, knowledge of the specific BRAF mutation and its biochemical effects on ERK signaling are critical for determining whether a patient could benefit from RAF-targeted therapy.	('patient', 'Species', '9606', (136, 143))	('ERK', 'Gene', (83, 86))	('mutation', 'Var', (43, 51))	('RAF', 'Gene', '22882', (163, 166))	('RAF', 'Gene', (163, 166))	('RAF', 'Gene', '22882', (39, 42))	('RAF', 'Gene', (39, 42))	('ERK', 'Gene', '5594', (83, 86))
142327	29487022	Methylation of PD-1 Promoter Gene as New Prognostic Marker for IDH Mutant Low-Grade Glioma?	('PD-1', 'Gene', '5133', (15, 19))	('IDH', 'Gene', (63, 66))	('Methylation', 'Var', (0, 11))	('PD-1', 'Gene', (15, 19))	('IDH', 'Gene', '3417', (63, 66))	('Glioma', 'Disease', 'MESH:D005910', (84, 90))	('Glioma', 'Phenotype', 'HP:0009733', (84, 90))	('Glioma', 'Disease', (84, 90))
142329	29487022	used a set of 419 low-grade glioma (LGG) patients from the TCGA database whose tumors showed a mutation in the isocitrate dehydrogenase 1 or 2 (IDHmt) to demonstrate that the promoters of the immune checkpoint genes PD-1, PD-L1, PD-L2 and CTLA-4 are differentially methylated within IDH mutated low-grade gliomas (LGG).	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('gliomas', 'Disease', (305, 312))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('glioma', 'Disease', (305, 311))	('glioma', 'Disease', 'MESH:D005910', (305, 311))	('IDH', 'Gene', (144, 147))	('PD-1', 'Gene', (216, 220))	('PD-1', 'Gene', '5133', (216, 220))	('PD-L1', 'Gene', (222, 227))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('gliomas', 'Disease', 'MESH:D005910', (305, 312))	('tumors', 'Disease', (79, 85))	('PD-L1', 'Gene', '29126', (222, 227))	('glioma', 'Phenotype', 'HP:0009733', (305, 311))	('mutation', 'Var', (95, 103))	('PD-L2', 'Gene', '80380', (229, 234))	('IDH', 'Gene', '3417', (144, 147))	('CTLA-4', 'Gene', '1493', (239, 245))	('gliomas', 'Phenotype', 'HP:0009733', (305, 312))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('IDH', 'Gene', (283, 286))	('CTLA-4', 'Gene', (239, 245))	('PD-L2', 'Gene', (229, 234))	('IDH', 'Gene', '3417', (283, 286))	('glioma', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
142330	29487022	The authors showed that methylation of the PD-1 promoter provides a significant survival gain in patients with LGG (HR = 0.44 [0.30-0.66], p < .001) in combination with age (HR 3.83 [2.04-7.17], p < .001, whereas methylation of the promoters of the other immune checkpoint genes did not show prognostic impact.	('PD-1', 'Gene', '5133', (43, 47))	('PD-1', 'Gene', (43, 47))	('gain', 'PosReg', (89, 93))	('methylation', 'Var', (24, 35))	('LGG', 'Disease', (111, 114))	('survival', 'CPA', (80, 88))	('patients', 'Species', '9606', (97, 105))
142331	29487022	High PD-1 expression on the immune cells infiltrating the LGG is a marker for immune evasion, whereas PD-1 promoter methylation might promote active anti-glioma immune responses.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('PD-1', 'Gene', (102, 106))	('promote', 'PosReg', (134, 141))	('promoter methylation', 'Var', (107, 127))	('immune evasion', 'MPA', (78, 92))	('PD-1', 'Gene', '5133', (102, 106))	('expression', 'MPA', (10, 20))	('glioma', 'Disease', (154, 160))	('PD-1', 'Gene', (5, 9))	('PD-1', 'Gene', '5133', (5, 9))
142332	29487022	There are methodological weak points related to the relatively low number of CPG sites for each of the genes examined such as on lacking correlations with known prognostic markers like 1p19q deletion and on the short follow-up of 24 months for LGG patients.	('patients', 'Species', '9606', (248, 256))	('1p19q deletion', 'Var', (185, 199))	('LGG', 'Disease', (244, 247))	('correlations', 'Interaction', (137, 149))
142333	29487022	The prognostic effect of PD-1 methylation is strong enough to be highly significant as early as after 2 years of follow-up.	('PD-1', 'Gene', '5133', (25, 29))	('methylation', 'Var', (30, 41))	('PD-1', 'Gene', (25, 29))
142337	29487022	showed that methylation of four DNA damage response genes predicts benefit from chemotherapy in IDHmt LGG.	('methylation', 'Var', (12, 23))	('benefit', 'PosReg', (67, 74))	('IDH', 'Gene', '3417', (96, 99))	('IDH', 'Gene', (96, 99))
142349	29487022	Potential advances besides the exploitation of immune-based strategies could include strategies against IDH-mutated cells as IDH mutation constitutes a very early event in the development of LGG, including either "repair" or bypassing of the mutation, or inhibition of the formation of the oncometabolite 2-hydroglutarate.	('IDH', 'Gene', (104, 107))	('mutation', 'Var', (129, 137))	('IDH', 'Gene', '3417', (104, 107))	('2-hydroglutarate', 'Chemical', '-', (305, 321))	('IDH', 'Gene', (125, 128))	('LGG', 'Disease', (191, 194))	('IDH', 'Gene', '3417', (125, 128))	('bypassing', 'Var', (225, 234))	('inhibition', 'Var', (255, 265))
142451	26208906	Emerging evidence has indicated that lncRNAs contribute to tumor initiation and progression through diverse mechanisms ranging from epigenetic regulation of key cancer genes and enhancer-associated activity to post-transcriptional processing of mRNAs.	('tumor initiation', 'Disease', 'MESH:D009369', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor initiation', 'Disease', (59, 75))	('epigenetic', 'Var', (132, 142))	('enhancer-associated', 'PosReg', (178, 197))	('lncRNAs', 'Protein', (37, 44))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('progression', 'CPA', (80, 91))	('contribute', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
142521	22662319	Deregulation of Ion Channel and Transporter Encoding Genes in Pediatric Gliomas Brain tumors, including the majority gliomas, are the leading cause of cancer-related death in children.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('Brain tumors', 'Phenotype', 'HP:0030692', (80, 92))	('Deregulation', 'Var', (0, 12))	('Brain tumors', 'Disease', (80, 92))	('Pediatric Gliomas', 'Disease', 'MESH:D005910', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Brain tumors', 'Disease', 'MESH:D001932', (80, 92))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('children', 'Species', '9606', (175, 183))	('Pediatric Gliomas', 'Disease', (62, 79))
142537	22662319	Gene mutations, copy number aberrations, structural rearrangements, or deregulation of the transcriptome have been shown to contribute to the development of brain tumors and currently play an integral role in their classification (Mischel et al.,; Dubuc et al.,).	('transcriptome', 'MPA', (91, 104))	('brain tumors', 'Disease', 'MESH:D001932', (157, 169))	('brain tumors', 'Phenotype', 'HP:0030692', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('copy number aberrations', 'Var', (16, 39))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('deregulation', 'MPA', (71, 83))	('brain tumors', 'Disease', (157, 169))	('brain tumor', 'Phenotype', 'HP:0030692', (157, 168))	('structural rearrangements', 'Var', (41, 66))	('contribute', 'Reg', (124, 134))
142606	22662319	While downregulation of ion channels may decrease the functioning of glial cells (Verkhratsky and Steinhauser,), deregulation of gene encoding transporters might have more complex consequences, contributing to multidrug resistance (Carboni et al.,; Lee et al.,; Chen et al.,), and/or enhanced cytotoxicity (Wakaumi et al.,; Blair et al.,).	('cytotoxicity', 'Disease', 'MESH:D064420', (293, 305))	('decrease', 'NegReg', (41, 49))	('functioning of glial cells', 'CPA', (54, 80))	('contributing', 'Reg', (194, 206))	('downregulation', 'NegReg', (6, 20))	('multidrug', 'MPA', (210, 219))	('deregulation', 'Var', (113, 125))	('enhanced', 'PosReg', (284, 292))	('cytotoxicity', 'Disease', (293, 305))
142641	30419305	Secondary objectives were to estimate PFS, event-free survival (EFS), and OS for patients treated with reduced-field CRT and to determine whether a high MIB-1 labeling index (LI) was correlated with shortened PFS and OS in these patients.	('OS', 'Chemical', '-', (217, 219))	('MIB-1', 'Gene', '57534', (153, 158))	('patients', 'Species', '9606', (229, 237))	('PFS', 'MPA', (209, 212))	('shortened', 'NegReg', (199, 208))	('patients', 'Species', '9606', (81, 89))	('high', 'Var', (148, 152))	('OS', 'Chemical', '-', (74, 76))	('MIB-1', 'Gene', (153, 158))
142734	30419305	However, young children and those receiving a high dose to the left temporal lobe/hippocampus experienced a significant decline in neurocognitive outcomes.	('high dose to', 'Var', (46, 58))	('neurocognitive outcomes', 'MPA', (131, 154))	('decline', 'NegReg', (120, 127))	('children', 'Species', '9606', (15, 23))
142761	30987208	Western blotting showed that treatment with LiCl or small molecule GSK-3 inhibitors led to the rapid downregulation of detergent soluble vimentin levels across a panel of GBM-derived cells.	('downregulation', 'NegReg', (101, 115))	('GSK-3', 'Gene', '56637', (67, 72))	('detergent soluble vimentin levels', 'MPA', (119, 152))	('LiCl', 'Chemical', 'MESH:D018021', (44, 48))	('GSK-3', 'Gene', (67, 72))	('inhibitors', 'Var', (73, 83))
142778	30987208	Here we show that LiCl and BIO, which block GBM cell migration, both affect the dynamic regulation of vimentin in GBM cells, and that vimentin knockdown partially blocks GBM migration.	('affect', 'Reg', (69, 75))	('GBM migration', 'CPA', (170, 183))	('vimentin', 'Protein', (102, 110))	('LiCl', 'Chemical', 'MESH:D018021', (18, 22))	('blocks', 'NegReg', (163, 169))	('knockdown', 'Var', (143, 152))	('dynamic regulation of', 'MPA', (80, 101))
142813	30987208	These data identify a novel relationship between GSK-3 and vimentin for the first time and suggest that alterations in vimentin dynamics may contribute to the inhibition of GBM cell migration in response to LiCl and BIO.	('alterations', 'Var', (104, 115))	('relationship', 'Interaction', (28, 40))	('GBM cell migration', 'CPA', (173, 191))	('LiCl', 'Chemical', 'MESH:D018021', (207, 211))	('GSK-3', 'Gene', (49, 54))	('vimentin', 'Protein', (119, 127))	('GSK-3', 'Gene', '56637', (49, 54))	('response to LiCl', 'MPA', (195, 211))	('inhibition', 'NegReg', (159, 169))
142816	30987208	Specifically, we establish that (1) GSK-3 regulates vimentin dynamics, (2) GSK-3 interacts with and phosphorylates vimentin, (3) vimentin facilitates GBM cell migration, and (4) vimentin is highly expressed in GBM patient specimens, and is prognostic, particularly in lower grade gliomas.	('patient', 'Species', '9606', (214, 221))	('GSK-3', 'Gene', '56637', (36, 41))	('GSK-3', 'Gene', '56637', (75, 80))	('vimentin dynamics', 'MPA', (52, 69))	('gliomas', 'Disease', 'MESH:D005910', (280, 287))	('facilitates', 'PosReg', (138, 149))	('gliomas', 'Disease', (280, 287))	('vimentin', 'Var', (129, 137))	('GSK-3', 'Gene', (36, 41))	('gliomas', 'Phenotype', 'HP:0009733', (280, 287))	('GBM cell migration', 'CPA', (150, 168))	('GSK-3', 'Gene', (75, 80))	('glioma', 'Phenotype', 'HP:0009733', (280, 286))
142842	30987208	Antibodies used for Western blotting were: mouse anti-vimentin V9 (MS-129-P, Thermo Scientific, (Waltham, MA, USA) mouse anti-GSK-3alphabeta (368662, EMD Millipore), mouse anti-alpha-tubulin (T6074, Sigma-Aldrich, St. Louis, MO, USA), mouse anti-GAPDH (ab9484-200, Abcam, Cambridge, MA, USA) and peroxidase-conjugated secondary antibodies (Jackson Laboratories, Bar Harbor, ME, USA).	('ab9484-200', 'Var', (253, 263))	('GSK-3alpha', 'Gene', '2931', (126, 136))	('GSK-3alpha', 'Gene', (126, 136))	('mouse', 'Species', '10090', (115, 120))	('mouse', 'Species', '10090', (166, 171))	('GAPDH', 'Gene', '2597', (246, 251))	('mouse', 'Species', '10090', (235, 240))	('GAPDH', 'Gene', (246, 251))	('mouse', 'Species', '10090', (43, 48))
142851	30987208	Co-localization of GSK-3 with vimentin was assayed on the same microscope system; U251 cells were transiently transfected with pcDNA4TO/CFP-hVimentin (NM_003380) and pcDNA4TO/YFP-GSK-3alpha/beta plasmids.	('GSK-3', 'Gene', (179, 184))	('GSK-3', 'Gene', '56637', (19, 24))	('hVimentin', 'Gene', (140, 149))	('GSK-3alpha', 'Gene', '2931', (179, 189))	('GSK-3', 'Gene', '56637', (179, 184))	('NM_003380', 'Var', (151, 160))	('GSK-3', 'Gene', (19, 24))	('hVimentin', 'Gene', '7431', (140, 149))	('GSK-3alpha', 'Gene', (179, 189))	('U251', 'CellLine', 'CVCL:0021', (82, 86))
142857	30987208	Knockdown of vimentin impairs GBM migration and its dynamics appear to be altered by LiCl treatment.	('LiCl', 'Chemical', 'MESH:D018021', (85, 89))	('Knockdown', 'Var', (0, 9))	('vimentin', 'Protein', (13, 21))	('GBM migration', 'CPA', (30, 43))	('impairs', 'NegReg', (22, 29))
142859	30987208	The following are available online at , Figure S1: (a) The mRNA levels of vimentin collected from the TCGA database, Levels of transcript are presented as Fragments Per Kilobase of exon per Million reads (FPKM), Figure S2: The small subset of tissues for vimentin and labeled with DAB, Figure S3: LiCl and BIO Treated GBM cells reduces cell motility.	('LiCl', 'Chemical', 'MESH:D018021', (297, 301))	('LiCl', 'Var', (297, 301))	('DAB', 'Chemical', 'MESH:C000469', (281, 284))	('cell motility', 'CPA', (336, 349))	('reduces', 'NegReg', (328, 335))
142864	30675227	Human reference DNA and samples were labeled using Cy3 cytidine 5'-triphosphate (CTP) and Cy5 CTP, respectively, while human Cot-1 DNA was used to reduce non-specific binding.	('Cy5 CTP', 'Var', (90, 97))	('Human', 'Species', '9606', (0, 5))	('CTP', 'Chemical', 'MESH:D003570', (94, 97))	('Cy3', 'Var', (51, 54))	("Cy3 cytidine 5'-triphosphate", 'Chemical', '-', (51, 79))	('Cy5 CTP', 'Chemical', '-', (90, 97))	('CTP', 'Chemical', 'MESH:D003570', (81, 84))	('human', 'Species', '9606', (119, 124))
142868	30675227	However, the most interesting result was from the next generation sequencing, where one anaplastic oligodendroglioma sample was demonstrated to have five novel fusion genes that may potentially serve a critical role in tumor pathogenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('serve', 'Reg', (194, 199))	('tumor', 'Disease', (219, 224))	('anaplastic oligodendroglioma', 'Disease', (88, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('fusion genes', 'Var', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (88, 116))
142877	30675227	This is particularly the case for oligodendrogliomas that have their own unique set of alterations, with the most notable being the loss of heterozygosity (LOH) on chromosomal arms 1p/19q.	('arms 1p', 'Gene', '3075', (176, 183))	('loss', 'NegReg', (132, 136))	('alterations', 'Reg', (87, 98))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (34, 52))	('arms 1p', 'Gene', (176, 183))	('chromosomal', 'Var', (164, 175))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('oligodendrogliomas', 'Disease', (34, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))
142878	30675227	LOH 1p/19q has emerged as an independent predictive marker of an improved response to radio- and chemotherapy in addition to prolonged overall survival in anaplastic oligodendrglioma.	('LOH 1p/19q', 'Var', (0, 10))	('anaplastic oligodendrglioma', 'Disease', 'MESH:D002277', (155, 182))	('improved', 'PosReg', (65, 73))	('anaplastic oligodendrglioma', 'Disease', (155, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('prolonged', 'PosReg', (125, 134))
142879	30675227	Combined with the status of isocitrate dehydrogenase 1 and 2 and tumor protein p53 (TP53) mutations, the prognosis and diagnosis of distinct subgroups of gliomas has become dependent on these genetic alterations due to their functions in these tumor types.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('mutations', 'Var', (90, 99))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (244, 249))	('TP53', 'Gene', '7157', (84, 88))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', (154, 161))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('TP53', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
142899	30675227	The CytoSure Genomic DNA aCGH labeling kit (Agilent Technologies, Inc.) was used to label the reference and tumor DNA with Cy-3 and Cy-5 respectively.	('Cy', 'Chemical', 'MESH:D003545', (4, 6))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Cy', 'Chemical', 'MESH:D003545', (132, 134))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Cy-3', 'Var', (123, 127))	('tumor', 'Disease', (108, 113))	('Cy-5', 'Var', (132, 136))	('Cy', 'Chemical', 'MESH:D003545', (123, 125))
142910	30675227	Based on the examination of sample 193, notable deletions in the majority of the chromosomes associated with amplifications were identified in the tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('deletions', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
142913	30675227	This included deletions in genes involved in the regulation of type I interferon-mediated signaling pathway, T-cell activation, complement activation of the classical pathway, circulating immunoglobulin complexes, immunoglobulin receptor binding and antigen binding.	('type I interferon-mediated signaling pathway', 'Pathway', (63, 107))	('immunoglobulin receptor', 'Gene', (214, 237))	('T-cell', 'CPA', (109, 115))	('antigen binding', 'Interaction', (250, 265))	('deletions', 'Var', (14, 23))	('circulating', 'MPA', (176, 187))	('immunoglobulin receptor', 'Gene', '80739', (214, 237))
142926	30675227	The aCGH results revealed that the most common deletion present in oligodendroglioma samples were on chromosomes 1p followed by 19q.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('oligodendroglioma', 'Disease', (67, 84))	('deletion', 'Var', (47, 55))	('oligodendroglioma', 'Disease', 'MESH:D009837', (67, 84))
142933	30675227	This included deletions in genes involved in the regulation of the type I interferon-mediated signaling pathway, T-cell activation, complement activation of the classical pathway, circulating immunoglobulin complexes, immunoglobulin receptor binding and antigen binding.	('deletions', 'Var', (14, 23))	('immunoglobulin receptor', 'Gene', '80739', (218, 241))	('immunoglobulin receptor', 'Gene', (218, 241))	('antigen binding', 'Interaction', (254, 269))
142935	30675227	NGS analysis revealed 5 novel fusion genes in sample 193 (anaplastic oligodendroglioma).	('anaplastic oligodendroglioma', 'Disease', (58, 86))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (58, 86))	('fusion genes', 'Var', (30, 42))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
142936	30675227	To the best of our knowledge, this is the first study to have identified the presence of 5 novel fusion genes in one anaplastic oligodendroglioma sample with 3 intra-chromosomal and 2 inter-chromosomal fusions.	('anaplastic oligodendroglioma', 'Disease', (117, 145))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (117, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('fusion', 'Var', (97, 103))
142937	30675227	Fusion genes are not uncommon in gliomas.	('Fusion genes', 'Var', (0, 12))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
142941	30675227	A mutation in the BRAF gene has been observed in a number of cancer types, and is not exclusive to gliomas.	('mutation', 'Var', (2, 10))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('observed', 'Reg', (37, 45))	('cancer', 'Disease', (61, 67))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('BRAF', 'Gene', '673', (18, 22))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BRAF', 'Gene', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
142948	30675227	Therefore, it is likely that a fusion between the ARID4B and GNG4 genes has a role in the signaling pathway that regulates DNA methylation.	('ARID4B', 'Gene', (50, 56))	('DNA methylation', 'MPA', (123, 138))	('signaling pathway', 'Pathway', (90, 107))	('GNG4', 'Gene', (61, 65))	('ARID4B', 'Gene', '51742', (50, 56))	('GNG4', 'Gene', '2786', (61, 65))	('role', 'Reg', (78, 82))	('fusion', 'Var', (31, 37))
142950	30675227	A mutated form of FAM111B protein is thought to be involved in hereditary fibrosing poikiloderma, characterised by mottled pigmentation, telangiectasia and atrophy of the epidermis, tendon contractors and progressive pulmonary fibrosis.	('mottled pigmentation', 'Phenotype', 'HP:0001070', (115, 135))	('atrophy', 'Disease', 'MESH:D001284', (156, 163))	('poikiloderma', 'Disease', (84, 96))	('atrophy', 'Disease', (156, 163))	('FAM111B', 'Gene', (18, 25))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (217, 235))	('poikiloderma', 'Phenotype', 'HP:0001029', (84, 96))	('mutated', 'Var', (2, 9))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (217, 235))	('involved', 'Reg', (51, 59))	('telangiectasia', 'Disease', (137, 151))	('telangiectasia', 'Phenotype', 'HP:0001009', (137, 151))	('poikiloderma', 'Disease', 'MESH:D011038', (84, 96))	('protein', 'Protein', (26, 33))	('telangiectasia', 'Disease', 'MESH:D013684', (137, 151))	('FAM111B', 'Gene', '374393', (18, 25))	('pulmonary fibrosis', 'Disease', (217, 235))
142966	30675227	The fusion between these two genes may imply the same manner by which high-grade gliomas including anaplastic oligodendroglioma progress, although further investigation is required in order to justify this.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('anaplastic oligodendroglioma', 'Disease', (99, 127))	('fusion', 'Var', (4, 10))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('progress', 'PosReg', (128, 136))	('gliomas', 'Disease', (81, 88))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (99, 127))
142968	30675227	NF1 mutations are mostly identified in low-grade gliomas, particularly with regards to the optic pathway.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('optic pathway', 'Pathway', (91, 104))	('identified', 'Reg', (25, 35))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
142970	30675227	In the majority of cases, there are mutations that occur in additional genes together with NF1, including TP53 and cyclin dependent kinase inhibitor 2A.	('TP53', 'Gene', '7157', (106, 110))	('NF1', 'Gene', (91, 94))	('mutations', 'Var', (36, 45))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (115, 151))	('cyclin dependent kinase inhibitor 2A', 'Gene', (115, 151))	('TP53', 'Gene', (106, 110))
142971	30675227	This is clearly observed in the anaplastic oligodendroglioma sample 193 that has multiple gene amplifications and deletions, along with gene fusions in different chromosomes.	('anaplastic oligodendroglioma', 'Disease', (32, 60))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (32, 60))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('deletions', 'Var', (114, 123))
142973	30675227	However, the full significance of the NF1 alteration has yet to be elucidated for this particular glioma subtype and requires further study.	('glioma subtype', 'Disease', 'MESH:D005910', (98, 112))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('alteration', 'Var', (42, 52))	('glioma subtype', 'Disease', (98, 112))	('NF1', 'Gene', (38, 41))
142980	30675227	SH3GL3 mutations have been implicated in a number of cancer types including colorectal cancer, multiple myeloma and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SH3GL3', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('implicated', 'Reg', (27, 37))	('multiple myeloma', 'Disease', (95, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('mutations', 'Var', (7, 16))	('cancer', 'Disease', (87, 93))	('breast cancer', 'Disease', (116, 129))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('multiple myeloma', 'Phenotype', 'HP:0006775', (95, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('multiple myeloma', 'Disease', 'MESH:D009101', (95, 111))	('colorectal cancer', 'Disease', (76, 93))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
142985	30675227	A mutation or deletion/amplification in part of the SH3 domain or GRB2 adaptor protein would affect the Ras/Raf/MEK/ERK cascade, affecting cellular responses including cell cycle progression and potentially contributing to the spread of solid tumor types through local invasion and metastasis, for example in oligodendroglioma.	('MEK', 'Gene', (112, 115))	('GRB2', 'Gene', '2885', (66, 70))	('Raf', 'Gene', '22882', (108, 111))	('ERK', 'Gene', (116, 119))	('GRB2', 'Gene', (66, 70))	('contributing to', 'Reg', (207, 222))	('affect', 'Reg', (93, 99))	('oligodendroglioma', 'Disease', 'MESH:D009837', (309, 326))	('solid tumor', 'Disease', (237, 248))	('oligodendroglioma', 'Disease', (309, 326))	('cellular responses', 'CPA', (139, 157))	('affecting', 'Reg', (129, 138))	('mutation', 'Var', (2, 10))	('SH3 domain', 'Gene', (52, 62))	('glioma', 'Phenotype', 'HP:0009733', (320, 326))	('solid tumor', 'Disease', 'MESH:D009369', (237, 248))	('Raf', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('cell cycle progression', 'CPA', (168, 190))	('MEK', 'Gene', '5609', (112, 115))	('deletion/amplification', 'Var', (14, 36))	('ERK', 'Gene', '5594', (116, 119))
142988	30675227	Loss of SH3GL2 may increase the activity of STAT3/matrix metalloproteinase-2 signaling and promote the migration and invasion of high-grade glioma cells.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('promote', 'PosReg', (91, 98))	('migration', 'CPA', (103, 112))	('matrix metalloproteinase-2', 'Gene', (50, 76))	('SH3GL2', 'Gene', '6456', (8, 14))	('activity', 'MPA', (32, 40))	('increase', 'PosReg', (19, 27))	('matrix metalloproteinase-2', 'Gene', '4313', (50, 76))	('STAT3', 'Gene', '6774', (44, 49))	('glioma', 'Disease', (140, 146))	('STAT3', 'Gene', (44, 49))	('Loss', 'Var', (0, 4))	('invasion', 'CPA', (117, 125))	('SH3GL2', 'Gene', (8, 14))
142998	25943885	More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear.	('promoter hypermethylation', 'Var', (107, 132))	('IDH1', 'Gene', '3417', (168, 172))	('oligodendroglioma', 'Disease', (278, 295))	('IDH2', 'Gene', '3418', (176, 180))	('MGMT', 'Gene', (140, 144))	('oligodendroglioma', 'Disease', 'MESH:D009837', (278, 295))	('CIC', 'Gene', (221, 224))	('enhanced', 'PosReg', (248, 256))	('mutations', 'Var', (191, 200))	('FUBP1', 'Gene', '8880', (204, 209))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('1p/19q', 'Var', (88, 94))	('IDH1', 'Gene', (168, 172))	('IDH2', 'Gene', (176, 180))	('FUBP1', 'Gene', (204, 209))	('mutations', 'Var', (151, 160))	('MGMT', 'Gene', '4255', (140, 144))
143009	25943885	Of note, in children, glioma variants with a more circumscribed growth pattern are more frequent than diffuse gliomas, and oligodendroglial tumors are rare (<4 % of the primary CNS tumors).	('CNS tumors', 'Disease', 'MESH:D009369', (177, 187))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('CNS tumors', 'Disease', (177, 187))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (123, 146))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CNS tumor', 'Phenotype', 'HP:0100006', (177, 186))	('gliomas', 'Disease', (110, 117))	('glioma', 'Disease', (110, 116))	('children', 'Species', '9606', (12, 20))	('glioma', 'Disease', (22, 28))	('oligodendroglial tumors', 'Disease', (123, 146))	('variants', 'Var', (29, 37))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
143044	25943885	The latter may include the 1p19q codeletion pattern of adult oligodendroglioma, but more frequently harbors 1p deletion without 19q loss.	('adult oligodendroglioma', 'Disease', 'MESH:D009837', (55, 78))	('1p19q', 'Var', (27, 32))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('adult oligodendroglioma', 'Disease', (55, 78))	('1p deletion', 'Var', (108, 119))
143058	25943885	The better prognosis of patients with GBM-O compared to those with classic glioblastoma in this series may then at least partly be explained by the fact that these GBM-Os were more often secondary glioblastomas with IDH mutation occurring in younger patients with dedifferentiated tumors, a clinical and molecular subtype already known for a better prognosis.	('dedifferentiated tumors', 'Disease', (264, 287))	('IDH', 'Gene', (216, 219))	('glioblastoma', 'Disease', (75, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('IDH', 'Gene', '3417', (216, 219))	('glioblastomas', 'Disease', 'MESH:D005909', (197, 210))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('patients', 'Species', '9606', (250, 258))	('glioblastomas', 'Disease', (197, 210))	('mutation', 'Var', (220, 228))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('dedifferentiated tumors', 'Disease', 'MESH:D008080', (264, 287))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('patients', 'Species', '9606', (24, 32))	('glioblastoma', 'Disease', (197, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (197, 209))	('glioblastomas', 'Phenotype', 'HP:0012174', (197, 210))
143073	25943885	Very recently, expression of phosphorylated cyclic-AMP responsive element binding protein (p-CREB, a transcription factor involved in gliomagenesis) was described to be present in astrocytomas but largely absent in prototypic oligodendrogliomas, but the sensitivity for identifying 1p19q codeleted oligodendrogliomas was only 70 % and the value of this tool for discrimination of diffuse gliomas awaits further elucidation.	('gliomas', 'Disease', 'MESH:D005910', (309, 316))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('glioma', 'Phenotype', 'HP:0009733', (388, 394))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('oligodendrogliomas', 'Disease', (298, 316))	('gliomas', 'Phenotype', 'HP:0009733', (388, 395))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('gliomas', 'Phenotype', 'HP:0009733', (309, 316))	('astrocytoma', 'Phenotype', 'HP:0009592', (180, 191))	('CREB', 'Gene', (93, 97))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (226, 244))	('astrocytomas', 'Disease', (180, 192))	('1p19q', 'Var', (282, 287))	('gliomas', 'Disease', (388, 395))	('glioma', 'Disease', (134, 140))	('glioma', 'Disease', (388, 394))	('gliomas', 'Disease', (237, 244))	('CREB', 'Gene', '1385', (93, 97))	('glioma', 'Disease', (237, 243))	('gliomas', 'Disease', (309, 316))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('glioma', 'Disease', (309, 315))	('glioma', 'Disease', 'MESH:D005910', (388, 394))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (298, 316))	('oligodendrogliomas', 'Disease', (226, 244))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('glioma', 'Disease', 'MESH:D005910', (309, 315))	('cyclic-AMP', 'Chemical', 'MESH:D000242', (44, 54))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('gliomas', 'Disease', 'MESH:D005910', (388, 395))	('astrocytomas', 'Disease', 'MESH:D001254', (180, 192))
143077	25943885	Like other neoplasms, diffuse gliomas develop as a result of genetic and molecular alterations that further accumulate with tumor progression.	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('alterations', 'Var', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('neoplasms', 'Disease', (11, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (11, 19))	('neoplasms', 'Disease', 'MESH:D009369', (11, 20))	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('tumor', 'Disease', (124, 129))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('gliomas', 'Disease', (30, 37))	('neoplasms', 'Phenotype', 'HP:0002664', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
143084	25943885	Recently, by using genome-wide, 50 base pair single-end sequencing, 1p/19q codeletion was demonstrated to be the only copy number aberration that was stable across spatial regions of low-grade diffuse gliomas and their recurrences.	('1p/19q', 'Var', (68, 74))	('gliomas', 'Disease', (201, 208))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))
143086	25943885	were the first to point out that recurrent anaplastic oligodendrogliomas with 1p/19q codeletion were far more responsive to PCV (procarbazine-ccnu-vincristine) chemotherapy, with virtually all tumors responding.	('more', 'PosReg', (105, 109))	('responsive', 'MPA', (110, 120))	('ccnu', 'Chemical', 'MESH:D008130', (142, 146))	('procarbazine', 'Chemical', 'MESH:D011344', (129, 141))	('vincristine', 'Chemical', 'MESH:D014750', (147, 158))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('1p/19q codeletion', 'Var', (78, 95))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (43, 72))	('anaplastic oligodendrogliomas', 'Disease', (43, 72))
143087	25943885	In large prospective randomized studies on diffuse glioma, 1p/19q codeletion was associated with improved overall survival but also with increased benefit of adjuvant PCV chemotherapy given after radiotherapy.	('1p/19q codeletion', 'Var', (59, 76))	('glioma', 'Disease', (51, 57))	('improved', 'PosReg', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('increased', 'PosReg', (137, 146))	('overall survival', 'MPA', (106, 122))
143088	25943885	Application of 'strict' (as opposed to 'relaxed') histopathological criteria for recognition of oligodendrogliomas results in a higher correlation with 1p/19q codeleted tumors.	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('1p/19q codeleted', 'Var', (152, 168))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (96, 114))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('oligodendrogliomas', 'Disease', (96, 114))	('higher', 'PosReg', (128, 134))
143089	25943885	In a large series of 'classic' glioblastomas, 2-8 % of the primary/de novo and 0-13 % of secondary tumors were reported to show 1p/19q codeletion.	('1p/19q codeletion', 'Var', (128, 145))	('glioblastomas', 'Phenotype', 'HP:0012174', (31, 44))	('glioblastomas', 'Disease', 'MESH:D005909', (31, 44))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('glioblastomas', 'Disease', (31, 44))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
143090	25943885	In some studies, GBM-Os showed a similar low frequency of 1p/19q codeletion, while others reported an increased frequency of codeletions in GBM-Os compared to conventional glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('1p/19q codeletion', 'Var', (58, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))	('glioblastoma', 'Disease', (172, 184))
143091	25943885	Following the initial discovery of isocitrate dehydrogenase (IDH) gene mutations in a small subset of especially younger glioblastoma patients with prolonged survival, a high percentage (70-80 %) of IDH1 and IDH2 mutations were identified in diffuse grade II and III gliomas, regardless of astrocytic or oligodendroglial cell type.	('IDH', 'Gene', '3417', (61, 64))	('diffuse', 'Disease', (242, 249))	('patients', 'Species', '9606', (134, 142))	('gliomas', 'Disease', (267, 274))	('IDH', 'Gene', (208, 211))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('IDH1', 'Gene', (199, 203))	('IDH', 'Gene', (199, 202))	('astrocytic or oligodendroglial', 'Disease', (290, 320))	('mutations', 'Var', (71, 80))	('gliomas', 'Disease', 'MESH:D005910', (267, 274))	('mutations', 'Var', (213, 222))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('IDH', 'Gene', '3417', (208, 211))	('astrocytic or oligodendroglial', 'Disease', 'MESH:D001254', (290, 320))	('IDH1', 'Gene', '3417', (199, 203))	('IDH', 'Gene', '3417', (199, 202))	('identified', 'Reg', (228, 238))	('gliomas', 'Phenotype', 'HP:0009733', (267, 274))	('glioblastoma', 'Disease', (121, 133))	('IDH', 'Gene', (61, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('IDH2', 'Gene', (208, 212))	('IDH2', 'Gene', '3418', (208, 212))
143092	25943885	Nearly all mutations involve codon 132 of IDH1 or the homologous codon 172 of IDH2, with c.395G>A (p.R132H) representing >90 % of all IDH1 mutations.	('IDH1', 'Gene', '3417', (42, 46))	('IDH2', 'Gene', (78, 82))	('p.R132H', 'Mutation', 'rs121913500', (99, 106))	('c.395G>A', 'Mutation', 'rs121913500', (89, 97))	('IDH2', 'Gene', '3418', (78, 82))	('IDH1', 'Gene', (134, 138))	('involve', 'Reg', (21, 28))	('IDH1', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (134, 138))	('c.395G>A', 'Var', (89, 97))
143093	25943885	The IDH1 R132H mutant protein can be detected reliably using immunohistochemistry.	('IDH1', 'Gene', '3417', (4, 8))	('R132H', 'Var', (9, 14))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('IDH1', 'Gene', (4, 8))	('protein', 'Protein', (22, 29))
143095	25943885	The IDH mutation rate in 1p/19q codeleted tumors approaches 100 %.	('IDH', 'Gene', '3417', (4, 7))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IDH', 'Gene', (4, 7))
143096	25943885	Further studies have shown that IDH mutation is an early event in gliomagenesis ('driver mutation'), and likely precedes the development of the 1p/19q codeletion, the latter possibly specifically driving a diffuse glioma towards the classic oligodendroglioma morphologic phenotype, whereas superimposed TP53 and ATRX mutations drive it towards the astrocytoma phenotype instead.	('TP53', 'Gene', '7157', (303, 307))	('astrocytoma', 'Disease', 'MESH:D001254', (348, 359))	('oligodendroglioma', 'Disease', 'MESH:D009837', (241, 258))	('astrocytoma', 'Disease', (348, 359))	('IDH', 'Gene', (32, 35))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))	('driving', 'Reg', (196, 203))	('glioma', 'Disease', (66, 72))	('oligodendroglioma', 'Disease', (241, 258))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('IDH', 'Gene', '3417', (32, 35))	('ATRX', 'Gene', (312, 316))	('glioma', 'Disease', (214, 220))	('TP53', 'Gene', (303, 307))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('ATRX', 'Gene', '546', (312, 316))	('astrocytoma', 'Phenotype', 'HP:0009592', (348, 359))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('glioma', 'Disease', (252, 258))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('glioma', 'Disease', 'MESH:D005910', (252, 258))	('mutation', 'Var', (36, 44))
143097	25943885	Through an altered substrate specificity, IDH mutations give rise to metabolic alterations, including an increase in production of 2-hydroxyglutarate (2-HG) which can inhibit histone demethylation and induces a glioma hypermethylation phenotype (glioma CpG island methylated phenotype or G-CIMP).	('IDH', 'Gene', (42, 45))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (131, 149))	('glioma', 'Disease', (211, 217))	('inhibit', 'NegReg', (167, 174))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('mutations', 'Var', (46, 55))	('IDH', 'Gene', '3417', (42, 45))	('production', 'MPA', (117, 127))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('glioma', 'Disease', (246, 252))	('increase', 'PosReg', (105, 113))	('glioma hypermethylation', 'Disease', (211, 234))	('induces', 'Reg', (201, 208))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('glioma hypermethylation', 'Disease', 'MESH:D005910', (211, 234))	('histone demethylation', 'MPA', (175, 196))	('altered', 'Reg', (11, 18))	('G-CIMP', 'Chemical', '-', (288, 294))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
143099	25943885	IDH mutant tumors without 1p/19q codeletion have a worse outcome compared to IDH mutant, 1p/19q codeleted grade III tumors, but better than grade II and III tumors without IDH mutations.	('III tumors', 'Disease', 'MESH:D009369', (153, 163))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('III tumors', 'Disease', 'MESH:D009369', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('IDH', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('IDH', 'Gene', (77, 80))	('tumors', 'Disease', (116, 122))	('IDH', 'Gene', (172, 175))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('IDH', 'Gene', '3417', (0, 3))	('tumors', 'Disease', (157, 163))	('III tumors', 'Disease', (153, 163))	('IDH', 'Gene', '3417', (77, 80))	('III tumors', 'Disease', (112, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('IDH', 'Gene', '3417', (172, 175))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Disease', (11, 17))	('1p/19q codeleted', 'Var', (89, 105))
143107	25943885	With the Illumina 450 HM beadchip, a specific epigenetic pattern for IDH mutated and 1p/19q codeleted tumors can be identified.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('IDH', 'Gene', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('IDH', 'Gene', '3417', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('1p/19q', 'Var', (85, 91))
143108	25943885	With combined analysis of IDH, MGMT and G-CIMP status, it has become clear that the prognostic role of MGMT status in grade III tumors is related to IDH mutated tumors, whereas MGMT methylation status is predictive for benefit to alkylating chemotherapy in the absence of IDH mutations in both grade III and IV gliomas (i.e., high-grade astrocytomas).	('tumors', 'Disease', (161, 167))	('IDH', 'Gene', (272, 275))	('MGMT', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('astrocytomas', 'Disease', 'MESH:D001254', (337, 349))	('tumors', 'Disease', (128, 134))	('MGMT', 'Gene', '4255', (177, 181))	('G-CIMP', 'Chemical', '-', (40, 46))	('astrocytoma', 'Phenotype', 'HP:0009592', (337, 348))	('IDH', 'Gene', '3417', (26, 29))	('MGMT', 'Gene', '4255', (103, 107))	('IDH', 'Gene', (149, 152))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('IDH', 'Gene', '3417', (272, 275))	('III tumors', 'Disease', (124, 134))	('IV gliomas', 'Disease', (308, 318))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('IV gliomas', 'Disease', 'MESH:D005910', (308, 318))	('related', 'Reg', (138, 145))	('MGMT', 'Gene', '4255', (31, 35))	('mutated', 'Var', (153, 160))	('IDH', 'Gene', '3417', (149, 152))	('MGMT', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('glioma', 'Phenotype', 'HP:0009733', (311, 317))	('MGMT', 'Gene', (103, 107))	('astrocytomas', 'Disease', (337, 349))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('III tumors', 'Disease', 'MESH:D009369', (124, 134))	('gliomas', 'Phenotype', 'HP:0009733', (311, 318))	('IDH', 'Gene', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
143109	25943885	In EORTC study 26951 on anaplastic oligodendroglial tumors the methylation of specific regions in the MGMT promoter was found to be the strongest predictive factor for benefit to PCV chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (24, 58))	('anaplastic oligodendroglial tumors', 'Disease', (24, 58))	('methylation', 'Var', (63, 74))	('MGMT', 'Gene', (102, 106))	('MGMT', 'Gene', '4255', (102, 106))
143110	25943885	Several other mutations have been identified in 1p/19q codeleted tumors.	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('identified', 'Reg', (34, 44))	('mutations', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
143111	25943885	These include inactivating mutations in the homolog of the Drosophila capicua (CIC) and far-upstream binding protein 1 (FUBP1) gene, considered to occur secondary to the unbalanced translocation and found to be present in ~50-70 % and 15-30 % of 1p/19q codeleted tumors, respectively.	('capicua', 'Gene', (70, 77))	('inactivating mutations', 'Var', (14, 36))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('FUBP1', 'Gene', (120, 125))	('Drosophila', 'Species', '7227', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('1p/19q', 'Var', (246, 252))	('capicua', 'Gene', '53560', (70, 77))	('FUBP1', 'Gene', '8880', (120, 125))	('tumors', 'Disease', (263, 269))
143114	25943885	The higher rate of CIC mutations in pure oligodendrogliomas suggests CIC mutations may be related to the phenotypic characteristics of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (41, 59))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (23, 32))	('CIC', 'Gene', (19, 22))	('oligodendrogliomas', 'Disease', (41, 59))
143115	25943885	CIC mutations occur almost invariably with IDH mutations, and they are exceedingly rare in other brain tumors.	('IDH', 'Gene', '3417', (43, 46))	('brain tumors', 'Phenotype', 'HP:0030692', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('brain tumors', 'Disease', (97, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', (43, 46))	('brain tumors', 'Disease', 'MESH:D001932', (97, 109))	('CIC', 'Gene', (0, 3))
143117	25943885	FUBP1 mutations may result in MYC activation or ribosome biogenesis.	('ribosome biogenesis', 'CPA', (48, 67))	('FUBP1', 'Gene', (0, 5))	('MYC activation', 'CPA', (30, 44))	('FUBP1', 'Gene', '8880', (0, 5))	('result in', 'Reg', (20, 29))	('mutations', 'Var', (6, 15))
143118	25943885	The additional impact of these alterations on the outcome of patients with 1p/19q codeleted glioma is presently unclear.	('patients', 'Species', '9606', (61, 69))	('glioma', 'Disease', (92, 98))	('1p/19q', 'Var', (75, 81))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
143119	25943885	Two mutually exclusive mutations play a role in telomere maintenance in gliomas: telomerase reverse transcriptase (TERT) mutations in hot spot promoter regions C228T, C250T result in increased expression of telomerase.	('C250T', 'Var', (167, 172))	('TERT', 'Gene', '7015', (115, 119))	('C250T', 'Mutation', 'c.250C>T', (167, 172))	('mutations', 'Var', (121, 130))	('telomerase reverse transcriptase', 'Gene', '7015', (81, 113))	('C228T', 'Mutation', 'c.228C>T', (160, 165))	('increased', 'PosReg', (183, 192))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('telomerase reverse transcriptase', 'Gene', (81, 113))	('C228T', 'Var', (160, 165))	('expression', 'MPA', (193, 203))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('telomerase', 'Protein', (207, 217))	('gliomas', 'Disease', (72, 79))	('TERT', 'Gene', (115, 119))
143120	25943885	Paradoxically, these mutations are present in both 1p/19q codeleted oligodendrogliomas and in IDH wild type high-grade gliomas.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (68, 86))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('IDH', 'Gene', (94, 97))	('1p/19q', 'Var', (51, 57))	('gliomas', 'Disease', (119, 126))	('IDH', 'Gene', '3417', (94, 97))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('oligodendrogliomas', 'Disease', (68, 86))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
143122	25943885	Gliomas with TERT mutations in the presence of 1p/19q codeletion (i.e., oligodendrogliomas), have a very favorable outcome where the same TERT mutations in the absence of this codeletion or IDH mutations herald a grim prognosis (comparable to glioblastoma).	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('glioblastoma', 'Disease', (243, 255))	('TERT', 'Gene', (13, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (243, 255))	('TERT', 'Gene', '7015', (13, 17))	('glioblastoma', 'Phenotype', 'HP:0012174', (243, 255))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('IDH', 'Gene', (190, 193))	('TERT', 'Gene', (138, 142))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (72, 90))	('Gliomas', 'Disease', (0, 7))	('1p/19q codeletion', 'Var', (47, 64))	('TERT', 'Gene', '7015', (138, 142))	('oligodendrogliomas', 'Disease', (72, 90))	('IDH', 'Gene', '3417', (190, 193))
143123	25943885	TERT mutations are mutually exclusive with ATRX (alpha thalassemia mental retardation syndrome X linked) mutations, which are instead seen in the majority of WHO grade II-III astrocytomas and secondary glioblastomas.	('astrocytomas', 'Disease', 'MESH:D001254', (175, 187))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('mental retardation', 'Phenotype', 'HP:0001249', (67, 85))	('ATRX', 'Gene', '546', (43, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (202, 215))	('mutations', 'Var', (5, 14))	('TERT', 'Gene', (0, 4))	('alpha thalassemia mental retardation syndrome X linked', 'Gene', '546', (49, 103))	('TERT', 'Gene', '7015', (0, 4))	('astrocytomas', 'Disease', (175, 187))	('mutations', 'Var', (105, 114))	('glioblastomas', 'Disease', 'MESH:D005909', (202, 215))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('glioblastomas', 'Disease', (202, 215))	('ATRX', 'Gene', (43, 47))
143124	25943885	Critical for normal telomere homeostasis, these mutations are associated with the alternative lengthening of telomeres (ALT) phenotype, IDH and TP53 mutations, but not with 1p/19q loss.	('TP53', 'Gene', '7157', (144, 148))	('IDH', 'Gene', (136, 139))	('TP53', 'Gene', (144, 148))	('IDH', 'Gene', '3417', (136, 139))	('mutations', 'Var', (149, 158))	('associated', 'Reg', (62, 72))	('mutations', 'Var', (48, 57))
143127	25943885	EGFR amplifications are virtually mutually exclusive with 1p/19q codeletion and with IDH mutations.	('IDH', 'Gene', '3417', (85, 88))	('amplifications', 'Var', (5, 19))	('EGFR', 'Gene', (0, 4))	('1p/19q', 'Disease', (58, 64))	('IDH', 'Gene', (85, 88))	('EGFR', 'Gene', '1956', (0, 4))
143129	25943885	The presence of polysomy of chromosome 7 and amplification of the epidermal growth factor receptor (EGFR) gene is associated with TERT mutations and a prognosis similar to primary glioblastoma in general.	('EGFR', 'Gene', '1956', (100, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (180, 192))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('epidermal growth factor receptor', 'Gene', (66, 98))	('EGFR', 'Gene', (100, 104))	('polysomy', 'Var', (16, 24))	('associated', 'Reg', (114, 124))	('epidermal growth factor receptor', 'Gene', '1956', (66, 98))	('presence', 'Var', (4, 12))	('glioblastoma', 'Disease', (180, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (180, 192))	('amplification', 'Var', (45, 58))
143130	25943885	The presence of EGFR amplification in histologically pure anaplastic oligodendrogliomas is indicative of glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('amplification', 'Var', (21, 34))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('presence', 'Reg', (4, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (58, 87))	('anaplastic oligodendrogliomas', 'Disease', (58, 87))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('EGFR', 'Gene', '1956', (16, 20))	('glioblastoma', 'Disease', (105, 117))	('EGFR', 'Gene', (16, 20))
143131	25943885	The small cell variant of glioblastoma has morphological similarities to anaplastic oligodendroglioma but carries EGFR amplification in 70 % of cases.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioblastoma', 'Disease', (26, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('EGFR', 'Gene', '1956', (114, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('oligodendroglioma', 'Disease', (84, 101))	('amplification', 'Var', (119, 132))	('oligodendroglioma', 'Disease', 'MESH:D009837', (84, 101))	('EGFR', 'Gene', (114, 118))
143132	25943885	Anaplastic oligodendroglial tumors usually have additional genetic aberrations, in particular 9p LOH and/or deletion of the CDKN2A gene (p16), PIK3CA mutations, and polysomies.	('CDKN2A', 'Gene', (124, 130))	('p16', 'Gene', (137, 140))	('Anaplastic oligodendroglial tumors', 'Disease', 'MESH:D002277', (0, 34))	('CDKN2A', 'Gene', '1029', (124, 130))	('Anaplastic oligodendroglial tumors', 'Disease', (0, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('PIK3CA', 'Gene', (143, 149))	('mutations', 'Var', (150, 159))	('PIK3CA', 'Gene', '5290', (143, 149))	('p16', 'Gene', '1029', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('deletion', 'Var', (108, 116))
143133	25943885	Recent data of The Cancer Genome Atlas (TCGA) consortium on lower grade (WHO grade II and III) gliomas show that IDH mutations in these gliomas are virtually mutually exclusive with homozygous deletion of CDKN2A and with amplification of EGFR.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('Cancer Genome Atlas', 'Disease', (19, 38))	('CDKN2A', 'Gene', '1029', (205, 211))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('EGFR', 'Gene', '1956', (238, 242))	('IDH', 'Gene', '3417', (113, 116))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('gliomas', 'Disease', (136, 143))	('mutations', 'Var', (117, 126))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Disease', (95, 102))	('EGFR', 'Gene', (238, 242))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('amplification', 'Var', (221, 234))	('CDKN2A', 'Gene', (205, 211))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (19, 38))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('IDH', 'Gene', (113, 116))
143134	25943885	As discussed above, EGFR amplification mainly occurs in 1p/19q intact, IDH wild type gliomas and indicates the diagnosis glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('EGFR', 'Gene', (20, 24))	('indicates', 'Reg', (97, 106))	('gliomas', 'Disease', (85, 92))	('EGFR', 'Gene', '1956', (20, 24))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('IDH', 'Gene', (71, 74))	('amplification', 'Var', (25, 38))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioblastoma', 'Disease', (121, 133))	('IDH', 'Gene', '3417', (71, 74))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('occurs', 'Reg', (46, 52))
143141	25943885	Recently, disseminated oligodendroglioma-like leptomeningeal neoplasms (an entity that predominantly affects children) were reported to frequently harbor concurrent BRAF-KIAA1549 gene fusions and 1p deletion, generally without 19q deletion.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('oligodendroglioma-like leptomeningeal neoplasms', 'Disease', (23, 70))	('neoplasm', 'Phenotype', 'HP:0002664', (61, 69))	('neoplasms', 'Phenotype', 'HP:0002664', (61, 70))	('BRAF', 'Gene', '673', (165, 169))	('children', 'Species', '9606', (109, 117))	('BRAF', 'Gene', (165, 169))	('KIAA1549', 'Gene', '57670', (170, 178))	('KIAA1549', 'Gene', (170, 178))	('oligodendroglioma-like leptomeningeal neoplasms', 'Disease', 'MESH:D008577', (23, 70))	('1p deletion', 'Var', (196, 207))
143147	25943885	In the study of Johnson et al., tumors from 6 of 10 patients treated with the temozolomide (TMZ) were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways, thereby bearing the signature of TMZ-induced mutagenesis.	('mammalian target of rapamycin', 'Gene', (186, 215))	('temozolomide', 'Chemical', 'MESH:D000077204', (78, 90))	('retinoblastoma', 'Phenotype', 'HP:0009919', (156, 170))	('mTOR', 'Gene', (180, 184))	('Akt', 'Gene', (176, 179))	('mTOR', 'Gene', '2475', (180, 184))	('mutations', 'Var', (135, 144))	('retinoblastoma', 'Disease', 'MESH:D012175', (156, 170))	('retinoblastoma', 'Disease', (156, 170))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TMZ', 'Chemical', 'MESH:D000077204', (260, 263))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))	('tumors', 'Disease', (32, 38))	('mammalian target of rapamycin', 'Gene', '2475', (186, 215))	('patients', 'Species', '9606', (52, 60))	('Akt', 'Gene', '207', (176, 179))
143151	25943885	Of note, 1p/19q status is most likely not the ultimate identifier of sensitivity to adjuvant (PCV) chemotherapy, better candidate markers being IDH mutation, G-CIMP and MGMT promoter methylation.	('IDH', 'Gene', (144, 147))	('IDH', 'Gene', '3417', (144, 147))	('MGMT', 'Gene', (169, 173))	('MGMT', 'Gene', '4255', (169, 173))	('mutation', 'Var', (148, 156))	('G-CIMP', 'Chemical', '-', (158, 164))	('G-CIMP', 'Var', (158, 164))
143154	25943885	Vice versa, in many larger series on glioma a limited number of tumors diagnosed as low grade or anaplastic astrocytoma (5-10 %) has combined 1p/19q loss, most of these are IDH mutated.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('anaplastic astrocytoma', 'Disease', (97, 119))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('glioma', 'Disease', (37, 43))	('IDH', 'Gene', (173, 176))	('1p/19q loss', 'Var', (142, 153))	('low grade', 'Disease', (84, 93))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (97, 119))	('IDH', 'Gene', '3417', (173, 176))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
143159	25943885	Elaborating on the suggestions in the ISN-Haarlem guidelines, a recent study on adult diffuse low- and high-grade gliomas demonstrated that the integrated morphological and molecular diagnosis (incorporating information on ATRX, IDH and 1p/19q codeletion) had significantly greater prognostic power for overall and progression-free survival than the original, histopathological diagnosis.	('progression-free survival', 'CPA', (315, 340))	('gliomas', 'Disease', (114, 121))	('1p/19q codeletion', 'Var', (237, 254))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('ATRX', 'Gene', (223, 227))	('IDH', 'Gene', (229, 232))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('ATRX', 'Gene', '546', (223, 227))	('IDH', 'Gene', '3417', (229, 232))	('overall', 'CPA', (303, 310))	('greater', 'PosReg', (274, 281))
143160	25943885	Acknowledging that ATRX mutations in IDH mutant diffuse gliomas almost never co-occur with 1p/19q codeletions and result in loss of immunohistochemical ATRX staining of tumor cell nuclei, an algorithm was proposed for a stepwise diagnostic approach that could reduce the number of molecular analyses needed for a final diagnosis: initial immunohistochemistry for ATRX and IDH1 R132H mutant protein, when necessary (e.g., in case of positive ATRX staining of tumor cell nuclei and negative staining for IDH1 R132H) followed by 1p/19q analysis and subsequently by IDH sequencing.	('IDH1', 'Gene', (502, 506))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('ATRX', 'Gene', (363, 367))	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('R132H', 'Mutation', 'rs121913500', (377, 382))	('ATRX', 'Gene', '546', (363, 367))	('IDH', 'Gene', (502, 505))	('ATRX', 'Gene', (441, 445))	('mutations', 'Var', (24, 33))	('IDH1', 'Gene', (372, 376))	('ATRX', 'Gene', '546', (441, 445))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('IDH1', 'Gene', '3417', (502, 506))	('IDH', 'Gene', (372, 375))	('IDH', 'Gene', '3417', (502, 505))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('tumor', 'Disease', (169, 174))	('ATRX', 'Gene', (19, 23))	('IDH', 'Gene', (562, 565))	('R132H', 'Mutation', 'rs121913500', (507, 512))	('ATRX', 'Gene', '546', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('IDH1', 'Gene', '3417', (372, 376))	('IDH', 'Gene', '3417', (372, 375))	('ATRX', 'Gene', (152, 156))	('IDH', 'Gene', (37, 40))	('ATRX', 'Gene', '546', (152, 156))	('IDH', 'Gene', '3417', (562, 565))	('gliomas', 'Disease', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('tumor', 'Disease', (458, 463))	('IDH', 'Gene', '3417', (37, 40))
143162	25943885	Immunohistochemistry for p53 protein (strong staining of a large percentage of tumor cell nuclei) has been reported as a highly specific, but moderately sensitive surrogate marker for the presence of a TP53 mutation in gliomas.	('p53', 'Gene', (25, 28))	('TP53', 'Gene', (202, 206))	('p53', 'Gene', '7157', (25, 28))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('tumor', 'Disease', (79, 84))	('gliomas', 'Disease', (219, 226))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('mutation', 'Var', (207, 215))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('TP53', 'Gene', '7157', (202, 206))
143166	25943885	Already in 1997 the finding that low-grade oligoastrocytomas generally have either 1p/19q codeletion or TP53 mutation made the authors question the presence of truly mixed gliomas.	('oligoastrocytomas', 'Disease', 'MESH:D001254', (43, 60))	('TP53', 'Gene', '7157', (104, 108))	('1p/19q codeletion', 'Var', (83, 100))	('TP53', 'Gene', (104, 108))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('gliomas', 'Disease', (172, 179))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('oligoastrocytomas', 'Disease', (43, 60))
143168	25943885	Distinct molecular subsets can easily be carved out of the GBM-O category and placed into more clinically uniform subtypes, such as primary/IDH wild type glioblastomas, secondary/IDH mutated glioblastomas, and 1p/19q codeleted anaplastic oligodendrogliomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (191, 204))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (140, 143))	('IDH', 'Gene', '3417', (179, 182))	('glioblastomas', 'Disease', 'MESH:D005909', (191, 204))	('1p/19q codeleted', 'Var', (210, 226))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (227, 256))	('glioblastomas', 'Phenotype', 'HP:0012174', (154, 167))	('anaplastic oligodendrogliomas', 'Disease', (227, 256))	('gliomas', 'Phenotype', 'HP:0009733', (249, 256))	('glioblastomas', 'Disease', (191, 204))	('glioblastomas', 'Disease', 'MESH:D005909', (154, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('glioblastomas', 'Disease', (154, 167))	('IDH', 'Gene', (140, 143))
143176	25943885	For instance, the presence of an IDH mutation may provide an opportunity to apply specific, IDH targeted treatment, no matter if the diagnosis was astrocytoma or (1p/19q codeleted) oligodendroglioma.	('astrocytoma', 'Disease', (147, 158))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('mutation', 'Var', (37, 45))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('oligodendroglioma', 'Disease', 'MESH:D009837', (181, 198))	('astrocytoma', 'Disease', 'MESH:D001254', (147, 158))	('IDH', 'Gene', (33, 36))	('IDH', 'Gene', (92, 95))	('IDH', 'Gene', '3417', (33, 36))	('IDH', 'Gene', '3417', (92, 95))	('oligodendroglioma', 'Disease', (181, 198))
143187	32503220	Large-Scale Drug Screening in Patient-Derived IDHmut Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology.	('Glioma', 'Phenotype', 'HP:0009733', (53, 59))	('Glioma', 'Disease', (53, 59))	('IDH', 'Gene', (46, 49))	('glioma', 'Disease', (211, 217))	('mutation', 'Var', (199, 207))	('glioma', 'Disease', (256, 262))	('Patient', 'Species', '9606', (30, 37))	('isocitrate dehydrogenase', 'Gene', (168, 192))	('IDH', 'Gene', (194, 197))	('IDH', 'Gene', '3417', (46, 49))	('isocitrate dehydrogenase', 'Gene', '3417', (168, 192))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('IDH', 'Gene', '3417', (194, 197))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('Glioma', 'Disease', 'MESH:D005910', (53, 59))
143196	32503220	The differentiation of glioma patients into isocitrate dehydrogenase (IDH) mutant and wildtype tumors (IDHmut/IDHwt) has proven to be a solid prognostic marker of patient outcome.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('isocitrate dehydrogenase', 'Gene', '3417', (44, 68))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', (103, 106))	('patients', 'Species', '9606', (30, 38))	('patient', 'Species', '9606', (30, 37))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('isocitrate dehydrogenase', 'Gene', (44, 68))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', '3417', (103, 106))	('patient', 'Species', '9606', (163, 170))	('glioma', 'Disease', (23, 29))	('IDH', 'Gene', '3417', (70, 73))	('mutant', 'Var', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
143197	32503220	Patients harboring an IDH mutation fare much better than patients without.	('mutation', 'Var', (26, 34))	('patients', 'Species', '9606', (57, 65))	('IDH', 'Gene', (22, 25))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', '3417', (22, 25))
143198	32503220	This has led to a revision of the WHO classification in 2016, in which molecular parameters, such as the IDH mutation and 1p/19q co-deletion status, are now being incorporated along with classical histology.	('IDH', 'Gene', '3417', (105, 108))	('IDH', 'Gene', (105, 108))	('1p/19q', 'Var', (122, 128))
143203	32503220	While IDHwt glioma cell models have shown easy expansion and maintenance, difficulties in cultivating IDHmut tumor cells have forced many to introduce the IDH mutation artificially into wildtype tumor cells, not accounting for the natural genetic background of the tumor.	('tumor', 'Disease', (195, 200))	('IDHwt glioma', 'Disease', 'MESH:D005910', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('introduce', 'Reg', (141, 150))	('tumor', 'Disease', (265, 270))	('mutation', 'Var', (159, 167))	('IDHwt glioma', 'Disease', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IDH', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('IDH', 'Gene', (6, 9))	('IDH', 'Gene', (155, 158))	('IDH', 'Gene', '3417', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('IDH', 'Gene', '3417', (6, 9))	('IDH', 'Gene', '3417', (155, 158))	('tumor', 'Disease', (109, 114))
143215	32503220	For the initial screen, these were added to the IDHmut GSC lines 24 h after cell plating at different concentrations (0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM).	('IDH', 'Gene', '3417', (48, 51))	('0.1 nM', 'Var', (118, 124))	('IDH', 'Gene', (48, 51))
143229	32503220	All cells were maintained as spheroid cultures in stem cell media, thus enriching tumorigenic stem cells and allowing them to produce significant levels of the oncometabolite D2HG by the mutant IDH enzyme (Table S1).	('produce', 'MPA', (126, 133))	('D2HG', 'Chemical', '-', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('levels of the oncometabolite D2HG', 'MPA', (146, 179))	('mutant', 'Var', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IDH', 'Gene', (194, 197))	('tumor', 'Disease', (82, 87))	('IDH', 'Gene', '3417', (194, 197))
143236	32503220	To corroborate our findings of the initial drug screening, the candidate drugs were tested on four additional IDHmut GSC lines (rGBM WHO IV: NCH620, NCH645, NCH3763; oligodendroglioma WHO III: NCH612).	('NCH3763', 'Var', (157, 164))	('tested', 'Reg', (84, 90))	('IDH', 'Gene', (110, 113))	('oligodendroglioma', 'Disease', (166, 183))	('NCH645', 'Var', (149, 155))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('NCH620', 'Var', (141, 147))	('IDH', 'Gene', '3417', (110, 113))	('oligodendroglioma', 'Disease', 'MESH:D009837', (166, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('NCH645', 'Chemical', '-', (149, 155))	('NCH612', 'Chemical', '-', (193, 199))
143248	32503220	NCH551b showed the most pronounced apoptotic effect for all tested drugs, followed by NCH1681 and NCH612.	('NCH1681', 'Chemical', '-', (86, 93))	('NCH612', 'Chemical', '-', (98, 104))	('NCH551b', 'Chemical', '-', (0, 7))	('apoptotic effect', 'CPA', (35, 51))	('NCH551b', 'Var', (0, 7))
143250	32503220	In addition, in NCH551b, both early and late apoptotic fractions increased, as compared to NCH1681 and NCH612, where mostly the late apoptotic fraction increased.	('NCH551b', 'Var', (16, 23))	('increased', 'PosReg', (65, 74))	('NCH1681', 'Chemical', '-', (91, 98))	('NCH551b', 'Chemical', '-', (16, 23))	('NCH612', 'Chemical', '-', (103, 109))
143251	32503220	In NCH1681 and NCH612, the apoptotic effect was less pronounced as in NCH551b, reaching statistical significance in 3/4 and 2/4 drugs, respectively.	('NCH1681', 'Chemical', '-', (3, 10))	('NCH612', 'Chemical', '-', (15, 21))	('NCH551b', 'Chemical', '-', (70, 77))	('NCH1681', 'Var', (3, 10))	('NCH612', 'Var', (15, 21))
143265	32503220	To our knowledge, this is the first study conducting a systematical identification process for novel but approved chemotherapeutic agents by using GSC lines with an endogenous IDH mutation.	('IDH', 'Gene', '3417', (176, 179))	('IDH', 'Gene', (176, 179))	('mutation', 'Var', (180, 188))
143267	32503220	In addition, the flow-cytometric measurements of Annexin V/PI-stained GSCs confirmed that the drugs not only inhibit cell growth, as measured by CellTiterGlo, but also effectively induce cell death.	('induce', 'Reg', (180, 186))	('inhibit', 'NegReg', (109, 116))	('Annexin V', 'Gene', '308', (49, 58))	('GSCs', 'Chemical', '-', (70, 74))	('Annexin V', 'Gene', (49, 58))	('drugs', 'Var', (94, 99))	('cell death', 'CPA', (187, 197))	('cell growth', 'CPA', (117, 128))
143291	32503220	This is demonstrated by the fact that GSC lines with an endogenous IDH mutation and a maintained 2HG production can be solely grown as sphere cultures.	('2HG production', 'MPA', (97, 111))	('2HG', 'Chemical', 'MESH:C019417', (97, 100))	('mutation', 'Var', (71, 79))	('IDH', 'Gene', (67, 70))	('IDH', 'Gene', '3417', (67, 70))
143303	32503220	IDH Isocitrate Dehydrogenase  mut mutant  wt wildtype  FDA Food and Drug Administration  LGG Lower grade glioma  HGG Higher grade glioma  GBM  Glioblastoma  PCV  Procarbazine, lomustine, Vincristine  GSC Glioma stem cell  DTP Developmental Therapeutics Program  NCI National Cancer Institute  bFGF Basic fibroblast growth factor   EGF Epidermal growth factor  TSC Tumor stem cell  STR Short tandem repeat  D2HG (D)-2-hydroxyglutarate  IC50 Half-maximal inhibitory concentration  AUC Area under the curve  Emax Maximum inhibitory effect  SD Standard deviation  PI Propidium iodide  BBB Blood brain barrier	('EGF', 'Gene', '1950', (331, 334))	('glioma', 'Disease', (130, 136))	('Cancer', 'Disease', (275, 281))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma  GBM  Glioblastoma', 'Disease', (130, 155))	('Glioma', 'Disease', (204, 210))	('IDH', 'Gene', (0, 3))	('Tumor', 'Phenotype', 'HP:0002664', (364, 369))	('glioma', 'Disease', (105, 111))	('D2HG', 'Chemical', '-', (406, 410))	('lomustine', 'Chemical', 'MESH:D008130', (176, 185))	('GBM', 'Phenotype', 'HP:0012174', (138, 141))	('Cancer', 'Disease', 'MESH:D009369', (275, 281))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('EGF', 'Gene', (331, 334))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma  GBM  Glioblastoma', 'Disease', 'MESH:D005909', (130, 155))	('Glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('IDH', 'Gene', '3417', (0, 3))	('bFGF', 'Gene', '2247', (293, 297))	('(D)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (411, 433))	('Glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (275, 281))	('bFGF', 'Gene', (293, 297))	('Glioma', 'Phenotype', 'HP:0009733', (204, 210))	('mutant', 'Var', (34, 40))
143333	31263189	Does P53 mutation hinder the neurogenesis or other cellular differentiation of GSCs?	('mutation', 'Var', (9, 17))	('P53', 'Gene', (5, 8))	('P53', 'Gene', '7157', (5, 8))	('neurogenesis', 'CPA', (29, 41))	('hinder', 'NegReg', (18, 24))
143353	31263189	Furthermore, another new model was constructed by introducing the P53 mutation (i.e., keeping it at constitutively inactive state) and the identified reaction motif of GSC development (Supplementary Fig.	('P53', 'Gene', (66, 69))	('mutation', 'Var', (70, 78))	('P53', 'Gene', '7157', (66, 69))
143355	31263189	It was observed that P53 mutation in GSCs did not influence the developmental dynamics of the stem cells and the cells still retained its self-renewal and differentiation properties like aNSCs.	('mutation', 'Var', (25, 33))	('P53', 'Gene', (21, 24))	('self-renewal', 'CPA', (138, 150))	('P53', 'Gene', '7157', (21, 24))	('differentiation properties', 'CPA', (155, 181))
143356	31263189	Apoptosis was missing in this simulation due the induction of P53 mutation in the GSCs.	('P53', 'Gene', '7157', (62, 65))	('P53', 'Gene', (62, 65))	('mutation', 'Var', (66, 74))
143359	31263189	This observation clearly indicated the origin of primary tumor cells (LGG) developing from P53 mutated GSCs in the GSC model simulation.	('P53', 'Gene', (91, 94))	('P53', 'Gene', '7157', (91, 94))	('primary tumor', 'Disease', (49, 62))	('mutated', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('primary tumor', 'Disease', 'MESH:D009369', (49, 62))
143360	31263189	Hence, to capture the effect of phenotypic plasticity of GSCs in which JAK2/STAT3 proteins are constitutively active, a new model was further formulated by introducing P53 mutation and over-expressions of JAK2 and STAT3 proteins in the cells used for GSC model simulation (see Supplementary Information).	('JAK2', 'Gene', '3717', (71, 75))	('STAT3', 'Gene', '6774', (76, 81))	('JAK2', 'Gene', (205, 209))	('STAT3', 'Gene', (76, 81))	('JAK2', 'Gene', (71, 75))	('STAT3', 'Gene', '6774', (214, 219))	('P53', 'Gene', (168, 171))	('mutation', 'Var', (172, 180))	('STAT3', 'Gene', (214, 219))	('P53', 'Gene', '7157', (168, 171))	('over-expressions', 'PosReg', (185, 201))	('JAK2', 'Gene', '3717', (205, 209))
143362	31263189	It was also able to maintain its stemness property and simultaneously produced different types of mutated primary astrocytes or glioma cells in the steady state (Supplementary Fig.	('stemness property', 'Disease', 'MESH:D020295', (33, 50))	('glioma', 'Disease', (128, 134))	('produced', 'Reg', (70, 78))	('stemness property', 'Disease', (33, 50))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('mutated', 'Var', (98, 105))
143371	31263189	In the high-grade (Grade-IV) GBM tumor states of general glioma model, increased activities of JAK2/STAT3, RBPJ, MAML1, YY1, gamma-Secretase complex (APH1, NCSTN, PSENEN, PEN2) and mutation of P53 were observed as a minimal number of deregulations (total mutations, mu = 10).	('P53', 'Gene', '7157', (193, 196))	('NCSTN', 'Gene', (156, 161))	('PEN2', 'Gene', (171, 175))	('GBM', 'Phenotype', 'HP:0012174', (29, 32))	('JAK2', 'Gene', '3717', (95, 99))	('YY1', 'Gene', '7528', (120, 123))	('glioma', 'Disease', (57, 63))	('NCSTN', 'Gene', '23385', (156, 161))	('YY1', 'Gene', (120, 123))	('PSENEN', 'Gene', (163, 169))	('MAML1', 'Gene', (113, 118))	('activities', 'MPA', (81, 91))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('STAT3', 'Gene', (100, 105))	('APH1', 'Gene', (150, 154))	('JAK2', 'Gene', (95, 99))	('APH1', 'Gene', '51107', (150, 154))	('MAML1', 'Gene', '9794', (113, 118))	('P53', 'Gene', (193, 196))	('STAT3', 'Gene', '6774', (100, 105))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('PEN2', 'Gene', '55851', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutation', 'Var', (181, 189))	('GBM tumor', 'Disease', 'MESH:D005910', (29, 38))	('GBM tumor', 'Disease', (29, 38))	('increased', 'PosReg', (71, 80))	('PSENEN', 'Gene', '55851', (163, 169))
143372	31263189	Hence, a new model was built by constitutively expressing Notch pathway molecules (RBPJ, MAML1, gamma-Secretase complex), JAK2/STAT3 and YY1 proteins and by mutating P53 protein in the GSCs to simulate the differentiation of primary GBM (Grade-IV) cells, and observed how much the model simulation having these higher number of mutations induce the development of GBM cells.	('P53', 'Gene', '7157', (166, 169))	('JAK2', 'Gene', '3717', (122, 126))	('YY1', 'Gene', '7528', (137, 140))	('GBM', 'Phenotype', 'HP:0012174', (233, 236))	('induce', 'Reg', (338, 344))	('development of GBM cells', 'CPA', (349, 373))	('YY1', 'Gene', (137, 140))	('JAK2', 'Gene', (122, 126))	('GBM', 'Phenotype', 'HP:0012174', (364, 367))	('mutations', 'Var', (328, 337))	('STAT3', 'Gene', '6774', (127, 132))	('MAML1', 'Gene', (89, 94))	('MAML1', 'Gene', '9794', (89, 94))	('mutating', 'Var', (157, 165))	('P53', 'Gene', (166, 169))	('STAT3', 'Gene', (127, 132))
143376	31263189	In contrast, the normalized frequencies of differentiated ASPCs (LGG-I state) and the cellular state "GSC Renewal/ASPC/NPC Differentiation" were significantly increased in the Grade-IV GBM model as compared to general glioma model (Fig.	('differentiated ASPCs', 'CPA', (43, 63))	('Grade-IV', 'Var', (176, 184))	('glioma', 'Disease', (218, 224))	('increased', 'PosReg', (159, 168))	('GBM', 'Phenotype', 'HP:0012174', (185, 188))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))
143384	31263189	Analysis of one such cluster extracted from the STG showed that the developmental dynamics of the tumor-initiating mutated GSCs were able to develop any of the three different sub-types of GBM viz.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutated', 'Var', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('GBM', 'Phenotype', 'HP:0012174', (189, 192))	('tumor', 'Disease', (98, 103))
143396	31263189	P53 knock-out, and increased activities of JAK2/STAT3, RBPJ, YY1 proteins, etc.	('JAK2', 'Gene', '3717', (43, 47))	('STAT3', 'Gene', (48, 53))	('YY1', 'Gene', '7528', (61, 64))	('JAK2', 'Gene', (43, 47))	('YY1', 'Gene', (61, 64))	('activities', 'MPA', (29, 39))	('P53', 'Gene', (0, 3))	('increased', 'PosReg', (19, 28))	('knock-out', 'Var', (4, 13))	('P53', 'Gene', '7157', (0, 3))	('STAT3', 'Gene', '6774', (48, 53))	('RBPJ', 'Protein', (55, 59))
143404	31263189	A similar result was also observed for "NPC differentiation" state, which showed that in the same tumorigenic niche, the heavily mutated tumor cells were least influenced (mean 40.372, 95% CI [39.804 40.940]) to differentiate into matured neurons as compared to normal aNSCs in the neurogenic niche.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('heavily mutated', 'Var', (121, 136))	('differentiate', 'CPA', (212, 225))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('least', 'NegReg', (154, 159))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
143405	31263189	A comparative analysis of LGG-I, LGG-II, and Grade-IV cellular states observed in general glioma, and Grade-IV GBM models revealed that the phenotype predictor scores for all of these cellular states were comparably higher in Grade-IV GBM model as compared to other model simulations.	('GBM', 'Phenotype', 'HP:0012174', (235, 238))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('higher', 'PosReg', (216, 222))	('Grade-IV', 'Var', (226, 234))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
143407	31263189	Thus, the induced alterations of the protein expressions in Grade-IV GBM models accelerated the growth of LGG-I, LGG-II and high grade (Grade-IV) glioblastoma cells, which in turn helped to predict the chances of occurrences of the oncogenic cells in the tumor ecosystem.	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('alterations', 'Var', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('growth', 'CPA', (96, 102))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('helped', 'Reg', (180, 186))	('glioblastoma', 'Disease', (146, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('protein', 'Protein', (37, 44))	('accelerated', 'PosReg', (80, 91))
143415	31263189	The transcriptomic profile of the transcripts of 9 out of 53 input molecules was found (Supplementary Table 6) in the differential expression analyses performed on the RNA-Seq data extracted from the cohort of P53 mutated, low-grade glioma (TCGA-LGG) tumor samples available in TCGA data portal.	('glioma', 'Disease', 'MESH:D005910', (233, 239))	('tumor', 'Disease', (251, 256))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('P53', 'Gene', (210, 213))	('P53', 'Gene', '7157', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('mutated', 'Var', (214, 221))	('glioma', 'Disease', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
143417	31263189	Hence, it proved that the neural stem cells having transcriptomics profile of TCGA-LGG cohort were more inclined to the development of glioblastoma stem-like (GSC) and mutated astrocytes or tumor cells (ASPC).	('mutated', 'Var', (168, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('TCGA-LGG', 'Gene', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('glioblastoma', 'Disease', (135, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('more inclined', 'PosReg', (99, 112))
143425	31263189	Another retrospective analysis was also performed by using the transcriptomic profile of the input molecules, which were differentially expressed in the P53 mutated TCGA-GBM tumor samples collected from the high-grade Glioblastoma patients' cohort (Supplementary Table 5).	('GBM', 'Phenotype', 'HP:0012174', (170, 173))	('Glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('P53', 'Gene', (153, 156))	('patients', 'Species', '9606', (231, 239))	('P53', 'Gene', '7157', (153, 156))	('GBM tumor', 'Disease', 'MESH:D005910', (170, 179))	('GBM tumor', 'Disease', (170, 179))	('Glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutated', 'Var', (157, 164))	('Glioblastoma', 'Disease', (218, 230))
143427	31263189	These astrocytes cells had a higher number of mutations, abundant expressions of Notch and JAK/STAT pathway molecules with rapid proliferation rate, which in turn helped these cells to differentiate and transform into tumorigenic states.	('mutations', 'Var', (46, 55))	('expressions', 'MPA', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('helped', 'PosReg', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('JAK/STAT pathway molecules', 'Gene', (91, 117))	('tumor', 'Disease', (218, 223))	('differentiate', 'CPA', (185, 198))	('transform', 'CPA', (203, 212))	('Notch', 'Gene', (81, 86))
143441	31263189	Hence, this result indicated that the transcriptomics profile of TCGA-GBM tumor sample cohort was not only triggering the differentiation of mutated GSCs but also lead to the development of Grade-IV (high-grade) GBM cells.	('mutated', 'Var', (141, 148))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('GBM tumor', 'Disease', 'MESH:D005910', (70, 79))	('GBM', 'Phenotype', 'HP:0012174', (212, 215))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('triggering', 'Reg', (107, 117))	('GBM tumor', 'Disease', (70, 79))	('lead to', 'Reg', (163, 170))
143447	31263189	On the other hand, inhibitions of PI3K/AKT and HIF1A simultaneously (TC6) was necessary to suppress the LGG-II tumor cells, but not the LGG-I and Grade-IV cells in the tumorigenic niche (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('HIF1A', 'Gene', (47, 52))	('HIF1A', 'Gene', '3091', (47, 52))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('suppress', 'NegReg', (91, 99))	('AKT', 'Gene', '207', (39, 42))	('inhibitions', 'Var', (19, 30))	('tumor', 'Disease', (111, 116))	('TC6', 'CellLine', 'CVCL:6A95', (69, 72))	('AKT', 'Gene', (39, 42))	('LGG-II', 'Disease', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
143453	31263189	In the previous experiments, inhibition of STAT3 protein is found highly effective to suppress Glioblastoma tumor cells.	('suppress', 'NegReg', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Glioblastoma tumor', 'Disease', (95, 113))	('STAT3', 'Gene', '6774', (43, 48))	('Glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('STAT3', 'Gene', (43, 48))	('Glioblastoma tumor', 'Disease', 'MESH:D005909', (95, 113))	('inhibition', 'Var', (29, 39))
143475	31263189	Furthermore, if the P53 protein was mutated but Notch pathway was active, then the stem cell dynamics would alter and redirect towards the development of self-renewing Glioblastoma stem cells (GSCs).	('stem cell dynamics', 'CPA', (83, 101))	('Glioblastoma', 'Phenotype', 'HP:0012174', (168, 180))	('protein', 'Protein', (24, 31))	('Glioblastoma', 'Disease', (168, 180))	('P53', 'Gene', (20, 23))	('Glioblastoma', 'Disease', 'MESH:D005909', (168, 180))	('mutated', 'Var', (36, 43))	('redirect', 'Reg', (118, 126))	('P53', 'Gene', '7157', (20, 23))	('alter', 'Reg', (108, 113))
143477	31263189	It was also observed that the same gliogenesis process could be malfunctioned and lead to the development of Glioblastoma tumor formation if the differentiating cells had mutant P53 protein.	('protein', 'Protein', (182, 189))	('lead to', 'Reg', (82, 89))	('P53', 'Gene', (178, 181))	('Glioblastoma tumor', 'Disease', (109, 127))	('P53', 'Gene', '7157', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('Glioblastoma tumor', 'Disease', 'MESH:D005909', (109, 127))	('mutant', 'Var', (171, 177))
143497	31263189	High-throughput, raw RNA-Seq counts data provided by The Cancer Genome Atlas (TCGA) were downloaded from high (TCGA-GBM) and low grade (TCGA-LGG) tumor sample cohorts with a P53 mutation on 27th April 2017 from GDC Data portal (https://portal.gdc.cancer.gov/).	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Cancer Genome Atlas', 'Disease', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('P53', 'Gene', (174, 177))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (57, 76))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('mutation', 'Var', (178, 186))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (146, 151))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('P53', 'Gene', '7157', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
143504	30196423	We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2.	('PDGFRA', 'Gene', '5156', (219, 225))	('RRAS2', 'Gene', '22800', (242, 247))	('PDGFRA', 'Gene', (219, 225))	('TP53', 'Gene', (34, 38))	('BRAF', 'Gene', '673', (232, 236))	('CDK4', 'Gene', '1019', (50, 54))	('CDK4', 'Gene', (50, 54))	('CDKN2A', 'Gene', '1029', (72, 78))	('BRAF', 'Gene', (232, 236))	('Raf', 'Gene', '22882', (180, 183))	('mutations', 'Var', (39, 48))	('MET', 'Gene', (227, 230))	('amplifications', 'Var', (104, 118))	('RRAS2', 'Gene', (242, 247))	('Raf', 'Gene', (180, 183))	('TP53', 'Gene', '7157', (34, 38))	('CDKN2A', 'Gene', (72, 78))	('rearrangements', 'Var', (122, 136))
143516	30196423	For example, we now know that primary glioblastomas arising in the cerebral hemispheres of older adults are genetically defined by frequent TERT promoter mutation, CDKN2A homozygous deletion, EGFR amplification plus mutation/rearrangement, trisomy 7, monosomy 10, and PTEN mutation or deletion.	('PTEN', 'Gene', (268, 272))	('mutation', 'Var', (273, 281))	('trisomy 7', 'Var', (240, 249))	('PTEN', 'Gene', '5728', (268, 272))	('TERT', 'Gene', (140, 144))	('glioblastomas', 'Phenotype', 'HP:0012174', (38, 51))	('monosomy 10', 'Var', (251, 262))	('amplification', 'Var', (197, 210))	('CDKN2A', 'Gene', (164, 170))	('TERT', 'Gene', '7015', (140, 144))	('glioblastomas', 'Disease', (38, 51))	('deletion', 'Var', (182, 190))	('glioblastomas', 'Disease', 'MESH:D005909', (38, 51))	('CDKN2A', 'Gene', '1029', (164, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('deletion', 'Var', (285, 293))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
143517	30196423	Diffuse lower-grade gliomas in the cerebral hemispheres of younger adults are genetically defined by a recurrent hotspot mutation in either the IDH1 or IDH2 oncogenes, with additional TERT promoter mutation and chromosomes 1p and 19q co-deletion in oligodendroglial neoplasms versus additional ATRX and TP53 mutations in diffuse astrocytic neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (340, 348))	('TP53', 'Gene', '7157', (303, 307))	('neoplasm', 'Phenotype', 'HP:0002664', (266, 274))	('IDH1', 'Gene', (144, 148))	('gliomas', 'Disease', (20, 27))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('astrocytic neoplasms', 'Disease', (329, 349))	('neoplasms', 'Phenotype', 'HP:0002664', (266, 275))	('mutation', 'Var', (121, 129))	('astrocytic neoplasms', 'Disease', 'MESH:D001254', (329, 349))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('IDH1', 'Gene', '3417', (144, 148))	('TP53', 'Gene', (303, 307))	('oligodendroglial neoplasms', 'Disease', 'MESH:D009369', (249, 275))	('oligodendroglial neoplasms', 'Disease', (249, 275))	('TERT', 'Gene', (184, 188))	('TERT', 'Gene', '7015', (184, 188))	('ATRX', 'Gene', (294, 298))	('IDH2', 'Gene', (152, 156))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('IDH2', 'Gene', '3418', (152, 156))	('astrocytic neoplasms', 'Phenotype', 'HP:0009592', (329, 349))	('ATRX', 'Gene', '546', (294, 298))	('neoplasms', 'Phenotype', 'HP:0002664', (340, 349))
143518	30196423	In children, diffuse gliomas arising in midline structures of the CNS are defined by p.K27M mutation in the H3F3A, HIST1H3B, or HIST1H3C genes, which are accompanied by a spectrum of additional alterations frequently involving TP53, PPM1D, ACVR1, PDGFRA, and PIK3CA.	('PPM1D', 'Gene', (233, 238))	('H3F3A', 'Gene', (108, 113))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('children', 'Species', '9606', (3, 11))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('TP53', 'Gene', (227, 231))	('HIST1H3C', 'Gene', '8352', (128, 136))	('p.K27M', 'Var', (85, 91))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('PIK3CA', 'Gene', '5290', (259, 265))	('H3F3A', 'Gene', '3020', (108, 113))	('ACVR1', 'Gene', (240, 245))	('HIST1H3B', 'Gene', (115, 123))	('HIST1H3B', 'Gene', '8358', (115, 123))	('HIST1H3C', 'Gene', (128, 136))	('PPM1D', 'Gene', '8493', (233, 238))	('PDGFRA', 'Gene', '5156', (247, 253))	('PDGFRA', 'Gene', (247, 253))	('TP53', 'Gene', '7157', (227, 231))	('diffuse', 'Disease', (13, 20))	('gliomas', 'Disease', (21, 28))	('PIK3CA', 'Gene', (259, 265))	('ACVR1', 'Gene', '90', (240, 245))	('p.K27M', 'Mutation', 'p.K27M', (85, 91))
143519	30196423	In contrast, diffuse gliomas arising in the cerebral hemispheres of children are often defined by mutually exclusive H3F3A p.G34R/V or SETD2 mutations, which are accompanied by frequent TP53, ATRX, and PDGFRA alterations.	('PDGFRA', 'Gene', (202, 208))	('SETD2', 'Gene', (135, 140))	('children', 'Species', '9606', (68, 76))	('mutations', 'Var', (141, 150))	('ATRX', 'Gene', (192, 196))	('PDGFRA', 'Gene', '5156', (202, 208))	('H3F3A', 'Gene', '3020', (117, 122))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('ATRX', 'Gene', '546', (192, 196))	('TP53', 'Gene', '7157', (186, 190))	('p.G34R', 'SUBSTITUTION', 'None', (123, 129))	('p.G34R', 'Var', (123, 129))	('gliomas', 'Disease', (21, 28))	('H3F3A', 'Gene', (117, 122))	('TP53', 'Gene', (186, 190))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('SETD2', 'Gene', '29072', (135, 140))
143520	30196423	However, the genetic alterations that are responsible for secondary gliomas arising after radiation therapy are largely unknown, with some studies suggesting differences with their spontaneous counterparts based on either gene expression analysis or single gene testing for IDH1/2 mutation or EGFR amplification.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('mutation', 'Var', (281, 289))	('EGFR', 'Gene', '1956', (293, 297))	('EGFR', 'Gene', (293, 297))	('IDH1', 'Gene', (274, 278))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('IDH1', 'Gene', '3417', (274, 278))	('amplification', 'Var', (298, 311))	('secondary gliomas', 'Disease', (58, 75))	('secondary gliomas', 'Disease', 'MESH:D005910', (58, 75))
143521	30196423	Studying the mutational and chromosomal patterns in thousands of human cancers across the spectrum of different cancer types has identified "mutational signatures" that are associated with specific cancer types and with specific mutational processes, including the intrinsic infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA, and defective DNA repair.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('human', 'Species', '9606', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (112, 118))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('defective', 'Var', (398, 407))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('associated', 'Reg', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
143522	30196423	For example, Mutational Signature 6 caused by mismatch repair deficiency is characterized by a predominance of small indels and C>T transitions and is seen most commonly in endometrial and colorectal carcinomas.	('Mutational', 'Var', (13, 23))	('seen', 'Reg', (151, 155))	('C>T transitions', 'Var', (128, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('endometrial', 'Disease', (173, 184))	('deficiency', 'Var', (62, 72))	('small indels', 'Var', (111, 123))	('caused by', 'Reg', (36, 45))	('colorectal carcinomas', 'Disease', (189, 210))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (189, 210))	('mismatch repair', 'Protein', (46, 61))
143523	30196423	In contrast, Mutational Signature 7 caused by ultraviolet irradiation is characterized by a predominance of C>T mononucleotide and CC>TT dinucleotide transitions and is seen most commonly in cutaneous melanomas and squamous cell carcinomas arising on sun-exposed skin.	('Mutational', 'Var', (13, 23))	('C>T mononucleotide', 'Var', (108, 126))	('CC>TT dinucleotide transitions', 'Var', (131, 161))	('mononucleotide', 'Chemical', '-', (112, 126))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (215, 239))	('cutaneous melanomas', 'Disease', (191, 210))	('TT dinucleotide', 'Chemical', '-', (134, 149))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (191, 210))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (191, 210))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (215, 239))	('carcinomas', 'Phenotype', 'HP:0030731', (229, 239))	('squamous cell carcinomas', 'Disease', (215, 239))	('melanomas', 'Phenotype', 'HP:0002861', (201, 210))
143524	30196423	One recent study assessed the mutational signature in a small cohort of radiation-associated osteosarcomas, spindle cell sarcomas, angiosarcomas, and breast cancers, which identified an excess of balanced inversions and small deletions (1-100 base pairs in size with microhomology at the junctions) compared to a cohort of spontaneous tumors.	('tumors', 'Disease', (335, 341))	('angiosarcomas', 'Phenotype', 'HP:0200058', (131, 144))	('sarcomas', 'Disease', (136, 144))	('osteosarcomas', 'Phenotype', 'HP:0002669', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('angiosarcomas', 'Disease', (131, 144))	('tumors', 'Disease', 'MESH:D009369', (335, 341))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('balanced inversions', 'Var', (196, 215))	('osteosarcomas', 'Disease', 'MESH:D012516', (93, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('angiosarcomas', 'Disease', 'MESH:D006394', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('breast cancers', 'Disease', 'MESH:D001943', (150, 164))	('sarcomas', 'Disease', (98, 106))	('breast cancers', 'Disease', (150, 164))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('osteosarcomas', 'Disease', (93, 106))	('sarcomas', 'Disease', (121, 129))	('breast cancers', 'Phenotype', 'HP:0003002', (150, 164))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
143526	30196423	Two recent studies of radiation- induced meningiomas found that they lacked somatic single nucleotide variants in the most common genes associated with spontaneous meningioma development including NF2, TRAF7, AKT1, SMO, and KLF4.	('meningioma', 'Disease', 'MESH:D008577', (164, 174))	('NF2', 'Gene', '4771', (197, 200))	('single nucleotide variants', 'Var', (84, 110))	('KLF4', 'Gene', '9314', (224, 228))	('TRAF7', 'Gene', '84231', (202, 207))	('NF2', 'Gene', (197, 200))	('meningioma', 'Disease', (41, 51))	('meningioma', 'Phenotype', 'HP:0002858', (41, 51))	('meningiomas', 'Disease', 'MESH:D008577', (41, 52))	('AKT1', 'Gene', '207', (209, 213))	('meningiomas', 'Phenotype', 'HP:0002858', (41, 52))	('SMO', 'Gene', '6608', (215, 218))	('meningiomas', 'Disease', (41, 52))	('TRAF7', 'Gene', (202, 207))	('meningioma', 'Disease', 'MESH:D008577', (41, 51))	('AKT1', 'Gene', (209, 213))	('meningioma', 'Disease', (164, 174))	('KLF4', 'Gene', (224, 228))	('meningioma', 'Phenotype', 'HP:0002858', (164, 174))	('lacked', 'NegReg', (69, 75))	('SMO', 'Gene', (215, 218))
143527	30196423	Instead, they harbored frequent structural rearrangements involving the NF2 tumor suppressor gene, which are only rarely seen in spontaneous meningiomas.	('meningiomas', 'Disease', 'MESH:D008577', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('structural rearrangements', 'Var', (32, 57))	('meningiomas', 'Phenotype', 'HP:0002858', (141, 152))	('NF2', 'Gene', (72, 75))	('NF2', 'Gene', '4771', (72, 75))	('meningioma', 'Phenotype', 'HP:0002858', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('meningiomas', 'Disease', (141, 152))
143534	30196423	To assess for differences in genomic signature of the radiation-associated gliomas compared to their spontaneous counterparts, we compared the sequencing results from the radiation-associated gliomas to a cohort of 12 spontaneous IDH-wildtype glioblastomas in the cerebral hemispheres of adults, 12 spontaneous IDH-mutant glioblastomas in the cerebral hemispheres of adults, 12 spontaneous H3 K27M-mutant diffuse midline gliomas in children, and 12 spontaneous IDH- and H3 K27-wildtype high-grade infiltrative gliomas in children.	('gliomas', 'Disease', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (421, 428))	('IDH', 'Gene', '3417', (311, 314))	('IDH', 'Gene', (230, 233))	('midline gliomas', 'Disease', 'MESH:D005910', (413, 428))	('gliomas', 'Disease', (510, 517))	('glioblastomas', 'Disease', (243, 256))	('IDH', 'Gene', (461, 464))	('glioblastomas', 'Disease', (322, 335))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Disease', (192, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (243, 255))	('glioblastoma', 'Phenotype', 'HP:0012174', (322, 334))	('K27M', 'SUBSTITUTION', 'None', (393, 397))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('glioblastomas', 'Disease', 'MESH:D005909', (243, 256))	('gliomas', 'Disease', (421, 428))	('glioblastomas', 'Disease', 'MESH:D005909', (322, 335))	('IDH', 'Gene', '3417', (230, 233))	('gliomas', 'Disease', 'MESH:D005910', (510, 517))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('IDH', 'Gene', '3417', (461, 464))	('IDH-wildtype glioblastomas', 'Disease', (230, 256))	('midline gliomas', 'Disease', (413, 428))	('glioma', 'Phenotype', 'HP:0009733', (510, 516))	('K27M', 'Var', (393, 397))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('gliomas', 'Disease', 'MESH:D005910', (421, 428))	('gliomas', 'Phenotype', 'HP:0009733', (510, 517))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (230, 256))	('IDH', 'Gene', (311, 314))	('children', 'Species', '9606', (521, 529))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('glioma', 'Phenotype', 'HP:0009733', (421, 427))	('children', 'Species', '9606', (432, 440))	('glioblastomas', 'Phenotype', 'HP:0012174', (243, 256))	('glioblastomas', 'Phenotype', 'HP:0012174', (322, 335))
143555	30196423	Among the ten high-grade gliomas, seven cases harbored inactivating mutations in the TP53 tumor suppressor gene with loss of the remaining wildtype allele (70%).	('TP53', 'Gene', (85, 89))	('inactivating mutations', 'Var', (55, 77))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('TP53', 'Gene', '7157', (85, 89))	('harbored', 'Reg', (46, 54))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
143557	30196423	In total, 8/10 of the high-grade gliomas had genetic alterations disrupting cell cycle regulation (80%).	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('disrupting', 'NegReg', (65, 75))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('cell', 'MPA', (76, 80))	('genetic alterations', 'Var', (45, 64))
143558	30196423	Focal high-level amplifications or pathogenic mutations involving receptor tyrosine kinase genes were seen in eight cases (80%), with five cases harboring PDGFRA amplification, two cases harboring MET amplification, and one case harboring EGFR amplification.	('amplification', 'Var', (162, 175))	('mutations', 'Var', (46, 55))	('PDGFRA', 'Gene', (155, 161))	('PDGFRA', 'Gene', '5156', (155, 161))	('EGFR', 'Gene', '1956', (239, 243))	('EGFR', 'Gene', (239, 243))
143559	30196423	Two of the cases with PDGFRA amplification harbored missense mutations on the amplified allele located in the extracellular ligand-binding domain (p.Y249C and p.G286R), and one of the cases with MET amplification harbored a missense mutation on the amplified allele located in the extracellular ligand-binding domain (p.A179T).	('p.Y249C', 'Mutation', 'p.Y249C', (147, 154))	('p.Y249C', 'Var', (147, 154))	('p.G286R', 'Var', (159, 166))	('p.G286R', 'Mutation', 'p.G286R', (159, 166))	('missense mutations', 'Var', (52, 70))	('PDGFRA', 'Gene', '5156', (22, 28))	('PDGFRA', 'Gene', (22, 28))	('p.A179T', 'Mutation', 'p.A179T', (318, 325))
143560	30196423	One case (#8) lacking amplification of receptor tyrosine kinase genes harbored three missense mutations in PDGFRA, all of which were located in the intracellular portion of the protein (p.P577R, p.P653L, and p.H845D), of which the p.H845D variant affected a codon within the tyrosine kinase domain that is recurrently mutated in gliomas and gastrointestinal stromal tumors (Catalog of Somatic Mutations In Cancer database, version 85 release).	('p.H845D', 'Mutation', 'p.H845D', (208, 215))	('glioma', 'Phenotype', 'HP:0009733', (329, 335))	('p.H845D', 'Mutation', 'p.H845D', (231, 238))	('PDGFRA', 'Gene', (107, 113))	('Cancer', 'Phenotype', 'HP:0002664', (406, 412))	('affected', 'Reg', (247, 255))	('PDGFRA', 'Gene', '5156', (107, 113))	('p.P653L', 'Mutation', 'p.P653L', (195, 202))	('p.P653L', 'Var', (195, 202))	('p.P577R', 'Mutation', 'p.P577R', (186, 193))	('gliomas', 'Phenotype', 'HP:0009733', (329, 336))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (341, 372))	('gliomas and gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (329, 372))	('p.H845D', 'Var', (231, 238))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumors', 'Phenotype', 'HP:0002664', (366, 372))
143562	30196423	Two cases harbored focal high-level amplifications of RRAS2, one of which also harbored a nonsense mutation in NF1, and two other cases harbored rearrangements of BRAF, one with intragenic deletion of exon 4 and one with GTF2I-BRAF gene fusion.	('nonsense mutation', 'Var', (90, 107))	('RRAS2', 'Gene', (54, 59))	('NF1', 'Gene', (111, 114))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('GTF2I', 'Gene', '2969', (221, 226))	('NF1', 'Gene', '4763', (111, 114))	('RRAS2', 'Gene', '22800', (54, 59))	('rearrangements', 'Var', (145, 159))	('amplifications', 'MPA', (36, 50))	('BRAF', 'Gene', '673', (227, 231))	('deletion', 'Var', (189, 197))	('BRAF', 'Gene', (227, 231))	('GTF2I', 'Gene', (221, 226))
143564	30196423	One case harbored an activating hotspot mutation in PIK3CA (p.Q546R), one case harbored focal high-level amplification of AKT3, and one case harbored a truncating frameshift mutation in TSC2.	('activating hotspot', 'PosReg', (21, 39))	('TSC2', 'Gene', '7249', (186, 190))	('p.Q546R', 'Var', (60, 67))	('PIK3CA', 'Gene', (52, 58))	('p.Q546R', 'Mutation', 'rs397517201', (60, 67))	('TSC2', 'Gene', (186, 190))	('AKT3', 'Gene', (122, 126))	('PIK3CA', 'Gene', '5290', (52, 58))	('AKT3', 'Gene', '10000', (122, 126))
143566	30196423	Alterations in other transcriptional regulatory genes were present in three cases, including two with KMT2D mutations and one with both BCOR focal homozygous deletion and a frameshift mutation in SETD2.	('frameshift mutation', 'Var', (173, 192))	('mutations', 'Var', (108, 117))	('KMT2D', 'Gene', (102, 107))	('KMT2D', 'Gene', '8085', (102, 107))	('SETD2', 'Gene', '29072', (196, 201))	('BCOR', 'Gene', (136, 140))	('BCOR', 'Gene', '54880', (136, 140))	('SETD2', 'Gene', (196, 201))	('Alterations', 'Reg', (0, 11))
143567	30196423	Two cases harbored truncating mutations in ATRX, which has been associated with alternative lengthening of telomeres.	('associated', 'Reg', (64, 74))	('truncating mutations', 'Var', (19, 39))	('harbored', 'Reg', (10, 18))	('ATRX', 'Gene', '546', (43, 47))	('ATRX', 'Gene', (43, 47))
143568	30196423	However, the remaining eight high-grade gliomas all lacked TERT amplification, promoter hotspot mutation, or rearrangement.	('TERT', 'Gene', (59, 63))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('lacked', 'NegReg', (52, 58))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('TERT', 'Gene', '7015', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('rearrangement', 'Var', (109, 122))
143569	30196423	None of the cases harbored pathogenic mutations, amplifications, deletions, and rearrangements in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, PPM1D, ACVR1, FGFR1, FGFR2, FGFR3, NTRK1, NTRK2, NTRK3, and PTEN.	('NTRK1', 'Gene', (172, 177))	('FGFR3', 'Gene', (165, 170))	('amplifications', 'Var', (49, 63))	('rearrangements', 'Var', (80, 94))	('PTEN', 'Gene', (197, 201))	('ACVR1', 'Gene', '90', (144, 149))	('IDH1', 'Gene', '3417', (98, 102))	('FGFR3', 'Gene', '2261', (165, 170))	('HIST1H3B', 'Gene', (117, 125))	('HIST1H3B', 'Gene', '8358', (117, 125))	('NTRK2', 'Gene', (179, 184))	('PPM1D', 'Gene', (137, 142))	('deletions', 'Var', (65, 74))	('FGFR1', 'Gene', (151, 156))	('PTEN', 'Gene', '5728', (197, 201))	('H3F3A', 'Gene', '3020', (110, 115))	('NTRK3', 'Gene', '4916', (186, 191))	('HIST1H3C', 'Gene', '8352', (127, 135))	('NTRK3', 'Gene', (186, 191))	('IDH2', 'Gene', (104, 108))	('H3F3A', 'Gene', (110, 115))	('FGFR2', 'Gene', (158, 163))	('IDH2', 'Gene', '3418', (104, 108))	('ACVR1', 'Gene', (144, 149))	('HIST1H3C', 'Gene', (127, 135))	('IDH1', 'Gene', (98, 102))	('NTRK1', 'Gene', '4914', (172, 177))	('NTRK2', 'Gene', '4915', (179, 184))	('PPM1D', 'Gene', '8493', (137, 142))	('FGFR1', 'Gene', '2260', (151, 156))	('FGFR2', 'Gene', '2263', (158, 163))
143572	30196423	The secondary glioma in the left frontal lobe of patient #12 with histologic features of ganglioglioma was found to harbor focal homozygous deletion of the SMARCB1 gene as the solitary pathogenic alteration, and immunohistochemical staining demonstrated somatic loss of the encoded SMARCB1/BAF47/INI-1 chromatin remodeling protein in the tumor cells [Supplementary Fig.	('glioma', 'Disease', (14, 20))	('SMARCB1', 'Gene', '6598', (156, 163))	('tumor', 'Disease', (338, 343))	('patient', 'Species', '9606', (49, 56))	('SMARCB1', 'Gene', (156, 163))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('BAF47', 'Gene', '6598', (290, 295))	('SMARCB1', 'Gene', '6598', (282, 289))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('SMARCB1', 'Gene', (282, 289))	('INI-1', 'Gene', '6598', (296, 301))	('secondary glioma', 'Disease', 'MESH:D005910', (4, 20))	('INI-1', 'Gene', (296, 301))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('glioma', 'Disease', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('deletion', 'Var', (140, 148))	('loss', 'NegReg', (262, 266))	('BAF47', 'Gene', (290, 295))	('secondary glioma', 'Disease', (4, 20))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))
143575	30196423	The medulloblastoma demonstrated a hotspot missense mutation in the CTNNB1 oncogene (p.G34V), a frameshift mutation in the ARID2 chromatin remodeling gene, monosomy 6, and loss of 17p in combination with gain of 17q consistent with isochromosome 17q.	('p.G34V', 'Mutation', 'rs28931589', (85, 91))	('ARID2', 'Gene', (123, 128))	('loss', 'Var', (172, 176))	('medulloblastoma', 'Disease', 'MESH:D008527', (4, 19))	('CTNNB1', 'Gene', (68, 74))	('medulloblastoma', 'Phenotype', 'HP:0002885', (4, 19))	('gain', 'PosReg', (204, 208))	('p.G34V', 'Var', (85, 91))	('CTNNB1', 'Gene', '1499', (68, 74))	('ARID2', 'Gene', '196528', (123, 128))	('medulloblastoma', 'Disease', (4, 19))	('missense mutation', 'Var', (43, 60))	('frameshift', 'Var', (96, 106))
143577	30196423	Instead, the glioblastoma harbored somatic mutations in TP53, STAG2, and GATA2, focal high level of amplification of PDGFRA with a missense mutation on the amplified allele, focal high-level amplification of MYCN, and focal homozygous deletion of BCOR.	('BCOR', 'Gene', '54880', (247, 251))	('STAG2', 'Gene', (62, 67))	('PDGFRA', 'Gene', (117, 123))	('STAG2', 'Gene', '10735', (62, 67))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('TP53', 'Gene', '7157', (56, 60))	('PDGFRA', 'Gene', '5156', (117, 123))	('missense mutation', 'Var', (131, 148))	('GATA2', 'Gene', (73, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', (56, 60))	('BCOR', 'Gene', (247, 251))	('MYCN', 'Gene', (208, 212))	('MYCN', 'Gene', '4613', (208, 212))	('GATA2', 'Gene', '2624', (73, 78))
143579	30196423	A peripheral blood sample was sequenced from six of the patients allowing for assessment of potential germline variants associated with increased cancer risk.	('patients', 'Species', '9606', (56, 64))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('variants', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
143581	30196423	No family history of colorectal adenocarcinoma or other cancers were present, and this patient's glioblastoma did not demonstrate hypermutation or a mutational signature associated with base excision repair deficiency (i.e., predominance of C>A transversions).	('cancers', 'Disease', (56, 63))	('base', 'MPA', (186, 190))	('colorectal adenocarcinoma', 'Disease', (21, 46))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (21, 46))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patient', 'Species', '9606', (87, 94))	('C>A transversions', 'Var', (241, 258))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
143585	30196423	These six tumors all demonstrated less than three somatic single nucleotide variants or small indels per Mb.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('single nucleotide variants', 'Var', (58, 84))
143588	30196423	Chromosomal copy number analysis of the ten high-grade gliomas arising after radiation therapy revealed markedly aneuploid genomes with multiple segmental gains and losses involving several chromosomes per tumor.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('aneuploid', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('losses', 'NegReg', (165, 171))
143590	30196423	To assess this hypothesis, we quantitated the number of intrachromosomal copy number breakpoints per genome in the 10 radiation-associated high-grade gliomas, alongside a cohort of 12 spontaneous IDH-wildtype glioblastomas in the cerebral hemispheres of adults, 12 spontaneous IDH-mutant glioblastomas in the cerebral hemispheres of adults, 12 spontaneous H3 K27M-mutant diffuse midline gliomas in children, and 12 spontaneous IDH- and H3 K27-wildtype high-grade infiltrative gliomas in children [Fig.	('K27M', 'Var', (359, 363))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (476, 483))	('children', 'Species', '9606', (487, 495))	('gliomas', 'Disease', 'MESH:D005910', (387, 394))	('IDH-wildtype glioblastomas', 'Disease', (196, 222))	('glioblastomas', 'Phenotype', 'HP:0012174', (288, 301))	('glioma', 'Phenotype', 'HP:0009733', (387, 393))	('glioblastomas', 'Phenotype', 'HP:0012174', (209, 222))	('IDH', 'Gene', (427, 430))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (196, 222))	('gliomas', 'Phenotype', 'HP:0009733', (387, 394))	('IDH', 'Gene', (277, 280))	('IDH', 'Gene', (196, 199))	('children', 'Species', '9606', (398, 406))	('midline gliomas', 'Disease', 'MESH:D005910', (379, 394))	('gliomas', 'Disease', (476, 483))	('glioblastomas', 'Disease', (288, 301))	('glioblastoma', 'Phenotype', 'HP:0012174', (288, 300))	('gliomas', 'Disease', (150, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (209, 221))	('glioblastomas', 'Disease', (209, 222))	('IDH', 'Gene', '3417', (427, 430))	('K27M', 'SUBSTITUTION', 'None', (359, 363))	('IDH', 'Gene', '3417', (277, 280))	('glioblastomas', 'Disease', 'MESH:D005909', (288, 301))	('IDH', 'Gene', '3417', (196, 199))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Disease', 'MESH:D005910', (476, 483))	('glioblastomas', 'Disease', 'MESH:D005909', (209, 222))	('gliomas', 'Disease', (387, 394))	('glioma', 'Phenotype', 'HP:0009733', (476, 482))	('midline gliomas', 'Disease', (379, 394))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
143591	30196423	The ten radiation-associated high-grade gliomas demonstrated a median of 58 intrachromosomal copy number breakpoints per genome (range 30-128), which was significantly greater than each of the four assessed spontaneous glioma tumor entities: IDH-wildtype glioblastoma in the cerebral hemispheres of adults, median 12, range 5-34 (p < 0.0001); IDH-mutant glioblastomas in the cerebral hemispheres of adults, median 12, range 0-64 (p < 0.0001); H3 K27M-mutant diffuse midline gliomas in children, median 2, range 0-25 (p < 0.0001); IDH- and H3 K27-wildtype highgrade infiltrative gliomas in children, median 7, range 0-37 (p < 0.0001).	('midline gliomas', 'Disease', (466, 481))	('gliomas', 'Disease', 'MESH:D005910', (578, 585))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('glioblastoma', 'Disease', (354, 366))	('glioma', 'Phenotype', 'HP:0009733', (578, 584))	('glioblastoma', 'Phenotype', 'HP:0012174', (354, 366))	('children', 'Species', '9606', (485, 493))	('gliomas', 'Disease', 'MESH:D005910', (474, 481))	('glioblastomas', 'Disease', (354, 367))	('IDH', 'Gene', '3417', (343, 346))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('gliomas', 'Phenotype', 'HP:0009733', (578, 585))	('children', 'Species', '9606', (589, 597))	('glioma', 'Phenotype', 'HP:0009733', (474, 480))	('glioblastoma', 'Disease', 'MESH:D005909', (255, 267))	('glioblastomas', 'Disease', 'MESH:D005909', (354, 367))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('gliomas', 'Phenotype', 'HP:0009733', (474, 481))	('glioma tumor', 'Disease', 'MESH:D005910', (219, 231))	('K27M', 'SUBSTITUTION', 'None', (446, 450))	('IDH', 'Gene', (530, 533))	('glioblastoma', 'Disease', (255, 267))	('gliomas', 'Disease', (40, 47))	('IDH', 'Gene', (242, 245))	('midline gliomas', 'Disease', 'MESH:D005910', (466, 481))	('glioblastoma', 'Phenotype', 'HP:0012174', (255, 267))	('glioma tumor', 'Disease', (219, 231))	('gliomas', 'Disease', (578, 585))	('glioblastomas', 'Phenotype', 'HP:0012174', (354, 367))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('IDH', 'Gene', '3417', (530, 533))	('IDH', 'Gene', '3417', (242, 245))	('IDH', 'Gene', (343, 346))	('K27M', 'Var', (446, 450))	('glioblastoma', 'Disease', 'MESH:D005909', (354, 366))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('gliomas', 'Disease', (474, 481))
143593	30196423	The ten radiation-associated high-grade gliomas demonstrated a median of five chromosomes with four or more intrachromosomal copy number breakpoints per genome (range 3-13), which was significantly greater than each of the four assessed spontaneous glioma tumor entities: IDH-wildtype glioblastoma in the cerebral hemispheres of adults, median 1, range 0-3 (p < 0.0001); IDH-mutant glioblastomas in the cerebral hemispheres of adults, median 1, range 0-3 (p < 0.0001); H3 K27M-mutant diffuse midline gliomas in children, median 0, range 0-3 (p < 0.0001); IDH- and H3 K27-wildtype high-grade infiltrative gliomas in children, median 1, range 0-4 (p < 0.0001).	('children', 'Species', '9606', (615, 623))	('IDH', 'Gene', (272, 275))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Phenotype', 'HP:0009733', (500, 507))	('children', 'Species', '9606', (511, 519))	('IDH', 'Gene', (555, 558))	('gliomas', 'Phenotype', 'HP:0009733', (604, 611))	('gliomas', 'Disease', 'MESH:D005910', (604, 611))	('IDH', 'Gene', '3417', (272, 275))	('glioblastomas', 'Phenotype', 'HP:0012174', (382, 395))	('glioblastoma', 'Disease', 'MESH:D005909', (382, 394))	('K27M', 'SUBSTITUTION', 'None', (472, 476))	('IDH', 'Gene', (371, 374))	('IDH', 'Gene', '3417', (555, 558))	('glioma', 'Phenotype', 'HP:0009733', (500, 506))	('midline gliomas', 'Disease', 'MESH:D005910', (492, 507))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Disease', (500, 507))	('glioma tumor', 'Disease', 'MESH:D005910', (249, 261))	('glioblastoma', 'Disease', (382, 394))	('glioblastoma', 'Disease', 'MESH:D005909', (285, 297))	('gliomas', 'Disease', (604, 611))	('glioma', 'Phenotype', 'HP:0009733', (604, 610))	('glioblastoma', 'Phenotype', 'HP:0012174', (382, 394))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('glioblastomas', 'Disease', (382, 395))	('IDH', 'Gene', '3417', (371, 374))	('glioma tumor', 'Disease', (249, 261))	('gliomas', 'Disease', 'MESH:D005910', (500, 507))	('K27M', 'Var', (472, 476))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('glioblastoma', 'Disease', (285, 297))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('midline gliomas', 'Disease', (492, 507))	('glioblastoma', 'Phenotype', 'HP:0012174', (285, 297))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioblastomas', 'Disease', 'MESH:D005909', (382, 395))
143595	30196423	The ten radiation-associated high-grade gliomas demonstrated a median of four focal amplifications or homozygous deletions per genome (range 1-27), which was significantly greater than three of the four assessed spontaneous glioma tumor entities: IDH-wildtype glioblastoma in the cerebral hemispheres of adults, median 3, range 1-4 (p = 0.09); IDH-mutant glioblastomas in the cerebral hemispheres of adults, median 0, range 0-6 (p = 0.0002); H3 K27M-mutant diffuse midline gliomas in children, median 0, range 0-3 (p < 0.0001); IDH- and H3 K27-wildtype high-grade infiltrative gliomas in children, median 1, range 0-8 (p = 0.004).	('IDH', 'Gene', (247, 250))	('IDH', 'Gene', '3417', (528, 531))	('K27M', 'Var', (445, 449))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('IDH', 'Gene', '3417', (344, 347))	('glioblastoma', 'Disease', 'MESH:D005909', (260, 272))	('gliomas', 'Disease', (473, 480))	('gliomas', 'Disease', 'MESH:D005910', (577, 584))	('glioblastoma', 'Disease', (355, 367))	('IDH', 'Gene', '3417', (247, 250))	('children', 'Species', '9606', (588, 596))	('glioblastoma', 'Phenotype', 'HP:0012174', (355, 367))	('glioblastoma', 'Disease', (260, 272))	('glioblastomas', 'Disease', (355, 368))	('glioma', 'Phenotype', 'HP:0009733', (577, 583))	('midline gliomas', 'Disease', (465, 480))	('glioblastoma', 'Phenotype', 'HP:0012174', (260, 272))	('gliomas', 'Disease', 'MESH:D005910', (473, 480))	('gliomas', 'Phenotype', 'HP:0009733', (577, 584))	('glioblastomas', 'Disease', 'MESH:D005909', (355, 368))	('children', 'Species', '9606', (484, 492))	('glioma', 'Phenotype', 'HP:0009733', (473, 479))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Phenotype', 'HP:0009733', (473, 480))	('K27M', 'SUBSTITUTION', 'None', (445, 449))	('IDH', 'Gene', (528, 531))	('glioma tumor', 'Disease', 'MESH:D005910', (224, 236))	('IDH', 'Gene', (344, 347))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('glioblastomas', 'Phenotype', 'HP:0012174', (355, 368))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('midline gliomas', 'Disease', 'MESH:D005910', (465, 480))	('glioma tumor', 'Disease', (224, 236))	('gliomas', 'Disease', (577, 584))	('glioblastoma', 'Disease', 'MESH:D005909', (355, 367))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
143596	30196423	The two radiation-associated low-grade gliomas histologically diagnosed as pleomorphic xanthoastrocytoma and ganglioglioma did not demonstrate an increased number of intrachromosomal copy number breakpoints or focal amplifications and homozygous deletions.	('focal amplifications', 'Var', (210, 230))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Disease', (39, 46))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('pleomorphic xanthoastrocytoma and ganglioglioma', 'Disease', 'MESH:D018303', (75, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
143604	30196423	Additionally, radiation-induced gliomas appear to be molecularly distinct from H3 K27M-mutant diffuse midline gliomas and from H3 G34R/V-mutant diffuse gliomas in the cerebral hemispheres of children and young adults.	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('midline gliomas', 'Disease', (102, 117))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('children', 'Species', '9606', (191, 199))	('K27M', 'SUBSTITUTION', 'None', (82, 86))	('gliomas', 'Disease', (32, 39))	('gliomas', 'Disease', (152, 159))	('G34R', 'SUBSTITUTION', 'None', (130, 134))	('midline gliomas', 'Disease', 'MESH:D005910', (102, 117))	('gliomas', 'Disease', (110, 117))	('G34R', 'Var', (130, 134))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('K27M', 'Var', (82, 86))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
143606	30196423	Additionally, they lack the TERT promoter hotspot mutations and PTEN mutation/deletion that genetically characterize the vast majority of spontaneous IDH-wildtype glioblastomas in adults.	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (150, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('TERT', 'Gene', (28, 32))	('IDH-wildtype glioblastomas', 'Disease', (150, 176))	('PTEN', 'Gene', (64, 68))	('lack', 'NegReg', (19, 23))	('PTEN', 'Gene', '5728', (64, 68))	('TERT', 'Gene', '7015', (28, 32))	('mutation/deletion', 'Var', (69, 86))	('glioblastomas', 'Phenotype', 'HP:0012174', (163, 176))
143607	30196423	We find that radiation-associated high-grade gliomas, which comprised 10 of the 12 cases in our cohort, are genetically characterized by a high frequency of biallelic TP53 inactivation, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2.	('inactivation', 'NegReg', (172, 184))	('PDGFRA', 'Gene', '5156', (355, 361))	('PDGFRA', 'Gene', (355, 361))	('amplifications', 'Var', (240, 254))	('TP53', 'Gene', '7157', (167, 171))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('CDKN2A', 'Gene', (208, 214))	('CDK4', 'Gene', (186, 190))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('Raf', 'Gene', (316, 319))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('MET', 'Gene', (363, 366))	('rearrangements', 'Var', (258, 272))	('CDK4', 'Gene', '1019', (186, 190))	('CDKN2A', 'Gene', '1029', (208, 214))	('RRAS2', 'Gene', (378, 383))	('RRAS2', 'Gene', '22800', (378, 383))	('BRAF', 'Gene', '673', (368, 372))	('TP53', 'Gene', (167, 171))	('BRAF', 'Gene', (368, 372))	('Raf', 'Gene', '22882', (316, 319))	('gliomas', 'Disease', (45, 52))
143608	30196423	We speculate that TP53 mutation is selected for early in the development of radiation-induced gliomas to permit survival and expansion of the tumor-initiating cell with numerous chromosomal rearrangements induced by the ionizing radiation.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('tumor', 'Disease', (142, 147))	('TP53', 'Gene', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('numerous chromosomal rearrangements', 'Phenotype', 'HP:0040012', (169, 204))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
143609	30196423	Notably, TP53 mutations have also been identified at high frequency in radiation-induced sarcomas.	('sarcomas', 'Disease', (89, 97))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('identified', 'Reg', (39, 49))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('mutations', 'Var', (14, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
143612	30196423	However, in contrast to IDH-wildtype glioblastomas in the cerebral hemispheres of adults, radiation-associated high-grade gliomas only rarely harbor EGFR amplification or mutation and instead more frequently demonstrate PDGFRA or MET amplifications or mutations.	('glioblastomas', 'Phenotype', 'HP:0012174', (37, 50))	('PDGFRA', 'Gene', (220, 226))	('mutation', 'Var', (171, 179))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('PDGFRA', 'Gene', '5156', (220, 226))	('EGFR', 'Gene', '1956', (149, 153))	('mutations', 'Var', (252, 261))	('MET amplifications', 'MPA', (230, 248))	('amplification', 'Var', (154, 167))	('EGFR', 'Gene', (149, 153))	('gliomas', 'Disease', (122, 129))	('IDH-wildtype glioblastomas', 'Disease', (24, 50))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (24, 50))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
143613	30196423	Compared with both high-grade gliomas in children and IDH-wildtype glioblastomas in adults, radiation-associated high-grade gliomas only rarely harbor NF1 inactivation and instead more frequently demonstrate BRAF rearrangement or RRAS2 focal high-level amplifications, the latter of which is not known to be recurrently present in any spontaneous glioma subtype.	('gliomas', 'Disease', (124, 131))	('RRAS2', 'Gene', (230, 235))	('BRAF', 'Gene', '673', (208, 212))	('glioma subtype', 'Disease', (347, 361))	('BRAF', 'Gene', (208, 212))	('glioma', 'Phenotype', 'HP:0009733', (347, 353))	('inactivation', 'Var', (155, 167))	('RRAS2', 'Gene', '22800', (230, 235))	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('IDH-wildtype glioblastomas', 'Disease', (54, 80))	('NF1', 'Gene', (151, 154))	('children', 'Species', '9606', (41, 49))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('glioblastomas', 'Phenotype', 'HP:0012174', (67, 80))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (54, 80))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('demonstrate', 'Reg', (196, 207))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('gliomas', 'Disease', (30, 37))	('glioma subtype', 'Disease', 'MESH:D005910', (347, 361))	('NF1', 'Gene', '4763', (151, 154))
143616	30196423	This large quantity of intrachromosomal copy number breakpoints was distributed across several chromosomes in the genome, and was not limited to one or two chromosomes that had undergone chromothripsis, which is sometimes seen for chromosomes 7 and 9 in spontaneous IDH-wildtype glioblastomas as the likely mechanism for causing EGFR amplification and CDKN2A homozygous deletion.	('amplification', 'Var', (334, 347))	('CDKN2A', 'Gene', '1029', (352, 358))	('CDKN2A', 'Gene', (352, 358))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (266, 292))	('IDH-wildtype glioblastomas', 'Disease', (266, 292))	('glioblastomas', 'Phenotype', 'HP:0012174', (279, 292))	('EGFR', 'Gene', '1956', (329, 333))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('EGFR', 'Gene', (329, 333))
143621	30196423	These radiation-induced double-strand breaks lead to a distinct genomic signature that differentiates these tumors from their spontaneous counterparts and is likely responsible for promoting the amplifications of oncogenes (e.g., PDGFRA, MET, RRAS2), homozygous deletions of tumor suppressor genes (e.g., CDKN2A), and rearrangements of oncogenes (e.g., BRAF) that characterize radiation-induced gliomas.	('PDGFRA', 'Gene', '5156', (230, 236))	('CDKN2A', 'Gene', (305, 311))	('tumor', 'Disease', (275, 280))	('PDGFRA', 'Gene', (230, 236))	('tumor', 'Disease', (108, 113))	('MET', 'Gene', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('amplifications', 'MPA', (195, 209))	('gliomas', 'Disease', 'MESH:D005910', (395, 402))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('glioma', 'Phenotype', 'HP:0009733', (395, 401))	('CDKN2A', 'Gene', '1029', (305, 311))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('gliomas', 'Phenotype', 'HP:0009733', (395, 402))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('BRAF', 'Gene', '673', (353, 357))	('BRAF', 'Gene', (353, 357))	('tumors', 'Disease', (108, 114))	('oncogenes', 'Gene', (213, 222))	('RRAS2', 'Gene', (243, 248))	('RRAS2', 'Gene', '22800', (243, 248))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('rearrangements', 'Var', (318, 332))	('gliomas', 'Disease', (395, 402))	('promoting', 'PosReg', (181, 190))
143629	30196423	However, the pathogenic alterations identified in both tumors (KIAA1549-BRAF fusion and SMARCB1 homozygous deletion) were caused by chromosomal breaks rather than single nucleotide variants, which may have been induced by ionizing radiation at the time of therapy for the primary malignancy.	('malignancy', 'Disease', (280, 290))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SMARCB1', 'Gene', '6598', (88, 95))	('chromosomal breaks', 'Var', (132, 150))	('KIAA1549-BRAF', 'Disease', (63, 76))	('caused by', 'Reg', (122, 131))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('SMARCB1', 'Gene', (88, 95))	('tumors', 'Disease', (55, 61))	('malignancy', 'Disease', 'MESH:D009369', (280, 290))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('KIAA1549-BRAF', 'Disease', 'None', (63, 76))
143633	29997438	Previous studies have shown that function loss of SIL1 is often associated with neurological diseases, such as Marinesco-Sjogren Syndrome.	('associated', 'Reg', (64, 74))	('Marinesco-Sjogren Syndrome', 'Disease', (111, 137))	('SIL1', 'Gene', (50, 54))	('neurological diseases', 'Disease', 'MESH:D019636', (80, 101))	('function loss', 'Var', (33, 46))	('neurological diseases', 'Disease', (80, 101))
143642	29997438	Transwell assay showed that cell migration of U251 was significantly inhibited by siSIL transfection, with an inhibitory rate reaching 69%.	('transfection', 'Var', (88, 100))	('U251', 'Gene', (46, 50))	('cell migration', 'CPA', (28, 42))	('U251', 'CellLine', 'CVCL:0021', (46, 50))	('inhibited', 'NegReg', (69, 78))	('siSIL', 'Gene', (82, 87))
143644	29997438	Mechanism studies demonstrated that siSIL1 transfection led to inactivation of AKT/mTOR signaling pathway, including decreased phosphorylation of AKT and mTOR without affecting protein expression, as well as decreased expression of the downstream effector p70S6K.	('mTOR', 'Gene', (154, 158))	('mTOR', 'Gene', (83, 87))	('p70S6K', 'Gene', (256, 262))	('siSIL1', 'Gene', (36, 42))	('transfection', 'Var', (43, 55))	('inactivation', 'NegReg', (63, 75))	('phosphorylation', 'MPA', (127, 142))	('AKT', 'Gene', (79, 82))	('AKT', 'Gene', '207', (146, 149))	('p70S6K', 'Gene', '6198', (256, 262))	('decreased', 'NegReg', (117, 126))	('AKT', 'Gene', (146, 149))	('AKT', 'Gene', '207', (79, 82))	('decreased', 'NegReg', (208, 217))	('expression', 'MPA', (218, 228))	('mTOR', 'Gene', '2475', (154, 158))	('mTOR', 'Gene', '2475', (83, 87))
143655	29997438	BiP and SIL1 are ubiquitously expressed in human tissues and their abnormal expression or structure disruption often leads to cell protein abnormal accumulation, impaired ER homeostasis and even cell apoptosis.	('cell protein abnormal accumulation', 'MPA', (126, 160))	('cell apoptosis', 'CPA', (195, 209))	('leads to', 'Reg', (117, 125))	('abnormal', 'Var', (67, 75))	('impaired ER homeostasis', 'Disease', (162, 185))	('impaired ER homeostasis', 'Disease', 'MESH:D001523', (162, 185))	('human', 'Species', '9606', (43, 48))
143657	29997438	Filezac de L'Etang et al find that in an ALS mouse model SIL1 protein exhibits a differential expression in different motor neurons and knocking out of Sil1 disrupts ER homeostasis and aggravates the degree of ALS.	('aggravates', 'PosReg', (185, 195))	('Sil1', 'Gene', '81500', (152, 156))	('disrupts', 'NegReg', (157, 165))	('ALS', 'Phenotype', 'HP:0007354', (210, 213))	('Sil1', 'Gene', (152, 156))	('mouse', 'Species', '10090', (45, 50))	('ER homeostasis', 'MPA', (166, 180))	('ALS', 'MPA', (210, 213))	('knocking out', 'Var', (136, 148))	('SIL1', 'Gene', (57, 61))	('ALS', 'Phenotype', 'HP:0007354', (41, 44))
143662	29997438	To explore the physiological action of SIL1, we applied RNA interference technology to knock down the SIL1 expression in U251 glioma cells and investigated the impact on tumor cell function.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('U251', 'CellLine', 'CVCL:0021', (121, 125))	('tumor', 'Disease', (170, 175))	('knock', 'Var', (87, 92))	('glioma', 'Disease', (126, 132))	('SIL1', 'Gene', (102, 106))
143692	29997438	The primary antibodies included anti-SIL1 (Cat#ab5639; Abcam, Cambridge, UK), anti-alpha-tubulin (Cat#ab18251; Abcam), anti-Bax (Cat#ab32503; Abcam), anti-active caspase3 p17-specific (Cat#25546-1-AP; Proteintech Group), anti-p-Akt (Cat#ab81283; Abcam), anti-Akt (Cat#ab32505; Abcam), anti-mTOR (Cat#ab2732; Abcam), anti-p-mTOR (Cat#ab131538; Abcam), anti-P70S6K (Cat#ab32529; Abcam).	('mTOR', 'Gene', '2475', (323, 327))	('p17', 'Gene', (171, 174))	('Cat', 'Var', (296, 299))	('Akt', 'Gene', (228, 231))	('P70S6K', 'Gene', (356, 362))	('mTOR', 'Gene', '2475', (290, 294))	('Akt', 'Gene', '207', (228, 231))	('caspase3', 'Gene', (162, 170))	('P70S6K', 'Gene', '6198', (356, 362))	('alpha-tubulin', 'Gene', '10376', (83, 96))	('Akt', 'Gene', (259, 262))	('Akt', 'Gene', '207', (259, 262))	('Cat#ab32505', 'Var', (264, 275))	('p17', 'Gene', '653820', (171, 174))	('Cat#ab131538;', 'Var', (329, 342))	('caspase3', 'Gene', '836', (162, 170))	('Cat#ab81283', 'Var', (233, 244))	('Bax', 'Gene', (124, 127))	('mTOR', 'Gene', (323, 327))	('alpha-tubulin', 'Gene', (83, 96))	('Bax', 'Gene', '581', (124, 127))	('mTOR', 'Gene', (290, 294))
143699	29997438	The results indicated that the survival rate of patients with a high SIL1 expression was significantly lower in both GBM (HR(high)=1.7, p(HR)=0.0053, n(high)=81, n(low)=81) and LGG (HR(high)=2, p(HR)=0.00011, n(high)=257, n(low)=257) compared to those with a low SIL1 expression.	('high', 'Var', (64, 68))	('survival rate', 'CPA', (31, 44))	('SIL1', 'Gene', (69, 73))	('lower', 'NegReg', (103, 108))	('patients', 'Species', '9606', (48, 56))
143700	29997438	It was suggested that high SIL1 expression represented a poor prognosis and SIL1 might play a role in promoting glioma progression.	('SIL1', 'Gene', (27, 31))	('high', 'Var', (22, 26))	('glioma', 'Disease', (112, 118))	('promoting', 'PosReg', (102, 111))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('expression', 'MPA', (32, 42))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
143705	29997438	In general, glioma patients with high SIL1 expression accounted for 65.79% (25/38) of total samples.	('SIL1', 'Gene', (38, 42))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('glioma', 'Disease', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
143707	29997438	To investigate the function of SIL1, we designed 4 siRNAs to knock down SIL1 in U251 cells.	('U251', 'CellLine', 'CVCL:0021', (80, 84))	('SIL1', 'Gene', (72, 76))	('knock down', 'Var', (61, 71))
143709	29997438	The result shown in Figure 2C indicated that after transfection for 72 h, the cell viability of siSIL1 transfected U251 cells was significantly decreased compared to that of siNC transfected cells (P<0.05).	('decreased', 'NegReg', (144, 153))	('U251', 'CellLine', 'CVCL:0021', (115, 119))	('transfected', 'Var', (103, 114))	('siSIL1', 'Gene', (96, 102))	('cell viability', 'CPA', (78, 92))
143710	29997438	The inhibitory effect of siSIL1 knockdown on U251 cell proliferation was also demonstrated in clone formation assay (Figure 2D).	('clone formation assay', 'CPA', (94, 115))	('U251', 'CellLine', 'CVCL:0021', (45, 49))	('inhibitory', 'NegReg', (4, 14))	('knockdown', 'Var', (32, 41))	('siSIL1', 'Gene', (25, 31))
143712	29997438	As shown in Figure 2E, the migrated cells (crystal violet stained) in siSIL1 transfected wells were significantly decreased compared to those in the siNC group.	('crystal violet', 'Chemical', 'MESH:D005840', (43, 57))	('decreased', 'NegReg', (114, 123))	('siSIL1', 'Gene', (70, 76))	('transfected', 'Var', (77, 88))
143713	29997438	In summary, siSIL1 transfection significantly inhibited U251 cell proliferation and migration, which suggested that SIL1 played an oncogenic role in glioma.	('siSIL1', 'Gene', (12, 18))	('transfection', 'Var', (19, 31))	('glioma', 'Disease', (149, 155))	('migration', 'CPA', (84, 93))	('U251', 'CellLine', 'CVCL:0021', (56, 60))	('U251 cell proliferation', 'CPA', (56, 79))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('inhibited', 'NegReg', (46, 55))
143716	29997438	However, we found that siSIL1 transfection significantly increased cell apoptosis percentage in U251 cells, from 8.78% of siNC group to 12.92% of siSIL1 group (Figure 3C and D, P<0.05).	('U251', 'CellLine', 'CVCL:0021', (96, 100))	('siSIL1', 'Gene', (23, 29))	('transfection', 'Var', (30, 42))	('increased', 'PosReg', (57, 66))	('increased cell apoptosis percentage', 'Phenotype', 'HP:0030887', (57, 92))	('cell apoptosis percentage', 'CPA', (67, 92))
143717	29997438	As shown in Figure 3E and F, siSIL1 transfection increased the expression of pro-apoptotic protein Bax by 2.35-fold and Caspase3-P17 by 1.7-fold.	('Caspase3', 'Gene', (120, 128))	('P17', 'Gene', (129, 132))	('Bax', 'Gene', '581', (99, 102))	('Bax', 'Gene', (99, 102))	('increased', 'PosReg', (49, 58))	('P17', 'Gene', '653820', (129, 132))	('expression', 'MPA', (63, 73))	('siSIL1', 'Gene', (29, 35))	('transfection', 'Var', (36, 48))	('Caspase3', 'Gene', '836', (120, 128))
143721	29997438	AKT plays a central regulatory role in this signaling pathway and phosphorylation-activated AKT regulates many cell processes by phosphorylating a cohort of substrates, including mTOR.	('AKT', 'Gene', (0, 3))	('cell processes', 'CPA', (111, 125))	('phosphorylation-activated', 'Var', (66, 91))	('AKT', 'Gene', '207', (92, 95))	('AKT', 'Gene', '207', (0, 3))	('regulates', 'Reg', (96, 105))	('phosphorylating', 'MPA', (129, 144))	('mTOR', 'Gene', (179, 183))	('AKT', 'Gene', (92, 95))	('mTOR', 'Gene', '2475', (179, 183))
143722	29997438	When phosphorylated, mTOR will be promoting cell protein synthesis by phosphorylating p70S6K.	('promoting', 'PosReg', (34, 43))	('p70S6K', 'Gene', '6198', (86, 92))	('phosphorylating', 'Var', (70, 85))	('p70S6K', 'Gene', (86, 92))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))	('cell protein synthesis', 'MPA', (44, 66))
143723	29997438	The Western blot results presented in Figure 4 showed that p-AKT and p-mTOR levels were significantly decreased in the siSIL1 group compared to the siNC group, while the expression of AKT and mTOR was not impacted.	('siSIL1', 'Var', (119, 125))	('AKT', 'Gene', '207', (184, 187))	('mTOR', 'Gene', '2475', (192, 196))	('AKT', 'Gene', '207', (61, 64))	('mTOR', 'Gene', '2475', (71, 75))	('mTOR', 'Gene', (71, 75))	('AKT', 'Gene', (184, 187))	('mTOR', 'Gene', (192, 196))	('AKT', 'Gene', (61, 64))	('decreased', 'NegReg', (102, 111))
143725	29997438	These data suggested that AKT/mTOR signaling pathway was significantly inhibited in siSIL1 transfected U251 cells.	('siSIL1', 'Gene', (84, 90))	('U251', 'CellLine', 'CVCL:0021', (103, 107))	('inhibited', 'NegReg', (71, 80))	('AKT', 'Gene', '207', (26, 29))	('AKT', 'Gene', (26, 29))	('mTOR', 'Gene', '2475', (30, 34))	('transfected', 'Var', (91, 102))	('mTOR', 'Gene', (30, 34))
143732	29997438	In our research, we investigate the functions of SIL1 by knocking down gene expression in U251 cells.	('gene expression', 'MPA', (71, 86))	('SIL1', 'Gene', (49, 53))	('knocking', 'Var', (57, 65))	('U251', 'CellLine', 'CVCL:0021', (90, 94))
143735	29997438	The survival plot of GBM and LGG suggested that patients with high SIL1 expression tended to have a poor survival.	('SIL1', 'Gene', (67, 71))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))
143742	29997438	The mechanism study demonstrated that SIL1 knockdown could inhibit phosphorylation level of both AKT and mTOR without impacting their protein expression, which represented an inactivated state of the AKT/mTOR pathway.	('AKT', 'Gene', '207', (97, 100))	('SIL1', 'Gene', (38, 42))	('phosphorylation level', 'MPA', (67, 88))	('AKT', 'Gene', '207', (200, 203))	('AKT', 'Gene', (97, 100))	('mTOR', 'Gene', (204, 208))	('knockdown', 'Var', (43, 52))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (204, 208))	('mTOR', 'Gene', '2475', (105, 109))	('AKT', 'Gene', (200, 203))	('inhibit', 'NegReg', (59, 66))
143744	29997438	AKT/mTOR signaling pathway is activated very frequently in human cancers through a series of genetic and epigenetic regulation.	('AKT', 'Gene', (0, 3))	('human', 'Species', '9606', (59, 64))	('epigenetic regulation', 'Var', (105, 126))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('AKT', 'Gene', '207', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('genetic', 'Var', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('mTOR', 'Gene', (4, 8))	('cancers', 'Disease', (65, 72))	('mTOR', 'Gene', '2475', (4, 8))
143802	29467871	According to the clinical records, the Karnofsky scores of patients with glioma were calculated as follows: >=80, 19 individuals; 60-80, 25 individuals; and <60, 7 individuals.	('glioma', 'Disease', (73, 79))	('60-80', 'Var', (130, 135))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('patients', 'Species', '9606', (59, 67))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))
143821	29467871	The data indicated that plasma IFN-gamma levels were negatively correlated with the expression of CEACAM1 on CD4+ T cells in TILs (r=-0.4316, P=0.0016; Fig.	('expression', 'Var', (84, 94))	('IFN-gamma', 'Gene', '3458', (31, 40))	('IFN-gamma', 'Gene', (31, 40))	('negatively', 'NegReg', (53, 63))	('CEACAM1', 'Gene', (98, 105))
143824	29467871	In general, these data demonstrated that the expression levels of CEACAM1 in the T cells of patients with glioma were associated with the antitumor factor IFN-gamma, and indicated that increased CEACAM1 expression may have a negative regulatory effect on T cells by suppressing the IFN-gamma-secreting capability of T cells.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('IFN-gamma', 'Gene', '3458', (282, 291))	('IFN-gamma', 'Gene', (282, 291))	('expression levels', 'MPA', (45, 62))	('IFN-gamma', 'Gene', (155, 164))	('CEACAM1', 'Var', (195, 202))	('IFN-gamma', 'Gene', '3458', (155, 164))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('tumor', 'Disease', (142, 147))	('expression', 'MPA', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('patients', 'Species', '9606', (92, 100))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('glioma', 'Disease', (106, 112))	('associated', 'Reg', (118, 128))	('negative', 'NegReg', (225, 233))	('increased', 'PosReg', (185, 194))	('suppressing', 'NegReg', (266, 277))
143838	29467871	The dysregulated expression of CEACAM1 in tumors is a key factor in the immune interaction between tumor cells and lymphocytes.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('expression', 'MPA', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('dysregulated', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('CEACAM1', 'Gene', (31, 38))
143850	29467871	The results of the present study revealed that the plasma level of IFN-gamma in the venous blood was negatively correlated with the expression of CEACAM1 on CD4+ and CD8+ T cells in TILs and peripheral CD4+ T cells in patients with glioma, indicating that CEACAM1 may inhibit antitumor immune responses by downregulating IFN-gamma.	('CEACAM1', 'Gene', (146, 153))	('downregulating', 'NegReg', (306, 320))	('patients', 'Species', '9606', (218, 226))	('glioma', 'Disease', (232, 238))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('CEACAM1', 'Var', (256, 263))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('negatively', 'NegReg', (101, 111))	('IFN-gamma', 'Gene', '3458', (67, 76))	('IFN-gamma', 'Gene', (67, 76))	('IFN-gamma', 'Gene', (321, 330))	('IFN-gamma', 'Gene', '3458', (321, 330))	('CD8', 'Gene', (166, 169))	('tumor', 'Disease', (280, 285))	('CD8', 'Gene', '925', (166, 169))	('inhibit', 'NegReg', (268, 275))
143852	29467871	The co-blockade of CEACAM1 and Tim-3 resulted in a synergistic therapeutic effect in mouse colorectal cancer models.	('mouse', 'Species', '10090', (85, 90))	('co-blockade', 'Var', (4, 15))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Tim-3', 'Gene', (31, 36))	('CEACAM1', 'Gene', (19, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))
143860	33072070	Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients.	('death', 'Disease', 'MESH:D003643', (218, 223))	('Cancer', 'Disease', (64, 70))	('death', 'Disease', (218, 223))	('CTLA4', 'Gene', (43, 48))	('Aberrant', 'Var', (25, 33))	('patients', 'Species', '9606', (267, 275))	('PD-1', 'Gene', (34, 38))	('Combination', 'Interaction', (114, 125))	('cytotoxic T lymphocyte-associated protein (CTLA)4', 'Gene', '1493', (153, 202))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (260, 266))	('CTLA4', 'Gene', '1493', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (101, 107))
143874	33072070	For example, tumor hypoxia-associated multi-omic investigations have shown that some molecular variants are correlated with antitumor drug sensitivity or resistance, which has important implications for cancer treatment.	('tumor', 'Disease', (13, 18))	('correlated', 'Reg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('variants', 'Var', (95, 103))	('tumor hypoxia', 'Disease', 'MESH:D000860', (13, 26))	('tumor hypoxia', 'Disease', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('resistance', 'MPA', (154, 164))	('cancer', 'Disease', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', (128, 133))	('drug sensitivity', 'Phenotype', 'HP:0020174', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
143881	33072070	PD-1 is a transmembrane protein that is expressed by immunocytes; blocking PD-1 signaling enhances the anticancer effect of T cells, thereby promoting cancer cell killing.	('PD-1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoting', 'PosReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('blocking', 'Var', (66, 74))	('cancer', 'Disease', (107, 113))	('enhances', 'PosReg', (90, 98))
143883	33072070	Although PD-1 and CTLA4 overexpression, mutations, and gene amplification have been reported in certain cancers, the studies had small sample sizes and used different experimental approaches, making it difficult to compare the findings.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CTLA4', 'Gene', (18, 23))	('gene amplification', 'Var', (55, 73))	('mutations', 'Var', (40, 49))	('overexpression', 'PosReg', (24, 38))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('PD-1', 'Gene', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
143911	33072070	Patients with high MSI (MSI-H) cancers benefit from immunotherapy, and MSI is an index used for cancer detection.	('MSI-H', 'Gene', (24, 29))	('MSI', 'Gene', '5928', (71, 74))	('MSI', 'Gene', (71, 74))	('MSI', 'Gene', (24, 27))	('cancer', 'Disease', (96, 102))	('MSI', 'Gene', '5928', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('MSI-H', 'Gene', '5928', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Disease', (31, 37))	('cancers', 'Disease', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('benefit', 'PosReg', (39, 46))	('MSI', 'Gene', (19, 22))	('immunotherapy', 'CPA', (52, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('MSI', 'Gene', '5928', (19, 22))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
143913	33072070	Gene mutation frequency may be increased in cancer cells as a result of downregulation of MMR genes or defective MMR.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('Gene mutation', 'Var', (0, 13))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('MMR', 'Gene', (113, 116))	('downregulation', 'NegReg', (72, 86))	('defective', 'NegReg', (103, 112))	('MMR genes', 'Gene', (90, 99))
143929	33072070	The Kaplan-Meier survival analysis showed that subjects with higher PD-1 levels had shorter OS than those with lower levels in GBM (P = 0.037), KIRP (P = 0.040), LAML (P = 0.002), low-grade glioma (LGG) (P < 0.001), and UVM (P < 0.001).	('glioma', 'Disease', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('levels', 'Var', (73, 79))	('shorter', 'NegReg', (84, 91))	('UVM', 'Phenotype', 'HP:0007716', (220, 223))	('PD-1', 'Gene', (68, 72))
143932	33072070	The Kaplan-Meier survival analysis showed that patients with higher CTLA4 expression had shorter OS than those with lower CTLA4 expression in KIRC (P = 0.008), LGG (P < 0.001), and THYM (P = 0.040).	('THYM', 'Phenotype', 'HP:0100522', (181, 185))	('expression', 'Var', (74, 84))	('CTLA4', 'Gene', (68, 73))	('patients', 'Species', '9606', (47, 55))	('higher', 'PosReg', (61, 67))	('shorter', 'NegReg', (89, 96))
143954	33072070	Our results showed that PD-1 and CTLA4 expression varies across cancer types and that most cancers are characterized by PD-1 and CTLA4 mutations that lead to their abnormal expression, which can serve as a prognostic biomarker.	('PD-1', 'Gene', (120, 124))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('expression', 'MPA', (173, 183))	('CTLA4', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
143957	33072070	Identifying aberrantly expressed genes in tumors is important for the development of individualized treatments, which can improve therapeutic outcomes.	('aberrantly expressed', 'Var', (12, 32))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
143963	33072070	Gene mutations are the major cause of cancer development, and specific mutations predict treatment response and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('treatment response', 'CPA', (89, 107))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (71, 80))	('predict', 'Reg', (81, 88))	('cancer', 'Disease', (38, 44))	('cause', 'Reg', (29, 34))
143964	33072070	TMB affects the generation of immunogenic peptides, thereby affecting patients' response to immune checkpoint inhibitor treatment.	('generation of immunogenic peptides', 'MPA', (16, 50))	('patients', 'Species', '9606', (70, 78))	('affecting', 'Reg', (60, 69))	('TMB', 'Chemical', '-', (0, 3))	('affects', 'Reg', (4, 11))	('TMB', 'Var', (0, 3))	('response to immune checkpoint inhibitor treatment', 'MPA', (80, 129))
143973	33072070	However, it remains to be determined whether the combination of PD-1 and CTLA4 inhibitors has greater efficacy than monotherapy in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PD-1', 'Gene', (64, 68))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('inhibitors', 'Var', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('CTLA4', 'Gene', (73, 78))
143974	33072070	Epigenetic modifications modulate gene expression and can be exploited by tumor cells to evade immune surveillance.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('gene expression', 'MPA', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('modulate', 'Reg', (25, 33))	('Epigenetic modifications', 'Var', (0, 24))
143994	30279958	For the available data, there were higher numbers of tumor size >= 2.5 cm compared to those < 2.5 cm.	('>= 2.5 cm', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
144015	30279958	Analyzing a subset of these patients based on IDH mutation (a potential marker for secondary GB), those without and with the mutation exhibited survival times at 11.3 months and 27.1 months, respectively.	('patients', 'Species', '9606', (28, 36))	('IDH', 'Gene', '3417', (46, 49))	('IDH', 'Gene', (46, 49))	('mutation', 'Var', (50, 58))
144021	30279958	The patients were further classified into two GB groups: Group A (reference group) - those with GB as the only primary tumor, and Group B - those with GB as a 2nd primary or subsequent tumor (defined per sequence coding) and with history of lower grade gliomas (presence of prior ICD-O-3 histology codes: 9380 glioma, 9381 gliomatosis, 9382 mixed glioma, 9383 subependymoma, 9384 SEGA, 9391-9394 ependymoma, 9400-9401 astrocytoma, 9410 protoplasmic astrocytoma, 9411 gemistocytic astrocytoma, 9412 desmoplastic infantile astrocytoma, 9420 fibrilillary astrocytoma, 9421 pilocytic astrocytoma, 9424 pleomorphic xanthoastrocytoma, 9444 chondroid glioma, and/or 9450-9451 oligodendroglioma]).	('chondroid glioma', 'Disease', 'MESH:D005910', (634, 650))	('astrocytoma', 'Disease', 'MESH:D001254', (580, 591))	('gliomatosis', 'Disease', (323, 334))	('astrocytoma', 'Disease', (580, 591))	('glioma', 'Disease', (323, 329))	('astrocytoma', 'Phenotype', 'HP:0009592', (552, 563))	('glioma', 'Phenotype', 'HP:0009733', (347, 353))	('ependymoma', 'Disease', (396, 406))	('glioma', 'Disease', 'MESH:D005910', (680, 686))	('oligodendroglioma', 'Disease', 'MESH:D009837', (669, 686))	('gliomas', 'Disease', 'MESH:D005910', (253, 260))	('glioma', 'Disease', 'MESH:D005910', (323, 329))	('astrocytoma', 'Disease', 'MESH:D001254', (521, 532))	('astrocytoma', 'Disease', (521, 532))	('ependymoma', 'Disease', (363, 373))	('astrocytoma', 'Disease', 'MESH:D001254', (418, 429))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (570, 591))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('astrocytoma', 'Disease', (418, 429))	('9411', 'Var', (462, 466))	('tumor', 'Disease', (185, 190))	('ependymoma', 'Phenotype', 'HP:0002888', (396, 406))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))	('oligodendroglioma', 'Disease', (669, 686))	('pilocytic astrocytoma', 'Disease', (570, 591))	('astrocytoma', 'Disease', 'MESH:D001254', (616, 627))	('astrocytoma', 'Disease', 'MESH:D001254', (480, 491))	('ependymoma', 'Phenotype', 'HP:0002888', (363, 373))	('gliomas', 'Phenotype', 'HP:0009733', (253, 260))	('chondroid glioma', 'Disease', (634, 650))	('astrocytoma', 'Disease', (616, 627))	('astrocytoma', 'Disease', (480, 491))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('patients', 'Species', '9606', (4, 12))	('astrocytoma', 'Disease', 'MESH:D001254', (449, 460))	('9412', 'Var', (493, 497))	('astrocytoma', 'Disease', (449, 460))	('astrocytoma', 'Disease', 'MESH:D001254', (552, 563))	('glioma', 'Phenotype', 'HP:0009733', (323, 329))	('astrocytoma', 'Phenotype', 'HP:0009592', (449, 460))	('9420', 'Var', (534, 538))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (598, 627))	('astrocytoma', 'Disease', (552, 563))	('glioma', 'Disease', (310, 316))	('ependymoma', 'Disease', 'MESH:D004806', (396, 406))	('glioma', 'Disease', (644, 650))	('9424', 'Var', (593, 597))	('glioma', 'Disease', 'MESH:D005910', (310, 316))	('ependymoma', 'Disease', 'MESH:D004806', (363, 373))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('9421', 'Var', (565, 569))	('astrocytoma', 'Phenotype', 'HP:0009592', (521, 532))	('astrocytoma', 'Phenotype', 'HP:0009592', (480, 491))	('desmoplastic infantile astrocytoma', 'Disease', 'MESH:C535945', (498, 532))	('glioma', 'Disease', (347, 353))	('glioma', 'Disease', 'MESH:D005910', (644, 650))	('subependymoma', 'Disease', 'MESH:D018315', (360, 373))	('tumor', 'Disease', (119, 124))	('pleomorphic xanthoastrocytoma', 'Disease', (598, 627))	('glioma', 'Disease', 'MESH:D005910', (347, 353))	('gliomatosis', 'Disease', 'MESH:D018302', (323, 334))	('astrocytoma', 'Phenotype', 'HP:0009592', (418, 429))	('subependymoma', 'Disease', (360, 373))	('gliomas', 'Disease', (253, 260))	('desmoplastic infantile astrocytoma', 'Disease', (498, 532))	('glioma', 'Disease', (253, 259))	('protoplasmic astrocytoma', 'Disease', (436, 460))	('protoplasmic astrocytoma', 'Disease', 'MESH:D001254', (436, 460))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('glioma', 'Phenotype', 'HP:0009733', (310, 316))	('glioma', 'Phenotype', 'HP:0009733', (644, 650))	('glioma', 'Disease', (680, 686))	('glioma', 'Disease', 'MESH:D005910', (253, 259))
144024	30279958	Occurrence of surgery was defined as such: "No surgery" - those coded as "no surgery (00)" OR "Surgery" - those coded as local tumor destruction NOS (10), biopsy (20), surgery NOS (90), partial resection NOS (40), and subtotal resection (21), gross total resection (55), or radical, total, gross total resection (30).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('gross total resection', 'Var', (243, 264))	('subtotal resection', 'Var', (218, 236))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('partial resection NOS', 'Var', (186, 207))
144025	30279958	Of those who underwent surgery, the extent of primary surgery was defined as follows, similar to previously described: "No GTR" - those coded as "local tumor destruction NOS (10), biopsy (20), partial resection NOS (40), and subtotal resection (21)" OR "GTR" - those coded as gross total resection (55) or radical, total, gross total resection (30).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('partial resection NOS', 'Var', (193, 214))	('subtotal resection', 'Var', (225, 243))	('tumor', 'Disease', (152, 157))	('gross total resection', 'Var', (276, 297))
144031	30279958	Moreover, this subset also exhibits different proportions of the GB variants, as well as differences in other key clinical factors (namely, gender and tumor size at presentation).	('variants', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('differences', 'Reg', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
144036	27386949	We generated a transcriptome signature to identify parainflammation in many primary human tumors and carcinoma cell lines as distinct from their normal tissue counterparts and the tumor microenvironment and show that parainflammation-positive tumors are enriched for p53 mutations and associated with poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('inflammation', 'Disease', (221, 233))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('parainflammation-positive tumors', 'Disease', (217, 249))	('mutations', 'Var', (271, 280))	('tumor', 'Disease', (243, 248))	('carcinoma cell', 'Disease', (101, 115))	('parainflammation-positive tumors', 'Disease', 'MESH:D009369', (217, 249))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('human', 'Species', '9606', (84, 89))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('carcinoma cell', 'Disease', 'MESH:C538614', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('tumors', 'Disease', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (180, 185))	('tumors', 'Disease', (90, 96))	('p53', 'Gene', (267, 270))	('inflammation', 'Disease', (55, 67))
144038	27386949	We conclude that parainflammation, a low-grade form of inflammation, is widely prevalent in human cancer, particularly in cancer types commonly harboring p53 mutations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('cancer', 'Disease', (98, 104))	('p53', 'Gene', (154, 157))	('inflammation', 'Disease', 'MESH:D007249', (21, 33))	('inflammation', 'Disease', (21, 33))	('mutations', 'Var', (158, 167))	('human', 'Species', '9606', (92, 97))	('prevalent', 'Reg', (79, 88))	('inflammation', 'Disease', (55, 67))
144039	27386949	Our data suggest that parainflammation may be a driver for p53 mutagenesis and a guide for cancer prevention by NSAID treatment.	('p53', 'Gene', (59, 62))	('mutagenesis', 'Var', (63, 74))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('inflammation', 'Disease', 'MESH:D007249', (26, 38))	('inflammation', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
144042	27386949	We recently developed and characterized a mouse model of intestinal cancer based on tissue-specific ablation of CKIalpha.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mouse', 'Species', '10090', (42, 47))	('intestinal cancer', 'Disease', 'MESH:D007414', (57, 74))	('CKIalpha', 'Gene', (112, 120))	('intestinal cancer', 'Disease', (57, 74))	('ablation', 'Var', (100, 108))
144043	27386949	Inducible ablation of CKIalpha in the gut epithelium has several immediate consequences, Wnt activation due to stabilization of beta-catenin, induction of DNA damage response with robust p53 activation, and elicitation of a low-grade inflammatory response in the epithelium.	('activation', 'PosReg', (93, 103))	('beta-catenin', 'Gene', (128, 140))	('activation', 'PosReg', (191, 201))	('beta-catenin', 'Gene', '1499', (128, 140))	('CKIalpha', 'Gene', (22, 30))	('ablation', 'Var', (10, 18))	('low-grade inflammatory response', 'CPA', (224, 255))	('elicitation', 'Reg', (207, 218))	('DNA damage response', 'MPA', (155, 174))	('stabilization', 'MPA', (111, 124))
144047	27386949	Upon p53 ablation, however, PI loses its beneficial role and, instead, contributes to carcinogenesis.	('carcinogenesis', 'Disease', (86, 100))	('beneficial', 'MPA', (41, 51))	('ablation', 'Var', (9, 17))	('loses', 'NegReg', (31, 36))	('p53', 'Gene', (5, 8))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('contributes', 'Reg', (71, 82))
144052	27386949	We then intersected the 840 genes with a list of genes found to be significantly upregulated in RNA-seq expression profiles of two mouse models featuring gut PI: CKIalpha-deficient and CKIalpha-p53-deficient gut epithelium (Additional file 2).	('deficient gut', 'Phenotype', 'HP:0005245', (198, 211))	('CKIalpha-deficient', 'Var', (162, 180))	('upregulated', 'PosReg', (81, 92))	('mouse', 'Species', '10090', (131, 136))
144059	27386949	We prepared organoid cultures from APC-mutated normal gut epithelium (MIN) and adenomatous polyps of APCmin/+ mice (adenoma) and analyzed them via RNA-seq (Additional file 5).	('adenoma', 'Disease', 'MESH:D000236', (116, 123))	('APC-mutated', 'Var', (35, 46))	('adenoma', 'Disease', (116, 123))	('adenomatous polyps', 'Disease', (79, 97))	('mice', 'Species', '10090', (110, 114))	('adenoma', 'Disease', 'MESH:D000236', (79, 86))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (79, 97))	('adenoma', 'Disease', (79, 86))	('adenomatous polyps', 'Disease', 'MESH:D018256', (79, 97))
144078	27386949	The median number of overexpressing cell lines was 125 (19.7 % of carcinoma samples) for the PI genes compared with 39 (6.2 %, U-test p value = 2.7e-5) across random inflammatory response genes and only 31 (4.9 %, p value = 2.6e-8) across random genes.	('carcinoma', 'Disease', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoma', 'Disease', 'MESH:D002277', (66, 75))	('PI genes', 'Var', (93, 101))
144091	27386949	Strikingly, over all cancer types 25.9 % of the tumor samples were PI+, compared with a null expectation of 5 %, with varying proportions among cancer types, from 77.7 % in pancreatic adenocarcinoma (PAAD) to none in kidney renal clear cell carcinoma (KIRC).	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (217, 250))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (173, 198))	('kidney renal clear cell carcinoma', 'Disease', (217, 250))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PI+', 'Var', (67, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (173, 198))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('pancreatic adenocarcinoma', 'Disease', (173, 198))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
144092	27386949	Accordingly, the median number of PI genes activated in PI+ samples is 17 (42.5 %; compared with eight in PI- samples), the same number we observed to be upregulated in the adenoma organoids.	('upregulated', 'PosReg', (154, 165))	('activated', 'PosReg', (43, 52))	('PI+', 'Var', (56, 59))	('PI genes', 'Gene', (34, 42))	('adenoma', 'Disease', 'MESH:D000236', (173, 180))	('adenoma', 'Disease', (173, 180))
144108	27386949	(Additional file 3: Table S5) and associated them with PI scores in tumor samples across cancer types.	('tumor', 'Disease', (68, 73))	('PI scores', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
144119	27386949	Our analysis revealed higher mortality rates for patients with high PI scores in most cancer types (Additional file 3: Table S9).	('higher', 'PosReg', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mortality rates', 'MPA', (29, 44))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('high PI scores', 'Var', (63, 77))	('cancer', 'Disease', (86, 92))
144120	27386949	Prominent examples of high PI score tumors associated with bad prognosis are head and neck squamous cell carcinoma (HNCS; Cox regression p value = 1.4e-3), low-grade glioma (LGG; p value = 8.4e-4), lung adenocarcinoma (LUAD; p value = 9.4e-3), and pancreatic adenocarcinoma (PAAD; p value = 6.7e-5).	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (248, 273))	('pancreatic adenocarcinoma', 'Disease', (248, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (198, 217))	('high PI score', 'Var', (22, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (198, 217))	('neck squamous cell carcinoma', 'Disease', (86, 114))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (86, 114))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (248, 273))	('tumors', 'Disease', (36, 42))	('glioma', 'Disease', (166, 172))	('lung adenocarcinoma', 'Disease', (198, 217))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))
144121	27386949	Median time of mortality of PI+ compared with PI- patients was 1.54-, 3.50-, 1.33-, and 3.53-fold faster, respectively (Fig.	('PI+', 'Var', (28, 31))	('faster', 'PosReg', (98, 104))	('patients', 'Species', '9606', (50, 58))
144122	27386949	A pan-cancer survival analysis of all samples confirmed a negative correlation of PI with survival, showing a consistent earlier mortality for the PI+ patients (p value = 7.1e-29; Fig.	('PI+', 'Var', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('patients', 'Species', '9606', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('earlier', 'PosReg', (121, 128))	('cancer', 'Disease', (6, 12))
144127	27386949	By analyzing the mutation data from whole-exome sequencing provided by TCGA across all samples with expression data, we found 1309 samples with mutations in the TP53 gene versus 2363 with wild-type (WT) TP53.	('TP53', 'Gene', '7157', (203, 207))	('TP53', 'Gene', (161, 165))	('TP53', 'Gene', (203, 207))	('TP53', 'Gene', '7157', (161, 165))	('mutations', 'Var', (144, 153))
144128	27386949	This result was recapitulated in the carcinoma cell lines:29.3 % PI+ in mutated p53 and 20.6 % in WT:although less significant (p value = 0.016).	('carcinoma cell', 'Disease', (37, 51))	('mutated', 'Var', (72, 79))	('PI+', 'Var', (65, 68))	('p53', 'Protein', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinoma cell', 'Disease', 'MESH:C538614', (37, 51))
144129	27386949	p53 mutations are observed more frequently in cell lines than in primary tumors (59.8 % versus 35.7 %), possibly reflecting the growth advantage of p53 mutants in tissue culture, which may hinder a stronger association between p53 mutations and PI in cancer cell lines.	('p53', 'Gene', (0, 3))	('p53', 'Gene', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutants', 'Var', (152, 159))	('primary tumors', 'Disease', (65, 79))	('primary tumors', 'Disease', 'MESH:D009369', (65, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (251, 257))
144130	27386949	Notably, cancer types with known, albeit unexplained low rates of p53 mutations, such as kidney cancer types and prostate adenocarcinoma (PRAD), tend to show low rates of PI, whereas cancers with high p53 mutation rates, such as pancreatic adenocarcinoma (PAAD) and colon adenocarcinoma (COAD), show high rates of PI (R = 0.740, p value = 0.002) (Fig.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (266, 286))	('prostate adenocarcinoma', 'Disease', (113, 136))	('cancer', 'Disease', (96, 102))	('kidney cancer', 'Disease', 'MESH:D007680', (89, 102))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (229, 254))	('pancreatic adenocarcinoma', 'Disease', (229, 254))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (113, 136))	('mutations', 'Var', (70, 79))	('kidney cancer', 'Phenotype', 'HP:0009726', (89, 102))	('COAD', 'Disease', 'MESH:D029424', (288, 292))	('kidney cancer', 'Disease', (89, 102))	('colon adenocarcinoma', 'Disease', (266, 286))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('COAD', 'Disease', (288, 292))	('p53', 'Gene', (66, 69))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (229, 254))
144131	27386949	Finally, it is well known that patients harboring tumors with p53 mutations have significantly worse prognosis (in TCGA: Cox regression p value = 4.9e-15).	('mutations', 'Var', (66, 75))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('p53', 'Gene', (62, 65))
144132	27386949	For 2954 patients with both mutations and clinical data, our analysis revealed only a small decrease in significance between controlled and uncontrolled Cox regression analyses (p value without controlling for p53 = 4.7e-17, p value with controlling for p53 = 2.4e-11), indicating that the poor survival associated with PI cannot entirely be attributed to p53 loss.	('patients', 'Species', '9606', (9, 17))	('loss', 'NegReg', (360, 364))	('mutations', 'Var', (28, 37))	('p53', 'Gene', (356, 359))
144157	27386949	Indeed, the p53 status of the tumor displays a high association with PI in a variety of cancer types.	('p53', 'Var', (12, 15))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('association', 'Interaction', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (30, 35))
144158	27386949	A similar association of p53 mutation or loss with PI occurs across the entire spectrum of cancer types: those with low PI, like prostate, liver, thyroid, and melanoma, have few p53 mutations.	('p53', 'Gene', (25, 28))	('liver', 'Disease', (139, 144))	('melanoma', 'Disease', (159, 167))	('mutation', 'Var', (29, 37))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('prostate', 'Disease', (129, 137))	('thyroid', 'Disease', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('p53', 'Gene', (178, 181))	('loss', 'NegReg', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
144159	27386949	Why certain cancer types have low p53 mutation frequencies with no evidence of p53 pathway suppression is an enigma.	('p53', 'Gene', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutation', 'Var', (38, 46))
144160	27386949	The strong association between PI and p53 mutations in cancer suggests that PI may be one of the major driving forces for inactivating the p53 pathway.	('p53', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inactivating', 'NegReg', (122, 134))	('p53 pathway', 'Pathway', (139, 150))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (55, 61))
144162	27386949	Such a tumorigenesis switch mechanism may be a particularly powerful cancer driver mechanism and is thus possibly one of the main mechanisms enforcing p53 mutations in cancer, which cannot be substituted by loss of other tumor suppressor genes.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (155, 164))	('tumor', 'Disease', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('p53', 'Gene', (151, 154))	('cancer', 'Disease', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
144163	27386949	While we are not aware yet of other means of switching PI from a cancer suppressor to a promoter, it is possible that certain other tumor-specific genetic aberrations may fulfill a function similar to p53 inactivation, pushing cancer progression.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('pushing', 'PosReg', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', (132, 137))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('inactivation', 'Var', (205, 217))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
144185	27386949	Of the carcinoma cell lines, 25.9 % have a PI score over 0.1859.	('carcinoma cell', 'Disease', 'MESH:C538614', (7, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('PI score', 'Var', (43, 51))	('carcinoma cell', 'Disease', (7, 21))
144201	24614622	Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson).	('mutation', 'Var', (34, 42))	('IDH1', 'Gene', '3417', (29, 33))	('IDH1', 'Gene', (29, 33))
144203	24614622	GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP.	('G-CIMP', 'Chemical', '-', (86, 92))	('IDH1', 'Gene', (68, 72))	('IDH1', 'Gene', '3417', (68, 72))	('mutation', 'Var', (73, 81))	('proneural', 'Disease', (45, 54))
144204	24614622	Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes.	('IDH1', 'Gene', '3417', (11, 15))	('better', 'PosReg', (59, 65))	('survival', 'CPA', (66, 74))	('G-CIMP', 'Chemical', '-', (24, 30))	('IDH1', 'Gene', (11, 15))	('G-CIMP', 'Var', (24, 30))
144205	24614622	Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs.	('better', 'PosReg', (105, 111))	('G-CIMP', 'Chemical', '-', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH1', 'Gene', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDH1', 'Gene', '3417', (46, 50))	('tumors', 'Disease', (80, 86))	('survival', 'MPA', (112, 120))	('mutation', 'Var', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
144206	24614622	Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.	('PTEN', 'Gene', (108, 112))	('Copy number changes', 'Var', (0, 19))	('changes', 'Var', (89, 96))	('GBMs', 'Disease', (157, 161))	('GII/IIIs', 'Disease', (67, 75))	('EGFR', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (117, 121))	('PTEN', 'Gene', '5728', (108, 112))	('associated', 'Reg', (51, 61))	('associated', 'Reg', (141, 151))	('CDKN2A', 'Gene', (100, 106))	('CDKN2A', 'Gene', '1029', (100, 106))
144215	24614622	Importantly, a subset of the proneural GBMs was later found to present a glioma associated CpG Island Methylator Phenotype (G-CIMP) and was tightly tied to the R132 mutation in IDH1.	('glioma', 'Disease', (73, 79))	('IDH1', 'Gene', (177, 181))	('R132', 'Var', (160, 164))	('G-CIMP', 'Chemical', '-', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH1', 'Gene', '3417', (177, 181))
144216	24614622	Mechanistic studies found that this mutation produced 2-hydroxyglutarate and remodels the methylome.	('2-hydroxyglutarate', 'MPA', (54, 72))	('remodels', 'Reg', (77, 85))	('methylome', 'MPA', (90, 99))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (54, 72))	('mutation', 'Var', (36, 44))
144217	24614622	The R132 IDH1 mutation, which was first reported in GBM, is a prevalent event in lower grade gliomas and is a prognostic marker for better prognosis in both GII/IIIs and GBMs.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('IDH1', 'Gene', (9, 13))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH1', 'Gene', '3417', (9, 13))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('R132', 'Var', (4, 8))
144218	24614622	The better survival of GII/IIIs, especially those with the proneural subtype, has been attributed in large part to the distinctive genetic and clinical characteristics of IDH1 mutant tumors.	('mutant', 'Var', (176, 182))	('better', 'PosReg', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('IDH1', 'Gene', '3417', (171, 175))	('IDH1', 'Gene', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumors', 'Disease', (183, 189))
144223	24614622	Besides the recent finding of the R132 IDH1 mutation, 1p/19q co-deletion is considered a favorable prognostic factor for GII/IIIs.	('1p/19q co-deletion', 'Var', (54, 72))	('IDH1', 'Gene', (39, 43))	('IDH1', 'Gene', '3417', (39, 43))	('GII/IIIs', 'Disease', (121, 129))	('R132', 'Var', (34, 38))
144229	24614622	The final DASL dataset consisted of 141 patients with annotated clinical information, of which 115 have a known IDH1 mutation status.	('mutation', 'Var', (117, 125))	('patients', 'Species', '9606', (40, 48))	('IDH1', 'Gene', '3417', (112, 116))	('IDH1', 'Gene', (112, 116))
144236	24614622	R132 IDH1 mutation information and annotated clinical information was gathered from corresponding supplementary files.	('R132', 'Var', (0, 4))	('IDH1', 'Gene', (5, 9))	('IDH1', 'Gene', '3417', (5, 9))
144239	24614622	R132 IDH1 mutation status was available for 286 gliomas (from DASL and JCO) and was used as a proxy for G-CIMP status.	('G-CIMP', 'Chemical', '-', (104, 110))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('IDH1', 'Gene', (5, 9))	('IDH1', 'Gene', '3417', (5, 9))	('R132', 'Var', (0, 4))	('gliomas', 'Disease', (48, 55))
144246	24614622	A new variable that unified G-CIMP predictions and R132 IDH1 mutation status was generated (IDH1/G-CIMP).	('G-CIMP', 'Chemical', '-', (28, 34))	('IDH1', 'Gene', (92, 96))	('G-CIMP', 'Chemical', '-', (97, 103))	('IDH1', 'Gene', '3417', (56, 60))	('IDH1', 'Gene', '3417', (92, 96))	('R132', 'Var', (51, 55))	('IDH1', 'Gene', (56, 60))
144252	24614622	However, the proneural subtype with IDH1 mutation was more prevalent among GII/IIIs compared with GBMs, seen in 53% of tumors across histological subtypes, as contrasted with only 24% of GBMs.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('IDH1', 'Gene', (36, 40))	('proneural subtype', 'Disease', (13, 30))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('GII/IIIs', 'Disease', (75, 83))	('mutation', 'Var', (41, 49))	('IDH1', 'Gene', '3417', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('prevalent', 'Reg', (59, 68))
144257	24614622	Comparing percentage distributions of G-CIMP negative in Rembrandt with IDH1 mutation negative in JCO and DASL, there were no significant differences between DASL and Rembrandt or between DASL and JCO, with Fisher's exact test P values of 4.28x10-1 and 7.75x10-2 respectively.	('IDH1', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('IDH1', 'Gene', '3417', (72, 76))	('negative', 'NegReg', (86, 94))	('G-CIMP', 'Chemical', '-', (38, 44))
144259	24614622	Figure 2 shows gene expression heatmaps for the 840-gene expression based signature in each of the three datasets, according to histological subtype and presence or absence of an IDH1 mutation or G-CIMP.	('G-CIMP', 'Chemical', '-', (196, 202))	('IDH1', 'Gene', '3417', (179, 183))	('IDH1', 'Gene', (179, 183))	('mutation', 'Var', (184, 192))
144261	24614622	However, the presence of an IDH1 mutation is associated with a different expression pattern, as most of proneural tumors had an IDH1 mutation and vice versa, compared to that of classical tumors (Table S4).	('classical tumors', 'Disease', (178, 194))	('mutation', 'Var', (133, 141))	('proneural tumors', 'Disease', (104, 120))	('IDH1', 'Gene', '3417', (28, 32))	('IDH1', 'Gene', '3417', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('proneural tumors', 'Disease', 'MESH:D009369', (104, 120))	('classical tumors', 'Disease', 'MESH:D005693', (178, 194))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('IDH1', 'Gene', (128, 132))	('IDH1', 'Gene', (28, 32))
144262	24614622	For instance, in the DASL data set, 32 of 35 cases with IDH1 R132 mutation were classified as Peroneural.	('Peroneural', 'Disease', (94, 104))	('IDH1', 'Gene', '3417', (56, 60))	('R132 mutation', 'Var', (61, 74))	('IDH1', 'Gene', (56, 60))
144263	24614622	The high correlation of IDH1 mutation and the Proneural subtype not only confirmed our previous report in GBM, but also illustrated the quality of our data set.	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (24, 28))	('IDH1', 'Gene', (24, 28))
144266	24614622	We aimed to evaluate the association between the five molecular subtypes (proneural and IDH1 mutant, proneural and IDH1 wildtype, neural, classical, mesenchymal) and overall survival, using samples for which survival annotation was available from the JCO, Rembrandt and DASL datasets (Figure 3A, B, C, oligodendrogliomas: N = 46, astrocytomas: N = 132 and GBM: N = 387)).	('oligodendrogliomas', 'Disease', (302, 320))	('IDH1', 'Gene', (115, 119))	('IDH1', 'Gene', (88, 92))	('astrocytomas', 'Disease', 'MESH:D001254', (330, 342))	('astrocytoma', 'Phenotype', 'HP:0009592', (330, 341))	('IDH1', 'Gene', '3417', (115, 119))	('glioma', 'Phenotype', 'HP:0009733', (313, 319))	('mutant', 'Var', (93, 99))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (302, 320))	('astrocytomas', 'Disease', (330, 342))	('IDH1', 'Gene', '3417', (88, 92))	('gliomas', 'Phenotype', 'HP:0009733', (313, 320))
144271	24614622	Codeletion of chromosomes 1p and 19qwas most frequent among IDH1+/G-CIMP Oligo II and Oligo III tumors compared with GBMs and IDH1-/non G-CIMP tumors (P = 1.58x10-8 for 1p and P = 1.20x10-7 for 19q, Figure 4).	('IDH1', 'Gene', '3417', (126, 130))	('G-CIMP', 'Chemical', '-', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('IDH1', 'Gene', (60, 64))	('Codeletion', 'Var', (0, 10))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('IDH1', 'Gene', (126, 130))	('IDH1', 'Gene', '3417', (60, 64))	('frequent', 'Reg', (45, 53))	('G-CIMP', 'Chemical', '-', (136, 142))	('II tumors', 'Disease', (93, 102))	('II tumors', 'Disease', 'MESH:D009369', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
144272	24614622	Within each histological group, the frequency of co-deletions was greater among IDH1+/G-CIMP tumors than IDH1-/non G-CIMP tumors, which is consistent with the Noushmehr et al findings.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('IDH1', 'Gene', (80, 84))	('G-CIMP', 'Chemical', '-', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('greater', 'PosReg', (66, 73))	('G-CIMP', 'Chemical', '-', (115, 121))	('IDH1', 'Gene', (105, 109))	('IDH1', 'Gene', '3417', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('IDH1', 'Gene', '3417', (105, 109))	('co-deletions', 'Var', (49, 61))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
144274	24614622	EGFR amplifciation, and CDKN2A deletions which frequently co-occur with gain of EGFR, consistently anti-correlated with IDH1 wildtype status across both GII/III and GBMs, (P = 1.31x10-4 for EGFR and P = 2.96x10-8 for CDKN2A; Figure 4).	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (190, 194))	('CDKN2A', 'Gene', (24, 30))	('EGFR', 'Gene', '1956', (80, 84))	('CDKN2A', 'Gene', (217, 223))	('gain', 'PosReg', (72, 76))	('deletions', 'Var', (31, 40))	('EGFR', 'Gene', (80, 84))	('IDH1', 'Gene', (120, 124))	('EGFR', 'Gene', (190, 194))	('CDKN2A', 'Gene', '1029', (24, 30))	('CDKN2A', 'Gene', '1029', (217, 223))	('IDH1', 'Gene', '3417', (120, 124))	('EGFR', 'Gene', '1956', (0, 4))
144275	24614622	Overall, the frequency of CDK4/PDGFRA amplification, markers for the proneural subtype, was found to be less than reported elsewhere in GBM (Figure 4).	('PDGFRA', 'Gene', (31, 37))	('PDGFRA', 'Gene', '5156', (31, 37))	('CDK4', 'Gene', '1019', (26, 30))	('CDK4', 'Gene', (26, 30))	('less', 'NegReg', (104, 108))	('amplification', 'Var', (38, 51))
144277	24614622	PTEN deletions were more common in GBM than GII/III s, except classical grade II/III gliomas (P = 2.84x10-8 for PTEN).	('common', 'Reg', (25, 31))	('III gliomas', 'Disease', 'MESH:D005910', (81, 92))	('PTEN', 'Gene', '5728', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('PTEN', 'Gene', (112, 116))	('III gliomas', 'Disease', (81, 92))	('PTEN', 'Gene', '5728', (112, 116))	('PTEN', 'Gene', (0, 4))	('deletions', 'Var', (5, 14))
144278	24614622	Genomic abnormalities of tumor suppressor NF1, which was reported as recurrently deleted and mutated in GBM, specifically the mesenchymal subtype, were rare in the Rembrandt data set.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Genomic abnormalities of tumor', 'Disease', (0, 30))	('mutated', 'Var', (93, 100))	('Genomic abnormalities of tumor', 'Disease', 'MESH:D042822', (0, 30))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
144284	24614622	But we have no reason to assume a technical bias introduced by the DASL platform rather than a natural fluctuation in tumor sampling, provided that 32 out of 35 cases with IDH R132 mutations were classified as Proneural in this data set.	('IDH', 'Gene', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('IDH', 'Gene', '3417', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (181, 190))
144288	24614622	CNKN2A deletion frequently coexists with EGFR amplification in these classical tumors.	('classical tumors', 'Disease', 'MESH:D005693', (69, 85))	('EGFR', 'Gene', (41, 45))	('CNKN2A', 'Gene', (0, 6))	('classical tumors', 'Disease', (69, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('EGFR', 'Gene', '1956', (41, 45))	('deletion', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
144290	24614622	Moreover, recent findings in Turcan et al and Lu et al demonstrated that IDH1 mutation is the molecular basis of G-CIMP in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('mutation', 'Var', (78, 86))	('IDH1', 'Gene', '3417', (73, 77))	('gliomas', 'Disease', (123, 130))	('G-CIMP', 'Chemical', '-', (113, 119))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('IDH1', 'Gene', (73, 77))
144291	24614622	demonstrated that the most IDH1 mutant tumors have a proneural subtype.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutant', 'Var', (32, 38))	('IDH1', 'Gene', (27, 31))	('proneural subtype', 'Disease', (53, 70))	('tumors', 'Disease', (39, 45))	('IDH1', 'Gene', '3417', (27, 31))
144293	24614622	IDH1+/G-CIMP status in GII/IIIs was significantly correlated with better prognosis among all subtypes across all 3 datasets, replicating the findings reported in Yan et al.	('G-CIMP', 'Chemical', '-', (6, 12))	('better', 'PosReg', (66, 72))	('GII/IIIs', 'Var', (23, 31))	('IDH1', 'Gene', (0, 4))	('prognosis', 'CPA', (73, 82))	('IDH1', 'Gene', '3417', (0, 4))
144296	24614622	These findings further confirm that IDH1 mutations are commonly reflective of favorable prognosis and are most commonly found in GII/IIIs.	('mutations', 'Var', (41, 50))	('IDH1', 'Gene', (36, 40))	('GII/IIIs', 'Disease', (129, 137))	('IDH1', 'Gene', '3417', (36, 40))	('commonly found', 'Reg', (111, 125))
144298	24614622	The inclusion of two additional validation datasets, including one (DASL) with newly-collected samples and IDH1 mutation status provides an effective and direct means to illustrate the relationships among IDH1 mutation, proneural subtype and G-CIMP status.	('IDH1', 'Gene', (107, 111))	('IDH1', 'Gene', (205, 209))	('IDH1', 'Gene', '3417', (107, 111))	('IDH1', 'Gene', '3417', (205, 209))	('mutation', 'Var', (210, 218))	('G-CIMP', 'Chemical', '-', (242, 248))	('relationships', 'Interaction', (185, 198))
144302	24614622	IDH1 also appears to be related to the copy number variation pattern of both GII/III s and GBMs.	('GII/III s', 'Disease', (77, 86))	('related', 'Reg', (24, 31))	('IDH1', 'Gene', (0, 4))	('copy number variation', 'Var', (39, 60))	('IDH1', 'Gene', '3417', (0, 4))
144303	24614622	There appears to be three distinct types of GII/III s, those with and IDH1 mutation and 1p and/or 19 q deletions (mostly oligodendrogliomas), those with and IDH1 mutation but no 1p/19q cytogenetic changes (further subdivided into whether they have ATRX or CIC and FUBP1 mutations) and IDH1 wild-type GII/III s, which tend to have EGFR amplification and have been described as "pre-GBM".	('CIC', 'Gene', '23152', (256, 259))	('FUBP1', 'Gene', (264, 269))	('IDH1', 'Gene', (285, 289))	('EGFR', 'Gene', '1956', (330, 334))	('mostly oligodendrogliomas', 'Disease', (114, 139))	('mutation', 'Var', (75, 83))	('IDH1', 'Gene', (157, 161))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('IDH1', 'Gene', (70, 74))	('IDH1', 'Gene', '3417', (285, 289))	('FUBP1', 'Gene', '8880', (264, 269))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('ATRX', 'Gene', (248, 252))	('CIC', 'Gene', (256, 259))	('IDH1', 'Gene', '3417', (157, 161))	('ATRX', 'Gene', '546', (248, 252))	('EGFR', 'Gene', (330, 334))	('mostly oligodendrogliomas', 'Disease', 'MESH:D009837', (114, 139))	('IDH1', 'Gene', '3417', (70, 74))
144304	24614622	Our findings mirror this classification, with 1p/19q deletions mostly confined to oligodendrogliomas with and IDH1 mutation or G-CIMP signature (Figure 4), and EGFR amplification observed mostly in IDH1 wild type GII/III s and GBMs.	('IDH1', 'Gene', '3417', (110, 114))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (82, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH1', 'Gene', (198, 202))	('EGFR', 'Gene', '1956', (160, 164))	('IDH1', 'Gene', '3417', (198, 202))	('oligodendrogliomas', 'Disease', (82, 100))	('EGFR', 'Gene', (160, 164))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('mutation', 'Var', (115, 123))	('IDH1', 'Gene', (110, 114))	('G-CIMP', 'Chemical', '-', (127, 133))
144305	24614622	Other copy number changes also seemed to be associated with IDH1/G-CIMP status.	('associated', 'Reg', (44, 54))	('IDH1', 'Gene', (60, 64))	('G-CIMP', 'Chemical', '-', (65, 71))	('IDH1', 'Gene', '3417', (60, 64))	('copy number changes', 'Var', (6, 25))
144306	24614622	CDK4 amplification was observed in proneural GBMs, but only if they also had an IDH1 mutation or G-CIMP signature (Figure 4).	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('G-CIMP', 'Chemical', '-', (97, 103))	('mutation', 'Var', (85, 93))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
144307	24614622	PTEN deletions were fairly common across all gene expressions subtypes, but absent in IDH1 mutant tumors.	('tumors', 'Disease', (98, 104))	('IDH1', 'Gene', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('IDH1', 'Gene', '3417', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('deletions', 'Var', (5, 14))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
144314	24614622	Gaining an even more detailed understanding of the association between these GBM subtype classifiers, GII/III s and IDH1 mutation/G-CIMP status could further our understanding of prognosis and disease progression and improve clinical management of this disease.	('mutation/G-CIMP', 'Var', (121, 136))	('IDH1', 'Gene', (116, 120))	('further', 'PosReg', (150, 157))	('G-CIMP', 'Chemical', '-', (130, 136))	('IDH1', 'Gene', '3417', (116, 120))
144315	32825279	Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas.	('observed', 'Reg', (152, 160))	('glioma', 'Disease', (176, 182))	('Isocitrate Dehydrogenase', 'Gene', '3417', (0, 24))	('isocitrate dehydrogenase', 'Gene', '3417', (108, 132))	('glioblastomas', 'Disease', 'MESH:D005909', (197, 210))	('Glioma', 'Disease', 'MESH:D005910', (38, 44))	('Glioma', 'Phenotype', 'HP:0009733', (38, 44))	('Mutations', 'Var', (95, 104))	('Glioma', 'Disease', (38, 44))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioblastomas', 'Disease', (197, 210))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('Isocitrate Dehydrogenase', 'Gene', (0, 24))	('isocitrate dehydrogenase', 'Gene', (108, 132))	('IDH', 'Gene', (134, 137))	('glioblastomas', 'Phenotype', 'HP:0012174', (197, 210))
144316	32825279	IDH mutants confer a neomorphic enzyme activity that converts alpha-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism.	('IDH', 'Gene', (0, 3))	('cellular epigenetics', 'MPA', (139, 159))	('converts', 'MPA', (53, 61))	('mutants', 'Var', (4, 11))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (103, 123))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (62, 81))	('metabolism', 'MPA', (164, 174))	('impacts', 'Reg', (131, 138))
144317	32825279	IDH mutation establishes distinctive patterns in metabolism, cancer biology, and the therapeutic sensitivity of glioma.	('IDH', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('mutation', 'Var', (4, 12))	('glioma', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
144318	32825279	Thus, a deeper understanding of the roles of IDH mutations is of great value to improve the therapeutic efficacy of glioma and other malignancies that share similar genetic characteristics.	('IDH', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('malignancies', 'Disease', (133, 145))	('glioma', 'Disease', (116, 122))	('improve', 'PosReg', (80, 87))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
144319	32825279	In this review, we focused on the genetics, biochemistry, and clinical impacts of IDH mutations in glioma.	('mutations', 'Var', (86, 95))	('glioma', 'Disease', (99, 105))	('IDH', 'Gene', (82, 85))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
144320	32825279	In 2008, compelling research showed that mutations in isocitrate dehydrogenase (IDH1 and IDH2) are frequently identified in the World Health Organization (WHO) grade II/III gliomas and secondary glioblastomas (GBMs).	('mutations', 'Var', (41, 50))	('IDH1', 'Gene', (80, 84))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('isocitrate dehydrogenase', 'Gene', (54, 78))	('III gliomas', 'Disease', (169, 180))	('glioblastomas', 'Phenotype', 'HP:0012174', (195, 208))	('isocitrate dehydrogenase', 'Gene', '3417', (54, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (195, 208))	('IDH2', 'Gene', (89, 93))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioblastomas', 'Disease', (195, 208))	('GBMs', 'Phenotype', 'HP:0012174', (210, 214))	('III gliomas', 'Disease', 'MESH:D005910', (169, 180))
144322	32825279	showed that IDH1 and IDH2 mutations frequently occur in WHO grade II/III astrocytomas and oligodendrogliomas.	('oligodendrogliomas', 'Disease', (90, 108))	('IDH1', 'Gene', (12, 16))	('III astrocytomas', 'Disease', 'MESH:D001254', (69, 85))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('mutations', 'Var', (26, 35))	('IDH2', 'Gene', (21, 25))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (90, 108))	('III astrocytomas', 'Disease', (69, 85))	('occur', 'Reg', (47, 52))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
144323	32825279	Besides gliomas, IDH mutations also occur in other non-central nervous system (CNS) malignancies, including acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, chondrosarcoma, and melanoma.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('melanoma', 'Disease', (191, 199))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (138, 169))	('intrahepatic cholangiocarcinoma', 'Disease', (138, 169))	('chondrosarcoma', 'Disease', 'MESH:D002813', (171, 185))	('chondrosarcoma', 'Disease', (171, 185))	('acute myeloid leukemia', 'Disease', (108, 130))	('gliomas', 'Disease', (8, 15))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (151, 169))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('AML', 'Disease', 'MESH:D015470', (132, 135))	('mutations', 'Var', (21, 30))	('malignancies', 'Disease', (84, 96))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (171, 185))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('AML', 'Disease', (132, 135))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('AML', 'Phenotype', 'HP:0004808', (132, 135))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('occur', 'Reg', (36, 41))	('IDH', 'Gene', (17, 20))
144324	32825279	The mutations are confined to a single arginine residue (Arg132) in IDH1 or two arginine residues (Arg172 and Arg140) in IDH2.	('Arg132', 'Chemical', '-', (57, 63))	('arginine', 'Chemical', 'MESH:D001120', (39, 47))	('Arg132', 'Var', (57, 63))	('Arg140', 'Var', (110, 116))	('IDH1', 'Gene', (68, 72))	('Arg140', 'Chemical', '-', (110, 116))	('arginine', 'Chemical', 'MESH:D001120', (80, 88))	('Arg172', 'Chemical', '-', (99, 105))	('Arg172', 'Var', (99, 105))
144325	32825279	In contrast to wild-type IDH, which transforms isocitrate into alpha-ketoglutarate (alpha-KG), the mutated IDHs convert alpha-KG into D-2-hydroxyglutarate (D-2-HG).	('IDHs', 'Gene', (107, 111))	('alpha-KG', 'Chemical', 'MESH:D007656', (84, 92))	('mutated', 'Var', (99, 106))	('alpha-KG', 'Chemical', 'MESH:D007656', (120, 128))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (63, 82))	('isocitrate', 'Chemical', 'MESH:C034219', (47, 57))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (134, 154))	('D-2-HG', 'Chemical', 'MESH:C019417', (156, 162))
144326	32825279	The altered catalytic activity that occurs because of cancer-associated IDH mutations was later termed "neomorphic activity".	('catalytic activity', 'MPA', (12, 30))	('altered', 'Reg', (4, 11))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('IDH', 'Gene', (72, 75))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
144327	32825279	The overproduction of the oncometabolite D-2-HG leads to widespread physiological consequences, including profound effects on cellular metabolism, epigenetic shift, genomic instability, and redox homeostasis.	('cellular metabolism', 'MPA', (126, 145))	('genomic instability', 'CPA', (165, 184))	('overproduction', 'PosReg', (4, 18))	('D-2-HG', 'Var', (41, 47))	('effects', 'Reg', (115, 122))	('D-2-HG', 'Chemical', 'MESH:C019417', (41, 47))	('redox homeostasis', 'MPA', (190, 207))	('epigenetic shift', 'MPA', (147, 163))
144328	32825279	On the other hand, the mutant IDH enzyme brings about substantial changes in cancer biology, thereby establishing novel therapeutic vulnerabilities that are not commonly identified in other neoplasms.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('neoplasms', 'Disease', 'MESH:D009369', (190, 199))	('neoplasms', 'Disease', (190, 199))	('changes', 'Reg', (66, 73))	('IDH', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutant', 'Var', (23, 29))	('neoplasms', 'Phenotype', 'HP:0002664', (190, 199))
144329	32825279	In the present review, we provide an overview of the current knowledge regarding IDH mutations in glioma and discuss the distinctive features in terms of genetic, biochemical, and clinical indications in detail.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('mutations', 'Var', (85, 94))	('glioma', 'Disease', (98, 104))	('IDH', 'Gene', (81, 84))
144330	32825279	IDH mutations occur in approximately 80% of all WHO grade II/III gliomas (also known as lower-grade glioma (LGG)) and secondary GBMs.	('glioma', 'Disease', (100, 106))	('GBMs', 'Phenotype', 'HP:0012174', (128, 132))	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('III gliomas', 'Disease', 'MESH:D005910', (61, 72))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('III gliomas', 'Disease', (61, 72))	('mutations', 'Var', (4, 13))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
144331	32825279	IDH mutations occur at the early stage of gliomagenesis, and often acquire secondary genetic abnormalities such as mutations in tumor protein 53 (TP53), loss of ATP-dependent helicase ATRX, X-linked helicase II (ATRX), or chromosomal region 1p/19q co-deletion.	('tumor protein 53', 'Gene', (128, 144))	('ATRX', 'Gene', (212, 216))	('ATRX', 'Gene', '546', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor protein 53', 'Gene', '7157', (128, 144))	('glioma', 'Disease', (42, 48))	('ATP-dependent helicase ATRX', 'Gene', '546', (161, 188))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('TP53', 'Gene', (146, 150))	('ATP-dependent helicase ATRX', 'Gene', (161, 188))	('genetic abnormalities', 'Disease', 'MESH:D030342', (85, 106))	('X-linked helicase II', 'Gene', (190, 210))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('loss', 'NegReg', (153, 157))	('genetic abnormalities', 'Disease', (85, 106))	('ATRX', 'Gene', (184, 188))	('X-linked helicase II', 'Gene', '546', (190, 210))	('mutations', 'Var', (4, 13))	('ATRX', 'Gene', '546', (184, 188))	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (146, 150))
144333	32825279	For example, IDH mutant diffuse astrocytomas frequently harbor TP53 mutations and loss of ATRX, while these changes are less likely to be observed in most IDH mutant oligodendrogliomas.	('oligodendrogliomas', 'Disease', (166, 184))	('astrocytomas', 'Disease', (32, 44))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('astrocytoma', 'Phenotype', 'HP:0009592', (32, 43))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (166, 184))	('loss', 'NegReg', (82, 86))	('ATRX', 'Gene', (90, 94))	('astrocytomas', 'Disease', 'MESH:D001254', (32, 44))	('mutations', 'Var', (68, 77))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('ATRX', 'Gene', '546', (90, 94))	('harbor', 'Reg', (56, 62))
144334	32825279	In contrast, most histologically confirmed IDH mutant oligodendrogliomas harbor 1p/19q co-deletion.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (54, 72))	('oligodendrogliomas', 'Disease', (54, 72))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('1p/19q co-deletion', 'Var', (80, 98))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
144335	32825279	Interestingly, a majority of glioma patients with IDH mutation and 1p/19q co-deletion also acquire mutations in the promoter regions of the telomerase reverse transcriptase (TERT).	('mutation', 'Var', (54, 62))	('glioma', 'Disease', (29, 35))	('patients', 'Species', '9606', (36, 44))	('TERT', 'Gene', (174, 178))	('TERT', 'Gene', '7015', (174, 178))	('mutations', 'Var', (99, 108))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('IDH', 'Gene', (50, 53))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('telomerase reverse transcriptase', 'Gene', (140, 172))	('telomerase reverse transcriptase', 'Gene', '7015', (140, 172))
144336	32825279	Moreover, mutations of homolog of Drosophila capicua transcriptional repressor (CIC) and far upstream element binding protein 1 (FUBP1) occur frequently in tumors with 1p/19q loss in oligodendrogliomas.	('FUBP1', 'Gene', (129, 134))	('far upstream element binding protein 1', 'Gene', '8880', (89, 127))	('CIC', 'Gene', (80, 83))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (183, 201))	('occur', 'Reg', (136, 141))	('Drosophila', 'Species', '7227', (34, 44))	('FUBP1', 'Gene', '8880', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('far upstream element binding protein 1', 'Gene', (89, 127))	('oligodendrogliomas', 'Disease', (183, 201))	('capicua transcriptional repressor', 'Gene', '53560', (45, 78))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('loss', 'NegReg', (175, 179))	('tumors', 'Disease', (156, 162))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('capicua transcriptional repressor', 'Gene', (45, 78))	('mutations', 'Var', (10, 19))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
144337	32825279	In contrast, these secondary genetic abnormalities are rare in IDH wild-type gliomas, while EGFR amplification appears to occur more frequently compared with IDH mutant gliomas (Figure 1B).	('gliomas', 'Disease', (169, 176))	('amplification', 'Var', (97, 110))	('genetic abnormalities', 'Disease', (29, 50))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Disease', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('genetic abnormalities', 'Disease', 'MESH:D030342', (29, 50))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
144339	32825279	However, IDH mutations are not associated with EGFR, suggesting no cooperation between these two genes during gliomagenesis.	('rat', 'Species', '10116', (72, 75))	('glioma', 'Disease', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('EGFR', 'Gene', '1956', (47, 51))	('mutations', 'Var', (13, 22))	('EGFR', 'Gene', (47, 51))
144341	32825279	With the high prevalence and distinct clinical phenotype of IDH-mutated glioma, the WHO updated the classification of CNS malignancies, with an emphasis on the consideration of IDH mutations as a marker for genetic diagnosis.	('glioma', 'Disease', (72, 78))	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('malignancies', 'Disease', (122, 134))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('IDH-mutated', 'Var', (60, 71))	('rat', 'Species', '10116', (167, 170))
144345	32825279	Furthermore, the researchers validated G-CIMP in non-TCGA GBMs and LGGs, and revealed a strong association between G-CIMP and IDH1 mutations.	('mutations', 'Var', (131, 140))	('G-CIMP', 'Chemical', '-', (115, 121))	('G-CIMP', 'Chemical', '-', (39, 45))	('IDH1', 'Gene', (126, 130))	('GBMs', 'Phenotype', 'HP:0012174', (58, 62))
144347	32825279	demonstrated that the acquisition of IDH mutation is sufficient to establish the genome-wide hypermethylation of CpG islands, which recapitulate the G-CIMP in patients.	('hypermethylation', 'MPA', (93, 109))	('G-CIMP', 'Chemical', '-', (149, 155))	('mutation', 'Var', (41, 49))	('rat', 'Species', '10116', (7, 10))	('IDH', 'Gene', (37, 40))	('patients', 'Species', '9606', (159, 167))
144348	32825279	These findings indicate that IDH mutations play a critical role in epigenetic modulation in gliomas.	('mutations', 'Var', (33, 42))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('IDH', 'Gene', (29, 32))	('epigenetic modulation', 'Var', (67, 88))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
144355	32825279	As cancer-associated mutations occur predominantly in IDH1, we mainly focus on IDH1 mutants and their impact on cancer biology.	('IDH1', 'Gene', (54, 58))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('IDH1', 'Gene', (79, 83))	('mutations', 'Var', (21, 30))
144356	32825279	Cancer-associated IDH mutations are mostly missense mutations, which lead to amino acid substitutions at specific arginine residues in the core active sites.	('arginine', 'Chemical', 'MESH:D001120', (114, 122))	('IDH', 'Gene', (18, 21))	('amino acid substitutions', 'Var', (77, 101))	('Cancer', 'Disease', (0, 6))	('substitutions', 'Var', (88, 101))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('lead to', 'Reg', (69, 76))	('mutations', 'Var', (22, 31))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
144357	32825279	In IDH1, the amino acid substitution commonly affects Arg132, whereas in IDH2, the mutations cluster in Arg140 or Arg172.	('Arg132', 'Chemical', '-', (54, 60))	('Arg140', 'Var', (104, 110))	('affects', 'Reg', (46, 53))	('Arg140', 'Chemical', '-', (104, 110))	('Arg132', 'Var', (54, 60))	('Arg172', 'Chemical', '-', (114, 120))	('Arg172', 'Var', (114, 120))
144358	32825279	The R132H and R132C variants of the IDH1 mutations are the most observed somatic changes in human malignancies, and are identified in 91.86% of all IDH1-mutated cancers (Figure 2C).	('IDH1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('malignancies', 'Disease', (98, 110))	('R132C', 'Var', (14, 19))	('R132C', 'Mutation', 'rs121913499', (14, 19))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('cancers', 'Disease', (161, 168))	('identified', 'Reg', (120, 130))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('human', 'Species', '9606', (92, 97))	('R132H', 'Var', (4, 9))
144359	32825279	The IDH1 R132H variant is predominantly found in gliomas, hematopoietic cancers, carcinoma, and chondrosarcoma (Figure 2C).	('carcinoma', 'Disease', (81, 90))	('chondrosarcoma', 'Disease', 'MESH:D002813', (96, 110))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('chondrosarcoma', 'Disease', (96, 110))	('R132H', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('carcinoma', 'Disease', 'MESH:D009369', (81, 90))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (96, 110))	('found', 'Reg', (40, 45))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('IDH1', 'Gene', (4, 8))	('gliomas, hematopoietic cancers', 'Disease', 'MESH:D009369', (49, 79))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))
144360	32825279	The amino acid substitution from Arg172 to lysine (K) is the most common variant present in IDH2-mutated glioma.	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('amino acid', 'Var', (4, 14))	('glioma', 'Disease', (105, 111))	('Arg172 to lysine', 'Mutation', 'p.R172K', (33, 49))	('Arg172 to', 'Var', (33, 42))	('glioma', 'Disease', 'MESH:D005910', (105, 111))
144361	32825279	IDH2 Arg132 and IDH2 Arg172 are highly conserved in the catalytic active sites, and play critical roles in the recognition of their substrate isocitrate.	('rat', 'Species', '10116', (148, 151))	('Arg132', 'Chemical', '-', (5, 11))	('Arg172', 'Chemical', '-', (21, 27))	('recognition', 'MPA', (111, 122))	('IDH2 Arg172', 'Var', (16, 27))	('rat', 'Species', '10116', (137, 140))	('isocitrate', 'Chemical', 'MESH:C034219', (142, 152))	('IDH2 Arg132', 'Var', (0, 11))
144362	32825279	It has been reported that IDH mutations lead to impaired NADPH production and a decreased affinity for isocitrate, which may suggest that mutations yield a dominant negative inhibition of the enzymes.	('impaired', 'NegReg', (48, 56))	('NADPH', 'Gene', '1666', (57, 62))	('isocitrate', 'Chemical', 'MESH:C034219', (103, 113))	('affinity for isocitrate', 'MPA', (90, 113))	('decreased', 'NegReg', (80, 89))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('negative inhibition', 'NegReg', (165, 184))	('NADPH', 'Gene', (57, 62))
144363	32825279	However, several subsequent investigations, particularly the pioneering work by Dang et al., have reported that cancer-associated IDH1 mutations led to an alteration in the substrate preference of the enzyme, such that the mutant enzyme exhibits a higher affinity for alpha-KG.	('alteration', 'Reg', (155, 165))	('alpha-KG', 'Protein', (268, 276))	('mutant', 'Var', (223, 229))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (135, 144))	('rat', 'Species', '10116', (159, 162))	('IDH1', 'Gene', (130, 134))	('rat', 'Species', '10116', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('substrate preference', 'MPA', (173, 193))	('alpha-KG', 'Chemical', 'MESH:D007656', (268, 276))	('higher', 'PosReg', (248, 254))
144364	32825279	In addition, IDH1 mutation results in a neomorphic activity that converts alpha-KG to D-2-HG, in an NADPH-dependent manner.	('converts alpha-KG to D-2-HG', 'MPA', (65, 92))	('alpha-KG', 'Chemical', 'MESH:D007656', (74, 82))	('NADPH', 'Gene', (100, 105))	('IDH1', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('NADPH', 'Gene', '1666', (100, 105))	('D-2-HG', 'Chemical', 'MESH:C019417', (86, 92))	('results in', 'Reg', (27, 37))	('neomorphic activity', 'MPA', (40, 59))
144365	32825279	Similarly, IDH2 mutants also showed a neomorphic activity by producing D-2-HG in glioma and leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('D-2-HG', 'MPA', (71, 77))	('neomorphic activity', 'CPA', (38, 57))	('D-2-HG', 'Chemical', 'MESH:C019417', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('producing', 'Reg', (61, 70))	('mutants', 'Var', (16, 23))	('glioma and leukemia', 'Disease', 'MESH:D005910', (81, 100))	('IDH2', 'Gene', (11, 15))
144366	32825279	The neomorphic activity of IDH mutants results in the production of a large quantity of D-2-HG.	('IDH', 'Gene', (27, 30))	('D-2-HG', 'MPA', (88, 94))	('mutants', 'Var', (31, 38))	('results in', 'Reg', (39, 49))	('neomorphic activity', 'CPA', (4, 23))	('production of', 'MPA', (54, 67))	('D-2-HG', 'Chemical', 'MESH:C019417', (88, 94))
144367	32825279	The accumulation of D-2-HG impacts cancer biology by affecting alpha-KG-dependent enzymes, which establishes a distinctive phenotype in the IDH-mutated glioma.	('D-2-HG', 'Var', (20, 26))	('alpha-KG-dependent enzymes', 'Enzyme', (63, 89))	('affecting', 'Reg', (53, 62))	('impacts cancer', 'Disease', (27, 41))	('impacts cancer', 'Disease', 'MESH:D009369', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('glioma', 'Disease', (152, 158))	('D-2-HG', 'Chemical', 'MESH:C019417', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('alpha-KG', 'Chemical', 'MESH:D007656', (63, 71))
144368	32825279	D-2-HG influences a wide spectrum of molecular pathways, including those of epigenetic modulation, DNA repair, metabolism, redox balance, and the immune system.	('metabolism', 'MPA', (111, 121))	('influences', 'Reg', (7, 17))	('epigenetic modulation', 'Var', (76, 97))	('DNA repair', 'MPA', (99, 109))	('redox balance', 'MPA', (123, 136))	('D-2-HG', 'Var', (0, 6))	('D-2-HG', 'Chemical', 'MESH:C019417', (0, 6))
144369	32825279	Investigations on these pathways provide a deep understanding of the IDH mutations in glioma biology, and justifications for targeting these pathways in the treatment of IDH mutant gliomas.	('glioma', 'Disease', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('gliomas', 'Disease', (181, 188))	('glioma', 'Disease', (181, 187))	('mutations', 'Var', (73, 82))
144372	32825279	D-2-HG has been shown to inhibit multiple histone demethylases, including KDM7A (demethylate H3K9me2 and H3K27me2), KDM4A/B (demethylate H3K9), and H3K36 demethylases.	('KDM4A/B', 'Gene', (116, 123))	('H3K36 demethylases', 'Enzyme', (148, 166))	('H3K27me2', 'Var', (105, 113))	('histone demethylases', 'Enzyme', (42, 62))	('KDM7A', 'Gene', '80853', (74, 79))	('KDM4A/B', 'Gene', '9682;23030', (116, 123))	('D-2-HG', 'Var', (0, 6))	('H3K9me2', 'Protein', (93, 100))	('KDM7A', 'Gene', (74, 79))	('D-2-HG', 'Chemical', 'MESH:C019417', (0, 6))	('inhibit', 'NegReg', (25, 32))
144373	32825279	demonstrated that D-2-HG competitively inhibits alpha-KG-dependent histone demethylases.	('alpha-KG-dependent histone demethylases', 'Enzyme', (48, 87))	('D-2-HG', 'Var', (18, 24))	('rat', 'Species', '10116', (7, 10))	('inhibits', 'NegReg', (39, 47))	('D-2-HG', 'Chemical', 'MESH:C019417', (18, 24))	('alpha-KG', 'Chemical', 'MESH:D007656', (48, 56))
144374	32825279	Molecular modeling revealed that D-2-HG occupies the alpha-KG binding site and hampers the demethylation reaction of histones.	('hampers', 'NegReg', (79, 86))	('alpha-KG', 'Chemical', 'MESH:D007656', (53, 61))	('demethylation reaction', 'MPA', (91, 113))	('D-2-HG', 'Var', (33, 39))	('histones', 'Protein', (117, 125))	('D-2-HG', 'Chemical', 'MESH:C019417', (33, 39))
144375	32825279	Similarly, D-2-HG competitively inhibits ten-eleven translocation methylcytosine dioxygenase 1 and 2 (TET1 and TET2).	('TET1', 'Gene', '80312', (102, 106))	('TET2', 'Gene', (111, 115))	('ten-eleven translocation methylcytosine', 'MPA', (41, 80))	('D-2-HG', 'Var', (11, 17))	('D-2-HG', 'Chemical', 'MESH:C019417', (11, 17))	('inhibits', 'NegReg', (32, 40))	('TET1', 'Gene', (102, 106))	('cytosine', 'Chemical', 'MESH:D003596', (72, 80))	('TET2', 'Gene', '54790', (111, 115))
144378	32825279	These findings later confirmed that the acquisition of IDH1 mutants or high amounts of D-2-HG is sufficient to induce the hypermethylation phenotype identified among patients with IDH-mutated gliomas.	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('induce', 'Reg', (111, 117))	('gliomas', 'Disease', (192, 199))	('patients', 'Species', '9606', (166, 174))	('mutants', 'Var', (60, 67))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('hypermethylation phenotype', 'MPA', (122, 148))	('D-2-HG', 'Chemical', 'MESH:C019417', (87, 93))	('IDH1', 'Gene', (55, 59))
144379	32825279	Epigenetic reprogramming may lead to the oncogenesis of glioma and other malignancies.	('glioma', 'Disease', (56, 62))	('lead to', 'Reg', (29, 36))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('Epigenetic', 'Var', (0, 10))	('malignancies', 'Disease', (73, 85))	('oncogenesis', 'MPA', (41, 52))
144380	32825279	reported that IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC binding factor (CTCF)-binding sites, which compromises the binding of this important insulator protein.	('hypermethylation', 'Var', (41, 57))	('IDH', 'Gene', (14, 17))	('CCCTC binding factor', 'Gene', (73, 93))	('CTCF', 'Gene', '10664', (95, 99))	('mutant', 'Var', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('binding', 'Interaction', (138, 145))	('compromises', 'NegReg', (122, 133))	('cohesin', 'Protein', (61, 68))	('CCCTC binding factor', 'Gene', '10664', (73, 93))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))	('CTCF', 'Gene', (95, 99))
144383	32825279	In addition, the D-2-HG-associated hypermethylation phenotype impedes cellular differentiation by inhibiting lysine-specific demethylase 4C (KDM4C), which may assist in the maintenance of stemness and gliomagenesis.	('hypermethylation', 'Var', (35, 51))	('stemness and gliomagenesis', 'Disease', 'MESH:D020295', (188, 214))	('lysine-specific demethylase 4C', 'Gene', '23081', (109, 139))	('D-2-HG', 'Chemical', 'MESH:C019417', (17, 23))	('cellular differentiation', 'CPA', (70, 94))	('impedes', 'NegReg', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('KDM4C', 'Gene', '23081', (141, 146))	('D-2-HG-associated', 'Var', (17, 34))	('lysine-specific demethylase 4C', 'Gene', (109, 139))	('KDM4C', 'Gene', (141, 146))	('inhibiting', 'NegReg', (98, 108))
144385	32825279	A growing body of evidence suggests that D-2-HG affects multiple DNA repair pathways.	('affects', 'Reg', (48, 55))	('DNA repair pathways', 'Pathway', (65, 84))	('D-2-HG', 'Chemical', 'MESH:C019417', (41, 47))	('D-2-HG', 'Var', (41, 47))
144386	32825279	reported that IDH-mutant-induced D-2-HG inhibits the alpha-KG-dependent alkB homolog (ALKBH) DNA repair enzymes, which sensitize IDH mutant cancers to DNA alkylating agents.	('alkB', 'Gene', (72, 76))	('alpha-KG', 'Chemical', 'MESH:D007656', (53, 61))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('alkB', 'Gene', '8846', (72, 76))	('cancers', 'Disease', (140, 147))	('ALKBH', 'Gene', (86, 91))	('inhibits', 'NegReg', (40, 48))	('IDH-mutant-induced', 'Var', (14, 32))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutant', 'Var', (133, 139))	('D-2-HG', 'Chemical', 'MESH:C019417', (33, 39))	('ALKBH', 'Gene', '8846', (86, 91))
144387	32825279	reported that mutant IDH1 drives a unique set of transformative events, resulting in increased RAD51-mediated homologous recombination (HR).	('RAD51', 'Gene', '5888', (95, 100))	('mutant', 'Var', (14, 20))	('IDH1', 'Gene', (21, 25))	('increased', 'PosReg', (85, 94))	('RAD51', 'Gene', (95, 100))
144388	32825279	reported that mutant IDH1 downregulates the DNA damage sensor ataxia-telangiectasia-mutated (ATM) signaling pathway by altering histone methylation, leading to sensitivity to DNA damaging agents.	('altering', 'Reg', (119, 127))	('sensor ataxia', 'Phenotype', 'HP:0010871', (55, 68))	('downregulates', 'NegReg', (26, 39))	('telangiectasia', 'Phenotype', 'HP:0001009', (69, 83))	('ATM', 'Gene', '472', (93, 96))	('mutant', 'Var', (14, 20))	('ataxia-telangiectasia-mutated', 'Gene', '472', (62, 91))	('ataxia-telangiectasia-mutated', 'Gene', (62, 91))	('ataxia', 'Phenotype', 'HP:0001251', (62, 68))	('sensitivity to DNA damaging agents', 'MPA', (160, 194))	('IDH1', 'Gene', (21, 25))	('ATM', 'Gene', (93, 96))	('leading to', 'Reg', (149, 159))	('histone methylation', 'MPA', (128, 147))
144389	32825279	showed that in the context of ATRX loss, IDH mutant cancers enhance DNA damage response via the up-regulation of the ATM pathway, suggesting that ATRX deficiency in diffusive astrocytoma may affect DNA repair pathways and sensitivity to therapy.	('IDH', 'Gene', (41, 44))	('cancers', 'Disease', (52, 59))	('DNA damage response', 'MPA', (68, 87))	('ATM', 'Gene', '472', (117, 120))	('up-regulation', 'PosReg', (96, 109))	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', (146, 150))	('ATRX', 'Gene', '546', (30, 34))	('enhance', 'PosReg', (60, 67))	('ATRX', 'Gene', '546', (146, 150))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('ATRX deficiency', 'Disease', 'MESH:C538258', (146, 161))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('diffusive astrocytoma', 'Disease', (165, 186))	('ATM', 'Gene', (117, 120))	('mutant', 'Var', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('affect', 'Reg', (191, 197))	('DNA repair pathways', 'Pathway', (198, 217))	('ATRX deficiency', 'Disease', (146, 161))	('diffusive astrocytoma', 'Disease', 'MESH:D001254', (165, 186))
144390	32825279	Finally, us and several groups have reported that the poly (ADP-ribose) polymerase-1 (PARP1)-associated DNA repair pathway is compromised extensively in mutant cells because of decreased NAD+ availability.	('PARP1', 'Gene', '142', (86, 91))	('NAD+ availability', 'MPA', (187, 204))	('PARP1', 'Gene', (86, 91))	('compromised', 'NegReg', (126, 137))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (54, 84))	('poly (ADP-ribose) polymerase-1', 'Gene', (54, 84))	('mutant', 'Var', (153, 159))	('decreased', 'NegReg', (177, 186))	('NAD+', 'Chemical', 'MESH:D009243', (187, 191))
144392	32825279	revealed that D-2-HG compromises HR DNA repair by influencing histone methylation and local chromatin signaling.	('D-2-HG', 'Chemical', 'MESH:C019417', (14, 20))	('D-2-HG', 'Var', (14, 20))	('histone methylation', 'MPA', (62, 81))	('local chromatin signaling', 'MPA', (86, 111))	('compromises', 'NegReg', (21, 32))	('influencing', 'Reg', (50, 61))	('HR DNA repair', 'CPA', (33, 46))
144394	32825279	The neomorphic activity of mutant IDH completely alters the metabolic flux in the Krebs cycle, and therefore establishes a distinctive pattern in cancer metabolism.	('cancer', 'Disease', (146, 152))	('Krebs', 'Chemical', '-', (82, 87))	('IDH', 'Gene', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mutant', 'Var', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('establishes', 'Reg', (109, 120))	('metabolic flux', 'MPA', (60, 74))	('alters', 'Reg', (49, 55))
144395	32825279	reported that cells expressing mutant IDH1 show increased oxidative tricarboxylic acid metabolism, along with suppressed reductive glutamine metabolism under hypoxic conditions.	('increased', 'PosReg', (48, 57))	('glutamine', 'Chemical', 'MESH:D005973', (131, 140))	('mutant', 'Var', (31, 37))	('reductive glutamine metabolism', 'MPA', (121, 151))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (68, 86))	('oxidative tricarboxylic acid metabolism', 'MPA', (58, 97))	('IDH1', 'Gene', (38, 42))	('suppressed', 'NegReg', (110, 120))
144396	32825279	profiled more than 200 metabolites in human oligodendroglioma cells in order to investigate metabolic reprogramming by the IDH1 mutant enzyme.	('oligodendroglioma', 'Disease', 'MESH:D009837', (44, 61))	('human', 'Species', '9606', (38, 43))	('IDH1', 'Gene', (123, 127))	('mutant', 'Var', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('oligodendroglioma', 'Disease', (44, 61))
144397	32825279	The researchers discovered that glutamate levels were reduced in cells with IDH mutants.	('glutamate levels', 'MPA', (32, 48))	('IDH', 'Gene', (76, 79))	('mutants', 'Var', (80, 87))	('reduced', 'NegReg', (54, 61))	('glutamate', 'Chemical', 'MESH:D018698', (32, 41))
144400	32825279	Furthermore, several studies have shown that the inhibition of glutaminases suppresses the growth of IDH mutant cancers, which indicates that reduced glutamate and increased dependence on glutaminolysis are key features of IDH mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('glutaminase', 'Gene', '2744', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutant', 'Var', (105, 111))	('glutamate', 'Chemical', 'MESH:D018698', (150, 159))	('increased', 'PosReg', (164, 173))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('glutaminase', 'Gene', (63, 74))	('cancers', 'Disease', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('reduced', 'NegReg', (142, 149))	('glutamate', 'MPA', (150, 159))	('IDH', 'Gene', (101, 104))	('suppresses', 'NegReg', (76, 86))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('growth', 'CPA', (91, 97))	('cancers', 'Disease', (234, 241))	('dependence on glutaminolysis', 'MPA', (174, 202))	('inhibition', 'NegReg', (49, 59))
144402	32825279	The neomorphic activity of the IDH mutant enzyme utilizes NADPH as a cofactor, and therefore exhausts the availability of the reductive equivalent for biosynthetic reactions.	('IDH', 'Gene', (31, 34))	('NADPH', 'Gene', (58, 63))	('mutant', 'Var', (35, 41))	('NADPH', 'Gene', '1666', (58, 63))	('exhausts', 'NegReg', (93, 101))	('neomorphic activity', 'MPA', (4, 23))
144403	32825279	Our previous studies have shown that the acquisition of IDH mutants is associated with elevated levels of reactive oxygen species (ROS), suggesting a distinctive pattern in redox homeostasis in malignancies with IDH mutants.	('malignancies', 'Disease', (194, 206))	('IDH', 'Gene', (56, 59))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (106, 129))	('mutants', 'Var', (60, 67))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('malignancies', 'Disease', 'MESH:D009369', (194, 206))	('elevated', 'PosReg', (87, 95))
144405	32825279	Moreover, we discovered that IDH mutant cells mobilize multiple anti-oxidative pathways to maintain the fragile redox homeostasis.	('fragile redox homeostasis', 'Disease', 'MESH:D005600', (104, 129))	('anti-oxidative pathways', 'Pathway', (64, 87))	('fragile redox homeostasis', 'Disease', (104, 129))	('IDH', 'Gene', (29, 32))	('mutant', 'Var', (33, 39))	('maintain', 'PosReg', (91, 99))
144406	32825279	NRF2-governed anti-oxidative pathways, such as that of de novo glutathione synthesis, play a pivotal role in the manifestation of IDH-mutated glioma.	('NRF2', 'Gene', (0, 4))	('glioma', 'Disease', (142, 148))	('IDH-mutated', 'Var', (130, 141))	('glutathione', 'Chemical', 'MESH:D005978', (63, 74))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('anti-oxidative', 'MPA', (14, 28))	('NRF2', 'Gene', '4780', (0, 4))
144408	32825279	In particular, IDH mutations have become some of the most important parameters in the differential diagnosis of gliomas.	('mutations', 'Var', (19, 28))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('IDH', 'Gene', (15, 18))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
144409	32825279	For example, diffuse astrocytomas often harbor IDH mutations, followed by other mutations such as TP53 and ATRX.	('mutations', 'Var', (51, 60))	('astrocytomas', 'Disease', 'MESH:D001254', (21, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (21, 32))	('harbor', 'Reg', (40, 46))	('astrocytomas', 'Disease', (21, 33))	('ATRX', 'Gene', (107, 111))	('TP53', 'Gene', '7157', (98, 102))	('IDH', 'Gene', (47, 50))	('ATRX', 'Gene', '546', (107, 111))	('TP53', 'Gene', (98, 102))
144410	32825279	Oligodendrogliomas are characterized by IDH mutations along with 1p/19q co-deletion (potentially along with CIC and FUBP1 mutations).	('FUBP1', 'Gene', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('mutations', 'Var', (44, 53))	('FUBP1', 'Gene', '8880', (116, 121))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
144411	32825279	Moreover, as IDH mutations frequently induce genome-wide DNA and histone hypermethylation, the introduction of methylation profiling allows for further improving the accuracy of glioma classification.	('induce', 'Reg', (38, 44))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('histone hypermethylation', 'MPA', (65, 89))	('IDH', 'Gene', (13, 16))	('glioma', 'Disease', (178, 184))	('mutations', 'Var', (17, 26))
144417	32825279	In IDH mutant gliomas, D-2-HG accumulates to sufficient levels as a brain metabolite, which renders its visibility on MRS.	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('mutant', 'Var', (7, 13))	('D-2-HG', 'Chemical', 'MESH:C019417', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('IDH', 'Gene', (3, 6))	('gliomas', 'Disease', (14, 21))
144418	32825279	reported that D-2-HG was detected unambiguously in mutant IDH1 glioma in vivo using 2D correlation spectroscopy (COSY) and J-difference spectroscopy.	('IDH1 glioma', 'Disease', (58, 69))	('mutant', 'Var', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('D-2-HG', 'Chemical', 'MESH:C019417', (14, 20))	('IDH1 glioma', 'Disease', 'MESH:D005910', (58, 69))
144425	32825279	first reported that mutations in IDH1 occurred in most patients with secondary GBM, and were associated with better overall survival (OS).	('IDH1', 'Gene', (33, 37))	('associated', 'Reg', (93, 103))	('overall survival', 'MPA', (116, 132))	('patients', 'Species', '9606', (55, 63))	('mutations', 'Var', (20, 29))	('better', 'PosReg', (109, 115))	('occurred', 'Reg', (38, 46))
144426	32825279	reported that GBM patients harboring IDH1 or IDH2 mutations tend to have a prolonged median OS compared with patients with IDH wild-type GBM.	('patients', 'Species', '9606', (109, 117))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', (37, 41))	('median OS', 'MPA', (85, 94))	('IDH2', 'Gene', (45, 49))	('patients', 'Species', '9606', (18, 26))
144429	32825279	Moreover, the progression-free survival (PFS) was also improved among GBM patients with IDH mutations compared with their counterparts.	('improved', 'PosReg', (55, 63))	('patients', 'Species', '9606', (74, 82))	('progression-free survival', 'CPA', (14, 39))	('mutations', 'Var', (92, 101))	('IDH', 'Gene', (88, 91))
144431	32825279	Several studies have reported that IDH mutations are associated with younger age at diagnosis and limited genome alterations among patients with WHO grade II/III gliomas and GBMs, which may bias the disease outcome (Figure 3C,D).	('patients', 'Species', '9606', (131, 139))	('rat', 'Species', '10116', (117, 120))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('IDH', 'Gene', (35, 38))	('III gliomas', 'Disease', 'MESH:D005910', (158, 169))	('mutations', 'Var', (39, 48))	('bias the disease', 'Disease', (190, 206))	('genome alterations', 'CPA', (106, 124))	('bias the disease', 'Disease', 'MESH:D003141', (190, 206))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('GBMs', 'Phenotype', 'HP:0012174', (174, 178))	('limited', 'NegReg', (98, 105))	('III gliomas', 'Disease', (158, 169))
144432	32825279	showed that the IDH mutation status is an independent predictor of favorable outcomes among glioma patients.	('mutation', 'Var', (20, 28))	('IDH', 'Gene', (16, 19))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
144435	32825279	Considering the high incidence of IDH mutations in LGG, it is likely that the epileptic changes are relevant to the unique patterns in the tumor microenvironment, which is associated with IDH mutants.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mutations', 'Var', (38, 47))	('epileptic', 'Disease', 'MESH:D004827', (78, 87))	('epileptic', 'Disease', (78, 87))	('LGG', 'Gene', (51, 54))
144436	32825279	Numerous studies have indicated that mutations in IDH are associated with a high prevalence of epilepsy.	('epilepsy', 'Disease', (95, 103))	('associated', 'Reg', (58, 68))	('epilepsy', 'Disease', 'MESH:D004827', (95, 103))	('mutations', 'Var', (37, 46))	('IDH', 'Gene', (50, 53))	('epilepsy', 'Phenotype', 'HP:0001250', (95, 103))
144437	32825279	showed that IDH mutations are independently correlated with seizures, regardless of WHO grade.	('correlated with', 'Reg', (44, 59))	('seizures', 'Phenotype', 'HP:0001250', (60, 68))	('seizures', 'Disease', (60, 68))	('seizure', 'Phenotype', 'HP:0001250', (60, 67))	('mutations', 'Var', (16, 25))	('IDH', 'Gene', (12, 15))	('seizures', 'Disease', 'MESH:D012640', (60, 68))
144440	32825279	Thus, D-2-HG may act as an analog of glutamate, which leads to the abnormal firing of neurons through activating N-Methyl-d-aspartic acid (NMDA) receptors, and hence epileptic changes.	('activating', 'PosReg', (102, 112))	('N-Methyl-d-aspartic acid', 'MPA', (113, 137))	('D-2-HG', 'Var', (6, 12))	('N-Methyl-d-aspartic acid', 'Chemical', 'MESH:D016202', (113, 137))	('epileptic', 'Disease', 'MESH:D004827', (166, 175))	('D-2-HG', 'Chemical', 'MESH:C019417', (6, 12))	('epileptic', 'Disease', (166, 175))	('firing', 'MPA', (76, 82))	('NMDA', 'Chemical', 'MESH:D016202', (139, 143))	('glutamate', 'Chemical', 'MESH:D018698', (37, 46))
144441	32825279	Treating cultured rat cortical neurons with exogenous D-2-HG resulted in an elevated firing rate.	('rat', 'Species', '10116', (18, 21))	('firing', 'CPA', (85, 91))	('elevated', 'PosReg', (76, 84))	('D-2-HG', 'Chemical', 'MESH:C019417', (54, 60))	('rat', 'Species', '10116', (92, 95))	('D-2-HG', 'Var', (54, 60))
144443	32825279	However, three millimolar D-2-HG induced an elevated burst frequency in the neuronal network in vitro, whereas this dose is over 30 times higher than the glutamate concentration for excitotoxicity.	('D-2-HG', 'Chemical', 'MESH:C019417', (26, 32))	('elevated', 'PosReg', (44, 52))	('burst frequency in the neuronal network', 'MPA', (53, 92))	('glutamate', 'Chemical', 'MESH:D018698', (154, 163))	('excitotoxicity', 'Disease', (182, 196))	('rat', 'Species', '10116', (171, 174))	('excitotoxicity', 'Disease', 'None', (182, 196))	('D-2-HG', 'Var', (26, 32))
144444	32825279	More effort is urged in order to elucidate the detailed molecular mechanism of the epileptic changes in IDH-mutated glioma.	('IDH-mutated', 'Var', (104, 115))	('glioma', 'Disease', (116, 122))	('epileptic', 'Disease', 'MESH:D004827', (83, 92))	('epileptic', 'Disease', (83, 92))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
144445	32825279	Because of the association between IDH mutations and seizures, therapies that target mutant IDH, such as mutant IDH inhibitors, could diminish D-2-HG production and potentially reduce epileptic seizures.	('seizures', 'Disease', (194, 202))	('seizures', 'Disease', (53, 61))	('seizures', 'Phenotype', 'HP:0001250', (194, 202))	('seizures', 'Phenotype', 'HP:0001250', (53, 61))	('seizure', 'Phenotype', 'HP:0001250', (53, 60))	('seizure', 'Phenotype', 'HP:0001250', (194, 201))	('D-2-HG production', 'MPA', (143, 160))	('epileptic seizures', 'Disease', (184, 202))	('D-2-HG', 'Chemical', 'MESH:C019417', (143, 149))	('seizures', 'Disease', 'MESH:D012640', (194, 202))	('diminish', 'NegReg', (134, 142))	('IDH', 'Gene', (92, 95))	('epileptic seizures', 'Disease', 'MESH:D004827', (184, 202))	('mutant', 'Var', (85, 91))	('mutant', 'Var', (105, 111))	('seizures', 'Disease', 'MESH:D012640', (53, 61))	('reduce', 'NegReg', (177, 183))
144446	32825279	Clinical data have shown that IDH mutant gliomas tend to exhibit a better disease outcome compared with wild-type IDH tumors.	('IDH tumors', 'Disease', 'MESH:D009369', (114, 124))	('IDH mutant', 'Var', (30, 40))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('IDH tumors', 'Disease', (114, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))
144448	32825279	IDH mutant gliomas likely harbor defects in multiple DNA repair pathways, which render them vulnerable to radiotherapy- or chemotherapy-induced DNA damage.	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (4, 10))	('gliomas likely harbor defects', 'Disease', (11, 40))	('gliomas likely harbor defects', 'Disease', 'MESH:D005910', (11, 40))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('DNA repair pathways', 'Pathway', (53, 72))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
144449	32825279	These findings indicate that IDH mutation could serve as an important predictive factor for treatment response among glioma patients.	('mutation', 'Var', (33, 41))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('IDH', 'Gene', (29, 32))	('glioma', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))
144450	32825279	reported that IDH1 mutation is an independent predictor of temozolomide response among LGG patients.	('mutation', 'Var', (19, 27))	('patients', 'Species', '9606', (91, 99))	('IDH1', 'Gene', (14, 18))	('LGG', 'Disease', (87, 90))	('temozolomide', 'Chemical', 'MESH:D000077204', (59, 71))	('predictor', 'Reg', (46, 55))
144452	32825279	In another study conducted by van de Bent et al., no correlation was found between IDH1 mutations and disease outcome in response to procarbazine (Matulane), lomustine (CCNU), and vincristine (Oncovin) chemotherapy.	('IDH1', 'Gene', (83, 87))	('Oncovin', 'Chemical', 'MESH:D014750', (193, 200))	('Matulane', 'Chemical', 'MESH:D011344', (147, 155))	('procarbazine', 'Chemical', 'MESH:D011344', (133, 145))	('mutations', 'Var', (88, 97))	('lomustine', 'Chemical', 'MESH:D008130', (158, 167))	('CCNU', 'Chemical', 'MESH:D008130', (169, 173))	('vincristine', 'Chemical', 'MESH:D014750', (180, 191))
144453	32825279	Because of the critical roles played by IDH mutations in the malignant transformation of glioma, targeting the neomorphic activity of IDH mutants has been heavily proposed as a direct therapeutic approach.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('malignant transformation of glioma', 'Phenotype', 'HP:0012174', (61, 95))	('IDH', 'Gene', (40, 43))	('mutations', 'Var', (44, 53))	('glioma', 'Disease', (89, 95))
144454	32825279	In 2012, the first-in-class mutant IDH inhibitor was discovered, which showed a specific and potent inhibitory effect on D-2-HG production in IDH mutant U87 cells and xenograft models.	('IDH', 'Gene', (142, 145))	('mutant', 'Var', (146, 152))	('inhibitory effect', 'NegReg', (100, 117))	('D-2-HG', 'Chemical', 'MESH:C019417', (121, 127))	('D-2-HG production', 'MPA', (121, 138))	('U87', 'CellLine', 'CVCL:0022', (153, 156))
144455	32825279	reported a novel synthetic inhibitor of IDH mutant, AGI-5198, which blocked D-2-HG production and subsequently reversed the malignant transformation effect of IDH mutations.	('D-2-HG production', 'MPA', (76, 93))	('IDH', 'Gene', (159, 162))	('mutations', 'Var', (163, 172))	('blocked', 'NegReg', (68, 75))	('D-2-HG', 'Chemical', 'MESH:C019417', (76, 82))	('malignant transformation effect', 'CPA', (124, 155))
144456	32825279	Besides glioma, the inhibition of mutant IDH promotes differentiation in leukemia harboring IDH mutations.	('IDH', 'Gene', (41, 44))	('glioma', 'Disease', (8, 14))	('inhibition', 'Var', (20, 30))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('promotes', 'PosReg', (45, 53))	('leukemia', 'Disease', (73, 81))	('IDH', 'Gene', (92, 95))	('differentiation', 'CPA', (54, 69))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('glioma', 'Disease', 'MESH:D005910', (8, 14))	('mutant', 'Var', (34, 40))	('mutations', 'Var', (96, 105))
144457	32825279	With the promising findings regarding AGI-5198, second-generation mutant IDH inhibitors are under development and are undergoing evaluation in clinical studies.	('IDH', 'Gene', (73, 76))	('rat', 'Species', '10116', (59, 62))	('mutant', 'Var', (66, 72))
144458	32825279	For example, ivosidenib (AG-120) and vorasidenib (AG-881) have been tested in AML and glioma with IDH mutations.	('vorasidenib', 'Chemical', '-', (37, 48))	('glioma', 'Disease', (86, 92))	('ivosidenib', 'Chemical', 'MESH:C000627630', (13, 23))	('AML', 'Disease', 'MESH:D015470', (78, 81))	('AG-881', 'Chemical', '-', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('mutations', 'Var', (102, 111))	('AML', 'Phenotype', 'HP:0004808', (78, 81))	('IDH', 'Gene', (98, 101))	('AML', 'Disease', (78, 81))
144459	32825279	In a recent phase I clinical study with ivosidenib in IDH1-mutated advanced glioma conducted by Mellinghoff et al., the mutant IDH inhibitor appeared to be well-tolerated throughout the experiment, which paved the way for subsequent clinical studies to evaluate its therapeutic efficacy.	('IDH', 'Gene', (127, 130))	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('rat', 'Species', '10116', (165, 168))	('ivosidenib', 'Chemical', 'MESH:C000627630', (40, 50))	('mutant', 'Var', (120, 126))
144460	32825279	Although the IDH mutant enzyme inhibitors suppress malignancy, several studies have suggested that this inhibitor reduces D-2-HG production and relieves the burden on the DNA repair pathway, resulting in chemoresistance to other therapies, such as PARP inhibitors.	('relieves', 'NegReg', (144, 152))	('PARP', 'Gene', '142', (248, 252))	('D-2-HG', 'Chemical', 'MESH:C019417', (122, 128))	('chemoresistance', 'CPA', (204, 219))	('malignancy', 'Disease', 'MESH:D009369', (51, 61))	('DNA repair pathway', 'Pathway', (171, 189))	('PARP', 'Gene', (248, 252))	('reduces', 'NegReg', (114, 121))	('inhibitor', 'Var', (104, 113))	('malignancy', 'Disease', (51, 61))	('D-2-HG production', 'MPA', (122, 139))	('burden', 'MPA', (157, 163))	('resulting in', 'Reg', (191, 203))	('IDH', 'Gene', (13, 16))	('mutant', 'Var', (17, 23))
144462	32825279	Genome-wide DNA and histone hypermethylation is a unique signature in IDH-mutated glioma, which is closely related to gliomagenesis by promoting oncogene expression and inhibiting tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH-mutated', 'Var', (70, 81))	('glioma', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('promoting', 'PosReg', (135, 144))	('oncogene expression', 'MPA', (145, 164))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioma', 'Disease', (82, 88))	('inhibiting', 'NegReg', (169, 179))	('histone hypermethylation', 'Var', (20, 44))
144463	32825279	This rectification of the epigenetic shift could be a reasonable strategy for halting D-2-HG-driven oncogenesis and the malignant phenotype.	('D-2-HG', 'Chemical', 'MESH:C019417', (86, 92))	('oncogenesis', 'CPA', (100, 111))	('epigenetic', 'Var', (26, 36))	('rat', 'Species', '10116', (67, 70))
144465	32825279	The D-2-HG-induced hypermethylation phenotype was reversed by demethylating compounds, and cell proliferation was suppressed in vitro and in vivo.	('rat', 'Species', '10116', (103, 106))	('hypermethylation', 'MPA', (19, 35))	('D-2-HG', 'Chemical', 'MESH:C019417', (4, 10))	('suppressed', 'NegReg', (114, 124))	('D-2-HG-induced', 'Var', (4, 18))	('cell proliferation', 'CPA', (91, 109))
144466	32825279	Several clinical trials are evaluating the therapeutic effects of 5-azacytidine among patients with recurrent gliomas with IDH mutations (NCT03666559 and NCT03684811).	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('5-azacytidine', 'Chemical', 'MESH:D001374', (66, 79))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('NCT03666559', 'Var', (138, 149))	('IDH', 'Gene', (123, 126))	('NCT03684811', 'Var', (154, 165))	('patients', 'Species', '9606', (86, 94))
144471	32825279	Several seminal studies have also indicated that D-2-HG compromises HR DNA repair, establishing a "BRCAness" in this type of malignancy.	('compromises', 'NegReg', (56, 67))	('BRCAness', 'Disease', 'None', (99, 107))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('malignancy', 'Disease', (125, 135))	('D-2-HG', 'Var', (49, 55))	('D-2-HG', 'Chemical', 'MESH:C019417', (49, 55))	('HR DNA repair', 'MPA', (68, 81))	('BRCAness', 'Disease', (99, 107))
144473	32825279	Our recent study indicated that IDH mutations led to defects in NAD metabolism, which compromised PARP-associated HR, as PARP repairs DNA damage in an NAD+ dependent manner.	('NAD metabolism', 'Disease', (64, 78))	('PARP', 'Gene', (98, 102))	('PARP', 'Gene', '142', (121, 125))	('NAD+', 'Chemical', 'MESH:D009243', (151, 155))	('defects', 'NegReg', (53, 60))	('mutations', 'Var', (36, 45))	('compromised', 'NegReg', (86, 97))	('PARP', 'Gene', '142', (98, 102))	('NAD metabolism', 'Disease', 'MESH:D008659', (64, 78))	('IDH', 'Gene', (32, 35))	('PARP', 'Gene', (121, 125))
144474	32825279	With the identification of the DNA repair deficiency in IDH-mutated glioma, numerous studies have attempted to evaluate DNA repair inhibitors, which may serve as a potential sensitization strategy.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('DNA repair', 'Gene', (31, 41))	('rat', 'Species', '10116', (190, 193))	('deficiency', 'Var', (42, 52))	('glioma', 'Disease', (68, 74))
144476	32825279	Several phase I/II clinical trials are currently recruiting patients to investigate the therapeutic effect of the PARP inhibitors, pamiparib (BGB-290) or olaparib, combined with temozolomide in IDH mutant gliomas (NCT03914742, NCT03749187, and NCT03212274).	('temozolomide', 'Chemical', 'MESH:D000077204', (178, 190))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Disease', (205, 212))	('olaparib', 'Chemical', 'MESH:C531550', (154, 162))	('PARP', 'Gene', '142', (114, 118))	('patients', 'Species', '9606', (60, 68))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('pamiparib', 'Chemical', '-', (131, 140))	('NCT03749187', 'Var', (227, 238))	('NCT03212274', 'Var', (244, 255))	('NCT03914742', 'Var', (214, 225))	('IDH', 'Disease', (194, 197))	('PARP', 'Gene', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
144477	32825279	As a result, ROS scavenging pathways are widely mobilized in the context of IDH mutation, so as to maintain cellular metabolism, thereby supporting cellular growth and survival.	('maintain', 'PosReg', (99, 107))	('IDH', 'Gene', (76, 79))	('cellular metabolism', 'MPA', (108, 127))	('ROS scavenging pathways', 'Pathway', (13, 36))	('supporting', 'PosReg', (137, 147))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('survival', 'CPA', (168, 176))	('cellular growth', 'CPA', (148, 163))	('mutation', 'Var', (80, 88))
144479	32825279	Targeting anti-oxidative pathways may be more effective in glioma with IDH mutations.	('anti-oxidative pathways', 'Pathway', (10, 33))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH', 'Gene', (71, 74))	('mutations', 'Var', (75, 84))
144480	32825279	Our recent study showed that NRF2-governed anti-oxidative pathways, such as that regarding de novo glutathione synthesis, were widespread in IDH mutant gliomas.	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('IDH', 'Gene', (141, 144))	('gliomas', 'Disease', (152, 159))	('mutant', 'Var', (145, 151))	('NRF2', 'Gene', '4780', (29, 33))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('NRF2', 'Gene', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('de novo glutathione synthesis', 'MPA', (91, 120))	('widespread', 'Reg', (127, 137))	('glutathione', 'Chemical', 'MESH:D005978', (99, 110))	('anti-oxidative', 'MPA', (43, 57))
144481	32825279	The blockade of NRF2 using natural compound inhibitors, brusatol, or triptolide significantly increased oxidative damage and subsequently suppressed the growth of IDH mutant xenografts with prolonged OS.	('blockade', 'NegReg', (4, 12))	('oxidative damage', 'MPA', (104, 120))	('increased', 'PosReg', (94, 103))	('IDH', 'Gene', (163, 166))	('NRF2', 'Gene', '4780', (16, 20))	('triptolide', 'Chemical', 'MESH:C001899', (69, 79))	('mutant', 'Var', (167, 173))	('suppressed', 'NegReg', (138, 148))	('brusatol', 'Chemical', 'MESH:C020237', (56, 64))	('NRF2', 'Gene', (16, 20))	('growth', 'MPA', (153, 159))
144485	32825279	The production of large quantities of D-2-HG inevitably depletes a substantial amount of carbohydrate from the Krebs cycle.	('carbohydrate', 'Chemical', 'MESH:D002241', (89, 101))	('depletes', 'NegReg', (56, 64))	('D-2-HG', 'Var', (38, 44))	('D-2-HG', 'Chemical', 'MESH:C019417', (38, 44))	('Krebs', 'Chemical', '-', (111, 116))
144487	32825279	For example, glutamate metabolism is greatly altered in IDH mutant glioma, as mentioned before.	('altered', 'Reg', (45, 52))	('glioma', 'Disease', (67, 73))	('glutamate', 'Chemical', 'MESH:D018698', (13, 22))	('IDH mutant', 'Var', (56, 66))	('glutamate metabolism', 'MPA', (13, 33))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
144488	32825279	The glutamate level is significantly lower in IDH mutant cancers, which leads to an increased dependence on glutaminolysis to compensate for the metabolism.	('dependence', 'MPA', (94, 104))	('glutamate', 'Chemical', 'MESH:D018698', (4, 13))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lower', 'NegReg', (37, 42))	('glutamate level', 'MPA', (4, 19))	('IDH mutant', 'Var', (46, 56))
144490	32825279	reported that bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES), an inhibitor of glutaminase, selectively suppresses tumor growth in IDH mutant glioma and AML by targeting the fragile glutamine metabolism.	('BPTES', 'Chemical', 'MESH:C523193', (77, 82))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('fragile glutamine metabolism', 'MPA', (196, 224))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('glutaminase', 'Gene', '2744', (101, 112))	('AML', 'Disease', 'MESH:D015470', (175, 178))	('AML', 'Phenotype', 'HP:0004808', (175, 178))	('AML', 'Disease', (175, 178))	('tumor', 'Disease', (137, 142))	('suppresses', 'NegReg', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('glutaminase', 'Gene', (101, 112))	('mutant', 'Var', (157, 163))	('glutamine', 'Chemical', 'MESH:D005973', (204, 213))	('targeting', 'Reg', (182, 191))	('bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide', 'Chemical', 'MESH:C523193', (14, 75))	('glioma', 'Disease', (164, 170))	('IDH', 'Disease', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
144491	32825279	Another glutaminase inhibitor (CB-839) was also reported to induce selective radio-sensitivity in IDH mutant cancers and terminal differentiation in IDH mutant AML.	('mutant', 'Var', (102, 108))	('induce', 'PosReg', (60, 66))	('terminal differentiation', 'CPA', (121, 145))	('IDH', 'Disease', (98, 101))	('AML', 'Disease', 'MESH:D015470', (160, 163))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('CB-839', 'Chemical', 'MESH:C000593334', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AML', 'Disease', (160, 163))	('glutaminase', 'Gene', '2744', (8, 19))	('AML', 'Phenotype', 'HP:0004808', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('glutaminase', 'Gene', (8, 19))
144492	32825279	An ongoing phase I clinical trial is investigating the side effects and the best dose of CB-839, in combination with radiation therapy and temozolomide, for treating IDH-mutated diffuse or anaplastic astrocytoma (NCT03528642).	('CB-839', 'Chemical', 'MESH:C000593334', (89, 95))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (189, 211))	('IDH-mutated', 'Var', (166, 177))	('astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('temozolomide', 'Chemical', 'MESH:D000077204', (139, 151))	('anaplastic astrocytoma', 'Disease', (189, 211))	('CB-839', 'Gene', (89, 95))
144493	32825279	In addition, IDH mutations lead to the depletion of NAD+ because of the increased methylation of the promoter region of NAPRT1, the rate-limiting enzyme in NAD+ biosynthesis, and suppression of the expression of NAPRT1.	('methylation of the promoter', 'MPA', (82, 109))	('suppression', 'NegReg', (179, 190))	('increased', 'PosReg', (72, 81))	('rat', 'Species', '10116', (132, 135))	('NAPRT1', 'Gene', (120, 126))	('NAPRT1', 'Gene', '93100', (212, 218))	('NAPRT1', 'Gene', (212, 218))	('depletion of NAD+', 'MPA', (39, 56))	('NAD+', 'Chemical', 'MESH:D009243', (52, 56))	('lead to', 'Reg', (27, 34))	('expression', 'MPA', (198, 208))	('NAPRT1', 'Gene', '93100', (120, 126))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('NAD+', 'Chemical', 'MESH:D009243', (156, 160))
144494	32825279	This renders the IDH mutant glioma vulnerable to inhibition through the nicotinamide phosphoribosyltransferase (NAMPT) catalyzed NAD+ salvage pathway.	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('nicotinamide phosphoribosyltransferase', 'Gene', (72, 110))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('NAMPT', 'Gene', '10135', (112, 117))	('IDH mutant', 'Var', (17, 27))	('NAMPT', 'Gene', (112, 117))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (72, 110))	('glioma', 'Disease', (28, 34))	('NAD+', 'Chemical', 'MESH:D009243', (129, 133))
144498	32825279	The accumulated pieces of evidence have indicated that IDH mutant cancers exhibit an immunosuppressive tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('IDH', 'Gene', (55, 58))	('tumor', 'Disease', (103, 108))	('mutant', 'Var', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
144499	32825279	reported that the D-2-HG produced by mutant IDH is taken up by T cells and suppresses T cell activity.	('suppresses', 'NegReg', (75, 85))	('mutant', 'Var', (37, 43))	('T cell activity', 'CPA', (86, 101))	('IDH', 'Gene', (44, 47))	('D-2-HG', 'Chemical', 'MESH:C019417', (18, 24))
144500	32825279	reported that IDH mutations inhibit STAT1 expression, and subsequently attenuate CD8+ T cell accumulation in gliomas.	('STAT1', 'Gene', '6772', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('CD8', 'Gene', (81, 84))	('IDH', 'Gene', (14, 17))	('CD8', 'Gene', '925', (81, 84))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('STAT1', 'Gene', (36, 41))	('attenuate', 'NegReg', (71, 80))	('inhibit', 'NegReg', (28, 35))	('mutations', 'Var', (18, 27))
144502	32825279	For example, cancer cells with the IDH1 R132H variant present a tumor-specific CD4+ T cell neoepitope.	('IDH1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (64, 69))	('CD4', 'Gene', (79, 82))	('CD4', 'Gene', '920', (79, 82))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('R132H', 'Var', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('R132H', 'Mutation', 'rs121913500', (40, 45))
144503	32825279	Peptide vaccination targeting the IDH1 R132H mutation results in an effective anti-tumor immune response, and suppresses the growth of pre-established IDH1 R132H-mutated tumors.	('suppresses', 'NegReg', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('growth', 'CPA', (125, 131))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('R132H', 'Var', (39, 44))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('IDH1', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumors', 'Disease', (170, 176))	('R132H', 'Mutation', 'rs121913500', (156, 161))
144504	32825279	Moreover, the inhibition of the mutant IDH neomorphic enzymatic activity improves the anti-tumor immunity of the IDH1-specific vaccine.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutant', 'Var', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('IDH', 'Gene', (39, 42))	('tumor', 'Disease', (91, 96))	('improves', 'PosReg', (73, 81))	('inhibition', 'NegReg', (14, 24))
144506	32825279	For example, EGFR variant III (EGFRvIII) is the most common mutation in IDH1 wild-type GBMs.	('variant III', 'Var', (18, 29))	('EGFR', 'Gene', '1956', (31, 35))	('IDH1', 'Gene', (72, 76))	('EGFR', 'Gene', (31, 35))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('GBMs', 'Phenotype', 'HP:0012174', (87, 91))
144508	32825279	reported that the inhibition of mutant IDH resulted in an enhanced anti-tumor effect of anti-PD-1 treatment.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibition', 'NegReg', (18, 28))	('PD-1', 'Gene', '6622', (93, 97))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (58, 66))	('mutant', 'Var', (32, 38))	('IDH', 'Gene', (39, 42))	('PD-1', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
144509	32825279	In summary, significant amounts of effort and progress have been made over the past decade to understand the biology of IDH mutations in glioma.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('mutations', 'Var', (124, 133))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioma', 'Disease', (137, 143))	('IDH', 'Gene', (120, 123))
144511	32825279	Moreover, with the increased knowledge of the molecular mechanism, targeting IDH mutations is suggested as a therapeutic approach to cancers bearing these mutations.	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('IDH', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
144514	32825279	Several recent advances in IDH1 mutant mouse models have been developed, which are discussed in our recent review, along with increased evidence reflecting the potential value of targeting mutant IDH in cancer treatment.	('mutant', 'Var', (189, 195))	('mutant', 'Var', (32, 38))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('IDH1', 'Gene', (27, 31))	('mouse', 'Species', '10090', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('IDH', 'Gene', (196, 199))
144515	32825279	Thus, more efforts are needed to elucidate the role of IDH mutation in tumorigenesis and clinical translation.	('IDH', 'Gene', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutation', 'Var', (59, 67))	('tumor', 'Disease', (71, 76))
144533	31923345	Although these advances resulted in more refined diagnoses and classifications of glioma tumors, integrating histological and molecular information (e.g., IDH1/2 mutations and 1p/19q codeletion) (Louis et al., 2016), significant improvements in therapies that truly impact on patient outcomes are still lacking.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (162, 171))	('IDH1/2', 'Gene', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH1/2', 'Gene', '3417;3418', (155, 161))	('glioma tumors', 'Disease', (82, 95))	('glioma tumors', 'Disease', 'MESH:D005910', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patient', 'Species', '9606', (276, 283))
144535	31923345	Functionally, WNT6 expression was associated with increased GBM cell viability, proliferation, invasion, migration, resistance to TMZ, and stemness capacity (Goncalves et al., 2018).	('resistance to TMZ', 'CPA', (116, 133))	('invasion', 'CPA', (95, 103))	('stemness capacity', 'CPA', (139, 156))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('GBM cell viability', 'CPA', (60, 78))	('increased', 'PosReg', (50, 59))	('expression', 'Var', (19, 29))	('proliferation', 'CPA', (80, 93))	('migration', 'CPA', (105, 114))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('WNT6', 'Gene', (14, 18))
144536	31923345	In vivo, WNT6 accelerated GBM-associated death in mice.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('WNT6', 'Var', (9, 13))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('mice', 'Species', '10090', (50, 54))	('accelerated', 'PosReg', (14, 25))
144540	31923345	Agilent G4502A 244K data were used for LGG and GBM (WNT6 and HOXA9-high expression was considered when TCGA level 3 value >= 0 [GBM median value] or 3, respectively), while RNAseq data (Illumina HiSeq 2000 Sequencing System) were downloaded for all cancers (WNT6-high expression was considered when TCGA FPKM-UQ value >= 6800 [GBM median value]) (The Cancer Genome Atlas Research Network, 2008).	('G4502A', 'Var', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('cancers', 'Disease', (249, 256))	('Cancer', 'Disease', (351, 357))	('G4502A', 'SUBSTITUTION', 'None', (8, 14))	('Cancer', 'Disease', 'MESH:D009369', (351, 357))	('Cancer', 'Phenotype', 'HP:0002664', (351, 357))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('GBM', 'Phenotype', 'HP:0012174', (327, 330))
144575	31923345	For beta-catenin IF (610153; BD Transduction Laboratories, San Jose, CA, USA, 1 : 200), U87-MSCV and U87-HOXA9 cells plated on coverslips were fixed in 95% EtOH and 5% acetic acid (v/v), followed by incubation in 1% BSA in PBS-0.1% Tween for 1 h, and overnight at 4  C with the primary antibody.	('Tween', 'Chemical', 'MESH:D011136', (232, 237))	('610153;', 'Var', (21, 28))	('EtOH', 'Chemical', 'MESH:D000431', (156, 160))	('acetic acid', 'Chemical', 'MESH:D019342', (168, 179))	('PBS', 'Chemical', 'MESH:D007854', (223, 226))	('MSCV', 'Species', '258023', (92, 96))	('beta-catenin', 'Protein', (4, 16))
144595	31923345	Together, these results show that high WNT6 expression associates with higher glioma grades independently of IDH mutation and 1p/19q codeletion status.	('higher', 'PosReg', (71, 77))	('IDH', 'Gene', '3417', (109, 112))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('WNT6', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('glioma', 'Disease', (78, 84))	('IDH', 'Gene', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
144596	31923345	To understand the mechanisms responsible for WNT6 overexpression in glioma, we started by investigating copy number alterations of the WNT6 locus in LGG (n = 509) and GBM (n = 565) patients from TCGA (Fig.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('WNT6', 'Gene', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('copy number alterations', 'Var', (104, 127))	('patients', 'Species', '9606', (181, 189))	('glioma', 'Disease', (68, 74))
144604	31923345	Interestingly, looking for the 28 DNA methylation sites within the WNT6 locus, in 516 LGG and 141 GBM patients, we identified regions that are consistently hypomethylated (e.g., from the 4th probe [cg16256504] to the 8th probe [cg02175741]) or hypermethylated (e.g., 16th probe [cg05618201]) both in LGG and in GBM (Figs 2A and S2), showing a remarkable homogeneity of DNA methylation levels of these particular regions across very heterogeneous glioma samples of different grades.	('GBM', 'Phenotype', 'HP:0012174', (311, 314))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (446, 452))	('glioma', 'Phenotype', 'HP:0009733', (446, 452))	('[cg16256504]', 'Var', (197, 209))	('[cg02175741]', 'Var', (227, 239))	('glioma', 'Disease', (446, 452))
144608	31923345	MSP analyses showed that five of the seven cell lines presented 5-Aza-mediated demethylation (A172, SNB19, KNS42, SW1783, and Res186; Fig.	('5-Aza', 'Chemical', 'MESH:D000077209', (64, 69))	('A172', 'Var', (94, 98))	('SW1783', 'CellLine', 'CVCL:1722', (114, 120))	('SNB19', 'Var', (100, 105))	('SW1783', 'Var', (114, 120))	('5-Aza-mediated demethylation', 'MPA', (64, 92))
144609	31923345	Interestingly, 5-Aza treatment successfully increased WNT6 expression in four of these five cell lines (fold changes between 1.7 and 3.15; for KNS42, SW1783, A172, and Res186).	('WNT6 expression', 'MPA', (54, 69))	('increased', 'PosReg', (44, 53))	('5-Aza', 'Chemical', 'MESH:D000077209', (15, 20))	('SW1783', 'CellLine', 'CVCL:1722', (150, 156))	('SW1783', 'Var', (150, 156))
144618	31923345	Interestingly, when performing GSEA to identify transcriptomic signatures reminiscent of WNT6-associated genes in GBM patients (Goncalves et al., 2018), we found that WNT6-negatively correlated genes were enriched for genes upregulated in LAML cells upon HOXA9 knockdown [enrichment score (ES) = -0.26 and false discovery rate, FDR = 0.18; Fig.	('knockdown', 'Var', (261, 270))	('GSEA', 'Chemical', '-', (31, 35))	('upregulated', 'PosReg', (224, 235))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('patients', 'Species', '9606', (118, 126))
144620	31923345	This association was not only observed in vitro but also in vivo, as U87+/-HOXA9 tumors grown subcutaneously in nude mice also showed significantly higher expression of WNT6 and beta-catenin (mainly in the nucleus) in HOXA9-positive tumors when compared to HOXA9-negative tumors (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('nude mice', 'Species', '10090', (112, 121))	('WNT6', 'Protein', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beta-catenin', 'Protein', (178, 190))	('higher', 'PosReg', (148, 154))	('U87+/-HOXA9', 'Var', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (272, 278))	('tumors', 'Disease', (233, 239))	('HOXA9-positive', 'Var', (218, 232))	('expression', 'MPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
144621	31923345	In addition, cyclin D1, a known transcriptional target of the canonical WNT/beta-catenin pathway, was also upregulated in HOXA9-positive tumors when compared to negative tumors (Fig.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cyclin D1', 'Gene', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HOXA9-positive', 'Var', (122, 136))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cyclin D1', 'Gene', '595', (13, 22))	('upregulated', 'PosReg', (107, 118))	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
144625	31923345	Thus, the clinical impact of WNT6 in GBM was evaluated using a multivariable Cox model to adjust to potential confounding effects of other putative prognostic factors, namely patient age, KPS, gender, therapy, IDH mutation status, and HOXA9 expression (Tables 2 and S2).	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutation', 'Var', (214, 222))	('IDH', 'Gene', '3417', (210, 213))	('patient', 'Species', '9606', (175, 182))	('IDH', 'Gene', (210, 213))
144627	31923345	Importantly, IDHwt GBM patients with both WNT6-high and HOXA9-high expression presented a shorter OS (median OS = 290 days) when compared to all other patients (median OS = 425; log-rank P = 0.002; Fig.	('IDH', 'Gene', '3417', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (151, 159))	('HOXA9-high expression', 'Var', (56, 77))	('IDH', 'Gene', (13, 16))
144639	31923345	In contrast, our findings demonstrated that DNA methylation, a critical epigenetic mechanism, associates with WNT6 expression levels in glioma (Figs 2, S2 and S3), similarly to what was observed for other WNT ligands in other cancer types (Carmona et al., 2013; Jung et al., 2015; Kim et al., 2015a; Liu et al., 2016; Xu et al., 2005).	('WNT6', 'Gene', (110, 114))	('DNA', 'MPA', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', (226, 232))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('methylation', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
144641	31923345	Interestingly, most of the CpG sites are more frequently methylated in LGG than GBM patients (19 out of 28; Fig.	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('LGG', 'Disease', (71, 74))	('methylated', 'Var', (57, 67))	('patients', 'Species', '9606', (84, 92))
144643	31923345	Although DNA methylation was clearly associated with WNT6 expression in glioma, this association was not universal.	('glioma', 'Disease', (72, 78))	('methylation', 'Var', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('WNT6', 'Gene', (53, 57))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('associated', 'Reg', (37, 47))	('DNA', 'MPA', (9, 12))
144653	31923345	Interestingly, WNT6 was also shown to be associated with shorter survival in LGG patients (Dao Trong et al., 2018), where HOXA9 overexpression is not frequent (Pojo et al., 2015).	('patients', 'Species', '9606', (81, 89))	('WNT6', 'Var', (15, 19))	('LGG', 'Disease', (77, 80))	('survival', 'MPA', (65, 73))	('shorter', 'NegReg', (57, 64))
144660	31881853	Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma.	('trametinib', 'Chemical', 'MESH:C560077', (32, 42))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('MEK', 'Gene', '5609', (9, 12))	('mutations', 'Var', (112, 121))	('ERK', 'Gene', '5594', (134, 137))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('melanoma', 'Disease', (154, 162))	('MEK', 'Gene', (9, 12))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('ERK', 'Gene', (134, 137))	('cancers', 'Disease', (94, 101))
144684	31881853	PLGG presents three major genetic alterations resulting in the activation of the MAPK pathway: NF1 mutation, BRAF fusion and BRAF mutation V600E.	('BRAF', 'Gene', (109, 113))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('BRAF', 'Gene', '673', (109, 113))	('NF1', 'Gene', (95, 98))	('mutation', 'Var', (99, 107))	('NF1', 'Gene', '4763', (95, 98))	('mutation V600E', 'Var', (130, 144))	('V600E', 'Var', (139, 144))	('BRAF', 'Gene', '673', (125, 129))	('MAPK pathway', 'Pathway', (81, 93))	('BRAF', 'Gene', (125, 129))	('activation', 'PosReg', (63, 73))
144685	31881853	NF1 mutations are mainly found in patients with neurofibromatosis type 1 (NF1).	('NF1', 'Gene', (74, 77))	('neurofibroma', 'Phenotype', 'HP:0001067', (48, 60))	('NF1', 'Gene', '4763', (74, 77))	('neurofibromatosis type 1', 'Gene', '4763', (48, 72))	('NF1', 'Gene', '4763', (0, 3))	('neurofibromatosis type 1', 'Gene', (48, 72))	('patients', 'Species', '9606', (34, 42))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('found', 'Reg', (25, 30))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (48, 65))
144690	31881853	The BRAF V600E mutation lies in the kinase domain and results in a constitutive activation of the MAPK/ERK pathway.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('ERK', 'Gene', (103, 106))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('ERK', 'Gene', '5594', (103, 106))	('activation', 'PosReg', (80, 90))
144692	31881853	The fusion between KIAA1549 (an uncharacterized gene) and the BRAF oncogene was reported to be a common feature of PA.	('KIAA1549', 'Gene', '57670', (19, 27))	('fusion', 'Var', (4, 10))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('KIAA1549', 'Gene', (19, 27))
144695	31881853	Finally, other mutations in PLGG were also found to activate the MAPK pathway through rare BRAF fusions or mutations, kinase domain duplications of FGFR1, and fusions of the NTRK gene (reviewed in Sturm et al., JCO 2017).	('fusions', 'Var', (159, 166))	('MAPK pathway', 'Pathway', (65, 77))	('mutations', 'Var', (107, 116))	('PLGG', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (91, 95))	('mutations', 'Var', (15, 24))	('kinase domain duplications', 'Var', (118, 144))	('BRAF', 'Gene', (91, 95))	('activate', 'PosReg', (52, 60))	('NTRK', 'Gene', (174, 178))	('FGFR1', 'Gene', (148, 153))	('fusions', 'Var', (96, 103))	('FGFR1', 'Gene', '2260', (148, 153))
144697	31881853	Despite distinctive histology and location of PNs when compared to PLGG, there is also an activation of the MAPK/ERK pathway through NF1 mutations.	('activation', 'PosReg', (90, 100))	('PNs', 'Phenotype', 'HP:0009732', (46, 49))	('NF1', 'Gene', (133, 136))	('ERK', 'Gene', '5594', (113, 116))	('mutations', 'Var', (137, 146))	('ERK', 'Gene', (113, 116))	('NF1', 'Gene', '4763', (133, 136))	('PN', 'Phenotype', 'HP:0009732', (46, 48))
144702	31881853	Dabrafenib, a selective BRAF inhibitor, was shown to be effective in PLGG with BRAF V600E mutations.	('V600E mutations', 'Var', (84, 99))	('V600E', 'Mutation', 'rs113488022', (84, 89))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('PLGG', 'Disease', (69, 73))	('BRAF', 'Gene', (79, 83))
144703	31881853	Additionally, a phase II clinical trial with dabrafenib and trametinib for patients with PLGG and high-grade glioma with V600E mutation is underway (NCT02684058).	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('V600E', 'Var', (121, 126))	('trametinib', 'Chemical', 'MESH:C560077', (60, 70))	('patients', 'Species', '9606', (75, 83))	('glioma', 'Disease', (109, 115))	('PLGG', 'Disease', (89, 93))	('V600E', 'Mutation', 'rs113488022', (121, 126))	('dabrafenib', 'Chemical', 'MESH:C561627', (45, 55))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
144717	31881853	demonstrated the efficacy of trametinib in murine xenografts with V600E high grade glioma.	('glioma', 'Disease', (83, 89))	('V600E', 'Var', (66, 71))	('murine', 'Species', '10090', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('trametinib', 'Chemical', 'MESH:C560077', (29, 39))	('V600E', 'Mutation', 'rs113488022', (66, 71))
144770	31881853	Participants must have normal organ and marrow function as defined below: Total leukocytes >=3000/muL Absolute neutrophil count (ANC) >= 1000/muL Hemoglobin > 80 g/l (transfusion independent within last 2 weeks) Platelet count >=100,000/muL (transfusion independent within last 2 weeks) Total bilirubin <=1.5 times the upper limit of normal (ULN) within normal institutional limits for age Alanine Aminotransferase (ALT) <= 2.5 times the upper limit of normal (ULN) Serum creatinine within normal institutional limits for age OR creatinine clearance >=60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.	('min/1', 'Gene', '966', (558, 563))	('muL', 'Gene', '4591', (237, 240))	('Alanine Aminotransferase', 'Gene', '2875', (390, 414))	('>=60', 'Var', (550, 554))	('muL', 'Gene', (98, 101))	('muL', 'Gene', '4591', (142, 145))	('creatinine clearance', 'MPA', (529, 549))	('min/1', 'Gene', (558, 563))	('muL', 'Gene', (237, 240))	('creatinine', 'Chemical', 'MESH:D003404', (529, 539))	('creatinine', 'Chemical', 'MESH:D003404', (472, 482))	('Participants', 'Species', '9606', (0, 12))	('muL', 'Gene', (142, 145))	('creatinine', 'Chemical', 'MESH:D003404', (592, 602))	('bilirubin', 'Chemical', 'MESH:D001663', (293, 302))	('Alanine Aminotransferase', 'Gene', (390, 414))	('participants', 'Species', '9606', (574, 586))	('muL', 'Gene', '4591', (98, 101))
144771	31881853	Creatine phosphokinase <=2x ULN A cardiac function defined as Corrected QT (QTcB) interval < 480 msec and LVEF >= lower limit of normal (LLN) by echocardiogram (ECHO).	('QTcB', 'Chemical', '-', (76, 80))	('ECHO', 'CellLine', 'None', (161, 165))	('cardiac function', 'Disease', (34, 50))	('<=2x', 'Var', (23, 27))	('Creatine', 'Chemical', 'MESH:D003401', (0, 8))
144781	31881853	Participants previously treated with a MEK inhibitor who showed less than stable disease during treatment Tumor with BRAF V600E mutation.	('men', 'Species', '9606', (101, 104))	('V600E', 'Mutation', 'rs113488022', (122, 127))	('Participants', 'Species', '9606', (0, 12))	('BRAF', 'Gene', '673', (117, 121))	('MEK', 'Gene', '5609', (39, 42))	('MEK', 'Gene', (39, 42))	('Tumor', 'Phenotype', 'HP:0002664', (106, 111))	('V600E', 'Var', (122, 127))	('BRAF', 'Gene', (117, 121))
144794	31881853	During the treatment phase, patients will receive trametinib at a fixed dose of 0.025 mg/kg (patients >=6 years) or 0.032 mg/kg (patients < 6 years) with no dose escalation.	('0.032 mg/kg', 'Var', (116, 127))	('trametinib', 'Chemical', 'MESH:C560077', (50, 60))	('patients', 'Species', '9606', (129, 137))	('men', 'Species', '9606', (16, 19))	('0.025 mg/kg', 'Var', (80, 91))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (93, 101))
144848	31881853	This group can include patients with KRAS mutation, rare fusion or BRAF mutation for example.	('BRAF', 'Gene', '673', (67, 71))	('patients', 'Species', '9606', (23, 31))	('BRAF', 'Gene', (67, 71))	('KRAS', 'Gene', (37, 41))	('rare fusion', 'Var', (52, 63))	('KRAS', 'Gene', '3845', (37, 41))
144859	31881853	Gliomas with specific mutations or methylation profiles might have better and more sustained response to trametinib.	('trametinib', 'Chemical', 'MESH:C560077', (105, 115))	('methylation profiles', 'Var', (35, 55))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('mutations', 'Var', (22, 31))	('Gliomas', 'Disease', (0, 7))
144868	28575062	The rs16906252:C>T SNP is not associated with increased overall survival or temozolomide response in a Han-Chinese glioma cohort The methylation status of O-6-methylguanine-DNA methyltransferase (MGMT) is associated with the prognosis in gliomas and in other cancers.	('glioma', 'Disease', (115, 121))	('rs16906252:C>T', 'DBSNP_MENTION', 'None', (4, 18))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('methylation', 'Var', (133, 144))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (155, 194))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('associated', 'Reg', (205, 215))	('MGMT', 'Gene', '4255', (196, 200))	('glioma', 'Disease', (238, 244))	('gliomas', 'Disease', (238, 245))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', (259, 266))	('rs16906252:C>T', 'Var', (4, 18))	('temozolomide', 'Chemical', 'MESH:D000077204', (76, 88))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (155, 194))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('MGMT', 'Gene', (196, 200))
144869	28575062	Recent studies showed that rs16906252, an SNP in the MGMT promoter, is associated with promoter methylation and is a predictor of the overall survival time (OST) and the response to temozolomide (TMZ) treatment.	('rs16906252', 'Var', (27, 37))	('promoter methylation', 'MPA', (87, 107))	('OST', 'Chemical', '-', (157, 160))	('temozolomide', 'Chemical', 'MESH:D000077204', (182, 194))	('overall survival time', 'CPA', (134, 155))	('rs16906252', 'Mutation', 'rs16906252', (27, 37))	('MGMT', 'Gene', (53, 57))	('MGMT', 'Gene', '4255', (53, 57))	('TMZ', 'Chemical', 'MESH:D000077204', (196, 199))	('associated', 'Reg', (71, 81))
144870	28575062	We analyzed the relevance between rs16906252 polymorphisms, the MGMT methylation status, and the OST in 72 Han-Chinese gliomas patients.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('rs16906252', 'Mutation', 'rs16906252', (34, 44))	('gliomas', 'Disease', (119, 126))	('patients', 'Species', '9606', (127, 135))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('MGMT', 'Gene', (64, 68))	('OST', 'Chemical', '-', (97, 100))	('rs16906252', 'Var', (34, 44))	('MGMT', 'Gene', '4255', (64, 68))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))
144872	28575062	Contrary to the previous findings, we found no association between rs16906252 genotypes and promoter methylation on MGMT.	('rs16906252', 'Mutation', 'rs16906252', (67, 77))	('rs16906252', 'Var', (67, 77))	('promoter', 'MPA', (92, 100))	('MGMT', 'Gene', (116, 120))	('MGMT', 'Gene', '4255', (116, 120))
144873	28575062	The lower-grade glioma (LGGs) patients carrying the C allele with rs16906252 showed a surprisingly better OST (P = 0.04).	('rs16906252', 'Var', (66, 76))	('OST', 'Chemical', '-', (106, 109))	('glioma', 'Disease', (16, 22))	('rs16906252', 'Mutation', 'rs16906252', (66, 76))	('patients', 'Species', '9606', (30, 38))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (16, 22))
144874	28575062	Furthermore, the LGG patients carrying hypo-methylated MGMT promoter and rs16906252 T allele showed significantly poorer prognosis.	('MGMT', 'Gene', '4255', (55, 59))	('MGMT', 'Gene', (55, 59))	('rs16906252 T', 'Var', (73, 85))	('poorer', 'NegReg', (114, 120))	('hypo-methylated', 'Var', (39, 54))	('patients', 'Species', '9606', (21, 29))	('rs16906252', 'Mutation', 'rs16906252', (73, 83))
144886	28575062	Recent studies suggested the rs16906252 genotype in tumors is associated with MGMT promoter methylation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('associated', 'Reg', (62, 72))	('rs16906252', 'Var', (29, 39))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('MGMT', 'Gene', '4255', (78, 82))	('MGMT', 'Gene', (78, 82))	('rs16906252', 'Mutation', 'rs16906252', (29, 39))
144887	28575062	Compared to the wild type of homozygous C, glioblastomas that carry the T allele of rs16906252, i.e.	('glioblastomas', 'Disease', 'MESH:D005909', (43, 56))	('rs16906252', 'Var', (84, 94))	('glioblastomas', 'Disease', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('rs16906252', 'Mutation', 'rs16906252', (84, 94))	('glioblastomas', 'Phenotype', 'HP:0012174', (43, 56))
144889	28575062	The studies supporting the clinical association on the tumoral rs16906252 polymorphisms and promoter methylation of MGMT are primarily on white patients.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('rs16906252', 'Var', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('white', 'Disease', 'MESH:D056784', (138, 143))	('white', 'Disease', (138, 143))	('tumor', 'Disease', (55, 60))	('patients', 'Species', '9606', (144, 152))	('MGMT', 'Gene', (116, 120))	('rs16906252', 'Mutation', 'rs16906252', (63, 73))	('MGMT', 'Gene', '4255', (116, 120))
144890	28575062	Interestingly, the T allele of the rs16906252 is 6.857% in whites according to the Exome Aggregation Consortium (ExAC) but is not seen in East Asia.	('rs16906252', 'Mutation', 'rs16906252', (35, 45))	('white', 'Disease', (59, 64))	('white', 'Disease', 'MESH:D056784', (59, 64))	('rs16906252', 'Var', (35, 45))
144902	28575062	Expected length of the PCR amplicons is 74 base pairs (bps) with or without a Hha1 site depending on the rs16906252 genotypes.	('rs16906252', 'Mutation', 'rs16906252', (105, 115))	('rs16906252', 'Var', (105, 115))	('Hha1', 'Gene', '3881', (78, 82))	('Hha1', 'Gene', (78, 82))
144903	28575062	The PCR amplicons were treated with the Hha1 enzyme (New England Biolabs), which recognizes the CGCG site presented with the C allele of rs16906252.	('Hha1', 'Gene', (40, 44))	('rs16906252', 'Mutation', 'rs16906252', (137, 147))	('Hha1', 'Gene', '3881', (40, 44))	('CGCG', 'Chemical', '-', (96, 100))	('rs16906252', 'Var', (137, 147))
144917	28575062	The allele frequency of the rs16906252 minor allele T in tumor samples was 15.3% and 9.8% in the matched-germline control samples.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('rs16906252', 'Mutation', 'rs16906252', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('rs16906252', 'Var', (28, 38))
144919	28575062	Previous studies suggested that the rs16906252 T allele is associated with methylated promoter in MGMT in lung, colorectal, and brain cancer.	('colorectal', 'Disease', 'MESH:D015179', (112, 122))	('rs16906252', 'Mutation', 'rs16906252', (36, 46))	('brain cancer', 'Disease', (128, 140))	('brain cancer', 'Phenotype', 'HP:0030692', (128, 140))	('colorectal', 'Disease', (112, 122))	('associated', 'Reg', (59, 69))	('methylated promoter', 'MPA', (75, 94))	('brain cancer', 'Disease', 'MESH:D001932', (128, 140))	('MGMT', 'Gene', (98, 102))	('rs16906252 T', 'Var', (36, 48))	('MGMT', 'Gene', '4255', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('lung', 'Disease', (106, 110))
144923	28575062	The rs16906252 genotypes in tumors are not correlated with OST in glioblastoma patients (HR: 0.9733; 95%CI: 0.6218-1.559; P = 0.949, S3 Table).	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('OST', 'Chemical', '-', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('rs16906252', 'Mutation', 'rs16906252', (4, 14))	('glioblastoma', 'Disease', (66, 78))	('patients', 'Species', '9606', (79, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('OST', 'Disease', (59, 62))	('rs16906252', 'Var', (4, 14))
144934	28575062	The rs16906252 genotypes surprisingly stratify the LGG patients with hypo-methylated MGMT promoter (Fig 4).	('LGG', 'Disease', (51, 54))	('rs16906252', 'Mutation', 'rs16906252', (4, 14))	('stratify', 'Reg', (38, 46))	('MGMT', 'Gene', (85, 89))	('patients', 'Species', '9606', (55, 63))	('MGMT', 'Gene', '4255', (85, 89))	('rs16906252', 'Var', (4, 14))
144935	28575062	The patients with hyper-methylated MGMT and homozygous C genotype on rs16906252 demonstrated better OST compared with the heterozygous CT genotypes, but this association is not statistically significant (HR: 0.7628; 95%CI: 0.1834-3.173; P = 0.7096; Fig 4A and S3 Table).	('rs16906252', 'Var', (69, 79))	('MGMT', 'Gene', (35, 39))	('MGMT', 'Gene', '4255', (35, 39))	('OST', 'Chemical', '-', (100, 103))	('rs16906252', 'Mutation', 'rs16906252', (69, 79))	('patients', 'Species', '9606', (4, 12))	('better', 'PosReg', (93, 99))	('hyper-methylated', 'Var', (18, 34))	('OST', 'CPA', (100, 103))
144942	28575062	Further analysis suggested that rs16906252 genotype is not correlated with OST in TMZ-treated glioblastoma patients (S3A Fig).	('rs16906252', 'Mutation', 'rs16906252', (32, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('OST', 'Chemical', '-', (75, 78))	('OST', 'Disease', (75, 78))	('rs16906252', 'Var', (32, 42))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('glioblastoma', 'Disease', (94, 106))	('patients', 'Species', '9606', (107, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
144943	28575062	The patients with hyper-methylated MGMT promoter showed a marginally prolonged OST (P = 0.1064, S3B Fig), and the mean OST of the patients with hyper- and hypo-methylated MGMT promoter were 25.7 months and 10 months, respectively.	('OST', 'Chemical', '-', (119, 122))	('OST', 'MPA', (79, 82))	('MGMT', 'Gene', (171, 175))	('MGMT', 'Gene', (35, 39))	('prolonged', 'PosReg', (69, 78))	('OST', 'Chemical', '-', (79, 82))	('MGMT', 'Gene', '4255', (35, 39))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (4, 12))	('MGMT', 'Gene', '4255', (171, 175))	('hyper-methylated', 'Var', (18, 34))
144944	28575062	On the other hand, the MGMT promoter genotypes and methylation were not associated with prolonged OSTs in all glioma patients without TMZ treatment (S4 and S5B Figs), except the LGGs patients having CC genotypes (S5A Fig).	('glioma', 'Disease', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('OSTs', 'Disease', (98, 102))	('MGMT', 'Gene', '4255', (23, 27))	('methylation', 'Var', (51, 62))	('MGMT', 'Gene', (23, 27))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('TMZ', 'Chemical', 'MESH:D000077204', (134, 137))	('patients', 'Species', '9606', (117, 125))	('OSTs', 'Chemical', '-', (98, 102))	('patients', 'Species', '9606', (183, 191))
144949	28575062	Furthermore, analysis of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and 1p19q shall provide further information on patient stratification.	('IDH1', 'Gene', '3417', (59, 63))	('1p19q', 'Var', (78, 83))	('IDH2', 'Gene', (68, 72))	('IDH2', 'Gene', '3418', (68, 72))	('IDH1', 'Gene', (59, 63))	('patient', 'Species', '9606', (121, 128))
144952	28575062	The MGMT promoter hyper-methylation has been repeatedly reported as a predictor to effective TMZ treatment in whites and in Han-Chinese, even though some contradictory results were also reported.	('MGMT', 'Gene', '4255', (4, 8))	('white', 'Disease', 'MESH:D056784', (110, 115))	('TMZ', 'Chemical', 'MESH:D000077204', (93, 96))	('white', 'Disease', (110, 115))	('hyper-methylation', 'Var', (18, 35))	('MGMT', 'Gene', (4, 8))
144953	28575062	Previous studies suggested that the rs16906252 T allele results in reduced promoter activity and MGMT expression and is associated with MGMT methylation in glioblastoma, colorectal cancer, and in a subset of malignant pleural mesothelioma patients.	('MGMT', 'Gene', '4255', (97, 101))	('MGMT', 'Gene', '4255', (136, 140))	('glioblastoma', 'Disease', (156, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('promoter activity', 'MPA', (75, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (208, 238))	('MGMT', 'Gene', (97, 101))	('rs16906252', 'Mutation', 'rs16906252', (36, 46))	('MGMT', 'Gene', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('methylation', 'MPA', (141, 152))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (218, 238))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('patients', 'Species', '9606', (239, 247))	('reduced', 'NegReg', (67, 74))	('rs16906252', 'Var', (36, 46))	('colorectal cancer', 'Disease', (170, 187))	('malignant pleural mesothelioma', 'Disease', (208, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (156, 168))
144958	28575062	The MAF of rs16906252 in tumors went up to 0.153, while 11 tumors underwent C>T somatic mutations.	('rs16906252', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('rs16906252', 'Mutation', 'rs16906252', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
144959	28575062	The increase of the rs16906252 T allele might drive a potentially evolutionary advantage, which presents a poor prognosis in our LGGs result.	('evolutionary advantage', 'CPA', (66, 88))	('increase', 'PosReg', (4, 12))	('rs16906252 T', 'Var', (20, 32))	('rs16906252', 'Mutation', 'rs16906252', (20, 30))
144963	28575062	In contrast, the LGGs patients showed a surprisingly prolonged OST when carrying the rs16906252 C allele while the T allele is in fact associated with a significantly poor prognosis.	('rs16906252', 'Mutation', 'rs16906252', (85, 95))	('patients', 'Species', '9606', (22, 30))	('OST', 'Chemical', '-', (63, 66))	('rs16906252 C', 'Var', (85, 97))	('OST', 'MPA', (63, 66))	('prolonged', 'PosReg', (53, 62))
144966	28575062	In summary, we showed that glioblastoma patients benefited by receiving TMZ treatment and confirmed that the glioblastoma patients with hyper-methylated promoter showed a prolonged OST although the difference is not statistical significant.	('glioblastoma', 'Disease', (109, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('OST', 'Chemical', '-', (181, 184))	('TMZ', 'Chemical', 'MESH:D000077204', (72, 75))	('patients', 'Species', '9606', (40, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('patients', 'Species', '9606', (122, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('benefited', 'PosReg', (49, 58))	('hyper-methylated promoter', 'Var', (136, 161))
144967	28575062	We identified a positive correlation between prolonged OST and the rs16906252 CC genotype in LGGs and that the rs16906252 genotypes predict two distinctive outcomes in the hypo-methylated LGG patients.	('LGG', 'Disease', (188, 191))	('prolonged', 'Disease', (45, 54))	('rs16906252', 'Mutation', 'rs16906252', (67, 77))	('rs16906252', 'Var', (111, 121))	('LGGs', 'Disease', (93, 97))	('rs16906252 CC', 'Var', (67, 80))	('predict', 'Reg', (132, 139))	('patients', 'Species', '9606', (192, 200))	('OST', 'Chemical', '-', (55, 58))	('rs16906252', 'Mutation', 'rs16906252', (111, 121))
144975	27574452	Although no differences were found in the 2-year OS between the TMZ + RT and RT-alone groups, there was a trend toward increased 2-year progression-free survival in the TMZ + RT group.	('TMZ + RT', 'Var', (169, 177))	('progression-free survival', 'CPA', (136, 161))	('OS', 'Chemical', '-', (49, 51))	('TMZ', 'Chemical', 'MESH:D000077204', (169, 172))	('TMZ', 'Chemical', 'MESH:D000077204', (64, 67))	('increased', 'PosReg', (119, 128))
145008	27574452	The overall 2-year PFS rate was 71.0% (83.9% for TMZ-RT group and 60.5% for RT-alone group).	('TMZ', 'Chemical', 'MESH:D000077204', (49, 52))	('TMZ-RT', 'Var', (49, 55))	('PFS', 'Disease', (19, 22))
145051	33194573	Recent studies recommended using an integrated classification system that combines histologic classification and genetic information, such as 1p/19q chromosomal co-deletion, IDH1 mutation, EGFR amplification, and BRAF mutation.	('EGFR', 'Gene', '1956', (189, 193))	('amplification', 'Var', (194, 207))	('EGFR', 'Gene', (189, 193))	('mutation', 'Var', (179, 187))	('BRAF', 'Gene', (213, 217))	('IDH1', 'Gene', (174, 178))	('BRAF', 'Gene', '673', (213, 217))	('1p/19q', 'Gene', (142, 148))	('IDH1', 'Gene', '3417', (174, 178))
145082	33194573	Then multivariable logistic regression analysis demonstrated that multiple variables, including age, SIRI, Tumor necrosis volume, annular enhancement, PTE, and tumor volume, were independent risk factors, while pKPS and pEO were independent protective factors (Table 2).	('Tumor necrosis', 'Disease', (107, 121))	('PTE', 'Disease', (151, 154))	('Tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SIRI', 'Var', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('annular enhancement', 'MPA', (130, 149))	('Tumor necrosis', 'Disease', 'MESH:D009336', (107, 121))	('tumor', 'Disease', (160, 165))
145091	33194573	In our current study, the decision curves in three cohorts showed that if the threshold probability was between 0 and 0.80, then using the comprehensive nomogram to preoperatively predict GBM added more benefit than treating either all or no patients, while the perfect model was the model with the highest net benefit under any threshold probability.	('GBM', 'Var', (188, 191))	('benefit', 'PosReg', (203, 210))	('patients', 'Species', '9606', (242, 250))
145123	33194573	found that the median overall survival rate in patients with SIRI<=1.2 was significantly higher than in patients with SIRI>1.2 and the nomogram including SIRI could more accurately predict OS compared with the TNM staging system.	('TNM', 'Gene', '10178', (210, 213))	('overall survival', 'MPA', (22, 38))	('patients', 'Species', '9606', (47, 55))	('higher', 'PosReg', (89, 95))	('SIRI<=1.2', 'Var', (61, 70))	('TNM', 'Gene', (210, 213))	('patients', 'Species', '9606', (104, 112))
145142	32144351	However, studies have shown that biological alterations in specific genes or molecules can affect the prognosis of glioma patients.	('glioma', 'Disease', (115, 121))	('prognosis', 'CPA', (102, 111))	('affect', 'Reg', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('patients', 'Species', '9606', (122, 130))	('alterations', 'Var', (44, 55))	('glioma', 'Disease', 'MESH:D005910', (115, 121))
145144	32144351	Dysregulation of miRNAs may lead to certain pathological states, such as cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lead to', 'Reg', (28, 35))
145145	32144351	Recently, many studies have revealed that miRNAs can function as oncogenes or tumor suppressors in cancer, affecting the clinical outcome.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', (99, 105))	('affecting', 'Reg', (107, 116))	('tumor', 'Disease', (78, 83))	('miRNAs', 'Var', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
145178	32144351	Figure 3 shows the Kaplan-Meier estimates for the high miR-21 expression group and the low miR-21 expression group.	('miR-21', 'Gene', (91, 97))	('miR-21', 'Gene', '406991', (91, 97))	('miR-21', 'Gene', (55, 61))	('high', 'Var', (50, 54))	('miR-21', 'Gene', '406991', (55, 61))
145182	32144351	Meanwhile, the results of the multivariate Cox regression analysis showed that high miR-21 expression was an independent prognostic biomarker for a poorer OS (HR = 1.27, 95% CI: 1.01, 1.59) and poorer PFS (HR = 1.46, 95% CI: 1.17, 1.82) in patients with gliomas (Tables 5 and 6).	('expression', 'MPA', (91, 101))	('Cox', 'Gene', (43, 46))	('OS', 'Chemical', '-', (155, 157))	('miR-21', 'Gene', '406991', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('poorer', 'NegReg', (148, 154))	('miR-21', 'Gene', (84, 90))	('high', 'Var', (79, 83))	('poorer', 'NegReg', (194, 200))	('patients', 'Species', '9606', (240, 248))	('PFS', 'MPA', (201, 204))	('gliomas', 'Disease', 'MESH:D005910', (254, 261))	('gliomas', 'Phenotype', 'HP:0009733', (254, 261))	('Cox', 'Gene', '1351', (43, 46))	('gliomas', 'Disease', (254, 261))
145226	32144351	For each included study, the following data were extracted: (1) first author's name, publication year, and location of sample collection; (2) characteristics of the studied population (sample size, follow-up period, tumor grade, sampling type); (3) miRNA test method, cut-off value to define high- or low-expression of miRNA, extracting method of HRs (95% CIs), outcome (OS or PFS), and NOS; and (4) HRs of miR-21 expression associated with survival of glioma patients in terms of OS and PFS with 95% CIs.	('tumor', 'Disease', (216, 221))	('HRs', 'Var', (400, 403))	('OS', 'Chemical', '-', (481, 483))	('glioma', 'Disease', 'MESH:D005910', (453, 459))	('associated with', 'Reg', (425, 440))	('miR-21', 'Gene', '406991', (407, 413))	('glioma', 'Phenotype', 'HP:0009733', (453, 459))	('low-expression', 'NegReg', (301, 315))	('miR-21', 'Gene', (407, 413))	('patients', 'Species', '9606', (460, 468))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('OS', 'Chemical', '-', (388, 390))	('glioma', 'Disease', (453, 459))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('OS', 'Chemical', '-', (371, 373))
145232	32144351	Unpaired t test and chi-square test were used for the comparison of high miR-21 expression group and low miR-21 expression group.	('miR-21', 'Gene', '406991', (73, 79))	('high', 'Var', (68, 72))	('miR-21', 'Gene', '406991', (105, 111))	('miR-21', 'Gene', (73, 79))	('miR-21', 'Gene', (105, 111))
145240	31576231	Cases in TCGA-LGG were classified to subtypes according to histopathological results, IDH1 mutation status and 1p19q status.	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('mutation status', 'Var', (91, 106))	('TCGA-LGG', 'Disease', (9, 17))	('1p19q status', 'Var', (111, 123))
145242	31576231	Results from GSE16011 showed that: glioma, LGG and LGG with IDH1 mutation patients with high EN1 expressions had significantly shorter 5, 10, and 15-year overall survival time (OS) (p < 0.001).	('shorter', 'NegReg', (127, 134))	('high', 'Var', (88, 92))	('EN1', 'Gene', (93, 96))	('LGG', 'Disease', (51, 54))	('IDH1', 'Gene', (60, 64))	('patients', 'Species', '9606', (74, 82))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('overall survival time', 'CPA', (154, 175))	('mutation', 'Var', (65, 73))	('IDH1', 'Gene', '3417', (60, 64))	('LGG', 'Disease', (43, 46))	('glioma', 'Disease', (35, 41))
145243	31576231	Similar results from TCGA-LGG showed that LGG patients with high EN1 expressions had significantly shorter 15-year OS, irrespective of IDH1 mutation and 1p19q co-deletion (p < 0.001).	('shorter', 'NegReg', (99, 106))	('15-year OS', 'CPA', (107, 117))	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (60, 64))	('IDH1', 'Gene', (135, 139))	('LGG', 'Disease', (42, 45))	('IDH1', 'Gene', '3417', (135, 139))	('EN1', 'Gene', (65, 68))
145245	31576231	EN1 can be used as a prognostic marker in LGG patients, combined with IDH1 mutation and 1p19q co-deletion.	('patients', 'Species', '9606', (46, 54))	('LGG', 'Disease', (42, 45))	('mutation', 'Var', (75, 83))	('IDH1', 'Gene', '3417', (70, 74))	('1p19q', 'Var', (88, 93))	('IDH1', 'Gene', (70, 74))
145254	31576231	IDH1 mutation and loss of 1p/19q in LGG patients usually comply to longer overall survival (OS).	('loss of 1p/19q', 'Var', (18, 32))	('patients', 'Species', '9606', (40, 48))	('overall survival', 'CPA', (74, 90))	('LGG', 'Disease', (36, 39))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('longer', 'PosReg', (67, 73))	('IDH1', 'Gene', '3417', (0, 4))
145256	31576231	High EN1 expression has been found in patients with breast tumors, salivary gland adenoid cystic carcinoma and adenoid cystic carcinoma, with increased recurrence and mortality rate.	('salivary gland adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (67, 106))	('breast tumors', 'Disease', 'MESH:D061325', (52, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('found', 'Reg', (29, 34))	('salivary gland adenoid cystic carcinoma', 'Disease', (67, 106))	('breast tumors', 'Phenotype', 'HP:0100013', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('expression', 'MPA', (9, 19))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (111, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('High EN1', 'Var', (0, 8))	('patients', 'Species', '9606', (38, 46))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (82, 106))	('adenoid cystic carcinoma', 'Disease', (111, 135))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('breast tumors', 'Disease', (52, 65))
145257	31576231	In this study, by data mining in large micro-array datasets, we characterized the expression profile of EN1 in LGGs with histological subtypes, IDH1 mutation and 1p19q co-deletion status to assess the associations between EN1 expression and OS.	('associations', 'Interaction', (201, 213))	('IDH1', 'Gene', (144, 148))	('mutation', 'Var', (149, 157))	('EN1', 'Gene', (104, 107))	('IDH1', 'Gene', '3417', (144, 148))
145260	31576231	46 cases were LGG with IDH1 mutation, and 45 cases were LGG without IDH1 mutation.	('LGG', 'Disease', (14, 17))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', (68, 72))	('mutation', 'Var', (28, 36))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', '3417', (68, 72))
145265	31576231	Survival data of LGG with or without IDH1 mutation was extracted for analysis.	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('IDH1', 'Gene', (37, 41))
145266	31576231	Three grouping methods were selected: histological type, IDH1 mutation and 1p19q co-deletion.	('IDH1', 'Gene', '3417', (57, 61))	('mutation', 'Var', (62, 70))	('1p19q co-deletion', 'Var', (75, 92))	('IDH1', 'Gene', (57, 61))
145273	31576231	Kaplan-Meier survival analysis was chosen to explore the association between EN1 expression and 5, 10 and 15 year OS in LGG patients with/without IDH1 mutation through data mining in R2 using data in  (Figs.	('IDH1', 'Gene', (146, 150))	('IDH1', 'Gene', '3417', (146, 150))	('EN1', 'Gene', (77, 80))	('mutation', 'Var', (151, 159))	('patients', 'Species', '9606', (124, 132))
145274	31576231	Higher expression of EN1 in LGG with IDH1 mutation correlated with shorter patient 5, 10 and 15- year OS (p < 0.001) (Figs.	('IDH1', 'Gene', (37, 41))	('expression', 'MPA', (7, 17))	('EN1', 'Protein', (21, 24))	('mutation', 'Var', (42, 50))	('Higher', 'PosReg', (0, 6))	('IDH1', 'Gene', '3417', (37, 41))	('shorter', 'NegReg', (67, 74))	('patient', 'Species', '9606', (75, 82))
145275	31576231	It seemed that higher expression of EN1 in LGG with IDH1 mutation correlated with shorter patient 5, 10 and 15- year OS, but there was no statistical significance (p > 0.05) (Figs.	('EN1', 'Protein', (36, 39))	('mutation', 'Var', (57, 65))	('IDH1', 'Gene', '3417', (52, 56))	('higher', 'PosReg', (15, 21))	('patient', 'Species', '9606', (90, 97))	('IDH1', 'Gene', (52, 56))	('expression', 'MPA', (22, 32))
145281	31576231	To further confirm the findings of data from the GEO dataset, we classified the cases in TCGA-LGG dataset into two groups: LGG with IDH1 mutation and LGG without IDH1 mutation.	('IDH1', 'Gene', (132, 136))	('mutation', 'Var', (137, 145))	('IDH1', 'Gene', '3417', (162, 166))	('IDH1', 'Gene', '3417', (132, 136))	('LGG', 'Disease', (123, 126))	('IDH1', 'Gene', (162, 166))
145282	31576231	Heat map and the corresponding box plots showed that LGG with IDH1 mutation patients had a lower EN1 expression (Figs.	('lower', 'NegReg', (91, 96))	('patients', 'Species', '9606', (76, 84))	('mutation', 'Var', (67, 75))	('IDH1', 'Gene', '3417', (62, 66))	('IDH1', 'Gene', (62, 66))	('EN1', 'Protein', (97, 100))
145283	31576231	Kaplan-Meier curves was generated and showed that the LGG with IDH1 mutation had significantly more 15-year OS (p < 0.001) (Figs.	('IDH1', 'Gene', '3417', (63, 67))	('15-year OS', 'CPA', (100, 110))	('mutation', 'Var', (68, 76))	('more', 'PosReg', (95, 99))	('IDH1', 'Gene', (63, 67))
145285	31576231	The negative correlation between EN1 expression and OS existed in both LGG irrespective of IDH1 mutation: Lower expression of EN1 correlated with improved patient 15-year OS (p < 0.05) (Figs.	('mutation', 'Var', (96, 104))	('patient 15-year OS', 'CPA', (155, 173))	('improved', 'PosReg', (146, 154))	('IDH1', 'Gene', (91, 95))	('patient', 'Species', '9606', (155, 162))	('Lower', 'NegReg', (106, 111))	('EN1', 'Gene', (126, 129))	('IDH1', 'Gene', '3417', (91, 95))	('expression', 'MPA', (112, 122))
145286	31576231	The results of Kaplan-Meier survival analysis showed that: (1) 15- year OS in LGG patients with 1p19q co-deletion is significantly higher than the ones without 1p19q co-deletion (p < 0.001) (Fig.	('patients', 'Species', '9606', (82, 90))	('LGG', 'Disease', (78, 81))	('1p19q co-deletion', 'Var', (96, 113))	('higher', 'PosReg', (131, 137))
145287	31576231	6C); (2) Higher EN1 expression is consistent with shorter 15- year OS in LGG patients with/without 1p19q co-deletion (p < 0.001) (Figs.	('expression', 'MPA', (20, 30))	('1p19q co-deletion', 'Var', (99, 116))	('LGG', 'Disease', (73, 76))	('patients', 'Species', '9606', (77, 85))	('shorter', 'NegReg', (50, 57))	('Higher', 'PosReg', (9, 15))	('EN1', 'Protein', (16, 19))
145290	31576231	In patients with tumors, high EN1 expression was associated with reduced survival time.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('reduced', 'NegReg', (65, 72))	('expression', 'MPA', (34, 44))	('EN1', 'Protein', (30, 33))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('survival time', 'CPA', (73, 86))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
145291	31576231	In mice with loss of EN1, Parkinson disease-like motor or non-motor symptoms will appear, which implies that EN1 probably can be a therapeutic target for Parkinson disease.	('appear', 'Reg', (82, 88))	('Parkinson disease', 'Disease', 'MESH:D010300', (26, 43))	('mice', 'Species', '10090', (3, 7))	('Parkinson disease', 'Disease', (154, 171))	('Parkinson disease', 'Disease', (26, 43))	('EN1', 'Gene', (21, 24))	('loss', 'Var', (13, 17))	('Parkinson disease', 'Disease', 'MESH:D010300', (154, 171))	('non-motor symptoms', 'CPA', (58, 76))
145298	31576231	LGG were grouped according to histological types, IDH1 mutation status and 1p19q co-deletion status.	('1p19q', 'Var', (75, 80))	('mutation status', 'Var', (55, 70))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', (50, 54))
145300	31576231	Kaplan-Meier survival curves were similar in LGG patients with IDH1 mutation and without mutation; although no significant difference was found in the latter group.	('mutation', 'Var', (68, 76))	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (63, 67))	('patients', 'Species', '9606', (49, 57))
145303	31576231	Compared with the corresponding group, LGG with IDH1 mutation or 1p19q co-deletion had a lower EN1 expression and a longer OS.	('lower', 'NegReg', (89, 94))	('IDH1', 'Gene', '3417', (48, 52))	('EN1', 'Protein', (95, 98))	('1p19q co-deletion', 'Var', (65, 82))	('IDH1', 'Gene', (48, 52))
145304	31576231	Whether with IDH1 mutation or not, LGG patients with lower EN1 expression had significantly more 15-year OS.	('more', 'PosReg', (92, 96))	('patients', 'Species', '9606', (39, 47))	('expression', 'MPA', (63, 73))	('IDH1', 'Gene', (13, 17))	('15-year OS', 'CPA', (97, 107))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', '3417', (13, 17))	('EN1', 'Gene', (59, 62))	('lower', 'NegReg', (53, 58))
145306	31576231	Previous studies showed that IDH1 mutation and 1p19q co-deletion may be related to the therapeutic effect in LGG patients and has been used as prognostic indicator.	('1p19q co-deletion', 'Var', (47, 64))	('IDH1', 'Gene', (29, 33))	('patients', 'Species', '9606', (113, 121))	('mutation', 'Var', (34, 42))	('IDH1', 'Gene', '3417', (29, 33))	('related', 'Reg', (72, 79))	('LGG', 'Disease', (109, 112))
145312	31576231	In conclusion, as the first research of EN1 in LGG is shown, these results support the importance and specificity of EN1 effect on survival rate in LGG patients with/without IDH1 mutation and 1p19q co-deletion.	('EN1', 'Gene', (117, 120))	('1p19q co-deletion', 'Var', (192, 209))	('mutation', 'Var', (179, 187))	('LGG', 'Disease', (148, 151))	('IDH1', 'Gene', (174, 178))	('IDH1', 'Gene', '3417', (174, 178))	('patients', 'Species', '9606', (152, 160))
145317	29618619	Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('disease-free survival time', 'CPA', (94, 120))	('shortened', 'NegReg', (73, 82))	('interferon', 'Gene', (37, 47))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (136, 142))	('deletion', 'Var', (25, 33))	('patients', 'Species', '9606', (158, 166))	('interferon', 'Gene', '3439', (37, 47))
145319	29618619	Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy.	('interferon', 'Gene', (107, 117))	('CTLA-4', 'Gene', '1493', (236, 242))	('deletion', 'Var', (95, 103))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('CTLA-4', 'Gene', (236, 242))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', '1493', (244, 287))	('interferon', 'Gene', '3439', (107, 117))	('associated with', 'Reg', (201, 216))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', (244, 287))	('defensin', 'Gene', (146, 154))	('resistance to', 'CPA', (217, 230))
145320	29618619	Our analysis reveals that the homozygous deletion of interferon and defensin genes are prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance.	('prevalent', 'Reg', (87, 96))	('interferon', 'Gene', '3439', (53, 63))	('human cancers', 'Disease', (100, 113))	('defensin', 'Gene', (68, 76))	('interferon', 'Gene', (53, 63))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('homozygous', 'Var', (30, 40))	('human cancers', 'Disease', 'MESH:D009369', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
145322	29618619	Previous studies estimate that 25% of the cancer genome is affected by arm-level SCNAs and 10% by focal SCNAs with 2% overlap.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('affected', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('SCNAs', 'Var', (81, 86))	('cancer', 'Disease', (42, 48))
145325	29618619	Another study exploring the copy number profiles of 3131 tumor genomes across 26 cancer types identified 158 recurrent focal SCNAs including 76 amplification affecting 1566 genes and 82 deletions affecting 2001 genes.	('amplification affecting', 'Var', (144, 167))	('focal SCNAs', 'Disease', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (57, 62))	('deletions', 'Var', (186, 195))
145331	29618619	Survival analyses of different tumor types indicated that patients with homozygous deletion of interferon or defensin genes exhibit much worse overall or disease-free survival.	('worse', 'NegReg', (137, 142))	('interferon', 'Gene', '3439', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('disease-free survival', 'CPA', (154, 175))	('tumor', 'Disease', (31, 36))	('overall', 'CPA', (143, 150))	('homozygous deletion', 'Var', (72, 91))	('interferon', 'Gene', (95, 105))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('defensin genes', 'Gene', (109, 123))
145332	29618619	RNA-seq gene expression analyses between patients with and without IFN/DEF deletion in 19 cancer types indicate that homozygous deletions of IFN and DEF activate oncogenic and cell cycle pathways but repress immune response pathways.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IFN', 'Gene', '3439', (141, 144))	('repress immune response', 'Phenotype', 'HP:0002721', (200, 223))	('patients', 'Species', '9606', (41, 49))	('DEF', 'Gene', (149, 152))	('immune response pathways', 'Pathway', (208, 232))	('IFN', 'Gene', '3439', (67, 70))	('activate', 'PosReg', (153, 161))	('repress', 'NegReg', (200, 207))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('IFN', 'Gene', (141, 144))	('deletions', 'Var', (128, 137))	('IFN', 'Gene', (67, 70))
145334	29618619	Since a large body of evidence suggest that interferons and defensins play major roles in tumor immunity by recognizing tumor cells and serve as a bridge to spontaneous adaptive T cell response, our findings suggest a common molecular mechanism mediated by the deletion of interferon and defensin genes, through which tumor cells escape immune detection and destruction.	('defensin genes', 'Gene', (288, 302))	('interferon', 'Gene', '3439', (273, 283))	('interferon', 'Gene', '3439', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('interferon', 'Gene', (44, 54))	('interferon', 'Gene', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('deletion', 'Var', (261, 269))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (120, 125))
145347	29618619	beta = 0.2), the minimum number of required events (K) is calculated as: where Zalpha/2 = 1.96, Zbeta = 0.84, pi1 and pi2 are the proportions to be allocated into two groups and were determined by the HDI/HDD frequencies in each cancer type.	('cancer', 'Disease', (229, 235))	('pi1', 'Var', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Zalpha/2 = 1.96', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pi2', 'Var', (118, 121))	('HDD', 'Disease', (205, 208))	('pi2', 'Species', '1214577', (118, 121))	('HDD', 'Disease', 'None', (205, 208))
145379	29618619	Since both interferons and defensins are involved in innate immune response and play important roles in recognizing tumor cells and inducing an anti-tumor immune response, the widespread, homozygous deletion of these genes suggests a common molecular mechanism through which tumor cells escape immune destruction.	('interferon', 'Gene', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('interferon', 'Gene', '3439', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (149, 154))	('deletion', 'Var', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (116, 121))
145404	29618619	We asked the question whether homozygous deletions of interferon genes are passive hitchhiking events due to the nearby CDKN2A deletion, or they play an active role in tumorigenesis and affect the patient survival.	('play', 'Reg', (145, 149))	('affect', 'Reg', (186, 192))	('interferon', 'Gene', '3439', (54, 64))	('tumor', 'Disease', (168, 173))	('CDKN2A', 'Gene', (120, 126))	('interferon', 'Gene', (54, 64))	('deletion', 'Var', (127, 135))	('CDKN2A', 'Gene', '1029', (120, 126))	('patient survival', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
145406	29618619	We performed the survival analyses on three patient groups: (I) patients only have CDKN2A deletion (CDKN2A-/IFN+); (II) patients have CDKN2A deletion and additional IFN gene deletions (CDKN2A-/IFN-); and (III) patients have neither CDKN2A nor IFN gene deletions (CDKN2A+/IFN+).	('deletion', 'Var', (90, 98))	('IFN', 'Gene', '3439', (271, 274))	('IFN', 'Gene', (243, 246))	('CDKN2A nor IFN', 'Gene', '1029;3439', (232, 246))	('CDKN2A', 'Gene', (83, 89))	('CDKN2A', 'Gene', '1029', (100, 106))	('CDKN2A', 'Gene', (263, 269))	('IFN', 'Gene', (193, 196))	('patient', 'Species', '9606', (64, 71))	('CDKN2A', 'Gene', (232, 238))	('patient', 'Species', '9606', (120, 127))	('CDKN2A-/IFN+);', 'Gene', '1029;3439', (100, 114))	('IFN', 'Gene', (271, 274))	('patients', 'Species', '9606', (210, 218))	('CDKN2A', 'Gene', (185, 191))	('deletion', 'Var', (141, 149))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDKN2A', 'Gene', '1029', (263, 269))	('CDKN2A', 'Gene', (134, 140))	('IFN', 'Gene', '3439', (165, 168))	('CDKN2A', 'Gene', '1029', (232, 238))	('IFN', 'Gene', '3439', (108, 111))	('CDKN2A-/IFN-', 'Gene', (185, 197))	('CDKN2A nor IFN', 'Gene', (232, 246))	('CDKN2A+/IFN+', 'Gene', '3439', (263, 275))	('IFN', 'Gene', '3439', (243, 246))	('CDKN2A', 'Gene', '1029', (185, 191))	('CDKN2A-/IFN+)', 'Gene', (100, 113))	('patient', 'Species', '9606', (44, 51))	('CDKN2A-/IFN-)', 'Gene', '1029;3439', (185, 198))	('patients', 'Species', '9606', (64, 72))	('CDKN2A+/IFN+', 'Gene', (263, 275))	('CDKN2A', 'Gene', '1029', (134, 140))	('IFN', 'Gene', (165, 168))	('patients', 'Species', '9606', (120, 128))	('CDKN2A', 'Gene', (100, 106))	('patient', 'Species', '9606', (210, 217))	('IFN', 'Gene', '3439', (193, 196))	('IFN', 'Gene', (108, 111))
145413	29618619	It could be also due to other confounding factors such as PTEN and RB1 deletions, which tend to be mutually exclusive with HDIs and HDDs (Supplementary Figure 7).	('deletions', 'Var', (71, 80))	('PTEN', 'Gene', '5728', (58, 62))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))	('HDIs and HDDs', 'Disease', 'None', (123, 136))	('PTEN', 'Gene', (58, 62))
145414	29618619	To identify gene expression signatures associated with the deletion of IFN and DEF genes, we performed gene expression analysis on each of the 19 cancer types (or 17 cancer types when COAD and READ are combined as colorectal cancer, LUSC and LUAD are combined as lung cancer) having high frequencies of HDI and HDD.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (225, 231))	('COAD', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('IFN', 'Gene', '3439', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('HDD', 'Disease', 'None', (311, 314))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('colorectal cancer', 'Disease', (214, 231))	('HDD', 'Disease', (311, 314))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('IFN', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('deletion', 'Var', (59, 67))	('cancer', 'Disease', (268, 274))	('COAD', 'Disease', 'MESH:D029424', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))
145428	29618619	In a recent report, copy loss of type I interferon genes are found in 6 out of 12 melanoma patients that resist to anti-CTLA-4 treatment, but in none of the 4 responders (P = 0.23, two-tailed Fisher exact test).	('copy loss', 'Var', (20, 29))	('patients', 'Species', '9606', (91, 99))	('interferon', 'Gene', '3439', (40, 50))	('CTLA-4', 'Gene', '1493', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('interferon', 'Gene', (40, 50))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CTLA-4', 'Gene', (120, 126))
145433	29618619	As a comparison, deletions of two tumor suppressor genes CDKN2A (P = 0.63) and PTEN (P = 0.55) are not associated with responders or non-responders (Fig.	('tumor', 'Disease', (34, 39))	('CDKN2A', 'Gene', (57, 63))	('deletions', 'Var', (17, 26))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PTEN', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', '5728', (79, 83))
145434	29618619	Taken together, our meta-analyses of two independent melanoma cohorts suggest the deletion of interferon and defensin genes is significantly associated anti-CTLA-4 treatment resistance, and might be a potential prognostic biomarker to predict resistance to other immunotherapies.	('CTLA-4', 'Gene', (157, 163))	('interferon', 'Gene', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('CTLA-4', 'Gene', '1493', (157, 163))	('deletion', 'Var', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('associated', 'Reg', (141, 151))	('interferon', 'Gene', '3439', (94, 104))
145436	29618619	In this study, we analyzed the copy number profiles of 10,759 primary cancer tissues and found the homozygous deletions of type I interferon and defensin genes are pervasive in 19 TCGA cancer types, and the alteration frequency is much higher than those of well-known tumor suppressors PTEN and RB1 in the same cancer type (Supplementary Figure 7).	('interferon', 'Gene', '3439', (130, 140))	('PTEN', 'Gene', '5728', (286, 290))	('cancer', 'Disease', (311, 317))	('defensin', 'Gene', (145, 153))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('RB1', 'Gene', '5925', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PTEN', 'Gene', (286, 290))	('tumor', 'Disease', (268, 273))	('interferon', 'Gene', (130, 140))	('RB1', 'Gene', (295, 298))	('deletions', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
145437	29618619	More importantly, homozygous deletions of interferon and defensin genes associate with worse overall or disease-free survival, and the resistance to anti-CTLA4 treatment in melanoma patients.	('defensin', 'Gene', (57, 65))	('CTLA4', 'Gene', (154, 159))	('worse', 'NegReg', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('interferon', 'Gene', '3439', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('disease-free survival', 'CPA', (104, 125))	('resistance', 'CPA', (135, 145))	('patients', 'Species', '9606', (182, 190))	('overall', 'CPA', (93, 100))	('interferon', 'Gene', (42, 52))	('CTLA4', 'Gene', '1493', (154, 159))	('homozygous deletions', 'Var', (18, 38))
145438	29618619	Defects in the type I interferon signaling pathway have been proposed as a potential mechanism of cancer escape (insensitivity) to immunotherapy in mice and prostate cancer cell line.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interferon', 'Gene', '3439', (22, 32))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('Defects', 'Var', (0, 7))	('interferon', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', (98, 104))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
145441	29618619	Homozygous deletions of interferon and defensin genes activate oncogenic pathways and repress immune response pathways further recapitulate their roles in promoting tumorigenesis and help tumor cells escape immunosurveillance.	('interferon', 'Gene', (24, 34))	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (165, 170))	('repress', 'NegReg', (86, 93))	('defensin', 'Gene', (39, 47))	('immune response pathways', 'Pathway', (94, 118))	('promoting', 'PosReg', (155, 164))	('repress immune response', 'Phenotype', 'HP:0002721', (86, 109))	('interferon', 'Gene', '3439', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Homozygous', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('oncogenic pathways', 'Pathway', (63, 81))	('activate', 'PosReg', (54, 62))	('escape immunosurveillance', 'CPA', (200, 225))	('help', 'PosReg', (183, 187))
145443	29618619	By analyzing the genomes of 10,759 cancer patients across 31 cancer types, we found interferon and defensin genes are homozygously deleted with high frequencies in 19 cancer types, and the surviving time of patients with these deletions are significantly reduced.	('reduced', 'NegReg', (255, 262))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('interferon', 'Gene', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('surviving time', 'CPA', (189, 203))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('interferon', 'Gene', '3439', (84, 94))	('deletions', 'Var', (227, 236))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (42, 50))	('defensin genes', 'Gene', (99, 113))	('cancer', 'Disease', (35, 41))
145512	33316976	Depending on the specific subunit of receptors, AgRP dysfunction leads to emaciation, starvation and death, while alteration of the POMC pathway leads to obesity.	('emaciation', 'Disease', (74, 84))	('POMC', 'Gene', (132, 136))	('obesity', 'Phenotype', 'HP:0001513', (154, 161))	('obesity', 'Disease', 'MESH:D009765', (154, 161))	('leads to', 'Reg', (65, 73))	('AgRP', 'Gene', '11604', (48, 52))	('obesity', 'Disease', (154, 161))	('starvation', 'Disease', (86, 96))	('POMC', 'Gene', '18976', (132, 136))	('leads to', 'Reg', (145, 153))	('dysfunction', 'Var', (53, 64))	('death', 'Disease', (101, 106))	('death', 'Disease', 'MESH:D003643', (101, 106))	('alteration', 'Var', (114, 124))	('AgRP', 'Gene', (48, 52))
145521	33316976	Activated STAT3 then upregulates the transcription of target genes, including SOCS3 (suppressor of cytokine signaling-3), which acts in a negative feedback loop to inhibit leptin signaling.	('suppressor of cytokine signaling-3', 'Gene', '9021', (85, 119))	('SOCS3', 'Gene', (78, 83))	('suppressor of cytokine signaling-3', 'Gene', (85, 119))	('inhibit', 'NegReg', (164, 171))	('Activated', 'Var', (0, 9))	('upregulates', 'PosReg', (21, 32))	('leptin signaling', 'MPA', (172, 188))	('STAT3', 'Gene', '6774', (10, 15))	('transcription', 'MPA', (37, 50))	('SOCS3', 'Gene', '9021', (78, 83))	('STAT3', 'Gene', (10, 15))
145530	33316976	Interestingly, crosstalk between leptin and soluble Phospholipase A2-IIa enhances proliferation and migration in astrocytoma cell lines via the PI3K/Akt/mTOR/P70S6K pathway (Figure 1).	('Akt', 'Gene', (149, 152))	('migration', 'CPA', (100, 109))	('P70S6K', 'Gene', '6198', (158, 164))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('mTOR', 'Gene', (153, 157))	('crosstalk', 'Var', (15, 24))	('mTOR', 'Gene', '2475', (153, 157))	('P70S6K', 'Gene', (158, 164))	('Akt', 'Gene', '207', (149, 152))	('soluble', 'Protein', (44, 51))	('proliferation', 'CPA', (82, 95))	('astrocytoma', 'Disease', 'MESH:D001254', (113, 124))	('astrocytoma', 'Disease', (113, 124))	('enhances', 'PosReg', (73, 81))
145531	33316976	Furthermore, ObR expression in glioblastoma cells imparts progenitor/stem cell-like properties through STAT3-mediated upregulation of the pluripotency-associated SOX2/OCT4 signaling axis, which underlies the self-renewal properties of glioma cells and resistance to drugs such as temozolomide (Figure 1).	('SOX2', 'Gene', (162, 166))	('STAT3', 'Gene', (103, 108))	('SOX2', 'Gene', '6657', (162, 166))	('glioma', 'Disease', (235, 241))	('OCT4', 'Gene', (167, 171))	('STAT3', 'Gene', '6774', (103, 108))	('glioma', 'Disease', 'MESH:D005910', (235, 241))	('upregulation', 'PosReg', (118, 130))	('ObR', 'Gene', (13, 16))	('progenitor/stem cell-like properties', 'CPA', (58, 94))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))	('ObR', 'Gene', '3953', (13, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('expression', 'Var', (17, 27))	('pluripotency-associated', 'MPA', (138, 161))	('glioblastoma', 'Disease', (31, 43))	('OCT4', 'Gene', '5460', (167, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('temozolomide', 'Chemical', 'MESH:D000077204', (280, 292))
145533	33316976	As mentioned above, STAT3 and Akt/PKB are known to be consistently upregulated in various glioblastoma cell lines due to leptin/ObR overexpression, which drives dysregulation of the cell cycle suppressor Rb (retinoblastoma protein), thus promoting uncontrolled cellular proliferation in the absence of normal suppressive mechanisms (Figure 1).	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('Akt/PKB', 'Gene', '207', (30, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('overexpression', 'PosReg', (132, 146))	('ObR', 'Gene', (128, 131))	('dysregulation', 'Var', (161, 174))	('retinoblastoma', 'Disease', 'MESH:D012175', (208, 222))	('retinoblastoma', 'Disease', (208, 222))	('promoting', 'PosReg', (238, 247))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (161, 192))	('Akt/PKB', 'Gene', (30, 37))	('STAT3', 'Gene', '6774', (20, 25))	('uncontrolled cellular proliferation', 'CPA', (248, 283))	('glioblastoma', 'Disease', (90, 102))	('STAT3', 'Gene', (20, 25))	('ObR', 'Gene', '3953', (128, 131))	('upregulated', 'PosReg', (67, 78))	('retinoblastoma', 'Phenotype', 'HP:0009919', (208, 222))
145534	33316976	Antagonism of ObR in glioblastoma cell lines peptide inhibits proliferation and invasiveness, and is associated with downregulation of leptin-responsive genes such as cyclin D1 (CCDN1), survivin (BIRC5), heat shock protein (HSP90A), hypoxia inducible factor (HIF1A) and vascular endothelial growth factor (VEGF).	('glioblastoma', 'Disease', (21, 33))	('hypoxia', 'Disease', 'MESH:D000860', (233, 240))	('vascular endothelial growth factor', 'Gene', '7422', (270, 304))	('cyclin D1', 'Gene', (167, 176))	('downregulation', 'NegReg', (117, 131))	('VEGF', 'Gene', '7422', (306, 310))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('leptin-responsive genes', 'Gene', (135, 158))	('BIRC5', 'Gene', '332', (196, 201))	('BIRC5', 'Gene', (196, 201))	('vascular endothelial growth factor', 'Gene', (270, 304))	('VEGF', 'Gene', (306, 310))	('Antagonism', 'Var', (0, 10))	('proliferation', 'CPA', (62, 75))	('cyclin D1', 'Gene', '595', (167, 176))	('HSP90A', 'Gene', (224, 230))	('HIF1A', 'Gene', (259, 264))	('inhibits', 'NegReg', (53, 61))	('HSP90A', 'Gene', '3320', (224, 230))	('ObR', 'Gene', (14, 17))	('invasiveness', 'CPA', (80, 92))	('shock', 'Phenotype', 'HP:0031273', (209, 214))	('ObR', 'Gene', '3953', (14, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('hypoxia', 'Disease', (233, 240))	('HIF1A', 'Gene', '3091', (259, 264))
145536	33316976	Selective LFDI-mediated antagonism of ObR abrogates NOTCH signaling, suggesting a critical role of leptin/ObR in the modulation of NOTCH-dependent growth, proliferation and migration of glioblastoma cells, and a previous study suggested that this invasiveness and migration were driven by increased levels of matrix metalloproteinase (MMP)-13 via the MAPK pathway (Figure 1).	('glioblastoma', 'Disease', (186, 198))	('ObR', 'Gene', (106, 109))	('ObR', 'Gene', (38, 41))	('migration', 'CPA', (264, 273))	('MAPK pathway', 'Pathway', (351, 363))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('proliferation', 'CPA', (155, 168))	('increased', 'PosReg', (289, 298))	('ObR', 'Gene', '3953', (38, 41))	('migration', 'CPA', (173, 182))	('matrix metalloproteinase (MMP)-13', 'Gene', '4322', (309, 342))	('LFDI', 'Chemical', '-', (10, 14))	('antagonism', 'Var', (24, 34))	('ObR', 'Gene', '3953', (106, 109))	('NOTCH signaling', 'MPA', (52, 67))	('invasiveness', 'CPA', (247, 259))	('abrogates', 'NegReg', (42, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))
145594	33316976	Given the associations of obesity/diabetes and glucose-lowering antidiabetic agents (e.g., metformin) with glioblastoma outcomes, metformin (drug re-purposing) is currently under investigation as an adjunctive therapy in an established pharmacotherapeutic/radiotherapy and behavioral (diet) treatment in LGG and GBM patients in several ongoing RCTs [(NCT01430351-phase 1-n = 144 patients), (NCT02496741-phase 1b-n = 15 patients), (NCT02149459-phase 1-n = 18 patients), (NCT02780024-phase 2-n = 50 patients), (NCT03243851-phase 2-n = 108 patients) and (NCT03151772-phase 1-n = 40 patients)] (Table 1).	('diabetes', 'Disease', (34, 42))	('NCT03151772-phase', 'Var', (552, 569))	('patients', 'Species', '9606', (419, 427))	('glucose', 'Chemical', 'MESH:D005947', (47, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('patients', 'Species', '9606', (316, 324))	('patients', 'Species', '9606', (537, 545))	('patients', 'Species', '9606', (379, 387))	('obesity', 'Disease', (26, 33))	('patients', 'Species', '9606', (458, 466))	('patients', 'Species', '9606', (497, 505))	('metformin', 'Chemical', 'MESH:D008687', (130, 139))	('metformin', 'Chemical', 'MESH:D008687', (91, 100))	('glioblastoma', 'Disease', (107, 119))	('NCT03243851-phase', 'Var', (509, 526))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('obesity', 'Disease', 'MESH:D009765', (26, 33))	('diabetes', 'Disease', 'MESH:D003920', (34, 42))	('diabetic', 'Disease', 'MESH:D003920', (68, 76))	('diabetic', 'Disease', (68, 76))	('patients', 'Species', '9606', (579, 587))	('obesity', 'Phenotype', 'HP:0001513', (26, 33))	('NCT02780024-phase', 'Var', (470, 487))
145607	33316976	observed the opposite effect, as MFRMN was significantly associated with increased overall survival (OS) and progression-free survival (PFS) in grade III gliomas (n = 231 subjects), while no improvement was observed for the HGG subgroup (n = 862 subjects), supporting the hypothesis that IDH 1/2-MT status and a lower grade may increase the likelihood of response to metabolically active drugs (Table 1).	('IDH 1/2', 'Gene', (288, 295))	('increased', 'PosReg', (73, 82))	('ob', 'Gene', '16846', (207, 209))	('overall survival', 'CPA', (83, 99))	('response', 'MPA', (355, 363))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH 1/2', 'Gene', '3418', (288, 295))	('MFRMN', 'Var', (33, 38))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', (154, 161))	('ob', 'Gene', '16846', (0, 2))	('MFRMN', 'Chemical', 'MESH:D008687', (33, 38))	('increase', 'PosReg', (328, 336))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('progression-free survival', 'CPA', (109, 134))
145613	33316976	In a patient-derived GBM preclinical model, IL-17A inhibitors increased overall survival and decreased tumor growth/tumor hypoxia, angiogenesis, VEGF expression, cell proliferation, leptin expression and adipogenesis compared to control samples.	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('angiogenesis', 'CPA', (131, 143))	('leptin expression', 'MPA', (182, 199))	('overall survival', 'CPA', (72, 88))	('decreased tumor', 'Disease', 'MESH:D002303', (93, 108))	('tumor hypoxia', 'Disease', (116, 129))	('IL-17A', 'Gene', '3605', (44, 50))	('decreased tumor', 'Disease', (93, 108))	('adipogenesis', 'MPA', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('VEGF', 'Gene', '7422', (145, 149))	('expression', 'MPA', (150, 160))	('VEGF', 'Gene', (145, 149))	('IL-17A', 'Gene', (44, 50))	('tumor hypoxia', 'Disease', 'MESH:D000860', (116, 129))	('patient', 'Species', '9606', (5, 12))	('cell proliferation', 'CPA', (162, 180))	('inhibitors', 'Var', (51, 61))
145619	33316976	Increasing evidence from experimental studies (e.g., glioblastoma C6 cells lines) and some clinical studies have led to randomized-controlled trials incorporating inhibitors of the leptin/ObR axis as adjunctive therapy with established protocols in newly diagnosed and recurrent glioblastoma.	('glioblastoma', 'Disease', (53, 65))	('ObR', 'Gene', (188, 191))	('glioblastoma', 'Disease', 'MESH:D005909', (53, 65))	('C6', 'CellLine', 'CVCL:X905', (66, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('glioblastoma', 'Disease', (279, 291))	('ObR', 'Gene', '3953', (188, 191))	('glioblastoma', 'Disease', 'MESH:D005909', (279, 291))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('inhibitors', 'Var', (163, 173))
145631	29625048	These integrated subtypes shared mutations, copy-number alterations, pathway commonalities, and micro-environment characteristics that appeared influential in the new molecular taxonomy, beyond any phenotypic contributions from tumor stage or tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy-number alterations', 'Var', (44, 67))
145645	29625048	Using aneuploidy (AN), CpG hypermethylation (METH), mRNA (MRNA), miRNA (MIR), and protein (P), the resultant number of groups ranged from 10 to 25 (Figure 1).	('hypermethylation', 'Var', (27, 43))	('METH', 'Chemical', '-', (45, 49))	('miRNA', 'MPA', (65, 70))	('mRNA', 'MPA', (52, 56))	('aneuploidy', 'Var', (6, 16))
145649	29625048	Over one-third of the samples displayed relatively sparse aneuploidy in AN7; these were enriched for THCA, LAML, PRAD, and THYM.	('aneuploidy', 'Var', (58, 68))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('AN7', 'Gene', (72, 75))	('THCA', 'Disease', (101, 105))
145652	29625048	Consistent with previous results, squamous (lung, head and neck, and esophageal) tumors clustered together by aneuploidy patterns, particularly 3p loss and 3q gain (AN3).	('3p loss', 'Var', (144, 151))	('3q gain', 'Var', (156, 163))	('esophageal) tumors clustered', 'Disease', 'MESH:D004938', (69, 97))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
145654	29625048	Despite the exclusion of loci known to be involved in tissue-specific DNA methylation, tumors originating from the same organ often aggregated by cancer-type-specific hypermethylation (Figure 1B; Table S2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('hypermethylation', 'Var', (167, 183))
145658	29625048	Gastrointestinal adenocarcinomas (ESCA, STAD, COAD and READ) were represented in a branch containing METH10 through METH13.	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('Gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (0, 32))	('METH13', 'Chemical', '-', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('COAD', 'Disease', (46, 50))	('STAD', 'Disease', (40, 44))	('METH10', 'Var', (101, 107))	('Gastrointestinal adenocarcinomas', 'Disease', (0, 32))	('METH10', 'Chemical', '-', (101, 107))
145670	29625048	We used clustering of cluster assignments (COCA) algorithm to assess the overlap of platform-specific memberships from each of the five molecular platforms (aneuploidy, mRNA, miRNA, DNA methylation, and RPPA) (Figure 2A).	('COCA', 'Species', '289672', (43, 47))	('miRNA', 'MPA', (175, 180))	('mRNA', 'MPA', (169, 173))	('DNA', 'MPA', (182, 185))	('aneuploidy', 'Var', (157, 167))
145681	29625048	Eight iClusters were dominated by a single tumor type (C24:LAML, C11:LGG [IDH1 mut], C6:OV, C8:UCEC, C12:THCA, C16:PRAD, C26:LIHC, C14:LUAD).	('C26', 'CellLine', 'CVCL:0240', (121, 124))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('C11', 'Gene', '51728', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C24:', 'Var', (55, 59))	('IDH1', 'Gene', '3417', (74, 78))	('C12:THCA', 'Var', (101, 109))	('tumor', 'Disease', (43, 48))	('C11', 'Gene', (65, 68))
145682	29625048	Others contained tumors from similar or related cells or tissues: C28:pan-kidney (KIRC, KIRP), C15:SKCM/UVM-melanoma of the skin (SKCM) and eye (UVM), C23:GBM/LGG (IDH1wt), and C5:CNS/ endocrine.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('C15', 'Gene', '51316', (95, 98))	('C23:GBM/LGG', 'Gene', '4691', (151, 162))	('UVM-melanoma of the skin', 'Disease', (104, 128))	('IDH1', 'Gene', (164, 168))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('C15', 'Gene', (95, 98))	('IDH1', 'Gene', '3417', (164, 168))	('C28', 'Var', (66, 69))	('UVM-melanoma of the skin', 'Disease', 'MESH:D008545', (104, 128))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('C23:GBM/LGG', 'Gene', (151, 162))
145686	29625048	C4:pan-GI (CRC) was predominantly COAD and READ with chromosomal instability (CIN) and a distinct aneuploidy profile (Figure 2B).	('CIN', 'Disease', (78, 81))	('COAD', 'Disease', (34, 38))	('pan-GI', 'Var', (3, 9))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('COAD', 'Disease', 'MESH:D029424', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('chromosomal instability', 'Disease', (53, 76))
145687	29625048	The pan-squamous cohort formed three iClusters (C10, C25, and C27).	('C10', 'Gene', '3226', (48, 51))	('C10', 'Gene', (48, 51))	('C25', 'Var', (53, 56))	('C27', 'Var', (62, 65))
145689	29625048	Even though all squamous iClusters were characterized by chromosome 3q amplification, unique features defined C10:pan-SCC (9p deletion) and C25:pan-SCC (Chr11 amp) (Figure 2B).	('amp', 'Chemical', 'MESH:D000249', (71, 74))	('SCC', 'Gene', (118, 121))	('C10', 'Gene', (110, 113))	('SCC', 'Gene', (148, 151))	('C10', 'Gene', '3226', (110, 113))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (148, 151))	('amp', 'Chemical', 'MESH:D000249', (159, 162))	('9p deletion', 'Var', (123, 134))
145690	29625048	Among mixed tumor type iClusters, three were defined by copy-number alterations.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy-number alterations', 'Var', (56, 79))
145691	29625048	C7:mixed was characterized by chr9 deletion, C2:BRCA (HER2 amp) mainly consisted of ERBB2-amplified tumors (BRCA, BLCA, and STAD), and C13:mixed (Chr8 del) contained highly aneuploid tumors, including a mixture of BRCA-Basal, UCEC (CN-high subtype), UCS, and BLCA.	('BRCA', 'Gene', '672', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BRCA', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (59, 62))	('BRCA', 'Gene', (214, 218))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('tumors', 'Disease', (183, 189))	('BLCA', 'Disease', (259, 263))	('aneuploid tumors', 'Disease', 'MESH:D000782', (173, 189))	('BRCA', 'Gene', (108, 112))	('UCEC', 'Disease', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HER2', 'Gene', '2064', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('ERBB2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C13', 'Gene', (135, 138))	('tumors', 'Disease', (100, 106))	('deletion', 'Var', (35, 43))	('ERBB2', 'Gene', '2064', (84, 89))	('UCS', 'Disease', (250, 253))	('C13', 'Gene', '3229', (135, 138))	('BRCA', 'Gene', '672', (48, 52))	('HER2', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA', 'Gene', '672', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('aneuploid tumors', 'Disease', (173, 189))
145699	29625048	The silhouette widths ranged from -0.05 to 0.59, with the highest silhouette widths belonging to single-cancer-type-dominant iClusters (C11:LGG [IDH1 mut], C12:THCA, C16:PRAD, and C24:LAML).	('IDH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1', 'Gene', '3417', (145, 149))	('C11', 'Gene', '51728', (136, 139))	('C16:PRAD', 'Var', (166, 174))	('C24:LAML', 'Var', (180, 188))	('C11', 'Gene', (136, 139))	('C12:THCA', 'Var', (156, 164))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
145700	29625048	Interestingly, 6 of the 7 pan-organ system iClusters (pan-GI: C1, C4, C18; pan-SCC: C25, C27, and pan-kidney: C28) had similar ranges of silhouette widths to those of single cancer-type dominant iClusters, suggesting that these were as robust as the cancer-type-dominant iClusters.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('C27', 'Var', (89, 92))	('SCC', 'Gene', (79, 82))	('C18', 'Gene', (70, 73))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('C18', 'Gene', '27241', (70, 73))	('SCC', 'Gene', '6317', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
145701	29625048	iClusters driven by a shared specific chromosomal alteration (e.g., C13:mixed [chr8 del]) tended to compose multiple tumor types and appeared to have among the lowest silhouette widths, suggesting substantial molecular heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mixed [chr8 del]', 'Var', (72, 88))	('tumor', 'Disease', (117, 122))	('C13', 'Gene', (68, 71))	('C13', 'Gene', '3229', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
145718	29625048	Melanomas and lung adenocarcinomas have been shown to have relatively high mutation rates, and we observed similar results with C15:SKCM/UVM and C14:LUAD.	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('C15', 'Gene', (128, 131))	('C14:LUAD', 'Var', (145, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('mutation', 'MPA', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('Melanomas and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('C15', 'Gene', '51316', (128, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
145719	29625048	Mutation frequencies varied widely within the two iClusters with the most diverse tumor compositions: C3:mesenchymal (immune) and C20:mixed (stromal/immune).	('C20', 'Var', (130, 133))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
145726	29625048	Despite having very different cancer type compositions, the pan-squamous iClusters C10:pan-SCC, C25:pan-SCC (chr11 amp), and C27:pan-SCC (HPV) shared many pathway characteristics.	('amp', 'Chemical', 'MESH:D000249', (115, 118))	('SCC', 'Gene', '6317', (133, 136))	('HPV', 'Species', '10566', (138, 141))	('C10', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (91, 94))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', (104, 107))	('C10', 'Gene', '3226', (83, 86))	('C25', 'Var', (96, 99))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('C27', 'Var', (125, 128))
145730	29625048	In addition, C20:mixed (stromal/immune) contained 32% Pan-GI samples and also displayed strong immune-related signaling.	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('C20:mixed', 'Var', (13, 22))	('Pan-GI', 'Protein', (54, 60))
145731	29625048	Beta-catenin/cell-cell adhesion signaling appeared high in C4:pan-GI (CRC), C18:pan-GI (MSI), and C20:mixed (stromal/immune), but not in the smaller C1:STAD (EBV-CIMP).	('SI', 'Disease', 'None', (89, 91))	('C18', 'Gene', (76, 79))	('C4:pan-GI', 'Var', (59, 68))	('Beta-catenin/cell-cell adhesion signaling', 'MPA', (0, 41))	('C20:mixed', 'Var', (98, 107))	('C18', 'Gene', '27241', (76, 79))	('EBV', 'Species', '10376', (158, 161))	('high', 'PosReg', (51, 55))
145749	29625048	Interrogation of individual iClusters for their differentiating PARADIGM pathway features, canonical pathways, and gene programs amenable to drug targeting identified strong immune-related signaling features for both C3:mesenchymal (immune) and C20:mixed (stromal/immune) tumors, suggesting that they may share potential susceptibility to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('C20', 'Var', (245, 248))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('C3', 'Var', (217, 219))	('immune-related signaling', 'MPA', (174, 198))	('AR', 'Gene', '367', (65, 67))
145752	29625048	Compared to the seemingly discohesive groupings of the 17 heterogeneous iClusters, the 11 most homogeneous iClusters (C6:OV, C8:UCEC, C11:LGG [IDH1 mut], C12:THCA, C14:LUAD, C15:SKCM/UVM, C16:PRAD, C19:BRCA [luminal], C21:DLBC, C24:LAML, C26:LIHC) had higher silhouette widths, uniform tumor types, and histopathologies, but showed surprising degrees of spatial discohesion in the TumorMap.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('C21', 'Gene', (218, 221))	('IDH1', 'Gene', (143, 147))	('C11', 'Gene', (134, 137))	('C24:LAML', 'Var', (228, 236))	('higher', 'PosReg', (252, 258))	('Tumor', 'Phenotype', 'HP:0002664', (381, 386))	('C16:PRAD', 'Var', (188, 196))	('C21', 'Gene', '79718', (218, 221))	('C19:BRCA', 'Gene', (198, 206))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (286, 291))	('C15', 'Gene', '51316', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('C15', 'Gene', (174, 177))	('C26', 'CellLine', 'CVCL:0240', (238, 241))	('silhouette widths', 'CPA', (259, 276))	('C11', 'Gene', '51728', (134, 137))	('C19:BRCA', 'Gene', '672', (198, 206))
145755	29625048	However, exceptions that challenge this concept have also become apparent from such notable examples as the unpredictable clinical responses to a potent BRAF inhibitor across diverse malignancies all expressing the same BRAF mutation.	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (220, 224))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('BRAF', 'Gene', (220, 224))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('mutation', 'Var', (225, 233))	('malignancies', 'Disease', (183, 195))
145780	29625048	Cervical squamous tumors clustered in high aneuploidy clusters AN1 and AN5.	('squamous tumors', 'Disease', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (9, 24))	('AN1', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
145781	29625048	These clusters were also enriched for other Pan-gyn tumors, including ovarian, high-copy number endometrial, and uterine carcinosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high-copy number', 'Var', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (121, 135))	('ovarian', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (113, 135))	('carcinosarcoma', 'Disease', (121, 135))
145782	29625048	Gynecologic tumors with fewer copy-number alterations including Luminal breast cancers and other endometrial tumors grouped separately in low aneuploidy clusters AN7 and AN8, respectively.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('low aneuploidy clusters', 'Disease', 'MESH:D000782', (138, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('copy-number alterations', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('low aneuploidy clusters', 'Disease', (138, 161))	('Gynecologic', 'Disease', (0, 11))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('endometrial tumors', 'Disease', 'MESH:D016889', (97, 115))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('AN7', 'Var', (162, 165))	('endometrial tumors', 'Disease', (97, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
145793	29625048	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta-value of >= 0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('positive DNA methylation', 'Var', (146, 170))
145795	29625048	For clustering analysis of tumors, we selected 3,139 CpG sites that were methylated at a beta-value of >= 0.3 in more than 10% of tumors within any of the 33 cancer types.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('methylated', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
145798	29625048	The heatmap was generated using the original beta-values for the top one-third (n = 1,035) of the most variability methylated CpGs across tumors (Figure 1B).	('CpGs', 'Gene', (126, 130))	('methylated', 'Var', (115, 125))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
145799	29625048	We noted that a fraction of ESCA and STAD was found in METH9 with LUAD and PAAD, a result that may be related to the low tumor cellularity of the cancers in this cluster.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('METH', 'Chemical', '-', (55, 59))	('low tumor', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCA', 'Disease', (28, 32))	('METH9', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('low tumor', 'Disease', 'MESH:D009800', (117, 126))
145823	29625048	MIR5 contained OV, MIR8 BRCA, MIR12 LGG, MIR13 LIHC, MIR14 THCA, and MIR15 PRAD.	('MIR1', 'Gene', '79187', (69, 73))	('MIR1', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (24, 28))	('MIR12', 'Gene', (30, 35))	('BRCA', 'Gene', (24, 28))	('MIR8', 'Var', (19, 23))	('MIR1', 'Gene', '79187', (53, 57))	('MIR12', 'Gene', '406905', (30, 35))	('MIR1', 'Gene', (53, 57))	('MIR1', 'Gene', '79187', (41, 45))	('MIR1', 'Gene', '79187', (30, 34))	('MIR1', 'Gene', (41, 45))	('MIR1', 'Gene', (30, 34))
145831	29625048	MIR6, the Pan-GI group, was largely COAD and STAD, but also had substantial PAAD, READ and ESCA, with smaller numbers of CHOL and LIHC.	('MIR6', 'Var', (0, 4))	('COAD', 'Disease', (36, 40))	('COAD', 'Disease', 'MESH:D029424', (36, 40))
145874	28765641	Hypomethylation of CNTFRalpha is associated with proliferation and poor prognosis in lower grade gliomas Ciliary neurotrophic factor receptor alpha subunit (CNTFRalpha) and CNTF play important roles in neuron survival, glial differentiation and brain tumor growth.	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('CNTFRalpha', 'Gene', '1271', (157, 167))	('glial differentiation', 'CPA', (219, 240))	('CNTFRalpha', 'Gene', (157, 167))	('Ciliary neurotrophic factor', 'Gene', (105, 132))	('roles', 'Reg', (193, 198))	('Hypomethylation', 'Var', (0, 15))	('CNTF', 'Gene', '1270', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('Ciliary neurotrophic factor', 'Gene', '25707', (105, 132))	('CNTF', 'Gene', (157, 161))	('CNTF', 'Gene', '1270', (173, 177))	('brain tumor', 'Phenotype', 'HP:0030692', (245, 256))	('gliomas', 'Disease', (97, 104))	('CNTFRalpha', 'Gene', '1271', (19, 29))	('CNTF', 'Gene', (173, 177))	('CNTFRalpha', 'Gene', (19, 29))	('brain tumor', 'Disease', (245, 256))	('brain tumor', 'Disease', 'MESH:D001932', (245, 256))	('CNTF', 'Gene', '1270', (19, 23))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('associated', 'Reg', (33, 43))	('CNTF', 'Gene', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
145878	28765641	Additionally, we observed that independent of IDH mutation status, methylation of CNTFRalpha was significantly correlated with down-regulated CNTFRalpha gene expression and longer LGG patient survival.	('down-regulated', 'NegReg', (127, 141))	('expression', 'MPA', (158, 168))	('CNTFRalpha gene', 'Gene', (142, 157))	('methylation', 'Var', (67, 78))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (46, 49))	('LGG patient survival', 'CPA', (180, 200))	('CNTFRalpha', 'Gene', (82, 92))	('patient', 'Species', '9606', (184, 191))	('longer', 'PosReg', (173, 179))
145879	28765641	Interestingly, combination of CNTFRalpha methylation and IDH mutation significantly (p < 0.05) improved the prognostic prediction in LGG patients.	('IDH', 'Gene', '3417', (57, 60))	('combination', 'Interaction', (15, 26))	('mutation', 'Var', (61, 69))	('patients', 'Species', '9606', (137, 145))	('methylation', 'Var', (41, 52))	('improved', 'PosReg', (95, 103))	('prognostic', 'MPA', (108, 118))	('CNTFRalpha', 'Gene', (30, 40))	('IDH', 'Gene', (57, 60))	('LGG', 'Disease', (133, 136))
145881	28765641	Our study demonstrated that hypomethylation leading to CNTFRalpha up-regulation, together with autocrine expression of CNTF, was involved in glioma growth regulation.	('involved', 'Reg', (129, 137))	('CNTF', 'Gene', (55, 59))	('up-regulation', 'PosReg', (66, 79))	('hypomethylation', 'Var', (28, 43))	('CNTF', 'Gene', '1270', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('glioma growth', 'Disease', (141, 154))	('glioma growth', 'Disease', 'MESH:D005910', (141, 154))	('CNTF', 'Gene', '1270', (55, 59))	('CNTF', 'Gene', (119, 123))
145882	28765641	Importantly, DNA methylation of CNTFRalpha might serve as a potential epigenetic theranostic target for LGG patients.	('DNA', 'Var', (13, 16))	('LGG', 'Disease', (104, 107))	('patients', 'Species', '9606', (108, 116))	('CNTFRalpha', 'Gene', (32, 42))
145901	28765641	# ab117115), anti-Ki67 Ab (Abcam, Cambridge, MA, USA, Cat.	('Cat', 'Gene', (54, 57))	('anti-Ki67', 'Var', (13, 22))	('Cat', 'Gene', '847', (54, 57))
145904	28765641	# 2920 S and 4060 P), anti-cleaved Caspase 3 Ab (Cell Signaling, Beverly, MA, USA,Cat.	('anti-cleaved', 'Var', (22, 34))	('Cat', 'Gene', (82, 85))	('4060 P', 'Var', (13, 19))	('Cat', 'Gene', '847', (82, 85))	('Caspase 3', 'Protein', (35, 44))
145907	28765641	# A11017 and A11071), anti-GAPDH Ab and mouse and rabbit secondary Ab (Kangcheng, Shanghai, China.	('rabbit', 'Species', '9986', (50, 56))	('mouse', 'Species', '10090', (40, 45))	('anti-GAPDH', 'Var', (22, 32))	('A11071', 'Var', (13, 19))
145910	28765641	#C1063and C1052), LY294002 (Cell Signaling, Beverly, MA, USA, Cat.	('C1052', 'Var', (10, 15))	('LY294002', 'Var', (18, 26))	('Cat', 'Gene', (62, 65))	('Cat', 'Gene', '847', (62, 65))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))
145957	28765641	Patients with hypomethylated CNTFRalpha showed poorer survival than those with hypermethylated CNTFRalpha in LGG cohort (p < 0.05, Fig.	('hypomethylated', 'Var', (14, 28))	('survival', 'MPA', (54, 62))	('Patients', 'Species', '9606', (0, 8))	('CNTFRalpha', 'Gene', (29, 39))	('poorer', 'NegReg', (47, 53))
145958	28765641	IDH mutation is an independent prognostic marker, so we incorporated this into our analysis.	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('mutation', 'Var', (4, 12))
145960	28765641	However, when the two factors were combined, CNTFRalpha hypo (hypomethylation of CNTFRalpha) in IDH wt (IDH wild type) patients was significantly correlated with poorer survival compared with CNTFRalpha hyper (hypermethylation of CNTFRalpha) patients (p < 0.05, Fig.	('patients', 'Species', '9606', (242, 250))	('IDH', 'Gene', (104, 107))	('IDH', 'Gene', '3417', (96, 99))	('CNTFRalpha', 'Gene', (45, 55))	('survival', 'MPA', (169, 177))	('IDH', 'Gene', '3417', (104, 107))	('patients', 'Species', '9606', (119, 127))	('CNTFRalpha', 'Gene', (81, 91))	('poorer', 'NegReg', (162, 168))	('hypo', 'Var', (56, 60))	('IDH', 'Gene', (96, 99))
145963	28765641	In summary, hypomethylation of CNTFRalpha was correlated with poorer overall survival in LGG, and the combination of IDH mutation and CNTFRalpha methylation seems to better predict survival in LGG.	('overall survival', 'MPA', (69, 85))	('CNTFRalpha', 'Gene', (31, 41))	('IDH', 'Gene', (117, 120))	('predict', 'Reg', (173, 180))	('poorer', 'NegReg', (62, 68))	('IDH', 'Gene', '3417', (117, 120))	('hypomethylation', 'Var', (12, 27))	('LGG', 'Disease', (89, 92))
145965	28765641	Pathway analysis showed that CNTFRalpha knockdown decreased the protein level of phosphorylated AKT (p-AKT S473) in A172 and U87 (Fig.	('AKT', 'Gene', '207', (103, 106))	('AKT', 'Gene', (96, 99))	('AKT', 'Gene', '207', (96, 99))	('p-AKT S473', 'Gene', (101, 111))	('p-AKT S473', 'Gene', '207', (101, 111))	('knockdown', 'Var', (40, 49))	('AKT', 'Gene', (103, 106))	('decreased', 'NegReg', (50, 59))	('CNTFRalpha', 'Gene', (29, 39))	('protein level', 'MPA', (64, 77))	('phosphorylated', 'MPA', (81, 95))
145966	28765641	4C), showing that CNTFRalpha knockdown could inhibit the PI3K/AKT pathway.	('AKT', 'Gene', (62, 65))	('knockdown', 'Var', (29, 38))	('CNTFRalpha', 'Gene', (18, 28))	('AKT', 'Gene', '207', (62, 65))	('inhibit', 'NegReg', (45, 52))
145968	28765641	Both CNTFRalpha knockdown and LY294002 treatment decreased p-AKT protein levels to about the same extent, and combination treatment down-regulated the p-AKT level only slightly compared with single treatment.	('CNTFRalpha', 'Gene', (5, 15))	('AKT', 'Gene', '207', (153, 156))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('AKT', 'Gene', '207', (61, 64))	('knockdown', 'Var', (16, 25))	('decreased', 'NegReg', (49, 58))	('AKT', 'Gene', (153, 156))	('AKT', 'Gene', (61, 64))	('down-regulated', 'NegReg', (132, 146))	('LY294002', 'Var', (30, 38))
145971	28765641	Both LY294002 treatment and CNTFRalpha knockdown overcame the increased cell viability induced by CNTF (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (5, 13))	('increased', 'PosReg', (62, 71))	('CNTF', 'Gene', '1270', (98, 102))	('cell viability', 'CPA', (72, 86))	('CNTF', 'Gene', (28, 32))	('knockdown', 'Var', (39, 48))	('overcame', 'PosReg', (49, 57))	('LY294002 treatment', 'Var', (5, 23))	('CNTF', 'Gene', '1270', (28, 32))	('CNTF', 'Gene', (98, 102))
145973	28765641	Both LY294002 treatment and CNTFRalpha knockdown negated the effect of exogenous CNTF, leading to pathway inactivation (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (5, 13))	('negated', 'NegReg', (49, 56))	('inactivation', 'NegReg', (106, 118))	('pathway', 'MPA', (98, 105))	('CNTF', 'Gene', (28, 32))	('knockdown', 'Var', (39, 48))	('CNTF', 'Gene', '1270', (81, 85))	('LY294002 treatment', 'Var', (5, 23))	('CNTF', 'Gene', '1270', (28, 32))	('CNTF', 'Gene', (81, 85))
145975	28765641	The expression of BCL2 was gradually decreased with time after CNTFRalpha knockdown, while BAX expression increased, reflecting the process of apoptosis over a period of 48 h (Fig.	('BCL2', 'Gene', '596', (18, 22))	('CNTFRalpha', 'Gene', (63, 73))	('expression', 'MPA', (4, 14))	('knockdown', 'Var', (74, 83))	('BCL2', 'Gene', (18, 22))	('BAX', 'Gene', (91, 94))	('increased', 'PosReg', (106, 115))	('decreased', 'NegReg', (37, 46))	('BAX', 'Gene', '581', (91, 94))	('expression', 'MPA', (95, 105))
145976	28765641	Exogenous CNTF treatment did not induce significant apoptosis-resistance, and did not prevent the increase in apoptosis caused by LY294002 or CNTFRalpha knockdown even though supplemented with CNTF (Fig.	('knockdown', 'Var', (153, 162))	('CNTF', 'Gene', (10, 14))	('CNTF', 'Gene', (142, 146))	('LY294002', 'Chemical', 'MESH:C085911', (130, 138))	('CNTF', 'Gene', '1270', (10, 14))	('CNTF', 'Gene', (193, 197))	('CNTF', 'Gene', '1270', (142, 146))	('CNTF', 'Gene', '1270', (193, 197))	('LY294002', 'Var', (130, 138))
145978	28765641	These results were consistent with the hypothesis that CNTFRalpha knockdown significantly inhibited glioma cell proliferation and induced apoptosis by suppressing the PI3K/AKT pathway in vitro.	('glioma', 'Disease', (100, 106))	('AKT', 'Gene', (172, 175))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('CNTFRalpha', 'Gene', (55, 65))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('suppressing', 'NegReg', (151, 162))	('AKT', 'Gene', '207', (172, 175))	('apoptosis', 'CPA', (138, 147))	('inhibited', 'NegReg', (90, 99))	('knockdown', 'Var', (66, 75))
145987	28765641	Here, we have demonstrated CNTFRalpha knockdown led to a significant inhibition of glioma growth in vivo by inhibiting proliferation and promoting apoptosis.	('CNTFRalpha', 'Gene', (27, 37))	('glioma growth', 'Disease', 'MESH:D005910', (83, 96))	('glioma growth', 'Disease', (83, 96))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('inhibiting', 'NegReg', (108, 118))	('apoptosis', 'CPA', (147, 156))	('promoting', 'PosReg', (137, 146))	('knockdown', 'Var', (38, 47))	('inhibition', 'NegReg', (69, 79))	('proliferation', 'CPA', (119, 132))
145990	28765641	In this study, it was demonstrated that methylation of CpG island shore of the CNTFRalpha gene could be a potential prognostic marker in LGG patients, Furthermore, CNTFRalpha, together with autocrine CNTF ligand, plays a tumor oncogene role by regulating the PI3K/AKT pathway.	('methylation', 'Var', (40, 51))	('CNTF', 'Gene', (164, 168))	('AKT', 'Gene', (264, 267))	('CNTF', 'Gene', (79, 83))	('patients', 'Species', '9606', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('CNTF', 'Gene', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('CNTF', 'Gene', '1270', (164, 168))	('CNTF', 'Gene', '1270', (79, 83))	('regulating', 'Reg', (244, 254))	('AKT', 'Gene', '207', (264, 267))	('CNTF', 'Gene', '1270', (200, 204))	('LGG', 'Disease', (137, 140))
145994	28765641	In glioma, methylation is an important epigenetic regulation factor in tumor initiation, progression and prognosis.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('methylation', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('glioma', 'Disease', (3, 9))	('tumor', 'Disease', (71, 76))
145995	28765641	Patients with hypermethylation of CNTFRalpha had better survival than the hypomethylation group in LGG with both IDH wild type and mutation status.	('IDH', 'Gene', '3417', (113, 116))	('CNTFRalpha', 'Gene', (34, 44))	('hypermethylation', 'Var', (14, 30))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (49, 55))	('survival', 'CPA', (56, 64))	('IDH', 'Gene', (113, 116))
145997	28765641	IDH mutation and hypermethylation of CNTFRalpha were both good prognostic factors.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('CNTFRalpha', 'Gene', (37, 47))	('hypermethylation', 'Var', (17, 33))
145998	28765641	The combination of IDH mutation and CNTFRalpha gene methylation provided a better prediction of survival.	('CNTFRalpha gene', 'Gene', (36, 51))	('mutation', 'Var', (23, 31))	('IDH', 'Gene', (19, 22))	('methylation', 'Var', (52, 63))	('IDH', 'Gene', '3417', (19, 22))
145999	28765641	Overall, this indicated methylation of the CNTFRalpha was a potential valuable prognostic marker in LGG patients.	('LGG', 'Disease', (100, 103))	('patients', 'Species', '9606', (104, 112))	('CNTFRalpha', 'Gene', (43, 53))	('methylation', 'Var', (24, 35))
146007	28765641	In our study, methylation of CNTFRalpha and autocrine CNTF from glioma cells activated the PI3K/AKT pathway, which could promote LGG progression.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('CNTF', 'Gene', '1270', (54, 58))	('CNTF', 'Gene', '1270', (29, 33))	('AKT', 'Gene', (96, 99))	('LGG progression', 'CPA', (129, 144))	('activated', 'PosReg', (77, 86))	('CNTF', 'Gene', (29, 33))	('methylation', 'Var', (14, 25))	('glioma', 'Disease', (64, 70))	('AKT', 'Gene', '207', (96, 99))	('CNTF', 'Gene', (54, 58))	('promote', 'PosReg', (121, 128))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
146016	28754121	Aberrant expression of such proteins has been shown to be associated with the malignant behavior of human cancers.	('proteins', 'Protein', (28, 36))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (58, 68))	('human', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('expression', 'MPA', (9, 19))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
146020	28754121	Then, a serious of cell functional assays were performed in human glioma cell lines, U87MG and U251, which indicated that silencing of CCDC109B attenuated glioma proliferation and migration/invasion both in vitro and in vivo.	('glioma', 'Disease', (66, 72))	('CCDC109B', 'Gene', (135, 143))	('migration/invasion', 'CPA', (180, 198))	('attenuated glioma', 'Disease', 'MESH:C538265', (144, 161))	('attenuated glioma', 'Disease', (144, 161))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('U87MG', 'CellLine', 'CVCL:0022', (85, 90))	('silencing', 'Var', (122, 131))	('human', 'Species', '9606', (60, 65))	('glioma', 'Disease', (155, 161))
146024	28754121	Our study elucidated a role for CCDC109B as an oncogene and a prognostic marker in human gliomas.	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('human', 'Species', '9606', (83, 88))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('CCDC109B', 'Var', (32, 40))
146025	28754121	CCDC109B may provide a novel therapeutic target for the treatment of human glioma.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('human', 'Species', '9606', (69, 74))	('CCDC109B', 'Var', (0, 8))	('glioma', 'Disease', (75, 81))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
146035	28754121	Increasing evidence suggests that aberrant expression of coiled-coil domain containing proteins influences the migration, invasion and proliferation of various human cancers, including bladder cancer, pancreatic cancer, gastric cancer, papillary thyroid carcinoma, leukemia, prostate cancer, breast cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('migration', 'CPA', (111, 120))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('aberrant', 'Var', (34, 42))	('coiled-coil domain containing proteins', 'Protein', (57, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('influences', 'Reg', (96, 106))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (246, 263))	('proliferation', 'CPA', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('invasion', 'CPA', (122, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (201, 218))	('breast cancer', 'Disease', (292, 305))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (236, 263))	('gastric cancer', 'Disease', (220, 234))	('human', 'Species', '9606', (160, 165))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Disease', (166, 173))	('papillary thyroid carcinoma', 'Disease', (236, 263))	('pancreatic cancer', 'Disease', (201, 218))	('leukemia', 'Phenotype', 'HP:0001909', (265, 273))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (236, 263))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('gastric cancer', 'Disease', 'MESH:D013274', (220, 234))	('prostate cancer', 'Disease', 'MESH:D011471', (275, 290))	('proteins', 'Protein', (87, 95))	('leukemia', 'Disease', 'MESH:D007938', (265, 273))	('prostate cancer', 'Phenotype', 'HP:0012125', (275, 290))	('leukemia', 'Disease', (265, 273))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('prostate cancer', 'Disease', (275, 290))
146036	28754121	CCDC109B, also known as mitochondrial calcium uniporter b (MCUb), is an MCU isogene.	('MCUb', 'Gene', (59, 63))	('MCU', 'Gene', (59, 62))	('CCDC109B', 'Var', (0, 8))	('mitochondrial calcium uniporter b', 'Gene', (24, 57))	('MCU', 'Gene', '90550', (59, 62))	('MCU', 'Gene', (72, 75))	('MCU', 'Gene', '90550', (72, 75))	('MCUb', 'Gene', '55013', (59, 63))	('mitochondrial calcium uniporter b', 'Gene', '55013', (24, 57))
146042	28754121	These results, support CCDC109B as a new therapeutic target for the treatment of human glioma.	('CCDC109B', 'Var', (23, 31))	('glioma', 'Disease', (87, 93))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('human', 'Species', '9606', (81, 86))
146052	28754121	Sequences of synthesized siRNAs (Genepharma) were the following: si-NC 5'-TTCTCCGAAGGTGTCACGG-3'; si-HIF1alpha-1 5'TACGTTGTGAGTGGTATTATT-3'; si-HIF1alpha-2 5'-CTGATGACCAGCAACTTGA-3'.	('HIF1alpha', 'Gene', (144, 153))	('si-NC', 'Var', (65, 70))	('HIF1alpha', 'Gene', '3091', (144, 153))	('HIF1alpha', 'Gene', (101, 110))	('HIF1alpha', 'Gene', '3091', (101, 110))
146059	28754121	The following primary antibodies (Abcam, Cambridge, UK) were used at the dilutions indicated: CCDC109B (1:200), HIF1alpha (1:200), Ki-67 (1:500), MMP2 (1:100) and MMP9 (1:200).	('1:100', 'Var', (152, 157))	('HIF1alpha', 'Gene', (112, 121))	('HIF1alpha', 'Gene', '3091', (112, 121))	('1:500', 'Var', (138, 143))	('MMP2', 'Gene', (146, 150))	('MMP9', 'Gene', '4318', (163, 167))	('MMP9', 'Gene', (163, 167))	('1:200', 'Var', (123, 128))	('1:200', 'Var', (104, 109))	('MMP2', 'Gene', '4313', (146, 150))
146061	28754121	Membranes were blocked with Tris Buffered Saline with Tween 20 (TBST, 10 mM Tris, 150 mM NaCl, 0.1% Tween 20) containing 5% bovine serum albumin (BSA, Thermo Fisher Scientific),and incubated overnight at 4  C with the following primary antibodies against CCDC109B (1:500), HIF1alpha (1:1000), MMP2 (1:1000), MMP9 (1:1000) and beta-Tubulin (1:1000; Cell Signaling Technology; Danvers, MA, USA).	('HIF1alpha', 'Gene', (273, 282))	('HIF1alpha', 'Gene', '3091', (273, 282))	('1:1000', 'Var', (340, 346))	('1:1000', 'Var', (299, 305))	('1:1000', 'Var', (314, 320))	('MMP9', 'Gene', '4318', (308, 312))	('MMP2', 'Gene', (293, 297))	('MMP2', 'Gene', '4313', (293, 297))	('bovine', 'Species', '9913', (124, 130))	('CCDC109B', 'Gene', (255, 263))	('MMP9', 'Gene', (308, 312))	('beta-Tubulin', 'Protein', (326, 338))
146067	28754121	To assess the distribution and expression levels of CCDC109B, NHA and glioma cells were seeded onto glass slides.	('CCDC109B', 'Var', (52, 60))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))
146084	28754121	For orthotopic xenografts, 4-week-old female nude mice (n = 16) were divided into two groups (sh-CCDC109B-1 and NC group), and U87MG or U87MG modified cells (1 x 106) were implanted into the brain using a stereotactic apparatus (KDS310, KD Scientific; Holliston, MA, USA).	('U87MG', 'CellLine', 'CVCL:0022', (136, 141))	('U87MG', 'Var', (136, 141))	('U87MG', 'CellLine', 'CVCL:0022', (127, 132))	('nude mice', 'Species', '10090', (45, 54))	('U87MG', 'Var', (127, 132))
146092	28754121	To further confirm the level of CCDC109B in normal brain tissue samples and different grades glioma tissues, we searched publicly available databases, Rembrandt, TCGA, Chinese Glioma Genome Atlas (CGGA) and found a relatively higher mRNA level of CCDC109B in HGG in contrast to low grade gliomas (LGG; WHOI-II) and normal brain tissues (P < 0.001, Fig.	('glioma', 'Disease', 'MESH:D005910', (288, 294))	('glioma', 'Disease', (93, 99))	('Glioma Genome Atlas', 'Disease', (176, 195))	('mRNA level', 'MPA', (233, 243))	('CCDC109B', 'Var', (247, 255))	('gliomas', 'Disease', (288, 295))	('HGG', 'Disease', (259, 262))	('glioma', 'Disease', (288, 294))	('higher', 'PosReg', (226, 232))	('gliomas', 'Disease', 'MESH:D005910', (288, 295))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('Glioma', 'Phenotype', 'HP:0009733', (176, 182))	('gliomas', 'Phenotype', 'HP:0009733', (288, 295))	('glioma', 'Phenotype', 'HP:0009733', (288, 294))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('Glioma Genome Atlas', 'Disease', 'MESH:D005910', (176, 195))
146093	28754121	Expression levels of CCDC109B were also stratified on the basis of the molecular subtypes of human glioma (mesenchymal, classical, neural, and proneural) in TCGA, CGGA and Gene Expression Omnibus (GSE4271) databases.	('CCDC109B', 'Var', (21, 29))	('human', 'Species', '9606', (93, 98))	('GSE4271', 'Chemical', '-', (197, 204))	('glioma', 'Disease', (99, 105))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
146094	28754121	Intriguingly, CCDC109B was increased in the mesenchymal glioma molecular subtype compared to other subtypes (P < 0.001, Fig.	('increased', 'PosReg', (27, 36))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('CCDC109B', 'Var', (14, 22))	('mesenchymal glioma molecular subtype', 'Disease', (44, 80))	('mesenchymal glioma molecular subtype', 'Disease', 'MESH:D005910', (44, 80))
146097	28754121	The difference in expression levels between these groups was statistically significant (P < 0.001, Table 1), with high CCDC109B expression correlating with increased tumor grade (P < 0.001, Fig.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('high', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('CCDC109B', 'Gene', (119, 127))	('increased', 'PosReg', (156, 165))	('tumor', 'Disease', (166, 171))
146098	28754121	The difference in expression levels of CCDC109B between HGG and LGG drove us to further investigate whether CCDC109B could serve as a prognostic marker in glioma patients.	('patients', 'Species', '9606', (162, 170))	('expression levels', 'MPA', (18, 35))	('CCDC109B', 'Gene', (39, 47))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('CCDC109B', 'Var', (108, 116))	('glioma', 'Disease', (155, 161))
146101	28754121	Furthermore, levels of CCDC109B also exhibited a significant inverse relationship with median survival time of GBM patients in TCGA (P < 0.01, Fig.	('patients', 'Species', '9606', (115, 123))	('CCDC109B', 'Var', (23, 31))	('inverse', 'NegReg', (61, 68))
146104	28754121	The results demonstrated that age (HR = 1.075, P < 0.001), WHO grade (HR = 9.560, P < 0.001), CCDC109B expression (HR = 1.861, P < 0.001), and mutation status of isocitrate dehydrogenase 1 (IDH1, HR = 0.244, P < 0.001), were all prognostic indicators for glioma patients (Table 2).	('CCDC109B', 'Gene', (94, 102))	('IDH1', 'Gene', (190, 194))	('patients', 'Species', '9606', (262, 270))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('IDH1', 'Gene', '3417', (190, 194))	('mutation', 'Var', (143, 151))	('isocitrate dehydrogenase 1', 'Gene', (162, 188))	('isocitrate dehydrogenase 1', 'Gene', '3417', (162, 188))	('glioma', 'Disease', (255, 261))
146106	28754121	Compared to NC constructs, the mRNA levels of CCDC109B in U87MG and U251 cells were significantly down-regulated after infection with three different shRNAs targeting CCDC109B (sh-CCDC109B-1; sh-CCDC109B-2; sh-CCDC109B-3; P < 0.001, Fig.	('mRNA levels', 'MPA', (31, 42))	('U87MG', 'CellLine', 'CVCL:0022', (58, 63))	('down-regulated', 'NegReg', (98, 112))	('CCDC109B', 'Var', (167, 175))
146109	28754121	3g), CCDC109B knockdown attenuated the number of U87MG and U251 cells that had migrated/invaded after a 24-h incubation (all P < 0.05, Fig.	('attenuated', 'NegReg', (24, 34))	('U87MG', 'CellLine', 'CVCL:0022', (49, 54))	('CCDC109B', 'Gene', (5, 13))	('knockdown', 'Var', (14, 23))
146110	28754121	Western blot analysis revealed that MMP2 and MMP9, two metalloproteinases which play critical roles in tumor invasion and migration, were also reduced after CCDC109B knockdown (Fig.	('knockdown', 'Var', (166, 175))	('MMP9', 'Gene', '4318', (45, 49))	('MMP9', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('MMP2', 'Gene', '4313', (36, 40))	('MMP2', 'Gene', (36, 40))	('CCDC109B', 'Gene', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('reduced', 'NegReg', (143, 150))
146112	28754121	We next established orthotopic tumor models by implanting U87MG-NC cells or U87MG-sh-CCDC109B-1 cells intracranially in nude mice to investigate whether CCDC109B mediated proliferation and invasion of glioma cells in vivo.	('CCDC109B', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('glioma', 'Disease', (201, 207))	('tumor', 'Disease', (31, 36))	('nude mice', 'Species', '10090', (120, 129))	('U87MG-NC', 'CellLine', 'CVCL:0022', (58, 66))	('U87MG', 'CellLine', 'CVCL:0022', (58, 63))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('invasion', 'CPA', (189, 197))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('proliferation', 'CPA', (171, 184))	('U87MG', 'CellLine', 'CVCL:0022', (76, 81))
146114	28754121	IHC staining for CCDC109B, and markers for proliferation (Ki-67), and invasion (MMP2 and MMP9) performed on sections from xenografts further established a potential role for CCDC109B in regulating these pathways (Fig.	('MMP9', 'Gene', '4318', (89, 93))	('MMP9', 'Gene', (89, 93))	('CCDC109B', 'Var', (174, 182))	('MMP2', 'Gene', (80, 84))	('MMP2', 'Gene', '4313', (80, 84))
146115	28754121	Lower levels of all three markers, Ki-67, MMP2, and MMP9, were observed in xenografts of U87MG-sh-CCDC109B-1 compared to controls (all P < 0.01, Fig.	('levels', 'MPA', (6, 12))	('MMP9', 'Gene', (52, 56))	('U87MG-sh-CCDC109B-1', 'Var', (89, 108))	('MMP2', 'Gene', (42, 46))	('MMP9', 'Gene', '4318', (52, 56))	('U87MG', 'CellLine', 'CVCL:0022', (89, 94))	('Lower', 'NegReg', (0, 5))	('MMP2', 'Gene', '4313', (42, 46))
146121	28754121	We cultured U87MG and U251 cells under hypoxia (1% O2) for 6, 12, 24 and 48 h. mRNAs levels of CCDC109B were increased by ~twofold under hypoxia (P < 0.001, Fig.	('CCDC109B', 'Var', (95, 103))	('hypoxia', 'Disease', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('U87MG', 'CellLine', 'CVCL:0022', (12, 17))	('hypoxia', 'Disease', (137, 144))	('mRNAs levels', 'MPA', (79, 91))	('O2', 'Chemical', '-', (51, 53))	('increased', 'PosReg', (109, 118))
146135	28754121	In contrast, glioma cell migration and invasion was significantly attenuated in U87MG- and U251-sh-CCDC109B-1 cells (all P < 0.01, Fig.	('U87MG', 'CellLine', 'CVCL:0022', (80, 85))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('attenuated', 'NegReg', (66, 76))	('U251-sh-CCDC109B-1', 'Var', (91, 109))	('glioma cell migration', 'Disease', (13, 34))	('U87MG-', 'Var', (80, 86))	('glioma cell migration', 'Disease', 'MESH:D005910', (13, 34))
146136	28754121	These results indicated that CCDC109B promoted hypoxia-induced invasion and migration in human glioma cell lines U87MG and U251 in vitro.	('human', 'Species', '9606', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('migration', 'CPA', (76, 85))	('hypoxia', 'Disease', (47, 54))	('glioma', 'Disease', (95, 101))	('U87MG', 'CellLine', 'CVCL:0022', (113, 118))	('promoted', 'PosReg', (38, 46))	('CCDC109B', 'Var', (29, 37))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
146139	28754121	Silencing of CCDC109B inhibited glioma proliferation, migration and invasion of glioma cells in vitro and led to decreased tumor volume and prolonged OS in vivo.	('glioma', 'Disease', (80, 86))	('invasion of', 'CPA', (68, 79))	('inhibited', 'NegReg', (22, 31))	('tumor', 'Disease', (123, 128))	('prolonged', 'PosReg', (140, 149))	('glioma', 'Disease', (32, 38))	('migration', 'CPA', (54, 63))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('CCDC109B', 'Gene', (13, 21))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('Silencing', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('decreased', 'NegReg', (113, 122))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
146140	28754121	Unexpectedly, we found CCDC109B expression to be drastically upregulated under hypoxia and that subsequent knockdown inhibited hypoxia-induced migration and invasion of glioma cells.	('knockdown', 'Var', (107, 116))	('upregulated', 'PosReg', (61, 72))	('glioma', 'Disease', (169, 175))	('hypoxia', 'Disease', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('CCDC109B', 'Gene', (23, 31))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('hypoxia', 'Disease', (79, 86))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('inhibited', 'NegReg', (117, 126))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('expression', 'MPA', (32, 42))
146142	28754121	Our study for the first time identifies CCDC109B as a potential tumor promotor in glioma progression and provides rational for targeting CCDC109B as novel treatment or prognostic marker in human glioma.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('CCDC109B', 'Var', (137, 145))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumor', 'Disease', (64, 69))	('human', 'Species', '9606', (189, 194))	('CCDC109B', 'Gene', (40, 48))	('glioma', 'Disease', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('glioma', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
146143	28754121	CCDC109B was first identified as a paralogue of MCU, with two predicted transmembrane domains.	('MCU', 'Gene', '90550', (48, 51))	('MCU', 'Gene', (48, 51))	('CCDC109B', 'Var', (0, 8))
146144	28754121	In Hela cells, CCDC109B acts as a dominant negative mediator of MCU, attenuating mitochondria calcium increases evoked by agonist stimulation.	('attenuating', 'NegReg', (69, 80))	('MCU', 'Gene', '90550', (64, 67))	('Hela cells', 'CellLine', 'CVCL:0030', (3, 13))	('calcium', 'Chemical', 'MESH:D002118', (94, 101))	('agonist stimulation', 'MPA', (122, 141))	('mitochondria calcium increases', 'MPA', (81, 111))	('CCDC109B', 'Var', (15, 23))	('MCU', 'Gene', (64, 67))
146149	28754121	Finally, CCDC109B overexpression has also been reported in leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('leukemia', 'Disease', 'MESH:D007938', (59, 67))	('leukemia', 'Disease', (59, 67))	('CCDC109B', 'Var', (9, 17))	('overexpression', 'PosReg', (18, 32))
146150	28754121	All together, these results indicate that CCDC109B might function as an oncogene in human gliomas and possibly other cancers as well.	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CCDC109B', 'Var', (42, 50))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
146151	28754121	Importantly, we took our molecular analysis a step further and examined the functional consequences of inactivating CCDC109B with shRNAs in human glioma cell lines.	('inactivating', 'Var', (103, 115))	('human', 'Species', '9606', (140, 145))	('glioma', 'Disease', (146, 152))	('CCDC109B', 'Gene', (116, 124))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))
146152	28754121	Our data demonstrated that knockdown of CCDC109B significantly attenuated proliferation, migration and invasion of glioma cells in vitro and led to decreased tumor volume and prolonged OS of tumor-bearing mouse in orthotopic models.	('knockdown', 'Var', (27, 36))	('tumor', 'Disease', (158, 163))	('glioma', 'Disease', (115, 121))	('prolonged', 'PosReg', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('attenuated', 'NegReg', (63, 73))	('CCDC109B', 'Gene', (40, 48))	('decreased', 'NegReg', (148, 157))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mouse', 'Species', '10090', (205, 210))	('proliferation', 'CPA', (74, 87))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
146153	28754121	Moreover, we demonstrated that decreased expression of MMP2 and MMP9, proteins linked to invasion/migration accompanied CCDC109B knockdown.	('MMP2', 'Gene', (55, 59))	('expression', 'MPA', (41, 51))	('knockdown', 'Var', (129, 138))	('decreased', 'NegReg', (31, 40))	('CCDC109B', 'Gene', (120, 128))	('MMP9', 'Gene', (64, 68))	('MMP2', 'Gene', '4313', (55, 59))	('MMP9', 'Gene', '4318', (64, 68))
146155	28754121	As one member of the family of coiled-coil motif proteins, CCDC109B plays an important role in facilitating Ca2+ flux across the inner mitochondrial membrane (IMM).	('Ca2+ flux across the inner mitochondrial membrane', 'MPA', (108, 157))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('CCDC109B', 'Var', (59, 67))
146156	28754121	Aberrant expression of CCDC109B has been shown to lead to mitochondrial Ca2+ remodeling and the subsequent activation of signaling cascades associated with cancer formation and maintenance.	('Aberrant expression', 'Var', (0, 19))	('lead to', 'Reg', (50, 57))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('signaling cascades', 'MPA', (121, 139))	('CCDC109B', 'Gene', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Ca2+', 'Chemical', 'MESH:D000069285', (72, 76))	('mitochondrial Ca2+ remodeling', 'MPA', (58, 87))	('activation', 'PosReg', (107, 117))
146158	28754121	Collectively, we and others have demonstrated that CCDC109B contributes to glioma and possibly more generally to cancer development by promoting cellular processes such as proliferation and invasion/migration.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('contributes', 'Reg', (60, 71))	('proliferation', 'CPA', (172, 185))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glioma', 'Disease', (75, 81))	('promoting', 'PosReg', (135, 144))	('cancer', 'Disease', (113, 119))	('CCDC109B', 'Var', (51, 59))	('invasion/migration', 'CPA', (190, 208))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
146162	28754121	Inhibition of HIF1alpha blocked hypoxia-induced CCDC109B both in vitro and in vivo, indicating that HIF1alpha could regulate CCDC109B expression.	('expression', 'MPA', (134, 144))	('regulate', 'Reg', (116, 124))	('HIF1alpha', 'Gene', (14, 23))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('HIF1alpha', 'Gene', '3091', (14, 23))	('HIF1alpha', 'Gene', (100, 109))	('Inhibition', 'Var', (0, 10))	('CCDC109B', 'Gene', (48, 56))	('blocked', 'NegReg', (24, 31))	('hypoxia', 'Disease', (32, 39))	('HIF1alpha', 'Gene', '3091', (100, 109))
146163	28754121	Silencing of CCDC109B decreased hypoxia-induced migration and invasion.	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('CCDC109B', 'Gene', (13, 21))	('invasion', 'CPA', (62, 70))	('Silencing', 'Var', (0, 9))	('hypoxia', 'Disease', (32, 39))	('decreased', 'NegReg', (22, 31))
146164	28754121	However, the underlying mechanisms in CCDC109B-mediated glioma invasion/migration under hypoxic conditions remains not fully clear.	('glioma invasion', 'Disease', (56, 71))	('glioma invasion', 'Disease', 'MESH:D005910', (56, 71))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('CCDC109B-mediated', 'Var', (38, 55))	('hypoxic conditions', 'Disease', (88, 106))	('hypoxic conditions', 'Disease', 'MESH:D009135', (88, 106))
146166	28754121	In summary, we discovered a potential role for CCDC109B as an oncogene and prognostic marker in human glioma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('CCDC109B', 'Var', (47, 55))	('human', 'Species', '9606', (96, 101))	('glioma', 'Disease', (102, 108))
146170	28659721	These sequence alterations exhibit a sufficient frequency in all tumor types investi-gated thus far to justify their use as a tumor marker.	('tumor', 'Disease', (65, 70))	('alterations', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (126, 131))
146173	28659721	Due to the wide distribution of the observed base substitutions, deletions or insertions within the mitochondrial genome, high efforts for whole mtDNA sequencing (16.5 kb) from bodily fluids would be required, if the method would be in-tended for initial tumor screening.	('insertions', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('deletions', 'Var', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('base substitutions', 'Var', (45, 63))
146176	28659721	It would be most important to inves-tigate precisely in the most relevant tumor types, if sequencing approaches in combination with simple PCR-assays for deletions/insertions in homopolymeric tracts has sufficient sensitivity to find most tu-mor-derived mtDNAs in bodily fluids.	('tumor', 'Disease', (74, 79))	('deletions/insertions', 'Var', (154, 174))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
146178	28659721	At the end of 1980s, the first reports on neuromuscular disorders due to large scale deletions of mtDNA and of a retinal disease due to a missense mutation were published.	('neuromuscular disorders', 'Disease', 'MESH:D009468', (42, 65))	('deletions', 'Var', (85, 94))	('missense mutation', 'Var', (138, 155))	('retinal disease', 'Phenotype', 'HP:0000479', (113, 128))	('mtDNA', 'Gene', (98, 103))	('retinal disease', 'Disease', 'MESH:D012164', (113, 128))	('neuromuscular disorders', 'Disease', (42, 65))	('retinal disease', 'Disease', (113, 128))
146179	28659721	They were immediately followed by two reports describing neuromuscular disorders elicited by single nucleotide exchanges in two tRNA genes within the mitochondrial genome.	('single nucleotide exchanges', 'Var', (93, 120))	('neuromuscular disorders', 'Disease', (57, 80))	('neuromuscular disorders', 'Disease', 'MESH:D009468', (57, 80))	('tRNA genes', 'Gene', (128, 138))	('elicited by', 'Reg', (81, 92))
146182	28659721	The mtDNA mutations in these classical mitochondrial disorders occur either newly in the diseased individual, such as large scale deletions, or are maternally inherited along with the general maternal inheritance of mtDNA.	('mitochondrial disorders', 'Disease', (39, 62))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (39, 62))	('mtDNA', 'Gene', (4, 9))	('mutations', 'Var', (10, 19))
146183	28659721	Since the mutations either affect a subunit of the mitochondrial electron transport chain (ETC), a subunit of the FoF1-ATPase or their protein biosynthesis on mitochondrial ribosomes, they obviously affect oxidative ATP-production (OXPHOS) and may cause oxidative stress in addition.	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('cause', 'Reg', (248, 253))	('ATP', 'Chemical', 'MESH:D000255', (216, 219))	('oxidative stress', 'Phenotype', 'HP:0025464', (254, 270))	('oxidative ATP-production', 'MPA', (206, 230))	('mutations', 'Var', (10, 19))	('oxidative stress', 'MPA', (254, 270))	('affect', 'Reg', (199, 205))	('affect', 'Reg', (27, 33))
146185	28659721	Since oxidative energy metabolism is essential for the nervous system and large scale deletions of mtDNA were early shown to accumulate in most parts of the brain during aging, the field of mitochondrial medicine became extended also to more prevalent neurodegenerative disorders, which often exhibit mitochondrial defects.	('accumulate', 'PosReg', (125, 135))	('deletions', 'Var', (86, 95))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (252, 279))	('mtDNA', 'Gene', (99, 104))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (252, 279))	('neurodegenerative disorders', 'Disease', (252, 279))
146186	28659721	The true impact of mitochondrial dysfunction and especially of mtDNA mutations in neurodegenerative disorders still remains unclear (for review see).	('mutations', 'Var', (69, 78))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (19, 44))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (82, 109))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (19, 44))	('mitochondrial dysfunction', 'Disease', (19, 44))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (82, 109))	('neurodegenerative disorders', 'Disease', (82, 109))	('mtDNA', 'Gene', (63, 68))
146198	28659721	In times of increasing sensitivity of analytical techniques, it cannot be excluded that potential hot-spot mutations, occurring in a small subset of crypts, become detectable in the stool, without any colorectal malignancy.	('colorectal malignancy', 'Disease', (201, 222))	('mutations', 'Var', (107, 116))	('colorectal malignancy', 'Disease', 'MESH:D009369', (201, 222))
146204	28659721	The forensics department of our university developed some PCR-based techniques to easily identify heteroplasmy in HVR-2 and other non-coding regions of mtDNA, such as heteroduplex analysis.	('HVR-2', 'Gene', (114, 119))	('heteroplasmy', 'Var', (98, 110))	('men', 'Species', '9606', (20, 23))
146205	28659721	Based on this technique, on fluorescent PCR of HVR-2 with subsequent capillary electrophoresis and by cloning and sequencing with proofreading polymerase, we detected low-level length-heteroplasmy of HVR-2 and sometimes synonymous base exchanges in HVR-1 and HVR-2 of various normal tissue samples.	('HVR-2', 'Gene', (200, 205))	('synonymous base exchanges', 'MPA', (220, 245))	('length-heteroplasmy', 'Var', (177, 196))	('HVR-1', 'Gene', (249, 254))	('HVR-1', 'Gene', '7433', (249, 254))
146206	28659721	Moreover, small percentages (<1%) of a 5 kb mtDNA deletion-actually designated as 'common deletion'-had been shown by several authors, including ourselves, to accumulate in most brain regions of aged individuals, confirming the original observation made by the group of Douglas Wallace, thus again rejecting the point of view that mtDNA is commonly homoplasmic outside mitochondrial disorders.	('deletion-actually', 'Var', (50, 67))	('accumulate', 'PosReg', (159, 169))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (369, 392))	('mtDNA', 'Gene', (44, 49))	('mitochondrial disorders', 'Disease', (369, 392))
146218	28659721	This may be especially astonishing, since D310 was later found to be a major hot-spot of 'mtDNA mutations' in tumors.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('D310', 'Var', (42, 46))
146220	28659721	MtDNA mutations have been meanwhile detected in a large percentage of colorectal cancers, lung cancers, head and neck cancers, urinary bladder carcinomas renal cell carcinomas, pancreatic cancers, ovarian carcionomas, breast cancers, gastric cancers, gliomas and several other solid tumors.	('solid tumors', 'Disease', (277, 289))	('pancreatic cancers', 'Disease', 'MESH:D010190', (177, 195))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('detected', 'Reg', (36, 44))	('gastric cancers', 'Disease', (234, 249))	('gastric cancers', 'Disease', 'MESH:D013274', (234, 249))	('gastric cancers', 'Phenotype', 'HP:0012126', (234, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (154, 174))	('ovarian carcionomas', 'Disease', 'MESH:D010051', (197, 216))	('colorectal cancers', 'Disease', (70, 88))	('gliomas', 'Disease', 'MESH:D005910', (251, 258))	('breast cancers', 'Disease', 'MESH:D001943', (218, 232))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('breast cancers', 'Disease', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lung cancers', 'Disease', 'MESH:D008175', (90, 102))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (135, 152))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('ovarian carcionomas', 'Disease', (197, 216))	('lung cancers', 'Disease', (90, 102))	('MtDNA', 'Gene', (0, 5))	('solid tumors', 'Disease', 'MESH:D009369', (277, 289))	('urinary bladder carcinomas renal cell carcinomas', 'Disease', (127, 175))	('breast cancers', 'Phenotype', 'HP:0003002', (218, 232))	('neck cancers', 'Disease', (113, 125))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('head and neck cancers', 'Phenotype', 'HP:0012288', (104, 125))	('mutations', 'Var', (6, 15))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('ovarian carcionomas', 'Phenotype', 'HP:0025318', (197, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('neck cancers', 'Disease', 'MESH:D006258', (113, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('lung cancers', 'Phenotype', 'HP:0100526', (90, 102))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colorectal cancers', 'Disease', 'MESH:D015179', (70, 88))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (154, 175))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (177, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('pancreatic cancers', 'Disease', (177, 195))	('urinary bladder carcinomas renal cell carcinomas', 'Disease', 'MESH:D001749', (127, 175))	('gliomas', 'Disease', (251, 258))	('head and neck cancer', 'Disease', 'MESH:D006258', (104, 124))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
146223	28659721	From these results, it could be reasonably deduced that in some entities two thirds or even all of the patients harbor an mtDNA mutation in their tumor, which is detectable at the sensitivity level of sequencing.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('harbor', 'Reg', (112, 118))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('mutation', 'Var', (128, 136))	('patients', 'Species', '9606', (103, 111))	('mtDNA', 'Gene', (122, 127))
146224	28659721	Maybe the frequency is even somewhat higher, if one considers that MitoChip technology is more sensitive to the detection of single base substitutions, but less sensitive to detection of length variation in the marker D310, found to be a hot spot in several tumor entities.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', (258, 263))	('single base substitutions', 'Var', (125, 150))	('D310', 'Var', (218, 222))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
146225	28659721	A supplementation of whole mt-genome sequencing by a specific PCR-approach for D310 may have yielded even higher percentages of tumors, which exhibit at least one mutation in the mitochondrial genome, as compared to the paired normal tissue of the same individual.	('D310', 'Var', (79, 83))	('men', 'Species', '9606', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
146232	28659721	The knowledge regarding the overall frequency of mtDNA mutations in solid tumors is still too incomplete to allow a faithful estimation of their suitability for screening of bodily fluids from patients at risk.	('patients', 'Species', '9606', (193, 201))	('solid tumors', 'Disease', (68, 80))	('mtDNA', 'Gene', (49, 54))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('solid tumors', 'Disease', 'MESH:D009369', (68, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
146251	28659721	If specific mutations are at all present, it is very likely to detect them with higher sensitivity as compared to cytologic identification of tumor cells.	('tumor', 'Disease', (142, 147))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
146270	28659721	While all the above mentioned assays are finally based on the detection of proteins with limited specificity for BC cells, the last well validated assay (UroVysion) relies on the detection of aneuploidy (chromosomes 3,7,17) and deletions of the 9p21 locus of the tumor suppressor p16 by FISH.	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('aneuploidy', 'Disease', 'MESH:D000782', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('9p21', 'Gene', (245, 249))	('tumor', 'Disease', (263, 268))	('aneuploidy', 'Disease', (192, 202))	('deletions', 'Var', (228, 237))	('men', 'Species', '9606', (20, 23))
146276	28659721	Correspondingly, it has been shown as a proof of principle that mtDNA mutations sequenced from pure tumor DNA are represented in matched bodily fluids at much higher abundance than mutations of the classical tumor suppressor p53, previously sequenced from the tumor tissue.	('tumor', 'Disease', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (100, 105))	('p53', 'Gene', (225, 228))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('p53', 'Gene', '7157', (225, 228))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('mtDNA', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('higher', 'PosReg', (159, 165))
146277	28659721	Secondly, mtDNA represents a relatively short stretch of DNA (16.5 kb), accumulating a relatively high burden of mutations in solid human tumors.	('mutations', 'Var', (113, 122))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('human', 'Species', '9606', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
146279	28659721	In the nearly 20-year old study of Fliss and colleagues, which still used conventional sequencing of only 80% of mtDNA, already 64% of bladder cancer tissues were found to harbor a somatic mutation by comparison with the constitutive mitochondrial genotype of the same patient.	('bladder cancer', 'Disease', 'MESH:D001749', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('bladder cancer', 'Disease', (135, 149))	('mutation', 'Var', (189, 197))	('patient', 'Species', '9606', (269, 276))	('harbor', 'Reg', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (135, 149))
146280	28659721	In addition, 46% of head and neck cancers and 43% of lung cancers contained a tumor-specific somatic mtDNA mutation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancers', 'Phenotype', 'HP:0100526', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('contained', 'Reg', (66, 75))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('neck cancers', 'Disease', (29, 41))	('neck cancers', 'Disease', 'MESH:D006258', (29, 41))	('mutation', 'Var', (107, 115))	('head and neck cancer', 'Phenotype', 'HP:0012288', (20, 40))	('mtDNA', 'Gene', (101, 106))	('tumor', 'Disease', (78, 83))	('head and neck cancer', 'Disease', 'MESH:D006258', (20, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('lung cancers', 'Disease', 'MESH:D008175', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('head and neck cancers', 'Phenotype', 'HP:0012288', (20, 41))	('lung cancers', 'Disease', (53, 65))
146281	28659721	This early study already suggested that solid human tumors of various origins were likely to harbor detectable mtDNA mutations in every second case.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (117, 126))	('mtDNA', 'Gene', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('human', 'Species', '9606', (46, 51))
146282	28659721	This estimation was supported by many other studies, which focused solely on the control region (1.2 kb) and also detected base substitutions or length alterations of the D310 marker in every third or fourth case of various solid tumors.	('detected', 'Reg', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('solid tumors', 'Disease', (224, 236))	('D310', 'Gene', (171, 175))	('base substitutions', 'Var', (123, 141))	('solid tumors', 'Disease', 'MESH:D009369', (224, 236))	('length', 'MPA', (145, 151))
146285	28659721	Mutations were identified in all BC cases, in 79% of lung cancers and 69% of renal cell cancers.	('renal cell cancers', 'Disease', 'MESH:C538614', (77, 95))	('lung cancers', 'Disease', 'MESH:D008175', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancers', 'Phenotype', 'HP:0100526', (53, 65))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('identified', 'Reg', (15, 25))	('Mutations', 'Var', (0, 9))	('renal cell cancers', 'Disease', (77, 95))	('lung cancers', 'Disease', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
146286	28659721	Simply by applying the same array, the authors were able to detect these altered mtDNA sequences in 1 out of 3 urine samples from BC, in 4 out of 12 kidney cancer urine specimens and in 3 out of 7 BAL specimens, i.e.	('altered', 'Var', (73, 80))	('kidney cancer', 'Disease', 'MESH:D007680', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mtDNA', 'Gene', (81, 86))	('kidney cancer', 'Phenotype', 'HP:0009726', (149, 162))	('detect', 'Reg', (60, 66))	('men', 'Species', '9606', (174, 177))	('kidney cancer', 'Disease', (149, 162))	('men', 'Species', '9606', (206, 209))
146289	28659721	4), the publication demonstrated that tumor-specific mutations can be principally found in corresponding urine specimens by a whole mtDNA approach.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('men', 'Species', '9606', (116, 119))
146292	28659721	In their study Mithani and colleagues were able to detect known mtDNA mutations of head and neck cancers in the corresponding salivary rinses in 76.9% (10 out of 13) of cases.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('mutations', 'Var', (70, 79))	('head and neck cancer', 'Phenotype', 'HP:0012288', (83, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('head and neck cancers', 'Phenotype', 'HP:0012288', (83, 104))	('neck cancers', 'Disease', (92, 104))	('head and neck cancer', 'Disease', 'MESH:D006258', (83, 103))	('neck cancers', 'Disease', 'MESH:D006258', (92, 104))
146295	28659721	It seems reasonable to assume, that next generation deep sequencing strategies can be developed, which detect minor sub-clones of cancer cells by mutations of low abundance.	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
146298	28659721	Last but not least, it has to be mentioned that mtDNA mutations can be expected to occur also in low-grade lesions.	('mtDNA', 'Gene', (48, 53))	('mutations', 'Var', (54, 63))	('occur', 'Reg', (83, 88))	('men', 'Species', '9606', (33, 36))
146299	28659721	Actually mtDNA mutations have been found in pre-cancerous and low-grade lesions.	('found', 'Reg', (35, 40))	('mtDNA', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('mutations', 'Var', (15, 24))	('cancerous', 'Disease', (48, 57))
146300	28659721	This early occurrence of mtDNA mutations during carcinogenesis is best documented for cancers of the gastrointestinal tract.	('mutations', 'Var', (31, 40))	('cancers of the gastrointestinal tract', 'Disease', (86, 123))	('cancers of the gastrointestinal tract', 'Disease', 'MESH:D004067', (86, 123))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('men', 'Species', '9606', (75, 78))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('carcinogenesis', 'Disease', (48, 62))	('mtDNA', 'Gene', (25, 30))
146310	28659721	A good example is acute myeloic leukemia (AML), where huge numbers of possible mutations or fusion-transcripts indeed required the development of a large panel of assays, from which the clinicians can choose for small subsets of patients.	('patients', 'Species', '9606', (229, 237))	('acute myeloic leukemia', 'Phenotype', 'HP:0004808', (18, 40))	('AML', 'Disease', (42, 45))	('men', 'Species', '9606', (138, 141))	('acute myeloic leukemia', 'Disease', (18, 40))	('acute myeloic leukemia', 'Disease', 'MESH:D015470', (18, 40))	('AML', 'Disease', 'MESH:D015470', (42, 45))	('leukemia', 'Phenotype', 'HP:0001909', (32, 40))	('myeloic leukemia', 'Phenotype', 'HP:0012324', (24, 40))	('fusion-transcripts', 'Var', (92, 110))	('mutations', 'Var', (79, 88))
146313	28659721	In a first step the mutations or translocations are assessed and then a specific test is chosen for most sensitive recognition of a reappearance of leukemic blasts in blood samples.	('translocations', 'Var', (33, 47))	('leukemic blasts', 'Disease', 'MESH:D007938', (148, 163))	('leukemic blasts', 'Disease', (148, 163))
146314	28659721	These individual assays are designed to find less than 1% of leukemic cells with mutant DNA in the blood.	('leukemic', 'Disease', 'MESH:D007938', (61, 69))	('leukemic', 'Disease', (61, 69))	('mutant', 'Var', (81, 87))	('DNA', 'Gene', (88, 91))
146318	28659721	It seems thus reasonable to have a close look on the stability of tumor-specific mtDNA mutations over time.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('mtDNA', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('mutations', 'Var', (87, 96))
146319	28659721	It is likely that a growing sensitivity of analytical techniques for heteroplasmic positions, will find an increasing frequency of mtDNA mutations in many cancer entities.	('mtDNA', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (137, 146))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
146321	28659721	This inconstant behavior of mtDNA is a prerequisite for the accumulation of mutations in the tumors, but at the same time determines the risk of instability over time.	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('determines', 'Reg', (122, 132))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
146324	28659721	deletions in conserved OXPHOS polypeptides) or which had been shown in mouse xenograft experiments to support tumor growth in vivo.	('men', 'Species', '9606', (93, 96))	('deletions', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('support', 'PosReg', (102, 109))	('mouse', 'Species', '10090', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
146326	28659721	Later this cyt b deletion was cloned and introduced into mouse BC cells, which not only exhibited an altered biochemical phenotype of mitochondria, including increased ROS production, but also faster proliferation, increased colony formation in soft-agar assays and increased matrigel invasion.	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('matrigel invasion', 'CPA', (276, 293))	('ROS production', 'MPA', (168, 182))	('faster', 'PosReg', (193, 199))	('deletion', 'Var', (17, 25))	('increased', 'PosReg', (215, 224))	('increased', 'PosReg', (266, 275))	('colony formation in soft-agar assays', 'CPA', (225, 261))	('increased ROS production', 'Phenotype', 'HP:0025464', (158, 182))	('mouse', 'Species', '10090', (57, 62))	('cyt b', 'Gene', (11, 16))	('increased', 'PosReg', (158, 167))
146331	28659721	Activation of transcription factors by ROS is generally a thinkable mechanism, how some mtDNA mutations may promote tumor growth and has also been suggested in other cases, e.g.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mtDNA', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('promote', 'PosReg', (108, 115))	('tumor', 'Disease', (116, 121))
146335	28659721	Recent NGS approaches combined with sophisticated data analysis to select mutations of likely functional relevance, may shed a much more systematic light on the potential role of mtDNA mutations for tumor biology in the future.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (185, 194))	('mtDNA', 'Gene', (179, 184))
146336	28659721	A group of researchers from Italy recently implemented a multistep bioinformatics analysis of NGS-based sequence data, which detected many, mostly low abundant heteroplasmic mtDNA mutations in glioblastomas and neuroblastomas, the vast majority of which was likely to represent merely passengers of the clonal cell expansion without any role for tumor growth.	('neuroblastomas', 'Phenotype', 'HP:0003006', (211, 225))	('men', 'Species', '9606', (48, 51))	('mutations', 'Var', (180, 189))	('glioblastomas', 'Phenotype', 'HP:0012174', (193, 206))	('glioblastomas and neuroblastomas', 'Disease', 'MESH:D005909', (193, 225))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('mtDNA', 'Gene', (174, 179))	('tumor', 'Disease', (346, 351))
146338	28659721	Only a limited number of mtDNA mutations survived the filter process in glioblastomas and neuroblastomas and may thus more likely play a pathogenic role in these tumors.	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glioblastomas and neuroblastomas', 'Disease', 'MESH:D005909', (72, 104))	('play', 'Reg', (130, 134))	('glioblastomas', 'Phenotype', 'HP:0012174', (72, 85))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('neuroblastomas', 'Phenotype', 'HP:0003006', (90, 104))	('mtDNA', 'Gene', (25, 30))
146339	28659721	It is thus highly important to use bioinformatics tools to reconstruct a collection of 'allowed heteroplasmic variants', as a basis to screen for clinically relevant private mutations, which do not occur in this collection, may drive tumor growth and could be eventually of prognostic value.	('tumor', 'Disease', (234, 239))	('drive', 'PosReg', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('mutations', 'Var', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
146341	28659721	However, the functional relevance of mtDNA mutations plays no role for its potential suitability in surveillance of patients.	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (116, 124))	('mtDNA', 'Gene', (37, 42))
146342	28659721	Nor does the question play a role, if the frequently observed sequence alterations can really be called 'somatic mutations' or may in part rely on heteroplasmy-shifts.	('sequence alterations', 'Var', (62, 82))	('heteroplasmy-shift', 'Disease', (147, 165))	('heteroplasmy-shift', 'Disease', 'MESH:D020178', (147, 165))
146345	28659721	However, there is also growing evidence connecting the copy number of mtDNA in the tumor tissue with prognosis of cancer patients.	('mtDNA', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('copy number', 'Var', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('patients', 'Species', '9606', (121, 129))	('cancer', 'Disease', (114, 120))
146352	28659721	An increased mtDNA-level in gliomas was observed as compared to (not matched) normal brain tissues, high copy number being associated with better prognosis.	('increased', 'PosReg', (3, 12))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('mtDNA-level', 'MPA', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('high copy number', 'Var', (100, 116))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
146358	28659721	While high copy number was associated with better survival in adrenocortical carcinoma, chromophobe renal cell carcinoma and low grade glioma, the opposite occurred in clear cell renal carcinoma and melanoma.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (62, 86))	('glioma', 'Disease', (135, 141))	('chromophobe renal cell carcinoma', 'Disease', (88, 120))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (62, 86))	('clear cell renal carcinoma and melanoma', 'Disease', 'MESH:C538614', (168, 207))	('survival', 'MPA', (50, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 120))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('renal carcinoma', 'Phenotype', 'HP:0005584', (179, 194))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('adrenocortical carcinoma', 'Disease', (62, 86))	('better', 'PosReg', (43, 49))	('high copy number', 'Var', (6, 22))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (100, 120))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
146359	28659721	In summary, tumor development is often associated with changes of mtDNA-levels, but direction and especially prognostic significance of this change seem to vary between entities.	('mtDNA-levels', 'MPA', (66, 78))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('associated', 'Reg', (39, 49))	('tumor', 'Disease', (12, 17))	('changes', 'Var', (55, 62))	('men', 'Species', '9606', (25, 28))
146360	28659721	It may thus not be surprising that studies trying to asses an individual's tumor risk based on its constitutive mtDNA copy number in blood led to interesting, but currently still inhomogenous results, demanding more generalized meta-analyses, as recently performed for the first time.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mtDNA', 'Gene', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('copy number', 'Var', (118, 129))	('tumor', 'Disease', (75, 80))
146361	28659721	For example, in a large study of 1108 cases and 1099 controls Lemnrau and colleagues had detected a positive association between a high mtDNA-content in peripheral blood cells and the risk for breast cancer.	('breast cancer', 'Disease', (193, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('mtDNA-content', 'Gene', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Lemnrau', 'Disease', 'None', (62, 69))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('Lemnrau', 'Disease', (62, 69))	('high', 'Var', (131, 135))
146362	28659721	An OR of 1.37 was found for the comparison of breast cancer risk between the highest and lowest quartiles of mtDNA copy number in blood samples taken prior to cancer diagnosis (mean time interval 6 years).	('copy number', 'Var', (115, 126))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mtDNA', 'Gene', (109, 114))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('breast cancer', 'Disease', (46, 59))
146364	28659721	A comparison of 500 melanoma patients with 500 controls also revealed a positive association between high mtDNA content and melanonma risk.	('patients', 'Species', '9606', (29, 37))	('melanonma', 'Disease', (124, 133))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('high', 'Var', (101, 105))	('melanoma', 'Disease', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
146370	28659721	Looking for specific tumor types, the positive association between high mtDNA copy number and increased risk for lymphoma (OR 1.76, p=0.023), but reduced risk for skeleton cancers (OR 0.39, p = 0.001) were important.	('high', 'Var', (67, 71))	('mtDNA', 'Gene', (72, 77))	('lymphoma', 'Disease', 'MESH:D008223', (113, 121))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('lymphoma', 'Disease', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('skeleton cancers', 'Disease', (163, 179))	('skeleton cancers', 'Disease', 'MESH:D000130', (163, 179))
146383	24339890	Despite facing a better prognosis when compared with higher grade glial tumors, 50-75% of patients harboring low-grade gliomas eventually die of their disease.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glial tumors', 'Disease', 'MESH:D005910', (66, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('glial tumors', 'Disease', (66, 78))	('low-grade', 'Var', (109, 118))	('patients', 'Species', '9606', (90, 98))
146507	33413657	For instance, BIRC3 genetic inactivation due to deletions or point mutations is consistently associated to shorter progression free survival and poor prognosis in chronic lymphocytic leukemia patients.	('point mutations', 'Var', (61, 76))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (163, 191))	('patients', 'Species', '9606', (192, 200))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (163, 191))	('genetic', 'Var', (20, 27))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('shorter', 'NegReg', (107, 114))	('deletions', 'Var', (48, 57))	('progression free survival', 'CPA', (115, 140))	('chronic lymphocytic leukemia', 'Disease', (163, 191))	('BIRC3', 'Gene', (14, 19))
146522	33413657	Genetic aberrations also represent a mechanism for IAPs disregulation.	('IAP', 'Gene', '84061', (51, 54))	('mechanism', 'Reg', (37, 46))	('Genetic aberrations', 'Var', (0, 19))	('IAP', 'Gene', (51, 54))
146524	33413657	This locus codes for cellular IAP1 (cIAP1) and cellular IAP2 (cIAP2) (BIRC2 and BIRC3, respectively) and its amplification is also associated to lymph node metastasis and radioresistance insurgence in OSCC, strongly supporting the oncogenic function of these two IAPs in this type of malignancy.	('lymph node metastasis', 'CPA', (145, 166))	('IAP', 'Gene', '84061', (30, 33))	('amplification', 'Var', (109, 122))	('IAP2', 'Gene', '329', (63, 67))	('malignancy', 'Disease', 'MESH:D009369', (284, 294))	('cIAP2', 'Gene', '330', (62, 67))	('cIAP1', 'Gene', '329', (36, 41))	('IAP2', 'Gene', '329', (56, 60))	('IAP', 'Gene', '84061', (37, 40))	('IAP1', 'Gene', '330', (37, 41))	('IAP', 'Gene', (263, 266))	('IAP1', 'Gene', '330', (30, 34))	('malignancy', 'Disease', (284, 294))	('IAP', 'Gene', (63, 66))	('IAP1', 'Gene', (37, 41))	('associated to', 'Reg', (131, 144))	('IAP', 'Gene', (56, 59))	('IAP1', 'Gene', (30, 34))	('IAP', 'Gene', (30, 33))	('OSCC', 'Disease', (201, 205))	('IAP', 'Gene', '84061', (263, 266))	('BIRC2', 'Gene', '329', (70, 75))	('radioresistance', 'CPA', (171, 186))	('IAP', 'Gene', (37, 40))	('IAP2', 'Gene', (63, 67))	('IAP', 'Gene', '84061', (63, 66))	('IAP2', 'Gene', (56, 60))	('cIAP2', 'Gene', (62, 67))	('cIAP1', 'Gene', (36, 41))	('BIRC2', 'Gene', (70, 75))	('IAP', 'Gene', '84061', (56, 59))
146526	33413657	However, several clinical studies published in recent years reported an unfavorable contribution of BIRC3 genetic inactivation or downregulation in cancer patients.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('downregulation', 'NegReg', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('genetic inactivation', 'Var', (106, 126))	('patients', 'Species', '9606', (155, 163))	('BIRC3', 'Gene', (100, 105))
146530	33413657	Some of the most relevant may be subdivided in these major groups: Dysregulation of anti-apoptotic BCL-2 members.	('BCL-2', 'Gene', '596', (99, 104))	('Dysregulation', 'Var', (67, 80))	('BCL-2', 'Gene', (99, 104))	('anti-apoptotic', 'Protein', (84, 98))
146550	33413657	Hsp90 inhibitors have been demonstrated to preferentially deplete mutated EGFR, with a consequent suppression of p-Akt and induction of cell death.	('Akt', 'Gene', '207', (115, 118))	('mutated', 'Var', (66, 73))	('induction', 'Reg', (123, 132))	('cell death', 'CPA', (136, 146))	('Hsp90', 'Gene', '3320', (0, 5))	('Akt', 'Gene', (115, 118))	('EGFR', 'Gene', '1956', (74, 78))	('deplete', 'NegReg', (58, 65))	('EGFR', 'Gene', (74, 78))	('Hsp90', 'Gene', (0, 5))	('suppression', 'NegReg', (98, 109))
146551	33413657	NSCLC targeted therapy had also been demonstrate to benefit of Hsp90 inhibition in tumors harboring EGFR mutations.	('Hsp90', 'Gene', (63, 68))	('EGFR', 'Gene', '1956', (100, 104))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Hsp90', 'Gene', '3320', (63, 68))	('EGFR', 'Gene', (100, 104))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('mutations', 'Var', (105, 114))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('NSCLC', 'Disease', (0, 5))	('inhibition', 'NegReg', (69, 79))
146552	33413657	Notably, BIRC5 (survivin) is a client protein of Hsp90 chaperone and results downregulated upon Hsp90 pharmacological inhibition in cancer cells.	('cancer', 'Disease', (132, 138))	('BIRC5', 'Gene', (9, 14))	('downregulated', 'NegReg', (77, 90))	('Hsp90', 'Gene', (96, 101))	('Hsp90', 'Gene', (49, 54))	('survivin', 'Gene', '11799', (16, 24))	('Hsp90', 'Gene', '3320', (96, 101))	('Hsp90', 'Gene', '3320', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('pharmacological inhibition', 'Var', (102, 128))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('survivin', 'Gene', (16, 24))	('BIRC5', 'Gene', '332', (9, 14))
146553	33413657	The nuclear pore complexes (NPC) became attractive therapeutic targets because the aberrant expression of the constituent proteins has been consistently observed in different cancers and has been linked to apoptosis resistance.	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('observed', 'Reg', (153, 161))	('apoptosis resistance', 'CPA', (206, 226))	('aberrant', 'Var', (83, 91))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('proteins', 'Protein', (122, 130))	('expression', 'MPA', (92, 102))	('linked to', 'Reg', (196, 205))
146559	33413657	The analysis of the experimental evidences point to an apparent paradox of this cIAP, since in many instances BIRC3 plays a role of tumor suppressor, its deficiency being associated to poor prognosis and insurgence of therapy resistance (please, see Table 1).	('BIRC3', 'Gene', (110, 115))	('IAP', 'Gene', '84061', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('deficiency', 'Var', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IAP', 'Gene', (81, 84))	('tumor', 'Disease', (132, 137))	('associated', 'Reg', (171, 181))
146563	33413657	In addition to deletion 17p (del17p), del11q, trisomy 12 and del13q, several point mutations have been described and may coexist with the deletion on the other allele (e.g.	('del13q', 'Var', (61, 67))	('deletion 17p (del17p', 'Var', (15, 35))	('del17p', 'Mutation', 'c.del17', (29, 35))	('trisomy 12', 'Disease', (46, 56))	('del11q', 'Var', (38, 44))
146565	33413657	BIRC3 deletions and mutations are recognized as rare albeit unfavorable events for CLL patients.	('CLL', 'Phenotype', 'HP:0005550', (83, 86))	('deletions', 'Var', (6, 15))	('BIRC3', 'Gene', (0, 5))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (20, 29))
146567	33413657	Del11q is a recurrent karyotypic abnormality acquired by patients with progressive CLL disease.	('CLL', 'Phenotype', 'HP:0005550', (83, 86))	('Del11q', 'Var', (0, 6))	('patients', 'Species', '9606', (57, 65))	('CLL disease', 'Disease', (83, 94))	('CLL disease', 'Disease', 'MESH:D015451', (83, 94))
146568	33413657	Initial karyotypic and FISH studies were complemented by genotypization of CLL patients, leading to the discovery that del11q is monoallelic, often large and includes a minimal deleted region encompassing ATM gene.	('ATM', 'Gene', (205, 208))	('ATM', 'Gene', '472', (205, 208))	('del11q', 'Var', (119, 125))	('CLL', 'Phenotype', 'HP:0005550', (75, 78))	('patients', 'Species', '9606', (79, 87))
146571	33413657	Furthermore, the patients with a biallelic lesion of BIRC3 (del and mut) were associated to a significant shorter time to first treatment when compared to BIRC3-del/wt or wild type patients.	('patients', 'Species', '9606', (181, 189))	('shorter', 'NegReg', (106, 113))	('patients', 'Species', '9606', (17, 25))	('biallelic lesion', 'Var', (33, 49))
146573	33413657	BIRC3 deletion occurs in 83% of del11q cases and always coexists with ATM deletion, as demonstrated by the CLL4 study.	('del11q', 'Var', (32, 38))	('CLL', 'Phenotype', 'HP:0005550', (107, 110))	('ATM', 'Gene', '472', (70, 73))	('BIRC3', 'Gene', (0, 5))	('deletion', 'Var', (6, 14))	('ATM', 'Gene', (70, 73))
146574	33413657	Concerning the response to therapies, it is known that BIRC3 inactivation is associated to fludarabine-chemoresistance and to adverse prognosis in a large cohort of chemotherapy-treated CLL patients.	('inactivation', 'Var', (61, 73))	('BIRC3', 'Gene', (55, 60))	('fludarabine-chemoresistance', 'MPA', (91, 118))	('patients', 'Species', '9606', (190, 198))	('fludarabine', 'Chemical', 'MESH:C024352', (91, 102))	('CLL', 'Phenotype', 'HP:0005550', (186, 189))	('CLL', 'Disease', (186, 189))	('associated', 'Reg', (77, 87))
146575	33413657	Furthermore, a target re-sequencing of 22 genes of the patients enrolled in the UK LRF CLL4 study confirms that bi-allelic BIRC3 lesions (del and mut in the same patient) are an independent marker of inferior progression free survival (PFS) and overall survival (OS).	('patient', 'Species', '9606', (162, 169))	('progression free survival', 'CPA', (209, 234))	('CLL', 'Phenotype', 'HP:0005550', (87, 90))	('bi-allelic', 'Var', (112, 122))	('overall survival', 'CPA', (245, 261))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))	('BIRC3', 'Gene', (123, 128))	('inferior', 'NegReg', (200, 208))
146577	33413657	BIRC3 point mutations can also co-occur with del11q and NOTCH1 point mutations.	('NOTCH1', 'Gene', (56, 62))	('BIRC3', 'Gene', (0, 5))	('del11q', 'Var', (45, 51))	('NOTCH1', 'Gene', '4851', (56, 62))
146578	33413657	At variance with this association, BIRC3 point mutations do not occur with ATM point mutations, but associate to del11q.	('ATM', 'Gene', (75, 78))	('associate', 'Reg', (100, 109))	('del11q', 'Var', (113, 119))	('ATM', 'Gene', '472', (75, 78))	('BIRC3 point', 'Disease', (35, 46))
146583	33413657	It is therefore correct to consider the actual BIRC3 mutations as NF-kB-activating, by MAP3K14 stabilization.	('BIRC3', 'Gene', (47, 52))	('MAP3K14', 'Gene', '9020', (87, 94))	('MAP3K14', 'Gene', (87, 94))	('mutations', 'Var', (53, 62))
146584	33413657	further demonstrates that BIRC3 mutations confer, at least partially, resistance to fludarabine treatment on primary CLL samples.	('CLL', 'Phenotype', 'HP:0005550', (117, 120))	('fludarabine', 'Chemical', 'MESH:C024352', (84, 95))	('BIRC3', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('resistance to fludarabine treatment', 'MPA', (70, 105))
146601	33413657	A focus on mature B-cell neoplasms reveals how BIRC3 mutations are common to another lymphoid malignancy: mantle-cell lymphoma (MCL).	('mantle-cell lymphoma', 'Disease', (106, 126))	('neoplasms', 'Phenotype', 'HP:0002664', (25, 34))	('neoplasm', 'Phenotype', 'HP:0002664', (25, 33))	('cell lymphoma', 'Phenotype', 'HP:0012191', (113, 126))	('B-cell neoplasms', 'Disease', (18, 34))	('common', 'Reg', (67, 73))	('mutations', 'Var', (53, 62))	('BIRC3', 'Gene', (47, 52))	('MCL', 'Disease', 'MESH:C535516', (128, 131))	('mantle-cell lymphoma', 'Disease', 'MESH:D020522', (106, 126))	('lymphoid malignancy', 'Disease', (85, 104))	('lymphoid malignancy', 'Phenotype', 'HP:0002665', (85, 104))	('B-cell neoplasms', 'Disease', 'MESH:D016393', (18, 34))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('MCL', 'Disease', (128, 131))	('lymphoid malignancy', 'Disease', 'MESH:D008223', (85, 104))
146603	33413657	Primary ibrutinib resistance may arise due to mutations in the B-cell receptor (BCR) pathway causing its constitutive activation (e.g.	('ibrutinib', 'Chemical', 'MESH:C551803', (8, 17))	('arise due', 'Reg', (33, 42))	('mutations', 'Var', (46, 55))	('constitutive', 'MPA', (105, 117))
146606	33413657	Mutations in the TRAF2, TRAF3, BIRC3 and MAP3K14 genes may lead to a constitutive activation of the non-canonical NF-kB pathway through MAP3K14 stabilization (Fig.	('MAP3K14', 'Gene', (136, 143))	('TRAF3', 'Gene', '7187', (24, 29))	('MAP3K14', 'Gene', (41, 48))	('TRAF2', 'Gene', '7186', (17, 22))	('MAP3K14', 'Gene', '9020', (41, 48))	('activation', 'PosReg', (82, 92))	('MAP3K14', 'Gene', '9020', (136, 143))	('Mutations', 'Var', (0, 9))	('TRAF3', 'Gene', (24, 29))	('non-canonical NF-kB pathway', 'Pathway', (100, 127))	('TRAF2', 'Gene', (17, 22))	('BIRC3', 'Gene', (31, 36))
146607	33413657	Furthermore, TRAF2, BIRC3 and MAP3K14 were recurrently mutated in approximately 17% of a cohort of 165 MCL tumor tissues investigated by genomic profiling.	('MAP3K14', 'Gene', (30, 37))	('MCL tumor', 'Disease', (103, 112))	('MCL tumor', 'Disease', 'MESH:C535516', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutated', 'Var', (55, 62))	('MAP3K14', 'Gene', '9020', (30, 37))	('TRAF2', 'Gene', '7186', (13, 18))	('TRAF2', 'Gene', (13, 18))	('BIRC3', 'Gene', (20, 25))
146608	33413657	Therefore, unmutated MCL should result sensitive to ibrutinib therapy while mutations in the non-canonical NF-kB activation pathway could represent a resistance mechanism through BCR-pathway bypass.	('ibrutinib', 'Chemical', 'MESH:C551803', (52, 61))	('mutations', 'Var', (76, 85))	('MCL', 'Disease', 'MESH:C535516', (21, 24))	('non-canonical NF-kB activation pathway', 'Pathway', (93, 131))	('MCL', 'Disease', (21, 24))
146609	33413657	Since it is estimated that 10-15% of MCL patients are BIRC3-mutated and that deletions (11q21-q23) involving ATM and BIRC3 are quite common, it is plausible that BIRC3 aberrations in MCL may result in decreased response to ibrutinib.	('response to ibrutinib', 'MPA', (211, 232))	('MCL', 'Disease', 'MESH:C535516', (37, 40))	('MCL', 'Disease', (183, 186))	('ATM', 'Gene', (109, 112))	('MCL', 'Disease', (37, 40))	('decreased', 'NegReg', (201, 210))	('patients', 'Species', '9606', (41, 49))	('ATM', 'Gene', '472', (109, 112))	('MCL', 'Disease', 'MESH:C535516', (183, 186))	('aberrations', 'Var', (168, 179))	('ibrutinib', 'Chemical', 'MESH:C551803', (223, 232))	('BIRC3', 'Gene', (162, 167))
146649	33413657	At variance with what described in gliomas, BIRC3 genetic inactivation due to deletions and/or point mutations is a negative prognostic factor and one of the drivers of therapy-resistance insurgence in CLL patients.	('negative', 'NegReg', (116, 124))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('point mutations', 'Var', (95, 110))	('CLL', 'Phenotype', 'HP:0005550', (202, 205))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('BIRC3', 'Gene', (44, 49))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('patients', 'Species', '9606', (206, 214))	('gliomas', 'Disease', (35, 42))	('deletions', 'Var', (78, 87))	('genetic inactivation', 'Var', (50, 70))
146654	33413657	Or, on the contrary, since BIRC3 inactivation due to deletion, mutation or both is a negative, unfavorable marker (as CLL demonstrates and MCL suggests), the above-mentioned strategies should be avoided?	('MCL', 'Disease', (139, 142))	('deletion', 'Var', (53, 61))	('mutation', 'Var', (63, 71))	('CLL', 'Phenotype', 'HP:0005550', (118, 121))	('inactivation', 'NegReg', (33, 45))	('BIRC3', 'Gene', (27, 32))	('MCL', 'Disease', 'MESH:C535516', (139, 142))
146671	33413657	Since p53 transcriptionally represses BIRC5 expression in normal tissues, mutations affecting p53 cause BIRC5 upregulation.	('upregulation', 'PosReg', (110, 122))	('p53', 'Gene', (6, 9))	('BIRC5', 'Gene', (104, 109))	('p53', 'Gene', '7157', (6, 9))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('mutations', 'Var', (74, 83))	('BIRC5', 'Gene', '332', (38, 43))	('BIRC5', 'Gene', (38, 43))	('BIRC5', 'Gene', '332', (104, 109))
146672	33413657	A significant subset of prostate cancer patients display mutated p53 and is characterized by tumor aggressiveness and significantly increased risk of progression after radical prostatectomy.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (24, 39))	('patients', 'Species', '9606', (40, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (24, 39))	('tumor aggressiveness', 'Disease', (93, 113))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('aggressiveness', 'Phenotype', 'HP:0000718', (99, 113))	('mutated', 'Var', (57, 64))	('prostate cancer', 'Disease', (24, 39))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (93, 113))
146674	33413657	Interestingly, from the same study emerges that cytoplasmic localization is associated to an aggressive disease (higher Gleason score), higher pathological tumor stage and higher Ki67 proliferative index.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('associated', 'Reg', (76, 86))	('cytoplasmic', 'Var', (48, 59))	('aggressive disease', 'Disease', 'MESH:D001523', (93, 111))	('tumor', 'Disease', (156, 161))	('aggressive disease', 'Disease', (93, 111))	('Ki67 proliferative index', 'CPA', (179, 203))
146686	33413657	Actually, it is well established that p53 activity is modulated also through post-translational, epigenetic modifications.	('modulated', 'Reg', (54, 63))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('activity', 'MPA', (42, 50))	('epigenetic modifications', 'Var', (97, 121))	('post-translational', 'Var', (77, 95))
146698	33413657	It was demonstrated already several years ago that high survivin expression associates to MB malignancy and poor-prognosis and this IAP-member is recognized as a therapeutic target with high priority in these subtypes.	('survivin', 'Gene', '11799', (56, 64))	('associates to', 'Reg', (76, 89))	('MB malignancy', 'Disease', 'MESH:D009369', (90, 103))	('survivin', 'Gene', (56, 64))	('IAP', 'Gene', (132, 135))	('expression', 'MPA', (65, 75))	('high', 'Var', (51, 55))	('MB malignancy', 'Disease', (90, 103))	('IAP', 'Gene', '84061', (132, 135))
146701	33413657	Importantly, cell proliferation upon genetic disruption is dramatically reduced, as demonstrated by a 90% reduction in radioactive-thymidine incorporation.	('reduced', 'NegReg', (72, 79))	('cell proliferation', 'CPA', (13, 31))	('genetic disruption', 'Var', (37, 55))	('reduction', 'NegReg', (106, 115))	('radioactive-thymidine incorporation', 'MPA', (119, 154))	('radioactive-thymidine', 'Chemical', '-', (119, 140))
146702	33413657	Cell cycle progression is also impaired upon disruption, demonstrating a survivin essential role in the processes leading to cell division.	('Cell cycle progression', 'CPA', (0, 22))	('survivin', 'Gene', (73, 81))	('disruption', 'Var', (45, 55))	('impaired', 'NegReg', (31, 39))	('survivin', 'Gene', '11799', (73, 81))
146708	33413657	All the documented inhibitors can be classified into 5 categories, based on the characterizing mechanism of action: (a) Inhibitors that disrupt survivin interactions with its partner proteins; (b) Inhibitors that disrupt survivin homodimerization; (c) Inhibitors that decrease survivin gene transcription; (d) Inhibitors that induce survivin mRNA degradation; and (e) survivin or its peptide for immunotherapy.	('mRNA degradation', 'MPA', (342, 358))	('transcription', 'MPA', (291, 304))	('survivin', 'Gene', (333, 341))	('survivin', 'Gene', (144, 152))	('survivin', 'Gene', '11799', (221, 229))	('survivin', 'Gene', '11799', (368, 376))	('homodimerization', 'MPA', (230, 246))	('survivin', 'Gene', (368, 376))	('survivin', 'Gene', '11799', (277, 285))	('survivin', 'Gene', '11799', (144, 152))	('decrease', 'NegReg', (268, 276))	('survivin', 'Gene', (221, 229))	('survivin', 'Gene', '11799', (333, 341))	('interactions', 'Interaction', (153, 165))	('disrupt', 'NegReg', (136, 143))	('survivin', 'Gene', (277, 285))	('disrupt', 'NegReg', (213, 220))	('Inhibitors', 'Var', (252, 262))
146721	33413657	IAPs Inhibitors of apoptosis proteins BIR Baculoviral IAP repeat domains UBC C-terminal ubiquitin-conjugating domain CARD Caspase recruitment domain RING C-terminal Ring zinc-finger domain BIRC Baculoviral IAP repeat containing XIAP X-linked IAP SMAC/Diablo Second Mitochondria-derived Activator of Caspases/Direct IAp Binding with Low pI DLBCL Diffuse large B-cell lymphoma CLL Chronic lymphocytic leukemia MCL Mantle cell lymphoma AML Acute myeloid leukemia cIAP Cellular IAP OSCC Oral squamous cell carcinoma PFS Progression free survival OS Overall survival FCR Fludarabine-cyclophosphamide-rituximab BTK Bruton tyrosine-kinase del11q- Deletion of 11q BCR B-cell receptor pathway LGG Low-grade gliomas HGG High-grade gliomas GBM Glioblastoma multiforme IL-1beta Inflammatory cytokine 1beta TCGA Tumor cancer genome atlas GDSC Genomics of Drug Sensitivity in Cancer database IHC Immunohistochemical FFPE Formalin fixed-paraffin embedded MB Medulloblastomas SHH-MB Sonic Hedgehog signaling-driven MB PDXs Patient-derived xenografts NPC Nuclear pore complexes SINE Selective inhibitors of nuclear export DEGs Differentially expressed genes GEO Gene Expression Omnibus ICGC International Cancer Genome Consortium RF conceived and wrote the manuscript.	('AML', 'Disease', (433, 436))	('Patient', 'Species', '9606', (1007, 1014))	('Diablo', 'Gene', '56616', (251, 257))	('lymphoma', 'Phenotype', 'HP:0002665', (424, 432))	('Acute myeloid leukemia', 'Disease', (437, 459))	('XIAP', 'Gene', (228, 232))	('gliomas', 'Phenotype', 'HP:0009733', (721, 728))	('SMAC', 'Gene', (246, 250))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (437, 459))	('gliomas', 'Phenotype', 'HP:0009733', (698, 705))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (359, 374))	('Formalin', 'Chemical', 'MESH:D005557', (907, 915))	('SHH', 'Gene', (960, 963))	('IL-1beta', 'Gene', (757, 765))	('HGG High', 'Phenotype', 'HP:0003237', (706, 714))	('Caspases', 'Gene', '841;842', (299, 307))	('Mantle cell lymphoma', 'Disease', (412, 432))	('XIAP', 'Gene', '331', (228, 232))	('Mantle cell lymphoma', 'Disease', 'MESH:D020522', (412, 432))	('IAP', 'Gene', '84061', (206, 209))	('IAP', 'Gene', '84061', (0, 3))	('CARD', 'Disease', 'None', (117, 121))	('gliomas', 'Disease', 'MESH:D005910', (721, 728))	('IAP', 'Gene', '84061', (229, 232))	('gliomas', 'Disease', 'MESH:D005910', (698, 705))	('cell lymphoma', 'Phenotype', 'HP:0012191', (419, 432))	('Cancer', 'Disease', (1188, 1194))	('MCL', 'Disease', 'MESH:C535516', (408, 411))	('Cancer', 'Disease', (862, 868))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (437, 459))	('IAP', 'Gene', '84061', (474, 477))	('IAP', 'Gene', '84061', (242, 245))	('X-linked IAP', 'Gene', (233, 245))	('Tumor cancer', 'Disease', (799, 811))	('Medulloblastomas', 'Disease', (943, 959))	('Cancer', 'Disease', 'MESH:D009369', (1188, 1194))	('cell lymphoma', 'Phenotype', 'HP:0012191', (361, 374))	('Cancer', 'Disease', 'MESH:D009369', (862, 868))	('IAP', 'Gene', (206, 209))	('IAP', 'Gene', (0, 3))	('IAP', 'Gene', (229, 232))	('paraffin', 'Chemical', 'MESH:D010232', (922, 930))	('IAp', 'Gene', '84061', (315, 318))	('gliomas', 'Disease', (698, 705))	('IAP', 'Gene', (474, 477))	('BIR', 'Chemical', '-', (189, 192))	('IAP', 'Gene', (242, 245))	('BIR', 'Chemical', '-', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (805, 811))	('BIRC', 'Chemical', '-', (189, 193))	('Tumor cancer', 'Disease', 'MESH:D009369', (799, 811))	('IL-1beta', 'Gene', '3552', (757, 765))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (733, 756))	('AML', 'Disease', 'MESH:D015470', (433, 436))	('IAP', 'Gene', '84061', (461, 464))	('BTK', 'Gene', (605, 608))	('BTK', 'Gene', '695', (605, 608))	('IAP', 'Gene', '84061', (54, 57))	('glioma', 'Phenotype', 'HP:0009733', (721, 727))	('del11q- Deletion', 'Var', (632, 648))	('glioma', 'Phenotype', 'HP:0009733', (698, 704))	('CARD', 'Disease', (117, 121))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (443, 459))	('Bruton tyrosine-kinase', 'Gene', (609, 631))	('UBC', 'Gene', (73, 76))	('IAP', 'Gene', (461, 464))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (359, 374))	('Chronic lymphocytic leukemia', 'Disease', (379, 407))	('Glioblastoma multiforme', 'Disease', (733, 756))	('IAP', 'Gene', (54, 57))	('Caspases', 'Gene', (299, 307))	('gliomas', 'Disease', (721, 728))	('IAp', 'Gene', (315, 318))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (488, 511))	('B-cell lymphoma', 'Disease', (359, 374))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (842, 858))	('Cancer', 'Phenotype', 'HP:0002664', (1188, 1194))	('Cancer', 'Phenotype', 'HP:0002664', (862, 868))	('Diablo', 'Gene', (251, 257))	('Medulloblastomas', 'Disease', 'MESH:D008527', (943, 959))	('FCR', 'Chemical', '-', (562, 565))	('leukemia', 'Phenotype', 'HP:0001909', (399, 407))	('Chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (379, 407))	('AML', 'Phenotype', 'HP:0004808', (433, 436))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (483, 511))	('carcinoma', 'Phenotype', 'HP:0030731', (502, 511))	('SHH', 'Gene', '6469', (960, 963))	('leukemia', 'Phenotype', 'HP:0001909', (451, 459))	('Fludarabine-cyclophosphamide', 'Chemical', '-', (566, 594))	('UBC', 'Gene', '7316', (73, 76))	('CLL', 'Phenotype', 'HP:0005550', (375, 378))	('Chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (379, 407))	('Oral squamous cell carcinoma', 'Disease', (483, 511))	('lymphoma', 'Phenotype', 'HP:0002665', (366, 374))	('Tumor', 'Phenotype', 'HP:0002664', (799, 804))	('SMAC', 'Gene', '56616', (246, 250))	('LGG Low', 'Phenotype', 'HP:0004315', (684, 691))	('MCL', 'Disease', (408, 411))	('Glioblastoma', 'Phenotype', 'HP:0012174', (733, 745))	('rituximab', 'Chemical', 'MESH:D000069283', (595, 604))	('Bruton tyrosine-kinase', 'Gene', '695', (609, 631))	('X-linked IAP', 'Gene', '331', (233, 245))
146730	32431498	In 2016 WHO included in the classification also molecular diagnostic criteria for infiltrating gliomas, including mutation of isocitrate dehydrogenase, deletion of 1p/19q chromosome, and histone mutations.	('hydrogen', 'Chemical', 'MESH:D006859', (139, 147))	('histone', 'Protein', (187, 194))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('rat', 'Species', '10116', (132, 135))	('1p/19q', 'Gene', (164, 170))	('deletion of', 'Var', (152, 163))	('rat', 'Species', '10116', (88, 91))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('isocitrate dehydrogenase', 'Gene', (126, 150))	('mutation', 'Var', (114, 122))
146754	32431498	In particular cis-linoleic acid conjugate with PTX (CLA-PTX) resulted in much higher plasmatic half-life and brain accumulation than free PTX, with encouraging therapeutic effect on brain tumour bearing rats.	('PTX', 'Chemical', 'MESH:D017239', (138, 141))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('PTX', 'Chemical', 'MESH:D017239', (56, 59))	('cis-linoleic acid', 'Chemical', '-', (14, 31))	('brain tumour', 'Disease', (182, 194))	('plasmatic half-life', 'MPA', (85, 104))	('higher', 'PosReg', (78, 84))	('CLA-PTX', 'Chemical', '-', (52, 59))	('rats', 'Species', '10116', (203, 207))	('cis-linoleic acid', 'Var', (14, 31))	('PTX', 'Chemical', 'MESH:D017239', (47, 50))	('brain accumulation', 'MPA', (109, 127))	('brain tumour', 'Disease', 'MESH:D001932', (182, 194))	('brain tumour', 'Phenotype', 'HP:0030692', (182, 194))
146757	32431498	Apart from monoclonal antibody bevacizumab, that selectively binds VEGF, potential therapeutic agents include thalidomide and VEGF receptor (VEGFR) inhibitors, belonging to receptor tyrosine kinase (RTK) inhibitors category.	('inhibitors', 'Var', (148, 158))	('VEGF receptor', 'Gene', '3791', (126, 139))	('RTK', 'Gene', '5979', (199, 202))	('VEGF receptor', 'Gene', (126, 139))	('receptor tyrosine kinase', 'Gene', (173, 197))	('bevacizumab', 'Chemical', 'MESH:D000068258', (31, 42))	('receptor tyrosine kinase', 'Gene', '5979', (173, 197))	('VEGFR', 'Gene', '3791', (141, 146))	('binds', 'Interaction', (61, 66))	('thalidomide', 'Chemical', 'MESH:D013792', (110, 121))	('VEGF', 'Protein', (67, 71))	('VEGFR', 'Gene', (141, 146))	('RTK', 'Gene', (199, 202))
146761	32431498	Furthermore, 25% of glioblastomas are characterized by the expression of an EGFR mutant (EGFRvIII), which is defective of the extracellular ligand-binding domain.	('EGFR', 'Gene', (89, 93))	('glioblastomas', 'Phenotype', 'HP:0012174', (20, 33))	('EGFR', 'Gene', '1956', (76, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (20, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('EGFR', 'Gene', (76, 80))	('mutant', 'Var', (81, 87))	('glioblastomas', 'Disease', (20, 33))	('EGFR', 'Gene', '1956', (89, 93))
146775	32431498	PI3K/Akt/mTOR is down-regulated by phosphatase and tensin homolog (PTEN), which, in turn, is altered (deleted, inactivated, or mutated) in nearly 40-70% glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (153, 166))	('Akt', 'Gene', '207', (5, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('altered', 'Reg', (93, 100))	('glioblastomas', 'Disease', (153, 166))	('down-regulated', 'NegReg', (17, 31))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (9, 13))	('phosphatase and tensin homolog', 'Gene', '5728', (35, 65))	('PTEN', 'Gene', (67, 71))	('Akt', 'Gene', (5, 8))	('PTEN', 'Gene', '5728', (67, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (153, 166))	('mutated', 'Var', (127, 134))
146808	32431498	Thus, P-gp inhibition can be considered as a potential dual strategy, suitable both to enhance drug penetration in the brain, and to reduce glioma chemoresistance.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('P-gp', 'Gene', '5243', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('rat', 'Species', '10116', (105, 108))	('reduce', 'NegReg', (133, 139))	('enhance', 'PosReg', (87, 94))	('drug penetration in the brain', 'CPA', (95, 124))	('P-gp', 'Gene', (6, 10))	('inhibition', 'Var', (11, 21))	('glioma', 'Disease', (140, 146))	('rat', 'Species', '10116', (62, 65))
146850	32431498	Nanocarriers can also increase drug half-life (for EPR effect), and/or favour endocytosis across BBTB endothelial cells, also owing to P-gp inhibition.	('P-gp', 'Gene', (135, 139))	('BBTB', 'Chemical', '-', (97, 101))	('drug half-life', 'MPA', (31, 45))	('Nanocarriers', 'Var', (0, 12))	('favour', 'PosReg', (71, 77))	('increase', 'PosReg', (22, 30))	('endocytosis across BBTB endothelial cells', 'MPA', (78, 119))	('P-gp', 'Gene', '5243', (135, 139))	('inhibition', 'NegReg', (140, 150))
146869	32431498	Within this concern, it is reported that active targeting of nanocarriers should benefit from employment of a "spacer" between the nanoparticles' surface and the grafted protein, and that grafting a low amount of protein should enhance selectivity for the BBB rather than nontarget tissues.	('BBB', 'CPA', (256, 259))	('rat', 'Species', '10116', (260, 263))	('enhance', 'PosReg', (228, 235))	('selectivity', 'MPA', (236, 247))	('grafting', 'Var', (188, 196))
146872	32431498	Previously mentioned overexpression of EGFR and EGFRvIII mutant at the BBTB allows a selective targeting.	('EGFR', 'Gene', '1956', (48, 52))	('BBTB', 'Chemical', '-', (71, 75))	('EGFR', 'Gene', (48, 52))	('mutant', 'Var', (57, 63))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
146889	32431498	With genetic modification, MSC are able to home cancer tissues and affect the tumor growth by the secretion of cytotoxic molecules.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('affect', 'Reg', (67, 73))	('secretion of cytotoxic molecules', 'MPA', (98, 130))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', (78, 83))	('genetic modification', 'Var', (5, 25))
146895	32431498	Even though drug-loaded MSC are a promising strategy, some major issues should be considered, such as the fact that the conjugation of nanodrugs to MSC surface could affect the tumour homing ability, as demonstrated by a lot of studies carried out on brain tumour xenografts.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('brain tumour', 'Disease', (251, 263))	('tumour', 'Disease', (177, 183))	('rat', 'Species', '10116', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('conjugation', 'Var', (120, 131))	('brain tumour', 'Disease', 'MESH:D001932', (251, 263))	('affect', 'Reg', (166, 172))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('brain tumour', 'Phenotype', 'HP:0030692', (251, 263))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumour', 'Disease', (257, 263))	('rat', 'Species', '10116', (210, 213))
146908	32431498	These modified CAR T cells can produce the lysis of the cells presenting the associated tumor antigen when administered intravenously in patients.	('CAR', 'Gene', '9970', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (137, 145))	('modified', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('lysis', 'MPA', (43, 48))	('CAR', 'Gene', (15, 18))
146933	31428936	Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles.	('NSUN5', 'Gene', '55695', (41, 46))	('NSUN5', 'Gene', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Disease', (50, 56))	('targets', 'Reg', (57, 64))	('Tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Tumors', 'Phenotype', 'HP:0002664', (124, 130))	('proteomes', 'MPA', (145, 154))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('Epigenetic loss', 'Var', (0, 15))	('Tumors', 'Disease', (124, 130))	('Tumors', 'Disease', 'MESH:D009369', (124, 130))	('stress adaptive translational program', 'MPA', (86, 123))
146934	31428936	Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine.	('glioma', 'Disease', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('methyl', 'Chemical', 'MESH:C031105', (146, 152))	('human', 'Species', '9606', (21, 26))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('methyl', 'Chemical', 'MESH:C031105', (122, 128))	('epigenetic silencing', 'Var', (75, 95))	('NSUN5', 'Gene', (99, 104))	('methyl', 'Chemical', 'MESH:C031105', (52, 58))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (144, 160))
146936	31428936	We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress.	('methyl', 'Chemical', 'MESH:C031105', (45, 51))	('adaptive translational program', 'MPA', (185, 215))	('survival', 'CPA', (220, 228))	('NSUN5', 'Gene', (19, 24))	('depletion of protein synthesis', 'MPA', (120, 150))	('unmethylated', 'MPA', (43, 55))	('leads to', 'Reg', (156, 164))	('loss', 'NegReg', (25, 29))	('C3782', 'Var', (70, 75))
146937	31428936	Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('renders', 'Reg', (50, 57))	('epigenetic inactivation', 'Var', (21, 44))	('NSUN5', 'Gene', (15, 20))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('sensitive', 'MPA', (72, 81))
146938	31428936	Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.	('hallmark of glioma', 'Disease', (53, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('epigenetic inactivation', 'Var', (24, 47))	('hallmark of glioma', 'Disease', 'MESH:D005910', (53, 71))	('NSUN5', 'Gene', (18, 23))	('patients', 'Species', '9606', (72, 80))
146939	31428936	Much effort has been devoted to the study of how events leading to aberrant RNA transcription regulation generate cancer transcriptomes.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RNA transcription regulation', 'MPA', (76, 104))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('aberrant', 'Var', (67, 75))	('cancer', 'Disease', (114, 120))
146941	31428936	Aberrant translational control occurs during the origin, maintenance, and progression of tumoral cells.	('translational control', 'MPA', (9, 30))	('Aberrant', 'Var', (0, 8))	('tumoral', 'Disease', (89, 96))	('tumoral', 'Disease', 'MESH:D009369', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
146943	31428936	In this regard, mutations in ribosomal proteins such as RPS19, RPL5, RPS26, and RPL11 occur in Diamond-Blackfan anemia, a syndrome that it is characterized by increased susceptibility to cancer.	('ribosomal proteins', 'Protein', (29, 47))	('RPS26', 'Gene', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('anemia', 'Disease', (112, 118))	('RPL5', 'Gene', '6125', (63, 67))	('RPL11', 'Gene', '6135', (80, 85))	('anemia', 'Disease', 'MESH:D000740', (112, 118))	('mutations', 'Var', (16, 25))	('occur', 'Reg', (86, 91))	('RPL11', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('RPS26', 'Gene', '6231', (69, 74))	('anemia', 'Phenotype', 'HP:0001903', (112, 118))	('RPS19', 'Gene', '6223', (56, 61))	('RPL5', 'Gene', (63, 67))	('RPS19', 'Gene', (56, 61))
146947	31428936	Here, we show that NSUN5, acting as the RNA methyltransferase for the C3782 position of human 28S rRNA, is an enzyme with tumor-suppressor properties that undergoes epigenetic loss in gliomas, leading to an overall deficiency in protein synthesis and the initiation of a specific translational program for adaptation to cellular stress conditions.	('deficiency', 'NegReg', (215, 225))	('gliomas', 'Disease', 'MESH:D005910', (184, 191))	('protein synthesis', 'MPA', (229, 246))	('initiation', 'Reg', (255, 265))	('NSUN5', 'Gene', (19, 24))	('gliomas', 'Disease', (184, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('methyl', 'Chemical', 'MESH:C031105', (44, 50))	('epigenetic loss', 'Var', (165, 180))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', (122, 127))
146948	31428936	Most important, and as it also occurs with the isocitrate dehydrogenase (IDH1) mutations, the presence of NSUN5 DNA methylation-associated silencing in human gliomagenesis identifies patients with good clinical outcome, which is an exceptional feature of people affected by this tumor type.	('methylation-associated', 'Var', (116, 138))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('people', 'Species', '9606', (255, 261))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('IDH1', 'Gene', '3417', (73, 77))	('silencing', 'NegReg', (139, 148))	('gliomagenesis', 'Disease', (158, 171))	('tumor', 'Disease', (279, 284))	('isocitrate', 'Chemical', 'MESH:D007523', (47, 57))	('methyl', 'Chemical', 'MESH:C031105', (116, 122))	('human', 'Species', '9606', (152, 157))	('NSUN5 DNA methylation-associated', 'Var', (106, 138))	('patients', 'Species', '9606', (183, 191))	('IDH1', 'Gene', (73, 77))	('gliomagenesis', 'Disease', 'None', (158, 171))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (79, 88))
146978	31428936	For tumor growth into the brain, 3 x 105 or 1.5 x 106 cells, respectively, for LN229 (EV or NSUN5) and DBTRG-05MG (scramble or shNSUN5) were inoculated into the corpus striatum of 9 (scramble and shNSUN5) or 10 (EV and NSUN5) mice for each cell line individually.	('tumor', 'Disease', (4, 9))	('LN229', 'CellLine', 'CVCL:0393', (79, 84))	('mice', 'Species', '10090', (226, 230))	('LN229', 'Var', (79, 84))	('DBTRG-05MG', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
146997	31428936	The expanded glioma validation cohort included 303 additional glioma patients from which NSUN5 methylation, IDH1 mutation, co-deletion of 1p19q, MGMT methylation, and progression-free survival are available.	('glioma', 'Disease', (62, 68))	('mutation', 'Var', (113, 121))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('IDH1', 'Gene', '3417', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('NSUN5', 'Gene', (89, 94))	('1p19q', 'Var', (138, 143))	('methyl', 'Chemical', 'MESH:C031105', (150, 156))	('MGMT', 'Gene', '4255', (145, 149))	('MGMT', 'Gene', (145, 149))	('co-deletion', 'Var', (123, 134))	('methyl', 'Chemical', 'MESH:C031105', (95, 101))	('patients', 'Species', '9606', (69, 77))	('glioma', 'Disease', (13, 19))	('IDH1', 'Gene', (108, 112))
147001	31428936	The available genomic data did not indicate the presence of NSUN5, NSUN1, or NSUN4 mutations, amplifications, or deletions in the cell lines considered (Suppl.	('NSUN4', 'Gene', (77, 82))	('deletions', 'Var', (113, 122))	('NSUN1', 'Gene', (67, 72))	('NSUN4', 'Gene', '387338', (77, 82))	('NSUN1', 'Gene', '4839', (67, 72))	('NSUN5', 'Gene', (60, 65))
147002	31428936	Although genetic defects in the described genes were not found, transcriptional silencing by promoter CpG island hypermethylation is another mechanism for inactivating genes in human cancer.	('cancer', 'Disease', (183, 189))	('methyl', 'Chemical', 'MESH:C031105', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('hypermethylation', 'Var', (113, 129))	('human', 'Species', '9606', (177, 182))	('inactivating', 'NegReg', (155, 167))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
147005	31428936	Data-mining of microarray expression results showed that NSUN5 hypermethylation was associated with transcript downregulation in the glioma cell lines (Fig.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('hypermethylation', 'Var', (63, 79))	('NSUN5', 'Gene', (57, 62))	('glioma', 'Disease', (133, 139))	('downregulation', 'NegReg', (111, 125))	('transcript', 'MPA', (100, 110))	('methyl', 'Chemical', 'MESH:C031105', (68, 74))
147010	31428936	We found the 5'-end region of NSUN5 of the LN229, A172, and KS-1 glioma cell lines to be hypermethylated in comparison with normal brain white matter (Fig.	('methyl', 'Chemical', 'MESH:C031105', (94, 100))	('KS-1 glioma', 'Disease', (60, 71))	('hypermethylated', 'Var', (89, 104))	('KS-1 glioma', 'Disease', 'MESH:D005910', (60, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('LN229', 'CellLine', 'CVCL:0393', (43, 48))	('NSUN5', 'Gene', (30, 35))
147013	31428936	Normal astrocytes, fetal brain, and different brain regions (such as frontal cortex, posterior cingulate cortex, and hippocampus) were unmethylated for NSUN5 in all cases (Dataset 1e).	('unmethylated', 'Var', (135, 147))	('methyl', 'Chemical', 'MESH:C031105', (137, 143))	('NSUN5', 'Gene', (152, 157))
147016	31428936	Conversely, the glioma cell lines unmethylated at the NSUN5 promoter (DBTRG-05MG, CAS-1, and MO59J) expressed NSUN5 RNA and protein (Fig.	('CAS-1', 'Gene', (82, 87))	('NSUN5 RNA', 'Var', (110, 119))	('CAS-1', 'Gene', '9564', (82, 87))	('glioma', 'Disease', (16, 22))	('methyl', 'Chemical', 'MESH:C031105', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (16, 22))
147019	31428936	We extend the study to three grade III glioma cell lines: BT142 mut/-, harboring a homozygous R132H mutation, and SW1088 and MOG-G-CCM, wild type for IDH1.	('MOG', 'Gene', (125, 128))	('SW1088', 'CellLine', 'CVCL:1715', (114, 120))	('glioma', 'Disease', (39, 45))	('R132H', 'Var', (94, 99))	('R132H', 'Mutation', 'rs121913500', (94, 99))	('IDH1', 'Gene', (150, 154))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('IDH1', 'Gene', '3417', (150, 154))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('MOG', 'Gene', '4340', (125, 128))
147020	31428936	We found DNA methylation-associated silencing of NSUN5 in BT142 mut/- cells, whereas the two remaining cell lines (SW1088 and MOG-G-CCM) were unmethylated and expressed NSUN5 (Suppl.	('NSUN5', 'Gene', (49, 54))	('methylation-associated', 'Var', (13, 35))	('MOG', 'Gene', '4340', (126, 129))	('silencing', 'NegReg', (36, 45))	('MOG', 'Gene', (126, 129))	('SW1088', 'CellLine', 'CVCL:1715', (115, 121))	('methyl', 'Chemical', 'MESH:C031105', (13, 19))	('methyl', 'Chemical', 'MESH:C031105', (144, 150))
147022	31428936	The study of 16 patient-derived xenograft (PDX) from primary gliomas engrafted in nude mice showed that NSUN5 was hypermethylated in three cases (19%).	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('NSUN5', 'Gene', (104, 109))	('nude mice', 'Species', '10090', (82, 91))	('gliomas', 'Disease', (61, 68))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('PDX', 'Chemical', 'MESH:C113421', (43, 46))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('methyl', 'Chemical', 'MESH:C031105', (119, 125))	('hypermethylated', 'Var', (114, 129))	('patient', 'Species', '9606', (16, 23))
147023	31428936	RNA was available for four cases (two unmethylated and two methylated) and NSUN5 hypermethylation was associated with diminished transcript levels (Suppl.	('methyl', 'Chemical', 'MESH:C031105', (59, 65))	('methyl', 'Chemical', 'MESH:C031105', (86, 92))	('transcript levels', 'MPA', (129, 146))	('NSUN5', 'Gene', (75, 80))	('methyl', 'Chemical', 'MESH:C031105', (40, 46))	('hypermethylation', 'Var', (81, 97))	('diminished', 'NegReg', (118, 128))
147024	31428936	Overall, these results indicate that cancer-specific promoter CpG island hypermethylation-associated silencing of the NSUN5 gene occurs in glioma cells.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('hypermethylation-associated', 'Var', (73, 100))	('silencing', 'NegReg', (101, 110))	('glioma', 'Disease', (139, 145))	('cancer', 'Disease', (37, 43))	('NSUN5', 'Gene', (118, 123))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('methyl', 'Chemical', 'MESH:C031105', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))
147025	31428936	Once we had demonstrated the existence of NSUN5 CpG island hypermethylation-associated transcriptional loss in glioma cell lines, we studied its contribution to the growth of these cells.	('NSUN5', 'Gene', (42, 47))	('glioma', 'Disease', (111, 117))	('transcriptional', 'MPA', (87, 102))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('methyl', 'Chemical', 'MESH:C031105', (64, 70))	('loss', 'NegReg', (103, 107))	('hypermethylation-associated', 'Var', (59, 86))
147034	31428936	NSUN5 restoration by transfection in hypermethylated glioblastoma cells also diminished proliferation in vitro (Suppl.	('diminished', 'NegReg', (77, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('transfection', 'Var', (21, 33))	('NSUN5 restoration', 'Gene', (0, 17))	('proliferation in vitro', 'CPA', (88, 110))	('hypermethylated glioblastoma', 'Disease', 'MESH:D005909', (37, 65))	('hypermethylated glioblastoma', 'Disease', (37, 65))
147039	31428936	The activity and targets of NSUN5 in human cells have not been formally identified, but the yeast S. cerevisiae (Rcm1) and worm C. elegans (nsun-5) homologues are responsible for methylating C2278 in the 25S rRNA and C2381 in the 26S rRNA, respectively.	('yeast', 'Species', '4932', (92, 97))	('C2278', 'Var', (191, 196))	('Rcm1', 'Gene', '855709', (113, 117))	('methyl', 'Chemical', 'MESH:C031105', (179, 185))	('C2381', 'Chemical', 'MESH:C120878', (217, 222))	('nsun-5', 'Gene', (140, 146))	('C2381', 'Var', (217, 222))	('C. elegans', 'Species', '6239', (128, 138))	('Rcm1', 'Gene', (113, 117))	('nsun-5', 'Gene', '175153', (140, 146))	('human', 'Species', '9606', (37, 42))	('methylating', 'MPA', (179, 190))	('S. cerevisiae', 'Species', '4932', (98, 111))
147040	31428936	Phylogenetic analyses show that the C2278 and C2381 positions in the yeast and worm 25S and 26S rRNAs, respectively, correspond to the C3782 position of the human 28S rRNA (Fig.	('C2278', 'Var', (36, 41))	('C3782', 'Var', (135, 140))	('yeast', 'Species', '4932', (69, 74))	('C2381', 'Chemical', 'MESH:C120878', (46, 51))	('C2381', 'Var', (46, 51))	('human', 'Species', '9606', (157, 162))
147041	31428936	Thus, we set out to demonstrate that NSUN5 is responsible for methylating C3782 28S rRNA in our glioma models.	('28S rRNA', 'Protein', (80, 88))	('C3782', 'Var', (74, 79))	('methylating', 'Var', (62, 73))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('methyl', 'Chemical', 'MESH:C031105', (62, 68))	('glioma', 'Disease', (96, 102))
147043	31428936	We observed that while the NSUN5-expressing DBTRG-05MG, MO59J, and CAS-1 cells showed high levels of C3782 28S rRNA methylation, the LN229, A172, and KS-1 cells undergoing NSUN5 epigenetic inactivation displayed a lack of C3782 28S rRNA methylation (Fig.	('methyl', 'Chemical', 'MESH:C031105', (237, 243))	('C3782', 'Var', (101, 106))	('CAS-1', 'Gene', '9564', (67, 72))	('epigenetic inactivation', 'Var', (178, 201))	('KS-1', 'Gene', '84911', (150, 154))	('C3782 28S', 'Var', (222, 231))	('methyl', 'Chemical', 'MESH:C031105', (116, 122))	('LN229', 'CellLine', 'CVCL:0393', (133, 138))	('lack', 'NegReg', (214, 218))	('KS-1', 'Gene', (150, 154))	('CAS-1', 'Gene', (67, 72))
147046	31428936	The LN229 and A172 cells, showing NSUN5 epigenetic silencing, also recovered C3782 28S rRNA methylation upon restoration of NSUN5 activity by transfection (Fig.	('C3782', 'Var', (77, 82))	('methyl', 'Chemical', 'MESH:C031105', (92, 98))	('recovered', 'PosReg', (67, 76))	('epigenetic silencing', 'Var', (40, 60))	('NSUN5', 'Gene', (34, 39))	('LN229', 'CellLine', 'CVCL:0393', (4, 9))
147049	31428936	Methods) confirmed the RNA bisulfite sequencing data for C3782 28S rRNA methylation (Suppl.	('C3782', 'Var', (57, 62))	('28S rRNA methylation', 'MPA', (63, 83))	('methyl', 'Chemical', 'MESH:C031105', (72, 78))	('bisulfite', 'Chemical', 'MESH:C042345', (27, 36))
147050	31428936	LN229 cells with NSUN5 epigenetic loss were depleted for C3782 28S rRNA methylation in both nuclear and cytoplasmic fraction, whereas NSUN5 transfection restored the methylation status at both compartments (Suppl.	('NSUN5', 'Gene', (17, 22))	('LN229', 'CellLine', 'CVCL:0393', (0, 5))	('methyl', 'Chemical', 'MESH:C031105', (72, 78))	('epigenetic loss', 'Var', (23, 38))	('methyl', 'Chemical', 'MESH:C031105', (166, 172))	('C3782 28S', 'Var', (57, 66))
147051	31428936	To demonstrate the specificity of our experimental approach, we showed that the transfection of NSUN5 in LN229 and A172 cells did not change the levels of the other two candidate human ribosome RNA methyltransferases, NSUN1 and NSUN4 (Suppl.	('NSUN5', 'Gene', (96, 101))	('human', 'Species', '9606', (179, 184))	('NSUN4', 'Gene', '387338', (228, 233))	('methyl', 'Chemical', 'MESH:C031105', (198, 204))	('NSUN1', 'Gene', '4839', (218, 223))	('NSUN1', 'Gene', (218, 223))	('LN229', 'CellLine', 'CVCL:0393', (105, 110))	('transfection', 'Var', (80, 92))	('NSUN4', 'Gene', (228, 233))
147054	31428936	Upon effective NSUN5 shRNA-mediated downregulation, we observed hypomethylation at the C3782 28S rRNA site in DBTRG-05MG and CAS-1 cells (Fig.	('downregulation', 'NegReg', (36, 50))	('hypomethylation', 'MPA', (64, 79))	('methyl', 'Chemical', 'MESH:C031105', (68, 74))	('CAS-1', 'Gene', (125, 130))	('CAS-1', 'Gene', '9564', (125, 130))	('C3782', 'Var', (87, 92))
147055	31428936	The link between NSUN5 epigenetic silencing and C3782 28S rRNA hypomethylation was also observed in the grade III glioma cell lines: BT142 mut/- cells, harboring DNA methylation-associated silencing of NSUN5, showed an unmethylated C3782 28S site, whereas SW1088 and MOG-G-CCM (both unmethylated and expressing NSUN5) showed a methylated C3782 28S rRNA position (Suppl.	('silencing', 'Var', (189, 198))	('methyl', 'Chemical', 'MESH:C031105', (285, 291))	('NSUN5', 'Gene', (202, 207))	('C3782', 'Var', (338, 343))	('MOG', 'Gene', '4340', (267, 270))	('glioma', 'Disease', (114, 120))	('MOG', 'Gene', (267, 270))	('methyl', 'Chemical', 'MESH:C031105', (327, 333))	('methyl', 'Chemical', 'MESH:C031105', (166, 172))	('methyl', 'Chemical', 'MESH:C031105', (67, 73))	('methyl', 'Chemical', 'MESH:C031105', (221, 227))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('methylation-associated', 'Var', (166, 188))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('SW1088', 'CellLine', 'CVCL:1715', (256, 262))
147056	31428936	To map NSUN5-dependent modified cytosine sites across the human transcriptome, we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) in NSUN5-transfected LN229 glioma cells and empty-vector-transfected cells.	('cytosine', 'Chemical', 'MESH:D003596', (32, 40))	('human', 'Species', '9606', (58, 63))	('glioma', 'Disease', (198, 204))	('NSUN5-transfected', 'Var', (174, 191))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('bisulfite', 'Chemical', 'MESH:C042345', (90, 99))	('LN229', 'CellLine', 'CVCL:0393', (192, 197))
147057	31428936	Upon efficient restoration of NSUN5 expression, we observed that the only cytosine site in RNA that reached methylation levels of over 90% following NSUN5 transfection was the C3782 position of the 28S rRNA (empirical Bayes moderated t test, P = 0.033).	('methyl', 'Chemical', 'MESH:C031105', (108, 114))	('cytosine', 'Chemical', 'MESH:D003596', (74, 82))	('NSUN5', 'Gene', (149, 154))	('methylation', 'MPA', (108, 119))	('transfection', 'Var', (155, 167))	('C3782', 'Var', (176, 181))
147058	31428936	Interestingly, the specificity of the approach was further confirmed by identifying that the only other methylated cytosine in 28S rRNA, the C4447 position corresponding to the C4099 position in mouse 28S rRNA and suggested to be mediated by the other RNA-methyltransferase NSUN1, was fully methylated in both empty-vector and NSUN5-transfected cells (Suppl.	('methyl', 'Chemical', 'MESH:C031105', (104, 110))	('C4099', 'Chemical', 'MESH:C074371', (177, 182))	('NSUN1', 'Gene', (274, 279))	('methyl', 'Chemical', 'MESH:C031105', (291, 297))	('methyl', 'Chemical', 'MESH:C031105', (256, 262))	('NSUN1', 'Gene', '4839', (274, 279))	('C4447', 'Var', (141, 146))	('C4099', 'Var', (177, 182))	('mouse', 'Species', '10090', (195, 200))	('cytosine', 'Chemical', 'MESH:D003596', (115, 123))
147059	31428936	Thus, all these results indicate that NSUN5 is the human C3782 28S rRNA methyltransferase and that epigenetic silencing of NSUN5 in glioma cells prevents the formation of this chemical modification in the rRNA transcript considered here.	('chemical modification', 'MPA', (176, 197))	('glioma', 'Disease', (132, 138))	('methyl', 'Chemical', 'MESH:C031105', (72, 78))	('formation', 'MPA', (158, 167))	('human', 'Species', '9606', (51, 56))	('rRNA transcript', 'MPA', (205, 220))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('epigenetic silencing', 'Var', (99, 119))	('NSUN5', 'Gene', (123, 128))	('prevents', 'NegReg', (145, 153))
147061	31428936	The simulation of the system with methylated C3782 (labelled r30A5mC) showed a stable methyl-pi interaction between methylated C3782 and C3781 (Fig.	('methyl-pi interaction', 'MPA', (86, 107))	('methyl', 'Chemical', 'MESH:C031105', (86, 92))	('methyl', 'Chemical', 'MESH:C031105', (116, 122))	('methylated C3782', 'Var', (116, 132))	('C3781', 'Chemical', 'MESH:C000591018', (137, 142))	('C3782', 'Var', (127, 132))	('methyl', 'Chemical', 'MESH:C031105', (34, 40))	('C3781', 'Var', (137, 142))
147063	31428936	The removal of the methyl group altered significantly the C3781-G3810 base pair and the conformation of the bulge at position C3809 (Fig.	('altered', 'Reg', (32, 39))	('methyl', 'Chemical', 'MESH:C031105', (19, 25))	('C3781', 'Chemical', 'MESH:C000591018', (58, 63))	('conformation', 'MPA', (88, 100))	('C3781-G3810', 'Var', (58, 69))
147065	31428936	The distortion on the hairpin observed in the simulation upon the removal of the methyl group (r30AC system) might be sufficient to impair normal protein synthesis by altering the P-site conformation.	('distortion', 'Var', (4, 14))	('altering', 'Reg', (167, 175))	('P-site conformation', 'MPA', (180, 199))	('impair', 'NegReg', (132, 138))	('methyl', 'Chemical', 'MESH:C031105', (81, 87))	('normal protein synthesis', 'MPA', (139, 163))
147070	31428936	Thus, we wondered whether the loss of the methylated site in the 28S rRNA mediated by NSUN5 epigenetic inactivation in glioma cells could act in this manner.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('NSUN5', 'Gene', (86, 91))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glioma', 'Disease', (119, 125))	('methyl', 'Chemical', 'MESH:C031105', (42, 48))	('epigenetic inactivation', 'Var', (92, 115))
147072	31428936	Using H2O2 in the medium to produce oxidative stress, we found that the three glioblastoma cell lines harboring NSUN5 epigenetic loss (LN229, A172, and KS1) show overall lower global protein synthesis than the three NSUN5 unmethylated cell lines (DBTRG-05MG, MO59 J and CAS-1) (Fig.	('KS1', 'Gene', (152, 155))	('glioblastoma', 'Disease', (78, 90))	('CAS-1', 'Gene', (270, 275))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('methyl', 'Chemical', 'MESH:C031105', (224, 230))	('CAS-1', 'Gene', '9564', (270, 275))	('LN229', 'CellLine', 'CVCL:0393', (135, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('H2O2', 'Chemical', 'MESH:D014867', (6, 10))	('NSUN5', 'Gene', (112, 117))	('global protein synthesis', 'MPA', (176, 200))	('lower', 'NegReg', (170, 175))	('KS1', 'Gene', '84911', (152, 155))	('epigenetic loss', 'Var', (118, 133))	('oxidative stress', 'Phenotype', 'HP:0025464', (36, 52))
147074	31428936	Upon another stress condition, nutrient deprivation, the NSUN5 epigenetically deficient LN229 cells transfected with the empty vector also showed low overall level of protein synthesis, whereas the transfection-mediated recovery of NSUN5 expression significantly increased global protein synthesis (Fig.	('low', 'NegReg', (146, 149))	('global protein synthesis', 'MPA', (273, 297))	('level', 'MPA', (158, 163))	('NSUN5', 'Gene', (232, 237))	('increased', 'PosReg', (263, 272))	('NSUN5', 'Gene', (57, 62))	('protein synthesis', 'MPA', (167, 184))	('LN229', 'CellLine', 'CVCL:0393', (88, 93))	('epigenetically', 'Var', (63, 77))	('expression', 'MPA', (238, 248))
147075	31428936	Similar results were obtained using [3H] leucine incorporation to measure global protein synthesis: the restoration of NSUN5 activity in the epigenetically inactivated LN229 cell significantly enhanced [3H] leucine incorporation and, thereby, global protein synthesis (Fig.	('global protein synthesis', 'MPA', (243, 267))	('LN229', 'CellLine', 'CVCL:0393', (168, 173))	('restoration', 'Var', (104, 115))	('[3H] leucine', 'Chemical', 'MESH:C048031', (36, 48))	('activity', 'MPA', (125, 133))	('[3H] leucine incorporation', 'MPA', (202, 228))	('enhanced', 'PosReg', (193, 201))	('NSUN5', 'Gene', (119, 124))	('[3H] leucine', 'Chemical', 'MESH:C048031', (202, 214))
147077	31428936	Overall, the results indicate that the transcriptional inactivation of NSUN5 by promoter CpG island and the mediated loss of methylated C3782 in 28S rRNA were associated with a restriction of overall protein synthesis.	('overall protein synthesis', 'MPA', (192, 217))	('loss', 'NegReg', (117, 121))	('inactivation', 'NegReg', (55, 67))	('methylated C3782', 'Var', (125, 141))	('restriction', 'NegReg', (177, 188))	('NSUN5', 'Gene', (71, 76))	('C3782', 'Var', (136, 141))	('methyl', 'Chemical', 'MESH:C031105', (125, 131))
147079	31428936	To identify the existence of a candidate translational program that directly depends on the loss of C3782 28S rRNA methylation upon NSUN5 epigenetic inactivation, we performed both RNA-Seq and Ribo-seq analyses comparing empty-vector and NSUN5-transfected LN229 cells in the absence of H2O2 stress.	('methyl', 'Chemical', 'MESH:C031105', (115, 121))	('NSUN5', 'Gene', (132, 137))	('loss', 'NegReg', (92, 96))	('epigenetic inactivation', 'Var', (138, 161))	('H2O2', 'Chemical', 'MESH:D014867', (286, 290))	('C3782', 'Gene', (100, 105))	('LN229', 'CellLine', 'CVCL:0393', (256, 261))
147081	31428936	We identified 1987 transcripts with greater translation efficiency in the LN229 empty-vector-transfected cells (harboring NSUN5 epigenetic silencing) in comparison with NSUN5-transfected cells (Fig.	('epigenetic silencing', 'Var', (128, 148))	('LN229', 'CellLine', 'CVCL:0393', (74, 79))	('translation efficiency', 'MPA', (44, 66))	('greater', 'PosReg', (36, 43))	('LN229', 'Gene', (74, 79))
147084	31428936	To confirm this scenario, in which NSUN5 epigenetic silencing promotes a global reduction in protein synthesis, but a specific protein production program emerges that is associated with enhanced translational efficiency to deal with cellular stress, we carried out stable isotopic labeling of amino acids in cell culture (SILAC) in empty-vector-transfected LN229 cells in comparison with NSUN5 stably transfected LN229 cells.	('amino', 'Chemical', 'MESH:D000596', (293, 298))	('LN229', 'CellLine', 'CVCL:0393', (357, 362))	('NSUN5', 'Gene', (35, 40))	('reduction', 'NegReg', (80, 89))	('epigenetic silencing', 'Var', (41, 61))	('LN229', 'CellLine', 'CVCL:0393', (413, 418))	('protein synthesis', 'MPA', (93, 110))
147085	31428936	At the level of resolution employed in the SILAC analyses, 128 proteins were identified that had significantly different expression upon NSUN5 transfection in LN229 cells (Suppl.	('transfection', 'Var', (143, 155))	('expression', 'MPA', (121, 131))	('LN229', 'CellLine', 'CVCL:0393', (159, 164))	('different', 'Reg', (111, 120))	('NSUN5', 'Gene', (137, 142))
147086	31428936	Thus, these data are consistent with the idea that the loss of NSUN5 in glioma cells restricts general protein synthesis.	('glioma', 'Disease', (72, 78))	('restricts', 'NegReg', (85, 94))	('loss', 'Var', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('general protein synthesis', 'MPA', (95, 120))	('NSUN5', 'Gene', (63, 68))
147089	31428936	Further development of additional RNA-seq experiments comparing empty-vector and NSUN5-transfected LN229 cells, but in the presence of H2O2 stress, confirmed that NSUN5 transfection had almost no effect in the transcriptome, remaining 99.5% of the transcripts unchanged (Suppl.	('transfection', 'Var', (169, 181))	('transcripts', 'MPA', (248, 259))	('transcriptome', 'MPA', (210, 223))	('H2O2', 'Chemical', 'MESH:D014867', (135, 139))	('NSUN5 transfection', 'Var', (163, 181))	('LN229', 'CellLine', 'CVCL:0393', (99, 104))
147090	31428936	Ribo-seq analysis in these cells, undergoing H2O2 stress, further confirmed that NQO1 showed greater translation efficiency in the LN229 empty-vector-transfected cells (having NSUN5 epigenetic loss) in comparison with NSUN5-transfected cells (Suppl.	('greater', 'PosReg', (93, 100))	('NQO1', 'Gene', (81, 85))	('epigenetic loss', 'Var', (182, 197))	('H2O2', 'Chemical', 'MESH:D014867', (45, 49))	('LN229', 'CellLine', 'CVCL:0393', (131, 136))	('translation efficiency', 'MPA', (101, 123))
147091	31428936	We also performed RNA-seq in the absence of H2O2 in another glioblastoma cell line, A172, that it also shows NSUN5 epigenetic inactivation obtaining near identical results: 99% of transcripts levels were unchanged upon NSUN5 transfection, including NQO1 (Suppl.	('glioblastoma', 'Disease', (60, 72))	('epigenetic', 'Var', (115, 125))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('H2O2', 'Chemical', 'MESH:D014867', (44, 48))	('transcripts levels', 'MPA', (180, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('transfection', 'Var', (225, 237))
147095	31428936	6a) in LN229 cells with NSUN5 epigenetic loss, was also identified as a target of enhanced translational efficiency in DBTRG-05MG cells with shRNA-mediated depletion of NSUN5 (Suppl.	('enhanced', 'PosReg', (82, 90))	('LN229', 'CellLine', 'CVCL:0393', (7, 12))	('epigenetic loss', 'Var', (30, 45))	('NSUN5', 'Gene', (169, 174))	('translational efficiency', 'MPA', (91, 115))	('NSUN5', 'Gene', (24, 29))	('depletion', 'Var', (156, 165))
147096	31428936	Altogether, these data are consistent with the idea that the loss of NSUN5 in glioma cells restricts general protein synthesis while activating the selective synthesis of specific stress-related proteins such as NQO1.	('restricts', 'NegReg', (91, 100))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('activating', 'PosReg', (133, 143))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('general protein synthesis', 'MPA', (101, 126))	('selective synthesis', 'MPA', (148, 167))	('glioma', 'Disease', (78, 84))	('loss', 'Var', (61, 65))	('NSUN5', 'Gene', (69, 74))
147097	31428936	The finding that NSUN5 epigenetic silencing was associated with NQO1 overexpression prompted us to study whether these glioma cells might be more vulnerable to compounds targeting this particular stress-related protein.	('overexpression', 'PosReg', (69, 83))	('NSUN5', 'Gene', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('associated', 'Reg', (48, 58))	('NQO1', 'Gene', (64, 68))	('glioma', 'Disease', (119, 125))	('epigenetic silencing', 'Var', (23, 43))
147101	31428936	First, we demonstrated by western-blot analyses that the three studied glioma cell lines with NSUN5 hypermethylation (LN229, A172, and KS-1) showed high levels of NQO1, whereas minimal expression of NQO1 was observed in the three NSUN5 unmethylated cell lines (DBTRG-05MG, MO59 J, and CAS-1) (Fig.	('KS-1', 'Gene', '84911', (135, 139))	('hypermethylation', 'Var', (100, 116))	('KS-1', 'Gene', (135, 139))	('methyl', 'Chemical', 'MESH:C031105', (238, 244))	('glioma', 'Disease', (71, 77))	('NQO1', 'MPA', (163, 167))	('LN229', 'CellLine', 'CVCL:0393', (118, 123))	('methyl', 'Chemical', 'MESH:C031105', (105, 111))	('CAS-1', 'Gene', (285, 290))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('CAS-1', 'Gene', '9564', (285, 290))	('NSUN5', 'Var', (94, 99))
147102	31428936	Most importantly, the determination of the corresponding IC50 values, according to the SRB assay for cell viability, showed that NSUN5 hypermethylated glioma cells were significantly more sensitive to the DNQ and IB-DNQ drugs than the NSUN5 unmethylated glioma cell lines (z test, P < 0.0001) (Fig.	('hypermethylated', 'Var', (135, 150))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('sensitive', 'MPA', (188, 197))	('methyl', 'Chemical', 'MESH:C031105', (140, 146))	('glioma', 'Disease', (254, 260))	('more', 'PosReg', (183, 187))	('methyl', 'Chemical', 'MESH:C031105', (243, 249))	('glioma', 'Disease', (151, 157))
147105	31428936	The use of the NQO1 bioactivatable substrate increased survival in those nude mice with tumors originated from NSUN5 hypermethylated A127 glioma cells in comparison with the mock-treated group (Fig.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('glioma', 'Disease', (138, 144))	('increased', 'PosReg', (45, 54))	('survival', 'CPA', (55, 63))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('methyl', 'Chemical', 'MESH:C031105', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hypermethylated', 'Var', (117, 132))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('nude mice', 'Species', '10090', (73, 82))	('NSUN5', 'Var', (111, 116))
147107	31428936	Thus, the occurrence of NSUN5 methylation pinpoints glioma cells that are more sensitive to the cytotoxic effect of NQO1 substrates.	('methylation', 'Var', (30, 41))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('methyl', 'Chemical', 'MESH:C031105', (30, 36))	('occurrence', 'Reg', (10, 20))	('glioma', 'Disease', (52, 58))	('NSUN5', 'Gene', (24, 29))
147108	31428936	Once we had determined in glioma cell lines and mouse models the effects of NSUN5 epigenetic silencing, we studied the impact of NSUN5 promoter CpG island hypermethylation in human primary gliomas.	('human', 'Species', '9606', (175, 180))	('glioma', 'Disease', (189, 195))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('mouse', 'Species', '10090', (48, 53))	('NSUN5', 'Gene', (76, 81))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('methyl', 'Chemical', 'MESH:C031105', (160, 166))	('glioma', 'Disease', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (189, 195))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('gliomas', 'Disease', (189, 196))	('epigenetic silencing', 'Var', (82, 102))
147109	31428936	The analyses of the collection of human gliomas available from The Cancer Genome Atlas (TCGA) (https://tcga-data.nci.nih.gov/tcga/), which used the same DNA methylation microarray platform as that used here for our initial Sanger cell line screening, showed the presence of NSUN5 promoter CpG island methylation in 28% (190 of 681) of gliomas of different grades (Fig.	('human', 'Species', '9606', (34, 39))	('glioma', 'Phenotype', 'HP:0009733', (335, 341))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('methyl', 'Chemical', 'MESH:C031105', (300, 306))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Disease', 'MESH:D005910', (335, 342))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('gliomas', 'Phenotype', 'HP:0009733', (335, 342))	('gliomas', 'Disease', (335, 342))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('methylation', 'Var', (300, 311))	('methyl', 'Chemical', 'MESH:C031105', (157, 163))
147110	31428936	TCGA RNA-sequencing data showed that NSUN5 hypermethylation was associated with transcript downregulation across glioma samples (Spearman's rank correlation, rho = - 0.7, P < 10-5) (Fig.	('downregulation', 'NegReg', (91, 105))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('P < 10-5', 'Gene', (171, 179))	('P < 10-5', 'Gene', '4790', (171, 179))	('NSUN5', 'Gene', (37, 42))	('glioma', 'Disease', (113, 119))	('hypermethylation', 'Var', (43, 59))	('methyl', 'Chemical', 'MESH:C031105', (48, 54))	('transcript', 'MPA', (80, 90))
147113	31428936	We observed the enrichment of NSUN5 hypermethylation in low-grade gliomas (34%, 180 of 527) relative to GBM (6%, 10 of 154) (Fisher's exact test, P = 3.8 10-9) (Fig.	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('hypermethylation', 'Var', (36, 52))	('NSUN5', 'Gene', (30, 35))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('methyl', 'Chemical', 'MESH:C031105', (41, 47))
147114	31428936	TCGA RNA-sequencing data showed NSUN5 hypermethylation to be associated with transcriptional downregulation in low- and high-grade gliomas (Fig.	('hypermethylation', 'Var', (38, 54))	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('transcriptional', 'MPA', (77, 92))	('NSUN5', 'Gene', (32, 37))	('methyl', 'Chemical', 'MESH:C031105', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('downregulation', 'NegReg', (93, 107))
147115	31428936	Beyond adult gliomas, we also detected NSUN5 hypermethylation in pediatric brain tumors, such as diffuse intrinsic pontine glioma (DIPG) (50%, 5 of 10) and medulloblastoma (25%, 2 of 8).	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('brain tumors', 'Disease', 'MESH:D001932', (75, 87))	('brain tumors', 'Phenotype', 'HP:0030692', (75, 87))	('NSUN5', 'Gene', (39, 44))	('glioma', 'Disease', (123, 129))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('brain tumors', 'Disease', (75, 87))	('medulloblastoma', 'Disease', 'MESH:D008527', (156, 171))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('medulloblastoma', 'Phenotype', 'HP:0002885', (156, 171))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('hypermethylation', 'Var', (45, 61))	('medulloblastoma', 'Disease', (156, 171))	('methyl', 'Chemical', 'MESH:C031105', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('gliomas', 'Disease', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('glioma', 'Disease', (13, 19))
147116	31428936	Importantly, we were able to obtain RNA from three DIPG tumors, where we observed that the two NSUN5 hypermethylated cases showed hypomethylation of the C3782 position of the 28S rRNA, while the NSUN5 unmethylated patient displayed high levels of rRNA methylation at this site (Suppl.	('patient', 'Species', '9606', (214, 221))	('hypomethylation', 'MPA', (130, 145))	('rRNA methylation', 'MPA', (247, 263))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('C3782', 'Var', (153, 158))	('28S rRNA', 'Protein', (175, 183))	('tumors', 'Disease', (56, 62))	('methyl', 'Chemical', 'MESH:C031105', (252, 258))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('methyl', 'Chemical', 'MESH:C031105', (134, 140))	('methyl', 'Chemical', 'MESH:C031105', (203, 209))	('methyl', 'Chemical', 'MESH:C031105', (106, 112))
147117	31428936	Given the known relation between glioma grade and clinical outcome, we wondered whether NSUN5 hypermethylation also conferred any prognostic value.	('glioma', 'Disease', (33, 39))	('hypermethylation', 'Var', (94, 110))	('NSUN5', 'Gene', (88, 93))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('methyl', 'Chemical', 'MESH:C031105', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
147118	31428936	We observed that NSUN5 hypermethylation was associated with increased overall survival (OS) in all glioma grades in the TCGA cohort [log-rank; P < 10-5; hazard ratio (HR) = 5.17, 95% CI = 2.78-9.61] (Fig.	('NSUN5', 'Gene', (17, 22))	('methyl', 'Chemical', 'MESH:C031105', (28, 34))	('overall survival', 'MPA', (70, 86))	('P < 10-5', 'Gene', (143, 151))	('P < 10-5', 'Gene', '4790', (143, 151))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('glioma', 'Disease', (99, 105))	('hypermethylation', 'Var', (23, 39))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('increased', 'PosReg', (60, 69))
147119	31428936	Interestingly, the value of NSUN5 hypermethylation as a predictor of better outcome was observed for low- and high-grade gliomas (Fig.	('NSUN5', 'Gene', (28, 33))	('hypermethylation', 'Var', (34, 50))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('methyl', 'Chemical', 'MESH:C031105', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))
147120	31428936	NSUN5 hypermethylation was associated with higher OS in LGG (log-rank; P = 0.044; HR = 2.05; 95% CI = 1.01-4.18) and GBM (log-rank; P = 0.012; HR = 8.26; 95% CI = 1.15-59.50) (Fig.	('GBM', 'Gene', (117, 120))	('methyl', 'Chemical', 'MESH:C031105', (11, 17))	('hypermethylation', 'Var', (6, 22))	('higher', 'PosReg', (43, 49))	('NSUN5', 'Gene', (0, 5))	('LGG', 'CPA', (56, 59))
147122	31428936	Low levels of the NSUN5 RNA transcript were also associated with increased OS in the TCGA cohort (log-rank; P < 10-5; HR = 4.57; 95% CI = 2.40-9.04) (Suppl.	('P < 10-5', 'Gene', '4790', (108, 116))	('P < 10-5', 'Gene', (108, 116))	('NSUN5 RNA', 'Gene', (18, 27))	('Low levels', 'Var', (0, 10))
147124	31428936	Table S5), where NSUN5 methylation status was determined by the pyrosequencing assay: NSUN5 promoter hypermethylation was associated with and increased OS (log-rank; P = 0.043; HR = 1.90; 95% CI = 1.01-3.58) and extended progression-free survival (PFS) (log-rank; P = 0.010; HR = 1.95; 95% CI = 1.16-3.27) (Fig.	('NSUN5', 'Gene', (86, 91))	('increased', 'PosReg', (142, 151))	('hypermethylation', 'Var', (101, 117))	('progression-free survival', 'CPA', (221, 246))	('extended', 'PosReg', (212, 220))	('methyl', 'Chemical', 'MESH:C031105', (23, 29))	('methyl', 'Chemical', 'MESH:C031105', (106, 112))
147126	31428936	We confirmed that NSUN5 promoter hypermethylation was associated with increased PFS (log-rank; P value 10-5; HR = 3.03; 95% CI = 2.35-3.74) (Fig.	('increased', 'PosReg', (70, 79))	('promoter hypermethylation', 'Var', (24, 49))	('PFS', 'Disease', (80, 83))	('NSUN5', 'Gene', (18, 23))	('methyl', 'Chemical', 'MESH:C031105', (38, 44))
147128	31428936	NSUN5 methylation is associated with extended PFS in low-grade gliomas (LGG, n = 183) (log-rank; P value 10-5; HR = 5.07; 95% CI = 3.46-7.41) (Fig.	('methyl', 'Chemical', 'MESH:C031105', (6, 12))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('associated', 'Reg', (21, 31))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('methylation', 'Var', (6, 17))	('NSUN5', 'Gene', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
147130	31428936	We examined whether other genetic and epigenetic alterations of clinical relevance in glioma helped define patients with NSUN5 methylation-associated extended survival.	('glioma', 'Disease', (86, 92))	('NSUN5', 'Gene', (121, 126))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('methylation-associated', 'Var', (127, 149))	('extended', 'PosReg', (150, 158))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('patients', 'Species', '9606', (107, 115))	('methyl', 'Chemical', 'MESH:C031105', (127, 133))
147131	31428936	In this regard, the presence of IDH1 mutations in gliomas is known to be a predictor of improved outcome.	('IDH1', 'Gene', (32, 36))	('gliomas', 'Disease', (50, 57))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('IDH1', 'Gene', '3417', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('mutations', 'Var', (37, 46))	('improved', 'PosReg', (88, 96))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('presence', 'Var', (20, 28))
147132	31428936	We found this to be the case for the gliomas included in the TCGA repository: IDH1 mutations are associated with longer OS (Suppl.	('mutations', 'Var', (83, 92))	('IDH1', 'Gene', (78, 82))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('associated with', 'Reg', (97, 112))	('gliomas', 'Disease', (37, 44))	('IDH1', 'Gene', '3417', (78, 82))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
147133	31428936	Interestingly, for those cases with a wild-type IDH1, which are all supposed to have an adverse prognosis, the presence of NSUN5 hypermethylation highlighted a subset of cases with long OS (Suppl.	('presence', 'Var', (111, 119))	('IDH1', 'Gene', '3417', (48, 52))	('long OS', 'Disease', 'MESH:C567932', (181, 188))	('methyl', 'Chemical', 'MESH:C031105', (134, 140))	('long OS', 'Disease', (181, 188))	('hypermethylation', 'Var', (129, 145))	('IDH1', 'Gene', (48, 52))	('NSUN5', 'Gene', (123, 128))
147135	31428936	Importantly, for those patients without 1p/19q co-deletion, which are all expected to have a poor outcome, NSUN5 hypermethylation pinpointed a subgroup with improved OS (Suppl.	('NSUN5', 'Gene', (107, 112))	('patients', 'Species', '9606', (23, 31))	('methyl', 'Chemical', 'MESH:C031105', (118, 124))	('hypermethylation', 'Var', (113, 129))	('improved', 'PosReg', (157, 165))
147137	31428936	Epigenetic inactivation of MGMT is linked to an enhanced response to chemotherapy-alkylating agents and increased OS in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('increased', 'PosReg', (104, 113))	('response to chemotherapy-alkylating agents', 'MPA', (57, 99))	('enhanced', 'PosReg', (48, 56))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('alkylating', 'Chemical', 'MESH:D000477', (82, 92))	('gliomas', 'Disease', (120, 127))	('MGMT', 'Gene', '4255', (27, 31))	('Epigenetic inactivation', 'Var', (0, 23))	('MGMT', 'Gene', (27, 31))
147139	31428936	In addition, here again, for those gliomas unmethylated at MGMT, which are supposed to show poor outcome, NSUN5 hypermethylation defined a subset with extended OS (Suppl.	('methyl', 'Chemical', 'MESH:C031105', (117, 123))	('methyl', 'Chemical', 'MESH:C031105', (45, 51))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('extended OS', 'Disease', (151, 162))	('NSUN5', 'Gene', (106, 111))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('hypermethylation', 'Var', (112, 128))	('MGMT', 'Gene', (59, 63))	('gliomas', 'Disease', (35, 42))	('MGMT', 'Gene', '4255', (59, 63))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))
147141	31428936	First, in this set of cases, we confirmed that the IDH1 mutation, the co-deletion of chromosome arms 1p and 19q and MGMT hypermethylation were all associated with longer PFS (Suppl.	('IDH1', 'Gene', '3417', (51, 55))	('associated', 'Reg', (147, 157))	('methyl', 'Chemical', 'MESH:C031105', (126, 132))	('MGMT', 'Gene', (116, 120))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))	('MGMT', 'Gene', '4255', (116, 120))
147142	31428936	Importantly, for those patients without 1p/19q co-deletion, NSUN5 hypermethylation pinpointed a subgroup with improved PFS (Suppl.	('hypermethylation', 'Var', (66, 82))	('patients', 'Species', '9606', (23, 31))	('improved', 'PosReg', (110, 118))	('methyl', 'Chemical', 'MESH:C031105', (71, 77))	('PFS', 'Disease', (119, 122))	('NSUN5', 'Gene', (60, 65))
147143	31428936	Related to IDH1 mutational status, we observed a trend between NSUN5 hypermethylation and longer PFS in the cases with a wild-type IDH1 that did not reach statistical significance (Suppl.	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', '3417', (11, 15))	('hypermethylation', 'Var', (69, 85))	('IDH1', 'Gene', '3417', (131, 135))	('PFS', 'MPA', (97, 100))	('methyl', 'Chemical', 'MESH:C031105', (74, 80))	('NSUN5', 'Gene', (63, 68))	('IDH1', 'Gene', (11, 15))
147144	31428936	Interestingly, NSUN5 hypermethylation defined a subset with extended PFS for both MGMT unmethylated and hypermethylated patients (Suppl.	('hypermethylation', 'Var', (21, 37))	('MGMT', 'Gene', '4255', (82, 86))	('methyl', 'Chemical', 'MESH:C031105', (26, 32))	('NSUN5', 'Gene', (15, 20))	('methyl', 'Chemical', 'MESH:C031105', (109, 115))	('patients', 'Species', '9606', (120, 128))	('MGMT', 'Gene', (82, 86))	('methyl', 'Chemical', 'MESH:C031105', (89, 95))
147145	31428936	For both TCGA and validation cohorts, we observed that NSUN5 methylation was associated with other biomarkers of clinical benefit such as IDH1 mutation (Fisher's exact test P < 10-5), co-deletion of 1p/19q (Fisher's exact test P < 10-5), and MGMT methylation (Fisher's exact test P < 10-5) (Suppl.	('P < 10-5', 'Gene', '4790', (173, 181))	('NSUN5', 'Gene', (55, 60))	('methylation', 'Var', (61, 72))	('IDH1', 'Gene', '3417', (138, 142))	('mutation', 'Var', (143, 151))	('co-deletion', 'Var', (184, 195))	('P < 10-5', 'Gene', (280, 288))	('P < 10-5', 'Gene', '4790', (280, 288))	('MGMT', 'Gene', (242, 246))	('P < 10-5', 'Gene', (227, 235))	('methyl', 'Chemical', 'MESH:C031105', (61, 67))	('MGMT', 'Gene', '4255', (242, 246))	('methyl', 'Chemical', 'MESH:C031105', (247, 253))	('P < 10-5', 'Gene', '4790', (227, 235))	('IDH1', 'Gene', (138, 142))	('P < 10-5', 'Gene', (173, 181))	('associated', 'Reg', (77, 87))
147146	31428936	Importantly, all these three last molecular markers are also significantly associated between them (IDH1 mutation/co-deletion 1p/19q, Fisher's exact test P < 10-5; IDH1 mutation/MGMT methylation, Fisher's exact test P < 10-5; co-deletion 1p/19q/MGMT methylation, Fisher's exact test P < 10-5) (Suppl.	('P < 10-5', 'Gene', (283, 291))	('MGMT', 'Gene', '4255', (178, 182))	('IDH1', 'Gene', '3417', (100, 104))	('P < 10-5', 'Gene', '4790', (283, 291))	('P < 10-5', 'Gene', (154, 162))	('methyl', 'Chemical', 'MESH:C031105', (183, 189))	('MGMT', 'Gene', (245, 249))	('IDH1', 'Gene', (100, 104))	('P < 10-5', 'Gene', (216, 224))	('P < 10-5', 'Gene', '4790', (154, 162))	('MGMT', 'Gene', '4255', (245, 249))	('P < 10-5', 'Gene', '4790', (216, 224))	('methyl', 'Chemical', 'MESH:C031105', (250, 256))	('IDH1', 'Gene', (164, 168))	('associated', 'Reg', (75, 85))	('mutation/co-deletion', 'Var', (105, 125))	('IDH1', 'Gene', '3417', (164, 168))	('MGMT', 'Gene', (178, 182))
147148	31428936	Methods), a common phenomenon in IDH1 mutant patients.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (33, 37))	('IDH1', 'Gene', (33, 37))	('patients', 'Species', '9606', (45, 53))
147149	31428936	As expected, the presence of the gCIMP phenotype in the TCGA glioma data set is associated with improved clinical outcome (Suppl.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('improved', 'PosReg', (96, 104))	('glioma', 'Disease', (61, 67))	('presence', 'Var', (17, 25))	('clinical', 'MPA', (105, 113))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
147150	31428936	Strikingly, when we stratified the TCGA data set according to gCIMP status and NUSN5 methylation, we observed that for those cases with a lack of the gCIMP phenotype, which are all supposed to have a poor clinical outcome, the presence of NSUN5 hypermethylation highlighted a subset of cases with long overall survival (Suppl.	('presence', 'Var', (227, 235))	('overall survival', 'MPA', (302, 318))	('hypermethylation', 'Var', (245, 261))	('NSUN5', 'Gene', (239, 244))	('methyl', 'Chemical', 'MESH:C031105', (250, 256))	('methyl', 'Chemical', 'MESH:C031105', (85, 91))
147151	31428936	Finally, and most importantly, to determine the value of NSUN5 methylation as a candidate independent biomarker, we performed multivariate analysis for NSUN5 methylation status and the described known biomarkers of clinical outcome (IDH1 mutational, 1p/19q co-deletion and MGMT methylation status) for the both studied glioma cohorts.	('NSUN5', 'Gene', (152, 157))	('IDH1', 'Gene', '3417', (233, 237))	('methyl', 'Chemical', 'MESH:C031105', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (319, 325))	('mutational', 'Var', (238, 248))	('glioma cohort', 'Disease', 'MESH:D005910', (319, 332))	('glioma cohort', 'Disease', (319, 332))	('MGMT', 'Gene', (273, 277))	('IDH1', 'Gene', (233, 237))	('MGMT', 'Gene', '4255', (273, 277))	('methyl', 'Chemical', 'MESH:C031105', (158, 164))	('methyl', 'Chemical', 'MESH:C031105', (278, 284))
147152	31428936	Multivariate Cox regression analysis showed that NSUN5 hypermethylation was an independent predictor of OS in the TCGA glioma cohort (HR = 0.50; 95% CI = 0.26-0.94; P = 0.032) (Fig.	('NSUN5', 'Gene', (49, 54))	('glioma cohort', 'Disease', 'MESH:D005910', (119, 132))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('hypermethylation', 'Var', (55, 71))	('glioma cohort', 'Disease', (119, 132))	('methyl', 'Chemical', 'MESH:C031105', (60, 66))
147154	31428936	More than 100 distinct nucleotide modifications have been reported in the RNA molecule across the range of all life forms, many of which are also present in human RNA molecules such as N6-methyladenosine, N1-methyladenosine, pseudouridine, or 5-methylcytosine.	('pseudouridine', 'Disease', (225, 238))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (185, 203))	('N6-methyladenosine', 'Var', (185, 203))	('N1-methyladenosine', 'Var', (205, 223))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (243, 259))	('N1-methyladenosine', 'Chemical', 'MESH:C010223', (205, 223))	('human', 'Species', '9606', (157, 162))	('pseudouridine', 'Chemical', 'MESH:D011560', (225, 238))
147155	31428936	We are at the dawn of our understanding of how disruption of the epitranscriptome can initiate and promote tumorigenesis, but the emerging findings indicate that altered RNA modification patterns play a fundamental role in cancer.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('disruption', 'Var', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('promote', 'PosReg', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', (223, 229))	('RNA modification', 'MPA', (170, 186))
147156	31428936	The occurrence of mutations in the pseudouridine synthase DKC1 in X-linked dyskeratosis congenita (X-DC), a disorder characterized by cancer susceptibility, is particularly interesting, because it directly affects a key cellular element, the ribosome.	('X-linked dyskeratosis congenita', 'Disease', 'MESH:D019871', (66, 97))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('affects', 'Reg', (206, 213))	('X-linked dyskeratosis congenita', 'Disease', (66, 97))	('DKC1', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('pseudouridine', 'Chemical', 'MESH:D011560', (35, 48))	('mutations', 'Var', (18, 27))
147158	31428936	Mice that are hypomorphically mutant for DKC1 exhibit decreased pseudouridine in their RNAs and a defect in translation that particularly affects mRNAs containing Internal Ribosome Entry Sites (IREs).	('defect', 'NegReg', (98, 104))	('pseudouridine', 'Chemical', 'MESH:D011560', (64, 77))	('DKC1', 'Gene', (41, 45))	('mRNAs containing Internal Ribosome Entry Sites', 'MPA', (146, 192))	('pseudouridine', 'MPA', (64, 77))	('decreased', 'NegReg', (54, 63))	('Mice', 'Species', '10090', (0, 4))	('affects', 'Reg', (138, 145))	('mutant', 'Var', (30, 36))	('translation', 'MPA', (108, 119))
147161	31428936	This idea is also supported by the existence of specialized ribosomes and complex machineries associated with these structures and rRNAs, in addition to the presence of mutations in ribosomal proteins in cancer-associated syndromes.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (169, 178))
147163	31428936	This RNA chemical modification also acts at the level of tRNAs, where loss of the 5-methylcytosine RNA-methyltransferase NSUN2 drives a global reduction in protein synthesis and altered translational programs, in a similar manner to that which occurs upon the loss of DKC1.	('methyl', 'Chemical', 'MESH:C031105', (103, 109))	('protein synthesis', 'MPA', (156, 173))	('translational programs', 'MPA', (186, 208))	('NSUN2', 'Gene', (121, 126))	('loss', 'Var', (70, 74))	('methyl', 'Chemical', 'MESH:C031105', (84, 90))	('reduction', 'NegReg', (143, 152))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (82, 98))	('altered', 'Reg', (178, 185))
147164	31428936	In this study, we combined genomic, epigenomic, and epitranscriptomic approaches to characterize the 5-methylcytosine RNA methyltransferase, NSUN5, and showed how its epigenetic silencing produces a hypomethylation event at a particular position of the 28S rRNA that depletes the overall protein synthesis, but engages glioma cells in a particular translational program for survival under conditions of cellular stress.	('methyl', 'Chemical', 'MESH:C031105', (103, 109))	('epigenetic silencing', 'Var', (167, 187))	('glioma', 'Disease', 'MESH:D005910', (319, 325))	('glioma', 'Phenotype', 'HP:0009733', (319, 325))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (101, 117))	('protein synthesis', 'MPA', (288, 305))	('depletes', 'NegReg', (267, 275))	('engages', 'Reg', (311, 318))	('hypomethylation', 'MPA', (199, 214))	('glioma', 'Disease', (319, 325))	('methyl', 'Chemical', 'MESH:C031105', (122, 128))	('methyl', 'Chemical', 'MESH:C031105', (203, 209))
147165	31428936	Interestingly, we also show by molecular dynamics that the methylation of the C3782 position of human 28S rRNA could mediate the structural stability of the tertiary complex rRNA-tRNA-mRNA, leading it loss to a structural distortion at the edge of the 28S subunit in the P-site cavity that might impair the physiological protein synthesis.	('methyl', 'Chemical', 'MESH:C031105', (59, 65))	('loss', 'NegReg', (201, 205))	('human', 'Species', '9606', (96, 101))	('impair', 'NegReg', (296, 302))	('C3782', 'Var', (78, 83))	('methylation', 'Var', (59, 70))	('structural distortion', 'MPA', (211, 232))	('physiological protein synthesis', 'MPA', (307, 338))
147167	31428936	Even oncogenic mutations that promote tumorigenesis in the early stages subsequently become a nuisance if they generate high levels of ROS that are toxic to cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ROS', 'MPA', (135, 138))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Disease', (157, 163))
147169	31428936	Another illustrative case is provided by NQO1, a multifunctional antioxidant enzyme regulated by the Keap1/Nrf2/ARE pathway, whose translational efficiency increases upon the loss of NSUN5 in glioma, as reported here, to overcome the many types of oxidative stress encountered by these transformed cells.	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('NSUN5', 'Gene', (183, 188))	('Keap1', 'Gene', '9817', (101, 106))	('Keap1', 'Gene', (101, 106))	('Nrf2', 'Gene', '4780', (107, 111))	('NQO1', 'Gene', (41, 45))	('translational efficiency', 'MPA', (131, 155))	('increases', 'PosReg', (156, 165))	('oxidative stress', 'Phenotype', 'HP:0025464', (248, 264))	('Nrf2', 'Gene', (107, 111))	('loss', 'Var', (175, 179))	('glioma', 'Disease', (192, 198))
147170	31428936	NSUN5 methylation-mediated overexpression of NQO1 can also constitute a therapeutic opportunity in these gliomas, because they become more sensitive to ROS-induced death upon the use NQO1-bioactivatable molecules.	('sensitive', 'MPA', (139, 148))	('methyl', 'Chemical', 'MESH:C031105', (6, 12))	('NSUN5', 'Var', (0, 5))	('more', 'PosReg', (134, 138))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('NQO1', 'Gene', (45, 49))	('overexpression', 'PosReg', (27, 41))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
147171	31428936	Thus, NSUN5 DNA methylation-associated inactivation, through its linked defect in 28S rRNA methylation, represents a bona fide mechanism that explains how human gliomas adapt to challenging cellular stress conditions by depleting overall synthesis while also promoting specific translational programs.	('overall synthesis', 'MPA', (230, 247))	('defect', 'NegReg', (72, 78))	('methylation-associated', 'Var', (16, 38))	('human', 'Species', '9606', (155, 160))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('methyl', 'Chemical', 'MESH:C031105', (91, 97))	('promoting', 'PosReg', (259, 268))	('methyl', 'Chemical', 'MESH:C031105', (16, 22))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Disease', (161, 168))	('translational', 'MPA', (278, 291))	('inactivation', 'NegReg', (39, 51))	('depleting', 'NegReg', (220, 229))	('NSUN5 DNA methylation-associated', 'Var', (6, 38))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('28S rRNA methylation', 'MPA', (82, 102))
147172	31428936	This role of NSUN5 epigenetic silencing in the toleration of cellular stress settings resembles another key molecular event in gliomagenesis: the occurrence of IDH1 mutations.	('gliomagenesis', 'Disease', 'None', (127, 140))	('IDH1', 'Gene', (160, 164))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('IDH1', 'Gene', '3417', (160, 164))	('gliomagenesis', 'Disease', (127, 140))	('mutations', 'Var', (165, 174))	('epigenetic silencing', 'Var', (19, 39))
147173	31428936	In a similar manner, the loss of IDH1 normal catalytic activity contributes to gliomagenesis, but it is also associated with good OS.	('contributes', 'Reg', (64, 75))	('gliomagenesis', 'Disease', 'None', (79, 92))	('loss', 'Var', (25, 29))	('IDH1', 'Gene', (33, 37))	('gliomagenesis', 'Disease', (79, 92))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', '3417', (33, 37))	('catalytic activity', 'MPA', (45, 63))
147174	31428936	Once again, we can consider how cancer cells avoid death when confronted by damaging stress conditions, because, as we have shown for NSUN5, the disruption of IDH1 is another way of dealing with metabolic and hypoxic stress.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('IDH1', 'Gene', (159, 163))	('cancer', 'Disease', (32, 38))	('hypoxic stress', 'Disease', 'MESH:D054549', (209, 223))	('IDH1', 'Gene', '3417', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('hypoxic stress', 'Disease', (209, 223))	('disruption', 'Var', (145, 155))
147175	31428936	Thus, those patients with gliomas exhibiting NSUN5 epigenetic silencing, like those carrying IDH1 mutations, have tumor cells that probably are on the verge of death, whose last resort in their struggle to survive is to restrict overall protein synthesis and to instigate particular emergency translational programs to deal with multiple stress conditions.	('restrict', 'NegReg', (220, 228))	('IDH1', 'Gene', (93, 97))	('instigate', 'Reg', (262, 271))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patients', 'Species', '9606', (12, 20))	('NSUN5 epigenetic silencing', 'Var', (45, 71))	('IDH1', 'Gene', '3417', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', (114, 119))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('protein synthesis', 'MPA', (237, 254))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
147177	31428936	Most significantly, we have shown that NSUN5 inactivation is a likely pathway used by glioma cells to overcome hostile stress conditions by restraining high energy-consuming global protein synthesis while stimulating the translation of adaptive proteins such as NQO1.	('glioma', 'Disease', (86, 92))	('translation', 'MPA', (221, 232))	('inactivation', 'Var', (45, 57))	('NSUN5', 'Gene', (39, 44))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('high energy-consuming global protein synthesis', 'MPA', (152, 198))	('restraining', 'NegReg', (140, 151))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('NQO1', 'Gene', (262, 266))	('stimulating', 'PosReg', (205, 216))
147178	31428936	These findings, if validated in larger sets of prospective clinical studies, might be useful for the management of glioma patients, because, in the context of a disease, whose prognosis is usually dismal, the NSUN5 epigenetic lesion contributes to identify those patients who are likely to have a good outcome.	('glioma', 'Disease', (115, 121))	('patients', 'Species', '9606', (263, 271))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('NSUN5 epigenetic lesion', 'Var', (209, 232))	('patients', 'Species', '9606', (122, 130))	('glioma', 'Disease', 'MESH:D005910', (115, 121))
147198	30867991	With the development of molecular pathology in gliomas, several biomarkers are routinely applied to evaluate gliomas including O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, EGFR alterations, Isocitrate dehydrogenase 1 (IDH1) or Isocitrate dehydrogenase 2 (IDH2) mutations, and 1p19q co-deletion as many of these markers have become standard of care for molecular testing and prerequisites for clinical trial enrollment.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (127, 166))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('Isocitrate dehydrogenase', 'Gene', '3417', (214, 238))	('IDH1', 'Gene', '3417', (242, 246))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('Isocitrate dehydrogenase', 'Gene', '3417', (251, 275))	('EGFR', 'Gene', '1956', (196, 200))	('MGMT', 'Gene', '4255', (168, 172))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('Isocitrate dehydrogenase', 'Gene', (214, 238))	('alterations', 'Var', (201, 212))	('Isocitrate dehydrogenase', 'Gene', (251, 275))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('1p19q co-deletion', 'Var', (300, 317))	('mutations', 'Var', (285, 294))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (127, 166))	('IDH2', 'Gene', (279, 283))	('IDH2', 'Gene', '3418', (279, 283))	('EGFR', 'Gene', (196, 200))	('MGMT', 'Gene', (168, 172))	('IDH1', 'Gene', (242, 246))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', (109, 116))
147231	30867991	We found both SAA1 and TIMP1 increase in both Isocitrate dehydrogenase (IDH) mutant IDH wild type.	('TIMP1', 'Gene', (23, 28))	('SAA1', 'Gene', (14, 18))	('increase', 'PosReg', (29, 37))	('TIMP1', 'Gene', '7076', (23, 28))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('Isocitrate dehydrogenase', 'Gene', '3417', (46, 70))	('SAA1', 'Gene', '6288', (14, 18))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', (84, 87))	('mutant', 'Var', (77, 83))	('Isocitrate dehydrogenase', 'Gene', (46, 70))
147232	30867991	The same results were found in MGMT promoter and non-deletion of chromosome 1p.19q.	('non-deletion', 'Var', (49, 61))	('MGMT', 'Gene', '4255', (31, 35))	('MGMT', 'Gene', (31, 35))
147270	30867991	More recently, demonstrated that Co-expression of TIMP-1 and CD63 might have effects in glioblastoma stemness and may predict the poor prognosis of patients through influencing tumor aggressiveness and resistance of therapy.	('CD63', 'Gene', (61, 65))	('glioblastoma stemness', 'Disease', 'MESH:D005909', (88, 109))	('patients', 'Species', '9606', (148, 156))	('Co-expression', 'Var', (33, 46))	('influencing', 'Reg', (165, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('TIMP-1', 'Gene', (50, 56))	('glioblastoma stemness', 'Disease', (88, 109))	('CD63', 'Gene', '967', (61, 65))	('tumor aggressiveness', 'Disease', (177, 197))	('TIMP-1', 'Gene', '7076', (50, 56))	('effects', 'Reg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('aggressiveness', 'Phenotype', 'HP:0000718', (183, 197))	('resistance of therapy', 'CPA', (202, 223))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (177, 197))
147298	33448230	Across all cancer types, the most common oncogene mutations in MAPK pathway regulation affect KRAS followed by BRAF, and the most common oncogenic BRAF mutation is the valine to glutamate, or BRAFV600E, mutation resulting in a constitutively activated kinase.	('constitutively activated kinase', 'MPA', (227, 258))	('BRAFV600E', 'Mutation', 'rs113488022', (192, 201))	('KRAS', 'Gene', (94, 98))	('affect', 'Reg', (87, 93))	('mutations', 'Var', (50, 59))	('glutamate', 'Chemical', 'MESH:D018698', (178, 187))	('BRAF', 'Gene', '673', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MAPK', 'Gene', (63, 67))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', (192, 196))	('BRAF', 'Gene', '673', (147, 151))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('KRAS', 'Gene', '3845', (94, 98))	('BRAF', 'Gene', '673', (111, 115))	('valine', 'Chemical', 'MESH:D014633', (168, 174))	('cancer', 'Disease', (11, 17))	('BRAF', 'Gene', (111, 115))
147299	33448230	PA is regarded as a single-hit disease resulting from MAPK dysfunction via a variety of mechanisms, including sporadic BRAF fusion in 60-70%, various single amino acid alterations in the BRAF gene in up to 10% and inherited germline mutations of the NF1 gene in approximately 15%, which all lead to constitutive MAPK activation.	('MAPK', 'Gene', (312, 316))	('NF1', 'Gene', (250, 253))	('BRAF', 'Gene', (187, 191))	('BRAF', 'Gene', '673', (187, 191))	('BRAF', 'Gene', '673', (119, 123))	('single amino acid alterations', 'Var', (150, 179))	('lead to', 'Reg', (291, 298))	('NF1', 'Gene', '4763', (250, 253))	('BRAF', 'Gene', (119, 123))	('germline mutations', 'Var', (224, 242))	('activation', 'PosReg', (317, 327))
147301	33448230	Focal duplication of chromosome 7q34 was reported as a frequent chromosomal abnormality in PA.	('chromosomal abnormality', 'Disease', (64, 87))	('Focal duplication', 'Var', (0, 17))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (64, 87))
147302	33448230	The 7q34 duplication is associated with gene fusion between KIAA1549 and the BRAF oncogenes (BK fusion).	('KIAA1549', 'Gene', '57670', (60, 68))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('associated with', 'Reg', (24, 39))	('gene fusion', 'Var', (40, 51))	('KIAA1549', 'Gene', (60, 68))	('7q34', 'Gene', (4, 8))
147303	33448230	The product for all BRAF fusions is absence of an inhibitory N-domain leading to constitutively active BRAF kinase.	('absence', 'NegReg', (36, 43))	('BRAF', 'Gene', '673', (20, 24))	('BRAF', 'Gene', '673', (103, 107))	('BRAF', 'Gene', (20, 24))	('fusions', 'Var', (25, 32))	('inhibitory N-domain', 'MPA', (50, 69))	('BRAF', 'Gene', (103, 107))
147306	33448230	Pediatric PA with BK fusions and other Class I and II BRAF mutations have both a constitutively activated MAPK pathway driving tumor growth and express markers of oncogene-induced senescence.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BRAF', 'Gene', (54, 58))	('tumor', 'Disease', (127, 132))	('BRAF', 'Gene', '673', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mutations', 'Var', (59, 68))	('MAPK pathway', 'Pathway', (106, 118))
147309	33448230	BRAF fusions are reported in multiple other glial neoplasms, including 50-77% of pilomyxoid astrocytoma, 18-21% of ganglioglioma, and in isolated cases of pleomorphic xanthoastrocytoma and ependymoma.	('ganglioglioma', 'Disease', 'MESH:D018303', (115, 128))	('glial neoplasms', 'Disease', (44, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('fusions', 'Var', (5, 12))	('glial neoplasms', 'Disease', 'MESH:D004194', (44, 59))	('BRAF', 'Gene', '673', (0, 4))	('ganglioglioma', 'Disease', (115, 128))	('pilomyxoid astrocytoma', 'Disease', 'MESH:D001254', (81, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('neoplasm', 'Phenotype', 'HP:0002664', (50, 58))	('BRAF', 'Gene', (0, 4))	('ependymoma', 'Phenotype', 'HP:0002888', (189, 199))	('pilomyxoid astrocytoma', 'Disease', (81, 103))	('pleomorphic xanthoastrocytoma and ependymoma', 'Disease', 'MESH:D004806', (155, 199))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
147310	33448230	BRAF fusions are class 2 mutations and are not responsive to first-generation BRAF inhibitors (e.g.	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', (78, 82))	('fusions', 'Var', (5, 12))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
147316	33448230	The second most common mechanism of MAPK pathway dysregulation in PA is hotspot activation due to substitutions at position 600 in the BRAF gene.	('hotspot', 'MPA', (72, 79))	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', (135, 139))	('MAPK pathway', 'Pathway', (36, 48))	('activation', 'PosReg', (80, 90))	('substitutions at position 600', 'Var', (98, 127))
147317	33448230	BRAFV600E mutations are found in approximately 50% of cutaneous melanomas and is an identified driver in a subset of colorectal cancer, non-small-cell lung cancer, papillary thyroid cancer, cholangiocarcinoma, hairy cell leukemia, multiple myeloma and Langerhans cell histiocytosis.	('histiocytosis', 'Phenotype', 'HP:0100727', (268, 281))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (164, 188))	('hairy cell leukemia', 'Disease', (210, 229))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('thyroid cancer', 'Phenotype', 'HP:0002890', (174, 188))	('multiple myeloma', 'Disease', (231, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('non-small-cell lung cancer', 'Disease', (136, 162))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (136, 162))	('BRAFV600E', 'Gene', (0, 9))	('Langerhans cell histiocytosis', 'Disease', (252, 281))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (54, 73))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (54, 73))	('found', 'Reg', (24, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (190, 208))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))	('papillary thyroid cancer', 'Disease', (164, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('cholangiocarcinoma', 'Disease', (190, 208))	('colorectal cancer', 'Disease', (117, 134))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (210, 229))	('multiple myeloma', 'Phenotype', 'HP:0006775', (231, 247))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (190, 208))	('cutaneous melanomas', 'Disease', (54, 73))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (136, 162))	('multiple myeloma', 'Disease', 'MESH:D009101', (231, 247))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (164, 188))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('mutations', 'Var', (10, 19))
147319	33448230	Of the 273 adult PAs with genetic aberrations reviewed here, 9.2% had BRAF mutations.	('BRAF', 'Gene', '673', (70, 74))	('PAs', 'Chemical', 'MESH:D011478', (17, 20))	('mutations', 'Var', (75, 84))	('BRAF', 'Gene', (70, 74))
147328	33448230	Several class 2, non-BRAFV600 mutations have been characterized in gliomas at undefined frequencies resulting in RAS independent dimers, unresponsive to first-generation BRAF inhibitors which only target monomers.	('BRAF', 'Gene', (170, 174))	('resulting in', 'Reg', (100, 112))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('RAS independent dimers', 'MPA', (113, 135))	('gliomas', 'Disease', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('BRAF', 'Gene', '673', (21, 25))	('mutations', 'Var', (30, 39))	('BRAF', 'Gene', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('BRAF', 'Gene', '673', (170, 174))
147329	33448230	Rational means of targeting such mutations is with paradox-breaking BRAF inhibitors, such as PLX8394, which provides BRAF inhibition without promotion of dimer formation.	('BRAF', 'Gene', '673', (68, 72))	('BRAF', 'Gene', (68, 72))	('mutations', 'Var', (33, 42))	('BRAF', 'Gene', '673', (117, 121))	('BRAF', 'Gene', (117, 121))
147335	33448230	Up to 33% of PA with anaplasia develop in patients with a clinical diagnosis of NF1, which have a more aggressive clinical course and have recurring mutations in ATRX leading to alternative lengthening of telomeres (ALT).	('mutations', 'Var', (149, 158))	('anaplasia', 'Disease', (21, 30))	('anaplasia', 'Disease', 'MESH:D000708', (21, 30))	('NF1', 'Gene', (80, 83))	('NF1', 'Gene', '4763', (80, 83))	('ATRX', 'Gene', (162, 166))	('patients', 'Species', '9606', (42, 50))	('ATRX', 'Gene', '546', (162, 166))
147341	33448230	In contrast with the predominant anatomic predilection of BRAF fusions (cerebellar) and BRAF V600 mutations (supratentorial), somatic RAS mutations seem to have a predilection for the midbrain/tectal region.	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('RAS', 'Gene', (134, 137))	('mutations', 'Var', (138, 147))
147344	33448230	Mutations, fusions or duplications of the upstream regulators of the MAPK pathway, including the tyrosine kinase FGFR1, can drive pathologic MAPK activation in adult PA.	('activation', 'PosReg', (146, 156))	('FGFR1', 'Gene', (113, 118))	('duplications', 'Var', (22, 34))	('Mutations', 'Var', (0, 9))	('MAPK', 'Gene', (141, 145))	('FGFR1', 'Gene', '2260', (113, 118))	('drive', 'Reg', (124, 129))	('fusions', 'Var', (11, 18))
147345	33448230	Duplication events and various mutations of FGFR1 have been described as a frequent occurrence in up to 60% of dysembryoplastic neuroepithelial tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (128, 150))	('mutations', 'Var', (31, 40))	('FGFR1', 'Gene', (44, 49))	('Duplication events', 'Var', (0, 18))	('FGFR1', 'Gene', '2260', (44, 49))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (111, 150))	('occurrence', 'Reg', (84, 94))	('dysembryoplastic neuroepithelial tumors', 'Disease', (111, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
147346	33448230	In PAs, hotspot point mutations in FGFR1 have been implicated in altered autophosphorylation and increased kinase activity.	('point mutations', 'Var', (16, 31))	('kinase activity', 'MPA', (107, 122))	('altered', 'Reg', (65, 72))	('increased', 'PosReg', (97, 106))	('PAs', 'Chemical', 'MESH:D011478', (3, 6))	('FGFR1', 'Gene', (35, 40))	('autophosphorylation', 'MPA', (73, 92))	('FGFR1', 'Gene', '2260', (35, 40))
147347	33448230	FGFR1 mutations were found in 15 of a series of 108 adult PA (patients age >15) and were associated with a significantly higher prevalence among sporadic optic pathway PA (6/9).	('higher prevalence', 'PosReg', (121, 138))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (6, 15))
147348	33448230	FGFR1 mutations increase in frequency in older PA patients (Figure 3).	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', (0, 5))	('patients', 'Species', '9606', (50, 58))	('mutations', 'Var', (6, 15))
147349	33448230	Compared with wild-type in a series of 69 PAs, the 7% of cases with FGFR1 mutation had decreased overall and event-free survival.	('mutation', 'Var', (74, 82))	('event-free survival', 'CPA', (109, 128))	('overall', 'CPA', (97, 104))	('decreased', 'NegReg', (87, 96))	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (68, 73))	('PAs', 'Chemical', 'MESH:D011478', (42, 45))
147351	33448230	Erdafitinib is now US FDA approved for urothelial carcinoma but has unknown CNS penetrance, though two advanced glioblastoma patients with FGFR3-TACC3 rearrangements experienced clinical improvement.	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('glioblastoma', 'Disease', (112, 124))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('rearrangements', 'Var', (151, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('TACC3', 'Gene', '10460', (145, 150))	('urothelial carcinoma', 'Disease', (39, 59))	('FGFR3', 'Gene', '2261', (139, 144))	('TACC3', 'Gene', (145, 150))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (39, 59))	('FGFR3', 'Gene', (139, 144))	('patients', 'Species', '9606', (125, 133))
147353	33448230	NTRK fusions have additionally been identified as a rare event involved in multiple solid malignancies, including colorectal cancer and papillary thyroid carcinoma.	('malignancies', 'Disease', (90, 102))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (146, 163))	('TRK', 'Gene', (1, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('TRK', 'Gene', '4914', (1, 4))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('fusions', 'Var', (5, 12))	('involved', 'Reg', (63, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('papillary thyroid carcinoma', 'Disease', (136, 163))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('colorectal cancer', 'Disease', (114, 131))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (136, 163))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (136, 163))
147354	33448230	In a whole genome assessment of 96 PAs, three pediatric patients were found to have oncogenic NTRK fusions implicated in tumorigenesis.	('patients', 'Species', '9606', (56, 64))	('TRK', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TRK', 'Gene', '4914', (95, 98))	('tumor', 'Disease', (121, 126))	('fusions', 'Var', (99, 106))	('PAs', 'Chemical', 'MESH:D011478', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
147355	33448230	NTRK fusions have demonstrated responsiveness to TRK inhibition resulting in US FDA approval of larotrectinib and entrectinib for solid tumors harboring the fusion, the latter with comparatively better CNS penetration.	('entrectinib', 'Chemical', 'MESH:C000607349', (114, 125))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (1, 4))	('fusion', 'Var', (157, 163))	('TRK', 'Gene', (49, 52))	('larotrectinib', 'Chemical', 'MESH:C000609083', (96, 109))	('TRK', 'Gene', '4914', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
147360	33448230	High-grade astrocytoma with piloid features has been associated with MAPK pathway gene alterations in 75% and CDKN2A/B deletion in 80%.	('CDKN2A/B', 'Gene', '1029;1030', (110, 118))	('astrocytoma', 'Disease', (11, 22))	('alterations', 'Var', (87, 98))	('deletion', 'Var', (119, 127))	('CDKN2A/B', 'Gene', (110, 118))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('associated', 'Reg', (53, 63))	('MAPK pathway', 'Gene', (69, 81))	('astrocytoma', 'Disease', 'MESH:D001254', (11, 22))
147362	33448230	H3-K27M has been implicated in development of anaplastic histology and aggressive behavior in circumscribed, nondiffuse glioma.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('aggressive behavior', 'CPA', (71, 90))	('H3-K27M', 'Var', (0, 7))	('aggressive behavior', 'Phenotype', 'HP:0000718', (71, 90))	('K27M', 'Mutation', 'p.K27M', (3, 7))	('glioma', 'Disease', (120, 126))	('implicated', 'Reg', (17, 27))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
147363	33448230	Though generally regarded as a defining mutation in grade IV diffuse midline gliomas, three case reports of less aggressive adult PA harboring H3-K27M mutations imply that this mutation may not have the same prognostic significance in PA. Aneuploidy, most frequently involving chromosomes 5, 7, 6 and 11, preferentially affects adult compared with pediatric PA (45 vs 17%), and is typically found in noncerebellar and non-BK fusion cases, suggesting another possible driver for worsened outcome in adults.	('Aneuploidy', 'Disease', 'MESH:D000782', (239, 249))	('midline gliomas', 'Disease', 'MESH:D005910', (69, 84))	('H3-K27M', 'Gene', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('K27M', 'Mutation', 'p.K27M', (146, 150))	('Aneuploidy', 'Disease', (239, 249))	('midline gliomas', 'Disease', (69, 84))	('mutations', 'Var', (151, 160))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
147368	33448230	Epigenetic analysis is further aiding the delineation of rosette-forming glioneuronal tumor from PA and other low grade neuroepithelial tumors with overlapping genomic signatures, with recent description of FGFR1 p.N546 or p.K656 mutation with PIK3CA or PIK3R1 appearing to represent a molecular signature specific to rosette-forming glioneuronal tumor.	('PIK3R1', 'Gene', '5295', (254, 260))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (120, 142))	('PIK3CA', 'Gene', (244, 250))	('p.K656', 'Var', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FGFR1', 'Gene', (207, 212))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (120, 142))	('PIK3R1', 'Gene', (254, 260))	('glioneuronal tumor', 'Disease', 'MESH:D009369', (334, 352))	('glioneuronal tumor', 'Disease', 'MESH:D009369', (73, 91))	('rosette-forming glioneuronal tumor', 'Phenotype', 'HP:0025171', (318, 352))	('rosette-forming glioneuronal tumor', 'Phenotype', 'HP:0025171', (57, 91))	('glioneuronal tumor', 'Disease', (334, 352))	('PIK3CA', 'Gene', '5290', (244, 250))	('glioneuronal tumor', 'Disease', (73, 91))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (334, 352))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (73, 91))	('neuroepithelial tumors', 'Disease', (120, 142))	('FGFR1', 'Gene', '2260', (207, 212))	('N546', 'Chemical', '-', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('rosette', 'Phenotype', 'HP:0031925', (318, 325))	('p.N546', 'Var', (213, 219))	('rosette', 'Phenotype', 'HP:0031925', (57, 64))
147376	33448230	In a study of anaplastic PA with ALT and ATRX loss, nine of 15 patients in whom anaplasia arose from a precursor PA had received prior irradiation, and in a separate series of three adult anaplastic PA patients with ATRX loss, all had received prior RT, one tumor had a PIK3CA mutation, and another a PDGFR mutation.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('PIK3CA', 'Gene', (270, 276))	('ATRX', 'Gene', (216, 220))	('ATRX', 'Gene', (41, 45))	('mutation', 'Var', (277, 285))	('tumor', 'Disease', (258, 263))	('PDGFR', 'Gene', (301, 306))	('PIK3CA', 'Gene', '5290', (270, 276))	('anaplasia', 'Disease', 'MESH:D000708', (80, 89))	('PDGFR', 'Gene', '5159', (301, 306))	('patients', 'Species', '9606', (202, 210))	('ATRX', 'Gene', '546', (216, 220))	('ATRX', 'Gene', '546', (41, 45))	('anaplasia', 'Disease', (80, 89))	('patients', 'Species', '9606', (63, 71))	('mutation', 'Var', (307, 315))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
147384	33448230	In short, identification of a class II or III BRAF mutation precludes the use of an early generation BRAF inhibitor, which can only target class I mutations.	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('mutation', 'Var', (51, 59))	('BRAF', 'Gene', '673', (101, 105))
147385	33448230	Class I V600E-mutant low-grade glioma appear to benefit from treatment with dabrafenib in the relapsed or refractory pediatric setting.	('V600E', 'Mutation', 'rs113488022', (8, 13))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('benefit', 'PosReg', (48, 55))	('V600E-mutant', 'Var', (8, 20))	('glioma', 'Disease', (31, 37))	('dabrafenib', 'Chemical', 'MESH:C561627', (76, 86))
147386	33448230	Randomized trials are currently evaluating targeted therapy versus chemotherapy in pediatric low-grade gliomas, including dabrafenib plus trametinib versus carboplatin plus vincristine (NCT02684058, 18 years or younger included), selumetinib versus carboplatin plus vincristine (NCT03871257, 21 years or younger included) and trametinib versus carboplatin plus vincristine in the Phase III LOGGIC trial (18 years or younger included).	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('selumetinib', 'Chemical', 'MESH:C517975', (230, 241))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('trametinib', 'Chemical', 'MESH:C560077', (326, 336))	('NCT03871257', 'Var', (279, 290))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('trametinib', 'Chemical', 'MESH:C560077', (138, 148))	('carboplatin', 'Chemical', 'MESH:D016190', (249, 260))	('carboplatin', 'Chemical', 'MESH:D016190', (344, 355))	('vincristine', 'Chemical', 'MESH:D014750', (173, 184))	('carboplatin', 'Chemical', 'MESH:D016190', (156, 167))	('vincristine', 'Chemical', 'MESH:D014750', (266, 277))	('vincristine', 'Chemical', 'MESH:D014750', (361, 372))
147387	33448230	Downstream MEK-inhibition is a reasonable adjunct for V600E mutants as shown in Figure 5A and B, as well as for class II mutations and fusions.	('MEK', 'Gene', (11, 14))	('V600E', 'Var', (54, 59))	('MEK', 'Gene', '5609', (11, 14))	('V600E', 'Mutation', 'rs113488022', (54, 59))
147390	33448230	For NF1 mutations, downstream MEK inhibition is potentially beneficial as discussed previously.	('mutations', 'Var', (8, 17))	('NF1', 'Gene', (4, 7))	('NF1', 'Gene', '4763', (4, 7))	('MEK', 'Gene', (30, 33))	('MEK', 'Gene', '5609', (30, 33))
147391	33448230	Further study is warranted to further define parallel PI3K-mTOR pathway inhibition as a strategy to overcome resistance to BRAF/MEK inhibition, with some suggested benefit of this approach in a series of five V600-mutated gliomas employing vemurafenib combined with everolimus.	('vemurafenib', 'Chemical', 'MESH:D000077484', (240, 251))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('MEK', 'Gene', (128, 131))	('MEK', 'Gene', '5609', (128, 131))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('everolimus', 'Chemical', 'MESH:D000068338', (266, 276))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('gliomas', 'Disease', (222, 229))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))	('mTOR', 'Gene', '2475', (59, 63))	('V600-mutated', 'Var', (209, 221))	('mTOR', 'Gene', (59, 63))
147398	33448230	BRAF, NF1 and FGFR1 mutations are additional well-characterized drivers of MAPK signaling in adult PA.	('FGFR1', 'Gene', (14, 19))	('BRAF', 'Gene', '673', (0, 4))	('FGFR1', 'Gene', '2260', (14, 19))	('NF1', 'Gene', (6, 9))	('BRAF', 'Gene', (0, 4))	('NF1', 'Gene', '4763', (6, 9))	('mutations', 'Var', (20, 29))
147409	32120790	In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype.	('mutation', 'Var', (263, 271))	('isocitrate dehydrogenase 1', 'Gene', '3417', (229, 255))	('patient', 'Species', '9606', (13, 20))	('GFSCAN', 'Chemical', '-', (81, 87))	('IDH1', 'Gene', (257, 261))	('GSC', 'Chemical', '-', (29, 32))	('isocitrate dehydrogenase 1', 'Gene', (229, 255))
147411	32120790	More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&F, which could be an aid in clinical decision-making for these DIGs.	('mutant', 'Var', (62, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('F', 'Chemical', 'MESH:D005461', (137, 138))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('IDH1', 'Gene', (57, 61))	('glioma GSCs', 'Disease', (98, 109))	('DIGs', 'Chemical', '-', (200, 204))	('glioblastoma', 'Disease', (69, 81))	('glioma GSCs', 'Disease', 'MESH:D005910', (98, 109))	('lower grade', 'Disease', (86, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
147413	32120790	Diffusely infiltrating gliomas (DIGs) are categorized by the World Health Organization (WHO) into diffuse astrocytomas, oligodendrogliomas, and isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant (mut) and wild-type (wt) glioblastomas, according to their histological grades, IDH1/2 status, and chromosome arm 1p and 19q (1p19q) co-deletion.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (120, 138))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('astrocytomas', 'Disease', 'MESH:D001254', (106, 118))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('glioblastomas', 'Phenotype', 'HP:0012174', (218, 231))	('gliomas', 'Disease', (131, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('oligodendrogliomas', 'Disease', (120, 138))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('IDH1/2', 'Gene', '3417;3418', (273, 279))	('IDH1/2', 'Gene', '3417;3418', (178, 184))	('IDH1/2', 'Gene', (273, 279))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('glioblastomas', 'Disease', (218, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('isocitrate dehydrogenase 1', 'Gene', (144, 170))	('isocitrate dehydrogenase 1', 'Gene', '3417', (144, 170))	('IDH1/2', 'Gene', (178, 184))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('glioblastomas', 'Disease', 'MESH:D005909', (218, 231))	('gliomas', 'Disease', (23, 30))	('astrocytomas', 'Disease', (106, 118))	('mutant', 'Var', (186, 192))	('DIGs', 'Chemical', '-', (32, 36))
147415	32120790	Glioblastoma is a WHO grade IV disease with poor prognosis, and only about 10% of these malignancies possess IDH1/2 mutation without 1p19q co-deletion.	('Glioblastoma', 'Disease', (0, 12))	('IDH1/2', 'Gene', (109, 115))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('mutation', 'Var', (116, 124))	('malignancies', 'Disease', (88, 100))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('IV disease', 'Disease', 'MESH:D020432', (28, 38))	('IDH1/2', 'Gene', '3417;3418', (109, 115))	('IV disease', 'Disease', (28, 38))
147416	32120790	On the other hand, diffuse astrocytomas (IDH mutant and 1p19q intact) and oligodendrogliomas (IDH mutant and 1p19q co-deleted) belong to WHO grades II and III, which represent "lower-grade gliomas" (LGGs) in The Cancer Genome Atlas (TCGA).	('IDH', 'Gene', (41, 44))	('astrocytomas', 'Disease', 'MESH:D001254', (27, 39))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (74, 92))	('Cancer', 'Disease', (212, 218))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('1p19q', 'Var', (56, 61))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('IDH', 'Gene', (94, 97))	('IDH', 'Gene', '3417', (41, 44))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('oligodendrogliomas', 'Disease', (74, 92))	('Cancer', 'Disease', 'MESH:D009369', (212, 218))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('IDH', 'Gene', '3417', (94, 97))	('astrocytomas', 'Disease', (27, 39))	('gliomas', 'Disease', (85, 92))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('gliomas', 'Disease', (189, 196))
147429	32120790	The obtained GFSCAN and genomic data were combined to determine the best culture conditions according to IDH1 mutations, 1p19q co-deletion, and ATRX chromatin remodeler (ATRX) gene mutations, which are key alterations in DIG (Figure 1).	('F', 'Chemical', 'MESH:D005461', (226, 227))	('mutations', 'Var', (110, 119))	('IDH1', 'Gene', (105, 109))	('F', 'Chemical', 'MESH:D005461', (14, 15))	('GFSCAN', 'Chemical', '-', (13, 19))	('DIG', 'Chemical', '-', (221, 224))	('mutations', 'Var', (181, 190))	('1p19q', 'Gene', (121, 126))
147438	32120790	Recently performed large-scale studies reported that the genomic profiles of LGGs and glioblastomas are distinct; glioblastomas show frequent alterations in the epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 2A (CDKN2A), whereas genes encoding IDH1/2, ATRX, tumor protein P53 (TP53), capicua transcriptional repressor (CIC), and far upstream element binding protein 1 (FUBP1) are frequently altered in LGGs with or without 1p19q co-deletion.	('glioblastomas', 'Disease', 'MESH:D005909', (114, 127))	('EGFR', 'Gene', (195, 199))	('far upstream element binding protein 1', 'Gene', (400, 438))	('alterations', 'Reg', (142, 153))	('1p19q co-deletion', 'Var', (494, 511))	('phosphatase and tensin homolog', 'Gene', '5728', (202, 232))	('CDKN2A', 'Gene', '1029', (283, 289))	('ATRX', 'Gene', (323, 327))	('TP53', 'Gene', (348, 352))	('LGGs', 'Disease', (473, 477))	('PTEN', 'Gene', (234, 238))	('FUBP1', 'Gene', (440, 445))	('IDH1/2', 'Gene', '3417;3418', (315, 321))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('glioblastomas', 'Disease', (86, 99))	('IDH1/2', 'Gene', (315, 321))	('tumor protein P53', 'Gene', '7157', (329, 346))	('glioblastomas', 'Phenotype', 'HP:0012174', (114, 127))	('glioblastomas', 'Disease', 'MESH:D005909', (86, 99))	('EGFR', 'Gene', '1956', (195, 199))	('PTEN', 'Gene', '5728', (234, 238))	('capicua transcriptional repressor', 'Gene', '23152', (355, 388))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('tumor protein P53', 'Gene', (329, 346))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (245, 281))	('FUBP1', 'Gene', '8880', (440, 445))	('TP53', 'Gene', '7157', (348, 352))	('far upstream element binding protein 1', 'Gene', '8880', (400, 438))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('CDKN2A', 'Gene', (283, 289))	('epidermal growth factor receptor', 'Gene', (161, 193))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (245, 281))	('glioblastomas', 'Disease', (114, 127))	('altered', 'Reg', (462, 469))	('epidermal growth factor receptor', 'Gene', '1956', (161, 193))	('glioblastomas', 'Phenotype', 'HP:0012174', (86, 99))	('capicua transcriptional repressor', 'Gene', (355, 388))
147440	32120790	In our cohort, all LGGs (n = 19) and six out of 53 (11.3%) of the glioblastomas harbored IDH1 mutations; among the LGGs, nine (47.4%) showed 1p19q co-deletion, while no samples showed 1p19q co-deletion in glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (205, 218))	('glioblastomas', 'Disease', (66, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('glioblastomas harbored IDH1', 'Disease', (66, 93))	('mutations', 'Var', (94, 103))	('glioblastomas', 'Disease', (205, 218))	('glioblastomas harbored IDH1', 'Disease', 'MESH:D005909', (66, 93))	('glioblastomas', 'Phenotype', 'HP:0012174', (66, 79))	('1p19q co-deletion', 'Var', (141, 158))	('glioblastomas', 'Phenotype', 'HP:0012174', (205, 218))	('glioblastomas', 'Disease', 'MESH:D005909', (66, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))
147441	32120790	Other frequently mutated genes in glioblastomas, such as EGFR and PTEN, displayed similar mutation frequencies as in previous reports, although IDH1, TP53, and ATRX mutations occur more frequently in this glioblastoma cohort (Figure 2A and Table S3).	('TP53', 'Gene', (150, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('IDH1', 'Gene', (144, 148))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('mutations', 'Var', (165, 174))	('TP53', 'Gene', '7157', (150, 154))	('EGFR', 'Gene', (57, 61))	('F', 'Chemical', 'MESH:D005461', (226, 227))	('PTEN', 'Gene', (66, 70))	('F', 'Chemical', 'MESH:D005461', (59, 60))	('glioblastoma', 'Disease', (34, 46))	('ATRX', 'Gene', (160, 164))	('glioblastomas', 'Disease', (34, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	('PTEN', 'Gene', '5728', (66, 70))	('glioblastomas', 'Disease', 'MESH:D005909', (34, 47))	('EGFR', 'Gene', '1956', (57, 61))	('glioblastoma', 'Disease', (205, 217))
147442	32120790	Additionally, FUBP1, CIC, Notch homolog 1, translocation-associated (Drosophila) (NOTCH1), ATRX, and TP53 mutations were accompanied by IDH1 mutation in GFSCAN LGGs (Figure 2A and Table S3), which is consistent with the results of previous studies.	('Notch', 'Gene', (26, 31))	('GFSCAN', 'Chemical', '-', (153, 159))	('FUBP1', 'Gene', '8880', (14, 19))	('F', 'Chemical', 'MESH:D005461', (154, 155))	('TP53', 'Gene', '7157', (101, 105))	('F', 'Chemical', 'MESH:D005461', (14, 15))	('FUBP1', 'Gene', (14, 19))	('IDH1', 'Gene', (136, 140))	('Notch', 'Gene', '4853', (26, 31))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('F', 'Chemical', 'MESH:D005461', (166, 167))	('mutation', 'Var', (141, 149))
147444	32120790	In general, IDH1 mutation is a critical biomarker that is used to classify DIGs into clinically and biologically similar subgroups.	('DIGs', 'Chemical', '-', (75, 79))	('mutation', 'Var', (17, 25))	('IDH1', 'Gene', (12, 16))
147445	32120790	Mutant IDH is frequent in LGGs but also detected in 50-88% of secondary glioblastomas and in 5% of primary glioblastomas, resulting in altered 2-hydroxyglutarate production and altered DNA methylation.	('IDH', 'Gene', (7, 10))	('glioblastomas', 'Disease', (107, 120))	('glioblastomas', 'Disease', (72, 85))	('IDH', 'Gene', '3417', (7, 10))	('glioblastomas', 'Disease', 'MESH:D005909', (107, 120))	('altered', 'Reg', (135, 142))	('altered', 'Reg', (177, 184))	('glioblastomas', 'Phenotype', 'HP:0012174', (107, 120))	('DNA methylation', 'MPA', (185, 200))	('glioblastomas', 'Disease', 'MESH:D005909', (72, 85))	('LGGs', 'Disease', (26, 30))	('glioblastomas', 'Phenotype', 'HP:0012174', (72, 85))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('Mutant', 'Var', (0, 6))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (143, 161))	('2-hydroxyglutarate production', 'MPA', (143, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
147452	32120790	For example, all four IDH1-wt glioblastoma GSCs with BRAF hotspot mutations (V600E and D594H) were classified into the E&F-independent group (Figure 3 and Table S4), although BRAF alterations are rarely observed in adult HGG or other diffusely infiltrating gliomas (2-5%).	('D594H', 'Mutation', 'rs397516896', (87, 92))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('glioblastoma GSCs', 'Disease', (30, 47))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('F', 'Chemical', 'MESH:D005461', (142, 143))	('F', 'Chemical', 'MESH:D005461', (56, 57))	('gliomas', 'Disease', (257, 264))	('glioblastoma GSCs', 'Disease', 'MESH:D005909', (30, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('V600E', 'Var', (77, 82))	('gliomas', 'Disease', 'MESH:D005910', (257, 264))	('BRAF', 'Gene', '673', (53, 57))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('BRAF', 'Gene', (53, 57))	('D594H', 'Var', (87, 92))	('gliomas', 'Phenotype', 'HP:0009733', (257, 264))	('F', 'Chemical', 'MESH:D005461', (178, 179))	('F', 'Chemical', 'MESH:D005461', (121, 122))
147460	32120790	We evaluated the effects of an MDK-neutralizing antibody on an E&F-independent GSC from our GFSCAN cohort (BT-030T) using gene expression profiling, and cell cycle and proliferation-associated gene sets were significantly down-regulated in the MDK-neutralizing antibody-treated sample compared to the control sample (Figure S3).	('MDK', 'Gene', '4192', (31, 34))	('and proliferation-associated gene', 'Gene', (164, 197))	('GSC', 'Chemical', '-', (79, 82))	('MDK', 'Gene', '4192', (244, 247))	('GFSCAN', 'Chemical', '-', (92, 98))	('MDK', 'Gene', (31, 34))	('significantly', 'NegReg', (208, 221))	('MDK', 'Gene', (244, 247))	('F', 'Chemical', 'MESH:D005461', (93, 94))	('F', 'Chemical', 'MESH:D005461', (317, 318))	('F', 'Chemical', 'MESH:D005461', (65, 66))	('and cell', 'Gene', (149, 157))	('the', 'Var', (240, 243))
147463	32120790	Consistent with the original screening dataset, the mesenchymal subtype and BRAF mutations were dominant in the E&F-independent group, and over 90% of proneural glioblastomas belonged to the E&F-dependent group (Figure S4B,C).	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('glioblastomas', 'Phenotype', 'HP:0012174', (161, 174))	('F', 'Chemical', 'MESH:D005461', (212, 213))	('glioblastomas', 'Disease', 'MESH:D005909', (161, 174))	('of proneural', 'Disease', (148, 160))	('F', 'Chemical', 'MESH:D005461', (79, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (161, 173))	('glioblastomas', 'Disease', (161, 174))	('mutations', 'Var', (81, 90))	('F', 'Chemical', 'MESH:D005461', (114, 115))	('F', 'Chemical', 'MESH:D005461', (193, 194))
147464	32120790	Among the E&F-independent samples, we selected three IDH1-wt GSCs (BT-S01T and BT-S02T: mesenchymal subtype; BT-S03T: classical subtype) and evaluated their growth rates with GFSCAN.	('their', 'MPA', (151, 156))	('and BT-S02T', 'Var', (75, 86))	('GFSCAN', 'Chemical', '-', (175, 181))	('BT-S01T', 'CellLine', 'CVCL:4134', (67, 74))	('S02T', 'Mutation', 'p.S02T', (82, 86))	('F', 'Chemical', 'MESH:D005461', (176, 177))	('GSCs', 'Var', (61, 65))	('F', 'Chemical', 'MESH:D005461', (12, 13))	('GSC', 'Chemical', '-', (61, 64))	('S03T', 'Mutation', 'p.S03T', (112, 116))
147466	32120790	It has been reported that patient-derived GSCs with IDH1 mutation were hardly grown in conventional culture conditions and scarcely established in preclinical platforms previously.	('patient', 'Species', '9606', (26, 33))	('mutation', 'Var', (57, 65))	('GSC', 'Chemical', '-', (42, 45))	('IDH1', 'Gene', (52, 56))
147467	32120790	IDH1/2 mutations have been estimated to occur in 54-100% of diffuse astrocytomas (WHO II), 66.1% of anaplastic astrocytomas (WHO III), and 64-93% of oligodendrogliomas (WHO II and III) cases.	('oligodendrogliomas', 'Disease', (149, 167))	('anaplastic astrocytomas', 'Disease', (100, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('mutations', 'Var', (7, 16))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('astrocytomas', 'Disease', (68, 80))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (100, 123))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (149, 167))	('IDH1/2', 'Gene', (0, 6))	('astrocytomas', 'Disease', 'MESH:D001254', (68, 80))	('occur', 'Reg', (40, 45))	('astrocytomas', 'Disease', (111, 123))
147468	32120790	In addition, 1p19q co-deletion is a genetic marker that can distinguish oligodendroglioma from astrocytoma.	('1p19q co-deletion', 'Var', (13, 30))	('oligodendroglioma', 'Disease', (72, 89))	('oligodendroglioma', 'Disease', 'MESH:D009837', (72, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('astrocytoma', 'Disease', 'MESH:D001254', (95, 106))	('astrocytoma', 'Disease', (95, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (95, 106))
147469	32120790	LGGs with an IDH1 mutation and 1p19q co-deletion show oligodendroglioma histological characteristics and arise from TERT activation, mutations in CIC and FUBP1, and activating alterations in the phosphoinositide-3-kinase (PI3K) pathway.	('TERT', 'Gene', (116, 120))	('TERT', 'Gene', '7015', (116, 120))	('FUBP1', 'Gene', (154, 159))	('CIC', 'Gene', (146, 149))	('oligodendroglioma', 'Disease', (54, 71))	('activating', 'PosReg', (165, 175))	('IDH1', 'Gene', (13, 17))	('phosphoinositide-3-kinase', 'Gene', (195, 220))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutations', 'Var', (133, 142))	('mutation', 'Var', (18, 26))	('1p19q', 'Var', (31, 36))	('phosphoinositide-3-kinase', 'Gene', '5295', (195, 220))	('FUBP1', 'Gene', '8880', (154, 159))	('oligodendroglioma', 'Disease', 'MESH:D009837', (54, 71))	('arise from', 'Reg', (105, 115))
147470	32120790	On the other hand, LGGs with IDH1 mutation and no 1p19q co-deletion accompanied by ATRX and TP53 mutations represent astrocytomas.	('IDH1', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('astrocytomas', 'Disease', 'MESH:D001254', (117, 129))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('no 1p19q co-deletion', 'Var', (47, 67))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('astrocytomas', 'Disease', (117, 129))
147473	32120790	When the cell growth index in each condition was evaluated depending on the 1p19q co-deletion status in IDH1-mut GSCs (Figure 5A,B), 1p19q-intact IDH1-mut GSCs were the most responsive to placental growth factor (PlGF)/interleukin-6 (IL-6)/E&F, and showed 1.44-fold higher cell growth index than under NBE conditions (Figure 5A, upper panel).	('placental growth factor', 'Gene', (188, 211))	('placental growth factor', 'Gene', '5228', (188, 211))	('GSC', 'Chemical', '-', (155, 158))	('interleukin-6', 'Gene', (219, 232))	('F', 'Chemical', 'MESH:D005461', (119, 120))	('1p19q-intact', 'Var', (133, 145))	('PlGF', 'Gene', (213, 217))	('responsive', 'MPA', (174, 184))	('interleukin-6', 'Gene', '3569', (219, 232))	('IL-6', 'Gene', (234, 238))	('F', 'Chemical', 'MESH:D005461', (216, 217))	('higher cell growth', 'CPA', (266, 284))	('1.44-fold', 'PosReg', (256, 265))	('GSC', 'Chemical', '-', (113, 116))	('F', 'Chemical', 'MESH:D005461', (318, 319))	('PlGF', 'Gene', '5228', (213, 217))	('IL-6', 'Gene', '3569', (234, 238))	('F', 'Chemical', 'MESH:D005461', (242, 243))
147474	32120790	On the other hand, the PEDF/sonic hedgehog (SHH)/E&F condition was the most effective for promoting cell proliferation in 1p19q co-deleted IDH1-mut GSCs, and the cell growth index of this condition was 1.75-fold higher than that of NBE condition (Figure 5B, upper panel).	('F', 'Chemical', 'MESH:D005461', (26, 27))	('1.75-fold', 'PosReg', (202, 211))	('the cell growth', 'CPA', (158, 173))	('PEDF/sonic hedgehog', 'Gene', (23, 42))	('promoting cell', 'CPA', (90, 104))	('F', 'Chemical', 'MESH:D005461', (247, 248))	('SHH', 'Gene', '6469', (44, 47))	('GSC', 'Chemical', '-', (148, 151))	('F', 'Chemical', 'MESH:D005461', (51, 52))	('SHH', 'Gene', (44, 47))	('PEDF/sonic hedgehog', 'Gene', '6469;5176', (23, 42))	('in 1p19q', 'Var', (119, 127))	('co-deleted', 'Gene', (128, 138))	('for', 'PosReg', (86, 89))
147477	32120790	This revealed that IDH1-mut GSCs with ATRX mutations showed higher cell propagation levels in culture media, which included transforming growth factor-beta (TGF-beta)-containing including 'neurTGF-beta/E&F', 'platelet-derived growth factor (PDGF)/TGF-beta/E&F', and 'MDK/TGF-beta/E&F' conditions compared to ATRX-wt IDH1-mut GSCs (Figure 5C and Table S4); this finding is supported by the observation that a TGF-beta-dependent pathway was significantly enriched in IDH1-mut DIGs with ATRX alterations compared to those without ATRX alterations (Figure 5D, NES = 1.994, false discovery rate < 0.001) in the TCGA LGG dataset.	('TGF-beta', 'Gene', '7039', (408, 416))	('F', 'Chemical', 'MESH:D005461', (159, 160))	('significantly', 'Gene', (439, 452))	('TGF-beta', 'Gene', '7039', (193, 201))	('MDK', 'Gene', '4192', (267, 270))	('observation', 'Gene', (389, 400))	('TGF-beta', 'Gene', (408, 416))	('IDH1-mut', 'Gene', (465, 473))	('pathway', 'PosReg', (427, 434))	('media', 'Species', '1115375', (102, 107))	('TGF-beta', 'Gene', '7039', (271, 279))	('DIGs', 'Chemical', '-', (474, 478))	('TGF-beta', 'Gene', '7039', (247, 255))	('TGF-beta', 'Gene', (193, 201))	('F', 'Chemical', 'MESH:D005461', (244, 245))	('F', 'Chemical', 'MESH:D005461', (331, 332))	('F', 'Chemical', 'MESH:D005461', (204, 205))	('F', 'Chemical', 'MESH:D005461', (410, 411))	('MDK', 'Gene', (267, 270))	('TGF-beta', 'Gene', (247, 255))	('TGF-beta', 'Gene', (271, 279))	('F', 'Chemical', 'MESH:D005461', (545, 546))	('F', 'Chemical', 'MESH:D005461', (195, 196))	('GSC', 'Chemical', '-', (28, 31))	('F', 'Chemical', 'MESH:D005461', (258, 259))	('F', 'Chemical', 'MESH:D005461', (282, 283))	('F', 'Chemical', 'MESH:D005461', (249, 250))	('F', 'Chemical', 'MESH:D005461', (273, 274))	('TGF-beta', 'Gene', '7039', (157, 165))	('DIGs', 'Var', (474, 478))	('GSC', 'Chemical', '-', (325, 328))	('TGF-beta', 'Gene', (157, 165))
147489	32120790	As IDH is a component of the Krebs cycle and converts isocitrate and cofactor NAD+ to carbon dioxide, NADH and alpha-ketoglutarate; IDH mutations cause a buildup of the onco-metabolite D-2-hydroxyglutarate, resulting in the distinct expression of a GSC phenotype.	('isocitrate', 'Chemical', 'MESH:C034219', (54, 64))	('onco-metabolite D-2-hydroxyglutarate', 'MPA', (169, 205))	('GSC phenotype', 'MPA', (249, 262))	('IDH', 'Gene', '3417', (3, 6))	('NAD+', 'Chemical', 'MESH:D009243', (78, 82))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (185, 205))	('expression', 'MPA', (233, 243))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (111, 130))	('IDH', 'Gene', (132, 135))	('IDH', 'Gene', '3417', (132, 135))	('mutations', 'Var', (136, 145))	('cause', 'Reg', (146, 151))	('GSC', 'Chemical', '-', (249, 252))	('Krebs', 'Chemical', '-', (29, 34))	('carbon dioxide', 'Chemical', 'MESH:D002245', (86, 100))	('IDH', 'Gene', (3, 6))	('NADH', 'Chemical', 'MESH:D009243', (102, 106))	('buildup', 'PosReg', (154, 161))
147499	32120790	The recent WHO 2016 criteria utilized 1p19q co-deletion to distinguish IDH-mutated DIGs with oligodendroglial phenotypes from astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (126, 138))	('DIGs', 'Chemical', '-', (83, 87))	('DIGs', 'Disease', (83, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('1p19q', 'Var', (38, 43))	('astrocytomas', 'Disease', (126, 138))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (71, 74))
147500	32120790	We tried to figure out the best culture condition for glioblastoma with IDH1 mutation and LGG with/without 1p19q co-deletion, previously known as hard to grow and easily eliminated in standard NBE culture conditions.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('IDH1', 'Gene', (72, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('mutation', 'Var', (77, 85))	('glioblastoma', 'Disease', (54, 66))
147503	32120790	In this study, the PEDF/SHH/E&F combination was critical for the steady propagation of a subset of IDH1-mut GSCs harboring 1p19q co-deletion and PlGF/IL-6/E&F was essential for another subset of IDH1-mut GSC spheroids with intact 1p19q.	('harboring 1p19q', 'Var', (113, 128))	('PlGF', 'Gene', (145, 149))	('F', 'Chemical', 'MESH:D005461', (157, 158))	('PEDF', 'Gene', '5176', (19, 23))	('F', 'Chemical', 'MESH:D005461', (30, 31))	('GSC', 'Chemical', '-', (108, 111))	('SHH', 'Gene', (24, 27))	('PlGF', 'Gene', '5228', (145, 149))	('GSC', 'Chemical', '-', (204, 207))	('IL-6', 'Gene', (150, 154))	('PEDF', 'Gene', (19, 23))	('F', 'Chemical', 'MESH:D005461', (148, 149))	('SHH', 'Gene', '6469', (24, 27))	('IL-6', 'Gene', '3569', (150, 154))	('F', 'Chemical', 'MESH:D005461', (22, 23))
147504	32120790	On the other hand, ATRX mutations are mutually exclusive from 1p19q co-deletion, but are associated with IDH1 mutation, suggesting that ATRX drives the lineage-specific formation of astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (182, 194))	('astrocytoma', 'Phenotype', 'HP:0009592', (182, 193))	('ATRX', 'Gene', (19, 23))	('1p19q', 'Var', (62, 67))	('astrocytomas', 'Disease', (182, 194))	('mutations', 'Var', (24, 33))
147505	32120790	Among all the 132 conditions, three containing TGF-beta (IGF1/TGF-beta/E&F, PDGF/TGF-beta/E&F, and MDK/TGF-beta/E&F) were particularly effective for cultivating IDH1-mut GSCs harboring ATRX mutations compared to ATRX-wt GSCs.	('F', 'Chemical', 'MESH:D005461', (105, 106))	('TGF-beta', 'Gene', (62, 70))	('F', 'Chemical', 'MESH:D005461', (79, 80))	('F', 'Chemical', 'MESH:D005461', (49, 50))	('MDK', 'Gene', '4192', (99, 102))	('F', 'Chemical', 'MESH:D005461', (73, 74))	('GSC', 'Chemical', '-', (220, 223))	('F', 'Chemical', 'MESH:D005461', (64, 65))	('IGF1', 'Gene', (57, 61))	('F', 'Chemical', 'MESH:D005461', (92, 93))	('IDH1-mut', 'Gene', (161, 169))	('MDK', 'Gene', (99, 102))	('TGF-beta', 'Gene', '7039', (81, 89))	('F', 'Chemical', 'MESH:D005461', (83, 84))	('F', 'Chemical', 'MESH:D005461', (59, 60))	('TGF-beta', 'Gene', '7039', (103, 111))	('GSC', 'Chemical', '-', (170, 173))	('TGF-beta', 'Gene', (81, 89))	('TGF-beta', 'Gene', '7039', (47, 55))	('TGF-beta', 'Gene', (103, 111))	('GSCs', 'Var', (170, 174))	('TGF-beta', 'Gene', '7039', (62, 70))	('IGF1', 'Gene', '3479', (57, 61))	('TGF-beta', 'Gene', (47, 55))	('F', 'Chemical', 'MESH:D005461', (114, 115))
147506	32120790	Interestingly, we also confirmed that TGF-beta signaling was up-regulated in ATRX-mut DIGs or astrocytomas in the independent public dataset, highlighting the tumor-promoting role of TGF-beta in DIGs with ATRX mutations.	('DIGs', 'Chemical', '-', (195, 199))	('TGF-beta', 'Gene', (38, 46))	('mutations', 'Var', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('TGF-beta', 'Gene', (183, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('up-regulated', 'PosReg', (61, 73))	('DIGs', 'Chemical', '-', (86, 90))	('tumor', 'Disease', (159, 164))	('astrocytomas', 'Disease', 'MESH:D001254', (94, 106))	('TGF-beta', 'Gene', '7039', (38, 46))	('TGF-beta', 'Gene', '7039', (183, 191))	('ATRX-mut DIGs', 'Disease', (77, 90))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('astrocytomas', 'Disease', (94, 106))
147532	32120790	For all 72 DIG samples (19 LGGs and 53 glioblastomas from 60 patients; summarized in Table S2) that were subjected to GFSCAN, either WES (n = 35) or glioma-specific targeted DNA sequencing (GliomaSCANTM, n = 37) was performed to reveal single-nucleotide variations, insertions and deletions, and copy number alterations (CNAs) (Tables S2 and S3).	('glioblastomas', 'Phenotype', 'HP:0012174', (39, 52))	('insertions', 'Var', (266, 276))	('GFSCAN', 'Chemical', '-', (118, 124))	('DIG', 'Chemical', '-', (11, 14))	('glioma', 'Disease', (149, 155))	('copy number alterations', 'Var', (296, 319))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('glioblastomas', 'Disease', 'MESH:D005909', (39, 52))	('deletions', 'Var', (281, 290))	('patients', 'Species', '9606', (61, 69))	('F', 'Chemical', 'MESH:D005461', (119, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioblastomas', 'Disease', (39, 52))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('single-nucleotide variations', 'Var', (236, 264))	('Glioma', 'Phenotype', 'HP:0009733', (190, 196))
147550	32120790	IDH1-mutant GSCs also showed significantly lower cell growth indexes than IDH1-wt GSCs under NBE.	('cell growth indexes', 'CPA', (49, 68))	('GSC', 'Chemical', '-', (12, 15))	('IDH1-mutant', 'Var', (0, 11))	('GSC', 'Chemical', '-', (82, 85))	('lower', 'NegReg', (43, 48))
147552	32120790	Furthermore, PIGF/IL-6/E&F and PEDF/SHH/E&F effectively increased cell growth indexes for IDH1-mut/1p19q intact GSCs and IDH1-mut/1p19q co-deleted GSCs, respectively.	('IL-6', 'Gene', '3569', (18, 22))	('GSC', 'Chemical', '-', (147, 150))	('SHH', 'Gene', '6469', (36, 39))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('F', 'Chemical', 'MESH:D005461', (34, 35))	('PEDF', 'Gene', (31, 35))	('F', 'Chemical', 'MESH:D005461', (25, 26))	('F', 'Chemical', 'MESH:D005461', (42, 43))	('SHH', 'Gene', (36, 39))	('effectively increased cell', 'CPA', (44, 70))	('PIGF', 'Gene', (13, 17))	('indexes', 'Var', (78, 85))	('GSC', 'Chemical', '-', (112, 115))	('PEDF', 'Gene', '5176', (31, 35))	('IL-6', 'Gene', (18, 22))	('GSCs', 'Var', (112, 116))	('F', 'Chemical', 'MESH:D005461', (16, 17))	('PIGF', 'Gene', '5281', (13, 17))
147558	32120790	D.-S.K., J.W.C., H.J.S., J.-I.L., and D.-H.N.	('J.-I.L.', 'Var', (25, 32))	('H.J.S.', 'Var', (17, 23))	('H.J.S', 'CellLine', 'CVCL:M891', (17, 22))
147585	30643174	Thus, the resulting 18 genes (POS_AP: ANXA2, CD44, DPEP1, IGBP2, IQGAP2, MMP2, MTTP, NCF1C, STEAP3, TCF19, TEAD, and TM6SF2; NEG_AP: ALOXE3, GABRD, LOC293392, LOC440905, PANX2, and SGSM1) not only represented genes that were significantly related to astrocytoma initiation and progression but also genes that exhibited heterogeneity among tumour samples and in terms of the prognosis (Fig.	('PANX2', 'Gene', (170, 175))	('tumour', 'Phenotype', 'HP:0002664', (339, 345))	('IQGAP2', 'Gene', '10788', (65, 71))	('astrocytoma initiation', 'Disease', (250, 272))	('ANXA2', 'Gene', (38, 43))	('tumour', 'Disease', 'MESH:D009369', (339, 345))	('SGSM1', 'Gene', '129049', (181, 186))	('ALOXE3', 'Gene', (133, 139))	('tumour', 'Disease', (339, 345))	('GABRD', 'Gene', '2563', (141, 146))	('ALOXE3', 'Gene', '59344', (133, 139))	('GABRD', 'Gene', (141, 146))	('astrocytoma', 'Phenotype', 'HP:0009592', (250, 261))	('MMP2', 'Gene', (73, 77))	('SGSM1', 'Gene', (181, 186))	('STEAP3', 'Gene', '55240', (92, 98))	('NCF1C', 'Gene', (85, 90))	('TM6SF2', 'Gene', '53345', (117, 123))	('ANXA2', 'Gene', '302', (38, 43))	('IQGAP2', 'Gene', (65, 71))	('MTTP', 'Gene', '4547', (79, 83))	('TM6SF2', 'Gene', (117, 123))	('CD44', 'Gene', '960', (45, 49))	('STEAP3', 'Gene', (92, 98))	('NCF1C', 'Gene', '654817', (85, 90))	('CD44', 'Gene', (45, 49))	('MMP2', 'Gene', '4313', (73, 77))	('TCF19', 'Gene', '6941', (100, 105))	('DPEP1', 'Gene', (51, 56))	('LOC440905', 'Var', (159, 168))	('DPEP1', 'Gene', '1800', (51, 56))	('MTTP', 'Gene', (79, 83))	('astrocytoma initiation', 'Disease', 'MESH:D001254', (250, 272))	('TCF19', 'Gene', (100, 105))	('PANX2', 'Gene', '56666', (170, 175))	('LOC293392', 'CellLine', 'CVCL:K268', (148, 157))	('LOC293392', 'Var', (148, 157))
147596	30643174	To validate this question, the patients in the training cohort were stratified based on several clinicopathological factors, including age, gender, grade, received therapy, IDH mutation status, MGMT methylation status and transcriptional subtypes.	('mutation', 'Var', (177, 185))	('IDH', 'Gene', (173, 176))	('MGMT', 'Gene', '4255', (194, 198))	('IDH', 'Gene', '3417', (173, 176))	('MGMT', 'Gene', (194, 198))	('patients', 'Species', '9606', (31, 39))
147607	30643174	Frequent mutations in IDH1, ATRX and TP53 were significantly enriched in cases with lower AP scores, whereas PTEN, EGFR, RB1, FLG, NF1, SPTA1, PIK3CA, SEMA3C, KEL, TTN, RYR2, MUC17 and PCLO were significantly enriched in cases with higher AP scores.	('RYR2', 'Gene', (169, 173))	('FLG', 'Gene', (126, 129))	('mutations', 'Var', (9, 18))	('KEL', 'Gene', (159, 162))	('RB1', 'Gene', '5925', (121, 124))	('PTEN', 'Gene', '5728', (109, 113))	('EGFR', 'Gene', (115, 119))	('RYR2', 'Gene', '6262', (169, 173))	('TP53', 'Gene', (37, 41))	('PCLO', 'Gene', '27445', (185, 189))	('FLG', 'Gene', '2312', (126, 129))	('KEL', 'Gene', '3792', (159, 162))	('ATRX', 'Gene', (28, 32))	('TTN', 'Gene', '7273', (164, 167))	('MUC17', 'Gene', (175, 180))	('PIK3CA', 'Gene', '5290', (143, 149))	('ATRX', 'Gene', '546', (28, 32))	('TTN', 'Gene', (164, 167))	('MUC17', 'Gene', '140453', (175, 180))	('SEMA3C', 'Gene', (151, 157))	('NF1', 'Gene', '4763', (131, 134))	('SPTA1', 'Gene', '6708', (136, 141))	('EGFR', 'Gene', '1956', (115, 119))	('IDH1', 'Gene', (22, 26))	('TP53', 'Gene', '7157', (37, 41))	('PCLO', 'Gene', (185, 189))	('SPTA1', 'Gene', (136, 141))	('NF1', 'Gene', (131, 134))	('SEMA3C', 'Gene', '10512', (151, 157))	('RB1', 'Gene', (121, 124))	('PIK3CA', 'Gene', (143, 149))	('PTEN', 'Gene', (109, 113))	('lower', 'NegReg', (84, 89))	('IDH1', 'Gene', '3417', (22, 26))	('AP scores', 'MPA', (90, 99))
147633	30643174	Increasing evidence suggests that genetic changes (mutations, deletions, amplifications and overexpression) are involved in the development and progression of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('involved', 'Reg', (112, 120))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('amplifications', 'Var', (73, 87))	('deletions', 'Var', (62, 71))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))
147634	30643174	Established astrocytoma biomarkers, such as TP53 and IDH1 mutations and the recently discovered ATRX mutations, are thought to be early events in these tumours.	('mutations', 'Var', (58, 67))	('mutations', 'Var', (101, 110))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (152, 159))	('ATRX', 'Gene', (96, 100))	('IDH1', 'Gene', (53, 57))	('astrocytoma', 'Disease', 'MESH:D001254', (12, 23))	('IDH1', 'Gene', '3417', (53, 57))	('astrocytoma', 'Disease', (12, 23))	('TP53', 'Gene', '7157', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('astrocytoma', 'Phenotype', 'HP:0009592', (12, 23))	('ATRX', 'Gene', '546', (96, 100))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('TP53', 'Gene', (44, 48))
147635	30643174	In our analysis, TP53, IDH1 and ATRX were more likely to be mutated in the lower AP score group than in the higher AP score group, suggesting their roles in astrocytoma oncogenesis.	('lower AP score', 'Var', (75, 89))	('ATRX', 'Gene', '546', (32, 36))	('astrocytoma oncogenesis', 'Disease', (157, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('IDH1', 'Gene', (23, 27))	('mutated', 'Var', (60, 67))	('IDH1', 'Gene', '3417', (23, 27))	('astrocytoma oncogenesis', 'Disease', 'MESH:D063646', (157, 180))	('ATRX', 'Gene', (32, 36))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
147636	30643174	However, more mutation in PTEN and EGFR were detected in the high AP score group.	('detected', 'Reg', (45, 53))	('high', 'Var', (61, 65))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('mutation', 'Var', (14, 22))	('PTEN', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (26, 30))
147637	30643174	Mutations in the tumour suppressor gene PTEN are frequent events and are associated with therapeutic resistance, because PTEN is a key player in regulating glioblastoma oncogenesis.	('glioblastoma oncogenesis', 'Disease', 'MESH:D063646', (156, 180))	('PTEN', 'Gene', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('PTEN', 'Gene', '5728', (121, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('PTEN', 'Gene', (40, 44))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('PTEN', 'Gene', '5728', (40, 44))	('associated', 'Reg', (73, 83))	('Mutations', 'Var', (0, 9))	('glioblastoma oncogenesis', 'Disease', (156, 180))	('tumour', 'Disease', (17, 23))
147638	30643174	Alterations in signature oncogenes of GBM, such as EGFR, always confer a worse prognosis.	('Alterations', 'Var', (0, 11))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
147639	30643174	Different CNV patterns were also observed, such as EGFR, PDGFRA, and CDK4 amplification and CDKN2A/CDKN2B and PTEN deletion.	('PTEN', 'Gene', '5728', (110, 114))	('deletion', 'Var', (115, 123))	('CDK4', 'Gene', '1019', (69, 73))	('CDKN2A', 'Gene', (92, 98))	('EGFR', 'Gene', (51, 55))	('CDKN2B', 'Gene', (99, 105))	('CDKN2A', 'Gene', '1029', (92, 98))	('EGFR', 'Gene', '1956', (51, 55))	('PDGFRA', 'Gene', (57, 63))	('CDKN2B', 'Gene', '1030', (99, 105))	('PDGFRA', 'Gene', '5156', (57, 63))	('CDK4', 'Gene', (69, 73))	('PTEN', 'Gene', (110, 114))	('amplification', 'MPA', (74, 87))
147642	30643174	Accumulated evidence indicates that abnormal cell cycle progression may confer tumour advancement and radio-resistance of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('cell cycle progression', 'CPA', (45, 67))	('tumour advancement', 'Disease', 'MESH:D006223', (79, 97))	('glioma', 'Disease', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('abnormal', 'Var', (36, 44))	('abnormal cell cycle', 'Phenotype', 'HP:0011018', (36, 55))	('tumour advancement', 'Disease', (79, 97))	('radio-resistance', 'CPA', (102, 118))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
147647	30643174	The relatively normal CNS processes associated with a low AP score also suggest that astrocytoma formation and progression occur at the cost of sacrificing regular CNS function while gaining malignant phenotypes.	('low', 'Var', (54, 57))	('astrocytoma', 'Disease', 'MESH:D001254', (85, 96))	('progression', 'CPA', (111, 122))	('astrocytoma', 'Disease', (85, 96))	('astrocytoma', 'Phenotype', 'HP:0009592', (85, 96))
147653	30643174	Thus, we designed the inclusion criteria based on the newest WHO classification, with the training cohort comprised of pure 1p/19q non-codeletion cases with a mutant or wild type (WT) IDH status.	('IDH', 'Gene', (184, 187))	('mutant', 'Var', (159, 165))	('IDH', 'Gene', '3417', (184, 187))
147669	29719265	Mutant IDH1 Promotes Glioma Formation In Vivo Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM).	('IDH1', 'Gene', '15926', (7, 11))	('IDH1', 'Gene', (74, 78))	('glioblastoma', 'Disease', (151, 163))	('glioma', 'Disease', (130, 136))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('Glioma', 'Disease', 'MESH:D005910', (21, 27))	('IDH1', 'Gene', '15926', (74, 78))	('Glioma', 'Phenotype', 'HP:0009733', (21, 27))	('Glioma', 'Disease', (21, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('Promotes', 'PosReg', (12, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
147670	29719265	A causal role for IDH1R132H in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated.	('causal role', 'Reg', (2, 13))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH1R132H', 'Var', (18, 27))	('glioma', 'Disease', (31, 37))
147672	29719265	Immortal astrocytes expressing IDH1R132H exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth.	('anchorage-independent growth', 'CPA', (135, 163))	('NADPH', 'Chemical', 'MESH:D009249', (99, 104))	('NADPH', 'MPA', (99, 104))	('reduced', 'NegReg', (91, 98))	('elevated', 'PosReg', (51, 59))	('proliferation', 'CPA', (116, 129))	('IDH1R132H', 'Var', (31, 40))	('increased', 'PosReg', (106, 115))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (60, 82))
147673	29719265	Although not sufficient on its own, IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo.	('PDGFA', 'Gene', '18590', (62, 67))	('glioma development', 'Disease', (114, 132))	('Pten', 'Gene', (98, 102))	('promote', 'PosReg', (106, 113))	('loss', 'Var', (72, 76))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('PDGFA', 'Gene', (62, 67))	('a, Atrx, and', 'Gene', '22589', (85, 97))	('glioma development', 'Disease', 'MESH:D005910', (114, 132))	('R132H', 'Mutation', 'rs121913500', (40, 45))
147674	29719265	These tumors resembled pro-neural human mutant IDH1 GBM genetically, histologically, and functionally.	('human', 'Species', '9606', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('mutant', 'Var', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
147675	29719265	Our findings support the hypothesis that IDH1R132H promotes glioma development.	('glioma development', 'Disease', 'MESH:D005910', (60, 78))	('promotes', 'PosReg', (51, 59))	('IDH1R132H', 'Var', (41, 50))	('glioma development', 'Disease', (60, 78))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
147676	29719265	This model enhances our understanding of the biology of IDH1R132H-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease.	('R132H', 'Mutation', 'rs121913500', (60, 65))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('IDH1R132H-driven', 'Var', (56, 72))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('enhances', 'PosReg', (11, 19))	('gliomas', 'Disease', (73, 80))
147677	29719265	show that mutant IDH1 cooperates with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote gliomagenesis in vivo in a mouse model of glioma.	('loss', 'NegReg', (48, 52))	('PDGFA', 'Gene', '18590', (38, 43))	('glioma', 'Disease', (132, 138))	('glioma', 'Disease', (90, 96))	('Pten', 'Gene', (74, 78))	('mutant', 'Var', (10, 16))	('promote', 'PosReg', (82, 89))	('mouse', 'Species', '10090', (117, 122))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('PDGFA', 'Gene', (38, 43))	('IDH1', 'Gene', (17, 21))	('a, Atrx, and', 'Gene', '22589', (61, 73))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
147678	29719265	These tumors resemble proneural human mutant IDH1 glioblastoma and exhibit enhanced sensitivity to PARP inhibition in combination with chemotherapy.	('mutant', 'Var', (38, 44))	('PARP', 'Gene', (99, 103))	('enhanced', 'PosReg', (75, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('PARP', 'Gene', '11545', (99, 103))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('human', 'Species', '9606', (32, 37))	('IDH1', 'Gene', (45, 49))	('glioblastoma', 'Disease', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
147680	29719265	In 2008, high-throughput sequencing of World Health Organization (WHO) grade IV glioblastoma multiforme (GBM) tumors identified a novel mutation at codon 132 (R132) in isocitrate dehydrogenase 1 (IDH1) in 12% of the samples analyzed.	('isocitrate', 'Chemical', 'MESH:C034219', (168, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('R132', 'Var', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('glioblastoma multiforme (GBM) tumors', 'Disease', 'MESH:D005909', (80, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('IDH1', 'Gene', (196, 200))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))
147681	29719265	Further studies have found this mutation, or an analogous mutation at codon 172 (R172) in isocitrate dehydrogenase 2 (IDH2), to be present in ~80% of WHO grade II-III gliomas and secondary GBM.	('secondary GBM', 'Disease', (179, 192))	('IDH2', 'Gene', (118, 122))	('R172', 'Var', (81, 85))	('isocitrate', 'Chemical', 'MESH:C034219', (90, 100))	('GBM', 'Phenotype', 'HP:0012174', (189, 192))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))
147683	29719265	Subsequent studies have identified IDH mutations in acute myelogenous leukemia (AML), cholangiocarcinoma, cartilaginous tumors, prostate cancer, papillary breast carcinoma, melanoma, acute lymphoblastic leukemia, angioimmunoblastic T cell lymphoma, and primary myelofibrosis indicating that these genes may be important players in multiple tumor types (reviewed in).	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('acute myelogenous leukemia', 'Disease', (52, 78))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (189, 211))	('cartilaginous tumors', 'Disease', (106, 126))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cell lymphoma', 'Phenotype', 'HP:0012191', (234, 247))	('angioimmunoblastic T cell lymphoma', 'Disease', (213, 247))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (232, 247))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (52, 78))	('prostate cancer', 'Disease', 'MESH:D011471', (128, 143))	('lymphoma', 'Phenotype', 'HP:0002665', (239, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('mutations', 'Var', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (106, 126))	('papillary breast carcinoma', 'Disease', 'MESH:D002291', (145, 171))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('tumor', 'Disease', (120, 125))	('prostate cancer', 'Disease', (128, 143))	('AML', 'Disease', 'MESH:D015470', (80, 83))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('leukemia', 'Phenotype', 'HP:0001909', (203, 211))	('melanoma', 'Disease', (173, 181))	('AML', 'Phenotype', 'HP:0004808', (80, 83))	('myelofibrosis', 'Phenotype', 'HP:0011974', (261, 274))	('AML', 'Disease', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('angioimmunoblastic T cell lymphoma', 'Disease', 'MESH:D016399', (213, 247))	('acute lymphoblastic leukemia', 'Disease', (183, 211))	('primary myelofibrosis', 'Disease', 'MESH:D055728', (253, 274))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (183, 211))	('tumor', 'Disease', (340, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('papillary breast carcinoma', 'Disease', (145, 171))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('IDH', 'Gene', (35, 38))	('cholangiocarcinoma', 'Disease', (86, 104))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (58, 78))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (183, 211))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (52, 78))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('primary myelofibrosis', 'Disease', (253, 274))	('breast carcinoma', 'Phenotype', 'HP:0003002', (155, 171))
147687	29719265	Mutated IDH proteins utilize NADPH to reduce alpha-KG to R(-)-2-hydroxyglutarate (2-HG), which is supported by findings that 2-HG levels are elevated in mutant IDH1 gliomas.	('elevated', 'PosReg', (141, 149))	('IDH1', 'Gene', (160, 164))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('2-HG levels', 'MPA', (125, 136))	('mutant', 'Var', (153, 159))	('reduce', 'NegReg', (38, 44))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (57, 80))	('alpha-KG', 'Chemical', 'MESH:D007656', (45, 53))	('gliomas', 'Disease', (165, 172))	('NADPH', 'Chemical', 'MESH:D009249', (29, 34))	('Mutated', 'Var', (0, 7))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
147688	29719265	Thus, mutant IDH lowers the bioavailability of alpha-KG, while increased 2-HG competitively inhibits alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methylcytosine (5mC) hydroxylases, which mediate DNA demethylation.	('lowers', 'NegReg', (17, 23))	('mutant', 'Var', (6, 12))	('increased', 'PosReg', (63, 72))	('histone demethylases', 'Enzyme', (144, 164))	('alpha-KG', 'Chemical', 'MESH:D007656', (101, 109))	('5mC', 'Chemical', 'MESH:D044503', (205, 208))	('alpha-KG', 'Chemical', 'MESH:D007656', (47, 55))	('alpha-KG-dependent dioxygenases', 'Enzyme', (101, 132))	('TET', 'Chemical', 'MESH:C010349', (173, 176))	('cytosine', 'Chemical', 'MESH:D003596', (195, 203))	('bioavailability', 'MPA', (28, 43))	('inhibits', 'NegReg', (92, 100))	('IDH', 'Gene', (13, 16))
147689	29719265	As a result, gliomas harboring mutant IDH manifest a glioma-CpG island methylator phenotype (G-CIMP), which epigenetically alters the expression of numerous genes through DNA hypermethylation.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('mutant', 'Var', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('expression', 'MPA', (134, 144))	('IDH', 'Gene', (38, 41))	('glioma', 'Disease', (53, 59))	('alters', 'Reg', (123, 129))	('G-CIMP', 'Chemical', '-', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('gliomas', 'Disease', (13, 20))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Disease', (13, 19))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
147690	29719265	Recent genomic analysis of diffuse, low-grade gliomas (LGGs) (WHO grades II or III) identified three subclasses consisting of wild-type IDH and mutant IDH with, or without, 1p/19q co-deletion.	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('diffuse', 'Disease', (27, 34))	('mutant', 'Var', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
147691	29719265	IDH mutation appears to be an early event in glioma development due to its presence in lower grade tumors.	('IDH', 'Gene', (0, 3))	('glioma development', 'Disease', (45, 63))	('glioma development', 'Disease', 'MESH:D005910', (45, 63))	('mutation', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
147692	29719265	Nearly 90% of LGGs with an IDH mutation but no 1p/19q co-deletion also contained TP53 mutations and inactivating alterations of Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX).	('mutations', 'Var', (86, 95))	('contained', 'Reg', (71, 80))	('Thalassemia/Mental Retardation Syndrome X-Linked', 'Disease', 'MESH:C538258', (134, 182))	('Mental Retardation', 'Phenotype', 'HP:0001249', (146, 164))	('mutation', 'Var', (31, 39))	('inactivating alterations', 'Var', (100, 124))	('Thalassemia/Mental Retardation Syndrome X-Linked', 'Disease', (134, 182))	('TP53', 'Gene', (81, 85))
147697	29719265	Expression of a conditional knockin allele of mutant IDH1 using Nestin-Cre was perinatal lethal in all mice, while expression of mutant IDH1 using GFAP-Cre was perinatal lethal in 92% of mice; no gliomas were observed in surviving mice.	('mice', 'Species', '10090', (103, 107))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('IDH1', 'Gene', (53, 57))	('IDH1', 'Gene', (136, 140))	('mice', 'Species', '10090', (187, 191))	('mutant', 'Var', (46, 52))	('mice', 'Species', '10090', (231, 235))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))
147699	29719265	However, no gliomas were observed in these mice, which suggests that expression of mutant IDH1 alone is insufficient for glioma development.	('IDH1', 'Gene', (90, 94))	('mice', 'Species', '10090', (43, 47))	('gliomas', 'Disease', (12, 19))	('glioma development', 'Disease', (121, 139))	('mutant', 'Var', (83, 89))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('glioma development', 'Disease', 'MESH:D005910', (121, 139))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
147700	29719265	In this study, we delivered mutant IDH1 postnatally to nestin-expressing cells using the established RCAS/TVA glioma model.	('IDH1', 'Gene', (35, 39))	('mutant', 'Var', (28, 34))	('TVA glioma', 'Disease', 'MESH:D005910', (106, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('TVA glioma', 'Disease', (106, 116))	('RCAS', 'Chemical', '-', (101, 105))
147701	29719265	IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to transform immortal astrocytes in vitro and promote glioma development in vivo.	('glioma development', 'Disease', (121, 139))	('PDGFA', 'Gene', (26, 31))	('promote', 'PosReg', (113, 120))	('glioma development', 'Disease', 'MESH:D005910', (121, 139))	('loss', 'Var', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('a, Atrx, and', 'Gene', '22589', (49, 61))	('Pten', 'Gene', (62, 66))	('PDGFA', 'Gene', '18590', (26, 31))	('transform', 'Reg', (70, 79))
147702	29719265	Our findings functionally validate the role of IDH1R132H in driving glioma formation.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('IDH1R132H', 'Var', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('R132H', 'Mutation', 'rs121913500', (51, 56))	('glioma', 'Disease', (68, 74))
147705	29719265	No differences in astrocyte proliferation were observed between cells infected with RCAS-Cre alone or in combination with either RCAS-IDH1 or RCAS-IDH1R132H, despite Cre-mediated loss of Cdkn2a and expression of wild-type (WT) or mutant IDH1 (data not shown).	('RCAS', 'Chemical', '-', (129, 133))	('mutant', 'Var', (230, 236))	('RCAS-IDH1', 'Disease', 'None', (142, 151))	('Cdkn2a', 'Gene', (187, 193))	('RCAS-IDH1', 'Disease', (129, 138))	('RCAS-IDH1', 'Disease', (142, 151))	('RCAS-IDH1', 'Disease', 'None', (129, 138))	('RCAS', 'Chemical', '-', (142, 146))	('astrocyte proliferation', 'CPA', (18, 41))	('loss', 'NegReg', (179, 183))	('RCAS', 'Chemical', '-', (84, 88))	('IDH1', 'Gene', (237, 241))
147708	29719265	While no significant difference in proliferation was observed between uninfected N::TVA; Cdkn2alox/lox;Atrxlox/lox astrocytes compared to astrocytes infected with RCAS-Cre alone, a 1.5-fold increase in proliferation was observed when these astrocytes were infected with both RCAS-Cre and RCAS-IDH1R132H relative to RCAS-Cre alone (p = 0.004; Figure S1B).	('Atrxlox', 'Chemical', '-', (103, 110))	('lox', 'Gene', '16948', (111, 114))	('increase', 'PosReg', (190, 198))	('lox', 'Gene', (111, 114))	('proliferation', 'MPA', (202, 215))	('lox', 'Gene', '16948', (99, 102))	('RCAS', 'Chemical', '-', (275, 279))	('lox', 'Gene', '16948', (107, 110))	('lox', 'Gene', (99, 102))	('RCAS', 'Chemical', '-', (315, 319))	('lox', 'Gene', (107, 110))	('RCAS-IDH1R132H', 'Var', (288, 302))	('RCAS', 'Chemical', '-', (163, 167))	('RCAS', 'Chemical', '-', (288, 292))	('lox', 'Gene', '16948', (95, 98))	('alox/lox', 'Gene', '16948', (94, 102))	('TVA', 'Chemical', 'MESH:C050413', (84, 87))	('alox/lox', 'Gene', (94, 102))	('lox', 'Gene', (95, 98))
147710	29719265	In addition, IDH mutation clusters from human gliomas frequently include gain of chromosome 7, which contains platelet-derived growth factor alpha (PDGFA;7q11.23), and we have observed specific upregulation of Pdgfra mRNA in the presence of PDGFA expression in vivo.	('(PDGFA;', 'Gene', '18590', (147, 154))	('gain', 'PosReg', (73, 77))	('PDGFA', 'Gene', '18590', (241, 246))	('upregulation', 'PosReg', (194, 206))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('mutation', 'Var', (17, 25))	('PDGFA', 'Gene', '18590', (148, 153))	('gliomas', 'Disease', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('PDGFA', 'Gene', (241, 246))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('mRNA', 'MPA', (217, 221))	('Pdgfra', 'Gene', (210, 216))	('IDH', 'Gene', (13, 16))	('PDGFA', 'Gene', (148, 153))	('PDGFA;', 'Gene', (148, 154))	('human', 'Species', '9606', (40, 45))
147713	29719265	Because expression of PDGFA only modestly increased cellular proliferation in this context, we crossed N::TVA;Cdkn2alox/lox;Atrxlox/lox mice with conditional Pten (Ptenlox) mice to generate N::TVA; Cdkn2alox/lox;Atrxlox/lox;Ptenlox/lox mice and model loss of chromosome 10q, which we observed associated with progression of lower grade mutant IDH1 gliomas to GBM.	('lox', 'Gene', '16948', (228, 231))	('PDGFA', 'Gene', (22, 27))	('lox', 'Gene', (120, 123))	('alox/lox', 'Gene', (203, 211))	('TVA', 'Chemical', 'MESH:C050413', (193, 196))	('alox/lox', 'Gene', '16948', (115, 123))	('gliomas', 'Disease', 'MESH:D005910', (348, 355))	('lox', 'Gene', '16948', (220, 223))	('Ptenlox', 'Chemical', '-', (164, 171))	('TVA', 'Chemical', 'MESH:C050413', (106, 109))	('glioma', 'Phenotype', 'HP:0009733', (348, 354))	('PDGFA', 'Gene', '18590', (22, 27))	('alox/lox', 'Gene', (115, 123))	('lox', 'Gene', (228, 231))	('Atrxlox', 'Chemical', '-', (212, 219))	('loss', 'Var', (251, 255))	('mice', 'Species', '10090', (173, 177))	('mutant', 'Var', (336, 342))	('lox', 'Gene', '16948', (132, 135))	('mice', 'Species', '10090', (236, 240))	('Atrxlox', 'Chemical', '-', (124, 131))	('lox', 'Gene', '16948', (204, 207))	('gliomas', 'Phenotype', 'HP:0009733', (348, 355))	('lox', 'Gene', (220, 223))	('lox', 'Gene', '16948', (116, 119))	('lox', 'Gene', (132, 135))	('lox', 'Gene', (204, 207))	('lox', 'Gene', '16948', (232, 235))	('lox', 'Gene', (116, 119))	('lox', 'Gene', '16948', (168, 171))	('lox', 'Gene', '16948', (216, 219))	('Ptenlox', 'Chemical', '-', (224, 231))	('lox', 'Gene', (232, 235))	('lox', 'Gene', '16948', (128, 131))	('GBM', 'Phenotype', 'HP:0012174', (359, 362))	('lox', 'Gene', '16948', (208, 211))	('mice', 'Species', '10090', (136, 140))	('gliomas', 'Disease', (348, 355))	('lox', 'Gene', (168, 171))	('lox', 'Gene', (216, 219))	('IDH1', 'Gene', (343, 347))	('lox', 'Gene', '16948', (120, 123))	('lox', 'Gene', (128, 131))	('alox/lox', 'Gene', '16948', (203, 211))	('lox', 'Gene', (208, 211))
147716	29719265	These data demonstrate that IDH1R132H promotes the growth of immortal Cdkn2a-deficient mouse astrocytes in vitro, and this effect is enhanced by expression of PDGFA in combination with loss of Atrx and Pten.	('mouse', 'Species', '10090', (87, 92))	('Cdkn2a-deficient', 'Gene', (70, 86))	('PDGFA', 'Gene', '18590', (159, 164))	('promotes', 'PosReg', (38, 46))	('Atrx', 'Chemical', '-', (193, 197))	('IDH1R132H', 'Var', (28, 37))	('PDGFA', 'Gene', (159, 164))	('growth', 'MPA', (51, 57))	('enhanced', 'PosReg', (133, 141))
147719	29719265	Similarly, very few colonies were detected in astrocytes lacking Cdkn2a, Atrx, and Pten (Figure 1B); however, IDH1R132H expression significantly increased anchorage-independent growth in this context (p = 0.008; Figure 1B).	('increased', 'PosReg', (145, 154))	('R132H', 'Mutation', 'rs121913500', (114, 119))	('anchorage-independent growth', 'CPA', (155, 183))	('IDH1R132H expression', 'Var', (110, 130))	('a, Atrx, and', 'Gene', '22589', (70, 82))
147720	29719265	Furthermore, PDGFA combined with IDH1R132H expression significantly increased colony number and size, compared with PDGFA expression alone (p < 0.01; Figures 1B and S1C).	('PDGFA', 'Gene', '18590', (13, 18))	('IDH1R132H expression', 'Var', (33, 53))	('PDGFA', 'Gene', (116, 121))	('PDGFA', 'Gene', (13, 18))	('colony number', 'CPA', (78, 91))	('PDGFA', 'Gene', '18590', (116, 121))	('increased', 'PosReg', (68, 77))
147723	29719265	These findings demonstrate that mutant IDH1 promotes anchorage-independent growth of immortal Cdkn2a-deficient mouse astrocytes in vitro in PDGFA-activated cells with loss of Atrx and Pten.	('promotes', 'PosReg', (44, 52))	('anchorage-independent growth', 'CPA', (53, 81))	('Atrx', 'Chemical', '-', (175, 179))	('PDGFA', 'Gene', (140, 145))	('mouse', 'Species', '10090', (111, 116))	('IDH1', 'Gene', (39, 43))	('mutant', 'Var', (32, 38))	('PDGFA', 'Gene', '18590', (140, 145))
147725	29719265	R132H substitution in IDH1 alters the structure of the enzyme's active site and its enzymatic activity.	('structure of', 'MPA', (38, 50))	('R132H', 'Mutation', 'rs121913500', (0, 5))	('IDH1', 'Gene', (22, 26))	('alters', 'Reg', (27, 33))	('enzymatic', 'MPA', (84, 93))	('R132H', 'Var', (0, 5))
147726	29719265	Thus, rather than generating NADPH, IDH1R132H consumes NADPH to generate 2-HG.	('IDH1R132H', 'Var', (36, 45))	('2-HG', 'MPA', (73, 77))	('NADPH', 'Chemical', 'MESH:D009249', (55, 60))	('NADPH', 'Chemical', 'MESH:D009249', (29, 34))	('NADPH', 'MPA', (55, 60))	('R132H', 'Mutation', 'rs121913500', (40, 45))
147728	29719265	In the presence of isocitrate, cells expressing WT IDH1 generated significantly higher levels of NADPH compared with cells expressing IDH1R132H (p < 0.001; Figure 1C).	('isocitrate', 'Chemical', 'MESH:C034219', (19, 29))	('R132H', 'Mutation', 'rs121913500', (138, 143))	('levels', 'MPA', (87, 93))	('IDH1', 'Var', (51, 55))	('NADPH', 'Chemical', 'MESH:D009249', (97, 102))	('higher', 'PosReg', (80, 86))	('NADPH', 'MPA', (97, 102))
147729	29719265	To assess the neomorphic enzymatic activity of IDH1R132H, the level of 2-HG produced in each astrocyte culture expressing IDH1R132H alone, PDGFA alone, PDGFA and IDH1R132H, or PDGFA and WT IDH1 was quantitated using liquid chromatography/mass spectrophotometry (LC/MS).	('PDGFA', 'Gene', (139, 144))	('IDH1R132H', 'Var', (122, 131))	('R132H', 'Mutation', 'rs121913500', (51, 56))	('PDGFA', 'Gene', '18590', (176, 181))	('R132H', 'Mutation', 'rs121913500', (166, 171))	('PDGFA', 'Gene', '18590', (152, 157))	('PDGFA', 'Gene', '18590', (139, 144))	('PDGFA', 'Gene', (152, 157))	('PDGFA', 'Gene', (176, 181))	('R132H', 'Mutation', 'rs121913500', (126, 131))
147730	29719265	As expected, significantly higher levels of 2-HG were detected in cells expressing IDH1R132H compared with the parental cells regardless of the presence or absence of PDGFA (p < 0.03).	('PDGFA', 'Gene', (167, 172))	('IDH1R132H', 'Var', (83, 92))	('2-HG', 'MPA', (44, 48))	('higher', 'PosReg', (27, 33))	('PDGFA', 'Gene', '18590', (167, 172))
147732	29719265	These data demonstrate that mouse astrocytes expressing IDH1R132H behave similarly to human glioma cells harboring IDH1R132H with respect to decreased NADPH production and increased levels of 2-HG.	('R132H', 'Mutation', 'rs121913500', (60, 65))	('R132H', 'Mutation', 'rs121913500', (119, 124))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('increased', 'PosReg', (172, 181))	('mouse', 'Species', '10090', (28, 33))	('levels of 2-HG', 'MPA', (182, 196))	('NADPH', 'Chemical', 'MESH:D009249', (151, 156))	('human', 'Species', '9606', (86, 91))	('glioma', 'Disease', (92, 98))	('decreased', 'NegReg', (141, 150))	('NADPH production', 'MPA', (151, 167))	('IDH1R132H', 'Var', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
147734	29719265	Treatment of these cells with TFMB-(R)-2HG significantly enhanced anchorage-independent growth in all cells analyzed relative to their vehicle-treated controls.	('TFMB-(R)-2HG', 'Var', (30, 42))	('TFMB', 'Chemical', '-', (30, 34))	('enhanced', 'PosReg', (57, 65))	('anchorage-independent growth', 'CPA', (66, 94))
147735	29719265	In cells expressing PDGFA and Cre, addition of TFMB-(R)-2HG mimicked the anchorage-independent growth observed in cells expressing IDH1R132H.	('PDGFA', 'Gene', (20, 25))	('IDH1R132H', 'Var', (131, 140))	('anchorage-independent growth', 'CPA', (73, 101))	('TFMB', 'Chemical', '-', (47, 51))	('PDGFA', 'Gene', '18590', (20, 25))
147736	29719265	Interestingly, TFMB-(R)-2HG further enhanced colony formation in cells expressing IDH1R132H (Figure 1E).	('IDH1R132H', 'Var', (82, 91))	('R132H', 'Mutation', 'rs121913500', (86, 91))	('TFMB', 'Chemical', '-', (15, 19))	('enhanced', 'PosReg', (36, 44))	('colony formation', 'CPA', (45, 61))
147738	29719265	Previous studies have demonstrated that IDH1R132H expression alone is insufficient to initiate glioma development in mice, and our data support these findings.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH1R132H expression', 'Var', (40, 60))	('mice', 'Species', '10090', (117, 121))	('glioma development', 'Disease', (95, 113))	('R132H', 'Mutation', 'rs121913500', (44, 49))	('glioma development', 'Disease', 'MESH:D005910', (95, 113))
147743	29719265	This demonstrates the significant cooperativity and necessity of these combined genetic alterations in promoting tumor development and demonstrates that IDH1R132H promotes glioma formation in this context.	('tumor', 'Disease', (113, 118))	('genetic alterations', 'Var', (80, 99))	('IDH1R132H', 'Gene', (153, 162))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('alterations', 'Var', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('promotes', 'PosReg', (163, 171))	('glioma', 'Disease', (172, 178))
147763	29719265	Based on GSEA, the signature gene sets associated with human proneural GBM subtype were significantly enriched in the gene expression profile of IDH1R132H-driven mouse tumors with a significant normalized enrichment score (NES) of 2.11.	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('GSEA', 'Chemical', '-', (9, 13))	('tumors', 'Disease', (168, 174))	('mouse', 'Species', '10090', (162, 167))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('IDH1R132H-driven', 'Var', (145, 161))	('human', 'Species', '9606', (55, 60))	('R132H', 'Mutation', 'rs121913500', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
147764	29719265	None of the signature gene sets from any of the other subtypes were significantly associated with the IDH1R132H-driven tumors (Figure 5).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('associated', 'Reg', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('IDH1R132H-driven', 'Var', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('R132H', 'Mutation', 'rs121913500', (106, 111))
147769	29719265	demonstrated that mutant IDH1 and IDH2 inhibit 5hmC production by TET.	('TET', 'Chemical', 'MESH:C010349', (66, 69))	('inhibit', 'NegReg', (39, 46))	('5hmC', 'Chemical', 'MESH:C011865', (47, 51))	('mutant', 'Var', (18, 24))	('IDH1', 'Gene', (25, 29))	('IDH2', 'Gene', (34, 38))	('5hmC production', 'MPA', (47, 62))
147777	29719265	Further analysis of the methylation targets between IDH1R132H and WT IDH1 tumors revealed 16,179 regions that were differentially methylated, including 3,433 differentially methylated CpG regions that intersect within 3 kb of a promoter.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('WT IDH1 tumors', 'Disease', 'MESH:C536751', (66, 80))	('IDH1R132H', 'Var', (52, 61))	('WT IDH1 tumors', 'Disease', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
147779	29719265	Previous studies revealed that IDH1 mutant cells are hypersensitive to poly-(adenosine 5'-diphosphateribose) polymerase (PARP) inhibitors.	('hypersensitive', 'Disease', 'MESH:D004342', (53, 67))	('mutant', 'Var', (36, 42))	('hypersensitive', 'Disease', (53, 67))	('PARP', 'Gene', (121, 125))	('PARP', 'Gene', '11545', (121, 125))	('IDH1', 'Gene', (31, 35))
147780	29719265	This phenotype was further validated by others in glioma cell lines ectopically expressing IDH1R132H, in primary patient-derived IDH1R132H glioma cells, and in subcutaneous xenograft tumor models.	('patient', 'Species', '9606', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('IDH1R132H', 'Var', (91, 100))	('glioma', 'Disease', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('tumor', 'Disease', (183, 188))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
147781	29719265	We assessed the cytotoxicity of the PARP inhibitor, olaparib, alone and in combination with temozolomide (TMZ), a DNA alkylating agent that is currently the standard of care for patients with IDH mutant gliomas, using primary tumor cells derived from IDH1R132H and WT IDH1 gliomas as well as astrocytes from N::TVA; Cdkn2alox/lox;Atrxlox/lox;Ptenlox/lox mice infected with viruses containing PDGFA, Cre, and IDH1R132H or IDH1.	('lox', 'Gene', (326, 329))	('lox', 'Gene', (350, 353))	('TVA', 'Chemical', 'MESH:C050413', (311, 314))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('mice', 'Species', '10090', (354, 358))	('PDGFA', 'Gene', (392, 397))	('lox', 'Gene', '16948', (338, 341))	('PARP', 'Gene', (36, 40))	('gliomas', 'Disease', (203, 210))	('cytotoxicity', 'Disease', (16, 28))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('lox', 'Gene', '16948', (322, 325))	('PDGFA', 'Gene', '18590', (392, 397))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('patients', 'Species', '9606', (178, 186))	('lox', 'Gene', (338, 341))	('gliomas', 'Disease', (273, 280))	('lox', 'Gene', '16948', (346, 349))	('IDH1R132H', 'Var', (408, 417))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('WT IDH1 gliomas', 'Disease', 'MESH:D005910', (265, 280))	('glioma', 'Phenotype', 'HP:0009733', (273, 279))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('lox', 'Gene', (322, 325))	('lox', 'Gene', (346, 349))	('gliomas', 'Disease', 'MESH:D005910', (273, 280))	('lox', 'Gene', '16948', (334, 337))	('gliomas', 'Phenotype', 'HP:0009733', (273, 280))	('WT IDH1 gliomas', 'Disease', (265, 280))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('lox', 'Gene', '16948', (326, 329))	('alox/lox', 'Gene', '16948', (321, 329))	('lox', 'Gene', '16948', (350, 353))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))	('lox', 'Gene', (334, 337))	('alox/lox', 'Gene', (321, 329))	('TMZ', 'Chemical', 'MESH:D000077204', (106, 109))	('PARP', 'Gene', '11545', (36, 40))	('tumor', 'Disease', (226, 231))
147782	29719265	We observed enhanced sensitivity to olaparib in cells harboring IDH1R132H compared with WT IDH1.	('R132H', 'Mutation', 'rs121913500', (68, 73))	('IDH1R132H', 'Var', (64, 73))	('enhanced', 'PosReg', (12, 20))	('olaparib', 'Chemical', 'MESH:C531550', (36, 44))	('sensitivity to olaparib', 'MPA', (21, 44))
147783	29719265	IC50 values from dose-response curves of olaparib were 26.6 and 85.3 muM for IDH1R132H astrocytes and tumor cells, respectively (Figure 7A), while the IC50 values of their WT counterparts were >100 muM (Figure 7B).	('olaparib', 'Chemical', 'MESH:C531550', (41, 49))	('IDH1R132H', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('R132H', 'Mutation', 'rs121913500', (81, 86))
147784	29719265	Furthermore, TMZ significantly enhanced the cytotoxic effects of olaparib in IDH1R132H cells.	('enhanced', 'PosReg', (31, 39))	('TMZ', 'Var', (13, 16))	('olaparib', 'Chemical', 'MESH:C531550', (65, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (13, 16))	('cytotoxic effects', 'CPA', (44, 61))
147786	29719265	In agreement with a previous study that reported enhanced vulnerability of glioma cells ectopically expressing IDHR132H to TMZ, we also observed sensitivity in astrocytes expressing IDH1R132H (Figure 7C, inset).	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('IDHR132H', 'Var', (111, 119))	('glioma', 'Disease', (75, 81))	('R132H', 'Mutation', 'rs121913500', (114, 119))	('TMZ', 'Chemical', 'MESH:D000077204', (123, 126))	('IDH1R132H', 'Var', (182, 191))	('R132H', 'Mutation', 'rs121913500', (186, 191))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
147787	29719265	However, the combination of TMZ and olaparib resulted in a significant reduction in cell viability compared with either agent alone for both astrocytes and tumor cells expressing IDH1R132H, suggesting that this is an effective therapeutic strategy for the treatment of IDH1R132H tumors (Figures 7C and 7D).	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('reduction', 'NegReg', (71, 80))	('tumor', 'Disease', (279, 284))	('IDH1R132H', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('cell viability', 'CPA', (84, 98))	('tumor', 'Disease', (156, 161))	('olaparib', 'Chemical', 'MESH:C531550', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('IDH1R132H tumors', 'Disease', 'MESH:D009369', (269, 285))	('IDH1R132H tumors', 'Disease', (269, 285))
147788	29719265	In this study, we provide in vivo evidence that IDH1R132H promotes gliomagenesis.	('glioma', 'Disease', (67, 73))	('promotes', 'PosReg', (58, 66))	('IDH1R132H', 'Var', (48, 57))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
147790	29719265	Our findings are consistent with a previous study in which specific expression of IDH1R132H in nestin-expressing cells within the SVZ in adult mice did not produce tumors but led to increased 2-HG, enhanced proliferation, and infiltration of neuronal and glial progenitor cells into neighboring regions.	('increased', 'PosReg', (182, 191))	('IDH1R132H', 'Var', (82, 91))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('proliferation', 'CPA', (207, 220))	('R132H', 'Mutation', 'rs121913500', (86, 91))	('2-HG', 'MPA', (192, 196))	('enhanced', 'PosReg', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mice', 'Species', '10090', (143, 147))
147791	29719265	reported similar findings using a human neural stem cell model in the context of mutant IDH1 with loss of TP53 and ATRX.	('human', 'Species', '9606', (34, 39))	('TP53', 'Protein', (106, 110))	('IDH1', 'Gene', (88, 92))	('loss', 'NegReg', (98, 102))	('mutant', 'Var', (81, 87))
147792	29719265	Likewise, did not observe glioma development using the RCAS/TVA glioma model when mutant IDH1 was expressed alone or in combination with TP53 loss and/or Cdkn2a loss.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('loss', 'NegReg', (142, 146))	('TVA glioma', 'Disease', (60, 70))	('glioma development', 'Disease', 'MESH:D005910', (26, 44))	('RCAS', 'Chemical', '-', (55, 59))	('glioma development', 'Disease', (26, 44))	('loss', 'NegReg', (161, 165))	('IDH1', 'Gene', (89, 93))	('TP53', 'Gene', (137, 141))	('TVA glioma', 'Disease', 'MESH:D005910', (60, 70))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('mutant', 'Var', (82, 88))
147793	29719265	Gliomas were induced when combined with PDGFA, but there was no significant difference in survival between mice harboring tumors expressing either wild-type or mutant IDH1 in the context of homozygous Cdkn2a loss.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('PDGFA', 'Gene', (40, 45))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('loss', 'NegReg', (208, 212))	('IDH1', 'Gene', (167, 171))	('mutant', 'Var', (160, 166))	('mice', 'Species', '10090', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))	('PDGFA', 'Gene', '18590', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
147794	29719265	Similarly, we did not observe a significant difference in survival between mice harboring tumors expressing either PDGFA alone or in combination with wild-type or mutant IDH1 in the context of homozygous Cdkn2a loss or in combination with Pten loss.	('Cdkn2a', 'Gene', (204, 210))	('mice', 'Species', '10090', (75, 79))	('IDH1', 'Gene', (170, 174))	('loss', 'NegReg', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutant', 'Var', (163, 169))	('PDGFA', 'Gene', '18590', (115, 120))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('PDGFA', 'Gene', (115, 120))
147795	29719265	Our data suggest that loss of all three tumor suppressors Cdkn2a, Atrx, and Pten in combination is necessary for IDH1R132H and PDGFA to significantly enhance tumor penetrance and decrease tumor latency (Figures 2 and S2).	('tumor', 'Disease', (188, 193))	('PDGFA', 'Gene', '18590', (127, 132))	('tumor', 'Disease', (158, 163))	('IDH1R132H', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('decrease', 'NegReg', (179, 187))	('PDGFA', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('a, Atrx, and', 'Gene', '22589', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (40, 45))	('enhance', 'PosReg', (150, 157))	('loss', 'Var', (22, 26))
147796	29719265	Loss of Cdkn2a eliminates expression of INK4A and alternative reading frame (ARF), which function to regulate the retinoblastoma (RB) and TP53 pathways, respectively.	('expression', 'MPA', (26, 36))	('RB', 'Phenotype', 'HP:0009919', (130, 132))	('ARF', 'Disease', 'MESH:D058186', (77, 80))	('Cdkn2a', 'Gene', (8, 14))	('ARF', 'Disease', (77, 80))	('retinoblastoma', 'Disease', (114, 128))	('retinoblastoma', 'Disease', 'MESH:D012175', (114, 128))	('INK4A', 'Gene', (40, 45))	('TP53 pathways', 'Pathway', (138, 151))	('eliminates', 'NegReg', (15, 25))	('retinoblastoma', 'Phenotype', 'HP:0009919', (114, 128))	('Loss', 'Var', (0, 4))	('regulate', 'Reg', (101, 109))
147797	29719265	Loss of Atrx enables these cells to use recombination as a mechanism to lengthen their telomeres and escape crisis in the absence of telomerase activation.	('escape crisis', 'MPA', (101, 114))	('telomeres', 'CPA', (87, 96))	('Atrx', 'Gene', (8, 12))	('lengthen', 'PosReg', (72, 80))	('Atrx', 'Chemical', '-', (8, 12))	('Loss', 'Var', (0, 4))
147798	29719265	However, it was recently reported that dysregulation of both the TP53 and RB pathways as well as ATRX loss was not sufficient to drive this process in human astrocytes.	('dysregulation', 'Var', (39, 52))	('RB pathways', 'Pathway', (74, 85))	('human', 'Species', '9606', (151, 156))	('RB', 'Phenotype', 'HP:0009919', (74, 76))	('ATRX', 'Gene', (97, 101))	('loss', 'NegReg', (102, 106))	('TP53', 'Pathway', (65, 69))
147799	29719265	Interestingly, combined loss of ATRX and expression of mutant IDH1 was required in T53/RB-deficient human astrocytes to produce the ALT phenotype, bypass telomere crisis, and escape cell death.	('RB-deficient', 'Disease', 'MESH:D012175', (87, 99))	('human', 'Species', '9606', (100, 105))	('RB-deficient', 'Disease', (87, 99))	('mutant', 'Var', (55, 61))	('ALT phenotype', 'MPA', (132, 145))	('produce', 'Reg', (120, 127))	('IDH1', 'Gene', (62, 66))	('RB', 'Phenotype', 'HP:0009919', (87, 89))	('loss', 'NegReg', (24, 28))
147804	29719265	The ability of mutant IDH1 to produce 2-HG is limited by the availability of its substrate alpha-KG.	('mutant', 'Var', (15, 21))	('IDH1', 'Gene', (22, 26))	('alpha-KG', 'Chemical', 'MESH:D007656', (91, 99))
147805	29719265	To generate 2-HG from alpha-KG, mutant IDH1 relies on wild-type IDH1 to convert isocitrate to alpha-KG.	('alpha-KG', 'Chemical', 'MESH:D007656', (94, 102))	('IDH1', 'Gene', (39, 43))	('alpha-KG', 'Chemical', 'MESH:D007656', (22, 30))	('mutant', 'Var', (32, 38))	('isocitrate', 'Chemical', 'MESH:C034219', (80, 90))
147809	29719265	Activation of PI3K/AKT signaling by PDGFA and loss of PTEN likely leads to increased glutamine uptake, which further cooperates with mutant IDH1 to promote tumorigenesis by providing a source of alpha-KG for further production of 2-HG.	('PDGFA', 'Gene', (36, 41))	('loss', 'NegReg', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('increased glutamine', 'Phenotype', 'HP:0003217', (75, 94))	('glutamine uptake', 'MPA', (85, 101))	('increased', 'PosReg', (75, 84))	('PTEN', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Activation', 'PosReg', (0, 10))	('IDH1', 'Gene', (140, 144))	('alpha-KG', 'Chemical', 'MESH:D007656', (195, 203))	('PI3K/AKT signaling', 'Pathway', (14, 32))	('tumor', 'Disease', (156, 161))	('glutamine', 'Chemical', 'MESH:D005973', (85, 94))	('promote', 'PosReg', (148, 155))	('mutant', 'Var', (133, 139))	('PDGFA', 'Gene', '18590', (36, 41))
147810	29719265	The mouse tumors resemble high-grade human mutant IDH1 gliomas genetically, histologically, and functionally.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('mouse', 'Species', '10090', (4, 9))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('IDH1', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mutant', 'Var', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('human', 'Species', '9606', (37, 42))
147811	29719265	The majority of human IDH1 mutant gliomas contain inactivating alterations of ATRX.	('ATRX', 'Gene', (78, 82))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('mutant', 'Var', (27, 33))	('inactivating alterations', 'Var', (50, 74))	('IDH1', 'Gene', (22, 26))	('human', 'Species', '9606', (16, 21))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
147812	29719265	Loss of 9p (CDKN2A; 9p21.3) and 10q (PTEN; 10q23) as well as gain of chromosomes 7 (PDGFA; 7q11.23) and 12q (CDK4; 12q13 and MDM2; 12q15) have also been observed.	('Loss', 'NegReg', (0, 4))	('(PDGFA;', 'Gene', '18590', (83, 90))	('MDM2', 'Var', (125, 129))	('PDGFA;', 'Gene', (84, 90))	('gain', 'PosReg', (61, 65))
147813	29719265	The majority of mutant IDH1 gliomas also contain TP53 mutations (94%), which was not directly evaluated in this study but is currently under investigation.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('TP53', 'Gene', (49, 53))	('contain', 'Reg', (41, 48))	('mutations', 'Var', (54, 63))	('IDH1', 'Gene', (23, 27))	('mutant', 'Var', (16, 22))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
147814	29719265	Deletion of the Cdkn2a locus results in loss of the tumor suppressor ARF, which normally regulates TP53 function via MDM2, and loss of the tumor suppressor p16, which normally regulates Rb function via CDK4/6.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ARF', 'Disease', (69, 72))	('loss of the tumor', 'Disease', 'MESH:D009369', (40, 57))	('loss of the tumor', 'Disease', (40, 57))	('Cdkn2a', 'Gene', (16, 22))	('loss of the tumor', 'Disease', 'MESH:D009369', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('regulates TP53 function', 'MPA', (89, 112))	('loss of the tumor', 'Disease', (127, 144))	('ARF', 'Disease', 'MESH:D058186', (69, 72))	('Deletion', 'Var', (0, 8))
147815	29719265	Histologically, the mutant IDH1 mouse tumors were highly proliferative, contained abnormal vasculature, and exhibited areas of pseudopalisading necrosis (Figures 3, S3, and S4).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('necrosis', 'Disease', 'MESH:D009336', (144, 152))	('abnormal vasculature', 'Phenotype', 'HP:0002597', (82, 102))	('mouse', 'Species', '10090', (32, 37))	('IDH1', 'Gene', (27, 31))	('mutant', 'Var', (20, 26))	('necrosis', 'Disease', (144, 152))
147816	29719265	Functionally, mouse astrocytes containing IDH1R132H produced over 100-fold greater levels of 2-HG than the parental cells or cells containing WT IDH1 (Figure 1D).	('mouse', 'Species', '10090', (14, 19))	('levels of 2-HG', 'MPA', (83, 97))	('IDH1R132H', 'Var', (42, 51))	('R132H', 'Mutation', 'rs121913500', (46, 51))	('greater', 'PosReg', (75, 82))
147821	29719265	performed a similar GSEA of conditional knockin mice induced to express IDH1R132H in SVZ cells at 5 weeks of age and also observed a significant association with the proneural subtype.	('mice', 'Species', '10090', (48, 52))	('proneural subtype', 'Disease', (166, 183))	('R132H', 'Mutation', 'rs121913500', (76, 81))	('association', 'Interaction', (145, 156))	('IDH1R132H', 'Var', (72, 81))	('GSEA', 'Chemical', '-', (20, 24))
147823	29719265	As a result, gliomas harboring mutant IDH manifest a G-CIMP, which epigenetically alters the expression of numerous genes through DNA hypermethylation.	('mutant', 'Var', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('IDH', 'Gene', (38, 41))	('alters', 'Reg', (82, 88))	('G-CIMP', 'Chemical', '-', (53, 59))	('expression', 'MPA', (93, 103))	('gliomas', 'Disease', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
147826	29719265	These observations suggest that IDH1R132H induces a global hypermethylation phenotype in the mouse gliomas similar to the human disease.	('human', 'Species', '9606', (122, 127))	('mouse', 'Species', '10090', (93, 98))	('IDH1R132H', 'Var', (32, 41))	('gliomas', 'Disease', (99, 106))	('global hypermethylation phenotype', 'MPA', (52, 85))	('induces', 'Reg', (42, 49))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('R132H', 'Mutation', 'rs121913500', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
147827	29719265	In a prospective analysis, grade II-IV glioma patients with mutated IDH1 or IDH2 had significantly longer overall survival than patients without IDH mutation.	('longer', 'PosReg', (99, 105))	('patients', 'Species', '9606', (46, 54))	('glioma', 'Disease', (39, 45))	('IDH1', 'Gene', (68, 72))	('mutated', 'Var', (60, 67))	('overall survival', 'MPA', (106, 122))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('patients', 'Species', '9606', (128, 136))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH2', 'Gene', (76, 80))
147828	29719265	GBM patients with mutated IDH1 or IDH2 have an average survival of 31 versus 15 months for patients without the mutation.	('patients', 'Species', '9606', (91, 99))	('mutated', 'Var', (18, 25))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('IDH1', 'Gene', (26, 30))	('IDH2', 'Gene', (34, 38))	('patients', 'Species', '9606', (4, 12))
147829	29719265	Patients with anaplastic astrocytomas containing IDH mutations also had a statistically significant increase in average overall survival when compared with patients without IDH mutations.	('patients', 'Species', '9606', (156, 164))	('IDH', 'Gene', (49, 52))	('astrocytomas', 'Disease', 'MESH:D001254', (25, 37))	('mutations', 'Var', (53, 62))	('Patients', 'Species', '9606', (0, 8))	('astrocytomas', 'Disease', (25, 37))	('overall survival', 'MPA', (120, 136))	('increase', 'PosReg', (100, 108))
147830	29719265	These clinical findings suggested that tumors harboring mutations in IDH are more sensitive to conventional chemotherapy and radio-therapy, and this was confirmed by two independent clinical studies, but the mechanistic basis for these observation was unclear.	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('IDH', 'Gene', (69, 72))	('more', 'PosReg', (77, 81))	('sensitive', 'MPA', (82, 91))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))
147831	29719265	Cancers with defects in DNA repair are often highly sensitive to PARP inhibitors.	('DNA repair', 'Gene', (24, 34))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('sensitive', 'Reg', (52, 61))	('PARP', 'Gene', (65, 69))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('PARP', 'Gene', '11545', (65, 69))	('defects', 'Var', (13, 20))
147832	29719265	Therapeutics developed based on this approach have been effective in treating hereditary breast and ovarian cancers, which have defects in BRCA1 and BRCA2, and the Food and Drug Administration (FDA) has approved two PARP inhibitors, rucaparib and olaparib, to treat certain BRCA mutant ovarian cancers.	('olaparib', 'Chemical', 'MESH:C531550', (247, 255))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (78, 115))	('ovarian cancers', 'Disease', (286, 301))	('ovarian cancers', 'Disease', 'MESH:D010051', (286, 301))	('BRCA', 'Disease', (149, 153))	('defects', 'Var', (128, 135))	('BRCA', 'Disease', (274, 278))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('PARP', 'Gene', '11545', (216, 220))	('rucaparib', 'Chemical', 'MESH:C531549', (233, 242))	('ovarian cancers', 'Disease', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('ovarian cancers', 'Disease', 'MESH:D010051', (100, 115))	('BRCA', 'Disease', 'MESH:C537443', (149, 153))	('BRCA', 'Disease', (139, 143))	('PARP', 'Gene', (216, 220))	('BRCA', 'Disease', 'MESH:C537443', (274, 278))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('ovarian cancers', 'Phenotype', 'HP:0100615', (286, 301))	('BRCA', 'Disease', 'MESH:C537443', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancers', 'Phenotype', 'HP:0100615', (100, 115))
147833	29719265	further demonstrated that mutant IDH tumor cells are sensitive to olaparib.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('sensitive', 'MPA', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('olaparib', 'Chemical', 'MESH:C531550', (66, 74))	('IDH', 'Gene', (33, 36))	('mutant', 'Var', (26, 32))
147835	29719265	The discovery of mutations in IDH has cast a new light on the molecular landscape in glioma and is changing the paradigm for how the disease is defined and treated.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('glioma', 'Disease', (85, 91))	('changing', 'Reg', (99, 107))	('IDH', 'Gene', (30, 33))	('mutations', 'Var', (17, 26))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
147836	29719265	A selective inhibitor of mutant IDH1 inhibited the production of 2-HG and the growth of cells expressing IDH1R132H, but this was independent of its epigenetic effects.	('mutant', 'Var', (25, 31))	('inhibited', 'NegReg', (37, 46))	('IDH1R132H', 'Var', (105, 114))	('growth', 'CPA', (78, 84))	('IDH1', 'Gene', (32, 36))	('production of 2-HG', 'MPA', (51, 69))	('R132H', 'Mutation', 'rs121913500', (109, 114))
147838	29719265	The model we described in this study will aid in furthering our understanding of the biology of mutant IDH1 gliomas and is ideally suited for assessing rational therapeutic strategies designed to combat this deadly disease.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('mutant', 'Var', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1', 'Gene', (103, 107))
147842	29719265	IDH1R132H and PDGFA cooperate with loss of Cdkn2a, Atrx, and Pten in gliomagenesis 2-HG mediates the oncogenic effects of IDH1R132H IDH1R132H-driven tumors mimic the human disease and resemble the proneural subtype IDH1R132H tumor cells have enhanced sensitivity to PARP inhibitors	('glioma', 'Disease', (69, 75))	('PARP', 'Gene', '11545', (266, 270))	('PDGFA', 'Gene', '18590', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (225, 230))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('PARP', 'Gene', (266, 270))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('R132H', 'Mutation', 'rs121913500', (136, 141))	('IDH1R132H', 'Var', (122, 131))	('human', 'Species', '9606', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('R132H', 'Mutation', 'rs121913500', (126, 131))	('a, Atrx, and', 'Gene', '22589', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('enhanced', 'PosReg', (242, 250))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('oncogenic effects', 'CPA', (101, 118))	('sensitivity to', 'MPA', (251, 265))	('R132H', 'Mutation', 'rs121913500', (219, 224))	('loss', 'Var', (35, 39))	('tumor', 'Disease', (149, 154))	('PDGFA', 'Gene', (14, 19))
147848	29207176	High expression of P4HB and PDIA3 was significantly correlated with high Ki-67 and a high frequency of the TP53 mutation.	('correlated', 'Reg', (52, 62))	('mutation', 'Var', (112, 120))	('P4HB', 'Gene', '5034', (19, 23))	('Ki-67', 'Protein', (73, 78))	('PDIA3', 'Gene', '2923', (28, 33))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('PDIA3', 'Gene', (28, 33))	('P4HB', 'Gene', (19, 23))
147849	29207176	Kaplan-Meier survival curve and Cox regression analyses showed that glioma patients with high P4HB and PDIA3 expression had a poor survival outcome, P4HB and PDIA3 could be independent prognostic biomarkers for diffuse gliomas.	('P4HB', 'Gene', '5034', (94, 98))	('Cox', 'Gene', (32, 35))	('glioma', 'Disease', 'MESH:D005910', (219, 225))	('PDIA3', 'Gene', (158, 163))	('PDIA3', 'Gene', '2923', (103, 108))	('high', 'Var', (89, 93))	('glioma', 'Disease', (68, 74))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('PDIA3', 'Gene', '2923', (158, 163))	('P4HB', 'Gene', (94, 98))	('P4HB', 'Gene', (149, 153))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('patients', 'Species', '9606', (75, 83))	('Cox', 'Gene', '1351', (32, 35))	('gliomas', 'Disease', (219, 226))	('PDIA3', 'Gene', (103, 108))	('glioma', 'Disease', (219, 225))	('P4HB', 'Gene', '5034', (149, 153))
147850	29207176	In vitro, knockdown of PDIA3 suppressed cell proliferation, induced cell apoptosis, and decreased the migration of glioma cells.	('knockdown', 'Var', (10, 19))	('glioma', 'Disease', (115, 121))	('PDIA3', 'Gene', (23, 28))	('induced', 'Reg', (60, 67))	('cell apoptosis', 'CPA', (68, 82))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('decreased', 'NegReg', (88, 97))	('PDIA3', 'Gene', '2923', (23, 28))	('cell proliferation', 'CPA', (40, 58))	('suppressed', 'NegReg', (29, 39))
147856	29207176	The pathogenesis of diffuse gliomas is extremely complicated, and involves the aberrant activation of proto-oncogenes and inactivation of anti-oncogenes.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('activation', 'PosReg', (88, 98))	('inactivation', 'Var', (122, 134))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('anti-oncogenes', 'Protein', (138, 152))	('proto-oncogenes', 'Protein', (102, 117))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
147874	29207176	The gene expression profiles of GSE4290, GSE4271, GSE4412 and GSE43378 were downloaded from the Gene Expression Omnibus (GEO; ) database.	('GSE4412', 'Chemical', '-', (50, 57))	('GSE4271', 'Var', (41, 48))	('GSE4412', 'Var', (50, 57))	('GSE4290', 'Chemical', '-', (32, 39))	('GSE4290', 'Var', (32, 39))	('GSE43378', 'Var', (62, 70))	('GSE4271', 'Chemical', '-', (41, 48))
147887	29207176	Briefly, U87 and U251 cells were seeded at a density of 1x103 cells per well in 96-well plates, and then transfected with siRNAs and cultured in 100 microl DMEM medium.	('U251', 'CellLine', 'CVCL:0021', (17, 21))	('U87', 'Gene', (9, 12))	('DMEM medium', 'Chemical', '-', (156, 167))	('U87', 'Gene', '641648', (9, 12))	('transfected', 'Var', (105, 116))
147909	29207176	3A, within TCGA, the overall survival of glioma patients with high P4HB expression (P<0.0001) was significantly worse than that of the low expression patients; survival of glioma patients with high PDIA3 expression (P<0.0001) was markedly worse than patients with low expression.	('PDIA3', 'Gene', (198, 203))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('P4HB', 'Gene', '5034', (67, 71))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('patients', 'Species', '9606', (250, 258))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('glioma', 'Disease', (41, 47))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (48, 56))	('P4HB', 'Gene', (67, 71))	('patients', 'Species', '9606', (179, 187))	('high', 'Var', (62, 66))	('glioma', 'Disease', (172, 178))	('worse', 'NegReg', (239, 244))	('worse', 'NegReg', (112, 117))	('PDIA3', 'Gene', '2923', (198, 203))
147910	29207176	What is more, in several GEO datasets, the overall survival of glioma patients with high P4HB and PDIA3 expression was also significantly worse than that of the low expression patients (P=0.0060 and P=0.0062 in GSE4271, P=0.0223 and P=0.0265 in GSE4412, P<0.0001 and P<0.0001 in GSE43378, respectively; Fig.	('patients', 'Species', '9606', (176, 184))	('P4HB', 'Gene', (89, 93))	('GSE4412', 'Chemical', '-', (245, 252))	('patients', 'Species', '9606', (70, 78))	('high', 'Var', (84, 88))	('PDIA3', 'Gene', (98, 103))	('GSE4271', 'Chemical', '-', (211, 218))	('worse', 'NegReg', (138, 143))	('P=0.0062', 'Var', (199, 207))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('P=0.0265', 'Var', (233, 241))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('P4HB', 'Gene', '5034', (89, 93))	('expression', 'Var', (104, 114))	('PDIA3', 'Gene', '2923', (98, 103))	('glioma', 'Disease', (63, 69))
147913	29207176	Subsequent multivariate analysis results revealed that high P4HB and PDIA3 expression (HR, 1.696, P=0.019; HR, 1.395, P=0.043, respectively) are independent prognosis factors for the survival of glioma patients, in addition to increased age, high KPS and grade.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('P4HB', 'Gene', '5034', (60, 64))	('PDIA3', 'Gene', '2923', (69, 74))	('patients', 'Species', '9606', (202, 210))	('glioma', 'Disease', (195, 201))	('high', 'Var', (55, 59))	('PDIA3', 'Gene', (69, 74))	('P4HB', 'Gene', (60, 64))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
147928	29207176	Mutations in the TP53 gene are associated with a variety of human cancers, including gliomas.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('gliomas', 'Disease', (85, 92))	('associated', 'Reg', (31, 41))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))	('TP53', 'Gene', '7157', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('TP53', 'Gene', (17, 21))
147933	29207176	5A, knockdown of PDIA3 significantly reduced the expression levels of PDIA3 in two cell lines, as compared with negative controls.	('expression levels', 'MPA', (49, 66))	('PDIA3', 'Gene', '2923', (17, 22))	('PDIA3', 'Gene', (17, 22))	('PDIA3', 'Gene', '2923', (70, 75))	('reduced', 'NegReg', (37, 44))	('PDIA3', 'Gene', (70, 75))	('knockdown', 'Var', (4, 13))
147936	29207176	Consistently, the colony formation assay showed that the number of colonies was evidently decreased after knockdown of PDIA3 in the U251 and U87 cells (Fig.	('PDIA3', 'Gene', '2923', (119, 124))	('U87', 'Gene', '641648', (141, 144))	('decreased', 'NegReg', (90, 99))	('PDIA3', 'Gene', (119, 124))	('U251', 'CellLine', 'CVCL:0021', (132, 136))	('knockdown', 'Var', (106, 115))	('U87', 'Gene', (141, 144))
147939	29207176	These were consistent with other reports that bacitracin, an inhibitor of PDIs, inhibited glioma cell migration and invasion in vitro by decreasing pFAK (phosphorylated focal adhesion kinase) and MMP2 (the secreted matrix metalloproteinase 2).	('glioma', 'Disease', (90, 96))	('matrix metalloproteinase 2', 'Gene', '4313', (215, 241))	('matrix metalloproteinase 2', 'Gene', (215, 241))	('PDI', 'Gene', (74, 77))	('PDI', 'Gene', '5034', (74, 77))	('bacitracin', 'Chemical', 'MESH:D001414', (46, 56))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('decreasing', 'NegReg', (137, 147))	('MMP2', 'Gene', '4313', (196, 200))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('bacitracin', 'Var', (46, 56))	('inhibited', 'NegReg', (80, 89))	('MMP2', 'Gene', (196, 200))
147943	29207176	6A and B, the overall survival of the low P4HB expression group was significantly better than that of the high expression group in glioma patients who received chemotherapy (P<0.0001) or radiotherapy (P<0.0001).	('glioma', 'Disease', (131, 137))	('better', 'PosReg', (82, 88))	('P4HB', 'Gene', (42, 46))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('P4HB', 'Gene', '5034', (42, 46))	('low', 'Var', (38, 41))	('patients', 'Species', '9606', (138, 146))
147945	29207176	This was consistent with a previous report that overexpression of P4HB is related to the development of TMZ resistance, and knockdown of P4HB or inhibition of PDI activity using bacitracin sensitizes glioma cells to TMZ in vitro and in vivo.	('glioma', 'Disease', (200, 206))	('knockdown', 'Var', (124, 133))	('TMZ', 'Chemical', 'MESH:D000077204', (104, 107))	('P4HB', 'Gene', (66, 70))	('related', 'Reg', (74, 81))	('P4HB', 'Gene', '5034', (66, 70))	('inhibition', 'NegReg', (145, 155))	('P4HB', 'Gene', '5034', (137, 141))	('PDI', 'Gene', '5034', (159, 162))	('activity', 'MPA', (163, 171))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('bacitracin', 'Chemical', 'MESH:D001414', (178, 188))	('TMZ', 'Chemical', 'MESH:D000077204', (216, 219))	('P4HB', 'Gene', (137, 141))	('PDI', 'Gene', (159, 162))	('sensitizes', 'Reg', (189, 199))
147952	29207176	High P4HB and PDIA3 expression was significantly correlated with high Ki-67 and more TP53 mutations.	('correlated', 'Reg', (49, 59))	('Ki-67', 'Protein', (70, 75))	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('expression', 'MPA', (20, 30))	('P4HB', 'Gene', '5034', (5, 9))	('PDIA3', 'Gene', '2923', (14, 19))	('PDIA3', 'Gene', (14, 19))	('high', 'Var', (65, 69))	('P4HB', 'Gene', (5, 9))	('TP53', 'Gene', '7157', (85, 89))
147957	29207176	Dysregulation of PDI expression, post-translational modification or enzymatic activity could cause many human diseases, such as neurodegenerative disorders, diabetes and cardiovascular disease.	('Dysregulation', 'Var', (0, 13))	('human diseases', 'Disease', (104, 118))	('diabetes', 'Disease', 'MESH:D003920', (157, 165))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (128, 155))	('neurodegenerative disorders', 'Disease', (128, 155))	('cardiovascular disease', 'Disease', (170, 192))	('expression', 'MPA', (21, 31))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (128, 155))	('cause', 'Reg', (93, 98))	('human', 'Species', '9606', (104, 109))	('PDI', 'Gene', (17, 20))	('post-translational modification', 'Var', (33, 64))	('PDI', 'Gene', '5034', (17, 20))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (170, 192))	('cardiovascular disease', 'Disease', 'MESH:D002318', (170, 192))	('diabetes', 'Disease', (157, 165))
147964	29207176	Through knockdown of PDIA3 in U87 and U251 cells, experimental results showed that the cell growth and colony formation ability were significantly suppressed, apoptosis was induced and migration ability was markedly decreased.	('decreased', 'NegReg', (216, 225))	('U251', 'CellLine', 'CVCL:0021', (38, 42))	('knockdown', 'Var', (8, 17))	('migration ability', 'CPA', (185, 202))	('suppressed', 'NegReg', (147, 157))	('induced', 'PosReg', (173, 180))	('U87', 'Gene', (30, 33))	('PDIA3', 'Gene', '2923', (21, 26))	('PDIA3', 'Gene', (21, 26))	('U87', 'Gene', '641648', (30, 33))	('apoptosis', 'CPA', (159, 168))
147975	29207176	Similarly, recent studies have reported that knockdown of P4HB or inhibition of PDI activity using bacitracin enhanced cisplatin cytotoxicity in ovarian cancer resistant A2780 cells.	('ovarian cancer', 'Disease', (145, 159))	('PDI', 'Gene', '5034', (80, 83))	('P4HB', 'Gene', (58, 62))	('cytotoxicity', 'Disease', (129, 141))	('PDI', 'Gene', (80, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('enhanced', 'PosReg', (110, 118))	('A2780', 'CellLine', 'CVCL:0134', (170, 175))	('bacitracin', 'Chemical', 'MESH:D001414', (99, 109))	('activity', 'MPA', (84, 92))	('ovarian cancer', 'Disease', 'MESH:D010051', (145, 159))	('cytotoxicity', 'Disease', 'MESH:D064420', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('P4HB', 'Gene', '5034', (58, 62))	('inhibition', 'NegReg', (66, 76))	('knockdown', 'Var', (45, 54))
147980	29207176	In vitro, knockdown of PDIA3 suppressed cell proliferation, induced apoptosis and decreased migration of glioma cells.	('knockdown', 'Var', (10, 19))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('PDIA3', 'Gene', (23, 28))	('induced', 'Reg', (60, 67))	('glioma', 'Disease', (105, 111))	('apoptosis', 'CPA', (68, 77))	('PDIA3', 'Gene', '2923', (23, 28))	('cell proliferation', 'CPA', (40, 58))	('decreased', 'NegReg', (82, 91))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('suppressed', 'NegReg', (29, 39))
148044	28603224	The same group compared endocrine outcomes in 77 patients with medulloblastoma treated with chemotherapy and PBT (n = 40) or photon radiotherapy (n = 37), and found that PBT reduced the requirement for endocrine replacement therapy (55% vs. 78%, P = 0.03).	('requirement for endocrine replacement therapy', 'MPA', (186, 231))	('PBT', 'Var', (170, 173))	('medulloblastoma', 'Disease', 'MESH:D008527', (63, 78))	('medulloblastoma', 'Phenotype', 'HP:0002885', (63, 78))	('patients', 'Species', '9606', (49, 57))	('reduced', 'NegReg', (174, 181))	('medulloblastoma', 'Disease', (63, 78))
148045	28603224	found a 1-year high-grade ototoxicity rate of 5% after PBT, and in 111 patients with medulloblastoma treated with PBT of >=50 GyE, Giantsoudi et al.	('PBT', 'Var', (55, 58))	('medulloblastoma', 'Disease', 'MESH:D008527', (85, 100))	('medulloblastoma', 'Phenotype', 'HP:0002885', (85, 100))	('patients', 'Species', '9606', (71, 79))	('medulloblastoma', 'Disease', (85, 100))	('ototoxicity', 'Disease', (26, 37))	('ototoxicity', 'Disease', 'MESH:D006311', (26, 37))
148077	28603224	showed that PBT for ependymoma reduces the dose for organs at risk, such as the brain, hypothalamus and cochlea.	('hypothalamus', 'Disease', 'MESH:D007029', (87, 99))	('PBT', 'Var', (12, 15))	('reduces', 'NegReg', (31, 38))	('ependymoma', 'Phenotype', 'HP:0002888', (20, 30))	('dose', 'MPA', (43, 47))	('ependymoma', 'Disease', 'MESH:D004806', (20, 30))	('ependymoma', 'Disease', (20, 30))	('hypothalamus', 'Disease', (87, 99))
148087	28603224	In a recent study by Gunther et al., imaging changes on magnetic resonance image (MRI) were more frequent in patients with intracranial ependymoma treated with PBT compared to those treated with IMRT, with 16 of 37 patients treated with PBT and 6 of 35 patients treated with IMRT showing MRI changes.	('patients', 'Species', '9606', (215, 223))	('intracranial ependymoma', 'Disease', (123, 146))	('intracranial ependymoma', 'Disease', 'MESH:C531673', (123, 146))	('patients', 'Species', '9606', (109, 117))	('PBT', 'Var', (160, 163))	('patients', 'Species', '9606', (253, 261))	('imaging', 'MPA', (37, 44))	('ependymoma', 'Phenotype', 'HP:0002888', (136, 146))
148090	28603224	Moreover, patients who received PBT had a trend for better 4-year OS.	('OS', 'Chemical', '-', (66, 68))	('PBT', 'Var', (32, 35))	('better', 'PosReg', (52, 58))	('patients', 'Species', '9606', (10, 18))
148114	28603224	The 1- and 5-year progression-free survival does not differ between these two treatments, but neurological deficits are higher after gross total resection.	('gross total resection', 'Var', (133, 154))	('higher', 'PosReg', (120, 126))	('neurological deficits', 'Phenotype', 'HP:0000707', (94, 115))	('neurological deficits', 'Disease', (94, 115))	('neurological deficits', 'Disease', 'MESH:D009461', (94, 115))
148127	28603224	showed that PBT reduced the dose to the total brain, cochlea and hypothalamus.	('dose', 'MPA', (28, 32))	('PBT', 'Var', (12, 15))	('cochlea and hypothalamus', 'Disease', 'MESH:D007029', (53, 77))	('reduced', 'NegReg', (16, 23))
148135	28603224	These studies indicated that PBT significantly reduces the dose to organs at risk and the risk of secondary cancer.	('dose to organs at risk', 'MPA', (59, 81))	('reduces', 'NegReg', (47, 54))	('PBT', 'Var', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
148152	25314060	TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk.	('gliomas', 'Phenotype', 'HP:0009733', (272, 279))	('glioma', 'Disease', 'MESH:D005910', (340, 346))	('TERT', 'Gene', (141, 145))	('glioma', 'Disease', (272, 278))	('TERT', 'Gene', '7015', (141, 145))	('gliomas', 'Disease', (27, 34))	('glioma', 'Disease', (27, 33))	('TERTp', 'Gene', (258, 263))	('rs2736100', 'Var', (319, 328))	('glioma', 'Phenotype', 'HP:0009733', (340, 346))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('TERTp', 'Gene', '7015', (258, 263))	('TERT', 'Gene', (258, 262))	('TERT', 'Gene', '7015', (258, 262))	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('gliomas', 'Disease', (272, 279))	('rs2736100', 'Mutation', 'rs2736100', (319, 328))	('TERT', 'Gene', (233, 237))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('glioma', 'Disease', (150, 156))	('TERT', 'Gene', '7015', (233, 237))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('influences', 'Reg', (329, 339))	('gliomas', 'Disease', 'MESH:D005910', (272, 279))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (302, 306))	('TERT', 'Gene', '7015', (302, 306))	('glioma', 'Disease', (340, 346))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
148153	25314060	TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.	('TCF', 'Gene', '3172', (41, 44))	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', (143, 147))	('binding', 'Interaction', (20, 27))	('rs2853669', 'Var', (87, 96))	('TERT', 'Gene', '7015', (143, 147))	('TCF', 'Gene', (131, 134))	('TERT', 'Gene', (0, 4))	('TCF', 'Gene', '3172', (131, 134))	('disrupts', 'NegReg', (110, 118))	('TERT', 'Gene', '7015', (0, 4))	('rs2853669', 'Mutation', 'rs2853669', (87, 96))	('TERTp', 'Gene', (0, 5))	('TCF', 'Gene', (41, 44))
148155	25314060	TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.	('TERTp', 'Gene', '7015', (0, 5))	('TERTp', 'Gene', (21, 26))	('correlated', 'Reg', (55, 65))	('TERT', 'Gene', (99, 103))	('TERTp', 'Gene', (0, 5))	('TERTp', 'Gene', '7015', (21, 26))	('TERT', 'Gene', (21, 25))	('rs2736100', 'Var', (142, 151))	('rs2853669', 'Mutation', 'rs2853669', (40, 49))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (99, 103))	('TERT', 'Gene', '7015', (21, 25))	('TERT', 'Gene', '7015', (0, 4))	('rs2736100', 'Mutation', 'rs2736100', (142, 151))	('rs2853669', 'Var', (40, 49))
148158	25314060	TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression.	('TERT', 'Gene', (115, 119))	('TERT', 'Gene', '7015', (115, 119))	('TERTp', 'Gene', '7015', (0, 5))	('lower', 'NegReg', (109, 114))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('higher', 'PosReg', (30, 36))	('rs2853669', 'Mutation', 'rs2853669', (71, 80))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', (0, 5))	('rs2853669', 'Var', (71, 80))
148159	25314060	The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.	('TERT', 'Gene', '7015', (101, 105))	('CIC', 'Gene', '23152', (16, 19))	('CIC', 'Gene', (16, 19))	('mutation', 'Var', (4, 12))	('ETV1', 'Gene', (36, 40))	('TERT', 'Gene', (101, 105))	('TCF', 'Gene', (64, 67))	('TCF', 'Gene', '3172', (64, 67))	('ETV1', 'Gene', '2115', (36, 40))
148161	25314060	We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression.	('rs2853669 variant', 'Var', (29, 46))	('TERTp', 'Gene', (18, 23))	('Tert', 'Gene', (74, 78))	('CIC', 'Gene', (51, 54))	('rs2853669', 'Mutation', 'rs2853669', (29, 38))	('TERTp', 'Gene', '7015', (18, 23))	('influence', 'Reg', (64, 73))	('Tert', 'Gene', '7015', (74, 78))	('mutation', 'Var', (55, 63))	('CIC', 'Gene', '23152', (51, 54))
148165	25314060	Somatic mutations of the TERT promoter (TERTp-mut) have recently been documented in various cancers, but particularly in glioma.	('TERT', 'Gene', '7015', (40, 44))	('documented', 'Reg', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('TERT', 'Gene', (25, 29))	('mutations', 'Var', (8, 17))	('glioma', 'Disease', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('TERT', 'Gene', '7015', (25, 29))	('cancers', 'Disease', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TERTp', 'Gene', (40, 45))	('TERTp', 'Gene', '7015', (40, 45))	('TERT', 'Gene', (40, 44))
148166	25314060	The two most common mutations in TERT, C228T and C250T, map -124 and -146 bp, respectively, upstream of the TERT ATG site (chr5, 1,295,228 C>T and 1,295,250 C>T, respectively), creating binding sites for Ets/TCF transcription factors that are associated with a two- to four-fold increased transcriptional activity.	('250 C>T', 'Mutation', 'rs1225908345', (153, 160))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('228 C>T', 'Mutation', 'rs763756456', (135, 142))	('increased', 'PosReg', (279, 288))	('C250T', 'Mutation', 'rs1225908345', (49, 54))	('C228T', 'Mutation', 'rs763756456', (39, 44))	('transcriptional activity', 'MPA', (289, 313))	('C250T', 'Var', (49, 54))	('TCF', 'Gene', (208, 211))	('C228T', 'Var', (39, 44))	('TERT', 'Gene', (108, 112))	('TCF', 'Gene', '3172', (208, 211))	('TERT', 'Gene', '7015', (108, 112))	('binding', 'Interaction', (186, 193))
148168	25314060	Notably, the SNP rs2736100 is associated with glioblastoma (GBM) risk, especially for IDH1 wild-type GBM.	('associated', 'Reg', (30, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('rs2736100', 'Mutation', 'rs2736100', (17, 26))	('SNP rs2736100', 'Var', (13, 26))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))
148169	25314060	Recently, germline mutation of the TERT promoter at position -57 has been shown to cause familial melanoma.	('familial melanoma', 'Disease', 'OMIM:155600', (89, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cause', 'Reg', (83, 88))	('germline mutation', 'Var', (10, 27))	('familial melanoma', 'Disease', (89, 106))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))
148170	25314060	Here, we have (1) determined the prevalence and prognostic impact of TERT promoter mutations, in 807 patients with glioma (WHO grades II, III and IV).	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (101, 109))	('glioma', 'Disease', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('TERT', 'Gene', (69, 73))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('TERT', 'Gene', '7015', (69, 73))
148189	25314060	Tumours from 491 of the 807 patients (60.8%) were TERTp-mut-355 C228T (72.3%) and 136 C250T (27.7%).	('TERTp', 'Gene', '7015', (50, 55))	('C250T', 'Mutation', 'rs1225908345', (86, 91))	('C250T', 'Var', (86, 91))	('C228T', 'Mutation', 'rs763756456', (64, 69))	('TERTp', 'Gene', (50, 55))	('patients', 'Species', '9606', (28, 36))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
148190	25314060	One GBM and two grade II oligodendrogliomas carried both C250T and C228T.	('C228T', 'Mutation', 'rs763756456', (67, 72))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (25, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('C228T', 'Var', (67, 72))	('C250T', 'Mutation', 'rs1225908345', (57, 62))	('oligodendrogliomas', 'Disease', (25, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('C250T', 'Var', (57, 62))
148193	25314060	rs2853669 genotypes were available for 385 of the tumours.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('rs2853669', 'Var', (0, 9))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('tumours', 'Disease', (50, 57))	('rs2853669', 'Mutation', 'rs2853669', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
148195	25314060	We then investigated a purported association between somatic TERTp-mut and rs2736100 genotype in 518 glioma patients, finding no association in the whole group (allele A frequency 371 out of 616=60% vs 249 out of 420=59%, P=0.9) or when stratifying by IDH status and tumour class (Supplementary Table 3).	('TERTp', 'Gene', '7015', (61, 66))	('IDH', 'Gene', '3417', (252, 255))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('tumour', 'Disease', (267, 273))	('rs2736100', 'Mutation', 'rs2736100', (75, 84))	('glioma', 'Disease', (101, 107))	('IDH', 'Gene', (252, 255))	('TERTp', 'Gene', (61, 66))	('patients', 'Species', '9606', (108, 116))	('rs2736100', 'Var', (75, 84))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (267, 273))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
148196	25314060	Case-control comparison of showed a stronger association with rs2736100 with IDH-wt gliomas but not with TERTp-mut gliomas (Supplementary Table 4).	('gliomas', 'Disease', (115, 122))	('rs2736100', 'Var', (62, 71))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('IDH', 'Gene', (77, 80))	('TERTp', 'Gene', (105, 110))	('rs2736100', 'Mutation', 'rs2736100', (62, 71))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('IDH', 'Gene', '3417', (77, 80))	('TERTp', 'Gene', '7015', (105, 110))
148197	25314060	Collectively, these data imply there is no association between TERTp-mut and rs2736100 genotype.	('TERTp', 'Gene', (63, 68))	('TERTp', 'Gene', '7015', (63, 68))	('rs2736100', 'Mutation', 'rs2736100', (77, 86))	('rs2736100', 'Var', (77, 86))
148198	25314060	In addition, we did not find any significant association between TERT promoter mutation and the other gliomas susceptibility SNPs rs11979158, rs2252586, rs4295627, rs4977756, rs498872 and rs6010620 (data not shown).	('rs2252586', 'Mutation', 'rs2252586', (142, 151))	('rs11979158', 'Var', (130, 140))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('rs4295627', 'Var', (153, 162))	('rs4295627', 'Mutation', 'rs4295627', (153, 162))	('rs4977756', 'Mutation', 'rs4977756', (164, 173))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('rs498872', 'Mutation', 'rs498872', (175, 183))	('rs2252586', 'Var', (142, 151))	('TERT', 'Gene', (65, 69))	('rs4977756', 'Var', (164, 173))	('TERT', 'Gene', '7015', (65, 69))	('gliomas', 'Disease', (102, 109))	('rs6010620', 'Mutation', 'rs6010620', (188, 197))	('rs11979158', 'Mutation', 'rs11979158', (130, 140))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('rs6010620', 'Var', (188, 197))	('rs498872', 'Var', (175, 183))
148202	25314060	TERTp-mut was identifiable in 87.9% (94 out of 107 of gliomas with 1p19q codeletion (90 oligodendrogliomas, 17 oligoastrocytomas; 26 (24.3%) on C250T and 68 (63.6%) on C228T) as compared with 58.8% of non-codeleted gliomas (341 out of 580, chi2 test P<0.0001).	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('oligodendrogliomas', 'Disease', (88, 106))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('1p19q codeletion', 'Var', (67, 83))	('gliomas', 'Disease', (215, 222))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('C228T', 'Mutation', 'rs763756456', (168, 173))	('C250T', 'Mutation', 'rs1225908345', (144, 149))	('TERTp', 'Gene', (0, 5))	('TERTp', 'Gene', '7015', (0, 5))	('C250T', 'Var', (144, 149))	('gliomas', 'Disease', (54, 61))	('gliomas', 'Disease', 'MESH:D005910', (215, 222))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (88, 106))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))
148203	25314060	EGFR amplification was present in 183 tumours (142 GBM) and was mutually exclusive with 1p19q codeletion: 163 (89.1%) having TERTp-mut (121, C228T) as compared with 51.8% (323 out of 624) of EGFR non-amplified tumours (chi2 test P<0.0001).	('tumours', 'Disease', (38, 45))	('EGFR', 'Gene', (0, 4))	('C228T', 'Var', (141, 146))	('TERTp', 'Gene', (125, 130))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('EGFR', 'Gene', '1956', (191, 195))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('EGFR', 'Gene', (191, 195))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('TERTp', 'Gene', '7015', (125, 130))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('tumours', 'Disease', 'MESH:D009369', (210, 217))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('EGFR', 'Gene', '1956', (0, 4))	('C228T', 'Mutation', 'rs763756456', (141, 146))	('tumours', 'Disease', (210, 217))
148204	25314060	The association of TERT promoter mutations with other molecular alterations commonly seen in glioma is detailed in Supplementary Table 5 and Supplementary Figure 1.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('glioma', 'Disease', (93, 99))	('mutations', 'Var', (33, 42))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
148205	25314060	We investigated whether there was a relationship between CIC inactivating mutations and TERTp-mut in grades II and III.	('CIC', 'Gene', '23152', (57, 60))	('TERTp', 'Gene', (88, 93))	('inactivating mutations', 'Var', (61, 83))	('TERTp', 'Gene', '7015', (88, 93))	('CIC', 'Gene', (57, 60))
148206	25314060	CIC mutation was associated with TERTp-mut in 85% of the cases (28 out of 33), compared with 61% (25 out of 41) in CIC-wt tumours (chi2 test P<0.04).	('CIC', 'Gene', '23152', (115, 118))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('associated', 'Reg', (17, 27))	('CIC', 'Gene', (115, 118))	('mutation', 'Var', (4, 12))	('TERTp', 'Gene', (33, 38))	('CIC', 'Gene', '23152', (0, 3))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('TERTp', 'Gene', '7015', (33, 38))	('tumours', 'Disease', (122, 129))	('CIC', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
148209	25314060	Since the presence of the rs2853669 -C allele disrupts an Ets2 binding site, we investigated the effect of rs2853669 genotype on TERT mRNA expression.	('rs2853669', 'Mutation', 'rs2853669', (107, 116))	('Ets2', 'Protein', (58, 62))	('TERT', 'Gene', '7015', (129, 133))	('rs2853669 -C', 'Var', (26, 38))	('rs2853669', 'Mutation', 'rs2853669', (26, 35))	('disrupts', 'NegReg', (46, 54))	('TERT', 'Gene', (129, 133))
148210	25314060	Tumours harbouring the variant allele (CC+CT) showed a two-fold reduction in TERT expression, as compared with TT homozygotes (respective means+-s.e.m.	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('variant', 'Var', (23, 30))	('reduction', 'NegReg', (64, 73))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
148213	25314060	We found TERT mRNA expression was two-fold higher in CIC mutant tumours, compared with CIC wild-type gliomas (Mann-Whitney test P=0.043) for the whole group (Figure 1D), and for the carriers of the variant allele (Figure 1E).	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('CIC', 'Gene', (87, 90))	('gliomas', 'Disease', (101, 108))	('higher', 'PosReg', (43, 49))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('CIC', 'Gene', '23152', (53, 56))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('mutant', 'Var', (57, 63))	('CIC', 'Gene', (53, 56))	('CIC', 'Gene', '23152', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('TERT', 'Gene', (9, 13))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('TERT', 'Gene', '7015', (9, 13))
148214	25314060	The variant allele C was also associated with a decrease in TERT mRNA expression in the CIC wt group.	('TERT', 'Gene', '7015', (60, 64))	('CIC', 'Gene', '23152', (88, 91))	('CIC', 'Gene', (88, 91))	('decrease', 'NegReg', (48, 56))	('variant', 'Var', (4, 11))	('TERT', 'Gene', (60, 64))
148218	25314060	There was no difference in outcome between C228T and C250T TERTp-mut in any of the analyses.	('TERTp', 'Gene', '7015', (59, 64))	('C228T', 'Mutation', 'rs763756456', (43, 48))	('C250T', 'Mutation', 'rs1225908345', (53, 58))	('C228T', 'Var', (43, 48))	('C250T', 'Var', (53, 58))	('TERTp', 'Gene', (59, 64))
148219	25314060	In a multivariate Cox model analysis incorporating IDH mutation, age at diagnosis, 1p19q codeletion, MGMT promoter methylation, Karnofsky performance status, WHO grade and extension of surgery (Table 2) TERTp-mut was seen to be an independent negative prognostic factor for OS (Hazard ratio (HR)=1.50; 95% CI: 1.07-2.09, P=0.018).	('TERTp', 'Gene', (203, 208))	('IDH', 'Gene', (51, 54))	('TERTp', 'Gene', '7015', (203, 208))	('MGMT', 'Gene', (101, 105))	('Cox', 'Gene', '1351', (18, 21))	('IDH', 'Gene', '3417', (51, 54))	('MGMT', 'Gene', '4255', (101, 105))	('Cox', 'Gene', (18, 21))	('mutation', 'Var', (55, 63))	('negative', 'NegReg', (243, 251))
148220	25314060	Given TERTp-mut is associated with both 1p19q codeletion and EGFR amplification, which are mutually exclusive alterations with opposite prognostic effects and TERTp-mut had a different effect in low- and high-grade gliomas, prompted us to refine our survival analysis (Figure 3).	('associated', 'Reg', (19, 29))	('TERTp', 'Gene', '7015', (6, 11))	('amplification', 'Var', (66, 79))	('1p19q codeletion', 'Var', (40, 56))	('TERTp', 'Gene', (159, 164))	('gliomas', 'Disease', (215, 222))	('TERTp', 'Gene', '7015', (159, 164))	('gliomas', 'Disease', 'MESH:D005910', (215, 222))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('TERTp', 'Gene', (6, 11))
148221	25314060	Gliomas can be stratified into four distinct prognostic groups according to IDH and TERTp-mut status: (1) TERTp-mut and IDH-mut, highly associated with 1p19q codeletion (83.9%, 94 out of 11), OS> 17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation (67.7%, 67 out of 99, OS=97.5 months); (3) TERTp-wt and IDH-wt, with no specific association (all negative), OS=31.6 months; (4) TERTp-mut and IDH-wt, highly associated with EGFR amplification (44.1%, 161 out of 365, OS=15.0 months) (Figure 4).	('EGFR', 'Gene', '1956', (436, 440))	('TP53', 'Gene', '7157', (248, 252))	('TERTp', 'Gene', (84, 89))	('IDH', 'Gene', '3417', (76, 79))	('TERTp', 'Gene', '7015', (84, 89))	('IDH', 'Gene', (318, 321))	('Gliomas', 'Disease', (0, 7))	('IDH', 'Gene', (120, 123))	('IDH', 'Gene', (405, 408))	('IDH', 'Gene', (223, 226))	('TERTp', 'Gene', (305, 310))	('TERTp', 'Gene', '7015', (305, 310))	('IDH', 'Gene', '3417', (318, 321))	('TERTp', 'Gene', (106, 111))	('TERTp', 'Gene', (391, 396))	('TERTp', 'Gene', '7015', (106, 111))	('TERTp', 'Gene', '7015', (391, 396))	('IDH', 'Gene', '3417', (120, 123))	('IDH', 'Gene', '3417', (405, 408))	('EGFR', 'Gene', (436, 440))	('TP53', 'Gene', (248, 252))	('TERTp', 'Gene', (210, 215))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('TERTp', 'Gene', '7015', (210, 215))	('IDH', 'Gene', '3417', (223, 226))	('mutation', 'Var', (253, 261))	('IDH', 'Gene', (76, 79))	('1p19q', 'Var', (152, 157))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))
148231	25314060	Stratifying tumours by both IDH1/2 and TERTp-mut status provides insight into this apparent paradox, identified four molecular subtypes of gliomas with distinct prognosis, In IDH mutated tumours, TERTp-mut is largely confined to 1p19q codeleted oligodendroglial tumours that have the best outcome.	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('IDH', 'Gene', '3417', (28, 31))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('IDH', 'Gene', (175, 178))	('1p19q', 'Var', (229, 234))	('TERTp', 'Gene', (196, 201))	('oligodendroglial tumours', 'Disease', (245, 269))	('IDH1/2', 'Gene', '3417;3418', (28, 34))	('gliomas', 'Disease', (139, 146))	('TERTp', 'Gene', '7015', (196, 201))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IDH1/2', 'Gene', (28, 34))	('mutated', 'Var', (179, 186))	('IDH', 'Gene', '3417', (175, 178))	('tumours', 'Disease', (262, 269))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('tumours', 'Phenotype', 'HP:0002664', (262, 269))	('tumours', 'Disease', 'MESH:D009369', (262, 269))	('IDH', 'Gene', (28, 31))	('oligodendroglial tumours', 'Disease', 'MESH:D009369', (245, 269))	('tumours', 'Disease', (187, 194))	('tumours', 'Disease', (12, 19))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('TERTp', 'Gene', (39, 44))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('TERTp', 'Gene', '7015', (39, 44))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
148232	25314060	Mutation of CIC, recently identified is also primarily a feature of this group (Figure 3).	('CIC', 'Gene', '23152', (12, 15))	('CIC', 'Gene', (12, 15))	('Mutation', 'Var', (0, 8))
148236	25314060	From a mechanistic point of view, TERTp mutation leads to the creation of a putative binding site for Ets/TCF transcription factors, leading to a two- to four-fold higher expression of telomerase.	('expression', 'MPA', (171, 181))	('mutation', 'Var', (40, 48))	('TCF', 'Gene', (106, 109))	('TCF', 'Gene', '3172', (106, 109))	('TERTp', 'Gene', '7015', (34, 39))	('higher', 'PosReg', (164, 170))	('telomerase', 'Enzyme', (185, 195))	('binding', 'Interaction', (85, 92))	('TERTp', 'Gene', (34, 39))
148239	25314060	Among the complex regulation of telomerase expression, rs2853669 has been shown to modulate both TERT expression and impact on prognosis in bladder cancer.	('rs2853669', 'Mutation', 'rs2853669', (55, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('bladder cancer', 'Disease', (140, 154))	('rs2853669', 'Var', (55, 64))	('impact', 'Reg', (117, 123))	('TERT', 'Gene', (97, 101))	('modulate', 'Reg', (83, 91))	('TERT', 'Gene', '7015', (97, 101))
148240	25314060	Indeed, the presence of the variant allele disrupts a pre-existing Ets2 binding site and results in the decrease of TERT expression in our series.	('TERT', 'Gene', (116, 120))	('TERT', 'Gene', '7015', (116, 120))	('binding', 'Interaction', (72, 79))	('decrease', 'NegReg', (104, 112))	('Ets2', 'Protein', (67, 71))	('variant', 'Var', (28, 35))	('disrupts', 'NegReg', (43, 51))
148241	25314060	However, unlike bladder cancer, rs2853669 variant does not modify the prognostic impact of TERTp mutation in our glioma series (data not shown).	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('rs2853669', 'Mutation', 'rs2853669', (32, 41))	('glioma', 'Disease', (113, 119))	('TERTp', 'Gene', (91, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('TERTp', 'Gene', '7015', (91, 96))	('rs2853669', 'Var', (32, 41))
148242	25314060	Our data also suggest a link between CIC mutation and TERT expression in the context of glial tumours.	('CIC', 'Gene', '23152', (37, 40))	('TERT', 'Gene', '7015', (54, 58))	('glial tumours', 'Disease', 'MESH:D009369', (88, 101))	('mutation', 'Var', (41, 49))	('CIC', 'Gene', (37, 40))	('glial tumours', 'Disease', (88, 101))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('link', 'Reg', (24, 28))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('TERT', 'Gene', (54, 58))
148243	25314060	Indeed, the presence of the variant allele of rs2853669 did not result in a reduction of TERT expression in the CIC mutant subgroup.	('reduction', 'NegReg', (76, 85))	('rs2853669', 'Mutation', 'rs2853669', (46, 55))	('CIC', 'Gene', '23152', (112, 115))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('CIC', 'Gene', (112, 115))	('rs2853669', 'Var', (46, 55))
148244	25314060	Among the 40% gliomas lacking TERTp mutation, ~50% harbour an IDH mutation (mostly astrocytomas (43 out of 180) and oligoastrocytomas (91 out of 180), which are frequently TP53 mutated.	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('IDH', 'Gene', '3417', (62, 65))	('oligoastrocytomas', 'Disease', (116, 133))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('mutation', 'Var', (66, 74))	('astrocytomas', 'Disease', (83, 95))	('gliomas', 'Disease', (14, 21))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('harbour', 'Reg', (51, 58))	('TERTp', 'Gene', (30, 35))	('IDH', 'Gene', (62, 65))	('TERTp', 'Gene', '7015', (30, 35))
148245	25314060	In this group, mutations in the ATRX gene (alpha thalassaemia/mental retardation syndrome X-linked), or in its partner death domain-associated protein (DAXX), which are involved in alternative lengthening telomere (ALT) phenotype, have been frequently documented and are mutually exclusive with telomerase reactivation.	('ATRX', 'Gene', '546', (32, 36))	('DAXX', 'Gene', '1616', (152, 156))	('mutations', 'Var', (15, 24))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('mental retardation', 'Phenotype', 'HP:0001249', (62, 80))	('ATRX', 'Gene', (32, 36))	('DAXX', 'Gene', (152, 156))	('alternative', 'MPA', (181, 192))
148252	25314060	TERTp mutations are mostly associated with poor outcome, except for 1p19q codeleted grade II and grade III, and for EGFR amplified grade III and grade IV (Supplementary Figure 2A and B, respectively).	('TERTp', 'Gene', '7015', (0, 5))	('1p19q', 'Var', (68, 73))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('TERTp', 'Gene', (0, 5))
148353	32483272	A neural network-based survival model was built on expression data from a selection of genes most affected by TET1 knockdown with a median cross-validated survival concordance of 82.5%.	('TET1', 'Gene', (110, 114))	('TET1', 'Gene', '80312', (110, 114))	('knockdown', 'Var', (115, 124))
148361	32483272	For example, the revised World Health Organization classifications now include 1p/19q co-deletion as a defining feature of oligodendroglial tumors.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (123, 146))	('1p/19q co-deletion', 'Var', (79, 97))	('oligodendroglial tumors', 'Disease', (123, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
148370	32483272	In a study examining the Cancer Genome Atlas, the levels of 5hmC were reported to be associated with poor survival in anaplastic glioma and GBM.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('poor', 'NegReg', (101, 105))	('GBM', 'Disease', (140, 143))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('5hmC', 'Var', (60, 64))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Disease', (25, 31))	('Cancer', 'Disease', 'MESH:D009369', (25, 31))	('glioma', 'Disease', (129, 135))	('levels', 'Var', (50, 56))
148376	32483272	Survival probability curves were developed for patients with high/low TET1 expression (tethigh/tetlow) relative to the median expression.	('TET1', 'Gene', (70, 74))	('patients', 'Species', '9606', (47, 55))	('high/low', 'Var', (61, 69))	('TET1', 'Gene', '80312', (70, 74))	('expression', 'MPA', (75, 85))
148392	32483272	The expression of TET1 is greater in tumors that harbor isocitrate dehydrogenase (IDH) mutations (Supplemental Fig.	('IDH', 'Gene', '3417', (82, 85))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('TET1', 'Gene', (18, 22))	('expression', 'MPA', (4, 14))	('TET1', 'Gene', '80312', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('greater', 'PosReg', (26, 33))	('IDH', 'Gene', (82, 85))	('mutations', 'Var', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
148441	32483272	Poorer survival is often associated with tumors with more deletions, mutations, and copy number variations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('copy number variations', 'Var', (84, 106))	('Poorer', 'NegReg', (0, 6))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('deletions', 'Var', (58, 67))
148442	32483272	Indeed, we found that glioma patients with a low mutation count (derived from GDC MAF files) had the highest survival probability, followed by moderate and then high mutation counts (Fig.	('MAF', 'Gene', '4094', (82, 85))	('patients', 'Species', '9606', (29, 37))	('MAF', 'Gene', (82, 85))	('glioma', 'Disease', (22, 28))	('low', 'NegReg', (45, 48))	('mutation count', 'Var', (49, 63))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
148443	32483272	At 1,000 days as evaluated from day 0 tumor biopsy, the survival probabilities for patients with low, moderate, and high mutation count were approximately 0.8, 0.4, and 0.2, respectively.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('high mutation count', 'Var', (116, 135))	('patients', 'Species', '9606', (83, 91))
148461	32483272	To assess the causal effects of TET1 deficiency on cell motility, migration was compared between a TET1-deficient and control A172 glioma cell line using the wound-healing assay.	('glioma', 'Disease', (131, 137))	('A172', 'CellLine', 'CVCL:0131', (126, 130))	('TET1', 'Gene', '80312', (99, 103))	('TET1', 'Gene', '80312', (32, 36))	('TET1', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('TET1', 'Gene', (99, 103))	('deficiency', 'Var', (37, 47))
148466	32483272	The hypothesis was based on our experimental findings that knocking down TET1 expression increased DNA strand breaks, attenuated cell cycle checkpoint, and increased resistance to ionizing radiation in glioma cell lines.	('TET1', 'Gene', (73, 77))	('DNA strand', 'MPA', (99, 109))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('increased', 'PosReg', (156, 165))	('TET1', 'Gene', '80312', (73, 77))	('resistance', 'CPA', (166, 176))	('attenuated', 'NegReg', (118, 128))	('glioma', 'Disease', (202, 208))	('increased', 'PosReg', (89, 98))	('cell cycle checkpoint', 'CPA', (129, 150))	('knocking down', 'Var', (59, 72))
148472	32483272	Higher numbers of mutations were found in gliomas with low levels of TET1 expression.	('TET1', 'Gene', (69, 73))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('TET1', 'Gene', '80312', (69, 73))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))	('mutations', 'Var', (18, 27))
148473	32483272	Genomic instability increases heterogeneity in the tumor cell population, which has been shown to increase the resistance of tumors to therapy.	('resistance', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('heterogeneity', 'MPA', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (51, 56))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('increase', 'PosReg', (98, 106))	('Genomic instability', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
148477	32483272	The DDR prevents the proliferation of cells that harbor an unstable genome.	('DDR', 'Var', (4, 7))	('DDR', 'Chemical', '-', (4, 7))	('prevents', 'NegReg', (8, 16))
148487	32483272	Increases in B7-H4 would attenuate the presentation of glioma antigens and result in a poor immune response.	('glioma', 'Disease', (55, 61))	('immune', 'MPA', (92, 98))	('poor immune', 'Phenotype', 'HP:0002721', (87, 98))	('presentation of', 'MPA', (39, 54))	('B7-H4', 'Gene', (13, 18))	('attenuate', 'NegReg', (25, 34))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('B7-H4', 'Gene', '79679', (13, 18))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('Increases', 'Var', (0, 9))
148510	32483272	Data from a TET1 knockdown experiment is provided (Supplemental Table 1).	('TET1', 'Gene', '80312', (12, 16))	('TET1', 'Gene', (12, 16))	('knockdown', 'Var', (17, 26))
148511	32483272	This dataset consists of gene expression signal values for the TET1 knockdown and control A172 glioma cell lines.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('TET1', 'Gene', (63, 67))	('TET1', 'Gene', '80312', (63, 67))	('glioma', 'Disease', (95, 101))	('A172', 'CellLine', 'CVCL:0131', (90, 94))	('knockdown', 'Var', (68, 77))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
148540	31294105	Epigenetic alterations are common and important hallmarks of various types of tumors, and lead to abnormal expression of genes.	('Epigenetic alterations', 'Var', (0, 22))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('expression of genes', 'MPA', (107, 126))	('lead to abnormal', 'Reg', (90, 106))
148541	31294105	Specifically, aberrant DNA methylation and histone acetylation in the promoter regions of GDNF are related to high GDNF transcription in glioma cells, where transcription factors have extremely important roles.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('transcription', 'MPA', (120, 133))	('DNA', 'MPA', (23, 26))	('related', 'Reg', (99, 106))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('GDNF', 'Gene', (90, 94))	('aberrant', 'Var', (14, 22))	('glioma', 'Disease', (137, 143))	('histone acetylation', 'MPA', (43, 62))	('high', 'PosReg', (110, 114))
148554	31294105	Given that altered expression of genes usually results from mutations or epigenetic alterations (see below), several studies have highlighted the influence of epigenetics on tumorigenesis, and epigenetic alterations appear to be common hallmark of various cancer types.	('tumor', 'Disease', (174, 179))	('expression', 'MPA', (19, 29))	('epigenetic alterations', 'Var', (73, 95))	('results from', 'Reg', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('altered', 'Reg', (11, 18))	('rat', 'Species', '10116', (208, 211))	('cancer', 'Disease', (256, 262))	('rat', 'Species', '10116', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('mutations', 'Var', (60, 69))
148557	31294105	Because they are reversible, epigenetic alterations are being targeted for therapeutics in cancer clinical trials.	('epigenetic alterations', 'Var', (29, 51))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('rat', 'Species', '10116', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
148558	31294105	With regard to glioma cells, although epigenetic alterations have been studied thoroughly (for review, see), little effort has been made to elucidate the epigenetic mechanism of high GDNF transcription.	('GDNF', 'Gene', (183, 187))	('rat', 'Species', '10116', (53, 56))	('glioma', 'Disease', (15, 21))	('high', 'Var', (178, 182))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
148559	31294105	This review explores recent advances regarding the epigenetic mechanism of high GDNF expression in glioma cells, and its potential clinical implications, to improve treatment for this lethal disease.	('GDNF', 'Gene', (80, 84))	('high', 'Var', (75, 79))	('glioma', 'Disease', (99, 105))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
148572	31294105	Markedly increased expression of any gene is usually the result of gene mutations or epigenetic alterations.	('expression', 'MPA', (19, 29))	('increased', 'PosReg', (9, 18))	('gene mutations', 'Var', (67, 81))	('epigenetic alterations', 'Var', (85, 107))	('rat', 'Species', '10116', (100, 103))
148574	31294105	Alongside known genetic changes, aberrant epigenetic alterations have emerged as common hallmarks of many cancers types.	('hallmarks of many cancers', 'Disease', 'MESH:D009369', (88, 113))	('aberrant epigenetic alterations', 'Var', (33, 64))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('rat', 'Species', '10116', (57, 60))	('hallmarks of many cancers', 'Disease', (88, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
148577	31294105	Hence, one could speculate that epigenetic modifications contribute to increased expression of GDNF, and some scholars have attempted to explore the underlying epigenetic mechanism of high GDNF expression in glioma cells.	('glioma', 'Disease', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('increased', 'PosReg', (71, 80))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('GDNF', 'Protein', (95, 99))	('epigenetic modifications', 'Var', (32, 56))	('expression', 'MPA', (81, 91))
148579	31294105	However, in many cancer types, a proportion of CGIs is hypermethylated, which is associated with silencing of tumor-suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', (110, 115))	('cancer', 'Disease', (17, 23))	('hypermethylated', 'Var', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
148580	31294105	Different patterns of DNA methylation occur in different cancers, and hypermethylation and hypomethylation have emerged as significant fators in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('hypermethylation', 'Var', (70, 86))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('tumor', 'Disease', (145, 150))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('hypomethylation', 'Var', (91, 106))
148581	31294105	The loci of DNA hypermethylation are in the promoter regions of tumor-suppressor genes, which results in the associated silencing of these genes.	('tumor', 'Disease', (64, 69))	('hypermethylation', 'Var', (16, 32))	('silencing', 'NegReg', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
148583	31294105	The patterns of DNA methylation are also likely to have important roles in developmental processes in the brain and in brain tumors, such as gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('brain tumors', 'Disease', 'MESH:D001932', (119, 131))	('brain tumors', 'Phenotype', 'HP:0030692', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('brain tumors', 'Disease', (119, 131))	('methylation', 'Var', (20, 31))	('roles', 'Reg', (66, 71))	('gliomas', 'Disease', (141, 148))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
148585	31294105	The authors proposed that these changes may enable glioma cells to self-renew perpetually, a hypothesis that is consistent with the increased cell proliferation observed in glioblastoma.	('glioma', 'Disease', (51, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (173, 185))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('rat', 'Species', '10116', (154, 157))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('self-renew', 'CPA', (67, 77))	('enable', 'PosReg', (44, 50))	('glioblastoma', 'Disease', (173, 185))	('changes', 'Var', (32, 39))
148586	31294105	With regard to gliomas, isocitrate dehydrogenase (IDH) mutations are strongly associated with a distinct phenotype of DNA methylation, and methylation of O6-methylguanine DNA methyltransferase (MGMT) helps to predict therapeutic responses: these are the two most well-characterized types of DNA methylation.	('associated', 'Reg', (78, 88))	('mutations', 'Var', (55, 64))	('isocitrate dehydrogenase', 'Gene', '3417', (24, 48))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('O6-methylguanine DNA methyltransferase', 'Gene', (154, 192))	('MGMT', 'Gene', '4255', (194, 198))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (154, 192))	('MGMT', 'Gene', (194, 198))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('IDH', 'Gene', (50, 53))	('isocitrate dehydrogenase', 'Gene', (24, 48))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('IDH', 'Gene', '3417', (50, 53))
148589	31294105	Glioma patients carrying the IDH mutation have signifcantly improved survivals.	('mutation', 'Var', (33, 41))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('survivals', 'CPA', (69, 78))	('IDH', 'Gene', (29, 32))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('improved', 'PosReg', (60, 68))	('IDH', 'Gene', '3417', (29, 32))	('patients', 'Species', '9606', (7, 15))
148595	31294105	The authors also showed that changes in the binding capacity of transcriptional factors mediated by methylation of promoter regions contributed to aberrantly high GDNF expression in glioma cells.	('expression', 'MPA', (168, 178))	('changes', 'Reg', (29, 36))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('GDNF', 'Gene', (163, 167))	('methylation', 'Var', (100, 111))	('high', 'PosReg', (158, 162))	('glioma', 'Disease', (182, 188))	('binding', 'Interaction', (44, 51))
148596	31294105	Subsequently, based on the different levels of methylation at different cis-acting elements in promoter region II of GDNF, in-depth investigation was undertaken by Zhang et al.. Based on "specific sequence methylation", they found that hypermethylation of silencer II of GDNF promoted high GDNF transcription in high-grade gliomas, in accordance with their previous results (Fig.	('gliomas', 'Disease', 'MESH:D005910', (323, 330))	('gliomas', 'Phenotype', 'HP:0009733', (323, 330))	('gliomas', 'Disease', (323, 330))	('glioma', 'Phenotype', 'HP:0009733', (323, 329))	('hypermethylation', 'Var', (236, 252))	('high GDNF transcription', 'MPA', (285, 308))	('GDNF', 'Gene', (271, 275))	('promoted', 'PosReg', (276, 284))
148597	31294105	During the development and progression of cancers, altered DNA methylation is not the only epigenetic process.	('cancers', 'Disease', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('altered', 'Var', (51, 58))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
148603	31294105	also showed that hyperacetylation of histone H3 within the NR4A1 promoter induced NR4A1 expression in hypercholesterolaemia.	('NR4A1', 'Gene', (59, 64))	('hypercholesterolaemia', 'Disease', (102, 123))	('NR4A1', 'Gene', '3164', (59, 64))	('hypercholesterolaemia', 'Disease', 'None', (102, 123))	('NR4A1', 'Gene', (82, 87))	('hyperacetylation', 'Var', (17, 33))	('expression', 'MPA', (88, 98))	('NR4A1', 'Gene', '3164', (82, 87))
148604	31294105	However, there are several exceptions related to hyperacetylation and hypoacetylation, as well as the effects of HDAC inhibitors and their role in gene activation/repression, which suggestes a dynamic perspective (for reviews, see).	('HDAC', 'Gene', (113, 117))	('hyperacetylation', 'Var', (49, 65))	('HDAC', 'Gene', '9734', (113, 117))
148612	31294105	revealed that acetylation of histone H3 in promoter region II was significantly and positively correlated with GDNF transcription based on curcumin-induced H3K9 hypoacetylation and Trichostatin A-induced H3K9 hyperacetylation.	('H3K9 hypoacetylation', 'Var', (156, 176))	('curcumin', 'Chemical', 'MESH:D003474', (139, 147))	('Trichostatin A', 'Chemical', 'MESH:C012589', (181, 195))	('hypoacetylation', 'Var', (161, 176))	('correlated', 'Reg', (95, 105))	('acetylation', 'MPA', (14, 25))	('GDNF transcription', 'Gene', (111, 129))
148613	31294105	They showed that hyperacetylation of histone H3K9 in the promoter region II of GDNF caused its aberrantly high transcription in glioma cells, in accordance with the traditional mechanism of acetylation regulation.	('glioma', 'Disease', (128, 134))	('transcription', 'MPA', (111, 124))	('histone H3K9', 'Protein', (37, 49))	('high', 'PosReg', (106, 110))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('hyperacetylation', 'Var', (17, 33))	('GDNF', 'Gene', (79, 83))
148614	31294105	Kim and co-workers investigated if histone hyperacetylation at Egr-1 (a transcription factor involved in GDNF activation) binding sites in GDNF promoter region II in glioma cells could upregulate the binding capability of Egr-1, and then induced aberrantly high GDNF transcription (Fig.	('Egr-1', 'Gene', '1958', (63, 68))	('glioma', 'Disease', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('Egr-1', 'Gene', (222, 227))	('high', 'PosReg', (257, 261))	('GDNF transcription', 'MPA', (262, 280))	('upregulate', 'PosReg', (185, 195))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('binding', 'Var', (122, 129))	('Egr-1', 'Gene', '1958', (222, 227))	('binding', 'Interaction', (200, 207))	('Egr-1', 'Gene', (63, 68))	('induced', 'Reg', (238, 245))
148621	31294105	In detail, hypermethylation of promoter II in high-grade gliomas lead to silencer deactivation, whereas hypomethylation of promoter II in low-grade glioma results in enhancer activation.	('silencer deactivation', 'Disease', (73, 94))	('glioma', 'Disease', (148, 154))	('hypermethylation', 'Var', (11, 27))	('glioma', 'Disease', (57, 63))	('hypomethylation', 'Var', (104, 119))	('enhancer activation', 'PosReg', (166, 185))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('silencer deactivation', 'Disease', 'MESH:C562567', (73, 94))
148622	31294105	Histone hyperacetylation in GDNF promoter II in glioma cells enhances GDNF transcription, in which Egr-1 has an important role.	('glioma', 'Disease', (48, 54))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('GDNF', 'Gene', (70, 74))	('hyperacetylation', 'Var', (8, 24))	('enhances', 'PosReg', (61, 69))	('Histone hyperacetylation', 'Var', (0, 24))	('Egr-1', 'Gene', (99, 104))	('Egr-1', 'Gene', '1958', (99, 104))	('transcription', 'MPA', (75, 88))
148623	31294105	Changes in the binding of transcription factors to the promoter regions of GDNF by methylation or acetylation contributes to high GDNF expression in glioma cells.	('glioma', 'Disease', (149, 155))	('GDNF', 'MPA', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('expression', 'MPA', (135, 145))	('GDNF', 'Gene', (75, 79))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('methylation', 'Var', (83, 94))	('acetylation', 'Var', (98, 109))	('high', 'PosReg', (125, 129))	('binding', 'Interaction', (15, 22))	('Changes', 'Reg', (0, 7))
148637	28759109	Activation of the phosphatidylinositol 3-kinase (PI3K) pathway is commonly seen LGGs and secondary malignant gliomas, often through inactivation of PTEN, an inhibitory regulator of the pathway.	('phosphatidylinositol 3-kinase', 'Gene', (18, 47))	('malignant gliomas', 'Disease', (99, 116))	('PTEN', 'Gene', (148, 152))	('PTEN', 'Gene', '5728', (148, 152))	('malignant gliomas', 'Disease', 'MESH:D005910', (99, 116))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('inactivation', 'Var', (132, 144))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('Activation', 'PosReg', (0, 10))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (18, 47))
148638	28759109	Immunohistochemistry for downstream targets of PI3K, including phosphorylated ribosomal S6 (p-S6) is seen in over half of patients with LGG, and is associated with PTEN promoter methylation.	('LGG', 'Disease', (136, 139))	('S6', 'Gene', '6194', (88, 90))	('S6', 'Gene', '6194', (94, 96))	('patients', 'Species', '9606', (122, 130))	('associated', 'Reg', (148, 158))	('PTEN', 'Gene', (164, 168))	('PI3K', 'Var', (47, 51))	('PTEN', 'Gene', '5728', (164, 168))
148640	28759109	Mammalian target of rapamycin (mTOR) is a downstream target of PI3K that, when activated, leads to abnormal cell growth, proliferation and angiogenesis.	('PI3K', 'Var', (63, 67))	('abnormal cell growth', 'CPA', (99, 119))	('angiogenesis', 'CPA', (139, 151))	('Mammalian target of rapamycin', 'Gene', '2475', (0, 29))	('leads to', 'Reg', (90, 98))	('Mammalian target of rapamycin', 'Gene', (0, 29))
148641	28759109	Targeted therapy with the mTOR inhibitor everolimus (RAD001) is highly effective in the treatment of subependymal giant-cell astrocytomas (SEGAs) in patients with mutations in the tuberous sclerosis complex (TSC), a key inhibitor of mTOR, as well as in other solid malignancies with PI3K pathway activation.	('patients', 'Species', '9606', (149, 157))	('mutations', 'Var', (163, 172))	('tuberous sclerosis', 'Disease', (180, 198))	('malignancies', 'Disease', 'MESH:D009369', (265, 277))	('subependymal giant-cell astrocytomas', 'Phenotype', 'HP:0009718', (101, 137))	('SEGAs', 'Phenotype', 'HP:0009718', (139, 144))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (180, 198))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('malignancies', 'Disease', (265, 277))	('subependymal giant-cell astrocytomas', 'Disease', 'MESH:D001254', (101, 137))	('everolimus', 'Chemical', 'MESH:D000068338', (41, 51))	('subependymal giant-cell astrocytomas', 'Disease', (101, 137))
148650	28759109	Dose delay and modifications were required for persistent thrombocytopenia (<75 x 199/L), neutropenia (ANC <1000/mm3), or any persistent non-hematologic grade 2 or 3 toxicity.	('neutropenia', 'Disease', (90, 101))	('thrombocytopenia', 'Disease', 'MESH:D013921', (58, 74))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (58, 74))	('neutropenia', 'Disease', 'MESH:D009503', (90, 101))	('<75 x 199/L', 'Var', (76, 87))	('thrombocytopenia', 'Disease', (58, 74))	('toxicity', 'Disease', 'MESH:D064420', (166, 174))	('toxicity', 'Disease', (166, 174))	('neutropenia', 'Phenotype', 'HP:0001875', (90, 101))
148657	28759109	Immunohistochemistry (IHC) was performed for phosphorylated PRAS40 (p-PRAS40Thr246), phosphorylated mTOR (p-mTORSer2448), two epitopes of phosphorylated S6 ribosomal protein (p-S6Ser240/244 and p-S6Ser235/236), and phosphorylated 4EBP1 (p-4EBP1Thr37/46); see Supplemental Data.	('p-PRAS40Thr246', 'Gene', '84335', (68, 82))	('PRAS40', 'Gene', '84335', (60, 66))	('p-4EBP1Thr37/46', 'Gene', (237, 252))	('S6', 'Gene', '6194', (196, 198))	('p-PRAS40Thr246', 'Gene', (68, 82))	('4EBP1', 'Gene', '1978', (239, 244))	('PRAS40', 'Gene', (60, 66))	('p-mTORSer2448', 'Var', (106, 119))	('S6', 'Gene', '6194', (153, 155))	('p-S6Ser240/244', 'Gene', '6194', (175, 189))	('4EBP1', 'Gene', (239, 244))	('4EBP1', 'Gene', '1978', (230, 235))	('PRAS40', 'Gene', '84335', (70, 76))	('PRAS40', 'Gene', (70, 76))	('p-S6Ser240/244', 'Gene', (175, 189))	('p-4EBP1Thr37/46', 'Gene', '1978', (237, 252))	('S6', 'Gene', '6194', (177, 179))	('4EBP1', 'Gene', (230, 235))
148660	28759109	Patients also underwent testing for 1p/19q codeletion by fluoresence in situ hybridization (FISH) and for IDH1-R132H mutation by IHC, and were placed into three molecular subgroups according to 2016 WHO classification: 1p/19q codeleted/IDH1 mutated (1p/19q codel), 1p/19q intact/IDH1 mutated (IDH1mut), and 1p/19q intact/IDH1 wild type (IDH1wt).	('1p/19q', 'Var', (219, 225))	('IDH', 'Gene', (279, 282))	('IDH', 'Gene', '3417', (106, 109))	('IDH', 'Gene', (337, 340))	('IDH', 'Gene', (293, 296))	('1p/19q', 'Var', (265, 271))	('IDH', 'Gene', '3417', (279, 282))	('IDH', 'Gene', (236, 239))	('R132H', 'Mutation', 'rs121913500', (111, 116))	('IDH', 'Gene', '3417', (337, 340))	('IDH', 'Gene', (321, 324))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', '3417', (293, 296))	('IDH', 'Gene', '3417', (236, 239))	('IDH', 'Gene', '3417', (321, 324))	('IDH', 'Gene', (106, 109))
148683	28759109	In general, patients with 1p/19q codeletion had lower median staining for PI3K activation compared with 1p/19q intact patients (Supplemental Table 1).	('patients', 'Species', '9606', (12, 20))	('staining', 'MPA', (61, 69))	('lower', 'NegReg', (48, 53))	('patients', 'Species', '9606', (118, 126))	('1p/19q codeletion', 'Var', (26, 43))	('codeletion', 'Var', (33, 43))	('PI3K activation', 'Pathway', (74, 89))
148688	28759109	Positivity for p-S6 was the only clinical or molecular factor found to be prognostic of PFS.	('PFS', 'Disease', (88, 91))	('S6', 'Gene', '6194', (17, 19))	('Positivity', 'Var', (0, 10))
148700	28759109	Prior studies evaluating mTOR inhibition in glioblastoma have yielded mixed results, with modest rates of response and scant evidence of improvement in clinical outcomes.	('glioblastoma', 'Disease', (44, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('inhibition', 'Var', (30, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('mTOR', 'Gene', (25, 29))
148721	28759109	Inhibition of mTOR with everolimus yielded a high rate of clinical stability in a phase II clinical trial of patients with recurrent low-grade gliomas.	('clinical stability', 'MPA', (58, 76))	('patients', 'Species', '9606', (109, 117))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('gliomas', 'Disease', (143, 150))	('Inhibition', 'Var', (0, 10))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('everolimus', 'Chemical', 'MESH:D000068338', (24, 34))	('mTOR', 'Gene', (14, 18))
148787	25608821	In this case, the number of cases remaining was 120, and the variables identified as independent predictors of high-grade tumors were enhancement (OR, 16.95; 95% CI, 3.89-71.43), necrosis (OR, 5.40; 95% CI, 1.32-21.74), and low rADC values (OR,0.22; 95% CI, 0.50-0.97) (Table 4).	('tumors', 'Disease', (122, 128))	('necrosis', 'Disease', (179, 187))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('men', 'Species', '9606', (141, 144))	('necrosis', 'Disease', 'MESH:D009336', (179, 187))	('rADC', 'Gene', (228, 232))	('enhancement', 'PosReg', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('low', 'Var', (224, 227))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('rADC', 'Gene', '366473', (228, 232))
148805	25608821	As a result, enhancement, necrosis, and low rADC were predictors of high tumor grade, and these variables provided higher accuracy (sensitivity 98.9%; specificity 75.9%) than those obtained with the other combinations analyzed (only MRI variables or MRI, PWI, DWI, and MRS variables).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('necrosis', 'Disease', 'MESH:D009336', (26, 34))	('MRS', 'Disease', 'MESH:D008556', (269, 272))	('low', 'Var', (40, 43))	('rADC', 'Gene', '366473', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('enhancement', 'PosReg', (13, 24))	('necrosis', 'Disease', (26, 34))	('higher', 'PosReg', (115, 121))	('rADC', 'Gene', (44, 48))	('MRS', 'Disease', (269, 272))	('men', 'Species', '9606', (20, 23))
148847	33173410	Genes encoding HNF1B transcription factors are prone to various types of mutations, causing the occurrence and progression of various diseases, including diabetes, renal insufficiency, and various malignant tumors.	('diabetes', 'Disease', (154, 162))	('malignant tumors', 'Disease', 'MESH:D009369', (197, 213))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('renal insufficiency', 'Disease', (164, 183))	('HNF1B', 'Gene', '6928', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('HNF1B', 'Gene', (15, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (164, 183))	('renal insufficiency', 'Phenotype', 'HP:0000083', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('causing', 'Reg', (84, 91))	('malignant tumors', 'Disease', (197, 213))	('mutations', 'Var', (73, 82))
148848	33173410	In the present study, we evaluated expression and mutations of HNF1B in different types of cancer from The Cancer Genome Atlas (TCGA) database.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HNF1B', 'Gene', '6928', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('HNF1B', 'Gene', (63, 68))
148854	33173410	The cBio cancer genomics portal was used to explore mutations and copy-number alterations of HNF1B in the TCGA pan-cancer studies.	('mutations', 'Var', (52, 61))	('HNF1B', 'Gene', (93, 98))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (9, 15))	('copy-number alterations', 'Var', (66, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HNF1B', 'Gene', '6928', (93, 98))
148868	33173410	As shown in Figure 2A, the mutation types of HNF1B included missense mutations, truncating mutations, in-frame mutations and other mutations.	('truncating', 'MPA', (80, 90))	('HNF1B', 'Gene', (45, 50))	('missense mutations', 'Var', (60, 78))	('in-frame mutations', 'Var', (102, 120))	('HNF1B', 'Gene', '6928', (45, 50))
148870	33173410	Additionally, cancer patients with HNF1B mutations are more susceptible to many other gene mutations, including TP53, TTN, MUC16, CSMD3, SYNE1, ZFHX4, LRP1B, XIRP2, PCLO, FLG, FAT4, DNAH5, HYDIN, PIK3CA, USH2A, HMCN1, RYR2, CSMD1, FAT3 and KMT2D (Figure 2C).	('ZFHX4', 'Gene', (144, 149))	('SYNE1', 'Gene', (137, 142))	('MUC16', 'Gene', '94025', (123, 128))	('HNF1B', 'Gene', (35, 40))	('DNAH5', 'Gene', '1767', (182, 187))	('PIK3CA', 'Gene', (196, 202))	('LRP1B', 'Gene', (151, 156))	('XIRP2', 'Gene', (158, 163))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (112, 116))	('PCLO', 'Gene', (165, 169))	('HYDIN', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('FAT3', 'Gene', (231, 235))	('SYNE1', 'Gene', '23345', (137, 142))	('TTN', 'Gene', '7273', (118, 121))	('mutations', 'Var', (41, 50))	('HMCN1', 'Gene', (211, 216))	('FLG', 'Gene', (171, 174))	('ZFHX4', 'Gene', '79776', (144, 149))	('FAT4', 'Gene', '79633', (176, 180))	('TTN', 'Gene', (118, 121))	('CSMD3', 'Gene', '114788', (130, 135))	('KMT2D', 'Gene', '8085', (240, 245))	('MUC16', 'Gene', (123, 128))	('CSMD1', 'Gene', '64478', (224, 229))	('DNAH5', 'Gene', (182, 187))	('CSMD1', 'Gene', (224, 229))	('LRP1B', 'Gene', '53353', (151, 156))	('FLG', 'Gene', '2312', (171, 174))	('FAT3', 'Gene', '120114', (231, 235))	('USH2A', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (196, 202))	('HMCN1', 'Gene', '83872', (211, 216))	('CSMD3', 'Gene', (130, 135))	('PCLO', 'Gene', '27445', (165, 169))	('TP53', 'Gene', (112, 116))	('cancer', 'Disease', (14, 20))	('XIRP2', 'Gene', '129446', (158, 163))	('FAT4', 'Gene', (176, 180))	('RYR2', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HYDIN', 'Gene', '54768', (189, 194))	('KMT2D', 'Gene', (240, 245))	('RYR2', 'Gene', '6262', (218, 222))	('USH2A', 'Gene', '7399', (204, 209))	('HNF1B', 'Gene', '6928', (35, 40))
148888	33173410	As shown in Figure 6A, CD8+ T cell levels were negatively associated with overall survival in the low HNF1B expression group of kidney renal papillary cell carcinoma (KIRP, HR=3.76, P=0.00305) and uveal melanoma (UVM, HR=2.99, P=0.0479).	('CD8', 'Gene', (23, 26))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (135, 165))	('CD8', 'Gene', '925', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('low', 'Var', (98, 101))	('HNF1B', 'Gene', '6928', (102, 107))	('uveal melanoma', 'Disease', (197, 211))	('HNF1B', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('overall', 'MPA', (74, 81))	('negatively', 'NegReg', (47, 57))
148890	33173410	In the low HNF1B expression group of liver hepatocellular carcinoma (LIHC), CD8+ T cells were revealed to be positively associated with overall survival.	('associated', 'Reg', (120, 130))	('HNF1B', 'Gene', '6928', (11, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('HNF1B', 'Gene', (11, 16))	('low', 'Var', (7, 10))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 67))	('overall', 'MPA', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('liver hepatocellular carcinoma', 'Disease', (37, 67))
148902	33173410	Moreover, it has been reported that the single nucleotide polymorphism (SNP) of HNF1B can affect the susceptibility of endometrial tumors.	('affect', 'Reg', (90, 96))	('endometrial tumors', 'Disease', 'MESH:D016889', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HNF1B', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('endometrial tumors', 'Disease', (119, 137))	('single nucleotide polymorphism', 'Var', (40, 70))	('HNF1B', 'Gene', '6928', (80, 85))
148903	33173410	conducted gene sequencing studies on endometrial cancer patients and control groups and found that HNF1B gene SNP (rs4430796, G A) can reduce the incidence of endometrial cancer.	('rs4430796', 'Var', (115, 124))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('endometrial cancer', 'Disease', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('HNF1B', 'Gene', '6928', (99, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HNF1B', 'Gene', (99, 104))	('reduce', 'NegReg', (135, 141))
148906	33173410	Most HNF1B mutations are clustered in the first 4 exons of the gene.	('HNF1B', 'Gene', (5, 10))	('mutations', 'Var', (11, 20))	('HNF1B', 'Gene', '6928', (5, 10))
148908	33173410	A total of 106 HNF1B gene mutations, including gene deletion (34%), missense mutation (31%), frameshift deletion or insertion mutation (15%), nonsense mutation (11%) and splicing point mutation (8%) have been reported.	('frameshift deletion', 'Var', (93, 112))	('gene deletion', 'Var', (47, 60))	('HNF1B', 'Gene', '6928', (15, 20))	('HNF1B', 'Gene', (15, 20))	('insertion mutation', 'Var', (116, 134))	('splicing', 'MPA', (170, 178))	('nonsense mutation', 'Var', (142, 159))	('missense mutation', 'Var', (68, 85))
148909	33173410	According to these results, our study found that HNF1B mutations occurred widely in human cancers and that the most common type is missense mutations.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNF1B', 'Gene', (49, 54))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('missense mutations', 'Var', (131, 149))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HNF1B', 'Gene', '6928', (49, 54))
148910	33173410	Additionally, patients with HNF1B mutations are more prone to mutations in other genes, such as TP53, TTN and MUC16.	('TTN', 'Gene', (102, 105))	('TP53', 'Gene', (96, 100))	('MUC16', 'Gene', (110, 115))	('mutations', 'Var', (62, 71))	('TTN', 'Gene', '7273', (102, 105))	('prone', 'Reg', (53, 58))	('MUC16', 'Gene', '94025', (110, 115))	('patients', 'Species', '9606', (14, 22))	('HNF1B', 'Gene', '6928', (28, 33))	('mutations', 'Var', (34, 43))	('TP53', 'Gene', '7157', (96, 100))	('HNF1B', 'Gene', (28, 33))
148922	33173410	HNF1B mutations are widely observed in tumors and interact with different genes in different cancer types, which may be the cause of the distinct prognostic values in cancers.	('interact', 'Reg', (50, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('HNF1B', 'Gene', '6928', (0, 5))	('HNF1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (6, 15))
148926	33081848	Homozygous deletion of CDKN2A has been proposed as a molecular correlate of aggressive behavior in these tumors, and may be incorporated into future grading systems in an effort to improve prognostic stratification.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('aggressive behavior', 'Phenotype', 'HP:0000718', (76, 95))	('CDKN2A', 'Gene', (23, 29))	('CDKN2A', 'Gene', '1029', (23, 29))	('Homozygous', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
148930	33081848	Multivariate Cox Proportional-Hazards analysis demonstrated that histologic grade and CDKN2A status are independent predictors of survival, and the prognostic value of CDKN2A is maximized by applying a threshold of >= 30% of tumor cells with homozygous deletion by FISH to define a positive result.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('CDKN2A', 'Gene', '1029', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('deletion', 'Var', (253, 261))	('tumor', 'Disease', (225, 230))	('CDKN2A', 'Gene', (168, 174))	('CDKN2A', 'Gene', '1029', (168, 174))	('CDKN2A', 'Gene', (86, 92))
148931	33081848	At this threshold, CDKN2A deletion significantly stratified survival of histologic grade 4 tumors, but grade 2 and 3 tumors rarely exceeded this cutoff value and did not show worse survival.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CDKN2A', 'Gene', (19, 25))	('deletion', 'Var', (26, 34))	('tumors', 'Disease', (117, 123))	('stratified', 'Reg', (49, 59))	('survival', 'MPA', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('CDKN2A', 'Gene', '1029', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
148933	33081848	Compared to prior studies, the lack of prognostic significance of CDKN2A homozygous deletion by FISH in grade 2-3 IDH-mutant astrocytomas may reflect differences in cohort populations or technical differences between testing modalities.	('CDKN2A', 'Gene', (66, 72))	('deletion', 'Var', (84, 92))	('IDH', 'Gene', (114, 117))	('IDH', 'Gene', '3417', (114, 117))	('astrocytomas', 'Disease', 'MESH:D001254', (125, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('CDKN2A', 'Gene', '1029', (66, 72))	('astrocytomas', 'Disease', (125, 137))
148935	33081848	Incorporation of somatic molecular alterations into the classification and grading of brain tumors continues to drive an ongoing revolution in the field of neuro-oncology.	('alterations', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('brain tumors', 'Disease', 'MESH:D001932', (86, 98))	('oncology', 'Phenotype', 'HP:0002664', (162, 170))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('brain tumors', 'Phenotype', 'HP:0030692', (86, 98))	('brain tumor', 'Phenotype', 'HP:0030692', (86, 97))	('brain tumors', 'Disease', (86, 98))
148941	33081848	Based on these studies, homozygous deletion of the CDKN2A gene, which encodes the cell-cycle regulators p16INK4A and p14ARF, has emerged as a leading candidate molecular marker of high-grade behavior in these tumors.	('CDKN2A', 'Gene', '1029', (51, 57))	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('p16INK4A', 'Gene', '1029', (104, 112))	('p14ARF', 'Gene', '1029', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('p14ARF', 'Gene', (117, 123))	('p16INK4A', 'Gene', (104, 112))	('CDKN2A', 'Gene', (51, 57))	('homozygous', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
148944	33081848	FISH testing is advantageous in the setting of diffusely infiltrative tumors with highly variable degrees of tumor cellularity relative to background non-neoplastic parenchyma, since the sensitivity of sequencing- and array-based techniques for accurately detecting homozygous deletion suffers in this situation.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('deletion', 'Var', (277, 285))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (109, 114))
148945	33081848	The choice of where to set the clinical cutoff for defining tumor wide CDKN2A deletion based on the proportion of tumor cells with homozygous deletion will be critically important if CDKN2A status is to be used for tumor grading and therapeutic decision-making.	('CDKN2A', 'Gene', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('CDKN2A', 'Gene', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CDKN2A', 'Gene', '1029', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('deletion', 'Var', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('CDKN2A', 'Gene', '1029', (71, 77))	('tumor', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (60, 65))
148949	33081848	In addition, cases of recurrent tumors that had developed new CDKN2A deletion compared to the original resection specimen led us to hypothesize that this molecular marker might have different prognostic implications at the time of recurrence compared to initial presentation.	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('CDKN2A', 'Gene', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('deletion', 'Var', (69, 77))	('tumors', 'Disease', (32, 38))	('CDKN2A', 'Gene', '1029', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
148950	33081848	To move beyond anecdotes, we systematically analyzed our institutional cohort of patients with IDHm astrocytomas and CDKN2A FISH analysis in order to better define the relationship between percentage of cells with homozygous CDKN2A deletion, histologic grade, and patient survival, in both primary and recurrent tumors.	('tumors', 'Disease', (312, 318))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('patient', 'Species', '9606', (81, 88))	('CDKN2A', 'Gene', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('patients', 'Species', '9606', (81, 89))	('deletion', 'Var', (232, 240))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('CDKN2A', 'Gene', '1029', (225, 231))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('patient', 'Species', '9606', (264, 271))	('CDKN2A', 'Gene', (117, 123))	('IDHm astrocytomas', 'Disease', 'MESH:D001254', (95, 112))	('IDHm astrocytomas', 'Disease', (95, 112))	('CDKN2A', 'Gene', '1029', (117, 123))
148957	33081848	A single case was originally diagnosed as oligodendroglioma despite intact 1p/19q, but was reclassified as astrocytic at recurrence.	('oligodendroglioma', 'Disease', 'MESH:D009837', (42, 59))	('1p/19q', 'Protein', (75, 81))	('intact', 'Var', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('oligodendroglioma', 'Disease', (42, 59))
148958	33081848	All of the astrocytomas included in this study were negative for 1p/19q codeletion as determined by FISH, loss of heterozygosity (LOH) PCR, and/or NGS testing.	('1p/19q codeletion', 'Var', (65, 82))	('astrocytomas', 'Disease', 'MESH:D001254', (11, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('negative', 'NegReg', (52, 60))	('astrocytomas', 'Disease', (11, 23))	('loss', 'Var', (106, 110))
148968	33081848	The UPMC lab uses the LSI 9p21/CEP9 dual color probe set for detection of CDKN2A deletion (Abbott Molecular, Abbott Park, IL).	('deletion', 'Var', (81, 89))	('CDKN2A', 'Gene', '1029', (74, 80))	('CDKN2A', 'Gene', (74, 80))
148975	33081848	Tumors of histologic grade 4 were over-represented in the tail of the distribution (including all four primary tumors with > 50% of cells having homozygous CDKN2A deletion), confirming a relationship between CDKN2A status and aggressive tumor behavior, but no intuitively obvious cutoff value emerged from this analysis.	('deletion', 'Var', (163, 171))	('CDKN2A', 'Gene', (208, 214))	('CDKN2A', 'Gene', (156, 162))	('primary tumors', 'Disease', (103, 117))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (226, 251))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CDKN2A', 'Gene', '1029', (208, 214))	('CDKN2A', 'Gene', '1029', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('aggressive tumor behavior', 'Disease', (226, 251))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('primary tumors', 'Disease', 'MESH:D001932', (103, 117))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('over-represented', 'PosReg', (34, 50))
148976	33081848	In contrast to primary tumors, high levels of homozygous CDKN2A deletion occurred at a much higher relative frequency in recurrent tumor specimens (Fig.	('primary tumors', 'Disease', 'MESH:D001932', (15, 29))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('CDKN2A', 'Gene', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('deletion', 'Var', (64, 72))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('primary tumors', 'Disease', (15, 29))	('tumor', 'Disease', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
148977	33081848	A smaller subset of grade 3 recurrences also showed increased levels of CDKN2A deletion, while all tumors that continued to have grade 2 histologic features at recurrence had no or very low levels of deletion (maximum homozygous deletion among grade 2 recurrences: 13% of cells).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('CDKN2A', 'Gene', (72, 78))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('deletion', 'Var', (79, 87))	('CDKN2A', 'Gene', '1029', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
148978	33081848	While a few grade 4 recurrences showed essentially complete (> 90%) homozygous CDKN2A deletion, a substantial number also showed intermediate levels, again failing to define an obvious cutoff value.	('CDKN2A', 'Gene', '1029', (79, 85))	('CDKN2A', 'Gene', (79, 85))	('deletion', 'Var', (86, 94))
148983	33081848	Using a multivariate Cox-PH model including patient age, sex, histologic grade, and percent CDKN2A homozygous deletion as a continuous variable, we verified that histologic grade and CDKN2A deletion were independently significant prognostic factors in our cohort (Additional file 1: table S1).	('CDKN2A', 'Gene', (183, 189))	('patient', 'Species', '9606', (44, 51))	('CDKN2A', 'Gene', (92, 98))	('deletion', 'Var', (190, 198))	('CDKN2A', 'Gene', '1029', (183, 189))	('CDKN2A', 'Gene', '1029', (92, 98))
148985	33081848	To determine a clinically appropriate cutoff, we constructed series of Cox-PH models as above, but with CDKN2A status binarized at cutoff thresholds ranging from 5-35% cells with homozygous deletion (Fig.	('CDKN2A', 'Gene', '1029', (104, 110))	('CDKN2A', 'Gene', (104, 110))	('deletion', 'Var', (190, 198))
148986	33081848	In our cohort of primary tumors, a cutoff of >= 30% homozygous deletion minimized the AIC of the model fit, minimized the Cox-PH p-value, and maximized the hazard ratio for CDKN2A loss (Fig.	('AIC', 'MPA', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('CDKN2A', 'Gene', (173, 179))	('primary tumors', 'Disease', (17, 31))	('Cox-PH p-value', 'MPA', (122, 136))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('loss', 'NegReg', (180, 184))	('CDKN2A', 'Gene', '1029', (173, 179))	('minimized', 'NegReg', (72, 81))	('primary tumors', 'Disease', 'MESH:D001932', (17, 31))	('minimized', 'NegReg', (108, 117))	('deletion', 'Var', (63, 71))
148989	33081848	Both CDKN2A homozygous deletion >= 30% (p = 0.01, HR = 4.22) and histologic grade (p = 0.01, HR = 1.77) emerged as independent predictors of outcome for primary tumors in our Cox-PH model (Additional file 1: table S2).	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('CDKN2A', 'Gene', (5, 11))	('homozygous', 'Var', (12, 22))	('CDKN2A', 'Gene', '1029', (5, 11))	('primary tumors', 'Disease', (153, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('primary tumors', 'Disease', 'MESH:D001932', (153, 167))
148992	33081848	Tumors with mid-level deletion (10-30%) fared somewhat worse than those with low level deletion (< 10%), but this difference was not significant (p = 0.0636, log-rank test).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('deletion', 'Var', (22, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
148998	33081848	Tumors with low (< 10%) and mid-level (10-30%) CDKN2A deletion showed similar survivals, while tumors with >= 30% deletion had significantly decreased survival (p = 0.0003, log-rank test).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('deletion', 'Var', (54, 62))	('CDKN2A', 'Gene', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('decreased', 'NegReg', (141, 150))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('CDKN2A', 'Gene', '1029', (47, 53))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
149002	33081848	We began by constructing K-M survival curves of primary IDHm astrocytomas, stratified both by WHO histologic grade and CDKN2A deletion (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('primary IDHm astrocytomas', 'Disease', (48, 73))	('CDKN2A', 'Gene', (119, 125))	('deletion', 'Var', (126, 134))	('CDKN2A', 'Gene', '1029', (119, 125))	('primary IDHm astrocytomas', 'Disease', 'MESH:D001254', (48, 73))
149003	33081848	Unlike the previously published studies using array-based data, FISH-based detection of CDKN2A deletion of >= 30% did not identify a subset of histologically low-grade tumors with highly aggressive behavior.	('CDKN2A', 'Gene', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('deletion', 'Var', (95, 103))	('CDKN2A', 'Gene', '1029', (88, 94))	('aggressive behavior', 'Phenotype', 'HP:0000718', (187, 206))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
149006	33081848	Grade 4 tumors with CDKN2A homozygous deletion had significantly shorter survival than those without loss (p = 0.032, log-rank test).	('survival', 'MPA', (73, 81))	('shorter', 'NegReg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('homozygous deletion', 'Var', (27, 46))	('CDKN2A', 'Gene', (20, 26))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('CDKN2A', 'Gene', '1029', (20, 26))
149009	33081848	There was no difference in survival in recurrent grade 3 tumors with deletion compared to those without deletion (p = 0.837, log-rank test), and all histologic grade 3 recurrences showed similar survival to histology grade 4 tumors without deletion.	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('deletion', 'Var', (69, 77))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
149010	33081848	Grade 4 recurrent tumors with CDKN2A homozygous deletion showed significantly shorter overall survival than grade 4 tumors without deletion (p = 0.0079, log-rank test).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('CDKN2A', 'Gene', (30, 36))	('homozygous', 'Var', (37, 47))	('CDKN2A', 'Gene', '1029', (30, 36))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('shorter', 'NegReg', (78, 85))	('overall survival', 'MPA', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
149011	33081848	In order to address the possibility that a >= 30% cutoff in primary IDHm astrocytomas might be too stringent, we performed additional K-M survival analysis on grade 2/3 tumors that would hypothetically be upgraded to grade 4 under the proposed cIMPACT-NOW 5/6 criteria using CDKN2A homozygous deletion thresholds of 10% and 20% tumor cells deleted (Fig.	('deletion', 'Var', (293, 301))	('CDKN2A', 'Gene', '1029', (275, 281))	('CDKN2A', 'Gene', (275, 281))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('primary IDHm astrocytomas', 'Disease', 'MESH:D001254', (60, 85))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumor', 'Disease', (169, 174))	('primary IDHm astrocytomas', 'Disease', (60, 85))	('tumors', 'Disease', (169, 175))	('tumor', 'Disease', (328, 333))
149022	33081848	Applying this cutoff value, very few primary treatment-naive tumors in our institutional cohort showed this level of deletion, and of the tumors that did exceed this threshold, the majority were already considered grade 4 by histology.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('deletion', 'Var', (117, 125))
149023	33081848	Compared to primary tumors, CDKN2A homozygous loss was more frequent in recurrent grade 3 and grade 4 tumors.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('homozygous loss', 'Var', (35, 50))	('tumors', 'Disease', (102, 108))	('frequent', 'Reg', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CDKN2A', 'Gene', (28, 34))	('primary tumors', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('CDKN2A', 'Gene', '1029', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('grade 3', 'Disease', (82, 89))	('primary tumors', 'Disease', 'MESH:D001932', (12, 26))
149026	33081848	At first blush, it may seem counterintuitive that the Cox-PH model developed using the full cohort of tumors spanning all grades confirms CDKN2A deletion as an independently significant prognostic factor, yet the optimal cutoff of 30% was exceeded by only a very small fraction of grade 2 and 3 tumors.	('first blush', 'Phenotype', 'HP:0001041', (3, 14))	('CDKN2A', 'Gene', '1029', (138, 144))	('CDKN2A', 'Gene', (138, 144))	('tumors', 'Disease', (295, 301))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('deletion', 'Var', (145, 153))
149028	33081848	Indeed, unlike lower grade tumors, grade 4 tumors with >= 30% CDKN2A deletion showed significantly shorter overall survival than grade 4 tumors with intact CDKN2A, in both primary and first recurrence tumors (Fig.	('tumors', 'Disease', (137, 143))	('CDKN2A', 'Gene', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('shorter', 'NegReg', (99, 106))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('CDKN2A', 'Gene', '1029', (156, 162))	('deletion', 'Var', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('CDKN2A', 'Gene', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Disease', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('overall survival', 'MPA', (107, 123))	('tumors', 'Disease', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('CDKN2A', 'Gene', '1029', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
149032	33081848	Contrary to the hypothesis that a lower threshold would perform better for lower grade tumors, both analyses show the opposite:in our cohort of patients, there is no evidence that a threshold at or below 30% homozygous deletion improves prognostication of lower-grade lesions.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('improves', 'PosReg', (228, 236))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (144, 152))	('tumors', 'Disease', (87, 93))	('homozygous deletion', 'Var', (208, 227))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
149033	33081848	We note, however, that it remains possible that lower grade IDHm astrocytomas with high level (>= 30%) CDKN2A deletion by FISH do in fact have a poor prognosis, but given the rarity of grade 2 or 3 tumors exceeding this threshold, there is insufficient evidence to determine the prognostic impact of this finding in our cohort.	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('IDHm astrocytomas', 'Disease', 'MESH:D001254', (60, 77))	('tumors', 'Disease', (198, 204))	('CDKN2A', 'Gene', (103, 109))	('IDHm astrocytomas', 'Disease', (60, 77))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('deletion', 'Var', (110, 118))	('CDKN2A', 'Gene', '1029', (103, 109))
149034	33081848	Our findings differ from those studies showing a significant prognostic impact of CDKN2A deletion in both grade 3 and grade 4 IDHm astrocytomas, as detected by array-based techniques.	('IDHm astrocytomas', 'Disease', 'MESH:D001254', (126, 143))	('grade 3', 'Disease', (106, 113))	('IDHm astrocytomas', 'Disease', (126, 143))	('CDKN2A', 'Gene', (82, 88))	('deletion', 'Var', (89, 97))	('CDKN2A', 'Gene', '1029', (82, 88))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))
149035	33081848	While our data show a similar poor prognosis of CDKN2A deletion in grade 4 IDHm astrocytomas, these findings do not extend to grade 3 tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('IDHm astrocytomas', 'Disease', 'MESH:D001254', (75, 92))	('CDKN2A', 'Gene', (48, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('deletion', 'Var', (55, 63))	('CDKN2A', 'Gene', '1029', (48, 54))	('IDHm astrocytomas', 'Disease', (75, 92))
149045	33081848	The existing literature on use of FISH specifically to detect CDKN2A homozygous deletion in gliomas is sparse.	('deletion', 'Var', (80, 88))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('CDKN2A', 'Gene', (62, 68))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('CDKN2A', 'Gene', '1029', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
149046	33081848	that used FISH to examine CDKN2A, CDK4, and PDGFRA copy number alterations in grade 2 and 3 astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (92, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('CDKN2A', 'Gene', (26, 32))	('astrocytomas', 'Disease', (92, 104))	('copy number alterations', 'Var', (51, 74))	('CDKN2A', 'Gene', '1029', (26, 32))	('CDK4', 'Gene', (34, 38))	('PDGFRA', 'Gene', '5156', (44, 50))	('CDK4', 'Gene', '1019', (34, 38))	('PDGFRA', 'Gene', (44, 50))
149047	33081848	The authors used a cutoff of >= 20% of tumor cells showing homozygous deletion, but a rationale for this threshold was not provided.	('deletion', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
149049	33081848	versus 10% for our cohort) with both grade 2 and grade 3 tumors showing deletion.	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('deletion', 'Var', (72, 80))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
149051	33081848	cohort cannot be directly evaluated, as the survival analysis in that study grouped tumors with CDKN2A deletion with those showing CDK4 amplification (i.e.	('CDKN2A', 'Gene', '1029', (96, 102))	('CDK4', 'Gene', (131, 135))	('CDK4', 'Gene', '1019', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('CDKN2A', 'Gene', (96, 102))	('deletion', 'Var', (103, 111))
149057	33081848	Like all testing modalities, however, FISH has certain intrinsic technical limitations, including insensitivity to deletions smaller than the region covered by the probe, and artifactual loss of signal due to partial sectioning of nuclei when performed on FFPE tissue sections.	('signal', 'MPA', (195, 201))	('artifactual loss', 'Disease', (175, 191))	('artifactual loss', 'Disease', 'MESH:D014786', (175, 191))	('deletions', 'Var', (115, 124))
149058	33081848	This result could accurately reflect monosomy 9 with additional 9p21 deletion, but could also arise in other ways: (1) homozygous 9p21 deletion with artifactual loss of one CEP9 signal; (2) monosomy 9 with artifactual loss of one 9p21 signal; (3) hemizygous 9p21 loss paired with artifactual loss of one CEP9 and one 9p21 signal; (4) wild type chromosome 9 with artifactual loss of three probes.	('deletion', 'Var', (135, 143))	('artifactual loss', 'Disease', 'MESH:D014786', (149, 165))	('artifactual loss', 'Disease', 'MESH:D014786', (280, 296))	('artifactual loss', 'Disease', (206, 222))	('artifactual loss', 'Disease', 'MESH:D014786', (206, 222))	('artifactual loss', 'Disease', (362, 378))	('artifactual loss', 'Disease', 'MESH:D014786', (362, 378))	('loss', 'NegReg', (263, 267))	('9p21', 'Gene', (130, 134))	('artifactual loss', 'Disease', (149, 165))	('artifactual loss', 'Disease', (280, 296))	('9p21', 'Gene', (258, 262))
149061	33081848	A more stringent criteria requiring two CEP9 signals would lead to even fewer tumors being identified as having homozygous CDKN2A deletion.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('deletion', 'Var', (130, 138))	('CDKN2A', 'Gene', (123, 129))	('CDKN2A', 'Gene', '1029', (123, 129))
149063	33081848	Comparative genomic hybridization arrays (aCGH) excel at detecting copy number alterations in aggregate tissue samples, but can struggle at detecting loss in the context of a sparsely infiltrating tumor.	('copy number alterations', 'Var', (67, 90))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (197, 202))
149067	33081848	Results from our cohort agree with the previous studies and suggest that testing grade 2 tumors for deletion would be very low yield at best, might lead to inappropriate upgrading of indolent tumors, and could impose an undue financial burden on the global healthcare system.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('impose', 'Reg', (210, 216))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('upgrading', 'PosReg', (170, 179))	('lead', 'Reg', (148, 152))	('deletion', 'Var', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
149068	33081848	In conclusion, CDKN2A homozygous deletion is a marker of poor prognosis in histologic grade 4 IDHm astrocytomas, but the impact of this finding in histologic grades 2 and 3 tumors is less clear.	('CDKN2A', 'Gene', (15, 21))	('CDKN2A', 'Gene', '1029', (15, 21))	('IDHm astrocytomas', 'Disease', 'MESH:D001254', (94, 111))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))	('IDHm astrocytomas', 'Disease', (94, 111))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('homozygous deletion', 'Var', (22, 41))
149078	32429941	cancer-related differentially expressed genes or structural variations, as well as predicting the clinical outcomes, such as the risk stratification for the patients in cancers.	('cancer', 'Disease', (169, 175))	('cancers', 'Disease', (169, 176))	('differentially expressed genes', 'Gene', (15, 45))	('structural variations', 'Var', (49, 70))	('cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
149107	32429941	In terms of details, for the easily predicted cancer types, the performance of SWT-CNN was better than that of SVM.	('better', 'PosReg', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('SWT-CNN', 'Var', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
149110	32429941	When predicting the tumor stages of KIRC, the mean AUC achieved by SWT-CNN (mean AUC = 0.74) was 0.19 higher than that achieved by SVM (mean AUC = 0.55).	('higher', 'PosReg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('AUC', 'MPA', (51, 54))	('SWT-CNN', 'Var', (67, 74))	('tumor', 'Disease', (20, 25))
149169	32429941	The gene fusion of SLC34A2 and ROS1 played an important role in the progression of non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('gene fusion', 'Var', (4, 15))	('SLC34A2', 'Gene', '10568', (19, 26))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (83, 109))	('ROS1', 'Gene', (31, 35))	('SLC34A2', 'Gene', (19, 26))	('ROS1', 'Gene', '6098', (31, 35))	('non-small cell lung cancer', 'Disease', (83, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))
149225	32085805	FGFR- gene family alterations in low-grade neuroepithelial tumors The discovery of fibroblast growth factor receptor (FGFR) gene family alterations as drivers of primary brain tumors has generated significant excitement, both as potential therapeutic targets as well as defining hallmarks of histologic entities.	('neuroepithelial tumors', 'Disease', (43, 65))	('brain tumors', 'Disease', 'MESH:D001932', (170, 182))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (43, 65))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('brain tumors', 'Disease', (170, 182))	('brain tumor', 'Phenotype', 'HP:0030692', (170, 181))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (43, 65))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (43, 64))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('alterations', 'Var', (136, 147))	('brain tumors', 'Phenotype', 'HP:0030692', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('FGFR', 'Gene', (118, 122))
149228	32085805	Therefore, understanding the underlying biology of tumors harboring specific FGFR alterations is critical.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('alterations', 'Var', (82, 93))	('FGFR', 'Gene', (77, 81))
149229	32085805	In this review, recent evidence for recurrent FGFR alterations in histologically and biologically low-grade neuroepithelial tumors (LGNTs) is examined (namely FGFR1 tyrosine kinase domain duplication in low grade glioma, FGFR1-TACC1 fusions in extraventricular neurocytoma [EVN], and FGFR2-CTNNA3 fusions in polymorphous low-grade neuroepithelial tumor of the young [PLNTY]).	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (331, 352))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (108, 130))	('CTNNA3', 'Gene', '29119', (290, 296))	('neurocytoma', 'Phenotype', 'HP:0030064', (261, 272))	('TACC1', 'Gene', (227, 232))	('neuroepithelial tumor', 'Disease', (331, 352))	('FGFR2', 'Gene', '2263', (284, 289))	('FGFR1', 'Gene', (159, 164))	('FGFR1', 'Gene', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (108, 129))	('fusions', 'Var', (297, 304))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (331, 352))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('neuroepithelial tumors', 'Disease', (108, 130))	('fusions', 'Var', (233, 240))	('TACC1', 'Gene', '6867', (227, 232))	('ventricular neurocytoma', 'Disease', 'MESH:D018306', (249, 272))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (108, 129))	('ventricular neurocytoma', 'Disease', (249, 272))	('glioma', 'Disease', (213, 219))	('FGFR1', 'Gene', '2260', (159, 164))	('FGFR1', 'Gene', '2260', (221, 226))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (108, 130))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('CTNNA3', 'Gene', (290, 296))	('EVN', 'Chemical', '-', (274, 277))	('FGFR2', 'Gene', (284, 289))
149230	32085805	Additionally, FGFR alterations with less well-defined prognostic implications are considered (FGFR3-TACC3 fusions, FGFR1 hotspot mutations).	('mutations', 'Var', (129, 138))	('FGFR3-TACC3', 'Gene', (94, 105))	('fusions', 'Var', (106, 113))	('FGFR1', 'Gene', (115, 120))	('FGFR1', 'Gene', '2260', (115, 120))
149231	32085805	Finally, a framework for practical interpretation of FGFR alterations in low grade glial/glioneuronal tumors is proposed.	('FGFR', 'Gene', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('glial/glioneuronal tumors', 'Disease', 'MESH:D004194', (83, 108))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (89, 107))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (89, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('glial/glioneuronal tumors', 'Phenotype', 'HP:0025170', (83, 108))	('glial/glioneuronal tumors', 'Disease', (83, 108))	('alterations', 'Var', (58, 69))
149232	32085805	The search for disease-defining genetic alterations in brain tumors has characterized the last several decades in neuropathology: one particularly exciting arena has been the discovery of a host of fibroblast growth factor receptor (FGFR) gene family alterations as apparent drivers of primary brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('alterations', 'Var', (251, 262))	('brain tumor', 'Phenotype', 'HP:0030692', (55, 66))	('brain tumors', 'Disease', 'MESH:D001932', (294, 306))	('drivers', 'Reg', (275, 282))	('brain tumors', 'Phenotype', 'HP:0030692', (294, 306))	('FGFR', 'Gene', (233, 237))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('brain tumors', 'Disease', (294, 306))	('brain tumors', 'Disease', 'MESH:D001932', (55, 67))	('brain tumors', 'Phenotype', 'HP:0030692', (55, 67))	('brain tumor', 'Phenotype', 'HP:0030692', (294, 305))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('brain tumors', 'Disease', (55, 67))
149234	32085805	In fact, FGFR alterations are implicated across a host of human cancers, promoting oncogenesis as a result of overexpression, amplification, mutations, and structural variations.	('alterations', 'Var', (14, 25))	('oncogenesis', 'Disease', (83, 94))	('mutations', 'Var', (141, 150))	('promoting', 'PosReg', (73, 82))	('human', 'Species', '9606', (58, 63))	('amplification', 'MPA', (126, 139))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('structural variations', 'Var', (156, 177))	('FGFR', 'Gene', (9, 13))	('overexpression', 'PosReg', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
149240	32085805	Ahead of this, understanding the biological implications of specific FGFR alterations, and how this relates to tumor subclassification, is paramount; this is particularly true among histologically low-grade tumors.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('FGFR', 'Gene', (69, 73))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('alterations', 'Var', (74, 85))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('tumor', 'Disease', (207, 212))
149242	32085805	In contrast to the IDH- wild type, diffuse gliomas encountered in adults, diffuse gliomas in children and adolescents most commonly harbor a different constellation of mutations and fusions including alterations in FGFR1.	('FGFR1', 'Gene', (215, 220))	('children', 'Species', '9606', (93, 101))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('alterations', 'Var', (200, 211))	('FGFR1', 'Gene', '2260', (215, 220))	('diffuse', 'Disease', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (82, 89))	('gliomas', 'Disease', (43, 50))	('IDH', 'Gene', (19, 22))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('IDH', 'Gene', '3417', (19, 22))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('mutations', 'Var', (168, 177))
149243	32085805	The guidelines recommend distinguishing these from adult-type tumors to provide more accurate prognostication, and in some instances guide therapy; delineating relevant diffuse gliomas as harboring either tyrosine kinase domain duplication (TKDD) or single nucleotide variants in FGFR1.	('FGFR1', 'Gene', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('gliomas', 'Disease', (177, 184))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('FGFR1', 'Gene', '2260', (280, 285))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('single nucleotide variants', 'Var', (250, 276))	('tyrosine kinase domain', 'MPA', (205, 227))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))
149246	32085805	In this review, recent evidence for recurrent FGFR alterations in histologically and biologically low grade neuroepithelial tumors (LGNTs) is examined.	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (108, 130))	('alterations', 'Var', (51, 62))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (108, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (108, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('neuroepithelial tumors', 'Disease', (108, 130))	('FGFR', 'Gene', (46, 50))
149247	32085805	These include FGFR1 tyrosine kinase domain duplication in low grade glioma, FGFR1-TACC1 fusions in extraventricular neurocytoma (EVN), and FGFR2-CTNNA3 fusions in polymorphous low grade neuroepithelial tumor of the young (PLNTY).	('FGFR2', 'Gene', (139, 144))	('glioma', 'Disease', (68, 74))	('EVN', 'Chemical', '-', (129, 132))	('CTNNA3', 'Gene', '29119', (145, 151))	('FGFR1', 'Gene', '2260', (76, 81))	('tyrosine kinase domain', 'MPA', (20, 42))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (186, 207))	('TACC1', 'Gene', (82, 87))	('FGFR1', 'Gene', (14, 19))	('FGFR2', 'Gene', '2263', (139, 144))	('neuroepithelial tumor', 'Disease', (186, 207))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('neurocytoma', 'Phenotype', 'HP:0030064', (116, 127))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (186, 207))	('TACC1', 'Gene', '6867', (82, 87))	('ventricular neurocytoma', 'Disease', 'MESH:D018306', (104, 127))	('FGFR1', 'Gene', (76, 81))	('ventricular neurocytoma', 'Disease', (104, 127))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('fusions', 'Var', (152, 159))	('fusions', 'Var', (88, 95))	('FGFR1', 'Gene', '2260', (14, 19))	('CTNNA3', 'Gene', (145, 151))
149248	32085805	Additionally, FGFR alterations with less well-defined prognostic implications are considered (FGR3-TACC3 fusions, FGFR1 hotspot mutations).	('FGFR1', 'Gene', '2260', (114, 119))	('mutations', 'Var', (128, 137))	('FGR3-TACC3', 'Gene', (94, 104))	('fusions', 'Var', (105, 112))	('FGFR1', 'Gene', (114, 119))
149249	32085805	Finally, a proposed framework for interpreting the implications of specific FGFR alterations regarding tumor subclassification and prognostication is presented.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('alterations', 'Var', (81, 92))	('FGFR', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
149250	32085805	As such, by and large, these alterations may be reasonably regarded as hallmarks of the following low grade neuroepithelial tumors.	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (108, 130))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (108, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (108, 130))	('alterations', 'Var', (29, 40))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('neuroepithelial tumors', 'Disease', (108, 130))
149251	32085805	Among the most important insights gained from landmark sequencing studies examining the molecular landscape of pediatric low grade glial and glioneuronal tumors was the identification of an intragenic duplication of the entire FGFR1 region encoding the tyrosine kinase domain (TKD).	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (141, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (141, 160))	('glioneuronal tumors', 'Disease', (141, 160))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (141, 160))	('FGFR1', 'Gene', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('FGFR1', 'Gene', '2260', (227, 232))	('duplication', 'Var', (201, 212))
149253	32085805	Duplication of the FGFR1 TKD has also been reported in low-grade astrocytomas more suggestive of other specific histologic entities including pilocytic astrocytoma (typically extracerebellar) and dysembryoplastic neuroepithelial tumor (DNET, Fig.	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (142, 163))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (213, 234))	('DNET', 'Disease', 'MESH:D018302', (236, 240))	('FGFR1', 'Gene', '2260', (19, 24))	('DNET', 'Disease', (236, 240))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('dysembryoplastic neuroepithelial tumor', 'Disease', 'MESH:D018302', (196, 234))	('pilocytic astrocytoma', 'Disease', (142, 163))	('astrocytomas', 'Disease', (65, 77))	('astrocytoma', 'Phenotype', 'HP:0009592', (152, 163))	('Duplication', 'Var', (0, 11))	('reported', 'Reg', (43, 51))	('dysembryoplastic neuroepithelial tumor', 'Disease', (196, 234))	('FGFR1', 'Gene', (19, 24))
149255	32085805	In the original report, a cohort of 33 HGG were screened for duplication of the FGFR1 region encoding the TKD, revealing only one tumor (diagnosed as anaplastic oligoastrocytoma, WHO grade III) that had progressed from a grade II tumor.	('FGFR1', 'Gene', '2260', (80, 85))	('tumor', 'Disease', (230, 235))	('duplication', 'Var', (61, 72))	('anaplastic oligoastrocytoma', 'Disease', 'MESH:D001254', (150, 177))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('anaplastic oligoastrocytoma', 'Disease', (150, 177))	('FGFR1', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (130, 135))
149256	32085805	No FGFR1-TKDD positive cases were detected in adult-type oligodendrogliomas, IDH-mutant and 1p/19q co-deleted.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('oligodendrogliomas', 'Disease', (57, 75))	('FGFR1', 'Gene', (3, 8))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('IDH', 'Gene', (77, 80))	('FGFR1', 'Gene', '2260', (3, 8))	('1p/19q co-deleted', 'Var', (92, 109))	('IDH', 'Gene', '3417', (77, 80))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (57, 75))
149258	32085805	One reported case of a rosette forming glioneuronal tumor (RGNT) having focal DNET-like features exhibited multiple local recurrences over a ten-year period, ultimately demonstrated elevated mitoses and high-grade histology, and was shown to harbor FGFR1-TKDD in addition to a frameshift mutation in ATRX.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('DNET', 'Disease', 'MESH:D018302', (78, 82))	('glioneuronal tumor', 'Disease', (39, 57))	('mitoses', 'CPA', (191, 198))	('DNET', 'Disease', (78, 82))	('FGFR1', 'Gene', '2260', (249, 254))	('rosette', 'Phenotype', 'HP:0031925', (23, 30))	('harbor', 'Reg', (242, 248))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (39, 57))	('ATRX', 'Gene', (300, 304))	('frameshift mutation', 'Var', (277, 296))	('elevated', 'PosReg', (182, 190))	('FGFR1', 'Gene', (249, 254))	('glioneuronal tumor', 'Disease', 'MESH:D009369', (39, 57))	('ATRX', 'Gene', '546', (300, 304))
149262	32085805	Among the most highly recurrent chromosomal translocations across human cancers are those involving fusions of FGFR genes with members of the purportedly oncogenic TACC protein family (TACC1, TACC2, and TACC3).	('fusions', 'Var', (100, 107))	('TACC1', 'Gene', '6867', (185, 190))	('TACC2', 'Gene', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TACC1', 'Gene', (185, 190))	('TACC2', 'Gene', '10579', (192, 197))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('FGFR genes', 'Gene', (111, 121))
149267	32085805	Homologous with regards to respective chromosomal locations, FGFR1 and TACC1 are located on chromosome 8p11; the molecular mechanisms with regards to downstream MAPK pathway activation as a result of FGFR1-TACC1 fusion are also thought to be similar to those of FGFR3-TACC3, though less extensively studied and modeled.	('FGFR1', 'Gene', '2260', (200, 205))	('FGFR1', 'Gene', (61, 66))	('TACC1', 'Gene', (71, 76))	('TACC1', 'Gene', '6867', (206, 211))	('TACC1', 'Gene', '6867', (71, 76))	('fusion', 'Var', (212, 218))	('FGFR1', 'Gene', '2260', (61, 66))	('downstream MAPK pathway', 'Pathway', (150, 173))	('TACC1', 'Gene', (206, 211))	('activation', 'PosReg', (174, 184))	('FGFR1', 'Gene', (200, 205))
149272	32085805	Importantly, copy number analysis and RNA sequencing demonstrated FGFR1-TACC1 fusion as a recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (FGFR3-TACC3, FGFR1-EVI5).	('fusion', 'Var', (78, 84))	('TACC1', 'Gene', '6867', (72, 77))	('EVI5', 'Gene', '7813', (227, 231))	('EVI5', 'Gene', (227, 231))	('FGFR1', 'Gene', (66, 71))	('EVN', 'Chemical', '-', (119, 122))	('FGFR1', 'Gene', '2260', (66, 71))	('FGFR1', 'Gene', (221, 226))	('FGFR1', 'Gene', '2260', (221, 226))	('TACC1', 'Gene', (72, 77))
149286	32085805	Several other alterations in FGFR genes have been reported in association with LGNTs, but their distribution is not limited to tumors with low grade histology or benign behavior.	('alterations', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('FGFR genes', 'Gene', (29, 39))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('association', 'Reg', (62, 73))	('LGNTs', 'Disease', (79, 84))
149288	32085805	The reality is that the implications of FGFR3 fusion are clear: as previously stated, FGFR3 fusions, most commonly FGFR3-TACC3, are by and large a feature of IDH-wild type glioblastoma, WHO grade IV.	('IDH-wild type glioblastoma', 'Disease', 'MESH:D005909', (158, 184))	('fusions', 'Var', (92, 99))	('IDH-wild type glioblastoma', 'Disease', (158, 184))	('FGFR3', 'Gene', (86, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
149290	32085805	Detection of FGFR3 fusions in histologically low-grade tumors is well-documented.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('fusions', 'Var', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('FGFR3', 'Gene', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
149291	32085805	This is not to say that FGFR3 fusions cannot be associated with benign histologic entities; the sole FGFR3-TACC3 fusion positive case in the original series of PLNTY for example was devoid of any high-grade features suggestive of GBM and demonstrated no evidence of disease or seizures after an extensive interval (89 months).	('fusion', 'Var', (113, 119))	('seizures', 'Phenotype', 'HP:0001250', (277, 285))	('seizures', 'Disease', (277, 285))	('FGFR3-TACC3', 'Gene', (101, 112))	('seizures', 'Disease', 'MESH:D012640', (277, 285))
149292	32085805	Of note, FGFR3-TACC3 fusions in GBM characteristically arise in order individuals, with frequent co-mutation of TERT promoter and loss of CDKN2A/2B, features that should help distinguish these cases from true LGNT, including PLNTY.	('fusions', 'Var', (21, 28))	('TERT', 'Gene', (112, 116))	('CDKN2A/2B', 'Gene', '1029', (138, 147))	('TERT', 'Gene', '7015', (112, 116))	('arise', 'Reg', (55, 60))	('CDKN2A/2B', 'Gene', (138, 147))	('loss', 'NegReg', (130, 134))	('FGFR3-TACC3', 'Gene', (9, 20))
149294	32085805	While this may be reflective of the common end-result of FGFR fusions in all tumors (namely enhanced downstream signaling through MAP kinase pathway effectors), the histologic similarities suggest the possibility of FGFR3-fusion positive GBM arising from lower-grade precursor lesions.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('GBM', 'Disease', (238, 241))	('downstream signaling through MAP kinase', 'MPA', (101, 140))	('FGFR3-fusion', 'Gene', (216, 228))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('fusions', 'Var', (62, 69))	('FGFR', 'Gene', (57, 61))	('enhanced', 'PosReg', (92, 100))
149296	32085805	Another frequently reported FGFR alteration among LGNTs is mutation of two hotspot residues (N546 & K656) in the tyrosine kinase domain of FGFR1, well-known to be activating and oncogenic.	('FGFR1', 'Gene', (139, 144))	('N546 & K656', 'Var', (93, 104))	('mutation', 'Var', (59, 67))	('FGFR1', 'Gene', '2260', (139, 144))
149298	32085805	Somatic hotspot and germline mutations in FGFR1 have also been implicated in the pathogenesis of DNET.	('FGFR1', 'Gene', (42, 47))	('germline mutations', 'Var', (20, 38))	('DNET', 'Disease', 'MESH:D018302', (97, 101))	('FGFR1', 'Gene', '2260', (42, 47))	('DNET', 'Disease', (97, 101))	('implicated', 'Reg', (63, 73))
149299	32085805	Of note, encephalocraniocutaneous lipomatosis (ECCL) a sporadic neurocutaneous syndrome with features of disordered RAS-MAPK signaling, appears to be mediated in at least a subset of cases by these very FGFR1 mutations (in mosaic, somatic distribution) and also carries an increased risk of low-grade gliomas, again predominately of pilocytic astrocytoma histology.	('neurocutaneous syndrome', 'Disease', (64, 87))	('neurocutaneous syndrome', 'Disease', 'MESH:D020752', (64, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (343, 354))	('ECCL', 'Disease', 'MESH:C535736', (47, 51))	('encephalocraniocutaneous lipomatosis', 'Disease', 'MESH:C535736', (9, 45))	('encephalocraniocutaneous lipomatosis', 'Disease', (9, 45))	('lipomatosis', 'Phenotype', 'HP:0001012', (34, 45))	('gliomas', 'Disease', 'MESH:D005910', (301, 308))	('gliomas', 'Phenotype', 'HP:0009733', (301, 308))	('pilocytic astrocytoma', 'Disease', (333, 354))	('gliomas', 'Disease', (301, 308))	('mediated', 'Reg', (150, 158))	('ECCL', 'Disease', (47, 51))	('FGFR1', 'Gene', (203, 208))	('FGFR1', 'Gene', '2260', (203, 208))	('mutations', 'Var', (209, 218))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (333, 354))	('glioma', 'Phenotype', 'HP:0009733', (301, 307))
149301	32085805	In fact, in some early studies, FGFR1 mutation in pilocytic astrocytoma was associated with a significantly poorer prognosis, although sample size was small.	('FGFR1', 'Gene', (32, 37))	('FGFR1', 'Gene', '2260', (32, 37))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (50, 71))	('mutation', 'Var', (38, 46))	('pilocytic astrocytoma', 'Disease', (50, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))
149302	32085805	While no specific differentiating histologic criteria have been reported, it has emerged that there are distinguishing clinicopathologic features of these tumors; subsequent larger studies have revealed that pilocytic astrocytoma with FGFR1 mutation are predominately extracerebellar and frequently midline in location, (in contrast to BRAF-fusion positive pilocytic astrocytomas, which predominate in the cerebellum).	('pilocytic astrocytomas', 'Disease', (357, 379))	('FGFR1', 'Gene', (235, 240))	('FGFR1', 'Gene', '2260', (235, 240))	('astrocytoma', 'Phenotype', 'HP:0009592', (218, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (367, 378))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (357, 379))	('BRAF', 'Gene', '673', (336, 340))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (208, 229))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('BRAF', 'Gene', (336, 340))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('mutation', 'Var', (241, 249))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (357, 378))	('pilocytic astrocytoma', 'Disease', (208, 229))
149303	32085805	At the same time, hotspot FGFR1 mutations have also been observed in adult and pediatric HGG, at the level of GBM (WHO grade IV).	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('observed', 'Reg', (57, 65))	('HGG', 'Disease', (89, 92))	('mutations', 'Var', (32, 41))
149304	32085805	Notably, FGFR1 hotspot mutations have been detected in up to 18% of adult midline glioma with high grade histology.	('FGFR1', 'Gene', '2260', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutations', 'Var', (23, 32))	('midline glioma', 'Disease', 'MESH:D005910', (74, 88))	('detected', 'Reg', (43, 51))	('midline glioma', 'Disease', (74, 88))	('FGFR1', 'Gene', (9, 14))
149306	32085805	Although this profile can be seen in tumors histologically equivalent to pilocytic astrocytoma, the underlying molecular features are strongly suggestive of biologic overlap with diffuse midline glioma, H3 K27M-mutant (WHO grade IV).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (73, 94))	('K27M', 'Mutation', 'p.K27M', (206, 210))	('midline glioma', 'Disease', 'MESH:D005910', (187, 201))	('midline glioma', 'Disease', (187, 201))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('pilocytic astrocytoma', 'Disease', (73, 94))	('tumors', 'Disease', (37, 43))	('H3 K27M-mutant', 'Var', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
149307	32085805	FGFR1 hotspot mutations have also emerged as a molecular hallmark of rosette-forming glioneuronal tumor (RGNT).	('rosette-forming glioneuronal tumor', 'Phenotype', 'HP:0025171', (69, 103))	('rosette', 'Phenotype', 'HP:0031925', (69, 76))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('glioneuronal tumor', 'Disease', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (85, 103))	('glioneuronal tumor', 'Disease', 'MESH:D009369', (85, 103))	('mutations', 'Var', (14, 23))
149309	32085805	While in recent studies FGFR1 hotspot mutations were invariably detected among RGNTs, their presence is not currently required for the diagnosis, (and as previously discussed, is certainly not unique to RGNT).	('RGNTs', 'Disease', (79, 84))	('FGFR1', 'Gene', (24, 29))	('FGFR1', 'Gene', '2260', (24, 29))	('mutations', 'Var', (38, 47))
149310	32085805	Of note, frequent co-mutation with PIK3CA as well as NF1 have been reported in RGNT.	('NF1', 'Gene', (53, 56))	('NF1', 'Gene', '4763', (53, 56))	('co-mutation', 'Var', (18, 29))	('PIK3CA', 'Gene', (35, 41))	('RGNT', 'Disease', (79, 83))	('reported', 'Reg', (67, 75))	('PIK3CA', 'Gene', '5290', (35, 41))
149311	32085805	On the whole, while there is clearly a role for FGFR1 hotspot mutations in the pathogenesis of LGNT, their specificity for low grade histology and clinical behavior is highly dependent on histologic features and broader molecular context.	('LGNT', 'Disease', (95, 99))	('FGFR1', 'Gene', '2260', (48, 53))	('mutations', 'Var', (62, 71))	('FGFR1', 'Gene', (48, 53))
149312	32085805	Based on available evidence, it appears that some FGFR alterations are more tightly correlated with specific histologic entities among LGNTs, while others may be encountered among variable tumor types, spanning histologic grades and clinical behavior.	('tumor', 'Disease', (189, 194))	('alterations', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('correlated', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('FGFR', 'Gene', (50, 54))
149313	32085805	For example, elevated mitotic activity, proliferation indices, and other indicators of high-grade histology should always be noted, even if only focally present in tumors bearing the FGFR alterations described herein.	('mitotic activity', 'CPA', (22, 38))	('proliferation indices', 'CPA', (40, 61))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('elevated', 'PosReg', (13, 21))	('FGFR', 'Gene', (183, 187))	('alterations', 'Var', (188, 199))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
149315	32085805	Although next-generation sequencing may not be possible to perform in every case, determining the absence of additional alterations (loss of CDKN2A/2B, TERT promoter mutation, H3- mutation etc.)	('TERT', 'Gene', '7015', (152, 156))	('loss', 'NegReg', (133, 137))	('CDKN2A/2B', 'Gene', '1029', (141, 150))	('TERT', 'Gene', (152, 156))	('CDKN2A/2B', 'Gene', (141, 150))	('H3- mutation', 'Var', (176, 188))
149321	32085805	As clinical trials of FGFR inhibitors in brain tumors are ongoing or only recently completed (NCT01975701, NCT028224133, NCT02052778, NCT01948297), we have yet to fully explore the efficacy of this therapeutic approach.	('FGFR', 'Gene', (22, 26))	('inhibitors', 'Var', (27, 37))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('brain tumors', 'Disease', 'MESH:D001932', (41, 53))	('brain tumors', 'Phenotype', 'HP:0030692', (41, 53))	('NCT01975701', 'Var', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('brain tumors', 'Disease', (41, 53))	('brain tumor', 'Phenotype', 'HP:0030692', (41, 52))
149322	32085805	Recently, for example, a study found that FGFR inhibitors (AZ4547, dovatinib, PD173074, ponatinib) were more effective in reducing the growth of pediatric diffuse midline glioma, H3 K27M-mutant (diffuse intrinsic pontine glioma, DIPG) cells in vitro compared to Temozolomide.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('reducing', 'NegReg', (122, 130))	('PD173074', 'Chemical', 'MESH:C115711', (78, 86))	('midline glioma', 'Disease', 'MESH:D005910', (163, 177))	('ponatinib', 'Chemical', 'MESH:C545373', (88, 97))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('dovatinib', 'Chemical', '-', (67, 76))	('PD173074', 'Var', (78, 86))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('DIPG', 'Chemical', 'MESH:C060938', (229, 233))	('midline glioma', 'Disease', (163, 177))	('K27M', 'Mutation', 'p.K27M', (182, 186))	('growth', 'MPA', (135, 141))	('Temozolomide', 'Chemical', 'MESH:D000077204', (262, 274))	('glioma', 'Disease', (221, 227))	('FGFR', 'Gene', (42, 46))	('glioma', 'Disease', (171, 177))	('AZ4547', 'Chemical', '-', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('H3 K27M-mutant', 'Var', (179, 193))
149324	32085805	Optimal design of clinical trials and interpretation of data will be directly dependent on accurate classification of tumors bearing these FGFR alterations.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('alterations', 'Var', (144, 155))	('FGFR', 'Gene', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
149337	31921684	Isocitrate dehydrogenase (IDH) mutations are one of the most common and earliest detectable genetic alterations in diffuse gliomas, and evidence supports this mutation as a driver of glioma genesis.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('mutations', 'Var', (31, 40))	('glioma', 'Disease', (183, 189))	('Isocitrate', 'Chemical', 'MESH:D007523', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('gliomas', 'Disease', (123, 130))	('IDH', 'Gene', (26, 29))	('glioma', 'Disease', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('IDH', 'Gene', '3417', (26, 29))
149370	31921684	For the group with a methylated MGMT promoter, compared to the low-risk patients, the OS of high-risk patients was also significantly lower (P = 0.0219; Figure 3J).	('lower', 'NegReg', (134, 139))	('patients', 'Species', '9606', (102, 110))	('methylated', 'Var', (21, 31))	('MGMT', 'Gene', '4255', (32, 36))	('MGMT', 'Gene', (32, 36))	('patients', 'Species', '9606', (72, 80))
149371	31921684	On the other hand, there were no significant differences between patients with a methylated MGMT promoter (P >0.05; Figure 3K).	('MGMT', 'Gene', '4255', (92, 96))	('methylated', 'Var', (81, 91))	('MGMT', 'Gene', (92, 96))	('patients', 'Species', '9606', (65, 73))
149386	31921684	Moreover, we found that 30.4 and 18.6% of samples in the low- and high-risk groups, respectively, were found to harbor mutations in the epidermal growth factor receptor (EGFR) gene (P = 0.029) (Table S2).	('EGFR', 'Gene', '1956', (170, 174))	('epidermal growth factor receptor', 'Gene', '1956', (136, 168))	('EGFR', 'Gene', (170, 174))	('mutations', 'Var', (119, 128))	('epidermal growth factor receptor', 'Gene', (136, 168))
149433	31427603	These almost always activate the MAPK pathway, with rearrangements generating the KIAA1549-BRAF fusion oncogene accounting for ~70% of PAs.	('activate', 'PosReg', (20, 28))	('rearrangements', 'Var', (52, 66))	('KIAA1549-BRAF', 'Disease', 'None', (82, 95))	('MAPK pathway', 'Pathway', (33, 45))	('KIAA1549-BRAF', 'Disease', (82, 95))
149441	31427603	Recent single-cell RNA-sequencing (scRNA-seq) efforts revealed transcriptional developmental hierarchies across sets of adult gliomas and pediatric histone mutant gliomas.	('gliomas', 'Disease', (163, 170))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('mutant', 'Var', (156, 162))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('histone', 'Gene', (148, 155))	('gliomas', 'Disease', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))
149445	31427603	However, low-grade tumors including PAs often exhibit few or no large-scale CNVs or expressed mutations.	('PAs', 'Disease', (36, 39))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
149453	31427603	Genetic profiling of bulk tissues confirmed that all tumors contained BRAF alterations, including five tumors with the classic KIAA1549-BRAF 16:9 translocation and one tumor with a noncanonical BRAF duplication event (Supplementary Data 2).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('contained', 'Reg', (60, 69))	('tumors', 'Disease', (103, 109))	('alterations', 'Var', (75, 86))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('KIAA1549-BRAF', 'Disease', (127, 140))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('BRAF', 'Gene', (70, 74))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('KIAA1549-BRAF', 'Disease', 'None', (127, 140))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
149485	31427603	To do so, we compared the two A2B5+, BRAF fusion-associated clusters to the tumor-associated cells in the other three clusters (Fig.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('BRAF', 'Gene', (37, 41))	('A2B5+', 'Var', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
149486	31427603	The A2B5+, BRAF+ population was marked by high levels of canonical markers of PA cancer cells, including oligodendrocyte-associated markers (OLIG1, OLIG2, PDGFRA), glial markers (GFAP, APOD, APOE), serine proteases (SERPINA3, SERPINE2), and other PA markers such as PLEKHB1.	('PA cancer', 'Disease', (78, 87))	('APOE', 'Gene', '348', (191, 195))	('OLIG1', 'Gene', '116448', (141, 146))	('GFAP', 'Gene', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('GFAP', 'Gene', '2670', (179, 183))	('APOE', 'Gene', (191, 195))	('PLEKHB1', 'Gene', (266, 273))	('SERPINA3', 'Gene', (216, 224))	('PDGFRA', 'Gene', (155, 161))	('PDGFRA', 'Gene', '5156', (155, 161))	('OLIG2', 'Gene', (148, 153))	('SERPINA3', 'Gene', '12', (216, 224))	('OLIG2', 'Gene', '10215', (148, 153))	('APOD', 'Gene', '347', (185, 189))	('PLEKHB1', 'Gene', '58473', (266, 273))	('SERPINE2', 'Gene', '5270', (226, 234))	('SERPINE2', 'Gene', (226, 234))	('A2B5+', 'Var', (4, 9))	('APOD', 'Gene', (185, 189))	('PA cancer', 'Disease', 'MESH:D011471', (78, 87))	('OLIG1', 'Gene', (141, 146))
149495	31427603	We compared PA tumor scRNAseq data to data from H3K27M-mutated midline high grade gliomas and from IDH-mutated astrocytomas and oligodendrogliomas of intermediate grade.	('IDH', 'Gene', '3417', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (128, 146))	('astrocytomas', 'Disease', (111, 123))	('PA tumor', 'Disease', (12, 20))	('gliomas', 'Disease', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('gliomas', 'Disease', (82, 89))	('midline', 'Disease', (63, 70))	('oligodendrogliomas', 'Disease', (128, 146))	('H3K27M-mutated', 'Var', (48, 62))	('midline', 'Disease', 'MESH:D009436', (63, 70))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('IDH', 'Gene', (99, 102))	('PA tumor', 'Disease', 'MESH:D011471', (12, 20))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('K27M', 'Mutation', 'p.K27M', (50, 54))
149515	31427603	Since we observed differential expression of oncogenic BRAF in cancer cells with different cell states, we hypothesized that expression of oncogenic BRAF may influence the state of PA cancer cells by modulating one or more of the gene programme identified above.	('expression', 'Var', (125, 135))	('cancer', 'Disease', (184, 190))	('BRAF', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('influence', 'Reg', (158, 167))	('PA cancer', 'Disease', (181, 190))	('modulating', 'Reg', (200, 210))	('PA cancer', 'Disease', 'MESH:D011471', (181, 190))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('state', 'Disease', (172, 177))	('cancer', 'Disease', (63, 69))
149517	31427603	In parallel, we examined mNSCs expressing BRAF-V600E, another common BRAF alteration found in pediatric gliomas, or vector only control.	('pediatric gliomas', 'Disease', (94, 111))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('BRAF-V600E', 'Var', (42, 52))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('pediatric gliomas', 'Disease', 'MESH:D005910', (94, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
149518	31427603	Single cell RNA-seq data were generated for 487 mNSCs after quality filtering (n = 170 vector control mNSCs, n = 154 KIAA1549-BRAF mNSCs, and n = 163 BRAF-V600E mNSCs).	('KIAA1549-BRAF mNSCs', 'Disease', (117, 136))	('BRAF-V600E', 'Var', (150, 160))	('V600E', 'Mutation', 'rs113488022', (155, 160))	('KIAA1549-BRAF mNSCs', 'Disease', 'None', (117, 136))
149519	31427603	Comparison of differentially expressed gene lists in the C2 MSigDB database revealed that mNSCs expressing oncogenic BRAF constructs has upregulation of genes in high-CpG-density promoters containing histone H3 dimethylation at K4 and trimethylation at K27 (H3K27M) in brain.	('K27M', 'Mutation', 'p.K27M', (260, 264))	('histone H3', 'Protein', (200, 210))	('upregulation', 'PosReg', (137, 149))	('genes', 'Gene', (153, 158))	('trimethylation at K27', 'Var', (235, 256))
149529	31427603	Second, the PA and H3K27M-derived AC-like gene programme were highly correlated with each other among AC-like cells derived from PA, H3K27M gliomas, or IDH-mutated gliomas (Spearman's rho > 0.45, P < 10-9 for each, Fig.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('K27M', 'Mutation', 'p.K27M', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('IDH', 'Gene', (152, 155))	('correlated', 'Interaction', (69, 79))	('K27M', 'Mutation', 'p.K27M', (135, 139))	('H3K27M', 'Var', (133, 139))	('IDH', 'Gene', '3417', (152, 155))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Disease', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (140, 147))
149540	31427603	To examine the developing brain cells that the PA cell subpopulations most resemble, we calculated enrichment scores for developing human midbrain cell types for PA cells expressing either gene programme, and for the stem and mature glia-like populations found in H3K27M and IDH-mutated gliomas.	('IDH', 'Gene', (275, 278))	('IDH', 'Gene', '3417', (275, 278))	('gliomas', 'Disease', (287, 294))	('gliomas', 'Disease', 'MESH:D005910', (287, 294))	('human', 'Species', '9606', (132, 137))	('gliomas', 'Phenotype', 'HP:0009733', (287, 294))	('K27M', 'Mutation', 'p.K27M', (266, 270))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('H3K27M', 'Var', (264, 270))
149541	31427603	Both of these PA subpopulations clustered with the AC-like cancer cells from IDH-mutated and H3K27M gliomas based on their developing brain cell type enrichment scores.	('H3K27M', 'Var', (93, 99))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('K27M', 'Mutation', 'p.K27M', (95, 99))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('IDH', 'Gene', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (59, 65))	('IDH', 'Gene', '3417', (77, 80))	('gliomas', 'Disease', (100, 107))
149557	31427603	If this is the case, we predict that tumors with high MAPK gene programme expression may have poor responses to therapy and poor long-term disease control.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('high', 'Var', (49, 53))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('MAPK', 'Gene', (54, 58))
149565	31427603	PAs exhibit substantial clinical differences from H3K27M-mutant pediatric high-grade gliomas and from IDH-mutant adult intermediate grade gliomas, including a more indolent course with high overall survival and a low incidence of malignant transformation.	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('gliomas', 'Disease', (138, 145))	('IDH', 'Gene', '3417', (102, 105))	('gliomas', 'Disease', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('K27M', 'Mutation', 'p.K27M', (52, 56))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('IDH', 'Gene', (102, 105))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('H3K27M-mutant', 'Var', (50, 63))
149568	31427603	Both IDH and H3K27M mutations block differentiation by modulating histone methylation marks, which may explain these differences in developmental hierarchies between the IDH-mutant and H3K27M-mutant tumors and the BRAF-driven PA tumors.	('tumors', 'Disease', (199, 205))	('PA tumors', 'Disease', 'MESH:D011471', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('H3K27M', 'Gene', (13, 19))	('differentiation', 'CPA', (36, 51))	('PA tumors', 'Disease', (226, 235))	('IDH', 'Gene', '3417', (170, 173))	('block', 'NegReg', (30, 35))	('histone methylation marks', 'MPA', (66, 91))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (229, 235))	('K27M', 'Mutation', 'p.K27M', (15, 19))	('modulating', 'Reg', (55, 65))	('IDH', 'Gene', (5, 8))	('K27M', 'Mutation', 'p.K27M', (187, 191))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('H3K27M-mutant', 'Var', (185, 198))	('IDH', 'Gene', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('IDH', 'Gene', '3417', (5, 8))
149575	31427603	To generate KIAA1549-BRAF expressing cells, mouse neural stem cells were plated on laminin coated dishes and transduced with pBabe (short-isoform) KIAA1549:BRAF (gift of David Jones) or pBabe BRAF-V600E or empty vector control with appropriate antibiotics.	('KIAA1549:BRAF', 'Var', (147, 160))	('V600E', 'Mutation', 'rs113488022', (197, 202))	('BRAF-V600E', 'Var', (192, 202))	('KIAA1549-BRAF', 'Disease', 'None', (12, 25))	('mouse', 'Species', '10090', (44, 49))	('KIAA1549-BRAF', 'Disease', (12, 25))
149615	31427603	mNSCs expressing vector control, KIAA1549-BRAF, or BRAF-V600E were generated using pBabeNeo retroviral vectors and cultured in growth factor-containing media.	('KIAA1549-BRAF', 'Disease', 'None', (33, 46))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('KIAA1549-BRAF', 'Disease', (33, 46))	('BRAF-V600E', 'Var', (51, 61))
149624	31427603	The datasets for H3K27M mutant pediatric midline gliomas, oligodendrogliomas, and intermediate grade astrocytomas referenced in the study are available from the Single Cell Portal with accession numbers SCP147, SCP12, and SCP50, respectively.	('mutant', 'Var', (24, 30))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('astrocytomas', 'Disease', (101, 113))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('H3K27M mutant', 'Var', (17, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (58, 76))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('midline gliomas', 'Disease', (41, 56))	('astrocytomas', 'Disease', 'MESH:D001254', (101, 113))	('oligodendrogliomas', 'Disease', (58, 76))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('K27M', 'Mutation', 'p.K27M', (19, 23))	('midline gliomas', 'Disease', 'MESH:D005910', (41, 56))
149720	29361062	RGBM has been used to identify the main regulators, of the gene expression signature activated in the FGFR3-TACC3 fusion-positive glioblastoma.	('GBM', 'Phenotype', 'HP:0012174', (1, 4))	('glioblastoma', 'Disease', (130, 142))	('FGFR3', 'Gene', (102, 107))	('FGFR3', 'Gene', '2261', (102, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('TACC3', 'Gene', '10460', (108, 113))	('activated', 'PosReg', (85, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('TACC3', 'Gene', (108, 113))	('fusion-positive', 'Var', (114, 129))
149733	29361062	The RVI score for a TF phi from the core Gradient Boosting Model is computed as: Here, , if TF phi results in the optimal split for the tth regression tree and the function  for all the other TFs at iteration t,  and  are the number of observations in the left  and right  branches of the tree and the coefficients , k   {l, r}, are the parameters of the decision tree as indicated in Equation 1 for the jth target gene.	('phi', 'Var', (95, 98))	('TF phi', 'Var', (92, 98))	('Boost', 'Chemical', '-', (50, 55))
149734	29361062	Similarly, for least-absolute deviation (LAD) loss,  and  are the median of all the pseudo-residuals in the disjoint regions  and  respectively.	('loss', 'NegReg', (46, 50))	('least-absolute deviation', 'Var', (15, 39))	('LAD', 'Chemical', '-', (41, 44))
149784	29361062	The first key division of human glioma is driven by the status of the IDH1 gene, whereby IDH1 mutations are typically characterized by a relatively more favorable clinical course of the disease.	('mutations', 'Var', (94, 103))	('glioma', 'Disease', (32, 38))	('IDH1', 'Gene', '3417', (70, 74))	('IDH1', 'Gene', '3417', (89, 93))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('IDH1', 'Gene', (89, 93))	('more', 'PosReg', (148, 152))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('human', 'Species', '9606', (26, 31))	('IDH1', 'Gene', (70, 74))
149785	29361062	IDH1 mutations are associated with a hypermethylation phenotype of glioma (G-CIMP,).	('associated', 'Reg', (19, 29))	('hypermethylation', 'MPA', (37, 53))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('mutations', 'Var', (5, 14))	('G-CIMP', 'Chemical', '-', (75, 81))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH1', 'Gene', '3417', (0, 4))
149792	29361062	Here, we applied our novel computational RGBM approach to infer the MRs responsible for the progression of G-CIMP-high into G-CIMP-low IDH-mutant glioma and those driving progression of PA-like LGG into LGm6-GBM IDH-wildtype tumors respectively.	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (212, 231))	('G-CIMP-high', 'Var', (107, 118))	('G-CIMP', 'Chemical', '-', (107, 113))	('IDH', 'Gene', '3417', (212, 215))	('PA', 'Chemical', 'MESH:D011478', (186, 188))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('G-CIMP', 'Chemical', '-', (124, 130))	('glioma', 'Disease', (146, 152))	('IDH-wildtype tumors', 'Disease', (212, 231))	('IDH', 'Gene', (135, 138))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('IDH', 'Gene', '3417', (135, 138))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('GBM', 'Phenotype', 'HP:0012174', (208, 211))	('IDH', 'Gene', (212, 215))
149803	29361062	Remarkably, while the G-CIMP-low subtype showed a general pattern of activation of MRs that includes this subtype within the IDH-mutant group of gliomas, when compared to the G-CIMP-high subtype, G-CIMP-low glioma displays a distinct loss of activation of neural cell fate/differentiation-specific MRs (see for example the activity of the crucial neural TFs NEUROD2, MEF2C and EMX1) with corresponding activation of a small but distinct set of TFs that drive cell cycle progression and proliferation (E2F1, E2F2, E2F7 and FOXM1).	('FOXM1', 'Gene', (522, 527))	('E2F7', 'Gene', (513, 517))	('E2F1', 'Gene', '1869', (501, 505))	('cell cycle progression', 'CPA', (459, 481))	('proliferation', 'CPA', (486, 499))	('gliomas', 'Disease', (145, 152))	('EMX1', 'Gene', '2016', (377, 381))	('glioma', 'Disease', (145, 151))	('EMX1', 'Gene', (377, 381))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('G-CIMP', 'Chemical', '-', (22, 28))	('NEUROD2', 'Gene', (358, 365))	('G-CIMP-low', 'Var', (196, 206))	('G-CIMP', 'Chemical', '-', (196, 202))	('FOXM1', 'Gene', '2305', (522, 527))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('MEF2C', 'Gene', (367, 372))	('E2F7', 'Gene', '144455', (513, 517))	('glioma', 'Disease', (207, 213))	('E2F2', 'Gene', (507, 511))	('IDH', 'Gene', (125, 128))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('NEUROD2', 'Gene', '4761', (358, 365))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('E2F2', 'Gene', '1870', (507, 511))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('G-CIMP', 'Chemical', '-', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('IDH', 'Gene', '3417', (125, 128))	('E2F1', 'Gene', (501, 505))	('MEF2C', 'Gene', '4208', (367, 372))	('activation', 'PosReg', (402, 412))
149807	29361062	Taken together, the application of the RGBM approach to the recently reported Pan-Glioma dataset revealed the identity and corresponding biological activities of the MRs driving transformation of the G-CIMP-high into the G-CIMP-low subtype of glioma and PA-like into LGm6-GBM, thus, providing a clue to the yet undetermined nature of the transcriptional events driving the evolution among these novel glioma subtypes.	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('glioma', 'Phenotype', 'HP:0009733', (401, 407))	('GBM', 'Phenotype', 'HP:0012174', (40, 43))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('G-CIMP', 'Chemical', '-', (200, 206))	('Glioma', 'Phenotype', 'HP:0009733', (82, 88))	('Pan-Glioma', 'Disease', (78, 88))	('Pan-Glioma', 'Disease', 'MESH:D005910', (78, 88))	('glioma', 'Disease', (401, 407))	('G-CIMP', 'Chemical', '-', (221, 227))	('GBM', 'Phenotype', 'HP:0012174', (272, 275))	('glioma', 'Disease', 'MESH:D005910', (401, 407))	('glioma', 'Disease', (243, 249))	('G-CIMP-high', 'Var', (200, 211))	('PA', 'Chemical', 'MESH:D011478', (254, 256))
149808	29361062	FGFR3-TACC3 fusions are recurrent chromosomal rearrangement that generate in-frame oncogenic gene fusions first discovered in glioblastoma (GBM) and subsequently found in many other tumors.	('fusions', 'Var', (12, 19))	('TACC3', 'Gene', '10460', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('TACC3', 'Gene', (6, 11))	('tumors', 'Disease', (182, 188))	('glioblastoma', 'Disease', (126, 138))	('FGFR3', 'Gene', (0, 5))	('glioblastoma', 'Disease', 'MESH:D005909', (126, 138))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('recurrent chromosomal rearrangement', 'Phenotype', 'HP:0040012', (24, 59))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('FGFR3', 'Gene', '2261', (0, 5))
149826	29361062	Identification and validation of the main regulators of the mechanism of action of FGFR3-TACC3 fusion in glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (105, 118))	('TACC3', 'Gene', '10460', (89, 94))	('FGFR3', 'Gene', '2261', (83, 88))	('TACC3', 'Gene', (89, 94))	('glioblastomas', 'Disease', (105, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('FGFR3', 'Gene', (83, 88))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('fusion', 'Var', (95, 101))
149829	33580181	Hypermutated phenotype in gliosarcoma of the spinal cord Gliosarcoma is a variant of glioblastoma with equally poor prognosis and characterized by mixed glial and mesenchymal pathology.	('gliosarcoma', 'Disease', (26, 37))	('gliosarcoma of the spinal cord', 'Phenotype', 'HP:0010302', (26, 56))	('glioblastoma', 'Disease', (85, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('Hypermutated', 'Var', (0, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('gliosarcoma', 'Disease', 'MESH:D018316', (26, 37))	('Gliosarcoma', 'Disease', 'MESH:D018316', (57, 68))	('Gliosarcoma', 'Disease', (57, 68))
149833	33580181	Whole-exome sequencing (WES) of this tumor revealed a hypermutated phenotype, characterized by somatic mutations in key DNA mismatch repair (MMR) pathway genes, an abundance of C>T transitions within the identified somatic single nucleotide variations, and microsatellite stability, together consistent with temozolomide-mediated hypermutagenesis.	('DNA', 'Gene', (120, 123))	('mutations', 'Var', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('C>T transitions', 'Var', (177, 192))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('MMR) pathway genes', 'Gene', (141, 159))	('temozolomide', 'Chemical', 'MESH:D000077204', (308, 320))	('microsatellite stability', 'Var', (257, 281))
149847	33580181	Further molecular testing was negative for the EGFR variant III, IDH1 mutation, and MGMT promoter methylation.	('IDH1', 'Gene', '3417', (65, 69))	('variant III', 'Var', (52, 63))	('MGMT', 'Gene', '4255', (84, 88))	('MGMT', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (47, 51))	('IDH1', 'Gene', (65, 69))	('EGFR', 'Gene', (47, 51))
149858	33580181	The Ki-67 index was elevated >10-15% and further routine molecular testing demonstrated MGMT promoter methylation but was otherwise negative for IDH1 mutation and ATRX loss.	('ATRX', 'Gene', '546', (163, 167))	('IDH1', 'Gene', (145, 149))	('mutation', 'Var', (150, 158))	('IDH1', 'Gene', '3417', (145, 149))	('MGMT', 'Gene', (88, 92))	('demonstrated', 'Reg', (75, 87))	('MGMT', 'Gene', '4255', (88, 92))	('ATRX', 'Gene', (163, 167))
149861	33580181	WES was performed on the gliosarcoma specimen, together with matching normal blood, to identify somatic single nucleotide variations (SNVs), insertions/deletions (INDEL), and copy number variations (CNV).	('gliosarcoma', 'Disease', 'MESH:D018316', (25, 36))	('gliosarcoma', 'Disease', (25, 36))	('insertions/deletions', 'Var', (141, 161))	('single nucleotide variations', 'Var', (104, 132))	('copy number variations', 'Var', (175, 197))
149863	33580181	These included deleterious missense (p.P656L) and stop-gain (p.W105X) mutations in MSH6 and a stop-gain mutation in MSH3 (p.R727X).	('MSH6', 'Gene', (83, 87))	('stop-gain', 'PosReg', (50, 59))	('MSH3', 'Gene', (116, 120))	('missense (p.P656L', 'Var', (27, 44))	('p.P656L', 'Var', (37, 44))	('p.W105X', 'Var', (61, 68))	('MSH6', 'Gene', '2956', (83, 87))	('p.R727X', 'Var', (122, 129))	('MSH3', 'Gene', '4437', (116, 120))	('p.P656L', 'Mutation', 'p.P656L', (37, 44))	('p.W105X', 'Mutation', 'rs1060502902', (61, 68))	('p.R727X', 'Mutation', 'rs376667075', (122, 129))
149864	33580181	Additionally, there was a heterozygous germline variant in MSH2 (p.H46Q) of unknown significance.	('MSH2', 'Gene', (59, 63))	('MSH2', 'Gene', '4436', (59, 63))	('p.H46Q', 'Mutation', 'rs33946261', (65, 71))	('p.H46Q', 'Var', (65, 71))
149875	33580181	Based on recommendations from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW), molecular testing to assess for EGFR amplification, chromosome 7 gain/chromosome 10 loss, and TERT promoter mutations to diagnose a diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV could have been performed to predict increased biological aggression and perhaps tailor clinical management.	('TERT', 'Gene', '7015', (221, 225))	('EGFR', 'Gene', '1956', (159, 163))	('loss', 'NegReg', (211, 215))	('aggression', 'Disease', 'MESH:D001523', (412, 422))	('IDH', 'Gene', (286, 289))	('CNS Tumor', 'Phenotype', 'HP:0100006', (93, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (327, 339))	('mutations', 'Var', (235, 244))	('astrocytic glioma', 'Disease', 'MESH:D001254', (267, 284))	('astrocytic glioma', 'Disease', (267, 284))	('EGFR', 'Gene', (159, 163))	('IDH', 'Gene', '3417', (286, 289))	('aggression', 'Phenotype', 'HP:0000718', (412, 422))	('glioblastoma', 'Disease', (327, 339))	('aggression', 'Disease', (412, 422))	('glioblastoma', 'Phenotype', 'HP:0012174', (327, 339))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('Tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TERT', 'Gene', (221, 225))
149879	33580181	In recent years, the prevalence of hypermutagenesis has been described across a variety of cancers, including gliomas and particularly after therapy-driven changes in tumor evolution at the time of recurrence.	('hypermutagenesis', 'Var', (35, 51))	('gliomas', 'Disease', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (167, 172))
149880	33580181	In particular, treatment with temozolomide may induce mutations in the MMR pathway, leading to therapeutic resistance and acquisition of the hypermutated phenotype.	('temozolomide', 'Chemical', 'MESH:D000077204', (30, 42))	('leading to', 'Reg', (84, 94))	('mutations', 'Var', (54, 63))	('MMR pathway', 'Pathway', (71, 82))	('hypermutated phenotype', 'MPA', (141, 163))	('therapeutic', 'MPA', (95, 106))	('induce', 'Reg', (47, 53))
149881	33580181	Strikingly, we found a hypermutated phenotype in our patient's specimen, including mutations in MMR genes, MSH3 and MSH6, which previously have not been associated with gliosarcoma pathology.	('mutations', 'Var', (83, 92))	('MSH6', 'Gene', '2956', (116, 120))	('MSH3', 'Gene', '4437', (107, 111))	('gliosarcoma', 'Disease', 'MESH:D018316', (169, 180))	('associated', 'Reg', (153, 163))	('MMR genes', 'Gene', (96, 105))	('MSH6', 'Gene', (116, 120))	('gliosarcoma', 'Disease', (169, 180))	('MSH3', 'Gene', (107, 111))	('patient', 'Species', '9606', (53, 60))
149882	33580181	Likewise, the abundance of C>T transitions detected within the somatic SNVs of our patient's tumor was consistent with a MMR deficient hypermutated phenotype.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('patient', 'Species', '9606', (83, 90))	('C>T transitions', 'Var', (27, 42))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
149889	33580181	Lastly, there are few reports of comprehensive genome sequencing of gliosarcomas, which have described key somatic mutations in known oncogenes including TP53, PTEN, RB1, and NF1 as well as amplification events of EGFR, CDK4/6, PDGFRA, MDM2, AKT1, and MET.	('RB1', 'Gene', (166, 169))	('MDM2', 'Gene', (236, 240))	('gliosarcomas', 'Disease', (68, 80))	('EGFR', 'Gene', '1956', (214, 218))	('PDGFRA', 'Gene', (228, 234))	('NF1', 'Gene', (175, 178))	('PDGFRA', 'Gene', '5156', (228, 234))	('MDM2', 'Gene', '4193', (236, 240))	('AKT1', 'Gene', '207', (242, 246))	('RB1', 'Gene', '5925', (166, 169))	('CDK4/6', 'Gene', (220, 226))	('MET', 'Gene', (252, 255))	('TP53', 'Gene', (154, 158))	('PTEN', 'Gene', (160, 164))	('gliosarcomas', 'Disease', 'MESH:D018316', (68, 80))	('EGFR', 'Gene', (214, 218))	('AKT1', 'Gene', (242, 246))	('mutations', 'Var', (115, 124))	('PTEN', 'Gene', '5728', (160, 164))	('CDK4/6', 'Gene', '1019;1021', (220, 226))	('amplification events', 'Var', (190, 210))	('MET', 'Gene', '79811', (252, 255))	('NF1', 'Gene', '4763', (175, 178))	('TP53', 'Gene', '7157', (154, 158))
149891	33580181	We considered whether our patient's gliosarcoma arose de novo with a predisposition from her detected germline MSH2 variant.	('patient', 'Species', '9606', (26, 33))	('gliosarcoma', 'Disease', (36, 47))	('variant', 'Var', (116, 123))	('MSH2', 'Gene', (111, 115))	('gliosarcoma', 'Disease', 'MESH:D018316', (36, 47))	('MSH2', 'Gene', '4436', (111, 115))
149892	33580181	Sa et al identified a subset of treatment-naive gliomas with de novo hypermutagenesis that had not been previously exposed to chemoradiation at the time of diagnosis.	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('hypermutagenesis', 'Var', (69, 85))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('gliomas', 'Disease', (48, 55))
149893	33580181	Notably, these patients demonstrated germline mutations of MMR associated genes, including MSH2, MSH3, MSH6, and MLH3 and relevant family histories of various cancers, together suggestive of diagnosis of Lynch syndrome.	('cancers', 'Disease', (159, 166))	('MSH6', 'Gene', (103, 107))	('MSH3', 'Gene', '4437', (97, 101))	('patients', 'Species', '9606', (15, 23))	('germline mutations', 'Var', (37, 55))	('MSH2', 'Gene', (91, 95))	('Lynch syndrome', 'Disease', (204, 218))	('MSH2', 'Gene', '4436', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('Lynch syndrome', 'Disease', 'MESH:D003123', (204, 218))	('MSH6', 'Gene', '2956', (103, 107))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('diagnosis', 'Reg', (191, 200))	('MLH3', 'Gene', (113, 117))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('MLH3', 'Gene', '27030', (113, 117))	('MMR associated', 'Gene', (59, 73))	('MSH3', 'Gene', (97, 101))
149895	33580181	In contrast, our patient's germline variant in MSH2 has been previously characterized as a benign variant, reported in individuals with colorectal, prostate, and ovarian cancers but not meeting clinical criteria for Lynch or Turcot syndrome or showing strong evidence for causality.	('MSH2', 'Gene', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('ovarian cancers', 'Disease', 'MESH:D010051', (162, 177))	('MSH2', 'Gene', '4436', (47, 51))	('colorectal', 'Disease', 'MESH:D015179', (136, 146))	('patient', 'Species', '9606', (17, 24))	('Lynch or Turcot syndrome', 'Disease', (216, 240))	('Lynch or Turcot syndrome', 'Disease', 'MESH:C536928', (216, 240))	('colorectal', 'Disease', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('germline variant', 'Var', (27, 43))	('ovarian cancers', 'Phenotype', 'HP:0100615', (162, 177))	('ovarian cancers', 'Disease', (162, 177))	('prostate', 'Disease', (148, 156))
149897	33580181	As such, it remains unlikely that our patient's germline MSH2 variant contributed to de novo tumor formation and/or acquisition of a hypermutator phenotype.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MSH2', 'Gene', '4436', (57, 61))	('tumor', 'Disease', (93, 98))	('patient', 'Species', '9606', (38, 45))	('variant', 'Var', (62, 69))	('MSH2', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
149898	33580181	In summary, we describe the first case of a hypermutator phenotype associated with a gliosarcoma, characterized by somatic mutations in known MMR genes and consistent with temozolomide-mediated hypermutagenesis.	('gliosarcoma', 'Disease', (85, 96))	('temozolomide', 'Chemical', 'MESH:D000077204', (172, 184))	('gliosarcoma', 'Disease', 'MESH:D018316', (85, 96))	('mutations', 'Var', (123, 132))	('MMR', 'Gene', (142, 145))
149915	32999733	Eight patients had contrast enhancement on neuroimaging, 9 of 21 tested had 1p19q co-deletion and 5 of 14 tested had an IDH1 mutation.	('men', 'Species', '9606', (35, 38))	('contrast enhancement', 'MPA', (19, 39))	('IDH1', 'Gene', (120, 124))	('patients', 'Species', '9606', (6, 14))	('1p19q co-deletion', 'Var', (76, 93))	('IDH1', 'Gene', '3417', (120, 124))
149917	32999733	On univariate analysis There was a statistically significant improvement in OS for patients with mixed histology (p=0.001), no midline shift at diagnosis (p=0.002) and with IDH1 mutation (p=0.003), LGG appear more aggressive in older patients.	('mutation', 'Var', (178, 186))	('IDH1', 'Gene', (173, 177))	('improvement', 'PosReg', (61, 72))	('IDH1', 'Gene', '3417', (173, 177))	('patients', 'Species', '9606', (234, 242))	('patients', 'Species', '9606', (83, 91))	('men', 'Species', '9606', (68, 71))
149931	32999733	Tumor-related risk factors for poor outcome include lack of 1p/19q deletion, no IDH-1 mutation and unmethylated MGMT; the G-CIMP phenotype is a positive prognostic marker in low-grade gliomas.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (184, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('gliomas', 'Disease', (184, 191))	('IDH-1', 'Gene', '3417', (80, 85))	('MGMT', 'Gene', (112, 116))	('lack', 'Var', (52, 56))	('IDH-1', 'Gene', (80, 85))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('MGMT', 'Gene', '4255', (112, 116))	('1p/19q deletion', 'Var', (60, 75))
149938	32999733	These factors included age, gender, initial clinical presentation, tumor crossing midline, tumor size, presence of contrast enhancement on neuroimaging, extent of resection, tumor histology and grade, IDH1 mutation and 1p19q deletion status (when available), adjuvant therapy including radiotherapy and chemotherapy.	('tumor', 'Disease', (174, 179))	('1p19q deletion status', 'Var', (219, 240))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('men', 'Species', '9606', (131, 134))	('IDH1', 'Gene', '3417', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutation', 'Var', (206, 214))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (91, 96))	('IDH1', 'Gene', (201, 205))
149966	32999733	The significant prognostic factors for improved OS identified within the cohort were mixed histology subtype (P=0.001), and presence of IDH1 mutation (P=0.003).	('presence', 'Var', (124, 132))	('IDH1', 'Gene', (136, 140))	('IDH1', 'Gene', '3417', (136, 140))	('improved', 'PosReg', (39, 47))	('mutation', 'Var', (141, 149))
149970	32999733	Prognosis measured by PFS was significantly for improved in patients with midline shift on initial neuroimaging (P=0.02), and with greater extent of resection (P=0.004).	('improved', 'PosReg', (48, 56))	('patients', 'Species', '9606', (60, 68))	('midline', 'Var', (74, 81))
149971	32999733	Absence of contrast enhancement (P=0.08), presence of IDH1 mutation (P=0.06) and post-operative treatment after diagnosis (P=0.13) had a positive trend for improved PFS.	('IDH1', 'Gene', (54, 58))	('PFS', 'MPA', (165, 168))	('improved', 'PosReg', (156, 164))	('men', 'Species', '9606', (101, 104))	('mutation', 'Var', (59, 67))	('IDH1', 'Gene', '3417', (54, 58))	('men', 'Species', '9606', (27, 30))	('Absence', 'NegReg', (0, 7))	('presence', 'Var', (42, 50))
149982	32999733	Consistent with prior analysis, it was observed in our cohort that the presence of IDH1 mutation status was associated with better OS and PFS (3-year OS for IDH1 (n=7) vs. no IDH1 (n=6): 100% vs. 21%, 3-year PFS for IDH1 (n=7) vs. no IDH1 (n=6): 67% vs. 0%).	('mutation', 'Var', (88, 96))	('IDH1', 'Gene', '3417', (83, 87))	('IDH1', 'Gene', (175, 179))	('presence', 'Var', (71, 79))	('better', 'PosReg', (124, 130))	('PFS', 'CPA', (138, 141))	('IDH1', 'Gene', (157, 161))	('IDH1', 'Gene', (216, 220))	('IDH1', 'Gene', (234, 238))	('IDH1', 'Gene', '3417', (157, 161))	('IDH1', 'Gene', '3417', (216, 220))	('IDH1', 'Gene', (83, 87))	('IDH1', 'Gene', '3417', (175, 179))	('IDH1', 'Gene', '3417', (234, 238))
149995	32635204	Monopolar Spindle 1 Kinase (MPS1/TTK) mRNA Expression is Associated with Earlier Development of Clinical Symptoms, Tumor Aggressiveness and Survival of Glioma Patients Inhibition of the protein kinase MPS1, a mitotic spindle-checkpoint regulator, reinforces the effects of multiple therapies against glioblastoma multiforme (GBM) in experimental settings.	('Glioma', 'Disease', (152, 158))	('Tumor Aggressiveness', 'Disease', 'MESH:D001523', (115, 135))	('Aggressiveness', 'Phenotype', 'HP:0000718', (121, 135))	('Monopolar Spindle 1 Kinase', 'Gene', '7272', (0, 26))	('Tumor Aggressiveness', 'Disease', (115, 135))	('glioblastoma multiforme', 'Disease', (300, 323))	('glioblastoma', 'Phenotype', 'HP:0012174', (300, 312))	('Monopolar Spindle 1 Kinase', 'Gene', (0, 26))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (300, 323))	('Inhibition', 'Var', (168, 178))	('MPS1/TTK', 'Gene', '7272', (28, 36))	('MPS1', 'Gene', (28, 32))	('Glioma', 'Disease', 'MESH:D005910', (152, 158))	('MPS1', 'Gene', (201, 205))	('Tumor', 'Phenotype', 'HP:0002664', (115, 120))	('MPS1', 'Gene', '7272', (28, 32))	('MPS1', 'Gene', '7272', (201, 205))	('Glioma', 'Phenotype', 'HP:0009733', (152, 158))	('MPS1/TTK', 'Gene', (28, 36))
150001	32635204	GBM patients with high MPS1 mRNA-expression developed clinical symptoms at an earlier stage.	('MPS1', 'Gene', '7272', (23, 27))	('high', 'Var', (18, 22))	('MPS1', 'Gene', (23, 27))	('patients', 'Species', '9606', (4, 12))
150010	32635204	Isocitrate dehydrogenase (IDH) mutant gliomas of WHO grade II or III (IDHmut glioma) are a slowly growing subcategory, with a comparatively good prognosis.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('mutant', 'Var', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('IDH', 'Gene', (70, 73))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH', 'Gene', '3417', (26, 29))	('IDH', 'Gene', '3417', (70, 73))	('IDH', 'Gene', (26, 29))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', (38, 44))	('gliomas', 'Disease', (38, 45))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
150016	32635204	Dysregulation of MPS1 activity has been reported to lead to chromosomal instability and cancerogenesis.	('chromosomal instability', 'Phenotype', 'HP:0040012', (60, 83))	('MPS1', 'Gene', '7272', (17, 21))	('Dysregulation', 'Var', (0, 13))	('MPS1', 'Gene', (17, 21))	('chromosomal instability', 'CPA', (60, 83))	('cancerogenesis', 'CPA', (88, 102))	('activity', 'MPA', (22, 30))	('lead to', 'Reg', (52, 59))
150019	32635204	Interestingly, aberrant MPS1 expression and its effects appear to be hugely influenced by their dysregulation of MPS1 mRNA and its regulator miR-132.	('ran', 'Gene', '5901', (19, 22))	('MPS1', 'Gene', (113, 117))	('mRNA', 'MPA', (118, 122))	('miR-132', 'Gene', (141, 148))	('MPS1', 'Gene', '7272', (24, 28))	('MPS1', 'Gene', (24, 28))	('miR-132', 'Gene', '406921', (141, 148))	('dysregulation', 'Var', (96, 109))	('expression', 'MPA', (29, 39))	('MPS1', 'Gene', '7272', (113, 117))	('ran', 'Gene', (19, 22))	('influenced', 'Reg', (76, 86))
150032	32635204	qPCR (Quantitative Real-Time Polymerase Chain Reaction) was performed on a StepOnePlus Real-time PCR System (Applied Biosystems, Foster City, CA, USA) to determine the MPS1 mRNA expression in a duplex setting utilizing the TaqMan Universal PCR Master Mix, TTK_FAM (Hs01009870_m1,) and GAPDH_VIC_PL (Hs99999905_m1) (all from Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instruction.	('Hs01009870_m1', 'Var', (265, 278))	('MPS1', 'Gene', '7272', (168, 172))	('TTK', 'Gene', (256, 259))	('Hs99999905_m1', 'Var', (299, 312))	('MPS1', 'Gene', (168, 172))	('TTK', 'Gene', '7272', (256, 259))
150067	32635204	Their observations are mirrored by Chen et al., who further suggest a dysregulation of the HLF/miR-132/MPS1 axis to be causal for the malignancy-dependent expression differences.	('miR-132', 'Gene', '406921', (95, 102))	('HLF', 'Gene', '3131', (91, 94))	('HLF', 'Gene', (91, 94))	('MPS1', 'Gene', '7272', (103, 107))	('dysregulation', 'Var', (70, 83))	('MPS1', 'Gene', (103, 107))	('miR-132', 'Gene', (95, 102))
150073	32635204	Therefore, we conclude that the MPS1 mRNA dysregulation in glial tumors is associated with tumor malignancy but occurs independently of recurrence or growth pattern.	('mRNA dysregulation', 'Var', (37, 55))	('glial tumors', 'Disease', 'MESH:D005910', (59, 71))	('glial tumors', 'Disease', (59, 71))	('tumor malignancy', 'Disease', (91, 107))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('associated', 'Reg', (75, 85))	('tumor malignancy', 'Disease', 'MESH:D009369', (91, 107))	('MPS1', 'Gene', '7272', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('MPS1', 'Gene', (32, 36))
150081	32635204	This misdistribution could be a further indication of MPS1 mRNA expression being associated with aggressive tumor growth.	('mRNA expression', 'Var', (59, 74))	('MPS1', 'Gene', '7272', (54, 58))	('MPS1', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('aggressive tumor', 'Disease', 'MESH:D001523', (97, 113))	('associated', 'Reg', (81, 91))	('aggressive tumor', 'Disease', (97, 113))
150087	32635204	describe a significant difference in survival between a group of high and intermediate MPS1 expression in gliomas of all WHO grades combined.	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('MPS1', 'Gene', '7272', (87, 91))	('high', 'Var', (65, 69))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('MPS1', 'Gene', (87, 91))	('gliomas', 'Disease', (106, 113))	('expression', 'MPA', (92, 102))
150103	32635204	At least four different MPS1-inhibitors (BOS-172722, CFI-402257, S81694, and BAY-1217389) are currently tested in Phase I trials on various advanced malignancies.	('malignancies', 'Disease', (149, 161))	('BOS-172722', 'Var', (41, 51))	('BAY-1217389', 'Var', (77, 88))	('S81694', 'Chemical', '-', (65, 71))	('S81694', 'Var', (65, 71))	('CFI', 'Gene', (53, 56))	('MPS1', 'Gene', '7272', (24, 28))	('CFI', 'Gene', '3426', (53, 56))	('MPS1', 'Gene', (24, 28))	('BAY-1217389', 'Chemical', '-', (77, 88))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))
150104	32635204	Consequently, the inhibition of MPS1 might soon be generally available as a treatment option.	('MPS1', 'Gene', (32, 36))	('MPS1', 'Gene', '7272', (32, 36))	('inhibition', 'Var', (18, 28))
150106	32635204	Therefore, we hypothesize that patients with gliomas WHO grade II/III and high MPS1 expression and especially glioma patients with the worst expected outcome might benefit most from a treatment directed against MPS1.	('MPS1', 'Gene', (211, 215))	('glioma', 'Disease', (110, 116))	('expression', 'MPA', (84, 94))	('high', 'Var', (74, 78))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('MPS1', 'Gene', '7272', (79, 83))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('patients', 'Species', '9606', (31, 39))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('MPS1', 'Gene', (79, 83))	('patients', 'Species', '9606', (117, 125))	('glioma', 'Disease', (45, 51))	('MPS1', 'Gene', '7272', (211, 215))	('gliomas', 'Disease', (45, 52))
150110	23242278	Alterations in BRAF have been discovered in the majority of pediatric low-grade gliomas.	('BRAF', 'Gene', (15, 19))	('discovered', 'Reg', (30, 40))	('gliomas', 'Disease', (80, 87))	('Alterations', 'Var', (0, 11))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
150111	23242278	Because the field has moved quickly over the past few years, there is not yet widespread awareness about what B-Raf normally does, how the BRAF gene is modified in gliomas, why mutant proteins promote gliomagenesis, and what an abnormal BRAF result means for diagnosis, prognosis, and treatment.	('promote', 'PosReg', (193, 200))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('glioma', 'Disease', (201, 207))	('proteins', 'Protein', (184, 192))	('mutant', 'Var', (177, 183))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('glioma', 'Disease', (164, 170))
150112	23242278	Depending on the data from ongoing clinical trials, however, BRAF mutation screening could quickly become mandatory for all pediatric gliomas, and perhaps even a subset of adult gliomas.	('adult gliomas', 'Disease', (172, 185))	('clinical', 'Species', '191496', (35, 43))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('pediatric gliomas', 'Disease', 'MESH:D005910', (124, 141))	('adult gliomas', 'Disease', 'MESH:D005910', (172, 185))	('BRAF', 'Gene', (61, 65))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('mutation', 'Var', (66, 74))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('pediatric gliomas', 'Disease', (124, 141))
150117	23242278	Herein, I will briefly review the signaling pathway in which B-Raf resides and study the 2 types of BRAF alterations in gliomas, specifically, in what sort of tumors they occur, how to test for them, and what each test result means for the patient.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('alterations', 'Var', (105, 116))	('patient', 'Species', '9606', (240, 247))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))
150122	23242278	Since each of these kinases is activated by Ras and can in turn phosphorylate MEK, it begs the question as to why mutations in B-Raf are apparently more common compared to A-Raf and C-Raf.	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('mutations', 'Var', (114, 123))	('common', 'Reg', (153, 159))	('B-Raf', 'Gene', (127, 132))	('A-Raf', 'Gene', (172, 177))	('C-Raf', 'Gene', '5894', (182, 187))	('A-Raf', 'Gene', '369', (172, 177))	('C-Raf', 'Gene', (182, 187))
150126	23242278	The most frequent BRAF alterations in gliomas are gene rearrangement and fusion.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('gene rearrangement', 'Var', (50, 68))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('alterations', 'Var', (23, 34))	('fusion', 'Var', (73, 79))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
150131	23242278	More recent work on PAs, however, discovered a tandem duplication and rearrangement on 7q34 between BRAF and a gene centromeric to BRAF, KIAA1549, producing a fusion gene.	('KIAA1549', 'Gene', (137, 145))	('KIAA1549', 'Gene', '57670', (137, 145))	('tandem duplication', 'Var', (47, 65))	('rearrangement', 'Var', (70, 83))	('BRAF', 'Gene', (100, 104))
150134	23242278	The end result in all these variants is to delete the N-terminal Ras-binding regulatory domain, producing constitutive B-Raf (or C-Raf) activity (Fig.	('B-Raf', 'MPA', (119, 124))	('C-Raf', 'Gene', '5894', (129, 134))	('variants', 'Var', (28, 36))	('delete', 'NegReg', (43, 49))	('C-Raf', 'Gene', (129, 134))	('producing', 'Reg', (96, 105))
150135	23242278	At first it might seem odd that mutating such a powerful oncogene would produce relatively indolent tumors like PAs, but recall that unmitigated activation of the MAPK pathway is a double-edged sword, capable of triggering differentiation and/or senescence as well as oncogenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors like PAs', 'Disease', 'MESH:D011471', (100, 115))	('senescence', 'CPA', (246, 256))	('triggering', 'Reg', (212, 222))	('mutating', 'Var', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('differentiation and/or', 'CPA', (223, 245))	('oncogenesis', 'CPA', (268, 279))	('tumors like PAs', 'Disease', (100, 115))	('produce', 'Reg', (72, 79))
150138	23242278	Specifically, loss of the p16 checkpoint protein produces more aggressive tumors in vivo; this correlates well with the finding that PAs with BRAF fusions have worse outcomes if the p16 gene (CDKN2A) is also deleted and/or its protein expression is absent (Fig.	('p16', 'Gene', (26, 29))	('aggressive tumors', 'Disease', (63, 80))	('loss', 'Var', (14, 18))	('PAs', 'Disease', (133, 136))	('p16', 'Gene', (182, 185))	('protein', 'Protein', (227, 234))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('p16', 'Gene', '1029', (26, 29))	('CDKN2A', 'Gene', (192, 198))	('p16', 'Gene', '1029', (182, 185))	('deleted', 'Var', (208, 215))	('CDKN2A', 'Gene', '1029', (192, 198))	('aggressive tumors', 'Disease', 'MESH:D001523', (63, 80))	('absent', 'NegReg', (249, 255))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
150149	23242278	The most common is exon 16 of KIAA1549 joined to exon 9 of BRAF (16-9) in over 60% of fusions, followed by 15-9 in nearly 25% of cases, and 16-11 in 10%-15% of cases (Fig.	('fusions', 'Var', (86, 93))	('KIAA1549', 'Gene', (30, 38))	('KIAA1549', 'Gene', '57670', (30, 38))
150155	23242278	Still, BRAF FISH can detect all BRAF fusion variants, including the FAM131B form, though, of course, it cannot distinguish between each variant.	('FAM131B', 'Gene', (68, 75))	('variants', 'Var', (44, 52))	('FAM131B', 'Gene', '9715', (68, 75))	('BRAF fusion', 'Gene', (32, 43))
150159	23242278	the constitutively active valine-to-glutamate (V600E) point mutation, which activates MEK without first needing upstream Ras phosphorylation.	('activates', 'PosReg', (76, 85))	('MEK', 'Gene', (86, 89))	('valine', 'Chemical', 'MESH:D014633', (26, 32))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('MEK', 'Gene', '5609', (86, 89))	('V600E', 'Var', (47, 52))	('glutamate', 'Chemical', 'MESH:D018698', (36, 45))
150160	23242278	B-Raf V600E exists in diverse tumors, including melanocytic nevi, melanoma, colon cancer, and papillary thyroid cancer.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('thyroid cancer', 'Phenotype', 'HP:0002890', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colon cancer', 'Disease', 'MESH:D015179', (76, 88))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (48, 64))	('nevi', 'Phenotype', 'HP:0003764', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('papillary thyroid cancer', 'Disease', (94, 118))	('tumors', 'Disease', (30, 36))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('colon cancer', 'Disease', (76, 88))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (94, 118))	('melanocytic nevi', 'Disease', (48, 64))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('V600E', 'Mutation', 'rs113488022', (6, 11))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (94, 118))	('B-Raf V600E', 'Var', (0, 11))	('colon cancer', 'Phenotype', 'HP:0003003', (76, 88))
150164	23242278	In adults, either V600E or BRAF fusions even occasionally coexist with IDH1/2 mutations.	('V600E', 'Var', (18, 23))	('IDH1/2', 'Gene', (71, 77))	('BRAF', 'Disease', (27, 31))	('IDH1/2', 'Gene', '3417;3418', (71, 77))	('V600E', 'Mutation', 'rs113488022', (18, 23))
150165	23242278	Although sometimes present in tumors with PA-like morphology, V600E is more associated with other tumors in the differential, including 20%-25% of pediatric and adult gangliogliomas and 60%-80% of pleomorphic xanthoastrocytomas in both age groups.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Disease', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('pleomorphic xanthoastrocytomas', 'Disease', (197, 227))	('V600E', 'Var', (62, 67))	('gangliogliomas', 'Disease', (167, 181))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('gangliogliomas', 'Disease', 'MESH:D018303', (167, 181))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('associated', 'Reg', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (197, 227))
150166	23242278	Thus, in the pediatric population, a V600E result is not quite as helpful as BRAF fusion in differentiating noninfiltrative from infiltrative gliomas, particularly if the differential is between a ganglioglioma and a diffuse glioma overtaking grey matter.	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('glioma', 'Disease', (142, 148))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('glioma', 'Disease', (204, 210))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('ganglioglioma', 'Disease', 'MESH:D018303', (197, 210))	('glioma', 'Disease', (225, 231))	('noninfiltrative', 'Disease', (108, 123))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('V600E', 'Var', (37, 42))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('ganglioglioma', 'Disease', (197, 210))	('glioma', 'Disease', 'MESH:D005910', (225, 231))
150167	23242278	Compared to BRAF fusion, fewer outcome-based studies have been done on V600E-mutant gliomas.	('V600E-mutant', 'Var', (71, 83))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))
150168	23242278	When both types of BRAF alteration were compared in a multivariate analysis of pediatric low-grade gliomas, BRAF fusions trended toward longer progression-free survival, whereas B-Raf V600E trended toward shorter progression-free survival.	('V600E', 'Mutation', 'rs113488022', (184, 189))	('fusions', 'Var', (113, 120))	('V600E', 'Var', (184, 189))	('longer', 'PosReg', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('progression-free survival', 'CPA', (143, 168))	('BRAF', 'Gene', (108, 112))
150170	23242278	This makes sense because loss of p16 inhibits BRAF-induced tumor senescence.	('p16', 'Gene', (33, 36))	('loss', 'Var', (25, 29))	('tumor', 'Disease', (59, 64))	('p16', 'Gene', '1029', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibits', 'NegReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
150173	23242278	The KIAA1549, FAM131B, and SRGAP3 components of the BRAF and RAF1 fusions might not be mere passive partners, and they might dictate where the fusion proteins localize, what controls their expression, and/or how easily they are degraded.	('dictate', 'Reg', (125, 132))	('SRGAP3', 'Gene', '9901', (27, 33))	('KIAA1549', 'Gene', (4, 12))	('KIAA1549', 'Gene', '57670', (4, 12))	('localize', 'MPA', (159, 167))	('FAM131B', 'Gene', (14, 21))	('RAF1', 'Gene', (61, 65))	('RAF1', 'Gene', '5894', (61, 65))	('expression', 'MPA', (189, 199))	('FAM131B', 'Gene', '9715', (14, 21))	('fusions', 'Var', (66, 73))	('SRGAP3', 'Gene', (27, 33))
150176	23242278	Of particular excitement is a V600E-specific antibody recently developed by the von Deimling group : the same laboratory that perfected the R132H IDH1 antibody, which is already a mainstay of surgical neuropathology.	('IDH1', 'Gene', (146, 150))	('V600E-specific', 'Var', (30, 44))	('IDH1', 'Gene', '3417', (146, 150))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('R132H', 'Var', (140, 145))	('R132H', 'Mutation', 'rs121913500', (140, 145))
150178	23242278	Nevertheless, it does work in FFPE tissues and is, therefore, likely to become a first-line test not just for certain gliomas, but also for melanomas and other V600E-mutant tumors elsewhere in the body.	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('melanomas', 'Disease', (140, 149))	('V600E', 'Mutation', 'rs113488022', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))	('V600E-mutant', 'Var', (160, 172))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
150179	23242278	Of note, there are also trinucleotide insertions in codon 598 of BRAF that cause constitutive activity similar to the V600E mutation.	('cause', 'Reg', (75, 80))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('trinucleotide', 'Chemical', '-', (24, 37))	('V600E', 'Var', (118, 123))	('BRAF', 'Gene', (65, 69))	('constitutive activity', 'MPA', (81, 102))
150180	23242278	These are seen in approximately 1%-2% of PAs, and would naturally be missed by the V600E antibody unless directly targeted by sequencing.	('V600E', 'Mutation', 'rs113488022', (83, 88))	('V600E', 'Var', (83, 88))	('PAs', 'Disease', (41, 44))
150181	23242278	As is often the case with molecular biomarkers, our ability to identify the diagnostic and prognostic value of BRAF alterations in gliomas has outpaced our ability to target it in adjuvant therapies.	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('alterations', 'Var', (116, 127))
150183	23242278	As of the time of this writing, the MEK inhibitor AZD6244 (selumetinib) is undergoing various phase I and II trials for B-Raf-mutant solid tumors, including pediatric gliomas.	('pediatric gliomas', 'Disease', 'MESH:D005910', (157, 174))	('selumetinib', 'Chemical', 'MESH:C517975', (59, 70))	('AZD6244', 'Chemical', 'MESH:C517975', (50, 57))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('pediatric gliomas', 'Disease', (157, 174))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MEK', 'Gene', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('MEK', 'Gene', '5609', (36, 39))	('solid tumors', 'Disease', (133, 145))	('B-Raf-mutant', 'Var', (120, 132))
150184	23242278	Certainly the experience with melanomas and PLX4032 (vemurafenib) is reason for some optimism.	('PLX4032', 'Chemical', 'MESH:D000077484', (44, 51))	('melanomas', 'Disease', (30, 39))	('PLX4032', 'Var', (44, 51))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('melanomas', 'Disease', 'MESH:D008545', (30, 39))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('vemurafenib', 'Chemical', 'MESH:D000077484', (53, 64))
150191	23242278	Depending on the success of current clinical trials, "low-grade glioma with BRAF fusion" or "low-grade glioma with BRAF V600E" could become de rigueur for the pediatric neurooncology world.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioma', 'Disease', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('clinical', 'Species', '191496', (36, 44))	('glioma', 'Disease', (64, 70))	('V600E', 'Var', (120, 125))	('BRAF', 'Disease', (76, 80))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
150197	33680972	Especially, high CD96 expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) in the TCGA lower grade glioma (LGG) cohort (OS, HR = 2.18, 95% CI = 1.79-2.66, P < 0.001).	('CD96', 'Gene', (17, 21))	('high', 'Var', (12, 16))	('glioma', 'Disease', (142, 148))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('disease-specific survival', 'CPA', (86, 111))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('poorer', 'NegReg', (53, 59))	('overall', 'MPA', (60, 67))	('DSS', 'Chemical', '-', (113, 116))	('expression', 'MPA', (22, 32))
150199	33680972	Notably, SKCM samples demonstrated the highest CD96 mutation frequency among all cancer types.	('CD96', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('SKCM', 'Chemical', '-', (9, 13))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
150201	33680972	CD96 was identified as a risk factor, protective factor, and irrelevant variable in LGG, SKCM and adrenocortical carcinoma (ACC), respectively.	('SKCM', 'Chemical', '-', (89, 93))	('adrenocortical carcinoma', 'Disease', (98, 122))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))	('CD96', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('LGG', 'Disease', (84, 87))	('SKCM', 'Disease', (89, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (98, 122))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (98, 122))
150216	33680972	Anti-CD96 monoclonal antibody (mAb) also demonstrates higher efficacy in combination with either anti-CTLA-4 or anti-PD-1 mAbs, depending on the activation of CD226 signaling in NK cells.	('CD226', 'Gene', (159, 164))	('higher', 'PosReg', (54, 60))	('Anti-CD96', 'Var', (0, 9))	('CD226', 'Gene', '10666', (159, 164))	('efficacy', 'MPA', (61, 69))	('combination', 'Interaction', (73, 84))
150232	33680972	Results based on eight cohorts [GSE5287, GSE13507, GSE19615, GSE2034, GSE17537, GSE8894, GSE17260, GSE19234 ] suggested that high expression of CD96 was significantly associated with better prognosis (COX P < 0.05;  Figures 3A-H ).	('GSE2034', 'Chemical', '-', (61, 68))	('CD96', 'Gene', (144, 148))	('GSE5287', 'Chemical', '-', (32, 39))	('high expression', 'Var', (125, 140))	('better', 'PosReg', (183, 189))	('GSE8894', 'Chemical', '-', (80, 87))
150240	33680972	We then employed cBioPortal to inspect the mutation frequency of CD96 in the TCGA database (10967 samples in 32 studies), and we found that LUSC and SKCM shared relatively high mutation level with the CD96 alteration frequency exceeding 8% ( Figures 4A, B ).	('mutation', 'MPA', (177, 185))	('SKCM', 'Chemical', '-', (149, 153))	('alteration', 'Var', (206, 216))	('CD96', 'Gene', (201, 205))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))
150241	33680972	Among them, E24K and E574K were the two most frequent mutation sites.	('E574K', 'Var', (21, 26))	('E574K', 'Mutation', 'p.E574K', (21, 26))	('E24K', 'Var', (12, 16))	('E24K', 'Mutation', 'rs758011865', (12, 16))
150242	33680972	COSMIC provided detailed information on the CD96 mutation types, including substitution missense, non-sense, and synonymous mutations in different cancers.	('CD96', 'Gene', (44, 48))	('synonymous mutations', 'Var', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('substitution missense', 'Var', (75, 96))	('cancers', 'Disease', (147, 154))	('non-sense', 'Var', (98, 107))
150243	33680972	Non-sense substitutions were found in cervix cancer (25%), large intestine cancer (2.47%), lung cancer (4.90%), and skin cancer (0.58%), while missense substitutions were observed in biliary tract cancer (5.56%), breast cancer (8.94%), cervix cancer (25%), central nervous system (CNS) cancer (33.33%), endometrial cancer (41.67%), hematopoietic and lymphoid cancer (7.41%), kidney cancer (25%), large intestine cancer (35.80%), liver cancer (8.70%), lung cancer (34.31%), esophageal cancer (25.53%), ovary cancer (12.50%), pancreas cancer (6.25%), prostate cancer (3.28%), skin cancer (44.77%), stomach cancer (16.22%), thyroid cancer (100%), upper aerodigestive tract cancer (46.15%), and urinary tract cancer (53.33%).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Disease', (629, 635))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (533, 539))	('cancer', 'Disease', (382, 388))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('kidney cancer', 'Disease', (375, 388))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (456, 462))	('cancer', 'Disease', 'MESH:D009369', (558, 564))	('thyroid cancer', 'Disease', (621, 635))	('ovary cancer', 'Disease', (501, 513))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (315, 321))	('cancer', 'Disease', (220, 226))	('large intestine cancer', 'Phenotype', 'HP:0100834', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('thyroid cancer', 'Disease', 'MESH:D013964', (621, 635))	('cancer', 'Disease', (75, 81))	('liver cancer', 'Disease', (429, 441))	('ovary cancer', 'Disease', 'MESH:D010051', (501, 513))	('cancer', 'Disease', (359, 365))	('large intestine cancer', 'Phenotype', 'HP:0100834', (396, 418))	('cancer', 'Disease', 'MESH:D009369', (435, 441))	('skin cancer', 'Disease', (116, 127))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (183, 203))	('stomach cancer', 'Phenotype', 'HP:0012126', (596, 610))	('ovary cancer', 'Phenotype', 'HP:0100615', (501, 513))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cervix cancer', 'Phenotype', 'HP:0030079', (236, 249))	('cancer', 'Disease', (507, 513))	('cancer', 'Disease', (579, 585))	('cancer', 'Disease', 'MESH:D009369', (604, 610))	('cancer', 'Disease', 'MESH:D009369', (484, 490))	('skin cancer', 'Disease', 'MESH:D012878', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('skin cancer', 'Disease', 'MESH:D012878', (574, 585))	('lymphoid cancer', 'Disease', (350, 365))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (691, 711))	('cancer', 'Disease', 'MESH:D009369', (705, 711))	('cancer', 'Disease', (121, 127))	('thyroid cancer', 'Phenotype', 'HP:0002890', (621, 635))	('cancer', 'Disease', (456, 462))	('cancer', 'Disease', (558, 564))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (549, 564))	('skin cancer', 'Disease', (574, 585))	('prostate cancer', 'Phenotype', 'HP:0012125', (549, 564))	('skin cancer', 'Phenotype', 'HP:0008069', (116, 127))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (670, 676))	('cancer', 'Disease', (705, 711))	('missense', 'Var', (143, 151))	('lung cancer', 'Disease', 'MESH:D008175', (451, 462))	('pancreas cancer', 'Disease', (524, 539))	('cancer', 'Disease', (435, 441))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (533, 539))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Disease', (243, 249))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (412, 418))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('kidney cancer', 'Disease', 'MESH:D007680', (375, 388))	('cancer', 'Disease', (604, 610))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cervix cancer', 'Phenotype', 'HP:0030079', (38, 51))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (484, 490))	('lung cancer', 'Disease', (451, 462))	('lymphoid cancer', 'Disease', 'MESH:D009369', (350, 365))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('prostate cancer', 'Disease', (549, 564))	('kidney cancer', 'Phenotype', 'HP:0009726', (375, 388))	('breast cancer', 'Disease', (213, 226))	('pancreas cancer', 'Disease', 'MESH:D010190', (524, 539))	('cancer', 'Disease', (412, 418))	('skin cancer', 'Phenotype', 'HP:0008069', (574, 585))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('central nervous system', 'Disease', (257, 279))	('lung cancer', 'Disease', (91, 102))	('pancreas cancer', 'Phenotype', 'HP:0002894', (524, 539))	('liver cancer', 'Disease', 'MESH:D006528', (429, 441))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (350, 365))	('cancer', 'Disease', 'MESH:D009369', (629, 635))	('cancer', 'Disease', (45, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (451, 462))	('liver cancer', 'Phenotype', 'HP:0002896', (429, 441))	('cancer', 'Disease', 'MESH:D009369', (507, 513))	('cancer', 'Disease', 'MESH:D009369', (579, 585))	('cancer', 'Disease', (670, 676))
150250	33680972	DNA mismatch repair deficiency and subsequent microsatellite instability (MSI), a hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, lead to the accumulation of mutation loads in cancer-related genes and the aggravation of tumor mutation burden (TMB).	('polymorphism', 'Var', (127, 139))	('deficiency', 'Disease', 'MESH:D007153', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Disease', (300, 305))	('cancer', 'Disease', (256, 262))	('TMB', 'Chemical', '-', (323, 326))	('mutation loads', 'MPA', (238, 252))	('microsatellite instability', 'MPA', (46, 72))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('aggravation', 'PosReg', (285, 296))	('deficiency', 'Disease', (20, 30))	('accumulation', 'PosReg', (222, 234))	('single nucleotide substitution', 'Var', (178, 208))
150256	33680972	Despite the significances of these correlations, the correlation coefficients between CD96 and TMB, as well as MSI, were below 0.6 in almost all cancers, suggesting that CD96 was rather unlikely to affect tumorigenesis by participating in the process of genetic alterations, and was not sufficient to independently predict the patient's response to ICBs either.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('affect', 'Reg', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('patient', 'Species', '9606', (327, 334))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('TMB', 'Chemical', '-', (95, 98))	('CD96', 'Var', (170, 174))
150258	33680972	As  Figure 7A  indicated, CD96 was most significantly associated with stromal scores in COAD, GBM, and HNSC.	('CD96', 'Var', (26, 30))	('associated', 'Interaction', (54, 64))	('HNSC', 'Disease', (103, 107))	('COAD', 'Disease', 'MESH:D029424', (88, 92))	('GBM', 'Disease', (94, 97))	('stromal scores', 'MPA', (70, 84))	('HNSC', 'Phenotype', 'HP:0012288', (103, 107))	('COAD', 'Disease', (88, 92))
150272	33680972	This intriguing difference suggested that CD96 mediated immunosuppressive effects in glioma patients, but participated in completely opposite immune processes in melanoma patients, highly indicating that CD96 impacted patient prognosis via an immune-related manner.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('impacted', 'Reg', (209, 217))	('patient', 'Species', '9606', (92, 99))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('patient', 'Species', '9606', (218, 225))	('melanoma', 'Disease', (162, 170))	('patient', 'Species', '9606', (171, 178))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('patients', 'Species', '9606', (92, 100))	('immunosuppressive effects', 'MPA', (56, 81))	('CD96', 'Gene', (42, 46))	('patients', 'Species', '9606', (171, 179))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('CD96', 'Var', (204, 208))
150283	33680972	On the one hand, it has an immunoreceptor tyrosine-based inhibition motif (ITIM) motif, which is conserved in inhibit receptors such as KIR2DL; On the other hand, similar to the activating receptor NKG2D, CD96 harbors a YXXM motif.	('YXXM', 'MPA', (220, 224))	('NKG2D', 'Gene', '22914', (198, 203))	('NKG2D', 'Gene', (198, 203))	('CD96', 'Var', (205, 209))	('tyrosine', 'Chemical', 'MESH:D014443', (42, 50))
150284	33680972	Therefore, whether CD96 activates NK cells to exert tumor cell killing effect or inhibits its activity is still inconclusive.	('inhibits', 'NegReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('activity', 'MPA', (94, 102))	('activates', 'PosReg', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CD96', 'Var', (19, 23))
150294	33680972	This suggests that CD96 can affect patient prognosis by influencing cancer malignant characteristics.	('affect', 'Reg', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patient', 'Species', '9606', (35, 42))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('influencing', 'Reg', (56, 67))	('cancer', 'Disease', (68, 74))	('CD96', 'Var', (19, 23))
150298	33680972	Notably, further analysis showed that CD96 in SKCM, but not in LGG, was positively associated with Th1 markers, again corroborating that CD96 participates in Th1 activation, thereby enhancing tumor inhibiting effects and prolonging patient survival time in SKCM, again suggesting CD96 impacted patient survival in an immunity-depended manner.	('patient', 'Species', '9606', (294, 301))	('patient survival time', 'CPA', (232, 253))	('tumor', 'Disease', (192, 197))	('CD96', 'Var', (137, 141))	('prolonging', 'PosReg', (221, 231))	('enhancing', 'PosReg', (182, 191))	('SKCM', 'Chemical', '-', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patient', 'Species', '9606', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('SKCM', 'Chemical', '-', (257, 261))
150299	33680972	Although the unique infiltration of immune cells in different tumors may affect our analysis results, we have reason to speculate that CD96 can influence the fate of immune infiltrates in TME, and may alter their distribution and subsequent interactions with malignancy cells, leading to distinct survival outcomes for different cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('alter', 'Reg', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('leading to', 'Reg', (277, 287))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (329, 335))	('influence', 'Reg', (144, 153))	('interactions', 'Interaction', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('malignancy', 'Disease', 'MESH:D009369', (259, 269))	('patients', 'Species', '9606', (336, 344))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('malignancy', 'Disease', (259, 269))	('CD96', 'Var', (135, 139))	('fate', 'MPA', (158, 162))	('distribution', 'MPA', (213, 225))
150301	33680972	Moreover, we mainly employed TCGA database to perform these analyses, the included studies did not cover all previous published literatures involved CD96 and certain cancers, for instance, CD96 did not significantly related to LGG patient survival in GEO datasets by Prognoscan site.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('LGG', 'Disease', (227, 230))	('CD96', 'Var', (189, 193))	('related', 'Reg', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
150302	33680972	In summary, we applied integrated bioinformatics approaches to suggest that CD96 expression may mediate immune infiltration and impact patient prognosis in pan-cancer, sharing the potential as a prognostic biomarker and providing a novel direction to explore the pathogenesis malignance of these prevailing cancers.	('impact', 'Reg', (128, 134))	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('immune infiltration', 'CPA', (104, 123))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('patient', 'Species', '9606', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('cancers', 'Disease', (307, 314))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('expression', 'Var', (81, 91))	('mediate', 'Reg', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CD96', 'Gene', (76, 80))	('patient prognosis', 'CPA', (135, 152))
150326	33680972	We also employed TISIDB  to assess whether CD96 had a significant expression difference between responders and non-responders to immunotherapy (e.g., anti-PD-L1 and anti-PD-1).	('PD-L1', 'Gene', '29126', (155, 160))	('PD-L1', 'Gene', (155, 160))	('anti-PD-1', 'Var', (165, 174))	('CD96', 'Gene', (43, 47))
150333	33182433	(3) Results: Hybrid PET-MRI shows promise in the evaluation of gliomas and germ cell tumours in (i) assessing early treatment response and (ii) discriminating tumour from treatment-related changes.	('cell tumours', 'Disease', (80, 92))	('tumour', 'Disease', (159, 165))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('Hybrid', 'Var', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumour', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('MR', 'Gene', '110784', (24, 26))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('cell tumours', 'Disease', 'MESH:D009369', (80, 92))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
150343	33182433	With the recent evidence that non-enhancing WHO grade II and III astrocytomas lacking the IDH1 mutation should be classified as glioblastoma (GBM) and that not all high-grade gliomas enhance, there is a need to investigate other imaging technologies to better assess tumour burden.	('IDH1', 'Gene', (90, 94))	('III astrocytomas', 'Disease', 'MESH:D001254', (61, 77))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('tumour', 'Disease', (267, 273))	('IDH1', 'Gene', '3417', (90, 94))	('III astrocytomas', 'Disease', (61, 77))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('glioblastoma', 'Disease', (128, 140))	('gliomas', 'Disease', (175, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('GBM', 'Phenotype', 'HP:0012174', (142, 145))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('tumour', 'Disease', 'MESH:D009369', (267, 273))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('mutation', 'Var', (95, 103))
150363	33182433	An important feature of radio-labelled choline is its low rate of distribution in normal grey and white matter.	('radio-labelled', 'Var', (24, 38))	('distribution', 'MPA', (66, 78))	('choline', 'Chemical', 'MESH:D002794', (39, 46))
150411	33182433	Patient 2: Early Response Assessment  A 13-year-old female with a large tumour involving left thalamus and basal ganglia, infiltrating into the adjacent white matter, insular cortex and left aspect of the upper brain stem underwent a biopsy of the thalamic component, which confirmed high-grade astrocytoma with a mutation of the variant H3.3 gene.	('astrocytoma', 'Disease', (295, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (295, 306))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('astrocytoma', 'Disease', 'MESH:D001254', (295, 306))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('variant', 'Var', (330, 337))	('tumour', 'Disease', (72, 78))	('mutation', 'Var', (314, 322))	('H3.3', 'Gene', (338, 342))
150418	33182433	Patient 4: Tumour Progression Versus Pseudoprogression  A 15-year-old male with a large tumour involving the left thalamus underwent gross resection of the thalamic tumour, and the histology confirmed this to be a high-grade astrocytoma with the known histone H3F3A K27M mutation.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('astrocytoma', 'Phenotype', 'HP:0009592', (225, 236))	('thalamic tumour', 'Disease', 'MESH:D013786', (156, 171))	('tumour', 'Disease', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('K27M', 'Var', (266, 270))	('K27M', 'Mutation', 'p.K27M', (266, 270))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('astrocytoma', 'Disease', 'MESH:D001254', (225, 236))	('Tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', (165, 171))	('astrocytoma', 'Disease', (225, 236))	('thalamic tumour', 'Disease', (156, 171))
150508	33182433	We have demonstrated a number of clinical situations where hybrid PET-MRI can improve diagnostic accuracy, and as improvements in PET-MRI scanners are made, the use in paediatric/TYA neuro-oncology is likely to increase.	('improve', 'PosReg', (78, 85))	('MR', 'Gene', '110784', (134, 136))	('diagnostic', 'MPA', (86, 96))	('hybrid', 'Var', (59, 65))	('oncology', 'Phenotype', 'HP:0002664', (189, 197))	('MR', 'Gene', '110784', (70, 72))
150510	31134296	MR Imaging phenotype correlates with extent of genome-wide copy number abundance in IDH mutant astrocytomas There is variability in survival within IDH-mutant gliomas determined by chromosomal events.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('astrocytoma', 'Phenotype', 'HP:0009592', (95, 106))	('astrocytomas', 'Disease', (95, 107))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', '3417', (148, 151))	('mutant', 'Var', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('IDH', 'Gene', (84, 87))	('astrocytomas', 'Disease', 'MESH:D001254', (95, 107))
150511	31134296	Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma have been reported.	('associated', 'Reg', (38, 48))	('Copy number variation', 'Var', (0, 21))	('IDH', 'Gene', (80, 83))	('astrocytoma', 'Disease', 'MESH:D001254', (91, 102))	('IDH', 'Gene', '3417', (80, 83))	('astrocytoma', 'Disease', (91, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
150521	31134296	One of the most significant and robust prognostic genetic markers in glioma recently discovered are recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes.	('glioma', 'Disease', (69, 75))	('IDH1', 'Gene', (155, 159))	('mutations', 'Var', (110, 119))	('IDH1', 'Gene', '3417', (155, 159))	('IDH2', 'Gene', (165, 169))	('isocitrate dehydrogenase 1', 'Gene', '3417', (127, 153))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('isocitrate dehydrogenase 1', 'Gene', (127, 153))	('IDH2', 'Gene', '3418', (165, 169))
150524	31134296	Genomic instability with copy number variations (CNVs), defined as structural variations involving a large-scale (>1 kilobase) genomic DNA changes, have been identified as potential susceptibility loci for a range of diseases including cancer in recent studies.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('susceptibility', 'Reg', (182, 196))	('Genomic', 'MPA', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('copy number variations', 'Var', (25, 47))
150527	31134296	has constructed an MR imaging, mRNA, and CNV radiogenomic association map of GBM patients, and they demonstrated the association between gene dose changes and MR features in GBM.	('association', 'Interaction', (117, 128))	('patients', 'Species', '9606', (81, 89))	('changes', 'Var', (147, 154))
150530	31134296	We retrospectively reviewed WHO grade II-IV IDH-mutant, 1p/19q non-codeleted gliomas (IDH-mutant astrocytomas) in which surgical resection and CNV plots had been performed at our institute from March 2004 to September 2016.	('IDH', 'Gene', (86, 89))	('gliomas', 'Disease', (77, 84))	('IDH', 'Gene', '3417', (86, 89))	('1p/19q', 'Var', (56, 62))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('astrocytomas', 'Disease', 'MESH:D001254', (97, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('astrocytomas', 'Disease', (97, 109))
150546	31134296	The tumors in CNV-S group were more likely to be lower grade glioma than the CNV-U group (P = .029).	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('lower', 'Disease', (49, 54))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('glioma', 'Disease', (61, 67))	('CNV-S', 'Var', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
150551	31134296	All tumors with CNV-S had larger proportion (>50%) of non-enhancing area, while two third tumors with CNV-U did, and the difference didn't reach statistical significance (P = .169).	('CNV-S', 'Var', (16, 21))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('larger', 'PosReg', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('non-enhancing', 'MPA', (54, 67))
150552	31134296	Tumors with CNV-S were more likely to show no enhancement, and tumors with CNV-U were more likely to have necrosis and foci of low or equal signal intensities on ADC map, but the difference didn't reach statistical significance (Table 1).	('enhancement', 'MPA', (46, 57))	('necrosis', 'Disease', (106, 114))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('necrosis', 'Disease', 'MESH:D009336', (106, 114))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('low', 'NegReg', (127, 130))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('men', 'Species', '9606', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CNV-U', 'Var', (75, 80))	('CNV-S', 'Var', (12, 17))
150556	31134296	There were slightly but not significantly more tumor progression events in CNV-S group in the follow up period (44.4%) than in the CNV-U group (33.3%) (P= 1).	('CNV-S', 'Var', (75, 80))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
150557	31134296	There has been increasing evidence that genomic instability is associated with poor prognosis in genetically otherwise favorable tumors.	('genomic instability', 'Var', (40, 59))	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
150558	31134296	To date, several studies have revealed associations between conventional and advanced MR imaging features and molecular characteristics, mainly focusing on IDH mutational and 1p19q codeletion status.	('IDH', 'Gene', (156, 159))	('associations', 'Interaction', (39, 51))	('1p19q', 'Var', (175, 180))	('IDH', 'Gene', '3417', (156, 159))
150559	31134296	Because IDH mutation and 1p/19q codeletion are validated prognostic markers in glioma, such non-invasive radiographic correlates have significant value for patient management.	('glioma', 'Disease', (79, 85))	('1p/19q codeletion', 'Var', (25, 42))	('IDH', 'Gene', (8, 11))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('IDH', 'Gene', '3417', (8, 11))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('men', 'Species', '9606', (170, 173))	('mutation', 'Var', (12, 20))	('patient', 'Species', '9606', (156, 163))
150563	31134296	A recent study of TCGA glioblastoma dataset indicated that there was weak correlation between imaging features and copy number variation of glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('glioblastoma', 'Disease', (140, 152))	('glioblastoma', 'Disease', 'MESH:D005909', (140, 152))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('copy number variation', 'Var', (115, 136))	('glioblastoma', 'Disease', (23, 35))
150564	31134296	In that study, alterations in CDKN2A, EGFR and PDGFRA were used to sub-classify tumors, and copy number variation was classified into 0-5%, 6-33% and 34-95% according to percentage of total abnormal tissue.	('EGFR', 'Gene', '1956', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('EGFR', 'Gene', (38, 42))	('CDKN2A', 'Gene', (30, 36))	('abnormal tissue', 'Phenotype', 'HP:0002664', (190, 205))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('alterations', 'Var', (15, 26))	('CDKN2A', 'Gene', '1029', (30, 36))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('PDGFRA', 'Gene', (47, 53))	('PDGFRA', 'Gene', '5156', (47, 53))
150574	31134296	demonstrated that the prognosis for patients with low-grade but highly perfused tumors was worse than that in patients with high-grade tumors with low perfusion.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('highly perfused', 'Var', (64, 79))	('patients', 'Species', '9606', (110, 118))
150582	31134296	We found that IDH-mutant astrocytomas with CVN-U tended to have foci of restricted diffusion, which suggests increased cellularity in these genomically more unstable astrocytomas, although the statistics did not show significant difference.	('CVN-U', 'Var', (43, 48))	('IDH', 'Gene', (14, 17))	('astrocytomas', 'Disease', 'MESH:D001254', (25, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('IDH', 'Gene', '3417', (14, 17))	('restricted diffusion', 'MPA', (72, 92))	('astrocytomas', 'Disease', 'MESH:D001254', (166, 178))	('astrocytomas', 'Disease', (25, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('increased', 'PosReg', (109, 118))	('astrocytomas', 'Disease', (166, 178))
150597	31134296	Importantly, our results go beyond the currently established genomic markers such as IDH mutational status and identify non-invasive imaging biomarkers that correlate with genomic markers associated with worse prognosis even within IDH mutant astrocytomas.	('IDH', 'Gene', '3417', (85, 88))	('astrocytomas', 'Disease', 'MESH:D001254', (243, 255))	('astrocytoma', 'Phenotype', 'HP:0009592', (243, 254))	('astrocytomas', 'Disease', (243, 255))	('IDH', 'Gene', (232, 235))	('mutant', 'Var', (236, 242))	('IDH', 'Gene', '3417', (232, 235))	('IDH', 'Gene', (85, 88))
150610	32539851	Among them, isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion (codel) are two most important genetic events for glioma grading.	('glioma', 'Disease', (125, 131))	('isocitrate dehydrogenase', 'Gene', '3417', (12, 36))	('IDH', 'Gene', (38, 41))	('mutation', 'Var', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('IDH', 'Gene', '3417', (38, 41))	('1p/19q co-deletion', 'Var', (56, 74))	('isocitrate dehydrogenase', 'Gene', (12, 36))
150612	32539851	And the 1p/19q codel is a distinctive feature of oligodendroglioma.	('oligodendroglioma', 'Disease', (49, 66))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('1p/19q codel', 'Var', (8, 20))	('oligodendroglioma', 'Disease', 'MESH:D009837', (49, 66))
150615	32539851	In addition, epigenetic modifications are also implicated in glioma.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('epigenetic modifications', 'Var', (13, 37))	('implicated', 'Reg', (47, 57))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
150616	32539851	One classical biomarker is O6-methylguanine-DNA-methyltransferase (MGMT); patients with methylated MGMT promoter have better clinical outcomes and are more sensitive to the alkylating chemotherapy than those without methylated MGMT promoter.	('sensitive', 'MPA', (156, 165))	('O6-methylguanine-DNA-methyltransferase', 'Gene', (27, 65))	('MGMT', 'Gene', (227, 231))	('MGMT', 'Gene', '4255', (227, 231))	('patients', 'Species', '9606', (74, 82))	('more', 'PosReg', (151, 155))	('MGMT', 'Gene', '4255', (67, 71))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (27, 65))	('MGMT', 'Gene', (67, 71))	('MGMT', 'Gene', (99, 103))	('methylated', 'Var', (88, 98))	('better', 'PosReg', (118, 124))	('MGMT', 'Gene', '4255', (99, 103))	('clinical outcomes', 'CPA', (125, 142))
150632	32539851	In addition, the fusion event between BCAN and NTRK1 (BCAN-NTRK1) is a potential glioma driver and therapeutic target.	('NTRK1', 'Gene', (59, 64))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('BCAN', 'Gene', (54, 58))	('fusion', 'Var', (17, 23))	('BCAN', 'Gene', '63827', (38, 42))	('NTRK1', 'Gene', '4914', (47, 52))	('glioma', 'Disease', (81, 87))	('BCAN', 'Gene', (38, 42))	('NTRK1', 'Gene', '4914', (59, 64))	('NTRK1', 'Gene', (47, 52))	('BCAN', 'Gene', '63827', (54, 58))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
150638	32539851	Previous studies have documented that unlike other PKC family members that are expressed in many tissues aside from brain, PRKCG is brain-specifically expressed and that mutations in PRKCG are associated with spinocerebellar ataxia.	('PKC', 'Gene', (51, 54))	('PRKCG', 'Gene', '5582', (123, 128))	('PRKCG', 'Gene', (183, 188))	('mutations', 'Var', (170, 179))	('PKC', 'Gene', '112476', (51, 54))	('associated with', 'Reg', (193, 208))	('PRKCG', 'Gene', (123, 128))	('PRKCG', 'Gene', '5582', (183, 188))	('spinocerebellar ataxia', 'Disease', (209, 231))	('ataxia', 'Phenotype', 'HP:0001251', (225, 231))	('spinocerebellar ataxia', 'Disease', 'MESH:D020754', (209, 231))
150656	32539851	Since PRKCG harbors two CpG sites (namely, cg26626089 and cg04518808) that are located in the promoter region and covered in both HumanMethylation27 (27 K) and HumanMethylation450 (450 K) BeadChip datasets, we then systematically investigated DNA methylation profiles of these two sites among normal, LGG and GBM samples.	('investigated', 'Reg', (230, 242))	('cg26626089', 'Chemical', '-', (43, 53))	('PRKCG', 'Gene', '5582', (6, 11))	('cg04518808', 'Var', (58, 68))	('cg04518808', 'Chemical', '-', (58, 68))	('cg26626089', 'Var', (43, 53))	('PRKCG', 'Gene', (6, 11))
150665	32539851	It is known that MGMT encodes a DNA-repair protein and hypermethylation of MGMT is associated with diminished DNA-repair activity, accordingly allowing the alkylating drug temozolomide (TMZ) to have greater effect in GBM treatment.	('GBM', 'Disease', (217, 220))	('hypermethylation', 'Var', (55, 71))	('DNA-repair activity', 'MPA', (110, 129))	('diminished', 'NegReg', (99, 109))	('TMZ', 'Chemical', 'MESH:D000077204', (186, 189))	('temozolomide', 'Chemical', 'MESH:D000077204', (172, 184))	('allowing', 'Reg', (143, 151))	('MGMT', 'Gene', '4255', (75, 79))	('MGMT', 'Gene', '4255', (17, 21))	('MGMT', 'Gene', (75, 79))	('MGMT', 'Gene', (17, 21))
150668	32539851	We discovered that among the two CpG sites of PRKCG (cg26626089 and cg04518808), cg26626089 is able to classify patients into two groups with distinct survival advantages, as patients with methylated cg26626089 have significantly longer survival than those with unmethylated cg26626089 (Fig.	('cg26626089', 'Chemical', '-', (53, 63))	('survival', 'MPA', (237, 245))	('PRKCG', 'Gene', (46, 51))	('cg26626089', 'Chemical', '-', (81, 91))	('cg04518808', 'Chemical', '-', (68, 78))	('longer', 'PosReg', (230, 236))	('patients', 'Species', '9606', (112, 120))	('cg26626089', 'Var', (200, 210))	('patients', 'Species', '9606', (175, 183))	('PRKCG', 'Gene', '5582', (46, 51))	('cg26626089', 'Chemical', '-', (275, 285))	('cg26626089', 'Var', (81, 91))	('cg26626089', 'Chemical', '-', (200, 210))
150671	32539851	5c), respectively, implying that the combined methylation signatures of PRKCG and MGMT might guide more accurate GBM stratification and achieve better personalized therapeutic decisions.	('PRKCG', 'Gene', (72, 77))	('methylation', 'Var', (46, 57))	('PRKCG', 'Gene', '5582', (72, 77))	('MGMT', 'Gene', (82, 86))	('MGMT', 'Gene', '4255', (82, 86))
150683	32539851	Although it contradicts the commonly accepted negative association between gene expression and promoter CpG methylation, a large-scale pan-cancer analysis has also revealed a positive correlation between promoter CpG methylation and gene expression.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('promoter CpG', 'Var', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gene expression', 'MPA', (233, 248))	('cancer', 'Disease', (139, 145))
150684	32539851	Consistently, we did observe significant positive correlations between PRKCG expression and CpG methylation within the promoter region (Additional file 9: Fig.	('expression', 'MPA', (77, 87))	('correlations', 'Interaction', (50, 62))	('PRKCG', 'Gene', (71, 76))	('methylation', 'Var', (96, 107))	('PRKCG', 'Gene', '5582', (71, 76))
150741	26468649	An increase or decrease in SUVmax between time points of an acquisition were determined by the SUV and TBR difference (SUV60-SUV10 and TBR60-TBR10), relative values (SUV60/SUV10 and TBR60/TBR10), and sums (SUV60+SUV10 and TBR60+TBR10).	('SUVmax', 'MPA', (27, 33))	('TBR', 'Chemical', '-', (103, 106))	('decrease', 'NegReg', (15, 23))	('TBR', 'Chemical', '-', (135, 138))	('TBR', 'Chemical', '-', (228, 231))	('TBR60+TBR10', 'Var', (222, 233))	('TBR', 'Chemical', '-', (141, 144))	('SUV60+SUV10', 'Var', (206, 217))	('TBR', 'Chemical', '-', (188, 191))	('TBR', 'Chemical', '-', (222, 225))	('SUV60-SUV10', 'Var', (119, 130))	('TBR60/TBR10', 'Var', (182, 193))	('TBR', 'Chemical', '-', (182, 185))	('SUV60/SUV10', 'Var', (166, 177))	('increase', 'PosReg', (3, 11))
150800	24667044	With the punctate enhancing components suspicious for high-grade glioma components possibly missed by sampling error, and corresponding foci of increased relative cerebral blood volume (rCBV) at dynamic susceptibility contrast (DSC) perfusion imaging, she received partial brain radiation therapy (RT) with 5940 cGy administered in 33 fractions over 6 weeks without concomitant chemotherapy.	('brain radiation', 'Disease', (273, 288))	('glioma', 'Disease', (65, 71))	('brain radiation', 'Disease', 'MESH:D011832', (273, 288))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('5940 cGy', 'Var', (307, 315))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))
150807	24667044	Subtotal resection revealed a low-grade oligodendroglioma with 1p36 and 19q co-deletions by fluorescence in-situ hybridization, R132H mutant isocitrate dehydrogenase-1 by liquid chromotagraphy-mass spectrometry and MIB-1 <3%.	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('R132H', 'Var', (128, 133))	('R132H', 'Mutation', 'rs121913500', (128, 133))	('oligodendroglioma', 'Disease', (40, 57))	('oligodendroglioma', 'Disease', 'MESH:D009837', (40, 57))
150832	24667044	The low-grade oligodendroglioma had multiple positive prognostic factors including 1p19q codeletions and mutant IDH1 .	('IDH1', 'Gene', '3417', (112, 116))	('oligodendroglioma', 'Disease', (14, 31))	('oligodendroglioma', 'Disease', 'MESH:D009837', (14, 31))	('IDH1', 'Gene', (112, 116))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('mutant', 'Var', (105, 111))	('1p19q codeletions', 'Var', (83, 100))
151052	33931704	For example, groundbreaking research revealed mutations in histone H3 in pediatric high-grade glioma (pHGG); the majority of histone H3 mutations were K27M mutations in which lysine 27 is substituted by methionine.	('lysine', 'MPA', (175, 181))	('glioma', 'Disease', (94, 100))	('lysine 27 is substituted by methionine', 'Mutation', 'p.K27M', (175, 213))	('K27M', 'Mutation', 'p.K27M', (151, 155))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('mutations', 'Var', (136, 145))	('K27M', 'Var', (151, 155))	('methionine', 'MPA', (203, 213))	('histone H3', 'Gene', (125, 135))
151054	33931704	Furthermore, a majority of gliomas with histone mutations cluster with mutations in ATRX (alpha-thalassemia/mental retardation syndrome X-linked), DAXX (death-domain associated protein), and p53.	('death-domain associated protein', 'Gene', '1616', (153, 184))	('histone', 'Protein', (40, 47))	('p53', 'Gene', '7157', (191, 194))	('ATRX', 'Gene', (84, 88))	('gliomas', 'Disease', (27, 34))	('mutations', 'Var', (48, 57))	('DAXX', 'Gene', (147, 151))	('mental retardation', 'Phenotype', 'HP:0001249', (108, 126))	('ATRX', 'Gene', '546', (84, 88))	('p53', 'Gene', (191, 194))	('mutations', 'Var', (71, 80))	('DAXX', 'Gene', '1616', (147, 151))	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('thalassemia/mental retardation syndrome', 'Disease', 'MESH:C538258', (96, 135))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('cluster', 'Reg', (58, 65))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('thalassemia/mental retardation syndrome', 'Disease', (96, 135))	('death-domain associated protein', 'Gene', (153, 184))
151077	33931704	WNT-alpha mutations occur mostly in children; these patients face an excellent prognosis, as the overwhelming majority of patients with WNT medulloblastoma are disease-free 5 years post diagnosis.	('WNT medulloblastoma', 'Disease', 'MESH:D008527', (136, 155))	('medulloblastoma', 'Phenotype', 'HP:0002885', (140, 155))	('children', 'Species', '9606', (36, 44))	('WNT medulloblastoma', 'Disease', (136, 155))	('patients', 'Species', '9606', (122, 130))	('WNT-alpha', 'Gene', (0, 9))	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (52, 60))
151082	33931704	Over 30% of medulloblastoma samples contained mutations, deletions, or amplifications of genes encoding epigenetic regulators across all four subgroups, and these aberrations can be used to stratify medulloblastomas.	('medulloblastoma', 'Phenotype', 'HP:0002885', (12, 27))	('deletions', 'Var', (57, 66))	('contained', 'Reg', (36, 45))	('mutations', 'Var', (46, 55))	('medulloblastoma', 'Disease', (12, 27))	('medulloblastomas', 'Disease', 'MESH:D008527', (199, 215))	('medulloblastoma', 'Disease', 'MESH:D008527', (199, 214))	('amplifications', 'MPA', (71, 85))	('medulloblastomas', 'Disease', (199, 215))	('medulloblastoma', 'Phenotype', 'HP:0002885', (199, 214))	('medulloblastoma', 'Disease', (199, 214))	('medulloblastoma', 'Disease', 'MESH:D008527', (12, 27))
151085	33931704	Compared with adult HGGs, pHGGs are more frequently associated with platelet-derived growth factor/platelet-derived growth factor receptor (PDGF/PDGFR) genomic alterations and mutations in the histone H3.3 gene and less frequently with PTEN and EGFR genomic alterations.	('PDGF', 'Gene', (140, 144))	('PDGFR', 'Gene', (145, 150))	('mutations', 'Var', (176, 185))	('PDGFR', 'Gene', '5159', (145, 150))	('histone H3.3', 'Gene', (193, 205))	('PDGF', 'Gene', '5156', (140, 144))	('associated', 'Reg', (52, 62))	('alterations', 'Var', (160, 171))	('PTEN', 'Gene', (236, 240))	('PDGF', 'Gene', (145, 149))	('PTEN', 'Gene', '5728', (236, 240))	('histone H3.3', 'Gene', '3020', (193, 205))	('PDGF', 'Gene', '5156', (145, 149))	('pHGGs', 'Disease', (26, 31))
151086	33931704	The major molecular groups are as follows: (1) histone mutations and H3.K27-mutated midline and H3.G34-mutated hemispheric pHGG; (2) rare isocitrate dehydrogenase (IDH)-mutated pHGG (mainly in adolescents); and (3) wild-type H3-/IDH pHGG, a heterogeneous group that remains to be fully characterized.	('isocitrate dehydrogenase', 'Gene', '3417', (138, 162))	('IDH', 'Gene', '3417', (164, 167))	('mutations', 'Var', (55, 64))	('IDH', 'Gene', (229, 232))	('IDH', 'Gene', '3417', (229, 232))	('isocitrate dehydrogenase', 'Gene', (138, 162))	('IDH', 'Gene', (164, 167))
151088	33931704	This study demonstrated specific changes in genes encoding histone H3 mutations and reported that histone wild-type tumors and tumors with BRAF mutations are less aggressive than tumors with different mutational profiles.	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (144, 153))	('aggressive', 'MPA', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('histone', 'Gene', (98, 105))	('tumors', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', (116, 122))	('mutations', 'Var', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors and tumors', 'Disease', 'MESH:D009369', (116, 133))	('less', 'NegReg', (158, 162))	('BRAF', 'Gene', '673', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('BRAF', 'Gene', (139, 143))	('tumors', 'Disease', (179, 185))
151093	33931704	Pilocytic astrocytoma is a "single-pathway" disease, with mutations primarily in the mitogen-activated protein kinase (MAPK) pathway.	('astrocytoma', 'Disease', (10, 21))	('mutations', 'Var', (58, 67))	('astrocytoma', 'Disease', 'MESH:D001254', (10, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))
151098	33931704	In children, oligodendrogliomas are often wild-type IDH, with mutations in the TERT (human telomerase reverse transcriptase) promoter and 1p/19q codeletion, in contrast to those in adults.	('children', 'Species', '9606', (3, 11))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (13, 31))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('oligodendrogliomas', 'Disease', (13, 31))	('mutations', 'Var', (62, 71))	('human', 'Species', '9606', (85, 90))
151100	33931704	Pediatric tumors usually have single pathogenic alterations in the fibroblast growth factor receptor 1 (FGFR1) oncogene.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('alterations', 'Var', (48, 59))	('fibroblast growth factor receptor 1', 'Gene', (67, 102))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('fibroblast growth factor receptor 1', 'Gene', '2260', (67, 102))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (104, 109))
151111	33931704	Posterior fossa ependymomas have global DNA hypomethylation and CpG island hypermethylation, resulting in the silencing of many genes that play a significant role in chromatin modification.	('ependymoma', 'Phenotype', 'HP:0002888', (16, 26))	('ependymomas', 'Disease', 'MESH:D004806', (16, 27))	('silencing', 'MPA', (110, 119))	('hypermethylation', 'Var', (75, 91))	('ependymomas', 'Disease', (16, 27))
151113	33931704	pHGG tumors with mutant H3, in which lysine is substituted by methionine at position 27 in histone 3.1, 3.2, or 3.3 (H3 K27M), are most exclusively found in midline structures.	('K27M', 'Mutation', 'p.K27M', (120, 124))	('pHGG tumors', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('pHGG tumors', 'Disease', 'MESH:D009369', (0, 11))	('lysine is substituted by methionine at position 27', 'Mutation', 'p.K27M', (37, 87))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mutant', 'Var', (17, 23))	('lysine', 'MPA', (37, 43))
151114	33931704	Eighty percent of DIPG patients have this mutation, which resulted in the WHO classification of these tumors as a new group of diffuse midline glioma (DMG) (i.e., H3 K27M-mutant).	('H3 K27M-mutant', 'Var', (163, 177))	('midline glioma', 'Disease', 'MESH:D005910', (135, 149))	('tumors', 'Disease', (102, 108))	('midline glioma', 'Disease', (135, 149))	('patients', 'Species', '9606', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('K27M', 'Mutation', 'p.K27M', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
151115	33931704	The point mutation in the histone H3 K27M gene is a defining feature of DIPG, and this mutation specifically impacts the epigenome.	('histone H3 K27M', 'Protein', (26, 41))	('point mutation', 'Var', (4, 18))	('impacts', 'Reg', (109, 116))	('DIPG', 'Disease', (72, 76))	('epigenome', 'MPA', (121, 130))	('K27M', 'Mutation', 'p.K27M', (37, 41))
151118	33931704	The diverse array of mutations contributes to significant intertumoral heterogeneity in DIPG, complicating treatment strategies.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('DIPG', 'Disease', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutations', 'Var', (21, 30))
151119	33931704	Knockdown of the histone H3 K27M mutation in animal models using DIPG xenografts restored the K27M-dependent loss of H3 K27M and delayed tumor growth.	('K27M', 'Mutation', 'p.K27M', (120, 124))	('H3 K27M', 'Protein', (117, 124))	('tumor', 'Disease', (137, 142))	('loss', 'NegReg', (109, 113))	('K27M-dependent', 'Var', (94, 108))	('K27M', 'Mutation', 'p.K27M', (28, 32))	('K27M', 'Mutation', 'p.K27M', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('delayed', 'NegReg', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
151120	33931704	Knockdown experiments illuminated the effects of the K27M mutation on the transcriptome and epigenome and pointed to genes associated with nervous system development.	('K27M', 'Var', (53, 57))	('K27M', 'Mutation', 'p.K27M', (53, 57))	('transcriptome', 'MPA', (74, 87))	('effects', 'Reg', (38, 45))
151122	33931704	The identification of genes that control epigenetic changes has produced novel targets for cancer treatments, particularly treatments for CNS tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CNS tumors', 'Disease', (138, 148))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('CNS tumor', 'Phenotype', 'HP:0100006', (138, 147))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CNS tumors', 'Disease', 'MESH:D016543', (138, 148))	('epigenetic', 'Var', (41, 51))
151126	33931704	"Writers" add groups (e.g., methyl, acetyl, and glycans), "erasers" remove posttranslational modifications, and "readers" recognize epigenetic markers and regulate epigenetic effects.	('regulate epigenetic effects', 'MPA', (155, 182))	('methyl', 'MPA', (28, 34))	('glycans', 'Chemical', 'MESH:D011134', (48, 55))	('acetyl', 'Chemical', '-', (36, 42))	('remove', 'NegReg', (68, 74))	('posttranslational modifications', 'MPA', (75, 106))	('acetyl', 'MPA', (36, 42))	('epigenetic markers', 'Var', (132, 150))
151129	33931704	For example, the H3F3A mutation is associated with changes in microRNA levels.	('H3F3A', 'Gene', '3020', (17, 22))	('mutation', 'Var', (23, 31))	('H3F3A', 'Gene', (17, 22))	('changes', 'Reg', (51, 58))	('microRNA levels', 'MPA', (62, 77))
151131	33931704	The association between epigenetic changes and cancer development has become key to understanding cancer development and to developing novel cancer treatments.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('epigenetic changes', 'Var', (24, 42))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (141, 147))
151132	33931704	Epigenetic changes are essential to malignant transformation, as tumor tissues exhibit abnormal patterns of methylation compared to healthy tissues.	('tumor', 'Disease', (65, 70))	('patterns', 'MPA', (96, 104))	('methylation', 'MPA', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Epigenetic changes', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
151133	33931704	Epigenetic profiles may be useful for: (a) potential drug targets; (b) cancer prognostics; (c) tumor classification; and (d) the basic science of tumor development.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', (71, 77))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Epigenetic profiles', 'Var', (0, 19))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
151135	33931704	Profiling each tumor for epigenetic changes (in addition to gene modifications) will improve stratification in clinical trials and predictions of responses to therapy.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('epigenetic changes', 'Var', (25, 43))	('tumor', 'Disease', 'MESH:D009369', (15, 20))
151139	33931704	DNA methylation characteristically represses gene transcription and can silence tumor suppressors when a gene promoter is methylated.	('silence tumor', 'Disease', (72, 85))	('represses', 'NegReg', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('gene transcription', 'MPA', (45, 63))	('methylation', 'Var', (4, 15))	('silence tumor', 'Disease', 'MESH:D009369', (72, 85))
151152	33931704	Thus, for pediatric CNS tumors, epigenetic modifications can also serve as therapeutic drug targets.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('CNS tumors', 'Disease', 'MESH:D016543', (20, 30))	('CNS tumor', 'Phenotype', 'HP:0100006', (20, 29))	('CNS tumors', 'Disease', (20, 30))	('epigenetic modifications', 'Var', (32, 56))
151153	33931704	For example, the identification of IDH1/2 mutations in adult gliomas was a landmark discovery in adult brain tumor management.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('brain tumor', 'Disease', 'MESH:D001932', (103, 114))	('brain tumor', 'Phenotype', 'HP:0030692', (103, 114))	('gliomas', 'Disease', (61, 68))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('brain tumor', 'Disease', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (42, 51))	('IDH1/2', 'Gene', (35, 41))
151154	33931704	IDH1/2 mutations are prevalent (over 80%) and often co-occur with p53 gene (TP53) mutations and total 1p/19q deletions.	('p53', 'Gene', '7157', (66, 69))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('TP53', 'Gene', '7157', (76, 80))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', (76, 80))	('co-occur', 'Reg', (52, 60))	('IDH1/2', 'Gene', (0, 6))	('p53', 'Gene', (66, 69))	('mutations', 'Var', (7, 16))
151156	33931704	Mutations in IDH1 or IDH2 reduce alpha-KG levels due to increased D-2-hydroxyglutarate (2-HG) levels.	('reduce', 'NegReg', (26, 32))	('alpha-KG levels', 'MPA', (33, 48))	('increased', 'PosReg', (56, 65))	('alpha-KG', 'Chemical', 'MESH:D007656', (33, 41))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (66, 86))	('IDH1', 'Gene', (13, 17))	('IDH2', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('2-HG', 'Chemical', 'MESH:C019417', (88, 92))	('IDH2', 'Gene', '3418', (21, 25))
151158	33931704	Hypermethylated histones and DNA are thought to be a result of IDH1/2 mutations.	('mutations', 'Var', (70, 79))	('DNA', 'Disease', (29, 32))	('IDH1/2', 'Gene', '3417;3418', (63, 69))	('Hypermethylated', 'Var', (0, 15))	('histones', 'Protein', (16, 24))	('IDH1/2', 'Gene', (63, 69))
151159	33931704	In contrast, IDH1/2 mutations are rare in pediatric glioma; IDH1 or IDH2 mutations in children occur in a small proportion (6.25%) of tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('children', 'Species', '9606', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('IDH1', 'Gene', (60, 64))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('IDH2', 'Gene', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH1', 'Gene', (13, 17))	('IDH1/2', 'Gene', (13, 19))	('IDH2', 'Gene', '3418', (68, 72))	('IDH1', 'Gene', '3417', (60, 64))	('IDH1', 'Gene', '3417', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('glioma', 'Disease', (52, 58))	('mutations', 'Var', (73, 82))
151160	33931704	Epigenetic profiles of pediatric brain tumors can be more informative than their mutational profiles.	('brain tumors', 'Phenotype', 'HP:0030692', (33, 45))	('brain tumors', 'Disease', 'MESH:D001932', (33, 45))	('brain tumors', 'Disease', (33, 45))	('brain tumor', 'Phenotype', 'HP:0030692', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Epigenetic', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
151168	33931704	There is significant heterogeneity within and between tumor subtypes, and thus, epigenetic profiling and targeted epidrugs could provide effective personalized therapy.	('epigenetic profiling', 'Var', (80, 100))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
151175	33931704	HDAC inhibitors alter gene expression and both histone and nonhistone proteins.	('HDAC', 'Gene', (0, 4))	('alter', 'Reg', (16, 21))	('gene expression', 'MPA', (22, 37))	('HDAC', 'Gene', '9734', (0, 4))	('inhibitors', 'Var', (5, 15))	('nonhistone proteins', 'Protein', (59, 78))
151187	33931704	HDACi sensitivity appears to be due to mutations in the HDACi resistance mechanism.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('HDAC', 'Gene', (56, 60))	('HDAC', 'Gene', '9734', (56, 60))	('mutations', 'Var', (39, 48))	('due to', 'Reg', (32, 38))
151188	33931704	HDACis were used in several completed trials and are being used in ongoing clinical trials on pediatric brain tumors (Table 1); most employ combination therapies such as chemotherapy (NCT00994500, NCT00867178, and NCT01076530; all completed), a proteasome inhibitor (marizomib; NCT04341311; ongoing), and radiation (NCT00867178; completed).	('HDAC', 'Gene', (0, 4))	('brain tumors', 'Phenotype', 'HP:0030692', (104, 116))	('HDAC', 'Gene', '9734', (0, 4))	('NCT00867178', 'Var', (197, 208))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('marizomib', 'Chemical', 'MESH:C475865', (267, 276))	('NCT01076530', 'Var', (214, 225))	('brain tumors', 'Disease', 'MESH:D001932', (104, 116))	('brain tumors', 'Disease', (104, 116))	('NCT00994500', 'Var', (184, 195))	('brain tumor', 'Phenotype', 'HP:0030692', (104, 115))
151192	33931704	However, this natural resistance to HDACis may be disrupted by the mutations inherent in tumors, which makes such tumors sensitive to HDACis.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('HDAC', 'Gene', (36, 40))	('mutations', 'Var', (67, 76))	('HDAC', 'Gene', '9734', (36, 40))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('HDAC', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('HDAC', 'Gene', '9734', (134, 138))
151208	33931704	This is most likely because children have fewer genetic mutations and more epigenetic alterations than adults.	('genetic mutations', 'Var', (48, 65))	('epigenetic alterations', 'MPA', (75, 97))	('children', 'Species', '9606', (28, 36))
151212	33931704	The low mutational load (and corresponding neoantigen level) in pediatric brain tumors is a central issue for immunotherapy since appropriate tumor antigens are needed as targets to induce an immune response against tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (216, 222))	('brain tumor', 'Phenotype', 'HP:0030692', (74, 85))	('tumors', 'Disease', (80, 86))	('tumor', 'Disease', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('brain tumors', 'Disease', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', (142, 147))	('mutational', 'Var', (8, 18))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('neoantigen', 'MPA', (43, 53))
151233	33931704	Multicenter trials generally have 30 to 50 participants and often include multiple pediatric brain cancer types (e.g., NCT02793466, NCT03206021, and NCT02672241), which can make it challenging to interpret the results.	('NCT02672241', 'Var', (149, 160))	('brain cancer', 'Disease', (93, 105))	('participants', 'Species', '9606', (43, 55))	('NCT03206021', 'Var', (132, 143))	('brain cancer', 'Disease', 'MESH:D001932', (93, 105))	('NCT02793466', 'Var', (119, 130))	('include', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('brain cancer', 'Phenotype', 'HP:0030692', (93, 105))
151250	33931704	The toxicity of anti-PD1 therapies is often immune related (e.g., pneumonitis, colitis, hepatitis, hypophysitis, autoimmune hemolytic anemia, thyroiditis, and dermatitis).	('dermatitis', 'Disease', 'MESH:D003872', (159, 169))	('dermatitis', 'Disease', (159, 169))	('thyroiditis', 'Disease', (142, 153))	('hepatitis', 'Phenotype', 'HP:0012115', (88, 97))	('autoimmune hemolytic anemia', 'Disease', 'MESH:D000744', (113, 140))	('anemia', 'Phenotype', 'HP:0001903', (134, 140))	('hepatitis', 'Disease', 'MESH:D056486', (88, 97))	('hypophysitis', 'Disease', (99, 111))	('anti-PD1', 'Var', (16, 24))	('pneumonitis', 'Disease', 'MESH:D011014', (66, 77))	('autoimmune hemolytic anemia', 'Phenotype', 'HP:0001890', (113, 140))	('colitis', 'Disease', (79, 86))	('dermatitis', 'Phenotype', 'HP:0011123', (159, 169))	('hepatitis', 'Disease', (88, 97))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (124, 140))	('autoimmune hemolytic anemia', 'Disease', (113, 140))	('pneumonitis', 'Disease', (66, 77))	('thyroiditis', 'Disease', 'MESH:D013959', (142, 153))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('colitis', 'Disease', 'MESH:D003092', (79, 86))	('hypophysitis', 'Disease', 'MESH:D000072659', (99, 111))	('thyroiditis', 'Phenotype', 'HP:0100646', (142, 153))	('toxicity', 'Disease', (4, 12))	('colitis', 'Phenotype', 'HP:0002583', (79, 86))
151253	33931704	Adoptive T cell therapy can also cause potentially fatal cytokine release syndrome, which can lead to multiple organ failure.	('cause', 'Reg', (33, 38))	('multiple organ failure', 'Disease', (102, 124))	('Adoptive', 'Var', (0, 8))	('lead to', 'Reg', (94, 101))	('multiple organ failure', 'Disease', 'MESH:D009102', (102, 124))	('fatal cytokine release syndrome', 'Disease', (51, 82))
151264	33931704	Indoleamine 2,3-dioxygenase (IDO) is another possible immunotherapy target, as its inhibition potentiates chemotherapy.	('IDO', 'Gene', (29, 32))	('Indoleamine 2,3-dioxygenase', 'Gene', '3620', (0, 27))	('chemotherapy', 'CPA', (106, 118))	('inhibition', 'Var', (83, 93))	('IDO', 'Gene', '3620', (29, 32))	('potentiates', 'PosReg', (94, 105))
151266	33931704	High levels of IDO expression are associated with poor outcomes in many cancers, including glioblastoma, and may contribute to resistance to immunotherapy.	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('associated', 'Reg', (34, 44))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('IDO', 'Gene', (15, 18))	('contribute', 'Reg', (113, 123))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('High levels', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('glioblastoma', 'Disease', (91, 103))	('IDO', 'Gene', '3620', (15, 18))
151267	33931704	The clinical activity of checkpoint blockade correlates with three main variables: (1) the number of nonsynonymous/frameshift somatic mutations in the tumor, which results in the production of "neoantigens"; (2) high expression of the PD-1 ligand in tumor cells; and (3) the frequency of activated CD8+ T cells in the circulation.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CD8', 'Gene', (298, 301))	('expression', 'MPA', (217, 227))	('tumor', 'Disease', (151, 156))	('CD8', 'Gene', '925', (298, 301))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('mutations', 'Var', (134, 143))	('PD-1', 'Protein', (235, 239))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
151277	33931704	These two patients were siblings with hypermutant glioblastoma associated with germline biallelic mismatch repair deficiency (bMMRD).	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('bMMRD', 'Disease', (126, 131))	('biallelic', 'Var', (88, 97))	('associated', 'Reg', (63, 73))	('deficiency', 'Disease', (114, 124))	('bMMRD', 'Disease', 'None', (126, 131))	('deficiency', 'Disease', 'MESH:D007153', (114, 124))	('patients', 'Species', '9606', (10, 18))	('glioblastoma', 'Disease', (50, 62))
151279	33931704	Except for children with a hereditary mismatch repair mutation, pediatric brain tumors generally do not exhibit high mutational rates.	('children', 'Species', '9606', (11, 19))	('mutation', 'Var', (54, 62))	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('mismatch', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('brain tumor', 'Phenotype', 'HP:0030692', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('brain tumors', 'Disease', (74, 86))
151310	33931704	For example, DIPGs often carry a mutation in histone 3.3 or 3.1 (K27M).	('K27M', 'Var', (65, 69))	('K27M', 'Mutation', 'p.K27M', (65, 69))	('histone 3.3', 'Protein', (45, 56))
151311	33931704	H3.3K27M-specific cancer peptide vaccines are in early phase clinical trials for pediatric patients with H3.3K27M-positive DIPG (ClinicalTrials.gov: NCT02960230).	('patients', 'Species', '9606', (91, 99))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('H3.3K27M-positive', 'Var', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('K27M', 'Mutation', 'p.K27M', (109, 113))
151322	33931704	In an in vivo immunocompetent tumor model of adoptive tumor-infiltrating lymphocyte therapy, adenovirus was the most effective therapy in synergy with T cell therapy.	('adenovirus', 'Species', '10508', (93, 103))	('adenovirus', 'Var', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (30, 35))
151344	33931704	Oncolytic HSV-1 G207 targets glioma cells and can induce a tumor-specific immune response in addition to its cytotoxic effects on its target cells.	('glioma', 'Disease', (29, 35))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('HSV-1', 'Gene', (10, 15))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('induce', 'PosReg', (50, 56))	('HSV-1', 'Species', '10298', (10, 15))	('G207', 'Var', (16, 20))
151354	33931704	Epigenetics and immunotherapy are providing many new and exciting opportunities to improve brain cancer treatment that need to be extensively validated in real-world settings.	('brain cancer', 'Phenotype', 'HP:0030692', (91, 103))	('Epigenetics', 'Var', (0, 11))	('brain cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('brain cancer', 'Disease', 'MESH:D001932', (91, 103))
151355	33931704	While modulating immune inhibitory pathways has been considered a significant breakthrough in cancer treatment in clinical trials, more data are needed to evaluate the success rates of these novel therapies, as they often require a personalized approach towards treatment depending on the molecular profile of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('tumors', 'Disease', (314, 320))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('modulating', 'Var', (6, 16))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
151361	32811569	BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young We present a case of a 14-year old boy with tumor-associated refractory epilepsy.	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (86, 107))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('neuroepithelial tumor', 'Disease', (86, 107))	('BRAF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (86, 107))	('V600E', 'Var', (5, 10))	('epilepsy', 'Phenotype', 'HP:0001250', (193, 201))	('boy', 'Species', '9606', (156, 159))	('FDG-methionine uptake mismatch', 'MPA', (29, 59))	('methionine', 'Chemical', 'MESH:D008715', (33, 43))	('FDG', 'Chemical', 'MESH:D019788', (29, 32))	('refractory epilepsy', 'Disease', 'MESH:D000069279', (182, 201))	('refractory epilepsy', 'Disease', (182, 201))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (165, 170))
151365	32811569	We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc.	('c-Myc', 'Gene', '4609', (121, 126))	('V600E', 'Var', (58, 63))	('activation', 'PosReg', (88, 98))	('BRAF', 'Gene', '673', (53, 57))	('LAT1', 'Gene', '8140', (19, 23))	('BRAF', 'Gene', (53, 57))	('LAT1', 'Gene', (19, 23))	('c-Myc', 'Gene', (121, 126))	('linked', 'Reg', (39, 45))	('MAPK signaling', 'Pathway', (102, 116))	('V600E', 'Mutation', 'rs113488022', (58, 63))
151366	32811569	Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells.	('expression', 'MPA', (85, 95))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('LAT1', 'Gene', '8140', (80, 84))	('LAT1', 'Gene', (80, 84))	('c-Myc', 'Gene', (70, 75))	('inhibition', 'Var', (28, 38))	('BRAF', 'Gene', (99, 103))	('suppressed', 'NegReg', (59, 69))	('BRAF', 'Gene', '673', (99, 103))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('c-Myc', 'Gene', '4609', (70, 75))
151370	32811569	P-LGNTs have different characteristics than their adult counterparts, and are commonly driven by genomic alterations in the Ras/mitogen-activated protein kinase (MAPK) pathway, such as mutations in BRAF and NF-1.	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('driven by', 'Reg', (87, 96))	('NF-1', 'Gene', (207, 211))	('P-LGNTs', 'Disease', (0, 7))	('mutations', 'Var', (185, 194))
151372	32811569	According to previous publications, PLNTYs are indolent tumors that generally exhibit a benign clinical course and harbor either a BRAF V600E mutation or FGFR2/FGFR3 fusion.	('FGFR3', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BRAF', 'Gene', (131, 135))	('FGFR2', 'Gene', '2263', (154, 159))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('V600E', 'Mutation', 'rs113488022', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('fusion', 'Var', (166, 172))	('FGFR3', 'Gene', '2261', (160, 165))	('PLNTYs', 'Disease', (36, 42))	('FGFR2', 'Gene', (154, 159))	('V600E', 'Var', (136, 141))	('BRAF', 'Gene', '673', (131, 135))
151377	32811569	Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 and inhibited tumor cell viability, suggesting that MAPK signaling and downstream c-Myc activates methionine metabolism and inhibition of this pathway induces therapeutic vulnerability in PLNTY.	('tumor', 'Disease', (99, 104))	('c-Myc', 'Gene', '4609', (70, 75))	('methionine metabolism', 'MPA', (183, 204))	('LAT1', 'Gene', '8140', (80, 84))	('therapeutic vulnerability', 'MPA', (244, 269))	('inhibited', 'NegReg', (89, 98))	('LAT1', 'Gene', (80, 84))	('c-Myc', 'Gene', (70, 75))	('inhibition', 'Var', (209, 219))	('activates', 'PosReg', (173, 182))	('inhibition', 'Var', (28, 38))	('suppressed', 'NegReg', (59, 69))	('c-Myc', 'Gene', '4609', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('induces', 'Reg', (236, 243))	('methionine', 'Chemical', 'MESH:D008715', (183, 193))	('c-Myc', 'Gene', (167, 172))
151402	32811569	After removal of the high-methionine-uptake and T2 hyperintense lesions, the surrounding tissue was resected until interictal epileptiform discharge could no longer be detected by electrocorticography.	('high-methionine-uptake', 'Var', (21, 43))	('high-methionine', 'Phenotype', 'HP:0003235', (21, 36))	('epileptiform', 'Disease', (126, 138))	('epileptiform', 'Disease', 'MESH:D014277', (126, 138))	('methionine', 'Chemical', 'MESH:D008715', (26, 36))	('interictal epileptiform discharge', 'Phenotype', 'HP:0011182', (115, 148))	('T2 hyperintense lesions', 'Var', (48, 71))
151408	32811569	Targeted DNA sequencing identified a BRAF V600E mutation in the tumor, without recurrent mutations in IDH1, IDH2, TERT promoter, FGFR1, H3F3A, or HIST3H1B (Fig.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('FGFR1', 'Gene', (129, 134))	('IDH2', 'Gene', '3418', (108, 112))	('tumor', 'Disease', (64, 69))	('V600E', 'Var', (42, 47))	('TERT', 'Gene', '7015', (114, 118))	('BRAF', 'Gene', '673', (37, 41))	('H3F3A', 'Gene', (136, 141))	('FGFR1', 'Gene', '2260', (129, 134))	('BRAF', 'Gene', (37, 41))	('IDH1', 'Gene', (102, 106))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('IDH1', 'Gene', '3417', (102, 106))	('IDH2', 'Gene', (108, 112))	('TERT', 'Gene', (114, 118))	('H3F3A', 'Gene', '3020', (136, 141))
151415	32811569	3a), suggesting activation of the MAPK pathway and c-Myc within the high-methionine-uptake lesion.	('c-Myc', 'Gene', '4609', (51, 56))	('MAPK pathway', 'Pathway', (34, 46))	('activation', 'PosReg', (16, 26))	('c-Myc', 'Gene', (51, 56))	('high-methionine-uptake', 'Var', (68, 90))	('high-methionine', 'Phenotype', 'HP:0003235', (68, 83))	('methionine', 'Chemical', 'MESH:D008715', (73, 83))
151416	32811569	To verify whether the BRAF V600E mutation can induce the expression of LAT1, we exposed primary cultured YMG83 PLNTY cells to a BRAF inhibitor (dabrafenib).	('expression', 'MPA', (57, 67))	('V600E', 'Var', (27, 32))	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', '673', (22, 26))	('LAT1', 'Gene', (71, 75))	('BRAF', 'Gene', (22, 26))	('LAT1', 'Gene', '8140', (71, 75))	('dabrafenib', 'Chemical', 'MESH:C561627', (144, 154))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('BRAF', 'Gene', (128, 132))
151422	32811569	Similarly, BRAF knockdown suppressed the expression of proteins in the MAPK pathway as well as c-Myc and LAT1 (Fig.	('c-Myc', 'Gene', (95, 100))	('proteins', 'Protein', (55, 63))	('suppressed', 'NegReg', (26, 36))	('expression of', 'MPA', (41, 54))	('LAT1', 'Gene', '8140', (105, 109))	('knockdown', 'Var', (16, 25))	('LAT1', 'Gene', (105, 109))	('c-Myc', 'Gene', '4609', (95, 100))	('MAPK pathway', 'Pathway', (71, 83))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
151423	32811569	Collectively, these findings indicated that activation of the MAPK pathway by the BRAF V600E mutation deregulates c-Myc and promotes LAT1 expression.	('c-Myc', 'Gene', '4609', (114, 119))	('V600E', 'Var', (87, 92))	('BRAF', 'Gene', '673', (82, 86))	('MAPK pathway', 'Pathway', (62, 74))	('activation', 'PosReg', (44, 54))	('LAT1', 'Gene', '8140', (133, 137))	('BRAF', 'Gene', (82, 86))	('LAT1', 'Gene', (133, 137))	('c-Myc', 'Gene', (114, 119))	('promotes', 'PosReg', (124, 132))	('V600E', 'Mutation', 'rs113488022', (87, 92))
151425	32811569	in 2017; BRAF V600E mutation was seen in 14 of the patients and BRAF fusion in 1 patient.	('BRAF', 'Gene', '673', (64, 68))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (9, 13))	('patient', 'Species', '9606', (81, 88))	('BRAF', 'Gene', (64, 68))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (51, 59))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (9, 13))
151426	32811569	These BRAF alterations were mutually exclusive with other genomic events, including FGFR3-TACC3 fusion, FGFR3 amplification, FGFR2-CTNNA3 fusion, FGFR2-INA fusion, FGFR2- KIAA1598 fusion, FGFR2 rearrangement, and NTRK2 disruption, suggesting that the vast majority of PLNTYs are induced by BRAF mutation or FGFR fusion and subsequent MAPK activation.	('FGFR2', 'Gene', (146, 151))	('NTRK2', 'Gene', (213, 218))	('FGFR2', 'Gene', '2263', (125, 130))	('FGFR3', 'Gene', '2261', (104, 109))	('induced', 'Reg', (279, 286))	('FGFR2', 'Gene', '2263', (188, 193))	('FGFR3', 'Gene', (84, 89))	('FGFR2', 'Gene', '2263', (164, 169))	('KIAA1598', 'Gene', (171, 179))	('MAPK', 'Gene', (334, 338))	('FGFR2', 'Gene', '2263', (146, 151))	('TACC3', 'Gene', '10460', (90, 95))	('BRAF', 'Gene', '673', (6, 10))	('FGFR3', 'Gene', '2261', (84, 89))	('TACC3', 'Gene', (90, 95))	('FGFR', 'Gene', (307, 311))	('BRAF', 'Gene', (6, 10))	('BRAF', 'Gene', '673', (290, 294))	('mutation', 'Var', (295, 303))	('BRAF', 'Gene', (290, 294))	('PLNTYs', 'Disease', (268, 274))	('NTRK2', 'Gene', '4915', (213, 218))	('CTNNA3', 'Gene', (131, 137))	('FGFR2', 'Gene', (125, 130))	('KIAA1598', 'Gene', '57698', (171, 179))	('activation', 'PosReg', (339, 349))	('FGFR3', 'Gene', (104, 109))	('FGFR2', 'Gene', (188, 193))	('CTNNA3', 'Gene', '29119', (131, 137))	('FGFR2', 'Gene', (164, 169))
151428	32811569	reported that the BRAF V600E mutation contributes to the intrinsic epileptogenicity in pediatric brain tumors, and that inhibition of BRAF suppressed epileptic seizures.	('epileptic seizures', 'Disease', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('seizures', 'Phenotype', 'HP:0001250', (160, 168))	('brain tumors', 'Disease', (97, 109))	('inhibition', 'Var', (120, 130))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('epileptic seizures', 'Disease', 'MESH:D004827', (150, 168))	('intrinsic epileptogenicity', 'MPA', (57, 83))	('BRAF', 'Gene', '673', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('BRAF', 'Gene', (134, 138))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', '673', (18, 22))	('brain tumors', 'Disease', 'MESH:D001932', (97, 109))	('brain tumors', 'Phenotype', 'HP:0030692', (97, 109))	('BRAF', 'Gene', (18, 22))	('suppressed', 'NegReg', (139, 149))
151433	32811569	A preclinical study has demonstrated that high uptake of 18F-FDG was correlated with increased Glut-1 and HK-2 expression in human cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('HK-2', 'Gene', (106, 110))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('Glut-1', 'Gene', '6513', (95, 101))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('human', 'Species', '9606', (125, 130))	('expression', 'MPA', (111, 121))	('18F-FDG', 'Chemical', '-', (57, 64))	('increased', 'PosReg', (85, 94))	('HK-2', 'Gene', '3099', (106, 110))	('18F-FDG', 'Var', (57, 64))	('Glut-1', 'Gene', (95, 101))
151444	32811569	As expected, levels of phospho-MEK, phospho-ERK, c-Myc, and LAT1 were higher in the high-methionine-uptake area than in the low-methionine-uptake area.	('high-methionine-uptake', 'MPA', (84, 106))	('c-Myc', 'Gene', '4609', (49, 54))	('MEK', 'Gene', (31, 34))	('c-Myc', 'Gene', (49, 54))	('MEK', 'Gene', '5609', (31, 34))	('LAT1', 'Gene', '8140', (60, 64))	('methionine', 'Chemical', 'MESH:D008715', (89, 99))	('phospho-ERK', 'Var', (36, 47))	('LAT1', 'Gene', (60, 64))	('high-methionine', 'Phenotype', 'HP:0003235', (84, 99))	('low-methionine-', 'Phenotype', 'HP:0003658', (124, 139))	('levels', 'MPA', (13, 19))	('higher', 'PosReg', (70, 76))	('methionine', 'Chemical', 'MESH:D008715', (128, 138))
151445	32811569	We also found that genetic and/or pharmacological BRAF inhibition suppressed MAPK pathway activation and attenuated LAT1 expression in BRAF V600E-mutated-PLNTY cells and -glioblastoma cell lines.	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', (50, 54))	('glioblastoma', 'Disease', (171, 183))	('LAT1', 'Gene', (116, 120))	('BRAF', 'Gene', (135, 139))	('expression', 'MPA', (121, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (171, 183))	('activation', 'MPA', (90, 100))	('V600E', 'Mutation', 'rs113488022', (140, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (171, 183))	('LAT1', 'Gene', '8140', (116, 120))	('V600E-mutated-PLNTY', 'Var', (140, 159))	('suppressed', 'NegReg', (66, 76))	('attenuated', 'NegReg', (105, 115))	('MAPK pathway', 'Pathway', (77, 89))	('BRAF', 'Gene', '673', (50, 54))
151460	32246865	siRNA-mediated RPS6 knock-down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and GSC marker expression; STAT3 was downregulated in GBM cells.	('GSC', 'Chemical', '-', (127, 130))	('GSC', 'Chemical', '-', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('knock-down', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('GSCs', 'Chemical', '-', (79, 83))	('suppressed', 'NegReg', (45, 55))	('characteristics', 'CPA', (60, 75))	('RPS6', 'Gene', (15, 19))	('downregulated', 'NegReg', (160, 173))	('tumors', 'Disease', (101, 107))
151463	32246865	Immunohistochemistry data herein indicated that RPS6 was predominant in GSC niches, concurrent with the data from IVY GAP databases.	('RPS6', 'Var', (48, 52))	('GSC', 'Chemical', '-', (72, 75))	('predominant', 'Reg', (57, 68))	('GSC niches', 'Disease', (72, 82))
151479	32246865	15  shRNA-mediated knock-down of RPS6 reportedly suppressed cancer cell proliferation and metastasis in lung cancer, 16  and RPS6 phosphorylation is important for pancreatic cancer pathogenesis.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('suppressed', 'NegReg', (49, 59))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (174, 180))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (109, 115))	('pancreatic cancer', 'Disease', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('knock-down', 'Var', (19, 29))	('metastasis', 'CPA', (90, 100))	('lung cancer', 'Disease', (104, 115))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('RPS6', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
151512	32246865	RPS6 was strongly inhibited in U251MG cells upon transfection of RPS6-specific siRNA (siRPS6) compared with that in cells transfected with control siRNA (siCont) (decreased by 54%) (Figure 2A).	('inhibited', 'NegReg', (18, 27))	('U251MG', 'CellLine', 'CVCL:0021', (31, 37))	('transfection', 'Var', (49, 61))	('RPS6', 'Enzyme', (0, 4))
151517	32246865	To determine the pathway involved in the acquisition of stemness properties, we assessed phosphorylated STAT3 (pSTAT3) levels because pSTAT3 is critical for chemoradioresistance, anti-apoptosis, stemness, and tumorigenesis.	('pSTAT3', 'Var', (134, 140))	('tumor', 'Disease', (209, 214))	('chemoradioresistance', 'CPA', (157, 177))	('stemness', 'CPA', (195, 203))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('anti-apoptosis', 'CPA', (179, 193))
151521	32246865	The sphere-forming potential of GBM cells was suppressed through treatment with 10 micromol/L (P < .05) and 25 micromol/L (P < .01) AG490 (Figure 3B).	('sphere-forming potential of GBM cells', 'CPA', (4, 41))	('AG490', 'Var', (132, 137))	('AG490', 'Chemical', 'MESH:C095512', (132, 137))	('suppressed', 'NegReg', (46, 56))
151522	32246865	Furthermore, the sphere-forming potential was suppressed by 67% upon AG490 treatment (25 micromol/L) compared with that of mock-OE-RPS6 upon RPS6 overexpression (Figure 3C and Figure S2C).	('AG490', 'Chemical', 'MESH:C095512', (69, 74))	('AG490', 'Var', (69, 74))	('sphere-forming potential', 'CPA', (17, 41))	('suppressed', 'NegReg', (46, 56))
151524	32246865	Thus, the sphere-forming potential of GBM cells was enhanced upon RPS6 overexpression, however it was attenuated upon treatment with AG490.	('AG490', 'Chemical', 'MESH:C095512', (133, 138))	('RPS6', 'Protein', (66, 70))	('enhanced', 'PosReg', (52, 60))	('overexpression', 'Var', (71, 85))	('sphere-forming potential of GBM cells', 'CPA', (10, 47))
151525	32246865	Expression of Nestin and SOX2 was also decreased by treatment with AG490 (Figure S5B).	('S5B', 'Gene', (81, 84))	('AG490', 'Var', (67, 72))	('Expression', 'MPA', (0, 10))	('AG490', 'Chemical', 'MESH:C095512', (67, 72))	('Nestin', 'Protein', (14, 20))	('decreased', 'NegReg', (39, 48))	('S5B', 'Gene', '5711', (81, 84))	('SOX2', 'Gene', (25, 29))
151530	32246865	These data suggest that RPS6 expression modulates stemness in high-grade gliomas; in other words, RPS6 expression induces malignant characters in GSCs.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('induces', 'PosReg', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('GSCs', 'Chemical', '-', (146, 150))	('RPS6 expression', 'Var', (98, 113))	('malignant characters', 'CPA', (122, 142))	('gliomas', 'Disease', (73, 80))
151551	32246865	Additionally, pRPS6 (Ser235/236) was detected in glioma tissues and its expression was higher in high-grade than in low-grade gliomas (Figure S7).	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('pRPS6', 'Gene', (14, 19))	('Ser235/236', 'Var', (21, 31))	('Ser235', 'Chemical', '-', (21, 27))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('expression', 'MPA', (72, 82))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('glioma', 'Disease', (126, 132))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('glioma', 'Disease', (49, 55))	('higher', 'PosReg', (87, 93))
151559	32246865	In addition, our preliminary result showed that RPS6 knock-down downregulated phospho-JAK2 (Figure S5A).	('downregulated', 'NegReg', (64, 77))	('RPS6', 'Gene', (48, 52))	('JAK2', 'Gene', '3717', (86, 90))	('knock-down', 'Var', (53, 63))	('JAK2', 'Gene', (86, 90))
151560	32246865	Furthermore, the sphere-forming ability induced by IL-6, a STAT3-activating ligand, was abrogated by siRPS6 transfection (Figure S6).	('abrogated', 'NegReg', (88, 97))	('siRPS6', 'Gene', (101, 107))	('IL-6', 'Gene', (51, 55))	('transfection', 'Var', (108, 120))	('sphere-forming ability', 'CPA', (17, 39))	('IL-6', 'Gene', '3569', (51, 55))
151573	28719033	Identification of driver copy number alterations in diverse cancer types and application in drug repositioning Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression.	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy number alterations', 'Var', (25, 48))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
151604	28719033	Our work reveals many driver non-coding RNAs in diverse cancer types.	('non-coding RNAs', 'Var', (29, 44))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))
151620	28719033	a + b + c + d is the total number of genes in the expression profile, and a + b is the number of census cancer genes in the expression profile.	('a + b + c + d', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('census cancer', 'Disease', (97, 110))	('census cancer', 'Disease', 'MESH:D009369', (97, 110))	('a + b', 'Var', (74, 79))
151633	28719033	Second, alterations, including SCNAs, that affect expression levels of other genes in the cancer genome have been used to identify key events for carcinogenesis (Masica and Karchin, 2011).	('carcinogenesis', 'Disease', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('alterations', 'Var', (8, 19))	('affect', 'Reg', (43, 49))	('expression levels', 'MPA', (50, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
151652	28719033	The drivers with deletions also significantly overlapped with tumor suppressor genes in the TSGene database in 11 of the 18 cancer types (Fig.	('overlapped', 'Reg', (46, 56))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('deletions', 'Var', (17, 26))	('tumor', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
151659	28719033	Many studies have reported aberrations in POU5F1B in cancer, such as in gastric and prostate cancer (Hayashi et al., 2015; Kastler et al., 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('gastric and prostate cancer', 'Disease', 'MESH:D013274', (72, 99))	('cancer', 'Disease', (53, 59))	('POU5F1B', 'Gene', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('POU5F1B', 'Gene', '5462', (42, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('aberrations', 'Var', (27, 38))
151660	28719033	5C, a total of nine non-coding drivers (hsa-mir-106b, hsa-mir-218-2, hsa-mir-548k, AP006216.10, CAPN10-AS1, RP11-1191J2.4, RP11-191L9.4, RP11-443B7.1 and RP11-794P6.1) were shared by two cancer types, and three non-coding drivers (PVT1, SOX2-OT and hsa-mir-429) by three cancer types.	('AS1', 'Gene', (103, 106))	('RP11', 'Gene', (108, 112))	('RP11', 'Gene', '26121', (154, 158))	('PVT1', 'Gene', '5820', (231, 235))	('RP11', 'Gene', (123, 127))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('RP11', 'Gene', (137, 141))	('RP11', 'Gene', (154, 158))	('SOX2-OT', 'Gene', (237, 244))	('AS1', 'Gene', '5729', (103, 106))	('CAPN10', 'Gene', (96, 102))	('SOX2-OT', 'Gene', '347689', (237, 244))	('RP11', 'Gene', '26121', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('CAPN10', 'Gene', '11132', (96, 102))	('hsa-mir-218-2', 'Gene', '407001', (54, 67))	('RP11', 'Gene', '26121', (123, 127))	('hsa-mir-218-2', 'Gene', (54, 67))	('cancer', 'Disease', (187, 193))	('AP006216.10', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hsa-mir-429', 'Gene', '554210', (249, 260))	('PVT1', 'Gene', (231, 235))	('RP11', 'Gene', '26121', (137, 141))	('hsa-mir-429', 'Gene', (249, 260))
151664	28719033	In total, seven drivers (MYC with amplification, PER2, HDAC4, PTPRG, PIK3R1, RAPGEF1 and PPP5C with deletion) were detected in both BRCA and OV.	('BRCA', 'Gene', '672', (132, 136))	('PIK3R1', 'Gene', (69, 75))	('MYC', 'Gene', (25, 28))	('HDAC4', 'Gene', '9759', (55, 60))	('RAPGEF1', 'Gene', '2889', (77, 84))	('PPP5C', 'Gene', (89, 94))	('PPP5C', 'Gene', '5536', (89, 94))	('BRCA', 'Gene', (132, 136))	('OV', 'Phenotype', 'HP:0100615', (141, 143))	('deletion', 'Var', (100, 108))	('amplification', 'Var', (34, 47))	('HDAC4', 'Gene', (55, 60))	('PIK3R1', 'Gene', '5295', (69, 75))	('MYC', 'Gene', '4609', (25, 28))	('PTPRG', 'Gene', (62, 67))	('PER2', 'Gene', (49, 53))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('RAPGEF1', 'Gene', (77, 84))	('PER2', 'Gene', '8864', (49, 53))	('PTPRG', 'Gene', '5793', (62, 67))
151675	28719033	Copy number alterations of non-coding RNAs play important roles in the progression of diverse types of cancer (Du et al., 2016).	('RNAs', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Copy number alterations', 'Var', (0, 23))	('roles', 'Reg', (58, 63))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
151678	28719033	For example, driver lncRNA GAS5 with amplification in liver hepatocellular carcinoma (LIHC) identified in our work has been reported with oncogenic roles in LIHC by Tao et al.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 84))	('GAS5', 'Gene', '60674', (27, 31))	('LIHC', 'Disease', (86, 90))	('LIHC', 'Disease', 'None', (86, 90))	('amplification', 'Var', (37, 50))	('GAS5', 'Gene', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('LIHC', 'Disease', (157, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('LIHC', 'Disease', 'None', (157, 161))	('liver hepatocellular carcinoma', 'Disease', (54, 84))
151679	28719033	Hsa-mir-134, a driver miRNA with a deletion in LUAD, was found to suppress NSCLC progression through down-regulation of CCND1 (Sun et al., 2016).	('LUAD', 'Gene', (47, 51))	('suppress', 'NegReg', (66, 74))	('down-regulation', 'NegReg', (101, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('Hsa-mir-134', 'Gene', '406924', (0, 11))	('CCND1', 'Gene', (120, 125))	('NSCLC', 'Disease', (75, 80))	('deletion', 'Var', (35, 43))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('Hsa-mir-134', 'Gene', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('CCND1', 'Gene', '595', (120, 125))
151703	28719033	Afatinib, another FDA approved drug, is used to treat late stage (metastatic) NSCLC with EGFR mutations (Dungo and Keating, 2013) (Fig.	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('mutations', 'Var', (94, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('NSCLC', 'Disease', (78, 83))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('EGFR', 'Gene', '1956', (89, 93))
151704	28719033	LUSC cell lines with amplification of EGFR show marginally significant sensitivity to lapatinib compared with those of LUSC cell lines with wild-type EGFR in the CCLE database (P = 0.049, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', (38, 42))	('lapatinib', 'Chemical', 'MESH:D000077341', (86, 95))	('sensitivity to lapatinib', 'MPA', (71, 95))	('CCLE', 'Chemical', '-', (162, 166))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('amplification', 'Var', (21, 34))	('EGFR', 'Gene', '1956', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
151705	28719033	LGG cell lines with amplification of EGFR show significant sensitivity to lapatinib compared with those of LGG cell lines with wild-type EGFR in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', (137, 141))	('sensitivity to lapatinib', 'MPA', (59, 83))	('EGFR', 'Gene', '1956', (37, 41))	('lapatinib', 'Chemical', 'MESH:D000077341', (74, 83))	('EGFR', 'Gene', '1956', (137, 141))	('amplification', 'Var', (20, 33))	('EGFR', 'Gene', (37, 41))
151706	28719033	BRCA cell lines with amplification of ERBB2 show significantly lower IC50 levels of afatinib compared with those of BRCA cell lines with wild-type ERBB2 in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('IC50 levels of afatinib', 'MPA', (69, 92))	('BRCA', 'Gene', (0, 4))	('lower', 'NegReg', (63, 68))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', (147, 152))	('ERBB2', 'Gene', '2064', (38, 43))	('ERBB2', 'Gene', '2064', (147, 152))	('afatinib', 'Chemical', 'MESH:D000077716', (84, 92))	('BRCA', 'Phenotype', 'HP:0003002', (116, 120))	('amplification', 'Var', (21, 34))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))	('BRCA', 'Gene', '672', (0, 4))
151718	28719033	Both CDKN2A and RB1 were reported to have deletions in BRCA and LGG (Bieche and Lidereau, 2000; Debniak et al., 2004).	('BRCA', 'Phenotype', 'HP:0003002', (55, 59))	('BRCA', 'Gene', '672', (55, 59))	('CDKN2A', 'Gene', (5, 11))	('BRCA', 'Gene', (55, 59))	('RB1', 'Gene', (16, 19))	('LGG', 'Gene', (64, 67))	('CDKN2A', 'Gene', '1029', (5, 11))	('deletions', 'Var', (42, 51))	('RB1', 'Gene', '5925', (16, 19))
151720	28719033	Notably, our work investigated the similarity and specificity of different cancer types from copy number alterations, which only represents one kind of molecular feature of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('copy number alterations', 'Var', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
151723	28719033	The drivers with amplifications in BRCA identified by our work significantly overlapped those detected by the Helios method (P = 9.46 x 10-10, hypergeometric test), including CCND1, MYC, ERBB2, ERLIN2, FOXA1, RAD52 and TOMM20.	('ERBB2', 'Gene', (187, 192))	('TOMM20', 'Gene', '9804', (219, 225))	('RAD52', 'Gene', '5893', (209, 214))	('BRCA', 'Phenotype', 'HP:0003002', (35, 39))	('ERLIN2', 'Gene', (194, 200))	('amplifications', 'Var', (17, 31))	('FOXA1', 'Gene', (202, 207))	('ERLIN2', 'Gene', '11160', (194, 200))	('BRCA', 'Gene', (35, 39))	('TOMM20', 'Gene', (219, 225))	('MYC', 'Gene', '4609', (182, 185))	('CCND1', 'Gene', (175, 180))	('BRCA', 'Gene', '672', (35, 39))	('FOXA1', 'Gene', '3169', (202, 207))	('RAD52', 'Gene', (209, 214))	('ERBB2', 'Gene', '2064', (187, 192))	('MYC', 'Gene', (182, 185))	('CCND1', 'Gene', '595', (175, 180))
151725	28719033	(2016) reported that gistic 2.0 tends to call larger deletion regions than amplification regions and identifies more drivers in deleted regions than in amplified regions for breast cancer.	('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))	('deletion', 'Var', (53, 61))
151726	28719033	Generally, our methods identified more drivers with deletions than drivers with amplifications for each cancer type, except for LIHC, which has 77 amplified drivers and 41 deleted drivers (Table S2).	('LIHC', 'Disease', 'None', (128, 132))	('LIHC', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('deletions', 'Var', (52, 61))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
151728	28719033	Some studies have also found that deletions or losses are more common than amplifications or gains in cancer (Cancer Genome Atlas Network, 2012; Schoch et al., 2002), which is an interesting phenomenon that warrants further exploration.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('deletions', 'Var', (34, 43))	('losses', 'NegReg', (47, 53))	('Cancer Genome Atlas', 'Disease', (110, 129))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gains in cancer', 'Disease', (93, 108))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (110, 129))	('gains in cancer', 'Disease', 'MESH:D015430', (93, 108))
151733	28719033	The mutation status of known cancer genes may affect the expression of CDEGs.	('expression', 'MPA', (57, 67))	('cancer', 'Disease', (29, 35))	('mutation', 'Var', (4, 12))	('CDEGs', 'Gene', (71, 76))	('affect', 'Reg', (46, 52))	('CDEGs', 'Chemical', '-', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
151770	27902458	First, we evaluated the BBB integrity in the xenotransplant models GBM27 and GBM38 as well as in control mice (Figure 2A and Supplementary Figure S2A) with MRI images.	('mice', 'Species', '10090', (105, 109))	('BBB integrity', 'CPA', (24, 37))	('GBM38', 'Var', (77, 82))
151775	27902458	This test showed that Evans Blue extravasation was significantly increased in the mice xenotransplanted with GBM38 cells compared to the GBM27 xenotransplanted ones (p < 0.05) (Figure 2BC), which confirmed that BBB was intact in GBM27 xenotransplants.	('mice', 'Species', '10090', (82, 86))	('GBM38 cells', 'Var', (109, 120))	('increased', 'PosReg', (65, 74))	('Evans Blue extravasation', 'MPA', (22, 46))	('Evans Blue', 'Chemical', 'MESH:D005070', (22, 32))
151778	27902458	Consistently, no albumin extravasation was detected in GBM27 xenotransplants nor in control mice (Figure 2 and Supplementary Figure S2D).	('GBM27', 'Var', (55, 60))	('mice', 'Species', '10090', (92, 96))	('albumin extravasation', 'MPA', (17, 38))
151793	27902458	To accomplish this, we screened peripheral blood EVs from 21 patients (20 diagnosed with low- and high-grade glioma and 1 brain metastasis) for the presence of IDH1 mutations, the most relevant mutation for human glioma diagnostic and prognostic (Table 1).	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('brain metastasis', 'Disease', (122, 138))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('IDH1', 'Gene', (160, 164))	('patients', 'Species', '9606', (61, 69))	('brain metastasis', 'Disease', 'MESH:D009362', (122, 138))	('glioma', 'Disease', (109, 115))	('IDH1', 'Gene', '3417', (160, 164))	('human', 'Species', '9606', (207, 212))	('mutations', 'Var', (165, 174))	('glioma', 'Disease', (213, 219))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
151815	27902458	Secondly, the relative presence of mutated gDNA versus wild type sequences within tumor-derived EVs cargo is questionable.	('mutated', 'Var', (35, 42))	('gDNA', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
151832	27902458	Here, we demonstrated for the first time, that fast Cold-PCR can be successfully used to enrich the mutated form of IDH1 in DNA sequences from peripheral blood EVs isolated from brain tumor patients.	('mutated', 'Var', (100, 107))	('patients', 'Species', '9606', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('brain tumor', 'Disease', (178, 189))	('IDH1', 'Gene', (116, 120))	('brain tumor', 'Disease', 'MESH:D001932', (178, 189))	('IDH1', 'Gene', '3417', (116, 120))	('brain tumor', 'Phenotype', 'HP:0030692', (178, 189))
151856	27902458	Formalin-fixed paraffin-embedded sections were stained (as per the manufacturer's staining protocol) with the Bond Polymer Refine Detection Kit on a Bond-max  fully automated staining system (Leica Microsystems GmbH, Germany), using a mouse monoclonal antibody against human IDH1R132H (Clon H09, Dianova) for the detection of mutant IDH1R132H.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('Leica Microsystems GmbH', 'Disease', (192, 215))	('IDH1', 'Gene', '3417', (333, 337))	('human', 'Species', '9606', (269, 274))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('mouse', 'Species', '10090', (235, 240))	('IDH1', 'Gene', (333, 337))	('IDH1', 'Gene', (275, 279))	('mutant', 'Var', (326, 332))	('IDH1', 'Gene', '3417', (275, 279))	('Leica Microsystems GmbH', 'Disease', 'None', (192, 215))
151863	27902458	For the enrichment and detection of IDH1 mutated gDNA sequences within EVs isolated from peripheral blood of human patients, DNA was amplified using the reported primers: forward 5'- CGGTCTTCAGAGAAGCCATT-3' and reverse 5'-GCAAAATCACATTATTGCCAAC-3' (Supplementary Figure S8A).	('mutated', 'Var', (41, 48))	('human', 'Species', '9606', (109, 114))	('IDH1', 'Gene', (36, 40))	('patients', 'Species', '9606', (115, 123))	('IDH1', 'Gene', '3417', (36, 40))	('gDNA', 'Gene', (49, 53))
151872	27440383	peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas Malignant transformation in tumors is a complex process requiring accumulation of numerous oncogenic abnormalities.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('astrocytomas', 'Disease', 'MESH:D001254', (102, 114))	('peIF4E', 'Var', (0, 6))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('numerous oncogenic abnormalities', 'Disease', (197, 229))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('astrocytomas', 'Disease', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('numerous oncogenic abnormalities', 'Disease', 'MESH:D000074723', (197, 229))
151878	27440383	Immunohistochemistry and PCR were used for IDH1 mutations.	('IDH1', 'Gene', '3417', (43, 47))	('mutations', 'Var', (48, 57))	('IDH1', 'Gene', (43, 47))
151881	27440383	In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target.	('peIF4E', 'Var', (62, 68))	('DIAs', 'Chemical', 'MESH:C076868', (56, 60))	('DIAs', 'Disease', (56, 60))	('activated', 'PosReg', (43, 52))	('cell signaling pathways', 'Pathway', (15, 38))
151882	27440383	Joint analysis of the expression of 4E-BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples.	('glioblastoma multiforme', 'Disease', (91, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('4E-BP1', 'Gene', (36, 42))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (91, 114))	('peIF4E', 'Var', (47, 53))	('4E-BP1', 'Gene', '1978', (36, 42))
151887	27440383	In molecular terms, amplification of epidermal growth factor receptor (EGFR) is the most distinctive marker of primary GBM, and mutations in IDH, TP53, and ATRX are the most distinctive markers of secondary GBM 2.	('ATRX', 'Gene', '546', (156, 160))	('TP53', 'Gene', '7157', (146, 150))	('IDH', 'Gene', (141, 144))	('mutations', 'Var', (128, 137))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('TP53', 'Gene', (146, 150))	('primary GBM', 'Disease', (111, 122))	('IDH', 'Gene', '3417', (141, 144))	('EGFR', 'Gene', '1956', (71, 75))	('ATRX', 'Gene', (156, 160))	('amplification', 'Var', (20, 33))	('epidermal growth factor receptor', 'Gene', (37, 69))	('EGFR', 'Gene', (71, 75))
151896	27440383	eIF4G is a major anchor in the recruitment of the ribosome to mRNA, which in addition to eIF4E interacts with other components of translational machinery, such as eIF4A.	('eIF4G', 'Gene', '1981', (0, 5))	('eIF4A', 'Gene', (163, 168))	('interacts', 'Reg', (95, 104))	('eIF4E', 'Var', (89, 94))	('eIF4A', 'Gene', '1973', (163, 168))	('recruitment', 'MPA', (31, 42))	('eIF4G', 'Gene', (0, 5))
151909	27440383	A histoscore (Hscore) was used to perform a semiquantitative evaluation of the antibodies EGFR, pMAPK, p4E-BP1, 4E-BP1, pS6, peIF4E, and eIF4E, as previously described 5, 7, 10.	('pMAPK', 'Var', (96, 101))	('4E-BP1', 'Gene', (104, 110))	('peIF4E', 'Var', (125, 131))	('EGFR', 'Gene', '1956', (90, 94))	('4E-BP1', 'Gene', (112, 118))	('pS6', 'Gene', '338413', (120, 123))	('eIF4E', 'Var', (137, 142))	('4E-BP1', 'Gene', '1978', (104, 110))	('EGFR', 'Gene', (90, 94))	('pS6', 'Gene', (120, 123))	('4E-BP1', 'Gene', '1978', (112, 118))
151911	27440383	The presence or absence of the R132H mutation in IDH1 was evaluated using immunohistochemistry or PCR 11.	('R132H', 'Var', (31, 36))	('IDH1', 'Gene', '3417', (49, 53))	('IDH1', 'Gene', (49, 53))	('R132H', 'Mutation', 'rs121913500', (31, 36))
151913	27440383	The qualitative variables were sex, location, laterality, and the presence of the IDH1 mutation.	('mutation', 'Var', (87, 95))	('IDH1', 'Gene', '3417', (82, 86))	('IDH1', 'Gene', (82, 86))
151940	27440383	In addition, significant differences in survival were found between patients with Ki67 above the cut-off (mean: 942 days) and patients with a lower proliferative index (mean: 1936 days, P = 0.014, Fig 3D).	('Ki67', 'Var', (82, 86))	('Ki67', 'Chemical', '-', (82, 86))	('survival', 'MPA', (40, 48))	('patients', 'Species', '9606', (68, 76))	('differences', 'Reg', (25, 36))	('patients', 'Species', '9606', (126, 134))
151942	27440383	The cut-off points that gave the best combinations were as follows: (1) 4E-BP1 >85 and peIF4E >30: diagnosis of GBM with a PPV of 100% (P < 0.001).	('4E-BP1', 'Gene', '1978', (72, 78))	('GBM', 'Disease', (112, 115))	('peIF4E >30', 'Var', (87, 97))	('4E-BP1', 'Gene', (72, 78))
151943	27440383	(2) Cyclin D1 > 2% and peIF4E >30: diagnosis of high-grade DIA with a PPV of 98.7% (P < 0.001).	('peIF4E', 'Var', (23, 29))	('Cyclin D1', 'Gene', (4, 13))	('Cyclin D1', 'Gene', '595', (4, 13))	('high-grade DIA', 'Disease', (48, 62))
151944	27440383	(3) peIF4E <30 and Ki67 < 12%: exclusion of GBM, with a negative predictive value of 100% (P < 0.001).	('GBM', 'Disease', (44, 47))	('peIF4E <30', 'Var', (4, 14))	('Ki67', 'Chemical', '-', (19, 23))	('Ki67', 'Var', (19, 23))
151948	27440383	These differences held for all three grades in p4E-BP1 and Ki67.	('Ki67', 'Chemical', '-', (59, 63))	('4E-BP1', 'Gene', (48, 54))	('Ki67', 'Var', (59, 63))	('4E-BP1', 'Gene', '1978', (48, 54))
151950	27440383	Expression of peIF4E in gliosis was similar to that found in anaplastic astrocytoma and higher than that observed in grade II astrocytomas.	('higher', 'PosReg', (88, 94))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (61, 83))	('peIF4E', 'Var', (14, 20))	('Expression', 'MPA', (0, 10))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('gliosis', 'Disease', 'MESH:D005911', (24, 31))	('II astrocytomas', 'Disease', (123, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('anaplastic astrocytoma', 'Disease', (61, 83))	('gliosis', 'Disease', (24, 31))	('gliosis', 'Phenotype', 'HP:0002171', (24, 31))	('II astrocytomas', 'Disease', 'MESH:D001254', (123, 138))
151954	27440383	We showed that the levels of these factors (p4E-BP1, peIF4E) increase during tumor progression and that peIF4E, age, and histologic grade were independent prognostic factors in the multivariate analysis.	('4E-BP1', 'Gene', (45, 51))	('peIF4E', 'Var', (104, 110))	('4E-BP1', 'Gene', '1978', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('levels', 'MPA', (19, 25))	('peIF4E', 'Var', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('increase', 'PosReg', (61, 69))	('tumor', 'Disease', (77, 82))
151955	27440383	These results are consistent with those of previous studies in several types of carcinomas, where p4E-BP1, eIF4E, and peIF4E were overexpressed, associated with a poorer prognosis, and considered critical "funnel factors" in cell signaling 3, 5, 6, 7, 8, 12, 13, 14.	('4E-BP1', 'Gene', '1978', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('carcinomas', 'Disease', (80, 90))	('associated', 'Reg', (145, 155))	('peIF4E', 'Var', (118, 124))	('4E-BP1', 'Gene', (99, 105))	('carcinomas', 'Disease', 'MESH:D002277', (80, 90))	('poorer', 'NegReg', (163, 169))	('eIF4E', 'Var', (107, 112))	('overexpressed', 'PosReg', (130, 143))
151963	27440383	In addition, no association was found with the mutational status of IDH1, although it is important to remember that the number of GBMs with the R132H mutation in our series is insufficient to draw statistical comparisons.	('R132H', 'Var', (144, 149))	('R132H', 'Mutation', 'rs121913500', (144, 149))	('IDH1', 'Gene', (68, 72))	('insufficient', 'Disease', 'MESH:D000309', (176, 188))	('IDH1', 'Gene', '3417', (68, 72))	('insufficient', 'Disease', (176, 188))
151977	27440383	In other tumors, expression of eIF4E was reported to be more marked in neoplastic lesions than in preneoplastic lesions (e.g., higher expression of eIF4E in adenocarcinoma than in adenomatous polyps in the colon 26 or in infiltrating carcinoma compared with benign tumors of the head and neck 29).	('neoplastic lesions', 'Disease', 'MESH:D051437', (101, 119))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('adenomatous polyps', 'Disease', (180, 198))	('higher', 'PosReg', (127, 133))	('carcinoma', 'Disease', 'MESH:D002277', (234, 243))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (101, 119))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (180, 198))	('carcinoma', 'Disease', 'MESH:D002277', (162, 171))	('adenocarcinoma', 'Disease', (157, 171))	('benign tumors', 'Disease', (258, 271))	('neoplastic lesions', 'Disease', (71, 89))	('adenomatous polyps', 'Disease', 'MESH:D018256', (180, 198))	('expression', 'MPA', (134, 144))	('neoplastic lesions', 'Disease', 'MESH:D051437', (71, 89))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('adenocarcinoma', 'Disease', 'MESH:D000230', (157, 171))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (71, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('neoplastic lesions', 'Disease', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('carcinoma', 'Disease', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('carcinoma', 'Disease', (162, 171))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', (9, 15))	('benign tumors', 'Disease', 'MESH:D009369', (258, 271))	('eIF4E', 'Var', (148, 153))
151983	27440383	In such cases, molecular data such as amplification of EGFR can be useful in clinical decision making.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (55, 59))	('amplification', 'Var', (38, 51))
151985	27440383	Thus, even if histologic criteria are not fulfilled, a DIA lesion showing expression of 4E-BP1 and peIF4E with Hscores >85/300 and 30/300, respectively, could suggest a diagnosis of GBM (with a positive predictive value of 100%, P < 0.001).	('4E-BP1', 'Gene', (88, 94))	('peIF4E', 'Var', (99, 105))	('4E-BP1', 'Gene', '1978', (88, 94))	('GBM', 'Disease', (182, 185))	('DIA lesion', 'Disease', (55, 65))	('DIA lesion', 'Disease', 'MESH:D051437', (55, 65))
151986	27440383	Phosphorylation of 4E-BP1 and eIF4E are examples of activation of multiple biochemical pathways upstream, where many oncogenic abnormalities may be activated.	('4E-BP1', 'Gene', '1978', (19, 25))	('Phosphorylation', 'Var', (0, 15))	('eIF4E', 'Var', (30, 35))	('4E-BP1', 'Gene', (19, 25))	('oncogenic abnormalities', 'Disease', (117, 140))	('oncogenic abnormalities', 'Disease', 'MESH:D000074723', (117, 140))	('activation', 'PosReg', (52, 62))
151987	27440383	Phosphorylation of eIF4E was recently shown to confer greater aggressivity in cells and in the development of metastasis in murine models 34.	('development of metastasis', 'CPA', (95, 120))	('eIF4E', 'Protein', (19, 24))	('aggressivity in cells', 'CPA', (62, 83))	('Phosphorylation', 'Var', (0, 15))	('greater', 'PosReg', (54, 61))	('murine', 'Species', '10090', (124, 130))
151991	27014635	Molecular Imaging of Metabolic Reprograming in Mutant IDH Cells Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) have recently been identified as drivers in the development of several tumor types.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('IDH', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('isocitrate dehydrogenase', 'Gene', (98, 122))	('IDH', 'Gene', '3417', (124, 127))	('tumor', 'Disease', (200, 205))	('IDH', 'Gene', (54, 57))	('Mutations', 'Var', (64, 73))	('isocitrate dehydrogenase', 'Gene', '3417', (98, 122))	('IDH', 'Gene', '3417', (54, 57))
151992	27014635	Most notably, cytosolic IDH1 is mutated in 70-90% of low-grade gliomas and upgraded glioblastomas, and mitochondrial IDH2 is mutated in ~20% of acute myeloid leukemia cases.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('glioblastomas', 'Disease', 'MESH:D005909', (84, 97))	('IDH1', 'Gene', '3417', (24, 28))	('IDH2', 'Gene', '3418', (117, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (150, 166))	('glioblastomas', 'Disease', (84, 97))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('mutated', 'Var', (32, 39))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (144, 166))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('acute myeloid leukemia', 'Disease', (144, 166))	('IDH1', 'Gene', (24, 28))	('IDH2', 'Gene', (117, 121))	('glioblastomas', 'Phenotype', 'HP:0012174', (84, 97))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (144, 166))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
151994	27014635	Mutations in the enzyme lead to loss of wild-type enzymatic activity and a neomorphic activity that converts alpha-KG to 2-hydroxyglutarate (2-HG).	('neomorphic activity', 'MPA', (75, 94))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (121, 139))	('loss', 'NegReg', (32, 36))	('alpha-KG', 'Chemical', 'MESH:D007656', (109, 117))	('wild-type enzymatic activity', 'MPA', (40, 68))	('Mutations', 'Var', (0, 9))	('2-HG', 'Chemical', 'MESH:C019417', (141, 145))
151995	27014635	In turn, 2-HG, which has been termed an "oncometabolite," inhibits key alpha-KG-dependent enzymes, resulting in alterations of the cellular epigenetic profile and, subsequently, inhibition of differentiation and initiation of tumorigenesis.	('2-HG', 'Var', (9, 13))	('cellular epigenetic profile', 'MPA', (131, 158))	('inhibits', 'NegReg', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('alpha-KG', 'Chemical', 'MESH:D007656', (71, 79))	('rat', 'Species', '10116', (116, 119))	('alterations', 'Reg', (112, 123))	('alpha-KG-dependent enzymes', 'Enzyme', (71, 97))	('2-HG', 'Chemical', 'MESH:C019417', (9, 13))	('inhibition', 'NegReg', (178, 188))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('differentiation', 'CPA', (192, 207))	('tumor', 'Disease', (226, 231))
151996	27014635	In addition, it is now clear that the IDH mutation also induces a broad metabolic reprograming that extends beyond 2-HG production, and this reprograming often differs from what has been previously reported in other cancer types.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('IDH', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('IDH', 'Gene', '3417', (38, 41))	('mutation', 'Var', (42, 50))	('induces', 'Reg', (56, 63))	('cancer', 'Disease', (216, 222))	('2-HG', 'Chemical', 'MESH:C019417', (115, 119))	('2-HG production', 'MPA', (115, 130))
151997	27014635	In this review, we will discuss in detail what is known to date about the metabolic reprograming of mutant IDH cells, and how this reprograming has been investigated using molecular metabolic imaging.	('mutant', 'Var', (100, 106))	('IDH', 'Gene', '3417', (107, 110))	('IDH', 'Gene', (107, 110))
151998	27014635	We will describe how metabolic imaging has helped shed light on the basic biology of mutant IDH cells, and how this information can be leveraged to identify new therapeutic targets and to develop new clinically translatable imaging methods to detect and monitor mutant IDH tumors in vivo.	('IDH tumors', 'Disease', 'MESH:D009369', (269, 279))	('IDH', 'Gene', (269, 272))	('mutant', 'Var', (262, 268))	('IDH', 'Gene', '3417', (269, 272))	('IDH tumors', 'Disease', (269, 279))	('IDH', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('mutant', 'Var', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('IDH', 'Gene', '3417', (92, 95))
152007	27014635	Mutations in the PI3K and LKB1-AMPK signaling pathways, Myc and Ras oncogenes, and the tumor suppressor p53 all reprogram metabolism.	('p53', 'Gene', (104, 107))	('Ras oncogenes', 'Gene', (64, 77))	('LKB1', 'Gene', '6794', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p53', 'Gene', '7157', (104, 107))	('tumor', 'Disease', (87, 92))	('PI3K', 'Pathway', (17, 21))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Myc', 'Gene', '4609', (56, 59))	('Myc', 'Gene', (56, 59))	('reprogram', 'Reg', (112, 121))	('LKB1', 'Gene', (26, 30))
152008	27014635	However, the discovery of tumors with gain-of-function mutations in metabolic enzymes provides strong evidence that altered metabolism can also result from mutations in metabolic enzymes.	('metabolic enzymes', 'Enzyme', (169, 186))	('metabolism', 'MPA', (124, 134))	('mutations', 'Var', (55, 64))	('mutations', 'Var', (156, 165))	('tumors', 'Disease', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('metabolic enzymes', 'Enzyme', (68, 85))	('gain-of-function', 'PosReg', (38, 54))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('altered', 'Reg', (116, 123))
152009	27014635	This is particularly true for tumors with mutations in the cytosolic or mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively).	('IDH1', 'Gene', (121, 125))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('IDH1', 'Gene', '3417', (121, 125))	('IDH2', 'Gene', (130, 134))	('isocitrate dehydrogenase', 'Gene', (95, 119))	('isocitrate dehydrogenase', 'Gene', '3417', (95, 119))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IDH2', 'Gene', '3418', (130, 134))	('mutations', 'Var', (42, 51))
152010	27014635	Mutations in IDH1 were first described in a whole-genome sequence analysis of glioblastoma patients.	('glioblastoma', 'Disease', (78, 90))	('patients', 'Species', '9606', (91, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))
152011	27014635	Subsequent studies confirmed the presence of IDH mutations in 70-90% of low-grade glioma and secondary glioblastoma, in ~20% of acute myeloid leukemia, and in intrahepatic cholangiocarcinoma, chondrosarcoma, and melanoma.	('acute myeloid leukemia', 'Disease', (128, 150))	('chondrosarcoma', 'Disease', (192, 206))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('mutations', 'Var', (49, 58))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (128, 150))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (192, 206))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (134, 150))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (128, 150))	('melanoma', 'Disease', (212, 220))	('glioma', 'Disease', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('IDH', 'Gene', (45, 48))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 190))	('intrahepatic cholangiocarcinoma', 'Disease', (159, 190))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH', 'Gene', '3417', (45, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (172, 190))	('glioblastoma', 'Disease', (103, 115))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('chondrosarcoma', 'Disease', 'MESH:D002813', (192, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
152012	27014635	The IDH1 mutation is one of the earliest known genetic events in low-grade gliomas, and it is thought to be a "driver" mutation for tumorigenesis.	('mutation', 'Var', (9, 17))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('IDH1', 'Gene', '3417', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('gliomas', 'Disease', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('tumor', 'Disease', (132, 137))	('IDH1', 'Gene', (4, 8))
152013	27014635	Discovery of the IDH1 mutation has also led to a molecular (rather than histological) classification of gliomas.	('gliomas', 'Disease', (104, 111))	('mutation', 'Var', (22, 30))	('rat', 'Species', '10116', (60, 63))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('IDH1', 'Gene', (17, 21))	('IDH1', 'Gene', '3417', (17, 21))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
152014	27014635	Presence of the IDH1 mutation in this new classification is associated with a more favorable prognosis compared to tumors with wild-type IDH1.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IDH1', 'Gene', (137, 141))	('IDH1', 'Gene', (16, 20))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('IDH1', 'Gene', '3417', (16, 20))	('IDH1', 'Gene', '3417', (137, 141))	('Presence', 'Var', (0, 8))
152015	27014635	From a metabolic perspective, mutations in IDH1 and IDH2 lead not only to the loss of wild-type enzyme activity [interconversion of isocitrate to alpha-ketoglutarate (alpha-KG)] but also to a gain-of-function that results in the conversion of alpha-KG to the "oncometabolite" 2-hydroxyglutarate (2-HG).	('wild-type', 'MPA', (86, 95))	('IDH2', 'Gene', '3418', (52, 56))	('activity', 'MPA', (103, 111))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (146, 165))	('results in', 'Reg', (214, 224))	('alpha-KG', 'Chemical', 'MESH:D007656', (243, 251))	('gain-of-function', 'PosReg', (192, 208))	('IDH1', 'Gene', (43, 47))	('alpha-KG', 'Chemical', 'MESH:D007656', (167, 175))	('2-HG', 'Chemical', 'MESH:C019417', (296, 300))	('loss', 'NegReg', (78, 82))	('conversion', 'MPA', (229, 239))	('mutations', 'Var', (30, 39))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (276, 294))	('IDH1', 'Gene', '3417', (43, 47))	('isocitrate', 'Chemical', 'MESH:C034219', (132, 142))	('IDH2', 'Gene', (52, 56))
152017	27014635	As a result, IDH1/2 mutant cells undergo extensive epigenetic modifications that ultimately result in tumorigenesis.	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('result in', 'Reg', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('IDH1/2', 'Gene', (13, 19))	('epigenetic modifications', 'MPA', (51, 75))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mutant', 'Var', (20, 26))
152018	27014635	Among other changes, the IDH mutation leads to alterations in cellular metabolism extending beyond 2-HG production.	('mutation', 'Var', (29, 37))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('2-HG', 'Chemical', 'MESH:C019417', (99, 103))	('cellular metabolism', 'MPA', (62, 81))	('alterations', 'Reg', (47, 58))	('rat', 'Species', '10116', (51, 54))
152020	27014635	To date, the metabolic characterization of mutant IDH cells has been carried out using either mass spectrometry (MS) or magnetic resonance spectroscopy (MRS).	('mutant', 'Var', (43, 49))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))
152024	27014635	In this review, we will discuss what is known about the metabolic reprograming of mutant IDH cells from a molecular imaging perspective.	('IDH', 'Gene', '3417', (89, 92))	('IDH', 'Gene', (89, 92))	('mutant', 'Var', (82, 88))
152026	27014635	This will be followed by a comprehensive discussion of metabolic alterations in mutant IDH tumors and the imaging methods used to investigate these changes.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutant', 'Var', (80, 86))	('IDH tumors', 'Disease', 'MESH:D009369', (87, 97))	('metabolic', 'MPA', (55, 64))	('IDH tumors', 'Disease', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('rat', 'Species', '10116', (69, 72))
152027	27014635	We will describe how molecular imaging has helped shed light on the basic biology of mutant IDH cells and will address how this knowledge could serve to identify new therapeutic targets and novel methods for imaging mutant IDH tumors in the clinic.	('IDH tumors', 'Disease', 'MESH:D009369', (223, 233))	('IDH', 'Gene', (223, 226))	('IDH tumors', 'Disease', (223, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('IDH', 'Gene', '3417', (223, 226))	('IDH', 'Gene', (92, 95))	('mutant', 'Var', (85, 91))	('IDH', 'Gene', '3417', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
152028	27014635	The most obvious metabolic change in IDH mutant cells is the production of 2-HG (Figure 1).	('2-HG', 'Chemical', 'MESH:C019417', (75, 79))	('mutant', 'Var', (41, 47))	('production of 2-HG', 'MPA', (61, 79))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3417', (37, 40))
152030	27014635	Gross et al., again using MS, reported elevated 2-HG levels (~10,000 ng/2 x 106 cells) in extracts from patients with IDH1/2 mutant acute myeloid leukemia.	('IDH1/2', 'Gene', (118, 124))	('acute myeloid leukemia', 'Disease', (132, 154))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (132, 154))	('2-HG levels', 'MPA', (48, 59))	('mutant', 'Var', (125, 131))	('elevated', 'PosReg', (39, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (132, 154))	('2-HG', 'Chemical', 'MESH:C019417', (48, 52))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('IDH1/2', 'Gene', '3417;3418', (118, 124))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (138, 154))	('patients', 'Species', '9606', (104, 112))
152032	27014635	2-HG levels correlated with the IDH1 mutation determined by immunohistochemistry with 86% concordance.	('2-HG levels', 'MPA', (0, 11))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('IDH1', 'Gene', '3417', (32, 36))
152034	27014635	This finding is consistent with the role of mutant IDH1 as a driver mutation essential for initiating tumorigenesis.	('IDH1', 'Gene', '3417', (51, 55))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('IDH1', 'Gene', (51, 55))	('mutant', 'Var', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
152036	27014635	In a randomized blinded analysis of 45 glioma samples, spectroscopic analysis was successful in quantifying the 2-HG cross-peaks in IDH mutant tissues with 97.8% accuracy.	('2-HG', 'Chemical', 'MESH:C019417', (112, 116))	('glioma', 'Disease', (39, 45))	('2-HG', 'Protein', (112, 116))	('IDH', 'Gene', (132, 135))	('IDH', 'Gene', '3417', (132, 135))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('mutant', 'Var', (136, 142))
152037	27014635	Although 2-HG levels are relatively high in IDH1 mutant tumors (5-35 mM), in vivo detection using 1H-MRS is hampered by the presence of overlapping resonances from glutamate and glutamine in the 2-3 ppm region of the spectrum.	('high', 'PosReg', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('glutamate', 'Chemical', 'MESH:D018698', (164, 173))	('mutant', 'Var', (49, 55))	('IDH1', 'Gene', (44, 48))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('IDH1', 'Gene', '3417', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('2-HG', 'Chemical', 'MESH:C019417', (9, 13))	('1H', 'Chemical', '-', (98, 100))	('glutamine', 'Chemical', 'MESH:D005973', (178, 187))	('glutamate', 'Protein', (164, 173))
152039	27014635	Two studies validated a single-voxel 1H-MR double-echo Point RESolved Spectroscopy (PRESS) sequence to estimate 2-HG levels in mutant IDH1 tumor patients.	('mutant', 'Var', (127, 133))	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('2-HG', 'Chemical', 'MESH:C019417', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('IDH1', 'Gene', (134, 138))	('IDH1', 'Gene', '3417', (134, 138))	('2-HG levels', 'MPA', (112, 123))	('1H', 'Chemical', '-', (37, 39))
152041	27014635	They found significantly elevated 2-HG levels in IDH mutant tumors compared to wild-type tumors and correlated the 2-HG levels with values measured by MS. Choi et al.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('IDH', 'Gene', (49, 52))	('2-HG', 'Chemical', 'MESH:C019417', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('IDH', 'Gene', '3417', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('elevated', 'PosReg', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('mutant', 'Var', (53, 59))	('2-HG', 'Chemical', 'MESH:C019417', (115, 119))	('2-HG levels', 'MPA', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', (60, 66))
152044	27014635	In every case where 2-HG was detected by MRS, the sample showed the presence of an IDH1/2 mutation.	('presence', 'Reg', (68, 76))	('2-HG', 'Chemical', 'MESH:C019417', (20, 24))	('IDH1/2', 'Gene', '3417;3418', (83, 89))	('mutation', 'Var', (90, 98))	('IDH1/2', 'Gene', (83, 89))
152046	27014635	used a more complex 2D-COSY MRS method to detect 2-HG in mutant IDH1 glioma patients and in ex vivo biopsy samples.	('IDH1 glioma', 'Disease', (64, 75))	('patients', 'Species', '9606', (76, 84))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('mutant', 'Var', (57, 63))	('IDH1 glioma', 'Disease', 'MESH:D005910', (64, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))
152054	27014635	We showed that, following injection of hyperpolarized [1-13C]-alpha-KG, the production of hyperpolarized [1-13C]-2-HG could be detected in lysates and in orthotopic mutant IDH1 tumors in rodents, but not in their wild-type counterparts (Figure 2).	('IDH1 tumors', 'Disease', (172, 183))	('mutant', 'Var', (165, 171))	('IDH1 tumors', 'Disease', 'MESH:D009369', (172, 183))	('1-13C', 'Chemical', '-', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('1-13C', 'Chemical', '-', (55, 60))	('2-HG', 'Chemical', 'MESH:C019417', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('detected', 'Reg', (127, 135))	('alpha-KG', 'Chemical', 'MESH:D007656', (62, 70))	('hyperpolarized [1-13C', 'Var', (90, 111))
152056	27014635	As such, the hyperpolarized method can inform in real-time on the presence of active mutant IDH1 and on potential inhibition of mutant IDH1 by novel therapies.	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1', 'Gene', '3417', (92, 96))	('mutant', 'Var', (85, 91))
152060	27014635	In a study by Pichumani et al., mutant IDH1 glioma patients received an infusion of [U-13C]-glucose during surgical tumor resection.	('IDH1 glioma', 'Disease', (39, 50))	('infusion of [U-13C]-glucose', 'MPA', (72, 99))	('[U-13C]-glucose', 'Chemical', '-', (84, 99))	('received', 'Reg', (60, 68))	('human', 'Species', '9606', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutant', 'Var', (32, 38))	('IDH1 glioma', 'Disease', 'MESH:D005910', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Disease', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
152062	27014635	In our laboratory, we incubated two IDH1 mutant glioma models with [1-13C]-glucose and [3-13C]-glutamine and analyzed the proportion of 13C-labeled 2-HG derived from each precursor.	('13C', 'Chemical', '-', (136, 139))	('IDH1', 'Gene', (36, 40))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('mutant', 'Var', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('[1-13C]-glucose', 'Chemical', '-', (67, 82))	('13C', 'Chemical', '-', (90, 93))	('2-HG', 'Chemical', 'MESH:C019417', (148, 152))	('13C', 'Chemical', '-', (70, 73))	('IDH1', 'Gene', '3417', (36, 40))	('3-13C', 'Chemical', '-', (88, 93))	('glutamine', 'Chemical', 'MESH:D005973', (95, 104))	('rat', 'Species', '10116', (11, 14))	('glioma', 'Disease', (48, 54))
152064	27014635	These findings have therapeutic implications since inhibiting glutaminase (the enzyme that converts glutamine to glutamate, the precursor of alpha-KG and 2-HG) has been explored as a therapeutic target for IDH mutant cells, without considering that glucose could serve as an alternate source of 2-HG.	('glutamine', 'Chemical', 'MESH:D005973', (100, 109))	('2-HG', 'Chemical', 'MESH:C019417', (295, 299))	('IDH', 'Gene', (206, 209))	('2-HG', 'Chemical', 'MESH:C019417', (154, 158))	('mutant', 'Var', (210, 216))	('glutamate', 'Chemical', 'MESH:D018698', (113, 122))	('alpha-KG', 'Chemical', 'MESH:D007656', (141, 149))	('IDH', 'Gene', '3417', (206, 209))	('glucose', 'Chemical', 'MESH:D005947', (249, 256))	('inhibiting', 'NegReg', (51, 61))	('glutaminase', 'Protein', (62, 73))
152065	27014635	Although the most obvious metabolic change in IDH mutant cells is the production of 2-HG, a number of studies indicate that IDH mutant cells undergo broader metabolic reprograming.	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (124, 127))	('mutant', 'Var', (128, 134))	('IDH', 'Gene', '3417', (46, 49))	('mutant', 'Var', (50, 56))	('2-HG', 'Chemical', 'MESH:C019417', (84, 88))
152066	27014635	conducted an MS-based metabolomic analysis of oligodendroglioma cells engineered to express wild-type or mutant IDH1 and IDH2.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('IDH1', 'Gene', '3417', (112, 116))	('IDH2', 'Gene', '3418', (121, 125))	('IDH1', 'Gene', (112, 116))	('oligodendroglioma', 'Disease', (46, 63))	('oligodendroglioma', 'Disease', 'MESH:D009837', (46, 63))	('mutant', 'Var', (105, 111))	('IDH2', 'Gene', (121, 125))
152067	27014635	Mutant IDH1/2 cells showed significantly increased levels of several amino acids, such as glycine, serine, threonine, asparagine, phenylalanine, tyrosine, tryptophan, and methionine (Figure 2).	('serine', 'MPA', (99, 105))	('asparagine', 'MPA', (118, 128))	('threonine', 'MPA', (107, 116))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('methionine', 'Chemical', 'MESH:D008715', (171, 181))	('glycine', 'Chemical', 'MESH:D005998', (90, 97))	('IDH1/2', 'Gene', (7, 13))	('serine', 'Chemical', 'MESH:D012694', (99, 105))	('levels of several amino acids', 'MPA', (51, 80))	('asparagine', 'Chemical', 'MESH:D001216', (118, 128))	('methionine', 'MPA', (171, 181))	('phenylalanine', 'MPA', (130, 143))	('threonine', 'Chemical', 'MESH:D013912', (107, 116))	('tryptophan', 'Chemical', 'MESH:D014364', (155, 165))	('Mutant', 'Var', (0, 6))	('tyrosine', 'MPA', (145, 153))	('glycine', 'MPA', (90, 97))	('increased', 'PosReg', (41, 50))	('tyrosine', 'Chemical', 'MESH:D014443', (145, 153))	('phenylalanine', 'Chemical', 'MESH:D010649', (130, 143))	('tryptophan', 'MPA', (155, 165))
152068	27014635	Glycerophosphocholine (GPC) levels were also higher, whereas glutamate, aspartate, and N-acetylated amino acid levels were reduced in IDH mutant cells compared to wild-type (Figure 2).	('N-acetylated amino acid', 'Chemical', '-', (87, 110))	('IDH', 'Gene', '3417', (134, 137))	('glutamate', 'MPA', (61, 70))	('PC', 'Chemical', 'MESH:D010767', (24, 26))	('mutant', 'Var', (138, 144))	('Glycerophosphocholine', 'Chemical', 'MESH:D005997', (0, 21))	('aspartate', 'Chemical', 'MESH:D001224', (72, 81))	('higher', 'PosReg', (45, 51))	('IDH', 'Gene', (134, 137))	('reduced', 'NegReg', (123, 130))	('glutamate', 'Chemical', 'MESH:D018698', (61, 70))
152069	27014635	also carried out an MS analysis of wild-type or mutant IDH patient glioma tissues and reported a significant decrease in the levels of N-acetylated amino acids and glutamate.	('decrease', 'NegReg', (109, 117))	('mutant', 'Var', (48, 54))	('glutamate', 'Chemical', 'MESH:D018698', (164, 173))	('glioma', 'Disease', (67, 73))	('IDH', 'Gene', (55, 58))	('patient', 'Species', '9606', (59, 66))	('N-acetylated amino acids', 'Chemical', '-', (135, 159))	('glutamate', 'MPA', (164, 173))	('IDH', 'Gene', '3417', (55, 58))	('levels of N-acetylated amino acids', 'MPA', (125, 159))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
152070	27014635	Additionally, both studies reported no change in glycolytic or pentose phosphate pathway intermediates in IDH mutant cells.	('pentose phosphate', 'Chemical', 'MESH:D010428', (63, 80))	('IDH', 'Gene', '3417', (106, 109))	('glycolytic', 'MPA', (49, 59))	('mutant', 'Var', (110, 116))	('IDH', 'Gene', (106, 109))
152071	27014635	We used high-resolution 1H-MRS to compare the metabolome of U87 cells expressing wild-type or mutant IDH1 and the metabolome of normal human astrocytes (NHA) expressing wild-type or mutant IDH1.	('IDH1', 'Gene', (101, 105))	('IDH1', 'Gene', '3417', (189, 193))	('IDH1', 'Gene', '3417', (101, 105))	('mutant', 'Var', (94, 100))	('1H', 'Chemical', '-', (24, 26))	('human', 'Species', '9606', (135, 140))	('IDH1', 'Gene', (189, 193))	('U87', 'CellLine', 'CVCL:0022', (60, 63))
152072	27014635	In line with MS observations, we found that the 1H-MRS-detectable steady-state levels of intracellular lactate, glutamate, and phosphocholine (PC) were significantly reduced in IDH1 mutant cells relative to wild-type, and GPC levels were higher (Figure 2).	('higher', 'PosReg', (238, 244))	('glutamate', 'Chemical', 'MESH:D018698', (112, 121))	('lactate', 'Chemical', 'MESH:D019344', (103, 110))	('1H', 'Chemical', '-', (48, 50))	('IDH1', 'Gene', (177, 181))	('levels of intracellular lactate', 'MPA', (79, 110))	('reduced', 'NegReg', (166, 173))	('GPC', 'MPA', (222, 225))	('IDH1', 'Gene', '3417', (177, 181))	('PC', 'Chemical', 'MESH:D010767', (143, 145))	('PC', 'Chemical', 'MESH:D010767', (223, 225))	('phosphocholine', 'Chemical', 'MESH:D010767', (127, 141))	('mutant', 'Var', (182, 188))
152073	27014635	Collectively, these studies demonstrated that mutant IDH cells broadly reprogram their metabolism and laid the foundation for more in-depth investigations, as reviewed below.	('metabolism', 'MPA', (87, 97))	('mutant', 'Var', (46, 52))	('IDH', 'Gene', (53, 56))	('reprogram', 'Reg', (71, 80))	('rat', 'Species', '10116', (35, 38))	('IDH', 'Gene', '3417', (53, 56))
152074	27014635	In our 1H-MRS study, we observed a reduction in intracellular lactate levels in IDH1 mutant glioma cells (Figure 2), suggesting that their metabolic reprograming could differ from other types of cancer cells.	('IDH1', 'Gene', (80, 84))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('1H', 'Chemical', '-', (7, 9))	('IDH1', 'Gene', '3417', (80, 84))	('intracellular lactate levels', 'MPA', (48, 76))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('glioma', 'Disease', (92, 98))	('lactate', 'Chemical', 'MESH:D019344', (62, 69))	('mutant', 'Var', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('reduction', 'NegReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
152075	27014635	confirmed this hypothesis and demonstrated that expression of lactate dehydrogenase A (LDHA), which catalyzes the production of lactate from pyruvate, was reduced in IDH mutant patient-derived glioma tissues compared to IDH wild-type glioblastoma that display elevated lactate production.	('glioblastoma', 'Disease', 'MESH:D005909', (234, 246))	('mutant', 'Var', (170, 176))	('lactate', 'Chemical', 'MESH:D019344', (62, 69))	('lactate', 'Chemical', 'MESH:D019344', (269, 276))	('LDHA', 'Gene', (87, 91))	('glioma', 'Disease', (193, 199))	('expression', 'MPA', (48, 58))	('IDH', 'Gene', (166, 169))	('glioblastoma', 'Disease', (234, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (234, 246))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('IDH', 'Gene', (220, 223))	('lactate dehydrogenase A', 'Gene', '3939', (62, 85))	('rat', 'Species', '10116', (37, 40))	('IDH', 'Gene', '3417', (166, 169))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('lactate dehydrogenase A', 'Gene', (62, 85))	('lactate production', 'MPA', (269, 287))	('reduced', 'NegReg', (155, 162))	('IDH', 'Gene', '3417', (220, 223))	('LDHA', 'Gene', '3939', (87, 91))	('pyruvate', 'Chemical', 'MESH:D019289', (141, 149))	('patient', 'Species', '9606', (177, 184))	('lactate', 'Chemical', 'MESH:D019344', (128, 135))
152077	27014635	In an effort to develop a complementary and clinically relevant imaging method for probing mutant IDH1-associated LDHA silencing, we recently investigated the fate of hyperpolarized [1-13C]-pyruvate in the BT142 patient-derived mutant IDH1 model in vivo.	('IDH1', 'Gene', (235, 239))	('IDH1', 'Gene', '3417', (98, 102))	('[1-13C]-pyruvate', 'Chemical', '-', (182, 198))	('patient', 'Species', '9606', (212, 219))	('IDH1', 'Gene', '3417', (235, 239))	('IDH1', 'Gene', (98, 102))	('silencing', 'NegReg', (119, 128))	('LDHA', 'Gene', (114, 118))	('LDHA', 'Gene', '3939', (114, 118))	('mutant', 'Var', (91, 97))
152078	27014635	We found that hyperpolarized [1-13C]-lactate produced from hyperpolarized [1-13C]-pyruvate was comparable between mutant IDH1 tumors and normal brain in the BT142 model, in contrast to wild-type IDH1 glioma models, wherein hyperpolarized [1-13C]-lactate is significantly higher than in normal brain.	('IDH1 tumors', 'Disease', (121, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('[1-13C]-pyruvate', 'Chemical', '-', (74, 90))	('IDH1 glioma', 'Disease', (195, 206))	('mutant', 'Var', (114, 120))	('IDH1 tumors', 'Disease', 'MESH:D009369', (121, 132))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('1-13C]-lactate', 'Chemical', '-', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('IDH1 glioma', 'Disease', 'MESH:D005910', (195, 206))	('1-13C]-lactate', 'Chemical', '-', (239, 253))
152079	27014635	Glutamate levels are reduced in IDH mutant cells compared to wild-type.	('reduced', 'NegReg', (21, 28))	('Glutamate levels', 'MPA', (0, 16))	('Glutamate', 'Chemical', 'MESH:D018698', (0, 9))	('IDH', 'Gene', '3417', (32, 35))	('IDH', 'Gene', (32, 35))	('mutant', 'Var', (36, 42))
152081	27014635	showed that mutant IDH1 tumors showed reduced glutamate levels compared to normal brain, indicating that reduced glutamate could serve as a biomarker of mutant IDH1 tumors.	('glutamate levels', 'MPA', (46, 62))	('IDH1 tumors', 'Disease', 'MESH:D009369', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('glutamate', 'Chemical', 'MESH:D018698', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('reduced', 'NegReg', (38, 45))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('glutamate', 'MPA', (113, 122))	('mutant', 'Var', (12, 18))	('IDH1 tumors', 'Disease', (160, 171))	('IDH1 tumors', 'Disease', (19, 30))	('reduced', 'NegReg', (105, 112))	('glutamate', 'Chemical', 'MESH:D018698', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('IDH1 tumors', 'Disease', 'MESH:D009369', (160, 171))	('reduced glutamate levels', 'Phenotype', 'HP:0500150', (38, 62))
152085	27014635	To image this reprograming, we expanded on our previous study and used hyperpolarized [1-13C]-alpha-KG to monitor hyperpolarized [1-13C]-glutamate production in mutant IDH1 tumors.	('mutant', 'Var', (161, 167))	('glutamate', 'Chemical', 'MESH:D018698', (137, 146))	('alpha-KG', 'Chemical', 'MESH:D007656', (94, 102))	('IDH1 tumors', 'Disease', 'MESH:D009369', (168, 179))	('1-13C', 'Chemical', '-', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('1-13C', 'Chemical', '-', (87, 92))	('IDH1 tumors', 'Disease', (168, 179))
152086	27014635	We showed that conversion of hyperpolarized [1-13C]-alpha-KG to glutamate was reduced in mutant IDH1 tumors compared to wild-type, in line with decreased BCAT1.	('alpha-KG', 'Chemical', 'MESH:D007656', (52, 60))	('IDH1 tumors', 'Disease', (96, 107))	('glutamate', 'Chemical', 'MESH:D018698', (64, 73))	('BCAT1', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('IDH1 tumors', 'Disease', 'MESH:D009369', (96, 107))	('mutant', 'Var', (89, 95))	('reduced', 'NegReg', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('conversion of hyperpolarized [1-13C]-alpha-KG', 'MPA', (15, 60))	('BCAT1', 'Gene', '586', (154, 159))	('1-13C', 'Chemical', '-', (45, 50))
152087	27014635	In addition, we observed decreased expression of aspartate transaminase (GOT1) and glutamate dehydrogenase (GDH), two other enzymes catalyzing alpha-KG to glutamate metabolism, suggesting additional metabolic reprograming associated with the IDH1 mutation (Figure 2).	('metabolic reprograming', 'CPA', (199, 221))	('mutation', 'Var', (247, 255))	('IDH1', 'Gene', (242, 246))	('glutamate', 'Chemical', 'MESH:D018698', (83, 92))	('decreased', 'NegReg', (25, 34))	('expression', 'MPA', (35, 45))	('glutamate', 'Chemical', 'MESH:D018698', (155, 164))	('IDH1', 'Gene', '3417', (242, 246))	('alpha-KG', 'Chemical', 'MESH:D007656', (143, 151))	('aspartate', 'Chemical', 'MESH:D001224', (49, 58))	('GOT1', 'Gene', '2805', (73, 77))	('GOT1', 'Gene', (73, 77))
152088	27014635	BCAT1 and GOT1 promoter methylation is higher in mutant IDH cells, providing a likely mechanistic link between the IDH1 mutations and reduced alpha-KG to glutamate conversion.	('higher', 'PosReg', (39, 45))	('mutant', 'Var', (49, 55))	('IDH1', 'Gene', (115, 119))	('BCAT1', 'Gene', (0, 5))	('glutamate', 'Chemical', 'MESH:D018698', (154, 163))	('alpha-KG to glutamate conversion', 'MPA', (142, 174))	('IDH', 'Gene', (56, 59))	('IDH1', 'Gene', '3417', (115, 119))	('BCAT1', 'Gene', '586', (0, 5))	('IDH', 'Gene', '3417', (56, 59))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('mutations', 'Var', (120, 129))	('reduced', 'NegReg', (134, 141))	('GOT1', 'Gene', '2805', (10, 14))	('alpha-KG', 'Chemical', 'MESH:D007656', (142, 150))	('GOT1', 'Gene', (10, 14))
152090	27014635	However, further optimization of pulse sequences for detection of both 2-HG and glutamate could provide a molecular imaging approach that would simultaneously image IDH mutational status and the metabolic reprograming specifically associated with the mutation.	('IDH', 'Gene', '3417', (165, 168))	('IDH', 'Gene', (165, 168))	('metabolic reprograming', 'CPA', (195, 217))	('mutation', 'Var', (251, 259))	('glutamate', 'Chemical', 'MESH:D018698', (80, 89))	('2-HG', 'Chemical', 'MESH:C019417', (71, 75))
152092	27014635	We found that there was a significant reduction in 13C-labeled-glutamate derived from [1-13C]-glucose in IDH mutant cells compared to wild-type resulting from lower PDH activity.	('[1-13C]-glucose', 'Chemical', '-', (86, 101))	('13C', 'Chemical', '-', (51, 54))	('glutamate', 'Chemical', 'MESH:D018698', (63, 72))	('PDH', 'Gene', '54704', (165, 168))	('PDH', 'Gene', (165, 168))	('activity', 'MPA', (169, 177))	('lower', 'NegReg', (159, 164))	('IDH', 'Gene', (105, 108))	('mutant', 'Var', (109, 115))	('reduction', 'NegReg', (38, 47))	('IDH', 'Gene', '3417', (105, 108))	('13C', 'Chemical', '-', (89, 92))	('13C-labeled-glutamate derived from', 'MPA', (51, 85))
152094	27014635	Importantly, treatment of IDH mutant cells with the PDH agonist dichloroacetate (DCA), not only reversed the metabolic changes induced by the IDH mutation but also abrogated the clonogenic potential of IDH1 mutant cells.	('IDH', 'Gene', (202, 205))	('mutation', 'Var', (146, 154))	('DCA', 'Chemical', 'MESH:D003999', (81, 84))	('PDH', 'Gene', '54704', (52, 55))	('IDH', 'Gene', '3417', (202, 205))	('IDH', 'Gene', (142, 145))	('clonogenic potential', 'CPA', (178, 198))	('IDH', 'Gene', '3417', (142, 145))	('mutant', 'Var', (207, 213))	('IDH', 'Gene', (26, 29))	('dichloroacetate', 'Chemical', 'MESH:D003999', (64, 79))	('IDH1', 'Gene', (202, 206))	('metabolic changes', 'MPA', (109, 126))	('PDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (26, 29))	('abrogated', 'NegReg', (164, 173))	('IDH1', 'Gene', '3417', (202, 206))
152095	27014635	This suggests that reprograming of PDH activity is essential for tumorigenesis of mutant IDH cells and that PDK inhibitors/PDH agonists deserve further investigation as potential therapeutic targets for low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('PDH', 'Gene', (123, 126))	('PDH', 'Gene', '54704', (35, 38))	('PDH', 'Gene', (35, 38))	('gliomas', 'Disease', (213, 220))	('IDH', 'Gene', (89, 92))	('PDH', 'Gene', '54704', (123, 126))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('IDH', 'Gene', '3417', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutant', 'Var', (82, 88))
152096	27014635	From an imaging perspective, we also demonstrated that PDH-mediated conversion of hyperpolarized [2-13C]-pyruvate to hyperpolarized [5-13C]-glutamate could be used to monitor the mutant IDH-driven drop in PDH activity in cells (Figure 2), with potential in vivo implementation.	('PDH', 'Gene', '54704', (55, 58))	('mutant', 'Var', (179, 185))	('PDH', 'Gene', '54704', (205, 208))	('rat', 'Species', '10116', (44, 47))	('PDH', 'Gene', (55, 58))	('[2-13C]-pyruvate', 'Chemical', '-', (97, 113))	('IDH', 'Gene', (186, 189))	('drop', 'NegReg', (197, 201))	('IDH', 'Gene', '3417', (186, 189))	('[5-13C]-glutamate', 'Chemical', '-', (132, 149))	('PDH', 'Gene', (205, 208))	('activity', 'MPA', (209, 217))
152097	27014635	As with glycolysis, the reprograming of glutamine metabolism differs in mutant IDH cells compared to other cancer cells.	('IDH', 'Gene', (79, 82))	('mutant', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('IDH', 'Gene', '3417', (79, 82))	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
152100	27014635	However, mutant IDH1 and IDH2 cannot catalyze reductive carboxylation, and IDH1 mutant cells show reduced metabolism of glutamine to citrate and acetyl CoA, resulting in altered fatty acid biosynthesis.	('acetyl CoA', 'Chemical', 'MESH:D000105', (145, 155))	('fatty acid biosynthesis', 'MPA', (178, 201))	('mutant', 'Var', (80, 86))	('IDH1', 'Gene', (16, 20))	('IDH1', 'Gene', (75, 79))	('altered', 'Reg', (170, 177))	('IDH2', 'Gene', (25, 29))	('glutamine', 'Chemical', 'MESH:D005973', (120, 129))	('reduced', 'NegReg', (98, 105))	('IDH1', 'Gene', '3417', (75, 79))	('citrate', 'Chemical', 'MESH:D019343', (133, 140))	('IDH1', 'Gene', '3417', (16, 20))	('fatty acid', 'Chemical', 'MESH:D005227', (178, 188))	('IDH2', 'Gene', '3418', (25, 29))
152103	27014635	Infusion of human glioma patients with [U-13C]-glutamine prior to surgery, followed by 13C-MR analysis of metabolites extracted from tumor tissue has been used to estimate glutamine metabolism in brain tumors, but it is challenging to implement in vivo.	('glutamine', 'Chemical', 'MESH:D005973', (172, 181))	('13C', 'Chemical', '-', (42, 45))	('[U-13C]-glutamine', 'Var', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('glutamine metabolism', 'MPA', (172, 192))	('tumor', 'Disease', (202, 207))	('13C', 'Chemical', '-', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('glioma', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('brain tumors', 'Phenotype', 'HP:0030692', (196, 208))	('glutamine', 'Chemical', 'MESH:D005973', (47, 56))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('brain tumors', 'Disease', 'MESH:D001932', (196, 208))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('[U-13C]-glutamine', 'Chemical', '-', (39, 56))	('brain tumors', 'Disease', (196, 208))	('human', 'Species', '9606', (12, 17))
152108	27014635	Mass spectrometry and 1H-MRS studies have shown a drop in PC and increase in GPC in mutant IDH1 cells compared to wild-type (Figure 2).	('increase', 'PosReg', (65, 73))	('GPC', 'MPA', (77, 80))	('IDH1', 'Gene', (91, 95))	('mutant', 'Var', (84, 90))	('drop', 'NegReg', (50, 54))	('PC', 'Chemical', 'MESH:D010767', (78, 80))	('IDH1', 'Gene', '3417', (91, 95))	('PC', 'Chemical', 'MESH:D010767', (58, 60))	('1H', 'Chemical', '-', (22, 24))
152110	27014635	They confirmed that IDH mutant tumors showed higher levels of GPC and also found lower levels of phosphoethanolamine (PE) (Figure 2).	('mutant', 'Var', (24, 30))	('lower', 'NegReg', (81, 86))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('PE', 'Chemical', 'MESH:C005448', (118, 120))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('levels', 'MPA', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('GPC', 'MPA', (62, 65))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (97, 116))	('higher', 'PosReg', (45, 51))	('levels of phosphoethanolamine', 'MPA', (87, 116))	('PC', 'Chemical', 'MESH:D010767', (63, 65))
152111	27014635	Furthermore, ratios of GPC:PE, PC:PE, GPC:glycerophosphoethanolamine (GPE), and (PC + PE:GPC + GPE) were higher in IDH mutant tumors relative to wild-type.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PE', 'Chemical', 'MESH:C005448', (86, 88))	('IDH', 'Gene', '3417', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('PC', 'Chemical', 'MESH:D010767', (90, 92))	('tumors', 'Disease', (126, 132))	('GPE', 'Chemical', '-', (70, 73))	('PC', 'Chemical', 'MESH:D010767', (81, 83))	('rat', 'Species', '10116', (13, 16))	('mutant', 'Var', (119, 125))	('PE', 'Chemical', 'MESH:C005448', (34, 36))	('PE', 'Chemical', 'MESH:C005448', (27, 29))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('PC', 'Chemical', 'MESH:D010767', (39, 41))	('PC', 'Chemical', 'MESH:D010767', (31, 33))	('PE', 'Chemical', 'MESH:C005448', (96, 98))	('PC', 'Chemical', 'MESH:D010767', (24, 26))	('glycerophosphoethanolamine', 'Chemical', 'MESH:C002449', (42, 68))	('higher', 'PosReg', (105, 111))	('GPE', 'Chemical', '-', (95, 98))	('PE', 'Chemical', 'MESH:C005448', (71, 73))	('IDH', 'Gene', (115, 118))
152113	27014635	Nonetheless, 31P-MRS could prove useful for non-invasive imaging of IDH mutant tumors.	('IDH', 'Gene', '3417', (68, 71))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('31P', 'Chemical', '-', (13, 16))	('31P-MRS', 'Var', (13, 20))	('IDH', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
152116	27014635	Further studies are needed to fully elucidate the wide range of metabolic changes occurring in mutant IDH cells.	('IDH', 'Gene', '3417', (102, 105))	('IDH', 'Gene', (102, 105))	('mutant', 'Var', (95, 101))
152117	27014635	Nonetheless, the unique features of glucose, glutamine, and lipid metabolism identified to date can already be exploited for molecular imaging of mutant IDH tumors.	('glutamine', 'Chemical', 'MESH:D005973', (45, 54))	('lipid', 'Chemical', 'MESH:D008055', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('IDH tumors', 'Disease', 'MESH:D009369', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('mutant', 'Var', (146, 152))	('IDH tumors', 'Disease', (153, 163))
152119	27014635	This work was supported by NIH R01CA172845 (SR), NIH R01CA154915 (SR), NIH R21CA161545 (SR), and the UCSF Brain Tumor Center Loglio Collective.	('Brain Tumor', 'Phenotype', 'HP:0030692', (106, 117))	('NIH R01CA154915', 'CellLine', 'CVCL:0601', (49, 64))	('UCSF Brain Tumor', 'Disease', 'MESH:D001932', (101, 117))	('UCSF Brain Tumor', 'Disease', (101, 117))	('Tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NIH R21CA161545', 'Var', (71, 86))	('NIH', 'Var', (27, 30))	('NIH R01CA154915', 'Var', (49, 64))
152187	22492246	However, disruption of the BBB may contribute to GFAP's ability to leave the brain and enter the bloodstream.	('GFAP', 'Gene', '2670', (49, 53))	('BBB', 'Protein', (27, 30))	('GFAP', 'Gene', (49, 53))	('ability', 'MPA', (56, 63))	('disruption', 'Var', (9, 19))
152201	32443727	Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer.	('IGF-IR', 'Gene', '3480', (160, 166))	('IGFBPs', 'Gene', (24, 30))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('IGFBPs', 'Gene', '3485;3486;16009;24484', (24, 30))	('IGF-I receptor', 'Gene', '3480', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('IGF-I receptor', 'Gene', (144, 158))	('IGFBP-3', 'Var', (61, 68))	('IGF-IR', 'Gene', (160, 166))
152202	32443727	Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer.	('prostate', 'Disease', (166, 174))	('implicated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('IGFBP-3', 'Gene', (14, 21))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('breast', 'Disease', (158, 164))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (141, 147))	('Disruption', 'Var', (0, 10))
152208	32443727	Dysregulation of the IGF system attributes to pathophysiology of a variety of human diseases such as cancer, diabetes, chronic inflammatory disease, and malnutrition.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('malnutrition', 'Phenotype', 'HP:0004395', (153, 165))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (101, 107))	('inflammatory disease', 'Disease', (127, 147))	('inflammatory disease', 'Disease', 'MESH:D007249', (127, 147))	('diabetes', 'Disease', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('diabetes', 'Disease', 'MESH:D003920', (109, 117))	('human', 'Species', '9606', (78, 83))	('malnutrition', 'Disease', (153, 165))
152237	32443727	Further studies using p53 mutants have revealed a link between p53's activation of IGFBP-3 transcription and its induction of apoptosis by showing that the mutants that lost the ability to activate IGFBP-3 could not induce apoptosis.	('transcription', 'MPA', (91, 104))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('IGFBP-3', 'Gene', (83, 90))	('p53', 'Gene', (22, 25))	('mutants', 'Var', (156, 163))	('apoptosis', 'CPA', (223, 232))	('mutants', 'Var', (26, 33))	('p53', 'Gene', '7157', (22, 25))	('activation', 'PosReg', (69, 79))
152238	32443727	Further research also demonstrated that the transfection of doxycycline-inducible p53 plasmids resulted in increased expression of p53 and IGFBP-3 and, subsequently, induced apoptosis in p53-negative PC-3 prostate cancer cells.	('induced', 'Reg', (166, 173))	('prostate cancer', 'Disease', (205, 220))	('transfection', 'Var', (44, 56))	('PC-3', 'CellLine', 'CVCL:0035', (200, 204))	('p53', 'Gene', (187, 190))	('increased', 'PosReg', (107, 116))	('expression', 'MPA', (117, 127))	('p53', 'Gene', (131, 134))	('apoptosis', 'CPA', (174, 183))	('p53', 'Gene', '7157', (131, 134))	('doxycycline', 'Chemical', 'MESH:D004318', (60, 71))	('p53', 'Gene', '7157', (187, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('IGFBP-3', 'Gene', (139, 146))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))
152239	32443727	This p53-depedent induction of apoptosis was inhibited by treating with IGF-I, IGFBP-3 blocking antibodies, and IGFBP-3 antisense oligonucleotides, which demonstrated p53-dependent IGFBP-3's proapoptotic function.	('antisense oligonucleotides', 'Var', (120, 146))	('IGFBP-3', 'Gene', (79, 86))	('oligonucleotides', 'Chemical', 'MESH:D009841', (130, 146))	('IGF-I', 'Gene', '3479', (72, 77))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('p53', 'Gene', '7157', (167, 170))	('apoptosis', 'CPA', (31, 40))	('inhibited', 'NegReg', (45, 54))	('IGF-I', 'Gene', (72, 77))	('IGFBP-3', 'Gene', (112, 119))	('p53', 'Gene', (167, 170))
152241	32443727	It appears that DeltaNp63alpha binds the p53 binding sites, Box A and Box B, in the IGFBP-3 gene, and, thereby, inhibits p53-dependent IGFBP-3 expression and presumably suppresses IGFBP-3-induced apoptosis.	('suppresses', 'NegReg', (169, 179))	('p53', 'Gene', '7157', (41, 44))	('DeltaNp63alpha', 'Var', (16, 30))	('expression', 'MPA', (143, 153))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('IGFBP-3', 'Gene', (135, 142))	('IGFBP-3', 'Gene', (84, 91))	('inhibits', 'NegReg', (112, 120))	('p53', 'Gene', (41, 44))
152270	32443727	Humanin is a mitochondrial-derived peptide that inhibits neuronal cell death induced by mutant genes in Alzheimer's disease.	('Human', 'Species', '9606', (0, 5))	('death', 'Disease', 'MESH:D003643', (71, 76))	('death', 'Disease', (71, 76))	('inhibits', 'NegReg', (48, 56))	('mutant genes', 'Var', (88, 100))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (104, 123))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (104, 123))	("Alzheimer's disease", 'Disease', (104, 123))
152285	32443727	On the contrary, IGFBP-3 has been shown to enhance the survival of cells subjected to glucose starvation and hypoxia by inducing autophagy in a GRP78-dependent manner in human breast cancer cells, which suggests that IGFBP-3 may play a key role in mediating an autophagic survival response.	('GRP78', 'Gene', (144, 149))	('inducing', 'Reg', (120, 128))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('survival', 'CPA', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('autophagy', 'CPA', (129, 138))	('IGFBP-3', 'Var', (17, 24))	('human', 'Species', '9606', (170, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('GRP78', 'Gene', '3309', (144, 149))	('enhance', 'PosReg', (43, 50))
152292	32443727	However, recent studies also showed that IGFBP-3 mutants that failed to translocate to the nucleus and lost binding ability to RXR-alpha, still induced apoptosis in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('IGFBP-3', 'Gene', (41, 48))	('mutants', 'Var', (49, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('binding', 'Interaction', (108, 115))	('RXR-alpha', 'Gene', '6256', (127, 136))	('induced', 'Reg', (144, 151))	('apoptosis', 'CPA', (152, 161))	('RXR-alpha', 'Gene', (127, 136))
152306	32443727	Additionally, IGFBP-3R activates caspase-8-induced apoptosis in unconventional ways: (1) IGFBP-3R and inactive procaspase-8 is pre-complexed at the resting stage, and IGFBP-3 binding to IGFBP-3R releases procaspase-8, and, thereby, activates caspase-8-dependent apoptosis, and (2) IGFBP-3R complexes with procasepase-8 without involvement of a typical death domain (DD) sequence.	('binding', 'Interaction', (175, 182))	('releases', 'PosReg', (195, 203))	('caspase-8', 'Gene', (33, 42))	('caspase-8', 'Gene', (114, 123))	('activates', 'PosReg', (232, 241))	('caspase-8', 'Gene', (207, 216))	('caspase-8', 'Gene', '841', (207, 216))	('IGFBP-3', 'Var', (167, 174))	('caspase-8', 'Gene', '841', (242, 251))	('caspase-8', 'Gene', (242, 251))	('caspase-8', 'Gene', '841', (114, 123))	('caspase-8', 'Gene', '841', (33, 42))	('death', 'Disease', 'MESH:D003643', (352, 357))	('death', 'Disease', (352, 357))
152317	32443727	This inhibitory action of IGFBP-3 was IGF/IGF-IR-independent since the IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect.	('IGF-IR', 'Gene', (42, 48))	('IGFBP-3', 'Gene', (71, 78))	('mutant', 'Var', (79, 85))	('IGF-IR', 'Gene', '3480', (42, 48))
152348	32443727	Survival in pan-kidney cohort (KICH+KIRC+KIRP), lower grade glioma, mesothelioma, colorectal adenocarcinoma was similarly affected by IGFBP-3 to a lesser extent (FDR = 1.74 10-6 (HR = 2.73), 1.25 10-5 (HR = 2.36), 1.22 10-3 (HR = 2.98), 3.87 10-3 (HR = 2.20), respectively) (Figure 6B,C).	('mesothelioma', 'Disease', (68, 80))	('colorectal adenocarcinoma', 'Disease', (82, 107))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (82, 107))	('KICH+KIRC+KIRP', 'Disease', 'None', (31, 45))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('affected', 'Reg', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('IGFBP-3', 'Var', (134, 141))	('glioma', 'Disease', (60, 66))	('KICH+KIRC+KIRP', 'Disease', (31, 45))
152351	32443727	Of note, the observed dichotomy of IGFBP-3 expression and patients' survival in various cancers may be attributed to other factors such as IGF-1/IGF-2 expression, IGFBP-3 polymorphism status, tumor suppressor p53 family status, tumor metabolic characteristics, and others.	('IGFBP-3', 'Gene', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('polymorphism', 'Var', (171, 183))	('IGF-1', 'Gene', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cancers', 'Disease', (88, 95))	('IGF-1', 'Gene', '3479', (139, 144))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patients', 'Species', '9606', (58, 66))	('p53', 'Gene', '7157', (209, 212))	('IGF-2', 'Gene', (145, 150))	('IGFBP-3', 'Gene', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('IGF-2', 'Gene', '3481', (145, 150))	('tumor', 'Disease', (228, 233))	('p53', 'Gene', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
152366	32443727	Similar results were observed for clinical subgroups in mesothelioma, the pan-kidney cohort, rectum adenocarcinoma, colorectal adenocarcinoma, and colon adenocarcinoma cancers, where low expression of IGFBP-3 was similarly associated with better survival outcome.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('colon adenocarcinoma cancers', 'Disease', 'MESH:D015179', (147, 175))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('rectum adenocarcinoma', 'Disease', (93, 114))	('associated', 'Reg', (223, 233))	('IGFBP-3', 'Gene', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (93, 114))	('mesothelioma', 'Disease', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('low expression', 'Var', (183, 197))	('colon adenocarcinoma cancers', 'Disease', (147, 175))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
152367	32443727	These results confirm previous observations that the expression of IGFBP-3 may affect survival in glioma, mesothelioma, kidney, and colorectal cancers.	('affect', 'Reg', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mesothelioma', 'Disease', (106, 118))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('expression', 'Var', (53, 63))	('kidney', 'Disease', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('colorectal cancers', 'Disease', 'MESH:D015179', (132, 150))	('IGFBP-3', 'Gene', (67, 74))	('survival', 'CPA', (86, 94))	('glioma', 'Disease', (98, 104))	('colorectal cancers', 'Disease', (132, 150))
152368	32443727	Further analyses of the effect of IGFBP-3 and TMEM219 expression in specific clinical subgroups revealed that kidney renal papillary cell carcinoma is the only cancer where the expression of both IGFBP-3 and TMEM219 is marginally associated with survival in "race-black or the African-American" subgroup.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (110, 147))	('cancer', 'Disease', (160, 166))	('associated', 'Reg', (230, 240))	('expression', 'Var', (177, 187))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (117, 147))	('TMEM219', 'Gene', '124446', (46, 53))	('TMEM219', 'Gene', '124446', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', (110, 147))	('IGFBP-3', 'Gene', (196, 203))	('TMEM219', 'Gene', (46, 53))	('TMEM219', 'Gene', (208, 215))
152375	32443727	Of note were race-specific survival effects with high expression of IGFBP-3 being beneficial in the "race-black or African-American" subgroup (FDR = 2.01 10-1 (HR = 0.42), Figure 10E) and TMEM219 high expression being beneficial in the "race-Asian" subgroup (FDR = 1.16 10-1 (HR = 0.00), Figure 10D).	('TMEM219', 'Gene', (188, 195))	('high expression', 'Var', (49, 64))	('TMEM219', 'Gene', '124446', (188, 195))	('beneficial', 'PosReg', (82, 92))	('IGFBP-3', 'Gene', (68, 75))
152376	32443727	Confirming our previous observations, the survival benefits of IGFBP-3 expression in breast cancer were consistently associated with high IGFBP-3 expression, while the effect of TMEM219 was more diverse and subgroup-specific.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('IGFBP-3', 'Gene', (63, 70))	('TMEM219', 'Gene', (178, 185))	('breast cancer', 'Disease', (85, 98))	('high', 'Var', (133, 137))	('IGFBP-3', 'Gene', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TMEM219', 'Gene', '124446', (178, 185))	('expression', 'MPA', (146, 156))	('benefits', 'PosReg', (51, 59))	('high IGFBP', 'Phenotype', 'HP:0030269', (133, 143))
152382	32443727	Given the fact that IGFBP-3/IGFBP-3R (TMEM219) axis is impaired and shown to have great impact on the survival outcome in specific cancers, IGFBP-3 and TMEM219 may serve as new diagnostic and prognostic biomarkers in specific cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('impact', 'Reg', (88, 94))	('TMEM219', 'Gene', '124446', (38, 45))	('cancers', 'Disease', (131, 138))	('TMEM219', 'Gene', '124446', (152, 159))	('TMEM219', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('IGFBP-3', 'Var', (140, 147))	('IGFBP-3/IGFBP-3R', 'Gene', (20, 36))	('TMEM219', 'Gene', (152, 159))	('impaired', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
152392	28954413	Owing to the widespread activation of this pathway in numerous neoplasms, MEK inhibitors have been in the process of development and study as a type of monotherapy or combination therapy with other targeted and cytotoxic drugs in a variety of clinical situations.	('numerous neoplasms', 'Disease', 'MESH:D009369', (54, 72))	('inhibitors', 'Var', (78, 88))	('neoplasms', 'Phenotype', 'HP:0002664', (63, 72))	('numerous neoplasms', 'Disease', (54, 72))	('activation', 'PosReg', (24, 34))	('MEK', 'Gene', (74, 77))
152405	28954413	Similar findings were observed in an A549 (KRAS (proto-oncogene corresponding to the oncogene first identified in Kirsten rat sarcoma virus) mutant cell line) xenograft model with tumor growth inhibition of 92% and 87% at 5.0 mg/kg and 2.5 mg/kg respectively, with inhibition to a lesser degree with a lower dose.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('mutant', 'Var', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('KRAS', 'Gene', (43, 47))	('A549', 'CellLine', 'CVCL:0023', (37, 41))	('rat sarcoma virus', 'Species', '11848', (122, 139))	('KRAS', 'Gene', '3845', (43, 47))
152407	28954413	In a global multi-center, randomized, open-label and controlled trial, 322 melanoma patients with the BRAF V600E or V600K-mutant were allocated with the ratio of 2:1 into either the trametinib group or conventional chemotherapy group (dacarbazine or paclitaxel), respectively.	('patients', 'Species', '9606', (84, 92))	('BRAF', 'Gene', '673', (102, 106))	('dacarbazine', 'Chemical', 'MESH:D003606', (235, 246))	('trametinib', 'Chemical', 'MESH:C560077', (182, 192))	('BRAF', 'Gene', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('V600K-mutant', 'Var', (116, 128))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('paclitaxel', 'Chemical', 'MESH:D017239', (250, 260))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('V600K', 'Mutation', 'rs121913227', (116, 121))
152411	28954413	The FDA first approved the combination of trametinib and dabrafenib for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations in January 2014, based on the results of median PFS extended from 8.8 months to 11.0 months when compared with dabrafenib monotherapy in a multi-center phase 3 trial.	('V600E', 'Mutation', 'rs113488022', (132, 137))	('V600K', 'Var', (141, 146))	('BRAF', 'Gene', '673', (127, 131))	('trametinib', 'Chemical', 'MESH:C560077', (42, 52))	('dabrafenib', 'Chemical', 'MESH:C561627', (57, 67))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BRAF', 'Gene', (127, 131))	('melanoma', 'Disease', (113, 121))	('V600K', 'Mutation', 'rs121913227', (141, 146))	('V600E', 'Var', (132, 137))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('dabrafenib', 'Chemical', 'MESH:C561627', (268, 278))	('patients', 'Species', '9606', (72, 80))
152413	28954413	MEK and BRAF inhibitors hence presented a new treatment method for metastatic melanoma.	('BRAF', 'Gene', '673', (8, 12))	('MEK', 'Gene', (0, 3))	('inhibitors', 'Var', (13, 23))	('BRAF', 'Gene', (8, 12))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))
152429	28954413	The compound was awarded the status of orphan drug by the FDA in 2014 for malignant melanoma with the BRAFV600 mutation, and was then approved for combination treatment with vemurafenib for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation in November 2015.	('vemurafenib', 'Chemical', 'MESH:D000077484', (174, 185))	('malignant melanoma', 'Disease', 'MESH:D008545', (74, 92))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('V600K', 'Mutation', 'rs121913227', (247, 252))	('malignant melanoma', 'Disease', (74, 92))	('BRAF', 'Gene', '673', (102, 106))	('V600E', 'Mutation', 'rs113488022', (238, 243))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))	('melanoma', 'Disease', (84, 92))	('BRAF', 'Gene', (102, 106))	('BRAF', 'Gene', (233, 237))	('BRAF', 'Gene', '673', (233, 237))	('V600K', 'Var', (247, 252))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
152433	28954413	Preclinical studies demonstrated that this agent was effective in inhibiting the growth of many tumor cells bearing a BRAF mutation.	('BRAF', 'Gene', '673', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutation', 'Var', (123, 131))	('BRAF', 'Gene', (118, 122))	('tumor', 'Disease', (96, 101))	('inhibiting', 'NegReg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('growth', 'CPA', (81, 87))
152434	28954413	In preclinical studies, cobimetinib was associated with sustained ERK/MAPK inhibition in tumor tissues, with minimal drug exposure in the brain.	('cobimetinib', 'Var', (24, 35))	('cobimetinib', 'Chemical', 'MESH:C574276', (24, 35))	('inhibition', 'NegReg', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('ERK', 'Gene', '5594', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('ERK', 'Gene', (66, 69))
152437	28954413	For example, there is the combination of cobimetinib with GDC-0941 (a PI3K inhibitor) or GDC-0994 (a Erk1/2 inhibitor) for metastatic solid tumors (ClinicalTrials.gov number, NCT02457793) and the combination with idasanutlin (p53-MDM2 inhibitor) and venetoclax (BCL-2 inhibitor) for the treatment of leukemia.	('venetoclax', 'Chemical', 'MESH:C579720', (250, 260))	('solid tumors', 'Disease', (134, 146))	('Erk1/2', 'Gene', '5595;5594', (101, 107))	('GDC-0994', 'Var', (89, 97))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('BCL-2', 'Gene', '596', (262, 267))	('leukemia', 'Phenotype', 'HP:0001909', (300, 308))	('BCL-2', 'Gene', (262, 267))	('solid tumors', 'Disease', 'MESH:D009369', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cobimetinib', 'Chemical', 'MESH:C574276', (41, 52))	('GDC-0941', 'Chemical', 'MESH:C532162', (58, 66))	('idasanutlin', 'Chemical', 'MESH:C586849', (213, 224))	('GDC-0941', 'Gene', (58, 66))	('GDC-0994', 'Chemical', '-', (89, 97))	('leukemia', 'Disease', (300, 308))	('MDM2', 'Gene', (230, 234))	('leukemia', 'Disease', 'MESH:D007938', (300, 308))	('Erk1/2', 'Gene', (101, 107))	('p53', 'Gene', '7157', (226, 229))	('MDM2', 'Gene', '4193', (230, 234))	('p53', 'Gene', (226, 229))
152449	28954413	The optimization of the hydroxamate side chain of CI-1040 for the improvement of solubility and exposure with oral doses resulted in the discovery of the clinical candidate PD-0325901 by Pfizer/Warner-Lambert.	('solubility', 'MPA', (81, 91))	('hydroxamate', 'Chemical', '-', (24, 35))	('CI-1040', 'Gene', (50, 57))	('PD-0325901', 'Chemical', '-', (173, 183))	('PD-0325901', 'Var', (173, 183))	('CI-1040', 'Chemical', '-', (50, 57))
152451	28954413	Inhibition of pMAPK in liver was generally comparable between the routes of administration, whereas inhibition of pMAPK in lung occurred for a longer duration following IV administration of PD-0325901, possibly due to higher PD-0325901 plasma maximum concentration (Cmax).	('PD-0325901', 'Chemical', '-', (225, 235))	('higher', 'PosReg', (218, 224))	('pMAPK', 'Gene', (114, 119))	('PD-0325901', 'Var', (190, 200))	('PD-0325901', 'Chemical', '-', (190, 200))
152452	28954413	PD-0325901 failed in its phase II clinical trials for the treatment of KRAS mutant non-small cell lung cancer by not meeting its primary efficacy end-point (ClinicalTrials.gov number, NCT00174369).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('mutant', 'Var', (76, 82))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('PD-0325901', 'Chemical', '-', (0, 10))	('KRAS', 'Gene', (71, 75))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (83, 109))	('KRAS', 'Gene', '3845', (71, 75))	('non-small cell lung cancer', 'Disease', (83, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))
152470	28954413	While markedly improved PFS was observed with the addition of selumetinib to the therapeutic regimen, no overall survival benefit was demonstrated.	('PFS', 'Disease', (24, 27))	('selumetinib', 'Chemical', 'MESH:C517975', (62, 73))	('improved', 'PosReg', (15, 23))	('addition', 'Var', (50, 58))
152489	28954413	AZD8330 is an orally active, selective MEK inhibitor with potential antineoplastic activity.	('AZD8330', 'Var', (0, 7))	('AZD8330', 'Chemical', 'MESH:C581956', (0, 7))	('MEK', 'Protein', (39, 42))	('antineoplastic activity', 'CPA', (68, 91))
152497	28954413	AZD8330 demonstrated a manageable toxicity profile with fewer class-effect AEs compared with other MEK inhibitors.	('AZD8330', 'Var', (0, 7))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('toxicity', 'Disease', (34, 42))	('AZD8330', 'Chemical', 'MESH:C581956', (0, 7))
152505	28954413	GDC-0623 has broad potency in cell-based assays, particularly in both KRAS and BRAF mutant cancer cell lines, with corresponding efficacy in xenograft tumor models.	('xenograft tumor', 'Disease', 'MESH:D009369', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('KRAS', 'Gene', (70, 74))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('KRAS', 'Gene', '3845', (70, 74))	('mutant', 'Var', (84, 90))	('BRAF', 'Gene', '673', (79, 83))	('GDC-0623', 'Chemical', 'MESH:C000622437', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('xenograft tumor', 'Disease', (141, 156))	('GDC-0623', 'Gene', (0, 8))	('BRAF', 'Gene', (79, 83))
152522	28954413	RO4987655 is an orally active small molecule, targeting MEK1 with potential antineoplastic activity.	('antineoplastic activity', 'CPA', (76, 99))	('RO4987655', 'Var', (0, 9))	('MEK1', 'Gene', (56, 60))	('RO4987655', 'Chemical', 'MESH:C559138', (0, 9))
152523	28954413	RO4987655 exhibited slow dissociation from the MEK1 enzyme, remarkable antitumor efficacy both as monotherapy and combination therapy in vivo, desirable metabolic stability, and insufficient MEK inhibition in mouse brain, implying few central nervous system (CNS)-related side effects in humans.	('MEK', 'Enzyme', (191, 194))	('insufficient', 'Disease', (178, 190))	('insufficient', 'Disease', 'MESH:D000309', (178, 190))	('RO4987655', 'Var', (0, 9))	('RO4987655', 'Chemical', 'MESH:C559138', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('humans', 'Species', '9606', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('mouse', 'Species', '10090', (209, 214))
152525	28954413	RO5126766, known as CH5126766, is a dual Raf/MEK inhibitor specifically for the kinase activities of Raf and MEK, resulting in the blockage of target gene transcription that promotes malignant transformation of cells.	('Raf', 'Gene', '22882', (41, 44))	('blockage', 'NegReg', (131, 139))	('promotes', 'PosReg', (174, 182))	('RO5126766', 'Chemical', 'MESH:C577924', (0, 9))	('Raf', 'Gene', (41, 44))	('malignant transformation of cells', 'CPA', (183, 216))	('Raf', 'Gene', '22882', (101, 104))	('RO5126766', 'Var', (0, 9))	('Raf', 'Gene', (101, 104))
152526	28954413	RO5126766 specifically inhibits the kinase activities of Raf and MEK, resulting in the inhibition of target gene transcription that promotes malignant transformation of cells.	('inhibition', 'NegReg', (87, 97))	('kinase activities', 'MPA', (36, 53))	('Raf', 'Gene', '22882', (57, 60))	('target gene transcription', 'MPA', (101, 126))	('RO5126766', 'Chemical', 'MESH:C577924', (0, 9))	('MEK', 'Gene', (65, 68))	('Raf', 'Gene', (57, 60))	('malignant transformation of cells', 'CPA', (141, 174))	('promotes', 'PosReg', (132, 140))	('inhibits', 'NegReg', (23, 31))	('RO5126766', 'Var', (0, 9))
152527	28954413	RO5126766, bearing a sulfamide moiety instead of aniline in coumarin, was identified as a clinical compound with enhanced inhibitory activity, satisfactory PK/PD profiles, and manageable toxicity.	('inhibitory activity', 'MPA', (122, 141))	('sulfamide', 'Chemical', '-', (21, 30))	('RO5126766', 'Chemical', 'MESH:C577924', (0, 9))	('RO5126766', 'Var', (0, 9))	('aniline', 'Chemical', 'MESH:C023650', (49, 56))	('toxicity', 'Disease', 'MESH:D064420', (187, 195))	('coumarin', 'Chemical', 'MESH:C030123', (60, 68))	('toxicity', 'Disease', (187, 195))	('enhanced', 'PosReg', (113, 121))
152535	28954413	HL-085 is effective in inhibiting tumor proliferation in other tumor cells as well.	('tumor', 'Disease', (63, 68))	('HL-085', 'Var', (0, 6))	('tumor', 'Disease', (34, 39))	('inhibiting', 'NegReg', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('HL-085', 'Chemical', '-', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
152538	28954413	CInQ-03 has a distinct chemical structure compared with current MEK inhibitors, such as PD318088, PD184352, PD0325901, and selumetinib.	('PD184352', 'Chemical', 'MESH:C120227', (98, 106))	('PD318088', 'Chemical', '-', (88, 96))	('PD184352', 'Var', (98, 106))	('PD0325901', 'Var', (108, 117))	('selumetinib', 'Chemical', 'MESH:C517975', (123, 134))	('CInQ-03', 'Var', (0, 7))	('CInQ-03', 'Chemical', '-', (0, 7))	('PD0325901', 'Chemical', 'MESH:C506614', (108, 117))
152541	28954413	Furthermore, CInQ-03 could decrease phosphorylation level of ERKs in a cell-based assay, which was highly consistent with the results in vivo.	('ERKs', 'Gene', '5595;5594;5595', (61, 65))	('decrease', 'NegReg', (27, 35))	('ERKs', 'Gene', (61, 65))	('CInQ-03', 'Var', (13, 20))	('CInQ-03', 'Chemical', '-', (13, 20))	('phosphorylation level', 'MPA', (36, 57))
152544	28954413	Structural and functional analysis illustrates that G-573 could form a strong hydrogen bond with MEK kinase.	('hydrogen bond', 'Interaction', (78, 91))	('hydrogen', 'Chemical', 'MESH:D006859', (78, 86))	('G-573', 'Chemical', '-', (52, 57))	('G-573', 'Var', (52, 57))	('MEK', 'Enzyme', (97, 100))
152545	28954413	The IC50 value for pERK inhibition in HCT116 tumor by G-573 was estimated to be 0.406 muM, and ED50 values in HCT116 and H2122 mouse xenograft models were estimated to be 4.6 and 1.9 mg/kg/day, respectively.	('HCT116', 'Gene', (38, 44))	('mouse', 'Species', '10090', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('muM', 'Gene', '56925', (86, 89))	('G-573', 'Chemical', '-', (54, 59))	('G-573', 'Var', (54, 59))	('tumor', 'Disease', (45, 50))	('HCT116', 'CellLine', 'CVCL:0291', (38, 44))	('muM', 'Gene', (86, 89))	('H2122', 'CellLine', 'CVCL:1531', (121, 126))	('inhibition', 'NegReg', (24, 34))	('ERK', 'Gene', '5594', (20, 23))	('HCT116', 'CellLine', 'CVCL:0291', (110, 116))	('ERK', 'Gene', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
152546	28954413	PD184161 is an orally-active MEK inhibitor which could inhibit MEK activity more effectively (IC50 = 10-100 nM) in a time- and concentration-dependent manner than PD098059 or U0126.	('U0126', 'Chemical', 'MESH:C113580', (175, 180))	('PD184161', 'Var', (0, 8))	('PD098059', 'Chemical', 'MESH:C093973', (163, 171))	('activity', 'MPA', (67, 75))	('MEK', 'Enzyme', (63, 66))	('PD184161', 'Chemical', 'MESH:C488185', (0, 8))	('inhibit', 'NegReg', (55, 62))
152547	28954413	PD184161, a structurally related analog of CI-1040 but distinct from PD098059 and U0126, joins the mechanistic class of agents that inhibit the downstream phosphorylation of ERK through their direct effects on MEK.	('inhibit', 'NegReg', (132, 139))	('PD184161', 'Var', (0, 8))	('CI-1040', 'Chemical', '-', (43, 50))	('effects', 'Reg', (199, 206))	('MEK', 'Protein', (210, 213))	('downstream phosphorylation', 'MPA', (144, 170))	('PD098059', 'Chemical', 'MESH:C093973', (69, 77))	('ERK', 'Gene', '5594', (174, 177))	('PD184161', 'Chemical', 'MESH:C488185', (0, 8))	('ERK', 'Gene', (174, 177))	('U0126', 'Chemical', 'MESH:C113580', (82, 87))
152548	28954413	Unlike PD098059 and U0126, PD184161 has the obvious advantages of solubility and oral bioavailability.	('PD184161', 'Var', (27, 35))	('PD098059', 'Chemical', 'MESH:C093973', (7, 15))	('solubility', 'MPA', (66, 76))	('PD184161', 'Chemical', 'MESH:C488185', (27, 35))	('U0126', 'Chemical', 'MESH:C113580', (20, 25))	('advantages', 'PosReg', (52, 62))	('oral bioavailability', 'MPA', (81, 101))
152550	28954413	PD184161 is unable to suppress MEK activity in HCC xenografts in the long term.	('PD184161', 'Var', (0, 8))	('HCC', 'Phenotype', 'HP:0001402', (47, 50))	('MEK', 'Protein', (31, 34))	('PD184161', 'Chemical', 'MESH:C488185', (0, 8))
152551	28954413	PD318088, an analog of CI-1040 with a biarylamine structure, is a novel non-ATP-competitive MEK1 inhibitor.	('CI-1040', 'Chemical', '-', (23, 30))	('biarylamine', 'Chemical', '-', (38, 49))	('ATP', 'Gene', (76, 79))	('ATP', 'Gene', '51761', (76, 79))	('PD318088', 'Chemical', '-', (0, 8))	('PD318088', 'Var', (0, 8))
152552	28954413	The compound-binding site of PD318088 is adjacent to the ATP binding site.	('ATP', 'Gene', (57, 60))	('ATP', 'Gene', '51761', (57, 60))	('PD318088', 'Chemical', '-', (29, 37))	('PD318088', 'Var', (29, 37))
152553	28954413	Its potency in inhibiting MEK1 activation is not affected by ATP concentration, suggesting that PD318088 is not competitive with ATP.	('ATP', 'Gene', (61, 64))	('ATP', 'Gene', '51761', (61, 64))	('MEK1', 'Protein', (26, 30))	('inhibiting', 'NegReg', (15, 25))	('PD318088', 'Chemical', '-', (96, 104))	('PD318088', 'Var', (96, 104))	('ATP', 'Gene', '51761', (129, 132))	('ATP', 'Gene', (129, 132))
152554	28954413	PD98059 is a potent and selective non-ATP-competitive MEK1 inhibitor.	('MEK1', 'Gene', (54, 58))	('PD98059', 'Var', (0, 7))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('ATP', 'Gene', (38, 41))	('ATP', 'Gene', '51761', (38, 41))
152556	28954413	PD98059 can interact with GST-MEK1 or partially activate MEK, but does not inhibit the MAPK homologues JNK and P38 (D.R.	('P38', 'Gene', '5594', (111, 114))	('PD98059', 'Var', (0, 7))	('activate', 'PosReg', (48, 56))	('GST-MEK1', 'Protein', (26, 34))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('MEK', 'Pathway', (57, 60))	('interact', 'Interaction', (12, 20))	('P38', 'Gene', (111, 114))
152557	28954413	In addition, PD98059 can highly inhibit MEK in a selective manner, but not the other kinases such as Raf kinase, cAMP (cyclic Adenosine monophosphate)-dependent kinase, protein kinase C, v-Src (a gene found in Rous sarcoma virus), epidermal growth factor (EGF) receptor kinase, and phosphatidyl inositol kinase 3.	('MEK', 'Enzyme', (40, 43))	('inhibit', 'NegReg', (32, 39))	('PD98059', 'Var', (13, 20))	('cyclic Adenosine monophosphate', 'Chemical', 'MESH:D000242', (119, 149))	('cAMP', 'Chemical', 'MESH:D000242', (113, 117))	('PD98059', 'Chemical', 'MESH:C093973', (13, 20))	('Raf', 'Gene', '22882', (101, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('Raf', 'Gene', (101, 104))
152558	28954413	RO5068760, a substituted hydantoin, is a potent, highly selective, non-ATP-competitive MEK1/2 inhibitor.	('hydantoin', 'Chemical', 'MESH:D006827', (25, 34))	('MEK1/2', 'Gene', '5604;5605', (87, 93))	('RO5068760', 'Var', (0, 9))	('MEK1/2', 'Gene', (87, 93))	('RO5068760', 'Chemical', 'MESH:C547875', (0, 9))	('ATP', 'Gene', '51761', (71, 74))	('ATP', 'Gene', (71, 74))
152559	28954413	In vitro, RO5068760 could inhibit MEK1 kinase activity potently with an IC50 value of 0.025 +- 0.012 mumol/L in Raf/MEK/ERK cascade assay.	('Raf', 'Gene', (112, 115))	('inhibit', 'NegReg', (26, 33))	('activity', 'MPA', (46, 54))	('ERK', 'Gene', '5594', (120, 123))	('RO5068760', 'Var', (10, 19))	('RO5068760', 'Chemical', 'MESH:C547875', (10, 19))	('Raf', 'Gene', '22882', (112, 115))	('ERK', 'Gene', (120, 123))	('MEK1', 'Enzyme', (34, 38))
152561	28954413	RO5068760 shows superior efficacy in tumors harboring the BRAF V600E mutation.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('V600E', 'Var', (63, 68))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('RO5068760', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('RO5068760', 'Chemical', 'MESH:C547875', (0, 9))	('BRAF', 'Gene', '673', (58, 62))	('tumors', 'Disease', (37, 43))	('BRAF', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
152563	28954413	U0126 is a potent and selective non-competitive MEK inhibitor, inhibiting MEK1 and MEK2 (IC50 values of 70 nM and 60 nM, respectively).	('MEK1', 'Gene', (74, 78))	('U0126', 'Var', (0, 5))	('MEK2', 'Gene', (83, 87))	('MEK2', 'Gene', '5605', (83, 87))	('inhibiting', 'NegReg', (63, 73))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))
152565	28954413	Surprisingly, U0126 also causes profound depletion of ATP in glucose-deprived cells, leading to death by necrosis.	('ATP', 'Gene', (54, 57))	('U0126', 'Chemical', 'MESH:C113580', (14, 19))	('ATP', 'Gene', '51761', (54, 57))	('death by necrosis', 'Disease', 'MESH:D003643', (96, 113))	('U0126', 'Var', (14, 19))	('glucose', 'Chemical', 'MESH:D005947', (61, 68))	('death by necrosis', 'Disease', (96, 113))	('depletion', 'MPA', (41, 50))
152566	28954413	It was reported and demonstrated that U0126 could inhibit the cellular target MEK, and have an antiviral potential not only in cell culture in vitro, but also in the mouse mode in vivo.	('inhibit', 'NegReg', (50, 57))	('mouse', 'Species', '10090', (166, 171))	('antiviral', 'MPA', (95, 104))	('U0126', 'Var', (38, 43))	('MEK', 'Protein', (78, 81))	('U0126', 'Chemical', 'MESH:C113580', (38, 43))
152570	28954413	In vivo, the study showed that the combination of SL327 with sunitinib malate induced significant additive suppression of doxorubicin-resistant anaplastic thyroid carcinoma (ATC) tumor growth.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('thyroid carcinoma', 'Disease', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('sunitinib malate', 'Chemical', 'MESH:D000077210', (61, 77))	('suppression', 'NegReg', (107, 118))	('doxorubicin-resistant', 'MPA', (122, 143))	('ATC', 'Phenotype', 'HP:0011779', (174, 177))	('doxorubicin', 'Chemical', 'MESH:D004317', (122, 133))	('SL327', 'Var', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (144, 172))	('combination', 'Interaction', (35, 46))	('SL327', 'Chemical', 'MESH:C424127', (50, 55))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('tumor', 'Disease', (179, 184))
152579	28954413	Novel small molecular inhibitors are expected to become the new breakthrough in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))	('small molecular', 'Var', (6, 21))
152590	28053498	Gliomas arise due to an accumulation of genetic and chromosomal alterations in non-neuronal glial cells, which provide a variety of support functions for the neurons in the CNS.	('Gliomas', 'Disease', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('chromosomal alterations', 'Var', (52, 75))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))
152618	28053498	Similar to the previous two contrast agents, mTHPC extravasation is observed with disruption of the BBB, although it does appear to localize favorably in tumor tissues.	('BBB', 'Protein', (100, 103))	('disruption', 'Var', (82, 92))	('mTHPC extravasation', 'MPA', (45, 64))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mTHPC', 'Chemical', 'MESH:C072269', (45, 50))	('tumor', 'Disease', (154, 159))
152624	28053498	Subsequently, their randomized phase-III trial showed that ALA mediated FGR resulted in significantly more complete resections (65% versus 35%), which increased the mean survival time by 4.9 months with respect to patients not receiving FGR.	('ALA', 'Chemical', 'MESH:C000614854', (59, 62))	('increased', 'PosReg', (151, 160))	('patients', 'Species', '9606', (214, 222))	('FGR', 'Var', (72, 75))
152662	28053498	Similar to the earlier study, two wavelength ranges were found important in distinguishing gliomas from normal brain tissue: 370-400 nm (the region of main peak emission for HGGN and NWM) and 440-480 nm (the region of main peak emission for NC as well as LGG and HGG).	('440-480 nm', 'Var', (192, 202))	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
152733	26228228	The MRI signals of the tumor were hypo- (n = 20), iso- (n = 2), or hyper-intense (n = 5) on T1-weighted images and were hyperintense (n = 27) on T2-weighted images.	('iso-', 'Var', (50, 54))	('hyper-intense', 'MPA', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
152800	31795520	The results showed that patients with deep white matter tracts and ependymal invasion on imaging (defined Class A) had a significant decrease in overall survival, whereas, in patients with the absence of such invasive imaging features (defined Class B), happened otherwise.	('decrease', 'NegReg', (133, 141))	('deep', 'Var', (38, 42))	('overall survival', 'MPA', (145, 161))	('ependymal invasion', 'CPA', (67, 85))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (24, 32))
152805	31795520	In more detail, these imaging features were associated with the IDH-1p/19q subtype, RNASeq cluster, copy number cluster, and the cluster of clusters subtype (for details on these clusters, see Brat et al.).	('associated', 'Reg', (44, 54))	('IDH-1p', 'Gene', '3417', (64, 70))	('rat', 'Species', '10116', (194, 197))	('RNASeq cluster', 'Disease', (84, 98))	('copy number cluster', 'Var', (100, 119))	('IDH-1p', 'Gene', (64, 70))
152814	31795520	Involved miRNA (miR-29b-3p, miR495-3p, miR30c/30d, miR-26a-5p, miR296-5p, miR128-3p, miR144-3p, and miR214-3p) and genes (PTEN, COL15A1, SPARC, ANPEP, CBFB, STRN, and TMED10) unveiled several networks of tumorogenesis interest, such as tight junction signaling and p53 signaling.	('p53', 'Gene', (265, 268))	('miR296', 'Gene', (63, 69))	('miR30c', 'Gene', '407031', (39, 45))	('miR30c', 'Gene', (39, 45))	('CBFB', 'Gene', '865', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SPARC', 'Gene', (137, 142))	('STRN', 'Gene', '6801', (157, 161))	('miR214-3p', 'Var', (100, 109))	('miR-29b-3p', 'Var', (16, 26))	('ANPEP', 'Gene', (144, 149))	('PTEN', 'Gene', (122, 126))	('miR128-3p', 'Var', (74, 83))	('COL15A1', 'Gene', (128, 135))	('tumorogenesis', 'Disease', (204, 217))	('SPARC', 'Gene', '6678', (137, 142))	('tumorogenesis', 'Disease', 'MESH:D002471', (204, 217))	('miR495-3p', 'Var', (28, 37))	('ANPEP', 'Gene', '290', (144, 149))	('miR296', 'Gene', '407022', (63, 69))	('p53', 'Gene', '7157', (265, 268))	('CBFB', 'Gene', (151, 155))	('tight junction signaling', 'MPA', (236, 260))	('miR144-3p', 'Var', (85, 94))	('COL15A1', 'Gene', '1306', (128, 135))	('miR-26a-5p', 'Var', (51, 61))	('STRN', 'Gene', (157, 161))
152827	31795520	Integrating molecular data suggested the roles of several genes/miRNA regulating proliferation (PGC1alpha/miR-199a, miR-125, and miR-129) and invasion (PAR1, HOXC6 / miR-499, miR-146b).	('miR-146b', 'Gene', '574447', (175, 183))	('miR-125', 'Var', (116, 123))	('miR-499', 'Gene', '574501', (166, 173))	('rat', 'Species', '10116', (88, 91))	('PGC1alpha', 'Gene', '10891', (96, 105))	('invasion', 'CPA', (142, 150))	('PGC1alpha', 'Gene', (96, 105))	('miR-499', 'Gene', (166, 173))	('rat', 'Species', '10116', (5, 8))	('proliferation', 'CPA', (81, 94))	('miR-129', 'Var', (129, 136))	('miR-146b', 'Gene', (175, 183))	('PAR1', 'Var', (152, 156))
152845	31795520	also showed that there were weak correlations between imaging features and copy number variation, in particular, a weak association between CDKN2A deletion and necrosis, amplification of EGFR, and an increased percentage of contrast enhancement.	('necrosis', 'Disease', 'MESH:D009336', (160, 168))	('amplification', 'Var', (170, 183))	('increased', 'PosReg', (200, 209))	('CDKN2A', 'Gene', (140, 146))	('EGFR', 'Protein', (187, 191))	('necrosis', 'Disease', (160, 168))	('deletion', 'Var', (147, 155))	('CDKN2A', 'Gene', '1029', (140, 146))	('contrast enhancement', 'MPA', (224, 244))
152847	31795520	Some significative mutations were related to volumetric features: EGFR mutations displayed a significantly higher necrosis/contrast enhancing ratio and a significantly lower contrast-enhancing/tumor bulk ratio.	('necrosis', 'Disease', (114, 122))	('EGFR', 'Gene', (66, 70))	('lower', 'NegReg', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('rat', 'Species', '10116', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mutations', 'Var', (71, 80))	('necrosis', 'Disease', 'MESH:D009336', (114, 122))	('tumor', 'Disease', (193, 198))	('higher', 'PosReg', (107, 113))	('rat', 'Species', '10116', (142, 145))
152848	31795520	Furthermore, RB1 mutations tumors showed significantly smaller T2-FLAIR hyperintensity, and TP53 significantly predicted necrosis and tumor volumes by contrast-enhancing.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RB1', 'Gene', '5925', (13, 16))	('tumor', 'Disease', (27, 32))	('necrosis', 'Disease', (121, 129))	('tumors', 'Disease', (27, 33))	('predicted', 'Reg', (111, 120))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('smaller', 'NegReg', (55, 62))	('necrosis', 'Disease', 'MESH:D009336', (121, 129))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TP53', 'Gene', (92, 96))	('RB1', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (134, 139))	('T2-FLAIR hyperintensity', 'MPA', (63, 86))
152849	31795520	Additionally, NF1 mutation status was significantly predicted by contrast-enhancing volume and tumor bulk volume, whereas PDGFR-alpha was significantly predicted by T2-FLAIR hyperintensity/total tumor volume and tumor bulk/total tumor volume ratios.	('tumor', 'Disease', (195, 200))	('predicted', 'Reg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PDGFR-alpha', 'Gene', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NF1', 'Gene', '4763', (14, 17))	('predicted', 'Reg', (152, 161))	('mutation', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('NF1', 'Gene', (14, 17))	('rat', 'Species', '10116', (242, 245))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', (95, 100))	('PDGFR-alpha', 'Gene', '5156', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (212, 217))
152850	31795520	The features that were significantly associated with survival were the proportion of tumor contrast enhancement on MRI and HRAS copy number variation.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('associated', 'Reg', (37, 47))	('copy number variation', 'Var', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HRAS', 'Gene', (123, 127))
152851	31795520	In the same study, which included 45 patients, combining epidermal growth factor receptor (EGFR) alteration (mutation or amplification) with a relative cerebral blood volume of the non-enhancing region (rCBVNER), a significant association with OS (overall survival) was found, with worst survival in the high-rCBVNER wild-type EGFR group.	('alteration', 'Var', (97, 107))	('EGFR', 'Gene', (91, 95))	('rat', 'Species', '10116', (101, 104))	('patients', 'Species', '9606', (37, 45))	('epidermal growth factor receptor', 'Gene', '1956', (57, 89))	('high-rCBVNER', 'Var', (304, 316))	('epidermal growth factor receptor', 'Gene', (57, 89))
152888	31795520	found several quantitative MRI features (such as tumor size, shape, margin, and blood flow kinetics) associated with different molecular profiles, such as DNA mutation, miRNA expression, protein expression, pathway gene expression, and copy number variation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('miRNA expression', 'MPA', (169, 185))	('copy number variation', 'Var', (236, 257))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('protein expression', 'MPA', (187, 205))	('associated', 'Reg', (101, 111))	('DNA mutation', 'Disease', (155, 167))	('pathway', 'MPA', (207, 214))
152892	31795520	ccRCC is the most common subtype of renal cell carcinoma (RCC), and it is distinctly caused by a somatic mutation in the Von Hippel-Lindau (VHL) tumor suppressor gene, even if several other genes have been associated with the advanced form of the disease using whole-genome sequencing.	('renal cell carcinoma', 'Disease', (36, 56))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (121, 150))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('mutation in', 'Var', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (36, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('caused by', 'Reg', (85, 94))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
152895	31795520	In detail, mutations in two distinct genes were associated with radiomic features: in the BAP1 gene, associated with ill-defined tumor margins and with the presence of calcification, and in the MUC4 gene, associated with exophytic growth.	('mutations', 'Var', (11, 20))	('calcification', 'Disease', (168, 181))	('ill-defined tumor', 'Disease', (117, 134))	('associated', 'Reg', (48, 58))	('BAP1', 'Gene', '8314', (90, 94))	('MUC4', 'Gene', '4585', (194, 198))	('exophytic growth', 'Disease', (221, 237))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('BAP1', 'Gene', (90, 94))	('associated', 'Reg', (101, 111))	('associated', 'Reg', (205, 215))	('MUC4', 'Gene', (194, 198))	('ill-defined tumor', 'Disease', 'MESH:D002908', (117, 134))	('calcification', 'Disease', 'MESH:D002114', (168, 181))
152904	31795520	m1 tumors (defined by genes related to chromatin remodeling processes and a higher frequency of PBRM1 gene mutations) were found positively correlated with a well-defined margin.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PBRM1', 'Gene', (96, 101))	('PBRM1', 'Gene', '55193', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
152905	31795520	On the other hand, m3 tumors (defined by frequently deletion of CDKN2A and mutations in PTEN) were found negatively correlated with CT features that are considered indicators of the infiltrative/invasive phenotype (well-defined margin, renal vein invasion, and urinary collecting system invasion).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('collecting system', 'Phenotype', 'HP:0000081', (269, 286))	('renal vein invasion', 'CPA', (236, 255))	('CDKN2A', 'Gene', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PTEN', 'Gene', (88, 92))	('CDKN2A', 'Gene', '1029', (64, 70))	('rat', 'Species', '10116', (188, 191))	('mutations', 'Var', (75, 84))	('negatively', 'NegReg', (105, 115))	('tumors', 'Disease', (22, 28))	('deletion', 'Var', (52, 60))
152934	31795520	The images represented the association between imaging features (radiomic and/or radiological) and molecular 'omic signature, which could be gene expressions, mutations, clusters, or cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mutations', 'Var', (159, 168))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
152955	31371348	Here, we describe a missense DNMT3A p.P904S mutation in an IDH1-mutant glioblastoma.	('IDH1', 'Gene', '3417', (59, 63))	('p.P904S', 'Mutation', 'rs997533180', (36, 43))	('glioblastoma', 'Disease', (71, 83))	('p.P904S', 'Var', (36, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('IDH1', 'Gene', (59, 63))	('DNMT3A', 'Gene', (29, 35))	('DNMT3A', 'Gene', '1788', (29, 35))
152957	31371348	Our report suggests that elucidating epigenetic control is important to understanding glioblastoma biology and may likely unveil targets potentially important to glioblastoma treatment in an effort to improve survival.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('glioblastoma', 'Disease', (162, 174))	('epigenetic', 'Var', (37, 47))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
152960	31371348	For instance, IDH1 mutations and 1p19q loss are associated with oligodendroglial histology, whereas ATRX mutations correlate with astrocytic tumors.	('oligodendroglial histology', 'Disease', (64, 90))	('astrocytic tumors', 'Disease', 'MESH:D001254', (130, 147))	('1p19q', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('associated', 'Reg', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('ATRX', 'Gene', (100, 104))	('mutations', 'Var', (19, 28))	('loss', 'NegReg', (39, 43))	('ATRX', 'Gene', '546', (100, 104))	('astrocytic tumors', 'Disease', (130, 147))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', '3417', (14, 18))
152961	31371348	Primary GBMs are associated with loss of PTEN and CDKN2A and with EGFR amplifications, whereas secondary GBMs frequently carry IDH1 R132H mutations.	('amplifications', 'Var', (71, 85))	('CDKN2A', 'Gene', (50, 56))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('loss', 'NegReg', (33, 37))	('CDKN2A', 'Gene', '1029', (50, 56))	('IDH1', 'Gene', (127, 131))	('IDH1', 'Gene', '3417', (127, 131))	('PTEN', 'Gene', (41, 45))	('R132H', 'Mutation', 'rs121913500', (132, 137))	('PTEN', 'Gene', '5728', (41, 45))	('Primary GBMs', 'Disease', (0, 12))
152965	31371348	Herein, we describe a patient with an IDH1-, ATRX-, and TP53-mutant GBM, who also harbored a somatic mutation in the DNA methyltransferase 3 alpha (DNMT3A) gene, all of which were preserved during progression and recurrence.	('IDH1', 'Gene', '3417', (38, 42))	('DNMT3A', 'Gene', '1788', (148, 154))	('patient', 'Species', '9606', (22, 29))	('ATRX', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (56, 60))	('GBM', 'Gene', (68, 71))	('TP53', 'Gene', (56, 60))	('IDH1', 'Gene', (38, 42))	('DNA methyltransferase 3 alpha', 'Gene', '1788', (117, 146))	('ATRX', 'Gene', '546', (45, 49))	('mutation', 'Var', (101, 109))	('DNMT3A', 'Gene', (148, 154))	('DNA methyltransferase 3 alpha', 'Gene', (117, 146))
152966	31371348	DNMT3A gene alterations relate to aberrant DNA methylation and associated tumorigenesis in other malignancies.	('DNA methylation', 'MPA', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('alterations', 'Var', (12, 23))	('aberrant', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('DNMT3A', 'Gene', (0, 6))	('tumor', 'Disease', (74, 79))	('DNMT3A', 'Gene', '1788', (0, 6))	('malignancies', 'Disease', (97, 109))
152967	31371348	The somatic mutation found, p.P904S, has previously been reported in other cancers, but never in GBM, and has been predicted to be pathogenic.	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('p.P904S', 'Mutation', 'rs997533180', (28, 35))	('p.P904S', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('reported', 'Reg', (57, 65))
152972	31371348	Pathology was consistent with an IDH1 R132H-mutant, MGMT-methylated GBM with a Ki67 of 10%-15%.	('MGMT', 'Gene', (52, 56))	('R132H', 'Mutation', 'rs121913500', (38, 43))	('R132H-mutant', 'Var', (38, 50))	('MGMT', 'Gene', '4255', (52, 56))	('IDH1', 'Gene', (33, 37))	('Ki67', 'Chemical', '-', (79, 83))	('IDH1', 'Gene', '3417', (33, 37))	('GBM', 'Disease', (68, 71))
152977	31371348	Postoperatively, he underwent treatment with INC280, a highly potent selective cMet inhibitor, and the VEGFR/PDGFR inhibitor, bevacizumab, and remained neurologically and radiographically stable through 22 cycles of treatment.	('INC280', 'Var', (45, 51))	('VEGFR', 'Gene', '3791', (103, 108))	('INC280', 'Chemical', 'MESH:C000613976', (45, 51))	('cMet', 'Gene', '4233', (79, 83))	('PDGFR', 'Gene', (109, 114))	('PDGFR', 'Gene', '5159', (109, 114))	('VEGFR', 'Gene', (103, 108))	('bevacizumab', 'Chemical', 'MESH:D000068258', (126, 137))	('cMet', 'Gene', (79, 83))
152985	31371348	2A; Supplemental Table 1), including IDH1 p.R132H, TP53 p.C176F, and ATRX p.Q2108R mutations.	('TP53', 'Gene', (51, 55))	('p.Q2108R', 'Var', (74, 82))	('p.C176F', 'Mutation', 'rs786202962', (56, 63))	('ATRX', 'Gene', (69, 73))	('p.R132H', 'Var', (42, 49))	('IDH1', 'Gene', (37, 41))	('p.C176F', 'Var', (56, 63))	('p.Q2108R', 'Mutation', 'p.Q2108R', (74, 82))	('IDH1', 'Gene', '3417', (37, 41))	('p.R132H', 'Mutation', 'rs121913500', (42, 49))	('ATRX', 'Gene', '546', (69, 73))	('TP53', 'Gene', '7157', (51, 55))
152986	31371348	Curiously, a missense DNMT3A p.P904S mutation affecting a highly conserved catalytic methyltransferase domain responsible for DNA/cofactor binding was identified in this tumor (Table 1).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('p.P904S', 'Mutation', 'rs997533180', (29, 36))	('DNMT3A', 'Gene', (22, 28))	('p.P904S', 'Var', (29, 36))	('DNMT3A', 'Gene', '1788', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('highly conserved catalytic', 'MPA', (58, 84))	('tumor', 'Disease', (170, 175))	('affecting', 'Reg', (46, 55))
152987	31371348	The DNMT3A p.P904S mutation was previously reported in AML, DLBCL, and esophageal squamous cell carcinoma, and mutations in DNMT3A residue 904 also have been reported in 25 cases in multiple other malignancies.	('DNMT3A', 'Gene', '1788', (124, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('AML', 'Disease', (55, 58))	('malignancies', 'Disease', (197, 209))	('AML', 'Disease', 'MESH:D015470', (55, 58))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('DLBCL', 'Disease', (60, 65))	('reported', 'Reg', (158, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('p.P904S', 'Var', (11, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('DNMT3A', 'Gene', '1788', (4, 10))	('p.P904S', 'Mutation', 'rs997533180', (11, 18))	('DNMT3A', 'Gene', (4, 10))	('malignancies', 'Disease', 'MESH:D009369', (197, 209))	('reported', 'Reg', (43, 51))	('DNMT3A', 'Gene', (124, 130))
152988	31371348	Of note, no DNMT3A mutations affecting residue 904 were reported in gliomas in COSMIC.	('DNMT3A', 'Gene', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('DNMT3A', 'Gene', '1788', (12, 18))	('mutations', 'Var', (19, 28))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))
152989	31371348	Analysis of the TCGA database identified eight DNMT3A mutations in six TCGA-GBM patients and 10 DNMT3A mutations in 10 TCGA-LGG patients in residues other than 904; two TCGA-GBM patients carried two DNMT3A mutations each, similar to AML patients.	('patients', 'Species', '9606', (80, 88))	('DNMT3A', 'Gene', (47, 53))	('DNMT3A', 'Gene', '1788', (47, 53))	('mutations', 'Var', (54, 63))	('DNMT3A', 'Gene', '1788', (199, 205))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (128, 136))	('DNMT3A', 'Gene', (199, 205))	('AML', 'Disease', 'MESH:D015470', (233, 236))	('DNMT3A', 'Gene', (96, 102))	('DNMT3A', 'Gene', '1788', (96, 102))	('patients', 'Species', '9606', (237, 245))	('AML', 'Disease', (233, 236))
152990	31371348	Of note, four of eight mutations in TCGA-GBM patients and five of 10 mutations in TCGA-LGG patients localized to the DNMT3A methyltransferase domain, suggestive of their functional relevance; three of 10 mutations in TCGA-LGG patients were premature STOP codons resulting in truncated dysfunctional protein, including one localized to methyltransferase domain.	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (204, 213))	('truncated dysfunctional protein', 'MPA', (275, 306))	('DNMT3A', 'Gene', (117, 123))	('patients', 'Species', '9606', (226, 234))	('DNMT3A', 'Gene', '1788', (117, 123))	('patients', 'Species', '9606', (45, 53))	('TCGA-LGG', 'Gene', (217, 225))
152991	31371348	Prevalence of DNMT3A mutations in 3106 CNS malignancies and in 2421 gliomas reported in COSMIC, all in residues other than P904, was 26, including 18 missense, three nonsense, and one frameshift; 10 of these localized to the methyltransferase domain.	('missense', 'Var', (150, 158))	('nonsense', 'Var', (166, 174))	('frameshift', 'Var', (184, 194))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('malignancies', 'Disease', (43, 55))	('DNMT3A', 'Gene', '1788', (14, 20))	('CNS', 'Disease', (39, 42))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('DNMT3A', 'Gene', (14, 20))	('malignancies', 'Disease', 'MESH:D009369', (43, 55))	('mutations', 'Var', (21, 30))
152994	31371348	Of these, only four mutations, IDH1 p.R132H, TP53 p.C176F, ATRX p.Q2146R, and DNMT3A p.P904S, are reported to be drivers in various cancer types.	('TP53', 'Gene', (45, 49))	('DNMT3A', 'Gene', (78, 84))	('p.P904S', 'Var', (85, 92))	('p.C176F', 'Mutation', 'rs786202962', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('p.R132H', 'Mutation', 'rs121913500', (36, 43))	('ATRX', 'Gene', (59, 63))	('ATRX', 'Gene', '546', (59, 63))	('p.R132H', 'Var', (36, 43))	('TP53', 'Gene', '7157', (45, 49))	('p.Q2146R', 'Var', (64, 72))	('IDH1', 'Gene', (31, 35))	('DNMT3A', 'Gene', '1788', (78, 84))	('p.C176F', 'Var', (50, 57))	('p.Q2146R', 'Mutation', 'p.Q2146R', (64, 72))	('cancer', 'Disease', (132, 138))	('p.P904S', 'Mutation', 'rs997533180', (85, 92))	('IDH1', 'Gene', '3417', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
152995	31371348	Interestingly, DNMT3A p.P904S, which was not reported in GBMs before, had high variant allele frequency in the second recurrent tumor, suggesting that it is in the founder clone preserved during tumor progression.	('p.P904S', 'Mutation', 'rs997533180', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('DNMT3A', 'Gene', (15, 21))	('tumor', 'Disease', (195, 200))	('DNMT3A', 'Gene', '1788', (15, 21))	('p.P904S', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
152996	31371348	In addition to the ATRX p.Q2108R mutation in the first recurrent tumor, a second frameshift mutation was identified in ATRX p.F1967fs.	('p.F1967fs', 'Mutation', 'p.F1967fsX', (124, 133))	('tumor', 'Disease', (65, 70))	('p.F1967fs', 'Var', (124, 133))	('ATRX', 'Gene', '546', (19, 23))	('ATRX', 'Gene', '546', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('ATRX', 'Gene', (19, 23))	('p.Q2108R', 'Var', (24, 32))	('p.Q2108R', 'Mutation', 'p.Q2108R', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ATRX', 'Gene', (119, 123))
153002	31371348	Mutations in any of these domains have been shown to be tumorigenic and particularly associated with AML, as well as other hematologic malignancies.	('AML', 'Disease', 'MESH:D015470', (101, 104))	('hematologic malignancies', 'Disease', (123, 147))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('AML', 'Disease', (101, 104))	('Mutations', 'Var', (0, 9))	('hematologic malignancies', 'Disease', 'MESH:D019337', (123, 147))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('associated', 'Reg', (85, 95))
153003	31371348	We describe a patient with an IDH1-mutant recurrent glioblastoma, carrying a somatic mutation in DNMT3A p.P904S localizing to the highly conserved catalytic domain, never previously reported in glioblastoma patients.	('DNMT3A', 'Gene', (97, 103))	('DNMT3A', 'Gene', '1788', (97, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (194, 206))	('patients', 'Species', '9606', (207, 215))	('glioblastoma', 'Phenotype', 'HP:0012174', (194, 206))	('IDH1', 'Gene', (30, 34))	('patient', 'Species', '9606', (14, 21))	('glioblastoma', 'Disease', (52, 64))	('p.P904S', 'Mutation', 'rs997533180', (104, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('patient', 'Species', '9606', (207, 214))	('glioblastoma', 'Disease', (194, 206))	('p.P904S', 'Var', (104, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('IDH1', 'Gene', '3417', (30, 34))
153004	31371348	Although most DNMT3A mutations affect R882 residue within the catalytic domain, resulting in 80% reduction in DNMT3A enzymatic activity and dominant negative effects on the wild-type DNMT3A by blocking the formation of active tetramers, other somatic mutations including frameshift, splice site, missense, and nonsense mutations at non-R882 residues result in expression of nonfunctional or truncated protein and a haploinsufficient phenotype.	('result', 'Reg', (350, 356))	('expression', 'MPA', (360, 370))	('blocking', 'NegReg', (193, 201))	('DNMT3A', 'Gene', (14, 20))	('activity', 'MPA', (127, 135))	('DNMT3A', 'Gene', '1788', (183, 189))	('haploinsufficient', 'Disease', 'MESH:D058495', (415, 432))	('missense', 'Var', (296, 304))	('reduction', 'NegReg', (97, 106))	('DNMT3A', 'Gene', '1788', (110, 116))	('nonfunctional', 'MPA', (374, 387))	('formation', 'MPA', (206, 215))	('haploinsufficient', 'Disease', (415, 432))	('R882 residue', 'Var', (38, 50))	('DNMT3A', 'Gene', '1788', (14, 20))	('DNMT3A', 'Gene', (183, 189))	('mutations', 'Var', (21, 30))	('active tetramers', 'MPA', (219, 235))	('DNMT3A', 'Gene', (110, 116))
153005	31371348	Studies suggest significantly diminished de novo methyltransferase activity with focal hypomethylation in R882-mutant AML and support worse overall survival and higher recurrences in AML patients carrying DNMT3A mutations.	('patients', 'Species', '9606', (187, 195))	('R882-mutant', 'Var', (106, 117))	('DNMT3A', 'Gene', (205, 211))	('diminished', 'NegReg', (30, 40))	('DNMT3A', 'Gene', '1788', (205, 211))	('AML', 'Disease', (183, 186))	('AML', 'Disease', (118, 121))	('activity', 'MPA', (67, 75))	('recurrences', 'MPA', (168, 179))	('methyltransferase', 'Enzyme', (49, 66))	('focal hypomethylation', 'Var', (81, 102))	('AML', 'Disease', 'MESH:D015470', (118, 121))	('AML', 'Disease', 'MESH:D015470', (183, 186))
153007	31371348	In the recent years, the epigenetic tumor landscape has been shown to play an increasingly important role in the tumor biology via transcriptional regulation, because of the changes in methylation of CpG islands within gene promoter regions, and histone modifications, with resulting changes in chromatin structure and accessibility to transcriptional activators or repressors.	('chromatin structure', 'MPA', (295, 314))	('tumor', 'Disease', (113, 118))	('changes', 'Reg', (284, 291))	('methylation', 'MPA', (185, 196))	('changes', 'Reg', (174, 181))	('accessibility', 'MPA', (319, 332))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('CpG islands', 'Protein', (200, 211))	('histone', 'MPA', (246, 253))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('modifications', 'Var', (254, 267))	('tumor', 'Disease', (36, 41))
153008	31371348	The association between altered DNA methylation and gliomagenesis has been well-described.	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('altered', 'Var', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('DNA', 'Protein', (32, 35))	('glioma', 'Disease', (52, 58))
153011	31371348	Conditional DNMT3A deletion in hematopoietic stem cells results in a marked increase in self-renewal in lieu of differentiation, possibly via its effects on Ctnnb1 with its concomitant promoter hypomethylation, beta-catenin overexpression, and up-regulation of target gene expression; DNMT3A has likewise been implicated in neural stem cell differentiation.	('up-regulation', 'PosReg', (244, 257))	('Ctnnb1', 'Gene', (157, 163))	('DNMT3A', 'Gene', (12, 18))	('DNMT3A', 'Gene', '1788', (12, 18))	('increase', 'PosReg', (76, 84))	('self-renewal', 'CPA', (88, 100))	('Ctnnb1', 'Gene', '1499', (157, 163))	('effects', 'Reg', (146, 153))	('deletion', 'Var', (19, 27))	('beta-catenin', 'Gene', (211, 223))	('beta-catenin', 'Gene', '1499', (211, 223))	('DNMT3A', 'Gene', (285, 291))	('DNMT3A', 'Gene', '1788', (285, 291))	('expression', 'MPA', (273, 283))
153012	31371348	Existence of DNMT3A mutations in TCGA-LGG (low-grade glioma) and TCGA-GBM patients, 50% of which affect methyltransferase domain containing DNMT3A P904S mutation, supports the notion that it likely is a premalignant driver event.	('methyltransferase', 'MPA', (104, 121))	('glioma', 'Disease', (53, 59))	('DNMT3A', 'Gene', (140, 146))	('patients', 'Species', '9606', (74, 82))	('DNMT3A', 'Gene', (13, 19))	('affect', 'Reg', (97, 103))	('DNMT3A', 'Gene', '1788', (140, 146))	('DNMT3A', 'Gene', '1788', (13, 19))	('P904S', 'Var', (147, 152))	('P904S', 'Mutation', 'rs997533180', (147, 152))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('mutations', 'Var', (20, 29))
153013	31371348	Indeed, DNMT3A mutations are present in founder AML clones, have been shown to be important in AML oncogenesis, and often confer resistance to conventional chemotherapy.	('DNMT3A', 'Gene', (8, 14))	('DNMT3A', 'Gene', '1788', (8, 14))	('AML', 'Disease', (48, 51))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('mutations', 'Var', (15, 24))	('resistance', 'MPA', (129, 139))	('important', 'Reg', (82, 91))	('AML', 'Disease', (95, 98))	('AML', 'Disease', 'MESH:D015470', (48, 51))
153014	31371348	Multiple DNMT3A mutations can cooccur in the same AML patient, similarly seen in the TCGA-GBM patient cohort carrying DNMT3A mutations.	('patient', 'Species', '9606', (54, 61))	('AML', 'Disease', 'MESH:D015470', (50, 53))	('mutations', 'Var', (16, 25))	('AML', 'Disease', (50, 53))	('patient', 'Species', '9606', (94, 101))	('DNMT3A', 'Gene', (9, 15))	('DNMT3A', 'Gene', (118, 124))	('DNMT3A', 'Gene', '1788', (9, 15))	('DNMT3A', 'Gene', '1788', (118, 124))
153015	31371348	It is possible that DNMT3A mutations are premalignant events that skew neural stem/progenitor cells toward self-renewal rather than differentiation, possibly via epigenetic mechanisms, contributing to glioma initiation.	('mutations', 'Var', (27, 36))	('contributing', 'Reg', (185, 197))	('skew', 'Reg', (66, 70))	('DNMT3A', 'Gene', (20, 26))	('DNMT3A', 'Gene', '1788', (20, 26))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('glioma initiation', 'Disease', 'MESH:D005910', (201, 218))	('glioma initiation', 'Disease', (201, 218))
153016	31371348	In this case, we describe a patient harboring a GBM with somatic co-mutations in IDH1, TP53, and ATRX, as well as DNMT3A.	('ATRX', 'Gene', '546', (97, 101))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('patient', 'Species', '9606', (28, 35))	('IDH1', 'Gene', (81, 85))	('co-mutations', 'Var', (65, 77))	('ATRX', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (81, 85))	('DNMT3A', 'Gene', (114, 120))	('DNMT3A', 'Gene', '1788', (114, 120))
153018	31371348	The IDH1 p.R132H mutation, in particular, has molecularly been well-described and clinically shown to carry a better prognostic significance for GBM patients.	('IDH1', 'Gene', '3417', (4, 8))	('patients', 'Species', '9606', (149, 157))	('GBM', 'Disease', (145, 148))	('p.R132H', 'Var', (9, 16))	('IDH1', 'Gene', (4, 8))	('p.R132H', 'Mutation', 'rs121913500', (9, 16))
153021	31371348	According to TCGA, up to 44% of AML patients carry mechanistically and prognostically important mutations in genes regulating genome methylation, including frequent mutations in DNMT3A in as much as 30% normal karyotype AML patients, Tet oncogene family member 2 deoxygenase (TET2), and isocitrate dehydrogenases 1/2 (IDH1/2).	('IDH1/2', 'Gene', (318, 324))	('AML', 'Disease', 'MESH:D015470', (32, 35))	('patients', 'Species', '9606', (36, 44))	('TET2', 'Gene', '54790', (276, 280))	('DNMT3A', 'Gene', (178, 184))	('AML', 'Disease', (32, 35))	('TET2', 'Gene', (276, 280))	('DNMT3A', 'Gene', '1788', (178, 184))	('IDH1/2', 'Gene', '3417;3418', (318, 324))	('AML', 'Disease', 'MESH:D015470', (220, 223))	('patients', 'Species', '9606', (224, 232))	('mutations', 'Var', (165, 174))	('mutations', 'Var', (96, 105))	('AML', 'Disease', (220, 223))
153022	31371348	In AML patients, DNMT3A somatic mutations are commonly present together with mutations in IDH1/2, FLT3, NPM1, and cKit and are mutually exclusive with mutations in TET2.	('FLT3', 'Gene', '2322', (98, 102))	('DNMT3A', 'Gene', (17, 23))	('IDH1/2', 'Gene', '3417;3418', (90, 96))	('DNMT3A', 'Gene', '1788', (17, 23))	('TET2', 'Gene', '54790', (164, 168))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('mutations', 'Var', (77, 86))	('NPM1', 'Gene', '4869', (104, 108))	('NPM1', 'Gene', (104, 108))	('FLT3', 'Gene', (98, 102))	('IDH1/2', 'Gene', (90, 96))	('TET2', 'Gene', (164, 168))	('patients', 'Species', '9606', (7, 15))	('AML', 'Disease', (3, 6))
153023	31371348	It has been proposed that the type of DNMT3A mutation and gene dosage effects, combined with secondary mutations, may dictate the type of hematologic disease.	('dictate', 'Reg', (118, 125))	('hematologic disease', 'Phenotype', 'HP:0001871', (138, 157))	('hematologic disease', 'Disease', (138, 157))	('DNMT3A', 'Gene', (38, 44))	('mutation', 'Var', (45, 53))	('type', 'Disease', (130, 134))	('DNMT3A', 'Gene', '1788', (38, 44))	('hematologic disease', 'Disease', 'MESH:D006402', (138, 157))
153024	31371348	Interestingly, IDH and DNMT3A mutations were shown to have mutually exclusive, opposing effects on the epigenome, with cooccurrence of both mutations resulting in epigenetic antagonism, in which CpG sites affected by either IDH or DNMT3A mutations alone are no longer affected in the presence of both, with the overall loss of differential methylation within gene compartments.	('methylation', 'MPA', (340, 351))	('IDH', 'Gene', (224, 227))	('DNMT3A', 'Gene', (231, 237))	('DNMT3A', 'Gene', (23, 29))	('DNMT3A', 'Gene', '1788', (231, 237))	('mutations', 'Var', (238, 247))	('DNMT3A', 'Gene', '1788', (23, 29))	('IDH', 'Gene', '3417', (224, 227))	('IDH', 'Gene', '3417', (15, 18))	('IDH', 'Gene', (15, 18))	('resulting', 'Reg', (150, 159))	('mutations', 'Var', (30, 39))	('mutations', 'Var', (140, 149))	('effects', 'Reg', (88, 95))	('epigenetic', 'MPA', (163, 173))
153029	31371348	Somatic SNVs were identified using MuTect (v2.7.1); somatic insertion or deletions (indels) were identified using Indelocator (v36.3).	('v2.7', 'Gene', (43, 47))	('deletions', 'Var', (73, 82))	('v2.7', 'Gene', '28803', (43, 47))
153030	31371348	Copy-number variations (CNVs) were assessed using tumor over normal coverage ratios, normalized by total coverage variation.	('Copy-number variations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
153037	29152101	Functional network analysis of gene-phenotype connectivity associated with temozolomide Glioma has a poor survival rate in patients even with aggressive treatment.	('Glioma', 'Disease', (88, 94))	('temozolomide', 'Var', (75, 87))	('patients', 'Species', '9606', (123, 131))	('Glioma', 'Disease', 'MESH:D005910', (88, 94))	('Glioma', 'Phenotype', 'HP:0009733', (88, 94))	('temozolomide', 'Chemical', 'MESH:D000077204', (75, 87))
153087	29152101	For CDKN2A (61%), most alterations were classified as deep deletions, with a few cases of truncating mutations.	('CDKN2A', 'Gene', '1029', (4, 10))	('CDKN2A', 'Gene', (4, 10))	('alterations', 'Var', (23, 34))
153088	29152101	For EGFR (53%), the majority of alterations were amplifications, with a small fraction of missense mutations.	('alterations', 'Var', (32, 43))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', '1956', (4, 8))
153089	29152101	For PTEN (31%) and TP53 (22%), the gene changes included deep deletions and truncating, missense and inframe mutations.	('truncating', 'Disease', (76, 86))	('PTEN', 'Gene', '5728', (4, 8))	('deep deletions', 'Var', (57, 71))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('PTEN', 'Gene', (4, 8))
153105	29152101	For CDKN2A, alterations also included missense and truncating mutations.	('CDKN2A', 'Gene', '1029', (4, 10))	('CDKN2A', 'Gene', (4, 10))	('truncating mutations', 'MPA', (51, 71))	('missense', 'Var', (38, 46))
153119	29152101	Notably, TMZ has been reported to induce apoptosis in melanoma cells, and the inactivation of MGMT results in a high level of resistance to TMZ and impairs the expression of MSH2/MSH6 through the over expression of P53.	('P53', 'Gene', (215, 218))	('expression', 'MPA', (160, 170))	('inactivation', 'Var', (78, 90))	('P53', 'Gene', '7157', (215, 218))	('MSH6', 'Gene', '2956', (179, 183))	('MGMT', 'Gene', '4255', (94, 98))	('over expression', 'PosReg', (196, 211))	('MGMT', 'Gene', (94, 98))	('MSH2', 'Gene', (174, 178))	('TMZ', 'Chemical', 'MESH:D000077204', (9, 12))	('MSH2', 'Gene', '4436', (174, 178))	('melanoma', 'Disease', (54, 62))	('resistance to TMZ', 'MPA', (126, 143))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('TMZ', 'Chemical', 'MESH:D000077204', (140, 143))	('impairs', 'NegReg', (148, 155))	('MSH6', 'Gene', (179, 183))
153120	29152101	Furthermore, other studies have shown that the expression levels of TOP2A/Bare significantly higher in human GBM and that TOP2B transcription is corrected in PDGF (+) PTEN (-/-) or PDGF (+) PTEN (-/-) P53 (-/-) models by susceptibility to cancer drugs.	('higher', 'PosReg', (93, 99))	('P53', 'Gene', '7157', (201, 204))	('TOP2B', 'Gene', (122, 127))	('TOP2A', 'Gene', (68, 73))	('human', 'Species', '9606', (103, 108))	('PTEN', 'Gene', (190, 194))	('TOP2B', 'Gene', '7155', (122, 127))	('PTEN', 'Gene', '5728', (190, 194))	('PDGF (+', 'Var', (158, 165))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('PTEN', 'Gene', (167, 171))	('TOP2A', 'Gene', '7153', (68, 73))	('PTEN', 'Gene', '5728', (167, 171))	('transcription', 'MPA', (128, 141))	('P53', 'Gene', (201, 204))	('expression levels', 'MPA', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
153121	29152101	For XRCC3, a double-strand break repair gene, the thr241Met polymorphism of XRCC3 has been associated with susceptibility to developing astrocytomas and GBM.	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('XRCC3', 'Gene', '7517', (76, 81))	('astrocytomas', 'Disease', 'MESH:D001254', (136, 148))	('XRCC3', 'Gene', (4, 9))	('thr241Met polymorphism', 'Var', (50, 72))	('astrocytomas', 'Disease', (136, 148))	('GBM', 'Disease', (153, 156))	('thr241Met', 'Chemical', '-', (50, 59))	('XRCC3', 'Gene', '7517', (4, 9))	('XRCC3', 'Gene', (76, 81))	('associated', 'Reg', (91, 101))
153126	29152101	In the case of GBM, most of the genetic alterations in CDKN2A, PTEN and TP53 were deletions or mutations (Figure 3B), which resulted in a reduction of their expression in conjunction with the development of carcinogenesis.	('deletions', 'Var', (82, 91))	('PTEN', 'Gene', '5728', (63, 67))	('reduction', 'NegReg', (138, 147))	('CDKN2A', 'Gene', '1029', (55, 61))	('expression', 'MPA', (157, 167))	('TP53', 'Gene', '7157', (72, 76))	('carcinogenesis', 'Disease', (207, 221))	('alterations', 'Var', (40, 51))	('TP53', 'Gene', (72, 76))	('mutations', 'Var', (95, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (207, 221))	('CDKN2A', 'Gene', (55, 61))	('PTEN', 'Gene', (63, 67))
153131	29152101	Finally, a survival analysis of the 6 genes was conducted in glioma cases (LGG or GBM) using OncoLnc, and the results indicated that high levels of PTEN predicted a statistically significantly longer survival in LGG.	('longer', 'PosReg', (193, 199))	('PTEN', 'Gene', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('LGG', 'Disease', (212, 215))	('PTEN', 'Gene', '5728', (148, 152))	('high', 'Var', (133, 137))	('survival', 'MPA', (200, 208))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
153132	29152101	This finding is in accordance with the diagnostic significance of PTEN mutation as a molecular marker for poor prognosis in LGG.	('mutation', 'Var', (71, 79))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('LGG', 'Disease', (124, 127))
153153	29097933	Glioma-associated neovascularization with aberrant structure and functionality is a typical tumor hallmark participating in multiple biological behaviors such as tumor progression, invasiveness, and therapy resistance.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (162, 167))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('aberrant', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
153213	29097933	It emphasizes the molecular classification for gliomas, such as isocitrate dehydrogenase (IDH) gene mutations, epidermal growth factor receptor (EGFR) status, methyl-guanine methyltransferase (MGMT) promoter methylation status, and chromosome 1p/19q codeletion.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('mutations', 'Var', (100, 109))	('isocitrate', 'Chemical', 'MESH:C034219', (64, 74))	('IDH', 'Gene', (90, 93))	('MGMT', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (145, 149))	('MGMT', 'Gene', '4255', (193, 197))	('IDH', 'Gene', '3417', (90, 93))	('methyl-guanine methyltransferase', 'Gene', '4255', (159, 191))	('gliomas', 'Disease', (47, 54))	('epidermal growth factor receptor', 'Gene', (111, 143))	('EGFR', 'Gene', (145, 149))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('methyl-guanine methyltransferase', 'Gene', (159, 191))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))
153217	29097933	IDH gene mutations are present in approximately 50%-80% of grades II and III glioma and nearly all secondary GBM, with IDH-1 much more common than IDH-2.	('IDH-1', 'Gene', '3417', (119, 124))	('IDH-1', 'Gene', (119, 124))	('secondary GBM', 'Disease', (99, 112))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (119, 122))	('IDH', 'Gene', '3417', (147, 150))	('IDH-2', 'Gene', (147, 152))	('IDH-2', 'Gene', '3418', (147, 152))	('mutations', 'Var', (9, 18))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioma', 'Disease', (77, 83))	('grades II', 'Disease', (59, 68))	('IDH', 'Gene', (119, 122))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH', 'Gene', (147, 150))
153218	29097933	Mutated IDH-1 induces a neomorphic enzyme activity, leading to the overproduction of metabolite 2-hydroxyglutarate (2-HG).	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (96, 114))	('induces', 'Reg', (14, 21))	('IDH-1', 'Gene', '3417', (8, 13))	('IDH-1', 'Gene', (8, 13))	('neomorphic', 'MPA', (24, 34))	('Mutated', 'Var', (0, 7))
153220	29097933	Patients with IDH1 gene mutations experience more favorable prognosis than those with wild-type IDH1 gliomas.	('IDH1 gliomas', 'Disease', 'MESH:D005910', (96, 108))	('IDH1', 'Gene', '3417', (96, 100))	('IDH1 gliomas', 'Disease', (96, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (14, 18))	('mutations', 'Var', (24, 33))	('IDH1', 'Gene', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH1', 'Gene', '3417', (14, 18))
153221	29097933	It has demonstrated that IDH1 mutations could serve as independent prognostic indicators.	('IDH1', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('IDH1', 'Gene', '3417', (25, 29))
153222	29097933	Noninvasive detection of IDH gene mutations is of great benefit in glioma stratification management.	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('mutations', 'Var', (34, 43))
153223	29097933	Water suppressed proton-magnetic resonance spectroscopy (1H-MRS) has been explored to noninvasively detect 2-HG in gliomas for identification of IDH-1 gene mutation.	('gliomas', 'Disease', (115, 122))	('Water', 'Chemical', 'MESH:D014867', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH-1', 'Gene', '3417', (145, 150))	('IDH-1', 'Gene', (145, 150))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('1H', 'Chemical', '-', (57, 59))	('mutation', 'Var', (156, 164))
153225	29097933	Considering that IDH mutation status is associated with hypoxia induced factor-1alpha, a driving factor in hypoxia-dependent angiogenesis, perfusion MRI may predict this genetic alteration indirectly.	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', '3417', (17, 20))	('mutation', 'Var', (21, 29))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('associated', 'Reg', (40, 50))	('hypoxia', 'Disease', (56, 63))	('hypoxia', 'Disease', (107, 114))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))
153226	29097933	found the potential of rCBV for predicting IDH mutation status in LGG and anaplastic glioma.	('rCBV', 'Chemical', '-', (23, 27))	('IDH', 'Gene', '3417', (43, 46))	('LGG', 'Disease', (66, 69))	('mutation', 'Var', (47, 55))	('anaplastic glioma', 'Disease', (74, 91))	('IDH', 'Gene', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('anaplastic glioma', 'Disease', 'MESH:D005910', (74, 91))
153227	29097933	The IDH mutant glioma clustered at decreased rCBV compared with the wild-type counterparts (Figure 3).	('IDH', 'Gene', '3417', (4, 7))	('rCBV', 'Chemical', '-', (45, 49))	('mutant', 'Var', (8, 14))	('decreased', 'NegReg', (35, 44))	('glioma', 'Disease', (15, 21))	('rCBV', 'MPA', (45, 49))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('IDH', 'Gene', (4, 7))
153228	29097933	A one-unit increase in rCBV corresponded to a 2/3 decrease in the odds for an IDH-1/2 mutation, verified successfully in 88% of patients.	('rCBV', 'Chemical', '-', (23, 27))	('rCBV', 'Gene', (23, 27))	('IDH-1', 'Gene', '3417', (78, 83))	('mutation', 'Var', (86, 94))	('patients', 'Species', '9606', (128, 136))	('IDH-1', 'Gene', (78, 83))	('decrease', 'NegReg', (50, 58))
153235	29097933	Various mutations in EGFR occur in approximately 57% of GBM patients, accompanied with EGFR rearrangement/amplification.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (87, 91))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', (87, 91))	('mutations', 'Var', (8, 17))
153236	29097933	EGFR variant III (EGFRvIII), characterized by exons 2-7 deletion in the extracellular domain, is the most common variant of EGFR present in 25%-35% of GBM patients.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', '1956', (124, 128))	('variant III', 'Var', (5, 16))	('EGFR', 'Gene', (124, 128))	('EGFR', 'Gene', (18, 22))	('patients', 'Species', '9606', (155, 163))	('EGFR', 'Gene', '1956', (0, 4))
153237	29097933	Cross-talk between EGFR and EGFRvIII enables activating downstream signal pathways such as phosphoinositide 3-kinase, RTK, and phosphatase and tensin homolog, participating in tumor progression, angiogenesis, and treatment resistance.	('EGFR', 'Gene', '1956', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('phosphoinositide 3-kinase', 'Pathway', (91, 116))	('RTK', 'Gene', (118, 121))	('tumor', 'Disease', (176, 181))	('activating', 'MPA', (45, 55))	('EGFR', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (19, 23))	('participating', 'Reg', (159, 172))	('EGFR', 'Gene', (19, 23))	('RTK', 'Gene', '5979', (118, 121))	('Cross-talk', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
153238	29097933	GBM carrying EGFRvIII mutation has a grim prognosis.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
153242	29097933	Increased T2 intensity to enhancing volume ratio was more likely to reveal EGFRvIII mutation.	('T2 intensity to enhancing volume ratio', 'MPA', (10, 48))	('Increased', 'PosReg', (0, 9))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('mutation', 'Var', (84, 92))
153247	29097933	They found that GBM with EGFR amplification presented as higher median rCBV and lower PSR.	('rCBV', 'Chemical', '-', (71, 75))	('EGFR', 'Gene', (25, 29))	('higher', 'PosReg', (57, 63))	('PS', 'Chemical', '-', (86, 88))	('PSR', 'MPA', (86, 89))	('amplification', 'Var', (30, 43))	('rCBV', 'MPA', (71, 75))	('lower', 'NegReg', (80, 85))	('EGFR', 'Gene', '1956', (25, 29))
153253	29097933	MGMT methylation has been reported in 30%-60% of GBM and 50%-84% of anaplastic glioma.	('MGMT', 'Gene', (0, 4))	('reported', 'Reg', (26, 34))	('methylation', 'Var', (5, 16))	('GBM', 'Disease', (49, 52))	('anaplastic glioma', 'Disease', 'MESH:D005910', (68, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('anaplastic glioma', 'Disease', (68, 85))	('MGMT', 'Gene', '4255', (0, 4))
153259	29097933	Several studies have demonstrated perfusion parameters as noninvasive radiophenotypic surrogates for predicting MGMT methylation in GBM.	('MGMT', 'Gene', '4255', (112, 116))	('methylation', 'Var', (117, 128))	('MGMT', 'Gene', (112, 116))
153266	29097933	The unbalanced translocation between chromosome arm 1p and 19q results in loss of heterozygosity (LOH).	('unbalanced translocation', 'Var', (4, 28))	('arm 1p', 'Gene', '11047', (48, 54))	('arm 1p', 'Gene', (48, 54))	('loss', 'NegReg', (74, 78))
153267	29097933	The 1p/19q codeletion is a typical characteristic in 40%-90% of oligodendroglioma.	('oligodendroglioma', 'Disease', (64, 81))	('1p/19q codeletion', 'Var', (4, 21))	('oligodendroglioma', 'Disease', 'MESH:D009837', (64, 81))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))
153268	29097933	Oligodendrogliomas harboring 1p/19q codeletion are associated with higher sensitivity to chemoradiotherapy and prolonged survival than those with intact 1p/19q alleles, irrespective of the tumor grade.	('tumor', 'Disease', (189, 194))	('higher', 'PosReg', (67, 73))	('sensitivity to chemoradiotherapy', 'MPA', (74, 106))	('1p/19q', 'Var', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('Oligodendrogliomas', 'Disease', (0, 18))	('survival', 'CPA', (121, 129))	('prolonged', 'PosReg', (111, 120))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
153269	29097933	reported that rCBV was associated with 1p/19q genotype of oligodendroglioma using ROI-based analysis.	('oligodendroglioma', 'Disease', (58, 75))	('oligodendroglioma', 'Disease', 'MESH:D009837', (58, 75))	('rCBV', 'Chemical', '-', (14, 18))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('1p/19q genotype', 'Var', (39, 54))	('rCBV', 'Gene', (14, 18))
153272	29097933	High rCBV is associated with angiogenesis and increased mitotic activity.	('angiogenesis', 'CPA', (29, 41))	('High', 'Var', (0, 4))	('increased', 'PosReg', (46, 55))	('rCBV', 'Gene', (5, 9))	('rCBV', 'Chemical', '-', (5, 9))	('mitotic activity', 'CPA', (56, 72))
153274	29097933	The incorporation of rCBVmax and metabolite ratios provided improved diagnostic accuracy in distinguishing 1p/19q genotypic profile of oligodendroglioma.	('rCBV', 'Chemical', '-', (21, 25))	('oligodendroglioma', 'Disease', (135, 152))	('oligodendroglioma', 'Disease', 'MESH:D009837', (135, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('1p/19q genotypic', 'Var', (107, 123))
153276	29097933	For example, EGFR amplification and mutation can result in the overexpression of various downstream effector molecules such as VEGF, interleukin-18, and angiopoietin-like 4 to make synergic effect on tumor neovascularization, consequently altering the vascular structure and function.	('result in', 'Reg', (49, 58))	('VEGF', 'Gene', '7422', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('vascular', 'MPA', (252, 260))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('function', 'MPA', (275, 283))	('EGFR', 'Gene', '1956', (13, 17))	('tumor', 'Disease', (200, 205))	('interleukin-18', 'Gene', '3606', (133, 147))	('VEGF', 'Gene', (127, 131))	('amplification', 'Var', (18, 31))	('interleukin-18', 'Gene', (133, 147))	('altering', 'Reg', (239, 247))	('EGFR', 'Gene', (13, 17))	('mutation', 'Var', (36, 44))	('overexpression', 'PosReg', (63, 77))
153286	29097933	In contrast, the absence of BBB components in brain metastasis often results in relatively low perfusion and uniformly increased capillary permeability throughout the tumor, causing pure vasogenic edema without infiltrative tumor cells or abundant angiogenesis.	('low', 'NegReg', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('increased capillary permeability', 'Phenotype', 'HP:0030005', (119, 151))	('perfusion', 'MPA', (95, 104))	('tumor', 'Disease', (224, 229))	('edema', 'Disease', 'MESH:D004487', (197, 202))	('absence', 'Var', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('capillary permeability', 'MPA', (129, 151))	('edema', 'Phenotype', 'HP:0000969', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('causing', 'Reg', (174, 181))	('edema', 'Disease', (197, 202))	('tumor', 'Disease', (167, 172))	('increased', 'PosReg', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
153328	29097933	Variations of Ktrans, Ve, and Vp are effective diagnostic indicators (Figure 5(b)).	('Ktrans', 'Gene', (14, 20))	('Variations', 'Var', (0, 10))	('Ktrans', 'Chemical', '-', (14, 20))	('Vp', 'Chemical', 'MESH:C038467', (30, 32))
153355	29097933	Subsequently, they segmented GBM into three components using DSC-MRI and DCE-MRI, which include enhancing permeable area, the nonenhancing hypoperfusion area representing vasogenic edema, and the nonenhancing hyperperfusion area representing infiltrative tumor.	('edema', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('DCE-MRI', 'Var', (73, 80))	('tumor', 'Disease', (255, 260))	('DSC', 'Gene', '1825', (61, 64))	('enhancing', 'PosReg', (96, 105))	('edema', 'Disease', 'MESH:D004487', (181, 186))	('edema', 'Phenotype', 'HP:0000969', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('DCE', 'Chemical', 'MESH:C024565', (73, 76))	('DSC', 'Gene', (61, 64))	('permeable area', 'MPA', (106, 120))
153383	29097933	In addition, rCBV of the nonenhancing region in GBM was associated with OS and PFS and could provide unique prognostic information independent of the morphologic, genomic, and clinical features.	('OS', 'Chemical', '-', (72, 74))	('rCBV', 'Chemical', '-', (13, 17))	('rCBV', 'Var', (13, 17))	('associated', 'Reg', (56, 66))	('GBM', 'Gene', (48, 51))	('PFS', 'Disease', (79, 82))
153413	28246407	Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas.	('brain cancer', 'Phenotype', 'HP:0030692', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('glioblastomas', 'Phenotype', 'HP:0012174', (119, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('ZEB1', 'Gene', '6935', (67, 71))	('glioblastomas', 'Disease', 'MESH:D005909', (119, 132))	('ZEB1', 'Gene', (67, 71))	('brain cancers', 'Disease', (39, 52))	('glioblastomas', 'Disease', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('brain cancers', 'Disease', 'MESH:D001932', (39, 52))	('deletion', 'Var', (72, 80))
153414	28246407	Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased survival.	('ZEB1', 'Gene', (86, 90))	('glioma', 'Disease', (59, 65))	('ZEB1', 'Gene', '6935', (86, 90))	('deletions', 'Var', (91, 100))	('decreased', 'NegReg', (117, 126))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('ZEB1', 'Gene', (17, 21))	('ZEB1', 'Gene', '6935', (17, 21))	('survival', 'MPA', (127, 135))
153416	28246407	ZEB1 knockdown in GCSCs caused LIF induction commensurate with GCSC self-renewal and inhibition of differentiation.	('GCSC', 'Chemical', '-', (18, 22))	('knockdown', 'Var', (5, 14))	('LIF', 'Gene', (31, 34))	('LIF', 'Gene', '3976', (31, 34))	('ZEB1', 'Gene', (0, 4))	('ZEB1', 'Gene', '6935', (0, 4))	('GCSC', 'Chemical', '-', (63, 67))
153420	28246407	Identifying genes that control stem cell regulation, especially those in which mutations or a loss in copy number of these stem cell regulatory genes can support the propagation of the cancer, is fundamental to the basic understanding of brain cancer lethality.	('brain cancer', 'Disease', (238, 250))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('propagation', 'CPA', (166, 177))	('loss', 'NegReg', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('support', 'PosReg', (154, 161))	('brain cancer', 'Disease', 'MESH:D001932', (238, 250))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('brain cancer', 'Phenotype', 'HP:0030692', (238, 250))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (244, 250))	('mutations', 'Var', (79, 88))
153421	28246407	To address this question, we utilized 2,988 brain cancer genomes for copy number analysis, 339 glioma genomes for mutations indicative of loss of function and 1,007 gliomas for mRNA expression analysis.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('brain cancer', 'Phenotype', 'HP:0030692', (44, 56))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('mutations', 'Var', (114, 123))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('brain cancer', 'Disease', (44, 56))	('loss of function', 'NegReg', (138, 154))	('glioma', 'Disease', (95, 101))	('brain cancer', 'Disease', 'MESH:D001932', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('gliomas', 'Disease', (165, 172))	('glioma', 'Disease', (165, 171))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
153422	28246407	We identified several genes which have previously been described in glioblastoma (GBM) and lower grade (WHO grade II and grade III) gliomas such as PTEN, NF1 and IDH1 and concentrated our efforts on a gene not previously implicated to have copy number loss, LOH or mutations in GBMs or low grade gliomas namely, Zinc Finger E-Box Binding Homeobox 1 gene (ZEB1).	('PTEN', 'Gene', (148, 152))	('mutations', 'Var', (265, 274))	('IDH1', 'Gene', '3417', (162, 166))	('gliomas', 'Disease', (132, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('gliomas', 'Disease', (296, 303))	('ZEB1', 'Gene', (355, 359))	('copy number loss', 'Var', (240, 256))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('PTEN', 'Gene', '5728', (148, 152))	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('NF1', 'Gene', '4763', (154, 157))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('gliomas', 'Disease', 'MESH:D005910', (296, 303))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('NF1', 'Gene', (154, 157))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('Zinc Finger E-Box Binding Homeobox 1', 'Gene', '6935', (312, 348))	('IDH1', 'Gene', (162, 166))	('gliomas', 'Phenotype', 'HP:0009733', (296, 303))	('ZEB1', 'Gene', '6935', (355, 359))	('Zinc Finger E-Box Binding Homeobox 1', 'Gene', (312, 348))	('GBM', 'Phenotype', 'HP:0012174', (278, 281))	('LOH', 'Var', (258, 261))
153424	28246407	Most insights into its action would suggest that ZEB1 expression would be associated with a negative outcome in cancer patients based on its role in increasing tumorigenicity and stemness.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('expression', 'Var', (54, 64))	('patients', 'Species', '9606', (119, 127))	('stemness', 'CPA', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('ZEB1', 'Gene', '6935', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('ZEB1', 'Gene', (49, 53))	('tumor', 'Disease', (160, 165))	('increasing', 'PosReg', (149, 159))
153426	28246407	Although evidence of decreased ZEB1 expression and deletion does exist, studies using The Cancer Genome Atlas (TCGA) datasets have not revealed decreased expression or loss of the ZEB1 gene either by copy number or mutation, particularly not in brain cancer.	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ZEB1', 'Gene', (31, 35))	('decreased', 'NegReg', (144, 153))	('ZEB1', 'Gene', (180, 184))	('brain cancer', 'Disease', (245, 257))	('mutation', 'Var', (215, 223))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (90, 109))	('deletion', 'Var', (51, 59))	('ZEB1', 'Gene', '6935', (31, 35))	('loss', 'NegReg', (168, 172))	('ZEB1', 'Gene', '6935', (180, 184))	('brain cancer', 'Phenotype', 'HP:0030692', (245, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('decreased', 'NegReg', (21, 30))	('Cancer Genome Atlas', 'Disease', (90, 109))	('brain cancer', 'Disease', 'MESH:D001932', (245, 257))	('copy number', 'Var', (200, 211))	('expression', 'MPA', (36, 46))	('expression', 'MPA', (154, 164))
153427	28246407	In contrast, we have observed ZEB1 deletions in more than 50% of GBMs and 15% in low grade gliomas (grade II and grade III) with frequent LOH.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('GBMs', 'Disease', (65, 69))	('ZEB1', 'Gene', (30, 34))	('deletions', 'Var', (35, 44))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('ZEB1', 'Gene', '6935', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
153430	28246407	These mutations along with other recently observed mutations of ZEB1 in gliomas could account for the decreased ZEB1 expression.	('decreased', 'NegReg', (102, 111))	('expression', 'MPA', (117, 127))	('ZEB1', 'Gene', '6935', (64, 68))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('ZEB1', 'Gene', (64, 68))	('ZEB1', 'Gene', (112, 116))	('gliomas', 'Disease', (72, 79))	('ZEB1', 'Gene', '6935', (112, 116))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('mutations', 'Var', (6, 15))
153431	28246407	These findings uncover important information about stem cell regulation by ZEB1 expression, copy number level in both GBMs and low grade gliomas with implications for prognostication and treatment of gliomas.	('copy number level', 'Var', (92, 109))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('gliomas', 'Disease', (200, 207))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('ZEB1', 'Gene', '6935', (75, 79))	('gliomas', 'Disease', (137, 144))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('ZEB1', 'Gene', (75, 79))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('GBM', 'Phenotype', 'HP:0012174', (118, 121))	('GBMs', 'Disease', (118, 122))
153432	28246407	Using the CGARS algorithm, we identified significant focal copy number alterations and observed deletions affecting 10p11.22, the ZEB1 locus in lower grade gliomas (grade II and III, q-values [False discovery rate] <0.001, Fig.	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('copy number alterations', 'Var', (59, 82))	('ZEB1', 'Gene', '6935', (130, 134))	('ZEB1', 'Gene', (130, 134))	('deletions', 'Var', (96, 105))	('10p11.22', 'Gene', (116, 124))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
153433	28246407	Similarly, cBioportal revealed in both lower grade gliomas consisting of WHO grade II and grade III gliomas (n = 527) and GBMs (n = 595) significant heterozygous deletions indicated as shallow deletions (data not shown).	('gliomas', 'Disease', (51, 58))	('shallow deletions', 'Var', (185, 202))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('GBM', 'Phenotype', 'HP:0012174', (122, 125))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Disease', (100, 107))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
153434	28246407	In over 50% of glioma cases, we observed a deletion that included ZEB1 on chromosome 10 (Fig.	('ZEB1', 'Gene', (66, 70))	('deletion', 'Var', (43, 51))	('glioma', 'Disease', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('ZEB1', 'Gene', '6935', (66, 70))
153435	28246407	Copy number alterations in ZEB1 could be identified in both primary and recurrent (n = 87) GBM patients in relation to well characterized genes determined by the TCGA GBM Analysis working group (Fig.	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('patients', 'Species', '9606', (95, 103))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('Copy number alterations', 'Var', (0, 23))	('GBM', 'Disease', (91, 94))	('ZEB1', 'Gene', '6935', (27, 31))	('ZEB1', 'Gene', (27, 31))
153437	28246407	Comparing the whole of chromosome 10 and the specific ZEB1 locus in glioblastoma patients indicated significant copy number loss (Fig.	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('ZEB1', 'Gene', (54, 58))	('patients', 'Species', '9606', (81, 89))	('ZEB1', 'Gene', '6935', (54, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('copy number loss', 'Var', (112, 128))
153440	28246407	Importantly, copy number loss of ZEB1 correlated with shortened patient survival in both lower grade gliomas (***P < 0.0001) and GBMs (**P = 0.002, Fig.	('patient', 'Species', '9606', (64, 71))	('gliomas', 'Disease', (101, 108))	('ZEB1', 'Gene', (33, 37))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('ZEB1', 'Gene', '6935', (33, 37))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('copy number loss', 'Var', (13, 29))	('patient survival', 'CPA', (64, 80))	('shortened', 'NegReg', (54, 63))
153441	28246407	In addition, data from the COSMIC database (data freeze Jan 2014) also revealed significant copy number loss where 110 of 138 GBMs (79.7%) had copy number loss at the ZEB1 locus (Table S2).	('loss', 'NegReg', (104, 108))	('copy number', 'Var', (92, 103))	('ZEB1', 'Gene', (167, 171))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('ZEB1', 'Gene', '6935', (167, 171))	('copy number loss', 'Var', (143, 159))
153443	28246407	Given the heterozygous nature of the observed copy number loss in both lower grade and GBM patients for ZEB1, we set out to determine if loss of heterozygosity (LOH) was present at the ZEB1 locus.	('copy number', 'Var', (46, 57))	('loss', 'NegReg', (58, 62))	('patients', 'Species', '9606', (91, 99))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('ZEB1', 'Gene', (185, 189))	('ZEB1', 'Gene', '6935', (104, 108))	('ZEB1', 'Gene', '6935', (185, 189))	('ZEB1', 'Gene', (104, 108))
153447	28246407	Sanger sequencing also revealed LOH at the ZEB1 locus in 21% (3/14) of samples (Table S3 and Fig.	('ZEB1', 'Gene', (43, 47))	('ZEB1', 'Gene', '6935', (43, 47))	('LOH', 'Var', (32, 35))
153451	28246407	Having examined four independent datasets for genome wide copy number and two datasets for LOH, and confirmed LOH in our own Cedars-Sinai Medical Center patients through Sanger sequencing, we wanted to determine if ZEB1 gene loss would lead to ZEB1 protein loss.	('gene', 'Var', (220, 224))	('ZEB1', 'Gene', '6935', (215, 219))	('patients', 'Species', '9606', (153, 161))	('loss', 'NegReg', (225, 229))	('ZEB1', 'Gene', (215, 219))	('ZEB1', 'Gene', (244, 248))	('loss', 'NegReg', (257, 261))	('ZEB1', 'Gene', '6935', (244, 248))
153457	28246407	Having identified copy number loss as a means of ZEB1 loss we turned our attention to mutations that may be affecting ZEB1 expression.	('mutations', 'Var', (86, 95))	('copy number loss', 'Var', (18, 34))	('expression', 'MPA', (123, 133))	('ZEB1', 'Gene', '6935', (118, 122))	('ZEB1', 'Gene', (118, 122))	('loss', 'NegReg', (54, 58))	('ZEB1', 'Gene', (49, 53))	('ZEB1', 'Gene', '6935', (49, 53))
153458	28246407	To comprehensively characterize mutations that affect gliomas we enriched for ZEB1 by combining low grade glioma data, GBM patient data including previously reported ZEB1 mutations, and exome sequencing data from Cedars-Sinai Medical Center.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('ZEB1', 'Gene', '6935', (166, 170))	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('patient', 'Species', '9606', (123, 130))	('ZEB1', 'Gene', (166, 170))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('ZEB1', 'Gene', '6935', (78, 82))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('ZEB1', 'Gene', (78, 82))	('glioma', 'Disease', (54, 60))	('mutations', 'Var', (32, 41))	('glioma', 'Disease', (106, 112))	('mutations', 'Var', (171, 180))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
153459	28246407	The data analyzed consisted of an initial 203 samples representing already reported mutations (n = 7), GBMs (n = 108) and lower grade gliomas (grade II and grade III) (n = 88).	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('gliomas', 'Disease', (134, 141))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('mutations', 'Var', (84, 93))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))
153461	28246407	Although it is unclear the impact of the identified ZEB1 mutations, the degree to which ZEB1 mutations occur suggests that these mutations contribute to ZEB1 loss in both lower grade gliomas and GBMs.	('ZEB1', 'Gene', (52, 56))	('gliomas', 'Disease', (183, 190))	('ZEB1', 'Gene', '6935', (153, 157))	('mutations', 'Var', (93, 102))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('GBMs', 'Disease', (195, 199))	('ZEB1', 'Gene', (153, 157))	('ZEB1', 'Gene', '6935', (88, 92))	('mutations', 'Var', (129, 138))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('ZEB1', 'Gene', (88, 92))	('GBM', 'Phenotype', 'HP:0012174', (195, 198))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('ZEB1', 'Gene', '6935', (52, 56))	('loss', 'NegReg', (158, 162))
153462	28246407	In support of ZEB1 mutations carrying out a pro-tumorigenic function, the top 10 genes which included well known contributors to both GBMs and low grade gliomas such as IDH1, TP53, NF1 and ZEB1 were for the most part mutually exclusive and strongly associated with missense or splice site mutations (Fig.	('IDH1', 'Gene', (169, 173))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('TP53', 'Gene', '7157', (175, 179))	('NF1', 'Gene', '4763', (181, 184))	('ZEB1', 'Gene', (189, 193))	('ZEB1', 'Gene', (14, 18))	('gliomas', 'Disease', (153, 160))	('IDH1', 'Gene', '3417', (169, 173))	('NF1', 'Gene', (181, 184))	('associated', 'Reg', (249, 259))	('tumor', 'Disease', (48, 53))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ZEB1', 'Gene', '6935', (14, 18))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('ZEB1', 'Gene', '6935', (189, 193))	('TP53', 'Gene', (175, 179))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('missense or splice site mutations', 'Var', (265, 298))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
153463	28246407	Given the copy number loss and increased number of mutations now identified for ZEB1, we sought to determine if there was a relationship between ZEB1 expression and survival in either lower grade glioma or GBM.	('GBM', 'Disease', (206, 209))	('ZEB1', 'Gene', '6935', (80, 84))	('mutations', 'Var', (51, 60))	('ZEB1', 'Gene', '6935', (145, 149))	('ZEB1', 'Gene', (80, 84))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('ZEB1', 'Gene', (145, 149))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('GBM', 'Phenotype', 'HP:0012174', (206, 209))	('glioma', 'Disease', (196, 202))	('copy number loss', 'Var', (10, 26))
153464	28246407	Consistent with our observation of poor patient survival due to ZEB1 deletion (Fig.	('patient', 'Species', '9606', (40, 47))	('ZEB1', 'Gene', '6935', (64, 68))	('ZEB1', 'Gene', (64, 68))	('deletion', 'Var', (69, 77))
153466	28246407	Given the deleterious effects of ZEB1 loss on patient survival, we wanted to determine if loss of ZEB1 was associated with increased stemness as the basis and link to both tumor virulence and poor patient survival.	('increased', 'PosReg', (123, 132))	('stemness', 'CPA', (133, 141))	('patient', 'Species', '9606', (197, 204))	('patient', 'Species', '9606', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('ZEB1', 'Gene', (33, 37))	('ZEB1', 'Gene', '6935', (33, 37))	('loss', 'Var', (90, 94))	('tumor virulence', 'Disease', (172, 187))	('ZEB1', 'Gene', (98, 102))	('ZEB1', 'Gene', '6935', (98, 102))	('tumor virulence', 'Disease', 'MESH:D009369', (172, 187))	('loss', 'NegReg', (38, 42))
153468	28246407	Examining GBM patient tumors (n = 269) for copy number and gene expression data revealed that ZEB1 deleted tumors demonstrated increased CD133 expression compared to ZEB1 wildtype tumors (Fig.	('ZEB1', 'Gene', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('CD133', 'Gene', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('ZEB1', 'Gene', (94, 98))	('CD133', 'Gene', '8842', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', (22, 28))	('ZEB1', 'Gene', '6935', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('expression', 'MPA', (143, 153))	('tumors', 'Disease', (107, 113))	('GBM', 'Phenotype', 'HP:0012174', (10, 13))	('patient', 'Species', '9606', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('ZEB1', 'Gene', '6935', (94, 98))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('deleted', 'Var', (99, 106))	('increased', 'PosReg', (127, 136))
153479	28246407	This led us to investigate whether knockdown of ZEB1 (Figs 4d, S3g) would maintain or enhance stem cell properties.	('ZEB1', 'Gene', '6935', (48, 52))	('knockdown', 'Var', (35, 44))	('stem cell properties', 'CPA', (94, 114))	('enhance', 'PosReg', (86, 93))	('ZEB1', 'Gene', (48, 52))
153482	28246407	In addition, the loss of ZEB1 led to an increase in CD133 expression in our GCSCs.	('CD133', 'Gene', (52, 57))	('CD133', 'Gene', '8842', (52, 57))	('GCSC', 'Chemical', '-', (76, 80))	('expression', 'MPA', (58, 68))	('increase', 'PosReg', (40, 48))	('ZEB1', 'Gene', (25, 29))	('ZEB1', 'Gene', '6935', (25, 29))	('loss', 'Var', (17, 21))
153487	28246407	Non-targeting shRNAs in GCSCs placed in culture conditions conducive to differentiation resulted in cell morphology changes (Fig.	('GCSC', 'Chemical', '-', (24, 28))	('Non-targeting', 'Var', (0, 13))	('cell morphology changes', 'CPA', (100, 123))
153495	28246407	These findings indicate that loss of ZEB1 expression led to the maintenance of the GCSC-like state and resistance to differentiation.	('ZEB1', 'Gene', (37, 41))	('resistance to differentiation', 'CPA', (103, 132))	('ZEB1', 'Gene', '6935', (37, 41))	('led to', 'Reg', (53, 59))	('loss', 'Var', (29, 33))	('GCSC-like state', 'CPA', (83, 98))	('GCSC', 'Chemical', '-', (83, 87))
153497	28246407	To investigate if loss of ZEB1 would confer GCSC resistance to differentiation, we cultured GCSCs under conditions of maintaining the stem cell-like state and alternatively, under differentiation conditions.	('loss', 'Var', (18, 22))	('ZEB1', 'Gene', '6935', (26, 30))	('ZEB1', 'Gene', (26, 30))	('GCSC', 'Chemical', '-', (44, 48))	('GCSC', 'Chemical', '-', (92, 96))
153512	28246407	We cloned the human LIF promoter into a luciferase reporter construct and made subsequent deletion constructs, which systematically eliminated the E-box binding sites to which ZEB1 could bind (Fig.	('deletion', 'Var', (90, 98))	('ZEB1', 'Gene', (176, 180))	('LIF', 'Gene', '3976', (20, 23))	('ZEB1', 'Gene', '6935', (176, 180))	('human', 'Species', '9606', (14, 19))	('LIF', 'Gene', (20, 23))	('bind', 'Interaction', (187, 191))	('E-box binding', 'MPA', (147, 160))	('eliminated', 'NegReg', (132, 142))
153515	28246407	Similarly, the deletion of the ZEB1 binding sites via the introduction of mutations in those sites also resulted in the rescue of LIF transcriptional activation (Fig.	('LIF', 'Gene', '3976', (130, 133))	('ZEB1', 'Gene', (31, 35))	('LIF', 'Gene', (130, 133))	('deletion', 'Var', (15, 23))	('mutations', 'Var', (74, 83))	('rescue', 'PosReg', (120, 126))	('ZEB1', 'Gene', '6935', (31, 35))
153516	28246407	A DNA pull-down of a biotinylated oligonucleotide of the ZEB1 binding site within the LIF promoter in GCSCs resulted in ZEB1 binding of exogenously expressed GFP tagged ZEB1 or to endogenously expressed ZEB1 after IFN-gamma treatment (Fig.	('ZEB1', 'Gene', (169, 173))	('LIF', 'Gene', (86, 89))	('ZEB1', 'Gene', '6935', (169, 173))	('LIF', 'Gene', '3976', (86, 89))	('ZEB1', 'Gene', (57, 61))	('IFN-gamma', 'Gene', '3458', (214, 223))	('IFN-gamma', 'Gene', (214, 223))	('ZEB1', 'Gene', (120, 124))	('ZEB1', 'Gene', '6935', (57, 61))	('binding', 'Interaction', (125, 132))	('ZEB1', 'Gene', '6935', (120, 124))	('GFP tagged', 'Var', (158, 168))	('ZEB1', 'Gene', '6935', (203, 207))	('GCSC', 'Chemical', '-', (102, 106))	('ZEB1', 'Gene', (203, 207))	('oligonucleotide', 'Chemical', 'MESH:D009841', (34, 49))
153517	28246407	GCSCs targeted with shRNAs against ZEB1 (shZ89 or shZ90) resulted in increased LIF protein secretion compared to GCSCs targeted with non-targeting shRNA (shSC-1) as measured by ELISA (Fig.	('shZ90', 'Var', (50, 55))	('ZEB1', 'Gene', '6935', (35, 39))	('increased', 'PosReg', (69, 78))	('ZEB1', 'Gene', (35, 39))	('LIF', 'Gene', (79, 82))	('LIF', 'Gene', '3976', (79, 82))	('GCSC', 'Chemical', '-', (113, 117))	('shZ89', 'Var', (41, 46))	('GCSC', 'Chemical', '-', (0, 4))
153519	28246407	Our data indicated that ZEB1 expression is lost in a significant number of glioma patients, and that the cause of ZEB1 loss is due in large part to heterozygous deletions in both GBMs and lower grade gliomas with frequent LOH in at least 20% of glioma patients.	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('glioma', 'Disease', (75, 81))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('glioma', 'Disease', (200, 206))	('patients', 'Species', '9606', (252, 260))	('deletions', 'Var', (161, 170))	('ZEB1', 'Gene', '6935', (114, 118))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('ZEB1', 'Gene', '6935', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('gliomas', 'Disease', (200, 207))	('patients', 'Species', '9606', (82, 90))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('loss', 'NegReg', (119, 123))	('expression', 'MPA', (29, 39))	('lost', 'NegReg', (43, 47))	('ZEB1', 'Gene', (114, 118))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('glioma', 'Disease', (245, 251))	('ZEB1', 'Gene', (24, 28))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
153520	28246407	Despite ZEB1 not being identified for copy number loss or mutations in TCGA analysis before, other cancers have shown the propensity for ZEB1 to be deleted.	('mutations', 'Var', (58, 67))	('ZEB1', 'Gene', (8, 12))	('ZEB1', 'Gene', '6935', (8, 12))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('TCGA', 'Gene', (71, 75))	('ZEB1', 'Gene', (137, 141))	('cancers', 'Disease', (99, 106))	('ZEB1', 'Gene', '6935', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
153522	28246407	The impact of ZEB1 copy number loss or decreased expression appears to be in the dysregulation of stemness.	('dysregulation of stemness', 'Disease', 'MESH:D021081', (81, 106))	('copy number loss', 'Var', (19, 35))	('expression', 'MPA', (49, 59))	('ZEB1', 'Gene', '6935', (14, 18))	('decreased', 'NegReg', (39, 48))	('dysregulation of stemness', 'Disease', (81, 106))	('ZEB1', 'Gene', (14, 18))
153525	28246407	A further increase in the enrichment of the stem cell marker CD133 after knockdown of ZEB1 in patient derived GCSCs all indicate gain of function attributes associated with the loss of ZEB1.	('enrichment', 'MPA', (26, 36))	('ZEB1', 'Gene', (86, 90))	('gain of function', 'PosReg', (129, 145))	('GCSC', 'Chemical', '-', (110, 114))	('ZEB1', 'Gene', '6935', (86, 90))	('ZEB1', 'Gene', '6935', (185, 189))	('CD133', 'Gene', (61, 66))	('loss', 'Var', (177, 181))	('patient', 'Species', '9606', (94, 101))	('ZEB1', 'Gene', (185, 189))	('CD133', 'Gene', '8842', (61, 66))	('increase', 'PosReg', (10, 18))	('knockdown', 'Var', (73, 82))
153527	28246407	Furthermore, recent papers now reveal mutations in ZEB1 as did our own sequencing.	('mutations', 'Var', (38, 47))	('ZEB1', 'Gene', '6935', (51, 55))	('ZEB1', 'Gene', (51, 55))
153528	28246407	Data portal sites that utilize TCGA data also identify the heterozygous deletions consistent with our findings, however, the implications of ZEB1 heterozygous deletions have never been explored.	('ZEB1', 'Gene', '6935', (141, 145))	('ZEB1', 'Gene', (141, 145))	('deletions', 'Var', (72, 81))
153529	28246407	Mutations and loss of heterozygosity may impact ZEB1 expression and play a role in the decreased survival noted.	('ZEB1', 'Gene', '6935', (48, 52))	('survival', 'MPA', (97, 105))	('decreased', 'NegReg', (87, 96))	('loss of heterozygosity', 'Var', (14, 36))	('Mutations', 'Var', (0, 9))	('expression', 'MPA', (53, 63))	('impact', 'Reg', (41, 47))	('ZEB1', 'Gene', (48, 52))
153530	28246407	Furthermore, we postulate that in the absence of mutations or LOH that would affect ZEB1, there is a haploinsufficiency that results in a shortened survival for patients who have low expression of ZEB1.	('mutations', 'Var', (49, 58))	('haploinsufficiency', 'Disease', (101, 119))	('survival', 'MPA', (148, 156))	('ZEB1', 'Gene', (84, 88))	('ZEB1', 'Gene', '6935', (84, 88))	('ZEB1', 'Gene', (197, 201))	('shortened', 'NegReg', (138, 147))	('ZEB1', 'Gene', '6935', (197, 201))	('patients', 'Species', '9606', (161, 169))	('haploinsufficiency', 'Disease', 'MESH:D058495', (101, 119))
153533	28246407	It is not surprising, given the dual nature of ZEB1 to be both activator and repressor, that the presence and absence of ZEB1 affects divergent GCSC functions.	('ZEB1', 'Gene', '6935', (121, 125))	('GCSC functions', 'CPA', (144, 158))	('presence', 'Var', (97, 105))	('ZEB1', 'Gene', (47, 51))	('ZEB1', 'Gene', '6935', (47, 51))	('affects', 'Reg', (126, 133))	('absence', 'Var', (110, 117))	('GCSC', 'Chemical', '-', (144, 148))	('ZEB1', 'Gene', (121, 125))
153546	28246407	LOH of chromosome 10 occurs only in GBMs while LOH of ZEB1 occurs in both GBM and lower grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('LOH', 'Var', (0, 3))	('ZEB1', 'Gene', (54, 58))	('ZEB1', 'Gene', '6935', (54, 58))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
153554	28246407	The fact that both lower grade gliomas and GBMs display similar rates of LOH of ZEB1 despite the chromosomal loss in GBMs but not in lower grade gliomas suggests the independent occurrence of LOH at ZEB1.	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('ZEB1', 'Gene', '6935', (80, 84))	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('ZEB1', 'Gene', (80, 84))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('chromosomal loss', 'Var', (97, 113))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('ZEB1', 'Gene', (199, 203))	('LOH', 'NegReg', (73, 76))	('ZEB1', 'Gene', '6935', (199, 203))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Disease', (145, 152))	('gliomas', 'Disease', (31, 38))
153563	28246407	These findings have the potential of impacting medical practice by demonstrating that ZEB1 mutation, gene deletion and LOH impact patient survival.	('ZEB1', 'Gene', (86, 90))	('patient', 'Species', '9606', (130, 137))	('mutation', 'Var', (91, 99))	('impacting', 'Reg', (37, 46))	('ZEB1', 'Gene', '6935', (86, 90))	('LOH', 'Var', (119, 122))	('impact', 'Reg', (123, 129))	('gene deletion', 'Var', (101, 114))	('patient survival', 'CPA', (130, 146))
153564	28246407	ZEB1 deletion and expression can be used to prognosticate glioblastoma patients with greater accuracy.	('deletion', 'Var', (5, 13))	('patients', 'Species', '9606', (71, 79))	('glioblastoma', 'Disease', (58, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('ZEB1', 'Gene', (0, 4))	('glioblastoma', 'Disease', 'MESH:D005909', (58, 70))	('ZEB1', 'Gene', '6935', (0, 4))
153565	28246407	Deletion may be evaluated with other gene mutations of gliomas to further aid prognostication.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('Deletion', 'Var', (0, 8))
153577	28246407	Our approach to the role of ZEB1 copy number loss utilized the following methods assembling a variety of resources.	('copy number loss', 'Var', (33, 49))	('ZEB1', 'Gene', (28, 32))	('ZEB1', 'Gene', '6935', (28, 32))
153580	28246407	Our findings were supported by analyzing GBM patient samples from Cedars-Sinai Medical Center and 238 glioblastoma patient samples for ZEB1 deletion downloaded from the TCGA data portal (https://tcga-data.nci.nih.gov/tcga/).	('ZEB1', 'Gene', (135, 139))	('glioblastoma', 'Disease', (102, 114))	('ZEB1', 'Gene', '6935', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (41, 44))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('patient', 'Species', '9606', (45, 52))	('deletion', 'Var', (140, 148))	('patient', 'Species', '9606', (115, 122))
153581	28246407	We further confirmed ZEB1 deletion through cBioportal and the COSMIC database (frozen Jan 2014).	('ZEB1', 'Gene', (21, 25))	('ZEB1', 'Gene', '6935', (21, 25))	('deletion', 'Var', (26, 34))
153610	18713462	have suggested that multiple class I HDAC members are also involved in repressing p21 and that the growth inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.	('HDAC', 'Gene', (223, 227))	('HDAC', 'Gene', '9734', (223, 227))	('p21', 'Gene', '1026', (82, 85))	('apoptotic effects', 'CPA', (121, 138))	('growth inhibitory', 'CPA', (99, 116))	('HDAC', 'Gene', (37, 41))	('inhibitors', 'Var', (155, 165))	('HDAC', 'Gene', (150, 154))	('HDAC', 'Gene', '9734', (37, 41))	('p21', 'Gene', (82, 85))	('HDAC', 'Gene', '9734', (150, 154))
153726	31171769	Silencing of microRNA-708 promotes cell growth and epithelial-to-mesenchymal transition by activating the SPHK2/AKT/beta-catenin pathway in glioma Aberrant microRNA-708 (miR-708) expression is frequently reported in cancer studies; however, its role in glioma has not been examined in detail.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('miR-708', 'Gene', (170, 177))	('cancer', 'Disease', (216, 222))	('Silencing', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('epithelial-to-mesenchymal transition', 'CPA', (51, 87))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('AKT', 'Gene', '207', (112, 115))	('SPHK2', 'Gene', (106, 111))	('SPHK2', 'Gene', '56848', (106, 111))	('miR-708', 'Gene', '100126333', (170, 177))	('microRNA-708', 'Gene', (13, 25))	('microRNA-708', 'Gene', '100126333', (156, 168))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('beta-catenin', 'Gene', (116, 128))	('activating', 'PosReg', (91, 101))	('beta-catenin', 'Gene', '1499', (116, 128))	('microRNA-708', 'Gene', (156, 168))	('microRNA-708', 'Gene', '100126333', (13, 25))	('promotes', 'PosReg', (26, 34))	('glioma', 'Disease', (253, 259))	('glioma', 'Disease', (140, 146))	('AKT', 'Gene', (112, 115))	('glioma', 'Disease', 'MESH:D005910', (253, 259))	('cell growth', 'CPA', (35, 46))
153728	31171769	Restoration of miR-708 inhibited glioma cell growth and invasion both in vitro and in vivo.	('inhibited', 'NegReg', (23, 32))	('glioma', 'Disease', (33, 39))	('Restoration', 'Var', (0, 11))	('miR-708', 'Gene', '100126333', (15, 22))	('miR-708', 'Gene', (15, 22))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('invasion', 'CPA', (56, 64))
153738	31171769	Abnormal expression of miRNAs often contributes to the progression and metastasis of human cancers, including glioma.	('metastasis of human cancers', 'Disease', (71, 98))	('Abnormal expression', 'Var', (0, 19))	('glioma', 'Disease', (110, 116))	('miR', 'Gene', (23, 26))	('miR', 'Gene', '220972', (23, 26))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('contributes to', 'Reg', (36, 50))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('metastasis of human cancers', 'Disease', 'MESH:D009362', (71, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('progression', 'CPA', (55, 66))
153740	31171769	Several studies have revealed that miR-708 functions as a tumor suppressor, and miR-708 misregulation often contributes to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('miR-708', 'Gene', '100126333', (35, 42))	('miR-708', 'Gene', (35, 42))	('miR-708', 'Gene', '100126333', (80, 87))	('miR-708', 'Gene', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('contributes', 'Reg', (108, 119))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('misregulation', 'Var', (88, 101))
153742	31171769	Several studies have demonstrated that abnormal AKT signaling activity is associated with tumor progression, including glioma.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('activity', 'MPA', (62, 70))	('AKT', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('glioma', 'Disease', (119, 125))	('abnormal', 'Var', (39, 47))	('AKT', 'Gene', '207', (48, 51))	('associated', 'Reg', (74, 84))
153748	31171769	Epigenetic silencing through DNA methylation is one of the many mechanisms by which miRNAs suppress cancer in humans.	('miR', 'Gene', '220972', (84, 87))	('humans', 'Species', '9606', (110, 116))	('miR', 'Gene', (84, 87))	('suppress', 'NegReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('DNA methylation', 'Var', (29, 44))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
153753	31171769	Our study elucidated a link between miR-708 inactivation and the SPHK2/AKT/beta-catenin pathway, thereby providing new insight into the potential use of miR-708 in the development of novel therapeutic strategies for treating glioma.	('miR-708', 'Gene', '100126333', (153, 160))	('beta-catenin', 'Gene', '1499', (75, 87))	('AKT', 'Gene', '207', (71, 74))	('SPHK2', 'Gene', (65, 70))	('miR-708', 'Gene', '100126333', (36, 43))	('miR-708', 'Gene', (153, 160))	('glioma', 'Disease', (225, 231))	('SPHK2', 'Gene', '56848', (65, 70))	('miR-708', 'Gene', (36, 43))	('beta-catenin', 'Gene', (75, 87))	('AKT', 'Gene', (71, 74))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('inactivation', 'Var', (44, 56))	('glioma', 'Disease', 'MESH:D005910', (225, 231))
153759	31171769	Thus, we determined whether the restoration of miR-708 expression inhibited glioma cell growth and invasion.	('glioma', 'Disease', (76, 82))	('miR-708', 'Gene', '100126333', (47, 54))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('expression', 'MPA', (55, 65))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('restoration', 'Var', (32, 43))	('inhibited', 'NegReg', (66, 75))	('miR-708', 'Gene', (47, 54))
153781	31171769	Overall, these results suggest that restoration of miR-708 can reverse the EMT phenotype in glioma cells.	('miR-708', 'Gene', (51, 58))	('restoration', 'Var', (36, 47))	('glioma', 'Disease', (92, 98))	('EMT', 'CPA', (75, 78))	('miR-708', 'Gene', '100126333', (51, 58))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
153816	31171769	Restoration of miR-708 could counteract EZH2 overexpression effect on glioma cell growth and invasion (Supplementary Fig.	('glioma', 'Disease', (70, 76))	('Restoration', 'Var', (0, 11))	('miR-708', 'Gene', '100126333', (15, 22))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('miR-708', 'Gene', (15, 22))	('invasion', 'CPA', (93, 101))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))
153827	31171769	Similarly, abnormal expression of miR-708 contributes to the incidence of breast cancer, bladder cancer, and larynx carcinoma.	('breast cancer', 'Disease', (74, 87))	('miR-708', 'Gene', (34, 41))	('larynx carcinoma', 'Phenotype', 'HP:0012118', (109, 125))	('expression', 'MPA', (20, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('abnormal', 'Var', (11, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('larynx carcinoma', 'Disease', (109, 125))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miR-708', 'Gene', '100126333', (34, 41))	('larynx carcinoma', 'Disease', 'MESH:D007822', (109, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
153834	31171769	However, in high-grade gliomas (WHO III-IV grade), patients with high expression of miR-708 exhibited better survival than those with low miR-708 levels.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('miR-708', 'Gene', (138, 145))	('better', 'PosReg', (102, 108))	('miR-708', 'Gene', '100126333', (84, 91))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('patients', 'Species', '9606', (51, 59))	('miR-708', 'Gene', (84, 91))	('high expression', 'Var', (65, 80))	('survival', 'CPA', (109, 117))	('miR-708', 'Gene', '100126333', (138, 145))
153839	31171769	IDH1 mutations in glioma have different clinical outcomes.	('glioma', 'Disease', (18, 24))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
153841	31171769	Further investigation is urgently required to clarify the association between miR-708 and IDH1 mutations in glioma.	('IDH1', 'Gene', (90, 94))	('association', 'Interaction', (58, 69))	('glioma', 'Disease', (108, 114))	('IDH1', 'Gene', '3417', (90, 94))	('miR-708', 'Gene', '100126333', (78, 85))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('miR-708', 'Gene', (78, 85))	('mutations', 'Var', (95, 104))
153843	31171769	Furthermore, the restoration of miR-708 inhibited glioma cell invasion both in vitro and in vivo.	('miR-708', 'Gene', '100126333', (32, 39))	('inhibited', 'NegReg', (40, 49))	('glioma', 'Disease', (50, 56))	('miR-708', 'Gene', (32, 39))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('restoration', 'Var', (17, 28))
153853	31171769	Abnormal SPHK2 expression usually promotes cancer cell proliferation and invasion, and SPHK2 protein expression is frequently elevated in glioma tissues and correlates with poor patient survival.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('glioma', 'Disease', (138, 144))	('cancer', 'Disease', (43, 49))	('promotes', 'PosReg', (34, 42))	('SPHK2', 'Gene', (87, 92))	('protein', 'Protein', (93, 100))	('patient', 'Species', '9606', (178, 185))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('SPHK2', 'Gene', (9, 14))	('expression', 'MPA', (15, 25))	('Abnormal', 'Var', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('elevated', 'PosReg', (126, 134))	('invasion', 'CPA', (73, 81))	('SPHK2', 'Gene', '56848', (87, 92))	('expression', 'MPA', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('SPHK2', 'Gene', '56848', (9, 14))
153861	31171769	AKT-mediated phosphorylation of beta-catenin causes it to disassociate from cell-cell contacts and accumulate in both the cytosol and the nucleus, and beta-catenin phosphorylation by AKT increases its transcriptional activity and promotes tumor cell invasion.	('AKT', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('beta-catenin', 'Gene', '1499', (151, 163))	('AKT', 'Gene', (183, 186))	('beta-catenin', 'Gene', (32, 44))	('promotes', 'PosReg', (230, 238))	('transcriptional', 'MPA', (201, 216))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('beta-catenin', 'Gene', '1499', (32, 44))	('increases', 'PosReg', (187, 196))	('phosphorylation', 'Var', (164, 179))	('AKT', 'Gene', '207', (0, 3))	('tumor', 'Disease', (239, 244))	('beta-catenin', 'Gene', (151, 163))	('AKT', 'Gene', '207', (183, 186))
153864	31171769	In addition, our findings revealed that beta-catenin knockdown decreased glioma cell growth and invasion.	('glioma', 'Disease', (73, 79))	('knockdown', 'Var', (53, 62))	('decreased', 'NegReg', (63, 72))	('invasion', 'CPA', (96, 104))	('beta-catenin', 'Gene', (40, 52))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('beta-catenin', 'Gene', '1499', (40, 52))
153872	31171769	A recent study revealed that PRC2-induced H3K27me3 contributed to the down-regulation of miR-708 in metastatic cancer cells.	('down-regulation', 'NegReg', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-708', 'Gene', '100126333', (89, 96))	('miR-708', 'Gene', (89, 96))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PRC2-induced', 'Gene', (29, 41))	('H3K27me3', 'Var', (42, 50))
153875	31171769	Inhibition of EZH2 or treatment with DZNep can elevate miR-708 expression in LN382 and GBM-GY cells.	('miR-708', 'Gene', '100126333', (55, 62))	('elevate', 'PosReg', (47, 54))	('miR-708', 'Gene', (55, 62))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('expression', 'MPA', (63, 73))	('DZNep', 'Chemical', '-', (37, 42))	('Inhibition', 'Var', (0, 10))
153895	31171769	Cells were co-transfected with the WT or MUT SPHK2 3'-UTR vector and the miR-708 mimic or inhibitor.	('miR-708', 'Gene', (73, 80))	('SPHK2', 'Gene', (45, 50))	('MUT', 'Var', (41, 44))	('SPHK2', 'Gene', '56848', (45, 50))	('miR-708', 'Gene', '100126333', (73, 80))
154008	30677090	The qualitative analysis of the grid voxels based on the HCP-488 template-based white matter architecture (Fig 3 and S1 and S2 Appendices) showed that the IFOF, UF, external capsule, and ATR were the white matter structures most frequently associated with the tumors in sub-insular/basal ganglia voxels (A2-C2-S2 and A3-C2-S2).	('A2-C2-S2', 'Disease', (304, 312))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('A3-C2-S2', 'Var', (317, 325))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('associated with', 'Reg', (240, 255))	('HCP', 'Gene', (57, 60))	('HCP', 'Gene', '1371', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (260, 266))	('A2-C2-S2', 'Disease', 'OMIM:217000', (304, 312))
154041	30677090	On re-analysis using the sovra-impression of the Brain-Grid classification system, the visible shrinkage of tumor volume in T2-FLAIR sequences was clearly associated with a reduced infiltration along the temporo-parietal portion of the sagittal stratum of Sachs.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('shrinkage', 'NegReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('T2-FLAIR', 'Var', (124, 132))	('reduced', 'NegReg', (173, 180))	('tumor', 'Disease', (108, 113))	('infiltration', 'CPA', (181, 193))
154049	30677090	For instance, the IFOF, UF, and external capsule were not the only white matter structures associated in right- and left-sided tumors harboring insular and basal ganglia grid voxels (A2-C2-S2 and A3-C2-S2), but even ATR was found as a different potential direction of tumor spread.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (268, 273))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('A2-C2-S2', 'Disease', 'OMIM:217000', (183, 191))	('A3-C2-S2', 'Var', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('A2-C2-S2', 'Disease', (183, 191))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
154096	27476114	In particular, miR-576-5p, miR-340 and miR-626 were significantly overexpressed, whereas miR-320, let-7 g-5p and miR-7-5p showed significantly low expression in GBM patients.	('miR-340', 'Gene', '442908', (27, 34))	('miR', 'Gene', (39, 42))	('miR-340', 'Gene', (27, 34))	('expression', 'MPA', (147, 157))	('miR-7-5p', 'Gene', (113, 121))	('miR', 'Gene', '220972', (27, 30))	('patients', 'Species', '9606', (165, 173))	('GBM', 'Disease', (161, 164))	('miR', 'Gene', '220972', (113, 116))	('miR-626', 'Gene', (39, 46))	('miR', 'Gene', '220972', (89, 92))	('overexpressed', 'PosReg', (66, 79))	('low', 'NegReg', (143, 146))	('miR', 'Gene', (27, 30))	('miR', 'Gene', (113, 116))	('miR', 'Gene', (89, 92))	('miR-7-5p', 'Gene', '407045', (113, 121))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', '220972', (39, 42))	('miR-626', 'Gene', '693211', (39, 46))	('let-7 g-5p', 'Var', (98, 108))	('miR', 'Gene', (15, 18))
154140	27476114	IDH mutation and MGMT methylation are grade-dependent markers in glioma specimens.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (65, 71))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('mutation', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('MGMT', 'Gene', '4255', (17, 21))	('MGMT', 'Gene', (17, 21))
154141	27476114	Interestingly, regarding IDH1 mutation status, we observed that patients who carry the IDH1 R132H mutation, usually associated with a lower grade glioma, are more likely to have levels of miR-125b and -497 higher while patients carrying IDH-wild type gene have levels of miR-125b and -497 lower than the cut-off values (data not shown).	('IDH', 'Gene', (25, 28))	('associated with', 'Reg', (116, 131))	('miR', 'Gene', (188, 191))	('R132H', 'Var', (92, 97))	('higher', 'PosReg', (206, 212))	('IDH1', 'Gene', (87, 91))	('IDH', 'Gene', (237, 240))	('IDH1', 'Gene', '3417', (25, 29))	('IDH', 'Gene', '3417', (25, 28))	('miR', 'Gene', '220972', (271, 274))	('glioma', 'Disease', (146, 152))	('IDH', 'Gene', (87, 90))	('125b', 'Chemical', '-', (275, 279))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('patients', 'Species', '9606', (219, 227))	('IDH', 'Gene', '3417', (237, 240))	('IDH1', 'Gene', '3417', (87, 91))	('miR', 'Gene', (271, 274))	('IDH', 'Gene', '3417', (87, 90))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('levels', 'MPA', (178, 184))	('patients', 'Species', '9606', (64, 72))	('125b', 'Chemical', '-', (192, 196))	('miR', 'Gene', '220972', (188, 191))	('IDH1', 'Gene', (25, 29))
154153	27476114	The highest accuracy was at a cut-off expression value 0.00083 (miR-497) and 0.00065 (miR-125b), where the negative predictive value, positive predictive value, sensitivity, and specificity to identify a patient with GBM were 0.909, 0.800, 0.889, 0.833 for miR-497 and 0.889, 0.667, 0.889, 0.667 for miR-125b.	('125b', 'Chemical', '-', (304, 308))	('miR-497', 'Gene', (64, 71))	('miR', 'Gene', '220972', (64, 67))	('miR-497', 'Gene', '574456', (64, 71))	('miR', 'Gene', (64, 67))	('miR', 'Gene', (257, 260))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('miR-497', 'Gene', (257, 264))	('miR', 'Gene', '220972', (257, 260))	('miR-497', 'Gene', '574456', (257, 264))	('125b', 'Chemical', '-', (90, 94))	('miR', 'Gene', '220972', (300, 303))	('miR', 'Gene', (300, 303))	('0.00065', 'Var', (77, 84))	('patient', 'Species', '9606', (204, 211))
154217	24714505	In a recent Children's Oncology Group study, GTR was associated with an 8-year progression-free survival (PFS) of 93% and an overall survival (OS) of >99%.	('Oncology', 'Phenotype', 'HP:0002664', (23, 31))	('progression-free survival', 'CPA', (79, 104))	('Children', 'Species', '9606', (12, 20))	('GTR', 'Var', (45, 48))	('OS', 'Chemical', '-', (143, 145))
154296	25243911	Glioma Cells with the IDH1 Mutation Modulate Metabolic Fractional Flux through Pyruvate Carboxylase Over 70% of low-grade gliomas carry a heterozygous R132H mutation in the gene coding for isocitrate dehydrogenase 1 (IDH1).	('R132H', 'Var', (151, 156))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('R132H', 'Mutation', 'rs121913500', (151, 156))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH1', 'Gene', (22, 26))	('Mutation', 'Var', (27, 35))	('IDH1', 'Gene', (217, 221))	('IDH1', 'Gene', '3417', (22, 26))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('isocitrate dehydrogenase 1', 'Gene', (189, 215))	('gliomas', 'Disease', (122, 129))	('isocitrate dehydrogenase 1', 'Gene', '3417', (189, 215))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('Modulate', 'Reg', (36, 44))	('IDH1', 'Gene', '3417', (217, 221))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
154300	25243911	The goal of this study was to determine whether PC serves as a source of TCA anaplerosis in IDH1 mutant cells wherein glutamine is used for 2-hydroxyglutarate production.	('PC', 'Gene', '5091', (48, 50))	('glutamine', 'Chemical', 'MESH:D005973', (118, 127))	('IDH1', 'Gene', (92, 96))	('mutant', 'Var', (97, 103))	('TCA', 'Chemical', 'MESH:D014233', (73, 76))	('IDH1', 'Gene', '3417', (92, 96))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (140, 158))	('TCA anaplerosis', 'MPA', (73, 88))
154301	25243911	Immortalized normal human astrocytes engineered to express heterozygous mutant IDH1 or wild-type IDH1 were investigated.	('IDH1', 'Gene', '3417', (79, 83))	('human', 'Species', '9606', (20, 25))	('IDH1', 'Gene', (97, 101))	('mutant', 'Var', (72, 78))	('IDH1', 'Gene', '3417', (97, 101))	('IDH1', 'Gene', (79, 83))
154305	25243911	Compared to wild-type cells, mutant IDH1 cells significantly increased fractional flux through PC.	('IDH1', 'Gene', (36, 40))	('mutant', 'Var', (29, 35))	('increased', 'PosReg', (61, 70))	('IDH1', 'Gene', '3417', (36, 40))	('PC', 'Gene', '5091', (95, 97))
154308	25243911	Consistent with the observation in cells, analysis of TCGA data indicated a significant increase in PC expression in mutant IDH-expressing human glioma samples compared to wild-type IDH.	('glioma', 'Disease', (145, 151))	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', '3417', (182, 185))	('mutant', 'Var', (117, 123))	('expression', 'MPA', (103, 113))	('PC', 'Gene', '5091', (100, 102))	('IDH', 'Gene', '3417', (124, 127))	('increase', 'PosReg', (88, 96))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('human', 'Species', '9606', (139, 144))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('IDH', 'Gene', (182, 185))
154309	25243911	Our findings suggest that changes in PC and PDH may be an important part of cellular adaptation to the IDH1 mutation and may serve as potential therapeutic targets.	('IDH1', 'Gene', '3417', (103, 107))	('PDH', 'Gene', (44, 47))	('PDH', 'Gene', '54704', (44, 47))	('mutation', 'Var', (108, 116))	('PC', 'Gene', '5091', (37, 39))	('IDH1', 'Gene', (103, 107))
154313	25243911	Specifically, 60-90% of low-grade gliomas and secondary glioblastomas harbor a heterozygous R132H mutation in the gene coding for the cytosolic isoform of isocitrate dehydrogenase (IDH1).	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('glioblastomas', 'Disease', (56, 69))	('isocitrate', 'Chemical', 'MESH:C034219', (155, 165))	('IDH1', 'Gene', (181, 185))	('glioblastomas', 'Phenotype', 'HP:0012174', (56, 69))	('R132H', 'Var', (92, 97))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('IDH1', 'Gene', '3417', (181, 185))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('glioblastomas', 'Disease', 'MESH:D005909', (56, 69))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
154315	25243911	The wild-type form of IDH1 catalyzes the conversion of isocitrate to alpha-ketoglutarate (alpha-KG) whereas the mutant enzyme acquires the novel ability to convert alpha-KG into 2-hydroxyglutarate (2-HG), a so-called "oncometabolite" not normally found in cells at appreciable concentrations.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (69, 88))	('alpha-KG', 'Chemical', 'MESH:D007656', (90, 98))	('convert', 'MPA', (156, 163))	('isocitrate', 'Chemical', 'MESH:C034219', (55, 65))	('isocitrate', 'MPA', (55, 65))	('IDH1', 'Gene', (22, 26))	('alpha-KG', 'Chemical', 'MESH:D007656', (164, 172))	('mutant', 'Var', (112, 118))	('IDH1', 'Gene', '3417', (22, 26))	('conversion', 'MPA', (41, 51))	('2-HG', 'Chemical', 'MESH:C019417', (198, 202))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (178, 196))
154317	25243911	Metabolically, glutamine is the primary source of 2-HG and mutant IDH1 cells are uniquely sensitive to inhibition of glutaminase, the enzyme that catalyzes the conversion of glutamine to glutamate, which, in turn, can be converted to alpha-KG by transamination.	('IDH1', 'Gene', '3417', (66, 70))	('mutant', 'Var', (59, 65))	('glutamine', 'Chemical', 'MESH:D005973', (15, 24))	('2-HG', 'Chemical', 'MESH:C019417', (50, 54))	('alpha-KG', 'Chemical', 'MESH:D007656', (234, 242))	('glutamine', 'Chemical', 'MESH:D005973', (174, 183))	('glutamate', 'Chemical', 'MESH:D018698', (187, 196))	('IDH1', 'Gene', (66, 70))
154324	25243911	In this context, we questioned whether PC could provide a significant source of TCA anaplerotic flux in mutant IDH1 glioma cells wherein significant amounts of glutamine are channeled towards 2-HG production.	('2-HG', 'Chemical', 'MESH:C019417', (192, 196))	('glutamine', 'Chemical', 'MESH:D005973', (160, 169))	('TCA anaplerotic flux', 'MPA', (80, 100))	('mutant', 'Var', (104, 110))	('glioma', 'Disease', (116, 122))	('IDH1', 'Gene', '3417', (111, 115))	('PC', 'Gene', '5091', (39, 41))	('TCA', 'Chemical', 'MESH:D014233', (80, 83))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('IDH1', 'Gene', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
154327	25243911	We show that fractional PC flux was elevated in cells expressing mutant IDH1 when compared to cells expressing wild-type IDH1.	('IDH1', 'Gene', (121, 125))	('IDH1', 'Gene', (72, 76))	('elevated', 'PosReg', (36, 44))	('IDH1', 'Gene', '3417', (121, 125))	('PC', 'Gene', '5091', (24, 26))	('mutant', 'Var', (65, 71))	('IDH1', 'Gene', '3417', (72, 76))
154329	25243911	Importantly, analysis of The Cancer Genome Atlas (TCGA) data demonstrates that the expression of PC was also significantly elevated in mutant IDH-expressing tumors when compared to wild-type IDH tumors, highlighting the clinical significance of our observations.	('IDH', 'Gene', (191, 194))	('elevated', 'PosReg', (123, 131))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('IDH tumors', 'Disease', (191, 201))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (29, 48))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('IDH', 'Gene', (142, 145))	('mutant', 'Var', (135, 141))	('IDH tumors', 'Disease', 'MESH:D009369', (191, 201))	('IDH', 'Gene', '3417', (191, 194))	('PC', 'Gene', '5091', (97, 99))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('clinical', 'Species', '191496', (220, 228))	('Cancer Genome Atlas', 'Disease', (29, 48))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', (157, 163))	('IDH', 'Gene', '3417', (142, 145))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (157, 163))
154330	25243911	Immortalized normal human astrocytes E6/E7/hTERT (NHA) expressing either the wild-type IDH1 gene (IDHwt cells) or the heterozygous R132H mutant IDH1 gene (IDHmut cells) were generated in the Pieper laboratory by lentiviral transduction as previously described.	('IDH', 'Gene', (144, 147))	('human', 'Species', '9606', (20, 25))	('IDH', 'Gene', (155, 158))	('IDH', 'Gene', '3417', (144, 147))	('R132H', 'Var', (131, 136))	('IDH1', 'Gene', '3417', (87, 91))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (155, 158))	('R132H', 'Mutation', 'rs121913500', (131, 136))	('IDH', 'Gene', '3417', (87, 90))	('IDH1', 'Gene', (144, 148))	('IDH', 'Gene', (98, 101))	('IDH1', 'Gene', (87, 91))	('hTERT', 'CellLine', 'CVCL:4388', (43, 48))	('IDH1', 'Gene', '3417', (144, 148))	('IDH', 'Gene', '3417', (98, 101))
154343	25243911	The subsequent turn of the TCA cycle leads to additional labeling of [2-13C]glutamate/glutamine for PC and [1-13C]glutamate/glutamine and 13CO2 for PDH.	('[1-13C]', 'Var', (107, 114))	('glutamine', 'Chemical', 'MESH:D005973', (124, 133))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('PDH', 'Gene', '54704', (148, 151))	('PC', 'Gene', '5091', (100, 102))	('labeling', 'MPA', (57, 65))	('[2-13C', 'Var', (69, 75))	('TCA', 'Chemical', 'MESH:D014233', (27, 30))	('13CO2', 'Chemical', '-', (138, 143))	('[2-13C]glutamate', 'Chemical', '-', (69, 85))	('[1-13C]glutamate', 'Chemical', '-', (107, 123))	('PDH', 'Gene', (148, 151))
154362	25243911	Cells grown in a 96-well plate were fixed with 4% paraformaldehyde then incubated in phospho-PDH antibodies (Ser293, Ser300, or Ser232) and PDH E1 subunit antibody at 4 C. Following this, cells were incubated in two secondary antibodies: one against the phospho-PDH antibody and conjugated to horseradish peroxidase, and another against the PDH E1 subunit antibody and conjugated to alkaline phosphatase.	('PDH', 'Gene', '54704', (262, 265))	('PDH', 'Gene', '54704', (93, 96))	('horseradish', 'Species', '3704', (293, 304))	('Ser293', 'Var', (109, 115))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (50, 66))	('Ser300', 'Chemical', '-', (117, 123))	('PDH', 'Gene', '54704', (341, 344))	('Ser300', 'Var', (117, 123))	('PDH', 'Gene', (140, 143))	('PDH', 'Gene', (262, 265))	('Ser232', 'Chemical', '-', (128, 134))	('PDH', 'Gene', (93, 96))	('PDH', 'Gene', '54704', (140, 143))	('Ser232', 'Var', (128, 134))	('PDH', 'Gene', (341, 344))
154364	25243911	A horseradish peroxidase substrate was subsequently added and color development was measured spectrophotometrically in kinetic mode at 600 nm (Tecan); the rate of color development represents the quantity of phospho-PDH at Ser232, Ser293, or Ser300.	('Ser293', 'Var', (231, 237))	('Ser232', 'Chemical', '-', (223, 229))	('Ser300', 'Var', (242, 248))	('horseradish', 'Species', '3704', (2, 13))	('Tecan', 'Chemical', '-', (143, 148))	('PDH', 'Gene', (216, 219))	('Ser300', 'Chemical', '-', (242, 248))	('Ser232', 'Var', (223, 229))	('PDH', 'Gene', '54704', (216, 219))
154370	25243911	To determine whether fractional flux via PC was increased in mutant IDH1 cells compared to wild-type, we therefore incubated cells with [2-13C]glucose and acquired 13C MR spectra of cell extracts post incubation (Figure 2).	('increased', 'PosReg', (48, 57))	('fractional flux', 'MPA', (21, 36))	('[2-13C]glucose', 'Chemical', '-', (136, 150))	('PC', 'Gene', '5091', (41, 43))	('IDH1', 'Gene', (68, 72))	('13C', 'Chemical', '-', (139, 142))	('mutant', 'Var', (61, 67))	('IDH1', 'Gene', '3417', (68, 72))	('13C', 'Chemical', '-', (164, 167))
154373	25243911	[5-13C]glutamate (182.0 ppm) and [5-13C]glutamine (178.4 ppm) result from the first turn of the TCA cycle after pyruvate flux through PDH, and [1-13C]glutamate (175.6 ppm) and [1-13C]glutamine (175.2 ppm) result from the second turn of the TCA cycle.	('182.0', 'Var', (18, 23))	('[5-13C]', 'Var', (33, 40))	('pyruvate', 'Chemical', 'MESH:D019289', (112, 120))	('[5-13C]glutamine', 'Chemical', '-', (33, 49))	('[1-13C]glutamate', 'Chemical', '-', (143, 159))	('TCA', 'Chemical', 'MESH:D014233', (96, 99))	('PDH', 'Gene', (134, 137))	('[5-13C]', 'Var', (0, 7))	('175.2', 'Var', (194, 199))	('TCA', 'Chemical', 'MESH:D014233', (240, 243))	('pyruvate flux', 'MPA', (112, 125))	('PDH', 'Gene', '54704', (134, 137))	('[5-13C]glutamate', 'Chemical', '-', (0, 16))	('178.4', 'Var', (51, 56))	('[1-13C]glutamine', 'Chemical', '-', (176, 192))
154374	25243911	When comparing mutant and wild-type IDH1 cells, we observed a significant decrease in both the PDH-derived and PC-derived labeled glutamate levels (Table 1).	('PDH', 'Gene', (95, 98))	('decrease', 'NegReg', (74, 82))	('IDH1', 'Gene', (36, 40))	('PDH', 'Gene', '54704', (95, 98))	('IDH1', 'Gene', '3417', (36, 40))	('PC', 'Gene', '5091', (111, 113))	('mutant', 'Var', (15, 21))	('glutamate', 'Chemical', 'MESH:D018698', (130, 139))
154388	25243911	Thus both an increase in cellular PC activity and a decrease in cellular PDH activity likely contribute to the change in fractional fluxes observed in our NHA cells expressing mutant IDH1 when compared to cells expressing wild-type IDH1.	('PDH', 'Gene', '54704', (73, 76))	('IDH1', 'Gene', '3417', (183, 187))	('mutant', 'Var', (176, 182))	('IDH1', 'Gene', (232, 236))	('fractional fluxes', 'MPA', (121, 138))	('IDH1', 'Gene', '3417', (232, 236))	('PDH', 'Gene', (73, 76))	('increase', 'PosReg', (13, 21))	('decrease', 'NegReg', (52, 60))	('activity', 'MPA', (77, 85))	('IDH1', 'Gene', (183, 187))	('PC', 'Gene', '5091', (34, 36))
154389	25243911	In an effort to explain the changes in cellular enzyme activities, we investigated whether the transcript expression of PC and PDH was altered in cells expressing mutant IDH1 (Figure 4B).	('IDH1', 'Gene', (170, 174))	('transcript', 'MPA', (95, 105))	('PDH', 'Gene', (127, 130))	('mutant', 'Var', (163, 169))	('IDH1', 'Gene', '3417', (170, 174))	('altered', 'Reg', (135, 142))	('PDH', 'Gene', '54704', (127, 130))	('PC', 'Gene', '5091', (120, 122))
154394	25243911	The activity of PDH is also modulated by inhibitory phosphorylation at three serine sites: Ser232, Ser293, and Ser300.	('Ser232', 'Chemical', '-', (91, 97))	('Ser293', 'Var', (99, 105))	('Ser232', 'Var', (91, 97))	('Ser300', 'Chemical', '-', (111, 117))	('PDH', 'Gene', '54704', (16, 19))	('activity', 'MPA', (4, 12))	('inhibitory phosphorylation', 'MPA', (41, 67))	('modulated', 'Reg', (28, 37))	('Ser300', 'Var', (111, 117))	('serine', 'Chemical', 'MESH:D012694', (77, 83))	('PDH', 'Gene', (16, 19))
154405	25243911	The mean normalized expression scores (z-scores) for PC were significantly elevated in IDH mutant de novo glioblastoma (1.364 vs. -0.1322, n = 8 and n = 146, respectively, p<0.0057).	('glioblastoma', 'Disease', (106, 118))	('IDH', 'Gene', (87, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('elevated', 'PosReg', (75, 83))	('IDH', 'Gene', '3417', (87, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('PC', 'Gene', '5091', (53, 55))	('expression scores', 'MPA', (20, 37))	('mutant', 'Var', (91, 97))
154411	25243911	In mutant IDH1 glioma cells, glutamine is used for the production of 2-HG.	('IDH1', 'Gene', '3417', (10, 14))	('mutant', 'Var', (3, 9))	('glutamine', 'Chemical', 'MESH:D005973', (29, 38))	('2-HG', 'Chemical', 'MESH:C019417', (69, 73))	('glioma', 'Disease', (15, 21))	('IDH1', 'Gene', (10, 14))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
154412	25243911	The goal of this study was to determine whether mutant IDH1 cells also increase their fractional flux via PC as a source of TCA anaplerosis.	('mutant', 'Var', (48, 54))	('PC', 'Gene', '5091', (106, 108))	('IDH1', 'Gene', '3417', (55, 59))	('TCA', 'Chemical', 'MESH:D014233', (124, 127))	('increase', 'PosReg', (71, 79))	('TCA', 'MPA', (124, 127))	('IDH1', 'Gene', (55, 59))
154413	25243911	By probing the metabolism of [2-13C]glucose into 13C-labeled glutamate in mutant and wild-type IDH1-expressing cells, we found that PC fractional flux ranges from 16% to 19% in our cells and that this flux increased significantly in mutant IDH1 cells when compared to wild-type cells.	('mutant', 'Var', (233, 239))	('IDH1', 'Gene', '3417', (95, 99))	('IDH1', 'Gene', '3417', (240, 244))	('increased', 'PosReg', (206, 215))	('13C', 'Chemical', '-', (49, 52))	('IDH1', 'Gene', (240, 244))	('IDH1', 'Gene', (95, 99))	('13C', 'Chemical', '-', (32, 35))	('PC', 'Gene', '5091', (132, 134))	('mutant', 'Var', (74, 80))	('[2-13C]glucose', 'Chemical', '-', (29, 43))	('glutamate', 'Chemical', 'MESH:D018698', (61, 70))
154418	25243911	Thus glioblastoma cells generally appear to have a lower PC flux than the normal brain, but, as indicated in our study, mutant IDH1 cells have a higher PC flux that wild-type IDH1 cells.	('IDH1', 'Gene', '3417', (175, 179))	('glioblastoma', 'Disease', (5, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (5, 17))	('glioblastoma', 'Phenotype', 'HP:0012174', (5, 17))	('IDH1', 'Gene', (127, 131))	('IDH1', 'Gene', (175, 179))	('PC', 'Gene', '5091', (152, 154))	('IDH1', 'Gene', '3417', (127, 131))	('PC', 'Gene', '5091', (57, 59))	('mutant', 'Var', (120, 126))	('higher', 'PosReg', (145, 151))
154419	25243911	This would indicate that mutant IDH1-expressing cells reduce their PC flux during transformation to a somewhat lesser degree than wild-type IDH1 cells.	('IDH1', 'Gene', '3417', (140, 144))	('mutant', 'Var', (25, 31))	('IDH1', 'Gene', (32, 36))	('reduce', 'NegReg', (54, 60))	('IDH1', 'Gene', '3417', (32, 36))	('IDH1', 'Gene', (140, 144))	('PC', 'Gene', '5091', (67, 69))
154423	25243911	When considering the level of 13C glutamate labeling in our mutant and wild-type IDH1 cells, it is of interest to compare this to the total cellular content of glutamate previously reported in our cells based on their 1H-MRS spectra.	('IDH1', 'Gene', '3417', (81, 85))	('13C glutamate', 'Chemical', '-', (30, 43))	('glutamate', 'Chemical', 'MESH:D018698', (34, 43))	('IDH1', 'Gene', (81, 85))	('glutamate', 'Chemical', 'MESH:D018698', (160, 169))	('mutant', 'Var', (60, 66))	('1H', 'Chemical', '-', (218, 220))
154437	25243911	In our model the IDH1 mutation was accompanied by an increase in cellular PC activity, as well as an increase in PC expression.	('mutation', 'Var', (22, 30))	('PC', 'Gene', '5091', (113, 115))	('increase', 'PosReg', (101, 109))	('increase', 'PosReg', (53, 61))	('IDH1', 'Gene', (17, 21))	('IDH1', 'Gene', '3417', (17, 21))	('PC', 'Gene', '5091', (74, 76))
154438	25243911	To our knowledge, no studies have reported on epigenetic changes associated with PC, and further studies are needed to assess the reasons for the increase in PC expression in mutant IDH1 cells.	('IDH1', 'Gene', '3417', (182, 186))	('PC', 'Gene', '5091', (158, 160))	('increase', 'PosReg', (146, 154))	('expression', 'MPA', (161, 171))	('IDH1', 'Gene', (182, 186))	('mutant', 'Var', (175, 181))	('PC', 'Gene', '5091', (81, 83))
154439	25243911	Nonetheless, our analysis of TCGA data indicates that PC expression is significantly up in mutant IDH-expressing human tumors when compared to wild-type IDH, both in the low-grade and high-grade cohorts, highlighting the clinical significance of our observations.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('expression', 'MPA', (57, 67))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('clinical', 'Species', '191496', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', '3417', (98, 101))	('mutant', 'Var', (91, 97))	('IDH', 'Gene', '3417', (153, 156))	('PC', 'Gene', '5091', (54, 56))	('human', 'Species', '9606', (113, 118))
154440	25243911	Thus, PC flux could serve as a source of TCA anaplerosis in mutant IDH1 cells that channel glutamine to 2-HG production.	('TCA', 'Chemical', 'MESH:D014233', (41, 44))	('2-HG', 'Chemical', 'MESH:C019417', (104, 108))	('IDH1', 'Gene', (67, 71))	('PC', 'Gene', '5091', (6, 8))	('glutamine', 'Chemical', 'MESH:D005973', (91, 100))	('IDH1', 'Gene', '3417', (67, 71))	('mutant', 'Var', (60, 66))	('channel glutamine to 2-HG production', 'MPA', (83, 119))
154441	25243911	As such, increased PC expression likely contributes to the metabolic adaptation of mutant IDH1 cells.	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (90, 94))	('mutant', 'Var', (83, 89))	('increased', 'PosReg', (9, 18))	('contributes', 'Reg', (40, 51))	('PC', 'Gene', '5091', (19, 21))
154443	25243911	Our IDHmut cell line showed decreased fractional flux through PDH, accompanied by a decrease in cellular PDH activity, which is most likely due to the increase in inhibitory phosphorylation of PDH observed at Ser293 and 300.	('decrease', 'NegReg', (84, 92))	('fractional flux', 'MPA', (38, 53))	('decreased', 'NegReg', (28, 37))	('IDH', 'Gene', '3417', (4, 7))	('cellular', 'MPA', (96, 104))	('PDH', 'Gene', '54704', (193, 196))	('Ser293', 'Var', (209, 215))	('increase', 'PosReg', (151, 159))	('PDH', 'Gene', '54704', (105, 108))	('PDH', 'Gene', (62, 65))	('PDH', 'Gene', '54704', (62, 65))	('inhibitory phosphorylation', 'MPA', (163, 189))	('PDH', 'Gene', (193, 196))	('PDH', 'Gene', (105, 108))	('IDH', 'Gene', (4, 7))
154446	25243911	Both kinases can phosphorylate Ser293 and Ser300, but only PDK1 is known to phosphorylate Ser232.	('Ser300', 'Chemical', '-', (42, 48))	('PDK1', 'Gene', '5163', (59, 63))	('PDK1', 'Gene', (59, 63))	('Ser232', 'Chemical', '-', (90, 96))	('Ser293', 'Var', (31, 37))	('Ser300', 'Var', (42, 48))
154448	25243911	A reduced PDH fractional flux, as observed in our mutant IDH1 cells, would facilitate the accumulation of metabolic building blocks required for cellular proliferation.	('reduced', 'NegReg', (2, 9))	('IDH1', 'Gene', (57, 61))	('PDH', 'Gene', (10, 13))	('mutant', 'Var', (50, 56))	('facilitate', 'PosReg', (75, 85))	('IDH1', 'Gene', '3417', (57, 61))	('PDH', 'Gene', '54704', (10, 13))
154450	25243911	In summary, we first performed an in-depth study in an immortalized astrocyte cell model that expresses heterozygous mutant IDH1 or wild-type IDH1.	('IDH1', 'Gene', '3417', (142, 146))	('mutant', 'Var', (117, 123))	('IDH1', 'Gene', '3417', (124, 128))	('IDH1', 'Gene', (124, 128))	('IDH1', 'Gene', (142, 146))
154451	25243911	The IDH1 mutation in low-grade gliomas is likely an early event in tumorigenesis and subsequent mutations follow, creating the characteristic cellular phenotype and natural history of disease in patients.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patients', 'Species', '9606', (195, 203))	('IDH1', 'Gene', (4, 8))	('tumor', 'Disease', (67, 72))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('mutations', 'Var', (96, 105))	('gliomas', 'Disease', (31, 38))
154453	25243911	However, because it provides a controlled system to isolate the effects of the IDH1 mutation, we hypothesized that this approach was valuable in identifying the metabolic events that result specifically from the IDH1 mutation.	('IDH1', 'Gene', '3417', (79, 83))	('mutation', 'Var', (217, 225))	('IDH1', 'Gene', (212, 216))	('IDH1', 'Gene', '3417', (212, 216))	('IDH1', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
154455	25243911	To the best of our knowledge this is the first study showing that presence of the IDH1 mutation leads to modulation of PC flux in glioma cells.	('PC', 'Gene', '5091', (119, 121))	('presence', 'Var', (66, 74))	('glioma', 'Disease', (130, 136))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (82, 86))	('mutation', 'Var', (87, 95))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('modulation', 'MPA', (105, 115))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
154456	25243911	Combined with the clinical data, our findings indicate that increased PC expression and activity could be essential for survival of mutant IDH1 cells and, as such, could serve as a potential therapeutic target for mutant IDH1 gliomas either alone or in combination with other therapies.	('IDH1', 'Gene', (221, 225))	('IDH1', 'Gene', (139, 143))	('clinical', 'Species', '191496', (18, 26))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('mutant', 'Var', (132, 138))	('PC', 'Gene', '5091', (70, 72))	('mutant', 'Var', (214, 220))	('activity', 'MPA', (88, 96))	('IDH1', 'Gene', '3417', (221, 225))	('IDH1', 'Gene', '3417', (139, 143))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', (226, 233))	('increased', 'PosReg', (60, 69))
154461	32314457	Data analyzed in cBioPortal showed that alterations in FUCA1 (1.4%) were correlated with worse survival in glioblastoma multiforme patients.	('patients', 'Species', '9606', (131, 139))	('glioblastoma multiforme', 'Disease', (107, 130))	('worse', 'NegReg', (89, 94))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (107, 130))	('alterations', 'Var', (40, 51))	('FUCA1', 'Gene', (55, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))
154464	32314457	Mechanistically, transient inhibition of FUCA1 promoted the formation of large acidic vacuoles, as revealed by staining with acridine orange, increased the ratio of LC3-B/LC3-A, and modified the expression of Beclin-1 and Atg12, which are autophagic markers.	('LC3-A', 'Gene', '84557', (171, 176))	('modified', 'Reg', (182, 190))	('expression', 'MPA', (195, 205))	('LC3-A', 'Gene', (171, 176))	('increased', 'PosReg', (142, 151))	('LC3-B', 'Gene', (165, 170))	('formation', 'MPA', (60, 69))	('promoted', 'PosReg', (47, 55))	('LC3-B', 'Gene', '81631', (165, 170))	('Atg12', 'Gene', '9140', (222, 227))	('Atg12', 'Gene', (222, 227))	('acridine orange', 'Chemical', 'MESH:D000165', (125, 140))	('Beclin-1', 'Gene', (209, 217))	('inhibition', 'Var', (27, 37))	('Beclin-1', 'Gene', '8678', (209, 217))	('FUCA1', 'Gene', (41, 46))	('ratio', 'MPA', (156, 161))
154485	32314457	Additionally, in vitro and in vivo functional experiments showed that FUCA1 silencing suppresses glioma growth by enhancing autophagy and inhibiting macrophage infiltration.	('silencing', 'Var', (76, 85))	('glioma growth', 'Disease', (97, 110))	('autophagy', 'CPA', (124, 133))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma growth', 'Disease', 'MESH:D005910', (97, 110))	('inhibiting', 'NegReg', (138, 148))	('suppresses', 'NegReg', (86, 96))	('enhancing', 'PosReg', (114, 123))	('FUCA1', 'Gene', (70, 75))
154491	32314457	The HRP-conjugated secondary Abs and Abs against Atg12 (4180), Beclin (3495), LC3-A/B (12741), F4/80 (70076S), CD11c (97585S), and GAPDH (5174) were from Cell Signaling Technology.	('GAPDH', 'Gene', (131, 136))	('CD11c', 'Gene', '3687', (111, 116))	('LC3-A/B', 'Gene', '84557;81631', (78, 85))	('CD11c', 'Gene', (111, 116))	('Atg12', 'Gene', '9140', (49, 54))	('Atg12', 'Gene', (49, 54))	('12741', 'Var', (87, 92))	('Abs', 'Gene', '51428', (37, 40))	('Abs', 'Gene', '51428', (29, 32))	('4180', 'Var', (56, 60))	('LC3-A/B', 'Gene', (78, 85))	('Beclin', 'Gene', (63, 69))	('HRP-conjugated', 'Protein', (4, 18))	('GAPDH', 'Gene', '2597', (131, 136))	('3495', 'Var', (71, 75))	('Abs', 'Gene', (37, 40))	('Abs', 'Gene', (29, 32))	('70076S', 'Var', (102, 108))	('97585S', 'Var', (118, 124))
154510	32314457	The paraffin-embedded brain tissues were sectioned into slides, and IHC was carried out on a YN-05MY automatic immunohistochemical staining system (Shenzhen Yongnian Technology) with Abs against FUCA1, CD68, F4/80, and CD11c.	('CD68', 'Gene', '968', (202, 206))	('F4/80', 'Var', (208, 213))	('Abs', 'Gene', (183, 186))	('FUCA1', 'Var', (195, 200))	('CD11c', 'Gene', '3687', (219, 224))	('CD11c', 'Gene', (219, 224))	('Abs', 'Gene', '51428', (183, 186))	('CD68', 'Gene', (202, 206))	('paraffin', 'Chemical', 'MESH:D010232', (4, 12))
154514	32314457	In total, 5 x 106 U87 cells stably transfected with LV16 or LV16-shFUCA1 were injected s.c. into the axillary fossa of male athymic BALB/c nude mice.	('nude mice', 'Species', '10090', (139, 148))	('LV16', 'Var', (52, 56))	('LV16-shFUCA1', 'Var', (60, 72))
154526	32314457	Moreover, the results obtained from the "Survival Analyses" module showed that high expression of FUCA1 was marginally associated with worse OS and DFS compared with low expression of FUCA1 in patients with LGG (n = 514) and GBM (n = 162) (Figure 2B).	('patients', 'Species', '9606', (193, 201))	('FUCA1', 'Gene', (98, 103))	('worse OS', 'Disease', (135, 143))	('high expression', 'Var', (79, 94))	('DFS', 'Disease', (148, 151))
154528	32314457	Therefore, it is conceivable that high FUCA1 expression leads to poor prognosis in glioma patients.	('glioma', 'Disease', (83, 89))	('FUCA1', 'Gene', (39, 44))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('high', 'Var', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('patients', 'Species', '9606', (90, 98))
154529	32314457	Furthermore, the data analyzed in cBioPortal showed that FUCA1 was altered in 7 (1.4%) of 585 sequenced patients in TCGA dataset (glioblastoma, TCGA Cell 2013, n = 585), which implied that mutation or DNA copy-number alteration of FUCA1 occurs at a low rate in GBM (Figure 2D).	('glioblastoma', 'Disease', (130, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('mutation', 'Var', (189, 197))	('altered', 'Reg', (67, 74))	('patients', 'Species', '9606', (104, 112))	('FUCA1', 'Gene', (231, 236))
154530	32314457	The alterations in FUCA1 were correlated with worse OS (P = 4.313E-4) in GBM patients; however, there was no significant difference in DFS between patients with and without FUCA1 alterations (P = .262) (Figure 2E).	('alterations', 'Var', (4, 15))	('FUCA1', 'Gene', (19, 24))	('GBM', 'Disease', (73, 76))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (147, 155))
154535	32314457	Furthermore, to evaluate the proof-of-principle influence of FUCA1 on glioma growth in vivo, the U87LV16-shFUCA1 cell line, which stably knocked down FUCA1, or the control cell line U87LV16 was implanted into the flanks of nude mice to establish a mouse s.c. model of human cancer.	('U87LV16', 'CellLine', 'CVCL:0022', (97, 104))	('mouse', 'Species', '10090', (248, 253))	('human', 'Species', '9606', (268, 273))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('FUCA1', 'Gene', (150, 155))	('glioma growth', 'Disease', (70, 83))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('cancer', 'Disease', (274, 280))	('knocked', 'Var', (137, 144))	('glioma growth', 'Disease', 'MESH:D005910', (70, 83))	('U87LV16', 'CellLine', 'CVCL:0022', (182, 189))	('nude mice', 'Species', '10090', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
154536	32314457	As shown in Figure 3G, the mean tumor volume of the mice in the LV16-shFUCA1 groups was dramatically reduced at 28, 35, and 42 days compared to that in the LV16 group.	('LV16-shFUCA1', 'Var', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mice', 'Species', '10090', (52, 56))	('reduced', 'NegReg', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
154537	32314457	At the end of the experiment, a significant decrease in tumor volume was observed in the LV16-shFUCA1-treated group (Figure 3G).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('decrease', 'NegReg', (44, 52))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('LV16-shFUCA1-treated', 'Var', (89, 109))
154538	32314457	This result is consistent with the effects of siFUCA1 on cultured human glioma cells in vitro, indicating that FUCA1 depletion inhibits glioma growth in vitro and in vivo.	('glioma', 'Disease', (72, 78))	('glioma growth', 'Disease', 'MESH:D005910', (136, 149))	('inhibits', 'NegReg', (127, 135))	('glioma growth', 'Disease', (136, 149))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('human', 'Species', '9606', (66, 71))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Disease', (136, 142))	('depletion', 'Var', (117, 126))	('FUCA1', 'Gene', (111, 116))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
154542	32314457	The results showed that the LC3-B to LC3-A conversion and the expression of Beclin and Atg12 was significantly increased in both U87 and U251 cells that were transfected with siFUCA1 compared to the expression in cells transfected with siScr.	('LC3-A', 'Gene', (37, 42))	('LC3-A', 'Gene', '84557', (37, 42))	('increased', 'PosReg', (111, 120))	('siScr', 'Disease', 'None', (236, 241))	('LC3-B', 'Gene', '81631', (28, 33))	('expression', 'MPA', (62, 72))	('LC3-B', 'Gene', (28, 33))	('siFUCA1', 'Var', (175, 182))	('Beclin', 'Gene', (76, 82))	('Atg12', 'Gene', '9140', (87, 92))	('U251', 'CellLine', 'CVCL:0021', (137, 141))	('Atg12', 'Gene', (87, 92))	('siScr', 'Disease', (236, 241))
154543	32314457	We then used 3-MA, an autophagy inhibitor, to confirm that FUCA1 knockdown-mediated cell death is autophagic cell death.	('death', 'Disease', 'MESH:D003643', (89, 94))	('knockdown-mediated', 'Var', (65, 83))	('FUCA1', 'Gene', (59, 64))	('death', 'Disease', (89, 94))	('3-MA', 'Chemical', '-', (13, 17))	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))
154544	32314457	The CCK-8 results showed that 3-MA blocked FUCA1 knockdown-induced cell death (Figure 4C).	('knockdown-induced', 'Var', (49, 66))	('FUCA1', 'Gene', (43, 48))	('death', 'Disease', 'MESH:D003643', (72, 77))	('death', 'Disease', (72, 77))	('CCK-8', 'Chemical', 'MESH:D012844', (4, 9))	('3-MA', 'Chemical', '-', (30, 34))
154547	32314457	Taken together, these results showed that silencing FUCA1 induces autophagic cell death in U87 and U251 glioma cells.	('silencing', 'Var', (42, 51))	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('induces', 'Reg', (58, 65))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('FUCA1', 'Gene', (52, 57))	('U251', 'CellLine', 'CVCL:0021', (99, 103))	('glioma', 'Disease', (104, 110))
154553	32314457	As shown in Figure 5C, FUCA1 silencing decreased the frequency of CD68+ macrophages (-30%, P < .001), F4/80+ macrophages (-50%, P < .001), and CD11c+ macrophages (-50%, P < .001) in glioma, which was consistent with the results obtained from TISIDB and TIMER.	('CD68', 'Gene', (66, 70))	('FUCA1', 'Gene', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('CD68', 'Gene', '968', (66, 70))	('silencing', 'Var', (29, 38))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('CD11c', 'Gene', '3687', (143, 148))	('F4/80+', 'Var', (102, 108))	('CD11c', 'Gene', (143, 148))	('glioma', 'Disease', (182, 188))	('decreased', 'NegReg', (39, 48))
154555	32314457	Taken together, these results confirmed that silencing FUCA1 inhibits macrophage infiltration into glioma through downregulation of CCL2/CCL5 expression.	('silencing', 'Var', (45, 54))	('CCL2/CCL5', 'Gene', (132, 141))	('glioma', 'Disease', (99, 105))	('FUCA1', 'Gene', (55, 60))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('downregulation', 'NegReg', (114, 128))	('inhibits', 'NegReg', (61, 69))
154560	32314457	Moreover, we found that the survival time of patients with higher FUCA1 expression was significantly shorter than that of patients with lower expression, and the cBioPortal results showed that alterations in FUCA1 were correlated with worse survival in GBM patients.	('FUCA1', 'Gene', (208, 213))	('alterations', 'Var', (193, 204))	('expression', 'MPA', (72, 82))	('shorter', 'NegReg', (101, 108))	('survival time', 'CPA', (28, 41))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (257, 265))	('FUCA1', 'Gene', (66, 71))	('GBM', 'Disease', (253, 256))
154563	32314457	In the functional cellular experiments, we synthesized FUCA1 siRNA and FUCA1 overexpression plasmids and transfected them into the glioma cell lines U87 and U251 and found that silencing FUCA1 led to glioma cell growth inhibition.	('glioma', 'Disease', (200, 206))	('FUCA1', 'Gene', (187, 192))	('glioma', 'Disease', (131, 137))	('U251', 'CellLine', 'CVCL:0021', (157, 161))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('silencing', 'Var', (177, 186))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))
154564	32314457	This result is consistent with the effects of FUCA1 siRNA on the U87 xenograft tumor model, indicating that FUCA1 silencing inhibits glioma growth in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('tumor', 'Disease', (79, 84))	('inhibits', 'NegReg', (124, 132))	('silencing', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('glioma growth', 'Disease', 'MESH:D005910', (133, 146))	('glioma growth', 'Disease', (133, 146))	('FUCA1', 'Gene', (108, 113))
154566	32314457	We found that FUCA1 depletion led to the formation of large acidic vacuoles, induced an increased LC3-B/LC3-A ratio, and modified the expression of Beclin-1 and Atg12, which indicated that autophagic cell death occurred.	('LC3-B', 'Gene', (98, 103))	('modified', 'Reg', (121, 129))	('expression', 'MPA', (134, 144))	('death', 'Disease', 'MESH:D003643', (205, 210))	('increased', 'PosReg', (88, 97))	('Atg12', 'Gene', '9140', (161, 166))	('depletion', 'Var', (20, 29))	('FUCA1', 'Gene', (14, 19))	('Atg12', 'Gene', (161, 166))	('LC3-A', 'Gene', (104, 109))	('Beclin-1', 'Gene', (148, 156))	('LC3-A', 'Gene', '84557', (104, 109))	('Beclin-1', 'Gene', '8678', (148, 156))	('increased LC3', 'Phenotype', 'HP:0003141', (88, 101))	('LC3-B', 'Gene', '81631', (98, 103))	('death', 'Disease', (205, 210))
154568	32314457	Our data indicated that FUCA1 silencing decreased CD68+ macrophages (-30%, P < .001), F4/80+ macrophages (-50%, P < .001), and CD11c+ macrophages (-50%, P < .001) in glioma, which was consistent with the results obtained from TISIDB and TIMER.	('CD11c', 'Gene', (127, 132))	('glioma', 'Disease', (166, 172))	('CD68', 'Gene', (50, 54))	('FUCA1', 'Gene', (24, 29))	('CD11c', 'Gene', '3687', (127, 132))	('CD68', 'Gene', '968', (50, 54))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('silencing', 'Var', (30, 39))	('decreased', 'NegReg', (40, 49))
154574	32314457	Fang et al 21  reported that extracellular ATP regulated glioma-associated microglia/macrophage infiltration by influencing macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1 expression, which was consistent with our speculation that silencing FUCA1 inhibits macrophage infiltration into glioma through downregulation of CCL2/CCL5 expression.	('expression', 'MPA', (202, 212))	('FUCA1', 'Gene', (271, 276))	('inhibits', 'NegReg', (277, 285))	('monocyte chemoattractant protein-1', 'Gene', (167, 201))	('macrophage inflammatory protein-1alpha', 'Gene', '1230', (124, 162))	('glioma', 'Phenotype', 'HP:0009733', (315, 321))	('silencing', 'Var', (261, 270))	('glioma', 'Disease', (57, 63))	('macrophage inflammatory protein-1alpha', 'Gene', (124, 162))	('expression', 'MPA', (358, 368))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('downregulation', 'NegReg', (330, 344))	('monocyte chemoattractant protein-1', 'Gene', '6347', (167, 201))	('CCL2/CCL5', 'Gene', (348, 357))	('ATP', 'Chemical', 'MESH:D000255', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('influencing', 'Reg', (112, 123))	('macrophage infiltration into', 'CPA', (286, 314))	('glioma', 'Disease', (315, 321))	('glioma', 'Disease', 'MESH:D005910', (315, 321))
154594	28819158	For RNA-seq, some examples include Reads Per Kilobase per Million mapped reads (RPKM), Remove Unwanted Variation (RUV), and approaches provided by software for differential gene expression analysis such as DESeq.	('Unwanted Variation', 'MPA', (94, 112))	('expression', 'Species', '29278', (178, 188))	('Reads', 'Var', (35, 40))
154669	28819158	To demonstrate the potential value of modules identified from the GMM tumor network we examined two GMM modules: M0057 and M0282.	('GMM', 'Chemical', '-', (66, 69))	('GMM', 'Chemical', '-', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('M0057', 'Var', (113, 118))	('M0282', 'Var', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
154670	28819158	The module M0057 demonstrates GMM's ability to find modules specific for a single tumor subtype as M0057 is enriched for thyroid tumors (p = 6.95 x 10-152) but is not enriched for other tumor groups (p = 1.00).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('thyroid tumors', 'Disease', (121, 135))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('GMM', 'Chemical', '-', (30, 33))	('thyroid tumors', 'Disease', 'MESH:D013959', (121, 135))	('M0057', 'Var', (99, 104))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (82, 87))
154673	28819158	M0057 is also enriched for "female" (p = 2.81 x 10-6), Stage I cancer (p = 1.07 x 10-21) and the vital status "alive" (p = 7.07 x 10-36).	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('I cancer', 'Disease', 'MESH:D009369', (61, 69))	('M0057', 'Var', (0, 5))	('I cancer', 'Disease', (61, 69))
154677	28819158	M0282 is also enriched for Stage IV cancer (p = 1.20 x 10-15) and the vital status "dead" (p = 1.51 x 10-47), indicating that this module may be relevant to more advanced tumors than M0057.	('Stage IV cancer', 'Disease', 'MESH:D009369', (27, 42))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('Stage IV cancer', 'Disease', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('M0282', 'Var', (0, 5))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
154678	28819158	For example, the most highly-enriched KEGG and Reactome annotations are "cell cycle" (hsa04110, R-HSA-1640170), and the second-most enriched Reactome annotation is "cell cycle, mitotic" (R-HSA-69278).	('R-HSA', 'Chemical', '-', (187, 192))	('hsa04110', 'Var', (86, 94))	('R-HSA', 'Chemical', '-', (96, 101))	('R-HSA-1640170', 'Var', (96, 109))
154680	28819158	M phase (R-HSA-68886) is the most-enriched of any phase, but three of the top-18 most-enriched Reactome annotations (R-HSA-453279, R-HSA-69206, R-HSA-69205) mention the G1/S checkpoint, the cell cycle's point of no return.	('R-HSA', 'Chemical', '-', (144, 149))	('R-HSA', 'Chemical', '-', (117, 122))	('mention', 'Reg', (157, 164))	('R-HSA-69205', 'Var', (144, 155))	('G1/S checkpoint', 'MPA', (169, 184))	('R-HSA', 'Chemical', '-', (9, 14))	('R-HSA', 'Chemical', '-', (131, 136))	('R-HSA-453279', 'Var', (117, 129))	('R-HSA-69206', 'Var', (131, 142))
154722	25875182	Perfusion MRI Derived Indices of Microvascular Shunting and Flow Control Correlate with Tumor Grade and Outcome in Patients with Cerebral Glioma Deficient microvascular blood flow control is thought to cause tumor hypoxia and increase resistance to therapy.	('Patients', 'Species', '9606', (115, 123))	('Cerebral Glioma', 'Disease', (129, 144))	('Cerebral Glioma', 'Disease', 'MESH:C564230', (129, 144))	('Glioma', 'Phenotype', 'HP:0009733', (138, 144))	('resistance to therapy', 'MPA', (235, 256))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('microvascular blood flow control', 'MPA', (155, 187))	('cause', 'Reg', (202, 207))	('tumor hypoxia', 'Disease', 'MESH:D000860', (208, 221))	('tumor hypoxia', 'Disease', (208, 221))	('increase', 'PosReg', (226, 234))	('Tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Deficient', 'Var', (145, 154))
154729	25875182	Our study confirms the importance of microvascular flow control in tumor growth by demonstrating that determining CTH improves tumor grading and outcome prediction in glioma patients compared to CBV alone.	('CTH', 'Var', (114, 117))	('glioma', 'Disease', 'MESH:D005910', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CTH', 'Chemical', '-', (114, 117))	('glioma', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', (67, 72))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('outcome prediction', 'CPA', (145, 163))	('improves', 'PosReg', (118, 126))
154739	25875182	In tumors, CTH can be elevated by abnormal capillary bed topology, shunts, microthrombosis, pericyte loss, edema pressure, etc..	('edema', 'Phenotype', 'HP:0000969', (107, 112))	('shunts', 'Disease', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('abnormal', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('CTH', 'Disease', (11, 14))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('microthrombosis', 'Disease', 'None', (75, 90))	('edema', 'Disease', (107, 112))	('elevated', 'PosReg', (22, 30))	('abnormal capillary', 'Phenotype', 'HP:0025016', (34, 52))	('microthrombosis', 'Disease', (75, 90))	('CTH', 'Chemical', '-', (11, 14))	('edema', 'Disease', 'MESH:D004487', (107, 112))
154753	25875182	The MRI protocol consisted of 3D T1-weighted images acquired before and after intravenous contrast (TR/TE 8.4/4ms; voxel size 0.94x0.94x1mm3; FOV 240x240mm; 0.15mmol/kg gadobutrol); sagittal T2 TSE (TR/TE 3000/80ms; voxel size 0.43x0.43x4mm3; FOV 240x231mm), and axial T2FLAIR (TR/TE/TI 11000/125/2800ms; voxel size 0.45x0.45x4mm3; FOV 230x183mm).	('FOV 230x183mm', 'Var', (332, 345))	('TR/TE/TI', 'Var', (278, 286))	('TR/TE', 'Var', (199, 204))	('FOV 240x240mm', 'Var', (142, 155))	('gadobutrol', 'Chemical', 'MESH:C090600', (169, 179))	('FOV 240x231mm', 'Var', (243, 256))
154782	25875182	The AUCs, calculated from ROC curves, to differentiate HGG from LGG are summarized in Table 2 and Fig 4: The highest AUC for single predictors is found for rCTH in the peri-focal edema (AUC = 0.811; p = 0.003), followed by rCTH in a combined region consisting of the enhancing tumor and the peri-focal edema (AUC = 0.807; p = 0.006).	('edema', 'Phenotype', 'HP:0000969', (302, 307))	('rCTH', 'Var', (156, 160))	('edema', 'Disease', (179, 184))	('edema', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('edema', 'Disease', 'MESH:D004487', (179, 184))	('CTH', 'Chemical', '-', (157, 160))	('edema', 'Phenotype', 'HP:0000969', (179, 184))	('tumor', 'Disease', (277, 282))	('edema', 'Disease', 'MESH:D004487', (302, 307))	('CTH', 'Chemical', '-', (224, 227))
154801	25875182	The combination of high CTH and high blood flow is therefore predicted to result in insufficient oxygen extraction, hypoxia, and necrosis.	('CTH', 'MPA', (24, 27))	('CTH', 'Chemical', '-', (24, 27))	('high', 'Var', (19, 23))	('necrosis', 'Disease', 'MESH:D009336', (129, 137))	('oxygen extraction', 'MPA', (97, 114))	('hypoxia', 'Disease', (116, 123))	('hypoxia', 'Disease', 'MESH:D000860', (116, 123))	('insufficient', 'NegReg', (84, 96))	('necrosis', 'Disease', (129, 137))	('oxygen', 'Chemical', 'MESH:D010100', (97, 103))
154816	25875182	In a normal capillary bed, CTH tends to increase linearly with MTT, and maps of COV therefore show little contrast in normal tissue (see Fig 2).	('MTT', 'Chemical', '-', (63, 66))	('MTT', 'Var', (63, 66))	('COV', 'Chemical', '-', (80, 83))	('increase', 'PosReg', (40, 48))	('CTH', 'Chemical', '-', (27, 30))	('CTH', 'MPA', (27, 30))
154966	18618497	Our next step will be to knock-down GLUT-1 in a xenographic model of GBM to evaluate its independent effects on tumor growth as well as its effects in concert with HIF-1alpha and VEGF.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('knock-down', 'Var', (25, 35))	('HIF-1alpha', 'Gene', '3091', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('GLUT-1', 'Gene', (36, 42))	('tumor', 'Disease', (112, 117))	('HIF-1alpha', 'Gene', (164, 174))
154974	33955303	Besides, overexpression and hypo-methylation of PD-1/PD-Ls were associated with worse prognosis.	('hypo-methylation', 'Var', (28, 44))	('PD-L', 'Gene', (53, 57))	('PD-1', 'Gene', (48, 52))	('PD-L', 'Gene', '5133', (53, 57))	('PD-1', 'Gene', '5133', (48, 52))
154977	33955303	To conclude, overexpression and hypo-methylation of PD-1/PD-Ls predicted unfavorable prognosis in LGG patients, suggesting those patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.	('PD-L', 'Gene', (159, 163))	('predicted', 'Reg', (63, 72))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (102, 110))	('PD-L', 'Gene', '5133', (159, 163))	('PD-L', 'Gene', (57, 61))	('PD-1', 'Gene', (52, 56))	('hypo-methylation', 'Var', (32, 48))	('PD-L', 'Gene', '5133', (57, 61))	('PD-1', 'Gene', '5133', (52, 56))	('unfavorable prognosis', 'MPA', (73, 94))	('LGG', 'Disease', (98, 101))
155019	33955303	The result showed patients with PD-1/PD-Ls high expression had significantly poor OS than other cohorts, and the prognosis of patients with PD-1/PD-Ls low expression was best (Figure 3D).	('PD-L', 'Gene', (145, 149))	('high expression', 'Var', (43, 58))	('PD-1', 'Gene', (140, 144))	('poor', 'NegReg', (77, 81))	('PD-L', 'Gene', (37, 41))	('PD-L', 'Gene', '5133', (145, 149))	('PD-1', 'Gene', '5133', (140, 144))	('PD-L', 'Gene', '5133', (37, 41))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (18, 26))	('PD-1', 'Gene', (32, 36))	('PD-1', 'Gene', '5133', (32, 36))
155023	33955303	DNA copy number variations (CNV) are most common genetic alterations that affect tumorigenesis of cancers via mediating tumor-related gene expression.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancers', 'Disease', (98, 105))	('affect', 'Reg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('copy number variations', 'Var', (4, 26))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mediating', 'Reg', (110, 119))	('tumor', 'Disease', (81, 86))
155025	33955303	Copy gain was associated with notably upregulated PD-L2 levels compared with the copy-neutral (diploid) and copy-loss (shallow deletion and deep deletion) samples (Figure S1C).	('shallow deletion', 'Var', (119, 135))	('upregulated', 'PosReg', (38, 49))	('PD-L2', 'Gene', (50, 55))	('PD-L2', 'Gene', '80380', (50, 55))	('deep deletion', 'Var', (140, 153))	('gain', 'PosReg', (5, 9))
155030	33955303	Taken together, DNA methylation was a crucial factor for dysregulated PD-1/PD-Ls expression, which might be used as an indicator for immune checkpoints expression prediction.	('PD-L', 'Gene', (75, 79))	('PD-1', 'Gene', (70, 74))	('PD-L', 'Gene', '5133', (75, 79))	('dysregulated', 'Var', (57, 69))	('PD-1', 'Gene', '5133', (70, 74))	('expression', 'MPA', (81, 91))
155035	33955303	DNA methylation has been identified as potential prognostic markers in tumors.	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
155037	33955303	When it came to mean methylation levels, as shown in Figure 6, patients with low PD-1 methylation in tumor tissues showed a significantly worse OS than the counterparts (Figure 6A).	('low', 'NegReg', (77, 80))	('PD-1', 'Gene', (81, 85))	('PD-1', 'Gene', '5133', (81, 85))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('methylation', 'Var', (86, 97))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
155038	33955303	Besides, hyper-methylation of PD-L1 (Figure 6B) and PD-L2 (Figure 6C) also predicted favorable OS in LGG patients.	('patients', 'Species', '9606', (105, 113))	('hyper-methylation', 'Var', (9, 26))	('PD-L1', 'Gene', (30, 35))	('LGG', 'Disease', (101, 104))	('PD-L1', 'Gene', '29126', (30, 35))	('PD-L2', 'Gene', (52, 57))	('PD-L2', 'Gene', '80380', (52, 57))
155039	33955303	When we combined PD-1/PD-Ls methylations to assess the prognosis of LGG patients, the result showed patients with PD-1/PD-Ls hypo-methylations had notably poor OS than other cohorts (Figure 6D).	('PD-1', 'Gene', (17, 21))	('PD-1', 'Gene', '5133', (17, 21))	('PD-1', 'Gene', '5133', (114, 118))	('PD-L', 'Gene', (119, 123))	('PD-L', 'Gene', (22, 26))	('PD-L', 'Gene', '5133', (22, 26))	('patients', 'Species', '9606', (100, 108))	('PD-L', 'Gene', '5133', (119, 123))	('PD-1', 'Gene', (114, 118))	('hypo-methylations', 'Var', (125, 142))	('poor', 'NegReg', (155, 159))	('patients', 'Species', '9606', (72, 80))
155040	33955303	To sum up, PD-1/PD-Ls methylations might be other effective prognostic indicators prognostic indicators in addition to mRNA expression in LGG.	('methylations', 'Var', (22, 34))	('PD-L', 'Gene', '5133', (16, 20))	('PD-L', 'Gene', (16, 20))	('PD-1', 'Gene', (11, 15))	('PD-1', 'Gene', '5133', (11, 15))
155075	33955303	Moreover, we also noticed that PD-1/PD-Ls methylations were more effective indicators for LGG subtypes and prognosis.	('PD-L', 'Gene', (36, 40))	('PD-L', 'Gene', '5133', (36, 40))	('LGG', 'Disease', (90, 93))	('methylations', 'Var', (42, 54))	('PD-1', 'Gene', (31, 35))	('PD-1', 'Gene', '5133', (31, 35))
155076	33955303	According to previous studies, PD-L1 methylation mediated PD-L1 expression and functioned as a promising prognostic marker in melanoma.	('PD-L1', 'Gene', '29126', (58, 63))	('expression', 'MPA', (64, 74))	('methylation', 'Var', (37, 48))	('PD-L1', 'Gene', '29126', (31, 36))	('mediated', 'Reg', (49, 57))	('PD-L1', 'Gene', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('PD-L1', 'Gene', (31, 36))
155078	33955303	Therapeutic subtype analysis revealed that the methylation of PD-1/PD-Ls had more broad-spectrum prognostic values in LGG patients receiving various therapeutic strategies.	('PD-L', 'Gene', (67, 71))	('methylation', 'Var', (47, 58))	('PD-1', 'Gene', (62, 66))	('PD-L', 'Gene', '5133', (67, 71))	('PD-1', 'Gene', '5133', (62, 66))	('LGG', 'Disease', (118, 121))	('patients', 'Species', '9606', (122, 130))
155083	33955303	Besides, PD-1/PD-Ls expression and methylation were both correlated TIICs infiltration.	('correlated', 'Reg', (57, 67))	('PD-L', 'Gene', (14, 18))	('methylation', 'Var', (35, 46))	('PD-1', 'Gene', (9, 13))	('PD-L', 'Gene', '5133', (14, 18))	('TIICs', 'Disease', (68, 73))	('PD-1', 'Gene', '5133', (9, 13))
155084	33955303	Although PD-1/PD-Ls methylation exhibited more obviously promising prognostic values, their expression had tighter associations with TIICs infiltration, suggesting the various roles of expression and methylation in assessing prognosis and immune infiltration, respectively.	('TIICs infiltration', 'Disease', (133, 151))	('tighter', 'PosReg', (107, 114))	('associations', 'Interaction', (115, 127))	('methylation', 'Var', (20, 31))	('PD-L', 'Gene', (14, 18))	('PD-1', 'Gene', (9, 13))	('PD-L', 'Gene', '5133', (14, 18))	('expression', 'MPA', (92, 102))	('PD-1', 'Gene', '5133', (9, 13))
155088	33955303	High PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with poor survival of LGG patients.	('hypo-methylation', 'Var', (31, 47))	('PD-1', 'Gene', '5133', (5, 9))	('PD-L', 'Gene', '5133', (56, 60))	('PD-1', 'Gene', (51, 55))	('LGG', 'Disease', (100, 103))	('PD-1', 'Gene', '5133', (51, 55))	('patients', 'Species', '9606', (104, 112))	('PD-L', 'Gene', (10, 14))	('poor', 'NegReg', (83, 87))	('PD-1', 'Gene', (5, 9))	('PD-L', 'Gene', '5133', (10, 14))	('expression', 'MPA', (16, 26))	('PD-L', 'Gene', (56, 60))
155134	31974804	In one patient preoperative KPS was missing, and a retrospective estimation based on notes from the medical record was done to classify the patient as functionally dependent (KPS < 70) or functionally independent (KPS >= 70).	('KPS < 70', 'Var', (175, 183))	('patient', 'Species', '9606', (140, 147))	('KPS', 'Var', (214, 217))	('patient', 'Species', '9606', (7, 14))
155164	31974804	In the multivariable analyses, low-grade histopathology, low KPS and moderate and/or severe complications were statistically significantly associated with postoperative high fatigue.	('postoperative high fatigue', 'Disease', (155, 181))	('fatigue', 'Phenotype', 'HP:0012378', (174, 181))	('postoperative high fatigue', 'Phenotype', 'HP:0030973', (155, 181))	('low-grade', 'Var', (31, 40))	('low KPS', 'Var', (57, 64))	('postoperative high fatigue', 'Disease', 'MESH:D005221', (155, 181))
155178	31974804	Female gender and low KPS were factors associated with preoperative high fatigue, while moderate and/or severe complications, low-grade histology and low KPS were associated with high fatigue one month after surgery.	('fatigue', 'Disease', 'MESH:D005221', (73, 80))	('fatigue', 'Disease', 'MESH:D005221', (184, 191))	('fatigue', 'Disease', (73, 80))	('low-grade histology', 'Var', (126, 145))	('fatigue', 'Disease', (184, 191))	('low KPS', 'Var', (150, 157))	('fatigue', 'Phenotype', 'HP:0012378', (73, 80))	('fatigue', 'Phenotype', 'HP:0012378', (184, 191))
155233	31974804	Female gender and low KPS were associated with high preoperative fatigue, and postoperative moderate and/or severe complications, low KPS and low-grade histopathology were associated with more postoperative fatigue.	('fatigue', 'Disease', (65, 72))	('low KPS', 'Var', (18, 25))	('fatigue', 'Disease', 'MESH:D005221', (207, 214))	('postoperative fatigue', 'Disease', 'MESH:D005221', (193, 214))	('postoperative fatigue', 'Phenotype', 'HP:0030973', (193, 214))	('fatigue', 'Phenotype', 'HP:0012378', (65, 72))	('low KPS', 'Var', (130, 137))	('fatigue', 'Disease', (207, 214))	('postoperative fatigue', 'Disease', (193, 214))	('fatigue', 'Phenotype', 'HP:0012378', (207, 214))	('fatigue', 'Disease', 'MESH:D005221', (65, 72))
155244	30170559	siRNA and lentivirus were used to knock down Notch1 and overexpress miR-139-5p, respectively.	('miR-139', 'Gene', (68, 75))	('Notch1', 'Gene', (45, 51))	('Notch1', 'Gene', '4851', (45, 51))	('miR-139', 'Gene', '406931', (68, 75))	('overexpress', 'PosReg', (56, 67))	('knock down', 'Var', (34, 44))
155248	30170559	It revealed the association of NOTCH1, CDH2, SNAI1 genomic alterations with decreases in DFS and OS.	('SNAI1', 'Gene', (45, 50))	('DFS', 'MPA', (89, 92))	('genomic alterations', 'Var', (51, 70))	('CDH2', 'Gene', (39, 43))	('decreases', 'NegReg', (76, 85))	('CDH2', 'Gene', '1000', (39, 43))	('OS', 'Chemical', '-', (97, 99))	('SNAI1', 'Gene', '6615', (45, 50))	('NOTCH1', 'Gene', '4851', (31, 37))	('NOTCH1', 'Gene', (31, 37))
155315	30170559	We first explored the alteration frequency of NOTCH1 in different type of brain tumors (n = 1300) (cBioPortal) and found the major type of genomic alterations in glioma was mutation or amplication (Fig.	('NOTCH1', 'Gene', '4851', (46, 52))	('NOTCH1', 'Gene', (46, 52))	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('glioma', 'Disease', (162, 168))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('brain tumors', 'Disease', (74, 86))	('amplication', 'Var', (185, 196))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('mutation', 'Var', (173, 181))
155350	30170559	The qRT-PCR and Western blotting assay confirmed specific knockdown of Notch1 by siRNA (Fig.	('Notch1', 'Gene', (71, 77))	('Notch1', 'Gene', '4851', (71, 77))	('knockdown', 'Var', (58, 67))
155368	30170559	A combination of Notch1 blockade and chemotherapy synergistically reduced chemotherapy-enriched cancer stem cells (CSC).	('reduced', 'NegReg', (66, 73))	('Notch1', 'Gene', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Notch1', 'Gene', '4851', (17, 23))	('blockade', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
155373	30170559	Interestingly, Notch1 also expressed in normal brain tissue, which could be explained by Notch1 signalling being involved in cell fate decision during normal development while abnormal activation would promote carcinogenesis.	('Notch1', 'Gene', (89, 95))	('Notch1', 'Gene', (15, 21))	('Notch1', 'Gene', '4851', (89, 95))	('promote', 'PosReg', (202, 209))	('abnormal', 'Var', (176, 184))	('carcinogenesis', 'Disease', 'MESH:D063646', (210, 224))	('activation', 'PosReg', (185, 195))	('carcinogenesis', 'Disease', (210, 224))	('Notch1', 'Gene', '4851', (15, 21))
155375	30170559	Knocking down Notch1 in these cells effectively suppressed glioma metastasis, invasion and EMT.	('glioma metastasis', 'Disease', (59, 76))	('Knocking down', 'Var', (0, 13))	('invasion', 'CPA', (78, 86))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('Notch1', 'Gene', (14, 20))	('Notch1', 'Gene', '4851', (14, 20))	('EMT', 'CPA', (91, 94))	('suppressed', 'NegReg', (48, 58))	('glioma metastasis', 'Disease', 'MESH:D009362', (59, 76))
155378	30170559	found that miR-139-5p is specifically downregulated in CN-AML with mutated FLT3 and acts as a strong tumour suppressor.	('tumour', 'Disease', (101, 107))	('miR-139', 'Gene', (11, 18))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('downregulated', 'NegReg', (38, 51))	('mutated', 'Var', (67, 74))	('FLT3', 'Gene', '2322', (75, 79))	('miR-139', 'Gene', '406931', (11, 18))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('FLT3', 'Gene', (75, 79))	('AML', 'Disease', (58, 61))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
155396	33935941	We compared the gray matter volume (GMV) of the contralesional insula according to histological grade [low-grade glioma (LGG) and high-grade glioma (HGG)] and molecular pathology status [isocitrate dehydrogenase (IDH) mutation, telomerase reverse-transcriptase (TERT) promoter mutation, and 1p19q codeletion] by voxel-based morphometry (VBM).	('IDH', 'Gene', '3417', (213, 216))	('telomerase reverse-transcriptase', 'Gene', '7015', (228, 260))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('isocitrate dehydrogenase', 'Gene', '3417', (187, 211))	('mutation', 'Var', (218, 226))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('telomerase reverse-transcriptase', 'Gene', (228, 260))	('TERT', 'Gene', (262, 266))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('glioma', 'Disease', (113, 119))	('GMV', 'Chemical', '-', (36, 39))	('1p19q codeletion]', 'Var', (291, 308))	('TERT', 'Gene', '7015', (262, 266))	('IDH', 'Gene', (213, 216))	('isocitrate dehydrogenase', 'Gene', (187, 211))	('glioma', 'Disease', (141, 147))
155397	33935941	A cluster of 320 voxels in contralesional insula with higher GMV was observed in glioma with IDH mutation as compared to IDH wild-type tumors by region of interest-based VBM analysis (family-wise error-corrected at p < 0.05).	('GMV', 'Chemical', '-', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH', 'Gene', (93, 96))	('IDH', 'Gene', (121, 124))	('glioma', 'Disease', (81, 87))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('IDH', 'Gene', '3417', (93, 96))	('IDH', 'Gene', '3417', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('mutation', 'Var', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
155398	33935941	The GMV of the entire contralesional insula was also larger in insular glioma patients with IDH mutation than in patients with wild-type IDH.	('GMV', 'Chemical', '-', (4, 7))	('IDH', 'Gene', '3417', (137, 140))	('patients', 'Species', '9606', (113, 121))	('patients', 'Species', '9606', (78, 86))	('mutation', 'Var', (96, 104))	('IDH', 'Gene', (92, 95))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('insular glioma', 'Disease', 'MESH:D005910', (63, 77))	('insular glioma', 'Disease', (63, 77))	('IDH', 'Gene', '3417', (92, 95))	('IDH', 'Gene', (137, 140))
155399	33935941	However, there was no association between histological grade, TERT promoter mutation, or 1p19q codeletion and GMV in the contralesional insula.	('TERT', 'Gene', (62, 66))	('TERT', 'Gene', '7015', (62, 66))	('GMV', 'Chemical', '-', (110, 113))	('1p19q codeletion', 'Var', (89, 105))
155400	33935941	Thus, IDH mutation is associated with greater structural compensation in insular glioma.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH', 'Gene', (6, 9))	('greater', 'PosReg', (38, 45))	('IDH', 'Gene', '3417', (6, 9))	('structural compensation', 'MPA', (46, 69))	('mutation', 'Var', (10, 18))	('insular glioma', 'Disease', 'MESH:D005910', (73, 87))	('insular glioma', 'Disease', (73, 87))
155410	33935941	It should be noted that the 2016 World Health Organization (WHO) classification for glioma added the molecular subtype [isocitrate dehydrogenase (IDH) or telomerase reverse-transcriptase promoter (TERTp) mutation and 1p19q codeletion], which is highly associated with tumor invasiveness and prognosis.	('tumor invasiveness', 'Disease', 'MESH:D009361', (268, 286))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('isocitrate dehydrogenase', 'Gene', '3417', (120, 144))	('glioma', 'Disease', (84, 90))	('telomerase reverse-transcriptase', 'Gene', '7015', (154, 186))	('IDH', 'Gene', (146, 149))	('isocitrate dehydrogenase', 'Gene', (120, 144))	('IDH', 'Gene', '3417', (146, 149))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('TERTp', 'Gene', (197, 202))	('associated', 'Reg', (252, 262))	('TERTp', 'Gene', '7015', (197, 202))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('telomerase reverse-transcriptase', 'Gene', (154, 186))	('tumor invasiveness', 'Disease', (268, 286))	('1p19q codeletion]', 'Var', (217, 234))
155417	33935941	The patients were grouped as IDH mutation (IDH-mu) and IDH wild type (IDH-wt), TERTp-mu and TERTp-wt, and 1p19q codeletion (1p19q-codel) and non-1p19q-codel.	('TERTp', 'Gene', (79, 84))	('IDH', 'Gene', '3417', (29, 32))	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', (55, 58))	('TERTp', 'Gene', '7015', (79, 84))	('IDH', 'Gene', (70, 73))	('1p19q codeletion', 'Var', (106, 122))	('IDH', 'Gene', '3417', (55, 58))	('IDH', 'Gene', '3417', (70, 73))	('IDH', 'Gene', (29, 32))	('patients', 'Species', '9606', (4, 12))	('TERTp', 'Gene', (92, 97))	('IDH', 'Gene', (43, 46))	('TERTp', 'Gene', '7015', (92, 97))
155448	33935941	However, no voxel survived in the comparison of TERTp-mu vs. TERTp-wt and 1p19q-codel vs. non-1p19q-codel.	('TERTp', 'Gene', '7015', (61, 66))	('TERTp', 'Gene', (48, 53))	('TERTp', 'Gene', '7015', (48, 53))	('1p19q-codel', 'Var', (74, 85))	('TERTp', 'Gene', (61, 66))
155450	33935941	The results of this study demonstrated for the first time that IDH mutation in insular glioma leads to morphologic compensation in the contralesional insula.	('mutation', 'Var', (67, 75))	('IDH', 'Gene', (63, 66))	('morphologic compensation', 'MPA', (103, 127))	('IDH', 'Gene', '3417', (63, 66))	('insular glioma', 'Disease', 'MESH:D005910', (79, 93))	('insular glioma', 'Disease', (79, 93))	('leads to', 'Reg', (94, 102))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))
155451	33935941	TERTp mutation and 1p19q codeletion did not have this effect.	('TERTp', 'Gene', '7015', (0, 5))	('TERTp', 'Gene', (0, 5))	('1p19q codeletion', 'Var', (19, 35))
155456	33935941	Along with this perspective, we could infer that insular glioma patients with IDH mutation had a longer disease course than those with wild-type IDH and accumulate damage to the insula slowly.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('patients', 'Species', '9606', (64, 72))	('mutation', 'Var', (82, 90))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('insular glioma', 'Disease', 'MESH:D005910', (49, 63))	('IDH', 'Gene', (78, 81))	('insular glioma', 'Disease', (49, 63))	('IDH', 'Gene', '3417', (78, 81))
155457	33935941	In fact, IDH mutation has also been reported to be an early event in gliomagenesis that precedes the occurrence of TERTp mutation and 1p19q codeletion, which might be the reason for the absence of contralesional reorganization in the latter two genetic alterations.	('glioma', 'Disease', (69, 75))	('1p19q', 'Var', (134, 139))	('mutation', 'Var', (13, 21))	('TERTp', 'Gene', (115, 120))	('TERTp', 'Gene', '7015', (115, 120))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('IDH', 'Gene', (9, 12))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH', 'Gene', '3417', (9, 12))
155458	33935941	IDH catalyzes the conversion of isocitrate into alpha-ketoglutarate (alpha-KG), whereas the enzyme produced by the mutated IDH gene further converts alpha-KG into 2-hydroxyglutarate (alpha-HG).	('IDH', 'Gene', (0, 3))	('alpha-KG', 'Chemical', 'MESH:D007656', (149, 157))	('IDH', 'Gene', (123, 126))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (163, 181))	('IDH', 'Gene', '3417', (0, 3))	('mutated', 'Var', (115, 122))	('isocitrate', 'Chemical', 'MESH:C034219', (32, 42))	('alpha-KG', 'Chemical', 'MESH:D007656', (69, 77))	('alpha-HG', 'Chemical', '-', (183, 191))	('IDH', 'Gene', '3417', (123, 126))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (48, 67))
155460	33935941	However, IDH mutation in AML and chondrosarcoma has been linked to worse prognosis, while the opposite is true for glioma.	('glioma', 'Disease', (115, 121))	('mutation', 'Var', (13, 21))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('chondrosarcoma', 'Disease', (33, 47))	('IDH', 'Gene', (9, 12))	('chondrosarcoma', 'Disease', 'MESH:D002813', (33, 47))	('AML', 'Disease', 'MESH:D015470', (25, 28))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('IDH', 'Gene', '3417', (9, 12))	('AML', 'Phenotype', 'HP:0004808', (25, 28))	('AML', 'Disease', (25, 28))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (33, 47))
155462	33935941	On one hand, IDH mutation may inhibit complement activation and help the tumor evade immune surveillance, leading to gliomagenesis.	('IDH', 'Gene', '3417', (13, 16))	('evade', 'NegReg', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inhibit', 'NegReg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('mutation', 'Var', (17, 25))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumor', 'Disease', (73, 78))	('leading to', 'Reg', (106, 116))	('IDH', 'Gene', (13, 16))	('glioma', 'Disease', (117, 123))	('complement activation', 'MPA', (38, 59))
155463	33935941	On the other hand, IDH mutation reduced cytoprotection and apoptosis resistance in tumor cells and increased the number of antitumor immune cells (M1 tumor-associated macrophages), resulting in tumor suppression.	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('IDH', 'Gene', '3417', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('reduced', 'NegReg', (32, 39))	('increased', 'PosReg', (99, 108))	('cytoprotection', 'CPA', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('apoptosis resistance', 'CPA', (59, 79))	('tumor', 'Disease', (150, 155))	('mutation', 'Var', (23, 31))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('IDH', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
155472	33935941	These findings may have clinical significance in that insular glioma patients with IDH mutation may be candidates for more complete resection when an intraoperative pathologic diagnosis is available.	('insular glioma', 'Disease', 'MESH:D005910', (54, 68))	('insular glioma', 'Disease', (54, 68))	('IDH', 'Gene', (83, 86))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH', 'Gene', '3417', (83, 86))	('patients', 'Species', '9606', (69, 77))	('mutation', 'Var', (87, 95))
155474	33192984	Thin-Slice Magnetic Resonance Imaging-Based Radiomics Signature Predicts Chromosomal 1p/19q Co-deletion Status in Grade II and III Gliomas Objective: Chromosomal 1p/19q co-deletion is recognized as a diagnostic, prognostic, and predictive biomarker in lower grade glioma (LGG).	('glioma', 'Disease', (264, 270))	('Chromosomal 1p/19q co-deletion', 'Var', (150, 180))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('Glioma', 'Phenotype', 'HP:0009733', (131, 137))	('Gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('III Gliomas', 'Disease', (127, 138))	('III Gliomas', 'Disease', 'MESH:D005910', (127, 138))
155476	33192984	Tumors with IDH mutations were also separately assessed.	('mutations', 'Var', (16, 25))	('Tumors', 'Disease', (0, 6))	('IDH', 'Gene', (12, 15))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('IDH', 'Gene', '3417', (12, 15))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
155478	33192984	Conclusions: The MRI-based radiomics signature can differentiate 1p/19q co-deletion status in LGG with or without predetermined IDH status.	('LGG', 'Disease', (94, 97))	('1p/19q co-deletion status', 'Var', (65, 90))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (128, 131))
155481	33192984	The co-deletion of chromosome arms 1p and 19q, which is mediated by 1;19 translocation, was strongly correlated with a oligodendroglial origin and is a biologically discrete subtype that harbors the mutation of CIC and FUBP1 as well as the activation of TERT.	('FUBP1', 'Gene', '8880', (219, 224))	('mutation', 'Var', (199, 207))	('CIC', 'Gene', (211, 214))	('arms 1p', 'Gene', (30, 37))	('TERT', 'Gene', (254, 258))	('FUBP1', 'Gene', (219, 224))	('TERT', 'Gene', '7015', (254, 258))	('arms 1p', 'Gene', '3075', (30, 37))	('oligodendroglial', 'Disease', (119, 135))	('correlated with', 'Reg', (101, 116))
155482	33192984	LGG patients with 1p/19q co-deletion have a significantly better prognosis than 1p/19q intact patients regardless of the therapeutic regimen and display higher sensitivity to the procarbazine, lomustine, and vincristine (PCV) regimen.	('lomustine', 'Chemical', 'MESH:D008130', (193, 202))	('higher', 'PosReg', (153, 159))	('patients', 'Species', '9606', (94, 102))	('better', 'PosReg', (58, 64))	('procarbazine', 'Chemical', 'MESH:D011344', (179, 191))	('patients', 'Species', '9606', (4, 12))	('sensitivity', 'MPA', (160, 171))	('1p/19q co-deletion', 'Var', (18, 36))	('vincristine', 'Chemical', 'MESH:D014750', (208, 219))
155484	33192984	In addition, only patients with 1p/19q intact tumors but not those with 1p/19q co-deleted tumors display a significant survival benefit from gross total resection (GTR) compared to subtotal resection (STR), highlighting the importance of acquiring the 1p/19q status prior to surgery.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('gross total', 'Var', (141, 152))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('1p/19q', 'Var', (32, 38))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Disease', (46, 52))	('survival benefit', 'CPA', (119, 135))	('GTR', 'Chemical', '-', (164, 167))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
155486	33192984	Although magnetic resonance imaging (MRI) is continuously employed in the evaluation of CNS diseases, the differences in tumor location, tumor border, contrast enhancement, diffusion, and perfusion patterns between 1p/19q co-deleted and 1p/19q intact LGGs were non-significant.	('diffusion', 'MPA', (173, 182))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CNS diseases', 'Disease', 'MESH:D002493', (88, 100))	('CNS diseases', 'Disease', (88, 100))	('tumor', 'Disease', (121, 126))	('perfusion', 'MPA', (188, 197))	('1p/19q co-deleted', 'Var', (215, 232))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
155490	33192984	This study retrospectively investigates pretreatment LGG MRI characteristics through a radiomics approach, aiming to build a reliable signature to non-invasively predict the 1p/19q co-deletion status in LGG patients.	('LGG', 'Disease', (203, 206))	('patients', 'Species', '9606', (207, 215))	('1p/19q co-deletion', 'Var', (174, 192))
155498	33192984	IDH1 and IDH 2 mutations were detected by direct sequencing as described by Horbinski et al..	('IDH 2', 'Gene', '3418', (9, 14))	('mutations', 'Var', (15, 24))	('IDH 2', 'Gene', (9, 14))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
155508	33192984	In addition, the IDH mutation status was also balanced between the training and validation datasets (p = 0.918), and in accordance with the 2016 WHO classification of CNS tumors, all 1p/19q co-deleted tumors harbored IDH1 or IDH2 mutations.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('CNS tumors', 'Disease', 'MESH:D016543', (167, 177))	('IDH', 'Gene', '3417', (17, 20))	('IDH', 'Gene', (217, 220))	('CNS tumors', 'Disease', (167, 177))	('IDH', 'Gene', (225, 228))	('IDH', 'Gene', '3417', (217, 220))	('IDH2', 'Gene', '3418', (225, 229))	('mutations', 'Var', (230, 239))	('tumors harbored IDH1', 'Disease', 'MESH:C537062', (201, 221))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('IDH', 'Gene', '3417', (225, 228))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('IDH', 'Gene', (17, 20))	('tumors harbored IDH1', 'Disease', (201, 221))	('IDH2', 'Gene', (225, 229))
155514	33192984	suggested that only the 1p/19q intact LGGs but not the 1p/19q co-deleted LGGs would benefit from GTR compared with STR both in the multi-centric local cohort and in the Cancer Genome Atlas (TCGA) validation cohort, and Kawaguchi et al.	('Cancer', 'Disease', 'MESH:D009369', (169, 175))	('GTR', 'Var', (97, 100))	('Cancer', 'Phenotype', 'HP:0002664', (169, 175))	('GTR', 'Chemical', '-', (97, 100))	('benefit', 'PosReg', (84, 91))	('Cancer', 'Disease', (169, 175))
155515	33192984	also reported a non-significant difference of survival between GTR and non-GTR in 1p/19q co-deleted grade III gliomas but a significant difference in 1p/19q intact grade III tumors.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('GTR', 'Chemical', '-', (63, 66))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('III gliomas', 'Disease', 'MESH:D005910', (106, 117))	('III tumors', 'Disease', 'MESH:D009369', (170, 180))	('GTR', 'Chemical', '-', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('1p/19q co-deleted', 'Var', (82, 99))	('III gliomas', 'Disease', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('III tumors', 'Disease', (170, 180))
155516	33192984	A recent systematic review suggested that the T2-FLAIR mismatch sign displayed a sensitivity and specificity of 30 and 73% in determining IDH mutated with 1p/19q co-deleted tumors, and 34 and 98% for IDH mutated with 1p/19q intact tumors.	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('IDH', 'Gene', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('IDH', 'Gene', '3417', (138, 141))	('IDH', 'Gene', (200, 203))	('1p/19q co-deleted', 'Var', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('IDH', 'Gene', '3417', (200, 203))	('tumors', 'Disease', (173, 179))	('T2-FLAIR mismatch', 'MPA', (46, 63))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Disease', (231, 237))
155518	33192984	FISH remains the most widely applicable technique with direct morphology evaluation of chromosomal abnormalities, yet it may be unable to detect the small intragenic variation or partial deletion of the hybridized region due to the relatively large size of the FISH probe.	('chromosomal abnormalities', 'Disease', (87, 112))	('partial deletion', 'Var', (179, 195))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (87, 112))
155522	33192984	In addition to chromosomal 1p/19q co-deletion status, IDH1/2 mutation status has also been recognized as a vital diagnostic, prognostic, and predictive biomarker for gliomas.	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('gliomas', 'Disease', (166, 173))	('IDH1/2', 'Gene', (54, 60))	('mutation', 'Var', (61, 69))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('IDH1/2', 'Gene', '3417;3418', (54, 60))
155523	33192984	LGGs with IDH mutations and 1p/19q co-deletion were classified as molecular pathological oligodendrogliomas, while LGGs with mutated IDH and intact 1p/19q or wild-type IDH were considered to have an astrocytoma origin.	('IDH', 'Gene', (10, 13))	('IDH', 'Gene', '3417', (133, 136))	('astrocytoma', 'Disease', 'MESH:D001254', (199, 210))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH', 'Gene', '3417', (168, 171))	('astrocytoma', 'Disease', (199, 210))	('IDH', 'Gene', '3417', (10, 13))	('mutated', 'Var', (125, 132))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (89, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (199, 210))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('1p/19q co-deletion', 'Var', (28, 46))	('oligodendrogliomas', 'Disease', (89, 107))	('IDH', 'Gene', (133, 136))	('mutations', 'Var', (14, 23))	('IDH', 'Gene', (168, 171))
155524	33192984	Thus, we validated our result in IDH-mutated LGGs and displayed AUCs of 0.950-1.000, suggesting the capability of our prediction model to predict 1p/19q status in all LGG patients and in IDH-mutated LGG cohorts.	('predict', 'Reg', (138, 145))	('IDH', 'Gene', (187, 190))	('IDH', 'Gene', '3417', (33, 36))	('patients', 'Species', '9606', (171, 179))	('IDH', 'Gene', '3417', (187, 190))	('IDH', 'Gene', (33, 36))	('1p/19q status', 'Var', (146, 159))	('LGG', 'Disease', (167, 170))
155528	33192984	Although the appearance of 1p deletion and 19q deletion are strongly correlated in diffuse gliomas and have been recognized as diagnostic criteria for oligodendroglioma, single 1p loss (with 19q intact) or single 19q loss (with 1p intact) can also occur less frequently with certain clinical meaning.	('oligodendroglioma', 'Disease', (151, 168))	('correlated', 'Reg', (69, 79))	('oligodendroglioma', 'Disease', 'MESH:D009837', (151, 168))	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('single 19q loss', 'Var', (206, 221))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
155531	33192984	In our dataset, 1p-loss/19q-retain was found in 3.1% (3/96) of patients, and 19q-loss/1p-retain was found in 6.3% (6/96).	('patients', 'Species', '9606', (63, 71))	('1p-loss/19q-retain', 'Var', (16, 34))	('19q-loss/1p-retain', 'Var', (77, 95))
155534	33192984	In conclusion, conventional MRI-based radiomics signature can differentiate 1p/19q co-deletion status in WHO grade II and III gliomas regardless of the predetermined IDH status.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('IDH', 'Gene', (166, 169))	('III gliomas', 'Disease', 'MESH:D005910', (122, 133))	('IDH', 'Gene', '3417', (166, 169))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('III gliomas', 'Disease', (122, 133))	('1p/19q co-deletion status', 'Var', (76, 101))
155551	29294371	The routine assessment of isocitrate dehydrogenase (IDH) mutation status, which are frequent in grade II and III infiltrating gliomas and a small subset of glioblastomas (GBM), improves histological diagnostic accuracy and has been observed to have a favorable prognostic implication for all glial tumors and to be predictive for chemotherapeutic responses in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('gliomas', 'Phenotype', 'HP:0009733', (382, 389))	('rat', 'Species', '10116', (32, 35))	('rat', 'Species', '10116', (119, 122))	('IDH', 'Gene', '3417', (52, 55))	('glial tumors', 'Disease', 'MESH:D005910', (292, 304))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('glioblastomas', 'Disease', (156, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('glial tumors', 'Disease', (292, 304))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('glioblastomas', 'Disease', 'MESH:D005909', (156, 169))	('mutation', 'Var', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('gliomas', 'Disease', (382, 389))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (360, 389))	('anaplastic oligodendrogliomas', 'Disease', (360, 389))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('improves', 'PosReg', (177, 185))	('gliomas', 'Disease', 'MESH:D005910', (382, 389))	('IDH', 'Gene', (52, 55))	('glioblastomas', 'Phenotype', 'HP:0012174', (156, 169))	('gliomas', 'Disease', (126, 133))	('glioma', 'Phenotype', 'HP:0009733', (382, 388))
155552	29294371	Glial tumors that contain chromosomal codeletion of 1p/19q, also defined as tumors of oligodendroglial lineage, have favorable prognosis.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('Glial tumors', 'Disease', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('Glial tumors', 'Disease', 'MESH:D005910', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('chromosomal codeletion of 1p/19q', 'Var', (26, 58))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
155553	29294371	GBM typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alternations and TERT promoter mutations.	('CDKN2A/B', 'Gene', '1029;1030', (101, 109))	('PTEN', 'Gene', '5728', (72, 76))	('PDGFRA', 'Gene', '5156', (84, 90))	('PDGFRA', 'Gene', (84, 90))	('IDH', 'Gene', '3417', (19, 22))	('EGFR', 'Gene', (66, 70))	('mutations', 'Var', (23, 32))	('NF1', 'Gene', '4763', (92, 95))	('TP53', 'Gene', '7157', (78, 82))	('NF1', 'Gene', (92, 95))	('CDKN2A/B', 'Gene', (101, 109))	('TERT', 'Gene', (127, 131))	('PTEN', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (127, 131))	('EGFR', 'Gene', '1956', (66, 70))	('lack', 'NegReg', (14, 18))	('IDH', 'Gene', (19, 22))	('TP53', 'Gene', (78, 82))	('alternations', 'Var', (110, 122))
155575	29294371	These alterations cause most cancers to induce unregulated glucose fermentation pathways for energy and to fuel growth, a factor that underlies the use of FDG-PET scans as an important diagnostic tool for oncologists.	('alterations', 'Var', (6, 17))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('FDG', 'Chemical', 'MESH:D019788', (155, 158))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('cause', 'Reg', (18, 23))	('rat', 'Species', '10116', (10, 13))	('glucose fermentation pathways for energy', 'MPA', (59, 99))	('induce', 'Reg', (40, 46))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))
155582	29294371	Importantly, many classic oncogene mutations confer a metabolic phenotype which supports survival and proliferation, and thus it is impossible to always separate genetic expression and metabolic signaling in tumors; indeed, these pathways are most often one in the same.	('survival', 'CPA', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('rat', 'Species', '10116', (109, 112))	('rat', 'Species', '10116', (157, 160))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('oncogene', 'Gene', (26, 34))	('proliferation', 'CPA', (102, 115))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('mutations', 'Var', (35, 44))
155603	29294371	In rats, single dose administration of BD-AcAc2 via intragastric gavage raised ketone levels to therapeutic levels (> 3 mM betaHB and > 3mM AcAc), and mimicked the anti-convulsant effects of the KD by increasing latency to oxygen toxicity-induced seizures.	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('seizures', 'Disease', (247, 255))	('raised ketone levels', 'Phenotype', 'HP:0001946', (72, 92))	('seizures', 'Disease', 'MESH:D012640', (247, 255))	('toxicity', 'Disease', (230, 238))	('seizures', 'Phenotype', 'HP:0001250', (247, 255))	('rats', 'Species', '10116', (3, 7))	('AcAc', 'Chemical', 'MESH:C016635', (140, 144))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (3, 6))	('increasing', 'PosReg', (201, 211))	('betaHB', 'Chemical', 'MESH:D020155', (123, 129))	('BD-AcAc2', 'Chemical', '-', (39, 47))	('AcAc', 'Chemical', 'MESH:C016635', (42, 46))	('BD-AcAc2', 'Var', (39, 47))	('ketone', 'Chemical', 'MESH:D007659', (79, 85))	('oxygen', 'Chemical', 'MESH:D010100', (223, 229))	('raised', 'PosReg', (72, 78))	('ketone levels', 'MPA', (79, 92))
155605	29294371	Indeed, exogenous BD-AcAc2 supplementation delivered in addition to standard high carbohydrate rodent chow was shown to be as effective as the KD in a glioma-derived model of metastatic cancer.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('supplementation', 'Var', (27, 42))	('BD-AcAc2', 'Chemical', '-', (18, 26))	('BD-AcAc2', 'Gene', (18, 26))	('carbohydrate', 'Chemical', 'MESH:D002241', (82, 94))	('glioma', 'Disease', (151, 157))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
155614	29294371	Similarly, AcAc was shown to produce a dose-dependent inhibition in ATP production and proliferation in four colon and three breast cancer cell lines, while eliciting no similar effect on three control fibroblast cell lines.	('ATP', 'Gene', (68, 71))	('ATP', 'Gene', '51761', (68, 71))	('rat', 'Species', '10116', (94, 97))	('AcAc', 'Var', (11, 15))	('proliferation', 'CPA', (87, 100))	('AcAc', 'Chemical', 'MESH:C016635', (11, 15))	('inhibition', 'NegReg', (54, 64))	('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))
155618	29294371	It is becoming increasingly clear that benefits and possible risks may be cancer type-specific, as recently a small number of studies have reported that ketones supplied without suppression of dietary carbohydrate, may serve as a substrate to fuel tumor growth, or in the presence of the BRAFV600E mutation, may enhance signaling cascades that promote tumor progression.	('cancer', 'Disease', (74, 80))	('signaling cascades', 'Pathway', (320, 338))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('fuel', 'PosReg', (243, 247))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('BRAFV600E', 'Var', (288, 297))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('rat', 'Species', '10116', (235, 238))	('rat', 'Species', '10116', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('enhance', 'PosReg', (312, 319))	('ketones', 'Chemical', 'MESH:D007659', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('carbohydrate', 'Chemical', 'MESH:D002241', (201, 213))	('BRAFV600E', 'Mutation', 'rs113488022', (288, 297))	('promote', 'PosReg', (344, 351))
155620	29294371	We discuss below evidence for a role of ketosis in preventing carcinogenesis or slowing tumor progression in sensitive tumors through the following mechanisms: 1) reduction of glucose and insulin; 2) modulation of oxidative stress; 3) reduction of inflammation; 4) enhancement of anti-tumor immunity; 5) alteration of gene expression; and 6) sensitization of tumors to standard of care and adjuvant therapies.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('reduction', 'NegReg', (235, 244))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('tumors', 'Disease', 'MESH:D009369', (359, 365))	('slowing tumor', 'Disease', 'MESH:D009369', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('oxidative stress', 'Phenotype', 'HP:0025464', (214, 230))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('gene', 'Gene', (318, 322))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumors', 'Disease', (119, 125))	('rat', 'Species', '10116', (308, 311))	('ketosis', 'Disease', (40, 47))	('tumor', 'Disease', (359, 364))	('modulation', 'Var', (200, 210))	('inflammation', 'Disease', 'MESH:D007249', (248, 260))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (359, 365))	('alteration', 'Reg', (304, 314))	('ketosis', 'Phenotype', 'HP:0001946', (40, 47))	('enhancement', 'PosReg', (265, 276))	('reduction of glucose and insulin', 'Disease', 'MESH:D007022', (163, 195))	('inflammation', 'Disease', (248, 260))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('oxidative stress', 'MPA', (214, 230))	('tumor', 'Disease', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Disease', (359, 365))	('slowing tumor', 'Disease', (80, 93))	('carcinogenesis', 'Disease', (62, 76))	('ketosis', 'Disease', 'MESH:D007662', (40, 47))
155638	29294371	High levels of circulating insulin, or hyperinsulinemia, is also associated with an increased risk of colorectal, pancreatic, and breast cancer, among others.	('pancreatic', 'Disease', 'MESH:D010195', (114, 124))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (39, 55))	('breast cancer', 'Disease', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hyperinsulinemia', 'Disease', (39, 55))	('insulin', 'Gene', (44, 51))	('High', 'Var', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('pancreatic', 'Disease', (114, 124))	('insulin', 'Gene', '3630', (44, 51))	('associated', 'Reg', (65, 75))	('insulin', 'Gene', (27, 34))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (39, 55))	('colorectal', 'Disease', (102, 112))	('insulin', 'Gene', '3630', (27, 34))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
155664	29294371	In a mouse model of metastatic cancer, animals fed standard rodent chow supplemented with 20% BD-AcAc2 by weight exhibited a 30% reduction in blood glucose.	('BD-AcAc2', 'Var', (94, 102))	('reduction in blood glucose', 'Disease', 'MESH:D007022', (129, 155))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('mouse', 'Species', '10090', (5, 10))	('cancer', 'Disease', (31, 37))	('reduction in blood glucose', 'Disease', (129, 155))	('BD-AcAc2', 'Chemical', '-', (94, 102))
155673	29294371	There still exists, however, a threshold point above which ROS will irreversibly damage and induce apoptosis in cancer cells.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('ROS', 'Var', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('apoptosis', 'CPA', (99, 108))	('induce', 'Reg', (92, 98))
155694	29294371	With reduced flux through glycolysis and subsequently PPP, it is possible the tumor is more vulnerable to rapid onset of oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('flux through glycolysis', 'MPA', (13, 36))	('reduced', 'NegReg', (5, 12))	('tumor', 'Disease', (78, 83))	('PPP', 'Var', (54, 57))
155707	29294371	We have demonstrated that chronic feeding of BD-AcAc2 reduces circulating inflammatory markers in healthy rats.	('rats', 'Species', '10116', (106, 110))	('circulating inflammatory markers', 'MPA', (62, 94))	('rat', 'Species', '10116', (15, 18))	('rat', 'Species', '10116', (106, 109))	('BD-AcAc2', 'Chemical', '-', (45, 53))	('BD-AcAc2', 'Var', (45, 53))	('reduces', 'NegReg', (54, 61))
155709	29294371	Furthermore, it has been demonstrated that radiation induces NLRP3 inflammasome activation which contributes to radio-resistance in glioma, and that inhibition of NLRP3 slows tumor growth and restores radio-sensitivity.	('inflammasome', 'MPA', (67, 79))	('NLRP3', 'Gene', (61, 66))	('glioma', 'Disease', (132, 138))	('tumor', 'Disease', (175, 180))	('rat', 'Species', '10116', (32, 35))	('restores', 'PosReg', (192, 200))	('slows', 'NegReg', (169, 174))	('radio-sensitivity', 'MPA', (201, 218))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('inhibition', 'Var', (149, 159))	('NLRP3', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('activation', 'PosReg', (80, 90))
155748	29294371	Importantly, many classic oncogene mutations confer a metabolic phenotype which supports survival and proliferation.	('survival', 'CPA', (89, 97))	('rat', 'Species', '10116', (109, 112))	('oncogene', 'Gene', (26, 34))	('proliferation', 'CPA', (102, 115))	('mutations', 'Var', (35, 44))
155750	29294371	Thus, it may be logical to utilize a systemic, broad spectrum approach to robusty target miltiple relevant molecular and metabolically regulation of growth and survival pathways that modulate the hallmarks of carcinogenesis, without clinically limiting toxicity.	('hallmarks of carcinogenesis', 'Disease', (196, 223))	('hallmarks of carcinogenesis', 'Disease', 'MESH:D063646', (196, 223))	('toxicity', 'Disease', 'MESH:D064420', (253, 261))	('toxicity', 'Disease', (253, 261))	('miltiple', 'Var', (89, 97))	('modulate', 'Reg', (183, 191))
155768	29294371	Still, we posit that tumors which consistently express abnormalities in mitochondrial structure and function would not be as efficient utilizers of ketones compared to tissues with normal mitochondria.	('ketones', 'Chemical', 'MESH:D007659', (148, 155))	('abnormalities', 'Var', (55, 68))	('function', 'MPA', (100, 108))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mitochondrial structure', 'MPA', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
155774	29294371	showed that blood glucose levels had a direct and positive correlation with tumor growth and that the R-KD significantly decreased plasma glucose.	('glucose', 'Chemical', 'MESH:D005947', (138, 145))	('glucose', 'Chemical', 'MESH:D005947', (18, 25))	('blood glucose', 'Disease', 'MESH:D007022', (12, 25))	('blood glucose', 'Disease', (12, 25))	('tumor', 'Disease', (76, 81))	('R-KD', 'Var', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('decreased', 'NegReg', (121, 130))	('plasma glucose', 'MPA', (131, 145))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
155775	29294371	The R-KD also decreased plasma insulin-like growth factor-1 (IGF-1) levels, a known biomarker for cancer progression and angiogenesis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('decreased', 'NegReg', (14, 23))	('IGF-1', 'Gene', '3479', (61, 66))	('insulin-like growth factor-1', 'Gene', (31, 59))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('insulin-like growth factor-1', 'Gene', '3479', (31, 59))	('IGF-1', 'Gene', (61, 66))	('R-KD', 'Var', (4, 8))	('cancer', 'Disease', (98, 104))
155794	29294371	Based on laboratory studies, it appears that ketosis is a promising therapy that substantially alters metabolic physiology to elicit a number of distinct yet simultaneous anti-cancer efects, including a reduction of glucose and insulin, modulation of oxidative stress, reduction of inflammation, enhancement of anti-tumor immunity, and alteration of gene expression, among others.	('reduction', 'NegReg', (269, 278))	('ketosis', 'Phenotype', 'HP:0001946', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gene expression', 'MPA', (350, 365))	('metabolic physiology', 'MPA', (102, 122))	('inflammation', 'Disease', 'MESH:D007249', (282, 294))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('oxidative stress', 'Phenotype', 'HP:0025464', (251, 267))	('ketosis', 'Disease', 'MESH:D007662', (45, 52))	('oxidative stress', 'MPA', (251, 267))	('rat', 'Species', '10116', (13, 16))	('rat', 'Species', '10116', (340, 343))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('inflammation', 'Disease', (282, 294))	('alteration', 'Reg', (336, 346))	('enhancement', 'PosReg', (296, 307))	('ketosis', 'Disease', (45, 52))	('modulation', 'Var', (237, 247))	('alters', 'Reg', (95, 101))	('tumor', 'Disease', (316, 321))	('cancer', 'Disease', (176, 182))	('reduction of glucose and insulin', 'Disease', 'MESH:D007022', (203, 235))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
155807	29294371	As previously noted, tumors containing the BRAFV600E mutation may also be contraindicated for ketogenic diet therapy.	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('BRAFV600E', 'Var', (43, 52))	('BRAFV600E', 'Mutation', 'rs113488022', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
155808	29294371	The ketogenic diet promoted the growth of human melanoma cells expressing this mutation in a xenograft mouse model by selectively enhancing BRAF V600E mutant-dependent MEK1 activation.	('V600E', 'Mutation', 'rs113488022', (145, 150))	('growth', 'MPA', (32, 38))	('melanoma', 'Disease', (48, 56))	('promoted', 'PosReg', (19, 27))	('enhancing', 'PosReg', (130, 139))	('MEK1', 'Gene', '26395', (168, 172))	('human', 'Species', '9606', (42, 47))	('mouse', 'Species', '10090', (103, 108))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('activation', 'MPA', (173, 183))	('MEK1', 'Gene', (168, 172))	('BRAF V600E', 'Var', (140, 150))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
155875	27363701	No statistically significant difference could be detected regarding V90  % and V95  % (percentage of PTV receiving a minimum of 90 and 95 % of the prescribed dose, respectively).	('V95  %', 'Var', (79, 85))	('PTV', 'Chemical', '-', (101, 104))	('V90  %', 'Var', (68, 74))
155895	27363701	performed a dosimetric comparison for optic pathway glioma focusing on the saving potential for the CL ON, showing that PRT has the potential to nearly halve the dose received (-47 %).	('PRT', 'Var', (120, 123))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('optic pathway glioma', 'Phenotype', 'HP:0009734', (38, 58))	('dose received', 'MPA', (162, 175))	('glioma', 'Disease', (52, 58))
155922	33227903	We demonstrated that integrating serum CHI3L1 and OPN protein level values and tumor isocitrate dehydrogenase 1 IDH1 mutational status into one parameter could predict low-grade astrocytoma patients' two-year survival with 93.8% accuracy.	('mutational', 'Var', (117, 127))	('astrocytoma', 'Disease', (178, 189))	('CHI3L1', 'Gene', '1116', (39, 45))	('tumor', 'Disease', (79, 84))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('patients', 'Species', '9606', (190, 198))	('IDH1', 'Gene', (112, 116))	('isocitrate dehydrogenase 1', 'Gene', (85, 111))	('isocitrate dehydrogenase 1', 'Gene', '3417', (85, 111))	('predict', 'Reg', (160, 167))	('CHI3L1', 'Gene', (39, 45))	('OPN', 'Gene', '6696', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('OPN', 'Gene', (50, 53))	('IDH1', 'Gene', '3417', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('astrocytoma', 'Disease', 'MESH:D001254', (178, 189))
155948	33227903	A high OPN concentration in GBM patient blood serum is related with poor prognosis.	('OPN', 'Gene', (7, 10))	('high', 'Var', (2, 6))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('patient', 'Species', '9606', (32, 39))	('OPN', 'Gene', '6696', (7, 10))
155965	33227903	The Patient Survival Score (PSS) according to the same methodology was also calculated including variables like tumor malignancy, MGMT promoter methylation status, IDH1 mutation status, gender, and age.	('Patient', 'Species', '9606', (4, 11))	('mutation', 'Var', (169, 177))	('MGMT', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor malignancy', 'Disease', (112, 128))	('MGMT', 'Gene', '4255', (130, 134))	('IDH1', 'Gene', (164, 168))	('tumor malignancy', 'Disease', 'MESH:D009369', (112, 128))	('IDH1', 'Gene', '3417', (164, 168))
155971	33227903	Next, the AREG concentrations in different IDH1 mutational status and different malignancy astrocytoma group samples and healthy control group serum samples are presented in Figure 1B.	('malignancy astrocytoma', 'Disease', (80, 102))	('malignancy astrocytoma', 'Disease', 'MESH:D020339', (80, 102))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))	('AREG', 'Gene', (10, 14))	('mutational', 'Var', (48, 58))	('AREG', 'Gene', '374', (10, 14))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
155972	33227903	The MMP-2 (Figure 1C) and GFAP (Figure 1D) proteins did not demonstrate any statistically significant expression differences between different malignancy grades and different IDH1 mutational status astrocytoma groups, or between the astrocytoma and healthy control groups.	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('astrocytoma', 'Disease', (233, 244))	('malignancy', 'Disease', (143, 153))	('astrocytoma', 'Phenotype', 'HP:0009592', (233, 244))	('mutational status', 'Var', (180, 197))	('MMP-2', 'Gene', (4, 9))	('GFAP', 'Gene', (26, 30))	('astrocytoma', 'Phenotype', 'HP:0009592', (198, 209))	('IDH1', 'Gene', (175, 179))	('MMP-2', 'Gene', '4313', (4, 9))	('astrocytoma', 'Disease', 'MESH:D001254', (198, 209))	('astrocytoma', 'Disease', (198, 209))	('GFAP', 'Gene', '2670', (26, 30))	('astrocytoma', 'Disease', 'MESH:D001254', (233, 244))	('IDH1', 'Gene', '3417', (175, 179))
155986	33227903	Although patients with low PSS0 lived significantly shorter than did those with higher scores (Log-rank test; chi2 = 7.076; df = 1; p = 0.008), the score showed only little improvement as compared to the individual CHI3L1 or OPN survival curves.	('patients', 'Species', '9606', (9, 17))	('CHI3L1', 'Gene', '1116', (215, 221))	('OPN', 'Gene', '6696', (225, 228))	('shorter', 'NegReg', (52, 59))	('PSS0', 'Var', (27, 31))	('low PSS0', 'Var', (23, 31))	('OPN', 'Gene', (225, 228))	('CHI3L1', 'Gene', (215, 221))
155987	33227903	Next, the same Cox regression analysis was repeated including clinical variables, like tumor malignancy, MGMT promoter methylation status, IDH1 mutation status, and patient gender and age (<50 or >=50 years) (Table 1).	('tumor malignancy', 'Disease', (87, 103))	('IDH1', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor malignancy', 'Disease', 'MESH:D009369', (87, 103))	('patient', 'Species', '9606', (165, 172))	('MGMT', 'Gene', '4255', (105, 109))	('mutation', 'Var', (144, 152))	('MGMT', 'Gene', (105, 109))	('IDH1', 'Gene', '3417', (139, 143))
155988	33227903	The variables selected as significant after univariate analysis were the CHI3L1 and OPN expression levels in patient serum, tumor IDH1 mutational status, patient age, and malignancy grade.	('mutational', 'Var', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('patient', 'Species', '9606', (109, 116))	('patient', 'Species', '9606', (154, 161))	('malignancy', 'Disease', 'MESH:D009369', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CHI3L1', 'Gene', '1116', (73, 79))	('tumor', 'Disease', (124, 129))	('OPN', 'Gene', '6696', (84, 87))	('IDH1', 'Gene', (130, 134))	('CHI3L1', 'Gene', (73, 79))	('IDH1', 'Gene', '3417', (130, 134))	('OPN', 'Gene', (84, 87))	('malignancy', 'Disease', (171, 181))
155991	33227903	The variables included in the Patient Survival Score calculation were as follows: CHI3L1, OPN, and IDH1 mutational status.	('CHI3L1', 'Gene', (82, 88))	('OPN', 'Gene', '6696', (90, 93))	('mutational status', 'Var', (104, 121))	('CHI3L1', 'Gene', '1116', (82, 88))	('Patient', 'Species', '9606', (30, 37))	('OPN', 'Gene', (90, 93))	('IDH1', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (99, 103))
155998	33227903	ROC curve analysis was also performed to evaluate all other variables that demonstrated significance in Univariate Cox regression analysis:individual CHI3L1 and OPN expressions, tumor malignancy grade, patient age, and IDH1 mutational status:in terms of their reliability in predicting the 24-month survival of the patient (Figure 4).	('mutational', 'Var', (224, 234))	('tumor malignancy', 'Disease', 'MESH:D009369', (178, 194))	('OPN', 'Gene', (161, 164))	('OPN', 'Gene', '6696', (161, 164))	('patient', 'Species', '9606', (315, 322))	('IDH1', 'Gene', '3417', (219, 223))	('CHI3L1', 'Gene', '1116', (150, 156))	('patient', 'Species', '9606', (202, 209))	('tumor malignancy', 'Disease', (178, 194))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('IDH1', 'Gene', (219, 223))	('CHI3L1', 'Gene', (150, 156))
156001	33227903	Dividing patients into groups depending on their astrocytoma malignancy grade, no improvement was observed in the GBM group (83.8% in both groups); however, in the grade II astrocytoma group, PSS demonstrated a solid improvement in predicting two-year survival compared to IDH1 mutational status alone:93.8% vs. 75.00%, respectively.	('patients', 'Species', '9606', (9, 17))	('astrocytoma malignancy', 'Disease', 'MESH:D020339', (49, 71))	('IDH1', 'Gene', (273, 277))	('PSS', 'Var', (192, 195))	('astrocytoma malignancy', 'Disease', (49, 71))	('IDH1', 'Gene', '3417', (273, 277))	('II astrocytoma', 'Disease', 'MESH:D001254', (170, 184))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('astrocytoma', 'Phenotype', 'HP:0009592', (49, 60))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('II astrocytoma', 'Disease', (170, 184))	('improvement', 'PosReg', (217, 228))
156017	33227903	Also, in the same study, Ramachandran and colleagues found MMP-2 expression to be associated with shorter overall survival in patients with grade II-IV astrocytic tumors.	('astrocytic tumors', 'Disease', (152, 169))	('MMP-2', 'Gene', (59, 64))	('grade', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('astrocytic tumors', 'Disease', 'MESH:D001254', (152, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('patients', 'Species', '9606', (126, 134))	('MMP-2', 'Gene', '4313', (59, 64))	('overall survival', 'MPA', (106, 122))	('expression', 'Var', (65, 75))	('shorter', 'NegReg', (98, 105))
156029	33227903	Their analysis also demonstrated a correlation between high OPN expression and tumor reoccurrence and indicated that OPN expression was significantly related to overall survival.	('tumor', 'Disease', (79, 84))	('OPN', 'Gene', '6696', (117, 120))	('related', 'Reg', (150, 157))	('OPN', 'Gene', (117, 120))	('OPN', 'Gene', '6696', (60, 63))	('high', 'Var', (55, 59))	('overall survival', 'CPA', (161, 177))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('OPN', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
156031	33227903	The same group also showed that GBM patients with high serum OPN levels had poorer survival than did those with low serum OPN levels.	('OPN', 'Gene', (122, 125))	('patients', 'Species', '9606', (36, 44))	('poorer', 'NegReg', (76, 82))	('survival', 'CPA', (83, 91))	('OPN', 'Gene', '6696', (122, 125))	('OPN', 'Gene', '6696', (61, 64))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))	('high', 'Var', (50, 54))	('OPN', 'Gene', (61, 64))
156038	33227903	Our group demonstrated that integrating the values of CHI3L1 and OPN protein expression in serum with IDH1 mutational status into one parameter could predict patient 24-month survival with 86.8% accuracy for astrocytoma patients of all grades.	('CHI3L1', 'Gene', (54, 60))	('OPN', 'Gene', '6696', (65, 68))	('mutational status', 'Var', (107, 124))	('CHI3L1', 'Gene', '1116', (54, 60))	('OPN', 'Gene', (65, 68))	('patient', 'Species', '9606', (158, 165))	('IDH1', 'Gene', (102, 106))	('astrocytoma', 'Disease', 'MESH:D001254', (208, 219))	('patient', 'Species', '9606', (220, 227))	('patients', 'Species', '9606', (220, 228))	('predict', 'Reg', (150, 157))	('IDH1', 'Gene', '3417', (102, 106))	('astrocytoma', 'Disease', (208, 219))	('astrocytoma', 'Phenotype', 'HP:0009592', (208, 219))
156043	33081358	IDH (isocitrate dehydrogenase) mutations can affect the great majority of these tumors with distinct genetic and clinical characteristics, carrying a more favorable prognosis compared with wild-type IDH.	('affect', 'Reg', (45, 51))	('IDH', 'Gene', (0, 3))	('mutations', 'Var', (31, 40))	('IDH', 'Gene', '3417', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('isocitrate dehydrogenase', 'Gene', (5, 29))	('IDH', 'Gene', '3417', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('isocitrate dehydrogenase', 'Gene', '3417', (5, 29))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('IDH', 'Gene', (199, 202))
156048	33081358	Advances in the knowledge of molecular profile of these tumors, including mutations in the isocitrate dehydrogenase genes, or 1p/19q codeletion, and in neuroradiological techniques have contributed to the diagnosis, prognostic stratification, and follow-up of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('isocitrate dehydrogenase', 'Gene', (91, 115))	('isocitrate dehydrogenase', 'Gene', '3417', (91, 115))	('mutations', 'Var', (74, 83))	('tumors', 'Disease', (56, 62))	('contributed', 'Reg', (186, 197))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
156052	33081358	The median survival of patients affected by LGG is widely variable, ranging from 5.6 to 13.3 years, depending on several factors, such as extent of resection and molecular features, including isocitrate dehydrogenase (IDH) 1 and 2 mutations, and 1p19q codeletion.	('1p19q codeletion', 'Var', (246, 262))	('mutations', 'Var', (231, 240))	('patients', 'Species', '9606', (23, 31))	('LGG', 'Disease', (44, 47))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (192, 230))
156061	33081358	According to the latest World Health Organization (WHO) Classification, diffuse LGGs include: oligodendroglioma Isocitrate Dehydogenase (IDH) mutant and 1p/19q codeleted; diffuse astrocytoma IDH mutant and diffuse astrocytoma IDH wild-type (wt).	('astrocytoma IDH', 'Disease', (179, 194))	('astrocytoma IDH', 'Disease', 'MESH:D001254', (214, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (214, 225))	('IDH', 'Gene', '3417', (226, 229))	('IDH', 'Gene', '3417', (137, 140))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('oligodendroglioma', 'Disease', (94, 111))	('astrocytoma IDH', 'Disease', (214, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (179, 190))	('IDH', 'Gene', (191, 194))	('mutant', 'Var', (142, 148))	('IDH', 'Gene', '3417', (191, 194))	('oligodendroglioma', 'Disease', 'MESH:D009837', (94, 111))	('astrocytoma IDH', 'Disease', 'MESH:D001254', (179, 194))	('mutant', 'Var', (195, 201))	('IDH', 'Gene', (226, 229))	('IDH', 'Gene', (137, 140))
156062	33081358	Among these, oligodendroglioma IDH mutant and 1p/19q codeleted carry the best prognosis, and IDH-wt astrocytoma the worst (Table 1).	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH-wt astrocytoma', 'Disease', (93, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('oligodendroglioma IDH', 'Disease', (13, 34))	('1p/19q', 'Var', (46, 52))	('oligodendroglioma IDH', 'Disease', 'MESH:D009837', (13, 34))	('IDH-wt astrocytoma', 'Disease', 'MESH:D001254', (93, 111))
156065	33081358	About 90% of IDH-mutant diffuse gliomas have IDH1 R132H mutation, which can be detected by immunohistochemistry using a specific antibody against the IDH1 R132H protein (Figure 1).	('IDH1', 'Gene', '3417', (45, 49))	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', (45, 48))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('IDH', 'Gene', '3417', (45, 48))	('R132H', 'Mutation', 'rs121913500', (155, 160))	('IDH', 'Gene', '3417', (150, 153))	('R132H', 'Var', (50, 55))	('IDH', 'Gene', (150, 153))	('IDH1', 'Gene', (150, 154))	('IDH1', 'Gene', (45, 49))	('IDH', 'Gene', (13, 16))	('R132H', 'Mutation', 'rs121913500', (50, 55))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('IDH1', 'Gene', '3417', (150, 154))
156066	33081358	A minority of cases have other (non-canonical) IDH1 mutations at R132 residue (5%) or IDH2 mutations at 172 residue (5%), the detection of which requires IDH1/IDH2 sequencing.	('IDH2', 'Gene', (86, 90))	('IDH2', 'Gene', (159, 163))	('IDH1', 'Gene', (47, 51))	('IDH2', 'Gene', '3418', (159, 163))	('IDH2', 'Gene', '3418', (86, 90))	('IDH1', 'Gene', (154, 158))	('mutations at R132 residue', 'Var', (52, 77))	('IDH1', 'Gene', '3417', (47, 51))	('IDH1', 'Gene', '3417', (154, 158))	('mutations at 172', 'Var', (91, 107))
156067	33081358	Interestingly, IDH2 mutations are mainly found in oligodendrogliomas, while IDH1 mutations differing from R132H are mostly seen in astrocytomas.	('astrocytomas', 'Disease', (131, 143))	('found', 'Reg', (41, 46))	('IDH1', 'Gene', (76, 80))	('IDH2', 'Gene', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('oligodendrogliomas', 'Disease', (50, 68))	('IDH2', 'Gene', '3418', (15, 19))	('IDH1', 'Gene', '3417', (76, 80))	('astrocytomas', 'Disease', 'MESH:D001254', (131, 143))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('R132H', 'Mutation', 'rs121913500', (106, 111))	('seen', 'Reg', (123, 127))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (50, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('mutations', 'Var', (20, 29))
156068	33081358	The combined deletion of chromosomes 1p and 19q in oligodendrogliomas is mediated by a balanced whole-arm translocation of chromosomes 1 and 19, leading to the formation of two derivative chromosomes.	('oligodendrogliomas', 'Disease', (51, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('deletion', 'Var', (13, 21))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (51, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
156070	33081358	FISH is the most widely used method, but, differently from CGH, it is unable to distinguish between whole arm deletion:which is specific to oligodendroglioma:and partial deletions:which can be also found in astrocytic tumors.	('oligodendroglioma', 'Disease', 'MESH:D009837', (140, 157))	('astrocytic tumors', 'Disease', (207, 224))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('astrocytic tumors', 'Disease', 'MESH:D001254', (207, 224))	('whole arm', 'Disease', (100, 109))	('partial deletions', 'Var', (162, 179))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('oligodendroglioma', 'Disease', (140, 157))
156071	33081358	IDH-mutant diffuse astrocytomas commonly display inactivating mutations in alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and missense mutation in TP53 that are mutually exclusive with 1p/19q codeletion.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('ATRX', 'Gene', '546', (131, 135))	('IDH', 'Gene', (0, 3))	('astrocytomas', 'Disease', (19, 31))	('inactivating mutations', 'Var', (49, 71))	('TP53', 'Gene', '7157', (162, 166))	('IDH', 'Gene', '3417', (0, 3))	('TP53', 'Gene', (162, 166))	('missense mutation', 'Var', (141, 158))	('astrocytomas', 'Disease', 'MESH:D001254', (19, 31))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (81, 129))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (81, 129))	('ATRX', 'Gene', (131, 135))	('mental retardation', 'Phenotype', 'HP:0001249', (93, 111))
156072	33081358	Since ATRX mutations result in protein loss and TP53 mutations in p53 nuclear accumulation, a diffuse low-grade IDH-mutated glioma with astrocytic morphology, ATRX loss, and p53 diffuse and strong staining can be diagnosed as IDH-mutant diffuse astrocytoma in the absence of 1p/19q testing (Figure 1)  In the latest WHO Classification, the diagnosis of oligoastrocytoma is strongly discouraged and reserved to cases with ambiguous morphology when molecular tests cannot be performed (Oligoastrocytoma, NOS) or in the rare instance of dual-genotype oligoastrocytoma.	('ATRX', 'Gene', '546', (159, 163))	('mutations', 'Var', (11, 20))	('Oligoastrocytoma', 'Disease', 'MESH:D001254', (484, 500))	('IDH', 'Gene', '3417', (226, 229))	('glioma', 'Disease', (124, 130))	('nuclear accumulation', 'MPA', (70, 90))	('ATRX', 'Gene', (6, 10))	('oligoastrocytoma', 'Disease', (548, 564))	('astrocytoma', 'Disease', 'MESH:D001254', (245, 256))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('ATRX', 'Gene', '546', (6, 10))	('astrocytoma', 'Disease', (245, 256))	('IDH', 'Gene', (112, 115))	('p53', 'Gene', '7157', (174, 177))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (353, 369))	('TP53', 'Gene', '7157', (48, 52))	('protein', 'Protein', (31, 38))	('astrocytoma', 'Disease', 'MESH:D001254', (553, 564))	('astrocytoma', 'Disease', (553, 564))	('astrocytoma', 'Disease', 'MESH:D001254', (489, 500))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (358, 369))	('astrocytoma', 'Disease', (489, 500))	('p53', 'Gene', (174, 177))	('IDH', 'Gene', '3417', (112, 115))	('oligoastrocytoma', 'Disease', (353, 369))	('astrocytoma', 'Phenotype', 'HP:0009592', (489, 500))	('mutations', 'Var', (53, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (245, 256))	('Oligoastrocytoma', 'Disease', (484, 500))	('IDH', 'Gene', (226, 229))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (548, 564))	('p53', 'Gene', '7157', (66, 69))	('astrocytoma', 'Disease', 'MESH:D001254', (358, 369))	('TP53', 'Gene', (48, 52))	('astrocytoma', 'Disease', (358, 369))	('loss', 'NegReg', (39, 43))	('ATRX', 'Gene', (159, 163))	('astrocytoma', 'Phenotype', 'HP:0009592', (553, 564))	('p53', 'Gene', (66, 69))
156073	33081358	The latter is an IDH mutant tumor composed of two distinct populations, showing the morphological features and genotype of astrocytoma (TP53 mutation/nuclear p53 accumulation, loss of nuclear ATRX expression and absence of 1p/19q codeletion) or oligodendroglioma (lack of TP53 mutation/nuclear p53 accumulation, retained nuclear ATRX expression and 1p/19 codeletion).	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('tumor', 'Disease', (28, 33))	('TP53', 'Gene', '7157', (272, 276))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('p53', 'Gene', '7157', (294, 297))	('p53', 'Gene', '7157', (158, 161))	('TP53', 'Gene', '7157', (136, 140))	('IDH', 'Gene', '3417', (17, 20))	('p53', 'Gene', (294, 297))	('p53', 'Gene', (158, 161))	('1p/19 codeletion', 'Var', (349, 365))	('astrocytoma', 'Disease', 'MESH:D001254', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('oligodendroglioma', 'Disease', 'MESH:D009837', (245, 262))	('astrocytoma', 'Disease', (123, 134))	('ATRX', 'Gene', (329, 333))	('loss', 'NegReg', (176, 180))	('ATRX', 'Gene', (192, 196))	('TP53', 'Gene', (272, 276))	('ATRX', 'Gene', '546', (192, 196))	('ATRX', 'Gene', '546', (329, 333))	('mutation/nuclear', 'Var', (141, 157))	('oligodendroglioma', 'Disease', (245, 262))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('TP53', 'Gene', (136, 140))	('IDH', 'Gene', (17, 20))
156081	33081358	For this reason, they are considered to be a different entity, which was named diffuse midline glioma H3 K27M-mutated and classified as grade IV in the latest WHO classification.	('midline glioma', 'Disease', (87, 101))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('H3 K27M-mutated', 'Var', (102, 117))	('K27M-mutated', 'Var', (105, 117))	('midline glioma', 'Disease', 'MESH:D005910', (87, 101))	('K27M', 'Mutation', 'p.K27M', (105, 109))
156083	33081358	A subgroup of IDH-wt/H3-wt diffuse LGGs in adults harbors a molecular profile similar to that of pediatric LGGs and consisting of BRAF V600E mutation, MYB or MYBL1 structural variation, and FGFR1 alterations (Table 1).	('MYBL1', 'Gene', '4603', (158, 163))	('IDH', 'Gene', (14, 17))	('V600E', 'Mutation', 'rs113488022', (135, 140))	('FGFR1', 'Gene', '2260', (190, 195))	('BRAF', 'Gene', '673', (130, 134))	('IDH', 'Gene', '3417', (14, 17))	('BRAF', 'Gene', (130, 134))	('diffuse LGGs', 'Disease', (27, 39))	('MYBL1', 'Gene', (158, 163))	('MYB', 'Gene', '4602', (158, 161))	('MYB', 'Gene', (158, 161))	('MYB', 'Gene', (151, 154))	('MYB', 'Gene', '4602', (151, 154))	('FGFR1', 'Gene', (190, 195))	('alterations', 'Var', (196, 207))
156084	33081358	Tumors with BRAFv600E mutation usually have astrocytic morphology, while those with MYB, MYBL1, or FGFR1 alterations harbor oligodendroglioma-like histology.	('oligodendroglioma', 'Disease', (124, 141))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FGFR1', 'Gene', (99, 104))	('MYB', 'Gene', '4602', (84, 87))	('oligodendroglioma', 'Disease', 'MESH:D009837', (124, 141))	('MYBL1', 'Gene', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('Tumors', 'Disease', (0, 6))	('FGFR1', 'Gene', '2260', (99, 104))	('astrocytic morphology', 'CPA', (44, 65))	('MYB', 'Gene', (84, 87))	('BRAFv600E', 'Mutation', 'rs113488022', (12, 21))	('MYBL1', 'Gene', '4603', (89, 94))	('MYB', 'Gene', '4602', (89, 92))	('BRAFv600E', 'Var', (12, 21))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MYB', 'Gene', (89, 92))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
156086	33081358	Finally, some LGGs without IDH and H3 K27M mutations have the same genetic alterations as IDH-wt glioblastoma, i.e., gains in chromosome 7, losses in chromosome 10, focal amplifications in EGFR, CDK4 and MDM4, focal deletions involving CDKN2A and RB1, mutations in telomerase reverse transcriptase (TERT) promoter.	('RB1', 'Gene', '5925', (247, 250))	('telomerase reverse transcriptase', 'Gene', (265, 297))	('IDH', 'Gene', '3417', (27, 30))	('IDH-wt glioblastoma', 'Disease', 'MESH:D005909', (90, 109))	('IDH', 'Gene', '3417', (90, 93))	('CDKN2A', 'Gene', '1029', (236, 242))	('TERT', 'Gene', (299, 303))	('TERT', 'Gene', '7015', (299, 303))	('CDK4', 'Gene', (195, 199))	('IDH-wt glioblastoma', 'Disease', (90, 109))	('focal deletions', 'Var', (210, 225))	('gains', 'PosReg', (117, 122))	('EGFR', 'Gene', '1956', (189, 193))	('telomerase reverse transcriptase', 'Gene', '7015', (265, 297))	('alterations', 'Reg', (75, 86))	('CDK4', 'Gene', '1019', (195, 199))	('K27M', 'Mutation', 'p.K27M', (38, 42))	('MDM4', 'Gene', '4194', (204, 208))	('MDM4', 'Gene', (204, 208))	('RB1', 'Gene', (247, 250))	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', (90, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('CDKN2A', 'Gene', (236, 242))	('EGFR', 'Gene', (189, 193))	('mutations', 'Reg', (252, 261))	('losses', 'NegReg', (140, 146))	('mutations', 'Var', (43, 52))
156122	33081358	In particular, PET with radiolabeled amino acids such as [11C-methyl]-methionine (11C-MET), O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET), and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) has been proven to have a moderately high diagnostic accuracy to discriminate high and low-grade gliomas, but the overlap between tumor subtypes hampers clear separation.	('C-MET', 'Gene', '4233', (84, 89))	('gliomas', 'Disease', 'MESH:D005910', (296, 303))	('[11C-methyl', 'Var', (57, 68))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('gliomas', 'Disease', (296, 303))	('high', 'Disease', (277, 281))	('C-MET', 'Gene', (84, 89))	('tumor', 'Disease', (329, 334))	('gliomas', 'Phenotype', 'HP:0009733', (296, 303))
156133	33081358	With regard to LGG close to or involving the motor pathways, it has been shown that there are lower risks of permanent postoperative deficits and higher EOR for lesions in eloquent areas when surgery is associated with intra-operative neurophysiological monitoring.	('postoperative deficits', 'Disease', (119, 141))	('postoperative deficits', 'Disease', 'MESH:D010149', (119, 141))	('lesions', 'Var', (161, 168))	('EOR', 'MPA', (153, 156))
156168	33081358	A recent molecular analysis on a fraction of patients from this trial confirmed that patients with IDH mutated gliomas with or without 1p/19q codeletion benefited from the addition of PCV to radiotherapy, but suggested that patients with IDH wild-type astrocytomas may not benefit from this combination.	('IDH', 'Gene', '3417', (99, 102))	('gliomas', 'Disease', (111, 118))	('mutated', 'Var', (103, 110))	('benefited', 'PosReg', (153, 162))	('astrocytomas', 'Disease', 'MESH:D001254', (252, 264))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('astrocytomas', 'Disease', (252, 264))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('IDH', 'Gene', (238, 241))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('patients', 'Species', '9606', (85, 93))	('IDH', 'Gene', '3417', (238, 241))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (224, 232))	('IDH', 'Gene', (99, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (252, 263))
156172	33081358	Moreover, the two MGMT CpGs identified (combined in a MGMT methylation score) might predict temozolomide benefits for IDH mutated patients regardless of codeletion status, suggesting a role for chemotherapy alone as initial treatment for a sub-group of patients with good prognosis and chemotherapy sensibility.	('temozolomide', 'Chemical', 'MESH:D000077204', (92, 104))	('MGMT', 'Gene', (18, 22))	('MGMT', 'Gene', '4255', (18, 22))	('benefits', 'PosReg', (105, 113))	('IDH', 'Gene', (118, 121))	('patients', 'Species', '9606', (253, 261))	('MGMT', 'Gene', (54, 58))	('temozolomide', 'MPA', (92, 104))	('patients', 'Species', '9606', (130, 138))	('MGMT', 'Gene', '4255', (54, 58))	('IDH', 'Gene', '3417', (118, 121))	('mutated', 'Var', (122, 129))
156175	33081358	The I-WOT study by the EORTC brain tumor group (EORTC-1635-BTG) is an ongoing randomized, phase 3 study analyzing patients with IDH mutated 1p/19q intact lower grade glioma following resection, without a need for immediate post-operative treatment; the study will establish whether early adjuvant treatment with radiotherapy and adjuvant temozolomide in this clinically favorable group of patients will improve outcome compared to active surveillance (see Figure 3).	('brain tumor', 'Disease', (29, 40))	('brain tumor', 'Disease', 'MESH:D001932', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('EORTC-1635-BTG', 'Chemical', '-', (48, 62))	('IDH', 'Gene', (128, 131))	('glioma', 'Disease', (166, 172))	('mutated', 'Var', (132, 139))	('brain tumor', 'Phenotype', 'HP:0030692', (29, 40))	('temozolomide', 'Chemical', 'MESH:D000077204', (338, 350))	('IDH', 'Gene', '3417', (128, 131))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('patients', 'Species', '9606', (389, 397))	('patients', 'Species', '9606', (114, 122))	('improve', 'PosReg', (403, 410))
156180	33081358	Moreover, ivosidenib, an inhibitor of mutant IDH1, showed interesting results in recurrent LGG with mutated IDH, and a randomized phase 3 study with the similar drug vorasidenib (AG-881) is currently ongoing.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (45, 49))	('mutated', 'Var', (100, 107))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (45, 48))	('ivosidenib', 'Chemical', 'MESH:C000627630', (10, 20))	('IDH', 'Gene', '3417', (108, 111))	('LGG', 'Disease', (91, 94))	('vorasidenib', 'Chemical', '-', (166, 177))	('AG-881', 'Chemical', '-', (179, 185))	('IDH1', 'Gene', (45, 49))
156198	33081358	To note, psychotic disorders are more commonly induced by levetiracetam and LGG patients are particularly vulnerable because of the presence of tumor, the effects of surgery, and the concomitant oncological treatments.	('tumor', 'Disease', (144, 149))	('levetiracetam', 'Var', (58, 71))	('patients', 'Species', '9606', (80, 88))	('psychotic disorders', 'Disease', 'MESH:D011618', (9, 28))	('induced', 'Reg', (47, 54))	('LGG', 'Disease', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('psychotic disorders', 'Phenotype', 'HP:0000725', (9, 28))	('psychotic disorders', 'Disease', (9, 28))	('levetiracetam', 'Chemical', 'MESH:D000077287', (58, 71))
156208	33081358	New targeted therapies and immunotherapy involving the mutated IDH protein could improve the outcome in selected cases.	('mutated', 'Var', (55, 62))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (63, 66))
156209	28066715	Challenges in Drug Discovery for Neurofibromatosis Type 1-Associated Low-Grade Glioma Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from germline mutations of the NF1 gene, creating a predisposition to low-grade gliomas (LGGs; pilocytic astrocytoma) in young children.	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (123, 150))	('Neurofibromatosis type 1', 'Gene', (86, 110))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (33, 50))	('NF', 'Phenotype', 'HP:0001067', (195, 197))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (259, 280))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('Neurofibromatosis Type 1-Associated Low-Grade Glioma', 'Disease', 'MESH:C537392', (33, 85))	('autosomal dominant disorder', 'Disease', (123, 150))	('pilocytic astrocytoma', 'Disease', (259, 280))	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('astrocytoma', 'Phenotype', 'HP:0009592', (269, 280))	('NF1', 'Gene', (195, 198))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (86, 103))	('results from', 'Reg', (156, 168))	('germline mutations', 'Var', (169, 187))	('NF', 'Phenotype', 'HP:0001067', (112, 114))	('Glioma', 'Phenotype', 'HP:0009733', (79, 85))	('children', 'Species', '9606', (291, 299))	('gliomas', 'Disease', (244, 251))	('Neurofibromatosis type 1', 'Gene', '4763', (86, 110))
156230	28066715	Pioneering genomic sequencing efforts by the Pfister laboratory and colleagues identified that the majority of sporadic PA tumors are caused by a somatic genomic rearrangement of the KIAA1549 and BRAF genes to result in a fusion protein containing an unregulated and active BRAF kinase domain.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('result in a', 'Reg', (210, 221))	('sporadic PA tumors', 'Disease', (111, 129))	('BRAF kinase domain', 'MPA', (274, 292))	('sporadic PA tumors', 'Disease', 'MESH:D011471', (111, 129))	('caused by', 'Reg', (134, 143))	('rearrangement', 'Var', (162, 175))	('rat', 'Species', '10116', (57, 60))	('BRAF', 'Gene', (196, 200))	('KIAA1549', 'Gene', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
156233	28066715	In addition to the KIAA1549:BRAF fusion, mutations in the fibroblast growth factor receptor 1 (FGFR1) and neurotrophic tyrosine kinase receptor 2 (NTRK2) genes are (more) common in non-cerebellar PAs.	('mutations', 'Var', (41, 50))	('non-cerebellar PAs', 'Disease', (181, 199))	('neurotrophic tyrosine kinase receptor 2', 'Gene', '4915', (106, 145))	('FGFR1', 'Gene', (95, 100))	('neurotrophic tyrosine kinase receptor 2', 'Gene', (106, 145))	('fibroblast growth factor receptor 1', 'Gene', '2260', (58, 93))	('non-cerebellar PAs', 'Disease', 'MESH:D002528', (181, 199))	('FGFR1', 'Gene', '2260', (95, 100))	('fibroblast growth factor receptor 1', 'Gene', (58, 93))	('NTRK2', 'Gene', (147, 152))	('common', 'Reg', (171, 177))	('NTRK2', 'Gene', '4915', (147, 152))
156234	28066715	The second group of children with PA includes those who harbor a germline mutation in the Neurofibromin (NF1) tumor suppressor gene and, therefore, have NF1 as the genetic etiology for their brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (191, 203))	('brain tumors', 'Phenotype', 'HP:0030692', (191, 203))	('Neurofibromin', 'Gene', (90, 103))	('brain tumors', 'Disease', (191, 203))	('NF1', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('brain tumor', 'Phenotype', 'HP:0030692', (191, 202))	('NF', 'Phenotype', 'HP:0001067', (105, 107))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('germline mutation', 'Var', (65, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('NF', 'Phenotype', 'HP:0001067', (153, 155))	('Neurofibromin', 'Gene', '4763', (90, 103))	('children', 'Species', '9606', (20, 28))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
156238	28066715	In this regard, loss of NF1 gene expression leads to increased RAS activation and hyperactivation of the downstream RAS effectors, including the RAF/MEK/ERK and the PI3K/AKT pathways, thereafter converging on the mechanistic target of rapamycin (mTOR) complex.	('activation', 'PosReg', (67, 77))	('AKT', 'Gene', '207', (170, 173))	('RAF', 'Gene', '22882', (145, 148))	('RAF', 'Gene', (145, 148))	('RAS', 'CPA', (63, 66))	('increased', 'PosReg', (53, 62))	('loss', 'Var', (16, 20))	('AKT', 'Gene', (170, 173))	('NF', 'Phenotype', 'HP:0001067', (24, 26))	('hyperactivation', 'PosReg', (82, 97))	('NF1', 'Gene', (24, 27))
156239	28066715	Similarly, the KIAA1549:BRAF mutation results in increased MEK activation, which also operates to control cell growth through the mTOR complex.	('mutation', 'Var', (29, 37))	('MEK', 'Protein', (59, 62))	('increased', 'PosReg', (49, 58))	('rat', 'Species', '10116', (89, 92))	('activation', 'MPA', (63, 73))	('BRAF', 'Gene', (24, 28))
156241	28066715	These insights have resulted in the execution of early-phase clinical trials of MEK and mTOR inhibitors (NCT02285439 and NCT01734512; ), yet it is clear that additional resources and research will be required in order to develop personalized and effective therapies for these brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (276, 288))	('brain tumors', 'Phenotype', 'HP:0030692', (276, 288))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('brain tumors', 'Disease', (276, 288))	('brain tumor', 'Phenotype', 'HP:0030692', (276, 287))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('mTOR', 'Gene', (88, 92))	('NCT01734512', 'Var', (121, 132))	('MEK', 'Gene', (80, 83))
156281	28066715	As such, continual passage of sporadic tumors is associated with loss of the signature fusion BRAF alteration (KIAA1549:BRAF) and oncogene-induced senescence.	('loss', 'NegReg', (65, 69))	('BRAF', 'Gene', (94, 98))	('sporadic tumors', 'Disease', 'MESH:D009369', (30, 45))	('rat', 'Species', '10116', (103, 106))	('alteration', 'Var', (99, 109))	('sporadic tumors', 'Disease', (30, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('oncogene-induced', 'CPA', (130, 146))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
156285	28066715	Importantly, these iPSC lines were instrumental in demonstrating that different germline NF1 gene mutations result in different levels of neurofibromin expression.	('neurofibromin', 'Gene', '4763', (138, 151))	('NF', 'Phenotype', 'HP:0001067', (89, 91))	('neurofibromin', 'Gene', (138, 151))	('mutations', 'Var', (98, 107))	('NF1', 'Gene', (89, 92))	('rat', 'Species', '10116', (58, 61))	('result', 'Reg', (108, 114))
156288	28066715	While mice with a germline Nf1 gene mutation (Nf1+/- mice) do not develop gliomas, neither do mice in which both copies of the Nf1 gene are inactivated in neuroglial progenitors, suggesting that bi-allelic Nf1 gene inactivation in the proper cell of origin is not sufficient for glioma formation.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Disease', (279, 285))	('Nf1', 'Gene', (27, 30))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('mice', 'Species', '10090', (6, 10))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('gliomas', 'Disease', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('glioma', 'Disease', (74, 80))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('mice', 'Species', '10090', (94, 98))	('mice', 'Species', '10090', (53, 57))	('mutation', 'Var', (36, 44))
156289	28066715	To better model NF1-PA arising in children with a germline NF1 gene mutation, Nf1+/- mice were generated in which somatic loss of the remaining functional Nf1 allele occurs in neuroglial progenitors.	('mice', 'Species', '10090', (85, 89))	('NF', 'Phenotype', 'HP:0001067', (16, 18))	('mutation', 'Var', (68, 76))	('rat', 'Species', '10116', (99, 102))	('NF', 'Phenotype', 'HP:0001067', (59, 61))	('NF1', 'Gene', (59, 62))	('children', 'Species', '9606', (34, 42))
156293	28066715	Recent studies have also discovered co-existing genetic changes in NF1-PA in addition to NF1 gene mutation, including heterozygous PTEN deletion and KIAA1549:BRAF duplication.	('NF1 gene', 'Gene', (89, 97))	('mutation', 'Var', (98, 106))	('PTEN', 'Gene', (131, 135))	('PTEN', 'Gene', '5728', (131, 135))	('NF', 'Phenotype', 'HP:0001067', (89, 91))	('deletion', 'Var', (136, 144))	('NF', 'Phenotype', 'HP:0001067', (67, 69))
156294	28066715	Based on these observations, two Nf1 optic glioma GEM models were generated that additionally harbored either a heterozygous Pten deletion or KIAA1549:BRAF overexpression.	('rat', 'Species', '10116', (70, 73))	('optic glioma', 'Disease', (37, 49))	('deletion', 'Var', (130, 138))	('Pten', 'Gene', (125, 129))	('optic glioma', 'Phenotype', 'HP:0009734', (37, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('optic glioma', 'Disease', 'MESH:D020339', (37, 49))
156295	28066715	While KIAA1549:BRAF overexpression did not provide an additional growth advantage, tumors from mice with a co-existing heterozygous Pten deletion had larger volumes, increased proliferation indices, and more microglia infiltration.	('rat', 'Species', '10116', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mice', 'Species', '10090', (95, 99))	('increased', 'PosReg', (166, 175))	('tumors', 'Disease', (83, 89))	('deletion', 'Var', (137, 145))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('more', 'PosReg', (203, 207))	('microglia infiltration', 'CPA', (208, 230))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('larger', 'PosReg', (150, 156))	('proliferation indices', 'CPA', (176, 197))	('rat', 'Species', '10116', (224, 227))	('Pten', 'Gene', (132, 136))
156296	28066715	Furthermore, inhibition of Nf1+/- non-neoplastic stromal cells (microglia) significantly decreases optic glioma growth and maintenance.	('optic glioma growth', 'Disease', (99, 118))	('inhibition', 'Var', (13, 23))	('Nf1+/-', 'Var', (27, 33))	('optic glioma', 'Phenotype', 'HP:0009734', (99, 111))	('decreases', 'NegReg', (89, 98))	('optic glioma growth', 'Disease', 'MESH:D020339', (99, 118))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
156297	28066715	These preclinical mouse models suggest that additional genetic changes in NF1-associated PA patients differentially influence tumor growth relevant to the design of future therapeutic strategies.	('NF1-associated', 'Gene', (74, 88))	('NF1-associated', 'Reg', (74, 88))	('influence', 'Reg', (116, 125))	('mouse', 'Species', '10090', (18, 23))	('rat', 'Species', '10116', (186, 189))	('NF', 'Phenotype', 'HP:0001067', (74, 76))	('genetic changes', 'Var', (55, 70))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
156316	28066715	While each RAS effector pathway has different functions in NSCs relative to proliferation and glial differentiation, both the PI3K/AKT and MEK/ERK pathways are hyperactivated in Nf1-/- astrocytes relative to their wild-type counterparts.	('AKT', 'Gene', '207', (131, 134))	('rat', 'Species', '10116', (83, 86))	('glial differentiation', 'CPA', (94, 115))	('AKT', 'Gene', (131, 134))	('Nf1-/-', 'Var', (178, 184))	('hyperactivated', 'PosReg', (160, 174))	('RAS', 'Pathway', (11, 14))	('NSCs', 'Disease', (59, 63))	('MEK/ERK pathways', 'Pathway', (139, 155))
156323	28066715	In mouse Nf1 optic gliomas, the monocytes are Cd11b+, Cd45low, Cx3cr1+ microglia.	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('mouse', 'Species', '10090', (3, 8))	('Cd11b', 'Gene', (46, 51))	('Cd45low', 'Var', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('optic gliomas', 'Phenotype', 'HP:0009734', (13, 26))	('optic gliomas', 'Disease', 'MESH:D020339', (13, 26))	('optic gliomas', 'Disease', (13, 26))	('optic glioma', 'Phenotype', 'HP:0009734', (13, 25))	('Cd11b', 'Gene', '16409', (46, 51))
156324	28066715	These microglia are critical for gliomagenesis, such that impairing their directional migration into the tumor by genetic reduction of the Cx3cl1 receptor (Cx3cr1) delays optic glioma formation.	('impairing', 'NegReg', (58, 67))	('optic glioma', 'Phenotype', 'HP:0009734', (171, 183))	('gliomagenesis', 'Disease', (33, 46))	('delays optic glioma', 'Disease', 'MESH:D020339', (164, 183))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('rat', 'Species', '10116', (89, 92))	('gliomagenesis', 'Disease', 'None', (33, 46))	('reduction', 'NegReg', (122, 131))	('genetic', 'Var', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('delays optic glioma', 'Disease', (164, 183))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('tumor', 'Disease', (105, 110))
156329	28066715	In this regard, Ccl5 was sufficient to increase Nf1-deficient astrocytes growth in vitro, and its inhibition using neutralizing antibodies reduced optic glioma proliferation in vivo.	('Nf1-deficient', 'Disease', (48, 61))	('optic glioma proliferation', 'Disease', 'MESH:D020339', (147, 173))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('inhibition', 'NegReg', (98, 108))	('increase', 'PosReg', (39, 47))	('Nf1-deficient', 'Disease', 'MESH:C537392', (48, 61))	('reduced', 'NegReg', (139, 146))	('Ccl5', 'Var', (16, 20))	('optic glioma proliferation', 'Disease', (147, 173))	('optic glioma', 'Phenotype', 'HP:0009734', (147, 159))
156334	28066715	As such, Nf1 optic glioma mice develop a time-dependent sequence of events, beginning with axonal injury at the tumor site, followed by axonal degeneration, RGC loss (apoptosis), retinal nerve fiber layer thinning, and reduced visual acuity.	('axonal degeneration', 'Phenotype', 'HP:0040078', (136, 155))	('reduced', 'NegReg', (219, 226))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('axonal injury', 'Disease', (91, 104))	('optic glioma', 'Disease', 'MESH:D020339', (13, 25))	('axonal degeneration, RGC loss', 'Disease', 'MESH:D009410', (136, 165))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('optic glioma', 'Phenotype', 'HP:0009734', (13, 25))	('optic glioma', 'Disease', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('visual acuity', 'CPA', (227, 240))	('reduced visual acuity', 'Phenotype', 'HP:0007663', (219, 240))	('tumor', 'Disease', (112, 117))	('axonal injury', 'Disease', 'MESH:D001480', (91, 104))	('thinning', 'NegReg', (205, 213))	('Nf1', 'Var', (9, 12))	('retinal nerve fiber layer', 'CPA', (179, 204))	('mice', 'Species', '10090', (26, 30))
156338	28066715	In addition, elevating cAMP levels greatly attenuates RGC cell death in Nf1 optic glioma mice in vivo.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('optic glioma', 'Disease', (76, 88))	('cAMP', 'Chemical', 'MESH:D000242', (23, 27))	('optic glioma', 'Disease', 'MESH:D020339', (76, 88))	('mice', 'Species', '10090', (89, 93))	('elevating', 'Var', (13, 22))	('RGC cell death', 'CPA', (54, 68))	('attenuates', 'NegReg', (43, 53))	('optic glioma', 'Phenotype', 'HP:0009734', (76, 88))	('cAMP levels', 'MPA', (23, 34))
156343	28066715	Everolimus (RAD001), a rapamycin analog that targets mTOR, is currently being explored as a potential treatment in two separate trials ( #NCT01158651 and #NCT01734512, recruiting).	('rat', 'Species', '10116', (123, 126))	('#NCT01734512', 'Var', (154, 166))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))	(' #NCT01158651', 'Var', (136, 149))
156349	28066715	While Nf1 mutant mouse models provide unprecedented opportunities for drug discovery and evaluation, the current collection of these strains does not fully capture the full spectrum of human clinical heterogeneity.	('human', 'Species', '9606', (185, 190))	('mouse', 'Species', '10090', (17, 22))	('mutant', 'Var', (10, 16))	('Nf1', 'Gene', (6, 9))
156351	28066715	First, genotype-phenotype correlation studies in people with NF1 have revealed intriguing associations; the most striking of which is the finding that individuals with p1809 codon mutations do not develop dermal neurofibromas.	('dermal neurofibromas', 'Disease', (205, 225))	('people', 'Species', '9606', (49, 55))	('NF', 'Phenotype', 'HP:0001067', (61, 63))	('neurofibromas', 'Phenotype', 'HP:0001067', (212, 225))	('associations', 'Interaction', (90, 102))	('develop', 'PosReg', (197, 204))	('p1809 codon mutations', 'Var', (168, 189))	('dermal neurofibromas', 'Disease', 'MESH:D009455', (205, 225))
156352	28066715	Relevant to brain tumors, NF1 patients with 5' NF1 gene mutations have higher chance developing optic gliomas compared to patients with mutations at other locations of the NF1 gene.	('brain tumors', 'Disease', (12, 24))	('mutations', 'Var', (56, 65))	('optic gliomas', 'Disease', 'MESH:D020339', (96, 109))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('optic glioma', 'Phenotype', 'HP:0009734', (96, 108))	('NF', 'Phenotype', 'HP:0001067', (47, 49))	('NF', 'Phenotype', 'HP:0001067', (172, 174))	('patients', 'Species', '9606', (30, 38))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	("5' NF1", 'Gene', (44, 50))	('patients', 'Species', '9606', (122, 130))	('brain tumors', 'Phenotype', 'HP:0030692', (12, 24))	('brain tumors', 'Disease', 'MESH:D001932', (12, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('brain tumor', 'Phenotype', 'HP:0030692', (12, 23))	('optic gliomas', 'Disease', (96, 109))	('NF', 'Phenotype', 'HP:0001067', (26, 28))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('optic gliomas', 'Phenotype', 'HP:0009734', (96, 109))
156353	28066715	Based on these types of clinical observations, human iPSCs have been used to demonstrate that different NF1 mutations lead to different levels of neurofibromin protein loss.	('loss', 'NegReg', (168, 172))	('neurofibromin', 'Gene', '4763', (146, 159))	('mutations', 'Var', (108, 117))	('rat', 'Species', '10116', (84, 87))	('neurofibromin', 'Gene', (146, 159))	('human', 'Species', '9606', (47, 52))	('NF', 'Phenotype', 'HP:0001067', (104, 106))	('NF1', 'Gene', (104, 107))
156354	28066715	To explore this further, GEM have recently been engineered to harbor specific Nf1 mutations seen in people with NF1.	('Nf1', 'Gene', (78, 81))	('mutations', 'Var', (82, 91))	('people', 'Species', '9606', (100, 106))	('NF', 'Phenotype', 'HP:0001067', (112, 114))
156355	28066715	This is in contrast to the current Nf1 optic glioma mouse model in which the Nf1 gene is inactivated by the insertion of a neomycin targeting cassette, a genetic alteration not seen in individuals with NF1.	('inactivated', 'NegReg', (89, 100))	('neomycin', 'Chemical', 'MESH:D009355', (123, 131))	('optic glioma', 'Disease', 'MESH:D020339', (39, 51))	('rat', 'Species', '10116', (166, 169))	('mouse', 'Species', '10090', (52, 57))	('optic glioma', 'Disease', (39, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('NF', 'Phenotype', 'HP:0001067', (202, 204))	('insertion', 'Var', (108, 117))	('optic glioma', 'Phenotype', 'HP:0009734', (39, 51))	('Nf1 gene', 'Gene', (77, 85))
156356	28066715	Strikingly, in these proof-of-principle studies, Nf1 mice harboring a representative missense mutation did not develop optic gliomas, whereas those with a representative nonsense mutation harbored optic gliomas with higher proliferative indices than the conventional Nf1 optic glioma strain.	('optic glioma', 'Disease', 'MESH:D020339', (271, 283))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('optic gliomas', 'Phenotype', 'HP:0009734', (119, 132))	('optic gliomas', 'Disease', (197, 210))	('rat', 'Species', '10116', (230, 233))	('mice', 'Species', '10090', (53, 57))	('optic glioma', 'Disease', 'MESH:D020339', (119, 131))	('optic gliomas', 'Phenotype', 'HP:0009734', (197, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('optic glioma', 'Phenotype', 'HP:0009734', (271, 283))	('optic gliomas', 'Disease', 'MESH:D020339', (119, 132))	('optic glioma', 'Disease', 'MESH:D020339', (197, 209))	('optic glioma', 'Phenotype', 'HP:0009734', (119, 131))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('optic gliomas', 'Disease', 'MESH:D020339', (197, 210))	('optic glioma', 'Phenotype', 'HP:0009734', (197, 209))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('optic gliomas', 'Disease', (119, 132))	('higher', 'PosReg', (216, 222))	('optic glioma', 'Disease', (271, 283))	('missense mutation', 'Var', (85, 102))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))
156357	28066715	Future preclinical studies should be designed to incorporate mice with different germline Nf1 gene mutations and cooperating genetic changes (heterozygous Pten loss; KIAA1549:BRAF expression) as a way of more accurately representing the full spectrum of disease in this patient population.	('mice', 'Species', '10090', (61, 65))	('rat', 'Species', '10116', (56, 59))	('rat', 'Species', '10116', (118, 121))	('Nf1', 'Gene', (90, 93))	('mutations', 'Var', (99, 108))	('rat', 'Species', '10116', (213, 216))	('patient', 'Species', '9606', (270, 277))
156361	28066715	Current mouse xenograft methodologies involve the isolation of single cells (CD133+) from the optic nerves of 3-month-old mice with NF1-LGG (Nf1+/-GFAPCKO mice).	('mice', 'Species', '10090', (122, 126))	('CD133+', 'Var', (77, 83))	('GFAP', 'Gene', (147, 151))	('mice', 'Species', '10090', (155, 159))	('mouse', 'Species', '10090', (8, 13))	('NF', 'Phenotype', 'HP:0001067', (132, 134))	('GFAP', 'Gene', '2670', (147, 151))
156363	28066715	The resulting mutations and genomic alterations can next be evaluated in preclinical model systems as a means of identifying their contributions to tumor growth and targets for therapeutic intervention.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('rat', 'Species', '10116', (40, 43))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
156364	28066715	Moreover, the incorporation of these cooperating genetic/genomic changes in combination with other factors, like the germline NF1 gene mutation, create a more representative spectrum of models that capture the innate clinical heterogeneity of these tumors for preclinical drug assessment and biomarker discovery.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('NF', 'Phenotype', 'HP:0001067', (126, 128))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('NF1', 'Gene', (126, 129))	('rat', 'Species', '10116', (21, 24))	('mutation', 'Var', (135, 143))	('rat', 'Species', '10116', (42, 45))	('tumors', 'Disease', (249, 255))
156370	26610392	Chromatin conformation capture (3C) identified a physical interaction between the enhancer element containing a functional SNP (rs73001406) and the promoter of the DDX6 gene.	('rs73001406', 'Var', (128, 138))	('rs73001406', 'Mutation', 'rs73001406', (128, 138))	('DDX6', 'Gene', (164, 168))
156371	26610392	These studies reveal the functional landscape of the 11q23.3 glioma susceptibility locus and identify a network of functional SNPs in regulatory elements and two target genes as a possible mechanism driving glioma risk association.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (207, 213))	('glioma', 'Disease', (61, 67))	('SNPs', 'Var', (126, 130))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
156378	26610392	Because of a need for better risk assessment and therapeutic strategies, several groups in recent years have conducted genome-wide association studies (GWAS) in order to identify single nucleotide polymorphisms (SNPs) that are associated with glioma susceptibility.	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('associated', 'Reg', (227, 237))	('glioma', 'Disease', (243, 249))	('single nucleotide polymorphisms', 'Var', (179, 210))
156379	26610392	These studies identified seven independent glioma risk loci in six chromosomal regions: 5p13.33 (TERT), 7p11.2 (EGFR, two loci), 8q24.21 (CCDC26), 9p21.3 (CDKN2A/B), 11q23.3 (PHLDB1) and 20q13.33 (RTEL1).	('EGFR', 'Gene', (112, 116))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('RTEL1', 'Gene', '51750', (197, 202))	('CDKN2A/B', 'Gene', (155, 163))	('9p21.3', 'Var', (147, 153))	('RTEL1', 'Gene', (197, 202))	('glioma', 'Disease', (43, 49))	('TERT', 'Gene', (97, 101))	('CCDC26', 'Gene', (138, 144))	('CCDC26', 'Gene', '137196', (138, 144))	('EGFR', 'Gene', '1956', (112, 116))	('CDKN2A/B', 'Gene', '1029;1030', (155, 163))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('TERT', 'Gene', '7015', (97, 101))
156383	26610392	Here, we have applied a systematic functional analysis to identify candidate functional SNPs and target genes within the 11q23.3 glioma susceptibility locus, a locus with relatively little annotation related to cancer predisposition.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('SNPs', 'Var', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('glioma', 'Disease', (129, 135))
156386	26610392	In order to identify candidate functional SNPs we retrieved all (n = 96) SNPs in LD with the associated SNP (rs498872) at a threshold of r2 >= 0.2 (Supplementary Table 1).	('SNPs', 'Var', (73, 77))	('rs498872', 'Var', (109, 117))	('rs498872', 'Mutation', 'rs498872', (109, 117))
156387	26610392	The GWAS-identified SNP, rs498872, lies within the 5'-UTR of the PHLDB1 gene.	('PHLDB1', 'Gene', (65, 71))	('rs498872', 'Mutation', 'rs498872', (25, 33))	('rs498872', 'Var', (25, 33))
156391	26610392	Interestingly, we found a consistently higher rate of alterations of these genes in LGG when compared to GBM according to The Cancer Genome Atlas (TCGA) records from cBioPortal (Supplementary Fig.	('LGG', 'Chemical', '-', (84, 87))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Cancer Genome Atlas', 'Disease', (126, 145))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (126, 145))	('alterations', 'Var', (54, 65))
156392	26610392	This observation is consistent with glioma GWAS findings, which report that the rs498872 variant is associated with LGG but not with GBM.	('LGG', 'Disease', (116, 119))	('LGG', 'Chemical', '-', (116, 119))	('associated', 'Reg', (100, 110))	('glioma', 'Disease', (36, 42))	('rs498872', 'Var', (80, 88))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('rs498872', 'Mutation', 'rs498872', (80, 88))
156394	26610392	We also conducted searches in COSMIC for information on somatic mutations in all genes within the locus, either in any cancer or specifically in brain cancers.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('brain cancers', 'Disease', 'MESH:D001932', (145, 158))	('brain cancers', 'Disease', (145, 158))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (151, 157))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
156399	26610392	To be comprehensive, we also chose to test the GWAS-tagged SNP (rs498872) and rs45540840 because of its relatively high LD (r2 >= 0.5) with the tagged SNP, for a total of 12 SNPs.	('rs45540840', 'Mutation', 'rs45540840', (78, 88))	('rs498872', 'Var', (64, 72))	('rs45540840', 'Var', (78, 88))	('rs498872', 'Mutation', 'rs498872', (64, 72))
156400	26610392	EMSA showed allele-specific protein binding in U87MG and/or NHA cells for nine of the ten SNPs, as well as for the one additional high LD SNP rs45540840 (Fig.	('protein', 'Protein', (28, 35))	('rs45540840', 'Mutation', 'rs45540840', (142, 152))	('U87MG', 'CellLine', 'CVCL:0022', (47, 52))	('rs45540840', 'Var', (142, 152))
156404	26610392	SNP rs73001406 lies within a tile that overlaps with a very sharp peak for H3K27Ac, H3K4me3, H3K4me1, DHS and FAIRE-seq in NHA cells as well as a sharp FAIRE-seq peak in Gliobla cells (Fig.	('H3K4me3', 'Var', (84, 91))	('H3', 'Chemical', 'MESH:C012616', (93, 95))	('H3K27Ac', 'Var', (75, 82))	('H3', 'Chemical', 'MESH:C012616', (75, 77))	('H3', 'Chemical', 'MESH:C012616', (84, 86))	('H3K4me1', 'Var', (93, 100))	('rs73001406', 'Mutation', 'rs73001406', (4, 14))	('DHS', 'Gene', (102, 105))	('DHS', 'Gene', '10774', (102, 105))	('SNP', 'Var', (0, 3))
156405	26610392	We examined publicly available RNA Polymerase II ChIA-PET data from 4 cell lines in ENCODE and found a very strong interaction between the region containing rs73001406 and the promoter region of DDX6, which is approximately 100 kb away, albeit in non-brain related K562 and MCF7 cells (Supplementary Fig.	('DDX6', 'Gene', (195, 199))	('rs73001406', 'Mutation', 'rs73001406', (157, 167))	('MCF7', 'CellLine', 'CVCL:0031', (274, 278))	('K562', 'CellLine', 'CVCL:0004', (265, 269))	('ChIA', 'Gene', '27159', (49, 53))	('interaction', 'Interaction', (115, 126))	('ChIA', 'Gene', (49, 53))	('rs73001406', 'Var', (157, 167))
156407	26610392	We used HindIII restriction sites in order to design 3C probes spanning the region from PHLDB1 to DDX6, with the tile containing rs73001406 as the anchor region.	('PHLDB1', 'Gene', (88, 94))	('rs73001406', 'Mutation', 'rs73001406', (129, 139))	('DDX6', 'Gene', (98, 102))	('rs73001406', 'Var', (129, 139))
156418	26610392	Therefore, we assessed the effects of knocking down the two candidate target genes, PHLDB1 or DDX6, in U87MG cells (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (103, 108))	('DDX6', 'Gene', (94, 98))	('knocking', 'Var', (38, 46))	('PHLDB1', 'Gene', (84, 90))
156419	26610392	We found that knockdown of DDX6 led to a significant reduction in the migratory phenotype of U87MG cells, while knockdown of PHLDB1 had no significant effect (Fig.	('migratory phenotype of U87MG cells', 'CPA', (70, 104))	('reduction', 'NegReg', (53, 62))	('knockdown', 'Var', (14, 23))	('DDX6', 'Gene', (27, 31))	('U87MG', 'CellLine', 'CVCL:0022', (93, 98))
156425	26610392	Interestingly, a recent report has demonstrated that silencing of DDX6 results in premature differentiation of human epidermal tissue.	('DDX6', 'Gene', (66, 70))	('human', 'Species', '9606', (111, 116))	('results in', 'Reg', (71, 81))	('silencing', 'Var', (53, 62))
156435	26610392	A glioma fine-mapping study in the Han Chinese population revealed rs17748, rs2236661, and rs494560 as potential correlated SNPs in the 11q23.3 locus.	('rs494560', 'Var', (91, 99))	('rs494560', 'Mutation', 'rs494560', (91, 99))	('rs17748', 'Var', (67, 74))	('glioma', 'Disease', (2, 8))	('rs2236661', 'Mutation', 'rs2236661', (76, 85))	('rs2236661', 'Var', (76, 85))	('glioma', 'Phenotype', 'HP:0009733', (2, 8))	('glioma', 'Disease', 'MESH:D005910', (2, 8))	('rs17748', 'Mutation', 'rs17748', (67, 74))
156436	26610392	Two of these (rs17748 and rs2236661) are in LD (r2 = 0.53) with rs498872.	('rs17748', 'Var', (14, 21))	('rs17748', 'Mutation', 'rs17748', (14, 21))	('rs498872', 'Var', (64, 72))	('rs2236661', 'Mutation', 'rs2236661', (26, 35))	('rs2236661', 'Var', (26, 35))	('rs498872', 'Mutation', 'rs498872', (64, 72))
156437	26610392	One SNP, rs2236661, lies within an enhancer region that showed activity in our luciferase assays, while rs17748 and rs494560 do not overlap with any functional elements in brain cells.	('activity', 'MPA', (63, 71))	('rs494560', 'Mutation', 'rs494560', (116, 124))	('luciferase', 'Enzyme', (79, 89))	('rs2236661', 'Mutation', 'rs2236661', (9, 18))	('rs2236661', 'Var', (9, 18))	('rs17748', 'Mutation', 'rs17748', (104, 111))
156439	26610392	It is notable that the region containing rs73001406 overlaps both promoter and enhancer marks (Supplementary Table 1), which suggests that the region could act as a distal promoter for the TREH gene.	('rs73001406', 'Var', (41, 51))	('TREH', 'Gene', (189, 193))	('TREH', 'Gene', '11181', (189, 193))	('rs73001406', 'Mutation', 'rs73001406', (41, 51))
156442	26610392	Our results and the previous ChIA-PET findings strongly link the rs73001406 region to DDX6 regulation, but a potential impact on TREH expression cannot be ruled out.	('ChIA', 'Gene', (29, 33))	('TREH', 'Gene', '11181', (129, 133))	('TREH', 'Gene', (129, 133))	('rs73001406', 'Mutation', 'rs73001406', (65, 75))	('DDX6 regulation', 'Gene', (86, 101))	('rs73001406', 'Var', (65, 75))	('ChIA', 'Gene', '27159', (29, 33))
156443	26610392	In addition, we identified a number of SNPs in this study that may have repressor activity in astrocyte and/or glioma cells.	('glioma', 'Disease', (111, 117))	('SNPs', 'Var', (39, 43))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('repressor activity', 'MPA', (72, 90))
156452	26610392	Experiments were conducted in hTERT immortalized normal human astrocytes (NHA) cells (Applied Biological Materials, Inc.) and/or U87MG glioma cells (ATCC).	('glioma', 'Disease', (135, 141))	('U87MG', 'CellLine', 'CVCL:0022', (129, 134))	('U87MG', 'Var', (129, 134))	('human', 'Species', '9606', (56, 61))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('hTERT', 'Gene', '7015', (30, 35))	('hTERT', 'Gene', (30, 35))
156490	26388977	Favorable prognostic factors in the univariate analysis using the Kaplan-Meier 10-year OS analysis were the following: age below 40, karnofsky performance status (KPS) more than 70, the presence of oligodendroglioma, tumor size of < 5 cm, and gross-total resection (p=0.02, p=0.01, p=0.03, p=0.01, p=0.02, respectively).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('gross-total', 'Var', (243, 254))	('OS', 'Chemical', '-', (87, 89))	('oligodendroglioma', 'Disease', (198, 215))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('oligodendroglioma', 'Disease', 'MESH:D009837', (198, 215))
156491	26388977	Good prognostic factors in multivariate analysis using the Cox regression model were as follows: age below 40, the presence of oligodendroglioma, tumor size< 5 cm, and gross total resection in10-year OS (p=0.01, p=0.03, p=0.00, p=0.02, respectively).	('oligodendroglioma', 'Disease', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('oligodendroglioma', 'Disease', 'MESH:D009837', (127, 144))	('OS', 'Chemical', '-', (200, 202))	('Cox', 'Gene', '1351', (59, 62))	('tumor', 'Disease', (146, 151))	('gross total resection', 'Var', (168, 189))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('Cox', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
156531	26388977	Then the favorable prognostic factors in our study based on univariate analysis, using the Kaplan-Meier 10-year DFS analysis and log-rank test, were as follows (Table 2): 1) Age below 40, 2) KPS greater than 70, 3) Presence of oligodendroglioma, 4) Tumor size <5cm, 5) Absence of motor or sensory deficit at diagnosis, 6) Gross-total resection and adjuvant radiotherapy.	('oligodendroglioma', 'Disease', (227, 244))	('motor or sensory deficit', 'CPA', (280, 304))	('sensory deficit', 'Phenotype', 'HP:0003474', (289, 304))	('oligodendroglioma', 'Disease', 'MESH:D009837', (227, 244))	('KPS greater than 70', 'Var', (191, 210))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('Tumor', 'Phenotype', 'HP:0002664', (249, 254))	('Presence', 'Reg', (215, 223))
156536	26388977	Based on the multivariate analysis, there were no statistically significant relationships between 10-year DFS and gender, headache, seizures at diagnosis, presence of mixed oligoastrocytoma, KPS greater than 70, and motor or sensory deficit at diagnosis (Table 2).	('seizure', 'Phenotype', 'HP:0001250', (132, 139))	('headache', 'Disease', (122, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('headache', 'Phenotype', 'HP:0002315', (122, 130))	('sensory deficit', 'Phenotype', 'HP:0003474', (225, 240))	('KPS greater than 70', 'Var', (191, 210))	('seizures', 'Disease', 'MESH:D012640', (132, 140))	('headache', 'Disease', 'MESH:D006261', (122, 130))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (173, 189))	('oligoastrocytoma', 'Disease', (173, 189))	('seizures', 'Disease', (132, 140))	('motor or', 'Disease', (216, 224))	('seizures', 'Phenotype', 'HP:0001250', (132, 140))
156538	26388977	Then the favorable prognostic factors in our study in univariate analysis using Kaplan-Meier 10-year OS analysis and Log-rank test, were: age below 40, KPS more than 70, presence of oligodendroglioma, tumor size<5 cm and gross-total resection (Table 3).	('oligodendroglioma', 'Disease', (182, 199))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('oligodendroglioma', 'Disease', 'MESH:D009837', (182, 199))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('OS', 'Chemical', '-', (101, 103))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('KPS more than 70', 'Var', (152, 168))	('tumor', 'Disease', (201, 206))	('gross-total', 'Var', (221, 232))
156542	26388977	There was no statistically significant relationship between 10-year OS and gender, headache or seizures at diagnosis, presence of mixed oligoastrocytoma, motor or sensory deficit at diagnosis, KPS more than 70 and radiation therapy at progression by multivariate analysis (Table 3).	('OS', 'Chemical', '-', (68, 70))	('seizures', 'Phenotype', 'HP:0001250', (95, 103))	('sensory deficit', 'Phenotype', 'HP:0003474', (163, 178))	('seizures', 'Disease', (95, 103))	('oligoastrocytoma', 'Disease', (136, 152))	('headache', 'Disease', (83, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (141, 152))	('seizure', 'Phenotype', 'HP:0001250', (95, 102))	('headache', 'Phenotype', 'HP:0002315', (83, 91))	('motor or sensory deficit', 'Disease', (154, 178))	('KPS more than 70', 'Var', (193, 209))	('seizures', 'Disease', 'MESH:D012640', (95, 103))	('headache', 'Disease', 'MESH:D006261', (83, 91))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (136, 152))
156559	26388977	Both the single-variable and multivariate analyses in our study demonstrated that gross-total resection had a better 10-year DFS and10-year OS than subtotal resection, gross-total resection, or no surgery.	('OS', 'Chemical', '-', (140, 142))	('better', 'PosReg', (110, 116))	('gross-total resection', 'Var', (82, 103))	('DFS', 'MPA', (125, 128))
156567	26388977	Based on the results of this study, a better 10-year DFS was observed in the adjuvant radiotherapy group, this group did not have a better 10-year OS in the multivariate analyses.	('adjuvant', 'Var', (77, 85))	('OS', 'Chemical', '-', (147, 149))	('DFS', 'MPA', (53, 56))	('better', 'PosReg', (38, 44))
156569	26388977	Likewise, in our study, adjuvant radiotherapy had a better 10-year DFS than radiation therapy at progression in both the univariate and multivariate analyses, but it did not have a better 10-year OS in either analysis.	('DFS', 'MPA', (67, 70))	('adjuvant', 'Var', (24, 32))	('OS', 'Chemical', '-', (196, 198))
156572	26388977	In addition, we demonstrated that gross-total resection, tumor size< 5cm, age below 40, and the presence of oligodendroglioma resulted in a better 10-year DFS both in univariate analyses and multivariate analyses.	('presence', 'Var', (96, 104))	('better', 'PosReg', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('10-year', 'CPA', (147, 154))	('oligodendroglioma', 'Disease', (108, 125))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('oligodendroglioma', 'Disease', 'MESH:D009837', (108, 125))	('DFS', 'MPA', (155, 158))	('tumor', 'Disease', (57, 62))
156581	26388977	We also proved that a KPS value greater than 70 indicated better 10-year DFS and 10-year OS rates in univariate analyses, but this value did not provide any advantage in the multivariate analyses.	('better', 'PosReg', (58, 64))	('DFS', 'CPA', (73, 76))	('OS', 'Chemical', '-', (89, 91))	('KPS', 'Var', (22, 25))
156582	26388977	We demonstrated that adjuvant radiotherapy had a better 10-year DFS rate both in univariate and multivariate analyses, but it did not have a better 10-year OS rate in either the univariate analyses or the multivariate analyses.	('OS', 'Chemical', '-', (156, 158))	('radiotherapy', 'Var', (30, 42))	('DFS', 'MPA', (64, 67))	('adjuvant', 'Var', (21, 29))
156603	25977902	The p53 gene (TP53) has been reported to be mutated in approximately 30-40% and the overall pathway has been reported to be disrupted in more than 80% of tumors.	('tumors', 'Disease', (154, 160))	('TP53', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('mutated', 'Var', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('disrupted', 'NegReg', (124, 133))	('p53 gene (TP53', 'Gene', (4, 18))
156604	25977902	Abnormalities in the p53 tumor suppression pathway can lead to genetic instability, reduced apoptosis, and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('apoptosis', 'CPA', (92, 101))	('Abnormalities', 'Var', (0, 13))	('tumor', 'Disease', (25, 30))	('reduced', 'NegReg', (84, 91))	('genetic', 'MPA', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('angiogenesis', 'CPA', (107, 119))
156605	25977902	The p53 tumor suppression pathway may be disrupted by mutation or deletion of the TP53 gene or by overexpression of inhibitors of p53 including murine double minute 2 which may result by direct mutation or by mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A).	('mutation', 'Var', (54, 62))	('TP53', 'Gene', (82, 86))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (221, 257))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutation', 'Var', (209, 217))	('murine', 'Species', '10090', (144, 150))	('disrupted', 'NegReg', (41, 50))	('tumor', 'Disease', (8, 13))	('result by', 'Reg', (177, 186))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (221, 257))	('deletion', 'Var', (66, 74))	('CDKN2A', 'Gene', (259, 265))
156608	25977902	The Rb1 tumor suppression pathway may be disrupted by a direct mutation of the RB1 gene or by overexpression of cyclin-dependent kinase 4 (CDK4).	('overexpression', 'PosReg', (94, 108))	('RB1', 'Gene', (79, 82))	('Rb1', 'Gene', '5925', (4, 7))	('CDK4', 'Gene', '1019', (139, 143))	('CDK4', 'Gene', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('RB1', 'Gene', '5925', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutation', 'Var', (63, 71))	('disrupted', 'NegReg', (41, 50))	('tumor', 'Disease', (8, 13))	('cyclin-dependent kinase 4', 'Gene', '1019', (112, 137))	('Rb1', 'Gene', (4, 7))	('cyclin-dependent kinase 4', 'Gene', (112, 137))
156609	25977902	Overexpression of CDK4 may result from amplification or more commonly through deletion of an inhibitor of CDK4, CDKN2A.	('CDKN2A', 'Gene', (112, 118))	('amplification', 'Var', (39, 52))	('deletion', 'Var', (78, 86))	('CDK4', 'Gene', (106, 110))	('result from', 'Reg', (27, 38))	('CDK4', 'Gene', '1019', (106, 110))	('CDK4', 'Gene', '1019', (18, 22))	('CDK4', 'Gene', (18, 22))
156612	25977902	EGFRvIII amplification can lead to increased downstream activity resulting in proangiogenic signaling, increased proliferation, increased tumor cell survival, and migration.	('downstream activity', 'MPA', (45, 64))	('increased', 'PosReg', (35, 44))	('amplification', 'Var', (9, 22))	('proangiogenic signaling', 'MPA', (78, 101))	('tumor', 'Disease', (138, 143))	('EGFR', 'Gene', (0, 4))	('increased', 'PosReg', (103, 112))	('migration', 'CPA', (163, 172))	('increased', 'PosReg', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('EGFR', 'Gene', '1956', (0, 4))	('proliferation', 'CPA', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
156613	25977902	EGFRvIII amplifications have been reported in approximately 40% of primary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (75, 88))	('EGFR', 'Gene', (0, 4))	('reported', 'Reg', (34, 42))	('glioblastomas', 'Disease', 'MESH:D005909', (75, 88))	('glioblastomas', 'Disease', (75, 88))	('primary glioblastoma', 'Disease', 'MESH:D005909', (67, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('primary glioblastoma', 'Disease', (67, 87))	('amplifications', 'Var', (9, 23))	('EGFR', 'Gene', '1956', (0, 4))
156614	25977902	EGFRvIII amplification has been reported to be a predictor of poor survival, however, other studies have failed to show this effect.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (9, 22))	('EGFR', 'Gene', '1956', (0, 4))	('poor survival', 'CPA', (62, 75))
156617	25977902	PTEN mutations are estimated to occur in 15-40% of primary glioblastomas but up to 80% of glioblastomas have loss of chromosome 10q in the region where PTEN is located (10q23).	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('primary glioblastoma', 'Disease', 'MESH:D005909', (51, 71))	('glioblastomas', 'Disease', (90, 103))	('primary glioblastoma', 'Disease', (51, 71))	('PTEN', 'Gene', (152, 156))	('loss', 'NegReg', (109, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', '5728', (152, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (59, 72))	('glioblastomas', 'Phenotype', 'HP:0012174', (59, 72))	('glioblastomas', 'Phenotype', 'HP:0012174', (90, 103))	('glioblastomas', 'Disease', (59, 72))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('glioblastomas', 'Disease', 'MESH:D005909', (90, 103))
156618	25977902	Chromosome 10q loss, PTEN mutations, and EGFR amplification are frequently seen together in the small cell phenotype of glioblastoma.	('EGFR', 'Gene', (41, 45))	('amplification', 'Var', (46, 59))	('PTEN', 'Gene', '5728', (21, 25))	('glioblastoma', 'Disease', (120, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('loss', 'NegReg', (15, 19))	('mutations', 'Var', (26, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('PTEN', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (41, 45))
156619	25977902	PTEN deletions have been reported to be a poor prognostic factor for pediatric glioblastomas, however, this has not been found true in adult patients.	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (69, 92))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('pediatric glioblastomas', 'Disease', (69, 92))	('PTEN', 'Gene', '5728', (0, 4))	('deletions', 'Var', (5, 14))	('PTEN', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('patients', 'Species', '9606', (141, 149))
156622	25977902	In addition, increased normalized tumor blood volume has been reported in tumors with EGFR amplification, PTEN deletion, and normal unmethylated O6-methylguanine-DNA methyl-transferase (MGMT).	('tumor', 'Disease', (74, 79))	('O6-methylguanine-DNA methyl-transferase', 'Gene', (145, 184))	('normalized', 'MPA', (23, 33))	('increased', 'PosReg', (13, 22))	('deletion', 'Var', (111, 119))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('EGFR', 'Gene', '1956', (86, 90))	('MGMT', 'Gene', (186, 190))	('amplification', 'Var', (91, 104))	('PTEN', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('O6-methylguanine-DNA methyl-transferase', 'Gene', '4255', (145, 184))	('PTEN', 'Gene', '5728', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('MGMT', 'Gene', '4255', (186, 190))	('EGFR', 'Gene', (86, 90))	('tumors', 'Disease', (74, 80))
156624	25977902	IDH1 gene mutations are seen in about 5% of patients with primary glioblastoma but are seen in 70-80% of grade II-III gliomas and secondary glioblastomas (glioblastomas arising from low grade gliomas).	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('glioblastomas arising from low grade gliomas', 'Phenotype', 'HP:0012174', (155, 199))	('glioblastomas', 'Phenotype', 'HP:0012174', (140, 153))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioblastomas', 'Phenotype', 'HP:0012174', (155, 168))	('IDH1', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('patients', 'Species', '9606', (44, 52))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (192, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('glioblastomas', 'Disease', (140, 153))	('IDH1', 'Gene', '3417', (0, 4))	('glioblastomas', 'Disease', (155, 168))	('primary glioblastoma', 'Disease', (58, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (140, 153))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (155, 168))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('gliomas', 'Disease', (118, 125))	('primary glioblastoma', 'Disease', 'MESH:D005909', (58, 78))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('mutations', 'Var', (10, 19))
156625	25977902	IDH2 mutations are mostly seen in oligodendroglial tumors.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (34, 57))	('mutations', 'Var', (5, 14))	('oligodendroglial tumors', 'Disease', (34, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('IDH2', 'Gene', (0, 4))	('seen', 'Reg', (26, 30))	('IDH2', 'Gene', '3418', (0, 4))
156626	25977902	Patients with IDH1/2 mutations have been reported to have better survival independent of therapy.	('better', 'PosReg', (58, 64))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('survival', 'CPA', (65, 73))	('IDH1/2', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
156627	25977902	On imaging IDH1 mutated tumors are reported to be more likely to be multi-focal, invasive, and have minimal or no contrast enhancement.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('IDH1', 'Gene', '3417', (11, 15))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mutated', 'Var', (16, 23))	('IDH1', 'Gene', (11, 15))
156628	25977902	The mutant IDH1 and 2 enzymes have shown neomorphic enzymatic capacity to covert alpha-ketoglutarate into 2-hydroxy-glutarate (2-HG), a small oncometabolite.	('mutant', 'Var', (4, 10))	('IDH1 and 2', 'Gene', '3417;3418', (11, 21))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (81, 100))	('alpha-ketoglutarate into 2-hydroxy-glutarate', 'MPA', (81, 125))	('2-hydroxy-glutarate', 'Chemical', 'MESH:C019417', (106, 125))	('2-HG', 'Chemical', 'MESH:C019417', (127, 131))
156630	25977902	1p/19q co-deletion is seen in approximately 80% of oligodendrogliomas, 60% of anaplastic oligodendrogliomas, 30-50% of oligoastrocytomas, and 20-30% of anaplastic oligoastrocytomas and is frequently seen with IDH1/2 mutations.	('IDH1/2', 'Gene', '3417;3418', (209, 215))	('oligodendrogliomas', 'Disease', (51, 69))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('oligoastrocytomas', 'Disease', (119, 136))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (89, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (168, 179))	('1p/19q co-deletion', 'Var', (0, 18))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (119, 136))	('IDH1/2', 'Gene', (209, 215))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (51, 69))	('oligodendrogliomas', 'Disease', (89, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('oligoastrocytomas', 'Disease', (163, 180))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (163, 180))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
156631	25977902	1p/19q co-deletion has been reported as a favorable prognostic factor and to indicate patients who would benefit from chemoradiation although this significance may be complicated by the frequency of favorable IDH1/2 mutations and unfavorable additional chromosomal mutations.	('IDH1/2', 'Gene', '3417;3418', (209, 215))	('mutations', 'Var', (216, 225))	('IDH1/2', 'Gene', (209, 215))	('patients', 'Species', '9606', (86, 94))
156632	25977902	1p/19q co-deleted tumors have been reported to be more likely to have indistinct/irregular margins and more heterogeneous T1 and T2 signal characteristics than tumors of the same histology but with 1p/19q intact although the differences were modest and subjective.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('1p/19q co-deleted', 'Var', (0, 17))	('more', 'PosReg', (103, 107))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
156633	25977902	Elevated perfusion has also been suggested in low-grade oligodendrogliomas with 1p/19q loss although in small studies.	('oligodendrogliomas', 'Disease', (56, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('1p/19q loss', 'Var', (80, 91))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (56, 74))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('perfusion', 'MPA', (9, 18))
156635	25977902	Methylation of the MGMT gene promoter reduces binding of transcription factors and decreases gene expression.	('reduces', 'NegReg', (38, 45))	('decreases', 'NegReg', (83, 92))	('Methylation', 'Var', (0, 11))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('binding', 'Interaction', (46, 53))	('gene expression', 'MPA', (93, 108))
156637	25977902	Multiple studies have shown a better prognosis and response for glioblastoma patients with MGMT promoter methylation receiving temozolamide.	('promoter methylation', 'Var', (96, 116))	('better', 'PosReg', (30, 36))	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('patients', 'Species', '9606', (77, 85))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))	('temozolamide', 'Chemical', '-', (127, 139))
156640	25977902	Activating BRAF mutations are seen in numerous malignancies, most frequently however in melanoma.	('Activating', 'PosReg', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('numerous malignancies', 'Disease', 'MESH:D009369', (38, 59))	('mutations', 'Var', (16, 25))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('numerous malignancies', 'Disease', (38, 59))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
156641	25977902	Pilocytic astrocytomas have been shown to have BRAF mutations with a specific duplication/fusion mutation occurring in 65-80% of pilocytic astrocytomas.	('Pilocytic astrocytomas', 'Disease', (0, 22))	('mutations', 'Var', (52, 61))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (129, 151))	('BRAF', 'Gene', (47, 51))	('duplication/fusion', 'Var', (78, 96))	('BRAF', 'Gene', '673', (47, 51))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('pilocytic astrocytomas', 'Disease', (129, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (139, 150))
156642	25977902	A separate specific point mutation (V600E) is seen in up to 80% of pleomorphic xanthoastrocytomas and 25% of gangliogliomas.	('pleomorphic xanthoastrocytomas', 'Disease', (67, 97))	('ganglioglioma', 'Disease', 'MESH:D018303', (109, 122))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('gliomas', 'Disease', (116, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (85, 96))	('V600E', 'Var', (36, 41))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (67, 97))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('ganglioglioma', 'Disease', (109, 122))
156644	25977902	ATRX mutations have been reported in tumors of astrocytic lineage.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('reported', 'Reg', (25, 33))	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('ATRX', 'Gene', '546', (0, 4))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
156645	25977902	ATRX mutations are associated with TP53 and IDH1 mutations and are generally not seen with 1p/19q co-deletions and are thus useful in distinguishing from tumors of oligodendroglial origin.	('tumors of oligodendroglial', 'Disease', (154, 180))	('associated', 'Reg', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('mutations', 'Var', (49, 58))	('ATRX', 'Gene', (0, 4))	('IDH1', 'Gene', (44, 48))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', '3417', (44, 48))	('ATRX', 'Gene', '546', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors of oligodendroglial', 'Disease', 'MESH:D009369', (154, 180))
156646	25977902	ATRX loss has been reported as a favorable prognostic indicator in patients whose tumors also had IDH1 mutations.	('mutations', 'Var', (103, 112))	('tumors', 'Disease', (82, 88))	('patients', 'Species', '9606', (67, 75))	('ATRX', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('loss', 'NegReg', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IDH1', 'Gene', (98, 102))	('ATRX', 'Gene', '546', (0, 4))	('IDH1', 'Gene', '3417', (98, 102))
156648	25977902	These mutations have been reported at distinct locations in the histone variants H3.1 and H3.3, one involving a Lysine (Lys27) in H3.1 and H3.3 and one involving a glycine in H3.3 (Gly34).	('H3.3', 'Gene', (90, 94))	('Gly34', 'Chemical', '-', (181, 186))	('Lysine', 'Chemical', 'MESH:D008239', (112, 118))	('glycine', 'Chemical', 'MESH:D005998', (164, 171))	('Lys27', 'Var', (120, 125))	('H3.1', 'CellLine', 'CVCL:L520', (81, 85))	('mutations', 'Var', (6, 15))	('Lys27', 'Chemical', '-', (120, 125))	('H3.1', 'CellLine', 'CVCL:L520', (130, 134))
156649	25977902	The H3F3A Lys27 mutation is reported to have a particularly poor prognosis.	('H3F3A', 'Gene', '3020', (4, 9))	('Lys27', 'Chemical', '-', (10, 15))	('Lys27', 'Var', (10, 15))	('H3F3A', 'Gene', (4, 9))
156650	25977902	These mutations are generally not seen together with IDH1 mutations and thus represent an alternative group of tumors with distinct molecular aberrations.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('IDH1', 'Gene', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('IDH1', 'Gene', '3417', (53, 57))	('mutations', 'Var', (6, 15))
156722	25977902	A related emerging method currently confined to research use is hyperpolarized 13C MR. Hyperpolarized 13C agents have a dramatically increased signal, which provides the opportunity to follow a substance such as pyruvate through its biochemical pathways as it is converted to alanine, lactate, and bicarbonate.	('follow', 'Reg', (185, 191))	('bicarbonate', 'MPA', (298, 309))	('Hyperpolarized 13C agents', 'Var', (87, 112))	('13C', 'Chemical', '-', (79, 82))	('pyruvate', 'Chemical', 'MESH:D019289', (212, 220))	('bicarbonate', 'Chemical', 'MESH:D001639', (298, 309))	('lactate', 'MPA', (285, 292))	('alanine', 'MPA', (276, 283))	('signal', 'MPA', (143, 149))	('alanine', 'Chemical', 'MESH:D000409', (276, 283))	('increased', 'PosReg', (133, 142))	('13C', 'Chemical', '-', (102, 105))	('lactate', 'Chemical', 'MESH:D019344', (285, 292))
156724	25977902	Hyperpolarized 13C MRS has also been shown to be able to detect IDH1 mutation status by analyzing the metabolites of hyperpolarized 13C alpha ketoglutarate in an animal tumor model.	('metabolites', 'MPA', (102, 113))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('13C alpha ketoglutarate', 'Chemical', '-', (132, 155))	('IDH1', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mutation', 'Var', (69, 77))	('13C', 'Chemical', '-', (15, 18))	('IDH1', 'Gene', '3417', (64, 68))	('13C', 'Chemical', '-', (132, 135))	('tumor', 'Disease', (169, 174))
156755	23724839	Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized.	('epileptic', 'Disease', 'MESH:D004827', (17, 26))	('Resection', 'Var', (0, 9))	('epileptic', 'Disease', (17, 26))	('seizure', 'Disease', (55, 62))	('seizure', 'Disease', 'MESH:D012640', (55, 62))	('seizure', 'Phenotype', 'HP:0001250', (55, 62))
156821	23724839	Postsurgical reversal of increased AMT uptake in nonresected cortex in the posterior temporal region (which was not involved in seizure onset) suggests that some of the AMT-PET abnormalities were either seizure induced or represented reversible inflammation not inducing epileptogenesis.	('AMT-PET', 'Gene', (169, 176))	('inflammation', 'Disease', 'MESH:D007249', (245, 257))	('inflammation', 'Disease', (245, 257))	('seizure', 'Phenotype', 'HP:0001250', (128, 135))	('seizure', 'Disease', (128, 135))	('seizure', 'Disease', (203, 210))	('AMT', 'Chemical', 'MESH:C020774', (35, 38))	('abnormalities', 'Var', (177, 190))	('seizure', 'Disease', 'MESH:D012640', (203, 210))	('seizure', 'Disease', 'MESH:D012640', (128, 135))	('AMT', 'Chemical', 'MESH:C020774', (169, 172))	('increased AMT', 'Phenotype', 'HP:0008151', (25, 38))	('seizure', 'Phenotype', 'HP:0001250', (203, 210))
156877	22846789	Among those with low-grade tumors, individuals with subtotal resection had worse prognosis than those with complete resection.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('subtotal resection', 'Var', (52, 70))
156914	30783384	The effects of 2-hydroxyglutarate on the tumorigenesis of gliomas Mutation of the isocitrate-dehydrogenase (IDH) enzymes is one of the central research topics regarding gliomagenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('isocitrate-dehydrogenase', 'Gene', '3417', (82, 106))	('glioma', 'Disease', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (15, 33))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('tumorigenesis', 'CPA', (41, 54))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('isocitrate-dehydrogenase', 'Gene', (82, 106))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('Mutation', 'Var', (66, 74))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Disease', (58, 64))
156915	30783384	Indeed, 70% of gliomas are associated with a gain-of-function IDH mutation and consequently synthesize the oncometabolite, 2-hydroxyglutarate (2-HG).	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('gain-of-function', 'PosReg', (45, 61))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('mutation', 'Var', (66, 74))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (123, 141))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('2-HG', 'Chemical', 'MESH:C019417', (143, 147))	('IDH', 'Gene', (62, 65))
156921	30783384	The hypermethylator phenotype induced by 2-HG also results in alterations of the interaction of the immune system with the tumour.	('2-HG', 'Chemical', 'MESH:C019417', (41, 45))	('interaction', 'Interaction', (81, 92))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Disease', (123, 129))	('2-HG', 'Var', (41, 45))	('hypermethylator phenotype', 'MPA', (4, 29))	('alterations', 'Reg', (62, 73))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
156926	30783384	Glioma research was revolutionized in 2008, when the genetic sequencing of glioblastomas revealed that the mutation of isocitrate dehydrogenase 1 and 2 (IDH1/2) is a prevalent mutation in various glioma entities.	('IDH1/2', 'Gene', (153, 159))	('glioblastomas', 'Phenotype', 'HP:0012174', (75, 88))	('glioma entities', 'Disease', (196, 211))	('glioblastomas', 'Disease', 'MESH:D005909', (75, 88))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('glioblastomas', 'Disease', (75, 88))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (153, 159))	('glioma entities', 'Disease', 'MESH:D005910', (196, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('Glioma', 'Disease', (0, 6))	('mutation', 'Var', (107, 115))	('isocitrate', 'Chemical', 'MESH:C034219', (119, 129))
156927	30783384	The most common IDH1 mutation is R132H, while the most prevalent IDH2 mutations are: R172G, R172K, and R172M.	('IDH2', 'Gene', '3418', (65, 69))	('R172K', 'Mutation', 'rs121913503', (92, 97))	('R172K', 'Var', (92, 97))	('R172M', 'Mutation', 'rs121913503', (103, 108))	('R172M', 'Var', (103, 108))	('R132H', 'Var', (33, 38))	('IDH1', 'Gene', (16, 20))	('R172G', 'Var', (85, 90))	('R132H', 'Mutation', 'rs121913500', (33, 38))	('IDH2', 'Gene', (65, 69))	('IDH1', 'Gene', '3417', (16, 20))	('R172G', 'Mutation', 'rs1057519906', (85, 90))
156929	30783384	The gain of function IDH1/2 mutations however allow the enzymes to reduce alpha-KG to the oncometabolite, 2-hydroxyglutarate (2-HG).	('reduce', 'NegReg', (67, 73))	('2-HG', 'Chemical', 'MESH:C019417', (126, 130))	('IDH1/2', 'Gene', '3417;3418', (21, 27))	('alpha-KG', 'Chemical', 'MESH:D007656', (74, 82))	('gain of function', 'PosReg', (4, 20))	('IDH1/2', 'Gene', (21, 27))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (106, 124))	('mutations', 'Var', (28, 37))
156931	30783384	Different glioma entities have different rates of IDH1 mutations.	('IDH1', 'Gene', (50, 54))	('mutations', 'Var', (55, 64))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('IDH1', 'Gene', '3417', (50, 54))	('glioma entities', 'Disease', (10, 25))	('glioma entities', 'Disease', 'MESH:D005910', (10, 25))
156932	30783384	The most common IDH1 mutated gliomas are anaplastic oligodendrogliomas WHO grade III and anaplastic astrocytomas WHO grade III with a 81.6% and 82% IDH1 mutation rate respectively.	('gliomas', 'Disease', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('anaplastic astrocytoma', 'Disease', (89, 111))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('mutated', 'Var', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('IDH1', 'Gene', (16, 20))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('astrocytomas', 'Disease', (100, 112))	('IDH1', 'Gene', (148, 152))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (89, 111))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (41, 70))	('anaplastic oligodendrogliomas', 'Disease', (41, 70))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('IDH1', 'Gene', '3417', (16, 20))	('gliomas', 'Disease', (63, 70))	('IDH1', 'Gene', '3417', (148, 152))	('astrocytomas', 'Disease', 'MESH:D001254', (100, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
156933	30783384	However, only 3.1% of gliomas carry IDH2 mutations.	('IDH2', 'Gene', (36, 40))	('mutations', 'Var', (41, 50))	('IDH2', 'Gene', '3418', (36, 40))	('gliomas', 'Disease', (22, 29))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))
156934	30783384	Interestingly, it was also established that IDH1 and IDH2 mutations are mutually exclusive in gliomas; barely any gliomas harbor both, IDH1 and IDH2 mutations.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('mutations', 'Var', (58, 67))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('gliomas', 'Disease', (114, 121))	('IDH2', 'Gene', (53, 57))	('IDH1', 'Gene', (135, 139))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('IDH1', 'Gene', (44, 48))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('IDH1', 'Gene', '3417', (135, 139))	('IDH2', 'Gene', '3418', (53, 57))	('IDH2', 'Gene', (144, 148))	('IDH1', 'Gene', '3417', (44, 48))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('IDH2', 'Gene', '3418', (144, 148))
156935	30783384	This indicates at the severity of IDH1/2 mutation, as only one mutation is enough to mediate tumorigenesis.	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('IDH1/2', 'Gene', (34, 40))	('mutation', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
156936	30783384	The relevance of IDH1/2 mutations is also demonstrated by the WHO classification system, which was updated in 2016 to accommodate the genetic makeup of the different glioma subtypes.	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('glioma', 'Disease', (166, 172))	('IDH1/2', 'Gene', (17, 23))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('mutations', 'Var', (24, 33))
156940	30783384	Regarding grade II-IV gliomas, the updated WHO classification of 2016 subdivides lesions according to molecular markers, such as the presence of IDH mutations or 1p/19q deletion.	('IDH', 'Gene', (145, 148))	('1p/19q deletion', 'Var', (162, 177))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('IV gliomas', 'Disease', (19, 29))	('IV gliomas', 'Disease', 'MESH:D005910', (19, 29))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))
156943	30783384	The distinctive genetic marker of secondary glioblastomas is the IDH1 mutation, as over 80% of secondary glioblastomas illustrate IDH1 mutations compared to only 5% of primary glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (105, 118))	('IDH1', 'Gene', '3417', (65, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('glioblastomas', 'Disease', (176, 189))	('glioblastomas', 'Phenotype', 'HP:0012174', (44, 57))	('glioblastomas', 'Disease', (105, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('mutations', 'Var', (135, 144))	('glioblastomas', 'Disease', 'MESH:D005909', (44, 57))	('IDH1', 'Gene', (130, 134))	('glioblastomas', 'Phenotype', 'HP:0012174', (176, 189))	('glioblastomas', 'Disease', (44, 57))	('IDH1', 'Gene', '3417', (130, 134))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('IDH1', 'Gene', (65, 69))	('glioblastomas', 'Disease', 'MESH:D005909', (176, 189))
156944	30783384	Secondary glioblastomas are also associated with a hypermethylator phenotype and exhibit a better prognosis than primary glioblastomas.	('glioblastomas', 'Disease', (121, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('hypermethylator', 'Var', (51, 66))	('glioblastomas', 'Phenotype', 'HP:0012174', (10, 23))	('glioblastomas', 'Phenotype', 'HP:0012174', (121, 134))	('glioblastomas', 'Disease', 'MESH:D005909', (10, 23))	('glioblastomas', 'Disease', 'MESH:D005909', (121, 134))	('glioblastomas', 'Disease', (10, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
156945	30783384	Due to the strong association with IDH1 mutations, this review will focus particularly on the pathogenesis of secondary glioblastomas.	('association', 'Reg', (18, 29))	('IDH1', 'Gene', (35, 39))	('glioblastomas', 'Phenotype', 'HP:0012174', (120, 133))	('IDH1', 'Gene', '3417', (35, 39))	('glioblastomas', 'Disease', 'MESH:D005909', (120, 133))	('mutations', 'Var', (40, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('glioblastomas', 'Disease', (120, 133))
156946	30783384	IDH1/2 mutations are one of the earliest known mutations occurring during glioma formation.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioma', 'Disease', (74, 80))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('mutations', 'Var', (7, 16))
156947	30783384	When measuring the catalytic activity of mutant IDH1, Dang et al.	('IDH1', 'Gene', '3417', (48, 52))	('mutant', 'Var', (41, 47))	('IDH1', 'Gene', (48, 52))	('catalytic activity', 'MPA', (19, 37))
156949	30783384	Conversely, studies suggest that cancers harboring IDH1/2 mutations produced 2-HG concentrations 10 to 100 times the levels of cancers with wild type IDH.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('IDH1/2', 'Gene', '3417;3418', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('IDH1/2', 'Gene', (51, 57))	('2-HG concentrations', 'MPA', (77, 96))	('2-HG', 'Chemical', 'MESH:C019417', (77, 81))
156950	30783384	Further, while wild-type IDH1/2 produces the reducing agent NADPH+H+ during the reaction isocitrate to alpha-KG, mutant IDH1/2 consumes NADPH+H+ during the catalyzation of alpha-KG to 2-HG (Fig.	('isocitrate', 'Chemical', 'MESH:C034219', (89, 99))	('mutant', 'Var', (113, 119))	('IDH1/2', 'Gene', '3417;3418', (120, 126))	('IDH1/2', 'Gene', '3417;3418', (25, 31))	('IDH1/2', 'Gene', (120, 126))	('NADPH+H+', 'Chemical', '-', (60, 68))	('IDH1/2', 'Gene', (25, 31))	('2-HG', 'Chemical', 'MESH:C019417', (184, 188))	('NADPH+H+', 'Chemical', '-', (136, 144))	('consumes NADPH+H+', 'MPA', (127, 144))	('alpha-KG', 'Chemical', 'MESH:D007656', (172, 180))	('alpha-KG', 'Chemical', 'MESH:D007656', (103, 111))
156952	30783384	IDH1/2 mutations could offset the cellular redox reactions, promoting tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('offset', 'NegReg', (23, 29))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('tumor', 'Disease', (70, 75))	('cellular redox reactions', 'MPA', (34, 58))	('IDH1/2', 'Gene', (0, 6))	('promoting', 'PosReg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutations', 'Var', (7, 16))
156954	30783384	In vivo and in vitro experiments established that mutant IDH1/2 produces almost exclusively D-2-HG.	('IDH1/2', 'Gene', (57, 63))	('D-2-HG', 'MPA', (92, 98))	('2-HG', 'Chemical', 'MESH:C019417', (94, 98))	('mutant', 'Var', (50, 56))	('IDH1/2', 'Gene', '3417;3418', (57, 63))
156957	30783384	While IDH1/2 mutations have a variety of consequences on tumorigenesis, the correlation between remarkably high levels of 2-HG in gliomas led to much investigation of the specific effect of 2-HG on gliomagenesis.	('2-HG', 'Chemical', 'MESH:C019417', (122, 126))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('glioma', 'Disease', (198, 204))	('glioma', 'Disease', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('consequences', 'Reg', (41, 53))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('2-HG', 'Chemical', 'MESH:C019417', (190, 194))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (57, 62))	('IDH1/2', 'Gene', (6, 12))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
156972	30783384	illustrated that in vivo, HIF-alpha1 levels increased after the knockdown of wild type IDH, introduction of mutant IDH or addition of 2-HG.	('2-HG', 'Chemical', 'MESH:C019417', (134, 138))	('mutant', 'Var', (108, 114))	('IDH', 'Gene', (115, 118))	('increased', 'PosReg', (44, 53))	('HIF-alpha1', 'Protein', (26, 36))
156973	30783384	Other research groups also noticed the correlation between IDH1/2 mutations and elevated HIF-1alpha expression.	('mutations', 'Var', (66, 75))	('elevated', 'PosReg', (80, 88))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('IDH1/2', 'Gene', '3417;3418', (59, 65))	('expression', 'MPA', (100, 110))	('HIF-1alpha', 'Gene', (89, 99))	('IDH1/2', 'Gene', (59, 65))
156979	30783384	On the other hand, research also suggests that D-2-HG promotes HIF-1alpha degradation by stimulating prolyl hydroxylase activity.	('D-2-HG', 'Var', (47, 53))	('HIF-1alpha', 'Gene', (63, 73))	('stimulating', 'PosReg', (89, 100))	('prolyl hydroxylase activity', 'MPA', (101, 128))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('degradation', 'MPA', (74, 85))	('prolyl', 'Chemical', '-', (101, 107))	('HIF-1alpha', 'Gene', '3091', (63, 73))	('promotes', 'PosReg', (54, 62))
156981	30783384	Surprisingly however, this research group also describes that instead of inhibiting, D-2-HG potentiated prolyl hydroxylase catalytic activity, resulting in HIF-1alpha degradation.	('HIF-1alpha', 'Gene', '3091', (156, 166))	('prolyl', 'Chemical', '-', (104, 110))	('2-HG', 'Chemical', 'MESH:C019417', (87, 91))	('potentiated', 'PosReg', (92, 103))	('HIF-1alpha', 'Gene', (156, 166))	('prolyl hydroxylase catalytic activity', 'MPA', (104, 141))	('D-2-HG', 'Var', (85, 91))
156982	30783384	The paper reports that HIF-1alpha levels were reduced in human IDH-mutated proneural tumors, compared to IDH-wild type samples.	('IDH-mutated', 'Var', (63, 74))	('HIF-1alpha', 'Gene', '3091', (23, 33))	('reduced', 'NegReg', (46, 53))	('HIF-1alpha', 'Gene', (23, 33))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('human', 'Species', '9606', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
156983	30783384	Other research groups also concluded that the addition of D-2-HG but not L-2-HG, reduced HIF-1alpha concentration in cells and that IDH mutation was not sufficient to upregulate HIF-1alpha concentrations in gliomas.	('2-HG', 'Chemical', 'MESH:C019417', (75, 79))	('gliomas', 'Disease', (207, 214))	('D-2-HG', 'Var', (58, 64))	('upregulate', 'PosReg', (167, 177))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('mutation', 'Var', (136, 144))	('gliomas', 'Disease', 'MESH:D005910', (207, 214))	('IDH', 'Gene', (132, 135))	('L-2', 'Gene', (73, 76))	('2-HG', 'Chemical', 'MESH:C019417', (60, 64))	('HIF-1alpha', 'Gene', '3091', (178, 188))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('L-2', 'Gene', '353174', (73, 76))	('reduced', 'NegReg', (81, 88))	('HIF-1alpha', 'Gene', (89, 99))	('HIF-1alpha', 'Gene', (178, 188))
156985	30783384	The consequence of this mechanism on tumor growth was also tested, as D-2-HG stimulates activity of prolyl 4-hydroxylase and subsequent HIF-1alpha degradation which reduced colony formation of immortalized human astrocytes.	('prolyl 4-hydroxylase', 'Enzyme', (100, 120))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('stimulates', 'PosReg', (77, 87))	('human', 'Species', '9606', (206, 211))	('HIF-1alpha', 'Gene', '3091', (136, 146))	('prolyl', 'Chemical', '-', (100, 106))	('colony formation of immortalized human astrocytes', 'CPA', (173, 222))	('activity', 'MPA', (88, 96))	('D-2-HG', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('2-HG', 'Chemical', 'MESH:C019417', (72, 76))	('HIF-1alpha', 'Gene', (136, 146))	('reduced', 'NegReg', (165, 172))
156986	30783384	Concluding, on the one hand 2-HG was associated with HIF-1 stabilisation while other studies have also reported that D-2-HG induces HIF-1alpha degradation.	('2-HG', 'Chemical', 'MESH:C019417', (119, 123))	('HIF-1', 'Gene', '3091', (132, 137))	('HIF-1', 'Gene', '3091', (53, 58))	('HIF-1alpha', 'Gene', (132, 142))	('D-2-HG', 'Var', (117, 123))	('HIF-1', 'Gene', (132, 137))	('2-HG', 'Chemical', 'MESH:C019417', (28, 32))	('HIF-1', 'Gene', (53, 58))	('HIF-1alpha', 'Gene', '3091', (132, 142))
156996	30783384	In fact, IDH-mutated gliomas were associated with reduced levels of endostatin and higher rates of blood vessel densities.	('higher rates', 'PosReg', (83, 95))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('endostatin', 'Gene', '80781', (68, 78))	('endostatin', 'Gene', (68, 78))	('IDH-mutated', 'Var', (9, 20))	('gliomas', 'Disease', (21, 28))	('reduced', 'NegReg', (50, 57))	('blood vessel densities', 'CPA', (99, 121))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
156999	30783384	While traditionally, 2-HG's impacts on gliomagenesis have been associated with alterations to tumor metabolism and vascularization, more recent research suggests that glioma formation is driven to a greater extent by epigenetic alterations induced by 2-HG.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('2-HG', 'Chemical', 'MESH:C019417', (251, 255))	('alterations', 'Reg', (79, 90))	('2-HG', 'Chemical', 'MESH:C019417', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Disease', (39, 45))	('glioma', 'Disease', (167, 173))	('tumor', 'Disease', (94, 99))	('vascularization', 'CPA', (115, 130))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('epigenetic alterations', 'Var', (217, 239))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
157000	30783384	Regarding gliomagenesis, the two most examined epigenetic mechanisms altering chromatin structure are DNA methylation and histone modification.	('histone modification', 'Var', (122, 142))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('DNA methylation', 'Var', (102, 117))	('glioma', 'Disease', (10, 16))
157006	30783384	reported that elevated 2-HG levels from mutant IDH1 can inhibit multiple alpha-KG dependent histone demethylases in vivo and in vitro.	('alpha-KG dependent histone demethylases', 'Enzyme', (73, 112))	('IDH1', 'Gene', (47, 51))	('2-HG', 'Chemical', 'MESH:C019417', (23, 27))	('IDH1', 'Gene', '3417', (47, 51))	('mutant', 'Var', (40, 46))	('2-HG levels', 'MPA', (23, 34))	('elevated', 'PosReg', (14, 22))	('alpha-KG', 'Chemical', 'MESH:D007656', (73, 81))	('inhibit', 'NegReg', (56, 63))
157009	30783384	While H3K9me3 has long been known as an epigenetic silencing mechanism, it also plays an important role during tumorigenesis.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('H3K9me3', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (111, 116))
157010	30783384	Intriguingly, H3K9me3 is associated with IDH1 mutation in different types of gliomas.	('associated', 'Reg', (25, 35))	('gliomas', 'Disease', (77, 84))	('H3K9me3', 'Protein', (14, 21))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('IDH1', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('IDH1', 'Gene', '3417', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
157011	30783384	Supporting this observation, in vitro experiments on cells of the central nervous system showed that IDH-mutated astrocytes or murine neurosphere cultures exhibited enhanced H3K9me3.	('H3K9me3', 'Protein', (174, 181))	('IDH-mutated', 'Var', (101, 112))	('murine', 'Species', '10090', (127, 133))	('enhanced', 'PosReg', (165, 173))
157016	30783384	The significance of histone methylation to tumorigenesis is also evident from much research showing that histone methylation inhibits cellular differentiation.	('cellular differentiation', 'CPA', (134, 158))	('histone methylation', 'Var', (105, 124))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('inhibits', 'NegReg', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
157017	30783384	For instance, a study reported that the "introduction of mutant but not wild-type IDH1 into astrocytes resulted in the upregulation of nestin (and other genes associated with stem cell identity) at the time of DNA methylation increase and the adoption of a neurosphere/stem-like phenotype".	('nestin', 'Gene', (135, 141))	('methylation', 'Var', (214, 225))	('IDH1', 'Gene', (82, 86))	('upregulation', 'PosReg', (119, 131))	('mutant', 'Var', (57, 63))	('IDH1', 'Gene', '3417', (82, 86))	('increase', 'PosReg', (226, 234))
157018	30783384	Regarding gliomas, IDH-mutated gliomas with methylated H3K9 exhibit lower levels of glial fibrillary acid protein (a protein important for central nervous system cell differentiation) and less cellular differentiation.	('methylated', 'Var', (44, 54))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('levels of glial fibrillary acid protein', 'MPA', (74, 113))	('lower', 'NegReg', (68, 73))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('cellular differentiation', 'CPA', (193, 217))	('H3K9', 'Gene', (55, 59))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))	('gliomas', 'Disease', (31, 38))
157019	30783384	Moreover, the cancerogenic effect of histone methylation is supported by the consideration that histone methylation can impact DNA methylation.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('impact', 'Reg', (120, 126))	('DNA methylation', 'MPA', (127, 142))	('methylation', 'Var', (104, 115))	('histone', 'Protein', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
157021	30783384	Both effects are pro-tumorigenic, as hypomethylation leads to genome instability, while promoter hypermethylation, amongst other things, silences tumor suppressor genes.	('silences tumor', 'Disease', 'MESH:D009369', (137, 151))	('genome instability', 'MPA', (62, 80))	('silences tumor', 'Disease', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (21, 26))	('promoter hypermethylation', 'Var', (88, 113))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('leads to', 'Reg', (53, 61))	('hypomethylation', 'Var', (37, 52))
157030	30783384	In fact, TET2 is described as a tumor suppressor because studies suggest that many solid cancers and 15% of myeloid cancers carry TET2 mutations.	('myeloid cancers', 'Disease', 'MESH:D009369', (108, 123))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('myeloid cancers', 'Disease', (108, 123))	('mutations', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Disease', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumor', 'Disease', (32, 37))	('TET2', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
157032	30783384	In a study by Xu et al., D-2-HG inhibited TET1 up to 47% and TET2 up to 83%.	('2-HG', 'Chemical', 'MESH:C019417', (27, 31))	('D-2-HG', 'Var', (25, 31))	('inhibited', 'NegReg', (32, 41))	('TET2', 'MPA', (61, 65))	('TET1', 'Gene', '80312', (42, 46))	('TET1', 'Gene', (42, 46))
157035	30783384	demonstrated that in vivo, 5-hmC was much lower in mutated IDH1 glioma samples compared to wild-type IDH1, indicating the impaired function of TET to demethylase DNA in the presence of abnormally high 2-HG levels.	('IDH1', 'Gene', (101, 105))	('IDH1', 'Gene', '3417', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('TET', 'Chemical', 'MESH:C010349', (143, 146))	('IDH1', 'Gene', '3417', (101, 105))	('lower', 'NegReg', (42, 47))	('2-HG', 'Chemical', 'MESH:C019417', (201, 205))	('5-hmC', 'MPA', (27, 32))	('glioma', 'Disease', (64, 70))	('impaired', 'NegReg', (122, 130))	('function', 'MPA', (131, 139))	('IDH1', 'Gene', (59, 63))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('mutated', 'Var', (51, 58))
157036	30783384	These findings are supported by observations that IDH-mutated acute myeloid leukemia cells showed impaired TET2 functions and hypermethylated phenotypes.	('TET2', 'MPA', (107, 111))	('myeloid leukemia', 'Disease', 'MESH:D007951', (68, 84))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (68, 84))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (62, 84))	('IDH-mutated', 'Var', (50, 61))	('impaired', 'NegReg', (98, 106))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('myeloid leukemia', 'Disease', (68, 84))
157038	30783384	2-HG induced hypermethylation silences tumor suppressors and inhibits cellular differentiation.	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('cellular differentiation', 'CPA', (70, 94))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('silences tumor', 'Disease', 'MESH:D009369', (30, 44))	('hypermethylation', 'Var', (13, 29))	('silences tumor', 'Disease', (30, 44))	('inhibits', 'NegReg', (61, 69))
157039	30783384	observed that the introduction of mutant IDH1 into astrocytes coincided with increasing DNA methylation and the adoption of a stem-cell-like phenotype.	('increasing', 'PosReg', (77, 87))	('DNA methylation', 'MPA', (88, 103))	('stem-cell-like', 'CPA', (126, 140))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('mutant', 'Var', (34, 40))
157040	30783384	Another study compared TET2 mutant mice to IDH-mutant mice exhibiting high levels of 2-HG.	('mutant', 'Var', (28, 34))	('2-HG', 'Chemical', 'MESH:C019417', (85, 89))	('mice', 'Species', '10090', (35, 39))	('TET2', 'Gene', (23, 27))	('mice', 'Species', '10090', (54, 58))
157041	30783384	Both types, TET2 mutant mice and IDH-mutant mice, showed "stem cell expansion and impaired hematopoietic differentiation".	('mice', 'Species', '10090', (24, 28))	('impaired', 'NegReg', (82, 90))	('hematopoietic differentiation', 'CPA', (91, 120))	('mutant', 'Var', (17, 23))	('mice', 'Species', '10090', (44, 48))
157043	30783384	This suggests that inhibition of TET2 through 2-HG could impair nerve cell differentiation.	('inhibition', 'Var', (19, 29))	('impair nerve cell', 'Phenotype', 'HP:0002180', (57, 74))	('nerve cell differentiation', 'CPA', (64, 90))	('2-HG', 'Chemical', 'MESH:C019417', (46, 50))	('impair', 'NegReg', (57, 63))
157046	30783384	Current research provides evidence of novel immune evasive mechanisms specific to IDH-mutated gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('IDH-mutated', 'Var', (82, 93))
157050	30783384	Thereby, a 2-HG induced abatement of STAT1 reduces CD8+ T-cell accumulation at the tumor site.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('2-HG', 'Chemical', 'MESH:C019417', (11, 15))	('CD8', 'Gene', (51, 54))	('STAT1', 'Gene', (37, 42))	('CD8', 'Gene', '925', (51, 54))	('abatement', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('STAT1', 'Gene', '6772', (37, 42))	('reduces', 'NegReg', (43, 50))
157056	30783384	However, evidence suggest that rather than stimulating immunoevasion of glioma cells, 2-HG reduces the immunosuppression usually associated with cancer and thereby impedes cancerous cell proliferation.	('cancer', 'Disease', (145, 151))	('glioma', 'Disease', (72, 78))	('2-HG', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancerous', 'Disease', 'MESH:D009369', (172, 181))	('impedes', 'NegReg', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('reduces', 'NegReg', (91, 98))	('2-HG', 'Chemical', 'MESH:C019417', (86, 90))	('cancer', 'Disease', (172, 178))	('immunosuppression', 'MPA', (103, 120))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancerous', 'Disease', (172, 181))
157058	30783384	Studies observed that IDH-wild type gliomas show a greater infiltration of immunosuppressive cells, such as T-regulatory cells (T-Regs) and tumor-associated macrophages (TAMs), than IDH-mutant gliomas.	('gliomas', 'Disease', (193, 200))	('type gliomas', 'Disease', 'MESH:D005910', (31, 43))	('IDH-wild', 'Var', (22, 30))	('gliomas', 'Disease', (36, 43))	('greater', 'PosReg', (51, 58))	('type gliomas', 'Disease', (31, 43))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('infiltration', 'MPA', (59, 71))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('tumor', 'Disease', (140, 145))
157060	30783384	Moreover, while macrophages usually exhibit anti-tumorigenic functions, in response to the local tumor microenvironment, TAMs alter their function and facilitate tumor growth instead.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('facilitate', 'PosReg', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (162, 167))	('alter', 'Reg', (126, 131))	('iron', 'Chemical', 'MESH:D007501', (111, 115))	('function', 'MPA', (138, 146))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (97, 102))	('TAMs', 'Var', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
157063	30783384	IDH-mutated glioblastomas are associated with a significantly lower expression of CD163, which could reduce immunosuppression and suppress tumor growth.	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('reduce', 'NegReg', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CD163', 'Gene', (82, 87))	('glioblastomas', 'Disease', 'MESH:D005909', (12, 25))	('expression', 'MPA', (68, 78))	('glioblastomas', 'Disease', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('lower', 'NegReg', (62, 67))	('suppress', 'NegReg', (130, 138))	('glioblastomas', 'Phenotype', 'HP:0012174', (12, 25))	('IDH-mutated', 'Var', (0, 11))	('CD163', 'Gene', '9332', (82, 87))	('immunosuppression', 'MPA', (108, 125))
157078	30783384	Therefore, elevated mutation rates in cancer cells increase the genetic diversity of the tumor and allow cancer cells to express a phenotype which is best suited to their environment.	('increase', 'PosReg', (51, 59))	('iron', 'Chemical', 'MESH:D007501', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('allow', 'Reg', (99, 104))	('genetic', 'MPA', (64, 71))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('mutation rates', 'Var', (20, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
157079	30783384	Thus, it can be argued that DNA mutations within existing cancerous tissue can promote tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancerous', 'Disease', 'MESH:D009369', (58, 67))	('tumor', 'Disease', (87, 92))	('DNA', 'Gene', (28, 31))	('mutations', 'Var', (32, 41))	('promote', 'PosReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancerous', 'Disease', (58, 67))
157080	30783384	These DNA mutations can result from methylation of DNA bases through environmental or endogenous alkylating agents.	('iron', 'Chemical', 'MESH:D007501', (72, 76))	('DNA', 'Disease', (6, 9))	('result from', 'Reg', (24, 35))	('mutations', 'Var', (10, 19))	('methylation', 'Var', (36, 47))
157081	30783384	The described microevolution of cancer is suppressed if DNA mutations, such as alkylated DNA bases, are repaired.	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('alkylated', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
157086	30783384	However in higher concentrations as of 0.5 mM, D-2-HG results in a 50% inhibition of ALKBH2.	('D-2-HG', 'Var', (47, 53))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('inhibition', 'NegReg', (71, 81))	('ALKBH2', 'Gene', '121642', (85, 91))	('ALKBH2', 'Gene', (85, 91))
157088	30783384	From this it can be hypothesized that D-2-HG's competitive inhibition of ALKBH elevates intra-cancerous mutation rate and promotes glioma microevolution.	('inhibition', 'NegReg', (59, 69))	('glioma', 'Disease', (131, 137))	('elevates', 'PosReg', (79, 87))	('D-2-HG', 'Var', (38, 44))	('promotes', 'PosReg', (122, 130))	('ALKBH', 'Gene', '8846', (73, 78))	('intra-cancerous', 'Disease', 'MESH:D009369', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('2-HG', 'Chemical', 'MESH:C019417', (40, 44))	('intra-cancerous', 'Disease', (88, 103))	('ALKBH', 'Gene', (73, 78))
157089	30783384	Intriguingly however, the inhibition of DNA repair mechanisms through D-2-HG enhances the effectiveness of chemotherapy.	('effectiveness of chemotherapy', 'CPA', (90, 119))	('inhibition', 'NegReg', (26, 36))	('enhances', 'PosReg', (77, 85))	('D-2-HG', 'Var', (70, 76))	('2-HG', 'Chemical', 'MESH:C019417', (72, 76))
157090	30783384	observed that IDH1/2 mutated glioma cells are more sensitive to alkylating chemotherapy and this sensitivity was abolished when D-2-HG production was disrupted.	('glioma', 'Disease', (29, 35))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('mutated', 'Var', (21, 28))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('sensitive to alkylating chemotherapy', 'MPA', (51, 87))	('more', 'PosReg', (46, 50))	('IDH1/2', 'Gene', (14, 20))	('2-HG', 'Chemical', 'MESH:C019417', (130, 134))
157091	30783384	Another study explored the performance of the alkylating chemotherapy, PCV (procarbazine, lomustine and vincristine), on patients with IDH-mutated anaplastic oligodendrogliomas and IDH-wild type anaplastic oligoastrocytomas.	('procarbazine', 'Chemical', 'MESH:D011344', (76, 88))	('anaplastic oligodendrogliomas', 'Disease', (147, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('IDH-mutated', 'Var', (135, 146))	('oligoastrocytomas', 'Disease', (206, 223))	('vincristine', 'Chemical', 'MESH:D014750', (104, 115))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (206, 223))	('lomustine', 'Chemical', 'MESH:D008130', (90, 99))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('astrocytoma', 'Phenotype', 'HP:0009592', (211, 222))	('patients', 'Species', '9606', (121, 129))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (147, 176))
157092	30783384	Here, patients with IDH mutations responded better to the alkylating agents than patients with wild-type IDH.	('better', 'PosReg', (44, 50))	('IDH', 'Gene', (20, 23))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (24, 33))	('responded', 'MPA', (34, 43))
157093	30783384	The study concludes that screening patients for IDH mutations is beneficial to decipher if they would benefit from neo-adjuvant PCV treatment.	('mutations', 'Var', (52, 61))	('IDH', 'Gene', (48, 51))	('patients', 'Species', '9606', (35, 43))
157095	30783384	Knockdown of ALKBH2 increased sensitivity to temozolomide.	('increased', 'PosReg', (20, 29))	('Knockdown', 'Var', (0, 9))	('sensitivity to temozolomide', 'MPA', (30, 57))	('temozolomide', 'Chemical', 'MESH:D000077204', (45, 57))	('ALKBH2', 'Gene', (13, 19))	('ALKBH2', 'Gene', '121642', (13, 19))
157097	30783384	While tumor metabolism and angiogenesis are also affected by 2-HG, epigenetic consequences stemming from the 2-HG induced hypermethylator phenotype, especially associated with secondary glioblastomas, are chiefly responsible for tumor progression.	('2-HG', 'Chemical', 'MESH:C019417', (61, 65))	('glioblastomas', 'Disease', (186, 199))	('glioblastomas', 'Disease', 'MESH:D005909', (186, 199))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('affected', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', (229, 234))	('angiogenesis', 'CPA', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('glioblastomas', 'Phenotype', 'HP:0012174', (186, 199))	('2-HG', 'Chemical', 'MESH:C019417', (109, 113))	('tumor', 'Disease', (6, 11))	('associated', 'Reg', (160, 170))	('hypermethylator', 'Var', (122, 137))
157098	30783384	A prominent example of the epigenetic alterations induced by 2-HG are the impacts on the immune system.	('impacts', 'Reg', (74, 81))	('2-HG', 'Chemical', 'MESH:C019417', (61, 65))	('2-HG', 'Var', (61, 65))	('epigenetic alterations', 'MPA', (27, 49))
157104	30696801	In this study, we extracted quantitative image features from T2-weighted MR images and revealed that the isocitrate dehydrogenase (IDH) wild type and mutant lower grade gliomas (LGGs) differed in their expression of 146 radiomic descriptors.	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('isocitrate dehydrogenase', 'Gene', (105, 129))	('isocitrate dehydrogenase', 'Gene', '3417', (105, 129))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('expression', 'MPA', (202, 212))	('IDH', 'Gene', (131, 134))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('mutant', 'Var', (150, 156))
157110	30696801	Mutations of IDH genes result in production of the oncometabolite 2-hydroxyglutarate (2-HG) instead of alpha-ketoglutarate.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (103, 122))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (66, 84))	('result in', 'Reg', (23, 32))	('production of the', 'MPA', (33, 50))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (13, 16))
157111	30696801	Previous research studies found that IDH mutations are a causative event in gliomagenesis, as well as a diagnostic, classification, and prognostic biomarker for LGG patients.	('mutations', 'Var', (41, 50))	('LGG', 'Disease', (161, 164))	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('patients', 'Species', '9606', (165, 173))	('IDH', 'Gene', (37, 40))
157113	30696801	In light of the crucial role of IDH mutations in glioma management, IDH examination has become a routine diagnostic modality in many neuropathology centers.	('mutations', 'Var', (36, 45))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH', 'Gene', (32, 35))	('glioma', 'Disease', (49, 55))
157119	30696801	Diffusion (the apparent diffusion coefficient and fractional anisotropy) and perfusion (the relative cerebral blood volume and normalized cerebral blood volume) MR imaging can also be used in distinguishing IDH wild type and mutant gliomas.	('gliomas', 'Disease', (232, 239))	('gliomas', 'Disease', 'MESH:D005910', (232, 239))	('gliomas', 'Phenotype', 'HP:0009733', (232, 239))	('mutant', 'Var', (225, 231))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))
157128	30696801	Of these, 118 (74.7%) had IDH mutant (IDHMUT) tumors and 40 (25.3%) had IDH wild type (IDHWT) tumors.	('IDH mutant', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
157133	30696801	By comparing the clinical parameters of the two clusters, we found that the second cluster was significantly associated with a high frequency of the IDH mutation (P = 0.0020, Fisher's exact test, Figure 1), which indicates a tight association between IDH mutation status and quantitative radiomic features.	('mutation', 'Var', (153, 161))	('associated', 'Reg', (109, 119))	('clinical', 'Species', '191496', (17, 25))	('IDH', 'Gene', (149, 152))
157142	30696801	Accumulating evidence has revealed that the IDH mutation is a crucial predictor for LGG patient outcomes.	('patient', 'Species', '9606', (88, 95))	('mutation', 'Var', (48, 56))	('IDH', 'Gene', (44, 47))	('LGG', 'Disease', (84, 87))
157153	30696801	The first case was a 39-year old male patient with IDH mutant LGG.	('LGG', 'Gene', (62, 65))	('patient', 'Species', '9606', (38, 45))	('IDH mutant', 'Var', (51, 61))
157164	30696801	First, IDH1 mutation results in dramatically elevated levels of 2HG, a potential oncometabolite, which could influence the whole metabolic profile.	('IDH1', 'Gene', '3417', (7, 11))	('whole metabolic profile', 'MPA', (123, 146))	('influence', 'Reg', (109, 118))	('elevated', 'PosReg', (45, 53))	('levels', 'MPA', (54, 60))	('mutation', 'Var', (12, 20))	('IDH1', 'Gene', (7, 11))	('2HG', 'MPA', (64, 67))
157165	30696801	Secondly, IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype, which is a powerful determinant of tumor pathogenicity.	('glioma', 'Disease', (55, 61))	('mutation', 'Var', (15, 23))	('IDH1', 'Gene', '3417', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH1', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
157166	30696801	In keeping with its biological significance, LGGs with large SVRs were found to be positively associated with a high expression of oncogenes, such as OTX1, HES1, BAG5; these genes are involved in biological processes that include the immune process and responses to stimuli.	('HES1', 'Gene', (156, 160))	('expression', 'MPA', (117, 127))	('BAG5', 'Gene', '9529', (162, 166))	('HES1', 'Gene', '3280', (156, 160))	('OTX1', 'Gene', (150, 154))	('large SVRs', 'Var', (55, 65))	('BAG5', 'Gene', (162, 166))	('OTX1', 'Gene', '5013', (150, 154))	('oncogenes', 'Gene', (131, 140))
157170	30696801	The discovery that IDH mutations lead to accumulation of the oncometabolite 2-HG indicates an oncogenic role of the IDH mutation in the genesis of malignant brain tumors.	('accumulation', 'PosReg', (41, 53))	('brain tumors', 'Phenotype', 'HP:0030692', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutations', 'Var', (23, 32))	('malignant brain tumors', 'Disease', (147, 169))	('malignant brain tumors', 'Disease', 'MESH:D001932', (147, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('IDH', 'Gene', (19, 22))	('oncometabolite 2-HG', 'MPA', (61, 80))
157171	30696801	Researchers suggested that the IDH mutation is correlated with the regulation of HIF1, the escape immune system, and aggregation.	('HIF1', 'Gene', (81, 85))	('HIF1', 'Gene', '3091', (81, 85))	('IDH', 'Gene', (31, 34))	('mutation', 'Var', (35, 43))
157172	30696801	A recent study showed that IDH mutant high grade gliomas were more amenable to a complete resection of enhancing tumors and had an improved survival with the resection of non-enhanced tissues.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('IDH mutant', 'Var', (27, 37))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('improved', 'PosReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('gliomas', 'Disease', (49, 56))	('survival', 'MPA', (140, 148))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
157173	30696801	An increasing number of studies indicate that patients harboring IDH mutations have a better prognosis.	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (46, 54))	('IDH', 'Gene', (65, 68))
157197	30696801	Lentiviral vectors carrying IDH1 wildtype or IDH1 R132H mutant cDNA sequences were transduced into the U87MG cells with polybrene (Sigma), as previously described.	('IDH1', 'Gene', '3417', (45, 49))	('IDH1', 'Gene', '3417', (28, 32))	('R132H', 'Var', (50, 55))	('cDNA', 'Gene', (63, 67))	('polybrene', 'Chemical', 'MESH:D006583', (120, 129))	('IDH1', 'Gene', (45, 49))	('U87MG', 'CellLine', 'CVCL:0022', (103, 108))	('R132H', 'Mutation', 'rs121913500', (50, 55))	('IDH1', 'Gene', (28, 32))
157199	30696801	The Western Blot was conducted to verify the expression of the mutant IDH1 enzyme using a cell lysate and the IDH1R132H antibody (1:200, DIA-H05, Dianova).	('IDH1', 'Gene', '3417', (110, 114))	('mutant', 'Var', (63, 69))	('IDH1', 'Gene', '3417', (70, 74))	('IDH1', 'Gene', (110, 114))	('IDH1', 'Gene', (70, 74))
157200	30696801	Then, IDH1 wild type or R132H mutant U87MG cells (5 x 105 cells per mouse in 5 microL) were intracranially injected into 5 to 6 weeks old female nude mice (Beijing Vital River Laboratory Animal Technology), as described earlier.	('IDH1', 'Gene', '3417', (6, 10))	('mouse', 'Species', '10090', (68, 73))	('nude mice', 'Species', '10090', (145, 154))	('U87MG', 'CellLine', 'CVCL:0022', (37, 42))	('R132H', 'Mutation', 'rs121913500', (24, 29))	('R132H mutant', 'Var', (24, 36))	('IDH1', 'Gene', (6, 10))
157270	28989289	Patients who had lower-grade gliomas with an IDH mutation and 1p/19q co-deletion had the most favorable clinical outcomes (median survival 8 years), while patients with LGGs with IDH mutations and no 1p/19q co-deletion frequently had mutations in TP53 and ATRX inactivation and had intermediate outcomes (median survival 6.3 years).	('IDH', 'Gene', '3417', (179, 182))	('1p/19q', 'Var', (62, 68))	('gliomas', 'Disease', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('patients', 'Species', '9606', (155, 163))	('mutation', 'Var', (49, 57))	('Patients', 'Species', '9606', (0, 8))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('TP53', 'Gene', (247, 251))	('IDH', 'Gene', (45, 48))	('inactivation', 'NegReg', (261, 273))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('LGG', 'Chemical', '-', (169, 172))	('mutations', 'Var', (234, 243))	('ATRX', 'Gene', (256, 260))	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (45, 48))	('ATRX', 'Gene', '546', (256, 260))	('TP53', 'Gene', '7157', (247, 251))
157272	28989289	In a similar study, again in adults, the presence of three mutations (TERT promoter, mutations in IDH, and 1p/19q co-deletion) was used to define roughly five groups of clinical behavior: triple-positive as well as TERT and IDH mutant had the best outcomes, with IDH-only mutant and triple-negatives having intermediate survival, and TERT-only tumors having the worst survival.	('IDH', 'Gene', (224, 227))	('TERT', 'Gene', '7015', (215, 219))	('TERT', 'Gene', '7015', (334, 338))	('IDH', 'Gene', '3417', (263, 266))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('IDH', 'Gene', '3417', (224, 227))	('TERT', 'Gene', (334, 338))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', (344, 350))	('IDH', 'Gene', (263, 266))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('TERT', 'Gene', (70, 74))	('IDH', 'Gene', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('TERT', 'Gene', (215, 219))	('IDH', 'Gene', '3417', (98, 101))	('TERT', 'Gene', '7015', (70, 74))
157274	28989289	However, in contrast to adult lesions, 1p/19q co-deletion is rare in children with oligodendrogliomas and may not confer similar responsiveness to therapy.	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (83, 101))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('oligodendrogliomas', 'Disease', (83, 101))	('1p/19q co-deletion', 'Var', (39, 57))	('children', 'Species', '9606', (69, 77))
157276	28989289	While the initial data were not tied to clinical outcomes per se, several actionable alterations were identified, including the potential therapeutic benefit of targeting upregulation of the MAPK/ERK and PI3K pathways in diffuse gliomas and BRAF fusion aberrations, that is, KIAA1549-BRAF fusions in Pas and BRAF:p. V600E mutations in pleomorphic xanthoastrocytomas.	('KIAA1549-BRAF', 'Disease', 'None', (275, 288))	('astrocytoma', 'Phenotype', 'HP:0009592', (353, 364))	('gliomas', 'Disease', 'MESH:D005910', (229, 236))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('BRAF', 'Gene', '673', (284, 288))	('V600E', 'Var', (316, 321))	('BRAF', 'Gene', (308, 312))	('BRAF', 'Gene', '673', (308, 312))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (335, 365))	('BRAF', 'Gene', (284, 288))	('Pas', 'Disease', (300, 303))	('gliomas', 'Phenotype', 'HP:0009733', (229, 236))	('MAPK', 'Gene', (191, 195))	('BRAF', 'Gene', (241, 245))	('MAPK', 'Gene', '5594', (191, 195))	('pleomorphic xanthoastrocytomas', 'Disease', (335, 365))	('V600E', 'SUBSTITUTION', 'None', (316, 321))	('upregulation', 'PosReg', (171, 183))	('KIAA1549-BRAF', 'Disease', (275, 288))	('ERK', 'Gene', '5594', (196, 199))	('gliomas', 'Disease', (229, 236))	('BRAF', 'Gene', '673', (241, 245))	('ERK', 'Gene', (196, 199))
157277	28989289	Methylation of the MGMT promoter, which thereby silences the repair gene, is associated with prolonged progression-free survival (PFS) in adults with HGG treated with temozolomide (TMZ).	('temozolomide', 'Chemical', 'MESH:D000077204', (167, 179))	('Methylation', 'Var', (0, 11))	('progression-free survival', 'CPA', (103, 128))	('silences', 'NegReg', (48, 56))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('prolonged', 'PosReg', (93, 102))	('TMZ', 'Chemical', 'MESH:D000077204', (181, 184))
157278	28989289	Methylated MGMT is present in a substantial proportion of adults with high-grade lesions (30%-50%) and in series of selected patients, and has also been detected in up to 93% with low-grade lesions, conferring a favorable PFS.	('patients', 'Species', '9606', (125, 133))	('MGMT', 'Gene', '4255', (11, 15))	('MGMT', 'Gene', (11, 15))	('Methylated', 'Var', (0, 10))
157279	28989289	The frequency of MGMT promoter methylation in newly diagnosed pediatric gliomas is lower than the proportion seen in adult gliomas.	('pediatric gliomas', 'Disease', (62, 79))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('adult gliomas', 'Disease', (117, 130))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('pediatric gliomas', 'Disease', 'MESH:D005910', (62, 79))	('lower', 'NegReg', (83, 88))	('methylation', 'Var', (31, 42))	('adult gliomas', 'Disease', 'MESH:D005910', (117, 130))	('MGMT', 'Gene', '4255', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('MGMT', 'Gene', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))
157325	28989289	The authors concluded that for grade 2 glioma patients with less than gross total tumor resection or >40 years of age, PCV+RT prolongs both OS and PFS compared with RT alone.	('patients', 'Species', '9606', (46, 54))	('CV', 'Chemical', '-', (120, 122))	('OS', 'Chemical', '-', (140, 142))	('glioma', 'Disease', (39, 45))	('PFS', 'CPA', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PCV+RT', 'Var', (119, 125))	('grade', 'Disease', (31, 36))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('prolongs', 'PosReg', (126, 134))	('tumor', 'Disease', (82, 87))
157329	28989289	1p deletion and IDH mutation were positive prognostic factors irrespective of treatment.	('mutation', 'Var', (20, 28))	('IDH', 'Gene', '3417', (16, 19))	('IDH', 'Gene', (16, 19))
157331	28989289	In concurrent combination, RT+TMZ seems to represent an improvement on historical controls for patients with higher-risk LGG.	('patients', 'Species', '9606', (95, 103))	('LGG', 'Disease', (121, 124))	('TMZ', 'Chemical', 'MESH:D000077204', (30, 33))	('LGG', 'Chemical', '-', (121, 124))	('RT+TMZ', 'Var', (27, 33))
157366	28989289	Classically, these lesions induce significant peritumoral edema, best visualized on fluid-attenuated inversion recovery sequences.	('lesions', 'Var', (19, 26))	('edema', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('edema', 'Disease', 'MESH:D004487', (58, 63))	('edema', 'Phenotype', 'HP:0000969', (58, 63))	('tumor', 'Disease', (50, 55))
157380	28989289	Mutations in histones H3.1, at position K27, and H3.3, at positions K27 and G34, have more recently been focused upon for their oncogenic tendencies and prognostic value.	('K27', 'Gene', '342574', (40, 43))	('K27', 'Gene', (40, 43))	('K27', 'Gene', '342574', (68, 71))	('K27', 'Gene', (68, 71))	('Mutations', 'Var', (0, 9))	('G34', 'Var', (76, 79))	('H3.3', 'Gene', (49, 53))
157382	28989289	MGMT silencing through methylation is associated with improved outcomes in adults with HGG treated with TMZ.	('MGMT', 'Gene', (0, 4))	('HGG', 'Disease', (87, 90))	('methylation', 'Var', (23, 34))	('silencing', 'NegReg', (5, 14))	('outcomes', 'MPA', (63, 71))	('improved', 'PosReg', (54, 62))	('MGMT', 'Gene', '4255', (0, 4))	('TMZ', 'Chemical', 'MESH:D000077204', (104, 107))
157386	28989289	Also, in the CCG-945 study of pediatric HGG, patients with overexpression of p53 and/or a mutation in the TP53 gene had significantly lower PFS, as compared to children who had neither of these findings.	('lower', 'NegReg', (134, 139))	('PFS', 'MPA', (140, 143))	('p53', 'Gene', (77, 80))	('children', 'Species', '9606', (160, 168))	('p53', 'Gene', '7157', (77, 80))	('patients', 'Species', '9606', (45, 53))	('overexpression', 'PosReg', (59, 73))	('CCG', 'Chemical', '-', (13, 16))	('mutation', 'Var', (90, 98))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
157387	28989289	TP53 mutations are thought to be one of several driving aberrations in the majority of adult HGG.	('TP53', 'Gene', '7157', (0, 4))	('adult HGG', 'Disease', (87, 96))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
157389	28989289	Epidermal growth factor receptor (EGFR) is found to be expressed in 30%-50% of adult GBM, mainly through amplification of the EGFR gene.	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', (126, 130))	('amplification', 'Var', (105, 118))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', '1956', (34, 38))	('EGFR', 'Gene', '1956', (126, 130))
157390	28989289	Several EGFR gene mutations have been reported in GBMs, with the most common being the truncated EGFRvIII that can be found in 45% of EGFR-amplified GBM and in 8.5% patients without amplification.	('EGFR', 'Gene', (134, 138))	('EGFR', 'Gene', '1956', (97, 101))	('truncated', 'Var', (87, 96))	('GBMs', 'Phenotype', 'HP:0012174', (50, 54))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (165, 173))	('EGFR', 'Gene', (8, 12))	('EGFR', 'Gene', '1956', (134, 138))	('mutations', 'Var', (18, 27))
157391	28989289	A pathologic review of adult patients with HGG showed on multivariate analysis that EGFR amplification was an independent and significant unfavorable predictor for OS, with EGFRvIII overexpression being the strongest indicator of a poor prognosis.	('patients', 'Species', '9606', (29, 37))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', '1956', (173, 177))	('amplification', 'Var', (89, 102))	('EGFR', 'Gene', (84, 88))	('OS', 'Chemical', '-', (164, 166))	('EGFR', 'Gene', (173, 177))
157392	28989289	EGFR gene amplification and mutation appear to occur less frequently in childhood gliomas.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('EGFR', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('mutation', 'Var', (28, 36))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('child', 'Species', '9606', (72, 77))	('EGFR', 'Gene', '1956', (0, 4))
157393	28989289	In adult anaplastic gliomas, loss of heterozygosity of 1p and 19q remains a key genetic marker that is highly prognostic of outcomes and response to therapy.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('loss of heterozygosity', 'Var', (29, 51))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
157394	28989289	As discussed above, in contrast to adult lesions, 1p/19q deletion is rare in children with anaplastic oligodendrogliomas and may not confer the same responsiveness to therapy.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (102, 120))	('anaplastic oligodendroglioma', 'Disease', (91, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('oligodendrogliomas', 'Disease', (102, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (91, 119))	('children', 'Species', '9606', (77, 85))	('1p/19q deletion', 'Var', (50, 65))
157395	28989289	A similar story holds for IDH1 and IDH2 mutations, as they are associated with prolonged survival and enhanced sensitivity to TMZ in adults, but are less common in pediatric HGG.	('enhanced', 'PosReg', (102, 110))	('IDH2', 'Gene', '3418', (35, 39))	('survival', 'CPA', (89, 97))	('IDH1', 'Gene', (26, 30))	('sensitivity to TMZ', 'MPA', (111, 129))	('mutations', 'Var', (40, 49))	('TMZ', 'Chemical', 'MESH:D000077204', (126, 129))	('IDH1', 'Gene', '3417', (26, 30))	('IDH2', 'Gene', (35, 39))
157406	28989289	TMZ increased median survival from 12.1 to 14.6 months, while increasing the 2-year survival from 10.4% to 26.5%.	('TMZ', 'Var', (0, 3))	('increasing', 'PosReg', (62, 72))	('median survival', 'MPA', (14, 29))	('increased', 'PosReg', (4, 13))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
157413	28989289	This lack of benefit persisted in the subgroup of patients with 1p/19q intact tumors.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('patients', 'Species', '9606', (50, 58))	('1p/19q intact', 'Var', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
157418	28989289	Furthermore, similar to the RTOG study, they also reported that the benefit from adjuvant PCV was even greater in a subset of 80 patients harboring the 1p/19q co-deletion.	('CV', 'Chemical', '-', (91, 93))	('1p/19q co-deletion', 'Var', (152, 170))	('patients', 'Species', '9606', (129, 137))	('van', 'Disease', (85, 88))	('van', 'Disease', 'MESH:C536530', (85, 88))
157456	28989289	The decision to add concurrent chemotherapy to RT for grade III lesions should depend on histology, co-deletion of molecular markers such as 1p/19q, and the patient's ability to tolerate therapy.	('1p/19q', 'Var', (141, 147))	('co-deletion', 'Var', (100, 111))	('patient', 'Species', '9606', (157, 164))
157463	28137267	However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('multidrug resistant', 'Var', (51, 70))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('original tumor', 'Disease', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (71, 76))	('original tumor', 'Disease', 'MESH:D009369', (125, 139))	('tumor', 'Disease', (134, 139))
157464	28137267	CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas.	('MDR1', 'Gene', '5243', (117, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('enhances', 'PosReg', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('expression', 'MPA', (123, 133))	('glioblastomas', 'Disease', (176, 189))	('CD133', 'Var', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('malignant brain', 'Phenotype', 'HP:0030692', (56, 71))	('MDR1', 'Gene', (117, 121))	('glioblastomas', 'Phenotype', 'HP:0012174', (176, 189))	('brain tumor', 'Phenotype', 'HP:0030692', (66, 77))	('brain tumors', 'Phenotype', 'HP:0030692', (66, 78))	('malignant brain tumors', 'Disease', (56, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (176, 189))	('malignant brain tumors', 'Disease', 'MESH:D001932', (56, 78))
157470	28137267	PI3K-Akt-NF-kappaB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-kappaB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy.	('NF-kappaB', 'Gene', (9, 18))	('MDR1', 'Gene', (211, 215))	('Akt', 'Gene', '207', (5, 8))	('MDR1', 'Gene', '5243', (211, 215))	('Suppressing', 'Var', (106, 117))	('Akt', 'Gene', (173, 176))	('NF-kappaB', 'Gene', (177, 186))	('decreased', 'NegReg', (148, 157))	('siCD133', 'Gene', (140, 147))	('CD133', 'Gene', (118, 123))	('increasing', 'PosReg', (223, 233))	('Akt', 'Gene', (5, 8))	('levels', 'MPA', (158, 164))	('cell chemosensitivity', 'CPA', (234, 255))	('NF-kappaB', 'Gene', '4790', (9, 18))	('NF-kappaB', 'Gene', '4790', (177, 186))	('Akt', 'Gene', '207', (173, 176))
157558	28137267	CD133, p-Akt (S473 and T308), phospho-NF-kappaB/p65, and MDR1 all increased in DOX-R, VIN-R and VCR-R cells, compared to WT cells (Fig.	('S473', 'Var', (14, 18))	('p65', 'Gene', '5970', (48, 51))	('increased', 'PosReg', (66, 75))	('MDR1', 'Gene', (57, 61))	('Akt', 'Gene', (9, 12))	('MDR1', 'Gene', '5243', (57, 61))	('NF-kappaB', 'Gene', '4790', (38, 47))	('VCR', 'Chemical', 'MESH:D014750', (96, 99))	('DOX-R', 'Chemical', '-', (79, 84))	('T308', 'Var', (23, 27))	('p65', 'Gene', (48, 51))	('NF-kappaB', 'Gene', (38, 47))	('CD133', 'Gene', (0, 5))	('VIN-R', 'Chemical', '-', (86, 91))	('Akt', 'Gene', '207', (9, 12))
157560	28137267	4c), p-Akt (S473 and T308), phospho-NF-kappaB/p65, and MDR1 (Fig.	('p65', 'Gene', '5970', (46, 49))	('NF-kappaB', 'Gene', (36, 45))	('Akt', 'Gene', '207', (7, 10))	('S473', 'Var', (12, 16))	('MDR1', 'Gene', (55, 59))	('Akt', 'Gene', (7, 10))	('MDR1', 'Gene', '5243', (55, 59))	('T308', 'Var', (21, 25))	('p65', 'Gene', (46, 49))	('NF-kappaB', 'Gene', '4790', (36, 45))
157562	28137267	Taken together, the present results, along with our previous findings implicate PI3K/AKT/NF-kappaB signaling as being of central importance to the effect of CD133 on MDR1 expression and hence chemosensitivity.	('expression', 'MPA', (171, 181))	('MDR1', 'Gene', '5243', (166, 170))	('NF-kappaB', 'Gene', '4790', (89, 98))	('NF-kappaB', 'Gene', (89, 98))	('AKT', 'Gene', '207', (85, 88))	('CD133', 'Var', (157, 162))	('AKT', 'Gene', (85, 88))	('MDR1', 'Gene', (166, 170))	('effect', 'Reg', (147, 153))
157568	28137267	5a) and encoded protein expression (MDR1), and reduced p-Akt (S473 and T308), phospho-NF-kappaB/p65, and CD133 (Fig.	('S473', 'Var', (62, 66))	('MDR1', 'Gene', '5243', (36, 40))	('encoded', 'MPA', (8, 15))	('CD133', 'MPA', (105, 110))	('Akt', 'Gene', '207', (57, 60))	('p65', 'Gene', (96, 99))	('NF-kappaB', 'Gene', '4790', (86, 95))	('protein', 'Protein', (16, 23))	('T308', 'Var', (71, 75))	('Akt', 'Gene', (57, 60))	('MDR1', 'Gene', (36, 40))	('reduced', 'NegReg', (47, 54))	('p65', 'Gene', '5970', (96, 99))	('NF-kappaB', 'Gene', (86, 95))
157574	28137267	High ABCB1 gene expression, which encodes MDR1, is associated with chemo-resistance and poor outcome in many types of brain tumors, including medulloblastomas, gliomas, ependymomas and PAs.	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('medulloblastomas', 'Disease', 'MESH:D008527', (142, 158))	('medulloblastoma', 'Phenotype', 'HP:0002885', (142, 157))	('High', 'Var', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('MDR1', 'Gene', (42, 46))	('brain tumors', 'Phenotype', 'HP:0030692', (118, 130))	('brain tumors', 'Disease', 'MESH:D001932', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('brain tumor', 'Phenotype', 'HP:0030692', (118, 129))	('gliomas', 'Disease', (160, 167))	('medulloblastomas', 'Disease', (142, 158))	('ABCB1', 'Gene', (5, 10))	('brain tumors', 'Disease', (118, 130))	('ABCB1', 'Gene', '5243', (5, 10))	('ependymoma', 'Phenotype', 'HP:0002888', (169, 179))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('associated', 'Reg', (51, 61))	('ependymomas and PAs', 'Disease', 'MESH:D004806', (169, 188))	('MDR1', 'Gene', '5243', (42, 46))
157594	28137267	Western blot results suggest that CD133 may impact MDR1 levels through PI3K-Akt-NF-kappaB signaling.	('Akt', 'Gene', (76, 79))	('impact', 'Reg', (44, 50))	('MDR1', 'Gene', (51, 55))	('NF-kappaB', 'Gene', '4790', (80, 89))	('CD133', 'Var', (34, 39))	('MDR1', 'Gene', '5243', (51, 55))	('Akt', 'Gene', '207', (76, 79))	('NF-kappaB', 'Gene', (80, 89))
157599	25245118	Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas The disease course of patients with diffuse low-grade glioma is notoriously unpredictable.	('glioma', 'Disease', (111, 117))	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('glioma', 'Disease', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('distal 10q deletion', 'Var', (34, 53))	('patients', 'Species', '9606', (141, 149))
157600	25245118	The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion.	('CNAs', 'Var', (41, 45))	('aggressive tumor', 'Disease', (69, 85))	('aggressive tumor', 'Disease', 'MESH:D001523', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))
157607	25245118	Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (145, 150))	('loss', 'NegReg', (64, 68))	('distal 10q', 'Var', (53, 63))	('tumor', 'Disease', (5, 10))
157611	25245118	The disease course of patients with LGGs is correlated with gene mutations, such as in p53 and IDH1, hypermethylation of MGMT as well as chromosomal copy number aberrations (CNAs).	('MGMT', 'Gene', '4255', (121, 125))	('p53', 'Gene', (87, 90))	('MGMT', 'Gene', (121, 125))	('p53', 'Gene', '7157', (87, 90))	('hypermethylation', 'Var', (101, 117))	('LGGs', 'Disease', (36, 40))	('patients', 'Species', '9606', (22, 30))	('correlated', 'Reg', (44, 54))	('IDH1', 'Gene', (95, 99))	('IDH1', 'Gene', '3417', (95, 99))	('chromosomal copy number aberrations', 'Var', (137, 172))
157612	25245118	Regarding the latter, assessment of combined loss of 1p and 19q currently is implemented in routine clinical care in specific glioma subgroups given its favorable prognostic and predictive value.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('loss', 'Var', (45, 49))	('glioma', 'Disease', (126, 132))	('19q', 'Protein', (60, 63))
157628	25245118	In the discovery cohort, absence of IDH1 or IDH2 mutation (11/98) was overrepresented in patients with distal 10q loss (7/11; five with whole chromosome 10 loss and two with distal 10q loss).	('IDH1', 'Gene', (36, 40))	('distal 10q loss', 'Var', (103, 118))	('IDH2', 'Gene', (44, 48))	('loss', 'NegReg', (156, 160))	('IDH2', 'Gene', '3418', (44, 48))	('absence', 'NegReg', (25, 32))	('IDH1', 'Gene', '3417', (36, 40))	('patients', 'Species', '9606', (89, 97))
157629	25245118	After splitting the cohort by IDH status, a trend for distal 10q loss was observed; in the IDH mutant subgroup (n =87) the log rank test for loss of 10q (n =11) yielded a P-value of 0.077, and in the IDH wild-type subgroup (n =11), a similar P-value of 0.068 was yielded through the test for distal loss of 10q (n =7).	('loss', 'Var', (141, 145))	('IDH', 'Gene', (200, 203))	('IDH', 'Gene', (91, 94))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (200, 203))	('IDH', 'Gene', '3417', (91, 94))	('IDH', 'Gene', '3417', (30, 33))
157630	25245118	This limited number of patients does not allow for proper statistical survival analysis, but median survival of the patients in these cohorts combined (13.4 years) suggests that loss of 1p/19q and distal 10q counteracts overall survival.	('loss', 'Var', (178, 182))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (116, 124))	('1p/19q', 'Var', (186, 192))	('distal 10q', 'Var', (197, 207))
157631	25245118	Simultaneous testing of both CNAs classified LGG patients with a favorable (1p/19q co-deletion), unfavorable (distal 10q loss), or intermediate (both) prognosis in all three cohorts (Figure 3A,B,C).	('distal 10q loss', 'Var', (110, 125))	('1p/19q co-deletion', 'Var', (76, 94))	('LGG', 'Disease', (45, 48))	('patients', 'Species', '9606', (49, 57))
157637	25245118	Intratumoral heterogeneity was detected in 15 out of 17 LGGs analyzed for this purpose; 68% of the CNAs (84/124) were not homogeneously present in spatially distinct regions obtained during the same surgery, such as loss of chromosomal arm 5q, chromosome 13 and gain of 11p (Figure 5A).	('loss', 'Var', (216, 220))	('chromosomal arm 5q', 'Protein', (224, 242))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('gain', 'PosReg', (262, 266))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('chromosome', 'Gene', (244, 254))
157642	25245118	A substantial proportion (37%, 77/207) of CNAs was uniquely identified in the recurrent tumor, such as loss of genomic regions at chromosomes 4, 10 and 15 (Figures 5C and 6).	('CNAs', 'Disease', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('loss', 'Var', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
157643	25245118	1p/19q co-deletion was consistently identified in initial as well as recurrent tumors and there were no cases with new 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('identified', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
157644	25245118	In four patients, de novo loss of 10q (including distal 10q losses) surfaced in the recurrence.	('loss', 'Var', (26, 30))	('losses', 'NegReg', (60, 66))	('10q', 'Gene', (34, 37))	('patients', 'Species', '9606', (8, 16))
157647	25245118	In one of the three patients for which both spatially distinct regions of the initial tumor and recurrences were analyzed, subclonal 10q loss was present in one of the regions of the initial tumor, but undetectable in the recurrence (Additional file 3).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (86, 91))	('subclonal 10q', 'Var', (123, 136))	('loss', 'NegReg', (137, 141))	('tumor', 'Disease', (191, 196))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
157648	25245118	In the other two patients, 10q loss was detected in both the initial and paired recurrent tumor.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('patients', 'Species', '9606', (17, 25))	('10q loss', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
157656	25245118	Partial loss of 10q is much more frequently detected in histological grade II diffuse gliomas compared with grade III and IV gliomas.	('gliomas', 'Disease', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('detected', 'Reg', (44, 52))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('Partial loss of 10q', 'Var', (0, 19))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
157659	25245118	Only after many years were mutations in CIC and FUBP1 associated with co-deletion of chromosomal arms 1p and 19q.	('mutations', 'Var', (27, 36))	('FUBP1', 'Gene', '8880', (48, 53))	('CIC', 'Gene', '23152', (40, 43))	('arms 1p', 'Gene', (97, 104))	('chromosomal', 'Gene', (85, 96))	('arms 1p', 'Gene', '3075', (97, 104))	('FUBP1', 'Gene', (48, 53))	('CIC', 'Gene', (40, 43))	('associated', 'Reg', (54, 64))	('co-deletion', 'Disease', (70, 81))
157681	25245118	The threshold settings were selected based on the fact that a deletion in 30% of the tumor cells, as observed for the chromosome 10 loss in LGG sample 240 (Figure S3 in Additional file 1), should not be missed.	('tumor', 'Disease', (85, 90))	('loss', 'NegReg', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('deletion', 'Var', (62, 70))
157686	14970853	Monitoring temozolomide treatment of low-grade glioma with proton magnetic resonance spectroscopy Low-grade gliomas (World Health Organisation (WHO) grade II astrocytoma, oligodendroglioma and mixed oligoastrocytoma) tend to be slow-growing tumours (Behin et al, 2003) and there remains considerable debate about the appropriate first-line treatment (Stieber, 2001; Rees, 2002).	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('gliomas', 'Disease', (108, 115))	('glioma', 'Disease', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('temozolomide', 'Chemical', 'MESH:D000077204', (11, 23))	('oligoastrocytoma', 'Disease', (199, 215))	('tumours', 'Phenotype', 'HP:0002664', (241, 248))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('men', 'Species', '9606', (345, 348))	('II astrocytoma', 'Disease', 'MESH:D001254', (155, 169))	('tumours', 'Disease', 'MESH:D009369', (241, 248))	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('glioma', 'Disease', (47, 53))	('Low-grade', 'Var', (98, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (204, 215))	('glioma', 'Disease', (182, 188))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('oligodendroglioma', 'Disease', 'MESH:D009837', (171, 188))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (199, 215))	('men', 'Species', '9606', (29, 32))	('II astrocytoma', 'Disease', (155, 169))	('tumours', 'Disease', (241, 248))	('oligodendroglioma', 'Disease', (171, 188))
157817	33645009	As ZM is a driver of glioma progression and an indicator of MET-inhibition sensitivity, it is meaningful to detect ZM fusions even when they are still present in tumors with relative fewer copies.	('fusions', 'Var', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('glioma', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
157836	33645009	Before surgical resection, the occurrence rate of seizures in patients with ZM+ sGBM was 7.69% (Figure 5C, Table S2); significantly lower than the occurrence rate of seizures in patients with ZM- sGBM (29.55%).	('seizure', 'Phenotype', 'HP:0001250', (166, 173))	('seizures', 'Disease', (50, 58))	('seizure', 'Phenotype', 'HP:0001250', (50, 57))	('seizures', 'Phenotype', 'HP:0001250', (50, 58))	('ZM- sGBM', 'Chemical', '-', (192, 200))	('lower', 'NegReg', (132, 137))	('ZM+ sGBM', 'Var', (76, 84))	('seizures', 'Phenotype', 'HP:0001250', (166, 174))
157854	32415731	Notably, white matter tracts in the right hemisphere might be vulnerable to the effects of a frontal or temporal lesion and might be associated with deficient cognitive function.	('lesion', 'Var', (113, 119))	('deficient cognitive function', 'Disease', (149, 177))	('deficient cognitive function', 'Disease', 'MESH:D003072', (149, 177))	('deficient cognitive function', 'Phenotype', 'HP:0100543', (149, 177))	('associated', 'Reg', (133, 143))
157922	32415731	Taken together, these results suggest that patients with glioma may exhibit microstructural changes in white matter, leading to the abnormalities in the structural connectivity network, which might explain the widespread cognitive dysfunction in patients with glioma (Korgaonkar, Fornito, Williams, & Grieve, 2014; Zhou et al., 2016).	('Williams', 'Disease', (289, 297))	('glioma', 'Disease', 'MESH:D005910', (260, 266))	('glioma', 'Phenotype', 'HP:0009733', (260, 266))	('leading', 'Reg', (117, 124))	('patients', 'Species', '9606', (246, 254))	('cognitive dysfunction', 'Disease', (221, 242))	('abnormalities', 'Var', (132, 145))	('glioma', 'Disease', (57, 63))	('patients', 'Species', '9606', (43, 51))	('Williams', 'Disease', 'MESH:D018980', (289, 297))	('glioma', 'Disease', (260, 266))	('cognitive dysfunction', 'Disease', 'MESH:D003072', (221, 242))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('structural connectivity network', 'MPA', (153, 184))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
157927	32415731	Edematous changes in the infiltrative tumor in WM tracts may induce a reduction in FA (Kinoshita, Nakada, Okita, Hamada, & Hayashi, 2014), which may result in the lower FA value in FCPm in patients with frontal glioma.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('lower FA value in', 'MPA', (163, 180))	('reduction', 'NegReg', (70, 79))	('tumor', 'Disease', (38, 43))	('Edematous changes', 'Phenotype', 'HP:0000969', (0, 17))	('the', 'NegReg', (159, 162))	('frontal glioma', 'Disease', (203, 217))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('frontal glioma', 'Disease', 'MESH:D005910', (203, 217))	('patients', 'Species', '9606', (189, 197))	('changes', 'Var', (10, 17))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))
157943	32415731	Furthermore, studies have also reported the possible relationship between altered WM tracts and cognitive impairments in patients with brain tumors.	('cognitive impairments', 'Disease', (96, 117))	('patients', 'Species', '9606', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('brain tumors', 'Disease', (135, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('brain tumor', 'Phenotype', 'HP:0030692', (135, 146))	('cognitive impairments', 'Phenotype', 'HP:0100543', (96, 117))	('cognitive impairments', 'Disease', 'MESH:D003072', (96, 117))	('brain tumors', 'Phenotype', 'HP:0030692', (135, 147))	('altered', 'Var', (74, 81))	('brain tumors', 'Disease', 'MESH:D001932', (135, 147))
157962	32415731	Third, although we selected the subjects with no evidence of shift of the midline, the mass effect from the lesion might distort the surrounding anatomy, resulting in imprecise parcellation.	('lesion', 'Var', (108, 114))	('midline', 'Disease', (74, 81))	('midline', 'Disease', 'MESH:D009436', (74, 81))	('distort', 'Reg', (121, 128))
157970	31131326	IDHs epigenetically control gene expression through effects on alphaKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH.	('maintain', 'PosReg', (95, 103))	('regulate', 'Reg', (231, 239))	('respiration', 'MPA', (240, 251))	('NADH', 'MPA', (296, 300))	('epigenetically', 'Var', (5, 19))	('anaplerosis', 'MPA', (130, 141))	('AD', 'Phenotype', 'HP:0002511', (297, 299))	('effects', 'Reg', (52, 59))	('AD', 'Phenotype', 'HP:0002511', (167, 169))	('gene expression', 'MPA', (28, 43))	('NADH', 'Chemical', 'MESH:D009243', (296, 300))	('IDHs', 'Gene', (0, 4))	('promote', 'PosReg', (122, 129))	('oxygen', 'Chemical', 'MESH:D010100', (83, 89))	('alphaKG-dependent dioxygenases', 'Enzyme', (63, 93))	('control', 'Reg', (20, 27))	('redox balance', 'MPA', (104, 117))	('energy production', 'MPA', (256, 273))
157971	31131326	Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect.	('IDH2', 'Gene', (40, 44))	('mutations', 'Var', (18, 27))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('IDH2', 'Chemical', '-', (40, 44))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('IDH1', 'Gene', (31, 35))
157972	31131326	Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits alphaKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('malignancy', 'Disease', (199, 209))	('increased', 'PosReg', (160, 169))	('function', 'MPA', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('oxygen', 'Chemical', 'MESH:D010100', (90, 96))	('global hypermethylation phenotype', 'MPA', (125, 158))	('tumor', 'Disease', (170, 175))	('Mutant', 'Var', (0, 6))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (23, 45))	('alphaKG-dependent dioxygenase', 'Enzyme', (70, 99))	('malignancy', 'Disease', 'MESH:D009369', (199, 209))	('inhibits', 'NegReg', (61, 69))
157988	31131326	Bacterial IDH is reversibly regulated by phosphorylation of Ser113.	('Ser113', 'Var', (60, 66))	('Ser113', 'Chemical', '-', (60, 66))	('Bacterial IDH', 'Disease', (0, 13))	('phosphorylation', 'Var', (41, 56))
157991	31131326	In the inactive enzyme configuration, Asp279 occupies the ICT-binding site and forms hydrogen bonds with Ser94.	('Asp279', 'Var', (38, 44))	('Ser94', 'Chemical', '-', (105, 110))	('hydrogen', 'Chemical', 'MESH:D006859', (85, 93))	('Asp279', 'Chemical', '-', (38, 44))	('forms', 'Reg', (79, 84))	('ICT', 'Chemical', 'MESH:C034219', (58, 61))	('hydrogen', 'MPA', (85, 93))
157992	31131326	ICT breaks the hydrogen bonds between these residues and enables Asp279 to chelate the metal ion in the active enzyme configuration.	('enables', 'Reg', (57, 64))	('chelate', 'Interaction', (75, 82))	('hydrogen', 'Chemical', 'MESH:D006859', (15, 23))	('hydrogen bonds', 'MPA', (15, 29))	('metal', 'Chemical', 'MESH:D008670', (87, 92))	('breaks', 'NegReg', (4, 10))	('ICT', 'Chemical', 'MESH:C034219', (0, 3))	('Asp279', 'Chemical', '-', (65, 71))	('Asp279', 'Var', (65, 71))
157994	31131326	Arg140 and Arg172, frequently mutated in cancer (see below), together with Arg149 and Lys256, stabilize the ICT-binding pocket.	('ICT-binding pocket', 'MPA', (108, 126))	('Arg140', 'Var', (0, 6))	('stabilize', 'Reg', (94, 103))	('Lys256', 'Chemical', '-', (86, 92))	('ICT', 'Chemical', 'MESH:C034219', (108, 111))	('Arg172', 'Chemical', '-', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Arg140', 'Chemical', '-', (0, 6))	('Arg172', 'Var', (11, 17))	('Arg149', 'Chemical', '-', (75, 81))	('Arg149', 'Var', (75, 81))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Lys256', 'Var', (86, 92))
157995	31131326	In particular, analysis of the IDH2 crystal structure revealed that Lys256 electrostatically repels a lysine-rich cluster on the opposing site of the active center and, in so doing, keeps the substrate binding pocket accessible for and enables binding of ICT.	('substrate binding pocket', 'MPA', (192, 216))	('repels', 'NegReg', (93, 99))	('binding', 'Interaction', (244, 251))	('IDH2', 'Chemical', '-', (31, 35))	('Lys256', 'Var', (68, 74))	('keeps', 'PosReg', (182, 187))	('lysine', 'Chemical', 'MESH:D008239', (102, 108))	('lysine-rich cluster', 'MPA', (102, 121))	('Lys256', 'Chemical', '-', (68, 74))	('ICT', 'Protein', (255, 258))	('ICT', 'Chemical', 'MESH:C034219', (255, 258))	('enables', 'PosReg', (236, 243))
157996	31131326	Consistent with this model, Lys256 acetylation results in less electrostatic repulsion and, consequently in a narrower binding pocket, and reduced IDH2 activity.	('electrostatic repulsion', 'MPA', (63, 86))	('narrower', 'NegReg', (110, 118))	('IDH2', 'Enzyme', (147, 151))	('activity', 'MPA', (152, 160))	('Lys256 acetylation', 'Var', (28, 46))	('less', 'NegReg', (58, 62))	('IDH2', 'Chemical', '-', (147, 151))	('reduced', 'NegReg', (139, 146))	('binding', 'Interaction', (119, 126))	('Lys256', 'Chemical', '-', (28, 34))
158006	31131326	Histones are frequently methylated at Lys and Arg residues, resulting in DNA supercoiling, and modulate gene expression through alterations in overall chromatin conformation.	('gene expression', 'MPA', (104, 119))	('Histones', 'Protein', (0, 8))	('Lys', 'Chemical', 'MESH:D008239', (38, 41))	('alterations', 'Reg', (128, 139))	('modulate', 'Reg', (95, 103))	('Arg', 'Chemical', 'MESH:D001120', (46, 49))	('methylated', 'Var', (24, 34))	('Arg', 'Var', (46, 49))	('Lys', 'Var', (38, 41))	('DNA', 'MPA', (73, 76))	('chromatin conformation', 'MPA', (151, 173))	('resulting in', 'Reg', (60, 72))
158012	31131326	Inactivating mutations in TET2 frequently occur in AML, MDS, myeloproliferative neoplasms (MPNs), and chronic myelomonocytic leukemia (CMML) and, as described below, are mutually exclusive with IDH mutations.	('AML', 'Disease', (51, 54))	('AML', 'Phenotype', 'HP:0004808', (51, 54))	('occur', 'Reg', (42, 47))	('TET2', 'Gene', '54790', (26, 30))	('myeloproliferative neoplasms', 'Disease', (61, 89))	('CMML', 'Disease', 'MESH:D054429', (135, 139))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (61, 89))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (102, 133))	('Inactivating mutations', 'Var', (0, 22))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('CMML', 'Disease', (135, 139))	('CMML', 'Phenotype', 'HP:0012325', (135, 139))	('MDS', 'Disease', 'MESH:D009190', (56, 59))	('chronic myelomonocytic leukemia', 'Disease', (102, 133))	('TET2', 'Gene', (26, 30))	('neoplasms', 'Phenotype', 'HP:0002664', (80, 89))	('MPNs', 'Phenotype', 'HP:0005547', (91, 95))	('MDS', 'Disease', (56, 59))	('AML', 'Disease', 'MESH:D015470', (51, 54))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (61, 89))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (102, 133))
158014	31131326	In addition to DNA modification, TET enzymes together with other alphaKG-dependent oxygenases, such as alphaKG-dependent dioxygenase alkB homolog 3 (ALKBH3) and fat mass and obesity-associated protein FTO, can demethylate mRNA to enhance mRNA stability and translation.	('TET', 'Chemical', '-', (33, 36))	('obesity', 'Phenotype', 'HP:0001513', (174, 181))	('FTO', 'Gene', (201, 204))	('alkB homolog 3', 'Gene', '221120', (133, 147))	('enhance', 'PosReg', (230, 237))	('oxygen', 'Chemical', 'MESH:D010100', (123, 129))	('obesity', 'Disease', 'MESH:D009765', (174, 181))	('demethylate', 'Var', (210, 221))	('FTO', 'Gene', '79068', (201, 204))	('obesity', 'Disease', (174, 181))	('mRNA', 'Protein', (222, 226))	('ALKBH3', 'Gene', (149, 155))	('translation', 'MPA', (257, 268))	('oxygen', 'Chemical', 'MESH:D010100', (83, 89))	('mRNA stability', 'MPA', (238, 252))	('ALKBH3', 'Gene', '221120', (149, 155))	('alkB homolog 3', 'Gene', (133, 147))
158029	31131326	Studies using a lox-stop-lox-controlled IDH1R13H2 mutant knockin mouse, which, in the absence of Cre recombination, is homozygously null for IDH1, revealed nonessential roles for IDH1 in normal pre- and postnatal development but critical roles in physiologic amino acid catabolism and in protecting against oxidative DNA damage.	('IDH1R13H2', 'Gene', (40, 49))	('mouse', 'Species', '10090', (65, 70))	('oxidative DNA damage', 'MPA', (307, 327))	('mutant', 'Var', (50, 56))	('physiologic', 'MPA', (247, 258))
158036	31131326	When ectopically expressed, miR-181a, through downregulation of IDH1 mRNA level, decreased the expression of genes implicated in lipid biosynthesis, possibly through alphaKG-dependent epigenetic effect, while increasing the expression of enzymes involved in beta-oxidation.	('decreased', 'NegReg', (81, 90))	('downregulation', 'NegReg', (46, 60))	('epigenetic', 'Var', (184, 194))	('miR-181a', 'Gene', (28, 36))	('lipid', 'Chemical', 'MESH:D008055', (129, 134))	('miR-181a', 'Gene', '387176', (28, 36))	('IDH1', 'Gene', (64, 68))	('increasing', 'PosReg', (209, 219))	('mRNA level', 'MPA', (69, 79))	('enzymes', 'Enzyme', (238, 245))	('expression', 'MPA', (224, 234))	('expression of genes', 'MPA', (95, 114))
158044	31131326	Further supporting critical roles of IDH2 in maintaining mitochondrial redox balance, IDH2 deficiency results in increased liver susceptibility to ischemia-reperfusion injury and enhanced oxidative damage to kidney tubule cells.	('IDH2', 'Gene', (86, 90))	('ischemia-reperfusion injury', 'Disease', 'MESH:D015427', (147, 174))	('damage to kidney', 'Phenotype', 'HP:0000112', (198, 214))	('deficiency', 'Var', (91, 101))	('enhanced', 'PosReg', (179, 187))	('IDH2', 'Chemical', '-', (86, 90))	('ischemia-reperfusion injury', 'Disease', (147, 174))	('oxidative damage', 'MPA', (188, 204))	('increased', 'PosReg', (113, 122))	('increased liver', 'Phenotype', 'HP:0002240', (113, 128))	('IDH2', 'Chemical', '-', (37, 41))
158063	31131326	Mutation at Arg132 of IDH1, and at the analogous codon Arg172 of IDH2, represents early initiating events that drive the evolution of low-grade glioma, including grade II to III astrocytoma, oligodendroglioma, and oligodendroglioma associated with Li-Fraumeni syndrome (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('Arg172', 'Chemical', '-', (55, 61))	('glioma', 'Disease', (202, 208))	('Arg132', 'Chemical', '-', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (202, 208))	('glioma', 'Disease', (225, 231))	('glioma', 'Disease', (144, 150))	('grade', 'Disease', (162, 167))	('oligodendroglioma', 'Disease', 'MESH:D009837', (191, 208))	('oligodendroglioma', 'Disease', 'MESH:D009837', (214, 231))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('astrocytoma', 'Disease', 'MESH:D001254', (178, 189))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('astrocytoma', 'Disease', (178, 189))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('oligodendroglioma', 'Disease', (214, 231))	('IDH1', 'Gene', (22, 26))	('oligodendroglioma', 'Disease', (191, 208))	('IDH2', 'Gene', (65, 69))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('Mutation at Arg132', 'Var', (0, 18))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH2', 'Chemical', '-', (65, 69))	('Li-Fraumeni syndrome', 'Disease', (248, 268))	('associated', 'Reg', (232, 242))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (248, 268))
131888	31131326	These mutations are also detected in grade IV glioblastoma (GBM), referred to as IDH1 mutant GBM, which account for ~10% of all grade IV clinical cases but are absent in pediatric high-grade malignancies and in nonglial subtypes of brain tumors.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('brain tumors', 'Disease', 'MESH:D001932', (232, 244))	('brain tumors', 'Phenotype', 'HP:0030692', (232, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('brain tumors', 'Disease', (232, 244))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('detected', 'Reg', (25, 33))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('malignancies', 'Disease', (191, 203))	('mutations', 'Var', (6, 15))
158064	31131326	In addition to brain cancers, somatic IDH mutations frequently occur in AML and less frequently in MDS and MPNs.	('AML', 'Disease', 'MESH:D015470', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('occur', 'Reg', (63, 68))	('AML', 'Phenotype', 'HP:0004808', (72, 75))	('AML', 'Disease', (72, 75))	('brain cancers', 'Disease', 'MESH:D001932', (15, 28))	('brain cancers', 'Disease', (15, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('MDS', 'Disease', (99, 102))	('MDS', 'Disease', 'MESH:D009190', (99, 102))	('MPNs', 'Phenotype', 'HP:0005547', (107, 111))	('mutations', 'Var', (42, 51))
158065	31131326	IDH mutations also contribute to the pathogenesis of skeletal disorders, including Ollier disease, defined by multiple centralized cartilaginous tumors, and Maffucci syndrome, which is characterized by soft tissue spindle cell hemangiomas accompanying cartilaginous tumors.	('cartilaginous tumors', 'Disease', (131, 151))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (157, 174))	('IDH', 'Gene', (0, 3))	('Ollier disease', 'Disease', 'MESH:D004687', (83, 97))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (131, 151))	('Ollier disease', 'Disease', (83, 97))	('skeletal disorders', 'Phenotype', 'HP:0000924', (53, 71))	('Ollier disease', 'Phenotype', 'HP:0500045', (83, 97))	('Maffucci syndrome', 'Disease', (157, 174))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('contribute', 'Reg', (19, 29))	('cartilaginous tumors', 'Disease', (252, 272))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('mutations', 'Var', (4, 13))	('skeletal disorders', 'Disease', 'MESH:C538496', (53, 71))	('hemangiomas', 'Disease', (227, 238))	('hemangiomas', 'Phenotype', 'HP:0001028', (227, 238))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (252, 272))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('hemangiomas', 'Disease', 'MESH:D006391', (227, 238))	('skeletal disorders', 'Disease', (53, 71))
158066	31131326	IDH mutations also define central chondrosarcoma, central and periosteal chondromas, and intracranial chondrosarcoma and have been identified in angioimmunoblastic T cell lymphoma, cholangiocarcinoma, and thyroid carcinomas and as a hallmark of a unique subtype of breast cancer known as solid papillary carcinoma with reverse polarity (Fig.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (34, 48))	('intracranial chondrosarcoma', 'Disease', 'MESH:D002813', (89, 116))	('chondrosarcoma', 'Disease', 'MESH:D002813', (102, 116))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (205, 223))	('chondrosarcoma', 'Disease', (102, 116))	('angioimmunoblastic T cell lymphoma', 'Disease', 'MESH:D016399', (145, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('thyroid carcinomas', 'Disease', (205, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinomas', 'Phenotype', 'HP:0030731', (213, 223))	('solid papillary carcinoma', 'Disease', (288, 313))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (164, 179))	('chondromas', 'Disease', (73, 83))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (102, 116))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (205, 223))	('intracranial chondrosarcoma', 'Disease', (89, 116))	('chondromas', 'Disease', 'MESH:D002812', (73, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (181, 199))	('solid papillary carcinoma', 'Disease', 'MESH:D002291', (288, 313))	('breast cancer', 'Phenotype', 'HP:0003002', (265, 278))	('mutations', 'Var', (4, 13))	('cholangiocarcinoma', 'Disease', (181, 199))	('chondrosarcoma', 'Disease', (34, 48))	('chondrosarcoma', 'Disease', 'MESH:D002813', (34, 48))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (181, 199))	('angioimmunoblastic T cell lymphoma', 'Disease', (145, 179))	('identified', 'Reg', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('lymphoma', 'Phenotype', 'HP:0002665', (171, 179))	('cell lymphoma', 'Phenotype', 'HP:0012191', (166, 179))	('breast cancer', 'Disease', 'MESH:D001943', (265, 278))	('breast cancer', 'Disease', (265, 278))
158067	31131326	Mutations of IDH genes in the aforementioned cancers are predominantly heterozygous.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('IDH genes', 'Gene', (13, 22))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))
158068	31131326	Patients diagnosed with IDH1 mutant GBM have a more favorable prognosis as compared to patients with IDH1 wild-type GBM.	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('mutant', 'Var', (29, 35))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (24, 28))	('patients', 'Species', '9606', (87, 95))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
158070	31131326	For example, AML patients harboring the same IDH2Arg140 mutation in conjunction with a mutation in nucleophosmin 1 (NMP1) have been identified as having a worse overall survival.	('IDH2Arg140', 'Gene', (45, 55))	('AML', 'Disease', 'MESH:D015470', (13, 16))	('IDH2Arg140', 'Chemical', '-', (45, 55))	('AML', 'Phenotype', 'HP:0004808', (13, 16))	('patients', 'Species', '9606', (17, 25))	('AML', 'Disease', (13, 16))	('mutation', 'Var', (56, 64))
158071	31131326	Other studies, however, did not find association between the overall survival of AML patients and the occurrence of IDH1Arg132, IDH2Arg140, or IDH2Arg172 mutations.	('IDH1Arg132', 'Gene', (116, 126))	('IDH2Arg172', 'Gene', (143, 153))	('Arg132', 'Chemical', '-', (120, 126))	('AML', 'Disease', 'MESH:D015470', (81, 84))	('IDH2Arg140', 'Gene', (128, 138))	('AML', 'Phenotype', 'HP:0004808', (81, 84))	('patients', 'Species', '9606', (85, 93))	('AML', 'Disease', (81, 84))	('IDH2Arg140', 'Chemical', '-', (128, 138))	('mutations', 'Var', (154, 163))
158072	31131326	In contrast, IDH mutations have been consistently associated with poor prognosis and the presence of late-stage disease in both MDS and MPN, suggesting that IDH mutation may contribute to or drive the progression of chronic MDS and MPN to leukemia.	('MDS', 'Disease', 'MESH:D009190', (224, 227))	('late-stage disease', 'Disease', (101, 119))	('MDS', 'Disease', (128, 131))	('drive', 'PosReg', (191, 196))	('MPN to leukemia', 'Disease', (232, 247))	('MDS', 'Disease', 'MESH:D009190', (128, 131))	('MPN to leukemia', 'Disease', 'MESH:D007938', (232, 247))	('late-stage disease', 'Disease', 'MESH:D058625', (101, 119))	('leukemia', 'Phenotype', 'HP:0001909', (239, 247))	('mutation', 'Var', (161, 169))	('contribute', 'Reg', (174, 184))	('mutations', 'Var', (17, 26))	('MDS', 'Disease', (224, 227))	('IDH', 'Gene', (157, 160))
158073	31131326	Mutations in IDH1 and IDH2 are neomorphic gain-of-function mutations, which affect cofactor binding affinity and conformation of the enzymes' active center.	('affect', 'Reg', (76, 82))	('IDH2', 'Chemical', '-', (22, 26))	('IDH2', 'Gene', (22, 26))	('cofactor', 'MPA', (83, 91))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('gain-of-function', 'PosReg', (42, 58))	('conformation', 'MPA', (113, 125))
158074	31131326	Arg100 and Arg132 in IDH1 and Arg140 and Arg172 in IDH2 form hydrogen bonds with the alpha-carboxyl and beta-carboxyl groups of ICT.	('IDH2', 'Chemical', '-', (51, 55))	('Arg140', 'Chemical', '-', (30, 36))	('Arg172', 'Chemical', '-', (41, 47))	('ICT', 'Chemical', 'MESH:C034219', (128, 131))	('hydrogen', 'Chemical', 'MESH:D006859', (61, 69))	('Arg172', 'Var', (41, 47))	('form', 'Reg', (56, 60))	('Arg132', 'Chemical', '-', (11, 17))	('Arg100', 'Chemical', '-', (0, 6))	('IDH2', 'Gene', (51, 55))	('Arg100', 'Var', (0, 6))	('Arg132', 'Var', (11, 17))	('Arg140', 'Var', (30, 36))	('hydrogen', 'Interaction', (61, 69))
158075	31131326	When mutated, the enzymes' binding affinity to ICT decreases, while affinity to NADPH increases.	('increases', 'PosReg', (86, 95))	('affinity', 'MPA', (68, 76))	('decreases', 'NegReg', (51, 60))	('AD', 'Phenotype', 'HP:0002511', (81, 83))	('mutated', 'Var', (5, 12))	('ICT', 'Protein', (47, 50))	('ICT', 'Chemical', 'MESH:C034219', (47, 50))	('binding affinity', 'Interaction', (27, 43))
158076	31131326	As a consequence, mutations abrogate the IDH forward reaction (i.e., the oxidative decarboxylation of ICT to alphaKG) and, due to the ensuing conformational change of the active center, result in the catalysis of a partial reverse reaction, in which alphaKG is reduced to (R)-2-hydroxyglutarate [(R)-2HG] but not further carboxylated.	('catalysis', 'MPA', (200, 209))	('result in', 'Reg', (186, 195))	('(R)-2-hydroxyglutarate', 'Chemical', '-', (272, 294))	('(R)-2HG', 'Chemical', '-', (296, 303))	('IDH forward reaction', 'MPA', (41, 61))	('conformational', 'MPA', (142, 156))	('oxidative decarboxylation', 'MPA', (73, 98))	('ICT', 'Chemical', 'MESH:C034219', (102, 105))	('abrogate', 'NegReg', (28, 36))	('mutations', 'Var', (18, 27))
158077	31131326	All neomorphic IDH mutant enzymes produce (R)-2HG; their allelic frequency, enzymatic property, and association with overall prognosis, however, are markedly different.	('(R)-2HG', 'Chemical', '-', (42, 49))	('mutant', 'Var', (19, 25))	('enzymes', 'Enzyme', (26, 33))	('neomorphic IDH', 'Gene', (4, 18))	('produce', 'Reg', (34, 41))
158079	31131326	Reflecting its lower intrinsic enzymatic activity, IDH2Arg140 produces less (R)-2HG.	('intrinsic enzymatic activity', 'MPA', (21, 49))	('IDH2Arg140', 'Var', (51, 61))	('IDH2Arg140', 'Chemical', '-', (51, 61))	('less', 'NegReg', (71, 75))	('(R)-2HG', 'Chemical', '-', (76, 83))	('lower', 'NegReg', (15, 20))
158081	31131326	This suggests that the lower (R)-2HG levels produced by IDH2Arg140 do not adversely affect embryogenesis and perinatal development; other germline IDH mutations, however, due to enhanced generation of pathogenic (R)-2HG, are lethal in utero.	('enhanced', 'PosReg', (178, 186))	('(R)-2HG', 'Chemical', '-', (29, 36))	('(R)-2HG', 'Chemical', '-', (212, 219))	('IDH2Arg140', 'Gene', (56, 66))	('IDH2Arg140', 'Chemical', '-', (56, 66))	('IDH', 'Gene', (147, 150))	('mutations', 'Var', (151, 160))
158082	31131326	Similarly, while Arg132 in IDH1 and Arg172 in IDH2 are structurally analogous residues important for alphaKG substrate binding, the cytoplasmic and peroxisomal IDH1Arg132 mutant enzyme produces less (R)-2HG compared to mitochondrial IDH2Arg172.	('IDH1Arg132', 'Gene', (160, 170))	('IDH2', 'Chemical', '-', (233, 237))	('Arg172', 'Chemical', '-', (237, 243))	('(R)-2HG', 'Chemical', '-', (199, 206))	('less', 'NegReg', (194, 198))	('Arg132', 'Chemical', '-', (164, 170))	('Arg132', 'Chemical', '-', (17, 23))	('IDH2', 'Chemical', '-', (46, 50))	('Arg132', 'Var', (17, 23))	('mutant', 'Var', (171, 177))	('Arg172', 'Chemical', '-', (36, 42))	('Arg172', 'Var', (36, 42))
158083	31131326	Targeting of mutant IDH1 to mitochondria results in enhanced (R)-2HG production, suggesting that IDH1 and IDH2 mutant enzymes have similar intrinsic enzymatic activity and that their activity is regulated through subcellular localization.	('mutant', 'Var', (13, 19))	('IDH2', 'Chemical', '-', (106, 110))	('IDH1', 'Gene', (97, 101))	('mutant', 'Var', (111, 117))	('IDH2', 'Gene', (106, 110))	('enhanced', 'PosReg', (52, 60))	('IDH1', 'Gene', (20, 24))	('(R)-2HG', 'Chemical', '-', (61, 68))
158085	31131326	Less abundant alphaKG levels in the cytosol result in lower (R)-2HG production by IDH1Arg132.	('IDH1Arg132', 'Var', (82, 92))	('alphaKG', 'Protein', (14, 21))	('Arg132', 'Chemical', '-', (86, 92))	('(R)-2HG', 'Chemical', '-', (60, 67))	('lower', 'NegReg', (54, 59))
158086	31131326	This functional interplay between mutant and wild-type IDH1 enzymes also suggests that targeting the remaining wild-type IDH1 allele to reduce local alphaKG availability may represent an additional therapeutic strategy to mitigate protumor effects of IDH1 mutation.	('local', 'MPA', (143, 148))	('IDH1', 'Gene', (121, 125))	('tumor', 'Disease', (234, 239))	('mutation', 'Var', (256, 264))	('reduce', 'NegReg', (136, 142))	('alphaKG', 'Protein', (149, 156))	('IDH1', 'Gene', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
158089	31131326	When expressed in a wide spectrum of primary and immortalized cells in vitro, including astrocytes, fibroblasts, erythroleukemia, murine hematopoietic stem, and myeloid progenitor cells, tumor-derived mutant IDH enzymes can stimulate proliferation, antagonize differentiation, and, together with concomitantly expressed oncogenes, promote soft agar colony formation and transformation.	('proliferation', 'CPA', (234, 247))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('IDH enzymes', 'Gene', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('murine', 'Species', '10090', (130, 136))	('antagonize', 'NegReg', (249, 259))	('mutant', 'Var', (201, 207))	('tumor', 'Disease', (187, 192))	('stimulate', 'PosReg', (224, 233))	('erythroleukemia', 'Disease', 'MESH:D004915', (113, 128))	('differentiation', 'CPA', (260, 275))	('erythroleukemia', 'Disease', (113, 128))	('transformation', 'CPA', (370, 384))	('soft agar colony formation', 'CPA', (339, 365))	('promote', 'PosReg', (331, 338))
158090	31131326	In particular, mutant IDH expression in immortalized astrocytes promotes proliferation and colony formation and, when expressed in erythroleukemia cells, induces differentiation and promotes proliferation independently of stimulation with growth factors.	('promotes', 'PosReg', (64, 72))	('induces', 'Reg', (154, 161))	('proliferation', 'CPA', (73, 86))	('colony formation', 'CPA', (91, 107))	('erythroleukemia', 'Disease', (131, 146))	('erythroleukemia', 'Disease', 'MESH:D004915', (131, 146))	('differentiation', 'CPA', (162, 177))	('IDH', 'Gene', (22, 25))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('promotes', 'PosReg', (182, 190))	('proliferation', 'CPA', (191, 204))	('mutant', 'Var', (15, 21))
158091	31131326	Studies in mice harboring conditional IDH1 and IDH2 mutant knockin alleles revealed that mutant IDH enzymes alone are insufficient to transform primary cells in vivo and instead require cooperating genetic events to promote tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (224, 229))	('promote', 'PosReg', (216, 223))	('mice', 'Species', '10090', (11, 15))	('IDH2', 'Chemical', '-', (47, 51))	('IDH enzymes', 'Gene', (96, 107))	('mutant', 'Var', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
158092	31131326	Studies using the aforementioned lox-stop-lox-controlled IDH1R132H allele, when expressed heterozygously and activated by Cre recombinase in either neural progenitor or hematopoietic cells, revealed that IDH1 mutation is insufficient to provoke a cancer phenotype.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('IDH1', 'Gene', (204, 208))	('IDH1R132H', 'Gene', (57, 66))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('mutation', 'Var', (209, 217))	('provoke', 'Reg', (237, 244))
158093	31131326	IDH1R132H expression in neural progenitor cells (NPCs) results in extensive cerebral hemorrhage and perinatal lethality.	('results in', 'Reg', (55, 65))	('cerebral hemorrhage', 'Disease', 'MESH:D002543', (76, 95))	('cerebral hemorrhage', 'Disease', (76, 95))	('perinatal lethality', 'CPA', (100, 119))	('IDH1R132H expression', 'Var', (0, 20))	('cerebral hemorrhage', 'Phenotype', 'HP:0001342', (76, 95))
158094	31131326	On molecular levels, high-level accumulation of (R)-2HG inhibits prolyl-hydroxylation and subsequent maturation of collagen.	('R)-2HG', 'Var', (49, 55))	('prolyl-hydroxylation', 'MPA', (65, 85))	('(R)-2HG', 'Chemical', '-', (48, 55))	('inhibits', 'NegReg', (56, 64))	('maturation of collagen', 'CPA', (101, 123))
158097	31131326	When heterozygously expressed in human neural stem cells (NSCs) modified for p53 and ATRX loss, IDH1 mutation promotes low-grade glioma formation in mice.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('ATRX', 'Gene', (85, 89))	('ATRX', 'Gene', '546', (85, 89))	('promotes', 'PosReg', (110, 118))	('human', 'Species', '9606', (33, 38))	('mice', 'Species', '10090', (149, 153))	('glioma', 'Disease', (129, 135))	('mutation', 'Var', (101, 109))	('IDH1', 'Gene', (96, 100))
158101	31131326	Studies using a genetically engineered AML mouse model with conditional monoallelic expression of IDH2R140Q indicated that IDH2 mutation cooperate with HoxA9 and Meis1a overexpression and with mutations in FMS-like tyrosine kinase 3 (FLT3) to initiate and maintain acute leukemia in vivo.	('FLT3', 'Gene', (234, 238))	('HoxA9', 'Gene', (152, 157))	('AML', 'Disease', 'MESH:D015470', (39, 42))	('IDH2', 'Gene', (123, 127))	('acute leukemia', 'Disease', (265, 279))	('acute leukemia', 'Disease', 'MESH:D015470', (265, 279))	('acute leukemia', 'Phenotype', 'HP:0002488', (265, 279))	('FMS-like tyrosine kinase 3', 'Gene', (206, 232))	('leukemia', 'Phenotype', 'HP:0001909', (271, 279))	('mutations', 'Var', (193, 202))	('AML', 'Disease', (39, 42))	('IDH2', 'Chemical', '-', (98, 102))	('AML', 'Phenotype', 'HP:0004808', (39, 42))	('mutation', 'Var', (128, 136))	('HoxA9', 'Gene', '15405', (152, 157))	('mouse', 'Species', '10090', (43, 48))	('IDH2', 'Chemical', '-', (123, 127))	('FMS-like tyrosine kinase 3', 'Gene', '14255', (206, 232))
158102	31131326	The impact of conditional expression of mutant IDHs on tumor progression has also been confirmed in other murine cancer models, which include models of enchondromas, T cell acute lymphoblastic leukemia, and angioimmunoblastic T cell lymphoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lymphoblastic leukemia', 'Disease', (179, 201))	('cancer', 'Disease', (113, 119))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (173, 201))	('cell lymphoma', 'Phenotype', 'HP:0012191', (228, 241))	('lymphoma', 'Phenotype', 'HP:0002665', (233, 241))	('angioimmunoblastic T cell lymphoma', 'Disease', (207, 241))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('IDHs', 'Gene', (47, 51))	('enchondromas', 'Disease', (152, 164))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (179, 201))	('mutant', 'Var', (40, 46))	('angioimmunoblastic T cell lymphoma', 'Disease', 'MESH:D016399', (207, 241))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('enchondromas', 'Phenotype', 'HP:0030038', (152, 164))	('leukemia', 'Phenotype', 'HP:0001909', (193, 201))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (226, 241))	('tumor', 'Disease', (55, 60))	('murine', 'Species', '10090', (106, 112))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (179, 201))	('enchondromas', 'Disease', 'MESH:D002812', (152, 164))
158106	31131326	Expression of IDH mutant enzymes, which exclusively generate the (R)-enantiomer, results in elevated (R)-2HG levels, which can range from 1 mM to as high as 30 mM in cells and exceeds 3 mM within a 2-cm radius from the center of an IDH mutant glioma.	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('IDH', 'Gene', (14, 17))	('mutant', 'Var', (18, 24))	('elevated', 'PosReg', (92, 100))	('IDH', 'Gene', (232, 235))	('mutant', 'Var', (236, 242))	('(R)-2HG', 'Chemical', '-', (101, 108))	('glioma', 'Disease', (243, 249))	('enzymes', 'Gene', (25, 32))
158109	31131326	High intracellular accumulation of (R)-2HG suggests that the rate of (R)-2HG production by mutant IDHs exceeds the rate of (R)-2HG oxidation by 2HGDH.	('(R)-2HG', 'Chemical', '-', (123, 130))	('(R)-2HG', 'Chemical', '-', (35, 42))	('IDHs', 'Gene', (98, 102))	('(R)-2HG', 'Chemical', '-', (69, 76))	('mutant', 'Var', (91, 97))
158110	31131326	Mutant IDH effect on cellular growth and differentiation can be mimicked by continuous addition of cell-permeable (R)-2HG, indicating that sustained provision of high intracellular concentrations of (R)-2HG is necessary and sufficient to mediate oncogenic effect of mutant IDHs.	('IDH', 'Gene', (7, 10))	('(R)-2HG', 'Chemical', '-', (199, 206))	('mutant', 'Var', (266, 272))	('(R)-2HG', 'Chemical', '-', (114, 121))	('Mutant', 'Var', (0, 6))
158113	31131326	IDH mutant tumors through accumulation of (R)-2HG progressively accumulate irreversible changes in the DNA and histone methylation landscape.	('accumulation', 'PosReg', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (4, 10))	('changes', 'Reg', (88, 95))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('(R)-2HG', 'Chemical', '-', (42, 49))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('accumulate', 'PosReg', (64, 74))
158114	31131326	IDH mutant gliomas showed extensive hypermethylation at CCCTC-binding factor (CTCF)-binding sites, DNA insulator sequences that block the interaction between enhancers and promoters.	('CTCF', 'Gene', '10664', (78, 82))	('mutant', 'Var', (4, 10))	('hypermethylation', 'MPA', (36, 52))	('interaction', 'Interaction', (138, 149))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('CTCF', 'Gene', (78, 82))	('CCCTC-binding factor', 'Gene', (56, 76))	('CCCTC-binding factor', 'Gene', '10664', (56, 76))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
158115	31131326	Hypermethylation reduces CTCF binding to DNA, impedes insulator function, and causes a constitutive enhancer to interact aberrantly with PDGF receptor alpha, a receptor tyrosine kinase and prominent glioma oncogene.	('reduces', 'NegReg', (17, 24))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('CTCF', 'Gene', (25, 29))	('causes', 'Reg', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('PD', 'Disease', 'MESH:D010300', (137, 139))	('Hypermethylation', 'Var', (0, 16))	('CTCF', 'Gene', '10664', (25, 29))	('interact', 'Interaction', (112, 120))	('insulator function', 'MPA', (54, 72))	('binding', 'Interaction', (30, 37))	('glioma', 'Disease', (199, 205))	('impedes', 'NegReg', (46, 53))
158116	31131326	It is likely that hypermethylation of CTCF-binding sites through impact on chromatin topography modulates the expression of other genes implicated in (brain) cancer pathogenesis.	('CTCF', 'Gene', (38, 42))	('hypermethylation', 'Var', (18, 34))	('chromatin', 'MPA', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('modulates', 'Reg', (96, 105))	('cancer', 'Disease', (158, 164))	('CTCF', 'Gene', '10664', (38, 42))	('expression', 'MPA', (110, 120))	('impact', 'Reg', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
158118	31131326	Mutual exclusivity of IDH1 and TET2 mutation in certain cancer types, particularly in AML, led to the widely accepted paradigm that mutant IDH1 modulates tumorigenesis through effect on TET2 activity to alter the tumor epigenetic landscape.	('modulates', 'Reg', (144, 153))	('TET2', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Disease', (56, 62))	('tumor', 'Disease', (154, 159))	('TET2', 'Gene', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('AML', 'Disease', 'MESH:D015470', (86, 89))	('TET2', 'Gene', '54790', (31, 35))	('AML', 'Phenotype', 'HP:0004808', (86, 89))	('AML', 'Disease', (86, 89))	('effect', 'Reg', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', (213, 218))	('TET2', 'Gene', '54790', (186, 190))	('IDH1', 'Gene', (139, 143))	('mutant', 'Var', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('alter', 'Reg', (203, 208))
158119	31131326	The lack of complete phenotypic overlap between IDH1 mutant and TET2 mutant cancers, however, suggests that IDH1 can modulate leukemogenesis independently of TET2.	('leukemogenesis', 'Disease', (126, 140))	('modulate', 'Reg', (117, 125))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('mutant', 'Var', (69, 75))	('cancers', 'Disease', (76, 83))	('TET2', 'Gene', '54790', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('TET2', 'Gene', '54790', (158, 162))	('TET2', 'Gene', (64, 68))	('mutant', 'Var', (53, 59))	('IDH1', 'Gene', (48, 52))	('TET2', 'Gene', (158, 162))
158120	31131326	In AML, mutations in the Wilm's tumor suppressor 1 (WT1), a zinc finger-containing transcription factor, are mutually exclusive from TET2 and IDH1/IDH2 mutations.	("Wilm's tumor suppressor 1", 'Gene', '7490', (25, 50))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (25, 37))	('TET2', 'Gene', '54790', (133, 137))	('mutations', 'Var', (8, 17))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('WT1', 'Gene', '7490', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TET2', 'Gene', (133, 137))	("Wilm's tumor suppressor 1", 'Gene', (25, 50))	('WT1', 'Gene', (52, 55))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('IDH2', 'Chemical', '-', (147, 151))	('AML', 'Disease', (3, 6))
158121	31131326	WT1 mutant AML showed a global reduction in 5hmC levels comparable to levels observed in TET2 and IDH1/2 mutant AML.	('TET2', 'Gene', (89, 93))	('reduction', 'NegReg', (31, 40))	('mutant', 'Var', (4, 10))	('WT1', 'Gene', '7490', (0, 3))	('AML', 'Disease', 'MESH:D015470', (112, 115))	('5hmC', 'Chemical', 'MESH:C011865', (44, 48))	('WT1', 'Gene', (0, 3))	('TET2', 'Gene', '54790', (89, 93))	('5hmC levels', 'MPA', (44, 55))	('AML', 'Disease', 'MESH:D015470', (11, 14))	('AML', 'Phenotype', 'HP:0004808', (112, 115))	('AML', 'Disease', (112, 115))	('AML', 'Phenotype', 'HP:0004808', (11, 14))	('AML', 'Disease', (11, 14))
158123	31131326	Analysis of mice harboring IDH1 mutant expression within their hematopoietic system, together with analysis of AML patient tumors, demonstrated that mutant IDH1 down-regulates ataxia telangiectasia mutated (ATM) through effect on histone methylation, resulting in impaired DNA repair, increased sensitivity to DNA damage, and reduced hematopoietic stem cell renewal.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('DNA repair', 'MPA', (273, 283))	('increased', 'PosReg', (285, 294))	('effect', 'Reg', (220, 226))	('ATM', 'Gene', (207, 210))	('telangiectasia', 'Phenotype', 'HP:0001009', (183, 197))	('ataxia', 'Phenotype', 'HP:0001251', (176, 182))	('mice', 'Species', '10090', (12, 16))	('impaired', 'NegReg', (264, 272))	('reduced', 'NegReg', (326, 333))	('ataxia telangiectasia mutated', 'Gene', '472', (176, 205))	('AML', 'Disease', 'MESH:D015470', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('IDH1', 'Gene', (156, 160))	('AML', 'Disease', (111, 114))	('mutant', 'Var', (149, 155))	('AML', 'Phenotype', 'HP:0004808', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('sensitivity to DNA damage', 'MPA', (295, 320))	('histone methylation', 'MPA', (230, 249))	('ATM', 'Gene', '472', (207, 210))	('down-regulates', 'NegReg', (161, 175))	('hematopoietic stem cell renewal', 'CPA', (334, 365))	('patient', 'Species', '9606', (115, 122))	('ataxia telangiectasia mutated', 'Gene', (176, 205))
158124	31131326	Similarly, in glioma cells and tumors, IDH1 mutation through production of (R)-2HG inhibits ALKBH DNA repair enzyme and, in so doing, reduces DNA repair kinetics, increases DNA damage, and sensitizes glioma cells to alkylating agents.	('glioma', 'Disease', (14, 20))	('mutation', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('increases', 'PosReg', (163, 172))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Disease', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('IDH1', 'Gene', (39, 43))	('ALKBH', 'Gene', '8846', (92, 97))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('reduces', 'NegReg', (134, 141))	('ALKBH', 'Gene', (92, 97))	('inhibits', 'NegReg', (83, 91))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('(R)-2HG', 'Chemical', '-', (75, 82))	('DNA repair kinetics', 'MPA', (142, 161))	('sensitizes', 'Reg', (189, 199))	('DNA damage', 'MPA', (173, 183))
158127	31131326	These amino acids are essential for cellular growth, and mutations in BCAT1 and BCAT2 result in autosomal recessive disorders, termed hypervalinemia and hyperleucine-isoleucinemia.	('hyperleucine-isoleucinemia', 'Disease', 'MESH:C562674', (153, 179))	('result in', 'Reg', (86, 95))	('-isoleucinemia', 'Phenotype', 'HP:0500144', (165, 179))	('hypervalinemia', 'Disease', (134, 148))	('hyperleucine-isoleucinemia', 'Phenotype', 'HP:0010913', (153, 179))	('hypervalinemia', 'Disease', 'MESH:C536524', (134, 148))	('BCAT1', 'Gene', '586', (70, 75))	('BCAT2', 'Gene', '587', (80, 85))	('autosomal recessive disorders', 'Disease', 'MESH:D030342', (96, 125))	('BCAT2', 'Gene', (80, 85))	('mutations', 'Var', (57, 66))	('hypervalinemia', 'Phenotype', 'HP:0010910', (134, 148))	('BCAT1', 'Gene', (70, 75))	('hyperleucine-isoleucinemia', 'Disease', (153, 179))	('hyperleucine-', 'Phenotype', 'HP:0010911', (153, 166))	('autosomal recessive disorders', 'Disease', (96, 125))
158128	31131326	Mutant IDH1-derived (R)-2HG can inhibit BCAT activity and, in so doing, decreases glutamate levels and increases glioma cell dependency on glutaminase for the synthesis of glutamate and glutathione.	('glutathione', 'Chemical', 'MESH:D005978', (186, 197))	('glutaminase', 'Gene', (139, 150))	('increases glioma', 'Disease', (103, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('inhibit', 'NegReg', (32, 39))	('decreases', 'NegReg', (72, 81))	('BCAT', 'Enzyme', (40, 44))	('glutamate', 'Chemical', 'MESH:D018698', (172, 181))	('decreases glutamate levels', 'Phenotype', 'HP:0500150', (72, 98))	('glutamate levels', 'MPA', (82, 98))	('glutaminase', 'Gene', '2744', (139, 150))	('(R)-2HG', 'Chemical', '-', (20, 27))	('IDH1-derived', 'Gene', (7, 19))	('increases glioma', 'Disease', 'MESH:D005910', (103, 119))	('Mutant', 'Var', (0, 6))	('glutamate', 'Chemical', 'MESH:D018698', (82, 91))
158129	31131326	As a result, IDH1R132H-expressing glioma cells and derivative orthotopic tumors are uniquely sensitive to pharmacological inhibition of glutaminase.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH1R132H-expressing', 'Var', (13, 33))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('glutaminase', 'Gene', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('sensitive', 'Reg', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('glutaminase', 'Gene', '2744', (136, 147))	('glioma', 'Disease', (34, 40))	('tumors', 'Disease', (73, 79))
158130	31131326	In addition to competitive inhibition of BCAT enzymatic activity by (R)-2HG, IDH1 mutation down-regulates BCAT expression through epigenetic effects, demonstrating that IDH1 mutant gliomas regulate BCAT activity through enzyme inhibition and epigenetic control of expression.	('down-regulates', 'NegReg', (91, 105))	('(R)-2HG', 'Chemical', '-', (68, 75))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('mutation', 'Var', (82, 90))	('IDH1', 'Gene', (169, 173))	('BCAT', 'Enzyme', (198, 202))	('IDH1', 'Gene', (77, 81))	('expression', 'MPA', (111, 121))	('regulate', 'Reg', (189, 197))	('BCAT', 'Enzyme', (106, 110))	('gliomas', 'Disease', (181, 188))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('activity', 'MPA', (203, 211))	('mutant', 'Var', (174, 180))
158132	31131326	BCAT1 knockdown causes accumulation of alphaKG, which, through activation of EGLN1, triggers HIF-1alpha protein degradation and growth arrest.	('growth arrest', 'Disease', (128, 141))	('alphaKG', 'Protein', (39, 46))	('triggers', 'Reg', (84, 92))	('HIF-1alpha', 'Gene', (93, 103))	('BCAT1', 'Gene', (0, 5))	('EGLN1', 'Gene', (77, 82))	('growth arrest', 'Phenotype', 'HP:0001510', (128, 141))	('growth arrest', 'Disease', 'MESH:D006323', (128, 141))	('EGLN1', 'Gene', '54583', (77, 82))	('knockdown', 'Var', (6, 15))	('accumulation', 'PosReg', (23, 35))	('BCAT1', 'Gene', '586', (0, 5))	('activation', 'PosReg', (63, 73))	('HIF-1alpha', 'Gene', '3091', (93, 103))
158133	31131326	Similar to leukemia cells carrying a mutant IDH1, expression of BCAT1 in IDH1 wild-type AML cells decreases intracellular alphaKG levels and causes TET enzyme-dependent DNA hypermethylation.	('AML', 'Disease', 'MESH:D015470', (88, 91))	('TET enzyme-dependent DNA hypermethylation', 'MPA', (148, 189))	('intracellular alphaKG levels', 'MPA', (108, 136))	('leukemia', 'Phenotype', 'HP:0001909', (11, 19))	('expression', 'Var', (50, 60))	('AML', 'Disease', (88, 91))	('BCAT1', 'Gene', (64, 69))	('causes', 'Reg', (141, 147))	('leukemia', 'Disease', 'MESH:D007938', (11, 19))	('AML', 'Phenotype', 'HP:0004808', (88, 91))	('leukemia', 'Disease', (11, 19))	('decreases', 'NegReg', (98, 107))	('IDH1', 'Gene', (73, 77))	('BCAT1', 'Gene', '586', (64, 69))	('TET', 'Chemical', '-', (148, 151))
158136	31131326	Leukemia cells treated with cell-permeable (R)-2HG or engineered to express mutant IDH1 showed decreased mRNA stability of cellular Myelocytomatosis (cMYC) and CCAAT enhancer-binding protein alpha (CEBPA), suggesting that (R)-2HG, while promoting tumor initiation, can antagonize later-stage progression of blood cancers.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('(R)-2HG', 'Chemical', '-', (43, 50))	('cMYC', 'Gene', '4609', (150, 154))	('blood cancers', 'Disease', (307, 320))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('Myelocytomatosis', 'Disease', (132, 148))	('antagonize', 'NegReg', (269, 279))	('Myelocytomatosis', 'Disease', 'None', (132, 148))	('CEBPA', 'Gene', '1050', (198, 203))	('Leukemia', 'Phenotype', 'HP:0001909', (0, 8))	('CCAAT enhancer-binding protein alpha', 'Gene', '1050', (160, 196))	('decreased', 'NegReg', (95, 104))	('(R)-2HG', 'Chemical', '-', (222, 229))	('Leukemia', 'Disease', 'MESH:D007938', (0, 8))	('tumor', 'Disease', (247, 252))	('CEBPA', 'Gene', (198, 203))	('CCAAT enhancer-binding protein alpha', 'Gene', (160, 196))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('IDH1', 'Gene', (83, 87))	('mRNA stability', 'MPA', (105, 119))	('cMYC', 'Gene', (150, 154))	('blood cancers', 'Disease', 'MESH:D007022', (307, 320))	('mutant', 'Var', (76, 82))	('Leukemia', 'Disease', (0, 8))	('blood cancers', 'Phenotype', 'HP:0001909', (307, 320))	('cancers', 'Phenotype', 'HP:0002664', (313, 320))	('promoting', 'PosReg', (237, 246))
158137	31131326	Furthermore, (R)-2HG can directly impair mitochondrial energy metabolism by inhibiting complex IV (cytochrome c oxidase) and complex V (ATP synthase) of the electron transport chain.	('R)-2HG', 'Var', (14, 20))	('(R)-2HG', 'Chemical', '-', (13, 20))	('impair', 'NegReg', (34, 40))	('ATP', 'Chemical', 'MESH:D000255', (136, 139))	('inhibiting', 'NegReg', (76, 86))	('mitochondrial energy metabolism', 'MPA', (41, 72))
158140	31131326	Consistent with this model, hypersuccinylation inhibits mitochondrial respiratory function, causing mitochondrial membrane hyperpolarization and induction of B cell lymphoma 2 (Bcl-2) protein expression, which, in turn, renders hypersuccinylated cancer cells apoptosis resistant.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('mitochondrial membrane hyperpolarization', 'MPA', (100, 140))	('B cell lymphoma 2', 'Gene', (158, 175))	('cancer', 'Disease', (246, 252))	('expression', 'MPA', (192, 202))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (158, 173))	('induction', 'Reg', (145, 154))	('Bcl-2', 'Gene', (177, 182))	('apoptosis resistant', 'CPA', (259, 278))	('Bcl-2', 'Gene', '596', (177, 182))	('mitochondrial respiratory function', 'MPA', (56, 90))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('lymphoma', 'Phenotype', 'HP:0002665', (165, 173))	('hypersuccinylation', 'Var', (28, 46))	('cell lymphoma', 'Phenotype', 'HP:0012191', (160, 173))	('B cell lymphoma 2', 'Gene', '596', (158, 175))	('inhibits', 'NegReg', (47, 55))
158141	31131326	Up-regulation of Bcl-2 can be exploited by treating IDH1 mutant cells with Bcl-2 inhibitors, as detailed below and summarized in Table 1.	('Bcl-2', 'Gene', (17, 22))	('Bcl-2', 'Gene', '596', (17, 22))	('mutant', 'Var', (57, 63))	('Bcl-2', 'Gene', (75, 80))	('Bcl-2', 'Gene', '596', (75, 80))	('IDH1', 'Gene', (52, 56))
158145	31131326	Elevated levels of (S)-2HG in the urine, plasma, and cerebral spinal fluid were found to be associated with psychomotor retardation, dystrophy, delayed skeletal age, and progressive central nervous system (CNS) deterioration.	('S)-2HG', 'Var', (20, 26))	('dystrophy', 'Disease', (133, 142))	('dystrophy', 'Disease', 'MESH:D008268', (133, 142))	('psychomotor retardation', 'Disease', (108, 131))	('delayed skeletal age', 'Phenotype', 'HP:0002750', (144, 164))	('psychomotor retardation', 'Disease', 'MESH:D011596', (108, 131))	('delayed skeletal age', 'CPA', (144, 164))	('associated', 'Reg', (92, 102))	('central nervous system (CNS) deterioration', 'Disease', 'MESH:D002493', (182, 224))	('psychomotor retardation', 'Phenotype', 'HP:0025356', (108, 131))
158147	31131326	Recessive D2HGDH mutation accounts for roughly half of all R2HGA cases, while autosomal dominant, heterozygous germline mutations in IDH2 characterize the remaining R2HGA cases (Fig.	('R2HGA', 'Disease', (59, 64))	('D2HGDH', 'Gene', (10, 16))	('IDH2', 'Gene', (133, 137))	('mutation', 'Var', (17, 25))	('D2HGDH', 'Gene', '728294', (10, 16))	('IDH2', 'Chemical', '-', (133, 137))
158148	31131326	R2HGA cases defined by IDH2 mutation exhibit a worse prognosis with more severe symptoms, including ataxia.	('R2HGA', 'Disease', (0, 5))	('IDH2', 'Gene', (23, 27))	('ataxia', 'Phenotype', 'HP:0001251', (100, 106))	('ataxia', 'Disease', 'MESH:D001259', (100, 106))	('mutation', 'Var', (28, 36))	('ataxia', 'Disease', (100, 106))	('IDH2', 'Chemical', '-', (23, 27))
158150	31131326	Combined S2HGA/R2HGA (type III) is characterized by elevated levels of both (S)-2HG and (R)-2HG.	('S2HGA/R2HGA', 'Var', (9, 20))	('levels', 'MPA', (61, 67))	('(R)-2HG', 'Chemical', '-', (88, 95))	('elevated', 'PosReg', (52, 60))
158153	31131326	Recently, recessive mutation in SLC25A1, the mitochondrial citrate carrier, was identified as the cause of type III 2HGA.	('cause', 'Reg', (98, 103))	('citrate', 'Chemical', 'MESH:D019343', (59, 66))	('SLC25A1', 'Gene', '6576', (32, 39))	('SLC25A1', 'Gene', (32, 39))	('type III 2HGA', 'Disease', (107, 120))	('recessive mutation', 'Var', (10, 28))
158154	31131326	Inability to import citrate into the mitochondria impairs IDH2 and IDH3 function, likely resulting in the buildup of cytotoxic ROS.	('citrate', 'Chemical', 'MESH:D019343', (20, 27))	('cytotoxic ROS', 'MPA', (117, 130))	('buildup', 'PosReg', (106, 113))	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('IDH2', 'Chemical', '-', (58, 62))	('IDH3', 'Gene', (67, 71))	('function', 'MPA', (72, 80))	('IDH2', 'Gene', (58, 62))	('Inability', 'Var', (0, 9))	('impairs', 'NegReg', (50, 57))
158155	31131326	Mutations in IDH3A have been identified in individuals with inherited retinal diseases (IRDs), which represent a major cause of incurable blindness in children and young adults, and are characterized by progressive degeneration of photoreceptor and/or retinal pigment epithelium cells.	('IDH3A', 'Gene', '3419', (13, 18))	('blindness', 'Disease', 'MESH:D001766', (138, 147))	('identified', 'Reg', (29, 39))	('degeneration', 'Disease', 'MESH:D012162', (215, 227))	('IDH3A', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('retinal diseases', 'Phenotype', 'HP:0000479', (70, 86))	('blindness', 'Phenotype', 'HP:0000618', (138, 147))	('inherited retinal diseases', 'Disease', (60, 86))	('inherited retinal diseases', 'Disease', 'MESH:D012164', (60, 86))	('children', 'Species', '9606', (151, 159))	('degeneration', 'Disease', (215, 227))	('blindness', 'Disease', (138, 147))
158159	31131326	identified a series of additional IDH3A variants in patients diagnosed with typical autosomal recessive RP (arRP) and with arRP and macular pseudocoloboma.	('RP', 'Phenotype', 'HP:0000510', (125, 127))	('macular pseudocoloboma', 'Phenotype', 'HP:0001116', (132, 154))	('IDH3A', 'Gene', '3419', (34, 39))	('IDH3A', 'Gene', (34, 39))	('autosomal recessive RP', 'Disease', (84, 106))	('RP', 'Phenotype', 'HP:0000510', (110, 112))	('variants', 'Var', (40, 48))	('RP', 'Phenotype', 'HP:0000510', (104, 106))	('patients', 'Species', '9606', (52, 60))
158162	31131326	While mutations in IDH3C as underlying cause or contributor to neurological defect remain elusive, biallelic variants in IDH3B were also found to be associated with typical arRP, but not with arRP with macular pseudocoloboma or systemic neurological impairment.	('IDH3B', 'Gene', (121, 126))	('neurological defect', 'Disease', 'MESH:D009421', (63, 82))	('neurological impairment', 'Disease', 'MESH:D009422', (237, 260))	('neurological impairment', 'Phenotype', 'HP:0000707', (237, 260))	('RP', 'Phenotype', 'HP:0000510', (194, 196))	('biallelic variants', 'Var', (99, 117))	('neurological defect', 'Phenotype', 'HP:0000707', (63, 82))	('neurological impairment', 'Disease', (237, 260))	('associated', 'Reg', (149, 159))	('IDH3B', 'Gene', '3420', (121, 126))	('typical arRP', 'Disease', (165, 177))	('neurological defect', 'Disease', (63, 82))	('RP', 'Phenotype', 'HP:0000510', (175, 177))	('macular pseudocoloboma', 'Phenotype', 'HP:0001116', (202, 224))	('IDH3C', 'Gene', (19, 24))	('mutations', 'Var', (6, 15))
158164	31131326	Consequently, retina cells are highly sensitive to mitochondrial dysfunction as a result of IDH3 compromise.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (51, 76))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (51, 76))	('mitochondrial dysfunction', 'Disease', (51, 76))	('IDH3', 'Gene', (92, 96))	('compromise', 'Var', (97, 107))
158165	31131326	As detailed above, oncogenic mutations in IDH1 have been reported for lower-grade gliomas and mutant IDH1 GBM, which represent approximately 10% of all clinical grade IV cases.	('IDH1', 'Gene', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutations', 'Var', (29, 38))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('mutant', 'Var', (94, 100))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('IDH1', 'Gene', (42, 46))
158172	31131326	Inhibition of lipogenic enzymes leads to an increase in the level of polyunsaturation, rendering cells more susceptible to oxidative stress-induced cell death and impairing the deformability and lateral fluidity of cell membranes.	('level', 'MPA', (60, 65))	('impairing the deformability', 'Disease', (163, 190))	('oxidative stress', 'Phenotype', 'HP:0025464', (123, 139))	('polyunsaturation', 'MPA', (69, 85))	('increase', 'PosReg', (44, 52))	('Inhibition', 'Var', (0, 10))	('death', 'Disease', 'MESH:D003643', (153, 158))	('lipogenic enzymes', 'Enzyme', (14, 31))	('death', 'Disease', (153, 158))	('impairing the deformability', 'Disease', 'MESH:D060825', (163, 190))
158175	31131326	Down-regulation of IDH3alpha in the tumor stroma promotes the transformation of fibroblasts into cancer-associated fibroblasts by up-regulating HIF-1alpha and inducing a switch from oxidative phosphorylation to glycolysis.	('tumor stroma', 'Disease', (36, 48))	('oxidative phosphorylation', 'MPA', (182, 207))	('IDH3alpha', 'Gene', (19, 28))	('cancer', 'Disease', (97, 103))	('glycolysis', 'MPA', (211, 221))	('Down-regulation', 'Var', (0, 15))	('IDH3alpha', 'Gene', '3419', (19, 28))	('inducing', 'Reg', (159, 167))	('up-regulating', 'PosReg', (130, 143))	('HIF-1alpha', 'Gene', '3091', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('switch', 'MPA', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor stroma', 'Disease', 'MESH:D009369', (36, 48))	('HIF-1alpha', 'Gene', (144, 154))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
158179	31131326	Reflecting its central role in regulating TCA cycle activity and cellular respiration, IDH3alpha ablation reduces carbon flux through the TCA cycle, shunts energy metabolism, induces a shift toward increased glycolysis and pentose phosphate shunt usage, and robustly reduces the tumorigenic potential of transformed astrocytes and patient-derived glioma-initiating cells.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('glioma', 'Phenotype', 'HP:0009733', (347, 353))	('TCA', 'Chemical', 'MESH:D014233', (138, 141))	('IDH3alpha', 'Gene', '3419', (87, 96))	('carbon flux', 'MPA', (114, 125))	('IDH3alpha', 'Gene', (87, 96))	('reduces', 'NegReg', (106, 113))	('shunts', 'Reg', (149, 155))	('TCA', 'Chemical', 'MESH:D014233', (42, 45))	('TCA cycle', 'MPA', (138, 147))	('ablation', 'Var', (97, 105))	('tumor', 'Disease', (279, 284))	('carbon', 'Chemical', 'MESH:D002244', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('patient', 'Species', '9606', (331, 338))	('glioma', 'Disease', (347, 353))	('energy metabolism', 'MPA', (156, 173))	('glycolysis', 'MPA', (208, 218))	('pentose phosphate', 'Chemical', 'MESH:D010428', (223, 240))	('glioma', 'Disease', 'MESH:D005910', (347, 353))	('increased', 'PosReg', (198, 207))	('reduces', 'NegReg', (267, 274))
158195	31131326	In addition to the regulation of neuronal redox homeostasis, deregulated IDH expression drives or contributes to extensive metabolic rewiring in pathogenic neurons from ALS, PD, and HD patients.	('metabolic rewiring', 'MPA', (123, 141))	('deregulated', 'Var', (61, 72))	('PD', 'Disease', 'MESH:D010300', (174, 176))	('ALS', 'Phenotype', 'HP:0007354', (169, 172))	('IDH expression', 'Gene', (73, 87))	('patients', 'Species', '9606', (185, 193))	('contributes to', 'Reg', (98, 112))	('HD', 'Disease', 'MESH:D006816', (182, 184))	('ALS', 'Disease', (169, 172))
158196	31131326	To compensate for reduced oxidative phosphorylation, ALS mutant motor neurons (bearing the SOD1G93A mutation) increase metabolic flux through other pathways, including fatty acid oxidation and TCA cycle.	('TCA', 'Chemical', 'MESH:D014233', (193, 196))	('increase', 'PosReg', (110, 118))	('fatty acid', 'Chemical', 'MESH:D005227', (168, 178))	('fatty acid oxidation', 'MPA', (168, 188))	('ALS', 'Phenotype', 'HP:0007354', (53, 56))	('mutant', 'Var', (57, 63))	('oxidative phosphorylation', 'MPA', (26, 51))	('metabolic flux', 'MPA', (119, 133))	('SOD1', 'Gene', (91, 95))	('SOD1', 'Gene', '6647', (91, 95))	('TCA cycle', 'MPA', (193, 202))
158199	31131326	Deregulation of IDH3 expression in neurodegeneration further reflects important function of this enzyme in neuronal function.	('Deregulation', 'Var', (0, 12))	('neurodegeneration', 'Disease', (35, 52))	('neurodegeneration', 'Disease', 'MESH:D019636', (35, 52))	('IDH3', 'Gene', (16, 20))	('neurodegeneration', 'Phenotype', 'HP:0002180', (35, 52))
158200	31131326	Homozygous mutation of IDH3A was associated with severe epileptic encephalopathy in infants.	('infants', 'Species', '9606', (84, 91))	('IDH3A', 'Gene', (23, 28))	('epileptic encephalopathy', 'Disease', 'MESH:D004827', (56, 80))	('encephalopathy', 'Phenotype', 'HP:0001298', (66, 80))	('epileptic encephalopathy', 'Phenotype', 'HP:0200134', (56, 80))	('Homozygous mutation', 'Var', (0, 19))	('epileptic encephalopathy', 'Disease', (56, 80))	('IDH3A', 'Gene', '3419', (23, 28))	('associated with', 'Reg', (33, 48))
158205	31131326	alphaKG directly enhanced Syt1-lipid interaction, caused a robust increase in fusion between vesicles, and antagonized synaptic transmission defect caused by IDH3alpha loss.	('Syt1', 'Gene', (26, 30))	('loss', 'NegReg', (168, 172))	('increase', 'PosReg', (66, 74))	('enhanced', 'PosReg', (17, 25))	('Syt1', 'Gene', '6857', (26, 30))	('synaptic transmission defect', 'MPA', (119, 147))	('antagonized', 'NegReg', (107, 118))	('lipid', 'Chemical', 'MESH:D008055', (31, 36))	('alphaKG', 'Var', (0, 7))	('fusion between vesicles', 'MPA', (78, 101))	('IDH3alpha', 'Gene', '3419', (158, 167))	('IDH3alpha', 'Gene', (158, 167))
158206	31131326	Mutations in IDHs characterize a broad spectrum of solid and systemic cancers with starkly different phenotypic and genotypic presentation.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('systemic cancers', 'Disease', 'MESH:D009369', (61, 77))	('IDHs', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('characterize', 'Reg', (18, 30))	('systemic cancers', 'Disease', (61, 77))
158207	31131326	In addition, IDH1 and IDH2 mutations occur at different frequencies in different tumor types and represent prognostication factors in patients diagnosed with some, but not all, tumor types.	('mutations', 'Var', (27, 36))	('IDH2', 'Gene', (22, 26))	('patients', 'Species', '9606', (134, 142))	('IDH1', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('IDH2', 'Chemical', '-', (22, 26))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (81, 86))
158208	31131326	Consequently, as detailed below, patient responses to mutant IDH inhibitors vary between tumor types, with hematological malignancies being exquisitely sensitive to mutant IDH inhibitors and with gliomas lacking pronounced treatment responses.	('IDH', 'Gene', (172, 175))	('patient', 'Species', '9606', (33, 40))	('mutant', 'Var', (165, 171))	('hematological malignancies', 'Phenotype', 'HP:0004377', (107, 133))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('hematological malignancies', 'Disease', (107, 133))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('hematological malignancies', 'Disease', 'MESH:D019337', (107, 133))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('mutant', 'Var', (54, 60))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
158209	31131326	A series of compounds have been developed to inhibit mutant IDH1, mutant IDH2, or both (see Table 2 for potency, specificity, cancer indication, and clinical trial identifiers).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutant', 'Var', (66, 72))	('IDH1', 'Gene', (60, 64))	('IDH2', 'Chemical', '-', (73, 77))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('IDH2', 'Gene', (73, 77))	('mutant', 'Var', (53, 59))	('inhibit', 'NegReg', (45, 52))
158210	31131326	GSK321 and IDH305 inhibit mutant IDH1 by engaging an allosteric pocket formed when the enzyme adopts an open configuration.	('inhibit', 'NegReg', (18, 25))	('GSK321', 'Chemical', '-', (0, 6))	('IDH1', 'Gene', (33, 37))	('mutant', 'Var', (26, 32))	('IDH305', 'Chemical', '-', (11, 17))	('allosteric pocket', 'MPA', (53, 70))
158212	31131326	The IDH2R140Q-specific inhibitors AGI-6780 and AG-221 bind tightly to the homodimer interface, locking the enzyme in an open, catalytically inactive conformation while at the same time blocking NADPH binding.	('IDH2R140Q-specific', 'Var', (4, 22))	('blocking', 'NegReg', (185, 193))	('IDH2', 'Chemical', '-', (4, 8))	('AG-221', 'Chemical', 'MESH:C000605269', (47, 53))	('AD', 'Phenotype', 'HP:0002511', (195, 197))	('binding', 'Interaction', (200, 207))	('AGI-6780', 'Chemical', 'MESH:C581155', (34, 42))	('AG-221', 'Gene', (47, 53))	('NADPH', 'MPA', (194, 199))
158213	31131326	Similarly, AG-881, the first dual-specific inhibitor targeted to both mutant IDH1 and IDH2, binds an allosteric pocket present in both enzymes and locks enzymes in an inactive conformation.	('IDH2', 'Gene', (86, 90))	('mutant', 'Var', (70, 76))	('IDH2', 'Chemical', '-', (86, 90))	('IDH1', 'Gene', (77, 81))	('allosteric pocket', 'MPA', (101, 118))	('AG-881', 'Chemical', '-', (11, 17))
158214	31131326	Another mechanism of inhibition is the direct interaction of a mutant IDH1 inhibitor with Asp279, one of the residues that chelate the Mg2+/Mn2+ ion essential for catalysis.	('mutant', 'Var', (63, 69))	('Mg2+', 'Chemical', '-', (135, 139))	('Mn2+', 'Chemical', '-', (140, 144))	('interaction', 'Interaction', (46, 57))	('Asp279', 'Chemical', '-', (90, 96))	('IDH1', 'Gene', (70, 74))
158216	31131326	A myriad of preclinical studies characterized the effects of mutant IDH inhibition on cell metabolism, growth, and tumorigenicity and demonstrated that small-molecule inhibition robustly reduces (R)-2HG level.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('(R)-2HG', 'Chemical', '-', (195, 202))	('growth', 'CPA', (103, 109))	('inhibition', 'NegReg', (167, 177))	('tumor', 'Disease', (115, 120))	('reduces', 'NegReg', (187, 194))	('mutant', 'Var', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('IDH', 'Gene', (68, 71))	('cell metabolism', 'CPA', (86, 101))	('inhibition', 'NegReg', (72, 82))
158217	31131326	Mutant IDH inhibition resulted in enhanced progenitor cell differentiation, which was associated with an increase in differentiation and a decrease in stem cell marker expression, as shown in AML blast cells ex vivo and in glioma-initiating cells in vitro and derivative tumors in vivo.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('enhanced', 'PosReg', (34, 42))	('tumors', 'Disease', (271, 277))	('AML', 'Disease', 'MESH:D015470', (192, 195))	('AML', 'Disease', (192, 195))	('AML', 'Phenotype', 'HP:0004808', (192, 195))	('stem cell marker', 'CPA', (151, 167))	('IDH', 'Gene', (7, 10))	('differentiation', 'MPA', (117, 132))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('glioma', 'Disease', (223, 229))	('decrease', 'NegReg', (139, 147))	('progenitor cell differentiation', 'CPA', (43, 74))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('increase', 'PosReg', (105, 113))	('inhibition', 'NegReg', (11, 21))	('Mutant', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))
158218	31131326	When treated with GSK321, IDH1 mutant AML cells showed genome-wide hypomethylation, predominantly within intergenic and intronic regions, mostly at >5 to <500 kb from the nearest transcription start site.	('hypomethylation', 'MPA', (67, 82))	('AML', 'Disease', (38, 41))	('mutant', 'Var', (31, 37))	('GSK321', 'Chemical', '-', (18, 24))	('IDH1', 'Gene', (26, 30))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('AML', 'Phenotype', 'HP:0004808', (38, 41))
158220	31131326	In contrast to the effect of mutant IDH inhibition in AML, the antitumor effect of mutant IDH inhibitors in glioma was more variable.	('AML', 'Disease', 'MESH:D015470', (54, 57))	('IDH', 'Gene', (90, 93))	('mutant', 'Var', (83, 89))	('glioma', 'Disease', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('AML', 'Phenotype', 'HP:0004808', (54, 57))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('AML', 'Disease', (54, 57))	('tumor', 'Disease', (67, 72))
158223	31131326	These data suggest that the epigenetic control of differentiation is not required for the antitumor effect in response to IDH1 inhibition and that mutant IDH1 regulates glioma cell proliferation and differentiation through distinct pathways characterized by different responsiveness toward (R)-2HG.	('(R)-2HG', 'Chemical', '-', (290, 297))	('mutant', 'Var', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('differentiation', 'CPA', (199, 214))	('glioma', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('IDH1', 'Gene', (154, 158))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('regulates', 'Reg', (159, 168))
158224	31131326	While this initial study pointed to mutant IDH1 as a druggable driver mutation that is required for the evolution of low-grade glioma, subsequent studies using different IDH1 inhibitors in multiple PDX models showed that IDH1 inhibition and depletion of (R)-2HG affect low-grade glioma growth in some, but not all, models.	('IDH1', 'Gene', (221, 225))	('PD', 'Disease', 'MESH:D010300', (198, 200))	('glioma', 'Disease', (279, 285))	('affect', 'Reg', (262, 268))	('inhibition', 'NegReg', (226, 236))	('glioma', 'Disease', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma growth', 'Disease', (279, 292))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('(R)-2HG', 'Chemical', '-', (254, 261))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('glioma growth', 'Disease', 'MESH:D005910', (279, 292))	('mutant', 'Var', (36, 42))	('mutation', 'Var', (70, 78))	('depletion', 'MPA', (241, 250))	('low-grade', 'Disease', (269, 278))
158225	31131326	It is conceivable that different IDH1 mutant glioma cell lines are characterized by distinct secondary driver mutations and may represent more or less advanced stages of glioma malignancy.	('mutant', 'Var', (38, 44))	('glioma malignancy', 'Disease', (170, 187))	('glioma', 'Disease', (170, 176))	('IDH1', 'Gene', (33, 37))	('glioma malignancy', 'Disease', 'MESH:D005910', (170, 187))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('glioma', 'Disease', (45, 51))
158226	31131326	In more malignant models, proliferation and differentiation block induced by IDH1 inhibition might be insufficient to halt tumor growth in response to strong mitogenic signaling, e.g., initiated by a hyperactivated phosphatidylinositol 3-kinase-Akt signaling pathway.	('Akt', 'Gene', '207', (245, 248))	('tumor', 'Disease', (123, 128))	('hyperactivated', 'PosReg', (200, 214))	('inhibition', 'Var', (82, 92))	('Akt', 'Gene', (245, 248))	('IDH1', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
158227	31131326	Consistent with this hypothesis, IDH2 mutant AML with co-occurring mutations in the Ras pathway show decreased sensitivity toward mutant IDH2 inhibition.	('mutant', 'Var', (38, 44))	('Ras pathway', 'Pathway', (84, 95))	('AML', 'Phenotype', 'HP:0004808', (45, 48))	('IDH2', 'Gene', (33, 37))	('decreased', 'NegReg', (101, 110))	('mutations', 'Var', (67, 76))	('IDH2', 'Chemical', '-', (33, 37))	('sensitivity', 'MPA', (111, 122))	('AML', 'Disease', 'MESH:D015470', (45, 48))	('IDH2', 'Chemical', '-', (137, 141))	('AML', 'Disease', (45, 48))
158228	31131326	It is also conceivable that more advanced gliomas with prolonged exposure to mutant IDH1 expression are less susceptible to reversing epigenetic changes once (R)-2HG levels have been normalized via inhibition of mutant IDH1.	('(R)-2HG', 'Chemical', '-', (158, 165))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH1', 'Gene', (84, 88))	('epigenetic changes', 'MPA', (134, 152))	('mutant', 'Var', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
158229	31131326	Treatment of glioma-initiating cells harboring high-level expression of wild-type IDH1 with GSK864, a compound structurally related to GSK321, resulted in a dose-dependent decrease of the NADPH/NADP+ ratio, while cells that have low IDH1 expression, including nontransformed cortical astrocytes, did not respond to treatment.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('GSK321', 'Chemical', '-', (135, 141))	('GSK864', 'Chemical', '-', (92, 98))	('IDH1', 'Gene', (82, 86))	('decrease', 'NegReg', (172, 180))	('expression', 'Var', (58, 68))	('AD', 'Phenotype', 'HP:0002511', (195, 197))	('NADP+', 'Chemical', 'MESH:D009249', (194, 199))	('glioma', 'Disease', (13, 19))	('GSK864', 'Gene', (92, 98))	('NADPH/NADP+ ratio', 'MPA', (188, 205))	('AD', 'Phenotype', 'HP:0002511', (189, 191))
158231	31131326	Most of the aforementioned compounds have been evaluated in phase 1 clinical trials for the treatment of IDH mutant AML, MDS, and glioma.	('MDS', 'Disease', (121, 124))	('MDS', 'Disease', 'MESH:D009190', (121, 124))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Disease', (130, 136))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('IDH', 'Gene', (105, 108))	('mutant', 'Var', (109, 115))	('AML', 'Phenotype', 'HP:0004808', (116, 119))	('AML', 'Disease', (116, 119))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
158234	31131326	Results from a recent phase 1 dose-escalation and dose-expansion study of AG-120 in AML patients harboring mutant IDH1 revealed a significant correlation between lower comutational burden and complete remission or complete remission with partial hematologic recovery.	('IDH1', 'Gene', (114, 118))	('mutant', 'Var', (107, 113))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('patients', 'Species', '9606', (88, 96))	('complete', 'Disease', (214, 222))	('lower', 'NegReg', (162, 167))	('AML', 'Phenotype', 'HP:0004808', (84, 87))	('AML', 'Disease', (84, 87))	('comutational burden', 'MPA', (168, 187))	('AG-120', 'Chemical', 'MESH:C000627630', (74, 80))
158235	31131326	While single-gene mutations were not predictive of clinical response or AG-120 treatment resistance, mutations in tyrosine kinase pathway components, including mutations in NRAS and FLT3 and less frequently KRAS and PTPN11 mutations, were enriched in nonresponding patients with relapsed or refractory AML.	('mutations', 'Var', (101, 110))	('FLT3', 'Gene', (182, 186))	('mutations', 'Var', (160, 169))	('AML', 'Disease', (302, 305))	('NRAS', 'Gene', (173, 177))	('KRAS', 'Gene', (207, 211))	('PTPN11', 'Gene', '5781', (216, 222))	('AG-120', 'Chemical', 'MESH:C000627630', (72, 78))	('AML', 'Phenotype', 'HP:0004808', (302, 305))	('KRAS', 'Gene', '3845', (207, 211))	('NRAS', 'Gene', '4893', (173, 177))	('PTPN11', 'Gene', (216, 222))	('relapsed', 'Disease', (279, 287))	('patients', 'Species', '9606', (265, 273))	('AML', 'Disease', 'MESH:D015470', (302, 305))
158239	31131326	The U.S. Food and Drug Administration (FDA) approved AG-221 in August 2017 and AG-120 in July 2018 for adult patients with IDH mutant relapsed or refractory AML.	('patients', 'Species', '9606', (109, 117))	('AG-221', 'Chemical', 'MESH:C000605269', (53, 59))	('IDH mutant', 'Disease', (123, 133))	('AG-120', 'Chemical', 'MESH:C000627630', (79, 85))	('AML', 'Disease', 'MESH:D015470', (157, 160))	('AG-120', 'Var', (79, 85))	('AG-221', 'Var', (53, 59))	('AML', 'Phenotype', 'HP:0004808', (157, 160))	('AML', 'Disease', (157, 160))
158240	31131326	Recent clinical studies in patients with mutant IDH1 relapsed/refractory AML revealed that AG-120 was well tolerated, with an overall response rate of 41.9%.	('AML', 'Disease', (73, 76))	('mutant', 'Var', (41, 47))	('AML', 'Phenotype', 'HP:0004808', (73, 76))	('patients', 'Species', '9606', (27, 35))	('IDH1', 'Gene', (48, 52))	('AML', 'Disease', 'MESH:D015470', (73, 76))	('AG-120', 'Chemical', 'MESH:C000627630', (91, 97))
158244	31131326	Specifically, the authors found that serum (R)-2HG levels can predict both IDH mutational status and patient prognosis; IDH mutant patients with serum levels of <200 ng/ml have shorter overall survival compared to patients with serum (R)-2HG of >200 ng/ml.	('patients', 'Species', '9606', (131, 139))	('(R)-2HG', 'Chemical', '-', (43, 50))	('patient', 'Species', '9606', (214, 221))	('overall survival', 'MPA', (185, 201))	('patients', 'Species', '9606', (214, 222))	('mutant', 'Var', (124, 130))	('(R)-2HG', 'Chemical', '-', (234, 241))	('shorter', 'NegReg', (177, 184))	('patient', 'Species', '9606', (131, 138))	('patient', 'Species', '9606', (101, 108))	('IDH', 'Gene', (120, 123))
158246	31131326	Correspondingly, patient response to mutant IDH inhibitors correlated with patient prognosis.	('patient', 'Species', '9606', (17, 24))	('mutant', 'Var', (37, 43))	('IDH', 'Gene', (44, 47))	('patient', 'Species', '9606', (75, 82))	('correlated', 'Reg', (59, 69))
158249	31131326	Last, phase 1 dose-escalation studies with the pan-specific mutant IDH inhibitor AG-881 in patients with recurrent/progressive mutant IDH1/2 glioma and nonglioma solid tumors revealed a favorable safety profile at doses below 100 mg daily.	('mutant', 'Var', (127, 133))	('patients', 'Species', '9606', (91, 99))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('glioma', 'Disease', (141, 147))	('AG-881', 'Chemical', '-', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('IDH1/2', 'Gene', (134, 140))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('nonglioma solid tumors', 'Disease', (152, 174))	('glioma', 'Disease', (155, 161))	('nonglioma solid tumors', 'Disease', 'MESH:D009369', (152, 174))	('AG-881', 'Gene', (81, 87))
158250	31131326	Mutant IDH inhibition and associated decrease in tumor-derived (R)-2HG reduces the tumorigenic potential of leukemic blast and glioma-initiating cells in vitro and in murine cancer models in vivo.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (83, 88))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('leukemic blast', 'Disease', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('IDH', 'Gene', (7, 10))	('decrease', 'NegReg', (37, 45))	('cancer', 'Disease', (174, 180))	('(R)-2HG', 'Chemical', '-', (63, 70))	('reduces', 'NegReg', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (49, 54))	('Mutant', 'Var', (0, 6))	('glioma', 'Disease', (127, 133))	('inhibition', 'NegReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('murine', 'Species', '10090', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('leukemic blast', 'Disease', 'MESH:D001753', (108, 122))
158251	31131326	While FDA-approved small-molecule inhibitors targeted to mutant IDHs elicit partial responses or complete remission in AML patients, preclinical responses in low-grade glioma are less consistent and robust.	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('IDHs', 'Gene', (64, 68))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('partial', 'NegReg', (76, 83))	('patients', 'Species', '9606', (123, 131))	('mutant', 'Var', (57, 63))	('AML', 'Phenotype', 'HP:0004808', (119, 122))	('AML', 'Disease', (119, 122))	('glioma', 'Disease', (168, 174))
158252	31131326	In addition, AML patients with mutant IDH2, while displaying initial responses to AG-221, can acquire clinical resistance toward the inhibitor and develop recurrent disease associated with an increase in (R)-2HG.	('develop', 'PosReg', (147, 154))	('mutant', 'Var', (31, 37))	('IDH2', 'Chemical', '-', (38, 42))	('AML', 'Disease', 'MESH:D015470', (13, 16))	('IDH2', 'Gene', (38, 42))	('recurrent disease', 'Disease', (155, 172))	('AML', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))	('increase', 'PosReg', (192, 200))	('AML', 'Phenotype', 'HP:0004808', (13, 16))	('(R)-2HG', 'Chemical', '-', (204, 211))	('AG-221', 'Chemical', 'MESH:C000605269', (82, 88))	('clinical resistance toward the inhibitor', 'MPA', (102, 142))
158253	31131326	Therapy resistance is driven by the emergence of second-site IDH2 mutations, which can occur in either cis or trans, and affects residues that are located at the dimer interface recognized by the inhibitor.	('mutations', 'Var', (66, 75))	('affects', 'Reg', (121, 128))	('residues', 'Protein', (129, 137))	('IDH2', 'Gene', (61, 65))	('Therapy resistance', 'MPA', (0, 18))	('IDH2', 'Chemical', '-', (61, 65))
158255	31131326	These studies point to selective pressure to maintain (R)-2HG production in IDH mutant cancers and suggest that recurrent tumors expressing both mutant IDH1 and IDH2 should be sensitive to treatment using dual-specific mutant IDH1/2 inhibitors or to cotreatment with mutant IDH1- and IDH2-specific small molecules.	('tumors', 'Disease', (122, 128))	('IDH1', 'Gene', (152, 156))	('cancers', 'Disease', (87, 94))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mutant', 'Var', (80, 86))	('mutant', 'Var', (145, 151))	('IDH', 'Gene', (76, 79))	('IDH2', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('maintain', 'PosReg', (45, 53))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('IDH2', 'Chemical', '-', (284, 288))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('(R)-2HG', 'Chemical', '-', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('IDH2', 'Chemical', '-', (161, 165))
158257	31131326	To enhance the antitumor effect of IDH mutant inhibitors, a series of preclinical studies investigated synthetic lethal interactions of mutant IDH compromise, in particular in low-grade gliomas, to inform combinatorial regimens to more effectively antagonize mutant IDH tumor progression (Table 1).	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('gliomas', 'Disease', (186, 193))	('gliomas', 'Disease', 'MESH:D005910', (186, 193))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('IDH tumor', 'Disease', 'MESH:D009369', (266, 275))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (19, 24))	('IDH compromise', 'Gene', (143, 157))	('mutant', 'Var', (136, 142))	('tumor', 'Disease', (270, 275))	('IDH tumor', 'Disease', (266, 275))
158258	31131326	Most IDH1 mutant gliomas are characterized by O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, which, in turn, results in decreased MGMT expression, reduced MGMT-dependent DNA repair, and increased sensitivity toward DNA-methylating chemotherapy, foremost temozolomide.	('MGMT', 'Gene', (86, 90))	('sensitivity', 'MPA', (217, 228))	('MGMT', 'Gene', '4255', (176, 180))	('MGMT', 'Gene', '4255', (151, 155))	('reduced', 'NegReg', (168, 175))	('mutant', 'Var', (10, 16))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('gliomas', 'Disease', (17, 24))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (46, 84))	('MGMT', 'Gene', (176, 180))	('MGMT', 'Gene', '4255', (86, 90))	('IDH1', 'Gene', (5, 9))	('temozolomide', 'Chemical', 'MESH:D000077204', (275, 287))	('decreased', 'NegReg', (141, 150))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('MGMT', 'Gene', (151, 155))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('O6-methylguanine-DNA methyltransferase', 'Gene', (46, 84))	('increased', 'PosReg', (207, 216))	('expression', 'MPA', (156, 166))
158259	31131326	In addition to impaired MGMT-dependent DNA repair, enhanced chemosensitivity of mutant IDH tumors is also a result of compromised oxidative metabolism and associated reduction in NAD+ level.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MGMT', 'Gene', '4255', (24, 28))	('chemosensitivity', 'MPA', (60, 76))	('reduction', 'NegReg', (166, 175))	('mutant', 'Var', (80, 86))	('NAD+ level', 'MPA', (179, 189))	('oxidative metabolism', 'MPA', (130, 150))	('NAD+', 'Chemical', 'MESH:D009243', (179, 183))	('IDH tumors', 'Disease', 'MESH:D009369', (87, 97))	('enhanced', 'PosReg', (51, 59))	('compromised', 'NegReg', (118, 129))	('AD', 'Phenotype', 'HP:0002511', (180, 182))	('IDH tumors', 'Disease', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('MGMT', 'Gene', (24, 28))
158260	31131326	When comparing the metabolic profiles of IDH1 mutant glioma-initiating cells in the presence or absence of an IDH1 inhibitor, Tateishi et al.	('glioma', 'Disease', (53, 59))	('mutant', 'Var', (46, 52))	('IDH1', 'Gene', (41, 45))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
158261	31131326	found that IDH1 mutant tumors through an (R)-2HG-independent mechanism down-regulate the expression of nicotinate phosphoribosyltransferase 1 (Naprt1), the rate-limiting enzyme of the NAD+ salvage pathway.	('Naprt1', 'Gene', (143, 149))	('nicotinate phosphoribosyltransferase 1', 'Gene', (103, 141))	('expression', 'MPA', (89, 99))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('(R)-2HG', 'Chemical', '-', (41, 48))	('nicotinate phosphoribosyltransferase 1', 'Gene', '93100', (103, 141))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutant', 'Var', (16, 22))	('Naprt1', 'Gene', '93100', (143, 149))	('AD', 'Phenotype', 'HP:0002511', (185, 187))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('NAD+', 'Chemical', 'MESH:D009243', (184, 188))	('down-regulate', 'NegReg', (71, 84))	('IDH1', 'Gene', (11, 15))
158262	31131326	As a result, IDH1 mutant tumors are vulnerable to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition, and local nanoparticle-mediated delivery of an NAMPT inhibitor (GMX-1778) reduces tumor progression selectively in IDH1 mutant low-grade glioma PDX models.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('glioma PDX', 'Disease', 'MESH:D005910', (277, 287))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (81, 119))	('NAMPT', 'Gene', '10135', (187, 192))	('mutant', 'Var', (18, 24))	('IDH1', 'Gene', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('nicotinamide phosphoribosyltransferase', 'Gene', (81, 119))	('NAMPT', 'Gene', '10135', (121, 126))	('tumor', 'Disease', (25, 30))	('NAMPT', 'Gene', (187, 192))	('tumor', 'Disease', (222, 227))	('mutant', 'Var', (260, 266))	('reduces', 'NegReg', (214, 221))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('AD', 'Phenotype', 'HP:0002511', (51, 53))	('NAMPT', 'Gene', (121, 126))	('GMX-1778', 'Chemical', 'MESH:C401312', (204, 212))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('IDH1', 'Gene', (255, 259))	('glioma PDX', 'Disease', (277, 287))	('NAD+', 'Chemical', 'MESH:D009243', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (277, 283))
158264	31131326	The combination of temozolomide and NAMPT inhibitor reduced tumor progression in IDH1 mutant gliomas more effectively compared to either monotherapy, independent of MGMT methylation and mismatch repair status.	('gliomas', 'Disease', (93, 100))	('MGMT', 'Gene', '4255', (165, 169))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('reduced', 'NegReg', (52, 59))	('mutant', 'Var', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('IDH1', 'Gene', (81, 85))	('NAMPT', 'Gene', (36, 41))	('NAMPT', 'Gene', '10135', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('tumor', 'Disease', (60, 65))	('MGMT', 'Gene', (165, 169))	('temozolomide', 'Chemical', 'MESH:D000077204', (19, 31))
158265	31131326	Additional tumor sensitivities associated with IDH mutations were identified in MPNs, AML, and intrahepatic cholangiocarcinomas (ICCs), an aggressive tumor of the liver bile duct.	('mutations', 'Var', (51, 60))	('intrahepatic cholangiocarcinomas', 'Disease', (95, 127))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('aggressive tumor', 'Disease', 'MESH:D001523', (139, 155))	('MPNs', 'Phenotype', 'HP:0005547', (80, 84))	('MPNs', 'Disease', (80, 84))	('tumor', 'Disease', (11, 16))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (95, 127))	('AML', 'Disease', 'MESH:D015470', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('IDH', 'Gene', (47, 50))	('AML', 'Phenotype', 'HP:0004808', (86, 89))	('aggressive tumor', 'Disease', (139, 155))	('AML', 'Disease', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (108, 126))
158266	31131326	In MPNs, gain-of-function mutations in the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway co-occur with IDH1 and IDH2 mutations, and the combined inhibition of both mutant JAK2 and mutant IDH enzymes had more pronounced antileukemic effects than either therapy alone.	('gain-of-function', 'PosReg', (9, 25))	('mutant', 'Var', (217, 223))	('IDH2', 'Gene', (149, 153))	('JAK2', 'Gene', (208, 212))	('IDH', 'Gene', (224, 227))	('STAT', 'Gene', '6772;20846', (112, 116))	('MPNs', 'Phenotype', 'HP:0005547', (3, 7))	('JAK', 'Gene', (57, 60))	('IDH2', 'Chemical', '-', (149, 153))	('mutant', 'Var', (201, 207))	('mutations', 'Var', (26, 35))	('antileukemic effects', 'CPA', (256, 276))	('IDH1', 'Gene', (140, 144))	('inhibition', 'NegReg', (182, 192))	('STAT', 'Gene', (112, 116))	('mutations', 'Var', (154, 163))	('Janus', 'Pathway', (43, 48))	('JAK2', 'Gene', '3717', (208, 212))
158268	31131326	IDH1 mutant AML cells and derivative tumors, when compared to specimens with IDH1 wild-type status, are more sensitive to the Bcl-2 inhibitor ABT-199 due to (R)-2HG inhibition of cytochrome c oxidase, which lowers the threshold for apoptosis induction in response to Bcl-2 inhibition.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('(R)-2HG', 'Chemical', '-', (157, 164))	('ABT', 'Chemical', 'MESH:C002502', (142, 145))	('AML', 'Disease', 'MESH:D015470', (12, 15))	('AML', 'Phenotype', 'HP:0004808', (12, 15))	('AML', 'Disease', (12, 15))	('sensitive', 'MPA', (109, 118))	('Bcl-2', 'Gene', '596', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Bcl-2', 'Gene', (267, 272))	('mutant', 'Var', (5, 11))	('more', 'PosReg', (104, 108))	('tumors', 'Disease', (37, 43))	('IDH1', 'Gene', (0, 4))	('inhibition', 'NegReg', (165, 175))	('Bcl-2', 'Gene', (126, 131))	('Bcl-2', 'Gene', '596', (126, 131))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
158270	31131326	Studies using a genetically engineered murine mouse model with virally induced overexpression of either IDH1R132H or IDH1 wild-type transgenes and concomitant p53 knockdown and PDGF expression suggested that IDH1 mutation through (R)-2HG-driven epigenetic effect down-regulates the expression of leukocyte chemotaxis factors.	('epigenetic effect', 'Var', (245, 262))	('murine', 'Species', '10090', (39, 45))	('IDH1', 'Gene', (208, 212))	('(R)-2HG', 'Chemical', '-', (230, 237))	('expression', 'MPA', (282, 292))	('mutation', 'Var', (213, 221))	('mouse', 'Species', '10090', (46, 51))	('down-regulates', 'NegReg', (263, 277))	('PD', 'Disease', 'MESH:D010300', (177, 179))
158271	31131326	In particular, the infiltration of immune cells linked to poor prognosis in many cancer types, such as macrophages, microglia, monocytes, and neutrophils, was dampened in IDH1 mutant gliomas, and consistently, the systemic depletion of neutrophils selectively slowed down the disease progression of IDH1 wild-type tumors but had no further effect on the progression of IDH1 mutant tumors.	('tumors', 'Phenotype', 'HP:0002664', (381, 387))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('mutant', 'Var', (176, 182))	('infiltration', 'CPA', (19, 31))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('tumors', 'Disease', (381, 387))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('IDH1', 'Gene', (299, 303))	('gliomas', 'Disease', (183, 190))	('slowed down', 'NegReg', (260, 271))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumors', 'Disease', 'MESH:D009369', (381, 387))	('IDH1', 'Gene', (171, 175))	('tumors', 'Disease', (314, 320))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('disease progression', 'CPA', (276, 295))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('dampened', 'NegReg', (159, 167))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))
158274	31131326	As demonstrated in TCGA clinical low-grade glioma specimens and syngeneic mouse tumors, IDH1 mutation through increased (R)-2HG production diminished intratumoral STAT1 activation, which, in turn, resulted in down-regulation of CTL-attracting chemokines, such as CXLC10, and reduced number of tumor-infiltrating CTLs.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH1', 'Gene', (88, 92))	('increased', 'PosReg', (110, 119))	('glioma', 'Disease', (43, 49))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('(R)-2HG', 'Chemical', '-', (120, 127))	('STAT1', 'Gene', '20846', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('CTL-attracting chemokines', 'MPA', (228, 253))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('CXLC10', 'MPA', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (80, 85))	('down-regulation', 'NegReg', (209, 224))	('mouse', 'Species', '10090', (74, 79))	('reduced', 'NegReg', (275, 282))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('STAT1', 'Gene', (163, 168))	('diminished', 'NegReg', (139, 149))	('tumor', 'Disease', (293, 298))	('mutation', 'Var', (93, 101))
158275	31131326	Pharmacological inhibition of mutant IDH1 reversed the observed immunosuppressive phenotype and enhanced the antitumor effect of peptide-based vaccine immunotherapy, supporting the notion that IDH1 mutant inhibitors enhance immunotherapy and tumor cell killing in IDH1 mutant glioma patients.	('inhibitors', 'MPA', (205, 215))	('enhanced', 'PosReg', (96, 104))	('immunotherapy', 'CPA', (224, 237))	('tumor', 'Disease', (242, 247))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('patients', 'Species', '9606', (283, 291))	('mutant', 'Var', (198, 204))	('tumor', 'Disease', (113, 118))	('IDH1', 'Gene', (37, 41))	('mutant', 'Var', (269, 275))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutant', 'Var', (30, 36))	('IDH1', 'Gene', (193, 197))	('enhance', 'PosReg', (216, 223))	('glioma', 'Disease', (276, 282))	('glioma', 'Disease', 'MESH:D005910', (276, 282))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
158276	31131326	IDH1 mutant low-grade glioma cells are also resistant toward NK cell-mediated cytotoxicity due to hypermethylation and epigenetic silencing of NK group 2D ligands.	('glioma', 'Disease', 'MESH:D005910', (22, 28))	('cytotoxicity', 'Disease', (78, 90))	('glioma', 'Disease', (22, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('mutant', 'Var', (5, 11))	('resistant', 'CPA', (44, 53))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('epigenetic silencing', 'Var', (119, 139))	('hypermethylation', 'Var', (98, 114))
158277	31131326	Treatment of IDH1 mutant cells with the DNA methytransferase inhibitor decitabine, by reversing the hypermethylation phenotype, increased glioma cell sensitivity toward NK cell lysis.	('glioma', 'Disease', (138, 144))	('increased', 'PosReg', (128, 137))	('mutant', 'Var', (18, 24))	('IDH1', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('decitabine', 'Chemical', 'MESH:D000077209', (71, 81))	('hypermethylation', 'MPA', (100, 116))
158278	31131326	In addition to (R)-2HG ability to cause tumor cell-intrinsic epigenetic alterations, high abundance of (R)-2HG levels in body fluids of IDH mutant AML and glioma patients also suggested that (R)-2HG may shape the tumor-associated immune system in an autonomous paracrine way.	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('(R)-2HG', 'Chemical', '-', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('IDH', 'Gene', (136, 139))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('(R)-2HG', 'Chemical', '-', (103, 110))	('(R)-2HG', 'Chemical', '-', (15, 22))	('patients', 'Species', '9606', (162, 170))	('epigenetic alterations', 'MPA', (61, 83))	('tumor', 'Disease', (40, 45))	('mutant', 'Var', (140, 146))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('AML', 'Disease', 'MESH:D015470', (147, 150))	('AML', 'Phenotype', 'HP:0004808', (147, 150))	('AML', 'Disease', (147, 150))	('glioma', 'Disease', (155, 161))
158279	31131326	(R)-2HG levels are significantly higher in T cells from AML patients with IDH2 mutation compared to healthy controls or AML patients with wild-type IDH2.	('higher', 'PosReg', (33, 39))	('IDH2', 'Gene', (74, 78))	('(R)-2HG', 'Chemical', '-', (0, 7))	('AML', 'Phenotype', 'HP:0004808', (56, 59))	('patients', 'Species', '9606', (60, 68))	('AML', 'Disease', (56, 59))	('IDH2', 'Chemical', '-', (148, 152))	('AML', 'Disease', 'MESH:D015470', (120, 123))	('mutation', 'Var', (79, 87))	('IDH2', 'Chemical', '-', (74, 78))	('AML', 'Disease', (120, 123))	('AML', 'Disease', 'MESH:D015470', (56, 59))	('AML', 'Phenotype', 'HP:0004808', (120, 123))	('patients', 'Species', '9606', (124, 132))
158280	31131326	Although (R)-2HG is cell impermeable and its mode of transport remains ill defined, (R)-2HG is secreted by IDH1 mutant tumor cells and taken up by T cells.	('IDH1', 'Gene', (107, 111))	('tumor', 'Disease', (119, 124))	('R)-2HG', 'Var', (85, 91))	('(R)-2HG', 'Chemical', '-', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutant', 'Var', (112, 118))	('(R)-2HG', 'Chemical', '-', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
158282	31131326	Collectively, the studies suggest that intratumoral immune suppression in IDH1 mutant tumors may occur through tumor cell-intrinsic effects of (R)-2HG on immune cell recruitment and through paracrine metabolic effect on tumor-infiltrating T cells.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('immune cell', 'CPA', (154, 165))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (44, 49))	('(R)-2HG', 'Chemical', '-', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('mutant', 'Var', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
158283	31131326	When presented on major histocompatibility complex class II, these neoantigens induced mutation-specific CD4+ T helper 1 (TH1) responses and reduced progression of murine syngeneic IDH1R132H gliomas.	('reduced', 'NegReg', (141, 148))	('gliomas', 'Disease', (191, 198))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('IDH1R132H', 'Var', (181, 190))	('CD4', 'Gene', (105, 108))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('murine', 'Species', '10090', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('progression', 'CPA', (149, 160))	('CD4', 'Gene', '12504', (105, 108))
158284	31131326	An IDH1 mutation-specific vaccine is currently being evaluated in two clinical trials in patients diagnosed with IDH1 mutant glioma (NCT02193347 and NCT02454643).	('glioma', 'Disease', (125, 131))	('IDH1', 'Gene', (113, 117))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('NCT02454643', 'Var', (149, 160))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('mutant', 'Var', (118, 124))	('patients', 'Species', '9606', (89, 97))	('NCT02193347', 'Var', (133, 144))
158285	31131326	Because of suppression of the tumor-associated immune system through (R)-2HG-dependent mechanisms described above, antitumor immunity induced by IDH1R132H-specific vaccines can likely be improved by cotreatment with IDH1 mutant small-molecule inhibitors to reduce tumor-derived (R)-2HG and with checkpoint inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutant', 'Var', (221, 227))	('(R)-2HG', 'Chemical', '-', (278, 285))	('(R)-2HG', 'Chemical', '-', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('reduce', 'NegReg', (257, 263))	('IDH1', 'Gene', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IDH1R132H-specific', 'Var', (145, 163))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (30, 35))
158286	31131326	The discovery of neomorphic cancer-associated IDH1 and IDH2 mutation more than 10 years ago fueled the field of cancer metabolism, ignited drug development efforts to pharmacologically target mutant enzymes, and resulted in the FDA approval of two small-molecule inhibitors for the treatment of AML.	('mutation', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (112, 118))	('IDH1', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('neomorphic cancer', 'Disease', (17, 34))	('IDH2', 'Chemical', '-', (55, 59))	('AML', 'Disease', 'MESH:D015470', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('AML', 'Disease', (295, 298))	('IDH2', 'Gene', (55, 59))	('cancer', 'Disease', (28, 34))	('AML', 'Phenotype', 'HP:0004808', (295, 298))	('neomorphic cancer', 'Disease', 'MESH:D009369', (17, 34))
158287	31131326	Among the many biological phenotypes caused by expression of mutant IDHs, the suppression of the tumor-associated immune system emerged as one of the latest and probably most intriguing examples.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('IDHs', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('mutant', 'Var', (61, 67))
158288	31131326	The exploration of IDHs will undoubtedly continue to establish IDH mutation as an important event in the genesis and progression of a wide spectrum of systemic and solid cancers and will unravel novel and unexpected functions of nonmutated IDHs in human disease.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('mutation', 'Var', (67, 75))	('cancers', 'Disease', (170, 177))	('IDH', 'Gene', (63, 66))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('human', 'Species', '9606', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('systemic', 'Disease', (151, 159))
158290	31131326	While region-specific differences in the tumor microenvironment likely influence tumor phenotypic and molecular characteristics, the concept of distinct progenitor cell of origin, as a contributing factor to phenotypic and genotypic differences between IDH1 wild-type and mutant GBM, has gained traction.	('mutant', 'Var', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('iron', 'Chemical', 'MESH:D007501', (55, 59))	('influence', 'Reg', (71, 80))	('tumor', 'Disease', (41, 46))	('IDH1', 'Gene', (253, 257))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('GBM', 'Phenotype', 'HP:0012174', (279, 282))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (81, 86))
158291	31131326	The restricted phenotypic and spatial presentation of IDH1 mutant GBM, combined with similarities these tumors share with fetal and adult brain parenchyma, is consistent with their origin from a lineage-committed precursor with limited differentiation potential.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('IDH1', 'Gene', (54, 58))	('mutant', 'Var', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))
158292	31131326	Although IDH1 mutation and associated CpG island methylator phenotype (CIMP) together with p53 mutation may occur in quiescent NSCs (cell of mutation), tumors can arise from a lineage-committed progeny (cell of origin), such as OPCs, following proliferative expansion related to forebrain maturation.	('IDH1', 'Gene', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p53', 'Gene', (91, 94))	('mutation', 'Var', (14, 22))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutation', 'Var', (95, 103))
158293	31131326	Mosaic analysis with double markers in a genetically engineered murine GBM model confirmed that mutations originally induced in NSCs can lie dormant and only trigger malignant transformation following differentiation into OPCs, suggesting that mutation may initially occur in either NSCs or OPCs, but only OPCs provide the suitable cellular context needed for transformation.	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('malignant transformation', 'CPA', (166, 190))	('murine', 'Species', '10090', (64, 70))	('trigger', 'Reg', (158, 165))	('mutations', 'Var', (96, 105))
158295	31131326	As a result of OPC transformation, low-grade gliomas develop, and through acquisition of additional genomic aberrations, these tumors progress into mutant IDH1 GBM.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH1', 'Gene', (155, 159))	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('progress', 'PosReg', (134, 142))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('mutant', 'Var', (148, 154))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
158297	31131326	Using Nestin-creERTM, Ascl1-creERTM, and NG2-creERTM transgenes that drive recombination selectively in NSCs or lineage-restricted progenitor cells, Parada and colleagues demonstrated that distinct GBM-initiating cell populations, in the setting of identical driver mutations, give rise to different GBM subtypes that can be distinguished on histopathologic and molecular levels.	('Nestin', 'Gene', (6, 12))	('NG2', 'Gene', (41, 44))	('NG2', 'Gene', '1464', (41, 44))	('GBM', 'Phenotype', 'HP:0012174', (198, 201))	('mutations', 'Var', (266, 275))	('GBM', 'Phenotype', 'HP:0012174', (300, 303))	('Nestin', 'Gene', '10763', (6, 12))	('Ascl1', 'Gene', (22, 27))	('Ascl1', 'Gene', '429', (22, 27))
158300	31131326	When expressed in p53-deficient murine NSCs, mutant IDH1 inhibits progenitor cell growth in vitro, reduces glioma formation in vivo, and increases overall animal subject survival.	('mutant', 'Var', (45, 51))	('increases', 'PosReg', (137, 146))	('murine', 'Species', '10090', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('reduces', 'NegReg', (99, 106))	('progenitor cell growth', 'CPA', (66, 88))	('animal subject survival', 'CPA', (155, 178))	('inhibits', 'NegReg', (57, 65))	('glioma', 'Disease', (107, 113))	('IDH1', 'Gene', (52, 56))
158301	31131326	IDH1R132H growth inhibitory effect is due to the diversion of alphaKG from wild-type IDH1 and reduced carbon flux from glucose or glutamine into lipids.	('growth inhibitory effect', 'MPA', (10, 34))	('carbon', 'Chemical', 'MESH:D002244', (102, 108))	('reduced', 'NegReg', (94, 101))	('IDH1R132H', 'Var', (0, 9))	('lipids', 'Chemical', 'MESH:D008055', (145, 151))	('glutamine', 'Chemical', 'MESH:D005973', (130, 139))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('carbon flux from glucose or glutamine into lipids', 'MPA', (102, 151))
158302	31131326	Replenishment of alphaKG through glutaminolysis compensates for these growth and flux deficiencies, suggesting that IDH1 mutant tumors require a specialized metabolic niche characterized by elevated glutamate flux for growth and expansion (Fig.	('mutant', 'Var', (121, 127))	('elevated', 'PosReg', (190, 198))	('glutamate', 'Chemical', 'MESH:D018698', (199, 208))	('IDH1', 'Gene', (116, 120))	('flux deficiencies', 'Disease', 'MESH:D007153', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('flux deficiencies', 'Disease', (81, 98))	('glutamate flux', 'MPA', (199, 213))	('elevated glutamate', 'Phenotype', 'HP:0500149', (190, 208))
158306	31131326	Reflecting distinct metabolic wiring in IDH1 mutant versus IDH1 wild-type GBM, NSC and OPC progenitor cells also exist in specific niches within the brain and demonstrate metabolic adaptability to specific and changing microenvironments.	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('iron', 'Chemical', 'MESH:D007501', (227, 231))	('mutant', 'Var', (45, 51))	('IDH1', 'Gene', (40, 44))
158311	31131326	While the studies outlined here point to OPCs as a cell of origin for IDH1 mutant tumors, single-cell RNA sequencing analysis of IDH1 mutant anaplastic astrocytoma and oligondrogliomas points to an NSC/NPC population as the cell of origin.	('tumors', 'Disease', (82, 88))	('IDH1', 'Gene', (129, 133))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('anaplastic astrocytoma and oligondrogliomas', 'Disease', 'MESH:D001254', (141, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutant', 'Var', (75, 81))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('astrocytoma', 'Phenotype', 'HP:0009592', (152, 163))	('mutant', 'Var', (134, 140))	('IDH1', 'Gene', (70, 74))
158312	31131326	In particular, studies by Suva and co-workers identified three subpopulations of malignant cells in IDH1 mutant gliomas, i.e., nonproliferating differentiated cells with oligodendrocyte- and astrocyte-like glial programs, respectively, and proliferative undifferentiated cells that resemble neural stem/progenitor cells.	('nonproliferating differentiated cells', 'CPA', (127, 164))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('IDH1', 'Gene', (100, 104))	('mutant', 'Var', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
158316	31131326	Furthermore, alternative therapeutic approaches to small-molecule IDH1 inhibitors, including gene regulatory small interfering RNA (siRNA) or microRNA (miRNA), antisense oligonucleotides (ASOs), CRISPR-Cas9 genome editing, and proteolysis targeting chimeras (PROTACs), could be considered to correct IDH1-mediated metabolic rewiring of tumor cells.	('oligonucleotides', 'Chemical', 'MESH:D009841', (170, 186))	('antisense', 'Var', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('small', 'Var', (109, 114))	('tumor', 'Disease', (336, 341))	('IDH1', 'Gene', (66, 70))
158323	31131326	Parkin mutations that alter its activity are linked to PD, while its loss of heterozygosity and copy number have been observed in a spectrum of cancers, such as breast and ovarian cancer.	('loss', 'NegReg', (69, 73))	('linked', 'Reg', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('activity', 'MPA', (32, 40))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (161, 186))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('PD', 'Disease', 'MESH:D010300', (55, 57))	('Parkin', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutations', 'Var', (7, 16))
158326	31131326	Future genome-wide association studies (GWAS) can determine whether IDHs represent risk loci in neurodegenerative diseases by identifying single-nucleotide variants (SNVs) that are associated with increased disease risk.	('neurodegenerative diseases', 'Disease', (96, 122))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (96, 122))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (96, 122))	('single-nucleotide variants', 'Var', (138, 164))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (96, 121))
158327	21479234	BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults.	('neoplasm', 'Phenotype', 'HP:0002664', (161, 169))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('Pleomorphic Xanthoastrocytoma', 'Disease', (35, 64))	('Pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (106, 135))	('Pleomorphic Xanthoastrocytoma', 'Disease', 'MESH:D008228', (35, 64))	('Pleomorphic xanthoastrocytoma', 'Disease', (106, 135))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('children', 'Species', '9606', (192, 200))	('BRAF', 'Gene', (0, 4))	('glial neoplasm', 'Disease', 'MESH:D005910', (155, 169))	('astrocytoma', 'Phenotype', 'HP:0009592', (53, 64))	('glial neoplasm', 'Disease', (155, 169))
158334	21479234	BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM).	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('giant cell GBM', 'Disease', (114, 128))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
158349	21479234	To date, molecular genetic analysis of PXA has been predominantly limited to TP53 revealing mutations in 6% of cases (7 of 123).	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('mutations', 'Var', (92, 101))
158350	21479234	There is no correlation between mutated TP53 and the presence of anaplastic features.	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutated', 'Var', (32, 39))	('anaplastic', 'Disease', (65, 75))
158364	21479234	, was expanded to include four additional assays that test for hotspot mutations in the isocitrate dehydrogenase genes 1 (IDH1) and 2 (IDH2), recently shown to be frequently altered in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('IDH2', 'Gene', (135, 139))	('IDH2', 'Gene', '3418', (135, 139))	('IDH1', 'Gene', (122, 126))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('mutations', 'Var', (71, 80))	('IDH1', 'Gene', '3417', (122, 126))	('gliomas', 'Disease', (185, 192))	('altered', 'Reg', (174, 181))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))
158365	21479234	The genotyping analysis queried 60 commonly mutated loci in 15 cancer genes (Table 1) testing for 140 previously described somatic mutations (COSMIC database, v49 release).	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('15 cancer', 'Disease', 'MESH:C567447', (60, 69))	('15 cancer', 'Disease', (60, 69))	('mutated', 'Var', (44, 51))
158378	21479234	The antibody is reported to detect endogenous levels of p44 and p42 MAP Kinase (Erk1 and Erk2) when phosphorylated at residues Thr202 and Tyr204 of Erk1 and (Thr185 and Tyr187 of Erk2), and singly phosphorylated at Thr202.	('Erk1', 'Gene', '5595', (80, 84))	('Tyr187', 'Var', (169, 175))	('Erk2', 'Gene', '5594', (89, 93))	('Erk1', 'Gene', (80, 84))	('Erk1', 'Gene', (148, 152))	('Thr185', 'Chemical', '-', (158, 164))	('Tyr204', 'Var', (138, 144))	('Tyr187', 'Chemical', '-', (169, 175))	('Thr202', 'Chemical', '-', (127, 133))	('Tyr204', 'Chemical', '-', (138, 144))	('Erk2', 'Gene', (179, 183))	('p44', 'Var', (56, 59))	('Erk2', 'Gene', (89, 93))	('Thr185', 'Var', (158, 164))	('Thr202', 'Chemical', '-', (215, 221))	('Erk1', 'Gene', '5595', (148, 152))	('Erk2', 'Gene', '5594', (179, 183))
158397	21479234	The BRAF V600E mutation was identified in 12 of the 20 PXA (60%).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('V600E', 'Var', (9, 14))
158402	21479234	Interestingly, the mutation was present in 8 of 9 PXA demonstrating prominent mesenchymal-like growth pattern (PXA (m)), revealing a significant association of BRAF V600E mutation with PXA (m) (p value 0.028).	('V600E', 'Var', (165, 170))	('BRAF', 'Gene', (160, 164))	('V600E', 'Mutation', 'rs113488022', (165, 170))	('BRAF', 'Gene', '673', (160, 164))
158406	21479234	The BRAF V600E mutation was present in only one of the six aPXA, in the single gcGBM arising from a PXA in our cohort and in one of nine additional gcGBM (11%).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('V600E', 'Var', (9, 14))
158411	21479234	BRAF V600E mutation has not been previously reported in gcGBM but it has been reported to occur at low frequency in glioblastoma and in one case of gliosarcoma.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('glioblastoma', 'Disease', (116, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('V600E', 'Var', (5, 10))	('gliosarcoma', 'Disease', 'MESH:D018316', (148, 159))	('BRAF', 'Gene', '673', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('BRAF', 'Gene', (0, 4))	('gliosarcoma', 'Disease', (148, 159))
158413	21479234	In line with this mutation frequency, review of 62 standard glioblastoma cases that had undergone clinical testing at MGH using SNaPshot mutation profiling identified only one case with a BRAF V600E mutation (1.6%).	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('BRAF', 'Gene', '673', (188, 192))	('V600E', 'Mutation', 'rs113488022', (193, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('BRAF', 'Gene', (188, 192))	('V600E', 'Var', (193, 198))
158415	21479234	Review of these GBM cases also revealed additional low frequency mutations in cancer genes that have been previously described to be altered in standard GBM (Table 3) including mutations in IDH1 (3; 4.8%), KRAS (1; 1.6%), PIK3CA (4; 6.5%), and TP53 (7; 11.3%) supporting the strength of using multiplexed tumor genotyping to identify low frequency mutations, some of which can be treated with targeted therapeutics.	('PIK3CA', 'Gene', (222, 228))	('PIK3CA', 'Gene', '5290', (222, 228))	('IDH1', 'Gene', (190, 194))	('KRAS', 'Gene', '3845', (206, 210))	('TP53', 'Gene', (244, 248))	('mutations', 'Var', (177, 186))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('IDH1', 'Gene', '3417', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (305, 310))	('KRAS', 'Gene', (206, 210))	('mutations', 'Var', (65, 74))	('TP53', 'Gene', '7157', (244, 248))
158416	21479234	Also highlighting the strengths of a multiplexed genotyping approach is the observation that one of the mutations identified in IDH1 (c.394C>T) results in a R132C substitution that would not be identified by IHC using an IDH1 R132H mutation specific antibody.	('R132C', 'Var', (157, 162))	('IDH1', 'Gene', (221, 225))	('R132C', 'Mutation', 'rs121913499', (157, 162))	('c.394C>T', 'Var', (134, 142))	('IDH1', 'Gene', '3417', (128, 132))	('IDH1', 'Gene', '3417', (221, 225))	('c.394C>T', 'Mutation', 'rs121913499', (134, 142))	('results in', 'Reg', (144, 154))	('R132H', 'Mutation', 'rs121913500', (226, 231))	('IDH1', 'Gene', (128, 132))
158417	21479234	One TP53 mutation (p.R248Q; c.743G>A) was found in a gcGBM tumor sample but additional mutations profiled by the SNaPshot system were absent in these gcGBM cases.	('tumor', 'Disease', (59, 64))	('TP53', 'Gene', (4, 8))	('p.R248Q; c.743G>A', 'Var', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('c.743G>A', 'Mutation', 'rs11540652', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('p.R248Q', 'Mutation', 'rs11540652', (19, 26))	('TP53', 'Gene', '7157', (4, 8))
158418	21479234	Mutations in the TP53 gene have been reported in 60-90% of gcGBM cases.	('gcGBM', 'Disease', (59, 64))	('Mutations', 'Var', (0, 9))	('reported', 'Reg', (37, 45))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
158419	21479234	Since the SNaPshot panels used in our experiments cover less than 30% of the TP53 mutations that have been reported in gcGBM (COSMIC database, v49 release), the odds dictate that we would have detected a TP53 mutation in about 2 of the 9 cases in this study.	('dictate', 'Reg', (166, 173))	('TP53', 'Gene', '7157', (204, 208))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', (204, 208))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (77, 81))
158420	21479234	Support for the existence of TP53 mutations in many of the gcGBMs analyzed in this study was provided by p53 immunohistochemistry which revealed increased p53 expression in 7 of the 9 (78%) gcGBM.	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('increased', 'PosReg', (145, 154))	('p53', 'Gene', (105, 108))	('expression', 'MPA', (159, 169))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (29, 33))	('p53', 'Gene', '7157', (105, 108))	('mutations', 'Var', (34, 43))
158422	21479234	Of note, mutations at the most frequently affected amino acid residues in the isocitrate dehydrogenase genes 1 (IDH1, R132) and 2 (IDH2, R172) and TP53 (R175, G245, R248, R273 and R306) were not identified in any of PXA samples.	('IDH2', 'Gene', (131, 135))	('TP53', 'Gene', (147, 151))	('R306', 'Var', (180, 184))	('IDH1', 'Gene', '3417', (112, 116))	('G245', 'Var', (159, 163))	('R175', 'Var', (153, 157))	('IDH2', 'Gene', '3418', (131, 135))	('IDH1', 'Gene', (112, 116))	('R273', 'Var', (171, 175))	('R248', 'Var', (165, 169))	('TP53', 'Gene', '7157', (147, 151))
158427	21479234	Since BRAF duplication has been identified as a mechanism for activation of the MAPK pathway in pilocytic astrocytomas we investigated copy number alterations at the BRAF locus by FISH.	('BRAF', 'Gene', (166, 170))	('pilocytic astrocytomas', 'Disease', (96, 118))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('MAPK pathway', 'Pathway', (80, 92))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (96, 118))	('duplication', 'Var', (11, 22))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('BRAF', 'Gene', '673', (166, 170))	('activation', 'PosReg', (62, 72))
158429	21479234	While some tumors showed polysomy of chromosome 7 (3-5 copies) in a portion of the tumor cells, none of the tumors analyzed by FISH showed BRAF duplication (Fig.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('BRAF', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (11, 16))	('tumors', 'Disease', (11, 17))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('polysomy', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('BRAF', 'Gene', '673', (139, 143))
158435	21479234	Also of interest, is that a number of common mutations found in some classes of human glial tumors are absent in our PXA cohort, including mutations in IDH1 and IDH2  and that BRAF is not duplicated in PXA.	('IDH1', 'Gene', (152, 156))	('mutations', 'Var', (139, 148))	('IDH1', 'Gene', '3417', (152, 156))	('IDH2', 'Gene', (161, 165))	('glial tumors', 'Disease', 'MESH:D005910', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('human', 'Species', '9606', (80, 85))	('BRAF', 'Gene', '673', (176, 180))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('glial tumors', 'Disease', (86, 98))	('IDH2', 'Gene', '3418', (161, 165))	('BRAF', 'Gene', (176, 180))
158436	21479234	Also of note, during the review process of this manuscript, a separate study was published identifying BRAF V600E mutations in 66% of PXA, consistent with the findings in our study.	('PXA', 'Disease', (134, 137))	('BRAF', 'Gene', '673', (103, 107))	('V600E mutations', 'Var', (108, 123))	('V600E', 'Mutation', 'rs113488022', (108, 113))	('BRAF', 'Gene', (103, 107))
158440	21479234	The gcGBM arising in a PXA which harbored a BRAF V600E mutation in our series also arose from a PXA demonstrating a mesenchymal-like growth pattern and was also located in the temporal lobe.	('BRAF', 'Gene', '673', (44, 48))	('V600E', 'Var', (49, 54))	('BRAF', 'Gene', (44, 48))	('mesenchymal-like growth pattern', 'CPA', (116, 147))	('V600E', 'Mutation', 'rs113488022', (49, 54))
158441	21479234	Analysis of more PXA cases will be required to see whether the strong association holds between BRAF V600E mutation and PXA (m).	('V600E', 'Mutation', 'rs113488022', (101, 106))	('V600E', 'Var', (101, 106))	('BRAF', 'Gene', '673', (96, 100))	('PXA', 'Disease', (120, 123))	('BRAF', 'Gene', (96, 100))
158447	21479234	While a more complete survey of other uncommon low-grade gliomas is still required, it appears likely that the high frequency of BRAF V600E mutations will be the hallmark of PXA and GG.	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('PXA', 'Disease', (174, 177))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('V600E', 'Var', (134, 139))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
158449	21479234	One of the cases in our study (BT 20) demonstrates such mixed features and was found to carry a BRAF V600E mutation.	('BRAF', 'Gene', '673', (96, 100))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('BRAF', 'Gene', (96, 100))	('V600E', 'Var', (101, 106))
158452	21479234	The absence of BRAF duplication in our PXA series can help distinguish PXA from the 40% of non-cerebellar PAs and 80% of cerebellar PAs that have BRAF rearrangements.	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (146, 150))	('non-cerebellar PAs', 'Disease', (91, 109))	('BRAF', 'Gene', (15, 19))	('PXA', 'Disease', (71, 74))	('cerebellar PAs', 'Disease', 'MESH:D002528', (95, 109))	('cerebellar PAs', 'Disease', (121, 135))	('duplication', 'Var', (20, 31))	('cerebellar PAs', 'Disease', 'MESH:D002528', (121, 135))	('BRAF', 'Gene', '673', (146, 150))	('non-cerebellar PAs', 'Disease', 'MESH:D002528', (91, 109))
158453	21479234	The absence of IDH1 and IDH2 mutations in our PXA cohort suggests that these mutations are rare or not present in PXA, a feature that can help discriminate PXA from the 87.5% of diffuse glioma that bear mutations in these gene.	('glioma', 'Disease', (186, 192))	('IDH1', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('IDH1', 'Gene', '3417', (15, 19))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('IDH2', 'Gene', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('mutations', 'Var', (203, 212))	('IDH2', 'Gene', '3418', (24, 28))
158456	21479234	These findings suggest that PXA may be responsive to treatment with orally available BRAF kinase inhibitors such as PLX-4032 as well as by HSP90 inhibitors which destabilize mutated BRAF.	('HSP90', 'Gene', '3320', (139, 144))	('PLX-4032', 'Chemical', 'MESH:D000077484', (116, 124))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('BRAF', 'Gene', '673', (182, 186))	('mutated', 'Var', (174, 181))	('HSP90', 'Gene', (139, 144))	('BRAF', 'Gene', (182, 186))	('destabilize', 'NegReg', (162, 173))
158457	21479234	BRAF V600E-positive melanomas seem to be highly dependent on activation of the MAPK pathway for proliferation and maintenance functions.	('MAPK pathway', 'Pathway', (79, 91))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('V600E-positive', 'Var', (5, 19))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('activation', 'PosReg', (61, 71))	('melanomas', 'Disease', (20, 29))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))
158459	21479234	These studies have provided the proof-of-principle for the use of BRAF inhibitors in melanoma, and raise the possibility of using targeted small molecule therapeutics like PLX-4032 in the treatment of PXA and GG, particularly in the setting of recurrence or in cases where noncytotoxic chemotherapy can serve as an adjuvant treatment to permit resection of complex lesions.	('PXA', 'Disease', (201, 204))	('inhibitors', 'Var', (71, 81))	('PLX-4032', 'Chemical', 'MESH:D000077484', (172, 180))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('BRAF', 'Gene', '673', (66, 70))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (66, 70))
158460	21479234	Most critical now will be to demonstrate sensitivity of BRAF V600E-positive glioma cell lines and tumors to BRAF targeted therapeutics.	('tumors', 'Disease', (98, 104))	('glioma', 'Disease', (76, 82))	('V600E-positive', 'Var', (61, 75))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('BRAF', 'Gene', '673', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))	('BRAF', 'Gene', (56, 60))
158461	23104868	Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma The molecular foundations of lower-grade gliomas (LGGs):astrocytoma, oligodendroglioma, and oligoastrocytoma:remain less well characterized than those of their fully malignant counterpart, glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (290, 302))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('oligodendroglioma', 'Disease', (170, 187))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('astrocytoma', 'Disease', 'MESH:D001254', (198, 209))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('astrocytoma', 'Disease', (198, 209))	('astrocytoma', 'Disease', 'MESH:D001254', (157, 168))	('glioblastoma', 'Disease', (290, 302))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('astrocytoma', 'Disease', (157, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (290, 302))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (193, 209))	('ATRX', 'Gene', (34, 38))	('ATRX', 'Gene', '546', (34, 38))	('oligoastrocytoma', 'Disease', (193, 209))	('astrocytoma', 'Phenotype', 'HP:0009592', (198, 209))	('gliomas', 'Disease', (142, 149))	('mutation', 'Var', (39, 47))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', (142, 148))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('oligodendroglioma', 'Disease', 'MESH:D009837', (170, 187))	('glioma', 'Disease', (181, 187))
158462	23104868	Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events.	('IDH1/2', 'Gene', '3417;3418', (47, 53))	('Mutations', 'Var', (0, 9))	('IDH1/2', 'Gene', (47, 53))
158463	23104868	We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, and found a high incidence of mutations in the ATRX gene (alpha thalassemia/mental retardation syndrome X-linked).	('mutations', 'Var', (131, 140))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (165, 213))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (165, 213))	('mental retardation', 'Phenotype', 'HP:0001249', (177, 195))	('ATRX', 'Gene', (148, 152))	('ATRX', 'Gene', '546', (148, 152))
158465	23104868	Mutations in ATRX have been identified in multiple tumor types and appear to cause alternative lengthening of telomeres (ALT), a presumed precursor to genomic instability.	('identified', 'Reg', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cause', 'Reg', (77, 82))	('ATRX', 'Gene', (13, 17))	('ATRX', 'Gene', '546', (13, 17))	('Mutations', 'Var', (0, 9))	('multiple tumor', 'Disease', (42, 56))	('multiple tumor', 'Disease', 'MESH:D009369', (42, 56))
158466	23104868	In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma.	('TP53', 'Gene', '7157', (100, 104))	('oligodendroglioma', 'Disease', (219, 236))	('mutation', 'Var', (105, 113))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (100, 104))	('correlated', 'Reg', (84, 94))	('astrocytic differentiation', 'CPA', (118, 144))	('ATRX', 'Gene', '546', (16, 20))	('oligodendroglioma', 'Disease', 'MESH:D009837', (219, 236))	('mutation', 'Var', (21, 29))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ATRX', 'Gene', (16, 20))
158467	23104868	Moreover, ATRX mutation was highly enriched in tumors of so-called early progenitor-like transcriptional subclass (~85%), which our prior work has linked to specific cells of origin in the forebrain subventricular zone.	('mutation', 'Var', (15, 23))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('ATRX', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ATRX', 'Gene', '546', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
158468	23104868	Finally, ATRX mutation correlated with ALT, providing a mechanistic link to genomic instability.	('ATRX', 'Gene', '546', (9, 13))	('ALT', 'Disease', (39, 42))	('mutation', 'Var', (14, 22))	('correlated', 'Reg', (23, 33))	('ATRX', 'Gene', (9, 13))
158469	23104868	In summary, our findings both identify ATRX mutation as a defining molecular determinant for a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs.	('ATRX', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('ATRX', 'Gene', '546', (39, 43))	('implications', 'Reg', (146, 158))	('gliomas', 'Disease', (122, 129))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('IDH-mutant', 'Gene', (111, 121))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
158474	23104868	Recently, point mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in 70-90% of LGGs spanning across all morphologic subtypes.	('IDH1', 'Gene', (64, 68))	('identified', 'Reg', (88, 98))	('IDH1', 'Gene', '3417', (64, 68))	('point mutations', 'Var', (10, 25))	('IDH2', 'Gene', (73, 77))	('LGGs', 'Disease', (112, 116))	('IDH2', 'Gene', '3418', (73, 77))
158475	23104868	IDH mutations induce a neomorphic enzymatic activity that preferentially generates the oncometabolite R(-)-2-hydroxyglutarate at the expense of the normal TCA cycle component alpha-ketoglutarate.	('IDH', 'Gene', (0, 3))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (102, 125))	('TCA', 'Chemical', 'MESH:D014238', (155, 158))	('mutations', 'Var', (4, 13))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (175, 194))	('preferentially', 'PosReg', (58, 72))
158476	23104868	And while this process appears to cause widespread disruptions in cellular physiology, particularly with respect to the epigenome, the precise mechanisms by which IDH mutation promotes tumorigenesis remain to be elucidated.	('tumor', 'Disease', (185, 190))	('mutation', 'Var', (167, 175))	('IDH', 'Gene', (163, 166))	('cellular', 'MPA', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('promotes', 'PosReg', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
158477	23104868	In this setting, it is highly likely that additional molecular aberrations conspire with IDH mutation to induce tumorigenesis.	('induce', 'PosReg', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('IDH', 'Gene', (89, 92))	('tumor', 'Disease', (112, 117))	('mutation', 'Var', (93, 101))
158478	23104868	It has been known for some time that coordinated loss of chromosomes 1p and 19q (1p/19q codeletion) designates a prognostically favorable LGG subgroup comprised primarily of oligodendrogliomas and, to a lesser extent, oligoastrocytomas, while largely excluding astrocytomas.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (218, 235))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (174, 192))	('loss', 'Var', (49, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (223, 234))	('astrocytomas', 'Disease', 'MESH:D001254', (261, 273))	('LGG', 'Disease', (138, 141))	('chromosomes 1p', 'Var', (57, 71))	('astrocytomas', 'Disease', 'MESH:D001254', (223, 235))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (261, 272))	('oligodendrogliomas', 'Disease', (174, 192))	('astrocytomas', 'Disease', (261, 273))	('astrocytomas', 'Disease', (223, 235))	('oligoastrocytomas', 'Disease', (218, 235))
158479	23104868	More recent work has demonstrated an almost invariable association between 1p/19q codeletion and IDH mutation, implying that both abnormalities are required for transformation in tumors of fundamentally oligodendroglial lineage.	('tumors of fundamentally oligodendroglial', 'Disease', (179, 219))	('IDH', 'Gene', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors of fundamentally oligodendroglial', 'Disease', 'MESH:D009369', (179, 219))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('1p/19q codeletion', 'Var', (75, 92))	('mutation', 'Var', (101, 109))
158480	23104868	By contrast, the molecular landscape of LGGs harboring intact 1p/19q:predominantly astrocytomas:appears less uniform, with mutations in TP53 representing their single most prevalent genomic anomaly apart from IDH mutation.	('anomaly', 'Disease', 'MESH:D000014', (190, 197))	('astrocytomas', 'Disease', 'MESH:D001254', (83, 95))	('anomaly', 'Disease', (190, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('astrocytomas', 'Disease', (83, 95))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))	('mutations', 'Var', (123, 132))	('prevalent', 'Reg', (172, 181))
158482	23104868	These latter two subclasses were further delineated by different rates of TP53 mutation and their associations, by way of gene expression patterns, to distinct neuroglial precursor cell pools.	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('associations', 'Interaction', (98, 110))
158484	23104868	We found a strikingly high incidence of mutations in the ATRX gene (alpha thalassemia/mental retardation syndrome X-linked), entirely restricted to IDH-mutant LGGs of astrocytic lineage:astrocytomas and oligoastrocytomas:and mutually exclusive with 1p/19q codeletion.	('mental retardation', 'Phenotype', 'HP:0001249', (86, 104))	('astrocytomas and oligoastrocytomas', 'Disease', 'MESH:D001254', (186, 220))	('ATRX', 'Gene', '546', (57, 61))	('mutations', 'Var', (40, 49))	('astrocytoma', 'Phenotype', 'HP:0009592', (186, 197))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (74, 122))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (74, 122))	('ATRX', 'Gene', (57, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (208, 219))
158486	23104868	Dysfunction of the ATRX/DAXX complex results in a phenomenon known as alternative lengthening of telomeres (ALT) along with more widespread genomic destabilization.	('results in', 'Reg', (37, 47))	('Dysfunction', 'Var', (0, 11))	('ATRX', 'Gene', '546', (19, 23))	('DAXX', 'Gene', (24, 28))	('ATRX', 'Gene', (19, 23))	('DAXX', 'Gene', '1616', (24, 28))
158487	23104868	Mutations in ATRX and, to a lesser extent, DAXX have recently been identified in a number of tumor subtypes, including pediatric and adult gliomas.	('adult gliomas', 'Disease', 'MESH:D005910', (133, 146))	('ATRX', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ATRX', 'Gene', '546', (13, 17))	('tumor', 'Disease', (93, 98))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (67, 77))	('adult gliomas', 'Disease', (133, 146))	('pediatric', 'Disease', (119, 128))	('DAXX', 'Gene', '1616', (43, 47))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('DAXX', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
158489	23104868	Moreover, we demonstrate that ATRX mutation represents the defining molecular abnormality delineating the EPL subclass of LGG from other IDH-mutant astrocytic tumors.	('LGG', 'Disease', (122, 125))	('astrocytic tumors', 'Disease', (148, 165))	('ATRX', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('astrocytic tumors', 'Disease', 'MESH:D001254', (148, 165))	('ATRX', 'Gene', '546', (30, 34))	('mutation', 'Var', (35, 43))
158490	23104868	Finally, we correlate ATRX mutation with ALT, recapitulating a functional association with mitotic instability seen in other ATRX-mutant tumor types.	('ATRX', 'Gene', (22, 26))	('ATRX', 'Gene', '546', (125, 129))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('ATRX', 'Gene', '546', (22, 26))	('mutation', 'Var', (27, 35))	('ATRX', 'Gene', (125, 129))	('mitotic instability', 'MPA', (91, 110))	('ALT', 'Disease', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
158493	23104868	We found that C:G to T:A transitions predominated, as has been reported for several other cancer subtypes (Tables S3-S4).	('C:G to T:A', 'Var', (14, 24))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
158494	23104868	The resulting list of confirmed mutations demonstrated only 3 genes altered in more than one tumor: IDH1, TP53, and ATRX (Table 1).	('ATRX', 'Gene', (116, 120))	('IDH1', 'Gene', '3417', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ATRX', 'Gene', '546', (116, 120))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (32, 41))	('IDH1', 'Gene', (100, 104))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
158495	23104868	ATRX mutation was present in 3 of 4 tumors, representing the most frequent genomic alteration in our sample set apart from IDH mutation.	('ATRX', 'Gene', (0, 4))	('ATRX', 'Gene', '546', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutation', 'Var', (5, 13))
158499	23104868	We found that ATRX mutations were present in 12 tumors, all of which also harbored IDH1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('IDH1', 'Gene', '3417', (83, 87))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('ATRX', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('ATRX', 'Gene', '546', (14, 18))	('harbored', 'Reg', (74, 82))	('IDH1', 'Gene', (83, 87))
158502	23104868	The pattern of ATRX mutations exhibited remarkable associations with other genomic abnormalities within IDH-mutant LGGs.	('ATRX', 'Gene', '546', (15, 19))	('associations', 'Interaction', (51, 63))	('LGGs', 'Disease', (115, 119))	('IDH-mutant', 'Var', (104, 114))	('ATRX', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('IDH-mutant', 'Gene', (104, 114))
158503	23104868	For instance, ATRX mutation was significantly correlated with TP53 mutation (P=0.0189) and anticorrelated with 1p/19q codeletion to the point of complete mutual exclusivity (P=0.0003).	('TP53', 'Gene', '7157', (62, 66))	('mutation', 'Var', (19, 27))	('TP53', 'Gene', (62, 66))	('correlated', 'Reg', (46, 56))	('ATRX', 'Gene', (14, 18))	('ATRX', 'Gene', '546', (14, 18))
158505	23104868	Given these findings, we were not surprised that ATRX mutation was also strongly linked to astrocytic and oligoastrocytic morphology, as opposed to pure oligodendroglial morphology (P=0.0009).	('mutation', 'Var', (54, 62))	('oligodendroglial morphology', 'Phenotype', 'HP:0100709', (153, 180))	('ATRX', 'Gene', (49, 53))	('ATRX', 'Gene', '546', (49, 53))	('linked', 'Reg', (81, 87))
158506	23104868	No significant correlations were found between ATRX mutation and either patient age, primary/recurrent tumor status, or tumor grade.	('ATRX', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('ATRX', 'Gene', '546', (47, 51))	('patient', 'Species', '9606', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mutation', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (120, 125))
158507	23104868	Similar to that seen previous reports, the distribution of ATRX mutations identified in our sample set was broad, spread across more than half of the protein, and consisted of frameshift (6), nonsense (2), missense (1), and in-frame deletion (3) variants.	('ATRX', 'Gene', (59, 63))	('in-frame deletion', 'Var', (224, 241))	('mutations', 'Var', (64, 73))	('ATRX', 'Gene', '546', (59, 63))
158508	23104868	There were no readily apparent associations between the type or location of specific ATRX mutations and other genomic, demographic, or histopathological parameters, although our sample size likely precluded robust analysis in this regard.	('ATRX', 'Gene', '546', (85, 89))	('ATRX', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))
158509	23104868	To determine the composition of ATRX mutations within each subclass, we developed a multiplexed mRNA profiling assay on the Nanostring platform consisting of a 75-gene signature (25 upregulated genes per subclass) and applied it to total RNA derived from 1p/19q-intact tumors in our sample set.	('ATRX', 'Gene', '546', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', (269, 275))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('ATRX', 'Gene', (32, 36))
158512	23104868	We found a striking association between ATRX mutation and EPL subclass (P=0.0044) (Table 2).	('EPL subclass', 'Disease', (58, 70))	('mutation', 'Var', (45, 53))	('ATRX', 'Gene', (40, 44))	('ATRX', 'Gene', '546', (40, 44))
158513	23104868	In total, 85% (11/13) of astrocytic LGGs designated as EPL by expression profiling harbored ATRX mutations, and 92% (11/12) of ATRX mutations were found in EPL tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (97, 106))	('ATRX', 'Gene', (92, 96))	('ATRX', 'Gene', (127, 131))	('EPL tumors', 'Disease', (156, 166))	('ATRX', 'Gene', '546', (92, 96))	('ATRX', 'Gene', '546', (127, 131))	('harbored', 'Reg', (83, 91))	('EPL tumors', 'Disease', 'MESH:D009369', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('astrocytic LGGs', 'Disease', (25, 40))
158514	23104868	Taken together, these findings indicate that ATRX mutation itself represents the defining molecular abnormality of a distinct astrocytoma subclass delineated by gene expression.	('astrocytoma', 'Disease', 'MESH:D001254', (126, 137))	('astrocytoma', 'Disease', (126, 137))	('ATRX', 'Gene', (45, 49))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('ATRX', 'Gene', '546', (45, 49))	('mutation', 'Var', (50, 58))
158515	23104868	Previous studies have directly linked ATRX mutation to ALT and genomic instability in a variety of tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('mutation', 'Var', (43, 51))	('ATRX', 'Gene', (38, 42))	('ALT', 'MPA', (55, 58))	('genomic', 'MPA', (63, 70))	('ATRX', 'Gene', '546', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))
158517	23104868	Consistent with earlier reports, we found a notably strong association between ATRX mutation and ALT (P<0.0001), as indicated by ultrabright foci of intranuclear positivity by telomere FISH in multiple tumor cells (FIG.	('ALT', 'Disease', (97, 100))	('intranuclear positivity', 'Phenotype', 'HP:0003493', (149, 172))	('multiple tumor', 'Disease', (193, 207))	('multiple tumor', 'Disease', 'MESH:D009369', (193, 207))	('ATRX', 'Gene', (79, 83))	('ATRX', 'Gene', '546', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('mutation', 'Var', (84, 92))
158518	23104868	In total, 11/12 (92% of LGGs with ATRX mutations exhibited ALT, and 11/12 (92%) of LGGs with ALT harbored ATRX mutations.	('ATRX', 'Gene', (106, 110))	('exhibited', 'Reg', (49, 58))	('ATRX', 'Gene', (34, 38))	('ALT', 'MPA', (59, 62))	('ATRX', 'Gene', '546', (106, 110))	('mutations', 'Var', (39, 48))	('ATRX', 'Gene', '546', (34, 38))
158520	23104868	The sheer frequency of IDH mutation in LGG demonstrates its biological relevance and highlights the unequivocal importance of epigenomics and metabolomics in gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('mutation', 'Var', (27, 35))	('glioma', 'Disease', (158, 164))	('IDH', 'Gene', (23, 26))
158521	23104868	Indeed, the inability of IDH mutation to promote glioma formation in mouse models thus far underscores this quandary, and further implies that additional molecular alterations are likely required for transformation.	('mutation', 'Var', (29, 37))	('IDH', 'Gene', (25, 28))	('mouse', 'Species', '10090', (69, 74))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('promote', 'PosReg', (41, 48))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Disease', (49, 55))
158522	23104868	We employed both whole exome and targeted next-generation sequencing approaches to identify ATRX mutations in a significant percentage of LGGs.	('mutations', 'Var', (97, 106))	('ATRX', 'Gene', '546', (92, 96))	('LGGs', 'Disease', (138, 142))	('ATRX', 'Gene', (92, 96))
158523	23104868	Intriguingly, the distribution of ATRX mutations tracked with specific diagnostic and molecularly defined tumor subclasses.	('ATRX', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ATRX', 'Gene', '546', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
158524	23104868	Specifically, their presence was entirely restricted to IDH-mutant, 1p/19q-intact LGGs, astrocytic and oligoastrocytic in their morphology, where they were found in ~70% of tumors and exhibited a tight correlation with TP53 mutation.	('1p/19q-intact', 'Var', (68, 81))	('TP53', 'Gene', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('IDH-mutant', 'Var', (56, 66))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('TP53', 'Gene', '7157', (219, 223))
158528	23104868	Indeed, frequent ATRX mutations (~79%) were revealed in a smaller cohort of tumors actually subjected to sequencing in this same study.	('ATRX', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ATRX', 'Gene', '546', (17, 21))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (22, 31))
158529	23104868	Regardless, together with ours, both reports support a fundamental molecular stratification of LGGs based on IDH and ATRX mutational status and 1p/19q codeletion.	('mutational', 'Var', (122, 132))	('LGGs', 'Disease', (95, 99))	('ATRX', 'Gene', (117, 121))	('ATRX', 'Gene', '546', (117, 121))
158530	23104868	Additionally, our data indicate that abnormalities in ATRX represent the defining molecular characteristic of the EPL subclass of astrocytic LGGs.	('abnormalities', 'Var', (37, 50))	('ATRX', 'Gene', '546', (54, 58))	('ATRX', 'Gene', (54, 58))
158531	23104868	We considered the possibility that functional loss of ATRX, a known chromatin regulator, might itself drive the EPL transcriptional signature.	('drive', 'PosReg', (102, 107))	('ATRX', 'Gene', '546', (54, 58))	('loss', 'Var', (46, 50))	('EPL transcriptional signature', 'MPA', (112, 141))	('ATRX', 'Gene', (54, 58))
158532	23104868	However, the recent finding that ATRX loss does not significantly alter H3.3 profiles across the coding genome argues against this, and suggests a more fundamental association between EPL subclass and specific cells of origin for IDH-mutant LGG.	('ATRX', 'Gene', (33, 37))	('LGG', 'Gene', (241, 244))	('IDH-mutant', 'Var', (230, 240))	('ATRX', 'Gene', '546', (33, 37))
158534	23104868	The high frequency of ATRX mutations in EPL tumors, therefore, implies either a unique propensity of this specific SVZ progenitor population to acquire ATRX mutation or a particular sensitivity to its biological effects.	('ATRX', 'Gene', (22, 26))	('mutations', 'Var', (27, 36))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('EPL tumors', 'Disease', (40, 50))	('ATRX', 'Gene', '546', (22, 26))	('mutation', 'Var', (157, 165))	('EPL tumors', 'Disease', 'MESH:D009369', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ATRX', 'Gene', (152, 156))	('ATRX', 'Gene', '546', (152, 156))
158535	23104868	The invariable co-occurrence of ATRX mutations with IDH mutations, and their frequent association with TP53 mutation support a cooperative pathogenic mechanism by which dysfunction in all three proteins is required for oncogenesis in a large subset of LGG.	('TP53', 'Gene', '7157', (103, 107))	('ATRX', 'Gene', '546', (32, 36))	('TP53', 'Gene', (103, 107))	('IDH', 'Gene', (52, 55))	('mutation', 'Var', (108, 116))	('mutations', 'Var', (37, 46))	('ATRX', 'Gene', (32, 36))
158536	23104868	Additionally, multiple studies have demonstrated that loss of ATRX protein or ATRX mutation results in ALT and genomic instability, and our own findings recapitulate these functional relationships in IDH-mutant LGGs.	('ATRX', 'Gene', (78, 82))	('ATRX', 'Gene', '546', (78, 82))	('loss', 'NegReg', (54, 58))	('ATRX', 'Gene', (62, 66))	('mutation', 'Var', (83, 91))	('genomic instability', 'CPA', (111, 130))	('LGGs', 'Disease', (211, 215))	('ATRX', 'Gene', '546', (62, 66))	('ALT', 'CPA', (103, 106))
158538	23104868	The recent identification of H3.3 histone protein mutations in pediatric GBM and diffuse intrinsic pontine glioma (DIPG) is particularly intriguing in light of our present findings.	('mutations', 'Var', (50, 59))	('H3.3', 'Gene', (29, 33))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('histone protein', 'Protein', (34, 49))	('glioma', 'Disease', (107, 113))
158539	23104868	Specifically, their frequent association with ATRX and TP53 mutations suggests a functional equivalence with IDH mutation in adult glioma, with both fundamentally altering global epigenomic landscape and cellular differentiation state.	('glioma', 'Disease', (131, 137))	('ATRX', 'Gene', '546', (46, 50))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('altering', 'Reg', (163, 171))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('ATRX', 'Gene', (46, 50))	('mutations', 'Var', (60, 69))	('association', 'Interaction', (29, 40))
158540	23104868	Similarly, the mutual exclusivity of ATRX mutation with 1p/19q deletion in adult IDH-mutant LGGs also implies analogous functionality, perhaps in the mediation of genomic instability.	('1p/19q deletion', 'Var', (56, 71))	('ATRX', 'Gene', '546', (37, 41))	('mutation', 'Var', (42, 50))	('ATRX', 'Gene', (37, 41))
158548	23104868	The data were filtered using cutoffs of 3% allelic frequency for the variant allele in tumor and 97% allelic frequency for the reference (hg19) allele in normal.	('variant', 'Var', (69, 76))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
158549	23104868	To assemble a list of high-value mutations for initial validation, we selected all recurrent mutations and non-recurrent mutations meeting the following criteria: 1) 20X and 9X coverage in normal and tumor samples respectively, 2) an average regional (100 bp) phred mapping quality score of >15, 3) presence of mutations on nonduplicated reads, 4) mutational allelic frequency of >15, and 4) a MutationAssessor functional impact score of >1.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutational', 'Var', (348, 358))	('tumor', 'Disease', (200, 205))	('mutations', 'Var', (311, 320))
158580	32382477	GBM was the first tumor characterized by TCGA, whose molecular studies identified three important genetic events in human GBM: 1) dysregulation of growth signaling via amplification and mutational activation of receptor tyrosine kinase (RTK) genes, 2) activation of the phosphatidylinositol-3-OH-kinase (PI(3)K) pathway, and 3) inactivation of the p53 and retinoblastoma tumor suppressor pathways.	('retinoblastoma', 'Phenotype', 'HP:0009919', (356, 370))	('mutational', 'Var', (186, 196))	('tumor', 'Disease', (371, 376))	('dysregulation', 'MPA', (130, 143))	('receptor tyrosine kinase', 'Gene', (211, 235))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('inactivation', 'NegReg', (328, 340))	('tumor', 'Disease', (18, 23))	('p53', 'Gene', '7157', (348, 351))	('retinoblastoma tumor', 'Disease', (356, 376))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('RTK', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('phosphatidylinositol-3-OH-kinase', 'Gene', (270, 302))	('phosphatidylinositol-3-OH-kinase', 'Gene', '5290', (270, 302))	('RTK', 'Gene', '5979', (237, 240))	('p53', 'Gene', (348, 351))	('human', 'Species', '9606', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('activation', 'PosReg', (252, 262))	('activation', 'PosReg', (197, 207))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (356, 376))	('receptor tyrosine kinase', 'Gene', '5979', (211, 235))	('growth signaling', 'MPA', (147, 163))
158588	32382477	This new classification includes GBM in the diffuse astrocytic and oligodendroglial tumors group and divides it into three subgroups based on isocitrate dehydrogenase (IDH) mutations: 1) glioblastoma, IDH-wildtype, clinically identified as primary GBM or de novo GBM and predominant in patients over 55 years of age (10% of cases), 2) glioblastoma, IDH-mutant, clinically identified as secondary GBM and more common in younger patients (90% of cases), and 3) glioblastoma NOS (not otherwise specified), which does not fit into the other categories and is not well defined (Table  1 ).	('glioblastoma', 'Disease', (459, 471))	('patients', 'Species', '9606', (427, 435))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (67, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (459, 471))	('IDH', 'Gene', '3417', (201, 204))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('glioblastoma', 'Disease', (187, 199))	('IDH', 'Gene', (349, 352))	('isocitrate dehydrogenase', 'Gene', (142, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('IDH', 'Gene', '3417', (168, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (335, 347))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('IDH', 'Gene', '3417', (349, 352))	('glioblastoma', 'Disease', (335, 347))	('glioblastoma', 'Phenotype', 'HP:0012174', (335, 347))	('mutations', 'Var', (173, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (459, 471))	('isocitrate dehydrogenase', 'Gene', '3417', (142, 166))	('oligodendroglial tumors', 'Disease', (67, 90))	('IDH', 'Gene', (201, 204))	('glioblastoma', 'Disease', 'MESH:D005909', (187, 199))	('patients', 'Species', '9606', (286, 294))	('IDH', 'Gene', (168, 171))
158594	32382477	By the integration and analysis of multi-dimensional genomic data, they identified four clinically relevant subtypes of GBM characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.	('GBM', 'Disease', (120, 123))	('IDH1', 'Gene', (166, 170))	('PDGFRA', 'Gene', '5156', (158, 164))	('EGFR', 'Gene', '1956', (172, 176))	('abnormalities', 'Var', (141, 154))	('IDH1', 'Gene', '3417', (166, 170))	('EGFR', 'Gene', (172, 176))	('NF1', 'Gene', (182, 185))	('NF1', 'Gene', '4763', (182, 185))	('PDGFRA', 'Gene', (158, 164))
158598	32382477	Primary GBMs harbor three main genetic aberrations, which has been confirmed by the analysis of single nucleotide polymorphisms (SNPs): 1) amplification and/or high rate of EGFR mutation in chromosome 7p, 2) homozygous deletion of CDKN2A-p16INK4a in chromosome 9p, and 3) deletion of PTEN, frequently associated with monosomy 10.	('p16INK4a', 'Gene', '1029', (238, 246))	('CDKN2A', 'Gene', (231, 237))	('mutation', 'Var', (178, 186))	('PTEN', 'Gene', (284, 288))	('EGFR', 'Gene', '1956', (173, 177))	('CDKN2A', 'Gene', '1029', (231, 237))	('PTEN', 'Gene', '5728', (284, 288))	('deletion', 'Var', (272, 280))	('p16INK4a', 'Gene', (238, 246))	('EGFR', 'Gene', (173, 177))	('associated', 'Reg', (301, 311))
158599	32382477	[  15  ] Amplification of oncogene MDM2 has also been observed, specially, in tumors with no TP53 and TERT mutations.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('TERT', 'Gene', (102, 106))	('TERT', 'Gene', '7015', (102, 106))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Amplification', 'Var', (9, 22))	('MDM2', 'Gene', '4193', (35, 39))	('MDM2', 'Gene', (35, 39))
158600	32382477	Other genetic aberrations were described in the TCGA study of GBM in 2008, such as NF1 mutations and homozygous deletion of PI3KR1.	('NF1', 'Gene', '4763', (83, 86))	('NF1', 'Gene', (83, 86))	('mutations', 'Var', (87, 96))	('PI3KR1', 'Gene', (124, 130))
158601	32382477	[  10  ]  In contrast to primary GBMs, TP53 mutations, associated with methylation of the promoter of MGMT, are observed in most secondary GBMs, along with partial loss of heterozygosity of 10q, 13q, 19q, and 22q.	('10q', 'Var', (190, 193))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('13q', 'Var', (195, 198))	('MGMT', 'Gene', (102, 106))	('19q', 'Var', (200, 203))	('MGMT', 'Gene', '4255', (102, 106))	('TP53', 'Gene', (39, 43))
158603	32382477	in 2009, when they found out that these mutations occurred in most patients with secondary GBM and were associated with an increase in overall survival OS).	('mutations', 'Var', (40, 49))	('increase', 'PosReg', (123, 131))	('overall survival', 'MPA', (135, 151))	('patients', 'Species', '9606', (67, 75))
158604	32382477	[  17  ] Nowadays, after subsequent studies regarding this issue, it is agreed that IDH1 mutation is the most reliable diagnostic molecular marker of secondary GBMs.	('mutation', 'Var', (89, 97))	('IDH1', 'Gene', (84, 88))	('secondary GBMs', 'Disease', (150, 164))	('IDH1', 'Gene', '3417', (84, 88))
158609	32382477	found that pediatric GBMs exhibit mutations in H3F3A and DAXX, rarely seen in adult GBMs.	('DAXX', 'Gene', (57, 61))	('H3F3A', 'Gene', '3020', (47, 52))	('H3F3A', 'Gene', (47, 52))	('DAXX', 'Gene', '1616', (57, 61))	('mutations', 'Var', (34, 43))
158610	32382477	to establish six distinct DNA methylation clusters: 1) "IDH," 2) "K27," 3) "G34," 4) "RTK I (PDGFRA)," 5) "mesenchymal," and 6) "RTK II (classic)."	('RTK', 'Gene', (86, 89))	('RTK', 'Gene', '5979', (129, 132))	('mesenchymal', 'CPA', (107, 118))	('IDH', 'Gene', (56, 59))	('PDGFRA', 'Gene', (93, 99))	('RTK', 'Gene', '5979', (86, 89))	('RTK', 'Gene', (129, 132))	('IDH', 'Gene', '3417', (56, 59))	('PDGFRA', 'Gene', '5156', (93, 99))	('K27', 'Gene', '342574', (66, 69))	('K27', 'Gene', (66, 69))	('G34', 'Var', (76, 79))
158627	32382477	This model is supported by the existence of common mutations in G1/S cell cycle checkpoint, RTK/MAPK/PI3K and TP53.	('RTK', 'Gene', '5979', (92, 95))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('RTK', 'Gene', (92, 95))	('G1/S cell cycle checkpoint', 'Gene', (64, 90))
158653	32382477	IDH mutations are common in secondary GBM (85%) and rarely found in primary GBM (5%).	('IDH', 'Gene', (0, 3))	('common', 'Reg', (18, 24))	('secondary GBM', 'Disease', (28, 41))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))
158654	32382477	They drive the tumor progression in early phases and are positively correlated with other genetic abnormalities found in low-grade gliomas, like TP53 and ATRX mutations and 1p/19q co-deletion; they display an inverse correlation with EGFR gene amplification and monosomy of chromosome 10, which are common events in primary GBM.	('gliomas', 'Disease', (131, 138))	('EGFR', 'Gene', (234, 238))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('ATRX', 'Gene', (154, 158))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('TP53', 'Gene', '7157', (145, 149))	('ATRX', 'Gene', '546', (154, 158))	('TP53', 'Gene', (145, 149))	('tumor', 'Disease', (15, 20))	('monosomy', 'Var', (262, 270))	('genetic abnormalities', 'Disease', 'MESH:D030342', (90, 111))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('EGFR', 'Gene', '1956', (234, 238))	('genetic abnormalities', 'Disease', (90, 111))
158655	32382477	[  17  ] In spite of these differences, the TCGA study identified, in 2008, three important genetic events in human GBMs: 1) dysregulation of growth signaling via amplification and mutational activation of RTK genes, 2) activation of the phosphatidylinositol-3-OH-kinase (PI(3)K) pathway, and 3) inactivation of the p53 and retinoblastoma tumor suppressor pathways.	('RTK', 'Gene', (206, 209))	('p53', 'Gene', (316, 319))	('dysregulation', 'MPA', (125, 138))	('p53', 'Gene', '7157', (316, 319))	('RTK', 'Gene', '5979', (206, 209))	('growth signaling', 'MPA', (142, 158))	('inactivation', 'NegReg', (296, 308))	('activation', 'PosReg', (220, 230))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('mutational', 'Var', (181, 191))	('human', 'Species', '9606', (110, 115))	('activation', 'PosReg', (192, 202))	('retinoblastoma', 'Phenotype', 'HP:0009919', (324, 338))	('phosphatidylinositol-3-OH-kinase', 'Gene', (238, 270))	('retinoblastoma tumor', 'Disease', (324, 344))	('phosphatidylinositol-3-OH-kinase', 'Gene', '5290', (238, 270))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (324, 344))
158659	32382477	Cancer cells are able to reprogram their metabolism in order to acquire survival adaptive advantages via genetic or epigenetic alterations of metabolism-related genes; for example, oncogene IDH.	('epigenetic alterations', 'Var', (116, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('IDH', 'Gene', (190, 193))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('IDH', 'Gene', '3417', (190, 193))	('genetic', 'Var', (105, 112))
158663	32382477	[  48  ] Mutations in IDH1 and IDH2 cause structural changes that result in the loss of affinity for isocitrate and acquisition of the ability to catalyze the NADPH-dependent reduction of alpha-KG to R(-)-2-hidroxyglutarate (2HG).	('Mutations', 'Var', (9, 18))	('alpha-KG to R(-)-2-hidroxyglutarate', 'Chemical', '-', (188, 223))	('ability', 'MPA', (135, 142))	('IDH2', 'Gene', '3418', (31, 35))	('loss', 'NegReg', (80, 84))	('affinity', 'Interaction', (88, 96))	('acquisition', 'PosReg', (116, 127))	('NADPH', 'Gene', (159, 164))	('IDH1', 'Gene', (22, 26))	('catalyze', 'MPA', (146, 154))	('isocitrate', 'Chemical', 'MESH:C034219', (101, 111))	('NADPH', 'Gene', '1666', (159, 164))	('IDH1', 'Gene', '3417', (22, 26))	('IDH2', 'Gene', (31, 35))	('2HG', 'Chemical', '-', (225, 228))
158668	32382477	[  51  ] Thus, degradation of 2HG occurs in tumors that exhibit IDH mutations, which is consistent with the idea that these tumors lack necrosis and microvascular proliferation.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('IDH', 'Gene', '3417', (64, 67))	('2HG', 'Chemical', '-', (30, 33))	('tumors lack necrosis', 'Disease', 'MESH:D001259', (124, 144))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('degradation', 'MPA', (15, 26))	('tumors lack necrosis', 'Disease', (124, 144))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (68, 77))	('IDH', 'Gene', (64, 67))
158674	32382477	The first one is the dysfunction of cadherin junctions that hold the primary mass together, which has been demonstrated to be a major contributor to cancer progression.	('cancer', 'Disease', (149, 155))	('dysfunction', 'Var', (21, 32))	('contributor', 'Reg', (134, 145))	('cadherin junctions', 'Protein', (36, 54))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
158677	32382477	[  61  ] Cell growth and phenotype are partially controlled by the cell-to-cell exchange of growth regulatory factors through gap junctions, so the impairment of this exchange can lead to unregulated growth and neoplasia.	('lead to', 'Reg', (180, 187))	('neoplasia', 'Disease', (211, 220))	('impairment', 'Var', (148, 158))	('neoplasia', 'Disease', 'MESH:D009369', (211, 220))	('neoplasia', 'Phenotype', 'HP:0002664', (211, 220))	('unregulated', 'MPA', (188, 199))
158679	32382477	[  59  ]  The third step is cleavage of CD44, which constitutes the anchor between the primary tumor mass and the ECM.	('CD44', 'Gene', (40, 44))	('cleavage', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CD44', 'Gene', '960', (40, 44))	('tumor', 'Disease', (95, 100))
158750	32382477	miRNAs are involved in essential pathways in GBM (proliferation, differentiation, apoptosis, migration, and angiogenesis) and have been associated with patient survival and therapy response.	('associated', 'Reg', (136, 146))	('apoptosis', 'CPA', (82, 91))	('migration', 'CPA', (93, 102))	('differentiation', 'CPA', (65, 80))	('involved', 'Reg', (11, 19))	('miRNAs', 'Var', (0, 6))	('patient', 'Species', '9606', (152, 159))
158751	32382477	Thus, 15 miRNAs with altered expression in GBM have been identified as potential biomarkers: miR-21, miR-221, miR-15-a/b, miR-182, miR128-a/b, miR-20a, miR-125b, miR-106-a/b, miR-17, miR-27a, miR-99-a/b, miR-130-a/b, miR-25, miR-23a, and miR-10b.	('miR-23a', 'Gene', '407010', (225, 232))	('miR-21', 'Gene', '406991', (93, 99))	('miR-23a', 'Gene', (225, 232))	('miR-106-a/b', 'Gene', (162, 173))	('miR-99-a/b', 'Gene', '407055', (192, 202))	('miR-99-a/b', 'Gene', (192, 202))	('miR-25', 'Gene', '407014', (217, 223))	('miR-27a', 'Gene', '407018', (183, 190))	('miR-130-a/b', 'Gene', (204, 215))	('miR128-a/b', 'Gene', '406915;406916', (131, 141))	('miR-15-a/b', 'Gene', (110, 120))	('miR-21', 'Gene', (93, 99))	('miR-17', 'Gene', (175, 181))	('miR-20a', 'Gene', (143, 150))	('miR-20a', 'Gene', '406982', (143, 150))	('miR128-a/b', 'Gene', (131, 141))	('miR-221', 'Gene', (101, 108))	('miR-106-a/b', 'Gene', '406899;406900', (162, 173))	('miR-221', 'Gene', '407006', (101, 108))	('miR-10b', 'Gene', (238, 245))	('miR-27a', 'Gene', (183, 190))	('miR-182', 'Gene', (122, 129))	('miR-15-a/b', 'Gene', '406948', (110, 120))	('miR-130-a/b', 'Gene', '406919;406920', (204, 215))	('miR-25', 'Gene', (217, 223))	('miR-10b', 'Gene', '406903', (238, 245))	('miR-182', 'Gene', '406958', (122, 129))	('miR-125b', 'Var', (152, 160))	('miR-17', 'Gene', '406952', (175, 181))
158756	32382477	In addition, exosomes can be found in the serum of GBM patients, so a blood test would provide information about mutations and splicing variants of mRNA and microRNA that are characteristic of tumor formation and progression, and their quantification would serve as a tool for monitoring response to therapies.	('microRNA', 'Protein', (157, 165))	('mRNA', 'Gene', (148, 152))	('splicing variants', 'Var', (127, 144))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mutations', 'Var', (113, 122))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', (193, 198))
158767	32382477	Aberrations in EGFR are present in  50% of GBMs.	('Aberrations', 'Var', (0, 11))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))
158771	32382477	[  123  ] Progression free survival (PFS) in phase I study was 30.8% and clinical development of ABT-414 is ongoing in randomized phase II trial for recurrent GBM (NCT02343406) and randomized phase IIb/III trial for newly diagnosed GBM (NCT02573324).	('NCT02573324', 'Var', (237, 248))	('ABT-414', 'Chemical', 'MESH:C000620234', (97, 104))	('NCT02343406', 'Var', (164, 175))
158776	32382477	In addition to mutation or deletion, inactivation of p53 may be due to amplification of MDM2 or MDM4.	('MDM2', 'Gene', '4193', (88, 92))	('MDM4', 'Gene', '4194', (96, 100))	('MDM2', 'Gene', (88, 92))	('MDM4', 'Gene', (96, 100))	('deletion', 'Var', (27, 35))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('inactivation', 'NegReg', (37, 49))
158777	32382477	Thus, inhibition of MDM2 has been proposed as a possible strategy to restore p53 function.	('function', 'MPA', (81, 89))	('MDM2', 'Gene', '4193', (20, 24))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('restore', 'PosReg', (69, 76))	('inhibition', 'Var', (6, 16))	('MDM2', 'Gene', (20, 24))
158780	32382477	[  30  ] Clinical trials evaluating CDK4/6 inhibitors are ongoing: ribociclib (NCT02345824) and palbociclib (NCT02255461) are two of these molecules.	('NCT02255461', 'Var', (109, 120))	('NCT02345824', 'Var', (79, 90))	('CDK4/6', 'Gene', '1019;1021', (36, 42))	('CDK4/6', 'Gene', (36, 42))
158784	32382477	Some of these molecules are veliparib (NCT03581292, NCT02152982, NCT01514201), olaparib (NCT03233204, NCT01390571, PARADIGM-2, NCT03212742), and pamiparib (NCT03150862, NCT03333915, NCT02361723).	('NCT03233204', 'Var', (89, 100))	('NCT03581292', 'Var', (39, 50))	('NCT03150862', 'Var', (156, 167))	('olaparib', 'Chemical', 'MESH:C531550', (79, 87))	('pamiparib', 'Chemical', '-', (145, 154))	('NCT03333915', 'Var', (169, 180))	('veliparib', 'Chemical', 'MESH:C521013', (28, 37))	('NCT01514201', 'Var', (65, 76))	('NCT02361723', 'Var', (182, 193))	('NCT02152982', 'Var', (52, 63))
158787	32382477	IDH1/2 mutations result in a gain of function, resulting in the production of 2HG, an oncometabolite that interferes with cell metabolism and epigenetic regulation.	('2HG', 'Chemical', '-', (78, 81))	('cell metabolism', 'MPA', (122, 137))	('production', 'MPA', (64, 74))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('epigenetic regulation', 'MPA', (142, 163))	('gain', 'PosReg', (29, 33))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
158788	32382477	Small inhibitory molecules of IDH mutants are being evaluated in clinical trials: ivosidenib (NCT02073994), vorasidenib (NCT02481154), enasidenib (NCT02273739), IDH305 (NCT02381886), DS-1001b (NCT03030066), and BAY1436032 (NCT02746081).	('DS-1001b', 'Chemical', '-', (183, 191))	('ivosidenib', 'Chemical', 'MESH:C000627630', (82, 92))	('IDH', 'Gene', '3417', (161, 164))	('NCT02381886', 'Var', (169, 180))	('IDH', 'Gene', (161, 164))	('vorasidenib', 'Chemical', '-', (108, 119))	('enasidenib', 'Chemical', 'MESH:C000605269', (135, 145))	('NCT02746081', 'Var', (223, 234))	('NCT02481154', 'Var', (121, 132))	('IDH', 'Gene', (30, 33))	('NCT02273739', 'Var', (147, 158))	('IDH305', 'Chemical', '-', (161, 167))	('NCT02073994', 'Var', (94, 105))	('IDH', 'Gene', '3417', (30, 33))	('NCT03030066', 'Var', (193, 204))	('BAY1436032', 'Chemical', 'MESH:C000622445', (211, 221))
158791	32382477	Vorinostat is a HDACi that is being evaluated in clinical trials alone or in combination with other drugs/radiation (NCT03426891, NCT00731731, NCT00268385, NCT00555399), despite showing no significant improvement in 6-month PFS and OS in combination with bevacizumab and TMZ.	('improvement', 'PosReg', (201, 212))	('NCT03426891', 'Var', (117, 128))	('PFS', 'CPA', (224, 227))	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('TMZ', 'Chemical', 'MESH:D000077204', (271, 274))	('NCT00555399', 'Var', (156, 167))	('bevacizumab', 'Chemical', 'MESH:D000068258', (255, 266))	('NCT00268385', 'Var', (143, 154))
158793	32382477	Givinostat counteracts GBM oncophenotype by inducing cell cycle arrest, apoptosis, autophagy-related nonapoptotic cell death and differentiation, and reduction on GBM stemness potential.	('arrest', 'Disease', (64, 70))	('Givinostat', 'Var', (0, 10))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('GBM stemness potential', 'CPA', (163, 185))	('inducing', 'PosReg', (44, 52))	('reduction', 'NegReg', (150, 159))	('autophagy-related', 'CPA', (83, 100))	('apoptosis', 'CPA', (72, 81))	('Givinostat', 'Chemical', 'MESH:C575255', (0, 10))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('differentiation', 'CPA', (129, 144))
158794	32382477	In vivo experiments showed that givinostat efficiently passes the BBB and impairs GBM growth in orthotopic xenotransplanted mice.	('givinostat', 'Var', (32, 42))	('impairs', 'NegReg', (74, 81))	('GBM growth', 'CPA', (82, 92))	('mice', 'Species', '10090', (124, 128))	('givinostat', 'Chemical', 'MESH:C575255', (32, 42))
158816	32382477	The most promising viruses undergoing clinical trials currently are DNX-2401 (NCT02798406), PVS-RIPO (NCT03043391), and Toca 511 (NCT02414165).	('NCT02798406', 'Var', (78, 89))	('NCT03043391', 'Var', (102, 113))	('DNX', 'Chemical', 'MESH:C426804', (68, 71))	('NCT02414165', 'Var', (130, 141))
158850	32382477	But still, GBM causes the death of thousands of people across the planet every year, with no possibilities to stop the progression of the disease.	('death', 'Disease', 'MESH:D003643', (26, 31))	('causes', 'Reg', (15, 21))	('people', 'Species', '9606', (48, 54))	('death', 'Disease', (26, 31))	('GBM', 'Var', (11, 14))
158881	31149044	Several inhibitors of PDI have been identified, including PACMA31 for the treatment of ovarian cancer, 16F16 and LOC14 for the prevention of neurodegeneration, CCF642 for the treatment of multiple myeloma, juniferdin for the inhibition of HIV-1 infection, bepristats and quercetin-3-rutinoside for the suppression of thrombus formation, and KSC-34 and analogs as a domain-selective PDI probes.	('LOC14', 'Var', (113, 118))	('thrombus formation', 'CPA', (317, 335))	('CCF642', 'Var', (160, 166))	('PACMA31', 'Chemical', '-', (58, 65))	('multiple myeloma', 'Disease', 'MESH:D009101', (188, 204))	('CCF642', 'Chemical', 'MESH:C000621540', (160, 166))	('bepristats', 'Chemical', '-', (256, 266))	('neurodegeneration', 'Disease', (141, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('KSC-34', 'Chemical', '-', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('multiple myeloma', 'Disease', (188, 204))	('16F16', 'CellLine', 'CVCL:0158', (103, 108))	('HIV-1 infection', 'Disease', (239, 254))	('ovarian cancer', 'Disease', (87, 101))	('neurodegeneration', 'Phenotype', 'HP:0002180', (141, 158))	('quercetin-3-rutinoside', 'Chemical', 'MESH:D012431', (271, 293))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('neurodegeneration', 'Disease', 'MESH:D019636', (141, 158))	('HIV-1 infection', 'Disease', 'MESH:D015658', (239, 254))	('multiple myeloma', 'Phenotype', 'HP:0006775', (188, 204))
158883	31149044	We previously validated PDI as a therapeutic target wherein PACMA31 was demonstrated to have anti-tumor activity.	('PACMA31', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PACMA31', 'Chemical', '-', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
158891	31149044	Bromouridine labeling and sequencing (Bru-seq) of nascent RNA demonstrated that PDI inhibition modulates transcriptional pathways associated with ER stress and the UPR.	('PDI', 'Gene', (80, 83))	('Bromouridine', 'Chemical', 'MESH:C006824', (0, 12))	('transcriptional pathways', 'Pathway', (105, 129))	('inhibition', 'Var', (84, 94))	('modulates', 'Reg', (95, 104))
158893	31149044	PDI (1:4000, #3501), E2F1 (1:500, #3742), RAD51 (1:500, #8875S), Sox2 (1:1000, #3579), phospho-histone H2A.X (1:500, #9718), PARP (1:1000, #5625), and cleaved caspase 3 (1:1000, #9664) antibodies were purchased from Cell Signaling Technology (Danvers, MA).	('Sox2', 'Gene', (65, 69))	('RAD51', 'Gene', (42, 47))	('RAD51', 'Gene', '5888', (42, 47))	('PARP', 'Gene', '1302', (125, 129))	('PARP', 'Gene', (125, 129))	('1:500', 'Var', (110, 115))	('E2F1', 'Gene', '1869', (21, 25))	('Sox2', 'Gene', '6657', (65, 69))	('E2F1', 'Gene', (21, 25))
158973	31149044	Patients with high P4HB expression (regardless of grade) exhibit reduced overall survival in Rembrandt (p = 5.28E-10, Figure 1D), Gravendeel (p = 1.77E-9, Figure 1E), and TCGA (p = 2.2E-16, Figure 1F) datasets.	('reduced', 'NegReg', (65, 72))	('P4HB', 'Gene', '5034', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('P4HB', 'Gene', (19, 23))	('overall survival', 'MPA', (73, 89))
158977	31149044	Our data show that PDI knockdown reduced cell viability in over 95 % of cancer cell lines transfected, further supporting PDI as a drug target in cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cell viability', 'CPA', (41, 55))	('PDI', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('knockdown', 'Var', (23, 32))	('reduced', 'NegReg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
159002	31149044	PACMA31 (100 muM) and 35G8 (1 muM) inhibit reductase activity of the isolated domains, whereas inhibitors estradiol, bepristat 1a, and BAP2 did not inhibit the activity of the isolated domains (Figure S6).	('muM', 'Gene', (30, 33))	('BAP2', 'Gene', '10458', (135, 139))	('muM', 'Gene', (13, 16))	('reductase', 'Enzyme', (43, 52))	('PACMA31', 'Chemical', '-', (0, 7))	('BAP2', 'Gene', (135, 139))	('muM', 'Gene', '56925', (30, 33))	('35G8', 'Var', (22, 26))	('inhibit', 'NegReg', (35, 42))	('muM', 'Gene', '56925', (13, 16))
159009	31149044	Reductase capabilities of PDI were not hindered by the histidine-to-alanine mutation H256A (Figure 3E); however, BAP2 was much less active against the H256A mutant than the wild-type protein (Figure 3F).	('histidine', 'Chemical', 'MESH:D006639', (55, 64))	('H256A', 'Var', (151, 156))	('H256A', 'Mutation', 'p.H256A', (85, 90))	('active', 'MPA', (132, 138))	('BAP2', 'Gene', '10458', (113, 117))	('less', 'NegReg', (127, 131))	('H256A', 'Mutation', 'p.H256A', (151, 156))	('BAP2', 'Gene', (113, 117))	('alanine', 'Chemical', 'MESH:D000409', (68, 75))	('H256A', 'Var', (85, 90))
159023	31149044	Furthermore, BAP2 was active in patient-derived primary GBM cells (HF2303, HF2598, HF2927, and HF3016), whereas inactive analog BAP30 did not show significant cytotoxicity (Figure 4C).	('HF2927', 'Var', (83, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (159, 171))	('BAP2', 'Gene', (13, 17))	('HF2927', 'CellLine', 'CVCL:M656', (83, 89))	('HF3016', 'CellLine', 'CVCL:Z877', (95, 101))	('HF2303', 'CellLine', 'CVCL:M656', (67, 73))	('BAP30', 'Chemical', '-', (128, 133))	('GBM', 'Phenotype', 'HP:0012174', (56, 59))	('BAP2', 'Gene', '10458', (13, 17))	('cytotoxicity', 'Disease', (159, 171))	('active', 'MPA', (22, 28))	('patient', 'Species', '9606', (32, 39))	('HF2598', 'CellLine', 'CVCL:V816', (75, 81))
159025	31149044	Consistently, BAP2 analogs at non-toxic doses inhibited sphere formation, whereas BAP30 showed no significant inhibition (Figure 4E, S10A).	('analogs', 'Var', (19, 26))	('BAP2', 'Gene', (14, 18))	('S10A', 'SUBSTITUTION', 'None', (133, 137))	('BAP30', 'Chemical', '-', (82, 87))	('BAP2', 'Gene', '10458', (14, 18))	('inhibited', 'NegReg', (46, 55))	('S10A', 'Var', (133, 137))	('sphere formation', 'CPA', (56, 72))
159026	31149044	Additionally, BAP2 dose-dependently inhibited sphere formation in patient-derived GBM cells, whereas BAP30 had no effect (Figure 4F, S10B).	('inhibited', 'NegReg', (36, 45))	('sphere formation', 'CPA', (46, 62))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('BAP2', 'Gene', (14, 18))	('S10B', 'Var', (133, 137))	('patient', 'Species', '9606', (66, 73))	('BAP2', 'Gene', '10458', (14, 18))	('S10B', 'SUBSTITUTION', 'None', (133, 137))	('BAP30', 'Chemical', '-', (101, 106))
159028	31149044	In addition, Sox2 protein expression, as an orthogonal stemness marker, was dose-dependently abrogated by BAP2 and PACMA31, but not by BAP30, and confirms the reduction in GBM cell stemness induced by BAP2 (Figure 4H).	('expression', 'MPA', (26, 36))	('reduction', 'NegReg', (159, 168))	('BAP2', 'Gene', (106, 110))	('PACMA31', 'Var', (115, 122))	('BAP30', 'Chemical', '-', (135, 140))	('abrogated', 'NegReg', (93, 102))	('BAP2', 'Gene', '10458', (201, 205))	('PACMA31', 'Chemical', '-', (115, 122))	('GBM cell stemness', 'CPA', (172, 189))	('Sox2', 'Gene', '6657', (13, 17))	('BAP2', 'Gene', '10458', (106, 110))	('GBM', 'Phenotype', 'HP:0012174', (172, 175))	('BAP2', 'Gene', (201, 205))	('Sox2', 'Gene', (13, 17))
159029	31149044	Our findings of the role of PDI in supporting stemness properties in GBM is consistent with a recent report showing that inhibition of PDI induced differentiation of acute myeloid leukemia cells through the activation of CCAAT enhancer-binding protein alpha levels.	('differentiation', 'CPA', (147, 162))	('PDI', 'Gene', (135, 138))	('activation', 'PosReg', (207, 217))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (166, 188))	('inhibition', 'Var', (121, 131))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (166, 188))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (172, 188))	('CCAAT enhancer-binding protein alpha', 'Gene', (221, 257))	('CCAAT enhancer-binding protein alpha', 'Gene', '1050', (221, 257))	('acute myeloid leukemia', 'Disease', (166, 188))
159035	31149044	TMZ was more efficacious than BAP2 compared to vehicle control (p = 0.0347) (Figure 5G); however, mice treated with TMZ had a 15 % decrease in body weight, while mice treated with BAP2 exhibited minimal loss in body weight (Figure 5D, 5H).	('BAP2', 'Gene', '10458', (180, 184))	('BAP2', 'Gene', (30, 34))	('body weight', 'CPA', (143, 154))	('TMZ', 'Var', (116, 119))	('mice', 'Species', '10090', (162, 166))	('BAP2', 'Gene', '10458', (30, 34))	('BAP2', 'Gene', (180, 184))	('decrease', 'NegReg', (131, 139))	('TMZ', 'Chemical', 'MESH:D000077204', (116, 119))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('mice', 'Species', '10090', (98, 102))
159047	31149044	In particular, transcription of heat shock proteins, HSPA6 (876-fold), HSPH1 (99-fold), and DNAJB4 (28-fold), was upregulated by BAP2 (Figure S11A-C).	('HSPA6', 'Gene', (53, 58))	('heat shock proteins', 'Disease', 'MESH:D012769', (32, 51))	('HSPH1', 'Gene', (71, 76))	('heat shock proteins', 'Disease', (32, 51))	('BAP2', 'Gene', '10458', (129, 133))	('HSPH1', 'Gene', '10808', (71, 76))	('S11A', 'Var', (142, 146))	('shock', 'Phenotype', 'HP:0031273', (37, 42))	('DNAJB4', 'Gene', '11080', (92, 98))	('S11A', 'SUBSTITUTION', 'None', (142, 146))	('HSPA6', 'Gene', '3310', (53, 58))	('transcription', 'MPA', (15, 28))	('BAP2', 'Gene', (129, 133))	('upregulated', 'PosReg', (114, 125))	('DNAJB4', 'Gene', (92, 98))
159048	31149044	Highly downregulated genes include mitochondrial methyltransferase-like gene METTL12 (125-fold), GTPase-activating ARHGAP22 (37-fold), and syntaxin 1A (27-fold), a gene that encodes for a membrane-trafficking protein (Figure S11D-F).	('S11D', 'Var', (225, 229))	('S11D', 'SUBSTITUTION', 'None', (225, 229))	('METTL12', 'Gene', (77, 84))	('syntaxin 1A', 'Gene', '6804', (139, 150))	('syntaxin 1A', 'Gene', (139, 150))	('downregulated', 'NegReg', (7, 20))	('METTL12', 'Gene', '751071', (77, 84))	('ARHGAP22', 'Gene', (115, 123))	('ARHGAP22', 'Gene', '58504', (115, 123))
159050	31149044	Multiple genes involved in homologous recombination, Fanconi anemia, non-homologous end-joining, base excision repair, nucleotide excision repair, and mismatch repair pathways were significantly downregulated upon PDI knockdown or BAP2 treatment (Figure 7).	('nucleotide excision repair', 'MPA', (119, 145))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (53, 67))	('non-homologous end-joining', 'MPA', (69, 95))	('BAP2', 'Gene', '10458', (231, 235))	('Fanconi anemia', 'Disease', (53, 67))	('knockdown', 'Var', (218, 227))	('base excision repair', 'MPA', (97, 117))	('mismatch repair pathways', 'Pathway', (151, 175))	('downregulated', 'NegReg', (195, 208))	('PDI', 'Gene', (214, 217))	('Fanconi anemia', 'Disease', 'MESH:D005199', (53, 67))	('anemia', 'Phenotype', 'HP:0001903', (61, 67))	('BAP2', 'Gene', (231, 235))
159051	31149044	From a more complete list of DNA repair and DDR genes, we observed a trend of downregulation not only by BAP2 and PDI-targeting siRNA but also by PACMA31 (Figure S12A, Table S8).	('PACMA31', 'Chemical', '-', (146, 153))	('siRNA', 'MPA', (128, 133))	('BAP2', 'Gene', '10458', (105, 109))	('downregulation', 'NegReg', (78, 92))	('BAP2', 'Gene', (105, 109))	('S12A', 'Var', (162, 166))	('S12A', 'SUBSTITUTION', 'None', (162, 166))	('PDI-targeting', 'Var', (114, 127))
159052	31149044	PDI knockdown, BAP2, and PACMA31 all downregulated E2F genes (Gene Set: Hallmark E2F Targets), further supporting this hypothesis and demonstrating the similarities between BAP2 treatment and PDI knockdown (Figure S12B, Table S9).	('E2F genes', 'Gene', (51, 60))	('downregulated', 'NegReg', (37, 50))	('BAP2', 'Gene', '10458', (15, 19))	('knockdown', 'Var', (4, 13))	('BAP2', 'Gene', '10458', (173, 177))	('S12B', 'Var', (214, 218))	('BAP2', 'Gene', (15, 19))	('PDI', 'Gene', (0, 3))	('PACMA31', 'Chemical', '-', (25, 32))	('BAP2', 'Gene', (173, 177))	('S12B', 'SUBSTITUTION', 'None', (214, 218))
159055	31149044	Furthermore, PACMA31 and BAP2 dose-dependently lower E2F1 and RAD51 protein expression in U87MG and D54 cells (Figure S13A).	('lower', 'NegReg', (47, 52))	('S13A', 'Var', (118, 122))	('RAD51', 'Gene', (62, 67))	('BAP2', 'Gene', (25, 29))	('RAD51', 'Gene', '5888', (62, 67))	('E2F1', 'Gene', '1869', (53, 57))	('PACMA31', 'Chemical', '-', (13, 20))	('E2F1', 'Gene', (53, 57))	('S13A', 'SUBSTITUTION', 'None', (118, 122))	('BAP2', 'Gene', '10458', (25, 29))	('U87MG', 'CellLine', 'CVCL:0022', (90, 95))
159056	31149044	Decrease in protein expression of BRCA2, ATR, ATM, WRM, E2F1, and RAD51 upon BAP2 treatment was confirmed with Western blotting (Figure S13B).	('ATM', 'Gene', (46, 49))	('BRCA2', 'Gene', '675', (34, 39))	('E2F1', 'Gene', '1869', (56, 60))	('E2F1', 'Gene', (56, 60))	('Decrease', 'NegReg', (0, 8))	('RAD51', 'Gene', (66, 71))	('S13B', 'SUBSTITUTION', 'None', (136, 140))	('RAD51', 'Gene', '5888', (66, 71))	('ATR', 'Gene', '545', (41, 44))	('ATM', 'Gene', '472', (46, 49))	('BAP2', 'Gene', '10458', (77, 81))	('ATR', 'Gene', (41, 44))	('protein expression', 'MPA', (12, 30))	('BRCA2', 'Gene', (34, 39))	('BAP2', 'Gene', (77, 81))	('S13B', 'Var', (136, 140))
159058	31149044	Although the mechanistic detail of such a link is beyond the scope of this current study, we hypothesize that PDI inhibition downregulates DNA repair genes such as RAD51 through decreased expression of E2F transcription factors.	('PDI', 'Gene', (110, 113))	('RAD51', 'Gene', (164, 169))	('decreased', 'NegReg', (178, 187))	('expression', 'MPA', (188, 198))	('RAD51', 'Gene', '5888', (164, 169))	('E2F', 'Protein', (202, 205))	('downregulates', 'NegReg', (125, 138))	('inhibition', 'Var', (114, 124))	('DNA repair genes', 'Gene', (139, 155))
159062	31149044	Taken together, expression of P4HB correlates with expression of E2F and DNA repair genes suggesting a potential mechanism by which targeting PDI in cancer cells may sensitize them to radiation and chemotherapy.	('P4HB', 'Gene', (30, 34))	('cancer', 'Disease', (149, 155))	('E2F', 'Gene', (65, 68))	('sensitize', 'Reg', (166, 175))	('P4HB', 'Gene', '5034', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA repair genes', 'Gene', (73, 89))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('PDI', 'Gene', (142, 145))	('targeting', 'Var', (132, 141))
159066	31149044	Here we describe a novel class of PDI inhibitors that inhibit the stem-like phenotype in patient-derived spheroid cultures.	('patient', 'Species', '9606', (89, 96))	('inhibit', 'NegReg', (54, 61))	('stem-like phenotype', 'CPA', (66, 85))	('inhibitors', 'Var', (38, 48))	('PDI', 'Gene', (34, 37))
159075	31149044	However, mutation of His256 blocks BAP2 activity even at high concentrations (100 muM).	('mutation', 'Var', (9, 17))	('BAP2', 'Gene', '10458', (35, 39))	('muM', 'Gene', (82, 85))	('His256', 'Chemical', '-', (21, 27))	('blocks', 'NegReg', (28, 34))	('activity', 'MPA', (40, 48))	('BAP2', 'Gene', (35, 39))	('muM', 'Gene', '56925', (82, 85))
159078	31149044	Additionally, BAP2 is active against PDI and PDIp, PDI family members that contain the histidine residue in the b' domain.	('BAP2', 'Gene', (14, 18))	('PDIp', 'Gene', (45, 49))	('histidine residue', 'Var', (87, 104))	('PDIp', 'Gene', '5034', (45, 49))	('BAP2', 'Gene', '10458', (14, 18))	('histidine', 'Chemical', 'MESH:D006639', (87, 96))
159086	31149044	Furthermore, with evidence that PDI inhibition lowers E2F1 mRNA and protein expression, a potential mechanism linking PDI to the DNA damage response emerges.	('PDI', 'Protein', (32, 35))	('inhibition', 'Var', (36, 46))	('E2F1', 'Gene', '1869', (54, 58))	('E2F1', 'Gene', (54, 58))	('lowers', 'NegReg', (47, 53))
159087	31149044	E2F1 expression may decrease in response to an ER stress signal triggered by PDI inhibition, which causes RAD51 downregulation.	('RAD51', 'Gene', '5888', (106, 111))	('expression', 'MPA', (5, 15))	('downregulation', 'NegReg', (112, 126))	('inhibition', 'Var', (81, 91))	('PDI', 'Gene', (77, 80))	('response to an ER stress signal', 'MPA', (32, 63))	('decrease', 'NegReg', (20, 28))	('E2F1', 'Gene', '1869', (0, 4))	('E2F1', 'Gene', (0, 4))	('RAD51', 'Gene', (106, 111))
159091	31149044	Our Bru-seq studies show that both PDI knockdown and inhibition of its enzymatic activity highly correlate with downregulation of multiple hypoxic response gene sets, further supporting BAP2 analogs as a potential treatment for hypoxic tumors.	('hypoxic tumors', 'Disease', (228, 242))	('BAP2', 'Gene', '10458', (186, 190))	('hypoxic tumors', 'Disease', 'MESH:D009369', (228, 242))	('inhibition', 'NegReg', (53, 63))	('downregulation', 'NegReg', (112, 126))	('knockdown', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('BAP2', 'Gene', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('PDI', 'Gene', (35, 38))
159198	28955599	IDH and ATRX mutation, 1p19q co-deletion, MGMT and TERT-promoter alteration) that are increasingly important in rendering final diagnosis.	('MGMT', 'Gene', (42, 46))	('1p19q co-deletion', 'Var', (23, 40))	('IDH', 'Gene', (0, 3))	('MGMT', 'Gene', '4255', (42, 46))	('ATRX', 'Gene', '546', (8, 12))	('TERT', 'Gene', (51, 55))	('IDH', 'Gene', '3417', (0, 3))	('TERT', 'Gene', '7015', (51, 55))	('ATRX', 'Gene', (8, 12))
159247	28955599	Primary tumor ICD-9 diagnosis and procedure code codes used include 191.0-191.9, 225.0, 237.5, and 01.53, 01.59, 01.13, 01.14, respectively.	('Primary tumor', 'Disease', 'MESH:D009369', (0, 13))	('Primary tumor', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('01.53', 'Var', (99, 104))
159257	27161301	MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in patients with diabetes.	('diabetes', 'Disease', (182, 190))	('deregulation', 'Var', (6, 18))	('associated', 'Reg', (28, 38))	('diabetes', 'Disease', 'MESH:D003920', (182, 190))	('MiRNA', 'Protein', (0, 5))	('age-related diseases', 'Disease', (91, 111))	('patients', 'Species', '9606', (168, 176))
159261	27161301	T2DM is a source of disability and morbidity, especially as a result of its vascular complications, which eventually lead to retinopathy, nephropathy, neuropathy, ischaemic heart disease and peripheral vasculopathy 2.	('peripheral vasculopathy', 'Phenotype', 'HP:0004950', (191, 214))	('nephropathy', 'Disease', 'MESH:D007674', (138, 149))	('retinopathy', 'Disease', 'MESH:D012164', (125, 136))	('disability', 'Disease', (20, 30))	('neuropathy', 'Disease', 'MESH:D009422', (151, 161))	('retinopathy', 'Disease', (125, 136))	('ischaemic heart disease', 'Disease', (163, 186))	('retinopathy', 'Phenotype', 'HP:0000488', (125, 136))	('nephropathy', 'Phenotype', 'HP:0000112', (138, 149))	('nephropathy', 'Disease', (138, 149))	('neuropathy', 'Phenotype', 'HP:0009830', (151, 161))	('T2DM', 'Var', (0, 4))	('peripheral vasculopathy', 'Disease', (191, 214))	('lead to', 'Reg', (117, 124))	('peripheral vasculopathy', 'Disease', 'MESH:D010523', (191, 214))	('disability', 'Disease', 'MESH:D009069', (20, 30))	('neuropathy', 'Disease', (151, 161))	('ischaemic heart disease', 'Disease', 'MESH:D003324', (163, 186))
159266	27161301	According to recent evidence, oscillating glucose levels may actually be more harmful, and induce more enduring effects on endothelial health, than hyperglycaemia itself 9.	('oscillating', 'Var', (30, 41))	('endothelial health', 'MPA', (123, 141))	('hyperglycaemia', 'Disease', (148, 162))	('hyperglycaemia', 'Disease', 'None', (148, 162))	('effects', 'Reg', (112, 119))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))	('induce', 'Reg', (91, 97))
159272	27161301	DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms involved in metabolic memory.	('ethyl', 'Chemical', '-', (5, 10))	('post-translational histone modifications', 'Var', (20, 60))	('methylation', 'Var', (4, 15))
159304	27161301	The demonstration that direct inhibition of miR-125b expression, or miR-146a-5p upregulation, improves endothelial function, blunting NF-kB signals, suggests that glucose-induced changes in miR-125b and miR-146a-5p are related to long-standing activation of the NF-kB pathway, and help perpetuate metabolic memory.	('long-standing', 'Phenotype', 'HP:0003698', (230, 243))	('miR-1', 'Gene', (190, 195))	('miR-1', 'Gene', '79187', (44, 49))	('miR-1', 'Gene', '79187', (68, 73))	('endothelial function', 'MPA', (103, 123))	('125b', 'Chemical', '-', (48, 52))	('improves', 'PosReg', (94, 102))	('glucose', 'Chemical', 'MESH:D005947', (163, 170))	('upregulation', 'PosReg', (80, 92))	('NF-kB pathway', 'Pathway', (262, 275))	('blunting', 'NegReg', (125, 133))	('changes', 'Var', (179, 186))	('inhibition', 'NegReg', (30, 40))	('miR-1', 'Gene', '79187', (190, 195))	('miR-1', 'Gene', (203, 208))	('miR-146a', 'Gene', (68, 76))	('miR-146a', 'Gene', (203, 211))	('miR-146a', 'Gene', '406938', (68, 76))	('miR-1', 'Gene', (44, 49))	('miR-1', 'Gene', (68, 73))	('miR-146a', 'Gene', '406938', (203, 211))	('NF-kB signals', 'MPA', (134, 147))	('metabolic memory', 'CPA', (297, 313))	('125b', 'Chemical', '-', (194, 198))	('miR-1', 'Gene', '79187', (203, 208))	('activation', 'PosReg', (244, 254))
159312	27161301	A recent meta-analysis has found 40 circulating miRNAs, including miR-21, miR-29a, miR-34a, miR-103, miR-107, miR-126, miR-132, miR-142-3p, miR-144 and miR-375, that are significantly deregulated in T2DM 43.	('T2DM 43', 'Disease', (199, 206))	('miR-107', 'Gene', (101, 108))	('miR-375', 'Gene', (152, 159))	('miR-1', 'Gene', (128, 133))	('miR-1', 'Gene', (119, 124))	('miR-29a', 'Gene', (74, 81))	('miR-29a', 'Gene', '407021', (74, 81))	('miR-107', 'Gene', '406901', (101, 108))	('miR-144', 'Gene', (140, 147))	('miR-34a', 'Gene', (83, 90))	('miR-132', 'Gene', '406921', (119, 126))	('miR-1', 'Gene', (101, 106))	('miR-1', 'Gene', (110, 115))	('miR-1', 'Gene', (92, 97))	('miR-1', 'Gene', (140, 145))	('miR-34a', 'Gene', '407040', (83, 90))	('miR-1', 'Gene', '79187', (128, 133))	('miR-1', 'Gene', '79187', (119, 124))	('miR-21', 'Var', (66, 72))	('miR-1', 'Gene', '79187', (101, 106))	('miR-1', 'Gene', '79187', (110, 115))	('deregulated', 'PosReg', (184, 195))	('miR-1', 'Gene', '79187', (92, 97))	('miR-1', 'Gene', '79187', (140, 145))	('miR-144', 'Gene', '406936', (140, 147))	('miR-132', 'Gene', (119, 126))	('miR-375', 'Gene', '494324', (152, 159))
159318	27161301	IRS-1 is a key insulin signalling protein, whose adipose tissue expression is reduced in humans and animals with T2DM, impairing downstream insulin signalling through the PI3K and AKT pathways, and resulting in reduced insulin-stimulated glucose uptake 66, 67.	('T2DM', 'Var', (113, 117))	('glucose', 'Chemical', 'MESH:D005947', (238, 245))	('insulin', 'Gene', '3630', (15, 22))	('insulin', 'Gene', (15, 22))	('reduced', 'NegReg', (211, 218))	('insulin', 'Gene', (140, 147))	('IRS-1', 'Gene', '3667', (0, 5))	('AKT', 'Gene', (180, 183))	('insulin', 'Gene', (219, 226))	('adipose', 'MPA', (49, 56))	('humans', 'Species', '9606', (89, 95))	('insulin', 'Gene', '3630', (140, 147))	('reduced', 'NegReg', (78, 85))	('insulin', 'Gene', '3630', (219, 226))	('impairing', 'NegReg', (119, 128))	('AKT', 'Gene', '207', (180, 183))	('IRS-1', 'Gene', (0, 5))
159323	27161301	A large prospective study of patients with stable coronary artery disease has shown that only MVs containing miR-126 predicted a CV event over the following 6 years, whereas circulating levels were uninformative 71.	('CV event', 'MPA', (129, 137))	('patients', 'Species', '9606', (29, 37))	('miR-126', 'Var', (109, 116))	('coronary artery disease', 'Disease', (50, 73))	('predicted', 'Reg', (117, 126))	('coronary artery disease', 'Disease', 'MESH:D003324', (50, 73))
159326	27161301	Unacylated ghrelin protects diabetic mice from peripheral artery disease by restoring miR-126 levels and consequently VCAM-1, SIRT1 and SOD-2 regulation, suggesting that miR-126 could have anti-inflammatory and anti-senescence activity 72.	('SOD-2', 'Gene', '20656', (136, 141))	('VCAM-1', 'MPA', (118, 124))	('ghrelin', 'Gene', '58991', (11, 18))	('ghrelin', 'Gene', (11, 18))	('miR-126 levels', 'MPA', (86, 100))	('restoring', 'PosReg', (76, 85))	('SOD-2', 'Gene', (136, 141))	('diabetic', 'Disease', 'MESH:D003920', (28, 36))	('anti-inflammatory', 'MPA', (189, 206))	('SIRT1', 'Gene', '93759', (126, 131))	('peripheral artery disease', 'Disease', 'MESH:D058729', (47, 72))	('peripheral artery disease', 'Disease', (47, 72))	('SIRT1', 'Gene', (126, 131))	('peripheral artery disease', 'Phenotype', 'HP:0004950', (47, 72))	('diabetic', 'Disease', (28, 36))	('anti-senescence', 'CPA', (211, 226))	('miR-126', 'Var', (170, 177))	('mice', 'Species', '10090', (37, 41))
159331	27161301	Moreover, it plays a crucial role in cardiac fibrosis and related heart failure in a mouse pressure-overload-induced model 79, an effect that seems to be mediated by miR-21* contained in fibroblast-derived exosomes 80.	('miR-21*', 'Var', (166, 173))	('heart failure', 'Phenotype', 'HP:0001635', (66, 79))	('mouse', 'Species', '10090', (85, 90))	('heart failure', 'Disease', 'MESH:D006333', (66, 79))	('cardiac fibrosis', 'Disease', (37, 53))	('mediated', 'Reg', (154, 162))	('heart failure', 'Disease', (66, 79))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (37, 53))
159343	27161301	For example, a number of clinical studies have shown that metformin, a hypoglycaemic agent, reduces the risk of myocardial infarction and all-cause mortality compared with other medications 113, 114.	('myocardial infarction', 'Disease', 'MESH:D009203', (112, 133))	('myocardial infarction', 'Phenotype', 'HP:0001658', (112, 133))	('metformin', 'Var', (58, 67))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('all-cause mortality', 'CPA', (138, 157))	('reduces', 'NegReg', (92, 99))	('myocardial infarction', 'Disease', (112, 133))
159383	27161301	miR-21, miR-146a and miR-155) and pro- or anti-angiogenic miRNAs (i.e.	('miR-146a', 'Gene', '406938', (8, 16))	('miR-155', 'Gene', (21, 28))	('miR-21', 'Var', (0, 6))	('miR-146a', 'Gene', (8, 16))	('miR-155', 'Gene', '406947', (21, 28))
159384	27161301	miR-126, miR-320 and miR-503) currently seem to be the most promising exploitable differences 62, 95, 98, 102, 153, 155, 160, 161, 162.	('miR-503', 'Gene', (21, 28))	('miR-126', 'Var', (0, 7))	('miR-320', 'Gene', (9, 16))	('miR-503', 'Gene', '574506', (21, 28))	('miR-320', 'Gene', '100314065', (9, 16))
159392	27161301	Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA expression modulation, have tremendously expanded our knowledge of some basic mechanisms of metabolic memory.	('methylation', 'Var', (37, 48))	('modulation', 'Reg', (102, 112))	('histone modifications', 'Var', (50, 71))	('ethyl', 'Chemical', '-', (38, 43))	('RNA expression', 'Gene', (87, 101))
159426	24570896	In HS, chain modification results in clusters of highly sulfated regions, while in CS it gives rise to the various different characteristic chains, CS-A, CS-C, CS-D, CS-E, and CS-B, the latter also being known as dermatan sulfate (DS).	('sulfate', 'Chemical', 'MESH:D013431', (56, 63))	('CS', 'Chemical', 'MESH:D002809', (176, 178))	('CS', 'Chemical', 'MESH:D002809', (83, 85))	('CS-D', 'Gene', '7045', (160, 164))	('HS', 'Chemical', 'MESH:D006497', (3, 5))	('sulfate', 'Chemical', 'MESH:D013431', (222, 229))	('highly sulfated regions', 'MPA', (49, 72))	('CS-A', 'Gene', '1442', (148, 152))	('clusters', 'MPA', (37, 45))	('dermatan sulfate', 'Chemical', 'MESH:D003871', (213, 229))	('DS', 'Chemical', 'MESH:D003871', (231, 233))	('results in', 'Reg', (26, 36))	('CS-B', 'Gene', '1443', (176, 180))	('chain modification', 'Var', (7, 25))	('CS', 'Chemical', 'MESH:D002809', (160, 162))	('CS-D', 'Gene', (160, 164))	('CS-A', 'Gene', (148, 152))	('CS', 'Chemical', 'MESH:D002809', (166, 168))	('CS-B', 'Gene', (176, 180))	('CS', 'Chemical', 'MESH:D002809', (148, 150))	('CS', 'Chemical', 'MESH:D002809', (154, 156))
159432	24570896	As a result of their ability to interact with diverse molecules, PGs also regulate signaling in non-neoplastic components of the tumor, and have important roles in regulating the immune response to cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('PGs', 'Var', (65, 68))	('regulate', 'Reg', (74, 82))	('cancer', 'Disease', (198, 204))	('interact', 'Interaction', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('regulating', 'Reg', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('immune response', 'CPA', (179, 194))	('signaling in non-neoplastic components of the', 'MPA', (83, 128))	('tumor', 'Disease', (129, 134))
159525	24570896	Many studies suggest that PGs regulate multiple oncogenic pathways in tumor cells and promote critical tumor-microenvironment interactions, such that these molecules are potentially important tumor markers and therapeutic targets.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (70, 75))	('regulate', 'Reg', (30, 38))	('PGs', 'Var', (26, 29))	('promote', 'PosReg', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('oncogenic pathways', 'Pathway', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
159536	24570896	Overexpression of SDC2 has been previously described in some malignances, including Lewis lung carcinoma, ovarian and brain tumors, mesothelioma, osteosarcoma, and colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colon cancer', 'Disease', 'MESH:D015179', (164, 176))	('Overexpression', 'Var', (0, 14))	('ovarian and brain tumors', 'Disease', 'MESH:D010051', (106, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('osteosarcoma', 'Disease', (146, 158))	('osteosarcoma', 'Disease', 'MESH:D012516', (146, 158))	('described', 'Reg', (43, 52))	('Lewis lung carcinoma', 'Disease', (84, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (118, 130))	('colon cancer', 'Disease', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SDC2', 'Gene', (18, 22))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (84, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (146, 158))	('colon cancer', 'Phenotype', 'HP:0003003', (164, 176))	('mesothelioma', 'Disease', (132, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (132, 144))
159568	24570896	The effects of loss of GPC3 on tumor development are compatible with its function as a tumor suppressor, since this molecule is an inhibitor of cell proliferation and can induce apoptosis.	('GPC3', 'Gene', (23, 27))	('cell proliferation', 'CPA', (144, 162))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (87, 92))	('GPC3', 'Gene', '2719', (23, 27))	('apoptosis', 'CPA', (178, 187))	('loss', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('induce', 'Reg', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
159598	22666451	By immunohistochemical analysis of 69 primary and 16 paired initial and recurrent glioma sections, we found that the loss of neogenin did not only correlate negatively with glioma malignancy (n = 69, p<0.01), but also glioma recurrence (n = 16, p<0.05).	('negatively', 'NegReg', (157, 167))	('neogenin', 'Gene', (125, 133))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('glioma malignancy', 'Disease', 'MESH:D005910', (173, 190))	('loss', 'Var', (117, 121))	('glioma', 'Disease', (173, 179))	('glioma', 'Disease', (218, 224))	('neogenin', 'Gene', '4756', (125, 133))	('glioma malignancy', 'Disease', (173, 190))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))
159599	22666451	Kaplan-Meier plot and Cox proportional hazards modelling showed that over-expressive neogenin could prolong the tumor latency (n = 69, p<0.001, 1187.6+-162.6 days versus 687.4+-254.2 days) and restrain high-grade glioma development (n = 69, p<0.01, HR: 0.264, 95% CI: 0.102 to 0.687).	('prolong', 'PosReg', (100, 107))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('men', 'Species', '9606', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('restrain', 'NegReg', (193, 201))	('over-expressive', 'Var', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('neogenin', 'Gene', (85, 93))	('glioma', 'Disease', (213, 219))	('tumor', 'Disease', (112, 117))	('neogenin', 'Gene', '4756', (85, 93))
159600	22666451	By Methylation specific polymerase chain reaction (MSP), we reported that neogenin promoter was methylated in 31.0% (9/29) gliomas, but absent in 3 kinds of glioma cell lines.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('neogenin', 'Gene', (74, 82))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('neogenin', 'Gene', '4756', (74, 82))	('methylated', 'Var', (96, 106))	('gliomas', 'Disease', (123, 130))	('glioma', 'Disease', (123, 129))	('glioma', 'Disease', (157, 163))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))
159603	22666451	These observations recapitulated the proposed role of neogenin as a tumor suppressor in gliomas and we suggest its down-regulation owing to promoter methylation is a selective advantage for glioma genesis, progression and recurrence.	('tumor', 'Disease', (68, 73))	('glioma genesis', 'Disease', 'MESH:D005910', (190, 204))	('neogenin', 'Gene', (54, 62))	('down-regulation', 'NegReg', (115, 130))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('neogenin', 'Gene', '4756', (54, 62))	('promoter methylation', 'Var', (140, 160))	('gliomas', 'Disease', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma genesis', 'Disease', (190, 204))
159620	22666451	It is reported that alteration of expression in the dependent receptors such as DCC, UNC5H, neogenin and their ligands, netrin-1 and RGMa would cause loss of pro-apoptotic activity and even lead to tumorigenesis.	('netrin-1', 'Gene', (120, 128))	('expression', 'MPA', (34, 44))	('DCC', 'Gene', (80, 83))	('neogenin', 'Gene', (92, 100))	('alteration', 'Var', (20, 30))	('pro-apoptotic activity', 'CPA', (158, 180))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('UNC5H', 'Gene', (85, 90))	('DCC', 'Gene', '1630', (80, 83))	('neogenin', 'Gene', '4756', (92, 100))	('netrin-1', 'Gene', '9423', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('RGMa', 'Gene', '56963', (133, 137))	('loss', 'NegReg', (150, 154))	('tumor', 'Disease', (198, 203))	('RGMa', 'Gene', (133, 137))	('lead to', 'Reg', (190, 197))
159629	22666451	1A), whereas in the typical tumor tissues, cells were more heterogenous: ranging from small to giant, disordered, polynuclear to karyokinetic (Fig.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('disordered', 'Disease', 'MESH:D030342', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('polynuclear', 'Var', (114, 125))	('disordered', 'Disease', (102, 112))
159652	22666451	Accumulating evidences indicate that cancer is the result of various genetic and epigenetic alterations of tumor suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', (37, 43))	('epigenetic alterations', 'Var', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
159657	22666451	By analysing the sequence of neogenin promoter, we found that there were two CpG islands prone to methylation.	('neogenin', 'Gene', '4756', (29, 37))	('neogenin', 'Gene', (29, 37))	('methylation', 'Var', (98, 109))
159658	22666451	Subsequent methylation-specific polymerase chain reaction (MSP) on the neogenin promoter validated the presence of epigenetic alteration in glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('epigenetic alteration', 'Var', (115, 136))	('neogenin', 'Gene', (71, 79))	('neogenin', 'Gene', '4756', (71, 79))	('glioma', 'Disease', (140, 146))
159659	22666451	In agreement with our hypothesis, 31.0% of gliomas (9/29) were methylated, while no methylation was observed in the non-neoplastic brain tissues (0/4) and cell lines U87MG, U251MG and SHG-44 (0/3).	('SHG-44', 'CellLine', 'CVCL:6728', (184, 190))	('men', 'Species', '9606', (8, 11))	('neoplastic brain', 'Phenotype', 'HP:0030692', (120, 136))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('methylated', 'Var', (63, 73))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('U251MG', 'CellLine', 'CVCL:0021', (173, 179))	('U87MG', 'CellLine', 'CVCL:0022', (166, 171))
159660	22666451	Intriguingly, it was observed that 12.5% (1/8) of grade II, all of grade III (2/2) and 35.3% (6/17) of grade IV glioma were methylated but no methylation in grade I (0/2).	('glioma', 'Disease', (112, 118))	('methylated', 'Var', (124, 134))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))
159662	22666451	Classified statistic showed that the methylation in high-grade gliomas was more frequent than low-grade gliomas and non-neoplastic brain tissues (Fig.	('gliomas', 'Disease', (104, 111))	('frequent', 'Reg', (80, 88))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('methylation', 'Var', (37, 48))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))	('neoplastic brain', 'Phenotype', 'HP:0030692', (120, 136))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
159677	22666451	As expected, the phenotype for loss of neogenin expression could be similar to DCC, inactivation of which helped to further glioma progression and glioblastoma regeneration.	('helped to', 'Reg', (106, 115))	('glioma', 'Disease', (124, 130))	('loss', 'NegReg', (31, 35))	('glioblastoma', 'Disease', (147, 159))	('neogenin', 'Gene', (39, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('expression', 'MPA', (48, 58))	('neogenin', 'Gene', '4756', (39, 47))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('inactivation', 'Var', (84, 96))	('further', 'PosReg', (116, 123))	('DCC', 'Gene', (79, 82))	('DCC', 'Gene', '1630', (79, 82))
159693	22666451	Promoter methylation is probably one of the reasons recognised to repress tumour suppressor genes in malignancy.	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('Promoter methylation', 'Var', (0, 20))	('malignancy', 'Disease', 'MESH:D009369', (101, 111))	('malignancy', 'Disease', (101, 111))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
159694	22666451	Our findings on neogenin methylation were in harmony with other dependent receptors such as DCC and UNC5H, where their loss of expression in several cancers was due to promoter methylation.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('neogenin', 'Gene', (16, 24))	('expression', 'MPA', (127, 137))	('neogenin', 'Gene', '4756', (16, 24))	('DCC', 'Gene', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('methylation', 'Var', (25, 36))	('DCC', 'Gene', '1630', (92, 95))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
159697	22666451	The observed methylation in gliomas reminisces the reports of existence of G-CIMP which was tightly associated with IDH1 mutation and exhibited better prognosis.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('associated', 'Reg', (100, 110))	('IDH1', 'Gene', (116, 120))	('G-CIMP', 'Chemical', '-', (75, 81))	('mutation', 'Var', (121, 129))	('IDH1', 'Gene', '3417', (116, 120))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
159698	22666451	Our observations in current study indicated neogenin did not belong to G-CIMP loci because of strong anti-correlation between neogenin methylation and G-CIMP-positive or IDH1 mutation status, similar to transmembrane protein tomoregulin (TMEFF2) which was hepermethylated and associated with worse prognosis.	('TMEFF2', 'Gene', (238, 244))	('G-CIMP', 'Chemical', '-', (151, 157))	('methylation', 'Var', (135, 146))	('IDH1', 'Gene', (170, 174))	('neogenin', 'Gene', (44, 52))	('TMEFF2', 'Gene', '23671', (238, 244))	('mutation', 'Var', (175, 183))	('IDH1', 'Gene', '3417', (170, 174))	('tomoregulin', 'Gene', (225, 236))	('neogenin', 'Gene', '4756', (44, 52))	('G-CIMP', 'Chemical', '-', (71, 77))	('neogenin', 'Gene', (126, 134))	('tomoregulin', 'Gene', '23671', (225, 236))	('neogenin', 'Gene', '4756', (126, 134))	('anti-correlation', 'NegReg', (101, 117))
159700	22666451	Perhaps other mechanisms like loss of heterozygosity or gene mutations which have been reported in DCC and Unc5H could further provide more evidence to elaborate neogenin's role in gliomas.	('neogenin', 'Gene', '4756', (162, 170))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('DCC', 'Gene', (99, 102))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('DCC', 'Gene', '1630', (99, 102))	('gliomas', 'Disease', (181, 188))	('loss', 'Var', (30, 34))	('neogenin', 'Gene', (162, 170))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
159701	22666451	How does the deficiency of neogenin lead to tumorigenesis?	('lead to', 'Reg', (36, 43))	('deficiency', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('neogenin', 'Gene', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('neogenin', 'Gene', '4756', (27, 35))	('tumor', 'Disease', (44, 49))
159703	22666451	If either or both of them happen, the surplus ligands would block apoptotic signal because of the mismatching of ligands and receptors, thus the atypical glial cell would be immortalized to the advantage of tumorigenesis and perhaps accelerated.	('mismatching', 'Var', (98, 109))	('ligands', 'Protein', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('apoptotic signal', 'MPA', (66, 82))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('block', 'NegReg', (60, 65))	('tumor', 'Disease', (207, 212))
159710	22666451	Methylated promoter of neogenin in gliomas may be one of the reasons for the downregulation of neogenin expression, indicating that adjustment of neogenin could be a strategy for glioma therapy.	('men', 'Species', '9606', (138, 141))	('gliomas', 'Disease', (35, 42))	('glioma', 'Disease', (179, 185))	('neogenin', 'Gene', (146, 154))	('glioma', 'Disease', (35, 41))	('downregulation', 'NegReg', (77, 91))	('neogenin', 'Gene', '4756', (146, 154))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('expression', 'MPA', (104, 114))	('Methylated', 'Var', (0, 10))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('neogenin', 'Gene', (95, 103))	('neogenin', 'Gene', '4756', (95, 103))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('neogenin', 'Gene', (23, 31))	('neogenin', 'Gene', '4756', (23, 31))
159711	22666451	Human glioma cell lines U251MG, U87MG and SHG-44 were obtained from the Cell Bank of Chinese Academy of Sciences (Shanghai, China), and were cultured in Dulbecco's Modified Eagle Medium (DMEM), supplemented with 10% newborn calf serum at 37 C in an atmosphere of 5% CO2.	('Human', 'Species', '9606', (0, 5))	('U251MG', 'Var', (24, 30))	('CO2', 'Chemical', '-', (266, 269))	('U87MG', 'CellLine', 'CVCL:0022', (32, 37))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('U251MG', 'CellLine', 'CVCL:0021', (24, 30))	('DMEM', 'Chemical', '-', (187, 191))	('U87MG', 'Var', (32, 37))	('calf', 'Species', '9913', (224, 228))	('men', 'Species', '9606', (200, 203))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (153, 185))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('SHG-44', 'CellLine', 'CVCL:6728', (42, 48))	('glioma', 'Disease', (6, 12))
159826	18989714	The eTUMOUR case et2274 was diagnosed by the original pathologist as oligodendroglioma 9450/3 (grade II, WHO), although a comment was added to the free text section of the eTUMOUR database (eTDB) making reference to the presence of areas of anaplastic oligodendroglioma (grade III, WHO).	('oligodendroglioma', 'Disease', 'MESH:D009837', (252, 269))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (241, 269))	('oligodendroglioma', 'Disease', (69, 86))	('oligodendroglioma', 'Disease', 'MESH:D009837', (69, 86))	('et2274', 'Var', (17, 23))	('oligodendroglioma', 'Disease', (252, 269))	('anaplastic oligodendroglioma', 'Disease', (241, 269))	('eTDB', 'Chemical', '-', (190, 194))
159829	18989714	This pattern has been observed before, for example in the INTERPRET cases I0450 (oligoastrocytoma) and I0179 (oligodendroglioma), which are also misplaced in the short TE latent space of the INTERPRET decision-support system (DSS) 2.0 (http://azizu.uab.es/INTERPRET).	('oligoastrocytoma', 'Disease', 'MESH:D001254', (81, 97))	('oligoastrocytoma', 'Disease', (81, 97))	('DSS', 'Chemical', '-', (226, 229))	('I0179', 'Var', (103, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('oligodendroglioma', 'Disease', (110, 127))	('PR', 'Chemical', '-', (196, 198))	('PR', 'Chemical', '-', (261, 263))	('oligodendroglioma', 'Disease', 'MESH:D009837', (110, 127))	('PR', 'Chemical', '-', (63, 65))	('I0450', 'Var', (74, 79))
159830	18989714	The eTUMOUR case et2206 was originally diagnosed as oligoastrocytoma 9382/3 (grade II, WHO), but there were some discrepancies regarding the glial subtype on the validation done by the pathological committee.	('et2206', 'Var', (17, 23))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (52, 68))	('oligoastrocytoma', 'Disease', (52, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (57, 68))
159876	33242424	While CTNNB1 mutation is an important oncogenic factor for pediatric CP, the proteomic clusters, C4 and C8, did not distinguish CTNNB1 mutation status (Fig.	('CTNNB1', 'Gene', '1499', (6, 12))	('CP', 'Gene', '1356', (69, 71))	('cluster', 'Species', '100569', (87, 94))	('CTNNB1', 'Gene', '1499', (128, 134))	('mutation', 'Var', (13, 21))	('CTNNB1', 'Gene', (6, 12))	('CTNNB1', 'Gene', (128, 134))
159880	33242424	This motivates the hypothesis that some pediatric CP might benefit from MEK inhibitor (MEKi) based treatment, a strategy that has been used for BRAFV600E LGG tumors and has shown preclinical promise in adult CP.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('CP', 'Gene', '1356', (208, 210))	('benefit', 'PosReg', (59, 66))	('LGG tumors', 'Disease', 'MESH:D009369', (154, 164))	('CP', 'Gene', '1356', (50, 52))	('MEK', 'Gene', (87, 90))	('MEK', 'Gene', '5609', (87, 90))	('MEK', 'Gene', (72, 75))	('MEK', 'Gene', '5609', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('LGG tumors', 'Disease', (154, 164))	('BRAFV600E', 'Var', (144, 153))	('BRAFV600E', 'Mutation', 'rs113488022', (144, 153))
159885	33242424	1E, 1F, S1C), consistent with the contrast between BRAFV600E and BRAFWT LGG tumors (Fig.	('BRAFWT LGG tumors', 'Disease', 'MESH:D009369', (65, 82))	('BRAFV600E', 'Var', (51, 60))	('BRAFV600E', 'Mutation', 'rs113488022', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('BRAFWT LGG tumors', 'Disease', (65, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
159916	33242424	It has been reported that glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion, and glutamine antagonism could serve as a "metabolic checkpoint" for tumor immunotherapy, which might benefit tumors like the ones in the Neuronal cluster.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('glutamine', 'Var', (120, 129))	('benefit', 'PosReg', (218, 225))	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('induces', 'Reg', (45, 52))	('glutamine', 'Chemical', 'MESH:D005973', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('glutamine', 'Chemical', 'MESH:D005973', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('antagonism', 'Var', (130, 140))	('metabolic programs', 'MPA', (63, 81))	('cluster', 'Species', '100569', (263, 270))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Disease', (226, 232))	('glutamine', 'Protein', (26, 35))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (226, 231))
159918	33242424	Interestingly, BRAFV600E and BRAFFusion events, important oncogenic drivers of LGG tumors, showed significant association with multiple immune signatures.	('BRAFFusion', 'Gene', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LGG tumors', 'Disease', (79, 89))	('BRAFV600E', 'Var', (15, 24))	('BRAFV600E', 'Mutation', 'rs113488022', (15, 24))	('LGG tumors', 'Disease', 'MESH:D009369', (79, 89))	('association', 'Interaction', (110, 121))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('BRAFFusion', 'Gene', '673', (29, 39))
159922	33242424	2G: BRAFFusion promoted more M2 microglia, while BRAFV600E promoted more M2 macrophages.	('BRAFV600E', 'Var', (49, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (49, 58))	('BRAFFusion', 'Gene', '673', (4, 14))	('M2 macrophages', 'CPA', (73, 87))	('promoted', 'PosReg', (59, 67))	('BRAFFusion', 'Gene', (4, 14))	('M2 microglia', 'CPA', (29, 41))
159931	33242424	CTNNB1 mutation resulted in elevated protein/RNA levels among CP samples, while NF1 mutation resulted in the downregulation of cognate protein and transcript in HGG (Figs.	('CTNNB1', 'Gene', '1499', (0, 6))	('downregulation', 'NegReg', (109, 123))	('NF1', 'Gene', (80, 83))	('NF1', 'Gene', '4763', (80, 83))	('CTNNB1', 'Gene', (0, 6))	('transcript', 'MPA', (147, 157))	('mutation', 'Var', (7, 15))	('CP', 'Gene', '1356', (62, 64))	('protein/RNA levels', 'MPA', (37, 55))	('elevated', 'PosReg', (28, 36))	('cognate protein', 'MPA', (127, 142))	('mutation', 'Var', (84, 92))
159932	33242424	SMARCB1 RNA/protein were significantly downregulated in ATRT samples compared to other diagnoses as expected, and the downregulation was the result of different types of DNA alterations, including mutation, deletion, and copy neutral LOH (Fig.	('downregulation', 'NegReg', (118, 132))	('deletion', 'Var', (207, 215))	('RNA/protein', 'Protein', (8, 19))	('copy neutral LOH', 'Var', (221, 237))	('SMARCB1', 'Gene', '6598', (0, 7))	('SMARCB1', 'Gene', (0, 7))	('mutation', 'Var', (197, 205))	('downregulated', 'NegReg', (39, 52))
159936	33242424	3B, 3C), whose amplification is associated with GTPase activation and RAB-GTPase binding and has been reported to be an independent predictor of tumor progression in EP.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('amplification', 'Var', (15, 28))	('RAB', 'Gene', '9545', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('EP', 'Gene', '2069', (166, 168))	('RAB', 'Gene', (70, 73))	('tumor', 'Disease', (145, 150))	('GTPase', 'Protein', (48, 54))	('associated', 'Reg', (32, 42))	('binding', 'Interaction', (81, 88))	('activation', 'PosReg', (55, 65))
159941	33242424	Besides BRAF mutation/fusion in LGG (discussed below), the only other profound trans-regulatory effects were detected between mutation of CTNNB1, which codes beta-catenin, and many proteins and phosphosites in CP (Fig.	('beta-catenin', 'Gene', (158, 170))	('BRAF', 'Gene', '673', (8, 12))	('CTNNB1', 'Gene', '1499', (138, 144))	('beta-catenin', 'Gene', '1499', (158, 170))	('BRAF', 'Gene', (8, 12))	('mutation/fusion', 'Var', (13, 28))	('mutation', 'Var', (126, 134))	('phosphosites', 'Chemical', '-', (194, 206))	('CTNNB1', 'Gene', (138, 144))	('CP', 'Gene', '1356', (210, 212))
159943	33242424	As expected, CTNNB1 mutation, which boosted beta-catenin abundance, is found to be associated with upregulation of proteins/phosphosites related to cell-to-cell adhesion, as well as upregulation of members of the WNT Signaling pathway such as APC, GSK3A and GSK3B (Fig.	('APC', 'Disease', (243, 246))	('phosphosites', 'Chemical', '-', (124, 136))	('mutation', 'Var', (20, 28))	('WNT Signaling pathway', 'Pathway', (213, 234))	('upregulation', 'PosReg', (99, 111))	('CTNNB1', 'Gene', (13, 19))	('beta-catenin', 'Gene', (44, 56))	('GSK3B', 'Gene', (258, 263))	('proteins/phosphosites related', 'MPA', (115, 144))	('GSK3A', 'Gene', (248, 253))	('GSK3A', 'Gene', '2931', (248, 253))	('GSK3B', 'Gene', '2932', (258, 263))	('beta-catenin', 'Gene', '1499', (44, 56))	('CTNNB1', 'Gene', '1499', (13, 19))	('boosted', 'PosReg', (36, 43))	('upregulation', 'PosReg', (182, 194))	('APC', 'Disease', 'MESH:D011125', (243, 246))
159944	33242424	Specifically, while phosphosite abundance of APC at Ser 2812 showed significant elevation in CTNNB1 mutation cases, this upregulation was not observed based on protein abundance of APC (Fig.	('Ser 2812', 'Chemical', '-', (52, 60))	('phosphosite', 'Chemical', '-', (20, 31))	('CTNNB1', 'Gene', '1499', (93, 99))	('APC', 'Disease', 'MESH:D011125', (181, 184))	('phosphosite abundance', 'MPA', (20, 41))	('mutation', 'Var', (100, 108))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (181, 184))	('APC', 'Disease', (45, 48))	('CTNNB1', 'Gene', (93, 99))	('elevation', 'PosReg', (80, 89))
159946	33242424	In our data, we observed significant association between RNA and protein/phosphosite abundance of TCF4, TCF25 and CTNNB1 mutation in CP.	('TCF25', 'Gene', '22980', (104, 109))	('CTNNB1', 'Gene', '1499', (114, 120))	('TCF25', 'Gene', (104, 109))	('phosphosite', 'Chemical', '-', (73, 84))	('TCF4', 'Gene', '6925', (98, 102))	('CP', 'Gene', '1356', (133, 135))	('mutation', 'Var', (121, 129))	('protein/phosphosite abundance', 'MPA', (65, 94))	('TCF4', 'Gene', (98, 102))	('CTNNB1', 'Gene', (114, 120))
159948	33242424	However, we observed that both RNA expression and phosphosite abundance of TCF4 were significantly lower in the CTNNB1 mutated group.	('TCF4', 'Gene', '6925', (75, 79))	('CTNNB1', 'Gene', (112, 118))	('lower', 'NegReg', (99, 104))	('CTNNB1', 'Gene', '1499', (112, 118))	('phosphosite', 'Chemical', '-', (50, 61))	('mutated', 'Var', (119, 126))	('RNA expression', 'MPA', (31, 45))	('phosphosite abundance', 'MPA', (50, 71))	('TCF4', 'Gene', (75, 79))
159949	33242424	Instead, both RNA and proteomic abundance of TCF25, another transcription factor that may play a role in cell death control, were upregulated in CTNNB1 mutated CP.	('upregulated', 'PosReg', (130, 141))	('mutated', 'Var', (152, 159))	('TCF25', 'Gene', (45, 50))	('CP', 'Gene', '1356', (160, 162))	('CTNNB1', 'Gene', '1499', (145, 151))	('CTNNB1', 'Gene', (145, 151))	('death', 'Disease', 'MESH:D003643', (110, 115))	('death', 'Disease', (110, 115))	('TCF25', 'Gene', '22980', (45, 50))
159950	33242424	These results suggest that, among this group of CP, downstream effects of mutation in CTNNB1 could be mediated by TCF25.	('mutation', 'Var', (74, 82))	('mediated', 'Reg', (102, 110))	('TCF25', 'Gene', (114, 119))	('CTNNB1', 'Gene', (86, 92))	('CP', 'Gene', '1356', (48, 50))	('TCF25', 'Gene', '22980', (114, 119))	('CTNNB1', 'Gene', '1499', (86, 92))
159962	33242424	Phosphorylation of connexin 43 at Ser 325 and Ser 314 promotes gap junction assembly between glioma and astrocytes and drives cancer cell migration as well as glioma invasion.	('glioma', 'Disease', (93, 99))	('connexin 43', 'Gene', (19, 30))	('Ser 314', 'Var', (46, 53))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('drives', 'PosReg', (119, 125))	('Phosphorylation', 'Var', (0, 15))	('cancer', 'Disease', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioma invasion', 'Disease', (159, 174))	('connexin 43', 'Gene', '2697', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('glioma', 'Disease', (159, 165))	('Ser', 'Chemical', 'MESH:D012694', (34, 37))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('gap', 'MPA', (63, 66))	('glioma invasion', 'Disease', 'MESH:D005910', (159, 174))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Ser', 'Chemical', 'MESH:D012694', (46, 49))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('promotes', 'PosReg', (54, 62))
159983	33242424	Compared to BRAFWT tumors, BRAFV600E and BRAFFusion cases showed both common as well as alteration-type specific changes (Fig.	('BRAFFusion', 'Gene', '673', (41, 51))	('BRAFV600E', 'Var', (27, 36))	('BRAFV600E', 'Mutation', 'rs113488022', (27, 36))	('BRAFWT tumors', 'Disease', 'MESH:D009369', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BRAFFusion', 'Gene', (41, 51))	('BRAFWT tumors', 'Disease', (12, 25))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
159984	33242424	Particularly, in BRAFV600E, we observed significant abundance changes of protein in the MAPK (ERK) signaling pathway (Fig.	('abundance changes', 'MPA', (52, 69))	('ERK', 'Gene', (94, 97))	('protein', 'Protein', (73, 80))	('ERK', 'Gene', '5594', (94, 97))	('BRAFV600E', 'Var', (17, 26))	('BRAFV600E', 'Mutation', 'rs113488022', (17, 26))
159988	33242424	Investigation of an RNA expression based "MEK inhibitor signature" in our data confirmed that genes downstream of MEK kinases are greatly upregulated in BRAFV600E as compared to the BRAFWT tumors (Fig.	('BRAFWT tumors', 'Disease', (182, 195))	('BRAFV600E', 'Mutation', 'rs113488022', (153, 162))	('MEK', 'Gene', (114, 117))	('MEK', 'Gene', (42, 45))	('MEK', 'Gene', '5609', (114, 117))	('BRAFV600E', 'Var', (153, 162))	('MEK', 'Gene', '5609', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('BRAFWT tumors', 'Disease', 'MESH:D009369', (182, 195))	('upregulated', 'PosReg', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('genes', 'Gene', (94, 99))
159991	33242424	5B and Table S5) showed significant upregulation in BRAFV600E tumors.	('BRAFV600E', 'Var', (52, 61))	('BRAFV600E', 'Mutation', 'rs113488022', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('upregulation', 'PosReg', (36, 48))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))
159994	33242424	Next, we employed a network-based approach to study the impact of BRAF alterations on the phosphoproteome.	('alterations', 'Var', (71, 82))	('BRAF', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (66, 70))
159996	33242424	5C, S5C) are significantly upregulated in BRAFV600E and BRAFFusion samples, respectively (Table S5).	('BRAFV600E', 'Var', (42, 51))	('BRAFV600E', 'Mutation', 'rs113488022', (42, 51))	('BRAFFusion', 'Gene', '673', (56, 66))	('upregulated', 'PosReg', (27, 38))	('BRAFFusion', 'Gene', (56, 66))
159998	33242424	5C) and G2M Checkpoint, confirming the upregulation of Cell-Cycle related pathways in BRAFV600E compared to BRAFWT LGG patients (Fig.	('BRAFWT', 'Gene', '673', (108, 114))	('BRAFWT', 'Gene', (108, 114))	('BRAFV600E', 'Var', (86, 95))	('BRAFV600E', 'Mutation', 'rs113488022', (86, 95))	('patients', 'Species', '9606', (119, 127))	('Cell-Cycle related pathways', 'Pathway', (55, 82))	('upregulation', 'PosReg', (39, 51))
160002	33242424	Taken together, these observations further support the concept of inhibiting mTOR/AKT in BRAFV600E LGG.	('inhibiting', 'NegReg', (66, 76))	('mTOR', 'Gene', '2475', (77, 81))	('AKT', 'Gene', '207', (82, 85))	('mTOR', 'Gene', (77, 81))	('AKT', 'Gene', (82, 85))	('BRAFV600E', 'Var', (89, 98))	('BRAFV600E', 'Mutation', 'rs113488022', (89, 98))
160005	33242424	PDGFRA is frequently mutated/amplified in pediatric HGG, and has been suggested to serve as a treatment target for pediatric HGG.	('PDGFRA', 'Gene', '5156', (0, 6))	('PDGFRA', 'Gene', (0, 6))	('mutated/amplified', 'Var', (21, 38))
160009	33242424	Mutations of IDH1 and IDH2 proteins, which can be effectively targeted by drugs, have been found in ~80% of grade II and III astrocytomas, oligodendrogliomas, and secondary glioblastomas.	('IDH', 'Gene', '3417', (13, 16))	('glioblastomas', 'Disease', 'MESH:D005909', (173, 186))	('oligodendrogliomas', 'Disease', (139, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('glioblastomas', 'Disease', (173, 186))	('found', 'Reg', (91, 96))	('IDH', 'Gene', (22, 25))	('III astrocytomas', 'Disease', 'MESH:D001254', (121, 137))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('Mutations', 'Var', (0, 9))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (139, 157))	('IDH', 'Gene', '3417', (22, 25))	('III astrocytomas', 'Disease', (121, 137))	('IDH', 'Gene', (13, 16))	('glioblastomas', 'Phenotype', 'HP:0012174', (173, 186))	('proteins', 'Protein', (27, 35))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
160012	33242424	Since point mutations in histone H3.3 (H3F3A, H3K27M) has been reported to lead to a worse prognosis in HGG, H3 status was adjusted for when assessing association between OS and abundance of IDH proteins (StarMethod).	('H3F3A', 'Gene', (39, 44))	('Star', 'Gene', (205, 209))	('H3K27M', 'Gene', (46, 52))	('lead', 'Reg', (75, 79))	('histone H3.3', 'Gene', '3020', (25, 37))	('IDH', 'Gene', (191, 194))	('point mutations', 'Var', (6, 21))	('IDH', 'Gene', '3417', (191, 194))	('H3F3A', 'Gene', '3020', (39, 44))	('histone H3.3', 'Gene', (25, 37))	('Star', 'Gene', '6770', (205, 209))	('HGG', 'Disease', (104, 107))
160030	33242424	S6D, IDH1 deletion, which was observed in about 20% of the HGG tumors, significantly downregulated the protein abundance of IDH1.	('downregulated', 'NegReg', (85, 98))	('IDH', 'Gene', (124, 127))	('HGG tumors', 'Disease', (59, 69))	('HGG tumors', 'Disease', 'MESH:D009369', (59, 69))	('IDH', 'Gene', '3417', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IDH', 'Gene', (5, 8))	('deletion', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('protein abundance', 'MPA', (103, 120))	('IDH', 'Gene', '3417', (5, 8))
160036	33242424	6G, S6F, S6G).	('S6G', 'Var', (9, 12))	('S6F', 'Var', (4, 7))	('S6G', 'Mutation', 'p.S6G', (9, 12))
160042	33242424	RP tumors carried 0%-52% (mean 18%) of the IN tumor mutations (Fig.	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RP tumor', 'Disease', 'MESH:C538365', (0, 8))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('IN tumor', 'Disease', (43, 51))	('RP tumor', 'Disease', (0, 8))	('IN tumor', 'Disease', 'MESH:D009369', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
160043	33242424	Remarkably, all three MB progression samples had a TP53 mutation that was absent in their paired primary tumors (Fig.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('TP53', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutation', 'Var', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', '7157', (51, 55))
160049	33242424	Consistently with the allocation of RP tumor to the Cranio/LGG BRAFV600E cluster, a higher kinase activity for ERK1/ERK2 was observed in RP tumor compared to IN tumor (Fig.	('RP tumor', 'Disease', (36, 44))	('BRAFV600E', 'Var', (63, 72))	('BRAFV600E', 'Mutation', 'rs113488022', (63, 72))	('cluster', 'Species', '100569', (73, 80))	('IN tumor', 'Disease', 'MESH:D009369', (158, 166))	('ERK', 'Gene', '5594', (111, 114))	('RP tumor', 'Disease', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ERK', 'Gene', (111, 114))	('ERK', 'Gene', '5594', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('kinase activity', 'MPA', (91, 106))	('RP tumor', 'Disease', 'MESH:C538365', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ERK', 'Gene', (116, 119))	('RP tumor', 'Disease', 'MESH:C538365', (137, 145))	('IN tumor', 'Disease', (158, 166))	('higher', 'PosReg', (84, 90))
160051	33242424	Another LGG case (pair 350.944) had the IN tumor allocated to Cranio/LGG BRAFV600E, while the RP sample allocated to the LGG BRAFWT-rich cluster, which resulted in opposite trend in pathway activities followed by a reversed trend in the activity of ERK1/ERK2 (Figs.	('ERK', 'Gene', (254, 257))	('BRAFWT', 'Gene', '673', (125, 131))	('BRAFWT', 'Gene', (125, 131))	('BRAFV600E', 'Var', (73, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (73, 82))	('ERK', 'Gene', '5594', (249, 252))	('IN tumor', 'Disease', (40, 48))	('ERK', 'Gene', (249, 252))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IN tumor', 'Disease', 'MESH:D009369', (40, 48))	('pathway activities', 'MPA', (182, 200))	('cluster', 'Species', '100569', (137, 144))	('ERK', 'Gene', '5594', (254, 257))
160063	33242424	A good illustration of this contribution is the ability to discern at the protein level the cis effects of copy number alterations by tracking the cascade of abundance from gene dose to transcript level to protein/phosphosite abundance.	('alterations', 'Var', (119, 130))	('copy', 'Var', (107, 111))	('phosphosite', 'Chemical', '-', (214, 225))
160068	33242424	Our characterization of proteome and phosphoproteome changes due to BRAF aberrations lends further rationale to this approach in LGG where resistance per se is not an issue but durability of response after treatment cessation is.	('LGG', 'Disease', (129, 132))	('aberrations', 'Var', (73, 84))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (68, 72))
160088	33242424	The patient selection was built based on specimen availability and defined two broad classes of tumors: (1) High grade tumors driven by epigenetic dysregulation (HGG, DIPG, ATRT and/or other embryonal tumors) and (2) Low grade tumors defined by receptor-tyrosine kinase and MAPK signaling alterations including kinase fusions.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('epigenetic dysregulation', 'Var', (136, 160))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (119, 125))	('receptor-tyrosine kinase', 'Gene', '5979', (245, 269))	('embryonal tumors', 'Phenotype', 'HP:0002898', (191, 207))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('embryonal tumors', 'Disease', (191, 207))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('embryonal tumors', 'Disease', 'MESH:D009373', (191, 207))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (227, 233))	('receptor-tyrosine kinase', 'Gene', (245, 269))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))
160145	33242424	Cysteine carbamidomethylation (+57.0215) and lysine TMT labeling (+229.1629) were specified as fixed modifications, and methionine oxidation (+15.9949), N-terminal protein acetylation (+42.0106), and TMT labeling of the peptide N terminus.	('+229.1629', 'Var', (66, 75))	('methionine', 'Chemical', 'MESH:D008715', (120, 130))	('+42.0106', 'Var', (185, 193))	('methionine oxidation', 'MPA', (120, 140))	('Cysteine', 'Chemical', 'MESH:D003545', (0, 8))	('+15.9949', 'Var', (142, 150))	('+57.0215', 'Var', (31, 39))	('lysine', 'Chemical', 'MESH:D008239', (45, 51))
160148	33242424	Phosphopeptide-enriched searches also included the phosphorylation modification of serine, threonine, and tyrosine residues (+79.9663).	('Phosphopeptide', 'Chemical', 'MESH:D010748', (0, 14))	('tyrosine', 'Chemical', 'MESH:D014443', (106, 114))	('serine', 'Chemical', 'MESH:D012694', (83, 89))	('serine', 'MPA', (83, 89))	('threonine', 'MPA', (91, 100))	('threonine', 'Chemical', 'MESH:D013912', (91, 100))	('+79.9663', 'Var', (125, 133))	('phosphorylation modification', 'MPA', (51, 79))
160166	33242424	For flagged samples, same subject tumor tissue and blood specimen DNA was further extracted and sent to Guardian Forensic Sciences (Abington, PA) for short tandem repeat (STR) testing using the GenePrint 24 assay (Promega, #B1870).	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('short tandem repeat', 'Var', (150, 169))
160198	33242424	Phosphopeptide identification for the phosphoproteomic data files were performed as in the whole proteome data analysis described above (e.g., peptide level FDR < 1%), with an additional dynamic phosphorylation (+79.9663 Da) on Ser, Thr, or Tyr residues.	('+79.9663 Da', 'Var', (212, 223))	('Phosphopeptide', 'Chemical', 'MESH:D010748', (0, 14))	('Thr', 'Chemical', 'MESH:D013912', (233, 236))	('peptide level', 'MPA', (143, 156))	('phosphorylation', 'MPA', (195, 210))	('Ser', 'Chemical', 'MESH:D012694', (228, 231))	('Tyr', 'Chemical', 'MESH:D014443', (241, 244))
160259	33242424	Each signature was normalized to z-score and then was modeled as function of BRAF status (i.e., BRAF wild-type, BRAF fusion and BRAF v600E) via linear model.	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', (77, 81))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', '673', (128, 132))	('v600E', 'Var', (133, 138))	('BRAF', 'Gene', (128, 132))
160277	33242424	Specifically, we considered association on chromosome arm 6q, 17p, 17q, and 22q in atypical teratoid rhabdoid tumor; CTNNB1 mutation and 11p in CP; 1q and 8q in EP; 7p in ganglioglioma; NF1 mutation, 1q, 6q, 7p, 9p, 9q, 11p, 13q, 14q, 16q, 17q and 21p in high grade astrocytoma; 1q, 7p, 7q, 8q, 10q, 11p, 11q, 16q, 17p, 17q and 18p in MB.	('ganglioglioma', 'Disease', (171, 184))	('CTNNB1', 'Gene', '1499', (117, 123))	('rhabdoid tumor', 'Disease', (101, 115))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('NF1', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('NF1', 'Gene', '4763', (186, 189))	('CTNNB1', 'Gene', (117, 123))	('CP', 'Gene', '1356', (144, 146))	('astrocytoma', 'Disease', 'MESH:D001254', (266, 277))	('ganglioglioma', 'Disease', 'MESH:D018303', (171, 184))	('astrocytoma', 'Disease', (266, 277))	('mutation', 'Var', (124, 132))	('EP', 'Gene', '2069', (161, 163))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (101, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (266, 277))
160279	33242424	For example, members of the "Cell Cell Contact Zone" pathway (purple) are enriched in the set of proteins upregulated in CTNNB1 mutant samples; while "Coagulation" pathway is enriched in proteins downregulated in CTNNB1 mutant samples.	('CTNNB1', 'Gene', '1499', (121, 127))	('upregulated', 'PosReg', (106, 117))	('CTNNB1', 'Gene', (213, 219))	('mutant', 'Var', (128, 134))	('CTNNB1', 'Gene', (121, 127))	('CTNNB1', 'Gene', '1499', (213, 219))
160293	33242424	Given a network module, the association with BRAFV600E and BRAFFusion was found via fisher-exact test.	('BRAFFusion', 'Gene', (59, 69))	('BRAFFusion', 'Gene', '673', (59, 69))	('BRAFV600E', 'Var', (45, 54))	('BRAFV600E', 'Mutation', 'rs113488022', (45, 54))
160305	33242424	We calculate the weighted score of IDH1 and IDH2 for the mutant samples as  and similarly for the H3 wild type samples as  In order to display the association between survival and weighted IDH1/2 scores in the H3 wild type group, Kaplan-Meier curves were derived based on IDH1/2WTpro; with median value chosen as the cut-off to stratify samples in higher and lower abundance groups (Fig.	('IDH', 'Gene', (189, 192))	('IDH1/2', 'Gene', '3417;3418', (272, 278))	('IDH', 'Gene', (272, 275))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (189, 192))	('IDH1/2', 'Gene', '3417;3418', (189, 195))	('IDH', 'Gene', '3417', (272, 275))	('IDH', 'Gene', '3417', (35, 38))	('IDH1/2', 'Gene', (272, 278))	('mutant', 'Var', (57, 63))	('IDH', 'Gene', (44, 47))	('IDH1/2', 'Gene', (189, 195))	('IDH', 'Gene', '3417', (44, 47))
160317	33242424	Potential driver mutations were either genes with known roles in cancer that were found to be mutated, or the ones whose allele frequency increased sufficiently between initial and recurrent samples to indicate the signs of evolutionary selection.	('mutated', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (65, 71))	('mutations', 'Var', (17, 26))
160319	33242424	To screen for germline TP53 variants that are likely to be pathogenic to or causing Li-Fraunemi syndrome, we checked WGS data fromblood/normal samples in CBTTC (n=893).	('Li-Fraunemi syndrome', 'Disease', 'MESH:D016864', (84, 104))	('Li-Fraunemi syndrome', 'Disease', (84, 104))	('variants', 'Var', (28, 36))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
160320	33242424	After filtering, we kept germline variants that were either reported before within Li-fraumeni syndrome patients in the literature according to professional version 2019Q2 of the Human Gene Mutation Database (HGMD) , or predicted to be deleterious in TP53, which are defined to be i) in the exonic/splicing region, ii) not synonoymous SNVs, and iii) with minor allele frequency <0.001 in both of the gnomAD exome and genome databases (version 2.1.1).	('variants', 'Var', (34, 42))	('TP53', 'Gene', (251, 255))	('patients', 'Species', '9606', (104, 112))	('Li-fraumeni syndrome', 'Disease', (83, 103))	('Li-fraumeni syndrome', 'Disease', 'MESH:D016864', (83, 103))	('TP53', 'Gene', '7157', (251, 255))
160321	33242424	Finally we obtained 19 TP53 variants in 19 CBTTC patients' germline WGS data.	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('variants', 'Var', (28, 36))	('patients', 'Species', '9606', (49, 57))
160322	33242424	The underlying data consists of quantitative information on mutation status, protein abundance, RNA-Seq gene expression, copy number variation, and phosphosite expression for 218 samples when available.	('RNA-Seq gene', 'Gene', (96, 108))	('mutation', 'Var', (60, 68))	('phosphosite', 'Chemical', '-', (148, 159))
160325	33242424	The genomic annotation tracks include the mutation status for key genes, including BRAF status for LGG, RELA for EP, CTNNB1 for CP, and H3F3A for HGG .	('CTNNB1', 'Gene', '1499', (117, 123))	('CP', 'Gene', '1356', (128, 130))	('H3F3A', 'Gene', (136, 141))	('CTNNB1', 'Gene', (117, 123))	('mutation', 'Var', (42, 50))	('EP', 'Gene', '2069', (113, 115))	('RELA', 'Gene', (104, 108))	('RELA', 'Gene', '5970', (104, 108))	('BRAF', 'Gene', '673', (83, 87))	('LGG', 'Disease', (99, 102))	('H3F3A', 'Gene', '3020', (136, 141))	('BRAF', 'Gene', (83, 87))
160335	29915361	Finally, we show that adult mice tolerate systemic deletion of AMPK supporting the utility of AMPK pharmacological inhibitors in the treatment of GBM.	('AMPK', 'Gene', (94, 98))	('deletion', 'Var', (51, 59))	('mice', 'Species', '10090', (28, 32))	('AMPK', 'Gene', '5564', (63, 67))	('AMPK', 'Gene', (63, 67))	('AMPK', 'Gene', '5564', (94, 98))
160346	29915361	In contrast, AMPKalpha1 knockout enhanced glycolysis and accelerated tumorigenesis in a lymphoma mouse model, demonstrating species-specific and tissue-specific effects.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('accelerated', 'PosReg', (57, 68))	('tumor', 'Disease', (69, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('mouse', 'Species', '10090', (97, 102))	('AMPKalpha1', 'Gene', (13, 23))	('glycolysis', 'MPA', (42, 52))	('knockout', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('lymphoma', 'Disease', (88, 96))	('enhanced', 'PosReg', (33, 41))	('lymphoma', 'Disease', 'MESH:D008223', (88, 96))
160348	29915361	HIF1alpha that is degraded in the presence of O2 was found to be stabilized under normoxic condition in LKB1 deficient MEFS (where AMPK activity is reduced).	('AMPK', 'Gene', (131, 135))	('AMPK', 'Gene', '5564', (131, 135))	('deficient', 'Var', (109, 118))	('O2', 'Chemical', '-', (46, 48))	('LKB1', 'Gene', '20869', (104, 108))	('LKB1', 'Gene', (104, 108))
160352	29915361	We provide evidence that through phosphorylation of CREB1, a transcription factor highly expressed in GBM, AMPK controls HIF1alpha and GABPA transcription to regulate GBM bioenergetics.	('AMPK', 'Gene', (107, 111))	('CREB1', 'Gene', (52, 57))	('phosphorylation', 'Var', (33, 48))	('HIF1alpha', 'Gene', (121, 130))	('regulate', 'Reg', (158, 166))	('AMPK', 'Gene', '5564', (107, 111))	('GBM', 'MPA', (167, 170))
160353	29915361	While querying the TCGA database for differentially expressed metabolic kinases in human cancer, we observed significantly higher expression of AMPK alpha1, beta1 and gamma1 subunits; p <= 10-7) in GBM than normal brain (Fig.	('GBM', 'Var', (198, 201))	('expression', 'MPA', (130, 140))	('beta1 and gamma1', 'Gene', '3779', (157, 173))	('AMPK', 'Var', (144, 148))	('higher', 'PosReg', (123, 129))	('human', 'Species', '9606', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
160369	29915361	Consistent with this observation, expression of oncogenic EGFR or KRAS, or reducing PTEN levels in detached human astrocytes increased AMPK phosphorylation (Supplementary Fig.	('AMPK', 'Gene', (135, 139))	('reducing', 'NegReg', (75, 83))	('EGFR', 'Gene', '1956', (58, 62))	('AMPK', 'Gene', '5564', (135, 139))	('increased', 'PosReg', (125, 134))	('EGFR', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (66, 70))	('astrocytes increased', 'Phenotype', 'HP:0002446', (114, 134))	('expression', 'Var', (34, 44))	('PTEN', 'Gene', (84, 88))	('PTEN', 'Gene', '5728', (84, 88))	('human', 'Species', '9606', (108, 113))	('KRAS', 'Gene', (66, 70))
160373	29915361	Cre-mediated deletion of AMPKbeta1 also reduced viability of oncogenic mouse neural stem cells (NPCs) (Fig.	('viability', 'CPA', (48, 57))	('AMPKbeta1', 'Gene', (25, 34))	('deletion', 'Var', (13, 21))	('reduced', 'NegReg', (40, 47))	('mouse', 'Species', '10090', (71, 76))	('AMPKbeta1', 'Gene', '5564', (25, 34))
160385	29915361	Control mice (nontarget shRNA) lived for 17-29 days, while mice transplanted with AMPKbeta1 shRNA or AMPKalpha1/alpha2shRNA-expressing GSCs either lived longer or remained tumor-free (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mice', 'Species', '10090', (59, 63))	('AMPKalpha1/alpha2shRNA-expressing', 'Var', (101, 134))	('tumor', 'Disease', (172, 177))	('AMPKbeta1', 'Gene', '5564', (82, 91))	('GSC', 'Chemical', '-', (135, 138))	('mice', 'Species', '10090', (8, 12))	('AMPKbeta1', 'Gene', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('lived', 'CPA', (147, 152))	('longer', 'PosReg', (153, 159))
160397	29915361	In AMPK-silenced cells, hyperactivated ACC1 can deplete NADPH, causing oxidative stress and death that can be rescued by the reducing agent N-Acetylcysteine (NAC).	('ACC1', 'Gene', '107476', (39, 43))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('ACC1', 'Gene', (39, 43))	('causing', 'Reg', (63, 70))	('N-Acetylcysteine', 'Chemical', 'MESH:D000111', (140, 156))	('NADPH', 'Chemical', 'MESH:D009249', (56, 61))	('oxidative stress', 'MPA', (71, 87))	('deplete NADPH', 'MPA', (48, 61))	('NAC', 'Chemical', 'MESH:D000111', (158, 161))	('hyperactivated', 'Var', (24, 38))	('AMPK', 'Gene', (3, 7))	('AMPK', 'Gene', '5564', (3, 7))
160398	29915361	AMPK silencing indeed raised superoxide anion (Supplementary Fig.	('superoxide anion', 'Chemical', 'MESH:D013481', (29, 45))	('raised', 'PosReg', (22, 28))	('silencing', 'Var', (5, 14))	('superoxide anion', 'MPA', (29, 45))	('AMPK', 'Gene', '5564', (0, 4))	('AMPK', 'Gene', (0, 4))
160402	29915361	However, AMPK silencing did not increase mTORC1 activity, and consistent with others the mTORC1 inhibitor rapamycin failed to protect AMPK-silenced GSCs (Supplementary Fig.	('silencing', 'Var', (14, 23))	('mTORC1', 'Gene', '382056', (89, 95))	('AMPK', 'Gene', (9, 13))	('mTORC1', 'Gene', '382056', (41, 47))	('AMPK', 'Gene', '5564', (9, 13))	('rapamycin', 'Chemical', 'MESH:D020123', (106, 115))	('GSC', 'Chemical', '-', (148, 151))	('AMPK', 'Gene', (134, 138))	('mTORC1', 'Gene', (89, 95))	('AMPK', 'Gene', '5564', (134, 138))	('mTORC1', 'Gene', (41, 47))
160403	29915361	AMPK silencing did not significantly affect the expression of stem cell markers in GSCs (Supplementary Fig.	('GSC', 'Chemical', '-', (83, 86))	('expression', 'MPA', (48, 58))	('silencing', 'Var', (5, 14))	('AMPK', 'Gene', '5564', (0, 4))	('AMPK', 'Gene', (0, 4))
160418	29915361	Total and acetylated PGC1alpha protein (a reaction regulated by the deacetylase SIRT1) remained unchanged in AMPK silenced GSCs (Supplementary Fig.	('SIRT1', 'Gene', (80, 85))	('AMPK', 'Gene', (109, 113))	('AMPK', 'Gene', '5564', (109, 113))	('silenced', 'Var', (114, 122))	('PGC1alpha', 'Gene', '19017', (21, 30))	('PGC1alpha', 'Gene', (21, 30))	('acetylated', 'MPA', (10, 20))	('GSC', 'Chemical', '-', (123, 126))	('SIRT1', 'Gene', '93759', (80, 85))
160428	29915361	5h, i).Consistent with previous reports, HIF1alpha silencing reduced GSC viability (Fig.	('silencing', 'Var', (51, 60))	('GSC', 'Chemical', '-', (69, 72))	('HIF1alpha', 'Protein', (41, 50))	('reduced', 'NegReg', (61, 68))	('GSC viability', 'CPA', (69, 82))
160440	29915361	6e-g) and silencing TFAM reduced GSC viability (Fig.	('reduced', 'NegReg', (25, 32))	('TFAM', 'Gene', (20, 24))	('GSC viability', 'CPA', (33, 46))	('GSC', 'Chemical', '-', (33, 36))	('silencing', 'Var', (10, 19))
160447	29915361	Accordingly, CREB1 knockdown reduced HIF1alpha promoter activity, HIF1alpha and GABPA transcriptional target expression, cell viability and GSC bioenergetics (Fig.	('CREB1', 'Gene', (13, 18))	('GSC', 'Chemical', '-', (140, 143))	('knockdown', 'Var', (19, 28))	('cell viability', 'CPA', (121, 135))	('reduced', 'NegReg', (29, 36))	('HIF1alpha', 'Gene', (66, 75))	('GABPA', 'Gene', (80, 85))	('HIF1alpha', 'Gene', (37, 46))
160456	29915361	Several glycolytic and mitochondrial targets of HIF1alpha and GABPA were down regulated in CREB1S133A expressing cells and upregulated in CREB1S133E expressing cells (Fig.	('S133A', 'Mutation', 'p.S133A', (96, 101))	('S133E', 'Mutation', 'p.S133E', (143, 148))	('upregulated', 'PosReg', (123, 134))	('CREB1S133A', 'Var', (91, 101))	('GABPA', 'Gene', (62, 67))	('HIF1alpha', 'Gene', (48, 57))	('down regulated', 'NegReg', (73, 87))
160457	29915361	Consistent with these results, CREB1 knockdown and CREB1S133A repressed HIF1alpha and GABPA protein while CREB1S133E increased HIF1alpha and GABPA (Fig 7l).	('S133A', 'Mutation', 'p.S133A', (56, 61))	('GABPA protein', 'Protein', (86, 99))	('increased', 'PosReg', (117, 126))	('S133E', 'Mutation', 'p.S133E', (111, 116))	('CREB1S133E', 'Var', (106, 116))	('HIF1alpha', 'Protein', (72, 81))
160468	29915361	CREB1S133A reduced ATP levels and diminished viability (Fig.	('ATP levels', 'MPA', (19, 29))	('reduced', 'NegReg', (11, 18))	('ATP', 'Chemical', 'MESH:D000255', (19, 22))	('diminished', 'NegReg', (34, 44))	('CREB1S133A', 'Var', (0, 10))	('viability', 'MPA', (45, 54))
160472	29915361	This suggests that AMPK is an appropriate target in GBM, and if so, the effect of deleting AMPK in GBM mouse models and the effects of whole-body AMPK inhibition to check systemic tolerance warrant investigation.	('AMPK', 'Gene', (146, 150))	('AMPK', 'Gene', '5564', (19, 23))	('deleting', 'Var', (82, 90))	('AMPK', 'Gene', (19, 23))	('mouse', 'Species', '10090', (103, 108))	('AMPK', 'Gene', (91, 95))	('AMPK', 'Gene', '5564', (91, 95))	('AMPK', 'Gene', '5564', (146, 150))
160497	29915361	The following reagents were used : Oligomycin, FCCP, Antimycin, Rotenone, Tunicamycin, Thapsigargin, Camptothecin B, Hydroxyurea, Puromycin, Doxycycline, DAPI, Hydrogen peroxide, Formamide, STO-609, KU55933, NAC, TOFA, PKI, Forskolin, Methyl Pyruvate, Sodium Succinate, Cycloheximide and Chloroquine, Glucose, Resveratrol and DMSO (all from Sigma), G418 (Invitrogen), Compound 991 (a gift from David Carling), A769662 and Rapamycin (LC Laboratories) and SIRT1720 (Apen Biotechnology).	('Oligomycin', 'Chemical', 'MESH:D009840', (35, 45))	('myc', 'Gene', (426, 429))	('DAPI', 'Chemical', 'MESH:C007293', (154, 158))	('FCCP', 'Chemical', 'MESH:D002259', (47, 51))	('TOFA', 'Chemical', 'MESH:C014289', (213, 217))	('SIRT1', 'Gene', '93759', (454, 459))	('myc', 'Gene', '17869', (40, 43))	('myc', 'Gene', '17869', (57, 60))	('myc', 'Gene', (40, 43))	('myc', 'Gene', (57, 60))	('myc', 'Gene', '17869', (80, 83))	('SIRT1', 'Gene', (454, 459))	('A769662', 'Var', (410, 417))	('G418', 'Chemical', 'MESH:C010680', (349, 353))	('myc', 'Gene', '17869', (134, 137))	('NAC', 'Chemical', 'MESH:D000111', (208, 211))	('myc', 'Gene', '17869', (426, 429))	('myc', 'Gene', (80, 83))	('myc', 'Gene', (134, 137))
160537	29915361	To generate mCreb1 S133A, mutagenesis was performed on mCreb1 (Acc # BC021649) in pCMV-SPORT6 with the Phusion Site Directed Mutagenesis Kit (Thermo Scientific, catalogue #F-541).	('S133A', 'Mutation', 'p.S133A', (19, 24))	('mCreb1', 'Gene', (55, 61))	('mutagenesis', 'Var', (26, 37))	('mCreb1', 'Gene', '12912', (55, 61))	('mCreb1', 'Gene', '12912', (12, 18))	('mCreb1', 'Gene', (12, 18))
160571	29915361	Activity of complex IV (cytochrome c oxidase) was measured in 50 mM KH2PO4 (pH 7.5), 2 microg/ml rotenone, and 0.03 mM reduced cytochrome c at 550 nm.	('KH2PO4', 'Chemical', '-', (68, 74))	('Activity', 'MPA', (0, 8))	('KH2PO4', 'Var', (68, 74))	('cytochrome c at 550 nm', 'MPA', (127, 149))	('reduced', 'NegReg', (119, 126))	('rotenone', 'Chemical', 'MESH:D012402', (97, 105))
160609	27028997	Specifically, methylation of cfDNA has been linked to cancer initiation and progression.	('cancer initiation', 'Disease', 'MESH:D009369', (54, 71))	('cancer initiation', 'Disease', (54, 71))	('cfDNA', 'Gene', (29, 34))	('methylation', 'Var', (14, 25))	('linked', 'Reg', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
160612	27028997	Abnormally methylated Alu might decrease genomic stability, thereby instigating tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Abnormally methylated', 'Var', (0, 21))	('Alu', 'Protein', (22, 25))	('Alu', 'Chemical', '-', (22, 25))	('tumor', 'Disease', (80, 85))	('instigating', 'Reg', (68, 79))	('genomic stability', 'CPA', (41, 58))	('decrease', 'NegReg', (32, 40))
160613	27028997	Indeed, Alu is rich in CpG and universally hypomethylated in tumor cells.	('CpG', 'Var', (23, 26))	('Alu', 'Chemical', '-', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
160615	27028997	To extend our previous findings, we tested whether Alu hypomethylation in cfDNA, as measured by a liquid chip system, could serve as a method to detect gliomas.	('Alu', 'Chemical', '-', (51, 54))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('hypomethylation', 'Var', (55, 70))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
160628	27028997	These results suggest Alu hypomethylation is associated with the malignancy of gliomas.	('malignancy of gliomas', 'Phenotype', 'HP:0012174', (65, 86))	('Alu', 'Protein', (22, 25))	('malignancy of gliomas', 'Disease', (65, 86))	('Alu', 'Chemical', '-', (22, 25))	('associated', 'Reg', (45, 55))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('malignancy of gliomas', 'Disease', 'MESH:D005910', (65, 86))	('hypomethylation', 'Var', (26, 41))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
160632	27028997	We grouped 61 paired cases into mutant IDH (Mut) and wild-type TERT (WT), IDH WT, TERT Mut, IDH WT and TERT Mut based on IDH-1, IDH-2 and TERT promotor mutations.	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', (121, 124))	('IDH-2', 'Gene', '3418', (128, 133))	('IDH', 'Gene', '3417', (74, 77))	('IDH-1', 'Gene', '3417', (121, 126))	('IDH', 'Gene', '3417', (128, 131))	('mutant', 'Var', (32, 38))	('TERT', 'Gene', (138, 142))	('IDH', 'Gene', '3417', (121, 124))	('IDH', 'Gene', (39, 42))	('TERT', 'Gene', '7015', (138, 142))	('TERT', 'Gene', (82, 86))	('TERT', 'Gene', '7015', (82, 86))	('IDH-2', 'Gene', (128, 133))	('IDH', 'Gene', (92, 95))	('IDH', 'Gene', '3417', (39, 42))	('IDH-1', 'Gene', (121, 126))	('IDH', 'Gene', (74, 77))	('TERT', 'Gene', (63, 67))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (63, 67))	('TERT', 'Gene', '7015', (103, 107))	('IDH', 'Gene', '3417', (92, 95))
160640	27028997	These data suggest that Alu hypomethylation in cfDNA serves as a promising biomarker for early glioma diagnosis.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('hypomethylation', 'Var', (28, 43))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('cfDNA', 'Gene', (47, 52))	('Alu', 'Chemical', '-', (24, 27))
160644	27028997	Alu elements have been proposed to contribute to disease by two mechanisms: through insertional mutagenesis and non-allelic homologous recombination that induces genetic deletions and duplications.	('contribute', 'Reg', (35, 45))	('induces', 'Reg', (154, 161))	('Alu', 'Chemical', '-', (0, 3))	('duplications', 'MPA', (184, 196))	('genetic', 'MPA', (162, 169))	('insertional mutagenesis', 'Var', (84, 107))
160646	27028997	On the other hand, aberrantly methylated Alu elements rich in CpG might influence the expression of downstream genes and result in genetic instability.	('aberrantly methylated', 'Var', (19, 40))	('expression', 'MPA', (86, 96))	('genetic instability', 'MPA', (131, 150))	('influence', 'Reg', (72, 81))	('CpG', 'Gene', (62, 65))	('Alu', 'Chemical', '-', (41, 44))	('result in', 'Reg', (121, 130))
160647	27028997	Tumorigenesis of glioma may rely considerably on aberrant genetic expression and non-integrity.	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('Tumorigenesis', 'CPA', (0, 13))	('aberrant genetic', 'Var', (49, 65))	('glioma', 'Disease', (17, 23))
160665	27028997	Numerous genetic studies have shown that glioma patients with wild type IDH or mutations in the TERT promoter have a worse prognosis.	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('TERT', 'Gene', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('TERT', 'Gene', '7015', (96, 100))	('glioma', 'Disease', (41, 47))	('patients', 'Species', '9606', (48, 56))	('mutations in', 'Var', (79, 91))
160681	27028997	We chose two well-known glioma-associated genes, IDH-1 (3417), IDH-2 (3418) and TERT (7015) promoter, for sequencing using Sanger Sequencing (Supplemental file 2).	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('3417', 'Var', (56, 60))	('IDH-2', 'Gene', (63, 68))	('IDH-2', 'Gene', '3418', (63, 68))	('IDH-1', 'Gene', '3417', (49, 54))	('IDH-1', 'Gene', (49, 54))	('glioma', 'Disease', (24, 30))	('3418', 'Var', (70, 74))	('TERT', 'Gene', '7015', (80, 84))	('TERT', 'Gene', (80, 84))
160706	25573605	The trajectory of cognitive and adaptive functioning was previously reported, and suggested cognition is generally preserved in patients treated with CRT, though patients who are younger (<5 years) at CRT remain at risk for declines.	('CRT', 'Var', (150, 153))	('patients', 'Species', '9606', (128, 136))	('patients', 'Species', '9606', (162, 170))	('cognition', 'CPA', (92, 101))
160719	25573605	Thresholds for clinical significance (borderline and clinical range; indicative of a possible need for intervention) vary by subscale, but typically result from T-scores that are 1-2 SDs above (problem scales) or below (competence scales) 50.	('SDs', 'Chemical', 'MESH:D012967', (183, 186))	('result from', 'Reg', (149, 160))	('T-scores', 'Var', (161, 169))
160726	25573605	Children who underwent a biopsy had higher parent-reported scores on the Externalizing Problems scale than those who underwent subtotal resection (P=.004).	('biopsy', 'Var', (25, 31))	('Children', 'Species', '9606', (0, 8))	('higher', 'PosReg', (36, 42))	('Externalizing Problems', 'Disease', (73, 95))
160727	25573605	However, children who underwent a biopsy were also engaged in more activities than those who underwent subtotal resection (P<.001).	('engaged', 'Reg', (51, 58))	('children', 'Species', '9606', (9, 17))	('more', 'PosReg', (62, 66))	('biopsy', 'Var', (34, 40))	('activities', 'MPA', (67, 77))
160749	25573605	The relative stability in emotional and behavioral functioning over time, coupled with the difficulties observed pre-CRT, begs the question of how a delay in CRT (by means of observation, multiple surgeries, and/or chemotherapy) could affect psychosocial outcomes.	('behavioral functioning', 'Phenotype', 'HP:0000708', (40, 62))	('delay', 'Var', (149, 154))	('psychosocial', 'Disease', (242, 254))	('affect', 'Reg', (235, 241))	('psychosocial', 'Disease', 'MESH:C535569', (242, 254))
160770	26370624	To this end, we identified dysregulation of NEDD9, a protein involved in cell migration, with probable prognostic potential.	('NEDD9', 'Gene', (44, 49))	('dysregulation', 'Var', (27, 40))	('NEDD9', 'Gene', '4739', (44, 49))
160771	26370624	Another subcategory of patients where the IDH1 gene is mutated, are known to have better prognosis as compared to patients carrying the wild type gene.	('IDH1', 'Gene', '3417', (42, 46))	('patients', 'Species', '9606', (23, 31))	('mutated', 'Var', (55, 62))	('IDH1', 'Gene', (42, 46))	('patients', 'Species', '9606', (114, 122))
160777	26370624	Gliomas have been sub-typed based on various molecular markers like IDH1, 1p/19q co-deletion, amplification of EGFR amplification, loss of PTEN, MGMT etc.	('amplification', 'Var', (94, 107))	('EGFR', 'Gene', '1956', (111, 115))	('MGMT', 'Gene', '4255', (145, 149))	('PTEN', 'Gene', (139, 143))	('IDH1', 'Gene', (68, 72))	('MGMT', 'Gene', (145, 149))	('loss', 'Var', (131, 135))	('EGFR', 'Gene', (111, 115))	('PTEN', 'Gene', '5728', (139, 143))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH1', 'Gene', '3417', (68, 72))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))
160781	26370624	Similarly, IDH1 (isocitrate dehydrogenase 1) mutations have been a powerful molecular marker to predict the prognosis of glioma subjects, where subjects with IDH1 mutations referred to as positive for IDH1 mutations (IDH1p) are known to have better prognosis than those with the wild type copy of the IDH1 gene (WT).	('IDH1', 'Gene', '3417', (201, 205))	('IDH1', 'Gene', '3417', (217, 221))	('glioma', 'Disease', (121, 127))	('IDH1', 'Gene', '3417', (11, 15))	('IDH1', 'Gene', (301, 305))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('IDH1', 'Gene', (158, 162))	('IDH1p', 'Gene', (217, 222))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('isocitrate dehydrogenase 1', 'Gene', (17, 43))	('IDH1', 'Gene', '3417', (301, 305))	('isocitrate dehydrogenase 1', 'Gene', '3417', (17, 43))	('IDH1', 'Gene', '3417', (158, 162))	('IDH1', 'Gene', (201, 205))	('mutations', 'Var', (45, 54))	('mutations', 'Var', (163, 172))	('IDH1p', 'Gene', '3417', (217, 222))	('IDH1', 'Gene', (217, 221))	('IDH1', 'Gene', (11, 15))
160796	26370624	Similarly there were 17 proteins, namely, RNF25, C11orf74, CALCOCO2, C14orf119, IMPDH2, TIPIN, CAMK2N1, LOC285382, MAPK3, HBG2, JUB, ZMYM3, PRPSAP2, LRFN1, DUPD1, TIRAP and ZNF397, which were dysregulated both in Grade III and IV (Fig.	('HBG2', 'Gene', '3048', (122, 126))	('RNF25', 'Gene', (42, 47))	('DUPD1', 'Gene', '338599', (156, 161))	('TIPIN', 'Gene', '54962', (88, 93))	('ZMYM3', 'Gene', '9203', (133, 138))	('JUB', 'Gene', '84962', (128, 131))	('ZNF397', 'Gene', '84307', (173, 179))	('PRPSAP2', 'Gene', (140, 147))	('CALCOCO2', 'Gene', '10241', (59, 67))	('MAPK3', 'Gene', (115, 120))	('MAPK3', 'Gene', '5595', (115, 120))	('CALCOCO2', 'Gene', (59, 67))	('C14orf119', 'Gene', '55017', (69, 78))	('CAMK2N1', 'Gene', (95, 102))	('IMPDH2', 'Gene', (80, 86))	('TIRAP', 'Gene', (163, 168))	('LOC285382', 'Var', (104, 113))	('IMPDH2', 'Gene', '3615', (80, 86))	('LRFN1', 'Gene', '57622', (149, 154))	('C14orf119', 'Gene', (69, 78))	('TIRAP', 'Gene', '114609', (163, 168))	('C11orf74', 'Gene', '119710', (49, 57))	('DUPD1', 'Gene', (156, 161))	('TIPIN', 'Gene', (88, 93))	('ZMYM3', 'Gene', (133, 138))	('RNF25', 'Gene', '64320', (42, 47))	('C11orf74', 'Gene', (49, 57))	('ZNF397', 'Gene', (173, 179))	('HBG2', 'Gene', (122, 126))	('PRPSAP2', 'Gene', '5636', (140, 147))	('CAMK2N1', 'Gene', '55450', (95, 102))	('LRFN1', 'Gene', (149, 154))	('JUB', 'Gene', (128, 131))
160800	26370624	Another analysis with IDH1 mutation as focus, revealed 22 proteins significantly dysregulated in a comparison of Grade II WT versus IDH1p (Supplementary Table 5).	('IDH1', 'Gene', (132, 136))	('proteins', 'Protein', (58, 66))	('IDH1', 'Gene', '3417', (132, 136))	('dysregulated', 'Reg', (81, 93))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('IDH1p', 'Gene', (132, 137))	('IDH1', 'Gene', '3417', (22, 26))	('IDH1p', 'Gene', '3417', (132, 137))
160834	26370624	In a study conducted by Li et al., IGHG1 was found to be up-regulated in human pancreatic carcinomas and the blockage of IGHG1 was correlated with retarded tumour development and better survival.	('retarded tumour', 'Disease', 'MESH:D009369', (147, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('better', 'PosReg', (179, 185))	('retarded tumour', 'Disease', (147, 162))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (79, 100))	('blockage', 'Var', (109, 117))	('pancreatic carcinomas', 'Disease', (79, 100))	('human', 'Species', '9606', (73, 78))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('up-regulated', 'PosReg', (57, 69))	('IGHG1', 'Gene', '3500', (121, 126))	('IGHG1', 'Gene', '3500', (35, 40))	('IGHG1', 'Gene', (121, 126))	('IGHG1', 'Gene', (35, 40))
160856	26370624	The mutation in IDH1 gene is widely associated with good prognosis of glioma patients.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('mutation', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1', 'Gene', (16, 20))	('patients', 'Species', '9606', (77, 85))	('IDH1', 'Gene', '3417', (16, 20))	('associated', 'Reg', (36, 46))
160859	26370624	Also, it is widely accepted that, IDH1 mutation is more frequent in younger patients, compared to that of older.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', (34, 38))	('patients', 'Species', '9606', (76, 84))	('mutation', 'Var', (39, 47))
160870	26370624	Genetic alterations in PI3K pathway has been found to be one of the critical signalling pathways resulting in the manifestation of gliomas and is also one of the pathways stringently regulated by the IL-4 signalling pathway which leads us to consider the upstream effectors of such critical pathways which may be deregulated due to autoimmune responses in addition to known genetic mutations.	('resulting', 'Reg', (97, 106))	('Genetic alterations', 'Var', (0, 19))	('IL-4', 'Gene', '3565', (200, 204))	('gliomas', 'Disease', (131, 138))	('autoimmune response', 'Phenotype', 'HP:0002960', (332, 351))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('PI3K pathway', 'Pathway', (23, 35))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('IL-4', 'Gene', (200, 204))
160944	32357912	Gene amplification, gene mutation, and abnormalities in upstream and downstream regulators of cyclin D, CDK4, and CDK6 can all lead to abnormal activation of the cyclin D-CDK4/6-Rb pathway.	('CDK6', 'Gene', (114, 118))	('CDK6', 'Gene', '1021', (114, 118))	('CDK4/6', 'Gene', '1019;1021', (171, 177))	('cyclin', 'Gene', (94, 100))	('cyclin', 'Gene', (162, 168))	('Rb', 'Phenotype', 'HP:0009919', (178, 180))	('abnormalities', 'Var', (39, 52))	('lead to', 'Reg', (127, 134))	('CDK4/6', 'Gene', (171, 177))	('CDK4', 'Gene', (171, 175))	('activation', 'PosReg', (144, 154))	('gene mutation', 'Var', (20, 33))	('CDK4', 'Gene', (104, 108))	('CDK4', 'Gene', '1019', (104, 108))	('CDK4', 'Gene', '1019', (171, 175))	('cyclin', 'Gene', '5111', (94, 100))	('cyclin', 'Gene', '5111', (162, 168))
160954	32357912	Moreover, the cdk4, cdk6, and e2f1 genes show extensive gene amplification and gene mutation in various tumors; deep deletion and gene mutation of the rb1 gene were observed in various tumors, while gene fusion and multiple alterations in these four genes are rare (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cdk4', 'Gene', (14, 18))	('gene mutation', 'Var', (130, 143))	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', (104, 110))	('rb1', 'Gene', '5925', (151, 154))	('cdk4', 'Gene', '1019', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('observed', 'Reg', (165, 173))	('cdk6', 'Gene', '1021', (20, 24))	('e2f1', 'Gene', (30, 34))	('deep deletion', 'Var', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('cdk6', 'Gene', (20, 24))	('rb1', 'Gene', (151, 154))	('e2f1', 'Gene', '1869', (30, 34))
160955	32357912	These gene changes may explain the difference in the clinical efficacy of and drug resistance to CDK4/6 inhibitors in different tumors.	('CDK4/6', 'Gene', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('changes', 'Var', (11, 18))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('drug resistance', 'Phenotype', 'HP:0020174', (78, 93))
160956	32357912	Based on the analysis from the UALCAN cancer database, moderate expression of the cdk4 gene in KIRC, LGG, KIRP, MESO, KICH, and SKCM was significantly negatively related to overall survival (p < 0.05); high expression of the cdk4 gene in LIHC was closely related to worse overall survival than low expression and may be a sensitive marker for predicting the prognosis of LIHC.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('negatively', 'NegReg', (151, 161))	('cdk4', 'Gene', '1019', (225, 229))	('high', 'Var', (202, 206))	('LIHC', 'Disease', (371, 375))	('cdk4', 'Gene', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cdk4', 'Gene', '1019', (82, 86))	('cdk4', 'Gene', (82, 86))
160962	32357912	CDK4/6 inhibitors hinder the transition from G1 phase to S phase by inhibiting Rb phosphorylation and E2F release and induce tumor cycle arrest at G1 phase, which can inhibit tumor cell growth and cause tumor regression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (203, 208))	('inhibit', 'NegReg', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('CDK4/6', 'Gene', (0, 6))	('inhibiting', 'NegReg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('inhibitors', 'Var', (7, 17))	('cause', 'Reg', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (175, 180))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('induce', 'Reg', (118, 124))	('hinder', 'NegReg', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('arrest', 'Disease', (137, 143))	('tumor', 'Disease', (125, 130))	('Rb', 'Phenotype', 'HP:0009919', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('E2F release', 'MPA', (102, 113))
160968	32357912	The mutation rate of cell cycle-related genes in breast cancer is as high as 38%.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (4, 12))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cell cycle-related genes', 'Gene', (21, 45))
160969	32357912	Increased expression of cyclin D causes continuous phosphorylation of Rb and leads to continuous proliferation of breast cancer cells; blocking CDK4/6 exerts a lethal effect on breast cancer cells.	('breast cancer', 'Disease', (177, 190))	('CDK4/6', 'Gene', '1019;1021', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cyclin', 'Gene', '5111', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('phosphorylation', 'MPA', (51, 66))	('CDK4/6', 'Gene', (144, 150))	('Rb', 'Phenotype', 'HP:0009919', (70, 72))	('cyclin', 'Gene', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('blocking', 'Var', (135, 143))	('breast cancer', 'Disease', (114, 127))	('leads to', 'Reg', (77, 85))
160988	32357912	The major adverse effects of CDK4/6 inhibitors are leukopenia and neutropenia, mainly caused by palbociclib and ribociclib.	('CDK4/6', 'Gene', (29, 35))	('leukopenia', 'Disease', 'MESH:D007970', (51, 61))	('leukopenia', 'Disease', (51, 61))	('ribociclib', 'Chemical', 'MESH:C000589651', (112, 122))	('neutropenia', 'Disease', 'MESH:D009503', (66, 77))	('palbociclib', 'Chemical', 'MESH:C500026', (96, 107))	('neutropenia', 'Phenotype', 'HP:0001875', (66, 77))	('palbociclib', 'Var', (96, 107))	('CDK4/6', 'Gene', '1019;1021', (29, 35))	('leukopenia', 'Phenotype', 'HP:0001882', (51, 61))	('neutropenia', 'Disease', (66, 77))
160989	32357912	CDK4/6 inhibitors can also cause gastrointestinal side effects such as diarrhea, nausea, and vomiting.	('nausea', 'Disease', (81, 87))	('nausea', 'Disease', 'MESH:D009325', (81, 87))	('diarrhea', 'Disease', (71, 79))	('diarrhea', 'Disease', 'MESH:D003967', (71, 79))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('diarrhea', 'Phenotype', 'HP:0002014', (71, 79))	('inhibitors', 'Var', (7, 17))	('cause', 'Reg', (27, 32))	('vomiting', 'Phenotype', 'HP:0002013', (93, 101))	('CDK4/6', 'Gene', (0, 6))	('vomiting', 'Disease', (93, 101))	('vomiting', 'Disease', 'MESH:D014839', (93, 101))	('gastrointestinal side effects', 'MPA', (33, 62))	('nausea', 'Phenotype', 'HP:0002018', (81, 87))
160997	32357912	CDK4/6 inhibitors may have the potential to be widely applied in multiple cancers, similar to traditional chemotherapy drugs such as cisplatin or paclitaxel.	('multiple cancers', 'Disease', (65, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('paclitaxel', 'Chemical', 'MESH:D017239', (146, 156))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('inhibitors', 'Var', (7, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('CDK4/6', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
160999	32357912	Yang's study showed that CDK4/6 inhibitors increased the sensitivity of acute myeloid leukemia cells to cytotoxic drugs.	('acute myeloid leukemia', 'Disease', (72, 94))	('inhibitors', 'Var', (32, 42))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (72, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (78, 94))	('CDK4/6', 'Gene', '1019;1021', (25, 31))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (72, 94))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('CDK4/6', 'Gene', (25, 31))
161000	32357912	Patnaik and Taylor's study showed that CDK4/6 inhibitors achieved disease control rates of 49% and 44%, respectively, in non-small-cell lung cancer patients (n = 68) and melanoma patients (n = 18).	('patients', 'Species', '9606', (148, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('inhibitors', 'Var', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('CDK4/6', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('disease control', 'CPA', (66, 81))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('patients', 'Species', '9606', (179, 187))	('CDK4/6', 'Gene', '1019;1021', (39, 45))	('lung cancer', 'Disease', (136, 147))
161001	32357912	Adkins' study indicated an objective response rate of 39% for CDK4/6 inhibitors in patients with head and neck squamous cell carcinoma (n = 62).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('CDK4/6', 'Gene', '1019;1021', (62, 68))	('patients', 'Species', '9606', (83, 91))	('CDK4/6', 'Gene', (62, 68))	('inhibitors', 'Var', (69, 79))
161012	32357912	First, CDK4/6 inhibitors downregulate E2F transcription factor-related gene expression and upregulate major histocompatibility complex class I molecule expression in breast cancer cell lines; CDK4/6 inhibitors activate endogenous retroviral components in tumor cells, stimulating the production of type III interferons to promote tumor antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('E2F transcription factor-related gene', 'Gene', (38, 75))	('tumor', 'Disease', (330, 335))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('inhibitors', 'Var', (199, 209))	('breast cancer', 'Disease', (166, 179))	('CDK4/6', 'Gene', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('activate', 'PosReg', (210, 218))	('CDK4/6', 'Gene', '1019;1021', (192, 198))	('stimulating', 'PosReg', (268, 279))	('expression', 'MPA', (152, 162))	('production', 'MPA', (284, 294))	('upregulate', 'PosReg', (91, 101))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('CDK4/6', 'Gene', '1019;1021', (7, 13))	('downregulate', 'NegReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('promote', 'PosReg', (322, 329))	('CDK4/6', 'Gene', (192, 198))	('expression', 'MPA', (76, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))
161013	32357912	Second, CDK4/6 inhibitors inhibit the proliferation of regulatory T (Treg) cells and DNA methyltransferase 1 expression in Treg cells, resulting in promoter hypomethylation and suppression of E2F release; other studies demonstrated that the expression of CDK6 in Treg cells was higher than that of other T cell subtypes.	('E2F release', 'MPA', (192, 203))	('proliferation', 'CPA', (38, 51))	('expression', 'MPA', (109, 119))	('CDK4/6', 'Gene', (8, 14))	('promoter hypomethylation', 'MPA', (148, 172))	('CDK6', 'Gene', (255, 259))	('inhibit', 'NegReg', (26, 33))	('expression', 'MPA', (241, 251))	('CDK6', 'Gene', '1021', (255, 259))	('DNA methyltransferase 1', 'Gene', '1786', (85, 108))	('suppression', 'NegReg', (177, 188))	('CDK4/6', 'Gene', '1019;1021', (8, 14))	('DNA methyltransferase 1', 'Gene', (85, 108))	('higher', 'PosReg', (278, 284))	('inhibitors', 'Var', (15, 25))
161015	32357912	Furthermore, CDK4/6 inhibitors promote tumor cell clearance by enhancing cytotoxic T cells (CTLs).	('cytotoxic T cells', 'CPA', (73, 90))	('CDK4/6', 'Gene', '1019;1021', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('enhancing', 'PosReg', (63, 72))	('inhibitors', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CDK4/6', 'Gene', (13, 19))	('promote', 'PosReg', (31, 38))	('tumor', 'Disease', (39, 44))
161016	32357912	CDK6 is an upstream regulatory element of nuclear factor of activated T cells (NFAT), and CDK4/6 inhibitors suppress NFAT phosphorylation, the activation of CTLs, and its ability to kill tumor cells.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('phosphorylation', 'CPA', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('NFAT', 'Protein', (117, 121))	('CDK6', 'Gene', (0, 4))	('CDK4/6', 'Gene', '1019;1021', (90, 96))	('tumor', 'Disease', (187, 192))	('CTLs', 'Protein', (157, 161))	('CDK6', 'Gene', '1021', (0, 4))	('activation', 'PosReg', (143, 153))	('CDK4/6', 'Gene', (90, 96))	('suppress', 'NegReg', (108, 116))	('inhibitors', 'Var', (97, 107))
161017	32357912	Finally, the Cyclin D1-CDK4 complex directly phosphorylates speckle-type POZ protein (SPOP), and CDK4/6 inhibitors can enhance the immune escape of tumors by decreasing the ubiquitination of SPOP and reducing the degradation of PD-L1.	('enhance', 'PosReg', (119, 126))	('CDK4/6', 'Gene', (97, 103))	('speckle-type POZ protein', 'Gene', '8405', (60, 84))	('SPOP', 'Gene', (86, 90))	('CDK4', 'Gene', '1019', (23, 27))	('reducing', 'NegReg', (200, 208))	('inhibitors', 'Var', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SPOP', 'Gene', '8405', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('CDK4', 'Gene', (97, 101))	('PD-L1', 'Gene', (228, 233))	('speckle-type POZ protein', 'Gene', (60, 84))	('SPOP', 'Gene', (191, 195))	('ubiquitination', 'MPA', (173, 187))	('PD-L1', 'Gene', '29126', (228, 233))	('tumors', 'Disease', (148, 154))	('Cyclin D1', 'Gene', '595', (13, 22))	('Cyclin D1', 'Gene', (13, 22))	('SPOP', 'Gene', '8405', (86, 90))	('CDK4', 'Gene', '1019', (97, 101))	('CDK4', 'Gene', (23, 27))	('decreasing', 'NegReg', (158, 168))	('degradation', 'MPA', (213, 224))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
161022	32357912	Teo's study showed that CDK4/6 inhibitors combined with PI3K inhibitors increased the apoptosis of triple-negative breast cancer cell lines and induced persistent tumor regression in vivo.	('PI3', 'Gene', (56, 59))	('increased', 'PosReg', (72, 81))	('CDK4/6', 'Gene', '1019;1021', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CDK4/6', 'Gene', (24, 30))	('induced', 'Reg', (144, 151))	('tumor', 'Disease', (163, 168))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PI3', 'Gene', '5266', (56, 59))	('breast cancer', 'Disease', (115, 128))	('inhibitors', 'Var', (31, 41))	('apoptosis', 'CPA', (86, 95))
161024	32357912	EGFR/HER2 inhibitors combined with CDK4/6 inhibitors may increase the sensitivity to EGFR inhibitor-resistant lung cancer cells.	('EGFR', 'Gene', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('EGFR', 'Gene', (0, 4))	('HER2', 'Gene', (5, 9))	('HER2', 'Gene', '2064', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('sensitivity', 'MPA', (70, 81))	('lung cancer', 'Disease', (110, 121))	('CDK4/6', 'Gene', '1019;1021', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('increase', 'PosReg', (57, 65))	('inhibitors', 'Var', (10, 20))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (0, 4))	('CDK4/6', 'Gene', (35, 41))
161025	32357912	Goel's study demonstrated that CDK4/6 inhibitors augmented the efficacy of EGFR inhibitors in esophageal squamous cell carcinoma and reversed drug resistance.	('reversed', 'Reg', (133, 141))	('augmented', 'PosReg', (49, 58))	('CDK4/6', 'Gene', (31, 37))	('inhibitors', 'Var', (38, 48))	('CDK4/6', 'Gene', '1019;1021', (31, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('EGFR', 'Gene', '1956', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('efficacy', 'MPA', (63, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (142, 157))	('drug resistance', 'MPA', (142, 157))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
161029	32357912	Chen's study showed that RAF inhibitors combined with CDK4/6 inhibitors improve the therapeutic effects of RAS or BRAF mutant tumors.	('RAS', 'Disease', (107, 110))	('RAF', 'Gene', '22882', (25, 28))	('BRAF', 'Gene', (114, 118))	('tumors', 'Disease', (126, 132))	('BRAF', 'Gene', '673', (114, 118))	('therapeutic effects', 'CPA', (84, 103))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('improve', 'PosReg', (72, 79))	('CDK4/6', 'Gene', (54, 60))	('RAF', 'Gene', '22882', (115, 118))	('RAF', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutant', 'Var', (119, 125))	('CDK4/6', 'Gene', '1019;1021', (54, 60))	('RAF', 'Gene', (25, 28))
161032	32357912	Ribociclib combined with the ALK inhibitor ceritinib showed excellent therapeutic effects in ALK mutant neuroblastoma.	('ALK', 'Gene', (29, 32))	('neuroblastoma', 'Disease', (104, 117))	('ALK', 'Gene', '238', (93, 96))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('mutant', 'Var', (97, 103))	('ceritinib', 'Chemical', 'MESH:C586847', (43, 52))	('ALK', 'Gene', '238', (29, 32))	('ALK', 'Gene', (93, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))
161035	32357912	Vijayaraghavan's research showed that CDK4/6 inhibitors combined with autophagy inhibitors can maintain the integrity of the G1/S checkpoint and may be a new therapeutic pattern for multiple solid tumors.	('maintain', 'PosReg', (95, 103))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('integrity', 'CPA', (108, 117))	('CDK4/6', 'Gene', '1019;1021', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('inhibitors', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('CDK4/6', 'Gene', (38, 44))	('tumors', 'Disease', (197, 203))
161036	32357912	Francis's study confirmed that CDK4/6 inhibitors resensitize Rb-positive sarcoma cells to the Weel kinase inhibitor AZD1775.	('Rb', 'Phenotype', 'HP:0009919', (61, 63))	('AZD1775', 'Chemical', 'MESH:C549567', (116, 123))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('CDK4/6', 'Gene', '1019;1021', (31, 37))	('inhibitors', 'Var', (38, 48))	('CDK4/6', 'Gene', (31, 37))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
161039	32357912	Some researchers believe that CCNE1 amplification causes acquired resistance to CDK4/6 inhibitors, and that sensitivity can be restored by targeting CDK2.	('CDK2', 'Gene', '1017', (149, 153))	('CCNE1', 'Gene', '898', (30, 35))	('CCNE1', 'Gene', (30, 35))	('amplification', 'Var', (36, 49))	('CDK2', 'Gene', (149, 153))	('causes', 'Reg', (50, 56))	('CDK4/6', 'Gene', '1019;1021', (80, 86))	('CDK4/6', 'Gene', (80, 86))
161040	32357912	In addition, activating cyclin D gene mutations may enhance sensitivity to CDK4/6 inhibitors, while cyclin D deficiency is associated with CDK4/6 inhibitor resistance.	('CDK4/6', 'Gene', (139, 145))	('CDK4/6', 'Gene', '1019;1021', (75, 81))	('activating', 'PosReg', (13, 23))	('CDK4/6', 'Gene', (75, 81))	('cyclin', 'Gene', '5111', (24, 30))	('enhance', 'PosReg', (52, 59))	('CDK4/6', 'Gene', '1019;1021', (139, 145))	('cyclin', 'Gene', '5111', (100, 106))	('cyclin', 'Gene', (24, 30))	('mutations', 'Var', (38, 47))	('cyclin', 'Gene', (100, 106))
161044	32357912	A recent study revealed that amplification of fibroblast growth factor receptor 1 (FGFR1) might cause resistance to CDK4/6 inhibitors.	('fibroblast growth factor receptor 1', 'Gene', (46, 81))	('amplification', 'Var', (29, 42))	('CDK4/6', 'Gene', (116, 122))	('cause', 'Reg', (96, 101))	('FGFR1', 'Gene', (83, 88))	('fibroblast growth factor receptor 1', 'Gene', '2260', (46, 81))	('FGFR1', 'Gene', '2260', (83, 88))	('CDK4/6', 'Gene', '1019;1021', (116, 122))
161046	32357912	Studies have shown that deletion of p16 decreases the endogenous inhibition of CDK4/6 and that low levels of p16 may suggest that cells are sensitive to CDK4/6 inhibitors.	('p16', 'Gene', (109, 112))	('CDK4/6', 'Gene', (153, 159))	('endogenous inhibition', 'MPA', (54, 75))	('p16', 'Gene', '1029', (36, 39))	('CDK4/6', 'Gene', '1019;1021', (79, 85))	('CDK4/6', 'Gene', '1019;1021', (153, 159))	('p16', 'Gene', '1029', (109, 112))	('deletion', 'Var', (24, 32))	('decreases', 'NegReg', (40, 49))	('CDK4/6', 'Gene', (79, 85))	('p16', 'Gene', (36, 39))
161048	32357912	However, Wang's study showed that approximately 85% of breast cancer cells have normal Rb status, but due to the rare Rb deletion in ER+ breast cancer, it is less sensitive as a predictive marker.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('Rb', 'Phenotype', 'HP:0009919', (118, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Rb status', 'MPA', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('Rb', 'Phenotype', 'HP:0009919', (87, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('deletion', 'Var', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
161053	32357912	CDK4/6 inhibitors achieve striking antitumor effects by regulating the cell cycle.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('inhibitors', 'Var', (7, 17))	('regulating', 'Reg', (56, 66))	('tumor', 'Disease', (39, 44))	('CDK4/6', 'Gene', (0, 6))	('cell cycle', 'CPA', (71, 81))
161056	32357912	CDK4/6 inhibitors have great potential to become broad-spectrum antitumor drugs.	('tumor', 'Disease', (68, 73))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDK4/6', 'Gene', (0, 6))
161186	19154582	Results shows that both DNA copy number alteration and transcriptome data sets induce a good separation of the gliomas according to the WHO classification.	('copy number alteration', 'Var', (28, 50))	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))
161214	19154582	Allelic alterations of chromosomes 1 (short arm) and 19 (long arm) are frequently reported as important events in gliomas and especially in oligodendrogliomas.	('gliomas', 'Disease', (114, 121))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (140, 158))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('short arm', 'Phenotype', 'HP:0009824', (38, 47))	('oligodendrogliomas', 'Disease', (140, 158))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('Allelic alterations', 'Var', (0, 19))
161228	19154582	Among these biological processes, 'protein metabolism' (GO:0019538), 'transport' (GO:0006810), and 'transcription DNA-dependent' (GO:0006350) annotate 18 genes of those located on 1p or 19q.	("'protein metabolism'", 'MPA', (34, 54))	('GO:0019538', 'Var', (56, 66))	('ose', 'Chemical', '-', (165, 168))
161294	19154582	We retrieved the corresponding publicly available data sets as 'Series Matrix Files' (GSE1991, GSE2223 and GSE4412) from the Gene Expression Omnibus (GEO) database.	('GSE1991', 'Var', (86, 93))	('GSE1991', 'Chemical', '-', (86, 93))	('GSE4412', 'Chemical', '-', (107, 114))	('GSE4412', 'Var', (107, 114))	('GSE2223', 'Chemical', '-', (95, 102))
161328	33105535	Analysis of Mutant Isocitrate Dehydrogenase 1 Immunoexpression, Ki-67 and Programmed Death Ligand 1 in Diffuse Astrocytic Tumours : Study of Single Center in Bandung, Indonesia Diffuse astrocytic tumour (DAT) is a diffuse infiltrative astrocytoma tumour accompanied by molecular parameters such as the presence or absence of isocitrate dehydrogenase (IDH) gene mutations.	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('Programmed Death Ligand 1', 'Gene', (74, 99))	('Diffuse Astrocytic Tumours', 'Disease', (103, 129))	('astrocytic tumour', 'Disease', (185, 202))	('mutations', 'Var', (361, 370))	('isocitrate dehydrogenase', 'Gene', (325, 349))	('IDH', 'Gene', (351, 354))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('astrocytoma tumour', 'Disease', (235, 253))	('IDH', 'Gene', '3417', (351, 354))	('isocitrate dehydrogenase', 'Gene', '3417', (325, 349))	('Programmed Death Ligand 1', 'Gene', '29126', (74, 99))	('astrocytoma tumour', 'Disease', 'MESH:D001254', (235, 253))	('Tumours', 'Phenotype', 'HP:0002664', (122, 129))	('astrocytic tumour', 'Disease', 'MESH:D001254', (185, 202))	('astrocytoma', 'Phenotype', 'HP:0009592', (235, 246))	('Diffuse Astrocytic Tumours', 'Disease', 'MESH:D001254', (103, 129))
161329	33105535	This study aimed to analyze the correlation among mutant IDH1 R132H, Ki-67, and PD-L1 immunoexpression in the DAT.	('R132H', 'Var', (62, 67))	('R132H', 'Mutation', 'rs121913500', (62, 67))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (57, 61))	('mutant', 'Var', (50, 56))
161332	33105535	In this study, the immunohistochemistry-staining of mutant IDH1 R132H, Ki-67, and PD-L1 were carried out to determine the frequency of DAT with IDH1 mutations.	('IDH1', 'Gene', '3417', (59, 63))	('R132H', 'Mutation', 'rs121913500', (64, 69))	('mutant', 'Var', (52, 58))	('IDH1', 'Gene', (144, 148))	('IDH1', 'Gene', (59, 63))	('R132H', 'Var', (64, 69))	('IDH1', 'Gene', '3417', (144, 148))
161333	33105535	Our study shown the frequency of IDH1 mutations in grade II 50.0% (7/14), grade III 37.5% (3/8), and grade IV 12.5% (1/8).	('mutations', 'Var', (38, 47))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (33, 37))
161334	33105535	There was an association between both mutant IDH1 R132H, and Ki-67 with PD-L1 expression in DAT (p=0.0087 and p=0.0049, respectively).	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (45, 49))	('R132H', 'Var', (50, 55))	('IDH1', 'Gene', (45, 49))	('Ki-67', 'Gene', (61, 66))	('PD-L1', 'Gene', (72, 77))	('R132H', 'Mutation', 'rs121913500', (50, 55))
161335	33105535	DAT with the mutant IDH1 is frequently observed in grade II and small number of grade III.	('mutant', 'Var', (13, 19))	('IDH1', 'Gene', (20, 24))	('observed', 'Reg', (39, 47))	('IDH1', 'Gene', '3417', (20, 24))
161337	33105535	There is a correlation between each of mutant IDH1 status and Ki-67 with PD-L1 expression in DAT.	('expression', 'MPA', (79, 89))	('IDH1', 'Gene', (46, 50))	('correlation', 'Interaction', (11, 22))	('IDH1', 'Gene', '3417', (46, 50))	('mutant', 'Var', (39, 45))	('PD-L1', 'Gene', (73, 78))
161341	33105535	Definition of DAT is an accompanied infiltrative diffuse astrocytoma tumour with molecular parameters in the form of the presence or absence of isocitrate dehydrogenase (IDH) gene mutations.	('DAT', 'Disease', (14, 17))	('mutations', 'Var', (180, 189))	('astrocytoma tumour', 'Disease', (57, 75))	('IDH', 'Gene', (170, 173))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (57, 68))	('isocitrate dehydrogenase', 'Gene', (144, 168))	('astrocytoma tumour', 'Disease', 'MESH:D001254', (57, 75))	('IDH', 'Gene', '3417', (170, 173))	('isocitrate dehydrogenase', 'Gene', '3417', (144, 168))
161347	33105535	Immunohistochemistry (ICH) markers, Ki-67, has been widely used as a marker of proliferation of tumour cells in humans.	('ICH', 'Disease', 'MESH:D002543', (22, 25))	('humans', 'Species', '9606', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('ICH', 'Disease', (22, 25))	('Ki-67', 'Var', (36, 41))	('tumour', 'Disease', (96, 102))
161352	33105535	Successful clinical trial results with programmed death 1 (PD-1) antibodies and many other immune-checkpoint inhibitors, have opened new discoveries in field of cancer immunology.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PD-1', 'Gene', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('antibodies', 'Var', (65, 75))	('cancer', 'Disease', (161, 167))
161366	33105535	After the initial processing step, sections were incubated with primary antibodies anti-human glial fibrillary acidic protein (GFAP) AB (CP 040 Biocare, Clone N/A, rabbit monoclonal AB, at 1 : 150 dilution); anti-human Ki-67 AB (Cellmarquee, Clone SP6, rabbit monoclonal AB, at 1 : 200 dilution); anti-human IDH1 R132H mutant specific AB (GTX57185 Genetex, IHC 132, mouse monoclonal AB, at 1 : 200 dilution); anti-human PD-L1 AB (ab205921 Abcam, clone 28-8, rabbit monoclonal AB, at 1 : 200 dilution) at the room temperature, respectively; followed by incubation with polyHRP non-biotin detection system for 30 minutes.	('SP6', 'Gene', '80320', (248, 251))	('IDH1', 'Gene', (308, 312))	('anti-human', 'Var', (409, 419))	('R132H', 'Mutation', 'rs121913500', (313, 318))	('GFAP', 'Gene', (127, 131))	('glial fibrillary acidic protein', 'Gene', (94, 125))	('glial fibrillary acidic protein', 'Gene', '2670', (94, 125))	('IDH1', 'Gene', '3417', (308, 312))	('GFAP', 'Gene', '2670', (127, 131))	('PD-L1 AB', 'Gene', (420, 428))	('SP6', 'Gene', (248, 251))
161369	33105535	Expression of mutant IDH1 R132H, Ki-67, and PD-L1 were determined by semi-quantitative assessment of the proportion of the positively stained tumour cells.	('tumour', 'Disease', (142, 148))	('mutant', 'Var', (14, 20))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('IDH1', 'Gene', (21, 25))	('R132H', 'Var', (26, 31))	('IDH1', 'Gene', '3417', (21, 25))	('R132H', 'Mutation', 'rs121913500', (26, 31))
161370	33105535	Cases with >=10% stained cells were label as positive; cases with <10% stained cells were label as negative (Ki-67 and mutant IDH1).	('IDH1', 'Gene', '3417', (126, 130))	('mutant', 'Var', (119, 125))	('IDH1', 'Gene', (126, 130))
161379	33105535	To gain some mechanistic knowledge that underlying malignancy in glioma patients, we performed IHC to examine several markers : GFAP, mutant IDH1 R132H, Ki-67, and PD-L1.	('IDH1', 'Gene', (141, 145))	('glioma', 'Disease', (65, 71))	('R132H', 'Var', (146, 151))	('malignancy', 'Disease', 'MESH:D009369', (51, 61))	('GFAP', 'Gene', '2670', (128, 132))	('IDH1', 'Gene', '3417', (141, 145))	('R132H', 'Mutation', 'rs121913500', (146, 151))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('malignancy', 'Disease', (51, 61))	('GFAP', 'Gene', (128, 132))	('mutant', 'Var', (134, 140))	('patients', 'Species', '9606', (72, 80))
161382	33105535	Mutant IDH1 status, as one of the recommended examination by WHO, was often observed in LGG specimens (50%; 7/14) than HGG (grade III 37.5%; 3/8 and grade IV 12.5%; 1/8, p=0.2137 respectively shown in Fig.	('IDH1', 'Gene', '3417', (7, 11))	('Mutant', 'Var', (0, 6))	('LGG', 'Disease', (88, 91))	('IDH1', 'Gene', (7, 11))	('observed', 'Reg', (76, 84))
161386	33105535	Mutant IDH1 status had no correlation with Ki-67 (p=0.0634).	('Mutant', 'Var', (0, 6))	('Ki-67', 'Disease', (43, 48))	('IDH1', 'Gene', (7, 11))	('IDH1', 'Gene', '3417', (7, 11))
161387	33105535	The mutant IDH1 status was significant inversely correlated with the higher PD-L1 immunopositivity (p=0.0087).	('inversely', 'NegReg', (39, 48))	('mutant', 'Var', (4, 10))	('IDH1', 'Gene', (11, 15))	('IDH1', 'Gene', '3417', (11, 15))
161388	33105535	As shown in Table 2, by univariate analysis, grade IV patients had lower survival probability rate vs. grade II and III patients (p=0.0039; HR, 10.29 [2.11-50.09]); patient with multiple lesions had lower survival probability rate vs. patients with single lesion only (p=0.0325; HR, 0.28 [0.09-0.90]); Ki-67 >=10% patients had lower survival probability rate vs. Ki-67 <10% patients (p=0.0016; HR, 6.63 [2.05-21.40]); wild type IDH1 patients had a tendency lower survival probability raye vs. mutant IDH1 patients, even not statistically significant (p=0.9980; HR, 6.10x10-9 161 [0-inf]); PD-L1 >80% and 50-80% patients had lower survival probability rate vs. PD-L1 0-50% (p=0.0008; HR, 7.46 [2.28-24.38]).	('PD-L1', 'Var', (589, 594))	('IDH1', 'Gene', (500, 504))	('lower', 'NegReg', (457, 462))	('lower', 'NegReg', (624, 629))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (505, 513))	('IDH1', 'Gene', (428, 432))	('patients', 'Species', '9606', (235, 243))	('patient', 'Species', '9606', (120, 127))	('patient', 'Species', '9606', (374, 381))	('patient', 'Species', '9606', (611, 618))	('IDH1', 'Gene', '3417', (500, 504))	('patients', 'Species', '9606', (433, 441))	('patient', 'Species', '9606', (54, 61))	('patients', 'Species', '9606', (314, 322))	('patient', 'Species', '9606', (165, 172))	('patient', 'Species', '9606', (505, 512))	('survival probability', 'MPA', (630, 650))	('IDH1', 'Gene', '3417', (428, 432))	('patient', 'Species', '9606', (235, 242))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (374, 382))	('patients', 'Species', '9606', (611, 619))	('patient', 'Species', '9606', (433, 440))	('patient', 'Species', '9606', (314, 321))
161389	33105535	By multivariate analysis, male patients had lower survival probability rate vs. female patients (p=0.0222; HR, 8.93 [1.37-58.32]) and Ki-67 >=10% patients had lower survival probability rate vs. Ki-67 <10% patients (p=0.0211; HR, 0.08 [0.01-0.69]).	('lower', 'NegReg', (44, 49))	('patients', 'Species', '9606', (87, 95))	('survival', 'MPA', (50, 58))	('lower', 'NegReg', (159, 164))	('patients', 'Species', '9606', (206, 214))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (146, 154))	('survival', 'MPA', (165, 173))	('Ki-67', 'Var', (134, 139))
161390	33105535	Studies shown that EGFR amplification and the combination of a positive finding for any two of the three other markers (pTERT mutant, or the chromosome 7/10 signatures) are highly specific for IDH WT GBM, while the combination of all three markers is exclusively seen in IDH WT GBM.	('IDH WT GBM', 'Disease', (193, 203))	('IDH WT GBM', 'Disease', 'MESH:D005910', (271, 281))	('EGFR', 'Gene', '1956', (19, 23))	('IDH WT GBM', 'Disease', (271, 281))	('amplification', 'Var', (24, 37))	('EGFR', 'Gene', (19, 23))	('IDH WT GBM', 'Disease', 'MESH:D005910', (193, 203))
161392	33105535	This is the first study ever conducted in Bandung, Indonesia; the anti-IDH1 R132H immuno-expression was seen in 30 surgical or biopsy which had previously been diagnosed with WHO based diagnosis for glioma tumours.	('glioma tumours', 'Disease', 'MESH:D005910', (199, 213))	('glioma tumours', 'Disease', (199, 213))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('R132H', 'Var', (76, 81))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('IDH1', 'Gene', (71, 75))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('R132H', 'Mutation', 'rs121913500', (76, 81))	('IDH1', 'Gene', '3417', (71, 75))
161393	33105535	A total of 11 of the 30 samples analyzed turned out to have heterozygous mutations in the 132 IDH1 codon that specifically changed from arginine to histidine; Omer et al., shown a variation in the percentage of mutant IDH1 R132H for gliomas from several countries in Asia such as Japan reported 29.2-31.2%; China 55.2-57.5%; Korea 53.7%; India 41.9%; Iraq 34.86-37.1%.	('IDH1', 'Gene', (94, 98))	('R132H', 'Var', (223, 228))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('arginine', 'Chemical', 'MESH:D001120', (136, 144))	('R132H', 'Mutation', 'rs121913500', (223, 228))	('IDH1', 'Gene', '3417', (94, 98))	('IDH1', 'Gene', (218, 222))	('mutant', 'Var', (211, 217))	('gliomas', 'Disease', (233, 240))	('IDH1', 'Gene', '3417', (218, 222))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('histidine', 'Chemical', 'MESH:D006639', (148, 157))
161395	33105535	in 2017, shown that IDH1 mutations are highly identified in Indonesian gliomas patients, as high as 74% (37/50) and significantly correlated with grading.	('IDH1', 'Gene', '3417', (20, 24))	('mutations', 'Var', (25, 34))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('correlated', 'Reg', (130, 140))	('patients', 'Species', '9606', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH1', 'Gene', (20, 24))
161396	33105535	However, in this study, we observed 36.7% (11/25) patients that possess IDH1 R132H mutation and exhibits no significant correlation with grading (p>0.05), it's in alignment with what has been observed by others; that stated the IDH1 mutation plays role in tumourigenesis of LGG.	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('IDH1', 'Gene', (72, 76))	('patients', 'Species', '9606', (50, 58))	('tumour', 'Disease', (256, 262))	('R132H mutation', 'Var', (77, 91))	('IDH1', 'Gene', (228, 232))	('IDH1', 'Gene', '3417', (72, 76))	('IDH1', 'Gene', '3417', (228, 232))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('LGG', 'Disease', (274, 277))	('R132H', 'Mutation', 'rs121913500', (77, 82))
161398	33105535	Other studies shown the median age of patients with and without IDH1 mutations are age 33 years and 53 years.	('mutations', 'Var', (69, 78))	('IDH1', 'Gene', '3417', (64, 68))	('IDH1', 'Gene', (64, 68))	('patients', 'Species', '9606', (38, 46))
161399	33105535	Our study in agreement with other that was specifically stated in glioblastoma, IDH1 mutations were significantly found in young age (mean, 47.9 years) and without IDH1 mutations in older age (mean, 60.6 years); in our study was 34, 44, and 55.5 years, respectively.	('found', 'Reg', (114, 119))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('mutations', 'Var', (85, 94))	('glioblastoma', 'Disease', (66, 78))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('IDH1', 'Gene', (164, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('IDH1', 'Gene', '3417', (164, 168))
161402	33105535	Study results prove the frequency of dominant IDH1 mutations found in secondary glioblastoma compared to primary one.	('mutations', 'Var', (51, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('IDH1', 'Gene', (46, 50))	('found', 'Reg', (61, 66))	('IDH1', 'Gene', '3417', (46, 50))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))
161403	33105535	The predominant frequency of IDH1 mutations found predominantly in diffuse (grade II) astrocytoma tumours and anaplastic (grade III) astrocytomas has a tendency to develop into secondary glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('develop', 'Reg', (164, 171))	('diffuse', 'Disease', (67, 74))	('IDH1', 'Gene', (29, 33))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('astrocytomas', 'Disease', (133, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('IDH1', 'Gene', '3417', (29, 33))	('astrocytoma tumours', 'Disease', 'MESH:D001254', (86, 105))	('astrocytoma tumours', 'Disease', (86, 105))	('glioblastoma', 'Disease', (187, 199))	('glioblastoma', 'Disease', 'MESH:D005909', (187, 199))	('mutations', 'Var', (34, 43))	('astrocytomas', 'Disease', 'MESH:D001254', (133, 145))
161404	33105535	A negative IDH1 R132H result (87.5%) in glioblastoma does not necessarily prove that the sample tested is the primary glioblastoma; for reasons not checked for wild type IDH markers and there is still a possibility of mutations other than R132H which may also occur in glioblastoma samples.	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('IDH1', 'Gene', '3417', (11, 15))	('IDH', 'Gene', '3417', (170, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('IDH', 'Gene', (170, 173))	('glioblastoma', 'Disease', (269, 281))	('R132H', 'Var', (239, 244))	('R132H', 'Mutation', 'rs121913500', (16, 21))	('R132H', 'Mutation', 'rs121913500', (239, 244))	('glioblastoma', 'Disease', 'MESH:D005909', (269, 281))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (269, 281))	('IDH1', 'Gene', (11, 15))	('glioblastoma', 'Disease', (40, 52))
161405	33105535	This study specifically stated that there was no significant difference (p=0.2137, Table 1) of the diagnostic ability of mutant IDH1 R132H in all three grade gliomas; also in this cohort, Ki-67 >=10% had no correlation with IDH1 status (p=0.0634), but the tendency Ki-67 >=10% was associated with wild type IDH1 (Fig.	('IDH1', 'Gene', (307, 311))	('IDH1', 'Gene', '3417', (224, 228))	('mutant', 'Var', (121, 127))	('IDH1', 'Gene', '3417', (128, 132))	('IDH1', 'Gene', '3417', (307, 311))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('IDH1', 'Gene', (224, 228))	('R132H', 'Var', (133, 138))	('gliomas', 'Disease', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('R132H', 'Mutation', 'rs121913500', (133, 138))	('IDH1', 'Gene', (128, 132))
161406	33105535	Recently found that wild type IDH is associated with significantly higher tumour infiltrating lymphocytes (TIL) and PD-L1 expression in all degrees of gliomas.	('expression', 'MPA', (122, 132))	('higher', 'PosReg', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('wild type', 'Var', (20, 29))	('tumour', 'Disease', (74, 80))	('PD-L1', 'Gene', (116, 121))	('IDH', 'Gene', (30, 33))	('gliomas', 'Disease', (151, 158))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('IDH', 'Gene', '3417', (30, 33))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
161412	33105535	Wang et al., who found that the PD-L1 expression in gliomas with mutants IDH1 showed low expression in different degrees of gliomas although statistically did not give significance in some groups.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('gliomas', 'Disease', (52, 59))	('expression', 'MPA', (89, 99))	('mutants', 'Var', (65, 72))	('PD-L1', 'Gene', (32, 37))	('IDH1', 'Gene', '3417', (73, 77))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('IDH1', 'Gene', (73, 77))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
161414	33105535	Berghoff et al., found the result that in mutants IDH1 in gliomas with co-deletion 1p/19q showed the lowest PD-L1 expression results, followed by mutant IDH1 with non co-deletion 1p/19q, wild type IDH1 and glioblastoma which then gave increasing PD-L1 expression in their sequence.	('lowest', 'NegReg', (101, 107))	('PD-L1', 'Gene', (108, 113))	('mutants', 'Var', (42, 49))	('IDH1', 'Gene', (153, 157))	('IDH1', 'Gene', (50, 54))	('IDH1', 'Gene', (197, 201))	('glioblastoma', 'Disease', (206, 218))	('IDH1', 'Gene', '3417', (153, 157))	('IDH1', 'Gene', '3417', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IDH1', 'Gene', '3417', (197, 201))	('co-deletion', 'Var', (71, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (206, 218))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('expression', 'MPA', (114, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
161417	33105535	According to WHO 2016, diffuse gliomas are lumped together, regardless of their histopathological aspect (whether astrocytoma or oligodendroglioma); co-deletion 1p/19q is a pathognomonic biomarker that defines a distinct gliomas entity; assessment of co-deletion 1p/19q, together with IDH mutation and other markers (e.g., ATRX and TP53), can help distinguish oligodendrogliomas which are IDH-mutant status and co-deletion 1p/19q, from tumours of astrocytic lineage which are non co-deletion 1p/19q.	('IDH', 'Gene', (389, 392))	('gliomas', 'Disease', 'MESH:D005910', (221, 228))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('oligodendrogliomas', 'Disease', (360, 378))	('ATRX', 'Gene', (323, 327))	('gliomas', 'Disease', 'MESH:D005910', (371, 378))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('astrocytoma or oligodendroglioma', 'Disease', (114, 146))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('ATRX', 'Gene', '546', (323, 327))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('IDH', 'Gene', (285, 288))	('glioma', 'Phenotype', 'HP:0009733', (371, 377))	('gliomas', 'Phenotype', 'HP:0009733', (221, 228))	('IDH', 'Gene', '3417', (389, 392))	('TP53', 'Gene', '7157', (332, 336))	('gliomas', 'Phenotype', 'HP:0009733', (371, 378))	('tumours of astrocytic', 'Disease', (436, 457))	('IDH', 'Gene', '3417', (285, 288))	('tumours', 'Phenotype', 'HP:0002664', (436, 443))	('co-deletion 1p/19q', 'Var', (411, 429))	('gliomas', 'Disease', (31, 38))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (360, 378))	('astrocytoma or oligodendroglioma', 'Disease', 'MESH:D009837', (114, 146))	('gliomas', 'Disease', (221, 228))	('tumour', 'Phenotype', 'HP:0002664', (436, 442))	('tumours of astrocytic', 'Disease', 'MESH:D001254', (436, 457))	('gliomas', 'Disease', (371, 378))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('TP53', 'Gene', (332, 336))
161420	33105535	The mechanism of the relationship between IDH1 mutations and the micro-tumour environment still needs to be re-examined.	('tumour', 'Disease', (71, 77))	('IDH1', 'Gene', '3417', (42, 46))	('mutations', 'Var', (47, 56))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('IDH1', 'Gene', (42, 46))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
161421	33105535	The lower PD-L1 expression is associated with increased methylation promoter in gliomas with mutants IDH.	('lower', 'NegReg', (4, 9))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('increased', 'PosReg', (46, 55))	('mutants', 'Var', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('methylation promoter', 'MPA', (56, 76))	('IDH', 'Gene', (101, 104))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('PD-L1', 'Gene', (10, 15))	('IDH', 'Gene', '3417', (101, 104))	('expression', 'MPA', (16, 26))
161422	33105535	The presence of a very high PD-L1 methylation promoter gene in mutants IDH compared to wild type IDH, indicates that the PD-L1 methylation promoter gene is likely to be associated with lower PD-L1 expression in mutant IDH vs. wild type IDH.	('PD-L1', 'Gene', (121, 126))	('lower', 'NegReg', (185, 190))	('PD-L1', 'Gene', (191, 196))	('mutants', 'Var', (63, 70))	('IDH', 'Gene', (97, 100))	('IDH', 'Gene', (236, 239))	('IDH', 'Gene', '3417', (97, 100))	('IDH', 'Gene', (71, 74))	('mutant', 'Var', (211, 217))	('IDH', 'Gene', '3417', (236, 239))	('PD-L1', 'Gene', (28, 33))	('IDH', 'Gene', (218, 221))	('IDH', 'Gene', '3417', (71, 74))	('expression', 'MPA', (197, 207))	('IDH', 'Gene', '3417', (218, 221))
161423	33105535	The increase in methylation promoter is related to the characteristics of the hypermethylate phenotype in gliomas with mutants IDH that have been shown to be induced on 2-hydroxyglutarate oncometabolite.	('hypermethylate', 'MPA', (78, 92))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (169, 187))	('methylation promoter', 'MPA', (16, 36))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('increase', 'PosReg', (4, 12))	('mutants', 'Var', (119, 126))
161424	33105535	Other factors that influence differences in immune phenotypes between gliomas with mutant IDH and wild type IDH are epigenetic changes in the immune signaling pathway and the effect of 2-hydroxyglutarate on the micro-tumour environment including TIL.	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('IDH', 'Gene', (90, 93))	('mutant', 'Var', (83, 89))	('IDH', 'Gene', (108, 111))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('IDH', 'Gene', '3417', (90, 93))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('immune signaling pathway', 'Pathway', (142, 166))	('IDH', 'Gene', '3417', (108, 111))	('tumour', 'Disease', (217, 223))	('gliomas', 'Disease', (70, 77))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (185, 203))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
161429	33105535	The frequency of mutant IDH1 R132H in grade II DAT in this study was lower than data from WHO.	('R132H', 'Mutation', 'rs121913500', (29, 34))	('R132H', 'Var', (29, 34))	('IDH1', 'Gene', '3417', (24, 28))	('IDH1', 'Gene', (24, 28))
161430	33105535	DAT with the mutant IDH1 is frequently observed in grade II and small number of grade III DAT.	('mutant', 'Var', (13, 19))	('IDH1', 'Gene', (20, 24))	('IDH1', 'Gene', '3417', (20, 24))
161462	32277141	Moreover, the extremely unbalance between the tumor region and the background region will further deteriorate the brain tumor segmentation performance with traditional U-Net-like models.	('brain tumor', 'Disease', 'MESH:D001932', (114, 125))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('brain tumor', 'Phenotype', 'HP:0030692', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('unbalance', 'Var', (24, 33))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('brain tumor', 'Disease', (114, 125))	('deteriorate', 'NegReg', (98, 109))	('tumor', 'Disease', (120, 125))	('U-Net', 'Chemical', '-', (168, 173))
161625	32131409	The features extracted from GLCM include contrast, correlation, energy, homogeneity, entropy, cluster shade, cluster prominence, and autocorrelation, and the features extracted from GLRLM include Long-Run-Emphasis, Short-Run-Emphasis, Run-Length-Non-Uniformity, Grey-Level-Non-Uniformity, High-Grey-Level-Run-Emphasis, Low-Grey-Level-Run-Emphasis, Short-Run-High-Grey-Level-Emphasis, Short-Run-Low-Grey-Level-Emphasis, Long-Run-High-Grey-Level-Emphasis, and Long-Run-Low-Grey-Level-Emphasis.	('Short-Run-Low-Grey-Level-Emphasis', 'Var', (384, 417))	('GLCM', 'Chemical', '-', (28, 32))	('Long-Run-High-Grey-Level-Emphasis', 'Var', (419, 452))
161691	31683535	Insulin-resistant obese monkeys treated with GW501516; a ligand PPARbeta/delta showed an increased serum high-density lipoprotein cholesterol and a decrease of low density lipoprotein, fasting triglycerides, and insulin.	('low density lipoprotein', 'MPA', (160, 183))	('decrease of low density lipoprotein', 'Phenotype', 'HP:0003563', (148, 183))	('Insulin-resistant obese', 'Phenotype', 'HP:0000831', (0, 23))	('GW501516', 'Var', (45, 53))	('cholesterol', 'Chemical', 'MESH:D002784', (130, 141))	('insulin', 'Gene', (212, 219))	('obese', 'Disease', 'MESH:D009765', (18, 23))	('decrease', 'NegReg', (148, 156))	('GW501516', 'Chemical', 'MESH:C425931', (45, 53))	('triglycerides', 'Chemical', 'MESH:D014280', (193, 206))	('serum high-density lipoprotein cholesterol', 'MPA', (99, 141))	('insulin', 'Gene', '3630', (212, 219))	('Insulin', 'Gene', '3630', (0, 7))	('Insulin', 'Gene', (0, 7))	('increased serum high-density lipoprotein', 'Phenotype', 'HP:0012184', (89, 129))	('increased', 'PosReg', (89, 98))	('obese', 'Disease', (18, 23))	('fasting triglycerides', 'MPA', (185, 206))
161704	31683535	Finally, beta-aminoisobutyric acid (BAIBA), belongs to a recent class of factors called "myometabokines," is able to regulate systemic metabolism crosstalk, and to induce browning phenotype in white adipose tissue.	('beta-aminoisobutyric', 'Var', (9, 29))	('adipose', 'Gene', (199, 206))	('induce', 'PosReg', (164, 170))	('beta-aminoisobutyric acid', 'Chemical', 'MESH:C033435', (9, 34))	('browning phenotype', 'MPA', (171, 189))	('systemic metabolism crosstalk', 'MPA', (126, 155))	('regulate', 'Reg', (117, 125))	('BAIBA', 'Chemical', 'MESH:C033435', (36, 41))	('adipose', 'Gene', '230796', (199, 206))
161707	31683535	During the fasting state: PPARalpha increases plasma high-density lipoproteins (HDL) levels and reduces low-density lipoproteins (LDL) levels; it also promotes peroxisomal and mitochondrial oxidation in the protection of the liver from lipotoxicity.	('reduces', 'NegReg', (96, 103))	('PPARalpha', 'Var', (26, 35))	('lipotoxicity', 'Disease', (236, 248))	('low-density lipoproteins (LDL) levels', 'MPA', (104, 141))	('promotes', 'PosReg', (151, 159))	('plasma high-density lipoproteins', 'MPA', (46, 78))	('mitochondrial oxidation', 'MPA', (176, 199))	('increases', 'PosReg', (36, 45))	('lipotoxicity', 'Disease', 'None', (236, 248))	('peroxisomal', 'MPA', (160, 171))
161713	31683535	Glucose Metabolism  PPARalpha decreases glycolysis, improves glycogen synthesis and fatty acid oxidation with consequently inhibiting lipid accumulation.	('decreases', 'NegReg', (30, 39))	('Glucose Metabolism', 'Disease', (0, 18))	('inhibiting', 'NegReg', (123, 133))	('decreases glycolysis', 'Phenotype', 'HP:0012270', (30, 50))	('glycolysis', 'MPA', (40, 50))	('Glucose Metabolism', 'Disease', 'MESH:D044882', (0, 18))	('fatty acid', 'Chemical', 'MESH:D005227', (84, 94))	('PPARalpha', 'Var', (20, 29))	('glycogen synthesis', 'MPA', (61, 79))	('fatty acid oxidation', 'MPA', (84, 104))	('improves', 'PosReg', (52, 60))	('lipid accumulation', 'MPA', (134, 152))
161714	31683535	PPARgamma increases gluconeogenesis in the liver and improves glucose-mediated insulin secretion in beta cells in pancreatic Langerhans islands.	('increases', 'PosReg', (10, 19))	('PPARgamma', 'Var', (0, 9))	('improves', 'PosReg', (53, 61))	('insulin', 'Gene', (79, 86))	('increases gluconeogenesis', 'Phenotype', 'HP:0005959', (10, 35))	('pancreatic Langerhans islands', 'Disease', 'MESH:D007516', (114, 143))	('insulin', 'Gene', '3630', (79, 86))	('gluconeogenesis', 'MPA', (20, 35))	('pancreatic Langerhans islands', 'Disease', (114, 143))	('glucose', 'Chemical', 'MESH:D005947', (62, 69))
161715	31683535	PPARbeta/delta unlocks its glycolytic action by improving glucose uptake, glycolysis, glycogen storage, and gluconeogenesis reduction.	('gluconeogenesis', 'MPA', (108, 123))	('PPARbeta/delta', 'Var', (0, 14))	('glycolysis', 'MPA', (74, 84))	('glucose uptake', 'MPA', (58, 72))	('improving', 'PosReg', (48, 57))	('glucose', 'Chemical', 'MESH:D005947', (58, 65))	('gluconeogenesis reduction', 'Phenotype', 'HP:0005959', (108, 133))	('glycogen storage', 'MPA', (86, 102))
161717	31683535	PPARalpha also manages to improve cholesterol transport through increased expression of apolipoprotein AI (Apo-AI).	('expression', 'MPA', (74, 84))	('cholesterol transport', 'MPA', (34, 55))	('Apo-AI', 'Gene', '335', (107, 113))	('apolipoprotein AI', 'Gene', '335', (88, 105))	('cholesterol', 'Chemical', 'MESH:D002784', (34, 45))	('PPARalpha', 'Var', (0, 9))	('Apo-AI', 'Gene', (107, 113))	('apolipoprotein AI', 'Gene', (88, 105))	('increased', 'PosReg', (64, 73))	('improve', 'PosReg', (26, 33))
161719	31683535	PPARbeta/delta also reduces the expression of Niemann Pick C1-like 1 (NPC1L1) in the intestine, leading to a reduction in cholesterol adsorption, improving its transintestinal efflux.	('NPC1L1', 'Gene', '29881', (70, 76))	('PPARbeta/delta', 'Var', (0, 14))	('Niemann Pick C1-like 1', 'Gene', '29881', (46, 68))	('reduces', 'NegReg', (20, 27))	('transintestinal efflux', 'Phenotype', 'HP:0000076', (160, 182))	('NPC1L1', 'Gene', (70, 76))	('reduction', 'NegReg', (109, 118))	('cholesterol', 'Chemical', 'MESH:D002784', (122, 133))	('cholesterol adsorption', 'MPA', (122, 144))	('expression', 'MPA', (32, 42))	('improving', 'PosReg', (146, 155))	('Niemann Pick C1-like 1', 'Gene', (46, 68))	('transintestinal efflux', 'MPA', (160, 182))
161723	31683535	Knockout of PPARgamma in mouse model causes cardiac hypertrophy which therefore influences cardiac function and metabolism.	('cardiac function', 'MPA', (91, 107))	('PPARgamma', 'Gene', (12, 21))	('cardiac hypertrophy', 'Disease', (44, 63))	('mouse', 'Species', '10090', (25, 30))	('metabolism', 'MPA', (112, 122))	('influences', 'Reg', (80, 90))	('Knockout', 'Var', (0, 8))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (44, 63))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (44, 63))	('causes', 'Reg', (37, 43))
161724	31683535	The agonist GW610742 increased PPARbeta/delta expression in murine cardiac tissue, improving oxidative and mitochondrial metabolism with a significant decrease in ventricular hypertrophy and a reduction in natriuretic peptide in rats with congestive heart failure.	('increased', 'PosReg', (21, 30))	('congestive heart failure', 'Disease', 'MESH:D006333', (239, 263))	('congestive heart failure', 'Phenotype', 'HP:0001635', (239, 263))	('reduction', 'NegReg', (193, 202))	('congestive heart failure', 'Disease', (239, 263))	('murine', 'Species', '10090', (60, 66))	('improving', 'PosReg', (83, 92))	('ventricular hypertrophy', 'Phenotype', 'HP:0001714', (163, 186))	('decrease', 'NegReg', (151, 159))	('ventricular hypertrophy', 'Disease', 'MESH:D024741', (163, 186))	('GW610742', 'Var', (12, 20))	('GW610742', 'Chemical', 'MESH:C503394', (12, 20))	('PPARbeta/delta', 'Gene', (31, 45))	('ventricular hypertrophy', 'Disease', (163, 186))	('natriuretic peptide', 'MPA', (206, 225))	('rats', 'Species', '10116', (229, 233))
161729	31683535	In fact, PPARbeta/delta knockdown leads to a reduction in Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) levels  PPARgamma is involved in the metabolism of glucose in skeletal muscle, improving its absorption.	('glucose', 'Chemical', 'MESH:D005947', (191, 198))	('Peroxisome proliferator-activated receptor gamma coactivator 1-alpha', 'Gene', '10891', (58, 126))	('reduction', 'NegReg', (45, 54))	('knockdown', 'Var', (24, 33))	('PPARgamma', 'Var', (148, 157))	('improving', 'PosReg', (219, 228))	('PGC-1alpha', 'Gene', (128, 138))	('PGC-1alpha', 'Gene', '10891', (128, 138))	('PPARbeta/delta', 'Gene', (9, 23))	('absorption', 'MPA', (233, 243))
161736	31683535	When PPARbeta/delta levels are low or absent, the gene expression associated with the lipoprotein metabolism pathway is diminished, confirming the regulation of triglycerides and cholesterol levels by the PPARbeta/delta.	('gene expression', 'MPA', (50, 65))	('diminished', 'NegReg', (120, 130))	('lipoprotein metabolism pathway', 'Pathway', (86, 116))	('cholesterol', 'Chemical', 'MESH:D002784', (179, 190))	('PPARbeta/delta', 'Var', (205, 219))	('triglycerides', 'Chemical', 'MESH:D014280', (161, 174))
161738	31683535	The deletion of PPARalpha in hepatocytes may induce steatosis.	('induce', 'Reg', (45, 51))	('steatosis', 'Phenotype', 'HP:0001397', (52, 61))	('steatosis', 'Disease', 'MESH:D005234', (52, 61))	('steatosis', 'Disease', (52, 61))	('PPARalpha', 'Gene', (16, 25))	('deletion', 'Var', (4, 12))
161785	31683535	Healthy visceral WAT contains resident macrophages referred to as ATMs, mainly with M2 phenotype (Arg1+, CD206+, CD301+,).	('Arg1', 'Gene', '383', (98, 102))	('Arg1', 'Gene', (98, 102))	('CD206+', 'Var', (105, 111))	('CD301+', 'Var', (113, 119))
161793	31683535	Specifically, these modifications comprise the limitation of visceral WAT to further accumulate lipids, and the presence of senescent cells in visceral WAT that result in increased levels of circulating free fatty acids (FFA) and in a systemic low-grade inflammation.	('inflammation', 'Disease', (254, 266))	('modifications', 'Var', (20, 33))	('fatty acids', 'Chemical', 'MESH:D005227', (208, 219))	('inflammation', 'Disease', 'MESH:D007249', (254, 266))	('increased', 'PosReg', (171, 180))	('levels of circulating free fatty acids', 'MPA', (181, 219))
161796	31683535	PPARalpha and PPARgamma disrupt also the activation of signal transducer and activator of transcription proteins (STATs).	('STATs', 'Gene', '6774', (114, 119))	('signal transducer', 'Pathway', (55, 72))	('PPARalpha', 'Var', (0, 9))	('activation', 'PosReg', (41, 51))	('STATs', 'Gene', (114, 119))
161801	31683535	In adipocytes, PPARgamma restores the expression and secretion of different anti-inflammatory adipokines; while on immune cells it has been demonstrated that this NR acts as a negative regulator of macrophages polarization toward M1 phenotype, promoting the M2 phenotype.	('promoting', 'PosReg', (244, 253))	('secretion', 'MPA', (53, 62))	('expression', 'MPA', (38, 48))	('restores', 'PosReg', (25, 33))	('PPARgamma', 'Var', (15, 24))	('N', 'Chemical', 'MESH:D009584', (163, 164))
161802	31683535	In macrophages, PPARgamma induces Arginase 1 (Arg1), a specific M2 marker and sustain beta-oxidation and mitochondrial biogenesis; at the same time, it reduces the expression of inflammatory markers.	('Arg1', 'Gene', (46, 50))	('Arginase 1', 'Gene', (34, 44))	('mitochondrial biogenesis', 'MPA', (105, 129))	('expression of inflammatory markers', 'MPA', (164, 198))	('reduces', 'NegReg', (152, 159))	('Arginase 1', 'Gene', '383', (34, 44))	('Arg1', 'Gene', '383', (46, 50))	('induces', 'PosReg', (26, 33))	('PPARgamma', 'Var', (16, 25))	('sustain beta-oxidation', 'MPA', (78, 100))
161815	31683535	Target genes of NFkappaB are involved in IR; the phosphorylation of IRS1 in serine-307 by JNKs inhibits the interaction between IRS1 and the insulin receptor, that in turn reduce the insulin receptor inducing IR.	('IRS1', 'Gene', '3667', (128, 132))	('NFkappaB', 'Gene', (16, 24))	('insulin', 'Gene', '3630', (183, 190))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('NFkappaB', 'Gene', '4790', (16, 24))	('IRS1', 'Gene', (128, 132))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('interaction', 'Interaction', (108, 119))	('reduce', 'NegReg', (172, 178))	('IRS1', 'Gene', '3667', (68, 72))	('phosphorylation', 'MPA', (49, 64))	('insulin', 'Gene', (141, 148))	('serine', 'Chemical', 'MESH:C047902', (76, 82))	('inhibits', 'NegReg', (95, 103))	('IRS1', 'Gene', (68, 72))	('JNKs', 'Var', (90, 94))	('insulin', 'Gene', '3630', (141, 148))	('insulin', 'Gene', (183, 190))
161863	31683535	In this regard, different clinical studies on the incidence of the PPARgamma Pro12Ala polymorphism in PCOS patients were reported; this polymorphism is associated with a lower degree of IR, an increased insulin clearance and a reduced risk of diabetes.	('diabetes', 'Disease', 'MESH:D003920', (243, 251))	('PCOS', 'Disease', (102, 106))	('PCOS', 'Disease', 'MESH:D011085', (102, 106))	('PPARgamma', 'Gene', (67, 76))	('reduced', 'NegReg', (227, 234))	('Pro12Ala', 'Var', (77, 85))	('increased', 'PosReg', (193, 202))	('diabetes', 'Disease', (243, 251))	('insulin', 'Gene', (203, 210))	('Pro12Ala', 'SUBSTITUTION', 'None', (77, 85))	('patients', 'Species', '9606', (107, 115))	('insulin', 'Gene', '3630', (203, 210))
161864	31683535	However, further clinical studies on the incidence of Pro12Ala in PCOS are necessary.	('Pro12Ala', 'SUBSTITUTION', 'None', (54, 62))	('PCOS', 'Disease', (66, 70))	('Pro12Ala', 'Var', (54, 62))	('PCOS', 'Disease', 'MESH:D011085', (66, 70))
161878	31683535	In a randomized clinical trial, including normoinsulinemic and non-obese PCOS patients, it was found that rosiglitazone, a PPARgamma agonist, significantly reduced testosterone levels, without changing insulin levels.	('obese', 'Disease', 'MESH:D009765', (67, 72))	('rosiglitazone', 'Var', (106, 119))	('obese', 'Disease', (67, 72))	('reduced testosterone', 'Phenotype', 'HP:0040171', (156, 176))	('insulin', 'Gene', (47, 54))	('PCOS', 'Disease', (73, 77))	('patients', 'Species', '9606', (78, 86))	('reduced', 'NegReg', (156, 163))	('insulin', 'Gene', (202, 209))	('insulin', 'Gene', '3630', (47, 54))	('testosterone levels', 'MPA', (164, 183))	('PCOS', 'Disease', 'MESH:D011085', (73, 77))	('insulin', 'Gene', '3630', (202, 209))
161895	31683535	Moreover, it has been shown that polymorphism in genes for lipid transport and lipid metabolism are related to the development of NAFLD.	('NAFLD', 'Disease', (130, 135))	('related to', 'Reg', (100, 110))	('polymorphism', 'Var', (33, 45))	('NAFLD', 'Disease', 'MESH:D065626', (130, 135))
161940	30854331	The first human phase III study of anti-human CTLA-4 (Ipilimumab) demonstrated improved survival in patients with advanced melanoma.	('human', 'Species', '9606', (10, 15))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (54, 64))	('improved', 'PosReg', (79, 87))	('CTLA-4', 'Gene', (46, 52))	('survival', 'MPA', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('patients', 'Species', '9606', (100, 108))	('melanoma', 'Disease', (123, 131))	('anti-human', 'Var', (35, 45))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('human', 'Species', '9606', (40, 45))	('rat', 'Species', '10116', (73, 76))
161949	30854331	Mutations in the gene isocitrate dehydrogenase (IDH) are very common in World Health Organization classification of Grade II and III gliomas and in 10% of GBM that have evolved from lower-grade tumors.	('IDH', 'Gene', (48, 51))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('gliomas', 'Disease', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('tumors', 'Disease', (194, 200))	('common', 'Reg', (62, 68))	('rat', 'Species', '10116', (28, 31))
161952	30854331	Patients with IDH-mutant gliomas have a substantial survival benefit following chemotherapy and radiation compared to patients with IDH wild type tumors.	('benefit', 'PosReg', (61, 68))	('type tumors', 'Disease', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('type tumors', 'Disease', 'MESH:D009369', (141, 152))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('IDH-mutant', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('survival', 'CPA', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('patients', 'Species', '9606', (118, 126))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
161954	30854331	It is known that IDH-mutant gliomas have fewer tumor-infiltrating immune cells, including T cells, microglia, and macrophages, compared to IDH wild-type tumors; thus IDH-mutant tumors typically exemplify "cold tumors" and may not respond to immunotherapies.	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('I', 'Chemical', 'MESH:D007455', (17, 18))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('I', 'Chemical', 'MESH:D007455', (166, 167))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('gliomas', 'Disease', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('tumor', 'Disease', (210, 215))	('type tumors', 'Disease', (148, 159))	('tumor', 'Disease', (153, 158))	('IDH-mutant', 'Var', (166, 176))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('rat', 'Species', '10116', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (47, 52))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('I', 'Chemical', 'MESH:D007455', (139, 140))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('type tumors', 'Disease', 'MESH:D009369', (148, 159))	('tumors', 'Disease', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (153, 159))	('tumors', 'Disease', (177, 183))
161955	30854331	The authors generated genetically engineered mice that were identical, except for the presence or absence of IDH mutation, with concomitant increase in 2-HG levels.	('mutation', 'Var', (113, 121))	('mice', 'Species', '10090', (45, 49))	('rat', 'Species', '10116', (16, 19))	('2-HG levels', 'MPA', (152, 163))	('IDH', 'Gene', (109, 112))	('increase', 'PosReg', (140, 148))
161957	30854331	Whether IDH-mutant gliomas or tumors with inherently lower immune infiltration (e.g., proneural) are inherently less responsive to immunotherapy due to their "cold" phenotype is hypothesized, but remains to be demonstrated clinically.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('rat', 'Species', '10116', (72, 75))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('gliomas or tumors', 'Disease', (19, 36))	('less', 'NegReg', (112, 116))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IDH-mutant', 'Var', (8, 18))	('rat', 'Species', '10116', (217, 220))	('gliomas or tumors', 'Disease', 'MESH:D005910', (19, 36))
161981	30854331	Deprivation of the critical amino acid tryptophan and exposure to metabolites inhibits the proliferation of cytotoxic CD4+ and CD8+ T cells, as well as natural killer (NK) cells.	('CD8', 'Gene', (127, 130))	('Deprivation', 'Var', (0, 11))	('amino acid tryptophan', 'Chemical', '-', (28, 49))	('CD4', 'Gene', (118, 121))	('CD8', 'Gene', '925', (127, 130))	('rat', 'Species', '10116', (98, 101))	('proliferation', 'CPA', (91, 104))	('CD4', 'Gene', '920', (118, 121))	('inhibits', 'NegReg', (78, 86))
162002	30854331	Examples include inhibitors targeting CTLA-4 (ipilimumab), PD-1 (pembrolizumab and nivolumab), and PD-L1 (atezolizumab and avelumab), that have collectively yielded profound impacts on the management of multiple systemic malignancies.	('malignancies', 'Disease', (221, 233))	('avelumab', 'Chemical', 'MESH:C000609138', (123, 131))	('atezolizumab', 'Chemical', 'MESH:C000594389', (106, 118))	('PD-1', 'Gene', (59, 63))	('PD-L1', 'Gene', (99, 104))	('impacts', 'Reg', (174, 181))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (83, 92))	('ipilimumab', 'Chemical', 'MESH:D000074324', (46, 56))	('inhibitors', 'Var', (17, 27))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('CTLA-4', 'Gene', (38, 44))
162038	30854331	demonstrated that combination therapy of anti-TIM-3 and anti-PD-1 improved survival in mice with GL261 intra-cranial tumors with optimal outcomes observed using both in combination with stereotactic radiosurgery.	('survival', 'CPA', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('intra-cranial tumors', 'Disease', (103, 123))	('anti-TIM-3', 'Var', (41, 51))	('GL261', 'Chemical', '-', (97, 102))	('improved', 'PosReg', (66, 74))	('mice', 'Species', '10090', (87, 91))	('anti-PD-1', 'Gene', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('intra-cranial tumors', 'Disease', 'MESH:D003390', (103, 123))	('rat', 'Species', '10116', (7, 10))	('combination', 'Interaction', (18, 29))
162051	30854331	Though originally described as pleiotropic cells simultaneously expressing both M1 and M2 polarization markers, more recent work has suggested that MDSC are malleable in their polarization phenotype with M1-polarized MDSCs exhibiting tumoricidal properties.	('C', 'Chemical', 'MESH:D002244', (151, 152))	('tumor', 'Disease', (234, 239))	('C', 'Chemical', 'MESH:D002244', (220, 221))	('M1-polarized', 'Var', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
162063	30854331	Additionally, CpG, in combination with tumor lysate, effectively induced maturation of DCs to control tumor growth.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('maturation', 'CPA', (73, 83))	('rat', 'Species', '10116', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('CpG', 'Var', (14, 17))	('tumor', 'Disease', (39, 44))	('induced', 'Reg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
162064	30854331	Recent work from the Lim laboratory found that that mice treated with poly(I:C) and anti-PD-1 in combination demonstrated increased DC activation, T cell proliferation, and improved tumor control.	('tumor', 'Disease', (182, 187))	('poly', 'Chemical', '-', (70, 74))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('I', 'Chemical', 'MESH:D007455', (75, 76))	('rat', 'Species', '10116', (29, 32))	('mice', 'Species', '10090', (52, 56))	('T cell proliferation', 'CPA', (147, 167))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('anti-PD-1', 'Gene', (84, 93))	('DC activation', 'MPA', (132, 145))	('poly(I:C', 'Var', (70, 78))	('improved', 'PosReg', (173, 181))	('rat', 'Species', '10116', (116, 119))	('increased', 'PosReg', (122, 131))	('rat', 'Species', '10116', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('C', 'Chemical', 'MESH:D002244', (77, 78))
162074	30854331	Anti-CD47 therapy has also been shown to boost antigen presentation and augment cytotoxic CD8+ T cell activity.	('antigen presentation', 'MPA', (47, 67))	('augment', 'NegReg', (72, 79))	('Anti-CD47', 'Var', (0, 9))	('CD8', 'Gene', (90, 93))	('CD8', 'Gene', '925', (90, 93))	('boost', 'PosReg', (41, 46))
162075	30854331	As an adjuvant to radiation therapy, CD47 blockade has the unique advantage of mitigating radiation-induced TSP-1 signaling, which promotes resistance to radiation injury due to decreased inhibition of nitric oxide signaling in normal tissues.	('inhibition', 'MPA', (188, 198))	('radiation injury', 'Disease', 'MESH:D011832', (154, 170))	('decreased', 'NegReg', (178, 187))	('nitric oxide signaling', 'MPA', (202, 224))	('TSP-1', 'Gene', (108, 113))	('blockade', 'Var', (42, 50))	('radiation injury', 'Disease', (154, 170))	('nitric oxide', 'Chemical', 'MESH:D009569', (202, 214))	('TSP-1', 'Gene', '7057', (108, 113))	('CD47', 'Gene', (37, 41))	('promotes', 'PosReg', (131, 139))	('mitigating', 'MPA', (79, 89))
162105	30854331	Thus, radiation-induced changes can facilitate activation and proliferation of T cell populations to augment anti-tumor immune response.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('proliferation', 'CPA', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('activation', 'CPA', (47, 57))	('tumor', 'Disease', (114, 119))	('augment', 'PosReg', (101, 108))	('facilitate', 'PosReg', (36, 46))	('T cell populations', 'CPA', (79, 97))	('changes', 'Var', (24, 31))	('rat', 'Species', '10116', (69, 72))
162128	30854331	Extracellular release of HMGB1 and ATP: Extracellular HMGB1 induces DC activation through TLR-4.	('induces', 'Reg', (60, 67))	('HMGB1', 'Gene', (54, 59))	('HMGB1', 'Gene', '3146', (54, 59))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('DC activation', 'MPA', (68, 81))	('HMGB1', 'Gene', (25, 30))	('ATP', 'Gene', (35, 38))	('ATP', 'Gene', '51761', (35, 38))	('TLR-4', 'Gene', '7099', (90, 95))	('Extracellular', 'Var', (40, 53))	('HMGB1', 'Gene', '3146', (25, 30))	('TLR-4', 'Gene', (90, 95))
162133	30854331	Given tumor cell death releases tumor-specific antigens to APCs, including DCs, such cross-presentation of antigens to cytotoxic CD8+ T cells facilitates an anti-tumor T cell response.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CD8', 'Gene', (129, 132))	('CD8', 'Gene', '925', (129, 132))	('APC', 'Gene', (59, 62))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('facilitates', 'PosReg', (142, 153))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('APC', 'Gene', '324', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (32, 37))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('tumor', 'Disease', (6, 11))	('cross-presentation', 'Var', (85, 103))
162147	30854331	Combined use of CTLA-4 blocking antibodies and pro-cytotoxic function CD137 (4-1BB) agonist antibodies with RT yielded 50% survival at 100 days in a GL261 orthotopic model, compared to 20% without RT, and 0% with radiotherapy alone.	('CD137', 'Gene', (70, 75))	('CD137', 'Gene', '3604', (70, 75))	('antibodies', 'Var', (92, 102))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('GL261', 'Chemical', '-', (149, 154))	('CTLA-4', 'Gene', (16, 22))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('C', 'Chemical', 'MESH:D002244', (0, 1))
162148	30854331	Radiotherapy plus dual checkpoint antibodies against PD-1 and TIM-3 yielded 100% survival of GL261-bearing mice at 100 days, compared to 60% with the best combination of only two of the three treatment modalities.	('PD-1', 'Gene', (53, 57))	('TIM-3', 'Gene', (62, 67))	('GL261', 'Chemical', '-', (93, 98))	('antibodies', 'Var', (34, 44))	('mice', 'Species', '10090', (107, 111))
162175	30854331	Nevertheless, the specific IDH1 (R132H) mutation itself could serve as a potential vaccine target.	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('R132H', 'Mutation', 'rs121913500', (33, 38))	('R132H', 'Var', (33, 38))
162207	30854331	In addition, the authors demonstrated that modulation of CMV-specific DCs with a potent tetanus/diphtheria antigen increased the migratory capacity of DCs and improved the clinical outcomes in patients with GBM.	('patients', 'Species', '9606', (193, 201))	('rat', 'Species', '10116', (132, 135))	('improved', 'PosReg', (159, 167))	('increased', 'PosReg', (115, 124))	('rat', 'Species', '10116', (32, 35))	('tetanus', 'Disease', 'MESH:D013746', (88, 95))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('migratory capacity', 'CPA', (129, 147))	('tetanus', 'Disease', (88, 95))	('modulation', 'Var', (43, 53))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('clinical outcomes', 'CPA', (172, 189))	('GBM', 'Phenotype', 'HP:0012174', (207, 210))
162213	30854331	Epidermal growth factor receptor (EGFR) variant III (vIII) is expressed in 20-30% of GBM.	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('EGFR', 'Gene', (34, 38))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('variant III', 'Var', (40, 51))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', '1956', (34, 38))
162221	30854331	SVN53-67/M57 produced cytotoxic T cell-mediated killing of human glioma cells in vitro and, in combination with GM-CSF, was able to control tumor burden in mice bearing GL-261 glioma tumors.	('GM-CSF', 'Gene', '1437', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mice', 'Species', '10090', (156, 160))	('glioma', 'Disease', (176, 182))	('glioma tumors', 'Disease', (176, 189))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('SVN53-67/M57', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('glioma', 'Disease', (65, 71))	('glioma tumors', 'Disease', 'MESH:D005910', (176, 189))	('GL-261', 'CellLine', 'CVCL:Y003', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('tumor', 'Disease', (183, 188))	('GM-CSF', 'Gene', (112, 118))	('human', 'Species', '9606', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cytotoxic T cell-mediated killing', 'CPA', (22, 55))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (140, 145))
162222	30854331	A phase II trial of SVN53-67/M57-KLH (SurVaxM) and TMZ is currently recruiting patients with malignant glioma and the therapy has shown to be well tolerated and generates anti-survivin antibody and survivin specific CD8+ T cells.	('malignant glioma', 'Disease', (93, 109))	('malignant glioma', 'Disease', 'MESH:D005910', (93, 109))	('rat', 'Species', '10116', (165, 168))	('CD8', 'Gene', (216, 219))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('anti-survivin antibody', 'Protein', (171, 193))	('CD8', 'Gene', '925', (216, 219))	('patients', 'Species', '9606', (79, 87))	('rat', 'Species', '10116', (151, 154))	('SVN53-67/M57-KLH', 'Var', (20, 36))	('TMZ', 'Chemical', 'MESH:D000077204', (51, 54))
162230	30854331	While TMZ may attenuate bone marrow immune responses, TMZ-induced mutations may provide important neoantigens to catalyze immune recognition of the tumor.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('attenuate', 'NegReg', (14, 23))	('tumor', 'Disease', (148, 153))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('bone marrow immune responses', 'CPA', (24, 52))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('TMZ', 'Chemical', 'MESH:D000077204', (6, 9))	('attenuate bone marrow', 'Phenotype', 'HP:0005528', (14, 35))
162251	30854331	The dramatic anti-tumor clinical responses observed in certain tumors treated with anti-CTLA-4 and anti-PD-1 antibodies have ushered in a new era for effective cancer therapies.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('anti-CTLA-4', 'Gene', (83, 94))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('anti-CTLA-4', 'Var', (83, 94))	('tumors', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('anti-PD-1', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
162287	29109450	Survival of patients diagnosed with infiltrating glioma depends on age, grade and molecular subtypes that are defined by IDH mutations and co-deletion of chromosomes 1p and 19q.	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (12, 20))	('glioma depends', 'Disease', (49, 63))	('IDH', 'Gene', (121, 124))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH', 'Gene', '3417', (121, 124))	('co-deletion', 'Var', (139, 150))	('glioma depends', 'Disease', 'MESH:D005910', (49, 63))
162289	29109450	Aggressive IDH wild-type (IDHwt-astrocytoma) gliomas having an expected survival of 18 months, where patients with gliomas having IDH mutations and 1p/19q co-deletions (oligodendroglioma) can survive 10+ years.	('IDH', 'Gene', '3417', (11, 14))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('IDH', 'Gene', '3417', (26, 29))	('oligodendroglioma', 'Disease', 'MESH:D009837', (169, 186))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('IDH', 'Gene', '3417', (130, 133))	('patients', 'Species', '9606', (101, 109))	('gliomas', 'Disease', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('oligodendroglioma', 'Disease', (169, 186))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (32, 43))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('1p/19q co-deletions', 'Var', (148, 167))	('Aggressive IDH wild-type (IDHwt-astrocytoma) gliomas', 'Disease', 'MESH:D005910', (0, 52))	('IDH', 'Gene', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', (130, 133))	('gliomas', 'Disease', (45, 52))
162298	29109450	HI+ CI provide prognostic value independent of molecular subtype, improving the subtype c-index from 0.70 to 0.76.	('HI+ CI', 'Chemical', '-', (0, 6))	('improving', 'PosReg', (66, 75))	('subtype', 'MPA', (80, 87))	('HI+ CI', 'Var', (0, 6))
162300	29109450	Finally, HI+ CI also have prognostic value independent of grade+ subtype, increasing median c-index to 0.78 (Wilcoxon p = 3.35e-11).	('c-index', 'MPA', (92, 99))	('increasing', 'PosReg', (74, 84))	('HI+ CI', 'Chemical', '-', (9, 15))	('HI+ CI', 'Var', (9, 15))
162355	25200831	GBM typically grows by invading surrounding neural structures, and it is arguably this feature that contributes to such a poor prognosis: invasion in gliomas restricts curative resection, limits effective delivery of chemotherapy and radiation, and can activate mechanisms to evade treatment effects.	('invasion', 'Var', (138, 146))	('restricts', 'NegReg', (158, 167))	('activate', 'Reg', (253, 261))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('curative resection', 'CPA', (168, 186))	('limits', 'NegReg', (188, 194))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
162406	25200831	Patients with>25 % staining of EMR2 did have a lower mean survival (Fig.	('lower', 'NegReg', (47, 52))	('EMR2', 'Gene', (31, 35))	('staining', 'Var', (19, 27))	('Patients', 'Species', '9606', (0, 8))	('EMR2', 'Gene', '30817', (31, 35))
162434	25200831	The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, and less expression of EGFR than other types.	('mutations', 'Var', (58, 67))	('less', 'NegReg', (101, 105))	('expression', 'MPA', (106, 116))	('NF1', 'Gene', (92, 95))	('alterations', 'Var', (77, 88))	('mesenchymal subtype', 'CPA', (4, 23))	('NF1', 'Gene', '4763', (92, 95))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (120, 124))
162462	25200831	Inhibition of EMR2 may represent one strategy for limiting local and systemic invasion of neoplastic cells.	('EMR2', 'Gene', (14, 18))	('limiting', 'NegReg', (50, 58))	('EMR2', 'Gene', '30817', (14, 18))	('Inhibition', 'Var', (0, 10))
162471	28036297	Mutation of IDH1 is known to drive the G-CIMP status.	('IDH1', 'Gene', (12, 16))	('G-CIMP', 'Chemical', '-', (39, 45))	('Mutation', 'Var', (0, 8))	('IDH1', 'Gene', '3417', (12, 16))	('drive', 'Reg', (29, 34))	('G-CIMP status', 'MPA', (39, 52))
162472	28036297	In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms.	('IDH1', 'Gene', (73, 77))	('mutation', 'Var', (78, 86))	('IDH1', 'Gene', '3417', (73, 77))	('involvement', 'Reg', (103, 114))
162479	28036297	Epigenetic gene regulation has emerged as an important mechanism controlling gene expression in low and high-grade gliomas.	('gliomas', 'Disease', (115, 122))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('Epigenetic gene regulation', 'Var', (0, 26))
162482	28036297	Although initially identified in a subset of high-grade gliomas, more extensive analysis showed that G-CIMP mostly characterizes low-grade tumors and confers improved survival.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('improved', 'PosReg', (158, 166))	('gliomas', 'Disease', (56, 63))	('G-CIMP', 'Chemical', '-', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('G-CIMP', 'Var', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('survival', 'MPA', (167, 175))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
162483	28036297	More recently, Turcan and colleagues identified IDH1 mutation as a genetic event responsible for the establishment of the G-CIMP phenotype through DNA methylation remodeling.	('IDH1', 'Gene', (48, 52))	('G-CIMP', 'Chemical', '-', (122, 128))	('mutation', 'Var', (53, 61))	('IDH1', 'Gene', '3417', (48, 52))
162484	28036297	Mechanistically, IDH1 mutation induces accumulation of histone alterations such as H3K9me2, H3K27me3 and H3K36me3 which in turn promote DNA methylation.	('H3K36me3', 'Var', (105, 113))	('mutation', 'Var', (22, 30))	('DNA methylation', 'MPA', (136, 151))	('H3K9me2', 'Protein', (83, 90))	('H3K27me3', 'Var', (92, 100))	('IDH1', 'Gene', (17, 21))	('promote', 'PosReg', (128, 135))	('histone', 'Protein', (55, 62))	('IDH1', 'Gene', '3417', (17, 21))	('accumulation', 'PosReg', (39, 51))
162485	28036297	Recently, it has been shown that IDH1 mutation causes disruption of chromosome topology leading to aberrant oncogene activation.	('IDH1', 'Gene', (33, 37))	('activation', 'MPA', (117, 127))	('IDH1', 'Gene', '3417', (33, 37))	('mutation', 'Var', (38, 46))	('oncogene', 'Protein', (108, 116))	('disruption', 'MPA', (54, 64))
162505	28036297	Analysis of different methylated CpGs in low-grade tumors, represented as a volcano plot, shows a significantly increased (pairwise comparison t-test) methylation (red) in the group with high DNMT1 expression and vice versa (Figure 2B).	('methylation', 'MPA', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('DNMT1', 'Gene', (192, 197))	('increased', 'PosReg', (112, 121))	('DNMT1', 'Gene', '1786', (192, 197))	('high', 'Var', (187, 191))
162513	28036297	Moreover, in the majority of the low-grade gliomas from TCGA samples analyzed, high p-c-Jun was also associated with high CpG methylation, suggesting a possible mechanistic link between p-c-Jun, DNMT1 and G-CIMP (Spearman's ranked correlation between p-c-Jun protein level and CpG methylation and Fisher's exact test for significance niveau p<0.05) (Figure 3C and 3D).	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('c-Jun', 'Gene', (86, 91))	('c-Jun', 'Gene', '3725', (188, 193))	('G-CIMP', 'Chemical', '-', (205, 211))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('c-Jun', 'Gene', (253, 258))	('high', 'Var', (79, 83))	('gliomas', 'Disease', (43, 50))	('DNMT1', 'Gene', (195, 200))	('DNMT1', 'Gene', '1786', (195, 200))	('c-Jun', 'Gene', '3725', (86, 91))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('CpG methylation', 'MPA', (122, 137))	('c-Jun', 'Gene', (188, 193))	('c-Jun', 'Gene', '3725', (253, 258))
162515	28036297	The observed effect of differential methylation was not as strong as in low-grade tumors but a high number of methylated CpG sites were significantly correlated to p-c-Jun level (Figure 3E).	('c-Jun', 'Gene', (166, 171))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('c-Jun', 'Gene', '3725', (166, 171))	('correlated', 'Reg', (150, 160))	('methylated', 'Var', (110, 120))
162522	28036297	Inhibition of c-Jun phosphorylation by the JNK inhibitor SP600125 in a proneural cell line (CL3021) expressing high levels of p-c-Jun reduced JNK and c-Jun phosphorylation (Figure 4D) and DNMT1 protein levels (Figure 4D-4F).	('c-Jun', 'Gene', (14, 19))	('JNK', 'Gene', '5599', (142, 145))	('DNMT1', 'Gene', (188, 193))	('c-Jun', 'Gene', '3725', (150, 155))	('c-Jun', 'Gene', (128, 133))	('SP600125', 'Chemical', 'MESH:C432165', (57, 65))	('JNK', 'Gene', (43, 46))	('c-Jun', 'Gene', '3725', (14, 19))	('SP600125', 'Var', (57, 65))	('reduced', 'NegReg', (134, 141))	('c-Jun', 'Gene', (150, 155))	('JNK', 'Gene', '5599', (43, 46))	('DNMT1', 'Gene', '1786', (188, 193))	('c-Jun', 'Gene', '3725', (128, 133))	('JNK', 'Gene', (142, 145))
162523	28036297	qRT-PCR analysis confirmed an effect of c-Jun phosphorylation on DNMT1 RNA levels upon Anisomycin or SP600125 treatment in BTSC168 and CL3021 cells respectively (Figure 4G and 4H).	('SP600125', 'Var', (101, 109))	('Anisomycin', 'Chemical', 'MESH:D000841', (87, 97))	('c-Jun', 'Gene', '3725', (40, 45))	('SP600125', 'Chemical', 'MESH:C432165', (101, 109))	('BTSC168', 'Chemical', '-', (123, 130))	('c-Jun', 'Gene', (40, 45))	('DNMT1', 'Gene', (65, 70))	('DNMT1', 'Gene', '1786', (65, 70))
162529	28036297	Conversely, global DNA methylation was reduced in CL3021 cells treated with JNK inhibitor SP600125 (Figure 5B).	('JNK', 'Gene', (76, 79))	('SP600125', 'Var', (90, 98))	('JNK', 'Gene', '5599', (76, 79))	('reduced', 'NegReg', (39, 46))	('global DNA methylation', 'MPA', (12, 34))	('SP600125', 'Chemical', 'MESH:C432165', (90, 98))
162530	28036297	In order to understand whether the differentially-methylated loci overlap with the previously reported G-CIMP signature, we performed a gene-set enrichment analysis and discovered a significant (p<0.0001) enrichment of methylation in the G-CIMP gene-set corresponding to c-Jun phosphorylation (Figure 5C).	('c-Jun', 'Gene', (271, 276))	('G-CIMP', 'Chemical', '-', (238, 244))	('G-CIMP', 'Gene', (238, 244))	('methylation', 'Var', (219, 230))	('c-Jun', 'Gene', '3725', (271, 276))	('G-CIMP', 'Chemical', '-', (103, 109))
162538	28036297	Treatment with the JNK inhibitor SP600125 produced an opposite effect as immunostaining analysis revealed an increased level of CD44, MMP9 and CHI3L1 protein (Figure 6G-6I, top and bottom panels).	('MMP9', 'Gene', '4318', (134, 138))	('CHI3L1', 'Gene', (143, 149))	('SP600125', 'Chemical', 'MESH:C432165', (33, 41))	('JNK', 'Gene', (19, 22))	('SP600125', 'Var', (33, 41))	('CHI3L1', 'Gene', '1116', (143, 149))	('JNK', 'Gene', '5599', (19, 22))	('CD44', 'Gene', '960', (128, 132))	('increased', 'PosReg', (109, 118))	('CD44', 'Gene', (128, 132))	('MMP9', 'Gene', (134, 138))
162540	28036297	These data indicate that JNK-pathway-dependent modifications of c-Jun phosphorylation status produce epigenetic alterations which affect gene expression of key mesenchymal genes.	('epigenetic alterations', 'MPA', (101, 123))	('JNK', 'Gene', '5599', (25, 28))	('gene expression', 'MPA', (137, 152))	('c-Jun', 'Gene', '3725', (64, 69))	('affect', 'Reg', (130, 136))	('modifications', 'Var', (47, 60))	('JNK', 'Gene', (25, 28))	('c-Jun', 'Gene', (64, 69))
162544	28036297	However, DNMT1 silencing did not affect NF-kB activity suggesting that other factors downstream of c-Jun could be implicated (Supplementary Figure 1C).	('DNMT1', 'Gene', (9, 14))	('c-Jun', 'Gene', '3725', (99, 104))	('DNMT1', 'Gene', '1786', (9, 14))	('activity', 'MPA', (46, 54))	('silencing', 'Var', (15, 24))	('NF-kB', 'Protein', (40, 45))	('c-Jun', 'Gene', (99, 104))
162546	28036297	Interestingly, Anisomycin treatment did not rescue DNMT1 knockdown effect indicating that DNMT1 is required for CHI3L1 transcriptional regulation (Supplementary Figure 1A and 1B).	('DNMT1', 'Gene', (90, 95))	('CHI3L1', 'Gene', '1116', (112, 118))	('DNMT1', 'Gene', '1786', (51, 56))	('DNMT1', 'Gene', '1786', (90, 95))	('knockdown', 'Var', (57, 66))	('Anisomycin', 'Chemical', 'MESH:D000841', (15, 25))	('CHI3L1', 'Gene', (112, 118))	('DNMT1', 'Gene', (51, 56))
162552	28036297	Instead, treatment with the JNK inhibitor SP600125 in proneural CL3021 cells significantly increased cell invasion compared to the control (p=1,6E-12) (Figure 7E), indicating that inhibition of c-Jun phosphorylation by JNK inhibitor increases cell invasion.	('JNK', 'Gene', (28, 31))	('increases', 'PosReg', (233, 242))	('JNK', 'Gene', '5599', (28, 31))	('JNK', 'Gene', '5599', (219, 222))	('c-Jun', 'Gene', (194, 199))	('c-Jun', 'Gene', '3725', (194, 199))	('cell invasion', 'CPA', (101, 114))	('SP600125', 'Chemical', 'MESH:C432165', (42, 50))	('increased', 'PosReg', (91, 100))	('cell invasion', 'CPA', (243, 256))	('inhibition', 'NegReg', (180, 190))	('JNK', 'Gene', (219, 222))	('SP600125', 'Var', (42, 50))
162554	28036297	We demonstrate that highly methylated gliomas contain high levels of p-c-Jun compared to sparsely methylated gliomas.	('c-Jun', 'Gene', '3725', (71, 76))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('c-Jun', 'Gene', (71, 76))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))	('gliomas', 'Disease', (38, 45))	('highly methylated', 'Var', (20, 37))
162559	28036297	It was demonstrated the IDH1 mutation leads to the establishment of the G-CIMP.	('mutation', 'Var', (29, 37))	('IDH1', 'Gene', '3417', (24, 28))	('G-CIMP', 'Chemical', '-', (72, 78))	('leads to', 'Reg', (38, 46))	('G-CIMP', 'CPA', (72, 78))	('IDH1', 'Gene', (24, 28))
162560	28036297	However, in some cases the hypermethylation phenotype also occurs in the absence of IDH1 mutations, suggesting that other mechanisms could be involved.	('hypermethylation', 'MPA', (27, 43))	('IDH1', 'Gene', '3417', (84, 88))	('IDH1', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))
162571	28036297	Nevertheless, since the highly methylated glioblastoma (G-CIMP) are mostly proneural, we would mostly expect association between DNMT1 expression and DNA methylation in proneural samples.	('highly methylated', 'Var', (24, 41))	('G-CIMP', 'Chemical', '-', (56, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('DNMT1', 'Gene', (129, 134))	('glioblastoma', 'Disease', (42, 54))	('DNMT1', 'Gene', '1786', (129, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('association', 'Interaction', (109, 120))
162574	28036297	Since mesenchymal gliomas are mostly G-CIMP-negative and have been identified as belonging to a molecular subclass that is mutually exclusive to the often G-CIMP-positive proneural tumors, it is possible that methylation and consequent downregulation of many mesenchymal genes in proneural gliomas is responsible for the improved outcome of these tumors.	('proneural gliomas', 'Disease', (280, 297))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('gliomas', 'Disease', (290, 297))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('downregulation', 'NegReg', (236, 250))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Disease', (347, 353))	('G-CIMP', 'Chemical', '-', (37, 43))	('gliomas', 'Disease', 'MESH:D005910', (290, 297))	('gliomas', 'Disease', (18, 25))	('glioma', 'Phenotype', 'HP:0009733', (290, 296))	('G-CIMP', 'Chemical', '-', (155, 161))	('tumors', 'Disease', (181, 187))	('methylation', 'Var', (209, 220))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('gliomas', 'Phenotype', 'HP:0009733', (290, 297))	('proneural gliomas', 'Disease', 'MESH:D005910', (280, 297))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))
162588	28036297	For inactivation of the JNK-pathway, cells were treated with 50mumol/ml SP600125 (Invivogene) according to the manufacturer's instructions.	('SP600125', 'Var', (72, 80))	('SP600125', 'Chemical', 'MESH:C432165', (72, 80))	('JNK', 'Gene', (24, 27))	('JNK', 'Gene', '5599', (24, 27))
162599	28036297	For the JNK inactivation experiment, SP600125 or DMSO was added and pictures were taken after 0h, 6h and 24h.	('JNK', 'Gene', (8, 11))	('JNK', 'Gene', '5599', (8, 11))	('SP600125', 'Chemical', 'MESH:C432165', (37, 45))	('SP600125', 'Var', (37, 45))	('DMSO', 'Chemical', 'MESH:D004121', (49, 53))
162637	24711712	These intrinsic molecular subtypes had prognostic significance for progression-free survival (PFS) independent of the previously recognized prognostic factors, including 1p/19q deletion, isocitrate dehydrogenase gene (IDH1) mutation, and O-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status.	('isocitrate dehydrogenase', 'Gene', '3417', (187, 211))	('IDH1', 'Gene', (218, 222))	('mutation', 'Var', (224, 232))	('MGMT', 'Gene', '4255', (277, 281))	('IDH1', 'Gene', '3417', (218, 222))	('MGMT', 'Gene', (277, 281))	('isocitrate dehydrogenase', 'Gene', (187, 211))
162638	24711712	One subgroup, with a 1p/19q deletion and IDH1 mutation, especially benefitted from the addition of chemotherapy to external beam radiation, demonstrating an overall survival (OS) of 12.8 years with adjuvant chemotherapy contrasted with 5.5 years for those patients treated with radiation alone.	('OS', 'Chemical', '-', (175, 177))	('1p/19q deletion', 'Var', (21, 36))	('patients', 'Species', '9606', (256, 264))	('IDH1', 'Gene', (41, 45))	('benefitted', 'PosReg', (67, 77))	('mutation', 'Var', (46, 54))	('IDH1', 'Gene', '3417', (41, 45))
162639	24711712	It is now recognized that patients with oligodendroglial tumors with 1p/19q deletions have a consistently better prognosis for survival than those with tumors of equivalent grade and similar histologic appearance that lack the deletions.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('1p/19q deletions', 'Var', (69, 85))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (40, 63))	('oligodendroglial tumors', 'Disease', (40, 63))	('better', 'PosReg', (106, 112))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
162640	24711712	In two recently reported prospective randomized trials of fractionated external beam radiotherapy (EBRT) with or without alkylator-based chemotherapy for newly diagnosed anaplastic astrocytoma, the presence of 1p deletions was a predictive marker for the cohort of patients in which the addition of chemotherapy led to prolonged OS.	('astrocytoma', 'Phenotype', 'HP:0009592', (181, 192))	('anaplastic astrocytoma', 'Disease', (170, 192))	('presence', 'Var', (198, 206))	('patients', 'Species', '9606', (265, 273))	('OS', 'Chemical', '-', (329, 331))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (170, 192))
162641	24711712	The identification of mutations in isocitrate dehydrogenase (IDH) isoenzymes 1 and 2 in a high percentage of low grade gliomas and in subsets of anaplastic astrocytoma, oligodendroglioma, and glioblastoma has further refined the delineation of prognosis.	('anaplastic astrocytoma', 'Disease', (145, 167))	('IDH', 'Gene', '3417', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('glioblastoma', 'Disease', (192, 204))	('glioblastoma', 'Disease', 'MESH:D005909', (192, 204))	('oligodendroglioma', 'Disease', 'MESH:D009837', (169, 186))	('gliomas', 'Disease', (119, 126))	('oligodendroglioma', 'Disease', (169, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (192, 204))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('isocitrate dehydrogenase', 'Gene', '3417', (35, 59))	('mutations', 'Var', (22, 31))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (145, 167))	('isocitrate dehydrogenase', 'Gene', (35, 59))	('IDH', 'Gene', (61, 64))
162643	24711712	For anaplastic astrocytoma, lack of an IDH1 mutation appears to identify a subgroup of histologically indistinguishable tumors with a prognosis similar to glioblastoma.	('tumors', 'Disease', (120, 126))	('mutation', 'Var', (44, 52))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (4, 26))	('IDH1', 'Gene', (39, 43))	('glioblastoma', 'Disease', (155, 167))	('IDH1', 'Gene', '3417', (39, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('lack', 'Var', (28, 32))	('anaplastic astrocytoma', 'Disease', (4, 26))	('astrocytoma', 'Phenotype', 'HP:0009592', (15, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
162644	24711712	The oncogenic mechanism appears to be the production of a metabolite, 2-hydroxyglutarate (2HG), which inhibits ketoglutarate-dependent dioxygenases, leading to aberrant histone and DNA methylation.	('aberrant', 'Var', (160, 168))	('ketoglutarate-dependent dioxygenases', 'Enzyme', (111, 147))	('inhibits', 'NegReg', (102, 110))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (70, 88))
162649	24711712	IDH and p53 mutations are rare in primary GBM.	('IDH', 'Gene', (0, 3))	('p53', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('IDH', 'Gene', '3417', (0, 3))	('p53', 'Gene', '7157', (8, 11))
162650	24711712	In contrast, primary GBMs are characterized by EGFR amplification and mutation, loss of heterozygosity on chromosome 10q, and inactivation of the phosphatase and tensin homolog (PTEN) gene.	('PTEN', 'Gene', (178, 182))	('PTEN', 'Gene', '5728', (178, 182))	('primary GBMs', 'Disease', (13, 25))	('loss', 'Var', (80, 84))	('EGFR', 'Gene', '1956', (47, 51))	('mutation', 'Var', (70, 78))	('amplification', 'Var', (52, 65))	('EGFR', 'Gene', (47, 51))	('inactivation', 'NegReg', (126, 138))
162651	24711712	Secondary GBMs are characterized by tumor protein p53 (TP53) mutations and platelet-derived growth factor receptor activation.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('Secondary GBMs', 'Disease', (0, 14))
162652	24711712	A poor prognosis subgroup of secondary GBM in older adults, in which relapse occurs in the first year after treatment, appears to be characterized by lack of IDH1 mutations, similar to primary GBM's molecular signature.	('lack', 'NegReg', (150, 154))	('mutations', 'Var', (163, 172))	('secondary GBM', 'Disease', (29, 42))	('IDH1', 'Gene', (158, 162))	('IDH1', 'Gene', '3417', (158, 162))
162658	24711712	In the context of the cancer genome atlas, Noushmehr et al profiled promoter DNA methylation alterations in 272 glioblastomas (43 low and intermediate grade gliomas and 57 additional primary GBMs).	('glioblastomas', 'Phenotype', 'HP:0012174', (112, 125))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('alterations', 'Var', (93, 104))	('glioblastomas', 'Disease', 'MESH:D005909', (112, 125))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('cancer', 'Disease', (22, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('methylation alterations', 'Var', (81, 104))	('glioblastomas', 'Disease', (112, 125))	('gliomas', 'Disease', (157, 164))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))
162660	24711712	Within the GBM cohort, the G-CIMP phenotype correlates with IDH1 mutation, younger age, proneural genotype, and a better prognosis.	('CIMP', 'Chemical', '-', (29, 33))	('IDH1', 'Gene', (60, 64))	('neu', 'Gene', '2064', (91, 94))	('neu', 'Gene', (91, 94))	('mutation', 'Var', (65, 73))	('IDH1', 'Gene', '3417', (60, 64))
162662	24711712	A specific in-frame deletion of exons 2-7 is present in 20%-30% of GBM overall and 50%-60% of GBM with EGFR gene amplification.	('deletion', 'Var', (20, 28))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', '1956', (103, 107))
162664	24711712	A specific genotype correlated with response in which EGFRvIII mutation was present in the context of intact AKT pathway function, with wild-type PTEN.	('PTEN', 'Gene', (146, 150))	('PTEN', 'Gene', '5728', (146, 150))	('AKT', 'Gene', '207', (109, 112))	('EGFRvIII', 'Gene', (54, 62))	('mutation', 'Var', (63, 71))	('AKT', 'Gene', (109, 112))
162666	24711712	The most common BRAF abnormalities involve gene duplication with fusions leading to a mutant protein with a constitutively active kinase domain.	('leading to', 'Reg', (73, 83))	('mutant', 'Var', (86, 92))	('BRAF', 'Gene', (16, 20))	('protein', 'Protein', (93, 100))	('BRAF', 'Gene', '673', (16, 20))	('gene duplication', 'Var', (43, 59))	('fusions', 'Var', (65, 72))
162667	24711712	Mutation in p53 and BRAF appear to be mutually exclusive.	('Mutation', 'Var', (0, 8))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('BRAF', 'Gene', '673', (20, 24))	('BRAF', 'Gene', (20, 24))
162668	24711712	The presence of activating BRAF mutations may identify a therapeutic target in the high-grade gliomas in which it is expressed.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('BRAF', 'Gene', '673', (27, 31))	('mutations', 'Var', (32, 41))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('BRAF', 'Gene', (27, 31))	('activating', 'PosReg', (16, 26))
162670	24711712	Molecular markers are also useful to predict a response to chemotherapy in three settings: 1p and 19q loss, MGMT methylation, and possibly the EGFR-PI3 kinase pathways in response of glioblastomas to specific EGFR inhibitors.	('glioblastomas', 'Disease', 'MESH:D005909', (183, 196))	('EGFR', 'Gene', (143, 147))	('MGMT', 'Gene', (108, 112))	('EGFR', 'Gene', (209, 213))	('glioblastomas', 'Phenotype', 'HP:0012174', (183, 196))	('glioblastomas', 'Disease', (183, 196))	('methylation', 'Var', (113, 124))	('MGMT', 'Gene', '4255', (108, 112))	('loss', 'NegReg', (102, 106))	('EGFR', 'Gene', '1956', (143, 147))	('EGFR', 'Gene', '1956', (209, 213))	('glioblastoma', 'Phenotype', 'HP:0012174', (183, 195))
162671	24711712	Allelic loss of chromosomes 1p and 19q is a powerful predictor of chemotherapeutic response and longer PFS and OS following chemotherapy with either temozolomide or procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendrogliomas.	('patients', 'Species', '9606', (215, 223))	('vincristine', 'Chemical', 'MESH:D014750', (194, 205))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('lomustine', 'Chemical', 'MESH:D008130', (179, 188))	('Allelic loss', 'Var', (0, 12))	('OS', 'Chemical', '-', (111, 113))	('procarbazine', 'Chemical', 'MESH:D011344', (165, 177))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (229, 258))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('temozolomide', 'Chemical', 'MESH:D000077204', (149, 161))	('anaplastic oligodendrogliomas', 'Disease', (229, 258))
162673	24711712	Allelic loss of 1p alone is also predictive of response to temozolomide in patients with grade II oligodendroglial tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Allelic loss', 'Var', (0, 12))	('patients', 'Species', '9606', (75, 83))	('II oligodendroglial tumors', 'Disease', 'MESH:D009369', (95, 121))	('temozolomide', 'Chemical', 'MESH:D000077204', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('II oligodendroglial tumors', 'Disease', (95, 121))	('response to temozolomide', 'MPA', (47, 71))
162674	24711712	In the course of tumor development, the MGMT gene may be silenced by methylation of its promoter, thereby preventing repair of DNA damage and increasing the potential effectiveness of chemotherapy.	('tumor', 'Disease', (17, 22))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('methylation', 'Var', (69, 80))	('preventing', 'NegReg', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('repair of DNA damage', 'MPA', (117, 137))	('increasing', 'PosReg', (142, 152))
162677	24711712	Furthermore, the studies showed associations between response and activation of EGFR itself (one report implicating the wild-type receptor and the other implicating the vIII mutant EGFR), as well as between response and whether the PI3 kinase pathway was functionally intact (one report measuring phosphorylated AKT and the other measuring PTEN expression).	('mutant', 'Var', (174, 180))	('vIII', 'Gene', (169, 173))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', '1956', (80, 84))	('AKT', 'Gene', '207', (312, 315))	('EGFR', 'Gene', (80, 84))	('PI3 kinase pathway', 'Pathway', (232, 250))	('vIII', 'Gene', '1351', (169, 173))	('AKT', 'Gene', (312, 315))	('PTEN', 'Gene', (340, 344))	('EGFR', 'Gene', '1956', (181, 185))	('PTEN', 'Gene', '5728', (340, 344))	('activation', 'PosReg', (66, 76))
162688	24711712	In lung adenocarcinoma, genetic alterations in homeobox protein Hox-B9 and lymphoid enhancer-binding factor 1 lead to hyperactivity of the Wnt/T Cell Factor (Wnt/TCF) pathway, which has been implicated in the growth of cancer stem cells and enhanced competence to metastasize to the bone and brain.	('competence', 'CPA', (250, 260))	('genetic alterations', 'Var', (24, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('hyperactivity', 'Disease', (118, 131))	('hyperactivity', 'Phenotype', 'HP:0000752', (118, 131))	('Hox-B9 and lymphoid enhancer-binding factor 1', 'Gene', '3219;51176', (64, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('enhanced', 'PosReg', (241, 249))	('TCF', 'Gene', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('TCF', 'Gene', '3172', (162, 165))	('cancer', 'Disease', (219, 225))	('hyperactivity', 'Disease', 'MESH:D006948', (118, 131))	('lung adenocarcinoma', 'Disease', (3, 22))
162731	24711712	Studies have looked into the significance of IDH mutational status in the diagnosis and classification of gliomas and the identification of an oncometabolite, 2HG, which accumulates in IDH mutant tumors.	('IDH', 'Gene', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', '3417', (185, 188))	('mutant', 'Var', (189, 195))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('IDH', 'Gene', '3417', (45, 48))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
162732	24711712	Recent investigations using ultrahigh field strength MRI suggest that the presence of IDH mutations in a tumor can be noninvasively detected by spectroscopic measurement of 2HG.	('IDH', 'Gene', (86, 89))	('mutations', 'Var', (90, 99))	('IDH', 'Gene', '3417', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
162734	24711712	Kalinina et al analyzed brain tumor specimens to show the feasibility of using MRS to quantitate 2HG for the classification of IDH mutant tumors.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('mutant', 'Var', (131, 137))	('brain tumor', 'Disease', (24, 35))	('tumors', 'Disease', (138, 144))	('brain tumor', 'Disease', 'MESH:D001932', (24, 35))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('brain tumor', 'Phenotype', 'HP:0030692', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
162736	24711712	In tumors with IDH1 mutations, 2HG levels, as measured in vivo using water suppressed proton (1H) MRS, correlate with measured amounts in the resected tumor specimens.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('IDH1', 'Gene', (15, 19))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', (151, 156))	('IDH1', 'Gene', '3417', (15, 19))	('1H', 'Chemical', '-', (94, 96))	('water', 'Chemical', 'MESH:D014867', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
162737	24711712	Tumors with IDH1 mutations have elevated choline and decreased glutathione levels.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('decreased glutathione', 'Phenotype', 'HP:0003343', (53, 74))	('elevated', 'PosReg', (32, 40))	('elevated choline', 'Phenotype', 'HP:0012706', (32, 48))	('IDH1', 'Gene', (12, 16))	('choline', 'Chemical', 'MESH:D002794', (41, 48))	('Tumors', 'Disease', (0, 6))	('glutathione', 'Chemical', 'MESH:D005978', (63, 74))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('IDH1', 'Gene', '3417', (12, 16))	('choline', 'MPA', (41, 48))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('decreased', 'NegReg', (53, 62))	('mutations', 'Var', (17, 26))	('glutathione levels', 'MPA', (63, 81))
162745	24711712	High-grade gliomas, in particular, are associated with disruption of the BBB, which causes more contrast extravasation and consequent adjustments to rCBV calculations with sophisticated mathematical models.	('contrast extravasation', 'MPA', (96, 118))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('BBB', 'Protein', (73, 76))	('disruption', 'Var', (55, 65))	('causes', 'Reg', (84, 90))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
162750	24711712	FDG is actively transported across the BBB into the cell and the 18F-FDG-6-phosphate formed when 18F-FDG enters the cell and prevents its further metabolism.	('18F-FDG', 'Chemical', 'MESH:D019788', (65, 72))	('18F-FDG', 'Var', (97, 104))	('18F-FDG-6-phosphate', 'Chemical', '-', (65, 84))	('further metabolism', 'MPA', (138, 156))	('18F-FDG', 'Chemical', 'MESH:D019788', (97, 104))	('prevents', 'NegReg', (125, 133))
162788	24711712	In low-grade gliomas, the uptake is increased in the absence of BBB breakdown, which is a significant advantage over CT, conventional MRI, and 18F-FDG PET.	('absence', 'Var', (53, 60))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('18F-FDG', 'Chemical', 'MESH:D019788', (143, 150))	('uptake', 'MPA', (26, 32))	('increased', 'PosReg', (36, 45))	('gliomas', 'Disease', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
162833	24711712	Seminal clinical trials by the early brain tumor clinical trial collaborative groups demonstrated that EBRT prolongs survival as compared with surgery alone, for GBM, anaplastic astrocytoma, and anaplastic oligodendrogliomas.	('survival', 'MPA', (117, 125))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (167, 189))	('brain tumor', 'Disease', 'MESH:D001932', (37, 48))	('brain tumor', 'Disease', (37, 48))	('EBRT', 'Var', (103, 107))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (195, 224))	('anaplastic oligodendrogliomas', 'Disease', (195, 224))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('anaplastic astrocytoma', 'Disease', (167, 189))	('brain tumor', 'Phenotype', 'HP:0030692', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('gliomas', 'Phenotype', 'HP:0009733', (217, 224))	('prolongs', 'PosReg', (108, 116))
162855	24711712	However, long-term follow-up demonstrated that for patients with tumors expressing 1p/19q deletions, chemotherapy confers a significant survival advantage.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('1p/19q deletions', 'Var', (83, 99))	('survival', 'CPA', (136, 144))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (51, 59))	('advantage', 'PosReg', (145, 154))
162869	24711712	High expression of VEGF is correlated with poor clinical outcome, and it has been demonstrated that inhibition of VEGF decreases the growth of glioma cell lines.	('decreases', 'NegReg', (119, 128))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('VEGF', 'Gene', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('VEGF', 'Gene', (19, 23))	('inhibition', 'Var', (100, 110))	('glioma', 'Disease', (143, 149))	('VEGF', 'Gene', '7422', (19, 23))	('VEGF', 'Gene', '7422', (114, 118))
162903	24711712	Notably, MGMT promoter methylation was strongly associated with improved PFS (14 versus 8 months for methylated versus unmethylated promoter, respectively) and OS (23 versus 14 months, respectively).	('MGMT', 'Gene', '4255', (9, 13))	('MGMT', 'Gene', (9, 13))	('PFS', 'MPA', (73, 76))	('OS', 'Chemical', '-', (160, 162))	('improved', 'PosReg', (64, 72))	('methylated', 'Var', (101, 111))
162910	24711712	A study by Lassman of anaplastic oligodendrogliomas suggest that for 1p/19q deleted tumors, the older PCV regimen may be associated with better outcomes.	('anaplastic oligodendrogliomas', 'Disease', (22, 51))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (22, 51))	('1p/19q deleted', 'Var', (69, 83))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
162939	24511389	For example, an early study in rodent xenograft models demonstrated that intra-arterial melphalan increased intratumoral tissue concentrations by fourfold and surrounding tissue concentrations by up to 20-fold compared with intravenous delivery.	('intra-arterial', 'Var', (73, 87))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('increased', 'PosReg', (98, 107))	('melphalan', 'Gene', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
162979	24511389	In a study involving 92 adults with newly diagnosed malignant glioma (80% of patients had glioblastoma) treated with surgical resection, implantation of Gliadel wafers, followed by chemoradiotherapy with temozolomide, progression-free survival was 10.5 months and overall survival was 18 months, which compared favorably with historical controls.	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('malignant glioma', 'Disease', 'MESH:D005910', (52, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('Gliadel', 'Chemical', 'MESH:C574855', (153, 160))	('patients', 'Species', '9606', (77, 85))	('implantation', 'Var', (137, 149))	('glioblastoma', 'Disease', (90, 102))	('temozolomide', 'Chemical', 'MESH:D000077204', (204, 216))	('malignant glioma', 'Disease', (52, 68))
163093	22679124	For instance, phenotypic and gene expression alterations, clonal selection, and genetic drift occur during the adaptation of tumor cells to monolayer cultures.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('genetic', 'Var', (80, 87))	('tumor', 'Disease', (125, 130))	('clonal selection', 'CPA', (58, 74))	('rat', 'Species', '10116', (49, 52))
163130	22679124	These results clearly indicate that brain tumor stem cell lines with an endogenous R132H mutation in IDH1 can develop a tumor-initiating capacity as well as 2-hydroxygluterate production.	('IDH1', 'Gene', (101, 105))	('R132H', 'Var', (83, 88))	('brain tumor', 'Disease', 'MESH:D001932', (36, 47))	('tumor', 'Disease', (42, 47))	('IDH1', 'Gene', '3417', (101, 105))	('2-hydroxygluterate production', 'MPA', (157, 186))	('R132H', 'Mutation', 'rs121913500', (83, 88))	('brain tumor', 'Phenotype', 'HP:0030692', (36, 47))	('develop', 'PosReg', (110, 117))	('2-hydroxygluterate', 'Chemical', '-', (157, 175))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('brain tumor', 'Disease', (36, 47))	('tumor', 'Disease', (120, 125))
163160	22679124	This includes genomic amplification and overexpression of known GBM oncogenes such as EGFR, MDM2, CDK6, and NYCN.	('genomic amplification', 'Var', (14, 35))	('MDM2', 'Gene', '4193', (92, 96))	('CDK6', 'Gene', (98, 102))	('MDM2', 'Gene', (92, 96))	('overexpression', 'PosReg', (40, 54))	('EGFR', 'Gene', '1956', (86, 90))	('CDK6', 'Gene', '1021', (98, 102))	('GBM', 'Gene', (64, 67))	('EGFR', 'Gene', (86, 90))
163175	22679124	Low-grade astrocytomas and oligodendrogliomas differ genetically from primary GBM and most other cancers in that they often sustain mutation of the isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) gene.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('cancers', 'Disease', (97, 104))	('primary GBM', 'Disease', (70, 81))	('IDH2', 'Gene', (188, 192))	('rat', 'Species', '10116', (154, 157))	('IDH1', 'Gene', '3417', (176, 180))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (27, 45))	('astrocytomas', 'Disease', 'MESH:D001254', (10, 22))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('IDH2', 'Gene', '3418', (188, 192))	('astrocytomas', 'Disease', (10, 22))	('mutation', 'Var', (132, 140))	('oligodendrogliomas', 'Disease', (27, 45))	('IDH1', 'Gene', (176, 180))
163176	22679124	The functional role of these mutations in glioma development is still unknown, but their occurrence appears to be an early mutational event, preceding 1p/19q loss in oligodendrogliomas and p53 mutation in low-grade astrocytomas.	('oligodendrogliomas', 'Disease', (166, 184))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('astrocytomas', 'Disease', (215, 227))	('glioma', 'Disease', (177, 183))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('astrocytomas', 'Disease', 'MESH:D001254', (215, 227))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (166, 184))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('mutation', 'Var', (193, 201))	('glioma', 'Disease', (42, 48))	('loss', 'NegReg', (158, 162))	('p53', 'Gene', (189, 192))
163177	22679124	Whether IDH mutations can initiate tumor development in a transgenic model or are necessary to sustain progression remains to be shown.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IDH', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', (35, 40))	('transgenic', 'Species', '10090', (58, 68))	('IDH', 'Gene', '15926', (8, 11))
163178	22679124	Additional genetic changes that are hallmarks of these tumors, such as 1p/19q loss in oligodendroglioma and p53 mutation in astrocytoma, are also missing in these models.	('p53', 'Gene', (108, 111))	('mutation', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('astrocytoma', 'Disease', 'MESH:D001254', (124, 135))	('oligodendroglioma', 'Disease', (86, 103))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('astrocytoma', 'Disease', (124, 135))	('oligodendroglioma', 'Disease', 'MESH:D009837', (86, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('loss', 'NegReg', (78, 82))	('tumors', 'Disease', (55, 61))	('1p/19q', 'Var', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
163187	22679124	As an example, the loss of RB is associated with retinoblastoma development in humans, whereas RB hemizygous mice develop an array of other cancer types but no retinoblastomas.	('retinoblastoma', 'Phenotype', 'HP:0009919', (160, 174))	('retinoblastoma', 'Gene', (49, 63))	('retinoblastoma', 'Gene', '5925', (49, 63))	('retinoblastomas', 'Disease', (160, 175))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('associated', 'Reg', (33, 43))	('retinoblastomas', 'Disease', 'MESH:D012175', (160, 175))	('loss', 'Var', (19, 23))	('retinoblastoma', 'Gene', '5925', (160, 174))	('mice', 'Species', '10090', (109, 113))	('retinoblastoma', 'Phenotype', 'HP:0009919', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('humans', 'Species', '9606', (79, 85))	('retinoblastomas', 'Phenotype', 'HP:0009919', (160, 175))	('retinoblastoma', 'Gene', (160, 174))
163188	22679124	By engineering targeted mutations in a cell- or tissue-specific as well as temporally limited manner, embryonic lethality issues can be avoided.	('embryonic lethality', 'Disease', 'MESH:D020964', (102, 121))	('mutations', 'Var', (24, 33))	('embryonic lethality', 'Disease', (102, 121))
163193	22679124	On the other hand, since the tumors are composed of cells with a number of specific homogeneously genetic changes, they cannot reflect the complete intratumoral genomic and phenotypic heterogeneity found in human gliomas.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('changes', 'Var', (106, 113))	('tumor', 'Disease', (153, 158))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))	('tumor', 'Disease', (29, 34))	('gliomas', 'Disease', (213, 220))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('human', 'Species', '9606', (207, 212))	('rat', 'Species', '10116', (151, 154))	('tumors', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))
163329	33654134	Identifying genes whose expression influences drug sensitivity can help address both of these needs, elucidating the molecular pathways involved in drug efficacy and providing potential ways to predict new patients' response to available therapies.	('genes', 'Var', (12, 17))	('drug sensitivity', 'Phenotype', 'HP:0020174', (46, 62))	('drug sensitivity', 'MPA', (46, 62))	('influences', 'Reg', (35, 45))	('patients', 'Species', '9606', (206, 214))	('expression', 'Var', (24, 34))
163339	33654134	However, in vitro studies indicate that gene expression variation accounts for even more variability in drug sensitivity than genomic changes do and may offer better insight into clinical drug efficacy; yet, there have been few systematic efforts to identify gene expression patterns that influence tumors' drug sensitivity.	('drug', 'MPA', (307, 311))	('tumors', 'Disease', (299, 305))	('variation', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('drug sensitivity', 'Phenotype', 'HP:0020174', (104, 120))	('influence', 'Reg', (289, 298))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('drug sensitivity', 'Phenotype', 'HP:0020174', (307, 323))
163366	33654134	In our literature search, we found studies showing that lower XRCC2 in cancer cells increases temozolomide efficacy by inhibiting their ability to repair the DNA damage induced by temozolomide.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('temozolomide efficacy', 'MPA', (94, 115))	('ability', 'MPA', (136, 143))	('inhibiting', 'NegReg', (119, 129))	('cancer', 'Disease', (71, 77))	('increases', 'PosReg', (84, 93))	('XRCC2', 'Gene', '7516', (62, 67))	('lower', 'Var', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('XRCC2', 'Gene', (62, 67))	('temozolomide', 'Chemical', 'MESH:D000077204', (94, 106))	('temozolomide', 'Chemical', 'MESH:D000077204', (180, 192))
163370	33654134	Studies have shown that silencing TWIST1 can increase certain cancer cells' sensitivity to fluorouracil, which agrees with our findings that, among patients taking fluorouracil for stomach adenocarcinoma, survival outcomes are better for patients with low expression levels of TWIST1 than for those with high TWIST1 expression (Fig.	('TWIST1', 'Gene', '7291', (34, 40))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (181, 203))	('better', 'PosReg', (227, 233))	('stomach adenocarcinoma', 'Disease', (181, 203))	('TWIST1', 'Gene', (277, 283))	('increase', 'PosReg', (45, 53))	('patients', 'Species', '9606', (148, 156))	('TWIST1', 'Gene', (309, 315))	('cancer', 'Disease', (62, 68))	('TWIST1', 'Gene', '7291', (277, 283))	('low', 'NegReg', (252, 255))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TWIST1', 'Gene', '7291', (309, 315))	('patients', 'Species', '9606', (238, 246))	('TWIST1', 'Gene', (34, 40))	('fluorouracil', 'Chemical', 'MESH:D005472', (91, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('fluorouracil', 'Chemical', 'MESH:D005472', (164, 176))	('expression levels', 'MPA', (256, 273))	('silencing', 'Var', (24, 33))	('sensitivity to fluorouracil', 'MPA', (76, 103))
163374	33654134	Mutations in the SMAD4 gene have been linked to resistance of platinum-based drugs like carboplatin, and our data suggest that head and neck cancer patients on carboplatin stratified by pre-treatment SMAD4 expression have significantly differential survival between the strata (Fig.	('differential', 'Reg', (236, 248))	('platinum', 'Chemical', 'MESH:D010984', (62, 70))	('linked', 'Reg', (38, 44))	('SMAD4', 'Gene', '4089', (17, 22))	('patients', 'Species', '9606', (148, 156))	('head and neck cancer', 'Phenotype', 'HP:0012288', (127, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SMAD4', 'Gene', '4089', (200, 205))	('survival', 'MPA', (249, 257))	('Mutations', 'Var', (0, 9))	('SMAD4', 'Gene', (17, 22))	('head and neck cancer', 'Disease', 'MESH:D006258', (127, 147))	('carboplatin', 'Chemical', 'MESH:D016190', (160, 171))	('carboplatin', 'Chemical', 'MESH:D016190', (88, 99))	('SMAD4', 'Gene', (200, 205))
163378	33654134	A previous study in ovarian tumor-bearing mice linked LPP silencing with increased chemosensitivity and improved delivery of paclitaxel to tumor cells, which improved the effectiveness of the drug.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('paclitaxel', 'Chemical', 'MESH:D017239', (125, 135))	('tumor', 'Disease', (28, 33))	('improved', 'PosReg', (104, 112))	('mice', 'Species', '10090', (42, 46))	('delivery', 'MPA', (113, 121))	('effectiveness', 'MPA', (171, 184))	('tumor', 'Disease', (139, 144))	('ovarian tumor', 'Disease', (20, 33))	('ovarian tumor', 'Phenotype', 'HP:0100615', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('LPP', 'Gene', (54, 57))	('ovarian tumor', 'Disease', 'MESH:D010051', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('silencing', 'Var', (58, 67))
163396	33654134	In addition, given that most of the gene-drug combinations that are significant in multiple cancers occur in the same tissue, it is possible that many of the identified effects are tissue-specific.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('multiple cancers', 'Disease', 'MESH:D009369', (83, 99))	('combinations', 'Var', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('multiple cancers', 'Disease', (83, 99))
163488	30977510	Treating the entire right hippocampus to 40 Gy (ie, V40 Gy 100%) was associated with 5-year and 10-year reductions in CVLT-T of 0.74 SD and 1.49 SD, respectively (Supplementary Figure 3).	('reductions', 'NegReg', (104, 114))	('1.49 SD', 'Disease', (140, 147))	('CVLT-T', 'Disease', (118, 124))	('1.49 SD', 'Disease', 'MESH:D029461', (140, 147))	('CVLT-T', 'Disease', 'MESH:D001260', (118, 124))	('V40 Gy', 'Var', (52, 58))
163492	30977510	After accounting for hydrocephalus, both left hippocampal V40 Gy (slope = -0.001 SD/y, P  = 0.025) and right hippocampal V40 Gy (slope = -0.001 SD/y, P = 0.019) remained significantly associated with a decline in CVLT-SD (Table 3).	('left hippocampal', 'Var', (41, 57))	('hydrocephalus', 'Disease', 'MESH:D006849', (21, 34))	('right hippocampal V40 Gy', 'Var', (103, 127))	('CVLT-SD', 'MPA', (213, 220))	('hydrocephalus', 'Disease', (21, 34))	('hydrocephalus', 'Phenotype', 'HP:0000238', (21, 34))	('decline', 'NegReg', (202, 209))
163495	30977510	Only left and right hippocampal V40 Gy and V45 Gy were both associated with CVLT-SD on multivariate regression, and model fitness utilizing V45 Gy was similar to that of the model utilizing V40 Gy, as determined by AIC and BIC values (Supplementary Table 4).	('AIC', 'Disease', 'MESH:D058540', (215, 218))	('CVLT-SD', 'Disease', (76, 83))	('fitness', 'Disease', (122, 129))	('V45 Gy', 'Var', (43, 49))	('AIC', 'Disease', (215, 218))	('fitness', 'Disease', 'MESH:D012640', (122, 129))	('associated', 'Reg', (60, 70))
163510	30977510	In children younger than 12 years, decline in long-delay recall was also associated with hippocampal dose.	('children', 'Species', '9606', (3, 11))	('long-delay recall', 'Disease', 'MESH:D008569', (46, 63))	('decline', 'NegReg', (35, 42))	('long-delay recall', 'Disease', (46, 63))	('hippocampal', 'Var', (89, 100))
163520	30977510	Zureick et al found that left hippocampal V20 Gy equivalent was significantly associated with a decline in immediate verbal memory, but not in delayed verbal memory, although patients did demonstrate a deficit in delayed verbal memory.	('left hippocampal V20 Gy equivalent', 'Var', (25, 59))	('patients', 'Species', '9606', (175, 183))	('immediate verbal memory', 'MPA', (107, 130))	('decline', 'NegReg', (96, 103))
163522	30977510	Merchant et al demonstrated that hippocampal dose was associated with a decline in emotional intelligence quotient in patients with medulloblastoma with a follow-up of 5 years; however, no association between hippocampal dose and verbal recall was reported.	('decline', 'NegReg', (72, 79))	('medulloblastoma', 'Disease', (132, 147))	('intelligence quotient', 'Phenotype', 'HP:0001249', (93, 114))	('hippocampal', 'Var', (33, 44))	('emotional intelligence quotient', 'MPA', (83, 114))	('medulloblastoma', 'Disease', 'MESH:D008527', (132, 147))	('medulloblastoma', 'Phenotype', 'HP:0002885', (132, 147))	('patients', 'Species', '9606', (118, 126))
163542	31399646	CRISPR knockin mutants demonstrate the essentiality of the polyamine acetyl transferase activity of SAT1 for its function as a transcriptional regulator.	('SAT1', 'Gene', (100, 104))	('knockin', 'Var', (7, 14))	('activity', 'MPA', (88, 96))	('polyamine acetyl', 'Chemical', 'MESH:D011073', (59, 75))	('mutants', 'Var', (15, 22))	('SAT1', 'Gene', '6303', (100, 104))	('polyamine acetyl transferase', 'Enzyme', (59, 87))
163543	31399646	Together, the data demonstrate that gene-specific polyamine removal is a major transcriptional regulatory mechanism active in high grade gliomas that drives poor outcomes.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('polyamine', 'Var', (50, 59))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('polyamine', 'Chemical', 'MESH:D011073', (50, 59))
163544	31399646	Polyamines putrescine, spermidine, and spermine are small, positively-charged molecules present in millimolar amounts in cells that bind acidic macromolecules, and broadly regulate functions such as replication, translation, chromatin condensation.	('bind', 'Interaction', (132, 136))	('replication', 'CPA', (199, 210))	('Polyamines putrescine', 'Chemical', 'MESH:D011073', (0, 21))	('translation', 'MPA', (212, 223))	('spermidine', 'Chemical', 'MESH:D013095', (23, 33))	('regulate', 'Reg', (172, 180))	('spermine', 'Var', (39, 47))	('chromatin condensation', 'CPA', (225, 247))	('spermine', 'Chemical', 'MESH:D013096', (39, 47))
163548	31399646	Polyamines and SAT1 are present in all cellular compartments, but specific roles in different locations are not well-desribed.	('Polyamines', 'Var', (0, 10))	('SAT1', 'Gene', (15, 19))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('SAT1', 'Gene', '6303', (15, 19))
163565	31399646	To validate gene expression changes in U87MG cells, we tested SAT1 knock down on a cohort of genes in two neurosphere lines (GBM821 and GBM913) that retain characteristics of tumor stem cells in vivo.	('GBM', 'Phenotype', 'HP:0012174', (125, 128))	('tumor', 'Disease', (175, 180))	('GBM', 'Disease', 'MESH:D005909', (136, 139))	('SAT1', 'Gene', (62, 66))	('U87MG', 'CellLine', 'CVCL:0022', (39, 44))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('GBM', 'Disease', (125, 128))	('knock down', 'Var', (67, 77))	('SAT1', 'Gene', '6303', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('GBM', 'Disease', 'MESH:D005909', (125, 128))	('tested', 'Reg', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('GBM', 'Disease', (136, 139))
163566	31399646	All of the genes demonstrated significant reductions in expression upon knock down of SAT1 (Figure 1B).	('knock down', 'Var', (72, 82))	('SAT1', 'Gene', (86, 90))	('expression', 'MPA', (56, 66))	('reductions', 'NegReg', (42, 52))	('SAT1', 'Gene', '6303', (86, 90))
163571	31399646	Furthermore, SAT1 expression correlates with poor outcome in the LGG + GBM (Low-Grade Glioma and Glioblastoma) cohort with a high level of significance (p<0.001, log rank test) (Figure 2B), largely because when ranked by SAT1 expression levels, 80% of the glioblastomas segregate to the upper-third of the tumors, and only 4.9% fall to the lower-third.	('SAT1', 'Gene', '6303', (221, 225))	('SAT1', 'Gene', '6303', (13, 17))	('glioblastomas', 'Disease', 'MESH:D005909', (256, 269))	('Glioma and Glioblastoma', 'Disease', 'MESH:D005909', (86, 109))	('SAT1', 'Gene', (221, 225))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('GBM', 'Disease', (71, 74))	('SAT1', 'Gene', (13, 17))	('GBM', 'Disease', 'MESH:D005909', (71, 74))	('glioblastomas', 'Phenotype', 'HP:0012174', (256, 269))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumors', 'Disease', (306, 312))	('expression', 'Var', (18, 28))	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('fall', 'Phenotype', 'HP:0002527', (328, 332))	('Glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('glioblastoma', 'Phenotype', 'HP:0012174', (256, 268))	('Glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioblastomas', 'Disease', (256, 269))
163586	31399646	We explored the interaction of MELK, FOXM1 and EZH2 at the gene expression level in three established cell lines (U87MG, LN229, and Gli36), and observed that knockdown of MELK caused reductions in expression of FOXM1, EZH2, and BRCA1 (Figure 3A).	('LN229', 'CellLine', 'CVCL:0393', (121, 126))	('FOXM1', 'Gene', (37, 42))	('MELK', 'Gene', '9833', (31, 35))	('U87MG', 'CellLine', 'CVCL:0022', (114, 119))	('MELK', 'Gene', '9833', (171, 175))	('FOXM1', 'Gene', (211, 216))	('EZH2', 'Gene', '2146', (47, 51))	('EZH2', 'Gene', (47, 51))	('FOXM1', 'Gene', '2305', (37, 42))	('expression', 'MPA', (197, 207))	('MELK', 'Gene', (31, 35))	('reductions', 'NegReg', (183, 193))	('FOXM1', 'Gene', '2305', (211, 216))	('MELK', 'Gene', (171, 175))	('BRCA1', 'Gene', '672', (228, 233))	('knockdown', 'Var', (158, 167))	('EZH2', 'Gene', '2146', (218, 222))	('BRCA1', 'Gene', (228, 233))	('EZH2', 'Gene', (218, 222))
163590	31399646	Using shGFP U87MG and shSAT1 U87MG, we found an association of SAT1 with both the MELK and EZH2 promoters, but not FOXM1, BRCA1, or NUSAP1 (Figure 3C).	('SAT1', 'Gene', (24, 28))	('EZH2', 'Gene', (91, 95))	('BRCA1', 'Gene', (122, 127))	('U87MG', 'CellLine', 'CVCL:0022', (29, 34))	('FOXM1', 'Gene', '2305', (115, 120))	('FOXM1', 'Gene', (115, 120))	('EZH2', 'Gene', '2146', (91, 95))	('SAT1', 'Gene', (63, 67))	('U87MG', 'Var', (29, 34))	('U87MG', 'CellLine', 'CVCL:0022', (12, 17))	('MELK', 'Gene', (82, 86))	('association', 'Interaction', (48, 59))	('MELK', 'Gene', '9833', (82, 86))	('NUSAP1', 'Gene', '51203', (132, 138))	('SAT1', 'Gene', '6303', (63, 67))	('SAT1', 'Gene', '6303', (24, 28))	('BRCA1', 'Gene', '672', (122, 127))	('NUSAP1', 'Gene', (132, 138))
163592	31399646	We then tested the effect of MELK knockdown in comparison to SAT1 knockdown over a range of identified target genes across the three cell lines.	('tested', 'Reg', (8, 14))	('MELK', 'Gene', (29, 33))	('MELK', 'Gene', '9833', (29, 33))	('SAT1', 'Gene', '6303', (61, 65))	('knockdown', 'Var', (34, 43))	('SAT1', 'Gene', (61, 65))
163593	31399646	We found in all genes tested, MELK knockdown with two shRNAs phenocopied SAT1 knockdown (Figure 3D).	('knockdown', 'Var', (35, 44))	('SAT1', 'Gene', (73, 77))	('MELK', 'Gene', (30, 34))	('MELK', 'Gene', '9833', (30, 34))	('SAT1', 'Gene', '6303', (73, 77))
163595	31399646	To gain a broader view of the roles of MELK/FOXM1 and EZH2 in SAT1 driven gene expression programs, we analyzed recently published ChIPseq data for both FOXM1 and H3K27me3 (the EZH2-directed histone modification) in cancer cells, and compared their target genes to SAT1 target genes.	('EZH2', 'Gene', (54, 58))	('EZH2', 'Gene', (177, 181))	('H3K27me3', 'Var', (163, 171))	('SAT1', 'Gene', (62, 66))	('FOXM1', 'Gene', '2305', (153, 158))	('MELK', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('FOXM1', 'Gene', (153, 158))	('SAT1', 'Gene', (265, 269))	('MELK', 'Gene', '9833', (39, 43))	('FOXM1', 'Gene', (44, 49))	('FOXM1', 'Gene', '2305', (44, 49))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('SAT1', 'Gene', '6303', (62, 66))	('EZH2', 'Gene', '2146', (54, 58))	('EZH2', 'Gene', '2146', (177, 181))	('SAT1', 'Gene', '6303', (265, 269))
163599	31399646	In both the GBM821 and GBM913 lines, we found that SAT1 depletion led to significant reductions in the ability to form neurospheres (Figure 3G-H).	('GBM', 'Disease', 'MESH:D005909', (23, 26))	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('GBM', 'Disease', (12, 15))	('ability to form neurospheres', 'CPA', (103, 131))	('SAT1', 'Gene', '6303', (51, 55))	('GBM', 'Disease', 'MESH:D005909', (12, 15))	('reductions', 'NegReg', (85, 95))	('GBM', 'Disease', (23, 26))	('depletion', 'Var', (56, 65))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('SAT1', 'Gene', (51, 55))
163607	31399646	To determine if SAT1 polyamine acetylation activity is required for target gene activation, we created a conditional CRISPR/Cas9 knockin cell line in which wild type SAT1 remains expressed by its endogenous promoter until CRE recombinase induces excision of wild type exons 4-6, resulting in inclusion of mutant exons 4-6 with point mutations in both the acetyl Co-A and polyamine binding sites (R101A and E152K, respectively) (Figure 4C).	('acetyl Co-A', 'Chemical', 'MESH:D000105', (355, 366))	('SAT1', 'Gene', '6303', (166, 170))	('E152K', 'Var', (406, 411))	('inclusion', 'Reg', (292, 301))	('polyamine', 'Chemical', 'MESH:D011073', (371, 380))	('SAT1', 'Gene', '6303', (16, 20))	('polyamine acetyl', 'Chemical', 'MESH:D011073', (21, 37))	('SAT1', 'Gene', (166, 170))	('R101A', 'Mutation', 'p.R101A', (396, 401))	('polyamine', 'Chemical', 'MESH:D011073', (21, 30))	('SAT1', 'Gene', (16, 20))	('R101A', 'Var', (396, 401))	('point mutations', 'Var', (327, 342))	('E152K', 'Mutation', 'p.E152K', (406, 411))
163608	31399646	The mutations have been shown to abrogate polyamine catabolism of SAT1.	('SAT1', 'Gene', (66, 70))	('abrogate', 'NegReg', (33, 41))	('polyamine', 'Chemical', 'MESH:D011073', (42, 51))	('mutations', 'Var', (4, 13))	('SAT1', 'Gene', '6303', (66, 70))	('polyamine catabolism', 'MPA', (42, 62))
163609	31399646	We then assessed the transcriptional activity of SAT1 mutants.	('SAT1', 'Gene', (49, 53))	('transcriptional', 'MPA', (21, 36))	('SAT1', 'Gene', '6303', (49, 53))	('mutants', 'Var', (54, 61))
163610	31399646	As see in Figure 4F-G, CRE recombination resulted in a moderate increase in SAT1 expression compared to control cells, but a dramatic loss of expression of both MELK and FOXM1 at both the mRNA and protein levels.	('SAT1', 'Gene', '6303', (76, 80))	('recombination', 'Var', (27, 40))	('CRE recombination', 'Var', (23, 40))	('FOXM1', 'Gene', (170, 175))	('FOXM1', 'Gene', '2305', (170, 175))	('SAT1', 'Gene', (76, 80))	('MELK', 'Gene', (161, 165))	('MELK', 'Gene', '9833', (161, 165))	('increase', 'PosReg', (64, 72))	('expression', 'MPA', (142, 152))	('loss', 'NegReg', (134, 138))	('expression', 'MPA', (81, 91))
163615	31399646	Physical association of SAT1 with the MELK and EZH2 promoters, and the requirement of SAT1 enzymatic function to regulate genes support a model in which localization of SAT1 to target genes, and acetylation and removal of polyamines from chromatin promote transcriptional activation.	('SAT1', 'Gene', (24, 28))	('SAT1', 'Gene', '6303', (169, 173))	('EZH2', 'Gene', (47, 51))	('polyamines', 'Var', (222, 232))	('polyamines', 'Chemical', 'MESH:D011073', (222, 232))	('SAT1', 'Gene', (86, 90))	('SAT1', 'Gene', '6303', (86, 90))	('SAT1', 'Gene', (169, 173))	('transcriptional', 'MPA', (256, 271))	('MELK', 'Gene', (38, 42))	('removal', 'Var', (211, 218))	('localization', 'MPA', (153, 165))	('MELK', 'Gene', '9833', (38, 42))	('SAT1', 'Gene', '6303', (24, 28))	('activation', 'PosReg', (272, 282))	('promote', 'PosReg', (248, 255))	('acetylation', 'Var', (195, 206))	('EZH2', 'Gene', '2146', (47, 51))
163620	31399646	Additionally recent studies have highlighted differential affinities of DNA sequences for polyamines, such that AT-rich regions bind more strongly than GC-rich regions; and polyamine binding stabilizes DNA duplexes.	('strongly', 'PosReg', (138, 146))	('stabilizes', 'Reg', (191, 201))	('bind', 'Interaction', (128, 132))	('polyamine', 'Var', (173, 182))	('DNA duplexes', 'MPA', (202, 214))	('polyamines', 'Chemical', 'MESH:D011073', (90, 100))	('binding', 'Interaction', (183, 190))	('polyamine', 'Chemical', 'MESH:D011073', (90, 99))	('polyamine', 'Chemical', 'MESH:D011073', (173, 182))
163625	31399646	For brain tumors, the data presented argue that SAT1 function controls two major pathways, both of which are implicated in tumor aggressiveness and therapeutic resistance.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor aggressiveness', 'Disease', (123, 143))	('SAT1', 'Gene', (48, 52))	('controls', 'Reg', (62, 70))	('brain tumors', 'Phenotype', 'HP:0030692', (4, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (123, 143))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('brain tumors', 'Disease', 'MESH:D001932', (4, 16))	('function', 'Var', (53, 61))	('brain tumors', 'Disease', (4, 16))	('SAT1', 'Gene', '6303', (48, 52))	('brain tumor', 'Phenotype', 'HP:0030692', (4, 15))
163663	30409554	Prognostic factors such as age (<40 years), sex (female), Karnofsky performance status (>80%), tumor size (<4 cm), extent of resection (gross total), molecular cytology (1p19q deletion), and molecular biomarkers (IDH mutant) are associated with better survival in patients with LGG.	('IDH', 'Gene', '3417', (213, 216))	('LGG', 'Disease', (278, 281))	('1p19q deletion', 'Var', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('patients', 'Species', '9606', (264, 272))	('IDH', 'Gene', (213, 216))	('better', 'PosReg', (245, 251))	('tumor', 'Disease', (95, 100))
163707	30409554	The WHO 2016 LGG pathologic guidelines focus the genetic analysis on four major biomarkers: (1) isocitrate dehydrogenase (IDH), (2) 1p19q chromosomes, (3) telomerase reverse transcriptase (TERT) promoter, and (4) methylguanine methyltransferase (MGMT).	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('TERT', 'Gene', (189, 193))	('1p19q chromosomes', 'Var', (132, 149))	('MGMT', 'Gene', '4255', (246, 250))	('isocitrate dehydrogenase', 'Gene', (96, 120))	('MGMT', 'Gene', (246, 250))	('TERT', 'Gene', '7015', (189, 193))	('methylguanine methyltransferase', 'Gene', (213, 244))	('isocitrate dehydrogenase', 'Gene', '3417', (96, 120))	('methylguanine methyltransferase', 'Gene', '4255', (213, 244))
163708	30409554	As noted in Table 2, the majority of subjects with available data had favorable prognostic biomarkers with IDH mutations (IDHmut -, 60%); TERT mutation (TERTmut -, 53%), and MGMT methylation (63%).	('MGMT', 'Gene', '4255', (174, 178))	('mutations', 'Var', (111, 120))	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('TERT', 'Gene', '7015', (153, 157))	('IDH', 'Gene', (107, 110))	('TERT', 'Gene', '7015', (138, 142))	('TERT', 'Gene', (138, 142))	('IDH', 'Gene', '3417', (107, 110))	('TERT', 'Gene', (153, 157))	('MGMT', 'Gene', (174, 178))
163718	30409554	Within the IDH mutation group, seizures are seen at each time point, with 44% (4/9) of patients reporting evidence of seizure at 2 months, 22% (2/9) at 4 months, and 22% (2/9) at 6 months from initial diagnosis.	('mutation', 'Var', (15, 23))	('seizures', 'Disease', 'MESH:D012640', (31, 39))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('seizure', 'Phenotype', 'HP:0001250', (118, 125))	('seizure', 'Disease', (31, 38))	('seizure', 'Disease', 'MESH:D012640', (31, 38))	('seizures', 'Phenotype', 'HP:0001250', (31, 39))	('seizure', 'Disease', (118, 125))	('seizures', 'Disease', (31, 39))	('seizure', 'Disease', 'MESH:D012640', (118, 125))	('seizure', 'Phenotype', 'HP:0001250', (31, 38))	('patients', 'Species', '9606', (87, 95))
163723	30409554	2, patients with 1p19qco-deletion reported lower QoL scores as determined by the specific FACT-Br subscale and less perceived fatigue, but had higher depression.	('1p19qco-deletion', 'Var', (17, 33))	('less', 'NegReg', (111, 115))	('fatigue', 'Phenotype', 'HP:0012378', (126, 133))	('depression', 'Disease', 'MESH:D003866', (150, 160))	('QoL scores', 'MPA', (49, 59))	('higher', 'PosReg', (143, 149))	('depression', 'Disease', (150, 160))	('patients', 'Species', '9606', (3, 11))	('depression', 'Phenotype', 'HP:0000716', (150, 160))	('Br', 'Chemical', 'MESH:C068746', (95, 97))	('fatigue', 'Disease', 'MESH:D005221', (126, 133))	('fatigue', 'Disease', (126, 133))	('lower', 'NegReg', (43, 48))
163749	30409554	Biomarker data for this LGG population were thought-provoking because patients with either 1p19qco-deletion, IDHmut, or TERTmut reported lower QoL.	('patients', 'Species', '9606', (70, 78))	('TERT', 'Gene', (120, 124))	('lower', 'NegReg', (137, 142))	('TERT', 'Gene', '7015', (120, 124))	('QoL', 'MPA', (143, 146))	('IDH', 'Gene', (109, 112))	('1p19qco-deletion', 'Var', (91, 107))	('IDH', 'Gene', '3417', (109, 112))
163756	26464434	Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites The epigenetic landscape of cancer includes both focal hypermethylation and broader hypomethylation in a genome-wide manner.	('focal hypermethylation', 'Var', (159, 181))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
163759	26464434	We found connections between CGI methylation and hypermutability, microsatellite instability, IDH1 mutation, 19p gain and polycomb features, and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains.	('IDH1', 'Gene', (94, 98))	('microsatellite instability', 'MPA', (66, 92))	('TP53', 'Gene', '7157', (207, 211))	('IDH1', 'Gene', '3417', (94, 98))	('backbone', 'MPA', (145, 153))	('NSD1', 'Gene', '64324', (198, 202))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (207, 211))	('gain', 'PosReg', (113, 117))	('mutations', 'Var', (212, 221))	('NSD1', 'Gene', (198, 202))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('loss', 'NegReg', (234, 238))
163760	26464434	These broad epigenetic patterns add a new dimension to our understanding of tumor biology and its clinical implications.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('epigenetic patterns', 'Var', (12, 31))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
163761	26464434	Epigenetic alterations have pivotal roles in development and cancer biology.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
163762	26464434	A canonical observation in many cancers is the de novo methylation of CpG islands (CGIs) in the promoters of tumor-related genes, which is significantly associated with clinical behavior in many tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Disease', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('associated', 'Reg', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('methylation', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (109, 114))
163769	26464434	TF-binding sites behaved differently according to TF contents; the binding sites of embryonic stem cell (ESC)-related TFs including polycomb proteins and CTBP2 were frequently de novo methylated while the binding sites of other differentiation-associated TFs were rather demethylated or unchanged.	('CTBP2', 'Gene', '1488', (154, 159))	('polycomb proteins', 'Protein', (132, 149))	('methylated', 'Var', (184, 194))	('binding', 'Interaction', (67, 74))	('CTBP2', 'Gene', (154, 159))
163789	26464434	Likewise, we selected 49 277 CpGs in backbone, as defined above, and averaged their methylation levels for each tumor.	('CpGs', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('methylation levels', 'MPA', (84, 102))
163794	26464434	Nonetheless, most tumors showed both CGI methylation and backbone demethylation with variable degrees (HC-LB; Figure 1F; Supplementary Figure S2).	('backbone demethylation', 'MPA', (57, 79))	('methylation', 'Var', (41, 52))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', 'MESH:D017034', (103, 144))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', (103, 144))	('CGI', 'MPA', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
163796	26464434	And in most tumors, DNA methylation correlated with mRNA expression, miRNA expression, copy number and pathway clusters suggesting an underlying biological background.	('copy number', 'Var', (87, 98))	('DNA', 'Gene', (20, 23))	('pathway clusters', 'Pathway', (103, 119))	('methylation', 'Var', (24, 35))	('correlated', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mRNA expression', 'MPA', (52, 67))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('miRNA expression', 'MPA', (69, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
163800	26464434	In THCA, histories of lymphocytic thyroiditis significantly correlated with high CGI methylation (P = 6.3 x 10-4).	('CGI', 'Protein', (81, 84))	('thyroiditis', 'Phenotype', 'HP:0100646', (34, 45))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('lymphocytic thyroiditis', 'Disease', (22, 45))	('lymphocytic thyroiditis', 'Phenotype', 'HP:0000872', (22, 45))	('lymphocytic thyroiditis', 'Disease', 'MESH:D013967', (22, 45))	('high', 'Var', (76, 80))
163802	26464434	In COADREAD, CGI methylation was highest in cecum tumors and became modest when moving towards the rectum (P = 1.3 x 10-16; Supplementary Figure S25A).	('highest', 'Reg', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('S25A', 'SUBSTITUTION', 'None', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('S25A', 'Var', (145, 149))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
163803	26464434	In HNSC, CGI methylation was highest in the oral cavity and lower in the caudal direction in the oropharangeal tract (P = 8.9 x 10-5; Supplementary Figure S25B).	('methylation', 'MPA', (13, 24))	('S25B', 'SUBSTITUTION', 'None', (155, 159))	('highest', 'Reg', (29, 36))	('S25B', 'Var', (155, 159))	('CGI', 'MPA', (9, 12))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('lower', 'NegReg', (60, 65))
163807	26464434	Type 2 KIRP, an eosinophilic tumor with worse prognosis, was associated with both CGI methylation and backbone demethylation (P = 4.4 x 10-5 and 1.9 x 10-3, respectively).	('backbone demethylation', 'MPA', (102, 124))	('Type 2 KIRP', 'Disease', (0, 11))	('eosinophilic tumor', 'Disease', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('methylation', 'Var', (86, 97))	('eosinophilic tumor', 'Disease', 'MESH:D004802', (16, 34))	('CGI', 'MPA', (82, 85))
163809	26464434	In PRAD, Gleason scores tended to be high both in CGI-methylated and backbone-demethylated tumors (P = 6.1 x 10-3 and 3.9 x 10-4, respectively).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CGI-methylated', 'Var', (50, 64))	('high', 'PosReg', (37, 41))	('PRAD', 'Disease', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Gleason', 'MPA', (9, 16))	('backbone-demethylated', 'Var', (69, 90))
163810	26464434	An association of CGI methylation with high mitosis was observed in ACC (P = 4.5 x 10-4).	('association', 'Interaction', (3, 14))	('high mitosis', 'Disease', (39, 51))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('high mitosis', 'Disease', 'MESH:D008228', (39, 51))	('ACC', 'Disease', (68, 71))	('CGI', 'Protein', (18, 21))	('methylation', 'Var', (22, 33))
163813	26464434	MSI-H tumors were very significantly associated with CGI methylation in COADREAD, STAD and UCEC (P = 3.2 x 10-12, 2.4 x 10-7 and 2.0 x 10-22, respectively) (Figure 2B).	('methylation', 'Var', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CGI', 'Protein', (53, 56))	('associated', 'Reg', (37, 47))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MSI-H tumors', 'Disease', (0, 12))
163814	26464434	In COADREAD, CGI methylation was associated with negative expression of MSH6 and PMS2 proteins (P = 9.3 x 10-3).	('MSH6', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('proteins', 'Protein', (86, 94))	('PMS2', 'Gene', '5395', (81, 85))	('methylation', 'Var', (17, 28))	('negative', 'NegReg', (49, 57))	('MSH6', 'Gene', '2956', (72, 76))	('PMS2', 'Gene', (81, 85))
163815	26464434	In BRCA, CGI methylation was significantly associated with positive expression of estrogen and HER2/neu receptors (P = 1.5 x 10-5 and 8.3 x 10-8, respectively) and thus with luminal B subtype (P = 1.3 x 10-9).	('CGI methylation', 'Var', (9, 24))	('expression', 'MPA', (68, 78))	('BRCA', 'Gene', (3, 7))	('methylation', 'Var', (13, 24))	('BRCA', 'Gene', '672', (3, 7))	('positive', 'PosReg', (59, 67))	('estrogen', 'Protein', (82, 90))	('HER2/neu receptors', 'Protein', (95, 113))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
163816	26464434	The number of gene mutations correlated positively with CGI methylation in THCA, KIRC, LAML, LGG, GBM, PRAD, STAD, BRCA, ACC and UCEC (Figure 2A and B).	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('CGI methylation', 'MPA', (56, 71))	('THCA', 'Phenotype', 'HP:0002890', (75, 79))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('BRCA', 'Gene', '672', (115, 119))	('mutations', 'Var', (19, 28))	('BRCA', 'Gene', (115, 119))
163817	26464434	In line with the previous knowledge, IDH1 mutation was associated with high CGI methylation in LGG (P = 2.1 x 10-20), GBM, PRAD and CESC, and IDH2 was so in LAML.	('IDH2', 'Gene', '3418', (142, 146))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('CGI methylation', 'MPA', (76, 91))	('IDH2', 'Gene', (142, 146))
163818	26464434	Mutations in CIC, NOTCH1 and FUBP1 were very significantly associated with high CGI methylation in LGG (P = 5.7 x 10-11, 5.2 x 10-7 and 9.9 x 10-5, respectively), mutation in PIK3CA was so in STAD (P = 7.4 x 10-9), and mutations in PTEN and PIK3R1 were so in UCEC (P = 5.9 x 10-7 and 1.6 x 10-4, respectively).	('PIK3CA', 'Gene', (175, 181))	('NOTCH1', 'Gene', (18, 24))	('UCEC', 'Disease', (259, 263))	('PIK3R1', 'Gene', '5295', (241, 247))	('PIK3R1', 'Gene', (241, 247))	('PIK3CA', 'Gene', '5290', (175, 181))	('associated', 'Reg', (59, 69))	('high CGI methylation', 'MPA', (75, 95))	('Mutations', 'Var', (0, 9))	('FUBP1', 'Gene', '8880', (29, 34))	('PTEN', 'Gene', '5728', (232, 236))	('PTEN', 'Gene', (232, 236))	('mutations', 'Var', (219, 228))	('CIC', 'Gene', (13, 16))	('mutation', 'Var', (163, 171))	('FUBP1', 'Gene', (29, 34))	('NOTCH1', 'Gene', '4851', (18, 24))
163819	26464434	NRAS mutation was frequent in THCA with higher CGI methylation and BRAF was so in THCA with lower backbone methylation (P = 5.9 x 10-3 and 9.9 x 10-7, respectively) but this may be confounded by the difference in methylation according to histological type, as described above, and high frequency of NRAS mutation in follicular and BRAF mutation in papillary types.	('THCA', 'Phenotype', 'HP:0002890', (82, 86))	('BRAF', 'Gene', (331, 335))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', '673', (331, 335))	('higher', 'PosReg', (40, 46))	('NRAS', 'Gene', '4893', (299, 303))	('backbone methylation', 'MPA', (98, 118))	('THCA', 'Phenotype', 'HP:0002890', (30, 34))	('BRAF', 'Gene', (67, 71))	('CGI methylation', 'MPA', (47, 62))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))	('NRAS', 'Gene', (299, 303))
163820	26464434	TP53 mutation was associated with backbone demethylation in STAD and PRAD (P = 5.1 x 10-5 and 4.9 x 10-3, respectively) (Figure 2C), and NSD1 mutation was so in HNSC (P = 3.2 x 10-9) (Supplementary Figure S17B).	('TP53', 'Gene', '7157', (0, 4))	('NSD1', 'Gene', (137, 141))	('TP53', 'Gene', (0, 4))	('backbone demethylation', 'MPA', (34, 56))	('S17B', 'Var', (205, 209))	('S17B', 'SUBSTITUTION', 'None', (205, 209))	('NSD1', 'Gene', '64324', (137, 141))	('HNSC', 'Phenotype', 'HP:0012288', (161, 165))	('mutation', 'Var', (5, 13))
163825	26464434	The most remarkable P value peak was in chromosome 5q showing recurrent correlations between deletion and backbone demethylation in many tumors (Figure 3A and B).	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('backbone demethylation', 'MPA', (106, 128))	('correlations', 'Reg', (72, 84))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('deletion', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
163826	26464434	Candidate genes in this region include CHD1, LMNB1, KDM3B, HDAC3 and NSD1, and among them, NSD1 was of particular interest in that mutation in this gene also showed the most significant association with backbone demethylation in HNSC and other tumors (Figure 3C).	('NSD1', 'Gene', (69, 73))	('backbone demethylation', 'MPA', (203, 225))	('mutation', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('HDAC3', 'Gene', (59, 64))	('CHD1', 'Gene', '1105', (39, 43))	('LMNB1', 'Gene', '4001', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('NSD1', 'Gene', '64324', (69, 73))	('NSD1', 'Gene', (91, 95))	('CHD1', 'Gene', (39, 43))	('HNSC', 'Disease', (229, 233))	('tumors', 'Disease', (244, 250))	('KDM3B', 'Gene', '51780', (52, 57))	('LMNB1', 'Gene', (45, 50))	('HDAC3', 'Gene', '8841', (59, 64))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('association', 'Reg', (186, 197))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('NSD1', 'Gene', '64324', (91, 95))	('KDM3B', 'Gene', (52, 57))
163827	26464434	Bi-allelic aberration of NSD1 either by mutation or copy loss showed more demethylation (Figure 3D).	('mutation', 'Var', (40, 48))	('NSD1', 'Gene', (25, 29))	('demethylation', 'MPA', (74, 87))	('copy loss', 'Var', (52, 61))	('NSD1', 'Gene', '64324', (25, 29))
163830	26464434	Among the pathways recurrently associated in several tumors, the bone morphogenic protein (BMP) receptor pathway was significantly suppressed among backbone-demethylated tumors in LGG, PRAD and LIHC and CGI-methylated tumors in LUAD.	('backbone-demethylated', 'Var', (148, 169))	('BMP', 'Gene', '649', (91, 94))	('LIHC', 'Disease', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CGI-methylated', 'Var', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('LIHC', 'Disease', 'None', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRAD', 'Disease', (185, 189))	('BMP', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('LGG', 'Disease', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('suppressed', 'NegReg', (131, 141))	('LUAD', 'Phenotype', 'HP:0030078', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
163837	26464434	In all tumor types, differentially methylated CpGs were highly enriched in binding sites of polycomb-related SUZ12, EZH2 and CTBP2, and the enrichment rate strongly correlated with the degree of CGI methylation (Supplementary Figure S30).	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('tumor', 'Disease', (7, 12))	('differentially', 'Var', (20, 34))	('correlated', 'Reg', (165, 175))	('CTBP2', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('CGI methylation', 'MPA', (195, 210))	('CTBP2', 'Gene', '1488', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('binding sites', 'Interaction', (75, 88))	('SUZ12', 'Gene', '23512', (109, 114))	('SUZ12', 'Gene', (109, 114))
163838	26464434	Demethylated CpGs were often enriched in IKZF1, BATF and ZNF217 binding sites but the enrichment rate usually did not correlate with the degree of backbone demethylation, suggesting a minor role of transcription factors in the genome-wide demethylation (Supplementary Figure S31).	('BATF', 'Gene', (48, 52))	('BATF', 'Gene', '10538', (48, 52))	('IKZF1', 'Gene', '10320', (41, 46))	('ZNF217', 'Gene', (57, 63))	('ZNF217', 'Gene', '7764', (57, 63))	('IKZF1', 'Gene', (41, 46))	('Demethylated', 'Var', (0, 12))
163842	26464434	Intriguingly, CGI-methylated tumors showed better primary responses in STAD and LUAD (P = 7.5 x 10-3 and 1.8 x 10-2, respectively).	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('LUAD', 'Disease', (80, 84))	('primary responses', 'CPA', (50, 67))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('better', 'PosReg', (43, 49))	('STAD', 'Disease', (71, 75))	('CGI-methylated', 'Var', (14, 28))
163849	26464434	As supporting evidence, we could observe correlation of HC-tumors with many CIMP-associated features such as MSI-H and IDH1 mutation.	('HC-tumors', 'Disease', (56, 65))	('CIMP', 'Chemical', '-', (76, 80))	('MSI-H', 'Disease', (109, 114))	('correlation', 'Interaction', (41, 52))	('IDH1', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MSI-H', 'Disease', 'MESH:D000848', (109, 114))	('mutation', 'Var', (124, 132))	('HC-tumors', 'Disease', 'MESH:D009369', (56, 65))	('IDH1', 'Gene', '3417', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
163854	26464434	Polycomb site methylation has now been accepted as a hallmark of cancers, and so the enrichment of polycomb proteins, SUZ12 and EZH2, should be an innate quality.	('hallmark of cancers', 'Disease', (53, 72))	('hallmark of cancers', 'Disease', 'MESH:D009369', (53, 72))	('Polycomb', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EZH2', 'Gene', (128, 132))	('SUZ12', 'Gene', '23512', (118, 123))	('EZH2', 'Gene', '2146', (128, 132))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('SUZ12', 'Gene', (118, 123))
163856	26464434	Global demethylation in repetitive elements has been suggested in many cancers and yet a systematical analysis is lacking.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Global demethylation', 'Var', (0, 20))
163857	26464434	Associations of demethylation with histological grade and stage have been suggested in several tumors, and we could find such an association in an expanded set of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Associations', 'Interaction', (0, 12))	('demethylation', 'Var', (16, 29))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
163859	26464434	Although it has been experimentally shown that demethylation is linked to mitotic dysfunction and genomic rearrangement and anticipated to cause chromosome instability, it remained uninvestigated in clinical series.	('mitotic dysfunction', 'Disease', (74, 93))	('demethylation', 'Var', (47, 60))	('chromosome instability', 'MPA', (145, 167))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (74, 93))	('linked', 'Reg', (64, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (145, 167))	('genomic rearrangement', 'CPA', (98, 119))	('cause', 'Reg', (139, 144))
163863	26464434	NSD1 is a SET domain histone methyltransferase that primarily dimethylates histone H3K36, implicated in Sotos and Weaver overgrowth syndromes.	('NSD1', 'Gene', (0, 4))	('dimethylates', 'Var', (62, 74))	('overgrowth', 'Phenotype', 'HP:0001548', (121, 131))	('Weaver overgrowth syndromes', 'Disease', 'MESH:C536687', (114, 141))	('histone H3K36', 'Protein', (75, 88))	('Weaver overgrowth syndromes', 'Disease', (114, 141))	('NSD1', 'Gene', '64324', (0, 4))
163868	26464434	TP53 was also among the most significant genes, and this can be understood on the basis that TP53 mutations can directly cause DNA demethylation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('cause', 'Reg', (121, 126))	('DNA demethylation', 'MPA', (127, 144))
163869	26464434	Moreover, TP53 plays critical roles DNA repair and maintaining genomic stability and its mutation may exhibit communal pathways with DNA demethylation leading to chromosome instability.	('chromosome instability', 'MPA', (162, 184))	('TP53', 'Gene', (10, 14))	('mutation', 'Var', (89, 97))	('TP53', 'Gene', '7157', (10, 14))	('genomic', 'MPA', (63, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (162, 184))	('leading to', 'Reg', (151, 161))	('exhibit', 'Reg', (102, 109))
163870	26464434	It is often hypothesized that demethylation in cancer cells can activate proto-oncogenes and thus contribute to tumorigenesis.	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('contribute to', 'Reg', (98, 111))	('cancer', 'Disease', (47, 53))	('demethylation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proto-oncogenes', 'Gene', (73, 88))	('activate', 'PosReg', (64, 72))
163871	26464434	As more supporting evidence, we found that many pathways such as BMP receptor, LPA receptor, Ephrin B, PLK1, Aurora A and B, FoxM1, neurotrophic factor and p75NTR pathways tended to be suppressed rather than activated in demethylated tumors.	('Ephrin B', 'Gene', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('LPA', 'Protein', (79, 82))	('neurotrophic factor', 'Gene', '4908', (132, 151))	('demethylated', 'Var', (221, 233))	('BMP', 'Gene', '649', (65, 68))	('Aurora A and B', 'Gene', '6790;9212', (109, 123))	('PLK1', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('activated', 'PosReg', (208, 217))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('neurotrophic factor', 'Gene', (132, 151))	('p75NTR', 'Gene', (156, 162))	('FoxM1', 'Gene', '2305', (125, 130))	('LPA', 'Chemical', 'MESH:C032881', (79, 82))	('BMP', 'Gene', (65, 68))	('PLK1', 'Gene', '5347', (103, 107))	('suppressed', 'NegReg', (185, 195))	('tumors', 'Disease', (234, 240))	('p75NTR', 'Gene', '4804', (156, 162))	('FoxM1', 'Gene', (125, 130))
163873	26464434	We observed that low BMP, especially BMP-7, activity is associated with backbone demethylation and such demethylated tumors show aggressive features like high Gleason score and prostate specific antigen level (Supplementary Figure S10B).	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('S10B', 'Var', (231, 235))	('BMP', 'Gene', '649', (37, 40))	('associated', 'Reg', (56, 66))	('prostate specific antigen', 'Gene', (177, 202))	('demethylated', 'Var', (104, 116))	('prostate specific antigen', 'Gene', '354', (177, 202))	('BMP', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BMP-7', 'Gene', '655', (37, 42))	('tumors', 'Disease', (117, 123))	('low', 'Var', (17, 20))	('BMP', 'Gene', (37, 40))	('BMP-7', 'Gene', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('activity', 'MPA', (44, 52))	('backbone demethylation', 'MPA', (72, 94))	('S10B', 'SUBSTITUTION', 'None', (231, 235))	('BMP', 'Gene', '649', (21, 24))
163875	26464434	We also noticed that the demethylated tumors also tended to have worse outcome although the significance varied according to the cutoffs for average backbone methylation (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('demethylated', 'Var', (25, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
163877	26464434	We observed low BMP activity in demethylated LGGs which showed higher histological grade and worse treatment response and survival (Supplementary Figure S9B).	('histological', 'CPA', (70, 82))	('BMP', 'Gene', '649', (16, 19))	('survival', 'CPA', (122, 130))	('treatment response', 'CPA', (99, 117))	('BMP', 'Gene', (16, 19))	('demethylated', 'Var', (32, 44))	('higher', 'PosReg', (63, 69))	('low', 'NegReg', (12, 15))
163884	26464434	We observed that Ephrin pathways are epigenetically suppressed in a set of tumors preferentially by backbone demethylation.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('suppressed', 'NegReg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ephrin pathways', 'Pathway', (17, 32))	('tumors', 'Disease', (75, 81))	('backbone demethylation', 'Var', (100, 122))
163886	26464434	We found that PLK1 and Aurora pathways are often suppressed and sometimes activated in backbone-demethylated or CGI-methylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('CGI-methylated', 'Var', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('activated', 'PosReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('suppressed', 'NegReg', (49, 59))	('backbone-demethylated', 'Var', (87, 108))	('PLK1', 'Gene', (14, 18))	('Aurora pathways', 'Pathway', (23, 38))	('PLK1', 'Gene', '5347', (14, 18))
163888	26464434	Either loss or gain of FoxM function can alter cell fate and promote tumorigenesis, and we observed epigenetic suppression of FoxM1 pathway in a set of tumors.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('loss', 'NegReg', (7, 11))	('FoxM', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', (69, 74))	('FoxM1', 'Gene', '2305', (126, 131))	('promote', 'PosReg', (61, 68))	('FoxM1', 'Gene', (126, 131))	('tumor', 'Disease', (152, 157))	('alter', 'Reg', (41, 46))	('gain', 'PosReg', (15, 19))	('epigenetic suppression', 'Var', (100, 122))	('cell fate', 'CPA', (47, 56))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
163898	26464434	The slightly-high tumors showed poor survival compared to slightly-low tumors.	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('slightly-high', 'Var', (4, 17))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
163903	26464434	Collectively, we present a pan-cancer model connecting CGI methylation with hypermutability, MSI-H, IDH1 mutation, 19p gain and polycomb proteins and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains (Figure 5).	('MSI-H', 'Disease', 'MESH:D000848', (93, 98))	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('NSD1', 'Gene', (203, 207))	('IDH1', 'Gene', (100, 104))	('loss', 'NegReg', (239, 243))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('TP53', 'Gene', '7157', (212, 216))	('MSI-H', 'Disease', (93, 98))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (217, 226))	('NSD1', 'Gene', '64324', (203, 207))	('gain', 'PosReg', (119, 123))	('TP53', 'Gene', (212, 216))
163905	26464434	Since many pathways are suppressed in methylated and demethylated tumors, thoughtful usage of new targeted drugs inhibiting such pathways is warranted.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('methylated', 'Var', (38, 48))	('tumors', 'Disease', (66, 72))	('suppressed', 'NegReg', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('demethylated', 'Var', (53, 65))
163940	25821815	Deregulated VEGF expression contributes to the development of solid tumors by promoting tumor angiogenesis and to the etiology of several additional diseases that are characterized by abnormal angiogenesis.	('tumor', 'Disease', (68, 73))	('Deregulated', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('VEGF', 'Gene', (12, 16))	('promoting', 'PosReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('contributes', 'Reg', (28, 39))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (88, 93))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))	('VEGF', 'Gene', '7422', (12, 16))
163971	25821815	Peritumoral brain edema was present in 56 out of 93 low-grade meningiomas, 23 tumors being evaluated as significant (II and III grades in Steinhoff classification).	('tumor', 'Disease', (4, 9))	('edema', 'Phenotype', 'HP:0000969', (18, 23))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('meningiomas', 'Disease', 'MESH:D008577', (62, 73))	('meningioma', 'Phenotype', 'HP:0002858', (62, 72))	('low-grade', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('meningiomas', 'Phenotype', 'HP:0002858', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (78, 83))	('brain edema', 'Phenotype', 'HP:0002181', (12, 23))	('brain edema', 'Disease', (12, 23))	('brain edema', 'Disease', 'MESH:D001929', (12, 23))	('meningiomas', 'Disease', (62, 73))
163988	25821815	They concluded that, in spinal meningiomas, high MMP-9 expression seems to be associated with the development of recurrences only in the absence of PR expression.	('associated', 'Reg', (78, 88))	('spinal meningiomas', 'Phenotype', 'HP:0100010', (24, 42))	('high', 'Var', (44, 48))	('PR', 'Gene', '5241', (148, 150))	('MMP-9', 'Gene', (49, 54))	('expression', 'MPA', (55, 65))	('spinal meningiomas', 'Disease', (24, 42))	('meningiomas', 'Phenotype', 'HP:0002858', (31, 42))	('spinal meningiomas', 'Disease', 'MESH:D008577', (24, 42))	('meningioma', 'Phenotype', 'HP:0002858', (31, 41))
164011	25821815	showed that PTBE in intracranial meningiomas has significant influence on prognosis in surgically treated patients in terms of increased risk of morbidity and postoperative complications.	('meningioma', 'Phenotype', 'HP:0002858', (33, 43))	('meningiomas', 'Phenotype', 'HP:0002858', (33, 44))	('intracranial meningiomas', 'Phenotype', 'HP:0100009', (20, 44))	('influence', 'Reg', (61, 70))	('patients', 'Species', '9606', (106, 114))	('intracranial meningioma', 'Phenotype', 'HP:0100009', (20, 43))	('intracranial meningiomas', 'Disease', (20, 44))	('PTBE', 'Var', (12, 16))	('intracranial meningiomas', 'Disease', 'MESH:D008577', (20, 44))
164012	25821815	Similar to our study, they showed that VEGF expression was strongly correlated with PTBE formation, which also affects the outcome in the management of patients with intracranial meningiomas.	('intracranial meningioma', 'Phenotype', 'HP:0100009', (166, 189))	('intracranial meningiomas', 'Disease', 'MESH:D008577', (166, 190))	('PTBE formation', 'Disease', (84, 98))	('VEGF', 'Gene', '7422', (39, 43))	('intracranial meningiomas', 'Disease', (166, 190))	('expression', 'Var', (44, 54))	('meningiomas', 'Phenotype', 'HP:0002858', (179, 190))	('VEGF', 'Gene', (39, 43))	('meningioma', 'Phenotype', 'HP:0002858', (179, 189))	('intracranial meningiomas', 'Phenotype', 'HP:0100009', (166, 190))	('correlated', 'Reg', (68, 78))	('affects', 'Reg', (111, 118))	('patients', 'Species', '9606', (152, 160))
164027	25821815	Treatment outcome was significantly better in patients with low VEGF expression (P < 0.05).	('patients', 'Species', '9606', (46, 54))	('low', 'Var', (60, 63))	('VEGF', 'Gene', '7422', (64, 68))	('VEGF', 'Gene', (64, 68))	('better', 'PosReg', (36, 42))
164029	25821815	The duration of intensive care treatment in the group with PTE (mean 6.85 days) was significantly longer than in the group without PTE (mean 3.68 days) (P = 0.003).	('PTE', 'Chemical', '-', (131, 134))	('PTE', 'Chemical', '-', (59, 62))	('PTE', 'Var', (59, 62))	('longer', 'PosReg', (98, 104))
164031	25821815	PTE in intracranial meningiomas had significant influence on prognosis in surgically treated patients in terms of increased risk of morbidity and postoperative complications.	('intracranial meningiomas', 'Phenotype', 'HP:0100009', (7, 31))	('PTE', 'Chemical', '-', (0, 3))	('patients', 'Species', '9606', (93, 101))	('intracranial meningioma', 'Phenotype', 'HP:0100009', (7, 30))	('meningioma', 'Phenotype', 'HP:0002858', (20, 30))	('PTE', 'Var', (0, 3))	('meningiomas', 'Phenotype', 'HP:0002858', (20, 31))	('intracranial meningiomas', 'Disease', 'MESH:D008577', (7, 31))	('influence', 'Reg', (48, 57))	('intracranial meningiomas', 'Disease', (7, 31))
164045	21139963	Case #1 had a small cell component (primitive neuroectodermal tumor-like areas), higher Ki67, and p53 labeling indices, and a relatively stable karyotype with only minimal single copy losses involving regions: Chr8;pter-30480019, Chr16;pter-29754532, Chr16;56160245-88668979, and Chr19;32848902-qter on retrospective comparative genomic hybridization using formalin-fixed, paraffin-embedded samples.	('Chr19;32848902-qter', 'Var', (280, 299))	('neuroectodermal tumor', 'Disease', (46, 67))	('Chr16;56160245-88668979', 'Var', (251, 274))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Chr16', 'Var', (230, 235))	('pter-29754532', 'Var', (236, 249))	('formalin', 'Chemical', 'MESH:D005557', (357, 365))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (36, 67))	('p53', 'Gene', (98, 101))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (46, 67))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (46, 67))	('p53', 'Gene', '7157', (98, 101))	('paraffin', 'Chemical', 'MESH:D010232', (373, 381))	('pter-30480019', 'Var', (215, 228))
164088	21139963	The neoplastic cells showed a high Ki67 (MIB1) immunohistochemical nuclear labeling index of up to about 20%, but a rather low p53 labeling index of less than 5% (Figure 2L and M, respectively).	('MIB1', 'Gene', '57534', (41, 45))	('low', 'NegReg', (123, 126))	('MIB1', 'Gene', (41, 45))	('Ki67', 'Var', (35, 39))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
164113	21139963	Pediatric high-grade gliomas in children over three years of age have been found to have a higher frequency of TP53 mutations and overexpression (40%), indicating potential existence of two different molecular pathways of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('TP53', 'Gene', '7157', (111, 115))	('children', 'Species', '9606', (32, 40))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('overexpression', 'PosReg', (130, 144))	('TP53', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('gliomas', 'Disease', (21, 28))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
164117	21139963	Loss of chromo some 10, deletion of the p16 gene in 9p21 (often homozygous) amplification of the EGFR locus, and gain of chromosome 7 are among the most common events seen in these tumors.	('p16', 'Gene', (40, 43))	('tumors', 'Disease', (181, 187))	('EGFR', 'Gene', '1956', (97, 101))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('p16', 'Gene', '1029', (40, 43))	('Loss', 'NegReg', (0, 4))	('EGFR', 'Gene', (97, 101))	('gain', 'PosReg', (113, 117))	('deletion', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
164119	21139963	Losses involving the long arm of chromosome 19 are also infrequent and more typically found in anaplastic oligodendroglioma.	('found', 'Reg', (86, 91))	('anaplastic oligodendroglioma', 'Disease', (95, 123))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (95, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('Losses', 'Var', (0, 6))
164120	21139963	In fact, losses involving 8p and 16q are far more typical of medulloblastomas.	('medulloblastomas', 'Disease', (61, 77))	('medulloblastomas', 'Disease', 'MESH:D008527', (61, 77))	('losses', 'Var', (9, 15))
164126	21139963	The spinal cord is less tolerant of radiation, so the radiation dose was restricted to 5040 cGy in both our patients, to avoid the risk of transverse myelitis.	('5040 cGy', 'Var', (87, 95))	('transverse myelitis', 'Disease', 'MESH:D009188', (139, 158))	('patients', 'Species', '9606', (108, 116))	('transverse myelitis', 'Disease', (139, 158))	('myelitis', 'Phenotype', 'HP:0012486', (150, 158))
164289	33363544	The immune-related risk score and clinical information, such as age, sex, World Health Organization (WHO) grade, and isocitrate dehydrogenase 1 (IDH1) mutation, were used to independently validate and develop a prognostic nomogram.	('IDH1', 'Gene', (145, 149))	('IDH1', 'Gene', '3417', (145, 149))	('mutation', 'Var', (151, 159))	('isocitrate dehydrogenase 1', 'Gene', (117, 143))	('isocitrate dehydrogenase 1', 'Gene', '3417', (117, 143))
164290	33363544	The risk score, age, grade, and IDH1 mutation were identified as independent prognostic factors in patients with LGGs.	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('LGGs', 'Disease', (113, 117))	('patients', 'Species', '9606', (99, 107))
164302	33363544	Moreover, the study found that the absence of isocitrate dehydrogenase 1 (IDH1) mutation in LGGs was similar to glioblastoma regarding molecular and clinical characteristics.	('glioblastoma', 'Disease', (112, 124))	('LGGs', 'Gene', (92, 96))	('isocitrate dehydrogenase 1', 'Gene', (46, 72))	('IDH1', 'Gene', (74, 78))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('isocitrate dehydrogenase 1', 'Gene', '3417', (46, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('IDH1', 'Gene', '3417', (74, 78))	('mutation', 'Var', (80, 88))
164303	33363544	IDH mutation, which is considerably associated with improved prognosis, is sporadic in glioblastoma, while it is common in LGGs.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('glioblastoma', 'Disease', (87, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))
164313	33363544	A nomogram that can be utilized to personalize prognosis predictions was constructed based on age, sex, IDH1 mutation, and risk score.	('IDH1', 'Gene', '3417', (104, 108))	('IDH1', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
164318	33363544	The survival curve of each included gene that divided into high expression group and low expression group was mapped by R. In addition, we also downloaded the corresponding clinical information of patients from the TCGA database, including survival time, vital status, sex, age, the emergence of IDH1 mutation, and tumor grade.	('patients', 'Species', '9606', (197, 205))	('mutation', 'Var', (301, 309))	('IDH1', 'Gene', '3417', (296, 300))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('IDH1', 'Gene', (296, 300))	('tumor', 'Disease', (315, 320))
164324	33363544	In addition, the risk scores of the grade II group are lower than the grade III group, as well as that in the IDH1 mutation and IDH1 wild type groups.	('IDH1', 'Gene', '3417', (110, 114))	('IDH1', 'Gene', '3417', (128, 132))	('risk scores', 'MPA', (17, 28))	('lower', 'NegReg', (55, 60))	('mutation', 'Var', (115, 123))	('IDH1', 'Gene', (110, 114))	('IDH1', 'Gene', (128, 132))
164334	33363544	Finally, a personalized predicted nomogram taking risk score combined with age, IDH1 mutation, and WHO grade was formed to predict prognosis.	('IDH1', 'Gene', '3417', (80, 84))	('IDH1', 'Gene', (80, 84))	('taking risk', 'Phenotype', 'HP:0031472', (43, 54))	('mutation', 'Var', (85, 93))
164336	33363544	However, beyond that, mutations in some favorable genes, such as IDH, TP53, and telomerase reverse transcriptase (TERT), are often used for prognostic predictions.	('TERT', 'Gene', '7015', (114, 118))	('IDH', 'Gene', (65, 68))	('TP53', 'Gene', '7157', (70, 74))	('IDH', 'Gene', '3417', (65, 68))	('telomerase reverse transcriptase', 'Gene', (80, 112))	('TP53', 'Gene', (70, 74))	('telomerase reverse transcriptase', 'Gene', '7015', (80, 112))	('mutations', 'Var', (22, 31))	('TERT', 'Gene', (114, 118))
164337	33363544	TP53 mutations seem to have a critical effect on altering the survival time of tumor patients, but there was no similar effect of TP53 mutations in LGG from our survival analysis as shown in  Figure 1A .	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', (79, 84))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
164340	33363544	In the current study, we found that older age, WHO grade III and IDH1 mutation absence were independent factors for poor outcomes in the univariate analysis as well as in the multivariate analysis.	('mutation', 'Var', (70, 78))	('IDH1', 'Gene', (65, 69))	('absence', 'NegReg', (79, 86))	('IDH1', 'Gene', '3417', (65, 69))
164342	33363544	The IDH1 mutation was the only protective factor, and the risk of patients with this mutation was 0.464 times that of the patients without this mutation ( Figure 3B ).	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('mutation', 'Var', (85, 93))	('patients', 'Species', '9606', (122, 130))	('IDH1', 'Gene', (4, 8))	('patients', 'Species', '9606', (66, 74))
164343	33363544	Similar results regarding older age and IDH1 mutation were put forward by Jones et al.. A multivariate analysis from  Figure 3B  indicated that grade III has been shown to lead to an elevated risk when compared with grade II.	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (40, 44))	('grade III', 'Var', (144, 153))
164348	33363544	Moreover, the risk score was higher in the grade III group and the IDH1 mutation group, representing a poor prognosis.	('higher', 'PosReg', (29, 35))	('grade III', 'Var', (43, 52))	('IDH1', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (67, 71))	('mutation', 'Var', (72, 80))	('risk score', 'MPA', (14, 24))
164365	33363544	Furthermore, we used the IDH1/2 mutation for the IDH1 mutation when validating in CGGA, which may lead to an imprecise validation.	('mutation', 'Var', (54, 62))	('IDH1', 'Gene', '3417', (49, 53))	('CGGA', 'Disease', (82, 86))	('IDH1', 'Gene', (25, 29))	('IDH1', 'Gene', (49, 53))	('IDH1', 'Gene', '3417', (25, 29))
164366	33363544	However, the incidence of IDH2 mutations in LGG is scarce; it was only 3.95% in TCGA, which can be neglected when validating the model.	('IDH2', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('TCGA', 'Disease', (80, 84))	('IDH2', 'Gene', '3418', (26, 30))
164382	31907037	According to the 2016 WHO classification of central nervous system (CNS) tumors, the diffuse gliomas are mainly divided into five subtypes based on the mutation status of isocitrate dehydrogenase (IDH) and Chromosome 1p/19q status, namely low-grade gliomas (LGG) with IDH-mutant and 1p/19q-intact subtype, IDH-mutant and 1p/19q-codeleted subtype, LGG with IDH-wildtype subtype, glioblastoma (GBM) with IDH-mutant subtype, and GBM with IDH-wildtype subtype.	('gliomas', 'Disease', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GBM', 'Disease', (392, 395))	('GBM', 'Phenotype', 'HP:0012174', (426, 429))	('1p/19q-codeleted', 'Var', (321, 337))	('IDH', 'Gene', '3417', (306, 309))	('glioblastoma', 'Disease', 'MESH:D005909', (378, 390))	('isocitrate dehydrogenase', 'Gene', '3417', (171, 195))	('GBM', 'Disease', 'MESH:D005909', (392, 395))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Disease', (249, 256))	('glioblastoma', 'Disease', (378, 390))	('IDH', 'Gene', (197, 200))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('GBM', 'Phenotype', 'HP:0012174', (392, 395))	('IDH', 'Gene', (435, 438))	('glioblastoma', 'Phenotype', 'HP:0012174', (378, 390))	('IDH', 'Gene', (402, 405))	('IDH', 'Gene', (356, 359))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH', 'Gene', (268, 271))	('LGG', 'Disease', (347, 350))	('gliomas', 'Disease', 'MESH:D005910', (249, 256))	('isocitrate dehydrogenase', 'Gene', (171, 195))	('IDH', 'Gene', '3417', (197, 200))	('IDH', 'Gene', '3417', (435, 438))	('GBM', 'Disease', (426, 429))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('GBM', 'Disease', 'MESH:D005909', (426, 429))	('IDH', 'Gene', '3417', (402, 405))	('central nervous system (CNS) tumors', 'Disease', 'MESH:D016543', (44, 79))	('IDH', 'Gene', '3417', (356, 359))	('gliomas', 'Phenotype', 'HP:0009733', (249, 256))	('IDH', 'Gene', (306, 309))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('IDH', 'Gene', '3417', (268, 271))
164415	31907037	We then established a signature for glioma patients based on the gene expression levels as follows: signature risk score = (- 0.143 x ATL1 expression) + (- 0.094 x GRIA3 expression) + (0.171 x HPX expression) + (- 0.305 x IL17D expression) + (- 0.132 x KLHDC1 expression) + (- 0.096 x NCAM2 expression) + (- 0.124 x TRIM67 expression).	('NCAM2', 'Gene', (285, 290))	('GRIA3', 'Gene', (164, 169))	('NCAM2', 'Gene', '4685', (285, 290))	('ATL1', 'Gene', '51062', (134, 138))	('GRIA3', 'Gene', '2892', (164, 169))	('patients', 'Species', '9606', (43, 51))	('HPX', 'Gene', '3263', (193, 196))	('glioma', 'Disease', (36, 42))	('- 0.143', 'Var', (124, 131))	('HPX', 'Gene', (193, 196))	('TRIM67', 'Gene', (316, 322))	('IL17D', 'Gene', (222, 227))	('ATL1', 'Gene', (134, 138))	('IL17D', 'Gene', '53342', (222, 227))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('TRIM67', 'Gene', '440730', (316, 322))
164418	31907037	We calculated the risk score of each patient by the formula and further detected its value in patients stratified by grade, subtype, MGMT promoter, IDH and 1p/19q status.	('patients', 'Species', '9606', (94, 102))	('patient', 'Species', '9606', (37, 44))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', '3417', (148, 151))	('MGMT', 'Gene', '4255', (133, 137))	('patient', 'Species', '9606', (94, 101))	('MGMT', 'Gene', (133, 137))	('1p/19q status', 'Var', (156, 169))
164427	31907037	As shown in the results, risk score, age, WHO grade, IDH mutation status, MGMT promoter methylation status, 1p/19q deletion status and radiotherapy were significantly associated with patients' survival in CGGA dataset (Fig.	('associated with', 'Reg', (167, 182))	('MGMT', 'Gene', (74, 78))	('MGMT', 'Gene', '4255', (74, 78))	('IDH', 'Gene', (53, 56))	('1p/19q deletion status', 'Var', (108, 130))	('IDH', 'Gene', '3417', (53, 56))	('patients', 'Species', '9606', (183, 191))
164437	31907037	Patients with MGMT promoter unmethylation and high risk score had the worst prognosis, while patients with MGMT promoter methylation and low risk score had the best prognosis.	('MGMT', 'Gene', (14, 18))	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('unmethylation', 'Var', (28, 41))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (93, 101))	('MGMT', 'Gene', '4255', (14, 18))
164476	31907037	NCAM2 and five other genes were significantly lower expressed in HCC1954 (drug resistance) than in BT474 (drug sensitivity) cell lines.	('HCC1954', 'CellLine', 'CVCL:1259', (65, 72))	('drug sensitivity', 'Phenotype', 'HP:0020174', (106, 122))	('lower', 'NegReg', (46, 51))	('NCAM2', 'Gene', (0, 5))	('NCAM2', 'Gene', '4685', (0, 5))	('BT474', 'Chemical', 'MESH:C400102', (99, 104))	('HCC1954', 'Var', (65, 72))	('expressed', 'MPA', (52, 61))	('drug resistance', 'Phenotype', 'HP:0020174', (74, 89))
164492	31186720	Therefore, the present study focused on the role of EPAC2 in glioma, and assessed the invasiveness of human glioma cell lines following EPAC2 overexpression.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (108, 114))	('overexpression', 'Var', (142, 156))	('glioma', 'Disease', (61, 67))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('focused', 'Reg', (29, 36))	('EPAC2', 'Gene', (136, 141))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('human', 'Species', '9606', (102, 107))
164503	31186720	Their pathogenesis has been suggested to be a result of the triggering of high secretion of proto-oncogenes and/or deletions, as well as inactivation of cancer suppressor genes, triggering idiosyncrasies in cell signaling transmission pathways, modification of the cell cycle, delay of life cycle, and apoptosis, which results in aggressive cell proliferation and malignant alterations.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('delay', 'CPA', (277, 282))	('inactivation', 'Var', (137, 149))	('modification', 'Reg', (245, 257))	('aggressive cell proliferation', 'CPA', (330, 359))	('delay of life', 'Phenotype', 'HP:0001263', (277, 290))	('cancer', 'Disease', (153, 159))	('triggering', 'Reg', (178, 188))	('cell cycle', 'CPA', (265, 275))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('secretion', 'MPA', (79, 88))	('apoptosis', 'CPA', (302, 311))	('cell signaling transmission pathways', 'Pathway', (207, 243))	('malignant alterations', 'CPA', (364, 385))	('deletions', 'Var', (115, 124))
164560	31186720	Relative protein expression levels of EPAC2 were elevated in cells transfected with EPAC2 overexpression plasmid compared with the plasmid control U251 cells (Fig.	('EPAC2', 'Gene', (38, 43))	('overexpression plasmid', 'Var', (90, 112))	('plasmid', 'Var', (105, 112))	('EPAC2', 'Gene', (84, 89))	('Relative protein expression levels', 'MPA', (0, 34))	('elevated', 'PosReg', (49, 57))	('U251', 'CellLine', 'CVCL:0021', (147, 151))
164561	31186720	Additionally, in U87 cell lines, relative EPAC2 expression was elevated in cells transfected with EPAC2 overexpression plasmid compared with the normal control and plasmid control cells (Fig.	('EPAC2', 'Gene', (42, 47))	('expression', 'MPA', (48, 58))	('plasmid', 'Var', (119, 126))	('EPAC2', 'Gene', (98, 103))	('U87', 'Gene', (17, 20))	('U87', 'Gene', '641648', (17, 20))	('overexpression', 'PosReg', (104, 118))	('elevated', 'PosReg', (63, 71))
164562	31186720	MMP-2 expression was relatively low in cells transfected with EPAC2 overexpression plasmid compared with the normal control and plasmid control U251 cells (Fig.	('low', 'NegReg', (32, 35))	('plasmid', 'Var', (83, 90))	('MMP-2', 'Gene', (0, 5))	('U251', 'CellLine', 'CVCL:0021', (144, 148))	('expression', 'MPA', (6, 16))	('EPAC2', 'Gene', (62, 67))	('overexpression plasmid', 'Var', (68, 90))
164563	31186720	Additionally, in U87 cells, MMP-2 expression was relatively low in cells transfected with EPAC2 overexpression plasmid compared with the normal control and plasmid control cells (Fig.	('plasmid', 'Var', (111, 118))	('expression', 'MPA', (34, 44))	('low', 'NegReg', (60, 63))	('MMP-2', 'Gene', (28, 33))	('EPAC2', 'Gene', (90, 95))	('overexpression', 'PosReg', (96, 110))	('U87', 'Gene', (17, 20))	('U87', 'Gene', '641648', (17, 20))
164564	31186720	This suggested that in U251 and U87 cell lines, EPAC2 overexpression may lead to decreased MMP-2 protein levels via the EPAC2/MMP-2 signaling pathway.	('decreased', 'NegReg', (81, 90))	('EPAC2', 'Gene', (48, 53))	('U87', 'Gene', (32, 35))	('MMP-2 protein levels', 'MPA', (91, 111))	('U87', 'Gene', '641648', (32, 35))	('overexpression', 'Var', (54, 68))	('U251', 'CellLine', 'CVCL:0021', (23, 27))
164581	31186720	The present study demonstrated that, in U251 and U87 cell lines, MMP-2 expression was decreased following EPAC2 overexpression plasmid transfection compared with the normal control and plasmid control cells.	('expression', 'MPA', (71, 81))	('MMP-2', 'Gene', (65, 70))	('U87', 'Gene', '641648', (49, 52))	('overexpression', 'PosReg', (112, 126))	('decreased', 'NegReg', (86, 95))	('plasmid', 'Var', (127, 134))	('U251', 'CellLine', 'CVCL:0021', (40, 44))	('transfection', 'Var', (135, 147))	('U87', 'Gene', (49, 52))	('EPAC2', 'Gene', (106, 111))
164592	31186720	Furthermore, in U251 and U87 cell lines, MMP-2 expression was relatively low following EPAC2 overexpression plasmid transfection.	('U87', 'Gene', '641648', (25, 28))	('EPAC2', 'Gene', (87, 92))	('transfection', 'Var', (116, 128))	('overexpression', 'PosReg', (93, 107))	('MMP-2', 'Gene', (41, 46))	('U251', 'CellLine', 'CVCL:0021', (16, 20))	('U87', 'Gene', (25, 28))	('low', 'NegReg', (73, 76))	('expression', 'MPA', (47, 57))
164603	30654849	Epigenetic mechanisms are deregulated in GBM as a result of aberrant expression/activity of epigenetic enzymes, including histone deacetylases (HDAC) which remove acetyl groups from histones regulating chromatin accessibility.	('acetyl groups', 'MPA', (163, 176))	('HDAC', 'Gene', '9734', (144, 148))	('expression/activity', 'MPA', (69, 88))	('deregulated', 'Reg', (26, 37))	('Epigenetic', 'Pathway', (0, 10))	('HDAC', 'Gene', (144, 148))	('aberrant', 'Var', (60, 68))
164616	30654849	In particular, alterations in sequence and/or expression of gene coding for HDACs may contribute to GBM pathogenesis and progression.	('GBM', 'Disease', (100, 103))	('HDAC', 'Gene', (76, 80))	('HDAC', 'Gene', '9734', (76, 80))	('alterations', 'Var', (15, 26))	('contribute', 'Reg', (86, 96))	('expression', 'MPA', (46, 56))
164620	30654849	In particular, we tested mocetinostat (1, MGCD0103) and compound 106 (2) as prototypes of HDAC1/2 and HDAC3 selective inhibitors, respectively; MC1746 (3) and MC2129 (4), belonging to the class of the uracil-based hydroxyamides (UBHAs) as new class I/IIb selective HDACi; and the FDA-approved SAHA (5, vorinostat) as reference pan-HDACi (Fig.	('HDAC', 'Gene', '9734', (265, 269))	('HDAC', 'Gene', '9734', (90, 94))	('HDAC1/2', 'Gene', (90, 97))	('uracil-based hydroxyamides', 'Chemical', '-', (201, 227))	('HDAC', 'Gene', (265, 269))	('HDAC', 'Gene', (90, 94))	('vorinostat', 'Chemical', 'MESH:D000077337', (302, 312))	('HDAC3', 'Gene', '8841', (102, 107))	('HDAC', 'Gene', '9734', (102, 106))	('MGCD0103', 'Chemical', 'MESH:C523184', (42, 50))	('HDAC', 'Gene', '9734', (331, 335))	('MC1746', 'Var', (144, 150))	('MC1746', 'Chemical', '-', (144, 150))	('HDAC', 'Gene', (102, 106))	('HDAC1/2', 'Gene', '3065;3066', (90, 97))	('UBHAs', 'Chemical', '-', (229, 234))	('MC2129', 'CellLine', 'CVCL:K891', (159, 165))	('mocetinostat', 'Chemical', 'MESH:C523184', (25, 37))	('HDAC', 'Gene', (331, 335))	('HDAC3', 'Gene', (102, 107))	('SAHA', 'Chemical', 'MESH:D000077337', (293, 297))
164631	30654849	Knockdown of HDAC 2 significantly reduced cell proliferation of U-87 MG cells and knockdown of HDAC 1 affected proliferation of LN18 cells.	('cell proliferation of U-87 MG cells', 'CPA', (42, 77))	('reduced', 'NegReg', (34, 41))	('HDAC 2', 'Gene', (13, 19))	('proliferation', 'CPA', (111, 124))	('knockdown', 'Var', (82, 91))	('HDAC 1', 'Gene', '3065', (95, 101))	('HDAC 2', 'Gene', '3066', (13, 19))	('HDAC 1', 'Gene', (95, 101))
164632	30654849	The effects of knockdown of both HDACs were not additive (Fig.	('HDAC', 'Gene', (33, 37))	('knockdown', 'Var', (15, 24))	('HDAC', 'Gene', '9734', (33, 37))
164657	30654849	Alterations in sequence and/or expression of HDAC coding genes may contribute to GBM pathogenesis and progression.	('Alterations', 'Var', (0, 11))	('expression', 'MPA', (31, 41))	('GBM', 'Disease', (81, 84))	('HDAC', 'Gene', (45, 49))	('HDAC', 'Gene', '9734', (45, 49))	('contribute', 'Reg', (67, 77))
164666	30654849	In particular, biochemical assays established that mocetinostat (1) is a HDAC 1/2 inhibitor, compound 106 (2) specifically inhibits HDAC 3, and MC1746 (3) and MC2129 (4) are two UBHA inhibitors selective against class I/IIb HDACs (Additional file 5: Table S1).	('mocetinostat', 'Var', (51, 63))	('HDAC', 'Gene', (73, 77))	('mocetinostat', 'Chemical', 'MESH:C523184', (51, 63))	('HDAC', 'Gene', '9734', (224, 228))	('HDAC', 'Gene', '9734', (73, 77))	('HDAC', 'Gene', (132, 136))	('MC1746', 'Var', (144, 150))	('MC1746', 'Chemical', '-', (144, 150))	('HDAC', 'Gene', '9734', (132, 136))	('HDAC 3', 'Gene', '8841', (132, 138))	('HDAC 3', 'Gene', (132, 138))	('UBHA', 'Chemical', '-', (178, 182))	('HDAC 1/2', 'Gene', '3065;3066', (73, 81))	('inhibits', 'NegReg', (123, 131))	('HDAC 1/2', 'Gene', (73, 81))	('HDAC', 'Gene', (224, 228))	('MC2129', 'CellLine', 'CVCL:K891', (159, 165))
164668	30654849	While all tested HDACi affected glioma cell proliferation, mocetinostat (1) and MC2129 (4) displayed the strongest cytotoxic and antiproliferative effects, higher than those showed by the reference SAHA (5), and such effects were substantially maintained even 3 days after drug removal (long-lasting changes), so providing support to the usefulness of class I HDAC inhibition in GBM cells.	('mocetinostat', 'Chemical', 'MESH:C523184', (59, 71))	('MC2129', 'Var', (80, 86))	('higher', 'PosReg', (156, 162))	('affected', 'Reg', (23, 31))	('SAHA', 'Chemical', 'MESH:D000077337', (198, 202))	('cytotoxic', 'CPA', (115, 124))	('glioma', 'Disease', (32, 38))	('antiproliferative effects', 'CPA', (129, 154))	('HDAC', 'Gene', '9734', (360, 364))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('HDAC', 'Gene', (17, 21))	('HDAC', 'Gene', (360, 364))	('MC2129', 'CellLine', 'CVCL:K891', (80, 86))	('HDAC', 'Gene', '9734', (17, 21))	('mocetinostat', 'Var', (59, 71))
164671	30654849	It is worthy to note that although all compounds induced histone H4 hyperacetylation in both cell lines, different cellular responses to HDACi were observed in LN18 and U-87 MG glioma cells.	('MG glioma', 'Disease', (174, 183))	('induced', 'Reg', (49, 56))	('histone H4 hyperacetylation', 'MPA', (57, 84))	('HDAC', 'Gene', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('HDAC', 'Gene', '9734', (137, 141))	('MG glioma', 'Disease', 'MESH:D005910', (174, 183))	('LN18', 'Var', (160, 164))
164675	30654849	In fact, Lee and coworkers showed that the tumor suppressor gene PTEN (phosphatase and tensin homolog), mutated in 36% of GBMs, is able to switch the cell fate of glioma cells exposed to ionizing radiation between apoptosis and senescence, with PTEN-proficient LN18 cells that enter apoptosis, while PTEN-deficient U-87 MG cells, with high levels of both AKT activation and intracellular reactive oxygen species (ROS), undergo senescence after exposure to ionizing radiation.	('glioma', 'Disease', (163, 169))	('PTEN', 'Gene', (300, 304))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('ROS', 'Chemical', 'MESH:D017382', (413, 416))	('PTEN', 'Gene', '5728', (245, 249))	('tumor', 'Disease', (43, 48))	('PTEN', 'Gene', '5728', (300, 304))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('senescence', 'CPA', (427, 437))	('AKT', 'Gene', (355, 358))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (388, 411))	('PTEN', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('undergo', 'Reg', (419, 426))	('AKT', 'Gene', '207', (355, 358))	('mutated', 'Var', (104, 111))	('PTEN', 'Gene', '5728', (65, 69))	('PTEN', 'Gene', (245, 249))
164685	30654849	Mocetinostat (1) and MC2129 (4) induced profound changes in LN18 glioma CSC-enriched spheres: rapid sphere disintegration, DNA damage response with upregulation of phosphoryled H2AX and p21WAF1 levels.	('rapid sphere disintegration', 'CPA', (94, 121))	('DNA damage response', 'CPA', (123, 142))	('glioma', 'Disease', (65, 71))	('upregulation', 'PosReg', (148, 160))	('H2AX', 'Gene', '3014', (177, 181))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('phosphoryled', 'MPA', (164, 176))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('p21WAF1 levels', 'MPA', (186, 200))	('H2AX', 'Gene', (177, 181))	('changes', 'Reg', (49, 56))	('MC2129', 'CellLine', 'CVCL:K891', (21, 27))	('Mocetinostat', 'Var', (0, 12))
164709	30654849	Antibodies recognizing HDAC 1 (#06-720 diluted 1:1000), HDAC 2 (#05-814 diluted 1:1000), acetylated histone H3 (#06-599 diluted 1:10000), and acetylated histone H4 (#06-866 diluted 1:5000) were all purchased from Merck Millipore.	('#05-814', 'Var', (64, 71))	('HDAC 1', 'Gene', '3065', (23, 29))	('HDAC 2', 'Gene', (56, 62))	('#06-599', 'Var', (112, 119))	('HDAC 2', 'Gene', '3066', (56, 62))	('HDAC 1', 'Gene', (23, 29))	('#06-720', 'Var', (31, 38))
164718	30654849	LN18 or U87 cells were cultured in the presence of HDACi for 24 or 48 h after gene silencing.	('gene silencing', 'Var', (78, 92))	('HDAC', 'Gene', (51, 55))	('U87', 'CellLine', 'CVCL:0022', (8, 11))	('HDAC', 'Gene', '9734', (51, 55))
164755	30407923	Inhibition of fatty acid beta-oxidation could reduce the proliferation of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('reduce', 'NegReg', (46, 52))	('fatty acid', 'Chemical', 'MESH:D005227', (14, 24))	('glioma', 'Disease', (74, 80))	('fatty acid beta-oxidation', 'Enzyme', (14, 39))	('Inhibition', 'Var', (0, 10))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
164773	30407923	Patients in cluster 1 were mainly younger, lower grade, proneural or neural subtype, IDH mutational and MGMT promoter methylated (P<0.001), while cluster 2 represented older, high grade, classical or mesenchymal subtype, IDH wild type, and MGMT promoter unmethylated (P<0.001) (Table 1).	('MGMT', 'Gene', (240, 244))	('MGMT', 'Gene', (104, 108))	('IDH', 'Gene', '3417', (85, 88))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', (221, 224))	('mutational', 'Var', (89, 99))	('methylated', 'Var', (118, 128))	('IDH', 'Gene', '3417', (221, 224))	('IDH', 'Gene', (85, 88))	('MGMT', 'Gene', '4255', (240, 244))	('MGMT', 'Gene', '4255', (104, 108))
164822	30115812	Identification of IDH-mutant gliomas by a prognostic signature according to gene expression profiling Background: Isocitrate dehydrogenase (IDH) mutations are the most common genetic aberrations in gliomagenesis.	('Isocitrate dehydrogenase', 'Gene', '3417', (114, 138))	('glioma', 'Disease', (29, 35))	('IDH', 'Gene', '3417', (140, 143))	('IDH', 'Gene', (18, 21))	('mutations', 'Var', (145, 154))	('glioma', 'Disease', (198, 204))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('IDH', 'Gene', '3417', (18, 21))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('Isocitrate dehydrogenase', 'Gene', (114, 138))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('IDH', 'Gene', (140, 143))
164832	30115812	According to the 2016 World Health Organization (WHO) Classification based on the mutation status of isocitrate dehydrogenase (IDH) and Chromosome 1p/19q status, the diffuse gliomas are mainly divided into five subtypes, Lower grade gliomas (LGG) with IDH-mutant and 1p/19q-codeleted subtype, LGG with IDH-mutant and 1p/19q-intact subtype, LGG with IDH-wildtype subtype, GBM with IDH-mutant subtype, and GBM with IDH-wildtype subtype.	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('isocitrate dehydrogenase', 'Gene', '3417', (101, 125))	('IDH', 'Gene', (413, 416))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('gliomas', 'Disease', (233, 240))	('IDH', 'Gene', (349, 352))	('IDH', 'Gene', (380, 383))	('IDH', 'Gene', (127, 130))	('mutation', 'Var', (82, 90))	('IDH', 'Gene', (302, 305))	('IDH', 'Gene', '3417', (413, 416))	('IDH', 'Gene', (252, 255))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('IDH', 'Gene', '3417', (380, 383))	('IDH', 'Gene', '3417', (349, 352))	('IDH', 'Gene', '3417', (127, 130))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('isocitrate dehydrogenase', 'Gene', (101, 125))	('IDH', 'Gene', '3417', (302, 305))	('gliomas', 'Disease', (174, 181))	('IDH', 'Gene', '3417', (252, 255))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))
164834	30115812	IDH1/2 mutations specifically change the catalytic activity of enzyme, and directly catalyze alpha-ketoglutarate (alpha-KG) to R-2-hydroxyglutarate (R-2-HG).	('change', 'Reg', (30, 36))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('R-2-hydroxyglutarate', 'Chemical', '-', (127, 147))	('catalytic activity', 'MPA', (41, 59))	('IDH1/2', 'Gene', (0, 6))	('alpha-KG', 'Chemical', 'MESH:D007656', (114, 122))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (93, 112))	('mutations', 'Var', (7, 16))
164836	30115812	IDH mutations have been discovered in plenty of tumors, covering adult acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, pheochromocytoma, etc.	('tumors', 'Disease', (48, 54))	('acute myeloid leukemia', 'Disease', (71, 93))	('pheochromocytoma', 'Disease', (134, 150))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 132))	('intrahepatic cholangiocarcinoma', 'Disease', (101, 132))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (134, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (114, 132))	('IDH', 'Gene', (0, 3))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('AML', 'Disease', (95, 98))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (71, 93))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (71, 93))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (77, 93))	('IDH', 'Gene', '3417', (0, 3))	('discovered', 'Reg', (24, 34))	('mutations', 'Var', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('pheochromocytoma', 'Disease', 'MESH:D010673', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
164837	30115812	Meanwhile, IDH mutations are present in nearly 80% of grade II~ III gliomas and secondary glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('II glioma', 'Disease', 'MESH:D005910', (65, 74))	('glioblastomas', 'Disease', (90, 103))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('II glioma', 'Disease', (65, 74))	('mutations', 'Var', (15, 24))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('glioblastomas', 'Phenotype', 'HP:0012174', (90, 103))	('glioblastomas', 'Disease', 'MESH:D005909', (90, 103))
164838	30115812	IDH mutations are stable markers to classify gliomas in progression and prognosis, and patients possessing IDH mutations have a significantly longer overall survival (OS) and progression free survival (PFS) in LGG and GBM.	('mutations', 'Var', (111, 120))	('IDH', 'Gene', (0, 3))	('progression free survival', 'CPA', (175, 200))	('LGG', 'Disease', (210, 213))	('IDH', 'Gene', '3417', (0, 3))	('overall', 'MPA', (149, 156))	('IDH', 'Gene', (107, 110))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH', 'Gene', '3417', (107, 110))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('OS', 'Chemical', '-', (167, 169))	('longer', 'PosReg', (142, 148))	('patients', 'Species', '9606', (87, 95))	('GBM', 'Disease', (218, 221))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
164841	30115812	For example, IDH-mutant patients with 1p/19q co-deletion lived longer significantly and ATRX mutation combined with IDH mutation was used to re-classify patients with astrocytic tumors.	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', '3417', (116, 119))	('patients', 'Species', '9606', (153, 161))	('1p/19q co-deletion', 'Var', (38, 56))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('ATRX', 'Gene', '546', (88, 92))	('astrocytic tumors', 'Disease', (167, 184))	('patients', 'Species', '9606', (24, 32))	('IDH', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('astrocytic tumors', 'Disease', 'MESH:D001254', (167, 184))	('ATRX', 'Gene', (88, 92))
164870	30115812	However, the time-dependent AUC of 2 years and 3 years in patients with IDH-wildtype glioma (0.6880, 0.8218 in CGGA ; 0.6997, 0.7747 in TCGA; Figure S2A and B) were not as well as patients with IDH-mutant glioma.	('0.6880', 'Var', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('IDH-wildtype glioma', 'Disease', 'MESH:D005910', (72, 91))	('glioma', 'Disease', (205, 211))	('patients', 'Species', '9606', (180, 188))	('0.7747', 'Var', (126, 132))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('IDH', 'Gene', (194, 197))	('patients', 'Species', '9606', (58, 66))	('IDH', 'Gene', '3417', (194, 197))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('IDH-wildtype glioma', 'Disease', (72, 91))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('0.6997', 'Var', (118, 124))
164890	30115812	Aberrant expression and carcinogenicity of HOX genes have been found in many solid tumors, such as colon, prostate, lung, bladder, ovarian, kidney, breast, etc.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('solid tumors', 'Disease', (77, 89))	('colon', 'Disease', (99, 104))	('Aberrant', 'Var', (0, 8))	('HOX genes', 'Gene', (43, 52))	('kidney', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('breast', 'Disease', (148, 154))	('prostate', 'Disease', (106, 114))	('ovarian', 'Disease', (131, 138))	('solid tumors', 'Disease', 'MESH:D009369', (77, 89))	('bladder', 'Disease', (122, 129))	('colon', 'Disease', 'MESH:D015179', (99, 104))	('found', 'Reg', (63, 68))	('lung', 'Disease', (116, 120))
164905	30115812	Chromosome 1p/19q co-deletion was detected in 64 (38%) patients in CGGA and 151 (40%) patients in TCGA.	('detected', 'Reg', (34, 42))	('patients', 'Species', '9606', (55, 63))	('Chromosome', 'Var', (0, 10))	('patients', 'Species', '9606', (86, 94))
164910	30115812	In CGGA dataset, pyrosequencing technique is commonly used to detect IDH1/2 mutation.	('mutation', 'Var', (76, 84))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('IDH1/2', 'Gene', (69, 75))
164925	23219067	P53 upregulation, BRAF-KIAA gene rearrangement, and IDH1 R132H mutation typically associated with low-grade astrocytic neoplasms were absent.	('IDH1', 'Gene', '3417', (52, 56))	('astrocytic neoplasms', 'Disease', 'MESH:D001254', (108, 128))	('men', 'Species', '9606', (42, 45))	('astrocytic neoplasms', 'Phenotype', 'HP:0009592', (108, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('P53', 'Gene', (0, 3))	('R132H', 'Var', (57, 62))	('BRAF', 'Gene', '673', (18, 22))	('neoplasm', 'Phenotype', 'HP:0002664', (119, 127))	('P53', 'Gene', '7157', (0, 3))	('astrocytic neoplasms', 'Disease', (108, 128))	('R132H', 'Mutation', 'rs121913500', (57, 62))	('upregulation', 'PosReg', (4, 16))	('BRAF', 'Gene', (18, 22))	('IDH1', 'Gene', (52, 56))
164937	23219067	This Study was Performed Under the Auspices of the Massachusetts Eye and Ear Infirmary Institutional Review Board (IRB): Examination of Archived Ocular Tissues for Research Studies on Ocular Structure, Function, Physiology and Association with Various Ocular Diseases, 196320-3; and the Emory Eye Center, Emory University School of Medicine IRB: Massive Retinal Gliosis, 00052749; and was conducted in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act and in adherence to the Declaration of Helsinki and all federal and state laws.	('Ocular Diseases', 'Disease', (252, 267))	('Ocular Diseases', 'Disease', 'MESH:D005128', (252, 267))	('00052749', 'Var', (371, 379))	('Retinal Gliosis', 'Disease', 'MESH:D012173', (354, 369))	('Gliosis', 'Phenotype', 'HP:0002171', (362, 369))	('Retinal Gliosis', 'Disease', (354, 369))	('Ocular Diseases', 'Phenotype', 'HP:0000478', (252, 267))
164945	23219067	The methodological characterization of IDH1, R132H, and the application of p53 to astrocytomas have also been previously described.	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('astrocytomas', 'Disease', (82, 94))	('R132H', 'Var', (45, 50))	('IDH1', 'Gene', (39, 43))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('IDH1', 'Gene', '3417', (39, 43))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('astrocytomas', 'Disease', 'MESH:D001254', (82, 94))
164949	23219067	Pyrosequencing for the activating BRAF V600E mutation was performed using a PyroMark W96d (Qiagen, Valencia, California, USA).	('V600E', 'Mutation', 'rs113488022', (39, 44))	('Valencia, California', 'Disease', 'MESH:D004670', (99, 119))	('V600E', 'Var', (39, 44))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))	('activating', 'PosReg', (23, 33))
164975	23219067	Antibodies for glial fibrillary acidic protein intensely and positively immunostained all lesions and disclosed very elongated cellular processes resulting in hair-like (pilocytic) bipolar cells (Figure 2, Bottom left).	('resulting in', 'Reg', (146, 158))	('Antibodies', 'Var', (0, 10))	('glial fibrillary acidic protein', 'Gene', (15, 46))	('glial fibrillary acidic protein', 'Gene', '2670', (15, 46))
164999	23219067	Xanthoma cells were also found in this case in the retina more posteriorly, where a break in the fibrous subretinal plaque allowed a choroidal vessel to contact the outer retina (Figure 4, Bottom right).	('break', 'Var', (84, 89))	('Xanthoma', 'Disease', 'MESH:D014973', (0, 8))	('Xanthoma', 'Disease', (0, 8))	('Xanthoma', 'Phenotype', 'HP:0001114', (0, 8))
165008	23219067	Immunohistochemical staining for the most frequent form of isocitrate dehydrogenase-1 (IDH1) mutant protein, corresponding to the R132H mutation and noted in 70%-80% of infiltrating forms of low-grade glial neoplasms, did not demonstrate immunoreactivity in any of the cases.	('R132H', 'Mutation', 'rs121913500', (130, 135))	('isocitrate dehydrogenase-1', 'Gene', (59, 85))	('isocitrate dehydrogenase-1', 'Gene', '3417', (59, 85))	('IDH1', 'Gene', '3417', (87, 91))	('neoplasms', 'Phenotype', 'HP:0002664', (207, 216))	('mutant', 'Var', (93, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (207, 215))	('glial neoplasms', 'Disease', (201, 216))	('IDH1', 'Gene', (87, 91))	('R132H', 'Var', (130, 135))	('glial neoplasms', 'Disease', 'MESH:D005910', (201, 216))
165011	23219067	Pyrosequencing of the BRAF gene for the activating V600E mutation, a frequent mutation in low-grade gliomas of various histopathologies, revealed no mutations in any of the 4 cases tested.	('activating', 'PosReg', (40, 50))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('BRAF', 'Gene', '673', (22, 26))	('V600E', 'Var', (51, 56))	('BRAF', 'Gene', (22, 26))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('gliomas', 'Disease', (100, 107))
165082	23219067	Immunohistochemical stains for the mutant form of IDH1 (R132H) and p53 upregulation and overexpression are characteristically positive in CNS low-grade infiltrative astrocytomas, but were negative in our cases.	('R132H', 'Var', (56, 61))	('IDH1', 'Gene', (50, 54))	('overexpression', 'PosReg', (88, 102))	('astrocytomas', 'Disease', 'MESH:D001254', (165, 177))	('R132H', 'Mutation', 'rs121913500', (56, 61))	('IDH1', 'Gene', '3417', (50, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('upregulation', 'PosReg', (71, 83))	('astrocytomas', 'Disease', (165, 177))
165084	23219067	KIAA-BRAF fusions have been detected in a large percentage of cerebellar pilocytic astrocytomas and BRAF mutations are found in a variety of lower-grade gliomas, including pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma.	('ganglioglioma', 'Disease', 'MESH:D018303', (230, 243))	('mutations', 'Var', (105, 114))	('KIAA-BRAF', 'Gene', (0, 9))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('gliomas', 'Disease', (153, 160))	('BRAF', 'Gene', '673', (100, 104))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (195, 224))	('BRAF', 'Gene', (100, 104))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (172, 193))	('BRAF', 'Gene', '673', (5, 9))	('KIAA-BRAF', 'Gene', '673', (0, 9))	('astrocytoma', 'Phenotype', 'HP:0009592', (213, 224))	('ganglioglioma', 'Disease', (230, 243))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('BRAF', 'Gene', (5, 9))	('astrocytoma', 'Phenotype', 'HP:0009592', (182, 193))	('pilocytic astrocytoma', 'Disease', (172, 193))	('found', 'Reg', (119, 124))	('pleomorphic xanthoastrocytoma', 'Disease', (195, 224))	('cerebellar pilocytic astrocytomas', 'Disease', (62, 95))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (73, 94))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('cerebellar pilocytic astrocytomas', 'Disease', 'MESH:D001254', (62, 95))
165086	23219067	High rates of spontaneous mutations of the gene encoding for cytosolic nicotinamide adenine dinucleotide phosphate (NADP+)-dependent IDH1 have been reported in pilocytic astrocytomas.	('NADP+', 'Chemical', 'MESH:D009249', (116, 121))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (71, 114))	('IDH1', 'Gene', (133, 137))	('mutations', 'Var', (26, 35))	('reported', 'Reg', (148, 156))	('pilocytic astrocytomas', 'Disease', (160, 182))	('IDH1', 'Gene', '3417', (133, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (160, 182))
165118	33614513	Due to the critical role of DPP4 in immunometabolism, our results indicate that pharmacological inhibition of DPP4 might provide beneficial therapeutic effects for SARS-CoV-2 treatment together with other strategies in specific tumor patients.	('DPP4', 'Gene', '1803', (110, 114))	('DPP4', 'Gene', '1803', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('patients', 'Species', '9606', (234, 242))	('DPP4', 'Gene', (28, 32))	('tumor', 'Disease', (228, 233))	('DPP4', 'Gene', (110, 114))	('beneficial', 'PosReg', (129, 139))	('pharmacological', 'Var', (80, 95))	('SARS-CoV-2', 'Species', '2697049', (164, 174))
165122	33614513	Cancer patients with defective immunity are especially susceptible to SARS-CoV-2 infection.	('patients', 'Species', '9606', (7, 15))	('defective immunity', 'Var', (21, 39))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (70, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('SARS-CoV-2 infection', 'Disease', (70, 90))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('susceptible', 'Reg', (55, 66))
165133	33614513	Additional DPP4 residues (Q286, I287, N338, V341, and R336) were also predicted to interact with the S1 domain of the spike protein of SARS-CoV-2.	('R336', 'Var', (54, 58))	('SARS-CoV-2', 'Species', '2697049', (135, 145))	('Q286', 'Var', (26, 30))	('interact', 'Interaction', (83, 91))	('DPP4', 'Gene', '1803', (11, 15))	('V341', 'Var', (44, 48))	('spike', 'Gene', (118, 123))	('N338', 'Var', (38, 42))	('spike', 'Gene', '43740568', (118, 123))	('DPP4', 'Gene', (11, 15))	('I287', 'Var', (32, 36))
165205	33614513	The results showed that DPP4 expression significantly correlated with infiltration of CD8+ T cells ( Figure 5A ), CD4+ T cells ( Figure 5B ), Treg ( Figure 5C ), B cells ( Figure 5D ), NK cells ( Figure 5E ), dendritic cells ( Figure 5F ), neutrophils ( Figure 5G ), macrophages ( Figure 5H ), monocytes ( Figure 5I ), and cancer-associated fibroblasts ( Figure 5J ) in pan-cancer patients.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('correlated with', 'Reg', (54, 69))	('infiltration', 'CPA', (70, 82))	('expression', 'Var', (29, 39))	('DPP4', 'Gene', '1803', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('cancer', 'Disease', (323, 329))	('CD4', 'Gene', (114, 117))	('cancer', 'Disease', (374, 380))	('CD8', 'Gene', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('DPP4', 'Gene', (24, 28))	('patients', 'Species', '9606', (381, 389))	('CD8', 'Gene', '925', (86, 89))	('CD4', 'Gene', '920', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))
165224	33614513	Taken together, these data suggested that expression of DPP4 may be closely associated with immune infiltration in specific cancers patients, which might also contribute to the cytokine storm in SARS-CoV-2 infected patients.	('immune infiltration', 'Disease', (92, 111))	('SARS-CoV-2 infected', 'Disease', 'MESH:C000657245', (195, 214))	('patients', 'Species', '9606', (215, 223))	('cytokine storm', 'MPA', (177, 191))	('DPP4', 'Gene', '1803', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('associated', 'Reg', (76, 86))	('expression', 'Var', (42, 52))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('contribute', 'Reg', (159, 169))	('DPP4', 'Gene', (56, 60))	('cancers', 'Disease', (124, 131))	('patients', 'Species', '9606', (132, 140))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('SARS-CoV-2 infected', 'Disease', (195, 214))
165242	33614513	High DPP4 expression indicated a poor prognosis in some specific cancer types, including LUSC, bladder cancer, prostate adenocarcinoma, and brain lower grade glioma, and we found that the unique cancer LUSC was associated with DPP4 expression and prognosis ( Figure 3 ,  Supplementary Table 1 ).	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('DPP4', 'Gene', '1803', (5, 9))	('cancer', 'Disease', (103, 109))	('expression', 'MPA', (232, 242))	('cancer', 'Disease', (65, 71))	('LUSC', 'Phenotype', 'HP:0030359', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('High', 'Var', (0, 4))	('DPP4', 'Gene', '1803', (227, 231))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('DPP4', 'Gene', (5, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cancer', 'Disease', (195, 201))	('prostate adenocarcinoma', 'Disease', (111, 134))	('glioma', 'Disease', (158, 164))	('DPP4', 'Gene', (227, 231))	('associated', 'Reg', (211, 221))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (111, 134))	('LUSC', 'Disease', (89, 93))
165265	33614513	DPP4 inhibitors such as sitagliptin, saxagliptin, and vildagliptin are now in clinical use as antidiabetic drugs and act by prolonging the insulinotropic effect of incretins through glucagonlike peptide-1 and the glucose-dependent insulinotropic polypeptide signaling pathway.	('DPP4', 'Gene', '1803', (0, 4))	('saxagliptin', 'Chemical', 'MESH:C502994', (37, 48))	('prolonging', 'PosReg', (124, 134))	('vildagliptin', 'Chemical', 'MESH:D000077597', (54, 66))	('insulinotropic effect', 'MPA', (139, 160))	('inhibitors', 'Var', (5, 15))	('DPP4', 'Gene', (0, 4))	('glucagonlike peptide-1', 'Gene', '2641', (182, 204))	('sitagliptin', 'Chemical', 'MESH:D000068900', (24, 35))	('glucagonlike peptide-1', 'Gene', (182, 204))	('glucose-dependent insulinotropic polypeptide', 'Gene', '2695', (213, 257))	('glucose-dependent insulinotropic polypeptide', 'Gene', (213, 257))
165266	33614513	Recent preclinical studies have further expanded the repertoire for the use of DPP4 inhibitors in the treatment of other metabolic diseases and their consequent complications, which may block the signaling pathway of DPP4 with NFkappaB and matrix metallopeptidase 9 in these patients.	('inhibitors', 'Var', (84, 94))	('DPP4', 'Gene', '1803', (79, 83))	('metabolic diseases', 'Disease', (121, 139))	('block', 'NegReg', (186, 191))	('matrix metallopeptidase 9', 'Gene', (240, 265))	('DPP4', 'Gene', (217, 221))	('metabolic diseases', 'Disease', 'MESH:D008659', (121, 139))	('DPP4', 'Gene', (79, 83))	('NFkappaB', 'Gene', (227, 235))	('patients', 'Species', '9606', (275, 283))	('signaling pathway', 'Pathway', (196, 213))	('NFkappaB', 'Gene', '4790', (227, 235))	('matrix metallopeptidase 9', 'Gene', '4318', (240, 265))	('DPP4', 'Gene', '1803', (217, 221))
165268	33614513	Furthermore, inhibition of DPP4 reveals IL-33-dependent eosinophil-mediated control of tumor growth.	('IL-33', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (87, 92))	('IL-33', 'Gene', '90865', (40, 45))	('DPP4', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('DPP4', 'Gene', '1803', (27, 31))
165276	33614513	As a potential receptor for SARS-CoV-2, DPP4 inhibitors might exhibit beneficial therapeutic effects on SARS-CoV-2 treatment together with other effective strategies ( Figure 8 ).	('DPP4', 'Gene', (40, 44))	('beneficial', 'PosReg', (70, 80))	('SARS-CoV-2', 'Disease', (104, 114))	('SARS-CoV-2', 'Species', '2697049', (104, 114))	('DPP4', 'Gene', '1803', (40, 44))	('inhibitors', 'Var', (45, 55))	('SARS-CoV-2', 'Species', '2697049', (28, 38))
165277	33614513	Animal experiments and clinical trials should be conducted in the future to evaluate whether DPP4 inhibitors have therapeutic potential in preventing or alleviating SARS-CoV-2 infection in obese or specific cancer patients.	('alleviating', 'NegReg', (153, 164))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('patients', 'Species', '9606', (214, 222))	('SARS-CoV-2 infection', 'Disease', (165, 185))	('cancer', 'Disease', (207, 213))	('inhibitors', 'Var', (98, 108))	('DPP4', 'Gene', '1803', (93, 97))	('obese', 'Disease', 'MESH:D009765', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('DPP4', 'Gene', (93, 97))	('obese', 'Disease', (189, 194))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (165, 185))
165289	30362964	In a recent study, utilization of IDH mutation and 1p/19q codeletion, LGGs could be classified into 3 distinct subgroups (IDH wild-type, IDH mutation and 1p/19q codeletion, and IDH mutation and 1p/19q non-codeletion) that capture the biologic characteristics with greater fidelity than does histological class.	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', '3417', (137, 140))	('LGGs', 'Disease', (70, 74))	('1p/19q codeletion', 'Var', (51, 68))	('IDH', 'Gene', (177, 180))	('IDH', 'Gene', '3417', (177, 180))	('1p/19q codeletion', 'Var', (154, 171))	('IDH', 'Gene', (137, 140))
165309	30362964	Notably, recent evidence has supported the hypothesis that radiological manifestations are tightly connected with genetic alterations of the tumor.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('genetic alterations', 'Var', (114, 133))	('tumor', 'Disease', (141, 146))
165344	25120686	The aim of the present study was to investigate the expression of B7-H3 and B7-H1 in the CSF, blood serum and tissues of patients with glioma and their correlation with clinicopathological data.	('glioma', 'Disease', (135, 141))	('B7-H1', 'Gene', (76, 81))	('B7-H3', 'Var', (66, 71))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('patients', 'Species', '9606', (121, 129))
165346	25120686	The expression of B7-H3 and B7-H1 in the CSF, blood serum and tumor samples of the patients with high-grade glioma was found to be higher than that in the patients with low-grade glioma.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('glioma', 'Disease', (108, 114))	('tumor', 'Disease', (62, 67))	('expression', 'MPA', (4, 14))	('B7-H3', 'Var', (18, 23))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('B7-H1', 'Var', (28, 33))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (83, 91))	('glioma', 'Disease', (179, 185))	('higher', 'PosReg', (131, 137))
165365	25120686	The aim of the present study was to evaluate whether patients with glioma have increased levels of B7-H3 and B7-H1 in their CSF, tumor tissue and blood serum and whether this correlates with the glioma grading.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('increased', 'PosReg', (79, 88))	('patients', 'Species', '9606', (53, 61))	('glioma', 'Disease', (67, 73))	('levels', 'MPA', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('B7-H1', 'Var', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('glioma', 'Disease', (195, 201))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('tumor', 'Disease', (129, 134))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (195, 201))	('B7-H3', 'Var', (99, 104))
165403	25120686	The CSF from four patients with moderate traumatic brain injury (GCS score, 9-12) served as a control and demonstrated that the levels of sB7-H3 and sB7-H1 were 0.306+-0.218 and 0.019+-0.003 ng/ml, respectively (Fig.	('traumatic brain injury', 'Disease', (41, 63))	('sB7-H1', 'Chemical', '-', (149, 155))	('sB7-H3', 'Chemical', '-', (138, 144))	('sB7-H1', 'Var', (149, 155))	('traumatic brain injury', 'Disease', 'MESH:D000070642', (41, 63))	('0.019+-0.003 ng/ml', 'Var', (178, 196))	('patients', 'Species', '9606', (18, 26))	('0.306+-0.218', 'Var', (161, 173))
165409	25120686	RT-qPCR analysis revealed that the mean RQ values of B7-H3 and B7-H1 in the glioma tissue of the patients with LGG were 0.610+-0.583 and 0.849+-0.397, respectively, and in the patients with HGG were 7.287+-5.207 and 3.813+-3.350, respectively (Fig.	('patients', 'Species', '9606', (176, 184))	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('B7-H1', 'Var', (63, 68))	('B7-H3', 'Var', (53, 58))	('patients', 'Species', '9606', (97, 105))
165410	25120686	The expression of B7-H3 and B7-H1 in the glioma tissue was found to be significantly correlated with LGG and HGG (P<0.001).	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('expression', 'MPA', (4, 14))	('HGG', 'Disease', (109, 112))	('LGG', 'Disease', (101, 104))	('correlated', 'Reg', (85, 95))	('B7-H1', 'Var', (28, 33))	('glioma', 'Disease', (41, 47))	('B7-H3', 'Protein', (18, 23))
165411	25120686	Furthermore, the average RQ values of B7-H3 and B7-H1 in the moderate traumatic brain injury tissues were 0.173+-0.064 and 0.273+-0.116, respectively.	('traumatic brain injury', 'Disease', 'MESH:D000070642', (70, 92))	('B7-H1', 'Var', (48, 53))	('B7-H3', 'Var', (38, 43))	('traumatic brain injury', 'Disease', (70, 92))
165412	25120686	These findings show that B7-H3 and B7-H1 were expressed at greater levels in the brain glioma tissue compared with the traumatic brain injury tissue.	('brain glioma', 'Disease', (81, 93))	('traumatic brain injury', 'Disease', 'MESH:D000070642', (119, 141))	('greater', 'PosReg', (59, 66))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('brain glioma', 'Disease', 'MESH:C564230', (81, 93))	('traumatic brain injury', 'Disease', (119, 141))	('B7-H3', 'Protein', (25, 30))	('B7-H1', 'Var', (35, 40))
165413	25120686	IHC analysis revealed that the expression of B7-H3 and B7-H1 was found to be correlated with the glioma grade in freshly dissected human glioma tissue, which is consistent with the study by Lemke et al.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioma', 'Disease', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('correlated', 'Reg', (77, 87))	('human', 'Species', '9606', (131, 136))	('B7-H3', 'Var', (45, 50))	('glioma', 'Disease', (137, 143))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('B7-H1', 'Var', (55, 60))
165415	25120686	Furthermore, recent studies have investigated the expression of B7-H3 and B7-H1 in the blood serum of patients with colorectal carcinoma and renal cell carcinoma, as well as in the CSF of patients with bacterial meningitis.	('bacterial meningitis', 'Disease', (202, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('B7-H3', 'Var', (64, 69))	('B7-H1', 'Var', (74, 79))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (141, 161))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (188, 196))	('colorectal carcinoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 161))	('meningitis', 'Phenotype', 'HP:0001287', (212, 222))	('bacterial meningitis', 'Disease', 'MESH:D016920', (202, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
165421	25120686	Furthermore, in the brain tissues of the patients with a moderate brain injury, the expression of sB7-H3 and sB7-H1 was found to be lower than that in the brain tumor tissue of the patients with glioma and was also found to correlate with the glioma grade.	('brain injury', 'Disease', (66, 78))	('patients', 'Species', '9606', (181, 189))	('glioma', 'Disease', (243, 249))	('lower', 'NegReg', (132, 137))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('brain injury', 'Disease', 'MESH:D001927', (66, 78))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('sB7-H1', 'Var', (109, 115))	('sB7-H3', 'Chemical', '-', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('expression', 'MPA', (84, 94))	('brain tumor', 'Phenotype', 'HP:0030692', (155, 166))	('brain tumor', 'Disease', (155, 166))	('brain tumor', 'Disease', 'MESH:D001932', (155, 166))	('glioma', 'Disease', (195, 201))	('sB7-H1', 'Chemical', '-', (109, 115))	('sB7-H3', 'Gene', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
165423	25120686	However, the present study identified no significant difference in the concentrations of sB7-H3 and sB7-H1 in the blood serum of the patients with brain glioma.	('sB7-H1', 'Chemical', '-', (100, 106))	('sB7-H1', 'Var', (100, 106))	('brain glioma', 'Disease', (147, 159))	('patients', 'Species', '9606', (133, 141))	('sB7-H3', 'Var', (89, 95))	('brain glioma', 'Disease', 'MESH:C564230', (147, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('sB7-H3', 'Chemical', '-', (89, 95))
165424	25120686	This may explain why the expression of B7-H3 and B7-H1 may not be as significant in the blood serum of patients with brain glioma compared with that in patients with other tumors.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('brain glioma', 'Disease', 'MESH:C564230', (117, 129))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('brain glioma', 'Disease', (117, 129))	('B7-H1', 'Var', (49, 54))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (152, 160))
165425	25120686	In addition, with regard to the expression of B7-H3 and B7-H1 in the tumor tissue, the results of the present study were similar to those reported by Lemke et al and our previous study, which showed that the expression of B7-H3 and B7-H1 in glioma tissue was correlated with the glioma grade.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glioma', 'Disease', (279, 285))	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('tumor', 'Disease', (69, 74))	('correlated', 'Reg', (259, 269))	('B7-H1', 'Gene', (232, 237))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('B7-H3', 'Var', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('glioma', 'Disease', (241, 247))
165426	25120686	In conclusion, the present study demonstrates that in patients with glioma, the expression of B7-H3 and B7-H1 in CSF and tumor tissues, although not in blood serum, correlates with the glioma grade.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('patients', 'Species', '9606', (54, 62))	('correlates', 'Reg', (165, 175))	('tumor', 'Disease', (121, 126))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('expression', 'MPA', (80, 90))	('glioma', 'Disease', (68, 74))	('B7-H3', 'Gene', (94, 99))	('B7-H1', 'Var', (104, 109))	('glioma', 'Disease', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
165493	22615883	The presence of mutated IDH1 R132H protein showed a trend towards longer survival in the univariate analysis and was entered as a variable in the multivariate model.	('protein', 'Protein', (35, 42))	('mutated', 'Var', (16, 23))	('survival', 'CPA', (73, 81))	('R132H', 'Var', (29, 34))	('IDH1', 'Gene', (24, 28))	('longer', 'PosReg', (66, 72))	('as', 'Chemical', 'MESH:D001151', (125, 127))	('R132H', 'Mutation', 'rs121913500', (29, 34))	('as', 'Chemical', 'MESH:D001151', (114, 116))
165496	22615883	As shown in Table 4, expression of rho2 subunits contributed to significantly longer survival in the multivariate model, together with seizures at onset, KPS>=90, and mutated IDH1 protein.	('seizures', 'Disease', (135, 143))	('longer', 'PosReg', (78, 84))	('IDH1', 'Gene', (175, 179))	('seizures', 'Disease', 'MESH:D012640', (135, 143))	('mutated', 'Var', (167, 174))	('expression', 'Var', (21, 31))	('survival', 'MPA', (85, 93))	('seizures', 'Phenotype', 'HP:0001250', (135, 143))
165581	22615883	All samples included in the TMA were studied by fluorescent in situ hybridization analysis (FISH) to identify losses of chromosomal arms 1p and 19q (LOH 1p/19q), as part of our previous study.	('as', 'Chemical', 'MESH:D001151', (162, 164))	('losses', 'NegReg', (110, 116))	('chromosomal arms 1p', 'Var', (120, 139))
165594	22615883	Molecular characterization confirmed the presence of mutated IDH1 R132H protein in 76/91 tumor samples (84%) and LOH 1p/19q in 26/91 tumor samples (29%) (Table 3).	('protein', 'Protein', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('R132H', 'Mutation', 'rs121913500', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutated', 'Var', (53, 60))	('IDH1', 'Gene', (61, 65))	('tumor', 'Disease', (133, 138))	('LOH 1p/19q', 'Var', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
165606	33902005	Moreover, although IRFs mutation rates were low (ranging from 0.5% to 2.3%) in glioma patients, genetic alterations in IRFs were associated with more favorable patient survival.	('genetic alterations', 'Var', (96, 115))	('glioma', 'Disease', (79, 85))	('patients', 'Species', '9606', (86, 94))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('patient', 'Species', '9606', (86, 93))	('patient survival', 'CPA', (160, 176))	('IRFs', 'Gene', (119, 123))	('patient', 'Species', '9606', (160, 167))	('more', 'PosReg', (145, 149))
165621	33902005	reported that IRF1 deletion decreased autophagy and increased apoptosis in glioma cell lines, which increased glioblastoma resistance to antiangiogenic therapy.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('increased', 'PosReg', (52, 61))	('increased', 'PosReg', (100, 109))	('decreased', 'NegReg', (28, 37))	('deletion', 'Var', (19, 27))	('IRF1', 'Gene', (14, 18))	('glioma', 'Disease', (75, 81))	('resistance', 'MPA', (123, 133))	('IRF1', 'Gene', '3659', (14, 18))	('apoptosis', 'CPA', (62, 71))	('glioblastoma', 'Disease', (110, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (110, 122))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('autophagy', 'CPA', (38, 47))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
165643	33902005	Among 5504 samples from 5300 patients in 14 glioma datasets, the overall alteration frequency of IRF genes ranged from 1.97% (4/203) to 20.48% (17/83); mutations, deep deletions, and amplification were the most common types of alteration (Figure 5A).	('IRF genes', 'Gene', (97, 106))	('patients', 'Species', '9606', (29, 37))	('deep deletions', 'Var', (163, 177))	('alteration', 'Reg', (73, 83))	('mutations', 'Var', (152, 161))	('amplification', 'Var', (183, 196))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
165645	33902005	We further assessed the impact of IRF gene alterations on prognosis and found that glioma patients with alterations exhibited a longer overall survival compared with those without alterations (p = 2.237E-6) (Figure 5C).	('glioma', 'Disease', (83, 89))	('alterations', 'Var', (104, 115))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('overall', 'MPA', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('longer', 'PosReg', (128, 134))	('patients', 'Species', '9606', (90, 98))	('IRF', 'Gene', (34, 37))
165661	33902005	Dysregulation of IRF family members has been observed in several types of malignancies, including leukemia, melanoma, breast cancer, and hepatocellular carcinoma.	('leukemia', 'Disease', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('leukemia', 'Disease', 'MESH:D007938', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('Dysregulation', 'Var', (0, 13))	('malignancies', 'Disease', (74, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('observed', 'Reg', (45, 53))	('breast cancer', 'Disease', (118, 131))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('IRF', 'Gene', (17, 20))	('hepatocellular carcinoma', 'Disease', (137, 161))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))
165668	33902005	found that IRF1 expression was significantly elevated in glioma cell lines and IRF1 knockdown increased apoptosis and enhanced the efficacy of anti-VEGF therapy in an animal model of glioma.	('VEGF', 'Gene', (148, 152))	('increased', 'PosReg', (94, 103))	('knockdown', 'Var', (84, 93))	('IRF1', 'Gene', (11, 15))	('efficacy', 'MPA', (131, 139))	('glioma', 'Disease', (57, 63))	('enhanced', 'PosReg', (118, 126))	('IRF1', 'Gene', (79, 83))	('IRF1', 'Gene', '3659', (11, 15))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('expression', 'MPA', (16, 26))	('glioma', 'Disease', (183, 189))	('IRF1', 'Gene', '3659', (79, 83))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('VEGF', 'Gene', '7422', (148, 152))	('elevated', 'PosReg', (45, 53))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('apoptosis', 'CPA', (104, 113))
165670	33902005	Furthermore, IRF7 depletion could suppress glioma progression and decrease cellular heterogeneity in vivo through interleukin-6 and Notch signaling.	('interleukin-6', 'Gene', '3569', (114, 127))	('cellular heterogeneity', 'MPA', (75, 97))	('decrease', 'NegReg', (66, 74))	('Notch signaling', 'MPA', (132, 147))	('glioma', 'Disease', (43, 49))	('depletion', 'Var', (18, 27))	('IRF7', 'Gene', (13, 17))	('suppress', 'NegReg', (34, 42))	('IRF7', 'Gene', '3665', (13, 17))	('interleukin-6', 'Gene', (114, 127))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
165675	33902005	We found that genetic alterations in IRFs were relatively uncommon in glioma, but patients with alterations exhibited more favorable overall survival, suggesting these changes may have a clinically significant impact on patient outcome.	('glioma', 'Disease', (70, 76))	('genetic alterations', 'Var', (14, 33))	('alterations', 'Var', (96, 107))	('patient', 'Species', '9606', (82, 89))	('patients', 'Species', '9606', (82, 90))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IRFs', 'Gene', (37, 41))	('patient', 'Species', '9606', (220, 227))	('more favorable', 'PosReg', (118, 132))	('impact', 'Reg', (210, 216))	('overall survival', 'CPA', (133, 149))
165690	33902005	Moreover, although genetic alterations in IRFs were relatively rare in glioma patients, they were associated with more favorable outcomes.	('IRFs', 'Gene', (42, 46))	('glioma', 'Disease', (71, 77))	('patients', 'Species', '9606', (78, 86))	('genetic alterations', 'Var', (19, 38))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('associated', 'Reg', (98, 108))
165699	33902005	Genetic alterations and their associations with patient prognosis were evaluated using cBioPortal, an online tool for visualization and analysis of multidimensional cancer genomics data.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('multidimensional cancer', 'Disease', (148, 171))	('patient', 'Species', '9606', (48, 55))	('multidimensional cancer', 'Disease', 'MESH:D009369', (148, 171))
165743	33738262	It has been shown that the complete resection of T1w contrast enhanced tumoral tissue together with the resection of more than 53,21% of the surrounding T2-weighted fluid-attenuated inversion recovery (FLAIR) abnormalities is associated whit a longer OS, than in case of less extensive resection.	('tumoral', 'Disease', 'MESH:D009369', (71, 78))	('enhanced', 'PosReg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('T1w', 'Var', (49, 52))	('tumoral', 'Disease', (71, 78))
165821	29093006	Using custom imaging programs in mu-Manager and ImageJ software, 400 x 400-mum images from two SRS channels, 2845 cm-1 (CH2/lipid channel) and 2930 cm-1 (CH3/protein channel) Raman shift wave numbers, were obtained in a raster fashion.	('mum', 'Gene', '56925', (75, 78))	('mum', 'Gene', (75, 78))	('lipid', 'Chemical', 'MESH:D008055', (124, 129))	('2845 cm-1', 'Var', (109, 118))	('2930 cm-1', 'Var', (143, 152))
165878	29093006	Selected specimens included normal brain tissue (294 FOVs, 6 mosaics) and low-grade (874 FOVs, 15 mosaics) and high-grade (683 FOVs, 10 mosaics) tumors.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('683', 'Var', (123, 126))	('tumors', 'Disease', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))
165898	29093006	By leveraging the image contrast contained in the 2845 cm-1 (CH2/lipid) and 2930 cm-1 (CH3/protein) channels, we were able to identify and segment TAMs and tumor nuclei for feature extraction and quantitative image analysis.	('2930 cm-1', 'Var', (76, 85))	('lipid', 'Chemical', 'MESH:D008055', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TAM', 'Chemical', '-', (147, 150))	('tumor', 'Disease', (156, 161))
165900	29093006	The increasing importance of molecular diagnostics in pediatric neuro-oncology, including WNT-activation, Shh-activation, BRAF mutations, RELA fusion, and H3 K27M-mutation, among others, requires a standardized and streamlined intraoperative histology system that ensures high diagnostic yield from sampled tissue.	('Shh', 'Gene', '6469', (106, 109))	('K27M', 'Mutation', 'p.K27M', (158, 162))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (122, 126))	('Shh', 'Gene', (106, 109))	('H3 K27M-mutation', 'Var', (155, 171))	('RELA', 'Gene', (138, 142))	('RELA', 'Gene', '5970', (138, 142))	('mutations', 'Var', (127, 136))	('oncology', 'Phenotype', 'HP:0002664', (70, 78))
165980	21331595	Systematically larger residual FLAIR tumour volumes (on average 5.7 cm3) were observed based on early postoperative MRI compared with late postoperative MRI (Fig.	('MRI', 'Var', (116, 119))	('tumour', 'Disease', (37, 43))	('larger', 'PosReg', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
165998	21331595	Nevertheless, FLAIR tumour volumes tend to be larger than T2 volumes on early postoperative MRI.	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))	('FLAIR', 'Var', (14, 19))	('tumour', 'Disease', (20, 26))
166052	18594540	For ANGII receptor detection, the following primers were used: sense AT1 5'-TTGCAGAGTGGGTGACAGAG-3'; antisense AT1 5'-TAGCTGAGCTTGCAGAA-3' -3' (393 base pairs (bp)); sense AT2 5'-TTATGGCTTTCCCACCTGAG-3' and reverse AT2 5'-GTTGGTGAATCCCAAGAGSGA-3' (342 bp); in a total reaction volume of 20 muL.	('AA', 'Phenotype', 'HP:0009592', (229, 231))	('AA', 'Phenotype', 'HP:0009592', (235, 237))	('antisense', 'Var', (101, 110))	('AT2', 'Gene', (172, 175))	('ANGII', 'Gene', (4, 9))	('ANGII', 'Gene', '183', (4, 9))	('AT2', 'Gene', '186', (172, 175))	('AA', 'Phenotype', 'HP:0009592', (133, 135))	('AT2', 'Gene', (215, 218))	('AT2', 'Gene', '186', (215, 218))
166086	18594540	In multivariate analysis, the only significant factors associated with the presence of AT1 were age (Hazard's ratio (HR) 3.2 (95% CI, 1.04-10.2); P=0.04) and histological grade (HR 13.4 (95% CI, 3.2-55); P<0.0001).	('AT1', 'Gene', (87, 90))	('rat', 'Species', '10116', (110, 113))	('presence', 'Var', (75, 83))
166091	18594540	In the multivariate analysis, only the grade of malignancy was associated with the presence of AT2 (HR 3.4; 95% CI, 1.08-10.86; P=0.036).	('presence', 'Var', (83, 91))	('malignancy', 'Disease', (48, 58))	('AT2', 'Gene', (95, 98))	('AT2', 'Gene', '186', (95, 98))	('malignancy', 'Disease', 'MESH:D009369', (48, 58))
166096	18594540	The presence of AT2 was also associated with a decrease in overall survival (3.3+-1.6 vs 12.8+-3; P=0.006).	('decrease', 'NegReg', (47, 55))	('AT2', 'Gene', (16, 19))	('presence', 'Var', (4, 12))	('AT2', 'Gene', '186', (16, 19))	('overall survival', 'MPA', (59, 75))
166099	18594540	Likewise, the presence of AT1 and AT2 in C6 glioma cells has been described, showing that their blockage can inhibit tumoral growth and angiogenesis (Rivera et al, 2001; Fogarty et al, 2002; Arrieta et al, 2005).	('tumoral growth', 'Disease', 'MESH:D006130', (117, 131))	('AT2', 'Gene', (34, 37))	('AT2', 'Gene', '186', (34, 37))	('inhibit', 'NegReg', (109, 116))	('tumoral growth', 'Disease', (117, 131))	('C6 glioma', 'Disease', 'MESH:C567307', (41, 50))	('C6 glioma', 'Disease', (41, 50))	('blockage', 'Var', (96, 104))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
166112	18594540	The presence of both receptors in the same tumour suggests that selective blockage of one receptor could increase the effect of the other (Arrieta et al, 2005).	('effect', 'MPA', (118, 124))	('tumour', 'Disease', (43, 49))	('increase', 'PosReg', (105, 113))	('selective', 'Var', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
166114	18594540	There are other endogenous peptide hormones of the RAAS, such as AT1-5 and AT1-7, which could regulate proliferation processes in neoplastic cells; it has been demonstrated that AT1-7 inhibits proliferation and induces apoptosis of human lung cancer cells through its receptor MAS (Gallagher and Tallant 2004).	('rat', 'Species', '10116', (110, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('AT1-7', 'Var', (178, 183))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('rat', 'Species', '10116', (200, 203))	('inhibits', 'NegReg', (184, 192))	('AA', 'Phenotype', 'HP:0009592', (52, 54))	('proliferation', 'CPA', (193, 206))	('lung cancer', 'Disease', (238, 249))	('apoptosis', 'CPA', (219, 228))	('rat', 'Species', '10116', (167, 170))	('human', 'Species', '9606', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('induces', 'Reg', (211, 218))
166124	18594540	The fact that AT1 is present in high-grade astrocytomas and in patients >47 years of age suggests that AT1 and AT2 could be associated with the progression of malignancy in secondary malignant astrocytomas.	('malignant astrocytomas', 'Disease', (183, 205))	('astrocytomas', 'Disease', (193, 205))	('malignant astrocytomas', 'Disease', 'MESH:D020339', (183, 205))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('astrocytomas', 'Disease', (43, 55))	('malignancy', 'Disease', 'MESH:D009369', (159, 169))	('associated with', 'Reg', (124, 139))	('malignancy', 'Disease', (159, 169))	('astrocytomas', 'Disease', 'MESH:D001254', (193, 205))	('patients', 'Species', '9606', (63, 71))	('AT1', 'Var', (103, 106))	('AT2', 'Gene', (111, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (193, 204))	('AT2', 'Gene', '186', (111, 114))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))
166126	18594540	Some studies have reported an interaction between age and genetic alterations (such as TP53 mutations and EGFR amplification) in GM, suggesting that tumorigenic pathways to GM vary according to the patient's age (Batchelor et al, 2004).	('amplification', 'Var', (111, 124))	('rat', 'Species', '10116', (70, 73))	('patient', 'Species', '9606', (198, 205))	('TP53', 'Gene', '7157', (87, 91))	('tumorigenic pathways', 'CPA', (149, 169))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (106, 110))
166129	18594540	This is the first report documenting the association between the presence of AT1/AT2 and poor prognosis in patients with high-grade astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (132, 143))	('association', 'Interaction', (41, 52))	('astrocytoma', 'Disease', (132, 143))	('astrocytoma', 'Phenotype', 'HP:0009592', (132, 143))	('AT2', 'Gene', (81, 84))	('patients', 'Species', '9606', (107, 115))	('AT2', 'Gene', '186', (81, 84))	('presence', 'Var', (65, 73))
166137	33031233	Eighty-six patients, who underwent 18F-FDOPA PET and MRI, and were diagnosed with new or recurrent LGGs were retrospectively evaluated with respect to their isocitrate dehydrogenase (IDH) and 1p19q status (10 IDH wild-type, 57 mutant, 19 unknown; 1p19q status in IDH mutant: 20 non-codeleted, 37 codeleted).	('IDH', 'Gene', (209, 212))	('IDH', 'Gene', '3417', (209, 212))	('mutant', 'Var', (227, 233))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (35, 44))	('IDH', 'Gene', '3417', (263, 266))	('IDH', 'Gene', (183, 186))	('IDH', 'Gene', (263, 266))	('isocitrate dehydrogenase', 'Gene', (157, 181))	('isocitrate dehydrogenase', 'Gene', '3417', (157, 181))	('IDH', 'Gene', '3417', (183, 186))	('patients', 'Species', '9606', (11, 19))	('LGGs', 'Disease', (99, 103))
166139	33031233	PET and MRI metrics combined with age predicted the IDH mutation and 1p19q codeletion statuses with sensitivities of 73% and 76%, specificities of 100% and 94%, respectively.	('IDH', 'Gene', '3417', (52, 55))	('1p19q', 'Var', (69, 74))	('IDH', 'Gene', (52, 55))
166140	33031233	Significant correlations were found between OS and the IDH mutation status (hazard ratio [HR] = 4.939), nSUVmax (HR = 2.827), 18F-FDOPA hypermetabolic volume (HR = 1.048), and FLAIRROI volume (HR = 1.006).	('18F-FDOPA', 'Chemical', 'MESH:C043437', (126, 135))	('correlations', 'Interaction', (12, 24))	('nSUVmax', 'MPA', (104, 111))	('IDH', 'Gene', (55, 58))	('FLAIRROI volume', 'MPA', (176, 191))	('IDH', 'Gene', '3417', (55, 58))	('mutation', 'Var', (59, 67))	('nSUVmax', 'Chemical', '-', (104, 111))	('18F-FDOPA hypermetabolic volume', 'MPA', (126, 157))
166151	33031233	In 2016, the World Health Organization (WHO) glioma classification was modified to include molecular subtypes including isocitrate dehydrogenase (IDH) gene mutations or chromosomal 1p19q codeletion.	('mutations', 'Var', (156, 165))	('IDH', 'Gene', (146, 149))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('isocitrate dehydrogenase', 'Gene', (120, 144))	('IDH', 'Gene', '3417', (146, 149))	('isocitrate dehydrogenase', 'Gene', '3417', (120, 144))	('chromosomal 1p19q codeletion', 'Var', (169, 197))	('glioma', 'Disease', (45, 51))
166178	33031233	Among the IDHm gliomas, 20 were 1p19q non-codeleted (IDHm-non-codel), and 37 were 1p19q codeleted (IDHm-codel).	('IDHm gliomas', 'Disease', (10, 22))	('IDHm', 'Gene', (53, 57))	('1p19q', 'Var', (82, 87))	('IDHm', 'Gene', '3418', (53, 57))	('IDHm', 'Gene', '3418', (99, 103))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('IDHm', 'Gene', (99, 103))	('IDHm', 'Gene', '3418', (10, 14))	('IDHm', 'Gene', (10, 14))	('IDHm gliomas', 'Disease', 'MESH:D005910', (10, 22))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('1p19q', 'Var', (32, 37))
166189	33031233	The AUC of IDH or 1p19q status was higher using both PET and MRI parameters than when using either of the parameters individually; however, the AUC incorporating patient age and MR-PET parameters yielded the highest value.	('IDH', 'Gene', '3417', (11, 14))	('patient', 'Species', '9606', (162, 169))	('IDH', 'Gene', (11, 14))	('1p19q status', 'Var', (18, 30))
166193	33031233	The Cox multivariate regression analysis controlling for age showed a significant increase in the hazard associated with the nSUVmax (HR = 3.208, CI = [1.272-8.090], P = 0.013) and 18F-FDOPA hypermetabolic volume (HR = 1.045, CI = [1.017-1.073], P = 0.001), but not with FLAIR volume (HR = 1.006, CI = [0.999-1.013], P = 0.08).	('nSUVmax', 'Chemical', '-', (125, 132))	('18F-FDOPA', 'Var', (181, 190))	('nSUVmax', 'MPA', (125, 132))	('increase', 'PosReg', (82, 90))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (181, 190))
166197	33031233	Our investigation revealed that combining PET and MRI information with patient age could predict IDH and 1p19q status more accurately than using PET or MRI information alone.	('IDH', 'Gene', (97, 100))	('IDH', 'Gene', '3417', (97, 100))	('predict', 'Reg', (89, 96))	('patient', 'Species', '9606', (71, 78))	('1p19q status', 'Var', (105, 117))
166203	33031233	One study stratified gliomas into IDHwt and IDHm groups, which included 1p19q non-codeleted and codeleted gliomas, and showed higher tracer uptake in IDHm than IDHwt.	('IDHm', 'Gene', (44, 48))	('IDH', 'Gene', (34, 37))	('IDHm', 'Gene', '3418', (44, 48))	('higher', 'PosReg', (126, 132))	('IDH', 'Gene', (160, 163))	('1p19q', 'Var', (72, 77))	('IDH', 'Gene', (150, 153))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('IDH', 'Gene', '3417', (34, 37))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('gliomas', 'Disease', (106, 113))	('IDH', 'Gene', '3417', (160, 163))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('IDH', 'Gene', '3417', (150, 153))	('tracer uptake', 'MPA', (133, 146))	('IDH', 'Gene', (44, 47))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('IDHm', 'Gene', '3418', (150, 154))	('IDHm', 'Gene', (150, 154))	('gliomas', 'Disease', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('IDH', 'Gene', '3417', (44, 47))
166204	33031233	Other studies stratified gliomas into 1p19q codeleted and non-codeleted groups, which included both IDHm-non-codel and IDHwt gliomas, and showed no significant differences between 1p19q codeleted and non-codeleted gliomas.	('gliomas', 'Disease', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('IDHwt gliomas', 'Disease', (119, 132))	('gliomas', 'Disease', 'MESH:D005910', (214, 221))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('gliomas', 'Disease', (214, 221))	('1p19q', 'Var', (180, 185))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('IDHm', 'Gene', '3418', (100, 104))	('IDHm', 'Gene', (100, 104))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('IDHwt gliomas', 'Disease', 'MESH:D005910', (119, 132))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
166209	33031233	In the current study, the combination of PET and MRI information with patient age successfully differentiated the IDH mutation and 1p19q codeletion status with AUCs higher than 0.90, although the performance, particularly for the IDH mutation status, was largely dependent on the patient age.	('IDH', 'Gene', (230, 233))	('patient', 'Species', '9606', (280, 287))	('IDH', 'Gene', '3417', (230, 233))	('IDH', 'Gene', (114, 117))	('patient', 'Species', '9606', (70, 77))	('IDH', 'Gene', '3417', (114, 117))	('1p19q', 'Var', (131, 136))
166214	33031233	The current large cohort study revealed that increased nSUVmax of 18F-FDOPA was associated with a worse prognosis in grade II gliomas; furthermore, the 18F-FDOPA hypermetabolic volume was also associated with a worse prognosis.	('18F-FDOPA', 'Chemical', 'MESH:C043437', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('increased', 'PosReg', (45, 54))	('nSUVmax', 'MPA', (55, 62))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (152, 161))	('II gliomas', 'Disease', (123, 133))	('hypermetabolic volume', 'MPA', (162, 183))	('II gliomas', 'Disease', 'MESH:D005910', (123, 133))	('18F-FDOPA', 'Var', (152, 161))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('nSUVmax', 'Chemical', '-', (55, 62))
166249	31410193	Currently, SDHB mutation status is the only genetic factor associated with poor prognosis.	('SDHB', 'Gene', '6390', (11, 15))	('SDHB', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))
166250	31410193	We recently reported that assessment of telomerase activation and ATRX mutations in tumor tissue may have clinical significance for identifying metastatic disease (mPPGLs).	('telomerase', 'Protein', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('metastatic disease', 'Disease', (144, 162))	('tumor', 'Disease', (84, 89))	('mutations', 'Var', (71, 80))	('ATRX', 'Gene', (66, 70))	('ATRX', 'Gene', '546', (66, 70))	('activation', 'PosReg', (51, 61))
166314	31410193	When segregating patients according to their classifier features, 72% of score 3 (high miR-183-5p and miR-21-3p levels; SDHB mutated) patients were metastatic, compared to the 4.7% of score 0 (low miR-183-5p and miR-21-3p expression, and no-SDHB mutated) (Figure 2B).	('SDHB', 'Gene', (241, 245))	('miR-183', 'Gene', (87, 94))	('miR-183', 'Gene', (197, 204))	('mutated', 'Var', (125, 132))	('miR-183', 'Gene', '406959', (197, 204))	('miR-21-3p', 'Gene', '406995', (102, 111))	('patients', 'Species', '9606', (134, 142))	('SDHB', 'Gene', '6390', (120, 124))	('metastatic', 'CPA', (148, 158))	('miR-21-3p', 'Gene', '406995', (212, 221))	('miR-21-3p', 'Gene', (102, 111))	('patients', 'Species', '9606', (17, 25))	('miR-21-3p', 'Gene', (212, 221))	('SDHB', 'Gene', (120, 124))	('SDHB', 'Gene', '6390', (241, 245))	('miR-183', 'Gene', '406959', (87, 94))
166336	31410193	Apart from PPGL, low-grade glioma (LGG) also exhibits a significant negative correlation between miR-21-3p and TSC2 (rho=-0.18, P=1.3 10-4), as well as a positive one with pS6 levels (in Ser235/236: rho=0.27, P=1.7 10-8; in Ser240/244: rho=0.23, P=6.6 10-7) (Figure 4A).	('glioma', 'Disease', (27, 33))	('miR-21-3p', 'Gene', (97, 106))	('pS6', 'Gene', (172, 175))	('negative', 'NegReg', (68, 76))	('Ser240', 'Chemical', '-', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('TSC2', 'Gene', '7249', (111, 115))	('pS6', 'Gene', '338413', (172, 175))	('TSC2', 'Gene', (111, 115))	('Ser240/244', 'Var', (224, 234))	('miR-21-3p', 'Gene', '406995', (97, 106))	('Ser235', 'Chemical', '-', (187, 193))
166345	31410193	Notably, circulating levels of all miRNAs of the signature (except miR-551b-3p and miR-202-5p) exhibited a tendency towards increased expression in mPPGLs compared to non-metastatic cases, reaching statistical significance in the mPPGL subgroup with evidence of progressive disease (Table S8).	('circulating levels', 'MPA', (9, 27))	('expression', 'MPA', (134, 144))	('progressive disease', 'Disease', 'MESH:D018450', (262, 281))	('increased', 'PosReg', (124, 133))	('mPPGLs', 'Var', (148, 154))	('miR-202', 'Gene', (83, 90))	('progressive disease', 'Disease', (262, 281))	('miR-202', 'Gene', '574448', (83, 90))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (35, 38))	('miR', 'Gene', (83, 86))	('miR-551b', 'Gene', '693136', (67, 75))	('miR', 'Gene', '220972', (67, 70))	('miR-551b', 'Gene', (67, 75))	('miR', 'Gene', (67, 70))	('mPPGL', 'Disease', (230, 235))
166349	31410193	Consistent with the findings in serum of PPGL patients, miR-202-5p and miR-551b-3p, which exhibited low levels in patients, were undetectable in imCCs, whereas the levels of all other miRNAs were higher in Sdhb-/- compared to WT cells (Figure S6).	('miR', 'Gene', (71, 74))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (114, 122))	('miR-202', 'Gene', (56, 63))	('Sdhb-/-', 'Var', (206, 213))	('miR-202', 'Gene', '574448', (56, 63))	('higher', 'PosReg', (196, 202))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('miR-551b', 'Gene', '693136', (71, 79))	('levels', 'MPA', (164, 170))	('miR', 'Gene', '220972', (184, 187))	('miR', 'Gene', (184, 187))	('miR', 'Gene', '220972', (71, 74))	('miR-551b', 'Gene', (71, 79))
166384	28181325	RECURRENT COPY NUMBER ALTERATIONS IN LOW-GRADE AND ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA WITH AND WITHOUT BRAF V600E MUTATION Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion.	('localized glioma', 'Disease', 'MESH:D005910', (175, 191))	('CDKN2A/B', 'Gene', '1029;1030', (242, 250))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (109, 113))	('localized glioma', 'Disease', (175, 191))	('COPY NUMBER ALTERATIONS', 'Var', (10, 33))	('Pleomorphic xanthoastrocytoma', 'Disease', (129, 158))	('BRAF', 'Gene', '673', (218, 222))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('CDKN2A/B', 'Gene', (242, 250))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('Pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (129, 158))	('PXA', 'Chemical', '-', (160, 163))	('V600E', 'Mutation', 'rs113488022', (223, 228))	('V600E', 'Mutation', 'rs113488022', (114, 119))
166385	28181325	We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('patient', 'Species', '9606', (136, 143))	('BRAF', 'Gene', '673', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('BRAF', 'Gene', (64, 68))	('tumor', 'Disease', (80, 85))	('PXA', 'Chemical', '-', (132, 135))	('patients', 'Species', '9606', (136, 144))	('patient', 'Species', '9606', (97, 104))
166386	28181325	Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%).	('BRAF', 'Gene', (107, 111))	('PXA', 'Chemical', '-', (69, 72))	('V600E', 'Mutation', 'rs113488022', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('A-PXA', 'Chemical', '-', (96, 101))	('anaplastic PXA', 'Disease', (80, 94))	('V600E mutant', 'Var', (112, 124))	('PXA', 'Chemical', '-', (91, 94))	('PXA', 'Disease', (69, 72))	('BRAF', 'Gene', '673', (107, 111))	('PXA', 'Chemical', '-', (98, 101))
166387	28181325	CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50-60%).	('deletion', 'Var', (101, 109))	('CDKN2A/B', 'Gene', '1029;1030', (92, 100))	('CDKN2A/B', 'Gene', (92, 100))	('involved', 'Reg', (54, 62))
166389	28181325	Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (p=0.009) and 14 (p=0.03).	('loss of', 'NegReg', (24, 31))	('A-PXA', 'Chemical', '-', (81, 86))	('copy-neutral', 'Var', (11, 23))	('A-PXA', 'Disease', (81, 86))	('Losses', 'Var', (0, 6))
166401	28181325	BRAF V600E is not specific to PXA and has been identified in a number of CNS tumors, including ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma.	('epithelioid glioblastoma', 'Disease', 'MESH:D005909', (137, 161))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CNS tumors', 'Disease', 'MESH:D009369', (73, 83))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('CNS tumors', 'Disease', (73, 83))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (110, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('ganglioglioma', 'Disease', 'MESH:D018303', (95, 108))	('V600E', 'Var', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pilocytic astrocytoma', 'Disease', (110, 131))	('identified', 'Reg', (47, 57))	('PXA', 'Chemical', '-', (30, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('ganglioglioma', 'Disease', (95, 108))	('epithelioid glioblastoma', 'Disease', (137, 161))
166403	28181325	Whole genome or exome sequencing of seven PXA negative for BRAF V600E demonstrated alterations in other known cancer drivers, including mutations of TSC2 and NF1 and ETV6-NTRK3 fusion.	('cancer', 'Disease', (110, 116))	('ETV6-NTRK3 fusion', 'Gene', (166, 183))	('PXA', 'Chemical', '-', (42, 45))	('NF1', 'Gene', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('TSC2', 'Gene', '7249', (149, 153))	('TSC2', 'Gene', (149, 153))	('BRAF', 'Gene', (59, 63))	('mutations', 'Var', (136, 145))	('NF1', 'Gene', '4763', (158, 161))	('BRAF', 'Gene', '673', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (166, 183))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('alterations', 'Reg', (83, 94))
166404	28181325	Fusions of NRF1-BRAF and ATG7-RAF were also identified in two anaplastic PXA using a targeted next-generation sequencing panel.	('Fusions', 'Var', (0, 7))	('PXA', 'Chemical', '-', (73, 76))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('ATG7', 'Gene', '10533', (25, 29))	('NRF1', 'Gene', '4899', (11, 15))	('anaplastic PXA', 'Disease', (62, 76))	('ATG7', 'Gene', (25, 29))	('RAF', 'Gene', '22882', (17, 20))	('RAF', 'Gene', '22882', (30, 33))	('RAF', 'Gene', (30, 33))	('identified', 'Reg', (44, 54))	('NRF1', 'Gene', (11, 15))	('RAF', 'Gene', (17, 20))
166406	28181325	Mutations of TP53 are also rare in PXA, present in approximately 6% of tumors.	('TP53', 'Gene', (13, 17))	('PXA', 'Chemical', '-', (35, 38))	('PXA', 'Disease', (35, 38))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('TP53', 'Gene', '7157', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
166409	28181325	A single large series of 50 PXA analyzed by comparative genomic hybridization (CGH) demonstrated frequent whole or partial loss of chromosome 9, present in 25 cases (50%) with homozygous deletion of 9p21.3 encompassing CDKN2A/B identified in 6 of 10 cases further analyzed by array CGH.	('deletion', 'Var', (187, 195))	('PXA', 'Chemical', '-', (28, 31))	('CDKN2A/B', 'Gene', (219, 227))	('loss', 'NegReg', (123, 127))	('CDKN2A/B', 'Gene', '1029;1030', (219, 227))
166411	28181325	To more fully explore these associations, we analyzed CNVs in a cohort of 41 PXA patients, 38 at primary diagnosis and 3 at recurrence only, using OncoScan chromosomal microarray and describe the association of CNVs with BRAF mutations, tumor grade and patient survival.	('BRAF', 'Gene', (221, 225))	('patient', 'Species', '9606', (253, 260))	('tumor', 'Disease', (237, 242))	('patient', 'Species', '9606', (81, 88))	('association', 'Interaction', (196, 207))	('CNVs', 'Gene', (211, 215))	('patients', 'Species', '9606', (81, 89))	('mutations', 'Var', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('PXA', 'Chemical', '-', (77, 80))	('BRAF', 'Gene', '673', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
166418	28181325	Genetic testing for NF1 mutation was negative.	('NF1', 'Gene', '4763', (20, 23))	('mutation', 'Var', (24, 32))	('NF1', 'Gene', (20, 23))
166437	28181325	BRAF V600E mutation was present in 23 cases (61%), including a comparable percentage of PXA (n=15, 63%) and A-PXA (n=8, 57%).	('V600E', 'Mutation', 'rs113488022', (5, 10))	('PXA', 'Chemical', '-', (110, 113))	('PXA', 'Disease', (88, 91))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('PXA', 'Chemical', '-', (88, 91))	('BRAF', 'Gene', (0, 4))	('A-PXA', 'Chemical', '-', (108, 113))
166454	28181325	CDKN2A/B deletion was identified in conjunction with other abnormalities of chromosome 9, most commonly whole chromosome loss (n=11), whole or partial loss of 9p (n=6), or copy-neutral loss of heterozygosity (cnLOH) (n=9).	('whole chromosome', 'CPA', (104, 120))	('CDKN2A/B', 'Gene', (0, 8))	('deletion', 'Var', (9, 17))	('loss', 'NegReg', (121, 125))	('copy-neutral', 'Var', (172, 184))	('CDKN2A/B', 'Gene', '1029;1030', (0, 8))	('loss', 'NegReg', (151, 155))	('loss', 'NegReg', (185, 189))
166456	28181325	In five tumors (all PXA), loss on chromosome 9 was the sole CNV identified (Figure 3A).	('PXA', 'Chemical', '-', (20, 23))	('loss on chromosome', 'Var', (26, 44))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
166457	28181325	Additional whole chromosome gains, losses, and cnLOH were frequent with many present as mosaic and subclonal abnormalities (Figure 3A).	('losses', 'CPA', (35, 41))	('whole chromosome gains', 'CPA', (11, 33))	('subclonal abnormalities', 'Disease', 'MESH:D000014', (99, 122))	('subclonal abnormalities', 'Disease', (99, 122))	('cnLOH', 'Var', (47, 52))
166459	28181325	With respect to BRAF mutation status, gains of +12 (p=0.03) and +21 (p=0.009) were significantly more common in BRAF mutant tumors (Table S1).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BRAF', 'Gene', (16, 20))	('mutant', 'Var', (117, 123))	('BRAF', 'Gene', '673', (16, 20))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('gains', 'PosReg', (38, 43))
166465	28181325	Apart from CDKN2A/B deletion, focal CNVs were largely non-recurrent, and most did not encompass genes known to be involved in gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('CDKN2A/B', 'Gene', (11, 19))	('deletion', 'Var', (20, 28))	('glioma', 'Disease', (126, 132))	('CDKN2A/B', 'Gene', '1029;1030', (11, 19))
166466	28181325	In three tumors negative for BRAF V600E, focal deletions were identified, which involved BRAF (cases 21 and 35) or RAF1 (case 22).	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('BRAF', 'Gene', '673', (89, 93))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('tumors', 'Disease', (9, 15))	('BRAF', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('RAF1', 'Gene', (115, 119))	('RAF1', 'Gene', '5894', (115, 119))	('V600E', 'Var', (34, 39))
166468	28181325	This included both deletion of ATRX at Xq13 in a male patient and deletion of 4q encompassing TENM3 (ODZ3), an alteration identified in epithelioid A-PXA and epithelioid glioblastoma.	('patient', 'Species', '9606', (54, 61))	('epithelioid A-PXA', 'Disease', (136, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('TENM3', 'Gene', (94, 99))	('TENM3', 'Gene', '55714', (94, 99))	('deletion', 'Var', (19, 27))	('ATRX', 'Gene', (31, 35))	('ODZ3', 'Gene', (101, 105))	('epithelioid glioblastoma', 'Disease', (158, 182))	('A-PXA', 'Chemical', '-', (148, 153))	('ODZ3', 'Gene', '55714', (101, 105))	('ATRX', 'Gene', '546', (31, 35))	('deletion', 'Var', (66, 74))	('epithelioid glioblastoma', 'Disease', 'MESH:D005909', (158, 182))
166473	28181325	Although not statistically significant, BRAF mutant tumors had longer overall survival (Figure 4B) (p=0.10).	('BRAF', 'Gene', '673', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutant', 'Var', (45, 51))	('overall survival', 'MPA', (70, 86))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('BRAF', 'Gene', (40, 44))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('longer', 'PosReg', (63, 69))
166476	28181325	Of the 33 tumors with CDKN2A/B deletion, tumors with multiple additional CNVs had shortened survival (Figure 4F; p=0.083), but this was not statistically significant.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('CDKN2A/B', 'Gene', '1029;1030', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('deletion', 'Var', (31, 39))	('survival', 'MPA', (92, 100))	('shortened', 'NegReg', (82, 91))	('CDKN2A/B', 'Gene', (22, 30))
166484	28181325	While the PXA component showed only CNVs of chromosome 9, additional mosaic gains/losses were present in the high-grade areas.	('gains/losses', 'PosReg', (76, 88))	('CNVs', 'Var', (36, 40))	('PXA', 'Chemical', '-', (10, 13))
166486	28181325	Case 31 presented as A-PXA with numerous whole chromosome gains (Figure 5C).	('whole', 'Var', (41, 46))	('presented', 'Reg', (8, 17))	('A-PXA', 'Chemical', '-', (21, 26))	('A-PXA', 'Disease', (21, 26))
166487	28181325	Intriguingly, at recurrence, the tumor showed only CNVs of chromosome 9 and homozygous deletion at Xq26.1 and Xq26.2, also present in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Xq26.2', 'Gene', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('deletion', 'Var', (87, 95))	('CNVs', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
166489	28181325	In case 2, only CNVs of chromosome 9 were identified in the primary tumor, while many additional gains/losses were present on recurrence and anaplastic transformation.	('tumor', 'Disease', (68, 73))	('gains/losses', 'PosReg', (97, 109))	('CNVs', 'Var', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
166491	28181325	At recurrence, the tumor showed a small cell pattern (Figure 1D-F) and additional superimposed focal gains and losses (Figure 5C), which included a new homozygous deletion at Xq13 involving ATRX.	('losses', 'NegReg', (111, 117))	('ATRX', 'Gene', '546', (190, 194))	('gains', 'PosReg', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ATRX', 'Gene', (190, 194))	('tumor', 'Disease', (19, 24))	('deletion at', 'Var', (163, 174))
166492	28181325	In case 6, the tumor recurred as PXA and showed new mosaic gains on chromosomes 5, 7, 8, 18, and 22.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PXA', 'Disease', (33, 36))	('tumor', 'Disease', (15, 20))	('mosaic', 'Var', (52, 58))	('gains', 'PosReg', (59, 64))	('PXA', 'Chemical', '-', (33, 36))
166496	28181325	Inactivation of p16 is a common finding in a wide variety of malignancies, including a high proportion of IDH-wild-type infiltrating gliomas.	('malignancies', 'Disease', 'MESH:D009369', (61, 73))	('IDH', 'Gene', '3417', (106, 109))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('p16', 'Gene', '1029', (16, 19))	('malignancies', 'Disease', (61, 73))	('IDH', 'Gene', (106, 109))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
166497	28181325	Loss of p16 has been shown to be associated with adverse outcomes in BRAF mutant pediatric low-grade gliomas and identified in BRAF mutant pediatric high-grade astrocytomas and secondary high-grade gliomas.	('astrocytomas', 'Disease', (160, 172))	('gliomas', 'Disease', (101, 108))	('BRAF', 'Gene', '673', (127, 131))	('BRAF', 'Gene', (127, 131))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('mutant', 'Var', (74, 80))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('p16', 'Gene', (8, 11))	('astrocytomas', 'Disease', 'MESH:D001254', (160, 172))	('BRAF', 'Gene', '673', (69, 73))	('astrocytoma', 'Phenotype', 'HP:0009592', (160, 171))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('BRAF', 'Gene', (69, 73))	('p16', 'Gene', '1029', (8, 11))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('Loss', 'Var', (0, 4))	('mutant', 'Var', (132, 138))	('gliomas', 'Disease', (198, 205))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))
166500	28181325	Rather, it appears that CDKN2A/B deletion, like BRAF V600E, is central to the underlying genetics of PXA.	('PXA', 'Disease', (101, 104))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('CDKN2A/B', 'Gene', (24, 32))	('PXA', 'Chemical', '-', (101, 104))	('V600E', 'Var', (53, 58))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('CDKN2A/B', 'Gene', '1029;1030', (24, 32))
166501	28181325	This finding is intriguing given the recognition that oncogenic activation of the MAPK pathway can lead to cellular senescence, as has been observed in models of BRAF mutant glioma, but this is abrogated by loss of p16.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('lead to', 'Reg', (99, 106))	('BRAF', 'Gene', (162, 166))	('p16', 'Gene', '1029', (215, 218))	('glioma', 'Disease', (174, 180))	('activation', 'PosReg', (64, 74))	('mutant', 'Var', (167, 173))	('MAPK pathway', 'Pathway', (82, 94))	('BRAF', 'Gene', '673', (162, 166))	('cellular senescence', 'CPA', (107, 126))	('p16', 'Gene', (215, 218))
166503	28181325	In 50 cases analyzed by CGH, alterations of chromosome 9 were frequent, identified in 25 cases (50%) with CDKN2A/B deletion in 6 of 10 (60%) cases further characterized by array CGH.	('deletion', 'Var', (115, 123))	('CDKN2A/B', 'Gene', (106, 114))	('CDKN2A/B', 'Gene', '1029;1030', (106, 114))
166507	28181325	While loss or cnLOH of chromosomes 14 and 22 were more common in A-PXA (Table 2), this did not correlate with patient survival (Figure 4).	('loss', 'NegReg', (6, 10))	('cnLOH', 'Var', (14, 19))	('A-PXA', 'Chemical', '-', (65, 70))	('patient', 'Species', '9606', (110, 117))	('A-PXA', 'Disease', (65, 70))
166512	28181325	On anaplastic transformation, PXA has been well-documented to show other histologic patterns, including epithelioid, fibrillary, or small cell morphology.	('anaplastic transformation', 'Var', (3, 28))	('epithelioid', 'Disease', (104, 115))	('PXA', 'Disease', (30, 33))	('small cell morphology', 'Disease', (132, 153))	('fibrillary', 'Disease', (117, 127))	('PXA', 'Chemical', '-', (30, 33))
166522	28181325	In our series, focal deletion of 4q encompassing TENM3 was identified in a single recurrent A-PXA (case 41, Figure S1), which did not show epithelioid morphology.	('A-PXA', 'Chemical', '-', (92, 97))	('TENM3', 'Gene', (49, 54))	('TENM3', 'Gene', '55714', (49, 54))	('A-PXA', 'Disease', (92, 97))	('deletion', 'Var', (21, 29))
166525	28181325	Prior studies have reported clearly defined focal CNVs leading to progression of low-grade astrocytomas.	('astrocytomas', 'Disease', (91, 103))	('CNVs', 'Var', (50, 54))	('astrocytomas', 'Disease', 'MESH:D001254', (91, 103))	('leading to', 'Reg', (55, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
166529	28181325	Upon anaplastic transformation, only three cases showed additional genetic alterations well-characterized in other CNS tumors, including the case described above with SMARCB1 loss and two recurrent tumors with focal deletion of ATRX.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('CNS tumors', 'Disease', (115, 125))	('loss', 'NegReg', (175, 179))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('ATRX', 'Gene', '546', (228, 232))	('SMARCB1', 'Gene', '6598', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('SMARCB1', 'Gene', (167, 174))	('deletion', 'Var', (216, 224))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('ATRX', 'Gene', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('CNS tumors', 'Disease', 'MESH:D009369', (115, 125))
166530	28181325	To our knowledge, activation of the alternative lengthening of telomeres pathway has been reported in a single A-PXA without loss of ATRX expression and deletion (vs. mutation) is an uncommon mechanism of ATRX inactivation.	('deletion', 'Var', (153, 161))	('ATRX', 'Gene', '546', (133, 137))	('A-PXA', 'Chemical', '-', (111, 116))	('ATRX', 'Gene', (205, 209))	('activation', 'PosReg', (18, 28))	('ATRX', 'Gene', '546', (205, 209))	('ATRX', 'Gene', (133, 137))
166531	28181325	In summary, our study confirms CDKN2A/B homozygous deletion as a key genetic alteration in PXA, irrespective of tumor grade, BRAF mutation, or clinical outcome.	('PXA', 'Chemical', '-', (91, 94))	('CDKN2A/B', 'Gene', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('PXA', 'Disease', (91, 94))	('homozygous', 'Var', (40, 50))	('CDKN2A/B', 'Gene', '1029;1030', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('BRAF', 'Gene', '673', (125, 129))	('tumor', 'Disease', (112, 117))	('BRAF', 'Gene', (125, 129))
166532	28181325	The prevalence of chromosomal gains, losses, and cnLOH may be useful in diagnostically challenging cases to differentiate PXA from other low-grade gliomas and from giant cell glioblastoma, which typically lack CDKN2A/B deletion.	('CDKN2A/B', 'Gene', (210, 218))	('giant cell glioblastoma', 'Disease', 'MESH:D005909', (164, 187))	('CDKN2A/B', 'Gene', '1029;1030', (210, 218))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('cnLOH', 'Var', (49, 54))	('losses', 'Var', (37, 43))	('PXA', 'Disease', (122, 125))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Disease', (147, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('giant cell glioblastoma', 'Disease', (164, 187))	('PXA', 'Chemical', '-', (122, 125))
166629	26890637	Orthotopic brain tumor visualization was possible with 18F-FSPG, 18F-FDG, and 18F-FET in a rodent model (Fig 2).	('18F-FDG', 'Var', (65, 72))	('18F-FDG', 'Chemical', 'MESH:D019788', (65, 72))	('brain tumor', 'Disease', 'MESH:D001932', (11, 22))	('brain tumor', 'Disease', (11, 22))	('18F-FET', 'Var', (78, 85))	('18F-FSPG', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('brain tumor', 'Phenotype', 'HP:0030692', (11, 22))
166633	26890637	Strong tracer uptake in the Harderian glands, a rodent-specific gland, was observed for 18F-FSPG and 18F-FDG but not for 18F-FET.	('tracer', 'MPA', (7, 13))	('18F-FDG', 'Var', (101, 108))	('18F-FDG', 'Chemical', 'MESH:D019788', (101, 108))	('18F-FSPG', 'Var', (88, 96))
166637	26890637	There was a higher tumor-to-normal brain ratio for 18F-FSPG over both 18F-FET and 18F-FDG.	('18F-FDG', 'Chemical', 'MESH:D019788', (82, 89))	('higher', 'PosReg', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('rat', 'Species', '10116', (41, 44))	('tumor', 'Disease', (19, 24))	('18F-FSPG', 'Var', (51, 59))
166667	26890637	The rat GS9L orthotopic brain tumor model evaluated in this study shows the potential utility of 18F-FSPG compared to 18F-FDG and 18F-FET under the conditions used.	('18F-FSPG', 'Var', (97, 105))	('brain tumor', 'Disease', (24, 35))	('brain tumor', 'Disease', 'MESH:D001932', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('rat', 'Species', '10116', (4, 7))	('brain tumor', 'Phenotype', 'HP:0030692', (24, 35))	('18F-FDG', 'Chemical', 'MESH:D019788', (118, 125))
166670	26890637	Despite the small sample size, significant differences were observed between 18F-FSPG & 18F-FDG and 18F-FSPG & 18F-FET but not between 18F-FDG & 18F-FET.	('and 18F-FSPG', 'Var', (96, 108))	('18F-FDG', 'Chemical', 'MESH:D019788', (88, 95))	('18F-FDG', 'Chemical', 'MESH:D019788', (135, 142))	('18F-FSPG &', 'Var', (77, 87))
166694	26890637	Other amino acid based PET tracers show generally lower lesion uptake and higher normal brain uptake resulting in T/B ratios of 4-5 (18F-Gln), 3.4-4.3 (18F-FET) and 3.3-3.6 (18F-FDOPA).	('18F-Gln', 'Var', (133, 140))	('lower', 'NegReg', (50, 55))	('rat', 'Species', '10116', (118, 121))	('higher', 'PosReg', (74, 80))	('-FDOPA', 'Chemical', 'MESH:C043437', (177, 183))	('brain uptake', 'MPA', (88, 100))	('18F-FET', 'Var', (152, 159))	('lesion uptake', 'MPA', (56, 69))	('Gln', 'Chemical', 'MESH:D005973', (137, 140))
166750	26544514	This observation was also the case for MD and ADC among grade II, III and IV gliomas (MD: 2.012 +- 0.443 for grade II, 1.604 +- 0.337 for grade III, 1.376 +- 0.259 for grade IV, P < 0.001; ADC: 1.900 +- 0.396 for grade II, 1.609 +- 0.346 for grade III, 1.344 +- 0.236 for grade IV, P < 0.001) as well as between each pair of grades in multiple comparisons (P < 0.05).	('1.376 +- 0.259', 'Var', (149, 163))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('IV gliomas', 'Disease', (74, 84))	('IV gliomas', 'Disease', 'MESH:D005910', (74, 84))	('1.344 +- 0.236', 'Var', (253, 267))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
166751	26544514	However, FA did not show significant differences among grade II, III and IV gliomas (0.362 +- 0.125 for grade II, 0.433 +- 0.137 for grade III, 0.409 +- 0.136 for grade IV, P = 0.155).	('IV gliomas', 'Disease', (73, 83))	('IV gliomas', 'Disease', 'MESH:D005910', (73, 83))	('0.409 +- 0.136', 'Var', (144, 158))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('0.433 +- 0.137', 'Var', (114, 128))
166765	26544514	The difference in Ki-67 LI among grade II, III and IV gliomas was also significant (P < 0.001), which was also the case for Ki-67 LI between each pair of grades (P < 0.05).	('Ki-67', 'Var', (18, 23))	('IV gliomas', 'Disease', (51, 61))	('IV gliomas', 'Disease', 'MESH:D005910', (51, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
166805	26544514	All these changes may increase the heterogeneity and complexity of the microstructure in the tumor and inhibit water molecule movement both inside and outside tumor cells.	('water', 'Chemical', 'MESH:D014867', (111, 116))	('complexity', 'MPA', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (93, 98))	('increase', 'PosReg', (22, 30))	('tumor', 'Disease', (159, 164))	('heterogeneity', 'MPA', (35, 48))	('changes', 'Var', (10, 17))	('water molecule movement', 'MPA', (111, 134))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('inhibit', 'NegReg', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
166808	26544514	In contrast, FA was decreased at all grades and also all levels of Ki-67, perhaps because diffusion is restricted to a similar degree in all directions in the solid region of the tumor.	('decreased', 'NegReg', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Ki-67', 'Var', (67, 72))	('diffusion', 'MPA', (90, 99))	('tumor', 'Disease', (179, 184))
166836	26544514	Although the scan matrix, slice thickness, spacing and FOV were different in enhanced T1-FLAIR, T2-FSE, DWI and DKI, the image resolutions ultimately generated by the scanner was 512 x 512, 512 x 512, 256 x 256 and 256 x 256, respectively, due to interpolation; in addition, these four sequences had the same scan coverage.	('T2-FSE', 'Gene', (96, 102))	('256 x', 'Var', (215, 220))	('T2-FSE', 'Gene', '292', (96, 102))	('T1-FLAIR', 'Gene', (86, 94))	('T1-FLAIR', 'Gene', '9173', (86, 94))	('256 x', 'Var', (201, 206))
166864	12592364	A strong association between the presence of telomerase and malignancy has been established in nearly all cancer types (reviewed in Shay et al, 2001).	('malignancy', 'Disease', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('telomerase', 'Protein', (45, 55))	('presence', 'Var', (33, 41))	('cancer', 'Disease', (106, 112))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
166865	12592364	Importantly, high telomerase activity is generally associated with high tumour aggressiveness.	('high tumour aggressiveness', 'Disease', (67, 93))	('high', 'Var', (13, 17))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('high tumour aggressiveness', 'Disease', 'MESH:D001523', (67, 93))	('activity', 'MPA', (29, 37))	('telomerase', 'Protein', (18, 28))	('associated', 'Reg', (51, 61))	('aggressiveness', 'Phenotype', 'HP:0000718', (79, 93))
166911	12592364	We found that the patients with high (>25%) hTERT mRNA levels had significantly shorter survival vs the patients with low (<=25%) levels (log-rank test, P=0.0082, Figure 3).	('high (>25%', 'Var', (32, 42))	('survival', 'MPA', (88, 96))	('shorter', 'NegReg', (80, 87))	('patients', 'Species', '9606', (18, 26))	('hTERT', 'Gene', '7015', (44, 49))	('patients', 'Species', '9606', (104, 112))	('hTERT', 'Gene', (44, 49))
166924	12592364	Previous studies have suggested that telomerase activity in gliomas may have utility in tumour prognosis, as the presence of such activity has been correlated with a poor prognosis for low-grade and anaplastic tumours (Nakatani et al, 1997; Hiraga et al, 1998; Huang et al, 1999).	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('activity', 'MPA', (48, 56))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('anaplastic tumours', 'Disease', (199, 217))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('presence', 'Var', (113, 121))	('anaplastic tumours', 'Disease', 'MESH:D065646', (199, 217))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('telomerase', 'Protein', (37, 47))	('activity', 'MPA', (130, 138))	('tumour', 'Disease', (210, 216))
166926	12592364	In the present study, we found that among hTERT-positive GBM patients, the overall survival was significantly worse in the patients with high levels of hTERT mRNA.	('hTERT', 'Gene', (42, 47))	('hTERT', 'Gene', '7015', (152, 157))	('high', 'Var', (137, 141))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (123, 131))	('hTERT', 'Gene', (152, 157))	('worse', 'NegReg', (110, 115))	('hTERT', 'Gene', '7015', (42, 47))
166932	12592364	Studies of hTERT-protein distribution using immunohistochemistry in cultured cells and tissue sections have shown that hTERT expression was detected in almost all neoplastic cells in cancer tissues with high telomerase activity, whereas cancers with low telomerase activity had fewer hTERT-positive cancer cells (Hiyama et al, 2001).	('hTERT', 'Gene', (11, 16))	('hTERT', 'Gene', '7015', (119, 124))	('detected', 'Reg', (140, 148))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('hTERT', 'Gene', '7015', (284, 289))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Disease', (237, 244))	('cancer', 'Disease', (237, 243))	('hTERT', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('high', 'Var', (203, 207))	('cancer', 'Disease', (299, 305))	('hTERT', 'Gene', '7015', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('hTERT', 'Gene', (284, 289))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancers', 'Disease', 'MESH:D009369', (237, 244))
166937	12592364	Evidence in support of this hypothesis has been reported in a study of telomere length in gliomas (Morii et al, 1997).	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('telomere length', 'Var', (71, 86))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
166938	12592364	Compared with telomerase-positive gliomas, telomerase-negative gliomas were found to have very long and heterogeneous telomeres, characteristics seen in tumour cells that have acquired an alternative mechanism for lengthening their telomeres.	('tumour', 'Disease', (153, 159))	('gliomas', 'Disease', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('telomerase-negative', 'Var', (43, 62))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
166978	33471214	The results of surgical resection can cause numerous pituitary problems, requiring the patient to be referred to a neuroendocrinologist in order to maintain essential hormones in the body.	('pituitary problems', 'Disease', (53, 71))	('cause', 'Reg', (38, 43))	('essential hormones', 'MPA', (157, 175))	('patient', 'Species', '9606', (87, 94))	('pituitary problems', 'Phenotype', 'HP:0011747', (53, 71))	('maintain', 'PosReg', (148, 156))	('surgical resection', 'Var', (15, 33))
167000	33471214	Adherence to these recommendations has been associated with an absolute risk reduction of death at 5 years in patients with certain types of cancer.	('Adherence', 'Var', (0, 9))	('patients', 'Species', '9606', (110, 118))	('reduction', 'NegReg', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
167078	33096928	During the last two decades, genetic analyses identified point mutation within the gene encoding the enzyme isocitrate dehydrogenase (IDH) to be an early event in gliomagenesis, thus showing an especially high prevalence in LGG.	('isocitrate dehydrogenase', 'Gene', '3417', (108, 132))	('IDH', 'Gene', '3417', (134, 137))	('glioma', 'Disease', (163, 169))	('LGG', 'Disease', (224, 227))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('point mutation', 'Var', (57, 71))	('isocitrate dehydrogenase', 'Gene', (108, 132))	('IDH', 'Gene', (134, 137))
167134	33096928	On a functional level, the latter has been attributed to production of the oncometabolite R-2-hydroxyglutarate by mutant IDH, which has been shown to impair T cell migration.	('T cell migration', 'CPA', (157, 173))	('impair', 'NegReg', (150, 156))	('IDH', 'Gene', (121, 124))	('mutant', 'Var', (114, 120))	('IDH', 'Gene', '3417', (121, 124))	('R-2-hydroxyglutarate', 'Chemical', '-', (90, 110))
167147	33096928	To date, there is considerable clinical data that combined radiochemotherapy causes lymphopenia, which, in turn, may lead to a lower T-cell infiltration from the periphery.	('T-cell infiltration from the periphery', 'CPA', (133, 171))	('radiochemotherapy', 'Var', (59, 76))	('lymphopenia', 'Disease', (84, 95))	('lower', 'NegReg', (127, 132))	('lymphopenia', 'Phenotype', 'HP:0001888', (84, 95))	('lymphopenia', 'Disease', 'MESH:D008231', (84, 95))
167149	33096928	Higher mutational loads are associated with increased numbers of intratumoral T cells, which might explain the opposing results we observed upon prior administration of chemotherapy.	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutational loads', 'Var', (7, 23))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
167178	31531299	Biopsy can lead to swelling or bleeding on the brain, infections, seizures, stroke or coma.	('Biopsy', 'Var', (0, 6))	('coma', 'Phenotype', 'HP:0001259', (86, 90))	('coma', 'Disease', (86, 90))	('bleeding on the brain', 'Phenotype', 'HP:0001342', (31, 52))	('swelling', 'Disease', 'MESH:D004487', (19, 27))	('infections', 'Disease', 'MESH:D007239', (54, 64))	('seizures', 'Disease', 'MESH:D012640', (66, 74))	('lead to', 'Reg', (11, 18))	('stroke', 'Disease', 'MESH:D020521', (76, 82))	('bleeding', 'Disease', 'MESH:D006470', (31, 39))	('stroke', 'Phenotype', 'HP:0001297', (76, 82))	('infections', 'Disease', (54, 64))	('bleeding', 'Disease', (31, 39))	('stroke', 'Disease', (76, 82))	('seizures', 'Phenotype', 'HP:0001250', (66, 74))	('swelling', 'Disease', (19, 27))	('seizures', 'Disease', (66, 74))	('coma', 'Disease', 'MESH:D003128', (86, 90))
167200	31186453	We found that Nlrp12 deficient microglia show increased colony formation while Nlrp12 deficient glioma cells show decreased cellular proliferation.	('cellular proliferation', 'CPA', (124, 146))	('colony formation', 'CPA', (56, 72))	('deficient glioma', 'Disease', (86, 102))	('increased', 'PosReg', (46, 55))	('deficient', 'Var', (21, 30))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('decreased', 'NegReg', (114, 123))	('Nlrp12', 'Gene', (14, 20))	('Nlrp12', 'Gene', (79, 85))	('deficient glioma', 'Disease', 'MESH:D005910', (86, 102))
167207	31186453	GBM is multiforme in every aspect; grossly (increased necrosis), microscopically (pleomorphic nuclei, microvascular proliferation) and genetically (gene deletion, mutation), with a median survival of less than 15 months.	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('necrosis', 'Disease', (54, 62))	('increased', 'PosReg', (44, 53))	('mutation', 'Var', (163, 171))	('increased necrosis', 'Phenotype', 'HP:0010885', (44, 62))	('necrosis', 'Disease', 'MESH:D009336', (54, 62))
167217	31186453	Dysregulated NLR function is associated with a wide array of diseases including microbial infections, diabetes, cardiac and metabolic disorders, autoimmune diseases and cancers.	('NLR', 'Gene', (13, 16))	('diabetes', 'Disease', 'MESH:D003920', (102, 110))	('infections', 'Disease', (90, 100))	('autoimmune diseases and cancers', 'Disease', 'MESH:D001327', (145, 176))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('metabolic disorders', 'Disease', 'MESH:D008659', (124, 143))	('Dysregulated', 'Var', (0, 12))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (145, 164))	('associated', 'Reg', (29, 39))	('infections', 'Disease', 'MESH:D007239', (90, 100))	('metabolic disorders', 'Disease', (124, 143))	('diabetes', 'Disease', (102, 110))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
167263	31186453	The cellular and molecular complexity of glioma and cross talk within the tumor microenvironment bring focus on genomic and epigenetic variations occurring in glioma.	('glioma', 'Disease', (159, 165))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cross talk within the tumor', 'Disease', 'MESH:D001929', (52, 79))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('cross talk within the tumor', 'Disease', (52, 79))	('glioma', 'Disease', (41, 47))	('epigenetic variations', 'Var', (124, 145))
167272	31186453	The network provides an overview of the altered genes in pathways related to glioma highlighting the frequency of alteration by mutation, CNA, and mRNA up- or down-regulation.	('down-regulation', 'NegReg', (159, 174))	('mutation', 'Var', (128, 136))	('glioma', 'Disease', (77, 83))	('up-', 'PosReg', (152, 155))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
167278	31186453	Interestingly, TP53 was more frequently altered and mutated in LGG as compared to the GBM and, EGFR was more frequently altered and mutated in GBM as compared to the LGG.	('altered', 'Reg', (120, 127))	('LGG', 'Disease', (63, 66))	('mutated', 'Var', (52, 59))	('GBM', 'Phenotype', 'HP:0012174', (143, 146))	('mutated', 'Var', (132, 139))	('TP53', 'Gene', '7157', (15, 19))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('TP53', 'Gene', (15, 19))	('altered', 'Reg', (40, 47))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (95, 99))
167279	31186453	EGFR and TP53 alterations are known to contribute significantly in various tumors, including glioma.	('alterations', 'Var', (14, 25))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('glioma', 'Disease', (93, 99))	('EGFR', 'Gene', (0, 4))	('contribute', 'Reg', (39, 49))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('EGFR', 'Gene', '1956', (0, 4))
167293	31186453	In GBM, EGFR overactivation triggers activation of multiple downstream signaling pathways such as PI3K/Akt/rapamycin-sensitive mTOR pathway, followed by poor prognosis and drug resistance.	('mTOR', 'Gene', '2475', (127, 131))	('Akt', 'Gene', (103, 106))	('activation', 'PosReg', (37, 47))	('drug resistance', 'CPA', (172, 187))	('drug resistance', 'Phenotype', 'HP:0020174', (172, 187))	('Akt', 'Gene', '207', (103, 106))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('EGFR', 'Gene', '1956', (8, 12))	('mTOR', 'Gene', (127, 131))	('EGFR', 'Gene', (8, 12))	('overactivation', 'Var', (13, 27))
167296	31186453	Targeting DNA methylation of specific biomarker gene promoter regions such as MGMT methylation has undoubtedly favored glioma prognosis and improved survival.	('improved', 'PosReg', (140, 148))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('favored', 'PosReg', (111, 118))	('MGMT', 'Gene', '4255', (78, 82))	('methylation', 'Var', (14, 25))	('MGMT', 'Gene', (78, 82))	('glioma', 'Disease', (119, 125))	('methylation', 'Var', (83, 94))	('survival', 'CPA', (149, 157))
167303	31186453	Interestingly, we found differential expression and significantly methylated CpG loci for NLRP3 (cg21991396, cg07313373) and CASP1 (cg21002651, cg13802966) in GBM.	('CASP1', 'Gene', (125, 130))	('NLRP3', 'Gene', '114548', (90, 95))	('cg07313373', 'Var', (109, 119))	('cg13802966', 'Var', (144, 154))	('cg21002651', 'Var', (132, 142))	('cg21991396', 'Var', (97, 107))	('CASP1', 'Gene', '834', (125, 130))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('NLRP3', 'Gene', (90, 95))
167304	31186453	Recently, Paugh et al., observed significantly high CASP1 and NLRP3 expression in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of same CASP1(cg13802966) and NLRP3 (cg21991396) promoter regions.	('NLRP3', 'Gene', '114548', (200, 205))	('lower', 'NegReg', (144, 149))	('expression', 'MPA', (68, 78))	('high', 'PosReg', (47, 51))	('CASP1', 'Gene', '834', (178, 183))	('cg21991396', 'Var', (207, 217))	('somatic methylation', 'MPA', (150, 169))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('NLRP3', 'Gene', (62, 67))	('CASP1', 'Gene', '834', (52, 57))	('CASP1', 'Gene', (178, 183))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('leukemia', 'Disease', (107, 115))	('CASP1', 'Gene', (52, 57))	('NLRP3', 'Gene', '114548', (62, 67))	('NLRP3', 'Gene', (200, 205))
167343	31186453	These finding suggest NLRP12 inhibition leads to increased microglial proliferation and reduced glioma cell proliferation in vitro.	('NLRP12', 'Gene', (22, 28))	('microglial proliferation', 'CPA', (59, 83))	('increased', 'PosReg', (49, 58))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('NLRP12', 'Gene', '91662', (22, 28))	('reduced', 'NegReg', (88, 95))	('inhibition', 'Var', (29, 39))	('glioma', 'Disease', (96, 102))
167345	31186453	We tested migration of microglia and glioma cells towards conditioned media from glioma cell or microglia cells derived from Nlrp12 deficient cells.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('glioma', 'Disease', (37, 43))	('tested', 'Reg', (3, 9))	('glioma', 'Disease', (81, 87))	('Nlrp12', 'Gene', (125, 131))	('deficient', 'Var', (132, 141))	('migration', 'CPA', (10, 19))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
167358	31186453	There have been some investigations into the prognostic markers for gliomas including Poly (ADP-ribose) polymerase-1 (PARP-1) Val762Ala polymorphism.	('polymorphism', 'Var', (136, 148))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('PARP-1', 'Gene', (118, 124))	('Val762Ala polymorphism', 'Var', (126, 148))	('PARP-1', 'Gene', '142', (118, 124))	('Poly (ADP-ribose) polymerase-1', 'Gene', '142', (86, 116))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('Val762Ala', 'Mutation', 'rs1136410', (126, 135))	('Poly (ADP-ribose) polymerase-1', 'Gene', (86, 116))
167367	31186453	Rare mutations in NLRP12, are associated with periodic fevers in humans.	('associated', 'Reg', (30, 40))	('fevers', 'Phenotype', 'HP:0001945', (55, 61))	('periodic fevers', 'Disease', (46, 61))	('mutations', 'Var', (5, 14))	('NLRP12', 'Gene', '91662', (18, 24))	('periodic fevers', 'Phenotype', 'HP:0032323', (46, 61))	('NLRP12', 'Gene', (18, 24))	('humans', 'Species', '9606', (65, 71))
167368	31186453	Nonsense and splice mutations within human NLRP12 diminish suppression of NF-kB signaling; however, some variants do not exhibit such activity and are associated with modestly enhanced or more rapid inflammasome activation.	('NF-kB signaling', 'MPA', (74, 89))	('Nonsense', 'Var', (0, 8))	('suppression', 'MPA', (59, 70))	('diminish', 'NegReg', (50, 58))	('enhanced', 'PosReg', (176, 184))	('variants', 'Var', (105, 113))	('human', 'Species', '9606', (37, 42))	('NLRP12', 'Gene', '91662', (43, 49))	('NLRP12', 'Gene', (43, 49))
167375	31186453	While activated dendritic cells from Nlrp12-deficient mice displayed normal IL-1beta secretion, activated THP-1 cells transduced with NLRP12 small interfering RNA were shown to secrete increased levels of IL-1beta and NLRP12 expressed in COS-7L cells was found to activate proIL-1beta secretion.	('COS-7L', 'CellLine', 'CVCL:0J76', (238, 244))	('mice', 'Species', '10090', (54, 58))	('NLRP12', 'Gene', (134, 140))	('secrete', 'MPA', (177, 184))	('small interfering RNA', 'Var', (141, 162))	('IL-1beta secretion', 'MPA', (76, 94))	('THP-1', 'CellLine', 'CVCL:0006', (106, 111))	('activate', 'PosReg', (264, 272))	('levels', 'MPA', (195, 201))	('proIL-1beta secretion', 'MPA', (273, 294))	('increased', 'PosReg', (185, 194))	('NLRP12', 'Gene', '91662', (218, 224))	('NLRP12', 'Gene', (218, 224))	('NLRP12', 'Gene', '91662', (134, 140))
167380	31186453	Enhanced immune cell infiltration and pro-inflammatory cytokine production leads to prolonged colon inflammation and increased tumorigenesis in the Nlrp12-deficient mice (Zaki et al., 2011).	('immune cell infiltration', 'CPA', (9, 33))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Nlrp12-deficient', 'Gene', (148, 164))	('Nlrp12-deficient', 'Var', (148, 164))	('mice', 'Species', '10090', (165, 169))	('increased', 'PosReg', (117, 126))	('tumor', 'Disease', (127, 132))	('prolonged colon inflammation', 'Disease', (84, 112))	('prolonged colon inflammation', 'Disease', 'MESH:D007249', (84, 112))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Enhanced', 'PosReg', (0, 8))
167391	31186453	In line with our results, Zhu et al., also found SSFA2 deletion inhibits glioma cell proliferation and increased cancer cell apoptosis.	('glioma', 'Disease', (73, 79))	('SSFA2', 'Gene', (49, 54))	('increased', 'PosReg', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('SSFA2', 'Gene', '6744', (49, 54))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('deletion', 'Var', (55, 63))	('inhibits', 'NegReg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
167415	31052553	According to recent publications, the direct methylation modification sites of C/D snoRNAs are located precisely 5 bp upstream of the D box of snoRNPs, reflecting the accurate positioning and effective regulatory contribution of snoRNAs.	('methylation modification', 'MPA', (45, 69))	('snoRNA', 'Gene', (229, 235))	('snoRNA', 'Gene', '85388', (229, 235))	('snoRNA', 'Gene', (83, 89))	('C/D', 'Var', (79, 82))	('snoRNA', 'Gene', '85388', (83, 89))	('D snoRNAs', 'Phenotype', 'HP:0025267', (81, 90))
167445	31052553	Ribosomal RNAs, transfer RNAs, and small nuclear RNAs are the three subgroups of snoRNAs.	('snoRNA', 'Gene', (81, 87))	('snoRNA', 'Gene', '85388', (81, 87))	('Ribosomal', 'Protein', (0, 9))	('small nuclear', 'Var', (35, 48))	('transfer', 'CPA', (16, 24))
167485	31052553	According to this rule, the high expression of U3 and low expression of SNORD123 and U94B may indicate that the potential tumor is LGG.	('SNORD123', 'Gene', '100113384', (72, 80))	('U94B', 'Var', (85, 89))	('low', 'NegReg', (54, 57))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('SNORD123', 'Gene', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('expression', 'MPA', (33, 43))	('tumor', 'Disease', (122, 127))
167490	31052553	According to a recent clinical study on LUSC progression, the expression of hTR snoRNA promotes tumorigenesis, corresponding with this rule.	('hTR', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('hTR', 'Gene', '7012', (76, 79))	('promotes', 'PosReg', (87, 95))	('snoRNA', 'Gene', (80, 86))	('snoRNA', 'Gene', '85388', (80, 86))	('expression', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
167546	29725480	Results from the image analysis using FDG-PET, MET-PET, ADC and FA may be affected by ROI design and the most discriminating ROI for non-enhancing glioma grading was different according to the imaging modality.	('MET', 'Chemical', '-', (47, 50))	('ADC', 'Chemical', '-', (56, 59))	('FDG', 'Chemical', 'MESH:D019788', (38, 41))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('ADC', 'Disease', (56, 59))	('glioma', 'Disease', (147, 153))	('MET-PET', 'Var', (47, 54))
167579	29725480	Although these differences were not significant (P=0.41, 0.85, 0.087, and 0.28, respectively), the difference between grade II and III gliomas tended to increase when utilizing 2D-HC ROI.	('2D-HC ROI', 'Var', (177, 186))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('increase', 'PosReg', (153, 161))
167589	29725480	The AUC of the ROC curve was also greatest for 2D-HC ROI for discriminating grade II and III non-enhancing gliomas (Fig.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('2D-HC', 'Var', (47, 52))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))
167594	29725480	Although these differences were not significant (P=0.95, 0.92, 0.25, and 0.66, respectively), the difference between grade II and III gliomas tended to increase when applying 2D-HC ROI.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('increase', 'PosReg', (152, 160))	('2D-HC ROI', 'Var', (175, 184))	('gliomas', 'Disease', (134, 141))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))
167661	29221154	Moreover, the GD2+ UMUC3 cells proliferated more rapidly than the GD2- UMUC3 cells (Figure 1F).	('proliferated', 'CPA', (31, 43))	('GD2', 'Chemical', '-', (14, 17))	('GD2', 'Chemical', '-', (66, 69))	('GD2+', 'Var', (14, 18))
167666	29221154	The analysis showed the alterations in the important lipid classes and identified 161 individual lipid species were altered between GD2+ and GD2- in both cell lines (Figure 3A).	('individual lipid species', 'MPA', (86, 110))	('altered', 'Reg', (116, 123))	('GD2', 'Chemical', '-', (141, 144))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('GD2', 'Chemical', '-', (132, 135))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('GD2+', 'Var', (132, 136))	('GD2-', 'Var', (141, 145))	('important lipid classes', 'MPA', (43, 66))	('alterations', 'Reg', (24, 35))
167667	29221154	We have identified that GD2+ cells have lower levels of phosphatidylserine (PS), plasmenyl-phosphatidylethanolamines (pPE), plasmenyl-phosphocholines (pPC), sphingomyelins (SM) tricylglycerols (TGs) and higher levels of Phosphatidylinositol (PI), Phosphatidic acid (PA), and Cardiolipin (CL) (Figure 3B).	('phosphatidylserine', 'Chemical', 'MESH:D010718', (56, 74))	('Phosphatidylinositol', 'Chemical', 'MESH:D010716', (220, 240))	('phosphatidylserine', 'MPA', (56, 74))	('Cardiolipin', 'Chemical', 'MESH:D002308', (275, 286))	('Phosphatidic acid', 'Chemical', 'MESH:D010712', (247, 264))	('plasmenyl-phosphocholines', 'MPA', (124, 149))	('SM', 'Chemical', 'MESH:D013109', (173, 175))	('GD2', 'Chemical', '-', (24, 27))	('levels', 'MPA', (46, 52))	('higher', 'PosReg', (203, 209))	('GD2+', 'Var', (24, 28))	('Phosphatidic acid', 'MPA', (247, 264))	('pPE', 'Chemical', '-', (118, 121))	('PA', 'Chemical', 'MESH:D010712', (266, 268))	('plasmenyl-phosphocholines', 'Chemical', '-', (124, 149))	('tricylglycerols', 'Chemical', '-', (177, 192))	('pPC', 'Chemical', '-', (151, 154))	('lower', 'NegReg', (40, 45))	('PS', 'Chemical', 'MESH:D010718', (76, 78))	('sphingomyelins', 'Chemical', 'MESH:D013109', (157, 171))	('levels of Phosphatidylinositol', 'MPA', (210, 240))	('sphingomyelins', 'MPA', (157, 171))	('TGs', 'Chemical', 'MESH:D014280', (194, 197))	('plasmenyl-phosphatidylethanolamines', 'MPA', (81, 116))	('plasmenyl-phosphatidylethanolamines', 'Chemical', '-', (81, 116))	('Cardiolipin', 'MPA', (275, 286))
167675	29221154	We further checked the GD3 synthase, a major regulatory enzyme for the synthesis of GD2 in UMUC3 BLCA cells and found it to be inhibited by PDMP (Figure 5C).	('GD3', 'Gene', '117189', (23, 26))	('GD3', 'Gene', (23, 26))	('inhibited', 'NegReg', (127, 136))	('GD2', 'Chemical', '-', (84, 87))	('BLCA', 'Phenotype', 'HP:0009725', (97, 101))	('GD2', 'Gene', (84, 87))	('PDMP', 'Var', (140, 144))
167682	29221154	Specifically, GD2+ cells displayed stem cell properties similar to those of the CD44hiCD24lo population.	('stem cell properties', 'CPA', (35, 55))	('CD44', 'Gene', (80, 84))	('GD2', 'Chemical', '-', (14, 17))	('GD2+', 'Var', (14, 18))	('CD44', 'Gene', '960', (80, 84))	('CD24', 'Gene', '100133941', (86, 90))	('CD24', 'Gene', (86, 90))
167687	29221154	Several studies have evidenced that GD2-specific antibodies inhibit tumor growth without the involvement of the immune system.	('tumor', 'Disease', (68, 73))	('inhibit', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('antibodies', 'Var', (49, 59))	('GD2', 'Chemical', '-', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('GD2-specific', 'Protein', (36, 48))
167702	29221154	Many evidences show that PLD has a role in cell migration which is key to cell invasion and metastasis and active PLD enhances lymphoma cell metastasis, where as the inactivation of PLD inhibited the metastasis, MMP-2 expression in glioma cell invasion.	('PLD', 'Gene', '2822', (25, 28))	('PLD', 'Gene', (25, 28))	('inhibited', 'NegReg', (186, 195))	('PLD', 'Gene', '2822', (182, 185))	('MMP-2', 'Gene', (212, 217))	('PLD', 'Gene', (182, 185))	('glioma', 'Disease', (232, 238))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('enhances', 'PosReg', (118, 126))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('lymphoma', 'Disease', (127, 135))	('metastasis', 'CPA', (200, 210))	('lymphoma', 'Disease', 'MESH:D008223', (127, 135))	('PLD', 'Gene', '2822', (114, 117))	('MMP-2', 'Gene', '4313', (212, 217))	('PLD', 'Gene', (114, 117))	('inactivation', 'Var', (166, 178))	('expression', 'MPA', (218, 228))
167705	29221154	An abnormal increase of cardiolipin in GD2+ needs to be further investigated for its role in cancer progression.	('GD2+', 'Var', (39, 43))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('increase', 'PosReg', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cardiolipin', 'Protein', (24, 35))	('GD2', 'Chemical', '-', (39, 42))
167708	29221154	This is supported by several recent reports that gangliosides including GD1a, GD1b, GD3, and GM3 help tumors evade the immune attack by inducing apoptosis in immune cells, including T and NK cells.	('inducing', 'Reg', (136, 144))	('GD3', 'Gene', '117189', (84, 87))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('GD3', 'Gene', (84, 87))	('GM3', 'Chemical', '-', (93, 96))	('gangliosides', 'Chemical', 'MESH:D005732', (49, 61))	('GM3', 'Var', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('apoptosis', 'CPA', (145, 154))
167715	29221154	In addition, we have ascertained that GD2+ cells promote rapid BLCA growth and display cancer stem cell properties.	('cancer', 'Disease', (87, 93))	('GD2+', 'Var', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rapid BLCA growth', 'CPA', (57, 74))	('GD2', 'Chemical', '-', (38, 41))	('BLCA', 'Phenotype', 'HP:0009725', (63, 67))	('promote', 'PosReg', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
167732	29221154	Cells were detached with trypsin, washed twice in PBS, then stained with anti GD2-APC, anti-CD24-FITC and anti-CD44-PE (Biolegend Antibodies) using 5 mul of antibody per 106 cells, and incubated in ice for 15 min.	('CD44', 'Gene', (111, 115))	('PC', 'Chemical', '-', (83, 85))	('CD24', 'Gene', '100133941', (92, 96))	('CD24', 'Gene', (92, 96))	('CD44', 'Gene', '960', (111, 115))	('anti GD2-APC', 'Var', (73, 85))	('GD2', 'Chemical', '-', (78, 81))
167743	26185825	We have also demonstrated that EOR >= 90% was significantly associated with progression-free survival and overall survival in low-grade glioma.	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('progression-free survival', 'CPA', (76, 101))	('glioma', 'Disease', (136, 142))	('overall survival', 'CPA', (106, 122))	('EOR >= 90%', 'Var', (31, 41))	('associated', 'Reg', (60, 70))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
167772	26185825	A recent meta-analysis demonstrated late severe neurological deficit in 3.4% of patients who underwent resection with stimulation mapping, compared to 8.3% of patients who underwent resection without mapping.	('neurological deficit', 'Disease', (48, 68))	('neurological deficit', 'Phenotype', 'HP:0000707', (48, 68))	('patients', 'Species', '9606', (80, 88))	('stimulation mapping', 'Var', (118, 137))	('neurological deficit', 'Disease', 'MESH:D009461', (48, 68))	('patients', 'Species', '9606', (159, 167))
167827	26185825	Examples include rapid immunohistochemistry devices and rapid isocitrate dehydrogenase (IDH) mutation analyses.	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', (88, 91))	('mutation analyses', 'Var', (93, 110))
167843	24691423	However, the presence of high CD4+ and low CD8+ TIL levels was an independent predictor of poor progress-free survival (multivariate hazard ratio (HR) 1.618, 95% confidence interval (CI) 1.245-2.101, P<0.001) and poor overall survival (multivariate HR 1.508, 95% CI 1.162-1.956, P=0.002).	('low CD8+ TIL levels', 'Phenotype', 'HP:0005415', (39, 58))	('CD8', 'Gene', (43, 46))	('CD8', 'Gene', '925', (43, 46))	('low', 'NegReg', (39, 42))	('TIL', 'Gene', '7096', (48, 51))	('progress-free survival', 'CPA', (96, 118))	('high', 'Var', (25, 29))	('poor', 'NegReg', (91, 95))	('TIL', 'Gene', (48, 51))	('poor', 'NegReg', (213, 217))	('overall', 'MPA', (218, 225))	('CD4', 'Gene', (30, 33))	('CD4', 'Gene', '920', (30, 33))
167921	24691423	Among 30 patients with methylated MGMT promoter, pseudoprogression was found in 10 (33.3%).	('patients', 'Species', '9606', (9, 17))	('methylated', 'Var', (23, 33))	('found', 'Reg', (71, 76))	('pseudoprogression', 'Disease', (49, 66))	('MGMT', 'Gene', (34, 38))	('MGMT', 'Gene', '4255', (34, 38))
167961	24691423	Interestingly, in GBM patients, low CD4+ and high CD8+ TIL levels were also associated with unfavourable prognosis, although their survival was better than that of patients with high CD4+ and low CD8+ TILs (Figure 3E).	('TIL', 'Gene', '7096', (201, 204))	('CD4', 'Gene', '920', (36, 39))	('low', 'NegReg', (32, 35))	('CD8', 'Gene', (50, 53))	('patients', 'Species', '9606', (22, 30))	('CD8', 'Gene', '925', (196, 199))	('high', 'Var', (45, 49))	('CD4', 'Gene', (36, 39))	('patients', 'Species', '9606', (164, 172))	('TIL', 'Gene', (201, 204))	('better', 'PosReg', (144, 150))	('TIL', 'Gene', '7096', (55, 58))	('TILs', 'Chemical', '-', (201, 205))	('CD4', 'Gene', '920', (183, 186))	('survival', 'CPA', (131, 139))	('CD8', 'Gene', '925', (50, 53))	('CD4', 'Gene', (183, 186))	('CD8', 'Gene', (196, 199))	('TIL', 'Gene', (55, 58))
167965	24691423	On the contrary, imbalance of CD4+ and CD8+ TILs may reflect or result in malfunction of anti-tumour immunity.	('tumour', 'Disease', (94, 100))	('imbalance', 'Phenotype', 'HP:0002172', (17, 26))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('TILs', 'Chemical', '-', (44, 48))	('result in', 'Reg', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('imbalance of CD4+', 'Phenotype', 'HP:0005407', (17, 34))	('reflect', 'Reg', (53, 60))	('imbalance', 'Var', (17, 26))	('CD4', 'Gene', (30, 33))	('CD4', 'Gene', '920', (30, 33))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
167986	32617678	The probable cause of deterioration was EEG-verified seizures in 7, ischemic lesion in 5 and both in 1, resection of eloquent tissue in 6, resection close to eloquent tissue including SMA in 11 and postoperative haematoma in 1 patient.	('seizures', 'Disease', (53, 61))	('postoperative haematoma', 'Disease', (198, 221))	('seizures', 'Phenotype', 'HP:0001250', (53, 61))	('seizure', 'Phenotype', 'HP:0001250', (53, 60))	('ischemic lesion', 'Disease', 'MESH:D007511', (68, 83))	('resection', 'Var', (139, 148))	('postoperative haematoma', 'Disease', 'MESH:D010149', (198, 221))	('SMA', 'Gene', (184, 187))	('patient', 'Species', '9606', (227, 234))	('ischemic lesion', 'Disease', (68, 83))	('SMA', 'Gene', '6606', (184, 187))	('seizures', 'Disease', 'MESH:D012640', (53, 61))
168065	32617678	We found that 12/24 (50%) patients with low-grade gliomas developed postoperative neurological deficits, 7 eloquent and 13 non-eloquent tumour locations, but there were complete or almost complete regression of neurological deficits in all these patients and no patients with low-grade gliomas showed remaining deficits.	('postoperative neurological deficits', 'Disease', 'MESH:D009461', (68, 103))	('gliomas', 'Disease', 'MESH:D005910', (286, 293))	('patients', 'Species', '9606', (246, 254))	('neurological deficits', 'Disease', 'MESH:D009461', (211, 232))	('neurological deficits', 'Phenotype', 'HP:0000707', (82, 103))	('gliomas', 'Phenotype', 'HP:0009733', (286, 293))	('gliomas', 'Disease', (50, 57))	('neurological deficit', 'Phenotype', 'HP:0000707', (211, 231))	('neurological deficits', 'Disease', (211, 232))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('neurological deficits', 'Disease', 'MESH:D009461', (82, 103))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('postoperative neurological deficits', 'Disease', (68, 103))	('tumour', 'Disease', (136, 142))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('low-grade', 'Var', (40, 49))	('neurological deficit', 'Phenotype', 'HP:0000707', (82, 102))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('gliomas', 'Disease', (286, 293))	('patients', 'Species', '9606', (26, 34))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('neurological deficits', 'Phenotype', 'HP:0000707', (211, 232))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('patients', 'Species', '9606', (262, 270))
168093	32617678	To summarize, the probable causes of neurological deterioration in the 41 patients were EEG-verified seizures in seven patients, EEG-verified seizures + ischemia in one patient, clinical suspicion of seizures in two patients, resection of eloquent tissue in six patients, resection close to eloquent tissue in nine patients and resection of the SMA in two patients, ischemia in five patients (plus one described above with seizures) and postoperative haematoma in one patient.	('patient', 'Species', '9606', (74, 81))	('neurological deterioration', 'Phenotype', 'HP:0002344', (37, 63))	('seizures', 'Phenotype', 'HP:0001250', (101, 109))	('resection', 'Var', (272, 281))	('patient', 'Species', '9606', (216, 223))	('SMA', 'Gene', (345, 348))	('ischemia', 'Disease', 'MESH:D007511', (153, 161))	('patients', 'Species', '9606', (356, 364))	('neurological deterioration', 'Disease', (37, 63))	('seizures', 'Disease', (423, 431))	('ischemia', 'Disease', 'MESH:D007511', (366, 374))	('seizure', 'Phenotype', 'HP:0001250', (423, 430))	('patient', 'Species', '9606', (119, 126))	('seizures', 'Disease', (200, 208))	('seizure', 'Phenotype', 'HP:0001250', (200, 207))	('seizures', 'Disease', 'MESH:D012640', (423, 431))	('patient', 'Species', '9606', (468, 475))	('seizures', 'Disease', 'MESH:D012640', (200, 208))	('patients', 'Species', '9606', (315, 323))	('seizures', 'Disease', (142, 150))	('patient', 'Species', '9606', (262, 269))	('seizures', 'Phenotype', 'HP:0001250', (423, 431))	('seizures', 'Phenotype', 'HP:0001250', (200, 208))	('seizure', 'Phenotype', 'HP:0001250', (142, 149))	('patient', 'Species', '9606', (315, 322))	('patient', 'Species', '9606', (356, 363))	('patients', 'Species', '9606', (74, 82))	('seizures', 'Disease', 'MESH:D012640', (142, 150))	('patients', 'Species', '9606', (216, 224))	('SMA', 'Gene', '6606', (345, 348))	('resection', 'Var', (226, 235))	('seizures', 'Phenotype', 'HP:0001250', (142, 150))	('seizures', 'Disease', (101, 109))	('seizure', 'Phenotype', 'HP:0001250', (101, 108))	('patients', 'Species', '9606', (383, 391))	('postoperative haematoma', 'Disease', 'MESH:D010149', (437, 460))	('ischemia', 'Disease', (153, 161))	('patients', 'Species', '9606', (119, 127))	('ischemia', 'Disease', (366, 374))	('neurological deterioration', 'Disease', 'MESH:D019636', (37, 63))	('patient', 'Species', '9606', (383, 390))	('patient', 'Species', '9606', (169, 176))	('seizures', 'Disease', 'MESH:D012640', (101, 109))	('patients', 'Species', '9606', (262, 270))	('postoperative haematoma', 'Disease', (437, 460))
168141	32617678	These numbers are too small for statistic calculations, but we think this trend seems to be reasonable and favours the fact that patients with low-grade gliomas have a better plasticity due to the slow growth of the tumour.	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('low-grade', 'Var', (143, 152))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('patients', 'Species', '9606', (129, 137))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('better', 'PosReg', (168, 174))	('slow growth', 'Phenotype', 'HP:0001510', (197, 208))	('tumour', 'Disease', 'MESH:D009369', (216, 222))	('tumour', 'Disease', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('plasticity', 'MPA', (175, 185))
168197	31578594	The results revealed that the expression levels of HHLA2 were significantly lower in high-grade glioma, as well as glioma with wild-type isocitrate dehydrogenase, no deletion of 1p/19q and telomerase reverse transcriptase promoter mutation.	('HHLA2', 'Gene', '11148', (51, 56))	('glioma', 'Disease', (115, 121))	('telomerase reverse transcriptase', 'Gene', (189, 221))	('isocitrate', 'Chemical', 'MESH:D007523', (137, 147))	('telomerase reverse transcriptase', 'Gene', '7015', (189, 221))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('lower', 'NegReg', (76, 81))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('HHLA2', 'Gene', (51, 56))	('no deletion of', 'Var', (163, 177))	('expression levels', 'MPA', (30, 47))	('glioma', 'Disease', (96, 102))
168225	31578594	Zhu et al indicated that the interaction between CD28H and B7-H7 on antigen-presenting cells (APCs) co-stimulated human T-cell proliferation and cytokine production via a pathway involving AKT phosphorylation.	('human T-cell proliferation', 'CPA', (114, 140))	('B7-H7', 'Var', (59, 64))	('CD28H', 'Gene', '126259', (49, 54))	('human', 'Species', '9606', (114, 119))	('interaction', 'Interaction', (29, 40))	('cytokine', 'CPA', (145, 153))	('CD28H', 'Gene', (49, 54))
168226	31578594	By contrast, Zhao et al proposed the opposite function for B7H7: In the presence of the T-cell antigen receptor (TCR) signaling pathway, B7-H7 inhibits the proliferation of CD4+ and CD8+ T cells.	('B7H7', 'Gene', (59, 63))	('inhibits', 'NegReg', (143, 151))	('B7-H7', 'Var', (137, 142))	('CD8', 'Gene', (182, 185))	('proliferation', 'CPA', (156, 169))	('CD4', 'Gene', (173, 176))	('CD8', 'Gene', '925', (182, 185))	('CD4', 'Gene', '920', (173, 176))	('B7H7', 'Gene', '11148', (59, 63))
168227	31578594	In addition, B7-H7 significantly reduces cytokine production by T cells, including interferon-gamma, tumor necrosis factor-alpha, IL-5, IL-10, IL-13, IL-17alpha and IL-22.	('tumor necrosis', 'Disease', (101, 115))	('B7-H7', 'Var', (13, 18))	('IL-5', 'Gene', '3567', (130, 134))	('IL-5', 'Gene', (130, 134))	('IL-13', 'Gene', (143, 148))	('cytokine production', 'MPA', (41, 60))	('IL-13', 'Gene', '3596', (143, 148))	('tumor necrosis', 'Disease', 'MESH:D009336', (101, 115))	('IL-10', 'Gene', (136, 141))	('IL-17alpha', 'Gene', (150, 160))	('IL-22', 'Gene', '50616', (165, 170))	('IL-22', 'Gene', (165, 170))	('IL-17alpha', 'Gene', '3605', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('reduces cytokine production', 'Phenotype', 'HP:0031407', (33, 60))	('reduces', 'NegReg', (33, 40))	('IL-10', 'Gene', '3586', (136, 141))
168242	31578594	HPA055478; Sigma-Aldrich; Merck KGaA) as a primary antibody and the tumor tissues were obtained from TCGA database.	('tumor', 'Disease', (68, 73))	('HPA055478', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('HPA055478', 'Chemical', 'MESH:C047158', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
168256	31578594	IDH-mutant and 1p/19q co-deletion types were associated with a better outcome in glioma.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', (81, 87))	('1p/19q co-deletion', 'Var', (15, 33))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
168258	31578594	Furthermore, compared with the 1p/19q no-deletion group, the 1p/19q co-deletion group had a higher expression of HHLA2 (P<0.05; Fig.	('expression', 'MPA', (99, 109))	('1p/19q co-deletion', 'Var', (61, 79))	('higher', 'PosReg', (92, 98))	('HHLA2', 'Gene', (113, 118))	('HHLA2', 'Gene', '11148', (113, 118))
168259	31578594	TERT promoter mutations are usually considered to be associated with poor outcome, and the present results revealed that in the TERT wild-type group, the expression of HHLA2 was significantly increased (P<0.05; Fig.	('TERT', 'Gene', (0, 4))	('expression', 'MPA', (154, 164))	('HHLA2', 'Gene', (168, 173))	('HHLA2', 'Gene', '11148', (168, 173))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (128, 132))	('TERT', 'Gene', '7015', (128, 132))	('mutations', 'Var', (14, 23))	('increased', 'PosReg', (192, 201))
168302	31578594	Furthermore, overexpression of HHLA2 was indicated to be significantly associated with a better outcome.	('HHLA2', 'Gene', '11148', (31, 36))	('HHLA2', 'Gene', (31, 36))	('overexpression', 'Var', (13, 27))
168311	31578594	According to a study by Eckel-Passow et al, a single TERT mutation predicted poor prognosis in glioma, while IDH mutation and 1p/19q co-deletion predicted a favorable outcome.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('1p/19q co-deletion', 'Var', (126, 144))	('glioma', 'Disease', (95, 101))	('IDH', 'Gene', (109, 112))	('IDH', 'Gene', '3417', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
168312	31578594	In the present study, tumors with IDH mutation, 1p/19q co-deletion and wild-type TERT expressed higher levels of HHLA2, which was in line with our previous assumption.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('TERT', 'Gene', (81, 85))	('HHLA2', 'Gene', (113, 118))	('TERT', 'Gene', '7015', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('HHLA2', 'Gene', '11148', (113, 118))	('1p/19q co-deletion', 'Var', (48, 66))	('higher', 'PosReg', (96, 102))	('tumors', 'Disease', (22, 28))	('levels', 'MPA', (103, 109))
168329	31578594	It was observed that IL-10 was significantly increased in the low HHLA2 expression group, which was also the case for TGF-beta.	('increased', 'PosReg', (45, 54))	('TGF-beta', 'Gene', (118, 126))	('IL-10', 'Gene', '3586', (21, 26))	('IL-10', 'Gene', (21, 26))	('low', 'Var', (62, 65))	('HHLA2', 'Gene', (66, 71))	('TGF-beta', 'Gene', '7040', (118, 126))	('HHLA2', 'Gene', '11148', (66, 71))
168394	30366279	Isocitrate dehydrogenase (IDH) mutations were detected by pyrosequencing in the CGGA training cohort and the molecular profiles of patients in the validation cohort were collected from the TCGA database.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (31, 40))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (26, 29))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
168400	30366279	Patients were divided into subgroups according to IDH status (wild-type vs. mutant), age (younger than 40 years vs. 40 years or older), sex (male vs. female), tumor grade (WHO II vs. WHO III), seizure (non-seizure vs. seizure), and presence of oligodendroglioma component (oligocomponent vs. astrocytomas).	('seizure', 'Disease', 'MESH:D012640', (218, 225))	('seizure', 'Phenotype', 'HP:0001250', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('seizure', 'Phenotype', 'HP:0001250', (218, 225))	('seizure', 'Disease', (193, 200))	('IDH', 'Gene', '3417', (50, 53))	('seizure', 'Disease', (218, 225))	('oligodendroglioma component', 'Disease', (244, 271))	('seizure', 'Disease', 'MESH:D012640', (206, 213))	('Patients', 'Species', '9606', (0, 8))	('astrocytomas', 'Disease', (292, 304))	('seizure', 'Phenotype', 'HP:0001250', (206, 213))	('seizure', 'Disease', (206, 213))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('oligodendroglioma component', 'Disease', 'MESH:D009837', (244, 271))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('mutant', 'Var', (76, 82))	('astrocytomas', 'Disease', 'MESH:D001254', (292, 304))	('IDH', 'Gene', (50, 53))	('seizure', 'Disease', 'MESH:D012640', (193, 200))
168435	28806393	CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway.	('CRAF', 'Gene', (0, 4))	('gene fusions', 'Var', (182, 194))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('associated', 'Reg', (161, 171))	('gliomas', 'Disease', (132, 139))	('BRAF', 'Gene', (177, 181))	('CRAF', 'Gene', '110157', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('activate', 'PosReg', (211, 219))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))
168438	28806393	Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways.	('PI3K/mTOR', 'Gene', (196, 205))	('dysregulate', 'Reg', (31, 42))	('MAPK signaling', 'MPA', (43, 57))	('mammalian target of rapamycin', 'Gene', '2475', (165, 194))	('mammalian target of rapamycin', 'Gene', (165, 194))	('fusions', 'Var', (13, 20))	('fusions', 'Var', (68, 75))	('PI3K/mTOR', 'Gene', '18708;56717', (196, 205))	('SRGAP3-RAF1', 'Gene', (89, 100))	('QKI-RAF1', 'Gene', (76, 84))	('activate', 'PosReg', (112, 120))
168441	28806393	Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI.	('QKI', 'Gene', '19317', (210, 213))	('protein-protein', 'Protein', (119, 134))	('PLX8394', 'Var', (8, 15))	('QKI', 'Gene', (210, 213))	('interactions', 'Interaction', (135, 147))	('BRAF-fusion dimerization', 'MPA', (26, 50))	('PLX8394', 'Chemical', 'MESH:C000602642', (8, 15))	('decreased', 'NegReg', (16, 25))
168442	28806393	The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling.	('suppress', 'NegReg', (46, 54))	('RAF', 'Gene', (8, 11))	('RAF', 'Gene', (56, 59))	('RAF', 'Gene', '387609', (56, 59))	('dimer-mediated signaling', 'MPA', (94, 118))	('LY3009120', 'Chemical', 'MESH:C000600963', (29, 38))	('RAF', 'Gene', '387609', (8, 11))	('inhibiting', 'NegReg', (83, 93))	('LY3009120', 'Var', (29, 38))
168443	28806393	In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors.	('PI3K/mTOR', 'Gene', (56, 65))	('tumors', 'Disease', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('MAPK', 'Pathway', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('PI3K/mTOR', 'Gene', '18708;56717', (56, 65))	('fusions', 'Var', (21, 28))	('activate', 'PosReg', (29, 37))
168444	28806393	Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy.	('patients', 'Species', '9606', (178, 186))	('fusions', 'Var', (89, 96))	('BRAF-', 'Gene', (69, 74))	('CRAF/RAF1', 'Gene', (79, 88))	('PLGG-associated', 'Disease', (53, 68))	('RAFi', 'Chemical', '-', (112, 116))
168445	28806393	Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('CRAF', 'Disease', (167, 171))	('fusions', 'Var', (172, 179))	('PLGG-associated', 'Gene', (151, 166))
168451	28806393	Recently, ATG7-RAF1 fusions were reported in anaplastic Pleomorphic Xanthoastrocytomas without BRAF-V600E.	('Pleomorphic Xanthoastrocytomas', 'Disease', (56, 86))	('ATG7-RAF1', 'Gene', (10, 19))	('reported', 'Reg', (33, 41))	('V600E', 'Mutation', 'rs113488022', (100, 105))	('fusions', 'Var', (20, 27))	('Pleomorphic Xanthoastrocytomas', 'Disease', 'MESH:D008228', (56, 86))
168455	28806393	ATP-competitive, first-generation RAFi, such as vemurafenib (research analog PLX4720), have been FDA-approved for BRAF-V600E malignant melanoma but were found to be ineffective in targeting BRAF fusions because of paradoxical activation of the MAPK pathway.	('RAFi', 'Chemical', '-', (34, 38))	('MAPK pathway', 'Pathway', (244, 256))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('malignant melanoma', 'Phenotype', 'HP:0002861', (125, 143))	('ineffective', 'NegReg', (165, 176))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('vemurafenib', 'Chemical', 'MESH:D000077484', (48, 59))	('PLX4720', 'Chemical', 'MESH:C528407', (77, 84))	('malignant melanoma', 'Disease', 'MESH:D008545', (125, 143))	('V600E', 'Mutation', 'rs113488022', (119, 124))	('malignant melanoma', 'Disease', (125, 143))	('BRAF-V600E', 'Var', (114, 124))	('activation', 'PosReg', (226, 236))
168457	28806393	These studies highlight the differential sensitivity of RAF mutations.	('mutations', 'Var', (60, 69))	('RAF', 'Gene', (56, 59))	('RAF', 'Gene', '387609', (56, 59))
168462	28806393	We previously identified QKI's contribution as a fusion partner in MYB-QKI fusion in angiocentric gliomas, corroborating previous findings that QKI deletions are oncogenic in cancers such as glioblastomas, prostate cancer, lung cancer and gastric cancer.	('oncogenic', 'Reg', (162, 171))	('QKI', 'Gene', '19317', (25, 28))	('glioblastomas', 'Disease', (191, 204))	('gastric cancer', 'Disease', (239, 253))	('QKI', 'Gene', '19317', (71, 74))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('glioblastomas', 'Disease', 'MESH:D005909', (191, 204))	('QKI', 'Gene', '19317', (144, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('QKI', 'Gene', (25, 28))	('gastric cancer', 'Disease', 'MESH:D013274', (239, 253))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('QKI', 'Gene', (71, 74))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (85, 105))	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('angiocentric gliomas', 'Disease', (85, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('QKI', 'Gene', (144, 147))	('prostate cancer', 'Disease', (206, 221))	('gastric cancer', 'Phenotype', 'HP:0012126', (239, 253))	('glioblastomas', 'Phenotype', 'HP:0012174', (191, 204))	('lung cancer', 'Disease', (223, 234))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('MYB', 'Gene', (67, 70))	('MYB', 'Gene', '17863', (67, 70))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('deletions', 'Var', (148, 157))	('cancers', 'Disease', 'MESH:D009369', (175, 182))
168465	28806393	We found that CRAF fusions activated both the MAPK and the phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathways and were unresponsive to 'paradox-breaker' RAFi.	('RAFi', 'Chemical', '-', (179, 183))	('PI3K/mTOR', 'Gene', '18708;56717', (116, 125))	('mammalian target of rapamycin', 'Gene', '2475', (85, 114))	('mammalian target of rapamycin', 'Gene', (85, 114))	('MAPK', 'Pathway', (46, 50))	('fusions', 'Var', (19, 26))	('PI3K/mTOR', 'Gene', (116, 125))	('activated', 'PosReg', (27, 36))
168467	28806393	To overcome this RAF-directed therapeutic challenge, we characterize other potential targeting approaches for CRAF-fusion-driven tumors including the pan-RAFi LY3009120 and combinatorial targeting of the MAPK and PI3K/mTOR pathways.	('PI3K/mTOR', 'Gene', (213, 222))	('RAFi', 'Chemical', '-', (154, 158))	('RAF', 'Gene', '387609', (17, 20))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('PI3K/mTOR', 'Gene', '18708;56717', (213, 222))	('LY3009120', 'Chemical', 'MESH:C000600963', (159, 168))	('RAF', 'Gene', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('RAF', 'Gene', '387609', (111, 114))	('LY3009120', 'Var', (159, 168))	('RAF', 'Gene', (154, 157))	('RAF', 'Gene', '387609', (154, 157))	('RAF', 'Gene', (17, 20))
168472	28806393	Nonetheless, the occurrence of diverse CRAF fusions across pediatric and adult cancers (Figure 1b) highlights the growing importance of CRAF fusions and need to understand its mechanism of oncogenicity and its sensitivity to targeted inhibition.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('adult cancers', 'Disease', 'MESH:C535836', (73, 86))	('adult cancers', 'Disease', (73, 86))	('fusions', 'Var', (141, 148))
168474	28806393	To circumvent the lack of established PLGG patient-derived CRAF-fusion cell lines, we generated two heterologous cell models by stably expressing SRGAP3-RAF1 and QKI-RAF1 in Tp53-null primary mouse astrocytes (PMAs) and NIH3T3 (Supplementary Figures 1a and b).	('mouse', 'Species', '10090', (192, 197))	('SRGAP3-RAF1', 'Gene', (146, 157))	('patient', 'Species', '9606', (43, 50))	('NIH3T3', 'CellLine', 'CVCL:0594', (220, 226))	('QKI-RAF1', 'Var', (162, 170))
168476	28806393	We also use NIH3T3s that have been predictive of oncogenic transformation and clinical response in the BRAF-fusion setting.	('clinical response', 'CPA', (78, 95))	('NIH3T3', 'CellLine', 'CVCL:0594', (12, 18))	('oncogenic transformation', 'CPA', (49, 73))	('NIH3T3s', 'Var', (12, 19))
168479	28806393	In CRAF-fusion expressing NIH3T3, we observed similar robust colony formation in soft agar assays (Figure 1e, P-value<0.05-0.001).	('NIH3T3', 'CellLine', 'CVCL:0594', (26, 32))	('colony formation', 'CPA', (61, 77))	('agar', 'Chemical', 'MESH:D000362', (86, 90))	('NIH3T3', 'Var', (26, 32))
168480	28806393	Both the MAPK and PI3K/mTOR pathways were aberrantly activated by QKI-RAF1 and SRGAP3-RAF1 as monitored by elevated phosphorylated-MEK and phospho-AKT/S6 levels in NIH3T3s, respectively (Figure 1f).	('NIH3T3', 'CellLine', 'CVCL:0594', (164, 170))	('activated', 'PosReg', (53, 62))	('PI3K/mTOR', 'Gene', (18, 27))	('MAPK', 'Pathway', (9, 13))	('MEK', 'Gene', '17242', (131, 134))	('PI3K/mTOR', 'Gene', '18708;56717', (18, 27))	('SRGAP3-RAF1', 'Var', (79, 90))	('MEK', 'Gene', (131, 134))	('AKT', 'Gene', '11651', (147, 150))	('QKI-RAF1', 'Gene', (66, 74))	('elevated', 'PosReg', (107, 115))	('AKT', 'Gene', (147, 150))
168486	28806393	In QKI-RAF1 expressing NIH3T3, both PLX4720 and PLX8394 caused paradoxical activation of the MAPK pathway as seen by increasing phosphorylated-MEK and -ERK with increasing drug concentrations (Figure 2a).	('MEK', 'Gene', (143, 146))	('PLX4720', 'Var', (36, 43))	('PLX8394', 'Var', (48, 55))	('MAPK pathway', 'Pathway', (93, 105))	('ERK', 'Gene', (152, 155))	('activation', 'PosReg', (75, 85))	('PLX4720', 'Chemical', 'MESH:C528407', (36, 43))	('ERK', 'Gene', '26413', (152, 155))	('increasing', 'PosReg', (117, 127))	('PLX8394', 'Chemical', 'MESH:C000602642', (48, 55))	('MEK', 'Gene', '17242', (143, 146))	('NIH3T3', 'Var', (23, 29))	('NIH3T3', 'CellLine', 'CVCL:0594', (23, 29))
168489	28806393	We observed similar paradoxical activation of the MAPK pathway, PI3K/mTOR pathway suppression (Figure 2c) and lack of growth suppression in soft agar (Figure 2d) upon treating SRGAP3-RAF1 expressing NIH3T3 with PLX4720 and PLX8394.	('NIH3T3', 'CellLine', 'CVCL:0594', (199, 205))	('PLX4720', 'Var', (211, 218))	('PI3K/mTOR', 'Gene', '18708;56717', (64, 73))	('PLX8394', 'Var', (223, 230))	('activation', 'PosReg', (32, 42))	('MAPK pathway', 'Pathway', (50, 62))	('PLX4720', 'Chemical', 'MESH:C528407', (211, 218))	('suppression', 'NegReg', (82, 93))	('PLX8394', 'Chemical', 'MESH:C000602642', (223, 230))	('agar', 'Chemical', 'MESH:D000362', (145, 149))	('NIH3T3', 'Gene', (199, 205))	('PI3K/mTOR', 'Gene', (64, 73))
168490	28806393	These findings distinguish CRAF fusions from BRAF-fusion (KIAA159-BRAF) that shows pathway suppression with PLX8394 (Supplementary Figure 2).	('fusions', 'Var', (32, 39))	('KIAA159-BRAF', 'Gene', '109880', (58, 70))	('KIAA159-BRAF', 'Gene', (58, 70))	('suppression', 'NegReg', (91, 102))	('pathway', 'MPA', (83, 90))	('PLX8394', 'Chemical', 'MESH:C000602642', (108, 115))
168492	28806393	In CRAF-fusion expressing PMAs, we observed no MAPK pathway suppression with PLX8394 treatment (Figure 2e) and no growth suppression of QKI-RAF1 (Figure 2f) and SRGAP3-RAF1 (Figure 2g) with increasing PLX4720 or PLX8394.	('PLX4720', 'Var', (201, 208))	('PLX8394', 'Chemical', 'MESH:C000602642', (77, 84))	('PLX4720', 'Chemical', 'MESH:C528407', (201, 208))	('QKI-RAF1', 'Gene', (136, 144))	('PLX8394', 'Gene', (77, 84))	('PLX8394', 'Chemical', 'MESH:C000602642', (212, 219))	('suppression', 'NegReg', (60, 71))	('MAPK pathway', 'Pathway', (47, 59))	('growth', 'MPA', (114, 120))
168501	28806393	We found that PLX8394 failed to disrupt QKI-RAF1 homodimerization and heterodimerization with wild-type B/CRAF or QKI (Figure 3b).	('QKI', 'Gene', (40, 43))	('PLX8394', 'Var', (14, 21))	('QKI', 'Gene', '19317', (114, 117))	('homodimerization', 'MPA', (49, 65))	('QKI', 'Gene', (114, 117))	('PLX8394', 'Chemical', 'MESH:C000602642', (14, 21))	('QKI', 'Gene', '19317', (40, 43))	('heterodimerization', 'MPA', (70, 88))
168504	28806393	Point mutation in a key RAF1 dimer interface residue R401H has been shown to disrupt RAF1 dimerization with little to no effect on basal kinase activity.	('dimerization', 'MPA', (90, 102))	('R401H', 'Mutation', 'p.R401H', (53, 58))	('Point mutation', 'Var', (0, 14))	('RAF1', 'Protein', (85, 89))	('disrupt', 'NegReg', (77, 84))	('R401H', 'Var', (53, 58))
168508	28806393	The QUA1 region of N-terminal QKI contains dimerization residues and the E48G point mutation causes disruption of QKI dimers and RNA-binding function.	('E48G', 'Var', (73, 77))	('dimers', 'MPA', (118, 124))	('QKI', 'Gene', (30, 33))	('QKI', 'Gene', '19317', (114, 117))	('RNA-binding', 'MPA', (129, 140))	('E48G', 'Mutation', 'p.E48G', (73, 77))	('QKI', 'Gene', (114, 117))	('dimerization', 'MPA', (43, 55))	('QKI', 'Gene', '19317', (30, 33))	('disruption', 'NegReg', (100, 110))
168511	28806393	One possibility is that QKI-RAF1 forms homodimers, followed by CRAF binding to form complex oligomers, so loss of QKIE48G-RAF1 homodimerization could be preventing CRAF interaction (Figure 4c), but this hypothesis needs to be tested further.	('QKIE48G-RAF1', 'Gene', '110157', (114, 126))	('homodimerization', 'MPA', (127, 143))	('CRAF', 'MPA', (164, 168))	('preventing', 'NegReg', (153, 163))	('QKIE48G-RAF1', 'Gene', (114, 126))	('loss', 'Var', (106, 110))
168519	28806393	For SRGAP3-RAF1, we observed decreased MAPK signaling and lower colony formation in soft agar for PMAs expressing SRGAP3-RAF1R401H versus SRGAP3-RAF1 (Supplementary Figures 3b and c), indicating partial importance of RAF1 dimerization motif in SRGAP3-RAF1.	('lower', 'NegReg', (58, 63))	('MAPK signaling', 'MPA', (39, 53))	('SRGAP3-RAF1R401H', 'Var', (114, 130))	('agar', 'Chemical', 'MESH:D000362', (89, 93))	('colony formation in soft agar', 'CPA', (64, 93))	('decreased', 'NegReg', (29, 38))
168525	28806393	To target the dimerization-dependent oncogenicity of CRAF fusions, we tested LY3009120, a novel RAF dimer inhibitor capable of binding and stabilizing both promoters of a RAF dimer in an inactive conformation.	('RAF', 'Gene', (96, 99))	('LY3009120', 'Var', (77, 86))	('RAF', 'Gene', (171, 174))	('binding', 'Interaction', (127, 134))	('RAF', 'Gene', '387609', (171, 174))	('RAF', 'Gene', '387609', (96, 99))	('stabilizing', 'MPA', (139, 150))	('RAF', 'Gene', (54, 57))	('LY3009120', 'Chemical', 'MESH:C000600963', (77, 86))	('RAF', 'Gene', '387609', (54, 57))
168526	28806393	LY3009120 has shown efficacy in suppressing mutant BRAF dimers in melanoma, colorectal and thyroid cancer lines and circumventing the paradoxical activation caused by vemurafenib that binds only one protomer of a RAF dimer.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('vemurafenib', 'Chemical', 'MESH:D000077484', (167, 178))	('LY3009120', 'Var', (0, 9))	('colorectal and thyroid cancer', 'Disease', 'MESH:D015179', (76, 105))	('thyroid cancer', 'Phenotype', 'HP:0002890', (91, 105))	('RAF', 'Gene', (52, 55))	('LY3009120', 'Chemical', 'MESH:C000600963', (0, 9))	('RAF', 'Gene', '387609', (52, 55))	('mutant', 'Var', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('RAF', 'Gene', (213, 216))	('RAF', 'Gene', '387609', (213, 216))	('suppressing', 'NegReg', (32, 43))
168527	28806393	In CRAF-fusion expressing NIH3T3s, LY3009120 led to potent, dose-dependent inhibition of both MAPK and PI3K/mTOR pathways (Figure 5a), and even low doses suppressed anchorage-independent growth (Figure 5b, P-value<0.001).	('PI3K/mTOR', 'Gene', (103, 112))	('suppressed', 'NegReg', (154, 164))	('MAPK', 'Pathway', (94, 98))	('LY3009120', 'Chemical', 'MESH:C000600963', (35, 44))	('inhibition', 'NegReg', (75, 85))	('anchorage-independent growth', 'CPA', (165, 193))	('PI3K/mTOR', 'Gene', '18708;56717', (103, 112))	('NIH3T3s', 'Var', (26, 33))	('LY3009120', 'Var', (35, 44))	('NIH3T3', 'CellLine', 'CVCL:0594', (26, 32))
168528	28806393	Similar suppression of the MAPK pathway was observed with LY3009120 in CRAF-fusion expressing PMAs (Figure 5c), whereas the PI3K pathway was not inhibited as strongly as in NIH3T3s.	('LY3009120', 'Chemical', 'MESH:C000600963', (58, 67))	('CRAF-fusion', 'Gene', (71, 82))	('suppression', 'NegReg', (8, 19))	('LY3009120', 'Var', (58, 67))	('NIH3T3', 'CellLine', 'CVCL:0594', (173, 179))	('MAPK pathway', 'Pathway', (27, 39))
168529	28806393	LY3009120 suppressed soft agar colony growth of PMAs (Figure 5d) verifying LY3009120 antitumor effects on CRAF fusions.	('agar', 'Chemical', 'MESH:D000362', (26, 30))	('LY3009120', 'Var', (75, 84))	('LY3009120', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('LY3009120', 'Chemical', 'MESH:C000600963', (0, 9))	('suppressed', 'NegReg', (10, 20))	('soft agar colony growth', 'CPA', (21, 44))	('LY3009120', 'Chemical', 'MESH:C000600963', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
168531	28806393	To evaluate the inhibitory mechanism of LY3009120 in CRAF fusions, we performed co-IP assays with LY3009120.	('LY3009120', 'Chemical', 'MESH:C000600963', (98, 107))	('LY3009120', 'Chemical', 'MESH:C000600963', (40, 49))	('LY3009120', 'Var', (40, 49))	('LY3009120', 'Var', (98, 107))
168532	28806393	Treatment with LY3009120 induced QKI-RAF1 homodimerization and QKI-RAF1/BRAF heterodimerization (Figure 5e, left panel) with minimal effect on QKI-RAF1/CRAF heterodimerization.	('LY3009120', 'Var', (15, 24))	('QKI-RAF1', 'Gene', (33, 41))	('homodimerization', 'MPA', (42, 58))	('heterodimerization', 'MPA', (77, 95))	('LY3009120', 'Chemical', 'MESH:C000600963', (15, 24))	('QKI-RAF1/BRAF', 'Gene', (63, 76))
168533	28806393	Interestingly, LY3009120 caused complete disruption of QKI-RAF1/full-length QKI heterodimerization but interaction with N-terminal-truncated QKI is retained (Figure 5e, right panel).	('LY3009120', 'Var', (15, 24))	('QKI', 'Gene', '19317', (141, 144))	('QKI', 'Gene', '19317', (55, 58))	('heterodimerization', 'Interaction', (80, 98))	('interaction', 'Interaction', (103, 114))	('QKI', 'Gene', (141, 144))	('QKI', 'Gene', (55, 58))	('QKI', 'Gene', '19317', (76, 79))	('LY3009120', 'Chemical', 'MESH:C000600963', (15, 24))	('QKI', 'Gene', (76, 79))	('disruption', 'NegReg', (41, 51))
168534	28806393	Despite stabilizing QKI-RAF1 homodimers and heterodimers with other RAF proteins, LY3009120 inhibits RAF1 kinase activity and downstream MAPK/PI3K signaling (Figures 5a-c).	('LY3009120', 'Var', (82, 91))	('MAPK/PI3K signaling', 'Pathway', (137, 156))	('RAF', 'Gene', (24, 27))	('RAF', 'Gene', '387609', (24, 27))	('homodimers', 'MPA', (29, 39))	('RAF', 'Gene', (101, 104))	('LY3009120', 'Chemical', 'MESH:C000600963', (82, 91))	('RAF', 'Gene', '387609', (101, 104))	('inhibits', 'NegReg', (92, 100))	('RAF', 'Gene', (68, 71))	('RAF', 'Gene', '387609', (68, 71))
168535	28806393	LY3009120 seems to affect the QKI-dimerization residues via some unknown mechanism, which could alter QKI-RAF1 homodimerization and downstream signaling.	('QKI', 'Gene', '19317', (102, 105))	('QKI', 'Gene', (30, 33))	('LY3009120', 'Var', (0, 9))	('QKI', 'Gene', (102, 105))	('affect', 'Reg', (19, 25))	('homodimerization', 'MPA', (111, 127))	('alter', 'Reg', (96, 101))	('QKI', 'Gene', '19317', (30, 33))	('LY3009120', 'Chemical', 'MESH:C000600963', (0, 9))
168536	28806393	Thus, LY3009120 may provide a therapeutic alternative to existing RAFi in CRAF-fusion-driven tumors and warrants additional testing.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('RAFi', 'Chemical', '-', (66, 70))	('LY3009120', 'Var', (6, 15))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('LY3009120', 'Chemical', 'MESH:C000600963', (6, 15))
168538	28806393	NIH3T3s overexpressing QKI-RAF1 showed a dose-dependent decrease in phospho-ERK with selumetinib and trametinib, indicating on-target MEK1/2 inhibition (Figure 6a, first and middle panels, respectively) and significant growth inhibition in soft agar assays (Figure 6b, top panel, P-value<0.01, 0.1).	('inhibition', 'NegReg', (141, 151))	('ERK', 'Gene', (76, 79))	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('QKI-RAF1', 'Var', (23, 31))	('growth', 'MPA', (219, 225))	('ERK', 'Gene', '26413', (76, 79))	('selumetinib', 'Chemical', 'MESH:C517975', (85, 96))	('MEK1/2', 'Gene', '26395;26396', (134, 140))	('agar', 'Chemical', 'MESH:D000362', (245, 249))	('decrease', 'NegReg', (56, 64))	('MEK1/2', 'Gene', (134, 140))	('trametinib', 'Chemical', 'MESH:C560077', (101, 111))
168546	28806393	As the PI3K/mTOR pathway is also activated in CRAF-fusion expressing NIH3T3, we performed combinatorial targeting of both MAPK and PI3K/mTOR pathways using MEKi trametinib and mTORi everolimus, and observed decreased phospho-ERK and phospho-S6 (Figure 7a, left panel).	('PI3K/mTOR', 'Gene', (7, 16))	('NIH3T3', 'Var', (69, 75))	('activated', 'PosReg', (33, 42))	('PI3K/mTOR', 'Gene', (131, 140))	('ERK', 'Gene', (225, 228))	('MEK', 'Gene', '17242', (156, 159))	('phospho-S6', 'MPA', (233, 243))	('NIH3T3', 'CellLine', 'CVCL:0594', (69, 75))	('PI3K/mTOR', 'Gene', '18708;56717', (7, 16))	('trametinib', 'Chemical', 'MESH:C560077', (161, 171))	('ERK', 'Gene', '26413', (225, 228))	('PI3K/mTOR', 'Gene', '18708;56717', (131, 140))	('MEK', 'Gene', (156, 159))	('everolimus', 'Chemical', 'MESH:D000068338', (182, 192))	('decreased', 'NegReg', (207, 216))
168550	28806393	Similar pathway suppression results upon co-targeting MEK and mTOR in SRGAP3-RAF1-expressing cells (Figure 7c), along with decreased colony formation in soft agar (Figure 7d).	('mTOR', 'Gene', (62, 66))	('decreased', 'NegReg', (123, 132))	('co-targeting', 'Var', (41, 53))	('agar', 'Chemical', 'MESH:D000362', (158, 162))	('MEK', 'Gene', '17242', (54, 57))	('suppression', 'NegReg', (16, 27))	('colony formation in soft agar', 'CPA', (133, 162))	('MEK', 'Gene', (54, 57))
168552	28806393	We next tested co-targeting in two in vivo models: NIH3T3 flank xenografts and orthotopic intracranial (IC) tumors with PMAs.	('tested', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('NIH3T3', 'Var', (51, 57))	('NIH3T3', 'CellLine', 'CVCL:0594', (51, 57))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
168553	28806393	Mice with QKI-RAF1 expressing NIH3T3 flank xenografts were treated with single-agent everolimus or trametinib and show initial suppression of tumor engraftment but the tumor eventually grows, whereas combinatorial treatment prolonged tumor suppression due to direct inhibition of both pathways (Figure 7e and Supplementary Figure 4c).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (168, 173))	('trametinib', 'Chemical', 'MESH:C560077', (99, 109))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('everolimus', 'Chemical', 'MESH:D000068338', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('NIH3T3', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('suppression', 'NegReg', (127, 138))	('NIH3T3', 'CellLine', 'CVCL:0594', (30, 36))
168558	28806393	To our knowledge, this is the first report to distinguish between BRAF and CRAF/RAF1 fusions found in PAs.	('PAs', 'Disease', (102, 105))	('CRAF/RAF1', 'Gene', (75, 84))	('PAs', 'Disease', 'MESH:D011471', (102, 105))	('fusions', 'Var', (85, 92))	('BRAF', 'Gene', (66, 70))
168559	28806393	Whereas vemurafenib paradoxically activates BRAF fusions, PLX8394 suppresses KIAA1549-BRAF tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('BRAF', 'CPA', (44, 48))	('PLX8394', 'Chemical', 'MESH:C000602642', (58, 65))	('vemurafenib', 'Chemical', 'MESH:D000077484', (8, 19))	('KIAA1549-BRAF tumors', 'Disease', 'MESH:D009369', (77, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('suppresses', 'NegReg', (66, 76))	('KIAA1549-BRAF tumors', 'Disease', (77, 97))	('PLX8394', 'Var', (58, 65))	('activates', 'PosReg', (34, 43))
168560	28806393	Contrastingly, CRAF fusions are resistant to both vemurafenib and PLX8394 but are responsive to RAF dimer inhibitor LY3009120 or co-targeting with MEKi and mTORi.	('RAF', 'Gene', (96, 99))	('co-targeting', 'Var', (129, 141))	('MEK', 'Gene', (147, 150))	('LY3009120', 'Var', (116, 125))	('RAF', 'Gene', '387609', (96, 99))	('RAF', 'Gene', (16, 19))	('RAF', 'Gene', '387609', (16, 19))	('PLX8394', 'Chemical', 'MESH:C000602642', (66, 73))	('vemurafenib', 'Chemical', 'MESH:D000077484', (50, 61))	('responsive', 'Reg', (82, 92))	('LY3009120', 'Chemical', 'MESH:C000600963', (116, 125))	('MEK', 'Gene', '17242', (147, 150))
168562	28806393	Compared with a small fraction of PAs reported with CRAF fusions, various BRAF mutations are found more frequently including BRAFV600E present in 6-10% of PAs and higher prevalence in other PLGG subtypes, KIAA1549-BRAF fusion found in majority of PAs and novel BRAF mutations reported by PLGG whole-genome sequencing studies.	('KIAA1549-BRAF', 'Disease', 'None', (205, 218))	('PAs', 'Disease', (247, 250))	('BRAFV600E', 'Mutation', 'rs113488022', (125, 134))	('PAs', 'Disease', (34, 37))	('BRAFV600E', 'Gene', (125, 134))	('PAs', 'Disease', (155, 158))	('mutations', 'Var', (266, 275))	('KIAA1549-BRAF', 'Disease', (205, 218))	('PAs', 'Disease', 'MESH:D011471', (247, 250))	('PAs', 'Disease', 'MESH:D011471', (34, 37))	('PAs', 'Disease', 'MESH:D011471', (155, 158))	('mutations', 'Var', (79, 88))
168567	28806393	These model systems indicate that CRAF fusions are oncogenic via the MAPK and PI3K/mTOR pathways.	('MAPK', 'Pathway', (69, 73))	('PI3K/mTOR', 'Gene', '18708;56717', (78, 87))	('CRAF', 'Gene', (34, 38))	('fusions', 'Var', (39, 46))	('PI3K/mTOR', 'Gene', (78, 87))
168568	28806393	Whereas KIAA1549-BRAF primarily exists as homodimers disrupted by PLX8394 (Figure 3c), CRAF fusions exist as RAFi-resistant homodimers and heterodimers with B/CRAF/N-terminal partner.	('KIAA1549-BRAF', 'Disease', 'None', (8, 21))	('fusions', 'Var', (92, 99))	('RAFi', 'Chemical', '-', (109, 113))	('PLX8394', 'Chemical', 'MESH:C000602642', (66, 73))	('KIAA1549-BRAF', 'Disease', (8, 21))	('PLX8394', 'Gene', (66, 73))
168569	28806393	Dependence on BRAF mutational status for RAFi sensitivity has been studied, but our findings suggest for the first time that BRAF- and CRAF fusions could be distinct signaling entities based on dimerization status primarily mediated by the non-kinase fusion partner.	('RAFi', 'Chemical', '-', (41, 45))	('dimerization', 'MPA', (194, 206))	('CRAF', 'Gene', (135, 139))	('BRAF-', 'Gene', (125, 130))	('fusions', 'Var', (140, 147))
168573	28806393	LY3009120 is a pan-RAFi that has shown promise in inhibiting various NRAS, KRAS and BRAF mutations.	('BRAF', 'Disease', (84, 88))	('inhibiting', 'NegReg', (50, 60))	('LY3009120', 'Var', (0, 9))	('KRAS', 'Gene', (75, 79))	('mutations', 'Var', (89, 98))	('KRAS', 'Gene', '16653', (75, 79))	('RAFi', 'Chemical', '-', (19, 23))	('NRAS', 'Gene', (69, 73))	('NRAS', 'Gene', '18176', (69, 73))	('LY3009120', 'Chemical', 'MESH:C000600963', (0, 9))
168574	28806393	We show LY3009120 treatment disrupting QKI-mediated interaction between QKI-RAF1 as well as stabilizing inactive homodimers and heterodimers with B/CRAF.	('LY3009120 treatment', 'Var', (8, 27))	('QKI', 'Gene', (39, 42))	('disrupting', 'NegReg', (28, 38))	('inactive homodimers', 'MPA', (104, 123))	('QKI', 'Gene', '19317', (72, 75))	('heterodimers', 'Interaction', (128, 140))	('LY3009120', 'Chemical', 'MESH:C000600963', (8, 17))	('QKI', 'Gene', (72, 75))	('QKI', 'Gene', '19317', (39, 42))
168577	28806393	In BRAF-mutant cancers, selumetinib is more potent than RAFi but multi-agent therapy combining MEKi with either vemurafenib or mTORi (everolimus) has shown the most promising preclinical results based on BRAF mutational status.	('selumetinib', 'Chemical', 'MESH:C517975', (24, 35))	('BRAF-mutant', 'Gene', (3, 14))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('RAFi', 'Chemical', '-', (56, 60))	('cancers', 'Disease', (15, 22))	('MEK', 'Gene', '17242', (95, 98))	('everolimus', 'Chemical', 'MESH:D000068338', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('MEK', 'Gene', (95, 98))	('BRAF-mutant', 'Var', (3, 14))	('vemurafenib', 'Chemical', 'MESH:D000077484', (112, 123))
168586	28806393	For example, introduction of the R401H substitution to ESRP1-RAF1, an oncogenic protein fusion that forms constitutive dimers driven by CRAF, significantly reduced MAPK signaling.	('R401H', 'Mutation', 'p.R401H', (33, 38))	('reduced', 'NegReg', (156, 163))	('ESRP1-RAF1', 'Gene', (55, 65))	('MAPK signaling', 'MPA', (164, 178))	('R401H', 'Var', (33, 38))
168600	28806393	QKI-RAF1 dimerization mutants were generated by polymerase chain reaction-based site-directed mutagenesis of MYC- and FLAG-tagged constructs.	('MYC-', 'Gene', (109, 113))	('MYC-', 'Gene', '17869', (109, 113))	('QKI-RAF1', 'Gene', (0, 8))	('mutants', 'Var', (22, 29))
141096	28806393	For MAPK and PI3K/mTOR pathway analysis, pMEK (#9154), MEK (#4694), pERK (#4370), ERK (#4695), pAKT Ser473 (#4060), pAKT Thr308 (#4056), AKT (#2920), pS6 (#2215) and S6 (#2317) antibodies from Cell Signaling were used.	('PI3K/mTOR', 'Gene', (13, 22))	('Ser473', 'Chemical', '-', (100, 106))	('#4370', 'Var', (74, 79))	('MEK', 'Gene', (55, 58))	('AKT', 'Gene', '11651', (137, 140))	('#4694', 'Var', (60, 65))	('AKT', 'Gene', '11651', (96, 99))	('#4695', 'Var', (87, 92))	('ERK', 'Gene', '26413', (69, 72))	('Thr308', 'Chemical', '-', (121, 127))	('AKT', 'Gene', (117, 120))	('#2920', 'Var', (142, 147))	('pERK', 'Gene', '13666', (68, 72))	('ERK', 'Gene', (82, 85))	('#4056', 'Var', (129, 134))	('MEK', 'Gene', '17242', (42, 45))	('#9154', 'Var', (47, 52))	('PI3K/mTOR', 'Gene', '18708;56717', (13, 22))	('#2215', 'Var', (155, 160))	('AKT', 'Gene', (137, 140))	('ERK', 'Gene', '26413', (82, 85))	('AKT', 'Gene', '11651', (117, 120))	('MEK', 'Gene', '17242', (55, 58))	('AKT', 'Gene', (96, 99))	('MEK', 'Gene', (42, 45))	('#4060', 'Var', (108, 113))	('ERK', 'Gene', (69, 72))	('pERK', 'Gene', (68, 72))
168613	28806393	IC tumor model: 1 x 106 PMAs expressing SRGAP3-RAF1, QKI-RAF1 and vector control were resuspended in Matrigel basement matrix (BD Biosciences, Franklin Lakes, NJ, USA) and 2 mul was injected into the right striatum of NSG mice (n=5/cell line).	('mice', 'Species', '10090', (222, 226))	('QKI-RAF1', 'Var', (53, 61))	('IC tumor', 'Disease', 'MESH:C537984', (0, 8))	('SRGAP3-RAF1', 'Gene', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('IC tumor', 'Disease', (0, 8))
168634	20704759	Of these, 37 patients were included in this study based on the following criteria: 1) MRI evidence of diffuse, increased signal intensity on the T2-weighted or FLAIR images accompanied by a low or absent signal in the affected areas on T1 images, 2) lesions involving more than two cerebral lobes, 3) available serial MR images and clinical follow-up data, 4) who underwent radiotherapy for GC.	('lesions', 'Var', (250, 257))	('patients', 'Species', '9606', (13, 21))	('signal intensity', 'MPA', (121, 137))	('increased', 'PosReg', (111, 120))
168709	30479695	In models of lung, breast and pancreatic cancers, macrophage-specific deletion of NRP1 shows profound effects on disease progression.	('deletion', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('NRP1', 'Gene', (82, 86))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('disease progression', 'CPA', (113, 132))	('lung', 'Disease', (13, 17))	('breast and pancreatic cancers', 'Disease', 'MESH:D010190', (19, 48))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (30, 48))	('effects', 'Reg', (102, 109))
168710	30479695	Our lab has previously shown that GAM-specific ablation of NRP1, or global pharmacological inhibition of this co-receptor, slows tumor progression in a mouse model of GB, in a similar fashion, by inhibiting neoangiogenesis and reducing immunosuppressive signaling.	('slows', 'NegReg', (123, 128))	('neoangiogenesis', 'CPA', (207, 222))	('GAM', 'Chemical', '-', (34, 37))	('immunosuppressive signaling', 'MPA', (236, 263))	('NRP1', 'Gene', (59, 63))	('inhibiting', 'NegReg', (196, 206))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mouse', 'Species', '10090', (152, 157))	('ablation', 'Var', (47, 55))	('reducing', 'NegReg', (227, 235))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
168734	30479695	It should be noted that high NRP1 expression was associated with wild-type IDH in grade IV glioma.	('expression', 'MPA', (34, 44))	('NRP1', 'Protein', (29, 33))	('associated', 'Reg', (49, 59))	('glioma', 'Disease', (91, 97))	('high', 'Var', (24, 28))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
168746	30479695	Our results demonstrate that both LGG and GB patients with high NRP1 expression have enriched monocytic, macrophage, and M2 macrophage populations (Figure 7A, 7B) (selected comparisons shown for clarity, full analysis can be found in Supplementary Figure 5).	('patients', 'Species', '9606', (45, 53))	('high', 'Var', (59, 63))	('LGG', 'Disease', (34, 37))	('NRP1', 'Gene', (64, 68))
168756	30479695	We have shown in the GL261 model of murine GB that GAM-specific knockout of NRP1 slows disease progression by reducing tumor vascularization and inhibiting immunosuppressive TGFbeta signaling.	('tumor', 'Disease', (119, 124))	('disease progression', 'CPA', (87, 106))	('murine', 'Species', '10090', (36, 42))	('knockout', 'Var', (64, 72))	('immunosuppressive TGFbeta signaling', 'MPA', (156, 191))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('reducing', 'NegReg', (110, 118))	('GAM', 'Chemical', '-', (51, 54))	('NRP1', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('inhibiting', 'NegReg', (145, 155))	('slows', 'NegReg', (81, 86))
168765	30479695	Thus, NRP1 ablation alone may constitute a 'two-hit' mechanism by which these cells slow tumor progression through reversing the M2-like phenotype while simultaneously stunting the neoangiogenic potential of GAMs.	('slow', 'NegReg', (84, 88))	('M2-like phenotype', 'MPA', (129, 146))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('neoangiogenic potential of GAMs', 'CPA', (181, 212))	('NRP1', 'Gene', (6, 10))	('reversing', 'NegReg', (115, 124))	('stunting', 'NegReg', (168, 176))	('GAM', 'Chemical', '-', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('ablation', 'Var', (11, 19))
168779	29186201	Prognostic markers for survival in patients with oligodendroglial tumors; a single-institution review of 214 cases In the 2016 WHO classification, the diagnosis of oligodendroglioma has been restricted to IDH mutated, 1p19q codeleted tumors (IDHmut-codel).	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('oligodendroglial tumors', 'Disease', (49, 72))	('IDH', 'Gene', (205, 208))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (49, 72))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('IDH', 'Gene', (242, 245))	('IDH', 'Gene', '3417', (205, 208))	('1p19q', 'Var', (218, 223))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('oligodendroglioma', 'Disease', 'MESH:D009837', (164, 181))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', (234, 240))	('IDH', 'Gene', '3417', (242, 245))	('oligodendroglioma', 'Disease', (164, 181))
168780	29186201	IDHmut oligoastrocytoma is now classified either as oligodendroglioma or astrocytoma based on presence of 1p19q codeletion.	('IDH', 'Gene', (0, 3))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (7, 23))	('oligoastrocytoma', 'Disease', (7, 23))	('astrocytoma', 'Disease', 'MESH:D001254', (73, 84))	('oligodendroglioma', 'Disease', (52, 69))	('IDH', 'Gene', '3417', (0, 3))	('astrocytoma', 'Disease', (73, 84))	('1p19q codeletion', 'Var', (106, 122))	('oligodendroglioma', 'Disease', 'MESH:D009837', (52, 69))	('astrocytoma', 'Disease', 'MESH:D001254', (12, 23))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('astrocytoma', 'Disease', (12, 23))	('astrocytoma', 'Phenotype', 'HP:0009592', (12, 23))
168789	29186201	Multivariate survival analysis identified young age (HR 1.78 >= 40 years), the absence of neurological deficits or personality changes (HR 0.57), frontal tumor location (HR 0.64) and the presence of IDHmut-codel (HR 0.50) as independent predictors for longer survival, whereas tumor grade was not.	('longer', 'PosReg', (252, 258))	('frontal tumor', 'Disease', (146, 159))	('presence', 'Var', (187, 195))	('IDH', 'Gene', '3417', (199, 202))	('frontal tumor', 'Disease', 'MESH:D001932', (146, 159))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('neurological deficits', 'Phenotype', 'HP:0000707', (90, 111))	('IDH', 'Gene', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('personality changes', 'Phenotype', 'HP:0000751', (115, 134))	('neurological deficits', 'Disease', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('neurological deficit', 'Phenotype', 'HP:0000707', (90, 110))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (277, 282))	('neurological deficits', 'Disease', 'MESH:D009461', (90, 111))	('personality change', 'Phenotype', 'HP:0000751', (115, 133))	('tumor', 'Disease', (154, 159))
168790	29186201	In this unselected single-institution cohort, the presence of IDHmut-codel was associated with more beneficial clinical parameters and was identified as an independent prognostic factor.	('more beneficial', 'PosReg', (95, 110))	('presence', 'Var', (50, 58))	('IDH', 'Gene', (62, 65))	('IDH', 'Gene', '3417', (62, 65))
168795	29186201	In the recent EORTC trial of low-grade gliomas (LGG) comparing standard radiotherapy with primary temozolomide chemotherapy, a significant impact of radiotherapy on progression-free survival was found only in IDHmut LGG with intact 1p19q.	('temozolomide', 'Chemical', 'MESH:D000077204', (98, 110))	('IDH', 'Gene', '3417', (209, 212))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Disease', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('1p19q', 'Var', (232, 237))	('IDH', 'Gene', (209, 212))
168816	29186201	Mutated isocitrate dehydrogenase 1 (IDH1) R132H protein was detected using a monoclonal mouse antibody targeting the mutated IDH1 R132H protein (mIDH1R132) as described previously.	('IDH1', 'Gene', (146, 150))	('R132H', 'Mutation', 'rs121913500', (130, 135))	('R132H', 'Var', (42, 47))	('IDH1', 'Gene', (36, 40))	('R132H', 'Mutation', 'rs121913500', (42, 47))	('IDH1', 'Gene', '3417', (146, 150))	('IDH1', 'Gene', '3417', (125, 129))	('IDH1', 'Gene', '3417', (36, 40))	('mouse', 'Species', '10090', (88, 93))	('IDH1', 'Gene', (125, 129))
168827	29186201	Thus, the following parameters were used: age at onset (>= 40 or < 40 years), gender, neurological deficit or personality change, KPS score >= 90 or < 90, type of surgery (i.e.	('< 90', 'Var', (149, 153))	('neurological deficit', 'Phenotype', 'HP:0000707', (86, 106))	('neurological deficit', 'Disease', 'MESH:D009461', (86, 106))	('KPS', 'Gene', (130, 133))	('personality change', 'Phenotype', 'HP:0000751', (110, 128))	('>= 90', 'Var', (140, 145))	('neurological deficit', 'Disease', (86, 106))
168842	29186201	The time to surgery, defined as the time period between first symptoms and operation, was shorter for patients with grade III (median 56 days) than grade II tumors (median 128 days) (p<0.001).	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('grade III', 'Var', (116, 125))	('patients', 'Species', '9606', (102, 110))	('shorter', 'NegReg', (90, 97))	('II tumors', 'Disease', 'MESH:D009369', (154, 163))	('II tumors', 'Disease', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
168854	29186201	For ten patients, the tumor was 1p19q codeleted but without IDH1 mutation detected by the mIDH1R132 antibody.	('IDH1', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('IDH1', 'Gene', (91, 95))	('1p19q codeleted', 'Var', (32, 47))	('IDH1', 'Gene', '3417', (91, 95))	('tumor', 'Disease', (22, 27))	('IDH1', 'Gene', '3417', (60, 64))	('patients', 'Species', '9606', (8, 16))
168855	29186201	Since the association between 1p19q codeletion and IDH mutation is very strong, we performed another post-hoc analysis, with these ten samples included in the IDHmut-codel group in the Kaplan Meier and Cox regression.	('IDH', 'Gene', (159, 162))	('IDH', 'Gene', (51, 54))	('Cox', 'Gene', '1351', (202, 205))	('IDH', 'Gene', '3417', (159, 162))	('IDH', 'Gene', '3417', (51, 54))	('Cox', 'Gene', (202, 205))	('1p19q codeletion', 'Var', (30, 46))
168857	29186201	In this study, we found that the presence of IDHmut-codel is an independent predictor of survival in patients with tumors of oligodendroglial morphology.	('patients', 'Species', '9606', (101, 109))	('oligodendroglial morphology', 'Phenotype', 'HP:0100709', (125, 152))	('IDH', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IDH', 'Gene', '3417', (45, 48))	('tumors of oligodendroglial morphology', 'Disease', 'MESH:D009369', (115, 152))	('presence', 'Var', (33, 41))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors of oligodendroglial morphology', 'Disease', (115, 152))
168865	29186201	the strong predilection of oligodendrogliomas harboring 1p19q codeletion for the anterior part of the brain.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('1p19q codeletion', 'Var', (56, 72))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (27, 45))	('oligodendrogliomas', 'Disease', (27, 45))
168870	29186201	A recent Australian survey of attitudes amongst neuro-oncology clinicians found that only 25% of the respondents used routinely tests for 1p19q status in diffuse low-grade gliomas at their institution, although 69% were of the opinion that all patients should be tested.	('oncology', 'Phenotype', 'HP:0002664', (54, 62))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('1p19q status', 'Var', (138, 150))	('tests', 'Reg', (128, 133))	('gliomas', 'Disease', (172, 179))	('patients', 'Species', '9606', (244, 252))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))
168880	29186201	Since the vast majority of IDH mutations involve codon 132 of the IDH1, this method will detect around 90% of IDH mutations and therefore the remaining 10% (mainly IDH2 mutations) will be missed.	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', (66, 69))	('mutations', 'Var', (31, 40))	('IDH', 'Gene', '3417', (164, 167))	('IDH1', 'Gene', '3417', (66, 70))	('IDH', 'Gene', (110, 113))	('codon 132', 'Var', (49, 58))	('mutations', 'Var', (114, 123))	('IDH', 'Gene', '3417', (66, 69))	('IDH', 'Gene', '3417', (27, 30))	('IDH1', 'Gene', (66, 70))	('IDH', 'Gene', '3417', (110, 113))	('IDH2', 'Gene', (164, 168))	('IDH', 'Gene', (164, 167))	('IDH2', 'Gene', '3418', (164, 168))
168881	29186201	Taking into account the strong association between 1p19q codeletion and IDH mutation, some underestimation of IDH mutations in this series is to be expected.	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (72, 75))	('1p19q codeletion', 'Var', (51, 67))
168882	29186201	This is particularly likely for the ten tumors with 1p19q codeletion but without IDH1 mutated protein that was included in the group of tumors unknown/incomplete molecular profile.	('tumors', 'Disease', (136, 142))	('tumors unknown', 'Disease', 'MESH:D009382', (136, 150))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors unknown', 'Disease', (136, 150))	('IDH1', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('1p19q codeletion', 'Var', (52, 68))	('IDH1', 'Gene', '3417', (81, 85))	('tumors', 'Disease', (40, 46))
168893	25302990	We showed that co-expression of STAT5b and PDGFB in mice yielded a significantly higher rate of high-grade gliomas than PDGFB expression alone.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('STAT5b', 'Gene', (32, 38))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('mice', 'Species', '10090', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('PDGFB', 'Gene', (43, 48))	('co-expression', 'Var', (15, 28))
168898	25302990	Mounting evidence suggests that STAT5b also contributes to the malignant progression of gliomas.	('STAT5b', 'Var', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('malignant progression', 'CPA', (63, 84))
168902	25302990	demonstrated that STAT5b expression is higher in glioblastomas (GBM) than in low-grade astrocytomas and normal cortex, and that silencing STAT5b in one GBM cell line caused cell cycle arrest, inhibited cell growth, and inhibited tumor cell invasion.	('glioblastomas', 'Disease', (49, 62))	('higher', 'PosReg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('silencing', 'Var', (128, 137))	('inhibited', 'NegReg', (219, 228))	('STAT5b', 'Gene', (138, 144))	('glioblastomas', 'Disease', 'MESH:D005909', (49, 62))	('astrocytomas', 'Disease', (87, 99))	('expression', 'MPA', (25, 35))	('STAT5b', 'Gene', (18, 24))	('cell cycle arrest', 'CPA', (173, 190))	('astrocytomas', 'Disease', 'MESH:D001254', (87, 99))	('inhibited', 'NegReg', (192, 201))	('tumor', 'Disease', (229, 234))	('glioblastomas', 'Phenotype', 'HP:0012174', (49, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (173, 190))	('cell growth', 'CPA', (202, 213))
168903	25302990	Silencing STAT5b was also accompanied by a decrease in the downstream signaling molecules Bcl-2, focal adhesion kinase, and vascular endothelial growth factor.	('decrease', 'NegReg', (43, 51))	('Bcl-2', 'Gene', (90, 95))	('focal adhesion kinase', 'MPA', (97, 118))	('Bcl-2', 'Gene', '12043', (90, 95))	('STAT5b', 'Gene', (10, 16))	('vascular endothelial growth factor', 'MPA', (124, 158))	('Silencing', 'Var', (0, 9))
168904	25302990	Phosphorylated STAT5b at tyrosine Y699 has been shown to be a downstream target of the mutated, constitutively active delta epidermal growth factor receptor (DeltaEGFR), which has been established as an important oncogene for GBM progression and is associated with increased anti-apoptotic Bcl-xL expression.	('mutated', 'Var', (87, 94))	('increased', 'PosReg', (265, 274))	('epidermal growth factor receptor', 'Gene', (124, 156))	('epidermal growth factor receptor', 'Gene', '13649', (124, 156))	('anti-apoptotic Bcl-xL', 'MPA', (275, 296))	('expression', 'MPA', (297, 307))	('tyrosine', 'Chemical', 'MESH:D014443', (25, 33))
168907	25302990	Gliomas with the DeltaEGFR mutation demonstrate resistance to cisplatin-based chemotherapy; this resistance is thought to be due to increased anti-apoptotic Bcl-xL expression from DeltaEGFR signaling, and is regulated by phosphorylated STAT5b.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('anti-apoptotic Bcl-xL expression', 'MPA', (142, 174))	('increased', 'PosReg', (132, 141))	('mutation', 'Var', (27, 35))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('DeltaEGFR', 'Gene', (17, 26))	('Gliomas', 'Disease', (0, 7))
168909	25302990	Based on our previous work demonstrating the ability of anti-apoptotic signaling to drive glioma progression, we hypothesized that STAT5b would promote the development of HGG.	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('promote', 'PosReg', (144, 151))	('HGG', 'Disease', (171, 174))	('STAT5b', 'Var', (131, 137))
168939	25302990	Tumors were distinguished as high grade by the presence of brisk mitosis, necrosis, or microvascular proliferation.	('necrosis', 'Disease', 'MESH:D009336', (74, 82))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('brisk', 'Var', (59, 64))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('necrosis', 'Disease', (74, 82))	('microvascular proliferation', 'CPA', (87, 114))	('mitosis', 'Disease', (65, 72))	('mitosis', 'Disease', 'None', (65, 72))
168962	25302990	Tumor incidence was 97% (33/34) for the combination injection cohort of RCAS-STAT5b + RCAS-PDGFB and 97% (28/29) for the RCAS-PDGFB alone group (Figure 2).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RCAS-STAT5b', 'Var', (72, 83))	('Tumor incidence', 'CPA', (0, 15))	('RCAS', 'Chemical', '-', (121, 125))	('RCAS', 'Chemical', '-', (86, 90))	('RCAS', 'Chemical', '-', (72, 76))
168967	25302990	The median time to symptomatic tumor formation for mice injected with RCAS-STAT5b + RCAS-PDGFB was 24 days (range, 12-90), and for the mice injected with RCAS-PDGFB alone was 76.5 days (range, 23-90).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('RCAS', 'Chemical', '-', (154, 158))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Disease', (31, 36))	('RCAS', 'Chemical', '-', (70, 74))	('mice', 'Species', '10090', (135, 139))	('RCAS-STAT5b +', 'Var', (70, 83))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('RCAS', 'Chemical', '-', (84, 88))
168970	25302990	There was a statistically significant decrease in apoptosis in the tumors from mice injected with RCAS-STAT5b + RCAS-PDGFB compared to RCAS-PDGFB alone (Student's t-test; P = 0.0001; 95% CI: 0.004-0.011).	('RCAS', 'Chemical', '-', (98, 102))	('RCAS', 'Chemical', '-', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('RCAS-STAT5b +', 'Var', (98, 111))	('mice', 'Species', '10090', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decrease', 'NegReg', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('RCAS', 'Chemical', '-', (135, 139))	('tumors', 'Disease', (67, 73))	('apoptosis', 'CPA', (50, 59))
168973	25302990	The mitotic rate was higher in the RCAS-PDGFB + RCAS-STAT5b injection set (1.6%) than in the RCAS-PDGFB injection set (1.0%), but this was not statistically significant (Student's t-test; P = 0.	('RCAS-STAT5b', 'Gene', (48, 59))	('RCAS', 'Chemical', '-', (48, 52))	('RCAS-PDGFB +', 'Var', (35, 47))	('mitotic rate', 'CPA', (4, 16))	('higher', 'PosReg', (21, 27))	('RCAS', 'Chemical', '-', (93, 97))	('RCAS', 'Chemical', '-', (35, 39))
168977	25302990	In concordance with this, avid staining of tumors induced by RCAS-STAT5b + RCAS-PDGFB with Olig2 was observed, confirming a PN signature (Figure 5F).	('RCAS', 'Chemical', '-', (75, 79))	('RCAS', 'Chemical', '-', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('RCAS-STAT5b', 'Var', (61, 72))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
168978	25302990	Based on our previous in vitro work identifying STAT5b targets, we further characterized tumors induced by STAT5b.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('STAT5b', 'Var', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
168982	25302990	A high expression of aurora kinase A within HGGs was demonstrated in the PDGFB+STAT5b group when compared to the LGGs from this group (Figures 6D-F. Cyclin D1 is a cell cycle regulatory protein whose promoter is a target of phosphorylated STAT5b.	('PDGFB+STAT5b', 'Var', (73, 85))	('Cyclin D1', 'Gene', (149, 158))	('expression', 'MPA', (7, 17))	('aurora kinase A', 'Enzyme', (21, 36))	('Cyclin D1', 'Gene', '12443', (149, 158))
168986	25302990	Our group has recently shown that STAT5b contributes to tumor cell survival by suppressing apoptosis and that apoptotic suppression (mediated by another STAT family member, STAT3) is a key contributor to the degeneration of LGGs to HGGs.	('apoptotic suppression', 'CPA', (110, 131))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('STAT3', 'Gene', '20848', (173, 178))	('apoptosis', 'CPA', (91, 100))	('tumor', 'Disease', (56, 61))	('STAT3', 'Gene', (173, 178))	('STAT5b', 'Var', (34, 40))	('suppressing', 'NegReg', (79, 90))	('LGGs', 'Gene', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
168987	25302990	Here, we show that co-expression of STAT5b with PDGFB promotes malignant progression in a PN model of glioma.	('co-expression', 'Var', (19, 32))	('PDGFB', 'Gene', (48, 53))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('glioma', 'Disease', (102, 108))	('malignant progression in a', 'CPA', (63, 89))	('promotes', 'PosReg', (54, 62))
168989	25302990	These results confirm and extend our previous work correlating STAT5b with a more aggressive tumor phenotype.	('STAT5b', 'Var', (63, 69))	('aggressive tumor', 'Disease', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aggressive tumor', 'Disease', 'MESH:D001523', (82, 98))
168996	25302990	This is consistent with our previous work demonstrating that human tumor samples with high STAT5b expression were associated with shorter survival where in, we have shown that STAT5b can be activated by DeltaEGFR and then associate together in the nucleus to affect gene transcription by directly binding to regulatory DNA regions.	('activated', 'PosReg', (190, 199))	('associate', 'Interaction', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('affect', 'Reg', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('STAT5b', 'Gene', (176, 182))	('tumor', 'Disease', (67, 72))	('gene transcription', 'MPA', (266, 284))	('human', 'Species', '9606', (61, 66))	('DeltaEGFR', 'Var', (203, 212))	('binding', 'Interaction', (297, 304))
168997	25302990	Although this would predict that STAT5b overexpression would drive tumor cell proliferation, we were unable to show a statistical increase in mitotic activity in tumors induced by STAT5b + PDGFB relative to those induced by PDGFB alone.	('STAT5b + PDGFB', 'Var', (180, 194))	('drive', 'PosReg', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PDGFB', 'Var', (189, 194))	('tumors', 'Disease', (162, 168))	('tumor', 'Disease', (67, 72))	('mitotic activity', 'CPA', (142, 158))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
169000	25302990	They also found that levels of the anti-apoptotic molecule Bcl-2 were decreased in cell lines treated with STAT5b silencing.	('silencing', 'Var', (114, 123))	('decreased', 'NegReg', (70, 79))	('STAT5b', 'Gene', (107, 113))	('Bcl-2', 'Gene', (59, 64))	('Bcl-2', 'Gene', '12043', (59, 64))
169010	25678837	New Developments in the Pathogenesis and Therapeutic Targeting of the IDH1 Mutation in Glioma In the last five years, IDH1 mutations in human malignancies have significantly shaped the diagnosis and management of cancer patients.	('human', 'Species', '9606', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Mutation', 'Var', (75, 83))	('IDH1', 'Gene', (118, 122))	('IDH1', 'Gene', '3417', (70, 74))	('IDH1', 'Gene', '3417', (118, 122))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('cancer', 'Disease', (213, 219))	('malignancies', 'Disease', (142, 154))	('Glioma', 'Disease', 'MESH:D005910', (87, 93))	('Glioma', 'Phenotype', 'HP:0009733', (87, 93))	('mutations', 'Var', (123, 132))	('Glioma', 'Disease', (87, 93))	('IDH1', 'Gene', (70, 74))
169011	25678837	Ongoing intense research efforts continue to alter our understanding of the role of the IDH1 mutation in tumor formation.	('IDH1', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mutation', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
169012	25678837	Currently, evidence suggests the IDH1 mutation to be an early event in tumorigenesis with multiple downstream oncogenic consequences including maintenance of a hypermethylator phenotype, alterations in HIF signalling, and disruption of collagen maturation contributing to a cancer-promoting extracellular matrix.	('HIF signalling', 'MPA', (202, 216))	('disruption', 'Var', (222, 232))	('hypermethylator phenotype', 'MPA', (160, 185))	('alterations', 'Reg', (187, 198))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('IDH1', 'Gene', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Disease', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('collagen maturation', 'CPA', (236, 255))	('mutation', 'Var', (38, 46))	('tumor', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
169013	25678837	The most recent reports elucidating these mechanisms is described in this review with an emphasis on the pathogenesis of the IDH1 mutation in glioma.	('glioma', 'Disease', (142, 148))	('mutation', 'Var', (130, 138))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('IDH1', 'Gene', (125, 129))
169021	25678837	In 2008, The Cancer Genome Atlas (TCGA) conducted a genome-wide profile study, which identified, for the first time, mutations in the gene of isocitrate dehydrogenase 1 (IDH1) in GBM tumor samples.	('GBM tumor', 'Disease', 'MESH:D005910', (179, 188))	('mutations', 'Var', (117, 126))	('IDH1', 'Gene', (170, 174))	('GBM tumor', 'Disease', (179, 188))	('Cancer Genome Atlas', 'Disease', (13, 32))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (13, 32))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('isocitrate dehydrogenase 1', 'Gene', (142, 168))	('isocitrate dehydrogenase 1', 'Gene', '3417', (142, 168))
169022	25678837	The novel discovery in GBM of a mutation in a gene expressing an enzyme involved in cellular metabolism mirrored findings in non-central nervous system (CNS) tumors of mutation of genes expressing the metabolic enzymes succinate dehydrogenase and fumarate hydratase.	('hydrogen', 'Chemical', 'MESH:D006859', (231, 239))	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('non-central nervous system (CNS) tumors', 'Disease', 'MESH:D016543', (125, 164))	('fumarate hydratase', 'Gene', '2271', (247, 265))	('fumarate hydratase', 'Gene', (247, 265))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutation', 'Var', (32, 40))
169023	25678837	Since then, IDH1 mutations have been linked to other histopathological forms of glioma and to non-CNS malignancies.	('glioma', 'Disease', (80, 86))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('IDH1', 'Gene', (12, 16))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('malignancies', 'Disease', (102, 114))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('linked', 'Reg', (37, 43))	('mutations', 'Var', (17, 26))
169024	25678837	This review describes the current role of IDH1 mutations in human malignancies, including glioma.	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('mutations', 'Var', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))	('IDH1', 'Gene', (42, 46))	('human', 'Species', '9606', (60, 65))
169028	25678837	They found that five of the samples (22%) had a heterozygous missense mutation in the IDH1 gene, a single base substitution of guanine for adenine, leading to arginine substituting for histidine at codon site 132 (R132H) in the mutant IDH1 protein.	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', (235, 239))	('protein', 'Protein', (240, 247))	('arginine substituting', 'Var', (159, 180))	('histidine', 'Chemical', 'MESH:D006639', (185, 194))	('arginine', 'Chemical', 'MESH:D001120', (159, 167))	('adenine', 'Chemical', 'MESH:D000225', (139, 146))	('R132H', 'Mutation', 'rs121913500', (214, 219))	('guanine', 'Chemical', 'MESH:D006147', (127, 134))
169029	25678837	A follow-up targeted sequence analysis of an additional 127 tumors found the same IDH1 mutation in 13 of the samples with 4/5 (80%) of the secondary GBM tumors demonstrating the IDH1 mutation.	('IDH1', 'Gene', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('GBM tumor', 'Disease', 'MESH:D005910', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (153, 159))	('GBM tumor', 'Disease', (149, 158))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('mutation', 'Var', (87, 95))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumors', 'Disease', (60, 66))
169030	25678837	Overall, the IDH1 mutation was found in 12% of the 149 tumors that were analysed.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('IDH1', 'Gene', (13, 17))	('149 tumors', 'Disease', (51, 61))	('mutation', 'Var', (18, 26))	('149 tumors', 'Disease', 'MESH:D009369', (51, 61))	('found', 'Reg', (31, 36))
169031	25678837	In a recent literature review, the IDH1 mutation was found in 5.6% of primary GBMs analysed across all studies (75/1345 tumors), and in 76% (94/123 tumors) of secondary GBMs, supporting the original findings of the TCGA study.	('mutation', 'Var', (40, 48))	('IDH1', 'Gene', (35, 39))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('GBM', 'Phenotype', 'HP:0012174', (169, 172))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('found', 'Reg', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Disease', (148, 154))	('primary GBMs', 'Disease', (70, 82))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
169032	25678837	The IDH1 mutation is also prevalent in lower grade gliomas, occurring in over 70% of grade II tumors, and 62-80% of grade II-III oligodendrogliomas, grade II-III oligoastrocytomas, and grade III astrocytomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (129, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (195, 206))	('II tumors', 'Disease', 'MESH:D009369', (91, 100))	('prevalent', 'Reg', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('gliomas', 'Disease', (140, 147))	('II-III oligoastrocytomas', 'Disease', 'MESH:D001254', (155, 179))	('gliomas', 'Disease', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('II tumors', 'Disease', (91, 100))	('II-III oligoastrocytomas', 'Disease', (155, 179))	('oligodendrogliomas', 'Disease', (129, 147))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('mutation', 'Var', (9, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (167, 178))	('II astrocytomas', 'Disease', 'MESH:D001254', (192, 207))	('II astrocytomas', 'Disease', (192, 207))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('IDH1', 'Gene', (4, 8))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
169033	25678837	The TCGA study also importantly found that IDH1 mutations were more frequent in younger patients.	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (48, 57))	('IDH1', 'Gene', (43, 47))
169034	25678837	The median age of patients with tumors harboring IDH1 mutations was 33.2 years, starkly contrasting the median age of 55.3 years in patients with wild type tumors.	('type tumors', 'Disease', (151, 162))	('type tumors', 'Disease', 'MESH:D009369', (151, 162))	('tumors', 'Disease', (156, 162))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Disease', (32, 38))	('IDH1', 'Gene', (49, 53))	('patients', 'Species', '9606', (132, 140))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
169035	25678837	This study also demonstrated that in GBM patients, the IDH1 mutation conferred a survival advantage compared to IDH1 wild type GBM, with a median overall survival of 3.8 years in the former and 1.1 years in the latter.	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutation', 'Var', (60, 68))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('patients', 'Species', '9606', (41, 49))	('GBM', 'Disease', (37, 40))	('advantage', 'PosReg', (90, 99))	('IDH1', 'Gene', (55, 59))
169036	25678837	This finding has been replicated in other studies, with a survival of 2.6 years in IDH1 mutated tumors compared to just 1.2 years in wild type IDH1 tumors.	('type IDH1 tumors', 'Disease', 'MESH:D009369', (138, 154))	('type IDH1 tumors', 'Disease', (138, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutated', 'Var', (88, 95))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('IDH1', 'Gene', (83, 87))
169037	25678837	Recently, Beiko et al (2014) demonstrated that IDH1 mutations were associated with higher rates of total surgical resection of enhancing regions in grade III and IV astrocytomas.	('mutations', 'Var', (52, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('IDH1', 'Gene', (47, 51))	('grade III', 'Disease', (148, 157))	('IV astrocytomas', 'Disease', 'MESH:D005909', (162, 177))	('IV astrocytomas', 'Disease', (162, 177))
169038	25678837	Furthermore, maximal resection of total tumor volume, including non-enhancing areas, led to improved overall survival in IDH1 mutated tumors but not in wild type counterparts.	('IDH1', 'Gene', (121, 125))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('overall survival', 'MPA', (101, 117))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('improved', 'PosReg', (92, 100))	('tumor', 'Disease', (134, 139))	('mutated', 'Var', (126, 133))
169040	25678837	Complete surgical resection of total tumor volume (enhancing and non-enhancing areas) may be of greater significance to patient prognosis in IDH1 mutated tumors, compared to wild types.	('IDH1', 'Gene', (141, 145))	('tumors', 'Disease', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutated', 'Var', (146, 153))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('patient', 'Species', '9606', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
169041	25678837	Further investigations are required to elucidate additional mechanisms behind the improved survival seen in patients with IDH1 mutated gliomas.	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('IDH1', 'Gene', (122, 126))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('patients', 'Species', '9606', (108, 116))	('mutated', 'Var', (127, 134))	('improved', 'PosReg', (82, 90))
169042	25678837	This may be aided by a study comparing the survival of patients with secondary gliomas having the IDH1 mutation with the survival of patients with secondary IDH1 wild type gliomas.	('gliomas', 'Disease', (79, 86))	('type gliomas', 'Disease', 'MESH:D005910', (167, 179))	('type gliomas', 'Disease', (167, 179))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('patients', 'Species', '9606', (133, 141))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('patients', 'Species', '9606', (55, 63))	('IDH1', 'Gene', (98, 102))	('gliomas', 'Disease', (172, 179))	('mutation', 'Var', (103, 111))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
169043	25678837	PTEN loss, EGFR amplification, and loss of heterozygosity (LOH) of chromosome 10 are associated with primary GBM while ATRX mutations, loss of p53, and LOH of chromosome 19 are common in secondary GBM.	('loss of', 'NegReg', (35, 42))	('mutations', 'Var', (124, 133))	('p53', 'Gene', '7157', (143, 146))	('GBM', 'Phenotype', 'HP:0012174', (197, 200))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('ATRX', 'Gene', '546', (119, 123))	('amplification', 'Var', (16, 29))	('primary GBM', 'Disease', (101, 112))	('loss', 'NegReg', (5, 9))	('loss', 'Var', (135, 139))	('PTEN', 'Gene', (0, 4))	('p53', 'Gene', (143, 146))	('PTEN', 'Gene', '5728', (0, 4))	('associated', 'Reg', (85, 95))	('ATRX', 'Gene', (119, 123))
169044	25678837	Extensive genomic profiling has identified that around 90% of IDH1 mutations involve the R132H substitution.	('IDH1', 'Gene', (62, 66))	('R132H', 'Mutation', 'rs121913500', (89, 94))	('R132H', 'Var', (89, 94))	('mutations', 'Var', (67, 76))
169046	25678837	Of the remaining 10% of IDH1 mutations, 4.3-4.7% are due to arginine being replaced with cysteine (R132C), 1.9-2.1% with glycine (R132G), 1.6-1.7% with serine (R132S), 0.6-0.8% with leucine (R132L), and 0.3% with glutamine (R132Q).	('arginine', 'Chemical', 'MESH:D001120', (60, 68))	('R132C', 'Mutation', 'rs121913499', (99, 104))	('R132S', 'Mutation', 'rs121913499', (160, 165))	('leucine', 'Chemical', 'MESH:D007930', (182, 189))	('R132G', 'Mutation', 'rs121913499', (130, 135))	('arginine', 'MPA', (60, 68))	('mutations', 'Var', (29, 38))	('R132G', 'Var', (130, 135))	('glycine', 'Chemical', 'MESH:D005998', (121, 128))	('R132L', 'Var', (191, 196))	('glutamine', 'Chemical', 'MESH:D005973', (213, 222))	('IDH1', 'Gene', (24, 28))	('R132Q', 'Mutation', 'p.R132Q', (224, 229))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('R132L', 'Mutation', 'rs121913500', (191, 196))	('R132S', 'Var', (160, 165))	('cysteine', 'Chemical', 'MESH:D003545', (89, 97))
169047	25678837	Although no studies have compared patient outcomes among different IDH1 R132 mutations, R132S- and R132L-transfected human embryonic kidney cells produce significantly higher levels of 2-HG and exhibit markedly reduced cell viabilities compared to R132H-transfected cells, in vitro.	('2-HG', 'MPA', (185, 189))	('R132S-', 'Var', (88, 94))	('R132S', 'Mutation', 'rs121913499', (88, 93))	('human', 'Species', '9606', (117, 122))	('R132H', 'Mutation', 'rs121913500', (248, 253))	('reduced', 'NegReg', (211, 218))	('IDH1 R132', 'Gene', (67, 76))	('higher', 'PosReg', (168, 174))	('patient', 'Species', '9606', (34, 41))	('levels', 'MPA', (175, 181))	('R132L-transfected', 'Var', (99, 116))	('cell viabilities', 'CPA', (219, 235))	('R132L', 'Mutation', 'rs121913500', (99, 104))
169048	25678837	For example, R132C mutations occur more frequently in astrocytoma than in oligodendroglioma.	('R132C', 'Mutation', 'rs121913499', (13, 18))	('oligodendroglioma', 'Disease', (74, 91))	('R132C mutations', 'Var', (13, 28))	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))	('astrocytoma', 'Disease', 'MESH:D001254', (54, 65))	('oligodendroglioma', 'Disease', 'MESH:D009837', (74, 91))	('astrocytoma', 'Disease', (54, 65))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
169049	25678837	The type of other genetic mutations co-occurring with the IDH1 mutation also influences the histological type of glioma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('mutation', 'Var', (63, 71))	('glioma', 'Disease', (113, 119))	('influences', 'Reg', (77, 87))	('IDH1', 'Gene', (58, 62))
169050	25678837	For example, astrocytomas tend to feature IDH1 and TP53 mutations, while IDH1 mutated oligodendrogliomas frequently have co-deletions of chromosomes 1p and 19q.	('mutations', 'Var', (56, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (13, 25))	('TP53', 'Gene', (51, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (13, 24))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('astrocytomas', 'Disease', (13, 25))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (86, 104))	('IDH1', 'Gene', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('TP53', 'Gene', '7157', (51, 55))	('oligodendrogliomas', 'Disease', (86, 104))
169051	25678837	Different patterns of the IDH1 mutation between primary and secondary GBM, as well as between other grades of astrocytomas, and between other types of gliomas, is very useful diagnostically, helping to differentiate between histological subtypes which can often be subject to human error.	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('mutation', 'Var', (31, 39))	('IDH1', 'Gene', (26, 30))	('human', 'Species', '9606', (276, 281))	('astrocytomas', 'Disease', 'MESH:D001254', (110, 122))	('astrocytoma', 'Phenotype', 'HP:0009592', (110, 121))	('astrocytomas', 'Disease', (110, 122))	('gliomas', 'Disease', (151, 158))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
169053	25678837	IDH1 mutations are also present in some tumors originating in cells outside of the CNS.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('present', 'Reg', (24, 31))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
169055	25678837	IDH mutations are more prevalent in AML if IDH2 mutations are also considered, with rates between 15-33%.	('AML', 'Disease', 'MESH:D015470', (36, 39))	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', (0, 3))	('IDH2', 'Gene', (43, 47))	('AML', 'Disease', (36, 39))	('IDH', 'Gene', '3417', (0, 3))	('AML', 'Phenotype', 'HP:0004808', (36, 39))	('prevalent', 'Reg', (23, 32))	('IDH2', 'Gene', '3418', (43, 47))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', (43, 46))
169056	25678837	IDH1/2 mutations have also been found in 5% of patients with myelodysplastic syndrome (MDS), 8.8% with myeloproliferative neoplasms (MPN) and just under 10% of patients with secondary AML.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('patients', 'Species', '9606', (47, 55))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (61, 85))	('IDH1/2', 'Gene', (0, 6))	('AML', 'Disease', 'MESH:D015470', (184, 187))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (61, 85))	('MDS', 'Phenotype', 'HP:0002863', (87, 90))	('AML', 'Disease', (184, 187))	('AML', 'Phenotype', 'HP:0004808', (184, 187))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('mutations', 'Var', (7, 16))	('MDS', 'Disease', 'MESH:D009190', (87, 90))	('MPN', 'Phenotype', 'HP:0005547', (133, 136))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (103, 131))	('found', 'Reg', (32, 37))	('myelodysplastic syndrome', 'Disease', (61, 85))	('myeloproliferative neoplasms', 'Disease', (103, 131))	('patients', 'Species', '9606', (160, 168))	('MDS', 'Disease', (87, 90))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (103, 131))
169057	25678837	Unlike in GBM, IDH mutations have a negative impact on prognosis in MPN and MDS.	('MPN', 'Disease', (68, 71))	('MDS', 'Phenotype', 'HP:0002863', (76, 79))	('MPN', 'Phenotype', 'HP:0005547', (68, 71))	('MDS', 'Disease', (76, 79))	('MDS', 'Disease', 'MESH:D009190', (76, 79))	('mutations', 'Var', (19, 28))	('GBM', 'Phenotype', 'HP:0012174', (10, 13))	('IDH', 'Gene', (15, 18))	('IDH', 'Gene', '3417', (15, 18))	('negative', 'NegReg', (36, 44))
169058	25678837	In a study, over one-half of central chondrosarcomas, central chondromas, and periosteal chondromas displayed IDH1/2 mutations.	('mutations', 'Var', (117, 126))	('chondrosarcomas', 'Disease', (37, 52))	('chondrosarcomas', 'Disease', 'MESH:D002813', (37, 52))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (37, 51))	('IDH1/2', 'Gene', (110, 116))	('chondromas', 'Disease', 'MESH:D002812', (62, 72))	('central chondromas', 'Disease', 'MESH:D002812', (54, 72))	('IDH1/2', 'Gene', '3417;3418', (110, 116))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (37, 52))	('chondromas', 'Disease', (89, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('central chondromas', 'Disease', (54, 72))	('chondromas', 'Disease', (62, 72))	('chondromas', 'Disease', 'MESH:D002812', (89, 99))
169059	25678837	This link between IDH mutations and connective tissue tumors was reported by the same group that identified IDH mutations to occur in patients with Ollier disease and Maffucci syndrome.	('Ollier disease', 'Phenotype', 'HP:0500045', (148, 162))	('Ollier disease', 'Disease', (148, 162))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('IDH', 'Gene', (18, 21))	('connective tissue tumors', 'Phenotype', 'HP:0100242', (36, 60))	('IDH', 'Gene', (108, 111))	('Ollier disease', 'Disease', 'MESH:D004687', (148, 162))	('patients', 'Species', '9606', (134, 142))	('occur', 'Reg', (125, 130))	('IDH', 'Gene', '3417', (18, 21))	('mutations', 'Var', (112, 121))	('IDH', 'Gene', '3417', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Maffucci syndrome', 'Disease', (167, 184))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (167, 184))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
169060	25678837	These mainly pediatric disorders are characterized by the development of multiple tumor types and by somatic mosaicism of the IDH1 mutation.	('mutation', 'Var', (131, 139))	('multiple tumor', 'Disease', 'MESH:D009369', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IDH1', 'Gene', (126, 130))	('multiple tumor', 'Disease', (73, 87))
169061	25678837	The majority of Ollier disease and Maffucci syndrome patients exhibit the R132C IDH1 mutation, in contrast to most secondary GBMs, which harbour the R132H mutation.	('Ollier disease', 'Disease', (16, 30))	('IDH1', 'Gene', (80, 84))	('Maffucci syndrome', 'Disease', (35, 52))	('patients', 'Species', '9606', (53, 61))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (35, 52))	('R132C', 'Mutation', 'rs121913499', (74, 79))	('Ollier disease', 'Disease', 'MESH:D004687', (16, 30))	('R132H', 'Mutation', 'rs121913500', (149, 154))	('R132C', 'Var', (74, 79))	('Ollier disease', 'Phenotype', 'HP:0500045', (16, 30))	('GBM', 'Phenotype', 'HP:0012174', (125, 128))
169063	25678837	In addition, 10% of cholangiocarcinomas harbor IDH1 or 2 mutations; the prognostic significance of the mutation in this malignancy is unknown.	('cholangiocarcinomas', 'Disease', (20, 39))	('malignancy', 'Disease', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('IDH1', 'Gene', (47, 51))	('mutations', 'Var', (57, 66))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (20, 39))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))
169064	25678837	Although less well documented, other CNS tumors including ganglioglioma and primitive neuroectodermal tumor have also been linked with the IDH1 mutation.	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (76, 107))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('IDH1', 'Gene', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('ganglioglioma', 'Disease', (58, 71))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutation', 'Var', (144, 152))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (86, 107))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (86, 107))	('ganglioglioma', 'Disease', 'MESH:D018303', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('neuroectodermal tumor', 'Disease', (86, 107))	('linked', 'Reg', (123, 129))
169075	25678837	Mutations to IDH1 appear to occur early on in glioma development, preceding loss of chromosomes 1p and 19q.	('loss', 'NegReg', (76, 80))	('glioma', 'Disease', (46, 52))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
169076	25678837	From a total of 321 biopsies taken over time from patients with grade II and III gliomas, there were no instances where TP53 mutations or 1p/19q co-deletions were found to develop prior to IDH1 mutation.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('mutation', 'Var', (194, 202))	('patients', 'Species', '9606', (50, 58))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('IDH1', 'Gene', (189, 193))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
169077	25678837	This may be due to a strand asymmetrical mechanism, in which the IDH1 mutation is found on the template strand while TP53 mutations are on the coding strand and are thus only able to be transcribed after DNA replication.	('TP53', 'Gene', '7157', (117, 121))	('mutation', 'Var', (70, 78))	('IDH1', 'Gene', (65, 69))	('TP53', 'Gene', (117, 121))
169078	25678837	Although the current understanding of IDH1 mutations in tumorigenesis remains incomplete, several important advances have been made that elucidate key molecular mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (43, 52))	('IDH1', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
169079	25678837	Unlike other metabolic enzymes associated with cancer such as fumarate hydratase and succinate dehydrogenase, the IDH1 mutation is a gain-of-function mutation, conferring neo-morphic activity upon IDH1.	('mutation', 'Var', (119, 127))	('IDH1', 'Gene', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('fumarate hydratase', 'Gene', '2271', (62, 80))	('fumarate hydratase', 'Gene', (62, 80))	('neo-morphic activity', 'CPA', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('hydrogen', 'Chemical', 'MESH:D006859', (97, 105))
169080	25678837	In a pivotal study profiling IDH1 wild type and mutant (R132H) glioma cells with liquid chromatography-mass spectrometry, Dang et al (2009) demonstrated that the mutant glioma cells express high levels of the metabolite 2-hydroxyglutarate (2-HG).	('mutant', 'Var', (48, 54))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (220, 238))	('glioma', 'Disease', (169, 175))	('R132H', 'Mutation', 'rs121913500', (56, 61))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('mutant', 'Var', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioma', 'Disease', (63, 69))
169081	25678837	Cellular levels of 2-HG in the wild type cells were usually below 0.1 mM, whereas levels in IDH1 mutated glioma cells reached 35 mM.	('mutated', 'Var', (97, 104))	('IDH1', 'Gene', (92, 96))	('glioma', 'Disease', (105, 111))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
169082	25678837	Specifically, the mutation reduces the affinity of the IDH1 active site for isocitrate while concomitantly increasing it for NADPH and a-KG.	('reduces', 'NegReg', (27, 34))	('affinity', 'MPA', (39, 47))	('isocitrate', 'Chemical', 'MESH:C034219', (76, 86))	('NADPH', 'Gene', (125, 130))	('mutation', 'Var', (18, 26))	('increasing', 'PosReg', (107, 117))	('NADPH', 'Gene', '1666', (125, 130))
169083	25678837	Reduced affinity for isocitrate occurs as a result of alterations to a binding site residue that forms hydrogen bonds between the alpha and beta carboxyl groups of isocitrate.	('hydrogen', 'Chemical', 'MESH:D006859', (103, 111))	('isocitrate', 'Chemical', 'MESH:C034219', (21, 31))	('isocitrate', 'Chemical', 'MESH:C034219', (164, 174))	('Reduced', 'NegReg', (0, 7))	('alterations', 'Var', (54, 65))	('affinity', 'MPA', (8, 16))	('hydrogen bonds', 'MPA', (103, 117))
169084	25678837	Consequently, the reverse reaction of IDH1 (a-KG to isocitrate) is favored but rather than carboxylate, the mutant enzyme reduces a-KG to form 2-HG (Fig.	('reduces', 'NegReg', (122, 129))	('carboxylate', 'Chemical', '-', (91, 102))	('a-KG', 'MPA', (130, 134))	('isocitrate', 'Chemical', 'MESH:C034219', (52, 62))	('mutant', 'Var', (108, 114))
169086	25678837	This has been recapitulated by Brooks et al (2014) who demonstrated that the heterodimer of wild type and mutant IDH1 proteins had a Km approximately 11-fold lower than that of the mutant homodimer.	('mutant', 'Var', (106, 112))	('proteins', 'Protein', (118, 126))	('IDH1', 'Gene', (113, 117))	('lower', 'NegReg', (158, 163))	('heterodimer', 'MPA', (77, 88))	('homodimer', 'Gene', '6647', (188, 197))	('homodimer', 'Gene', (188, 197))
169087	25678837	In an experiment using TF-1 leukemia cells, introduction of cell-permeable R-2-HG inhibited differentiation in response to erythropoietin (EPO) and induced growth factor resistance.	('R-2-HG', 'Var', (75, 81))	('inhibited', 'NegReg', (82, 91))	('leukemia', 'Disease', (28, 36))	('TF-1', 'CellLine', 'CVCL:0559', (23, 27))	('leukemia', 'Disease', 'MESH:D007938', (28, 36))	('erythropoietin', 'Gene', (123, 137))	('EPO', 'Gene', (139, 142))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('growth factor resistance', 'MPA', (156, 180))	('differentiation', 'CPA', (92, 107))	('induced', 'Reg', (148, 155))	('erythropoietin', 'Gene', '2056', (123, 137))	('EPO', 'Gene', '2056', (139, 142))
169089	25678837	This study demonstrated that continuously elevated levels of R-2-HG were needed to maintain tumor phenotype in IDH1 mutant cells as withdrawal of R-2-HG restored the normal differentiation response to EPO and growth factors.	('EPO', 'Gene', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('mutant', 'Var', (116, 122))	('EPO', 'Gene', '2056', (201, 204))	('restored', 'PosReg', (153, 161))	('IDH1', 'Gene', (111, 115))
169091	25678837	Interestingly however, patients with D-2-hydroxyglutaric aciduria, a similar metabolic disorder that is characterized by elevated R-2-HG, are not at increased risk for glioma or formation of other tumors.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('patients', 'Species', '9606', (23, 31))	('D-2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0012321', (37, 65))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('D-2-hydroxyglutaric aciduria', 'Var', (37, 65))	('R-2-HG', 'MPA', (130, 136))	('metabolic disorder', 'Disease', (77, 95))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('aciduria', 'Phenotype', 'HP:0012072', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('glioma', 'Disease', (168, 174))	('tumors', 'Disease', (197, 203))	('metabolic disorder', 'Phenotype', 'HP:0001939', (77, 95))	('elevated', 'PosReg', (121, 129))	('metabolic disorder', 'Disease', 'MESH:D008659', (77, 95))
169092	25678837	A number of potential mechanisms have been proposed to explain how R-2-HG produced by the mutant IDH1 protein promotes tumor formation.	('tumor', 'Disease', (119, 124))	('IDH1', 'Gene', (97, 101))	('mutant', 'Var', (90, 96))	('promotes', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('protein', 'Protein', (102, 109))
169093	25678837	Epigenetic modification, via inhibition of a-KG-dependent dioxygenases leading to DNA and histone hypermethylation, has been at the forefront of research efforts.	('oxygen', 'Chemical', 'MESH:D010100', (60, 66))	('DNA', 'MPA', (82, 85))	('inhibition', 'NegReg', (29, 39))	('histone hypermethylation', 'MPA', (90, 114))	('a-KG-dependent dioxygenases', 'Enzyme', (43, 70))	('Epigenetic modification', 'Var', (0, 23))
169100	25678837	As such, HIF1-a degradation is circumvented and instead HIF1-a combines with the corresponding beta subunit, translocates to the nucleus, and activates target genes that facilitate cell survival in hypoxia and also may contribute to tumor formation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('cell survival', 'CPA', (181, 194))	('activates', 'PosReg', (142, 151))	('hypoxia', 'Disease', (198, 205))	('tumor', 'Disease', (233, 238))	('hypoxia', 'Disease', 'MESH:D000860', (198, 205))	('translocates', 'MPA', (109, 121))	('HIF1-a', 'Var', (56, 62))	('contribute', 'Reg', (219, 229))	('facilitate', 'PosReg', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
169101	25678837	Considering that the Eg1N PHD is 2-KG-dependent, it was initially proposed that IDH1 mutations could cause tumor formation due to failure of HIF degradation secondary to impaired HIF1-a proline residue hydroxylation (Fig.	('is 2', 'Species', '1433131', (30, 34))	('IDH1', 'Gene', (80, 84))	('HIF1-a proline residue hydroxylation', 'MPA', (179, 215))	('impaired', 'NegReg', (170, 178))	('tumor', 'Disease', (107, 112))	('PHD', 'Disease', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('failure', 'NegReg', (130, 137))	('mutations', 'Var', (85, 94))	('cause', 'Reg', (101, 106))	('HIF degradation', 'Disease', 'MESH:D055959', (141, 156))	('proline', 'Chemical', 'MESH:D011392', (186, 193))	('PHD', 'Disease', 'MESH:D011547', (26, 29))	('HIF degradation', 'Disease', (141, 156))
169103	25678837	More recently, it was shown that transfection of the IDH1 mutation into glioma cell lines upregulated HIF1-a and increased cell proliferation.	('glioma', 'Disease', (72, 78))	('cell proliferation', 'CPA', (123, 141))	('IDH1', 'Gene', (53, 57))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('mutation', 'Var', (58, 66))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('increased', 'PosReg', (113, 122))	('upregulated', 'PosReg', (90, 101))	('HIF1-a', 'Protein', (102, 108))
169104	25678837	The authors suggested that this was mediated by transcriptional activity of HIF1-a dependent nuclear factor-kappaB (NF-kappaB) as mutant IDH1-mediated activation of NF-kappaB was abolished in a HIF1-a-dependent manner.	('NF-kappaB', 'Gene', '4790', (116, 125))	('NF-kappaB', 'Gene', '4790', (165, 174))	('NF-kappaB', 'Gene', (116, 125))	('NF-kappaB', 'Gene', (165, 174))	('IDH1-mediated', 'Gene', (137, 150))	('mutant', 'Var', (130, 136))	('activation', 'PosReg', (151, 161))
169107	25678837	In renal cell carcinoma, HIF1-a and HIF2-a have been shown to have tumor suppressive and promoting effects, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('HIF1-a', 'Var', (25, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promoting effects', 'CPA', (89, 106))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('HIF2-a', 'Gene', (36, 42))	('renal cell carcinoma', 'Disease', (3, 23))	('HIF2-a', 'Gene', '2034', (36, 42))	('tumor', 'Disease', (67, 72))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))
169108	25678837	These observations have extended to IDH1 mutated glioma.	('mutated', 'Var', (41, 48))	('IDH1', 'Gene', (36, 40))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Disease', (49, 55))
169109	25678837	In contrast to aforementioned studies demonstrating elevated levels of HIF1-a in IDH1 mutated glioma, other groups have found HIF1-a levels to be low.	('mutated', 'Var', (86, 93))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('IDH1', 'Gene', (81, 85))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
169110	25678837	The possibility that the IDH1 mutation drives cell proliferation via diminished HIF expression has been corroborated in several glioma studies.	('HIF', 'Protein', (80, 83))	('glioma', 'Disease', (128, 134))	('mutation', 'Var', (30, 38))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('IDH1', 'Gene', (25, 29))	('diminished', 'NegReg', (69, 79))	('drives', 'PosReg', (39, 45))	('cell proliferation', 'CPA', (46, 64))
169111	25678837	Williams et al (2011) looked at 120 human glioma samples and found that HIF1-a was only upregulated in a small subset of IDH1 mutated gliomas and was generally limited to necrotic areas.	('IDH1', 'Gene', (121, 125))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('upregulated', 'PosReg', (88, 99))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('HIF1-a', 'Gene', (72, 78))	('gliomas', 'Disease', (134, 141))	('necrotic areas', 'Disease', (171, 185))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('necrotic areas', 'Disease', 'MESH:D009336', (171, 185))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('glioma', 'Disease', (134, 140))	('human', 'Species', '9606', (36, 41))	('glioma', 'Disease', (42, 48))	('mutated', 'Var', (126, 133))
169112	25678837	Immunohistochemical analysis showed that in non-necrotic areas that were strongly reactive for the R132H IDH1 mutation, there was no evidence of HIF1-a overexpression.	('R132H', 'Mutation', 'rs121913500', (99, 104))	('necrotic areas', 'Disease', 'MESH:D009336', (48, 62))	('IDH1', 'Gene', (105, 109))	('non-necrotic', 'Disease', 'MESH:D009336', (44, 56))	('necrotic areas', 'Disease', (48, 62))	('R132H', 'Var', (99, 104))	('non-necrotic', 'Disease', (44, 56))
169114	25678837	Mouse models of the IDH1 mutation have been associated with hemorrhage and high perinatal mortality and therefore it is difficult to exclude that the observed upregulation of HIF and corresponding target genes were not secondary to these events.	('associated', 'Reg', (44, 54))	('mutation', 'Var', (25, 33))	('Mouse', 'Species', '10090', (0, 5))	('IDH1', 'Gene', (20, 24))	('hemorrhage', 'Disease', (60, 70))	('hemorrhage', 'Disease', 'MESH:D006470', (60, 70))
169115	25678837	Undoubtedly, further work is needed to clarify the role of HIFs in IDH1 mutated glioma.	('glioma', 'Disease', (80, 86))	('mutated', 'Var', (72, 79))	('IDH1', 'Gene', (67, 71))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
169117	25678837	As such, pharmacological inhibition of Eg1N activity has been proposed as a potential target for IDH1 mutant glioma and may be an important topic of future study.	('mutant', 'Var', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH1', 'Gene', (97, 101))	('glioma', 'Disease', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
169121	25678837	In the animal model of the IDH1 R132H mutation described earlier, mice were found to have higher levels of immature type IV collagen.	('R132H mutation', 'Var', (32, 46))	('levels of immature type IV collagen', 'MPA', (97, 132))	('mice', 'Species', '10090', (66, 70))	('IDH1', 'Gene', (27, 31))	('higher', 'PosReg', (90, 96))	('R132H', 'Mutation', 'rs121913500', (32, 37))
169122	25678837	Additionally, impairment of perivascular type IV collagen may promote progression and breakdown of the physiological BBB in IDH1 mutated gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('impairment', 'Var', (14, 24))	('mutated', 'Var', (129, 136))	('gliomas', 'Disease', (137, 144))	('promote', 'PosReg', (62, 69))	('progression', 'CPA', (70, 81))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('perivascular type IV', 'Phenotype', 'HP:0012520', (28, 48))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('breakdown', 'MPA', (86, 95))	('IDH1', 'Gene', (124, 128))
169123	25678837	Given mutations in collagen synthesizing genes have been associated with IDH mutations in non-CNS tumors, future research may uncover similar findings in glioma as well as better define the role of IDH1 mutations in BBB disruption.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('IDH', 'Gene', (73, 76))	('non-CNS tumors', 'Disease', (90, 104))	('IDH', 'Gene', '3417', (198, 201))	('glioma', 'Disease', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH', 'Gene', '3417', (73, 76))	('mutations', 'Var', (77, 86))	('non-CNS tumors', 'Disease', 'MESH:D009369', (90, 104))	('IDH', 'Gene', (198, 201))	('associated', 'Reg', (57, 67))
169125	25678837	Methylation at these sites results in gene silencing, raising the possibility that tumor suppressor genes can be targets of this silencing and thus promote tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('silencing', 'NegReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('promote', 'PosReg', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('gene', 'MPA', (38, 42))
169126	25678837	Recently, a quantitative analysis of the methylation status of five known tumor suppressor genes was performed in glioma cells and in glioma cell-free DNA from serum, which found that tumor methylation of PARP-1, SHP-1, DAPK-1 and TIMP-3 genes was positively correlated with tumor grade and negatively correlated with prognosis.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('tumor', 'Disease', (275, 280))	('TIMP-3', 'Gene', '7078', (231, 237))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('positively', 'PosReg', (248, 258))	('methylation', 'Var', (190, 201))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('glioma', 'Disease', (114, 120))	('PARP-1', 'Gene', (205, 211))	('tumor', 'Disease', (184, 189))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('SHP-1', 'Gene', '8431', (213, 218))	('TIMP-3', 'Gene', (231, 237))	('correlated', 'Reg', (302, 312))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Disease', (134, 140))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('correlated', 'Reg', (259, 269))	('SHP-1', 'Gene', (213, 218))	('PARP-1', 'Gene', '142', (205, 211))	('DAPK-1', 'Gene', (220, 226))	('negatively', 'NegReg', (291, 301))	('DAPK-1', 'Gene', '1612', (220, 226))
169129	25678837	They found that the G-CIMP phenotype was strongly associated with the IDH1 mutation and was more common in younger patients and associated with improved prognosis.	('patients', 'Species', '9606', (115, 123))	('G-CIMP', 'Chemical', '-', (20, 26))	('mutation', 'Var', (75, 83))	('associated', 'Reg', (50, 60))	('IDH1', 'Gene', (70, 74))
169130	25678837	Similar associations between global hypermethylation and IDH1/2 mutations have been observed in IDH1/2 mutated AML cells.	('AML', 'Disease', 'MESH:D015470', (111, 114))	('IDH1/2', 'Gene', (57, 63))	('mutated', 'Var', (103, 110))	('IDH1/2', 'Gene', '3417;3418', (96, 102))	('AML', 'Disease', (111, 114))	('observed', 'Reg', (84, 92))	('AML', 'Phenotype', 'HP:0004808', (111, 114))	('global hypermethylation', 'MPA', (29, 52))	('mutations', 'Var', (64, 73))	('IDH1/2', 'Gene', (96, 102))	('IDH1/2', 'Gene', '3417;3418', (57, 63))
169131	25678837	The G-CIMP phenotype has also recently been found to include tumor suppressive miRNAs with the finding that methylation of miR-148a is associated with IDH1 mutated glioma cells.	('G-CIMP', 'Chemical', '-', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('miR-148a', 'Gene', (123, 131))	('miR-148a', 'Gene', '406940', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutated', 'Var', (156, 163))	('associated', 'Reg', (135, 145))	('IDH1', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('methylation', 'Var', (108, 119))	('glioma', 'Disease', (164, 170))	('tumor', 'Disease', (61, 66))
169132	25678837	Transfection of mutant IDH1 into immortalized primary human astrocytes resulted in the hypermethylator phenotype.	('resulted in', 'Reg', (71, 82))	('IDH1', 'Gene', (23, 27))	('mutant', 'Var', (16, 22))	('human', 'Species', '9606', (54, 59))	('hypermethylator phenotype', 'MPA', (87, 112))
169133	25678837	Similarly, introduction of ectopic mutant IDH1 into normal human astrocytes caused total genome hypermethylation as seen in IDH1 mutated LGG.	('human', 'Species', '9606', (59, 64))	('genome hypermethylation', 'MPA', (89, 112))	('ectopic mutant', 'Var', (27, 41))	('mutated', 'Var', (129, 136))	('IDH1', 'Gene', (42, 46))
169134	25678837	In the IDH1 mutation mouse model described by Sasaki et al (2012), mice with the mutant gene in the myeloid lineage alone had a similar hypermethylation pattern as seen in AML patients with IDH1/2 mutations and interestingly developed hematological malignancy-associated features of anemia, splenomegaly and extramedullary hematopoiesis.	('IDH1/2', 'Gene', (190, 196))	('hematological malignancy', 'Disease', (235, 259))	('anemia', 'Disease', 'MESH:D000740', (283, 289))	('hematopoiesis', 'Disease', (323, 336))	('extramedullary hematopoiesis', 'Phenotype', 'HP:0001978', (308, 336))	('hematological malignancy', 'Disease', 'MESH:D019337', (235, 259))	('mutant', 'Var', (81, 87))	('hematological malignancy', 'Phenotype', 'HP:0004377', (235, 259))	('splenomegaly', 'Disease', (291, 303))	('anemia', 'Phenotype', 'HP:0001903', (283, 289))	('IDH1', 'Gene', (7, 11))	('mice', 'Species', '10090', (67, 71))	('anemia', 'Disease', (283, 289))	('mouse', 'Species', '10090', (21, 26))	('mutations', 'Var', (197, 206))	('developed', 'PosReg', (225, 234))	('AML', 'Disease', 'MESH:D015470', (172, 175))	('AML', 'Disease', (172, 175))	('splenomegaly', 'Disease', 'MESH:D013163', (291, 303))	('patients', 'Species', '9606', (176, 184))	('splenomegaly', 'Phenotype', 'HP:0001744', (291, 303))	('AML', 'Phenotype', 'HP:0004808', (172, 175))	('IDH1/2', 'Gene', '3417;3418', (190, 196))	('mutation', 'Var', (12, 20))	('hematopoiesis', 'Disease', 'MESH:C536227', (323, 336))
169137	25678837	As such, further studies are required to corroborate whether genes hypermethylated by IDH1 and IDH2 mutations are indeed tumor suppressor genes.	('mutations', 'Var', (100, 109))	('IDH1', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('IDH2', 'Gene', (95, 99))	('IDH2', 'Gene', '3418', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
169139	25678837	The leading mechanism attributed to the observed hypermethylation phenotype in IDH1 mutants involves silencing of the a-KG-dependent DNA modifying enzyme, Tet methylcytosine dioxygenase 2 (TET2).	('silencing', 'NegReg', (101, 110))	('Tet methylcytosine dioxygenase 2', 'Gene', '54790', (155, 187))	('mutants', 'Var', (84, 91))	('Tet methylcytosine dioxygenase 2', 'Gene', (155, 187))	('hypermethylation', 'MPA', (49, 65))	('IDH1', 'Gene', (79, 83))
169143	25678837	Heterozygous loss-of-function TET2 mutations are seen in 10-25% of myeloid disorders such as AML, MDS, and chronic myelomonocytic leukemia (CMML).	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (107, 138))	('loss-of-function', 'NegReg', (13, 29))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('AML', 'Phenotype', 'HP:0004808', (93, 96))	('CMML', 'Phenotype', 'HP:0012325', (140, 144))	('AML', 'Disease', (93, 96))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (107, 138))	('myeloid disorders', 'Disease', 'MESH:D007951', (67, 84))	('MDS', 'Phenotype', 'HP:0002863', (98, 101))	('mutations', 'Var', (35, 44))	('MDS', 'Disease', 'MESH:D009190', (98, 101))	('MDS', 'Disease', (98, 101))	('TET2', 'Gene', (30, 34))	('chronic myelomonocytic leukemia', 'Disease', (107, 138))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('myeloid disorders', 'Disease', (67, 84))
169144	25678837	Genetic and epigenetic profiling of AML patients has revealed that TET2 mutated AML cells possess a hypermethylation signature that may contribute to impaired differentiation and elevation of stem cell markers.	('AML', 'Disease', 'MESH:D015470', (36, 39))	('mutated', 'Var', (72, 79))	('differentiation', 'CPA', (159, 174))	('patients', 'Species', '9606', (40, 48))	('AML', 'Disease', (36, 39))	('elevation', 'PosReg', (179, 188))	('AML', 'Phenotype', 'HP:0004808', (80, 83))	('AML', 'Phenotype', 'HP:0004808', (36, 39))	('hypermethylation signature', 'MPA', (100, 126))	('AML', 'Disease', (80, 83))	('TET2', 'Gene', (67, 71))	('impaired', 'NegReg', (150, 158))	('stem cell markers', 'CPA', (192, 209))	('AML', 'Disease', 'MESH:D015470', (80, 83))
169145	25678837	In fact several studies have reported the reverse pattern, with hypomethylation in TET2 mutated AML cells and hypermethylation in TET2 wild type cells.	('AML', 'Disease', (96, 99))	('TET2', 'Gene', (83, 87))	('hypomethylation', 'MPA', (64, 79))	('mutated', 'Var', (88, 95))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('hypermethylation', 'MPA', (110, 126))	('AML', 'Phenotype', 'HP:0004808', (96, 99))
169146	25678837	As such, it is evident that although loss of TET2 is strongly linked to malignancy, the precise mechanism underlying this observation is undoubtedly still unclear.	('TET2', 'Gene', (45, 49))	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('malignancy', 'Disease', (72, 82))	('loss', 'Var', (37, 41))	('linked', 'Reg', (62, 68))
169147	25678837	Other factors likely contribute to whether loss of TET2 leads to a hypermethylator phenotype and tumor formation.	('TET2', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('leads to', 'Reg', (56, 64))	('tumor', 'Disease', (97, 102))	('hypermethylator phenotype', 'MPA', (67, 92))	('loss', 'Var', (43, 47))
169148	25678837	Evidence of reduced levels of 5hmc in IDH1 mutated cells compared to wild types has been reproduced across several studies in glioma cells and in AML cells.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('5hmc', 'Chemical', 'MESH:C011865', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('AML', 'Disease', (146, 149))	('reduced', 'NegReg', (12, 19))	('AML', 'Phenotype', 'HP:0004808', (146, 149))	('mutated', 'Var', (43, 50))	('IDH1', 'Gene', (38, 42))	('glioma', 'Disease', (126, 132))	('levels', 'MPA', (20, 26))	('AML', 'Disease', 'MESH:D015470', (146, 149))
169149	25678837	Transfection of TET2-expressing AML cells with the IDH1 mutation nearly halved 5hmc levels.	('AML', 'Disease', 'MESH:D015470', (32, 35))	('5hmc', 'Chemical', 'MESH:C011865', (79, 83))	('halved', 'NegReg', (72, 78))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('AML', 'Disease', (32, 35))	('5hmc levels', 'MPA', (79, 90))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))
169150	25678837	Similarly, expression of the IDH1 and IDH2 mutations in cell lines derived from GBM led to reduced 5hmc levels whereas expression of IDH1 and TET1/2 wild types increased 5hmc levels, suggesting an inverse relationship between the IDH1 mutation and 5hmc levels.	('5hmc', 'Chemical', 'MESH:C011865', (99, 103))	('5hmc levels', 'MPA', (99, 110))	('5hmc', 'MPA', (170, 174))	('TET1', 'Gene', (142, 146))	('IDH1', 'Gene', (29, 33))	('5hmc', 'Chemical', 'MESH:C011865', (248, 252))	('5hmc', 'Chemical', 'MESH:C011865', (170, 174))	('IDH2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('TET1', 'Gene', '80312', (142, 146))	('reduced', 'NegReg', (91, 98))	('IDH2', 'Gene', '3418', (38, 42))	('GBM', 'Phenotype', 'HP:0012174', (80, 83))
169151	25678837	In the IDH1 mutant mouse model, mice expressing the IDH1 mutation in brain cells alone were found to have lower levels of 5hmc.	('mutation', 'Var', (57, 65))	('levels of 5hmc', 'MPA', (112, 126))	('lower', 'NegReg', (106, 111))	('mice', 'Species', '10090', (32, 36))	('mouse', 'Species', '10090', (19, 24))	('5hmc', 'Chemical', 'MESH:C011865', (122, 126))	('IDH1', 'Gene', (52, 56))
169152	25678837	Perhaps, the most significant study demonstrating that the tumorigenic effects of the IDH1 mutation arise due to TET2 dysfunction was the discovery that IDH1/2 and TET2 mutations were mutually exclusive in 300 AML samples.	('IDH1/2', 'Gene', (153, 159))	('AML', 'Disease', (210, 213))	('mutation', 'Var', (91, 99))	('IDH1', 'Gene', (86, 90))	('tumor', 'Disease', (59, 64))	('TET2 dysfunction', 'Disease', (113, 129))	('TET2 dysfunction', 'Disease', 'MESH:D006331', (113, 129))	('AML', 'Disease', 'MESH:D015470', (210, 213))	('IDH1/2', 'Gene', '3417;3418', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('AML', 'Phenotype', 'HP:0004808', (210, 213))
169153	25678837	However, these results have not been replicated in glioma where one group demonstrated that none of 35 IDH1 wild type LGGs was found to have TET2 mutations.	('glioma', 'Disease', (51, 57))	('mutations', 'Var', (146, 155))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('IDH1', 'Gene', (103, 107))
169154	25678837	This finding suggested that IDH1 mutations and TET2 methylation could be mutually exclusive, with TET2 methylation providing an alternative mechanism for tumorigenesis in IDH1 wild type LGG.	('tumor', 'Disease', (154, 159))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('IDH1', 'Gene', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('IDH1', 'Gene', (28, 32))
169155	25678837	Exclusivity of IDH1 and TET2 mutations in leukemia has been suggested to result from a clonal disadvantage of IDH1 mutations for TET2 mutants.	('mutations', 'Var', (115, 124))	('IDH1', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('leukemia', 'Disease', (42, 50))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('leukemia', 'Disease', 'MESH:D007938', (42, 50))	('mutants', 'Var', (134, 141))	('IDH1', 'Gene', (110, 114))	('TET2', 'Gene', (24, 28))
169157	25678837	Muller et al (2012) found that 61% of gliomas (wild type and IDH1 mutants) showed non-existent levels of 5hmc whereas high levels of 5hmc were found in 33% of IDH1 mutants.	('mutants', 'Var', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('gliomas', 'Disease', (38, 45))	('5hmc', 'MPA', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('IDH1', 'Gene', (61, 65))	('5hmc', 'Chemical', 'MESH:C011865', (105, 109))	('5hmc', 'Chemical', 'MESH:C011865', (133, 137))	('non-existent levels', 'MPA', (82, 101))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
169159	25678837	Interestingly nuclear exclusion occurred more frequently in IDH1 wild types whereas IDH1 mutant gliomas were associated with nuclear accumulation of TET1.	('associated', 'Reg', (109, 119))	('TET1', 'Gene', (149, 153))	('IDH1', 'Gene', (84, 88))	('nuclear exclusion', 'CPA', (14, 31))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('TET1', 'Gene', '80312', (149, 153))	('mutant', 'Var', (89, 95))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
169161	25678837	Secondly, TET2 knockout and IDH1 gain-of-function mouse models have been shown to differ to a wide extent phenotypically, suggesting these mutations may contribute to tumor formation in a parallel rather than in a cooperative manner.	('contribute', 'Reg', (153, 163))	('gain-of-function', 'PosReg', (33, 49))	('mutations', 'Var', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mouse', 'Species', '10090', (50, 55))	('tumor', 'Disease', (167, 172))	('IDH1', 'Gene', (28, 32))
169166	25678837	R-2-HG appears to have an inhibitory effect on a number of histone demethylases including members of the Jumonji transcription factor family (JMJD2A, JMJD2C and JHDM1A/FBXL11), which may contribute to tumorigenesis (Fig.	('contribute', 'Reg', (187, 197))	('JMJD2A', 'Gene', '9682', (142, 148))	('JHDM1A', 'Gene', (161, 167))	('JMJD2A', 'Gene', (142, 148))	('JHDM1A', 'Gene', '22992', (161, 167))	('histone demethylases', 'Enzyme', (59, 79))	('FBXL11', 'Gene', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('JMJD2C', 'Gene', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('FBXL11', 'Gene', '22992', (168, 174))	('R-2-HG', 'Var', (0, 6))	('JMJD2C', 'Gene', '23081', (150, 156))	('tumor', 'Disease', (201, 206))	('inhibitory', 'NegReg', (26, 36))
169167	25678837	Furthermore, evidence of hypermethylation of the H3 family of histones H3K4, H3K9, H3K27, H3K36 and H3K79 has been found following mutant IDH1 expression or R-2-HG exposure in multiple human cancer cell lines as well as in normal astrocytes and adipocyte precursors.	('cancer', 'Disease', (191, 197))	('H3K4', 'Protein', (71, 75))	('H3K9', 'Protein', (77, 81))	('found', 'Reg', (115, 120))	('human', 'Species', '9606', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('H3 family', 'Protein', (49, 58))	('mutant', 'Var', (131, 137))	('H3K79', 'Protein', (100, 105))	('hypermethylation', 'MPA', (25, 41))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('IDH1', 'Gene', (138, 142))	('H3K36', 'Protein', (90, 95))	('H3K27', 'Protein', (83, 88))
169169	25678837	Notably, the particular sites of histone methylation overlapped with those found in IDH1 mutant glioma cells.	('IDH1', 'Gene', (84, 88))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('mutant', 'Var', (89, 95))	('glioma', 'Disease', (96, 102))
169171	25678837	Overexpression of JHDM2A has been associated with poor prognosis in colorectal cancer, while overexpression of JMJD2C has been demonstrated in esophageal cancer, MALT-lymphoma and breast cancer.	('JHDM2A', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('JMJD2C', 'Gene', '23081', (111, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (167, 175))	('MALT-lymphoma', 'Disease', 'MESH:D018442', (162, 175))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('breast cancer', 'Disease', (180, 193))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('JHDM2A', 'Gene', '55818', (18, 24))	('JMJD2C', 'Gene', (111, 117))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('esophageal cancer', 'Disease', (143, 160))	('colorectal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('MALT-lymphoma', 'Disease', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
169173	25678837	As previously discussed, H3K9 hypermethylation occurs in IDH1 mutated gliomas, but it has also been found in their wild type counterparts.	('H3K9', 'Protein', (25, 29))	('IDH1', 'Gene', (57, 61))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Disease', (70, 77))	('hypermethylation', 'Var', (30, 46))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('mutated', 'Var', (62, 69))
169174	25678837	Trimethylation of H3K9 has been strongly linked to IDH1 mutations in oligodendrogliomas and grade II astrocytomas, but has not been associated with IDH1 mutations in grade III/IV astrocytomas, despite the majority of these tumors exhibiting evidence of the hypermethylation phenotype.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (179, 190))	('IV astrocytomas', 'Disease', (176, 191))	('linked', 'Reg', (41, 47))	('mutations', 'Var', (56, 65))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('II astrocytomas', 'Disease', 'MESH:D001254', (98, 113))	('II astrocytomas', 'Disease', (98, 113))	('Trimethylation', 'MPA', (0, 14))	('IV astrocytomas', 'Disease', 'MESH:D005909', (176, 191))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (69, 87))	('H3K9', 'Protein', (18, 22))	('IDH1', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('oligodendrogliomas', 'Disease', (69, 87))
169175	25678837	It may be the case that histone hypermethylation is a common feature broadly across all gliomas rather than being a mechanism by which IDH1 exerts its tumorigenic effects.	('histone hypermethylation', 'Var', (24, 48))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('IDH1', 'Gene', (135, 139))	('tumor', 'Disease', (151, 156))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('hypermethylation', 'Var', (32, 48))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
169176	25678837	Alternatively, histone hypermethylation may be propagated by IDH1 mutations in some glioma subtypes (e.g.	('mutations', 'Var', (66, 75))	('glioma', 'Disease', (84, 90))	('IDH1', 'Gene', (61, 65))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('histone hypermethylation', 'MPA', (15, 39))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('propagated', 'Reg', (47, 57))
169179	25678837	The first small molecule inhibitor of the mutated IDH1 protein was reported by Popovici-Muller et al (2012) who performed a high-throughput screening of compounds against the R132H IDH1 mutant protein homodimer.	('R132H', 'Mutation', 'rs121913500', (175, 180))	('homodimer', 'Gene', '6647', (201, 210))	('homodimer', 'Gene', (201, 210))	('protein', 'Protein', (193, 200))	('R132H', 'Var', (175, 180))
169182	25678837	However, given mounting evidence that the mutant IDH1 protein acts as a heterodimer with the wild type protein, this study's approach to screen against a mutant protein homodimer was not ideal.	('mutant', 'Var', (42, 48))	('homodimer', 'Gene', '6647', (169, 178))	('homodimer', 'Gene', (169, 178))	('protein', 'Protein', (54, 61))	('IDH1', 'Gene', (49, 53))
169183	25678837	Recently, a quantitative high throughput compound screen identified ML309 as a potent inhibitor of the R132H mutant IDH1 enzyme.	('ML309', 'Chemical', '-', (68, 73))	('R132H', 'Mutation', 'rs121913500', (103, 108))	('R132H', 'Var', (103, 108))	('IDH1', 'Gene', (116, 120))
169184	25678837	Additionally, ML309 demonstrated preferential activity against the mutant IDH1 over the wild type, with an IC50 of 96 nM for the former and 35 muM for the latter, respectively.	('IDH1', 'Gene', (74, 78))	('ML309', 'Chemical', '-', (14, 19))	('mutant', 'Var', (67, 73))
169185	25678837	More recently, ML309 was shown to inhibit the R132C IDH1 mutation with similar efficacy.	('R132C', 'Var', (46, 51))	('R132C', 'Mutation', 'rs121913499', (46, 51))	('inhibit', 'NegReg', (34, 41))	('ML309', 'Chemical', '-', (15, 20))	('IDH1', 'Gene', (52, 56))
169186	25678837	Furthermore, ML309 exhibited good aqueous solubility, was stable in human plasma, and had a moderate half-life of 3.76 hours.	('ML309', 'Var', (13, 18))	('human', 'Species', '9606', (68, 73))	('ML309', 'Chemical', '-', (13, 18))	('aqueous solubility', 'MPA', (34, 52))
169189	25678837	Similarly, via high throughput screening, another compound, AGI-5198, has been identified as a potent inhibitor of R132H mutated IDH1.	('R132H', 'Mutation', 'rs121913500', (115, 120))	('R132H mutated', 'Var', (115, 128))	('IDH1', 'Gene', (129, 133))	('AGI-5198', 'Chemical', 'MESH:C581156', (60, 68))
169190	25678837	AGI-5198 exhibited higher selectivity than ML309 against mutant IDH1 with an IC50 of 70 nM and an IC50 of >100 muM for the wild type enzyme and may be administered orally.	('ML309', 'Chemical', '-', (43, 48))	('IDH1', 'Gene', (64, 68))	('mutant', 'Var', (57, 63))	('AGI-5198', 'Chemical', 'MESH:C581156', (0, 8))	('selectivity', 'MPA', (26, 37))
169191	25678837	AGI-5198 administration was able to reduce R-2-HG levels in a dose-dependent manner in R132H-mutated TS603 grade III glioma cells and effectively prevented colony formation.	('TS603', 'Gene', (101, 106))	('colony formation', 'CPA', (156, 172))	('reduce', 'NegReg', (36, 42))	('TS603', 'CellLine', 'CVCL:2612', (101, 106))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('R132H', 'Mutation', 'rs121913500', (87, 92))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('prevented', 'NegReg', (146, 155))	('R-2-HG levels', 'MPA', (43, 56))	('R132H-mutated', 'Var', (87, 100))	('AGI-5198', 'Chemical', 'MESH:C581156', (0, 8))	('glioma', 'Disease', (117, 123))
169193	25678837	In addition, in support of an association of IDH1 mutations with the hypermethylation phenotype, ex vivo treatment of TS603 glioma cells with AGI-5198 induced differentiation of nestin-positive neural progenitor cells into glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQ-4)-positive astrocytes with a concomitant reduction in histone methylation associated with these latter genes.	('aquaporin-4', 'Gene', '361', (266, 277))	('reduction', 'NegReg', (324, 333))	('AGI-5198', 'Chemical', 'MESH:C581156', (142, 150))	('glioma', 'Disease', (124, 130))	('AQ-4', 'Gene', (279, 283))	('GFAP', 'Gene', (256, 260))	('glial fibrillary acidic protein', 'Gene', (223, 254))	('mutations', 'Var', (50, 59))	('AQ-4', 'Gene', '361', (279, 283))	('TS603', 'CellLine', 'CVCL:2612', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glial fibrillary acidic protein', 'Gene', '2670', (223, 254))	('aquaporin-4', 'Gene', (266, 277))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('GFAP', 'Gene', '2670', (256, 260))	('IDH1', 'Gene', (45, 49))	('histone methylation', 'MPA', (337, 356))
169195	25678837	Further development of AGI-5198 has led to development of AG-120 and AG-221 (Agios Pharmaceuticals, Cambridge, MA), orally administered drugs targeting IDH1 and IDH2 mutations, respectively.	('IDH1', 'Gene', (152, 156))	('AG-120', 'Chemical', 'MESH:C000627630', (58, 64))	('mutations', 'Var', (166, 175))	('IDH2', 'Gene', (161, 165))	('AG-221', 'Gene', (69, 75))	('AGI-5198', 'Chemical', 'MESH:C581156', (23, 31))	('IDH2', 'Gene', '3418', (161, 165))
169202	25678837	The compound, EXEL-9324, was found to be the most potent inhibitor of R-2-HG production and exhibited an IC50 of 800 nM against the a-KG to R-2-HG reaction catalysed by the R132H/wild type heterodimer IDH1 protein, transfected into E. Coli cells.	('R132H/wild', 'Var', (173, 183))	('R132H', 'Mutation', 'rs121913500', (173, 178))	('E. Coli', 'Species', '562', (232, 239))	('inhibitor', 'NegReg', (57, 66))	('R-2-HG production', 'MPA', (70, 87))	('a-KG to R-2-HG reaction', 'MPA', (132, 155))
169203	25678837	Importantly, the authors also demonstrated that EXEL-9324 selectively targeted this oncogenic heterodimer complex as the affinities of the compound for the wild type and mutant homodimers were exceedingly diminished.	('targeted', 'Reg', (70, 78))	('homodimer', 'Gene', '6647', (177, 186))	('homodimer', 'Gene', (177, 186))	('mutant', 'Var', (170, 176))	('affinities', 'MPA', (121, 131))	('diminished', 'NegReg', (205, 215))
169206	25678837	Administration of this drug in R132H IDH1 mutated immortalized human astrocytes as well as in R132C IDH1 mutated HT1080 fibrosarcoma cells led to potent reduction of R-2-HG in a concentration dependent manner.	('human', 'Species', '9606', (63, 68))	('reduction', 'NegReg', (153, 162))	('R-2-HG', 'MPA', (166, 172))	('fibrosarcoma', 'Disease', (120, 132))	('R132H', 'Var', (31, 36))	('R132H', 'Mutation', 'rs121913500', (31, 36))	('HT1080', 'CellLine', 'CVCL:0317', (113, 119))	('mutated', 'Var', (105, 112))	('R132C', 'Var', (94, 99))	('R132C', 'Mutation', 'rs121913499', (94, 99))	('fibrosarcoma', 'Disease', 'MESH:D005354', (120, 132))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (120, 132))
169211	25678837	However, a handful of studies have demonstrated that inhibition of glutaminase inhibits glioma cells, suggesting that targeting glutaminase may be a potential strategy for inhibiting mutant IDH1 enzymatic activity.	('glutaminase', 'Gene', (67, 78))	('IDH1', 'Gene', (190, 194))	('inhibits', 'NegReg', (79, 87))	('glutaminase', 'Gene', '2744', (128, 139))	('glioma', 'Disease', (88, 94))	('mutant', 'Var', (183, 189))	('inhibiting', 'NegReg', (172, 182))	('activity', 'MPA', (205, 213))	('glutaminase', 'Gene', '2744', (67, 78))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glutaminase', 'Gene', (128, 139))
169214	25678837	Using 15-mer peptides from the R132H IDH1 mutant protein loaded onto MHC class II complexes, vaccination of MHC-humanized transgenic mice generated robust Th1-cell responses as evidenced by increased interferon-gamma production and detectable levels of anti-IDH1 (R132H) in the serum.	('increased interferon-', 'Phenotype', 'HP:0009709', (190, 211))	('interferon-gamma', 'Gene', '15978', (200, 216))	('R132H', 'Mutation', 'rs121913500', (264, 269))	('interferon-gamma', 'Gene', (200, 216))	('R132H', 'Var', (31, 36))	('R132H', 'Mutation', 'rs121913500', (31, 36))	('IDH1', 'Gene', (37, 41))	('increased', 'PosReg', (190, 199))	('Th1-cell responses', 'CPA', (155, 173))	('transgenic mice', 'Species', '10090', (122, 137))	('human', 'Species', '9606', (112, 117))
169215	25678837	Furthermore, these findings were reproduced in IDH1 (R132H) mutated sarcomas in mouse xenografts, resulting in potent tumor growth suppression and absence of overt toxicities.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('sarcomas', 'Disease', (68, 76))	('R132H) mutated', 'Var', (53, 67))	('IDH1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('toxicities', 'Disease', 'MESH:D064420', (164, 174))	('mouse', 'Species', '10090', (80, 85))	('tumor', 'Disease', (118, 123))	('mutated', 'Var', (60, 67))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('toxicities', 'Disease', (164, 174))
169216	25678837	Interestingly, the authors screened 25 patients with R132H IDH1 mutated gliomas and found detectable levels of IFN-gamma producing Th1 cells against this specific epitope in four patients.	('patients', 'Species', '9606', (39, 47))	('IFN-gamma', 'Gene', '3458', (111, 120))	('IFN-gamma', 'Gene', (111, 120))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('levels', 'MPA', (101, 107))	('R132H', 'Var', (53, 58))	('patients', 'Species', '9606', (179, 187))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('IDH1', 'Gene', (59, 63))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
169217	25678837	However, it is unclear whether the presence of an anti-IDH1 mutant T-cell response in these select patients conferred any survival benefit.	('patients', 'Species', '9606', (99, 107))	('mutant', 'Var', (60, 66))	('anti-IDH1', 'Gene', (50, 59))	('T-cell', 'CPA', (67, 73))
169218	25678837	HLA typing of all 25 patients was non-specific suggesting the mutant IDH1 protein is not limited to any particular HLA class II type.	('protein', 'Protein', (74, 81))	('patients', 'Species', '9606', (21, 29))	('mutant', 'Var', (62, 68))	('IDH1', 'Gene', (69, 73))
169220	25678837	Furthermore, many questions remain regarding the prognostic significance of patients who are able to mount an IDH1 mutant specific immune response without intervention.	('patients', 'Species', '9606', (76, 84))	('mutant', 'Var', (115, 121))	('IDH1', 'Gene', (110, 114))
169221	25678837	Just six years since the IDH1 mutation was first discovered in GBM, our understanding of the prevalence and pathogenesis of this mutation in both CNS and non-CNS tumors has grown at a rapid rate.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('non-CNS tumors', 'Disease', 'MESH:D009369', (154, 168))	('CNS', 'Disease', (146, 149))	('mutation', 'Var', (30, 38))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('IDH1', 'Gene', (25, 29))	('non-CNS tumors', 'Disease', (154, 168))
169223	25678837	Diagnosis of IDH1 mutations has been able to provide important diagnostic and prognostic information for patients, removing some of the burden of uncertainty.	('IDH1', 'Gene', (13, 17))	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (18, 27))
169224	25678837	Furthermore, as previously mentioned, two Phase-1 multicentre dose escalation trials are underway that are evaluating an oral medication targeting the IDH1 mutant protein in patients with hematological and solid malignancies.	('solid malignancies', 'Disease', (206, 224))	('protein', 'Protein', (163, 170))	('patients', 'Species', '9606', (174, 182))	('IDH1', 'Gene', (151, 155))	('mutant', 'Var', (156, 162))	('solid malignancies', 'Disease', 'MESH:D009369', (206, 224))
169226	25678837	This has revealed that R-2-HG has a diverse set of targets that in theory, could explain how IDH1 mutations mediate tumor formation.	('IDH1', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutations', 'Var', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
169227	25678837	Both DNA and histone methylation generate epigenetic changes resulting in altered cellular developmental programs that may be unique to IDH1 mutated tumors.	('cellular developmental programs', 'CPA', (82, 113))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('epigenetic changes', 'Var', (42, 60))	('methylation', 'Var', (21, 32))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('altered', 'Reg', (74, 81))
169230	25678837	Although many additional questions remain, research in the oncogenic mechanisms of the IDH1 mutation has provided rich new findings for the field of cancer biology.	('cancer', 'Disease', (149, 155))	('mutation', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('IDH1', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
169254	33842328	APOBEC3B, a member of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like) enzymes with cytidine deaminase activity, can induce prevalent mutagen of genomic DNA in multiple cancers.	('cytidine deaminase', 'Gene', (109, 127))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('APOBEC3B', 'Gene', (0, 8))	('mutagen', 'Var', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('induce', 'Reg', (142, 148))	('cytidine deaminase', 'Gene', '978', (109, 127))
169256	33842328	High expression of APOBEC3B is associated with immune evasion of cancer.	('High', 'Var', (0, 4))	('APOBEC3B', 'Gene', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
169257	33842328	Notably, high expression of APOBEC3B also enhances the sensitivity to immune checkpoint blockade in melanoma.	('APOBEC3B', 'Gene', (28, 36))	('sensitivity to immune checkpoint blockade', 'MPA', (55, 96))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('enhances', 'PosReg', (42, 50))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('high', 'Var', (9, 13))
169277	33842328	To figure out the relationship between APOBEC3B and molecular subtypes, we further investigated the expression level of APOBEC3B among subtypes: increased expression level of APBOEC3B was found in CL and ME compared to PN and NE (P <.05, respectively;  Figure 1C ).	('APBOEC3B', 'Var', (175, 183))	('ME', 'Chemical', '-', (204, 206))	('CL', 'Disease', 'None', (197, 199))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))
169280	33842328	Glioma patients with codeletion of 1p and 19q derived more benefits in several clinical trials.	('codeletion', 'Var', (21, 31))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('benefits', 'PosReg', (59, 67))	('patients', 'Species', '9606', (7, 15))
169281	33842328	We observed that the expression of APOBEC3B was decreased in the 1p19q codeletion cluster in pan-glioma analysis (P <.05, respectively;  Figure 1D ).	('glioma', 'Disease', (97, 103))	('1p19q', 'Var', (65, 70))	('decreased', 'NegReg', (48, 57))	('expression', 'MPA', (21, 31))	('APOBEC3B', 'Gene', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
169296	33842328	We revealed that APOBEC3Bhigh patients showed shorter overall survival (OS) than APOBEC3Blow patients in pan-glioma, LGG, and GBM (P <.05, respectively;  Figures 3A, B ).	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('APOBEC3Bhigh', 'Var', (17, 29))	('overall survival', 'MPA', (54, 70))	('glioma', 'Disease', (109, 115))	('patients', 'Species', '9606', (30, 38))	('shorter', 'NegReg', (46, 53))	('patients', 'Species', '9606', (93, 101))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
169299	33842328	High APOBEC3B expression was significantly correlated to worse prognosis in nine cancer types, including ACC, CHOL, ESCA, LIHC, LUAD, PAAD, UCEC, UCS, and KICH (P <.0001, respectively;  Figure 3C ).	('CHOL', 'Disease', 'None', (110, 114))	('LUAD', 'Phenotype', 'HP:0030078', (128, 132))	('cancer', 'Disease', (81, 87))	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('ACC', 'Disease', (105, 108))	('LIHC', 'Disease', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ESCA', 'Phenotype', 'HP:0011459', (116, 120))	('KICH', 'Disease', 'None', (155, 159))	('High', 'Var', (0, 4))	('LUAD', 'Disease', (128, 132))	('CHOL', 'Disease', (110, 114))	('UCEC', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('CHOL', 'Phenotype', 'HP:0030153', (110, 114))	('PAAD', 'Phenotype', 'HP:0006725', (134, 138))	('KICH', 'Disease', (155, 159))	('APOBEC3B', 'Gene', (5, 13))	('ESCA', 'Disease', (116, 120))	('PAAD', 'Disease', (134, 138))	('expression', 'MPA', (14, 24))	('UCS', 'Disease', (146, 149))
169302	33842328	Besides the variation of chr1 and chr19, amplification of chr7 and deletion of chr10 most frequently occurred in glioma patients ( Figure 4A ).	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('occurred', 'Reg', (101, 109))	('deletion', 'Var', (67, 75))	('chr7', 'Gene', (58, 62))	('glioma', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('amplification', 'Var', (41, 54))	('chr10', 'Gene', (79, 84))
169303	33842328	As a genomic symbol of oligodendroglioma, deletion of 1p and 19q tended to appear in APOBEC3Blow cluster ( Figure 4B ).	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('APOBEC3Blow', 'Gene', (85, 96))	('oligodendroglioma', 'Disease', (23, 40))	('oligodendroglioma', 'Disease', 'MESH:D009837', (23, 40))	('deletion', 'Var', (42, 50))
169309	33842328	Common carcinogenic pathways were found to be more active in APOBEC3Bhigh group ( Figures 5E, G ).	('carcinogenic', 'Disease', (7, 19))	('carcinogenic', 'Disease', 'MESH:D063646', (7, 19))	('APOBEC3Bhigh', 'Var', (61, 73))	('more active', 'PosReg', (46, 57))
169310	33842328	The strongest co-occurrent pairs of gene alteration in the APOBEC3Bhigh group were ATRX-TP53, and in the APOBEC3Blow groups were ATRX-TP53 as well as ATRX-IDH1, which was in line with previous studies> Meanwhile, the most mutually exclusive pairs in APOBEC3Bhigh and APOBEC3Blow groups were CIC-TP53 and EGFR-IDH1, respectively ( Figures 5F, H ).	('TP53', 'Gene', (134, 138))	('ATRX', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (155, 159))	('TP53', 'Gene', '7157', (88, 92))	('ATRX', 'Gene', '546', (150, 154))	('IDH1', 'Gene', (309, 313))	('EGFR', 'Gene', (304, 308))	('TP53', 'Gene', '7157', (295, 299))	('ATRX', 'Gene', (83, 87))	('ATRX', 'Gene', '546', (83, 87))	('TP53', 'Gene', '7157', (134, 138))	('ATRX', 'Gene', (129, 133))	('rat', 'Species', '10116', (45, 48))	('IDH1', 'Gene', '3417', (309, 313))	('ATRX', 'Gene', '546', (129, 133))	('EGFR', 'Gene', '1956', (304, 308))	('alteration', 'Var', (41, 51))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', (295, 299))	('IDH1', 'Gene', (155, 159))
169335	33842328	Generally, somatic mutation has been considered as a therapy evasion promoter of cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('somatic mutation', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
169336	33842328	Correspondingly, mutation can also promote antitumor T-cell response.	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('promote', 'PosReg', (35, 42))	('tumor', 'Disease', (47, 52))
169339	33842328	For example, highly expressed APOBEC3B is regarded as an unfavorable prognostic factors in myeloma, ovarian cancer, and clear cell renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('APOBEC3B', 'Gene', (30, 38))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 151))	('clear cell renal cell carcinoma', 'Disease', (120, 151))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 151))	('myeloma, ovarian cancer', 'Disease', 'MESH:D009101', (91, 114))	('highly expressed', 'Var', (13, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
169342	33842328	Most recently, the duality of APOBEC3B in immunotherapy has been demonstrated, in which APOBEC3B not only acts as the general driving force of therapy escape but also significantly activates the immune system in melanoma.	('rat', 'Species', '10116', (72, 75))	('APOBEC3B', 'Var', (88, 96))	('immune system', 'CPA', (195, 208))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('activates', 'PosReg', (181, 190))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))
169346	33842328	But the activation of tumor-infiltrating immune cells also mediates APOBEC3B deletion in breast cancer in Asian patients.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('APOBEC3B', 'Gene', (68, 76))	('breast cancer', 'Disease', (89, 102))	('patients', 'Species', '9606', (112, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('deletion', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('rat', 'Species', '10116', (34, 37))
169354	33842328	Several immune infiltrating cell types possess the features of immunosuppression: It is well documented that MDSC is able to inhibit innate and adaptive immunity, and macrophages have been indicated to promote cancer cell proliferation, immunosuppression, and angiogenesis in cancers.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('inhibit', 'NegReg', (125, 132))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('rat', 'Species', '10116', (229, 232))	('cancers', 'Disease', (276, 283))	('promote', 'PosReg', (202, 209))	('immunosuppression', 'CPA', (237, 254))	('angiogenesis', 'CPA', (260, 272))	('rat', 'Species', '10116', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MDSC', 'Var', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
169357	33842328	Cell type enrichment analysis further revealed that APOBEC3B was significantly correlated with MDSC, macrophage, regulatory T cells, and Th2 cells in glioma, KICH, PAAD, and UCS, providing evidence to the statement that APOBEC3B was an immunotherapy escape driver in LGG.	('KICH', 'Disease', (158, 162))	('PAAD', 'Phenotype', 'HP:0006725', (164, 168))	('APOBEC3B', 'Var', (220, 228))	('Th2', 'Chemical', '-', (137, 140))	('glioma', 'Disease', (150, 156))	('KICH', 'Disease', 'None', (158, 162))	('UCS', 'Phenotype', 'HP:0002891', (174, 177))	('APOBEC3B', 'Gene', (52, 60))	('correlated', 'Reg', (79, 89))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
169365	33842328	CD276 has become a novel Cart-T target for GBM while inhibition of PD-1/PD-L1 pathway can be a latent treatment strategy for glioma.	('glioma', 'Disease', (125, 131))	('inhibition', 'Var', (53, 63))	('PD-1', 'Gene', (67, 71))	('PD-1', 'Gene', '5133', (67, 71))	('rat', 'Species', '10116', (114, 117))	('PD-L1', 'Gene', '29126', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('CD276', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('CD276', 'Gene', '80381', (0, 5))	('PD-L1', 'Gene', (72, 77))
169378	32986017	High YTHDF2 expression was associated with poor overall survival in lower-grade glioma (LGG).	('glioma', 'Disease', (80, 86))	('overall survival', 'MPA', (48, 64))	('High', 'Var', (0, 4))	('poor', 'NegReg', (43, 47))	('YTHDF2', 'Gene', (5, 11))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('expression', 'MPA', (12, 22))	('YTHDF2', 'Gene', '51441', (5, 11))
169384	32986017	Immunotherapy based on cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) inhibitors has emerged as an effective treatment in melanoma and non-small-cell lung carcinoma.	('programmed death ligand-1', 'Gene', (107, 132))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (23, 66))	('CTLA4', 'Gene', '1493', (68, 73))	('programmed death ligand-1', 'Gene', '29126', (107, 132))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Disease', (193, 201))	('lung carcinoma', 'Disease', (221, 235))	('PD-L1', 'Gene', (134, 139))	('CTLA4', 'Gene', (68, 73))	('lung carcinoma', 'Disease', 'MESH:D008175', (221, 235))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (206, 235))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (23, 66))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (210, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('PD-L1', 'Gene', '29126', (134, 139))	('inhibitors', 'Var', (141, 151))
169391	32986017	m6A modification by FTO increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy.	('increases', 'PosReg', (24, 33))	('m6A', 'Gene', '56339', (0, 3))	('modification', 'Var', (4, 16))	('decreases', 'NegReg', (54, 63))	('response to anti-PD-1 blockade immunotherapy', 'MPA', (64, 108))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('m6A', 'Gene', (0, 3))
169392	32986017	METTL3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function.	('m6A', 'Gene', '56339', (21, 24))	('function', 'CPA', (81, 89))	('METTL3', 'Gene', '56339', (0, 6))	('mRNA', 'Var', (16, 20))	('METTL3', 'Gene', (0, 6))	('methylation', 'Var', (25, 36))	('m6A', 'Gene', (21, 24))	('promotes', 'PosReg', (37, 45))
169423	32986017	In the GEPIA database, high YTHDF2 expression was associated with poorer overall survival (OS) and disease-free survival (DFS) in KICH (OS hazard ratio [HR] = 9.2, P= 0.011; DFS HR = 4.7, P = 0.031) and LGG (OS HR = 1.8, P = 0.0024; DFS HR = 2, P = 1.60e-05) (Figure 2A and 2B), whereas it was associated with better prognosis in KIRC (OS HR = 0.63, P = 0.0035; DFS HR = 0.63, P = 0.012).	('overall survival', 'CPA', (73, 89))	('high', 'Var', (23, 27))	('disease-free survival', 'CPA', (99, 120))	('YTHDF2', 'Gene', '51441', (28, 34))	('KICH', 'Disease', 'None', (130, 134))	('poorer', 'NegReg', (66, 72))	('YTHDF2', 'Gene', (28, 34))	('KICH', 'Disease', (130, 134))	('expression', 'Var', (35, 45))
169424	32986017	In addition, high YTHDF2 expression was associated with poorer OS but not poorer DFS in LIHC (OS HR = 1.6, P = 0.0068; DFS HR = 1.3, P = 0.081) (Figure 2C and 2D) and SARC (OS HR = 2.1, P = 0.00044; DFS HR = 1.3, P = 0.16) (Figure 2E and 2F), whereas it was associated with superior OS but not superior DFS in UCEC (OS HR = 0.48, P = 0.045; DFS HR = 0.63, P = 1.6).	('high', 'Var', (13, 17))	('YTHDF2', 'Gene', (18, 24))	('expression', 'MPA', (25, 35))	('YTHDF2', 'Gene', '51441', (18, 24))
169426	32986017	In the OncoLnc database, high YTHDF2 expression was associated with poor prognosis in LGG (Cox coefficient = 0.329, P = 0.00038), LIHC (Cox coefficient = 0.316, P = 0.00088) and SARC (Cox coefficient = 0.428, P = 0.00012), whereas it was associated with superior prognosis in READ (Cox coefficient = -0.53, P = 0.022).	('SARC', 'Disease', (178, 182))	('YTHDF2', 'Gene', (30, 36))	('LGG', 'Disease', (86, 89))	('high', 'Var', (25, 29))	('YTHDF2', 'Gene', '51441', (30, 36))
169427	32986017	In the Kaplan-Meier plotter database, high YTHDF2 expression was associated with poor OS in LIHC (HR = 2.71, 95% CI = 1.9-3.87, P = 1.00e-08) and SARC (HR = 2.71, 95% CI = 1.62-4.55, P = 8.20e-05), whereas it was associated with superior OS in BLCA (HR = 0.69, 95% CI = 0.51-0.92, P = 0.011), KIRC (HR = 0.58, 95% CI = 0.43-0.78, P = 0.00029), LUAD (HR = 0.67, 95% CI = 0.5-0.9, P = 0.0078), OV (HR = 0.73, 95% CI = 0.56-0.95, P = 0.021), READ (HR = 0.47, 95% CI = 0.22-1.01, P = 0.048), and THYM (HR = 0, 95% CI = 0-inf, P = 0.038).	('YTHDF2', 'Gene', '51441', (43, 49))	('high', 'Var', (38, 42))	('YTHDF2', 'Gene', (43, 49))
169437	32986017	YTHDF2 expression also impacted the OS in LGG, LIHC, and SARC with different clinicopathological parameters, such as gender and tumor grade (Supplementary Figure 1 and Supplementary Table 4).	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('LGG', 'Disease', (42, 45))	('YTHDF2', 'Gene', '51441', (0, 6))	('expression', 'Var', (7, 17))	('LIHC', 'Disease', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('YTHDF2', 'Gene', (0, 6))	('impacted', 'Reg', (23, 31))	('SARC', 'Disease', (57, 61))
169444	32986017	In addition, YTHDF2 expression was associated with CD8+ T cell levels in 12 cancer types, CD4+T cell levels in 14 cancer types, macrophage levels in 14 cancer types, neutrophil levels in 12 cancer types, and DC levels in 12 cancer types (Supplementary Table 5).	('macrophage levels', 'MPA', (128, 145))	('DC levels', 'MPA', (208, 217))	('expression', 'Var', (20, 30))	('YTHDF2', 'Gene', (13, 19))	('CD8', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('CD4', 'Gene', '920', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('YTHDF2', 'Gene', '51441', (13, 19))	('CD4', 'Gene', (90, 93))	('CD8', 'Gene', '925', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('neutrophil levels', 'MPA', (166, 183))	('cancer', 'Disease', (114, 120))
169459	32986017	IDH1 mutations often occur in gliomas and AML.	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('AML', 'Disease', (42, 45))	('occur', 'Reg', (21, 26))	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('mutations', 'Var', (5, 14))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('gliomas', 'Disease', (30, 37))	('AML', 'Disease', 'MESH:D015470', (42, 45))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
169460	32986017	In addition, mutant IDH is highly associated with the regulation of the immune microenvironment in LGG.	('mutant', 'Var', (13, 19))	('associated', 'Reg', (34, 44))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))
169464	32986017	Interestingly, data from the GEPIA database showed that high IDH1 expression was associated with poor OS in LGG (HR = 1.7, P = 0.0061) (Figure 4A).	('expression', 'MPA', (66, 76))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (61, 65))	('LGG', 'CPA', (108, 111))	('high', 'Var', (56, 60))
169465	32986017	LGG patients with IDH1 mutations had a superior OS according to the cBioPortal for Cancer Genomics analysis (Figure 4B).	('IDH1', 'Gene', '3417', (18, 22))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (23, 32))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('patients', 'Species', '9606', (4, 12))	('IDH1', 'Gene', (18, 22))
169466	32986017	Chinese Glioma Cooperative Group (CGGA) data also indicated that the IDH1 mutation led to a superior OS in glioma (Figure 4C).	('mutation', 'Var', (74, 82))	('IDH1', 'Gene', '3417', (69, 73))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('superior', 'PosReg', (92, 100))	('Glioma', 'Disease', 'MESH:D005910', (8, 14))	('Glioma', 'Phenotype', 'HP:0009733', (8, 14))	('Glioma', 'Disease', (8, 14))	('IDH1', 'Gene', (69, 73))	('glioma', 'Disease', (107, 113))
169467	32986017	However, the IDH1 mutation had no impact on OS in AML (Figure 4D).	('AML', 'Disease', 'MESH:D015470', (50, 53))	('IDH1', 'Gene', (13, 17))	('AML', 'Disease', (50, 53))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', '3417', (13, 17))
169479	32986017	Importantly, multivariate analysis confirmed that high YTHDF2 expression was an independent prognostic factor in patients with LGG, LIHC, or SARC.	('LGG', 'Disease', (127, 130))	('patients', 'Species', '9606', (113, 121))	('expression', 'MPA', (62, 72))	('YTHDF2', 'Gene', '51441', (55, 61))	('SARC', 'Disease', (141, 145))	('YTHDF2', 'Gene', (55, 61))	('high', 'Var', (50, 54))	('LIHC', 'Disease', (132, 136))
169484	32986017	Moreover, high YTHDF2 expression was a prognostic factor in LGG with astrocytoma but not with oligoastrocytoma and oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('astrocytoma', 'Disease', 'MESH:D001254', (69, 80))	('YTHDF2', 'Gene', (15, 21))	('astrocytoma', 'Disease', (69, 80))	('oligoastrocytoma and oligodendroglioma', 'Disease', 'MESH:D001254', (94, 132))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('high', 'Var', (10, 14))	('YTHDF2', 'Gene', '51441', (15, 21))	('astrocytoma', 'Disease', 'MESH:D001254', (99, 110))	('LGG', 'Disease', (60, 63))	('astrocytoma', 'Disease', (99, 110))	('expression', 'MPA', (22, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
169493	32986017	In addition, inhibition of colony-stimulating factor-1 receptor (CSF1R) in TAMs suppressed the metastasis of pancreatic tumors.	('TAMs', 'Chemical', '-', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('colony-stimulating factor-1 receptor', 'Gene', (27, 63))	('CSF1R', 'Gene', '1436', (65, 70))	('inhibition', 'Var', (13, 23))	('CSF1R', 'Gene', (65, 70))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (109, 126))	('pancreatic tumors', 'Disease', 'MESH:D010190', (109, 126))	('colony-stimulating factor-1 receptor', 'Gene', '1436', (27, 63))	('metastasis of', 'CPA', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('suppressed', 'NegReg', (80, 90))	('pancreatic tumors', 'Disease', (109, 126))
169499	32986017	DCs can promote tumor metastasis by increasing Treg cells and reducing CD8+T cell cytotoxicity.	('DCs', 'Var', (0, 3))	('increasing', 'PosReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('CD8+T', 'MPA', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('reducing', 'NegReg', (62, 70))	('Treg cells', 'CPA', (47, 57))	('tumor', 'Disease', (16, 21))	('promote', 'PosReg', (8, 15))
169503	32986017	PD-1 (PDCD1) promoter methylation is a prognostic factor in patients with LGG harboring IDH mutations.	('PDCD1', 'Gene', '5133', (6, 11))	('PDCD1', 'Gene', (6, 11))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (92, 101))	('IDH', 'Gene', (88, 91))	('LGG', 'Disease', (74, 77))	('IDH', 'Gene', '3417', (88, 91))	('methylation', 'Var', (22, 33))
169509	32986017	Blocking PD-1/PD-L1 interactions together with MLN4924 therapy is a potential strategy for glioma treatment.	('PD-L1', 'Gene', '29126', (14, 19))	('interactions', 'Interaction', (20, 32))	('MLN4924 therapy', 'Var', (47, 62))	('glioma', 'Disease', (91, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('PD-L1', 'Gene', (14, 19))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
169513	32986017	The analysis showed that high IDH1 expression was associated with poor OS in LGG.	('poor OS', 'Disease', (66, 73))	('expression', 'MPA', (35, 45))	('IDH1', 'Gene', (30, 34))	('high', 'Var', (25, 29))	('LGG', 'Disease', (77, 80))	('IDH1', 'Gene', '3417', (30, 34))
169514	32986017	IDH1 mutations were associated with a superior OS.	('mutations', 'Var', (5, 14))	('associated with', 'Reg', (20, 35))	('IDH1', 'Gene', (0, 4))	('superior OS', 'Disease', (38, 49))	('IDH1', 'Gene', '3417', (0, 4))
169515	32986017	This is consistent with previous studies showing that IDH1 mutation is an independent favorable prognostic marker in glioma.	('IDH1', 'Gene', (54, 58))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mutation', 'Var', (59, 67))	('IDH1', 'Gene', '3417', (54, 58))	('glioma', 'Disease', (117, 123))
169519	32986017	IDH1 mutations in gliomas caused leukocyte chemotaxis downregulation, resulting in suppression of the tumor-associated immune system.	('gliomas', 'Disease', (18, 25))	('suppression', 'NegReg', (83, 94))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('downregulation', 'NegReg', (54, 68))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('leukocyte chemotaxis', 'MPA', (33, 53))	('IDH1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('IDH1', 'Gene', '3417', (0, 4))
169527	32986017	High YTHDF2 expression correlates with poor prognosis and increased immune infiltration levels (including infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs) in LGG.	('increased', 'PosReg', (58, 67))	('High', 'Var', (0, 4))	('CD4', 'Gene', (145, 148))	('YTHDF2', 'Gene', (5, 11))	('infiltration', 'MPA', (106, 118))	('CD4', 'Gene', '920', (145, 148))	('immune infiltration levels', 'MPA', (68, 94))	('expression', 'MPA', (12, 22))	('CD8', 'Gene', (131, 134))	('YTHDF2', 'Gene', '51441', (5, 11))	('CD8', 'Gene', '925', (131, 134))
169548	32986017	A total of 118 glioma samples (82 samples with IDH1 mutation and 37 with wild-type IDH1) from CGGA were analyzed to determine the association of IDH1 with survival.	('IDH1', 'Gene', '3417', (83, 87))	('IDH1', 'Gene', (145, 149))	('IDH1', 'Gene', (47, 51))	('IDH1', 'Gene', '3417', (145, 149))	('glioma', 'Disease', (15, 21))	('mutation', 'Var', (52, 60))	('IDH1', 'Gene', '3417', (47, 51))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('IDH1', 'Gene', (83, 87))
169550	32986017	The survival associated with IDH1 alterations in LGG was analyzed, and the log-rank test P-value was calculated.	('alterations', 'Var', (34, 45))	('IDH1', 'Gene', '3417', (29, 33))	('IDH1', 'Gene', (29, 33))
169556	27869828	Six of 783 non-pseudoautosomal region (PAR) chrX genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) more frequently harbored loss-of-function mutations in males (based on false discovery rate <0.1), compared to zero of 18,055 autosomal and PAR genes (P<0.0001).	('ATRX', 'Gene', '546', (56, 60))	('KDM6A', 'Gene', '7403', (84, 89))	('MAGEC3', 'Gene', (95, 101))	('KDM5C', 'Gene', (77, 82))	('mutations', 'Var', (145, 154))	('DDX3X', 'Gene', '1654', (70, 75))	('MAGEC3', 'Gene', '139081', (95, 101))	('KDM5C', 'Gene', '8242', (77, 82))	('loss-of-function', 'NegReg', (128, 144))	('KDM6A', 'Gene', (84, 89))	('ATRX', 'Gene', (56, 60))	('chrX genes', 'Gene', (44, 54))	('CNKSR2', 'Gene', '22866', (62, 68))	('DDX3X', 'Gene', (70, 75))	('CNKSR2', 'Gene', (62, 68))
169557	27869828	Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('mutations', 'Var', (12, 21))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('genes', 'Gene', (25, 30))	('men', 'Species', '9606', (182, 185))
169558	27869828	We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence compared to males across a variety of tumor types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('reduced', 'NegReg', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancer', 'Disease', (98, 104))	('biallelic expression', 'Var', (17, 37))
169565	27869828	Previous reports have identified chrX genes outside of the pseudoautosomal region (PAR) with higher mutation frequencies in male cancers compared to female cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('male cancers', 'Disease', (124, 136))	('male cancers', 'Disease', 'MESH:D018567', (151, 163))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('male cancers', 'Disease', 'MESH:D018567', (124, 136))	('chrX genes', 'Gene', (33, 43))	('mutation', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('male cancers', 'Disease', (151, 163))
169566	27869828	For example, KDM6A at Xp11.2, which encodes the histone lysine demethylase UTX, has loss-of-function mutations more predominately in male cancers across multiple subtypes.	('loss-of-function', 'NegReg', (84, 100))	('KDM6A', 'Gene', (13, 18))	('mutations', 'Var', (101, 110))	('KDM6A', 'Gene', '7403', (13, 18))	('UTX', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('male cancers', 'Disease', (133, 145))	('UTX', 'Gene', '7403', (75, 78))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('male cancers', 'Disease', 'MESH:D018567', (133, 145))
169567	27869828	Among female cancers with KDM6A mutations, homozygous mutations are common, suggesting that some tumor suppressor genes (TSGs) on chrX outside of the PAR follow the classic Knudson two-hit hypothesis in females.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('male cancers', 'Disease', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('KDM6A', 'Gene', '7403', (26, 31))	('male cancers', 'Disease', 'MESH:D018567', (8, 20))	('tumor', 'Disease', (97, 102))	('mutations', 'Var', (32, 41))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('KDM6A', 'Gene', (26, 31))
169568	27869828	We hypothesized that mutations in TSGs that escape X-inactivation could underlie a significant fraction of excess male cancers, as males would require only a single deleterious mutation while females would require two (Figure 1b-c).	('excess male cancers', 'Disease', (107, 126))	('TSGs', 'Gene', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('excess male cancers', 'Disease', 'MESH:D018567', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (21, 30))
169569	27869828	ChrX is among the most frequently aneuploid chromosomes in female cancers, and alteration of X-inactivation by targeted deletion of Xist promotes tumorigenesis.	('promotes', 'PosReg', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Xist', 'Gene', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (146, 151))	('alteration', 'Var', (79, 89))	('male cancers', 'Disease', (61, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('Xist', 'Gene', '7503', (132, 136))	('male cancers', 'Disease', 'MESH:D018567', (61, 73))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
169572	27869828	Thus, a second corollary to the EXITS hypothesis is that chrY loss will co-occur in male tumors that have mutated an EXITS gene with a functional chrY homolog (Figure 1c).	('loss', 'NegReg', (62, 66))	('male tumors', 'Disease', 'MESH:D018567', (84, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('EXITS gene', 'Gene', (117, 127))	('chrY', 'Gene', (57, 61))	('male tumors', 'Disease', (84, 95))	('mutated', 'Var', (106, 113))
169575	27869828	We used a conservative mutation classification algorithm to ensure that the included variants were restricted to somatic truncating and missense alterations that were most likely loss-of-function ("LOF", see Methods), or DNA copy number (CN) loss of at least one allele (Supplementary Figure 3).	('loss-of-function', 'NegReg', (179, 195))	('variants', 'Var', (85, 93))	('loss', 'NegReg', (242, 246))	('men', 'Species', '9606', (277, 280))	('missense alterations', 'Var', (136, 156))
169577	27869828	We performed this analysis for only LOF mutations (SNVs and InDels) in the 4126 patients with exome data and then again for LOF mutation or CN loss (LOF mutation/CN loss) in the 1994 patients with both exome and copy number data available.	('patients', 'Species', '9606', (80, 88))	('LOF', 'NegReg', (36, 39))	('mutations', 'Var', (40, 49))	('mutation', 'Var', (128, 136))	('LOF', 'NegReg', (124, 127))	('patients', 'Species', '9606', (183, 191))
169578	27869828	At a false discovery rate (FDR) <0.1, there were no autosomal or PAR genes (n=18,055) that had LOF mutations more frequently in male cancers.	('male cancers', 'Disease', (128, 140))	('PAR genes', 'Gene', (65, 74))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('LOF', 'NegReg', (95, 98))	('male cancers', 'Disease', 'MESH:D018567', (128, 140))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('autosomal', 'Gene', (52, 61))
169580	27869828	In contrast, at FDR<0.1, six of 783 non-PAR chrX genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored LOF mutation or LOF mutation/CN loss more frequently in male cancers (P<0.0001 compared to zero of 18,055 autosomal or PAR genes; Table 1, Figure 2a-b, and Supplementary Tables 5-6).	('ATRX', 'Gene', '546', (56, 60))	('mutation', 'Var', (116, 124))	('MAGEC3', 'Gene', '139081', (95, 101))	('DDX3X', 'Gene', (70, 75))	('KDM6A', 'Gene', '7403', (84, 89))	('MAGEC3', 'Gene', (95, 101))	('KDM5C', 'Gene', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('LOF', 'NegReg', (128, 131))	('CNKSR2', 'Gene', (62, 68))	('DDX3X', 'Gene', '1654', (70, 75))	('male cancers', 'Disease', 'MESH:D018567', (168, 180))	('LOF', 'NegReg', (112, 115))	('KDM6A', 'Gene', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('male cancers', 'Disease', (168, 180))	('mutation/CN', 'Var', (132, 143))	('KDM5C', 'Gene', '8242', (77, 82))	('men', 'Species', '9606', (274, 277))	('ATRX', 'Gene', (56, 60))	('chrX genes', 'Gene', (44, 54))	('CNKSR2', 'Gene', '22866', (62, 68))
169581	27869828	Of note, ATRX, DDX3X, KDM5C, and KDM6A have been previously implicated as TSGs, via recurrent loss-of-function alterations in cancer genomes and/or by direct experimental evidence.	('KDM6A', 'Gene', '7403', (33, 38))	('ATRX', 'Gene', '546', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('DDX3X', 'Gene', (15, 20))	('KDM5C', 'Gene', (22, 27))	('alterations', 'Var', (111, 122))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('KDM5C', 'Gene', '8242', (22, 27))	('KDM6A', 'Gene', (33, 38))	('DDX3X', 'Gene', '1654', (15, 20))	('TSGs', 'Disease', (74, 78))	('loss-of-function', 'NegReg', (94, 110))	('ATRX', 'Gene', (9, 13))	('men', 'Species', '9606', (164, 167))
169583	27869828	LOF mutation/CN loss was enriched in ATRX among male lower-grade gliomas (LGG; FDR<10-4) and in KDM5C among male clear cell kidney cancers (KIRC, FDR=0.044) (Table 1, Figure 2c-d).	('cell kidney cancers', 'Disease', (119, 138))	('gliomas', 'Disease', (65, 72))	('KDM5C', 'Gene', '8242', (96, 101))	('cell kidney cancers', 'Disease', 'MESH:D007680', (119, 138))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (113, 137))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('kidney cancer', 'Phenotype', 'HP:0009726', (124, 137))	('ATRX', 'Gene', '546', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('loss', 'NegReg', (16, 20))	('kidney cancers', 'Phenotype', 'HP:0009726', (124, 138))	('clear cell kidney cancer', 'Disease', (113, 137))	('mutation/CN', 'Var', (4, 15))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (113, 137))	('KDM5C', 'Gene', (96, 101))	('ATRX', 'Gene', (37, 41))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
169584	27869828	There were no autosomal or PAR genes with male-biased LOF mutation in any of the individual cancer types at FDR<0.1.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('LOF', 'NegReg', (54, 57))	('mutation', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
169586	27869828	Five (CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) of the 6 genes were re-discovered as significantly more frequently mutated across all male cancers in this analysis (FDR<0.1), as were ATRX in male LGG and KDM5C in male KIRC (Supplementary Figure 4 and Supplementary Table 7).	('MAGEC3', 'Gene', '139081', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ATRX', 'Gene', (182, 186))	('men', 'Species', '9606', (256, 259))	('ATRX', 'Gene', '546', (182, 186))	('DDX3X', 'Gene', (14, 19))	('CNKSR2', 'Gene', (6, 12))	('CNKSR2', 'Gene', '22866', (6, 12))	('MAGEC3', 'Gene', (39, 45))	('KDM6A', 'Gene', '7403', (28, 33))	('KDM5C', 'Gene', (21, 26))	('KDM5C', 'Gene', (203, 208))	('DDX3X', 'Gene', '1654', (14, 19))	('mutated', 'Var', (114, 121))	('men', 'Species', '9606', (229, 232))	('male cancers', 'Disease', 'MESH:D018567', (133, 145))	('KDM6A', 'Gene', (28, 33))	('male cancers', 'Disease', (133, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('KDM5C', 'Gene', '8242', (21, 26))	('KDM5C', 'Gene', '8242', (203, 208))
169588	27869828	Considering that 42% of male LGGs in our dataset had ATRX mutations compared to 26% of female LGGs, approximately 80% of the excess male LGGs in our cohort had ATRX mutations.	('mutations', 'Var', (58, 67))	('ATRX', 'Gene', (53, 57))	('ATRX', 'Gene', '546', (160, 164))	('ATRX', 'Gene', '546', (53, 57))	('ATRX', 'Gene', (160, 164))
169589	27869828	Similarly, 8.6% of the excess male head and neck squamous cell carcinomas had KDM6A mutations and 12.1% of the excess male clear cell kidney cancer had KDM5C mutations (see Methods for calculations).	('KDM5C', 'Gene', '8242', (152, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (123, 147))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (44, 73))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (35, 73))	('KDM6A', 'Gene', '7403', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (84, 93))	('neck squamous cell carcinomas', 'Disease', (44, 73))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (49, 73))	('clear cell kidney cancer', 'Disease', (123, 147))	('KDM6A', 'Gene', (78, 83))	('KDM5C', 'Gene', (152, 157))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (123, 147))	('kidney cancer', 'Phenotype', 'HP:0009726', (134, 147))
169590	27869828	To address the latter limitation, we calculated the number of tumor/normal pairs needed for 80% power to detect a coding LOF mutation on chrX with a significant male bias given different M:F disease incidence ratios, basal mutation rates, and prevalence of an alteration in a specific population (Figure 3a).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutation', 'Var', (125, 133))	('tumor', 'Disease', (62, 67))	('chrX', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
169591	27869828	For example, clear cell kidney cancer (KIRC) has a M:F incidence ratio of ~2:1 and therefore, as expected, ~50% of all mutations on the X chromosome across all KIRCs are in males because they have only one chrX.	('kidney cancer', 'Phenotype', 'HP:0009726', (24, 37))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (13, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('clear cell kidney cancer', 'Disease', (13, 37))	('mutations', 'Var', (119, 128))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (13, 37))
169592	27869828	If an EXITS gene were mutated in 5% of all KIRCs it would require sequencing >1000 tumors to have 80% power to detect a 4-fold male mutation bias.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mutated', 'Var', (22, 29))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
169595	27869828	Essentially all tumors with downregulation of EXITS genes (defined as expression <5th percentile of the male cancers) in the absence of a DNA mutation were from males (22/469 males vs 2/218 females for DDX3X, P=0.012 by Fisher's exact test; 16/450 males vs 2/216 females for KDM5C, P=0.071; 23/465 males vs 2/217 females for KDM6A, P=0.0077; Figure 3b).	('male cancers', 'Disease', (104, 116))	('KDM6A', 'Gene', (325, 330))	('KDM5C', 'Gene', '8242', (275, 280))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('DDX3X', 'Gene', '1654', (202, 207))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('male cancers', 'Disease', 'MESH:D018567', (104, 116))	('KDM6A', 'Gene', '7403', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('downregulation', 'NegReg', (28, 42))	('absence', 'NegReg', (125, 132))	('mutation', 'Var', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', (16, 22))	('KDM5C', 'Gene', (275, 280))	('DDX3X', 'Gene', (202, 207))
169597	27869828	We compiled a list of 59 chrX genes with evidence of X-inactivation escape in multiple contexts from studies of human lymphoblastoid cells and hybrid fibroblasts (Supplementary Table 8).	('human', 'Species', '9606', (112, 117))	('men', 'Species', '9606', (169, 172))	('X-inactivation', 'Var', (53, 67))	('chrX genes', 'Gene', (25, 35))
169598	27869828	These 59 genes had a higher M:F ratio of LOF mutation/CN loss compared to other chrX genes (P=0.022; Supplementary Figure 5a).	('LOF', 'NegReg', (41, 44))	('mutation/CN', 'Var', (45, 56))	('men', 'Species', '9606', (107, 110))
169599	27869828	Similarly, we identified 17 chrX genes with predicted functional Y homologs (Supplementary Table 8) and found that they had a trend toward higher M:F ratio for LOF mutation/CN loss compared to other chrX genes (P=0.058; Supplementary Figure 5b).	('LOF', 'NegReg', (160, 163))	('men', 'Species', '9606', (83, 86))	('mutation/CN', 'Var', (164, 175))	('M:F ratio', 'MPA', (146, 155))	('higher', 'PosReg', (139, 145))	('chrX genes', 'Gene', (28, 38))	('men', 'Species', '9606', (226, 229))
169600	27869828	A permutation test limited to genes previously reported to either escape X-inactivation (n=59) or have chrY homologs in humans or in recent mammalian evolution (n=33) identified two additional genes with higher frequencies of LOF mutation and/or CN loss in male cancers (FDR<0.1): NLGN4X and RBM10 (Supplementary Table 9).	('RBM10', 'Gene', '8241', (292, 297))	('male cancers', 'Disease', 'MESH:D018567', (257, 269))	('NLGN4X', 'Gene', '57502', (281, 287))	('RBM10', 'Gene', (292, 297))	('male cancers', 'Disease', (257, 269))	('humans', 'Species', '9606', (120, 126))	('men', 'Species', '9606', (305, 308))	('mutation', 'Var', (230, 238))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('LOF', 'NegReg', (226, 229))	('mammalian', 'Species', '9606', (140, 149))	('NLGN4X', 'Gene', (281, 287))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))
169602	27869828	We next tested the hypothesis that EXITS genes will harbor biallelic inactivation when mutated in female tumors.	('tested', 'Reg', (8, 14))	('biallelic inactivation', 'Var', (59, 81))	('male tumors', 'Disease', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('male tumors', 'Disease', 'MESH:D018567', (100, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
169603	27869828	We used SNP array data to infer which female tumors had lost an entire chrX and compared this to the incidence of LOF mutation or focal CN loss on the remaining chrX (Supplementary Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('male tumors', 'Disease', 'MESH:D018567', (40, 51))	('male tumors', 'Disease', (40, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('loss', 'NegReg', (139, 143))	('men', 'Species', '9606', (173, 176))	('mutation', 'Var', (118, 126))	('lost', 'NegReg', (56, 60))
169604	27869828	Female tumors with EXITS mutations were more likely to have lost the whole other chrX than tumors without EXITS mutations (23.3% [10/43] vs 6.2% [45/726], P=0.0005 by Fisher's exact test), suggesting an enrichment for biallelic loss.	('lost', 'NegReg', (60, 64))	('tumors', 'Disease', (91, 97))	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('Female tumors', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('men', 'Species', '9606', (209, 212))	('Female tumors', 'Disease', 'MESH:D009369', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
169605	27869828	In addition, 6.3% of the female tumors with an EXITS mutation had two LOF mutations in that gene, although with short read sequencing we are unable to determine whether these are in cis or trans.	('LOF', 'NegReg', (70, 73))	('mutation', 'Var', (53, 61))	('male tumors', 'Disease', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('male tumors', 'Disease', 'MESH:D018567', (27, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
169606	27869828	To determine whether chrY loss is enriched among male tumors with EXITS gene mutations, we utilized a conservative approach to classify chrY copy number based on exome sequencing data across 1443 male tumors in our dataset (Supplementary Figure 6 and Supplementary Methods).	('men', 'Species', '9606', (257, 260))	('men', 'Species', '9606', (230, 233))	('male tumors', 'Disease', (196, 207))	('male tumors', 'Disease', 'MESH:D018567', (196, 207))	('male tumors', 'Disease', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('male tumors', 'Disease', 'MESH:D018567', (49, 60))	('mutations', 'Var', (77, 86))	('loss', 'NegReg', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
169607	27869828	Male tumors with loss-of-function mutations in any of the three EXITS genes with Y homologs (DDX3X, KDM5C, and KDM6A) had a trend toward enrichment for chrY loss compared to tumors without mutations (10.2% [9/88] versus 5.8% [78/1355], P=0.077).	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('KDM5C', 'Gene', '8242', (100, 105))	('Male tumors', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('DDX3X', 'Gene', (93, 98))	('Male tumors', 'Disease', 'MESH:D018567', (0, 11))	('chrY loss', 'Disease', (152, 161))	('tumors', 'Disease', (174, 180))	('loss-of-function', 'NegReg', (17, 33))	('KDM6A', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('men', 'Species', '9606', (143, 146))	('KDM5C', 'Gene', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('DDX3X', 'Gene', '1654', (93, 98))	('tumors', 'Disease', (5, 11))	('KDM6A', 'Gene', '7403', (111, 116))	('mutations', 'Var', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
169608	27869828	Male tumors with an LOF mutation in any chrX gene with a predicted functional Y homolog were more likely to have lost chrY than those without (10.6% [15/142] versus 5.5% [72/1301], P=0.019).	('lost', 'NegReg', (113, 117))	('chrX gene', 'Gene', (40, 49))	('chrY', 'MPA', (118, 122))	('Male tumors', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutation', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('LOF', 'NegReg', (20, 23))	('Male tumors', 'Disease', 'MESH:D018567', (0, 11))
169609	27869828	Therefore, age- and tobacco-associated spontaneous loss of chrY could disproportionately increase the frequency of some cancers in males, as LOF mutation/CN loss of EXITS genes with functional chrY homologs would lead to complete gene inactivation in male cells that have lost chrY (Figure 1c).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('tobacco', 'Species', '4097', (20, 27))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('gene', 'MPA', (230, 234))	('mutation/CN', 'Var', (145, 156))	('loss', 'NegReg', (157, 161))	('LOF', 'NegReg', (141, 144))
169610	27869828	To assess the relative functional contribution of X-X pairs in females compared to X-Y homologs in males, we determined the rate of concurrent mutation and chrX loss in female tumors with the rate of concurrent mutation and chrY loss in male tumors for the three EXITS genes with Y homologs (DDX3X, KDM5C, and KDM6A).	('KDM5C', 'Gene', '8242', (299, 304))	('chrX', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('male tumors', 'Disease', (171, 182))	('male tumors', 'Disease', (237, 248))	('DDX3X', 'Gene', '1654', (292, 297))	('male tumors', 'Disease', 'MESH:D018567', (171, 182))	('KDM6A', 'Gene', (310, 315))	('mutation', 'Var', (143, 151))	('male tumors', 'Disease', 'MESH:D018567', (237, 248))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('loss', 'NegReg', (161, 165))	('KDM5C', 'Gene', (299, 304))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('KDM6A', 'Gene', '7403', (310, 315))	('DDX3X', 'Gene', (292, 297))
169611	27869828	Female tumors with LOF/CN mutations were more likely to lose chrX than male tumors with LOF/CN mutations were to lose chrY (36% [9/25] versus 8.2% [6/73], P=0.0022).	('male tumors', 'Disease', 'MESH:D018567', (2, 13))	('chrX', 'MPA', (61, 65))	('lose', 'NegReg', (113, 117))	('chrY', 'MPA', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('Female tumors', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('mutations', 'Var', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('male tumors', 'Disease', (71, 82))	('Female tumors', 'Disease', 'MESH:D009369', (0, 13))	('male tumors', 'Disease', 'MESH:D018567', (71, 82))	('lose', 'NegReg', (56, 60))
169617	27869828	Nearly all of the excess male cancers with ATRX mutations in our dataset were in lower-grade gliomas (Table 1).	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('mutations', 'Var', (48, 57))	('excess male cancers', 'Disease', (18, 37))	('ATRX', 'Gene', '546', (43, 47))	('excess male cancers', 'Disease', 'MESH:D018567', (18, 37))	('ATRX', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
169620	27869828	We took two approaches using RNA-seq to demonstrate evidence of X-inactivation escape in putative EXITS genes in tumors and normal tissues: allele-specific expression in female cells and male vs. female expression levels.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('X-inactivation', 'Var', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
169622	27869828	This included tumor types where male-biased mutations were significant in single cancer analysis (e.g., ATRX in LGG, KDM5C in KIRC).	('tumor', 'Disease', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('ATRX', 'Gene', (104, 108))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (44, 53))	('ATRX', 'Gene', '546', (104, 108))	('KDM5C', 'Gene', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('KDM5C', 'Gene', '8242', (117, 122))
169625	27869828	Notably, ATRX was only higher in female LGG and CNKSR2 only in female LUAD, the tumor types for each gene where the male loss-of-function mutation bias was also seen (Supplementary Figure 8).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('ATRX', 'Gene', '546', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('men', 'Species', '9606', (173, 176))	('tumor', 'Disease', (80, 85))	('loss-of-function', 'NegReg', (121, 137))	('mutation', 'Var', (138, 146))	('CNKSR2', 'Gene', '22866', (48, 54))	('ATRX', 'Gene', (9, 13))	('CNKSR2', 'Gene', (48, 54))
169627	27869828	Indeed, that is what we observed for EXITS genes, including high minor allele expression of ATRX in brain biopsies from several donors in multiple anatomic sites suggesting X-inactivation escape (P<0.0001 vs non-escape genes in cortex, P=0.0224 in cerebellum by K-S test; Supplementary Figure 9).	('ATRX', 'Gene', (92, 96))	('men', 'Species', '9606', (278, 281))	('P<0.0001', 'Var', (196, 204))	('ATRX', 'Gene', '546', (92, 96))
169634	27869828	Depletion of Cnksr2 from murine 3T3 fibroblasts using two independent lentiviral shRNAs resulted in expression changes that were enriched in genes associated with oncogene signatures by Gene Set Enrichment Analysis (GSEA) in the Molecular Signatures Database (MSigDB, Broad Institute) C2:CGP collection, including transformation by HRAS, KRAS, and the Ras-like protein RHOA (Supplementary Figure 11a-c, Supplementary Table 10).	('RHOA', 'Gene', '11848', (369, 373))	('men', 'Species', '9606', (381, 384))	('T3', 'CellLine', 'CVCL:0594', (33, 35))	('men', 'Species', '9606', (409, 412))	('men', 'Species', '9606', (201, 204))	('Depletion', 'Var', (0, 9))	('expression', 'MPA', (100, 110))	('RHOA', 'Gene', (369, 373))	('HRAS', 'Gene', '15461', (332, 336))	('GSEA', 'Chemical', '-', (216, 220))	('murine', 'Species', '10090', (25, 31))	('changes', 'Reg', (111, 118))	('Cnksr2', 'Gene', (13, 19))	('HRAS', 'Gene', (332, 336))
169637	27869828	Consistent with activation of the RAS/MAPK pathway, cells expressing Cnksr2 shRNAs had increased ERK phosphorylation and enhanced colony-forming activity in soft agar, consistent with in vitro transformation (Supplementary Figure 11e-g).	('increased', 'PosReg', (87, 96))	('enhanced', 'PosReg', (121, 129))	('ERK phosphorylation', 'MPA', (97, 116))	('men', 'Species', '9606', (215, 218))	('agar', 'Chemical', 'MESH:D000362', (162, 166))	('colony-forming activity in soft agar', 'CPA', (130, 166))	('RAS/MAPK pathway', 'Pathway', (34, 50))	('Cnksr2', 'Var', (69, 75))
169640	27869828	The EXITS hypothesis is that biallelic expression of these genes affords females with enhanced cancer protection, which substantively contributes to the observed higher incidence of some tumors in males.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (95, 101))	('biallelic expression', 'Var', (29, 49))	('enhanced', 'PosReg', (86, 94))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
169641	27869828	Our data have provided evidence to support this hypothesis, as the genes with an increased incidence of loss-of-function mutations in males across many cancer types were exclusively non-PAR genes on chrX, including several that are known to be TSGs and/or known to escape X-inactivation in certain contexts.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('mutations', 'Var', (121, 130))	('loss-of-function', 'NegReg', (104, 120))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('chrX', 'Gene', (199, 203))
169644	27869828	Undoubtedly, EXITS gene mutations are not the sole explanation for differences in cancer incidence between men and women.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('men', 'Species', '9606', (107, 110))	('men', 'Species', '9606', (117, 120))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (24, 33))	('women', 'Species', '9606', (115, 120))
169647	27869828	For example, a clastogenic carcinogen could disproportionately affect men if the process of carcinogenesis involves inactivation of an EXITS gene or loss of chrY, as has been shown for tobacco smoking.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('inactivation', 'Var', (116, 128))	('carcinogenesis', 'Disease', (92, 106))	('loss', 'NegReg', (149, 153))	('men', 'Species', '9606', (70, 73))	('tobacco', 'Species', '4097', (185, 192))	('chrY', 'Gene', (157, 161))	('EXITS gene', 'Gene', (135, 145))
169650	27869828	Alternatively, they could result in more general effects in a population because male and female cancers of a specific type may be effectively distinct diseases (i.e., male tumors without EXITS mutations might behave similarly to female tumors, while EXITS-mutated cancers could have their own biology).	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('male cancers', 'Disease', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('male tumors', 'Disease', 'MESH:D018567', (232, 243))	('male tumors', 'Disease', 'MESH:D018567', (168, 179))	('male tumors', 'Disease', (232, 243))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('male tumors', 'Disease', (168, 179))	('mutations', 'Var', (194, 203))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))	('male cancers', 'Disease', 'MESH:D018567', (92, 104))
169654	27869828	autism, schizophrenia) have been associated with polymorphisms on chrX.	('schizophrenia', 'Disease', (8, 21))	('autism', 'Disease', 'MESH:D001321', (0, 6))	('schizophrenia', 'Disease', 'MESH:D012559', (8, 21))	('autism', 'Disease', (0, 6))	('schizophrenia', 'Phenotype', 'HP:0100753', (8, 21))	('associated', 'Reg', (33, 43))	('polymorphisms', 'Var', (49, 62))	('chrX', 'Gene', (66, 70))	('autism', 'Phenotype', 'HP:0000717', (0, 6))
169655	27869828	These data suggest that, besides the obvious link between male sex and monogenic diseases associated with chrX gene mutation, the haploid nature of chrX in males may increase the risk of developing polygenic diseases other than cancer.	('polygenic diseases', 'Disease', (198, 216))	('cancer', 'Disease', (228, 234))	('increase', 'PosReg', (166, 174))	('mutation', 'Var', (116, 124))	('chrX', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('polygenic diseases', 'Disease', 'MESH:D004194', (198, 216))	('haploid nature', 'Var', (130, 144))	('chrX', 'Gene', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
169656	23638004	Modulation of HJURP (Holliday Junction-Recognizing Protein) Levels Is Correlated with Glioblastoma Cells Survival Diffuse astrocytomas are the most common type of primary brain cancer in adults.	('Modulation', 'Var', (0, 10))	('brain cancer', 'Disease', 'MESH:D001932', (171, 183))	('HJURP', 'Gene', '55355', (14, 19))	('astrocytomas', 'Disease', 'MESH:D001254', (122, 134))	('HJURP', 'Gene', (14, 19))	('Glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('astrocytoma', 'Phenotype', 'HP:0009592', (122, 133))	('brain cancer', 'Phenotype', 'HP:0030692', (171, 183))	('Glioblastoma', 'Disease', (86, 98))	('astrocytomas', 'Disease', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('brain cancer', 'Disease', (171, 183))	('Glioblastoma', 'Disease', 'MESH:D005909', (86, 98))
169662	23638004	More importantly, we found that HJURP knockdown strongly affects the maintenance of glioblastoma cells in a selective manner.	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('affects', 'Reg', (57, 64))	('HJURP', 'Gene', '55355', (32, 37))	('HJURP', 'Gene', (32, 37))	('knockdown', 'Var', (38, 47))	('glioblastoma', 'Disease', (84, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))
169675	23638004	Hypo-methylation of the MGMT promoter is correlated with glioblastoma resistance to temozolomide (TMZ) chemotherapy, and consequently with worse prognosis, due to the reduction in TMZ induced alkylation when MGMT is overexpressed.	('TMZ induced alkylation', 'MPA', (180, 202))	('MGMT', 'Gene', '4255', (24, 28))	('glioblastoma', 'Disease', (57, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (180, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('resistance to temozolomide', 'MPA', (70, 96))	('reduction', 'NegReg', (167, 176))	('Hypo-methylation', 'Var', (0, 16))	('MGMT', 'Gene', '4255', (208, 212))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('MGMT', 'Gene', (208, 212))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('temozolomide', 'Chemical', 'MESH:D000077204', (84, 96))	('MGMT', 'Gene', (24, 28))
169684	23638004	Furthermore, we demonstrated that HJURP knockdown in different cell lines significantly affected the survival of glioblastoma cells but did not impact non-tumoral cells.	('glioblastoma', 'Disease', (113, 125))	('HJURP', 'Gene', (34, 39))	('affected', 'Reg', (88, 96))	('non-tumor', 'Disease', (151, 160))	('HJURP', 'Gene', '55355', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('knockdown', 'Var', (40, 49))	('non-tumor', 'Disease', 'MESH:D009369', (151, 160))	('survival', 'CPA', (101, 109))
169685	23638004	After HJURP silencing, T98G and U87MG cells showed cell cycle arrest and premature senescence, respectively, which culminated in elevated levels of cell death for both cell lines.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('HJURP', 'Gene', (6, 11))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (51, 68))	('arrest', 'Disease', (62, 68))	('cell death', 'MPA', (148, 158))	('U87MG', 'CellLine', 'CVCL:0022', (32, 37))	('silencing', 'Var', (12, 21))	('U87MG', 'Var', (32, 37))	('T98G', 'Var', (23, 27))	('premature senescence', 'CPA', (73, 93))	('HJURP', 'Gene', '55355', (6, 11))
169700	23638004	Individuals suffering with tumors expressing higher levels of HJURP (RE >39.7, n = 31) showed a mean survival period of 16 months, while individuals whose tumors presented lower amounts of HJURP (RE <39.7, n = 9) showed a mean survival period of 45 months (Table S1).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('HJURP', 'Gene', '55355', (189, 194))	('HJURP', 'Gene', '55355', (62, 67))	('HJURP', 'Gene', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('HJURP', 'Gene', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('RE >39.7', 'Var', (69, 77))
169701	23638004	To strength our observation of HJURP as a predictive variable of survival prognosis, we performed a meta-analysis with 3 different expression datasets of glioma samples: the Repository of Molecular Brain Neoplasia DaTa (REMBRANDT), The Cancer Genome Atlas (TCGA) and two publically available microarray experiments (GSE4271 and GSE4412).	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (236, 242))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('GSE4271', 'Chemical', '-', (316, 323))	('Molecular Brain Neoplasia DaTa', 'Disease', 'MESH:D009369', (188, 218))	('Cancer Genome Atlas', 'Disease', (236, 255))	('GSE4271', 'Var', (316, 323))	('GSE4412', 'Var', (328, 335))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (236, 255))	('GSE4412', 'Chemical', '-', (328, 335))	('HJURP', 'Gene', '55355', (31, 36))	('HJURP', 'Gene', (31, 36))	('glioma', 'Disease', (154, 160))	('Brain Neoplasia', 'Phenotype', 'HP:0030692', (198, 213))	('Molecular Brain Neoplasia DaTa', 'Disease', (188, 218))	('Neoplasia', 'Phenotype', 'HP:0002664', (204, 213))
169705	23638004	Higher-grade tumors also showed a significant correlation with worse survival prognosis in the analysis of public data when microarray data were combined (hazard ratio = 2.41; p = 0.006) or evaluated separately (GSE4271, hazard ratio = 5.07; p = 0.047; GSE4412, hazard ratio = 3.21; p = 0.001).	('GSE4412', 'Chemical', '-', (253, 260))	('GSE4412', 'Var', (253, 260))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('GSE4271', 'Chemical', '-', (212, 219))	('GSE4271', 'Var', (212, 219))
169710	23638004	The amounts of HJURP mRNA measured in T98G cells were 4.4 and 11.3 fold the quantities detected in RO and U87MG cells, respectively (Figure 2A).	('HJURP', 'Gene', '55355', (15, 20))	('T98G', 'Var', (38, 42))	('HJURP', 'Gene', (15, 20))	('U87MG', 'CellLine', 'CVCL:0022', (106, 111))
169715	23638004	After three days of HJURP knockdown the majority of T98G cells were detached, having a rounded morphology (Figure 3C-D), while non-tumoral control cells were not morphologically altered (Figure 3A-B, Figure S3B).	('HJURP', 'Gene', (20, 25))	('T98G', 'Var', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('non-tumor', 'Disease', 'MESH:D009369', (127, 136))	('knockdown', 'Var', (26, 35))	('HJURP', 'Gene', '55355', (20, 25))	('non-tumor', 'Disease', (127, 136))
169717	23638004	On the basis of these morphology alterations, HJURP knockdown seems to induce cell death in both tumoral cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('HJURP', 'Gene', '55355', (46, 51))	('cell death', 'CPA', (78, 88))	('tumor', 'Disease', (97, 102))	('HJURP', 'Gene', (46, 51))	('induce', 'Reg', (71, 77))	('knockdown', 'Var', (52, 61))
169719	23638004	The percentage of T98G cells in G2/M phases of the cell cycle increased from approximately 15% up to 44% at the third day after HJURP silencing (Figure 4B, Figure S2).	('T98G', 'Var', (18, 22))	('increased', 'PosReg', (62, 71))	('HJURP', 'Gene', '55355', (128, 133))	('HJURP', 'Gene', (128, 133))	('silencing', 'Var', (134, 143))	('G2/M phases of the cell cycle', 'CPA', (32, 61))
169721	23638004	Non-tumoral cells showed only a slight but significant increment in the number of cells in G1 phase and a correspondent decrease in S phase cells after 5 days of HJURP knockdown (Figure 4A, Figure S2).	('tumor', 'Disease', (4, 9))	('S phase cells', 'CPA', (132, 145))	('HJURP', 'Gene', '55355', (162, 167))	('decrease', 'NegReg', (120, 128))	('HJURP', 'Gene', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('knockdown', 'Var', (168, 177))
169723	23638004	U87MG cells were affected in a different manner by HJURP knockdown.	('HJURP', 'Gene', '55355', (51, 56))	('knockdown', 'Var', (57, 66))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('HJURP', 'Gene', (51, 56))
169724	23638004	U87MG cells, which are usually elongated and grow loosely attached as a sparse network (Figure 5A-1, A-3 and A-5), become flat, and spread out when HJURP levels are diminished (Figure 5A-2).	('HJURP', 'Gene', '55355', (148, 153))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('HJURP', 'Gene', (148, 153))	('diminished', 'NegReg', (165, 175))	('U87MG', 'Var', (0, 5))
169726	23638004	U87MG beta-Gal positive cells were initially detected after three days of HJURP knockdown and increased dramatically (up to ~37 fold) after five days (Figure 5B, Table S2).	('knockdown', 'Var', (80, 89))	('beta-Gal', 'Chemical', '-', (6, 14))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('HJURP', 'Gene', '55355', (74, 79))	('beta-Gal', 'Protein', (6, 14))	('HJURP', 'Gene', (74, 79))	('U87MG', 'Var', (0, 5))
169728	23638004	After five days of HJURP depletion many U87MG cells also presented membrane blebs (Figure 5A-4) and at the seventh day a significant proportion of cells were round, shrunk and detached (Figure 5A-6).	('shrunk', 'CPA', (165, 171))	('membrane blebs', 'CPA', (67, 81))	('U87MG', 'CellLine', 'CVCL:0022', (40, 45))	('HJURP', 'Gene', '55355', (19, 24))	('U87MG', 'Var', (40, 45))	('HJURP', 'Gene', (19, 24))
169731	23638004	The viability of RO and HDPC non-tumoral cells was not significantly affected by HJURP knockdown during the period evaluated (Figure 6B, Figure S3C).	('HDPC', 'Gene', '167227', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('non-tumor', 'Disease', (29, 38))	('HJURP', 'Gene', '55355', (81, 86))	('non-tumor', 'Disease', 'MESH:D009369', (29, 38))	('HJURP', 'Gene', (81, 86))	('HDPC', 'Gene', (24, 28))	('knockdown', 'Var', (87, 96))
169742	23638004	The modulation of ATM expression was reported to be associated with radiosensitivity of U87MG cells.	('modulation', 'Var', (4, 14))	('ATM', 'Gene', '472', (18, 21))	('associated', 'Reg', (52, 62))	('U87MG', 'CellLine', 'CVCL:0022', (88, 93))	('radiosensitivity', 'CPA', (68, 84))	('ATM', 'Gene', (18, 21))
169743	23638004	It was shown that demethylation of ATM promoter increased the levels of ATM protein and decreased the radiosensitivety of U87MG cells.	('increased', 'PosReg', (48, 57))	('ATM', 'Gene', '472', (35, 38))	('ATM', 'Gene', '472', (72, 75))	('U87MG', 'CellLine', 'CVCL:0022', (122, 127))	('ATM', 'Gene', (35, 38))	('decreased', 'NegReg', (88, 97))	('demethylation', 'Var', (18, 31))	('ATM', 'Gene', (72, 75))	('radiosensitivety of U87MG cells', 'CPA', (102, 133))
169746	23638004	We also observed that HJURP knockdown strongly affects the maintenance of glioblastoma cells in a selective manner.	('glioblastoma', 'Disease', (74, 86))	('affects', 'Reg', (47, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('HJURP', 'Gene', '55355', (22, 27))	('knockdown', 'Var', (28, 37))	('HJURP', 'Gene', (22, 27))
169747	23638004	After HJURP knockdown, T98G cells showed a remarkable cell cycle arrest at the third day of silencing (Figure 4B) and U87MG cells entered in premature senescence (Figure 5B).	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('HJURP', 'Gene', (6, 11))	('U87MG', 'CellLine', 'CVCL:0022', (118, 123))	('U87MG', 'Var', (118, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('knockdown', 'Var', (12, 21))	('silencing', 'Var', (92, 101))	('arrest', 'Disease', (65, 71))	('T98G', 'Var', (23, 27))	('entered', 'Reg', (130, 137))	('premature senescence', 'CPA', (141, 161))	('HJURP', 'Gene', '55355', (6, 11))
169748	23638004	Previous studies have demonstrated that CENP-A and HJURP knockdown in primary fibroblasts elicits premature senescence in a p53 dependent manner.	('p53', 'Gene', (124, 127))	('elicits', 'Reg', (90, 97))	('HJURP', 'Gene', '55355', (51, 56))	('p53', 'Gene', '7157', (124, 127))	('knockdown', 'Var', (57, 66))	('HJURP', 'Gene', (51, 56))	('CENP-A', 'Gene', '1058', (40, 46))	('premature senescence', 'MPA', (98, 118))	('CENP-A', 'Gene', (40, 46))
169749	23638004	Once T98G cells harbor a mutation in p53, while U87MG cells are wild type, a reduction in CENP-A deposition, due to HJURP knockdown, could explain the different phenotype of these cells.	('mutation', 'Var', (25, 33))	('reduction', 'NegReg', (77, 86))	('CENP-A', 'Gene', (90, 96))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('U87MG', 'CellLine', 'CVCL:0022', (48, 53))	('HJURP', 'Gene', '55355', (116, 121))	('CENP-A', 'Gene', '1058', (90, 96))	('HJURP', 'Gene', (116, 121))
169750	23638004	Despite the differences in the behavior of T98G and U87MG cells, both presented elevated cell death levels after HJURP silencing (Figure 4D and 6) suggesting that HJURP is critical for different pathways of cell cycle progression.	('elevated', 'PosReg', (80, 88))	('HJURP', 'Gene', (163, 168))	('HJURP', 'Gene', '55355', (163, 168))	('T98G', 'Var', (43, 47))	('silencing', 'NegReg', (119, 128))	('U87MG', 'CellLine', 'CVCL:0022', (52, 57))	('cell death levels', 'MPA', (89, 106))	('HJURP', 'Gene', (113, 118))	('U87MG', 'Var', (52, 57))	('HJURP', 'Gene', '55355', (113, 118))
169752	23638004	In fact, T98G and U87MG cells present a doubling time approximately 2.6 fold shorter than HDPC and RO cells (data not shown).	('HDPC', 'Gene', (90, 94))	('doubling time', 'CPA', (40, 53))	('T98G', 'Var', (9, 13))	('HDPC', 'Gene', '167227', (90, 94))	('U87MG', 'CellLine', 'CVCL:0022', (18, 23))	('shorter', 'NegReg', (77, 84))	('U87MG', 'Var', (18, 23))
169753	23638004	Thus, control cells undergo fewer divisions than GBM cells during the period of HJURP knockdown and possibly do not have CENP-A completely depleted at the centromeres.	('fewer', 'NegReg', (28, 33))	('knockdown', 'Var', (86, 95))	('CENP-A', 'Gene', (121, 127))	('HJURP', 'Gene', '55355', (80, 85))	('divisions', 'CPA', (34, 43))	('HJURP', 'Gene', (80, 85))	('CENP-A', 'Gene', '1058', (121, 127))
169754	23638004	This could explain the absence of a significant effect in the viability of control cells subjected to HJURP silencing.	('HJURP', 'Gene', '55355', (102, 107))	('silencing', 'Var', (108, 117))	('HJURP', 'Gene', (102, 107))
169756	23638004	Tumor cells are characterized by an accumulation of genetic alterations that drive tumorigenesis, including copy number variations, chromosomal rearrangements, point mutations and small insertions and deletions.	('small insertions', 'Var', (180, 196))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number variations', 'Var', (108, 130))	('tumor', 'Disease', (83, 88))	('chromosomal rearrangements', 'Var', (132, 158))	('deletions', 'Var', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('point mutations', 'Var', (160, 175))
169757	23638004	Recently, a comparison of the genome of lymphoblastoid cells and breast tumor cells isolated from the same patient has shown that structural variations in DNA are much more frequent in tumor than in non-tumoral cells.	('structural variations', 'Var', (130, 151))	('tumor', 'Disease', (185, 190))	('breast tumor', 'Disease', (65, 77))	('frequent', 'Reg', (173, 181))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (72, 77))	('non-tumor', 'Disease', 'MESH:D009369', (199, 208))	('DNA', 'Gene', (155, 158))	('breast tumor', 'Phenotype', 'HP:0100013', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('breast tumor', 'Disease', 'MESH:D001943', (65, 77))	('patient', 'Species', '9606', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('non-tumor', 'Disease', (199, 208))
169758	23638004	The breast cancer cell presented 94 structural variations including translocations, deletions, inversions and duplications, while the lymphoblastoid cell showed only four DNA structural alterations.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('inversions', 'Var', (95, 105))	('translocations', 'Var', (68, 82))	('duplications', 'Var', (110, 122))	('deletions', 'Var', (84, 93))
169771	23638004	The glioblastoma cell lines utilized (T98G and U87MG) are commercially available and were obtained from ATCC collection.	('glioblastoma', 'Disease', (4, 16))	('U87MG', 'CellLine', 'CVCL:0022', (47, 52))	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('U87MG', 'Var', (47, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('T98G', 'Var', (38, 42))
169799	23638004	Here, the NCBI/GEO dataset refers to the GSE4271 and GSE4412 microarray experiments, which were combined and normalized by the Robust Multi-Array Average software (Bioconductor, GCRMA package).	('GSE4271', 'Var', (41, 48))	('GSE4412', 'Chemical', '-', (53, 60))	('GSE4412', 'Var', (53, 60))	('GSE4271', 'Chemical', '-', (41, 48))
169814	32049048	Somatic evolution of cancers may follow convergent patterns across mammalian species by selecting cells that carry beneficial mutations in highly conserved regions, i.e., genes and their regulatory non-coding regions enabling one or more cancer hallmarks.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('enabling', 'PosReg', (217, 225))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('mammalian', 'Species', '9606', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('mutations', 'Var', (126, 135))	('cancers', 'Disease', (21, 28))	('cancer', 'Disease', (21, 27))
169822	32049048	Studies involving comparative genomics of spontaneous canine cancers have already enabled identification of breed-specific, disease-risk loci under strong evolutionary constraints and with known roles in human cancer, e.g., germline FGF4 retrogene expression in chondrodysplasia, somatic BRAF V600E mutation in canine invasive transitional cell carcinoma of the bladder, recurrent somatic SETD2 mutations in canine osteosarcoma, and TP53 pathway alterations in canine melanoma.	('V600E', 'Mutation', 'rs113488022', (293, 298))	('osteosarcoma', 'Phenotype', 'HP:0002669', (415, 427))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('transitional cell carcinoma of the bladder', 'Phenotype', 'HP:0006740', (327, 369))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (345, 369))	('canine', 'Species', '9615', (408, 414))	('melanoma', 'Phenotype', 'HP:0002861', (468, 476))	('melanoma', 'Disease', (468, 476))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('chondrodysplasia', 'Disease', 'MESH:D010009', (262, 278))	('carcinoma of the bladder', 'Disease', (345, 369))	('canine', 'Species', '9615', (311, 317))	('mutations', 'Var', (395, 404))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('SETD2', 'Gene', '476643', (389, 394))	('SETD2', 'Gene', (389, 394))	('canine', 'Species', '9615', (461, 467))	('TP53 pathway', 'Pathway', (433, 445))	('osteosarcoma', 'Disease', (415, 427))	('osteosarcoma', 'Disease', 'MESH:D012516', (415, 427))	('chondrodysplasia', 'Disease', (262, 278))	('cancer', 'Disease', (61, 67))	('FGF4', 'Gene', (233, 237))	('human', 'Species', '9606', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('alterations', 'Reg', (446, 457))	('melanoma', 'Disease', 'MESH:D008545', (468, 476))	('BRAF', 'Gene', (288, 292))	('BRAF', 'Gene', '673', (288, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('canine', 'Species', '9615', (54, 60))	('cancers', 'Disease', (61, 68))	('cancer', 'Disease', (210, 216))	('FGF4', 'Gene', '2249', (233, 237))
169830	32049048	We detected mutations in genes associated with human pediatric and adult glioma such as the TP53, PDGFRA, PIK3CA, and EGFR (Figure S1B), as well as recurrent hotspot and mutually exclusive mutations with high oncogenic impact according to the Catalog of Somatic Mutations in Cancer (COSMIC) database in PIK3CA H1047R/L (n = 8), PDGFRA K385I/M (n = 6), IDH1 R132C (n = 3), and SPOP P94R (n = 1; 1 shared with PIK3CA H1047R) (Figure 1B and Table S3).	('H1047R', 'SUBSTITUTION', 'None', (415, 421))	('H1047R', 'SUBSTITUTION', 'None', (310, 316))	('SPOP', 'Gene', '8405', (376, 380))	('Cancer', 'Disease', (275, 281))	('adult glioma', 'Disease', (67, 79))	('R132C', 'Mutation', 'rs121913499', (357, 362))	('SPOP', 'Gene', (376, 380))	('human', 'Species', '9606', (47, 52))	('Cancer', 'Disease', 'MESH:D009369', (275, 281))	('mutations', 'Var', (189, 198))	('adult glioma', 'Disease', 'MESH:D005910', (67, 79))	('K385I', 'SUBSTITUTION', 'None', (335, 340))	('H1047R', 'Var', (415, 421))	('H1047R', 'Var', (310, 316))	('H1047R', 'Mutation', 'rs121913279', (415, 421))	('mutations', 'Var', (12, 21))	('K385I', 'Var', (335, 340))	('P94R', 'Mutation', 'rs754245638', (381, 385))	('H1047R', 'Mutation', 'rs121913279', (310, 316))	('Cancer', 'Phenotype', 'HP:0002664', (275, 281))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))
169831	32049048	These mutations were also identified as being under positive selection or as significantly mutated genes using the dNdS approach (Table S2) and thus indicating driver mutations of canine gliomas.	('canine', 'Species', '9615', (180, 186))	('gliomas', 'Disease', (187, 194))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('mutated', 'Var', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('mutations', 'Var', (6, 15))
169832	32049048	Mutations affecting the IDH1 R132 codon are a defining characteristic of low-grade adult gliomas and were detected infrequently in pediatric and canine gliomas (n = 3/81).	('canine', 'Species', '9615', (145, 151))	('adult gliomas', 'Disease', (83, 96))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('adult gliomas', 'Disease', 'MESH:D005910', (83, 96))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (24, 28))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
169835	32049048	To demonstrate similarity between canine gliomas and human gliomas, we summarized levels of somatic coding mutations, high-level copy amplifications and deep deletions in gene sets reflecting previously reported cancer hallmarks (Table S4).	('deep deletions', 'Var', (153, 167))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('cancer', 'Disease', (212, 218))	('canine', 'Species', '9615', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('human', 'Species', '9606', (53, 58))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
169837	32049048	Adult glioma is commonly separated into subtypes on the basis of IDH mutation as well as chromosome arm 1p and 19q deletion, resulting in three subtypes: (1) IDH wild type; (2) IDH mutant with codeletion (IDHmut-codel); and (3) IDH mutant without codeletion (IDHmut-noncodel).	('IDH', 'Gene', (65, 68))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('IDH', 'Gene', '3417', (177, 180))	('IDH', 'Gene', (158, 161))	('IDH', 'Gene', '3417', (65, 68))	('IDH', 'Gene', (205, 208))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('IDH', 'Gene', (228, 231))	('IDH', 'Gene', '3417', (158, 161))	('IDH', 'Gene', '3417', (205, 208))	('IDH', 'Gene', (259, 262))	('IDH', 'Gene', '3417', (228, 231))	('deletion', 'Var', (115, 123))	('mutant', 'Var', (181, 187))	('IDH', 'Gene', (177, 180))	('codeletion', 'MPA', (193, 203))	('mutation', 'Var', (69, 77))	('glioma', 'Disease', (6, 12))	('IDH', 'Gene', '3417', (259, 262))
169838	32049048	Pediatric high-grade gliomas are separated based on histone H3 mutation status into two subtypes: histone H3 gene mutant (H3 mutant) versus wild type (H3 wild type).	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('histone H3', 'Gene', '483172', (98, 108))	('histone H3', 'Gene', (98, 108))	('mutant', 'Var', (114, 120))	('gliomas', 'Disease', (21, 28))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('histone H3', 'Gene', '483172', (52, 62))	('histone H3', 'Gene', (52, 62))
169841	32049048	Pediatric H3 mutant, adult IDH wild type, and IDHmut-noncodel gliomas showed increased frequency of gene mutations in cancer hallmarks such as deregulating cellular energetics, genomic instability, and resisting cell death (Figures 1C and S1C).	('mutant', 'Var', (13, 19))	('IDH', 'Gene', (27, 30))	('cancer', 'Disease', (118, 124))	('IDH', 'Gene', '3417', (27, 30))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('genomic', 'MPA', (177, 184))	('IDH', 'Gene', (46, 49))	('death', 'Disease', 'MESH:D003643', (217, 222))	('death', 'Disease', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IDH', 'Gene', '3417', (46, 49))	('deregulating cellular energetics', 'MPA', (143, 175))	('gliomas', 'Disease', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
169845	32049048	High-grade canine gliomas (n = 63/81) had mutation rates comparable with those of pediatric H3-mutant and H3 wild-type subtypes (0.34, 0.27, 0.25 coding mutations per megabase, respectively; Wilcoxon p value 0.18 and 0.1; Figure S1E), but significantly lower than in human adult IDH-mutant and IDH wild-type gliomas (0.77 and 1.67 coding mutations per megabase, respectively; Wilcoxon p values of 8 x 10-9 or less).	('gliomas', 'Disease', (18, 25))	('IDH', 'Gene', '3417', (294, 297))	('IDH', 'Gene', (279, 282))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('human', 'Species', '9606', (267, 272))	('IDH', 'Gene', '3417', (279, 282))	('gliomas', 'Disease', (308, 315))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('mutation', 'Var', (42, 50))	('gliomas', 'Disease', 'MESH:D005910', (308, 315))	('gliomas', 'Phenotype', 'HP:0009733', (308, 315))	('canine', 'Species', '9615', (11, 17))	('IDH', 'Gene', (294, 297))	('glioma', 'Phenotype', 'HP:0009733', (308, 314))
169847	32049048	These results demonstrate that the landscape of somatic single-nucleotide variants is similar to that of human glioma, and suggests that canine glioma aligns more closely with human pediatric glioma than with adult disease.	('glioma', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('adult disease', 'Disease', 'MESH:C538052', (209, 222))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('adult disease', 'Disease', (209, 222))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('human', 'Species', '9606', (176, 181))	('glioma', 'Disease', (144, 150))	('canine', 'Species', '9615', (137, 143))	('human', 'Species', '9606', (105, 110))	('glioma', 'Disease', (192, 198))	('single-nucleotide variants', 'Var', (56, 82))
169850	32049048	Human glioma tumor-suppressor gene CDKN2A/B was homozygously deleted in 8/67 (12%, all astrocytomas), and PTEN in 2/67 (3%) of canine glioma genomes (Figures 2A and S2A).	('Human', 'Species', '9606', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('CDKN2A/B', 'Gene', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('glioma tumor', 'Disease', 'MESH:D005910', (6, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (87, 99))	('CDKN2A/B', 'Gene', '1029;1030', (35, 43))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('glioma tumor', 'Disease', (6, 18))	('glioma', 'Disease', (134, 140))	('canine', 'Species', '9615', (127, 133))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('astrocytomas', 'Disease', (87, 99))	('glioma', 'Disease', (6, 12))	('deleted', 'Var', (61, 68))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
169851	32049048	Together, 67/81 (83%) patients with canine glioma contained somatic mutations and/or focal copy alterations in known human glioma drivers (Figure S1E).	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('focal copy alterations', 'Var', (85, 107))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('human', 'Species', '9606', (117, 122))	('glioma', 'Disease', (43, 49))	('patients', 'Species', '9606', (22, 30))	('canine', 'Species', '9615', (36, 42))	('glioma', 'Disease', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('contained', 'Reg', (50, 59))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
169854	32049048	Other common arm-level alterations included PIK3CA (canine 34q+) and the HIST1 cluster (canine 35q+) as well as hemizygous loss of heterozygosity of tumor-suppressor genes TP53, RB1, and PTEN (Figure 2A).	('PIK3CA', 'Gene', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('canine 35q+', 'Var', (88, 99))	('PTEN', 'Gene', (187, 191))	('TP53', 'Gene', (172, 176))	('canine', 'Species', '9615', (88, 94))	('RB1', 'Gene', '476915', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('canine', 'Species', '9615', (52, 58))	('HIST1 cluster', 'Gene', (73, 86))	('tumor', 'Disease', (149, 154))	('RB1', 'Gene', (178, 181))	('canine 34q+', 'Var', (52, 63))
169859	32049048	In contrast, pediatric H3 wild type (19% of genome) and H3 mutant (26% of genome) showed rates of aneuploidy comparable with that of canine glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('mutant', 'Var', (59, 65))	('canine', 'Species', '9615', (133, 139))	('aneuploidy', 'Disease', (98, 108))	('glioma', 'Disease', (140, 146))	('aneuploidy', 'Disease', 'MESH:D000782', (98, 108))
169865	32049048	None of three IDH1 mutant canine gliomas shared these syntenic aberrations, suggesting a mutually exclusive pattern as observed in human gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('human', 'Species', '9606', (131, 136))	('canine', 'Species', '9615', (26, 32))	('gliomas', 'Disease', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (137, 144))	('mutant', 'Var', (19, 25))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('IDH1', 'Gene', (14, 18))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
169866	32049048	The third cluster (black dendrogram) consisted of human 4p/8q and syntenic canine 13q arm, which contains the genes PDGFRA and MYC, amplified in 78% of canine gliomas.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('MYC', 'Gene', '403924', (127, 130))	('canine', 'Species', '9615', (152, 158))	('canine', 'Species', '9615', (75, 81))	('amplified', 'Var', (132, 141))	('syntenic canine', 'Phenotype', 'HP:0012738', (66, 81))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('PDGFRA', 'Gene', (116, 122))	('human', 'Species', '9606', (50, 55))	('MYC', 'Gene', (127, 130))
169867	32049048	The ACVR1 and the HIST1 genes are frequently mutated in pediatric high-grade gliomas and in particular H3.1K27M diffuse intrinsic pontine glioma.	('glioma', 'Disease', (138, 144))	('gliomas', 'Disease', (77, 84))	('ACVR1', 'Gene', '478757', (4, 9))	('ACVR1', 'Gene', (4, 9))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('HIST1', 'Gene', (18, 23))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('H3.1K27M', 'Var', (103, 111))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
169868	32049048	We observed loss of the syntenic human 2q/canine 36q region (containing ACVR1) within 37%, 28%, and 17% of canine, pediatric H3 wild-type, and H3-mutant gliomas, respectively.	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('loss', 'NegReg', (12, 16))	('human', 'Species', '9606', (33, 38))	('ACVR1', 'Gene', (72, 77))	('ACVR1', 'Gene', '478757', (72, 77))	('canine', 'Species', '9615', (42, 48))	('H3-mutant', 'Var', (143, 152))	('canine', 'Species', '9615', (107, 113))
169870	32049048	Similarly, human chromosome arm 6p/canine chromosome arm 35q, containing the HIST1 gene cluster, was frequently amplified in canine gliomas (70%) and pediatric H3 wild-type (50%) and H3-mutant gliomas (13%) but not in pediatric low-grade or adult gliomas (<5%).	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('canine', 'Species', '9615', (35, 41))	('adult gliomas', 'Disease', (241, 254))	('gliomas', 'Disease', (193, 200))	('gliomas', 'Disease', (132, 139))	('human', 'Species', '9606', (11, 16))	('H3-mutant', 'Var', (183, 192))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('adult gliomas', 'Disease', 'MESH:D005910', (241, 254))	('gliomas', 'Disease', (247, 254))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('gliomas', 'Disease', 'MESH:D005910', (247, 254))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))	('canine', 'Species', '9615', (125, 131))
169872	32049048	Shannon entropy value correlated with the proportion of variants per subclone and the total number of subclones in a tumor sample, i.e., values near zero indicated lower intratumoral diversity (homogeneity or a dominant clone), while values closer to 1 or higher were associated with increased diversity and tumors consisting of more than one subclone.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('lower', 'NegReg', (164, 169))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('variants', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('Shannon entropy value', 'MPA', (0, 21))	('tumor', 'Disease', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumors', 'Disease', (308, 314))
169875	32049048	In contrast, canine gliomas had significantly higher heterogeneity over H3 wild-type (p value 0.002) and H3-mutant (p value 0.007) pediatric gliomas (Figure S2D).	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('heterogeneity', 'MPA', (53, 66))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('higher', 'PosReg', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))	('H3-mutant', 'Var', (105, 114))	('canine', 'Species', '9615', (13, 19))	('gliomas', 'Disease', (141, 148))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
169876	32049048	To better understand the potential functional versus non-functional nature of intratumor heterogeneity, we asked whether frequent driver mutations found in canine gliomas (Figure 1A) are part of major (dominant) versus minor clone, and how these driver events compare with measured heterogeneity across molecular subtypes in human pediatric and adult gliomas.	('gliomas', 'Disease', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('gliomas', 'Disease', (351, 358))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('gliomas', 'Disease', 'MESH:D005910', (351, 358))	('tumor', 'Disease', (83, 88))	('gliomas', 'Phenotype', 'HP:0009733', (351, 358))	('canine', 'Species', '9615', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (351, 357))	('adult gliomas', 'Disease', (345, 358))	('mutations', 'Var', (137, 146))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('adult gliomas', 'Disease', 'MESH:D005910', (345, 358))	('human', 'Species', '9606', (325, 330))
169877	32049048	We observed that among less heterogeneous tumor samples (Shannon entropy near 0), shared driver events across canine and adult gliomas are part of major clones, including PIK3CA mutations in canine gliomas, IDH1/2 mutations in IDH-mutant adult gliomas, and EGFR somatic mutations in adult IDH wild-type GBM (Figure 2D).	('IDH1/2', 'Gene', (207, 213))	('PIK3CA', 'Gene', (171, 177))	('EGFR', 'Gene', (257, 261))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('IDH', 'Gene', '3417', (227, 230))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('IDH', 'Gene', '3417', (289, 292))	('IDH', 'Gene', (207, 210))	('mutations', 'Var', (178, 187))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))	('tumor', 'Disease', (42, 47))	('adult gliomas', 'Disease', (121, 134))	('mutations', 'Var', (214, 223))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('IDH', 'Gene', '3417', (207, 210))	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('canine', 'Species', '9615', (191, 197))	('adult gliomas', 'Disease', (238, 251))	('adult gliomas', 'Disease', 'MESH:D005910', (121, 134))	('gliomas', 'Disease', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IDH1/2', 'Gene', '478889;479043', (207, 213))	('canine', 'Species', '9615', (110, 116))	('IDH', 'Gene', (227, 230))	('IDH', 'Gene', (289, 292))	('gliomas', 'Disease', (198, 205))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('gliomas', 'Disease', (244, 251))	('adult gliomas', 'Disease', 'MESH:D005910', (238, 251))
169878	32049048	Among tumor samples with increased heterogeneity, we found mutations in PDGFRA in canine gliomas (n = 7/60) and H3 wild-type pediatric gliomas (n = 2/14), whereas mutations in TP53 (n = 9/20) and PTEN (3/20) were seen among IDH wild-type and IDHmut-noncodel patients.	('IDH', 'Gene', (224, 227))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('IDH', 'Gene', '3417', (224, 227))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (89, 96))	('canine', 'Species', '9615', (82, 88))	('patients', 'Species', '9606', (258, 266))	('IDH', 'Gene', (242, 245))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', (6, 11))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('PDGFRA', 'Gene', (72, 78))	('gliomas', 'Disease', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('IDH', 'Gene', '3417', (242, 245))
169883	32049048	Among the nine canine gliomas with the highest mutation rates (median coding mutation rate of 0.55 per megabase) (Figure 3A), there was significant (Wilcoxon p value 0.025) enrichment of two additional mismatch repair signatures (pediatric signature T9 or COSMIC signature 6, 15) (Figure S3B).	('gliomas', 'Disease', (22, 29))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('canine', 'Species', '9615', (15, 21))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('pediatric signature T9', 'Var', (230, 252))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('COSMIC signature', 'Var', (256, 272))
169884	32049048	A frameshift indel in mismatch repair gene MSH6 was detected in one case with an outlier mutation frequency (coding mutation rate of 5.04 per MB) (Figure S3C).	('MSH6', 'Gene', (43, 47))	('MSH6', 'Gene', '474585', (43, 47))	('frameshift indel', 'Var', (2, 18))
169885	32049048	Among the remaining cases (median coding mutation rate of 0.25 per MB), homologous repair defect or "BRCAness" signatures (COSMIC signature 3 or pediatric signature T3, COSMIC signature 8 or pediatric signature T6) were the second most prominent signatures after clock-like signatures (COSMIC signature 1, 5).	('homologous repair defect', 'CPA', (72, 96))	('COSMIC signature', 'Var', (169, 185))	('BRCAness', 'Disease', 'None', (101, 109))	('BRCAness', 'Disease', (101, 109))
169886	32049048	Homologous repair defect signatures have been reported to be enriched in pediatric high-grade gliomas with higher genomic instability.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('defect', 'Var', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
169889	32049048	Next, we determined the relative contribution of mutational processes (with deconvoluted human signatures as a proxy) in generating mutations within significantly mutated genes, thus to identify the dominant mutational process(es) active during tumor evolution (Figure 3C).	('human', 'Species', '9606', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', (245, 250))
169890	32049048	Although clock-like processes (COSMIC signature 1, 5) largely contributed to an age-related increase in mutations, including in driver genes, we found that homologous repair defect signatures (COSMIC signature 3, 8) contributed (26%, 21/81 cases) to driver mutations across all three cohorts, emphasizing that homologous repair defect can not only serve as a potential source for driver mutations but also fuel progressive genomic instability along with observed high aneuploidy in high-grade gliomas across all three cohorts.	('genomic instability', 'CPA', (423, 442))	('aneuploidy', 'Disease', (468, 478))	('gliomas', 'Disease', (493, 500))	('gliomas', 'Disease', 'MESH:D005910', (493, 500))	('aneuploidy', 'Disease', 'MESH:D000782', (468, 478))	('gliomas', 'Phenotype', 'HP:0009733', (493, 500))	('mutations', 'Var', (387, 396))	('glioma', 'Phenotype', 'HP:0009733', (493, 499))
169892	32049048	In brief, significantly mutated genes were timed as occurring early (clonal) to late (subclonal) during tumor evolution based on their cancer cell fraction after accounting for tumor purity, ploidy, and copy-number status (STAR Methods).	('mutated', 'Var', (24, 31))	('cancer', 'Disease', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
169893	32049048	Subsequent whole chromosome 13 amplification bearing the PDGFRA mutant allele marked the emergence of the most recent common ancestor in six canine gliomas (Figure S3E), which grew to be a dominant clone at the time of diagnosis.	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('PDGFRA', 'Gene', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('mutant', 'Var', (64, 70))	('canine', 'Species', '9615', (141, 147))
169894	32049048	IDH1 mutation marks an initiating event in IDH-mutant human gliomas.	('human', 'Species', '9606', (54, 59))	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('IDH', 'Gene', (43, 46))	('mutation', 'Var', (5, 13))
169895	32049048	Correspondingly, IDH1 mutations were ubiquitously timed as an initiating event (cancer cell fraction [CCF] > 0.9) in three canine and three human adult IDH1 mutant cases, and as an early event in one case of pediatric glioma (CCF = 0.83).	('IDH1', 'Gene', (152, 156))	('human', 'Species', '9606', (140, 145))	('mutant', 'Var', (157, 163))	('glioma', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('IDH1', 'Gene', (17, 21))	('canine', 'Species', '9615', (123, 129))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('cancer', 'Disease', (80, 86))
169896	32049048	We observed NF1 frameshift mutations mostly as a late event across all cohorts, whereas PIK3CA mutations appeared as an early event for canine and human pediatric gliomas.	('gliomas', 'Disease', (163, 170))	('NF1', 'Gene', (12, 15))	('human', 'Species', '9606', (147, 152))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('NF1', 'Gene', '480618', (12, 15))	('frameshift mutations', 'Var', (16, 36))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('canine', 'Species', '9615', (136, 142))
169897	32049048	Although the relatively uniform timing patterns of these known glioma drivers suggest convergent evolution in varied contexts, i.e., presence of hotspot mutations in shared drivers (PDGFRA, PIK3CA) during clonal evolution of glioma across two species and different age groups, we also observed an oscillating pattern of timing and consequent underlying natural selection for a set of epigenetic drivers in the lysine methyltransferase (MLL) family.	('PDGFRA', 'Gene', (182, 188))	('mutations', 'Var', (153, 162))	('MLL', 'Gene', (436, 439))	('glioma', 'Disease', (225, 231))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('lysine', 'Chemical', 'MESH:D008239', (410, 416))	('PIK3CA', 'Gene', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('oscillating pattern', 'Phenotype', 'HP:0032104', (297, 316))	('MLL', 'Gene', '479417', (436, 439))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('glioma', 'Disease', (63, 69))
169898	32049048	MLL3 (KMT2C) gene mutations were clonal events in canine and pediatric gliomas but subclonal in adult gliomas, whereas ARID5B mutations showed the inverse pattern (Figure 3D).	('ARID5B', 'Gene', '479217', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('adult gliomas', 'Disease', (96, 109))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('canine', 'Species', '9615', (50, 56))	('ARID5B', 'Gene', (119, 125))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('MLL3', 'Gene', (0, 4))	('KMT2C', 'Gene', (6, 11))	('MLL3', 'Gene', '611094', (0, 4))	('adult gliomas', 'Disease', 'MESH:D005910', (96, 109))	('gliomas', 'Disease', (102, 109))	('KMT2C', 'Gene', '611094', (6, 11))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('mutations', 'Var', (18, 27))
169900	32049048	We hypothesized that epigenetic deregulation in canine gliomas may carry a tumor-specific methylation pattern reflecting underlying tumor pathology, as has been observed across human brain tumors.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('tumor', 'Disease', (132, 137))	('human', 'Species', '9606', (177, 182))	('brain tumors', 'Phenotype', 'HP:0030692', (183, 195))	('brain tumors', 'Disease', 'MESH:D001932', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (75, 80))	('methylation pattern', 'MPA', (90, 109))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('brain tumor', 'Phenotype', 'HP:0030692', (183, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('epigenetic deregulation', 'Var', (21, 44))	('canine', 'Species', '9615', (48, 54))	('brain tumors', 'Disease', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (189, 194))	('gliomas', 'Disease', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
169905	32049048	Of the three samples carrying an IDH1 R132 mutation, one was classified as IDH-mutant adult glioma, with a classification probability of 99%, while a second IDH-mutant sample had a relatively high classification probability for IDH-mutant adult glioma (40%), in parallel with a 57% pediatric glioma classification probability.	('glioma', 'Phenotype', 'HP:0009733', (292, 298))	('adult glioma', 'Disease', 'MESH:D005910', (86, 98))	('IDH', 'Gene', (33, 36))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('mutation', 'Var', (43, 51))	('IDH', 'Gene', (228, 231))	('IDH', 'Gene', '3417', (33, 36))	('IDH', 'Gene', (157, 160))	('adult glioma', 'Disease', (239, 251))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (228, 231))	('glioma', 'Disease', (292, 298))	('adult glioma', 'Disease', 'MESH:D005910', (239, 251))	('IDH', 'Gene', '3417', (157, 160))	('glioma', 'Disease', 'MESH:D005910', (292, 298))	('glioma', 'Disease', (245, 251))	('glioma', 'Disease', (92, 98))	('IDH', 'Gene', '3417', (75, 78))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('adult glioma', 'Disease', (86, 98))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
169924	32049048	First, convergent evolution of gliomas is observed across canine, human pediatric, and human adult gliomas, with shared molecular traits such as shared hotspot and mutually exclusive mutations in PDGFRA and PIK3CA, and in genes associated with the p53 and cell-cycle pathways, among others.	('PDGFRA', 'Gene', (196, 202))	('mutations', 'Var', (183, 192))	('p53', 'Gene', (248, 251))	('p53', 'Gene', '7157', (248, 251))	('human', 'Species', '9606', (87, 92))	('adult gliomas', 'Disease', (93, 106))	('human', 'Species', '9606', (66, 71))	('gliomas', 'Disease', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('adult gliomas', 'Disease', 'MESH:D005910', (93, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('PIK3CA', 'Gene', (207, 213))	('canine', 'Species', '9615', (58, 64))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
169926	32049048	Also, DNA damagerelated mutational processes such as homologous recombination defects constitute a major source for progressive genomic instability, and generate somatic variations upon which natural selection acts to produce shared molecular and histopathological features of glioma.	('glioma', 'Phenotype', 'HP:0009733', (277, 283))	('glioma', 'Disease', (277, 283))	('glioma', 'Disease', 'MESH:D005910', (277, 283))	('defects', 'Var', (78, 85))
169934	32049048	Accordingly, cancer is largely a disease of old age except in cases with early exposures to mutagens, e.g., germline or acquired defects in one or more hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (13, 19))	('germline', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
169969	32049048	Final, analysis-ready bam file per sample - tumor and normal bam, if available - was created by series of steps following best practices guidelines from GATK4 (version 4.0.8.1), namely MarkDuplicates, Indel Realignment, and Base Quality Score Recalibration (BQSR).	('MarkDuplicates', 'Var', (185, 199))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Indel Realignment', 'Var', (201, 218))	('tumor', 'Disease', (44, 49))
169986	32049048	LoFreq paired mode was run using command: somatic and arguments: -threads 4 -call-indels -min-cov 7 -verbose and tumor-only mode was run using command: call and arguments: -call-indels -sig 0.05 -min-cov 7 -verbose -s. Resulting raw somatic calls - single nucleotide variants (SNV) and small insertions and/or deletions (Indels) - from three callers were then subject to filtering based on caller-specific filters and hard filters.	('tumor', 'Disease', (113, 118))	('cov', 'Species', '11118', (94, 97))	('single nucleotide variants', 'Var', (249, 275))	('cov', 'Species', '11118', (200, 203))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('deletions', 'Var', (310, 319))
170001	32049048	Segmented copy number calls were used to generate Integrated Genome Viewer (IGV) copy-number plots and GISTIC2 (version 2.0.22) based somatic copy number significance, including calling gene-level deep deletions, loss-of-heterozygosity (LOH), and amplifications (Figure 2A) as well as inferring aneuploidy metrics (Figures 2B and 2C).	('aneuploidy', 'Disease', 'MESH:D000782', (295, 305))	('amplifications', 'Var', (247, 261))	('deep deletions', 'Var', (197, 211))	('aneuploidy', 'Disease', (295, 305))	('loss-of-heterozygosity', 'NegReg', (213, 235))
170029	32049048	The methylation categories designated as regression outcome variables were derived from the World Health Organization classification of gliomas: IDH-wild-type adult glioma, IDH-mutant, 1p/19q-intact adult glioma, IDH-mutant, 1p/19q-codeleted adult glioma, adult normal control, pediatric glioma, and pediatric normal control.	('adult glioma', 'Disease', (242, 254))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('IDH', 'Gene', '3417', (145, 148))	('adult glioma', 'Disease', 'MESH:D005910', (242, 254))	('IDH', 'Gene', (213, 216))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('IDH', 'Gene', (173, 176))	('1p/19q-codeleted', 'Var', (225, 241))	('gliomas', 'Disease', (136, 143))	('glioma', 'Disease', (288, 294))	('glioma', 'Disease', (136, 142))	('adult glioma', 'Disease', (159, 171))	('IDH', 'Gene', '3417', (213, 216))	('glioma', 'Disease', 'MESH:D005910', (288, 294))	('glioma', 'Disease', (248, 254))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('adult glioma', 'Disease', 'MESH:D005910', (159, 171))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('IDH', 'Gene', '3417', (173, 176))	('adult glioma', 'Disease', (199, 211))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (288, 294))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('adult glioma', 'Disease', 'MESH:D005910', (199, 211))	('IDH', 'Gene', (145, 148))	('glioma', 'Disease', (205, 211))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('glioma', 'Disease', (165, 171))
170045	32049048	Processed RNA-seq expression matrices from canine (n=40; 25 HGG, 14 LGG, 1 unknown grade), adult (n=703; 529 LGG, 174 GBM), and pediatric glioma (n=92; 42 LGG, 50 HGG) were each run as separate jobs into the CIBERSORT webserver (https://cibersort.stanford.edu) and processed in relative mode using the following parameters: Signature Genes: LM22 CIBERSORT default, Permutations run: 100, Quantile normalization disabled.	('LM22', 'Var', (341, 345))	('glioma', 'Disease', (138, 144))	('canine', 'Species', '9615', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('LM22', 'CellLine', 'CVCL:5998', (341, 345))
170064	24172591	PET has been used for evaluation of glioma metabolism, and the most popular radiolabeled tracers are 18F-fluorodeoxyglucose (FDG), 18F-fluorothymidine (FLT), and 11C-methionine (MET).	('MET', 'Chemical', '-', (178, 181))	('18F-fluorothymidine', 'Chemical', '-', (131, 150))	('FDG', 'Chemical', 'MESH:D019788', (125, 128))	('FLT', 'Chemical', '-', (152, 155))	('glioma metabolism', 'Disease', (36, 53))	('11C-methionine', 'Var', (162, 176))	('18F-fluorothymidine', 'Var', (131, 150))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('glioma metabolism', 'Disease', 'MESH:D005910', (36, 53))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (101, 123))	('11C-methionine', 'Chemical', '-', (162, 176))
170178	24309609	This double-stranded RNA molecule directly suppresses tumor cell proliferation, and this is hypothesized to partly derive from interferon induction, while the overall antitumor effect also stems from immune enhancement.	('double-stranded', 'Var', (5, 20))	('suppresses', 'NegReg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
170179	24309609	Poly-ICLC may activate/amplify the antibody response to antigen, and thus potentiate the activation of natural killer cells, T cells, macrophages, and cytokines.	('T cells', 'CPA', (125, 132))	('antibody response to antigen', 'MPA', (35, 63))	('potentiate', 'PosReg', (74, 84))	('Poly-ICLC', 'Var', (0, 9))	('natural killer cells', 'CPA', (103, 123))	('Poly-ICLC', 'Chemical', 'MESH:C019531', (0, 9))	('activation', 'PosReg', (89, 99))	('activate/amplify', 'PosReg', (14, 30))
170189	24309609	Other adult trials with recurrent and newly diagnosed glioblastoma found that poly-ICLC was well tolerated as a single agent and in combination, but did not improve progression-free survival.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('poly-ICLC', 'Var', (78, 87))	('poly-ICLC', 'Chemical', '-', (78, 87))	('glioblastoma', 'Disease', (54, 66))
170192	24309609	In this context, the key findings were the low systemic toxicity of poly-ICLC and the induction of stable disease in 4 of 9 LGG patients for over 18 months, with an additional patient stable for 6 months.	('poly-ICLC', 'Chemical', '-', (68, 77))	('toxicity', 'Disease', 'MESH:D064420', (56, 64))	('patient', 'Species', '9606', (128, 135))	('patient', 'Species', '9606', (176, 183))	('toxicity', 'Disease', (56, 64))	('poly-ICLC', 'Var', (68, 77))	('patients', 'Species', '9606', (128, 136))
170199	24309609	Patients were also required to have adequate bone marrow function at study entry, defined as ANC >= 1000/mm3, platelets >=75,000/muL (transfusion independent), and hemoglobin >8.0 gm/dL (may receive PRBC transfusions).	('muL', 'Gene', (129, 132))	('Patients', 'Species', '9606', (0, 8))	('>8.0', 'Var', (175, 179))	('muL', 'Gene', '4591', (129, 132))	('bone marrow function', 'CPA', (45, 65))
170207	24309609	In multiple previous reports it was shown that poly-ICLC induced greater activation of natural killer cells at 10 mcg/kg as compared with higher doses, and the most active biological dose of 20 mcg/kg was established in adult trials.	('activation', 'PosReg', (73, 83))	('poly-ICLC', 'Chemical', '-', (47, 56))	('natural killer cells', 'CPA', (87, 107))	('poly-ICLC', 'Var', (47, 56))
170293	24309609	This report describes the results of the first prospective pediatric trials of poly-ICLC to assess its toxicity and activity for the treatment of brain tumors.	('poly-ICLC', 'Var', (79, 88))	('brain tumors', 'Disease', (146, 158))	('brain tumor', 'Phenotype', 'HP:0030692', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('poly-ICLC', 'Chemical', '-', (79, 88))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))	('toxicity', 'Disease', (103, 111))	('brain tumors', 'Phenotype', 'HP:0030692', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('brain tumors', 'Disease', 'MESH:D001932', (146, 158))
170298	24309609	Our pediatric data confirm that there is little concern about the safety of poly-ICLC, and in general it is much better tolerated than standard treatments for pediatric brain tumors.	('brain tumors', 'Phenotype', 'HP:0030692', (169, 181))	('brain tumor', 'Phenotype', 'HP:0030692', (169, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (159, 181))	('poly-ICLC', 'Var', (76, 85))	('pediatric brain tumors', 'Disease', (159, 181))	('poly-ICLC', 'Chemical', '-', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
170308	24309609	One trial with 97 patients found that poly-ICLC may improve the efficacy of chemoradiation and adjuvant TMZ in newly diagnosed glioblastoma, whereas another in 38 adults suggested a possible beneficial effect of poly-ICLC with newly diagnosed and recurrent glioblastoma multiforme and anaplastic astrocytoma.	('poly-ICLC', 'Var', (38, 47))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (257, 280))	('poly-ICLC', 'Chemical', '-', (212, 221))	('anaplastic astrocytoma', 'Disease', (285, 307))	('glioblastoma', 'Disease', (127, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (127, 139))	('glioblastoma', 'Disease', (257, 269))	('glioblastoma', 'Disease', 'MESH:D005909', (257, 269))	('poly-ICLC', 'Chemical', '-', (38, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('astrocytoma', 'Phenotype', 'HP:0009592', (296, 307))	('improve', 'PosReg', (52, 59))	('glioblastoma multiforme', 'Disease', (257, 280))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (285, 307))	('patients', 'Species', '9606', (18, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (257, 269))	('TMZ', 'Chemical', 'MESH:D000077204', (104, 107))
170319	24309609	Recent whole-genome sequencing of pediatric LGG may provide a further frame work for the identification of informative biomarkers, such as identification of the truncating rearrangements in the MYBL1 transcription factor.	('MYBL1', 'Gene', (194, 199))	('truncating rearrangements', 'Var', (161, 186))	('MYBL1', 'Gene', '4603', (194, 199))
170476	22362370	Furthermore, dominant temporal lobe resections have been correlated with verbal memory decline in a subset of patients, whereas non-dominant temporal lobe resections were correlated with visuospatial memory decline.	('visuospatial memory decline', 'Disease', 'MESH:D008569', (187, 214))	('memory decline', 'Phenotype', 'HP:0002354', (200, 214))	('resections', 'Var', (36, 46))	('memory decline', 'Phenotype', 'HP:0002354', (80, 94))	('visuospatial memory decline', 'Disease', (187, 214))	('verbal memory decline', 'Disease', (73, 94))	('verbal memory decline', 'Disease', 'MESH:D008569', (73, 94))	('patients', 'Species', '9606', (110, 118))
170481	22362370	Long-term improvement of verbal memory compared to preoperative assessment has been reported after low-grade glioma resections in frontal premotor and anterior temporal areas, usually after a transient immediate postoperative worsening.	('improvement', 'PosReg', (10, 21))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('resections', 'Var', (116, 126))	('verbal memory', 'CPA', (25, 38))	('glioma', 'Disease', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
170482	22362370	Additionally, regardless the precise tumor location, patients with low-grade gliomas in the right hemisphere run a lower risk of developing cognitive deficits after surgery.	('cognitive deficits', 'Disease', 'MESH:D003072', (140, 158))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('patients', 'Species', '9606', (53, 61))	('gliomas', 'Disease', (77, 84))	('cognitive deficits', 'Phenotype', 'HP:0100543', (140, 158))	('cognitive deficits', 'Disease', (140, 158))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('low-grade', 'Var', (67, 76))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
170490	22362370	For instance, some patients demonstrated minor deterioration in attention after resection of parenchymal frontal or precentral tumors and resection of the right prefrontal cortex rather than the left was associated with a selective attentional impairment in Stroop test performance.	('selective attentional impairment', 'Phenotype', 'HP:0000736', (222, 254))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('resection', 'Var', (138, 147))	('patients', 'Species', '9606', (19, 27))	('impairment', 'NegReg', (244, 254))	('tumors', 'Disease', (127, 133))	('Stroop test performance', 'MPA', (258, 281))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('deterioration', 'NegReg', (47, 60))	('attention', 'MPA', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('deterioration in attention', 'Phenotype', 'HP:0000736', (47, 73))	('attentional impairment', 'Phenotype', 'HP:0007018', (232, 254))
170493	22362370	Furthermore, severe executive deficits in a reward learning task were observed in patients after bilateral fronto-orbital resections for various tumor types and impaired virtual planning of real life activities after resections in the left and right prefrontal cortex, which could not be explained by memory deficits.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('resections', 'Var', (122, 132))	('memory deficits', 'Phenotype', 'HP:0002354', (301, 316))	('executive', 'MPA', (20, 29))	('memory deficits', 'Disease', (301, 316))	('virtual planning of real life activities', 'CPA', (170, 210))	('tumor', 'Disease', (145, 150))	('memory deficits', 'Disease', 'MESH:D008569', (301, 316))	('severe executive deficits', 'Phenotype', 'HP:0010864', (13, 38))	('impaired', 'NegReg', (161, 169))	('observed', 'Reg', (70, 78))
170508	22362370	While short-term follow-up studies show limited or transient effects of radiotherapy, a number of studies in long-term survivors of low-grade glioma (i.e., more than 5 years following radiotherapy) concluded that radiotherapy in these patients poses a significant risk of long-term leukoencephalopathy and cognitive impairment.	('cognitive impairment', 'Disease', 'MESH:D003072', (306, 326))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (282, 301))	('glioma', 'Disease', (142, 148))	('patients', 'Species', '9606', (235, 243))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (282, 301))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('cognitive impairment', 'Phenotype', 'HP:0100543', (306, 326))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('encephalopathy', 'Phenotype', 'HP:0001298', (287, 301))	('cognitive impairment', 'Disease', (306, 326))	('radiotherapy', 'Var', (213, 225))	('leukoencephalopathy', 'Disease', (282, 301))
170525	22362370	The classical AEDs (phenytoin, carbamazepine, and valproic acid) are known to decrease cognitive functioning.	('decrease', 'NegReg', (78, 86))	('carbamazepine', 'Chemical', 'MESH:D002220', (31, 44))	('phenytoin', 'Chemical', 'MESH:D010672', (20, 29))	('cognitive functioning', 'CPA', (87, 108))	('valproic acid', 'Var', (50, 63))	('valproic acid', 'Chemical', 'MESH:D014635', (50, 63))
170529	22362370	Moreover, AED use in low-grade glioma patients may be associated with highly elevated levels of fatigue, which in itself is also associated with poorer cognitive outcome.	('associated', 'Reg', (129, 139))	('fatigue', 'Disease', (96, 103))	('fatigue', 'Phenotype', 'HP:0012378', (96, 103))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('AED', 'Var', (10, 13))	('elevated', 'PosReg', (77, 85))	('patients', 'Species', '9606', (38, 46))	('glioma', 'Disease', (31, 37))	('fatigue', 'Disease', 'MESH:D005221', (96, 103))
170548	22362370	The potentially neurotoxic effects of corticosteroids are often misdiagnosed and underestimated and corticosteroids may induce behavioral, psychic, and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas.	('induce', 'Reg', (120, 126))	('neurotoxic', 'Disease', (16, 26))	('steroids', 'Chemical', 'MESH:D013256', (45, 53))	('psychic', 'CPA', (139, 146))	('behavioral', 'CPA', (127, 137))	('cognitive disturbances', 'Disease', 'MESH:D003072', (152, 174))	('steroids', 'Chemical', 'MESH:D013256', (107, 115))	('cognitive disturbances', 'Phenotype', 'HP:0100543', (152, 174))	('cognitive disturbances', 'Disease', (152, 174))	('corticosteroids', 'Var', (100, 115))	('neurotoxic', 'Disease', 'MESH:D020258', (16, 26))
170549	22362370	Corticosteroids may cause mood disturbances, psychosis, and cognitive deficits particularly in declarative memory performance.	('mood disturbances', 'Disease', (26, 43))	('mood disturbances', 'Disease', 'MESH:D019964', (26, 43))	('Corticosteroids', 'Var', (0, 15))	('psychosis', 'Phenotype', 'HP:0000709', (45, 54))	('psychosis', 'Disease', (45, 54))	('cause', 'Reg', (20, 25))	('steroids', 'Chemical', 'MESH:D013256', (7, 15))	('cognitive deficits', 'Phenotype', 'HP:0100543', (60, 78))	('psychosis', 'Disease', 'MESH:D011605', (45, 54))	('cognitive deficits', 'Disease', (60, 78))	('declarative memory performance', 'CPA', (95, 125))	('cognitive deficits', 'Disease', 'MESH:D003072', (60, 78))	('mood disturbances', 'Phenotype', 'HP:0001575', (26, 43))
170587	31138328	Our results show that ITH is associated with survival time in several cancer types and its effect can be modified by other covariates, such as mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', (70, 76))	('ITH', 'Var', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
170588	31138328	Somatic mutations, including somatic point mutations (SPMs; e.g., single nucleotide variants or indels) and somatic copy number alterations (SCNAs), are the underlying driving force for tumor growth.	('single nucleotide variants', 'Var', (66, 92))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))
170600	31138328	An alternative metric to quantify ITH is mutant-allele tumor heterogeneity (MATH), which is defined as 100xMAD/median, where median is the median of the variant allele frequencies (VAFs) of all somatic point mutations within a sample, and MAD is the median absolute deviation of the VAFs.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('VAF', 'Chemical', '-', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('VAF', 'Chemical', '-', (181, 184))	('mutant-allele', 'Var', (41, 54))
170612	31138328	This assumption implies that tumor evolution is consistent with a "perfect and persistent phylogeny" such that each subclone has only one parental subclone and all mutations of the parental subclone.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (164, 173))
170615	31138328	We obtain SCNA-related information, including tumor purity, ploidy, and allele-specific copy numbers per SPM through ASCAT.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('copy numbers', 'Var', (88, 100))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
170624	31138328	The linear tree is characterized by Q3=(q31,q32,q33), whereas a branching tree is characterized by Q4=(q31,q33,q34).	('ran', 'Gene', '5901', (65, 68))	('q31', 'Var', (103, 106))	('ran', 'Gene', (65, 68))
170667	31138328	On average with 100 mutations, SMASH ran in less than 5 min for ITH inference.	('ran', 'Gene', (37, 40))	('ran', 'Gene', '5901', (37, 40))	('mutations', 'Var', (20, 29))
170673	31138328	Before running PyClone, PhyloWGS, and SMASH, we applied a set of filters to the SPM data by retaining the base substitution SPMs that are located along autosomes and have at least seven reads supporting the alternative allele.	('eta', 'Gene', (93, 96))	('SPMs', 'Gene', (124, 128))	('eta', 'Gene', '1909', (93, 96))	('base substitution', 'Var', (106, 123))
170675	31138328	The relative ordering of tumor types by mutation rate is consistent with the results reported in an earlier study.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
170687	31138328	TP53 mutations have average cellular prevalences near 1.0 for all cancer types except KIRC, which was the same observation made by Morris et al.. IDH1 mutations were subclonal in GBM and clonal in LGG and SKCM.	('IDH1', 'Gene', (146, 150))	('TP53', 'Gene', '7157', (0, 4))	('SKCM', 'Disease', (205, 209))	('TP53', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('LGG', 'Disease', (197, 200))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutations', 'Var', (151, 160))	('cancer', 'Disease', (66, 72))
170709	31138328	Total mutation burden (TMB) was statistically significant for 7 cancer types: BLCA, COAD, GBM, LGG, LUAD, OV, and STAD (Additional file 1: Figure S17).	('LUAD', 'Disease', (100, 104))	('significant', 'Reg', (46, 57))	('mutation burden', 'Var', (6, 21))	('COAD', 'Disease', 'MESH:D029424', (84, 88))	('BLCA', 'Disease', (78, 82))	('GBM', 'Disease', (90, 93))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('STAD', 'Disease', (114, 118))	('LGG', 'Disease', (95, 98))	('COAD', 'Disease', (84, 88))	('TMB', 'Chemical', '-', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
170710	31138328	Significant associations between gene-level mutation status and OS include TP53 for BLCA, GBM, HNSC, LIHC, LUSC and STAD, TTN for GBM and LUSC, and MUC16 for SKCM (Additional file 1: Table S6-S19).	('mutation', 'Var', (44, 52))	('MUC16', 'Gene', (148, 153))	('TTN', 'Gene', (122, 125))	('TTN', 'Gene', '7273', (122, 125))	('MUC16', 'Gene', '94025', (148, 153))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
170714	31138328	Other tumor type-specific covariates associated with OS include PAM50 for BRCA, tumor grade for KIRC, and IDH/CNV status for LGG (Additional file 1: Table S6-S19).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IDH', 'Gene', '3417', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('PAM50', 'Var', (64, 69))	('BRCA', 'Gene', '672', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRCA', 'Gene', (74, 78))	('IDH', 'Gene', (106, 109))	('tumor', 'Disease', (6, 11))
170730	31138328	In most cancer types, when TMB is included in the final model, it is negatively associated with hazard, and thus higher mutation burden leads to longer survival time (Additional file 1: Figure S18).	('survival time', 'MPA', (152, 165))	('cancer', 'Disease', (8, 14))	('mutation burden', 'Var', (120, 135))	('TMB', 'Chemical', '-', (27, 30))	('negatively', 'NegReg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('longer', 'PosReg', (145, 151))	('hazard', 'MPA', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
170737	31138328	In LUSC, we also observed interaction between entropy and TP53 mutation.	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('interaction', 'Interaction', (26, 37))	('mutation', 'Var', (63, 71))
170738	31138328	When TP53 is mutated, higher entropy is associated with longer survival time for both OS and PFS (Additional file 1: Figure S20).	('higher', 'PosReg', (22, 28))	('entropy', 'MPA', (29, 36))	('survival time', 'CPA', (63, 76))	('longer', 'PosReg', (56, 62))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('mutated', 'Var', (13, 20))
170742	31138328	ASCAT Allele-specific copy number analysis of tumors ITH Intra-tumor heterogeneity MATH Mutant-allele tumor heterogeneity SCNA Somatic copy number alterations SMASH Subclone multiplicity allocation and somatic heterogeneity SPMs Somatic point mutations TCGA The Cancer Genome Atlas TMB Tumor mutation burden VAF Variant allele frequencies WS and DYL conceived the study.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (262, 281))	('VAF', 'Chemical', '-', (308, 311))	('TMB', 'Chemical', '-', (282, 285))	('tumors', 'Disease', (46, 52))	('Cancer Genome Atlas', 'Disease', (262, 281))	('tumor', 'Disease', (63, 68))	('WS', 'Disease', 'MESH:D018980', (339, 341))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Cancer', 'Phenotype', 'HP:0002664', (262, 268))	('Variant', 'Var', (312, 319))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
170770	28740446	Jenkinson et al., found that ODs with intact 1p19q were more likely to show an infiltrating growth pattern despite having more sharp edges towards the surrounding brain on T2-weighted MRI.13 Perilesional microscopic tumor infiltration that is not visualized on morphological MRI may give rise to local tumor recurrence also in patients operated with radiologically radical tumor resection.	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', (373, 378))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('intact 1p19q', 'Var', (38, 50))	('tumor', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('1p19q', 'Var', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (373, 378))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('patients', 'Species', '9606', (327, 335))	('give rise to', 'Reg', (283, 295))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
170866	21949549	ABT-737 and/or folate reverse the PDGF-induced alterations in the mitochondrial apoptotic pathway in low-grade glioma patients Elevated activation of the platelet-derived growth factor (PDGF) pathway, apoptosis evasion phenotype, and global DNA hypomethylation are hallmarks frequently observed in cancers, such as in low-grade glioma (LGG).	('glioma', 'Disease', (111, 117))	('mitochondrial apoptotic pathway', 'Pathway', (66, 97))	('glioma', 'Disease', 'MESH:D005910', (328, 334))	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('ABT-737', 'Chemical', 'MESH:C501332', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('PDGF-induced', 'Gene', (34, 46))	('activation', 'PosReg', (136, 146))	('cancers', 'Disease', (298, 305))	('glioma', 'Disease', (328, 334))	('folate', 'Chemical', 'MESH:D005492', (15, 21))	('alterations', 'Var', (47, 58))	('apoptosis evasion phenotype', 'CPA', (201, 228))	('global DNA', 'MPA', (234, 244))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
170868	21949549	Our data also indicate that the apoptosis evasion phenotype of these cells harboring a hypomethylation-induced activation of the PDGF pathway is associated with a hypomethylation of the bcl-xl and bcl-w genes and the phosphorylation and/or downregulation of three major pro-apoptotic BH3-only proteins: PUMA, Bad, and Bim.	('activation', 'PosReg', (111, 121))	('PDGF pathway', 'Pathway', (129, 141))	('apoptosis', 'CPA', (32, 41))	('PUMA', 'Disease', (303, 307))	('Bad', 'Disease', (309, 312))	('Bim', 'Disease', (318, 321))	('hypomethylation-induced', 'Var', (87, 110))	('bcl-w', 'Gene', (197, 202))	('hypomethylation', 'Var', (163, 178))	('phosphorylation', 'Var', (217, 232))	('downregulation', 'NegReg', (240, 254))	('bcl-w', 'Gene', '599', (197, 202))	('bcl-xl', 'Gene', (186, 192))	('BH3', 'Chemical', 'MESH:C006008', (284, 287))	('bcl-xl', 'Gene', '598', (186, 192))
170874	21949549	Thus, the presence of an "apoptosis evasion phenotype" in tumor cells is largely associated with the overexpression of certain anti-apoptotic proteins such as Bcl-2, Bcl-xl, and Bcl-w and/or is frequently correlated with the silencing, a low expression level, mutations, proteosomal degradation, and/or sequestration of certain pro-apoptotic proteins such as Bax, Bim, Bad, HRK, Bik, or Noxa (Martin et al.).	('Bcl-2', 'Gene', '596', (159, 164))	('Bcl-w', 'Gene', '599', (178, 183))	('sequestration', 'MPA', (303, 316))	('Bcl-xl', 'Gene', '598', (166, 172))	('Bim', 'Disease', (364, 367))	('low', 'NegReg', (238, 241))	('Bik', 'Disease', (379, 382))	('tumor', 'Disease', (58, 63))	('overexpression', 'PosReg', (101, 115))	('Bax', 'Gene', (359, 362))	('Bcl-xl', 'Gene', (166, 172))	('Bax', 'Gene', '581', (359, 362))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('silencing', 'MPA', (225, 234))	('Bcl-w', 'Gene', (178, 183))	('proteosomal', 'MPA', (271, 282))	('expression level', 'MPA', (242, 258))	('Bad', 'Disease', (369, 372))	('HRK', 'Disease', (374, 377))	('mutations', 'Var', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Bcl-2', 'Gene', (159, 164))	('correlated', 'Reg', (205, 215))	('associated', 'Reg', (81, 91))
170876	21949549	), (2) Bax deficiency confers a high resistance to apoptosis induction (Cartron et al.	('Bax', 'Gene', '581', (7, 10))	('resistance', 'MPA', (37, 47))	('deficiency', 'Var', (11, 21))	('Bax', 'Gene', (7, 10))
170881	21949549	Several additional small-molecule inhibitors of anti-apoptotic proteins have been described including theaflavins and epigallechatechins, terphenyl derivates, NSC365400 (compound 6), gossypol derivates, GX015-070, and ABT-737 (Enyedy et al.	('theaflavins', 'Chemical', 'MESH:C056068', (102, 113))	('NSC365400', 'Var', (159, 168))	('anti-apoptotic proteins', 'Protein', (48, 71))	('gossypol', 'Chemical', 'MESH:D006072', (183, 191))	('epigallechatechins', 'Chemical', '-', (118, 136))	('ABT-737', 'Chemical', 'MESH:C501332', (218, 225))
170916	21949549	Thus, these observations reinforced and corroborated the relationship underlined above and existing between the low expression level of Bim and the low apoptosis level seen in Ntv-a/PDGF cells because literature reports that the Bim phosphorylation abrogates the pro-apoptotic function of this BH3-only protein via its degradation or via its incapacity to activate Bax (Harada et al.	('Bax', 'Gene', (365, 368))	('BH3', 'Chemical', 'MESH:C006008', (294, 297))	('abrogates', 'NegReg', (249, 258))	('degradation', 'MPA', (319, 330))	('BH3-only protein', 'Protein', (294, 310))	('Bim', 'Var', (229, 232))	('Bax', 'Gene', '581', (365, 368))	('incapacity', 'NegReg', (342, 352))	('phosphorylation', 'Var', (233, 248))	('pro-apoptotic function', 'MPA', (263, 285))
170921	21949549	Based on the DNA-methylating function of folate, we hypothesized that the downregulation of both Bcl-wmRNA and Bcl-xlmRNA observed in Ntv-a/PDGF cells treated with folate could be due to the methylation of the promoters of both bcl-x and bcl-w.	('Bcl-w', 'Gene', (97, 102))	('folate', 'Chemical', 'MESH:D005492', (41, 47))	('downregulation', 'NegReg', (74, 88))	('folate', 'Chemical', 'MESH:D005492', (164, 170))	('Bcl-xl', 'Gene', '598', (111, 117))	('methylation', 'Var', (191, 202))	('bcl-w', 'Gene', (238, 243))	('Bcl-w', 'Gene', '599', (97, 102))	('bcl-w', 'Gene', '599', (238, 243))	('Bcl-xl', 'Gene', (111, 117))
170927	21949549	Under these conditions, the comparison of co-immunoprecipitated proteins from Ntv-a/PDGF cells treated or not with folate or PDGFri revealed that the Ntv-a/PDGF cells were characterized by the strong inhibition of Bax by Bcl-2, Bcl-xl, and Bcl-w, a high antagonism of PUMA and Bim by Bcl-2, Bcl-xl, and Bcl-w, and a low neutralization of Bcl-2, Bcl-xl, and Bcl-w by Bad (Fig.	('Bcl-2', 'Gene', '596', (221, 226))	('Bcl-w', 'Gene', '599', (240, 245))	('Bcl-2', 'Gene', (284, 289))	('Bcl-xl', 'Gene', '598', (228, 234))	('folate', 'Chemical', 'MESH:D005492', (115, 121))	('PDGFr', 'Gene', '5159', (125, 130))	('Bcl-xl', 'Gene', '598', (291, 297))	('Bcl-xl', 'Gene', (228, 234))	('Bcl-2', 'Gene', (338, 343))	('Ntv-a/PDGF', 'Var', (150, 160))	('Bcl-xl', 'Gene', (291, 297))	('Bcl-xl', 'Gene', '598', (345, 351))	('Bcl-2', 'Gene', '596', (284, 289))	('Bcl-w', 'Gene', '599', (303, 308))	('Bcl-xl', 'Gene', (345, 351))	('Bcl-w', 'Gene', (240, 245))	('Bcl-w', 'Gene', '599', (357, 362))	('Bcl-2', 'Gene', '596', (338, 343))	('Bax', 'Gene', (214, 217))	('Bax', 'Gene', '581', (214, 217))	('PDGFr', 'Gene', (125, 130))	('inhibition', 'NegReg', (200, 210))	('Bcl-w', 'Gene', (303, 308))	('Bcl-2', 'Gene', (221, 226))	('Bcl-w', 'Gene', (357, 362))
170933	21949549	), we noted that BadBH3 displaced PUMA and Bim from anti-apoptotic proteins such as Bcl-xl, while PUMABH3 or BimBH3 was unable to displace Bad, Bim, or PUMA from Bcl-xl (Fig.	('BadBH3', 'Var', (17, 23))	('Bcl-xl', 'Gene', (84, 90))	('Bcl-xl', 'Gene', (162, 168))	('BH3', 'Chemical', 'MESH:C006008', (112, 115))	('BH3', 'Chemical', 'MESH:C006008', (102, 105))	('BH3', 'Chemical', 'MESH:C006008', (20, 23))	('Bcl-xl', 'Gene', '598', (162, 168))	('Bcl-xl', 'Gene', '598', (84, 90))
170936	21949549	Our analyses revealed that it was the case because the high levels of pBadS136 and Akt activity were associated with the weak neutralization of the anti-apoptotic proteins by Bad in Ntv-a/PDGF cells, while the inverse situation was observed when these cells were treated with PDGFri, Akt, and strikingly with folate (Fig.	('pBadS136', 'Var', (70, 78))	('activity', 'MPA', (87, 95))	('Akt', 'CPA', (83, 86))	('folate', 'Chemical', 'MESH:D005492', (309, 315))	('neutralization', 'MPA', (126, 140))	('PDGFr', 'Gene', '5159', (276, 281))	('PDGFr', 'Gene', (276, 281))
170937	21949549	Our previous experiments demonstrate that a folate treatment abrogates the PDGF-induced apoptosis evasion phenotype of Ntv-a/PDGF cells by methylating certain genes (bcl-w and bcl-xl), and by reorchestrating the hierarchical interactions of the Bcl-2 family members, we next compared the effect of folate and/or ABT-737 on etoposide-induced apopto-sensibility of primary cultured tumor cells obtained from human LGG (PCTC-LGG).	('tumor', 'Disease', (380, 385))	('PCTC-LGG', 'Chemical', '-', (417, 425))	('folate', 'Chemical', 'MESH:D005492', (44, 50))	('folate', 'Chemical', 'MESH:D005492', (298, 304))	('etoposide', 'Chemical', 'MESH:D005047', (323, 332))	('Bcl-2', 'Gene', (245, 250))	('abrogates', 'NegReg', (61, 70))	('bcl-w', 'Gene', (166, 171))	('bcl-w', 'Gene', '599', (166, 171))	('Bcl-2', 'Gene', '596', (245, 250))	('PDGF-induced', 'Gene', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('human', 'Species', '9606', (406, 411))	('ABT-737', 'Chemical', 'MESH:C501332', (312, 319))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('bcl-xl', 'Gene', (176, 182))	('methylating', 'Var', (139, 150))	('bcl-xl', 'Gene', '598', (176, 182))
170939	21949549	PCTC-LGG used were obtained from tumors characterized by the presence of a high PDGFrbeta activity, a low level of 5-methylcytosine, and a low level of intratumor apoptosis intratumor of a high level, a high level of pBad, and the unmethylation of the bcl-w and bcl-xl genes, i.e., by molecular signatures characterizing the Ntv-a/PDGF cells.	('activity', 'MPA', (90, 98))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (115, 131))	('bcl-xl', 'Gene', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('bcl-w', 'Gene', (252, 257))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('PDGFrbeta', 'Gene', (80, 89))	('bcl-xl', 'Gene', '598', (262, 268))	('tumor', 'Disease', (178, 183))	('PDGFrbeta', 'Gene', '5159', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('unmethylation', 'Var', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('PCTC-LGG', 'Chemical', '-', (0, 8))	('tumors', 'Disease', (33, 39))	('bcl-w', 'Gene', '599', (252, 257))
170942	21949549	Secondly, our data indicated that ABT-737 and folate promoted massive cell death (equal or superior to 60%) in PCTC#LGG-1 when used in association with etoposide.	('ABT-737', 'Chemical', 'MESH:C501332', (34, 41))	('etoposide', 'Chemical', 'MESH:D005047', (152, 161))	('PCTC#', 'Var', (111, 116))	('cell death', 'CPA', (70, 80))	('folate', 'Chemical', 'MESH:D005492', (46, 52))	('ABT-737', 'Gene', (34, 41))
170946	21949549	Lastly, similar experiments done with PCTC#LGG-2 indicated that ABT-737/etoposide was weakly toxic in these cells in comparison with folate/etoposide (18%, 22%, and 67% cell death, p = 0.0016 and p = 0.0017).	('folate', 'Chemical', 'MESH:D005492', (133, 139))	('ABT-737/etoposide', 'Var', (64, 81))	('ABT-737', 'Chemical', 'MESH:C501332', (64, 71))	('etoposide', 'Chemical', 'MESH:D005047', (140, 149))	('cell', 'CPA', (169, 173))	('etoposide', 'Chemical', 'MESH:D005047', (72, 81))
170957	21949549	However, the incorporation of folate into anti-glioma therapy must be supported by other experiments since folate as other epigenetic drugs may have a dual role in cancer prevention or progression because folate supplementation may decrease the risk of common cancers.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('decrease', 'NegReg', (232, 240))	('folate', 'Chemical', 'MESH:D005492', (30, 36))	('folate', 'MPA', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('folate', 'Chemical', 'MESH:D005492', (107, 113))	('glioma', 'Disease', (47, 53))	('cancers', 'Disease', (260, 267))	('cancer', 'Disease', (260, 266))	('supplementation', 'Var', (212, 227))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('folate', 'Chemical', 'MESH:D005492', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
170958	21949549	Besides, numerous reports support this duality suggesting that high folate treatment may be associated with an increase in the risk of colorectal and prostate cancers in a randomized controlled trial and increase risk of breast cancer, while a low dose of folate may protect against colorectal cancer (Stolzenberg-Solomon et al.	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('prostate cancers', 'Phenotype', 'HP:0012125', (150, 166))	('folate', 'Chemical', 'MESH:D005492', (68, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (283, 300))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('colorectal and prostate cancers', 'Disease', 'MESH:D015179', (135, 166))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('colorectal cancer', 'Phenotype', 'HP:0003003', (283, 300))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('high', 'Var', (63, 67))	('breast cancer', 'Disease', (221, 234))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('colorectal cancer', 'Disease', (283, 300))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('folate', 'Chemical', 'MESH:D005492', (256, 262))
170970	21949549	This point is crucial for the future use of ABT-737 in preclinical and/or clinical application because there are reports that ABT-737 can reduce lymphocyte counts and can cause dose-dependent acute thrombocytopenia by reducing the number of circulating platelets, whose turnover is regulated by apoptosis, even if ABT-737 seems to be well tolerated in animal model, or by normal hematopoietic and bone marrow cells (Oltersdorf et al.	('ABT-737', 'Var', (126, 133))	('cause', 'Reg', (171, 176))	('reducing', 'NegReg', (218, 226))	('lymphocyte counts', 'CPA', (145, 162))	('reduce lymphocyte counts', 'Phenotype', 'HP:0001888', (138, 162))	('ABT-737', 'Chemical', 'MESH:C501332', (314, 321))	('acute thrombocytopenia', 'Disease', 'MESH:D013921', (192, 214))	('ABT-737', 'Chemical', 'MESH:C501332', (44, 51))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (198, 214))	('ABT-737', 'Chemical', 'MESH:C501332', (126, 133))	('acute thrombocytopenia', 'Disease', (192, 214))	('reduce', 'NegReg', (138, 144))
170995	31116423	These genomic changes can serve as biomarkers of both response prediction (indicating tumor and patient outcome/response to a specific therapy) and a patient's prognosis (describing innate tumor aggressiveness, which aligns with patient survival regardless of treatment received).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (189, 194))	('patient', 'Species', '9606', (150, 157))	('tumor aggressiveness', 'Disease', (189, 209))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (86, 91))	('patient', 'Species', '9606', (96, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (195, 209))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('changes', 'Var', (14, 21))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (189, 209))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('patient', 'Species', '9606', (229, 236))
171005	31116423	Gene fusions commonly occur in epithelial cancers as a result of genomic rearrangements or abnormal mRNA processing.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Gene fusions', 'Var', (0, 12))	('mRNA processing', 'CPA', (100, 115))	('epithelial cancers', 'Disease', 'MESH:D009369', (31, 49))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('occur', 'Reg', (22, 27))	('epithelial cancers', 'Disease', (31, 49))	('genomic rearrangements', 'CPA', (65, 87))
171007	31116423	NGS is a high-throughput technique that rapidly examines and more broadly detects DNA mutations (often used for circulating tumor DNA), copy number variations (CNVs), and gene fusions (using an RNA sequencing panel) across the genome.	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('copy number variations', 'Var', (136, 158))	('pan', 'Gene', (209, 212))	('gene fusions', 'Var', (171, 183))	('DNA', 'Gene', (82, 85))	('pan', 'Gene', '51816', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
171012	31116423	Any treating physician should know what, when, and how to test and how to make subsequent informed, patient-personalized treatment decisions.4, 5 Correct interpretation of profiling results is critical; many fear that overinterpretation or misinterpretation will lead to treatment of patients with ineffective but expensive therapies, negatively affecting not only patient lives but also the health care budget.	('lead to', 'Reg', (263, 270))	('patients', 'Species', '9606', (284, 292))	('misinterpretation', 'Var', (240, 257))	('patient', 'Species', '9606', (100, 107))	('overinterpretation', 'Var', (218, 236))	('patient', 'Species', '9606', (284, 291))	('patient', 'Species', '9606', (365, 372))
171019	31116423	Microsatellite instability (MSI) is the result of inactivation of the DNA mismatch repair (MMR) system and is characterized by a high frequency of frameshift mutations in microsatellite DNA.	('frameshift mutations', 'Var', (147, 167))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('Microsatellite instability', 'Disease', (0, 26))	('inactivation', 'NegReg', (50, 62))	('microsatellite', 'Gene', (171, 185))	('DNA', 'Pathway', (70, 73))
171020	31116423	In a portion of tumors, MSI is caused by germline mutations in one of the MMR genes (MLH1, MSH2, MSH6, or PMS2), which results in hereditary Lynch syndrome.	('MSH2', 'Gene', '4436', (91, 95))	('PMS2', 'Gene', '5395', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (16, 22))	('MLH1', 'Gene', (85, 89))	('hereditary Lynch syndrome', 'Disease', 'MESH:D061325', (130, 155))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('PMS2', 'Gene', (106, 110))	('MLH1', 'Gene', '4292', (85, 89))	('MMR', 'Gene', (74, 77))	('results in', 'Reg', (119, 129))	('caused by', 'Reg', (31, 40))	('MSH2', 'Gene', (91, 95))	('MSH6', 'Gene', (97, 101))	('hereditary Lynch syndrome', 'Disease', (130, 155))	('MSI', 'Disease', (24, 27))	('germline mutations', 'Var', (41, 59))	('MSH6', 'Gene', '2956', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
171026	31116423	NTRK1, NTRK2, and NTRK3 fusions and the proteins they encode (neurotrophin receptor kinase A [TRKA], TRKB, and TRKC, respectively) are observed at an increased frequency in highly aggressive cancers such as glioblastoma multiforme, and recognition of their potential oncogenic activity led to the use of this fusion family as a predictive biomarker as well as a drug target.25  Larotrectinib is an oral and highly selective TRK inhibitor that was granted accelerated approval by the FDA on November 26, 2018, for the treatment of adult and pediatric patients with metastatic or unresectable solid tumors that have an NTRK fusion without a known acquired resistance mutation (NTRK kinase domain mutations, including solvent front mutations).	('glioblastoma multiforme', 'Disease', (207, 230))	('TRK', 'Gene', '4914', (111, 114))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (207, 230))	('NTRK2', 'Gene', (7, 12))	('TRK', 'Gene', '4914', (101, 104))	('TRK', 'Gene', (424, 427))	('fusion', 'Var', (622, 628))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('TRK', 'Gene', (19, 22))	('cancers', 'Disease', (191, 198))	('NTRK1', 'Gene', '4914', (0, 5))	('TRKB', 'Gene', (101, 105))	('solid tumors', 'Disease', (591, 603))	('TRK', 'Gene', (676, 679))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('TRK', 'Gene', (8, 11))	('NTRK1', 'Gene', (0, 5))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (424, 427))	('TRK', 'Gene', (618, 621))	('TRK', 'Gene', '4914', (19, 22))	('TRKA', 'Gene', '4914', (94, 98))	('TRK', 'Gene', '4914', (676, 679))	('NTRK3', 'Gene', '4916', (18, 23))	('TRK', 'Gene', (94, 97))	('TRK', 'Gene', '4914', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (597, 602))	('NTRK2', 'Gene', '4915', (7, 12))	('TRK', 'Gene', (111, 114))	('patients', 'Species', '9606', (550, 558))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('solid tumors', 'Disease', 'MESH:D009369', (591, 603))	('tumors', 'Phenotype', 'HP:0002664', (597, 603))	('TRKB', 'Gene', '4915', (101, 105))	('TRK', 'Gene', '4914', (1, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (207, 219))	('NTRK3', 'Gene', (18, 23))	('TRK', 'Gene', '4914', (618, 621))	('TRKC', 'Gene', '4916', (111, 115))	('TRKC', 'Gene', (111, 115))	('TRKA', 'Gene', (94, 98))	('TRK', 'Gene', '4914', (94, 97))	('TRK', 'Gene', (101, 104))
171031	31116423	Tumor genetic (somatic) testing detects mutations that may actually be germline alterations, but germline alterations require confirmation in matched normal samples (eg, DNA extracted from white blood cells, buccal swabs, or cultured skin fibroblasts) from the tumor-bearing host.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
171034	31116423	This table indicates the cancer types for which germline testing should be carried out if the specified somatic mutations are found in a patient's tumor profile.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('patient', 'Species', '9606', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (25, 31))
171036	31116423	The first comprises common tumor mutations associated with rare germline alterations.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (33, 42))
171037	31116423	For example, mutations in TP53 are found in greater than 60% of lung cancers.33 Although TP53 mutations can be inherited in the Li-Fraumeni syndrome, such familial syndromes are rare.	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (89, 93))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (128, 148))	('TP53', 'Gene', (89, 93))	('lung cancers', 'Disease', 'MESH:D008175', (64, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancers', 'Phenotype', 'HP:0100526', (64, 76))	('Li-Fraumeni syndrome', 'Disease', (128, 148))	('inherited', 'Reg', (111, 120))	('TP53', 'Gene', '7157', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('lung cancers', 'Disease', (64, 76))
171038	31116423	For example, in colon cancer, dMMR is found by routine MSI or IHC testing in about 12% of tumors.34 Molecular germline testing demonstrates that about one-quarter of these dMMR alterations are inherited.	('alterations', 'Var', (177, 188))	('colon cancer', 'Disease', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('dMMR', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (16, 28))	('colon cancer', 'Disease', 'MESH:D015179', (16, 28))
171042	31116423	With routine molecular genetic tumor testing, BRCA1/BRCA2 mutations are being found in patients with other tumors where it is less expected.	('BRCA2', 'Gene', (52, 57))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('found', 'Reg', (78, 83))	('BRCA1', 'Gene', '672', (46, 51))	('tumors', 'Disease', (107, 113))	('tumor', 'Disease', (31, 36))	('BRCA2', 'Gene', '675', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('BRCA1', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
171043	31116423	An analysis of 100 patients with pancreatic cancer found that 7 had mutations in BRCA2, 4 of which were in the germline.35 Finding BRCA1/BRCA2 mutations in the tumor may aid in choosing therapy but requires germline testing for confirmation and consideration of genetic counseling for the family.	('BRCA2', 'Gene', '675', (137, 142))	('patients', 'Species', '9606', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('aid', 'Reg', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('BRCA2', 'Gene', (137, 142))	('BRCA1', 'Gene', (131, 136))	('pancreatic cancer', 'Disease', (33, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('tumor', 'Disease', (160, 165))	('mutations', 'Var', (143, 152))
171050	31116423	Patients with uncommon mutations of EGFR may also be treated with tyrosine kinase inhibitor therapy.	('EGFR', 'Gene', '1956', (36, 40))	('mutations', 'Var', (23, 32))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', (36, 40))	('tyrosine', 'Chemical', 'None', (66, 74))
171051	31116423	Other recommended markers of interest include EGFR insertion 20 mutations, RET rearrangements, and MET exon 14 mutations.	('mutations', 'Var', (111, 120))	('RET', 'Gene', (75, 78))	('rearrangements', 'Var', (79, 93))	('EGFR', 'Gene', '1956', (46, 50))	('insertion 20 mutations', 'Var', (51, 73))	('RET', 'Gene', '5979', (75, 78))	('mutations', 'Var', (64, 73))	('EGFR', 'Gene', (46, 50))
171056	31116423	Finally, guidelines now recommend universal MSI testing in all stages of CRC to determine whether patients have a germline mutation indicative of Lynch syndrome.41 If both the tumor DNA and the patient's germline DNA harbor an MMR defect, this indicates that the patient has Lynch syndrome.	('patient', 'Species', '9606', (263, 270))	('patient', 'Species', '9606', (194, 201))	('MMR', 'Gene', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('patient', 'Species', '9606', (98, 105))	('Lynch syndrome', 'Disease', 'MESH:D003123', (275, 289))	('Lynch syndrome', 'Disease', (146, 160))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (98, 106))	('Lynch syndrome', 'Disease', 'MESH:D003123', (146, 160))	('defect', 'Var', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('Lynch syndrome', 'Disease', (275, 289))
171061	31116423	Mutations in or overexpression of additional genes that are predictive of outcomes include BRAF, HER2, KRAS, NRAS, NTRK, POLE, PIK3CA, PTEN, and RSP03.	('HER2', 'Gene', (97, 101))	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('overexpression', 'PosReg', (16, 30))	('HER2', 'Gene', '2064', (97, 101))	('BRAF', 'Gene', '673', (91, 95))	('NRAS', 'Gene', (109, 113))	('PTEN', 'Gene', (135, 139))	('PIK3CA', 'Gene', (127, 133))	('TRK', 'Gene', (116, 119))	('BRAF', 'Gene', (91, 95))	('TRK', 'Gene', '4914', (116, 119))	('PTEN', 'Gene', '5728', (135, 139))	('PIK3CA', 'Gene', '5290', (127, 133))	('NRAS', 'Gene', '4893', (109, 113))	('Mutations in', 'Var', (0, 12))	('RSP03', 'Gene', (145, 150))
171065	31116423	BRAF mutational status is used as a strong predictor for overall survival (OS) at all stages of disease; patients with BRAF-mutated CRC have a generally poor prognosis.46, 47, 48, 49, 50, 51, 52 BRAF V600E is the best known mutation assessed using NGS.53 Compared with patients who have CRC with BRAF wild-type tumors, patients whose tumors manifest a BRAF mutation are generally older and more likely to be female.	('tumors', 'Disease', (311, 317))	('BRAF', 'Gene', (296, 300))	('BRAF', 'Gene', '673', (352, 356))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('BRAF', 'Gene', '673', (119, 123))	('V600E', 'Mutation', 'p.V600E', (200, 205))	('BRAF', 'Gene', (352, 356))	('tumors', 'Disease', (334, 340))	('BRAF', 'Gene', (119, 123))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (269, 277))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (357, 365))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('patients', 'Species', '9606', (319, 327))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('BRAF', 'Gene', '673', (296, 300))
171068	31116423	In The Cancer Genome Atlas extended 2017 study carried out by Robertson et al, findings from the complete cohort of 412 muscle-invasive bladder cancer cases revealed that mutations in the DNA repair genes ATM (n = 57; 14%) and ERCC2 (n = 40; 10%), and deletions in RAD51B (n = 10; 2%) were significant.55  It was found that all nonsilent somatic ERCC2 mutations were missense, and many could be mapped within the conserved helicase domain.	('ERCC2', 'Gene', (346, 351))	('ATM', 'Gene', (205, 208))	('RAD51B', 'Gene', (265, 271))	('missense', 'Var', (367, 375))	('RAD51B', 'Gene', '5890', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('invasive bladder', 'Phenotype', 'HP:0100645', (127, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('ERCC2', 'Gene', (227, 232))	('mutations', 'Var', (352, 361))	('muscle-invasive bladder cancer', 'Disease', (120, 150))	('Cancer', 'Disease', (7, 13))	('ERCC2', 'Gene', '2068', (346, 351))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (120, 150))	('ATM', 'Gene', '472', (205, 208))	('Cancer', 'Disease', 'MESH:D009369', (7, 13))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('ERCC2', 'Gene', '2068', (227, 232))
171069	31116423	Dominant negative effects on ERCC2 function were observed.56 Thus, bladder cancer missense mutations in ERCC2 were associated with improved response to cisplatin-based chemotherapy.	('ERCC2', 'Gene', '2068', (104, 109))	('ERCC2', 'Gene', '2068', (29, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('bladder cancer', 'Disease', (67, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('response to cisplatin-based chemotherapy', 'MPA', (140, 180))	('ERCC2', 'Gene', (104, 109))	('missense mutations', 'Var', (82, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('improved', 'PosReg', (131, 139))	('ERCC2', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
171071	31116423	Recently, Li et al reported developing a microscopy-based assay that measures the nucleotide excision repair function of clinically observed ERCC2 mutations.	('ERCC2', 'Gene', (141, 146))	('mutations', 'Var', (147, 156))	('nucleotide excision repair function', 'MPA', (82, 117))	('ERCC2', 'Gene', '2068', (141, 146))
171074	31116423	Current evidence presented here supports the idea that ERCC2 and ATM are potentially useful markers in muscle-invasive bladder cancer.55, 56, 57  It was recently reported that patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline mutations in BRCA1/BRCA2 and ATM have superior clinical outcomes after first-line treatment with abiraterone and enzalutamide (see Table 2.5).58 The authors suggested that this improved response is likely driven by mutations in BRCA1, BRCA2, and ATM.	('ATM', 'Gene', (511, 514))	('muscle-invasive bladder cancer', 'Disease', (103, 133))	('ATM', 'Gene', (65, 68))	('enzalutamide', 'Chemical', 'MESH:C540278', (378, 390))	('ATM', 'Gene', (294, 297))	('BRCA2', 'Gene', (500, 505))	('BRCA1', 'Gene', '672', (493, 498))	('abiraterone', 'Chemical', 'MESH:C089740', (362, 373))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('BRCA1', 'Gene', (493, 498))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('BRCA1', 'Gene', '672', (278, 283))	('BRCA2', 'Gene', (284, 289))	('BRCA1', 'Gene', (278, 283))	('ERCC2', 'Gene', (55, 60))	('invasive bladder', 'Phenotype', 'HP:0100645', (110, 126))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (103, 133))	('ATM', 'Gene', '472', (511, 514))	('prostate cancer', 'Disease', 'MESH:D011471', (222, 237))	('BRCA2', 'Gene', '675', (500, 505))	('ATM', 'Gene', '472', (65, 68))	('patients', 'Species', '9606', (176, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('ERCC2', 'Gene', '2068', (55, 60))	('prostate cancer', 'Disease', (222, 237))	('mutations', 'Var', (480, 489))	('ATM', 'Gene', '472', (294, 297))	('BRCA2', 'Gene', '675', (284, 289))
171076	31116423	A separate, small, retrospective study found that all responders to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy harbored BRCA2 mutations, whereas nonresponders did not.59 However, it was agreed that the functional relevance of mutations in DNA repair genes other than BRCA2 should be considered before committing to PARP inhibitor therapy.	('PARP', 'Gene', (349, 353))	('mutations', 'Var', (160, 169))	('PARP', 'Gene', '142', (121, 125))	('poly(adenosine diphosphate [ADP]-ribose)', 'Chemical', 'MESH:D011064', (68, 108))	('BRCA2', 'Gene', (301, 306))	('BRCA2', 'Gene', (154, 159))	('PARP', 'Gene', '142', (349, 353))	('harbored', 'Reg', (145, 153))	('BRCA2', 'Gene', '675', (301, 306))	('BRCA2', 'Gene', '675', (154, 159))	('PARP', 'Gene', (121, 125))
171079	31116423	Of note, the response rate was numerically higher in patients with somatic BRCA1/BRCA2 or ATM mutations (12%), indicating that these could be predictive markers of response to checkpoint inhibitors.	('BRCA1', 'Gene', (75, 80))	('patients', 'Species', '9606', (53, 61))	('higher', 'PosReg', (43, 49))	('mutations', 'Var', (94, 103))	('ATM', 'Gene', '472', (90, 93))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('response', 'MPA', (13, 21))	('BRCA1', 'Gene', '672', (75, 80))	('ATM', 'Gene', (90, 93))
171083	31116423	Abnormalities in MLH1 should prompt hypermethylation testing, as this can also cause tumors to be MSI-H in the absence of a germline mutation.	('Abnormalities', 'Var', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('MLH1', 'Gene', '4292', (17, 21))	('hype', 'Gene', '11153', (36, 40))	('MLH1', 'Gene', (17, 21))	('hype', 'Gene', (36, 40))	('cause', 'Reg', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
171084	31116423	The detection of a germline mutation affects subsequent screening for colon and ovarian cancer and prompts cascade testing to identify other affected family members.	('germline mutation', 'Var', (19, 36))	('affects', 'Reg', (37, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colon and ovarian cancer', 'Disease', 'MESH:D010051', (70, 94))
171085	31116423	The presence of MSI-H because of either a germline mutation or hypermethylation provides an indication for pembrolizumab in the setting of recurrent uterine cancer, based on site-agnostic FDA approval granted in 2017.13 Women with POLE-aberrant endometrial cancers demonstrate a favorable prognosis and may require less aggressive therapy, although this remains theoretical at present.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('hype', 'Gene', (63, 67))	('uterine cancer', 'Phenotype', 'HP:0010784', (149, 163))	('POLE-aberrant endometrial cancers', 'Disease', (231, 264))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Women', 'Species', '9606', (220, 225))	('hype', 'Gene', '11153', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('POLE-aberrant endometrial cancers', 'Disease', 'MESH:D016889', (231, 264))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('germline mutation', 'Var', (42, 59))	('MSI-H', 'Gene', (16, 21))	('cancer', 'Disease', (257, 263))
171086	31116423	Identification of hotspot mutations in genes such as BRAF, KRAS, PIK3CA, and PTEN may correlate with biological behavior but are not yet targetable.	('KRAS', 'Gene', '3845', (59, 63))	('PIK3CA', 'Gene', '5290', (65, 71))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('PTEN', 'Gene', (77, 81))	('mutations', 'Var', (26, 35))	('PIK3CA', 'Gene', (65, 71))	('PTEN', 'Gene', '5728', (77, 81))	('hotspot', 'PosReg', (18, 25))	('KRAS', 'Gene', (59, 63))
171087	31116423	Phase 2 data demonstrate activity of mTOR inhibitors in endometrioid carcinoma of the uterus, but these trials were not assay-directed to determine whether molecular testing can select for potential activity.64  The presence of pathogenic mutations in BRCA-related genes identify an important subset of high-grade serous epithelial ovarian cancers that have a specific biology, natural history, and susceptibility to platinum and PARP inhibitors.	('ovarian cancer', 'Phenotype', 'HP:0100615', (332, 346))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (56, 78))	('pathogenic', 'Reg', (228, 238))	('mutations', 'Var', (239, 248))	('BRCA', 'Gene', '672', (252, 256))	('mTOR', 'Gene', '2475', (37, 41))	('serous epithelial ovarian cancers', 'Disease', (314, 347))	('endometrioid carcinoma of the uterus', 'Disease', 'MESH:D018269', (56, 92))	('PARP', 'Gene', '142', (430, 434))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('BRCA', 'Gene', (252, 256))	('endometrioid carcinoma of the uterus', 'Disease', (56, 92))	('PARP', 'Gene', (430, 434))	('serous epithelial ovarian cancers', 'Disease', 'MESH:D010051', (314, 347))	('cancers', 'Phenotype', 'HP:0002664', (340, 347))	('platinum', 'Chemical', 'MESH:D010984', (417, 425))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('ovarian cancers', 'Phenotype', 'HP:0100615', (332, 347))	('mTOR', 'Gene', (37, 41))	('presence', 'Var', (216, 224))
171088	31116423	The spectrum of mutations in this category includes those in BRCA1, BRCA2, RAD51C, RAD51D, BARD1, BRIP1, PALB2, MLH1, MSH2, MSH6, PMS2, and STK11 (see Table 2.7).65, 66, 67 Patients with these mutations have an improved prognosis with a higher likelihood of platinum sensitivity and long-term survival.	('BRCA1', 'Gene', (61, 66))	('STK11', 'Gene', (140, 145))	('PMS2', 'Gene', '5395', (130, 134))	('MLH1', 'Gene', '4292', (112, 116))	('PALB2', 'Gene', '79728', (105, 110))	('BRIP1', 'Gene', (98, 103))	('RAD51D', 'Gene', '5892', (83, 89))	('mutations', 'Var', (193, 202))	('higher', 'PosReg', (237, 243))	('long-term survival', 'CPA', (283, 301))	('BRCA2', 'Gene', '675', (68, 73))	('MSH6', 'Gene', (124, 128))	('platinum sensitivity', 'CPA', (258, 278))	('MSH6', 'Gene', '2956', (124, 128))	('STK11', 'Gene', '6794', (140, 145))	('MSH2', 'Gene', (118, 122))	('PMS2', 'Gene', (130, 134))	('RAD51D', 'Gene', (83, 89))	('RAD51C', 'Gene', '5889', (75, 81))	('BRIP1', 'Gene', '83990', (98, 103))	('MSH2', 'Gene', '4436', (118, 122))	('Patients', 'Species', '9606', (173, 181))	('PALB2', 'Gene', (105, 110))	('BARD1', 'Gene', '580', (91, 96))	('MLH1', 'Gene', (112, 116))	('BARD1', 'Gene', (91, 96))	('RAD51C', 'Gene', (75, 81))	('BRCA2', 'Gene', (68, 73))	('BRCA1', 'Gene', '672', (61, 66))	('platinum', 'Chemical', 'MESH:D010984', (258, 266))
171090	31116423	Identification of these mutations directly affects therapy, as patients should be considered for treatment with PARP inhibitors immediately after upfront therapy with platinum and a taxane, based on the improved progression-free survival (PFS) observed in the SOLO-1 trial (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy; ClinicalTrials.gov identifier NCT01844986).68 This international superiority trial showed a 70% reduction in risk of ovarian cancer progression in women with BRCA germline or somatic mutations who received maintenance olaparib after primary therapy with paclitaxel and carboplatin.	('reduction', 'NegReg', (498, 507))	('paclitaxel', 'Chemical', 'MESH:D017239', (656, 666))	('BRCA', 'Gene', '672', (324, 328))	('women', 'Species', '9606', (549, 554))	('ovarian cancer', 'Disease', 'MESH:D010051', (519, 533))	('taxane', 'Chemical', 'MESH:C080625', (182, 188))	('Platinum', 'Chemical', 'MESH:D010984', (373, 381))	('BRCA', 'Gene', (560, 564))	('BRCA', 'Gene', (324, 328))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (337, 351))	('mutations', 'Var', (585, 594))	('ovarian cancer', 'Disease', (519, 533))	('Patients', 'Species', '9606', (310, 318))	('PARP', 'Gene', '142', (112, 116))	('BRCA Mutated Ovarian Cancer', 'Disease', 'MESH:D010051', (324, 351))	('ovarian cancer', 'Phenotype', 'HP:0100615', (519, 533))	('BRCA Mutated Ovarian Cancer', 'Disease', (324, 351))	('PARP', 'Gene', (112, 116))	('patients', 'Species', '9606', (63, 71))	('carboplatin', 'Chemical', 'MESH:D016190', (671, 682))	('Cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancer', 'Phenotype', 'HP:0002664', (527, 533))	('BRCA', 'Gene', '672', (560, 564))
171091	31116423	Conversely, patients without BRCA-related mutations may be better served by antiangiogenic therapy with bevacizumab concurrent with upfront platinum and taxane therapy followed by maintenance bevacizumab therapy (Gynecologic Oncology Group study 0218 [GOG-7]).69, 70  In the recurrent setting, PARP inhibitors (olaparib and rucaparib) as monotherapy were first approved for ovarian cancer patients with BRCA1/BRCA2 mutations or HRD.	('BRCA', 'Gene', '672', (29, 33))	('BRCA', 'Gene', '672', (403, 407))	('BRCA', 'Gene', '672', (409, 413))	('patients', 'Species', '9606', (12, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (374, 388))	('HRD', 'Disease', (428, 431))	('GOG-7', 'Chemical', 'MESH:C520805', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('BRCA', 'Gene', (29, 33))	('BRCA', 'Gene', (403, 407))	('HRD', 'Disease', 'MESH:C537157', (428, 431))	('BRCA', 'Gene', (409, 413))	('PARP', 'Gene', '142', (294, 298))	('BRCA2', 'Gene', (409, 414))	('ovarian cancer', 'Disease', (374, 388))	('patients', 'Species', '9606', (389, 397))	('PARP', 'Gene', (294, 298))	('ovarian cancer', 'Phenotype', 'HP:0100615', (374, 388))	('Oncology', 'Phenotype', 'HP:0002664', (225, 233))	('taxane', 'Chemical', 'MESH:C080625', (153, 159))	('BRCA1', 'Gene', '672', (403, 408))	('platinum', 'Chemical', 'MESH:D010984', (140, 148))	('BRCA1', 'Gene', (403, 408))	('mutations', 'Var', (415, 424))	('BRCA2', 'Gene', '675', (409, 414))
171092	31116423	This indication has now been expanded to include olaparib, rucaparib, and niraparib as switch maintenance therapy for patients with platinum-sensitive ovarian cancer who have responded to platinum in the second-line or third-line setting.65, 66, 67, 71  The identification of BRCA-related gene mutations is also necessary to perform cascade testing on family members to identify affected family members who may be candidates for risk-reducing surgery and surveillance to prevent subsequent ovarian, tubal, peritoneal, and breast cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (522, 535))	('BRCA', 'Gene', (276, 280))	('ovarian', 'Disease', 'MESH:D010049', (151, 158))	('breast cancer', 'Disease', 'MESH:D001943', (522, 535))	('pan', 'Gene', '51816', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', (522, 535))	('niraparib', 'Chemical', 'MESH:C545685', (74, 83))	('ovarian', 'Disease', 'MESH:D010049', (490, 497))	('mutations', 'Var', (294, 303))	('pan', 'Gene', (31, 34))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('platinum', 'Chemical', 'MESH:D010984', (188, 196))	('peritoneal', 'Disease', (506, 516))	('ovarian', 'Disease', (151, 158))	('tubal', 'Disease', (499, 504))	('platinum', 'Chemical', 'MESH:D010984', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (529, 535))	('BRCA', 'Gene', '672', (276, 280))	('ovarian', 'Disease', (490, 497))	('patients', 'Species', '9606', (118, 126))	('ovarian cancer', 'Disease', (151, 165))
171102	31116423	The well-established biomarkers that drive treatment decisions for patients with breast cancers are estrogen receptor (ER) expression, progesterone receptor (PR) expression, and human epidermal growth factor receptor-2 (HER2) overexpression or amplification in the tumor (see Table 2.8).	('human', 'Species', '9606', (178, 183))	('overexpression', 'PosReg', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PR', 'Gene', '5241', (158, 160))	('ER', 'Gene', '2099', (119, 121))	('estrogen receptor', 'Gene', (100, 117))	('tumor', 'Disease', (265, 270))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('ER', 'Gene', '2099', (221, 223))	('HER2', 'Gene', '2064', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('breast cancers', 'Disease', (81, 95))	('patients', 'Species', '9606', (67, 75))	('progesterone receptor', 'Gene', (135, 156))	('progesterone receptor', 'Gene', '5241', (135, 156))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('epidermal growth factor receptor-2', 'Gene', (184, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('epidermal growth factor receptor-2', 'Gene', '2064', (184, 218))	('estrogen receptor', 'Gene', '2099', (100, 117))	('HER2', 'Gene', (220, 224))	('amplification', 'Var', (244, 257))
171106	31116423	Overexpression of AR occurs in a subset of triple-negative breast cancers (TNBC).72 Clinical trials of AR-targeted treatments have shown promising preliminary results in patients with metastatic, AR-positive TNBC.73 Mutations in ESR1 occur in the ligand-binding domain of the ER and can lead to a ligand-independent, constitutively active form of the ER.	('patients', 'Species', '9606', (170, 178))	('AR', 'Gene', '367', (18, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (59, 73))	('ER', 'Gene', '2099', (351, 353))	('lead to', 'Reg', (287, 294))	('ESR1', 'Gene', '2099', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Mutations', 'Var', (216, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('breast cancers', 'Disease', 'MESH:D001943', (59, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('breast cancers', 'Disease', (59, 73))	('ER', 'Gene', '2099', (276, 278))	('ligand-independent', 'MPA', (297, 315))	('AR', 'Gene', '367', (196, 198))	('ESR1', 'Gene', (229, 233))	('AR', 'Gene', '367', (103, 105))
171107	31116423	De novo ESR1 mutations have been most commonly detected during or after treatment with aromatase inhibitors for hormone receptor-positive breast cancer.74 The treatment implication is to consider using selective ER downregulators that target ER directly in the setting of an ESR1 mutation.	('hormone receptor', 'Gene', '3164', (112, 128))	('mutation', 'Var', (280, 288))	('ER', 'Gene', '2099', (212, 214))	('ESR1', 'Gene', '2099', (8, 12))	('ESR1', 'Gene', (275, 279))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ER', 'Gene', '2099', (242, 244))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ESR1', 'Gene', (8, 12))	('breast cancer', 'Disease', (138, 151))	('ESR1', 'Gene', '2099', (275, 279))	('hormone receptor', 'Gene', (112, 128))
171121	31116423	It is encouraging that these drugs could be effective agents that allow us to replace chemotherapy entirely for pediatric glioma.86  Other central nervous system types for which molecular profiling has a role include ependymoma (RELA fusion), diffuse midline cerebellar gliomas (histone 3 mutations), medulloblastoma (WNT vs SHH activated), and ependymoma (C19MC amplification).	('glioma', 'Phenotype', 'HP:0009733', (270, 276))	('RELA', 'Gene', (229, 233))	('pediatric glioma', 'Disease', (112, 128))	('RELA', 'Gene', '5970', (229, 233))	('mutations', 'Var', (289, 298))	('SHH', 'Gene', '6469', (325, 328))	('midline cerebellar gliomas', 'Disease', 'MESH:D005910', (251, 277))	('medulloblastoma', 'Disease', (301, 316))	('gliomas', 'Phenotype', 'HP:0009733', (270, 277))	('ependymoma', 'Disease', (345, 355))	('cerebellar gliomas', 'Phenotype', 'HP:0010795', (259, 277))	('SHH', 'Gene', (325, 328))	('ependymoma', 'Disease', (217, 227))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('ependymoma', 'Phenotype', 'HP:0002888', (345, 355))	('ependymoma', 'Phenotype', 'HP:0002888', (217, 227))	('medulloblastoma', 'Disease', 'MESH:D008527', (301, 316))	('ependymoma', 'Disease', 'MESH:D004806', (345, 355))	('midline cerebellar gliomas', 'Disease', (251, 277))	('ependymoma', 'Disease', 'MESH:D004806', (217, 227))	('pediatric glioma', 'Disease', 'MESH:D005910', (112, 128))	('medulloblastoma', 'Phenotype', 'HP:0002885', (301, 316))
171124	31116423	Of other mutations tested, the epidermal growth factor gene EGFR variant vIII encodes a promising molecular target.	('vIII', 'Gene', '1351', (73, 77))	('EGFR', 'Gene', '1956', (60, 64))	('variant', 'Var', (65, 72))	('vIII', 'Gene', (73, 77))	('EGFR', 'Gene', (60, 64))
171129	31116423	It is assumed that this alteration constitutively activates the RAS/RAK/MEK/ERK kinase pathway.	('activates', 'PosReg', (50, 59))	('RAK', 'Gene', '2444', (68, 71))	('RAK', 'Gene', (68, 71))	('ER', 'Gene', '2099', (76, 78))	('alteration', 'Var', (24, 34))	('MEK', 'Gene', (72, 75))	('MEK', 'Gene', '5609', (72, 75))
171134	31116423	There are several prominent exceptions to this diagnosis-only rule in gastrointestinal (GI) stromal tumors, in which mutations in KIT (particularly exon 11) and PDGFRA are notable biomarkers for therapeutic intervention with the tyrosine kinase inhibitors imatinib and sunitinib.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (117, 126))	('PDGFRA', 'Gene', (161, 167))	('tyrosine', 'Chemical', 'None', (229, 237))	('PDGFRA', 'Gene', '5156', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('KIT', 'Gene', '3815', (130, 133))	('imatinib', 'Chemical', 'MESH:C097613', (256, 264))	('gastrointestinal (GI) stromal tumors', 'Disease', 'MESH:D046152', (70, 106))	('KIT', 'Gene', (130, 133))	('sunitinib', 'Chemical', 'MESH:C473478', (269, 278))
171145	31116423	It is important to be aware that selective inhibitors of BRAF encoded by mutant BRAF V600 can cause paradoxical activation of the MAPK pathway in cells that are BRAF V600 wild-type (particularly if they harbor a RAS mutation).	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (57, 61))	('activation', 'PosReg', (112, 122))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', (161, 165))	('mutant', 'Var', (73, 79))	('BRAF', 'Gene', '673', (161, 165))	('MAPK pathway', 'Pathway', (130, 142))	('BRAF', 'Gene', '673', (80, 84))
171146	31116423	This effect occurs through RAF dimerization, leading to increased cell proliferation rather than inhibition.99 The combination of selective BRAF inhibitors with MEK1/MEK2 inhibitors is now FDA approved only for patients with BRAF V600-mutant melanoma.	('RAF', 'Gene', (27, 30))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('MEK2', 'Gene', '5605', (166, 170))	('MEK2', 'Gene', (166, 170))	('RAF', 'Gene', '22882', (141, 144))	('patients', 'Species', '9606', (211, 219))	('V600-mutant', 'Var', (230, 241))	('MEK1', 'Gene', '5604', (161, 165))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('RAF', 'Gene', (141, 144))	('BRAF', 'Gene', '673', (140, 144))	('BRAF', 'Gene', (140, 144))	('RAF', 'Gene', '22882', (27, 30))	('RAF', 'Gene', '22882', (226, 229))	('BRAF', 'Gene', (225, 229))	('BRAF', 'Gene', '673', (225, 229))	('MEK1', 'Gene', (161, 165))	('RAF', 'Gene', (226, 229))
171147	31116423	In patients with resected, stage III, BRAF V600E/V600K-mutant melanoma, dabrafenib plus trametinib improves relapse-free survival by 53%.100 Similarly, dabrafenib plus trametinib and other BRAF/MEK inhibitor combinations have demonstrated objective response rates of up to 68% in patients with unresectable advanced BRAF V600E/K mutant melanoma.101  Other oncogenic driver mutations have been identified in melanomas for which targeted therapies have demonstrated clinical activity.	('melanoma', 'Phenotype', 'HP:0002861', (407, 415))	('melanoma', 'Disease', (407, 415))	('dabrafenib', 'Chemical', 'MESH:C561627', (72, 82))	('V600K', 'Var', (49, 54))	('dabrafenib', 'Chemical', 'MESH:C561627', (152, 162))	('melanomas', 'Disease', 'MESH:D008545', (407, 416))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', '673', (189, 193))	('BRAF', 'Gene', '673', (316, 320))	('melanoma', 'Disease', 'MESH:D008545', (336, 344))	('mutations', 'Var', (373, 382))	('MEK', 'Gene', '5609', (194, 197))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanomas', 'Disease', (407, 416))	('melanoma', 'Disease', (62, 70))	('BRAF', 'Gene', (316, 320))	('patients', 'Species', '9606', (280, 288))	('melanoma', 'Disease', 'MESH:D008545', (407, 415))	('patients', 'Species', '9606', (3, 11))	('V600E', 'Var', (321, 326))	('MEK', 'Gene', (194, 197))	('V600E', 'Var', (43, 48))	('trametinib', 'Chemical', 'MESH:C560077', (88, 98))	('trametinib', 'Chemical', 'MESH:C560077', (168, 178))	('V600K', 'SUBSTITUTION', 'None', (49, 54))	('melanomas', 'Phenotype', 'HP:0002861', (407, 416))	('melanoma', 'Phenotype', 'HP:0002861', (336, 344))	('melanoma', 'Disease', (336, 344))	('V600E', 'SUBSTITUTION', 'None', (321, 326))	('V600E', 'SUBSTITUTION', 'None', (43, 48))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))
171148	31116423	KIT mutations (and amplifications) have been identified in up to 20% of patients with advanced melanoma, particular those with chronic sun-damaged, acral, or mucosal melanoma subtypes.102, 103 Of note, KIT mutations are often seen across multiple exons, and hotspot mutations are not typically observed.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mutations', 'Var', (206, 215))	('melanoma', 'Disease', (166, 174))	('mucosal melanoma', 'Disease', (158, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('mucosal melanoma', 'Disease', 'MESH:D008545', (158, 174))	('patients', 'Species', '9606', (72, 80))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('KIT', 'Gene', '3815', (0, 3))	('KIT', 'Gene', '3815', (202, 205))	('KIT', 'Gene', (0, 3))	('KIT', 'Gene', (202, 205))
171155	31116423	Improvement in PFS with the combination approach was best seen in patients whose tumors harbored a BRAF V600 mutation or had <1% PD-L1 staining (hazard ratios, 0.62 and 0.68, respectively).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('PD-L1', 'Gene', (129, 134))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('PFS', 'MPA', (15, 18))	('PD-L1', 'Gene', '29126', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('V600', 'Var', (104, 108))	('Improvement', 'PosReg', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('patients', 'Species', '9606', (66, 74))
171171	31116423	The TAPUR study is an ongoing, nonrandomized, multicenter clinical trial that opened in 2016.115 This trial is testing the use of drugs already approved by the FDA that target a specific tumor mutation in individuals with advanced cancer outside of the drug's approved indication.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('mutation', 'Var', (193, 201))
171180	31116423	There have been cross assay comparisons, particularly in NSCLC, for which the staining patterns were similar among the 28-8, 22C3, and SP142 antibodies.133, 134 However, SP142 staining of tumor cell membranes was shown to be weaker, resulting in fewer positive tumor cells than some other assays.	('tumor', 'Disease', (188, 193))	('NSCLC', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('SP142', 'Var', (170, 175))	('fewer', 'NegReg', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('positive', 'MPA', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
171186	31116423	Assays have been developed to test for PD-L1 expression, including the PD-L1 IHC assay with 28-8 Dako (developed for nivolumab), 22C3 Dako (developed for pembrolizumab), SP142 Ventana (atezolizumab), SP263 Ventana (durvalumab), and 73-10 Dako (avelumab).	('SP263 Ventana', 'Var', (200, 213))	('PD-L1', 'Gene', (39, 44))	('SP142 Ventana', 'Var', (170, 183))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', '29126', (39, 44))	('PD-L1', 'Gene', '29126', (71, 76))	('22C3', 'Var', (129, 133))
171192	31116423	When microsatellites contain a clonal change in several repeated DNA nucleotide units, this results in MSI (tumors with such MSI are characterized as MSI-H, and this occurs when at least one of the MMR genes:MSH2, MLH1, MSH6, and PMS2:are inactivated, causing dMMR).10 Since MSI-H was established as a possible biomarker, the MSI status of a tumor has always required microdissection and PCR-based detection strategies.	('MSH2', 'Gene', (208, 212))	('MSH6', 'Gene', (220, 224))	('MLH1', 'Gene', (214, 218))	('MSH2', 'Gene', '4436', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('PMS2', 'Gene', (230, 234))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PMS2', 'Gene', '5395', (230, 234))	('MSH6', 'Gene', '2956', (220, 224))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('microsatellites', 'Var', (5, 20))	('tumor', 'Disease', (342, 347))	('MLH1', 'Gene', '4292', (214, 218))
171193	31116423	A sensitive and specific MSI assay by NGS has recently been developed that is comparable to the existing gold standard of PCR-based methods without requiring matched samples from tumor and normal tissues.10 MSI appears to be a generalized cancer phenotype in about 4% of all adult cancers in total.	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Disease', (239, 245))	('tissues.10 MSI', 'Var', (196, 210))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancers', 'Disease', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Disease', (179, 184))
171203	31116423	Immunogenicity is certainly associated with mutation load, suggesting that an increase in the number of somatic mutations present in tumor cells increases potential recognition by the immune system.135 Indeed, the presence of mutations in the tumor generates neoantigens (not expressed by normal cells), and the more mutations there are, the more the tumor is likely to be immunogenic.	('mutations', 'Var', (317, 326))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (351, 356))	('neoantigens', 'MPA', (259, 270))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
171206	31116423	This, of course, also shows that high TMB is in strong concordance with MSI-high in CRC.	('high', 'Var', (33, 37))	('CRC', 'Disease', (84, 87))	('TMB', 'Chemical', 'MESH:D014289', (38, 41))
171211	31116423	A population of tumors exhibiting MSI-H status but low TMB and no PD-L1 expression was identified.	('TMB', 'MPA', (55, 58))	('PD-L1', 'Gene', '29126', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('MSI-H status', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('TMB', 'Chemical', 'MESH:D014289', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('PD-L1', 'Gene', (66, 71))
171216	31116423	In the past, large-scale sequencing studies demonstrated that PBRM1 loss of function (LOF) alterations are present in a large portion (up to 41%) of ccRCC tumors.	('loss of function', 'NegReg', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('alterations', 'Var', (91, 102))	('PBRM1', 'Gene', (62, 67))	('ccRCC tumors', 'Disease', 'MESH:D009369', (149, 161))	('PBRM1', 'Gene', '55193', (62, 67))	('ccRCC tumors', 'Disease', (149, 161))
171219	31116423	HR is a complex DNA repair pathway involving multiple steps and has been reviewed extensively.143, 144 The BRCA1 and BRCA2 genes are critical for efficient double-strand DNA repair via HR and play an important role in the development and clinical progression of many cancers.145, 146 If a cell carries BRCA1/BRCA2 LOF mutations, it loses the ability to repair double-strand breaks by HR and is termed the HRD pathway.	('BRCA1', 'Gene', '672', (107, 112))	('mutations', 'Var', (318, 327))	('BRCA1', 'Gene', (107, 112))	('repair double-strand breaks', 'MPA', (353, 380))	('HRD', 'Disease', (405, 408))	('LOF', 'NegReg', (314, 317))	('BRCA2', 'Gene', (308, 313))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('HRD', 'Disease', 'MESH:C537157', (405, 408))	('BRCA2', 'Gene', (117, 122))	('BRCA1', 'Gene', '672', (302, 307))	('ability', 'MPA', (342, 349))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('BRCA1', 'Gene', (302, 307))	('BRCA2', 'Gene', '675', (308, 313))	('BRCA2', 'Gene', '675', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('cancers', 'Disease', (267, 274))	('loses', 'NegReg', (332, 337))
171220	31116423	Such HRD cells are highly sensitive to DNA-damaging agents, such as platinum-based chemotherapies and other cytotoxic agents that can cause DNA strand breaks.147, 148 PARP plays a major role in DNA strand break repair.	('breaks.147', 'Var', (151, 161))	('PARP', 'Gene', (167, 171))	('HRD', 'Disease', 'MESH:C537157', (5, 8))	('DNA strand break', 'MPA', (194, 210))	('HRD', 'Disease', (5, 8))	('PARP', 'Gene', '142', (167, 171))	('platinum', 'Chemical', 'MESH:D010984', (68, 76))
171224	31116423	Defects in HR repair can be because of epigenetic changes such as BRCA1 promoter methylation, somatic mutations in key HR-related genes, and frequent copy number alterations.149 In addition, mutations in other genes may result in HR-defective tumors and include but are not limited to PALB2, RAD51, CHEK2, and ATM.150, 151, 152, 153  The most common approach to test for HRD is genomic testing for alterations in BRCA1 and BRCA2 on the basis that BRCA1 and BRCA2 germline and somatic mutations are known to cause HRD.	('CHEK2', 'Gene', '11200', (299, 304))	('BRCA2', 'Gene', '675', (457, 462))	('ATM', 'Gene', '472', (310, 313))	('mutations', 'Var', (484, 493))	('PALB2', 'Gene', (285, 290))	('cause', 'Reg', (507, 512))	('BRCA1', 'Gene', '672', (447, 452))	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', '675', (423, 428))	('mutations', 'Var', (191, 200))	('BRCA1', 'Gene', (447, 452))	('BRCA1', 'Gene', (66, 71))	('HRD', 'Disease', (371, 374))	('alterations', 'Var', (398, 409))	('PALB2', 'Gene', '79728', (285, 290))	('ATM', 'Gene', (310, 313))	('HR-defective tumors', 'Disease', (230, 249))	('HRD', 'Disease', (513, 516))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('HRD', 'Disease', 'MESH:C537157', (371, 374))	('RAD51', 'Gene', (292, 297))	('RAD51', 'Gene', '5888', (292, 297))	('BRCA1', 'Gene', '672', (413, 418))	('HR-defective tumors', 'Disease', 'MESH:D009369', (230, 249))	('HRD', 'Disease', 'MESH:C537157', (513, 516))	('BRCA1', 'Gene', (413, 418))	('BRCA2', 'Gene', (457, 462))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('CHEK2', 'Gene', (299, 304))	('result in', 'Reg', (220, 229))	('BRCA2', 'Gene', (423, 428))
171226	31116423	A tumor can be characterized as HR-deficient or HR-nondeficient by combining the HRD score that it generates and its BRCA1/BRCA2 mutation status.	('HRD', 'Disease', 'MESH:C537157', (81, 84))	('BRCA2', 'Gene', '675', (123, 128))	('HR-deficient or HR-nondeficient', 'Disease', 'MESH:D001919', (32, 63))	('HR-deficient or HR-nondeficient', 'Disease', (32, 63))	('BRCA1', 'Gene', '672', (117, 122))	('mutation', 'Var', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('HRD', 'Disease', (81, 84))	('BRCA1', 'Gene', (117, 122))	('tumor', 'Disease', (2, 7))	('BRCA2', 'Gene', (123, 128))
171227	31116423	HRD is defined as an HRD score >=42 or the presence of a mutation in BRCA1/BRCA2.	('mutation', 'Var', (57, 65))	('BRCA1', 'Gene', '672', (69, 74))	('HRD', 'Disease', 'MESH:C537157', (21, 24))	('HRD', 'Disease', 'MESH:C537157', (0, 3))	('BRCA2', 'Gene', (75, 80))	('BRCA1', 'Gene', (69, 74))	('HRD', 'Disease', (21, 24))	('BRCA2', 'Gene', '675', (75, 80))	('HRD', 'Disease', (0, 3))	('presence', 'Reg', (43, 51))
171228	31116423	As an example of its accuracy, the myChoice HRD assay was seen to identify 100% of BRCA-mutated tumors and 57% of non-BRCA-mutated tumors that had HR deficiencies in patients with platinum-sensitive, high-grade, serous or BRCA-mutated, recurrent ovarian cancer.65  The FoundationFocus CDx BRCA (Foundation Medicine, Inc) assay was used to detect both germline and somatic BRCA1/BRCA2 mutation types associated with response to PARP inhibitor therapy.155, 156 This modified NGS-based assay determined the percentage of genomic loss of heterozygosity, mutations in BRCA1/BRCA2, and other HR genes in tumor tissue of patients with ovarian cancers taking part in the ARIEL PARP inhibitor rucaparib trial.	('BRCA', 'Gene', '672', (563, 567))	('BRCA2', 'Gene', '675', (569, 574))	('mutations', 'Var', (550, 559))	('BRCA2', 'Gene', '675', (378, 383))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('BRCA', 'Gene', '672', (118, 122))	('BRCA', 'Gene', (372, 376))	('tumor', 'Disease', (131, 136))	('PARP', 'Gene', '142', (427, 431))	('HR deficiencies', 'Disease', 'MESH:D001919', (147, 162))	('PARP', 'Gene', (427, 431))	('BRCA', 'Gene', (222, 226))	('AR', 'Gene', '367', (670, 672))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('BRCA', 'Gene', '672', (569, 573))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BRCA', 'Gene', '672', (83, 87))	('BRCA', 'Gene', '672', (378, 382))	('BRCA', 'Gene', '672', (289, 293))	('BRCA', 'Gene', (563, 567))	('cancers', 'Phenotype', 'HP:0002664', (636, 643))	('ovarian cancers', 'Phenotype', 'HP:0100615', (628, 643))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (628, 642))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', (598, 603))	('BRCA', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (636, 642))	('PARP', 'Gene', '142', (669, 673))	('ovarian cancer', 'Disease', 'MESH:D010051', (246, 260))	('loss', 'NegReg', (526, 530))	('tumor', 'Disease', 'MESH:D009369', (598, 603))	('BRCA', 'Gene', (569, 573))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('BRCA1', 'Gene', '672', (372, 377))	('BRCA', 'Gene', (289, 293))	('BRCA', 'Gene', (83, 87))	('BRCA', 'Gene', (378, 382))	('tumor', 'Disease', (96, 101))	('patients', 'Species', '9606', (614, 622))	('PARP', 'Gene', (669, 673))	('BRCA1', 'Gene', (372, 377))	('tumors', 'Disease', (131, 137))	('BRCA2', 'Gene', (569, 574))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('myChoice HRD', 'Disease', (35, 47))	('BRCA2', 'Gene', (378, 383))	('BRCA1', 'Gene', '672', (563, 568))	('myChoice HRD', 'Disease', 'MESH:C537157', (35, 47))	('BRCA1', 'Gene', (563, 568))	('ovarian cancer', 'Phenotype', 'HP:0100615', (628, 642))	('platinum', 'Chemical', 'MESH:D010984', (180, 188))	('ovarian cancer', 'Disease', (246, 260))	('BRCA', 'Gene', '672', (372, 376))	('ovarian cancers', 'Disease', (628, 643))	('AR', 'Gene', '367', (428, 430))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (598, 603))	('HR deficiencies', 'Disease', (147, 162))	('ovarian cancers', 'Disease', 'MESH:D010051', (628, 643))	('AR', 'Gene', '367', (663, 665))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('BRCA', 'Gene', '672', (222, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))	('patients', 'Species', '9606', (166, 174))
171231	31116423	Certain cancers, including ovarian, fallopian tube, breast, primary peritoneal, and GI (specifically a subgroup of pancreatic adenocarcinomas and gastric/esophageal cancers), have been shown to harbor aberrations in genes involved in the HRD pathway.	('HRD', 'Disease', (238, 241))	('HRD', 'Disease', 'MESH:C537157', (238, 241))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('ovarian', 'Disease', (27, 34))	('cancers', 'Disease', (8, 15))	('breast', 'Disease', (52, 58))	('fallopian tube', 'Disease', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('fallopian tube', 'Disease', 'MESH:D005184', (36, 50))	('pancreatic adenocarcinomas and gastric/esophageal cancers', 'Disease', 'MESH:D013274', (115, 172))	('fall', 'Phenotype', 'HP:0002527', (36, 40))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (115, 141))	('cancers', 'Disease', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('ovarian', 'Disease', 'MESH:D010049', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('aberrations', 'Var', (201, 212))	('primary peritoneal', 'Disease', (60, 78))
171236	31116423	The primary outcome of the study will be the objective response rate to entrectinib.27   NTRK fusions may act as actionable targets in conjunction with other potentially targetable alterations, such as PD-L1-positive or MSI-H status, meaning that therapeutic combinations (TRK inhibitors plus immune checkpoint inhibitors, for example) are a promising strategy.159  The fibroblast growth factor receptor (FGFR) family comprises part of a tyrosine kinase signaling pathway that plays a role in oncogenesis through gene amplification, activating mutations, or translocation in several tumor types.	('tyrosine', 'Chemical', 'None', (438, 446))	('FGFR', 'Gene', (405, 409))	('PD-L1', 'Gene', '29126', (202, 207))	('tumor', 'Disease', (583, 588))	('TRK', 'Gene', (273, 276))	('gene amplification', 'Var', (513, 531))	('TRK', 'Gene', '4914', (273, 276))	('translocation', 'Var', (558, 571))	('activating', 'MPA', (533, 543))	('tumor', 'Disease', 'MESH:D009369', (583, 588))	('TRK', 'Gene', (90, 93))	('PD-L1', 'Gene', (202, 207))	('TRK', 'Gene', '4914', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (583, 588))
171238	31116423	Earlier this year, the FDA granted Breakthrough Therapy Designation for erdafitinib in the treatment of urothelial cancer, which is based on data from a multicenter phase 2 clinical trial focused on evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer harboring specific FGFR mutations.160 The overall response rate was 42% in 59 patients for whom data were available.160 Erdafitinib is also under investigation in the NCI-MATCH trial as a treatment for patients with tumors that have an FGFR mutation, fusion, or amplification (Table 7).	('patients', 'Species', '9606', (540, 548))	('amplification', 'Var', (600, 613))	('tumors', 'Phenotype', 'HP:0002664', (554, 560))	('patients', 'Species', '9606', (275, 283))	('tumor', 'Phenotype', 'HP:0002664', (554, 559))	('fusion', 'Var', (589, 595))	('tumors', 'Disease', (554, 560))	('urothelial cancer', 'Disease', 'MESH:D014523', (320, 337))	('mutation', 'Var', (579, 587))	('erdafitinib', 'Chemical', 'None', (72, 83))	('urothelial cancer', 'Disease', (320, 337))	('tumors', 'Disease', 'MESH:D009369', (554, 560))	('patients', 'Species', '9606', (416, 424))	('urothelial cancer', 'Disease', 'MESH:D014523', (104, 121))	('erdafitinib', 'Chemical', 'None', (237, 248))	('Erdafitinib', 'Chemical', 'None', (458, 469))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('urothelial cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('FGFR', 'Gene', (574, 578))
171239	31116423	Also in the NCI-MATCH trial, 5 of 50 patients with an aberrant FGFR pathway had a partial response to AZD4547 (another FGFR tyrosine kinase inhibitor).161 Two of these patient's tumors had point mutations in FGFR2/FGFR3, and 2 others had FGFR3 fusions, suggesting that these particular types of mutation have increased sensitivity to the drug, which warrants further study in this patient subtype.	('FGFR3', 'Gene', (238, 243))	('FGFR3', 'Gene', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('patient', 'Species', '9606', (168, 175))	('point mutations', 'Var', (189, 204))	('FGFR3', 'Gene', '2261', (238, 243))	('FGFR3', 'Gene', '2261', (214, 219))	('sensitivity', 'MPA', (319, 330))	('patients', 'Species', '9606', (37, 45))	('patient', 'Species', '9606', (381, 388))	('FGFR2', 'Gene', (208, 213))	('AZD4547', 'Chemical', 'MESH:C572463', (102, 109))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('FGFR2', 'Gene', '2263', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('increased', 'PosReg', (309, 318))	('patient', 'Species', '9606', (37, 44))	('tumors', 'Disease', (178, 184))	('tyrosine', 'Chemical', 'None', (124, 132))
171240	31116423	Aberrant activation of MET receptor tyrosine kinase signaling occurs in various cancer types as result of various MET alterations, including amplification and an exon 14 mutation.	('amplification', 'Var', (141, 154))	('activation', 'PosReg', (9, 19))	('tyrosine', 'Chemical', 'None', (36, 44))	('MET receptor tyrosine kinase signaling', 'MPA', (23, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('exon 14 mutation', 'Var', (162, 178))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
171241	31116423	Crizotinib is an ALK/ROS1/MET inhibitor that is already FDA approved in ALK-positive or ROS1-positive NSCLC but also has proven clinical activity in cases of MET exon 14 alterations and MET amplification.	('ALK', 'Gene', '238', (17, 20))	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('Crizotinib', 'Chemical', 'MESH:C551994', (0, 10))	('ROS1', 'Gene', '6098', (88, 92))	('ROS1', 'Gene', (21, 25))	('ALK', 'Gene', (17, 20))	('ALK', 'Gene', '238', (72, 75))	('ROS1', 'Gene', '6098', (21, 25))	('MET exon 14 alterations', 'Var', (158, 181))	('ROS1', 'Gene', (88, 92))	('MET amplification', 'Var', (186, 203))	('NSCLC', 'Disease', (102, 107))	('ALK', 'Gene', (72, 75))
171243	31116423	Crizotinib was generally well tolerated163 and is currently under study in the ASCO TAPUR trial for patients with tumors that have ALK, ROS1, or MET mutations and in the NCI-MATCH trial as a treatment for patients with tumors that have a MET amplification, MET exon 14 mutation, ALK translocation, or ROS1 translocation or inversion (Table 7).	('patients', 'Species', '9606', (205, 213))	('ROS1', 'Gene', (136, 140))	('patients', 'Species', '9606', (100, 108))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('MET amplification', 'Var', (238, 255))	('ROS1', 'Gene', (301, 305))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('ALK', 'Gene', '238', (131, 134))	('ALK', 'Gene', (131, 134))	('ALK', 'Gene', '238', (279, 282))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('ROS1', 'Gene', '6098', (136, 140))	('ALK', 'Gene', (279, 282))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('inversion', 'Var', (323, 332))	('Crizotinib', 'Chemical', 'MESH:C551994', (0, 10))	('ROS1', 'Gene', '6098', (301, 305))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('MET exon 14 mutation', 'Var', (257, 277))
171246	31116423	Sapanisertib (TAK-228) demonstrated a reasonable safety profile as well as promising preliminary antitumor activity in a range of tumor types with aberrant MTOR.164 Tuberous sclerosis complex 1 and 2 (TSC1 and TSC2) mutations are also observed in certain tumor subtypes and may be targeted by sapanisertib.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('sapanisertib', 'Chemical', 'None', (293, 305))	('tumor', 'Disease', (130, 135))	('TSC2', 'Gene', '7249', (210, 214))	('TSC1', 'Gene', (201, 205))	('Tuberous sclerosis', 'Disease', (165, 183))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TSC1', 'Gene', '7248', (201, 205))	('Sapanisertib', 'Chemical', 'None', (0, 12))	('TSC2', 'Gene', (210, 214))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('MTOR', 'Gene', (156, 160))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (165, 183))	('tumor', 'Disease', (101, 106))	('MTOR', 'Gene', '2475', (156, 160))	('mutations', 'Var', (216, 225))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
171247	31116423	The agent is under investigation in the NCI-MATCH trial as a treatment for patients with tumors that have MTOR or TSC1/TSC2 mutations (Table 7).	('tumors', 'Disease', (89, 95))	('TSC1', 'Gene', '7248', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (124, 133))	('TSC1', 'Gene', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('patients', 'Species', '9606', (75, 83))	('MTOR', 'Gene', (106, 110))	('TSC2', 'Gene', '7249', (119, 123))	('MTOR', 'Gene', '2475', (106, 110))	('TSC2', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
171248	31116423	In the NCI-MATCH trial, 65 patients with a mutated phosphatidylinositol 3-kinase gene (PIK3CA) were treated with taselisib (a PIK3CA inhibitor) and, although there were no ORs to the drug, 24% of patients had prolonged stable disease for more than 6 months.	('PIK3CA', 'Gene', '5290', (87, 93))	('PIK3CA', 'Gene', (126, 132))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (51, 71))	('patients', 'Species', '9606', (196, 204))	('PIK3CA', 'Gene', '5290', (126, 132))	('patients', 'Species', '9606', (27, 35))	('PIK3CA', 'Gene', (87, 93))	('mutated', 'Var', (43, 50))
171250	31116423	Palbociclib, an inhibitor of aberrant CDK4/CDK6, is FDA approved for the treatment of hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.166 Its effect on certain GI tumors is under investigation in the clinic.167 Palbociclib is also under investigation in the NCI-MATCH trial as a treatment for patients with tumors that have CDK4 or CDK6 amplification or CCND1, CCND2, or CCND3 amplification (and Rb expression/protein in both study arms).	('CDK6', 'Gene', (43, 47))	('CCND1', 'Gene', (487, 492))	('tumors', 'Disease', 'MESH:D009369', (440, 446))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('CCND3', 'Gene', (504, 509))	('patients', 'Species', '9606', (426, 434))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (457, 461))	('hormone receptor', 'Gene', (86, 102))	('HER2', 'Gene', (113, 117))	('CCND2', 'Gene', (494, 499))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('GI tumors', 'Disease', (293, 302))	('breast cancer', 'Disease', (151, 164))	('amplification', 'Var', (470, 483))	('women', 'Species', '9606', (261, 266))	('CCND2', 'Gene', '894', (494, 499))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CDK4', 'Gene', '1019', (457, 461))	('CDK6', 'Gene', '1021', (465, 469))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('CCND3', 'Gene', '896', (504, 509))	('tumors', 'Phenotype', 'HP:0002664', (440, 446))	('CDK6', 'Gene', (465, 469))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('CDK6', 'Gene', '1021', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('hormone receptor', 'Gene', '3164', (86, 102))	('GI tumors', 'Phenotype', 'HP:0007378', (293, 302))	('tumors', 'Disease', (440, 446))	('HER2', 'Gene', '2064', (113, 117))	('tumors', 'Disease', (296, 302))	('GI tumors', 'Disease', 'MESH:D046152', (293, 302))	('CCND1', 'Gene', '595', (487, 492))	('CDK4', 'Gene', (38, 42))
171251	31116423	The ASCO TAPUR trial is also investigating palbociclib in the treatment of patients with tumors that harbor CDKN2A, CDK4, or CDK6 amplifications (Table 7).	('amplifications', 'Var', (130, 144))	('tumors', 'Disease', (89, 95))	('CDKN2A', 'Gene', '1029', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('patients', 'Species', '9606', (75, 83))	('CDK4', 'Gene', '1019', (116, 120))	('CDK4', 'Gene', (116, 120))	('CDK6', 'Gene', (125, 129))	('CDKN2A', 'Gene', (108, 114))	('CDK6', 'Gene', '1021', (125, 129))
171253	31116423	DDR2 mutations are seen in several tumor types, including lung cancer, breast cancer, brain cancer, gynecologic cancer, and prostate cancer.168 The multikinase inhibitor dasatinib blocks DDR2 kinase activity to various degrees and is under investigation in the treatment of patients with tumors that possess a DDR2 S768R, I638F, or L239R mutation (NCI-MATCH).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('S768R', 'Var', (315, 320))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('brain cancer', 'Phenotype', 'HP:0030692', (86, 98))	('brain cancer', 'Disease', 'MESH:D001932', (86, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('DDR2', 'Gene', '4921', (310, 314))	('I638F', 'Var', (322, 327))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('breast cancer', 'Disease', (71, 84))	('activity', 'MPA', (199, 207))	('L239R', 'SUBSTITUTION', 'None', (332, 337))	('patients', 'Species', '9606', (274, 282))	('tumor', 'Disease', (35, 40))	('dasatinib', 'Chemical', 'MESH:C488369', (170, 179))	('S768R', 'SUBSTITUTION', 'None', (315, 320))	('DDR2', 'Gene', (0, 4))	('DDR2', 'Gene', '4921', (187, 191))	('L239R', 'Var', (332, 337))	('cancer', 'Disease', (63, 69))	('tumor', 'Disease', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('DDR2', 'Gene', (310, 314))	('cancer', 'Disease', (92, 98))	('brain cancer', 'Disease', (86, 98))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('DDR2', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('blocks', 'NegReg', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('I638F', 'SUBSTITUTION', 'None', (322, 327))	('prostate cancer', 'Disease', (124, 139))	('tumors', 'Disease', (288, 294))
171254	31116423	The agent is also under investigation in the treatment of patients with tumors that harbor Bcr-abl, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, or YES1 mutations (TAPUR trial) (Table 7).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('LCK', 'Gene', '3932', (130, 133))	('PDGFRB', 'Gene', (110, 116))	('tumors', 'Disease', (72, 78))	('PDGFRB', 'Gene', '5159', (110, 116))	('Bcr-abl', 'Gene', '25', (91, 98))	('EPHA2', 'Gene', (118, 123))	('FYN', 'Gene', (125, 128))	('KIT', 'Gene', (105, 108))	('YES1', 'Gene', '7525', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('SRC', 'Gene', '6714', (100, 103))	('Bcr-abl', 'Gene', (91, 98))	('mutations', 'Var', (143, 152))	('LCK', 'Gene', (130, 133))	('FYN', 'Gene', '2534', (125, 128))	('EPHA2', 'Gene', '1969', (118, 123))	('patients', 'Species', '9606', (58, 66))	('SRC', 'Gene', (100, 103))	('KIT', 'Gene', '3815', (105, 108))	('YES1', 'Gene', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
171267	31116423	An illustrated example of this was a recent patient's lung cancer demonstrating an actionable mutation in BRAF.	('lung cancer', 'Disease', (54, 65))	('patient', 'Species', '9606', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('BRAF', 'Gene', '673', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('BRAF', 'Gene', (106, 110))	('mutation', 'Var', (94, 102))
171275	31116423	These fall into several categories, such as reimbursement issues, evaluating the tumor genomic data for potential germline testing, paring results to clinical trial opportunities, and collecting and collating the genomic data to clinical information and outcomes, as well as the incorporation of new opportunities such as sequencing cell-free DNA or routine pharmacogenetic testing.	('fall', 'Phenotype', 'HP:0002527', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('sequencing', 'Var', (322, 332))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
171284	31116423	Examples of major drivers for which there are currently no approved drugs include mutated beta-catenin, mutated P53, or mutated RAS, among others.	('P53', 'Gene', (112, 115))	('mutated', 'Var', (104, 111))	('RAS', 'Gene', (128, 131))	('beta-catenin', 'Gene', (90, 102))	('P53', 'Gene', '7157', (112, 115))	('mutated', 'Var', (82, 89))	('beta-catenin', 'Gene', '1499', (90, 102))	('mutated', 'Var', (120, 127))
171286	31116423	There are some exceptions with mutated EGFR, ALK, or BCR-ABL.	('ALK', 'Gene', '238', (45, 48))	('BCR-ABL', 'Gene', (53, 60))	('BCR-ABL', 'Gene', '25', (53, 60))	('ALK', 'Gene', (45, 48))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('mutated', 'Var', (31, 38))
171291	31116423	However, it is not unreasonable to expect that the many genomic changes representing the tail end of the curve of drivers may affect patient outcomes, especially if there are available drugs that target their pathways.	('patient', 'Species', '9606', (133, 140))	('changes', 'Var', (64, 71))	('affect', 'Reg', (126, 132))	('patient outcomes', 'MPA', (133, 149))
171306	31116423	Only patients with MSI-H, stage III colon cancer will be eligible for randomization, and the eligibility determination mandates genomic testing for defective MMR in patients with localized disease.	('patients', 'Species', '9606', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('localized disease', 'Disease', (179, 196))	('colon cancer', 'Disease', (36, 48))	('defective', 'Var', (148, 157))	('localized disease', 'Disease', 'MESH:D004828', (179, 196))	('patients', 'Species', '9606', (165, 173))	('MMR', 'Gene', (158, 161))	('MSI-H', 'Var', (19, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))
171353	26528388	Instead, DeltaFA% less than -35 can be suggestive of either "infiltration" or "disruption" that cannot be subdivided.	('disruption', 'Disease', (79, 89))	('DeltaFA% less than -35', 'Var', (9, 31))	('DeltaFA', 'Chemical', '-', (9, 16))
171354	26528388	In addition, as no "disrupted" fiber was found in the fourth quartile with positive DeltaFA%, we deduced that a positive DeltaFA% can rule out the diagnosis of "disruption".	('DeltaFA', 'Chemical', '-', (121, 128))	('disruption', 'Disease', (161, 171))	('DeltaFA%', 'Var', (121, 129))	('DeltaFA', 'Chemical', '-', (84, 91))	('positive DeltaFA%', 'Var', (112, 129))
171381	24986089	Correlative studies to establish the predictive role of molecular and cytogenetic characteristics [isocitrate dehydrogenase (IDH) mutations, loss of heterozygosity of 1p/19q, as well as methylation of methylguanine methyl transferase (MGMT) status] clinical outcome are pending.	('loss', 'Var', (141, 145))	('MGMT', 'Gene', (235, 239))	('IDH', 'Gene', (125, 128))	('mutations', 'Var', (130, 139))	('MGMT', 'Gene', '4255', (235, 239))	('IDH', 'Gene', '3417', (125, 128))
171387	24986089	Patients with low-grade oligodendroglial tumors with 1p/19q deletion or t(1p; 19q) have longer PFS and OS than those without and consequently, 1p/19q determination is important in stratification in future clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('OS', 'Chemical', '-', (103, 105))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('Patients', 'Species', '9606', (0, 8))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (24, 47))	('1p/19q deletion', 'Var', (53, 68))	('oligodendroglial tumors', 'Disease', (24, 47))	('PFS', 'MPA', (95, 98))
171391	24986089	Recent studies have identified alterations in the BRAF serine/threonine kinase gene as the likely causative mutation in childhood LGG and approaches to target this abnormality are being explored.	('alterations', 'Var', (31, 42))	('childhood LGG', 'Disease', (120, 133))	('BRAF', 'Gene', (50, 54))	('BRAF', 'Gene', '673', (50, 54))
171395	24986089	They demonstrated the potential for TMZ to induce specific driver mutations that could contribute to the malignant transformation of grade II astrocytoma to glioblastoma.	('mutations', 'Var', (66, 75))	('contribute', 'Reg', (87, 97))	('astrocytoma to glioblastoma', 'Disease', (142, 169))	('astrocytoma to glioblastoma', 'Disease', 'MESH:D005909', (142, 169))	('TMZ', 'Chemical', 'MESH:D000077204', (36, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('astrocytoma', 'Phenotype', 'HP:0009592', (142, 153))	('induce', 'Reg', (43, 49))
171400	24986089	At initial report, survival in the two groups was the same and patients with 1p/19q deletions had significantly better outcomes, regardless of type of treatment.	('1p/19q deletions', 'Var', (77, 93))	('better', 'PosReg', (112, 118))	('patients', 'Species', '9606', (63, 71))
171404	24986089	The survival was not statistically significant for patients with tumors lacking 1p/19q deletion irrespective of treatment (median survival 2.6 vs. 2.7 years).	('1p/19q deletion', 'Var', (80, 95))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
171413	24986089	An international intergroup trial is being conducted in patients with newly diagnosed grade III glioma with 1p/19q status codeletion (NCT00887146).	('patients', 'Species', '9606', (56, 64))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('1p/19q status codeletion', 'Var', (108, 132))	('glioma', 'Disease', (96, 102))
171428	24986089	Methylguanine DNA-methyltransferase (MGMT) promoter methylation and IDH1 mutations were included in the correlative part of the study due to their prognostic value.	('IDH1', 'Gene', (68, 72))	('MGMT', 'Gene', '4255', (37, 41))	('Methylguanine DNA-methyltransferase', 'Gene', '4255', (0, 35))	('MGMT', 'Gene', (37, 41))	('Methylguanine DNA-methyltransferase', 'Gene', (0, 35))	('IDH1', 'Gene', '3417', (68, 72))	('mutations', 'Var', (73, 82))
171429	24986089	Patients with hypermethylation of the MGMT promoter had prolonged PFS both in the RT and the chemotherapy arm.	('MGMT', 'Gene', '4255', (38, 42))	('hypermethylation', 'Var', (14, 30))	('prolonged', 'PosReg', (56, 65))	('PFS', 'MPA', (66, 69))	('Patients', 'Species', '9606', (0, 8))	('MGMT', 'Gene', (38, 42))
171430	24986089	Hypermethylation of MGMT promoter, IDH1 mutations and oligodendroglioma histology was associated with a decreased risk of progression.	('MGMT', 'Gene', (20, 24))	('IDH1', 'Gene', (35, 39))	('IDH1', 'Gene', '3417', (35, 39))	('Hypermethylation', 'Var', (0, 16))	('oligodendroglioma', 'Disease', (54, 71))	('decreased', 'NegReg', (104, 113))	('progression', 'MPA', (122, 133))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutations', 'Var', (40, 49))	('oligodendroglioma', 'Disease', 'MESH:D009837', (54, 71))	('MGMT', 'Gene', '4255', (20, 24))
171431	24986089	The study demonstrated the prognostic value of IDH1 mutations in anaplastic gliomas, with a favorable impact that was more significant than that of 1p/19q codeletion or MGMT promoter methylation.	('mutations', 'Var', (52, 61))	('gliomas', 'Disease', (76, 83))	('MGMT', 'Gene', (169, 173))	('IDH1', 'Gene', (47, 51))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('MGMT', 'Gene', '4255', (169, 173))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('IDH1', 'Gene', '3417', (47, 51))
171443	24986089	Accompanying correlative study demonstrated that methylation of the promoter region of the MGMT gene in the tumor was associated with superior survival, regardless of treatment received, but the benefit was primarily seen in methylated patients.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('survival', 'CPA', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (236, 244))	('tumor', 'Disease', (108, 113))	('superior', 'PosReg', (134, 142))	('methylation', 'Var', (49, 60))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))
171497	24986089	There were reports that tumors with the variant 3 mutant (EGFRvIII), with resulting constitutive activation of EGFR tyrosine kinase activity, along with intact phosphatase and tensin analogue (PTEN) may be more responsive to EGFR inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('EGFR', 'Gene', '1956', (58, 62))	('tumors', 'Disease', (24, 30))	('activation', 'PosReg', (97, 107))	('EGFR', 'Gene', '1956', (111, 115))	('PTEN', 'Gene', (193, 197))	('EGFR', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('PTEN', 'Gene', '5728', (193, 197))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('variant 3', 'Var', (40, 49))	('EGFR', 'Gene', '1956', (225, 229))	('EGFR', 'Gene', (111, 115))	('EGFR', 'Gene', (225, 229))
171514	24986089	Aberrations and differential gene expression of EGFR, NF1, and PDGFRA/IDH1 help define the various subtypes and these pathways can be targeted using novel therapies.	('EGFR', 'Gene', '1956', (48, 52))	('PDGFRA', 'Gene', (63, 69))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('EGFR', 'Gene', (48, 52))	('IDH1', 'Gene', '3417', (70, 74))	('PDGFRA', 'Gene', '5156', (63, 69))	('Aberrations', 'Var', (0, 11))	('IDH1', 'Gene', (70, 74))
171516	24986089	Considerable research in genetic alterations in WHO grade II astrocytoma in adults has shown the role of inactivation of the TP53 tumor suppressor gene, heterozygous point mutations of the IDH1, and loss of chromosome 22q in these tumors.	('loss', 'Var', (199, 203))	('TP53', 'Gene', (125, 129))	('astrocytoma', 'Disease', 'MESH:D001254', (61, 72))	('astrocytoma', 'Disease', (61, 72))	('tumor', 'Disease', (130, 135))	('tumors', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (231, 236))	('IDH1', 'Gene', (189, 193))	('inactivation', 'Var', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('TP53', 'Gene', '7157', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('heterozygous point mutations', 'Var', (153, 181))	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('IDH1', 'Gene', '3417', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
171519	24986089	These mutations lead to conversion of alpha-ketoglutarate into D-2-hydroxyglutarate, an oncometabolite that drives the oncogenic activity of IDH mutations.	('lead to', 'Reg', (16, 23))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (63, 83))	('IDH', 'Gene', (141, 144))	('IDH', 'Gene', '3417', (141, 144))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (38, 57))	('conversion', 'MPA', (24, 34))	('mutations', 'Var', (6, 15))
171521	24986089	Recent discoveries of pathogenic mutations in IDH1, IDH2, ATRX, CIC, and FUBP1, have helped genomic characterization of low grade gliomas.	('IDH2', 'Gene', '3418', (52, 56))	('IDH1', 'Gene', (46, 50))	('CIC', 'Gene', '23152', (64, 67))	('ATRX', 'Gene', (58, 62))	('pathogenic', 'Reg', (22, 32))	('mutations', 'Var', (33, 42))	('gliomas', 'Disease', (130, 137))	('IDH1', 'Gene', '3417', (46, 50))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('FUBP1', 'Gene', '8880', (73, 78))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('CIC', 'Gene', (64, 67))	('IDH2', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (58, 62))	('FUBP1', 'Gene', (73, 78))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
171522	24986089	These mutations form the framework of molecular pathogenesis of these tumors and offers robust markers that not only enhance classification but also guide treatment.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('enhance', 'PosReg', (117, 124))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('classification', 'MPA', (125, 139))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (6, 15))
171523	24986089	Common cytogenetic alteration in oligodendroglial histology consists of an unbalanced t(1;19)(q10;p10) translocation that results in combined loss of chromosomal arms 1p/19q and leads to the loss of one hybrid chromosome and thus loss of heterozygosity.	('loss of heterozygosity', 'NegReg', (230, 252))	('loss', 'NegReg', (142, 146))	('loss', 'NegReg', (191, 195))	('chromosomal', 'Var', (150, 161))	('t(1;19)(q10;p10)', 'STRUCTURAL_ABNORMALITY', 'None', (86, 102))
171524	24986089	Tumors with 1p/19q-codeletions have a better prognosis than do histologically identical tumors of the same grade that do not harbor this codeletion.	('1p/19q-codeletions', 'Var', (12, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (88, 94))
171525	24986089	The key to successful treatment of these tumors will lie in the realization that these molecularly defined subsets are different disease entities and it is likely that specific targeted therapies aimed at the driver mutations will be more likely to be efficacious.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('mutations', 'Var', (216, 225))
171632	33937046	A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction.	('IDH', 'Gene', '3417', (161, 164))	('1p19q co-deletion', 'Var', (179, 196))	('glioma', 'Disease', (33, 39))	('TNFRSF12A', 'Gene', '51330', (73, 82))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('IDH', 'Gene', (161, 164))	('TNFRSF12A', 'Gene', (73, 82))
171638	33937046	The World Health Organization (WHO) recently proposed a novel glioma classification method based on the presence or absence of IDH mutations and 1p/19q co-deletion.	('IDH', 'Gene', (127, 130))	('mutations', 'Var', (131, 140))	('IDH', 'Gene', '3417', (127, 130))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('1p/19q co-deletion', 'Var', (145, 163))	('glioma', 'Disease', (62, 68))
171644	33937046	For example, it has been reported that the accumulation of regulatory T (T reg) cells in glioblastoma (GBM) contributes to the suppression of anti-tumor immunity, and the combined blockade of IL-12 and CTLA-4 acts on CD4 (+) cells, resulting in the reduction of FoxP3 (+) T reg cells and increases in effector T cells, thereby inhibiting tumor growth.	('tumor', 'Disease', (338, 343))	('CTLA-4', 'Gene', '1493', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('suppression', 'NegReg', (127, 138))	('tumor', 'Disease', (147, 152))	('CTLA-4', 'Gene', (202, 208))	('reduction', 'NegReg', (249, 258))	('FoxP3', 'Gene', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('increases', 'PosReg', (288, 297))	('FoxP3', 'Gene', '50943', (262, 267))	('IL-12', 'Gene', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('CD4', 'Gene', '920', (217, 220))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('effector T cells', 'CPA', (301, 317))	('inhibiting', 'NegReg', (327, 337))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CD4', 'Gene', (217, 220))	('glioblastoma', 'Disease', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('blockade', 'Var', (180, 188))
171646	33937046	PD-L1 inhibition therapy resulted in a significant inhibitory effect on GBM.	('GBM', 'Disease', (72, 75))	('PD-L1', 'Gene', (0, 5))	('inhibition', 'Var', (6, 16))	('inhibitory effect', 'NegReg', (51, 68))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('PD-L1', 'Gene', '29126', (0, 5))
171660	33937046	The variables used for screening the CGGA data included single gene expression, primary-recurrent-secondary (PRS) type, histology, grade, gender, age, radiation therapy, chemotherapy, IDH mutations, and 1p19q co-deletion.	('IDH', 'Gene', (184, 187))	('1p19q co-deletion', 'Var', (203, 220))	('single gene expression', 'Var', (56, 78))	('IDH', 'Gene', '3417', (184, 187))
171680	33937046	The survival data from glioma patients in the CGGA and GSE43378 datasets were significantly different between the high and low TNFRSF12A expression groups (p < 0.001).	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('high', 'Var', (114, 118))	('low', 'NegReg', (123, 126))	('TNFRSF12A', 'Gene', '51330', (127, 136))	('glioma', 'Disease', (23, 29))	('patients', 'Species', '9606', (30, 38))	('different', 'Reg', (92, 101))	('TNFRSF12A', 'Gene', (127, 136))
171685	33937046	We constructed a nomogram based on seven meaningful prognosis-related variables in the CGGA data, including TNFRSF12A expression, PRS type, grade, age, chemotherapy, IDH mutations, and 1p19q co-deletion.	('TNFRSF12A', 'Gene', (108, 117))	('IDH', 'Gene', (166, 169))	('1p19q co-deletion', 'Var', (185, 202))	('IDH', 'Gene', '3417', (166, 169))	('TNFRSF12A', 'Gene', '51330', (108, 117))
171688	33937046	Clinical correlation analysis of the CGGA data demonstrated that the expression level for TNFRSF12A was significantly correlated with PRS type, histology, grade, age, chemotherapy, IDH mutations, and 1p19q co-deletion in glioma samples.	('expression level', 'MPA', (69, 85))	('IDH', 'Gene', (181, 184))	('TNFRSF12A', 'Gene', '51330', (90, 99))	('TNFRSF12A', 'Gene', (90, 99))	('PRS', 'Disease', (134, 137))	('glioma', 'Disease', (221, 227))	('IDH', 'Gene', '3417', (181, 184))	('correlated', 'Reg', (118, 128))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('1p19q co-deletion', 'Var', (200, 217))
171690	33937046	TNFRSF12A exhibited higher expression in wildtype and 1p19q non-coding glioma compared to IDH mutants or 1p19q co-deletions (  Figures 7C, D  ).	('1p19q', 'Var', (54, 59))	('IDH', 'Gene', (90, 93))	('TNFRSF12A', 'Gene', '51330', (0, 9))	('higher', 'PosReg', (20, 26))	('glioma', 'Disease', (71, 77))	('IDH', 'Gene', '3417', (90, 93))	('expression', 'MPA', (27, 37))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('TNFRSF12A', 'Gene', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
171737	33937046	Anti-TNFRSF12A antibodies can inhibit tumor growth moderately and significantly prolong life expectancy by alleviating tumor-induced weight loss.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (119, 124))	('weight loss', 'Disease', (133, 144))	('alleviating', 'NegReg', (107, 118))	('TNFRSF12A', 'Gene', '51330', (5, 14))	('weight loss', 'Phenotype', 'HP:0001824', (133, 144))	('TNFRSF12A', 'Gene', (5, 14))	('inhibit', 'NegReg', (30, 37))	('prolong', 'PosReg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('life expectancy', 'CPA', (88, 103))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('weight loss', 'Disease', 'MESH:D015431', (133, 144))	('antibodies', 'Var', (15, 25))
171738	33937046	This suggests that anti-TNFRSF12A antibodies prevent tumors from auto-damage and deterioration, which could preserve body mass.	('body', 'MPA', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('antibodies', 'Var', (34, 44))	('TNFRSF12A', 'Gene', '51330', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prevent', 'NegReg', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('TNFRSF12A', 'Gene', (24, 33))	('tumors', 'Disease', (53, 59))
171745	33937046	Moreover, the accumulation of mutations also causes over-activation of the PI3K/Akt/mTOR signaling pathway.	('Akt', 'Gene', '207', (80, 83))	('Akt', 'Gene', (80, 83))	('mTOR', 'Gene', '2475', (84, 88))	('mTOR', 'Gene', (84, 88))	('mutations', 'Var', (30, 39))	('over-activation', 'PosReg', (52, 67))
171752	33937046	Patients with IDH mutations presented significantly longer survival periods than those without mutations.	('survival periods', 'CPA', (59, 75))	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', '3417', (14, 17))	('longer', 'PosReg', (52, 58))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (18, 27))
171753	33937046	Furthermore, IDH mutations increased sensitivity to TMZ by disrupting the repair process of parp1-mediated DNA.	('IDH', 'Gene', '3417', (13, 16))	('parp1', 'Gene', '142', (92, 97))	('increased', 'PosReg', (27, 36))	('parp1', 'Gene', (92, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('sensitivity', 'MPA', (37, 48))	('disrupting', 'NegReg', (59, 69))	('repair', 'MPA', (74, 80))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
171760	33937046	RG7212 effectively inhibited tumor growth in athymic (nude) mice tumor xenograft models of renal cell carcinoma (ACHN, Caki-1), breast cancer (MDA-MB-231), and non-small cell lung cancer (Calu-3).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('renal cell carcinoma', 'Disease', (91, 111))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('RG7212', 'Var', (0, 6))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (160, 186))	('inhibited', 'NegReg', (19, 28))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('non-small cell lung cancer', 'Disease', (160, 186))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RG7212', 'Chemical', 'MESH:C000601202', (0, 6))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (143, 153))	('tumor', 'Disease', (29, 34))	('nude) mice', 'Species', '10090', (54, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
171782	33937046	Studies have revealed that specific drug modifications can improve the precision therapy of TNFRSF12A for gliomas.	('TNFRSF12A', 'Gene', '51330', (92, 101))	('precision therapy', 'MPA', (71, 88))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('improve', 'PosReg', (59, 66))	('TNFRSF12A', 'Gene', (92, 101))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('modifications', 'Var', (41, 54))
171795	33691023	New technologies provided a comprehensive list of genomic and epigenetic aberrations for tumor growth and proliferation.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('epigenetic aberrations', 'Var', (62, 84))	('proliferation', 'CPA', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
171797	33691023	For example, gliomas with mutated IDH1 and IDH2 have improved prognosis compared to gliomas with wild-type IDH.	('IDH', 'Gene', (34, 37))	('gliomas', 'Disease', (84, 91))	('IDH', 'Gene', '3417', (107, 110))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('IDH1', 'Gene', '3417', (34, 38))	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', '3417', (34, 37))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('prognosis', 'MPA', (62, 71))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('IDH2', 'Gene', (43, 47))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('mutated', 'Var', (26, 33))	('IDH2', 'Gene', '3418', (43, 47))	('improved', 'PosReg', (53, 61))	('IDH', 'Gene', (43, 46))	('IDH', 'Gene', (107, 110))	('gliomas', 'Disease', (13, 20))	('IDH1', 'Gene', (34, 38))
171814	33691023	Biased random walks are applied to each sample separately by considering the mutated genes as seeds hence prioritizing local neighborhood of genomic alterations (See Supplementary Method Section S1.1).	('S1.1', 'Gene', '6267', (195, 199))	('S1.1', 'Gene', (195, 199))	('mutated', 'Var', (77, 84))
171829	33691023	On the other hand, uveal melanoma patients are enriched for cluster 89, which shows dysregulation in GPCR signaling, the main biological processes impacted by the recurrent mutations in uveal melonama.	('dysregulation', 'MPA', (84, 97))	('GPCR signaling', 'MPA', (101, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('mutations', 'Var', (173, 182))	('uveal', 'Disease', (19, 24))	('patients', 'Species', '9606', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))
171848	33691023	However separately from Rectum and Colon Adenocarcinomas, Stomach Adenocarcinoma is highly enriched for Defective CSF2RA/CSF2RB causes pulmonary surfactant metabolism dysfunction pathway, which has been previously associated with Stomach Adenocarcinomas.	('Stomach Adenocarcinomas', 'Disease', 'MESH:D000230', (230, 253))	('Defective', 'Var', (104, 113))	('CSF2RB', 'Gene', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('pulmonary surfactant metabolism dysfunction', 'Disease', 'MESH:C580477', (135, 178))	('Stomach Adenocarcinomas', 'Disease', (230, 253))	('pulmonary surfactant metabolism dysfunction', 'Disease', (135, 178))	('Colon Adenocarcinomas, Stomach Adenocarcinoma', 'Disease', 'MESH:D000230', (35, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('CSF2RA', 'Gene', (114, 120))	('CSF2RA', 'Gene', '1438', (114, 120))	('causes', 'Reg', (128, 134))	('CSF2RB', 'Gene', '1439', (121, 127))
171874	33691023	Furthermore, we have shown that the proposed approach is able to elucidate increased functional relevance by strictly enforcing frequency requirements hence decreasing false positives in contrast with previously established methods that either focus on gene-level approaches or do not consider the underlying topology of the patient data.	('decreasing', 'NegReg', (157, 167))	('false positives', 'MPA', (168, 183))	('patient', 'Species', '9606', (325, 332))	('frequency', 'Var', (128, 137))
171900	33026636	The most frequent aberration is the KIAA1549:BRAF-fusion, beside less frequent alterations such as other BRAF fusions, BRAF mutations, FGFR1 mutations, NF1 mutations, KRAS mutations and PTPN11 mutations or NTRK2 fusions.	('NF1', 'Gene', (152, 155))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('mutations', 'Var', (193, 202))	('NTRK2', 'Gene', (206, 211))	('FGFR1', 'Gene', (135, 140))	('KIAA1549', 'Gene', '57670', (36, 44))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('fusions', 'Reg', (212, 219))	('KRAS', 'Gene', '3845', (167, 171))	('PTPN11', 'Gene', (186, 192))	('KIAA1549', 'Gene', (36, 44))	('mutations', 'Var', (141, 150))	('mutations', 'Var', (156, 165))	('PTPN11', 'Gene', '5781', (186, 192))	('KRAS', 'Gene', (167, 171))	('NTRK2', 'Gene', '4915', (206, 211))	('FGFR1', 'Gene', '2260', (135, 140))	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (124, 133))	('NF1', 'Gene', '4763', (152, 155))	('BRAF', 'Gene', (105, 109))
171909	33026636	Eight of the 11 patients with low-grade tumors received trametinib monotherapy, of which four had a BRAF-fusion, one had a BRAF V600E mutation, one an NF1 alteration and two no detected MAPK alteration.	('V600E', 'Mutation', 'rs113488022', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (16, 24))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('BRAF', 'Gene', '673', (100, 104))	('NF1', 'Gene', (151, 154))	('V600E', 'Var', (128, 133))	('trametinib', 'Chemical', 'MESH:C560077', (56, 66))	('NF1', 'Gene', '4763', (151, 154))	('BRAF', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
171911	33026636	The most recently published case series reported on eleven pLGG patients treated with trametinib, four of which had a KIAA1549:BRAF-fusion, four an NF1 mutation, one had an FGFR mutation and one had a CDKN2A loss.	('NF1', 'Gene', (148, 151))	('CDKN2A', 'Gene', (201, 207))	('patients', 'Species', '9606', (64, 72))	('CDKN2A', 'Gene', '1029', (201, 207))	('BRAF', 'Gene', '673', (127, 131))	('NF1', 'Gene', '4763', (148, 151))	('BRAF', 'Gene', (127, 131))	('trametinib', 'Chemical', 'MESH:C560077', (86, 96))	('KIAA1549', 'Gene', '57670', (118, 126))	('pLGG', 'Chemical', '-', (59, 63))	('KIAA1549', 'Gene', (118, 126))	('mutation', 'Var', (152, 160))
171921	33026636	NF1 alterations were detected by sequencing of the NF1 locus or gene panel sequencing.	('alterations', 'Var', (4, 15))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', (51, 54))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', '4763', (51, 54))
171922	33026636	BRAF and FGFR1 mutations were detected by gene panel sequencing.	('FGFR1', 'Gene', '2260', (9, 14))	('mutations', 'Var', (15, 24))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('FGFR1', 'Gene', (9, 14))
171941	33026636	In total 7/18 (38%) patients were classified as low-grade gliomas by methylation array (full match).	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('patients', 'Species', '9606', (20, 28))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('methylation', 'Var', (69, 80))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
171943	33026636	Information on the underlying MAPK alteration was already available for 11/18 (61%) patients and was retrospectively detected in 2/18 (11%) patients (patients 15 and 17) leading to a total of 13/18 (72%) of patients with molecularly detected MAPK alteration.	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (84, 92))	('MAPK', 'Gene', (30, 34))	('alteration', 'Var', (247, 257))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (140, 148))	('alteration', 'Var', (35, 45))	('MAPK', 'Gene', (242, 246))
171944	33026636	Alterations detected included 8 KIAA1549:BRAF-fusions, three NF1 alterations, one BRAF V600E mutation and one FGFR1 K654Q mutation.	('alterations', 'Var', (65, 76))	('K654Q', 'Var', (116, 121))	('V600E', 'Var', (87, 92))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('NF1', 'Gene', (61, 64))	('FGFR1', 'Gene', (110, 115))	('BRAF', 'Gene', '673', (41, 45))	('NF1', 'Gene', '4763', (61, 64))	('K654Q', 'Mutation', 'p.K654Q', (116, 121))	('BRAF', 'Gene', (41, 45))	('KIAA1549', 'Gene', '57670', (32, 40))	('V600E', 'Mutation', 'rs113488022', (87, 92))	('KIAA1549', 'Gene', (32, 40))	('FGFR1', 'Gene', '2260', (110, 115))
171945	33026636	Of note, molecular NF1 testing was performed in blood and tumor in two patients (patient 2: p.514_514del, and patient 18: p.888fs, both detected by gene panel sequencing) and only in blood in one patient (patient 4: p.1153fs detected by targeted sequencing of the NF1 gene including exon-flanking intronic regions).	('NF1', 'Gene', '4763', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patient', 'Species', '9606', (205, 212))	('patient', 'Species', '9606', (81, 88))	('NF1', 'Gene', (19, 22))	('patients', 'Species', '9606', (71, 79))	('p.514_514del', 'Mutation', 'p.514_514del', (92, 104))	('patient', 'Species', '9606', (196, 203))	('p.888fs', 'Var', (122, 129))	('NF1', 'Gene', '4763', (19, 22))	('p.514_514del', 'Var', (92, 104))	('patient', 'Species', '9606', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('p.1153fs', 'Mutation', 'p.1153fs', (216, 224))	('p.1153fs', 'Var', (216, 224))	('patient', 'Species', '9606', (71, 78))	('NF1', 'Gene', (264, 267))
171988	33026636	Selumetinib was shown to be active in different genetic backgrounds including KIAA1549:BRAF fusions, BRAF V600E mutation and NF1 mutations in clinical phase 1 and 2 trials.	('KIAA1549', 'Gene', (78, 86))	('BRAF', 'Gene', (101, 105))	('NF1', 'Gene', (125, 128))	('KIAA1549', 'Gene', '57670', (78, 86))	('NF1', 'Gene', '4763', (125, 128))	('V600E mutation', 'Var', (106, 120))	('mutations', 'Var', (129, 138))	('V600E', 'Mutation', 'rs113488022', (106, 111))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', (87, 91))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('BRAF', 'Gene', '673', (87, 91))
172026	33026636	In summary, we can confirm that oral trametinib treatment results in clinically meaningful responses in progressive pLGG patients with either KIAA1549:BRAF-fusion or NF1 mutation.	('NF1', 'Gene', (166, 169))	('trametinib', 'Chemical', 'MESH:C560077', (37, 47))	('NF1', 'Gene', '4763', (166, 169))	('BRAF', 'Gene', '673', (151, 155))	('KIAA1549', 'Gene', '57670', (142, 150))	('pLGG', 'Chemical', '-', (116, 120))	('BRAF', 'Gene', (151, 155))	('KIAA1549', 'Gene', (142, 150))	('responses', 'MPA', (91, 100))	('patients', 'Species', '9606', (121, 129))	('mutation', 'Var', (170, 178))
172047	32103982	Microenvironment analysis referred that high IFI30 expression accompanied with more infiltration of M2 type macrophages.	('high', 'Var', (40, 44))	('infiltration', 'CPA', (84, 96))	('IFI30', 'Gene', '10437', (45, 50))	('expression', 'MPA', (51, 61))	('more', 'PosReg', (79, 83))	('IFI30', 'Gene', (45, 50))
172061	32103982	Further studies defined IFI30's relationship with tumor malignancy and enhanced immune response and the effects and molecular mechanism of knocking down of IFI30 on re-sensitize to TMZ were finally explored, which offered novel insights for GBM's chemotherapy.	('enhanced', 'PosReg', (71, 79))	('GBM', 'Disease', (241, 244))	('IFI30', 'Gene', (156, 161))	('IFI30', 'Gene', '10437', (24, 29))	('GBM', 'Disease', 'MESH:D005909', (241, 244))	('tumor malignancy', 'Disease', (50, 66))	('IFI30', 'Gene', (24, 29))	('GBM', 'Phenotype', 'HP:0012174', (241, 244))	('knocking down', 'Var', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor malignancy', 'Disease', 'MESH:D009369', (50, 66))	('IFI30', 'Gene', '10437', (156, 161))	('TMZ', 'Chemical', 'MESH:D000077204', (181, 184))	('immune response', 'CPA', (80, 95))
172070	32103982	Limma R package was used to calculate the differential CNV genes between high and low IFI30 groups which were demonstrated by Rcircos packages.	('high', 'Var', (73, 77))	('IFI30', 'Gene', '10437', (86, 91))	('IFI30', 'Gene', (86, 91))
172072	32103982	Gene set enrichment analysis (GSEA) was conducted to explore differential signal pathway, immune response and regulation of leukocyte mediated immunity between patients with low and high IFI30.	('patients', 'Species', '9606', (160, 168))	('low', 'Var', (174, 177))	('IFI30', 'Gene', '10437', (187, 192))	('GSEA', 'Chemical', '-', (30, 34))	('IFI30', 'Gene', (187, 192))
172076	32103982	Human brain cancer cell lines U87MG, 229MG, 251MG, T98MG and Normal Human Astrocytes (NHA) were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences (Shanghai, China).	('Human', 'Species', '9606', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('Human', 'Species', '9606', (68, 73))	('cancer', 'Disease', (12, 18))	('U87MG', 'CellLine', 'CVCL:0022', (30, 35))	('T98MG', 'Var', (51, 56))	('brain cancer', 'Phenotype', 'HP:0030692', (6, 18))	('T98MG', 'CellLine', 'CVCL:B368', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
172078	32103982	IFI30 knockdown small-interfering RNA (siRNA) and the negative control RNA (siNC) were obtained from Sangon Biotech (Shanghai, China).	('IFI30', 'Gene', '10437', (0, 5))	('siNC', 'Chemical', 'MESH:C052464', (76, 80))	('small-interfering', 'Var', (16, 33))	('IFI30', 'Gene', (0, 5))	('knockdown small-interfering', 'Var', (6, 33))
172120	32103982	Moreover, we found that IFI30 expression value elevated in GBM patients with IDH1 wild-type, MGMT promoter unmethylated as well as mesenchymal sub-type, recognized as more aggressive subtypes of glioma (Figure 2D-F).	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('GBM', 'Disease', (59, 62))	('expression', 'MPA', (30, 40))	('MGMT', 'Gene', '4255', (93, 97))	('IFI30', 'Gene', '10437', (24, 29))	('MGMT', 'Gene', (93, 97))	('unmethylated', 'Var', (107, 119))	('elevated', 'PosReg', (47, 55))	('GBM', 'Disease', 'MESH:D005909', (59, 62))	('IDH1', 'Gene', (77, 81))	('IFI30', 'Gene', (24, 29))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('glioma', 'Disease', (195, 201))	('IDH1', 'Gene', '3417', (77, 81))	('patients', 'Species', '9606', (63, 71))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
172124	32103982	IDH1 mutation and MGMT promoter methylation status are two main factors driving the malignancy of GBM.	('GBM', 'Disease', 'MESH:D005909', (98, 101))	('MGMT', 'Gene', (18, 22))	('MGMT', 'Gene', '4255', (18, 22))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('IDH1', 'Gene', (0, 4))	('GBM', 'Disease', (98, 101))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
172126	32103982	Interestingly, we found there was a robust survival difference between low and high IFI30 expression groups in IDH1 wild-type patients, but not in those patients with IDH1 mutation (Figure 3A and B).	('patients', 'Species', '9606', (153, 161))	('IDH1', 'Gene', '3417', (111, 115))	('IDH1', 'Gene', (167, 171))	('high', 'Var', (79, 83))	('patients', 'Species', '9606', (126, 134))	('IFI30', 'Gene', '10437', (84, 89))	('IDH1', 'Gene', '3417', (167, 171))	('IDH1', 'Gene', (111, 115))	('IFI30', 'Gene', (84, 89))
172128	32103982	High IFI30 expression patients exhibited a significant worse survival compared with low ones just in GBM with MGMT promoter methylation, but not in those patients with MGMT promoter unmethylated (Figure 3C and D).	('MGMT', 'Gene', '4255', (110, 114))	('MGMT', 'Gene', (168, 172))	('MGMT', 'Gene', (110, 114))	('IFI30', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (154, 162))	('GBM', 'Disease', (101, 104))	('GBM', 'Disease', 'MESH:D005909', (101, 104))	('IFI30', 'Gene', '10437', (5, 10))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('MGMT', 'Gene', '4255', (168, 172))
172131	32103982	In the high IFI30 expression group, somatic mutation profiles revealed a high mutation frequency in RB1, while IDH1, ATRX, PDGFRA and MROH2B mutated more frequently in the low IFI30 group (Figure 4B).	('IFI30', 'Gene', (12, 17))	('mutated', 'Var', (141, 148))	('MROH2B', 'Gene', (134, 140))	('RB1', 'Gene', (100, 103))	('mutation', 'Var', (78, 86))	('IDH1', 'Gene', '3417', (111, 115))	('MROH2B', 'Gene', '133558', (134, 140))	('RB1', 'Gene', '5925', (100, 103))	('IFI30', 'Gene', '10437', (176, 181))	('ATRX', 'Gene', (117, 121))	('PDGFRA', 'Gene', '5156', (123, 129))	('IFI30', 'Gene', '10437', (12, 17))	('IFI30', 'Gene', (176, 181))	('ATRX', 'Gene', '546', (117, 121))	('IDH1', 'Gene', (111, 115))	('PDGFRA', 'Gene', (123, 129))
172132	32103982	To characterize IFI30-specific SCNAs, we identified differential copy number variation genes between low and high IFI30 groups (Figure 4C).	('copy number variation genes', 'Var', (65, 92))	('low', 'Var', (101, 104))	('IFI30', 'Gene', (16, 21))	('IFI30', 'Gene', '10437', (114, 119))	('IFI30', 'Gene', '10437', (16, 21))	('IFI30', 'Gene', (114, 119))
172133	32103982	High IFI30 groups existed Chromosome 5, 22 and X partial fragments amplification and Chromosome 8 partial fragments deletion (Figure 4D).	('partial fragments deletion', 'Var', (98, 124))	('IFI30', 'Gene', '10437', (5, 10))	('IFI30', 'Gene', (5, 10))
172137	32103982	However, there was no significant difference between high and low IFI30 groups in GBM patients without chemotherapy (Figure 5B).	('GBM', 'Disease', 'MESH:D005909', (82, 85))	('high', 'Var', (53, 57))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('IFI30', 'Gene', '10437', (66, 71))	('IFI30', 'Gene', (66, 71))	('GBM', 'Disease', (82, 85))	('patients', 'Species', '9606', (86, 94))
172143	32103982	Nevertheless, the survival time of MGMT promoter-methylated patients with high IFI30 was just similar to that of unmethylated patients (Figure 5E and F).	('high', 'Var', (74, 78))	('MGMT', 'Gene', (35, 39))	('IFI30', 'Gene', '10437', (79, 84))	('patients', 'Species', '9606', (60, 68))	('MGMT', 'Gene', '4255', (35, 39))	('IFI30', 'Gene', (79, 84))	('patients', 'Species', '9606', (126, 134))
172153	32103982	To further explore the molecular mechanism mediated by IFI30, we conducted GSEA and identified that interleukin 6 (IL6) and signal transducer and activator of transcription (STAT) signal pathway enriched distinctly in high IFI30 group (Figure 6F).	('interleukin 6', 'Gene', '3569', (100, 113))	('high', 'Var', (218, 222))	('IFI30', 'Gene', '10437', (223, 228))	('IL6', 'Gene', (115, 118))	('IFI30', 'Gene', (223, 228))	('IL6', 'Gene', '3569', (115, 118))	('interleukin 6', 'Gene', (100, 113))	('GSEA', 'Chemical', '-', (75, 79))	('IFI30', 'Gene', '10437', (55, 60))	('IFI30', 'Gene', (55, 60))
172154	32103982	Finally, we performed Western blotting and confirmed that IFI30 knockdown deregulated the expression of IL6 and STAT6 level, which might further regulate GBM chemotherapy sensitivity (Figure 6G).	('GBM', 'Disease', 'MESH:D005909', (154, 157))	('IFI30', 'Gene', '10437', (58, 63))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('knockdown', 'Var', (64, 73))	('deregulated', 'NegReg', (74, 85))	('IL6', 'Gene', '3569', (104, 107))	('IFI30', 'Gene', (58, 63))	('STAT6', 'Gene', (112, 117))	('expression', 'MPA', (90, 100))	('GBM', 'Disease', (154, 157))	('IL6', 'Gene', (104, 107))	('STAT6', 'Gene', '6778', (112, 117))	('regulate', 'Reg', (145, 153))
172156	32103982	GSEA further verified the biological functions of IFI30, and the results suggested that the high IFI30 group possessed enhanced immune response and regulation of leukocyte mediated immunity in the CGGA RNA-seq cohort (Figure 7B) and other two cohorts (Supplementary Figure S3A and B).	('IFI30', 'Gene', '10437', (50, 55))	('high', 'Var', (92, 96))	('IFI30', 'Gene', (50, 55))	('S3A and B', 'Gene', '6189', (273, 282))	('regulation', 'MPA', (148, 158))	('leukocyte mediated immunity', 'MPA', (162, 189))	('IFI30', 'Gene', '10437', (97, 102))	('immune response', 'CPA', (128, 143))	('GSEA', 'Chemical', '-', (0, 4))	('enhanced', 'PosReg', (119, 127))	('IFI30', 'Gene', (97, 102))
172172	32103982	However, considering the fact of chemoresistance of glioma cells to TMZ, the treatment is still unsatisfactory even in those patients with MGMT promoter methylated.	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('MGMT', 'Gene', (139, 143))	('MGMT', 'Gene', '4255', (139, 143))	('TMZ', 'Chemical', 'MESH:D000077204', (68, 71))	('glioma', 'Disease', (52, 58))	('methylated', 'Var', (153, 163))	('patients', 'Species', '9606', (125, 133))
172181	32103982	IDH1 mutation is a crucial molecular event in glioma and predicts a better prognosis in GBM.	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('glioma', 'Disease', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('GBM', 'Disease', (88, 91))	('IDH1', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('GBM', 'Disease', 'MESH:D005909', (88, 91))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
172183	32103982	We found IFI30 highly expressed in IDH1 wild-type and more IDH1 mutation enrichment in the low IFI30 group.	('IFI30', 'Gene', (9, 14))	('IDH1', 'Gene', '3417', (59, 63))	('IDH1', 'Gene', (35, 39))	('IFI30', 'Gene', '10437', (95, 100))	('mutation', 'Var', (64, 72))	('IDH1', 'Gene', '3417', (35, 39))	('IFI30', 'Gene', (95, 100))	('IFI30', 'Gene', '10437', (9, 14))	('IDH1', 'Gene', (59, 63))
172193	32103982	We conducted somatic mutation profiles in GBM patients stratified by IFI30 expression, the results exhibited that IDH1 and ATRX mutated more frequently in low IFI30 group, increasing evidences indicated that IDH1 and ATRX wild type conferred a higher incidence of TMZ resistance, which may indicate that IFI30 also has the ability in TMZ sensitivity regulation.	('TMZ', 'Chemical', 'MESH:D000077204', (264, 267))	('TMZ', 'Chemical', 'MESH:D000077204', (334, 337))	('IDH1', 'Gene', (114, 118))	('patients', 'Species', '9606', (46, 54))	('IDH1', 'Gene', (208, 212))	('IFI30', 'Gene', '10437', (304, 309))	('ATRX', 'Gene', (123, 127))	('IFI30', 'Gene', (304, 309))	('GBM', 'Disease', (42, 45))	('TMZ resistance', 'MPA', (264, 278))	('GBM', 'Disease', 'MESH:D005909', (42, 45))	('ATRX', 'Gene', '546', (123, 127))	('IDH1', 'Gene', '3417', (208, 212))	('IDH1', 'Gene', '3417', (114, 118))	('ATRX', 'Gene', (217, 221))	('IFI30', 'Gene', '10437', (159, 164))	('ATRX', 'Gene', '546', (217, 221))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('IFI30', 'Gene', (159, 164))	('mutated', 'Var', (128, 135))	('IFI30', 'Gene', '10437', (69, 74))	('IFI30', 'Gene', (69, 74))
172194	32103982	By performing analyses in CGGA and TCGA cohorts, we found that high IFI30 expression indeed conferred chemotherapy resistance in GBM.	('GBM', 'Disease', 'MESH:D005909', (129, 132))	('chemotherapy resistance', 'MPA', (102, 125))	('IFI30', 'Gene', '10437', (68, 73))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('IFI30', 'Gene', (68, 73))	('conferred', 'Reg', (92, 101))	('high', 'Var', (63, 67))	('GBM', 'Disease', (129, 132))
172200	32103982	Furthermore, we found there existed a close relationship between IFI30 expression and IDH1 mutant status, IFI30's overexpression often occurs in IDH1 wild-type subgroup, and commonly accompanied with a more inhibitory immune microenvironment, which was characterized with more infiltration of M2 macrophage and highly expression of inhibitory check points as well as inflammatory genes.	('accompanied with', 'Reg', (183, 199))	('overexpression', 'PosReg', (114, 128))	('IFI30', 'Gene', '10437', (106, 111))	('inhibitory immune', 'MPA', (207, 224))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', (145, 149))	('IDH1', 'Gene', '3417', (86, 90))	('IFI30', 'Gene', (106, 111))	('IFI30', 'Gene', '10437', (65, 70))	('IDH1', 'Gene', '3417', (145, 149))	('more', 'PosReg', (202, 206))	('more infiltration', 'PosReg', (272, 289))	('IFI30', 'Gene', (65, 70))	('mutant', 'Var', (91, 97))
172216	31885736	Abnormality of metabolism is the hallmark of cancer, and identification of the metabolic weaknesses of cancer cells has prompted new therapeutic approaches toward tumor treatments.	('Abnormality', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('metabolism', 'MPA', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', (45, 51))
172219	31885736	Fatty acid is the cornerstone of cell membrane formation, energy storage, and signaling molecule production in carcinogenesis; thus targeting at the pathway of fatty acid metabolism might inhibit rapid proliferation of the cancer cells.	('carcinogenesis', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('inhibit', 'NegReg', (188, 195))	('Fatty acid', 'Chemical', 'MESH:D005227', (0, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('fatty acid', 'Chemical', 'MESH:D005227', (160, 170))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))	('targeting', 'Var', (132, 141))
172244	31885736	Kaplan-Meier survival analysis showed that patients with gliomas in cluster1 had a significantly poorer prognosis than in cluster2 (Figure 1(e)).	('patients', 'Species', '9606', (43, 51))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('poorer', 'NegReg', (97, 103))	('cluster1', 'Var', (68, 76))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
172245	31885736	Cluster1 had a strong correlation with older age at diagnosis (median age: 45, p < 0.001), classical or mesenchymal subtypes (66.85%, p < 0.001), glioblastoma phenotype (63.54%, p < 0.001), IDH wildtype (75.14%, p < 0.001), and 1p/19q non-codeletion (87.29%, p < 0.001; ).	('Cluster1', 'Gene', (0, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('1p/19q non-codeletion', 'Var', (228, 249))	('IDH', 'Gene', (190, 193))	('IDH', 'Gene', '3417', (190, 193))	('glioblastoma', 'Disease', (146, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))
172246	31885736	By contrast, cluster2 mainly represented younger age at diagnosis (median age: 39, p < 0.001), proneural or neural subtypes (86.92%, p < 0.001), lower grade phenotype (80.77%, p < 0.001), IDH mutation (86.15%, p < 0.001), and 1p/19q non-codeletion (68.66%, p < 0.001, ).	('IDH', 'Gene', '3417', (188, 191))	('IDH', 'Gene', (188, 191))	('1p/19q non-codeletion', 'Var', (226, 247))
172255	31885736	Patients in high risk groups were linked to older age at diagnosis (median age: 47.5, p < 0.001), classical or mesenchymal subtypes (73.45%, p < 0.001), glioblastoma phenotype (70.37%, p < 0.001), IDH wildtype (75.31%, p < 0.001), and 1p/19q non-codeletion (93.96%, p < 0.001, ).	('1p/19q non-codeletion', 'Var', (235, 256))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', '3417', (197, 200))	('IDH', 'Gene', (197, 200))	('glioblastoma', 'Disease', (153, 165))
172256	31885736	By contrast, patients in low risk groups were associated with younger age at diagnosis (median age: 39, p < 0.001), proneural or neural subtypes (85.89%, p < 0.001), lower grade phenotype (81.60%, p < 0.001), IDH mutation (77.91%, p < 0.001) and 1p/19q non-codeletion (70.51%, p < 0.001, ).	('1p/19q non-codeletion', 'Var', (246, 267))	('patients', 'Species', '9606', (13, 21))	('IDH', 'Gene', (209, 212))	('IDH', 'Gene', '3417', (209, 212))
172257	31885736	In TCGA dataset, we also observed that patients in high risk group were correlated with older age at diagnosis (median age: 54, p < 0.001), classical or mesenchymal subtypes (65.19%, p < 0.001), IDH wildtype (64.74%, p < 0.001), and 1p/19q non-codeletion (96.32%, p < 0.001, ); while patients in low risk group had a strong correlation with younger age at diagnosis (median age: 40, p < 0.001), proneural or neural subtypes (97.31%, p < 0.001), lower grade phenotype (99.70%, p < 0.001), IDH mutation (93.36%, p < 0.001) and 1p/19q non-codeletion (53.29%, p < 0.001, ).	('IDH', 'Gene', (195, 198))	('IDH', 'Gene', (488, 491))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (284, 292))	('1p/19q non-codeletion', 'Var', (525, 546))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', '3417', (488, 491))	('lower grade phenotype', 'CPA', (445, 466))	('proneural', 'CPA', (395, 404))
172283	31885736	Furthermore, several oncometabolites have been confirmed to be the accumulated metabolic products of IDH mutation.	('IDH', 'Gene', '3417', (101, 104))	('IDH', 'Gene', (101, 104))	('mutation', 'Var', (105, 113))
172293	31885736	Clinical trials of anti-B7-H3 (NCT02475213) and anti-Tim-3 (NCT02817633) are carrying on, and our study showed the fatty acid catabolic metabolism-related gene risk signature might be a possible metabolic marker of the immunotherapy for gliomas.	('NCT02475213', 'Var', (31, 42))	('NCT02817633', 'Var', (60, 71))	('fatty acid', 'Chemical', 'MESH:D005227', (115, 125))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('Tim-3', 'Gene', (53, 58))	('B7-H3', 'Gene', (24, 29))	('Tim-3', 'Gene', '84868', (53, 58))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('gliomas', 'Disease', (237, 244))	('B7-H3', 'Gene', '80381', (24, 29))
172303	29887919	MEGF10, a Glioma Survival-Associated Molecular Signature, Predicts IDH Mutation Status Glioma is the most common primary brain tumor with various genetic alterations; among which, IDH mutation is the most common mutation and plays an important role in glioma early development, especially in lower grade glioma (LGG, WHO II-III).	('brain tumor', 'Phenotype', 'HP:0030692', (121, 132))	('MEGF10', 'Gene', (0, 6))	('Mutation', 'Var', (71, 79))	('brain tumor', 'Disease', (121, 132))	('brain tumor', 'Disease', 'MESH:D001932', (121, 132))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))	('Glioma', 'Disease', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MEGF10', 'Gene', '84466', (0, 6))	('glioma', 'Disease', (304, 310))	('Glioma', 'Disease', 'MESH:D005910', (10, 16))	('glioma', 'Disease', 'MESH:D005910', (304, 310))	('mutation', 'Var', (184, 192))	('IDH', 'Gene', (180, 183))	('IDH', 'Gene', (67, 70))	('Glioma', 'Phenotype', 'HP:0009733', (10, 16))	('Glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (304, 310))	('glioma', 'Disease', (252, 258))	('Glioma', 'Disease', (10, 16))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', '3417', (67, 70))	('glioma', 'Disease', 'MESH:D005910', (252, 258))	('Glioma', 'Phenotype', 'HP:0009733', (87, 93))
172304	29887919	Previous studies have found that IDH mutation is tightly associated with extensive methylation across whole genome in glioma.	('glioma', 'Disease', (118, 124))	('mutation', 'Var', (37, 45))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('IDH', 'Gene', (33, 36))	('extensive methylation across whole', 'MPA', (73, 107))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('IDH', 'Gene', '3417', (33, 36))
172306	29887919	A package compiled under R language called Tspair was used as the main analytic tool to find potential probes that were significantly affected by IDH mutation.	('mutation', 'Var', (150, 158))	('IDH', 'Gene', '3417', (146, 149))	('IDH', 'Gene', (146, 149))
172307	29887919	As a result, we found one pair of probes, cg06940792 and cg26025891, which was capable of predicting IDH mutation status precisely.	('predicting', 'Reg', (90, 100))	('cg26025891', 'Var', (57, 67))	('cg26025891', 'Chemical', '-', (57, 67))	('IDH', 'Gene', (101, 104))	('cg06940792', 'Var', (42, 52))	('IDH', 'Gene', '3417', (101, 104))	('cg06940792', 'Chemical', '-', (42, 52))
172308	29887919	The hypermethylated probe was cg06940792, designed in the promoter region of MEGF10, while the hypomethylated probe was cg26025891, designed in the promoter region of PSTPIP1.	('PSTPIP1', 'Gene', (167, 174))	('cg06940792', 'Var', (30, 40))	('cg06940792', 'Chemical', '-', (30, 40))	('cg26025891', 'Chemical', '-', (120, 130))	('MEGF10', 'Gene', (77, 83))	('PSTPIP1', 'Gene', '9051', (167, 174))	('MEGF10', 'Gene', '84466', (77, 83))
172309	29887919	Survival analysis proved that hypermethylation or low expression of MEGF10 indicated a favorable prognosis in 983 glioma samples.	('expression', 'MPA', (54, 64))	('MEGF10', 'Gene', '84466', (68, 74))	('low', 'NegReg', (50, 53))	('MEGF10', 'Gene', (68, 74))	('glioma', 'Disease', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('hypermethylation', 'Var', (30, 46))
172311	29887919	In a word, our results suggested that methylation level and mRNA expression of MEGF10 in glioma were not only correlated with IDH mutation but also associated with clinical outcome of patients, providing potential guide for future dissection of IDH role in glioma.	('methylation level', 'MPA', (38, 55))	('IDH', 'Gene', '3417', (126, 129))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('correlated', 'Reg', (110, 120))	('mRNA expression', 'MPA', (60, 75))	('mutation', 'Var', (130, 138))	('MEGF10', 'Gene', (79, 85))	('patients', 'Species', '9606', (184, 192))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('MEGF10', 'Gene', '84466', (79, 85))	('IDH', 'Gene', (245, 248))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('glioma', 'Disease', (89, 95))	('associated', 'Reg', (148, 158))	('IDH', 'Gene', '3417', (245, 248))	('glioma', 'Disease', (257, 263))	('IDH', 'Gene', (126, 129))
172314	29887919	Along with WHO grade, extent of tumor resection, and Karnofsky performance status (KPS) score, IDH mutation is one of the most robust prognosticators for glioma patients.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutation', 'Var', (99, 107))	('glioma', 'Disease', (154, 160))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('tumor', 'Disease', (32, 37))
172317	29887919	Glioma with IDH mutation shows distinct genetic and clinical patterns from those with wild-type IDH.	('mutation', 'Var', (16, 24))	('IDH', 'Gene', '3417', (96, 99))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('IDH', 'Gene', (96, 99))
172318	29887919	Due to high frequency and widespread impact on tumor genome, IDH mutation has been proposed to be one of the initiators of glioma.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('IDH', 'Gene', '3417', (61, 64))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutation', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('glioma', 'Disease', (123, 129))	('IDH', 'Gene', (61, 64))	('tumor', 'Disease', (47, 52))
172320	29887919	As previously reported, IDH mutation induces increased methylation of numerous genes, including many oncogenes.	('IDH', 'Gene', (24, 27))	('increased', 'PosReg', (45, 54))	('IDH', 'Gene', '3417', (24, 27))	('methylation', 'MPA', (55, 66))	('mutation', 'Var', (28, 36))
172322	29887919	With Tspair package, we asked the correlation between IDH mutation status and methylation levels of whole genome gene in LGG and GBM samples and revealed that probe cg06940792 of MEGF10 together with probe cg26025891 of PSTPIP1 was the best paired probe to predict IDH mutation status.	('cg26025891', 'Chemical', '-', (206, 216))	('PSTPIP1', 'Gene', '9051', (220, 227))	('cg06940792', 'Chemical', '-', (165, 175))	('IDH', 'Gene', (265, 268))	('MEGF10', 'Gene', (179, 185))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('probe cg06940792', 'Var', (159, 175))	('IDH', 'Gene', '3417', (265, 268))	('MEGF10', 'Gene', '84466', (179, 185))	('IDH', 'Gene', (54, 57))	('PSTPIP1', 'Gene', (220, 227))	('IDH', 'Gene', '3417', (54, 57))	('cg26025891', 'Var', (206, 216))
172323	29887919	Hypermethylation or low expression of MEGF10 indicated a favorable prognosis by Kaplan-Meier survival analysis.	('MEGF10', 'Gene', (38, 44))	('expression', 'MPA', (24, 34))	('Hypermethylation', 'Var', (0, 16))	('MEGF10', 'Gene', '84466', (38, 44))	('low', 'NegReg', (20, 23))
172330	29887919	Pyrosequencing of IDH1/2 mutations was supported by Gene-tech (Shanghai, China).	('IDH1/2', 'Gene', '3417;3418', (18, 24))	('mutations', 'Var', (25, 34))	('IDH1/2', 'Gene', (18, 24))
172333	29887919	Top scoring pair (Tspair) package developed by Leek was used as the main tool to find methylation probe pairs that was able of predicting IDH mutation status.	('IDH', 'Gene', (138, 141))	('Leek', 'Species', '4681', (47, 51))	('IDH', 'Gene', '3417', (138, 141))	('mutation', 'Var', (142, 150))	('predicting', 'Reg', (127, 137))
172336	29887919	To identify candidate probes that can predict IDH mutation, we compared gene methylation levels between IDH mutation and wild-type IDH in 24 GBM samples by Tspair analysis, a method for calculating the top scoring pair for classification of high-dimensional data sets.	('IDH', 'Gene', (104, 107))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', '3417', (104, 107))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (131, 134))	('IDH', 'Gene', '3417', (46, 49))	('GBM', 'Phenotype', 'HP:0012174', (141, 144))	('mutation', 'Var', (108, 116))	('gene methylation levels', 'MPA', (72, 95))
172337	29887919	Then, we overlapped the candidate probes and finally validated 2 pairs of probes:cg06940792 versus cg26025891 and cg11465971 versus cg18342900 (Figure 1(a)).	('cg18342900', 'Var', (132, 142))	('cg06940792', 'Var', (81, 91))	('cg11465971', 'Chemical', '-', (114, 124))	('cg18342900', 'Chemical', '-', (132, 142))	('cg06940792', 'Chemical', '-', (81, 91))	('cg26025891', 'Var', (99, 109))	('cg11465971', 'Var', (114, 124))	('cg26025891', 'Chemical', '-', (99, 109))
172338	29887919	We projected these probes into TCGA LGG patients as validation, and only the first pair, cg06940792 versus cg26025891, showed consistent prediction value for IDH mutation (Figure 1(b)).	('IDH', 'Gene', '3417', (158, 161))	('patients', 'Species', '9606', (40, 48))	('cg06940792', 'Var', (89, 99))	('cg06940792', 'Chemical', '-', (89, 99))	('IDH', 'Gene', (158, 161))	('cg26025891', 'Chemical', '-', (107, 117))	('cg26025891', 'Var', (107, 117))
172339	29887919	Therefore, in TCGA dataset, the methylation levels of MEGF10 (cg06940792) had the best specificity to predict IDH mutation status (Figure 1(c)).	('methylation levels', 'MPA', (32, 50))	('IDH', 'Gene', (110, 113))	('IDH', 'Gene', '3417', (110, 113))	('cg06940792', 'Var', (62, 72))	('predict', 'Reg', (102, 109))	('cg06940792', 'Chemical', '-', (62, 72))	('MEGF10', 'Gene', '84466', (54, 60))	('MEGF10', 'Gene', (54, 60))
172340	29887919	Increasing evidence has shown that hypermethylation of genes caused by IDH mutation usually results in downregulation of expression.	('hypermethylation', 'Var', (35, 51))	('mutation', 'Var', (75, 83))	('expression', 'MPA', (121, 131))	('downregulation', 'NegReg', (103, 117))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (71, 74))
172343	29887919	It is noteworthy that the correlations between them seem to be significantly affected by IDH mutation status.	('affected', 'Reg', (77, 85))	('correlations', 'Interaction', (26, 38))	('IDH', 'Gene', (89, 92))	('mutation', 'Var', (93, 101))	('IDH', 'Gene', '3417', (89, 92))
172345	29887919	Interestingly, robust relevance was observed between MEGF10 methylation and mRNA in IDH mutation group, but not in wild-type group (Figure 2(b)).	('mRNA', 'MPA', (76, 80))	('methylation', 'Var', (60, 71))	('IDH', 'Gene', (84, 87))	('MEGF10', 'Gene', (53, 59))	('IDH', 'Gene', '3417', (84, 87))	('MEGF10', 'Gene', '84466', (53, 59))
172347	29887919	Kaplan-Meier survival analysis showed that low expression of MEGF10 conferred a longer overall survival (Figure 2(c)).	('longer', 'PosReg', (80, 86))	('MEGF10', 'Gene', (61, 67))	('low expression', 'Var', (43, 57))	('overall survival', 'MPA', (87, 103))	('MEGF10', 'Gene', '84466', (61, 67))
172359	29887919	IDH mutation, as a high-frequency mutation, makes an increasing sense since discovered.	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('mutation', 'Var', (4, 12))
172360	29887919	It is generally accepted that IDH mutation plays an important role in early glioma development and predicts improved clinical outcomes compared with wild-type IDH.	('IDH', 'Gene', (159, 162))	('glioma', 'Disease', (76, 82))	('IDH', 'Gene', '3417', (159, 162))	('mutation', 'Var', (34, 42))	('improved', 'PosReg', (108, 116))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (30, 33))
172362	29887919	Previous researches show that IDH mutation is closely related to glioma CpG island methylator phenotype (G-CIMP+).	('glioma', 'Disease', (65, 71))	('related', 'Reg', (54, 61))	('mutation', 'Var', (34, 42))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH', 'Gene', (30, 33))	('G-CIMP+', 'Chemical', '-', (105, 112))	('IDH', 'Gene', '3417', (30, 33))
172363	29887919	Hypermethylation of some CpG islands in cancer has been reported to be associated with silencing of oncogenes or tumor suppressor genes.	('tumor', 'Disease', (113, 118))	('oncogenes', 'Protein', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('Hypermethylation', 'Var', (0, 16))	('silencing', 'MPA', (87, 96))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('associated', 'Reg', (71, 81))
172365	29887919	In this study, we use gene methylation level to predict IDH mutation status in glioma for the first time.	('mutation', 'Var', (60, 68))	('glioma', 'Disease', (79, 85))	('IDH', 'Gene', (56, 59))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH', 'Gene', '3417', (56, 59))
172369	29887919	Fortunately, we obtained MEGF10 (cg06940792), the best candidate that could be used to predict IDH mutation status accurately in LGG and GBM patients.	('cg06940792', 'Var', (33, 43))	('MEGF10', 'Gene', (25, 31))	('GBM', 'Phenotype', 'HP:0012174', (137, 140))	('MEGF10', 'Gene', '84466', (25, 31))	('cg06940792', 'Chemical', '-', (33, 43))	('IDH', 'Gene', (95, 98))	('LGG', 'Disease', (129, 132))	('IDH', 'Gene', '3417', (95, 98))	('GBM', 'Disease', (137, 140))	('patients', 'Species', '9606', (141, 149))
172371	29887919	These findings prompt that expression of MEGF10 is downregulated by the corresponding hypermethylation, which is most likely caused by IDH mutation.	('hypermethylation', 'Var', (86, 102))	('MEGF10', 'Gene', (41, 47))	('MEGF10', 'Gene', '84466', (41, 47))	('expression', 'MPA', (27, 37))	('IDH', 'Gene', (135, 138))	('downregulated', 'NegReg', (51, 64))	('IDH', 'Gene', '3417', (135, 138))
172377	29887919	In conclusion, our findings shed a new light on understanding the fundamental basis of IDH mutation in glioma.	('mutation', 'Var', (91, 99))	('IDH', 'Gene', (87, 90))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('IDH', 'Gene', '3417', (87, 90))	('glioma', 'Disease', (103, 109))
172386	23704910	The diagnostic accuracy of nCBV C99 was significantly higher than that of the mean nCBV (P = 0.016) in distinguishing high- from low-grade gliomas and was comparable to that of the peak height (P = 1.000).	('C99', 'Var', (32, 35))	('higher', 'PosReg', (54, 60))	('gliomas', 'Disease', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('high-', 'Disease', (118, 123))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))
172400	23704910	demonstrated that a histogram analysis of normalized CBV (nCBV) heterogeneity offered higher sensitivity, equal specificity and increased interobserver agreement compared with the hot-spot method in glioma grading.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('increased', 'PosReg', (128, 137))	('sensitivity', 'MPA', (93, 104))	('higher', 'PosReg', (86, 92))	('glioma', 'Disease', (199, 205))	('heterogeneity', 'Var', (64, 77))
172443	23704910	The diagnostic accuracy of the nCBV C99 was significantly higher than that of the mean nCBV in distinguishing high- from low-grade gliomas and was comparable to that of the peak height.	('C99', 'Var', (36, 39))	('gliomas', 'Disease', (131, 138))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('high-', 'Disease', (110, 115))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('higher', 'PosReg', (58, 64))
172444	23704910	There have been many reports of glioma grading using PWI, although only a few studies have dealt with the histogram method to date.	('PWI', 'Var', (53, 56))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Disease', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
172472	23704910	We admit that the separation of grade III gliomas from other tumors was not satisfactory with the suggested cutoff values; however, the value of this grading schema is that we could accurately differentiate low- from high-grade-gliomas and grade IV from grade II and III gliomas.	('gliomas', 'Disease', 'MESH:D005910', (228, 235))	('II gliomas', 'Disease', (268, 278))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('II gliomas', 'Disease', 'MESH:D005910', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('low-', 'Var', (207, 211))	('gliomas', 'Disease', (271, 278))	('gliomas', 'Disease', (42, 49))	('II gliomas', 'Disease', 'MESH:D005910', (268, 278))	('tumors', 'Disease', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Disease', 'MESH:D005910', (271, 278))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('gliomas', 'Disease', (228, 235))	('II gliomas', 'Disease', (39, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (271, 278))
172475	23704910	First, only a small number of low-grade gliomas (n = 9) was included; however, it is well known that low-grade gliomas account for 10-15% of all adult primary intracranial tumors, which is very similar to our study setting.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('gliomas', 'Disease', (111, 118))	('intracranial tumors', 'Disease', (159, 178))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('low-grade', 'Var', (101, 110))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('intracranial tumors', 'Disease', 'MESH:D001932', (159, 178))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
172599	21059263	Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma The Sonic hedgehog (Shh) signaling pathway is critical for cell growth and differentiation.	('epigenetic', 'Var', (115, 125))	('Cyclin D2', 'Gene', '894', (65, 74))	('GLI1', 'Gene', '2735', (29, 33))	('PAX6', 'Gene', (89, 93))	('Shh', 'Gene', (188, 191))	('astrocytoma', 'Disease', 'MESH:D001254', (156, 167))	('PAX6', 'Gene', '5080', (89, 93))	('astrocytoma', 'Disease', (156, 167))	('PTCH1', 'Gene', '5727', (58, 63))	('Cyclin D2', 'Gene', (65, 74))	('GLI1', 'Gene', (29, 33))	('Sonic hedgehog', 'Gene', '6469', (172, 186))	('medulloblastoma', 'Disease', 'MESH:D008527', (136, 151))	('Shh', 'Gene', '6469', (188, 191))	('sonic hedgehog', 'Gene', '6469', (14, 28))	('medulloblastoma', 'Phenotype', 'HP:0002885', (136, 151))	('NKX2.2', 'Gene', (98, 104))	('PTCH1', 'Gene', (58, 63))	('medulloblastoma', 'Disease', (136, 151))	('sonic hedgehog', 'Gene', (14, 28))	('Sonic hedgehog', 'Gene', (172, 186))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('NKX2.2', 'Gene', '4821', (98, 104))
172600	21059263	Impairment of this pathway can result in both birth defects and cancer.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('birth defects', 'Disease', 'MESH:D000014', (46, 59))	('Impairment', 'Var', (0, 10))	('birth defects', 'Disease', (46, 59))	('result in', 'Reg', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
172607	21059263	Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma.	('astrocytoma', 'Disease', (143, 154))	('up-regulation', 'PosReg', (38, 51))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('GLI1', 'Gene', (24, 28))	('medulloblastoma cell', 'Disease', (79, 99))	('astrocytoma', 'Disease', 'MESH:D001254', (143, 154))	('medulloblastoma', 'Phenotype', 'HP:0002885', (79, 94))	('Silencing', 'Var', (0, 9))	('GLI1', 'Gene', '2735', (24, 28))	('medulloblastoma cell', 'Disease', 'MESH:D008527', (79, 99))
172613	21059263	This pathway is initiated by ligation of the Shh protein with its receptor PTCH1 on a target cell.	('Shh', 'Gene', '6469', (45, 48))	('protein', 'Protein', (49, 56))	('ligation', 'Var', (29, 37))	('Shh', 'Gene', (45, 48))
172628	21059263	Gorlin syndrome is caused by PTCH1 mutations in about 85% of cases.	('Gorlin syndrome', 'Disease', 'MESH:D001478', (0, 15))	('caused by', 'Reg', (19, 28))	('Gorlin syndrome', 'Disease', (0, 15))	('PTCH1', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
172629	21059263	At least 25% of medulloblastoma sporadic tumors show PTCH1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('medulloblastoma sporadic tumors', 'Disease', (16, 47))	('medulloblastoma sporadic tumors', 'Disease', 'MESH:D008527', (16, 47))	('mutations', 'Var', (59, 68))	('PTCH1', 'Gene', (53, 58))	('medulloblastoma', 'Phenotype', 'HP:0002885', (16, 31))
172641	21059263	For this study, we chose 6 medulloblastoma cell lines (TE671, PFSK-1, Daoy, TE671c2, D283Med and SK-PN-DW) and 8 high-grade astrocytoma cell lines (U87MG, A172, LN405, SW1783, T98G, SW1088, CCF-STTG1, and GOS-3).	('U87MG', 'Var', (148, 153))	('SW1783', 'CellLine', 'CVCL:1722', (168, 174))	('SW1783', 'Var', (168, 174))	('astrocytoma', 'Disease', 'MESH:D001254', (124, 135))	('SW1088', 'CellLine', 'CVCL:1715', (182, 188))	('astrocytoma', 'Disease', (124, 135))	('GOS-3', 'Gene', '2354', (205, 210))	('medulloblastoma cell lines', 'Disease', 'MESH:D008527', (27, 53))	('SK-PN-DW', 'Chemical', '-', (97, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('medulloblastoma', 'Phenotype', 'HP:0002885', (27, 42))	('TE671c2', 'Var', (76, 83))	('GOS-3', 'Gene', (205, 210))	('U87MG', 'CellLine', 'CVCL:0022', (148, 153))	('medulloblastoma cell lines', 'Disease', (27, 53))
172643	21059263	A172, T98G and U87MG were purchased from the European Collection of Cell Culture (Salisbury, Wiltshire, UK).	('U87MG', 'Var', (15, 20))	('U87MG', 'CellLine', 'CVCL:0022', (15, 20))	('T98G', 'Var', (6, 10))
172644	21059263	TE671, TE671c2, LN405 and GOS-3 were obtained from the Deutsche Sammlung von Mikroorganismen und Zellkulturen (Braunschweig, Germany).	('TE671c2', 'Var', (7, 14))	('GOS-3', 'Gene', (26, 31))	('von', 'Disease', 'MESH:D014842', (73, 76))	('von', 'Disease', (73, 76))	('GOS-3', 'Gene', '2354', (26, 31))	('LN405', 'Var', (16, 21))	('TE671', 'Var', (0, 5))
172684	21059263	Silencing of GLI1 resulted in a 50% and 60% decrease in PTCH1 expression in Daoy and U87MG cell lines respectively (Figures 2C-D).	('decrease', 'NegReg', (44, 52))	('expression', 'MPA', (62, 72))	('U87MG', 'CellLine', 'CVCL:0022', (85, 90))	('PTCH1', 'Gene', (56, 61))	('GLI1', 'Gene', '2735', (13, 17))	('GLI1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))
172695	21059263	Silencing GLI1 in the Daoy cell line resulted in a 17% decrease in Cyclin D2 expression compared with scrambled siRNA and untransfected cell lines (Figure 2E).	('expression', 'MPA', (77, 87))	('Cyclin D2', 'Gene', (67, 76))	('GLI1', 'Gene', (10, 14))	('decrease', 'NegReg', (55, 63))	('Cyclin D2', 'Gene', '894', (67, 76))	('Silencing', 'Var', (0, 9))	('GLI1', 'Gene', '2735', (10, 14))
172701	21059263	We observed a 30% decrease in expression of Plakoglobin in upon silencing of GLI1 in Daoy transfected cells (Figure 2G).	('expression', 'MPA', (30, 40))	('GLI1', 'Gene', '2735', (77, 81))	('decrease', 'NegReg', (18, 26))	('GLI1', 'Gene', (77, 81))	('silencing', 'Var', (64, 73))
172704	21059263	Among the 8 astrocytic cell lines, 5 (U87MG, A172, LN405, SW1783 and T98G) showed low levels of Plakoglobin expression, and the remaining 3 (SW1088, CCF-STTG-1 and GOS3) expressed Plakoglobin at levels higher than seen in normal adult brain tissue (p = 0.02) (Figure 4D).	('SW1783', 'CellLine', 'CVCL:1722', (58, 64))	('SW1783', 'Var', (58, 64))	('low', 'NegReg', (82, 85))	('SW1088', 'CellLine', 'CVCL:1715', (141, 147))	('LN405', 'Var', (51, 56))	('GOS3', 'Gene', (164, 168))	('U87MG', 'CellLine', 'CVCL:0022', (38, 43))	('Plakoglobin expression', 'MPA', (96, 118))	('SW1088', 'Var', (141, 147))	('GOS3', 'Gene', '2354', (164, 168))	('T98G', 'Var', (69, 73))	('U87MG', 'Var', (38, 43))
172708	21059263	Our results show a 35% reduction in expression of PAX6 gene upon GLI1 silencing in the Daoy cell line compared with scrambled and untransfected controls (Figure 2I).	('GLI1', 'Gene', '2735', (65, 69))	('GLI1', 'Gene', (65, 69))	('silencing', 'Var', (70, 79))	('reduction', 'NegReg', (23, 32))	('PAX6', 'Gene', (50, 54))	('expression', 'MPA', (36, 46))	('PAX6', 'Gene', '5080', (50, 54))
172711	21059263	Most of the astrocytic cell lines (A172, SW1783, T98G, SW1088, CCF-STTG-1 and GOS-3) expressed PAX6 at low levels, and only 2 (U87MG and LN405) expressed PAX6 at high levels compared to normal adult brain tissues (p = 0.006) (Figure 4F).	('PAX6', 'Gene', (95, 99))	('LN405', 'Var', (137, 142))	('SW1783', 'CellLine', 'CVCL:1722', (41, 47))	('PAX6', 'Gene', (154, 158))	('CCF-STTG-1 and GOS-3', 'Gene', '2354', (63, 83))	('PAX6', 'Gene', '5080', (95, 99))	('PAX6', 'Gene', '5080', (154, 158))	('SW1088', 'CellLine', 'CVCL:1715', (55, 61))	('U87MG', 'CellLine', 'CVCL:0022', (127, 132))	('U87MG', 'Var', (127, 132))
172714	21059263	Silencing of GLI1 resulted in a decrease in NKX2.2 by 50% in the Daoy cell line compared with scrambled siRNA transfected and untransfected cells (Figure 2K).	('NKX2.2', 'Gene', (44, 50))	('NKX2.2', 'Gene', '4821', (44, 50))	('GLI1', 'Gene', '2735', (13, 17))	('GLI1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('decrease', 'NegReg', (32, 40))
172717	21059263	Six astrocytic cell lines (A172, LN405, T98G, SW1088, CCF-STTG-1 and GOS-3) showed very low expression of NKX2.2, and the remaining 2 cell lines (U87MG and SW178) did not express it at all, compared with expression levels in normal adult brain tissue (p = 0.0001) (Figure 4H).	('NKX2.2', 'Gene', (106, 112))	('low', 'NegReg', (88, 91))	('SW1088', 'CellLine', 'CVCL:1715', (46, 52))	('T98G', 'Var', (40, 44))	('SW178', 'CellLine', 'CVCL:N709', (156, 161))	('CCF-STTG-1 and GOS-3', 'Gene', '2354', (54, 74))	('U87MG', 'CellLine', 'CVCL:0022', (146, 151))	('NKX2.2', 'Gene', '4821', (106, 112))	('expression', 'MPA', (92, 102))
172722	21059263	However, very low expression of Cyclin D2 protein was observed in the following seven cell lines: U87MG, A172, LN405, SW1088, T98G, CCF-STTG-1 and GOS-3; moreover, there was no expression of Cyclin D2 in one cell line (SW1783) (Figure 5D).	('SW1783', 'CellLine', 'CVCL:1722', (219, 225))	('Cyclin D2', 'Gene', (32, 41))	('U87MG', 'CellLine', 'CVCL:0022', (98, 103))	('CCF-STTG-1 and GOS-3', 'Gene', '2354', (132, 152))	('Cyclin D2', 'Gene', '894', (191, 200))	('expression', 'MPA', (18, 28))	('low', 'NegReg', (14, 17))	('T98G', 'Var', (126, 130))	('Cyclin D2', 'Gene', '894', (32, 41))	('SW1088', 'CellLine', 'CVCL:1715', (118, 124))	('Cyclin D2', 'Gene', (191, 200))
172725	21059263	However, treatment with these compounds resulted in the onset of Cyclin D2 expression, assessed by both RT-PCR and qRT-PCR in five astrocytoma cell lines that did not initially express Cyclin D2 (A172, SW1783, T98G, CCF-STTG-1 and GOS-3) (Figures 6A-B) (Table 3).	('SW1783', 'CellLine', 'CVCL:1722', (202, 208))	('CCF-STTG-1 and GOS-3', 'Gene', '2354', (216, 236))	('Cyclin D2', 'Gene', '894', (65, 74))	('Cyclin D2', 'Gene', (185, 194))	('astrocytoma', 'Disease', 'MESH:D001254', (131, 142))	('Cyclin D2', 'Gene', (65, 74))	('astrocytoma', 'Disease', (131, 142))	('T98G', 'Var', (210, 214))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('expression', 'MPA', (75, 85))	('Cyclin D2', 'Gene', '894', (185, 194))
172728	21059263	Methylation associated with low Cyclin D2 expression was evident only in the SK-PN-DW cell line (Table 1).	('SK-PN-DW', 'Chemical', '-', (77, 85))	('Cyclin D2', 'Gene', (32, 41))	('Methylation', 'Var', (0, 11))	('expression', 'MPA', (42, 52))	('Meth', 'Chemical', '-', (0, 4))	('low', 'NegReg', (28, 31))	('Cyclin D2', 'Gene', '894', (32, 41))
172734	21059263	U87MG, which showed partial methylation also expressed Cyclin D2, albeit at lower levels compared with normal adult brain tissue (Table 3).	('U87MG', 'Var', (0, 5))	('Cyclin D2', 'Gene', (55, 64))	('Cyclin D2', 'Gene', '894', (55, 64))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))
172736	21059263	MSP-PCR identified 12/44 (27%) of the samples as methylated at the Cyclin D2 promoter (Figure 7H).	('Cyclin D2', 'Gene', (67, 76))	('methylated', 'Var', (49, 59))	('Cyclin D2', 'Gene', '894', (67, 76))
172746	21059263	After siRNA-mediated GLI1 silencing in Daoy and U87MG cell lines, expression of PTCH1 decreased, compared with scrambled siRNA-transfected and untransfected cell lines, which may suggest positive regulation of PTCH1 by GLI1 in medulloblastomas and astrocytomas.	('medulloblastomas and astrocytomas', 'Disease', 'MESH:D008527', (227, 260))	('GLI1', 'Gene', (219, 223))	('astrocytoma', 'Phenotype', 'HP:0009592', (248, 259))	('expression', 'MPA', (66, 76))	('positive regulation', 'PosReg', (187, 206))	('medulloblastoma', 'Phenotype', 'HP:0002885', (227, 242))	('decreased', 'NegReg', (86, 95))	('silencing', 'Var', (26, 35))	('PTCH1', 'Gene', (210, 215))	('U87MG', 'CellLine', 'CVCL:0022', (48, 53))	('PTCH1', 'Gene', (80, 85))	('GLI1', 'Gene', '2735', (21, 25))	('GLI1', 'Gene', '2735', (219, 223))	('GLI1', 'Gene', (21, 25))
172752	21059263	As a putative explanation, high expression of GLI1 associated with low expression of PTCH1 may indicate a switch-on of Shh signaling (phase 1), trying to exit from a previous resting point -phase 0- (GLI1 low expression/PTCH1 low expression), to advance towards phase 2, a GLI1 high expression/PTCH1 high expression phase characterized by PTCH1 demethylation and expression, to finally reach phase 3 (GLI1 low expression/PTCH1 high expression), equivalent to switching off the Shh signaling process.	('low expression', 'Var', (67, 81))	('PTCH1', 'Gene', (85, 90))	('Shh', 'Gene', '6469', (477, 480))	('GLI1', 'Gene', '2735', (46, 50))	('GLI1', 'Gene', '2735', (200, 204))	('GLI1', 'Gene', (200, 204))	('Shh', 'Gene', (119, 122))	('GLI1', 'Gene', '2735', (273, 277))	('GLI1', 'Gene', (46, 50))	('GLI1', 'Gene', (273, 277))	('GLI1', 'Gene', '2735', (401, 405))	('Shh', 'Gene', (477, 480))	('GLI1', 'Gene', (401, 405))	('Shh', 'Gene', '6469', (119, 122))
172753	21059263	For epigenetic studies, we chose the distal region 1C of the PTCH1 promoter, and found only 1/6 of the medulloblastoma cell lines bearing methylation at the promoter, although two other cell lines also showed low expression levels of PTCH1.	('PTCH1', 'Gene', (61, 66))	('medulloblastoma cell lines', 'Disease', (103, 129))	('medulloblastoma cell lines', 'Disease', 'MESH:D008527', (103, 129))	('methylation', 'Var', (138, 149))	('medulloblastoma', 'Phenotype', 'HP:0002885', (103, 118))
172756	21059263	Our results identified methylation of the promoter region in only 1/8 astrocytoma cell lines and 3/27 (11%) astrocytic tumor samples of high histologic grades.	('astrocytoma', 'Disease', 'MESH:D001254', (70, 81))	('methylation', 'Var', (23, 34))	('astrocytoma', 'Disease', (70, 81))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (108, 124))	('astrocytic tumor', 'Disease', (108, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('astrocytic tumor', 'Disease', 'MESH:D001254', (108, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
172759	21059263	To determine whether GLI1 regulates Cyclin D2 in medulloblastomas, we quantified levels of Cyclin D2 transcript upon silencing of GLI1 by siRNA in the Daoy medulloblastoma cell line.	('Cyclin D2', 'Gene', (91, 100))	('silencing', 'Var', (117, 126))	('Cyclin D2', 'Gene', (36, 45))	('medulloblastomas', 'Disease', 'MESH:D008527', (49, 65))	('medulloblastoma cell', 'Disease', 'MESH:D008527', (156, 176))	('medulloblastoma cell', 'Disease', (156, 176))	('medulloblastomas', 'Disease', (49, 65))	('GLI1', 'Gene', '2735', (130, 134))	('medulloblastoma', 'Phenotype', 'HP:0002885', (49, 64))	('GLI1', 'Gene', (130, 134))	('Cyclin D2', 'Gene', '894', (91, 100))	('GLI1', 'Gene', '2735', (21, 25))	('Cyclin D2', 'Gene', '894', (36, 45))	('medulloblastoma', 'Phenotype', 'HP:0002885', (156, 171))	('GLI1', 'Gene', (21, 25))
172764	21059263	GLI1 silencing in the astrocytic cell line U87MG led to increased Cyclin D2 expression in comparison with controls transfected with scrambled siRNA and untransfected cells.	('GLI1', 'Gene', (0, 4))	('increased', 'PosReg', (56, 65))	('Cyclin D2', 'Gene', '894', (66, 75))	('U87MG', 'CellLine', 'CVCL:0022', (43, 48))	('silencing', 'Var', (5, 14))	('Cyclin D2', 'Gene', (66, 75))	('expression', 'MPA', (76, 86))	('GLI1', 'Gene', '2735', (0, 4))
172775	21059263	Our study revealed, to a certain extent, hypermethylation of the Cyclin D2 promoter, although methylation did not fully correlate with silencing of expression in medulloblastoma cell lines.	('hypermethylation', 'Var', (41, 57))	('medulloblastoma cell lines', 'Disease', (162, 188))	('Cyclin D2', 'Gene', '894', (65, 74))	('Cyclin D2', 'Gene', (65, 74))	('medulloblastoma cell lines', 'Disease', 'MESH:D008527', (162, 188))	('medulloblastoma', 'Phenotype', 'HP:0002885', (162, 177))
172776	21059263	Interestingly, the methylation of the promoter in primary tumor samples was associated with low or no expression of Cyclin D2.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('methylation', 'Var', (19, 30))	('Cyclin D2', 'Gene', (116, 125))	('expression', 'MPA', (102, 112))	('low', 'NegReg', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Cyclin D2', 'Gene', '894', (116, 125))
172782	21059263	However, after 5-Aza-2'-deoxycytidine and TSA treatment, there was an increase in expression of Cyclin D2 in T98G, but not in U87MG cell line (accompanied by low expression levels of the Cyclin D2 protein).	('Cyclin D2', 'Gene', (187, 196))	('increase', 'PosReg', (70, 78))	('Cyclin D2', 'Gene', '894', (96, 105))	('expression', 'MPA', (82, 92))	('T98G', 'Var', (109, 113))	('U87MG', 'CellLine', 'CVCL:0022', (126, 131))	('Cyclin D2', 'Gene', (96, 105))	('expression', 'MPA', (162, 172))	('TSA', 'Chemical', 'MESH:C012589', (42, 45))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (15, 37))	('Cyclin D2', 'Gene', '894', (187, 196))
172783	21059263	Despite hemi-methylation of the Cyclin D2 promoter in U87MG cells, there was no change in Cyclin D2 expression after treatment.	('Cyclin D2', 'Gene', (32, 41))	('U87MG', 'CellLine', 'CVCL:0022', (54, 59))	('Cyclin D2', 'Gene', '894', (90, 99))	('expression', 'MPA', (100, 110))	('Cyclin D2', 'Gene', (90, 99))	('Cyclin D2', 'Gene', '894', (32, 41))	('hemi-methylation', 'Var', (8, 24))
172785	21059263	SW1783 and CCF-STTG-1 cells appeared to be methylated by MSP but not by MCA-Meth.	('MSP', 'Gene', (57, 60))	('SW1783', 'CellLine', 'CVCL:1722', (0, 6))	('methylated', 'Var', (43, 53))	('MCA-Meth', 'Chemical', '-', (72, 80))
172790	21059263	We attempted to determine Plakoglobin expression in the Daoy medulloblastoma cell line upon GLI1 silencing.	('medulloblastoma', 'Phenotype', 'HP:0002885', (61, 76))	('silencing', 'Var', (97, 106))	('GLI1', 'Gene', '2735', (92, 96))	('medulloblastoma cell', 'Disease', 'MESH:D008527', (61, 81))	('GLI1', 'Gene', (92, 96))	('medulloblastoma cell', 'Disease', (61, 81))
172797	21059263	High levels of Plakoglobin expression after GLI1 silencing in the U87MG astrocytoma cell line is not indicative of positive regulation of this gene by GLI1.	('GLI1', 'Gene', '2735', (151, 155))	('silencing', 'Var', (49, 58))	('astrocytoma', 'Disease', 'MESH:D001254', (72, 83))	('astrocytoma', 'Disease', (72, 83))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('GLI1', 'Gene', '2735', (44, 48))	('GLI1', 'Gene', (44, 48))	('U87MG', 'CellLine', 'CVCL:0022', (66, 71))	('GLI1', 'Gene', (151, 155))
172804	21059263	Silencing of GLI1 in Daoy cells indicated that GLI1 may up-regulate the expression of the homeodomain transcription factor I PAX6 in medulloblastomas.	('medulloblastomas', 'Disease', (133, 149))	('medulloblastoma', 'Phenotype', 'HP:0002885', (133, 148))	('expression', 'MPA', (72, 82))	('GLI1', 'Gene', '2735', (47, 51))	('medulloblastomas', 'Disease', 'MESH:D008527', (133, 149))	('up-regulate', 'PosReg', (56, 67))	('PAX6', 'Gene', (125, 129))	('GLI1', 'Gene', '2735', (13, 17))	('PAX6', 'Gene', '5080', (125, 129))	('GLI1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('GLI1', 'Gene', (47, 51))
172812	21059263	Subsequent to GLI1 silencing, we observed an increase in PAX6 expression in the transfected astrocytoma cell line U87MG.	('U87MG', 'CellLine', 'CVCL:0022', (114, 119))	('GLI1', 'Gene', (14, 18))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('GLI1', 'Gene', '2735', (14, 18))	('increase', 'PosReg', (45, 53))	('PAX6', 'Gene', '5080', (57, 61))	('expression', 'MPA', (62, 72))	('silencing', 'Var', (19, 28))	('astrocytoma', 'Disease', 'MESH:D001254', (92, 103))	('astrocytoma', 'Disease', (92, 103))	('PAX6', 'Gene', (57, 61))
172815	21059263	GLI1 silencing suggests that GLI1 may up-regulate the homeodomain transcription factor II NKX2.2.	('GLI1', 'Gene', (0, 4))	('up-regulate', 'PosReg', (38, 49))	('NKX2.2', 'Gene', '4821', (90, 96))	('silencing', 'Var', (5, 14))	('GLI1', 'Gene', '2735', (29, 33))	('GLI1', 'Gene', (29, 33))	('NKX2.2', 'Gene', (90, 96))	('GLI1', 'Gene', '2735', (0, 4))
172819	21059263	GLI1 silencing did not perturb NKX2.2 expression in the astrocytic cell line U87MG.	('GLI1', 'Gene', (0, 4))	('NKX2.2', 'Gene', '4821', (31, 37))	('expression', 'MPA', (38, 48))	('silencing', 'Var', (5, 14))	('NKX2.2', 'Gene', (31, 37))	('U87MG', 'CellLine', 'CVCL:0022', (77, 82))	('GLI1', 'Gene', '2735', (0, 4))
172863	33198332	They achieved an accuracy of the IDH mutational status of 0.853 (Area Under the Curve (AUC) = 0.927).	('mutational status', 'Var', (37, 54))	('IDH', 'Gene', '3417', (33, 36))	('IDH', 'Gene', (33, 36))
172873	33198332	implemented a novel architecture combining several sets of features to identify IDH mutations and TERT promoter (pTERT) mutations.	('TERT', 'Gene', (98, 102))	('TERT', 'Gene', '7015', (114, 118))	('TERT', 'Gene', '7015', (98, 102))	('IDH', 'Gene', (80, 83))	('mutations', 'Var', (84, 93))	('IDH', 'Gene', '3417', (80, 83))	('TERT', 'Gene', (114, 118))
172877	33198332	applied the ResNet50 deep learning model to noninvasively predict IDH1 and IDH2 mutations in glioma grades II-IV.	('IDH1', 'Gene', '3417', (66, 70))	('glioma', 'Disease', (93, 99))	('mutations', 'Var', (80, 89))	('IDH2', 'Gene', (75, 79))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH2', 'Gene', '3418', (75, 79))	('IDH1', 'Gene', (66, 70))
172889	33198332	Indeed, they realized modifying loss function or using the sum of the loss functions such as cross-entropy and interval, the model accuracy would improve.	('modifying', 'Var', (22, 31))	('cross-entropy', 'Disease', (93, 106))	('cross-entropy', 'Disease', 'MESH:C537866', (93, 106))	('loss function', 'MPA', (32, 45))	('improve', 'PosReg', (146, 153))
173013	33167414	We further reveal that small cell lung cancer (SCLC) and isocitrate dehydrogenase (IDH1/2)-mutant brain tumors show enrichment of pro-ferroptosis gene signature, suggesting a unique vulnerability of SCLC and IDH-mutant tumors to ferroptosis inducers.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('small cell lung cancer', 'Disease', 'MESH:D055752', (23, 45))	('brain tumors', 'Disease', 'MESH:D001932', (98, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('isocitrate dehydrogenase', 'Gene', (57, 81))	('brain tumors', 'Phenotype', 'HP:0030692', (98, 110))	('IDH', 'Gene', '3417', (83, 86))	('tumors', 'Disease', (104, 110))	('IDH', 'Gene', (208, 211))	('small cell lung cancer', 'Disease', (23, 45))	('SCLC', 'Disease', 'MESH:D018288', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('brain tumors', 'Disease', (98, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('SCLC', 'Disease', 'MESH:D018288', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('-mutant', 'Var', (90, 97))	('IDH', 'Gene', '3417', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (23, 45))	('isocitrate dehydrogenase', 'Gene', '3417', (57, 81))	('SCLC', 'Disease', (199, 203))	('SCLC', 'Phenotype', 'HP:0030357', (199, 203))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('IDH', 'Gene', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('SCLC', 'Disease', (47, 51))	('SCLC', 'Phenotype', 'HP:0030357', (47, 51))
173014	33167414	Finally, we demonstrate that targeting class I histone deacetylase (HDAC) significantly enhances ferroptotic cell death caused by Erastin, an ferroptosis inducer, in lung cancer cells, revealing a previously underappreciated role for HDAC in ferroptosis regulation.	('HDAC', 'Gene', (234, 238))	('HDAC', 'Gene', '9734', (234, 238))	('histone deacetylase', 'Gene', '9734', (47, 66))	('enhances', 'PosReg', (88, 96))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('Erastin', 'Gene', (130, 137))	('Erastin', 'Chemical', 'MESH:C477224', (130, 137))	('histone deacetylase', 'Gene', (47, 66))	('rat', 'Species', '10116', (19, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('HDAC', 'Gene', (68, 72))	('lung cancer', 'Disease', (166, 177))	('death', 'Disease', 'MESH:D003643', (114, 119))	('HDAC', 'Gene', '9734', (68, 72))	('death', 'Disease', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('targeting', 'Var', (29, 38))
173020	33167414	Antagonizing GPX4 with small molecules, such as the rat sarcoma viral oncogene homolog (RAS)-selective lethal 3 (RSL3), efficiently induces ferroptosis.	('rat', 'Species', '10116', (52, 55))	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('induces', 'Reg', (132, 139))	('Antagonizing', 'Var', (0, 12))	('ferroptosis', 'CPA', (140, 151))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
173022	33167414	GSH synthesis depends on intracellular availability of the precursor cysteine that is mainly generated from the reduction of cystine; thus, cystine depletion also induces ferroptosis.	('cystine', 'Chemical', 'MESH:D003553', (140, 147))	('cysteine', 'Chemical', 'MESH:D003545', (69, 77))	('rat', 'Species', '10116', (97, 100))	('ferroptosis', 'Disease', (171, 182))	('cystine', 'MPA', (140, 147))	('cystine', 'Chemical', 'MESH:D003553', (125, 132))	('induces', 'Reg', (163, 170))	('depletion', 'Var', (148, 157))	('GSH', 'Chemical', '-', (0, 3))
173024	33167414	In addition to GPX4 and xCT/SLC7A11, the ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria associated 2 (AIFM2), plays a GPX4-independent anti-ferroptosis role and combined inhibition of GPX4 and FSP1 synergistically enhances ferroptosis.	('apoptosis-inducing factor mitochondria associated 2', 'Gene', '84883', (96, 147))	('FSP1', 'Gene', (75, 79))	('xCT', 'Gene', (24, 27))	('FSP1', 'Gene', (240, 244))	('inhibition', 'Var', (217, 227))	('AIFM2', 'Gene', '84883', (149, 154))	('SLC7A11', 'Gene', (28, 35))	('AIFM2', 'Gene', (149, 154))	('ferroptosis suppressor protein 1', 'Gene', '51062', (41, 73))	('enhances', 'PosReg', (261, 269))	('SLC7A11', 'Gene', '23657', (28, 35))	('FSP1', 'Gene', '51062', (75, 79))	('xCT', 'Gene', '23657', (24, 27))	('ferroptosis', 'CPA', (270, 281))	('ferroptosis suppressor protein 1', 'Gene', (41, 73))	('FSP1', 'Gene', '51062', (240, 244))
173027	33167414	Genetic alterations that inactivate KEAP1, common in lung cancer, lead to NRF2 activation and subsequently expression of NRF2 target genes to promote antioxidant defense, indicating that the KEAP1-NRF2 axis is closely related to ferroptosis.	('KEAP1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('NRF2', 'Gene', '4780', (74, 78))	('NRF2', 'Gene', (197, 201))	('lung cancer', 'Disease', (53, 64))	('NRF2', 'Gene', '4780', (121, 125))	('KEAP1', 'Gene', '9817', (191, 196))	('activation', 'PosReg', (79, 89))	('promote', 'PosReg', (142, 149))	('NRF2', 'Gene', (74, 78))	('KEAP1', 'Gene', (191, 196))	('rat', 'Species', '10116', (12, 15))	('alterations', 'Var', (8, 19))	('NRF2', 'Gene', (121, 125))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('ferroptosis', 'Disease', (229, 240))	('antioxidant defense', 'MPA', (150, 169))	('NRF2', 'Gene', '4780', (197, 201))	('KEAP1', 'Gene', '9817', (36, 41))
173039	33167414	This analysis identified a total of 139 drug candidates whose AUC values significantly (empirical p-value < 0.01) positively correlate with SLC7A11 (Figure 1D; Table S1), including ML162, ML210, RSL3, PX-12, PRIMA-1, Piperlongumine, and Erastin that were previously shown to trigger ferroptosis, validating the robustness of the systematic correlation study and the accountability of our results.	('Piperlongumine', 'Chemical', 'MESH:C498077', (217, 231))	('PRIMA-1', 'Gene', (208, 215))	('SLC7A11', 'Gene', (140, 147))	('SLC7A11', 'Gene', '23657', (140, 147))	('ML210', 'Var', (188, 193))	('correlate', 'Reg', (125, 134))	('AUC', 'MPA', (62, 65))	('PRIMA-1', 'Gene', '145270', (208, 215))	('Erastin', 'Chemical', 'MESH:C477224', (237, 244))	('ferroptosis', 'Disease', (283, 294))	('ML162', 'Var', (181, 186))
173044	33167414	To verify our finding, we treated NSCLC cells (H1650, PC9 and HCC827) with Erastin and Vorinostat, a clinically-approved class I HDAC inhibitor, alone or in combination, which showed that the presence of Vorinostat significantly enhances the anti-proliferative effect of Erastin (Figure 2A).	('Vorinostat', 'Chemical', 'MESH:D000077337', (204, 214))	('H1650', 'CellLine', 'CVCL:1483', (47, 52))	('NSCLC', 'Disease', (34, 39))	('enhances', 'PosReg', (229, 237))	('anti-proliferative effect', 'CPA', (242, 267))	('Erastin', 'Chemical', 'MESH:C477224', (75, 82))	('HCC827', 'CellLine', 'CVCL:2063', (62, 68))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('SCLC', 'Phenotype', 'HP:0030357', (35, 39))	('HDAC', 'Gene', (129, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('HDAC', 'Gene', '9734', (129, 133))	('rat', 'Species', '10116', (254, 257))	('Erastin', 'Chemical', 'MESH:C477224', (271, 278))	('PC9', 'Gene', '255738', (54, 57))	('presence', 'Var', (192, 200))	('PC9', 'Gene', (54, 57))	('Vorinostat', 'Chemical', 'MESH:D000077337', (87, 97))
173060	33167414	Gliomas with mutations in IDH (isocitrate dehydrogenase), which leads to loss of its normal enzymatic function and the abnormal production of oncometabolite 2-hydroxyglutarate, represent a unique subset genetically and clinically distinct from that carrying wild-type IDH, particularly in LGG.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (157, 175))	('normal enzymatic function', 'MPA', (85, 110))	('mutations', 'Var', (13, 22))	('IDH', 'Gene', (268, 271))	('IDH', 'Gene', '3417', (26, 29))	('LGG', 'Disease', (289, 292))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('production of', 'MPA', (128, 141))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (268, 271))	('Gliomas', 'Disease', (0, 7))	('isocitrate dehydrogenase', 'Gene', (31, 55))	('isocitrate dehydrogenase', 'Gene', '3417', (31, 55))
173061	33167414	Importantly, we found that IDH1/2-mutant LGG was associated with a significantly higher FS score than IDH1/2-wild-type LGG (Figure 4C), prioritizing an innovative strategy to target IDH1/2-mutant LGG.	('rat', 'Species', '10116', (165, 168))	('higher', 'PosReg', (81, 87))	('LGG', 'Gene', (41, 44))	('IDH1/2-mutant', 'Var', (27, 40))
173062	33167414	Supporting our finding, recent studies showed that accumulation of oncometabolite 2-hydroxyglutarate, the product of the mutant IDH, sensitizes cells to ferroptosis and that shRNA-based knockdown of IDH2 increases the sensitivity to Erastin-induced ferroptosis.	('sensitivity', 'MPA', (218, 229))	('cells', 'CPA', (144, 149))	('mutant', 'Var', (121, 127))	('IDH', 'Gene', '3417', (199, 202))	('IDH', 'Gene', (128, 131))	('increases', 'PosReg', (204, 213))	('accumulation', 'PosReg', (51, 63))	('IDH', 'Gene', '3417', (128, 131))	('sensitizes', 'Reg', (133, 143))	('Erastin', 'Chemical', 'MESH:C477224', (233, 240))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (82, 100))	('IDH', 'Gene', (199, 202))
173064	33167414	The KEAP1-NRF2 axis is well known to negatively regulate ferroptosis, and cancer cells with KEAP1 mutations are associated with increased resistance to ferroptosis.	('resistance to ferroptosis', 'MPA', (138, 163))	('KEAP1', 'Gene', (92, 97))	('NRF2', 'Gene', (10, 14))	('KEAP1', 'Gene', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('increased', 'PosReg', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (74, 80))	('ferroptosis', 'MPA', (57, 68))	('KEAP1', 'Gene', '9817', (92, 97))	('NRF2', 'Gene', '4780', (10, 14))	('KEAP1', 'Gene', '9817', (4, 9))
173065	33167414	In line with this notion, interrogation of a LUAD cohort in TCGA revealed that tumors with KEAP1 mutations, frequent in LUAD samples, display significantly higher FR signature scores (Figure 4D).	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('mutations', 'Var', (97, 106))	('higher', 'PosReg', (156, 162))	('KEAP1', 'Gene', (91, 96))	('FR signature scores', 'MPA', (163, 182))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('KEAP1', 'Gene', '9817', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('LUAD', 'Phenotype', 'HP:0030078', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
173082	33167414	Informed by these findings, we show, for the first time, that the effect of ROS-related cell death induced by class I HDAC inhibitors may relate to ferroptosis, and that targeting class I HDAC with the clinically approved Vorinostat enhances the anti-proliferative effect of Erastin that is known to induce ferroptosis.	('Vorinostat', 'Chemical', 'MESH:D000077337', (222, 232))	('rat', 'Species', '10116', (258, 261))	('anti-proliferative effect', 'CPA', (246, 271))	('Erastin', 'Chemical', 'MESH:C477224', (275, 282))	('ROS-related', 'Gene', (76, 87))	('HDAC', 'Gene', (118, 122))	('death', 'Disease', 'MESH:D003643', (93, 98))	('HDAC', 'Gene', '9734', (118, 122))	('enhances', 'PosReg', (233, 241))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('HDAC', 'Gene', (188, 192))	('death', 'Disease', (93, 98))	('HDAC', 'Gene', '9734', (188, 192))	('targeting', 'Var', (170, 179))
173124	32658870	Genome-wide analyses of the prognosis-related mRNA alternative splicing landscape and novel splicing factors based on large-scale low grade glioma cohort Alternative splicing (AS) changes are considered to be critical in predicting treatment response.	('changes', 'Var', (180, 187))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('glioma', 'Disease', (140, 146))
173139	32658870	Mutations in splicing factor (SF) expression may not only cause the activation of oncogenes or cancer pathways but may also be related to the loss of tumor suppressor function.	('loss', 'NegReg', (142, 146))	('splicing factor', 'Gene', '10569', (13, 28))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('SF', 'Gene', '10569', (30, 32))	('cause', 'Reg', (58, 63))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('activation', 'PosReg', (68, 78))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('oncogenes', 'Pathway', (82, 91))	('splicing factor', 'Gene', (13, 28))	('tumor', 'Disease', (150, 155))
173165	32658870	The results of GO analyses showed that changes in BPs of SFs were significantly enriched in RNA processing and mRNA processing, changes in CCs of SFs were mostly enriched in RNA binding and mRNA binding, and changes in MFs of SFs were mostly enriched in spliceosomal snRNP complexes and U2-type prespliceosomes.	('SF', 'Gene', '10569', (146, 148))	('mRNA', 'MPA', (190, 194))	('changes', 'Reg', (208, 215))	('changes', 'Var', (39, 46))	('SF', 'Gene', '10569', (57, 59))	('SF', 'Gene', '10569', (226, 228))	('RNA', 'MPA', (92, 95))	('mRNA processing', 'MPA', (111, 126))	('changes', 'Var', (128, 135))
173180	32658870	<80) was significantly correlated with DFS in LGG patients (HR=1.914; P=0.045).	('DFS', 'Disease', (39, 42))	('LGG', 'Disease', (46, 49))	('patients', 'Species', '9606', (50, 58))	('<80', 'Var', (0, 3))
173181	32658870	More importantly, a subgroup analysis of SNRNP70 expression showed that in this cohort, amplification of SNRNP70 was significantly correlated with DFS (HR=3.048; P=0.001).	('correlated', 'Reg', (131, 141))	('SNRNP70', 'Gene', '6625', (41, 48))	('SNRNP70', 'Gene', (105, 112))	('amplification', 'Var', (88, 101))	('DFS', 'Disease', (147, 150))	('SNRNP70', 'Gene', (41, 48))	('SNRNP70', 'Gene', '6625', (105, 112))
173183	32658870	SF gene amplification was significantly associated with OS in AHYMUN patients (HR=6.246; P<0.001).	('patients', 'Species', '9606', (69, 77))	('amplification', 'Var', (8, 21))	('associated with', 'Reg', (40, 55))	('SF', 'Gene', '10569', (0, 2))
173203	32658870	Therefore, this is not conducive to the recovery of LGG, and the likelihood is that LGG recurrence will increase in patients with high expression.	('increase', 'PosReg', (104, 112))	('patients', 'Species', '9606', (116, 124))	('high expression', 'Var', (130, 145))	('LGG', 'Disease', (84, 87))
173255	31737567	The IDH mutation leads to a D2-hydroxyglutamate overproduction, involved in a large number of cellular reactions and in histone and DNA hypermethylation.	('D2-hydroxyglutamate', 'Protein', (28, 47))	('leads to', 'Reg', (17, 25))	('overproduction', 'PosReg', (48, 62))	('IDH', 'Gene', '3417', (4, 7))	('D2-hydroxyglutamate', 'Chemical', 'MESH:D015084', (28, 47))	('mutation', 'Var', (8, 16))	('IDH', 'Gene', (4, 7))
173257	31737567	The other 10% with the IDH-mutant variant is seen in younger patients with secondary glioblastoma, with a prior history of lower grade diffuse glioma.	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('patients', 'Species', '9606', (61, 69))	('glioblastoma', 'Disease', (85, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('variant', 'Var', (34, 41))	('glioma', 'Disease', (143, 149))	('IDH', 'Gene', (23, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('IDH', 'Gene', '3417', (23, 26))
173263	31737567	However, a better efficacy is observed in patients with a methylated MGMT promoter.	('patients', 'Species', '9606', (42, 50))	('MGMT', 'Gene', (69, 73))	('methylated', 'Var', (58, 68))	('MGMT', 'Gene', '4255', (69, 73))
173266	31737567	Glioblastomas conventionally appear as hypo or iso-intense on T1, enhanced in "a ring pattern" in T1 with gadolinium, and are hyper-intense on T2 and FLAIR acquisitions.	('iso-intense', 'Var', (47, 58))	('hypo', 'Disease', 'MESH:D052456', (39, 43))	('iso', 'Chemical', 'MESH:C080501', (47, 50))	('gadolinium', 'Chemical', 'MESH:D005682', (106, 116))	('enhanced', 'PosReg', (66, 74))	('Glioblastomas', 'Disease', (0, 13))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('ring pattern', 'Phenotype', 'HP:0100305', (81, 93))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('hypo', 'Disease', (39, 43))
173268	31737567	This concerns about 20% of patients, with an incidence twice higher in patients with glioblastoma harboring a methylation of the MGMT promoter for which the prognosis is better.	('patients', 'Species', '9606', (71, 79))	('glioblastoma', 'Disease', (85, 97))	('MGMT', 'Gene', (129, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('patients', 'Species', '9606', (27, 35))	('MGMT', 'Gene', '4255', (129, 133))	('methylation', 'Var', (110, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))
173330	31737567	The use of radiolabeled amino acids, mainly 11C-methionine, 18F-FDOPA, and 18F-FET in gliomas, and more specifically glioblastomas, is actively being investigated.	('18F-FDOPA', 'Chemical', 'MESH:C586095', (60, 69))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('11C-methionine', 'Chemical', 'MESH:C086242', (44, 58))	('glioblastomas', 'Disease', (117, 130))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('18F-FET', 'Var', (75, 82))	('18F-FET', 'Chemical', 'MESH:C528727', (75, 82))	('glioblastomas', 'Phenotype', 'HP:0012174', (117, 130))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('glioblastomas', 'Disease', 'MESH:D005909', (117, 130))	('gliomas', 'Disease', (86, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
173337	31737567	The captation significantly correlated with IDH1 mutation status in the majority of gliomas, with the exception of glioblastomas.	('mutation status', 'Var', (49, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('glioblastomas', 'Disease', (115, 128))	('IDH1', 'Gene', (44, 48))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('IDH1', 'Gene', '3417', (44, 48))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioblastomas', 'Phenotype', 'HP:0012174', (115, 128))	('captation', 'MPA', (4, 13))	('glioblastomas', 'Disease', 'MESH:D005909', (115, 128))	('correlated', 'Reg', (28, 38))
173391	31737567	To overcome the limitations for the use of 11C-methionine, 18F-labeled amino acids have been synthesized, such as 18F-FET.18F-FET enters tumor cells through a specific amino acid transport system (LAT) and is not metabolized or incorporated into proteins.	('18F-FET', 'Chemical', 'MESH:C528727', (122, 129))	('11C-methionine', 'Chemical', 'MESH:C086242', (43, 57))	('tumor', 'Disease', (137, 142))	('18F-FET', 'Chemical', 'MESH:C528727', (114, 121))	('18F-FET.18F-FET', 'Var', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
173412	31737567	The ratio between the radiation necrosis captation and the normal cortex uptake is lower for 18F-FET compared with 18F-FDG and 18F-fluorocholine.	('ratio', 'MPA', (4, 9))	('18F-FET', 'Var', (93, 100))	('18F-FET', 'Chemical', 'MESH:C528727', (93, 100))	('radiation necrosis', 'Disease', 'MESH:D011832', (22, 40))	('lower', 'NegReg', (83, 88))	('radiation necrosis', 'Disease', (22, 40))	('18F-FDG', 'Chemical', 'MESH:D019788', (115, 122))	('18F-fluorocholine', 'Chemical', 'MESH:C514960', (127, 144))
173463	31737567	The sensitivity and specificity in glioblastoma detection were higher using 18F-FMISO than using 18F-FDG.	('18F-FMISO', 'Var', (76, 85))	('glioblastoma', 'Disease', (35, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('18F-FDG', 'Chemical', 'MESH:D019788', (97, 104))	('higher', 'PosReg', (63, 69))	('18F-FMISO', 'Chemical', 'MESH:C031843', (76, 85))
173489	31737567	A few case reports have shown glioblastomas with PSMA radiolabeled with either 68Ga or 18F, the intense uptake being consistent with contrast-enhancing tumor on MRI (Figure 4).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('PSMA', 'Gene', '2346', (49, 53))	('18F', 'Var', (87, 90))	('glioblastomas', 'Phenotype', 'HP:0012174', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('glioblastomas', 'Disease', 'MESH:D005909', (30, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('glioblastomas', 'Disease', (30, 43))	('PSMA', 'Gene', (49, 53))	('68Ga', 'Var', (79, 83))
173519	31737567	A radiolabeled 18F-glutamine analog 4-18F-(2S,4R)-fluoroglutamine or 18F-FGln demonstrated a very high lesion/background ratio, no uptake in neuroinflammatory lesions, an absence of leakage through the permeable BBB, and a correlation between the decrease in its fixation and tumor shrinkage.	('leakage', 'MPA', (182, 189))	('fixation', 'MPA', (263, 271))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('neuroinflammatory lesions', 'Disease', 'MESH:D051437', (141, 166))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('decrease', 'NegReg', (247, 255))	('neuroinflammatory lesions', 'Disease', (141, 166))	('18F-FGln', 'Var', (69, 77))	('lesion/background ratio', 'MPA', (103, 126))	('tumor', 'Disease', (276, 281))	('4-18F-(2S,4R)-fluoroglutamine', 'Chemical', 'MESH:C586095', (36, 65))	('18F-glutamine', 'Chemical', 'MESH:C586095', (15, 28))	('uptake', 'MPA', (131, 137))
173524	31737567	Another 18F-labeled ligand investigated in patients followed for pre- or post-treatment glioblastoma, the 18F-GE-180, displayed a significant tumor-to-background contrast.	('glioblastoma', 'Disease', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('tumor', 'Disease', (142, 147))	('patients', 'Species', '9606', (43, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('18F-GE-180', 'Var', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
173525	31737567	The PET volume based on tracer uptake was larger than the volume based on MRI-enhanced tumor, thanks to tumor areas capturing the 18F-GE-180 even outside the areas enhanced on MRI.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('18F-GE-180', 'Var', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
173595	29114182	For example, the real proportion of five classes in BRATS 2015 is 92.42%, 0.43%, 4.87%, 1.02%, and 1.27% for healthy, necrosis, edema, and nonenhancing and enhancing tumor, respectively.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('edema', 'Disease', 'MESH:D004487', (128, 133))	('necrosis', 'Disease', (118, 126))	('edema', 'Phenotype', 'HP:0000969', (128, 133))	('tumor', 'Disease', (166, 171))	('necrosis', 'Disease', 'MESH:D009336', (118, 126))	('edema', 'Disease', (128, 133))	('nonenhancing', 'Var', (139, 151))	('enhancing', 'PosReg', (156, 165))
173613	29114182	used the CNN architecture ConvNet pretrained by AlexNet on the ImageNet database for breast cancer classification on dynamic contrast-enhanced MR images (DCE-MRI) and showed that transfer learning can enhance the predicting performance of breast cancer malignancy.	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer malignancy', 'Disease', 'MESH:D001943', (239, 263))	('DCE', 'Chemical', 'MESH:C024565', (154, 157))	('breast cancer', 'Disease', (85, 98))	('predicting', 'CPA', (213, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('transfer', 'Var', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('enhance', 'PosReg', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer malignancy', 'Disease', (239, 263))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
173633	28135248	In this group, telomere length positively correlated with TP53 and RB1 mutations.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('RB1', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('correlated', 'Reg', (42, 52))	('telomere length', 'MPA', (15, 30))
173638	28135248	The telomerase enzymatic subunit is encoded by TERT, and while it is transcriptionally silent in most non-neoplastic cells, reactivation may endow a small population of cells with the ability to survive crisis, at which point they become immortalized.	('TERT', 'Gene', (47, 51))	('reactivation', 'Var', (124, 136))	('TERT', 'Gene', '7015', (47, 51))	('ran', 'Gene', (70, 73))	('ran', 'Gene', '5901', (70, 73))
173642	28135248	Deactivating mutations in ATRX and its binding partner DAXX were found tightly correlated with long telomeres in pancreatic neuroendocrine tumors and glioma.	('ATRX', 'Gene', (26, 30))	('long telomeres', 'MPA', (95, 109))	('DAXX', 'Gene', (55, 59))	('Deactivating mutations', 'Var', (0, 22))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (124, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ATRX', 'Gene', '546', (26, 30))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('correlated', 'Reg', (79, 89))	('pancreatic neuroendocrine tumors', 'Disease', (113, 145))	('DAXX', 'Gene', '1616', (55, 59))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (113, 145))
173643	28135248	Recent evidence suggested that loss of ATRX may contribute to ALT by promoting sustained sister telomere cohesion and chromatid exchange.	('ATRX', 'Gene', (39, 43))	('promoting', 'PosReg', (69, 78))	('ATRX', 'Gene', '546', (39, 43))	('loss', 'Var', (31, 35))	('contribute', 'Reg', (48, 58))	('ALT', 'Disease', (62, 65))	('chromatid exchange', 'CPA', (118, 136))
173655	28135248	We curated a core sample set that consisted of 473 T/N pairs with the most comprehensive molecular profiling and an extended set that consisted of 6,835 T/N pairs with varying numbers of cases profiled by each individual platform (Figure 1a, Online Methods).	('835 T/N', 'Var', (149, 156))	('835 T/N', 'SUBSTITUTION', 'None', (149, 156))	('473 T/N', 'Var', (47, 54))	('473 T/N', 'SUBSTITUTION', 'None', (47, 54))
173656	28135248	TERT promoter (TERTp) mutations, predominantly C250T and C228T, were detected in 27% of the extended set for the cases where TERTp status could be determined (n=1,581).	('C250T', 'Var', (47, 52))	('TERT', 'Gene', '7015', (15, 19))	('C250T', 'Mutation', 'c.250C>T', (47, 52))	('C228T', 'Mutation', 'c.228C>T', (57, 62))	('TERTp', 'Gene', (125, 130))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', '7015', (125, 130))	('TERTp', 'Gene', (15, 20))	('TERT', 'Gene', (125, 129))	('C228T', 'Var', (57, 62))	('TERTp', 'Gene', '7015', (15, 20))	('TERT', 'Gene', '7015', (125, 129))	('TERT', 'Gene', (15, 19))
173657	28135248	In agreement with previous reports; high incidence of TERTp mutations was found in bladder cancer (42/60, 70%), liver cancer (73/162, 45%), melanoma (93/129, 72%), lower grade glioma (127/285, 45%) and glioblastoma (25/28, 89%, Supplementary Figure 4a).	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioblastoma', 'Disease', (202, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('bladder cancer', 'Disease', (83, 97))	('liver cancer', 'Disease', (112, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (60, 69))
173663	28135248	In the majority of TERTp structural variants (65%), at least one predicted super enhancer was found to directly overlap with the juxtaposed position (Supplementary Table 3).	('TERTp', 'Gene', (19, 24))	('TERTp', 'Gene', '7015', (19, 24))	('variants', 'Var', (36, 44))
173672	28135248	Taken together, we found somatic TERT alterations including TERTp mutations, TERT amplifications and TERT structural variants involving gene promoter or gene body in 32% of core set samples.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (60, 64))	('TERT', 'Gene', '7015', (77, 81))	('variants', 'Var', (117, 125))	('TERT', 'Gene', (101, 105))	('TERTp', 'Gene', (60, 65))	('TERTp', 'Gene', '7015', (60, 65))	('TERT', 'Gene', (60, 64))
173678	28135248	As previously described in pediatric brain tumors, TERT promoter probe cg11625005 demonstrated a strong correlation with TERT expression (Rho=0.52, FDR<0.0001).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (37, 49))	('pediatric brain tumors', 'Disease', (27, 49))	('TERT', 'Gene', (51, 55))	('correlation', 'Interaction', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cg11625005', 'Var', (71, 81))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (27, 49))
173683	28135248	TERTp methylation (two-sided t-test P<0.05) and TERTp mutations (two-sided t-test P<0.0001) were associated with relative TL shortening compared to other types of TERT alterations (Supplementary Figure 5c).	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', '7015', (163, 167))	('TERTp', 'Gene', (48, 53))	('TERTp', 'Gene', '7015', (48, 53))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', (48, 52))	('shortening', 'NegReg', (125, 135))	('TERT', 'Gene', '7015', (0, 4))	('methylation', 'Var', (6, 17))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (48, 52))	('TERTp', 'Gene', (0, 5))
173687	28135248	Focal TERC amplifications were associated with increased TERC expression (two-sided t-test P<0.0001) (Supplementary Figure 5d), and were enriched in TERT expressing samples (Odds Ratio (OR) 2.59, Fisher's Exact P<0.0001).	('TERT', 'Gene', '7015', (149, 153))	('TERC', 'Gene', (57, 61))	('TERC', 'Gene', (6, 10))	('amplifications', 'Var', (11, 25))	('TERC', 'Gene', '7012', (57, 61))	('increased', 'PosReg', (47, 56))	('TERT', 'Gene', (149, 153))	('TERC', 'Gene', '7012', (6, 10))
173697	28135248	TERC amplification was additionally associated with higher telomerase signature scores compared to non-amplified samples (two-sided t-test, P<0.0001), which may in part be explained by the co-expression patterns of TERT and TERC.	('TERT', 'Gene', '7015', (215, 219))	('amplification', 'Var', (5, 18))	('TERC', 'Gene', (0, 4))	('TERC', 'Gene', (224, 228))	('higher', 'PosReg', (52, 58))	('telomerase signature scores', 'MPA', (59, 86))	('TERC', 'Gene', '7012', (0, 4))	('TERT', 'Gene', (215, 219))	('TERC', 'Gene', '7012', (224, 228))
173700	28135248	We found alterations of ATRX and IDH1 as the most significantly associated with relative TL elongation (both FDR<0.0001; Figure 3a).	('associated', 'Reg', (64, 74))	('relative TL elongation', 'CPA', (80, 102))	('IDH1', 'Gene', (33, 37))	('ATRX', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('IDH1', 'Gene', '3417', (33, 37))	('ATRX', 'Gene', '546', (24, 28))
173701	28135248	Since IDH1 mutations frequently co-occur with ATRX in glioma, we tested a model with both tumor type and IDH1 as covariates, and found IDH1 no longer associated with TL ratio (two-sided t-test P=0.15).	('associated', 'Reg', (150, 160))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (6, 10))	('ATRX', 'Gene', '546', (46, 50))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Disease', (54, 60))	('ATRX', 'Gene', (46, 50))	('IDH1', 'Gene', (6, 10))	('TL ratio', 'MPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
173703	28135248	Alterations of the VHL were found to be associated with relative TL shortening (TL ratio 0.7, 95%CI 0.61-0.8, FDR<0.0001).	('relative TL shortening', 'MPA', (56, 78))	('Alterations', 'Var', (0, 11))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('VHL', 'Disease', (19, 22))
173706	28135248	A linear regression model showed that in addition to older age, positive TERRA expression, TP53 deletion, TP53 mutations, ATRX deletion, ATRX structural variants and absent/undetectable TERT expression were all independently associated with relative TL elongation (Figure 3b-c).	('mutations', 'Var', (111, 120))	('ATRX', 'Gene', (137, 141))	('TP53', 'Gene', (91, 95))	('positive', 'PosReg', (64, 72))	('TP53', 'Gene', '7157', (106, 110))	('ATRX', 'Gene', (122, 126))	('ATRX', 'Gene', '546', (122, 126))	('TP53', 'Gene', '7157', (91, 95))	('ATRX', 'Gene', '546', (137, 141))	('deletion', 'Var', (127, 135))	('deletion', 'Var', (96, 104))	('variants', 'Var', (153, 161))	('associated', 'Reg', (225, 235))	('TERT', 'Gene', (186, 190))	('relative TL elongation', 'CPA', (241, 263))	('TERT', 'Gene', '7015', (186, 190))	('TP53', 'Gene', (106, 110))
173707	28135248	Although DAXX has been linked to telomere length and ALT, DAXX mutations (n=51/6,835) and deletions (n=5/6,835) did not associate with TL.	('mutations', 'Var', (63, 72))	('DAXX', 'Gene', (58, 62))	('DAXX', 'Gene', '1616', (9, 13))	('deletions', 'Var', (90, 99))	('DAXX', 'Gene', (9, 13))	('DAXX', 'Gene', '1616', (58, 62))
173709	28135248	In addition to non-synonymous mutations and deletions, we detected ATRX structural variants from WGS data in 5% of the core set samples (n=26/473).	('variants', 'Var', (83, 91))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (67, 71))
173715	28135248	We observed a significant decrease in ATRX expression in samples showing mutations, deletions, fusions and structural variants compared to cases with wild type ATRX (Figure 4a).	('ATRX', 'Gene', '546', (160, 164))	('decrease', 'NegReg', (26, 34))	('structural variants', 'Var', (107, 126))	('ATRX', 'Gene', (38, 42))	('fusions', 'Var', (95, 102))	('ATRX', 'Gene', (160, 164))	('ATRX', 'Gene', '546', (38, 42))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (73, 82))	('deletions', 'Var', (84, 93))
173716	28135248	We found that all of types of ATRX alteration associated with significantly longer TL compared to wild type ATRX, consistent with the previously established association between ATRX deactivation and ALT (Figure 4b).	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', '546', (177, 181))	('longer', 'PosReg', (76, 82))	('ATRX', 'Gene', (108, 112))	('ATRX', 'Gene', '546', (30, 34))	('alteration', 'Var', (35, 45))	('ATRX', 'Gene', '546', (108, 112))	('ATRX', 'Gene', (177, 181))
173717	28135248	Recent studies found that ATRX knockdown resulted in elevated levels of telomeric repeat containing RNA (TERRA).	('ATRX', 'Gene', '546', (26, 30))	('ATRX', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))	('elevated', 'PosReg', (53, 61))
173718	28135248	Our results demonstrate a significantly higher fraction of TERRA expressing samples in all groups of ATRX altered samples (Figure 4c, Fisher's Exact test P<0.05) compared to the group of ATRX wild type samples.	('ATRX', 'Gene', '546', (187, 191))	('higher', 'PosReg', (40, 46))	('TERRA expressing', 'MPA', (59, 75))	('ATRX', 'Gene', (187, 191))	('ATRX', 'Gene', (101, 105))	('ATRX', 'Gene', '546', (101, 105))	('altered', 'Var', (106, 113))
173722	28135248	ATRX/DAXX mutations were found in 210 TERT expressing samples, representing 3% of the cohort.	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', '1616', (5, 9))	('TERT', 'Gene', (38, 42))	('DAXX', 'Gene', (5, 9))	('ATRX', 'Gene', '546', (0, 4))	('TERT', 'Gene', '7015', (38, 42))	('mutations', 'Var', (10, 19))
173723	28135248	These events were in majority non-truncating, while ATRX/DAXX mutations in TERT-negative cases were mostly truncating (Supplementary Methods, Supplementary Figure 9a).	('non-truncating', 'MPA', (30, 44))	('mutations', 'Var', (62, 71))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('DAXX', 'Gene', '1616', (57, 61))	('ATRX', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (52, 56))	('DAXX', 'Gene', (57, 61))	('truncating', 'MPA', (107, 117))
173724	28135248	TERT-expressing ATRX/DAXX mutants showed higher telomerase signature scores compared to ATRX/DAXX altered samples lacking TERT expression (Supplementary Figure 9b).	('TERT', 'Gene', (122, 126))	('DAXX', 'Gene', '1616', (93, 97))	('TERT', 'Gene', '7015', (122, 126))	('DAXX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (88, 92))	('ATRX', 'Gene', '546', (16, 20))	('TERT', 'Gene', (0, 4))	('DAXX', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (0, 4))	('mutants', 'Var', (26, 33))	('telomerase signature scores', 'MPA', (48, 75))	('higher', 'PosReg', (41, 47))	('DAXX', 'Gene', '1616', (21, 25))	('ATRX', 'Gene', (88, 92))	('ATRX', 'Gene', (16, 20))
173738	28135248	In addition to IDH1 and TP53, RB1 (TL ratio 1.5, 95%CI 1.2-1.87, FDR=0.001) and MDM2 (TL ratio 1.51, 95%CI 1.14-2, FDR=0.01) were revealed to associate with relatively long TLs.	('MDM2', 'Gene', (80, 84))	('IDH1', 'Gene', (15, 19))	('TP53', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (15, 19))	('RB1', 'Var', (30, 33))	('MDM2', 'Gene', '4193', (80, 84))	('TP53', 'Gene', '7157', (24, 28))
173739	28135248	The finding of RB1 is consistent with experimental data demonstrating markedly elongated telomeres in Rb1 deficient mice independent of telomerase.	('mice', 'Species', '10090', (116, 120))	('telomeres', 'CPA', (89, 98))	('deficient', 'Var', (106, 115))	('elongated', 'PosReg', (79, 88))	('Rb1', 'Gene', (102, 105))	('Rb1', 'Gene', '19645', (102, 105))
173740	28135248	In the opposite direction, somatic alterations in PBRM1 (TL ratio 0.67, 95%CI 0.55-0.83, FDR=0.001), NRAS (TL ratio 0.68, 95%CI 0.52-0.9, FDR=0.02) and VHL (TL ratio 0.7, 95%CI 0.57-0.85, FDR=0.002) were associated with relative TL shortening (Figure 5d).	('NRAS', 'Gene', (101, 105))	('PBRM1', 'Gene', (50, 55))	('alterations', 'Var', (35, 46))	('PBRM1', 'Gene', '55193', (50, 55))	('NRAS', 'Gene', '4893', (101, 105))	('VHL', 'Disease', (152, 155))	('VHL', 'Disease', 'MESH:D006623', (152, 155))
173750	28135248	This paradoxical association between TERT promoter methylation and increased TERT expression may result from loss of CTCF binding, a transcriptional repressor reported to bind to the unmethylated TERT promoter.	('TERT', 'Gene', (37, 41))	('binding', 'Interaction', (122, 129))	('TERT', 'Gene', (77, 81))	('ran', 'Gene', (134, 137))	('ran', 'Gene', '5901', (134, 137))	('TERT', 'Gene', '7015', (37, 41))	('TERT', 'Gene', '7015', (77, 81))	('TERT', 'Gene', (196, 200))	('loss', 'NegReg', (109, 113))	('CTCF', 'Gene', (117, 121))	('TERT', 'Gene', '7015', (196, 200))	('increased', 'PosReg', (67, 76))	('methylation', 'Var', (51, 62))	('CTCF', 'Gene', '10664', (117, 121))
173751	28135248	Structural TERT variants have been documented and we detected these across several novel cancer types, including sarcoma, prostate and liver carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('liver carcinoma', 'Phenotype', 'HP:0001402', (135, 150))	('liver carcinoma', 'Disease', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('prostate', 'Disease', (122, 130))	('liver carcinoma', 'Disease', 'MESH:D006528', (135, 150))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('detected', 'Reg', (53, 61))	('cancer', 'Disease', (89, 95))	('sarcoma', 'Disease', (113, 120))	('TERT', 'Gene', (11, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('TERT', 'Gene', '7015', (11, 15))	('variants', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
173752	28135248	Hepatitis B virus and adeno-associated virus type 2 integration in TERT was found in about 5% of hepatocellular carcinomas.	('TERT', 'Gene', (67, 71))	('integration', 'Var', (52, 63))	('found', 'Reg', (76, 81))	('TERT', 'Gene', '7015', (67, 71))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (97, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (97, 122))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('adeno-associated virus type 2', 'Species', '10804', (22, 51))	('hepatocellular carcinomas', 'Disease', (97, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('Hepatitis B virus', 'Disease', (0, 17))
173757	28135248	An estimated 5-10% of TERC and TERRA carry the poly-A tails required for oligo-dT primer based RNA sequencing quantification.	('poly-A', 'Chemical', 'MESH:D011061', (47, 53))	('TERC', 'Gene', '7012', (22, 26))	('TERC', 'Gene', (22, 26))	('poly-A tails', 'Var', (47, 59))
173762	28135248	Deactivation of ATRX and/or DAXX has been related to ALT, and was observed in five percent of the cases in our core set.	('Deactivation', 'Var', (0, 12))	('ATRX', 'Gene', '546', (16, 20))	('DAXX', 'Gene', (28, 32))	('ALT', 'Disease', (53, 56))	('DAXX', 'Gene', '1616', (28, 32))	('related', 'Reg', (42, 49))	('ATRX', 'Gene', (16, 20))
173763	28135248	A detailed review of ATRX somatic changes revealed a large spectrum of potentially protein truncating changes, including inactivating mutations, deletions and structural variants.	('inactivating mutations', 'Var', (121, 143))	('protein truncating changes', 'MPA', (83, 109))	('structural variants', 'Var', (159, 178))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('deletions', 'Var', (145, 154))
173765	28135248	Our analysis reinforced the association of inactivate ATRX/DAXX and ALT, demonstrating relative TL elongation in samples affected by somatic alterations in one of these two genes and a higher frequency of TERRA expression in tumors with these alterations.	('alterations', 'Var', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('DAXX', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ATRX', 'Gene', '546', (54, 58))	('TL elongation', 'CPA', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('affected', 'Reg', (121, 129))	('DAXX', 'Gene', '1616', (59, 63))	('tumors', 'Disease', (225, 231))	('ATRX', 'Gene', (54, 58))	('inactivate', 'Var', (43, 53))
173768	28135248	Such mechanisms may involve some RB1 and TP53 alterations, as somatic changes in these genes were associated with telomere elongation within this group.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('telomere elongation', 'CPA', (114, 133))	('RB1', 'Gene', (33, 36))	('changes', 'Var', (70, 77))	('associated', 'Reg', (98, 108))
173787	28135248	There was sufficient coverage for TERTp mutation calling in 903 samples, and we detected TERTp mutations in n=183, including C228T (n=128), C250T (n=49), C242/243T (n=5) and C169T (n=1).	('TERTp', 'Gene', '7015', (89, 94))	('C250T', 'Var', (140, 145))	('C250T', 'Mutation', 'c.250C>T', (140, 145))	('TERTp', 'Gene', '7015', (34, 39))	('C228T', 'Var', (125, 130))	('detected', 'Reg', (80, 88))	('C169T', 'Var', (174, 179))	('C169T', 'Mutation', 'c.169C>T', (174, 179))	('C242/243T', 'Var', (154, 163))	('C228T', 'Mutation', 'c.228C>T', (125, 130))	('TERTp', 'Gene', (89, 94))	('TERTp', 'Gene', (34, 39))
173790	28135248	Because we were only interested in variants involving TERT (chr5:1253287-1315162, including 20kb upstream of the TSS) and ATRX (chrX:76760356-77041719), variants not overlapping one of these regions were excluded.	('ATRX', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (54, 58))	('chrX:76760356-77041719', 'STRUCTURAL_ABNORMALITY', 'None', (128, 150))	('variants', 'Var', (35, 43))	('chr5:1253287-1315162', 'STRUCTURAL_ABNORMALITY', 'None', (60, 80))	('ATRX', 'Gene', '546', (122, 126))	('TERT', 'Gene', (54, 58))
173801	28135248	This analysis found overlapping super-enhancers in 11/17 TERTp structural variants, and this was significantly more than expected by chance (Chi-Square test P=0.001).	('super-enhancers', 'PosReg', (32, 47))	('variants', 'Var', (74, 82))	('TERTp', 'Gene', (57, 62))	('TERTp', 'Gene', '7015', (57, 62))
173802	28135248	For each structural variant proximal (adjacent to the TERT promoter) and distal breakpoint (juxtaposed to the TERT promoter) we calculated the number of reads mapping to each of three histone marks (H3K27ac, H3K27me3 and H3Kme1) individually within each tissue and cell/type.	('H3Kme1', 'Var', (221, 227))	('H3K27ac', 'Var', (199, 206))	('H3K27me3', 'Var', (208, 216))	('TERT', 'Gene', '7015', (54, 58))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', (54, 58))
173814	28135248	Spearman correlation was used to associate TERT expression and methylation, and to correlate gene expression and TL.	('TERT', 'Gene', (43, 47))	('methylation', 'Var', (63, 74))	('TERT', 'Gene', '7015', (43, 47))
173830	28018994	The integration of genome-wide data from multiple platforms uncovered three molecular classes of lower-grade gliomas that were best represented by IDH and 1p/19q status: wild-type IDH, IDH mutation with 1p/19q codeletion, and IDH mutation without 1p/19q codeletion.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH', 'Gene', '3417', (147, 150))	('IDH', 'Gene', '3417', (226, 229))	('1p/19q codeletion', 'Var', (203, 220))	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', '3417', (185, 188))	('IDH', 'Gene', (180, 183))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('mutation', 'Var', (189, 197))	('gliomas', 'Disease', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (147, 150))	('IDH', 'Gene', (226, 229))
173832	32958546	Glutamate is a non-invasive metabolic biomarker of IDH1 mutant glioma response to temozolomide treatment Although lower-grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('temozolomide', 'Chemical', 'MESH:D000077204', (82, 94))	('IDH', 'Gene', '3417', (51, 54))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH', 'Gene', '3417', (193, 196))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('mutant', 'Var', (56, 62))	('isocitrate dehydrogenase', 'Gene', (165, 189))	('driven by', 'Reg', (138, 147))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (241, 253))	('mutations', 'Var', (148, 157))	('Glutamate', 'Chemical', 'MESH:D018698', (0, 9))	('glioblastoma', 'Disease', (241, 253))	('glioma', 'Disease', (126, 132))	('gliomas', 'Disease', (126, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (241, 253))	('glioma', 'Disease', (63, 69))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', (193, 196))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('isocitrate dehydrogenase', 'Gene', '3417', (165, 189))
173833	32958546	IDH1 mutant patients are increasingly being treated with temozolomide (TMZ), but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage.	('patients', 'Species', '9606', (12, 20))	('IDH', 'Gene', (0, 3))	('temozolomide', 'Chemical', 'MESH:D000077204', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('IDH', 'Gene', '3417', (0, 3))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('mutant', 'Var', (5, 11))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))
173834	32958546	The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to TMZ in both genetically engineered and patient-derived mutant IDH1 models.	('IDH', 'Gene', (206, 209))	('IDH', 'Gene', '3417', (206, 209))	('patient', 'Species', '9606', (183, 190))	('TMZ', 'Chemical', 'MESH:D000077204', (144, 147))	('mutant', 'Var', (199, 205))
173835	32958546	Using 1H MRS in combination with chemometrics identified several metabolic alterations in TMZ-treated cells, including a significant increase in steady-state glutamate levels.	('steady-state glutamate levels', 'MPA', (145, 174))	('glutamate', 'Chemical', 'MESH:D018698', (158, 167))	('TMZ', 'Chemical', 'MESH:D000077204', (90, 93))	('metabolic', 'MPA', (65, 74))	('1H', 'Chemical', '-', (6, 8))	('alterations', 'Reg', (75, 86))	('TMZ-treated', 'Var', (90, 101))	('increase', 'PosReg', (133, 141))
173839	32958546	Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or alpha-ketoglutarate as potential translatable metabolic biomarkers of response to TMZ treatment in mutant IDH1 glioma.	('elevation', 'PosReg', (54, 63))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('TMZ', 'Chemical', 'MESH:D000077204', (242, 245))	('glutamate', 'MPA', (67, 76))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (160, 179))	('glutamate', 'Chemical', 'MESH:D018698', (115, 124))	('mutant', 'Var', (259, 265))	('IDH1 glioma', 'Disease', 'MESH:D005910', (266, 277))	('pyruvate', 'Chemical', 'MESH:D019289', (148, 156))	('1H', 'Chemical', '-', (36, 38))	('glutamate', 'Chemical', 'MESH:D018698', (67, 76))	('13C', 'Chemical', 'MESH:C000615229', (96, 99))	('IDH1 glioma', 'Disease', (266, 277))	('hyperpolarized', 'MPA', (81, 95))
173842	32958546	The more recent World Health Organization (WHO) classification also includes molecular parameters, which characterize astrocytoma and oligodendroglioma primarily by mutations in the isocitrate dehydrogenase (IDH, mostly IDH1) gene.	('IDH', 'Gene', (220, 223))	('oligodendroglioma', 'Disease', 'MESH:D009837', (134, 151))	('astrocytoma', 'Disease', 'MESH:D001254', (118, 129))	('IDH', 'Gene', '3417', (220, 223))	('astrocytoma', 'Disease', (118, 129))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('isocitrate dehydrogenase', 'Gene', (182, 206))	('IDH', 'Gene', (208, 211))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('mutations', 'Var', (165, 174))	('oligodendroglioma', 'Disease', (134, 151))	('isocitrate dehydrogenase', 'Gene', '3417', (182, 206))	('IDH', 'Gene', '3417', (208, 211))
173852	32958546	We have previously used 1H MRS to study mutant IDH1 glioma and showed that in addition to elevated levels of 2-hydroxyglutarate (2-HG), these cells have lower glutamate, lactate and phosphocholine when compared to wild-type IDH1 cells.	('IDH', 'Gene', (224, 227))	('glutamate', 'Chemical', 'MESH:D018698', (159, 168))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH', 'Gene', '3417', (224, 227))	('1H', 'Chemical', '-', (24, 26))	('lower', 'NegReg', (153, 158))	('elevated levels of 2-hydroxyglutarate', 'Phenotype', 'HP:0012402', (90, 127))	('mutant', 'Var', (40, 46))	('IDH1 glioma', 'Disease', 'MESH:D005910', (47, 58))	('phosphocholine', 'Chemical', 'MESH:D010767', (182, 196))	('IDH', 'Gene', (47, 50))	('2-HG', 'Chemical', 'MESH:C019417', (129, 133))	('glutamate', 'MPA', (159, 168))	('elevated', 'PosReg', (90, 98))	('IDH1 glioma', 'Disease', (47, 58))	('IDH', 'Gene', '3417', (47, 50))	('lactate', 'Chemical', 'MESH:D019344', (170, 177))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (109, 127))	('levels of 2-hydroxyglutarate', 'MPA', (99, 127))
173853	32958546	We also investigated mutant IDH1 glioma using another translational metabolic imaging method, namely hyperpolarized 13C MRS, which provides complementary information by probing metabolic fluxes.	('mutant', 'Var', (21, 27))	('IDH1 glioma', 'Disease', 'MESH:D005910', (28, 39))	('IDH1 glioma', 'Disease', (28, 39))	('13C', 'Chemical', 'MESH:C000615229', (116, 119))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
173854	32958546	Using this method, we showed that mutant IDH1 cells have a lower flux to glutamate from both pyruvate and alpha-ketoglutarate (alpha-KG).	('alpha-ketoglutarate', 'MPA', (106, 125))	('IDH', 'Gene', (41, 44))	('IDH', 'Gene', '3417', (41, 44))	('lower', 'NegReg', (59, 64))	('glutamate', 'Chemical', 'MESH:D018698', (73, 82))	('flux to glutamate from', 'MPA', (65, 87))	('alpha-KG', 'Chemical', 'MESH:D007656', (127, 135))	('pyruvate', 'Chemical', 'MESH:D019289', (93, 101))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (106, 125))	('mutant', 'Var', (34, 40))
173855	32958546	The goal of this study was to determine whether MRS-based metabolic imaging biomarkers could be used to assess the response of mutant IDH1 glioma to TMZ treatment.	('mutant', 'Var', (127, 133))	('TMZ', 'Chemical', 'MESH:D000077204', (149, 152))	('IDH1 glioma', 'Disease', (134, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IDH1 glioma', 'Disease', 'MESH:D005910', (134, 145))
173857	32958546	We first investigated the effects of TMZ on the global metabolic profile of our cells using 1H MRS combined with chemometrics, and then probed specific metabolic pathways using thermal equilibrium 13C MRS and hyperpolarized 13C MRS. We found that across our models, response to TMZ treatment was associated with an increase in 1H MRS glutamate levels as well as an increase in glutamate production from glucose and glutamine, resulting in hyperpolarized 13C MRS-detectable elevated flux from both pyruvate and alpha-KG.	('increase in 1H MRS glutamate levels', 'Phenotype', 'HP:0500200', (315, 350))	('glucose', 'Chemical', 'MESH:D005947', (403, 410))	('13C', 'Chemical', 'MESH:C000615229', (197, 200))	('increase', 'PosReg', (365, 373))	('elevated', 'PosReg', (473, 481))	('glutamate', 'Chemical', 'MESH:D018698', (334, 343))	('1H', 'Chemical', '-', (327, 329))	('TMZ', 'Var', (278, 281))	('glutamine', 'Chemical', 'MESH:D005973', (415, 424))	('TMZ', 'Chemical', 'MESH:D000077204', (278, 281))	('increase in glutamate production', 'Phenotype', 'HP:0500149', (365, 397))	('alpha-KG', 'Chemical', 'MESH:D007656', (510, 518))	('increase', 'PosReg', (315, 323))	('1H MRS glutamate levels', 'MPA', (327, 350))	('TMZ', 'Chemical', 'MESH:D000077204', (37, 40))	('13C', 'Chemical', 'MESH:C000615229', (454, 457))	('13C', 'Chemical', 'MESH:C000615229', (224, 227))	('1H', 'Chemical', '-', (92, 94))	('glutamate', 'Chemical', 'MESH:D018698', (377, 386))	('hyperpolarized', 'PosReg', (439, 453))	('pyruvate', 'Chemical', 'MESH:D019289', (497, 505))
173859	32958546	NHAIDHmut and U87IDHmut cells (immortalized normal human astrocytes and glioblastoma engineered to express the IDH1 R132H mutant gene) were maintained in culture as described.	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', '3417', (3, 6))	('IDH', 'Gene', '3417', (17, 20))	('IDH', 'Gene', (111, 114))	('human', 'Species', '9606', (51, 56))	('glioblastoma', 'Disease', (72, 84))	('IDH', 'Gene', '3417', (111, 114))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('R132H', 'Var', (116, 121))	('IDH', 'Gene', (3, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))	('R132H', 'SUBSTITUTION', 'None', (116, 121))
173860	32958546	SF10602 and SF10417, patient-derived mutant IDH1 astrocytoma and oligodendroglioma respectively, courtesy of the Costello Lab (UCSF), were cultured as described.	('oligodendroglioma', 'Disease', (65, 82))	('astrocytoma', 'Disease', 'MESH:D001254', (49, 60))	('patient', 'Species', '9606', (21, 28))	('astrocytoma', 'Disease', (49, 60))	('SF10417', 'Chemical', '-', (12, 19))	('oligodendroglioma', 'Disease', 'MESH:D009837', (65, 82))	('SF10602', 'Chemical', '-', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (49, 60))	('SF10417', 'Var', (12, 19))	('IDH', 'Gene', (44, 47))	('SF10602', 'Var', (0, 7))	('IDH', 'Gene', '3417', (44, 47))
173863	32958546	Pieper (NHAIDHmut, U87IDHmut), Costello (SF10602/SF10417) and Luchman (BT142).	('SF10417', 'Chemical', '-', (49, 56))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('BT142', 'Chemical', '-', (71, 76))	('IDH', 'Gene', (22, 25))	('SF10602/SF10417', 'Var', (41, 56))	('SF10602', 'Chemical', '-', (41, 48))	('IDH', 'Gene', '3417', (22, 25))
173864	32958546	Cells were treated with TMZ (Sigma-Aldrich) doses based on literature that were confirmed to result in ~50% reduction in cell number: NHAIDHmut and U87IDHmut-100muM for 3 days; SF10417-400muM for 3 days; SF10602-400muM for 7 days.	('TMZ', 'Chemical', 'MESH:D000077204', (24, 27))	('SF10602', 'Chemical', '-', (204, 211))	('IDH', 'Gene', '3417', (137, 140))	('SF10417-400muM', 'Var', (177, 191))	('IDH', 'Gene', '3417', (151, 154))	('SF10417', 'Chemical', '-', (177, 184))	('IDH', 'Gene', (137, 140))	('SF10602-400muM', 'Var', (204, 218))	('cell number', 'CPA', (121, 132))	('IDH', 'Gene', (151, 154))	('reduction', 'NegReg', (108, 117))
173884	32958546	Mice were randomly divided into control and TMZ-treated groups when tumor size was comparable and large enough to perform the MRS study: for U87IDHmut xenografts at 0.06+-0.03cm3 (33+-11 days post-implantation, n=16), for SF10417 xenografts at 0.07+-0.04cm3 (257+-26 days post-implantation, n=13) and for BT142 at 0.08+-0.03cm3 (124+-5 days post-implantation, n=19).	('tumor', 'Disease', (68, 73))	('IDH', 'Gene', (144, 147))	('IDH', 'Gene', '3417', (144, 147))	('BT142', 'Chemical', '-', (305, 310))	('TMZ', 'Chemical', 'MESH:D000077204', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SF10417', 'Chemical', '-', (222, 229))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('0.06+-0.03cm3', 'Var', (165, 178))
173893	32958546	For SF10417, 10-30mg of frozen tumor were extracted using the dual-phase extraction and 1H MRS spectra recorded as described except that metabolite levels were normalized to total signal.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SF10417', 'Var', (4, 11))	('tumor', 'Disease', (31, 36))	('1H', 'Chemical', '-', (88, 90))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('SF10417', 'Chemical', '-', (4, 11))
173900	32958546	As illustrated in Figure 1A, treatment of NHAIDHmut, U87IDHmut, SF10602 and SF10417 cells led to a reduction in cell number by 48% (p-value<0.01), 49% (p-value<0.01), 56% (p-value<0.01) and 50% (p-value<0.01), respectively.	('IDH', 'Gene', (45, 48))	('SF10417 cells', 'Var', (76, 89))	('cell number', 'CPA', (112, 123))	('SF10602', 'Chemical', '-', (64, 71))	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3417', (45, 48))	('SF10417', 'Chemical', '-', (76, 83))	('reduction', 'NegReg', (99, 108))	('IDH', 'Gene', '3417', (56, 59))	('SF10602', 'Var', (64, 71))
173902	32958546	In addition, assessment of phospho-H2AX (Fig.1B and S1), an early indicator of TMZ-induced DNA double-strand breaks (DSBs), indicated that TMZ treatment was associated with a significant increase in phospho-H2AX (p-value<0.01 in all cell lines; Fig.1B).	('H2AX', 'Gene', '3014', (207, 211))	('H2AX', 'Gene', '3014', (35, 39))	('TMZ', 'Var', (139, 142))	('increase', 'PosReg', (187, 195))	('H2AX', 'Gene', (207, 211))	('H2AX', 'Gene', (35, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (139, 142))	('TMZ', 'Chemical', 'MESH:D000077204', (79, 82))
173910	32958546	Importantly, when we then investigated our two clinically relevant patient-derived mutant IDH1 cell lines, SF10602 and SF10417, we observed similar significant changes in glutamate, glutamine and phosphocholine following treatment, however SF10602 showed no change in 2-HG and myo-inositol (Fig.3C and 3D).	('changes', 'Reg', (160, 167))	('SF10602', 'Var', (240, 247))	('glutamate', 'Chemical', 'MESH:D018698', (171, 180))	('IDH', 'Gene', (90, 93))	('2-HG', 'MPA', (268, 272))	('glutamine', 'Chemical', 'MESH:D005973', (182, 191))	('SF10602', 'Var', (107, 114))	('glutamate', 'MPA', (171, 180))	('IDH', 'Gene', '3417', (90, 93))	('2-HG', 'Chemical', 'MESH:C019417', (268, 272))	('SF10417', 'Chemical', '-', (119, 126))	('SF10602', 'Chemical', '-', (240, 247))	('phosphocholine', 'Chemical', 'MESH:D010767', (196, 210))	('myo-inositol', 'Chemical', 'MESH:D007294', (277, 289))	('SF10417', 'Var', (119, 126))	('patient', 'Species', '9606', (67, 74))	('SF10602', 'Chemical', '-', (107, 114))
173914	32958546	To that end we investigated orthotopically implanted tumors of U87IDHmut and SF10417.	('IDH', 'Gene', (66, 69))	('IDH', 'Gene', '3417', (66, 69))	('SF10417', 'Chemical', '-', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('SF10417', 'Var', (77, 84))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
173916	32958546	Figure 4A illustrates anatomical T2-weighted images of control and TMZ-treated U87IDHmut tumor-bearing mice at D0, D4+-1 and D7+-1 of treatment.	('IDH', 'Gene', '3417', (82, 85))	('mice', 'Species', '10090', (103, 107))	('TMZ', 'Chemical', 'MESH:D000077204', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('D7+-1', 'Var', (125, 130))	('IDH', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('D4+-1', 'Var', (115, 120))
173918	32958546	The Kaplan-Meyer survival plot illustrates that treatment with TMZ led to a significantly longer survival of 38+-5 days in the TMZ-treated group compared to 10+-4 days in the control (Chi-square value=42.2; p-value<0.01; Fig.4D).	('TMZ', 'Chemical', 'MESH:D000077204', (63, 66))	('longer', 'PosReg', (90, 96))	('survival', 'CPA', (97, 105))	('TMZ', 'Var', (63, 66))	('TMZ', 'Chemical', 'MESH:D000077204', (127, 130))
173922	32958546	This effect was slightly reduced by D7+-1 but still demonstrated a significant increase in the concentration of glutamate (by 17%; p-value<0.01) and GLX (by 22%; p-value<0.01) although the concentration of glutamine was comparable (p-value>0.05) (controls: n=4, TMZ-treated: n=4) (Fig.4F-H).	('increase', 'PosReg', (79, 87))	('glutamine', 'Chemical', 'MESH:D005973', (206, 215))	('GLX', 'MPA', (149, 152))	('glutamate', 'Chemical', 'MESH:D018698', (112, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (262, 265))	('concentration', 'MPA', (95, 108))	('D7+-1', 'Var', (36, 41))
173923	32958546	The concentration of total choline-containing metabolites (tCho) was also significantly increased (by 62%; p-value<0.01) in TMZ-treated U87IDHmut tumors at D4 (controls: n=3, TMZ-treated: n=4), but this effect was reversed by D7+-1 demonstrating a significant decrease of tCho (by 34%; p-value<0.01) in response to TMZ treatment (controls: n=3, TMZ-treated: n=4) (Table S2 and S3).	('TMZ', 'Chemical', 'MESH:D000077204', (124, 127))	('concentration', 'MPA', (4, 17))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tCho', 'Chemical', '-', (59, 63))	('tCho', 'Chemical', '-', (272, 276))	('TMZ', 'Chemical', 'MESH:D000077204', (345, 348))	('choline', 'Chemical', 'MESH:D002794', (27, 34))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('increased', 'PosReg', (88, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (315, 318))	('TMZ', 'Chemical', 'MESH:D000077204', (175, 178))	('IDH', 'Gene', (139, 142))	('TMZ-treated', 'Var', (124, 135))	('tumors', 'Disease', (146, 152))	('IDH', 'Gene', '3417', (139, 142))
173924	32958546	Additionally, we also detected a significant decrease in myo-inositol in TMZ-treated tumors at D4 (by 21%; p-value<0.01) and D7+-1 (by 46%; p-value<0.01) (Table S2 and S3) and other metabolites were modulated differentially (Table S2 and S3).	('TMZ', 'Chemical', 'MESH:D000077204', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('myo-inositol', 'MPA', (57, 69))	('D7+-1', 'Var', (125, 130))	('decrease', 'NegReg', (45, 53))	('tumors', 'Disease', (85, 91))	('myo-inositol', 'Chemical', 'MESH:D007294', (57, 69))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
173926	32958546	As in the case of the U87IDHmut, quantification of average tumor volume at D6+-1 showed no difference in tumor size following TMZ treatment, 132% of D0 for control and 120% for TMZ-treated (n=9 for both groups, p-value>0.05), but by D15+-1 TMZ treatment resulted in a significant difference compared to controls growing to 176% of D0, and treated tumors shrinking to 88% of D0 (n=6 for both groups, p-value<0.01; Fig.S4A-C).	('IDH', 'Gene', (25, 28))	('tumor', 'Disease', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('shrinking', 'NegReg', (354, 363))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('IDH', 'Gene', '3417', (25, 28))	('tumors', 'Disease', (347, 353))	('D15+-1', 'Var', (233, 239))	('TMZ', 'Chemical', 'MESH:D000077204', (126, 129))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (347, 352))	('TMZ', 'Chemical', 'MESH:D000077204', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('TMZ', 'Chemical', 'MESH:D000077204', (240, 243))
173927	32958546	1H MRS spectra and quantification of the metabolite concentrations at D6+-1, prior to visible tumor changes, and at D15+-1, when tumor shrinkage was observed are shown in Figure S4D-G.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('1H', 'Chemical', '-', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('D6+-1', 'Var', (70, 75))
173928	32958546	Consistent with results from U87IDHmut tumors, at D6+-1 BT142 tumors showed significant increases in glutamate by 4% (p-value<0.01), glutamine by 50% (p-value<0.01) and GLX by 17% (p-value<0.01) (controls: n=9, TMZ-treated: n=11) (Fig.S4D-G).	('GLX', 'MPA', (169, 172))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IDH', 'Gene', (32, 35))	('glutamine', 'MPA', (133, 142))	('tumors', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('IDH', 'Gene', '3417', (32, 35))	('increases', 'PosReg', (88, 97))	('glutamate', 'Chemical', 'MESH:D018698', (101, 110))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('BT142', 'Chemical', '-', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (211, 214))	('glutamine', 'Chemical', 'MESH:D005973', (133, 142))	('BT142', 'Gene', (56, 61))	('glutamate', 'MPA', (101, 110))	('D6+-1', 'Var', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
173929	32958546	By D15+-1 a generally smaller but still significant increase in the concentration of glutamate (by 8%; p-value<0.01), glutamine (by 13%; p-value<0.01) and GLX (by 7%; p-value<0.01) was observed (controls: n=6, TMZ-treated: n=6).	('TMZ', 'Chemical', 'MESH:D000077204', (210, 213))	('concentration of glutamate', 'MPA', (68, 94))	('glutamate', 'Chemical', 'MESH:D018698', (85, 94))	('increase', 'PosReg', (52, 60))	('glutamine', 'Chemical', 'MESH:D005973', (118, 127))	('D15+-1', 'Var', (3, 9))	('glutamine', 'MPA', (118, 127))	('GLX', 'MPA', (155, 158))
173930	32958546	tCho was significantly reduced in TMZ-treated tumors by 13% (p-value<0.01) at D6+-1 and by 27% (p-value<0.01) at D15+-1 (Table S4 and S5).	('reduced', 'NegReg', (23, 30))	('tCho', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('D15+-1', 'Var', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tCho', 'MPA', (0, 4))	('D6+-1', 'Var', (78, 83))	('tumors', 'Disease', (46, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (34, 37))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
173931	32958546	We also detected a significant decrease in myo-inositol at D6+-1 (by 18%; p-value<0.01) and D15+-1 (by 24%; p-value<0.01) and several other metabolites were modulated in different ways (Table S4 and S5).	('D15+-1', 'Var', (92, 98))	('myo-inositol', 'MPA', (43, 55))	('decrease', 'NegReg', (31, 39))	('D6+-1', 'Var', (59, 64))	('myo-inositol', 'Chemical', 'MESH:D007294', (43, 55))
173935	32958546	In line with the effects of TMZ on tumor size and animal survival we observed higher levels of phospho-H2AX and caspase-3 in TMZ-treated U87IDHmut (Fig.S6) and BT142 tumors (Fig.S7) when compared to their controls.	('IDH', 'Gene', '3417', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('caspase-3', 'Gene', (112, 121))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('higher', 'PosReg', (78, 84))	('tumor', 'Disease', (35, 40))	('levels', 'MPA', (85, 91))	('tumors', 'Disease', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('H2AX', 'Gene', (103, 107))	('TMZ', 'Chemical', 'MESH:D000077204', (125, 128))	('BT142', 'Chemical', '-', (160, 165))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('TMZ-treated', 'Var', (125, 136))	('IDH', 'Gene', (140, 143))	('H2AX', 'Gene', '3014', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('BT142', 'Gene', (160, 165))	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('caspase-3', 'Gene', '836', (112, 121))
173944	32958546	In line with this observation, the activity of pyruvate dehydrogenase (PDH), the rate limiting enzyme for pyruvate metabolism to glutamate, was significantly increased by TMZ-treatment in both our cell lines (Fig.S8A and S8B).	('activity', 'MPA', (35, 43))	('pyruvate', 'Chemical', 'MESH:D019289', (47, 55))	('pyruvate', 'Chemical', 'MESH:D019289', (106, 114))	('TMZ-treatment', 'Var', (171, 184))	('PDH', 'Gene', '54704', (71, 74))	('pyruvate dehydrogenase', 'Gene', '54704', (47, 69))	('pyruvate dehydrogenase', 'Gene', (47, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (171, 174))	('glutamate', 'Chemical', 'MESH:D018698', (129, 138))	('PDH', 'Gene', (71, 74))	('increased', 'PosReg', (158, 167))
173948	32958546	As illustrated in Figure 7A build-up of hyperpolarized [1-13C]glutamate could be detected following injection of hyperpolarized [1-13C]alpha-KG and [1-13C]glutamate accumulation was significantly higher in both NHAIDHmut (p-value<0.05; Fig.7B;) and U87IDHmut cells (p-value<0.01; Fig.7C) following TMZ-treatment.	('[1-13C]', 'Var', (148, 155))	('hyperpolarized [1-13C', 'MPA', (40, 61))	('C]alpha', 'Species', '342041', (133, 140))	('13C', 'Chemical', 'MESH:C000615229', (131, 134))	('alpha-KG', 'Chemical', 'MESH:D007656', (135, 143))	('13C', 'Chemical', 'MESH:C000615229', (58, 61))	('[1-13C]glutamate', 'Chemical', '-', (55, 71))	('higher', 'PosReg', (196, 202))	('IDH', 'Gene', (252, 255))	('IDH', 'Gene', (214, 217))	('13C', 'Chemical', 'MESH:C000615229', (151, 154))	('TMZ', 'Chemical', 'MESH:D000077204', (298, 301))	('[1-13C]glutamate', 'Chemical', '-', (148, 164))	('glutamate accumulation', 'Phenotype', 'HP:0500149', (155, 177))	('IDH', 'Gene', '3417', (252, 255))	('IDH', 'Gene', '3417', (214, 217))
173949	32958546	Consistent with this observation the activities of enzymes known to catalyze the alpha-KG to glutamate conversion, namely aspartate transaminase (AST), glutamate dehydrogenase (GDH) and alanine aminotransferase (ALT) were significantly higher in cells treated with TMZ when compared with controls (Fig.S9A-F).	('GDH', 'Gene', (177, 180))	('alanine aminotransferase', 'Gene', (186, 210))	('higher', 'PosReg', (236, 242))	('aspartate transaminase', 'MPA', (122, 144))	('glutamate dehydrogenase', 'Gene', '2746', (152, 175))	('alanine aminotransferase', 'Gene', '2875', (186, 210))	('GDH', 'Gene', '2746', (177, 180))	('alpha-KG', 'Chemical', 'MESH:D007656', (81, 89))	('glutamate', 'Chemical', 'MESH:D018698', (93, 102))	('alpha-KG to glutamate conversion', 'MPA', (81, 113))	('TMZ', 'Var', (265, 268))	('glutamate', 'Chemical', 'MESH:D018698', (152, 161))	('activities', 'MPA', (37, 47))	('glutamate dehydrogenase', 'Gene', (152, 175))	('TMZ', 'Chemical', 'MESH:D000077204', (265, 268))
173950	32958546	Chemotherapeutic treatment, including with TMZ, which had previously been reserved for the treatment of GBM, is increasingly being used in the treatment of mutant IDH1 LGG alone or in combination with other treatments.	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('IDH', 'Gene', '3417', (163, 166))	('IDH', 'Gene', (163, 166))	('mutant', 'Var', (156, 162))
173954	32958546	In addition, studies have demonstrated the utility of MRS for monitoring response to other treatments including inhibitors of mutant IDH, glutaminase, HDAC and PI3K/mTOR.	('IDH', 'Gene', '3417', (133, 136))	('mTOR', 'Gene', (165, 169))	('glutaminase', 'Gene', '2744', (138, 149))	('HDAC', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (165, 169))	('glutaminase', 'Gene', (138, 149))	('IDH', 'Gene', (133, 136))	('mutant', 'Var', (126, 132))	('HDAC', 'Gene', '9734', (151, 155))
173955	32958546	To model the behavior of mutant IDH1 gliomas, we initially investigated NHAIDHmut and U87IDHmut cells genetically engineered to express mutant IDH1.	('IDH', 'Gene', '3417', (143, 146))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('IDH1 glioma', 'Disease', 'MESH:D005910', (32, 43))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('IDH', 'Gene', (32, 35))	('gliomas', 'Disease', (37, 44))	('IDH', 'Gene', '3417', (32, 35))	('IDH', 'Gene', (89, 92))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('mutant', 'Var', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('IDH', 'Gene', '3417', (89, 92))	('IDH1 glioma', 'Disease', (32, 43))	('IDH', 'Gene', (143, 146))
173956	32958546	NHAIDHmut cells provide a good model for mutant IDH1 but do not reproduce the full set of oncogenic events that occur in mutant IDH1 patients.	('IDH', 'Gene', (48, 51))	('mutant', 'Var', (121, 127))	('IDH', 'Gene', '3417', (3, 6))	('mutant', 'Var', (41, 47))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (48, 51))	('patients', 'Species', '9606', (133, 141))	('IDH', 'Gene', '3417', (128, 131))	('IDH', 'Gene', (3, 6))
173959	32958546	We therefore further confirmed our findings by expanding our investigations to patient-derived mutant IDH1 models derived from both oligodendroglioma and astrocytoma.	('IDH', 'Gene', '3417', (102, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (154, 165))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('patient', 'Species', '9606', (79, 86))	('oligodendroglioma and astrocytoma', 'Disease', 'MESH:D009837', (132, 165))	('mutant', 'Var', (95, 101))	('IDH', 'Gene', (102, 105))
173962	32958546	Importantly, the loss of either wild-type or mutant IDH1 allele was reported in over 10% of mutant IDH1 glioma upon recurrence.	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('IDH1 glioma', 'Disease', 'MESH:D005910', (99, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('mutant', 'Var', (92, 98))	('IDH', 'Gene', (99, 102))	('IDH1 glioma', 'Disease', (99, 110))
173973	32958546	In contrast, however, we found that in all of our cell lines as well as our in vivo orthotopic tumor models, TMZ treatment is associated with a significant increase in glutamate/glutamine and the composite GLX peak.	('glutamate/glutamine', 'MPA', (168, 187))	('TMZ', 'Var', (109, 112))	('glutamate', 'Chemical', 'MESH:D018698', (168, 177))	('increase', 'PosReg', (156, 164))	('composite GLX peak', 'MPA', (196, 214))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('glutamine', 'Chemical', 'MESH:D005973', (178, 187))	('tumor', 'Disease', (95, 100))
173976	32958546	Importantly, the increase in GLX is likely specifically associated with response to TMZ in mutant IDH1 tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('IDH1 tumors', 'Disease', 'MESH:D009369', (98, 109))	('GLX', 'MPA', (29, 32))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('increase', 'PosReg', (17, 25))	('mutant', 'Var', (91, 97))	('IDH1 tumors', 'Disease', (98, 109))
173981	32958546	Furthermore, optimized 1H MRS sequences that help resolve the potential overlap of 2-HG, glutamate, glutamine and GABA in patients with mutant IDH1 tumors have been developed, pointing to the potential utility of glutamate/glutamine/GLX to assess the early effects of TMZ in the clinic.	('1H', 'Chemical', '-', (23, 25))	('glutamine', 'Chemical', 'MESH:D005973', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('TMZ', 'Chemical', 'MESH:D000077204', (268, 271))	('glutamate', 'Chemical', 'MESH:D018698', (89, 98))	('glutamate', 'Chemical', 'MESH:D018698', (213, 222))	('IDH1 tumors', 'Disease', 'MESH:D009369', (143, 154))	('2-HG', 'Chemical', 'MESH:C019417', (83, 87))	('patients', 'Species', '9606', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('glutamine', 'Chemical', 'MESH:D005973', (223, 232))	('mutant', 'Var', (136, 142))	('IDH1 tumors', 'Disease', (143, 154))	('GABA', 'Chemical', 'MESH:D005680', (114, 118))
173985	32958546	In GBM, TMZ was shown to affect the expression of pyruvate kinase (PKM2), and in mutant IDH1 tumors, various mechanisms of TMZ-induced metabolic stress were described.	('PKM2', 'Gene', '5315', (67, 71))	('metabolic stress', 'Disease', 'MESH:D000079225', (135, 151))	('pyruvate', 'Chemical', 'MESH:D019289', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('metabolic stress', 'Disease', (135, 151))	('TMZ', 'Chemical', 'MESH:D000077204', (8, 11))	('TMZ', 'Chemical', 'MESH:D000077204', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutant', 'Var', (81, 87))	('IDH1 tumors', 'Disease', (88, 99))	('PKM2', 'Gene', (67, 71))	('expression', 'MPA', (36, 46))	('IDH1 tumors', 'Disease', 'MESH:D009369', (88, 99))	('affect', 'Reg', (25, 31))
173989	32958546	However, in the case of LGG, our group has found that hyperpolarized [1-13C]lactate production was not significantly altered in response to TMZ treatment in BT142 tumor-bearing mice, in line with the mutant IDH1-mediated promoter hypermethylation and downregulation of LDHA expression demonstrated in mutant IDH1 tumors.	('tumor', 'Disease', (313, 318))	('mutant', 'Var', (200, 206))	('IDH', 'Gene', (207, 210))	('[1-13C]lactate', 'Chemical', '-', (69, 83))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('downregulation', 'NegReg', (251, 265))	('hyperpolarized [1-13C]lactate production', 'MPA', (54, 94))	('mutant', 'Var', (301, 307))	('IDH', 'Gene', '3417', (207, 210))	('IDH', 'Gene', (308, 311))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('IDH1 tumors', 'Disease', 'MESH:D009369', (308, 319))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('LDHA', 'Gene', (269, 273))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('BT142', 'Chemical', '-', (157, 162))	('TMZ', 'Chemical', 'MESH:D000077204', (140, 143))	('mice', 'Species', '10090', (177, 181))	('IDH', 'Gene', '3417', (308, 311))	('IDH1 tumors', 'Disease', (308, 319))
173990	32958546	Furthermore, as shown here with [2-13C]pyruvate, even in our genetically engineered cells that do express LDHA, TMZ did not affect hyperpolarized lactate production consistently in our two cell lines, confirming the limited utility of hyperpolarized lactate production as a biomarker of response to TMZ in mutant IDH1 cells.	('IDH', 'Gene', (313, 316))	('mutant', 'Var', (306, 312))	('lactate', 'Chemical', 'MESH:D019344', (250, 257))	('lactate', 'Chemical', 'MESH:D019344', (146, 153))	('IDH', 'Gene', '3417', (313, 316))	('TMZ', 'Chemical', 'MESH:D000077204', (112, 115))	('[2-13C]pyruvate', 'Chemical', '-', (32, 47))	('TMZ', 'Chemical', 'MESH:D000077204', (299, 302))
173995	32958546	In summary, our findings demonstrate that 1H MRS-detectable glutamate/glutamine/ GLX can be used as early biomarkers of TMZ response in mutant IDH1 models, and 13C MRS-detectable production of hyperpolarized [1-13C]glutamate and [5-13C]glutamate from hyperpolarized [1-13C]alpha-KG and [2-13C]pyruvate, respectively, have potential as complementary approaches to monitor response.	('C]alpha', 'Species', '342041', (271, 278))	('TMZ', 'Chemical', 'MESH:D000077204', (120, 123))	('mutant', 'Var', (136, 142))	('IDH', 'Gene', (143, 146))	('glutamate', 'Chemical', 'MESH:D018698', (215, 224))	('13C', 'Chemical', 'MESH:C000615229', (211, 214))	('[5-13C]glutamate', 'Chemical', '-', (229, 245))	('alpha-KG', 'Chemical', 'MESH:D007656', (273, 281))	('13C', 'Chemical', 'MESH:C000615229', (289, 292))	('[1-13C]glutamate', 'Chemical', '-', (208, 224))	('glutamate', 'Chemical', 'MESH:D018698', (236, 245))	('IDH', 'Gene', '3417', (143, 146))	('13C', 'Chemical', 'MESH:C000615229', (232, 235))	('glutamine', 'Chemical', 'MESH:D005973', (70, 79))	('glutamate', 'Chemical', 'MESH:D018698', (60, 69))	('1H', 'Chemical', '-', (42, 44))	('13C', 'Chemical', 'MESH:C000615229', (160, 163))	('[2-13C]pyruvate', 'Chemical', '-', (286, 301))	('13C', 'Chemical', 'MESH:C000615229', (269, 272))
173997	32958546	Findings show that glutamate can be used as a non-invasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('temozolomide', 'Chemical', 'MESH:D000077204', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('IDH', 'Gene', (205, 208))	('tumor', 'Disease', (111, 116))	('mutant', 'Var', (198, 204))	('glutamate', 'Protein', (19, 28))	('IDH', 'Gene', '3417', (205, 208))	('patients', 'Species', '9606', (210, 218))	('glutamate', 'Chemical', 'MESH:D018698', (19, 28))
174006	32642801	Our results suggested that aberrant SERINC2 expression existed in glioma and that its expression might be a potential prognostic marker in LGG patients.	('glioma', 'Disease', (66, 72))	('expression', 'MPA', (44, 54))	('aberrant', 'Var', (27, 35))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('patients', 'Species', '9606', (143, 151))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('SERINC2', 'Gene', (36, 43))	('LGG', 'Disease', (139, 142))
174011	32642801	The 2016 WHO classification generated a combination of the histological and molecular characteristics of glioma, including IDH-1 mutation and 1p/19q codeletion (1p19q co-del) (Louis et al.).	('IDH-1', 'Gene', '3417', (123, 128))	('IDH-1', 'Gene', (123, 128))	('rat', 'Species', '10116', (32, 35))	('mutation', 'Var', (129, 137))	('glioma', 'Disease', (105, 111))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
174020	32642801	Irradiation can induce phosphatidylserine exposure on the surface of the vascular endothelium, and the presence of exposed phosphatidylserine enhanced the anticancer effect of an antivascularization drug in an in vivo experiment (Chang et al.).	('cancer', 'Disease', (159, 165))	('presence', 'Var', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (23, 41))	('enhanced', 'PosReg', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (123, 141))
174021	32642801	Interference with distinct steps of sphingolipid synthesis and signaling attenuates the proliferation of glioma cells (Bernhart et al.).	('rat', 'Species', '10116', (95, 98))	('glioma', 'Disease', (105, 111))	('attenuates', 'NegReg', (73, 83))	('Interference', 'Var', (0, 12))	('sphingolipid', 'Chemical', 'MESH:D013107', (36, 48))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
174044	32642801	The Cox regression results showed that LGG was ranked statistically first among 21 different cancer types based on the FDR correlation, which further confirmed that SERINC2 is an independent predictor of OS in LGG (Table 1).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('SERINC2', 'Var', (165, 172))	('LGG', 'Disease', (39, 42))
174049	32642801	The findings showed that higher SERINC2 expression remarkably reduced the 5-, 10-, and 15-year OS of IDH-1 mutation-type LGG patients in two independent cohorts (Fig.	('expression', 'MPA', (40, 50))	('IDH-1', 'Gene', '3417', (101, 106))	('LGG', 'Disease', (121, 124))	('IDH-1', 'Gene', (101, 106))	('higher', 'PosReg', (25, 31))	('SERINC2', 'Protein', (32, 39))	('mutation-type', 'Var', (107, 120))	('reduced', 'NegReg', (62, 69))	('patients', 'Species', '9606', (125, 133))
174070	32642801	The effects of many molecules on the prognosis of glioma have been confirmed, such as IDH-1 and 1p19q (Louis et al.).	('effects', 'Reg', (4, 11))	('IDH-1', 'Gene', '3417', (86, 91))	('glioma', 'Disease', (50, 56))	('IDH-1', 'Gene', (86, 91))	('1p19q', 'Var', (96, 101))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
174084	32642801	showed that IDH-1 mutation-type glioma had different lipid metabolism compared with IDH-1 wild-type glioma.	('glioma', 'Disease', (100, 106))	('lipid metabolism', 'MPA', (53, 69))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Disease', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('IDH-1', 'Gene', '3417', (84, 89))	('IDH-1', 'Gene', '3417', (12, 17))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('mutation-type', 'Var', (18, 31))	('IDH-1', 'Gene', (84, 89))	('IDH-1', 'Gene', (12, 17))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('different', 'Reg', (43, 52))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
174085	32642801	All the detected differential phosphatidylserine molecules were increased in IDH-1 mutation glioma, but sphingolipid was decreased.	('IDH-1', 'Gene', '3417', (77, 82))	('differential phosphatidylserine molecules', 'MPA', (17, 58))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('sphingolipid', 'Chemical', 'MESH:D013107', (104, 116))	('glioma', 'Disease', (92, 98))	('mutation', 'Var', (83, 91))	('sphingolipid', 'MPA', (104, 116))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (30, 48))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('increased', 'PosReg', (64, 73))	('IDH-1', 'Gene', (77, 82))
174088	32642801	Although the present study confirmed the importance of SERINC2 in OS of IDH-1 mutation-type LGG patients and the underlying regulation mechanism with DNA methylation, further investigation of SERINC2 expression and its regulation mechanism is needed.	('mutation-type', 'Var', (78, 91))	('IDH-1', 'Gene', '3417', (72, 77))	('IDH-1', 'Gene', (72, 77))	('patients', 'Species', '9606', (96, 104))	('LGG', 'Disease', (92, 95))
174091	32642801	found that SERINC2 knockdown inhibited lung adenocarcinoma proliferation, migration, and invasion but without significant differences in the cell cycle.	('inhibited', 'NegReg', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('SERINC2', 'Gene', (11, 18))	('rat', 'Species', '10116', (77, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('knockdown', 'Var', (19, 28))	('rat', 'Species', '10116', (66, 69))	('invasion', 'CPA', (89, 97))	('migration', 'CPA', (74, 83))	('lung adenocarcinoma proliferation', 'Disease', (39, 72))	('lung adenocarcinoma proliferation', 'Disease', 'MESH:D000077192', (39, 72))
174102	32642801	Aberrant kinesin family member 2C (KIF2C) expression in glioma has been confirmed and predicted as a potential independent prognosis marker for glioma patients (Bie et al.).	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('Aberrant', 'Var', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('patients', 'Species', '9606', (151, 159))	('KIF2C', 'Gene', (35, 40))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioma', 'Disease', (144, 150))	('KIF2C', 'Gene', '11004', (35, 40))
174113	31420939	Using an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential co-expression between grade II and grade III IDH1-mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample-level genomic features.	('astrocytoma progression', 'Disease', 'MESH:D001254', (90, 113))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('astrocytoma progression', 'Disease', (90, 113))	('euploid', 'Var', (226, 233))	('astrocytomas', 'Disease', 'MESH:D001254', (234, 246))	('astrocytoma', 'Phenotype', 'HP:0009592', (234, 245))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('astrocytomas', 'Disease', (234, 246))	('IDH1', 'Gene', (202, 206))	('patient', 'Species', '9606', (317, 324))	('1p/19q euploid', 'Var', (219, 233))	('cancer', 'Disease', (292, 298))	('IDH1', 'Gene', '3417', (202, 206))
174117	31420939	These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation.	('expression', 'MPA', (79, 89))	('gene mutation', 'Var', (54, 67))	('disruption', 'NegReg', (33, 43))	('altered', 'Reg', (71, 78))	('astrocytoma transformation', 'Disease', 'MESH:D001254', (125, 151))	('astrocytoma transformation', 'Disease', (125, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))
174133	31420939	For RNA-seq data, fragments per million reads mapped (FPKM) was calculated for all genes.23 The genes with very low expression were removed and the gene expression was corrected for batch effects.24 We selected 49 grade II and 70 grade III IDH1-mutated and 1p/19q euploid astrocytomas for the analysis.	('IDH1', 'Gene', '3417', (240, 244))	('1p/19q', 'Var', (257, 263))	('astrocytomas', 'Disease', 'MESH:D001254', (272, 284))	('astrocytoma', 'Phenotype', 'HP:0009592', (272, 283))	('astrocytomas', 'Disease', (272, 284))	('IDH1', 'Gene', (240, 244))
174143	31420939	Genes in which germline mutations increase the risk of developing cancer (n = 114) were acquired from Supplementary Table S1 in Rahman33 and from the Catalogue Of Somatic Mutations In Cancer (COSMIC) v76 Cancer Gene Census catalogue (n = 84) (http://cancer.sanger.ac.uk/census).	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (204, 210))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (184, 190))	('Cancer', 'Disease', (204, 210))	('Cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (66, 72))	('germline mutations', 'Var', (15, 33))
174155	31420939	Transcriptional changes can be related to a disease state via two paradigms, the analysis of gene covariation (differential gene co-expression) and gene expression levels (differential gene expression).57 In order to identify sets of genes differentially covarying in the progression of LGA, we selected supratentorial IDH1 mutant and 1p/19q euploid adult astrocytoma samples from the TCGA database (Supplementary Table S1).	('astrocytoma', 'Disease', (356, 367))	('mutant', 'Var', (324, 330))	('astrocytoma', 'Phenotype', 'HP:0009592', (356, 367))	('LGA', 'Disease', (287, 290))	('IDH1', 'Gene', (319, 323))	('IDH1', 'Gene', '3417', (319, 323))	('astrocytoma', 'Disease', 'MESH:D001254', (356, 367))
174163	31420939	Survival analysis among the AA cohort (n = 70, number of events = 19) using the Cox proportional-hazards regression model62 revealed that AA patient survival was slightly but significantly dependent on average expression of module M2 (Hazard Ratio (HR) = 1.74, 95% CI [1.14-2.64], P-value = 0.01), but not average expression of module M1 (HR = 1.68, 95% CI [0.83-3.369], P-value = 0.142) or age at diagnosis (HR = 1.03, 95% CI [0.98-1.08], P-value = 0.25) (Fig.	('AA', 'Phenotype', 'HP:0009592', (138, 140))	('patient', 'Species', '9606', (141, 148))	('module M2', 'Var', (224, 233))	('dependent', 'Reg', (189, 198))	('AA', 'Phenotype', 'HP:0009592', (28, 30))	('Cox', 'Gene', '1351', (80, 83))	('Cox', 'Gene', (80, 83))
174166	31420939	Among the TCGA cohort of IDH1 mut LGA and AA, we observed that AA samples had on average more single nucleotide variants and INDEL mutations per sample than LGAs (Supplementary Fig.	('single nucleotide variants', 'Var', (94, 120))	('INDEL mutations', 'Var', (125, 140))	('AA', 'Phenotype', 'HP:0009592', (42, 44))	('IDH1', 'Gene', (25, 29))	('AA', 'Phenotype', 'HP:0009592', (63, 65))	('IDH1', 'Gene', '3417', (25, 29))
174169	31420939	In contrast, we observed recurrent somatic CNVs in multiple samples including copy number loss of well-known TSG CDKN2A at 9p21.3 (n del = 45/119), RB1 at 13q14.3 (n del = 40/119) and PTEN at 10q23.31 (n del = 22/119) (Supplementary Fig.	('PTEN', 'Gene', (184, 188))	('RB1', 'Gene', (148, 151))	('PTEN', 'Gene', '5728', (184, 188))	('CDKN2A', 'Gene', (113, 119))	('copy number loss', 'Var', (78, 94))	('RB1', 'Gene', '5925', (148, 151))	('CDKN2A', 'Gene', '1029', (113, 119))
174171	31420939	We observed, however, that the gene dosage of 61 of 338 (18.1%) oncogenes and TSG and 36 of 156 (23.1%) oncogenes and TSG affected by FCNA were significantly (FDR < 0.05) associated with an increase in the average expression level of module M2 across the patient cohort (n = 119) (Supplementary Table S9).	('FCNA', 'Gene', (134, 138))	('increase', 'PosReg', (190, 198))	('gene dosage', 'Var', (31, 42))	('patient', 'Species', '9606', (255, 262))	('average expression level', 'MPA', (206, 230))
174173	31420939	3).64, 65, 66 Additionally, strong associations were found between PDGFRA amplification (FDR < 0.001) and CIC deletion (FDR < 0.001).	('amplification', 'Var', (74, 87))	('PDGFRA', 'Gene', (67, 73))	('CIC', 'Gene', '23152', (106, 109))	('PDGFRA', 'Gene', '5156', (67, 73))	('CIC', 'Gene', (106, 109))
174194	31420939	We used low-passage IDH1 mutant human tumor-derived TB98 cells and exposed them to 20 micromol/L resveratrol or DMSO or left the cells untreated in triplicates for 24 h in vitro.	('IDH1', 'Gene', '3417', (20, 24))	('tumor', 'Disease', (38, 43))	('mutant', 'Var', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('DMSO', 'Chemical', 'MESH:D004121', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('human', 'Species', '9606', (32, 37))	('IDH1', 'Gene', (20, 24))	('resveratrol', 'Chemical', 'MESH:C059514', (97, 108))
174212	31420939	Using the TCGA dataset, we uncovered two modules of differentially co-expressed genes between low and high-grade IDH1-mutated and 1p/19q euploid astrocytomas (M1 and M2).	('astrocytomas', 'Disease', (145, 157))	('IDH1', 'Gene', (113, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('IDH1', 'Gene', '3417', (113, 117))	('1p/19q euploid', 'Var', (130, 144))	('astrocytomas', 'Disease', 'MESH:D001254', (145, 157))
174213	31420939	M2 had higher intramodular gene correlation in AA compared to LGA and the average expression of M2 module was significantly increased in samples with loss of chromosome 10q - an event previously identified as prognostically unfavorable in 1p/19q euploid low-grade gliomas.64 In addition to loss of TSG on 10q such as PTEN, M2 expression was higher in individuals with oncogene PDGFRA locus amplification and deletion of TSG CIC.	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('gliomas', 'Disease', (264, 271))	('M2 expression', 'MPA', (323, 336))	('PTEN', 'Gene', (317, 321))	('PDGFRA', 'Gene', (377, 383))	('PDGFRA', 'Gene', '5156', (377, 383))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('CIC', 'Gene', '23152', (424, 427))	('PTEN', 'Gene', '5728', (317, 321))	('deletion', 'Var', (408, 416))	('AA', 'Phenotype', 'HP:0009592', (47, 49))	('CIC', 'Gene', (424, 427))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('higher', 'PosReg', (341, 347))
174218	31420939	We therefore posited that targeting expression could represent a novel therapeutic approach to delaying glioma progression.	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Disease', (104, 110))	('targeting', 'Var', (26, 35))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))
174233	31420939	While resveratrol's potential antineoplastic effect is likely not unique to IDH1-mutated 1p/19q euploid astrocytomas, this drug would be of particular interest in these tumors due to their less aggressive clinical course compared to IDH1wt astrocytomas, and hence the undesirable use strong chemotherapeutic drugs in this clinical context.	('IDH1', 'Gene', (76, 80))	('IDH1', 'Gene', '3417', (233, 237))	('astrocytomas', 'Disease', 'MESH:D001254', (240, 252))	('astrocytomas', 'Disease', 'MESH:D001254', (104, 116))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('IDH1', 'Gene', '3417', (76, 80))	('astrocytoma', 'Phenotype', 'HP:0009592', (240, 251))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('resveratrol', 'Chemical', 'MESH:C059514', (6, 17))	('1p/19q euploid', 'Var', (89, 103))	('astrocytomas', 'Disease', (240, 252))	('astrocytomas', 'Disease', (104, 116))	('IDH1', 'Gene', (233, 237))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
174236	31420939	R13061, ICHTB Human Tissue Authority (HTA) license 12275].	('R13061', 'Chemical', 'MESH:C109126', (0, 6))	('Human', 'Species', '9606', (14, 19))	('ICHTB', 'Disease', (8, 13))	('ICHTB', 'Disease', 'None', (8, 13))	('R13061', 'Var', (0, 6))
174371	27935819	A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK- and PI3K-induced malignant growth Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders.	('brain tumour', 'Disease', 'MESH:D001932', (8, 20))	('tumours', 'Phenotype', 'HP:0002664', (200, 207))	('tumours and brain developmental disorders', 'Disease', 'MESH:D001927', (200, 241))	('MAPK', 'Gene', (147, 151))	('brain tumour', 'Phenotype', 'HP:0030692', (8, 20))	('brain tumour', 'Disease', (8, 20))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (126, 135))	('YAP', 'Gene', (60, 63))	('YAP', 'Gene', '561411', (60, 63))	('zebrafish', 'Species', '7955', (30, 39))
174376	27935819	Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours.	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('YAP', 'Gene', (41, 44))	('heterotopias', 'Disease', (95, 107))	('heterotopias', 'Disease', 'MESH:D054091', (95, 107))	('HRAS', 'Gene', (58, 62))	('heterotopias', 'Phenotype', 'HP:0002282', (95, 107))	('aggressive tumours', 'Disease', 'MESH:D001523', (145, 163))	('aggressive tumours', 'Disease', (145, 163))	('heterotopia', 'Phenotype', 'HP:0002282', (95, 106))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('abolishes', 'NegReg', (66, 75))	('dominant-active', 'Var', (25, 40))	('leads to', 'Reg', (112, 120))	('HRAS', 'Gene', '550286', (58, 62))
174377	27935819	Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (45, 73))	('brain tumour', 'Phenotype', 'HP:0030692', (236, 248))	('activation', 'PosReg', (122, 132))	('hallmark of malignant brain tumours', 'Disease', (214, 249))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (45, 73))	('brain tumours', 'Disease', 'MESH:D001932', (78, 91))	('brain tumours', 'Phenotype', 'HP:0030692', (78, 91))	('neurodevelopmental disorders', 'Disease', (45, 73))	('activation', 'PosReg', (198, 208))	('brain tumours', 'Phenotype', 'HP:0030692', (236, 249))	('YAP', 'Gene', (194, 197))	('brain tumours', 'Disease', 'MESH:D001932', (236, 249))	('originate from', 'Reg', (98, 112))	('mutations', 'Var', (162, 171))	('hallmark of malignant brain tumours', 'Disease', 'MESH:D001932', (214, 249))	('brain tumour', 'Phenotype', 'HP:0030692', (78, 90))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('brain tumours', 'Disease', (78, 91))	('tumours', 'Phenotype', 'HP:0002664', (242, 249))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
174379	27935819	Disorders of brain growth are known to cause a wide range of physiological and pathological symptoms such as intractable epilepsy, intellectual disability, autism, and cognitive and motor impairment.	('Disorders', 'Var', (0, 9))	('cause', 'Reg', (39, 44))	('epilepsy', 'Disease', 'MESH:D004827', (121, 129))	('intellectual disability', 'Phenotype', 'HP:0001249', (131, 154))	('epilepsy', 'Phenotype', 'HP:0001250', (121, 129))	('cognitive and motor impairment', 'Disease', 'MESH:D003072', (168, 198))	('autism', 'Phenotype', 'HP:0000717', (156, 162))	('autism', 'Disease', 'MESH:D001321', (156, 162))	('epilepsy', 'Disease', (121, 129))	('intellectual disability', 'Disease', (131, 154))	('autism', 'Disease', (156, 162))
174384	27935819	NF1 is caused by loss-of-function mutations in the tumour suppressor gene NF1, which encodes neurofibromin 1, a negative regulator of the proto-oncogene RAS and in 50% of cases occurs as the result of de novo somatic mutations.	('NF1', 'Gene', (74, 77))	('loss-of-function', 'NegReg', (17, 33))	('neurofibromin 1', 'Gene', '326708', (93, 108))	('tumour', 'Disease', (51, 57))	('NF1', 'Gene', '4763', (74, 77))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('neurofibromin 1', 'Gene', (93, 108))	('NF1', 'Gene', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('NF1', 'Gene', '4763', (0, 3))	('mutations', 'Var', (34, 43))
174385	27935819	Between 5% and 10% of individuals with tuberous sclerosis (caused by mutations in TSC1 or TSC2, OMIN 191100) develop slowly growing subependymal giant cell astrocytomas and in 50% of individuals with focal cortical dysplasia type 3b cortical disorganisation masks slowly developing brain tumours.	('focal cortical dysplasia', 'Phenotype', 'HP:0032046', (200, 224))	('subependymal giant cell astrocytomas', 'Disease', (132, 168))	('brain tumour', 'Phenotype', 'HP:0030692', (282, 294))	('tumours', 'Phenotype', 'HP:0002664', (288, 295))	('subependymal giant cell astrocytomas', 'Phenotype', 'HP:0009718', (132, 168))	('brain tumours', 'Disease', (282, 295))	('TSC1', 'Gene', (82, 86))	('cortical dysplasia', 'Phenotype', 'HP:0002539', (206, 224))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('subependymal giant cell astrocytomas', 'Disease', 'MESH:D001254', (132, 168))	('mutations', 'Var', (69, 78))	('TSC2', 'Gene', '567524', (90, 94))	('focal cortical dysplasia type 3b cortical disorganisation masks', 'Disease', 'MESH:C537067', (200, 263))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (39, 57))	('brain tumours', 'Disease', 'MESH:D001932', (282, 295))	('brain tumours', 'Phenotype', 'HP:0030692', (282, 295))	('TSC1', 'Gene', '100330617', (82, 86))	('tuberous sclerosis', 'Disease', (39, 57))	('TSC2', 'Gene', (90, 94))	('caused by', 'Reg', (59, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))
174386	27935819	Conversely, for most developmental disorders of the brain it is currently unknown whether focal or diffuse growth disorders might progress to tumours as a result of additional mutations or epigenetic events.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('mutations', 'Var', (176, 185))	('developmental disorders', 'Disease', 'MESH:D002658', (21, 44))	('progress', 'PosReg', (130, 138))	('focal', 'Disease', (90, 95))	('epigenetic events', 'Var', (189, 206))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('growth disorders', 'Disease', (107, 123))	('growth disorders', 'Disease', 'MESH:D006130', (107, 123))	('developmental disorders', 'Disease', (21, 44))
174387	27935819	Although the molecular pathogeneses of these disorders are currently unknown, for most of them genetic studies show that activation of MAPK, PI3K or mTOR signals resulting from de novo somatic mutations or inherited germline mutations might be causative (for review see).	('mTOR', 'Gene', (149, 153))	('PI3K', 'Gene', (141, 145))	('MAPK', 'Gene', (135, 139))	('germline mutations', 'Var', (216, 234))	('mTOR', 'Gene', '324254', (149, 153))	('activation', 'PosReg', (121, 131))
174388	27935819	These pathways are also altered in gliomas, as leading mutations in high-grade gliomas include EGFR amplification (in 27-36% of cases) or mutations (18-31% of cases), deletion of PTEN, the inhibitor of AKT and mTOR (15-40% of cases) and inactivation of NF1, a RAS inhibitor (18% of cases).	('mTOR', 'Gene', (210, 214))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('lif', 'Gene', '555717', (103, 106))	('NF1', 'Gene', '4763', (253, 256))	('inactivation', 'Var', (237, 249))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('deletion', 'Var', (167, 175))	('gliomas', 'Disease', (35, 42))	('PTEN', 'Gene', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('NF1', 'Gene', (253, 256))	('mTOR', 'Gene', '324254', (210, 214))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('mutations', 'Var', (55, 64))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('lif', 'Gene', (103, 106))	('mutations', 'Var', (138, 147))	('gliomas', 'Disease', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('EGFR', 'Gene', (95, 99))	('PTEN', 'Gene', '368415', (179, 183))
174389	27935819	Whereas only few gliomas contain mutation in RAS itself, the leading mutations reported above affect its activity in nearly all glioma cases.	('mutations', 'Var', (69, 78))	('mutation', 'Var', (33, 41))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('glioma', 'Disease', (128, 134))	('affect', 'Reg', (94, 100))	('RAS', 'Protein', (45, 48))	('activity', 'MPA', (105, 113))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Disease', (17, 23))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))	('gliomas', 'Disease', (17, 24))
174429	27935819	In our model, the same oncogenes lead to two types of lesions, one resembling cancer and the other resembling heterotopia, thus providing an opportunity to study possible co-factors that might induce benign developmental lesions instead of tumours.	('heterotopia', 'Disease', 'MESH:D054091', (110, 121))	('oncogenes', 'Var', (23, 32))	('lead to', 'Reg', (33, 40))	('heterotopia', 'Phenotype', 'HP:0002282', (110, 121))	('cancer', 'Disease', (78, 84))	('heterotopia', 'Disease', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumours', 'Phenotype', 'HP:0002664', (240, 247))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumours', 'Disease', 'MESH:D009369', (240, 247))	('tumours', 'Disease', (240, 247))
174491	27935819	Our model suggests that somatic embryonic mutations activating MAPK/ERK signalling can drive both malformation of brain development and brain tumours, proving that upregulation of YAP signalling is necessary for tumour development.	('tumour', 'Disease', (142, 148))	('brain tumours', 'Disease', 'MESH:D001932', (136, 149))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('malformation of brain development', 'CPA', (98, 131))	('brain tumour', 'Phenotype', 'HP:0030692', (136, 148))	('activating', 'PosReg', (52, 62))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('drive', 'PosReg', (87, 92))	('tumour', 'Disease', (212, 218))	('ERK', 'Gene', (68, 71))	('brain tumours', 'Phenotype', 'HP:0030692', (136, 149))	('brain tumours', 'Disease', (136, 149))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('mutations', 'Var', (42, 51))	('ERK', 'Gene', '26413', (68, 71))
174493	27935819	By contrast, somatic pro-oncogenic mutations occurring in post-developmental stages are often associated with cancer.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('mutations', 'Var', (35, 44))
174494	27935819	Several studies have suggested a possible progression between neuro-developmental lesions and brain cancer, especially when the activating mutations induce MAPK/ERK signalling.	('brain cancer', 'Disease', (94, 106))	('neuro-developmental lesions', 'Disease', 'MESH:C536203', (62, 89))	('mutations', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('brain cancer', 'Disease', 'MESH:D001932', (94, 106))	('ERK', 'Gene', (161, 164))	('neuro-developmental lesions', 'Disease', (62, 89))	('brain cancer', 'Phenotype', 'HP:0030692', (94, 106))	('ERK', 'Gene', '26413', (161, 164))
174495	27935819	If a progression is possible from non-cancerous neuro-developmental lesions caused by activating mutations in a pro-oncogenic pathway and brain cancer, then an important topic for future research is to identify the mechanisms that restrain affected cells from developing cancer during development, and lead to reactivation of a dormant oncogenic program in case of progression to cancer.	('mutations', 'Var', (97, 106))	('cancer', 'Disease', (144, 150))	('brain cancer', 'Phenotype', 'HP:0030692', (138, 150))	('cancer', 'Disease', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('reactivation', 'PosReg', (310, 322))	('non-cancerous neuro-developmental lesions', 'Disease', (34, 75))	('brain cancer', 'Disease', 'MESH:D001932', (138, 150))	('cancer', 'Disease', (380, 386))	('restrain', 'NegReg', (231, 239))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('non-cancerous neuro-developmental lesions', 'Disease', 'MESH:C536203', (34, 75))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('dormant', 'CPA', (328, 335))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('brain cancer', 'Disease', (138, 150))	('cancer', 'Disease', 'MESH:D009369', (380, 386))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
174507	27935819	Moreover, cancer cells can use YAP to compensate for loss of mutant KRAS as shown in cell lines and mouse models of pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mouse', 'Species', '10090', (100, 105))	('KRAS', 'Gene', (68, 72))	('loss', 'NegReg', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('mutant', 'Var', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (127, 133))	('pancreatic cancer', 'Disease', (116, 133))	('cancer', 'Disease', (10, 16))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
174510	27935819	Indeed, inhibition of NF2 (encoded by MERLIN) induces nuclear localisation and activation of YAP, which can be rescued by YAP inhibition.	('MERLIN', 'Gene', '561184', (38, 44))	('nuclear localisation', 'MPA', (54, 74))	('NF2', 'Gene', (22, 25))	('NF2', 'Gene', '405887', (22, 25))	('MERLIN', 'Gene', (38, 44))	('YAP', 'CPA', (93, 96))	('activation', 'PosReg', (79, 89))	('inhibition', 'Var', (8, 18))	('induces', 'Reg', (46, 53))
174511	27935819	Interestingly, the inheritable brain dysplasia Van Maldergem syndrome (VMS; MIM601390) results from mutations of the Hippo upstream regulators Dchs1 and Fat4, and the phenotype in relevant mouse models can be rescued by YAP inhibition.	('mutations', 'Var', (100, 109))	('VMS', 'Disease', 'None', (71, 74))	('brain dysplasia Van Maldergem syndrome', 'Disease', (31, 69))	('mouse', 'Species', '10090', (189, 194))	('Hippo', 'Gene', (117, 122))	('VMS', 'Disease', (71, 74))	('results from', 'Reg', (87, 99))	('Dchs1', 'Gene', (143, 148))	('Fat4', 'Gene', (153, 157))	('Dchs1', 'Gene', '233651', (143, 148))	('Fat4', 'Gene', '329628', (153, 157))	('brain dysplasia Van Maldergem syndrome', 'Disease', 'MESH:C536530', (31, 69))	('brain dysplasia', 'Phenotype', 'HP:0012443', (31, 46))
174516	27935819	Our study shows an additional role of YAP in tumour development as expression of dominant-active YAP demonstrates its co-operation with oncogenic RAS in the induction of brain cancer instead of neuro-developmental lesions.	('brain cancer', 'Disease', (170, 182))	('neuro-developmental lesions', 'Disease', (194, 221))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('dominant-active', 'Var', (81, 96))	('YAP', 'Gene', (97, 100))	('neuro-developmental lesions', 'Disease', 'MESH:C536203', (194, 221))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('brain cancer', 'Disease', 'MESH:D001932', (170, 182))	('tumour', 'Disease', (45, 51))	('brain cancer', 'Phenotype', 'HP:0030692', (170, 182))
174517	27935819	The mechanisms through which oncogenic RAS induces YAP activation only in some lesions and after some time (3 weeks) from its initial expression are currently unknown, but might involve a downregulation of members of the ubiquitin ligase complex that target YAP for degradation (SOCS5/6), or F-actin through GPCRs or IQGAP1.	('IQGAP1', 'Gene', '100002928', (317, 323))	('F-actin', 'Protein', (292, 299))	('IQGAP1', 'Gene', (317, 323))	('downregulation', 'NegReg', (188, 202))	('YAP', 'MPA', (51, 54))	('SOCS5', 'Gene', '768142', (279, 284))	('RAS', 'Gene', (39, 42))	('oncogenic', 'Var', (29, 38))	('SOCS5', 'Gene', (279, 284))	('activation', 'PosReg', (55, 65))
174539	27935819	All sections were stained with fluorescently labelled secondary antibodies against rabbit or mouse immunoglobulins (1:200, Life Technologies, A11017, A11018, A11070, A11071, A21050, A21070).	('A21050', 'Var', (174, 180))	('rabbit', 'Species', '9986', (83, 89))	('mouse', 'Species', '10090', (93, 98))	('A21070', 'Var', (182, 188))	('A11071', 'Var', (166, 172))	('A11070', 'Var', (158, 164))	('A11017', 'Var', (142, 148))	('A11018', 'Var', (150, 156))
174561	27935819	For the generation of transgenes expressing UAS:BRAFV600E, UAS:Xmrk, UAS:EGFR splice variant III (shortened in vIII), UAS:YapS5A and UAS:lifeact-GFP we used different strategies.	('lif', 'Gene', (137, 140))	('lif', 'Gene', '555717', (137, 140))	('BRAFV600E', 'Var', (48, 57))	('BRAFV600E', 'Mutation', 'rs113488022', (48, 57))
174576	33713047	Herein, we first comprehensively explored the potential correlation between growth-arrest-specific two family genes (GAS2, GAS2L1, GAS2L2, GAS2L3) and gliomas by bioinformatics analysis and cellular experiments.	('GAS2L2', 'Var', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('GAS2L1', 'Gene', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('gliomas', 'Disease', (151, 158))	('GAS2', 'Gene', (117, 121))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('GAS2L3', 'Gene', (139, 145))
174580	33713047	We further observed the relationship between the high expressed GAS2L3 and poor clinical prognosis of brain low-grade glioma (LGG) cases in our Cox proportional hazard model (hazard ratio [HR] = 0.1715, p < 0.001).	('glioma', 'Disease', (118, 124))	('GAS2L3', 'Gene', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('high expressed', 'Var', (49, 63))
174592	33713047	Members of GAS2 family include GAS2, GAS2-like 1 (GAS2L1), GAS2-like 2 (GAS2L2), and GAS2-like 3 (GAS2L3).	('GAS2L2', 'Var', (72, 78))	('GAS2-like 3', 'Gene', (85, 96))	('GAS2-like 3', 'Gene', '283431', (85, 96))
174599	33713047	In addition, we used the basic local alignment search tool (BLAST, https://blast.ncbi.nlm.nih.gov/Blast.cgi) of NCBI to perform the protein sequence alignment analysis of human GAS2 (NP_808221.1), GAS2L1 (NP_006469.2), GAS2L2 (NP_644814.1), and GAS2L3 (NP_777602.1).	('NP_777602.1', 'Var', (253, 264))	('NP_006469.2', 'Var', (205, 216))	('NP_644814.1', 'Var', (227, 238))	('NP_808221.1', 'Var', (183, 194))	('human', 'Species', '9606', (171, 176))
174627	33713047	The protein structures of GAS2, GAS2L1, GAS2L2, and GAS2L3 are conservative among the different species (e.g., Homo sapiens, Pan troglodytes, Macaca mulatta, etc.)	('Macaca mulatta', 'Species', '9544', (142, 156))	('Pan troglodytes', 'Species', '9598', (125, 140))	('Homo sapiens', 'Species', '9606', (111, 123))	('GAS2L3', 'Var', (52, 58))	('GAS2L2', 'Var', (40, 46))
174629	33713047	We further performed a protein sequence alignment analysis and found that the N-terminus structures of GAS2 (313aa), GAS2L1 (681aa), GAS2L2 (880aa), and GAS2L3 (694aa) in H. sapiens exhibit the similarities (Figure S1C).	('H. sapiens', 'Species', '9606', (171, 181))	('313aa', 'Var', (109, 114))	('GAS2', 'Gene', (103, 107))	('681aa', 'Var', (125, 130))	('880aa', 'Var', (141, 146))
174638	33713047	Furthermore, we included the covariables of age, gender, race, and tumor purity for a Cox proportional hazard model and observed the association between the poor prognosis of LGG and high expression of GAS2L2 (Table S1, Cox_p < 0.001, HR = 1.315), GAS2L3 (Cox_p < 0.001, HR = 1.526), and low-expression GAS2L1 (Cox_p = 0.010, HR = 0.642).	('GAS2L3', 'Gene', (248, 254))	('LGG', 'Disease', (175, 178))	('GAS2L2', 'Gene', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('high', 'Var', (183, 187))	('tumor', 'Disease', (67, 72))	('low-expression', 'Var', (288, 302))	('GAS2L1', 'Gene', (303, 309))
174653	33713047	Besides, as shown in Figure S11A, we utilized the BioGRID analysis to obtain a total of 20 potential interacting proteins of GAS2L3 with the experimental evidence of "affinity capture-mass spectrometric," "two-hybrid," "reconstituted complex", or "proximity Label-mass spectrometric."	('BioGRID', 'Gene', (50, 57))	('interacting', 'Interaction', (101, 112))	('S11A', 'Var', (28, 32))	('BioGRID', 'Gene', '9402', (50, 57))	('S11A', 'SUBSTITUTION', 'None', (28, 32))	('GAS2L3', 'Gene', (125, 131))
174654	33713047	And the MF (molecular function) data of our GO enrichment analysis (Figure S11B) suggested that these proteins mainly were associated with the biological processes of cell adhesion, actin-binding, and protein phosphatase activity.	('associated', 'Reg', (123, 133))	('S11B', 'SUBSTITUTION', 'None', (75, 79))	('S11B', 'Var', (75, 79))	('protein', 'Protein', (201, 208))	('cell adhesion', 'CPA', (167, 180))
174660	33713047	The results (Figure 7A) showed that, compared with the vector group, the down-regulation of the GAS2L3 gene in the sh-GAS2L3-#1 and sh-GAS2L3-#2 groups led to a reduced migration trend of glioma cells, especially at the point of 48 h (Figure 7B, p < 0.05).	('down-regulation', 'NegReg', (73, 88))	('sh-GAS2L3-', 'Var', (115, 125))	('reduced', 'NegReg', (161, 168))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('migration trend', 'CPA', (169, 184))	('GAS2L3 gene', 'Gene', (96, 107))	('glioma', 'Disease', (188, 194))
174675	33713047	CGGA-based data analysis indicated that high expression of GAS2L3 is associated with poor clinical prognosis of the primary glioma cases, but not the recurrent glioma cases.	('high expression', 'Var', (40, 55))	('glioma', 'Disease', (124, 130))	('glioma', 'Disease', (160, 166))	('primary glioma', 'Disease', 'MESH:D005910', (116, 130))	('primary glioma', 'Disease', (116, 130))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('GAS2L3', 'Gene', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
174678	33713047	1 ,  2  A pathogenic variant of the GAS2L2 gene was reportedly associated with a genetic defect in ciliary orientation and mucociliary clearance.	('ciliary orientation', 'CPA', (99, 118))	('pathogenic', 'Reg', (10, 20))	('associated', 'Reg', (63, 73))	('genetic defect', 'Disease', 'MESH:D030342', (81, 95))	('genetic defect', 'Disease', (81, 95))	('variant', 'Var', (21, 28))	('GAS2L2', 'Gene', (36, 42))	('mucociliary clearance', 'CPA', (123, 144))
174681	33713047	Due to the limited data, we only analyzed the correlation between GAS2 family member mutation and the clinical prognosis of overall cancer patients and obtained negative results.	('cancer', 'Disease', (132, 138))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutation', 'Var', (85, 93))	('GAS2', 'Gene', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
174682	33713047	DNA methylation is associated with the gene expression, clinical prognosis, or the pathological classification of gliomas 1 ,  31 ; with regard to GAS2L3, we detected the correlation between DNA hypomethylation and the high expression level, or the poor prognosis of LGG cases.	('gliomas', 'Disease', (114, 121))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('hypomethylation', 'Var', (195, 210))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('high expression level', 'MPA', (219, 240))	('LGG', 'Disease', (267, 270))
174684	33713047	9 ,  29 ,  32 ,  33 ,  34  For instance, the data of GAS2L3-deficient mice indicates an important role of GAS2L3 in the cardiomyocyte cytokinesis during heart development.	('mice', 'Species', '10090', (70, 74))	('cardiomyocyte cytokinesis', 'Disease', 'MESH:C536085', (120, 145))	('cardiomyocyte cytokinesis', 'Disease', (120, 145))	('GAS2L3', 'Var', (106, 112))
174686	33713047	32  In line with the above cell cycle/division-associated functional attributes of GAS2L3, our cellular experiment data supported the association between the high GAS2L3 expression and an increased proliferation and migration capabilities within glioma cells.	('glioma', 'Disease', (246, 252))	('GAS2L3', 'Gene', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))	('high', 'Var', (158, 162))	('proliferation', 'CPA', (198, 211))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('increased', 'PosReg', (188, 197))	('expression', 'MPA', (170, 180))
174691	33713047	38  It is meaningful to investigate the potential effect of GAS2L3 expression on the medication treatment and clinical treatment of LGG, and other factors, such as TP53 mutation, 1p19q codeletion, and isocitrate dehydrogenase (IDH) 1/2 mutation, should be fully considered as well.	('TP53', 'Gene', '7157', (164, 168))	('mutation', 'Var', (169, 177))	('TP53', 'Gene', (164, 168))	('1p19q codeletion', 'Var', (179, 195))	('GAS2L3', 'Gene', (60, 66))	('isocitrate dehydrogenase (IDH) 1/2', 'Gene', '3417;3418', (201, 235))	('LGG', 'Disease', (132, 135))
174697	33658560	Somatic mutations of gliomas with high B2M expression are associated with PTEN deletion and EGFR amplification.	('amplification', 'Var', (97, 110))	('associated', 'Reg', (58, 68))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('PTEN', 'Gene', (74, 78))	('gliomas', 'Disease', (21, 28))	('PTEN', 'Gene', '5728', (74, 78))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('deletion', 'Var', (79, 87))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))
174698	33658560	Isocitrate dehydrogenase (IDH) mutations accounted for 82% in gliomas with low B2M expression.	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('mutations', 'Var', (31, 40))	('B2M', 'Protein', (79, 82))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('IDH', 'Gene', '3417', (26, 29))	('IDH', 'Gene', (26, 29))	('low B2M', 'Phenotype', 'HP:0045082', (75, 82))	('gliomas', 'Disease', (62, 69))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
174699	33658560	B2M also suppressed anti-tumor immunity through immune related processes.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('suppressed', 'NegReg', (9, 19))	('immune related processes', 'CPA', (48, 72))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('B2M', 'Var', (0, 3))
174712	33658560	In mice with B2M deficiency, defective antibody responses are observed since the sensitivity of NK cells to MHC-I heavy chain mediated inhibition increased and IgG catabolism increased.	('B2M', 'Gene', (13, 16))	('increased', 'PosReg', (146, 155))	('mice', 'Species', '10090', (3, 7))	('deficiency', 'Var', (17, 27))	('heavy chain', 'Protein', (114, 125))	('IgG catabolism increased', 'Phenotype', 'HP:0003237', (160, 184))	('increased', 'PosReg', (175, 184))	('sensitivity', 'MPA', (81, 92))	('IgG catabolism', 'MPA', (160, 174))
174717	33658560	Based on CRISPR screening, B2M mutation frequently occurred in glioblastoma (GBM).	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('B2M', 'Gene', (27, 30))	('mutation', 'Var', (31, 39))	('glioblastoma', 'Disease', (63, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('occurred', 'Reg', (51, 59))
174718	33658560	Specifically, gene disruption of B2M enhanced activity of CAR T cells and resistance to PD-1 inhibition in preclinical model of GBM.	('resistance', 'CPA', (74, 84))	('PD-1', 'Gene', '5133', (88, 92))	('gene disruption', 'Var', (14, 29))	('CAR', 'Gene', (58, 61))	('activity', 'MPA', (46, 54))	('CAR', 'Gene', '653108', (58, 61))	('PD-1', 'Gene', (88, 92))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('enhanced', 'PosReg', (37, 45))	('B2M', 'Gene', (33, 36))
174727	33658560	B2M expression differences in tumor characteristics such as WHO grades, MGMT status, 1p19q status, IDH status, and GBM subtypes were analyzed using Wilcoxon rank testing.	('IDH', 'Gene', '3417', (99, 102))	('1p19q status', 'Var', (85, 97))	('MGMT', 'Gene', '4255', (72, 76))	('MGMT', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IDH', 'Gene', (99, 102))	('GBM', 'Phenotype', 'HP:0012174', (115, 118))	('tumor', 'Disease', (30, 35))
174741	33658560	The above findings indicated that B2M predicted a more aggressive glioma subtypes and served as a crucial part in the tumorigenic process of gliomas.	('B2M', 'Var', (34, 37))	('aggressive glioma', 'Disease', (55, 72))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('aggressive glioma', 'Disease', 'MESH:D005910', (55, 72))	('gliomas', 'Disease', (141, 148))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
174743	33658560	In pan-gliomas and LGGs from TCGA dataset, disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI) of patients with high B2M were significantly shorter than those with low B2M (Fig.	('pan', 'Gene', '51816', (3, 6))	('disease-specific survival', 'CPA', (43, 68))	('patients', 'Species', '9606', (138, 146))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('progression-free interval', 'CPA', (103, 128))	('overall survival', 'CPA', (76, 92))	('low B2M', 'Phenotype', 'HP:0045082', (204, 211))	('shorter', 'NegReg', (180, 187))	('gliomas', 'Disease', (7, 14))	('high B2M', 'Var', (152, 160))	('DSS', 'Chemical', '-', (70, 73))	('gliomas', 'Disease', 'MESH:D005910', (7, 14))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))	('pan', 'Gene', (3, 6))
174744	33658560	Glioma patients with high B2M expression had worse prognosis in several molecular subgroups.	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('high', 'Var', (21, 25))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('B2M', 'Protein', (26, 29))	('patients', 'Species', '9606', (7, 15))
174745	33658560	We also evaluated the prognostic value of B2M in combination with five prognostic factors including 1p19q, MGMT, IDH, chemotherapy, and radiotherapy (Fig.	('IDH', 'Gene', '3417', (113, 116))	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('1p19q', 'Var', (100, 105))	('IDH', 'Gene', (113, 116))
174746	33658560	B2M showed worse prognosis when glioma patients were stratified by the five clinical prognostic factors (Fig.	('patients', 'Species', '9606', (39, 47))	('glioma', 'Disease', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('B2M', 'Var', (0, 3))
174747	33658560	In pan-cancer samples, B2M predicted worse OS (Supplementary Fig.	('pan', 'Gene', '51816', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('B2M', 'Var', (23, 26))	('pan', 'Gene', (3, 6))
174750	33658560	Moreover, in terms of OS, B2M was a hazardous factor in 9 independent cancer types and a favorable factor in 5 independent cancer types with statistical significance of p < 0.05 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('B2M', 'Var', (26, 29))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
174751	33658560	Likewise, B2M was a hazardous factor in 4 independent cancer types and a favorable factor in 5 independent cancer types in terms of DSS with statistical significance of p < 0.05 (Fig.	('B2M', 'Var', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('DSS', 'MPA', (132, 135))	('DSS', 'Chemical', '-', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (107, 113))
174752	33658560	In sum, B2M can predict the poor prognosis of gliomas.	('B2M', 'Var', (8, 11))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
174756	33658560	More frequent mutations in IDH1 (32%), TTN (22%), ATRX (21%), EGFR (20%), and PTEN (18%) were observed in the cluster with high B2M expression, while more frequent mutations in IDH1 (82%), ATRX (28%), CIC (21%) occurred in cluster with B2M low expression (Fig.	('IDH1', 'Gene', (177, 181))	('ATRX', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (78, 82))	('low', 'NegReg', (240, 243))	('ATRX', 'Gene', '546', (189, 193))	('EGFR', 'Gene', '1956', (62, 66))	('TTN', 'Gene', '7273', (39, 42))	('CIC', 'Disease', (201, 204))	('IDH1', 'Gene', '3417', (177, 181))	('ATRX', 'Gene', (50, 54))	('mutations', 'Var', (14, 23))	('TTN', 'Gene', (39, 42))	('ATRX', 'Gene', '546', (50, 54))	('high', 'Var', (123, 127))	('IDH1', 'Gene', (27, 31))	('CIC', 'Disease', 'None', (201, 204))	('B2M', 'Protein', (128, 131))	('EGFR', 'Gene', (62, 66))	('PTEN', 'Gene', (78, 82))	('expression', 'MPA', (244, 254))	('expression', 'MPA', (132, 142))	('IDH1', 'Gene', '3417', (27, 31))
174764	33658560	GSEA with all transcripts showed that B2M was associated with diverse immune-related pathways in GO (Fig.	('B2M', 'Var', (38, 41))	('GSEA', 'Chemical', '-', (0, 4))	('immune-related pathways', 'Pathway', (70, 93))	('associated with', 'Reg', (46, 61))
174765	33658560	S10A) also indicated that B2M had diverse influences on immune related biological processes, including neutrophil activation, T cell mediated cytotoxicity, regulation of lymphocyte activation, regulation of T cell activation, and macrophage activation.	('T cell', 'CPA', (207, 213))	('influences', 'Reg', (42, 52))	('S10A', 'Var', (0, 4))	('cytotoxicity', 'Disease', 'MESH:D064420', (142, 154))	('neutrophil activation', 'CPA', (103, 124))	('macrophage activation', 'CPA', (230, 251))	('B2M', 'Var', (26, 29))	('S10A', 'SUBSTITUTION', 'None', (0, 4))	('cytotoxicity', 'Disease', (142, 154))
174766	33658560	In both CGGA and TCGA cohorts, B2M was associated with natural killer cell mediated cytotoxicity, apoptosis, T cell and B cell receptor signaling pathway (Fig.	('cytotoxicity', 'Disease', (84, 96))	('apoptosis', 'CPA', (98, 107))	('B2M', 'Var', (31, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (84, 96))	('associated', 'Reg', (39, 49))	('B cell receptor signaling pathway', 'Pathway', (120, 153))
174770	33658560	As mentioned above, tumor with high B2M expression had increased MHC-I-based antigen presentation and associated CD8 cytolytic responses, which gliomas were likely to adopt immune evasive mechanisms through expression of immune checkpoint molecules.	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('CD8', 'Gene', (113, 116))	('CD8', 'Gene', '925', (113, 116))	('increased', 'PosReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('increased MHC', 'Phenotype', 'HP:0025548', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('high', 'Var', (31, 35))	('B2M', 'Protein', (36, 39))	('tumor', 'Disease', (20, 25))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('MHC-I-based antigen presentation', 'MPA', (65, 97))
174772	33658560	Previous research has proved that B2M was associated with inflammation in breast cancer.	('B2M', 'Var', (34, 37))	('breast cancer', 'Disease', (74, 87))	('associated', 'Reg', (42, 52))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('inflammation', 'Disease', (58, 70))
174786	33658560	B2M was significantly downregulated in methylated samples in pan-gliomas and LGGs.	('gliomas', 'Disease', (65, 72))	('pan', 'Gene', '51816', (61, 64))	('B2M', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('LGGs', 'Disease', (77, 81))	('methylated', 'Var', (39, 49))	('pan', 'Gene', (61, 64))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('downregulated', 'NegReg', (22, 35))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
174787	33658560	In addition, B2M was highly enriched in CL and ME subtypes of gliomas and could be used as a predictor with high sensitivity for gliomas.	('ME', 'Chemical', '-', (47, 49))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('gliomas', 'Disease', (62, 69))	('B2M', 'Var', (13, 16))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
174789	33658560	Taken together, B2M was associated with the malignancy of gliomas.	('malignancy of gliomas', 'Disease', (44, 65))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('associated with', 'Reg', (24, 39))	('B2M', 'Var', (16, 19))	('malignancy of gliomas', 'Disease', 'MESH:D005910', (44, 65))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('malignancy of gliomas', 'Phenotype', 'HP:0012174', (44, 65))
174791	33658560	Plenty of researches have shown that the concentration of B2M in serum or urine raised in diverse diseases, such as breast cancer, prostate cancer, lung cancer, renal cancer, multiple myeloma, and especially non-Hodgkin's lymphoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (208, 230))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (212, 230))	("non-Hodgkin's lymphoma", 'Disease', (208, 230))	('concentration', 'MPA', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('multiple myeloma', 'Disease', (175, 191))	('lung cancer', 'Disease', (148, 159))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('renal cancer', 'Disease', (161, 173))	('breast cancer', 'Disease', (116, 129))	('renal cancer', 'Phenotype', 'HP:0009726', (161, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('multiple myeloma', 'Phenotype', 'HP:0006775', (175, 191))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('renal cancer', 'Disease', 'MESH:D007680', (161, 173))	('raised', 'Reg', (80, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('multiple myeloma', 'Disease', 'MESH:D009101', (175, 191))	('B2M', 'Var', (58, 61))	('prostate cancer', 'Disease', (131, 146))
174793	33658560	Further, B2M was significantly associated with five prognosis factors including IDH, 1p19q, MGMT, chemotherapy, and radiotherapy in multivariable survival analysis.	('IDH', 'Gene', (80, 83))	('associated', 'Reg', (31, 41))	('MGMT', 'Gene', '4255', (92, 96))	('MGMT', 'Gene', (92, 96))	('B2M', 'Var', (9, 12))	('IDH', 'Gene', '3417', (80, 83))	('1p19q', 'Disease', (85, 90))
174794	33658560	In patients stratified by the five prognosis factors, B2M predicted worse survival.	('patients', 'Species', '9606', (3, 11))	('B2M', 'Var', (54, 57))	('worse', 'NegReg', (68, 73))
174796	33658560	In samples with high B2M expression, oncogenic drivers, including PDGFRA, EGFR and CDK4 were frequently amplified genomic peaks.	('CDK4', 'Gene', '1019', (83, 87))	('B2M', 'Protein', (21, 24))	('PDGFRA', 'Gene', '5156', (66, 72))	('PDGFRA', 'Gene', (66, 72))	('high', 'Var', (16, 20))	('EGFR', 'Gene', '1956', (74, 78))	('CDK4', 'Gene', (83, 87))	('EGFR', 'Gene', (74, 78))
174797	33658560	Besides, we observed the deletion peaks of tumor suppressive genes such as CDKN2A/CDKN2B and PTEN.	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('CDKN2A', 'Gene', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CDKN2B', 'Gene', (82, 88))	('deletion', 'Var', (25, 33))	('CDKN2A', 'Gene', '1029', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('CDKN2B', 'Gene', '1030', (82, 88))
174798	33658560	Importantly, the alternation and heterogeneity of the genome has a positive impact on the transformation of the tumor proliferation, tumor progression, tumor microenvironment, and treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('positive', 'PosReg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (152, 157))	('alternation', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (112, 117))	('heterogeneity', 'Var', (33, 46))	('impact', 'Reg', (76, 82))	('treatment resistance', 'CPA', (180, 200))
174799	33658560	In addition, GSVA analysis suggested that B2M suppressed the anti-tumor immune response associated with T cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('B2M', 'Var', (42, 45))	('tumor', 'Disease', (66, 71))	('GSVA', 'Chemical', '-', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('suppressed', 'NegReg', (46, 56))
174802	33658560	While in KEGG analysis, B2M was associated with natural killer cell mediated cytotoxicity, and apoptosis.	('B2M', 'Var', (24, 27))	('cytotoxicity', 'Disease', (77, 89))	('apoptosis', 'CPA', (95, 104))	('associated', 'Reg', (32, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))
174804	33658560	Because immune checkpoint blockage has demonstrated remarkable results in cancer treatment, combinations of immune checkpoint inhibitors play an important role for melanoma and brain metastases patients by enhancing their response rates and longer survival.	('combinations', 'Var', (92, 104))	('patients', 'Species', '9606', (194, 202))	('metastases', 'Disease', (183, 193))	('immune checkpoint blockage', 'Phenotype', 'HP:0002958', (8, 34))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('longer', 'PosReg', (241, 247))	('cancer', 'Disease', (74, 80))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('enhancing', 'PosReg', (206, 215))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('response rates', 'CPA', (222, 236))	('melanoma', 'Disease', (164, 172))
174806	33658560	In melanoma, B2M mutation was also associated with resistance of T cell and PD-1 blockage.	('B2M', 'Gene', (13, 16))	('associated', 'Reg', (35, 45))	('mutation', 'Var', (17, 25))	('melanoma', 'Disease', (3, 11))	('PD-1', 'Gene', '5133', (76, 80))	('PD-1', 'Gene', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('resistance of T cell', 'CPA', (51, 71))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
174808	33658560	Notably, B2M potentially participated in inflammatory activities as B2M positively correlated with MHC-I, MHC-II, STAT1 and interferon.	('correlated', 'Reg', (83, 93))	('MHC-II', 'Disease', (106, 112))	('participated', 'Reg', (25, 37))	('MHC-I', 'Disease', (99, 104))	('STAT1', 'Gene', (114, 119))	('STAT1', 'Gene', '6772', (114, 119))	('B2M', 'Var', (68, 71))
174810	33658560	Therefore, the high expression of immune checkpoint molecules might represent an immune suppressive microenvironment that was more likely to exist in gliomas with high B2M expression.	('expression', 'MPA', (20, 30))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('high B2M expression', 'Var', (163, 182))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
174811	33658560	Thus, inhibitors targeting the B2M in combination with other immune checkpoint molecules may revolutionize the treatment of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('B2M', 'Protein', (31, 34))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('inhibitors', 'Var', (6, 16))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
174814	33658560	B2M was positively related with the high malignant degree of glioma and the poor survival of patients.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('related', 'Reg', (19, 26))	('glioma', 'Disease', (61, 67))	('patients', 'Species', '9606', (93, 101))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('B2M', 'Var', (0, 3))
174815	33658560	Additionally, B2M potentially participated in the inflammatory response in the glioma microenvironment, interacted with other immune checkpoint molecules, and suppressed the anti-tumor immunity.	('glioma', 'Disease', (79, 85))	('B2M', 'Var', (14, 17))	('participated', 'Reg', (30, 42))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('inflammatory response', 'CPA', (50, 71))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('suppressed', 'NegReg', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))	('interacted', 'Reg', (104, 114))
174817	25153720	Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', (108, 114))	('mutations', 'Var', (159, 168))	('glioma', 'Disease', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('glioblastoma', 'Disease', (51, 63))	('gliomas', 'Disease', (81, 88))	('glioblastoma', 'Disease', 'MESH:D005909', (51, 63))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
174818	25153720	We hypothesized that microsatellite variation could expand the understanding of glioma etiology.	('glioma', 'Disease', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('microsatellite variation', 'Var', (21, 45))
174819	25153720	Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancer-associated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('glioma', 'Disease', (221, 227))	('microsatellite loci', 'Var', (145, 164))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('glioma', 'Disease', (34, 40))	('cancer', 'Disease', (127, 133))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
174826	25153720	The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('glioma', 'Disease', (26, 32))	('mutations', 'Var', (212, 221))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
174833	25153720	In this study, we have chosen to identify and characterize a specific component of glioma genomics- DNA microsatellite variants - a feature that is understudied relative to SNPs or epigenetic markers.	('glioma', 'Disease', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('microsatellite variants', 'Var', (104, 127))	('glioma', 'Disease', 'MESH:D005910', (83, 89))
174834	25153720	Expansion of tri-nucleotide repeat sequences are notably contributive to over 40 different neurological disorders including Fragile X, Huntington's and Parkinson's Disease.	('neurological disorders', 'Disease', 'MESH:D009422', (91, 113))	('tri-nucleotide', 'Chemical', '-', (13, 27))	('neurological disorders', 'Disease', (91, 113))	("Fragile X, Huntington's and Parkinson's Disease", 'Disease', 'MESH:D006816', (124, 171))	('contributive', 'Reg', (57, 69))	('tri-nucleotide repeat sequences', 'Var', (13, 44))	('Expansion', 'Var', (0, 9))
174835	25153720	Thus, changes to microsatellite sequences elicit phenotypes and contribute to diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('phenotypes', 'MPA', (49, 59))	('contribute', 'Reg', (64, 74))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('changes', 'Var', (6, 13))	('elicit', 'Reg', (42, 48))	('cancer', 'Disease', (98, 104))	('microsatellite', 'Gene', (17, 31))
174836	25153720	Therefore, we hypothesize that gliomagenesis is correlated with microsatellite variability at specific loci in germline DNA.	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('correlated', 'Reg', (48, 58))	('microsatellite variability', 'Var', (64, 90))	('glioma', 'Disease', (31, 37))
174838	25153720	We further hypothesize that these loci could influence tumor biology, including a potential contribution to early glioma tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('loci', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('glioma', 'Disease', (114, 120))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (55, 60))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('influence', 'Reg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
174841	25153720	Signatures consist of variant allelic pairs (genotypes) from cancer-associated microsatellite loci (CAMLs).	('CAML', 'Gene', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('variant', 'Var', (22, 29))	('cancer', 'Disease', (61, 67))	('CAML', 'Gene', '819', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
174851	25153720	Two loci (9:52626-52640 and 2:91886031-91886042) are in the GBM signature and one locus was found amongst significant GBM genotypes (SSX2).	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('SSX2', 'Gene', '6757', (133, 137))	('9:52626-52640', 'Var', (10, 23))	('SSX2', 'Gene', (133, 137))	('2:91886031-91886042', 'Var', (28, 47))	('GBM', 'Phenotype', 'HP:0012174', (118, 121))
174854	25153720	Additionally, malfunctions by the UPS are frequently linked to neuropathies and gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('neuropathies', 'Phenotype', 'HP:0009830', (63, 75))	('linked', 'Reg', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('neuropathies and gliomas', 'Disease', 'MESH:D005910', (63, 87))	('malfunctions', 'Var', (14, 26))
174858	25153720	Illustrated in Figure S2 are the six helicase genes with CAMLs from the GBM signature: all six loci are within ENCODE methylation marker sites (H3KMe1 and H3KMe3), 5 of the loci are within transcription factor binding sites, and 2 are located within expressed sequence tags (EST).	('helicase', 'Gene', '164045', (37, 45))	('CAML', 'Gene', '819', (57, 61))	('CAML', 'Gene', (57, 61))	('methylation', 'MPA', (118, 129))	('helicase', 'Gene', (37, 45))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('H3KMe3', 'Var', (155, 161))	('H3KMe1', 'Var', (144, 150))
174862	25153720	INDEL, frame shift, non-frame shift etc...) to identify connections between driver mutations loci (36 mutations in total identified in 7 genes and 6 mis-match repair genes (MMR)) closely identified with gliomas and the signature.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('mutations', 'Var', (102, 111))	('gliomas', 'Disease', (203, 210))
174864	25153720	However, an increase in CAMLs was identified in most samples with an average of 5 driver mutations, in both GBM and LGG.	('increase', 'PosReg', (12, 20))	('mutations', 'Var', (89, 98))	('CAML', 'Gene', '819', (24, 28))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('CAML', 'Gene', (24, 28))	('GBM', 'Gene', (108, 111))
174867	25153720	These data show microsatellite genotypes can differentiate cancer from non-cancer populations and also lower grade from GBM.	('differentiate', 'Reg', (45, 58))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('non-cancer', 'Disease', 'MESH:D009369', (71, 81))	('cancer', 'Disease', (75, 81))	('non-cancer', 'Disease', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lower', 'NegReg', (103, 108))	('GBM', 'Phenotype', 'HP:0012174', (120, 123))	('microsatellite genotypes', 'Var', (16, 40))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
174871	25153720	Additionally, when we inspected samples with driver mutations, observed in gliomas, the relative percentage of CAMLs is similar in individuals with 1-4 mutations.	('mutations', 'Var', (52, 61))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('CAML', 'Gene', (111, 115))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('CAML', 'Gene', '819', (111, 115))
174877	25153720	Since some microsatellites are associated with DNA 'fragile sites', locations within chromatin susceptible to constrictions or break-points that are linked to cancers and neuro-developmental disorders, we analyzed our MST loci to determine which are located in these regions, as a possible mechanism for tumor potentiation.	('cancers', 'Disease', (159, 166))	('microsatellites', 'Var', (11, 26))	('neuro-developmental disorders', 'Disease', 'MESH:C536203', (171, 200))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('tumor', 'Disease', (304, 309))	('neuro-developmental disorders', 'Disease', (171, 200))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
174878	25153720	BRWD2, found in our GBM signature, is located at a break-point on chromosome 10 and allelic deletions within 10p, 10q 25-26, and 19q 13.3-13.4 are the most common alterations in glial tumors.	('glial tumors', 'Disease', 'MESH:D005910', (178, 190))	('allelic', 'Var', (84, 91))	('glial tumors', 'Disease', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('GBM', 'Phenotype', 'HP:0012174', (20, 23))	('common', 'Reg', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('BRWD2', 'Gene', (0, 5))	('BRWD2', 'Gene', '55717', (0, 5))
174880	25153720	Interestingly, FGFR2 and BRWD2, both genes included in the GBM signature, are an oncogene and tumor suppressor pair located at a recombination locus in which deletion of exon 21 of FGFR2 results in the exclusion of BRWD2 (the tumor suppressor) and amplification of FGFR2; thus intronic CAMLs harbored by these genes could be biological indicators for tumorigenic activity.	('FGFR2', 'Gene', '2263', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('deletion of exon', 'Var', (158, 174))	('amplification', 'MPA', (248, 261))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('CAML', 'Gene', '819', (286, 290))	('BRWD2', 'Gene', (25, 30))	('BRWD2', 'Gene', '55717', (25, 30))	('FGFR2', 'Gene', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (351, 356))	('BRWD2', 'Gene', (215, 220))	('BRWD2', 'Gene', '55717', (215, 220))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('CAML', 'Gene', (286, 290))	('FGFR2', 'Gene', '2263', (265, 270))	('FGFR2', 'Gene', (15, 20))	('FGFR2', 'Gene', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumor', 'Disease', (94, 99))	('FGFR2', 'Gene', '2263', (15, 20))	('exclusion', 'NegReg', (202, 211))	('tumor', 'Disease', (226, 231))
174882	25153720	In the original account of 'the two-hit hypotheses' for somatic retinoblastoma, the first hit was an inherited mutation in Rb, rendering individuals more susceptible to the disease later in life.	('susceptible', 'MPA', (154, 165))	('retinoblastoma', 'Phenotype', 'HP:0009919', (64, 78))	('somatic retinoblastoma', 'Disease', (56, 78))	('somatic retinoblastoma', 'Disease', 'MESH:D012175', (56, 78))	('mutation', 'Var', (111, 119))	('more', 'PosReg', (149, 153))
174883	25153720	Our data suggests the 'first hit' may also be somatic microsatellite instability which then increases the sensitivity to, and probability of, greater genomic aberrance theoretically by stress factors such as environment, inflammation or age leading to the 'second hit'.	('sensitivity', 'MPA', (106, 117))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('inflammation', 'Disease', (221, 233))	('microsatellite instability', 'Var', (54, 80))	('increases', 'PosReg', (92, 101))
174884	25153720	These tentatively 'predisposed' variants may highlight a connection between cancer-associated microsatellites and developmental and cell cycle genes notably mutated in cancer (such as those identified in our study: SRC, NPAT and CBL); thus, these MST variants may be additive to gene mutations (including, SNPs) that contribute to cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('variants', 'Var', (251, 259))	('cancer', 'Disease', (331, 337))	('SRC', 'Gene', '6714', (215, 218))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('SRC', 'Gene', (215, 218))	('NPAT', 'Gene', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('NPAT', 'Gene', '4863', (220, 224))	('variants', 'Var', (32, 40))	('cancer', 'Disease', (168, 174))	('CBL', 'Gene', (229, 232))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('CBL', 'Gene', '867', (229, 232))
174888	25153720	Additionally, this further supports the possibility of tumor initiating cells with irregular genetic variations that generate disease relative to an underlying combination and abundance of affected microsatellite loci.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('irregular genetic variations', 'Var', (83, 111))	('disease', 'Disease', (126, 133))	('generate', 'Reg', (117, 125))
174889	25153720	The aberrant alteration of six helicase genes in GBM suggests that genes important to microsatellite identification and correction, along with transcription and RNA synthesis are themselves modified with MST variants.	('modified', 'Reg', (190, 198))	('helicase', 'Gene', '164045', (31, 39))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('variants', 'Var', (208, 216))	('helicase', 'Gene', (31, 39))	('MST', 'Gene', (204, 207))
174891	25153720	In our data we observed minimal MMR gene coding SNP mutations in both GBM and LGG tumors (see, Fig 3B) but found CAMLs significantly associated with helicases, suggesting modifications to these genes may also be important to genomic instability in glioma or that there may be more MMR genes that remain to be discovered.	('LGG tumors', 'Disease', (78, 88))	('glioma', 'Disease', (248, 254))	('CAML', 'Gene', '819', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('LGG tumors', 'Disease', 'MESH:D009369', (78, 88))	('MMR', 'Gene', (32, 35))	('helicase', 'Gene', (149, 157))	('CAML', 'Gene', (113, 117))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('helicase', 'Gene', '164045', (149, 157))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('modifications', 'Var', (171, 184))	('important', 'Reg', (212, 221))	('associated', 'Reg', (133, 143))
174895	25153720	With the abundance of helicase and UPS associated genes in our glioma signatures, another cancer promoting scenario may be introduced through changes to gene-products that compose spliceosome complexes (snRNA, snRNP, or snoRNP); through these genetic modifications, alternatively spliced RNAs may support spliceosome-associated proteins differently, which may further modify mature RNAs.	('modifications', 'Var', (251, 264))	('spliceosome-associated proteins', 'Protein', (305, 336))	('modify', 'Reg', (368, 374))	('snRNP', 'Gene', '57819', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('support', 'MPA', (297, 304))	('helicase', 'Gene', '164045', (22, 30))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('mature RNAs', 'MPA', (375, 386))	('helicase', 'Gene', (22, 30))	('snRNP', 'Gene', (210, 215))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('glioma', 'Disease', (63, 69))
174897	25153720	Other functional associations important to changes in RNA transcription included, SLC44A4 transcript isoforms uniquely identified in GBM (and with expression significantly greater than normal tissue).	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('greater', 'PosReg', (172, 179))	('expression', 'MPA', (147, 157))	('changes', 'Var', (43, 50))	('SLC44A4', 'Gene', (82, 89))	('SLC44A4', 'Gene', '80736', (82, 89))	('GBM', 'Disease', (133, 136))	('identified', 'Reg', (119, 129))
174900	25153720	Therefore, decreased expression of SEMAs in GBM suggests that these microsatellite variants could contribute to glioma angiogenesis.	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('contribute', 'Reg', (98, 108))	('SEMAs', 'Protein', (35, 40))	('decreased', 'NegReg', (11, 20))	('expression', 'MPA', (21, 31))	('microsatellite variants', 'Var', (68, 91))	('glioma', 'Disease', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
174902	25153720	Since these loci can be identified from germline (non-tumor) DNA, it further suggests that there is a tumor initiating cell population in which developmental cell signaling and patterning pathways may result in aberrant differentiation and proliferation due to an underlying transcriptional landscape determined by cancer-associated MST variants.	('proliferation', 'CPA', (240, 253))	('MST', 'Gene', (333, 336))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Disease', (315, 321))	('non-tumor', 'Disease', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('variants', 'Var', (337, 345))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('tumor', 'Disease', (54, 59))	('non-tumor', 'Disease', 'MESH:D009369', (50, 59))	('tumor', 'Disease', (102, 107))	('result in', 'Reg', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
174904	25153720	If so, we can predict that specific microsatellite instability contributes to cancer-specific genomics and may occur during embryogenesis, which has also been predicted in other MST associated diseases, including Huntington's disease and Fragile X syndrome.	('Fragile X syndrome', 'Disease', 'MESH:D005600', (238, 256))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	("Huntington's disease", 'Disease', (213, 233))	('contributes', 'Reg', (63, 74))	("Huntington's disease", 'Disease', 'MESH:D006816', (213, 233))	('microsatellite instability', 'Var', (36, 62))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Fragile X syndrome', 'Disease', (238, 256))
174917	33820494	Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('GKAP1', 'Gene', '80318', (20, 25))	('TRK', 'Gene', (27, 30))	('TRK', 'Gene', (107, 110))	('tumor', 'Disease', (263, 268))	('NTRK2', 'Gene', '4915', (26, 31))	('TRK', 'Gene', '4914', (27, 30))	('TRK', 'Gene', '4914', (107, 110))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('GKAP1', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('girl', 'Species', '9606', (175, 179))	('glioma', 'Disease', (64, 70))	('larotrectinib', 'Chemical', 'MESH:C000609083', (121, 134))	('fusion', 'Var', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('hypothalamus', 'Disease', 'MESH:D007029', (225, 237))	('hypothalamus', 'Disease', (225, 237))	('NTRK2', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
174919	33820494	Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32-33 leading to breakpoints within the GKAP1 and NTRK2 genes.	('GKAP1', 'Gene', (139, 144))	('tumor', 'Disease', (48, 53))	('GKAP1', 'Gene', '80318', (139, 144))	('NTRK2', 'Gene', '4915', (149, 154))	('breakpoints', 'Var', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('NTRK2', 'Gene', (149, 154))
174920	33820494	RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10-16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain.	('fusion', 'Var', (68, 74))	('GKAP1', 'Gene', (36, 41))	('GKAP1', 'Gene', '80318', (36, 41))	('NTRK2', 'Gene', (42, 47))	('tyrosine', 'MPA', (148, 156))	('NTRK2', 'Gene', '4915', (42, 47))
174921	33820494	Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705).	('GKAP1', 'Gene', '80318', (73, 78))	('activated', 'PosReg', (106, 115))	('NTRK2', 'Gene', (79, 84))	('phosphorylation', 'MPA', (124, 139))	('Tyr705', 'Var', (158, 164))	('HEK293', 'CellLine', 'CVCL:0045', (49, 55))	('NTRK2', 'Gene', '4915', (79, 84))	('GKAP1', 'Gene', (73, 78))	('Tyr705', 'Chemical', '-', (158, 164))
174931	33820494	optic glioma, where radical surgical resection are associated with high risk for morbidity., To date, progressive residual disease from pLGG is treated with adjuvant chemotherapy or radiation, which may cause long-lasting morbidity and permanent psychosocial and physical dysfunction and, particularly for radiation, result in increased mortality., Gene fusions resulting from chromosomal rearrangements are common, accounting for around 60% of pLGG.	('optic glioma', 'Phenotype', 'HP:0009734', (0, 12))	('chromosomal rearrangements', 'Var', (377, 403))	('Gene fusions', 'Var', (349, 361))	('optic glioma', 'Disease', 'MESH:D020339', (0, 12))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('mortality', 'Disease', 'MESH:D003643', (337, 346))	('optic glioma', 'Disease', (0, 12))	('pLGG', 'Disease', (445, 449))	('mortality', 'Disease', (337, 346))
174933	33820494	Also, 40% of pLGG are driven by point-mutations where BRAFV600E is the most prevalent, followed by mutations in FGFR1.	('pLGG', 'Disease', (13, 17))	('prevalent', 'Reg', (76, 85))	('FGFR1', 'Gene', (112, 117))	('FGFR1', 'Gene', '2260', (112, 117))	('BRAFV600E', 'Var', (54, 63))	('BRAFV600E', 'Mutation', 'rs113488022', (54, 63))
174962	33820494	The wild-type NTRK2 (NM_006180, 838 aa, #RC221794) and pCMV6 empty vector (#PS10000) constructs were ordered from Origene (Origene, Rockville, MD, USA).	('NM_006180', 'Var', (21, 30))	('NTRK2', 'Gene', (14, 19))	('NTRK2', 'Gene', '4915', (14, 19))
175002	33820494	Routine clinical molecular analysis revealed the tumor to be negative for BRAF-fusion and BRAF V600E mutation.	('BRAF', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('tumor', 'Disease', (49, 54))	('BRAF', 'Gene', '673', (90, 94))	('V600E', 'Var', (95, 100))
175005	33820494	Reverse transcription PCR (RT-PCR) targeting the putative GKAP1-NTRK2 fusion generated a PCR-product length of 235bp (Figure 3a; Supplementary Table S2).	('GKAP1', 'Gene', (58, 63))	('NTRK2', 'Gene', (64, 69))	('fusion', 'Var', (70, 76))	('GKAP1', 'Gene', '80318', (58, 63))	('NTRK2', 'Gene', '4915', (64, 69))
175006	33820494	Further characterization by Sanger sequencing, showed a fusion junction between GKAP1 exon 10 , and NTRK2 exon 16 (Figure 3b).	('NTRK2', 'Gene', '4915', (100, 105))	('fusion', 'Var', (56, 62))	('NTRK2', 'Gene', (100, 105))	('GKAP1', 'Gene', (80, 85))	('GKAP1', 'Gene', '80318', (80, 85))
175015	33820494	The DDK bands corresponding to the GKAP1-NTRK2 fusion matched the size of phosphorylated TRKB bands.	('TRKB', 'Gene', (89, 93))	('NTRK2', 'Gene', '4915', (41, 46))	('fusion', 'Var', (47, 53))	('GKAP1', 'Gene', (35, 40))	('TRKB', 'Gene', '4915', (89, 93))	('NTRK2', 'Gene', (41, 46))	('GKAP1', 'Gene', '80318', (35, 40))
175023	33820494	The study includes children with advanced primary CNS - or solid tumors harboring a fusion involving NTRK1, NTRK2 or NTRK3.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('NTRK3', 'Gene', (117, 122))	('NTRK2', 'Gene', '4915', (108, 113))	('solid tumors', 'Disease', (59, 71))	('NTRK1', 'Gene', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('children', 'Species', '9606', (19, 27))	('solid tumors', 'Disease', 'MESH:D009369', (59, 71))	('fusion', 'Var', (84, 90))	('NTRK2', 'Gene', (108, 113))	('NTRK1', 'Gene', '4914', (101, 106))	('NTRK3', 'Gene', '4916', (117, 122))
175039	33820494	Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins with constitutively activated, or overexpressed, kinase function, conferring their oncogenic potential.	('oncogenic potential', 'CPA', (164, 183))	('Gene fusions', 'Var', (0, 12))	('transcription', 'MPA', (42, 55))	('TRK', 'Gene', (68, 71))	('TRK', 'Gene', '4914', (68, 71))	('lead to', 'Reg', (34, 41))	('TRK', 'Gene', (24, 27))	('TRK', 'Gene', '4914', (24, 27))	('chimeric', 'Var', (59, 67))
175040	33820494	Previously reported NTRK2 fusions in low-grade glioma include AFAP1-NTRK2, NACC2-NTRK2, QKI-NTRK2, KANK1-NTRK2, BRC-NTRK2 and PML-NTRK2.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('PML', 'Gene', '5371', (126, 129))	('AFAP1', 'Gene', (62, 67))	('NTRK2', 'Gene', '4915', (130, 135))	('NTRK2', 'Gene', '4915', (20, 25))	('NTRK2', 'Gene', '4915', (68, 73))	('NTRK2', 'Gene', (92, 97))	('KANK1', 'Gene', (99, 104))	('QKI', 'Gene', '9444', (88, 91))	('NTRK2', 'Gene', (116, 121))	('NTRK2', 'Gene', '4915', (105, 110))	('NTRK2', 'Gene', (20, 25))	('NTRK2', 'Gene', '4915', (81, 86))	('NACC2', 'Gene', (75, 80))	('NACC2', 'Gene', '138151', (75, 80))	('QKI', 'Gene', (88, 91))	('fusions', 'Var', (26, 33))	('NTRK2', 'Gene', (68, 73))	('NTRK2', 'Gene', (130, 135))	('glioma', 'Disease', (47, 53))	('PML', 'Gene', (126, 129))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('KANK1', 'Gene', '23189', (99, 104))	('NTRK2', 'Gene', (105, 110))	('NTRK2', 'Gene', (81, 86))	('BRC-NTRK2', 'CellLine', 'CVCL:B979', (112, 121))	('NTRK2', 'Gene', '4915', (92, 97))	('NTRK2', 'Gene', '4915', (116, 121))	('AFAP1', 'Gene', '60312', (62, 67))
175041	33820494	Reviewing the literature, we found GKAP1-NTRK2 fusions listed in two recent screening studies; one in a pLGG tumor harboring a exon 9-15 fusion junction, and another in an adult glioblastoma multiforme patient with the same exon 10-16 fusion junction as the one detected in this study.	('NTRK2', 'Gene', '4915', (41, 46))	('patient', 'Species', '9606', (202, 209))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('glioblastoma multiforme', 'Disease', (178, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('fusions', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('GKAP1', 'Gene', (35, 40))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (178, 201))	('NTRK2', 'Gene', (41, 46))	('GKAP1', 'Gene', '80318', (35, 40))	('tumor', 'Disease', (109, 114))
175044	33820494	However, it has been noted that a predominant proportion of upstream fusion partners contain oligomerization domains, such as coiled-coil domains, zinc finger domains or WD repeats, that are thought to contribute to activation via dimerization and/or autophosphorylation of the kinase domain.	('coiled-coil', 'MPA', (126, 137))	('WD', 'Disease', 'MESH:D006527', (170, 172))	('zinc finger domains', 'Var', (147, 166))	('dimerization', 'MPA', (231, 243))	('autophosphorylation', 'MPA', (251, 270))	('activation', 'PosReg', (216, 226))	('oligomerization', 'MPA', (93, 108))
175046	33820494	In the current study, we show that the GKAP1-NTRK2 fusion gets activated through phosphorylation of the TK domain (Tyr705), leading to downstream endogenous activation of the MAPK and PI3K pathways.	('GKAP1', 'Gene', (39, 44))	('Tyr705', 'Var', (115, 121))	('activated', 'PosReg', (63, 72))	('GKAP1', 'Gene', '80318', (39, 44))	('NTRK2', 'Gene', '4915', (45, 50))	('Tyr705', 'Chemical', '-', (115, 121))	('activation', 'PosReg', (157, 167))	('NTRK2', 'Gene', (45, 50))
175066	33820494	We discovered a rare GKAP1-NTRK2 fusion gene in a pediatric low-grade glioma activating the MAPK and PI3K proliferation pathways.	('glioma', 'Disease', (70, 76))	('NTRK2', 'Gene', '4915', (27, 32))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('fusion gene', 'Var', (33, 44))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('GKAP1', 'Gene', (21, 26))	('NTRK2', 'Gene', (27, 32))	('GKAP1', 'Gene', '80318', (21, 26))	('activating', 'PosReg', (77, 87))
175097	24610491	Moreover, genetic modifications of C6 rat glioma cells facilitated creation of cell lines that release excessive amounts of Glu along with non-secreting lines.	('genetic modifications', 'Var', (10, 31))	('C6', 'CellLine', 'CVCL:X905', (35, 37))	('release', 'MPA', (95, 102))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))
175128	24610491	Of particular interest is the fact that glioblastoma-tumor initiating cells express high levels of functional, calcium-permeable AMPA receptors containing GluR1 and GluR4 subunits, when compared with the differentiated tumor cultures consisting of non-stem cells derived from the same tumor tissues (Oh et al.).	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('glioblastoma-tumor', 'Disease', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('GluR1', 'Var', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('glioblastoma-tumor', 'Disease', 'MESH:D005909', (40, 58))
175146	24610491	In contrast, mGluR1 and mGluR5 were highly represented in the neuronal components of brain tumors (Aronica et al.).	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('brain tumors', 'Phenotype', 'HP:0030692', (85, 97))	('mGluR5', 'Var', (24, 30))	('brain tumors', 'Disease', 'MESH:D001932', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mGluR1', 'Var', (13, 19))	('brain tumors', 'Disease', (85, 97))
175151	24610491	Given the fact that mGluR4 mediates 5-fluorouracil resistance in human colon cancer cells, which is a major obstacle in chemotherapy of this cancer type (Yoo et al.	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (36, 50))	('mGluR4', 'Var', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mediates', 'Reg', (27, 35))	('5-fluorouracil resistance', 'MPA', (36, 61))
175153	24610491	Very low presence of mGluR4 was demonstrated in thyroid, adrenal glands, and kidney cancers (8-13 %), whereas it was not detected in esophageal, endometrial and prostate cancers, as well as in neoplasms derived from salivary glands and testis (Chang et al.).	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (193, 202))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('kidney cancers', 'Disease', (77, 91))	('thyroid', 'Disease', (48, 55))	('mGluR4', 'Var', (21, 27))	('prostate cancers', 'Phenotype', 'HP:0012125', (161, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('kidney cancers', 'Disease', 'MESH:D007680', (77, 91))	('adrenal glands', 'Disease', (57, 71))	('endometrial and prostate cancers', 'Disease', 'MESH:D016889', (145, 177))	('kidney cancers', 'Phenotype', 'HP:0009726', (77, 91))
175159	24610491	Chen's group was the first to demonstrate that ectopic expression of mGluR1 in melanocytes, which normally lack this receptor, was sufficient to induce transformation to malignant melanoma in vivo (Pollock et al.).	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('ectopic expression', 'Var', (47, 65))	('induce', 'Reg', (145, 151))	('malignant melanoma', 'Phenotype', 'HP:0002861', (170, 188))	('transformation', 'CPA', (152, 166))	('mGluR1', 'Gene', (69, 75))	('malignant melanoma', 'Disease', 'MESH:D008545', (170, 188))	('malignant melanoma', 'Disease', (170, 188))
175165	24610491	Parallel, siRNA-mediated inhibition of mGluR1 expression in renal cancer cells impaired tumor growth in vivo, thus suggesting that sustained expression of mGluR1 is necessary for neoplastic transformation and tumor progression (Martino et al.	('renal cancer', 'Phenotype', 'HP:0009726', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inhibition', 'Var', (25, 35))	('impaired tumor', 'Disease', 'MESH:D015417', (79, 93))	('mGluR1', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('impaired tumor', 'Disease', (79, 93))
175166	24610491	), whereas gene silencing of GluR4 modulated the mRNA expression of various tumor-suppressor genes, oncogenes and other genes involved in invasion, adhesion and metastatic capabilities, which resulted in significant increase of cell viability of human rhabdomyosarcoma/medulloblastoma (TE671) and human multiple myeloma RPMI8226 cells.	('metastatic', 'CPA', (161, 171))	('tumor-suppressor genes', 'Gene', (76, 98))	('multiple myeloma', 'Phenotype', 'HP:0006775', (303, 319))	('GluR4', 'Gene', (29, 34))	('myeloma', 'Disease', (312, 319))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('RPMI8226', 'CellLine', 'CVCL:0014', (320, 328))	('modulated', 'Reg', (35, 44))	('mRNA expression', 'MPA', (49, 64))	('medulloblastoma', 'Phenotype', 'HP:0002885', (269, 284))	('gene silencing', 'Var', (11, 25))	('cell viability', 'CPA', (228, 242))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (252, 268))	('increase', 'PosReg', (216, 224))	('myeloma', 'Disease', 'MESH:D009101', (312, 319))	('oncogenes', 'Gene', (100, 109))
175167	24610491	Likewise, somatic mutations within mGluR3 gene result in an activation of GPCR-mediated mitogen-activated protein kinase 1/2 signaling that results in a transformed cells' phenotype, which renders an increased migration of melanoma cells along with a loss of anchorage dependency in growth regulation (Prickett et al.).	('mGluR3', 'Gene', (35, 41))	('migration', 'CPA', (210, 219))	('loss of anchorage dependency', 'Disease', (251, 279))	('increased', 'PosReg', (200, 209))	('loss of anchorage dependency', 'Disease', 'MESH:D019966', (251, 279))	('activation', 'PosReg', (60, 70))	('results in', 'Reg', (140, 150))	("transformed cells' phenotype", 'CPA', (153, 181))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('mutations', 'Var', (18, 27))
175168	24610491	Moreover, a very recent study highlighted the importance of naturally occurring GRM1 somatic mutations for mGluR1 surface expression, altered basal and agonist-dependent activity, and disruption of intracellular signaling pathways downstream of the receptor, including inositol phosphate (IP) formation, and altered ERK1/2 kinases activity (Esseltine et al.).	('IP', 'Chemical', 'MESH:D007295', (289, 291))	('mutations', 'Var', (93, 102))	('intracellular signaling pathways', 'Pathway', (198, 230))	('ERK1/2', 'Gene', (316, 322))	('ERK1/2', 'Gene', '5595;5594', (316, 322))	('activity', 'MPA', (331, 339))	('disruption', 'Reg', (184, 194))	('inositol phosphate', 'Chemical', 'MESH:D007295', (269, 287))	('GRM1', 'Gene', (80, 84))	('mGluR1', 'Gene', (107, 113))	('altered', 'Reg', (134, 141))	('altered', 'Reg', (308, 315))	('GRM1', 'Gene', '2911', (80, 84))
175169	24610491	Clinical genetic analysis of GRM1 showed that single nucleotide polymorphism of the C allele of rs362962 (coding mGluR1) contributes to human melanoma susceptibility, especially in a subgroup of patients with a low level of sun exposure and tumors located on the trunk and extremities (Ortiz et al.).	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('contributes', 'Reg', (121, 132))	('rs362962', 'Gene', (96, 104))	('single nucleotide polymorphism', 'Var', (46, 76))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('rs362962', 'Mutation', 'rs362962', (96, 104))
175170	24610491	A similar study performed in women carrying breast cancer revealed a significant correlation between the GRM1 CC genotype of rs362962 and the development of hormone receptor-negative breast cancer and association of rs6923492 and rs362962 genotypes with age at diagnosis (Mehta et al.).	('rs362962', 'DBSNP_MENTION', 'None', (230, 238))	('women', 'Species', '9606', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('rs6923492', 'Mutation', 'rs6923492', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('rs362962', 'Var', (230, 238))	('association', 'Interaction', (201, 212))	('rs362962', 'DBSNP_MENTION', 'None', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', (183, 196))	('rs6923492', 'Var', (216, 225))	('rs362962', 'Var', (125, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
175175	24610491	Moreover, reintroduction of this gene in esophageal cancer or forced expression in gastric cancer cell lines was accompanied by apoptosis or inhibited cell colony formation, respectively, suggesting tumor-suppressor activity for NR2B (Kim et al.	('NR2B', 'Gene', (229, 233))	('reintroduction', 'Var', (10, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('cell colony formation', 'CPA', (151, 172))	('tumor-suppressor activity', 'MPA', (199, 224))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('inhibited', 'NegReg', (141, 150))	('esophageal cancer', 'Disease', (41, 58))
175180	24610491	This suggests that the presence of GluR2 in benign glands, including post-atrophic and adenosis-type ones, readily distinguishes them from prostate cancer (Hechtman et al.).	('atrophic', 'Disease', 'MESH:D020966', (74, 82))	('adenosis-type ones', 'Disease', (87, 105))	('atrophic', 'Disease', (74, 82))	('prostate cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('adenosis-type ones', 'Disease', 'MESH:D005348', (87, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('GluR2', 'Var', (35, 40))
175183	24610491	Only a few reports demonstrated that the tumor size, presence of lymph node metastases and cancer stage were significantly related to high NR1 (Choi et al.)	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NR1', 'Gene', (139, 142))	('high', 'Var', (134, 138))	('related', 'Reg', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lymph node metastases', 'Disease', 'MESH:D009362', (65, 86))	('lymph node metastases', 'Disease', (65, 86))
175185	24610491	On the contrary, overexpression of mGluR4 is associated with a poor prognosis in colorectal carcinoma (Chang et al.).	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('colorectal carcinoma', 'Disease', (81, 101))	('overexpression', 'PosReg', (17, 31))	('mGluR4', 'Var', (35, 41))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (81, 101))
175193	31802314	Neurocognitive changes after awake surgery in glioma patients: a retrospective cohort study Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients.	('cognitive changes', 'Phenotype', 'HP:0100543', (5, 22))	('Deficits', 'Var', (92, 100))	('patients', 'Species', '9606', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioma', 'Disease', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Disease', (157, 163))	('patients', 'Species', '9606', (164, 172))	('neurocognitive functioning', 'MPA', (104, 130))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
175253	31802314	In addition to such a structural effect, we found that the classification of the tumor as a grade II/III 1p19q-intact and IDH-wildtype glioma predicted cognitive decline in visuospatial functioning.	('cognitive decline', 'Disease', (152, 169))	('IDH-wildtype glioma', 'Disease', 'MESH:D005910', (122, 141))	('1p19q-intact', 'Var', (105, 117))	('cognitive decline', 'Disease', 'MESH:D003072', (152, 169))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cognitive decline', 'Phenotype', 'HP:0001268', (152, 169))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('IDH-wildtype glioma', 'Disease', (122, 141))	('tumor', 'Disease', (81, 86))
175256	31802314	This hypothesis is supported by a recent study by Wefel et al., who found a complex interrelationship between patients' NCF, tumor growth velocity and the presence or absence of an IDH-mutation.	('presence', 'Var', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('IDH', 'Gene', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('IDH', 'Gene', '3417', (181, 184))	('tumor', 'Disease', (125, 130))	('patients', 'Species', '9606', (110, 118))
175280	29743610	The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.	('glioma', 'Disease', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('variants', 'Var', (45, 53))
175304	29743610	Odds ratio for rs55705857 in all glioma was significantly higher in females (ORF = 2.45 [95% CI = 2.14-2.80], pF = 1.22 x 10-39) as compared to males (ORM = 1.56 [95% CI = 1.40-1.75], pM = 1.09 x 10-14) with pD = 3.46 x 10-7.	('ORM = 1', 'Gene', (151, 158))	('rs55705857', 'Var', (15, 25))	('glioma', 'Disease', (33, 39))	('rs55705857', 'Mutation', 'rs55705857', (15, 25))	('higher', 'PosReg', (58, 64))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('ORM = 1', 'Gene', '5004', (151, 158))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
175307	29743610	Previous studies have found a strong association between rs55705857 and oligodendroglial tumors (particularly tumors with isocitrate dehydrogenase 1/2 (IDH1/2) mutation and loss of the short arm of chromosome 1 [1p] and the long arm of chromosome 19 [19q]), so this association was further explored in the non-GBM (lower grade glioma [LGG]) histology groups (Table 3).	('tumors', 'Disease', (89, 95))	('IDH1/2', 'Gene', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('loss', 'NegReg', (173, 177))	('oligodendroglial tumors', 'Disease', (72, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('rs55705857', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('short arm', 'Phenotype', 'HP:0009824', (185, 194))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (72, 95))	('mutation', 'Var', (160, 168))	('glioma', 'Disease', (327, 333))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (327, 333))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (327, 333))	('IDH1/2', 'Gene', '3417;3418', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('rs55705857', 'Mutation', 'rs55705857', (57, 67))
175311	29743610	In a previous eight study meta-analysis, ~12,000 SNPs (INFO > 0.7, MAF > 0.01) were identified as having a nominally significant (p < 5 x 10-4) association with all glioma, GBM, or non-GBM.	('non-GBM', 'Disease', (181, 188))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('GBM', 'Disease', (173, 176))	('SNPs', 'Var', (49, 53))	('glioma', 'Disease', (165, 171))
175312	29743610	One large region within 3p21.31 (49400kb-49600kb, ~200 kb) was identified as being significantly associated with glioma and GBM in females only (Fig.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('GBM', 'Disease', (124, 127))	('associated', 'Reg', (97, 107))	('glioma', 'Disease', (113, 119))	('49400kb-49600kb', 'Var', (33, 48))
175315	29743610	The strongest association in females within this region was at rs9841110, in both all glioma (ORF = 1.22 [95% CI = 1.14-1.32], pF = 5.55 x 10-8) with pD = 1.77 x 10-4) and GBM only (ORF = 1.27 [95% CI = 1.16-1.38], pF = 3.86 x 10-7) with pD = 6.04 x 10-4), while there were no significant associations detected in males (Fig.	('glioma', 'Disease', (86, 92))	('rs9841110', 'Var', (63, 72))	('ORF = 1', 'Gene', (182, 189))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('ORF = 1', 'Gene', '55354', (182, 189))	('ORF = 1', 'Gene', (94, 101))	('rs9841110', 'Mutation', 'rs9841110', (63, 72))	('ORF = 1', 'Gene', '55354', (94, 101))
175319	29743610	Overall, slightly more females (53.2%) as compared to males (47.2%) had IDH1/2 mutant glioma, but this difference was not statistically significant (p = 0.1104) (Supplemental Fig.	('glioma', 'Disease', (86, 92))	('mutant', 'Var', (79, 85))	('IDH1/2', 'Gene', '3417;3418', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('IDH1/2', 'Gene', (72, 78))	('men', 'Species', '9606', (168, 171))
175320	29743610	When tumors were stratified by histological type, approximately equal proportions of males and females had IDH1/2 mutations present in their tumors (GBM: 6.0% in males, and 5.2% in females; LGG: 17.9% in males, and 17.7% in females).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mutations', 'Var', (114, 123))	('IDH1/2', 'Gene', '3417;3418', (107, 113))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('IDH1/2', 'Gene', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
175324	29743610	In the overall meta-analysis, there was a nominally significant signal in the case-only meta-analysis for the proxy SNP in 3p21.31 in glioblastoma (Table 4).	('significant', 'Reg', (52, 63))	('glioblastoma', 'Disease', (134, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (134, 146))	('SNP in 3p21.31', 'Var', (116, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))
175326	29743610	MAF in LGG and IDH1/2 mutant glioma was similar among males and females.	('glioma', 'Disease', (29, 35))	('IDH1/2', 'Gene', (15, 21))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('mutant', 'Var', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('LGG', 'Gene', (7, 10))	('IDH1/2', 'Gene', '3417;3418', (15, 21))
175328	29743610	Among both LGG and IDH1/2 mutant, RAF was elevated in females as opposed to males.	('RAF', 'CPA', (34, 37))	('IDH1/2', 'Gene', (19, 25))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('LGG', 'Gene', (11, 14))	('mutant', 'Var', (26, 32))	('elevated', 'PosReg', (42, 50))
175329	29743610	In order to estimate the cumulative effects of significant variants by sex, unweighted risk scores (URS) were calculated by summing all risk alleles for each individual using the 10 SNPs (rs12752552, rs9841110, rs10069690, rs11979158, rs55705857, rs634537, rs12803321, rs3751667, rs78378222, and rs2297440) found to be significantly associated with glioma in this analysis.	('glioma', 'Phenotype', 'HP:0009733', (349, 355))	('rs55705857', 'Var', (235, 245))	('rs12752552', 'Var', (188, 198))	('associated', 'Reg', (333, 343))	('rs12803321', 'Mutation', 'rs12803321', (257, 267))	('rs10069690', 'Var', (211, 221))	('rs9841110', 'Mutation', 'rs9841110', (200, 209))	('rs11979158', 'Var', (223, 233))	('rs78378222', 'Var', (280, 290))	('rs3751667', 'Mutation', 'rs3751667', (269, 278))	('rs3751667', 'Var', (269, 278))	('rs9841110', 'Var', (200, 209))	('glioma', 'Disease', (349, 355))	('rs634537', 'Var', (247, 255))	('rs2297440', 'Mutation', 'rs2297440', (296, 305))	('rs55705857', 'Mutation', 'rs55705857', (235, 245))	('rs634537', 'Mutation', 'rs634537', (247, 255))	('rs78378222', 'Mutation', 'rs78378222', (280, 290))	('rs11979158', 'Mutation', 'rs11979158', (223, 233))	('glioma', 'Disease', 'MESH:D005910', (349, 355))	('rs12752552', 'Mutation', 'rs12752552', (188, 198))	('URS', 'Chemical', '-', (100, 103))	('rs10069690', 'Mutation', 'rs10069690', (211, 221))	('rs12803321', 'Var', (257, 267))	('rs2297440', 'Var', (296, 305))
175330	29743610	GBM (URS-GBM) and non-GBM (URS-NGBM) specific URS were calculated only using sets of 6 SNPs in this set that were significantly associated with these histologies (URS-GBM: rs9841110, rs10069690, rs11979158, rs634537, rs78378222, and rs2297440, and URS-NGBM: rs10069690, rs55705857, rs634537, rs12803321, rs78378222, and rs2297440).	('URS', 'Chemical', '-', (27, 30))	('rs2297440', 'Var', (320, 329))	('associated', 'Reg', (128, 138))	('rs10069690', 'Var', (258, 268))	('rs55705857', 'Mutation', 'rs55705857', (270, 280))	('rs10069690', 'Mutation', 'rs10069690', (183, 193))	('rs11979158', 'Mutation', 'rs11979158', (195, 205))	('rs9841110', 'Var', (172, 181))	('URS', 'Chemical', '-', (248, 251))	('rs78378222', 'Var', (217, 227))	('rs12803321', 'Var', (292, 302))	('rs78378222', 'Var', (304, 314))	('rs634537', 'Var', (282, 290))	('rs634537', 'Mutation', 'rs634537', (282, 290))	('rs78378222', 'Mutation', 'rs78378222', (217, 227))	('rs55705857', 'Var', (270, 280))	('rs10069690', 'Mutation', 'rs10069690', (258, 268))	('URS', 'Chemical', '-', (46, 49))	('rs2297440', 'Mutation', 'rs2297440', (233, 242))	('rs78378222', 'Mutation', 'rs78378222', (304, 314))	('rs10069690', 'Var', (183, 193))	('rs11979158', 'Var', (195, 205))	('rs2297440', 'Var', (233, 242))	('rs12803321', 'Mutation', 'rs12803321', (292, 302))	('rs2297440', 'Mutation', 'rs2297440', (320, 329))	('URS', 'Chemical', '-', (163, 166))	('rs634537', 'Var', (207, 215))	('rs634537', 'Mutation', 'rs634537', (207, 215))	('URS', 'Chemical', '-', (5, 8))	('rs9841110', 'Mutation', 'rs9841110', (172, 181))
175335	29743610	This is the first analysis of inherited risk variants in sporadic glioma focused specifically on sex differences, and the first agnostic unbiased scan for glioma risk variants on the X and Y sex chromosomes.	('glioma', 'Disease', (66, 72))	('variants', 'Var', (45, 53))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('glioma', 'Disease', (155, 161))
175336	29743610	One SNP at the 7p11.2 locus (rs11979158) showed significant association in males only, in both all glioma and GBM (Table 2, see Supplemental Table 5 and Supplemental Fig.	('men', 'Species', '9606', (159, 162))	('rs11979158', 'Mutation', 'rs11979158', (29, 39))	('glioma', 'Disease', (99, 105))	('rs11979158', 'Var', (29, 39))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('men', 'Species', '9606', (134, 137))
175337	29743610	This variant is within one of two previously identified independent glioma risk loci located near epidermal growth factor receptor (EGFR) and is most strongly associated with risk for GBM.	('epidermal growth factor receptor', 'Gene', (98, 130))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('EGFR', 'Gene', '1956', (132, 136))	('associated with', 'Reg', (159, 174))	('EGFR', 'Gene', (132, 136))	('variant', 'Var', (5, 12))	('epidermal growth factor receptor', 'Gene', '1956', (98, 130))	('GBM', 'Disease', (184, 187))	('glioma', 'Disease', (68, 74))
175343	29743610	The association at 8q24.21 (rs55705857) is the strongest that has been identified by glioma GWAS to date, with an odds ratio of 1.99 (95% CI = 1.85-2.13, p = 9.53 x 10-79) in glioma overall, and an odds ratio of 3.39 (95% CI = 3.09-3.71, p = 7.28 x 10-149) in non-GBM (see Supplemental Table 5 and Supplemental Fig.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('men', 'Species', '9606', (279, 282))	('glioma GWAS', 'Disease', 'MESH:D005910', (85, 96))	('rs55705857', 'Mutation', 'rs55705857', (28, 38))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('non-GBM', 'Disease', (260, 267))	('glioma GWAS', 'Disease', (85, 96))	('glioma', 'Disease', (85, 91))	('men', 'Species', '9606', (304, 307))	('rs55705857', 'Var', (28, 38))	('glioma', 'Disease', (175, 181))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
175344	29743610	The identified SNP, rs55705857, is located in an intergenic region near coiled-coil domain containing 26 (CCDC26, a long non-coding RNA).	('rs55705857', 'Mutation', 'rs55705857', (20, 30))	('CCDC26', 'Gene', (106, 112))	('CCDC26', 'Gene', '137196', (106, 112))	('rs55705857', 'Var', (20, 30))
175348	29743610	A histology-specific analysis found a similar sex differences in ORs for rs55705957 for both non-GBM astrocytoma, and oligodendroglioma (Table 3, see Supplemental Table 7 for study-specific estimates).	('rs55705957', 'Var', (73, 83))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('men', 'Species', '9606', (156, 159))	('astrocytoma', 'Disease', 'MESH:D001254', (101, 112))	('astrocytoma', 'Disease', (101, 112))	('oligodendroglioma', 'Disease', (118, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('oligodendroglioma', 'Disease', 'MESH:D009837', (118, 135))	('rs55705957', 'Mutation', 'rs55705957', (73, 83))
175349	29743610	This variant is strongly associated with IDH1/2 mutant and 1p/19q codeleted glioma tumors, but data on these molecular markers was not available for the four GWAS datasets used.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutant', 'Var', (48, 54))	('glioma tumors', 'Disease', (76, 89))	('associated', 'Reg', (25, 35))	('glioma tumors', 'Disease', 'MESH:D005910', (76, 89))	('1p/19q', 'Var', (59, 65))	('IDH1/2', 'Gene', '3417;3418', (41, 47))	('variant', 'Var', (5, 12))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('IDH1/2', 'Gene', (41, 47))
175350	29743610	The TCGA GBM and LGG datasets were used to assess potential sex differences in frequency of IDH1/2 mutation within histologies.	('IDH1/2', 'Gene', '3417;3418', (92, 98))	('IDH1/2', 'Gene', (92, 98))	('mutation', 'Var', (99, 107))
175351	29743610	Approximately the same proportion of males as females with histologically confirmed GBM had IDH1/2 mutations (5.2% vs 6.0%, respectively, Supplemental Fig.	('mutations', 'Var', (99, 108))	('men', 'Species', '9606', (144, 147))	('IDH1/2', 'Gene', '3417;3418', (92, 98))	('IDH1/2', 'Gene', (92, 98))
175354	29743610	The strongest association in this region was rs9841110, an intronic variant located upstream of dystroglycan 1 (DAG1) within an enhancer region.	('dystroglycan 1', 'Gene', (96, 110))	('rs9841110', 'Var', (45, 54))	('dystroglycan 1', 'Gene', '1605', (96, 110))	('DAG1', 'Gene', (112, 116))	('DAG1', 'Gene', '1605', (112, 116))	('rs9841110', 'Mutation', 'rs9841110', (45, 54))
175358	29743610	If increased lifetime estrogen exposure decreases glioma risk, as some have hypothesized, it is reasonable that variants which increase age at menarche (potentially decreasing total lifetime estrogen exposure) may increase glioma risk in females.	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('glioma', 'Disease', (50, 56))	('decreases glioma', 'Disease', (40, 56))	('increase', 'PosReg', (214, 222))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('increase', 'PosReg', (127, 135))	('decreases glioma', 'Disease', 'MESH:D005910', (40, 56))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('men', 'Species', '9606', (143, 146))	('glioma', 'Disease', (223, 229))	('variants', 'Var', (112, 120))
175360	29743610	As compared to a model containing age at diagnosis and sex alone, the three SNPs (rs55705857, rs9841110 and rs11979158) identified as having sex-specific effects explain an additional 1.4% of trait variance within the GICC set.	('rs55705857', 'Mutation', 'rs55705857', (82, 92))	('rs11979158', 'Mutation', 'rs11979158', (108, 118))	('rs55705857', 'Var', (82, 92))	('rs9841110', 'Var', (94, 103))	('rs11979158', 'Var', (108, 118))	('having sex', 'Phenotype', 'HP:0030214', (134, 144))	('rs9841110', 'Mutation', 'rs9841110', (94, 103))
175362	29743610	Unweighted risk scores (URS) were generated to compare the cumulative effects of glioma risk variants by sex by summing all risk alleles using the 10 SNPs found to be significantly associated with glioma in this analysis.	('associated', 'Reg', (181, 191))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('URS', 'Chemical', '-', (24, 27))	('variants', 'Var', (93, 101))	('glioma', 'Disease', (197, 203))	('glioma', 'Disease', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
175366	29743610	Development of risk scores that weight alleles by effect size, and use sex-specific estimates for variants for which effect size varies by sex (such as 7p11.2 and 8q24.21), may lead to better predictive values.	('men', 'Species', '9606', (7, 10))	('7p11.2', 'Var', (152, 158))	('8q24.21', 'Var', (163, 170))
175374	29743610	Males and females within histology groups have different frequencies of IDH1/2 mutation, which may have confounded the estimates for 8q24.21.	('IDH1/2', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('IDH1/2', 'Gene', '3417;3418', (72, 78))
175380	29743610	The array included 37,000 beadchips customized to include previously-identified glioma-specific candidate single nucleotide polymorphisms (SNPs).	('single nucleotide polymorphisms', 'Var', (106, 137))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Disease', (80, 86))
175381	29743610	GliomaScan cases were genotyped on the Illumina 660 W, while controls were selected from cohort studies and were genotyped on Illumina 370D, 550 K, 610Q, or 660 W (See Rajaraman et al.	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('550 K', 'Var', (141, 146))	('Glioma', 'Disease', (0, 6))
175389	29743610	An overall unweighted risk score (URS) was generated using the sum of risk alleles at rs12752552, rs9841110, rs10069690, rs11979158, rs55705857, rs634537, rs12803321, rs3751667, rs78378222, and rs2297440.	('rs12752552', 'Var', (86, 96))	('rs3751667', 'Mutation', 'rs3751667', (167, 176))	('rs12803321', 'Mutation', 'rs12803321', (155, 165))	('rs10069690', 'Var', (109, 119))	('rs11979158', 'Var', (121, 131))	('rs9841110', 'Mutation', 'rs9841110', (98, 107))	('rs3751667', 'Var', (167, 176))	('URS', 'Chemical', '-', (34, 37))	('rs78378222', 'Var', (178, 188))	('rs9841110', 'Var', (98, 107))	('rs55705857', 'Mutation', 'rs55705857', (133, 143))	('rs11979158', 'Mutation', 'rs11979158', (121, 131))	('rs2297440', 'Mutation', 'rs2297440', (194, 203))	('rs78378222', 'Mutation', 'rs78378222', (178, 188))	('rs12803321', 'Var', (155, 165))	('rs12752552', 'Mutation', 'rs12752552', (86, 96))	('rs10069690', 'Mutation', 'rs10069690', (109, 119))	('rs55705857', 'Var', (133, 143))	('rs2297440', 'Var', (194, 203))	('rs634537', 'Var', (145, 153))	('rs634537', 'Mutation', 'rs634537', (145, 153))
175390	29743610	GBM-specific URS (URS-G) was calculated by summing the number of risk alleles at rs9841110, rs10069690, rs11979158, rs634537, rs78378222, and rs2297440.	('rs2297440', 'Var', (142, 151))	('rs10069690', 'Mutation', 'rs10069690', (92, 102))	('rs10069690', 'Var', (92, 102))	('rs78378222', 'Var', (126, 136))	('rs78378222', 'Mutation', 'rs78378222', (126, 136))	('URS', 'Chemical', '-', (18, 21))	('rs11979158', 'Mutation', 'rs11979158', (104, 114))	('rs11979158', 'Var', (104, 114))	('rs9841110', 'Mutation', 'rs9841110', (81, 90))	('rs634537', 'Var', (116, 124))	('rs634537', 'Mutation', 'rs634537', (116, 124))	('URS', 'Chemical', '-', (13, 16))	('rs2297440', 'Mutation', 'rs2297440', (142, 151))	('rs9841110', 'Var', (81, 90))
175391	29743610	Non-GBM-specific (URS-N) specific URS was calculated by summing the number of risk alleles at rs10069690, rs55705857, rs634537, rs12803321, rs78378222, and rs2297440.	('URS', 'Chemical', '-', (34, 37))	('rs634537', 'Var', (118, 126))	('rs2297440', 'Mutation', 'rs2297440', (156, 165))	('rs78378222', 'Var', (140, 150))	('rs78378222', 'Mutation', 'rs78378222', (140, 150))	('rs2297440', 'Var', (156, 165))	('rs55705857', 'Mutation', 'rs55705857', (106, 116))	('URS', 'Chemical', '-', (18, 21))	('rs12803321', 'Mutation', 'rs12803321', (128, 138))	('rs634537', 'Mutation', 'rs634537', (118, 126))	('rs12803321', 'Var', (128, 138))	('rs55705857', 'Var', (106, 116))	('rs10069690', 'Mutation', 'rs10069690', (94, 104))	('rs10069690', 'Var', (94, 104))
175395	29743610	Proportion of variance in odds of glioma explained by sex-specific SNPs was calculated using R2 estimated using the log likelihood of the null model (sex, age at diagnosis, and the first two principal components only) and the full model (including identified SNPs, rs9841110, rs11979158, rs55705857), calculated as follows: Proportion of variance explained was also calculated separately by sex for each histology (null model adjusted for age at diagnosis, and the first two principal components only).	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('rs9841110', 'Mutation', 'rs9841110', (265, 274))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('rs55705857', 'Var', (288, 298))	('rs9841110', 'Var', (265, 274))	('rs11979158', 'Mutation', 'rs11979158', (276, 286))	('glioma', 'Disease', (34, 40))	('rs11979158', 'Var', (276, 286))	('rs55705857', 'Mutation', 'rs55705857', (288, 298))
175401	26810070	Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy.	('CNS tumors', 'Disease', 'MESH:D009369', (200, 210))	('MYB', 'Gene', '4602', (83, 86))	('MYB', 'Gene', (83, 86))	('CNS tumors', 'Disease', (200, 210))	('neuroepithelial tumors', 'Disease', (157, 179))	('children', 'Species', '9606', (225, 233))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('FGFR1', 'Gene', (72, 77))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (42, 64))	('mutations', 'Var', (87, 96))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (157, 179))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (42, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('epilepsy', 'Disease', 'MESH:D004827', (276, 284))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (157, 179))	('neuroepithelial tumors', 'Disease', (42, 64))	('FGFR1', 'Gene', '2260', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('epilepsy', 'Phenotype', 'HP:0001250', (276, 284))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (157, 178))	('BRAF', 'Gene', '673', (66, 70))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (42, 64))	('epilepsy', 'Disease', (276, 284))	('BRAF', 'Gene', (66, 70))
175405	26810070	Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82% of DNETs and 40% of d-OTs.	('FGFR1', 'Gene', '2260', (15, 20))	('DNET', 'Chemical', '-', (114, 118))	('Alterations', 'Var', (0, 11))	('occurred', 'Reg', (21, 29))	('d-OTs', 'Chemical', '-', (131, 136))	('FGFR1', 'Gene', (15, 20))
175407	26810070	A BRAF:p.V600E mutation was present in 35% of gangliogliomas and 18% of DAs.	('BRAF:p.V600E', 'Var', (2, 14))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (2, 14))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
175409	26810070	Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy.	('d-OTs', 'Chemical', '-', (11, 16))	('IDH1', 'Gene', (25, 29))	('occurred', 'Reg', (41, 49))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (25, 29))
175411	26810070	Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications.	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (95, 117))	('MYB', 'Gene', (31, 34))	('MYB', 'Gene', '4602', (31, 34))	('Alterations', 'Var', (0, 11))	('FGFR1', 'Gene', (21, 26))	('LGNTs', 'Disease', (78, 83))	('FGFR1', 'Gene', '2260', (21, 26))	('pilocytic astrocytomas', 'Disease', (95, 117))	('BRAF,', 'Gene', '673', (15, 20))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
175418	26810070	The NF1 gene product, neurofibromin 1, is a negative regulator of the MAPK pathway, and recurrent genetic alterations in other members of this pathway have been discovered in multiple types of LGNT.	('genetic', 'Var', (98, 105))	('MAPK pathway', 'Pathway', (70, 82))	('is a', 'Gene', (39, 43))	('is a', 'Gene', '312', (39, 43))	('discovered', 'Reg', (161, 171))
175426	26810070	Point mutations within FGFR1 and FGFR3 were sequenced using primer pairs listed in Supp.	('FGFR1', 'Gene', (23, 28))	('FGFR1', 'Gene', '2260', (23, 28))	('FGFR3', 'Gene', '2261', (33, 38))	('Point mutations', 'Var', (0, 15))	('FGFR3', 'Gene', (33, 38))
175436	26810070	Four cases were found to contain multiple driver abnormalities: LGNT57 contained mutations within FGFR1 and BRAF, and LGNT58 contained mutations within FGFR1, KRAS and NF1, and LGNT69 and LGNT63 contained both a MYB-QKI gene fusion and a BRAF:p.V600E mutation (Supp.	('FGFR1', 'Gene', (98, 103))	('MYB', 'Gene', (212, 215))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (238, 250))	('FGFR1', 'Gene', '2260', (98, 103))	('mutations', 'Var', (135, 144))	('BRAF,', 'Gene', '673', (108, 113))	('mutations', 'Var', (81, 90))	('FGFR1', 'Gene', (152, 157))	('MYB', 'Gene', '4602', (212, 215))	('BRAF:p.V600E', 'Var', (238, 250))	('FGFR1', 'Gene', '2260', (152, 157))
175437	26810070	These alterations were dominated by SNVs, SVs, or tyrosine kinase domain (TKD) duplications in FGFR1 (33% of tumors), SVs involving MYB (22%), and BRAF fusions or mutations (18%), mainly BRAF:p.V600E.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (187, 199))	('FGFR1', 'Gene', (95, 100))	('MYB', 'Gene', '4602', (132, 135))	('MYB', 'Gene', (132, 135))	('BRAF', 'Gene', '673', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('FGFR1', 'Gene', '2260', (95, 100))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('duplications', 'Var', (79, 91))	('BRAF:p.V600E', 'Var', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('BRAF', 'Gene', (187, 191))
175438	26810070	FGFR1 abnormalities were greatly enriched in LGNTs with an oligodendroglial phenotype - dysembryoplastic neuroepithelial tumors (DNETs) and the diffuse oligodendroglial tumors (d-OTs), while practically all MYB abnormalities were detected in angiocentric gliomas and diffuse astrocytomas, and BRAF alterations were most frequent among gangliogliomas.	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (105, 127))	('FGFR1', 'Gene', (0, 5))	('MYB abnormalities', 'Disease', 'MESH:D000014', (207, 224))	('gliomas', 'Phenotype', 'HP:0009733', (342, 349))	('BRAF', 'Gene', '673', (293, 297))	('BRAF', 'Gene', (293, 297))	('oligodendroglial', 'Disease', (59, 75))	('dysembryoplastic neuroepithelial tumors', 'Disease', (88, 127))	('oligodendroglial tumors', 'Disease', (152, 175))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (105, 126))	('MYB abnormalities', 'Disease', (207, 224))	('astrocytomas', 'Disease', (275, 287))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (242, 262))	('gliomas', 'Disease', (255, 262))	('angiocentric gliomas', 'Disease', (242, 262))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (152, 175))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('FGFR1', 'Gene', '2260', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('gliomas', 'Disease', (342, 349))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (88, 127))	('gliomas', 'Disease', 'MESH:D005910', (255, 262))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('d-OTs', 'Chemical', '-', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('DNET', 'Chemical', '-', (129, 133))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('astrocytomas', 'Disease', 'MESH:D001254', (275, 287))	('astrocytoma', 'Phenotype', 'HP:0009592', (275, 286))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('gliomas', 'Disease', 'MESH:D005910', (342, 349))	('gliomas', 'Phenotype', 'HP:0009733', (255, 262))	('abnormalities', 'Var', (6, 19))
175439	26810070	Genetic alterations were detected in 39/42 (93%) of LGNTs with an oligodendroglial phenotype - DNETs and d-OTs (Fig.	('Genetic alterations', 'Var', (0, 19))	('DNET', 'Chemical', '-', (95, 99))	('d-OTs', 'Chemical', '-', (105, 110))	('detected', 'Reg', (25, 33))
175440	26810070	FGFR1 alterations were detected in 26/42 (62%) and comprised SNVs, TKD duplications, and fusions.	('alterations', 'Var', (6, 17))	('SNVs', 'Disease', (61, 65))	('fusions', 'Var', (89, 96))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', (0, 5))
175441	26810070	Pathogenic FGFR1 SNVs, which were single or 'doublet' missense mutations in the TKD, occurred only in DNETs or d-OTs across the LGNT series.	('missense mutations', 'Var', (54, 72))	('Pathogenic', 'Reg', (0, 10))	('DNET', 'Chemical', '-', (102, 106))	('FGFR1', 'Gene', (11, 16))	('d-OTs', 'Chemical', '-', (111, 116))	('FGFR1', 'Gene', '2260', (11, 16))
175442	26810070	In LGNT34, two FGFR1 mutations (N544K & R659L) were identified on different alleles.	('N544K', 'Var', (32, 37))	('N544K', 'Mutation', 'rs779707422', (32, 37))	('FGFR1', 'Gene', '2260', (15, 20))	('LGNT34', 'Gene', (3, 9))	('R659L', 'Mutation', 'p.R659L', (40, 45))	('FGFR1', 'Gene', (15, 20))
175443	26810070	Most (14/17; 82%) FGFR1 TKD duplications were detected among DNETs or d-OTs; only two were in diffuse astrocytomas and one occurred in a ganglioglioma (Supp.	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('astrocytomas', 'Disease', 'MESH:D001254', (102, 114))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('FGFR1', 'Gene', (18, 23))	('astrocytomas', 'Disease', (102, 114))	('DNET', 'Chemical', '-', (61, 65))	('glioma', 'Disease', (144, 150))	('d-OTs', 'Chemical', '-', (70, 75))	('FGFR1', 'Gene', '2260', (18, 23))	('TKD', 'Var', (24, 27))
175444	26810070	Three of five FGFR1 fusions, all FGFR1-TACC1, were detected in DNETs or d-OTs; two others, one FGFR1-TACC1 and one FGFR3-TACC3, occurred in diffuse astrocytomas.	('TACC1', 'Gene', '6867', (39, 44))	('diffuse', 'Disease', (140, 147))	('DNET', 'Chemical', '-', (63, 67))	('occurred', 'Reg', (128, 136))	('FGFR1', 'Gene', (95, 100))	('TACC1', 'Gene', (101, 106))	('TACC1', 'Gene', '6867', (101, 106))	('TACC3', 'Gene', '10460', (121, 126))	('FGFR1', 'Gene', (14, 19))	('TACC3', 'Gene', (121, 126))	('FGFR3', 'Gene', (115, 120))	('astrocytomas', 'Disease', (148, 160))	('fusions', 'Var', (20, 27))	('FGFR1', 'Gene', '2260', (33, 38))	('FGFR3', 'Gene', '2261', (115, 120))	('TACC1', 'Gene', (39, 44))	('FGFR1', 'Gene', '2260', (95, 100))	('astrocytomas', 'Disease', 'MESH:D001254', (148, 160))	('FGFR1', 'Gene', '2260', (14, 19))	('astrocytoma', 'Phenotype', 'HP:0009592', (148, 159))	('d-OTs', 'Chemical', '-', (72, 77))	('FGFR1', 'Gene', (33, 38))
175445	26810070	Other pathogenic alterations occurred at low frequency in DNETs and d-OTs: two CNAs in FGFR2 (5%), two PDGFRA mutations (5%), one BRAF:p.V600E (2%), one BRAF:p.G503>GVLR (2%), one BRAF-RNF130 (2%), one NAV1-NTRK2 (2%), and one MYB-MAML2 (2%).	('MYB', 'Gene', '4602', (227, 230))	('BRAF', 'Gene', (153, 157))	('NTRK2', 'Gene', (207, 212))	('MYB', 'Gene', (227, 230))	('BRAF:p.V600E', 'Var', (130, 142))	('p.G503>GVLR', 'Var', (158, 169))	('BRAF', 'Gene', '673', (180, 184))	('FGFR2', 'Gene', (87, 92))	('BRAF', 'Gene', (180, 184))	('NTRK2', 'Gene', '4915', (207, 212))	('d-OTs', 'Chemical', '-', (68, 73))	('PDGFRA', 'Gene', (103, 109))	('FGFR2', 'Gene', '2263', (87, 92))	('PDGFRA', 'Gene', '5156', (103, 109))	('BRAF', 'Gene', '673', (130, 134))	('BRAF', 'Gene', (130, 134))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (130, 142))	('DNET', 'Chemical', '-', (58, 62))	('BRAF', 'Gene', '673', (153, 157))
175446	26810070	Four dOTs harbored an IDH1/2 mutation and other genetic alterations characteristic of 'adult-type' diffuse grade II oligodendrogliomas.	('mutation', 'Var', (29, 37))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('IDH1', 'Gene', (22, 26))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('II oligodendrogliomas', 'Disease', (113, 134))	('IDH1', 'Gene', '3417', (22, 26))	('II oligodendrogliomas', 'Disease', 'MESH:D009837', (113, 134))
175448	26810070	All FGFR1 SNVs occurred in DNETs, with one exception, an oligoastrocytoma that had an FGFR1:p.N544K mutation and concurrent NF1:p.T653fs and KRAS:p.G12D mutations.	('oligoastrocytoma', 'Disease', (57, 73))	('FGFR1', 'Gene', (4, 9))	('FGFR1:p.N544K', 'SUBSTITUTION', 'None', (86, 99))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('FGFR1:p.N544K', 'Var', (86, 99))	('KRAS:p.G12D', 'SUBSTITUTION', 'None', (141, 152))	('FGFR1', 'Gene', '2260', (4, 9))	('FGFR1', 'Gene', (86, 91))	('FGFR1', 'Gene', '2260', (86, 91))	('DNET', 'Chemical', '-', (27, 31))	('NF1:p.T653fs', 'FRAMESHIFT', 'None', (124, 136))	('NF1:p.T653fs', 'Var', (124, 136))	('KRAS:p.G12D', 'Var', (141, 152))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (57, 73))
175449	26810070	Tumors with an FGFR1 SNV presented at an older mean age, 14.2 years, than those with an FGFR1 TKD duplication, 7.4 years (p=0.0002), though this partly reflects a higher mean age at presentation among patients with DNET, 12.4 years, than those with d-OTs, 9.2 (p=0.036).	('patients', 'Species', '9606', (201, 209))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('d-OTs', 'Chemical', '-', (249, 254))	('FGFR1', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (15, 20))	('DNET', 'Chemical', '-', (215, 219))	('FGFR1', 'Gene', '2260', (88, 93))	('SNV', 'Var', (21, 24))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('FGFR1', 'Gene', (15, 20))
175456	26810070	Most MYB-QKI fusions (78%) were between MYB exon 15 and QKI exon 5.	('MYB', 'Gene', '4602', (40, 43))	('fusions', 'Var', (13, 20))	('MYB', 'Gene', (5, 8))	('MYB', 'Gene', '4602', (5, 8))	('MYB', 'Gene', (40, 43))
175457	26810070	Fusions were also identified between MYB exon 9 and QKI exon 5 (Supp.	('Fusions', 'Var', (0, 7))	('MYB', 'Gene', '4602', (37, 40))	('MYB', 'Gene', (37, 40))
175458	26810070	Two tumors with a MYB-QKI fusion also harbored a BRAF:p.V600E mutation (Supp.	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (49, 61))	('MYB', 'Gene', '4602', (18, 21))	('MYB', 'Gene', (18, 21))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('BRAF:p.V600E', 'Var', (49, 61))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
175460	26810070	MYB or MYBL1 rearrangements were detected in 7/17 tumors (41%), while BRAF or FGFR1/3 alterations were present in 4 tumors each (Fig.	('tumors', 'Disease', (116, 122))	('MYB', 'Gene', (0, 3))	('FGFR1', 'Gene', (78, 83))	('rearrangements', 'Var', (13, 27))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('FGFR1', 'Gene', '2260', (78, 83))	('MYB', 'Gene', '4602', (0, 3))	('detected', 'Reg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('MYB', 'Gene', '4602', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BRAF', 'Gene', '673', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('MYB', 'Gene', (7, 10))	('BRAF', 'Gene', (70, 74))
175461	26810070	One tumor had an H3F3A:p.K27M mutation, which we have reported before.	('tumor', 'Disease', (4, 9))	('H3F3A:p.K27M', 'SUBSTITUTION', 'None', (17, 29))	('H3F3A:p.K27M', 'Var', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
175462	26810070	Another tumor harbored only an ELAC2 duplication of uncertain significance, although variants in this gene have been implicated in susceptibility to hereditary prostatic cancer.	('hereditary prostatic cancer', 'Disease', (149, 176))	('prostatic cancer', 'Phenotype', 'HP:0012125', (160, 176))	('variants', 'Var', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('hereditary prostatic cancer', 'Disease', 'MESH:C537243', (149, 176))	('tumor', 'Disease', (8, 13))	('implicated', 'Reg', (117, 127))
175464	26810070	Among diffuse astrocytomas, there was no obvious difference in radiological characteristics, including anatomic site, or outcome between those tumors with MYB, those with MYBL1 alterations, and those with other genetic alterations (data not shown).	('MYB', 'Gene', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('MYB', 'Gene', '4602', (155, 158))	('MYB,', 'Gene', '4602', (155, 159))	('alterations', 'Var', (177, 188))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('astrocytomas', 'Disease', 'MESH:D001254', (14, 26))	('astrocytoma', 'Phenotype', 'HP:0009592', (14, 25))	('diffuse', 'Disease', (6, 13))	('MYB', 'Gene', '4602', (171, 174))	('astrocytomas', 'Disease', (14, 26))	('MYB', 'Gene', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
175466	26810070	Otherwise, abnormalities in gangliogliomas most frequently involved BRAF (9/17; 53%), specifically a BRAF:p.V600E mutation in 6/17 tumors (35%), and a MACF1-BRAF, AGK-BRAF, or GNAI1-BRAF fusion in each of three others (Fig.	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('gliomas', 'Disease', (35, 42))	('BRAF,', 'Gene', '673', (157, 162))	('BRAF', 'Gene', '673', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('BRAF', 'Gene', '673', (182, 186))	('BRAF', 'Gene', (157, 161))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', (182, 186))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', '673', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (101, 113))	('BRAF', 'Gene', (68, 72))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('tumors', 'Disease', (131, 137))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('involved', 'Reg', (59, 67))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('BRAF:p.V600E', 'Var', (101, 113))	('BRAF,', 'Gene', '673', (167, 172))
175467	26810070	All of these alterations are predicted to activate the downstream effects of BRAF in a constitutive manner.	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('activate', 'PosReg', (42, 50))	('alterations', 'Var', (13, 24))
175470	26810070	Hierarchical clustering analysis of the DNA methylation profiles of 71 LGNTs with FGFR1, MYB/MYBL1, BRAF, or IDH1/2 alterations segregated tumors primarily by genetic alteration (Fig.	('FGFR1', 'Gene', (82, 87))	('FGFR1', 'Gene', '2260', (82, 87))	('IDH1', 'Gene', (109, 113))	('BRAF,', 'Gene', '673', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('IDH1', 'Gene', '3417', (109, 113))	('tumors', 'Disease', (139, 145))	('MYB/MYBL1', 'Gene', (89, 98))	('alterations', 'Var', (116, 127))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
175472	26810070	Of six such tumors, two gangliogliomas segregated with most other gangliogliomas in a genetic group characterized mainly by BRAF alterations, while a DNET and oligodendroglioma were placed among tumors with FGFR1 alterations.	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('FGFR1', 'Gene', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('DNET', 'Chemical', '-', (150, 154))	('oligodendroglioma', 'Disease', 'MESH:D009837', (159, 176))	('alterations', 'Var', (129, 140))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('BRAF', 'Gene', '673', (124, 128))	('BRAF', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('gliomas', 'Disease', (73, 80))	('tumors', 'Disease', (195, 201))	('oligodendroglioma', 'Disease', (159, 176))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('gliomas', 'Disease', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('FGFR1', 'Gene', '2260', (207, 212))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
175473	26810070	Recurrent changes included 1p/19q codeletion among the four adult-type d-OTs, and gains of chromosomes 5, 7, and 12 were found among disparate LGNTs with a various genetic alterations.	('d-OTs', 'Chemical', '-', (71, 76))	('1p/19q codeletion', 'Var', (27, 44))	('gains', 'PosReg', (82, 87))
175478	26810070	Combinations of common genetic alterations did occur in a few tumors from the series, including an oligoastrocytoma with pathogenic FGFR1, KRAS, and NF1 mutations and two angiocentric gliomas with a MYB-QKI fusion and BRAF:p.V600E mutation.	('mutations', 'Var', (153, 162))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('NF1', 'Gene', (149, 152))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (99, 115))	('FGFR1', 'Gene', '2260', (132, 137))	('BRAF:p.V600E', 'Var', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('KRAS,', 'Gene', '3845', (139, 144))	('MYB', 'Gene', '4602', (199, 202))	('occur', 'Reg', (47, 52))	('oligoastrocytoma', 'Disease', (99, 115))	('MYB', 'Gene', (199, 202))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (171, 191))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('angiocentric gliomas', 'Disease', (171, 191))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('FGFR1', 'Gene', (132, 137))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (218, 230))
175479	26810070	Instead, FGFR1, MYB, and BRAF alterations dominated our series of LGNTs and showed clear alignment with tumor morphology.	('FGFR1', 'Gene', '2260', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MYB,', 'Gene', '4602', (16, 20))	('tumor', 'Disease', (104, 109))	('BRAF', 'Gene', '673', (25, 29))	('alterations', 'Var', (30, 41))	('BRAF', 'Gene', (25, 29))	('FGFR1', 'Gene', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
175480	26810070	LGNTs with an oligodendroglial phenotype and composed primarily of oligodendrocyte-like cells (OLCs) were characterized by recurrent FGFR1 alterations.	('alterations', 'Var', (139, 150))	('FGFR1', 'Gene', (133, 138))	('FGFR1', 'Gene', '2260', (133, 138))
175483	26810070	FGFR1 alterations in this axis of tumors encompassed TKD duplications, fusion genes, and mutations within the TKD, all of which have been reported before in diverse tumor types of varying malignancy, including LGGs, malignant melanoma, and glioblastoma, though FGFR1 amplification is a more common alteration in several types of carcinoma, including lung, breast, and bladder.	('carcinoma', 'Disease', (329, 338))	('alterations', 'Var', (6, 17))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('FGFR1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('malignancy', 'Disease', 'MESH:D009369', (188, 198))	('lung', 'Disease', (350, 354))	('LGGs', 'Disease', (210, 214))	('tumor', 'Disease', (34, 39))	('malignant melanoma', 'Phenotype', 'HP:0002861', (216, 234))	('malignant melanoma', 'Disease', 'MESH:D008545', (216, 234))	('is a', 'Gene', (281, 285))	('carcinoma', 'Disease', 'MESH:D002277', (329, 338))	('glioblastoma', 'Disease', 'MESH:D005909', (240, 252))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('FGFR1', 'Gene', (261, 266))	('is a', 'Gene', '312', (281, 285))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('bladder', 'Disease', (368, 375))	('malignancy', 'Disease', (188, 198))	('FGFR1', 'Gene', '2260', (0, 5))	('glioblastoma', 'Disease', (240, 252))	('glioblastoma', 'Phenotype', 'HP:0012174', (240, 252))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (165, 170))	('tumors', 'Disease', (34, 40))	('duplications', 'Var', (57, 69))	('is a', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('malignant melanoma', 'Disease', (216, 234))	('is a', 'Gene', '312', (23, 27))	('FGFR1', 'Gene', '2260', (261, 266))	('breast', 'Disease', (356, 362))
175484	26810070	Such alterations result in constitutively activated signaling pathways downstream of FGFR1.	('FGFR1', 'Gene', (85, 90))	('FGFR1', 'Gene', '2260', (85, 90))	('result in', 'Reg', (17, 26))	('alterations', 'Var', (5, 16))
175485	26810070	Published studies of genetic alterations in DNETs are limited, focusing on BRAF, rather then FGFR1.	('FGFR1', 'Gene', '2260', (93, 98))	('DNET', 'Chemical', '-', (44, 48))	('FGFR1', 'Gene', (93, 98))	('genetic alterations', 'Var', (21, 40))	('BRAF,', 'Gene', '673', (75, 80))	('DNETs', 'Gene', (44, 49))
175486	26810070	These find BRAF alterations at a higher frequency than in our dataset (Table 1).	('alterations', 'Var', (16, 27))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
175488	26810070	With the exception of a single oligoastrocytoma, FGFR1 SNVs occurred only in DNETs, and pathogenic FGFR1 alterations, including TKD duplications, dominated these tumors, occurring in 82%.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('DNET', 'Chemical', '-', (77, 81))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (31, 47))	('FGFR1', 'Gene', (99, 104))	('oligoastrocytoma', 'Disease', (31, 47))	('alterations', 'Var', (105, 116))	('FGFR1', 'Gene', '2260', (99, 104))	('tumors', 'Disease', (162, 168))	('FGFR1', 'Gene', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))	('TKD', 'Var', (128, 131))	('FGFR1', 'Gene', '2260', (49, 54))
175489	26810070	In contrast, d-OTs mainly harbored FGFR1 TKD duplications, rather than SNVs, and were more heterogeneous, with FGFR2, PDGFRA, BRAF, and single NTRK and MYB alterations.	('MYB', 'Gene', '4602', (152, 155))	('MYB', 'Gene', (152, 155))	('FGFR2', 'Gene', (111, 116))	('FGFR2', 'Gene', '2263', (111, 116))	('PDGFRA,', 'Gene', '5156', (118, 125))	('d-OTs', 'Chemical', '-', (13, 18))	('FGFR1', 'Gene', (35, 40))	('TKD duplications', 'Var', (41, 57))	('BRAF,', 'Gene', '673', (126, 131))	('FGFR1', 'Gene', '2260', (35, 40))
175490	26810070	These genetic alterations would be predicted to have similar effects on the MAPK and PI3K pathways as the recurrent FGFR1 alterations.	('PI3K pathways', 'Pathway', (85, 98))	('FGFR1', 'Gene', (116, 121))	('FGFR1', 'Gene', '2260', (116, 121))	('alterations', 'Var', (122, 133))	('effects', 'Reg', (61, 68))
175491	26810070	In 4/8 DNETs with FGFR1 SNVs, 'doublet' missense FGFR1 mutations were located 1-9 codons apart on the same allele (Fig.	('mutations', 'Var', (55, 64))	('FGFR1', 'Gene', (18, 23))	('DNET', 'Chemical', '-', (7, 11))	('FGFR1', 'Gene', '2260', (18, 23))	('FGFR1', 'Gene', (49, 54))	('missense', 'Var', (40, 48))	('FGFR1', 'Gene', '2260', (49, 54))
175492	26810070	Similar 'doublet' mutations have been recorded in other genes, such as KRAS in pilocytic astrocytoma or EGFR in lung carcinoma, but the mechanistic basis of any selective advantage that 'doublet' FGFR1 mutations might have is unknown.	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('EGFR', 'Gene', (104, 108))	('lung carcinoma', 'Disease', 'MESH:D008175', (112, 126))	('mutations', 'Var', (202, 211))	('advantage', 'PosReg', (171, 180))	('lung carcinoma', 'Disease', (112, 126))	('FGFR1', 'Gene', (196, 201))	('pilocytic astrocytoma', 'Disease', (79, 100))	('FGFR1', 'Gene', '2260', (196, 201))	("'doublet'", 'PosReg', (186, 195))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (79, 100))	('mutations', 'Var', (18, 27))
175497	26810070	In contrast, the histologically related DAs appear more heterogeneous; some tumors harbor MYB or MYBL1 fusions or CNAs, while others show mutations or SVs of BRAF or TKD duplication or SVs of FGFR1.	('fusions', 'Var', (103, 110))	('MYB', 'Gene', '4602', (90, 93))	('MYB', 'Gene', '4602', (97, 100))	('MYB', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('MYB', 'Gene', (97, 100))	('FGFR1', 'Gene', (192, 197))	('BRAF', 'Gene', '673', (158, 162))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('FGFR1', 'Gene', '2260', (192, 197))	('BRAF', 'Gene', (158, 162))	('TKD duplication', 'Var', (166, 181))	('mutations', 'Var', (138, 147))
175500	26810070	MYB duplications and balanced reciprocal t(6;7)(q23;q34) translocations between the regulatory sequence for the T-cell receptor-beta gene and MYB have been demonstrated in some patients with T-ALL, and high-level amplifications have been found in one third of hereditary (BRAC1) breast cancers.	('MYB', 'Gene', (0, 3))	('MYB', 'Gene', (142, 145))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('receptor-beta gene and MYB', 'Gene', '4602', (119, 145))	('translocations', 'Var', (57, 71))	('hereditary', 'Disease', (260, 270))	('duplications', 'Var', (4, 16))	('breast cancers', 'Disease', 'MESH:D001943', (279, 293))	('t(6;7)(q23;q34)', 'STRUCTURAL_ABNORMALITY', 'None', (41, 56))	('breast cancers', 'Disease', (279, 293))	('breast cancers', 'Phenotype', 'HP:0003002', (279, 293))	('breast cancer', 'Phenotype', 'HP:0003002', (279, 292))	('MYB', 'Gene', '4602', (0, 3))	('MYB', 'Gene', '4602', (142, 145))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))
175502	26810070	The rearrangement removes the final exon and 3'UTR of MYB.	('rearrangement', 'Var', (4, 17))	('final exon', 'MPA', (30, 40))	("3'UTR", 'MPA', (45, 50))	('MYB', 'Gene', '4602', (54, 57))	('removes', 'NegReg', (18, 25))	('MYB', 'Gene', (54, 57))
175504	26810070	MYB-QKI rearrangements in AGs that fuse exon 15 of MYB with exon 5 of QKI also remove this 3'UTR regulatory site, while the fusion between MYB exon 9 and QKI exon 5 in LGNT62 and LGNT71 also removes the entire inhibitory C-terminal domain of MYB (Supp.	('MYB', 'Gene', (0, 3))	('MYB', 'Gene', '4602', (51, 54))	('MYB', 'Gene', (51, 54))	('MYB', 'Gene', '4602', (242, 245))	('MYB', 'Gene', '4602', (139, 142))	('MYB', 'Gene', (242, 245))	('MYB', 'Gene', '4602', (0, 3))	('removes', 'NegReg', (191, 198))	('MYB', 'Gene', (139, 142))	('inhibitory C-terminal domain', 'MPA', (210, 238))	('fusion', 'Var', (124, 130))	('remove', 'NegReg', (79, 85))	('rearrangements', 'Var', (8, 22))	("3'UTR regulatory site", 'MPA', (91, 112))
175505	26810070	Other mechanisms that increase expression of MYB, which we have previously demonstrated at the protein level in AGs and diffuse LGGs, are amplification and fusions with other gene partners.	('AGs', 'Disease', (112, 115))	('fusions', 'Var', (156, 163))	('increase', 'PosReg', (22, 30))	('expression', 'MPA', (31, 41))	('MYB,', 'Gene', '4602', (45, 49))
175510	26810070	However, our data demonstrate that angiocentric gliomas harbor alterations that are found in pediatric-type low-grade astrocytomas, rather than ependymomas.	('alterations', 'Var', (63, 74))	('ependymomas', 'Disease', (144, 155))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (35, 55))	('astrocytomas', 'Disease', 'MESH:D001254', (118, 130))	('angiocentric gliomas', 'Disease', (35, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('astrocytomas', 'Disease', (118, 130))	('ependymomas', 'Disease', 'MESH:D004806', (144, 155))
175511	26810070	Most pediatric supratentorial ependymomas harbor a characteristic C11orf95-RELA fusion, but this SV was not found in any angiocentric glioma from the present series.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('C11orf95-RELA', 'Var', (66, 79))	('ependymomas', 'Disease', (30, 41))	('angiocentric glioma', 'Disease', (121, 140))	('angiocentric glioma', 'Disease', 'MESH:D005910', (121, 140))	('ependymomas', 'Disease', 'MESH:D004806', (30, 41))
175513	26810070	Both of these tumors, which were not included among LGNTs in the present series, demonstrated an iFISH profile consistent with the presence of a C11orf95-RELA fusion, but no alteration in MYB or QKI.	('C11orf95-RELA', 'Var', (145, 158))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('MYB', 'Gene', '4602', (188, 191))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('iFISH', 'MPA', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('MYB', 'Gene', (188, 191))
175516	26810070	Alterations in BRAF are recognized as the most frequent genetic alteration in gangliogliomas, particularly BRAF:p.V600E mutation, which has been reported in up to 50% of these tumors.	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (107, 119))	('BRAF', 'Gene', (15, 19))	('Alterations', 'Var', (0, 11))	('gliomas', 'Disease', (85, 92))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('BRAF:p.V600E', 'Var', (107, 119))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('BRAF', 'Gene', '673', (107, 111))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
175517	26810070	In the present series, 53% of gangliogliomas harbored BRAF alterations, both BRAF:p.V600E mutation and fusions.	('fusions', 'Var', (103, 110))	('BRAF:p.V600E', 'Var', (77, 89))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (77, 89))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
175519	26810070	A novel SLMAP-NTRK2 gene fusion was identified by RNAseq in one parietal ganglioglioma (Supp.	('SLMAP-NTRK2', 'Gene', (8, 19))	('fusion', 'Var', (25, 31))	('parietal ganglioglioma', 'Disease', (64, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('parietal ganglioglioma', 'Disease', 'MESH:D018303', (64, 86))
175521	26810070	QKI-NTRK2 and NACC2-NTRK2 fusions have previously been reported in pilocytic astrocytoma, in pediatric high-grade glioma and adult glioblastoma.	('pilocytic astrocytoma', 'Disease', (67, 88))	('NACC2', 'Gene', '138151', (14, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('glioma', 'Disease', (114, 120))	('fusions', 'Var', (26, 33))	('reported', 'Reg', (55, 63))	('NTRK2', 'Gene', (4, 9))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (67, 88))	('NTRK2', 'Gene', '4915', (4, 9))	('NTRK2', 'Gene', (20, 25))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (77, 88))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('NTRK2', 'Gene', '4915', (20, 25))	('NACC2', 'Gene', (14, 19))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
175526	26810070	Rearrangement of EWSR1 is found in intracranial Ewing sarcomas that involve the inner table of the skull and extraosseous meningeal 'peripheral' primitive neuroectodermal tumors.	('Rearrangement', 'Var', (0, 13))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (145, 177))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (155, 177))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (48, 62))	('intracranial Ewing sarcomas', 'Disease', 'MESH:C563168', (35, 62))	('neuroectodermal tumors', 'Disease', (155, 177))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (155, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('EWSR1', 'Gene', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('intracranial Ewing sarcomas', 'Disease', (35, 62))
175527	26810070	Additionally, exceptional examples of other intracranial neoplasms with an EWSR1 rearrangement and variable malignancy have been reported.	('intracranial neoplasms', 'Disease', 'MESH:D001932', (44, 66))	('neoplasms', 'Phenotype', 'HP:0002664', (57, 66))	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy', 'Disease', (108, 118))	('EWSR1', 'Gene', (75, 80))	('intracranial neoplasms', 'Disease', (44, 66))	('rearrangement', 'Var', (81, 94))
175529	26810070	Platelet-derived growth factor receptor alpha (PDGFRA) amplification and mutations have previously been reported in pediatric high-grade glioma and adult glioblastoma.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioblastoma', 'Disease', (154, 166))	('reported', 'Reg', (104, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('growth factor receptor alpha (PDGFRA)', 'Gene', '5156', (17, 54))	('glioma', 'Disease', (137, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('growth factor receptor alpha (PDGFRA', 'Gene', (17, 53))	('mutations', 'Var', (73, 82))
175530	26810070	Dinucleotide PDGFRA somatic mutations were identified in 2 LGNTs; 1 DNET (LGNT42) and 1 oligoastrocytoma (LGNT92) (Supp.	('PDGFRA', 'Gene', '5156', (13, 19))	('oligoastrocytoma', 'Disease', (88, 104))	('PDGFRA', 'Gene', (13, 19))	('Dinucleotide', 'Chemical', 'MESH:D015226', (0, 12))	('Dinucleotide', 'Var', (0, 12))	('DNET', 'Chemical', '-', (68, 72))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('mutations', 'Var', (28, 37))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (88, 104))
175532	26810070	These changes introduced K385L and K385I mutations in LGNT42 and LGNT92, respectively.	('K385L', 'Mutation', 'p.K385L', (25, 30))	('LGNT42', 'Gene', (54, 60))	('LGNT92', 'Gene', (65, 71))	('K385L', 'Var', (25, 30))	('K385I', 'Var', (35, 40))	('K385I', 'Mutation', 'rs1383333777', (35, 40))
175533	26810070	Notably, both mutations changed K385 from a basic amino acid to a hydrophobic amino acid.	('changed', 'Reg', (24, 31))	('basic amino acid', 'Chemical', 'MESH:D024361', (44, 60))	('K385', 'Var', (32, 36))	('K385', 'Chemical', '-', (32, 36))
175534	26810070	A dinucleotide PDGFRA mutation at K385 (AG>TA) introducing K385I has previously been reported in one pediatric high-grade glioma.	('reported', 'Reg', (85, 93))	('K385 (AG>TA)', 'Mutation', 'c.385K,AG>TA', (34, 46))	('K385I', 'Var', (59, 64))	('glioma', 'Disease', (122, 128))	('K385I', 'Mutation', 'rs1383333777', (59, 64))	('PDGFRA', 'Gene', '5156', (15, 21))	('PDGFRA', 'Gene', (15, 21))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
175535	26810070	Additional PDGFRA K385M mutations have also been reported in one adult LGG and one adult HGG.	('PDGFRA', 'Gene', (11, 17))	('reported', 'Reg', (49, 57))	('PDGFRA', 'Gene', '5156', (11, 17))	('K385M', 'Mutation', 'p.K385M', (18, 23))	('K385M', 'Var', (18, 23))
175536	26810070	BRAF:p.V600E mutation was the most prevalent SNV (12/91) identified in the cohort, followed by SNVs in FGFR1 (9/91) and IDH1 (3/91).	('BRAF:p.V600E', 'Var', (0, 12))	('IDH1', 'Gene', (120, 124))	('FGFR1', 'Gene', (103, 108))	('IDH1', 'Gene', '3417', (120, 124))	('FGFR1', 'Gene', '2260', (103, 108))	('BRAF:p.V600E', 'SUBSTITUTION', 'None', (0, 12))
175538	26810070	Adult-type disease demonstrates a high frequency of IDH1/2 mutation, while recurrent genetic alterations in MYB, BRAF, or FGFR1 have been found in small series of pediatric tumors.	('IDH1', 'Gene', '3417', (52, 56))	('pediatric tumors', 'Disease', (163, 179))	('FGFR1', 'Gene', (122, 127))	('FGFR1', 'Gene', '2260', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutation', 'Var', (59, 67))	('Adult-type disease', 'Disease', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('MYB,', 'Gene', '4602', (108, 112))	('IDH1', 'Gene', (52, 56))	('pediatric tumors', 'Disease', 'MESH:D063766', (163, 179))	('BRAF,', 'Gene', '673', (113, 118))
175614	26464129	Height <-2SDS was more prevalent at last follow-up (21.4%) vs. at completion of GnRHa (2.4%; p=0.02) or onset of puberty (2.4%; p=0.005) (Appendix Table A3).	('onset of puberty', 'Phenotype', 'HP:0000826', (104, 120))	('GnRH', 'Gene', (80, 84))	('Height <-2SDS', 'Var', (0, 13))	('SDS', 'Chemical', 'MESH:D012967', (10, 13))	('GnRH', 'Gene', '2796', (80, 84))
175629	26464129	Final height was not significantly different in patients with CPP and HPA low-grade glioma (-0.8+- 1.5) compared to those with the same tumor diagnosis but without CPP (-1.0+- 1.8; p=0.62).	('glioma', 'Disease', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('HPA', 'Var', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('CPP', 'Var', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Disease', (136, 141))
175712	24384239	Alternatively, surgery may damage the normal surrounding tissue and cause (mainly transient) neurological and cognitive deficits, thereby decreasing HRQoL.	('cognitive deficits', 'Disease', (110, 128))	('damage', 'Reg', (27, 33))	('HRQoL', 'MPA', (149, 154))	('cause', 'Reg', (68, 73))	('cognitive deficits', 'Disease', 'MESH:D003072', (110, 128))	('surgery', 'Var', (15, 22))	('cognitive deficits', 'Phenotype', 'HP:0100543', (110, 128))	('decreasing', 'NegReg', (138, 148))
175729	24384239	Long-term follow-up (12 years) of these LGG patients indicated that patients who underwent radiotherapy had significantly worse cognitive functioning compared with patients who did not.	('worse', 'NegReg', (122, 127))	('radiotherapy', 'Var', (91, 103))	('patients', 'Species', '9606', (44, 52))	('worse cognitive functioning', 'Phenotype', 'HP:0001268', (122, 149))	('cognitive functioning', 'CPA', (128, 149))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (164, 172))
175757	24384239	AEDs are intended to reduce the seizure frequency, which should improve HRQoL.	('improve', 'PosReg', (64, 71))	('AEDs', 'Var', (0, 4))	('seizure', 'Phenotype', 'HP:0001250', (32, 39))	('reduce', 'NegReg', (21, 27))	('seizure', 'Disease', 'MESH:D012640', (32, 39))	('seizure', 'Disease', (32, 39))
175815	28540130	noted hyperintense lesions on FLAIR sequences that correlated with increased accumulations of CA with hippocampal atrophy.	('hippocampal atrophy', 'Disease', (102, 121))	('increased', 'PosReg', (67, 76))	('hippocampal atrophy', 'Disease', 'MESH:D001284', (102, 121))	('hyperintense lesions', 'Var', (6, 26))	('hippocampal atrophy', 'Phenotype', 'HP:0410170', (102, 121))
175830	25304720	The HRQoL of pediatric brain tumor survivors treated with PRT compare favorably to those treated with XRT and similar to healthy controls in the PhSD.	('PRT', 'Var', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('pediatric brain tumor', 'Disease', (13, 34))	('brain tumor', 'Phenotype', 'HP:0030692', (23, 34))	('pediatric brain tumor', 'Disease', 'MESH:D001932', (13, 34))	('SD', 'Disease', 'MESH:D029461', (147, 149))
175857	25304720	There were statistically significant differences in the total core score of the children treated for M/PNET, E/HGG, and LGG, favoring the proton cohorts.	('M/PNET', 'Var', (101, 107))	('children', 'Species', '9606', (80, 88))	('E/HGG', 'Var', (109, 114))	('core score', 'MPA', (62, 72))
175869	25304720	Children with a diagnosis of M/PNET, E/HGG, or LGG, and treated with protons scored higher in overall core measures and in many of the sub-domains than children in the photon cohort.	('Children', 'Species', '9606', (0, 8))	('M/PNET', 'Var', (29, 35))	('children', 'Species', '9606', (152, 160))	('core measures', 'MPA', (102, 115))	('higher', 'PosReg', (84, 90))	('E/HGG', 'Var', (37, 42))
175996	33562253	Since we found a significantly lower median overall survival in low-grade glioma patients with high (63 months) vs. low/intermediate (131 months) heme biosynthesis mRNA expression signature, this important information might support the selection of low-grade glioma patients requiring early initiation of postoperative adjuvant treatment.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('patients', 'Species', '9606', (266, 274))	('glioma', 'Disease', (259, 265))	('high', 'Var', (95, 99))	('patients', 'Species', '9606', (81, 89))	('heme biosynthesis mRNA expression signature', 'MPA', (146, 189))	('overall survival', 'MPA', (44, 60))	('lower', 'NegReg', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (259, 265))	('glioma', 'Disease', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('heme', 'Chemical', 'MESH:D006418', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
176002	33562253	Nowadays, molecular markers are increasingly applied for further characterization of gliomas aside from the WHO tumor grades.3 Consequently, we plan to correlate the heme biosynthesis mRNA expression signature with specific molecular markers such isocitrate dehydrogenase (IDH) mutations, 1p/19q co-deletion and p53 mutation in the next step.	('mutations', 'Var', (278, 287))	('heme', 'Chemical', 'MESH:D006418', (166, 170))	('p53', 'Gene', '7157', (312, 315))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('isocitrate dehydrogenase', 'Gene', (247, 271))	('gliomas', 'Disease', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('isocitrate dehydrogenase', 'Gene', '3417', (247, 271))	('IDH', 'Gene', (273, 276))	('1p/19q co-deletion', 'Var', (289, 307))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (312, 315))	('mutation', 'Var', (316, 324))	('IDH', 'Gene', '3417', (273, 276))
176084	33604380	In particular, evaluation of the mutations in immune cells is capable of predicting the outcome of patients with cancerous tumors.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous tumors', 'Disease', 'MESH:D009369', (113, 129))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (99, 107))	('cancerous tumors', 'Disease', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
176094	33604380	We discovered that the related immune cell infiltration signatures were differently expressed between low and high CDCA3 expression groups.	('CDCA3', 'Gene', (115, 120))	('high', 'Var', (110, 114))	('CDCA3', 'Gene', '83461', (115, 120))
176095	33604380	We also found that the higher proportion of CD8+ T cells, CD4+ T cells, and B cells appeared in the high CDCA3 expression group.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD4', 'Gene', '920', (58, 61))	('CDCA3', 'Gene', '83461', (105, 110))	('high', 'Var', (100, 104))	('CDCA3', 'Gene', (105, 110))	('CD4', 'Gene', (58, 61))
176096	33604380	Our data suggested that the high CDCA3 expression promoted the infiltration of T cells and exhausted these cells, and the patients with high CDCA3 expression might have poorer outcomes by analyzing the information of HCC patients obtained from The Cancer Genome Atlas (TCGA) database.	('CDCA3', 'Gene', '83461', (141, 146))	('patients', 'Species', '9606', (221, 229))	('promoted', 'PosReg', (50, 58))	('CDCA3', 'Gene', (141, 146))	('expression', 'Var', (39, 49))	('CDCA3', 'Gene', '83461', (33, 38))	('CDCA3', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Disease', (248, 254))	('high', 'Var', (28, 32))	('Cancer', 'Disease', 'MESH:D009369', (248, 254))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('infiltration of T cells', 'CPA', (63, 86))
176106	33604380	Significance of HR referred to the ratio of risk rate produced by high CDCA3 expression to the risk rate produced by low CDCA3 expression, on the premise that p < 0.05.	('expression', 'MPA', (77, 87))	('CDCA3', 'Gene', (121, 126))	('CDCA3', 'Gene', '83461', (71, 76))	('CDCA3', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('CDCA3', 'Gene', '83461', (121, 126))
176107	33604380	The higher the HR value, the bigger the ratio of risk rate produced by high CDCA3 expression on survival.	('CDCA3', 'Gene', '83461', (76, 81))	('expression', 'MPA', (82, 92))	('high', 'Var', (71, 75))	('CDCA3', 'Gene', (76, 81))	('HR value', 'MPA', (15, 23))
176118	33604380	Here, we established a standard to describe the association between CDCA3 expression and gene markers of infiltrating immune cells, where 0.00-0.29 was considered weak, 0.30-0.59 was considered moderate, 0.60-0.79 was considered strong, and 0.80-1.00 was considered very strong expression.	('CDCA3', 'Gene', '83461', (68, 73))	('0.30-0.59', 'Var', (169, 178))	('association', 'Interaction', (48, 59))	('CDCA3', 'Gene', (68, 73))
176124	33604380	Here, logrank p < 0.05 was statistically significant, and significance of HR referred to the ratio of risk rate produced by the application of high expression of CDCA3 to the risk rate produced by low expression of CDCA3.	('CDCA3', 'Gene', '83461', (162, 167))	('high expression', 'Var', (143, 158))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (215, 220))	('CDCA3', 'Gene', '83461', (215, 220))
176146	33604380	As revealed by PPS (HR = 0.67, 95%CI = 0.54-0.84, p = 0.00038) (Figure 2(j)), the high CDCA3 expression was associated with the better prognosis in gastric cancer because the HR < 1 and p < 0.05.	('PPS', 'Chemical', '-', (15, 18))	('gastric cancer', 'Disease', (148, 162))	('CDCA3', 'Gene', (87, 92))	('high', 'Var', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CDCA3', 'Gene', '83461', (87, 92))
176149	33604380	These results indicated that a high expression of CDCA3 had a strong association with poor outcomes for patients with various cancers, especially in HCC, and the correlation depended on the type of tumor.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('CDCA3', 'Gene', '83461', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancers', 'Disease', (126, 133))	('CDCA3', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('high', 'Var', (31, 35))	('tumor', 'Disease', (198, 203))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (36, 46))	('HCC', 'Disease', (149, 152))
176156	33604380	p < 0.05 was statistically significant, and the hazard ratio > 1 represented the higher risk factors produced by high CDCA3 expression affected in the prognosis of patients with different clinicopathologic features.	('high', 'Var', (113, 117))	('CDCA3', 'Gene', '83461', (118, 123))	('CDCA3', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('patients', 'Species', '9606', (164, 172))	('affected', 'Reg', (135, 143))
176160	33604380	It was remarkable that the hazard ratio (HR) of CDCA3 expression in univariate analysis equaled to 2.075, the value of HR and the p < 0.001 both indicated that CDCA3 can predict the prognosis in HCC, and the hazard ratio revealed that the patients with high CDCA3 expression had 2.075 times of higher risk in poor OS than the patients with low CDCA3 expression in univariate analysis.	('CDCA3', 'Gene', (258, 263))	('high', 'Var', (253, 257))	('CDCA3', 'Gene', (48, 53))	('CDCA3', 'Gene', '83461', (344, 349))	('poor OS', 'Disease', (309, 316))	('CDCA3', 'Gene', (344, 349))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (326, 334))	('CDCA3', 'Gene', '83461', (160, 165))	('CDCA3', 'Gene', (160, 165))	('HCC', 'Disease', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('expression', 'Var', (264, 274))	('CDCA3', 'Gene', '83461', (258, 263))	('CDCA3', 'Gene', '83461', (48, 53))
176162	33604380	The results showed that high expression of CDCA3 was associated with poor outcomes in HCC patients, and it could act as a potential independent predictor of survival (HR = 2.037; 95%CI = 1.484-2.796; p < 0.001; Figure 3(d)) by excluding confounding factors.	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('high', 'Var', (24, 28))	('HCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
176163	33604380	Besides, the value of the hazard ratio revealed that the patients with high CDCA3 expression had 2.037 times of higher risk in poor OS than the patients with low CDCA3 expression.	('poor OS', 'Disease', (127, 134))	('CDCA3', 'Gene', '83461', (162, 167))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (76, 81))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))
176170	33604380	The results showed that high expression of CDCA3 was associated with poor prognosis of patients, high levels of infiltrating immune cells, and tumor purity in HCC and ACC.	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (87, 95))	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'MPA', (29, 39))	('HCC', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
176173	33604380	The high CDCA3 expression was also correlated with a poorer survival (OS: HR = 2.5, p = 6.4E - 07; DFS: HR = 1.8, p = 0.00026) (Figure S1 ac-ad) but was positively related to the infiltrating levels of B cells (partial cor = 0.252, p = 2.42E - 08), CD4+ T cells (partial cor = 0.222, p = 1.01E - 06), macrophages (partial cor = 0.207, p = 5.93E - 06), neutrophils (partial cor = 0.174, p = 1.35E - 04), and dendritic cells (partial cor = 0.229, p = 4.54E - 07) in LGG (Figure S2 s).	('CDCA3', 'Gene', '83461', (9, 14))	('CDCA3', 'Gene', (9, 14))	('related', 'Reg', (164, 171))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('CD4', 'Gene', (249, 252))	('CD4', 'Gene', '920', (249, 252))
176201	33604380	According to the univariate and multivariate analyses, we identified that T stage, M stage, and CDCA3 expression had significant prognostic values for predicting the survival of patients with HCC; in fact, the high expression determined poor OS of patients with HCC and suggested that increased CDCA3 expression deteriorated the state of patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (262, 265))	('HCC', 'Disease', (352, 355))	('CDCA3', 'Gene', (96, 101))	('increased', 'PosReg', (285, 294))	('HCC', 'Phenotype', 'HP:0001402', (352, 355))	('patients', 'Species', '9606', (178, 186))	('determined', 'Reg', (226, 236))	('HCC', 'Phenotype', 'HP:0001402', (192, 195))	('high', 'Var', (210, 214))	('CDCA3', 'Gene', '83461', (295, 300))	('patients', 'Species', '9606', (338, 346))	('patients', 'Species', '9606', (248, 256))	('HCC', 'Disease', (262, 265))	('CDCA3', 'Gene', (295, 300))	('CDCA3', 'Gene', '83461', (96, 101))
176205	33604380	Thus, CDCA3 expression can potentially influence the immunosuppressive effect in HCC.	('influence', 'Reg', (39, 48))	('HCC', 'Disease', (81, 84))	('expression', 'Var', (12, 22))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('immunosuppressive', 'MPA', (53, 70))	('CDCA3', 'Gene', '83461', (6, 11))	('CDCA3', 'Gene', (6, 11))
176216	33604380	According to the results of the univariate and multivariate analyses, T stage, M stage, and CDCA3 expression were important prognostic factors for the survival of patients with HCC; importantly, high CDCA3 expression had the potential to be an independent predictor for poor outcome for patients with HCC according to the results of multivariate analyses.	('patients', 'Species', '9606', (163, 171))	('HCC', 'Disease', (301, 304))	('CDCA3', 'Gene', '83461', (200, 205))	('expression', 'MPA', (206, 216))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('HCC', 'Phenotype', 'HP:0001402', (301, 304))	('patients', 'Species', '9606', (287, 295))	('CDCA3', 'Gene', (200, 205))	('CDCA3', 'Gene', '83461', (92, 97))	('high', 'Var', (195, 199))	('CDCA3', 'Gene', (92, 97))
176232	31450822	Additionally, the concordance of low ALDOC and high non-mutated IDH1 expressions predicted a stronger poor prognosis in glioblastoma patients compared to each of above tests presented alone.	('low', 'NegReg', (33, 36))	('ALDOC', 'Gene', '230', (37, 42))	('high', 'Var', (47, 51))	('glioblastoma', 'Disease', (120, 132))	('IDH1', 'Gene', (64, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('patients', 'Species', '9606', (133, 141))	('IDH1', 'Gene', '3417', (64, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('ALDOC', 'Gene', (37, 42))
176234	31450822	Our results support high ALDOC expression in glioblastomas that might imply the mutated status of IDH1, less possibility of mesenchymal subtype, and predict a favorable prognosis.	('imply', 'Reg', (70, 75))	('ALDOC', 'Gene', (25, 30))	('glioblastomas', 'Phenotype', 'HP:0012174', (45, 58))	('mutated', 'Var', (80, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('high', 'Var', (20, 24))	('IDH1', 'Gene', (98, 102))	('glioblastomas', 'Disease', 'MESH:D005909', (45, 58))	('ALDOC', 'Gene', '230', (25, 30))	('IDH1', 'Gene', '3417', (98, 102))	('glioblastomas', 'Disease', (45, 58))
176264	31450822	We collected information of survival time, MGMT methylated status, CIMP status, and IDH1 mutant status from TCGA glioblastoma cohort (Figure 1A).	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('glioblastoma cohort', 'Disease', (113, 132))	('IDH1', 'Gene', (84, 88))	('MGMT', 'Gene', '4255', (43, 47))	('IDH1', 'Gene', '3417', (84, 88))	('glioblastoma cohort', 'Disease', 'MESH:D005909', (113, 132))	('MGMT', 'Gene', (43, 47))	('mutant', 'Var', (89, 95))
176271	31450822	We further validated high ALDOC expression in IDH1 R132 mutant form compared with wild-type (p = 0.0279, Figure 1D).	('ALDOC', 'Gene', (26, 31))	('IDH1', 'Gene', (46, 50))	('mutant', 'Var', (56, 62))	('ALDOC', 'Gene', '230', (26, 31))	('IDH1', 'Gene', '3417', (46, 50))	('high', 'PosReg', (21, 25))
176272	31450822	Besides, ALDOC showed an inversed trend of mutation status of IDH1 in glioblastomas (Spearmen rho = ~0.169, p = 0.001, Figure 1E).	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastomas', 'Disease', (70, 83))	('IDH1', 'Gene', '3417', (62, 66))	('mutation status', 'Var', (43, 58))	('ALDOC', 'Gene', (9, 14))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('IDH1', 'Gene', (62, 66))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))	('ALDOC', 'Gene', '230', (9, 14))
176274	31450822	Similar to ALDOC in glioblastomas, our results showed a significantly inverse correlation between ALDOC and IDH1 mutation status in TCGA glioma cohort (TCGA_GBMLGG, n = 1119, Figure 2A).	('glioma cohort', 'Disease', 'MESH:D005910', (137, 150))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('ALDOC', 'Gene', (98, 103))	('mutation', 'Var', (113, 121))	('IDH1', 'Gene', '3417', (108, 112))	('ALDOC', 'Gene', '230', (98, 103))	('GBM', 'Disease', 'MESH:D005909', (157, 160))	('glioma cohort', 'Disease', (137, 150))	('GBM', 'Phenotype', 'HP:0012174', (157, 160))	('glioblastomas', 'Phenotype', 'HP:0012174', (20, 33))	('ALDOC', 'Gene', (11, 16))	('glioblastomas', 'Disease', 'MESH:D005909', (20, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('inverse', 'NegReg', (70, 77))	('ALDOC', 'Gene', '230', (11, 16))	('glioblastomas', 'Disease', (20, 33))	('GBM', 'Disease', (157, 160))	('IDH1', 'Gene', (108, 112))
176276	31450822	The results showed higher ALDOC mRNA level significantly in gain of chromosome 7, combined with loss of chromosome 10 group or chromosome 1p/19q co-deletion group (p < 0.0001, p < 0.0001, respectively) (Figure 2B).	('ALDOC', 'Gene', (26, 31))	('higher', 'PosReg', (19, 25))	('ALDOC', 'Gene', '230', (26, 31))	('gain', 'PosReg', (60, 64))	('chromosome 7', 'Var', (68, 80))
176293	31450822	From the heat map and boxplot, ALDOC expression in IDH1 mutant patients (n = 10) is higher than the IDH1 wild-type group (n = 29) (p = 0.0384, Figure 4A,B).	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', '3417', (100, 104))	('mutant', 'Var', (56, 62))	('ALDOC', 'Gene', (31, 36))	('patients', 'Species', '9606', (63, 71))	('IDH1', 'Gene', (100, 104))	('ALDOC', 'Gene', '230', (31, 36))	('IDH1', 'Gene', (51, 55))	('higher', 'PosReg', (84, 90))
176294	31450822	Moreover, our results reveal lower ALDOC expression level in wild-type (n = 165) compared with mutant form (n = 132) in the CGGA cohort (p < 0.001, Figure 4C).	('lower', 'NegReg', (29, 34))	('ALDOC', 'Gene', (35, 40))	('ALDOC', 'Gene', '230', (35, 40))	('mutant', 'Var', (95, 101))
176295	31450822	Similarly, most of all cohorts presented ALDOC expression in IDH1 mutant patients is higher than IDH1 wild-type groups (Figure 4D).	('IDH1', 'Gene', (97, 101))	('mutant', 'Var', (66, 72))	('higher', 'PosReg', (85, 91))	('IDH1', 'Gene', '3417', (97, 101))	('IDH1', 'Gene', (61, 65))	('ALDOC', 'Gene', (41, 46))	('ALDOC', 'Gene', '230', (41, 46))	('IDH1', 'Gene', '3417', (61, 65))	('patients', 'Species', '9606', (73, 81))
176296	31450822	Our results show that ALDOC expression significantly positively correlated with long-term survival in GSE53733 group (Figure 5A,B).	('ALDOC', 'Gene', (22, 27))	('ALDOC', 'Gene', '230', (22, 27))	('correlated with', 'Reg', (64, 79))	('positively', 'PosReg', (53, 63))	('long-term survival', 'CPA', (80, 98))	('GSE53733', 'Var', (102, 110))
176297	31450822	However, non-mutated IDH1 expression did not reveal significant prognostic correlation (Figure S3).	('non-mutated', 'Var', (9, 20))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (21, 25))
176299	31450822	GSE4290 showed significant suppression of ALDOC in glioblastoma patients with non-tumor or low-grade groups (Figure 5C).	('GSE4290', 'Var', (0, 7))	('patients', 'Species', '9606', (64, 72))	('ALDOC', 'Gene', (42, 47))	('ALDOC', 'Gene', '230', (42, 47))	('glioblastoma', 'Disease', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (51, 63))	('non-tumor', 'Disease', (78, 87))	('non-tumor', 'Disease', 'MESH:C580335', (78, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('suppression', 'NegReg', (27, 38))
176312	31450822	Our data also show that age, expression level of AxL, TP53 mutant status, or loss of ATRX could be regarded as independent prognostic factors (Figure 6D and Table 1 and Table 2).	('ATRX', 'Gene', (85, 89))	('AxL', 'Gene', '558', (49, 52))	('expression level', 'MPA', (29, 45))	('AxL', 'Gene', (49, 52))	('TP53', 'Gene', '7157', (54, 58))	('ATRX', 'Gene', '546', (85, 89))	('mutant status', 'Var', (59, 72))	('TP53', 'Gene', (54, 58))
176314	31450822	To verify our observations from several in silico data sets and clinical cohorts, we further establisished the two-way models, including overexpression and knockdown of ALDOC in GBM cell lines.	('GBM', 'Disease', (178, 181))	('ALDOC', 'Gene', '230', (169, 174))	('knockdown', 'Var', (156, 165))	('GBM', 'Disease', 'MESH:D005909', (178, 181))	('GBM', 'Phenotype', 'HP:0012174', (178, 181))	('overexpression', 'PosReg', (137, 151))	('ALDOC', 'Gene', (169, 174))
176315	31450822	In this study, we established the ALDOC overexpression model in T-98G and LN-229 cells, and created the ALDOC knockdown model in U-87MG cells.	('T-98G', 'SUBSTITUTION', 'None', (64, 69))	('ALDOC', 'Gene', (34, 39))	('overexpression', 'PosReg', (40, 54))	('ALDOC', 'Gene', '230', (34, 39))	('ALDOC', 'Gene', (104, 109))	('T-98G', 'Var', (64, 69))	('ALDOC', 'Gene', '230', (104, 109))
176322	31450822	The most common point of mutation of IDH1 is localized to codon 132 and IDH2, located at codon 172.	('IDH2', 'Gene', (72, 76))	('IDH2', 'Gene', '3418', (72, 76))	('mutation', 'Var', (25, 33))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))
176324	31450822	The detection of IDH1/2 mutation is predominantly on diffuse astrocytomas, anaplastic astrocytomas, and secondary glioblastomas, but rarely identified on primary glioblastomas.	('astrocytomas', 'Disease', 'MESH:D001254', (61, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('glioblastomas', 'Disease', 'MESH:D005909', (114, 127))	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('glioblastomas', 'Disease', (162, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('glioblastomas', 'Disease', (114, 127))	('astrocytomas', 'Disease', (61, 73))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('astrocytomas', 'Disease', 'MESH:D001254', (86, 98))	('IDH1/2', 'Gene', (17, 23))	('glioblastomas', 'Phenotype', 'HP:0012174', (162, 175))	('mutation', 'Var', (24, 32))	('glioblastomas', 'Phenotype', 'HP:0012174', (114, 127))	('glioblastomas', 'Disease', 'MESH:D005909', (162, 175))	('astrocytomas', 'Disease', (86, 98))
176325	31450822	In the recent studies, some genetic aberrations are associated with IDH1/2 mutation, including TP53 and ATRX mutation and 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (122, 140))	('IDH1/2', 'Gene', '3417;3418', (68, 74))	('aberrations', 'Disease', 'MESH:D002869', (36, 47))	('ATRX', 'Gene', (104, 108))	('mutation', 'Var', (75, 83))	('associated', 'Reg', (52, 62))	('IDH1/2', 'Gene', (68, 74))	('ATRX', 'Gene', '546', (104, 108))	('aberrations', 'Disease', (36, 47))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
176331	31450822	Unlike low-grade glioma (LGG), GBM cancer cell lines do not have IDH1 mutants available for experimental applications.	('IDH1', 'Gene', '3417', (65, 69))	('mutants', 'Var', (70, 77))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('GBM', 'Disease', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('GBM', 'Disease', 'MESH:D005909', (31, 34))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('glioma', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('IDH1', 'Gene', (65, 69))	('cancer', 'Disease', (35, 41))
176333	31450822	Through established transcriptomics data sets, proteomics, and metabolomics between parental or IDH1 R132 mutant in U-87 cells, combined with our available microarray data sets from ALDOC knockdown models, we expected to find the interaction partners, signaling pathways, or metabolites by ALDOC regulated in only wild-type or R132 mutant of IDH1 in GBM.	('ALDOC', 'Gene', (290, 295))	('R132', 'Var', (327, 331))	('mutant', 'Var', (106, 112))	('IDH1', 'Gene', '3417', (96, 100))	('GBM', 'Disease', 'MESH:D005909', (350, 353))	('GBM', 'Phenotype', 'HP:0012174', (350, 353))	('ALDOC', 'Gene', '230', (290, 295))	('R132', 'Gene', (101, 105))	('ALDOC', 'Gene', (182, 187))	('IDH1', 'Gene', (342, 346))	('ALDOC', 'Gene', '230', (182, 187))	('IDH1', 'Gene', '3417', (342, 346))	('IDH1', 'Gene', (96, 100))	('GBM', 'Disease', (350, 353))
176340	31450822	demonstrated that mutated IDH1 could keep the stability of HIF-1alpha existence, which proceeded glycolytic pathway and resulted in gliomagenesis.	('IDH1', 'Gene', '3417', (26, 30))	('HIF-1alpha', 'Gene', (59, 69))	('mutated', 'Var', (18, 25))	('proceeded', 'Reg', (87, 96))	('IDH1', 'Gene', (26, 30))	('resulted in', 'Reg', (120, 131))	('glycolytic', 'Pathway', (97, 107))	('gliomagenesis', 'Disease', 'None', (132, 145))	('stability', 'MPA', (46, 55))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('HIF-1alpha', 'Gene', '3091', (59, 69))	('gliomagenesis', 'Disease', (132, 145))
176355	31450822	Therefore, we will try to create the glioblastoma with IDH1 knockout stable cells by CRISPR strategy and further knock-in several mutant forms of IDH1, including R132H, R132Q, and S92A, through virus infection.	('IDH1', 'Gene', (146, 150))	('R132H', 'Mutation', 'p.R132H', (162, 167))	('IDH1', 'Gene', '3417', (55, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (37, 49))	('IDH1', 'Gene', '3417', (146, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('R132H', 'Var', (162, 167))	('virus infection', 'Disease', (194, 209))	('virus infection', 'Disease', 'MESH:D014412', (194, 209))	('R132Q', 'Var', (169, 174))	('knock-in', 'Reg', (113, 121))	('R132Q', 'Chemical', 'MESH:C053205', (169, 174))	('S92A', 'Mutation', 'p.S92A', (180, 184))	('S92A', 'Var', (180, 184))	('IDH1', 'Gene', (55, 59))	('glioblastoma', 'Disease', (37, 49))
176369	31450822	All the included cases were reclassified as 1 pilocytic astrocytoma, 3 diffuse astrocytomas with IDH mutant, 7 diffuse astrocytomas with IDH wildtype, 3 anaplastic astrocytomas with IDH mutant, 6 anaplastic astrocytomas with IDH wildtype, 3 glioblastomas with IDH mutant, 24 glioblastomas with IDH wildtype, 11 diffuse midline gliomas, H3 K27M-mutant, 2 oligodendrogliomas, NOS, and 4 anaplastic oligodendrogliomas, NOS by immunohistochemical stains.	('astrocytomas', 'Disease', (207, 219))	('oligodendrogliomas', 'Disease', (354, 372))	('astrocytomas', 'Disease', 'MESH:D001254', (164, 176))	('IDH', 'Gene', (97, 100))	('gliomas', 'Phenotype', 'HP:0009733', (327, 334))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (46, 67))	('astrocytomas', 'Disease', (119, 131))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (396, 414))	('H3 K27M-mutant', 'Var', (336, 350))	('glioblastomas', 'Phenotype', 'HP:0012174', (275, 288))	('astrocytomas', 'Disease', (79, 91))	('IDH', 'Gene', '3417', (225, 228))	('midline gliomas', 'Disease', 'MESH:D005910', (319, 334))	('glioblastoma', 'Phenotype', 'HP:0012174', (275, 287))	('IDH', 'Gene', (294, 297))	('pilocytic astrocytoma', 'Disease', (46, 67))	('IDH', 'Gene', (182, 185))	('IDH', 'Gene', '3417', (137, 140))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (385, 414))	('gliomas', 'Phenotype', 'HP:0009733', (365, 372))	('anaplastic oligodendrogliomas', 'Disease', (385, 414))	('IDH', 'Gene', '3417', (97, 100))	('glioblastomas', 'Phenotype', 'HP:0012174', (241, 254))	('IDH', 'Gene', (260, 263))	('astrocytomas', 'Disease', 'MESH:D001254', (207, 219))	('astrocytoma', 'Phenotype', 'HP:0009592', (207, 218))	('astrocytomas', 'Disease', 'MESH:D001254', (119, 131))	('oligodendrogliomas', 'Disease', (396, 414))	('IDH', 'Gene', '3417', (294, 297))	('glioblastomas', 'Disease', (275, 288))	('IDH', 'Gene', '3417', (182, 185))	('astrocytoma', 'Phenotype', 'HP:0009592', (119, 130))	('astrocytomas', 'Disease', 'MESH:D001254', (79, 91))	('midline gliomas', 'Disease', (319, 334))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('astrocytomas', 'Disease', (164, 176))	('astrocytoma', 'Phenotype', 'HP:0009592', (56, 67))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (354, 372))	('IDH', 'Gene', '3417', (260, 263))	('glioblastomas', 'Disease', 'MESH:D005909', (275, 288))	('glioma', 'Phenotype', 'HP:0009733', (407, 413))	('glioblastoma', 'Phenotype', 'HP:0012174', (241, 253))	('astrocytoma', 'Phenotype', 'HP:0009592', (164, 175))	('glioblastomas', 'Disease', (241, 254))	('gliomas', 'Phenotype', 'HP:0009733', (407, 414))	('IDH', 'Gene', (225, 228))	('K27M', 'Mutation', 'p.K27M', (339, 343))	('glioma', 'Phenotype', 'HP:0009733', (365, 371))	('glioma', 'Phenotype', 'HP:0009733', (327, 333))	('glioblastomas', 'Disease', 'MESH:D005909', (241, 254))	('IDH', 'Gene', (137, 140))
176383	31450822	GBM cell lines T-98G and U-87MG were maintained in MEM supplemented with 10% FBS and 1% Penicillin-Streptomycin-Glutamine (PSG) (Invitrogen).	('GBM', 'Disease', (0, 3))	('GBM', 'Disease', 'MESH:D005909', (0, 3))	('T-98G', 'Var', (15, 20))	('PSG', 'Chemical', 'MESH:D013307', (123, 126))	('FBS', 'Disease', (77, 80))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('Penicillin-Streptomycin-Glutamine', 'Chemical', 'MESH:D013307', (88, 121))	('T-98G', 'SUBSTITUTION', 'None', (15, 20))	('FBS', 'Disease', 'MESH:D005198', (77, 80))
176394	31450822	These findings prove that loss of ALDOC expression is an independent factor for predicting poor prognosis and has a stronger prognostic ability than ALDOA/ALDOB in glioblastoma patients.	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('ALDOA', 'Gene', (149, 154))	('ALDOC', 'Gene', (34, 39))	('patients', 'Species', '9606', (177, 185))	('glioblastoma', 'Disease', (164, 176))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('ALDOC', 'Gene', '230', (34, 39))	('ALDOA', 'Gene', '226', (149, 154))	('ALDOB', 'Gene', '229', (155, 160))	('loss', 'Var', (26, 30))	('ALDOB', 'Gene', (155, 160))
176398	31450822	Figure S3: Boxplot showed the distribution of ALDOC expression in clinical patients according to the IDH1 mutant event in the GSE36245 cohort (p = 0.0384).	('IDH1', 'Gene', (101, 105))	('mutant event', 'Var', (106, 118))	('IDH1', 'Gene', '3417', (101, 105))	('patients', 'Species', '9606', (75, 83))	('ALDOC', 'Gene', (46, 51))	('ALDOC', 'Gene', '230', (46, 51))
176403	31450822	Figure S6: Representative Giemsa staining to estimate the invasion abilities of LN-229 and T-98G cells with forced expression of the vector control or exogenous ALDOC gene, respectively.	('ALDOC', 'Gene', '230', (161, 166))	('T-98G', 'SUBSTITUTION', 'None', (91, 96))	('T-98G', 'Var', (91, 96))	('ALDOC', 'Gene', (161, 166))
176418	29322428	These deficits can cause difficulties in patients' everyday lives and affect their quality of life.	('affect', 'Reg', (70, 76))	('deficits', 'Var', (6, 14))	('cause', 'Reg', (19, 24))	('patients', 'Species', '9606', (41, 49))	('quality of life', 'CPA', (83, 98))
176522	26840267	Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations of cells co-exist, resulting in intratumor genetic heterogeneity (ITH).	('tumors', 'Disease', (91, 97))	('alterations', 'Var', (117, 128))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (28, 33))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('genetic alterations', 'Var', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (250, 255))
176525	26840267	While some gene mutations are subclonal, the majority of driver gene mutations are clonal events, present in nearly all cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
176527	26840267	High ITH tends to be associated with lower levels of tumor-infiltrating immune cells, but this association is not able to explain the observed survival differences.	('lower', 'NegReg', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('High ITH', 'Var', (0, 8))
176530	26840267	Many of the somatic mutations found in cancer are clonal events, which occur in the founding cell at the time of tumor initiation, and are then propagated during clonal expansion.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor initiation', 'Disease', 'MESH:D009369', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor initiation', 'Disease', (113, 129))	('mutations', 'Var', (20, 29))
176531	26840267	The model of branching evolution in cancer proposes that these "trunk mutations" are found in every cancer cell comprising a solid tumor.	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('solid tumor', 'Disease', (125, 136))	('solid tumor', 'Disease', 'MESH:D009369', (125, 136))
176532	26840267	Subsequent "branch mutations" are subclonal events that only exist in a subpopulation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
176544	26840267	The strongest evidence for this comes from a study of head and neck cancers, in which the degree of variation in mutational allelic frequencies was associated with poorer outcome.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('neck cancers', 'Disease', (63, 75))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('neck cancers', 'Disease', 'MESH:D006258', (63, 75))	('mutational', 'Var', (113, 123))	('head and neck cancer', 'Phenotype', 'HP:0012288', (54, 74))	('head and neck cancers', 'Phenotype', 'HP:0012288', (54, 75))
176549	26840267	To measure intratumor genetic heterogeneity (ITH) in cancers, we analyzed data from studies performed by The Cancer Genome Atlas Network (TCGA), for which 3 types of complete data were available for >100 tumors: 1) SNP 6.0 array copy number, 2) single nucleotide variant read counts, and 3) clinical patient and tumor data (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (312, 317))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('patient', 'Species', '9606', (300, 307))	('tumors', 'Disease', (204, 210))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('single nucleotide variant', 'Var', (245, 270))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (204, 209))
176557	26840267	PyClone estimates the cancer cell prevalence for each somatic mutation in a sequenced tumor sample, and subsequently uses Bayesian methodology to cluster cancer cell prevalence estimates into clonal populations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (86, 91))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutation', 'Var', (62, 70))	('cluster cancer', 'Disease', 'MESH:D009369', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cluster cancer', 'Disease', (146, 160))
176575	26840267	For each cancer type, the majority of MutSig significantly (q<.10) mutated genes had SNVs with mean cancer cell prevalence (CCP) >90%.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutated', 'Var', (67, 74))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
176576	26840267	This indicates that most recurrent cancer gene mutations are present in every cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (35, 41))
176578	26840267	For example, frequent mutations in driver genes such as TP53, RB1, CTNNB1, KEAP1, MLL2, PTEN and CDKN2A were almost universally clonal events (>90% mean CCP).	('KEAP1', 'Gene', (75, 80))	('CDKN2A', 'Gene', (97, 103))	('MLL2', 'Gene', '9757', (82, 86))	('RB1', 'Gene', '5925', (62, 65))	('TP53', 'Gene', '7157', (56, 60))	('CDKN2A', 'Gene', '1029', (97, 103))	('CTNNB1', 'Gene', '1499', (67, 73))	('MLL2', 'Gene', (82, 86))	('PTEN', 'Gene', (88, 92))	('TP53', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (88, 92))	('mutations', 'Var', (22, 31))	('KEAP1', 'Gene', '9817', (75, 80))	('CTNNB1', 'Gene', (67, 73))	('RB1', 'Gene', (62, 65))
176581	26840267	In fact, nearly all mutated genes in clear cell renal carcinoma, which had the highest overall degree of ITH, were commonly subclonal (Figure 2C and Supplementary Figure 1).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (37, 63))	('mutated', 'Var', (20, 27))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (37, 63))	('clear cell renal carcinoma', 'Disease', (37, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (48, 63))
176584	26840267	Analyzing clinical, pathologic and genetic data from 280 tumors in the TCGA HNSC dataset, we confirmed that a number of known prognostic factors were associated with overall survival (OS), including clinical stage (tumor/node/metastasis), human papillomavirus (HPV) status, TP53 mutation, degree of copy number alteration and mutational load, and predominance of copy number alteration (C class) or mutations (M class) (Supplementary Figure 2).	('mutations', 'Var', (399, 408))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('TP53', 'Gene', (274, 278))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('associated', 'Reg', (150, 160))	('mutational', 'Var', (326, 336))	('mutation', 'Var', (279, 287))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TP53', 'Gene', '7157', (274, 278))	('tumor', 'Disease', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('overall', 'Disease', (166, 173))	('human papillomavirus', 'Species', '10566', (239, 259))	('HPV', 'Species', '10566', (261, 264))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('copy number alteration', 'Var', (363, 385))
176585	26840267	Perhaps because MATH is based on variability in mutation allelic frequencies, MATH scores were most strongly associated with each tumor's degree of copy number alteration (p < 0.001), moreso than with measures of (sub)clonal populations (p = 0.35) (Supplementary Figure 4, Supplementary Table 3).	('associated', 'Interaction', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('copy number alteration', 'Var', (148, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
176588	26840267	This demonstrated that high ITH was independently associated with OS (HR = 2.51; p = .007), when adjusting for HPV status, TP53 mutation, and stage (Figure 3B, Supplementary Table 5A).	('associated with', 'Reg', (50, 65))	('high ITH', 'Var', (23, 31))	('HPV', 'Species', '10566', (111, 114))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
176589	26840267	The association between high ITH and OS was independent of adjuvant radiotherapy administration (Supplementary Table 5D, Supplementary Figure 5), indicating that ITH reflects prognostic aspects of tumor biology, rather than simply response to therapy.	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (197, 202))
176590	26840267	Having established that high ITH had prognostic value in HNSC, we then asked if this factor was informative in the 8 other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('high ITH', 'Var', (24, 32))	('HNSC', 'Disease', (57, 61))
176594	26840267	We found that high ITH was associated with significantly poorer survival in LGG (HR = 8.30, p = .011), PRAD (HR = 5.76, p = .016), KIRC (HR = 6.06, p = .003), HNSC (HR = 3.75, p = .007), and BRCA (HR = 2.50, p = .015).	('survival', 'CPA', (64, 72))	('BRCA', 'Gene', (191, 195))	('BRCA', 'Gene', '672', (191, 195))	('high ITH', 'Var', (14, 22))	('poorer', 'NegReg', (57, 63))
176597	26840267	We performed additional analyses to determine if tumors with high ITH had poorer prognosis due to an association with more aggressive molecular subtypes, and found that this was not the case.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('high ITH', 'Var', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('association', 'Interaction', (101, 112))	('tumors', 'Disease', (49, 55))
176601	26840267	Within this category of tumors, high ITH remained associated with poorer survival (p = .01) (Supplementary Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('survival', 'MPA', (73, 81))	('high ITH', 'Var', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('poorer', 'NegReg', (66, 72))
176602	26840267	In the BRCA cohort, we found that high ITH was associated with poorer survival, independent of clinical stage and receptor status.	('BRCA', 'Gene', '672', (7, 11))	('survival', 'MPA', (70, 78))	('BRCA', 'Gene', (7, 11))	('poorer', 'NegReg', (63, 69))	('high ITH', 'Var', (34, 42))
176603	26840267	High ITH was not more common in poorer-prognosis tumors such as triple negative receptor status or basal-like molecular subtype.	('basal-like molecular subtype', 'Disease', (99, 127))	('triple negative', 'Var', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))
176605	26840267	The prognostic impact of high ITH appeared to affect all molecular subtypes but was most significant in the Her2-enriched tumors (p = .04) (Supplementary Figure 7B).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('Her2', 'Gene', '2064', (108, 112))	('affect', 'Reg', (46, 52))	('high ITH', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('Her2', 'Gene', (108, 112))
176606	26840267	As would be expected, the degree of ITH was strongly correlated with mutation number in most cancer types - all except LUAD and LUSC (Supplementary Table 6A).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('correlated', 'Reg', (53, 63))	('LUSC', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutation', 'Var', (69, 77))	('LUAD', 'Disease', (119, 123))
176608	26840267	In fact, any prognostic aspect of mutational load in tumors could be mediated by ITH.	('mutational load', 'Var', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
176609	26840267	High ITH was associated with older age in 1 of 9 cancer types - LGG (p = .001) (Supplementary Table 7A).	('High ITH', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
176612	26840267	Recent data in melanoma and non-small cell lung cancer have shown that tumors with a higher mutational burden have an increased number of predicted neoantigens, and are more likely to respond to immunotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('neoantigens', 'MPA', (148, 159))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (28, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (32, 54))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('mutational', 'Var', (92, 102))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (28, 54))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('respond', 'Reg', (184, 191))	('non-small cell lung cancer', 'Disease', (28, 54))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
176613	26840267	It is believed that the neoantigens resulting from tumor mutations promote anti-tumor immunity and thereby facilitate therapeutic responses.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('facilitate', 'PosReg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (80, 85))	('mutations', 'Var', (57, 66))	('therapeutic responses', 'CPA', (118, 139))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('promote', 'PosReg', (67, 74))
176618	26840267	Tumors with high ITH tended to have lower levels of immune cell infiltration, or T cell infiltration, controlling for cancer type with logistic regression (immune infiltration p = .020, T cell infiltration p = .055) (Supplementary Table 8; Supplementary Figure 8C-E).	('lower levels of immune cell', 'Phenotype', 'HP:0002721', (36, 63))	('lower', 'NegReg', (36, 41))	('cancer', 'Disease', (118, 124))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('high', 'Var', (12, 16))	('T cell infiltration', 'MPA', (81, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('immune cell infiltration', 'MPA', (52, 76))
176632	26840267	The association between high ITH and poorer survival was most evident in lower grade glioma, prostate, clear cell kidney, head and neck, and breast cancers, and had borderline significance in melanoma.	('prostate', 'Disease', (93, 101))	('clear cell kidney', 'Disease', (103, 120))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('glioma', 'Disease', (85, 91))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('high ITH', 'Var', (24, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
176637	26840267	For example, in a study of patients with relapsed chronic lymphocytic leukemia, subclonal mutations were associated with more aggressive disease.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (58, 78))	('lymphocytic leukemia', 'Disease', (58, 78))	('aggressive disease', 'Disease', 'MESH:D001523', (126, 144))	('patients', 'Species', '9606', (27, 35))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (50, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('aggressive disease', 'Disease', (126, 144))	('subclonal mutations', 'Var', (80, 99))	('associated with', 'Reg', (105, 120))
176638	26840267	Similar findings were observed in 11 patients with lung adenocarcinoma: recurrent tumors had more subclonal mutations.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (37, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (51, 70))	('subclonal mutations', 'Var', (98, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('lung adenocarcinoma', 'Disease', (51, 70))
176642	26840267	In a pan-cancer study examining the landscape of ITH, Andor et al did not observe a clear association between ITH and survival within individual cancers, but did observe that prognosis appeared poorest among tumors with intermediate levels of copy number variation.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (9, 15))	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('copy number variation', 'Var', (243, 264))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('poorest', 'NegReg', (194, 201))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
176648	26840267	We also noted a tendency for high ITH tumors to have lower levels of immune infiltration.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('high ITH', 'Var', (29, 37))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('lower levels of immune infiltration', 'Phenotype', 'HP:0002721', (53, 88))	('lower', 'NegReg', (53, 58))
176657	26840267	However, if immunoediting can in fact constrain ITH, one could speculate that the cancers most likely to benefit from immunotherapy would be those with high mutational loads (and thus, many neoantigens), but low ITH (thereby, having undergone more immunoediting by a functional immune surveillance system).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('high mutational loads', 'Var', (152, 173))
176658	26840267	The vast majority of highly prevalent driver mutations tended to be clonal events, present in every cancer cell, suggestive that these are generally early or "trunk" mutational events.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('driver', 'Disease', (38, 44))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
176660	26840267	These findings provide empirical evidence for recent theoretical models of tumor evolution, showing that driver mutations with even a small fitness advantage are able to expand and become dominant within a short period of time, whereas passenger mutations without a major fitness advantage are more likely to remain subclonal.	('fitness advantage', 'Disease', (140, 157))	('fitness advantage', 'Disease', (272, 289))	('fitness advantage', 'Disease', 'MESH:D012640', (140, 157))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('fitness advantage', 'Disease', 'MESH:D012640', (272, 289))	('tumor', 'Disease', (75, 80))
176662	26840267	Furthermore, in other cancer types, some prevalent driver gene mutations appeared to be frequently subclonal.	('mutations', 'Var', (63, 72))	('driver gene', 'Gene', (51, 62))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
176663	26840267	This phenomenon has also been observed in a prior study, which reported that 15-20% of mutations in driver genes such as IDH1, PIK3CA and EGFR were subclonal, and linked many of these to a mutational signature of APOBEC-mediated mutagenesis.	('IDH1', 'Gene', (121, 125))	('EGFR', 'Gene', '1956', (138, 142))	('IDH1', 'Gene', '3417', (121, 125))	('PIK3CA', 'Gene', (127, 133))	('EGFR', 'Gene', (138, 142))	('PIK3CA', 'Gene', '5290', (127, 133))	('mutations', 'Var', (87, 96))
176669	26840267	Higher levels of heterogeneity increase the likelihood of a tumor harboring a subclonal population with a driver mutation that will be resistant to treatment.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutation', 'Var', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (60, 65))
176746	20975976	It is known that several mutations may contribute to the formation of secondary high-grade glioma which arise from preexisting low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('mutations', 'Var', (25, 34))	('contribute', 'Reg', (39, 49))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioma', 'Disease', (91, 97))	('gliomas', 'Disease', (137, 144))	('glioma', 'Disease', (137, 143))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
176747	20975976	This type of tumor is relatively rare, has a female predominance and often has a characteristic mutation of TP53 and RB1, and increased expression of PDGFR.	('tumor', 'Disease', (13, 18))	('expression', 'MPA', (136, 146))	('RB1', 'Gene', (117, 120))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('mutation', 'Var', (96, 104))	('PDGFR', 'Gene', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('RB1', 'Gene', '5925', (117, 120))	('PDGFR', 'Gene', '5159', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('increased', 'PosReg', (126, 135))
176757	32762776	Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth.	('expression', 'MPA', (19, 29))	('RBP', 'Gene', (15, 18))	('function', 'MPA', (34, 42))	('tumor initiation', 'Disease', 'MESH:D009369', (118, 134))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor initiation', 'Disease', (118, 134))	('critical pathways', 'Pathway', (86, 103))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('RBP', 'Gene', '57794', (15, 18))	('influence', 'Reg', (76, 85))
176760	32762776	High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy.	('GBMs', 'Disease', (39, 43))	('High', 'Var', (0, 4))	('poor', 'NegReg', (64, 68))	('SERBP1', 'Gene', (5, 11))	('patient', 'Species', '9606', (69, 76))	('expression', 'MPA', (12, 22))
176761	32762776	SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines.	('SERBP1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('delay', 'NegReg', (24, 29))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('GBM', 'Disease', (88, 91))	('knockdown', 'Var', (7, 16))	('tumor growth and impacts cancer', 'Disease', 'MESH:D009369', (33, 64))	('glioma', 'Disease', (96, 102))
176764	32762776	SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function.	('methionine levels', 'MPA', (27, 44))	('SERBP1', 'Gene', (0, 6))	('upregulation', 'PosReg', (125, 137))	('neuronal differentiation', 'CPA', (177, 201))	('decreases', 'NegReg', (17, 26))	('decreases methionine levels', 'Phenotype', 'HP:0003658', (17, 44))	('H3K27me3', 'Protein', (112, 120))	('H3', 'Chemical', 'MESH:C012616', (112, 114))	('methionine', 'Chemical', 'MESH:D008715', (27, 37))	('histone', 'Gene', (79, 86))	('knockdown', 'Var', (7, 16))	('histone', 'Gene', '43229', (79, 86))	('neurogenesis', 'CPA', (163, 175))	('reduction', 'NegReg', (66, 75))
176765	32762776	Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites.	('H3K27me3 sites', 'Var', (157, 171))	('epigenetic silencing', 'Var', (104, 124))	('downregulated', 'NegReg', (62, 75))	('H3', 'Chemical', 'MESH:C012616', (157, 159))
176770	32762776	In this respect, The Cancer Genome Atlas (TCGA) has produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important GBM driver mutations.	('mutations', 'Var', (173, 182))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Cancer', 'Disease', (21, 27))
176771	32762776	Post-transcriptional processes such as splicing, poly adenylation, decay, and translation are often linked to tumorigenesis while many of their regulators have been shown to display tumor suppressive or oncogenic activity.	('tumor', 'Disease', (182, 187))	('splicing', 'MPA', (39, 47))	('poly adenylation', 'Var', (49, 65))	('linked', 'Reg', (100, 106))	('decay', 'MPA', (67, 72))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('oncogenic activity', 'CPA', (203, 221))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
176789	32762776	SERBP1 knockdown produced strong effects on cancer-related phenotypes and tumor growth.	('SERBP1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('effects', 'Reg', (33, 40))	('tumor', 'Disease', (74, 79))	('knockdown', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
176794	32762776	High SERBP1 expression was associated with poor survival in glioma patients in the TCGA and CGGA cohorts (Fig.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (67, 75))	('poor', 'NegReg', (43, 47))	('glioma', 'Disease', (60, 66))	('SERBP1', 'Gene', (5, 11))	('expression', 'MPA', (12, 22))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
176796	32762776	S1B) and data in the R2 database indicated that high SERBP1 expression is associated with poor prognosis in the cases of neuroblastoma, pancreatic adenocarcinoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, and sarcomas (Additional File 1: Fig.	('neuroblastoma', 'Disease', (121, 134))	('expression', 'MPA', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('R2', 'Gene', '913', (21, 23))	('pancreatic adenocarcinoma, bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (136, 191))	('neuroblastoma', 'Phenotype', 'HP:0003006', (121, 134))	('sarcomas', 'Disease', 'MESH:D012509', (231, 239))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 225))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (136, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (231, 239))	('neuroblastoma', 'Disease', 'MESH:D009447', (121, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('SERBP1', 'Gene', (53, 59))	('cervical squamous cell carcinoma', 'Disease', (193, 225))	('high', 'Var', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('sarcomas', 'Disease', (231, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))
176804	32762776	The median survival was 13.12 +- 1.12 months (95% confidence intervals [CI] 10.91-15.33) for patients with high SERBP1 expression and 23.73 +- 1.76 (95% CI 20.23-27.23) months for patients with low SERBP1 expression (P < 0.0001) (Fig.	('high', 'Var', (107, 111))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (180, 188))	('SERBP1', 'Gene', (112, 118))
176807	32762776	Similarly, patients with low SERBP1 levels gained more benefit from radiotherapy in terms of survival (18.81 +- 2.69 months, 95% CI 13.09-24.54) than those with high SERBP1 levels (9.24 +- 1.15 months, 95% CI 6.90-11.57) (P < 0.0001) (Fig.	('SERBP1', 'Gene', (29, 35))	('benefit', 'PosReg', (55, 62))	('survival', 'CPA', (93, 101))	('low', 'Var', (25, 28))	('patients', 'Species', '9606', (11, 19))
176810	32762776	SERBP1 knockdown caused a dramatic impact on U251 and U343 cell viability as detected via MTS assay (Fig.	('U343', 'Chemical', '-', (54, 58))	('SERBP1', 'Gene', (0, 6))	('impact', 'Reg', (35, 41))	('knockdown', 'Var', (7, 16))
176811	32762776	We examined PARP1 cleavage by Western blot as well as annexin-V staining using flow cytometry; in both scenarios, we observed an increase in product in cells transfected with siSERBP1 compared to control siRNA (Fig.	('annexin-V', 'Gene', (54, 63))	('product', 'MPA', (141, 148))	('PARP1', 'Gene', '142', (12, 17))	('PARP1', 'Gene', (12, 17))	('increase', 'PosReg', (129, 137))	('siSERBP1', 'Var', (175, 183))	('annexin-V', 'Gene', '308', (54, 63))
176812	32762776	Similarly, we observed a higher caspase 3/7 activity in SERBP1 knockdown cells compared to control, corroborating the role of SERBP1 in apoptosis (Fig.	('caspase 3/7', 'Gene', '836;840', (32, 43))	('caspase 3/7', 'Gene', (32, 43))	('SERBP1', 'Gene', (56, 62))	('activity', 'MPA', (44, 52))	('higher', 'PosReg', (25, 31))	('knockdown', 'Var', (63, 72))
176824	32762776	To understand how SERBP1 contributes to cancer-relevant phenotypes, we performed an RNA-Seq analysis in control vs. SERBP1 knockdown U251 cells.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('SERBP1', 'Gene', (116, 122))	('knockdown', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
176826	32762776	In particular, two interconnected metabolic routes, serine biosynthesis and one-carbon (1C) cycle, are highly affected by SERBP1 knockdown (Fig.	('serine', 'Chemical', 'MESH:D012694', (52, 58))	('knockdown', 'Var', (129, 138))	('carbon', 'Chemical', 'MESH:D002244', (80, 86))	('affected', 'Reg', (110, 118))	('serine biosynthesis', 'MPA', (52, 71))	('SERBP1', 'Gene', (122, 128))
176827	32762776	Immunostaining of xenografts also showed that SERBP1 knockdown also produced a dramatic decrease in PHGDH expression in tumors (Fig.	('decrease', 'NegReg', (88, 96))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('knockdown', 'Var', (53, 62))	('expression', 'MPA', (106, 116))	('PHGDH', 'Gene', '26227', (100, 105))	('SERBP1', 'Gene', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PHGDH', 'Gene', (100, 105))
176837	32762776	High PSAT1 expression correlates with poor prognosis in many tumors including breast cancer, colorectal, nasopharyngeal, and esophageal carcinomas and is linked to drug resistance.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('drug resistance', 'Phenotype', 'HP:0020174', (164, 179))	('expression', 'MPA', (11, 21))	('nasopharyngeal', 'Disease', (105, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('colorectal', 'Disease', 'MESH:D015179', (93, 103))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', (78, 91))	('PSAT1', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('PSAT1', 'Gene', '29968', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (61, 67))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (125, 146))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (125, 146))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('colorectal', 'Disease', (93, 103))	('esophageal carcinomas', 'Disease', (125, 146))
176838	32762776	Since SERBP1 siRNA knockdown markedly affected viability and apoptosis, we opted to use a U251 stable line with a tet-inducible shRNA.	('SERBP1', 'Gene', (6, 12))	('apoptosis', 'CPA', (61, 70))	('knockdown', 'Var', (19, 28))	('affected', 'Reg', (38, 46))	('tet', 'Chemical', 'MESH:C010349', (114, 117))	('viability', 'CPA', (47, 56))
176856	32762776	Gene set enrichment analysis (GSEA) identified strong similarities between the list of upregulated genes in SERBP1 knockdown cells and binding profiles of H3K27me3 and EZH2 and SUZ12, two members of PRC2 which trimethylate histone H3 on lysine 27 (Additional File 11: Table S10).	('histone', 'Gene', '43229', (223, 230))	('lysine', 'Chemical', 'MESH:D008239', (237, 243))	('EZH2', 'Gene', (168, 172))	('EZH2', 'Gene', '2146', (168, 172))	('SERBP1', 'Gene', (108, 114))	('H3', 'Chemical', 'MESH:C012616', (231, 233))	('histone', 'Gene', (223, 230))	('H3K27me3', 'Protein', (155, 163))	('SUZ12', 'Gene', '23512', (177, 182))	('upregulated', 'PosReg', (87, 98))	('GSEA', 'Chemical', '-', (30, 34))	('SUZ12', 'Gene', (177, 182))	('H3', 'Chemical', 'MESH:C012616', (155, 157))	('knockdown', 'Var', (115, 124))
176857	32762776	Analysis of H3K27me3 profiles in GBM cells confirmed that several genes "repressed" by SERBP1 show H3K27me3 sites (Fig.	('H3', 'Chemical', 'MESH:C012616', (12, 14))	('SERBP1', 'Gene', (87, 93))	('H3K27me3 sites', 'Var', (99, 113))	('H3', 'Chemical', 'MESH:C012616', (99, 101))
176858	32762776	Corroborating the association between SERBP1 and H3K27me3, we determined by Western analysis that SERBP1 knockdown in GBM cells reduced H3K27me3 levels (Fig.	('reduced', 'NegReg', (128, 135))	('H3K27me3 levels', 'MPA', (136, 151))	('H3', 'Chemical', 'MESH:C012616', (136, 138))	('knockdown', 'Var', (105, 114))	('SERBP1', 'Gene', (98, 104))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
176861	32762776	While control cells showed almost no response to EED226 treatment, SERBP1 knockdown cells showed decreased proliferation in response to treatment (Additional File 1: Fig.	('EED226', 'Chemical', 'MESH:C000618736', (49, 55))	('proliferation', 'CPA', (107, 120))	('knockdown', 'Var', (74, 83))	('SERBP1', 'Gene', (67, 73))	('decreased', 'NegReg', (97, 106))
176863	32762776	In line with these findings, we observed that SERBP1 knockdown decreased expression of several genes associated with PI3K/AKT signaling (Additional File 1: Fig.	('knockdown', 'Var', (53, 62))	('decreased', 'NegReg', (63, 72))	('expression of several genes', 'MPA', (73, 100))	('SERBP1', 'Gene', (46, 52))	('AKT', 'Gene', '207', (122, 125))	('AKT', 'Gene', (122, 125))
176865	32762776	Corroborating the connection between SERBP1 and the PI3K/AKT pathway, knockdown of SERBP1 reduced levels of AKT and p-AKT in U251 and U343 cells as observed by Western blot (Additional File 1: Fig.	('AKT', 'Gene', '207', (108, 111))	('AKT', 'Gene', '207', (118, 121))	('knockdown', 'Var', (70, 79))	('reduced', 'NegReg', (90, 97))	('SERBP1', 'Gene', (83, 89))	('U343', 'Chemical', '-', (134, 138))	('AKT', 'Gene', (108, 111))	('AKT', 'Gene', (118, 121))	('AKT', 'Gene', '207', (57, 60))	('levels', 'MPA', (98, 104))	('AKT', 'Gene', (57, 60))
176870	32762776	Consistent with the finding that that high SERBP1 expression influences response to radiation in GBM patients (Fig.	('patients', 'Species', '9606', (101, 109))	('GBM', 'Disease', (97, 100))	('high', 'Var', (38, 42))	('SERBP1', 'Gene', (43, 49))	('response to radiation', 'MPA', (72, 93))	('influences', 'Reg', (61, 71))
176877	32762776	Consistent with this claim, the depletion of key methyl and MTA cycle metabolites (e.g., methionine, SAH, and cysteine) in SERBP1 knockdown cells indicates that SERBP1 controls a variety of processes including methylation of proteins, DNA, RNA, and lipids as well as biosynthesis of nucleotides and polyamines.	('SERBP1', 'Gene', (161, 167))	('methylation', 'MPA', (210, 221))	('cysteine', 'Chemical', 'MESH:D003545', (110, 118))	('biosynthesis', 'MPA', (267, 279))	('SAH', 'Disease', (101, 104))	('controls', 'Reg', (168, 176))	('methionine', 'Chemical', 'MESH:D008715', (89, 99))	('methyl', 'MPA', (49, 55))	('knockdown', 'Var', (130, 139))	('proteins', 'Protein', (225, 233))	('depletion', 'MPA', (32, 41))	('MTA', 'Chemical', 'MESH:C008500', (60, 63))	('methionine', 'MPA', (89, 99))	('lipids', 'Chemical', 'MESH:D008055', (249, 255))	('polyamines', 'Chemical', 'MESH:D011073', (299, 309))	('SERBP1', 'Gene', (123, 129))	('SAH', 'Disease', 'MESH:D013345', (101, 104))
176889	32762776	Overexpression of PCK1 in glucose-starved HCC cells induced TCA cataplerosis, leading to energy crisis and oxidative stress.	('oxidative stress', 'MPA', (107, 123))	('TCA cataplerosis', 'Disease', 'None', (60, 76))	('glucose', 'Chemical', 'MESH:D005947', (26, 33))	('leading to', 'Reg', (78, 88))	('Overexpression', 'Var', (0, 14))	('TCA cataplerosis', 'Disease', (60, 76))	('oxidative stress', 'Phenotype', 'HP:0025464', (107, 123))	('PCK1', 'Gene', (18, 22))	('induced', 'Reg', (52, 59))	('energy crisis', 'MPA', (89, 102))
176894	32762776	In agreement with SERBP1's positive effect on expression of genes associated with 1C and methyl cycles, SERBP1 knockdown produced marked changes in the levels of several metabolites including methionine.	('knockdown', 'Var', (111, 120))	('SERBP1', 'Gene', (104, 110))	('methionine', 'Chemical', 'MESH:D008715', (192, 202))	('changes', 'Reg', (137, 144))	('levels of several metabolites including methionine', 'MPA', (152, 202))
176895	32762776	Disruption in methionine production can affect gene expression by interfering with DNA, RNA, and histone methylation.	('methionine production', 'MPA', (14, 35))	('interfering', 'NegReg', (66, 77))	('histone', 'Gene', '43229', (97, 104))	('gene expression', 'MPA', (47, 62))	('RNA', 'MPA', (88, 91))	('affect', 'Reg', (40, 46))	('histone', 'Gene', (97, 104))	('DNA', 'MPA', (83, 86))	('methionine', 'Chemical', 'MESH:D008715', (14, 24))	('Disruption', 'Var', (0, 10))
176902	32762776	Altogether, this data suggests that SERBP1 might be critical for neuronal function and its aberrant expression could be linked to neurological disorders.	('neurological disorders', 'Disease', 'MESH:D009422', (130, 152))	('SERBP1', 'Gene', (36, 42))	('neurological disorders', 'Disease', (130, 152))	('linked', 'Reg', (120, 126))	('aberrant', 'Var', (91, 99))
176912	32762776	Several mutations in NTNG2 have been described and they cause global developmental delay, hypotonia, secondary microcephaly, Rett-like phenotype, and autistic features.	('autistic features', 'Phenotype', 'HP:0000729', (150, 167))	('secondary microcephaly', 'Phenotype', 'HP:0005484', (101, 123))	('microcephaly', 'Phenotype', 'HP:0000252', (111, 123))	('autistic features', 'Disease', (150, 167))	('hypotonia', 'Disease', (90, 99))	('secondary microcephaly', 'Disease', (101, 123))	('mutations', 'Var', (8, 17))	('hypotonia', 'Disease', 'MESH:D009123', (90, 99))	('secondary microcephaly', 'Disease', 'MESH:D060085', (101, 123))	('NTNG2', 'Gene', '84628', (21, 26))	('Rett-like phenotype', 'Disease', (125, 144))	('cause', 'Reg', (56, 61))	('global developmental delay', 'Phenotype', 'HP:0001263', (62, 88))	('hypotonia', 'Phenotype', 'HP:0001290', (90, 99))	('developmental delay', 'Disease', 'MESH:D002658', (69, 88))	('developmental delay', 'Disease', (69, 88))	('NTNG2', 'Gene', (21, 26))
176913	32762776	Knockdown of murine Ntng2 caused severe impairments of neuronal morphology and cortical migration while knockout of Ntng2 in a cellular model resulted in short neurites.	('impairments', 'NegReg', (40, 51))	('cortical migration', 'CPA', (79, 97))	('Ntng2', 'Gene', (116, 121))	('Ntng2', 'Gene', (20, 25))	('murine', 'Species', '10090', (13, 19))	('short neurites', 'CPA', (154, 168))	('neuronal morphology', 'CPA', (55, 74))	('Ntng2', 'Gene', '171171', (116, 121))	('Ntng2', 'Gene', '171171', (20, 25))	('knockout', 'Var', (104, 112))
176915	32762776	Dysfunction or reduced expression of SLC1A2 has been linked to neurodegenerative diseases.	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (63, 89))	('Dysfunction', 'Var', (0, 11))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (63, 89))	('linked', 'Reg', (53, 59))	('reduced', 'NegReg', (15, 22))	('SLC1A2', 'Gene', (37, 43))	('neurodegenerative diseases', 'Disease', (63, 89))	('expression', 'MPA', (23, 33))
176917	32762776	In this respect, inhibition of SLC1A2 in rats reduced glutamate uptake by glial cells and caused neuronal cell death.	('glutamate uptake by glial cells', 'MPA', (54, 85))	('SLC1A2', 'Gene', (31, 37))	('caused', 'Reg', (90, 96))	('rats', 'Species', '10116', (41, 45))	('inhibition', 'Var', (17, 27))	('reduced', 'NegReg', (46, 53))	('glutamate', 'Chemical', 'MESH:D018698', (54, 63))	('neuronal cell death', 'CPA', (97, 116))
176918	32762776	Studies using TCGA data showed many mutations in RBPs and alterations in their expression levels across tumor types.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('expression levels', 'MPA', (79, 96))	('RBP', 'Gene', (49, 52))	('tumor', 'Disease', (104, 109))	('mutations', 'Var', (36, 45))	('RBP', 'Gene', '57794', (49, 52))	('alterations', 'Reg', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
176921	32762776	In the case of SERBP1, its blockage could hit cancer metabolism and epigenetic regulation.	('epigenetic regulation', 'MPA', (68, 89))	('SERBP1', 'Gene', (15, 21))	('hit', 'Reg', (42, 45))	('cancer metabolism', 'Disease', 'MESH:D009369', (46, 63))	('cancer metabolism', 'Disease', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('blockage', 'Var', (27, 35))
176926	32762776	In particular, we observed that SERBP1 knockdown in GBM cells decreased methionine production causing a subsequent reduction in H3K27me3 levels and upregulation of genes associated with neurogenesis, synaptogenesis, neuronal differentiation, and function.	('H3', 'Chemical', 'MESH:C012616', (128, 130))	('reduction', 'NegReg', (115, 124))	('upregulation', 'PosReg', (148, 160))	('decreased methionine', 'Phenotype', 'HP:0003658', (62, 82))	('decreased', 'NegReg', (62, 71))	('methionine production', 'MPA', (72, 93))	('knockdown', 'Var', (39, 48))	('genes', 'MPA', (164, 169))	('SERBP1', 'Gene', (32, 38))	('neuronal differentiation', 'CPA', (216, 240))	('methionine', 'Chemical', 'MESH:D008715', (72, 82))	('H3K27me3 levels', 'MPA', (128, 143))
176935	32762776	We selected genes with increased expression after SERBP1 knockdown and compared their expression levels in non-treated neural stem cells (NSCs) vs. differentiated cells (4 days after being transferred to differentiation media).	('knockdown', 'Var', (57, 66))	('NSC', 'Disease', 'OMIM:617394', (138, 141))	('SERBP1', 'Gene', (50, 56))	('increased', 'PosReg', (23, 32))	('expression', 'MPA', (33, 43))	('NSC', 'Disease', (138, 141))
176938	32762776	Next, expression levels of genes upregulated after SERBP1 knockdown were compared to those of genes differentially expressed between non-treated NSCs and differentiated cells.	('upregulated', 'PosReg', (33, 44))	('SERBP1', 'Gene', (51, 57))	('NSC', 'Disease', 'OMIM:617394', (145, 148))	('NSC', 'Disease', (145, 148))	('knockdown', 'Var', (58, 67))	('expression levels', 'MPA', (6, 23))
176939	32762776	Finally, we built a heatmap for normalized expression levels of genes upregulated both upon SERBP1 knockdown and in differentiated NSCs, using the R package gplots (https://cran.r-project.org/package=gplots).	('NSC', 'Disease', (131, 134))	('NSC', 'Disease', 'OMIM:617394', (131, 134))	('knockdown', 'Var', (99, 108))	('SERBP1', 'Gene', (92, 98))	('upregulated', 'PosReg', (70, 81))
176961	32762776	ENRICHR was used to conduct GSEA and identify factors that potentially affect the expression of genes upregulated upon SERBP1 knockdown.	('GSEA', 'Chemical', '-', (28, 32))	('upregulated', 'PosReg', (102, 113))	('knockdown', 'Var', (126, 135))	('SERBP1', 'Gene', (119, 125))	('expression of genes', 'MPA', (82, 101))
176962	32762776	The EZH2, SUZ12, and H3K27me3 ChIP-Seq datasets showing the greatest number matches were selected for further analysis.	('SUZ12', 'Gene', '23512', (10, 15))	('EZH2', 'Gene', '2146', (4, 8))	('SUZ12', 'Gene', (10, 15))	('EZH2', 'Gene', (4, 8))	('H3K27me3', 'Var', (21, 29))	('H3', 'Chemical', 'MESH:C012616', (21, 23))
176963	32762776	To evaluate whether genes upregulated upon SERBP1 knockdown are methylated in GBM, we obtained Chip-Seq peak calls for H3K27me3 in 9 GBM samples from a previous study.	('upregulated', 'PosReg', (26, 37))	('knockdown', 'Var', (50, 59))	('H3K27me3', 'Var', (119, 127))	('SERBP1', 'Gene', (43, 49))	('H3', 'Chemical', 'MESH:C012616', (119, 121))
177004	32762776	2.5 x 105 cells were prepared following an Annexin V-FITC kit (catalog #: A13199, V13246 Thermo Fisher).	('V13246', 'Var', (82, 88))	('Annexin V', 'Gene', (43, 52))	('kit', 'Gene', '3815', (58, 61))	('Annexin V', 'Gene', '308', (43, 52))	('kit', 'Gene', (58, 61))
177086	29572636	On the basis of this, it has been common practice to interpret non-enhancing intrinsic tumours as probable low grade gliomas (LGG).	('non-enhancing', 'Var', (63, 76))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('intrinsic tumours', 'Disease', (77, 94))	('intrinsic tumours', 'Disease', 'MESH:D020919', (77, 94))
177088	29572636	The discovery of several key genetic alterations as principal determinants of glioma prognosis has challenged the reference standard of glioma grouping by histology.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('genetic alterations', 'Var', (29, 48))	('glioma', 'Disease', (136, 142))	('alterations', 'Var', (37, 48))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
177089	29572636	Mutations in isocitrate dehydrogenase (IDH) represent a common (> 70%) defining event in the development of LGG, conversely more than 90% of glioblastomas belong to the IDH wild-type group.	('glioblastomas', 'Disease', 'MESH:D005909', (141, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('LGG', 'Disease', (108, 111))	('glioblastomas', 'Disease', (141, 154))	('IDH', 'Gene', (169, 172))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', '3417', (169, 172))	('IDH', 'Gene', (39, 42))	('glioblastomas', 'Phenotype', 'HP:0012174', (141, 154))	('IDH', 'Gene', '3417', (39, 42))
177090	29572636	Despite its oncogenic effect through production of a toxic metabolite D2-hydroxyglutarate (2HG), the presence of an IDH mutation is associated with a favourable prognosis.	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (116, 119))	('presence', 'Var', (101, 109))	('mutation', 'Var', (120, 128))	('D2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (70, 89))
177104	29572636	For comparison of the molecular groups, control samples of IDH (IDH1-R132H) mutant gliomas (34 IDHmut1p19qint and 32 IDHmut1p19qdel) were randomly selected.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('R132H', 'Var', (69, 74))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', '3417', (64, 67))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (59, 62))	('R132H', 'SUBSTITUTION', 'None', (69, 74))	('IDH', 'Gene', '3417', (117, 120))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', (64, 67))
177148	29572636	In this analysis, we observed that ADC values obtained from standard clinical DWI are a highly significant predictor of non-enhancing glioma IDH status and may permit non-invasive molecular subtyping in accordance with the 2016 WHO classification.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma IDH status', 'Disease', (134, 151))	('ADC values', 'Var', (35, 45))	('permit', 'Reg', (160, 166))	('glioma IDH status', 'Disease', 'MESH:D005910', (134, 151))
177151	29572636	Low ADC values are associated with increased glioma cellularity and worse prognosis, supported by comparisons of diffusivity, histological specimens and clinical data in multiple studies.	('increased glioma', 'Disease', 'MESH:D005910', (35, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('ADC', 'MPA', (4, 7))	('increased glioma', 'Disease', (35, 51))	('Low', 'Var', (0, 3))
177152	29572636	Low diffusivity predicts poor astrocytoma survival independent from WHO grade, although no linear relation exists between ADC and glioma prognosis.	('astrocytoma', 'Phenotype', 'HP:0009592', (30, 41))	('glioma', 'Disease', (130, 136))	('poor', 'NegReg', (25, 29))	('astrocytoma', 'Disease', 'MESH:D001254', (30, 41))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('astrocytoma', 'Disease', (30, 41))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('Low', 'Var', (0, 3))
177167	29572636	It remains unknown why intermediate ADC values were observed in the 1p19q co-deleted gliomas, despite their best prognosis.	('gliomas', 'Disease', (85, 92))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('1p19q co-deleted', 'Var', (68, 84))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
177173	27282637	IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant.	('rs55705857', 'Mutation', 'rs55705857', (133, 143))	('IDH', 'Gene', (0, 3))	('rs55705857', 'Mutation', 'rs55705857', (42, 52))	('MYC', 'Gene', '4609', (81, 84))	('rs55705857', 'Var', (133, 143))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('glioma', 'Disease', (256, 262))	('IDH', 'Gene', (245, 248))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('rs55705857', 'Var', (42, 52))	('MYC', 'Gene', (81, 84))	('IDH', 'Gene', '3417', (245, 248))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('glioma', 'Disease', (11, 17))	('associated with', 'Reg', (229, 244))
177180	27282637	Single nucleotide polymorphisms (SNPs) at 8q24.21 have been associated with increased risk of IDH1/2-mutated gliomas.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('IDH1/2', 'Gene', '3417;3418', (94, 100))	('IDH1/2', 'Gene', (94, 100))
177181	27282637	A more recent study analyzed this region in more detail by pooled next-generation sequencing/imputation and identified a low-frequency SNP (rs55705857) that appeared very likely to be the causative-variant among several glioma-associated SNPs located at 8q24.21.	('rs55705857', 'Mutation', 'rs55705857', (140, 150))	('causative-variant', 'Reg', (188, 205))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('rs55705857', 'Var', (140, 150))	('glioma', 'Disease', (220, 226))
177183	27282637	However, the genomic region where rs55705857 is located (8q24.21) contains no protein coding genes, no micro-RNAs and had no previously demonstrated mechanistic link to glioma development.	('rs55705857', 'Mutation', 'rs55705857', (34, 44))	('glioma', 'Disease', (169, 175))	('rs55705857', 'Var', (34, 44))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('protein', 'Protein', (78, 85))
177184	27282637	Nevertheless, the strict phylogenetic conservation of the region centered on rs55705857 in mammals and the exceptionally strong association with IDH-mutant gliomas suggested a functional role.	('rs55705857', 'Mutation', 'rs55705857', (77, 87))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('IDH', 'Gene', (145, 148))	('rs55705857', 'Var', (77, 87))	('gliomas', 'Disease', (156, 163))	('IDH', 'Gene', '3417', (145, 148))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('association', 'Interaction', (128, 139))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
177185	27282637	The hypothesis of this study was that rs55705857 played a direct role in glioma oncogenesis and we sought clues by demographic-, clinical-, molecular-, transcriptomic- and proteomic- comparisons.	('rs55705857', 'Mutation', 'rs55705857', (38, 48))	('rs55705857', 'Var', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('glioma oncogenesis', 'Disease', 'MESH:D063646', (73, 91))	('glioma oncogenesis', 'Disease', (73, 91))
177186	27282637	Turkey has a diverse genetic makeup; therefore in order to confirm and recapitulate the previously reported association between rs55705857 and glioma-risk in the Turkish population, we performed a case-control experiment.	('rs55705857', 'Var', (128, 138))	('Turkey', 'Species', '9103', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('rs55705857', 'Mutation', 'rs55705857', (128, 138))	('glioma', 'Disease', (143, 149))
177194	27282637	WHO grade-II and -III oligodendrogliomas, oligoastrocytomas and astrocytomas) were strongly associated with the risk-allele of rs55705857 (ORs of 10.55, 9.41 and 8.91; n = 67, 32, 38, respectively; all p < 0.0001) (Supplementary Table 2).	('astrocytomas', 'Disease', 'MESH:D001254', (47, 59))	('astrocytomas', 'Disease', 'MESH:D001254', (64, 76))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (22, 40))	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('astrocytoma', 'Phenotype', 'HP:0009592', (64, 75))	('oligoastrocytomas', 'Disease', (42, 59))	('rs55705857', 'Mutation', 'rs55705857', (127, 137))	('oligodendrogliomas', 'Disease', (22, 40))	('astrocytomas', 'Disease', (47, 59))	('astrocytomas', 'Disease', (64, 76))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (42, 59))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('rs55705857', 'Var', (127, 137))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
177195	27282637	There was only a marginally significant association between IDH-mutant GBM and rs55705857.	('IDH', 'Gene', '3417', (60, 63))	('IDH', 'Gene', (60, 63))	('rs55705857', 'Mutation', 'rs55705857', (79, 89))	('rs55705857', 'Var', (79, 89))
177196	27282637	On the other hand, an almost two-fold difference of rs55705857-associated risk between IDH-mutated WHO grade-II and grade-III tumors (ORs 11.51 vs. 6.11; p < 0.0001 vs. p = 0.0003, respectively) suggests a strong grade-specific bias of rs55705857-glioma association (Fig.	('tumors', 'Disease', (126, 132))	('rs55705857', 'Var', (236, 246))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('rs55705857', 'DBSNP_MENTION', 'None', (52, 62))	('IDH', 'Gene', (87, 90))	('rs55705857', 'Mutation', 'rs55705857', (52, 62))	('IDH', 'Gene', '3417', (87, 90))	('rs55705857', 'DBSNP_MENTION', 'None', (236, 246))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('rs55705857', 'Var', (52, 62))	('rs55705857', 'Mutation', 'rs55705857', (236, 246))
177199	27282637	Next, we tested association of rs55705857 with molecular subtypes of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('rs55705857', 'Mutation', 'rs55705857', (31, 41))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('association', 'Interaction', (16, 27))	('rs55705857', 'Var', (31, 41))	('tested', 'Reg', (9, 15))
177204	27282637	Several SNPs in the 8q24.21 locus have been associated with various cancer types including colorectal, prostate, lung, and breast cancers.	('associated', 'Reg', (44, 54))	('colorectal', 'Disease', 'MESH:D015179', (91, 101))	('SNPs', 'Var', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('breast cancers', 'Disease', 'MESH:D001943', (123, 137))	('breast cancers', 'Disease', (123, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('breast cancers', 'Phenotype', 'HP:0003002', (123, 137))	('cancer', 'Disease', (130, 136))	('colorectal', 'Disease', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung', 'Disease', (113, 117))	('prostate', 'Disease', (103, 111))
177205	27282637	Hence, we hypothesized that rs55705857's effect on gliomas may not be specific to a possible involvement in 8q24.21-associated cancers.	('gliomas', 'Disease', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs55705857', 'Mutation', 'rs55705857', (28, 38))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('rs55705857', 'Var', (28, 38))	('cancers', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
177216	27282637	Besides gliomas, IDH1-IDH2 mutations are frequently observed in chondrosarcomas and cartilaginous tumors, some of them in patients with Ollier disease and Maffucci syndrome.	('mutations', 'Var', (27, 36))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('IDH1', 'Gene', '3417', (17, 21))	('IDH2', 'Gene', (22, 26))	('chondrosarcomas and cartilaginous tumors', 'Disease', 'MESH:D002813', (64, 104))	('IDH2', 'Gene', '3418', (22, 26))	('gliomas', 'Disease', (8, 15))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (64, 78))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('patients', 'Species', '9606', (122, 130))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (64, 79))	('Ollier disease', 'Disease', 'MESH:D004687', (136, 150))	('observed', 'Reg', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Ollier disease', 'Phenotype', 'HP:0500045', (136, 150))	('Maffucci syndrome', 'Disease', (155, 172))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('Ollier disease', 'Disease', (136, 150))	('IDH1', 'Gene', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))
177219	27282637	None of the syndromic patients were rs55705857-G allele carriers and the MAF for all tumors was 4.80, compared to 6.59 for the British population (Table 2).	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('patients', 'Species', '9606', (22, 30))	('syndromic', 'Disease', (12, 21))	('syndromic', 'Disease', 'MESH:D013577', (12, 21))	('rs55705857-G', 'Var', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('rs55705857', 'Mutation', 'rs55705857', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
177220	27282637	Overall, there was no significant association between rs55705857 and IDH-mutant bone/cartilaginous tumors collectively (OR = 0.72; p = 0.46), CHS (OR = 0.99; p = 0.99) or LGCTs (OR = 0.32; p = 0.14; n = 47).	('CHS', 'Disease', 'MESH:D002609', (142, 145))	('IDH', 'Gene', (69, 72))	('rs55705857', 'Var', (54, 64))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (85, 105))	('IDH', 'Gene', '3417', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CHS', 'Disease', (142, 145))	('cartilaginous tumors', 'Disease', (85, 105))	('rs55705857', 'Mutation', 'rs55705857', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
177221	27282637	Despite previous reports that linked rs55705857 with younger age, our analysis of the age of onset failed to identify any statistically significant difference between risk allele carriers and non-carriers within the same glioma subtype (Supplementary Figure 1a).	('rs55705857', 'Var', (37, 47))	('glioma subtype', 'Disease', 'MESH:D005910', (221, 235))	('glioma subtype', 'Disease', (221, 235))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('rs55705857', 'Mutation', 'rs55705857', (37, 47))
177225	27282637	On the other hand, the picture was less clear with astrocytomas: Both histopathologic and molecular classification of IDH-mutant grade-II astrocytomas revealed a trend toward younger age of patients with A/G genotype, compared to those with A/A genotype; however, the difference did not reach the significance level of p < 0.05 (p = 0.22, Kruskall-Wallis test).	('patients', 'Species', '9606', (190, 198))	('astrocytomas', 'Disease', 'MESH:D001254', (51, 63))	('astrocytomas', 'Disease', 'MESH:D001254', (138, 150))	('IDH', 'Gene', (118, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (51, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (138, 149))	('IDH', 'Gene', '3417', (118, 121))	('astrocytomas', 'Disease', (51, 63))	('astrocytomas', 'Disease', (138, 150))	('A/G', 'Var', (204, 207))
177227	27282637	), n = 7 vs. n = 33, for astrocytomas with A/G and A/A genotypes, respectively (Supplementary Figure 1a, right panel).	('astrocytomas', 'Disease', 'MESH:D001254', (25, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('A/A', 'Var', (51, 54))	('astrocytomas', 'Disease', (25, 37))	('A/G', 'Var', (43, 46))
177231	27282637	In WHO grade-II oligodendrogliomas, median, mean and standard error values were as follows: 0.03 vs. 0.03 (median), 0.050 +- 0.0098 vs. 0.075 +- 0.015 (mean +- S.E.M.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (16, 34))	('0.03 vs.', 'Var', (92, 100))	('oligodendrogliomas', 'Disease', (16, 34))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('0.050 +- 0.0098', 'Var', (116, 131))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('0.075 +- 0.015', 'Var', (136, 150))
177232	27282637	IDH-mutant 1p/19q co-deleted ATRX-wt WHO grade-II DGs: 0.05 vs. 0.04 (median), 0.053 +- 0.0107 vs. 0.076 +- 0.0169 (mean +- S.E.M.	('IDH', 'Gene', (0, 3))	('ATRX', 'Gene', '546', (29, 33))	('0.053 +- 0.0107', 'Var', (79, 94))	('IDH', 'Gene', '3417', (0, 3))	('ATRX', 'Gene', (29, 33))
177233	27282637	Similarly, analysis of WHO grade-II astrocytomas yielded no significant difference between the two genotypes, either: 0.04 vs. 0.03 (median), 0.036 +- 0.0078 vs. 0.034 +- 0.0046 (mean +- S.E.M.	('astrocytomas', 'Disease', (36, 48))	('0.036 +- 0.0078', 'Var', (142, 157))	('0.034 +- 0.0046', 'Var', (162, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (36, 48))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))
177234	27282637	Neither did it among IDH-mutant 1p/19q-intact ATRX-mut WHO grade-II DGs: 0.02 vs. 0.03 (median), 0.026 +- 0.0036 vs. 0.043 +- 0.012 (mean +- S.E.M.	('IDH', 'Gene', (21, 24))	('ATRX', 'Gene', '546', (46, 50))	('IDH', 'Gene', '3417', (21, 24))	('ATRX', 'Gene', (46, 50))	('0.026 +- 0.0036', 'Var', (97, 112))
177235	27282637	Therefore, we conclude that there is no association between rs55705857 genotype status and Ki-67 index.	('Ki-67 index', 'Disease', (91, 102))	('rs55705857', 'Var', (60, 70))	('rs55705857', 'Mutation', 'rs55705857', (60, 70))
177240	27282637	Among them, TERT promoter (TERTp) mutations C228T and C250T were recently described in gliomas and a possible relation with rs55705857 has never been explored so far.	('TERTp', 'Gene', (27, 32))	('C250T', 'Var', (54, 59))	('C228T', 'Mutation', 'rs373690274', (44, 49))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('TERT', 'Gene', '7015', (12, 16))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('TERTp', 'Gene', '7015', (27, 32))	('TERT', 'Gene', (27, 31))	('TERT', 'Gene', '7015', (27, 31))	('rs55705857', 'Mutation', 'rs55705857', (124, 134))	('C250T', 'Mutation', 'rs12917', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('C228T', 'Var', (44, 49))	('TERT', 'Gene', (12, 16))	('gliomas', 'Disease', (87, 94))
177241	27282637	Rs55705857-G allele showed the strongest association with IDH1 mutation in "all gliomas" group (53% vs. 81%, for A/A and A/G, respectively; p = 0.001, determined by chi-square test) (Fig.	('Rs55705857-G', 'Var', (0, 12))	('IDH1', 'Gene', '3417', (58, 62))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('mutation', 'Var', (63, 71))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('Rs55705857', 'Mutation', 'Rs55705857', (0, 10))	('IDH1', 'Gene', (58, 62))
177244	27282637	p53 protein has a very short half-life of 5-20 min and widespread nuclear accumulation of p53 is not observable in normal tissues; it is indicative of mutations in the p53 pathway.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (90, 93))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', '7157', (168, 171))	('p53', 'Gene', (168, 171))	('mutations', 'Var', (151, 160))
177246	27282637	On the other hand, frequency of TERTp-mutations (52% vs. 53%), loss-of-PTEN expression (PTEN-LOE, 80% vs. 76%), copy number gain of PDGFs (PDGFA, PDGFB, PDGFRA, PDGFRB; 13% vs. 13%) and MGMT promoter methylation above an arbitrary 30% level (59% vs. 59%) was almost identical between A/A and A/G groups (Fig.	('PTEN', 'Gene', '5728', (71, 75))	('PDGFA', 'Gene', (139, 144))	('MGMT', 'Gene', (186, 190))	('copy number', 'Var', (112, 123))	('expression', 'Species', '29278', (76, 86))	('PDGFB', 'Gene', '5155', (146, 151))	('PTEN', 'Gene', (88, 92))	('PDGFRA', 'Gene', (153, 159))	('PDGFRA', 'Gene', '5156', (153, 159))	('PDGFRB', 'Gene', '5159', (161, 167))	('PDGFB', 'Gene', (146, 151))	('gain', 'PosReg', (124, 128))	('PDGFRB', 'Gene', (161, 167))	('PDGFA', 'Gene', '5154', (139, 144))	('MGMT', 'Gene', '4255', (186, 190))	('PTEN', 'Gene', (71, 75))	('expression', 'MPA', (76, 86))	('TERTp', 'Gene', (32, 37))	('PTEN', 'Gene', '5728', (88, 92))	('TERTp', 'Gene', '7015', (32, 37))
177248	27282637	Interestingly, we noted that p16INK4A-LOE was observed in 6 out of 13 (46%) IDH-mutant 1p/19q co-deleted ATRX-wt WHO grade-II DGs with the A/A genotype but in none of those with the A/G genotype (n = 9, p = 0.009) (Fig.	('A/A', 'Var', (139, 142))	('ATRX', 'Gene', '546', (105, 109))	('p16INK4A', 'Gene', '1029', (29, 37))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', '3417', (76, 79))	('ATRX', 'Gene', (105, 109))	('p16INK4A', 'Gene', (29, 37))
177252	27282637	Frequency of p53-NE, p16INK4A-LOE, PTEN-LOE and copy number gain of PDGFs (PDGFA, PDGFB, PDGFRA, PDGFRB) were similar between the two groups.	('PDGFRA', 'Gene', '5156', (89, 95))	('PDGFA', 'Gene', (75, 80))	('p16INK4A', 'Gene', (21, 29))	('PTEN', 'Gene', (35, 39))	('PDGFB', 'Gene', '5155', (82, 87))	('PTEN', 'Gene', '5728', (35, 39))	('PDGFRB', 'Gene', '5159', (97, 103))	('PDGFB', 'Gene', (82, 87))	('PDGFA', 'Gene', '5154', (75, 80))	('gain', 'PosReg', (60, 64))	('PDGFRB', 'Gene', (97, 103))	('p53', 'Gene', (13, 16))	('p16INK4A', 'Gene', '1029', (21, 29))	('copy number', 'Var', (48, 59))	('p53', 'Gene', '7157', (13, 16))	('PDGFRA', 'Gene', (89, 95))
177253	27282637	Although investigation of possible correlations between rs55705857 and well-known molecular changes in gliomas provides valuable information, a mechanistic explanation necessitates an understanding of its function.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('rs55705857', 'Mutation', 'rs55705857', (56, 66))	('rs55705857', 'Var', (56, 66))
177254	27282637	Therefore, we hypothesized that rs55705857 may affect the expression of the CCDC26 lncRNA gene that it resides within.	('rs55705857', 'Var', (32, 42))	('expression', 'Species', '29278', (58, 68))	('expression', 'MPA', (58, 68))	('affect', 'Reg', (47, 53))	('CCDC26', 'Gene', (76, 82))	('CCDC26', 'Gene', '137196', (76, 82))	('rs55705857', 'Mutation', 'rs55705857', (32, 42))
177257	27282637	The 8q24 locus is commonly amplified in gliomas and an obvious question is whether rs55705857 has any association with copy number variations (CNV) at this locus or elsewhere in the genome.	('association', 'Interaction', (102, 113))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('rs55705857', 'Mutation', 'rs55705857', (83, 93))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('rs55705857', 'Var', (83, 93))
177259	27282637	None of the 4 tumors in the A/G group had any CNV at 8q24, while 2/18 (11%) tumors in the A/A group had copy number gain (p = 1.00 by Fisher's exact test) (Supplementary Figure 2 and Supplementary Table 3).	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('copy number', 'Var', (104, 115))	('gain', 'PosReg', (116, 120))	('CNV', 'Var', (46, 49))
177260	27282637	These findings suggest that rs55705857 is unlikely to be associated with mechanisms that affect 8q24.21 copy number or require copy-number changes to show its effects.	('rs55705857', 'Mutation', 'rs55705857', (28, 38))	('rs55705857', 'Var', (28, 38))	('8q24.21', 'Gene', (96, 103))
177261	27282637	Candidate based analysis of molecular alterations hinted at a differential involvement of certain genes/pathways in tumors with rs55705857-G allele compared to those with A-allele.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('involvement', 'Reg', (75, 86))	('rs55705857-G', 'Var', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('rs55705857', 'Mutation', 'rs55705857', (128, 138))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
177264	27282637	By choosing tumors that are low-grade and highly similar to each other in terms of molecular alterations, we aimed at minimizing the confounding factors and maximize the chances of identifying differences that are associated with rs55705857 genotype.	('rs55705857', 'Mutation', 'rs55705857', (230, 240))	('rs55705857', 'Var', (230, 240))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
177265	27282637	Another important aspect of the strategy that we used to maximize differences due to rs55705857 and minimize the others was to compare tumors-to-tumors (i.e.	('tumors-to-tumors', 'Disease', 'MESH:D009369', (135, 151))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors-to-tumors', 'Disease', (135, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('rs55705857', 'Var', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('rs55705857', 'Mutation', 'rs55705857', (85, 95))
177267	27282637	The results suggested "neurotrophin signaling pathway", "Ras/Rap1/MAPK pathways", "osteoclast differentiation pathway" as the most significant KEGG pathways being differentially regulated between WHO grade-II IDH-mutant 1p/19q co-deleted DGs with rs55705857-A/G and rs55705857-A/A genotypes (Supplementary Table 5).	('IDH', 'Gene', '3417', (209, 212))	('rs55705857', 'Mutation', 'rs55705857', (247, 257))	('Rap1', 'Gene', (61, 65))	('regulated', 'Reg', (178, 187))	('rs55705857-A/A', 'Var', (266, 280))	('neurotrophin', 'Gene', (23, 35))	('neurotrophin', 'Gene', '627', (23, 35))	('Rap1', 'Gene', '5906', (61, 65))	('rs55705857-A/G', 'Var', (247, 261))	('IDH', 'Gene', (209, 212))	('rs55705857', 'Mutation', 'rs55705857', (266, 276))
177273	27282637	The second most significant TF was CREB1 (cAMP Response Element Binding Protein 1) - top hit in IDH-mutant 1p/19q-intact ATRX-mut WHO grade-II DGs (p-value 1.83E-52) and third top hit in IDH-mutant 1p/19q co-deleted ATRX-wt WHO grade-II DGs (p-value 4.53E-14).	('ATRX', 'Gene', (216, 220))	('IDH', 'Gene', '3417', (96, 99))	('CREB1', 'Gene', (35, 40))	('IDH', 'Gene', (187, 190))	('cAMP Response Element Binding Protein 1', 'Gene', (42, 81))	('1p/19q-intact', 'Var', (107, 120))	('cAMP Response Element Binding Protein 1', 'Gene', '1385', (42, 81))	('ATRX', 'Gene', (121, 125))	('ATRX', 'Gene', '546', (216, 220))	('IDH', 'Gene', '3417', (187, 190))	('CREB1', 'Gene', '1385', (35, 40))	('ATRX', 'Gene', '546', (121, 125))	('IDH', 'Gene', (96, 99))
177274	27282637	Of note, GO processes associated with both transcription factor networks were nearly identical between molecular oligodendrogliomas and astrocytomas, implying common processes are affected in both types of gliomas in the presence of the G-allele.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('oligodendrogliomas and astrocytomas', 'Disease', 'MESH:D009837', (113, 148))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('G-allele', 'Var', (237, 245))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('gliomas', 'Disease', (206, 213))	('gliomas', 'Disease', 'MESH:D005910', (206, 213))	('affected', 'Reg', (180, 188))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
177275	27282637	Considering the well-known roles of MYC in various cancer types including gliomas and its relative proximity to rs55705857 on chromosome 8, we hypothesized that rs55705857 may modulate MYC expression.	('modulate', 'Reg', (176, 184))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('rs55705857', 'Mutation', 'rs55705857', (161, 171))	('expression', 'Species', '29278', (189, 199))	('MYC', 'Protein', (185, 188))	('gliomas', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('expression', 'MPA', (189, 199))	('rs55705857', 'Var', (161, 171))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('rs55705857', 'Mutation', 'rs55705857', (112, 122))
177278	27282637	Studies on AML and ALL suggested that 100 kb region flanking rs55705857 contains 5 tissue-specific MYC enhancers and, despite being 1.9 Mb apart from MYC gene, interacts with SWI/SNF chromatin remodeling complex subunit Brg1 (in AML) or transcription factor Tal1 (in ALL).	('AML', 'Disease', 'MESH:D015470', (229, 232))	('interacts', 'Reg', (160, 169))	('rs55705857', 'Var', (61, 71))	('Brg1', 'Gene', '6597', (220, 224))	('Tal1', 'Gene', '6886', (258, 262))	('AML', 'Disease', (229, 232))	('Tal1', 'Gene', (258, 262))	('enhancers', 'PosReg', (103, 112))	('Brg1', 'Gene', (220, 224))	('AML', 'Disease', 'MESH:D015470', (11, 14))	('MYC', 'Gene', (99, 102))	('rs55705857', 'Mutation', 'rs55705857', (61, 71))	('AML', 'Disease', (11, 14))
177281	27282637	The genomic region encompassing rs55705857 showed evidence of high sequence conservation between evolutionarily-divergent species, with a GERP score 5.98.	('sequence', 'MPA', (67, 75))	('rs55705857', 'Mutation', 'rs55705857', (32, 42))	('rs55705857', 'Var', (32, 42))
177282	27282637	To infer a possible regulatory function, we assessed regulatory features using UCSC Genome Browser, revealing that rs55705857 overlaps a DNase I hypersensitivity site (one of the three cell lines with hypersensitivity is HA-h, a hippocampal astrocyte line), histone marks that are associated with regulatory elements in H1-derived neuronal progenitor cultured cells, a RNA-Pol2 binding signal, and small RNA-seq data showing a balanced short RNA transcription, characteristic of enhancer-associated RNA (eRNA), a hallmark of active enhancers (Fig.	('hypersensitivity', 'Disease', (201, 217))	('hypersensitivity', 'Disease', 'MESH:D004342', (201, 217))	('rs55705857', 'Mutation', 'rs55705857', (115, 125))	('hypersensitivity', 'Disease', (145, 161))	('hypersensitivity', 'Disease', 'MESH:D004342', (145, 161))	('rs55705857', 'Var', (115, 125))
177283	27282637	All these features suggest that rs55705857 may be a regulatory SNP, residing in a cancer-specific enhancer element.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rs55705857', 'Var', (32, 42))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('rs55705857', 'Mutation', 'rs55705857', (32, 42))
177285	27282637	Both constructs with the enhancer element displayed a higher firefly luciferase activity (normalized to Renilla luciferase activity) than the construct with the MYC promoter alone, supporting the enhancer activity hypothesis of the conserved region.	('higher', 'PosReg', (54, 60))	('element', 'Var', (34, 41))	('Renilla luciferase activity', 'Disease', 'OMIM:612348', (104, 131))	('firefly luciferase', 'Enzyme', (61, 79))	('activity', 'MPA', (80, 88))	('Renilla luciferase activity', 'Disease', (104, 131))
177288	27282637	These results indicate that the conserved region around rs55705857 can enhance the transcriptional activity of the MYC promoter specifically and the risk allele further augments this effect.	('transcriptional activity', 'MPA', (83, 107))	('rs55705857', 'Mutation', 'rs55705857', (56, 66))	('enhance', 'PosReg', (71, 78))	('MYC', 'Protein', (115, 118))	('rs55705857', 'Var', (56, 66))	('augments', 'NegReg', (169, 177))
177289	27282637	Although multiple lines of evidence we obtained showed that rs55705857 is associated with altered MYC activity, we did not find difference in MYC protein expression by immunohistochemical staining of 31 LGG samples (n = 21 vs. n = 10, for A/G and A/A, respectively; Supplementary Figure 3a).	('expression', 'Species', '29278', (154, 164))	('altered', 'Reg', (90, 97))	('rs55705857', 'Var', (60, 70))	('MYC activity', 'MPA', (98, 110))	('rs55705857', 'Mutation', 'rs55705857', (60, 70))
177290	27282637	Neither did we observe any difference between the two groups in terms of copy number gain of MYC (Supplementary Figure 3b) or any oncogenic copy number alteration of the MYC-MAX-FBXW7 module (Supplementary Figure 3c).	('gain', 'PosReg', (85, 89))	('FBXW7', 'Gene', '55294', (178, 183))	('MYC', 'Gene', (93, 96))	('FBXW7', 'Gene', (178, 183))	('copy number', 'Var', (73, 84))
177291	27282637	A plausible explanation is that the effect exerted by rs55705857 shifts MYC expression only modestly and possibly only in a certain cell type, such as glioma initiating cells.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('shifts', 'Reg', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('rs55705857', 'Var', (54, 64))	('expression', 'Species', '29278', (76, 86))	('expression', 'MPA', (76, 86))	('MYC', 'Protein', (72, 75))	('glioma', 'Disease', (151, 157))	('rs55705857', 'Mutation', 'rs55705857', (54, 64))
177292	27282637	Indeed, a study that investigated the effects of the deletion of a MYC enhancer that is implicated in colorectal cancer showed that the deletion led to cancer resistance while having only slight or no impact on MYC expression.	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('colorectal cancer', 'Disease', (102, 119))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('led to', 'Reg', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('deletion', 'Var', (53, 61))	('MYC', 'Gene', (67, 70))	('cancer', 'Disease', (113, 119))	('deletion', 'Var', (136, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('expression', 'Species', '29278', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
177294	27282637	Our study has three main findings: First, the rs55705857-associated glioma risk was confirmed in the Turkish population.	('rs55705857-associated', 'Var', (46, 67))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('rs55705857', 'Mutation', 'rs55705857', (46, 56))	('glioma', 'Disease', (68, 74))
177296	27282637	Third, the evolutionarily conserved region encompassing rs55705857 may act as a MYC-enhancer and the presence of the risk allele further potentiates this activity.	('MYC-enhancer', 'MPA', (80, 92))	('rs55705857', 'Mutation', 'rs55705857', (56, 66))	('rs55705857', 'Var', (56, 66))	('potentiates', 'PosReg', (137, 148))
177297	27282637	We found the minor allele frequency (MAF) for rs55705857 as 1.7% in the general Turkish population and 7.5% in hemispheric adult gliomas.	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('rs55705857', 'Var', (46, 56))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('rs55705857', 'Mutation', 'rs55705857', (46, 56))
177302	27282637	Therefore, rs55705857 may only be interfering with the oncogenic process in IDH-mutant gliomas.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('rs55705857', 'Mutation', 'rs55705857', (11, 21))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', '3417', (76, 79))	('rs55705857', 'Var', (11, 21))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('gliomas', 'Disease', (87, 94))
177303	27282637	Even though evidence strongly suggests a causal role for rs55705857 in gliomagenesis, the fact that only a tiny fraction of rs55705857-G allele carriers develop glioma points to a modulatory role for this SNP.	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Disease', (71, 77))	('rs55705857-G', 'Var', (124, 136))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('develop', 'PosReg', (153, 160))	('rs55705857', 'Mutation', 'rs55705857', (124, 134))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('rs55705857', 'Mutation', 'rs55705857', (57, 67))
177307	27282637	Our speculation that rs55705857 marks less malignant cases is supported by findings from clinical studies, which showed that rs55705857 is a marker of longer progression-free survival in patients with oligodendrogliomas.	('patients', 'Species', '9606', (187, 195))	('oligodendrogliomas', 'Disease', (201, 219))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('rs55705857', 'Mutation', 'rs55705857', (21, 31))	('longer', 'PosReg', (151, 157))	('rs55705857', 'Mutation', 'rs55705857', (125, 135))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('rs55705857', 'Var', (125, 135))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (201, 219))
177308	27282637	In our patient cohort, the carriers of the risk allele at rs55705857 had a trend towards longer "overall-survival" or longer "time to malignant degeneration" in oligodendrogliomas but not in astrocytomas.	('astrocytomas', 'Disease', (191, 203))	('rs55705857', 'Mutation', 'rs55705857', (58, 68))	('patient', 'Species', '9606', (7, 14))	('longer', 'PosReg', (89, 95))	('time', 'CPA', (126, 130))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('malignant degeneration', 'Disease', 'MESH:D009369', (134, 156))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (161, 179))	('rs55705857', 'Var', (58, 68))	('malignant degeneration', 'Disease', (134, 156))	('oligodendrogliomas', 'Disease', (161, 179))	('astrocytomas', 'Disease', 'MESH:D001254', (191, 203))	('astrocytoma', 'Phenotype', 'HP:0009592', (191, 202))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))
177310	27282637	The association of rs55705857 with IDH-mutant gliomas is the strongest reported so far for any cancer and the minor allele frequency is very low.	('rs55705857', 'Mutation', 'rs55705857', (19, 29))	('IDH', 'Gene', (35, 38))	('association', 'Interaction', (4, 15))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('rs55705857', 'Var', (19, 29))	('cancer', 'Disease', (95, 101))	('gliomas', 'Disease', (46, 53))	('IDH', 'Gene', '3417', (35, 38))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
177313	27282637	To exclude a general cancer predisposition related to rs55705857, we tested several systemic cancers including lung, colorectal, breast and prostate but a possible association with rs55705857 was excluded for all (n = 411) or each cancer type individually.	('systemic cancers', 'Disease', 'MESH:D009369', (84, 100))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('rs55705857', 'Mutation', 'rs55705857', (181, 191))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (231, 237))	('lung', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tested', 'Reg', (69, 75))	('colorectal', 'Disease', (117, 127))	('rs55705857', 'Mutation', 'rs55705857', (54, 64))	('prostate', 'Disease', (140, 148))	('rs55705857', 'Var', (181, 191))	('cancer', 'Disease', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('breast', 'Disease', (129, 135))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('rs55705857', 'Var', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal', 'Disease', 'MESH:D015179', (117, 127))	('systemic cancers', 'Disease', (84, 100))
177317	27282637	Subtype specific associations of rs55705857 with loss of p16INK4A expression, EGFR overexpression and p53 nuclear accumulation suggests that the G-allele may increase tumorigenic potential of tumor initiating cells through partially different routes in oligodendrogliomas and astrocytomas.	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('expression', 'Species', '29278', (87, 97))	('expression', 'MPA', (66, 76))	('EGFR', 'Gene', '1956', (78, 82))	('increase', 'PosReg', (158, 166))	('p16INK4A', 'Gene', (57, 65))	('rs55705857', 'Var', (33, 43))	('oligodendrogliomas and astrocytomas', 'Disease', 'MESH:D009837', (253, 288))	('p16INK4A', 'Gene', '1029', (57, 65))	('p53', 'Gene', '7157', (102, 105))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (192, 197))	('loss', 'NegReg', (49, 53))	('expression', 'Species', '29278', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('p53', 'Gene', (102, 105))	('EGFR', 'Gene', (78, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (276, 287))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('rs55705857', 'Mutation', 'rs55705857', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
177321	27282637	rs4295627, rs891835), but an underlying mechanism has not been reported for any of them.	('rs891835', 'Mutation', 'rs891835', (11, 19))	('rs4295627', 'Var', (0, 9))	('rs891835', 'Var', (11, 19))	('rs4295627', 'Mutation', 'rs4295627', (0, 9))
177322	27282637	With rs55705857, the first plausible explanation would be an effect on local gene expression, namely of CCDC26 (RAM).	('rs55705857', 'Mutation', 'rs55705857', (5, 15))	('expression', 'Species', '29278', (82, 92))	('local gene expression', 'MPA', (71, 92))	('rs55705857', 'Var', (5, 15))	('CCDC26', 'Gene', '137196', (104, 110))	('effect', 'Reg', (61, 67))	('CCDC26', 'Gene', (104, 110))
177325	27282637	In agreement, our quantitative analysis using qPCR (n = 38) and RNA-seq methods (n = 7) did not detect significant expression of CCDC26 in the majority (90%) of glioma tumor samples, which indicated that rs55705857 is unlikely to exert its effect by modulating the expression of major isoforms of CCDC26 in tumor cells.	('rs55705857', 'Var', (204, 214))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('CCDC26', 'Gene', (129, 135))	('tumor', 'Disease', (168, 173))	('CCDC26', 'Gene', '137196', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('expression', 'Species', '29278', (265, 275))	('expression', 'Species', '29278', (115, 125))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', (307, 312))	('glioma tumor', 'Disease', (161, 173))	('glioma tumor', 'Disease', 'MESH:D005910', (161, 173))	('rs55705857', 'Mutation', 'rs55705857', (204, 214))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CCDC26', 'Gene', (297, 303))	('CCDC26', 'Gene', '137196', (297, 303))	('modulating', 'Reg', (250, 260))
177326	27282637	Some of the SNPs at the 8q24 locus that had been linked to systemic cancers including prostate, colorectal and breast were shown to have long-distance interactions with the MYC promoter and regulate its expression in a tissue-specific manner.	('colorectal', 'Disease', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('systemic cancers', 'Disease', (59, 75))	('SNPs', 'Var', (12, 16))	('expression', 'Species', '29278', (203, 213))	('interactions', 'Interaction', (151, 163))	('linked', 'Reg', (49, 55))	('breast', 'Disease', (111, 117))	('expression', 'MPA', (203, 213))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('colorectal', 'Disease', 'MESH:D015179', (96, 106))	('systemic cancers', 'Disease', 'MESH:D009369', (59, 75))	('prostate', 'Disease', (86, 94))	('regulate', 'Reg', (190, 198))
177327	27282637	So far, no mechanistic link has been demonstrated in gliomas between rs55705857 and MYC, which is located approximately 1.9 Mb centromeric to rs55705857 (as opposed to aforementioned systemic cancer associated-SNPs, which are situated centromeric to MYC).	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('MYC', 'Disease', (84, 87))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('rs55705857', 'Mutation', 'rs55705857', (69, 79))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('rs55705857', 'Mutation', 'rs55705857', (142, 152))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('rs55705857', 'Var', (69, 79))
177330	27282637	Furthermore, in vitro luciferase assays showed that the genomic region centered on rs55705857 has a positive modulatory effect on the MYC promoter and that the presence of the risk allele significantly augmented this already positive modulation.	('MYC promoter', 'MPA', (134, 146))	('augmented', 'PosReg', (202, 211))	('positive', 'PosReg', (100, 108))	('rs55705857', 'Mutation', 'rs55705857', (83, 93))	('rs55705857', 'Var', (83, 93))
177337	27282637	We speculate that rs55705857 increases MYC expression in a particular spatial and temporal context and therefore increases the probability of tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('rs55705857', 'Var', (18, 28))	('rs55705857', 'Mutation', 'rs55705857', (18, 28))	('increases', 'PosReg', (29, 38))	('expression', 'Species', '29278', (43, 53))	('expression', 'MPA', (43, 53))	('increases', 'PosReg', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('MYC', 'Protein', (39, 42))
177342	27282637	Therefore, rs55705857 mediated increase in MYC expression do not have to be sustained through all stages of gliomagenesis and instead may very well be largely restricted to a certain cell type (e.g.	('MYC', 'Protein', (43, 46))	('glioma', 'Disease', (108, 114))	('rs55705857', 'Mutation', 'rs55705857', (11, 21))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('rs55705857', 'Var', (11, 21))	('expression', 'Species', '29278', (47, 57))	('increase', 'PosReg', (31, 39))
177344	27282637	In line with this hypothesis, the 8q24 localized and prostate cancer associated SNP (rs6983267) was shown to increase MYC expression only during prostate development/maturation before the onset of tumorigenesis.	('expression', 'MPA', (122, 132))	('prostate cancer', 'Disease', (53, 68))	('rs6983267', 'Mutation', 'rs6983267', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('increase', 'PosReg', (109, 117))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('MYC', 'Protein', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('rs6983267', 'Var', (85, 94))	('tumor', 'Disease', (197, 202))	('expression', 'Species', '29278', (122, 132))
177345	27282637	A similar impact may be exerted by rs55705857 during brain development and/or in NSCs/OPCs.	('rs55705857', 'Mutation', 'rs55705857', (35, 45))	('NSCs/OPCs', 'Disease', (81, 90))	('rs55705857', 'Var', (35, 45))
177347	27282637	Knock-down of Rap1 has been identified to be synthetic lethal to MYC overexpression in human mammary epithelial cells (HMECs) Despite being altered in many different cancer types, deregulation of MYC expression could be toxic to cells and induce apoptosis.	('cancer', 'Disease', (166, 172))	('MYC', 'Gene', (196, 199))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('apoptosis', 'CPA', (246, 255))	('Rap1', 'Gene', '5906', (14, 18))	('human', 'Species', '9606', (87, 92))	('expression', 'Species', '29278', (73, 83))	('deregulation', 'Var', (180, 192))	('expression', 'Species', '29278', (200, 210))	('Rap1', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('induce', 'Reg', (239, 245))
177350	27282637	CREB is also a classical mediator of neurotrophin response in neurons and may explain differential regulation of neurotrophin pathway in gliomas with and without rs55705857-G allele.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('CREB', 'Gene', (0, 4))	('rs55705857-G', 'Var', (162, 174))	('rs55705857', 'Mutation', 'rs55705857', (162, 172))	('gliomas', 'Disease', (137, 144))	('CREB', 'Gene', '1385', (0, 4))	('neurotrophin', 'Gene', (37, 49))	('neurotrophin', 'Gene', '627', (37, 49))	('neurotrophin', 'Gene', (113, 125))	('neurotrophin', 'Gene', '627', (113, 125))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))
177351	27282637	Recently, CREB phosphorylation has been inversely associated with 1p/19q-codeletion, the hallmark alteration of oligodendrogliomas.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('inversely', 'NegReg', (40, 49))	('phosphorylation', 'Var', (15, 30))	('1p/19q-codeletion', 'Disease', (66, 83))	('CREB', 'Gene', (10, 14))	('oligodendrogliomas', 'Disease', (112, 130))	('CREB', 'Gene', '1385', (10, 14))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('associated', 'Reg', (50, 60))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (112, 130))
177352	27282637	However, the molecular machinery that links rs55705857 to altered CREB network is the subject of further studies.	('rs55705857', 'Mutation', 'rs55705857', (44, 54))	('rs55705857', 'Var', (44, 54))	('CREB', 'Gene', (66, 70))	('CREB', 'Gene', '1385', (66, 70))
177359	27282637	Fluorescent PCR and fragment analysis by capillary electrophoresis of D1S162, D1S199, D1S226, D1S186, D1S312, D19S112, D19S918 and D19S206 STR regions for detection of loss of heterozygosity (LOH) in 1p and 19q in the tumor tissue was performed in ABI PRISM  3100 Genetic Analyzer (Applied Biosystems, ThermoFisher, Carlsbad, CA).	('D19S918', 'Var', (119, 126))	('D1S199', 'Var', (78, 84))	('D19S206', 'Var', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('D1S186', 'Var', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('D1S312', 'Var', (102, 108))	('D19S918', 'CellLine', 'CVCL:8471', (119, 126))	('D1S162', 'Var', (70, 76))	('tumor', 'Disease', (218, 223))	('D19S112', 'Var', (110, 117))	('D1S226', 'Var', (86, 92))
177374	27282637	IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation.	('IDH', 'Gene', (0, 3))	('rs55705857', 'Mutation', 'rs55705857', (42, 52))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('MYC', 'Disease', (81, 84))	('rs55705857', 'Var', (42, 52))	('glioma', 'Disease', (11, 17))
177401	24660024	Conversely, failure to detect that a particular area does have functional significance (false negative or type II error) can lead to a resection that causes a patient to have a neurological deficit.	('neurological deficit', 'Disease', (177, 197))	('causes', 'Reg', (150, 156))	('type II error', 'Disease', (106, 119))	('neurological deficit', 'Phenotype', 'HP:0000707', (177, 197))	('resection', 'Var', (135, 144))	('neurological deficit', 'Disease', 'MESH:D009461', (177, 197))	('type II error', 'Disease', 'MESH:D005776', (106, 119))	('patient', 'Species', '9606', (159, 166))	('lead to', 'Reg', (125, 132))
177429	24660024	Four patterns of differences in anisotropy have been described in disease states: altered position and direction but normal signal, which corresponds to tract displacement; decreased anisotropy but normal direction and location, thought to correspond to vasogenic edema; decreased anisotropy signal with disrupted direction maps, thought to correspond to infiltration; and loss of anisotropic signal corresponding to tract obliteration or destruction.	('edema', 'Phenotype', 'HP:0000969', (264, 269))	('differences', 'Var', (17, 28))	('anisotropy', 'MPA', (32, 42))	('direction maps', 'MPA', (314, 328))	('position', 'MPA', (90, 98))	('edema', 'Disease', (264, 269))	('decreased', 'NegReg', (271, 280))	('anisotropic signal', 'MPA', (381, 399))	('anisotropy signal', 'MPA', (281, 298))	('loss', 'NegReg', (373, 377))	('direction', 'MPA', (103, 112))	('decreased', 'NegReg', (173, 182))	('edema', 'Disease', 'MESH:D004487', (264, 269))	('altered', 'Reg', (82, 89))	('anisotropy', 'MPA', (183, 193))
177449	24660024	Another group showed that in the periphery of low-grade gliomas, there was higher FA and fiber density index compared with high-grade gliomas, which they attributed to less disruption of WM tracts by low-grade gliomas compared with high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('FA and', 'MPA', (82, 88))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('gliomas', 'Disease', (243, 250))	('gliomas', 'Disease', (210, 217))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('low-grade', 'Var', (200, 209))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))	('less', 'NegReg', (168, 172))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('higher', 'PosReg', (75, 81))	('gliomas', 'Disease', (134, 141))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('disruption', 'MPA', (173, 183))
177469	24660024	As these patients had permanent language deficits as a result of these lesions, the idea of specifically localized brain function began to be developed.	('patients', 'Species', '9606', (9, 17))	('language deficit', 'Phenotype', 'HP:0000750', (32, 48))	('language deficits', 'Disease', 'MESH:D007806', (32, 49))	('language deficits', 'Disease', (32, 49))	('lesions', 'Var', (71, 78))
177489	24660024	Another piece of evidence suggesting that the kinetics of the insult on the brain is important in modulating plasticity is considering that meta-analyses of patients harboring low-grade gliomas suggested that over 90% were able to return to work within 1 year of surgery, while only 50% of young patients with strokes returned to work.	('strokes', 'Phenotype', 'HP:0001297', (310, 317))	('gliomas', 'Disease', (186, 193))	('low-grade', 'Var', (176, 185))	('gliomas', 'Disease', 'MESH:D005910', (186, 193))	('patients', 'Species', '9606', (157, 165))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('stroke', 'Phenotype', 'HP:0001297', (310, 316))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('return', 'MPA', (231, 237))	('strokes', 'Disease', 'MESH:D020521', (310, 317))	('patients', 'Species', '9606', (296, 304))	('strokes', 'Disease', (310, 317))
177497	24660024	Consistent with this, it has been shown that in patients where BOLD activation of SMA occurred despite infiltration of tumor, surgical resection of tumor caused transient 'SMA syndrome' in at least 50% of patients.	('SMA', 'Gene', '6606', (82, 85))	('tumor', 'Disease', (119, 124))	('SMA', 'Gene', (172, 175))	('patients', 'Species', '9606', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SMA', 'Gene', '6606', (172, 175))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('surgical resection', 'Var', (126, 144))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('SMA', 'Gene', (82, 85))	('patients', 'Species', '9606', (48, 56))	('caused', 'Reg', (154, 160))
177503	24660024	Similarly, in patients with low-grade gliomas invading language areas, activation of remote areas not necessarily associated with language functions such as left frontolateral regions, including Brodmann areas 46, 47 and the left putamen have been observed.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('low-grade', 'Var', (28, 37))	('activation', 'PosReg', (71, 81))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('patients', 'Species', '9606', (14, 22))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
177511	24660024	Similarly for tumors located in SMA, total resections are possible, which usually result in a transient 'SMA syndrome', which consists of spectrum of symptoms from mutism to decreased spontaneous contralateral movements and an eventual return to neurological baseline in approximately 6 weeks.	('decreased', 'NegReg', (174, 183))	('resections', 'Var', (43, 53))	('result in', 'Reg', (82, 91))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('SMA', 'Gene', '6606', (32, 35))	('SMA', 'Gene', (32, 35))	('SMA', 'Gene', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SMA', 'Gene', '6606', (105, 108))	('mutism', 'Phenotype', 'HP:0002300', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
177563	24066240	In an effort to compensate there is enhancement in the rate of diffusion, which the tumour cell performs by escalating its surface area per unit nuclear mass, a feature that is seen histologically by the severe pleomorphism in shape of the cells (i.e., deformity in its shape from ideal spherical one).	('escalating', 'PosReg', (108, 118))	('deformity', 'Disease', 'MESH:D009140', (253, 262))	('enhancement', 'PosReg', (36, 47))	('rate', 'MPA', (55, 59))	('diffusion', 'MPA', (63, 72))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('surface area', 'MPA', (123, 135))	('deformity', 'Disease', (253, 262))	('pleomorphism', 'Var', (211, 223))
177565	22681957	However, the association of miR-221/222 with glioma cell invasion and survival remains unknown.	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Disease', (45, 51))	('miR-221/222', 'Var', (28, 39))
177571	22681957	In addition, knockdown of miR-221/222 increased TIMP3 expression and considerably inhibited tumor growth in a xenograft model.	('expression', 'MPA', (54, 64))	('inhibited', 'NegReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('TIMP3', 'Gene', (48, 53))	('knockdown', 'Var', (13, 22))	('TIMP3', 'Gene', '7078', (48, 53))	('increased', 'PosReg', (38, 47))	('miR-221/222', 'Var', (26, 37))
177572	22681957	Finally, the increased level of miR-221/222 expression in high-grade gliomas confers poorer overall survival.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('poorer', 'NegReg', (85, 91))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('overall', 'MPA', (92, 99))	('increased', 'PosReg', (13, 22))	('miR-221/222', 'Var', (32, 43))
177578	22681957	MicroRNAs (miRNAs), a recently identified class of endogenous, small (~22 nt), non-protein coding, single-stranded RNA molecules, negatively regulate protein-coding genes by base-pair matching with the 3' UTRs of mRNAs.	('base-pair matching', 'Var', (174, 192))	('miR', 'Gene', '220972', (11, 14))	('regulate', 'Reg', (141, 149))	('miR', 'Gene', (11, 14))	('negatively', 'NegReg', (130, 140))	('protein-coding genes', 'Gene', (150, 170))
177585	22681957	However, there is little direct evidence to show the mechanism by which miR-221/222 controls glioma invasion.	('glioma', 'Disease', (93, 99))	('miR-221/222', 'Var', (72, 83))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('controls', 'Reg', (84, 92))
177586	22681957	In the current study, we demonstrate that high levels of miR-221/222 expression in gliomas confer highly aggressive invasion and poorer overall survival.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('aggressive invasion', 'CPA', (105, 124))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('poorer', 'NegReg', (129, 135))	('overall survival', 'CPA', (136, 152))	('miR-221/222', 'Var', (57, 68))
177587	22681957	Furthermore, knockdown of miR-221/222 decreased invasion capability, reduced tumor growth and up-regulated the expression of the target, TIMP3, whereas ectopic expression of miR-221/222 exhibited the opposite effects.	('decreased', 'NegReg', (38, 47))	('reduced', 'NegReg', (69, 76))	('tumor', 'Disease', (77, 82))	('up-regulated', 'PosReg', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'MPA', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('knockdown', 'Var', (13, 22))	('TIMP3', 'Gene', '7078', (137, 142))	('TIMP3', 'Gene', (137, 142))	('invasion capability', 'CPA', (48, 67))	('miR-221/222', 'Gene', (26, 37))
177624	22681957	The pGL3-WT-TIMP3-3'UTR-Luc reporter was created by the ligation of TIMP3 3' UTR PCR products into the XbaI site of the pGL3 control vector (Promega, USA).	('pGL3', 'Gene', '6391', (120, 124))	('ligation', 'Var', (56, 64))	('TIMP3', 'Gene', (12, 17))	('TIMP3', 'Gene', '7078', (12, 17))	('pGL3', 'Gene', '6391', (4, 8))	('TIMP3', 'Gene', (68, 73))	('TIMP3', 'Gene', '7078', (68, 73))	('pGL3', 'Gene', (120, 124))	('pGL3', 'Gene', (4, 8))
177628	22681957	Each group was treated with 200 pmol scramble oligo, As-miR-221/222 in 10 mul Lipofectamine, miR-221/222 or PBS through local injection of the xenograft tumor at multiple sites (3-4 injected sites).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Lipofectamine', 'Chemical', 'MESH:C086724', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('miR-221/222', 'Var', (93, 104))	('PBS', 'Chemical', '-', (108, 111))
177638	22681957	These findings suggest that miR-221/222 may have an important role in glioma invasion.	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('miR-221/222', 'Var', (28, 39))
177640	22681957	Consistent with the results of the transwell assay, in the wound healing assay, repression of miR-221/222 significantly inhibited cell migration, while over-expression of miR-221/222 increased migration in both U251 and LN229 cells (Figure 2B).	('repression', 'NegReg', (80, 90))	('LN229', 'CellLine', 'CVCL:0393', (220, 225))	('increased', 'PosReg', (183, 192))	('miR-221/222', 'Var', (171, 182))	('inhibited', 'NegReg', (120, 129))	('migration', 'CPA', (193, 202))	('miR-221/222', 'Gene', (94, 105))	('cell migration', 'CPA', (130, 144))
177642	22681957	The expression and secretion of MMP2 and MMP9 were significantly reduced in the As-miR-221/222 group but were up-regulated in the miR-221/222 group (Figure 2C).	('MMP9', 'Gene', (41, 45))	('miR-221/222', 'Var', (130, 141))	('MMP2', 'Gene', '4313', (32, 36))	('reduced', 'NegReg', (65, 72))	('up-regulated', 'PosReg', (110, 122))	('MMP9', 'Gene', '4318', (41, 45))	('expression', 'MPA', (4, 14))	('MMP2', 'Gene', (32, 36))	('As-miR-221/222', 'Var', (80, 94))	('secretion', 'MPA', (19, 28))
177645	22681957	To detect whether TIMP3 is indeed regulated by miR-221 and miR-222 in glioma cells, we knocked-down miR-221/222 and ectopically expressed miR-221/222 in U251 and LN229 cells.	('miR-221', 'Gene', (138, 145))	('miR-221', 'Gene', (100, 107))	('glioma cells', 'Disease', (70, 82))	('LN229', 'CellLine', 'CVCL:0393', (162, 167))	('miR-221', 'Gene', '407006', (47, 54))	('miR-222', 'Gene', '407007', (59, 66))	('glioma cells', 'Disease', 'MESH:D005910', (70, 82))	('TIMP3', 'Gene', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('miR-221', 'Gene', '407006', (138, 145))	('TIMP3', 'Gene', '7078', (18, 23))	('miR-221', 'Gene', (47, 54))	('knocked-down', 'Var', (87, 99))	('miR-222', 'Gene', (59, 66))	('miR-221', 'Gene', '407006', (100, 107))
177646	22681957	Western blot analysis showed that TIMP3 expression was up-regulated in cells with reduced levels of miR-221/222, whereas TIMP3 expression was down-regulated in cells over-expressing miR-221/222 (Figure 3B).	('expression', 'MPA', (40, 50))	('up-regulated', 'PosReg', (55, 67))	('TIMP3', 'Gene', (121, 126))	('miR-221/222', 'Var', (182, 193))	('miR-221/222', 'Var', (100, 111))	('TIMP3', 'Gene', '7078', (34, 39))	('down-regulated', 'NegReg', (142, 156))	('TIMP3', 'Gene', (34, 39))	('reduced', 'NegReg', (82, 89))	('TIMP3', 'Gene', '7078', (121, 126))
177648	22681957	Reporter assays revealed that a reduction of miR-221/222 triggered a marked increase of luciferase activity from pGL3-WT-TIMP3-3'UTR (Figure 3C).	('TIMP3', 'Gene', (121, 126))	('luciferase', 'Enzyme', (88, 98))	('increase', 'PosReg', (76, 84))	('miR-221/222', 'Var', (45, 56))	('pGL3', 'Gene', (113, 117))	('reduction', 'NegReg', (32, 41))	('pGL3', 'Gene', '6391', (113, 117))	('activity', 'MPA', (99, 107))	('TIMP3', 'Gene', '7078', (121, 126))
177649	22681957	These data indicate that miR-221/222 can directly modulate TIMP3 expression by binding to the 3' UTR of TIMP3 in gliomas.	('TIMP3', 'Gene', '7078', (104, 109))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('modulate', 'Reg', (50, 58))	('gliomas', 'Disease', (113, 120))	('binding', 'Interaction', (79, 86))	('miR-221/222', 'Var', (25, 36))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('expression', 'MPA', (65, 75))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('TIMP3', 'Gene', '7078', (59, 64))	('TIMP3', 'Gene', (59, 64))	('TIMP3', 'Gene', (104, 109))
177653	22681957	However, expression of TIMP3 largely abrogated the effects of miR-221/222 on cell invasion (Figure 4A and B).	('expression', 'Var', (9, 19))	('TIMP3', 'Gene', (23, 28))	('TIMP3', 'Gene', '7078', (23, 28))	('miR-221/222', 'Var', (62, 73))	('abrogated', 'NegReg', (37, 46))	('cell invasion', 'CPA', (77, 90))
177657	22681957	Reduction of miR-221/222 levels inhibited tumor growth in vivo, and over-expression of miR-221/222 slightly increased tumor growth (Figure 5A).	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('inhibited', 'NegReg', (32, 41))	('increased', 'PosReg', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('Reduction', 'NegReg', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('miR-221/222', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('over-expression', 'PosReg', (68, 83))
177658	22681957	Immunohistochemistry then revealed that TIMP3 levels were up-regulated in As-miR-221/222 treated tumors and down-regulated in miR-221/222 treated tumors.	('up-regulated', 'PosReg', (58, 70))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('As-miR-221/222', 'Var', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TIMP3', 'Gene', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('TIMP3', 'Gene', '7078', (40, 45))	('tumors', 'Disease', (97, 103))	('down-regulated', 'NegReg', (108, 122))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
177660	22681957	Thus, As-miR-221/222 could be a therapeutic target for glioma intervention.	('glioma', 'Disease', (55, 61))	('As-miR-221/222', 'Var', (6, 20))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioma', 'Disease', 'MESH:D005910', (55, 61))
177664	22681957	There was an inverse relationship between miR-221/222 and TIMP3 levels in glioma tissues.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('inverse', 'NegReg', (13, 20))	('miR-221/222', 'Var', (42, 53))	('glioma', 'Disease', (74, 80))	('TIMP3', 'Gene', (58, 63))	('TIMP3', 'Gene', '7078', (58, 63))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
177665	22681957	Our present data and previous studies have shown that miR-221/222 affects the behavior of glioma cells including invasion, proliferation, apoptosis and radioresistance, by regulating multiple targets, including TIMP3, p27, PUMA, and PTEN.	('radioresistance', 'CPA', (152, 167))	('proliferation', 'CPA', (123, 136))	('p27', 'Gene', '3429', (218, 221))	('p27', 'Gene', (218, 221))	('PTEN', 'Gene', '5728', (233, 237))	('invasion', 'CPA', (113, 121))	('TIMP3', 'Gene', (211, 216))	('behavior', 'CPA', (78, 86))	('TIMP3', 'Gene', '7078', (211, 216))	('glioma cells', 'Disease', (90, 102))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('miR-221/222', 'Var', (54, 65))	('regulating', 'Reg', (172, 182))	('apoptosis', 'CPA', (138, 147))	('affects', 'Reg', (66, 73))	('glioma cells', 'Disease', 'MESH:D005910', (90, 102))	('PTEN', 'Gene', (233, 237))
177666	22681957	Thus, we reasoned that miR-221/222 should have a critical prognostic value for glioma patients (Figure 6B).	('miR-221/222', 'Var', (23, 34))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('patients', 'Species', '9606', (86, 94))
177674	22681957	In high-grade glioma, DTI indicated a decrease and deflection of the fibers surrounding the glioma that was associated with high levels of miR-221/222.	('glioma', 'Disease', (14, 20))	('deflection of the fibers surrounding', 'CPA', (51, 87))	('glioma', 'Disease', (92, 98))	('decrease', 'NegReg', (38, 46))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('miR-221/222', 'Var', (139, 150))
177678	22681957	Our recent data have shown that miR-221/222 inhibit cell apoptosis in human glioma cells by targeting the proapoptotic gene, PUMA.	('PUMA', 'Gene', (125, 129))	('targeting', 'Reg', (92, 101))	('inhibit', 'NegReg', (44, 51))	('glioma cells', 'Disease', (76, 88))	('human', 'Species', '9606', (70, 75))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('cell apoptosis', 'CPA', (52, 66))	('glioma cells', 'Disease', 'MESH:D005910', (76, 88))	('miR-221/222', 'Var', (32, 43))
177679	22681957	Here, we demonstrated that miR-221/222 play an important role in the regulation of glioma invasion by directly targeting TIMP3, an inhibitor of MMPs.	('glioma', 'Disease', (83, 89))	('TIMP3', 'Gene', (121, 126))	('miR-221/222', 'Var', (27, 38))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('targeting', 'Reg', (111, 120))	('TIMP3', 'Gene', '7078', (121, 126))
177686	22681957	Furthermore, expression of TIMP3 could largely override miR-221/222-mediated invasion.	('miR-221/222-mediated', 'Var', (56, 76))	('expression', 'Var', (13, 23))	('TIMP3', 'Gene', '7078', (27, 32))	('override', 'PosReg', (47, 55))	('TIMP3', 'Gene', (27, 32))
177687	22681957	These results demonstrate that TIMP3 is a core target of miR-221/222 in glioma cell invasion.	('glioma', 'Disease', (72, 78))	('TIMP3', 'Gene', '7078', (31, 36))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('TIMP3', 'Gene', (31, 36))	('miR-221/222', 'Var', (57, 68))
177693	22681957	In this study, our data suggest that a high miR-221/222 expression level is a valuable marker for pathological diagnosis and prognosis prediction in high-grade glioma; high miR-221/222 expression levels were significantly associated with poor survival in high-grade glioma patients as determined by Kaplan-Meier analysis.	('patients', 'Species', '9606', (273, 281))	('expression', 'MPA', (185, 195))	('poor', 'NegReg', (238, 242))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('glioma', 'Disease', (266, 272))	('glioma', 'Disease', (160, 166))	('miR-221/222', 'Var', (173, 184))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('glioma', 'Disease', 'MESH:D005910', (266, 272))	('glioma', 'Phenotype', 'HP:0009733', (266, 272))
177695	22681957	In summary, our data demonstrate that miR-221/222 regulate glioma cell invasion by directly targeting TIMP3.	('regulate', 'Reg', (50, 58))	('targeting', 'Reg', (92, 101))	('glioma', 'Disease', (59, 65))	('miR-221/222', 'Var', (38, 49))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('TIMP3', 'Gene', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TIMP3', 'Gene', '7078', (102, 107))
177696	22681957	To conclude, our data suggest that miR-221/222 could be intrinsic regulators of progression in glioma cells and could be used as potential targets and predictors of survival in this devastating disease.	('miR-221/222', 'Var', (35, 46))	('glioma cells', 'Disease', 'MESH:D005910', (95, 107))	('glioma cells', 'Disease', (95, 107))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))
177704	19336571	Even though PEITC treatment suppressed activating phosphorylations of Akt and mTOR, which are implicated in regulation of autophagy by different stimuli, processing and recruitment of LC3 was only partially/marginally reversed by ectopic expression of constitutively active Akt or overexpression of mTOR positive regulator Rheb.	('mTOR', 'Gene', (299, 303))	('Rheb', 'Gene', (323, 327))	('LC3', 'Protein', (184, 187))	('mTOR', 'Gene', '2475', (299, 303))	('recruitment', 'MPA', (169, 180))	('Akt', 'Gene', '207', (274, 277))	('PEITC', 'Chemical', 'MESH:C058305', (12, 17))	('Akt', 'Gene', (70, 73))	('Rheb', 'Gene', '6009', (323, 327))	('men', 'Species', '9606', (176, 179))	('suppressed', 'NegReg', (28, 38))	('Akt', 'Gene', (274, 277))	('mTOR', 'Gene', (78, 82))	('ectopic', 'Var', (230, 237))	('men', 'Species', '9606', (23, 26))	('mTOR', 'Gene', '2475', (78, 82))	('Akt', 'Gene', '207', (70, 73))	('activating phosphorylations', 'MPA', (39, 66))
177716	19336571	Prevention of chemical carcinogenesis by PEITC has also been observed against diethylnitrosamine-induced hepatocellular adenomas in C3H mice, and N-nitrosobenzylmethylamine-induced esophageal cancer in rats.	('esophageal cancer', 'Disease', (181, 198))	('carcinogenesis', 'Disease', (23, 37))	('mice', 'Species', '10090', (136, 140))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (78, 96))	('rats', 'Species', '10116', (202, 206))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (105, 128))	('N-nitrosobenzylmethylamine-induced', 'Var', (146, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('diethylnitrosamine-induced', 'MPA', (78, 104))	('N-nitrosobenzylmethylamine', 'Chemical', 'MESH:C014707', (146, 172))	('hepatocellular adenomas', 'Disease', (105, 128))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (105, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (23, 37))	('PEITC', 'Chemical', 'MESH:C058305', (41, 46))
177726	19336571	Antibody against microtubule-associated protein 1 light chain 3 (LC3) was from MBL and the antibodies against cleaved caspase-3, Atg5, phospho-(S473)-Akt, total Akt, phospho-(S2448)-mTOR, phospho-(T389)-p70s6k, total p70s6k, and Rheb were from Cell Signaling.	('mTOR', 'Gene', (182, 186))	('MBL', 'Gene', '50639', (79, 82))	('Rheb', 'Gene', (229, 233))	('mTOR', 'Gene', '2475', (182, 186))	('Akt', 'Gene', '207', (150, 153))	('caspase-3', 'Gene', (118, 127))	('p70s6k', 'Gene', (203, 209))	('p70s6k', 'Gene', (217, 223))	('Akt', 'Gene', '207', (161, 164))	('Rheb', 'Gene', '6009', (229, 233))	('p70s6k', 'Gene', '6198', (217, 223))	('Akt', 'Gene', (150, 153))	('MBL', 'Gene', (79, 82))	('p70s6k', 'Gene', '6198', (203, 209))	('caspase-3', 'Gene', '836', (118, 127))	('Akt', 'Gene', (161, 164))	('phospho-', 'Var', (188, 196))
177777	19336571	To gain insight into the mechanism of PEITC-mediated autophagy in our model, initially we determined the effect of PEITC treatment on activating phosphorylations of Akt (S473) and mTOR (S2448) using LNCaP and PC-3 cells (Fig.	('men', 'Species', '9606', (126, 129))	('activating phosphorylations', 'MPA', (134, 161))	('PEITC', 'Chemical', 'MESH:C058305', (115, 120))	('S473', 'Var', (170, 174))	('mTOR', 'Gene', (180, 184))	('mTOR', 'Gene', '2475', (180, 184))	('LNCaP', 'CellLine', 'CVCL:0395', (199, 204))	('Akt', 'Gene', '207', (165, 168))	('S2448', 'Var', (186, 191))	('PEITC', 'Chemical', 'MESH:C058305', (38, 43))	('Akt', 'Gene', (165, 168))
177793	19336571	The cleavage of LC3 resulting from a 9 h exposure to 5 mumol/L PEITC was suppressed by about 50% in PC-3 cells with knockdown of Atg5 protein (Fig.	('suppressed', 'NegReg', (73, 83))	('cleavage', 'MPA', (4, 12))	('knockdown', 'Var', (116, 125))	('PEITC', 'Chemical', 'MESH:C058305', (63, 68))	('LC3', 'Protein', (16, 19))
177804	19336571	Together these results indicated that PEITC can trigger both apoptosis (type I cell death) and autophagy (type II cell death) in prostate cancer cells.	('apoptosis', 'CPA', (61, 70))	('type II cell death', 'Disease', (106, 124))	('prostate cancer', 'Disease', (129, 144))	('PEITC', 'Var', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('PEITC', 'Chemical', 'MESH:C058305', (38, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (129, 144))	('autophagy', 'CPA', (95, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))	('type II cell death', 'Disease', 'MESH:D003643', (106, 124))
177809	19336571	4D) resulting from PEITC exposure (5 mumol/L, 9 h) was significantly attenuated by knockdown of Atg5 protein level in both PC-3 and LNCaP cells.	('LNCaP', 'CellLine', 'CVCL:0395', (132, 137))	('Atg5', 'Gene', (96, 100))	('attenuated', 'NegReg', (69, 79))	('PEITC', 'Chemical', 'MESH:C058305', (19, 24))	('knockdown', 'Var', (83, 92))
177816	19336571	For example, cleaved LC3-II protein was detectable in each tumor sample from the PEITC treatment group but not in each tumor from control mice (Fig.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (59, 64))	('detectable', 'Reg', (40, 50))	('LC3-II protein', 'Protein', (21, 35))	('mice', 'Species', '10090', (138, 142))	('PEITC', 'Chemical', 'MESH:C058305', (81, 86))	('cleaved', 'MPA', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('men', 'Species', '9606', (92, 95))	('PEITC treatment', 'Var', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
177822	19336571	6, treatment of DA2123 with either 10 or 25 mumol/L PEITC resulted in the formation of punctate lgg-1:GFP foci in the intestine of worm in contrast to the diffuse GFP expression seen in control worms.	('DA2123', 'Var', (16, 22))	('lgg-1', 'Gene', (96, 101))	('lgg-1', 'Gene', '174050', (96, 101))	('men', 'Species', '9606', (8, 11))	('PEITC', 'Chemical', 'MESH:C058305', (52, 57))
177836	19336571	Furthermore, 3-MA and chloroquine have been shown to synergistically augment the proapoptotic response to a histone deacetylase inhibitor.	('chloroquine', 'Var', (22, 33))	('men', 'Species', '9606', (72, 75))	('augment', 'NegReg', (69, 76))	('chloroquine', 'Chemical', 'MESH:D002738', (22, 33))	('3-MA', 'Chemical', 'MESH:C025946', (13, 17))
177838	19336571	Apoptosis was associated with calpain-mediated cleavage of Atg5 resulting in translocation of truncated Atg5 to mitochondria for its association with Bcl-xL.	('association', 'Interaction', (133, 144))	('Atg5', 'Gene', (59, 63))	('translocation', 'MPA', (77, 90))	('Atg5', 'Gene', (104, 108))	('Bcl-xL', 'Gene', (150, 156))	('truncated', 'Var', (94, 103))	('calpain-mediated', 'Protein', (30, 46))	('associated', 'Reg', (14, 24))	('Apoptosis', 'CPA', (0, 9))	('Bcl-xL', 'Gene', '598', (150, 156))	('cleavage', 'Var', (47, 55))
177840	19336571	Atg5 knockdown confers marked protection against PEITC-mediated cleavage of LC3 in both PC-3 and LNCaP cell lines.	('cleavage', 'MPA', (64, 72))	('Atg5', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('LC3', 'Protein', (76, 79))	('LNCaP', 'CellLine', 'CVCL:0395', (97, 102))	('PEITC', 'Chemical', 'MESH:C058305', (49, 54))
177841	19336571	PEITC-mediated apoptotic DNA fragmentation in PC-3 and LNCaP cells is also significantly suppressed by knockdown of Atg5 protein level.	('suppressed', 'NegReg', (89, 99))	('PEITC', 'Chemical', 'MESH:C058305', (0, 5))	('men', 'Species', '9606', (33, 36))	('apoptotic DNA fragmentation', 'CPA', (15, 42))	('LNCaP', 'CellLine', 'CVCL:0395', (55, 60))	('knockdown', 'Var', (103, 112))
177845	33363203	Phosphatase and Tensin Homolog Mutation in Immune Cell Infiltration and Clinicopathological Features of Low-Grade Gliomas The mutation of phosphatase and tensin homolog (PTEN) genes frequently occur in low-grade gliomas (LGGs) and are deeply associated with a poor prognosis and survival rate.	('Gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('Gliomas', 'Disease', (114, 121))	('PTEN', 'Gene', (170, 174))	('phosphatase and tensin homolog', 'Gene', '5728', (138, 168))	('PTEN', 'Gene', '5728', (170, 174))	('mutation', 'Var', (126, 134))	('Phosphatase and Tensin Homolog', 'Gene', '5728', (0, 30))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('gliomas', 'Disease', (212, 219))	('associated', 'Reg', (242, 252))	('Gliomas', 'Disease', 'MESH:D005910', (114, 121))	('occur', 'Reg', (193, 198))
177846	33363203	In order to identify the crucial signaling pathways and genes associated with the PTEN mutation, we performed bioinformatics analysis on the RNA sequencing results, which were obtained from The Cancer Genome Atlas database.	('Cancer', 'Disease', 'MESH:D009369', (194, 200))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('PTEN', 'Gene', '5728', (82, 86))	('PTEN', 'Gene', (82, 86))	('mutation', 'Var', (87, 95))	('Cancer', 'Disease', (194, 200))
177848	33363203	In addition, the PTEN mutation was associated with an abundance of B cells, neutrophils, macrophages, dendritic cells, and CD8+ T cells during tumor infiltration.	('CD8', 'Gene', (123, 126))	('mutation', 'Var', (22, 30))	('tumor', 'Disease', (143, 148))	('CD8', 'Gene', '925', (123, 126))	('PTEN', 'Gene', (17, 21))	('PTEN', 'Gene', '5728', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
177849	33363203	The results showed that patients with LGGs harboring the PTEN mutation had a poor prognosis and more serious immune cell infiltration occurred depending on the mRNA expression level.	('PTEN', 'Gene', (57, 61))	('patients', 'Species', '9606', (24, 32))	('mutation', 'Var', (62, 70))	('PTEN', 'Gene', '5728', (57, 61))
177850	33363203	These results demonstrated that multiple genes and signaling pathways play a key role in LGG from low grade to high grade, and are associated with PTEN mutations.	('mutations', 'Var', (152, 161))	('associated', 'Reg', (131, 141))	('PTEN', 'Gene', (147, 151))	('PTEN', 'Gene', '5728', (147, 151))	('LGG', 'Disease', (89, 92))
177851	33363203	In this study, we outlined an approach to assess the influence of PTEN mutations on prognosis, overall survival, and messenger RNA (mRNA) expression.	('PTEN', 'Gene', '5728', (66, 70))	('mutations', 'Var', (71, 80))	('PTEN', 'Gene', (66, 70))
177852	33363203	Our results provided alternative strategies for the personalized treatment of patients with LGGs harboring the PTEN mutation.	('PTEN', 'Gene', '5728', (111, 115))	('mutation', 'Var', (116, 124))	('patients', 'Species', '9606', (78, 86))	('PTEN', 'Gene', (111, 115))
177858	33363203	Owing to the tumor suppressing functions of the PTEN gene, it has been found to mutate with high frequency in several types of carcinomas, including LGGs.	('tumor', 'Disease', (13, 18))	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('carcinomas', 'Disease', (127, 137))	('LGGs', 'Disease', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mutate', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('carcinomas', 'Disease', 'MESH:D009369', (127, 137))
177862	33363203	Patients harboring the PTEN mutation exhibit increasing alterations of multiple signaling pathways and cellular metabolism compared with those harboring the wild-type PTEN gene.	('alterations', 'Reg', (56, 67))	('cellular metabolism', 'MPA', (103, 122))	('PTEN', 'Gene', (23, 27))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (28, 36))	('PTEN', 'Gene', (167, 171))	('PTEN', 'Gene', '5728', (23, 27))	('PTEN', 'Gene', '5728', (167, 171))
177863	33363203	Thus, a variation in the PTEN status may affect the tumor progression by regulating the immune microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('affect', 'Reg', (41, 47))	('PTEN', 'Gene', '5728', (25, 29))	('PTEN', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('regulating', 'Reg', (73, 83))	('variation', 'Var', (8, 17))
177867	33363203	After the enrichment of differentially expressed genes, the association between differentially expressed genes and immune cell infiltration was further analyzed using the TIMER database, which elucidated the effect of the PTEN mutation on the tumor-related genes and signaling pathways.	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('PTEN', 'Gene', (222, 226))	('mutation', 'Var', (227, 235))	('PTEN', 'Gene', '5728', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
177870	33363203	Furthermore, the enriched signal pathways of LGG patients with or without the PTEN mutation were obtained.	('LGG', 'Disease', (45, 48))	('PTEN', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('PTEN', 'Gene', '5728', (78, 82))	('patients', 'Species', '9606', (49, 57))
177872	33363203	In this study, the R software (version 3.5.2) containing the bioconductor software package (EdgeR) was used to identify the differential gene expression in LGG patients harboring various PTEN mutations compared with wild-type patients.	('patients', 'Species', '9606', (160, 168))	('PTEN', 'Gene', (187, 191))	('PTEN', 'Gene', '5728', (187, 191))	('LGG', 'Disease', (156, 159))	('patients', 'Species', '9606', (226, 234))	('mutations', 'Var', (192, 201))
177879	33363203	Among these patients, 6% of LGG patients had mutated genes, which included missense mutations, nonsense mutations, amplifications, and deep deletions.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (32, 40))	('missense mutations', 'Var', (75, 93))	('deep deletions', 'Var', (135, 149))	('LGG', 'Disease', (28, 31))	('amplifications', 'Var', (115, 129))	('nonsense mutations', 'Var', (95, 113))	('mutated', 'Var', (45, 52))
177880	33363203	For the PTEN mutation (Figure 1B), there were 13 amino acid sites of the PTEN protein that were identified as the commonly mutated sites, located at the DSPc and PTEN_C2 domains.	('PTEN', 'Gene', (162, 166))	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (162, 166))	('PTEN', 'Gene', '5728', (73, 77))	('mutation', 'Var', (13, 21))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))
177883	33363203	The average age (54.44, 35-74 years old) of patients with the PTEN mutation was higher than the wild-type patient (42.52, 14-87 years old), indicating that age may promote the mutation of the PTEN gene.	('PTEN', 'Gene', (62, 66))	('patient', 'Species', '9606', (44, 51))	('mutation', 'Var', (67, 75))	('patients', 'Species', '9606', (44, 52))	('PTEN', 'Gene', '5728', (62, 66))	('promote', 'PosReg', (164, 171))	('patient', 'Species', '9606', (106, 113))	('PTEN', 'Gene', (192, 196))	('PTEN', 'Gene', '5728', (192, 196))	('mutation', 'Var', (176, 184))
177884	33363203	Moreover, the histological grade (G4:G3 = 16:2) of LGG patients harboring the PTEN mutation was higher than the wild-type group (G4:G3 = 247:250), indicating that LGG with a PTEN mutation is more serious.	('PTEN', 'Gene', '5728', (174, 178))	('LGG', 'Disease', (51, 54))	('PTEN', 'Gene', (78, 82))	('LGG', 'Disease', (163, 166))	('mutation', 'Var', (83, 91))	('PTEN', 'Gene', '5728', (78, 82))	('patients', 'Species', '9606', (55, 63))	('higher', 'PosReg', (96, 102))	('PTEN', 'Gene', (174, 178))
177885	33363203	Initially, the PTEN mRNA expression level of the wild-type PTEN and PTEN mutation groups were identified.	('PTEN', 'Gene', (68, 72))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (68, 72))	('PTEN', 'Gene', '5728', (15, 19))	('mutation', 'Var', (73, 81))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
177887	33363203	Meanwhile, the PTEN expression dependence on the PTEN status (as shown in Figure 2B) showed that the expression level of shallow deletion and diploid was significantly higher than the gain and deep deletion status.	('PTEN', 'Gene', '5728', (49, 53))	('expression level', 'MPA', (101, 117))	('PTEN', 'Gene', (15, 19))	('higher', 'PosReg', (168, 174))	('PTEN', 'Gene', '5728', (15, 19))	('shallow deletion', 'Var', (121, 137))	('PTEN', 'Gene', (49, 53))
177888	33363203	The PTEN gene is known as the tumor suppressor gene, while PTEN mutation can decrease the inhibition of tumorigenesis.	('PTEN', 'Gene', '5728', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutation', 'Var', (64, 72))	('PTEN', 'Gene', '5728', (59, 63))	('decrease', 'NegReg', (77, 85))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PTEN', 'Gene', (59, 63))	('tumor', 'Disease', (30, 35))	('PTEN', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
177890	33363203	Thus, early treatment may be helpful for precise therapy in LGG patients harboring the PTEN mutation.	('PTEN', 'Gene', (87, 91))	('PTEN', 'Gene', '5728', (87, 91))	('mutation', 'Var', (92, 100))	('patients', 'Species', '9606', (64, 72))	('LGG', 'Disease', (60, 63))
177893	33363203	The results showed that the PTEN mutation is significantly and positively correlated with the infiltration of B cells, macrophages, neutrophils, CD8+ T cells, and dendritic cells in LGG patients (Figure 4), but not CD4+ T cells.	('PTEN', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('infiltration', 'CPA', (94, 106))	('PTEN', 'Gene', '5728', (28, 32))	('CD8', 'Gene', (145, 148))	('CD4', 'Gene', (215, 218))	('correlated', 'Reg', (74, 84))	('CD4', 'Gene', '920', (215, 218))	('CD8', 'Gene', '925', (145, 148))	('patients', 'Species', '9606', (186, 194))
177894	33363203	Among these differential groups, the immune cell infiltration of PTEN mutation was significantly higher than the wild-type group.	('higher', 'PosReg', (97, 103))	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (65, 69))	('immune cell infiltration', 'CPA', (37, 61))	('mutation', 'Var', (70, 78))
177898	33363203	The enrichment results indicated that the PTEN mutation may play a pivotal role in various pathways involved in cancer cell migration, metabolism, and immune response regulation.	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('play', 'Reg', (60, 64))	('mutation', 'Var', (47, 55))	('role', 'Reg', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
177899	33363203	DEGs were identified by querying the RNA-seq datasets from the PTEN mutation (n = 18) or wild-type PTEN groups (n = 498).	('PTEN', 'Gene', '5728', (63, 67))	('mutation', 'Var', (68, 76))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('PTEN', 'Gene', (63, 67))
177911	33363203	In this study, we carefully evaluated the critical role of PTEN mutation in LGG progression and prognosis, which may provide therapeutic scope for precise LGG therapy.	('LGG', 'Disease', (76, 79))	('PTEN', 'Gene', (59, 63))	('mutation', 'Var', (64, 72))	('PTEN', 'Gene', '5728', (59, 63))
177912	33363203	Firstly, the clinical analysis (Figure 1A) results showed that 6% of patients with LGG harbored PTEN mutations, including four types of mutations (missense mutations, nonsense mutations, amplifications, and deep deletions).	('PTEN', 'Gene', '5728', (96, 100))	('mutations', 'Var', (101, 110))	('deep deletions', 'Var', (207, 221))	('LGG', 'Disease', (83, 86))	('missense mutations', 'Var', (147, 165))	('harbored', 'Reg', (87, 95))	('nonsense mutations', 'Var', (167, 185))	('amplifications', 'Var', (187, 201))	('patients', 'Species', '9606', (69, 77))	('PTEN', 'Gene', (96, 100))
177913	33363203	Furthermore, the survival curve clearly revealed that patients with the PTEN mutation suffered a poorer prognosis, a lower survival rate, and greater disease recurrence than the wild-type group (Figures 2C,D).	('survival rate', 'CPA', (123, 136))	('disease recurrence', 'CPA', (150, 168))	('PTEN', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('patients', 'Species', '9606', (54, 62))	('PTEN', 'Gene', '5728', (72, 76))	('lower', 'NegReg', (117, 122))
177914	33363203	On the basis of the clinical results, early clinical intervention for LGG PTEN mutation groups would be helpful for improving the patient survival period.	('patient survival period', 'CPA', (130, 153))	('patient', 'Species', '9606', (130, 137))	('improving', 'PosReg', (116, 125))	('PTEN', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('PTEN', 'Gene', '5728', (74, 78))
177915	33363203	Second, the Cox analysis revealed that the mRNA expression level of the PTEN mutation group was lower than the wild-type group (P < 0.01).	('PTEN', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('PTEN', 'Gene', '5728', (72, 76))	('lower', 'NegReg', (96, 101))	('mRNA expression level', 'MPA', (43, 64))
177916	33363203	And shallow deletion and normal diploid types of PTEN mRNA level were also higher than the deep deletion and gain status (Figure 2B).	('diploid', 'MPA', (32, 39))	('PTEN', 'Gene', '5728', (49, 53))	('higher', 'PosReg', (75, 81))	('shallow deletion', 'Var', (4, 20))	('PTEN', 'Gene', (49, 53))
177917	33363203	Considering the PTEN mutation types (missense), a mutation of PTEN led to the dysfunction of tumorigenesis suppression.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', '5728', (16, 20))	('mutation', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
177923	33363203	By further analysis, B cells, neutrophils, CD4+ T cells, macrophages, CD8+ T cells, and dendritic cells were more significantly abundant in the PTEN mutation group than the wild-type PTEN group.	('PTEN', 'Gene', (183, 187))	('PTEN', 'Gene', '5728', (144, 148))	('PTEN', 'Gene', '5728', (183, 187))	('abundant', 'PosReg', (128, 136))	('CD8', 'Gene', (70, 73))	('PTEN', 'Gene', (144, 148))	('CD8', 'Gene', '925', (70, 73))	('mutation', 'Var', (149, 157))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))
177924	33363203	Therefore, these results revealed that some specific genes or signaling may lead to immune cell infiltration in the PTEN mutation group.	('immune cell infiltration', 'CPA', (84, 108))	('mutation', 'Var', (121, 129))	('PTEN', 'Gene', (116, 120))	('PTEN', 'Gene', '5728', (116, 120))	('lead to', 'Reg', (76, 83))
177925	33363203	Finally, we explored the role of critical molecular annotations that led to the poor prognosis of PTEN mutation LGG patients (Figures 5, 6).	('patients', 'Species', '9606', (116, 124))	('PTEN', 'Gene', '5728', (98, 102))	('PTEN', 'Gene', (98, 102))	('mutation', 'Var', (103, 111))	('LGG', 'Disease', (112, 115))
177928	33363203	By deeply affecting these signal pathways, LGGs with PTEN mutations can lead to a higher tumor grade and poor survival (Figures 2C,D).	('mutations', 'Var', (58, 67))	('poor', 'NegReg', (105, 109))	('signal pathways', 'Pathway', (26, 41))	('higher', 'PosReg', (82, 88))	('affecting', 'Reg', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
177933	33363203	These results revealed that a PTEN mutation can promote the tumorigenesis process and lead to more immune cell infiltration.	('tumor', 'Disease', (60, 65))	('immune cell infiltration', 'CPA', (99, 123))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutation', 'Var', (35, 43))	('PTEN', 'Gene', (30, 34))	('promote', 'PosReg', (48, 55))	('PTEN', 'Gene', '5728', (30, 34))	('more', 'PosReg', (94, 98))
177938	30786920	We report the frequency of IDH mutations in a large cohort of nearly 1550 patients, EGFR amplifications in almost 1900 IDH-wildtype glioblastomas, and histone mutations in 70 adult gliomas.	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', '3417', (119, 122))	('mutations', 'Var', (31, 40))	('amplifications', 'Var', (89, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('IDH', 'Gene', '3417', (27, 30))	('patients', 'Species', '9606', (74, 82))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('EGFR', 'Gene', '1956', (84, 88))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (119, 145))	('glioblastomas', 'Phenotype', 'HP:0012174', (132, 145))	('gliomas', 'Disease', (181, 188))	('IDH-wildtype glioblastomas', 'Disease', (119, 145))	('EGFR', 'Gene', (84, 88))	('IDH', 'Gene', (119, 122))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
177939	30786920	For example, EGFR amplification which is 95% concordant with our Real-Time PCR-based copy number assays.	('amplification', 'Var', (18, 31))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
177940	30786920	The diagnosis of brain tumours is achieved by combining morphological features, immunohistochemical (IHC) detection of lineage-related markers, and more recently by the detection of genetic biomarkers, for example mutations in the isocitrate dehydrogenase genes 1 and 2 (IDH1 and IDH2), BRAF, or histone genes.	('brain tumours', 'Disease', (17, 30))	('IDH1', 'Gene', '3417', (271, 275))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('IDH2', 'Gene', (280, 284))	('BRAF', 'Gene', '673', (287, 291))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('BRAF', 'Gene', (287, 291))	('histone', 'Gene', (296, 303))	('mutations', 'Var', (214, 223))	('IDH2', 'Gene', '3418', (280, 284))	('brain tumour', 'Phenotype', 'HP:0030692', (17, 29))	('IDH1', 'Gene', (271, 275))	('brain tumours', 'Disease', 'MESH:D001932', (17, 30))	('brain tumours', 'Phenotype', 'HP:0030692', (17, 30))
177941	30786920	The development of mutation-specific antibodies to the most common IDH1 mutation R132H, BRAF V600E or Histone H3 K27 M has facilitated the introduction of these tests into routine neuropathology diagnostics and their use is our first diagnostic step.	('K27 M', 'Mutation', 'p.K27M', (113, 118))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('IDH1', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (67, 71))	('R132H', 'Var', (81, 86))	('V600E', 'Mutation', 'rs113488022', (93, 98))	('R132H', 'Mutation', 'rs121913500', (81, 86))
177942	30786920	To refine the diagnostic accuracy, we use Sanger sequencing, for example to detect rarer mutations in the IDH1, or IDH2 genes, histones, or to detect mutations in the TERT promoter either to support glioma diagnostics in the context of other mutations or to prognosticate meningioma recurrence risk.	('TERT', 'Gene', (167, 171))	('IDH2', 'Gene', (115, 119))	('support', 'PosReg', (191, 198))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('TERT', 'Gene', '7015', (167, 171))	('IDH2', 'Gene', '3418', (115, 119))	('meningioma', 'Disease', (272, 282))	('IDH1', 'Gene', (106, 110))	('mutations', 'Var', (150, 159))	('mutations', 'Var', (89, 98))	('meningioma', 'Phenotype', 'HP:0002858', (272, 282))	('glioma', 'Disease', (199, 205))	('IDH1', 'Gene', '3417', (106, 110))	('meningioma', 'Disease', 'MESH:D008577', (272, 282))
177943	30786920	Yet, a significant number of CNS tumours still lack distinctive, and diagnostically informative mutations that can be readily implemented into routine diagnostic practice, or such tests (e.g.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('number of CNS tumours', 'Disease', 'MESH:D016543', (19, 40))	('number of CNS tumours', 'Disease', (19, 40))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('CNS tumour', 'Phenotype', 'HP:0100006', (29, 39))	('mutations', 'Var', (96, 105))
177948	30786920	Methylation profiles of tumours result from a combination of somatically acquired DNA methylation changes and the cell of origin.	('tumours', 'Disease', (24, 31))	('result from', 'Reg', (32, 43))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('Methylation', 'MPA', (0, 11))	('DNA methylation changes', 'Var', (82, 105))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))
177976	30786920	Classifier results with a calibrated score below 0.84 can still yield informative results, in particular when taking into account copy number profiles (such as 7p gain; 10q loss in IDH-wildtype glioblastoma, 1p/19q codeletion in IDH-mutant oligodendroglioma, or copy number variation and CDKN2A/B deletions in IDH-mutant astrocytomas).	('IDH-', 'Gene', (181, 185))	('oligodendroglioma', 'Disease', 'MESH:D009837', (240, 257))	('gain', 'PosReg', (163, 167))	('loss', 'NegReg', (173, 177))	('oligodendroglioma', 'Disease', (240, 257))	('deletions', 'Var', (297, 306))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('CDKN2A/B', 'Gene', '1029;1030', (288, 296))	('1p/19q codeletion', 'Var', (208, 225))	('copy number variation', 'Var', (262, 283))	('codeletion', 'Var', (215, 225))	('astrocytomas', 'Disease', (321, 333))	('glioblastoma', 'Phenotype', 'HP:0012174', (194, 206))	('IDH-', 'Gene', '3417', (310, 314))	('IDH-wildtype glioblastoma', 'Disease', 'MESH:D005909', (181, 206))	('IDH-', 'Gene', '3417', (229, 233))	('IDH-wildtype glioblastoma', 'Disease', (181, 206))	('IDH-', 'Gene', '3417', (181, 185))	('astrocytomas', 'Disease', 'MESH:D001254', (321, 333))	('IDH-', 'Gene', (310, 314))	('CDKN2A/B', 'Gene', (288, 296))	('astrocytoma', 'Phenotype', 'HP:0009592', (321, 332))	('IDH-', 'Gene', (229, 233))
177978	30786920	Confirmation of diagnosis (outcome 1): this category includes cases in which the Classifier confirmed the integrated diagnosis, such as IDH-mutant and 1p/19q co-deleted oligodendroglioma, IDH-mutant glioblastoma, subependymoma, H3 K27M-mutant diffuse midline glioma, and similar.	('IDH-', 'Gene', (188, 192))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('oligodendroglioma', 'Disease', 'MESH:D009837', (169, 186))	('K27M', 'Mutation', 'p.K27M', (231, 235))	('1p/19q co-deleted', 'Var', (151, 168))	('subependymoma', 'Disease', 'MESH:D018315', (213, 226))	('subependymoma', 'Disease', (213, 226))	('oligodendroglioma', 'Disease', (169, 186))	('IDH-', 'Gene', '3417', (136, 140))	('midline glioma', 'Disease', (251, 265))	('glioblastoma', 'Disease', 'MESH:D005909', (199, 211))	('IDH-', 'Gene', '3417', (188, 192))	('IDH-', 'Gene', (136, 140))	('glioblastoma', 'Disease', (199, 211))	('H3 K27M-mutant', 'Var', (228, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (199, 211))	('midline glioma', 'Disease', 'MESH:D005910', (251, 265))	('ependymoma', 'Phenotype', 'HP:0002888', (216, 226))
177987	30786920	For example, the methylation class IDH-wildtype glioma in a previously confirmed IDH-mutant glioma.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('IDH-', 'Gene', (81, 85))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('methylation', 'Var', (17, 28))	('IDH-', 'Gene', '3417', (35, 39))	('glioma', 'Disease', (92, 98))	('IDH-', 'Gene', '3417', (81, 85))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('IDH-', 'Gene', (35, 39))	('glioma', 'Disease', (48, 54))
177995	30786920	Low- and high-grade gliomas and poorly differentiated supratentorial intrinsic tumours with PNET morphology undergo immunostaining for IDH1 R132H and ATRX.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('intrinsic tumours', 'Disease', (69, 86))	('ATRX', 'Gene', (150, 154))	('intrinsic tumours', 'Disease', 'MESH:D020919', (69, 86))	('IDH1', 'Gene', (135, 139))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('IDH1', 'Gene', '3417', (135, 139))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('ATRX', 'Gene', '546', (150, 154))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('PNET', 'Phenotype', 'HP:0030065', (92, 96))	('R132H', 'Var', (140, 145))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('R132H', 'Mutation', 'rs121913500', (140, 145))	('gliomas', 'Disease', (20, 27))
177999	30786920	IDH1 R132H negative gliomas undergo a targeted sequencing for known mutations in the IDH1/2, histone H3.3 (H3F3A), BRAF genes and the TERT promoter, and copy number assays (1p/19q, CDKN2A/B, 7p (EGFR), and 10q (PTEN locus)).	('EGFR', 'Gene', (195, 199))	('H3.3', 'Gene', (101, 105))	('TERT', 'Gene', (134, 138))	('PTEN', 'Gene', (211, 215))	('R132H', 'Var', (5, 10))	('1p/19q', 'Var', (173, 179))	('TERT', 'Gene', '7015', (134, 138))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Disease', (20, 27))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('H3.3', 'Gene', '3020', (101, 105))	('PTEN', 'Gene', '5728', (211, 215))	('EGFR', 'Gene', '1956', (195, 199))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('IDH1', 'Gene', '3417', (0, 4))	('H3F3A', 'Gene', '3020', (107, 112))	('IDH1', 'Gene', (85, 89))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('BRAF', 'Gene', '673', (115, 119))	('BRAF', 'Gene', (115, 119))	('CDKN2A/B, 7p', 'Gene', '1029;1030', (181, 193))	('mutations', 'Var', (68, 77))	('H3F3A', 'Gene', (107, 112))	('IDH1', 'Gene', '3417', (85, 89))
178002	30786920	The Classifier was also used for confirmation of rare tumour entities which do not have any of the above-mentioned gene mutations.	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour entities', 'Disease', 'MESH:D009369', (54, 69))	('mutations', 'Var', (120, 129))	('tumour entities', 'Disease', (54, 69))
178004	30786920	All supra- and infratentorial ependymomas undergo methylation studies.	('infratentorial ependymomas', 'Disease', (15, 41))	('ependymoma', 'Phenotype', 'HP:0002888', (30, 40))	('methylation', 'Var', (50, 61))	('infratentorial ependymomas', 'Disease', 'MESH:D004806', (15, 41))
178013	30786920	The most common reason for further workup with methylation array is a confirmed IDH mutation in combination with an inconclusive ATRX, TERT promoter and 1p/19q status; for example IDH-mutant gliomas with retained ATRX expression and ambiguous 1p/19q status; or rare diffuse gliomas with ATRX loss in which the IDH- or histone H3 mutation cannot be established by IHC or sequencing.	('TERT', 'Gene', '7015', (135, 139))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('ATRX', 'Gene', (213, 217))	('gliomas', 'Disease', (274, 281))	('ATRX', 'Gene', '546', (213, 217))	('IDH-', 'Gene', (180, 184))	('IDH', 'Gene', (80, 83))	('gliomas', 'Disease', 'MESH:D005910', (274, 281))	('IDH', 'Gene', (310, 313))	('TERT', 'Gene', (135, 139))	('ATRX', 'Gene', (129, 133))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('gliomas', 'Disease', (191, 198))	('ATRX', 'Gene', '546', (129, 133))	('IDH-', 'Gene', '3417', (310, 314))	('IDH', 'Gene', (180, 183))	('gliomas', 'Phenotype', 'HP:0009733', (274, 281))	('IDH', 'Gene', '3417', (80, 83))	('IDH', 'Gene', '3417', (310, 313))	('ATRX', 'Gene', (287, 291))	('ATRX', 'Gene', '546', (287, 291))	('IDH-', 'Gene', '3417', (180, 184))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('IDH', 'Gene', '3417', (180, 183))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('IDH-', 'Gene', (310, 314))	('mutation', 'Var', (84, 92))
178014	30786920	In order to establish if an upper age limit can be justified for the testing of IDH1/IDH2 mutations beyond the use of immunostaining with the IDH1 R132H mutation-specific antibody, we analysed the age distribution in 1546 tumours.	('IDH1', 'Gene', (80, 84))	('mutations', 'Var', (90, 99))	('IDH1', 'Gene', '3417', (142, 146))	('tumours', 'Phenotype', 'HP:0002664', (222, 229))	('R132H', 'Mutation', 'rs121913500', (147, 152))	('IDH1', 'Gene', '3417', (80, 84))	('IDH2', 'Gene', (85, 89))	('tumours', 'Disease', 'MESH:D009369', (222, 229))	('tumours', 'Disease', (222, 229))	('IDH2', 'Gene', '3418', (85, 89))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('IDH1', 'Gene', (142, 146))
178015	30786920	The frequency distribution of the distinct IDH1 and IDH2 mutations is comparable to previous reports of similar scale (Fig.	('IDH2', 'Gene', '3418', (52, 56))	('IDH1', 'Gene', (43, 47))	('mutations', 'Var', (57, 66))	('IDH1', 'Gene', '3417', (43, 47))	('IDH2', 'Gene', (52, 56))
178019	30786920	In our opinion, this justifies molecular testing for these rarer IDH1/IDH2 mutations in patients over 55 years, in contrast to previous recommendations.	('IDH1', 'Gene', '3417', (65, 69))	('IDH2', 'Gene', '3418', (70, 74))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (75, 84))	('IDH1', 'Gene', (65, 69))	('IDH2', 'Gene', (70, 74))
178022	30786920	Importantly, mutations in TERT promoter may be observed in these tumours.	('TERT', 'Gene', (26, 30))	('TERT', 'Gene', '7015', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('observed', 'Reg', (47, 55))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('mutations', 'Var', (13, 22))	('tumours', 'Disease', (65, 72))
178023	30786920	We and most other centres use ATRX IHC as a surrogate marker for ATRX mutations, however, the loss of function mutations with retained protein expression are not detected.	('mutations', 'Var', (70, 79))	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', (65, 69))	('ATRX', 'Gene', '546', (30, 34))	('ATRX', 'Gene', '546', (65, 69))
178024	30786920	As shown in our cohort and other studies, such mutations are relatively infrequent but provide an explanation for the discrepancies between ATRX sequencing and immunohistochemistry.	('ATRX', 'Gene', '546', (140, 144))	('ATRX', 'Gene', (140, 144))	('mutations', 'Var', (47, 56))
178025	30786920	In our cohort, we observed mutations in the TERT promoter in all IDH-mutant, 1p/19q co-deleted oligodendrogliomas, where testing was successful.	('mutations', 'Var', (27, 36))	('TERT', 'Gene', (44, 48))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (95, 113))	('TERT', 'Gene', '7015', (44, 48))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('oligodendrogliomas', 'Disease', (95, 113))	('IDH-', 'Gene', (65, 69))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('IDH-', 'Gene', '3417', (65, 69))
178029	30786920	In our practice, all H3 K27M mutant gliomas (n = 49) have been located in the midline, its proximity, or there was an anatomical connection to the midline.	('gliomas', 'Disease', (36, 43))	('K27M', 'Mutation', 'p.K27M', (24, 28))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('H3 K27M mutant', 'Var', (21, 35))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
178034	30786920	In our experience, loss of ATRX protein expression occurs in nearly all (18/19; 95%) H3 G34 mutant gliomas but only in a subset (19/45; 42%) of H3 K27M mutant gliomas.	('expression', 'MPA', (40, 50))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('K27M', 'Mutation', 'p.K27M', (147, 151))	('loss', 'NegReg', (19, 23))	('ATRX', 'Gene', (27, 31))	('gliomas', 'Disease', (99, 106))	('ATRX', 'Gene', '546', (27, 31))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('mutant', 'Var', (92, 98))	('H3 G34', 'Gene', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
178035	30786920	Rarely, we observed biphasic patterns of ATRX loss in H3 K27M (1 case) - and H3 G34R mutant gliomas (1 case) (Fig.	('H3 G34R mutant', 'Var', (77, 91))	('K27M', 'Mutation', 'p.K27M', (57, 61))	('ATRX', 'Gene', (41, 45))	('loss', 'NegReg', (46, 50))	('H3 K27M', 'Var', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('ATRX', 'Gene', '546', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('G34R', 'Mutation', 'p.G34R', (80, 84))
178036	30786920	In another case of a recurrent high-grade glioma with ATRX loss, the methylation class was "H3 G34 mutant glioblastoma", but we could not identify any H3 G34 mutation on the H3F3A, HIST1H3B and HIST1H3C genes.	('HIST1H3C', 'Gene', (194, 202))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('H3F3A', 'Gene', '3020', (174, 179))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('HIST1H3B', 'Gene', (181, 189))	('glioblastoma', 'Disease', (106, 118))	('ATRX', 'Gene', '546', (54, 58))	('H3F3A', 'Gene', (174, 179))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('HIST1H3B', 'Gene', '8358', (181, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('mutant', 'Var', (99, 105))	('glioma', 'Disease', (42, 48))	('ATRX', 'Gene', (54, 58))	('HIST1H3C', 'Gene', '8352', (194, 202))
178037	30786920	In our cohort, the brain tumours with loss of ATRX protein expression are IDH-mutant low- and high-grade astrocytomas, H3 K27M and G34 mutant gliomas, anaplastic pilocytic astrocytomas (methylation class ANA_PA, also termed anaplastic astrocytomas with piloid features), and rarely IDH-wildtype glioblastomas, confirmed with the Classifier.	('ATRX', 'Gene', '546', (46, 50))	('IDH-', 'Gene', '3417', (282, 286))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('K27M', 'Mutation', 'p.K27M', (122, 126))	('astrocytomas', 'Disease', 'MESH:D001254', (172, 184))	('anaplastic pilocytic astrocytomas', 'Disease', (151, 184))	('expression', 'MPA', (59, 69))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('IDH-', 'Gene', '3417', (74, 78))	('astrocytomas', 'Disease', 'MESH:D001254', (105, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))	('IDH-wildtype glioblastomas', 'Disease', (282, 308))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('anaplastic astrocytoma', 'Disease', (224, 246))	('brain tumour', 'Phenotype', 'HP:0030692', (19, 31))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('brain tumours', 'Disease', (19, 32))	('IDH-', 'Gene', (282, 286))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (282, 308))	('IDH-', 'Gene', (74, 78))	('glioblastomas', 'Phenotype', 'HP:0012174', (295, 308))	('astrocytomas', 'Disease', (235, 247))	('astrocytoma', 'Phenotype', 'HP:0009592', (235, 246))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (224, 246))	('astrocytomas', 'Disease', (172, 184))	('G34 mutant', 'Var', (131, 141))	('anaplastic pilocytic astrocytomas', 'Disease', 'MESH:D001254', (151, 184))	('gliomas', 'Disease', (142, 149))	('astrocytomas', 'Disease', (105, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (172, 183))	('H3 K27M', 'Var', (119, 126))	('brain tumours', 'Disease', 'MESH:D001932', (19, 32))	('brain tumours', 'Phenotype', 'HP:0030692', (19, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (295, 307))	('ATRX', 'Gene', (46, 50))	('loss', 'NegReg', (38, 42))	('astrocytomas', 'Disease', 'MESH:D001254', (235, 247))
178042	30786920	For 18 (41%) of these tumours, the Classifier returned the diagnosis of IDH-wildtype glioblastoma, IDH-mutant high-grade astrocytoma, anaplastic pilocytic astrocytoma or H3 K27M- or G34R/V-mutant glioma (the discrepant IDH-mutant case was confirmed to carry an IDH mutation on repeat sequencing).	('IDH', 'Gene', '3417', (99, 102))	('IDH-', 'Gene', '3417', (219, 223))	('IDH', 'Gene', '3417', (219, 222))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('astrocytoma', 'Phenotype', 'HP:0009592', (121, 132))	('G34R/V-mutant', 'Var', (182, 195))	('IDH-', 'Gene', '3417', (99, 103))	('IDH', 'Gene', (261, 264))	('astrocytoma', 'Disease', 'MESH:D001254', (155, 166))	('astrocytoma', 'Disease', (155, 166))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('IDH', 'Gene', (72, 75))	('IDH-', 'Gene', (219, 223))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('IDH-wildtype glioblastoma', 'Disease', 'MESH:D005909', (72, 97))	('astrocytoma', 'Disease', 'MESH:D001254', (121, 132))	('IDH-wildtype glioblastoma', 'Disease', (72, 97))	('astrocytoma', 'Disease', (121, 132))	('IDH', 'Gene', '3417', (261, 264))	('IDH-', 'Gene', '3417', (72, 76))	('IDH-', 'Gene', (99, 103))	('tumours', 'Disease', (22, 29))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (99, 102))	('K27M', 'Mutation', 'p.K27M', (173, 177))	('IDH', 'Gene', (219, 222))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (145, 166))	('astrocytoma', 'Phenotype', 'HP:0009592', (155, 166))	('H3 K27M- or G34R/V-mutant', 'Var', (170, 195))	('G34R', 'Mutation', 'p.G34R', (182, 186))	('glioma', 'Disease', (196, 202))	('pilocytic astrocytoma', 'Disease', (145, 166))	('IDH-', 'Gene', (72, 76))
178046	30786920	Characteristic signatures are chromosome 7 gains and 10 losses, EGFR amplification and TERT promoter mutation.	('losses', 'NegReg', (56, 62))	('TERT', 'Gene', (87, 91))	('chromosome', 'Gene', (30, 40))	('gains', 'PosReg', (43, 48))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (87, 91))	('amplification', 'Var', (69, 82))
178060	30786920	The Classifier result (of anaplastic) PXA prompted us to test for, and confirm the BRAF V600E mutation, and the patient underwent treatment with BRAF inhibitors.	('BRAF', 'Gene', (145, 149))	('patient', 'Species', '9606', (112, 119))	('V600E', 'Mutation', 'rs113488022', (88, 93))	('V600E', 'Var', (88, 93))	('BRAF', 'Gene', '673', (83, 87))	('PXA', 'Disease', (38, 41))	('test', 'Reg', (57, 61))	('BRAF', 'Gene', (83, 87))	('BRAF', 'Gene', '673', (145, 149))
178061	30786920	Another tumour with histological features of anaplastic ependymoma was reclassified as H3 K27M-mutant diffuse midline glioma, and this mutation was confirmed subsequently by IHC and H3F3A gene sequencing.	('tumour', 'Disease', (8, 14))	('ependymoma', 'Disease', 'MESH:D004806', (56, 66))	('ependymoma', 'Disease', (56, 66))	('H3F3A', 'Gene', '3020', (182, 187))	('midline glioma', 'Disease', (110, 124))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('H3F3A', 'Gene', (182, 187))	('ependymoma', 'Phenotype', 'HP:0002888', (56, 66))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('anaplastic ependymoma', 'Phenotype', 'HP:0030066', (45, 66))	('K27M', 'Mutation', 'p.K27M', (90, 94))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('H3 K27M-mutant', 'Var', (87, 101))	('midline glioma', 'Disease', 'MESH:D005910', (110, 124))
178064	30786920	IHC, targeted sequencing, copy number assay) is in our practice the first line diagnostic approach and is adequate for the majority of intrinsic tumours, such as IDH-mutant astrocytomas, oligodendrogliomas, histone-mutant, or EGFR-amplified, TERT promoter-mutant IDH-wildtype glioblastomas.	('IDH-', 'Gene', '3417', (162, 166))	('oligodendrogliomas', 'Disease', (187, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (276, 288))	('intrinsic tumours', 'Disease', (135, 152))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('IDH-', 'Gene', '3417', (263, 267))	('EGFR', 'Gene', '1956', (226, 230))	('IDH-', 'Gene', (162, 166))	('TERT', 'Gene', (242, 246))	('TERT', 'Gene', '7015', (242, 246))	('astrocytomas', 'Disease', (173, 185))	('IDH-wildtype glioblastomas', 'Disease', (263, 289))	('intrinsic tumours', 'Disease', 'MESH:D020919', (135, 152))	('glioblastomas', 'Phenotype', 'HP:0012174', (276, 289))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (187, 205))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (263, 289))	('IDH-', 'Gene', (263, 267))	('histone-mutant', 'Var', (207, 221))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('astrocytomas', 'Disease', 'MESH:D001254', (173, 185))	('EGFR', 'Gene', (226, 230))
178072	30405766	Furthermore, 5 target genes of GALNT7 involved in these signaling pathways were identified, including Crk, Rac family small GTPase 1, STAT3, poliovirus receptor and Tenascin C. In summary, high expression of GALNT7 was associated with poor prognosis of glioma, and may be used as an effective biomarker of glioma.	('glioma', 'Disease', (306, 312))	('Rac', 'Gene', '5879', (107, 110))	('GALNT7', 'Gene', '51809', (208, 214))	('Crk', 'Gene', '1398', (102, 105))	('glioma', 'Phenotype', 'HP:0009733', (306, 312))	('Rac', 'Gene', (107, 110))	('poliovirus', 'Species', '138950', (141, 151))	('GALNT7', 'Gene', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (306, 312))	('STAT3', 'Gene', '6774', (134, 139))	('glioma', 'Disease', (253, 259))	('high expression', 'Var', (189, 204))	('Crk', 'Gene', (102, 105))	('GALNT7', 'Gene', '51809', (31, 37))	('STAT3', 'Gene', (134, 139))	('GALNT7', 'Gene', (208, 214))	('glioma', 'Disease', 'MESH:D005910', (253, 259))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))
178098	30405766	Together with Kaplan-Meier survival analysis, this suggests that patients with glioma exhibiting high expression of GALNT7 have relatively shorter disease-free (Fig.	('GALNT7', 'Gene', (116, 122))	('disease-free', 'CPA', (147, 159))	('glioma', 'Disease', (79, 85))	('GALNT7', 'Gene', '51809', (116, 122))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('patients', 'Species', '9606', (65, 73))	('high expression', 'Var', (97, 112))	('shorter', 'NegReg', (139, 146))
178161	30405766	In conclusion, high expression of GALNT7 was demonstrated to be associated with poor prognosis of glioma, likely via promoting invasion and proliferation through multiple signaling pathways.	('associated', 'Reg', (64, 74))	('proliferation', 'CPA', (140, 153))	('high expression', 'Var', (15, 30))	('GALNT7', 'Gene', (34, 40))	('promoting', 'PosReg', (117, 126))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('GALNT7', 'Gene', '51809', (34, 40))	('invasion', 'CPA', (127, 135))	('glioma', 'Disease', (98, 104))
178166	29889582	Mutant ATRX: uncovering a new therapeutic target for glioma ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3.	('glioma', 'Disease', (53, 59))	('ATRX', 'Gene', (7, 11))	('H3', 'Chemical', 'MESH:C012616', (160, 162))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('ATRX', 'Gene', '546', (60, 64))	('H3.3', 'Protein', (160, 164))	('ATRX', 'Gene', '546', (7, 11))	('Mutant', 'Var', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('ATRX', 'Gene', (60, 64))
178167	29889582	ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation.	('ATRX', 'Gene', (0, 4))	('affect', 'Reg', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('mutations', 'Var', (5, 14))	('ALT', 'Chemical', '-', (106, 109))	('glioma', 'Disease', (41, 47))
178169	29889582	We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('pediatric glioma', 'Disease', 'MESH:D005910', (139, 155))	('ATRX', 'Gene', (40, 44))	('cancer', 'Disease', (58, 64))	('pediatric glioma', 'Disease', (139, 155))
178176	29889582	There is a correlation between ATRX mutations and Alternative Lengthening of Telomeres (ALT), a non-telomerase-dependent telomere lengthening mechanism.	('ALT', 'Chemical', '-', (88, 91))	('mutations', 'Var', (36, 45))	('ATRX', 'Gene', (31, 35))
178178	29889582	ATRX loss may occur by mutations, deletions, or gene fusions and correlates with other defined molecular changes such as the ALT phenotype, PDGFRA (platelet-derived growth factor receptor alpha) amplification, and TP53 (tumor protein P53) mutation.	('P53', 'Gene', (215, 218))	('tumor', 'Disease', (220, 225))	('loss', 'NegReg', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('PDGFRA', 'Gene', '5156', (140, 146))	('PDGFRA', 'Gene', (140, 146))	('P53', 'Gene', '7157', (215, 218))	('deletions', 'Var', (34, 43))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('mutation', 'Var', (239, 247))	('ALT', 'Chemical', '-', (125, 128))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (148, 193))	('P53', 'Gene', (234, 237))	('ATRX', 'Gene', (0, 4))	('platelet-derived growth factor receptor alpha', 'Gene', (148, 193))	('TP53', 'Gene', (214, 218))	('P53', 'Gene', '7157', (234, 237))
178180	29889582	There is a strong association between IDH (isocitrate dehydrogenase) mutations and ATRX mutations.	('mutations', 'Var', (69, 78))	('IDH', 'Gene', (38, 41))	('mutations', 'Var', (88, 97))	('ATRX', 'Gene', (83, 87))	('isocitrate dehydrogenase', 'Gene', (43, 67))	('IDH', 'Gene', '3417', (38, 41))	('isocitrate dehydrogenase', 'Gene', '3417', (43, 67))
178182	29889582	For instance, ATRX mutations confer a better progression free and overall survival in low grade glioma harboring IDH mutations without 1p/19q co-deletion.	('IDH', 'Gene', '3417', (113, 116))	('mutations', 'Var', (117, 126))	('better', 'PosReg', (38, 44))	('ATRX', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('progression', 'MPA', (45, 56))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH', 'Gene', (113, 116))	('glioma', 'Disease', (96, 102))
178183	29889582	In genome-wide sequencing of gliomas, 30% of younger patients have ATRX mutations.	('ATRX', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (53, 61))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
178184	29889582	ATRX is mutated rarely in adult primary high grade gliomas (glioblastoma: GBMs), but it is more common in younger adult patients with lower grade gliomas.	('glioblastoma', 'Disease', (60, 72))	('gliomas', 'Disease', (51, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('common', 'Reg', (96, 102))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('ATRX', 'Gene', (0, 4))	('gliomas', 'Disease', (146, 153))	('mutated', 'Var', (8, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('patients', 'Species', '9606', (120, 128))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
178187	29889582	Current studies demonstrate important characteristics of ATRX mutations in glioma.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('mutations', 'Var', (62, 71))	('rat', 'Species', '10116', (23, 26))	('glioma', 'Disease', (75, 81))	('ATRX', 'Gene', (57, 61))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
178189	29889582	Recently, an ATRX-deficient genetically engineered glioma model demonstrated that loss of ATRX reduces median survival and increases genetic instability.	('median', 'MPA', (103, 109))	('genetic instability', 'MPA', (133, 152))	('glioma', 'Disease', (51, 57))	('rat', 'Species', '10116', (71, 74))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('ATRX', 'Gene', (90, 94))	('loss', 'Var', (82, 86))	('reduces', 'NegReg', (95, 102))	('increases', 'PosReg', (123, 132))
178190	29889582	ATRX mutation was found to be associated with increased mutation rate at the single-nucleotide variant level.	('mutation rate', 'MPA', (56, 69))	('ATRX', 'Gene', (0, 4))	('increased', 'PosReg', (46, 55))	('mutation', 'Var', (5, 13))	('rat', 'Species', '10116', (65, 68))
178193	29889582	They found that only 29% (2/7) of the K27M-shp53 group displayed tumors at 4-6 months compared to 65% (11/17) for the K27M-shp53-shAtrx group, suggesting that Atrx knock down could be accelerating tumor development in this model as well.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('rat', 'Species', '10116', (190, 193))	('p53', 'Gene', (125, 128))	('K27M', 'Mutation', 'p.K27M', (38, 42))	('p53', 'Gene', '7157', (125, 128))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('knock down', 'Var', (164, 174))	('accelerating', 'PosReg', (184, 196))	('tumor', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('K27M', 'Mutation', 'p.K27M', (118, 122))
178201	29889582	Even mutations in ATRX interacting genes were not found to cause ATRX syndrome.	('ATRX', 'Gene', (18, 22))	('ATRX syndrome', 'Disease', (65, 78))	('mutations', 'Var', (5, 14))	('ATRX syndrome', 'Disease', 'MESH:C538258', (65, 78))
178203	29889582	It also has a distinctive domain termed ADD (ATRX-DNMT3-DNMT3L, ADDATRX), which binds to histone H3 preferentially when it is lysine 9-trimethylated (H3K9me3) as opposed to lysine 4-trimethylated (H3K4me3).	('ATRX-DNMT3', 'Gene', '546', (45, 55))	('H3', 'Chemical', 'MESH:C012616', (197, 199))	('preferentially', 'PosReg', (100, 114))	('H3', 'Chemical', 'MESH:C012616', (97, 99))	('DNMT3L', 'Gene', (56, 62))	('histone H3', 'Protein', (89, 99))	('binds', 'Interaction', (80, 85))	('lysine', 'Chemical', 'MESH:D008239', (173, 179))	('H3', 'Chemical', 'MESH:C012616', (150, 152))	('lysine', 'Chemical', 'MESH:D008239', (126, 132))	('ATRX-DNMT3', 'Gene', (45, 55))	('DNMT3L', 'Gene', '29947', (56, 62))	('lysine 9-trimethylated', 'Var', (126, 148))
178207	29889582	Most ATRX mutations in the ATRX syndrome are located in the ADD and the ATPase/helicase domains and the mutated domain is related with the severity of the condition.	('located', 'Reg', (45, 52))	('ATPase/helicase', 'Protein', (72, 87))	('ATRX syndrome', 'Disease', 'MESH:C538258', (27, 40))	('ATRX', 'Gene', (5, 9))	('related', 'Reg', (122, 129))	('mutations', 'Var', (10, 19))	('ATRX syndrome', 'Disease', (27, 40))
178208	29889582	Interestingly, some of the mutations appearing in ATRX syndrome may be partially rescued by the synthesis of alternative splicing products that exclude the mutated exon.	('mutations', 'Var', (27, 36))	('ATRX syndrome', 'Disease', 'MESH:C538258', (50, 63))	('ATRX syndrome', 'Disease', (50, 63))	('mutated exon', 'MPA', (156, 168))
178209	29889582	This has led to the hypothesis that most of the mutations in the ATRX syndrome represent hypomorphs and not loss of function mutations.	('hypomorphs', 'Disease', 'None', (89, 99))	('hypomorphs', 'Disease', (89, 99))	('ATRX syndrome', 'Disease', 'MESH:C538258', (65, 78))	('ATRX syndrome', 'Disease', (65, 78))	('mutations', 'Var', (48, 57))
178212	29889582	In recent years, with the growth of available genomic and expression data in cancer, ATRX mutations have been identified in pancreatic neuroendocrine tumors (PanNETs), gliomas (Glioblastoma multiforme (GBM), diffuse pontine glioma (DIPG) and lower grade glioma (LGG)), neuroblastoma (NB), osteosarcoma and adrenocortical tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('ATRX', 'Gene', (85, 89))	('osteosarcoma', 'Disease', (289, 301))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (306, 327))	('glioma', 'Disease', (254, 260))	('glioma', 'Disease', (168, 174))	('osteosarcoma', 'Disease', 'MESH:D012516', (289, 301))	('gliomas', 'Disease', (168, 175))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('glioma', 'Disease', (224, 230))	('Glioblastoma multiforme', 'Disease', (177, 200))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('neuroblastoma', 'Disease', (269, 282))	('identified', 'Reg', (110, 120))	('cancer', 'Disease', (77, 83))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (124, 156))	('neuroblastoma', 'Phenotype', 'HP:0003006', (269, 282))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('DIPG', 'Chemical', '-', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('neuroblastoma', 'Disease', 'MESH:D009447', (269, 282))	('adrenocortical tumors', 'Disease', (306, 327))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('osteosarcoma', 'Phenotype', 'HP:0002669', (289, 301))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (177, 200))	('pancreatic neuroendocrine tumors', 'Disease', (124, 156))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('Glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (135, 156))
178221	29889582	DAXX mutations are commonly found in pediatric high-grade gliomas and pediatric diffuse intrinsic pontine glioma (DIPG) and are usually mutually exclusive with ATRX mutations.	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('DAXX', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('DIPG', 'Chemical', '-', (114, 118))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('glioma', 'Disease', (106, 112))	('found', 'Reg', (28, 33))	('gliomas', 'Disease', (58, 65))	('DAXX', 'Gene', '1616', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('glioma', 'Disease', (58, 64))
178223	29889582	Alternatively, DAXX mutations are not commonly observed in adult low-grade gliomas, indicating that DAXX-independent mechanisms of mutant ATRX may play a role in the phenotype of these tumor cells (Figure 2).	('tumor', 'Disease', (185, 190))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('mutant', 'Var', (131, 137))	('gliomas', 'Disease', (75, 82))	('DAXX', 'Gene', (100, 104))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('DAXX', 'Gene', '1616', (15, 19))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('ATRX', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('DAXX', 'Gene', (15, 19))	('DAXX', 'Gene', '1616', (100, 104))
178241	29889582	Both H3K9me3 and H3K27me3 contribute to genomic stability, therefore this genetic shift is proposed to be a compensatory mechanism to preserve heterochromatin integrity when ATRX cannot be directed to PADs.	('H3K9me3', 'Var', (5, 12))	('contribute', 'Reg', (26, 36))	('H3', 'Chemical', 'MESH:C012616', (5, 7))	('H3K27me3', 'Var', (17, 25))	('heterochromatin integrity', 'MPA', (143, 168))	('H3', 'Chemical', 'MESH:C012616', (17, 19))	('genomic stability', 'CPA', (40, 57))
178244	29889582	The upstream region of the alpha-globin gene contains G-rich tandem repeats that associate to form G-quadruplexes (G4) structures.	('G-rich tandem repeats', 'Var', (54, 75))	('G4', 'Chemical', '-', (115, 117))	('alpha-globin', 'Gene', (27, 39))
178258	29889582	In addition, as a consequence of fork degradation, ATRX-mutated cells activate poly (ADP- ribose) polymerase-1 (Parp-1), which encodes a protein involved in DNA repair.	('Parp-1', 'Gene', '142', (112, 118))	('ATRX-mutated', 'Var', (51, 63))	('Parp-1', 'Gene', (112, 118))	('activate', 'PosReg', (70, 78))	('fork', 'MPA', (33, 37))	('poly (ADP- ribose) polymerase-1', 'Gene', '142', (79, 110))
178261	29889582	ChIP-seq approaches revealed that approximately one quarter of H3.3 is incorporated in condensed chromatin regions, which also display the repressive histone mark, H3K9me3.	('H3.3', 'Protein', (63, 67))	('H3K9me3', 'Var', (164, 171))	('rat', 'Species', '10116', (78, 81))	('H3', 'Chemical', 'MESH:C012616', (164, 166))	('H3', 'Chemical', 'MESH:C012616', (63, 65))
178263	29889582	Silencing of ERVs by means of epigenetically repressive H3.3 (with H3K9me3 and H4K20me3, as well as high levels of DNA methylation) is particularly important in embryonic stem (ES) cells because these cells undergo genome-wide demethylation.	('ERVs', 'Gene', (13, 17))	('epigenetically', 'Var', (30, 44))	('H3', 'Chemical', 'MESH:C012616', (67, 69))	('Silencing', 'NegReg', (0, 9))	('H4K20me3', 'Var', (79, 87))	('H3', 'Chemical', 'MESH:C012616', (56, 58))	('H3K9me3', 'Var', (67, 74))
178266	29889582	However, a recent report demonstrates that cells with ATRX mutations affecting the DAXX interaction domain do not show ERVs activation, indicating that DAXX has an ATRX-independent mechanism to maintain ERVs silencing.	('DAXX', 'Gene', '1616', (83, 87))	('rat', 'Species', '10116', (32, 35))	('DAXX', 'Gene', '1616', (152, 156))	('DAXX', 'Gene', (83, 87))	('ERVs silencing', 'MPA', (203, 217))	('mutations', 'Var', (59, 68))	('DAXX', 'Gene', (152, 156))	('ATRX', 'Gene', (54, 58))
178269	29889582	ZNF genes contain an atypical chromatin signature: they are enriched in H3K36me3 (mark of actively transcribed genes) and H3K9me3 (repressive mark), although they are actively transcribed.	('H3', 'Chemical', 'MESH:C012616', (122, 124))	('H3K9me3', 'Var', (122, 129))	('H3', 'Chemical', 'MESH:C012616', (72, 74))	('H3K36me3', 'Protein', (72, 80))	('ZNF genes', 'Gene', (0, 9))
178270	29889582	ATRX inactivation leads to a decrease of H3K9me3 in these regions and a concomitant increase in DNA-damage.	('DNA-damage', 'MPA', (96, 106))	('ATRX', 'Gene', (0, 4))	('H3K9me3', 'Protein', (41, 48))	('increase', 'PosReg', (84, 92))	('H3', 'Chemical', 'MESH:C012616', (41, 43))	('inactivation', 'Var', (5, 17))	('decrease', 'NegReg', (29, 37))
178273	29889582	H3K27me3 is associated with negative regulation of gene expression.	('negative regulation', 'MPA', (28, 47))	('H3K27me3', 'Var', (0, 8))	('H3', 'Chemical', 'MESH:C012616', (0, 2))
178290	29889582	These findings may indicate that loss of ATRX confers an advantage for developing cancer cells by means of repressing senescence pathways.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ATRX', 'Gene', (41, 45))	('advantage', 'PosReg', (57, 66))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('loss', 'Var', (33, 37))	('senescence pathways', 'Pathway', (118, 137))	('repressing', 'NegReg', (107, 117))
178296	29889582	Approximately 90% of adult classical oligodendrogliomas have IDH mutation and 1p/19q codeletion, while most adult diffuse astrocytomas are IDH-mutant but have an intact 1p/19q, allowing discriminating the two major adult groups based on their molecular features.	('IDH', 'Gene', '3417', (61, 64))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('astrocytomas', 'Disease', 'MESH:D001254', (122, 134))	('oligodendrogliomas', 'Disease', (37, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (122, 133))	('diffuse astrocytoma', 'Disease', (114, 133))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (114, 133))	('astrocytomas', 'Disease', (122, 134))	('IDH', 'Gene', (139, 142))	('1p/19q codeletion', 'Var', (78, 95))	('IDH', 'Gene', (61, 64))	('IDH', 'Gene', '3417', (139, 142))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (37, 55))
178298	29889582	ATRX loss-of-function mutations (detected by lack of nuclear staining by immunohistochemistry) occur in approximately 75% of astrocytomas grade II and III, and IDH-mutant secondary glioblastomas, and are exclusive with 1p/19q codeletion, so they are rarely detected in IDH-mutant oligodendrogliomas.	('IDH', 'Gene', (160, 163))	('glioblastomas', 'Disease', (181, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (181, 193))	('glioma', 'Phenotype', 'HP:0009733', (291, 297))	('III', 'Disease', (151, 154))	('IDH', 'Gene', (269, 272))	('oligodendrogliomas', 'Disease', (280, 298))	('glioblastomas', 'Disease', 'MESH:D005909', (181, 194))	('IDH', 'Gene', '3417', (160, 163))	('astrocytomas', 'Disease', (125, 137))	('IDH', 'Gene', '3417', (269, 272))	('gliomas', 'Phenotype', 'HP:0009733', (291, 298))	('mutations', 'Var', (22, 31))	('ATRX', 'Gene', (0, 4))	('glioblastomas', 'Phenotype', 'HP:0012174', (181, 194))	('astrocytomas', 'Disease', 'MESH:D001254', (125, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('loss-of-function', 'NegReg', (5, 21))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (280, 298))
178300	29889582	On the other hand, adult WT- IDH tumors with ATRX mutations, which represent a small proportion of the total tumors of the group (around 3%), have an increased survival compared with the ATRX-WT group.	('survival', 'CPA', (160, 168))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('ATRX', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IDH tumors', 'Disease', 'MESH:D009369', (29, 39))	('IDH tumors', 'Disease', (29, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('increased', 'PosReg', (150, 159))	('tumors', 'Disease', (33, 39))	('tumors', 'Disease', (109, 115))
178301	29889582	Mutations in the ATRX gene in glioma were found to be distributed evenly across the gene.	('ATRX', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('glioma', 'Disease', (30, 36))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
178305	29889582	Identifying recurrent mutations and subgrouping gliomas in terms of their molecular features allow the identification of interesting targets to develop personalized therapies.	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('mutations', 'Var', (22, 31))	('gliomas', 'Disease', (48, 55))
178306	29889582	In glioma, essentially all mutations in ATRX are inactivating and can lead to loss of protein expression.	('mutations', 'Var', (27, 36))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('protein expression', 'MPA', (86, 104))	('loss', 'NegReg', (78, 82))	('glioma', 'Disease', (3, 9))	('ATRX', 'Gene', (40, 44))
178307	29889582	These are rarely found in adult high grade glioma (HGG) (age >= 21 years) (6-7.1%), but are frequent in grade II and III gliomas (33.2-71%) and secondary glioblastoma (53-57%) in which ATRX mutations are associated with IDH1 and TP53 mutations (Figure 3).	('III gliomas', 'Disease', (117, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('glioma', 'Disease', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Disease', (121, 127))	('mutations', 'Var', (190, 199))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('TP53', 'Gene', '7157', (229, 233))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('associated', 'Reg', (204, 214))	('IDH1', 'Gene', (220, 224))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('ATRX', 'Gene', (185, 189))	('glioblastoma', 'Disease', (154, 166))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('III gliomas', 'Disease', 'MESH:D005910', (117, 128))	('mutations', 'Var', (234, 243))	('IDH1', 'Gene', '3417', (220, 224))	('TP53', 'Gene', (229, 233))
178308	29889582	Mutations in IDH define a subgroup that is mostly comprised of young adults (median: 40 years, range 13-71 years) and tumors tend to arise in the cerebral hemispheres and frontal cortex.	('IDH', 'Gene', '3417', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (118, 124))	('IDH', 'Gene', (13, 16))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
178309	29889582	In general, ATRX mutations are found to be significantly associated with a mutation in the tail of the histone H3.3 (H3F3A gene), e.g.	('associated', 'Reg', (57, 67))	('H3F3A', 'Gene', '3020', (117, 122))	('mutation in', 'Var', (75, 86))	('ATRX', 'Gene', (12, 16))	('histone H3.3', 'Gene', '3020', (103, 115))	('H3F3A', 'Gene', (117, 122))	('mutations', 'Var', (17, 26))	('histone H3.3', 'Gene', (103, 115))
178310	29889582	H3.3G34R/V, accounting for 9-15% of pediatric HGG, as well as with mutations in TP53 (Figure 3).	('HGG', 'Disease', (46, 49))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('H3.3G34R/V', 'Var', (0, 10))	('H3', 'Chemical', 'MESH:C012616', (0, 2))
178311	29889582	However, K27M mutation in the H3F3A gene, another frequent genetic alteration in the pediatric landscape (15-33%) which also usually cooccurs with TP53 mutations, overlaps less frequently with ATRX mutations (22-60 %).	('TP53', 'Gene', (147, 151))	('K27M', 'Var', (9, 13))	('rat', 'Species', '10116', (71, 74))	('H3F3A', 'Gene', (30, 35))	('TP53', 'Gene', '7157', (147, 151))	('H3F3A', 'Gene', '3020', (30, 35))	('K27M', 'Mutation', 'p.K27M', (9, 13))
178312	29889582	These two types of histone mutations define two separate groups in terms of their genetic, epigenetic and clinical characteristics.	('mutations', 'Var', (27, 36))	('rat', 'Species', '10116', (52, 55))	('histone', 'Protein', (19, 26))
178314	29889582	Additionally, while H3.3G34R/V mutations are predominantly restricted to tumors of the cerebral hemispheres, H3K27M mutations are usually found in midline locations, such as the thalamus (40 %), and in 78% of DIPG.	('midline locations', 'Disease', 'MESH:D009436', (147, 164))	('H3K27M', 'Gene', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('H3', 'Chemical', 'MESH:C012616', (109, 111))	('tumors of the cerebral hemispheres', 'Disease', 'MESH:D001932', (73, 107))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (116, 125))	('DIPG', 'Chemical', '-', (209, 213))	('tumors of the cerebral hemispheres', 'Disease', (73, 107))	('H3', 'Chemical', 'MESH:C012616', (20, 22))	('H3.3G34R/V', 'Gene', (20, 30))	('midline locations', 'Disease', (147, 164))
178315	29889582	In both cases, the great majority of these alterations are truncating mutations, such as frameshifts and nonsense mutations.	('frameshifts', 'Var', (89, 100))	('nonsense mutations', 'Var', (105, 123))	('rat', 'Species', '10116', (47, 50))
178316	29889582	ATRX mutations are not frequently observed in diffuse intrinsic pontine glioma (DIPG), a type of infiltrating midline glioma that occurs primarily in children.	('glioma', 'Disease', (72, 78))	('rat', 'Species', '10116', (103, 106))	('glioma', 'Disease', (118, 124))	('DIPG', 'Chemical', '-', (80, 84))	('ATRX', 'Gene', (0, 4))	('midline glioma', 'Disease', (110, 124))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('mutations', 'Var', (5, 14))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('children', 'Species', '9606', (150, 158))	('midline glioma', 'Disease', 'MESH:D005910', (110, 124))
178318	29889582	Through Next Generation Sequencing (NGS) technology, the histone H3K27M mutation has been identified as the most common mutation in DIPG, occurring in 78% of DIPG tumors.	('DIPG tumors', 'Disease', 'MESH:D000080443', (158, 169))	('DIPG', 'Chemical', '-', (132, 136))	('DIPG', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('DIPG tumors', 'Disease', (158, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('rat', 'Species', '10116', (17, 20))	('DIPG', 'Chemical', '-', (158, 162))	('occurring', 'Reg', (138, 147))	('H3K27M', 'Var', (65, 71))
178319	29889582	In DIPG, the H3K27M mutation occurs more in H3F3A, the gene encoding histone variant H3.3, and less frequently in HIST1H3B/C, the genes that encode histone variant H3.1 (Figure 3).	('H3F3A', 'Gene', (44, 49))	('variant H3.1', 'CellLine', 'CVCL:7204', (156, 168))	('H3K27M', 'Var', (13, 19))	('HIST1H3B', 'Gene', (114, 122))	('H3', 'Chemical', 'MESH:C012616', (85, 87))	('H3', 'Chemical', 'MESH:C012616', (119, 121))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('H3', 'Chemical', 'MESH:C012616', (164, 166))	('H3', 'Chemical', 'MESH:C012616', (13, 15))	('HIST1H3B', 'Gene', '8358', (114, 122))	('DIPG', 'Chemical', '-', (3, 7))	('H3F3A', 'Gene', '3020', (44, 49))
178320	29889582	ATRX mutations are present in 5-12.5% of H3.3 K27M DIPG tumors and are mainly found in older patients.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('DIPG tumors', 'Disease', 'MESH:D000080443', (51, 62))	('H3', 'Chemical', 'MESH:C012616', (41, 43))	('K27M', 'Mutation', 'p.K27M', (46, 50))	('H3.3', 'Gene', (41, 45))	('patients', 'Species', '9606', (93, 101))	('DIPG tumors', 'Disease', (51, 62))
178321	29889582	ATRX alterations are more frequently found at autopsy than at diagnosis, suggesting that the mutation may be a secondary event in these tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('rat', 'Species', '10116', (9, 12))	('ATRX', 'Gene', (0, 4))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
178323	29889582	In this report, the authors focus on the role of ATRX as a H3.3 depositor and study the epigenetic consequences of Atrx knock down.	('H3', 'Chemical', 'MESH:C012616', (59, 61))	('knock down', 'Var', (120, 130))	('Atrx', 'Gene', (115, 119))
178329	29889582	Genomic instability induces somatic mutations that contribute to malignant phenotypes in glioma.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('induces', 'Reg', (20, 27))	('Genomic instability', 'Var', (0, 19))	('glioma', 'Disease', (89, 95))	('contribute', 'Reg', (51, 61))
178334	29889582	Consequently, the accumulation of G4 and other secondary structures in ATRX mutated cells may be a major contributor to genomic instability.	('G4', 'Chemical', '-', (34, 36))	('genomic', 'MPA', (120, 127))	('mutated', 'Var', (76, 83))	('accumulation', 'PosReg', (18, 30))	('ATRX', 'Gene', (71, 75))
178337	29889582	RNAi knock-down of ATRX in mouse embryonic stem cells also induces a telomere-dysfunction phenotype and reduces chromobox homolog 5 (CBX5) enrichment at telomeres, suggesting that ATRX participates in telomere chromatin integrity maintenance.	('knock-down', 'Var', (5, 15))	('mouse', 'Species', '10090', (27, 32))	('CBX5', 'Gene', '12419', (133, 137))	('reduces', 'NegReg', (104, 111))	('induces', 'Reg', (59, 66))	('CBX5', 'Gene', (133, 137))	('telomere-dysfunction', 'Disease', (69, 89))	('telomere-dysfunction', 'Disease', 'MESH:C536801', (69, 89))	('ATRX', 'Gene', (19, 23))
178344	29889582	The first study that associated ATRX with ALT mechanisms also identified G2/M checkpoint deficiency as a hallmark of ALT cells.	('ALT', 'Chemical', '-', (117, 120))	('G2/M checkpoint', 'Gene', (73, 88))	('deficiency', 'Var', (89, 99))	('ALT', 'Chemical', '-', (42, 45))
178345	29889582	This work shows that ALT is associated with recurrent copy number alterations, nonreciprocal translocations, deletions, complex rearrangements, and hyper-triploid chromosome number.	('copy number alterations', 'Var', (54, 77))	('hyper-triploid chromosome number', 'Disease', (148, 180))	('rat', 'Species', '10116', (70, 73))	('deletions', 'Var', (109, 118))	('associated', 'Reg', (28, 38))	('hyper-triploid chromosome number', 'Disease', 'MESH:D057885', (148, 180))	('ALT', 'Chemical', '-', (21, 24))	('ALT', 'Disease', (21, 24))	('complex rearrangements', 'Var', (120, 142))
178350	29889582	This is reflected in higher levels of single nucleotides variants (SNVs), which prompt ALT.	('ALT', 'Chemical', '-', (87, 90))	('ALT', 'MPA', (87, 90))	('prompt', 'PosReg', (80, 86))	('single nucleotides variants', 'Var', (38, 65))
178357	29889582	The DNA damage that results from the loss of ATRX in NPCs induces ataxia-telangiectasia mutated kinase (ATM).	('telangiectasia', 'Phenotype', 'HP:0001009', (73, 87))	('ATM', 'Gene', '472', (104, 107))	('ATRX', 'Gene', (45, 49))	('induces', 'Reg', (58, 65))	('ataxia', 'Phenotype', 'HP:0001251', (66, 72))	('ataxia-telangiectasia mutated kinase', 'Gene', '472', (66, 102))	('loss', 'Var', (37, 41))	('ATM', 'Gene', (104, 107))	('ataxia-telangiectasia mutated kinase', 'Gene', (66, 102))
178361	29889582	Defects in DDR can impact tumor malignancy and its response to DNA-damaging therapies.	('impact', 'Reg', (19, 25))	('DDR', 'Gene', (11, 14))	('Defects', 'Var', (0, 7))	('tumor malignancy', 'Disease', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor malignancy', 'Disease', 'MESH:D018198', (26, 42))
178373	29889582	Dysfunction in H3.3-ATRX-DAXX chromatin remodeling complex leads to reduced incorporation of H3.3 at telomeric chromatin allowing for a permissive environment for telomere-telomere recombination.	('rat', 'Species', '10116', (83, 86))	('H3', 'Chemical', 'MESH:C012616', (93, 95))	('Dysfunction', 'Var', (0, 11))	('DAXX', 'Gene', (25, 29))	('H3.3', 'Protein', (93, 97))	('H3', 'Chemical', 'MESH:C012616', (15, 17))	('incorporation', 'MPA', (76, 89))	('DAXX', 'Gene', '1616', (25, 29))	('reduced', 'NegReg', (68, 75))
178374	29889582	The telomere sister chromatid exchange (T-SCE) model proposes that loss of ATRX suppresses the proper resolution of sister telomere cohesion that normally occurs prior to mitosis.	('ATRX', 'Gene', (75, 79))	('mitosis', 'Disease', (171, 178))	('loss', 'Var', (67, 71))	('resolution of sister telomere cohesion', 'MPA', (102, 140))	('mitosis', 'Disease', 'None', (171, 178))	('suppresses', 'NegReg', (80, 90))
178375	29889582	In the absence of ATRX, the histone variant macroH2A1.1 inhibitis the ability of the telomere-associated poly-ADP ribose polymerase tankyrase to dissociate components of the shelterin complex that mediates telomere cohesion.	('macroH2A1.1', 'Gene', '9555', (44, 55))	('variant', 'Var', (36, 43))	('ability', 'MPA', (70, 77))	('macroH2A1.1', 'Gene', (44, 55))	('inhibitis', 'NegReg', (56, 65))	('dissociate', 'MPA', (145, 155))
178376	29889582	The NuRD-ZNF827 complex anchors neighboring telomeres by partial displacement of telomeric repeat-binding factor 2 (TERF2), a component of the shelterin complex, and favors an environment for ALT through enabling the interaction of telomeres on the same or different chromosomes, the recruitment of HR proteins and deacetylating the chromatin which causes its compaction and could diminish shelterin binding to telomeres (Figure 4).	('telomeric repeat-binding factor 2', 'Gene', '7014', (81, 114))	('telomeric repeat-binding factor 2', 'Gene', (81, 114))	('enabling', 'PosReg', (204, 212))	('shelterin', 'Protein', (390, 399))	('causes', 'Reg', (349, 355))	('binding', 'Interaction', (400, 407))	('interaction', 'Interaction', (217, 228))	('ZNF827', 'Gene', (9, 15))	('diminish', 'NegReg', (381, 389))	('ZNF827', 'Gene', '152485', (9, 15))	('HR proteins', 'Disease', (299, 310))	('recruitment', 'PosReg', (284, 295))	('deacetylating', 'Var', (315, 328))	('favors', 'PosReg', (166, 172))	('TERF2', 'Gene', (116, 121))	('ALT', 'Chemical', '-', (192, 195))	('TERF2', 'Gene', '7014', (116, 121))	('HR proteins', 'Disease', 'MESH:D011488', (299, 310))	('compaction', 'MPA', (360, 370))
178403	29889582	ATRX has a broad spectrum of functions in normal cells and its disruption has been associated with several alterations in glioma and other cancers.	('rat', 'Species', '10116', (111, 114))	('ATRX', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('glioma', 'Disease', (122, 128))	('associated', 'Reg', (83, 93))	('disruption', 'Var', (63, 73))	('alterations', 'Disease', (107, 118))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
178405	29889582	Although the initial discovery of ATRX mutations in cancer was associated with ALT, recently uncovered functions of ATRX in different molecular processes suggest a broader and more complex role (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ATRX', 'Gene', (34, 38))	('associated', 'Reg', (63, 73))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('ALT', 'Chemical', '-', (79, 82))	('ALT', 'Disease', (79, 82))
178406	29889582	Taking into account the findings over the last few years, it now seems clear that the contributions of ATRX mutations in cancer have been understated.	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ATRX', 'Gene', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
178407	29889582	Additional work is needed to further dissect the role of ATRX mutations in glioma.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('mutations', 'Var', (62, 71))	('glioma', 'Disease', (75, 81))	('ATRX', 'Gene', (57, 61))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
178409	29889582	The interchangeability of ATRX and DAXX mutations in some gliomas subtypes (HGG) whilst not in others (such as in LGG), suggests that ATRX DAXX-dependent functions (particularly H3.3 deposition) are more relevant in pediatric CNS tumors than in adult gliomas.	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('H3', 'Chemical', 'MESH:C012616', (178, 180))	('gliomas', 'Disease', 'MESH:D005910', (251, 258))	('gliomas', 'Disease', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('mutations', 'Var', (40, 49))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('DAXX', 'Gene', (139, 143))	('DAXX', 'Gene', '1616', (139, 143))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('DAXX', 'Gene', (35, 39))	('ATRX', 'Gene', (26, 30))	('DAXX', 'Gene', '1616', (35, 39))	('CNS tumors', 'Disease', 'MESH:D009369', (226, 236))	('gliomas', 'Disease', (251, 258))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('CNS tumors', 'Disease', (226, 236))
178410	29889582	The co-occurrence of ATRX mutations with H3.3/H3.1 mutations and mutations in other epigenetic regulators also suggests that there may be collaborative/addictive effects among them.	('mutations', 'Var', (51, 60))	('addictive effects', 'Phenotype', 'HP:0030858', (152, 169))	('H3', 'Chemical', 'MESH:C012616', (46, 48))	('ATRX', 'Gene', (21, 25))	('H3.1', 'Gene', (46, 50))	('mutations', 'Var', (26, 35))	('H3', 'Chemical', 'MESH:C012616', (41, 43))	('rat', 'Species', '10116', (145, 148))	('H3.1', 'Gene', '8353', (46, 50))
178411	29889582	The study of the emergence of these mutations in the context of the tumor evolution could provide insights determining the importance of ATRX mutations in the development of cancer.	('tumor', 'Disease', (68, 73))	('ATRX', 'Gene', (137, 141))	('mutations', 'Var', (142, 151))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
178412	29889582	Since ATRX is involved in DNA repair, it is important to determine whether ATRX mutations have an effect on increasing the mutation rate in tumor cells, which could be related with evolution of the tumor to a more malignant phenotype.	('ATRX', 'Gene', (75, 79))	('rat', 'Species', '10116', (132, 135))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('increasing', 'PosReg', (108, 118))	('tumor', 'Disease', (198, 203))	('mutation rate', 'MPA', (123, 136))	('tumor', 'Disease', (140, 145))
178414	29889582	It is also important to determine whether ATRX mutations in cancer are loss-of-function or whether some functions are retained.	('loss-of-function', 'NegReg', (71, 87))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutations', 'Var', (47, 56))	('ATRX', 'Gene', (42, 46))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
178417	29889582	Considering that ATRX mutations are not sufficient to establish ALT, molecular studies aiming at elucidating other contributors to the mechanism and the role they play will likely provide new therapeutic targets.	('ATRX', 'Gene', (17, 21))	('ALT', 'Chemical', '-', (64, 67))	('mutations', 'Var', (22, 31))
178422	29889582	Mutations in ATRX were found in various cancers and the occurrence of these mutations has a close association with the development of the Alternative Lengthening of Telomeres (ALT) mechanism, a recombination-based telomere maintenance mechanism (TMM).	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('mutations', 'Var', (76, 85))	('ATRX', 'Gene', (13, 17))	('found', 'Reg', (23, 28))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ALT', 'Chemical', '-', (176, 179))
178423	29889582	ATRX mutations occur in some types of glioma, eliciting changes in the features of the cancer, from molecular to clinical perspectives.	('cancer', 'Disease', (87, 93))	('eliciting changes', 'Reg', (46, 63))	('ATRX', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (15, 20))	('glioma', 'Disease', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
178424	29889582	The occurrence of mutations in epigenetic regulators is frequent in glioma, indicating that epigenetic reprogramming is a critical event in glioma development.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('glioma', 'Disease', (140, 146))	('glioma', 'Disease', (68, 74))	('mutations', 'Var', (18, 27))
178426	29889582	Cancer cells harboring ATRX mutations exhibit chromatin instability and impaired DNA damage response, which make them vulnerable to DNA damaging treatments.	('impaired', 'NegReg', (72, 80))	('chromatin instability', 'MPA', (46, 67))	('DNA damage response', 'MPA', (81, 100))	('ATRX', 'Gene', (23, 27))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (28, 37))
178427	29889582	While in animal models ATRX mutant gliomas progress faster than the ATRX wild type counterparts, they are more responsive to DNA damaging treatments.	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('mutant', 'Var', (28, 34))	('progress', 'CPA', (43, 51))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('gliomas', 'Disease', (35, 42))	('ATRX', 'Gene', (23, 27))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))
178428	29889582	There is also a correlation between the presence of ATRX mutations and extended survival in treated patients.	('mutations', 'Var', (57, 66))	('ATRX', 'Gene', (52, 56))	('extended survival', 'CPA', (71, 88))	('patients', 'Species', '9606', (100, 108))
178463	28486641	The updated WHO classification incorporates molecular markers along with histology and defines specific entities on the basis of IDH mutation and 1p19q chromosomal deletion.	('IDH', 'Gene', (129, 132))	('mutation', 'Var', (133, 141))	('1p19q chromosomal deletion', 'Var', (146, 172))	('IDH', 'Gene', '3417', (129, 132))
178542	28486641	Although there are no definitive conventional MRI features with negative predictive value for pseudoprogression, some findings, such as multifocality, signal abnormality extending across the corpus callosum, and subependymal involvement, are suggestive of progression.	('subependymal involvement', 'Disease', 'MESH:D018315', (212, 236))	('signal abnormality', 'Var', (151, 169))	('subependymal involvement', 'Disease', (212, 236))	('multifocality', 'Disease', (136, 149))
178576	28567708	Significant positive correlation was observed between T/N ratios of 18F-FDG and 18F-FAMT (r s = 0.454, p = 0.004), but median T/N ratio of 18F-FAMT PET was significantly higher than that of 18F-FDG PET in all grades of glioma.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('18F-FDG', 'Chemical', 'MESH:D019788', (190, 197))	('18F-FAMT', 'Chemical', '-', (80, 88))	('higher', 'PosReg', (170, 176))	('18F-FAMT', 'Chemical', '-', (139, 147))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('18F-FAMT', 'Var', (139, 147))	('18F-FDG', 'Chemical', 'MESH:D019788', (68, 75))	('glioma', 'Disease', 'MESH:D005910', (219, 225))	('T/N', 'MPA', (126, 129))	('glioma', 'Disease', (219, 225))	('N', 'Chemical', 'MESH:D009584', (56, 57))
178590	28567708	Recently, the 18F-based PET tracers, O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) and L-6-[18F]fluoro-3,4-dihydroxyphenylalnine have been used for the imaging of brain tumors.	('brain tumor', 'Phenotype', 'HP:0030692', (161, 172))	('L-6-[18F]', 'Var', (85, 94))	('brain tumors', 'Disease', 'MESH:D001932', (161, 173))	('brain tumors', 'Phenotype', 'HP:0030692', (161, 173))	('brain tumors', 'Disease', (161, 173))	('L-6-[18F]fluoro-3,4-dihydroxyphenylalnine', 'Chemical', '-', (85, 126))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('O-(2-[18F]fluoroethyl)-L-tyrosine', 'Chemical', 'MESH:C117289', (37, 70))
178591	28567708	Previously, we developed L-[3-18F]-alpha-methyltyrosine (18F-FAMT), a new amino acid tracer for PET imaging and demonstrated its potential for detecting neoplasms using experimental tumor models.	('tumor', 'Disease', (182, 187))	('18F-FAMT', 'Chemical', '-', (57, 65))	('L-[3-18F', 'Var', (25, 33))	('neoplasms', 'Disease', 'MESH:D009369', (153, 162))	('neoplasms', 'Disease', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('L-[3-18F]-alpha-methyltyrosine', 'Chemical', '-', (25, 55))	('men', 'Species', '9606', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
178654	28567708	Significant positive correlation was observed between the T/N ratios of 18F-FDG and 18F-FAMT in all gliomas (r s = 0.454, p = 0.004; Fig.	('18F-FDG', 'Var', (72, 79))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('18F-FAMT', 'Chemical', '-', (84, 92))	('18F-FAMT', 'Var', (84, 92))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('18F-FDG', 'Chemical', 'MESH:D019788', (72, 79))	('gliomas', 'Disease', (100, 107))
178663	28567708	Radiosynthesis of 18F-FAMT, an amino acid analog with a relatively high chemical yield, was originally developed at our institute, and experimental and clinical investigations have demonstrated that accumulation of 18F-FAMT in tumor cells occurs via an amino acid transport system.	('men', 'Species', '9606', (141, 144))	('18F-FAMT', 'Var', (215, 223))	('18F-FAMT', 'Chemical', '-', (215, 223))	('tumor', 'Disease', (227, 232))	('amino acid transport system', 'MPA', (253, 280))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('18F-FAMT', 'Chemical', '-', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
178671	28567708	Uptake of L-3-[123I]iodo-alpha-methyl tyrosine and of 11C-MET involves almost the same transport mechanism, system L, which is a Na-independent amino acid transport system, in cultured glioma cell lines.	('L-3-[123I]iodo-alpha-methyl tyrosine', 'Chemical', 'MESH:C030855', (10, 46))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('11C-MET', 'Chemical', 'MESH:C038344', (54, 61))	('glioma', 'Disease', (185, 191))	('L-3-[123I]', 'Var', (10, 20))
178672	28567708	In fact, L-3-[123I]iodo-alpha-methyl tyrosine single photon emission computed tomography and 11C-MET PET have equivalent clinical value in the diagnostic evaluation of glioma.	('L-3-[123I]', 'Var', (9, 19))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('L-3-[123I]iodo-alpha-methyl tyrosine', 'Chemical', 'MESH:C030855', (9, 45))	('11C-MET', 'Chemical', 'MESH:C038344', (93, 100))	('glioma', 'Disease', (168, 174))
178675	28567708	L-type amino acid transporter 1 (LAT1) is a major route for the transport of large neutral amino acids, including L-tyrosine, L-leucine, and L-methionine, through the plasma membrane.	('L-methionine', 'Var', (141, 153))	('L-methionine', 'Chemical', 'MESH:D008715', (141, 153))	('LAT1', 'Gene', '8140', (33, 37))	('L-tyrosine', 'Chemical', 'MESH:D014443', (114, 124))	('LAT1', 'Gene', (33, 37))	('L-type amino acid transporter 1', 'Gene', '8140', (0, 31))	('L-leucine', 'Var', (126, 135))	('L-leucine', 'Chemical', 'MESH:D007930', (126, 135))	('L-tyrosine', 'Var', (114, 124))	('L-type amino acid transporter 1', 'Gene', (0, 31))
178688	28567708	In contrast, WHO grade is a direct index of the malignancy grade, based on the consideration of various pathological factors, including the presence of necrosis, nuclear polymorphism, microvascular proliferation, mitotic activity, etc.	('necrosis', 'Disease', (152, 160))	('malignancy', 'Disease', (48, 58))	('mitotic activity', 'CPA', (213, 229))	('malignancy', 'Disease', 'MESH:D009369', (48, 58))	('necrosis', 'Disease', 'MESH:D009336', (152, 160))	('nuclear', 'Var', (162, 169))	('microvascular proliferation', 'CPA', (184, 211))
178699	28567708	In our study, the T/N ratios of 18F-FAMT PET and 18F-FDG PET in the ROC analysis were almost equivalent for the differential diagnosis of tumor grade.	('18F-FAMT', 'Chemical', '-', (32, 40))	('tumor', 'Disease', (138, 143))	('18F-FAMT PET', 'Var', (32, 44))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('18F-FDG', 'Chemical', 'MESH:D019788', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('18F-FDG', 'Var', (49, 56))
178701	28567708	18F-FAMT PET provided clearer imaging with higher T/N ratio and better contrast in all gliomas compared to 18F-FDG PET.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('higher', 'PosReg', (43, 49))	('18F-FAMT', 'Chemical', '-', (0, 8))	('contrast', 'MPA', (71, 79))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('T/N ratio', 'MPA', (50, 59))	('18F-FDG', 'Chemical', 'MESH:D019788', (107, 114))	('18F-FAMT PET', 'Var', (0, 12))	('gliomas', 'Disease', (87, 94))
178730	33936093	Immune infiltration analysis demonstrated that high SAMD9 expression resulted in an accumulation of macrophages by CIBERSORT and TIMER databases, especially positively related to macrophage total marker gene AIF1 and Macrophage M2 marker gene CD163.	('AIF1', 'Gene', '199', (208, 212))	('CD163', 'Gene', '9332', (243, 248))	('macrophages', 'CPA', (100, 111))	('high', 'Var', (47, 51))	('SAMD9', 'Gene', (52, 57))	('CD163', 'Gene', (243, 248))	('SAMD9', 'Gene', '54809', (52, 57))	('accumulation', 'PosReg', (84, 96))	('AIF1', 'Gene', (208, 212))
178733	33936093	Silencing of SAMD9 by shRNA in LN229 cells attenuated the infiltration abilities of M2 macrophage.	('SAMD9', 'Gene', (13, 18))	('LN229', 'CellLine', 'CVCL:0393', (31, 36))	('SAMD9', 'Gene', '54809', (13, 18))	('infiltration abilities of M2 macrophage', 'CPA', (58, 97))	('attenuated', 'NegReg', (43, 53))	('Silencing', 'Var', (0, 9))
178748	33936093	Deleterious mutations of SAMD9 are key enabling factors for some autoimmune diseases and cancers, as well as the pathogenesis of myelodysplastic syndromes (MDS), esophageal and lung tumorigenesis.	('autoimmune diseases', 'Disease', 'MESH:D001327', (65, 84))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('MDS', 'Disease', (156, 159))	('autoimmune diseases', 'Disease', (65, 84))	('cancers', 'Disease', (89, 96))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (65, 84))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('esophageal', 'Disease', (162, 172))	('Deleterious', 'Var', (0, 11))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (129, 154))	('myelodysplastic syndromes', 'Disease', (129, 154))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('SAMD9', 'Gene', (25, 30))	('SAMD9', 'Gene', '54809', (25, 30))	('tumor', 'Disease', (182, 187))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (129, 154))	('MDS', 'Disease', 'MESH:D009190', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
178749	33936093	Our previous studies have shown that knocking down SAMD9 in glioma cells decreases glioblastoma progression.	('glioma cells decreases glioblastoma', 'Disease', 'MESH:D005909', (60, 95))	('SAMD9', 'Gene', (51, 56))	('knocking down', 'Var', (37, 50))	('SAMD9', 'Gene', '54809', (51, 56))	('glioma cells decreases glioblastoma', 'Disease', (60, 95))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
178751	33936093	Furthermore, knockdown of SAMD9 attenuated the proliferation, migration and invasion of glioblastoma cells and reduced the activity of the PI3K/AKT signaling pathway.	('glioblastoma', 'Disease', (88, 100))	('SAMD9', 'Gene', '54809', (26, 31))	('AKT', 'Gene', (144, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('reduced', 'NegReg', (111, 118))	('attenuated', 'NegReg', (32, 42))	('proliferation', 'CPA', (47, 60))	('activity', 'MPA', (123, 131))	('knockdown', 'Var', (13, 22))	('SAMD9', 'Gene', (26, 31))	('AKT', 'Gene', '207', (144, 147))
178753	33936093	In this paper we show that SAMD9 was elevated in low grade gliomasand acted as an indicator of poor prognosis with malignancy characteristics, IDH wild type, MGMT unmethylation and 1p/19q non-codeletion.	('met', 'Gene', '79811', (165, 168))	('1p/19q', 'Var', (181, 187))	('met', 'Gene', (165, 168))	('IDH', 'Gene', '3417', (143, 146))	('elevated', 'PosReg', (37, 45))	('SAMD9', 'Gene', (27, 32))	('malignancy', 'Disease', 'MESH:D009369', (115, 125))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('SAMD9', 'Gene', '54809', (27, 32))	('malignancy', 'Disease', (115, 125))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('MGMT', 'Gene', '4255', (158, 162))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('MGMT', 'Gene', (158, 162))	('IDH', 'Gene', (143, 146))
178790	33936093	IDH mutation is a principal driver gene in low grade gliomas, with an incidence of more than 70%.	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('mutation', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
178798	33936093	Patients with high expressions of SAMD9 were more concentrated in the astrocytoma than oligodendrocyte type.	('SAMD9', 'Gene', (34, 39))	('astrocytoma', 'Disease', 'MESH:D001254', (70, 81))	('astrocytoma', 'Disease', (70, 81))	('SAMD9', 'Gene', '54809', (34, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('Patients', 'Species', '9606', (0, 8))	('high expressions', 'Var', (14, 30))
178803	33936093	Furthermore, MGMT promoter unmethylation and fewer ATRX mutations appeared frequently in SAMD9 high expressing patients.	('SAMD9', 'Gene', (89, 94))	('mutations', 'Var', (56, 65))	('SAMD9', 'Gene', '54809', (89, 94))	('fewer', 'NegReg', (45, 50))	('ATRX', 'Gene', (51, 55))	('met', 'Gene', '79811', (29, 32))	('ATRX', 'Gene', '546', (51, 55))	('MGMT', 'Gene', (13, 17))	('met', 'Gene', (29, 32))	('MGMT', 'Gene', '4255', (13, 17))	('patients', 'Species', '9606', (111, 119))
178814	33936093	In addition, univariate and multivariate Cox regression analyses showed SAMD9, together with classical malignancy features of glioma (gender, age, WHO grade, IDH status, 1p/19q status, MGMT promoter status, radiotherapy, and chemotherapy).	('MGMT', 'Gene', '4255', (185, 189))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('IDH', 'Gene', '3417', (158, 161))	('MGMT', 'Gene', (185, 189))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('malignancy', 'Disease', (103, 113))	('1p/19q status', 'Var', (170, 183))	('SAMD9', 'Gene', (72, 77))	('SAMD9', 'Gene', '54809', (72, 77))	('glioma', 'Disease', (126, 132))	('IDH', 'Gene', (158, 161))
178815	33936093	The univariate and multivariate Cox regression analysis in CGGA database1 LGG identified SAMD9 expression (univariate hazard ratio (HR): 3.17, p = 8.71E-12; multivariate HR: 1.58, p = 3.61E-02), WHO grade (univariate HR: 3.75, p = 1.82E-09; multivariate HR: 3.29, p = 1.82E-09), 1p/19q codeletion (univariate HR: 0.15, p = 7.82E-09; multivariate HR: 0.22, p = 5.50E-05), radiotherapy (univariate HR: 0.54, p = 3.99E-02; multivariate HR: 0.44, p = 1.40E-02) ( Figure 4A ).	('1p/19q codeletion', 'Var', (279, 296))	('SAMD9', 'Gene', (89, 94))	('SAMD9', 'Gene', '54809', (89, 94))
178818	33936093	SAMD9 expression (univariate HR: 2.16, p = 1.42E-09; multivariate HR: 1.64, p=2.59E-04), WHO Grade (univariate HR: 3.32, p = 2.86E-06; multivariate HR: 1.94, p = 1.53E-02) and age (univariate HR: 1.07, p = 1.39E-12; multivariate HR:1.06, p = 1.15E-08), IDH mutation (univariate HR: 0.16, p = 1.22E-14; multivariate HR:0.29, p = 5.87E-04) ( Figure 4C ).	('SAMD9', 'Gene', (0, 5))	('SAMD9', 'Gene', '54809', (0, 5))	('mutation', 'Var', (257, 265))	('IDH', 'Gene', (253, 256))	('IDH', 'Gene', '3417', (253, 256))
178821	33936093	These nomograms can easily be used by providers to estimate a patient's prognosis; the only clinical details a provider needs to use these nomograms effectively are grade, 1p/19q codeletion status, radiotherapy status and SAMD9 expression levels.	('1p/19q codeletion status', 'Var', (172, 196))	('SAMD9', 'Gene', (222, 227))	('patient', 'Species', '9606', (62, 69))	('SAMD9', 'Gene', '54809', (222, 227))
178843	33936093	Stable silencing of SAMD9 in LN229 cells reduced the infiltration of M2 macrophage (NC group & shSAMD9 1, p <0.01; NC group & shSAMD9 2, p <0.001) ( Figure 7H ).	('reduced', 'NegReg', (41, 48))	('infiltration of', 'CPA', (53, 68))	('SAMD9', 'Gene', (20, 25))	('SAMD9', 'Gene', '54809', (20, 25))	('SAMD9', 'Gene', (97, 102))	('LN229', 'CellLine', 'CVCL:0393', (29, 34))	('SAMD9', 'Gene', (128, 133))	('SAMD9', 'Gene', '54809', (97, 102))	('SAMD9', 'Gene', '54809', (128, 133))	('silencing', 'Var', (7, 16))
178848	33936093	SAMD9 expression levels maybe a robust index for the evaluation of the degree of the immune response, deleterious mutations of SAMD9 is the cause of some autoimmune diseases and cancers.	('autoimmune diseases', 'Disease', (154, 173))	('SAMD9', 'Gene', (0, 5))	('SAMD9', 'Gene', '54809', (0, 5))	('SAMD9', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (114, 123))	('cause', 'Reg', (140, 145))	('SAMD9', 'Gene', '54809', (127, 132))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (154, 173))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('autoimmune diseases', 'Disease', 'MESH:D001327', (154, 173))
178850	33936093	We have revealed that knocking down SAMD9 expression levels in glioma cells decreased the glioblastoma cell progression via the AKT/PI3K pathway, but the detailed mechanism of how SAMD9 affected the occurrence of gliomas and its impact on tumor immunity has not been reported in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('AKT', 'Gene', '207', (128, 131))	('SAMD9', 'Gene', (36, 41))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('SAMD9', 'Gene', '54809', (36, 41))	('tumor', 'Disease', (239, 244))	('gliomas', 'Disease', (279, 286))	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioma', 'Disease', (279, 285))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('gliomas', 'Disease', (213, 220))	('knocking down', 'Var', (22, 35))	('glioblastoma', 'Disease', (90, 102))	('glioma', 'Disease', (213, 219))	('gliomas', 'Disease', 'MESH:D005910', (279, 286))	('affected', 'Reg', (186, 194))	('glioma', 'Disease', (63, 69))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('SAMD9', 'Gene', (180, 185))	('AKT', 'Gene', (128, 131))	('decreased', 'NegReg', (76, 85))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('SAMD9', 'Gene', '54809', (180, 185))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))	('gliomas', 'Phenotype', 'HP:0009733', (279, 286))
178863	33567561	Thirty-five (69%) patients had IDH-mutated tumors, of which 17 were 1p/19q codeleted (i.e., oligodendroglioma) and 18 non-1p/19q codeleted (i.e., IDHmut astrocytoma).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('IDH', 'Gene', (31, 34))	('astrocytoma', 'Disease', 'MESH:D001254', (153, 164))	('IDH', 'Gene', '3417', (31, 34))	('IDH', 'Gene', (146, 149))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('astrocytoma', 'Disease', (153, 164))	('oligodendroglioma', 'Disease', (92, 109))	('IDH', 'Gene', '3417', (146, 149))	('astrocytoma', 'Phenotype', 'HP:0009592', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Disease', (43, 49))	('non-1p/19q codeleted', 'Var', (118, 138))	('1p/19q codeleted', 'Var', (68, 84))	('oligodendroglioma', 'Disease', 'MESH:D009837', (92, 109))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
178872	33567561	The latest WHO classification for dLGG has incorporated molecular markers based on genetic classification, such as isocitrate dehydrogenase (IDH1 or IDH2) mutation and codeletion of chromosome arms 1p and 19q, thereby addressing the previous limitations in the histological classification with problematic inter-rater variability and imperfect prediction of outcomes.	('IDH1', 'Gene', (141, 145))	('IDH2', 'Gene', (149, 153))	('arms 1p', 'Gene', '3075', (193, 200))	('IDH1', 'Gene', '3417', (141, 145))	('arms 1p', 'Gene', (193, 200))	('dLGG', 'Disease', (34, 38))	('IDH2', 'Gene', '3418', (149, 153))	('mutation', 'Var', (155, 163))
178891	33567561	To assess the presence of IDH mutations, immunohistochemistry staining for IDH1 R132H mutant protein was performed.	('R132H', 'Var', (80, 85))	('R132H', 'Mutation', 'rs121913500', (80, 85))	('IDH1', 'Gene', (75, 79))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('IDH1', 'Gene', '3417', (75, 79))	('IDH', 'Gene', '3417', (26, 29))
178892	33567561	If negative next generation sequencing (NGS) to detect other IDH1 mutations or IDH2 mutations were applied.	('mutations', 'Var', (66, 75))	('IDH2', 'Gene', '3418', (79, 83))	('mutations', 'Var', (84, 93))	('IDH1', 'Gene', (61, 65))	('IDH2', 'Gene', (79, 83))	('IDH1', 'Gene', '3417', (61, 65))
178906	33567561	For the measures of quality of life, QLQ-C30 and QLQ-BN20 were both converted to a continuous index from 0 to 100 according to the scoring manual.	('QLQ-C30', 'Var', (37, 44))	('QLQ-BN20', 'Var', (49, 57))	('QLQ-BN20', 'Chemical', '-', (49, 57))
178913	33567561	Patients with suspected dLGG were classified into three categories based on molecular subtypes: patients with IDH mutation and 1p/19q codeletion (i.e., oligodendroglioma), patients with IDH mutation and non-1p/19q codeletion (i.e., IDHmut astrocytoma), and patients with IDHwt (i.e., IDHwt astrocytoma).	('astrocytoma', 'Phenotype', 'HP:0009592', (290, 301))	('IDHwt astrocytoma', 'Disease', 'MESH:D001254', (284, 301))	('oligodendroglioma', 'Disease', 'MESH:D009837', (152, 169))	('IDH', 'Gene', '3417', (186, 189))	('IDH', 'Gene', '3417', (232, 235))	('IDH', 'Gene', '3417', (271, 274))	('IDH', 'Gene', (110, 113))	('oligodendroglioma', 'Disease', (152, 169))	('IDHwt astrocytoma', 'Disease', (284, 301))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('Patients', 'Species', '9606', (0, 8))	('astrocytoma', 'Disease', 'MESH:D001254', (290, 301))	('patients', 'Species', '9606', (257, 265))	('IDH', 'Gene', (284, 287))	('astrocytoma', 'Disease', (290, 301))	('patients', 'Species', '9606', (172, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (239, 250))	('IDH', 'Gene', '3417', (110, 113))	('non-1p/19q codeletion', 'Var', (203, 224))	('patients', 'Species', '9606', (96, 104))	('IDH', 'Gene', '3417', (284, 287))	('1p/19q codeletion', 'Var', (127, 144))	('IDH', 'Gene', (232, 235))	('IDH', 'Gene', (186, 189))	('astrocytoma', 'Disease', 'MESH:D001254', (239, 250))	('astrocytoma', 'Disease', (239, 250))	('IDH', 'Gene', (271, 274))
179009	31228076	For computing APT-w contrast, the present study used four types of normalizations: Type-1: APT-w contrast when normalized with :  where Msat(+3.5ppm) and Msat(-3.5ppm) are the signal intensities with downfield and upfield of water resonating frequency.	('APT-w', 'Chemical', '-', (14, 19))	('Msat(+3.5ppm', 'Var', (136, 148))	('Msat(-3.5ppm', 'Var', (154, 166))	('APT-w', 'Chemical', '-', (91, 96))	('water', 'Chemical', 'MESH:D014867', (225, 230))
179033	31228076	For all types of normalizations, APT-w contrast corresponding to ROI-1 and ROI-2 were significantly (p < 0.01) higher compared to cROI-1 and cROI-2 respectively.	('ROI-1', 'Var', (65, 70))	('ROI-2', 'Var', (75, 80))	('APT-w', 'MPA', (33, 38))	('APT-w', 'Chemical', '-', (33, 38))	('higher', 'PosReg', (111, 117))
179041	31228076	This showed that mean APT-w contrast is higher in Type-2 than Type-1 normalization.	('APT-w', 'Chemical', '-', (22, 27))	('APT-w contrast', 'CPA', (22, 36))	('Type-2', 'Var', (50, 56))	('higher', 'PosReg', (40, 46))
179066	31228076	Thus, mean APT-w contrast is always higher in Type-2 than Type-1 normalizations.	('Type-2', 'Var', (46, 52))	('APT-w', 'Chemical', '-', (11, 16))	('higher', 'PosReg', (36, 42))	('APT-w contrast', 'MPA', (11, 25))
179070	31228076	In the current study, APT-w contrast in NAWM were negative; therefore, Type-3 and Type-4 normalizations resulted in an increase in values compared to Type-1 and Type-2 normalizations.	('Type-3', 'Var', (71, 77))	('normalizations', 'Var', (89, 103))	('APT-w', 'Chemical', '-', (22, 27))	('increase', 'PosReg', (119, 127))	('Type-4 normalizations', 'Var', (82, 103))	('values', 'MPA', (131, 137))
179078	31228076	The APT-w contrast corresponding to the necrotic region for all types of normalizations was slightly lower than active tumor region.	('normalizations', 'Var', (73, 87))	('necrotic', 'Disease', 'MESH:D009336', (40, 48))	('tumor', 'Disease', (119, 124))	('lower', 'NegReg', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('necrotic', 'Disease', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('APT-w', 'Chemical', '-', (4, 9))
179102	30235224	Radiation was more common in treatment of elderly patients, 1p/19q co-deletion (37.3% versus 24.3%, p<0.01), and tumors with midline location.	('patients', 'Species', '9606', (50, 58))	('tumors', 'Disease', (113, 119))	('1p/19q co-deletion', 'Var', (60, 78))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('midline location', 'Disease', (125, 141))	('midline location', 'Disease', 'MESH:D009436', (125, 141))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
179112	30235224	Watchful waiting until progression may be an acceptable option in selected patients, however surgical resection often results in improved outcomes and symptom control, particularly tumor-related epilepsy, which is of especial interest due to the higher rate of seizures in isocitrate dehydrogenase (IDH) mutant tumors.	('tumors', 'Disease', (311, 317))	('epilepsy', 'Disease', 'MESH:D004827', (195, 203))	('mutant', 'Var', (304, 310))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('epilepsy', 'Phenotype', 'HP:0001250', (195, 203))	('epilepsy', 'Disease', (195, 203))	('seizures', 'Disease', (261, 269))	('tumor', 'Disease', (311, 316))	('IDH', 'Gene', (299, 302))	('seizures', 'Disease', 'MESH:D012640', (261, 269))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('seizures', 'Phenotype', 'HP:0001250', (261, 269))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Disease', (181, 186))	('IDH', 'Gene', '3417', (299, 302))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('improved', 'PosReg', (129, 137))
179113	30235224	This has translated into treatment decisions; presence of IDH mutation, 1p/19q co-deletion, ATRX expression, and TERT promoter mutation are used in diagnosis and provide prognosis estimates.	('ATRX', 'Gene', (92, 96))	('IDH', 'Gene', '3417', (58, 61))	('ATRX', 'Gene', '546', (92, 96))	('TERT', 'Gene', '7015', (113, 117))	('1p/19q co-deletion', 'Var', (72, 90))	('IDH', 'Gene', (58, 61))	('TERT', 'Gene', (113, 117))
179120	30235224	Cases of diffuse glioma were identified using the International Classification of Disease for Oncology (ICD-03) histology codes 9380-9382, 9400, 9401, 9410, 9411, 9420, 9421, 9424, 9425, 9431, 9450, 9451, 9460.	('9401', 'Var', (145, 149))	('Oncology', 'Phenotype', 'HP:0002664', (94, 102))	('9400', 'Var', (139, 143))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('9411', 'Var', (157, 161))	('9410', 'Var', (151, 155))	('9424', 'Var', (175, 179))	('9380-9382', 'Var', (128, 137))	('glioma', 'Disease', (17, 23))	('9421', 'Var', (169, 173))	('9425', 'Var', (181, 185))	('9420', 'Var', (163, 167))
179135	30235224	A higher frequency of patients with 1p/19q co-deletion had a midline primary site location compared to those with 1p/19q non-co-deleted (2.1% versus 0.3%, p<0.01).	('midline primary site location', 'CPA', (61, 90))	('midline', 'Chemical', '-', (61, 68))	('1p/19q co-deletion', 'Var', (36, 54))	('patients', 'Species', '9606', (22, 30))
179147	30235224	Radiation was more frequent in patients with 1p/19q co-deleted than in patients with non-co-deleted status (37.3% versus 24.3%, p<0.01) (Table 3, Fig 1).	('patients', 'Species', '9606', (71, 79))	('Radiation', 'Disease', (0, 9))	('patients', 'Species', '9606', (31, 39))	('1p/19q co-deleted', 'Var', (45, 62))
179148	30235224	Chemotherapy was more common in patients with 1p/19q non-co-deleted than in those with 1p/19q co-deleted (37.4% versus 28.1%, p<0.01).	('Chemotherapy', 'Disease', (0, 12))	('patients', 'Species', '9606', (32, 40))	('common', 'Reg', (22, 28))	('1p/19q non-co-deleted', 'Var', (46, 67))
179160	30235224	Survival varied by age, comorbidities, tumor location, histology group, and molecular predictors; younger age, fewer comorbidities, oligodendroglial histology, 1p/19q co-deletion, and cerebrum location had the best prognosis (Fig 2, Fig 3).	('1p/19q co-deletion', 'Var', (160, 178))	('oligodendroglial', 'Disease', (132, 148))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
179161	30235224	Median survival was greater in patients younger than 60 years of age (12.4 and 11.7 years for <40 and 41-60 years old), compared to 2.2 years in patients older than 60 years.	('patients', 'Species', '9606', (145, 153))	('<40', 'Var', (94, 97))	('greater', 'PosReg', (20, 27))	('Median survival', 'MPA', (0, 15))	('patients', 'Species', '9606', (31, 39))
179164	30235224	Medicaid and Medicare, and treatment in community facilities were associated with an increased risk of death as compared to not insured.	('death', 'Disease', (103, 108))	('death', 'Disease', 'MESH:D003643', (103, 108))	('Medicaid', 'Var', (0, 8))	('Medicare', 'Var', (13, 21))
179166	30235224	Risk assessment is based on three groups: IDH mutant tumors with 1p/19q co-deletion (predominantly oligodendroglial), IDH mutant without 1p/19q co-deletion (predominantly astrocytic), and IDH wild-type tumors.	('IDH', 'Gene', '3417', (188, 191))	('IDH', 'Gene', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('IDH', 'Gene', '3417', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('IDH', 'Gene', (118, 121))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IDH', 'Gene', '3417', (118, 121))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('IDH', 'Gene', (188, 191))	('1p/19q co-deletion', 'Var', (65, 83))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
179171	30235224	Age 60 years and younger, 1p19q co-deletion, and oligodendroglial tumors were factors associated with best survival in Kaplan-Meier analyses (Fig 2), and the results held in multivariate proportional hazards models (Fig 3).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('1p19q co-deletion', 'Var', (26, 43))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('best', 'PosReg', (102, 106))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (49, 72))	('oligodendroglial tumors', 'Disease', (49, 72))
179192	30235224	Radiation use was significantly higher in patients with 1p/19q co-deleted, older age, and astrocytic histology.	('higher', 'PosReg', (32, 38))	('1p/19q co-deleted', 'Var', (56, 73))	('Radiation use', 'MPA', (0, 13))	('patients', 'Species', '9606', (42, 50))	('astrocytic', 'Disease', (90, 100))
179194	30235224	As to why 1p/19q co-deletion are more associated with radiation, it is possibly due to late disease presentation, or being more aggressive on a treatment responsive cancer.	('radiation', 'Disease', (54, 63))	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('1p/19q co-deletion', 'Var', (10, 28))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
179239	27748708	In the occipital lobe, however, DLB patients showed significantly decreased NAA (p < 0.001), Cr (p < 0.01), Glu (p < 0.001), and Glx (p < 0.001) compared with healthy volunteers, whereas AD patients only showed decreases in Glu (p < 0.01) and Glx (p < 0.05).	('AD', 'Disease', 'MESH:D000544', (187, 189))	('AD', 'Disease', (187, 189))	('Glu', 'Chemical', 'MESH:D018698', (224, 227))	('DLB', 'Var', (32, 35))	('Glu', 'Chemical', 'MESH:D018698', (108, 111))	('patients', 'Species', '9606', (36, 44))	('decreased', 'NegReg', (66, 75))	('NAA', 'MPA', (76, 79))	('patients', 'Species', '9606', (190, 198))	('AD', 'Phenotype', 'HP:0002511', (187, 189))	('Glx', 'MPA', (129, 132))	('Glx', 'MPA', (243, 246))	('NAA', 'Chemical', 'MESH:C000179', (76, 79))	('Cr', 'Chemical', 'MESH:D003401', (93, 95))	('Glu', 'MPA', (224, 227))	('Glu', 'MPA', (108, 111))
179296	27748708	The methamphetamine dependent group also had decreased Cho metabolites in the right dorsolateral prefrontal cortex (p < 0.05) compared with healthy volunteers.	('Cho metabolites', 'MPA', (55, 70))	('methamphetamine', 'Chemical', 'MESH:D008694', (4, 19))	('decreased', 'NegReg', (45, 54))	('Cho', 'Chemical', 'MESH:D002794', (55, 58))	('methamphetamine dependent', 'Var', (4, 29))
179323	27748708	Statistical analysis with ANOVA (p < 0.05) revealed significant differences between groups for Cho/Cr in the head of the hippocampus, NAA/Cr in the head, body, and tail of the hippocampus, and NAA/Cho+Cr in the body and tail of the left and right hippocampus.	('Cr', 'Chemical', 'MESH:D003401', (99, 101))	('NAA', 'Chemical', 'MESH:C000179', (134, 137))	('Cho', 'Chemical', 'MESH:D002794', (197, 200))	('Cho', 'Chemical', 'MESH:D002794', (95, 98))	('differences', 'Reg', (64, 75))	('Cho/Cr', 'Gene', (95, 101))	('Cr', 'Chemical', 'MESH:D003401', (138, 140))	('Cr', 'Chemical', 'MESH:D003401', (201, 203))	('NAA', 'Chemical', 'MESH:C000179', (193, 196))	('NAA/Cr', 'Var', (134, 140))
179351	27748708	Since patients with IDH1 mutations, after correcting for the age factor, have a greater 5-year survival than those without the mutation, identifying patients with this mutation could help inform diagnosis and treatment in the clinic.	('IDH1', 'Gene', '3417', (20, 24))	('mutations', 'Var', (25, 34))	('5-year survival', 'CPA', (88, 103))	('patients', 'Species', '9606', (149, 157))	('greater', 'PosReg', (80, 87))	('patients', 'Species', '9606', (6, 14))	('IDH1', 'Gene', (20, 24))
179352	27748708	2HG can be measured with in vivo MRS. 3T MRS 2HG measurements for two glioma and four primary glioblastoma (IV) patients, all with known IDH1 mutations, and four healthy volunteers were shown in Figure 3.	('mutations', 'Var', (142, 151))	('glioma', 'Disease', (70, 76))	('MRS', 'Disease', 'MESH:D008556', (41, 44))	('MRS', 'Disease', 'MESH:D008556', (33, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('MRS', 'Disease', (33, 36))	('IDH1', 'Gene', (137, 141))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('patients', 'Species', '9606', (112, 120))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('primary', 'Disease', (86, 93))	('MRS', 'Disease', (41, 44))	('IDH1', 'Gene', '3417', (137, 141))	('glioblastoma', 'Disease', (94, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
179353	27748708	In patients with IDH1 mutations, the Halpha-Hbeta cross-peaks of 2HG were present at 4.02/1.91 ppm in a two-dimensional (2D) spectrum, providing clear evidence of elevated 2HG levels that, due to chemical shift overlap, is hard to identify within 1D spectra.	('elevated', 'PosReg', (163, 171))	('IDH1', 'Gene', (17, 21))	('2HG levels', 'MPA', (172, 182))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', '3417', (17, 21))
179354	27748708	As expected, 2HG cross-peaks do not appear in 2D spectra from tumor patients without IDH1 mutations and healthy volunteers.	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('patients', 'Species', '9606', (68, 76))	('IDH1', 'Gene', (85, 89))	('IDH1', 'Gene', '3417', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
179356	27748708	2HG levels can also been rapidly detected in tissue samples from surgically resected gliomas to immediately identify IDH1 mutations, using desorption electrospray ionization (DESI) MS.	('IDH1', 'Gene', '3417', (117, 121))	('gliomas', 'Disease', (85, 92))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('mutations', 'Var', (122, 131))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('IDH1', 'Gene', (117, 121))
179402	27748708	During hormone therapy, while there were no significant correlations between MRSI/DCEMR variations and patient age, pretreatment serum prostate specific antigen (PSA) levels, or Gleason score, there was a significant time-dependent loss of all prostate metabolites in both healthy and PCa tissue during hormone therapy (p < 0.01), resulting in complete metabolic atrophy after 24 weeks of hormone therapy for 30% of patients.	('metabolic atrophy', 'Disease', 'MESH:D001284', (353, 370))	('PCa', 'Phenotype', 'HP:0012125', (285, 288))	('MRSI', 'Disease', (77, 81))	('variations', 'Var', (88, 98))	('PC', 'Chemical', 'MESH:D010767', (285, 287))	('prostate specific antigen', 'Gene', (135, 160))	('MRSI', 'Disease', 'None', (77, 81))	('metabolic atrophy', 'Disease', (353, 370))	('PSA', 'Gene', '354', (162, 165))	('PSA', 'Gene', (162, 165))	('prostate specific antigen', 'Gene', '354', (135, 160))	('patient', 'Species', '9606', (416, 423))	('loss', 'NegReg', (232, 236))	('patient', 'Species', '9606', (103, 110))	('prostate metabolites', 'MPA', (244, 264))	('DCEMR', 'Chemical', '-', (82, 87))	('patients', 'Species', '9606', (416, 424))	('serum prostate specific antigen', 'Phenotype', 'HP:0025020', (129, 160))
179405	27748708	Patients with detectable Cit had significantly (p < 0.05) higher mean PSA levels (at 24 weeks, mean: 3.5 +- 0.5 ng/mL) than those without detectable Cit (at 24 weeks, mean: 0.85 +- 0.9 ng/mL).	('Cit', 'Var', (25, 28))	('Cit', 'Chemical', 'MESH:D019343', (149, 152))	('PSA', 'Gene', '354', (70, 73))	('PSA', 'Gene', (70, 73))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (58, 64))	('Cit', 'Chemical', 'MESH:D019343', (25, 28))
179406	27748708	With DCEMR, the parameters of onset-time of signal enhancement and time-to-peak significantly (p < 0.05) increased at 12 and 24 weeks.	('enhancement', 'PosReg', (51, 62))	('DCEMR', 'Var', (5, 10))	('time-to-peak', 'MPA', (67, 79))	('DCEMR', 'Chemical', '-', (5, 10))	('increased', 'PosReg', (105, 114))
179440	27748708	Modified point resolved spectroscopy pulse (PRESS) at 7T in vivo has also been optimized for detection of GABA, Glu, and Gln, which overlapped in short TE MRS and made precise quantifications of these metabolites difficult.	('Gln', 'Chemical', 'MESH:D005973', (121, 124))	('GABA', 'Chemical', 'MESH:D005680', (106, 110))	('GABA', 'Var', (106, 110))	('MRS', 'Disease', 'MESH:D008556', (155, 158))	('Glu', 'MPA', (112, 115))	('7T', 'Chemical', '-', (54, 56))	('Glu', 'Chemical', 'MESH:D018698', (112, 115))	('MRS', 'Disease', (155, 158))	('Gln', 'Var', (121, 124))
179467	25889239	Ktrans and Ve were correlated with glioma grade (P < 0.01), while ITSS was moderately correlated (P < 0.01).	('Ktrans', 'Chemical', '-', (0, 6))	('Ktrans', 'Var', (0, 6))	('correlated', 'Reg', (19, 29))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('ITSS', 'Chemical', '-', (66, 70))	('glioma', 'Disease', (35, 41))
179475	25889239	Ktrans is the volume transfer constant in unit time for the transfer of contrast medium from the vessel into the EES, which reflects the intratumoral microvascular permeability.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Ktrans', 'Var', (0, 6))	('Ktrans', 'Chemical', '-', (0, 6))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
179514	25889239	Ktrans values were also strongly correlated with Ve values (r = 0.823, P < 0.01) and moderately correlated with the degree of ITSS (r = 0.473, p < 0.01) (Table 4).	('Ve values', 'MPA', (49, 58))	('ITSS', 'Chemical', '-', (126, 130))	('Ktrans values', 'Var', (0, 13))	('Ktrans', 'Chemical', '-', (0, 6))
179555	25889239	The cut-off value of Ve (0.345) also provided the best combination of sensitivity (88.9%) and specificity (93.3%), which helped differentiate grade II from grade IV gliomas.	('IV gliomas', 'Disease', (162, 172))	('IV gliomas', 'Disease', 'MESH:D005910', (162, 172))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('Ve (0.345', 'Var', (21, 30))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
179569	25889239	The cut-off values of Ktrans = 0.045 min-1 and Ve = 0.296 were adopted for differentiation between grade II and grade III gliomas, and high sensitivity and specificity (greater than 85%) were achieved.	('III gliomas', 'Disease', 'MESH:D005910', (118, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('III gliomas', 'Disease', (118, 129))	('Ktrans', 'Var', (22, 28))	('min-1', 'Gene', (37, 42))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('Ktrans', 'Chemical', '-', (22, 28))	('min-1', 'Gene', '966', (37, 42))
179594	25889239	Ktrans and Ve values, and ITSS were capable of differentiating LGGs from HGGs as well as grade II from grade III or IV gliomas.	('HGGs', 'Disease', (73, 77))	('LGGs', 'Disease', (63, 67))	('Ktrans', 'Var', (0, 6))	('Ktrans', 'Chemical', '-', (0, 6))	('ITSS', 'Chemical', '-', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('differentiating', 'Reg', (47, 62))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('IV gliomas', 'Disease', (116, 126))	('IV gliomas', 'Disease', 'MESH:D005910', (116, 126))
179611	31861976	We used two cohorts with acute myeloid leukemia (AML), one exclusively with individuals over the age of 60 (GSE6891) (461 patients) with samples collected from both blood and bone marrow and the second (GSE15434) of exclusively normal karyotype (NK) AML (251 patients) with samples collected from mononuclear cells.	('AML', 'Disease', (49, 52))	('AML', 'Disease', 'MESH:D015470', (250, 253))	('patients', 'Species', '9606', (259, 267))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (25, 47))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (31, 47))	('AML', 'Disease', (250, 253))	('patients', 'Species', '9606', (122, 130))	('GSE15434', 'Var', (203, 211))	('acute myeloid leukemia', 'Disease', (25, 47))	('AML', 'Phenotype', 'HP:0004808', (250, 253))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('leukemia', 'Phenotype', 'HP:0001909', (39, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (25, 47))	('AML', 'Phenotype', 'HP:0004808', (49, 52))
179656	31861976	We hypothesize that deviations between the methylation of loci between patient sub-groups creates tail regions.	('methylation', 'Var', (43, 54))	('patient', 'Species', '9606', (71, 78))	('deviations', 'Var', (20, 30))
179721	31832216	Methods of performing IDH1 R132H immunohistochemistry and exon 4 DNA sequencing have been described previously.	('R132H', 'Var', (27, 32))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('R132H', 'Mutation', 'rs121913500', (27, 32))
179735	31832216	Because grade and IDH mutations interact too strongly, we did not analyze them together in the same model.	('IDH', 'Gene', '3417', (18, 21))	('mutations', 'Var', (22, 31))	('interact', 'Reg', (32, 40))	('IDH', 'Gene', (18, 21))
179751	31832216	Univariable logistic regression analysis showed that age, histology (glioblastoma), WHO grade (IV), presence of an IDH mutation, and preoperative T2/FLAIR volume correlated significantly with the risk of impairment in all 5 different domains (Supplementary Table 2).	('mutation', 'Var', (119, 127))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('presence', 'Var', (100, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
179752	31832216	In multivariable logistic regression, the presence of an IDH mutation negatively correlated with the risk of impairments (-2SD) in Memory, Psychomotor Speed, and Visuospatial Functioning, even when corrected for tumor volume (Table 4).	('IDH', 'Gene', '3417', (57, 60))	('Psychomotor Speed', 'Phenotype', 'HP:0025356', (139, 156))	('negatively', 'NegReg', (70, 80))	('mutation', 'Var', (61, 69))	('Visuospatial Functioning', 'CPA', (162, 186))	('impairments', 'MPA', (109, 120))	('Memory', 'CPA', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('Psychomotor Speed', 'CPA', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('IDH', 'Gene', (57, 60))	('presence', 'Var', (42, 50))	('tumor', 'Disease', (212, 217))
179766	31832216	In our series of patients, IDH mutations were correlated with relatively good performance in Memory, Psychomotor Speed, and Visuospatial Functioning, independent of tumor volume.	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (31, 40))	('IDH', 'Gene', '3417', (27, 30))	('Visuospatial Functioning', 'CPA', (124, 148))	('Psychomotor Speed', 'CPA', (101, 118))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('patients', 'Species', '9606', (17, 25))	('Psychomotor Speed', 'Phenotype', 'HP:0025356', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Memory', 'CPA', (93, 99))	('tumor', 'Disease', (165, 170))
179768	31832216	It is unlikely that the protective cognitive effect of IDH mutations is due to the gene's metabolic product.	('IDH', 'Gene', (55, 58))	('protective cognitive effect', 'CPA', (24, 51))	('mutations', 'Var', (59, 68))	('IDH', 'Gene', '3417', (55, 58))
179769	31832216	IDH1 mutations result in the production of 2-hydroxyglutarate, the accumulation of which can cause neurodegeneration and cognitive decline, as in D-2-hydroxyglutaric aciduria, a neurometabolic disease caused by germline IDH1 mutations.	('cognitive decline', 'Disease', 'MESH:D003072', (121, 138))	('aciduria', 'Disease', 'MESH:C537358', (166, 174))	('neurodegeneration', 'Phenotype', 'HP:0002180', (99, 116))	('aciduria', 'Phenotype', 'HP:0012072', (166, 174))	('caused', 'Reg', (201, 207))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (43, 61))	('IDH1', 'Gene', (0, 4))	('neurodegeneration', 'Disease', 'MESH:D019636', (99, 116))	('cause', 'Reg', (93, 98))	('neurometabolic disease', 'Disease', (178, 200))	('IDH1', 'Gene', (220, 224))	('D-2-hydroxyglutaric', 'Disease', (146, 165))	('IDH1', 'Gene', '3417', (0, 4))	('cognitive decline', 'Disease', (121, 138))	('mutations', 'Var', (5, 14))	('neurometabolic disease', 'Disease', 'MESH:D030342', (178, 200))	('neurodegeneration', 'Disease', (99, 116))	('IDH1', 'Gene', '3417', (220, 224))	('result in', 'Reg', (15, 24))	('mutations', 'Var', (225, 234))	('cognitive decline', 'Phenotype', 'HP:0001268', (121, 138))	('aciduria', 'Disease', (166, 174))	('D-2-hydroxyglutaric', 'Chemical', 'MESH:C019417', (146, 165))	('D-2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0012321', (146, 174))
179771	31832216	The latter explanation is supported by a recent study by Wefel et al, who found a complex interrelationship between patients' NCF, tumor growth velocity, and the presence or absence of an IDH mutation.	('IDH', 'Gene', '3417', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (116, 124))	('mutation', 'Var', (192, 200))	('tumor', 'Disease', (131, 136))	('IDH', 'Gene', (188, 191))
179775	31832216	Because we established IDH mutation in most cases by immunohistochemistry, it is possible that we missed a small proportion of IDH mutations, as immunohistochemistry determines only the presence of an IDH1 R132H mutation.	('IDH', 'Gene', (127, 130))	('R132H', 'Var', (206, 211))	('IDH', 'Gene', '3417', (127, 130))	('R132H', 'Mutation', 'rs121913500', (206, 211))	('IDH', 'Gene', (201, 204))	('IDH1', 'Gene', '3417', (201, 205))	('IDH', 'Gene', '3417', (201, 204))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (23, 26))	('IDH1', 'Gene', (201, 205))
179776	31832216	Based on the literature, patients with other IDH1/2 mutations represent less than 10% of patients with an IDH mutation, so less than 5.5% of our sample wherein an IDH mutation was found in approximately 50% of patients.	('mutations', 'Var', (52, 61))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', '3417', (106, 109))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('IDH', 'Gene', '3417', (45, 48))	('IDH', 'Gene', (163, 166))	('patients', 'Species', '9606', (89, 97))	('IDH1/2', 'Gene', (45, 51))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (210, 218))	('IDH', 'Gene', '3417', (163, 166))	('IDH', 'Gene', (106, 109))
179834	31104065	Hypomethylation leading to CNTFRalpha upregulation has been proposed to be involved in glioma growth regulation.	('involved', 'Reg', (75, 83))	('CNTFRalpha', 'Gene', (27, 37))	('Hypomethylation', 'Var', (0, 15))	('glioma growth', 'Disease', 'MESH:D005910', (87, 100))	('glioma growth', 'Disease', (87, 100))	('CNTFRalpha', 'Gene', '1271', (27, 37))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('upregulation', 'PosReg', (38, 50))
179853	31104065	The effect of mesenchymal-associated genes on cell invasion and gliomasphere initiation were identified in vitro, by silencing of COL1A1, in which the gene has the potential for stratifying patients with glioma into subgroups for diagnosis of recurrence risk, as well as prognostic and therapeutic evolution.	('gliomasphere initiation', 'Disease', (64, 87))	('gliomasphere initiation', 'Disease', 'MESH:D007319', (64, 87))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('silencing', 'Var', (117, 126))	('patients', 'Species', '9606', (190, 198))	('glioma', 'Disease', (204, 210))	('COL1A1', 'Gene', (130, 136))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('COL1A1', 'Gene', '1277', (130, 136))	('glioma', 'Disease', (64, 70))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
179867	31104065	Abnormal gene expression of NTS/NTSR1 results in the proliferation of glioblastoma cells.	('NTS', 'Gene', '4922', (32, 35))	('NTSR1', 'Gene', (32, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('NTS', 'Gene', '4922', (28, 31))	('Abnormal gene expression', 'Var', (0, 24))	('results in', 'Reg', (38, 48))	('NTS', 'Gene', (28, 31))	('proliferation', 'CPA', (53, 66))	('glioblastoma', 'Disease', (70, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('NTS', 'Gene', (32, 35))	('NTSR1', 'Gene', '4923', (32, 37))
179963	28217379	Many recent studies have shown that methylation profiling of solid tumors has revealed biologic subtypes that often carry clinical implications.	('solid tumors', 'Disease', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('solid tumors', 'Disease', 'MESH:D009369', (61, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('methylation', 'Var', (36, 47))
179973	28217379	In addition, recent studies have revealed that these lesions are characterized by mutations in IDH, TP53, and ATRX.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('ATRX', 'Gene', (110, 114))	('mutations', 'Var', (82, 91))	('ATRX', 'Gene', '546', (110, 114))	('IDH', 'Gene', (95, 98))
179975	28217379	These tumors are characterized by 1p/19q codeletion, as well as mutations of IDH, CIC, FUBP1, and the TERT promoter.	('FUBP1', 'Gene', '8880', (87, 92))	('TERT', 'Gene', (102, 106))	('TERT', 'Gene', '7015', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CIC', 'Gene', '23152', (82, 85))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('IDH', 'Gene', (77, 80))	('mutations', 'Var', (64, 73))	('FUBP1', 'Gene', (87, 92))	('CIC', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
179979	28217379	These classes were distinguished first by IDH mutation, and the IDH mutant tumors further by 1p/19q codeletion status.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mutation', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))
179984	28217379	When all 558 tumors were examined by Cox multivariate analysis, IDH status (mutant vs wildtype), 1p/19q status (codeleted vs non-codeleted), mitotic index (low vs high) and patient age at diagnosis were all significant predictors of overall survival.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('Cox', 'Gene', '1351', (37, 40))	('overall survival', 'MPA', (233, 249))	('1p/19q status', 'Var', (97, 110))	('patient', 'Species', '9606', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mitotic', 'MPA', (141, 148))	('IDH', 'Gene', (64, 67))	('Cox', 'Gene', (37, 40))
179994	28217379	Several years ago, mutations in IDH were found in a subset of glioblastoma, particularly tumors that had progressed from lower-grade lesions.	('found', 'Reg', (41, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('mutations', 'Var', (19, 28))	('glioblastoma', 'Disease', (62, 74))	('IDH', 'Gene', (32, 35))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
179995	28217379	Immunohistochemical detection of mutant IDH1 protein is now used as a specific marker of tumor cells.	('IDH1', 'Gene', (40, 44))	('protein', 'Protein', (45, 52))	('IDH1', 'Gene', '3417', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutant', 'Var', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
179996	28217379	The presence of IDH mutation is also associated with improved survival in glioblastoma and anaplastic astrocytoma, and in fact has greater prognostic significance than grade.	('glioblastoma', 'Disease', (74, 86))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (91, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('mutation', 'Var', (20, 28))	('anaplastic astrocytoma', 'Disease', (91, 113))	('IDH', 'Gene', (16, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('survival', 'CPA', (62, 70))	('presence', 'Var', (4, 12))	('improved', 'PosReg', (53, 61))
179997	28217379	Furthermore, mutant IDH1 has demonstrated potential as an immunological target, with a vaccine targeting the neoantigen protein inducing CD4+ T-cells.	('mutant', 'Var', (13, 19))	('IDH1', 'Gene', '3417', (20, 24))	('CD4', 'Gene', (137, 140))	('CD4', 'Gene', '920', (137, 140))	('IDH1', 'Gene', (20, 24))
179999	28217379	While biomarker detection currently relies on physical sampling of tumor or blood, the effects of the neomorphic enzyme on cellular redox state and epigenetic modification may in future be exploited to identify IDH mutations in a noninvasive manner.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('IDH', 'Gene', (211, 214))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (215, 224))	('tumor', 'Disease', (67, 72))	('man', 'Species', '9606', (242, 245))
180000	28217379	For instance, magnetic resonance spectroscopy (MRS) can be used to detect 2-hydroxyglutarate in tumors in vivo, the presence of which is correlated with mutation in IDH.	('IDH', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('2-hydroxyglutarate', 'MPA', (74, 92))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (74, 92))	('correlated', 'Reg', (137, 147))	('mutation', 'Var', (153, 161))
180001	28217379	In addition, MRS imaging of hyperpolarized [13C]alpha-ketoglutarate can provide highly sensitive noninvasive, real-time in vivo monitoring of mutant IDH1 activity.	('hyperpolarized [13C]alpha-ketoglutarate', 'MPA', (28, 67))	('IDH1', 'Gene', (149, 153))	('IDH1', 'Gene', '3417', (149, 153))	('mutant', 'Var', (142, 148))	('13C]alpha-ketoglutarate', 'Chemical', '-', (44, 67))	('activity', 'MPA', (154, 162))
180013	28217379	Other significant factors were NER crossing midline, as well as Karnofsky performance status and age - but not contrast enhancement.	('man', 'Species', '9606', (80, 83))	('NER', 'Var', (31, 34))	('Karnofsky', 'Disease', (64, 73))	('men', 'Species', '9606', (127, 130))
180016	28217379	For instance, the tumor volume identified by 18F-FET PET is larger than the enhancing region on T1+gadolinium sequences, but is itself smaller than the volume marked by T2 change.	('gadolinium', 'Chemical', 'MESH:D005682', (99, 109))	('tumor', 'Disease', (18, 23))	('larger', 'PosReg', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('smaller', 'NegReg', (135, 142))	('18F-FET PET', 'Var', (45, 56))
180107	28217379	Delta-24-RGD is a tumor selective, replication-competent, oncolytic adenovirus with enhanced infectivity, developed by Juan Fueyo, MD (Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center).	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('men', 'Species', '9606', (141, 144))	('tumor', 'Disease', (18, 23))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (179, 203))	('Texas MD Anderson Cancer', 'Disease', (179, 203))	('Delta-24-RGD', 'Var', (0, 12))	('Oncology', 'Phenotype', 'HP:0002664', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('Delta-24', 'Chemical', '-', (0, 8))
180109	28217379	Delta-24-RGD is also tumor selective.	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('Delta-24-RGD', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Delta-24', 'Chemical', '-', (0, 8))
180110	28217379	The basis of Delta-24-RGD's tumor selectivity is a 24-base pair deletion in the E1a gene, which renders the viral E1a protein incapable of inactivating the cellular Retinoblastoma (Rb) protein, which guards the cell cycle by holding cells in G0 and sequestering cellular E2F.	('tumor', 'Disease', (28, 33))	('E1a', 'Gene', (80, 83))	('sequestering', 'NegReg', (249, 261))	('deletion', 'Var', (64, 72))	('Retinoblastoma', 'Gene', '5925', (165, 179))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (165, 179))	('inactivating', 'MPA', (139, 151))	('Rb', 'Phenotype', 'HP:0009919', (181, 183))	('Rb', 'Gene', '5925', (181, 183))	('Retinoblastoma', 'Gene', (165, 179))	('Delta-24', 'Chemical', '-', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
180112	28217379	However, Delta-24-RGD replicates freely in tumor cells because Rb is inactivated in most tumors, either due to mutation of the Rb gene or through loss of the upstream regulator p16.	('loss', 'NegReg', (146, 150))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('inactivated', 'NegReg', (69, 80))	('Delta-24', 'Chemical', '-', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Rb', 'Phenotype', 'HP:0009919', (127, 129))	('Rb', 'Gene', '5925', (127, 129))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Rb', 'Phenotype', 'HP:0009919', (63, 65))	('mutation', 'Var', (111, 119))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('Rb', 'Gene', '5925', (63, 65))
180113	28217379	Finally, Delta-24-RGD has enhanced infectivity.	('enhanced', 'PosReg', (26, 34))	('Delta-24', 'Chemical', '-', (9, 17))	('infectivity', 'MPA', (35, 46))	('Delta-24-RGD', 'Var', (9, 21))
180115	28217379	Preclinical in vitro and in vivo studies proved that Delta-24-RGD was capable of curing animals harboring "professional" glioma tumors, such as U87 and D54, and that it was also effective against patient derived cancer stem cells, also known as Glioma Stem Cells, which drive glioma formation.	('Glioma', 'Phenotype', 'HP:0009733', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('glioma', 'Disease', (121, 127))	('Glioma', 'Disease', (245, 251))	('glioma tumors', 'Disease', (121, 134))	('U87', 'CellLine', 'CVCL:0022', (144, 147))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma tumors', 'Disease', 'MESH:D005910', (121, 134))	('patient', 'Species', '9606', (196, 203))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('Delta-24', 'Chemical', '-', (53, 61))	('cancer', 'Disease', (212, 218))	('Glioma', 'Disease', 'MESH:D005910', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('Delta-24-RGD', 'Var', (53, 65))	('glioma', 'Disease', (276, 282))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (276, 282))
180117	28217379	Based on these preclinical results Delta-24-RGD was evaluated in a recently completed Phase I clinical trial, which showed that direct intratumoral injection of Delta-24-RGD was safe in patients.	('Delta-24', 'Chemical', '-', (35, 43))	('Delta-24', 'Chemical', '-', (161, 169))	('Delta-24-RGD', 'Var', (161, 173))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (186, 194))	('tumor', 'Disease', (140, 145))
180118	28217379	Analyses of post-treatment specimens taken 14 days after intratumoral injection proved that Delta-24-RGD could replicate in and kill human glioma cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('kill', 'CPA', (128, 132))	('glioma', 'Disease', (139, 145))	('Delta-24', 'Chemical', '-', (92, 100))	('replicate', 'CPA', (111, 120))	('Delta-24-RGD', 'Var', (92, 104))	('tumor', 'Disease', (62, 67))	('men', 'Species', '9606', (32, 35))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('men', 'Species', '9606', (22, 25))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('human', 'Species', '9606', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
180120	28217379	First, in all complete responders, 1-4 months after injection of Delta-24-RGD, the contrast enhancement on MRI worsened before it resolved, a pattern consistent with an inflammatory reaction; and second, analyses of tumors surgically resected from several patients during this period of increased enhancement revealed almost no tumor cells, but large numbers of macrophages and CD8 cytotoxic T cells, consistent with a TH1 immune response.	('Delta-24', 'Chemical', '-', (65, 73))	('tumors', 'Disease', (216, 222))	('Delta-24-RGD', 'Var', (65, 77))	('men', 'Species', '9606', (304, 307))	('tumor', 'Disease', (328, 333))	('contrast enhancement', 'MPA', (83, 103))	('tumor', 'Disease', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('TH1', 'Gene', (419, 422))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CD8 cytotoxic T cells', 'CPA', (378, 399))	('TH1', 'Gene', '51497', (419, 422))	('patients', 'Species', '9606', (256, 264))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('men', 'Species', '9606', (99, 102))	('worsened', 'NegReg', (111, 119))
180123	28217379	In recently published reports, we have shown that Delta-24-RGD increases inflammatory cell infiltration that is tumor specific and that Delta-24-RGD promotes increase in presentation of tumor-associated antigens, activating CD8 cells.	('inflammatory cell infiltration', 'CPA', (73, 103))	('increases', 'PosReg', (63, 72))	('Delta-24-RGD', 'Var', (50, 62))	('increase', 'PosReg', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (186, 191))	('Delta-24-RGD', 'Var', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Delta-24', 'Chemical', '-', (50, 58))	('RGD increases', 'Phenotype', 'HP:0410246', (59, 72))	('tumor', 'Disease', (112, 117))	('CD8 cells', 'CPA', (224, 233))	('presentation', 'MPA', (170, 182))	('Delta-24', 'Chemical', '-', (136, 144))
180124	28217379	In conclusion, Delta-24-RGD is a novel biological agent whose intrinsic properties have been exploited to provide hard-to-replicate solutions to many of the problems of cancer therapy.	('cancer', 'Disease', (169, 175))	('Delta-24-RGD', 'Var', (15, 27))	('Delta-24', 'Chemical', '-', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('man', 'Species', '9606', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
180129	28217379	The general approach to a new glioma diagnosis is to first determine whether an IDH1/2 mutation is present.	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('glioma', 'Disease', (30, 36))	('mutation', 'Var', (87, 95))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('IDH1/2', 'Gene', (80, 86))
180130	28217379	Tumors containing mutant IDH (mIDH), are then stratified by 1p/19q codeletion status.	('IDH', 'Gene', (25, 28))	('mutant', 'Var', (18, 24))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
180136	28217379	The NOA-16 trial is the first-in-man trial of the IDH1 peptide vaccine targeting the IDHR132H mutation.	('man', 'Species', '9606', (33, 36))	('IDH1', 'Gene', '3417', (50, 54))	('IDH1', 'Gene', (50, 54))	('IDHR132H', 'Var', (85, 93))
180141	28217379	The frequent occurrence of EGFR amplification as well as deletion resulting in expression of the EGFRvIII mutant in glioblastoma makes it an appealing target for therapy.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('mutant', 'Var', (106, 112))	('expression', 'MPA', (79, 89))	('glioblastoma', 'Disease', (116, 128))	('deletion', 'Var', (57, 65))	('EGFR', 'Gene', '1956', (97, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('amplification', 'Var', (32, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('EGFR', 'Gene', (97, 101))
180142	28217379	A number of strategies have been developed, including tyrosine kinase inhibitors, monoclonal antibodies, toxin conjugates, anti-EGFR vaccines, and chimeric antigen receptor T-cell, and investigations continue in hopes that one of these may prove effective.	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('tyrosine', 'Var', (54, 62))
180163	28217379	Cognitive deterioration was significantly greater at 3 months in the SRS + WBRT group, involving immediate recall, delayed recall and verbal fluency, whereas intracranial disease control was better in this group at 6 and 12 months.	('Cognitive deterioration', 'Disease', 'MESH:D003072', (0, 23))	('immediate recall', 'CPA', (97, 113))	('delayed recall', 'MPA', (115, 129))	('Cognitive deterioration', 'Phenotype', 'HP:0001268', (0, 23))	('intracranial disease', 'Disease', (158, 178))	('verbal fluency', 'MPA', (134, 148))	('Cognitive deterioration', 'Disease', (0, 23))	('intracranial disease', 'Disease', 'MESH:D020765', (158, 178))	('SRS + WBRT', 'Var', (69, 79))
180164	28217379	These studies support the existing body of evidence indicating that WBRT causes worse cognitive decline than SRS alone in patients with brain metastases.	('cognitive decline', 'Disease', (86, 103))	('worse cognitive decline', 'Phenotype', 'HP:0001268', (80, 103))	('cognitive decline', 'Disease', 'MESH:D003072', (86, 103))	('cognitive decline', 'Phenotype', 'HP:0001268', (86, 103))	('WBRT', 'Var', (68, 72))	('patients', 'Species', '9606', (122, 130))	('brain metastases', 'Disease', 'MESH:D009362', (136, 152))	('brain metastases', 'Disease', (136, 152))
180170	26618723	In two independent datasets, copy number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR=0.15, 95% CI: 0.08-0.29).	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('copy number alterations', 'Var', (29, 52))	('reduced', 'NegReg', (113, 120))	('tumor', 'Disease', (88, 93))
180202	26618723	A gene was included as significantly associated with a given cancer type based on: i) prior experimental evidence; ii) frequency of gene-mutations in our sample cohort and iii) mutation deleteriousness (Online Methods).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('associated', 'Reg', (37, 47))	('gene-mutations', 'Var', (132, 146))
180207	26618723	Citing an example, TP53 SNVs were found in larger clones (EXPANDS: 0.811; PyClone: 0.746 average cancer-cell fraction) in all nine cancers significantly associated with TP53 genetic aberrations.	('cancer', 'Disease', (131, 137))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancer', 'Disease', (97, 103))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('associated', 'Reg', (153, 163))	('TP53', 'Gene', (169, 173))	('genetic aberrations', 'Var', (174, 193))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
180210	26618723	For example, clones with ERBB3 mutations were larger in bladder cancer than they were in any other cancer type, while clones with PTEN mutations grew particularly large in Glioblastoma (Fig.	('mutations', 'Var', (31, 40))	('Glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('Glioblastoma', 'Disease', (172, 184))	('cancer', 'Disease', (99, 105))	('ERBB3', 'Gene', (25, 30))	('Glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('PTEN', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
180212	26618723	Next, we used the size-rankings of clones with CAN-gene mutations to compare cancer types (Fig.	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (77, 83))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
180213	26618723	For CAN-genes that are critical among different tumor types, we measured whether clones containing mutations in these genes are of similar size, regardless of tumor type.	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
180216	26618723	Per cancer type, silent SNVs in non-CAN-genes accounted for an average of 25% of the variability in the number of clones.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('non-CAN-genes', 'Gene', (32, 45))	('silent SNVs', 'Var', (17, 28))	('cancer', 'Disease', (4, 10))
180236	26618723	CNVs affecting either a very low or a very high fraction of the tumor-metagenome, was predictive of improved survival (Log-rank test: P=5E-6; HR=0.15; Fig.	('tumor', 'Disease', (64, 69))	('improved', 'PosReg', (100, 108))	('metagenome', 'Species', '256318', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CNVs', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('survival', 'CPA', (109, 117))
180241	26618723	Of the 12 tumor types, Glioblastoma was the only cancer for which >75% CNV abundance was associated with the worst prognosis (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('tumor', 'Disease', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('>75%', 'Var', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Glioblastoma', 'Disease', (23, 35))	('Glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('cancer', 'Disease', (49, 55))
180246	26618723	Across cancers, both, genomic instability and genetic ITH remained significantly associated to survival in the multivariate setting (Table 1).	('survival', 'Disease', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('genomic instability', 'Var', (22, 41))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('genetic ITH', 'Var', (46, 57))	('associated', 'Reg', (81, 91))
180257	26618723	Our results show that mutations in particular driver genes are associated with clones of a characteristic size, often independent of tumor type.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('associated', 'Reg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('clones', 'Disease', (79, 85))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', (133, 138))
180259	26618723	The significant association between high clone number and poor survival detected in the combined analysis of low-grade glioma and glioblastoma may be interesting in the context of the highly variable clinical behavior of low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glioblastoma', 'Disease', (130, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('gliomas', 'Disease', (231, 238))	('glioma', 'Disease', (231, 237))	('gliomas', 'Disease', 'MESH:D005910', (231, 238))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('glioma', 'Disease', (119, 125))	('high clone number', 'Var', (36, 53))	('glioma', 'Disease', 'MESH:D005910', (231, 237))
180268	26618723	Previously, low ITH has been found to predict favorable prognosis in Barrett's esophagus, head and neck cancer, as well as leukemia.	('leukemia', 'Disease', (123, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('low', 'Var', (12, 15))	('ITH', 'MPA', (16, 19))	('leukemia', 'Disease', 'MESH:D007938', (123, 131))	('head and neck cancer', 'Phenotype', 'HP:0012288', (90, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('head and neck cancer', 'Disease', 'MESH:D006258', (90, 110))	("Barrett's esophagus", 'Disease', (69, 88))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (69, 88))
180309	25683986	Age (p=0.012), KPS (p=0.041), and GTR (p=0.002) were associated with significant improvements in median overall survival for grade-4 malignant glioma.	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('improvements', 'PosReg', (81, 93))	('malignant glioma', 'Disease', (133, 149))	('malignant glioma', 'Disease', 'MESH:D005910', (133, 149))	('KPS', 'Var', (15, 18))	('GTR', 'Var', (34, 37))	('overall survival', 'MPA', (104, 120))
180354	25683986	Additionally, we were also able to achieve a relatively high rate (92.9%) of GTR in non-enhancing glioma, such that the method appears to be a valid option to increase the accuracy of conventional neuro-navigation.	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('GTR', 'Var', (77, 80))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Disease', (98, 104))
180435	20529377	Markers for mitotic dysregulation, such as supernumerary centrosomes and altered expression of centrosome-related mRNA and proteins were more frequently detected in higher grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('altered', 'Reg', (73, 80))	('detected', 'Reg', (153, 161))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('gliomas', 'Disease', (178, 185))	('centrosome-related', 'Protein', (95, 113))	('supernumerary', 'Var', (43, 56))	('expression', 'MPA', (81, 91))
180442	20529377	If mitosis becomes dysregulated in a cell often due to centrosome abnormalities, aneuploidy may result, which may contribute to cellular transformation.	('cellular transformation', 'CPA', (128, 151))	('aneuploidy', 'Disease', 'MESH:D000782', (81, 91))	('due to', 'Reg', (48, 54))	('aneuploidy', 'Disease', (81, 91))	('mitosis', 'Disease', (3, 10))	('result', 'Reg', (96, 102))	('centrosome abnormalities', 'Var', (55, 79))	('mitosis', 'Disease', 'None', (3, 10))	('contribute', 'Reg', (114, 124))
180504	20529377	Supernumerary centrosomes and abnormal nuclei were detected in GBM8401 cells and in high- but not low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('detected', 'Reg', (51, 59))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('Supernumerary centrosomes', 'CPA', (0, 25))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('GBM8401', 'Var', (63, 70))
180508	20529377	Over 100 years ago, researchers proposed the idea that supernumerary centrosomes could lead to abnormal chromosome segregation and cancer.	('cancer', 'Disease', (131, 137))	('supernumerary centrosomes', 'Var', (55, 80))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (95, 114))	('abnormal chromosome segregation', 'Phenotype', 'HP:0002916', (95, 126))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('abnormal chromosome segregation', 'CPA', (95, 126))	('lead to', 'Reg', (87, 94))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
180512	20529377	Each glioma may have acquired different types of genetic (or epigenetic) changes that were all related to the same selective pressure to alter mitotic regulation.	('glioma', 'Disease', (5, 11))	('epigenetic', 'Var', (61, 71))	('mitotic regulation', 'MPA', (143, 161))	('glioma', 'Disease', 'MESH:D005910', (5, 11))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))
180520	20529377	An Aurora A gene mutation is characterized by a centrosome separation defect.	('mutation', 'Var', (17, 25))	('Aurora A', 'Gene', '6790', (3, 11))	('Aurora A', 'Gene', (3, 11))
180521	20529377	In addition, mutations in the Increase for Ploidy 1(Ipl1) gene in Saccharomyces cerevisiae, that is closely homologous to Aurora A, resulted in chromosome segregation defects.	('Aurora A', 'Gene', '6790', (122, 130))	('Saccharomyces cerevisiae', 'Species', '4932', (66, 90))	('Aurora A', 'Gene', (122, 130))	('chromosome segregation defects', 'CPA', (144, 174))	('mutations', 'Var', (13, 22))	('resulted in', 'Reg', (132, 143))	('Ipl1', 'Gene', (52, 56))
180524	20529377	Although the effects of Aurora A overexpression and gene mutation have been well-characterized in many cancers, its influence on cancer progression and therefore grade are not as clear.	('overexpression', 'PosReg', (33, 47))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Aurora A', 'Gene', '6790', (24, 32))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Aurora A', 'Gene', (24, 32))	('gene mutation', 'Var', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancers', 'Disease', (103, 110))
180532	20529377	CHFR: checkpoint with forkhead and ring finger domails; Plk: Polo-like kinases; NIMA: Nek kinases; ATCC: American Type Culture Collection; Ipl1: Increase for Ploidy 1 The authors declare that they have no competing interests.	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('Plk', 'Gene', (56, 59))	('Plk', 'Gene', '5347', (56, 59))	('Ploidy', 'Var', (158, 164))
180541	18781179	In these tumours, SEMA3B, SEMA3G and NRP2 expressions were related to prolonged survival.	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('tumours', 'Disease', (9, 16))	('SEMA3G', 'Gene', '56920', (26, 32))	('prolonged survival', 'CPA', (70, 88))	('SEMA3B', 'Var', (18, 24))	('SEMA3G', 'Gene', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('NRP2', 'Gene', (37, 41))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))	('related', 'Reg', (59, 66))
180645	18781179	Direct functional evidence for a function of semaphorins and their receptors in epilepsy is supported by Sema3F knockout mice (Sahay et al, 2005) and some NRP2 mutant mice (Giger et al, 2000; Chen et al, 2000) that are more prone to seizures.	('epilepsy', 'Disease', (80, 88))	('prone', 'Reg', (224, 229))	('seizures', 'Disease', 'MESH:D012640', (233, 241))	('epilepsy', 'Disease', 'MESH:D004827', (80, 88))	('NRP2', 'Gene', (155, 159))	('seizures', 'Phenotype', 'HP:0001250', (233, 241))	('mutant', 'Var', (160, 166))	('mice', 'Species', '10090', (121, 125))	('epilepsy', 'Phenotype', 'HP:0001250', (80, 88))	('seizures', 'Disease', (233, 241))	('mice', 'Species', '10090', (167, 171))
180669	18781179	However, the very recent data by Rolny et al (2008) suggest a reconsideration of this semaphorin as a multifaceted regulator of cancer progression: SEMA3B inhibited tumour growth in mice but simultaneously and unexpectedly triggered metastasis by activating the signalling kinase p38.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumour growth', 'Disease', (165, 178))	('triggered', 'Reg', (223, 232))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('activating', 'PosReg', (247, 257))	('tumour growth', 'Disease', 'MESH:D006130', (165, 178))	('mice', 'Species', '10090', (182, 186))	('p38', 'Gene', (280, 283))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('p38', 'Gene', '26416', (280, 283))	('inhibited', 'NegReg', (155, 164))	('SEMA3B', 'Var', (148, 154))	('metastasis', 'CPA', (233, 243))	('cancer', 'Disease', (128, 134))
180677	18781179	NRP1 was also significantly correlated with poor prognosis in non-small-cell lung carcinomas (Kawakami et al, 2002), and blocking VEGF and NRP1 significantly increased survival (Pan et al, 2007).	('lung carcinomas', 'Disease', 'MESH:D008175', (77, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('NRP1', 'Gene', '8829', (0, 4))	('survival', 'MPA', (168, 176))	('NRP1', 'Gene', (0, 4))	('blocking', 'Var', (121, 129))	('NRP1', 'Gene', (139, 143))	('lung carcinomas', 'Disease', (77, 92))	('VEGF', 'Protein', (130, 134))	('NRP1', 'Gene', '8829', (139, 143))	('increased', 'PosReg', (158, 167))
180688	31391125	TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG.	('HGG', 'Disease', (73, 76))	('BRAFV600E-mutated', 'Var', (55, 72))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('BRAFV600E', 'Mutation', 'rs113488022', (92, 101))
180690	31391125	Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells.	('TERT', 'Gene', (39, 43))	('attenuated', 'NegReg', (28, 38))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('TERT', 'Gene', (59, 63))	('TERT', 'Gene', '7015', (39, 43))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('TERT', 'Gene', '7015', (59, 63))	('double-mutant', 'Var', (97, 110))	('TERT', 'Gene', (125, 129))	('TERT', 'Gene', '7015', (125, 129))	('BRAFV600E', 'Mutation', 'rs113488022', (161, 170))
180692	31391125	Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279.	('ETS', 'Chemical', '-', (81, 84))	('ETS1', 'Gene', '2113', (81, 85))	('ETS1', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('ETS', 'Chemical', '-', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('double-mutant', 'Var', (108, 121))	('tumor', 'Disease', (122, 127))
180693	31391125	In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization.	('support', 'PosReg', (103, 110))	('immortalization', 'CPA', (141, 156))	('BRAFV600E', 'Var', (49, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TERT', 'Gene', (63, 67))	('TERT', 'Gene', '7015', (63, 67))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
180701	31391125	In the pediatric patient population, more than half of LGG are characterized by genetic alterations of the BRAF gene resulting in increased cellular proliferation due to hyperactivation of downstream signaling.	('BRAF', 'Gene', (107, 111))	('genetic alterations', 'Var', (80, 99))	('LGG', 'Disease', (55, 58))	('downstream signaling', 'MPA', (189, 209))	('patient', 'Species', '9606', (17, 24))	('hyperactivation', 'PosReg', (170, 185))	('cellular proliferation', 'CPA', (140, 162))	('increased', 'PosReg', (130, 139))	('BRAF', 'Gene', '673', (107, 111))
180702	31391125	Moreover, the missense mutation BRAFV600E is present in a considerable amount of LGG namely pleomorphic xanthoastrocyma (PXA) and ganglioglioma (GG), but also other subtypes of astrocytoma.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('ganglioglioma', 'Disease', (130, 143))	('PXA', 'Chemical', '-', (121, 124))	('ganglioglioma', 'Disease', 'MESH:D018303', (130, 143))	('pleomorphic xanthoastrocyma', 'Disease', (92, 119))	('astrocytoma', 'Disease', 'MESH:D001254', (177, 188))	('BRAFV600E', 'Var', (32, 41))	('astrocytoma', 'Disease', (177, 188))	('BRAFV600E', 'Mutation', 'rs113488022', (32, 41))	('astrocytoma', 'Phenotype', 'HP:0009592', (177, 188))	('pleomorphic xanthoastrocyma', 'Disease', 'MESH:D008228', (92, 119))
180703	31391125	With respect to HGG, BRAFV600E has been described in anaplastic PXA or anaplastic GG, as well as pediatric (6-12%) and adult (7.7%) glioblastoma (GBM), often accompanied by an epithelioid phenotype.	('BRAFV600E', 'Var', (21, 30))	('BRAFV600E', 'Mutation', 'rs113488022', (21, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('described', 'Reg', (40, 49))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))	('glioblastoma', 'Disease', (132, 144))	('PXA', 'Chemical', '-', (64, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('anaplastic PXA', 'Disease', (53, 67))
180705	31391125	To date, only concomitant deletion of the CDKN2A locus has been described to synergistically promote glioma development and to define inferior outcome in BRAFV600E-positive glioma.	('glioma', 'Disease', (173, 179))	('glioma', 'Disease', (101, 107))	('BRAFV600E-positive', 'Var', (154, 172))	('deletion', 'Var', (26, 34))	('CDKN2A', 'Gene', (42, 48))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('CDKN2A', 'Gene', '1029', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('promote', 'PosReg', (93, 100))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
180706	31391125	Small-molecule inhibitors of BRAF and its downstream-target MEK have already been approved for other BRAF-driven cancer types, such as melanoma and have been shown to effectively inhibit glioma growth both in preclinical models and small patient cohorts.	('glioma', 'Disease', (187, 193))	('cancer', 'Disease', (113, 119))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('patient', 'Species', '9606', (238, 245))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('inhibitors', 'Var', (15, 25))	('MEK', 'Gene', '5609', (60, 63))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('clinical', 'Species', '191496', (212, 220))	('BRAF', 'Gene', '673', (101, 105))	('MEK', 'Gene', (60, 63))	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('inhibit', 'NegReg', (179, 186))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))
180707	31391125	Consequently, phase I/II trials with BRAF- or MEK-inhibitors either as single agent (NCT01677741, NCT01748149, NCT03363217, NCT01089101, NCT02285439, NCT03213691) or in combination (NCT02684058, NCT03340506, NCT02034110) have already been initiated.	('NCT03340506', 'Var', (195, 206))	('BRAF', 'Gene', '673', (37, 41))	('NCT01748149', 'Var', (98, 109))	('NCT02684058', 'Var', (182, 193))	('NCT01089101', 'Var', (124, 135))	('BRAF', 'Gene', (37, 41))	('NCT03363217', 'Var', (111, 122))	('MEK', 'Gene', (46, 49))	('NCT01677741', 'Var', (85, 96))	('MEK', 'Gene', '5609', (46, 49))
180711	31391125	Specific mutations within the TERT promoter, C250T (-146C > T), C228T (-124C > T) and A161C (-57A > C), have been identified to play an important role in telomerase re-activation in multiple tumor types including HGG.	('-57A > C', 'Mutation', 'rs878855297', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('TERT', 'Gene', (30, 34))	('TERT', 'Gene', '7015', (30, 34))	('C250T', 'Mutation', 'c.250C>T', (45, 50))	('A161C', 'Mutation', 'c.161A>C', (86, 91))	('HGG', 'Disease', (213, 216))	('tumor', 'Disease', (191, 196))	('A161C (-57A > C', 'Var', (86, 101))	('telomerase', 'Enzyme', (154, 164))	('-146C > T', 'Mutation', 'c.-146C>T', (52, 61))	('C228T', 'Mutation', 'rs763756456', (64, 69))	('-124C > T', 'Mutation', 'rs1242535815', (71, 80))	('C250T (-146C > T', 'Var', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('C228T (-124C > T', 'Var', (64, 80))
180712	31391125	C228T represents the most frequent of either mutation in both LGG as well as HGG.	('HGG', 'Disease', (77, 80))	('frequent', 'Reg', (26, 34))	('C228T', 'Mutation', 'rs763756456', (0, 5))	('C228T', 'Var', (0, 5))	('LGG', 'Disease', (62, 65))
180713	31391125	Functionally, all three non-coding mutations open new binding-sites for e-twenty-six (ETS/TCF) family transcription factors involved in TERT promoter hyperactivation.	('TERT', 'Gene', (136, 140))	('binding-sites', 'Interaction', (54, 67))	('TCF', 'Gene', (90, 93))	('TERT', 'Gene', '7015', (136, 140))	('TCF', 'Gene', '3172', (90, 93))	('ETS', 'Chemical', '-', (86, 89))	('mutations', 'Var', (35, 44))
180716	31391125	Interestingly, re-expression of TERT has been shown to promote escape from OIS in BRAF-mutant cancer cells.	('TERT', 'Gene', '7015', (32, 36))	('re-expression', 'Var', (15, 28))	('BRAF', 'Gene', '673', (82, 86))	('escape from', 'CPA', (63, 74))	('BRAF', 'Gene', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('promote', 'PosReg', (55, 62))	('cancer', 'Disease', (94, 100))	('TERT', 'Gene', (32, 36))
180718	31391125	In brain tumors, cases with concurrent mutations of BRAF and the TERT promoter have been identified and appear to be associated with an aggressive tumor biology.	('aggressive tumor', 'Disease', 'MESH:D001523', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('associated', 'Reg', (117, 127))	('aggressive tumor', 'Disease', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('TERT', 'Gene', (65, 69))	('TERT', 'Gene', '7015', (65, 69))	('BRAF', 'Gene', '673', (52, 56))	('brain tumors', 'Disease', 'MESH:D001932', (3, 15))	('brain tumors', 'Phenotype', 'HP:0030692', (3, 15))	('brain tumors', 'Disease', (3, 15))	('BRAF', 'Gene', (52, 56))
180719	31391125	Hence, in this study we sought to elucidate the role of concomitant BRAFV600E and TERT promoter mutations in the malignant phenotype of glioma, to dissect the involvement of different ETS-factors and investigate potential therapeutic implications.	('ETS', 'Chemical', '-', (184, 187))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('TERT', 'Gene', (82, 86))	('BRAFV600E', 'Gene', (68, 77))	('TERT', 'Gene', '7015', (82, 86))	('glioma', 'Disease', (136, 142))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('mutations', 'Var', (96, 105))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
180723	31391125	All primary glioma cell lines originating from the Department of Neurosurgery, Neuromed Campus, Kepler University Hospital, Linz (BTL53, BTL1333, BTL1304, BTL2231, BTL2176) and from the Medical University of Vienna (VBT4, VBT92, VBT125, VBT150, VBT172) were cultured in RPMI-1640 medium (Sigma-Aldrich, Missouri, USA) supplemented with 10% fetal calf serum (FCS, Gibco, Thermo Fisher Scientific, MA, USA).	('calf', 'Species', '9913', (346, 350))	('glioma', 'Disease', (12, 18))	('RPMI-1640 medium', 'Chemical', '-', (270, 286))	('BTL2231', 'Var', (155, 162))	('BTL1304', 'Var', (146, 153))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
180725	31391125	DNA of tumor tissues and cell cultures was extracted and characterized for the respective BRAFV600E and TERT promoter mutation status by direct sequencing as previously published.	('tumor', 'Disease', (7, 12))	('BRAFV600E', 'Var', (90, 99))	('BRAFV600E', 'Mutation', 'rs113488022', (90, 99))	('TERT', 'Gene', (104, 108))	('TERT', 'Gene', '7015', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
180727	31391125	Copy number variants of the CDNK2A and TERT locus were confirmed using array comparative genome hybridization data either derived from COSMIC database (NMC-G1, DBTRG-05MG, AM38) or analyzed in house as previously published (BTL1333, BTL53, BTL2176, VBT92, VBT125).	('TERT', 'Gene', (39, 43))	('TERT', 'Gene', '7015', (39, 43))	('CDNK2A', 'Gene', (28, 34))	('variants', 'Var', (12, 20))	('DBTRG', 'Chemical', '-', (160, 165))
180728	31391125	The p53-pathway was evaluated through expression analysis of total p53 and the downstream target p21 by Western blot as well as sequencing data from COSMIC database (NMC-G1, DBTRG-05MG, AM38) or established by Ion Torrent sequencing (BTL53, BTL1333, BTL2176, BTL2231, VBT92, VBT125, BTL1304).	('p53', 'Gene', '7157', (4, 7))	('DBTRG', 'Chemical', '-', (174, 179))	('p21', 'Gene', '1026', (97, 100))	('p53', 'Gene', (67, 70))	('BTL53', 'Var', (234, 239))	('p53', 'Gene', '7157', (67, 70))	('p21', 'Gene', (97, 100))	('BTL2176', 'Var', (250, 257))	('p53', 'Gene', (4, 7))	('BTL2231', 'Var', (259, 266))
180729	31391125	The Ion Torrent PGM System, the "Ion AmpliSeq Cancer Hotspot Panel v2 with 207 Amplicons" library and "Ion Torrent Suite Software (Version 5.10.1)" software were used to sequence tumor hotspot mutations.	('Cancer', 'Disease', (46, 52))	('Cancer', 'Disease', 'MESH:D009369', (46, 52))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', (179, 184))
180731	31391125	RNA sequencing data derived from the cancer genome atlas (TCGA) from GBM (n = 166), skin cutaneous melanoma (n = 469) and bladder urothelial carcinoma (n = 408) were stratified according to their BRAF mutation status.	('bladder urothelial carcinoma', 'Disease', (122, 150))	('skin cutaneous melanoma', 'Disease', (84, 107))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cancer genome atlas', 'Disease', 'MESH:D009369', (37, 56))	('cancer genome atlas', 'Disease', (37, 56))	('BRAF', 'Gene', '673', (196, 200))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('BRAF', 'Gene', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('mutation', 'Var', (201, 209))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 107))
180751	31391125	DNA was isolated by phenol-chloroform (Sigma Aldrich) purification and genomic fragments were quantified with qRT-PCR as described above using primers adjacent to the prominent TERT promoter mutations C228T and C250T.	('TERT', 'Gene', (177, 181))	('C250T', 'Mutation', 'c.250C>T', (211, 216))	('TERT', 'Gene', '7015', (177, 181))	('C228T', 'Mutation', 'rs763756456', (201, 206))	('C228T', 'Var', (201, 206))	('phenol', 'Chemical', 'MESH:D019800', (20, 26))	('chloroform', 'Chemical', 'MESH:D002725', (27, 37))	('C250T', 'Var', (211, 216))
180758	31391125	We analyzed the TERT promoter mutation status in a small cohort of pediatric cases with BRAFV600E-mutated glioma (n = 8, Additional file 1: Table S3) treated at the General Hospital of Vienna.	('TERT', 'Gene', (16, 20))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('TERT', 'Gene', '7015', (16, 20))	('glioma', 'Disease', (106, 112))	('BRAFV600E-mutated', 'Var', (88, 105))	('BRAFV600E', 'Mutation', 'rs113488022', (88, 97))
180762	31391125	Corroboratively, double-mutant tumors were significantly enriched (Fisher's exact test, p = 0.003) in HGG (WHO grade III/IV; 19/69, 28%) as compared to LGG (WHO grade I/II, 1/34, 3%).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('double-mutant', 'Var', (17, 30))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('HGG', 'Disease', (102, 105))
180763	31391125	To investigate the underlying oncogenic mechanisms of concomitant TERT promoter and BRAFV600E mutations in glioma, we analyzed the expression of different ETS-factors (ETS1, GABPA, GABPB-1S, GABPB-1 L, GABPB-2) and their downstream targets cyclin D1 and TERT in tissues of BRAFV600E-positive glioma (n = 8) (Additional file 3: Figure S1).	('BRAFV600E-positive', 'Var', (273, 291))	('GABPB', 'Gene', '2553', (202, 207))	('GABPA', 'Gene', (174, 179))	('glioma', 'Phenotype', 'HP:0009733', (292, 298))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('cyclin D1', 'Gene', '595', (240, 249))	('ETS', 'Chemical', '-', (155, 158))	('GABPB', 'Gene', (191, 196))	('GABPB-1S', 'Gene', '2553', (181, 189))	('GABPB', 'Gene', (181, 186))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('GABPB-2', 'Gene', '126626', (202, 209))	('GABPB', 'Gene', '2553', (191, 196))	('BRAFV600E', 'Mutation', 'rs113488022', (84, 93))	('GABPB-2', 'Gene', (202, 209))	('GABPB', 'Gene', '2553', (181, 186))	('ETS1', 'Gene', '2113', (168, 172))	('ETS', 'Chemical', '-', (168, 171))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('BRAFV600E', 'Mutation', 'rs113488022', (273, 282))	('glioma', 'Disease', (292, 298))	('GABPA', 'Gene', '2551', (174, 179))	('BRAFV600E', 'Gene', (84, 93))	('glioma', 'Disease', 'MESH:D005910', (292, 298))	('ETS1', 'Gene', (168, 172))	('GABPB', 'Gene', (202, 207))	('GABPB-1S', 'Gene', (181, 189))	('TERT', 'Gene', (254, 258))	('TERT', 'Gene', '7015', (254, 258))	('cyclin D1', 'Gene', (240, 249))	('glioma', 'Disease', (107, 113))
180764	31391125	Strikingly, TERT mRNA was only expressed in the tumor with concomitant TERT promoter and BRAFV600E mutations, whereas neither differences in expression of ETS-factors nor the downstream target cyclin D1 were observed (Additional file 3: Figure S1).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('BRAFV600E', 'Gene', (89, 98))	('TERT', 'Gene', (71, 75))	('tumor', 'Disease', (48, 53))	('TERT', 'Gene', '7015', (12, 16))	('cyclin D1', 'Gene', '595', (193, 202))	('TERT', 'Gene', '7015', (71, 75))	('cyclin D1', 'Gene', (193, 202))	('mutations', 'Var', (99, 108))	('ETS', 'Chemical', '-', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TERT', 'Gene', (12, 16))	('BRAFV600E', 'Mutation', 'rs113488022', (89, 98))
180767	31391125	Based on these data, we sought to elucidate the interplay of BRAFV600E signaling and downstream effects on the TERT promoter in more detail.	('BRAFV600E', 'Mutation', 'rs113488022', (61, 70))	('TERT', 'Gene', (111, 115))	('TERT', 'Gene', '7015', (111, 115))	('BRAFV600E', 'Var', (61, 70))
180769	31391125	The latter were considered as references to dissect the effect of oncogenic BRAF activation in the background of both a mutated (BTL2176) and a wild-type (BTL1333, BTL53) TERT promoter.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('TERT', 'Gene', (171, 175))	('TERT', 'Gene', '7015', (171, 175))	('BTL2176', 'Gene', (129, 136))	('mutated', 'Var', (120, 127))
180776	31391125	All analyzed BRAFV600E cell models lacked TP53 mutations and, in contrast to BRAF wild-type cells, homogenously expressed the p53 downstream target p21 (Additional file 3: Figure S3).	('p53', 'Gene', '7157', (126, 129))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('TP53', 'Gene', '7157', (42, 46))	('p21', 'Gene', '1026', (148, 151))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', '673', (13, 17))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (77, 81))	('BRAF', 'Gene', (13, 17))	('p21', 'Gene', (148, 151))	('lacked', 'NegReg', (35, 41))	('p53', 'Gene', (126, 129))
180777	31391125	Notably, only tumor cell explants with a BRAFV600E-mutated background harboring loss of CDKN2A expression in combination with TERT promoter mutation developed into stable, immortalized cell lines (Table 1, Additional file 3: Figure S3).	('CDKN2A', 'Gene', (88, 94))	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('tumor', 'Disease', (14, 19))	('CDKN2A', 'Gene', '1029', (88, 94))	('loss', 'NegReg', (80, 84))	('TERT', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('TERT', 'Gene', '7015', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BRAFV600E-mutated', 'Var', (41, 58))	('expression', 'MPA', (95, 105))
180778	31391125	In line with CDKN2A loss-of-function and consecutive activation of the cyclin D1/cyclin dependent kinase (CDK) 4/6 complex, Rb was hyperphosphorylated in the majority of double-mutant glioma cells, indicating functional inhibition (Additional file 3: Figure S3).	('glioma', 'Disease', (184, 190))	('cyclin D1', 'Gene', '595', (71, 80))	('loss-of-function', 'NegReg', (20, 36))	('cyclin D1', 'Gene', (71, 80))	('CDKN2A', 'Gene', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('double-mutant', 'Var', (170, 183))	('CDKN2A', 'Gene', '1029', (13, 19))
180779	31391125	Based on the well-described activation of ETS-factors via MAPK-signaling and having confirmed ETS-factor expression in the respective tumor tissues, we hypothesized that BRAFV600E mutant glioma cells were characterized by hyperactivated ETS-signaling.	('BRAFV600E mutant', 'Var', (170, 186))	('glioma', 'Disease', (187, 193))	('BRAFV600E', 'Mutation', 'rs113488022', (170, 179))	('ETS', 'Chemical', '-', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ETS', 'Chemical', '-', (42, 45))	('hyperactivated', 'PosReg', (222, 236))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('ETS-signaling', 'MPA', (237, 250))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ETS', 'Chemical', '-', (94, 97))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('tumor', 'Disease', (134, 139))
180782	31391125	In contrast, cyclin D1 displayed significantly higher expression in BRAFV600E positive cell models as compared to wild-type cells.	('expression', 'MPA', (54, 64))	('higher', 'PosReg', (47, 53))	('cyclin D1', 'Gene', '595', (13, 22))	('BRAFV600E positive', 'Var', (68, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('cyclin D1', 'Gene', (13, 22))
180788	31391125	In line with our qRT-PCR results, cyclin D1 was predominantly detectable in cell models harboring BRAF alterations (Fig.	('detectable', 'Reg', (62, 72))	('alterations', 'Var', (103, 114))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', (98, 102))	('cyclin D1', 'Gene', '595', (34, 43))	('cyclin D1', 'Gene', (34, 43))
180792	31391125	In contrast, cell proliferation of cell models lacking BRAFV600E mutation was not inhibited but rather increased (Fig.	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('BRAFV600E', 'Var', (55, 64))	('cell proliferation', 'CPA', (13, 31))	('increased', 'PosReg', (103, 112))
180798	31391125	Moreover, dabrafenib treatment resulted in downregulation of cyclin D1 in double-mutant cell models (Fig.	('dabrafenib', 'Chemical', 'MESH:C561627', (10, 20))	('downregulation', 'NegReg', (43, 57))	('cyclin D1', 'Gene', '595', (61, 70))	('cyclin D1', 'Gene', (61, 70))	('double-mutant', 'Var', (74, 87))
180802	31391125	3a) or vemurafenib (Additional file 3: Figure S6) in double-mutant glioma models only.	('double-mutant', 'Var', (53, 66))	('glioma', 'Disease', (67, 73))	('vemurafenib', 'Chemical', 'MESH:D000077484', (7, 18))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('vemurafenib', 'Gene', (7, 18))
180804	31391125	In order to clarify the role of TERT promoter mutation in telomerase re-activation in the respective genotypes, we analyzed activation of the wild-type and mutant promoter sequences in each genotype via luciferase reporter assays.	('TERT', 'Gene', '7015', (32, 36))	('mutation', 'Var', (46, 54))	('mutant', 'Var', (156, 162))	('TERT', 'Gene', (32, 36))
180805	31391125	As expected, the C228T-mutated TERT promoter construct was significantly more active as compared to the wild-type promoter in most of the cell models.	('C228T', 'Mutation', 'rs763756456', (17, 22))	('more', 'PosReg', (73, 77))	('TERT', 'Gene', (31, 35))	('active', 'MPA', (78, 84))	('C228T-mutated', 'Var', (17, 30))	('TERT', 'Gene', '7015', (31, 35))
180807	31391125	In contrast, BRAF-inhibition increased the activity of the mutated TERT promoter in a double wild-type background (Fig.	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (29, 38))	('activity', 'MPA', (43, 51))	('mutated', 'Var', (59, 66))
180815	31391125	With respect to other ETS-factors, only GABPB-1S expression was also predominately inhibited by dabrafenib in a BRAFV600E-mutated background whereas GABPA, GABPB-1 L and GABPB-2 showed variable response patterns (Fig.	('GABPB-2', 'Gene', '126626', (170, 177))	('GABPB', 'Gene', (156, 161))	('GABPB', 'Gene', (40, 45))	('GABPA', 'Gene', '2551', (149, 154))	('expression', 'MPA', (49, 59))	('inhibited', 'NegReg', (83, 92))	('GABPB', 'Gene', '2553', (170, 175))	('GABPB-1S', 'Gene', '2553', (40, 48))	('GABPB-2', 'Gene', (170, 177))	('GABPA', 'Gene', (149, 154))	('dabrafenib', 'Chemical', 'MESH:C561627', (96, 106))	('GABPB', 'Gene', '2553', (156, 161))	('GABPB', 'Gene', (170, 175))	('BRAFV600E-mutated', 'Var', (112, 129))	('BRAFV600E', 'Mutation', 'rs113488022', (112, 121))	('GABPB-1S', 'Gene', (40, 48))	('GABPB', 'Gene', '2553', (40, 45))	('ETS', 'Chemical', '-', (22, 25))
180817	31391125	To more specifically dissect the link between MAPK-signaling and telomerase re-activation, we applied siRNA mediated knock-down of ETS1.	('ETS1', 'Gene', (131, 135))	('knock-down', 'Var', (117, 127))	('ETS1', 'Gene', '2113', (131, 135))
180819	31391125	Moreover, by ChIP-qRT-PCR we confirmed strong binding of ETS1 and GABPA selectively to the mutant TERT promoter locus, paralleled by activating H3K27-acetylation.	('ETS1', 'Gene', '2113', (57, 61))	('ETS1', 'Gene', (57, 61))	('activating', 'PosReg', (133, 143))	('TERT', 'Gene', (98, 102))	('GABPA', 'Gene', '2551', (66, 71))	('TERT', 'Gene', '7015', (98, 102))	('GABPA', 'Gene', (66, 71))	('binding', 'Interaction', (46, 53))	('mutant', 'Var', (91, 97))	('H3K27-acetylation', 'Protein', (144, 161))
180820	31391125	In one double mutant cell model ETS1 even was the dominant of the investigated ETS-factors bound to the mutant promoter site (Fig.	('mutant', 'Var', (104, 110))	('ETS', 'Chemical', '-', (79, 82))	('ETS1', 'Gene', '2113', (32, 36))	('ETS1', 'Gene', (32, 36))	('ETS', 'Chemical', '-', (32, 35))
180824	31391125	Moreover, TERT re-expression partly rescued double-mutant glioma cells from the YK-4-279-induced growth inhibitory effect (Additional file 3: Figure S9).	('double-mutant', 'Var', (44, 57))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('growth inhibitory effect', 'MPA', (97, 121))	('TERT', 'Gene', (10, 14))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('TERT', 'Gene', '7015', (10, 14))	('glioma', 'Disease', (58, 64))
180825	31391125	Combination of the BRAF inhibitor dabrafenib and the ETS-factor inhibitor YK-4-279 revealed additive to rather antagonistic effects, especially in the double-mutant glioma cell models (Additional file 3: Figure S10).	('BRAF', 'Gene', '673', (19, 23))	('ETS', 'Chemical', '-', (53, 56))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('BRAF', 'Gene', (19, 23))	('double-mutant', 'Var', (151, 164))	('dabrafenib', 'Chemical', 'MESH:C561627', (34, 44))	('glioma', 'Disease', (165, 171))
180826	31391125	The discovery of genomic aberrations in BRAF as drivers of certain glioma subtypes has resulted in a magnificent extension of the therapeutic repertoire for these patients.	('BRAF', 'Gene', '673', (40, 44))	('patients', 'Species', '9606', (163, 171))	('BRAF', 'Gene', (40, 44))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('genomic aberrations', 'Var', (17, 36))
180827	31391125	Recent studies, however, indicate that additional factors such as loss of CDKN2A or telomerase re-activation may significantly influence the clinical outcome of glioma patients with oncogenic BRAF, suggesting a biological heterogeneity within this subgroup.	('loss', 'Var', (66, 70))	('clinical', 'Species', '191496', (141, 149))	('telomerase', 'CPA', (84, 94))	('BRAF', 'Gene', '673', (192, 196))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('re-activation', 'PosReg', (95, 108))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('BRAF', 'Gene', (192, 196))	('influence', 'Reg', (127, 136))	('patients', 'Species', '9606', (168, 176))	('glioma', 'Disease', (161, 167))
180831	31391125	Consequently, we systematically investigated the cellular factors contributing to the interplay of BRAFV600E and TERT promoter mutations in glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('TERT', 'Gene', '7015', (113, 117))	('glioma', 'Disease', (140, 146))	('BRAFV600E', 'Var', (99, 108))	('BRAFV600E', 'Mutation', 'rs113488022', (99, 108))	('TERT', 'Gene', (113, 117))
180832	31391125	To begin with, we analyzed the clinical impact of telomerase re-activation in a small cohort of BRAFV600E-mutated glioma.	('BRAFV600E-mutated', 'Var', (96, 113))	('glioma', 'Disease', (114, 120))	('BRAFV600E', 'Mutation', 'rs113488022', (96, 105))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('clinical', 'Species', '191496', (31, 39))
180834	31391125	Moreover, only this double-mutant tumor expressed detectable levels of TERT mRNA.	('tumor', 'Disease', (34, 39))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (71, 75))	('double-mutant', 'Var', (20, 33))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
180835	31391125	Consistent with this observation, an in silico analysis of 103 BRAFV600E-mutated glioma showed that TERT promoter mutations are significantly enriched in WHO grade III/IV tumors.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('BRAFV600E-mutated', 'Var', (63, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (63, 72))	('TERT', 'Gene', (100, 104))	('glioma', 'Disease', (81, 87))	('IV tumors', 'Disease', 'MESH:D009369', (168, 177))	('TERT', 'Gene', '7015', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('IV tumors', 'Disease', (168, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
180836	31391125	Within this dataset, 28% of BRAFV600E-mutated HGG harbored additional TERT promoter mutations, which is consistent with earlier reports of secondary HGG and anaplastic PXA.	('BRAFV600E', 'Mutation', 'rs113488022', (28, 37))	('BRAFV600E-mutated', 'Var', (28, 45))	('HGG', 'Disease', (46, 49))	('secondary HGG', 'Disease', (139, 152))	('TERT', 'Gene', (70, 74))	('PXA', 'Chemical', '-', (168, 171))	('harbored', 'Reg', (50, 58))	('TERT', 'Gene', '7015', (70, 74))
180838	31391125	In order to elucidate the potential role of TERT promoter mutations in the malignant phenotype of certain BRAFV600E-mutated glioma, we curated a unique set of cell models containing nine BRAFV600E-mutant gliomas, the largest panel reported to date.	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('glioma', 'Disease', (124, 130))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('glioma', 'Disease', (204, 210))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('BRAFV600E-mutant', 'Var', (187, 203))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('BRAFV600E', 'Mutation', 'rs113488022', (187, 196))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('BRAFV600E', 'Mutation', 'rs113488022', (106, 115))
180839	31391125	Notably, all stable BRAFV600E-positive cell lines harbored TERT promoter mutations corroborating the aggressive biology of double-mutant tumors.	('BRAFV600E', 'Mutation', 'rs113488022', (20, 29))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('TERT', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('TERT', 'Gene', '7015', (59, 63))	('mutations', 'Var', (73, 82))
180845	31391125	The pathogenic mechanism of TERT promoter mutations is widely mediated by transcriptional activation which involves the binding of ETS-factors.	('ETS', 'Chemical', '-', (131, 134))	('binding', 'Interaction', (120, 127))	('TERT', 'Gene', (28, 32))	('transcriptional', 'MPA', (74, 89))	('TERT', 'Gene', '7015', (28, 32))	('mutations', 'Var', (42, 51))
180849	31391125	Accordingly, with respect to BRAFV600E-mutated melanoma, both phosphorylation of ETS1 and upregulation of GABPB via Fos have been shown to link oncogenic BRAF signaling to activation of the mutant TERT promoter.	('upregulation', 'PosReg', (90, 102))	('TERT', 'Gene', (197, 201))	('Fos', 'Gene', '2353', (116, 119))	('Fos', 'Gene', (116, 119))	('TERT', 'Gene', '7015', (197, 201))	('phosphorylation', 'MPA', (62, 77))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutant', 'Var', (190, 196))	('melanoma', 'Disease', (47, 55))	('BRAF', 'Gene', '673', (29, 33))	('ETS1', 'Gene', '2113', (81, 85))	('BRAF', 'Gene', (29, 33))	('GABPB', 'Gene', (106, 111))	('ETS1', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (154, 158))	('BRAF', 'Gene', (154, 158))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('GABPB', 'Gene', '2553', (106, 111))
180851	31391125	In contrast, TERT mRNA was only detectable in BRAFV600E cells with additional TERT promoter mutations.	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('BRAFV600E', 'Mutation', 'rs113488022', (46, 55))	('mutations', 'Var', (92, 101))
180856	31391125	In a following step, we demonstrated that activation of TERT transcription is dependent on BRAF signaling solely in the background of BRAFV600E and TERT promoter double-mutation.	('BRAF', 'Gene', '673', (91, 95))	('BRAF', 'Gene', '673', (134, 138))	('double-mutation', 'Var', (162, 177))	('BRAF', 'Gene', (91, 95))	('BRAF', 'Gene', (134, 138))	('activation', 'PosReg', (42, 52))	('TERT', 'Gene', (56, 60))	('TERT', 'Gene', (148, 152))	('TERT', 'Gene', '7015', (148, 152))	('BRAFV600E', 'Mutation', 'rs113488022', (134, 143))	('TERT', 'Gene', '7015', (56, 60))
180858	31391125	Oncogenic BRAF signaling has been shown to bridge telomerase re-activation via the mutated TERT promoter sequence.	('mutated', 'Var', (83, 90))	('TERT', 'Gene', (91, 95))	('telomerase', 'Enzyme', (50, 60))	('TERT', 'Gene', '7015', (91, 95))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))
180862	31391125	Additionally, we show that knock-down of ETS1 reduces TERT expression confirming it as mediator of BRAFV600E-driven TERT promoter activation.	('TERT', 'Gene', (116, 120))	('TERT', 'Gene', '7015', (54, 58))	('TERT', 'Gene', '7015', (116, 120))	('ETS1', 'Gene', (41, 45))	('ETS1', 'Gene', '2113', (41, 45))	('knock-down', 'Var', (27, 37))	('reduces', 'NegReg', (46, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (99, 108))	('TERT', 'Gene', (54, 58))
180863	31391125	Accordingly, ChIP-analysis revealed ETS1 and GABPA-binding specifically to the mutant TERT promoter site.	('GABPA', 'Gene', '2551', (45, 50))	('mutant', 'Var', (79, 85))	('GABPA', 'Gene', (45, 50))	('TERT', 'Gene', (86, 90))	('ETS1', 'Gene', '2113', (36, 40))	('ETS1', 'Gene', (36, 40))	('TERT', 'Gene', '7015', (86, 90))
180864	31391125	Previous studies in BRAF wild-type glioblastoma models have already demonstrated a central role of GABPA in activation of the mutant TERT promoter.	('GABPA', 'Gene', (99, 104))	('TERT', 'Gene', (133, 137))	('TERT', 'Gene', '7015', (133, 137))	('glioblastoma', 'Disease', (35, 47))	('BRAF', 'Gene', '673', (20, 24))	('GABPA', 'Gene', '2551', (99, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('BRAF', 'Gene', (20, 24))	('mutant', 'Var', (126, 132))	('activation', 'PosReg', (108, 118))
180865	31391125	Our data point towards cooperation of GABPA with ETS1, especially in a BRAFV600E-mutant glioma background.	('GABPA', 'Gene', (38, 43))	('glioma', 'Disease', (88, 94))	('ETS1', 'Gene', '2113', (49, 53))	('ETS1', 'Gene', (49, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (71, 80))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('GABPA', 'Gene', '2551', (38, 43))	('BRAFV600E-mutant', 'Var', (71, 87))
180866	31391125	Accordingly, a recent study in melanoma has shown that the C228T variant, the predominant mutation detected in our panel, is more efficiently activated by ETS1 as compared to the other TERT promoter mutations.	('C228T', 'Var', (59, 64))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('TERT', 'Gene', (185, 189))	('TERT', 'Gene', '7015', (185, 189))	('ETS1', 'Gene', (155, 159))	('ETS1', 'Gene', '2113', (155, 159))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('C228T', 'Mutation', 'rs763756456', (59, 64))	('melanoma', 'Disease', (31, 39))
180872	31391125	In line with previous reports from our group concerning meningioma, also glioma cell models harboring mutant TERT promoters were hypersensitive towards YK-4-279 treatment and YK-4-279 distinctly reduced TERT mRNA expression.	('mutant', 'Var', (102, 108))	('glioma', 'Disease', (73, 79))	('reduced', 'NegReg', (195, 202))	('TERT', 'Gene', '7015', (109, 113))	('TERT', 'Gene', '7015', (203, 207))	('meningioma', 'Disease', 'MESH:D008577', (56, 66))	('meningioma', 'Phenotype', 'HP:0002858', (56, 66))	('TERT', 'Gene', (203, 207))	('YK-4-279', 'Var', (175, 183))	('hypersensitive', 'Disease', 'MESH:D004342', (129, 143))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('hypersensitive', 'Disease', (129, 143))	('meningioma', 'Disease', (56, 66))	('TERT', 'Gene', (109, 113))
180873	31391125	Strikingly, BRAFV600E-mutant models were even more sensitive towards YK-4-279, irrespective of the underlying TERT promoter status.	('BRAFV600E-mutant', 'Var', (12, 28))	('TERT', 'Gene', (110, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (12, 21))	('TERT', 'Gene', '7015', (110, 114))	('more', 'PosReg', (46, 50))	('sensitive', 'MPA', (51, 60))
180875	31391125	As we found that both dabrafenib as well as YK-4-279 were highly active against BRAFV600E mutated glioma, we aimed to investigate interactions between the two drugs.	('BRAFV600E mutated', 'Var', (80, 97))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('active', 'MPA', (65, 71))	('dabrafenib', 'Chemical', 'MESH:C561627', (22, 32))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('BRAFV600E', 'Mutation', 'rs113488022', (80, 89))	('glioma', 'Disease', (98, 104))
180876	31391125	No synergistic, but rather antagonistic effects were identified particularly in the double-mutant glioma cell models.	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('double-mutant', 'Var', (84, 97))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Disease', (98, 104))
180878	31391125	Taken together, our data suggest that apart from the demonstrated TERT promoter activating properties, ETS-factors appear to play an important role in tumor biology of BRAFV600E-mutated glioma.	('glioma', 'Disease', (186, 192))	('BRAFV600E-mutated', 'Var', (168, 185))	('BRAFV600E', 'Mutation', 'rs113488022', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('ETS', 'Chemical', '-', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
180879	31391125	Summarizing, we prove that telomerase re-activation based on a mutant TERT promoter sequence in BRAFV600E-mutant glioma is driven by oncogenic BRAF signaling predominantly via downstream activation of ETS-factors.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('mutant', 'Var', (63, 69))	('BRAFV600E', 'Mutation', 'rs113488022', (96, 105))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('glioma', 'Disease', (113, 119))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('TERT', 'Gene', (70, 74))	('re-activation', 'PosReg', (38, 51))	('ETS', 'Chemical', '-', (201, 204))	('telomerase', 'Enzyme', (27, 37))	('TERT', 'Gene', '7015', (70, 74))
180886	28978068	Analysis of long non-coding RNA expression profiles identifies novel lncRNA biomarkers in the tumorigenesis and malignant progression of gliomas Long non-coding RNAs have been shown to be associated with cancer development and progression, demonstrating potential applications as novel diagnostic or prognostic molecular markers in clinical management and treatment.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('associated', 'Reg', (188, 198))	('Long non-coding RNAs', 'Var', (145, 165))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('malignant progression', 'CPA', (112, 133))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('tumorigenesis', 'CPA', (94, 107))
180889	28978068	By using differential expression analysis, we identified a large number of lncRNAs that were associated with the tumorigenesis and malignant progression of gliomas in the training dataset and showed their robustness in the testing dataset.	('malignant progression', 'CPA', (131, 152))	('tumor', 'Disease', (113, 118))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('lncRNAs', 'Var', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('associated with', 'Reg', (93, 108))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
180892	28978068	Functional analysis suggested that the four lncRNAs associated with survival of patients with GBM may be involved in cancer-related biological processes and pathways and their deregulation may lead to GBM tumorigenesis and progression.	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('deregulation', 'Var', (176, 188))	('involved', 'Reg', (105, 113))	('progression', 'CPA', (223, 234))	('GBM', 'Disease', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('cancer', 'Disease', (117, 123))	('lead to', 'Reg', (193, 200))
180896	28978068	The median overall survival of patients with gliomas varied significantly across different grades: Patients with low-grade gliomas tended to have a favorable prognosis with a median survival of 11 years to 16.7 years, whereas patients with low-grade gliomas often faced poor prognosis with a median survival of 15 months to three years.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('gliomas', 'Disease', (250, 257))	('gliomas', 'Disease', 'MESH:D005910', (250, 257))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('gliomas', 'Phenotype', 'HP:0009733', (250, 257))	('gliomas', 'Disease', (123, 130))	('patients', 'Species', '9606', (226, 234))	('Patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (31, 39))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('low-grade', 'Var', (113, 122))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
180926	28978068	Then a multivariable Cox regression analysis was performed for all 78 candidate lncRNAs and identified four independent lncRNA biomarkers (AK098425, AL833059, AK056155 and CR613436) significantly associated with the outcome of patients with GBM.	('AK098425', 'Var', (139, 147))	('GBM', 'Disease', (241, 244))	('Cox', 'Gene', '1351', (21, 24))	('AL833059', 'Var', (149, 157))	('associated with', 'Reg', (196, 211))	('CR613436', 'Var', (172, 180))	('Cox', 'Gene', (21, 24))	('AK056155', 'Var', (159, 167))	('patients', 'Species', '9606', (227, 235))
180927	28978068	This four-lncRNA expression signature was defined as a linear combination of the expression levels of the four lncRNA biomarkers and the multivariate Cox regression coefficient as the weight as follows: Risk score=(0.229*expression value of AK098425)+(-0.210*expression value of AL833059)+ (0.257*expression value of AK056155)+(0.291*expression value of CR613436).	('AK098425)+(-0.210*', 'Var', (241, 259))	('Cox', 'Gene', (150, 153))	('AK056155)+(0.291*', 'Var', (317, 334))	('0.229*', 'Var', (215, 221))	('AL833059)+ (0.257*', 'Var', (279, 297))	('Cox', 'Gene', '1351', (150, 153))
180938	28978068	Although traditional histopathologic classification is well established based on histological features, histological classifications did not well reflect clinical characteristics and prognosis of patients with grade II-III glioma and glioblastoma (grade IV glioma).	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('grade II-III', 'Var', (210, 222))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('patients', 'Species', '9606', (196, 204))	('glioblastoma', 'Disease', (234, 246))	('glioblastoma', 'Disease', 'MESH:D005909', (234, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (234, 246))	('glioma', 'Disease', (223, 229))	('glioma', 'Disease', (257, 263))
180941	28978068	A recent study performed by Eckel-Passow also proposed a new molecular classification of glioma into three molecular subtypes: IDH wild-type cases, IDH mutant-codel and IDH-mutant-non-codel.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', (169, 172))	('IDH', 'Gene', '3417', (148, 151))	('glioma', 'Disease', (89, 95))	('IDH', 'Gene', '3417', (169, 172))	('mutant-codel', 'Var', (152, 164))
180944	28978068	Aberrant lncRNA expression has been widely observed in various human cancers by transcriptional profiling analysis, highlighting their hallmark feature in cancer.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('human', 'Species', '9606', (63, 68))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lncRNA expression', 'Protein', (9, 26))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (155, 161))	('cancers', 'Disease', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
180949	28978068	Our results demonstrated that dysregulated lncRNA expression played important roles in the tumorigenesis and malignant progression of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('malignant progression', 'CPA', (109, 130))	('gliomas', 'Disease', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lncRNA expression', 'Protein', (43, 60))	('dysregulated', 'Var', (30, 42))	('tumor', 'Disease', (91, 96))
180954	28978068	Thus it is a plausible inference that the four lncRNAs associated with survival of patients with GBM may be involved in cancer-related biological processes and pathways and their deregulation may lead to GBM tumorigenesis and progress.	('deregulation', 'Var', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('progress', 'CPA', (226, 234))	('lead to', 'Reg', (196, 203))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('involved', 'Reg', (108, 116))	('tumor', 'Disease', (208, 213))	('GBM', 'Disease', (204, 207))	('patients', 'Species', '9606', (83, 91))
180974	26373278	Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint.	('glioblastoma', 'Disease', (112, 124))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('upregulated', 'PosReg', (24, 35))	('promoter hypomethylation', 'Var', (44, 68))
180975	26373278	These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.	('epigenetic', 'Var', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('brain tumor', 'Phenotype', 'HP:0030692', (94, 105))	('brain tumor', 'Disease', 'MESH:D001932', (94, 105))	('brain tumor', 'Disease', (94, 105))
180982	26373278	In fact, adjuvant treatment with alkylating chemotherapeutics such as temozolomide (TMZ) can induce hypermutation that emerges in recurrent tumors, and we recently linked treatment-associated driver mutations in these two pathways to malignant progression of grade II glioma to GBM.	('glioma', 'Disease', (268, 274))	('ape', 'Gene', (53, 56))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('ape', 'Gene', '328', (53, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('GBM', 'Phenotype', 'HP:0012174', (278, 281))	('glioma', 'Disease', 'MESH:D005910', (268, 274))	('temozolomide', 'Chemical', 'MESH:D000077204', (70, 82))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (199, 208))	('hypermutation', 'MPA', (100, 113))	('linked', 'Reg', (164, 170))
180983	26373278	It remains unknown, however, how epigenetic alterations contribute to the different courses of evolution of low-grade gliomas and how or if they relate to concurrent mutational evolution.	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('epigenetic alterations', 'Var', (33, 55))	('gliomas', 'Disease', (118, 125))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('contribute', 'Reg', (56, 66))
180984	26373278	The critical role that epigenetic alterations play in the development and therapeutic response of gliomas is increasingly being appreciated.	('ape', 'Gene', (78, 81))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('epigenetic alterations', 'Var', (23, 45))	('ape', 'Gene', '328', (78, 81))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))
180985	26373278	Epigenetic mechanisms can alter gene expression, and have been shown to affect tumor suppressors and oncogenes in gliomas.	('gene expression', 'MPA', (32, 47))	('oncogenes', 'Gene', (101, 110))	('gliomas', 'Disease', (114, 121))	('affect', 'Reg', (72, 78))	('tumor', 'Disease', (79, 84))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('alter', 'Reg', (26, 31))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Epigenetic mechanisms', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
180987	26373278	Genetic mutations in IDH genes induce a pattern of early epigenetic alterations known as the glioma CpG island methylator phenotype (G-CIMP) characterized by extensive remodeling of the DNA methylome.	('IDH', 'Gene', (21, 24))	('glioma', 'Disease', (93, 99))	('induce', 'Reg', (31, 37))	('IDH', 'Gene', '3417', (21, 24))	('epigenetic alterations', 'MPA', (57, 79))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('G-CIMP', 'Chemical', '-', (133, 139))	('Genetic mutations', 'Var', (0, 17))
180988	26373278	The inactivation of other genes mutated in low-grade gliomas, such as ATRX and SMARCA4, is known to induce specific DNA methylation changes as well.	('ATRX', 'Gene', '546', (70, 74))	('inactivation', 'Var', (4, 16))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('SMARCA4', 'Gene', (79, 86))	('gliomas', 'Disease', (53, 60))	('induce', 'Reg', (100, 106))	('SMARCA4', 'Gene', '6597', (79, 86))	('ATRX', 'Gene', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('DNA methylation changes', 'MPA', (116, 139))
180996	26373278	From these methylation array data we confirmed that G-CIMP was present in all initial tumors and always maintained at recurrence (Figure S1B), highlighting that these epigenetic changes arise very early and are potentially tumor-initiating.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('epigenetic', 'Var', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('G-CIMP', 'Chemical', '-', (52, 58))
180999	26373278	This result reflects patient-specific methylation patterns, consistent with a previous report on glioma, and may be indicative of normal inter-individual epigenetic variation, patient-specific aberrant methylation from early stages of gliomagenesis, or both.	('methylation', 'MPA', (38, 49))	('aberrant methylation', 'Var', (193, 213))	('glioma', 'Disease', (97, 103))	('patient', 'Species', '9606', (21, 28))	('methylation', 'Var', (202, 213))	('glioma', 'Disease', (235, 241))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('patient', 'Species', '9606', (176, 183))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (235, 241))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))
181001	26373278	At the most lenient cutoff, the methylation patterns separated GBM recurrences, as well as two initial tumors that recurred as GBM, from the grade II and III gliomas (Figure 1A).	('methylation', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GBM', 'Disease', (63, 66))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('III gliomas', 'Disease', 'MESH:D005910', (154, 165))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('III gliomas', 'Disease', (154, 165))
181004	26373278	DNA methylation differences between normal brain and glioma may be aberrant events in the tumor, or may reflect differences between the normal brain tissue sample and the methylation patterns of the tumor's cell of origin.	('tumor', 'Disease', (199, 204))	('glioma', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('differences', 'Reg', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
181008	26373278	There were few common methylation changes evident in patients that recurred at grade II or III, whereas a strong pattern of hypomethylation was associated with malignant progression to GBM (Figures 1B, 1C and S1I).	('malignant progression', 'CPA', (160, 181))	('GBM', 'Disease', (185, 188))	('associated with', 'Reg', (144, 159))	('patients', 'Species', '9606', (53, 61))	('hypomethylation', 'Var', (124, 139))	('GBM', 'Phenotype', 'HP:0012174', (185, 188))
181011	26373278	Given the G-CIMP-associated hypermethylation in these tumors, we first set out to determine if the hypomethylation in GBM recurrences affected G-CIMP genes.	('hypomethylation', 'Var', (99, 114))	('G-CIMP', 'Chemical', '-', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('affected', 'Reg', (134, 142))	('G-CIMP genes', 'Gene', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('G-CIMP', 'Chemical', '-', (143, 149))	('GBM', 'Phenotype', 'HP:0012174', (118, 121))	('tumors', 'Disease', (54, 60))
181012	26373278	identified 50 genes that were hypermethylated and downregulated in a G-CIMP specific manner.	('downregulated', 'NegReg', (50, 63))	('G-CIMP', 'Chemical', '-', (69, 75))	('hypermethylated', 'Var', (30, 45))
181013	26373278	Only two of those genes (ACSS3 and RAB36) showed GBM-specific hypomethylation, but in neither case did the genes show concurrent decreased expression.	('ACSS3', 'Gene', (25, 30))	('hypomethylation', 'Var', (62, 77))	('RAB36', 'Gene', '9609', (35, 40))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('expression', 'MPA', (139, 149))	('ACSS3', 'Gene', '79611', (25, 30))	('RAB36', 'Gene', (35, 40))
181014	26373278	This is contrary to the typical pattern in cancer in which CpG sites that are hypermethylated during aging are also hypermethylated in cancer.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (43, 49))	('hypermethylated', 'Var', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
181015	26373278	Among genes with GBM-specific promoter hypermethylation, only NTSR2 showed consistent transcriptional downregulation.	('transcriptional', 'MPA', (86, 101))	('downregulation', 'NegReg', (102, 116))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('NTSR2', 'Gene', (62, 67))	('NTSR2', 'Gene', '23620', (62, 67))	('hypermethylation', 'Var', (39, 55))
181017	26373278	Among the epigenetically modified cell cycle genes, we noted that the hypomethylation in TP73 was at an internal gene body promoter.	('TP73', 'Gene', '7161', (89, 93))	('TP73', 'Gene', (89, 93))	('hypomethylation', 'Var', (70, 85))
181030	26373278	For Patient17, the CpG sites that underlie the first major branch point were enriched for a variety of developmental, biosynthetic and metabolic processes, indicating that methylation changes during tumor progression may influence cellular metabolic states, in parallel with the genetic events disrupting cell cycle that separate these two main branches on the phylogenetic tree (Table S4).	('tumor', 'Disease', (199, 204))	('Patient', 'Species', '9606', (4, 11))	('changes', 'Reg', (184, 191))	('cellular metabolic states', 'MPA', (231, 256))	('methylation', 'Var', (172, 183))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('influence', 'Reg', (221, 230))
181038	26373278	Thus, even in extreme evolutionary events such as chemotherapy-associated hypermutation, both DNA methylation changes and mutational landscapes encode similar tumor evolutionary relationships.	('ape', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ape', 'Gene', '328', (139, 142))	('tumor', 'Disease', (159, 164))	('encode', 'Reg', (144, 150))	('changes', 'Var', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
181040	26373278	These results suggest a potentially quantitative relationship between the number of mutations and epimutations in each tumor cell clone.	('tumor', 'Disease', (119, 124))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('epimutations', 'Var', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
181054	26373278	However, the vast majority of mutations and methylation changes occur in different sets of genes, consistent with our prior low-resolution analysis of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('mutations', 'Var', (30, 39))	('gliomas', 'Disease', (151, 158))	('methylation', 'MPA', (44, 55))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
181055	26373278	In contrast to single genes, single pathways such as the cell cycle pathway are commonly altered by multiple genetic and epigenetic (Figure 2B) alterations within and across tumor samples.	('tumor', 'Disease', (174, 179))	('cell cycle pathway', 'Pathway', (57, 75))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('epigenetic', 'Var', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('altered', 'Reg', (89, 96))
181056	26373278	Here, we show that despite epigenome plasticity, chemotherapy, and the ubiquitous IDH1 mutation-driven G-CIMP pattern, patient-specific tumor phyloepigenetic analyses replicated and extended tumor phylogenetic analyses.	('patient', 'Species', '9606', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mutation-driven', 'Var', (87, 102))	('IDH1', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('IDH1', 'Gene', '3417', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('G-CIMP', 'Chemical', '-', (103, 109))
181059	26373278	Thus, genomicepigenomic co-dependency may be a feature of multiple types of cancer, and may span somatic mutations, copy number, and DNA methylation.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('copy number', 'Var', (116, 127))
181062	26373278	Somatic genetic events, like IDH1 mutations, have been directly linked to alterations in the methylome, while germline variants have been indirectly associated with specific DNA methylation patterns.	('IDH1', 'Gene', (29, 33))	('methylome', 'MPA', (93, 102))	('IDH1', 'Gene', '3417', (29, 33))	('alterations', 'Reg', (74, 85))	('linked', 'Reg', (64, 70))	('mutations', 'Var', (34, 43))
181063	26373278	Consistent with these theories, the widespread correlation between somatic mutations and DNA methylation patterns suggests that in addition to IDH1 mutation and G-CIMP, other epigenetic patterns might be directly or indirectly induced by mutations, or vice versa.	('G-CIMP', 'Disease', (161, 167))	('induced', 'Reg', (227, 234))	('IDH1', 'Gene', (143, 147))	('mutation', 'Var', (148, 156))	('IDH1', 'Gene', '3417', (143, 147))	('G-CIMP', 'Chemical', '-', (161, 167))
181065	26373278	We previously found that recurrent tumors that underwent malignant progression to GBM acquired somatic mutations in the RB pathway that inactivate the G1/S cell cycle checkpoint.	('mutations', 'Var', (103, 112))	('RB pathway', 'Pathway', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('inactivate', 'NegReg', (136, 146))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('G1/S', 'MPA', (151, 155))
181066	26373278	Of note, we identify hypomethylation at TP73 as a recurrent event.	('TP73', 'Gene', (40, 44))	('TP73', 'Gene', '7161', (40, 44))	('hypomethylation', 'Var', (21, 36))
181068	26373278	By combining the information from somatic mutations, copy number alteration and DNA methylation patterns, we derived a comprehensive model of glioma evolution (Figure 5).	('glioma', 'Disease', (142, 148))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('copy number alteration', 'Var', (53, 75))
181069	26373278	Chronological ordering of IDH1, TP53, and ATRX mutations and copy number alterations was derived from our previous tumor phylogenetic analyses, other studies, and additional data presented here.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TP53', 'Gene', '7157', (32, 36))	('tumor', 'Disease', (115, 120))	('IDH1', 'Gene', (26, 30))	('ATRX', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('ATRX', 'Gene', '546', (42, 46))	('TP53', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
181089	26373278	Phenotypically, mutations and promoter region DNA hypomethylation converge to deregulate the cell cycle as indolent low-grade tumors progress to high-grade malignancies.	('malignancies', 'Disease', (156, 168))	('progress', 'PosReg', (133, 141))	('deregulate', 'Reg', (78, 88))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (16, 25))	('malignancies', 'Disease', 'MESH:D009369', (156, 168))	('cell cycle', 'CPA', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
181090	26373278	This study suggests strong interdependency of genetic and epigenetic alterations in these human brain tumors.	('brain tumor', 'Phenotype', 'HP:0030692', (96, 107))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('human', 'Species', '9606', (90, 95))	('brain tumors', 'Phenotype', 'HP:0030692', (96, 108))	('brain tumors', 'Disease', 'MESH:D001932', (96, 108))	('brain tumors', 'Disease', (96, 108))	('epigenetic alterations', 'Var', (58, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
181103	31554255	However, in common clinical practice, radiosensitive areas of cerebral tissues, like the hippocampi and temporal lobes, are most often overlooked as organs at risk (OAR) in treatment planning, with damage of medial temporal lobe that results ino amnesia whereas lateral temporal lobe involvement is related to language disorders.	('language disorders', 'Phenotype', 'HP:0002463', (310, 328))	('amnesia', 'Disease', 'MESH:D000647', (246, 253))	('amnesia', 'Disease', (246, 253))	('damage', 'Var', (198, 204))	('language disorders', 'Disease', 'MESH:D007806', (310, 328))	('results ino', 'Reg', (234, 245))	('language disorders', 'Disease', (310, 328))
181152	31554255	Moreover, in case of neoplastic transformation, brain cells will show molecular alterations associated with functional impairments that can be detected before any structural change occurs; in fact, 18F-FDG PET/CT demonstrated greater specificity than CT or MRI to monitor therapeutic response in brain tumors.	('18F-FDG', 'Chemical', 'MESH:D019788', (198, 205))	('brain tumors', 'Phenotype', 'HP:0030692', (296, 308))	('brain tumors', 'Disease', (296, 308))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('rat', 'Species', '10116', (84, 87))	('functional impairments', 'Disease', (108, 130))	('functional impairments', 'Disease', 'MESH:D003072', (108, 130))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('18F-FDG', 'Var', (198, 205))	('brain tumors', 'Disease', 'MESH:D001932', (296, 308))	('rat', 'Species', '10116', (220, 223))	('brain tumor', 'Phenotype', 'HP:0030692', (296, 307))
181154	31554255	More specifically, in the differentiation of tumor recurrence and RN, 18F-FDG has also a low specificity, ranging from 40 to 94%, mainly during the first few weeks post therapy, with a study that showed a sensitivity of 81-86%.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('18F-FDG', 'Var', (70, 77))	('tumor', 'Disease', (45, 50))	('18F-FDG', 'Chemical', 'MESH:D019788', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
181177	31554255	Unlike 18F-FDG and similarly to 18F-DOPA, 18F-FMISO shows no uptake in normal brain tissue, thus providing high contrast images of hypoxic brain tumors.	('brain tumors', 'Phenotype', 'HP:0030692', (139, 151))	('hypoxic brain tumors', 'Disease', 'MESH:D001932', (131, 151))	('hypoxic brain tumors', 'Disease', (131, 151))	('18F-FDG', 'Chemical', 'MESH:D019788', (7, 14))	('uptake', 'MPA', (61, 67))	('brain tumor', 'Phenotype', 'HP:0030692', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('18F-FMISO', 'Chemical', 'MESH:C031843', (42, 51))	('18F-FMISO', 'Var', (42, 51))	('18F-DOPA', 'Chemical', 'MESH:D007980', (32, 40))
181186	31554255	More in particular, in the differentiation of tumor recurrence and radiation necrosis, 18F-FLT has shown its potential superiority over 18F-FDG in terms of specificity, due to minimum neuronal cell division, which corresponds to lower levels of uptake in most regions of the brain, in contrast with widespread uptake of 18F-FDG by grey matter.	('18F-FLT', 'Var', (87, 94))	('18F-FDG', 'Chemical', 'MESH:D019788', (136, 143))	('radiation necrosis', 'Disease', 'MESH:D011832', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('neuronal cell division', 'CPA', (184, 206))	('uptake', 'MPA', (245, 251))	('tumor', 'Disease', (46, 51))	('radiation necrosis', 'Disease', (67, 85))	('minimum', 'NegReg', (176, 183))	('18F-FDG', 'Chemical', 'MESH:D019788', (320, 327))	('lower', 'NegReg', (229, 234))	('18F-FLT', 'Chemical', 'MESH:C002854', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
181204	31554255	One of the most interesting studies in this sense is one by Tomura et al., which demonstrated that 11C-MET PET was superior to 18F-FDG-PET in differentiating RN from tumor recurrence, mainly in patients that already underwent gamma knife radiosurgery.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('patients', 'Species', '9606', (194, 202))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('18F-FDG', 'Chemical', 'MESH:D019788', (127, 134))	('11C-MET PET', 'Var', (99, 110))	('rat', 'Species', '10116', (88, 91))	('tumor', 'Disease', (166, 171))
181206	31554255	Unfortunately, as most of the studies focused on the differentiation of RN and tumor recurrence, it is limited by the small cohort size that included only 15 patients with 18 lesions; therefore, larger studies are needed to prove the superiority of 11C-MET PET over 18F-FDG-PET in a direct per-lesion comparison.	('11C-MET PET', 'Var', (249, 260))	('tumor', 'Disease', (79, 84))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('18F-FDG', 'Chemical', 'MESH:D019788', (266, 273))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
181211	31554255	In particular, they agreed on the superiority of 11C-MET over both FDG and 18F-choline due to a lower uptake in RN than in recurrence and with a sensitivity of 91.2% and a specificity of 87.5%.	('18F-choline', 'Chemical', 'MESH:C516370', (75, 86))	('FDG', 'Chemical', 'MESH:C554683', (67, 70))	('uptake in', 'MPA', (102, 111))	('lower', 'NegReg', (96, 101))	('11C-MET', 'Var', (49, 56))
181216	31554255	The first PET tracer that has been used for over 20 years to image neuroinflammation is 11C-(R)-PK111956 (Figure 4).	('image neuroinflammation', 'Disease', 'MESH:C564543', (61, 84))	('image neuroinflammation', 'Disease', (61, 84))	('11C-(R)-PK111956', 'Var', (88, 104))
181221	31554255	In this sense, several papers have already been published on 18F-GE180 and on its possible role as a neuroinflammation-specific tracer for clinical routine; most of them are still at a preclinical stage but the results are promising in multiple scenarios.	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('inflammation', 'Disease', (106, 118))	('18F-GE180', 'Var', (61, 70))
181263	30241204	There was one suggestion to consider genetic testing and another one to test the tumor for BRAF fusion/ mutation.	('BRAF', 'Gene', '673', (91, 95))	('BRAF', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutation', 'Var', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
181266	30241204	Interestingly, during this more recent era, there were 16 suggestions for molecular testing, including BRAF fusion/mutation, medulloblastoma subgrouping, and genetic testing.	('fusion/mutation', 'Var', (108, 123))	('medulloblastoma', 'Phenotype', 'HP:0002885', (125, 140))	('medulloblastoma', 'Disease', 'MESH:D008527', (125, 140))	('BRAF', 'Gene', '673', (103, 107))	('medulloblastoma', 'Disease', (125, 140))	('BRAF', 'Gene', (103, 107))
181267	30241204	In six cases (38%), the suggestions were followed (two BRAF mutation testing, two medulloblastoma subgrouping, one biallelic mismatch repair testing, and one 1p/19q testing).	('medulloblastoma', 'Disease', 'MESH:D008527', (82, 97))	('mutation testing', 'Var', (60, 76))	('medulloblastoma', 'Phenotype', 'HP:0002885', (82, 97))	('medulloblastoma', 'Disease', (82, 97))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))
181271	30241204	Lately, this facilitated the compassionate access to a BRAF inhibitor in a patient with disseminated recurrence of a pleomorphic xanthoastrocytoma after positive testing for BRAF mutation at the Sickkids laboratory.	('pleomorphic xanthoastrocytoma', 'Disease', (117, 146))	('mutation', 'Var', (179, 187))	('BRAF', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (174, 178))	('BRAF', 'Gene', '673', (55, 59))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (117, 146))	('patient', 'Species', '9606', (75, 82))
181290	27437179	Hyperpolarized 13C MR imaging detects no lactate production in mutant IDH1 gliomas: Implications for diagnosis and response monitoring Metabolic imaging of brain tumors using 13C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-13C] pyruvate is a promising neuroimaging strategy which, after a decade of preclinical success in glioblastoma (GBM) models, is now entering clinical trials in multiple centers.	('IDH1 gliomas', 'Disease', 'MESH:D005910', (70, 82))	('13C', 'Chemical', 'MESH:C000615229', (15, 18))	('brain tumors', 'Disease', (156, 168))	('MRS', 'Gene', '148398', (212, 215))	('glioblastoma', 'Disease', 'MESH:D005909', (337, 349))	('MRS', 'Gene', (212, 215))	('glioblastoma', 'Disease', (337, 349))	('[1-13C] pyruvate', 'Chemical', '-', (235, 251))	('glioblastoma', 'Phenotype', 'HP:0012174', (337, 349))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutant', 'Var', (63, 69))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('brain tumors', 'Phenotype', 'HP:0030692', (156, 168))	('13C', 'Chemical', 'MESH:C000615229', (238, 241))	('brain tumors', 'Disease', 'MESH:D001932', (156, 168))	('rat', 'Species', '10116', (282, 285))	('brain tumor', 'Phenotype', 'HP:0030692', (156, 167))	('IDH1 gliomas', 'Disease', (70, 82))	('13C', 'Chemical', 'MESH:C000615229', (175, 178))	('lactate', 'Chemical', 'MESH:D019344', (41, 48))
181291	27437179	Typically, the presence of GBM has been associated with elevated hyperpolarized [1-13C] lactate produced from [1-13C] pyruvate, and response to therapy has been associated with a drop in hyperpolarized [1-13C] lactate.	('drop', 'NegReg', (179, 183))	('elevated', 'PosReg', (56, 64))	('[1-13C] lactate', 'Chemical', '-', (202, 217))	('hyperpolarized [1-13C] lactate', 'MPA', (187, 217))	('presence', 'Var', (15, 23))	('[1-13C] lactate', 'Chemical', '-', (80, 95))	('[1-13C] pyruvate', 'Chemical', '-', (110, 126))	('GBM', 'Gene', (27, 30))
181293	27437179	The most prevalent mutation in lower grade gliomas is the isocitrate dehydrogenase 1 (IDH1) mutation, which, in addition to initiating tumor development, also induces metabolic reprogramming.	('IDH1', 'Gene', (86, 90))	('mutation', 'Var', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('prevalent', 'Reg', (9, 18))	('IDH1', 'Gene', '3417', (86, 90))	('tumor', 'Disease', (135, 140))	('metabolic reprogramming', 'CPA', (167, 190))	('isocitrate dehydrogenase 1', 'Gene', (58, 84))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('induces', 'Reg', (159, 166))	('isocitrate dehydrogenase 1', 'Gene', '3417', (58, 84))	('gliomas', 'Disease', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
181294	27437179	In particular, mutant IDH1 gliomas are associated with low levels of lactate dehydrogenase A (LDHA) and monocarboxylate transporters 1 and 4 (MCT1, MCT4), three proteins involved in pyruvate metabolism to lactate.	('lactate dehydrogenase A', 'Gene', (69, 92))	('pyruvate metabolism', 'Disease', (182, 201))	('gliomas', 'Disease', (27, 34))	('lactate', 'Chemical', 'MESH:D019344', (205, 212))	('IDH1 glioma', 'Disease', 'MESH:D005910', (22, 33))	('pyruvate metabolism', 'Disease', 'MESH:D015323', (182, 201))	('low', 'NegReg', (55, 58))	('lactate', 'Chemical', 'MESH:D019344', (69, 76))	('MCT4', 'Gene', (148, 152))	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('MCT4', 'Gene', '9123', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('MCT1', 'Gene', (142, 146))	('mutant', 'Var', (15, 21))	('IDH1 glioma', 'Disease', (22, 33))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('lactate dehydrogenase A', 'Gene', '3939', (69, 92))	('MCT1', 'Gene', '6566', (142, 146))	('low levels of lactate dehydrogenase', 'Phenotype', 'HP:0045041', (55, 90))
181295	27437179	We therefore investigated the potential of 13C MRS of hyperpolarized [1-13C] pyruvate for detection of mutant IDH1 gliomas and for monitoring of their therapeutic response.	('13C', 'Chemical', 'MESH:C000615229', (72, 75))	('IDH1 glioma', 'Disease', 'MESH:D005910', (110, 121))	('MRS', 'Gene', (47, 50))	('gliomas', 'Disease', (115, 122))	('MRS', 'Gene', '148398', (47, 50))	('mutant', 'Var', (103, 109))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('13C', 'Chemical', 'MESH:C000615229', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('IDH1 glioma', 'Disease', (110, 121))	('[1-13C] pyruvate', 'Chemical', '-', (69, 85))
181296	27437179	We studied patient-derived mutant IDH1 glioma cells that underexpress LDHA, MCT1 and MCT4, and wild-type IDH1 GBM cells that express high levels of these proteins.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1 glioma', 'Disease', (34, 45))	('mutant', 'Var', (27, 33))	('IDH1', 'Gene', (105, 109))	('LDHA', 'Gene', (70, 74))	('MCT4', 'Gene', (85, 89))	('IDH1', 'Gene', '3417', (105, 109))	('underexpress', 'NegReg', (57, 69))	('patient', 'Species', '9606', (11, 18))	('IDH1 glioma', 'Disease', 'MESH:D005910', (34, 45))	('MCT1', 'Gene', (76, 80))	('MCT4', 'Gene', '9123', (85, 89))	('IDH1', 'Gene', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('MCT1', 'Gene', '6566', (76, 80))
181297	27437179	Mutant IDH1 cells and tumors produced significantly less hyperpolarized [1-13C] lactate compared to GBM, consistent with their metabolic reprogramming.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('IDH1', 'Gene', '3417', (7, 11))	('[1-13C] lactate', 'Chemical', '-', (72, 87))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('hyperpolarized [1-13C] lactate', 'MPA', (57, 87))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (22, 28))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('less', 'NegReg', (52, 56))
181298	27437179	Furthermore, hyperpolarized [1-13C] lactate production was not affected by chemotherapeutic treatment with temozolomide (TMZ) in mutant IDH1 tumors, in contrast to previous reports in GBM.	('IDH1 tumors', 'Disease', 'MESH:D009369', (136, 147))	('TMZ', 'Chemical', 'MESH:D000077204', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('temozolomide', 'Chemical', 'MESH:D000077204', (107, 119))	('[1-13C] lactate', 'Chemical', '-', (28, 43))	('IDH1 tumors', 'Disease', (136, 147))	('hyperpolarized [1-13C] lactate production', 'MPA', (13, 54))	('mutant', 'Var', (129, 135))
181299	27437179	Our results demonstrate the unusual metabolic imaging profile of mutant IDH1 gliomas, which, when combined with other clinically available imaging methods, could be used to detect the presence of the IDH1 mutation in vivo.	('metabolic imaging', 'MPA', (36, 53))	('IDH1', 'Gene', (200, 204))	('IDH1', 'Gene', (72, 76))	('gliomas', 'Disease', (77, 84))	('IDH1', 'Gene', '3417', (200, 204))	('mutant', 'Var', (65, 71))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('IDH1 glioma', 'Disease', (72, 83))	('IDH1', 'Gene', '3417', (72, 76))	('rat', 'Species', '10116', (19, 22))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('IDH1 glioma', 'Disease', 'MESH:D005910', (72, 83))
181300	27437179	Metabolic imaging of mutant IDH1 gliomas using hyperpolarized 13C MRS is described.	('mutant', 'Var', (21, 27))	('IDH1 glioma', 'Disease', 'MESH:D005910', (28, 39))	('MRS', 'Gene', (66, 69))	('MRS', 'Gene', '148398', (66, 69))	('IDH1 glioma', 'Disease', (28, 39))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('gliomas', 'Disease', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('13C', 'Chemical', 'MESH:C000615229', (62, 65))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
181301	27437179	In contrast to GBM, mutant IDH1 gliomas produce no hyperpolarized [1-13C] lactate.	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('[1-13C] lactate', 'Chemical', '-', (66, 81))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('IDH1 glioma', 'Disease', (27, 38))	('IDH1 glioma', 'Disease', 'MESH:D005910', (27, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('mutant', 'Var', (20, 26))	('hyperpolarized [1-13C] lactate', 'MPA', (51, 81))
181302	27437179	Hyperpolarized [1-13C] lactate is not reduced by treatment in mutant IDH1 tumors.	('mutant', 'Var', (62, 68))	('IDH1 tumors', 'Disease', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('IDH1 tumors', 'Disease', 'MESH:D009369', (69, 80))	('[1-13C] lactate', 'Chemical', '-', (15, 30))	('Hyperpolarized [1-13C] lactate', 'MPA', (0, 30))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
181303	27437179	Mutant IDH1 gliomas present an unusual metabolic imaging profile.	('gliomas', 'Disease', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('IDH1 glioma', 'Disease', (7, 18))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('Mutant', 'Var', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('IDH1 glioma', 'Disease', 'MESH:D005910', (7, 18))
181312	27437179	A decrease in the hyperpolarized lactate-to-pyruvate ratio was observed in GBM cells following treatment with inhibitors of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway.	('decrease', 'NegReg', (2, 10))	('mTOR', 'Gene', '2475', (190, 194))	('lactate', 'Chemical', 'MESH:D019344', (33, 40))	('mammalian target of rapamycin', 'Gene', '2475', (154, 183))	('hyperpolarized lactate-to-pyruvate ratio', 'MPA', (18, 58))	('mTOR', 'Gene', (190, 194))	('mammalian target of rapamycin', 'Gene', (154, 183))	('rat', 'Species', '10116', (53, 56))	('inhibitors', 'Var', (110, 120))	('pyruvate', 'Chemical', 'MESH:D019289', (44, 52))
181318	27437179	Primary Grade IV GBM are associated with multiple genetic alterations including EGFR amplification and TP53, PTEN, and RB1 mutation/loss.	('TP53', 'Gene', '7157', (103, 107))	('Primary Grade IV GBM', 'Disease', (0, 20))	('associated', 'Reg', (25, 35))	('TP53', 'Gene', (103, 107))	('PTEN', 'Gene', (109, 113))	('EGFR', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (109, 113))	('amplification', 'Var', (85, 98))	('mutation/loss', 'Var', (123, 136))	('rat', 'Species', '10116', (62, 65))	('RB1', 'Gene', (119, 122))	('RB1', 'Gene', '5925', (119, 122))
181320	27437179	In contrast, in lower grade Grade II and III oligodendroglioma and astrocytoma, as well as in secondary upgraded GBM, up to 90% of tumors harbor a mutation in the isocitrate dehydrogenase 1 (IDH1) enzyme.	('isocitrate dehydrogenase 1', 'Gene', (163, 189))	('IDH1', 'Gene', (191, 195))	('isocitrate dehydrogenase 1', 'Gene', '3417', (163, 189))	('IDH1', 'Gene', '3417', (191, 195))	('mutation', 'Var', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('oligodendroglioma and astrocytoma', 'Disease', 'MESH:D009837', (45, 78))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))
181321	27437179	Mutant IDH1 catalyzes the reduction of alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG), resulting in non-physiological levels of this oncometabolite that induces epigenetic perturbations and ultimately leads to tumorigenesis.	('IDH1', 'Gene', '3417', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (73, 91))	('HG', 'Chemical', 'MESH:D008628', (95, 97))	('alpha-KG', 'Chemical', 'MESH:D007656', (60, 68))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (39, 58))	('non-physiological levels', 'MPA', (113, 137))	('induces', 'Reg', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('epigenetic perturbations', 'MPA', (174, 198))	('Mutant', 'Var', (0, 6))	('leads to', 'Reg', (214, 222))	('IDH1', 'Gene', (7, 11))
181322	27437179	Importantly, the IDH1 mutation also leads to a broad and unusual reprogramming of cellular metabolism.	('mutation', 'Var', (22, 30))	('reprogramming of', 'CPA', (65, 81))	('IDH1', 'Gene', (17, 21))	('leads to', 'Reg', (36, 44))	('IDH1', 'Gene', '3417', (17, 21))
181323	27437179	By investigating clinically derived samples and cell models, we demonstrated that the genes coding for LDHA (LDHA), MCT4 (SLC16A3) and MCT1 (SLC16A1), that are typically overexpressed in GBM, are silenced or underexpressed in IDH1 mutant gliomas, suggesting an atypical pyruvate metabolism in these tumors.	('rat', 'Species', '10116', (71, 74))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('pyruvate metabolism', 'Disease', (270, 289))	('underexpressed', 'NegReg', (208, 222))	('silenced', 'NegReg', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('pyruvate metabolism', 'Disease', 'MESH:D015323', (270, 289))	('LDHA', 'Gene', (103, 107))	('SLC16A3', 'Gene', '9123', (122, 129))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('mutant', 'Var', (231, 237))	('gliomas', 'Disease', (238, 245))	('MCT4', 'Gene', (116, 120))	('tumors', 'Disease', (299, 305))	('IDH1', 'Gene', (226, 230))	('MCT1', 'Gene', (135, 139))	('MCT4', 'Gene', '9123', (116, 120))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('SLC16A3', 'Gene', (122, 129))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('SLC16A1', 'Gene', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('IDH1', 'Gene', '3417', (226, 230))	('SLC16A1', 'Gene', '6566', (141, 148))	('MCT1', 'Gene', '6566', (135, 139))
181325	27437179	To do so, we investigated a recently developed patient-derived model of Grade III mutant IDH1 oligoastrocytoma, in which LDHA, MCT4 and MCT1 were shown to be underexpressed.	('patient', 'Species', '9606', (47, 54))	('MCT1', 'Gene', (136, 140))	('MCT1', 'Gene', '6566', (136, 140))	('MCT4', 'Gene', (127, 131))	('IDH1', 'Gene', '3417', (89, 93))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (94, 110))	('oligoastrocytoma', 'Disease', (94, 110))	('IDH1', 'Gene', (89, 93))	('MCT4', 'Gene', '9123', (127, 131))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))	('mutant', 'Var', (82, 88))
181327	27437179	Our metabolic imaging results show that hyperpolarized [1-13C] lactate levels were barely detectable in mutant IDH1 glioma neurospheres and tumors, in contrast to the high levels detected in GBM.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mutant', 'Var', (104, 110))	('[1-13C] lactate', 'Chemical', '-', (55, 70))	('hyperpolarized [1-13C] lactate levels', 'MPA', (40, 77))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('IDH1 glioma neurospheres and tumors', 'Disease', 'MESH:D005910', (111, 146))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
181328	27437179	Furthermore, we found that TMZ treatment did not induce any significant changes in hyperpolarized [1-13C] lactate levels in mutant IDH1 tumors, even though this therapeutic approach led to significant tumor shrinkage and increased survival.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('[1-13C] lactate', 'Chemical', '-', (98, 113))	('increased', 'PosReg', (221, 230))	('hyperpolarized [1-13C] lactate levels', 'MPA', (83, 120))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('mutant', 'Var', (124, 130))	('IDH1 tumors', 'Disease', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IDH1 tumors', 'Disease', 'MESH:D009369', (131, 142))	('survival', 'CPA', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (201, 206))	('TMZ', 'Chemical', 'MESH:D000077204', (27, 30))	('tumor', 'Disease', (136, 141))	('shrinkage', 'NegReg', (207, 216))
181329	27437179	Considering the increasing translation of 13C MRS of hyperpolarized [1-13C] pyruvate to the clinic, our findings are highly significant for the proper interpretation of DNP-MR imaging data from brain tumor patients and point to an unexpected metabolic imaging signature of mutant IDH1 tumors.	('metabolic imaging', 'MPA', (242, 259))	('brain tumor', 'Disease', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('[1-13C] pyruvate', 'Chemical', '-', (68, 84))	('13C', 'Chemical', 'MESH:C000615229', (71, 74))	('brain tumor', 'Disease', 'MESH:D001932', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('brain tumor', 'Phenotype', 'HP:0030692', (194, 205))	('IDH1 tumors', 'Disease', (280, 291))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('patients', 'Species', '9606', (206, 214))	('mutant', 'Var', (273, 279))	('13C', 'Chemical', 'MESH:C000615229', (42, 45))	('MRS', 'Gene', '148398', (46, 49))	('MRS', 'Gene', (46, 49))	('IDH1 tumors', 'Disease', 'MESH:D009369', (280, 291))
181334	27437179	For MRS studies of live cells, mutant IDH1 glioma cells (n = 3 BT142) were encapsulated in agarose beads and GBM cells (n = 3 U87) grown on microcarrier beads (NUNC).	('agarose', 'Chemical', 'MESH:D012685', (91, 98))	('mutant', 'Var', (31, 37))	('IDH1 glioma', 'Disease', (38, 49))	('MRS', 'Gene', '148398', (4, 7))	('MRS', 'Gene', (4, 7))	('BT142', 'Chemical', '-', (63, 68))	('IDH1 glioma', 'Disease', 'MESH:D005910', (38, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
181373	27437179	MCT1 expression was significantly lower in BT142 mutant IDH1 glioma cells as compared to U87 GBM cells, albeit to a lesser extent (Fig.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('expression', 'MPA', (5, 15))	('BT142', 'Gene', (43, 48))	('mutant', 'Var', (49, 55))	('MCT1', 'Gene', (0, 4))	('IDH1 glioma', 'Disease', 'MESH:D005910', (56, 67))	('lower', 'NegReg', (34, 39))	('BT142', 'Chemical', '-', (43, 48))	('MCT1', 'Gene', '6566', (0, 4))	('IDH1 glioma', 'Disease', (56, 67))
181374	27437179	Following injection of hyperpolarized [1-13C] pyruvate (delta = 172.9 ppm) into the medium of live U87 GBM cells and BT142 mutant IDH1 glioma neurospheres, production of hyperpolarized [1-13C] lactate could be detected at 185 ppm.	('hyperpolarized [1-13C] lactate', 'MPA', (170, 200))	('[1-13C] lactate', 'Chemical', '-', (185, 200))	('[1-13C] pyruvate', 'Chemical', '-', (38, 54))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('IDH1 glioma', 'Disease', 'MESH:D005910', (130, 141))	('BT142', 'Chemical', '-', (117, 122))	('mutant', 'Var', (123, 129))	('IDH1 glioma', 'Disease', (130, 141))
181376	27437179	However, when assessing the ratio of hyperpolarized [1-13C] lactate to pyruvate AUC for each cell type, our analysis showed that the hyperpolarized lactate/pyruvate AUC ratio was significantly lower (97 +- 3%) in mutant IDH1 cells as compared to GBM cells, as shown in Fig.	('rat', 'Species', '10116', (169, 172))	('pyruvate', 'Chemical', 'MESH:D019289', (71, 79))	('lactate', 'Chemical', 'MESH:D019344', (60, 67))	('hyperpolarized lactate/pyruvate AUC ratio', 'MPA', (133, 174))	('rat', 'Species', '10116', (28, 31))	('IDH1', 'Gene', '3417', (220, 224))	('[1-13C] lactate', 'Chemical', '-', (52, 67))	('IDH1', 'Gene', (220, 224))	('pyruvate', 'Chemical', 'MESH:D019289', (156, 164))	('lactate', 'Chemical', 'MESH:D019344', (148, 155))	('lower', 'NegReg', (193, 198))	('mutant', 'Var', (213, 219))
181379	27437179	BT142 mutant IDH1 glioma tumors reached 100 mm3 in 95 +- 12 days post intracranial injection whereas U87 GBM tumors reached the same size at 19 +- 6 days, consistent with the slower growth of lower grade mutant IDH1 tumors compared to GBM in patient data.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('GBM tumors', 'Disease', (105, 115))	('IDH1 tumors', 'Disease', (211, 222))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('glioma tumors', 'Disease', (18, 31))	('GBM tumors', 'Disease', 'MESH:D005910', (105, 115))	('BT142', 'Chemical', '-', (0, 5))	('IDH1 glioma', 'Disease', 'MESH:D005910', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('glioma tumors', 'Disease', 'MESH:D005910', (18, 31))	('BT142', 'Gene', (0, 5))	('patient', 'Species', '9606', (242, 249))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('IDH1 tumors', 'Disease', 'MESH:D009369', (211, 222))	('mutant', 'Var', (6, 12))	('IDH1 glioma', 'Disease', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))
181388	27437179	We therefore wanted to rule out reduced hyperpolarized pyruvate delivery to the tumor as an explanation for the low levels of hyperpolarized lactate production observed in our mutant IDH1 tumor.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IDH1', 'Gene', '3417', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pyruvate delivery to the tumor', 'Disease', 'MESH:D015325', (55, 85))	('mutant', 'Var', (176, 182))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('pyruvate delivery to the tumor', 'Disease', (55, 85))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('lactate', 'Chemical', 'MESH:D019344', (141, 148))	('IDH1', 'Gene', (183, 187))
181392	27437179	Finally, we wanted to assess whether hyperpolarized [1-13C] lactate production, which was previously shown to be altered by TMZ treatment in GBM, would be affected in any way by TMZ treatment in mutant IDH1 tumors.	('TMZ', 'Chemical', 'MESH:D000077204', (124, 127))	('IDH1 tumors', 'Disease', 'MESH:D009369', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('hyperpolarized [1-13C] lactate production', 'MPA', (37, 78))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('[1-13C] lactate', 'Chemical', '-', (52, 67))	('affected', 'Reg', (155, 163))	('TMZ', 'Chemical', 'MESH:D000077204', (178, 181))	('mutant', 'Var', (195, 201))	('IDH1 tumors', 'Disease', (202, 213))
181393	27437179	Our anatomic imaging showed that TMZ treatment induced a significant decrease in tumor size starting at day 14 of treatment, and ultimately led to a complete disappearance of the tumor on the T2-weighted MR images (after day 62, n = 3, Fig.	('TMZ', 'Var', (33, 36))	('disappearance', 'NegReg', (158, 171))	('TMZ', 'Chemical', 'MESH:D000077204', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('decrease', 'NegReg', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (179, 184))
181396	27437179	This study investigated the value of hyperpolarized 13C MRS for detecting mutant IDH1 tumors and their response to treatment.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('IDH1 tumors', 'Disease', 'MESH:D009369', (81, 92))	('13C', 'Chemical', 'MESH:C000615229', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('MRS', 'Gene', (56, 59))	('IDH1 tumors', 'Disease', (81, 92))	('MRS', 'Gene', '148398', (56, 59))	('mutant', 'Var', (74, 80))
181397	27437179	We compared findings from the recently isolated, clinically-derived BT142 grade III mutant IDH1 model, to observations in a previously established primary Grade IV GBM model.	('mutant', 'Var', (84, 90))	('BT142', 'Chemical', '-', (68, 73))	('IDH1', 'Gene', '3417', (91, 95))	('IDH1', 'Gene', (91, 95))
181398	27437179	Unlike pairs of genetically-engineered mutant and wild-type IDH1-expressing cells used in prior studies, this approach precludes a direct comparison between wild-type and mutant IDH1-associated events.	('IDH1', 'Gene', '3417', (178, 182))	('IDH1', 'Gene', (60, 64))	('IDH1', 'Gene', '3417', (60, 64))	('IDH1', 'Gene', (178, 182))	('mutant', 'Var', (171, 177))
181399	27437179	However, it should be noted that an in vivo comparison between genetically engineered mutant and wild-type IDH1-expressing tumors is not straightforward.	('IDH1', 'Gene', (107, 111))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('mutant', 'Var', (86, 92))	('IDH1', 'Gene', '3417', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
181401	27437179	Furthermore, when investigating genetically engineered models, mutant IDH1-associated reprogramming depends on the number of passages that cells have been in culture, also potentially limiting the significance of results.	('mutant', 'Var', (63, 69))	('reprogramming', 'CPA', (86, 99))	('IDH1', 'Gene', '3417', (70, 74))	('limiting', 'NegReg', (184, 192))	('IDH1', 'Gene', (70, 74))
181407	27437179	In contrast, in BT142 mutant IDH1 orthotopic tumors, hyperpolarized [1-13C] lactate production was barely above noise level.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('IDH1', 'Gene', (29, 33))	('BT142', 'Chemical', '-', (16, 21))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('IDH1', 'Gene', '3417', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mutant', 'Var', (22, 28))	('hyperpolarized [1-13C] lactate production', 'MPA', (53, 94))	('[1-13C] lactate', 'Chemical', '-', (68, 83))	('BT142', 'Gene', (16, 21))
181413	27437179	indicating LDHA and MCT4 silencing in mutant IDH1 BT142 gliomas, both in cell lysates and in resected tumor lysates.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', '3417', (45, 49))	('LDHA', 'MPA', (11, 15))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('BT142', 'Gene', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('BT142', 'Chemical', '-', (50, 55))	('MCT4', 'Gene', (20, 24))	('IDH1', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('silencing', 'NegReg', (25, 34))	('MCT4', 'Gene', '9123', (20, 24))
181414	27437179	Additionally, we showed that MCT1 expression was lower in BT142 cell lysates than in U87 cell lysates, also in line with the report by Viswanath et al..	('MCT1', 'Gene', '6566', (29, 33))	('expression', 'MPA', (34, 44))	('BT142', 'Var', (58, 63))	('lower', 'NegReg', (49, 54))	('MCT1', 'Gene', (29, 33))	('BT142', 'Chemical', '-', (58, 63))
181415	27437179	A possible reason for this is that MCT1 levels were only 19 +- 5% lower in BT142 cells than in U87 cells, as compared to > 99% lower for LDHA and MCT4.	('MCT4', 'Gene', (146, 150))	('MCT4', 'Gene', '9123', (146, 150))	('lower', 'NegReg', (66, 71))	('BT142', 'Chemical', '-', (75, 80))	('MCT1', 'Gene', (35, 39))	('BT142', 'Var', (75, 80))	('MCT1', 'Gene', '6566', (35, 39))
181419	27437179	As such, LDHA silencing in mutant IDH1 tumors is entirely consistent with the low level of hyperpolarized [1-13C] lactate detected in perfused cells and tumors in this study.	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('IDH1 tumors', 'Disease', 'MESH:D009369', (34, 45))	('[1-13C] lactate', 'Chemical', '-', (106, 121))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('mutant', 'Var', (27, 33))	('LDHA', 'MPA', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IDH1 tumors', 'Disease', (34, 45))	('tumors', 'Disease', (153, 159))	('silencing', 'NegReg', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', (39, 45))
181421	27437179	Interestingly, elevated expression of MCT4 has been linked to lower hyperpolarized [1-13C] lactate production, through a decreased intracellular lactate pool.	('MCT4', 'Gene', '9123', (38, 42))	('elevated', 'PosReg', (15, 23))	('lactate', 'Chemical', 'MESH:D019344', (91, 98))	('[1-13C] lactate', 'Chemical', '-', (83, 98))	('decreased', 'NegReg', (121, 130))	('intracellular lactate pool', 'MPA', (131, 157))	('lower', 'NegReg', (62, 67))	('hyperpolarized [1-13C] lactate production', 'MPA', (68, 109))	('MCT4', 'Gene', (38, 42))	('expression', 'Var', (24, 34))	('lactate', 'Chemical', 'MESH:D019344', (145, 152))
181426	27437179	Preclinical studies have also shown that intracellular lactate levels are lower in mutant IDH1 expressing cells compared to wild-type.	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (90, 94))	('mutant', 'Var', (83, 89))	('intracellular lactate levels', 'MPA', (41, 69))	('lower', 'NegReg', (74, 79))	('lactate', 'Chemical', 'MESH:D019344', (55, 62))
181431	27437179	We therefore wanted to clearly demonstrate that, unlike in other cancers, hyperpolarized [1-13C] lactate is unlikely to be informative of response in mutant IDH1 gliomas.	('[1-13C] lactate', 'Chemical', '-', (89, 104))	('cancers', 'Disease', (65, 72))	('gliomas', 'Disease', (162, 169))	('hyperpolarized [1-13C] lactate', 'MPA', (74, 104))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('IDH1 glioma', 'Disease', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('rat', 'Species', '10116', (38, 41))	('mutant', 'Var', (150, 156))	('IDH1 glioma', 'Disease', 'MESH:D005910', (157, 168))
181432	27437179	Our study showed that TMZ treatment induced a dramatic shrinkage of mutant IDH1 tumors that was associated with a significant increase in survival.	('IDH1 tumors', 'Disease', 'MESH:D009369', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IDH1 tumors', 'Disease', (75, 86))	('shrinkage', 'NegReg', (55, 64))	('increase', 'PosReg', (126, 134))	('mutant', 'Var', (68, 74))
181433	27437179	This is in line with previous reports of high chemo-sensitivity for mutant IDH1 glioma, and points to the likely relevance of the BT142 model for assessment of therapeutic approaches for mutant IDH1 tumors.	('IDH1 glioma', 'Disease', (75, 86))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('BT142', 'Chemical', '-', (130, 135))	('IDH1 tumors', 'Disease', (194, 205))	('IDH1 glioma', 'Disease', 'MESH:D005910', (75, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutant', 'Var', (68, 74))	('IDH1 tumors', 'Disease', 'MESH:D009369', (194, 205))
181436	27437179	This result not only demonstrates the unique metabolic profile of mutant IDH1 tumors following therapy, but also confirms the need for alternative imaging approaches for early assessment of drug action and for predicting response to TMZ in mutant IDH1 tumors.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('IDH1 tumors', 'Disease', 'MESH:D009369', (247, 258))	('mutant', 'Var', (66, 72))	('IDH1 tumors', 'Disease', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('IDH1 tumors', 'Disease', 'MESH:D009369', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('TMZ', 'Chemical', 'MESH:D000077204', (233, 236))	('rat', 'Species', '10116', (28, 31))	('IDH1 tumors', 'Disease', (247, 258))
181437	27437179	Our results demonstrate that mutant IDH1 gliomas present a highly unusual metabolic imaging profile.	('mutant', 'Var', (29, 35))	('IDH1 glioma', 'Disease', 'MESH:D005910', (36, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('rat', 'Species', '10116', (19, 22))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('IDH1 glioma', 'Disease', (36, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))
181439	27437179	On one hand, this study highlights the limitation of 13C MRS of hyperpolarized [1-13C] pyruvate as a method for detection and monitoring of therapeutic response in mutant IDH1.	('mutant', 'Var', (164, 170))	('MRS', 'Gene', (57, 60))	('MRS', 'Gene', '148398', (57, 60))	('13C', 'Chemical', 'MESH:C000615229', (53, 56))	('13C', 'Chemical', 'MESH:C000615229', (82, 85))	('[1-13C] pyruvate', 'Chemical', '-', (79, 95))	('IDH1', 'Gene', (171, 175))	('IDH1', 'Gene', '3417', (171, 175))
181440	27437179	On the other hand, the absence of elevated hyperpolarized [1-13C] lactate can be viewed as a unique feature of mutant IDH1 gliomas.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('mutant', 'Var', (111, 117))	('[1-13C] lactate', 'Chemical', '-', (58, 73))	('IDH1 glioma', 'Disease', 'MESH:D005910', (118, 129))	('gliomas', 'Disease', (123, 130))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('IDH1 glioma', 'Disease', (118, 129))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('elevated hyperpolarized [1-13C] lactate', 'MPA', (34, 73))
181441	27437179	This imaging strategy could thus be combined with other metabolic imaging approaches such as 1H MRS to detect elevated 2-HG levels, or hyperpolarized 13C MRS to monitor elevated [1-13C] 2-HG and reduced [1-13C] glutamate synthesis and, collectively, these imageable mutant IDH1-associated metabolic alterations that are detectable by MRS could serve to specifically identify mutant IDH1 tumors in patients.	('rat', 'Species', '10116', (303, 306))	('patients', 'Species', '9606', (397, 405))	('IDH1', 'Gene', (382, 386))	('HG', 'Chemical', 'MESH:D008628', (188, 190))	('mutant', 'Var', (375, 381))	('[1-13C] glutamate synthesis', 'MPA', (203, 230))	('IDH1', 'Gene', '3417', (273, 277))	('1-13C', 'Chemical', '-', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('13C', 'Chemical', 'MESH:C000615229', (181, 184))	('IDH1 tumors', 'Disease', 'MESH:D009369', (382, 393))	('MRS', 'Gene', '148398', (154, 157))	('rat', 'Species', '10116', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (387, 393))	('IDH1', 'Gene', '3417', (382, 386))	('HG', 'Chemical', 'MESH:D008628', (121, 123))	('MRS', 'Gene', (154, 157))	('MRS', 'Gene', '148398', (96, 99))	('IDH1 tumors', 'Disease', (382, 393))	('1H', 'Chemical', '-', (93, 95))	('MRS', 'Gene', '148398', (334, 337))	('[1-13C', 'MPA', (178, 184))	('glutamate', 'Chemical', 'MESH:D018698', (211, 220))	('13C', 'Chemical', 'MESH:C000615229', (150, 153))	('IDH1', 'Gene', (273, 277))	('MRS', 'Gene', (96, 99))	('MRS', 'Gene', (334, 337))	('mutant', 'Var', (266, 272))	('13C', 'Chemical', 'MESH:C000615229', (206, 209))	('1-13C', 'Chemical', '-', (204, 209))
181455	26389964	Genetic changes such as EGFR and p53 mutations have been of diagnostic importance but failed to give reliable prognostic or predictive information.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutations', 'Var', (37, 46))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))
181456	26389964	In anaplastic oligodendroglioma, 1p/19q deletions are associated with better response to chemotherapy while loss of heterozygosity (LOH) 10q is shown to be a negative factor.	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('response', 'MPA', (77, 85))	('better', 'PosReg', (70, 76))	('anaplastic oligodendroglioma', 'Disease', (3, 31))	('1p/19q deletions', 'Var', (33, 49))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (3, 31))
181457	26389964	In GBM methylation of the methyl-guanin-methyl transferase (MGMT) promotor has been shown to be a positive predictive factor for temozolomide treatment in GBM.	('temozolomide', 'Chemical', 'MESH:D000077204', (129, 141))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('methylation', 'Var', (7, 18))	('MGMT', 'Gene', (60, 64))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('temozolomide treatment', 'MPA', (129, 151))
181458	26389964	More recently isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) mutations have been associated with a favorable outcome for low grade gliomas in particular but also in GBM.	('IDH2', 'Gene', (54, 58))	('IDH1', 'Gene', '3417', (48, 52))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('IDH2', 'Gene', '3418', (54, 58))	('GBM', 'Phenotype', 'HP:0012174', (164, 167))	('gliomas', 'Disease', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('IDH1', 'Gene', (48, 52))	('associated', 'Reg', (80, 90))	('mutations', 'Var', (60, 69))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
181468	26389964	Investigation of the significance of the detected metabolic patterns by means of orthogonal partial least squares-discriminant analysis (OPLS-DA) showed that it was possible to distinguish between glioblastomas and oligodendrogliomas in both tumor and serum (A = 1 + 0 + 0, R2X = 0.39, R2Y = 0.379, Q2 = 0.341, p = 2.46 x 10-8 and A = 1 + 0 + 0, R2X = 0.25 R2Y = 0.251 Q2 = 0.223, p = 1.3 x 10-5) (Figure 1).	('A = 1 + 0 + 0', 'Var', (331, 344))	('R2Y', 'Mutation', 'p.R2Y', (357, 360))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('R2Y', 'Mutation', 'p.R2Y', (286, 289))	('tumor', 'Disease', (242, 247))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('glioblastomas and oligodendrogliomas', 'Disease', 'MESH:D005909', (197, 233))	('glioblastomas', 'Phenotype', 'HP:0012174', (197, 210))
181479	26389964	Furthermore, we detected a significant association with survival time in serum samples from the same patients in an OPLS-DA model based on five resolved features (A = 1 + 0 + 0, R2X = 0.536, R2Y = 0.572, Q2 = 0.478, p = 0.004; Figure 2).	('patients', 'Species', '9606', (101, 109))	('R2X', 'Var', (178, 181))	('R2Y', 'Var', (191, 194))	('R2Y', 'Mutation', 'p.R2Y', (191, 194))	('survival time', 'CPA', (56, 69))
181481	26389964	In tumor tissue, eight resolved features passed the significance criteria and provided a significant metabolic pattern (OPLS-DA model) in relation to time of survival (A = 1 + 0 + 0, R2X = 0.56, R2Y = 0.796, Q2 = 0.767, p = 0.01; Figure 2).	('metabolic pattern', 'MPA', (101, 118))	('tumor', 'Disease', (3, 8))	('R2Y', 'Mutation', 'p.R2Y', (195, 198))	('R2Y', 'Var', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
181506	26389964	have by repeated MRS in glioma patients undergoing surgery and radiotherapy demonstrated that changes in choline could provide prognostic information.	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('choline', 'MPA', (105, 112))	('MRS', 'Disease', (17, 20))	('patients', 'Species', '9606', (31, 39))	('glioma', 'Disease', (24, 30))	('changes', 'Var', (94, 101))	('choline', 'Chemical', 'MESH:D002794', (105, 112))	('MRS', 'Disease', 'MESH:D008556', (17, 20))
181562	26389964	[13C12]-sucrose, [13C4]-palmitic acid and [2H4]- butanediamine 2HCl were from Campro (Veenendaal, The Netherlands).	('[13C12]-sucrose', 'Var', (0, 15))	('[13C4]-palmitic acid', 'Chemical', '-', (17, 37))	('[13C12]-sucrose', 'Chemical', '-', (0, 15))	('[13C4]-palmitic acid', 'Var', (17, 37))	('Campro', 'Chemical', '-', (78, 84))	('[2H4]- butanediamine 2HCl', 'Chemical', '-', (42, 67))
181587	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
181616	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
181633	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
181650	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('cytolytic levels', 'MPA', (156, 172))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
181675	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
181676	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('PRF1', 'Gene', (188, 192))
181680	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
181681	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('TCGA-UCEC', 'Disease', (242, 251))	('GSE13876', 'Var', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
181682	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('improved', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
181683	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
181686	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
181688	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
181694	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('GSE10846', 'Var', (10, 18))	('PRF1', 'Var', (120, 124))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
181695	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
181733	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
181738	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('patients', 'Species', '9606', (95, 103))	('blockage', 'Var', (56, 64))	('non-small cell lung cancer', 'Disease', (139, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
181746	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
181752	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('enhance', 'PosReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (53, 58))
181766	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
181770	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('viral infection', 'Disease', (183, 198))	('tumor', 'Disease', (212, 217))	('mutations', 'Var', (144, 153))
181777	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('LUAD/LUSC', 'Disease', (163, 172))	('improved', 'PosReg', (109, 117))	('tumor', 'Disease', (8, 13))	('THYM', 'Disease', (157, 161))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
181778	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('GZMA', 'Gene', (90, 94))	('associated', 'Reg', (123, 133))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
181818	26997445	Our results indicate that changes in miR-31 and miR-17-5p reflect the transformation of follicular lymphoma to an aggressive large B-cell lymphoma and may, along with their targets, be viable markers for this process.	('miR-31', 'Gene', '407035', (37, 43))	('follicular lymphoma', 'Disease', 'MESH:D008224', (88, 107))	('changes', 'Var', (26, 33))	('miR-17-5p', 'Gene', '406952', (48, 57))	('lymphoma', 'Disease', (99, 107))	('miR-17-5p', 'Gene', (48, 57))	('lymphoma', 'Disease', 'MESH:D008223', (99, 107))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (131, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('lymphoma', 'Disease', (138, 146))	('lymphoma', 'Disease', 'MESH:D008223', (138, 146))	('miR-31', 'Gene', (37, 43))	('cell lymphoma', 'Phenotype', 'HP:0012191', (133, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))	('follicular lymphoma', 'Disease', (88, 107))
181820	26997445	Translocation of the anti-apoptotic gene BCL2 to the immunoglobulin heavy chain locus IGH, t(14:18) occurs in 85% of cases.	('Translocation', 'Var', (0, 13))	('BCL2', 'Gene', (41, 45))	('IGH', 'Gene', '3492', (86, 89))	('IGH', 'Gene', (86, 89))	('BCL2', 'Gene', '596', (41, 45))
181821	26997445	Additionally, chromosomal rearrangements of the transcriptional repressor BCL6 are present in 5-15% of FL.	('BCL6', 'Gene', '604', (74, 78))	('FL', 'Gene', '100306940', (103, 105))	('present', 'Reg', (83, 90))	('BCL6', 'Gene', (74, 78))	('chromosomal rearrangements', 'Var', (14, 40))
181837	26997445	Diagnostic slides from those patients with biopsies of both low-grade FL and FL3 or DLBCL were reviewed by two hematopathologists (MAT and SM-T).	('MAT', 'Disease', (131, 134))	('patients', 'Species', '9606', (29, 37))	('MAT', 'Disease', 'MESH:C564683', (131, 134))	('FL', 'Gene', '100306940', (70, 72))	('FL', 'Gene', '100306940', (77, 79))	('low-grade', 'Var', (60, 69))
181839	26997445	Only DLBCL with CD10 positivity were included, and DLBCL with cytogenetic documentation of MYC translocation were excluded.	('positivity', 'Var', (21, 31))	('MYC', 'Gene', '4609', (91, 94))	('MYC', 'Gene', (91, 94))	('CD10', 'Gene', (16, 20))	('CD10', 'Gene', '4311', (16, 20))
181852	26997445	FISH probes for the MIR31 locus (chromosome 9p21) and the CDKN2A locus (chromosome 9p22) were prepared by labeling BAC-PAC clones RP11-354P17 and RP11-149I2, respectively, (Children's Hospital and Research Center).	('PAC', 'Phenotype', 'HP:0006699', (119, 122))	('p21', 'Gene', '1026', (45, 48))	('p21', 'Gene', (45, 48))	('RP11-149I2', 'Disease', 'MESH:C563991', (146, 156))	('RP11-354P17', 'Var', (130, 141))	('CDKN2A', 'Gene', (58, 64))	('Children', 'Species', '9606', (173, 181))	('RP11-149I2', 'Disease', (146, 156))	('MIR31', 'Gene', '407035', (20, 25))	('MIR31', 'Gene', (20, 25))	('CDKN2A', 'Gene', '1029', (58, 64))
181853	26997445	DNA was labeled by nick translation (Abbott Laboratories, Des Plaines, IL) using Spectrum Green dUDP for RP11-354P17 (MIR31) and Spectrum Orange dUDP for RP11-149I2 (CDKN2A) following manufacturer's protocol.	('CDKN2A', 'Gene', (166, 172))	('CDKN2A', 'Gene', '1029', (166, 172))	('Spectrum Orange', 'Chemical', 'MESH:C058672', (129, 144))	('MIR31', 'Gene', '407035', (118, 123))	('MIR31', 'Gene', (118, 123))	('dUDP', 'Chemical', '-', (96, 100))	('RP11-354P17', 'Var', (105, 116))	('Spectrum Green', 'Chemical', '-', (81, 95))	('RP11-149I2', 'Disease', 'MESH:C563991', (154, 164))	('dUDP', 'Chemical', '-', (145, 149))	('RP11-149I2', 'Disease', (154, 164))
181882	26997445	Deletions in the CDKN2A and CDKN2B loci encoding the cell cycle inhibitor p15INK4B and the tumor suppressors 16INK4A/p14ARF, respectively are detected in approximately 36% of DLBCL.	('INK4A', 'Gene', '1029', (111, 116))	('p14ARF', 'Gene', '1029', (117, 123))	('detected', 'Reg', (142, 150))	('INK4A', 'Gene', (111, 116))	('DLBCL', 'Disease', (175, 180))	('p15INK4B', 'Gene', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CDKN2A', 'Gene', (17, 23))	('p14ARF', 'Gene', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CDKN2B', 'Gene', (28, 34))	('CDKN2A', 'Gene', '1029', (17, 23))	('p15INK4B', 'Gene', '1030', (74, 82))	('tumor', 'Disease', (91, 96))	('Deletions', 'Var', (0, 9))	('CDKN2B', 'Gene', '1030', (28, 34))
181886	26997445	Deletion of one copy of the CDKN2A/B locus was demonstrated in 3 DLBCL samples (Fig 5B; Table 1).	('CDKN2A/B', 'Gene', (28, 36))	('CDKN2A/B', 'Gene', '1029;1030', (28, 36))	('Deletion', 'Var', (0, 8))
181896	26997445	Alterations in MYC and TP53 are linked to lymphomagenesis.	('MYC', 'Gene', '4609', (15, 18))	('Alterations', 'Var', (0, 11))	('lymphoma', 'Disease', (42, 50))	('MYC', 'Gene', (15, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (42, 50))	('linked', 'Reg', (32, 38))	('lymphoma', 'Disease', 'MESH:D008223', (42, 50))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
181904	26997445	Elevated TP53 protein levels, indicative of mutant TP53 and experimentally defined as TP53 expressed in >=50% of cells, were detected by IHC in eight lymphomas (Table 1).	('lymphomas', 'Phenotype', 'HP:0002665', (150, 159))	('TP53', 'Gene', (51, 55))	('lymphomas', 'Disease', 'MESH:D008223', (150, 159))	('TP53', 'Gene', '7157', (86, 90))	('Elevated', 'PosReg', (0, 8))	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', (9, 13))	('TP53', 'Gene', '7157', (9, 13))	('lymphomas', 'Disease', (150, 159))	('lymphoma', 'Phenotype', 'HP:0002665', (150, 158))	('mutant', 'Var', (44, 50))	('TP53', 'Gene', '7157', (51, 55))
181908	26997445	The data suggest there may be functional links between miR-31 and miR-17-5p and up-regulation of MYC and mutated TP53.	('up-regulation', 'PosReg', (80, 93))	('miR-17-5p', 'Gene', '406952', (66, 75))	('miR-31', 'Gene', (55, 61))	('MYC', 'Gene', (97, 100))	('miR-17-5p', 'Gene', (66, 75))	('TP53', 'Gene', '7157', (113, 117))	('mutated', 'Var', (105, 112))	('MYC', 'Gene', '4609', (97, 100))	('miR-31', 'Gene', '407035', (55, 61))	('TP53', 'Gene', (113, 117))
181909	26997445	The most significant correlation is between miR-17-5p and mutated TP53.	('miR-17-5p', 'Gene', (44, 53))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('significant', 'Reg', (9, 20))	('correlation', 'Interaction', (21, 32))	('miR-17-5p', 'Gene', '406952', (44, 53))	('mutated', 'Var', (58, 65))
181930	26997445	Two of the most common causes for why a miRNA is expressed at lower levels in a cancer are deletion of its gene locus and altered methylation of its promoter.	('deletion', 'Var', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('methylation', 'MPA', (130, 141))	('cancer', 'Disease', (80, 86))	('altered', 'Reg', (122, 129))
181931	26997445	Our FISH data show that the reduction in miR-31 levels is not due to deletion of the MIR31 locus, even when the nearby CDKN2A/B locus was deleted.	('miR-31', 'Gene', (41, 47))	('CDKN2A/B', 'Gene', (119, 127))	('CDKN2A/B', 'Gene', '1029;1030', (119, 127))	('MIR31', 'Gene', '407035', (85, 90))	('MIR31', 'Gene', (85, 90))	('miR-31', 'Gene', '407035', (41, 47))	('deletion', 'Var', (69, 77))	('reduction', 'NegReg', (28, 37))
181933	26997445	In support of this concept, the promoter of MIR31 in breast and prostate cancer has been reported to be hypermethylated or transcriptionally repressed due to methylation of H3K4 or H3K27, leading to reduced miR-31 expression.	('H3K4', 'Protein', (173, 177))	('miR-31', 'Gene', '407035', (207, 213))	('methylation', 'Var', (158, 169))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MIR31', 'Gene', '407035', (44, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))	('miR-31', 'Gene', (207, 213))	('MIR31', 'Gene', (44, 49))	('H3K27', 'Protein', (181, 186))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (53, 79))	('expression', 'MPA', (214, 224))	('reduced', 'NegReg', (199, 206))
181939	26997445	Genome wide copy number analysis showed amplifications at 13q31.3, including the miR-17-92 polycistron, in 7% of FL and 15% of transformed FL cases tested, demonstrating one mechanism for elevated expression.	('FL', 'Gene', '100306940', (113, 115))	('miR-17-92', 'Gene', '407975', (81, 90))	('FL', 'Gene', '100306940', (139, 141))	('miR-17-92', 'Gene', (81, 90))	('amplifications', 'Var', (40, 54))
181964	25424847	Interestingly, high level expression of Survivin was associated with poor prognosis in patients with grade II or III astrocytomas.	('high', 'Var', (15, 19))	('Survivin', 'Protein', (40, 48))	('patients', 'Species', '9606', (87, 95))	('astrocytomas', 'Disease', 'MESH:D001254', (117, 129))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('astrocytomas', 'Disease', (117, 129))	('II astrocytoma', 'Disease', (114, 128))	('II astrocytoma', 'Disease', 'MESH:D001254', (114, 128))	('grade II', 'Disease', (101, 109))
181982	25424847	Batched Ficoll-isolated PBMC samples from each patient were evaluated simultaneously following in vitro stimulation with irradiated autologous dendritic cells loaded with wild-type IL-13Ralpha345-353, EphA2883-891, Survivin96-104, WT1 126-134 and TetA830-845.	('TetA830', 'Chemical', '-', (247, 254))	('patient', 'Species', '9606', (47, 54))	('EphA2', 'Gene', (201, 206))	('TetA830-845', 'Var', (247, 258))	('WT1', 'Gene', '7490', (231, 234))	('EphA2', 'Gene', '1969', (201, 206))	('WT1', 'Gene', (231, 234))
182036	25424847	Our preclinical studies and prior phase I/II clinical study in recurrent WHO grade III/IV HGG patients have indicated that poly-ICLC promotes type-1 polarization of T-cell responses against vaccine-targeted GAAs.	('promotes', 'PosReg', (133, 141))	('T-cell responses', 'CPA', (165, 181))	('poly-ICLC', 'Chemical', 'MESH:C019531', (123, 132))	('type-1 polarization', 'MPA', (142, 161))	('patients', 'Species', '9606', (94, 102))	('GAA', 'Gene', (207, 210))	('GAA', 'Gene', '2548', (207, 210))	('poly-ICLC', 'Var', (123, 132))
182054	25424847	In regard to common genetic mutations and novel immunotherapy targets in LGG, mutations of the isocitrate dehydrogenase (IDH) metabolic enzymes IDH1 and IDH2 have been found to be frequent and early genetic alterations in astrocytomas and oligodendrogliomas.	('IDH2', 'Gene', (153, 157))	('IDH', 'Gene', (144, 147))	('astrocytoma', 'Phenotype', 'HP:0009592', (222, 233))	('IDH', 'Gene', '3417', (144, 147))	('IDH2', 'Gene', '3418', (153, 157))	('isocitrate dehydrogenase', 'Gene', (95, 119))	('IDH', 'Gene', (121, 124))	('mutations', 'Var', (78, 87))	('gliomas', 'Phenotype', 'HP:0009733', (250, 257))	('isocitrate dehydrogenase', 'Gene', '3417', (95, 119))	('IDH', 'Gene', '3417', (121, 124))	('IDH', 'Gene', (153, 156))	('IDH1', 'Gene', (144, 148))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('IDH', 'Gene', '3417', (153, 156))	('IDH1', 'Gene', '3417', (144, 148))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (222, 257))
182055	25424847	Mutation of IDH1 occurs early in glioma progression, with somatic mutations of the R132 residue of IDH1 identified in the majority (>70%) of grades II and III astrocytomas and oligodendrogliomas, as well as in secondary GBMs that develop from these LGG.	('mutations', 'Var', (66, 75))	('II astrocytoma', 'Disease', (156, 170))	('II astrocytoma', 'Disease', 'MESH:D001254', (156, 170))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('IDH1', 'Gene', (12, 16))	('glioma', 'Disease', (33, 39))	('identified', 'Reg', (104, 114))	('glioma', 'Disease', (187, 193))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('astrocytoma', 'Phenotype', 'HP:0009592', (159, 170))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (159, 194))	('IDH1', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (12, 16))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('IDH1', 'Gene', '3417', (99, 103))
182056	25424847	It has been recently reported that the IDH1(R132H) mutation contains an immunogenic epitope suitable for mutation-specific vaccination in the context of major histocompatibility complexes (MHC) class II.	('R132H', 'SUBSTITUTION', 'None', (44, 49))	('IDH1', 'Gene', (39, 43))	('R132H', 'Var', (44, 49))
182067	20593220	However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB).	('astrocytoma', 'Disease', 'MESH:D001254', (166, 177))	('astrocytoma', 'Disease', (166, 177))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (155, 177))	('MGMT', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (79, 83))	('AII', 'Gene', '114548', (147, 150))	('AII', 'Gene', '114548', (179, 182))	('GB', 'Phenotype', 'HP:0012174', (214, 216))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('AII', 'Gene', (147, 150))	('AII', 'Gene', (179, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (199, 211))	('mutations', 'Var', (84, 93))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('MGMT', 'Gene', '4255', (51, 55))	('anaplastic astrocytoma', 'Disease', (155, 177))	('TP53', 'Gene', (79, 83))	('glioblastoma', 'Disease', (199, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (199, 211))	('astrocytoma', 'Disease', 'MESH:D001254', (134, 145))	('astrocytoma', 'Disease', (134, 145))
182068	20593220	In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations.	('malignancy', 'Disease', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('patients', 'Species', '9606', (39, 47))	('TP53', 'Gene', (233, 237))	('astrocytic tumors', 'Disease', (53, 70))	('mutations', 'Var', (238, 247))	('MGMT', 'Gene', (198, 202))	('MGMT', 'Gene', '4255', (198, 202))	('astrocytic tumors', 'Disease', 'MESH:D001254', (53, 70))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (53, 69))	('malignancy', 'Disease', 'MESH:D009369', (133, 143))	('TP53', 'Gene', '7157', (233, 237))
182071	20593220	It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time.	('mutations', 'Var', (58, 67))	('MGMT', 'Gene', (18, 22))	('MGMT', 'Gene', '4255', (18, 22))	('astrocytomas', 'Disease', 'MESH:D001254', (125, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('astrocytomas', 'Disease', (125, 137))
182072	20593220	No correlation was found between MGMT methylation status and the presence of TP53 mutations.	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (33, 37))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
182073	20593220	In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations.	('MGMT', 'Gene', (46, 50))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('MGMT', 'Gene', '4255', (46, 50))	('mutations', 'Var', (98, 107))
182081	20593220	Mutations in the TP53 gene have been reported as early and frequent events in sGB and their precursor lesions whereas de-novo primary glioblastomas reportedly lack TP53 mutations or acquire them late in tumorigenesis.	('TP53', 'Gene', '7157', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('TP53', 'Gene', (164, 168))	('glioblastomas', 'Phenotype', 'HP:0012174', (134, 147))	('GB', 'Phenotype', 'HP:0012174', (79, 81))	('lack', 'NegReg', (159, 163))	('glioblastomas', 'Disease', 'MESH:D005909', (134, 147))	('Mutations', 'Var', (0, 9))	('sGB', 'Disease', (78, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('glioblastomas', 'Disease', (134, 147))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
182082	20593220	However, the presence of TP53 mutations in the progression of AII to AIII and sGB has mostly been determined in investigations of series of astrocytic tumors with different grades of malignancy without following individual tumors for their tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('AII', 'Gene', (62, 65))	('tumors', 'Disease', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('AII', 'Gene', '114548', (69, 72))	('malignancy', 'Disease', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (240, 245))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Disease', (151, 157))	('AII', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('TP53', 'Gene', (25, 29))	('tumor', 'Disease', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('GB', 'Phenotype', 'HP:0012174', (79, 81))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('astrocytic tumors', 'Disease', (140, 157))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('astrocytic tumors', 'Disease', 'MESH:D001254', (140, 157))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (140, 156))	('AII', 'Gene', '114548', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', (151, 156))	('malignancy', 'Disease', 'MESH:D009369', (183, 193))	('TP53', 'Gene', '7157', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
182083	20593220	In some but not all studies on AII, the TP53 mutation was found to be an independent unfavorable predictor of survival and/or malignant transformation.	('AII', 'Gene', '114548', (31, 34))	('AII', 'Gene', (31, 34))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('survival', 'CPA', (110, 118))	('TP53', 'Gene', (40, 44))	('malignant transformation', 'CPA', (126, 150))
182084	20593220	Other genetic aberrations in the TP53 pathway, for example MDM2 amplification and p14ARF deletion or hypermethylation are also frequently observed in low-grade diffuse astrocytomas.	('observed', 'Reg', (138, 146))	('p14ARF', 'Gene', (82, 88))	('astrocytomas', 'Disease', 'MESH:D001254', (168, 180))	('amplification', 'Var', (64, 77))	('hypermethylation', 'Var', (101, 117))	('MDM2', 'Gene', '4193', (59, 63))	('TP53', 'Gene', '7157', (33, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (168, 179))	('MDM2', 'Gene', (59, 63))	('deletion', 'Var', (89, 97))	('astrocytomas', 'Disease', (168, 180))	('TP53', 'Gene', (33, 37))	('p14ARF', 'Gene', '1029', (82, 88))
182085	20593220	Over the last decade, epigenetic silencing of the O6-methylguanine-methyltransferase (MGMT) gene by promoter hypermethylation has been found to be associated with chemosensitivity of a variety of tumor types, including gliomas.	('MGMT', 'Gene', (86, 90))	('tumor', 'Disease', (196, 201))	('associated', 'Reg', (147, 157))	('MGMT', 'Gene', '4255', (86, 90))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('O6-methylguanine-methyltransferase', 'Gene', '4255', (50, 84))	('epigenetic silencing', 'Var', (22, 42))	('gliomas', 'Disease', (219, 226))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('O6-methylguanine-methyltransferase', 'Gene', (50, 84))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
182089	20593220	High-grade gliomas, in particular glioblastomas, with hypermethylated MGMT promoters proved to be more sensitive to chemotherapeutic agents, including temozolomide (TMZ), resulting in an overall survival benefit for these patients.	('more', 'PosReg', (98, 102))	('MGMT', 'Gene', (70, 74))	('temozolomide', 'Chemical', 'MESH:D000077204', (151, 163))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('hypermethylated', 'Var', (54, 69))	('MGMT', 'Gene', '4255', (70, 74))	('patients', 'Species', '9606', (222, 230))	('particular glioblastomas', 'Disease', 'MESH:D005909', (23, 47))	('sensitive', 'MPA', (103, 112))	('particular glioblastomas', 'Disease', (23, 47))	('benefit', 'PosReg', (204, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
182091	20593220	In several reports an association between MGMT promoter hypermethylation and an increased frequency of TP53 mutations, with predominance of G>A or C>T transitions (G:C>A:T transition mutations), especially at CpG sites, has been mentioned.	('MGMT', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (103, 107))	('MGMT', 'Gene', '4255', (42, 46))	('mutations', 'Var', (108, 117))	('TP53', 'Gene', (103, 107))	('G>A', 'Var', (140, 143))	('C>T transitions', 'Var', (147, 162))
182092	20593220	Further, in a recent population-based study of glioblastomas a higher frequency of TP53 G:C>A:T transition mutations in tumors with MGMT promoter hypermethylation (25%) than in glioblastomas without MGMT methylation (16%, P = 0.0385) was reported.	('tumors', 'Disease', (120, 126))	('glioblastomas', 'Disease', 'MESH:D005909', (177, 190))	('MGMT', 'Gene', (132, 136))	('glioblastomas', 'Disease', (47, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('MGMT', 'Gene', '4255', (199, 203))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('glioblastomas', 'Disease', 'MESH:D005909', (47, 60))	('TP53', 'Gene', (83, 87))	('glioblastomas', 'Phenotype', 'HP:0012174', (177, 190))	('G:C>A:T transition mutations', 'Var', (88, 116))	('MGMT', 'Gene', '4255', (132, 136))	('MGMT', 'Gene', (199, 203))	('TP53', 'Gene', '7157', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (107, 116))	('glioblastomas', 'Phenotype', 'HP:0012174', (47, 60))	('glioblastomas', 'Disease', (177, 190))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('promoter hypermethylation', 'Var', (137, 162))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
182094	20593220	The objective of this study was to investigate the association of MGMT promoter methylation status and TP53 mutations and to determine the consistency of these molecular characteristics over time, in a series of diffuse astrocytomas and their recurrences.	('TP53', 'Gene', '7157', (103, 107))	('MGMT', 'Gene', (66, 70))	('mutations', 'Var', (108, 117))	('MGMT', 'Gene', '4255', (66, 70))	('astrocytomas', 'Disease', 'MESH:D001254', (220, 232))	('TP53', 'Gene', (103, 107))	('association', 'Interaction', (51, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (220, 231))	('astrocytomas', 'Disease', (220, 232))
182108	20593220	The probe mix was developed to detect CpG island methylation of six mismatch repair genes and includes three specific probes for semiquantitative hypermethylation detection of the MGMT promoter region.	('detect', 'Reg', (31, 37))	('mismatch repair genes', 'Gene', (68, 89))	('MGMT', 'Gene', '4255', (180, 184))	('MGMT', 'Gene', (180, 184))	('methylation', 'Var', (49, 60))
182113	20593220	This probe is located within the widely used CpG island region for MGMT promoter hypermethylation detection by methylation-specific PCR (MS-PCR), and hypermethylation of this region has been found to be an independent predictor of the response of gliomas to TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (258, 261))	('MGMT', 'Gene', '4255', (67, 71))	('MGMT', 'Gene', (67, 71))	('gliomas', 'Disease', (247, 254))	('hypermethylation', 'Var', (150, 166))	('gliomas', 'Disease', 'MESH:D005910', (247, 254))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))
182118	20593220	Tumor samples from each patient were screened for TP53 mutations in exons 4-9, including intron-exon boundaries, by polymerase chain reaction (PCR) followed by bi-directional direct DNA sequencing using the M13-tailed primer method.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (55, 64))	('TP53', 'Gene', '7157', (50, 54))	('patient', 'Species', '9606', (24, 31))	('TP53', 'Gene', (50, 54))
182128	20593220	Although the DO-7 antibody binds to both normal and mutant p53 protein, in general, normal levels of wild-type p53 protein are too low to be detected by immunohistochemistry.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutant', 'Var', (52, 58))	('protein', 'Protein', (63, 70))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))
182129	20593220	After molecular investigation of the 27 cases of paired primary tumors and recurrences (Table 1, cases 18-44) four cases with different TP53 mutations and/or reverse LOH patterns were regarded as two clonally independent entities (cases 18, 34, 36, and 44).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (141, 150))	('primary tumors', 'Disease', (56, 70))	('primary tumors', 'Disease', 'MESH:D009369', (56, 70))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))
182130	20593220	The strongest indication of clonally independent entities is the finding of specific molecular aberrations in the primary tumors which are not found in the recurrences.	('primary tumors', 'Disease', 'MESH:D009369', (114, 128))	('molecular aberrations', 'Var', (85, 106))	('primary tumors', 'Disease', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
182149	20593220	There was no relationship between tumor grade (viz., AII, AIII or sGB) and methylation status (53% vs. 64% vs. 56% hypermethylated, respectively).	('AII', 'Gene', (58, 61))	('hypermethylated', 'Var', (115, 130))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('AII', 'Gene', '114548', (58, 61))	('AIII or sGB', 'Gene', (58, 69))	('AIII or sGB', 'Gene', '2719', (58, 69))	('GB', 'Phenotype', 'HP:0012174', (67, 69))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('AII', 'Gene', '114548', (53, 56))	('AII', 'Gene', (53, 56))
182151	20593220	In 18 of 20 cases (90%), primary and recurrent tumors had a similar MGMT promoter methylation status (nine tumor pairs hypermethylated; nine tumor pairs not methylated).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('hypermethylated', 'Var', (119, 134))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('MGMT', 'Gene', '4255', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MGMT', 'Gene', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))
182156	20593220	TP53 mutation analysis revealed mutations in 40 of the 52 (77%) independent cases.	('TP53', 'Gene', '7157', (0, 4))	('mutations', 'Var', (32, 41))	('TP53', 'Gene', (0, 4))	('revealed', 'Reg', (23, 31))
182158	20593220	TP53 mutations were detected in 28 of 41 (68%) tumors with histological diagnosis of AII, in 10 of 10 (100%) AIII, and in 13 of 18 (72%) GB (Table 1).	('detected', 'Reg', (20, 28))	('AII', 'Gene', (85, 88))	('tumors', 'Disease', (47, 53))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('GB', 'Phenotype', 'HP:0012174', (137, 139))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('AII', 'Gene', '114548', (109, 112))	('AII', 'Gene', (109, 112))	('AII', 'Gene', '114548', (85, 88))
182159	20593220	Mutation of TP53 was found in 17 of 23 (74%) tumor pairs (primary tumors and their recurrences) regarded as clonally related.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('primary tumors', 'Disease', (58, 72))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (45, 50))	('Mutation', 'Var', (0, 8))	('primary tumors', 'Disease', 'MESH:D009369', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('TP53', 'Gene', '7157', (12, 16))	('found', 'Reg', (21, 26))	('TP53', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
182160	20593220	In three of these 17 tumor pairs two different TP53 mutations in the same tumor sample were detected and these mutations all remained present in the recurrent tumors.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (74, 79))	('TP53', 'Gene', '7157', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('TP53', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
182161	20593220	Two tumor pairs had TP53 mutations in the recurrent tumors only, and in one case TP53 mutation was only found in the primary tumor.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('TP53', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
182164	20593220	A total of 45 TP53 mutations were detected in 40 of 55 independent tumors.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
182167	20593220	Of all the TP53 mutations identified in independent cases, 20 of 45 (44%) were G:C>A:T transition mutations; of these, 18 of 20 (90%) were located at CpG sites.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))
182168	20593220	The two G:C>A:T transition mutations that were not located at CpG sites were found in exon 9, the exon of TP53 without CpG sites.	('mutations', 'Var', (27, 36))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
182169	20593220	Positive immunohistochemistry for p53 was associated with either mutation of the TP53 gene (Fisher's exact test, P = 0.02) or LOH of the TP53 locus (Fisher's exact test, P = 0.02) or both (Fisher's exact test, P < 0.001).	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('LOH', 'Var', (126, 129))	('mutation', 'Var', (65, 73))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('TP53', 'Gene', (137, 141))
182171	20593220	The remaining three samples without p53 expression had TP53 frameshift mutations and, in accordance with this type of mutation, p53 expression was absent.	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('frameshift mutations', 'Var', (60, 80))
182173	20593220	In 38 of 48 (78%) tumors with a single TP53 mutation, LOH of the TP53 locus was found.	('TP53', 'Gene', '7157', (65, 69))	('mutation', 'Var', (44, 52))	('TP53', 'Gene', (65, 69))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
182174	20593220	In all tumors in which two TP53 mutations were found, no allelic loss on 17p13 was observed.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
182175	20593220	LOH of the TP53 locus was found in five out of 13 (38%) AII without TP53 mutation and in four out of seven (57%) recurrent tumors without TP53 mutation.	('tumors', 'Disease', (123, 129))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('TP53', 'Gene', (138, 142))	('AII', 'Gene', (56, 59))	('AII', 'Gene', '114548', (56, 59))	('TP53', 'Gene', '7157', (68, 72))	('mutation', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
182177	20593220	Further, reverse allelic loss of the primary and recurrent tumor was detected in three patients.	('allelic loss', 'Var', (17, 29))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
182178	20593220	One of these had a different mutation in each tumor whereas two patients had a mutation in only one of the tumor pairs.	('mutation', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
182180	20593220	In addition, there was no significant correlation between MGMT promoter hypermethylation and the presence of G:C>A:T transition mutations in TP53.	('MGMT', 'Gene', '4255', (58, 62))	('MGMT', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('G:C>A:T transition', 'Var', (109, 127))
182181	20593220	G:C>A:T transition mutations were found in 10 of 21 (48%) independent tumors with a hypermethylated MGMT promoter and a TP53 mutation, and in nine of 16 (56%) MGMT promoter unmethylated tumors with a TP53 mutation (Fisher's exact test, P = 0.80; Table 3).	('TP53', 'Gene', '7157', (200, 204))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('found', 'Reg', (34, 39))	('TP53', 'Gene', '7157', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('MGMT', 'Gene', '4255', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (70, 76))	('MGMT', 'Gene', '4255', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('TP53', 'Gene', (200, 204))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (186, 192))	('TP53', 'Gene', (120, 124))	('MGMT', 'Gene', (159, 163))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('mutation', 'Var', (125, 133))	('MGMT', 'Gene', (100, 104))
182182	20593220	In this study we demonstrated that MGMT promoter hypermethylation and TP53 aberrations are early and frequent events in the progression of astrocytomas and that both are largely consistent over time.	('astrocytomas', 'Disease', (139, 151))	('TP53', 'Gene', '7157', (70, 74))	('MGMT', 'Gene', (35, 39))	('MGMT', 'Gene', '4255', (35, 39))	('TP53', 'Gene', (70, 74))	('aberrations', 'Var', (75, 86))	('astrocytomas', 'Disease', 'MESH:D001254', (139, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (139, 150))
182184	20593220	These results argue against the putative TP53 G:C>A:T transition mutations which have been suggested to occur preferentially in MGMT hypermethylated tumors.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('G:C>A:T', 'Var', (46, 53))	('MGMT hypermethylated tumors', 'Disease', 'MESH:D009369', (128, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('MGMT hypermethylated tumors', 'Disease', (128, 155))
182193	20593220	MGMT methylation status changed in 37% of the patients and more frequently in methylated than in unmethylated tumors.	('MGMT', 'Gene', (0, 4))	('changed', 'Reg', (24, 31))	('patients', 'Species', '9606', (46, 54))	('methylated', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('methylation status', 'MPA', (5, 23))	('MGMT', 'Gene', '4255', (0, 4))
182198	20593220	The high percentage of mutations of TP53 (77%) detected in the astrocytic tumors in this study is in accordance with the highest frequencies reported in the literature.	('astrocytic tumor', 'Phenotype', 'HP:0009592', (63, 79))	('astrocytic tumors', 'Disease', 'MESH:D001254', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TP53', 'Gene', '7157', (36, 40))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', (36, 40))	('astrocytic tumors', 'Disease', (63, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
182200	20593220	Significant correlation between p53 expression, TP53 mutations, and TP53 locus LOH was shown in other studies.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('expression', 'MPA', (36, 46))
182201	20593220	In 13 cases with high p53 expression and/or LOH of chromosome 17p13 no TP53 mutations were detected.	('expression', 'MPA', (26, 36))	('LOH', 'Var', (44, 47))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
182202	20593220	This may be the result of intratumoral heterogeneity of TP53 gene mutations or TP53 mutations escaping detection by our sequencing method (especially in cases without detected LOH, probably because of admixture of normal DNA).	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (56, 60))	('tumor', 'Disease', (31, 36))	('TP53', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
182203	20593220	Yet another explanation may be that TP53 mutations were located outside the investigated region of the gene (especially in cases with LOH).	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
182204	20593220	In ten cases a single TP53 mutation was detected without concomitant TP53 locus LOH.	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('mutation', 'Var', (27, 35))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
182206	20593220	In addition, TP53 LOH could be absent because of the presence of a dominant-negative TP53 mutation in the tumors without concomitant loss of the wild type allele.	('TP53', 'Gene', (85, 89))	('TP53', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TP53', 'Gene', '7157', (85, 89))	('TP53', 'Gene', '7157', (13, 17))	('mutation', 'Var', (90, 98))
182207	20593220	In five cases two TP53 mutations were found and in all eight tumor samples from these cases no LOH of the TP53 locus was observed, which is more supportive of monoclonal tumor cell populations with bi-allelic TP53 mutations than of dual clonality.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', (209, 213))	('TP53', 'Gene', '7157', (18, 22))	('monoclonal tumor', 'Disease', 'MESH:D010265', (159, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('monoclonal tumor', 'Disease', (159, 175))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TP53', 'Gene', '7157', (209, 213))	('TP53', 'Gene', '7157', (106, 110))	('tumor', 'Disease', (61, 66))	('TP53', 'Gene', (106, 110))
182208	20593220	TP53 mutations are consistent during astrocytoma progression, because we demonstrate identical TP53 mutation and TP53 locus LOH status in 21 of 27 investigated pairs of primary tumor and recurrence, indicating clonal relationships between these tumor pairs.	('tumor', 'Disease', (177, 182))	('TP53', 'Gene', '7157', (0, 4))	('astrocytoma', 'Phenotype', 'HP:0009592', (37, 48))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('mutation', 'Var', (100, 108))	('TP53', 'Gene', '7157', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('astrocytoma', 'Disease', 'MESH:D001254', (37, 48))	('tumor', 'Disease', (245, 250))	('LOH', 'NegReg', (124, 127))	('astrocytoma', 'Disease', (37, 48))	('TP53', 'Gene', (113, 117))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
182212	20593220	In four of 27 (15%) patients differences in TP53 mutation and TP53 LOH between the primary tumors and recurrences were unequivocally found.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('TP53', 'Gene', '7157', (62, 66))	('primary tumors', 'Disease', (83, 97))	('TP53', 'Gene', (62, 66))	('primary tumors', 'Disease', 'MESH:D009369', (83, 97))	('mutation', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (20, 28))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('LOH', 'NegReg', (67, 70))
182214	20593220	Intratumoral heterogeneity for TP53 aberrations has been described previously for astrocytic brain tumors and in the setting of systemic metastasis of glioblastomas.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (99, 104))	('glioblastomas', 'Disease', 'MESH:D005909', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('glioblastomas', 'Phenotype', 'HP:0012174', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('described', 'Reg', (57, 66))	('aberrations', 'Var', (36, 47))	('astrocytic brain tumors', 'Disease', (82, 105))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (93, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('astrocytic brain tumors', 'Disease', 'MESH:D001254', (82, 105))	('glioblastomas', 'Disease', (151, 164))
182217	20593220	In addition, in cases 34 and 44 (Table 1) the TP53 mutation identified in the primary tumor was not found in the recurrence and, vice versa, the mutation detected in the recurrence was not present in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('TP53', 'Gene', '7157', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (212, 217))
182220	20593220	Thirteen of the 23 clonally related pairs of primary tumor and recurrence demonstrated histologically confirmed malignant progression and all cases were consistent with regard to TP53 aberrations (mutation, LOH and p53 expression).	('expression', 'MPA', (219, 229))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('p53', 'Gene', (215, 218))	('malignant progression', 'CPA', (112, 133))	('p53', 'Gene', '7157', (215, 218))	('TP53', 'Gene', '7157', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('LOH', 'Var', (207, 210))	('TP53', 'Gene', (179, 183))
182224	20593220	Methylation of the MGMT promoter, and thus absence of AGT expression in gliomas reportedly correlates with G:C>A:T transition mutations of TP53, in particular at CpG sites.	('absence', 'NegReg', (43, 50))	('Methylation', 'MPA', (0, 11))	('expression', 'MPA', (58, 68))	('AGT', 'Gene', (54, 57))	('MGMT', 'Gene', '4255', (19, 23))	('TP53', 'Gene', '7157', (139, 143))	('MGMT', 'Gene', (19, 23))	('G:C>A:T transition mutations', 'Var', (107, 135))	('TP53', 'Gene', (139, 143))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
182225	20593220	The mechanism of the preferential occurrence of these mutations may be related to the cytosine methylation-enhanced formation of adducts at methylated CpG sites.	('adducts', 'Interaction', (129, 136))	('mutations', 'Var', (54, 63))	('cytosine methylation-enhanced', 'MPA', (86, 115))	('formation of', 'MPA', (116, 128))	('cytosine', 'Chemical', 'MESH:D003596', (86, 94))
182227	20593220	Accordingly, inactivation of MGMT gene expression causes retention of the methylated adducts at the O6 position of guanine.	('methylated adducts', 'MPA', (74, 92))	('inactivation', 'Var', (13, 25))	('MGMT', 'Gene', '4255', (29, 33))	('MGMT', 'Gene', (29, 33))	('retention', 'MPA', (57, 66))	('guanine', 'Chemical', 'MESH:D006147', (115, 122))
182229	20593220	During DNA replication thymine is incorporated and subsequently a G:C to A:T transition mutation may originate at that spot.	('thymine', 'Chemical', 'MESH:D013941', (23, 30))	('originate', 'Reg', (101, 110))	('G:C to A:T', 'Var', (66, 76))
182230	20593220	This would support the relationship between epigenetic inactivation of MGMT and accumulation of this mutation in TP53 at CpG sites.	('epigenetic inactivation', 'Var', (44, 67))	('TP53', 'Gene', '7157', (113, 117))	('MGMT', 'Gene', '4255', (71, 75))	('MGMT', 'Gene', (71, 75))	('TP53', 'Gene', (113, 117))
182231	20593220	However, we neither found a significant correlation between MGMT hypermethylation and TP53 mutation, nor a correlation between MGMT hypermethylation and specific TP53 G:C>A:T transition mutations.	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('MGMT', 'Gene', (60, 64))	('TP53', 'Gene', (86, 90))	('MGMT', 'Gene', '4255', (60, 64))	('G:C>A:T', 'Var', (167, 174))	('MGMT', 'Gene', (127, 131))	('MGMT', 'Gene', '4255', (127, 131))
182232	20593220	found a significantly higher frequency of TP53 G:C>A:T transition mutations in MGMT promoter hypermethylated glioblastomas, whereas the total frequency of TP53 mutations in MGMT promoter hypermethylated and unmethylated glioblastomas was similar.	('mutations', 'Var', (66, 75))	('glioblastomas', 'Phenotype', 'HP:0012174', (109, 122))	('TP53', 'Gene', '7157', (42, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (220, 232))	('MGMT', 'Gene', (173, 177))	('glioblastomas', 'Disease', (220, 233))	('MGMT', 'Gene', '4255', (79, 83))	('higher', 'PosReg', (22, 28))	('TP53', 'Gene', (155, 159))	('glioblastomas', 'Disease', 'MESH:D005909', (220, 233))	('glioblastomas', 'Disease', (109, 122))	('glioblastomas', 'Disease', 'MESH:D005909', (109, 122))	('TP53', 'Gene', (42, 46))	('MGMT', 'Gene', '4255', (173, 177))	('MGMT', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (155, 159))	('glioblastomas', 'Phenotype', 'HP:0012174', (220, 233))	('hypermethylated', 'Var', (93, 108))
182234	20593220	However, in colorectal tumorigenesis and gastric cancer inactivation of MGMT by promoter hypermethylation seemed to be associated with G>A mutations in K-ras.	('K-ras', 'Gene', (152, 157))	('gastric cancer', 'Disease', (41, 55))	('G>A mutations', 'Var', (135, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))	('MGMT', 'Gene', '4255', (72, 76))	('inactivation', 'NegReg', (56, 68))	('K-ras', 'Gene', '3845', (152, 157))	('MGMT', 'Gene', (72, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('colorectal tumorigenesis', 'Disease', 'MESH:D015179', (12, 36))	('colorectal tumorigenesis', 'Disease', (12, 36))	('associated', 'Reg', (119, 129))
182235	20593220	recently reported no correlation between methylation of the MGMT promoter and G:C>A:T TP53 mutations in a series of 32 primary glioblastomas treated with radiotherapy and surgery.	('TP53', 'Gene', '7157', (86, 90))	('glioblastomas', 'Phenotype', 'HP:0012174', (127, 140))	('MGMT', 'Gene', (60, 64))	('TP53', 'Gene', (86, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('mutations', 'Var', (91, 100))	('glioblastomas', 'Disease', 'MESH:D005909', (127, 140))	('MGMT', 'Gene', '4255', (60, 64))	('glioblastomas', 'Disease', (127, 140))
182236	20593220	Future studies may reveal whether the specific methylation of MGMT is representative of a generalized status of genomic methylation and whether there is a gene-specificity of the G:C>A:T transition mutations.	('G:C>A:T', 'Var', (179, 186))	('MGMT', 'Gene', (62, 66))	('MGMT', 'Gene', '4255', (62, 66))
182243	18829483	An inhibitor toJAK2/STAT3, JSI-124, significantly reduced expression of STAT3 target genes, suppressed cancer cell growth, and induced apoptosis.	('apoptosis', 'CPA', (135, 144))	('JSI-124', 'Var', (27, 34))	('suppressed', 'NegReg', (92, 102))	('expression', 'Species', '29278', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (58, 68))	('JAK2', 'Gene', (15, 19))	('JAK2', 'Gene', '3717', (15, 19))	('JSI-124', 'Chemical', 'MESH:C038106', (27, 34))	('reduced', 'NegReg', (50, 57))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('induced', 'PosReg', (127, 134))
182246	18829483	JSI-124 also sensitized malignant glioma and medulloblastoma cells to temozolomide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and cisplatin in which a synergism existed between JSI-124 and cisplatin.	('sensitized', 'Reg', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('JSI-124', 'Gene', (173, 180))	('JSI-124', 'Chemical', 'MESH:C038106', (173, 180))	('1,3-bis(2-chloroethyl)-1-nitrosourea', 'Chemical', 'MESH:D002330', (84, 120))	('medulloblastoma', 'Disease', 'MESH:D008527', (45, 60))	('JSI-124', 'Chemical', 'MESH:C038106', (0, 7))	('medulloblastoma', 'Phenotype', 'HP:0002885', (45, 60))	('temozolomide', 'Chemical', 'MESH:D000077204', (70, 82))	('malignant glioma', 'Disease', 'MESH:D005910', (24, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('JSI-124', 'Var', (0, 7))	('malignant glioma', 'Disease', (24, 40))	('medulloblastoma', 'Disease', (45, 60))
182247	18829483	STAT3 constitutive activation, alone and in concurrence with EGFR expression, plays an important role in high-grade/malignant gliomas and targeting STAT3/JAK2 sensitizes these tumors to anti-EGFR and alkylating agents.	('sensitizes', 'Reg', (159, 169))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('malignant gliomas', 'Disease', 'MESH:D005910', (116, 133))	('JAK2', 'Gene', '3717', (154, 158))	('expression', 'Species', '29278', (66, 76))	('activation', 'PosReg', (19, 29))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('targeting', 'Var', (138, 147))	('JAK2', 'Gene', (154, 158))	('EGFR', 'Gene', '1956', (61, 65))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('malignant gliomas', 'Disease', (116, 133))	('EGFR', 'Gene', (61, 65))
182271	18829483	EGFRvIII is a product of rearrangement with an in-frame deletion of 801 bp of the coding sequence of the extracellular domain, resulting in a deletion of residues 6 to 273 and a glycine insertion as residue 6.	('deletion', 'Var', (142, 150))	('glycine', 'Chemical', 'MESH:D005998', (178, 185))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
182274	18829483	The efficacy of anti-EGFR small-molecule inhibitors and monoclonal antibodies in treating glioma patients has been evaluated in clinical trials as single agent and in combination with other chemotherapeutic agents but showed only modest effects.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('glioma', 'Disease', (90, 96))	('small-molecule', 'Var', (26, 40))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('patients', 'Species', '9606', (97, 105))
182277	18829483	Nevertheless, PTEN mutation and deregulated phosphatidylinositol 3-kinase pathway have been shown to correlate positively with resistance of GBM patients to EGFR inhibitors.	('patients', 'Species', '9606', (145, 153))	('EGFR', 'Gene', (157, 161))	('PTEN', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('PTEN', 'Gene', '5728', (14, 18))	('deregulated', 'Reg', (32, 43))	('EGFR', 'Gene', '1956', (157, 161))	('resistance', 'MPA', (127, 137))	('phosphatidylinositol 3-kinase pathway', 'Pathway', (44, 81))
182279	18829483	On the cell surface, activated EGFR recruits and phosphorylates STAT3 at Y705, and in turn, phosphorylated STAT3 (p-STAT3) enters the nucleus to activate expression of several cancer-related genes.	('expression', 'Species', '29278', (154, 164))	('Y705', 'Var', (73, 77))	('EGFR', 'Gene', '1956', (31, 35))	('p-STAT3', 'Gene', (114, 121))	('EGFR', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('p-STAT3', 'Gene', '6774', (114, 121))	('activate', 'PosReg', (145, 153))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('expression', 'MPA', (154, 164))
182286	18829483	Together, these findings revealed that deregulated EGFR and STAT3 pathways significantly cross-talk at multilevels, leading to more aggressive tumor behaviors.	('EGFR', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('more', 'PosReg', (127, 131))	('deregulated', 'Var', (39, 50))	('aggressive tumor behaviors', 'Disease', (132, 158))	('cross-talk', 'Reg', (89, 99))	('STAT3 pathways', 'Pathway', (60, 74))	('aggressive tumor behaviors', 'Disease', 'MESH:D001523', (132, 158))	('leading to', 'Reg', (116, 126))	('EGFR', 'Gene', '1956', (51, 55))
182289	18829483	These findings prompted us to examine whether inhibition of STAT3 alone led to medulloblastoma and malignant glioma cell death.	('medulloblastoma', 'Disease', (79, 94))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('inhibition', 'Var', (46, 56))	('malignant glioma cell death', 'Disease', (99, 126))	('medulloblastoma', 'Disease', 'MESH:D008527', (79, 94))	('medulloblastoma', 'Phenotype', 'HP:0002885', (79, 94))	('STAT3', 'Gene', (60, 65))	('malignant glioma cell death', 'Disease', 'MESH:D005910', (99, 126))
182291	18829483	Finally, we addressed whether inhibitors to EGFR and JAK2/STAT3 synergistically targeted EGFR- and EGFRvIII-expressing human GBM cells and if the anti-JAK2/STAT3 agent sensitized malignant glioma and medulloblastoma cells to clinically used chemotherapeutic agents, such as DNA-damaging alkylating agents.	('JAK2', 'Gene', '3717', (151, 155))	('EGFR', 'Gene', (99, 103))	('sensitized', 'Reg', (168, 178))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('JAK2', 'Gene', (151, 155))	('EGFR', 'Gene', '1956', (44, 48))	('JAK2', 'Gene', '3717', (53, 57))	('human', 'Species', '9606', (119, 124))	('EGFR', 'Gene', (89, 93))	('inhibitors', 'Var', (30, 40))	('medulloblastoma', 'Disease', 'MESH:D008527', (200, 215))	('malignant glioma', 'Disease', (179, 195))	('medulloblastoma', 'Phenotype', 'HP:0002885', (200, 215))	('malignant glioma', 'Disease', 'MESH:D005910', (179, 195))	('EGFR', 'Gene', '1956', (99, 103))	('medulloblastoma', 'Disease', (200, 215))	('JAK2', 'Gene', (53, 57))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (89, 93))
182299	18829483	Rabbit polyclonal, p-STAT3 (Y705), phosphorylated JAK2 (p-JAK2; Y1007/1008), and phosphorylated EGFR (Y1045) antibodies were from Cell Signaling.	('Y1045', 'Var', (102, 107))	('p-STAT3', 'Gene', '6774', (19, 26))	('JAK2', 'Gene', (50, 54))	('EGFR', 'Gene', (96, 100))	('p-STAT3', 'Gene', (19, 26))	('JAK2', 'Gene', '3717', (58, 62))	('JAK2', 'Gene', '3717', (50, 54))	('JAK2', 'Gene', (58, 62))	('Rabbit', 'Species', '9986', (0, 6))	('EGFR', 'Gene', '1956', (96, 100))
182313	18829483	Membranes were incubated with antibodies, including rabbit polyclonal EGFR, phosphorylated EGFR (Y1045), STAT3, p-STAT3 (Y705), cyclin D1, JAK2, p-JAK2 (Y1007/1008), and VEGF antibodies as well as mouse monoclonal beta-actin and alpha-tubulin antibodies.	('JAK2', 'Gene', (139, 143))	('p-STAT3', 'Gene', '6774', (112, 119))	('Y1045', 'Var', (97, 102))	('VEGF', 'Gene', '7422', (170, 174))	('Y1007/1008', 'Var', (153, 163))	('EGFR', 'Gene', (91, 95))	('beta-actin', 'Gene', '728378', (214, 224))	('VEGF', 'Gene', (170, 174))	('EGFR', 'Gene', '1956', (70, 74))	('cyclin D1', 'Gene', (128, 137))	('mouse', 'Species', '10090', (197, 202))	('cyclin D1', 'Gene', '595', (128, 137))	('JAK2', 'Gene', '3717', (147, 151))	('EGFR', 'Gene', '1956', (91, 95))	('JAK2', 'Gene', '3717', (139, 143))	('beta-actin', 'Gene', (214, 224))	('JAK2', 'Gene', (147, 151))	('EGFR', 'Gene', (70, 74))	('p-STAT3', 'Gene', (112, 119))	('rabbit', 'Species', '9986', (52, 58))
182325	18829483	While the relationship of STAT3 constitutive activation with glioma grade remains elusive, we aimed to determine the extent of STAT3 activation in primary human glioma specimens by immunostaining a tissue array slide for p-STAT3 (Y705), the active phosphorylated form of STAT3, and correlated the extent with glioma grade.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (309, 315))	('p-STAT3', 'Gene', '6774', (221, 228))	('p-STAT3', 'Gene', (221, 228))	('human', 'Species', '9606', (155, 160))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('glioma', 'Disease', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (309, 315))	('glioma', 'Disease', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('Y705', 'Var', (230, 234))
182342	18829483	2C), p-JAK2 (Y1007/1008), indicating that constitutively activated JAK2 may contribute to the observed constitutive activation of STAT3 in cultured human malignant glioma and medulloblastoma cells.	('STAT3', 'MPA', (130, 135))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('medulloblastoma', 'Phenotype', 'HP:0002885', (175, 190))	('Y1007/1008', 'Var', (13, 23))	('medulloblastoma', 'Disease', 'MESH:D008527', (175, 190))	('JAK2', 'Gene', (67, 71))	('JAK2', 'Gene', '3717', (7, 11))	('human', 'Species', '9606', (148, 153))	('activation', 'PosReg', (116, 126))	('malignant glioma', 'Disease', (154, 170))	('JAK2', 'Gene', (7, 11))	('medulloblastoma', 'Disease', (175, 190))	('malignant glioma', 'Disease', 'MESH:D005910', (154, 170))	('JAK2', 'Gene', '3717', (67, 71))
182353	18829483	The efficacy of anti-STAT3 approaches in targeting medulloblastomas has yet been evaluated, whereas gliomas are targeted by small-molecule inhibitors, dominant-negative STAT3, and STAT3 small interfering RNA.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('medulloblastomas', 'Disease', 'MESH:D008527', (51, 67))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('medulloblastomas', 'Disease', (51, 67))	('medulloblastoma', 'Phenotype', 'HP:0002885', (51, 66))	('small interfering RNA', 'Var', (186, 207))	('gliomas', 'Disease', (100, 107))
182358	18829483	Consistently, JSI-124 IC50 values in C8-D30 normal astrocytes were 22- to 83-fold higher than those in human glioma and medulloblastoma cells.	('JSI-124', 'Gene', (14, 21))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('medulloblastoma', 'Disease', 'MESH:D008527', (120, 135))	('C8-D30', 'Var', (37, 43))	('human', 'Species', '9606', (103, 108))	('medulloblastoma', 'Phenotype', 'HP:0002885', (120, 135))	('higher', 'PosReg', (82, 88))	('glioma', 'Disease', (109, 115))	('JSI-124', 'Chemical', 'MESH:C038106', (14, 21))	('medulloblastoma', 'Disease', (120, 135))	('IC50 values', 'MPA', (22, 33))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
182365	18829483	In MGR3 cells, cyclin D1 levels time-dependently decreased after JSI-124 treatments (Supplementary Fig.	('treatments', 'Var', (73, 83))	('JSI-124', 'Gene', (65, 72))	('cyclin D1', 'Gene', '595', (15, 24))	('cyclin D1', 'Gene', (15, 24))	('decreased', 'NegReg', (49, 58))	('MGR3', 'Gene', '337892', (3, 7))	('JSI-124', 'Chemical', 'MESH:C038106', (65, 72))	('MGR3', 'Gene', (3, 7))
182367	18829483	Consistently, JSI-124 significantly reduced the ability of STAT3 to activate both cyclin D1 and GAS-containing promoters in MGR1 (Fig.	('activate', 'PosReg', (68, 76))	('JSI-124', 'Var', (14, 21))	('JSI-124', 'Chemical', 'MESH:C038106', (14, 21))	('cyclin D1', 'Gene', '595', (82, 91))	('cyclin D1', 'Gene', (82, 91))	('MGR1', 'Gene', '192115', (124, 128))	('reduced', 'NegReg', (36, 43))	('ability', 'MPA', (48, 55))	('MGR1', 'Gene', (124, 128))	('GAS-containing promoters', 'MPA', (96, 120))
182383	18829483	Western blot analysis confirmed the expression of EGFR (170 kDa) and EGFRvIII (145 kDa) in U87MG-EGFR and U87MG-EGFRvIII cells, respectively (Fig.	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (69, 73))	('U87MG-EGFR', 'Gene', '1956', (91, 101))	('EGFR', 'Gene', '1956', (97, 101))	('expression', 'Species', '29278', (36, 46))	('EGFR', 'Gene', (69, 73))	('EGFR', 'Gene', '1956', (50, 54))	('170 kDa', 'Var', (56, 63))	('EGFR', 'Gene', (97, 101))	('U87MG-EGFR', 'Gene', '1956', (106, 116))	('U87MG-EGFR', 'Gene', (91, 101))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', (50, 54))	('145 kDa', 'Var', (79, 86))	('U87MG-EGFR', 'Gene', (106, 116))
182388	18829483	Iressa and JSI-124 alone did not completely reduce EGF-induced STAT3 activation in U87MG-EGFR cells despite that Iressa successfully inhibited EGF-induced EGFR activation by means of EGFR autophosphorylation at Y1045 (Supplementary Fig.	('EGF', 'Gene', '1950', (155, 158))	('U87MG-EGFR', 'Gene', (83, 93))	('EGF', 'Gene', (143, 146))	('EGFR', 'Gene', (155, 159))	('JSI-124', 'Chemical', 'MESH:C038106', (11, 18))	('Iressa', 'Chemical', 'MESH:D000077156', (0, 6))	('EGF', 'Gene', '1950', (51, 54))	('EGFR', 'Gene', (183, 187))	('EGF', 'Gene', '1950', (89, 92))	('EGF', 'Gene', (155, 158))	('U87MG-EGFR', 'Gene', '1956', (83, 93))	('EGF', 'Gene', '1950', (183, 186))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (155, 159))	('activation', 'PosReg', (160, 170))	('EGF', 'Gene', (51, 54))	('EGF', 'Gene', (183, 186))	('EGF', 'Gene', '1950', (143, 146))	('EGF', 'Gene', (89, 92))	('EGFR', 'Gene', '1956', (183, 187))	('inhibited', 'NegReg', (133, 142))	('Iressa', 'Chemical', 'MESH:D000077156', (113, 119))	('EGFR', 'Gene', '1956', (89, 93))	('Y1045', 'Var', (211, 216))
182402	18829483	Importantly, JSI-124 strongly sensitized all cell lines, except for MGR2, to cisplatin and the effects were achieved by low doses of cisplatin (1-20 micromol/L; Fig.	('MGR2', 'Gene', (68, 72))	('cisplatin', 'MPA', (77, 86))	('JSI-124', 'Chemical', 'MESH:C038106', (13, 20))	('MGR2', 'Gene', '8249', (68, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('JSI-124', 'Var', (13, 20))	('sensitized', 'Reg', (30, 40))
182404	18829483	S6) show that combined uses of cisplatin and JSI-124 yielded significant synergistic cell kill in all four cell lines, as indicated by CI values <1.0.	('JSI-124', 'Gene', (45, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('synergistic cell kill', 'CPA', (73, 94))	('JSI-124', 'Chemical', 'MESH:C038106', (45, 52))	('cisplatin', 'Var', (31, 40))
182408	18829483	In this study, using p-STAT3 (Y705) as a measure of STAT3 activation, we found 40% (22 of 55) of grade I-IV primary gliomas to have constitutively active STAT3.	('STAT3', 'MPA', (154, 159))	('p-STAT3', 'Gene', '6774', (21, 28))	('gliomas', 'Disease', (116, 123))	('p-STAT3', 'Gene', (21, 28))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('Y705', 'Var', (30, 34))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
182426	18829483	WP1066, more potent than AG490, suppressed the growth of s.c. U87MG malignant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('malignant gliomas', 'Disease', 'MESH:D005910', (68, 85))	('WP1066', 'Var', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('s.c. U87MG', 'Var', (57, 67))	('growth', 'CPA', (47, 53))	('malignant gliomas', 'Disease', (68, 85))	('U87MG', 'CellLine', 'CVCL:0022', (62, 67))	('suppressed', 'NegReg', (32, 42))
182429	18829483	To our best knowledge, JSI-124 displays the most potent killing effect thus far in cultured human glioma cells compared with other anti-STAT3 agents, such as AG490 and WP1066.	('killing', 'CPA', (56, 63))	('JSI-124', 'Chemical', 'MESH:C038106', (23, 30))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Disease', (98, 104))	('JSI-124', 'Var', (23, 30))	('human', 'Species', '9606', (92, 97))
182431	18829483	JSI-124 was identified as a JAK2 inhibitor that suppresses STAT3 phosphorylation but displays much lower activities toward JAK1 and src.	('src', 'Gene', (132, 135))	('STAT3 phosphorylation', 'MPA', (59, 80))	('JAK1', 'Gene', (123, 127))	('src', 'Gene', '6714', (132, 135))	('JSI-124', 'Chemical', 'MESH:C038106', (0, 7))	('JAK2', 'Gene', '3717', (28, 32))	('suppresses', 'NegReg', (48, 58))	('JAK1', 'Gene', '3716', (123, 127))	('JAK2', 'Gene', (28, 32))	('JSI-124', 'Var', (0, 7))
182432	18829483	Although it is likely that JSI-124 may also inhibit STAT1 and STAT5 phosphorylation in addition to STAT3, the report by Nefedova et al.	('JSI-124', 'Var', (27, 34))	('STAT5', 'Gene', (62, 67))	('inhibit', 'NegReg', (44, 51))	('STAT1', 'Gene', (52, 57))	('STAT1', 'Gene', '6772', (52, 57))	('JSI-124', 'Chemical', 'MESH:C038106', (27, 34))	('STAT5', 'Gene', '6776', (62, 67))
182441	18829483	Activated cell-surface EGFR recruits and phosphorylates STAT3 at Y705, and in turn, p-STAT3 enters the nucleus to activate expression of several cancer-related genes.	('cancer', 'Disease', (145, 151))	('Y705', 'Var', (65, 69))	('expression', 'MPA', (123, 133))	('p-STAT3', 'Gene', '6774', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('p-STAT3', 'Gene', (84, 91))	('activate', 'PosReg', (114, 122))	('EGFR', 'Gene', '1956', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('EGFR', 'Gene', (23, 27))	('expression', 'Species', '29278', (123, 133))
182448	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
182450	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
182451	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('CCLE', 'Chemical', '-', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Oncomine', 'Chemical', '-', (54, 62))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancer', 'Disease', (286, 292))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('cancers', 'Disease', (394, 401))	('cancer', 'Disease', (394, 400))	('PGs', 'Gene', (255, 258))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (286, 292))
182456	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('PGC', 'Gene', (120, 123))	('signal transduction pathways', 'Pathway', (81, 109))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('inhibition', 'NegReg', (62, 72))	('PGC', 'Gene', '5225', (120, 123))	('PGs', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
182462	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
182463	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('PGC', 'Gene', (0, 3))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
182467	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
182469	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (268, 274))	('cancers', 'Disease', (375, 382))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('tumor', 'Disease', (123, 128))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('copy number variation', 'Var', (212, 233))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CCLE', 'Chemical', '-', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('PGs', 'Gene', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))
182489	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
182490	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
182495	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
182508	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
182520	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
182531	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('inhibition', 'NegReg', (84, 94))	('carcinogenic', 'Disease', (198, 210))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
182555	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
182558	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('PGA5', 'Gene', '5222', (16, 20))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('PGA4', 'Gene', (6, 10))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
182559	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
182560	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
182561	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('PGs', 'Gene', (24, 27))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
182564	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('CCLE', 'Chemical', '-', (66, 70))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
182565	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('associated', 'Reg', (211, 221))	('immune cell infiltration', 'CPA', (273, 297))	('cancer', 'Disease', (245, 251))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('PGC', 'Gene', (328, 331))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
182584	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
182586	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
182607	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
182608	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
182609	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
182610	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
182612	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
182613	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('PGC', 'Gene', '5225', (175, 178))
182615	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
182626	32923170	IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM).	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('mutated', 'Var', (135, 142))	('glioma', 'Disease', (11, 17))	('gliomas', 'Disease', (11, 18))	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (185, 197))	('humans', 'Species', '9606', (54, 60))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (0, 3))	('glioblastoma', 'Disease', (185, 197))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('glioma', 'Disease', (158, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (185, 197))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('IDH', 'Gene', '3417', (117, 120))
182630	32923170	An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry.	('IDH', 'Gene', (83, 86))	('murine', 'Species', '10090', (25, 31))	('mutant', 'Var', (76, 82))	('Treg', 'Chemical', '-', (90, 94))
182635	32923170	Gliomas harboring mutations in isocitrate dehydrogenase 1 (IDH1) represent the great majority of World Health Organization (WHO) grade II and grade III gliomas (80-90%), known as "lower grade glioma (LGG)."	('III gliomas', 'Disease', 'MESH:D005910', (148, 159))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('III gliomas', 'Disease', (148, 159))	('glioma', 'Disease', (152, 158))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('Gliomas', 'Disease', (0, 7))	('IDH1', 'Gene', (59, 63))	('glioma', 'Disease', (192, 198))	('mutations', 'Var', (18, 27))
182641	32923170	The relationship between IDH mutations and Treg infiltration is not well-understood.	('Treg', 'Chemical', '-', (43, 47))	('IDH', 'Gene', (25, 28))	('mutations', 'Var', (29, 38))
182642	32923170	Here, we use multispectral imaging analysis to compare Treg infiltration in IDH-mutant and IDH wild-type glioma using human subject samples of LGG, and we correlate these results with those in an orthotopic syngeneic glioma rodent model.	('glioma', 'Disease', 'MESH:D005910', (217, 223))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('glioma', 'Disease', (105, 111))	('IDH-mutant', 'Var', (76, 86))	('glioma', 'Disease', (217, 223))	('human', 'Species', '9606', (118, 123))	('IDH-mutant', 'Gene', (76, 86))	('Treg', 'Chemical', '-', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
182643	32923170	We demonstrate that IDH-mutant glioma is associated with fewer infiltrating Tregs than their wild-type counterparts, suggesting distinct tumor microenvironments.	('Tregs', 'Chemical', '-', (76, 81))	('IDH-mutant', 'Var', (20, 30))	('tumor', 'Disease', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('infiltrating Tregs', 'CPA', (63, 81))	('fewer', 'NegReg', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('glioma', 'Disease', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
182654	32923170	Using a Hamilton 11701 Gastight syringe (Hamilton Company), GL261 IDH1 and GL261 IDH1R132H (7.5 x 104 cells per mouse) cells were suspended in 3 mul of cold PBS and stereotactically (Kopf Instruments) injected into the brain (2.5 mm right of the bregma and 3.0 mm below the skull) of seven-week-old mice.	('GL261', 'CellLine', 'CVCL:Y003', (75, 80))	('GL261', 'CellLine', 'CVCL:Y003', (60, 65))	('GL261 IDH1R132H', 'Var', (75, 90))	('mice', 'Species', '10090', (299, 303))	('cold PBS', 'Disease', (152, 160))	('mouse', 'Species', '10090', (112, 117))	('cold PBS', 'Disease', 'MESH:D011535', (152, 160))
182682	32923170	Our analysis identified 19 Treg-associated genes to be significantly downregulated in IDH-mutant cases (Supplementary Table 1).	('Treg-associated genes', 'Gene', (27, 48))	('IDH-mutant', 'Var', (86, 96))	('downregulated', 'NegReg', (69, 82))	('Treg', 'Chemical', '-', (27, 31))	('IDH-mutant', 'Gene', (86, 96))
182683	32923170	Genes critical for the function and stability of Tregs (e.g., FOXP3 and ICOS), inducible Treg factors (e.g., IDO1 and TGFB1), as well as Treg chemoattractants (e.g., CCL2), were significantly downregulated in IDH-mutant cases when compared to IDH wild-type cases (Figure 1a).	('ICOS', 'Gene', (72, 76))	('IDH-mutant', 'Var', (209, 219))	('FOXP3', 'Gene', (62, 67))	('FOXP3', 'Gene', '20371', (62, 67))	('Tregs', 'Chemical', '-', (49, 54))	('Treg', 'Chemical', '-', (137, 141))	('Treg', 'Chemical', '-', (49, 53))	('downregulated', 'NegReg', (192, 205))	('CCL2', 'Gene', '20296', (166, 170))	('CCL2', 'Gene', (166, 170))	('ICOS', 'Gene', '54167', (72, 76))	('Treg', 'Chemical', '-', (89, 93))	('IDO1', 'Gene', (109, 113))	('TGFB1', 'Gene', '21803', (118, 123))	('TGFB1', 'Gene', (118, 123))	('IDO1', 'Gene', '15930', (109, 113))
182688	32923170	We transduced GL261 cells with a lentiviral construct encoding either IDH1 cDNA or IDH1R132H cDNA and then probed for tumor expression of mutant IDH1 protein and 2HG levels (Supplementary Figure 1).	('IDH1', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutant', 'Var', (138, 144))	('IDH1R132H', 'Var', (83, 92))	('GL261', 'CellLine', 'CVCL:Y003', (14, 19))	('tumor', 'Disease', (118, 123))	('protein', 'Protein', (150, 157))
182691	32923170	Furthermore, in tumors harboring the IDH1 mutation, immunohistochemistry showed significant reductions in the total number of FoxP3+ cells as well as decreased proportions of Tregs within the CD4+ compartment (IDH-mutant: 24.7% vs. IDH wild-type: 44.3%) (p < .05; Figure 2c).	('FoxP3', 'Gene', (126, 131))	('CD4', 'Gene', '12504', (192, 195))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('Tregs', 'CPA', (175, 180))	('FoxP3', 'Gene', '20371', (126, 131))	('reductions', 'NegReg', (92, 102))	('IDH1', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('Tregs', 'Chemical', '-', (175, 180))	('mutation', 'Var', (42, 50))	('tumors', 'Disease', (16, 22))	('decreased', 'NegReg', (150, 159))	('CD4', 'Gene', (192, 195))
182695	32923170	Moreover, IDH-mutant tumors displayed significantly decreased Tregs when considered as a proportion of CD4+ cells (IDH-mutant: 1.37% vs. IDH wild-type: 3.32%) (p < .05; Figure 3d).	('decreased', 'NegReg', (52, 61))	('CD4', 'Gene', (103, 106))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('CD4', 'Gene', '12504', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Tregs', 'CPA', (62, 67))	('IDH-mutant', 'Var', (10, 20))	('Tregs', 'Chemical', '-', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
182696	32923170	There was a trend toward fewer total CD3+ (p = .18; Supplementary Figure 2B) and CD4+ (p < .05; Figure 3b) cells in IDH-mutant gliomas.	('CD3', 'Gene', '12503', (37, 40))	('IDH-mutant', 'Var', (116, 126))	('fewer', 'NegReg', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('CD4', 'Gene', (81, 84))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('CD4', 'Gene', '12504', (81, 84))	('CD3', 'Gene', (37, 40))
182697	32923170	Altogether, these data indicate that glioma-associated Treg infiltration is less abundant in both murine models and patient samples of IDH-mutant glioma.	('patient', 'Species', '9606', (116, 123))	('glioma', 'Disease', (37, 43))	('glioma', 'Disease', (146, 152))	('murine', 'Species', '10090', (98, 104))	('IDH-mutant', 'Var', (135, 145))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('Treg', 'Chemical', '-', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
182704	32923170	The downstream metabolite of mutant IDH, 2-HG, is also known to drive downregulation of leukocyte chemotactic factors, though the impact of this phenomenon on Tregs in particular is unknown .	('2-HG', 'Chemical', 'MESH:C019417', (41, 45))	('mutant', 'Var', (29, 35))	('leukocyte chemotactic factors', 'MPA', (88, 117))	('IDH', 'Gene', (36, 39))	('downregulation', 'NegReg', (70, 84))	('Tregs', 'Chemical', '-', (159, 164))
182705	32923170	Recent studies have demonstrated that T cells can take up 2-HG derived from tumors harboring IDH mutations.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('IDH', 'Gene', (93, 96))	('2-HG', 'Chemical', 'MESH:C019417', (58, 62))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
182706	32923170	In addition to altered chemotaxis, the decreased Tregs in IDH-mutant gliomas may be due to the accumulation of intracellular 2-HG, resulting in increased apoptosis and reduced proliferation as evidenced by Bunse and colleagues .	('accumulation', 'PosReg', (95, 107))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('intracellular 2-HG', 'MPA', (111, 129))	('IDH-mutant', 'Var', (58, 68))	('apoptosis', 'CPA', (154, 163))	('proliferation', 'CPA', (176, 189))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('Tregs', 'CPA', (49, 54))	('2-HG', 'Chemical', 'MESH:C019417', (125, 129))	('IDH-mutant', 'Gene', (58, 68))	('decreased', 'NegReg', (39, 48))	('Tregs', 'Chemical', '-', (49, 54))	('increased', 'PosReg', (144, 153))	('reduced', 'NegReg', (168, 175))
182708	32923170	Our data support mounting evidence that IDH mutations in gliomas are associated with a distinct immune microenvironment.	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('IDH', 'Gene', (40, 43))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('mutations', 'Var', (44, 53))	('gliomas', 'Disease', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
182710	32923170	Additional work is needed to examine whether this phenomenon is mediated through neomorphic metabolic activity of the IDH-mutant enzyme and whether Treg infiltration is impacted by the use of specific IDH-inhibitors.	('IDH-mutant', 'Var', (118, 128))	('Treg', 'Chemical', '-', (148, 152))	('enzyme', 'Enzyme', (129, 135))	('IDH-mutant', 'Gene', (118, 128))
182712	32923170	We used a GL261 glioma murine model to investigate whether IDH-mutations are associated with degree of Treg infiltration.	('IDH-mutations', 'Var', (59, 72))	('IDH-mutations', 'Gene', (59, 72))	('GL261', 'CellLine', 'CVCL:Y003', (10, 15))	('glioma', 'Disease', (16, 22))	('murine', 'Species', '10090', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('Treg', 'Chemical', '-', (103, 107))	('glioma', 'Disease', 'MESH:D005910', (16, 22))
182714	32923170	In summary, we have identified a considerable reduction in Treg infiltrate in IDH-mutant gliomas in both humans and mice.	('mice', 'Species', '10090', (116, 120))	('IDH-mutant', 'Var', (78, 88))	('reduction', 'NegReg', (46, 55))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('humans', 'Species', '9606', (105, 111))	('IDH-mutant', 'Gene', (78, 88))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('Treg', 'Chemical', '-', (59, 63))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('Treg', 'CPA', (59, 63))
182715	32923170	These data provide additional support for the concept that IDH mutational status may be used as an immunological biomarker in glioma.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('mutational status', 'Var', (63, 80))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('IDH', 'Gene', (59, 62))	('glioma', 'Disease', (126, 132))
182718	30558073	IDH mutations but not TERTp mutations are associated with seizures in lower-grade gliomas Supplemental Digital Content is available in the text Glioma is the most common malignant tumor in the central nervous system (CNS).	('seizures', 'Disease', (58, 66))	('TERTp', 'Gene', (22, 27))	('TERTp', 'Gene', '7015', (22, 27))	('IDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Glioma', 'Disease', 'MESH:D005910', (144, 150))	('seizures', 'Disease', 'MESH:D012640', (58, 66))	('gliomas', 'Disease', (82, 89))	('seizures', 'Phenotype', 'HP:0001250', (58, 66))	('Glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH', 'Gene', '3417', (0, 3))	('malignant tumor', 'Disease', (170, 185))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('mutations', 'Var', (4, 13))	('malignant tumor', 'Disease', 'MESH:D018198', (170, 185))	('malignant tumor in the central nervous system', 'Phenotype', 'HP:0100836', (170, 215))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('associated', 'Reg', (42, 52))	('Glioma', 'Disease', (144, 150))	('tumor in the central nervous system', 'Phenotype', 'HP:0100006', (180, 215))	('seizure', 'Phenotype', 'HP:0001250', (58, 65))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))
182722	30558073	In this study, we investigate the potential relationship between isocitrate dehydrogenase (IDH)/telomerase reverse transcriptase promoter (TERTp) mutations and preoperative seizures in patients with LGG.	('isocitrate dehydrogenase', 'Gene', '3417', (65, 89))	('seizures', 'Phenotype', 'HP:0001250', (173, 181))	('seizure', 'Phenotype', 'HP:0001250', (173, 180))	('mutations', 'Var', (146, 155))	('seizures', 'Disease', (173, 181))	('LGG', 'Disease', (199, 202))	('TERTp', 'Gene', (139, 144))	('TERTp', 'Gene', '7015', (139, 144))	('IDH', 'Gene', (91, 94))	('patients', 'Species', '9606', (185, 193))	('isocitrate dehydrogenase', 'Gene', (65, 89))	('IDH', 'Gene', '3417', (91, 94))	('seizures', 'Disease', 'MESH:D012640', (173, 181))
182724	30558073	Sanger sequencing was used to detect IDH/TERTp mutations.	('TERTp', 'Gene', (41, 46))	('TERTp', 'Gene', '7015', (41, 46))	('mutations', 'Var', (47, 56))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3417', (37, 40))
182725	30558073	Chi-square test was performed to determine if the IDH/TERTp mutations were associated with seizures and seizure types.	('seizures', 'Disease', (91, 99))	('seizures', 'Phenotype', 'HP:0001250', (91, 99))	('seizure', 'Disease', (91, 98))	('seizures', 'Disease', 'MESH:D012640', (91, 99))	('seizure', 'Phenotype', 'HP:0001250', (91, 98))	('seizure', 'Disease', (104, 111))	('TERTp', 'Gene', (54, 59))	('seizure', 'Disease', 'MESH:D012640', (104, 111))	('IDH', 'Gene', (50, 53))	('mutations', 'Var', (60, 69))	('associated', 'Reg', (75, 85))	('seizure', 'Phenotype', 'HP:0001250', (104, 111))	('TERTp', 'Gene', '7015', (54, 59))	('IDH', 'Gene', '3417', (50, 53))	('seizure', 'Disease', 'MESH:D012640', (91, 98))
182726	30558073	In 289 LGG patients, preoperative seizures accounted for 25.3% (73/289), IDH mutations accounted for 34.3%(99/289), and TERTp mutations accounted for 44.3% (128/289).	('LGG', 'Disease', (7, 10))	('TERTp', 'Gene', '7015', (120, 125))	('seizures', 'Disease', 'MESH:D012640', (34, 42))	('IDH', 'Gene', (73, 76))	('seizures', 'Phenotype', 'HP:0001250', (34, 42))	('IDH', 'Gene', '3417', (73, 76))	('mutations', 'Var', (77, 86))	('seizures', 'Disease', (34, 42))	('patients', 'Species', '9606', (11, 19))	('seizure', 'Phenotype', 'HP:0001250', (34, 41))	('TERTp', 'Gene', (120, 125))
182727	30558073	The correlation analysis demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related epilepsy (P <.001, chi-square test).	('IDH', 'Gene', '3417', (43, 46))	('epilepsy', 'Disease', 'MESH:D004827', (124, 132))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('epilepsy', 'Phenotype', 'HP:0001250', (124, 132))	('epilepsy', 'Disease', (124, 132))	('IDH', 'Gene', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
182728	30558073	On the other hand, the statistical analysis revealed no significant correlation between TERTp mutations and seizure in LGG patients (P = .102, chi-square test).	('mutations', 'Var', (94, 103))	('seizure', 'Disease', (108, 115))	('patients', 'Species', '9606', (123, 131))	('seizure', 'Disease', 'MESH:D012640', (108, 115))	('TERTp', 'Gene', (88, 93))	('TERTp', 'Gene', '7015', (88, 93))	('LGG', 'Disease', (119, 122))	('seizure', 'Phenotype', 'HP:0001250', (108, 115))
182729	30558073	The tumor-related epilepsy rates vary among different subgroups according to IDH/TERTp mutations.	('tumor', 'Disease', (4, 9))	('TERTp', 'Gene', '7015', (81, 86))	('epilepsy', 'Disease', 'MESH:D004827', (18, 26))	('epilepsy', 'Phenotype', 'HP:0001250', (18, 26))	('epilepsy', 'Disease', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('IDH', 'Gene', (77, 80))	('TERTp', 'Gene', (81, 86))	('IDH', 'Gene', '3417', (77, 80))	('mutations', 'Var', (87, 96))
182730	30558073	However, there is no definite correlation between the IDH (P = 1.000, chi-square test)/TERTp (P = .613, chi-square test) mutations and the types of epileptic seizure.	('seizure', 'Disease', (158, 165))	('mutations', 'Var', (121, 130))	('TERTp', 'Gene', (87, 92))	('seizure', 'Disease', 'MESH:D012640', (158, 165))	('TERTp', 'Gene', '7015', (87, 92))	('epileptic', 'Disease', 'MESH:D004827', (148, 157))	('epileptic', 'Disease', (148, 157))	('IDH', 'Gene', (54, 57))	('seizure', 'Phenotype', 'HP:0001250', (158, 165))	('IDH', 'Gene', '3417', (54, 57))
182731	30558073	IDH mutations are more common in preoperative LGG patients with epileptic symptoms, suggesting that this mutation is positively correlated with seizures.	('epileptic', 'Disease', 'MESH:D004827', (64, 73))	('IDH', 'Gene', (0, 3))	('correlated', 'Reg', (128, 138))	('seizures', 'Disease', 'MESH:D012640', (144, 152))	('patients', 'Species', '9606', (50, 58))	('epileptic', 'Disease', (64, 73))	('IDH', 'Gene', '3417', (0, 3))	('seizures', 'Disease', (144, 152))	('seizures', 'Phenotype', 'HP:0001250', (144, 152))	('LGG', 'Disease', (46, 49))	('seizure', 'Phenotype', 'HP:0001250', (144, 151))	('mutations', 'Var', (4, 13))
182732	30558073	However, there was no significant correlation between TERTp mutations and seizures.	('seizures', 'Phenotype', 'HP:0001250', (74, 82))	('seizures', 'Disease', (74, 82))	('seizure', 'Phenotype', 'HP:0001250', (74, 81))	('seizures', 'Disease', 'MESH:D012640', (74, 82))	('mutations', 'Var', (60, 69))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))
182739	30558073	The isocitrate dehydrogenase (IDH)1 and IDH2 mutations occur in more than 70% of patients with LGG and have been identified as potential biomarkers for glioma-associated epilepsy.	('isocitrate dehydrogenase (IDH)1', 'Gene', '3417', (4, 35))	('mutations', 'Var', (45, 54))	('IDH2', 'Gene', (40, 44))	('glioma', 'Disease', (152, 158))	('patients', 'Species', '9606', (81, 89))	('IDH2', 'Gene', '3418', (40, 44))	('epilepsy', 'Disease', 'MESH:D004827', (170, 178))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('epilepsy', 'Phenotype', 'HP:0001250', (170, 178))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('LGG', 'Disease', (95, 98))	('epilepsy', 'Disease', (170, 178))
182740	30558073	The telomerase reverse transcriptase promoter (TERTp) mutation is another molecular marker of glioma discovered in recent years.	('TERTp', 'Gene', '7015', (47, 52))	('mutation', 'Var', (54, 62))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('TERTp', 'Gene', (47, 52))
182741	30558073	The mutations are mainly concentrated in C228T and C250T sites in the promoter region.	('C250T', 'Mutation', 'c.250C>T', (51, 56))	('C228T', 'Var', (41, 46))	('C228T', 'Mutation', 'c.228C>T', (41, 46))	('C250T', 'Var', (51, 56))
182744	30558073	However, as far as we know, the study exploring the relationship between TERTp mutation and tumor-related epilepsy is not reported by far.	('epilepsy', 'Phenotype', 'HP:0001250', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('TERTp', 'Gene', (73, 78))	('epilepsy', 'Disease', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutation', 'Var', (79, 87))	('TERTp', 'Gene', '7015', (73, 78))	('tumor', 'Disease', (92, 97))	('epilepsy', 'Disease', 'MESH:D004827', (106, 114))
182745	30558073	A better understanding of the relationship between molecular pathology such as IDH/TERTp mutations and seizures in LGG patients has a very important clinical and social value for setting therapeutic regimen and improving the life quality of the patients.	('TERTp', 'Gene', (83, 88))	('IDH', 'Gene', (79, 82))	('patients', 'Species', '9606', (245, 253))	('patients', 'Species', '9606', (119, 127))	('IDH', 'Gene', '3417', (79, 82))	('TERTp', 'Gene', '7015', (83, 88))	('seizures', 'Disease', 'MESH:D012640', (103, 111))	('LGG', 'Disease', (115, 118))	('mutations', 'Var', (89, 98))	('seizures', 'Disease', (103, 111))	('seizures', 'Phenotype', 'HP:0001250', (103, 111))	('seizure', 'Phenotype', 'HP:0001250', (103, 110))
182746	30558073	We aimed to investigate the potential relationship between IDH/TERTp mutations and preoperative seizures in patients with LGG and to reveal whether the IDH/TERTp mutations are related to the onset of seizure and seizure types.	('seizure', 'Disease', 'MESH:D012640', (96, 103))	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', (152, 155))	('seizures', 'Disease', (96, 104))	('seizure', 'Phenotype', 'HP:0001250', (96, 103))	('patients', 'Species', '9606', (108, 116))	('seizure', 'Disease', 'MESH:D012640', (200, 207))	('seizures', 'Disease', 'MESH:D012640', (96, 104))	('seizure', 'Disease', (96, 103))	('seizure', 'Phenotype', 'HP:0001250', (200, 207))	('seizures', 'Phenotype', 'HP:0001250', (96, 104))	('seizure', 'Disease', (200, 207))	('IDH', 'Gene', '3417', (152, 155))	('TERTp', 'Gene', (156, 161))	('TERTp', 'Gene', '7015', (156, 161))	('mutations', 'Var', (69, 78))	('seizure', 'Disease', 'MESH:D012640', (212, 219))	('seizure', 'Phenotype', 'HP:0001250', (212, 219))	('TERTp', 'Gene', (63, 68))	('seizure', 'Disease', (212, 219))	('IDH', 'Gene', (59, 62))	('TERTp', 'Gene', '7015', (63, 68))
182762	30558073	The univariate analysis was performed using a chi-square test to determine whether the IDH/TERTp mutations were associated with preoperative epilepsy in patients with LGG.	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (153, 161))	('epilepsy', 'Disease', 'MESH:D004827', (141, 149))	('IDH', 'Gene', (87, 90))	('epilepsy', 'Phenotype', 'HP:0001250', (141, 149))	('IDH', 'Gene', '3417', (87, 90))	('TERTp', 'Gene', (91, 96))	('epilepsy', 'Disease', (141, 149))	('associated', 'Reg', (112, 122))	('TERTp', 'Gene', '7015', (91, 96))
182763	30558073	Using multivariate logistic regression analysis, molecular pathology, tumor location, and epileptic seizure types were analyzed to determine whether IDH/TERTp mutations were involved in premonitory seizure.	('seizure', 'Disease', 'MESH:D012640', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('involved', 'Reg', (174, 182))	('IDH', 'Gene', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutations', 'Var', (159, 168))	('tumor', 'Disease', (70, 75))	('IDH', 'Gene', '3417', (149, 152))	('seizure', 'Phenotype', 'HP:0001250', (198, 205))	('seizure', 'Disease', (100, 107))	('epileptic', 'Disease', 'MESH:D004827', (90, 99))	('TERTp', 'Gene', (153, 158))	('seizure', 'Disease', 'MESH:D012640', (100, 107))	('TERTp', 'Gene', '7015', (153, 158))	('epileptic', 'Disease', (90, 99))	('seizure', 'Disease', (198, 205))	('seizure', 'Phenotype', 'HP:0001250', (100, 107))
182767	30558073	IDH mutations were found in 99 (34.3%) cases while mutations in the TERTp mutations were found in 128 (44.3%) cases.	('TERTp', 'Gene', (68, 73))	('IDH', 'Gene', (0, 3))	('TERTp', 'Gene', '7015', (68, 73))	('found', 'Reg', (19, 24))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))
182768	30558073	Among the 289 LGG patients enrolled in the study, 99 had IDH mutations, including 94 (94.95%) with IDH1 mutation, 5 (5.05%) with IDH2 mutation, 96 (96.97%) with R132 mutation, and 3 (3.03%) with R172 mutation.	('IDH', 'Gene', '3417', (57, 60))	('IDH', 'Gene', '3417', (99, 102))	('IDH2', 'Gene', (129, 133))	('LGG', 'Disease', (14, 17))	('IDH2', 'Gene', '3418', (129, 133))	('mutation', 'Var', (104, 112))	('IDH1', 'Gene', (99, 103))	('R132 mutation', 'Var', (161, 174))	('patients', 'Species', '9606', (18, 26))	('IDH', 'Gene', (129, 132))	('IDH', 'Gene', (57, 60))	('IDH', 'Gene', (99, 102))	('IDH1', 'Gene', '3417', (99, 103))	('IDH', 'Gene', '3417', (129, 132))
182769	30558073	128 patients had TERTp mutations, including 95 (74.22%) with C228T mutation, 33 (25.78%) with C250T mutation.	('TERTp', 'Gene', (17, 22))	('TERTp', 'Gene', '7015', (17, 22))	('C228T', 'Mutation', 'c.228C>T', (61, 66))	('C250T', 'Mutation', 'c.250C>T', (94, 99))	('patients', 'Species', '9606', (4, 12))	('C228T', 'Var', (61, 66))	('C250T', 'Var', (94, 99))
182771	30558073	Among 289 LGG patients, preoperative seizures accounted for 25.3% (73/289), IDH mutations accounted for 34.3% (99/289), and TERTp mutations accounted for 44.3% (128/289).	('LGG', 'Disease', (10, 13))	('mutations', 'Var', (80, 89))	('seizures', 'Disease', (37, 45))	('seizures', 'Phenotype', 'HP:0001250', (37, 45))	('IDH', 'Gene', (76, 79))	('TERTp', 'Gene', (124, 129))	('seizure', 'Phenotype', 'HP:0001250', (37, 44))	('TERTp', 'Gene', '7015', (124, 129))	('IDH', 'Gene', '3417', (76, 79))	('patients', 'Species', '9606', (14, 22))	('seizures', 'Disease', 'MESH:D012640', (37, 45))
182772	30558073	The correlation analysis between IDH mutation and preoperative seizures in patients with LGG (Fig.	('seizure', 'Phenotype', 'HP:0001250', (63, 70))	('mutation', 'Var', (37, 45))	('patients', 'Species', '9606', (75, 83))	('seizures', 'Disease', 'MESH:D012640', (63, 71))	('seizures', 'Phenotype', 'HP:0001250', (63, 71))	('IDH', 'Gene', (33, 36))	('seizures', 'Disease', (63, 71))	('IDH', 'Gene', '3417', (33, 36))	('LGG', 'Disease', (89, 92))
182773	30558073	1A, P <.001, X2 = 20.816, v = 1, chi-square test, Table 2) demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related epilepsy.	('tumor', 'Disease', (144, 149))	('epilepsy', 'Phenotype', 'HP:0001250', (158, 166))	('mutation', 'Var', (81, 89))	('epilepsy', 'Disease', (158, 166))	('IDH', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('IDH', 'Gene', '3417', (77, 80))	('epilepsy', 'Disease', 'MESH:D004827', (158, 166))
182774	30558073	On the other hand, the statistical analysis revealed no significant correlation between TERTp mutations and seizure (Fig.	('mutations', 'Var', (94, 103))	('seizure', 'Disease', (108, 115))	('seizure', 'Disease', 'MESH:D012640', (108, 115))	('TERTp', 'Gene', (88, 93))	('TERTp', 'Gene', '7015', (88, 93))	('seizure', 'Phenotype', 'HP:0001250', (108, 115))
182775	30558073	Multivariate logistic regression analysis was used to determine the potential association between IDH mutations and tumor-associated seizures.	('seizures', 'Disease', 'MESH:D012640', (133, 141))	('seizures', 'Phenotype', 'HP:0001250', (133, 141))	('seizures', 'Disease', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('seizure', 'Phenotype', 'HP:0001250', (133, 140))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('IDH', 'Gene', (98, 101))	('tumor', 'Disease', (116, 121))	('IDH', 'Gene', '3417', (98, 101))
182776	30558073	On this basis, in order to further study whether the epilepsy is related to molecular pathological types of IDH/TERTp, we divided 289 subjects into 4 subgroups according to the IDH/TERTp mutations:IDH mut/TERTp mut (n=44),IDH wt /TERTp wt (n=106),IDH mut /TERTp wt (n=55)and IDH wt /TERTp mut (n=84).	('IDH', 'Gene', (247, 250))	('TERTp', 'Gene', '7015', (181, 186))	('IDH', 'Gene', '3417', (177, 180))	('TERTp', 'Gene', (283, 288))	('TERTp', 'Gene', (205, 210))	('TERTp', 'Gene', '7015', (205, 210))	('TERTp', 'Gene', '7015', (283, 288))	('epilepsy', 'Phenotype', 'HP:0001250', (53, 61))	('epilepsy', 'Disease', (53, 61))	('IDH', 'Gene', '3417', (247, 250))	('IDH', 'Gene', (197, 200))	('IDH', 'Gene', (222, 225))	('IDH', 'Gene', (275, 278))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (197, 200))	('TERTp', 'Gene', (256, 261))	('TERTp', 'Gene', (112, 117))	('TERTp', 'Gene', (230, 235))	('TERTp', 'Gene', '7015', (112, 117))	('TERTp', 'Gene', '7015', (256, 261))	('IDH', 'Gene', '3417', (222, 225))	('TERTp', 'Gene', '7015', (230, 235))	('IDH', 'Gene', '3417', (275, 278))	('IDH', 'Gene', (177, 180))	('IDH', 'Gene', '3417', (108, 111))	('mutations', 'Var', (187, 196))	('epilepsy', 'Disease', 'MESH:D004827', (53, 61))	('TERTp', 'Gene', (181, 186))
182777	30558073	We compare the frequency of epilepsy between the 4 groups based on IDH/TERTp mutations and conduct a chi-square test to analyze the potential impact of IDH/TERTp mutations on seizures (Supplementary Table 1).	('epilepsy', 'Disease', 'MESH:D004827', (28, 36))	('seizures', 'Disease', 'MESH:D012640', (175, 183))	('seizure', 'Phenotype', 'HP:0001250', (175, 182))	('epilepsy', 'Phenotype', 'HP:0001250', (28, 36))	('seizures', 'Phenotype', 'HP:0001250', (175, 183))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', (67, 70))	('seizures', 'Disease', (175, 183))	('mutations', 'Var', (77, 86))	('TERTp', 'Gene', (71, 76))	('epilepsy', 'Disease', (28, 36))	('IDH', 'Gene', '3417', (152, 155))	('IDH', 'Gene', '3417', (67, 70))	('TERTp', 'Gene', (156, 161))	('TERTp', 'Gene', '7015', (156, 161))	('TERTp', 'Gene', '7015', (71, 76))
182785	30558073	These results further suggest that the IDH mutation may be one of the molecular pathological causes of preoperative seizures, whereas the TERTp mutation is not correlated with seizures.	('seizures', 'Disease', (176, 184))	('seizure', 'Phenotype', 'HP:0001250', (176, 183))	('mutation', 'Var', (43, 51))	('seizures', 'Disease', (116, 124))	('TERTp', 'Gene', (138, 143))	('TERTp', 'Gene', '7015', (138, 143))	('seizures', 'Phenotype', 'HP:0001250', (116, 124))	('seizures', 'Disease', 'MESH:D012640', (176, 184))	('seizure', 'Phenotype', 'HP:0001250', (116, 123))	('IDH', 'Gene', (39, 42))	('seizures', 'Phenotype', 'HP:0001250', (176, 184))	('causes', 'Reg', (93, 99))	('IDH', 'Gene', '3417', (39, 42))	('seizures', 'Disease', 'MESH:D012640', (116, 124))
182790	30558073	The results showed that in LGG patients, IDH/TERTp mutations did not have specific effects on the type of epileptic seizures.	('IDH', 'Gene', (41, 44))	('LGG', 'Disease', (27, 30))	('epileptic', 'Disease', 'MESH:D004827', (106, 115))	('mutations', 'Var', (51, 60))	('epileptic', 'Disease', (106, 115))	('IDH', 'Gene', '3417', (41, 44))	('seizures', 'Disease', (116, 124))	('seizures', 'Phenotype', 'HP:0001250', (116, 124))	('TERTp', 'Gene', (45, 50))	('TERTp', 'Gene', '7015', (45, 50))	('seizure', 'Phenotype', 'HP:0001250', (116, 123))	('patients', 'Species', '9606', (31, 39))	('seizures', 'Disease', 'MESH:D012640', (116, 124))
182801	30558073	However, the relationship between the IDH mutation and glioma-related epilepsy has only begun to be studied in recent years.	('glioma', 'Disease', (55, 61))	('IDH', 'Gene', (38, 41))	('epilepsy', 'Disease', 'MESH:D004827', (70, 78))	('epilepsy', 'Phenotype', 'HP:0001250', (70, 78))	('IDH', 'Gene', '3417', (38, 41))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('mutation', 'Var', (42, 50))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('epilepsy', 'Disease', (70, 78))
182802	30558073	The relationship between TERTp mutations and seizures is by far not explored.	('mutations', 'Var', (31, 40))	('seizures', 'Disease', 'MESH:D012640', (45, 53))	('TERTp', 'Gene', (25, 30))	('TERTp', 'Gene', '7015', (25, 30))	('seizures', 'Disease', (45, 53))	('seizures', 'Phenotype', 'HP:0001250', (45, 53))	('seizure', 'Phenotype', 'HP:0001250', (45, 52))
182803	30558073	In this study, we retrospectively analyzed the clinical and molecular pathologic data of 289 low-grade glioma patients to investigate whether the IDH/TERTp mutations are associated with preoperative seizures and types of seizures.	('IDH', 'Gene', '3417', (146, 149))	('seizures', 'Disease', (199, 207))	('seizure', 'Phenotype', 'HP:0001250', (199, 206))	('glioma', 'Disease', (103, 109))	('low-grade', 'Disease', (93, 102))	('seizures', 'Disease', (221, 229))	('seizures', 'Disease', 'MESH:D012640', (199, 207))	('seizure', 'Phenotype', 'HP:0001250', (221, 228))	('mutations', 'Var', (156, 165))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('seizures', 'Phenotype', 'HP:0001250', (199, 207))	('seizures', 'Disease', 'MESH:D012640', (221, 229))	('TERTp', 'Gene', (150, 155))	('seizures', 'Phenotype', 'HP:0001250', (221, 229))	('IDH', 'Gene', (146, 149))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('associated', 'Reg', (170, 180))	('patients', 'Species', '9606', (110, 118))	('TERTp', 'Gene', '7015', (150, 155))
182810	30558073	In this study, we demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related seizures which is in line with the previous studies.	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('seizures', 'Disease', 'MESH:D012640', (117, 125))	('IDH', 'Gene', (36, 39))	('IDH', 'Gene', '3417', (36, 39))	('seizures', 'Disease', (117, 125))	('seizures', 'Phenotype', 'HP:0001250', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('seizure', 'Phenotype', 'HP:0001250', (117, 124))
182813	30558073	The mutated IDH reduces ketoglutarate to 2-hydroxyvalerate (2Hg) instead of converting isocitrate to ketoglutarate.	('mutated', 'Var', (4, 11))	('ketoglutarate', 'Chemical', '-', (101, 114))	('isocitrate', 'Chemical', 'MESH:C034219', (87, 97))	('ketoglutarate', 'MPA', (24, 37))	('IDH', 'Gene', (12, 15))	('isocitrate', 'MPA', (87, 97))	('reduces', 'NegReg', (16, 23))	('2-hydroxyvalerate', 'Chemical', '-', (41, 58))	('IDH', 'Gene', '3417', (12, 15))	('ketoglutarate', 'Chemical', '-', (24, 37))
182815	30558073	Linninger, et al found that in the low millimolar range, a relatively large D2HG concentration may be present in and around the glioma in which the IDH1 mutation occurs.	('IDH1', 'Gene', '3417', (148, 152))	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('D2HG', 'MPA', (76, 80))	('occurs', 'Reg', (162, 168))	('mutation', 'Var', (153, 161))	('IDH1', 'Gene', (148, 152))
182817	30558073	Chen, et al's research obtained similar conclusions, the D2HG product of the mutated IDH1 may increase neuronal activity by mimicking glutamate activity on the NMDA receptor, and glioma patients with IDH1 mutations are more likely to develop seizures.	('seizures', 'Phenotype', 'HP:0001250', (242, 250))	('IDH1', 'Gene', (200, 204))	('mutated', 'Var', (77, 84))	('mimicking glutamate activity', 'MPA', (124, 152))	('glioma', 'Disease', (179, 185))	('glutamate', 'Chemical', 'MESH:D018698', (134, 143))	('increase', 'PosReg', (94, 102))	('IDH1', 'Gene', '3417', (200, 204))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('patients', 'Species', '9606', (186, 194))	('mutations', 'Var', (205, 214))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('IDH1', 'Gene', (85, 89))	('neuronal activity', 'MPA', (103, 120))	('seizures', 'Disease', (242, 250))	('seizure', 'Phenotype', 'HP:0001250', (242, 249))	('develop', 'PosReg', (234, 241))	('seizures', 'Disease', 'MESH:D012640', (242, 250))	('IDH1', 'Gene', '3417', (85, 89))
182820	30558073	Recent studies have found that mutations in the TERTp are common in gliomas and that TERTp promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations.TERTp promoter mutations often occur in all types of gliomas, suggesting that telomerase-regulated telomere extension may play an important role in the pathogenesis of gliomas.	('TERTp', 'Gene', (206, 211))	('gliomas', 'Disease', (259, 266))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('TERTp', 'Gene', '7015', (206, 211))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('gliomas', 'Disease', (68, 75))	('glioma', 'Disease', (68, 74))	('TERTp', 'Gene', (85, 90))	('gliomas', 'Phenotype', 'HP:0009733', (374, 381))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('IDH', 'Gene', '3417', (192, 195))	('mutations', 'Var', (221, 230))	('TERTp', 'Gene', '7015', (85, 90))	('gliomas', 'Disease', 'MESH:D005910', (259, 266))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('glioma', 'Disease', (374, 380))	('glioma', 'Disease', 'MESH:D005910', (374, 380))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('occur', 'Reg', (237, 242))	('gliomas', 'Phenotype', 'HP:0009733', (259, 266))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (374, 381))	('glioma', 'Disease', (141, 147))	('glioma', 'Phenotype', 'HP:0009733', (374, 380))	('TERTp', 'Gene', (48, 53))	('glioma', 'Disease', (259, 265))	('TERTp', 'Gene', '7015', (48, 53))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('glioma', 'Disease', 'MESH:D005910', (259, 265))	('IDH', 'Gene', (192, 195))	('gliomas', 'Disease', 'MESH:D005910', (374, 381))
182822	30558073	Mutations in the TERTp promoter region most commonly occur in C228 T and C250T.	('TERTp', 'Gene', (17, 22))	('TERTp', 'Gene', '7015', (17, 22))	('C228 T', 'Mutation', 'c.228C>T', (62, 68))	('C250T', 'Var', (73, 78))	('C250T', 'Mutation', 'c.250C>T', (73, 78))	('C228 T', 'Var', (62, 68))	('occur', 'Reg', (53, 58))
182823	30558073	This mutation can increase the activity of the TERTp promoter and provide a new binding site for E-twenty-six (ETS).	('activity', 'MPA', (31, 39))	('increase', 'PosReg', (18, 26))	('TERTp', 'Gene', '7015', (47, 52))	('TERTp', 'Gene', (47, 52))	('binding', 'Interaction', (80, 87))	('mutation', 'Var', (5, 13))	('ETS', 'Chemical', '-', (111, 114))
182824	30558073	Although studies on TERTp mutations and gliomas in etiology and prognosis have seen initial successes in recent years, studies on the potential link between TERTp mutations and tumor-related seizures have been lacking.	('TERTp', 'Gene', '7015', (20, 25))	('seizures', 'Disease', (191, 199))	('seizure', 'Phenotype', 'HP:0001250', (191, 198))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('mutations', 'Var', (26, 35))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('seizures', 'Disease', 'MESH:D012640', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('TERTp', 'Gene', (157, 162))	('tumor', 'Disease', (177, 182))	('TERTp', 'Gene', '7015', (157, 162))	('seizures', 'Phenotype', 'HP:0001250', (191, 199))	('TERTp', 'Gene', (20, 25))
182825	30558073	In the present study, we first explored the effect of TERTp mutations on preoperative epilepsy in LGG patients but revealed no definite correlation between the 2.	('epilepsy', 'Disease', 'MESH:D004827', (86, 94))	('patients', 'Species', '9606', (102, 110))	('epilepsy', 'Disease', (86, 94))	('epilepsy', 'Phenotype', 'HP:0001250', (86, 94))	('mutations', 'Var', (60, 69))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('LGG', 'Disease', (98, 101))
182826	30558073	This finding reinforced the dominating position of IDH mutations in the initiation of seizures in LGG patients.	('IDH', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (102, 110))	('IDH', 'Gene', '3417', (51, 54))	('seizures', 'Disease', 'MESH:D012640', (86, 94))	('LGG', 'Disease', (98, 101))	('seizure', 'Phenotype', 'HP:0001250', (86, 93))	('seizures', 'Phenotype', 'HP:0001250', (86, 94))	('seizures', 'Disease', (86, 94))
182828	30558073	Finally, the specific mechanism of IDH mutation affecting epilepsy remains to be further studied and demonstrated.	('mutation', 'Var', (39, 47))	('IDH', 'Gene', (35, 38))	('epilepsy', 'Phenotype', 'HP:0001250', (58, 66))	('IDH', 'Gene', '3417', (35, 38))	('epilepsy', 'Disease', (58, 66))	('epilepsy', 'Disease', 'MESH:D004827', (58, 66))
182829	30558073	To sum up, in patients with LGG with epileptic seizures as the initial symptom, IDH mutations are more common, suggesting that this genotype is positively correlated with preoperative seizures.	('seizures', 'Disease', (184, 192))	('seizures', 'Disease', 'MESH:D012640', (47, 55))	('seizures', 'Phenotype', 'HP:0001250', (184, 192))	('seizure', 'Phenotype', 'HP:0001250', (184, 191))	('LGG', 'Disease', (28, 31))	('seizures', 'Disease', (47, 55))	('seizures', 'Phenotype', 'HP:0001250', (47, 55))	('IDH', 'Gene', (80, 83))	('mutations', 'Var', (84, 93))	('seizure', 'Phenotype', 'HP:0001250', (47, 54))	('seizures', 'Disease', 'MESH:D012640', (184, 192))	('IDH', 'Gene', '3417', (80, 83))	('patients', 'Species', '9606', (14, 22))	('epileptic', 'Disease', 'MESH:D004827', (37, 46))	('epileptic', 'Disease', (37, 46))
182830	30558073	IDH/TERTp mutations have no definite effect on the type of epileptic seizures in patients with LGG.	('TERTp', 'Gene', (4, 9))	('epileptic', 'Disease', 'MESH:D004827', (59, 68))	('IDH', 'Gene', (0, 3))	('TERTp', 'Gene', '7015', (4, 9))	('IDH', 'Gene', '3417', (0, 3))	('epileptic', 'Disease', (59, 68))	('patients', 'Species', '9606', (81, 89))	('seizures', 'Disease', 'MESH:D012640', (69, 77))	('seizures', 'Phenotype', 'HP:0001250', (69, 77))	('LGG', 'Disease', (95, 98))	('mutations', 'Var', (10, 19))	('seizure', 'Phenotype', 'HP:0001250', (69, 76))	('seizures', 'Disease', (69, 77))
182934	30498643	Glioma shape is a well-known factor associated with malignancy, as irregular tumor shape is often associated with higher malignancy and poor prognosis.	('irregular', 'Var', (67, 76))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('malignancy', 'Disease', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('malignancy', 'Disease', (52, 62))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Glioma', 'Disease', (0, 6))	('tumor', 'Disease', (77, 82))
182948	30498643	It breaks up the glioma into five grades considering not only histological information but also isocitrate dehydrogenase mutation and 1p/19q codeletion.	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('breaks up', 'Phenotype', 'HP:0001061', (3, 12))	('mutation', 'Var', (121, 129))	('glioma', 'Disease', (17, 23))
182961	29675474	The risk to develop a glioma of a certain grade increases with certain mutations.	('glioma', 'Disease', (22, 28))	('develop', 'PosReg', (12, 19))	('mutations', 'Var', (71, 80))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
183030	29675474	In addition, compared with nCBF-T, the biometrics Vol-E/Vol-T and nCBV-T showed equal specificity of 100%, albeit a lower AUC (0.91; P-value <.001/0.87 and <.002, respectively), and also lower sensitivity (80% and 60%, respectively) (Figure 4, A and B; Table 7).	('lower', 'NegReg', (116, 121))	('CBF-T', 'Disease', 'MESH:D001260', (28, 33))	('CBF-T', 'Disease', (28, 33))	('Vol-E/Vol-T', 'Var', (50, 61))	('lower', 'NegReg', (187, 192))	('sensitivity', 'MPA', (193, 204))
183048	29675474	In the present study, combining VOL-E, VOL-E/VOL-T, nADC-T, nADC-E, nCBF-T, nCBV-T yielded a sensitivity of 93.3% but still 100% specificity for distinguishing LGG from MET.	('VOL-E', 'Var', (32, 37))	('nADC-E', 'Chemical', '-', (60, 66))	('CBF-T', 'Disease', (69, 74))	('nADC-T', 'Chemical', '-', (52, 58))	('LGG', 'Disease', (160, 163))	('MET', 'Disease', (169, 172))	('CBF-T', 'Disease', 'MESH:D001260', (69, 74))
183077	27256851	The ROC analysis showed that beta (AUC = 0.853) produced a higher AUC than D (0.781) or mu (0.703), and offered a sensitivity of 87.5%, specificity of 76.7%, and diagnostic accuracy of 82.1%.	('beta', 'Chemical', '-', (29, 33))	('D', 'Chemical', '-', (75, 76))	('beta (AUC = 0.853', 'Var', (29, 46))	('higher', 'PosReg', (59, 65))	('AUC', 'MPA', (66, 69))
183085	27256851	Conventional MRI techniques, including pre-contrast T1-weighted (T1W), T2-weighted (T2W), T2W FLAIR, and post-contrast T1W imaging, have limited sensitivity (e.g., 72.5%) and specificity (e.g., 65.0%) for differentiating low-from high-grade gliomas.	('low-from', 'Disease', (221, 229))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('T2W', 'Var', (90, 93))	('gliomas', 'Phenotype', 'HP:0009733', (241, 248))	('gliomas', 'Disease', (241, 248))	('gliomas', 'Disease', 'MESH:D005910', (241, 248))
183101	27256851	The imaging protocol included pre-contrast T1W FLAIR, T2W FLAIR, T2W PROPELLER, and multi-b-value diffusion-weighted (DW) sequences, followed by post-contrast T1W imaging.	('T2W', 'Var', (65, 68))	('D', 'Chemical', '-', (118, 119))	('T1W FLAIR', 'Var', (43, 52))	('T2W FLAIR', 'Var', (54, 63))
183103	27256851	The DW images were produced using a single-shot echo-planar imaging (EPI) sequence with 17 b-values (01, 201, 501, 1001, 2001, 4001, 6001, 8001, 10001, 12001, 16001, 20002, 24002, 28002, 32004, 36004 and 40004 s/mm2, where the subscript denotes the number of averages).	('D', 'Chemical', '-', (4, 5))	('32004', 'Var', (187, 192))	('01', 'Var', (101, 103))
183133	27256851	The sensitivity was noticeably improved by beta or the combination of beta and D, which resulted in the best accuracy (82.1%).	('improved', 'PosReg', (31, 39))	('beta', 'Chemical', '-', (70, 74))	('beta', 'Chemical', '-', (43, 47))	('sensitivity', 'MPA', (4, 15))	('D', 'Chemical', '-', (79, 80))	('beta', 'Var', (43, 47))
183181	33937395	In the bladder cancer, high expression of NRP2 is associated with chemoresistance and epithelial-to-mesenchymal transition and poor patient prognosis.	('epithelial-to-mesenchymal transition', 'CPA', (86, 122))	('high expression', 'Var', (23, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (7, 21))	('NRP2', 'Gene', (42, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (7, 21))	('bladder cancer', 'Disease', (7, 21))	('patient', 'Species', '9606', (132, 139))	('associated', 'Reg', (50, 60))	('chemoresistance', 'CPA', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
183194	33937395	In addition, high NRP1 expression was associated with higher stroma, microenvironment, and immune scores, as well as more endothelial cell infiltration in most tumours.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('higher', 'PosReg', (54, 60))	('high', 'Var', (13, 17))	('tumours', 'Disease', (160, 167))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('stroma', 'CPA', (61, 67))	('immune scores', 'CPA', (91, 104))	('NRP1', 'Gene', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (23, 33))
183195	33937395	In KIRC, a high NRP1 expression was associated with a larger tumour size, higher risk of distant metastases, and worse stage staging and grade staging.	('metastases', 'Disease', (97, 107))	('NRP1', 'Protein', (16, 20))	('expression', 'MPA', (21, 31))	('tumour size', 'CPA', (61, 72))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('high', 'Var', (11, 15))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
183198	33937395	Anti-NRP1 therapy can block tumour angiogenesis and upregulate the antitumour immune response.	('Anti-NRP1', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('antitumour immune response', 'CPA', (67, 93))	('upregulate', 'PosReg', (52, 62))	('block tumour', 'Disease', (22, 34))	('block tumour', 'Disease', 'MESH:D006327', (22, 34))
183199	33937395	NRP2 has also been found to be closely associated with metastasis and BRAFV600E in thyroid cancer.	('NRP2', 'Gene', (0, 4))	('metastasis', 'CPA', (55, 65))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('BRAFV600E', 'Var', (70, 79))	('BRAFV600E', 'Mutation', 'rs113488022', (70, 79))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))
183319	31387579	CNV copy number variation TCGA The Cancer Genome Atlas BLCA bladder urothelial carcinoma LGG Brain Lower Grade Glioma PAAD pancreatic adenocarcinoma STAD stomach adenocarcinoma AUC area under the curve ROC receiver operating characteristic HR hazard ratio CI confidence intervals YPZ, XL and YJX conceived and designed the overall study.	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (154, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BLCA', 'Chemical', '-', (55, 59))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (123, 148))	('Glioma', 'Disease', 'MESH:D005910', (111, 117))	('stomach adenocarcinoma', 'Disease', (154, 176))	('PAAD', 'Chemical', '-', (118, 122))	('Glioma', 'Phenotype', 'HP:0009733', (111, 117))	('bladder urothelial carcinoma', 'Disease', (60, 88))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (123, 148))	('PAAD', 'Phenotype', 'HP:0006725', (118, 122))	('pancreatic adenocarcinoma', 'Disease', (123, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('copy number variation', 'Var', (4, 25))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (60, 88))	('Glioma', 'Disease', (111, 117))	('STAD', 'Chemical', '-', (149, 153))
183371	25706286	Differentiation assays revealed that the 253G1-NS/PCs differentiated into beta-III tubulin-positive neurons and GFAP-positive astrocytes in vitro, but not into Oligo-1-positive oligodendrocyte progenitor cells (Fig.	('Oligo-1', 'Gene', '50914', (160, 167))	('GFAP', 'Gene', '14580', (112, 116))	('beta-III tubulin-positive', 'Protein', (74, 99))	('GFAP', 'Gene', (112, 116))	('Oligo-1', 'Gene', (160, 167))	('253G1-NS/PCs', 'Var', (41, 53))
183372	25706286	To examine the sensitivity of BLI, we used the Xenogen-IVIS system (Caliper Life-Sciences) to detect the luminescence intensity of the 253G1-NS/PCs at various cell numbers (ranging from 1.5 x 105 to 1.2 x 106 cells per well) in the presence of D-luciferin.	('luminescence intensity', 'MPA', (105, 127))	('253G1-NS/PCs', 'Var', (135, 147))	('D-luciferin', 'Chemical', 'MESH:C532924', (244, 255))
183375	25706286	The bioluminescent ffLuc signals emanating from the transduced 253G1-NS/PCs disappeared between 14 and 21 days after transplantation in the Without-IS mice (Table 1, Fig.	('bioluminescent ffLuc signals', 'MPA', (4, 32))	('disappeared', 'NegReg', (76, 87))	('mice', 'Species', '10090', (151, 155))	('253G1-NS/PCs', 'Var', (63, 75))
183376	25706286	This result suggests that immune rejection of the xenografted 253G1-NS/PCs occurred within 3 weeks in all of the mice without immunosuppressants, even though the spinal cord is a so-called immune-privileged site.	('253G1-NS/PCs', 'Var', (62, 74))	('mice', 'Species', '10090', (113, 117))	('immune rejection', 'CPA', (26, 42))
183377	25706286	Graft survival rate was 100% in the With-IS (FK506 plus anti-cluster of differentiation (CD4) monoclonal antibody) group, versus 0% in the Without-IS group.	('rat', 'Species', '10116', (15, 18))	('FK506', 'Var', (45, 50))	('CD4', 'Gene', (89, 92))	('FK506', 'Chemical', 'MESH:D016559', (45, 50))	('Graft survival rate', 'CPA', (0, 19))
183393	25706286	The grafted 253G1-NS/PCs differentiated into beta-III tubulin-positive neurons, GFAP-positive astrocytes, and Oligo-1-positive oligodendrocyte progenitor cells.	('GFAP', 'Gene', (80, 84))	('253G1-NS/PCs', 'Var', (12, 24))	('GFAP', 'Gene', '14580', (80, 84))	('beta-III tubulin-positive', 'Protein', (45, 70))	('Oligo-1', 'Gene', '50914', (110, 117))	('Oligo-1', 'Gene', (110, 117))
183403	25706286	During the course of immune rejection, CD11b-positive microglia, CD3-positive lymphocytes, and NKp46-positive natural killer (NK) T-cells infiltrated the tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('CD11b-positive', 'Var', (39, 53))	('CD3', 'Gene', (65, 68))	('CD3', 'Gene', '12501', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('rat', 'Species', '10116', (144, 147))
183420	25706286	Furthermore, our unpublished data revealed a low survival rate for xenografted hiPSC-NS/PCs in the mouse spinal cord when FK506, a clinically employed IL-2 blocker, was used as monotherapy (data not shown).	('mouse', 'Species', '10090', (99, 104))	('IL-2', 'Gene', (151, 155))	('FK506', 'Var', (122, 127))	('FK506', 'Chemical', 'MESH:D016559', (122, 127))	('hiPSC-NS/PCs', 'Gene', (79, 91))	('rat', 'Species', '10116', (58, 61))	('IL-2', 'Gene', '16183', (151, 155))
183421	25706286	For this reason, the current study used FK506 and anti-CD4 mAb as combination immunosuppressant therapy along with stem cell transplantation for SCI with reference to recent studies.	('anti-CD4', 'Var', (50, 58))	('FK506', 'Chemical', 'MESH:D016559', (40, 45))	('FK506', 'Var', (40, 45))
183426	25706286	The ESCs were immune rejected in both models, but the survival period was significantly longer in the CD4-positive T-cell-knockout mice than in the CD8-positive T-cell-knockout mice.	('CD8', 'Gene', '925', (148, 151))	('CD4-positive', 'Var', (102, 114))	('survival period', 'CPA', (54, 69))	('CD8', 'Gene', (148, 151))	('mice', 'Species', '10090', (131, 135))	('mice', 'Species', '10090', (177, 181))	('longer', 'PosReg', (88, 94))
183440	25706286	For example, mutations in the tumor suppressor gene in transplanted NS/PCs increased the risk of astrocytoma in a mouse model.	('increased', 'Reg', (75, 84))	('astrocytoma', 'Disease', 'MESH:D001254', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('astrocytoma', 'Disease', (97, 108))	('mouse', 'Species', '10090', (114, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (30, 35))
183458	25706286	In addition, immune rejection might occur due to a mismatch between the donor and recipient in a locus other than HLA-A, -B, and -DR or in the minor histocompatibility antigen.	('donor', 'Species', '9606', (72, 77))	('occur due', 'Reg', (36, 45))	('mismatch', 'Var', (51, 59))	('immune rejection', 'CPA', (13, 29))	('HLA-A, -B, and -DR', 'Gene', '3105;3106', (114, 132))
183492	22736438	The dissociation of Galphai subunit from Gbetagamma activates, among others, MAP-kinase and Akt signaling.	('Galphai subunit', 'Protein', (20, 35))	('dissociation', 'Var', (4, 16))	('Akt', 'Gene', '207', (92, 95))	('MAP-kinase', 'Pathway', (77, 87))	('Akt', 'Gene', (92, 95))	('activates', 'PosReg', (52, 61))
183532	22736438	Downregulation of CXCR7 also significantly decreased the growth of HT1197 cells (Cell number: control: 6.5+-0.45x104; CXCR7 siRNA: 3.4+-0.25; P<0.001).	('CXCR7', 'Gene', (118, 123))	('growth', 'MPA', (57, 63))	('CXCR7', 'Gene', '57007', (18, 23))	('Downregulation', 'Var', (0, 14))	('HT1197', 'CellLine', 'CVCL:1291', (67, 73))	('CXCR7', 'Gene', (18, 23))	('CXCR7', 'Gene', '57007', (118, 123))	('decreased', 'NegReg', (43, 52))
183570	22736438	However, CXCR7 staining was significantly higher in both low- and high-grade tissues when compared to NBL tissues (P 0.002; Figure 2D).	('CXCR7', 'Gene', '57007', (9, 14))	('higher', 'PosReg', (42, 48))	('NBL', 'Gene', (102, 105))	('NBL', 'Gene', '9253', (102, 105))	('low-', 'Var', (57, 61))	('CXCR7', 'Gene', (9, 14))
183583	22736438	Contrarily, CXCR7 levels were significantly elevated in patients with high-grade BCa (Fig 3B, Table 3A).	('patients', 'Species', '9606', (56, 64))	('CXCR7', 'Gene', (12, 17))	('elevated', 'PosReg', (44, 52))	('high-grade', 'Var', (70, 80))	('CXCR7', 'Gene', '57007', (12, 17))	('BCa', 'Disease', (81, 84))
183586	22736438	The differences in CXCR7 levels among patients with low-grade BCa and the control categories were not significant (P>0.05).	('BCa', 'Disease', (62, 65))	('CXCR7', 'Gene', (19, 24))	('CXCR7', 'Gene', '57007', (19, 24))	('low-grade', 'Var', (52, 61))	('patients', 'Species', '9606', (38, 46))
183621	22736438	Nevertheless, in exfoliated bladder tumor cells, CXCR7 mRNA expression was higher (1.3+-1.5) in patients with high-grade bladder tumors than in healthy individuals, patients with benign conditions or in patients with a history of BCa (~ 0.5+-0.3).	('patients', 'Species', '9606', (165, 173))	('bladder tumor', 'Phenotype', 'HP:0009725', (121, 134))	('high-grade', 'Var', (110, 120))	('bladder tumor', 'Disease', (28, 41))	('patients', 'Species', '9606', (203, 211))	('exfoliated bladder', 'Phenotype', 'HP:0100645', (17, 35))	('bladder tumors', 'Phenotype', 'HP:0009725', (121, 135))	('bladder tumors', 'Disease', 'MESH:D001749', (121, 135))	('bladder tumor', 'Disease', 'MESH:D001749', (28, 41))	('higher', 'PosReg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (96, 104))	('CXCR7', 'Gene', (49, 54))	('BCa', 'Disease', (230, 233))	('bladder tumor', 'Disease', 'MESH:D001749', (121, 134))	('bladder tumors', 'Disease', (121, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('CXCR7', 'Gene', '57007', (49, 54))	('bladder tumor', 'Phenotype', 'HP:0009725', (28, 41))
183625	22736438	Contrarily, CXCR7 mRNA levels were significantly elevated in the exfoliated urothelial cells from high-grade BCa patients; 90% sensitivity.	('CXCR7', 'Gene', (12, 17))	('patients', 'Species', '9606', (113, 121))	('CXCR7', 'Gene', '57007', (12, 17))	('high-grade', 'Var', (98, 108))	('elevated', 'PosReg', (49, 57))
183626	22736438	Based on a recent study which showed that bind of bacterial lipopolysaccarhide to the toll-like receptor 4 (TLR4) increased CXCR7 expression in a colon carcinoma cell line, one would have expected a consistent increase in CXCR7 expression among patients with urinary tract infection.	('TLR4', 'Gene', '7099', (108, 112))	('CXCR7', 'Gene', (222, 227))	('urinary tract infection', 'Phenotype', 'HP:0000010', (259, 282))	('urinary tract infection', 'Disease', 'MESH:D014552', (259, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('bind', 'Var', (42, 46))	('CXCR7', 'Gene', (124, 129))	('patients', 'Species', '9606', (245, 253))	('TLR4', 'Gene', (108, 112))	('toll-like receptor 4', 'Gene', (86, 106))	('increased', 'PosReg', (114, 123))	('colon carcinoma', 'Disease', (146, 161))	('CXCR7', 'Gene', '57007', (124, 129))	('toll-like receptor 4', 'Gene', '7099', (86, 106))	('CXCR7', 'Gene', '57007', (222, 227))	('colon carcinoma', 'Disease', 'MESH:D015179', (146, 161))	('urinary tract infection', 'Disease', (259, 282))	('increase', 'PosReg', (210, 218))
183636	29057925	Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG).	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('inhibition', 'NegReg', (65, 75))	('IDH1', 'Gene', (152, 156))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('IDH1', 'Gene', '3417', (152, 156))	('gliomas', 'Disease', (49, 56))	('R132H', 'Mutation', 'rs121913500', (158, 163))	('IDH1', 'Gene', (36, 40))	('Bcl-xL', 'Gene', (79, 85))	('2-R-2-hydroxyglutarate', 'Chemical', '-', (218, 240))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))	('gliomas', 'Disease', (94, 101))	('R132H', 'Gene', (158, 163))	('2-HG', 'Chemical', '-', (242, 246))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1', 'Gene', '3417', (36, 40))	('mutation in', 'Var', (117, 128))
183637	29057925	In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells.	('more', 'PosReg', (129, 133))	('I', 'Chemical', 'MESH:D007455', (184, 185))	('apoptosis', 'CPA', (134, 143))	('IDH1-mutated', 'Gene', (147, 159))	('glioblastoma', 'Disease', (63, 75))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('inhibition', 'Var', (86, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('I', 'Chemical', 'MESH:D007455', (147, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('patient', 'Species', '9606', (32, 39))	('Bcl-xL', 'Protein', (100, 106))
183638	29057925	Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('glioblastoma', 'Disease', (157, 169))	('sensitizes', 'Reg', (146, 156))	('IDH1', 'Gene', (44, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('mutated', 'Var', (36, 43))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('levels of Mcl-1', 'MPA', (63, 78))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('lower levels of Mcl', 'Phenotype', 'HP:0025066', (57, 76))	('Anaplastic astrocytoma', 'Disease', (0, 22))	('Anaplastic astrocytoma', 'Disease', 'MESH:D001254', (0, 22))	('lower', 'NegReg', (57, 62))
183639	29057925	Addition of 2-HG to glioblastoma cultures recapitulates the effects of the IDH mutation on intrinsic apoptosis, shuts down oxidative phosphorylation and reduces ATP levels in glioblastoma cells.	('intrinsic apoptosis', 'CPA', (91, 110))	('glioblastoma', 'Disease', (20, 32))	('ATP', 'Chemical', 'MESH:D000255', (161, 164))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('ATP levels', 'MPA', (161, 171))	('reduces', 'NegReg', (153, 160))	('glioblastoma', 'Disease', (175, 187))	('2-HG', 'Chemical', '-', (12, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (175, 187))	('oxidative phosphorylation', 'MPA', (123, 148))	('mutation', 'Var', (79, 87))	('shuts down', 'NegReg', (112, 122))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))
183641	29057925	In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival.	('I', 'Chemical', 'MESH:D007455', (65, 66))	('leads to', 'Reg', (89, 97))	('glioblastoma', 'Disease', (17, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (17, 29))	('inhibition', 'NegReg', (78, 88))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('glioblastoma', 'Phenotype', 'HP:0012174', (17, 29))	('Bcl-xL', 'MPA', (71, 77))	('IDH1', 'Gene', (65, 69))	('mutated', 'Var', (57, 64))	('long-term survival', 'CPA', (98, 116))
183643	29057925	Glioblastoma (GBM) cells are often characterized by the presence of the IDH1 R132H mutation and high expression of anti-apoptotic proteins.	('Glioblastoma', 'Disease', (0, 12))	('IDH1', 'Gene', (72, 76))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('R132H', 'Var', (77, 82))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('expression', 'MPA', (101, 111))	('R132H', 'Mutation', 'rs121913500', (77, 82))
183647	29057925	Deep-sequencing technologies have greatly assisted in the identification of novel mutations in cancers.	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
183648	29057925	Examples are mutations of IDH1 at codon 132 (R132H) and IDH2 at codon 172 (R172K) in diffuse gliomas and acute myeloid leukemia.	('gliomas', 'Disease', (93, 100))	('R172K', 'Mutation', 'rs121913503', (75, 80))	('IDH2', 'Gene', '3418', (56, 60))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (111, 127))	('R132H', 'Var', (45, 50))	('R172K', 'Var', (75, 80))	('acute myeloid leukemia', 'Disease', (105, 127))	('IDH1', 'Gene', (26, 30))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (105, 127))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('mutations', 'Var', (13, 22))	('IDH2', 'Gene', (56, 60))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (105, 127))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))
183649	29057925	The majority of low-grade gliomas and secondary glioblastomas harbor the IDH1 mutation.	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('mutation', 'Var', (78, 86))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('glioblastomas', 'Phenotype', 'HP:0012174', (48, 61))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('IDH1', 'Gene', (73, 77))	('harbor', 'Reg', (62, 68))	('glioblastomas', 'Disease', 'MESH:D005909', (48, 61))	('glioblastomas', 'Disease', (48, 61))
183652	29057925	While the initial discovery of IDH mutations raised significant excitement in the field, the identification of 2-HG in IDH-mutated tumors received as much attention due to the potential translational implications.	('IDH', 'Gene', '3417', (119, 122))	('IDH', 'Gene', (31, 34))	('2-HG', 'Chemical', '-', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('IDH', 'Gene', '3417', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('IDH', 'Gene', (119, 122))	('mutations', 'Var', (35, 44))
183659	29057925	Transduced U87MG and T98G glioblastoma cells, bearing the wild-type or mutated form of IDH1 were treated with increasing concentrations of the BH-3 mimetic ABT263, a known inhibitor of both Bcl-xL and Bcl-2.	('glioblastoma', 'Disease', (26, 38))	('ABT263', 'Chemical', 'MESH:C528561', (156, 162))	('mutated', 'Var', (71, 78))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('IDH1', 'Gene', (87, 91))	('U87MG', 'CellLine', 'CVCL:0022', (11, 16))
183660	29057925	U87MG (IDH1-R132H) cells displayed an approximately thirty times higher sensitivity to ABT263 (IC50 = 0.1195 muM:nanomolar range) than their wild-type counterparts (IC50 = 3.314 muM) (Fig.	('muM', 'Gene', (109, 112))	('ABT263', 'Chemical', 'MESH:C528561', (87, 93))	('muM', 'Gene', '56925', (109, 112))	('muM', 'Gene', (178, 181))	('I', 'Chemical', 'MESH:D007455', (95, 96))	('sensitivity', 'MPA', (72, 83))	('I', 'Chemical', 'MESH:D007455', (165, 166))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('R132H', 'Mutation', 'rs121913500', (12, 17))	('higher', 'PosReg', (65, 71))	('U87MG', 'Var', (0, 5))	('I', 'Chemical', 'MESH:D007455', (7, 8))	('muM', 'Gene', '56925', (178, 181))
183663	29057925	In concordance with our findings in the virally transduced glioblastoma cell lines, HCT116 IDH1-R132H cells (heterozygous knock-in mutation) showed higher sensitivity to ABT263 with a threefold decrease of the IC50 value (Fig.	('sensitivity', 'MPA', (155, 166))	('HCT116', 'Var', (84, 90))	('ABT263', 'Chemical', 'MESH:C528561', (170, 176))	('R132H', 'Mutation', 'rs121913500', (96, 101))	('I', 'Chemical', 'MESH:D007455', (91, 92))	('glioblastoma', 'Disease', (59, 71))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('HCT116', 'CellLine', 'CVCL:0291', (84, 90))	('IC50 value', 'MPA', (210, 220))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('I', 'Chemical', 'MESH:D007455', (210, 211))	('decrease', 'NegReg', (194, 202))	('higher', 'PosReg', (148, 154))
183665	29057925	IC50-values for ABT263 in glioma stem-like cells bearing IDH1-WT or IDH1-R132H are displayed in Supplementary Table 1.	('I', 'Chemical', 'MESH:D007455', (57, 58))	('ABT263', 'Chemical', 'MESH:C528561', (16, 22))	('glioma', 'Disease', (26, 32))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('ABT263', 'Gene', (16, 22))	('I', 'Chemical', 'MESH:D007455', (68, 69))	('IDH1-R132H', 'Var', (68, 78))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
183667	29057925	U87MG, T98G, LN229, SF188 (pediatric), MGPP-3 (mouse) glioblastoma cells, NCH644 glioma stem-like cells and GBM12 (derived from a patient-derived xenograft) glioma cells were treated with ABT263, 2-HG, the combination of both or vehicle.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('patient', 'Species', '9606', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('glioma', 'Disease', (81, 87))	('NCH644', 'Chemical', '-', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('ABT263', 'Chemical', 'MESH:C528561', (188, 194))	('2-HG', 'Chemical', '-', (196, 200))	('glioma', 'Disease', (157, 163))	('T98G', 'Var', (7, 11))	('LN229', 'CellLine', 'CVCL:0393', (13, 18))	('mouse', 'Species', '10090', (47, 52))	('glioblastoma', 'Disease', (54, 66))
183668	29057925	To gain a deeper understanding of the molecular mechanism(s) responsible for the preferential response of IDH1-mutated cancer cells to ABT263 treatment, we performed knockdown experiments with small-interfering RNA (siRNA) against Bcl-xL, a known major target of ABT263.	('ABT263', 'Chemical', 'MESH:C528561', (135, 141))	('small-interfering', 'Var', (193, 210))	('ABT263', 'Chemical', 'MESH:C528561', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
183669	29057925	Knockdown of Bcl-xL resulted in a significant increase in the subG1 fraction of U87MG IDH1-R132H and HCT116 IDH1-R132H cells when compared to the respective IDH1 wild-type cells (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (80, 85))	('R132H', 'Mutation', 'rs121913500', (113, 118))	('increase', 'PosReg', (46, 54))	('subG1 fraction', 'MPA', (62, 76))	('U87MG IDH1-R132H', 'Var', (80, 96))	('R132H', 'Mutation', 'rs121913500', (91, 96))	('HCT116', 'CellLine', 'CVCL:0291', (101, 107))	('IDH1-R132H', 'Var', (86, 96))
183672	29057925	We, therefore, silenced U251 and LN229 glioblastoma cells for Bcl-xL.	('glioblastoma', 'Disease', (39, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('LN229', 'CellLine', 'CVCL:0393', (33, 38))	('silenced', 'Var', (15, 23))
183673	29057925	In both cell lines, knockdown of Bcl-xL resulted in a significant decrease in the fraction of viable cells among those cells treated in addition with 2-HG (Fig.	('Bcl-xL', 'Gene', (33, 39))	('fraction of viable cells', 'CPA', (82, 106))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('2-HG', 'Chemical', '-', (150, 154))	('decrease', 'NegReg', (66, 74))	('knockdown', 'Var', (20, 29))
183674	29057925	In addition, treatment with the Bcl-2 inhibitor ABT199 did not result in a marked enhancement of the pro-apoptotic response in SF188, U251 and LN229 cells treated with ABT199/2-HG when compared to single-agent treatments (Supplementary Fig.	('LN229', 'CellLine', 'CVCL:0393', (143, 148))	('ABT199', 'Chemical', 'MESH:C579720', (48, 54))	('ABT199', 'Chemical', 'MESH:C579720', (168, 174))	('ABT199/2-HG', 'Var', (168, 179))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('pro-apoptotic response', 'MPA', (101, 123))	('enhancement', 'PosReg', (82, 93))	('2-HG', 'Chemical', '-', (175, 179))
183676	29057925	Analysis of cell morphology lead to the observation that cells carrying the IDH1-R132H mutation developed typical features of apoptosis upon treatment with ABT263.	('IDH1-R132H', 'Var', (76, 86))	('ABT263', 'Chemical', 'MESH:C528561', (156, 162))	('apoptosis', 'CPA', (126, 135))	('R132H', 'Mutation', 'rs121913500', (81, 86))
183678	29057925	Similarly, in IDH1-mutated T98G glioblastoma cells, PICPG-4 glioma cells (IDH1-R132H + , PDGF + , TP53-/-; derived from a transgenic mouse model) and isogenic HCT116 IDH1-R132H cells treatment with ABT263 resulted in an enhanced fraction of subG1 cells (apoptotic cells) when compared to T98G IDH1-WT, PPC2 (IDH1-WT) or HCT116 IDH1-WT cells (Fig.	('glioma', 'Disease', (60, 66))	('transgenic', 'Species', '10090', (122, 132))	('HCT116', 'CellLine', 'CVCL:0291', (320, 326))	('mouse', 'Species', '10090', (133, 138))	('I', 'Chemical', 'MESH:D007455', (166, 167))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('R132H', 'Mutation', 'rs121913500', (79, 84))	('ABT263', 'Chemical', 'MESH:C528561', (198, 204))	('I', 'Chemical', 'MESH:D007455', (308, 309))	('HCT116', 'CellLine', 'CVCL:0291', (159, 165))	('I', 'Chemical', 'MESH:D007455', (14, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (32, 44))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('TP53', 'Gene', (98, 102))	('enhanced', 'PosReg', (220, 228))	('I', 'Chemical', 'MESH:D007455', (53, 54))	('I', 'Chemical', 'MESH:D007455', (293, 294))	('ABT263', 'Var', (198, 204))	('subG1 cells', 'CPA', (241, 252))	('glioblastoma', 'Disease', (32, 44))	('R132H', 'Mutation', 'rs121913500', (171, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('I', 'Chemical', 'MESH:D007455', (74, 75))	('TP53', 'Gene', '7157', (98, 102))	('I', 'Chemical', 'MESH:D007455', (327, 328))
183679	29057925	On the molecular level, these findings were mirrored by enhanced cleavage of caspases 3, 9 and PARP in IDH1-mutated U87MG, T98G and HCT116 cells (Fig.	('PARP', 'Gene', (95, 99))	('U87MG', 'CellLine', 'CVCL:0022', (116, 121))	('cleavage', 'MPA', (65, 73))	('U87MG', 'Var', (116, 121))	('IDH1-mutated', 'Gene', (103, 115))	('enhanced', 'PosReg', (56, 64))	('HCT116', 'CellLine', 'CVCL:0291', (132, 138))	('caspases 3, 9', 'Gene', '836;842', (77, 90))	('PARP', 'Gene', '1302', (95, 99))
183682	29057925	As anticipated, treatment with ABT263 and 2-HG resulted in a synergistic increase in the fraction of annexin V-positive (apoptotic) U87MG, LN229, T98G, and SF188 glioblastoma cells and the fraction of subG1 cells in SF188 pediatric glioblastoma cells (Fig.	('2-HG', 'Chemical', '-', (42, 46))	('U87MG', 'CellLine', 'CVCL:0022', (132, 137))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (222, 244))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('T98G', 'Var', (146, 150))	('annexin V', 'Gene', (101, 110))	('glioblastoma', 'Disease', (162, 174))	('2-HG', 'Var', (42, 46))	('ABT263', 'Chemical', 'MESH:C528561', (31, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('annexin V', 'Gene', '308', (101, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (232, 244))	('ABT263', 'Var', (31, 37))	('glioblastoma', 'Disease', (232, 244))	('increase', 'PosReg', (73, 81))	('pediatric glioblastoma', 'Disease', (222, 244))	('glioblastoma', 'Phenotype', 'HP:0012174', (232, 244))	('LN229', 'CellLine', 'CVCL:0393', (139, 144))	('LN229', 'Var', (139, 144))
183685	29057925	IDH1-mutated U87MG glioblastoma cells showed a marked decrease in the mitochondrial membrane potential when subjected to treatment with increasing concentrations of ABT263 when compared to U87MG IDH1-WT cells (Fig.	('glioblastoma', 'Disease', (19, 31))	('decrease', 'NegReg', (54, 62))	('ABT263', 'Gene', (165, 171))	('mitochondrial membrane potential', 'MPA', (70, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('U87MG', 'CellLine', 'CVCL:0022', (13, 18))	('U87MG', 'CellLine', 'CVCL:0022', (189, 194))	('ABT263', 'Chemical', 'MESH:C528561', (165, 171))	('IDH1-mutated', 'Var', (0, 12))
183686	29057925	In support of this finding, treatment with the death receptor ligand TRAIL did not result in enhanced pro-apoptotic response in IDH1-mutant cells (Supplementary Fig.	('TRAIL', 'Gene', '8743', (69, 74))	('IDH1-mutant', 'Gene', (128, 139))	('I', 'Chemical', 'MESH:D007455', (128, 129))	('TRAIL', 'Gene', (69, 74))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('enhanced', 'PosReg', (93, 101))	('pro-apoptotic response', 'MPA', (102, 124))	('I', 'Chemical', 'MESH:D007455', (72, 73))	('IDH1-mutant', 'Var', (128, 139))
183687	29057925	Furthermore, pro-apoptotic chemotherapeutics such as etoposide or paclitaxel did not display a varying response dependent on different IDH1 genotypes (Supplementary Fig.	('IDH1', 'Gene', (135, 139))	('genotypes', 'Var', (140, 149))	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('etoposide', 'Chemical', 'MESH:D005047', (53, 62))
183690	29057925	5A and B, U87MG and murine glioblastoma cells bearing the IDH1 mutation showed decreased expression of Mcl-1, Bcl-xL, and Bcl-2.	('Bcl-2', 'MPA', (122, 127))	('expression', 'MPA', (89, 99))	('decreased', 'NegReg', (79, 88))	('glioblastoma', 'Disease', (27, 39))	('mutation', 'Var', (63, 71))	('Bcl-xL', 'MPA', (110, 116))	('murine', 'Species', '10090', (20, 26))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('U87MG', 'CellLine', 'CVCL:0022', (10, 15))	('IDH1', 'Gene', (58, 62))	('Mcl-1', 'MPA', (103, 108))
183694	29057925	In contrast, no significant difference was found with respect to Bcl-2 or Bcl-xL expression among different IDH1 mutation status (Supplementary Fig.	('mutation', 'Var', (113, 121))	('I', 'Chemical', 'MESH:D007455', (108, 109))	('Bcl-2', 'MPA', (65, 70))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('Bcl-xL expression', 'MPA', (74, 91))	('IDH1', 'Gene', (108, 112))
183699	29057925	Silencing Noxa results in a significant inhibition of ABT263/2-HG-mediated apoptosis (Fig.	('ABT263/2-HG-mediated apoptosis', 'CPA', (54, 84))	('inhibition', 'NegReg', (40, 50))	('Noxa', 'Gene', '5366', (10, 14))	('2-HG', 'Chemical', '-', (61, 65))	('Noxa', 'Gene', (10, 14))	('ABT263', 'Chemical', 'MESH:C528561', (54, 60))	('Silencing', 'Var', (0, 9))
183702	29057925	Given that 1) the Noxa/Mcl-1 ratio is markedly increased upon treatment with AB263/2-HG and 2) Noxa knockdown results in an attenuation of the pro-apoptotic response, one would expect that knockdown of Bak also attenuates ABT263/2-HG-mediated apoptosis.	('knockdown', 'Var', (100, 109))	('Noxa', 'Gene', '5366', (95, 99))	('pro-apoptotic response', 'MPA', (143, 165))	('2-HG', 'Chemical', '-', (229, 233))	('knockdown', 'Var', (189, 198))	('Noxa', 'Gene', (95, 99))	('ABT263', 'Chemical', 'MESH:C528561', (222, 228))	('increased', 'PosReg', (47, 56))	('Noxa', 'Gene', '5366', (18, 22))	('attenuates', 'NegReg', (211, 221))	('Noxa', 'Gene', (18, 22))	('Bak', 'Gene', (202, 205))	('Bak', 'Gene', '578', (202, 205))	('attenuation', 'NegReg', (124, 135))	('2-HG', 'Chemical', '-', (83, 87))
183703	29057925	As anticipated, selective knockdown of Bak resulted in a significant reduction of apoptosis in cells treated with ABT263 and 2-HG (Fig.	('ABT263', 'Chemical', 'MESH:C528561', (114, 120))	('2-HG', 'Chemical', '-', (125, 129))	('apoptosis', 'CPA', (82, 91))	('Bak', 'Gene', (39, 42))	('Bak', 'Gene', '578', (39, 42))	('knockdown', 'Var', (26, 35))	('reduction', 'NegReg', (69, 78))
183705	29057925	Both U87MG and GBM12 cells displayed a concentration-dependent decrease in Mcl-1 expression when treated with 2-HG for 24 h (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (5, 10))	('Mcl-1', 'Gene', (75, 80))	('U87MG', 'Var', (5, 10))	('decrease', 'NegReg', (63, 71))	('2-HG', 'Chemical', '-', (110, 114))
183708	29057925	To address this finding, we analyzed the basal oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in wild-type and mutant IDH1 cells.	('oxygen', 'Chemical', 'MESH:D010100', (47, 53))	('IDH1', 'Gene', (145, 149))	('mutant', 'Var', (138, 144))	('extracellular acidification rate', 'MPA', (81, 113))	('basal oxygen consumption rate', 'MPA', (41, 70))
183709	29057925	Based on these findings, we analyzed the metabolic phenotype of IDH1 wild-type and IDH1 R132H-mutated glioblastoma cells.	('glioblastoma', 'Disease', (102, 114))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('R132H-mutated', 'Var', (88, 101))	('R132H', 'Mutation', 'rs121913500', (88, 93))	('IDH1', 'Gene', (83, 87))
183710	29057925	In agreement, IDH1 R132H-mutated or 2-HG-treated glioblastoma cells showed less mitochondrial respiration and significant reduction in ATP production (Fig.	('2-HG', 'Chemical', '-', (36, 40))	('glioblastoma', 'Disease', (49, 61))	('ATP production', 'MPA', (135, 149))	('less', 'NegReg', (75, 79))	('reduction', 'NegReg', (122, 131))	('mitochondrial respiration', 'MPA', (80, 105))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('IDH1', 'Gene', (14, 18))	('I', 'Chemical', 'MESH:D007455', (14, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('ATP', 'Chemical', 'MESH:D000255', (135, 138))	('R132H-mutated', 'Var', (19, 32))
183713	29057925	Consistently, total ATP levels were also reduced in 2-HG-treated and IDH1 R132H-mutated cells (Supplementary Fig.	('reduced', 'NegReg', (41, 48))	('total ATP levels', 'MPA', (14, 30))	('ATP', 'Chemical', 'MESH:D000255', (20, 23))	('2-HG', 'Chemical', '-', (52, 56))	('R132H', 'Mutation', 'rs121913500', (74, 79))	('R132H-mutated', 'Var', (74, 87))	('IDH1', 'Gene', (69, 73))
183720	29057925	5a, U87MG IDH1-R132H cells treated with puromycin show a significantly decreased puromycin labeling when compared to IDH1-WT cells confirming decreased protein synthesis.	('puromycin labeling', 'MPA', (81, 99))	('IDH1-R132H', 'Var', (10, 20))	('U87MG IDH1-R132H', 'Var', (4, 20))	('protein synthesis', 'MPA', (152, 169))	('decreased', 'NegReg', (142, 151))	('U87MG', 'CellLine', 'CVCL:0022', (4, 9))	('puromycin', 'Chemical', 'MESH:D011691', (40, 49))	('puromycin', 'Chemical', 'MESH:D011691', (81, 90))	('R132H', 'Mutation', 'rs121913500', (15, 20))	('decreased', 'NegReg', (71, 80))
183721	29057925	Moreover, U87MG cells treated with increasing concentrations of 2-HG show a marked decrease in puromycin signal, which indicates a decrease in translational activity (Fig.	('puromycin signal', 'MPA', (95, 111))	('2-HG', 'Var', (64, 68))	('2-HG', 'Chemical', '-', (64, 68))	('translational activity', 'MPA', (143, 165))	('decrease', 'NegReg', (83, 91))	('U87MG', 'CellLine', 'CVCL:0022', (10, 15))	('puromycin', 'Chemical', 'MESH:D011691', (95, 104))	('decrease', 'NegReg', (131, 139))
183728	29057925	Furthermore, we found that glioblastoma cells treated with, 2-HG, Oligomycin, and 2-DG showed an increase of phosphorylation of AMPK (Fig.	('Oligomycin', 'Chemical', 'MESH:D009840', (66, 76))	('increase', 'PosReg', (97, 105))	('2-DG', 'Var', (82, 86))	('glioblastoma', 'Disease', (27, 39))	('2-DG', 'Chemical', 'MESH:D003847', (82, 86))	('2-HG', 'Chemical', '-', (60, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('AMPK', 'Protein', (128, 132))	('Oligomycin', 'Var', (66, 76))	('phosphorylation', 'MPA', (109, 124))
183733	29057925	Combined treatment with 2-HG and MG132 leads to a rescue of Mcl-1 levels, indicating that the 2-HG-mediated decrease in Mcl-1 is at least in part mediated by enhanced proteasomal degradation (Supplementary Fig.	('2-HG', 'Chemical', '-', (94, 98))	('Mcl-1 levels', 'MPA', (60, 72))	('enhanced', 'PosReg', (158, 166))	('Mcl-1', 'MPA', (120, 125))	('MG132', 'Chemical', 'MESH:C072553', (33, 38))	('decrease', 'NegReg', (108, 116))	('rescue', 'MPA', (50, 56))	('MG132', 'Var', (33, 38))	('2-HG', 'Chemical', '-', (24, 28))	('proteasomal degradation', 'MPA', (167, 190))
183736	29057925	In a heterotopic subcutaneous glioblastoma model, animals with U87MG IDH1-R132H tumors subjected to treatment with ABT263 had a significantly decreased tumor growth rate and even showed tumor regression when compared to vehicle treatment (Fig.	('decreased tumor', 'Disease', (142, 157))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ABT263', 'Gene', (115, 121))	('tumor', 'Disease', (186, 191))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('heterotopic subcutaneous glioblastoma', 'Disease', 'MESH:D005909', (5, 42))	('tumor', 'Disease', (152, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('U87MG', 'CellLine', 'CVCL:0022', (63, 68))	('R132H', 'Var', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('heterotopic subcutaneous glioblastoma', 'Disease', (5, 42))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (80, 85))	('R132H', 'SUBSTITUTION', 'None', (74, 79))	('I', 'Chemical', 'MESH:D007455', (69, 70))	('decreased tumor', 'Disease', 'MESH:D009369', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ABT263', 'Chemical', 'MESH:C528561', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))
183737	29057925	In contrast, no significant difference in tumor growth was noted between vehicle and ABT263-treated animals with U87MG IDH1-WT tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH1-WT tumors', 'Disease', 'MESH:C536751', (119, 133))	('tumor', 'Disease', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('ABT263', 'Chemical', 'MESH:C528561', (85, 91))	('I', 'Chemical', 'MESH:D007455', (119, 120))	('IDH1-WT tumors', 'Disease', (119, 133))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('U87MG', 'CellLine', 'CVCL:0022', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('U87MG', 'Var', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
183739	29057925	To this end, U87MG IDH1-R132H glioblastoma cells were implanted intracranially and allowed to form tumors.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('R132H', 'Mutation', 'rs121913500', (24, 29))	('glioblastoma', 'Disease', (30, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (30, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('U87MG', 'CellLine', 'CVCL:0022', (13, 18))	('U87MG', 'Var', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
183743	29057925	We next assessed whether ABT263 also yields a stronger anti-cancer activity in an IDH1 R132H-expressing isogenic tumor model.	('tumor', 'Disease', (113, 118))	('ABT263', 'Var', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('R132H', 'Mutation', 'rs121913500', (87, 92))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('stronger', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ABT263', 'Chemical', 'MESH:C528561', (25, 31))
183745	29057925	6g, h, treatment with ABT263 resulted in a marked reduction of the tumor growth rate of both HCT116 IDH1 WT- as well as HCT116 IDH1 R132H-expressing tumors.	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('reduction of the tumor', 'Disease', 'MESH:D009369', (50, 72))	('HCT116 IDH1', 'Var', (93, 104))	('ABT263', 'Chemical', 'MESH:C528561', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('HCT116 IDH1 R132H-expressing', 'Var', (120, 148))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('ABT263', 'Var', (22, 28))	('reduction of the tumor', 'Disease', (50, 72))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))	('R132H', 'Mutation', 'rs121913500', (132, 137))
183746	29057925	However, toward the end of the study, the mean size of tumors expressing the IDH1 mutation in animals treated with ABT263 was significantly smaller when compared to tumors from vehicle-treated animals.	('smaller', 'NegReg', (140, 147))	('mutation', 'Var', (82, 90))	('ABT263', 'Chemical', 'MESH:C528561', (115, 121))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('IDH1', 'Gene', (77, 81))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
183751	29057925	Intracranial tumors (PDGF + , PTEN -/-, p53 -/-, luciferase + ) were induced through retroviral injection and tumor formation was verified by IVIS imaging (Fig.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('Intracranial tumors', 'Disease', 'MESH:D001932', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('I', 'Chemical', 'MESH:D007455', (144, 145))	('PTEN -/-', 'Var', (30, 38))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('I', 'Chemical', 'MESH:D007455', (142, 143))	('p53 -/-', 'Var', (40, 47))	('Intracranial tumors', 'Disease', (0, 19))
183752	29057925	Convection-enhanced delivery was used for local application of 2-HG in order to mimic its local distribution as seen in IDH1-mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IDH1-mutant', 'Var', (120, 131))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('IDH1-mutant', 'Gene', (120, 131))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('2-HG', 'Chemical', '-', (63, 67))
183757	29057925	In low-grade gliomas and IDH-mutant glioblastomas, mutations in IDH1 and less commonly in IDH2 predict significantly improved overall survival when compared to wild-type IDH glioblastomas.	('I', 'Chemical', 'MESH:D007455', (90, 91))	('IDH', 'Gene', (25, 28))	('mutations', 'Var', (51, 60))	('IDH', 'Gene', '3417', (90, 93))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('glioblastomas', 'Disease', (174, 187))	('IDH', 'Gene', '3417', (170, 173))	('I', 'Chemical', 'MESH:D007455', (25, 26))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('IDH', 'Gene', (64, 67))	('glioblastomas', 'Phenotype', 'HP:0012174', (36, 49))	('IDH', 'Gene', '3417', (25, 28))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('I', 'Chemical', 'MESH:D007455', (64, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (174, 187))	('overall survival', 'MPA', (126, 142))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('IDH', 'Gene', '3417', (64, 67))	('IDH glioblastomas', 'Disease', 'MESH:D005909', (170, 187))	('improved', 'PosReg', (117, 125))	('glioblastomas', 'Disease', (36, 49))	('IDH glioblastomas', 'Disease', (170, 187))	('IDH2', 'Gene', (90, 94))	('I', 'Chemical', 'MESH:D007455', (170, 171))	('IDH', 'Gene', (90, 93))	('IDH2', 'Gene', '3418', (90, 94))	('glioblastomas', 'Disease', 'MESH:D005909', (36, 49))	('glioblastomas', 'Phenotype', 'HP:0012174', (174, 187))	('glioblastoma', 'Phenotype', 'HP:0012174', (174, 186))	('IDH', 'Gene', (170, 173))	('gliomas', 'Disease', (13, 20))
183769	29057925	In this study, we utilized the concept of synthetic lethality to efficiently target glioblastomas bearing the IDH1 mutation.	('I', 'Chemical', 'MESH:D007455', (110, 111))	('glioblastomas', 'Disease', 'MESH:D005909', (84, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('glioblastomas', 'Disease', (84, 97))	('glioblastomas', 'Phenotype', 'HP:0012174', (84, 97))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('mutation', 'Var', (115, 123))	('IDH1', 'Gene', (110, 114))
183770	29057925	This strategy might be a welcome contribution for the treatment of IDH-mutated neoplasms for several reasons, including the notion that IDH inhibitors might not be efficient in every patient with an IDH mutation and the concern of targeting a mutated enzyme that confers a better prognosis.	('IDH', 'Gene', (136, 139))	('neoplasms', 'Disease', (79, 88))	('IDH', 'Gene', '3417', (136, 139))	('IDH', 'Gene', '3417', (199, 202))	('neoplasms', 'Disease', 'MESH:D009369', (79, 88))	('IDH', 'Gene', (67, 70))	('mutation', 'Var', (203, 211))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))	('patient', 'Species', '9606', (183, 190))	('IDH', 'Gene', '3417', (67, 70))	('IDH', 'Gene', (199, 202))
183772	29057925	Despite the fact that glioblastomas are heterogeneous, the IDH1 mutation is uniformly present within a mutated tumor, suggesting that "synthetic lethality"-based treatment approaches should affect the majority of cancer cells within IDH-mutated tumors.	('glioblastomas', 'Phenotype', 'HP:0012174', (22, 35))	('IDH', 'Gene', '3417', (233, 236))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('IDH', 'Gene', '3417', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('glioblastomas', 'Disease', (22, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('cancer', 'Disease', (213, 219))	('tumors', 'Disease', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutation', 'Var', (64, 72))	('glioblastomas', 'Disease', 'MESH:D005909', (22, 35))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('IDH', 'Gene', (233, 236))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (213, 219))
183773	29057925	Our findings suggest that in solid tumors, such as glioblastomas, the inhibition of Bcl-xL elicits synthetic lethality in IDH1-mutated neoplasms.	('inhibition', 'NegReg', (70, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (135, 144))	('Bcl-xL', 'Protein', (84, 90))	('glioblastomas', 'Disease', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('neoplasms', 'Disease', 'MESH:D009369', (135, 144))	('neoplasms', 'Disease', (135, 144))	('synthetic lethality', 'MPA', (99, 118))	('glioblastomas', 'Phenotype', 'HP:0012174', (51, 64))	('glioblastomas', 'Disease', 'MESH:D005909', (51, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('solid tumors', 'Disease', (29, 41))	('IDH1-mutated', 'Var', (122, 134))
183774	29057925	We utilized several experimental approaches to verify this observation, including patient-derived IDH1-mutated sphere cultures, isogenic cell cultures and cells that were transfected or transduced with either wild-type IDH1 or mutated IDH1 R132H.	('R132H', 'Mutation', 'rs121913500', (240, 245))	('patient', 'Species', '9606', (82, 89))	('IDH1', 'Gene', (235, 239))	('mutated', 'Var', (227, 234))	('R132H', 'Var', (240, 245))
183775	29057925	All model system unequivocally confirmed that IDH1 R132H renders tumor cells more prone to the effects of inhibition of Bcl-xL either by siRNA or pharmacologically through the BH3-mimetic, ABT263.	('tumor', 'Disease', (65, 70))	('Bcl-xL', 'Gene', (120, 126))	('more prone', 'PosReg', (77, 87))	('BH3', 'Chemical', 'MESH:C006008', (176, 179))	('R132H', 'Mutation', 'rs121913500', (51, 56))	('IDH1 R132H', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('inhibition', 'NegReg', (106, 116))	('ABT263', 'Chemical', 'MESH:C528561', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
183777	29057925	Our findings extend previous studies of glioblastomas indicating a special role for mutated IDH1 to modulate cell death pathways, such as autophagy and apoptosis.	('autophagy', 'CPA', (138, 147))	('glioblastomas', 'Phenotype', 'HP:0012174', (40, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('IDH1', 'Gene', (92, 96))	('glioblastomas', 'Disease', 'MESH:D005909', (40, 53))	('mutated', 'Var', (84, 91))	('glioblastomas', 'Disease', (40, 53))	('cell death pathways', 'CPA', (109, 128))	('modulate', 'Reg', (100, 108))	('apoptosis', 'CPA', (152, 161))
183778	29057925	Our mechanistic findings are in contrast to an earlier report, which suggested that in non-solid tumors (myeloid leukemia) Bcl-2 antagonism is synthetically lethal with mutated IDH1 or IDH2.	('IDH2', 'Gene', '3418', (185, 189))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (105, 121))	('IDH1', 'Gene', (177, 181))	('Bcl-2 antagonism', 'MPA', (123, 139))	('mutated', 'Var', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('myeloid leukemia', 'Disease', (105, 121))	('non-solid tumors', 'Disease', 'MESH:D009369', (87, 103))	('IDH2', 'Gene', (185, 189))	('non-solid tumors', 'Disease', (87, 103))	('leukemia', 'Phenotype', 'HP:0001909', (113, 121))	('myeloid leukemia', 'Disease', 'MESH:D007951', (105, 121))
183781	29057925	However, in patients that are predicted to be sensitive to Bcl-xL inhibition, low platelet counts may not be a concern since tumor cells due to a genetic alteration may be more prone to Bcl-xL inhibition than platelets.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('genetic alteration', 'Var', (146, 164))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Bcl-xL inhibition', 'MPA', (186, 203))	('tumor', 'Disease', (125, 130))	('low platelet counts', 'Phenotype', 'HP:0001873', (78, 97))	('prone', 'PosReg', (177, 182))
183782	29057925	To elucidate the mechanisms by which IDH1 R132H-mutated cells are more prone to Bcl-xL inhibition, we hypothesized that these effects might be mediated by the oncometabolite, 2-HG.	('R132H', 'Mutation', 'rs121913500', (42, 47))	('prone', 'MPA', (71, 76))	('Bcl-xL inhibition', 'MPA', (80, 97))	('R132H-mutated', 'Var', (42, 55))	('IDH1', 'Gene', (37, 41))	('2-HG', 'Chemical', '-', (175, 179))
183785	29057925	While there are multiple possibilities of suppression of mTOR signaling, 2-HG appears to interfere with oxidative phosphorylation at the level of the ATP-synthase, culminating in a state of energy depletion and suppression of mTORC1 signaling.	('oxidative phosphorylation', 'MPA', (104, 129))	('2-HG', 'Chemical', '-', (73, 77))	('mTORC1', 'Gene', '382056', (226, 232))	('ATP', 'Chemical', 'MESH:D000255', (150, 153))	('interfere', 'NegReg', (89, 98))	('energy depletion', 'MPA', (190, 206))	('suppression', 'NegReg', (211, 222))	('mTORC1', 'Gene', (226, 232))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('mTOR', 'Gene', (226, 230))	('mTOR', 'Gene', '2475', (226, 230))	('2-HG', 'Var', (73, 77))
183786	29057925	As a result, both mutant IDH1 and 2-HG-treated cells displayed lower baseline OCRs and ATP levels, which in part mediated a reduction of protein synthesis, mTORC1 signaling and finally a decline in Mcl-1.	('reduction', 'NegReg', (124, 133))	('mTORC1', 'Gene', (156, 162))	('lower', 'NegReg', (63, 68))	('Mcl-1', 'MPA', (198, 203))	('mutant', 'Var', (18, 24))	('protein synthesis', 'MPA', (137, 154))	('decline', 'NegReg', (187, 194))	('ATP', 'Chemical', 'MESH:D000255', (87, 90))	('mTORC1', 'Gene', '382056', (156, 162))	('ATP levels', 'MPA', (87, 97))	('IDH1', 'Gene', (25, 29))	('OCRs', 'Chemical', '-', (78, 82))	('2-HG', 'Chemical', '-', (34, 38))
183794	29057925	Finally, we demonstrated that Bcl-xL inhibition is highly efficacious in several in vivo model systems of mutated IDH1, including an orthotopic xenograft model of glioblastoma and a patient-derived xenograft.	('IDH1', 'Gene', (114, 118))	('patient', 'Species', '9606', (182, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('glioblastoma', 'Disease', (163, 175))	('Bcl-xL inhibition', 'MPA', (30, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))	('mutated', 'Var', (106, 113))
183795	29057925	For instance, the Lai group demonstrated that IDH1 mutations render glioblastoma cells more sensitive to radiation.	('mutations', 'Var', (51, 60))	('glioblastoma', 'Disease', (68, 80))	('IDH1', 'Gene', (46, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('sensitive to radiation', 'MPA', (92, 114))	('more', 'PosReg', (87, 91))
183801	29057925	In summary, our work suggests that glioblastomas harboring an IDH1 mutation might benefit from the addition of a compound that efficiently interferes with Bcl-xL.	('glioblastomas', 'Disease', 'MESH:D005909', (35, 48))	('glioblastomas', 'Disease', (35, 48))	('mutation', 'Var', (67, 75))	('interferes', 'NegReg', (139, 149))	('Bcl-xL', 'MPA', (155, 161))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))	('IDH1', 'Gene', (62, 66))	('I', 'Chemical', 'MESH:D007455', (62, 63))
183811	29057925	MGPP-3 (PDGF + , p53(-/-), PTEN (-/-)) are murine proneural glioblastoma cells, which were generated by Dr Peter Canoll (Columbia University, New York, NY).	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('murine', 'Species', '10090', (43, 49))	('p53', 'Var', (17, 20))
183814	29057925	T98G, LN229, U251, and MGPP-3 cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum (FBS), 4.5 g l-1 glucose, 4mM L-glutamine, 1 mM pyruvate and 5 mug ml-1 PlasmocinTM for maintenance.	('ml-1', 'Gene', (190, 194))	('LN229', 'CellLine', 'CVCL:0393', (6, 11))	('DMEM', 'Chemical', '-', (89, 93))	('FBS', 'Disease', (124, 127))	('pyruvate', 'Chemical', 'MESH:D019289', (171, 179))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (53, 87))	('l-1', 'Chemical', 'MESH:D000077543', (191, 194))	('L-glutamine', 'Chemical', 'MESH:D005973', (153, 164))	('bovine', 'Species', '9913', (110, 116))	('T98G', 'Var', (0, 4))	('FBS', 'Disease', 'MESH:D005198', (124, 127))	('glucose', 'Chemical', 'MESH:D005947', (140, 147))	('ml-1', 'Gene', '51761', (190, 194))	('l-1', 'Chemical', 'MESH:D000077543', (136, 139))
183818	29057925	For the generation of retroviral particles for IDH1 R132H and IDH1 wild-type we utilized the following plasmids: pLPCX-IDH1 and pLPCX-IDH1 R132H.	('R132H', 'Mutation', 'rs121913500', (52, 57))	('R132H', 'Var', (139, 144))	('R132H', 'Mutation', 'rs121913500', (139, 144))	('R132H', 'Var', (52, 57))
183825	29057925	Specific protein expression in cell lines was determined by western blot analysis as described before using the following primary antibodies: Mcl-1 (1:500; #5453 CST: Cell Signaling Technology, Danvers, MA), Bcl-2 (1:500; #4223 CST), mutation specific IDH1 R132H antibody (1:250; #DIA-H09 Dianova GmbH, Hamburg, Germany), human caspase-9 (1:1,000; #9502 CST), cleaved caspase-3 (1:250; #9664 CST), total PARP (1:1000; #9532 CST), cleaved PARP (Asp214, 1:1000; #9541 CST), Bcl-xL (1:500; #2764 CST), Bim (1:500; #2933 CST), Bak (1:500; #6947 CST) Noxa (1:500, clone 114C307; Calbiochem), beta-actin (1:8,000, clone AC15; A1978 Sigma Aldrich), Vinculin (1:1000, #ab129002 Abcam).	('Vinculin', 'Gene', (642, 650))	('R132H', 'Mutation', 'rs121913500', (257, 262))	('Bim', 'Gene', (499, 502))	('Noxa', 'Gene', '5366', (546, 550))	('caspase-9', 'Gene', '842', (328, 337))	('Bak', 'Gene', (523, 526))	('beta-actin', 'Gene', '728378', (587, 597))	('PARP', 'Gene', '1302', (438, 442))	('1:500; #6947 CST', 'Var', (528, 544))	('Noxa', 'Gene', (546, 550))	('I', 'Chemical', 'MESH:D007455', (252, 253))	('Vinculin', 'Gene', '7414', (642, 650))	('caspase-9', 'Gene', (328, 337))	('PARP', 'Gene', '1302', (404, 408))	('human', 'Species', '9606', (322, 327))	('I', 'Chemical', 'MESH:D007455', (282, 283))	('PARP', 'Gene', (438, 442))	('Bak', 'Gene', '578', (523, 526))	('PARP', 'Gene', (404, 408))	('A1978 Sigma Aldrich', 'Disease', 'MESH:D014923', (620, 639))	('beta-actin', 'Gene', (587, 597))	('Bim', 'Gene', '10018', (499, 502))	('A1978 Sigma Aldrich', 'Disease', (620, 639))
183833	29057925	Silencing of PMAIP1 was performed using Silencer  Select siRNA-1 (s10708; AGA UAU GAA UGU UUC UAA ATT) and siRNA-2 (s10709; AGU CGA GUG UGC UAC UCA ATT) from Ambion.	('GAA', 'Gene', '2548', (82, 85))	('CGA', 'Gene', (128, 131))	('s10709;', 'Var', (116, 123))	('s10708;', 'Var', (66, 73))	('GAA', 'Gene', (82, 85))	('PMAIP1', 'Gene', (13, 19))	('CGA', 'Gene', '1113', (128, 131))	('PMAIP1', 'Gene', '5366', (13, 19))
183836	29057925	Affymetrix Human Gene 2.0 ST microarrays were utilized to assess the transcriptome for U87MG IDH1 wild-type vs. IDH1 R132H.	('IDH1', 'Gene', (93, 97))	('U87MG', 'Var', (87, 92))	('R132H', 'Mutation', 'rs121913500', (117, 122))	('Human', 'Species', '9606', (11, 16))	('U87MG', 'CellLine', 'CVCL:0022', (87, 92))
183838	29057925	In all, 1 x 106 U87MG/HCT116 IDH1-WT/IDH1-R132H cells suspended in Matrigel (1:1) or IDH1-mutant GBM164 cryomush were implanted subcutaneously into the flanks of 6-8-week-old SCID SHO mice as previously described.	('I', 'Chemical', 'MESH:D007455', (29, 30))	('HCT116', 'CellLine', 'CVCL:0291', (22, 28))	('R132H', 'Mutation', 'rs121913500', (42, 47))	('U87MG', 'CellLine', 'CVCL:0022', (16, 21))	('I', 'Chemical', 'MESH:D007455', (37, 38))	('I', 'Chemical', 'MESH:D007455', (177, 178))	('IDH1-mutant', 'Var', (85, 96))	('SCID', 'Disease', 'MESH:D053632', (175, 179))	('I', 'Chemical', 'MESH:D007455', (85, 86))	('SCID', 'Disease', (175, 179))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('mice', 'Species', '10090', (184, 188))	('GBM164', 'Gene', (97, 103))
183840	29057925	The GBM164 is a patient-derived xenograft (PDX) from a 38-year-old female with a glioblastoma, harboring mutated IDH (R132H) (WHO 2007 classification).	('IDH', 'Gene', '3417', (113, 116))	('glioblastoma', 'Disease', (81, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('mutated', 'Var', (105, 112))	('R132H', 'Mutation', 'rs121913500', (118, 123))	('IDH', 'Gene', (113, 116))	('patient', 'Species', '9606', (16, 23))
183849	29057925	Development of methodology: G.K.-M., J.N.B., P.C., C.T.I.	('J.N.B.', 'Var', (37, 43))	('I', 'Chemical', 'MESH:D007455', (55, 56))	('P.C.', 'Var', (45, 49))
183850	29057925	Acquisition of data: G.K.-M., C.T.I., C.S., T.T., E.B., M.A.B., Y.Z., F.G. and M.D.S.	('M.A.B.', 'Var', (56, 62))	('T.T.', 'Var', (44, 48))	('I', 'Chemical', 'MESH:D007455', (34, 35))
183851	29057925	Analysis and interpretation of data: G.K.-M., C.T.I., K.A.R., J.N.B., P.C.	('K.A.R.', 'Var', (54, 60))	('I', 'Chemical', 'MESH:D007455', (50, 51))	('C.T.I.', 'Var', (46, 52))	('J.N.B.', 'Var', (62, 68))
183852	19924296	Profiling Critical Cancer Gene Mutations in Clinical Tumor Samples Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach.	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Critical Cancer', 'Disease', 'MESH:D016638', (10, 25))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('patient', 'Species', '9606', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Tumor', 'Phenotype', 'HP:0002664', (53, 58))	('predict', 'Reg', (143, 150))	('Critical Cancer', 'Disease', (10, 25))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
183854	19924296	We developed and implemented an optimized mutation profiling platform ("OncoMap") to interrogate ~400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies.	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('mutations', 'Var', (102, 111))	('tumor suppressor', 'Gene', '7248', (138, 154))	('tumor suppressor', 'Gene', (138, 154))
183857	19924296	We detected known mutations at the expected frequencies in common cancers, as well as novel mutations in adult and pediatric cancers that are likely to predict heightened response or resistance to existing or developmental cancer therapies.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('developmental cancer', 'Disease', 'MESH:D009369', (209, 229))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('adult', 'Disease', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (92, 101))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('pediatric cancers', 'Disease', 'MESH:D009369', (115, 132))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('pediatric cancers', 'Disease', (115, 132))	('developmental cancer', 'Disease', (209, 229))	('mutations', 'Var', (18, 27))
183858	19924296	OncoMap profiles also support a new molecular stratification of pediatric low-grade gliomas based on BRAF mutations that may have immediate clinical impact.	('BRAF', 'Gene', (101, 105))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('mutations', 'Var', (106, 115))	('BRAF', 'Gene', '673', (101, 105))
183859	19924296	Our results demonstrate the clinical feasibility of high-throughput mutation profiling to query a large panel of "actionable" cancer gene mutations.	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('mutations', 'Var', (138, 147))
183861	19924296	Many tumors contain hallmark mutations within oncogenes or tumor suppressor (TS) genes that may confer a heightened susceptibility to targeted anticancer therapies.	('tumors', 'Disease', (5, 11))	('oncogenes', 'Gene', (46, 55))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor suppressor', 'Gene', '7248', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('tumor suppressor', 'Gene', (59, 75))	('cancer', 'Disease', (147, 153))	('TS', 'Gene', '7248', (77, 79))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
183862	19924296	Well-established examples include KIT mutations in gastrointestinal stromal tumors (GISTs) that predict response to imatinib or nilotinib, and non-small cell lung cancers with EGFR mutations that are sensitive to erlotinib.	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (143, 170))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (143, 169))	('response to imatinib', 'MPA', (104, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (147, 169))	('gastrointestinal stromal tumors', 'Disease', (51, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('EGFR', 'Gene', (176, 180))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (147, 170))	('mutations', 'Var', (181, 190))	('imatinib', 'Chemical', 'MESH:D000068877', (116, 124))	('mutations', 'Var', (38, 47))	('GISTs', 'Phenotype', 'HP:0100723', (84, 89))	('KIT', 'Gene', (34, 37))	('predict', 'Reg', (96, 103))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (143, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('erlotinib', 'Chemical', 'MESH:D000069347', (213, 222))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('EGFR', 'Gene', '1956', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (51, 82))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (51, 82))	('nilotinib', 'Chemical', 'MESH:C498826', (128, 137))	('lung cancers', 'Phenotype', 'HP:0100526', (158, 170))	('non-small cell lung cancers', 'Disease', (143, 170))
183863	19924296	For example, lung and colorectal cancers that harbor mutations in the KRAS oncogene are unresponsive to treatment with anti-EGFR agents, and inactivating PTEN mutations (or protein loss) in glioblastomas predict resistance to erlotinib.	('KRAS', 'Gene', (70, 74))	('glioblastomas', 'Disease', (190, 203))	('predict', 'Reg', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('resistance', 'MPA', (212, 222))	('colorectal cancers', 'Disease', (22, 40))	('glioblastomas', 'Disease', 'MESH:D005909', (190, 203))	('EGFR', 'Gene', '1956', (124, 128))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('mutations', 'Var', (159, 168))	('lung', 'Disease', (13, 17))	('PTEN', 'Gene', (154, 158))	('mutations', 'Var', (53, 62))	('colorectal cancers', 'Disease', 'MESH:D015179', (22, 40))	('glioblastomas', 'Phenotype', 'HP:0012174', (190, 203))	('PTEN', 'Gene', '5728', (154, 158))	('inactivating', 'Var', (141, 153))	('KRAS', 'Gene', '3845', (70, 74))	('EGFR', 'Gene', (124, 128))	('erlotinib', 'Chemical', 'MESH:D000069347', (226, 235))	('loss', 'NegReg', (181, 185))
183869	19924296	We now demonstrate the clinical feasibility of mass-spectrometric based cancer gene mutation profiling for a large panel of oncogene and TS gene mutations.	('TS', 'Gene', '7248', (137, 139))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
183871	19924296	Using this genomic profiling approach coupled to an analytical mutation-calling algorithm and orthogonal validation step, we identified numerous mutations present in genomic DNA from both frozen and FFPE tumor tissue.	('DNA', 'Gene', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mutations', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))
183876	19924296	Selection of cancer gene mutations for assay design and mass spectrometric genotyping were performed as previously described with modifications indicated in Methods S1.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
183883	19924296	To facilitate cancer gene mutation profiling in clinical tumor specimens, we developed OncoMap, a panel of genotyping assays that assessed 396 unique mutations in 33 cancer genes.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutations', 'Var', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', (57, 62))
183889	19924296	Of the 903 clinical tumor specimens profiled, 37% (n = 335) contained one or more mutations.	('contained', 'Reg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('mutations', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
183891	19924296	As expected, the distribution of mutations reflected patterns previously observed in human tumors, although the frequency of TS mutations was lower (reflective of the reduced coverage of such mutations by OncoMap).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('TS', 'Gene', '7248', (125, 127))	('mutations', 'Var', (128, 137))	('lower', 'NegReg', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('human', 'Species', '9606', (85, 90))
183892	19924296	Examples include PIK3CA (26%) and TP53 (13%) mutations in breast cancer; APC (11%), BRAF (10%), KRAS (38%), PIK3CA (11%) and TP53 (9%) mutations in colorectal cancer, and EGFR (12%), KRAS (23%) and STK11 (8%) mutations in lung cancer.	('EGFR', 'Gene', (171, 175))	('STK11', 'Gene', '6794', (198, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('PIK3CA', 'Gene', '5290', (17, 23))	('TP53', 'Gene', (125, 129))	('PIK3CA', 'Gene', (108, 114))	('KRAS', 'Gene', '3845', (96, 100))	('lung cancer', 'Disease', (222, 233))	('KRAS', 'Gene', '3845', (183, 187))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EGFR', 'Gene', '1956', (171, 175))	('KRAS', 'Gene', (96, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('TP53', 'Gene', (34, 38))	('KRAS', 'Gene', (183, 187))	('BRAF', 'Gene', '673', (84, 88))	('TP53', 'Gene', '7157', (125, 129))	('PIK3CA', 'Gene', (17, 23))	('BRAF', 'Gene', (84, 88))	('colorectal cancer', 'Disease', (148, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('STK11', 'Gene', (198, 203))	('PIK3CA', 'Gene', '5290', (108, 114))	('mutations', 'Var', (45, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('breast cancer', 'Disease', (58, 71))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('mutations', 'Var', (209, 218))	('APC', 'Disease', (73, 76))	('TP53', 'Gene', '7157', (34, 38))
183893	19924296	Table 2  indicates a set of "actionable" cancer gene mutations identified herein.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))	('mutations', 'Var', (53, 62))
183894	19924296	For example, EGFR mutations predictive of response to erlotinib and gefitinib were identified at the expected frequency (12%) in non-small cell lung cancer, and KIT mutations linked to sensitivity to imatinib and nilotinib were detected in 76% of GISTs.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (129, 155))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (129, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('GISTs', 'Phenotype', 'HP:0100723', (247, 252))	('imatinib', 'Chemical', 'MESH:D000068877', (200, 208))	('nilotinib', 'Chemical', 'MESH:C498826', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (133, 155))	('non-small cell lung cancer', 'Disease', (129, 155))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('gefitinib', 'Chemical', 'MESH:D000077156', (68, 77))	('mutations', 'Var', (18, 27))
183895	19924296	Interestingly, ERBB2 mutations were detected in four gastric adenocarcinomas, raising the possibility of testing a HER-2 inhibitor such as trastuzumab in gastric cancer patients selected based on this genetic criterion.	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('gastric adenocarcinomas', 'Disease', (53, 76))	('ERBB2', 'Gene', (15, 20))	('HER-2', 'Gene', (115, 120))	('patients', 'Species', '9606', (169, 177))	('HER-2', 'Gene', '2064', (115, 120))	('detected', 'Reg', (36, 44))	('gastric cancer', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('trastuzumab', 'Chemical', 'MESH:D000068878', (139, 150))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (53, 76))	('ERBB2', 'Gene', '2064', (15, 20))	('mutations', 'Var', (21, 30))
183896	19924296	Several tumors harbored mutations that may predict response to investigational agents.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('mutations', 'Var', (24, 33))
183898	19924296	Tumors harboring these mutations may respond to a selective BRAF inhibitor.	('respond', 'Reg', (37, 44))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('mutations', 'Var', (23, 32))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
183899	19924296	We also identified 96 samples across seven different cancer types (breast n = 14, colorectal n = 24, endometrial n = 15, esophageal n = 4, gastric n = 34, prostate n = 3, and pediatric astrocytoma n = 2) harboring mutations in either PIK3CA or PTEN.	('PTEN', 'Gene', '5728', (244, 248))	('esophageal', 'Disease', 'MESH:D004941', (121, 131))	('astrocytoma', 'Disease', 'MESH:D001254', (185, 196))	('endometrial', 'Disease', (101, 112))	('astrocytoma', 'Disease', (185, 196))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (214, 223))	('PIK3CA', 'Gene', (234, 240))	('esophageal', 'Disease', (121, 131))	('harboring', 'Reg', (204, 213))	('colorectal', 'Disease', (82, 92))	('PIK3CA', 'Gene', '5290', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (185, 196))	('prostate', 'Disease', (155, 163))	('gastric', 'Disease', (139, 146))	('PTEN', 'Gene', (244, 248))
183900	19924296	These mutations might be expected to enrich for tumors responsive to the PI3 kinase inhibitors currently in development.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (6, 15))
183901	19924296	Established examples include KRAS mutations in non-small cell lung cancer (23%) and colorectal cancer (38%) that confer resistance to erlotinib, gefitinib (lung) or cetuximab (colorectal).	('colorectal cancer', 'Disease', (84, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (51, 73))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (47, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('KRAS', 'Gene', (29, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('non-small cell lung cancer', 'Disease', (47, 73))	('gefitinib', 'Chemical', 'MESH:D000077156', (145, 154))	('resistance', 'MPA', (120, 130))	('erlotinib', 'Chemical', 'MESH:D000069347', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('KRAS', 'Gene', '3845', (29, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cetuximab', 'Chemical', 'MESH:D000068818', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (34, 43))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (47, 73))
183902	19924296	While 94% of KRAS mutations identified localized to codons 12 or 13, 6% occurred elsewhere in the gene (most commonly at codon 61).	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('occurred', 'Reg', (72, 80))	('mutations', 'Var', (18, 27))
183903	19924296	Since most studies of KRAS-associated resistance have focused exclusively on codons 12 and 13, OncoMap identified additional KRAS mutations that may influence sensitivity to anti-EGFR treatment.	('EGFR', 'Gene', (179, 183))	('influence', 'Reg', (149, 158))	('KRAS', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (125, 129))	('mutations', 'Var', (130, 139))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (22, 26))	('EGFR', 'Gene', '1956', (179, 183))
183904	19924296	OncoMap also identified an HRAS mutation in a lung adenocarcinoma and an NRAS mutation in a colorectal adenocarcinoma.	('NRAS', 'Gene', '4893', (73, 77))	('mutation', 'Var', (78, 86))	('HRAS', 'Gene', (27, 31))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (92, 117))	('lung adenocarcinoma', 'Disease', (46, 65))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 65))	('HRAS', 'Gene', '3265', (27, 31))	('mutation', 'Var', (32, 40))	('NRAS', 'Gene', (73, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('colorectal adenocarcinoma', 'Disease', (92, 117))
183905	19924296	Mutations involving alternate RAS isoforms are rare in these cancer types; conceivably, these might also confer resistance to anti-EGFR therapy.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
183907	19924296	In particular, several KIT mutations involving exon 9 (KIT Y503_or F504insAY; 5 cases) were detected in untreated GIST tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('KIT Y503_or', 'Var', (55, 66))	('GIST tumors', 'Disease', 'MESH:D046152', (114, 125))	('GIST tumors', 'Disease', (114, 125))	('F504insAY', 'Var', (67, 76))	('F504insAY', 'Mutation', 'c.504insF,AY', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
183908	19924296	A PDGFRA mutation (D842V) predictive of resistance to imatinib was also identified in one GIST sample.	('D842V', 'Mutation', 'rs121908585', (19, 24))	('imatinib', 'Chemical', 'MESH:D000068877', (54, 62))	('D842V', 'Var', (19, 24))	('PDGFRA', 'Gene', '5156', (2, 8))	('PDGFRA', 'Gene', (2, 8))	('resistance to imatinib', 'MPA', (40, 62))
183910	19924296	The OncoMap platform identified rare AKT1 mutations in these tumor types, as well as single AKT1E17K instances in endometrial, esophageal squamous, gastric, and prostate cancers.	('AKT1', 'Gene', (92, 96))	('esophageal squamous', 'Disease', 'MESH:D000077277', (127, 146))	('AKT1', 'Gene', (37, 41))	('esophageal squamous', 'Disease', (127, 146))	('endometrial', 'Disease', (114, 125))	('AKT1', 'Gene', '207', (37, 41))	('prostate cancers', 'Disease', 'MESH:D011471', (161, 177))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('prostate cancers', 'Phenotype', 'HP:0012125', (161, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('prostate cancers', 'Disease', (161, 177))	('gastric', 'Disease', (148, 155))	('AKT1', 'Gene', '207', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (61, 66))
183911	19924296	The presence of co-occurring mutations involving critical cancer genes may modify the clinical response to single-agent targeted therapy.	('clinical response', 'MPA', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (29, 38))	('modify', 'Reg', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
183912	19924296	Here, 20 adenocarcinomas (10 colorectal, two endometrial and 8 gastric) exhibited co-occurring PIK3CA and KRAS mutations.	('KRAS', 'Gene', '3845', (106, 110))	('mutations', 'Var', (111, 120))	('PIK3CA', 'Gene', (95, 101))	('colorectal', 'Disease', (29, 39))	('PIK3CA', 'Gene', '5290', (95, 101))	('KRAS', 'Gene', (106, 110))	('adenocarcinomas', 'Disease', 'MESH:D000230', (9, 24))	('adenocarcinomas', 'Disease', (9, 24))
183913	19924296	While coincident mutations in these genes have previously been reported in cancers of the large intestine, PIK3CA and KRAS mutations have typically exhibited a mutually exclusive pattern of occurrence in endometrial cancer.	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('reported', 'Reg', (63, 71))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('KRAS', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancers', 'Disease', (75, 82))	('endometrial cancer', 'Disease', (204, 222))	('cancers of the large intestine', 'Phenotype', 'HP:0100834', (75, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PIK3CA', 'Gene', (107, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (204, 222))	('KRAS', 'Gene', '3845', (118, 122))	('PIK3CA', 'Gene', '5290', (107, 113))	('occurrence', 'Reg', (190, 200))	('endometrial cancer', 'Disease', 'MESH:D016889', (204, 222))	('mutations', 'Var', (17, 26))	('mutations', 'Var', (123, 132))
183914	19924296	An endometrial adenocarcinoma with co-occurring FGFR2 and PTEN mutations was also identified.	('mutations', 'Var', (63, 72))	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('PTEN', 'Gene', '5728', (58, 62))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (3, 29))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (3, 29))	('endometrial adenocarcinoma', 'Disease', (3, 29))	('PTEN', 'Gene', (58, 62))
183915	19924296	Two tumors harbored coincident BRAF and PTEN mutations (one endometrial, one colorectal), and an additional colorectal sample contained both a PIK3CA and a BRAF mutation.	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (156, 160))	('PTEN', 'Gene', (40, 44))	('PIK3CA', 'Gene', (143, 149))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('PTEN', 'Gene', '5728', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PIK3CA', 'Gene', '5290', (143, 149))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', '673', (156, 160))	('BRAF', 'Gene', (31, 35))
183922	19924296	Two pediatric LGAs harbored mutations in MYC, a well established oncogene homologue of NMYC, which is amplified and indicative of poor prognosis in pediatric neuroblastoma.	('pediatric neuroblastoma', 'Disease', (148, 171))	('NMYC', 'Gene', '4613', (87, 91))	('MYC', 'Gene', '4609', (88, 91))	('pediatric neuroblastoma', 'Disease', 'MESH:D009447', (148, 171))	('MYC', 'Gene', '4609', (41, 44))	('MYC', 'Gene', (88, 91))	('NMYC', 'Gene', (87, 91))	('mutations', 'Var', (28, 37))	('neuroblastoma', 'Phenotype', 'HP:0003006', (158, 171))	('MYC', 'Gene', (41, 44))
183924	19924296	Duplication of the BRAF locus has been reported as the most frequent aberration in pediatric LGAs (66%), whereas activating point mutations in BRAF occur less commonly (4-6%).	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('Duplication', 'Var', (0, 11))	('LGAs', 'Disease', (93, 97))
183926	19924296	Interestingly, the BRAFV600E mutation was most prevalent within the ganglioglioma subtype of pediatric LGAs (classical and non-classical; 8/14 tumors, p = 0.00005), as shown in  Fig.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('14 tumors', 'Disease', 'MESH:C567448', (140, 149))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('ganglioglioma', 'Disease', (68, 81))	('14 tumors', 'Disease', (140, 149))	('BRAFV600E', 'Var', (19, 28))	('BRAFV600E', 'Mutation', 'rs113488022', (19, 28))	('prevalent', 'Reg', (47, 56))	('ganglioglioma', 'Disease', 'MESH:D018303', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
183927	19924296	BRAFV600E mutations were not identified in any of the adult tumors examined, although TP53 mutations commonly occurred in this setting (10/28 cases).	('adult tumors', 'Disease', (54, 66))	('occurred', 'Reg', (110, 118))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (91, 100))	('adult tumors', 'Disease', 'MESH:C538052', (54, 66))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
183928	19924296	Conversely, only 2 pediatric gliomas harbored a TP53 mutation; in both cases, this was coincident with another mutation (EGFR and FLNB, respectively).	('TP53', 'Gene', '7157', (48, 52))	('FLNB', 'Gene', '2317', (130, 134))	('mutation', 'Var', (53, 61))	('EGFR', 'Gene', '1956', (121, 125))	('FLNB', 'Gene', (130, 134))	('pediatric gliomas', 'Disease', (19, 36))	('TP53', 'Gene', (48, 52))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('EGFR', 'Gene', (121, 125))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('pediatric gliomas', 'Disease', 'MESH:D005910', (19, 36))
183931	19924296	New diagnostic approaches are therefore needed to profile any tumor for pivotal genetic mutations in multiple cancer genes simultaneously, in contrast to most existing tests that focus on single genes (or proteins).	('genetic mutations', 'Var', (80, 97))	('cancer', 'Disease', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
183933	19924296	We robustly detected cancer gene mutations that direct clinical use and predict resistance to existing agents such as tyrosine kinase inhibitors (e.g., EGFR and KRAS mutations).	('resistance', 'MPA', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('EGFR', 'Gene', '1956', (152, 156))	('mutations', 'Var', (33, 42))	('EGFR', 'Gene', (152, 156))	('cancer', 'Disease', (21, 27))	('KRAS', 'Gene', (161, 165))	('KRAS', 'Gene', '3845', (161, 165))
183934	19924296	Finally, in a specific investigation of pediatric low-grade astrocytomas, we demonstrated the special value this platform may have for rare "orphan" cancers by identifying mutations that may inform molecular classification as well as new therapeutic avenues for children with these malignancies.	('mutations', 'Var', (172, 181))	('children', 'Species', '9606', (262, 270))	('astrocytomas', 'Disease', (60, 72))	('cancers', 'Disease', (149, 156))	('inform', 'Reg', (191, 197))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('malignancies', 'Disease', 'MESH:D009369', (282, 294))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('astrocytomas', 'Disease', 'MESH:D001254', (60, 72))	('malignancies', 'Disease', (282, 294))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
183943	19924296	Knowledge of the genetic abnormalities present in pediatric LGAs is limited, though recent studies have identified BRAF translocations, chromosomal duplications, and occasional base mutations in low-grade astrocytomas, as well as diverse mechanisms for activating the ERK/MAPK pathway in pilocytic astrocytomas.	('BRAF', 'Gene', '673', (115, 119))	('astrocytomas', 'Disease', 'MESH:D001254', (298, 310))	('BRAF', 'Gene', (115, 119))	('ERK', 'Gene', (268, 271))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (288, 310))	('ERK', 'Gene', '5594', (268, 271))	('genetic abnormalities', 'Disease', 'MESH:D030342', (17, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (298, 309))	('astrocytomas', 'Disease', (298, 310))	('translocations', 'Var', (120, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (205, 216))	('genetic abnormalities', 'Disease', (17, 38))	('astrocytomas', 'Disease', 'MESH:D001254', (205, 217))	('activating', 'Reg', (253, 263))	('pilocytic astrocytomas', 'Disease', (288, 310))	('astrocytomas', 'Disease', (205, 217))	('chromosomal duplications', 'Var', (136, 160))
183945	19924296	Our results indicate that the frequency of BRAF point mutations in pediatric LGAs as a whole may be higher than previously reported, and specifically that gangliogliomas possess BRAF V600E mutations at very high frequency.	('BRAF', 'Gene', (178, 182))	('V600E', 'Mutation', 'rs113488022', (183, 188))	('gliomas', 'Disease', (162, 169))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('BRAF', 'Gene', '673', (43, 47))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('BRAF', 'Gene', (43, 47))	('ganglioglioma', 'Disease', (155, 168))	('point mutations', 'Var', (48, 63))	('BRAF', 'Gene', '673', (178, 182))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('ganglioglioma', 'Disease', 'MESH:D018303', (155, 168))	('V600E mutations', 'Var', (183, 198))
183947	19924296	Gangliogliomas, which tend to be indolent tumors, may therefore share some properties with cutaneous nevi, whose melanocyte precursors also derive from the nervous system (neural crest), exhibit indolent growth, and where the BRAF V600E mutation is also highly prevalent.	('nevi', 'Phenotype', 'HP:0003764', (101, 105))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('BRAF', 'Gene', '673', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('V600E', 'Var', (231, 236))	('BRAF', 'Gene', (226, 230))	('cutaneous nevi', 'Disease', (91, 105))	('gliomas', 'Disease', (7, 14))	('gliomas', 'Disease', 'MESH:D005910', (7, 14))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('V600E', 'Mutation', 'rs113488022', (231, 236))
183949	19924296	In concordance with previous reports we observe that mutations in genes frequently observed in adult anaplastic astrocytomas and/or glioblastomas, such as TP53 or PTEN, are only rarely encountered in pediatric pilocytic and low-grade diffuse astrocytomas.	('encountered', 'Reg', (185, 196))	('astrocytoma', 'Phenotype', 'HP:0009592', (112, 123))	('TP53', 'Gene', '7157', (155, 159))	('glioblastomas', 'Disease', (132, 145))	('astrocytomas', 'Disease', (112, 124))	('PTEN', 'Gene', (163, 167))	('PTEN', 'Gene', '5728', (163, 167))	('TP53', 'Gene', (155, 159))	('mutations', 'Var', (53, 62))	('astrocytomas', 'Disease', 'MESH:D001254', (242, 254))	('astrocytoma', 'Phenotype', 'HP:0009592', (242, 253))	('glioblastomas', 'Phenotype', 'HP:0012174', (132, 145))	('astrocytomas', 'Disease', 'MESH:D001254', (112, 124))	('glioblastomas', 'Disease', 'MESH:D005909', (132, 145))	('astrocytomas', 'Disease', (242, 254))
183951	19924296	These include the finite number of specific point mutations that can be assayed (designated a priori within a subset of cancer genes), difficulties in designing genotyping assays that identify small insertions or deletions ("in-dels") larger than ~50bp in size, an inability to detect most TS gene mutations (which may occur anywhere within the gene, not just "hotspot" regions) or additional genomic alterations such as high-level gene amplifications or deletions that may also affect key cancer genes, and the somewhat labor-intensive nature of manual review and orthogonal assay validation.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('inability', 'NegReg', (265, 274))	('cancer', 'Disease', (490, 496))	('cancer', 'Disease', (120, 126))	('deletions', 'Var', (213, 222))	('cancer', 'Disease', 'MESH:D009369', (490, 496))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('affect', 'Reg', (479, 485))	('mutations', 'Var', (298, 307))	('cancer', 'Phenotype', 'HP:0002664', (490, 496))	('deletions', 'Var', (455, 464))	('TS', 'Gene', '7248', (290, 292))
183967	33982764	Concomitant NEAT1 knockdown and inhibition of miR-324-5p partially reversed the effects of NEAT1 knockdown on cell proliferation and apoptosis, and further regulated KCTD20 expression.	('knockdown', 'Var', (97, 106))	('NEAT1', 'Gene', (91, 96))	('apoptosis', 'CPA', (133, 142))	('KCTD20', 'Gene', (166, 172))	('miR-324-5p', 'Chemical', '-', (46, 56))	('cell proliferation', 'CPA', (110, 128))	('expression', 'MPA', (173, 183))	('regulated', 'Reg', (156, 165))
183977	33982764	The lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), located on chromosome 11, has been reported to be a transcriptional regulator of numerous genes, and abnormal NEAT1 expression has been implicated in the promotion of tumorigenesis in a variety of human cancer types.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('promotion', 'PosReg', (216, 225))	('tumor', 'Disease', (229, 234))	('NEAT1', 'Gene', (172, 177))	('abnormal', 'Var', (163, 171))	('human', 'Species', '9606', (259, 264))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))
184006	33982764	When cells reached a confluence of 80%, cells were transfected with siRNAs (100 nM), mimics (100 nM) or miRNA inhibitors (100 nM) using Lipofectamine  2000 transfection reagent (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol.	('100 nM', 'Var', (76, 82))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (136, 155))	('100 nM', 'Var', (93, 99))	('100 nM', 'Var', (122, 128))
184057	33982764	The complementary DNA fragment containing the wild-type (WT) or mutant (MUT) sequences of NEAT1 or KCTD20 were subcloned downstream of the luciferase gene within the pGL3-luciferase reporter plasmid vectors (Promega Corporation).	('pGL3', 'Gene', (166, 170))	('pGL3', 'Gene', '6391', (166, 170))	('KCTD20', 'Gene', (99, 105))	('NEAT1', 'Gene', (90, 95))	('mutant', 'Var', (64, 70))
184090	33982764	Based on the dual luciferase reporter assay results, lncRNASNP2 was used to predict the binding site between NEAT1 and miR-324-5p.	('miR-324-5p', 'Chemical', '-', (119, 129))	('miR-324-5p', 'Var', (119, 129))	('binding', 'Interaction', (88, 95))	('B', 'Chemical', 'MESH:D001895', (0, 1))
184105	33982764	The results demonstrated that high NEAT1 expression was significantly associated with a larger tumor size (P=0.047) and advanced World Health Organization glioma stage (P=0.044; Table I).	('expression', 'MPA', (41, 51))	('larger', 'PosReg', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('high', 'Var', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NEAT1', 'Gene', (35, 40))	('tumor', 'Disease', (95, 100))	('glioma', 'Disease', (155, 161))
184111	33982764	The results revealed significantly reduced proliferation in cells expressing siNEAT1 compared in cells transfected with siCtrl (Fig.	('siCtrl', 'Disease', 'None', (120, 126))	('reduced', 'NegReg', (35, 42))	('siCtrl', 'Disease', (120, 126))	('proliferation', 'CPA', (43, 56))	('siNEAT1', 'Var', (77, 84))
184121	33982764	3E, knockdown of NEAT1 was associated with decreased expression levels of cycle-related proteins (CDK-4 and cyclin D1) and apoptosis-related protein Bcl-2 but the expression levels of apoptosis-related protein Bax were increased.	('CDK-4', 'Gene', (98, 103))	('cyclin D1', 'Gene', (108, 117))	('expression levels of', 'MPA', (163, 183))	('Bax', 'Gene', '581', (210, 213))	('Bcl-2', 'Gene', (149, 154))	('apoptosis-related', 'MPA', (123, 140))	('Bcl-2', 'Gene', '596', (149, 154))	('cyclin D1', 'Gene', '595', (108, 117))	('NEAT1', 'Gene', (17, 22))	('CDK-4', 'Gene', '1019', (98, 103))	('Bax', 'Gene', (210, 213))	('expression levels of', 'MPA', (53, 73))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (43, 52))	('increased', 'PosReg', (219, 228))
184125	33982764	3F and G, silencing of NEAT1 markedly inhibited the growth of intracranial tumors at all examined time points and also significantly increased the survival of mice.	('intracranial tumors', 'Disease', (62, 81))	('NEAT1', 'Gene', (23, 28))	('inhibited', 'NegReg', (38, 47))	('intracranial tumors', 'Disease', 'MESH:D001932', (62, 81))	('survival of mice', 'CPA', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mice', 'Species', '10090', (159, 163))	('increased', 'PosReg', (133, 142))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('silencing', 'Var', (10, 19))
184126	33982764	H&E and IHC staining of tumors excised from experimental mice demonstrated the effect of NEAT1 knockdown on tumor growth.	('mice', 'Species', '10090', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumor', 'Disease', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('NEAT1', 'Var', (89, 94))	('tumor', 'Disease', (108, 113))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
184128	33982764	These data indicated that silencing of NEAT1 inhibited glioma cell proliferation by inducing cell cycle arrest and promoting apoptosis, and demonstrated the carcinogenic activity of NEAT1 in glioma in vivo.	('glioma', 'Disease', (55, 61))	('NEAT1', 'Gene', (39, 44))	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('promoting', 'PosReg', (115, 124))	('carcinogenic', 'Disease', 'MESH:D063646', (157, 169))	('glioma', 'Disease', (191, 197))	('carcinogenic', 'Disease', (157, 169))	('arrest', 'Disease', (104, 110))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('inducing', 'NegReg', (84, 92))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('apoptosis', 'CPA', (125, 134))	('silencing', 'Var', (26, 35))	('inhibited', 'NegReg', (45, 54))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))
184132	33982764	The results identified four miRNAs (miR-125a, miR-324-5p, miR-495-3p and miR-504) that were expressed at significantly lower levels in GBM tissues compared with normal brain tissues (Figs.	('miR-504', 'Gene', '574507', (73, 80))	('miR-495-3p', 'Var', (58, 68))	('miR-504', 'Gene', (73, 80))	('miR-125a', 'Gene', (36, 44))	('lower', 'NegReg', (119, 124))	('miR-324-5p', 'Var', (46, 56))	('miR-125a', 'Gene', '406910', (36, 44))	('miR-324-5p', 'Chemical', '-', (46, 56))	('B', 'Chemical', 'MESH:D001895', (136, 137))
184135	33982764	Co-transfection of cells with a NEAT1-driven luciferase expression vector and miR-125a or miR-324-5p mimics significantly inhibited luciferase activity compared with that of cells co-transfected with controls (Fig.	('luciferase', 'Enzyme', (132, 142))	('miR-324-5p', 'Var', (90, 100))	('inhibited', 'NegReg', (122, 131))	('miR-324-5p', 'Chemical', '-', (90, 100))	('miR-125a', 'Gene', (78, 86))	('activity', 'MPA', (143, 151))	('miR-125a', 'Gene', '406910', (78, 86))
184136	33982764	Of the two inhibitory miRNAs, miR-324-5p had the greatest inhibitory activity and was therefore selected for further analysis.	('inhibitory activity', 'MPA', (58, 77))	('miR-324-5p', 'Chemical', '-', (30, 40))	('miR-324-5p', 'Var', (30, 40))
184138	33982764	4F, the luciferase activity of U251 and LN229 cells co-transfected with WT-NEAT1 and miR-324-5p was significantly reduced compared with that of cells transfected with miR-NC, but there was no significant change in the MUT-NEAT1 group, which demonstrated a direct association between NEAT1 and miR-324-5p.	('miR-324-5p', 'Chemical', '-', (85, 95))	('luciferase', 'Enzyme', (8, 18))	('reduced', 'NegReg', (114, 121))	('miR-324-5p', 'Chemical', '-', (293, 303))	('activity', 'MPA', (19, 27))	('miR-324-5p', 'Var', (85, 95))	('LN229', 'CellLine', 'CVCL:0393', (40, 45))
184140	33982764	The RIP analysis revealed that NEAT1 was highly enriched in Ago2 immmunoprecipitates from cells transfected with the miR-324-5p mimics compared with the anti-IgG group (Fig.	('miR-324-5p', 'Chemical', '-', (117, 127))	('miR-324-5p mimics', 'Var', (117, 134))	('Ago2', 'Gene', (60, 64))	('Ago2', 'Gene', '27161', (60, 64))
184141	33982764	The assessment of the functional association between NEAT1 and miR-324-5p by RT-qPCR, and it was revealed that knockdown of NEAT1 was associated with the upregulation of miR-324-5p in U251 and LN229 cells.	('knockdown', 'Var', (111, 120))	('miR-324-5p', 'MPA', (170, 180))	('miR-324-5p', 'Chemical', '-', (63, 73))	('miR-324-5p', 'Chemical', '-', (170, 180))	('LN229', 'CellLine', 'CVCL:0393', (193, 198))	('NEAT1', 'Gene', (124, 129))	('upregulation', 'PosReg', (154, 166))
184142	33982764	The downregulation or upregulation of miR-324-5p had no significant effect on NEAT1 expression (Fig.	('miR-324-5p', 'Chemical', '-', (38, 48))	('NEAT1', 'Gene', (78, 83))	('downregulation', 'NegReg', (4, 18))	('upregulation', 'PosReg', (22, 34))	('miR-324-5p', 'Var', (38, 48))
184144	33982764	These results demonstrated that NEAT1 may directly bind to and modulate the expression levels of miR-324-5p in glioma cells.	('glioma', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('expression levels', 'MPA', (76, 93))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('miR-324-5p', 'Var', (97, 107))	('miR-324-5p', 'Chemical', '-', (97, 107))	('modulate', 'Reg', (63, 71))	('bind', 'Interaction', (51, 55))
184145	33982764	The expression levels of miR-324-5p were detected in NHA, U251 and LN229 cells by RT-qPCR, and the results revealed that, compared those in with NHA cells, the expression levels of miR-324-5p in U251 and LN229 were significantly reduced (Fig.	('miR-324-5p', 'Chemical', '-', (25, 35))	('LN229', 'CellLine', 'CVCL:0393', (204, 209))	('reduced', 'NegReg', (229, 236))	('LN229', 'CellLine', 'CVCL:0393', (67, 72))	('expression levels', 'MPA', (160, 177))	('miR-324-5p', 'Var', (181, 191))	('miR-324-5p', 'Chemical', '-', (181, 191))
184146	33982764	Furthermore, miR-324-5p expression was significantly lower in human glioma tissues compared with in normal tissues (Fig.	('miR-324-5p', 'Chemical', '-', (13, 23))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('human', 'Species', '9606', (62, 67))	('glioma', 'Disease', (68, 74))	('miR-324-5p', 'Var', (13, 23))	('lower', 'NegReg', (53, 58))
184147	33982764	4J), and Spearman's correlation analysis demonstrated a significant negative correlation between the expression levels of NEAT1 and miR-324-5p in glioma tissues (Fig.	('negative', 'NegReg', (68, 76))	('NEAT1', 'Gene', (122, 127))	('glioma', 'Disease', (146, 152))	('expression levels', 'MPA', (101, 118))	('miR-324-5p', 'Var', (132, 142))	('miR-324-5p', 'Chemical', '-', (132, 142))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))
184149	33982764	Having established an association between NEAT1 and miR-324-5p, it was next examined whether miR-324-5p mediates the NEAT1-induced changes in glioma cell biology.	('glioma', 'Disease', (142, 148))	('miR-324-5p', 'Chemical', '-', (52, 62))	('miR-324-5p', 'Var', (93, 103))	('miR-324-5p', 'Chemical', '-', (93, 103))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('association', 'Interaction', (22, 33))
184153	33982764	In addition, the experiments demonstrated that overexpression of miR-324-5p significantly inhibited the progression of glioma in vitro.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('miR-324-5p', 'Var', (65, 75))	('miR-324-5p', 'Chemical', '-', (65, 75))	('overexpression', 'PosReg', (47, 61))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glioma', 'Disease', (119, 125))	('progression', 'CPA', (104, 115))	('inhibited', 'NegReg', (90, 99))
184155	33982764	Colony formation and EdU assays revealed that overexpression of miR-324-5p significantly inhibited the cell proliferation rate (Fig.	('inhibited', 'NegReg', (89, 98))	('cell proliferation rate', 'CPA', (103, 126))	('miR-324-5p', 'Var', (64, 74))	('EdU', 'Chemical', '-', (21, 24))	('miR-324-5p', 'Chemical', '-', (64, 74))
184156	33982764	Additionally, upregulation of miR-324-5p resulted in an increase in the number of apoptotic cells (Fig.	('increase', 'PosReg', (56, 64))	('miR-324-5p', 'Chemical', '-', (30, 40))	('miR-324-5p', 'Var', (30, 40))	('upregulation', 'PosReg', (14, 26))
184157	33982764	Western blotting was used to analyze the expression levels of cycle-related proteins and apoptosis-related proteins after cells were transfected with miR-324-5p mimics (Fig.	('expression', 'MPA', (41, 51))	('miR-324-5p', 'Chemical', '-', (150, 160))	('miR-324-5p', 'Var', (150, 160))
184161	33982764	Collectively, these data suggested that a potential interaction between NEAT1 and miR-324-5p may be involved in the development of glioma.	('miR-324-5p', 'Chemical', '-', (82, 92))	('glioma', 'Disease', (131, 137))	('interaction', 'Interaction', (52, 63))	('involved', 'Reg', (100, 108))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('NEAT1', 'Gene', (72, 77))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('miR-324-5p', 'Var', (82, 92))
184162	33982764	The present study next sought to identify the target mRNAs of miR-324-5p through which NEAT1 and miR-324-5p regulate glioma cell proliferation.	('miR-324-5p', 'Chemical', '-', (62, 72))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('miR-324-5p', 'Chemical', '-', (97, 107))	('miR-324-5p', 'Var', (97, 107))	('regulate', 'Reg', (108, 116))	('glioma', 'Disease', (117, 123))
184167	33982764	This analysis revealed that miR-324-5p suppression significantly increased the expression levels of all six genes.	('increased', 'PosReg', (65, 74))	('miR-324-5p', 'Chemical', '-', (28, 38))	('expression levels', 'MPA', (79, 96))	('miR-324-5p suppression', 'Var', (28, 50))
184173	33982764	To verify that KCTD20 mRNA was directly regulated by miR-324-5p in glioma cells, a luciferase reporter assay was performed in cells expressing plasmids with the WT 3'-UTR of KCTD20 or MUT 3'-UTR carrying mutations in the putative binding site for miR-324-5p (Fig.	('miR-324-5p', 'Chemical', '-', (247, 257))	('glioma', 'Disease', (67, 73))	('mutations', 'Var', (204, 213))	('miR-324-5p', 'Chemical', '-', (53, 63))	('KCTD20', 'Gene', (15, 21))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
184175	33982764	Furthermore, KCTD20 protein and mRNA expression was increased following the transfection of glioma cells with the miR-324-5p inhibitor and suppressed by their transfection with miR-324-5p mimics (Fig.	('mRNA expression', 'MPA', (32, 47))	('increased', 'PosReg', (52, 61))	('miR-324-5p', 'Var', (114, 124))	('KCTD20 protein', 'Protein', (13, 27))	('glioma', 'Disease', (92, 98))	('miR-324-5p', 'Chemical', '-', (114, 124))	('miR-324-5p', 'Chemical', '-', (177, 187))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('suppressed', 'NegReg', (139, 149))
184181	33982764	Luciferase reporter assays demonstrated that miR-324-5p could bind to NEAT1 and the 3' UTR of KCTD20.	('bind', 'Interaction', (62, 66))	('miR-324-5p', 'Chemical', '-', (45, 55))	('miR-324-5p', 'Var', (45, 55))
184185	33982764	The experimental results also showed that changes in the expression of NEAT1 could affect the expression levels of miR-324-5p; however, changes in the expression levels of miR-324-5p had no effect on NEAT1 (Fig.	('expression levels of miR-324-5p', 'MPA', (94, 125))	('miR-324-5p', 'Chemical', '-', (172, 182))	('affect', 'Reg', (83, 89))	('NEAT1', 'Gene', (71, 76))	('miR-324-5p', 'Chemical', '-', (115, 125))	('changes', 'Var', (42, 49))
184187	33982764	In combination, these data suggested that NEAT1 regulated the expression levels of KCTD20 in glioma cells by post-transcriptional modulation of miR-324-5p.	('KCTD20', 'Gene', (83, 89))	('miR-324-5p', 'Chemical', '-', (144, 154))	('glioma', 'Disease', (93, 99))	('expression levels', 'MPA', (62, 79))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('regulated', 'Reg', (48, 57))	('miR-324-5p', 'Var', (144, 154))
184188	33982764	Subsequently, it was determined whether the functional effects of NEAT1 and miR-324-5p on glioma cell biology were mediated through their control of KCTD20 expression.	('glioma', 'Disease', (90, 96))	('miR-324-5p', 'Chemical', '-', (76, 86))	('miR-324-5p', 'Var', (76, 86))	('KCTD20', 'Gene', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('expression', 'MPA', (156, 166))
184189	33982764	Transfection of U251 and LN229 cells with siKCTD20 effectively decreased KCTD20 mRNA and protein expression compared with that in control cells (Fig.	('decreased', 'NegReg', (63, 72))	('siKCTD20', 'Var', (42, 50))	('LN229', 'CellLine', 'CVCL:0393', (25, 30))
184190	33982764	Notably, the silencing of KCTD20 significantly inhibited U251 and LN229 proliferation, based on the results of CCK-8, colony formation and EdU incorporation assays (Fig.	('colony formation', 'CPA', (118, 134))	('inhibited', 'NegReg', (47, 56))	('LN229', 'CellLine', 'CVCL:0393', (66, 71))	('EdU', 'Chemical', '-', (139, 142))	('CCK-8', 'Chemical', '-', (111, 116))	('EdU', 'CPA', (139, 142))	('KCTD20', 'Gene', (26, 32))	('silencing', 'Var', (13, 22))
184191	33982764	7B-D), Furthermore, the results demonstrated that more cells were in the G0/G1 phase and fewer cells were in S phase of the cell cycle after cells were transfected with siKCTD20 (Fig.	('B', 'Chemical', 'MESH:D001895', (1, 2))	('G0/G1 phase', 'CPA', (73, 84))	('siKCTD20', 'Var', (169, 177))
184196	33982764	Consistent with the results of the in vitro assays, silencing of KCTD20 markedly inhibited glioma growth and significantly improved the survival time of tumor-bearing mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mice', 'Species', '10090', (167, 171))	('glioma growth', 'Disease', 'MESH:D005910', (91, 104))	('KCTD20', 'Gene', (65, 71))	('silencing', 'Var', (52, 61))	('survival time', 'CPA', (136, 149))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('improved', 'PosReg', (123, 131))	('glioma growth', 'Disease', (91, 104))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
184198	33982764	In addition, transfection of miR-324-5p inhibitor in addition to knockdown of KCTD20 in glioma cell lines partially reversed the effects of KCTD20 knockdown (Figs.	('glioma', 'Disease', (88, 94))	('miR-324-5p', 'Chemical', '-', (29, 39))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('KCTD20', 'Gene', (78, 84))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('KCTD20', 'Gene', (140, 146))	('knockdown', 'Var', (147, 156))
184200	33982764	Furthermore, the concomitant knockdown of miR-324-5p and KCTD20 in U251 and LN229 cells abrogated the effects of knockdown of KCTD20 on cell cycle arrest (Fig.	('miR-324-5p', 'Chemical', '-', (42, 52))	('arrest', 'Disease', (147, 153))	('abrogated', 'NegReg', (88, 97))	('KCTD20', 'Gene', (57, 63))	('LN229', 'CellLine', 'CVCL:0393', (76, 81))	('arrest', 'Disease', 'MESH:D006323', (147, 153))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (136, 153))	('KCTD20', 'Gene', (126, 132))	('miR-324-5p', 'Var', (42, 52))
184202	33982764	Finally, a statistically significant inverse correlation was detected between the expression levels of miR-324-5p and KCTD20 in the clinical glioma tissues (r=-0.4582; P=0.002; Fig.	('miR-324-5p', 'Var', (103, 113))	('miR-324-5p', 'Chemical', '-', (103, 113))	('expression', 'MPA', (82, 92))	('inverse', 'NegReg', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('KCTD20', 'Gene', (118, 124))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('glioma', 'Disease', (141, 147))
184203	33982764	In combination, the data presented in the current study provided substantial evidence that NEAT1 is oncogenic in glioma cells and exerts its effects through the modulation of miR-324-5p-regulated KCTD20 expression.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('NEAT1', 'Gene', (91, 96))	('expression', 'MPA', (203, 213))	('miR-324-5p-regulated', 'Var', (175, 195))	('effects', 'MPA', (141, 148))	('glioma', 'Disease', (113, 119))	('modulation', 'Reg', (161, 171))	('KCTD20', 'Gene', (196, 202))	('miR-324-5p', 'Chemical', '-', (175, 185))
184222	33982764	These results suggested that miR-324-5p may normally serve an inhibitory role in NHAs, and that its aberrantly low expression in glioma cells may contribute to tumor progression.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('contribute', 'Reg', (146, 156))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('miR-324-5p', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('expression', 'MPA', (115, 125))	('NHAs', 'Disease', (81, 85))	('miR-324-5p', 'Chemical', '-', (29, 39))	('glioma', 'Disease', (129, 135))	('tumor', 'Disease', (160, 165))	('low', 'NegReg', (111, 114))
184232	33982764	The present study demonstrated that miR-324-5p may bind directly to the KCTD20 3'-UTR to regulate its expression.	('KCTD20', 'Gene', (72, 78))	('expression', 'MPA', (102, 112))	('miR-324-5p', 'Var', (36, 46))	('regulate', 'Reg', (89, 97))	('miR-324-5p', 'Chemical', '-', (36, 46))
184233	33982764	Notably, it was demonstrated that knockdown of KCTD20 in a mouse model of glioma not only reduced tumor growth but also extended mouse survival.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('reduced', 'NegReg', (90, 97))	('mouse', 'Species', '10090', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('knockdown', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glioma', 'Disease', (74, 80))	('extended', 'PosReg', (120, 128))	('KCTD20', 'Gene', (47, 53))	('tumor', 'Disease', (98, 103))	('mouse', 'Species', '10090', (129, 134))	('mouse survival', 'CPA', (129, 143))
184234	33982764	In addition, miR-324-5p expression in glioma specimens was inversely correlated with the expression levels of both NEAT1 and KCTD20, while NEAT1 expression was positively correlated with KCTD20 expression.	('miR-324-5p', 'Chemical', '-', (13, 23))	('KCTD20', 'Gene', (125, 131))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('correlated', 'Interaction', (69, 79))	('inversely', 'NegReg', (59, 68))	('NEAT1', 'Gene', (115, 120))	('glioma', 'Disease', (38, 44))	('miR-324-5p', 'Var', (13, 23))	('expression levels', 'MPA', (89, 106))
184262	33925547	Indeed, most (>70%) diffuse grade II gliomas carry a recurrent missense mutation in the IDH1 or IDH2 (isocitrate dehydrogenase 1/2) genes, with IDH1R132H being the most commonly identified mutation (90%).	('IDH', 'Gene', (144, 147))	('missense mutation', 'Var', (63, 80))	('isocitrate', 'Chemical', 'MESH:C034219', (102, 112))	('IDH', 'Gene', '3417', (96, 99))	('IDH', 'Gene', '3417', (144, 147))	('R132H', 'Mutation', 'rs1034749666', (148, 153))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('IDH', 'Gene', (88, 91))	('gliomas', 'Disease', (37, 44))	('IDH', 'Gene', '3417', (88, 91))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('IDH', 'Gene', (96, 99))
184263	33925547	IDH-mutant oligodendrogliomas additionally have an unbalanced translocation of chromosomes 1 and 19, resulting in deletions of 1p and 19q (1p/19q codeletion).	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (11, 29))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('oligodendrogliomas', 'Disease', (11, 29))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('deletions', 'Var', (114, 123))
184265	33925547	IDH-mutant grade II astrocytomas most often carry ATRX and TP53 mutations (abbreviations are listed in Table S5).	('ATRX', 'Gene', '546', (50, 54))	('IDH', 'Gene', (0, 3))	('TP53', 'Gene', (59, 63))	('astrocytomas', 'Disease', 'MESH:D001254', (20, 32))	('IDH', 'Gene', '3417', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (20, 31))	('astrocytomas', 'Disease', (20, 32))	('mutations', 'Var', (64, 73))	('ATRX', 'Gene', (50, 54))	('TP53', 'Gene', '7157', (59, 63))	('carry', 'Reg', (44, 49))
184282	33925547	The tumors used in the article are (1) diffuse grade II astrocytomas, showing IDH1 R132H, and TP53 stainings and loss of nuclear staining for ATRX by IHC, and (2) diffuse grade II oligodendrogliomas based on IDH1 R132H IHC staining and 1p19q codeletion.	('R132H', 'Mutation', 'rs1034749666', (213, 218))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('TP53', 'Gene', (94, 98))	('IDH', 'Gene', (208, 211))	('astrocytomas', 'Disease', (56, 68))	('R132H', 'Mutation', 'rs1034749666', (83, 88))	('loss', 'NegReg', (113, 117))	('nuclear staining', 'MPA', (121, 137))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (180, 198))	('IDH', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('IDH', 'Gene', '3417', (208, 211))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('1p19q codeletion', 'Var', (236, 252))	('TP53', 'Gene', '7157', (94, 98))	('astrocytomas', 'Disease', 'MESH:D001254', (56, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (56, 67))	('IDH', 'Gene', '3417', (78, 81))	('oligodendrogliomas', 'Disease', (180, 198))	('tumors', 'Disease', (4, 10))	('ATRX', 'Gene', (142, 146))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('ATRX', 'Gene', '546', (142, 146))
184283	33925547	IDH1 mutation was also confirmed by the sequencing of exon 4, and 1p/19q codeletion was assessed by molecular detection of loss of heterozygosity using polymorphic markers within 1p and 19q chromosome arms, as described previously.	('mutation', 'Var', (5, 13))	('IDH', 'Gene', '3417', (0, 3))	('loss', 'NegReg', (123, 127))	('IDH', 'Gene', (0, 3))
184301	33925547	For the DLL4 ligand experiment (Figure S13A), plates were coated with DLL4 (5 microg/mL; Peprotech) or BSA at 4  C overnight before seeding the cells.	('DLL4', 'Gene', '54567', (70, 74))	('S13A', 'Var', (39, 43))	('DLL4', 'Gene', '54567', (8, 12))	('DLL4', 'Gene', (70, 74))	('S13A', 'SUBSTITUTION', 'None', (39, 43))	('DLL4', 'Gene', (8, 12))
184303	33925547	KCNN3/SK3 channel currents were measured in LGG275 cells transduced with control-YFP or NICD-YFP viruses 3 days after the infection.	('SK3', 'Gene', '3782', (6, 9))	('infection', 'Disease', (122, 131))	('infection', 'Disease', 'MESH:D007239', (122, 131))	('LGG275', 'CellLine', 'CVCL:D760', (44, 50))	('KCNN3', 'Gene', '3782', (0, 5))	('NICD-YFP', 'Var', (88, 96))	('SK3', 'Gene', (6, 9))	('KCNN3', 'Gene', (0, 5))
184311	33925547	In order to distinguish several cell populations in IDH-DGIIG tumors, we examined three diffuse grade II astrocytoma tumors with IDH1 R132H and ATRX mutations and three diffuse grade II oligodendroglioma tumors with an IDH1 R132H mutation and a 1p19q codeletion (Table S1).	('II astrocytoma tumors', 'Disease', (102, 123))	('IDH', 'Gene', '3417', (219, 222))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('IDH-DGIIG tumors', 'Disease', (52, 68))	('IDH', 'Gene', '3417', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('IDH', 'Gene', '3417', (129, 132))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('IDH-DGIIG tumors', 'Disease', 'MESH:D009369', (52, 68))	('II oligodendroglioma tumors', 'Disease', 'MESH:D009837', (183, 210))	('mutations', 'Var', (149, 158))	('II astrocytoma tumors', 'Disease', 'MESH:D001254', (102, 123))	('diffuse', 'Disease', (88, 95))	('IDH', 'Gene', (219, 222))	('ATRX', 'Gene', (144, 148))	('II oligodendroglioma tumors', 'Disease', (183, 210))	('IDH', 'Gene', (52, 55))	('R132H', 'Mutation', 'rs1034749666', (224, 229))	('ATRX', 'Gene', '546', (144, 148))	('IDH', 'Gene', (129, 132))	('R132H', 'Mutation', 'rs1034749666', (134, 139))
184322	33925547	Stainings for these four proteins were performed in one oligodendroglioma and one astrocytoma mutated for IDH1, along with 1p/19q codeletion or ATRX mutation, respecttively.	('astrocytoma', 'Disease', (82, 93))	('mutated', 'Var', (94, 101))	('IDH', 'Gene', '3417', (106, 109))	('oligodendroglioma', 'Disease', (56, 73))	('ATRX', 'Gene', (144, 148))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('oligodendroglioma', 'Disease', 'MESH:D009837', (56, 73))	('ATRX', 'Gene', '546', (144, 148))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('astrocytoma', 'Disease', 'MESH:D001254', (82, 93))	('IDH', 'Gene', (106, 109))
184360	33925547	To evaluate this possibility, we derived primary cultures from IDH-DGIIG resections mutated for ATRX and IDH1 R132H (Figure S10).	('IDH', 'Gene', (63, 66))	('ATRX', 'Gene', (96, 100))	('R132H', 'Mutation', 'rs1034749666', (110, 115))	('IDH', 'Gene', '3417', (63, 66))	('mutated', 'Var', (84, 91))	('IDH', 'Gene', (105, 108))	('ATRX', 'Gene', '546', (96, 100))	('IDH', 'Gene', '3417', (105, 108))
184361	33925547	The presence of tumoral cells in the cultures was evaluated by IF against IDH1 R132H and ATRX.	('R132H', 'Mutation', 'rs1034749666', (79, 84))	('tumoral', 'Disease', (16, 23))	('tumoral', 'Disease', 'MESH:D009369', (16, 23))	('ATRX', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('IDH', 'Gene', (74, 77))	('ATRX', 'Gene', '546', (89, 93))	('IDH', 'Gene', '3417', (74, 77))	('R132H', 'Var', (79, 84))
184363	33925547	When few mutated cells were present, the cultures mainly consisted of highly-branched cells (Figure S11A,B) with small nuclei (perimeter = 22.9 microm +- 0.3, n = 200 cells), expressing a high level of ATRX, CNP, OLIG1, O4, and SOX10, whereas stainings for IDH1 R132H, EGFR, GFAP, and SOX9 were rare or absent in these cells (Figure S11C,D).	('IDH', 'Gene', '3417', (257, 260))	('SOX10', 'Gene', (228, 233))	('SOX9', 'Gene', '6662', (285, 289))	('ATRX', 'Gene', (202, 206))	('S11A', 'Var', (100, 104))	('EGFR', 'Gene', '1956', (269, 273))	('ATRX', 'Gene', '546', (202, 206))	('S11A', 'SUBSTITUTION', 'None', (100, 104))	('CNP', 'Gene', (208, 211))	('S11C', 'SUBSTITUTION', 'None', (333, 337))	('CNP', 'Gene', '1267', (208, 211))	('OLIG1', 'Gene', '116448', (213, 218))	('IDH', 'Gene', (257, 260))	('OLIG1', 'Gene', (213, 218))	('SOX10', 'Gene', '6663', (228, 233))	('SOX9', 'Gene', (285, 289))	('R132H', 'Mutation', 'rs1034749666', (262, 267))	('EGFR', 'Gene', (269, 273))	('GFAP', 'Gene', (275, 279))	('S11C', 'Var', (333, 337))	('GFAP', 'Gene', '2670', (275, 279))
184365	33925547	In contrast, in cultures containing lots of tumoral cells (Figure S10A,B), we noted that these have a larger and often abnormal nucleus (perimeter = 30.7 microm +- 0.4, n = 200 cells) and express high levels of EGFR, OLIG1, and SOX9 and weak stainings for CNP and SOX10 (Figure S10C,D).	('tumoral', 'Disease', (44, 51))	('tumoral', 'Disease', 'MESH:D009369', (44, 51))	('SOX9', 'Gene', '6662', (228, 232))	('S10A', 'SUBSTITUTION', 'None', (66, 70))	('OLIG1', 'Gene', '116448', (217, 222))	('S10A', 'Var', (66, 70))	('OLIG1', 'Gene', (217, 222))	('EGFR', 'Gene', '1956', (211, 215))	('SOX10', 'Gene', '6663', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('EGFR', 'Gene', (211, 215))	('CNP', 'Gene', (256, 259))	('SOX9', 'Gene', (228, 232))	('SOX10', 'Gene', (264, 269))	('S10C', 'Mutation', 'p.S10C', (278, 282))	('CNP', 'Gene', '1267', (256, 259))
184367	33925547	To test the influence of the NOTCH1 pathway on IDH-DGIIG cells, we selected four independent cultures containing >70% of IDH1 R132H ATRX mutated cells.	('NOTCH1', 'Gene', (29, 35))	('R132H', 'Mutation', 'rs1034749666', (126, 131))	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', (121, 124))	('ATRX', 'Gene', (132, 136))	('IDH', 'Gene', '3417', (121, 124))	('R132H', 'Var', (126, 131))	('mutated', 'Var', (137, 144))	('IDH', 'Gene', (47, 50))	('ATRX', 'Gene', '546', (132, 136))	('NOTCH1', 'Gene', '4851', (29, 35))
184374	33925547	To confirm these results, we used a cell line (named LGG275) that was derived from a diffuse low-grade glioma patient with IDH1 and ATRX mutations (Table S1).	('LGG275', 'CellLine', 'CVCL:D760', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('mutations', 'Var', (137, 146))	('ATRX', 'Gene', (132, 136))	('patient', 'Species', '9606', (110, 117))	('IDH', 'Gene', (123, 126))	('glioma', 'Disease', (103, 109))	('ATRX', 'Gene', '546', (132, 136))	('IDH', 'Gene', '3417', (123, 126))
184375	33925547	This cell line contains bipolar and multipolar cells (Figure S12A) expressing IDH1 R132H but not ATRX (Figure S12B, Lanes 1,3) that grow very slowly (doubling time = 9.6 +- 0.1 days, n = 6 wells).	('ATRX', 'Gene', '546', (97, 101))	('S12B', 'Var', (110, 114))	('bipolar', 'Disease', 'MESH:D001714', (24, 31))	('S12A', 'Var', (61, 65))	('R132H', 'Mutation', 'rs1034749666', (83, 88))	('S12A', 'SUBSTITUTION', 'None', (61, 65))	('bipolar', 'Disease', (24, 31))	('S12B', 'SUBSTITUTION', 'None', (110, 114))	('ATRX', 'Gene', (97, 101))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', '3417', (78, 81))
184376	33925547	Figure S12B,C shows that LGG275 cells express both SOX9 and OLIG1 proteins (Lane 4) together with EGFR, CNP, and SOX10 (Lanes 1-3), as seen in primary tumoral cultures (Figure S10).	('EGFR', 'Gene', (98, 102))	('S12B', 'Var', (7, 11))	('OLIG1', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CNP', 'Gene', (104, 107))	('SOX9', 'Gene', (51, 55))	('SOX10', 'Gene', '6663', (113, 118))	('LGG275', 'CellLine', 'CVCL:D760', (25, 31))	('S12B', 'SUBSTITUTION', 'None', (7, 11))	('tumoral', 'Disease', (151, 158))	('SOX10', 'Gene', (113, 118))	('SOX9', 'Gene', '6662', (51, 55))	('tumoral', 'Disease', 'MESH:D009369', (151, 158))	('CNP', 'Gene', '1267', (104, 107))	('EGFR', 'Gene', '1956', (98, 102))	('OLIG1', 'Gene', '116448', (60, 65))
184377	33925547	These cells were transduced with YFP and YFP-NICD lentiviruses, which led to strong upregulation of NOTCH1 RNA (Figure 5B) and a clear nuclear localization of the NICD fragment (Figure 5C).	('upregulation', 'PosReg', (84, 96))	('nuclear localization', 'MPA', (135, 155))	('YFP', 'Var', (33, 36))	('NOTCH1', 'Gene', '4851', (100, 106))	('YFP-NICD', 'Var', (41, 49))	('NOTCH1', 'Gene', (100, 106))
184379	33925547	SOX9 was moderately but significantly downregulated by NICD in this cell line.	('downregulated', 'NegReg', (38, 51))	('SOX9', 'Gene', '6662', (0, 4))	('NICD', 'Var', (55, 59))	('SOX9', 'Gene', (0, 4))
184380	33925547	We could confirm the upregulation of APOE, CRYAB, HEY1, and KCNN3 proteins by NICD by IF (Figure 5C and Figure 6A).	('CRYAB', 'Gene', '1410', (43, 48))	('NICD', 'Var', (78, 82))	('KCNN3', 'Gene', '3782', (60, 65))	('HEY1', 'Gene', '23462', (50, 54))	('CRYAB', 'Gene', (43, 48))	('upregulation', 'PosReg', (21, 33))	('HEY1', 'Gene', (50, 54))	('KCNN3', 'Gene', (60, 65))
184382	33925547	This resulted in the significant upregulation of APOE, HEY1, and KCNN3, while the expression of all oligodendrocytic genes was reduced (Figure S13A).	('HEY1', 'Gene', (55, 59))	('expression', 'MPA', (82, 92))	('KCNN3', 'Gene', (65, 70))	('HEY1', 'Gene', '23462', (55, 59))	('S13A', 'Var', (143, 147))	('upregulation', 'PosReg', (33, 45))	('KCNN3', 'Gene', '3782', (65, 70))	('APOE', 'Gene', (49, 53))	('reduced', 'NegReg', (127, 134))	('S13A', 'SUBSTITUTION', 'None', (143, 147))
184394	33925547	We reasoned that, in fact, the high level and, maybe, already saturated expression of SOX9 in these cells (Figures S10C and S12B) might preclude an upregulation after NICD transduction.	('S12B', 'Var', (124, 128))	('upregulation', 'PosReg', (148, 160))	('S10C', 'Mutation', 'p.S10C', (115, 119))	('SOX9', 'Gene', (86, 90))	('S12B', 'SUBSTITUTION', 'None', (124, 128))	('SOX9', 'Gene', '6662', (86, 90))
184396	33925547	In these cultures, SOX9 could be barely detected by IF (Figure S11C; Lane 6).	('S11C', 'Var', (63, 67))	('SOX9', 'Gene', (19, 23))	('SOX9', 'Gene', '6662', (19, 23))	('S11C', 'SUBSTITUTION', 'None', (63, 67))
184397	33925547	QPCR for SOX9 validated this low level of expression compared to tumoral IDH-DGIIG primary cultures and LGG275 cells (Figure S13B).	('expression', 'MPA', (42, 52))	('tumoral IDH', 'Disease', 'MESH:D009369', (65, 76))	('S13B', 'Var', (125, 129))	('S13B', 'SUBSTITUTION', 'None', (125, 129))	('SOX9', 'Gene', (9, 13))	('LGG275', 'CellLine', 'CVCL:D760', (104, 110))	('SOX9', 'Gene', '6662', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumoral IDH', 'Disease', (65, 76))
184398	33925547	Figure S13E shows that overexpression of NICD in these cells induced a sharp upregulation of SOX9 (fold change = 14.8) that could also be observed at the protein level by IF (Figure S13C,D).	('overexpression', 'PosReg', (23, 37))	('S13C', 'Mutation', 'p.S13C', (182, 186))	('NICD', 'Var', (41, 45))	('SOX9', 'Gene', (93, 97))	('upregulation', 'PosReg', (77, 89))	('SOX9', 'Gene', '6662', (93, 97))	('S13E', 'Mutation', 'p.S13E', (7, 11))
184427	33925547	This was observed using an antibody for the mutated form of IDH1 (R132H) but also confirmed with an antibody against wild-type IDH1.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('R132H', 'Var', (66, 71))	('R132H', 'Mutation', 'rs1034749666', (66, 71))	('IDH', 'Gene', (60, 63))	('IDH', 'Gene', '3417', (60, 63))
184437	33925547	CRYAB is also upregulated by NICD overexpression in LGG275 cells (Figure 5B), suggesting a potential double regulation by NOTCH1 and BMP signalling.	('CRYAB', 'Gene', '1410', (0, 5))	('NOTCH1', 'Gene', '4851', (122, 128))	('NOTCH1', 'Gene', (122, 128))	('BMP', 'Gene', '649', (133, 136))	('LGG275', 'CellLine', 'CVCL:D760', (52, 58))	('CRYAB', 'Gene', (0, 5))	('upregulated', 'PosReg', (14, 25))	('BMP', 'Gene', (133, 136))	('NICD', 'Var', (29, 33))
184448	33925547	Using nontumoral human O4-purified oligodendrocytic cells, we also found that the activation of NOTCH1 reduced oligodendrocytic gene expression while upregulating CRYAB, KCNN3, and SOX9.	('activation', 'Var', (82, 92))	('upregulating', 'PosReg', (150, 162))	('SOX9', 'Gene', (181, 185))	('SOX9', 'Gene', '6662', (181, 185))	('oligodendrocytic gene', 'Gene', (111, 132))	('reduced', 'NegReg', (103, 110))	('human', 'Species', '9606', (17, 22))	('CRYAB', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('KCNN3', 'Gene', (170, 175))	('NOTCH1', 'Gene', '4851', (96, 102))	('NOTCH1', 'Gene', (96, 102))	('CRYAB', 'Gene', '1410', (163, 168))	('KCNN3', 'Gene', '3782', (170, 175))	('tumoral', 'Disease', (9, 16))	('tumoral', 'Disease', 'MESH:D009369', (9, 16))
184451	33925547	This was, however, not observed in these cells, which, in fact, already expressed a high and maybe saturated level of SOX9 (Figures S10C and S12B).	('S10C', 'Mutation', 'p.S10C', (132, 136))	('S12B', 'Var', (141, 145))	('SOX9', 'Gene', (118, 122))	('S12B', 'SUBSTITUTION', 'None', (141, 145))	('SOX9', 'Gene', '6662', (118, 122))
184453	33925547	In contrast, in nontumoral oligodendrocytic O4+ cells, which do not express SOX9 (Figure S11C), both SOX9 gene and protein were strongly induced by NOTCH1 activation.	('induced', 'PosReg', (137, 144))	('NOTCH1', 'Gene', (148, 154))	('nontumoral oligodendrocytic', 'Disease', (16, 43))	('S11C', 'SUBSTITUTION', 'None', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SOX9', 'Gene', (76, 80))	('protein', 'Protein', (115, 122))	('SOX9', 'Gene', (101, 105))	('SOX9', 'Gene', '6662', (76, 80))	('SOX9', 'Gene', '6662', (101, 105))	('nontumoral oligodendrocytic', 'Disease', 'MESH:D056784', (16, 43))	('S11C', 'Var', (89, 93))	('NOTCH1', 'Gene', '4851', (148, 154))	('activation', 'PosReg', (155, 165))
184506	32392361	Reduced immune infiltrates were observed in IDH mutant glioma (Amankulor et al., 2017), while Wang found increased macrophage infiltration in NF1 mutant tumors (Wang et al., 2017).	('glioma', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('NF1', 'Gene', '4763', (142, 145))	('immune infiltrates', 'CPA', (8, 26))	('Reduced immune infiltrates', 'Phenotype', 'HP:0012648', (0, 26))	('increased macrophage infiltration', 'Phenotype', 'HP:0004311', (105, 138))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('mutant', 'Var', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', (44, 47))	('tumors', 'Disease', (153, 159))	('increased', 'PosReg', (105, 114))	('macrophage infiltration', 'CPA', (115, 138))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('NF1', 'Gene', (142, 145))
184535	32392361	When stratified by immune subtypes, improved survival was observed in association with cytolytic activity in Im2, and Im1 patients with high scores of neutrophils or Treg tended to have better outcome (Fig.	('Im2', 'Gene', (109, 112))	('cytolytic activity', 'Var', (87, 105))	('Im1', 'Gene', '114314', (118, 121))	('patients', 'Species', '9606', (122, 130))	('improved', 'PosReg', (36, 44))	('better', 'PosReg', (186, 192))	('Im1', 'Gene', (118, 121))	('survival', 'MPA', (45, 53))	('Im2', 'Gene', '114686', (109, 112))
184536	32392361	Likewise, we assessed the prognostic value of major immune checkpoints, and found that high expression of PDCD1, HAVCR2, and IDO1 implied worse outcome (Fig.	('PDCD1', 'Gene', (106, 111))	('IDO1', 'Gene', '3620', (125, 129))	('PDCD1', 'Gene', '5133', (106, 111))	('HAVCR2', 'Gene', (113, 119))	('IDO1', 'Gene', (125, 129))	('high', 'Var', (87, 91))	('HAVCR2', 'Gene', '84868', (113, 119))
184541	32392361	Im2 tumors showed high aneuploidy, homologous recombination deficiency, and copy-number burden scores, as well as increased tumor mutation burden (Fig.	('tumor', 'Disease', (4, 9))	('Im2', 'Gene', '114686', (0, 3))	('aneuploidy', 'Disease', 'MESH:D000782', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (4, 10))	('increased', 'PosReg', (114, 123))	('Im2', 'Gene', (0, 3))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('aneuploidy', 'Disease', (23, 33))	('copy-number burden scores', 'Var', (76, 101))	('deficiency', 'Disease', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('homologous', 'Var', (35, 45))	('deficiency', 'Disease', 'MESH:D007153', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
184542	32392361	Im1 was enriched in IDH1, 1p/19q codeletion, CIC, FUBP1, and NOTCH1 mutations.	('IDH1', 'Gene', '3417', (20, 24))	('FUBP1', 'Gene', (50, 55))	('NOTCH1', 'Gene', '4851', (61, 67))	('CIC', 'Disease', (45, 48))	('NOTCH1', 'Gene', (61, 67))	('Im1', 'Gene', (0, 3))	('FUBP1', 'Gene', '8880', (50, 55))	('Im1', 'Gene', '114314', (0, 3))	('mutations', 'Var', (68, 77))	('IDH1', 'Gene', (20, 24))	('1p/19q codeletion', 'Var', (26, 43))
184543	32392361	Im2 was enriched in mutations in driver genes, such as PTEN, EGFR, and NF1, a finding of note since tumors with NF1 mutation had increased macrophage infiltration (Wang et al., 2017).	('Im2', 'Gene', '114686', (0, 3))	('PTEN', 'Gene', '5728', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('NF1', 'Gene', (71, 74))	('mutation', 'Var', (116, 124))	('increased macrophage infiltration', 'Phenotype', 'HP:0004311', (129, 162))	('NF1', 'Gene', '4763', (71, 74))	('Im2', 'Gene', (0, 3))	('increased', 'PosReg', (129, 138))	('macrophage infiltration', 'CPA', (139, 162))	('tumors', 'Disease', (100, 106))	('NF1', 'Gene', (112, 115))	('NF1', 'Gene', '4763', (112, 115))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('PTEN', 'Gene', (55, 59))
184544	32392361	Im3 was enriched in IDH1, ATRX, and TP53 mutations (Fig.	('mutations', 'Var', (41, 50))	('Im3', 'Gene', (0, 3))	('IDH1', 'Gene', '3417', (20, 24))	('ATRX', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (36, 40))	('ATRX', 'Gene', '546', (26, 30))	('Im3', 'Gene', '492980', (0, 3))	('TP53', 'Gene', (36, 40))	('IDH1', 'Gene', (20, 24))
184555	32392361	The Kaplan-Meier analysis revealed that high scores implied significantly poorer outcome in patients of diffuse LGG or each immune subtype (Fig.	('poorer', 'NegReg', (74, 80))	('diffuse LGG', 'Disease', (104, 115))	('high scores', 'Var', (40, 51))	('patients', 'Species', '9606', (92, 100))
184565	32392361	Recently, Amankulor and colleagues reported that the IDH1 mutation is associated with a decreased number of immune cells in the glioma tumor microenvironment (Amankulor et al., 2017).	('glioma tumor', 'Disease', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('glioma tumor', 'Disease', 'MESH:D005910', (128, 140))	('IDH1', 'Gene', (53, 57))	('mutation', 'Var', (58, 66))	('IDH1', 'Gene', '3417', (53, 57))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('decreased', 'NegReg', (88, 97))
184566	32392361	Consistently, we showed that Im1 and Im2, which were enriched in IDH1 mutation, had lower immune infiltrate.	('IDH1', 'Gene', '3417', (65, 69))	('Im2', 'Gene', (37, 40))	('immune infiltrate', 'CPA', (90, 107))	('Im1', 'Gene', '114314', (29, 32))	('lower', 'NegReg', (84, 89))	('Im2', 'Gene', '114686', (37, 40))	('mutation', 'Var', (70, 78))	('IDH1', 'Gene', (65, 69))	('Im1', 'Gene', (29, 32))
184567	32392361	We also observed that Im2, which was enriched in NF1 mutation, was characterized by high macrophages, in agreement with the finding that tumors with NF1 mutation had increased macrophage infiltration in glioma (Wang et al., 2017).	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('mutation', 'Var', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('increased', 'PosReg', (166, 175))	('NF1', 'Gene', '4763', (149, 152))	('macrophage infiltration', 'CPA', (176, 199))	('Im2', 'Gene', '114686', (22, 25))	('increased macrophage infiltration', 'Phenotype', 'HP:0004311', (166, 199))	('Im2', 'Gene', (22, 25))	('NF1', 'Gene', (149, 152))	('NF1', 'Gene', (49, 52))	('glioma', 'Disease', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mutation', 'Var', (153, 161))	('NF1', 'Gene', '4763', (49, 52))
184571	32392361	When we associated immune subtype with IDH or 1p/19q status in TCGA cohort, 95% (130/137) of IDH mutant and 1p/19q codeleted LGG were enriched in Im1.	('and 1p', 'Gene', '11169', (104, 110))	('and 1p', 'Gene', (104, 110))	('Im1', 'Gene', '114314', (146, 149))	('IDH', 'Gene', (93, 96))	('mutant', 'Var', (97, 103))	('IDH', 'Gene', '3417', (93, 96))	('IDH', 'Gene', (39, 42))	('Im1', 'Gene', (146, 149))	('IDH', 'Gene', '3417', (39, 42))
184573	32392361	23% (45/192), 23% (44/192), and 54% (103/192) of IDH mutant and 1p/19q non-codeleted LGG were enriched in Im1, Im2, and Im3, respectively.	('Im3', 'Gene', (120, 123))	('IDH', 'Gene', (49, 52))	('Im1', 'Gene', (106, 109))	('Im1', 'Gene', '114314', (106, 109))	('Im3', 'Gene', '492980', (120, 123))	('Im2', 'Gene', '114686', (111, 114))	('IDH', 'Gene', '3417', (49, 52))	('and 1p', 'Gene', '11169', (60, 66))	('mutant', 'Var', (53, 59))	('and 1p', 'Gene', (60, 66))	('Im2', 'Gene', (111, 114))
184579	32434559	The clinical significance of the T2-FLAIR mismatch sign in grade II and III gliomas: a population-based study The T2-FLAIR mismatch sign is an imaging finding highly suggestive of isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted (non-codel) gliomas (astrocytomas).	('III gliomas', 'Disease', (72, 83))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('astrocytomas', 'Disease', 'MESH:D001254', (264, 276))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('1p19q', 'Var', (223, 228))	('T2-FLAIR', 'MPA', (114, 122))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (264, 275))	('IDH', 'Gene', (214, 217))	('III gliomas', 'Disease', 'MESH:D005910', (72, 83))	('astrocytomas', 'Disease', (264, 276))	('gliomas', 'Phenotype', 'HP:0009733', (255, 262))	('gliomas', 'Disease', (255, 262))	('IDH', 'Gene', '3417', (214, 217))	('gliomas', 'Disease', 'MESH:D005910', (255, 262))
184588	32434559	The sensitivity and specificity of the mismatch sign for IDH-mut detection were 26.4 and 97.6%, respectively.	('IDH', 'Gene', '3417', (57, 60))	('IDH', 'Gene', (57, 60))	('mismatch', 'Var', (39, 47))
184594	32434559	These subgroups are based upon determination of mutation in the isocitrate dehydrogenase genes 1 or 2 (IDH1 and IDH2), and 1p19q codeletion status.	('IDH1', 'Gene', '3417', (103, 107))	('1p19q', 'Var', (123, 128))	('IDH2', 'Gene', (112, 116))	('IDH2', 'Gene', '3418', (112, 116))	('mutation', 'Var', (48, 56))	('IDH1', 'Gene', (103, 107))
184600	32434559	The tumors showing a mismatch sign on MRI differ radiologically from gliomas without the mismatch sign with their distinct features.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('mismatch', 'Var', (21, 29))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
184604	32434559	In addition, we analyzed if IDH-mut astrocytomas with mismatch sign had similar methylation profiles compared to samples without mismatch sign.	('IDH', 'Gene', (28, 31))	('mismatch sign', 'Var', (54, 67))	('astrocytomas', 'Disease', (36, 48))	('IDH', 'Gene', '3417', (28, 31))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))	('astrocytomas', 'Disease', 'MESH:D001254', (36, 48))
184638	32434559	Of these, 53 patients had known status of IDH-mutation and 1p19q codeletion.	('IDH', 'Gene', '3417', (42, 45))	('IDH', 'Gene', (42, 45))	('1p19q codeletion', 'Var', (59, 75))	('patients', 'Species', '9606', (13, 21))
184645	32434559	The only significant difference was a more conspicuous tumor border in the group with mismatch sign (p = 0.02).	('mismatch sign', 'Var', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (55, 60))
184647	32434559	Nine patients (10.9%) in the retrospective part of the cohort showed mismatch signs and all of them had IDH-mutated gliomas.	('patients', 'Species', '9606', (5, 13))	('IDH', 'Gene', (104, 107))	('mismatch', 'Var', (69, 77))	('IDH', 'Gene', '3417', (104, 107))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
184648	32434559	There were no patients with a glioma with IDH-wild type and mismatch sign in the retrospective cohort.	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (42, 45))	('glioma', 'Disease', (30, 36))	('patients', 'Species', '9606', (14, 22))	('mismatch', 'Var', (60, 68))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
184649	32434559	However, we identified two patients with 1p19q codeletion (codel) tumors (oligodendrogliomas) and mismatch sign (see Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (74, 92))	('mismatch sign', 'Var', (98, 111))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('oligodendrogliomas', 'Disease', (74, 92))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (27, 35))	('1p19q codeletion', 'Var', (41, 57))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
184652	32434559	In the joint cohort with known molecular status, including both IDH-mutation and 1p19q codeletion (N = 135), the specificity for IDH-mut astrocytomas was 97.6% and the sensitivity was 26.4%.	('IDH', 'Gene', (64, 67))	('astrocytomas', 'Disease', 'MESH:D001254', (137, 149))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('astrocytomas', 'Disease', (137, 149))	('1p19q codeletion', 'Var', (81, 97))	('IDH', 'Gene', (129, 132))	('IDH', 'Gene', '3417', (64, 67))	('IDH', 'Gene', '3417', (129, 132))
184659	32434559	The only difference we found between the patients with IDH-mut astrocytomas with mismatch sign and those without was related to the imaging finding itself.	('IDH', 'Gene', (55, 58))	('astrocytomas', 'Disease', 'MESH:D001254', (63, 75))	('mismatch sign', 'Var', (81, 94))	('IDH', 'Gene', '3417', (55, 58))	('patients', 'Species', '9606', (41, 49))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('astrocytomas', 'Disease', (63, 75))
184667	32434559	This far, the mismatch sign has been reported in pilomyxoid astrocytoma, LGG harboring MYB rearrangement, oligodendroglioma (IDH-mut codel), and even in one patient with a non-neoplastic lesion.	('MYB', 'Gene', '4602', (87, 90))	('rearrangement', 'Var', (91, 104))	('pilomyxoid astrocytoma', 'Disease', 'MESH:D001254', (49, 71))	('oligodendroglioma', 'Disease', 'MESH:D009837', (106, 123))	('patient', 'Species', '9606', (157, 164))	('MYB', 'Gene', (87, 90))	('pilomyxoid astrocytoma', 'Disease', (49, 71))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('IDH', 'Gene', (125, 128))	('IDH', 'Gene', '3417', (125, 128))	('oligodendroglioma', 'Disease', (106, 123))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (176, 193))
184679	32434559	ADC Apparent diffusion coefficient CBV Cerebral blood volume Codel 1p19q codeleted DNET Dysembryoplastic neuroepithelial tumor FLAIR Fluid-attenuated inversion recovery IDH1 and 2 Isocitrate dehydrogenase genes 1 and 2 IDH-mut Isocitrate dehydrogenase gene mutation LGG Lower-grade gliomas, defined as WHO grade II and grade III diffuse gliomas MDT Multidisciplinary team MRI Magnetic resonance imaging NPV Negative predictive value Non-codel 1p19q non-codeleted NPV Negative predictive value Mismatch sign T2-FLAIR mismatch sign Supplementary information accompanies this paper at 10.1186/s12885-020-06951-w. AC, AS, LC, ASJ, NH and IBB performed the clinical and radiological data collection and analysis.	('ASJ', 'Gene', (622, 625))	('IDH', 'Gene', '3417', (219, 222))	('IDH1', 'Gene', (169, 173))	('mutation', 'Var', (257, 265))	('IDH', 'Gene', '3417', (169, 172))	('Dysembryoplastic neuroepithelial tumor', 'Disease', 'MESH:D018302', (88, 126))	('gliomas', 'Disease', (337, 344))	('gliomas', 'Disease', (282, 289))	('glioma', 'Phenotype', 'HP:0009733', (282, 288))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (105, 126))	('glioma', 'Phenotype', 'HP:0009733', (337, 343))	('IDH1', 'Gene', '3417', (169, 173))	('gliomas', 'Disease', 'MESH:D005910', (282, 289))	('gliomas', 'Disease', 'MESH:D005910', (337, 344))	('DNET', 'Chemical', '-', (83, 87))	('ADC', 'Chemical', '-', (0, 3))	('ASJ', 'Gene', '79642', (622, 625))	('IDH', 'Gene', (219, 222))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('gliomas', 'Phenotype', 'HP:0009733', (282, 289))	('gliomas', 'Phenotype', 'HP:0009733', (337, 344))	('IDH', 'Gene', (169, 172))	('Dysembryoplastic neuroepithelial tumor', 'Disease', (88, 126))
184910	31856727	For both datasets, the results using multi-omics data (all four data types combined) significantly outperform those using a single type of -omics data.	('a', 'Gene', '351', (10, 11))	('a', 'Gene', '351', (147, 148))	('a', 'Gene', '351', (93, 94))	('multi-omics', 'Var', (37, 48))	('a', 'Gene', '351', (52, 53))	('outperform', 'NegReg', (99, 109))	('a', 'Gene', '351', (55, 56))	('a', 'Gene', '351', (65, 66))	('a', 'Gene', '351', (149, 150))	('a', 'Gene', '351', (67, 68))	('a', 'Gene', '351', (12, 13))	('a', 'Gene', '351', (50, 51))	('a', 'Gene', '351', (122, 123))
185015	30373168	It has been shown that combined used of fMRI and DTI-FT together with brain mapping techniques and the use of neuronavitagion systems enhances the accuracy in identification of functional areas and eloquent tracts.	('enhances', 'PosReg', (134, 142))	('DTI-FT', 'Chemical', '-', (49, 55))	('fMRI', 'Var', (40, 44))
185041	30373168	demonstrated that a complete tumour resection is associated with 8-years SO in 98% of patients; moreover, it has been confirmed that gross total resection is independently associated with higher OS.	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (29, 35))	('gross total resection', 'Var', (133, 154))	('associated', 'Reg', (172, 182))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('higher OS', 'Disease', (188, 197))	('OS', 'Chemical', '-', (195, 197))	('patients', 'Species', '9606', (86, 94))
185042	30373168	Secondly, OS in LGG patients appears to be directly related to EOR and it has been demonstrated that incomplete resection results in 4.9 times greater risk of death than complete resection.	('incomplete resection', 'Var', (101, 121))	('OS', 'Chemical', '-', (10, 12))	('death', 'Disease', 'MESH:D003643', (159, 164))	('patients', 'Species', '9606', (20, 28))	('LGG', 'Disease', (16, 19))	('death', 'Disease', (159, 164))
185077	27187376	Methods: In order to realize Nrf2 protein expression in gliomas, Western blot analysis was performed in normal brain tissue and U87MG, LN229, GBM8401 and U118MG glioma cell lines protein lysates.	('Nrf2', 'Gene', (29, 33))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('glioma', 'Disease', (56, 62))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('U118MG', 'CellLine', 'CVCL:0633', (154, 160))	('U87MG', 'CellLine', 'CVCL:0022', (128, 133))	('LN229', 'CellLine', 'CVCL:0393', (135, 140))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('Nrf2', 'Gene', '4780', (29, 33))	('glioma', 'Disease', (161, 167))	('U118MG', 'Var', (154, 160))
185090	27187376	A recent study suggested that various molecular epidemiologic factors including mutative DNA damage, cell-cycle disarrangement, metabolic disorders, and long-term inflammatory conditions can contribute to the development of PBTs.	('mutative', 'Var', (80, 88))	('contribute', 'Reg', (191, 201))	('metabolic disorders', 'Disease', (128, 147))	('PBT', 'Gene', '3815', (224, 227))	('cell-cycle disarrangement', 'Phenotype', 'HP:0011018', (101, 126))	('cell-cycle disarrangement', 'CPA', (101, 126))	('metabolic disorders', 'Disease', 'MESH:D008659', (128, 147))	('PBT', 'Gene', (224, 227))
185108	27187376	Compared with normal brain tissue cell lysate, the Western blot analysis showed higher Nrf2 protein production in U87MG, LN229, GBM8401 and U118MG human glioma cell lines.	('U87MG', 'CellLine', 'CVCL:0022', (114, 119))	('U118MG', 'CellLine', 'CVCL:0633', (140, 146))	('U87MG', 'Var', (114, 119))	('Nrf2', 'Gene', '4780', (87, 91))	('glioma', 'Disease', (153, 159))	('GBM8401', 'Var', (128, 135))	('LN229', 'CellLine', 'CVCL:0393', (121, 126))	('human', 'Species', '9606', (147, 152))	('LN229', 'Var', (121, 126))	('Nrf2', 'Gene', (87, 91))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('protein', 'Protein', (92, 99))	('higher', 'PosReg', (80, 86))	('U118MG', 'Var', (140, 146))
185112	27187376	In addition, the degree of Nrf2 mRNA expression in U87MG and GBM8401 was higher than LN229 (Figure 2).	('mRNA expression', 'MPA', (32, 47))	('U87MG', 'Var', (51, 56))	('Nrf2', 'Gene', '4780', (27, 31))	('Nrf2', 'Gene', (27, 31))	('GBM8401', 'Var', (61, 68))	('U87MG', 'CellLine', 'CVCL:0022', (51, 56))	('LN229', 'CellLine', 'CVCL:0393', (85, 90))	('higher', 'PosReg', (73, 79))
185158	27187376	U87MG, LN229, GBM8401 and U118MG human glioma cells lines were maintained in Duobecco's modified Eagle's medium (DMEM) containing 10% fetal boving serum (FBS), penicillin, and streptomycin.	('GBM8401', 'Var', (14, 21))	('LN229', 'CellLine', 'CVCL:0393', (7, 12))	('FBS', 'Disease', 'MESH:D005198', (154, 157))	('streptomycin', 'Chemical', 'MESH:D013307', (176, 188))	('glioma', 'Disease', (39, 45))	('penicillin', 'Chemical', 'MESH:D010406', (160, 170))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('DMEM', 'Chemical', '-', (113, 117))	('FBS', 'Disease', (154, 157))	('human', 'Species', '9606', (33, 38))	('U118MG', 'Var', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	("Duobecco's modified Eagle's medium", 'Chemical', '-', (77, 111))	('U118MG', 'CellLine', 'CVCL:0633', (26, 32))
185159	27187376	Glioma protein lysates were prepared from 2 x 107 U87MG, LN229, GBM8401 and U118MG glioma cells.	('glioma', 'Disease', (83, 89))	('U118MG', 'Var', (76, 82))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('U87MG', 'CellLine', 'CVCL:0022', (50, 55))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('U118MG', 'CellLine', 'CVCL:0633', (76, 82))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('Glioma', 'Disease', (0, 6))	('LN229', 'CellLine', 'CVCL:0393', (57, 62))
185186	27187376	Although the details of pathogenesis in PBT remain unclear, pharmacological targeting of Nrf2 could delay disease progression and tumor infiltration.	('Nrf2', 'Gene', '4780', (89, 93))	('pharmacological targeting', 'Var', (60, 85))	('delay', 'NegReg', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PBT', 'Gene', (40, 43))	('Nrf2', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('disease progression', 'CPA', (106, 125))	('PBT', 'Gene', '3815', (40, 43))	('tumor', 'Disease', (130, 135))
185192	26539503	Univariate analysis showed that TR is influenced by the following: extent of resection (EOR) (P < 0.002), DeltaVT2T1 value (P < 0.001), histological diagnosis of oligodendroglioma (P = 0.017), and mutation of IDH1 (P = 0.022).	('IDH', 'Gene', '3417', (209, 212))	('oligodendroglioma', 'Disease', (162, 179))	('DeltaVT2T1', 'Var', (106, 116))	('mutation', 'Var', (197, 205))	('IDH1', 'Gene', (209, 213))	('oligodendroglioma', 'Disease', 'MESH:D009837', (162, 179))	('influenced', 'Reg', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('IDH', 'Gene', (209, 212))	('IDH1', 'Gene', '3417', (209, 213))
185216	26539503	They may cause pain during the opening; moreover, adhesions between dura mater and cortex, on the dominant side, may represent a risk of damage to the cortical language areas.	('damage', 'Reg', (137, 143))	('pain', 'Phenotype', 'HP:0012531', (15, 19))	('adhesions', 'Var', (50, 59))	('cause', 'Reg', (9, 14))	('pain', 'Disease', 'MESH:D010146', (15, 19))	('pain', 'Disease', (15, 19))	('cortical language areas', 'CPA', (151, 174))
185219	24176859	Phosphorylated SATB1 is associated with the progression and prognosis of glioma Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene regulator, and high expression of SATB1 is associated with progression and poor prognosis in several malignancies.	('malignancies', 'Disease', 'MESH:D009369', (273, 285))	('glioma', 'Disease', (73, 79))	('SATB1', 'Gene', '6304', (15, 20))	('Special AT-rich sequence-binding protein 1', 'Gene', (80, 122))	('malignancies', 'Disease', (273, 285))	('SATB1', 'Gene', (206, 211))	('SATB1', 'Gene', '6304', (206, 211))	('SATB1', 'Gene', '6304', (124, 129))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('associated', 'Reg', (215, 225))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('SATB1', 'Gene', (124, 129))	('Special AT-rich sequence-binding protein 1', 'Gene', '6304', (80, 122))	('high expression', 'Var', (187, 202))	('SATB1', 'Gene', (15, 20))
185236	24176859	Previous studies reported that high SATB1 expression was correlated with metastasis and unfavorable clinical outcome in several cancer forms including breast carcinoma, gastric carcinoma, colorectal carcinoma and bladder carcinoma.	('SATB1', 'Gene', (36, 41))	('metastasis', 'CPA', (73, 83))	('expression', 'MPA', (42, 52))	('colorectal carcinoma and bladder carcinoma', 'Disease', 'MESH:D015179', (188, 230))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (169, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('cancer', 'Disease', (128, 134))	('SATB1', 'Gene', '6304', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('correlated', 'Reg', (57, 67))	('breast carcinoma', 'Disease', 'MESH:D001943', (151, 167))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (213, 230))	('high', 'Var', (31, 35))	('clinical', 'Species', '191496', (100, 108))	('breast carcinoma', 'Phenotype', 'HP:0003002', (151, 167))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('breast carcinoma', 'Disease', (151, 167))	('gastric carcinoma', 'Disease', 'MESH:D013274', (169, 186))	('gastric carcinoma', 'Disease', (169, 186))
185264	24176859	Unlike our in vivo data, SATB1 knockdown resulted in a decrease in phospho-SATB1 levels (Figure 4b).	('SATB1', 'Gene', (75, 80))	('SATB1', 'Gene', '6304', (75, 80))	('SATB1', 'Gene', (25, 30))	('SATB1', 'Gene', '6304', (25, 30))	('decrease', 'NegReg', (55, 63))	('knockdown', 'Var', (31, 40))
185290	24176859	As an important post-translational modification, phosphorylation significantly affects the ability of SATB1 to bind with DNA and act as a global regulator of gene expression.	('SATB1', 'Gene', (102, 107))	('SATB1', 'Gene', '6304', (102, 107))	('bind', 'Interaction', (111, 115))	('DNA', 'Protein', (121, 124))	('affects', 'Reg', (79, 86))	('phosphorylation', 'Var', (49, 64))	('ability', 'MPA', (91, 98))
185292	24176859	The role of SATB1 in the proliferation and invasion of GBM cells has been investigated in cell lines; therefore, in the present study, we performed similar analyses by specifically knocking down or upregulating SATB1 expression in GBM cells.	('upregulating', 'PosReg', (198, 210))	('SATB1', 'Gene', (211, 216))	('SATB1', 'Gene', '6304', (211, 216))	('knocking', 'Var', (181, 189))	('expression', 'MPA', (217, 227))	('SATB1', 'Gene', (12, 17))	('SATB1', 'Gene', '6304', (12, 17))
185293	24176859	Our results showed that SATB1 knockdown reduced U251 cell proliferation and invasion, whereas SATB1 overexpression promoted U87 cell proliferation and invasion.	('promoted', 'PosReg', (115, 123))	('U87', 'Gene', (124, 127))	('U87', 'Gene', '641648', (124, 127))	('U251', 'CellLine', 'CVCL:0021', (48, 52))	('U251 cell proliferation', 'CPA', (48, 71))	('SATB1', 'Gene', (24, 29))	('SATB1', 'Gene', '6304', (24, 29))	('invasion', 'CPA', (151, 159))	('reduced', 'NegReg', (40, 47))	('SATB1', 'Gene', (94, 99))	('SATB1', 'Gene', '6304', (94, 99))	('knockdown', 'Var', (30, 39))	('invasion', 'CPA', (76, 84))
185300	24176859	Transfection of cells with decoy SATB1 resulted in the inhibition of proliferation and invasion in SATB1-overexpressing glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('decoy', 'Var', (27, 32))	('SATB1', 'Gene', (99, 104))	('proliferation', 'CPA', (69, 82))	('SATB1', 'Gene', '6304', (99, 104))	('glioma', 'Disease', (120, 126))	('invasion', 'CPA', (87, 95))	('SATB1', 'Gene', (33, 38))	('SATB1', 'Gene', '6304', (33, 38))	('inhibition', 'NegReg', (55, 65))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
185314	24176859	In another study, high SATB1 expression was not associated with poor clinical outcome.	('clinical', 'Species', '191496', (69, 77))	('high', 'Var', (18, 22))	('SATB1', 'Gene', (23, 28))	('SATB1', 'Gene', '6304', (23, 28))
185359	24176859	The proportion of positively stained tumor cells was graded as follows: 0 (no positive tumor cells), 1 (<10% positive tumor cells), 2 (10-50% positive tumor cells) and 3 (>50% positive tumor cells).	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('10-50', 'Var', (135, 140))
185395	32116623	Experimental results on BraTS 2018 online validation set achieve average Dice scores of 0.9048, 0.8364, and 0.7748 for whole tumor, tumor core and enhancing tumor, respectively.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('0.8364', 'Var', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('0.7748', 'Var', (108, 114))
185457	32116623	The segmentation results on BraTS 2018 online validation set achieve average Dice scores of 0.9048, 0.8364, and 0.7768 for whole tumor, tumor core, and enhancing tumor, respectively.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('0.7768', 'Var', (112, 118))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('0.8364', 'Var', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
185462	32116623	The segmentation results on BraTS 2018 online testing set achieve average Dice scores of 0.8761, 0.7953, and 0.7364 for whole tumor, tumor core and enhancing tumor, respectively.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('0.8761', 'Var', (89, 95))	('0.7364', 'Var', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('0.7953', 'Var', (97, 103))	('tumor', 'Disease', (126, 131))
185465	32116623	Overall, the images from China-Japan Union Hospital of Jilin University which are acquired using 2D MRI sequences achieve better segmentation results with Dice scores of 0.8635, 0.8036, and 0.7217 for whole tumor, tumor core, and enhancing tumor, respectively.	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('0.7217', 'Var', (190, 196))	('0.8036', 'Var', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
185469	32116623	Specifically, the experimental results on BraTS 2018 online validation set achieve average Dice scores of 0.9048, 0.8364, and 0.7768 for whole tumor, tumor core and enhancing tumor, respectively.	('tumor', 'Disease', (175, 180))	('0.9048', 'Var', (106, 112))	('tumor', 'Disease', (143, 148))	('0.7768', 'Var', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('0.8364', 'Var', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
185477	32116623	The experimental results on BraTS 2018 online validation set achieve average Dice scores of 0.9048, 0.8364, and 0.7768 for whole tumor, tumor core and enhancing tumor, respectively.	('tumor', 'Disease', (161, 166))	('0.7768', 'Var', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('0.8364', 'Var', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('0.9048', 'Var', (92, 98))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (136, 141))
185482	24083241	The EMP3 promoter hypermethylation has been found in 39.5% of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('hypermethylation', 'Var', (18, 34))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('EMP3', 'Gene', '2014', (4, 8))	('found', 'Reg', (44, 49))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('EMP3', 'Gene', (4, 8))
185484	24083241	In oligodendroglial tumors, it was strongly associated with both IDH1/IDH2 mutations and total 1p/19q codeletion and inversely with EGFR gene amplification.	('associated', 'Reg', (44, 54))	('IDH1', 'Gene', '3417', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('IDH2', 'Gene', '3418', (70, 74))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', (132, 136))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (3, 26))	('oligodendroglial tumors', 'Disease', (3, 26))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH1', 'Gene', (65, 69))	('IDH2', 'Gene', (70, 74))
185485	24083241	No association was found with MGMT hypermethylation and TP53 mutations.	('TP53', 'Gene', '7157', (56, 60))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (56, 60))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))
185486	24083241	In the whole series, the EMP3 hypermethylation status correlated with 19q13.3 loss and lack of EMP3 expression at protein level.	('EMP3', 'Gene', '2014', (95, 99))	('EMP3', 'Gene', (25, 29))	('EMP3', 'Gene', '2014', (25, 29))	('hypermethylation status', 'Var', (30, 53))	('lack', 'NegReg', (87, 91))	('expression', 'MPA', (100, 110))	('loss', 'NegReg', (78, 82))	('19q13.3', 'Gene', (70, 77))	('EMP3', 'Gene', (95, 99))
185498	24083241	Within tumors of the nervous system, DNA hypermethylation and aberrant expression of the EMP3 gene have been reported in both gliomas (24%) and neuroblastoma (39%).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors of the nervous system', 'Phenotype', 'HP:0004375', (7, 35))	('neuroblastoma', 'Disease', (144, 157))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('neuroblastoma', 'Phenotype', 'HP:0003006', (144, 157))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('neuroblastoma', 'Disease', 'MESH:D009447', (144, 157))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('expression', 'MPA', (71, 81))	('EMP3', 'Gene', (89, 93))	('tumors of the nervous system', 'Disease', 'MESH:D009423', (7, 35))	('aberrant', 'Var', (62, 70))	('reported', 'Reg', (109, 117))	('tumors of the nervous system', 'Disease', (7, 35))	('DNA hypermethylation', 'Var', (37, 57))	('EMP3', 'Gene', '2014', (89, 93))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('gliomas', 'Disease', (126, 133))
185501	24083241	By methylation-specific polymerase chain reaction (MS-PCR), a hypermethylation in the CpG island of the EMP3 promoter region has been found in 83% and 84% of WHO grades II and III astrocytomas, respectively; in 80% and 73% of WHO grades II and III oligoastrocytomas, respectively; and in 73% and 78% of WHO grades II and III oligodendroglial tumors, respectively.	('astrocytoma', 'Phenotype', 'HP:0009592', (253, 264))	('hypermethylation', 'Var', (62, 78))	('EMP3', 'Gene', (104, 108))	('astrocytomas', 'Disease', (180, 192))	('astrocytomas', 'Disease', (253, 265))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (325, 348))	('oligodendroglial tumors', 'Disease', (325, 348))	('found', 'Reg', (134, 139))	('III oligoastrocytomas', 'Disease', (244, 265))	('grades II', 'Disease', (230, 239))	('EMP3', 'Gene', '2014', (104, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('III oligoastrocytomas', 'Disease', 'MESH:D001254', (244, 265))	('astrocytomas', 'Disease', 'MESH:D001254', (180, 192))	('astrocytomas', 'Disease', 'MESH:D001254', (253, 265))	('tumors', 'Phenotype', 'HP:0002664', (342, 348))
185502	24083241	EMP3 is hypermethylated in 17% of primary GBMs (pGBMs) and in 89% of secondary GBMs (sGBMs), respectively.	('primary GBMs', 'Disease', (34, 46))	('hypermethylated', 'Var', (8, 23))	('EMP3', 'Gene', (0, 4))	('EMP3', 'Gene', '2014', (0, 4))
185538	24083241	Putative functional effects of the identified TP53 missense mutations were determined by in silico prediction using PMUT (http://mmb.pcb.ub.es/PMut/), PolyPhen (http://genetics.bwh.harvard.edu/pph/), and SNAP (https://rostlab.org/services/snap/) programs.	('N', 'Chemical', 'MESH:D009584', (205, 206))	('missense mutations', 'Var', (51, 69))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))
185552	24083241	A multivariate analysis with the Cox proportional-hazards regression model was performed for the following variables: age (<=40 or >40 years), histologic tumor grade, and the molecular variables emerged as significant by univariate analysis (IDH1/IDH2 mutations, EMP3 promoter hypermethylation, total 1p/19q codeletion and EGFR amplification).	('EGFR', 'Gene', '1956', (323, 327))	('IDH1', 'Gene', (242, 246))	('IDH2', 'Gene', (247, 251))	('IDH1', 'Gene', '3417', (242, 246))	('EGFR', 'Gene', (323, 327))	('mutations', 'Var', (252, 261))	('EMP3', 'Gene', (263, 267))	('IDH2', 'Gene', '3418', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('1p/19q codeletion', 'Var', (301, 318))	('EMP3', 'Gene', '2014', (263, 267))	('tumor', 'Disease', (154, 159))
185557	24083241	Among the histological types, the frequency of EMP3 hypermethylation was higher in tumors with an oligodendroglial component, as oligoastrocytomas (14 of 20 cases, 70%) and oligodendrogliomas (46 of 73, 63%), than in astrocytic tumors (18 of 100 cases, 18%), with statistical significance (P < 0.0001) (Table 2).	('EMP3', 'Gene', '2014', (47, 51))	('astrocytic tumors', 'Disease', 'MESH:D001254', (217, 234))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (173, 191))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('oligodendroglial component', 'Disease', (98, 124))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('EMP3', 'Gene', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('oligodendroglial component', 'Disease', 'MESH:C562869', (98, 124))	('oligoastrocytomas', 'Disease', (129, 146))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (129, 146))	('oligodendrogliomas', 'Disease', (173, 191))	('hypermethylation', 'Var', (52, 68))	('tumors', 'Disease', (83, 89))	('astrocytic tumors', 'Disease', (217, 234))	('higher', 'PosReg', (73, 79))
185558	24083241	In oligodendroglial tumors, the EMP3 gene was hypermethylated in 33 of 42 WHO grade II tumors (78.6%) and in 13 of 31 WHO grade III tumors (41.9%) (Table 3).	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('hypermethylated', 'Var', (46, 61))	('II tumors', 'Disease', (84, 93))	('II tumors', 'Disease', 'MESH:D009369', (84, 93))	('II tumors', 'Disease', 'MESH:D009369', (129, 138))	('III tumors', 'Disease', 'MESH:D009369', (128, 138))	('EMP3', 'Gene', '2014', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('EMP3', 'Gene', (32, 36))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (3, 26))	('oligodendroglial tumors', 'Disease', (3, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('III tumors', 'Disease', (128, 138))
185559	24083241	In oligoastrocytomas, it was hypermethylated in nine of 12 WHO grade II tumors (75%) and in five of eight WHO grade III tumors (62.5%) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('III tumors', 'Disease', (116, 126))	('hypermethylated', 'Var', (29, 44))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('oligoastrocytomas', 'Disease', (3, 20))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (3, 20))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (8, 19))	('III tumors', 'Disease', 'MESH:D009369', (116, 126))	('II tumors', 'Disease', (69, 78))	('II tumors', 'Disease', 'MESH:D009369', (69, 78))	('II tumors', 'Disease', 'MESH:D009369', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
185567	24083241	EGFR amplification was identified in 23 of 61 GBMs (37.7%) and in one of the seven WHO grade III astrocytomas (14.3%).	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (97, 109))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('EGFR', 'Gene', '1956', (0, 4))	('astrocytomas', 'Disease', (97, 109))
185571	24083241	Somatic point mutations at hot-spot codons Arg132 (R132) of the IDH1 gene and Arg172 (R172) of the IDH2 genes were identified in 61 of 178 gliomas (34.3%).	('Arg132', 'Chemical', '-', (43, 49))	('Arg172 (R172', 'Var', (78, 90))	('identified', 'Reg', (115, 125))	('IDH2', 'Gene', (99, 103))	('gliomas', 'Disease', (139, 146))	('IDH1', 'Gene', (64, 68))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('IDH1', 'Gene', '3417', (64, 68))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('Arg172', 'Chemical', '-', (78, 84))	('IDH2', 'Gene', '3418', (99, 103))
185573	24083241	All mutations affected codon R132 of the IDH1 gene, with the exception of one oligodendroglial tumor with mutation at codon R172 of the IDH2 gene.	('mutation at codon R172', 'Var', (106, 128))	('IDH2', 'Gene', (136, 140))	('affected', 'Reg', (14, 22))	('IDH1', 'Gene', (41, 45))	('codon R132', 'Var', (23, 33))	('mutations', 'Var', (4, 13))	('oligodendroglial tumor', 'Disease', (78, 100))	('IDH2', 'Gene', '3418', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('oligodendroglial tumor', 'Disease', 'MESH:D009369', (78, 100))	('IDH1', 'Gene', '3417', (41, 45))
185574	24083241	The spectrum of IDH1/IDH2 mutations is available elsewhere.	('IDH1', 'Gene', (16, 20))	('mutations', 'Var', (26, 35))	('IDH2', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (16, 20))	('IDH2', 'Gene', '3418', (21, 25))
185575	24083241	The TP53 mutation status was investigated in 116 gliomas and mutations were identified in 32 of them (27.6%).	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('gliomas', 'Disease', (49, 56))	('TP53', 'Gene', '7157', (4, 8))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
185577	24083241	The spectrum of TP53 mutations in low- and high-grade tumors has been already described.	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TP53', 'Gene', '7157', (16, 20))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('TP53', 'Gene', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (21, 30))
185579	24083241	The frequency of the total 1p/19q codeletion in tumor types is reported in Table 4.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('1p/19q codeletion', 'Var', (27, 44))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
185581	24083241	In oligodendrogliomas, total 1p/19q codeletion prevailed in WHO grade II tumors (18 of 32 cases, 56.3%) upon WHO grade III tumors (13 of 33 cases, 39.4%).	('II tumors', 'Disease', (70, 79))	('II tumors', 'Disease', 'MESH:D009369', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (3, 21))	('III tumors', 'Disease', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('II tumors', 'Disease', 'MESH:D009369', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('1p/19q codeletion', 'Var', (29, 46))	('III tumors', 'Disease', 'MESH:D009369', (119, 129))	('oligodendrogliomas', 'Disease', (3, 21))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
185582	24083241	Patient stratification for the histological type revealed that EMP3 promoter hypermethylation was significantly associated with IDH1/IDH2 mutations in astrocytic tumors (P = 0.0088), GBMs included (P = 0.0012), in oligodendroglial tumors (P = 0.0006), and in oligoastrocytomas (P = 0.0095).	('IDH2', 'Gene', (133, 137))	('IDH2', 'Gene', '3418', (133, 137))	('astrocytic tumors', 'Disease', (151, 168))	('IDH1', 'Gene', '3417', (128, 132))	('astrocytic tumors', 'Disease', 'MESH:D001254', (151, 168))	('oligodendroglial tumors', 'Disease', (214, 237))	('astrocytoma', 'Phenotype', 'HP:0009592', (264, 275))	('oligoastrocytomas', 'Disease', (259, 276))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (259, 276))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (214, 237))	('EMP3', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (138, 147))	('GBMs included', 'Disease', (183, 196))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('EMP3', 'Gene', '2014', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('associated', 'Reg', (112, 122))	('Patient', 'Species', '9606', (0, 7))	('IDH1', 'Gene', (128, 132))
185583	24083241	No association was found with MGMT promoter hypermethylation and TP53 mutations either in oligodendrogliomas or in the whole tumor series.	('oligodendrogliomas', 'Disease', (90, 108))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('tumor', 'Disease', (125, 130))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (90, 108))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))
185584	24083241	In contrast, an inverse significant correlation was identified with the EGFR gene amplification (P = 0.004) in both oligodendroglial tumors and the whole series of gliomas (P = 0.0005).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('EGFR', 'Gene', '1956', (72, 76))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (116, 139))	('oligodendroglial tumors', 'Disease', (116, 139))	('amplification', 'Var', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'Gene', (72, 76))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))
185585	24083241	In the whole series of 185 glial tumors, the EMP3 hypermethylation was associated with loss of the 19q13.3 locus, as defined by loss of the two consecutive MLPA probes ZNF342 and PPP1R15A, tightly flanking the EMP3 gene (P = 0.0001).	('loss', 'NegReg', (87, 91))	('PPP1R15A', 'Gene', '23645', (179, 187))	('PPP1R15A', 'Gene', (179, 187))	('EMP3', 'Gene', (45, 49))	('loss', 'NegReg', (128, 132))	('glial tumors', 'Disease', 'MESH:D005910', (27, 39))	('EMP3', 'Gene', '2014', (45, 49))	('EMP3', 'Gene', '2014', (210, 214))	('19q13.3', 'Gene', (99, 106))	('glial tumors', 'Disease', (27, 39))	('hypermethylation', 'Var', (50, 66))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('N', 'Chemical', 'MESH:D009584', (169, 170))	('EMP3', 'Gene', (210, 214))
185586	24083241	In oligodendroglial tumors, a significant correlation was found with the total 1p/19q codeletion (P = 0.0266).	('1p/19q codeletion', 'Var', (79, 96))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (3, 26))	('oligodendroglial tumors', 'Disease', (3, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
185598	24083241	In oligodendrogliomas, univariate analysis by the Kaplan-Meier method revealed that EMP3 promoter hypermethylation as detected by MS-PCR correlates with a significantly longer OS (P = 0.001) (Figure 5(a)), also in WHO grade III tumors (P = 0.034) (Figure 5(b)).	('OS', 'Chemical', '-', (176, 178))	('III tumors', 'Disease', 'MESH:D009369', (224, 234))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (3, 21))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('III tumors', 'Disease', (224, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('EMP3', 'Gene', (84, 88))	('oligodendrogliomas', 'Disease', (3, 21))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('longer', 'PosReg', (169, 175))	('EMP3', 'Gene', '2014', (84, 88))	('hypermethylation', 'Var', (98, 114))
185600	24083241	Total 1p/19q codeletion was strongly prognostic on OS (P = 0.001) (Figure 5(c)), especially in WHO grade III tumors (P = 0.001) (Figure 5(d)).	('1p/19q codeletion', 'Var', (6, 23))	('prognostic', 'Reg', (37, 47))	('III tumors', 'Disease', (105, 115))	('OS', 'Chemical', '-', (51, 53))	('III tumors', 'Disease', 'MESH:D009369', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
185603	24083241	Multivariate analysis by Cox's proportional hazard regression model in oligodendroglial tumors identified total 1p/19 codeletion as the main independent prognostic factor (P < 0.0001), followed by the histologic tumor grade (P = 0.001) and the EMP3 promoter hypermethylation (P = 0.071).	('EMP3', 'Gene', (244, 248))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (71, 94))	('oligodendroglial tumors', 'Disease', (71, 94))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('EMP3', 'Gene', '2014', (244, 248))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('1p/19 codeletion', 'Var', (112, 128))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (212, 217))
185604	24083241	In the present study the EMP3 promoter hypermethylation has been found in 39.5% of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('EMP3', 'Gene', (25, 29))	('EMP3', 'Gene', '2014', (25, 29))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('hypermethylation', 'Var', (39, 55))	('found', 'Reg', (65, 70))
185606	24083241	EMP3 promoter hypermethylation is prevalent in oligodendroglial tumors (63%) and in oligoastrocytomas (70%) upon astrocytic tumors (18%), as already reported.	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('EMP3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('EMP3', 'Gene', '2014', (0, 4))	('promoter hypermethylation', 'Var', (5, 30))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (47, 70))	('astrocytic tumors', 'Disease', 'MESH:D001254', (113, 130))	('astrocytic tumors', 'Disease', (113, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('oligoastrocytomas', 'Disease', (84, 101))	('oligodendroglial tumors', 'Disease', (47, 70))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (84, 101))	('prevalent', 'Reg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
185618	24083241	EMP3 promoter hypermethylation is significantly associated with IDH1/IDH2 mutations in both astrocytic and oligodendroglial tumors.	('EMP3', 'Gene', (0, 4))	('IDH2', 'Gene', '3418', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('EMP3', 'Gene', '2014', (0, 4))	('associated', 'Reg', (48, 58))	('IDH1', 'Gene', (64, 68))	('mutations', 'Var', (74, 83))	('IDH1', 'Gene', '3417', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('promoter', 'MPA', (5, 13))	('IDH2', 'Gene', (69, 73))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (92, 130))
185623	24083241	As a matter of fact, the G-CIMP is triggered by IDH1/IDH2 mutations alone by remodelling both the methylome and the transcriptome.	('mutations', 'Var', (58, 67))	('transcriptome', 'MPA', (116, 129))	('IDH2', 'Gene', (53, 57))	('remodelling', 'Reg', (77, 88))	('triggered', 'Reg', (35, 44))	('IDH1', 'Gene', '3417', (48, 52))	('G-CIMP', 'Disease', (25, 31))	('IDH2', 'Gene', '3418', (53, 57))	('methylome', 'MPA', (98, 107))	('IDH1', 'Gene', (48, 52))	('G-CIMP', 'Chemical', '-', (25, 31))
185628	24083241	The lack of correlation with TP53 mutations is in agreement with the prevalence of EMP3 promoter hypermethylation in tumors with an oligodendroglial component upon astrocytic tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('EMP3', 'Gene', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('EMP3', 'Gene', '2014', (83, 87))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('oligodendroglial component upon astrocytic tumors', 'Disease', (132, 181))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('mutations', 'Var', (34, 43))	('oligodendroglial component upon astrocytic tumors', 'Disease', 'MESH:D001254', (132, 181))
185629	24083241	In contrast, the inverse association with EGFR amplification may be explained by its prevalence in WHO grade II tumors.	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('II tumors', 'Disease', 'MESH:D009369', (109, 118))	('II tumors', 'Disease', (109, 118))	('inverse', 'NegReg', (17, 24))	('amplification', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
185630	24083241	The higher frequency of EMP3 promoter hypermethylation in low- than high-grade gliomas, as well as its association with other well-known early genetic aberrations, indicates EMP3 methylation as an early epigenetic event during gliomagenesis, preceding the differentiation of precursors.	('EMP3', 'Gene', (24, 28))	('hypermethylation', 'Var', (38, 54))	('gliomas', 'Disease', (79, 86))	('glioma', 'Disease', (79, 85))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('EMP3', 'Gene', '2014', (174, 178))	('EMP3', 'Gene', '2014', (24, 28))	('methylation', 'Var', (179, 190))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('glioma', 'Disease', (227, 233))	('EMP3', 'Gene', (174, 178))
185632	24083241	Previous clinical observations in favor of EMP3 as a TSG in gliomas were based on EMP3 gene expression and knockdown studies, as well as on the demonstration of EMP3 hypermethylation as marker of poor outcome in neuroblastoma patients.	('EMP3', 'Gene', '2014', (82, 86))	('EMP3', 'Gene', (43, 47))	('EMP3', 'Gene', '2014', (161, 165))	('neuroblastoma', 'Disease', 'MESH:D009447', (212, 225))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('EMP3', 'Gene', '2014', (43, 47))	('hypermethylation', 'Var', (166, 182))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('neuroblastoma', 'Disease', (212, 225))	('TSG', 'Gene', (53, 56))	('patients', 'Species', '9606', (226, 234))	('EMP3', 'Gene', (82, 86))	('neuroblastoma', 'Phenotype', 'HP:0003006', (212, 225))	('EMP3', 'Gene', (161, 165))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('TSG', 'Gene', '57045', (53, 56))
185635	24083241	In previous studies, aberrant methylation in the promoter region of the EMP3 gene has been found to be associated with loss of heterozygosity (LOH) on 19q13.3 in both oligodendrogliomas and neuroblastomas.	('methylation', 'Var', (30, 41))	('oligodendrogliomas and neuroblastomas', 'Disease', 'MESH:D009447', (167, 204))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (190, 203))	('EMP3', 'Gene', (72, 76))	('aberrant methylation', 'Var', (21, 41))	('EMP3', 'Gene', '2014', (72, 76))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('loss', 'NegReg', (119, 123))	('neuroblastomas', 'Phenotype', 'HP:0003006', (190, 204))
185637	24083241	In the literature, the EMP3 hypermethylation has been found to be significantly associated with lower transcript levels in both astrocytic and oligodendroglial tumors, with one exception for the latter, suggesting in these tumors the existence of alternative EMP3 epigenetic mechanisms.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('hypermethylation', 'Var', (28, 44))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('lower', 'NegReg', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('EMP3', 'Gene', (23, 27))	('EMP3', 'Gene', (259, 263))	('transcript levels', 'MPA', (102, 119))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (128, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('EMP3', 'Gene', '2014', (259, 263))	('EMP3', 'Gene', '2014', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
185642	24083241	However, it must be stressed that the CIC gene on chromosome 19q has been recently found to be mutated in the majority of 1p/19q codeleted oligodendrogliomas, suggesting that it may be a potential TSG in this region.	('CIC', 'Gene', (38, 41))	('oligodendrogliomas', 'Disease', (139, 157))	('TSG', 'Gene', (197, 200))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('CIC', 'Gene', '23152', (38, 41))	('TSG', 'Gene', '57045', (197, 200))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (139, 157))	('1p/19q', 'Var', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
185643	24083241	This reduces the importance of the EMP3 as TSG that, apparently, it could be just one of the several G-CIMP genes regulated by the 2-hydroxyglutarate (2-HG) increase as a consequence of IDH1/IDH2 mutations.	('IDH1', 'Gene', (186, 190))	('IDH2', 'Gene', '3418', (191, 195))	('IDH1', 'Gene', '3417', (186, 190))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (131, 149))	('EMP3', 'Gene', (35, 39))	('TSG', 'Gene', (43, 46))	('G-CIMP', 'Chemical', '-', (101, 107))	('IDH2', 'Gene', (191, 195))	('EMP3', 'Gene', '2014', (35, 39))	('TSG', 'Gene', '57045', (43, 46))	('mutations', 'Var', (196, 205))
185645	24083241	Therefore, the relationship between the EMP3 hypermethylation and the favorable prognosis may not be due to the biological consequence of the EMP3 gene inactivation but more probably to the prevalence in oligodendrogliomas of both total 1p/19q codeletion and IDH1/IDH2 mutations and to their prognostic significance in these tumors.	('tumors', 'Disease', (325, 331))	('tumors', 'Disease', 'MESH:D009369', (325, 331))	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('IDH2', 'Gene', '3418', (264, 268))	('IDH1', 'Gene', (259, 263))	('mutations', 'Var', (269, 278))	('oligodendrogliomas', 'Disease', (204, 222))	('EMP3', 'Gene', (142, 146))	('EMP3', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (259, 263))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('EMP3', 'Gene', '2014', (142, 146))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (204, 222))	('IDH2', 'Gene', (264, 268))	('prevalence', 'Reg', (190, 200))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('EMP3', 'Gene', '2014', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))
185649	24083241	In the whole series, the EMP3 hypermethylation status correlates with 19q13.3 loss and with lack of EMP3 expression at the protein level.	('EMP3', 'Gene', (100, 104))	('EMP3', 'Gene', (25, 29))	('EMP3', 'Gene', '2014', (25, 29))	('hypermethylation status', 'Var', (30, 53))	('EMP3', 'Gene', '2014', (100, 104))	('loss', 'NegReg', (78, 82))	('lack', 'NegReg', (92, 96))	('19q13.3', 'Gene', (70, 77))	('expression', 'MPA', (105, 115))
185650	24083241	In oligodendroglial tumors, it is strongly associated with both IDH1/IDH2 mutations and total 1p/19q codeletion and inversely with EGFR gene amplification.	('IDH2', 'Gene', '3418', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('IDH1', 'Gene', (64, 68))	('mutations', 'Var', (74, 83))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (3, 26))	('IDH1', 'Gene', '3417', (64, 68))	('oligodendroglial tumors', 'Disease', (3, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('associated', 'Reg', (43, 53))	('IDH2', 'Gene', (69, 73))
185651	24083241	The EMP3 promoter hypermethylation correlates with statistical significance with better OS in patients with oligodendroglial tumors.	('oligodendroglial tumors', 'Disease', (108, 131))	('patients', 'Species', '9606', (94, 102))	('hypermethylation', 'Var', (18, 34))	('better OS', 'Disease', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('EMP3', 'Gene', '2014', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('OS', 'Chemical', '-', (88, 90))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (108, 131))	('EMP3', 'Gene', (4, 8))
185653	32732530	Prevalence of mitochondrial DNA common deletion in patients with gliomas and meningiomas: A first report from a Malaysian study group The 4977-bp common deletion (mtDNA4977) is a well-established mitochondrial genome alteration that has been described in various types of human cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('meningiomas', 'Phenotype', 'HP:0002858', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('mitochondrial DNA common', 'Gene', (14, 38))	('human', 'Species', '9606', (272, 277))	('4977-bp', 'Var', (138, 145))	('meningioma', 'Phenotype', 'HP:0002858', (77, 87))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('deletion', 'Var', (39, 47))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('patients', 'Species', '9606', (51, 59))	('gliomas and meningiomas', 'Disease', 'MESH:D005910', (65, 88))	('cancers', 'Disease', (278, 285))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
185657	32732530	Overall, mtDNA4977 was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients.	('patients', 'Species', '9606', (44, 52))	('HGG group', 'Disease', (152, 161))	('common', 'Reg', (138, 144))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mtDNA4977', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
185659	32732530	This study provides initial insights into mtDNA4977 in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database.	('brain tumor', 'Phenotype', 'HP:0030692', (55, 66))	('mtDNA4977', 'Var', (42, 51))	('brain tumor', 'Disease', 'MESH:D001932', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('brain tumor', 'Disease', (55, 66))
185673	32732530	Warburg's view believed that mitochondrial alterations in function might enhance tumor growth or promote cancer progression.	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (29, 54))	('cancer', 'Disease', (105, 111))	('promote', 'PosReg', (97, 104))	('mitochondrial alterations', 'Var', (29, 54))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('enhance', 'PosReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('alterations', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
185674	32732530	From then on, different types of mtDNA aberrations have been characterized in human cancers such as point mutations, deletions, rearrangements, and changes in mtDNA content.	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('point mutations', 'Var', (100, 115))	('rearrangements', 'Var', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('deletions', 'Var', (117, 126))	('human', 'Species', '9606', (78, 83))	('changes', 'Reg', (148, 155))
185678	32732530	Furthermore, oxidative damage to mtDNA can also result in mtDNA deletions by causing double-strand breaks in the DNA.	('deletions', 'Var', (64, 73))	('age', 'Gene', '5973', (26, 29))	('result', 'Reg', (48, 54))	('causing', 'Reg', (77, 84))	('double-strand breaks', 'MPA', (85, 105))	('age', 'Gene', (26, 29))	('mtDNA', 'Gene', (58, 63))
185679	32732530	In fact, large-scale mtDNA deletions were among the first mtDNA alterations to be discovered to cause human diseases.	('mtDNA', 'Gene', (21, 26))	('deletions', 'Var', (27, 36))	('human', 'Species', '9606', (102, 107))
185681	32732530	mtDNA4977 eliminates all five tRNA genes (tRNAGly, tRNAArg, tRNAHis, tRNASer, and tRNALeu) and seven genes encoding four Complex I subunits (ND3, ND4, ND4L, partial ND5), one Complex IV subunit (COX III), and two Complex V subunits (ATP6 and partial ATP8), that are vital for sustaining a normal mitochondrial OXPHOS function.	('mtDNA4977', 'Var', (0, 9))	('ND4', 'Gene', '4538', (146, 149))	('ND3', 'Gene', (141, 144))	('ATP8', 'Gene', (250, 254))	('ATP6', 'Gene', '4508', (233, 237))	('ND4', 'Gene', (146, 149))	('ND5', 'Gene', '4540', (165, 168))	('ND5', 'Gene', (165, 168))	('ND3', 'Gene', '4537', (141, 144))	('tRNA genes', 'Gene', (30, 40))	('ND4L', 'Gene', (151, 155))	('ND4', 'Gene', '4538', (151, 154))	('ATP6', 'Gene', (233, 237))	('ND4', 'Gene', (151, 154))	('eliminates', 'NegReg', (10, 20))	('ND4L', 'Gene', '4539', (151, 155))	('ATP8', 'Gene', '4509', (250, 254))
185683	32732530	The present study is the first prospective study to determine the prevalence of mtDNA4977 and its accumulation in patients with common primary CNS tumors, namely, gliomas and meningiomas.	('accumulation', 'PosReg', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('meningioma', 'Phenotype', 'HP:0002858', (175, 185))	('CNS tumors', 'Disease', 'MESH:D016543', (143, 153))	('CNS tumor', 'Phenotype', 'HP:0100006', (143, 152))	('meningiomas', 'Phenotype', 'HP:0002858', (175, 186))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('mtDNA4977', 'Var', (80, 89))	('patients', 'Species', '9606', (114, 122))	('gliomas and meningiomas', 'Disease', 'MESH:D005910', (163, 186))	('CNS tumors', 'Disease', (143, 153))
185700	32732530	To detect mtDNA4977 in glioma and meningioma tissues of patients, mtDNA fragments were amplified using a multiplex PCR assay consisting of two pairs of primers (P1/P2 and P3/P4) (Fig.	('P3/P4', 'Var', (171, 176))	('patients', 'Species', '9606', (56, 64))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('P1/P2', 'Var', (161, 166))	('glioma and meningioma', 'Disease', 'MESH:D005910', (23, 44))	('meningioma', 'Phenotype', 'HP:0002858', (34, 44))
185701	32732530	mtDNA4977 was identified in the patient tumor tissue, whereas this deletion was not observed in the normal control tissues.	('mtDNA4977', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patient', 'Species', '9606', (32, 39))
185708	32732530	mtDNA4977 was significantly more frequently detected in the HGG group (55.0%) than in the LGG (15.4%) and meningioma (17.6%) groups.	('mtDNA4977', 'Var', (0, 9))	('meningioma', 'Disease', 'MESH:D008577', (106, 116))	('HGG', 'Disease', (60, 63))	('meningioma', 'Disease', (106, 116))	('detected', 'Reg', (44, 52))	('meningioma', 'Phenotype', 'HP:0002858', (106, 116))
185709	32732530	Our data also showed that, mtDNA4977 frequency in male patients was 52.4% (n = 11/21), which was significantly higher than that in female patients (17.2%; n = 5/29) (p = 0.0137).	('patients', 'Species', '9606', (55, 63))	('mtDNA4977', 'Var', (27, 36))	('patients', 'Species', '9606', (138, 146))	('higher', 'PosReg', (111, 117))
185714	32732530	The accumulation of genetic alterations is believed to be a direct reflection of the multiple steps involved in brain tumorigenesis.	('brain tumor', 'Disease', (112, 123))	('brain tumor', 'Disease', 'MESH:D001932', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('brain tumor', 'Phenotype', 'HP:0030692', (112, 123))	('genetic alterations', 'Var', (20, 39))
185716	32732530	The deletion between nucleotides 8470 and 13 447 of the human mitochondrial genome (established known as mtDNA4977), which may lead to OXPHOS system failure, seems to be particularly crucial because of the elimination of some tRNAs and coding region genes, which are essential for the entire normal mitochondrial function and biogenesis process.	('elimination', 'NegReg', (206, 217))	('OXPHOS system failure', 'Disease', 'MESH:D012131', (135, 156))	('OXPHOS system failure', 'Disease', (135, 156))	('human', 'Species', '9606', (56, 61))	('deletion', 'Var', (4, 12))	('tRNAs', 'Gene', (226, 231))
185719	32732530	As a consequence of alterations/deletions of mtDNA in cells, in particular mtDNA-encoded core subunits, cells exhibit increased oxidative stress and a defective OXPHOS function, which leads to pro-tumorigenic effects.	('mtDNA', 'Gene', (45, 50))	('oxidative stress', 'MPA', (128, 144))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('increased', 'PosReg', (118, 127))	('defective', 'NegReg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('oxidative stress', 'Phenotype', 'HP:0025464', (128, 144))	('OXPHOS function', 'MPA', (161, 176))	('alterations/deletions', 'Var', (20, 41))	('tumor', 'Disease', (197, 202))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (118, 144))
185720	32732530	Complex 1 failure (due to heteroplasmic ND5 mutations) has been demonstrated to induce apoptosis resistance and activation of the PI3K/Akt pathway, which can potentially result in higher tumorigenicity.	('Complex 1 failure', 'Disease', 'MESH:D006333', (0, 17))	('ND5', 'Gene', (40, 43))	('Akt', 'Gene', '207', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('activation', 'PosReg', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('Akt', 'Gene', (135, 138))	('tumor', 'Disease', (187, 192))	('mutations', 'Var', (44, 53))	('Complex 1 failure', 'Disease', (0, 17))	('induce', 'PosReg', (80, 86))	('apoptosis resistance', 'CPA', (87, 107))	('ND5', 'Gene', '4540', (40, 43))	('higher', 'PosReg', (180, 186))
185721	32732530	In addition, the loss or disruption of some mitochondrial tRNA genes, particularly in mtDNA4977, is believed to trigger the impairment of the mtDNA-encoded proteins translation, consequently resulting in an enhanced ROS production and disease.	('impairment', 'MPA', (124, 134))	('mitochondrial tRNA genes', 'Gene', (44, 68))	('ROS', 'Chemical', 'MESH:D017382', (216, 219))	('ROS production', 'MPA', (216, 230))	('mtDNA4977', 'Var', (86, 95))	('disease', 'Disease', (235, 242))	('enhanced', 'PosReg', (207, 215))	('disruption', 'Var', (25, 35))	('loss', 'NegReg', (17, 21))	('enhanced ROS production', 'Phenotype', 'HP:0025464', (207, 230))
185722	32732530	mtDNA4977 has been previously reported to accumulate in various disorders, including mitochondrial diseases and many types of cancer.	('mtDNA4977', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mitochondrial diseases', 'Disease', (85, 107))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (85, 107))
185724	32732530	mtDNA4977 has been reported in patients with cancer since the earliest descriptions by Maximo et al, who revealed a high frequency of mtDNA4977 in primary sporadic gastric carcinomas.	('mtDNA4977', 'Var', (134, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('patients', 'Species', '9606', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('gastric carcinomas', 'Disease', 'MESH:D013274', (164, 182))	('gastric carcinomas', 'Disease', (164, 182))	('cancer', 'Disease', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
185725	32732530	Furthermore, mtDNA4977 was discovered to vary between 0% and 100% in a variety of human cancers.	('mtDNA4977', 'Var', (13, 22))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (82, 87))
185726	32732530	In this study, the prevalence of mtDNA4977 in brain tumors, particularly in gliomas and meningiomas, and its association with clinicopathological parameters was investigated.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('meningioma', 'Phenotype', 'HP:0002858', (88, 98))	('meningiomas', 'Phenotype', 'HP:0002858', (88, 99))	('brain tumors', 'Disease', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('brain tumors', 'Disease', 'MESH:D001932', (46, 58))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('brain tumor', 'Phenotype', 'HP:0030692', (46, 57))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('mtDNA4977', 'Var', (33, 42))	('gliomas and meningiomas', 'Disease', 'MESH:D005910', (76, 99))	('brain tumors', 'Phenotype', 'HP:0030692', (46, 58))
185732	32732530	A study in Vietnam reported that 68.8% of breast cancer cases had the mtDNA4977, while another study in China reported a 48% mtDNA4977 percentage in the blood of breast carcinoma patients.	('breast carcinoma', 'Phenotype', 'HP:0003002', (162, 178))	('age', 'Gene', '5973', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('age', 'Gene', (142, 145))	('patients', 'Species', '9606', (179, 187))	('mtDNA4977', 'Var', (70, 79))	('breast carcinoma', 'Disease', (162, 178))	('breast carcinoma', 'Disease', 'MESH:D001943', (162, 178))
185733	32732530	A separate study conducted in China revealed the accumulation of mtDNA4977 in all cases of primary breast cancer and benign breast disease.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('mtDNA4977', 'Var', (65, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('benign breast disease', 'Disease', 'MESH:D001943', (117, 138))	('benign breast disease', 'Disease', (117, 138))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
185734	32732530	Other than breast cancer, mtDNA4977 has also been reported in other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mtDNA4977', 'Var', (26, 35))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('breast cancer', 'Disease', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
185735	32732530	Perhaps the earliest study, by Lee et al reported a 49% mtDNA4977 percentage in oral cancer Taiwanese patients.	('age', 'Gene', '5973', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('patients', 'Species', '9606', (102, 110))	('mtDNA4977', 'Var', (56, 65))	('cancer', 'Disease', (85, 91))	('age', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
185736	32732530	A previous study involving Chinese patients performed by Dai et al on lung cancer determined a 54.1% mtDNA4977 frequency.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', (70, 81))	('mtDNA4977', 'Var', (101, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
185737	32732530	In a study that involved gastric cancer also in China patients, Wang and Lu reported a higher rate (79.6%) of mtDNA4977 in gastric cancer tissues.	('patients', 'Species', '9606', (54, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mtDNA4977', 'Var', (110, 119))	('gastric cancer', 'Disease', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('gastric cancer', 'Disease', (25, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
185739	32732530	A lower percentage of the mtDNA4977 in cancerous tissues has also been reported in other cancers.	('mtDNA4977', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('age', 'Gene', '5973', (15, 18))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancerous', 'Disease', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancers', 'Disease', (89, 96))	('cancerous', 'Disease', 'MESH:D009369', (39, 48))	('age', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
185740	32732530	A study in Taiwan reported that 5% of breast cancer cases had the mtDNA4977, whereas also in Taiwanese cases, Wu et al detected only a 9.7% of mtDNA4977 frequency in gastric carcinomas.	('gastric carcinomas', 'Disease', 'MESH:D013274', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('mtDNA4977', 'Var', (66, 75))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('gastric carcinomas', 'Disease', (166, 184))
185741	32732530	In another study, Upadhyay et al identified a low frequency of mtDNA4977 (5.1%) in Indian patients with esophageal cancer.	('cancer', 'Disease', (115, 121))	('age', 'Gene', (109, 112))	('mtDNA4977', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('age', 'Gene', '5973', (109, 112))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
185742	32732530	The lower incidence of the mtDNA4977 has also been identified in hepatocellular cancer in Korean (11.1%) and Chinese (9.52%) patients, in two previous studies by Gwak et al and Guo et al, respectively.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mtDNA4977', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (65, 86))	('cancer', 'Disease', (80, 86))	('patients', 'Species', '9606', (125, 133))
185748	32732530	Genetic variations among racial/ethnic groups, as well as the difference in cancer types, may influence the wide variation of mtDNA4977 rates in Asian and Caucasian populations.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('Genetic variations', 'Var', (0, 18))	('influence', 'Reg', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
185751	32732530	However, it has been hypothesized that mtDNA deletions might appear either through spontaneous errors during mtDNA replication (replication slippage) or aberrancy of double-strand break repair (DBS).	('double-strand break repair', 'MPA', (166, 192))	('mtDNA', 'Gene', (39, 44))	('age', 'Gene', (145, 148))	('deletions', 'Var', (45, 54))	('aberrancy', 'Var', (153, 162))	('age', 'Gene', '5973', (145, 148))	('appear', 'Reg', (61, 67))
185753	32732530	Therefore, it is suggested that under oxidative stress conditions, excessive ROS production can trigger the accumulation of deletions.	('ROS production', 'MPA', (77, 91))	('oxidative stress', 'Phenotype', 'HP:0025464', (38, 54))	('excessive ROS production', 'Phenotype', 'HP:0025464', (67, 91))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('deletions', 'Var', (124, 133))
185754	32732530	Wei and his colleagues demonstrated that a self-accelerating vicious cycle of mitochondrial ROS is induced in cybrids harboring mtDNA4977, following a brief intense oxidative stress treatment.	('ROS', 'Chemical', 'MESH:D017382', (92, 95))	('mitochondrial ROS', 'MPA', (78, 95))	('induced', 'Reg', (99, 106))	('oxidative stress', 'Phenotype', 'HP:0025464', (165, 181))	('mtDNA4977', 'Var', (128, 137))
185755	32732530	The combination of endogenous and exogenous factors may lead to deletion accumulation of mtDNA, which in turn may lead to the induction of human cancer.	('cancer', 'Disease', (145, 151))	('induction', 'Reg', (126, 135))	('deletion accumulation', 'Var', (64, 85))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('human', 'Species', '9606', (139, 144))	('mtDNA', 'Gene', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('lead to', 'Reg', (114, 121))	('lead to', 'Reg', (56, 63))
185756	32732530	mtDNA4977 was detected in some tumor tissues, and this deletion was absent in all peripheral blood of patients and normal brain tissue subjects.	('mtDNA4977', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
185758	32732530	The rationale for the absence of deletions in other patients might be that cells undergo apoptosis when the mitochondrial mutation load increases to a certain threshold value.	('undergo', 'Reg', (81, 88))	('apoptosis', 'CPA', (89, 98))	('mutation', 'Var', (122, 130))	('mitochondrial', 'MPA', (108, 121))	('increases', 'PosReg', (136, 145))	('patients', 'Species', '9606', (52, 60))
185763	32732530	In the present study, we found a significant correlation between mtDNA4977 and the tumor group (LGG, HGG, and meningioma), which means mtDNA4977 was more common in HGG than in other groups (p = 0.0172).	('meningioma', 'Phenotype', 'HP:0002858', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('HGG', 'Disease', (101, 104))	('tumor', 'Disease', (83, 88))	('meningioma', 'Disease', 'MESH:D008577', (110, 120))	('HGG', 'Disease', (164, 167))	('common', 'Reg', (154, 160))	('meningioma', 'Disease', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mtDNA4977', 'Var', (135, 144))
185766	32732530	The older age cases in this study may have influenced the deletion prevalence, as mtDNA4977 has been found to be significantly higher in elderly individuals.	('influenced', 'Reg', (43, 53))	('mtDNA4977', 'Gene', (82, 91))	('age', 'Gene', (10, 13))	('higher', 'PosReg', (127, 133))	('deletion', 'Var', (58, 66))	('age', 'Gene', '5973', (10, 13))
185767	32732530	Corral-Debrinski et al suggested that the accumulation of mtDNA deletions might contribute to the neurological impairment, often associated with human aging.	('neurological impairment', 'Disease', 'MESH:D009422', (98, 121))	('neurological impairment', 'Phenotype', 'HP:0000707', (98, 121))	('neurological impairment', 'Disease', (98, 121))	('deletions', 'Var', (64, 73))	('accumulation', 'PosReg', (42, 54))	('human', 'Species', '9606', (145, 150))	('contribute', 'Reg', (80, 90))	('mtDNA', 'Gene', (58, 63))
185769	32732530	There was a significant correlation between mtDNA4977 and the tumor group, which shows that mtDNA4977 was higher in the HGG group than in the LGG, and meningioma groups.	('meningioma', 'Disease', 'MESH:D008577', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('higher', 'PosReg', (106, 112))	('meningioma', 'Disease', (151, 161))	('HGG', 'Disease', (120, 123))	('meningioma', 'Phenotype', 'HP:0002858', (151, 161))	('mtDNA4977', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
185770	32732530	This study provides initial insights into how mtDNA4977 might contribute to brain tumor, and this finding can serve as new data for the global database of mtDNA mutations.	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('brain tumor', 'Disease', (76, 87))	('contribute', 'Reg', (62, 72))	('mtDNA4977', 'Var', (46, 55))	('brain tumor', 'Disease', 'MESH:D001932', (76, 87))	('brain tumor', 'Phenotype', 'HP:0030692', (76, 87))
185797	28289245	Besides BCR-ABL, Gleevec's major targets include c-KIT and PDGFR, both of which were found to be mutually exclusively mutated in gastrointestinal stromal tumors (GISTs) in 80% and 10% of cases, respectively.	('BCR-ABL', 'Gene', (8, 15))	('BCR-ABL', 'Gene', '25', (8, 15))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (129, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (129, 160))	('c-KIT', 'Gene', (49, 54))	('Gleevec', 'Chemical', 'MESH:D000068877', (17, 24))	('mutated', 'Var', (118, 125))	('GISTs', 'Phenotype', 'HP:0100723', (162, 167))	('gastrointestinal stromal tumors', 'Disease', (129, 160))	('PDGFR', 'Gene', (59, 64))	('c-KIT', 'Gene', '3815', (49, 54))	('PDGFR', 'Gene', '5159', (59, 64))
185798	28289245	These mutations lead to the constitutive activation of c-KIT and PDGFR-alpha, and within GIST signify oncogene dependency.	('c-KIT', 'Gene', (55, 60))	('PDGFR-alpha', 'Gene', '5156', (65, 76))	('c-KIT', 'Gene', '3815', (55, 60))	('activation', 'PosReg', (41, 51))	('PDGFR-alpha', 'Gene', (65, 76))	('mutations', 'Var', (6, 15))
185800	28289245	The patients who have primary resistant tumors are enriched with c-KIT mutations in exon 9, D842V mutations in PDGFRA or are both wild-type in c-KIT and PDGFRA.	('c-KIT', 'Gene', (65, 70))	('c-KIT', 'Gene', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('PDGFRA', 'Gene', '5156', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('PDGFRA', 'Gene', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('D842V', 'Mutation', 'rs121908585', (92, 97))	('c-KIT', 'Gene', '3815', (143, 148))	('mutations in', 'Var', (71, 83))	('PDGFRA', 'Gene', (153, 159))	('c-KIT', 'Gene', '3815', (65, 70))	('patients', 'Species', '9606', (4, 12))	('PDGFRA', 'Gene', '5156', (153, 159))	('D842V mutations', 'Var', (92, 107))	('tumors', 'Disease', (40, 46))
185801	28289245	Acquired resistance is largely driven by the acquisition of secondary c-KIT mutations and c-KIT amplifications.	('mutations', 'Var', (76, 85))	('c-KIT', 'Gene', (70, 75))	('amplifications', 'Var', (96, 110))	('c-KIT', 'Gene', (90, 95))	('c-KIT', 'Gene', '3815', (70, 75))	('c-KIT', 'Gene', '3815', (90, 95))
185802	28289245	Another success within targeted therapy includes EGFR inhibition of EGFR-mutated (mostly including exon 19 deletions and L858R mutations) lung adenocarcinomas.	('EGFR', 'Gene', '1956', (49, 53))	('L858R mutations', 'Var', (121, 136))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (138, 158))	('EGFR', 'Gene', (49, 53))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (138, 158))	('inhibition', 'NegReg', (54, 64))	('exon 19 deletions', 'Var', (99, 116))	('EGFR', 'Gene', '1956', (68, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (138, 157))	('L858R', 'Mutation', 'rs121434568', (121, 126))	('EGFR', 'Gene', (68, 72))	('lung adenocarcinomas', 'Disease', (138, 158))
185804	28289245	Secondary mutations of EGFR occur in more than half of the patients and involve the selection of the EGFR T790M mutation during treatment.	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('T790M', 'Mutation', 'rs121434569', (106, 111))	('EGFR', 'Gene', '1956', (23, 27))	('T790M', 'Var', (106, 111))	('patients', 'Species', '9606', (59, 67))	('EGFR', 'Gene', (23, 27))
185805	28289245	This has led to the development of third-generation EGFR inhibitors (including rociletinib, AZD9291, and EAI045), which have shown potent activity against EGFR T790M-mutant cells.	('EAI045', 'Chemical', 'MESH:C000608614', (105, 111))	('AZD9291', 'Chemical', 'MESH:C000596361', (92, 99))	('EGFR', 'Gene', '1956', (155, 159))	('rociletinib', 'Chemical', 'MESH:C000589977', (79, 90))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('T790M-mutant', 'Var', (160, 172))	('T790M', 'Mutation', 'rs121434569', (160, 165))	('EGFR', 'Gene', (155, 159))
185806	28289245	These drugs have enabled the sequential application of first- and second-generation EGFR inhibitors followed by third-generation EGFR inhibitors.	('inhibitors', 'Var', (89, 99))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', (129, 133))
185808	28289245	For example, in the setting of monoclonal EGFR-targeting antibodies for the treatment of metastatic colorectal cancer cells, KRAS mutations (downstream effector) and MET amplifications (parallel pathway) are characterized as causes of bypass resistance mechanisms.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('EGFR', 'Gene', '1956', (42, 46))	('KRAS', 'Gene', (125, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('MET amplifications', 'Var', (166, 184))	('KRAS', 'Gene', '3845', (125, 129))	('EGFR', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bypass resistance', 'Disease', (235, 252))	('colorectal cancer', 'Disease', (100, 117))	('mutations', 'Var', (130, 139))	('causes', 'Reg', (225, 231))
185810	28289245	Parallel and convergent cancer evolution, the phenomenon of different subclones originating from the same or different cancer-initiating cells acquiring genetic aberrations in similar pathways, lend support to the concept of pathway dependency.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('genetic aberrations', 'Var', (153, 172))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
185819	28289245	They performed long-term drug exposure experiments on initially sensitive PC9 cells and found significant differences in the rate in which an EGFR T790M-mutant cell line emerged.	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('T790M', 'Mutation', 'rs121434569', (147, 152))	('PC9', 'Gene', '255738', (74, 77))	('T790M-mutant', 'Var', (147, 159))	('PC9', 'Gene', (74, 77))
185820	28289245	This difference ultimately relied on the presence of preexisting EGFR T790M-mutant cells within the largely dominating EGFR T790M wild-type population.	('T790M-mutant', 'Var', (70, 82))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('relied', 'Reg', (27, 33))	('EGFR', 'Gene', '1956', (119, 123))	('T790M', 'Mutation', 'rs121434569', (70, 75))	('EGFR', 'Gene', (119, 123))	('T790M', 'Mutation', 'rs121434569', (124, 129))
185821	28289245	When they exposed a single-cell-cloned EGFR T790M wild-type culture to gefitinib, it could take up to 40 weeks to derive an EGFR T790M-mutant cell line.	('T790M', 'Mutation', 'rs121434569', (129, 134))	('EGFR', 'Gene', '1956', (124, 128))	('T790M', 'Mutation', 'rs121434569', (44, 49))	('EGFR', 'Gene', (124, 128))	('T790M', 'Var', (44, 49))	('EGFR', 'Gene', '1956', (39, 43))	('gefitinib', 'Chemical', 'MESH:D000077156', (71, 80))	('EGFR', 'Gene', (39, 43))
185822	28289245	However, this process was accelerated to 2 weeks in the presence of only one EGFR T790M-mutant cell.	('T790M', 'Mutation', 'rs121434569', (82, 87))	('accelerated', 'PosReg', (26, 37))	('T790M-mutant', 'Var', (82, 94))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))
185824	28289245	Second, even if the bulk of the drug-sensitive cancer cells is successfully killed, a portion of the EGFR T790M wild-type cells tolerates the drug (drug-tolerant persister cells) and may form a reservoir to produce bona fide genetically resistant cancer cells (also see).	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', '1956', (101, 105))	('cancer', 'Disease', (47, 53))	('EGFR', 'Gene', (101, 105))	('T790M', 'Mutation', 'rs121434569', (106, 111))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tolerates the', 'MPA', (128, 141))	('T790M', 'Var', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
185827	28289245	Recent studies comparing pre- and post-chemotherapy-treated clinical samples, have explored how (1) chemotherapy-induced elimination of sensitive subclones, and (2) how chemotherapy-induced mutagenesis influences the course of cancer evolution.	('influences', 'Reg', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('mutagenesis', 'Var', (190, 201))	('clinical samples', 'Species', '191496', (60, 76))	('course', 'CPA', (217, 223))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))
185834	28289245	Furthermore, found that patients with a subclonal driver had significantly faster progression of their CLL.	('CLL', 'Phenotype', 'HP:0005550', (103, 106))	('CLL', 'Disease', (103, 106))	('progression', 'CPA', (82, 93))	('faster', 'PosReg', (75, 81))	('patients', 'Species', '9606', (24, 32))	('subclonal driver', 'Var', (40, 56))
185841	28289245	They performed STAR-FISH (allele-specific in situ PCR combined with FISH) for PIK3CA mutations and HER2 amplifications, which are known to respectively confer resistance and sensitivity to trastuzumab, in breast cancer treated with neo-adjuvant chemotherapy.	('PIK3CA', 'Gene', (78, 84))	('trastuzumab', 'Chemical', 'MESH:D000068878', (189, 200))	('PIK3CA', 'Gene', '5290', (78, 84))	('HER2', 'Gene', (99, 103))	('mutations', 'Var', (85, 94))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('HER2', 'Gene', '2064', (99, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('breast cancer', 'Disease', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
185843	28289245	These tumors could possibly benefit from anti-HER2 targeted therapy (such as trastuzumab), because the trastuzumab-resistant, PIC3CA-mutant population is only present as a minor subclone.	('HER2', 'Gene', (46, 50))	('HER2', 'Gene', '2064', (46, 50))	('PIC3CA-mutant', 'Var', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('trastuzumab', 'Chemical', 'MESH:D000068878', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('trastuzumab', 'Chemical', 'MESH:D000068878', (77, 88))
185850	28289245	They catalogued each of these 96 different types of base substitutions in 30 different cancer types, and accordingly described more than 30 different mutational signatures.	('cancer', 'Disease', (87, 93))	('base substitutions', 'Var', (52, 70))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
185858	28289245	investigated whether any of these TMZ-induced mutations occurred in any of previously identified driver genes in glioblastoma.	('glioblastoma', 'Disease', (113, 125))	('occurred', 'Reg', (56, 64))	('mutations', 'Var', (46, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('TMZ', 'Chemical', 'MESH:D000077204', (34, 37))
185859	28289245	Accordingly, they found mutations in RB1, CDKN2A, PIK3CA, PTEN, and MTOR within a TMZ mutational context.	('PTEN', 'Gene', '5728', (58, 62))	('PIK3CA', 'Gene', '5290', (50, 56))	('MTOR', 'Gene', (68, 72))	('CDKN2A', 'Gene', (42, 48))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('MTOR', 'Gene', '2475', (68, 72))	('RB1', 'Gene', (37, 40))	('CDKN2A', 'Gene', '1029', (42, 48))	('found', 'Reg', (18, 23))	('mutations', 'Var', (24, 33))	('RB1', 'Gene', '5925', (37, 40))	('PIK3CA', 'Gene', (50, 56))	('PTEN', 'Gene', (58, 62))
185860	28289245	These findings caused further concern regarding the use of TMZ in the treatment of low-grade gliomas; besides chemotherapy-induced competitive release, TMZ also appeared to induce mutations in driver genes, suggesting it might fuel a more aggressive, higher-grade glioma at recurrence.	('glioma', 'Disease', (264, 270))	('gliomas', 'Disease', (93, 100))	('glioma', 'Disease', (93, 99))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('mutations', 'Var', (180, 189))	('TMZ', 'Chemical', 'MESH:D000077204', (152, 155))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('driver genes', 'Gene', (193, 205))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('induce', 'Reg', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('aggressive', 'CPA', (239, 249))	('TMZ', 'Var', (152, 155))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
185864	28289245	Collectively, these studies indicate that TMZ can induce a hypermutation phenotype in recurrent tumors of primary as well as secondary glioblastomas, albeit secondary glioblastomas appear more prone to this phenomenon.	('glioblastomas', 'Phenotype', 'HP:0012174', (167, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('glioblastomas', 'Disease', (135, 148))	('hypermutation phenotype', 'MPA', (59, 82))	('glioblastomas', 'Disease', 'MESH:D005909', (167, 180))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('glioblastomas', 'Disease', (167, 180))	('TMZ', 'Var', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))	('glioblastomas', 'Phenotype', 'HP:0012174', (135, 148))	('induce', 'Reg', (50, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))	('glioblastomas', 'Disease', 'MESH:D005909', (135, 148))
185868	28289245	Apart from driver mutations, chemotherapeutic regimens may increase intratumor heterogeneity by contributing to the burden of subclonal mutations.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('subclonal', 'Var', (126, 135))	('tumor', 'Disease', (73, 78))	('increase', 'PosReg', (59, 67))
185871	28289245	They found that the tumors of these two patients were enriched for signature 11 mutations, which is associated with the mutagenic effects of alkylating agents.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (80, 89))	('signature 11', 'Gene', (67, 79))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
185933	28570587	The full treatment consists of a total dose, D, split in a series of N radiation fractions with doses per fraction {dj}j = 1,  , N, such that d1 +   + dN = D, given at irradiation times {tj}j = 1,  , N. The tumor amplitude U(t) at the irradiation times satisfies.	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('d1 +   + dN = D', 'Var', (142, 157))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))
185951	28570587	Specifically we present results for proliferation rates: rho = 0.01 day-1 (fast-growing tumor, Fig 3(a)) and rho = 0.005 day-1 (slowly-growing tumor, Fig 3(b)).	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (143, 148))	('rho', 'Var', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('rho = 0.005 day-1', 'Var', (109, 126))
186012	18817556	There was no statistically significant difference in either overall survival or progression-free survival (PFS) demonstrated, although a trend in decreased PFS was observed with high nestin expression (p = 0.06).	('nestin', 'Gene', '10763', (183, 189))	('nestin', 'Gene', (183, 189))	('rat', 'Species', '10116', (119, 122))	('decreased', 'NegReg', (146, 155))	('high', 'Var', (178, 182))	('expression', 'MPA', (190, 200))
186052	18817556	The 12-month survival rates for the patients with low, intermediate, and high nestin expression were 59%, 49%, and 48% respectively.	('expression', 'MPA', (85, 95))	('patients', 'Species', '9606', (36, 44))	('nestin', 'Gene', '10763', (78, 84))	('rat', 'Species', '10116', (22, 25))	('nestin', 'Gene', (78, 84))	('high', 'Var', (73, 77))
186053	18817556	The 12-month PFS rates for the patients with low, intermediate, and high nestin expression were 29%, 27%, and 23% respectively.	('high', 'Var', (68, 72))	('nestin', 'Gene', (73, 79))	('PFS', 'CPA', (13, 16))	('patients', 'Species', '9606', (31, 39))	('expression', 'MPA', (80, 90))	('rat', 'Species', '10116', (17, 20))	('nestin', 'Gene', '10763', (73, 79))
186061	18817556	Other investigators have suggested a more definitive correlation of nestin expression with decreased overall survival, although these studies included all high-grade glioma.	('overall survival', 'MPA', (101, 117))	('nestin', 'Gene', '10763', (68, 74))	('glioma', 'Disease', (166, 172))	('expression', 'Var', (75, 85))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('nestin', 'Gene', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('decreased', 'NegReg', (91, 100))
186120	33346568	In contrast, both the NAA/Cr and NAA/Cho ratios were significantly lower in HGGs than in LGGs (0.626 +- 0.351 vs 1.084 +- 0.504, P < 0.001; and 0.258 +- 0.130 vs 0.612 +- 0.399, P < 0.001, respectively).	('Cho', 'Chemical', 'MESH:D002794', (37, 40))	('HGGs', 'Disease', (76, 80))	('Cr', 'Chemical', 'MESH:D003401', (26, 28))	('NAA', 'Chemical', 'MESH:C000179', (33, 36))	('NAA', 'Chemical', 'MESH:C000179', (22, 25))	('lower', 'NegReg', (67, 72))	('0.258 +- 0.130', 'Var', (144, 158))
186181	33255474	Gene mutations can cause significant metabolome alterations, suggesting that tumor cells rely on specific metabolic pathways to complete biological processes.	('cause', 'Reg', (19, 24))	('metabolome alterations', 'MPA', (37, 59))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('Gene mutations', 'Var', (0, 14))
186182	33255474	For example, isocitrate dehydrogenases (IDH) mutations, the common genetic abnormalities in gliomas, could lead to accumulation of 2-hydroxyglutaric acid and changes in related metabolites.	('mutations', 'Var', (45, 54))	('isocitrate dehydrogenases', 'Gene', '3417', (13, 38))	('changes', 'Reg', (158, 165))	('genetic abnormalities', 'Disease', (67, 88))	('2-hydroxyglutaric acid', 'Chemical', 'MESH:C019417', (131, 153))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('IDH', 'Gene', (40, 43))	('2-hydroxyglutaric acid', 'MPA', (131, 153))	('accumulation', 'PosReg', (115, 127))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('lead', 'Reg', (107, 111))	('IDH', 'Gene', '3417', (40, 43))	('isocitrate dehydrogenases', 'Gene', (13, 38))	('genetic abnormalities', 'Disease', 'MESH:D030342', (67, 88))
186185	33255474	explored the role of EGFR mutants in IDH1 wild-type gliomas through whole-exome sequencing, transcriptomics and transposon mutagenesis forward genetic screening, and found new putative tumor suppressors.	('tumor', 'Disease', (185, 190))	('EGFR', 'Gene', '1956', (21, 25))	('gliomas', 'Disease', (52, 59))	('EGFR', 'Gene', (21, 25))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH1', 'Gene', (37, 41))	('mutants', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('IDH1', 'Gene', '3417', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
186211	33255474	reported that gray matter and white matter were characterized by increased abundance of peaks at m/z 834 (PS 40:6[-H]) and m/z 788 (PS 18:1_18:0[-H]) compared with glioma, respectively.	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('m/z 788', 'Var', (123, 130))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('glioma', 'Disease', (164, 170))	('m/z 834', 'Var', (97, 104))
186218	33255474	Among these 17 important metabolites, four acylcarnitines and N-methyl-glutamic acid were significantly increased both in grade III/IV compared with grade II glioma tissues (Figure 3A), and in glioma tissue compared with para-tumor tissues (Figure 2C).	('glioma tissue', 'Disease', 'MESH:D005910', (158, 171))	('II glioma', 'Disease', 'MESH:D005910', (155, 164))	('N-methyl-glutamic acid', 'Chemical', '-', (62, 84))	('para-tumor', 'Disease', (221, 231))	('increased', 'PosReg', (104, 113))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('II glioma', 'Disease', (155, 164))	('glioma tissue', 'Disease', (193, 206))	('acylcarnitines', 'MPA', (43, 57))	('acylcarnitines', 'Chemical', 'MESH:C116917', (43, 57))	('para-tumor', 'Disease', 'MESH:D009369', (221, 231))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('glioma tissue', 'Disease', 'MESH:D005910', (193, 206))	('glioma tissue', 'Disease', (158, 171))	('N-methyl-glutamic acid', 'MPA', (62, 84))	('grade III/IV', 'Var', (122, 134))
186221	33255474	Interestingly, gene clustering analysis found that the profile of lipid metabolism-related genes showed obvious differences between low-grade and high-grade gliomas, and low-grade gliomas exhibited an enrichment in the phosphatidylinositol metabolism process.	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (219, 239))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('differences', 'Reg', (112, 123))	('low-grade', 'Var', (170, 179))	('phosphatidylinositol metabolism process', 'MPA', (219, 258))	('lipid', 'Chemical', 'MESH:D008055', (66, 71))	('gliomas', 'Disease', (157, 164))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('lipid', 'Gene', (66, 71))
186245	33255474	As a result, C2/C0 showed no significant difference, whereas C3/C0 showed a significantly higher level in high-grade gliomas than low-grade gliomas (Figure S2C,D).	('C0', 'Chemical', '-', (16, 18))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('C0', 'Chemical', '-', (64, 66))	('gliomas', 'Disease', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('higher', 'PosReg', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('C3/C0', 'Var', (61, 66))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))
186254	33255474	Elevated C4-CN and C6-CN were found in high-grade glioma tissues (Figure 3B).	('C6-CN', 'Var', (19, 24))	('glioma tissue', 'Disease', (50, 63))	('C4-CN', 'Var', (9, 14))	('glioma tissue', 'Disease', 'MESH:D005910', (50, 63))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
186309	32681296	High-grade neoplastic lesions have shown to demonstrate a mean Cho/Cr ratio of 2.4 on short TE MRS, compared with a mean Cho/Cr ratio of 1.5 for low-grade neoplastic lesions.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (11, 29))	('short TE', 'Var', (86, 94))	('Cr', 'Chemical', 'MESH:D003401', (125, 127))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (155, 173))	('Cho', 'Chemical', 'MESH:D002794', (63, 66))	('Cho/Cr', 'MPA', (63, 69))	('Cr', 'Chemical', 'MESH:D003401', (67, 69))	('Cho', 'Chemical', 'MESH:D002794', (121, 124))
186369	32681296	In this case, the lack of enhancement, low rCBV, high ADC, normal choline as well as presence of glutamine and glutamate at 2.3 and 2.4 ppm excluded glioma.	('enhancement', 'MPA', (26, 37))	('glutamine', 'Chemical', 'MESH:D005973', (97, 106))	('rCBV', 'Chemical', '-', (43, 47))	('glioma', 'Disease', (149, 155))	('choline', 'Chemical', 'MESH:D002794', (66, 73))	('ADC', 'MPA', (54, 57))	('glutamate', 'Protein', (111, 120))	('low rCBV', 'Phenotype', 'HP:0025066', (39, 47))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('rCBV', 'MPA', (43, 47))	('normal choline', 'MPA', (59, 73))	('ADC', 'Chemical', '-', (54, 57))	('glutamate', 'Chemical', 'MESH:D018698', (111, 120))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('presence', 'Var', (85, 93))	('excluded', 'NegReg', (140, 148))	('glutamine', 'Protein', (97, 106))
186388	32355035	MicroRNA-1298-3p inhibits proliferation and invasion of glioma cells by downregulating Nidogen-1 Glioma is the most prevalent tumor of the central nervous system.	('inhibits', 'NegReg', (17, 25))	('glioma', 'Disease', (56, 62))	('MicroRNA-1298-3p', 'Var', (0, 16))	('downregulating', 'NegReg', (72, 86))	('invasion', 'CPA', (44, 52))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (126, 161))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Nidogen-1', 'MPA', (87, 96))	('Glioma', 'Disease', 'MESH:D005910', (97, 103))	('Glioma', 'Phenotype', 'HP:0009733', (97, 103))	('Glioma', 'Disease', (97, 103))	('proliferation', 'CPA', (26, 39))	('tumor', 'Disease', (126, 131))
186391	32355035	Downregulation of miR-1298-3p correlated with poor overall survival rates in glioma patients.	('poor', 'NegReg', (46, 50))	('patients', 'Species', '9606', (84, 92))	('miR-1298-3p', 'Chemical', '-', (18, 29))	('Downregulation', 'NegReg', (0, 14))	('glioma', 'Disease', (77, 83))	('overall survival rates', 'CPA', (51, 73))	('miR-1298-3p', 'Var', (18, 29))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
186392	32355035	Overexpression of miR-1298-3p induced apoptosis of glioma cells and inhibited glioma cell proliferation, migration, and invasion.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioma', 'Disease', (51, 57))	('miR-1298-3p', 'Chemical', '-', (18, 29))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('inhibited', 'NegReg', (68, 77))	('apoptosis', 'CPA', (38, 47))	('invasion', 'CPA', (120, 128))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', (78, 84))	('miR-1298-3p', 'Var', (18, 29))	('migration', 'CPA', (105, 114))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
186393	32355035	The basement membrane protein Nidogen-1 (NID1) was identified as a direct binding target of miR-1298-3p in glioma cells.	('miR-1298-3p', 'Var', (92, 103))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('miR-1298-3p', 'Chemical', '-', (92, 103))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('Nidogen-1', 'Gene', (30, 39))	('NID1', 'Gene', '4811', (41, 45))	('Nidogen-1', 'Gene', '4811', (30, 39))	('binding', 'Interaction', (74, 81))	('glioma', 'Disease', (107, 113))	('NID1', 'Gene', (41, 45))
186394	32355035	MiR-1298-3p agonist downregulated the NID1 and vimentin levels, but upregulated the level of E-cadherin in glioma cells.	('E-cadherin', 'Gene', (93, 103))	('upregulated', 'PosReg', (68, 79))	('MiR-1298-3p', 'Chemical', '-', (0, 11))	('MiR-1298-3p agonist', 'Var', (0, 19))	('E-cadherin', 'Gene', '999', (93, 103))	('downregulated', 'NegReg', (20, 33))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('glioma', 'Disease', (107, 113))	('vimentin', 'Gene', '7431', (47, 55))	('NID1', 'Gene', '4811', (38, 42))	('vimentin', 'Gene', (47, 55))	('NID1', 'Gene', (38, 42))
186395	32355035	Importantly, overexpression of miR-1298-3p induced apoptosis and reduced tumor growth in a mouse xenograft model of glioma.	('reduced tumor', 'Disease', (65, 78))	('reduced tumor', 'Disease', 'MESH:C536418', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('glioma', 'Disease', (116, 122))	('mouse', 'Species', '10090', (91, 96))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('overexpression', 'PosReg', (13, 27))	('miR-1298-3p', 'Var', (31, 42))	('apoptosis', 'CPA', (51, 60))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('miR-1298-3p', 'Chemical', '-', (31, 42))
186396	32355035	Our results show that miR-1298-3p functions as a tumor suppressor in glioma cells, and suggest that it might serve as a potential biomarker and therapeutic target in glioma patients.	('glioma', 'Disease', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patients', 'Species', '9606', (173, 181))	('glioma', 'Disease', (166, 172))	('tumor', 'Disease', (49, 54))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('miR-1298-3p', 'Chemical', '-', (22, 33))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('miR-1298-3p', 'Var', (22, 33))
186403	32355035	Recent studies have suggested that miRNAs are involved in glioma tumorigenesis by functioning as oncogenes or tumor suppressors, and might thus serve as diagnostic and prognostic glioma biomarkers.	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (58, 78))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('tumor', 'Disease', (110, 115))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('glioma tumorigenesis', 'Disease', (58, 78))	('involved', 'Reg', (46, 54))	('glioma', 'Disease', (58, 64))	('miRNAs', 'Var', (35, 41))	('glioma', 'Disease', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
186405	32355035	Our data show that low levels of miR-1298-3p correlate with poor survival rates in glioma patients.	('glioma', 'Disease', (83, 89))	('miR-1298-3p', 'Var', (33, 44))	('poor', 'NegReg', (60, 64))	('miR-1298-3p', 'Chemical', '-', (33, 44))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('patients', 'Species', '9606', (90, 98))	('survival rates', 'CPA', (65, 79))
186406	32355035	In addition, our results demonstrate that miR-1298-3p inhibits proliferation, migration, and invasion of glioma cells, and suggest that it may serve as a potential biomarker in glioma tumorigenesis.	('proliferation', 'CPA', (63, 76))	('miR-1298-3p', 'Chemical', '-', (42, 53))	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (177, 197))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('glioma', 'Disease', (105, 111))	('glioma', 'Disease', (177, 183))	('miR-1298-3p', 'Var', (42, 53))	('migration', 'CPA', (78, 87))	('inhibits', 'NegReg', (54, 62))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioma tumorigenesis', 'Disease', (177, 197))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
186408	32355035	In addition, RT-qPCR results indicated that obviously decreased expression of miR-1298-3p was observed in the high-grade gliomas group (Figure 1D).	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('expression', 'MPA', (64, 74))	('miR-1298-3p', 'Var', (78, 89))	('gliomas', 'Disease', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('decreased', 'NegReg', (54, 63))	('miR-1298-3p', 'Chemical', '-', (78, 89))
186410	32355035	Low levels of miR-1298-3p correlated with decreased overall survival rates in glioma patients in the CGGA dataset (Figure 2A).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('overall survival', 'MPA', (52, 68))	('miR-1298-3p', 'Chemical', '-', (14, 25))	('decreased', 'NegReg', (42, 51))	('patients', 'Species', '9606', (85, 93))	('miR-1298-3p', 'Var', (14, 25))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
186411	32355035	In addition, low levels of miR-1298-3p correlated with poor overall survival rates in glioma patients in the TCGA dataset (Figure 2B).	('glioma', 'Disease', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('miR-1298-3p', 'Var', (27, 38))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('poor', 'NegReg', (55, 59))	('miR-1298-3p', 'Chemical', '-', (27, 38))	('patients', 'Species', '9606', (93, 101))
186412	32355035	These data indicate that the low miR-1298-3p expression is associated with a poor survival in glioma patients.	('patients', 'Species', '9606', (101, 109))	('miR-1298-3p expression', 'Var', (33, 55))	('low', 'NegReg', (29, 32))	('glioma', 'Disease', (94, 100))	('poor', 'NegReg', (77, 81))	('miR-1298-3p', 'Chemical', '-', (33, 44))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
186414	32355035	As shown in Figure 3A, the level of miR-1298-3p was significantly downregulated in U87MG, SHG-44, and U251 cells, compared with HA1800 cells.	('downregulated', 'NegReg', (66, 79))	('miR-1298-3p', 'Chemical', '-', (36, 47))	('U87MG', 'CellLine', 'CVCL:0022', (83, 88))	('U251', 'CellLine', 'CVCL:0021', (102, 106))	('miR-1298-3p', 'Var', (36, 47))
186416	32355035	In addition, the level of miR-1298-3p had no obvious change in human neurons and human microglia groups, compared with HA1800 group (Supplementary Figure 1A).	('miR-1298-3p', 'Var', (26, 37))	('human', 'Species', '9606', (63, 68))	('human neurons', 'CPA', (63, 76))	('miR-1298-3p', 'Chemical', '-', (26, 37))	('human', 'Species', '9606', (81, 86))
186417	32355035	As shown in Figure 3B, 3C, the level of miR-1298-3p was upregulated in U87MG and SHG-44 cells after transfection with miR-1298-3p agonist.	('miR-1298-3p', 'Var', (40, 51))	('miR-1298-3p', 'Chemical', '-', (118, 129))	('U87MG', 'CellLine', 'CVCL:0022', (71, 76))	('miR-1298-3p', 'Chemical', '-', (40, 51))	('miR-1298-3p', 'Var', (118, 129))	('upregulated', 'PosReg', (56, 67))
186418	32355035	Meanwhile, overexpression of miR-1298-3p significantly reduced proliferation of U87MG and SHG-44 cells (Figure 3D-3G).	('U87MG', 'CellLine', 'CVCL:0022', (80, 85))	('miR-1298-3p', 'Var', (29, 40))	('proliferation', 'CPA', (63, 76))	('reduced', 'NegReg', (55, 62))	('U87MG', 'CPA', (80, 85))	('miR-1298-3p', 'Chemical', '-', (29, 40))
186419	32355035	Furthermore, downregulation of miR-1298-3p exhibited a slight increase in the cell proliferation of U251 cells, while overexpression of miR-1298-3p exhibited a significant decrease in the cell proliferation of U251 cells (Supplementary Figure 1B).	('cell proliferation', 'CPA', (188, 206))	('cell proliferation of U251 cells', 'CPA', (78, 110))	('miR-1298-3p', 'Var', (136, 147))	('U251', 'CellLine', 'CVCL:0021', (100, 104))	('U251', 'CellLine', 'CVCL:0021', (210, 214))	('downregulation', 'NegReg', (13, 27))	('miR-1298-3p', 'Chemical', '-', (136, 147))	('decrease', 'NegReg', (172, 180))	('miR-1298-3p', 'Var', (31, 42))	('miR-1298-3p', 'Chemical', '-', (31, 42))	('increase', 'PosReg', (62, 70))
186420	32355035	These data suggested that overexpression of miR-1298-3p inhibits proliferation of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('miR-1298-3p', 'Var', (44, 55))	('overexpression', 'PosReg', (26, 40))	('inhibits', 'NegReg', (56, 64))	('miR-1298-3p', 'Chemical', '-', (44, 55))	('glioma', 'Disease', (82, 88))
186422	32355035	As illustrated in Figure 4A-4D, miR-1298-3p agonist markedly induced apoptosis in U87MG and SHG-44 cells.	('U87MG', 'CellLine', 'CVCL:0022', (82, 87))	('miR-1298-3p', 'Chemical', '-', (32, 43))	('induced', 'Reg', (61, 68))	('apoptosis', 'CPA', (69, 78))	('miR-1298-3p agonist', 'Var', (32, 51))
186423	32355035	In addition, levels of the pro-apoptotic protein Bax and active caspase 3 were increased, and levels of the anti-apoptotic protein Bcl-2 were decreased in U87MG and SHG-44 cells transfected with miR-1298-3p agonist, compared with NC group (Figure 4E-4H).	('increased', 'PosReg', (79, 88))	('Bcl-2', 'Gene', (131, 136))	('Bcl-2', 'Gene', '596', (131, 136))	('Bax', 'Gene', '581', (49, 52))	('miR-1298-3p', 'Var', (195, 206))	('decreased', 'NegReg', (142, 151))	('miR-1298-3p', 'Chemical', '-', (195, 206))	('Bax', 'Gene', (49, 52))	('caspase 3', 'Gene', (64, 73))	('caspase 3', 'Gene', '836', (64, 73))	('U87MG', 'CellLine', 'CVCL:0022', (155, 160))
186424	32355035	Moreover, overexpression of miR-1298-3p markedly induced apoptosis in U251 cells as well, while downregulation of miR-1298-3p slightly increased apoptosis of U251 cells (Supplementary Figure 1C, 1D).	('U251', 'CellLine', 'CVCL:0021', (158, 162))	('miR-1298-3p', 'Chemical', '-', (28, 39))	('apoptosis', 'CPA', (57, 66))	('miR-1298-3p', 'Chemical', '-', (114, 125))	('U251', 'CellLine', 'CVCL:0021', (70, 74))	('increased', 'PosReg', (135, 144))	('miR-1298-3p', 'Var', (28, 39))	('induced', 'Reg', (49, 56))	('downregulation', 'NegReg', (96, 110))	('overexpression', 'PosReg', (10, 24))	('miR-1298-3p', 'Var', (114, 125))
186425	32355035	These data indicate that overexpression of miR-1298-3p induces apoptosis of glioma cells.	('glioma', 'Disease', (76, 82))	('miR-1298-3p', 'Var', (43, 54))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('induces', 'Reg', (55, 62))	('miR-1298-3p', 'Chemical', '-', (43, 54))	('apoptosis', 'CPA', (63, 72))	('overexpression', 'PosReg', (25, 39))
186427	32355035	As shown in Figure 5A and 5B, upregulation of miR-1298-3p significantly suppressed the migration ability of U87MG cells.	('U87MG', 'CellLine', 'CVCL:0022', (108, 113))	('migration ability of U87MG cells', 'CPA', (87, 119))	('miR-1298-3p', 'Chemical', '-', (46, 57))	('suppressed', 'NegReg', (72, 82))	('upregulation', 'PosReg', (30, 42))	('miR-1298-3p', 'Var', (46, 57))
186428	32355035	In addition, the transwell invasion assay showed that miR-1298-3p agonist markedly inhibited the invasion ability of U87MG cells (Figure 5C, 5D).	('miR-1298-3p', 'Var', (54, 65))	('invasion ability of U87MG cells', 'CPA', (97, 128))	('inhibited', 'NegReg', (83, 92))	('miR-1298-3p', 'Chemical', '-', (54, 65))	('U87MG', 'CellLine', 'CVCL:0022', (117, 122))
186429	32355035	Furthermore, overexpression of miR-1298-3p obviously inhibited the migration and invasion abilities of U251 cells as well, while downregulation of miR-1298-3p slightly promoted the migration and invasion abilities of U251 cells (Supplementary Figure 1E-1H).	('invasion abilities', 'CPA', (195, 213))	('inhibited', 'NegReg', (53, 62))	('downregulation', 'NegReg', (129, 143))	('U251', 'CellLine', 'CVCL:0021', (103, 107))	('U251', 'CellLine', 'CVCL:0021', (217, 221))	('miR-1298-3p', 'Var', (147, 158))	('overexpression', 'PosReg', (13, 27))	('miR-1298-3p', 'Var', (31, 42))	('promoted', 'PosReg', (168, 176))	('migration', 'CPA', (181, 190))	('miR-1298-3p', 'Chemical', '-', (147, 158))	('miR-1298-3p', 'Chemical', '-', (31, 42))
186430	32355035	These results indicate that overexpression of miR-1298-3p inhibits migration and invasion of glioma cells.	('glioma', 'Disease', (93, 99))	('inhibits', 'NegReg', (58, 66))	('miR-1298-3p', 'Chemical', '-', (46, 57))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('overexpression', 'PosReg', (28, 42))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('miR-1298-3p', 'Var', (46, 57))
186432	32355035	As shown in Figure 6A, Nidogen-1 (NID1) was identified as a potential target of miR-1298-3p.	('NID1', 'Gene', (34, 38))	('miR-1298-3p', 'Chemical', '-', (80, 91))	('Nidogen-1', 'Gene', '4811', (23, 32))	('Nidogen-1', 'Gene', (23, 32))	('miR-1298-3p', 'Var', (80, 91))	('NID1', 'Gene', '4811', (34, 38))
186433	32355035	To validate that NID1 is indeed a target of miR-1298-3p, we used a dual-luciferase reporter assay.	('NID1', 'Gene', '4811', (17, 21))	('NID1', 'Gene', (17, 21))	('miR-1298-3p', 'Var', (44, 55))	('miR-1298-3p', 'Chemical', '-', (44, 55))
186434	32355035	As shown in Figure 6B, 6C, miR-1298-3p agonist suppressed the luciferase activity of NID1-WT, but it did not affect the luciferase activity of NID1-MT.	('suppressed', 'NegReg', (47, 57))	('activity', 'MPA', (73, 81))	('NID1', 'Gene', '4811', (143, 147))	('miR-1298-3p agonist', 'Var', (27, 46))	('NID1', 'Gene', '4811', (85, 89))	('luciferase', 'Enzyme', (62, 72))	('miR-1298-3p', 'Chemical', '-', (27, 38))	('NID1', 'Gene', (143, 147))	('NID1', 'Gene', (85, 89))
186435	32355035	Overexpression of miR-1298-3p significantly decreased the NID1 gene expression in U87MG cells (Figure 6D).	('NID1', 'Gene', (58, 62))	('expression', 'MPA', (68, 78))	('miR-1298-3p', 'Chemical', '-', (18, 29))	('U87MG', 'CellLine', 'CVCL:0022', (82, 87))	('miR-1298-3p', 'Var', (18, 29))	('NID1', 'Gene', '4811', (58, 62))	('decreased', 'NegReg', (44, 53))
186436	32355035	In addition, miR-1298-3p agonist markedly decreased the protein levels of NID1 and vimentin, but increased the protein level of E-cadherin in U87MG cells, compared with NC group (Figure 6E-6H).	('E-cadherin', 'Gene', (128, 138))	('E-cadherin', 'Gene', '999', (128, 138))	('vimentin', 'Gene', (83, 91))	('increased', 'PosReg', (97, 106))	('decreased', 'NegReg', (42, 51))	('NID1', 'Gene', '4811', (74, 78))	('miR-1298-3p agonist', 'Var', (13, 32))	('miR-1298-3p', 'Chemical', '-', (13, 24))	('NID1', 'Gene', (74, 78))	('U87MG', 'CellLine', 'CVCL:0022', (142, 147))	('vimentin', 'Gene', '7431', (83, 91))
186437	32355035	These data indicate that NID1 is a direct target of miR-1298-3p.	('miR-1298-3p', 'Chemical', '-', (52, 63))	('NID1', 'Gene', (25, 29))	('NID1', 'Gene', '4811', (25, 29))	('miR-1298-3p', 'Var', (52, 63))
186439	32355035	As shown in Figure 7A-7C and Supplementary Figure 2A-2C, miR-1298-3p agonist treatment significantly inhibited the tumor volume and tumor weight of U87MG or U251 subcutaneous xenografts, compared with NC group.	('U87MG', 'Var', (148, 153))	('U251', 'CellLine', 'CVCL:0021', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (115, 120))	('miR-1298-3p', 'Chemical', '-', (57, 68))	('tumor', 'Disease', (132, 137))	('inhibited', 'NegReg', (101, 110))	('miR-1298-3p', 'Var', (57, 68))	('U87MG', 'CellLine', 'CVCL:0022', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
186440	32355035	In addition, TUNEL assay showed that overexpression of miR-1298-3p markedly induced apoptosis in tumor tissues, compared with the NC group (Figure 7D, 7E).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('overexpression', 'PosReg', (37, 51))	('miR-1298-3p', 'Chemical', '-', (55, 66))	('apoptosis in', 'CPA', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('induced', 'PosReg', (76, 83))	('miR-1298-3p', 'Var', (55, 66))
186441	32355035	Moreover, IHC assay indicated that overexpression of miR-1298-3p notably inhibited proliferation in tumor tissues, compared with the NC group (Figure 7F, 7G).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('miR-1298-3p', 'Chemical', '-', (53, 64))	('inhibited', 'NegReg', (73, 82))	('overexpression', 'PosReg', (35, 49))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('miR-1298-3p', 'Var', (53, 64))
186442	32355035	Meanwhile, miR-1298-3p agonist markedly decreased the protein levels of NID1 and vimentin, but increased the protein level of E-cadherin in tumor tissues, compared with NC group (Figure 7H-7K).	('NID1', 'Gene', '4811', (72, 76))	('increased', 'PosReg', (95, 104))	('NID1', 'Gene', (72, 76))	('protein levels', 'MPA', (54, 68))	('E-cadherin', 'Gene', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('miR-1298-3p agonist', 'Var', (11, 30))	('E-cadherin', 'Gene', '999', (126, 136))	('vimentin', 'Gene', '7431', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('vimentin', 'Gene', (81, 89))	('decreased', 'NegReg', (40, 49))	('miR-1298-3p', 'Chemical', '-', (11, 22))	('tumor', 'Disease', (140, 145))
186443	32355035	Furthermore, the body weights of mice had no obvious change between miR-1298-3p agonist group and NC group, indicating that miR-1298-3p had no system toxicity on mice (Figure 7L and Supplementary Figure 2D).	('miR-1298-3p', 'Chemical', '-', (124, 135))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('toxicity', 'Disease', (150, 158))	('mice', 'Species', '10090', (162, 166))	('miR-1298-3p', 'Chemical', '-', (68, 79))	('mice', 'Species', '10090', (33, 37))	('miR-1298-3p', 'Var', (124, 135))
186444	32355035	These data show that upregulation of miR-1298-3p inhibits the glioma tumorigenesis in vivo.	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('miR-1298-3p', 'Var', (37, 48))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('inhibits', 'NegReg', (49, 57))	('miR-1298-3p', 'Chemical', '-', (37, 48))	('upregulation', 'PosReg', (21, 33))	('glioma tumorigenesis', 'Disease', (62, 82))
186453	32355035	Previously, a lower miR-1298-3p expression was associated with poor overall survival rates and lymph node metastasis in patients with gastric cancer.	('overall survival rates', 'CPA', (68, 90))	('lower', 'NegReg', (14, 19))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('miR-1298-3p', 'Var', (20, 31))	('lymph node metastasis', 'CPA', (95, 116))	('patients', 'Species', '9606', (120, 128))	('poor', 'NegReg', (63, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('miR-1298-3p', 'Chemical', '-', (20, 31))
186454	32355035	Moreover, the level of miR-1298 was downregulated in bladder cancer tissues, implying that miR-1298 might be a diagnostic marker of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (132, 146))	('bladder cancer', 'Disease', (132, 146))	('bladder cancer', 'Disease', 'MESH:D001749', (53, 67))	('level', 'MPA', (14, 19))	('bladder cancer', 'Disease', (53, 67))	('miR-1298', 'Var', (91, 99))	('bladder cancer', 'Phenotype', 'HP:0009725', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('downregulated', 'NegReg', (36, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
186455	32355035	Our study demonstrates that overexpression of miR-1298-3p inhibits proliferation, migration, and invasion of glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('inhibits', 'NegReg', (58, 66))	('miR-1298-3p', 'Chemical', '-', (46, 57))	('glioma', 'Disease', (109, 115))	('migration', 'CPA', (82, 91))	('proliferation', 'CPA', (67, 80))	('overexpression', 'PosReg', (28, 42))	('miR-1298-3p', 'Var', (46, 57))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
186456	32355035	Moreover, our data show that upregulation of miR-1298-3p induces glioma cell apoptosis in vitro and in vivo, and indicate that overexpression of miR-1298-3p inhibits the glioma tumorigenesis.	('inhibits', 'NegReg', (157, 165))	('glioma', 'Disease', (65, 71))	('miR-1298-3p', 'Chemical', '-', (145, 156))	('glioma', 'Disease', (170, 176))	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (170, 190))	('upregulation', 'PosReg', (29, 41))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('overexpression', 'PosReg', (127, 141))	('miR-1298-3p', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('miR-1298-3p', 'Var', (145, 156))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('glioma tumorigenesis', 'Disease', (170, 190))	('induces', 'PosReg', (57, 64))	('miR-1298-3p', 'Chemical', '-', (45, 56))
186457	32355035	Our data identify Nidogen-1 (NID1) as a binding target of miR-1298-3p.	('NID1', 'Gene', '4811', (29, 33))	('Nidogen-1', 'Gene', '4811', (18, 27))	('Nidogen-1', 'Gene', (18, 27))	('miR-1298-3p', 'Var', (58, 69))	('NID1', 'Gene', (29, 33))	('miR-1298-3p', 'Chemical', '-', (58, 69))
186463	32355035	We have found that overexpression of miR-1298-3p downregulates the levels of NID1 and vimentin, and upregulates the level of E-cadherin in glioma cells, indicating that overexpression of miR-1298-3p inhibits glioma cell invasion.	('inhibits', 'NegReg', (199, 207))	('E-cadherin', 'Gene', '999', (125, 135))	('glioma', 'Disease', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('miR-1298-3p', 'Var', (187, 198))	('glioma', 'Disease', (208, 214))	('miR-1298-3p', 'Var', (37, 48))	('NID1', 'Gene', '4811', (77, 81))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('NID1', 'Gene', (77, 81))	('miR-1298-3p', 'Chemical', '-', (187, 198))	('miR-1298-3p', 'Chemical', '-', (37, 48))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('downregulates', 'NegReg', (49, 62))	('upregulates', 'PosReg', (100, 111))	('vimentin', 'Gene', '7431', (86, 94))	('vimentin', 'Gene', (86, 94))	('E-cadherin', 'Gene', (125, 135))
186464	32355035	These data indicate that miR-1298-3p inhibits proliferation and invasion of glioma cells by regulating the NID1 expression, as well as the downstream targets vimentin and E-cadherin.	('regulating', 'Reg', (92, 102))	('glioma', 'Disease', (76, 82))	('vimentin', 'Gene', (158, 166))	('NID1', 'Gene', '4811', (107, 111))	('E-cadherin', 'Gene', (171, 181))	('NID1', 'Gene', (107, 111))	('E-cadherin', 'Gene', '999', (171, 181))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('proliferation', 'CPA', (46, 59))	('miR-1298-3p', 'Var', (25, 36))	('vimentin', 'Gene', '7431', (158, 166))	('inhibits', 'NegReg', (37, 45))	('miR-1298-3p', 'Chemical', '-', (25, 36))	('expression', 'MPA', (112, 122))
186465	32355035	Together, our data show that the low level of miR-1298-3p correlates with a poor prognosis in glioma patients.	('patients', 'Species', '9606', (101, 109))	('glioma', 'Disease', (94, 100))	('miR-1298-3p', 'Chemical', '-', (46, 57))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('miR-1298-3p', 'Var', (46, 57))
186466	32355035	In addition, our results indicate that miR-1298-3p functions as a tumor suppressor that inhibits proliferation and invasion of glioma cells by suppressing the NID1 expression, and suggest that miR-1298-3p might serve as a potential biomarker for the glioma treatment.	('NID1', 'Gene', '4811', (159, 163))	('miR-1298-3p', 'Var', (39, 50))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma', 'Disease', (250, 256))	('NID1', 'Gene', (159, 163))	('glioma', 'Disease', 'MESH:D005910', (250, 256))	('invasion', 'CPA', (115, 123))	('tumor', 'Disease', (66, 71))	('miR-1298-3p', 'Chemical', '-', (39, 50))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('miR-1298-3p', 'Var', (193, 204))	('glioma', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('expression', 'MPA', (164, 174))	('suppressing', 'NegReg', (143, 154))	('miR-1298-3p', 'Chemical', '-', (193, 204))	('inhibits', 'NegReg', (88, 96))
186498	32355035	Oligonucleotides containing wild-type (WT) or mutant (MT) miR-1298-3p binding sites of 3'-UTR of the NID1 mRNA cDNA fragment were ligated into the psiCHECK-2 vector (Promega, Corp., Singapore).	('Oligonucleotides', 'Chemical', 'MESH:D009841', (0, 16))	('NID1', 'Gene', (101, 105))	('psiCHECK', 'Disease', (147, 155))	('mutant', 'Var', (46, 52))	('miR-1298-3p', 'Gene', (58, 69))	('psiCHECK', 'Disease', 'None', (147, 155))	('miR-1298-3p', 'Chemical', '-', (58, 69))	('NID1', 'Gene', '4811', (101, 105))
186499	32355035	NID1 reporter construct (WT or MT) was co-transfected with miR-1298-3p agonist or agonist NC using Lipofectamine 2000 (Thermo Fisher Scientific).	('NID1', 'Gene', (0, 4))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (99, 117))	('miR-1298-3p', 'Var', (59, 70))	('NID1', 'Gene', '4811', (0, 4))	('miR-1298-3p', 'Chemical', '-', (59, 70))
186527	29876236	Different changes exemplified by FGFRs mutations and translocations, as well as alterations in mRNA splicing and gene amplification of FGF/FGFR pathway and protein expressions levels have been documented in different cancers.	('mRNA splicing', 'MPA', (95, 108))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('mutations', 'Var', (39, 48))	('protein expressions levels', 'MPA', (156, 182))	('FGFRs', 'Gene', (33, 38))	('gene amplification', 'MPA', (113, 131))	('translocations', 'Var', (53, 67))	('men', 'Species', '9606', (197, 200))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancers', 'Disease', (217, 224))	('FGF/FGFR pathway', 'Pathway', (135, 151))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('alterations', 'Reg', (80, 91))
186528	29876236	Aberrations of the FGFR signaling pathway can activate downstream pathways, PI3K/ AKT, MAPK signaling cascade, those which contribute to tumor progression.	('tumor', 'Disease', (137, 142))	('MAPK signaling cascade', 'Pathway', (87, 109))	('contribute', 'Reg', (123, 133))	('FGFR signaling pathway', 'Pathway', (19, 41))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('AKT', 'Gene', '207', (82, 85))	('activate', 'PosReg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Aberrations', 'Var', (0, 11))	('AKT', 'Gene', (82, 85))
186529	29876236	The FGFR1 and FGFR3 mutations and over expression have been reported in BC, while FGFR3 alterations were significantly involved in the pathogenesis of urothelial carcinoma (UC) as a whole.	('involved', 'Reg', (119, 127))	('FGFR3', 'Gene', (82, 87))	('FGFR3', 'Gene', '2261', (14, 19))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (151, 171))	('over expression', 'PosReg', (34, 49))	('FGFR1', 'Gene', (4, 9))	('FGFR1', 'Gene', '2260', (4, 9))	('FGFR3', 'Gene', (14, 19))	('FGFR3', 'Gene', '2261', (82, 87))	('urothelial carcinoma', 'Disease', (151, 171))	('BC', 'Phenotype', 'HP:0009725', (72, 74))	('reported', 'Reg', (60, 68))	('mutations', 'Var', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
186531	29876236	The FGFR1 gene expression alteration is also related to certain cancers.	('FGFR1', 'Gene', (4, 9))	('alteration', 'Var', (26, 36))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('FGFR1', 'Gene', '2260', (4, 9))	('cancers', 'Disease', (64, 71))	('related', 'Reg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
186532	29876236	More notably, a recent study using next generation sequencing in advanced BC has demonstrated a gene fusion of FGFR1 and NTM(FGFR1-NTM).	('FGFR1', 'Gene', '2260', (125, 130))	('FGFR1', 'Gene', '2260', (111, 116))	('NTM', 'Gene', (131, 134))	('gene fusion', 'Var', (96, 107))	('FGFR1', 'Gene', (111, 116))	('BC', 'Phenotype', 'HP:0009725', (74, 76))	('NTM', 'Gene', '50863', (121, 124))	('NTM', 'Gene', '50863', (131, 134))	('FGFR1', 'Gene', (125, 130))	('NTM', 'Gene', (121, 124))
186565	29876236	Such aberrations in FGFR3 are one of the most common molecular events in UCs, but some of them such as gene amplification are relatively rare.	('FGFR3', 'Gene', '2261', (20, 25))	('aberrations', 'Var', (5, 16))	('UCs', 'Disease', (73, 76))	('FGFR3', 'Gene', (20, 25))
186572	29876236	Mainly mediated by FGFR3 gene mutations, over expression of FGFR3 mRNA and protein levels have been evident frequently in different cancers, which may suggest more clearly its oncogenic properties.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('FGFR3', 'Gene', (60, 65))	('over expression', 'PosReg', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FGFR3', 'Gene', '2261', (19, 24))	('mediated', 'Reg', (7, 15))	('mutations', 'Var', (30, 39))	('FGFR3', 'Gene', '2261', (60, 65))	('FGFR3', 'Gene', (19, 24))
186604	29658967	A greater understanding of aberrant miRNA in pediatric brain tumors may support development of novel therapies.	('brain tumor', 'Phenotype', 'HP:0030692', (55, 66))	('aberrant', 'Var', (27, 35))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (45, 67))	('pediatric brain tumors', 'Disease', (45, 67))	('brain tumors', 'Phenotype', 'HP:0030692', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
186612	29658967	In previous studies, some miRNAs such as miR-129 were strongly down-regulated in brain tumor samples compared to normal tissue, while miR-142-5p and miR-25 were significantly upregulated in all tumor samples compared to normal tissue.	('brain tumor', 'Disease', 'MESH:D001932', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('brain tumor', 'Disease', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('upregulated', 'PosReg', (175, 186))	('brain tumor', 'Phenotype', 'HP:0030692', (81, 92))	('miR-129', 'Gene', (41, 48))	('down-regulated', 'NegReg', (63, 77))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('miR-25', 'Gene', '407014', (149, 155))	('miR-25', 'Gene', (149, 155))	('miR-142-5p', 'Var', (134, 144))
186613	29658967	More recently, it was demonstrated that miR-19a, miR-15b and miR-106b were significantly up-regulated in MED, while miR-128, miR-299-5p, miR-138 were significantly down-regulated compared to normal control samples.	('miR-106b', 'Gene', (61, 69))	('miR-19a', 'Gene', '406979', (40, 47))	('down-regulated', 'NegReg', (164, 178))	('miR-106b', 'Gene', '406900', (61, 69))	('miR-299-5p', 'Var', (125, 135))	('miR-29', 'Chemical', '-', (125, 131))	('miR-15b', 'Gene', '406949', (49, 56))	('miR-128', 'Var', (116, 123))	('MED', 'Disease', (105, 108))	('miR-19a', 'Gene', (40, 47))	('up-regulated', 'PosReg', (89, 101))	('miR-15b', 'Gene', (49, 56))
186614	29658967	In another study, it was observed that inhibition of miR-106b can induce G1 arrest and apoptosis in MED cells.	('arrest', 'Disease', 'MESH:D006323', (76, 82))	('inhibition', 'Var', (39, 49))	('miR-106b', 'Gene', '406900', (53, 61))	('induce', 'Reg', (66, 72))	('arrest', 'Disease', (76, 82))	('apoptosis', 'CPA', (87, 96))	('miR-106b', 'Gene', (53, 61))
186629	29658967	The most significantly over-expressed miRNAs were miR-19a/b, miR-24, miR-27a, miR-584, and miR-527 in LGG, miR-10b, and miR-29a in EPN, and miR-101, miR-222, miR-139, miR-1827, and miR-34c in MED.	('miR-527', 'Gene', '574497', (91, 98))	('miR-34c', 'Gene', '407042', (181, 188))	('miR-34c', 'Gene', (181, 188))	('miR-1827', 'Gene', (167, 175))	('miR-27a', 'Gene', (69, 76))	('miR-101', 'Chemical', '-', (140, 147))	('miR-101', 'Var', (140, 147))	('miR-1827', 'Gene', '100302217', (167, 175))	('miR-19a', 'Gene', (50, 57))	('miR-29a', 'Gene', '407021', (120, 127))	('miR-10b', 'Gene', (107, 114))	('miR-222', 'Gene', (149, 156))	('miR-19a', 'Gene', '406979', (50, 57))	('miR-29a', 'Gene', (120, 127))	('miR-139', 'Gene', '406931', (158, 165))	('miR-10b', 'Gene', '406903', (107, 114))	('over-expressed', 'PosReg', (23, 37))	('miR-24', 'Var', (61, 67))	('miR-139', 'Gene', (158, 165))	('miR-584', 'Gene', '693169', (78, 85))	('miR-27a', 'Gene', '407018', (69, 76))	('miR-222', 'Gene', '407007', (149, 156))	('miR-584', 'Gene', (78, 85))	('miR-527', 'Gene', (91, 98))
186630	29658967	The most significantly under-expressed miRNAs were miR-26a in LGG, miR-10a in EPN, and miR-221, miR-9, and miR-181c/d in MED.	('miR-10a', 'Gene', (67, 74))	('miR-26a', 'Gene', '407015', (51, 58))	('under-expressed', 'NegReg', (23, 38))	('EPN', 'Disease', (78, 81))	('miR-221', 'Gene', (87, 94))	('miR-26a', 'Gene', (51, 58))	('miR-10a', 'Gene', '406902', (67, 74))	('miR-181c', 'Gene', (107, 115))	('miR-9', 'Var', (96, 101))	('miR-181c', 'Gene', '406957', (107, 115))	('miR-221', 'Gene', '407006', (87, 94))	('LGG', 'Disease', (62, 65))
186635	29658967	Low expression of miR-10a and miR-29a and high expression of miR-361-5p, miR- 617, miR-92a, miR-527, and miR-206 were detected in LGG non-responders and identified as independent factors for treatment response.	('LGG', 'Disease', (130, 133))	('miR-92a', 'Var', (83, 90))	('miR-10a', 'Gene', '406902', (18, 25))	('miR-361-5p', 'Gene', '100500847', (61, 71))	('miR-206', 'Gene', '406989', (105, 112))	('miR-29a', 'Gene', '407021', (30, 37))	('expression', 'MPA', (4, 14))	('miR- 617', 'Gene', '693202', (73, 81))	('miR-361-5p', 'Gene', (61, 71))	('miR-527', 'Gene', '574497', (92, 99))	('miR-10a', 'Gene', (18, 25))	('miR-29a', 'Gene', (30, 37))	('miR- 617', 'Gene', (73, 81))	('miR-527', 'Gene', (92, 99))	('miR-206', 'Gene', (105, 112))
186651	29658967	A previous study showed that overexpression of miR-135a/b increased the resistance of lung cell lines treated with cisplatin.	('miR-135a/b', 'Var', (47, 57))	('overexpression', 'PosReg', (29, 43))	('increased', 'PosReg', (58, 67))	('miR-135a', 'Chemical', '-', (47, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('resistance of lung cell lines', 'CPA', (72, 101))
186660	26614510	PLCbeta1 expression is significantly higher in grade III gliomas than that in grade IV gliomas from GDS1815 (n = 24 vs. 76), GDS1962 (n = 19 vs. 81), and GDS1975 (n = 26 vs. 59).	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('GDS1962', 'Var', (125, 132))	('PLCbeta1', 'Gene', (0, 8))	('higher', 'PosReg', (37, 43))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('II gliomas', 'Disease', 'MESH:D005910', (54, 64))	('GDS1815', 'Var', (100, 107))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('expression', 'MPA', (9, 19))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('GDS1975', 'Var', (154, 161))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('II gliomas', 'Disease', (54, 64))	('gliomas', 'Disease', (87, 94))
186662	26614510	In GDS1962, PLCbeta1 expression is the highest in nontumor brain tissue (n = 23) and is significantly higher than its expression in grade II gliomas [astrocytomas (n = 7) and oligodendrogliomas (n = 37)].	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (175, 193))	('II gliomas', 'Disease', 'MESH:D005910', (138, 148))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('astrocytomas', 'Disease', 'MESH:D001254', (150, 162))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('astrocytomas', 'Disease', (150, 162))	('expression', 'MPA', (21, 31))	('higher', 'PosReg', (102, 108))	('gliomas', 'Phenotype', 'HP:0009733', (186, 193))	('oligodendrogliomas', 'Disease', (175, 193))	('GDS1962', 'Var', (3, 10))	('II gliomas', 'Disease', (138, 148))	('PLCbeta1', 'Gene', (12, 20))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
186663	26614510	A Kaplan-Meier survival curve from a REMBRANDT cohort demonstrates that glioma patients with intermediate PLCbeta1 expression (n = 103) survived significantly longer than PLCbeta1 downregulated (2X) groups (n = 226).	('glioma', 'Disease', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('rat', 'Species', '10116', (61, 64))	('intermediate', 'Var', (93, 105))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('patients', 'Species', '9606', (79, 87))	('longer', 'PosReg', (159, 165))	('PLCbeta1', 'Gene', (106, 114))
186668	26614510	Originally established by the World Health Organization (WHO) in 1993 and then updated in 2007, the four-tiered grading system for glioma outlines grade I as the least aggressive and grade IV as the most aggressive type of gliomas.	('grade I', 'Var', (147, 154))	('glioma', 'Disease', (131, 137))	('least', 'NegReg', (162, 167))	('gliomas', 'Disease', 'MESH:D005910', (223, 230))	('gliomas', 'Phenotype', 'HP:0009733', (223, 230))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('glioma', 'Disease', (223, 229))	('gliomas', 'Disease', (223, 230))
186705	26614510	Based on the information on the HPA website, glioma tissue was stained with four different PLCbeta1 antibodies [HPA034743 and HPA057910 (Sigma-Aldrich, St. Louis, MO); CAB004275 and CAB005334 (Santa Cruz Biotechnology, Dallas, TX)].	('San', 'Gene', (193, 196))	('San', 'Gene', '80218', (193, 196))	('CAB005334', 'Var', (182, 191))	('CAB004275', 'Var', (168, 177))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('PLCbeta1', 'Gene', (91, 99))	('glioma', 'Disease', (45, 51))
186709	26614510	Microarray data, presenting as signal strengths generated by probe 213222_at, is highly correlated with other two groups of PLCbeta1 microarray data generated by probes 215687_x_at and 211925_s_at.	('rat', 'Species', '10116', (153, 156))	('probe 213222_at', 'Var', (61, 76))	('211925_s_at', 'Var', (185, 196))	('rat', 'Species', '10116', (52, 55))
186714	26614510	In combined samples of grade III and IV gliomas, the average PLCbeta1 signal level in PN subtypes (2642 +- 207, n = 37) is still significantly higher than its level in Mes (852 +- 120, n = 35) and in proliferative subtypes (1242 +- 170, n = 28; both p < 0.05).	('rat', 'Species', '10116', (207, 210))	('2642 +- 207', 'Var', (99, 110))	('signal level', 'MPA', (70, 82))	('gliomas', 'Disease', (40, 47))	('Mes', 'Chemical', '-', (168, 171))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('higher', 'PosReg', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('PLCbeta1', 'Gene', (61, 69))
186724	26614510	We further validated the relationship between PLCbeta1 expression and gliomas' pathological grades using other three independent GEO datasets (GDS2853, GDS1962, GDS1975).	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('GDS2853', 'Var', (143, 150))	('PLCbeta1', 'Gene', (46, 54))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
186738	26614510	In GDS1975, PLCbeta1 expression was also significantly lower in grade IV (n = 59) than in grade III gliomas (n = 26, p = 0.3.0E-6; Fig.	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('II gliomas', 'Disease', 'MESH:D005910', (97, 107))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('expression', 'MPA', (21, 31))	('II gliomas', 'Disease', (97, 107))	('PLCbeta1', 'Gene', (12, 20))	('lower', 'NegReg', (55, 60))	('grade IV', 'Disease', (64, 72))	('GDS1975', 'Var', (3, 10))
186743	26614510	We analyzed the relationship between PLCbeta1 gene expression using probe 213222_at and patient survival information in the REMBRANDT cohort.	('patient', 'Species', '9606', (88, 95))	('PLCbeta1', 'Gene', (37, 45))	('probe 213222_at', 'Var', (68, 83))
186759	26614510	7b); both HPA057910 and CAB004275 antibodies yield negative staining in glioma cells in 11 glioma samples (data not shown).	('glioma', 'Disease', (72, 78))	('staining', 'MPA', (60, 68))	('CAB004275', 'Var', (24, 33))	('negative', 'NegReg', (51, 59))	('glioma', 'Disease', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
186760	26614510	Only HPA034743 and CAB005334 show different intensities of positive staining in glioma tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glioma tumor', 'Disease', (80, 92))	('glioma tumor', 'Disease', 'MESH:D005910', (80, 92))	('CAB005334', 'Var', (19, 28))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
186767	26614510	Patients with CpG island hypermethylation (G-CIMP) and isocitrate dehydrogenase 1 (IDH1) mutation have better prognoses.	('IDH1', 'Gene', '3417', (83, 87))	('mutation', 'Var', (89, 97))	('G-CIMP', 'Chemical', '-', (43, 49))	('Patients', 'Species', '9606', (0, 8))	('isocitrate dehydrogenase 1', 'Gene', (55, 81))	('IDH1', 'Gene', (83, 87))	('isocitrate dehydrogenase 1', 'Gene', '3417', (55, 81))
186768	26614510	However, IDH1 mutation (~10 %) and G-CIMP methylation positive (~9 %) only account for a small percentage of primary GBM.	('G-CIMP', 'Chemical', '-', (35, 41))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('mutation', 'Var', (14, 22))	('primary GBM', 'Disease', (109, 120))
186769	26614510	IDH mutated glioma patients are significantly younger than those with IDH wild type, and IDH1/2 mutation is strongly associated with low grade astrocytomas.	('IDH', 'Gene', (0, 3))	('astrocytomas', 'Disease', 'MESH:D001254', (143, 155))	('patients', 'Species', '9606', (19, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('glioma', 'Disease', (12, 18))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (0, 3))	('associated with', 'Reg', (117, 132))	('mutation', 'Var', (96, 104))	('astrocytomas', 'Disease', (143, 155))	('IDH', 'Gene', '3417', (70, 73))	('IDH', 'Gene', (89, 92))	('IDH1', 'Gene', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('IDH', 'Gene', '3417', (89, 92))	('IDH1', 'Gene', '3417', (89, 93))
186770	26614510	Paul Mazaris and his colleagues demonstrated that none of 31 GBM samples being tested harbored either IDH1 or IDH2 mutation.	('IDH2', 'Gene', '3418', (110, 114))	('harbored', 'Reg', (86, 94))	('IDH1', 'Gene', (102, 106))	('rat', 'Species', '10116', (39, 42))	('IDH1', 'Gene', '3417', (102, 106))	('IDH2', 'Gene', (110, 114))	('mutation', 'Var', (115, 123))
186771	26614510	Furthermore, studies demonstrated that prognostic signature genes that work well in long-term GBM survivors who have IDH mutations have no predictive value in IDH wild-type cases.	('IDH', 'Gene', (159, 162))	('mutations', 'Var', (121, 130))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (159, 162))	('IDH', 'Gene', '3417', (117, 120))	('rat', 'Species', '10116', (28, 31))
186777	26614510	It regulates neurogenesis since the knockout PLCbeta1 gene affects cortical barrel formation in mouse model.	('knockout', 'Var', (36, 44))	('PLCbeta1', 'Gene', (45, 53))	('mouse', 'Species', '10090', (96, 101))	('regulates', 'Reg', (3, 12))	('neurogenesis', 'CPA', (13, 25))	('cortical barrel formation', 'CPA', (67, 92))	('affects', 'Reg', (59, 66))
186784	26614510	1), the presence of PLCbeta1 transcripts are associated with PN subtype GBM from Mes (Figs.	('Mes', 'Chemical', '-', (81, 84))	('PLCbeta1', 'Gene', (20, 28))	('presence', 'Var', (8, 16))	('associated', 'Reg', (45, 55))	('PN subtype GBM', 'Disease', (61, 75))
186787	26614510	Average PLCbeta1 levels from normal tissue controls are significantly higher than those from low-grade tumors and its level is further downregulated in higher grade tumors, including astrocytomas and oligodendrogliomas in GDS1962 (Figs.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Disease', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('higher', 'PosReg', (70, 76))	('oligodendrogliomas', 'Disease', (200, 218))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('astrocytomas', 'Disease', 'MESH:D001254', (183, 195))	('astrocytoma', 'Phenotype', 'HP:0009592', (183, 194))	('downregulated', 'NegReg', (135, 148))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('gliomas', 'Phenotype', 'HP:0009733', (211, 218))	('tumors', 'Disease', (165, 171))	('PLCbeta1', 'Gene', (8, 16))	('GDS1962', 'Var', (222, 229))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (200, 218))	('levels', 'MPA', (17, 23))	('level', 'MPA', (118, 123))	('astrocytomas', 'Disease', (183, 195))
186803	26614510	Interestingly, GBM patients with an oligodendroglial component (n = 57) who survived longer (12 vs. 5.8 months; p = 0.006), comparing to 50 cases of other primary GBM, showed no difference in the frequency of common genetic defects, such as loss of heterozygosity of chromosome 1p/19q, MGMT promoter methylation, or IDH1 mutation.	('mutation', 'Var', (321, 329))	('IDH1', 'Gene', (316, 320))	('patients', 'Species', '9606', (19, 27))	('oligodendroglial component', 'Disease', (36, 62))	('MGMT', 'Gene', '4255', (286, 290))	('loss of heterozygosity', 'Var', (241, 263))	('MGMT', 'Gene', (286, 290))	('IDH1', 'Gene', '3417', (316, 320))	('genetic defects', 'Disease', (216, 231))	('genetic defects', 'Disease', 'MESH:D030342', (216, 231))	('oligodendroglial component', 'Disease', 'MESH:C562869', (36, 62))
186814	26614510	As a result, abnormal PLCbeta1 expression has been studied for its role in neurological diseases extensively such as seizure and epilepsy.	('epilepsy', 'Disease', (129, 137))	('epilepsy', 'Phenotype', 'HP:0001250', (129, 137))	('seizure', 'Phenotype', 'HP:0001250', (117, 124))	('seizure', 'Disease', (117, 124))	('seizure', 'Disease', 'MESH:D012640', (117, 124))	('epilepsy', 'Disease', 'MESH:D004827', (129, 137))	('neurological diseases', 'Disease', 'MESH:D019636', (75, 96))	('abnormal', 'Var', (13, 21))	('PLCbeta1', 'Gene', (22, 30))	('neurological diseases', 'Disease', (75, 96))
186819	26614510	Pathological reports from the Human Protein Atlas show that PLCbeta1 antibodies mainly stain neurons and neuropils in a normal brain without staining glial cells (Fig.	('Human', 'Species', '9606', (30, 35))	('stain', 'Reg', (87, 92))	('PLCbeta1', 'Gene', (60, 68))	('antibodies', 'Var', (69, 79))
186828	26614510	Upon stimuli, PI3K converts PIP2 to phosphatidylinositol 3,4,5-trisphosphate (PIP3), which leads to cascade downstream reaction involving AKT and mTOR.	('mTOR', 'Gene', '2475', (146, 150))	('PIP2', 'Chemical', 'MESH:D019269', (28, 32))	('PIP3', 'Chemical', '-', (78, 82))	('mTOR', 'Gene', (146, 150))	('AKT', 'Gene', (138, 141))	('PI3K', 'Var', (14, 18))	('phosphatidylinositol 3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (36, 76))	('leads to', 'Reg', (91, 99))	('AKT', 'Gene', '207', (138, 141))
186833	26614510	At the protein level, typical ERBB4 signaling in the central nervous system involves downstream PLC and PI3K-AKT activation; cleaved intracellular fragment translocates into nucleus and regulates gene transcription; cleaved ERBB4 protein also plays an important role in regulating the timing of astrogenesis in the developing brain.	('ERBB4', 'Gene', '2066', (30, 35))	('cleaved', 'Var', (216, 223))	('gene transcription', 'MPA', (196, 214))	('PLC', 'Gene', '3339', (96, 99))	('AKT', 'Gene', '207', (109, 112))	('PLC', 'Gene', (96, 99))	('ERBB4', 'Gene', '2066', (224, 229))	('ERBB4', 'Gene', (30, 35))	('astrogenesis', 'CPA', (295, 307))	('regulates', 'Reg', (186, 195))	('AKT', 'Gene', (109, 112))	('ERBB4', 'Gene', (224, 229))
186849	23774303	Fourteen of the 16 genes found to be mutated in this study have been reported to be mutated in other cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutated', 'Var', (37, 44))
186853	23774303	The mutant genes described herein represent novel candidates for the pathogenesis of ovarian SBT.	('ovarian SBT', 'Disease', 'MESH:D010051', (85, 96))	('mutant', 'Var', (4, 10))	('ovarian SBT', 'Disease', (85, 96))
186861	23774303	Type II serous ovarian carcinomas are notable for the ubiquitous nature of TP53 mutations, low but statistically recurrent somatic mutations in nine additional genes, and an average of 61 additional rare somatic mutations per tumor.	('mutations', 'Var', (80, 89))	('Type II serous ovarian carcinomas', 'Disease', 'MESH:D010051', (0, 33))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (15, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('Type II serous ovarian carcinomas', 'Disease', (0, 33))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (15, 33))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('tumor', 'Disease', (226, 231))
186864	23774303	Since the initial observation that SBTs frequently harbor KRAS mutations, subsequent studies have confirmed this observation and further demonstrated that KRAS and BRAF mutations are common in SBTs and low-grade serous carcinomas.	('KRAS', 'Gene', (58, 62))	('mutations', 'Var', (63, 72))	('SBTs', 'Disease', (193, 197))	('KRAS', 'Gene', '3845', (58, 62))	('KRAS', 'Gene', (155, 159))	('mutations', 'Var', (169, 178))	('serous carcinomas', 'Disease', 'MESH:D018284', (212, 229))	('KRAS', 'Gene', '3845', (155, 159))	('serous carcinomas', 'Disease', (212, 229))	('common', 'Reg', (183, 189))	('BRAF', 'Gene', '673', (164, 168))	('BRAF', 'Gene', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))
186866	23774303	Finally, a 12-bp insertion mutation in ERBB2, which ultimately results in KRAS activation, has also been described in a small proportion of SBTs that lack mutations in KRAS or BRAF.	('ERBB2', 'Gene', '2064', (39, 44))	('insertion mutation', 'Var', (17, 35))	('KRAS', 'Gene', '3845', (168, 172))	('KRAS', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (176, 180))	('activation', 'PosReg', (79, 89))	('KRAS', 'Gene', '3845', (74, 78))	('results in', 'Reg', (63, 73))	('KRAS', 'Gene', (168, 172))	('BRAF', 'Gene', (176, 180))	('ERBB2', 'Gene', (39, 44))
186889	23774303	The purpose of this study was to determine the degree to which ovarian SBTs of the ovary are affected by somatic genetic mutations generally, and to identify mutations potentially pathogenic for SBTs as well.	('ovarian SBTs of the ovary', 'Disease', (63, 88))	('mutations', 'Var', (121, 130))	('ovarian SBTs of the ovary', 'Disease', 'MESH:D010049', (63, 88))	('mutations', 'Var', (158, 167))	('affected', 'Reg', (93, 101))
186891	23774303	It is likely that additional genes, including tumor suppressors, play a role in this tumor type; the mutually exclusive alterations observed in BRAF and KRAS are found in only a proportion of SBTs and low-grade serous ovarian carcinomas.	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (218, 236))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (226, 236))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('KRAS', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (144, 148))	('serous ovarian carcinomas', 'Disease', (211, 236))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (218, 235))	('KRAS', 'Gene', '3845', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('SBTs', 'Disease', (192, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('BRAF', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('alterations', 'Var', (120, 131))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (211, 236))
186892	23774303	For those low-grade carcinomas, however, mutational activation of the mitogen-activated protein kinase pathway suggests a potential target-based therapeutic approach.	('carcinomas', 'Disease', (20, 30))	('mitogen-activated protein kinase pathway', 'Pathway', (70, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (20, 30))	('carcinomas', 'Disease', 'MESH:D002277', (20, 30))	('mutational', 'Var', (41, 51))	('activation', 'PosReg', (52, 62))
186896	23774303	Interestingly, the BRAF mutation in tumor SBT-s2 (D594G) is distinct from the common activating mutation in BRAF (V600E), although it occurs in the kinase domain, has been observed in 39 independent tumor specimens listed in the Wellcome Trust Sanger Institute COSMIC (catalogue of somatic mutations in cancer) database, and is functionally classified as a "low-activity BRAF mutation".	('tumor', 'Disease', (36, 41))	('cancer', 'Disease', (303, 309))	('BRAF', 'Gene', '673', (371, 375))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('BRAF', 'Gene', (371, 375))	('BRAF', 'Gene', '673', (108, 112))	('SBT-s2', 'Gene', (42, 48))	('BRAF', 'Gene', (108, 112))	('V600E', 'Mutation', 'rs113488022', (114, 119))	('tumor', 'Disease', (199, 204))	('D594G', 'Mutation', 'rs121913338', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('BRAF', 'Gene', '673', (19, 23))	('D594G', 'Var', (50, 55))	('BRAF', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
186900	23774303	The FBXW7 gene was found to harbor a deleterious nonsense mutation in tumor SBT-s5, and is a well characterized tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('FBXW7', 'Gene', '55294', (4, 9))	('FBXW7', 'Gene', (4, 9))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('nonsense mutation', 'Var', (49, 66))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
186903	23774303	Interestingly, however, the only two ovarian cancers from the TCGA project that are listed in the COSMIC database as having FBXW7 mutations are characteristic of low-grade ovarian carcinomas; tumor TCGA-24-1565 has a BRAF mutation and tumor TCGA-25-1316 has a KRAS mutation, and neither has a mutation in TP53.	('KRAS', 'Gene', '3845', (260, 264))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (172, 190))	('ovarian cancers', 'Phenotype', 'HP:0100615', (37, 52))	('FBXW7', 'Gene', '55294', (124, 129))	('KRAS', 'Gene', (260, 264))	('ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (172, 189))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('TP53', 'Gene', (305, 309))	('tumor', 'Disease', (192, 197))	('low-grade ovarian carcinomas', 'Disease', (162, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('ovarian cancers', 'Disease', (37, 52))	('ovarian cancers', 'Disease', 'MESH:D010051', (37, 52))	('low-grade ovarian carcinomas', 'Disease', 'MESH:D008228', (162, 190))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('FBXW7', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('BRAF', 'Gene', '673', (217, 221))	('tumor', 'Disease', (235, 240))	('mutations', 'Var', (130, 139))	('BRAF', 'Gene', (217, 221))	('TP53', 'Gene', '7157', (305, 309))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
186904	23774303	The presence of mutant FBXW7 in SBT-s5 suggests that this mutation may represent an early event in the pathogenic progression of SBT to low-grade serous carcinoma.	('FBXW7', 'Gene', (23, 28))	('serous carcinoma', 'Disease', 'MESH:D018284', (146, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('SBT-s5', 'Gene', (32, 38))	('mutant', 'Var', (16, 22))	('FBXW7', 'Gene', '55294', (23, 28))	('SBT', 'Disease', (129, 132))	('serous carcinoma', 'Disease', (146, 162))
186905	23774303	Furthermore, these observations raise the intriguing possibility that loss of FBXW7 function in low-grade serous tumorigenesis would lead to increased Notch signaling (as described above), a phenomenon associated with platinum resistance and characteristic of low-grade serous tumors.	('tumor', 'Disease', (113, 118))	('FBXW7', 'Gene', (78, 83))	('loss', 'Var', (70, 74))	('increased', 'PosReg', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('serous tumors', 'Disease', 'MESH:D018284', (270, 283))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('serous tumors', 'Disease', (270, 283))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (277, 282))	('Notch signaling', 'MPA', (151, 166))	('FBXW7', 'Gene', '55294', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
186906	23774303	Targeting Notch may therefore represent a novel therapeutic opportunity for low-grade serous ovarian tumors.	('serous ovarian tumors', 'Disease', (86, 107))	('ovarian tumors', 'Phenotype', 'HP:0100615', (93, 107))	('Notch', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian tumor', 'Phenotype', 'HP:0100615', (93, 106))	('Targeting', 'Var', (0, 9))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (86, 107))
186907	23774303	The KIAA1462 gene, which contains a deleterious 4-bp deletion in tumor SBT-s5, is widely expressed and evolutionarily conserved.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('deletion', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('KIAA1462', 'Gene', '57608', (4, 12))	('KIAA1462', 'Gene', (4, 12))
186909	23774303	Three additional TCGA ovarian tumors with KIAA1462 mutations, two of which are also potentially deleterious, are listed in the COSMIC database, implying a tumor suppressor function for this protein.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('KIAA1462', 'Gene', (42, 50))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ovarian tumor', 'Phenotype', 'HP:0100615', (22, 35))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('ovarian tumors', 'Disease', (22, 36))	('ovarian tumors', 'Phenotype', 'HP:0100615', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ovarian tumors', 'Disease', 'MESH:D010051', (22, 36))	('tumor', 'Disease', (30, 35))	('KIAA1462', 'Gene', '57608', (42, 50))
186910	23774303	Two of these tumors (one of which is TCGA-24-1565) are wild-type for TP53, again suggesting that inactivation of KIAA1462 may play a role in the pathogenesis of type I ovarian tumors.	('ovarian tumors', 'Phenotype', 'HP:0100615', (168, 182))	('type I ovarian tumors', 'Disease', 'MESH:D010051', (161, 182))	('TP53', 'Gene', (69, 73))	('KIAA1462', 'Gene', '57608', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('role', 'Reg', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('play', 'Reg', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('type I ovarian tumors', 'Disease', (161, 182))	('tumors', 'Disease', (13, 19))	('TP53', 'Gene', '7157', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('inactivation', 'Var', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (176, 182))	('KIAA1462', 'Gene', (113, 121))	('ovarian tumor', 'Phenotype', 'HP:0100615', (168, 181))
186911	23774303	Of the additional genes with somatic missense mutations in tumor SBT-s5 (other than BRAF), NCCRP1 (non-specific cytotoxic cell receptor protein 1 homolog) is also mutated in a TCGA ovarian cancer with mutant TP53, as is OXGR1 (oxoglutarate receptor 1), which is mutated in a melanoma sample as well.	('oxoglutarate receptor 1', 'Gene', '27199', (227, 250))	('tumor', 'Disease', (59, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('mutant', 'Var', (201, 207))	('TP53', 'Gene', '7157', (208, 212))	('NCCRP1', 'Gene', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('OXGR1', 'Gene', (220, 225))	('mutated', 'Var', (163, 170))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('melanoma', 'Disease', (275, 283))	('missense mutations', 'Var', (37, 55))	('oxoglutarate receptor 1', 'Gene', (227, 250))	('BRAF', 'Gene', '673', (84, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (181, 195))	('OXGR1', 'Gene', '27199', (220, 225))	('BRAF', 'Gene', (84, 88))	('TP53', 'Gene', (208, 212))	('NCCRP1', 'Gene', '342897', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('ovarian cancer', 'Disease', (181, 195))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))
186913	23774303	With respect to tumor BST-s2, there was the unusual finding of an activating BRAF mutation together with an activating mutation in codon 61 of the HRAS gene (Table 1).	('HRAS', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mutation', 'Var', (82, 90))	('BRAF', 'Gene', '673', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BRAF', 'Gene', (77, 81))	('activating', 'PosReg', (66, 76))	('tumor', 'Disease', (16, 21))	('HRAS', 'Gene', '3265', (147, 151))
186914	23774303	Mutations in HRAS are common in skin and thyroid tumors but have not been described in ovarian cancers, and as noted before, mutations in BRAF and KRAS are mutually exclusive in SBTs and low grade ovarian cancers.	('HRAS', 'Gene', (13, 17))	('skin', 'Disease', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('common', 'Reg', (22, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (197, 211))	('KRAS', 'Gene', (147, 151))	('ovarian cancers', 'Disease', (87, 102))	('ovarian cancers', 'Disease', 'MESH:D010051', (87, 102))	('ovarian cancers', 'Disease', (197, 212))	('ovarian cancers', 'Disease', 'MESH:D010051', (197, 212))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('skin', 'Disease', 'MESH:D012871', (32, 36))	('thyroid tumors', 'Disease', 'MESH:D013959', (41, 55))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('SBTs', 'Disease', (178, 182))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('ovarian cancers', 'Phenotype', 'HP:0100615', (87, 102))	('ovarian cancers', 'Phenotype', 'HP:0100615', (197, 212))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('thyroid tumors', 'Disease', (41, 55))	('HRAS', 'Gene', '3265', (13, 17))	('KRAS', 'Gene', '3845', (147, 151))
186915	23774303	Of the remaining eight genes mutated in this tumor, six have been reported to be mutated in ovarian cancers.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ovarian cancers', 'Phenotype', 'HP:0100615', (92, 107))	('ovarian cancers', 'Disease', (92, 107))	('tumor', 'Disease', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ovarian cancers', 'Disease', 'MESH:D010051', (92, 107))	('mutated', 'Var', (29, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
186916	23774303	The PEAR1 gene (platelet endothelial aggregation receptor 1) sustained a 15-bp deletion and has been reported as mutated in two ovarian cancers from the TCGA project, one of which is a splice-site mutation.	('ovarian cancers', 'Disease', 'MESH:D010051', (128, 143))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PEAR1', 'Gene', '375033', (4, 9))	('platelet endothelial aggregation receptor 1', 'Gene', '375033', (16, 59))	('PEAR1', 'Gene', (4, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('platelet endothelial aggregation receptor 1', 'Gene', (16, 59))	('mutated', 'Var', (113, 120))	('ovarian cancers', 'Phenotype', 'HP:0100615', (128, 143))	('ovarian cancers', 'Disease', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
186917	23774303	Remarkably, this same tumor (TCGA-24-1565) contains mutations in PEAR1, KIAA1462, FBXW7, and BRAF, four of the genes reported as mutated in one or another of the two tumors in this study.	('mutations', 'Var', (52, 61))	('BRAF', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('KIAA1462', 'Gene', '57608', (72, 80))	('FBXW7', 'Gene', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KIAA1462', 'Gene', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PEAR1', 'Gene', '375033', (65, 70))	('PEAR1', 'Gene', (65, 70))	('tumor', 'Disease', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('FBXW7', 'Gene', '55294', (82, 87))	('tumors', 'Disease', (166, 172))	('BRAF', 'Gene', '673', (93, 97))
186921	23774303	Somatic missense mutations of the DST gene (dystonin) gene are reported in five high grade serous carcinomas in the TCGA database.	('serous carcinomas', 'Disease', (91, 108))	('reported', 'Reg', (63, 71))	('DST', 'Gene', '667', (34, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('DST', 'Gene', (34, 37))	('dystonin', 'Gene', (44, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('serous carcinomas', 'Disease', 'MESH:D018284', (91, 108))	('missense mutations', 'Var', (8, 26))
186922	23774303	Six additional mutations are described in melanomas.	('mutations', 'Var', (15, 24))	('melanomas', 'Disease', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('melanomas', 'Disease', 'MESH:D008545', (42, 51))
186924	23774303	The UBR2 gene (ubiquitin-protein ligase E3 component N-recognin 2) is mutated in two ovarian cancers from the TCGA database, as well as a pancreatic cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('pancreatic cancer', 'Disease', (138, 155))	('UBR2', 'Gene', '23304', (4, 8))	('ubiquitin-protein ligase E3 component N-recognin 2', 'Gene', (15, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('ovarian cancers', 'Phenotype', 'HP:0100615', (85, 100))	('ovarian cancers', 'Disease', (85, 100))	('ovarian cancers', 'Disease', 'MESH:D010051', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('UBR2', 'Gene', (4, 8))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('mutated', 'Var', (70, 77))	('ubiquitin-protein ligase E3 component N-recognin 2', 'Gene', '23304', (15, 65))
186925	23774303	The HAUS6 gene is also mutated in two ovarian cancers from the TCGA database, one of which is wild-type for TP53.	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('HAUS6', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('ovarian cancers', 'Phenotype', 'HP:0100615', (38, 53))	('ovarian cancers', 'Disease', (38, 53))	('mutated', 'Var', (23, 30))	('ovarian cancers', 'Disease', 'MESH:D010051', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HAUS6', 'Gene', '54801', (4, 9))
186927	23774303	Finally, mutation of the FOXRED2 gene (FAD-dependent oxidoreductase domain containing 2) has not been reported for ovarian carcinoma, but one mutation each has been described in a kidny and lung tumor.	('mutation', 'Var', (9, 17))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (115, 132))	('lung tumor', 'Disease', 'MESH:D008175', (190, 200))	('lung tumor', 'Disease', (190, 200))	('ovarian carcinoma', 'Disease', (115, 132))	('lung tumor', 'Phenotype', 'HP:0100526', (190, 200))	('FOXRED2', 'Gene', '80020', (25, 32))	('FOXRED2', 'Gene', (25, 32))	('FAD-dependent oxidoreductase domain containing 2', 'Gene', '80020', (39, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('FAD-dependent oxidoreductase domain containing 2', 'Gene', (39, 87))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (115, 132))
186930	23774303	As might be expected, low grade serous invasive carcinomas have a DNA content and level of copy number alterations that more closely resembles SBTs than high grade serous tumors, but which are intermediate between the two.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('low', 'Disease', (22, 25))	('invasive carcinomas', 'Disease', (39, 58))	('SBTs', 'Disease', (143, 147))	('serous tumors', 'Disease', 'MESH:D018284', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('copy number alterations', 'Var', (91, 114))	('serous tumors', 'Disease', (164, 177))	('invasive carcinomas', 'Disease', 'MESH:D009361', (39, 58))
186932	23774303	Although it is challenging to predict the functional relevance of a specific genetic mutation to SBTs without the appropriate functional studies, the mutations found in FBXW7 and KIAA1462 render them compelling candidate genes.	('FBXW7', 'Gene', '55294', (169, 174))	('mutations', 'Var', (150, 159))	('KIAA1462', 'Gene', '57608', (179, 187))	('KIAA1462', 'Gene', (179, 187))	('FBXW7', 'Gene', (169, 174))
186933	23774303	Both sustain clear loss of function mutations, one is a well established tumor suppressor gene (FBXW7), and mutations in both are observed in ovarian tumors that are likely to be low grade serous carcinomas.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('FBXW7', 'Gene', (96, 101))	('loss of function', 'NegReg', (19, 35))	('ovarian tumors', 'Phenotype', 'HP:0100615', (142, 156))	('serous carcinomas', 'Disease', (189, 206))	('FBXW7', 'Gene', '55294', (96, 101))	('tumor', 'Disease', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('tumor', 'Disease', (150, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('ovarian tumors', 'Disease', (142, 156))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('serous carcinomas', 'Disease', 'MESH:D018284', (189, 206))	('mutations', 'Var', (108, 117))	('ovarian tumors', 'Disease', 'MESH:D010051', (142, 156))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('ovarian tumor', 'Phenotype', 'HP:0100615', (142, 155))
186935	23863747	Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2 Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS).	('cancers', 'Disease', (28, 35))	('Isocitrate dehydrogenase', 'Gene', '3417', (87, 111))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (235, 249))	('EBF1', 'Gene', (47, 51))	('Isocitrate dehydrogenase', 'Gene', (87, 111))	('CC', 'Phenotype', 'HP:0030153', (227, 229))	('AML', 'Disease', 'MESH:D015470', (183, 186))	('IDH', 'Gene', '3417', (113, 116))	('IDH', 'Gene', '3417', (17, 20))	('AML', 'Phenotype', 'HP:0004808', (183, 186))	('AML', 'Disease', (183, 186))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (158, 181))	('glioma', 'Disease', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('mutated', 'Var', (147, 154))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (164, 181))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (158, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (207, 225))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('cholangiocarcinoma', 'Disease', (207, 225))	('chondrosarcoma', 'Disease', 'MESH:D002813', (235, 249))	('CS', 'Phenotype', 'HP:0006765', (251, 253))	('chondrosarcoma', 'Disease', (235, 249))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (207, 225))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('acute myeloid leukaemia', 'Disease', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('EBF1', 'Gene', '1879', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('IDH', 'Gene', (113, 116))	('IDH', 'Gene', (17, 20))
186936	23863747	For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers.	('AML', 'Disease', (4, 7))	('IDH', 'Gene', (41, 44))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('IDH', 'Gene', '3417', (41, 44))	('associated', 'Reg', (55, 65))	('glioma', 'Disease', (19, 25))	('AML', 'Disease', 'MESH:D015470', (4, 7))	('CC', 'Phenotype', 'HP:0030153', (30, 32))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('DNA hypermethylation phenotype', 'MPA', (73, 103))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('mutant', 'Var', (34, 40))	('AML', 'Phenotype', 'HP:0004808', (4, 7))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
186937	23863747	Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation.	('TET', 'Chemical', 'MESH:C010349', (251, 254))	('increased', 'PosReg', (107, 116))	('CS', 'Phenotype', 'HP:0006765', (38, 40))	('IDH', 'Gene', (200, 203))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', '3417', (200, 203))	('IDH', 'Gene', '3417', (22, 25))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (150, 168))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (213, 231))	('hypermethylation phenotype', 'MPA', (68, 94))	('variants', 'Var', (26, 34))
186940	23863747	Cancer-associated mutations in isocitrate dehydrogenase are proposed to impair TET2-dependent DNA demethylation.	('TET2', 'Gene', (79, 83))	('mutations', 'Var', (18, 27))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('impair', 'NegReg', (72, 78))	('isocitrate dehydrogenase', 'Gene', (31, 55))	('TET2', 'Gene', '54790', (79, 83))	('isocitrate dehydrogenase', 'Gene', '3417', (31, 55))
186945	23863747	In this setting, the mosaic distribution of tumours is caused by somatic early post-zygotic mutations of IDH1 and IDH2 (ref.).	('IDH2', 'Gene', (114, 118))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('caused by', 'Reg', (55, 64))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('IDH1', 'Gene', (105, 109))	('IDH2', 'Gene', '3418', (114, 118))	('tumours', 'Disease', (44, 51))	('mutations', 'Var', (92, 101))	('IDH1', 'Gene', '3417', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
186946	23863747	The same mutations have been previously identified in ~70% of sporadic high-grade gliomas and secondary glioblastomas, ~10% of acute myeloid leukemias (AMLs) and cholangiocarcinomas (CCs), and much less commonly in other neoplasms.	('mutations', 'Var', (9, 18))	('neoplasms', 'Disease', 'MESH:D009369', (221, 230))	('AMLs', 'Phenotype', 'HP:0004808', (152, 156))	('AML', 'Disease', 'MESH:D015470', (152, 155))	('glioblastomas', 'Disease', 'MESH:D005909', (104, 117))	('leukemias', 'Phenotype', 'HP:0001909', (141, 150))	('AML', 'Disease', (152, 155))	('AML', 'Phenotype', 'HP:0004808', (152, 155))	('neoplasms', 'Disease', (221, 230))	('gliomas', 'Disease', (82, 89))	('identified', 'Reg', (40, 50))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (127, 150))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (133, 150))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('glioblastomas', 'Phenotype', 'HP:0012174', (104, 117))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (127, 150))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (162, 181))	('acute myeloid leukemias', 'Disease', (127, 150))	('neoplasms', 'Phenotype', 'HP:0002664', (221, 230))	('CC', 'Phenotype', 'HP:0030153', (183, 185))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('cholangiocarcinomas', 'Disease', (162, 181))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (162, 180))	('glioblastomas', 'Disease', (104, 117))
186947	23863747	The mutant (mt) IDH enzyme catalyses the reduction of alpha-ketoglutarate (alpha-KG) to D-2-hydroxyglutarate (2-HG), an oncometabolite affecting the activity of alpha-KG-dependent dioxygenases: these events affect a number of cellular responses, and have been shown to induce CpG island DNA hypermethylation in low-grade gliomas (LGGs), CCs and AMLs harbouring IDH1 and IDH2 mutations.	('AML', 'Disease', 'MESH:D015470', (345, 348))	('IDH', 'Gene', '3417', (370, 373))	('mutant', 'Var', (4, 10))	('mutations', 'Var', (375, 384))	('AML', 'Disease', (345, 348))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (54, 73))	('gliomas', 'Disease', (321, 328))	('IDH', 'Gene', (16, 19))	('AML', 'Phenotype', 'HP:0004808', (345, 348))	('IDH1', 'Gene', '3417', (361, 365))	('IDH', 'Gene', '3417', (361, 364))	('CC', 'Phenotype', 'HP:0030153', (337, 339))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (90, 108))	('gliomas', 'Disease', 'MESH:D005910', (321, 328))	('cellular responses', 'CPA', (226, 244))	('alpha-KG', 'Chemical', 'MESH:D007656', (75, 83))	('IDH2', 'Gene', (370, 374))	('alpha-KG', 'Chemical', 'MESH:D007656', (161, 169))	('IDH', 'Gene', '3417', (16, 19))	('glioma', 'Phenotype', 'HP:0009733', (321, 327))	('IDH2', 'Gene', '3418', (370, 374))	('induce', 'Reg', (269, 275))	('gliomas', 'Phenotype', 'HP:0009733', (321, 328))	('IDH', 'Gene', (370, 373))	('IDH1', 'Gene', (361, 365))	('IDH', 'Gene', (361, 364))	('affect', 'Reg', (207, 213))	('AMLs', 'Phenotype', 'HP:0004808', (345, 349))	('CpG', 'Var', (276, 279))
186949	23863747	The evidence supporting the concept that the IDH1 and IDH2 mutations occur early in the genesis of these IDH-mt tumours suggests that the different neoplasms share a major regulatory effector.	('IDH1', 'Gene', '3417', (45, 49))	('IDH2', 'Gene', (54, 58))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('neoplasms', 'Disease', (148, 157))	('IDH2', 'Gene', '3418', (54, 58))	('neoplasms', 'Disease', 'MESH:D009369', (148, 157))	('IDH-mt tumours', 'Disease', (105, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (59, 68))	('IDH-mt tumours', 'Disease', 'MESH:D009369', (105, 119))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))	('IDH1', 'Gene', (45, 49))
186951	23863747	To investigate the effects of IDH1 and IDH2 mutations on the CS methylome, we conducted genome-wide DNA methylation (DNAm) profiling of 44 central CS tumour samples using the Illumina Infinium 450 K BeadChips.	('CS', 'Phenotype', 'HP:0006765', (61, 63))	('IDH2', 'Gene', (39, 43))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (150, 156))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', '3418', (39, 43))	('CS', 'Phenotype', 'HP:0006765', (147, 149))	('mutations', 'Var', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('IDH1', 'Gene', '3417', (30, 34))
186960	23863747	Moreover, of the 3,057 MVPs between mt and wt CS, 99.5% (3,042/3,057) were hyper-MVPs in the mt group relative to the wt group, thereby revealing a strong hypermethylation phenotype associated with mutation(s) in the IDH genes in central CS (Fig.	('CS', 'Phenotype', 'HP:0006765', (46, 48))	('IDH', 'Gene', (217, 220))	('IDH', 'Gene', '3417', (217, 220))	('central CS', 'Disease', (230, 240))	('hypermethylation', 'MPA', (155, 171))	('CS', 'Phenotype', 'HP:0006765', (238, 240))	('mutation', 'Var', (198, 206))
186961	23863747	DNA methylation profiles of tumours with IDH mutations have also been studied in the context of three other malignancies: AML, LGG and CC.	('IDH', 'Gene', (41, 44))	('LGG', 'Disease', (127, 130))	('mutations', 'Var', (45, 54))	('CC', 'Phenotype', 'HP:0030153', (135, 137))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('IDH', 'Gene', '3417', (41, 44))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('malignancies', 'Disease', (108, 120))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('AML', 'Disease', (122, 125))
186963	23863747	To determine whether this particular mechanism affects shared pathways and/or tissue-specific processes in each cancer type, we performed a meta-analysis using publically available methylation profiles from AML, LGG and CC (accession codes GSE24505, GSE30339 and GSE32286, respectively) and our own CS data (GSE40853).	('GSE30339', 'Var', (250, 258))	('AML', 'Disease', 'MESH:D015470', (207, 210))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('affects', 'Reg', (47, 54))	('GSE24505', 'Var', (240, 248))	('AML', 'Phenotype', 'HP:0004808', (207, 210))	('AML', 'Disease', (207, 210))	('GSE32286', 'Var', (263, 271))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CS', 'Phenotype', 'HP:0006765', (299, 301))	('CC', 'Phenotype', 'HP:0030153', (220, 222))
186968	23863747	Retinol-binding protein 1, for example, was differentially methylated in CS, LGG and CC, and found in our cohort to display significant hypermethylation in the promoter region and downregulation of gene expression (Supplementary Fig.	('CS', 'Phenotype', 'HP:0006765', (73, 75))	('gene expression', 'MPA', (198, 213))	('CC', 'Phenotype', 'HP:0030153', (85, 87))	('Retinol-binding protein 1', 'Gene', (0, 25))	('LGG', 'Disease', (77, 80))	('Retinol-binding protein 1', 'Gene', '5947', (0, 25))	('hypermethylation', 'Var', (136, 152))	('downregulation', 'NegReg', (180, 194))
186989	23863747	The effects of gain-of-function mutations in the IDH1/2 enzymes on the methylome have been extensively studied in the context of AML and LGG, and more recently in CC.	('CC', 'Phenotype', 'HP:0030153', (163, 165))	('gain-of-function', 'PosReg', (15, 31))	('IDH1', 'Gene', '3417', (49, 53))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('AML', 'Phenotype', 'HP:0004808', (129, 132))	('mutations', 'Var', (32, 41))	('AML', 'Disease', (129, 132))	('methylome', 'MPA', (71, 80))	('IDH1', 'Gene', (49, 53))	('LGG', 'Disease', (137, 140))
186990	23863747	Here, we report methylation profiling data supporting a similar mechanism in central CS, where specific IDH mutations are correlated with increased levels of the 2-HG oncometabolite compared with wt tumours, and a widespread hypermethylation phenotype.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('increased', 'PosReg', (138, 147))	('IDH', 'Gene', (104, 107))	('central CS', 'Disease', (77, 87))	('mutations', 'Var', (108, 117))	('levels of the 2-HG oncometabolite', 'MPA', (148, 181))	('CS', 'Phenotype', 'HP:0006765', (85, 87))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('IDH', 'Gene', '3417', (104, 107))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))
186991	23863747	While many epigenetic effector proteins, such as DNA methyl-transferases or histone deacetylases, are known to be mutated in human cancers, thus directly affecting tumour development, the indirect inhibition of demethylation via IDH mutation suggests a new role for metabolism in the regulation of the epigenome.	('demethylation', 'MPA', (211, 224))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', (131, 138))	('inhibition', 'NegReg', (197, 207))	('affecting', 'Reg', (154, 163))	('human', 'Species', '9606', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutation', 'Var', (233, 241))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('IDH', 'Gene', (229, 232))	('tumour', 'Disease', (164, 170))	('IDH', 'Gene', '3417', (229, 232))
186992	23863747	Although inhibition of TET enzymes is likely to be the main mechanism by which IDH mutations are linked to DNA hypermethylation in the cancers studied here, it is noteworthy that 2-HG accumulation also affects other dioxygenases, such as histone demethylases and prolyl hydroxylases, which could contribute to the observed phenotype.	('mutations', 'Var', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('IDH', 'Gene', (79, 82))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('IDH', 'Gene', '3417', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('histone demethylases', 'Enzyme', (238, 258))	('affects', 'Reg', (202, 209))	('prolyl hydroxylases', 'Enzyme', (263, 282))	('dioxygenases', 'Enzyme', (216, 228))	('TET', 'Chemical', 'MESH:C010349', (23, 26))
186993	23863747	It is also important to note that although mutations in TET genes are frequently found in AML without IDH1/2 mutations, they are extremely rare in CS and therefore such mutations are unlikely to account for a common pathogenic alternative to IDH mutation in this cancer.	('IDH', 'Gene', '3417', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('AML', 'Phenotype', 'HP:0004808', (90, 93))	('AML', 'Disease', (90, 93))	('cancer', 'Disease', (263, 269))	('TET genes', 'Gene', (56, 65))	('found', 'Reg', (81, 86))	('IDH1', 'Gene', (102, 106))	('IDH', 'Gene', (242, 245))	('mutations', 'Var', (43, 52))	('TET', 'Chemical', 'MESH:C010349', (56, 59))	('CS', 'Phenotype', 'HP:0006765', (147, 149))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('AML', 'Disease', 'MESH:D015470', (90, 93))	('IDH1', 'Gene', '3417', (102, 106))	('IDH', 'Gene', '3417', (242, 245))	('IDH', 'Gene', (102, 105))
186994	23863747	A separate study has revealed that of 90 CS analysed by either exome sequencing or a more targeted approach, only one tumour was found to contain a TET2 mutation.	('tumour', 'Disease', (118, 124))	('TET2', 'Gene', (148, 152))	('CS', 'Phenotype', 'HP:0006765', (41, 43))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('mutation', 'Var', (153, 161))	('TET2', 'Gene', '54790', (148, 152))
186996	23863747	This is supported by the fact that in LGG, where IDH mutations occur at the even higher frequency of 70-80%, no functional TET2 mutations have been reported.	('LGG', 'Disease', (38, 41))	('IDH', 'Gene', (49, 52))	('TET2', 'Gene', '54790', (123, 127))	('IDH', 'Gene', '3417', (49, 52))	('mutations', 'Var', (53, 62))	('TET2', 'Gene', (123, 127))
186997	23863747	The shared IDH mutation-correlated hypermethylation phenotype in AML, LGG, CC and now also in CS suggests that the same biological processes are likely to be affected in all four cancer types.	('hypermethylation', 'Var', (35, 51))	('AML', 'Disease', (65, 68))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('AML', 'Phenotype', 'HP:0004808', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('CC', 'Phenotype', 'HP:0030153', (75, 77))	('affected', 'Reg', (158, 166))	('LGG', 'Disease', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('CS', 'Phenotype', 'HP:0006765', (94, 96))	('cancer', 'Disease', (179, 185))	('mutation-correlated', 'Reg', (15, 34))
187000	23863747	Finally, Retinol-binding protein 1, a downstream target of RAR, has recently been shown to become hypermethylated following knock-in of a mt IDH1 gene into a cancer cell line and we have confirmed hypermethylation of the Retinol-binding protein 1 promoter and associated downregulation of gene expression in IDH mt CS.	('Retinol-binding protein 1', 'Gene', (9, 34))	('RAR', 'Gene', (59, 62))	('Retinol-binding protein 1', 'Gene', (221, 246))	('IDH', 'Gene', (141, 144))	('Retinol-binding protein 1', 'Gene', '5947', (9, 34))	('hypermethylation', 'Var', (197, 213))	('cancer', 'Disease', (158, 164))	('IDH', 'Gene', (308, 311))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('IDH1', 'Gene', (141, 145))	('Retinol-binding protein 1', 'Gene', '5947', (221, 246))	('CS', 'Phenotype', 'HP:0006765', (315, 317))	('IDH', 'Gene', '3417', (141, 144))	('RAR', 'Gene', '5914', (59, 62))	('gene expression', 'MPA', (289, 304))	('IDH', 'Gene', '3417', (308, 311))	('IDH1', 'Gene', '3417', (141, 145))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('downregulation', 'NegReg', (271, 285))
187001	23863747	As TET is a key enzyme in the active demethylation pathway, it can be expected (at least in healthy cells) to be under tissue-specific regulation, and disruption of its function in cancer cells should therefore result in patterns of hypermethylation unique to its cell type of origin.	('TET', 'Chemical', 'MESH:C010349', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('result in', 'Reg', (211, 220))	('hypermethylation', 'MPA', (233, 249))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('disruption', 'Var', (151, 161))	('cancer', 'Disease', (181, 187))
187009	23863747	IDH mutations were tested and validated by at least 2 of the following techniques including Sequenom MassARRAY, capillary sequencing, exome sequencing and a custom-made Taqman array.	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))
187054	23077581	And GBM samples with IDH1 mutation were detected as previously report.	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('IDH1', 'Gene', '3417', (21, 25))	('IDH1', 'Gene', (21, 25))	('mutation', 'Var', (26, 34))
187071	23077581	High KIF23 expression was defined as a staining score >4, while low expression was defined as a staining score <=4.	('expression', 'MPA', (11, 21))	('KIF23', 'Gene', (5, 10))	('KIF23', 'Gene', '9493', (5, 10))	('High', 'Var', (0, 4))
187080	23077581	Karnofsky performance status (KPS), extent of resection, and IDH1 mutation were incorporated into a Cox multivariate analysis.	('Cox', 'Gene', '1351', (100, 103))	('Cox', 'Gene', (100, 103))	('IDH1', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('IDH1', 'Gene', '3417', (61, 65))
187089	23077581	High levels of miR-328 expression was a "protective" factor in GBM (p<0.01, HR = 0.46, 95%CI = 0.27-0.79).	('GBM', 'Disease', (63, 66))	('miR-328', 'Gene', (15, 22))	('High levels', 'Var', (0, 11))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('miR-328', 'Gene', '442901', (15, 22))
187090	23077581	Next, we performed multivariate Cox proportional hazards analysis incorporating miR-328 expression, KPS, IDH1 mutation and extent of resection.	('miR-328', 'Gene', (80, 87))	('IDH1', 'Gene', (105, 109))	('KPS', 'Gene', (100, 103))	('IDH1', 'Gene', '3417', (105, 109))	('mutation', 'Var', (110, 118))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))	('miR-328', 'Gene', '442901', (80, 87))
187101	23077581	3, cell growth was significantly suppressed by miR-328 mimics and the maximum inhibition rate was 48 h after transfection.	('miR-328', 'Gene', '442901', (47, 54))	('cell growth', 'CPA', (3, 14))	('mimics', 'Var', (55, 61))	('miR-328', 'Gene', (47, 54))	('suppressed', 'NegReg', (33, 43))
187102	23077581	The clonogenic assay showed that miR-328 mimics significantly inhibited the formation of cell clones.	('mimics', 'Var', (41, 47))	('miR-328', 'Gene', (33, 40))	('formation of cell clones', 'CPA', (76, 100))	('inhibited', 'NegReg', (62, 71))	('miR-328', 'Gene', '442901', (33, 40))
187105	23077581	In glioma, down-regulation of KIF23 could suppress glioma proliferation both in vivo and in vitro, and glioma patients with high levels of KIF23 expression also tend to show poorer prognosis compared with patients with low KIF23 expression.	('patients', 'Species', '9606', (205, 213))	('glioma', 'Disease', (3, 9))	('suppress', 'NegReg', (42, 50))	('KIF23', 'Gene', (30, 35))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('KIF23', 'Gene', '9493', (223, 228))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Disease', (103, 109))	('high', 'Var', (124, 128))	('KIF23', 'Gene', (139, 144))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('down-regulation', 'NegReg', (11, 26))	('KIF23', 'Gene', '9493', (30, 35))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('KIF23', 'Gene', (223, 228))	('KIF23', 'Gene', '9493', (139, 144))	('patients', 'Species', '9606', (110, 118))
187124	23077581	IDH1 mutation, KPS, extent of resection and miR-328 expression were subjected to multivariate Cox proportional hazards analysis, which showed that miR-328 could be used as an independent prognostic biomarker for GBM.	('GBM', 'Disease', (212, 215))	('miR-328', 'Gene', '442901', (147, 154))	('Cox', 'Gene', '1351', (94, 97))	('miR-328', 'Gene', (44, 51))	('GBM', 'Phenotype', 'HP:0012174', (212, 215))	('miR-328', 'Gene', (147, 154))	('Cox', 'Gene', (94, 97))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('miR-328', 'Gene', '442901', (44, 51))	('IDH1', 'Gene', '3417', (0, 4))
187130	23077581	In vitro functional analysis showed that ectopic miR-328 expression significantly suppressed U87MG cells proliferation.	('suppressed', 'NegReg', (82, 92))	('ectopic', 'Var', (41, 48))	('miR-328', 'Gene', '442901', (49, 56))	('U87MG cells proliferation', 'CPA', (93, 118))	('miR-328', 'Gene', (49, 56))	('U87MG', 'CellLine', 'CVCL:0022', (93, 98))
187134	23077581	We also show that miR-328 is closely related to cell cycle progression; ectopic miR-328 expression in GBM cells could significantly suppress cell proliferation.	('miR-328', 'Gene', (80, 87))	('suppress', 'NegReg', (132, 140))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('cell proliferation', 'CPA', (141, 159))	('ectopic', 'Var', (72, 79))	('miR-328', 'Gene', '442901', (18, 25))	('miR-328', 'Gene', '442901', (80, 87))	('miR-328', 'Gene', (18, 25))
187137	33553421	Qualitative and Quantitative MRI Analysis in IDH1 Genotype Prediction of Lower-Grade Gliomas: A Machine Learning Approach Preoperative prediction of isocitrate dehydrogenase 1 (IDH1) mutation in lower-grade gliomas (LGGs) is crucial for clinical decision-making.	('isocitrate dehydrogenase 1', 'Gene', (149, 175))	('isocitrate dehydrogenase 1', 'Gene', '3417', (149, 175))	('IDH1', 'Gene', (177, 181))	('Gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('IDH', 'Gene', '3417', (177, 180))	('Gliomas', 'Disease', (85, 92))	('mutation', 'Var', (183, 191))	('IDH1', 'Gene', '3417', (177, 181))	('IDH1', 'Gene', (45, 49))	('IDH', 'Gene', (45, 48))	('gliomas', 'Disease', (207, 214))	('glioma', 'Disease', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('IDH1', 'Gene', '3417', (45, 49))	('gliomas', 'Disease', 'MESH:D005910', (207, 214))	('IDH', 'Gene', '3417', (45, 48))	('IDH', 'Gene', (177, 180))	('Gliomas', 'Disease', 'MESH:D005910', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))
187144	33553421	Patients with an IDH-mutated glioma have a longer survival duration than those with an IDH-wildtype tumor.	('longer', 'PosReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('glioma', 'Disease', (29, 35))	('survival', 'MPA', (50, 58))	('Patients', 'Species', '9606', (0, 8))	('IDH-mutated', 'Var', (17, 28))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('Patient', 'Species', '9606', (0, 7))
187145	33553421	The inclusion criteria for the study patients were as follows: (a) histologically proven LGG; (b) available IDH1 mutation records; (c) complete preoperative MRI data including native T1- and T2-weighted imaging (T1W and T2W); T2 fluid attenuation inversion recovery (FLAIR), DWI, and postcontrast T1W; and (d) sufficient image quality.	('mutation', 'Var', (113, 121))	('DWI', 'MPA', (275, 278))	('T2 fluid', 'MPA', (226, 234))	('native T1- and', 'MPA', (176, 190))	('IDH1', 'Gene', (108, 112))	('LGG', 'Disease', (89, 92))	('T2W', 'Mutation', 'p.T2W', (220, 223))
187154	33147752	Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype In the present work we have confirmed that gliomas with isocitrate dehydrogenase 1/2 mutations are "cold" tumors, whereas the immune content of their wild-type counterparts is more heterogeneous.	('Gliomas', 'Disease', (20, 27))	('Tau', 'Gene', '4137', (72, 75))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('IDH1/2', 'Gene', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('mutations', 'Var', (197, 206))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('Tau', 'Gene', (72, 75))	('Gliomas', 'Disease', 'MESH:D005910', (20, 27))	('Gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (155, 162))	('IDH1/2', 'Gene', '3417;3418', (54, 60))	('tumors', 'Disease', (218, 224))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
187161	33147752	Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IDH1/2', 'Gene', (53, 59))	('mutations', 'Var', (61, 70))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
187164	33147752	Results: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH1/2', 'Gene', (61, 67))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('mutant', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
187165	33147752	Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile.	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('IDH1/2', 'Gene', (166, 172))	('gliomas', 'Disease', (173, 180))	('mutant', 'Var', (159, 165))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))
187168	33147752	Conclusions: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas.	('reduced', 'NegReg', (35, 42))	('infiltration', 'MPA', (43, 55))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('IDH1/2', 'Gene', (75, 81))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('mutant', 'Var', (82, 88))
187172	33147752	Among the first, detection of 1p/19q co-deletions discriminates oligodendrogliomas from astrocytomas, the latter being enriched in alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations.	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (137, 185))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('co-deletions', 'Var', (37, 49))	('1p/19q', 'Gene', (30, 36))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (64, 82))	('ATRX', 'Gene', '546', (187, 191))	('mental retardation', 'Phenotype', 'HP:0001249', (149, 167))	('astrocytomas', 'Disease', 'MESH:D001254', (88, 100))	('astrocytomas', 'Disease', (88, 100))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('oligodendrogliomas', 'Disease', (64, 82))	('ATRX', 'Gene', (187, 191))	('discriminates', 'Reg', (50, 63))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (137, 185))
187173	33147752	Gliomas must be now classified based on the presence or absence of isocitrate dehydrogenase 1/2 (IDH1/2) mutations, as this is a strong prognosis indicator.	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('mutations', 'Var', (105, 114))	('Gliomas', 'Disease', (0, 7))	('IDH1/2', 'Gene', (97, 103))
187213	33147752	Tumors were classified based on the histology (GBM vs. LGG) and based on the presence of IDH mutations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (93, 102))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('IDH', 'Gene', (89, 92))	('IDH', 'Gene', '3417', (89, 92))
187221	33147752	As expected, epidermal growth factor receptor (EGFR) alterations were enriched in IDH1wt GBMs, whereas TP53 mutations were common among the IDH1mut gliomas (Figure S2A).	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', (140, 143))	('TP53', 'Gene', '7157', (103, 107))	('epidermal growth factor receptor', 'Gene', (13, 45))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('IDH', 'Gene', '3417', (140, 143))	('mutations', 'Var', (108, 117))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('TP53', 'Gene', (103, 107))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('alterations', 'Var', (53, 64))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('EGFR', 'Gene', '1956', (47, 51))	('IDH', 'Gene', (82, 85))	('EGFR', 'Gene', (47, 51))
187223	33147752	Regarding the clinical data (Table 1), patients carrying IDH mutations were significantly younger (p = 0.003) (IDHmut: median age: 40 years, range: 30-76 years; GBMwt_lo: median age: 57 years, range: 42-70 years; GBMwt_high: median age: 65 years, range: 38-82 years) and survived longer than their wild-type counterparts (Figure S2B).	('IDH', 'Gene', '3417', (57, 60))	('patients', 'Species', '9606', (39, 47))	('mutations', 'Var', (61, 70))	('IDH', 'Gene', (111, 114))	('younger', 'NegReg', (90, 97))	('IDH', 'Gene', '3417', (111, 114))	('survived', 'CPA', (271, 279))	('IDH', 'Gene', (57, 60))
187227	33147752	We observed that the percentage of neutrophils (Figure 2A), myeloid-derived suppressor cells (MDSCs) (Figure 2B) and macrophages (Figure 2C) was increased in GBMwt _hi compared to both IDHmut and GBMwt_lo gliomas.	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', '3417', (185, 188))	('gliomas', 'Disease', (205, 212))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('increased', 'PosReg', (145, 154))	('myeloid-derived suppressor cells', 'CPA', (60, 92))	('GBMwt _hi', 'Var', (158, 167))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
187234	33147752	Notably, the ratio of myeloid to lymphoid cells was lower in GBMwt_hi compared to the other two subgroups (Figure 2E), suggesting that T cells infiltrate this subgroup of gliomas in particular.	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('lower', 'NegReg', (52, 57))	('GBMwt_hi', 'Var', (61, 69))	('gliomas', 'Disease', (171, 178))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))
187236	33147752	However, there was an increase in the percentage of CD3+ cells in GBMwt_lo compared to IDHmut gliomas (Figure 2F).	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('IDH', 'Gene', (87, 90))	('increase', 'PosReg', (22, 30))	('IDH', 'Gene', '3417', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('CD3+ cells', 'MPA', (52, 62))	('GBMwt_lo', 'Var', (66, 74))
187238	33147752	As a result, the CD4/CD8 ratio was lower in the GBMwt_lo compared to GBMwt_hi tumors (Figure 2I).	('CD4', 'Gene', (17, 20))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('CD4', 'Gene', '920', (17, 20))	('CD8', 'Gene', (21, 24))	('CD8', 'Gene', '925', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lower', 'NegReg', (35, 40))	('GBMwt_lo', 'Var', (48, 56))
187240	33147752	Moreover, the proportion of PD1+ cells, which labels T cell exhaustion, was higher in GBMwt_hi compared to GBMwt_lo gliomas (Figure 2J), whereas the amount of regulatory T cells (Tregs) was similar in the two groups (Figure 2K).	('T cell exhaustion', 'Phenotype', 'HP:0005435', (53, 70))	('higher', 'PosReg', (76, 82))	('PD1+ cells', 'Var', (28, 38))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('GBMwt_hi', 'Var', (86, 94))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
187254	33147752	However, the T1+C and T2 images of GBMwt_lo tumors were very similar to the ones obtained in the immune-high GBM subgroup (Figure 4A).	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('GBMwt_lo', 'Var', (35, 43))
187257	33147752	Accordingly, the number of vessels with a large lumen (herein called dilated blood vessels (BVs)) were higher in the GBMwt_hi tumors (Figure 4E and Figure S5).	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('higher', 'PosReg', (103, 109))	('GBMwt_hi', 'Var', (117, 125))
187260	33147752	Moreover, the transcription of CD34 (Figure 4J), EMCN (another marker of endothelial tumor cells) (Figure 4K) and CD248 (Figure 4L) was increased in the GBMwt_hi group compared to the rest of gliomas.	('tumor', 'Disease', (85, 90))	('GBMwt_hi', 'Var', (153, 161))	('CD248', 'Gene', '57124', (114, 119))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('transcription', 'MPA', (14, 27))	('gliomas', 'Disease', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('EMCN', 'Gene', (49, 53))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('increased', 'PosReg', (136, 145))	('CD248', 'Gene', (114, 119))	('EMCN', 'Gene', '51705', (49, 53))	('CD34', 'Gene', (31, 35))
187261	33147752	Notably, only the expression of CD248, was increased in GBMwt_lo tumors compared to IDHmut gliomas (Figure 4L), which correlated with the higher CD248 score measured by IHC (Figure 4D and Figure S5), suggesting a direct correlation between the absence of IDH mutations and the increase in tumor pericytes, as we have recently described.	('IDH', 'Gene', (255, 258))	('CD248', 'Gene', (32, 37))	('gliomas', 'Disease', (91, 98))	('CD248', 'Gene', '57124', (32, 37))	('tumors', 'Disease', (65, 71))	('increase', 'PosReg', (277, 285))	('tumor', 'Disease', (65, 70))	('IDH', 'Gene', '3417', (255, 258))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('tumor', 'Disease', (289, 294))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('expression', 'MPA', (18, 28))	('increased', 'PosReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('IDH', 'Gene', (84, 87))	('CD248', 'Gene', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('GBMwt_lo', 'Var', (56, 64))	('CD248', 'Gene', '57124', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('IDH', 'Gene', '3417', (84, 87))
187265	33147752	This result was not surprising given that the MAPT/Tau gene is epigenetically induced by the presence of mutant IDH proteins.	('MAPT', 'Gene', '4137', (46, 50))	('Tau', 'Gene', (51, 54))	('Tau', 'Gene', '4137', (51, 54))	('MAPT', 'Gene', (46, 50))	('IDH', 'Gene', (112, 115))	('mutant', 'Var', (105, 111))	('proteins', 'Protein', (116, 124))	('IDH', 'Gene', '3417', (112, 115))
187276	33147752	Moreover, the expression of Tau reduced a signature of cytokines and chemokines (Figure 5M) already described as inducers of immune recruitment in brain tumors (Figure 5G).	('expression', 'Var', (14, 24))	('Tau', 'Gene', (28, 31))	('reduced', 'NegReg', (32, 39))	('brain tumors', 'Disease', 'MESH:D001932', (147, 159))	('brain tumors', 'Phenotype', 'HP:0030692', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('brain tumors', 'Disease', (147, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('signature of cytokines', 'MPA', (42, 64))	('Tau', 'Gene', '4137', (28, 31))
187279	33147752	We have previously shown that the Tau expression is induced by IDH mutations and repressed by wild-type IDH1.	('Tau', 'Gene', (34, 37))	('IDH', 'Gene', (104, 107))	('IDH', 'Gene', (63, 66))	('expression', 'MPA', (38, 48))	('IDH', 'Gene', '3417', (104, 107))	('IDH', 'Gene', '3417', (63, 66))	('mutations', 'Var', (67, 76))	('Tau', 'Gene', '4137', (34, 37))	('induced', 'Reg', (52, 59))
187282	33147752	However, we cannot discard that epigenetic changes induced by a higher amount of wild-type IDH could be affecting the expression of other immunomodulatory molecules as well.	('epigenetic changes', 'Var', (32, 50))	('IDH', 'Gene', (91, 94))	('affecting', 'Reg', (104, 113))	('expression', 'MPA', (118, 128))	('IDH', 'Gene', '3417', (91, 94))
187285	33147752	When we analyzed our cohort, we observed that HLA-A transcription was elevated in the GBMwt_hi subgroup, in comparison with the rest of gliomas (Figure S7C).	('elevated', 'PosReg', (70, 78))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('gliomas', 'Disease', (136, 143))	('GBMwt_hi', 'Var', (86, 94))	('HLA-A', 'Gene', '3105', (46, 51))	('HLA-A', 'Gene', (46, 51))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
187287	33147752	Taken together, our results suggest that the balance between mutant and wild-type IDH function in gliomas is controlling the expression of Tau, and probably other proteins, to shape the vascular and the immune niche of gliomas.	('IDH', 'Gene', '3417', (82, 85))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('Tau', 'Gene', '4137', (139, 142))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('expression', 'MPA', (125, 135))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', (219, 226))	('mutant', 'Var', (61, 67))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('IDH', 'Gene', (82, 85))	('Tau', 'Gene', (139, 142))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))
187289	33147752	Our detailed characterization of the immune content of different gliomas suggests that the presence of IDH1/2 mutations, even more than the histological grading, is the best predictor of a reduced immune infiltration in gliomas.	('gliomas', 'Disease', (65, 72))	('mutations', 'Var', (110, 119))	('reduced', 'NegReg', (189, 196))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('immune infiltration', 'CPA', (197, 216))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH1/2', 'Gene', (103, 109))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Disease', (220, 227))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
187292	33147752	As a drawback, tumors bearing IDH mutations could have an inferior response to immunotherapy.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (30, 33))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
187293	33147752	For that reason, several clinical trials have been designed combining inhibitors of mutant IDH with ICIs and vaccinations, a strategy that has proven to be effective in preclinical models.	('mutant', 'Var', (84, 90))	('IDH', 'Gene', '3417', (91, 94))	('IDH', 'Gene', (91, 94))	('inhibitors', 'Var', (70, 80))
187309	33147752	However, these mutations could be affecting other components of the TME, specially macrophages and MDSCs through different mechanisms, such as implementing a specific cytokine program as it has been discovered in IDH mutant gliomas.	('IDH', 'Gene', '3417', (213, 216))	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('mutations', 'Var', (15, 24))	('affecting', 'Reg', (34, 43))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('IDH', 'Gene', (213, 216))	('gliomas', 'Disease', (224, 231))	('gliomas', 'Disease', 'MESH:D005910', (224, 231))
187310	33147752	Here, we propose that, secondary to IDH mutations and/or to a reduction in the amount of wild-type IDH enzymes, Tau accumulates in the tumors.	('IDH', 'Gene', '3417', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('amount', 'MPA', (79, 85))	('IDH', 'Gene', (36, 39))	('Tau', 'Gene', '4137', (112, 115))	('mutations', 'Var', (40, 49))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('accumulates', 'PosReg', (116, 127))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('IDH', 'Gene', '3417', (36, 39))	('IDH', 'Gene', (99, 102))	('Tau', 'Gene', (112, 115))	('reduction', 'NegReg', (62, 71))
187312	33147752	It is important to point out that the balance of wild-type and mutant IDH proteins controls the clinical outcome of gliomas, including their sensitivity to radiation and chemotherapy.	('mutant', 'Var', (63, 69))	('controls', 'Reg', (83, 91))	('IDH', 'Gene', (70, 73))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('IDH', 'Gene', '3417', (70, 73))	('proteins', 'Protein', (74, 82))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (141, 165))
187328	33147752	Moreover, other proteins epigenetically induced or repressed by the balance between mutant and wild-type IDH will probably participate in the formation of the different immune-vascular landscapes.	('mutant', 'Var', (84, 90))	('IDH', 'Gene', '3417', (105, 108))	('IDH', 'Gene', (105, 108))	('participate', 'Reg', (123, 134))
187329	33147752	In any case, our results suggest that combined strategies targeting these two components of the tumors  stroma might lead to promising results, as it is already being tested in recurrent GBMs, using nivolumab and bevacizumab (NCT03452579, NCT03743662, NCT03890952).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors  stroma', 'Disease', (96, 110))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors  stroma', 'Disease', 'MESH:D009369', (96, 110))	('nivolumab', 'Chemical', 'MESH:D000077594', (199, 208))	('bevacizumab', 'Chemical', 'MESH:D000068258', (213, 224))	('NCT03452579', 'Var', (226, 237))	('NCT03890952', 'Var', (252, 263))	('NCT03743662', 'Var', (239, 250))
187331	33147752	Our results show that there is a reduced infiltration of immune cells in IDH mutant gliomas.	('infiltration of immune cells', 'CPA', (41, 69))	('gliomas', 'Disease', (84, 91))	('IDH', 'Gene', (73, 76))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('IDH', 'Gene', '3417', (73, 76))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('reduced', 'NegReg', (33, 40))	('mutant', 'Var', (77, 83))
187396	32398659	Compiling together the prognostic powers of TIL-B, MS4A1 mRNA, and CD20 protein levels on patient outcomes across 29 TCGA cancers by Cox-regression analyses, we identified a total of five cancer types in which intratumoral MS4A1 and TIL-B levels were consistently prognostic: TIL-B-high or MS4A1-high were positively prognostic for HNSCC, lung adenocarcinoma (LUAD), and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), but negatively prognostic for brain lower grade glioma (LGG) and kidney renal papillary cell carcinoma (KIRP) (Fig.	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (509, 546))	('LUAD', 'Phenotype', 'HP:0030078', (360, 364))	('TIL-B-high', 'Var', (276, 286))	('MS4A1', 'Gene', '931', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('negatively', 'NegReg', (448, 458))	('glioma', 'Phenotype', 'HP:0009733', (492, 498))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('MS4A1', 'Gene', (223, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (380, 403))	('cancers', 'Disease', (122, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (339, 358))	('CD20', 'Gene', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (371, 435))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (339, 358))	('HNSCC', 'Disease', (332, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('kidney renal papillary cell carcinoma', 'Disease', (509, 546))	('CD20', 'Gene', '931', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (537, 546))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancer', 'Disease', (188, 194))	('tumor', 'Disease', (215, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (394, 403))	('carcinoma', 'Phenotype', 'HP:0030731', (426, 435))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('glioma', 'Disease', (492, 498))	('MS4A1', 'Gene', '931', (290, 295))	('MS4A1', 'Gene', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cancer', 'Disease', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (492, 498))	('patient', 'Species', '9606', (90, 97))	('MS4A1', 'Gene', '931', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung adenocarcinoma', 'Disease', (339, 358))	('MS4A1', 'Gene', (51, 56))
187407	32398659	With regard to Be2 signature genes, the B-cell stimulatory cytokine IL2 was the most elevated in TIL-B-high HNSCC/CESC/LUAD, while IL6, a pro-inflammatory signal for cancer progression and initiation of germinal center formation, was elevated in TIL-B-high KIRP/LGG tumors (Fig.	('LGG tumors', 'Disease', (262, 272))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('TIL-B-high', 'Var', (97, 107))	('LGG tumors', 'Disease', 'MESH:D009369', (262, 272))	('elevated', 'PosReg', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('elevated', 'PosReg', (234, 242))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('B-cell stimulatory cytokine IL2', 'MPA', (40, 71))
187419	32398659	We found that GPR18 mRNA expression level was markedly upregulated in HPV(+)HNSCC when compared with HPV(-)HNSCC (Fig.	('HPV(+)HNSCC', 'Var', (70, 81))	('GPR18', 'Gene', '2841', (14, 19))	('HPV', 'Species', '10566', (70, 73))	('HPV', 'Species', '10566', (101, 104))	('upregulated', 'PosReg', (55, 66))	('GPR18', 'Gene', (14, 19))
187453	32398659	Thus, Breg-expressed CD20 protein may indicate poor prognosis in STAD.	('STAD', 'Disease', (65, 69))	('CD20', 'Gene', (21, 25))	('CD20', 'Gene', '931', (21, 25))	('Breg-expressed', 'Var', (6, 20))
187481	32398659	The low rate of apparent loss-of-function mutations of MS4A1, including nonsense and frameshift mutations or gene fusions (<1% of TCGA pan-cancer total of 10437 samples) cannot fully account for such as major discrepancies between CD20 protein expressions and full-length MS4A1 mRNA expressions in tumors.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('CD20', 'Gene', (231, 235))	('tumors', 'Disease', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('MS4A1', 'Gene', '931', (272, 277))	('loss-of-function', 'NegReg', (25, 41))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('MS4A1', 'Gene', (272, 277))	('MS4A1', 'Gene', '931', (55, 60))	('MS4A1', 'Gene', (55, 60))	('CD20', 'Gene', '931', (231, 235))	('mutations', 'Var', (42, 51))	('frameshift mutations', 'Var', (85, 105))	('cancer', 'Disease', (139, 145))
187482	32398659	Though methylation could silence the expression of MS4A1 gene, MS4A1 gene methylation only negatively correlated with CD20 protein expressions in two cancer types (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('methylation', 'Var', (74, 85))	('MS4A1', 'Gene', '931', (63, 68))	('silence', 'NegReg', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('methylation', 'Var', (7, 18))	('cancer', 'Disease', (150, 156))	('MS4A1', 'Gene', (63, 68))	('correlated', 'Reg', (102, 112))	('MS4A1', 'Gene', '931', (51, 56))	('negatively', 'NegReg', (91, 101))	('expression', 'MPA', (37, 47))	('CD20', 'Gene', (118, 122))	('MS4A1', 'Gene', (51, 56))	('CD20', 'Gene', '931', (118, 122))
187485	32398659	In fact, 9 out of 13 known MS4A1 transcripts (Supplementary Table 5) represent shorter forms of CD20 protein, which if expressed, would be undetectable by the current TCPA CD20 antibody per epitope consideration ([EP459Y], Abcam, ab78237).	('CD20', 'Gene', '931', (96, 100))	('CD20', 'Gene', '931', (172, 176))	('CD20', 'Gene', (96, 100))	('MS4A1', 'Gene', '931', (27, 32))	('CD20', 'Gene', (172, 176))	('MS4A1', 'Gene', (27, 32))	('[EP459Y', 'Var', (213, 220))
187608	32302317	The amino acid 18F-FET is not metabolized or incorporated into proteins, but its accumulation in tissue is due to the transport mediated by the L-type amino acid transport system.	('18F-FET', 'Chemical', 'MESH:C545932', (15, 22))	('18F-FET', 'Var', (15, 22))	('accumulation', 'PosReg', (81, 93))
187623	29617664	Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2.	('BRCA1/2', 'Gene', (110, 117))	('TP53', 'Gene', '7157', (101, 105))	('BRCA1/2', 'Gene', '672;675', (110, 117))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (101, 105))	('DDR genes', 'Gene', (80, 89))
187624	29617664	Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples.	('MGMT', 'Gene', '4255', (91, 95))	('EXO5', 'Gene', (85, 89))	('MGMT', 'Gene', (91, 95))	('epigenetic silencing', 'Var', (37, 57))	('ALKBH3', 'Gene', (101, 107))	('ALKBH3', 'Gene', '221120', (101, 107))	('EXO5', 'Gene', '64789', (85, 89))
187627	29617664	A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations.	('mutations', 'Var', (143, 152))	('TP53', 'Gene', '7157', (138, 142))	('TP53', 'Gene', (138, 142))
187628	29617664	These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.	('human', 'Species', '9606', (44, 49))	('alterations', 'Var', (24, 35))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('DDR gene', 'Gene', (15, 23))	('determine', 'Reg', (96, 105))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
187630	29617664	They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('alterations', 'Var', (77, 88))	('DDR', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
187633	29617664	Homology-dependent recombination (HR), non-homologous end joining (NHEJ), the Fanconi anemia (FA) pathway, and translesion DNA synthesis (TLS) act alone or together to repair DNA strand breaks and complex events like interstrand crosslinks.	('anemia', 'Phenotype', 'HP:0001903', (86, 92))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (78, 92))	('Fanconi anemia', 'Disease', (78, 92))	('DNA', 'Var', (175, 178))	('Fanconi anemia', 'Disease', 'MESH:D005199', (78, 92))
187634	29617664	The consequences of DDR deficiency are becoming better understood through analyses of DDR gene alterations in cancer.	('cancer', 'Disease', (110, 116))	('DDR gene', 'Gene', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (95, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
187635	29617664	For example, frequent TP53 somatic mutations in many cancer types can disrupt the DNA damage response, apoptosis, or senescence pathways active in many early-stage cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('disrupt', 'NegReg', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('senescence pathways', 'Pathway', (117, 136))	('cancer', 'Disease', (164, 170))	('DNA damage response', 'Pathway', (82, 101))	('somatic mutations', 'Var', (27, 44))	('cancers', 'Disease', (164, 171))	('apoptosis', 'Pathway', (103, 112))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('TP53', 'Gene', '7157', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TP53', 'Gene', (22, 26))
187636	29617664	DDR deficiency may also lead to specific mutational "signatures," e.g., the short tandem repeat instability linked to the inactivation or silencing of DNA MMR in colorectal, ovarian, or endometrial cancer  The therapeutic implications of altered DDR function are becoming better known.	('silencing', 'NegReg', (138, 147))	('endometrial cancer', 'Disease', (186, 204))	('inactivation', 'Var', (122, 134))	('colorectal', 'Disease', 'MESH:D015179', (162, 172))	('short', 'MPA', (76, 81))	('deficiency', 'Var', (4, 14))	('endometrial cancer', 'Phenotype', 'HP:0012114', (186, 204))	('lead', 'Reg', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('endometrial cancer', 'Disease', 'MESH:D016889', (186, 204))	('ovarian', 'Disease', (174, 181))	('DNA MMR', 'Gene', (151, 158))	('colorectal', 'Disease', (162, 172))
187640	29617664	The loss of specific DDR pathways in cancer, in contrast to other cellular "hallmarks" of cancer, often generates stable:and thus more readily interpretable:"footprints" in cancer genomes, detected as an increased mutation burden, altered mutational signatures, or copy-number alterations including loss of heterozygosity (LOH).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('increased', 'PosReg', (204, 213))	('loss of heterozygosity', 'Var', (299, 321))	('altered', 'Reg', (231, 238))	('cancer', 'Disease', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('loss', 'NegReg', (4, 8))	('DDR pathways', 'Pathway', (21, 33))
187641	29617664	We provide below the most comprehensive analysis to date of DDR pathway gene alterations and their consequences in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (115, 120))	('alterations', 'Var', (77, 88))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('DDR pathway gene', 'Gene', (60, 76))	('cancer', 'Disease', (121, 127))
187644	29617664	We first determined the prevalence of DDR alterations across PanCanAtlas cancer types by integrating data on somatic truncating and missense mutations (Figures S1C and S1D), deep copy-number deletions defined by GISTIC, and epigenetic silencing events.	('deep copy-number deletions', 'Var', (174, 200))	('alterations', 'Var', (42, 53))	('epigenetic silencing events', 'Var', (224, 251))	('PanCanAtlas cancer', 'Disease', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('DDR', 'Gene', (38, 41))	('PanCanAtlas cancer', 'Disease', 'MESH:D009369', (61, 79))	('missense mutations', 'Var', (132, 150))
187647	29617664	Similarly, cancer types with a large number of somatic copy-number alterations (SCNAs; e.g., OV [ovarian serous cystadenocarcinoma], SARC [sarcoma], ESCA [esophageal carcinoma], and STAD [stomach adenocarcinoma]) also had a larger number of SCNAs in DDR pathways.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (155, 175))	('ovarian serous cystadenocarcinoma', 'Disease', (97, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('esophageal carcinoma', 'Disease', (155, 175))	('DDR pathways', 'Pathway', (250, 262))	('copy-number alterations', 'Var', (55, 78))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('stomach adenocarcinoma', 'Disease', (188, 210))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (97, 130))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (155, 175))	('sarcoma', 'Disease', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('STAD', 'Disease', (182, 186))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('cancer', 'Disease', (11, 17))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (97, 130))
187650	29617664	Some DDR genes were affected predominantly by one type of alteration, e.g., ALKBH3 and MGMT by epigenetic silencing.	('MGMT', 'Gene', (87, 91))	('MGMT', 'Gene', '4255', (87, 91))	('ALKBH3', 'Gene', (76, 82))	('affected', 'Reg', (20, 28))	('ALKBH3', 'Gene', '221120', (76, 82))	('epigenetic silencing', 'Var', (95, 115))	('DDR genes', 'Gene', (5, 14))
187651	29617664	Other genes were altered in two or more ways, e.g., mutations in TP53, PTEN, PER1, and BRCA1/2 were frequently accompanied by LOH (Figure 1D).	('mutations', 'Var', (52, 61))	('BRCA1/2', 'Gene', (87, 94))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('PER1', 'Gene', (77, 81))	('accompanied', 'Reg', (111, 122))	('BRCA1/2', 'Gene', '672;675', (87, 94))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('LOH', 'Disease', (126, 129))
187652	29617664	Gene-level mutation frequencies varied widely by cancer type and subtype.	('mutation', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
187653	29617664	For example, mutations in TP53, PTEN, ERCC5, and IDH1 were highly enriched, while other genes such as SOX4, SLX1A, and GTF2H2 were much less frequently mutated (Figure S1J).	('TP53', 'Gene', (26, 30))	('ERCC5', 'Gene', '2073', (38, 43))	('IDH1', 'Gene', '3417', (49, 53))	('GTF2H2', 'Gene', '2966', (119, 125))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('GTF2H2', 'Gene', (119, 125))	('SLX1A', 'Gene', (108, 113))	('SOX4', 'Gene', (102, 106))	('SOX4', 'Gene', '6659', (102, 106))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (13, 22))	('ERCC5', 'Gene', (38, 43))	('IDH1', 'Gene', (49, 53))	('SLX1A', 'Gene', '548593', (108, 113))
187654	29617664	It is already well established that cancers with somatic POLE and POLD1 mutations in their exonuclease domains or with microsatellite instability (MSI) exhibit a substantially higher mutation burden.	('mutations', 'Var', (72, 81))	('POLD1', 'Gene', (66, 71))	('microsatellite', 'MPA', (119, 133))	('mutation burden', 'MPA', (183, 198))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('MSI', 'Disease', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('higher', 'PosReg', (176, 182))	('POLD1', 'Gene', '5424', (66, 71))	('MSI', 'Disease', 'None', (147, 150))
187655	29617664	Here, we observed only two DDR genes (TP53 and POLE) that demonstrated a substantially different association between alterations and overall mutation burden when compared against a background of all other non-DDR genes (Figure S1K).	('alterations', 'Var', (117, 128))	('TP53', 'Gene', (38, 42))	('mutation', 'MPA', (141, 149))	('TP53', 'Gene', '7157', (38, 42))
187661	29617664	In order to assess potential genomic consequences of DDR gene alterations, we performed a mutation signature correlation analysis focusing on loss-of-function alterations in the 48 genes we identified as putative cancer drivers (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('loss-of-function', 'NegReg', (142, 158))	('cancer', 'Disease', (213, 219))	('alterations', 'Var', (62, 73))
187663	29617664	We confirmed that mutational signature #19 (POLE signature, corresponding to COSMIC [Catalog of Somatic Mutations in Cancer] signature #10) is increased by over 4-fold in POLE-altered cancers (p = 1.0e-6) at the PanCanAtlas level, and in UCEC with greater significance (fold change = 10.1 and p = 4.8e-7, Figure S2B).	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('increased', 'PosReg', (143, 152))	('mutational', 'Var', (18, 28))	('POLE-altered cancers', 'Disease', 'MESH:D009369', (171, 191))	('POLE-altered cancers', 'Disease', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (117, 123))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))
187664	29617664	We also confirmed the association of signature #15 (temozolomide signature, corresponding to COSMIC signature #11) with MGMT alterations (Figure S2C).	('signature #', 'Var', (37, 48))	('temozolomide', 'Chemical', 'MESH:D000077204', (52, 64))	('MGMT', 'Gene', '4255', (120, 124))	('association', 'Interaction', (22, 33))	('MGMT', 'Gene', (120, 124))
187665	29617664	Epigenetic silencing was identified as an alternative prominent mechanism leading to recurrent gene deficiency.	('gene deficiency', 'Disease', (95, 110))	('Epigenetic silencing', 'Var', (0, 20))	('gene deficiency', 'Disease', 'MESH:D025063', (95, 110))
187667	29617664	Epigenetic silencing was less often observed for genes in the HR and FA pathways, e.g., BRCA1, RAD51C, NSMCE3, and FANCF.	('BRCA1', 'Gene', (88, 93))	('FANCF', 'Gene', '2188', (115, 120))	('NSMCE3', 'Gene', '56160', (103, 109))	('RAD51C', 'Gene', (95, 101))	('Epigenetic', 'Var', (0, 10))	('RAD51C', 'Gene', '5889', (95, 101))	('BRCA1', 'Gene', '672', (88, 93))	('FANCF', 'Gene', (115, 120))	('NSMCE3', 'Gene', (103, 109))	('FA pathways', 'Pathway', (69, 80))
187668	29617664	Methylation silencing was the dominant alteration in MGMT (92.4% of all alterations) and was significantly associated with signature #15 through mutation signature analysis (Figure S2C).	('Methylation', 'MPA', (0, 11))	('associated', 'Reg', (107, 117))	('signature #', 'Var', (123, 134))	('MGMT', 'Gene', (53, 57))	('MGMT', 'Gene', '4255', (53, 57))
187669	29617664	The high frequency of EXO5 silencing (94.5% of all EXO5 alterations) was both unexpected and intriguing.	('EXO5', 'Gene', (22, 26))	('alterations', 'Var', (56, 67))	('EXO5', 'Gene', '64789', (22, 26))	('EXO5', 'Gene', (51, 55))	('EXO5', 'Gene', '64789', (51, 55))
187675	29617664	Furthermore, EXO5 deficiency was significantly linked to signature #1 (Figure S2E).	('linked', 'Reg', (47, 53))	('EXO5', 'Gene', (13, 17))	('EXO5', 'Gene', '64789', (13, 17))	('signature #1', 'Disease', (57, 69))	('deficiency', 'Var', (18, 28))
187680	29617664	We observed positive correlations among six different SCNA scores that were used to characterize the extent of aneuploidy, LOH, and homologous recombination deficiency in PanCancer Atlas samples (Figure 3A).	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('deficiency in PanCancer Atlas', 'Disease', 'MESH:D007153', (157, 186))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('deficiency in PanCancer Atlas', 'Disease', (157, 186))
187681	29617664	We also found moderate, statistically significant positive correlations between mutation burden and SCNA scores, contrary to a previously reported inverse correlation between SCNA and mutation frequency in 12 cancer types.	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('mutation burden', 'Var', (80, 95))	('cancer', 'Disease', (209, 215))	('correlations', 'Interaction', (59, 71))	('SCNA scores', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
187694	29617664	We identified additional contributions of DDR gene alterations to HRD scores by using a Bayesian ridge regression to model HRD scoring as a function of DDR gene alterations while controlling for cancer type as a covariate (Table S3).	('HRD', 'Disease', 'None', (123, 126))	('DDR gene', 'Gene', (152, 160))	('HRD', 'Disease', 'None', (66, 69))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('HRD', 'Disease', (123, 126))	('HRD', 'Disease', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('alterations', 'Var', (161, 172))
187697	29617664	BRCA1 alterations had the largest positive weight for predicting higher HRD scores.	('alterations', 'Var', (6, 17))	('BRCA1', 'Gene', (0, 5))	('HRD', 'Disease', (72, 75))	('BRCA1', 'Gene', '672', (0, 5))	('HRD', 'Disease', 'None', (72, 75))	('higher', 'PosReg', (65, 71))
187698	29617664	Alterations in either BRCA1 or RAD51B increased HRD score in most cancer types including the top two cancer types with the greatest number of alterations in either gene (Figure 3E).	('RAD51B', 'Gene', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RAD51B', 'Gene', '5890', (31, 37))	('HRD', 'Disease', 'None', (48, 51))	('BRCA1', 'Gene', '672', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('HRD', 'Disease', (48, 51))	('BRCA1', 'Gene', (22, 27))	('increased', 'PosReg', (38, 47))	('cancer', 'Disease', (66, 72))
187699	29617664	TP53 alterations were also associated with higher HRD scores, consistent with previous observations of a higher SCNA burden in TP53-mutated cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('higher', 'PosReg', (43, 49))	('HRD', 'Disease', (50, 53))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('alterations', 'Var', (5, 16))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('TP53', 'Gene', '7157', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TP53', 'Gene', (127, 131))	('HRD', 'Disease', 'None', (50, 53))
187700	29617664	Other alterations in several MMR and NER genes had significant negative associations with HRD score, e.g., MLH1, TCEB3, and MSH2, suggesting a potential mutually exclusive relationship between HR and MMR or NER deficiencies.	('alterations', 'Var', (6, 17))	('negative', 'NegReg', (63, 71))	('NER genes', 'Gene', (37, 46))	('MMR', 'Gene', (29, 32))	('TCEB3', 'Gene', (113, 118))	('MSH2', 'Gene', (124, 128))	('HRD', 'Disease', 'None', (90, 93))	('MSH2', 'Gene', '4436', (124, 128))	('MLH1', 'Gene', '4292', (107, 111))	('MLH1', 'Gene', (107, 111))	('HRD', 'Disease', (90, 93))	('TCEB3', 'Gene', '6924', (113, 118))
187703	29617664	A majority of the fusions, including 18 in HR and 5 in MMR genes, had breakpoints in DDR functional domains that were predicted to disrupt function with readily predictable therapeutic consequences, e.g., for the HR gene fusions involving RAD51B and BRCA1 (Figure S4E).	('BRCA1', 'Gene', (250, 255))	('fusions', 'Var', (221, 228))	('RAD51B', 'Gene', (239, 245))	('disrupt', 'NegReg', (131, 138))	('RAD51B', 'Gene', '5890', (239, 245))	('BRCA1', 'Gene', '672', (250, 255))	('DDR', 'MPA', (85, 88))	('function', 'MPA', (139, 147))
187705	29617664	These included MGMT, PARP1, TOP3A, BLM, ERCC2, HFM1, POLE, POLD1, and POLQ, which collectively harbored 1,380 unique rare, recurrent non-synonymous mutations.	('PARP1', 'Gene', '142', (21, 26))	('BLM', 'Gene', (35, 38))	('TOP3A', 'Gene', '7156', (28, 33))	('POLQ', 'Gene', (70, 74))	('HFM1', 'Gene', (47, 51))	('MGMT', 'Gene', '4255', (15, 19))	('POLQ', 'Gene', '10721', (70, 74))	('MGMT', 'Gene', (15, 19))	('ERCC2', 'Gene', '2068', (40, 45))	('HFM1', 'Gene', '164045', (47, 51))	('TOP3A', 'Gene', (28, 33))	('BLM', 'Gene', '641', (35, 38))	('POLD1', 'Gene', (59, 64))	('POLD1', 'Gene', '5424', (59, 64))	('non-synonymous mutations', 'Var', (133, 157))	('ERCC2', 'Gene', (40, 45))	('PARP1', 'Gene', (21, 26))
187707	29617664	Molecular dynamics simulations of a subset of mutations (n = 86) in six proteins (POLE, POLD1, POLQ, ERCC2, HFM1, and BLM) revealed many additional mutations that were not predicted to be destabilizing but did alter protein dynamics (Figure S5).	('protein dynamics', 'MPA', (216, 232))	('POLQ', 'Gene', '10721', (95, 99))	('ERCC2', 'Gene', '2068', (101, 106))	('mutations', 'Var', (148, 157))	('HFM1', 'Gene', '164045', (108, 112))	('mutations', 'Var', (46, 55))	('BLM', 'Gene', (118, 121))	('POLD1', 'Gene', (88, 93))	('ERCC2', 'Gene', (101, 106))	('HFM1', 'Gene', (108, 112))	('POLD1', 'Gene', '5424', (88, 93))	('alter', 'Reg', (210, 215))	('BLM', 'Gene', '641', (118, 121))	('POLQ', 'Gene', (95, 99))
187708	29617664	Many genes displayed an inverse relationship between these two burden scores, with, e.g., destabilizing mutations in POLB associated with higher mutation and lower SCNA burden, whereas destabilizing PARP1 mutations were associated with lower mutation and higher SCNA burden (Figures 4D-4F).	('mutation', 'MPA', (145, 153))	('mutations', 'Var', (104, 113))	('lower', 'NegReg', (158, 163))	('POLB', 'Gene', '5423', (117, 121))	('SCNA burden', 'MPA', (262, 273))	('PARP1', 'Gene', '142', (199, 204))	('POLB', 'Gene', (117, 121))	('higher', 'PosReg', (138, 144))	('SCNA burden', 'MPA', (164, 175))	('PARP1', 'Gene', (199, 204))
187710	29617664	Cancer-associated TP53 mutations may promote these consequences through simple loss of function, as well as by altering transcription or through dominant-negative, gain-of-function mechanisms.	('transcription', 'MPA', (120, 133))	('TP53', 'Gene', '7157', (18, 22))	('loss of function', 'NegReg', (79, 95))	('TP53', 'Gene', (18, 22))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (23, 32))	('altering', 'Reg', (111, 119))	('gain-of-function', 'PosReg', (164, 180))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
187714	29617664	The remaining gene, MPDU1, may have been identified by virtue of being located ~80 kb downstream of TP53 and thus sensitive to TP53 copy loss.	('TP53', 'Gene', '7157', (100, 104))	('MPDU1', 'Gene', '9526', (20, 25))	('TP53', 'Gene', (100, 104))	('MPDU1', 'Gene', (20, 25))	('copy loss', 'Var', (132, 141))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
187717	29617664	The classifier was also able to distinguish TP53 mutant from wild-type BRCA and UCEC, with nearly all basal-subtype BRCA cancers predicted to be TP53 deficient (Figures S6G and S6H).	('deficient', 'NegReg', (150, 159))	('mutant', 'Var', (49, 55))	('BRCA', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('TP53', 'Gene', '7157', (44, 48))	('BRCA', 'Gene', '672', (71, 75))	('basal-subtype BRCA cancers', 'Disease', (102, 128))	('basal-subtype BRCA cancers', 'Disease', 'MESH:D002280', (102, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('BRCA', 'Gene', (71, 75))	('TP53', 'Gene', (44, 48))	('BRCA', 'Gene', '672', (116, 120))
187719	29617664	The classifier enabled the identification of phenocopying mutations both in TP53 and in other functionally related genes.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))
187720	29617664	Consistent with previous pan-cancer analyses, we observed that predicted TP53 loss-of-function samples, including cancers with synonymous TP53 c.375G>T mutation, had an increased SCNA burden when compared with wild-type samples (Figure 5C).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('TP53', 'Gene', '7157', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', '7157', (138, 142))	('cancers', 'Disease', (114, 121))	('SCNA burden', 'MPA', (179, 190))	('loss-of-function', 'NegReg', (78, 94))	('c.375G>T', 'Mutation', 'rs55863639', (143, 151))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('c.375G>T', 'Var', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
187721	29617664	This synonymous mutation may act by altering a splice donor to produce alternatively spliced transcripts that compromise TP53 function.	('mutation', 'Var', (16, 24))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('donor', 'Species', '9606', (54, 59))	('altering', 'Reg', (36, 44))	('compromise', 'NegReg', (110, 120))
187722	29617664	Samples with c.375G>T or c.375G>A mutations were also enriched for a 200 base pair truncation in exon 4 when compared with wild-type TP53 samples (OR [odds ratio] = 61.9, p < 2.2e-16).	('c.375G>A', 'Mutation', 'rs55863639', (25, 33))	('c.375G>T', 'Mutation', 'rs55863639', (13, 21))	('c.375G>T', 'Var', (13, 21))	('c.375G>A', 'Var', (25, 33))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
187723	29617664	This mutation/truncation pairing was previously observed in a pancreatic cancer cell line and as a SNP (rs55863639) likely pathogenic for Li-Fraumeni syndrome.	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Li-Fraumeni syndrome', 'Disease', (138, 158))	('pathogenic', 'Reg', (123, 133))	('rs55863639', 'Var', (104, 114))	('rs55863639', 'Mutation', 'rs55863639', (104, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (138, 158))
187724	29617664	Significantly increased classifier scores were also noted for cancers with MDM2 copy-number amplification and CDK2NA copy-number deletion in an analysis including only non-hypermutated cancers without deleterious TP53 mutation (Figure 5D).	('increased', 'PosReg', (14, 23))	('copy-number amplification', 'Var', (80, 105))	('copy-number deletion', 'Var', (117, 137))	('TP53', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('MDM2', 'Gene', '4193', (75, 79))	('CDK2', 'Gene', (110, 114))	('MDM2', 'Gene', (75, 79))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('CDK2', 'Gene', '1017', (110, 114))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancers', 'Disease', (185, 192))	('TP53', 'Gene', '7157', (213, 217))
187725	29617664	We had observed a copy-number dosage effect for CDK2NA copy-number deletions, where loss of the CDKN2A-encoded P14ARF protein can phenocopy TP53 alterations.	('P14ARF', 'Gene', (111, 117))	('CDKN2A', 'Gene', '1029', (96, 102))	('deletions', 'Var', (67, 76))	('TP53', 'Gene', (140, 144))	('CDK2', 'Gene', (48, 52))	('protein', 'Protein', (118, 125))	('loss', 'Var', (84, 88))	('CDKN2A', 'Gene', (96, 102))	('P14ARF', 'Gene', '1029', (111, 117))	('CDK2', 'Gene', '1017', (48, 52))	('TP53', 'Gene', '7157', (140, 144))
187726	29617664	Among eight other tested genes, MDM4 and PPM1D copy-number amplification and ATM and CREBBP gene mutations were associated with increased TP53 classifier scores, while ATR, CHEK1/2, or RP6SKA3 mutations were not (Figure 5E).	('mutations', 'Var', (97, 106))	('TP53', 'Gene', '7157', (138, 142))	('CHEK1/2', 'Gene', '1111;11200', (173, 180))	('CREBBP', 'Gene', (85, 91))	('ATM', 'Gene', (77, 80))	('ATR', 'Gene', '545', (168, 171))	('ATR', 'Gene', (168, 171))	('increased', 'PosReg', (128, 137))	('CHEK1/2', 'Gene', (173, 180))	('TP53', 'Gene', (138, 142))	('ATM', 'Gene', '472', (77, 80))	('MDM4', 'Gene', '4194', (32, 36))	('CREBBP', 'Gene', '1387', (85, 91))	('PPM1D', 'Gene', (41, 46))	('MDM4', 'Gene', (32, 36))	('PPM1D', 'Gene', '8493', (41, 46))
187731	29617664	Fewer mutation-based associations with clinical outcomes were identified: e.g., a high mutation burden was associated with better prognosis in UCEC and STAD cancers, but worse prognosis in LGG and ACC cancers (Figure S7C).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('better', 'PosReg', (123, 129))	('STAD cancers', 'Disease', (152, 164))	('cancers', 'Disease', (201, 208))	('LGG', 'Disease', (189, 192))	('STAD cancers', 'Disease', 'MESH:D009369', (152, 164))	('UCEC', 'Disease', (143, 147))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('mutation burden', 'Var', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Disease', (157, 164))
187735	29617664	We used TCGA PanCanAtlas data to systematically analyze the prevalence, nature, and consequences of DDR gene and pathway alterations across 9,125 samples representing 33 different cancer types.	('alterations', 'Var', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('DDR gene', 'Gene', (100, 108))
187736	29617664	DDR gene alterations were ubiquitous: approximately 1/3 of TCGA PanCanAtlas cancer types showed significant enrichment of somatic mutations in DDR genes, often accompanied by SCNA/LOH events.	('PanCanAtlas cancer', 'Disease', (64, 82))	('DDR genes', 'Gene', (143, 152))	('TCGA', 'Disease', (59, 63))	('accompanied', 'Reg', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (130, 139))	('PanCanAtlas cancer', 'Disease', 'MESH:D009369', (64, 82))
187738	29617664	DNA methylation-dependent epigenetic silencing was also surprisingly frequent:though more variable:than mutation or deletion calls and encompassed one-third of TCGA cancer types.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('methylation-dependent', 'Var', (4, 25))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('epigenetic silencing', 'Var', (26, 46))
187740	29617664	Epigenetic silencing of DR pathway genes in gastrointestinal, central nervous, and lymphoid cancers were all associated with a high mutation burden.	('associated', 'Reg', (109, 119))	('lymphoid cancers', 'Disease', (83, 99))	('DR pathway genes', 'Gene', (24, 40))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('gastrointestinal', 'Disease', (44, 60))	('Epigenetic silencing', 'Var', (0, 20))	('central nervous', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gastrointestinal', 'Disease', 'MESH:D005767', (44, 60))	('lymphoid cancers', 'Disease', 'MESH:D009369', (83, 99))
187743	29617664	These findings highlight the role of epigenetics in shaping the DDR deficiency landscape in cancer and may provide useful biomarkers for enhanced response to, e.g., alkylating agent therapy.	('enhanced', 'PosReg', (137, 145))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('epigenetics', 'Var', (37, 48))	('DDR', 'MPA', (64, 67))
187745	29617664	Analyses of loss-of-function alterations within DDR pathways identified co-occurring alterations (largely consisting of mutations and epigenetic silencing) in the MMR pathway in UCEC and STAD cancers, though no pathway by cancer-type-specific, mutually exclusive combinations.	('epigenetic silencing', 'Var', (134, 154))	('STAD cancers', 'Disease', 'MESH:D009369', (187, 199))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('STAD cancers', 'Disease', (187, 199))	('cancer', 'Disease', (222, 228))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('alterations', 'Var', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (192, 198))	('MMR pathway', 'Pathway', (163, 174))	('loss-of-function', 'NegReg', (12, 28))	('DDR pathways', 'Gene', (48, 60))	('mutations', 'Var', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('UCEC', 'Disease', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
187746	29617664	Thus, the loss of both MMR and NER might markedly sensitize cancer cells to alkylating agent therapy and provide a starting point to identify effective treatment combinations.	('loss', 'Var', (10, 14))	('NER', 'Gene', (31, 34))	('sensitize', 'Reg', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MMR', 'Gene', (23, 26))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
187748	29617664	EXO5 deficiency, identified here as an often epigenetically silenced DDR gene, was associated with signature 1 across multiple cancer types (Figure S2E) and has been associated with poor clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deficiency', 'Var', (5, 15))	('multiple cancer', 'Disease', 'MESH:D009369', (118, 133))	('EXO5', 'Gene', (0, 4))	('associated', 'Reg', (83, 93))	('multiple cancer', 'Disease', (118, 133))	('associated', 'Reg', (166, 176))	('EXO5', 'Gene', '64789', (0, 4))
187749	29617664	Co-occurrence plots of mutations and SCNA/LOH for the top 50 mutated DDR genes in TCGA samples (Figure 1D) and genome-wide DNA damage scores that further encompass LOH and aneuploidy (Figure 3A) suggest the potential for additional complex interactions among DDR gene alterations.	('DDR genes', 'Gene', (69, 78))	('interactions', 'Interaction', (240, 252))	('aneuploidy', 'Disease', 'MESH:D000782', (172, 182))	('mutations', 'Var', (23, 32))	('mutated', 'Var', (61, 68))	('aneuploidy', 'Disease', (172, 182))
187750	29617664	We extended the insights gained from analyzing the type and distribution of DDR gene alterations in cancer by using additional approaches.	('DDR gene', 'Gene', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (85, 96))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
187751	29617664	We found that POLD1 mutations, despite being less common than the POLE or POLQ mutations that contribute to hereditary colorectal cancer risk and the hypermutated phenotype, were as strongly associated with genomic instability.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('hereditary colorectal cancer', 'Disease', (108, 136))	('POLD1', 'Gene', '5424', (14, 19))	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (108, 136))	('POLQ', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('POLQ', 'Gene', '10721', (74, 78))	('associated', 'Reg', (191, 201))	('mutations', 'Var', (20, 29))	('POLD1', 'Gene', (14, 19))	('genomic instability', 'MPA', (207, 226))
187752	29617664	Molecular dynamics simulations further identified a subset of DDR gene mutations with the potential to alter protein conformational changes independent of effects on protein stability (Figure S5), raising the provocative question of whether destabilizing mutations alone contribute to genomic instability in cancer.	('DDR gene', 'Gene', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('protein conformational changes', 'MPA', (109, 139))	('cancer', 'Disease', (308, 314))	('mutations', 'Var', (71, 80))	('alter', 'Reg', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))
187754	29617664	This approach identified both TP53 mutant and TP53 mutant phenocopies, as well as potential TP53 tissue-specific roles in, e.g., ESCA and CESC cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TP53', 'Gene', (30, 34))	('mutant', 'Var', (51, 57))	('ESCA', 'Disease', (129, 133))	('mutant', 'Var', (35, 41))	('TP53', 'Gene', '7157', (46, 50))	('CESC cancers', 'Disease', (138, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('TP53', 'Gene', (46, 50))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (30, 34))	('CESC cancers', 'Disease', 'MESH:D009369', (138, 150))
187757	29617664	These associations were consistent in linking a high mutation burden or genomic instability with worse clinical outcomes across almost all cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('genomic instability', 'Var', (72, 91))	('mutation burden', 'Var', (53, 68))	('cancer', 'Disease', (139, 145))
187760	29617664	This extends the recognition of a bimodal distribution of HRD scores in breast and ovarian cancers and the enrichment of BRCA1/2 mutant or methylated cancers among HRD-high cancers that are more likely to respond to platinum-containing therapy.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('ovarian cancers', 'Phenotype', 'HP:0100615', (83, 98))	('platinum', 'Chemical', 'MESH:D010984', (216, 224))	('HRD-high cancers', 'Disease', (164, 180))	('mutant', 'Var', (129, 135))	('BRCA1/2', 'Gene', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (72, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('cancers', 'Disease', (150, 157))	('HRD', 'Disease', (164, 167))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('HRD', 'Disease', 'None', (164, 167))	('cancers', 'Disease', (173, 180))	('HRD-high cancers', 'Disease', 'MESH:D009369', (164, 180))	('HRD', 'Disease', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('BRCA1/2', 'Gene', '672;675', (121, 128))	('methylated', 'Var', (139, 149))	('HRD', 'Disease', 'None', (58, 61))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
187765	29617664	The many different cancer types that show epigenetic silencing of DR pathway genes such as MGMT and ALKBH3 may be especially vulnerable to types of DNA damage normally repaired by these proteins.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('ALKBH3', 'Gene', (100, 106))	('epigenetic silencing', 'Var', (42, 62))	('DR pathway genes', 'Gene', (66, 82))	('cancer', 'Disease', (19, 25))	('ALKBH3', 'Gene', '221120', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('MGMT', 'Gene', (91, 95))	('MGMT', 'Gene', '4255', (91, 95))
187775	29617664	For each combination of a cancer type and DDR pathway, we have three binary vectors that indicate for the samples of that cancer type whether at least one gene in a DDR pathway was mutated, deleted or silenced.	('silenced', 'NegReg', (201, 209))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('deleted', 'Var', (190, 197))	('mutated', 'Var', (181, 188))
187777	29617664	To estimate the probability of missense mutations being damaging, we further annotated these missense mutations using six commonly used functional prediction algorithms (Figure S1D): PolyPhen-2, SIFT, Mutation Taster, Mutation Assessor, LR and LRT.	('SIFT', 'Disease', 'None', (195, 199))	('missense', 'Var', (31, 39))	('SIFT', 'Disease', (195, 199))
187778	29617664	TP53 hotspot mutation substitutions such as R175H and R273H that didn't meet this threshold were manually rescued.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('R273H', 'Var', (54, 59))	('R273H', 'Mutation', 'rs28934576', (54, 59))	('R175H', 'Mutation', 'rs28934578', (44, 49))	('R175H', 'Var', (44, 49))
187785	29617664	However, probe cg14837411 on HM27 and probe cg27221688 on HM450 were only 100bp apart and both correlated with gene expression.	('HM27', 'CellLine', 'CVCL:8807', (29, 33))	('correlated', 'Reg', (95, 105))	('gene expression', 'MPA', (111, 126))	('cg14837411', 'Var', (15, 25))
187786	29617664	We manually added these back based on a beta value cutoff of 0.2 or above and combining both probes to call RAD51C epigenetic silencing.	('epigenetic silencing', 'Var', (115, 135))	('RAD51C', 'Gene', (108, 114))	('RAD51C', 'Gene', '5889', (108, 114))
187787	29617664	The aneuploidy score reports the total number of arm-level amplifications and deletions in each cancer and was computed using ABSOLUTE and an arm-level clustering algorithm, as described in.	('aneuploidy', 'Disease', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aneuploidy', 'Disease', 'MESH:D000782', (4, 14))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('deletions', 'Var', (78, 87))
187810	29617664	In order to provide a detailed assessment for the most recurrent variants in selected DDR proteins (n = 86; observed in at least 2 samples for POLQ or 3 samples for others), we utilized Generalized Born implicit solvent molecular dynamics (MD) simulations, which were carried out using NAMD and the CHARMM27 with CMAP force field.	('variants', 'Var', (65, 73))	('CMAP', 'Gene', (313, 317))	('POLQ', 'Gene', (143, 147))	('POLQ', 'Gene', '10721', (143, 147))	('CMAP', 'Gene', '8530', (313, 317))
187811	29617664	For POLE we studied in greater depth the recurrent V411A/D/I/L/M and P286R substitutions.	('V411A', 'Var', (51, 56))	('P286R', 'Var', (69, 74))	('P286R', 'Mutation', 'rs764973641', (69, 74))	('V411A', 'SUBSTITUTION', 'None', (51, 56))
187816	29617664	The labels (y) for the supervised task included samples with MC3 annotated deleterious TP53 mutations (samples with silent mutations were considered TP53 wild-type) and samples with TP53 deep copy number loss as predicted by the GISTIC2.0 algorithm.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('deep copy number loss', 'Disease', (187, 208))	('TP53', 'Gene', '7157', (149, 153))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('TP53', 'Gene', (149, 153))	('MC3', 'Gene', (61, 64))	('deep copy number loss', 'Disease', 'MESH:D057887', (187, 208))
187821	29617664	We tested MDM2, MDM4, and PPM1D amplifications, CDKN2A deletions, and ATM, ATR, CHEK1, CHEK2, CREBBP, and RPS6KA3 mutations.	('ATR', 'Gene', '545', (75, 78))	('CREBBP', 'Gene', '1387', (94, 100))	('CHEK1', 'Gene', '1111', (80, 85))	('RPS6KA3', 'Gene', '6197', (106, 113))	('PPM1D', 'Gene', (26, 31))	('ATM', 'Gene', '472', (70, 73))	('RPS6KA3', 'Gene', (106, 113))	('CDKN2A', 'Gene', (48, 54))	('MDM2', 'Gene', (10, 14))	('CHEK1', 'Gene', (80, 85))	('MDM4', 'Gene', '4194', (16, 20))	('MDM4', 'Gene', (16, 20))	('ATR', 'Gene', (75, 78))	('CHEK2', 'Gene', (87, 92))	('MDM2', 'Gene', '4193', (10, 14))	('CDKN2A', 'Gene', '1029', (48, 54))	('CREBBP', 'Gene', (94, 100))	('ATM', 'Gene', (70, 73))	('CHEK2', 'Gene', '11200', (87, 92))	('PPM1D', 'Gene', '8493', (26, 31))	('deletions', 'Var', (55, 64))
187823	29617664	We removed tumors with deleterious TP53 mutations or deep copy number loss (n = 4,037).	('deep copy number loss', 'Disease', 'MESH:D057887', (53, 74))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('deep copy number loss', 'Disease', (53, 74))	('mutations', 'Var', (40, 49))	('tumors', 'Disease', (11, 17))
187828	29617664	DNA damage repair (DDR) gene alterations are prevalent in many human cancer types Homology-dependent recombination (HR) and direct repair were most frequently altered Loss of DDR function is linked to frequency and types of cancer genomic aberrations Altered HR function can be associated with better or worse outcomes by cancer type	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('human', 'Species', '9606', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (69, 75))
187928	25744346	In all patients, MEP alterations elicited by TCS were consistent with that obtained using DCS.	('TCS', 'Chemical', '-', (45, 48))	('TCS', 'Var', (45, 48))	('DCS', 'Chemical', '-', (90, 93))	('MEP alterations', 'MPA', (17, 32))	('patients', 'Species', '9606', (7, 15))
187930	25744346	reported that the MEP elicited by DCS, and not TCS, could be used to detect brain ischemia during brain tumor resection.	('brain ischemia', 'Disease', (76, 90))	('MEP', 'MPA', (18, 21))	('brain tumor', 'Disease', (98, 109))	('TCS', 'Chemical', '-', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('brain tumor', 'Disease', 'MESH:D001932', (98, 109))	('DCS', 'Var', (34, 37))	('DCS', 'Chemical', '-', (34, 37))	('brain ischemia', 'Phenotype', 'HP:0002637', (76, 90))	('brain tumor', 'Phenotype', 'HP:0030692', (98, 109))	('brain ischemia', 'Disease', 'MESH:D002545', (76, 90))
187932	25744346	demonstrated that MEP loss elicited by TCS bears a higher risk than MEP deterioration (> 50% amplitude decrease and/or motor threshold increase) for postoperative motor deficits resulting from subcortical postoperative magnetic resonance changes in the pyramidal tract.	('TCS', 'Var', (39, 42))	('increase', 'PosReg', (135, 143))	('motor threshold', 'MPA', (119, 134))	('amplitude', 'MPA', (93, 102))	('postoperative motor deficits', 'Disease', (149, 177))	('loss', 'NegReg', (22, 26))	('postoperative motor deficits', 'Disease', 'MESH:D010149', (149, 177))	('TCS', 'Chemical', '-', (39, 42))
187963	24079673	There was no correlation with p53, reflecting the disruption of the VRK-p53-DRAM autoregulatory loop as a consequence of p53 mutations.	('DRAM', 'Gene', '55332', (76, 80))	('mutations', 'Var', (125, 134))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('DRAM', 'Gene', (76, 80))
188002	24079673	Specimens were considered to have an amplification of EFGR when more than 20% of tumor cells exhibited an EGFR/CEP7 ratio >2 or inestimable tight clusters of signals of the locus probe; and PTEN deletion was defined as more than 20% of tumor cells containing one or no PTEN locus signal and the presence of reference CEP signal.	('PTEN', 'Gene', (190, 194))	('PTEN', 'Gene', (269, 273))	('PTEN', 'Gene', '5728', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('PTEN', 'Gene', '5728', (269, 273))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('deletion', 'Var', (195, 203))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('EGFR', 'Gene', '1956', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', (81, 86))	('EGFR', 'Gene', (106, 110))
188022	24079673	Considering each marker individually, p63 and ki67 significantly correlated with high-grade astrocytomas, reflecting a higher proliferative component in these tumors (Tables 3 and 4), however, the correlation between p63 and ki67 was not significant (data not shown), indicating that these two proliferation markers might vary among tumors.	('astrocytomas', 'Disease', 'MESH:D001254', (92, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (92, 103))	('astrocytomas', 'Disease', (92, 104))	('tumors', 'Disease', (333, 339))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('p63', 'Gene', (38, 41))	('p63', 'Gene', (217, 220))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('ki67', 'Var', (46, 50))	('p63', 'Gene', '8626', (38, 41))	('p63', 'Gene', '8626', (217, 220))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('correlated', 'Reg', (65, 75))
188025	24079673	To genetically characterize this astrocytoma series, we determined several alterations in IDH1/2, p53, MGMT, EGFR and PTEN genes that are known to be frequent in astrocytomas.	('PTEN', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (109, 113))	('alterations', 'Var', (75, 86))	('p53', 'Gene', (98, 101))	('astrocytomas', 'Disease', 'MESH:D001254', (162, 174))	('astrocytoma', 'Phenotype', 'HP:0009592', (162, 173))	('MGMT', 'Gene', '4255', (103, 107))	('PTEN', 'Gene', '5728', (118, 122))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('astrocytoma', 'Disease', 'MESH:D001254', (162, 173))	('IDH1/2', 'Gene', '3417;3418', (90, 96))	('astrocytoma', 'Disease', (162, 173))	('EGFR', 'Gene', (109, 113))	('astrocytomas', 'Disease', (162, 174))	('IDH1/2', 'Gene', (90, 96))	('MGMT', 'Gene', (103, 107))	('astrocytoma', 'Disease', 'MESH:D001254', (33, 44))	('astrocytoma', 'Disease', (33, 44))	('p53', 'Gene', '7157', (98, 101))
188026	24079673	The frequency of p53 mutations was significantly higher in low-grade astrocytomas (12/24, 50.0%) than in high-grade astrocytomas (17/73, 23.3%) (p = 0.013).	('astrocytomas', 'Disease', 'MESH:D001254', (116, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (116, 127))	('astrocytomas', 'Disease', 'MESH:D001254', (69, 81))	('astrocytomas', 'Disease', (116, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('astrocytomas', 'Disease', (69, 81))	('p53', 'Gene', (17, 20))	('higher', 'PosReg', (49, 55))	('p53', 'Gene', '7157', (17, 20))	('mutations', 'Var', (21, 30))
188027	24079673	IDH1/2 mutations were also correlated with low-grade astrocytomas (15/24, 62.5%), and are infrequent in high-grade tumors (3/74, 4.1%) (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('astrocytomas', 'Disease', (53, 65))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('astrocytomas', 'Disease', 'MESH:D001254', (53, 65))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (53, 64))	('IDH1/2', 'Gene', (0, 6))	('correlated', 'Reg', (27, 37))	('mutations', 'Var', (7, 16))
188033	24079673	Those patients with high VRK2 protein expression had a better median overall survival (13.7 months vs. 10.2 months) (Table 7) (Figure 2A).	('overall survival', 'MPA', (69, 85))	('VRK2', 'Gene', '7444', (25, 29))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('protein', 'Protein', (30, 37))	('VRK2', 'Gene', (25, 29))
188035	24079673	In addition, low-grade astrocytomas with high VRK2 protein levels also had better prognosis but this association did not reach statistical significance probably due to the lower number of cases in this group (Figure 2B).	('better', 'PosReg', (75, 81))	('astrocytoma', 'Phenotype', 'HP:0009592', (23, 34))	('astrocytomas', 'Disease', (23, 35))	('VRK2', 'Gene', (46, 50))	('high', 'Var', (41, 45))	('astrocytomas', 'Disease', 'MESH:D001254', (23, 35))	('VRK2', 'Gene', '7444', (46, 50))
188037	24079673	Next, we constructed a prognostic index based on multivariate analysis for predicting patients' survival with the following prognostic index formula derived from Cox coefficients: 0.744 x VRK2 expression + 0.585 x age + 0.697 x treatment.	('VRK2', 'Gene', '7444', (188, 192))	('0.744', 'Var', (180, 185))	('VRK2', 'Gene', (188, 192))	('Cox', 'Gene', '1351', (162, 165))	('Cox', 'Gene', (162, 165))	('patients', 'Species', '9606', (86, 94))
188042	24079673	All cell lines express similar levels of VRK1 and VRK2, but LN18 has a higher level of EGFR and higher EGFR/VRK ratios (Figure 3A), as well as lower cyclin D1.	('VRK2', 'Gene', '7444', (50, 54))	('LN18', 'Var', (60, 64))	('cyclin D1', 'Gene', '595', (149, 158))	('EGFR', 'Gene', '1956', (87, 91))	('VRK1', 'Gene', (41, 45))	('EGFR', 'Gene', '1956', (103, 107))	('cyclin D1', 'Gene', (149, 158))	('VRK2', 'Gene', (50, 54))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', (87, 91))	('lower', 'NegReg', (143, 148))	('higher', 'PosReg', (96, 102))	('VRK1', 'Gene', '7443', (41, 45))
188044	24079673	If this interpretation is correct LN18 cells should grow faster than A172 or LN229 cells.	('grow', 'CPA', (52, 56))	('LN18', 'Var', (34, 38))	('LN229', 'CellLine', 'CVCL:0393', (77, 82))
188050	24079673	However, the lack of correlation between VRK1 or VRK2 with p53 levels could be due as a result of mutations in p53 gene that inactivate the downregulation of VRK1 that is mediated in the autophagic pathway by DRAM.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('VRK2', 'Gene', (49, 53))	('VRK1', 'Gene', (41, 45))	('VRK1', 'Gene', (158, 162))	('DRAM', 'Gene', (209, 213))	('p53', 'Gene', (111, 114))	('downregulation', 'NegReg', (140, 154))	('p53', 'Gene', '7157', (111, 114))	('mutations', 'Var', (98, 107))	('DRAM', 'Gene', '55332', (209, 213))	('VRK2', 'Gene', '7444', (49, 53))	('VRK1', 'Gene', '7443', (158, 162))	('inactivate', 'NegReg', (125, 135))	('VRK1', 'Gene', '7443', (41, 45))
188051	24079673	In our series, low-grade astrocytomas are characterized with p53 and IDH1/2 mutations, consistent with known frequencies for this group; whereas PTEN loss and EGFR amplification that facilitate survival signaling by the resulting constitutive activation of the PI3K pathway were more represented in high-grade astrocytomas.	('EGFR', 'Gene', '1956', (159, 163))	('activation', 'PosReg', (243, 253))	('amplification', 'Var', (164, 177))	('astrocytomas', 'Disease', (310, 322))	('astrocytomas', 'Disease', 'MESH:D001254', (25, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (310, 321))	('IDH1/2', 'Gene', (69, 75))	('PTEN', 'Gene', (145, 149))	('facilitate', 'PosReg', (183, 193))	('EGFR', 'Gene', (159, 163))	('astrocytomas', 'Disease', 'MESH:D001254', (310, 322))	('p53', 'Gene', '7157', (61, 64))	('survival', 'CPA', (194, 202))	('mutations', 'Var', (76, 85))	('PTEN', 'Gene', '5728', (145, 149))	('astrocytomas', 'Disease', (25, 37))	('loss', 'NegReg', (150, 154))	('p53', 'Gene', (61, 64))	('PI3K pathway', 'Pathway', (261, 273))
188053	24079673	Furthermore, survival analysis showed that high levels of VRK2 were significantly associated with longer survival in high-grade astrocytomas independently of age or treatment of patients.	('astrocytomas', 'Disease', (128, 140))	('high levels', 'Var', (43, 54))	('VRK2', 'Gene', (58, 62))	('longer', 'PosReg', (98, 104))	('patients', 'Species', '9606', (178, 186))	('astrocytomas', 'Disease', 'MESH:D001254', (128, 140))	('VRK2', 'Gene', '7444', (58, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))
188057	24079673	In addition, high VRK2 levels also inhibit the cellular response to stress induced by hypoxia and by inflammatory interleukins.	('VRK2', 'Gene', (18, 22))	('cellular response to stress', 'MPA', (47, 74))	('high', 'Var', (13, 17))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('VRK2', 'Gene', '7444', (18, 22))	('inhibit', 'NegReg', (35, 42))
188058	24079673	Thus, high VRK2 expression might reduce the strength of the mitogenic signals and contribute to a reduced growth rate as detected in the astrocytoma cell line with higher VRK2 relative level.	('mitogenic signals', 'MPA', (60, 77))	('strength', 'MPA', (44, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('VRK2', 'Gene', (11, 15))	('growth rate', 'CPA', (106, 117))	('VRK2', 'Gene', '7444', (171, 175))	('astrocytoma', 'Disease', (137, 148))	('reduced growth rate', 'Phenotype', 'HP:0001510', (98, 117))	('high', 'Var', (6, 10))	('VRK2', 'Gene', '7444', (11, 15))	('reduced', 'NegReg', (98, 105))	('astrocytoma', 'Disease', 'MESH:D001254', (137, 148))	('VRK2', 'Gene', (171, 175))	('expression', 'MPA', (16, 26))	('reduce', 'NegReg', (33, 39))
188062	24079673	In summary, in this work we have identified the potential value of VRK2 expression as marker of a better prognosis in astrocytomas.	('VRK2', 'Gene', '7444', (67, 71))	('astrocytomas', 'Disease', 'MESH:D001254', (118, 130))	('VRK2', 'Gene', (67, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('expression', 'Var', (72, 82))	('astrocytomas', 'Disease', (118, 130))
188064	24079673	High levels of VRK2 protein is an indicator of a better prognosis in primary high-grade astrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('protein', 'Protein', (20, 27))	('astrocytomas', 'Disease', (88, 100))	('High levels', 'Var', (0, 11))	('VRK2', 'Gene', (15, 19))	('VRK2', 'Gene', '7444', (15, 19))	('astrocytomas', 'Disease', 'MESH:D001254', (88, 100))
188070	33643908	Radiomics Features Predict Telomerase Reverse Transcriptase Promoter Mutations in World Health Organization Grade II Gliomas via a Machine-Learning Approach The detection of mutations in telomerase reverse transcriptase promoter (pTERT) is important since preoperative diagnosis of pTERT status helps with evaluating prognosis and determining the surgical strategy.	('Telomerase Reverse Transcriptase', 'Gene', (27, 59))	('TERT', 'Gene', '7015', (231, 235))	('Gliomas', 'Disease', (117, 124))	('TERT', 'Gene', '7015', (283, 287))	('telomerase reverse transcriptase', 'Gene', (187, 219))	('Telomerase Reverse Transcriptase', 'Gene', '7015', (27, 59))	('telomerase reverse transcriptase', 'Gene', '7015', (187, 219))	('mutations', 'Var', (174, 183))	('TERT', 'Gene', (231, 235))	('Gliomas', 'Disease', 'MESH:D005910', (117, 124))	('Gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('TERT', 'Gene', (283, 287))
188071	33643908	Here, we aimed to establish a radiomics-based machine-learning algorithm and evaluated its performance with regard to the prediction of mutations in pTERT in patients with World Health Organization (WHO) grade II gliomas.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('TERT', 'Gene', (150, 154))	('TERT', 'Gene', '7015', (150, 154))	('II gliomas', 'Disease', (210, 220))	('mutations', 'Var', (136, 145))	('patients', 'Species', '9606', (158, 166))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('II gliomas', 'Disease', 'MESH:D005910', (210, 220))
188074	33643908	Posterior probabilities of pTERT mutations were significantly different between patients with wild-type and mutant TERT promoters.	('TERT', 'Gene', '7015', (115, 119))	('patients', 'Species', '9606', (80, 88))	('different', 'Reg', (62, 71))	('mutations', 'Var', (33, 42))	('mutant', 'Var', (108, 114))	('TERT', 'Gene', (28, 32))	('TERT', 'Gene', '7015', (28, 32))	('TERT', 'Gene', (115, 119))
188078	33643908	Based on these new classification standards, glioblastomas and oligodendrogliomas often exhibit mutations in the telomerase reverse transcriptase promoter (pTERT).	('TERT', 'Gene', (157, 161))	('TERT', 'Gene', '7015', (157, 161))	('glioblastomas', 'Phenotype', 'HP:0012174', (45, 58))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (63, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('telomerase reverse transcriptase', 'Gene', (113, 145))	('glioblastomas', 'Disease', 'MESH:D005909', (45, 58))	('exhibit', 'Reg', (88, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('mutations', 'Var', (96, 105))	('oligodendrogliomas', 'Disease', (63, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('glioblastomas', 'Disease', (45, 58))	('telomerase reverse transcriptase', 'Gene', '7015', (113, 145))
188080	33643908	When pTERT is mutated, TERT is upregulated, resulting in maintenance of cellular growth.	('mutated', 'Var', (14, 21))	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('TERT', 'Gene', (6, 10))	('cellular growth', 'CPA', (72, 87))	('TERT', 'Gene', '7015', (6, 10))
188081	33643908	Mutations in pTERT can be detected in a variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TERT', 'Gene', (14, 18))	('tumors', 'Disease', (51, 57))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('detected', 'Reg', (26, 34))
188082	33643908	In high-grade glioma glioblastoma and low-grade glioma oligodendroglioma, mutations in pTERT can be detected with a high probability.	('TERT', 'Gene', '7015', (88, 92))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('mutations', 'Var', (74, 83))	('glioma oligodendroglioma', 'Disease', (48, 72))	('glioma glioblastoma', 'Disease', 'MESH:D005909', (14, 33))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('glioma glioblastoma', 'Disease', (14, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('glioma oligodendroglioma', 'Disease', 'MESH:D005910', (48, 72))	('detected', 'Reg', (100, 108))	('TERT', 'Gene', (88, 92))
188083	33643908	According to the cIMPACT-NOW update, mutations in pTERT usually suggest a better prognosis in IDH-mutant diffuse gliomas.	('better', 'PosReg', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH', 'Gene', (94, 97))	('TERT', 'Gene', (51, 55))	('gliomas', 'Disease', (113, 120))	('IDH', 'Gene', '3417', (94, 97))	('mutations', 'Var', (37, 46))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('TERT', 'Gene', '7015', (51, 55))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))
188084	33643908	Conversely, mutations in pTERT in IDH-wild-type diffuse gliomas and glioblastomas suggest a poor prognosis.	('diffuse', 'Disease', (48, 55))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('IDH', 'Gene', (34, 37))	('TERT', 'Gene', (26, 30))	('gliomas', 'Disease', (56, 63))	('IDH', 'Gene', '3417', (34, 37))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('mutations', 'Var', (12, 21))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('TERT', 'Gene', '7015', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (68, 81))	('glioblastomas', 'Disease', (68, 81))
188097	33643908	Polymerase chain reaction (PCR) and Sanger sequencing were used to identify mutations in pTERT.	('TERT', 'Gene', '7015', (90, 94))	('mutations', 'Var', (76, 85))	('TERT', 'Gene', (90, 94))
188101	33643908	Regions of interest (ROIs) were drawn in slices presenting with tumors based on T2WI, in which the abnormal area could accurately represent the region implicated in low-grade gliomas.	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('T2WI', 'Var', (80, 84))	('gliomas', 'Disease', (175, 182))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
188112	33643908	The linear SVM model decision values of patients with wild-type or mutant pTERT were compared using unpaired t-test.	('TERT', 'Gene', (75, 79))	('patients', 'Species', '9606', (40, 48))	('TERT', 'Gene', '7015', (75, 79))	('mutant', 'Var', (67, 73))
188116	33643908	The proportion of patients with a mutation in pTERT was 56.7% (93/164).	('TERT', 'Gene', (47, 51))	('TERT', 'Gene', '7015', (47, 51))	('mutation', 'Var', (34, 42))	('patients', 'Species', '9606', (18, 26))
188117	33643908	The proportion of patients with a mutation in IDH and a 1p/19q codeletion were 86% (141/164) and 48.2% (79/164), respectively.	('IDH', 'Gene', '3417', (46, 49))	('IDH', 'Gene', (46, 49))	('patients', 'Species', '9606', (18, 26))	('mutation', 'Var', (34, 42))
188120	33643908	The z-score-transformed value of each important radiomics feature and pTERT status were compared, revealing that all valuable radiomics features in patients with mutations in pTERT were significantly different from patients with wild-type pTERT (p < 0.05).	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (215, 223))	('mutations', 'Var', (162, 171))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (71, 75))	('TERT', 'Gene', (240, 244))	('different', 'Reg', (200, 209))	('TERT', 'Gene', '7015', (240, 244))	('TERT', 'Gene', (176, 180))	('TERT', 'Gene', '7015', (176, 180))
188124	33643908	Further, we compared the posterior probability between wild-type and mutant pTERT, revealing a p-value <0.0001, which indicated that our model can be used to predict the pTERT status of WHO grade II gliomas ( Figure 3 ).	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('TERT', 'Gene', (77, 81))	('mutant', 'Var', (69, 75))	('TERT', 'Gene', '7015', (77, 81))	('TERT', 'Gene', (171, 175))	('II gliomas', 'Disease', (196, 206))	('TERT', 'Gene', '7015', (171, 175))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('II gliomas', 'Disease', 'MESH:D005910', (196, 206))
188125	33643908	Furthermore, the performances of the prediction model in the subgroup of IDH and 1p/19q were evaluated.	('1p/19q', 'Var', (81, 87))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', (73, 76))
188126	33643908	Although the AUCs of the ROC analysis reached a value of 0.853 (95% CI, 0.7834-0.9153), 0.8333 (95% CI, 0.6445-0.9732), and 0.8868 (95% CI, 0.8094-0.9501) for mutant IDH, wild-type IDH, and 1p/19q non-deletion groups, respectively, the AUC for the 1p/19q codeletion showed a rather low value of 0.4595 (95% CI, 0.1638-0.7114).	('IDH', 'Gene', (181, 184))	('0.8333', 'Var', (88, 94))	('mutant', 'Var', (159, 165))	('IDH', 'Gene', '3417', (181, 184))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', '3417', (166, 169))	('0.8868', 'Var', (124, 130))
188127	33643908	Regarding the high rate of pTERT mutations in the 1p/19q codeletion (74/79), the P-R Curve, which is suitable for describing imbalances in binary data, showed a more reliable result to evaluate the model performance.	('TERT', 'Gene', '7015', (28, 32))	('imbalances', 'Phenotype', 'HP:0002172', (125, 135))	('mutations', 'Var', (33, 42))	('TERT', 'Gene', (28, 32))
188128	33643908	In addition, the accuracies were 0.8085 (95% CI, 0.7447-0.8652), 0.7826 (95% CI, 0.6087-0.913), 0.9367 (95% CI, 0.8734-0.9873), and 0.8706 (95% CI, 0.8-0.9412) in mutant IDH, wild-type IDH, 1p/19q codeletion, and 1p/19q non-deletion groups, respectively.	('IDH', 'Gene', (185, 188))	('0.9367', 'Var', (96, 102))	('IDH', 'Gene', '3417', (185, 188))	('mutant', 'Var', (163, 169))	('0.7826', 'Var', (65, 71))	('IDH', 'Gene', (170, 173))	('IDH', 'Gene', '3417', (170, 173))	('0.8706', 'Var', (132, 138))
188130	33643908	The clinical characteristics of patients with mutations in pTERT were associated with poor prognosis with glioblastomas and a good prognosis with oligodendroglioma.	('glioblastomas', 'Phenotype', 'HP:0012174', (106, 119))	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (46, 55))	('oligodendroglioma', 'Disease', (146, 163))	('TERT', 'Gene', '7015', (60, 64))	('glioblastomas', 'Disease', 'MESH:D005909', (106, 119))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioblastomas', 'Disease', (106, 119))	('oligodendroglioma', 'Disease', 'MESH:D009837', (146, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('TERT', 'Gene', (60, 64))
188131	33643908	Based on the presence of pTERT mutations, IDH1/2 mutations, and 1p/19q codeletion status, gliomas were divided into five subtypes with different overall survival.	('gliomas', 'Disease', (90, 97))	('mutations', 'Var', (31, 40))	('TERT', 'Gene', (26, 30))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('mutations', 'Var', (49, 58))	('IDH1/2', 'Gene', '3417;3418', (42, 48))	('TERT', 'Gene', '7015', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1/2', 'Gene', (42, 48))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
188132	33643908	Since patients with lower-grade gliomas (LGGs) who carry mutations in pTERT always have a better survival, the determination of pTERT status by a non-invasive MRI scan may help patients make better decisions regarding their treatment plan.	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (129, 133))	('gliomas', 'Disease', (32, 39))	('TERT', 'Gene', '7015', (71, 75))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('patients', 'Species', '9606', (177, 185))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('mutations', 'Var', (57, 66))	('better', 'PosReg', (90, 96))	('patients', 'Species', '9606', (6, 14))	('survival', 'CPA', (97, 105))	('men', 'Species', '9606', (229, 232))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('TERT', 'Gene', (129, 133))
188143	33643908	Based on the radiomics analysis of conventional MRI, a LASSO regression model was used for predicting molecular subtypes of LGGs including mutant IDH1/2, mutant IDH1/2 with pTERT mutations, and wild-type IDH.	('IDH', 'Gene', '3417', (161, 164))	('IDH1/2', 'Gene', (146, 152))	('IDH1/2', 'Gene', '3417;3418', (161, 167))	('TERT', 'Gene', (174, 178))	('IDH', 'Gene', (146, 149))	('TERT', 'Gene', '7015', (174, 178))	('mutant', 'Var', (139, 145))	('IDH', 'Gene', (204, 207))	('IDH1/2', 'Gene', (161, 167))	('IDH', 'Gene', '3417', (146, 149))	('IDH1/2', 'Gene', '3417;3418', (146, 152))	('IDH', 'Gene', '3417', (204, 207))	('IDH', 'Gene', (161, 164))
188147	33643908	Further, the prediction of mutations in pTERT in the subgroup of IDH also reached stable performances, where the random forest model achieved an AUC of 0.824 (95% CI, 0.639-1) and 0.750 (95% CI, 0.260-1) in the mutant IDH and wild-type IDH groups, respectively.	('mutations', 'Var', (27, 36))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (65, 68))	('TERT', 'Gene', (41, 45))	('IDH', 'Gene', (236, 239))	('TERT', 'Gene', '7015', (41, 45))	('mutant', 'Var', (211, 217))	('IDH', 'Gene', '3417', (236, 239))	('IDH', 'Gene', (218, 221))	('IDH', 'Gene', '3417', (218, 221))
188148	33643908	Although the above radiomics-based analysis achieved good performance in the predication of mutations in pTERT, previous studies have focused on LGGs, which are composed of WHO grades II and III gliomas, with limited sample sizes.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('III gliomas', 'Disease', 'MESH:D005910', (191, 202))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('III gliomas', 'Disease', (191, 202))	('mutations', 'Var', (92, 101))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))
188152	33643908	In addition, the performance of the prediction was also evaluated in the subgroups with IDH and 1p/19q alterations, which reached high and stable accuracies.	('1p/19q alterations', 'Var', (96, 114))	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', (88, 91))
188153	33643908	However, because of the highly skewed dataset of the 1p/19q codeletion group (74 pTERT mutant and five wild-type samples), the ROC curve was limited, and the P-R curve gave a more informative picture of performance, which showed a high F1-score of 0.9673 (95% CI, 0.936-0.9936) and a high accuracy of 0.9367 (95% CI, 0.8734-0.9873).	('mutant', 'Var', (87, 93))	('TERT', 'Gene', (82, 86))	('TERT', 'Gene', '7015', (82, 86))
188172	33184096	sPD-L1+ patients had longer overall survival in GBM (p=0.006) and worse OS in LGG (p=0.028).	('patients', 'Species', '9606', (8, 16))	('overall', 'MPA', (28, 35))	('GBM', 'Disease', (48, 51))	('longer', 'PosReg', (21, 27))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('sPD-L1', 'Chemical', '-', (0, 6))	('sPD-L1+', 'Var', (0, 7))
188184	33184096	Lower-grade glioma (LGG), especially in the presence of isocitrate dehydrogenase (IDH) mutation, presents with even less TILs, potentially due to the immunosuppressive effect of 2-hydroxyglutarate.	('IDH', 'Gene', '3417', (82, 85))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('isocitrate dehydrogenase', 'Gene', '3417', (56, 80))	('glioma', 'Disease', (12, 18))	('TIL', 'Gene', '7096', (121, 124))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (178, 196))	('IDH', 'Gene', (82, 85))	('mutation', 'Var', (87, 95))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('TIL', 'Gene', (121, 124))	('isocitrate dehydrogenase', 'Gene', (56, 80))
188202	33184096	In patients in whom IDH mutational status was not assessed in clinical routine and formalin-fixed, paraffin-embedded (FFPE) tissue was available, IHC for the IDH1 R132H mutation was performed.	('paraffin', 'Chemical', 'MESH:D010232', (99, 107))	('IDH', 'Gene', '3417', (158, 161))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('R132H', 'Var', (163, 168))	('patients', 'Species', '9606', (3, 11))	('R132H', 'Mutation', 'rs121913500', (163, 168))	('formalin', 'Chemical', 'MESH:D005557', (83, 91))	('IDH1', 'Gene', (158, 162))	('IDH', 'Gene', (158, 161))	('IDH1', 'Gene', '3417', (158, 162))
188213	33184096	Patients with glioma presented most frequently with sPD-L1, followed by controls and patients with meningioma and BM (p=0.002, chi2 test).	('glioma', 'Disease', (14, 20))	('meningioma', 'Disease', (99, 109))	('meningioma', 'Phenotype', 'HP:0002858', (99, 109))	('patients', 'Species', '9606', (85, 93))	('Patients', 'Species', '9606', (0, 8))	('sPD-L1', 'Var', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('meningioma', 'Disease', 'MESH:D008577', (99, 109))	('sPD-L1', 'Chemical', '-', (52, 58))
188219	33184096	Similarly, 8 out of 10 (80.0%) pretreated LGG patients were sPD-L1+, while only 5 out of 16 (31.3%) non-pretreated LGG patients had detectable sPD-L1 (p=0.041, chi2 test).	('patients', 'Species', '9606', (46, 54))	('LGG', 'Disease', (42, 45))	('patients', 'Species', '9606', (119, 127))	('sPD-L1+', 'Var', (60, 67))	('sPD-L1', 'Chemical', '-', (60, 66))	('sPD-L1', 'Chemical', '-', (143, 149))
188246	33184096	Interestingly, patients with GBM presented with improved survival prognosis in the presence of sPD-L1 (median OS 20.9 months; 95% CI 16.5 to 25.3 months) as compared with those without sPD-L1 (median OS 8.4 months; 95% CI 4.0 to 12.7 months, p=0.006, figure 4D).	('survival prognosis', 'CPA', (57, 75))	('patients', 'Species', '9606', (15, 23))	('GBM', 'Phenotype', 'HP:0012174', (29, 32))	('sPD-L1', 'Var', (95, 101))	('improved', 'PosReg', (48, 56))	('sPD-L1', 'Chemical', '-', (95, 101))	('sPD-L1', 'Chemical', '-', (185, 191))
188247	33184096	In contrast, LGG patients with detectable sPD-L1 had significantly shorter OS (median OS 38.9 months; 95% CI 21.3 to 56.5 months) compared with patients without sPD-L1 (median OS 89.6 months; 95% CI 75.4 to 103.7 months; p=0.028, figure 4E).	('sPD-L1', 'Var', (42, 48))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (17, 25))	('shorter', 'NegReg', (67, 74))	('LGG', 'Disease', (13, 16))	('sPD-L1', 'Chemical', '-', (161, 167))	('sPD-L1', 'Chemical', '-', (42, 48))
188256	33184096	sPD-L1 was correlated with prognosis as well as response to immune checkpoint inhibitors in extracranial tumours and might be a promising marker to measure systemic immune suppression.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('sPD-L1', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('sPD-L1', 'Chemical', '-', (0, 6))	('correlated', 'Reg', (11, 21))
188257	33184096	Using a sandwich ELISA, we detected sPD-L1 in the plasma of patients with brain tumour and the highest concentration was evident in patients with glioma.	('brain tumour', 'Phenotype', 'HP:0030692', (74, 86))	('sPD-L1', 'Var', (36, 42))	('patients', 'Species', '9606', (60, 68))	('glioma', 'Disease', (146, 152))	('brain tumour', 'Disease', 'MESH:D001932', (74, 86))	('sPD-L1', 'Chemical', '-', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('brain tumour', 'Disease', (74, 86))	('patients', 'Species', '9606', (132, 140))	('detected', 'Reg', (27, 35))
188259	33184096	However, high sPD-L1 was associated with impaired OS prognosis in GBM and improved OS prognosis in LGG, supporting further research of systemic inflammatory processes in glioma.	('sPD-L1', 'Chemical', '-', (14, 20))	('glioma', 'Disease', (170, 176))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('impaired', 'NegReg', (41, 49))	('improved', 'PosReg', (74, 82))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('sPD-L1', 'Gene', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('OS prognosis', 'MPA', (83, 95))	('high', 'Var', (9, 13))
188279	33184096	Interestingly, the presence of sPD-L1 was linked to longer OS in GBM, whereas an impaired association was found in LGG, indicating that the impact of systemic inflammation might differ between glioma subtypes.	('inflammation', 'Disease', (159, 171))	('GBM', 'Disease', (65, 68))	('glioma', 'Disease', (193, 199))	('presence', 'Var', (19, 27))	('sPD-L1', 'Var', (31, 37))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('inflammation', 'Disease', 'MESH:D007249', (159, 171))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('sPD-L1', 'Chemical', '-', (31, 37))
188282	33184096	Previous studies from extracranial malignancies suggest that sPD-L1 is negatively associated with survival in various advanced malignant diseases.	('sPD-L1', 'Var', (61, 67))	('malignant diseases', 'Disease', 'MESH:D009369', (127, 145))	('malignancies', 'Disease', 'MESH:D009369', (35, 47))	('sPD-L1', 'Chemical', '-', (61, 67))	('negatively', 'NegReg', (71, 81))	('malignant diseases', 'Disease', (127, 145))	('malignancies', 'Disease', (35, 47))
188287	33184096	We further acknowledge that analyses with respect to molecular glioma subgroups could not be performed as only 12 patients had verified IDH mutations and IDH sequencing was not performed.	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('IDH', 'Gene', '3417', (154, 157))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('mutations', 'Var', (140, 149))	('IDH', 'Gene', (154, 157))	('patients', 'Species', '9606', (114, 122))	('glioma', 'Disease', (63, 69))
188297	30634925	Although many explorations have revealed that high TMB may yield many neoantigens to incite antitumor immune response, a systematic exploration of the correlation between TMB and immune signatures in different cancer types is lacking.	('neoantigens', 'MPA', (70, 81))	('incite', 'PosReg', (85, 91))	('high', 'Var', (46, 50))	('TMB', 'Chemical', '-', (171, 174))	('TMB', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TMB', 'Chemical', '-', (51, 54))	('tumor', 'Disease', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', (210, 216))
188301	30634925	Importantly, high TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('PD-L1', 'Gene', '29126', (65, 70))	('cancers', 'Disease', (93, 100))	('high', 'Var', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('TMB', 'Chemical', '-', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PD-L1', 'Gene', (65, 70))	('expression', 'MPA', (51, 61))	('elevated', 'PosReg', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
188303	30634925	High TMB may inhibit immune cell infiltrations while promote CTAs expression and inflammatory response in cancer.	('CTAs expression', 'CPA', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('High TMB', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('immune cell infiltrations', 'CPA', (21, 46))	('cancer', 'Disease', (106, 112))	('inhibit', 'NegReg', (13, 20))	('inflammatory response', 'CPA', (81, 102))	('TMB', 'Chemical', '-', (5, 8))	('promote', 'PosReg', (53, 60))
188305	30634925	Our data implicate that higher-TMB patients could gain a more favorable prognosis in diverse cancer types if treated with immunotherapy, otherwise would have a poorer prognosis compared to lower-TMB patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TMB', 'Chemical', '-', (195, 198))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gain', 'PosReg', (50, 54))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (35, 43))	('higher-TMB', 'Var', (24, 34))
188309	30634925	Some well-recognized molecular determinants include PD-L1 expression on tumor, DNA mismatch-repair deficiency, neoantigen load, and tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deficiency', 'Var', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PD-L1', 'Gene', '29126', (52, 57))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PD-L1', 'Gene', (52, 57))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
188312	30634925	These studies demonstrated that higher nonsynonymous mutation burden in tumors is inclined to form more neoantigens that make tumors to have higher immunogenicity, and thus result to improved clinical response to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('improved', 'PosReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('make tumors', 'Disease', (121, 132))	('higher', 'PosReg', (141, 147))	('clinical response', 'CPA', (192, 209))	('nonsynonymous mutation burden', 'Var', (39, 68))	('make tumors', 'Disease', 'MESH:C537705', (121, 132))	('immunogenicity', 'MPA', (148, 162))
188325	30634925	These results suggest that the relatedness between TMB and Treg cells infiltration degree depends on cancer types, whereas the lower-TMB subtype is likely to have stronger Treg cells infiltration than the higher-TMB subtype in diverse cancers.	('TMB', 'Chemical', '-', (133, 136))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('TMB', 'Chemical', '-', (212, 215))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('TMB', 'Chemical', '-', (51, 54))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('Treg cells infiltration', 'CPA', (172, 195))	('lower-TMB', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('stronger', 'PosReg', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
188345	30634925	Again, this suggests that high TMB tends to inhibit immune cell infiltration in cancer.	('high', 'Var', (26, 30))	('inhibit', 'NegReg', (44, 51))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('immune cell infiltration', 'CPA', (52, 76))	('cancer', 'Disease', (80, 86))
188353	30634925	These results indicated that although the association between TMB and TILs infiltration was cancer type dependent, high TMB tended to inhibit TILs infiltration in various cancer types.	('high', 'Var', (115, 119))	('TILs infiltration', 'MPA', (142, 159))	('TMB', 'Chemical', '-', (120, 123))	('TMB', 'Chemical', '-', (62, 65))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('inhibit', 'NegReg', (134, 141))	('association', 'Interaction', (42, 53))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TMB', 'Gene', (120, 123))
188364	30634925	These results suggest that high TMB is associated with elevated expression of many CTAs in cancer.	('expression', 'MPA', (64, 74))	('CTAs', 'Disease', (83, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TMB', 'Chemical', '-', (32, 35))	('elevated', 'PosReg', (55, 63))
188377	30634925	It suggests that high TMB may lead to depressed cytokine activity in diverse cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('depressed cytokine activity', 'Phenotype', 'HP:0031407', (38, 65))	('cancers', 'Disease', (77, 84))	('high', 'Var', (17, 21))	('TMB', 'Chemical', '-', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cytokine', 'Gene', '943', (48, 56))	('cytokine', 'Gene', (48, 56))	('depressed', 'NegReg', (38, 47))
188396	30634925	However, the Treg cells, immune cell infiltrate, TILs, and CCR signatures were inclined to be upregulated in the lower-TMB subtype of various cancer types, suggesting that high TMB may inhibit immune cell infiltration in the TIM.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('immune cell infiltration in the', 'CPA', (193, 224))	('lower-TMB', 'Disease', (113, 122))	('TMB', 'Chemical', '-', (119, 122))	('high TMB', 'Var', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TMB', 'Chemical', '-', (177, 180))	('upregulated', 'PosReg', (94, 105))	('inhibit', 'NegReg', (185, 192))	('cancer', 'Disease', (142, 148))
188397	30634925	In contrast, the CTA and pro-inflammatory signatures tended to be upregulated in the higher-TMB subtype of various cancer types, suggesting that high TMB may promote CTA expression and tumor inflammatory response.	('tumor', 'Disease', (185, 190))	('cancer', 'Disease', (115, 121))	('CTA', 'MPA', (17, 20))	('promote', 'PosReg', (158, 165))	('upregulated', 'PosReg', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CTA', 'Protein', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('TMB', 'Chemical', '-', (150, 153))	('TMB', 'Chemical', '-', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('high', 'Var', (145, 149))
188400	30634925	In fact, when we compared survival prognosis between the lower-TMB subtype and the higher-TMB subtype of cancers, we found that the lower-TMB subtype had better OS and/or DFS prognosis than the higher-TMB subtype in three of the four cancer types including HNSC, ACC, and LIHC (Fig.	('HNSC', 'Disease', (257, 261))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancers', 'Disease', (105, 112))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LIHC', 'Disease', (272, 276))	('OS', 'Chemical', '-', (161, 163))	('better', 'PosReg', (154, 160))	('TMB', 'Chemical', '-', (90, 93))	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('lower-TMB', 'Var', (132, 141))	('DFS', 'MPA', (171, 174))	('ACC', 'Gene', '31', (263, 266))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('ACC', 'Gene', (263, 266))	('TMB', 'Chemical', '-', (63, 66))	('cancer', 'Disease', (234, 240))
188402	30634925	Interestingly, we found that high TMB was associated with elevated pro-inflammatory immune activity while depressed immune cell infiltration in diverse cancers.	('high', 'Var', (29, 33))	('pro-inflammatory immune activity', 'MPA', (67, 99))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('TMB', 'Chemical', '-', (34, 37))	('depressed immune cell', 'Phenotype', 'HP:0002721', (106, 127))	('elevated', 'PosReg', (58, 66))	('immune cell infiltration', 'CPA', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('depressed', 'NegReg', (106, 115))	('TMB', 'Gene', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
188403	30634925	These findings appear to be contradictory and disagree with the established notion that high TMB may yield numerous neoantigens that incite anti-tumor immune response.	('high', 'Var', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('incite', 'PosReg', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('TMB', 'Chemical', '-', (93, 96))	('neoantigens', 'MPA', (116, 127))
188404	30634925	The possible explanations are that high TMB is often associated with genome instability that may inhibit anti-tumor immune response, and that the increased pro-inflammatory immune activity could be attributed to the higher percent of tumor necrosis component elicited by gene mutations in the higher-TMB cancer.	('pro-inflammatory immune activity', 'MPA', (156, 188))	('inhibit', 'NegReg', (97, 104))	('tumor', 'Disease', (234, 239))	('cancer', 'Disease', (304, 310))	('TMB', 'Chemical', '-', (300, 303))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gene mutations', 'Var', (271, 285))	('increased', 'PosReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor necrosis', 'Disease', 'MESH:D009336', (234, 248))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('tumor necrosis', 'Disease', (234, 248))	('high', 'Disease', (35, 39))	('TMB', 'Chemical', '-', (40, 43))	('tumor', 'Disease', (110, 115))	('higher', 'PosReg', (216, 222))	('higher-TMB', 'Disease', (293, 303))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
188425	30634925	High TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('elevated', 'PosReg', (29, 37))	('High', 'Var', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('expression', 'MPA', (38, 48))	('PD-L1', 'Gene', '29126', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TMB', 'Chemical', '-', (5, 8))	('PD-L1', 'Gene', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
188428	30634925	Consistent with a method we proposed previously, the TMB score of a tumor sample was calculated as follows:  total number of truncating mutations * 2.0 + total number of non-truncating mutations * 1.0  Nonsense, frame-shift deletion or insertion, and splice-site mutations were included in the truncating mutation category, and missense, in-frame deletion or insertion, and nonstop mutations were included in the non-truncating mutation category.	('tumor', 'Disease', (68, 73))	('missense', 'Var', (328, 336))	('frame-shift deletion', 'Var', (212, 232))	('insertion', 'Var', (236, 245))	('splice-site mutations', 'Var', (251, 272))	('Nonsense', 'Var', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('in-frame deletion', 'Var', (338, 355))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TMB', 'Chemical', '-', (53, 56))
188467	27843499	Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme LINE-1 (L1) retrotransposons are a notable endogenous source of mutagenesis in mammals.	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (86, 109))	('rearrangements', 'Var', (31, 45))	('L1', 'Gene', '6137', (118, 120))	('L1', 'Gene', '6137', (61, 63))	('LINE-1 (L1', 'Gene', '3897', (110, 120))	('glioblastoma multiforme', 'Disease', (86, 109))	('L1', 'Gene', '6137', (13, 15))
188470	27843499	Here, using retrotransposon capture sequencing (RC-seq), we surveyed L1 mutations in 14 tumours classified as glioblastoma multiforme (GBM) or as a lower grade glioma.	('mutations', 'Var', (72, 81))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (110, 133))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('glioma', 'Disease', (160, 166))	('L1', 'Gene', '6137', (69, 71))	('14 tumours', 'Disease', (85, 95))	('14 tumours', 'Disease', 'MESH:C567448', (85, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('glioblastoma multiforme', 'Disease', (110, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
188471	27843499	In four GBM tumours, we characterised one probable endonuclease-independent L1 insertion, two L1-associated rearrangements and one likely Alu-Alu recombination event adjacent to an L1.	('Alu', 'Chemical', '-', (142, 145))	('Alu', 'Chemical', '-', (138, 141))	('L1', 'Gene', '6137', (181, 183))	('L1', 'Gene', '6137', (76, 78))	('L1', 'Gene', '6137', (94, 96))	('GBM tumours', 'Disease', 'MESH:D005910', (8, 19))	('insertion', 'Var', (79, 88))	('GBM tumours', 'Disease', (8, 19))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))
188472	27843499	These mutations included PCR validated intronic events in MeCP2 and EGFR.	('MeCP2', 'Gene', '4204', (58, 63))	('EGFR', 'Gene', '1956', (68, 72))	('MeCP2', 'Gene', (58, 63))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (6, 15))
188474	27843499	Whole genome sequencing analysis of the tumours carrying the MeCP2 and EGFR L1 mutations also revealed no endonuclease-dependent L1 insertions.	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('MeCP2', 'Gene', '4204', (61, 66))	('MeCP2', 'Gene', (61, 66))	('L1', 'Gene', '6137', (76, 78))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('EGFR', 'Gene', '1956', (71, 75))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('EGFR', 'Gene', (71, 75))	('L1', 'Gene', '6137', (129, 131))	('mutations', 'Var', (79, 88))
188475	27843499	In a complementary in vitro assay, wild-type and endonuclease mutant L1 reporter constructs each mobilised very inefficiently in four cultured GBM cell lines.	('L1', 'Gene', '6137', (69, 71))	('mutant', 'Var', (62, 68))	('mobilised', 'MPA', (97, 106))
188476	27843499	These experiments altogether highlight the consistent absence of canonical L1 retrotransposition in GBM tumours and cultured cell lines, as well as atypical L1-associated sequence rearrangements following DNA damage in vivo.	('absence', 'NegReg', (54, 61))	('GBM tumours', 'Disease', 'MESH:D005910', (100, 111))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('GBM tumours', 'Disease', (100, 111))	('rearrangements', 'Var', (180, 194))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('L1', 'Gene', '6137', (75, 77))	('L1', 'Gene', '6137', (157, 159))
188481	27843499	Defects in several DNA repair mechanisms, especially in the repair of DNA double strand breaks (DSBs), are known to enable genomic aberrations, such as deletions and amplifications, in GBM.	('DSBs', 'Chemical', '-', (96, 100))	('amplifications', 'Var', (166, 180))	('Defects', 'Var', (0, 7))	('deletions', 'Var', (152, 161))
188487	27843499	Once the RNP enters the nucleus, the L1-encoded EN can cleave genomic DNA and, typically, generate a new L1 insertion via target-primed reverse transcription (TPRT).	('generate', 'Reg', (90, 98))	('RNP', 'Gene', '55599', (9, 12))	('cleave', 'Reg', (55, 61))	('TPRT', 'Chemical', '-', (159, 163))	('insertion', 'Var', (108, 117))	('L1', 'Gene', '6137', (37, 39))	('L1', 'Gene', '6137', (105, 107))	('RNP', 'Gene', (9, 12))
188488	27843499	Hallmarks of L1 integration by TPRT include use of an L1 EN recognition motif (5'-TT/AAAA), target site duplications (TSDs), and an L1 poly-A tail.	('TSDs', 'Disease', (118, 122))	('TSDs', 'Disease', 'None', (118, 122))	('L1', 'Gene', '6137', (132, 134))	('TPRT', 'Chemical', '-', (31, 35))	('L1', 'Gene', '6137', (54, 56))	('duplications', 'Var', (104, 116))	('L1', 'Gene', '6137', (13, 15))
188492	27843499	Although TPRT-mediated L1 mobilisation occurs in many cancers and neural cells, several recent studies employing high-throughput sequencing have reported a surprising absence of somatic L1 insertions in brain tumours.	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('cancers', 'Disease', (54, 61))	('absence', 'NegReg', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('L1', 'Gene', '6137', (186, 188))	('insertions', 'Var', (189, 199))	('brain tumour', 'Phenotype', 'HP:0030692', (203, 215))	('L1', 'Gene', '6137', (23, 25))	('brain tumours', 'Phenotype', 'HP:0030692', (203, 216))	('TPRT', 'Chemical', '-', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('brain tumours', 'Disease', 'MESH:D001932', (203, 216))	('brain tumours', 'Disease', (203, 216))
188493	27843499	We hypothesised that L1-associated DNA rearrangements in GBM might occur via recombination or an atypical retrotransposition mechanism and therefore may lack the TPRT hallmarks required for L1 insertion recognition by previous genomic analyses.	('L1', 'Gene', '6137', (21, 23))	('L1', 'Gene', '6137', (190, 192))	('GBM', 'Gene', (57, 60))	('rearrangements', 'Var', (39, 53))	('TPRT', 'Chemical', '-', (162, 166))	('occur', 'Reg', (67, 72))
188495	27843499	We therefore applied deep retrotransposon capture sequencing (RC-seq) to 14 brain tumour patients (9 GBM and 5 lower grade glioma) and detected tumour-specific L1-associated mutations lacking TPRT hallmarks in 4 GBM tumour samples, and also found no examples of TPRT-driven L1 mobilisation.	('GBM tumour', 'Disease', (212, 222))	('glioma', 'Disease', (123, 129))	('L1', 'Gene', '6137', (160, 162))	('brain tumour', 'Phenotype', 'HP:0030692', (76, 88))	('brain tumour', 'Disease', 'MESH:D001932', (76, 88))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('brain tumour', 'Disease', (76, 88))	('mutations', 'Var', (174, 183))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('TPRT', 'Chemical', '-', (192, 196))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('tumour', 'Disease', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (216, 222))	('tumour', 'Disease', (216, 222))	('L1', 'Gene', '6137', (274, 276))	('TPRT', 'Chemical', '-', (262, 266))	('patients', 'Species', '9606', (89, 97))	('GBM tumour', 'Disease', 'MESH:D005910', (212, 222))
188498	27843499	Unusual endonuclease-independent L1 retrotransposition or L1-associated recombination events can however occasionally occur, and may impact the expression of genes relevant to GBM aetiology and neural cell morphology.	('L1', 'Gene', '6137', (58, 60))	('expression', 'MPA', (144, 154))	('recombination', 'Var', (72, 85))	('impact', 'Reg', (133, 139))	('genes', 'Gene', (158, 163))	('L1', 'Gene', '6137', (33, 35))
188512	27843499	Split-read mappings joining an L1 to the reference genome were then clustered and annotated for the presence of TSDs or deletions.	('L1', 'Gene', '6137', (31, 33))	('TSDs', 'Disease', 'None', (112, 116))	('deletions', 'Var', (120, 129))	('TSDs', 'Disease', (112, 116))
188520	27843499	Four putative tumour-specific L1 mutations were reported at these thresholds (Additional file 1: Table S2).	('tumour', 'Disease', (14, 20))	('mutations', 'Var', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('L1', 'Gene', '6137', (30, 32))
188521	27843499	Empty/filled site PCR assays were used to validate tumour-specific L1 mutations detected by RC-seq.	('mutations', 'Var', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('L1', 'Gene', '6137', (67, 69))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
188522	27843499	PCR reactions involved the following reagents: 1U MyTaq DNA polymerase (Bioline, Australia, #BIO-21106), 1x MyTaq Reaction Buffer, 2 muM primers and 20 ng template DNA in a 25 muL reaction volume with the following cycling conditions for the MeCP2 L1 mutation: 3 min at 92  C, then 10 cycles of 30s at 92  C, 30s at 60  C and 6 min 30s at 68  C, followed by 20 cycles of 30s at 92  C, 30s at 58  C and 6 min 30s at 68  C (increasing by 20s per cycle), followed by a single extension step at 68  C for 10 min.	('MeCP2', 'Gene', (242, 247))	('MeCP2', 'Gene', '4204', (242, 247))	('mutation', 'Var', (251, 259))	('L1', 'Gene', '6137', (248, 250))
188523	27843499	For the EGFR L1 mutation, PCR was performed using primers targeting the 5' L1-genome junction with the following cycling conditions: 2 min at 95  C, then 20 cycles of 15 s at 95  C, 30s at 59  C and 30s at 72  C, followed by a single extension step at 72  C for 10 min.	('mutation', 'Var', (16, 24))	('EGFR', 'Gene', '1956', (8, 12))	('L1', 'Gene', '6137', (75, 77))	('EGFR', 'Gene', (8, 12))	('L1', 'Gene', '6137', (13, 15))
188552	27843499	To obtain wild-type L1.3 (L1.3 WT) and L1.3-D205A/D702A (EN and RT double mutant) constructs, plasmids carrying the individual mutations were digested with EcoRI (New England Biolabs USA, #R3101), NotI and BstZ17I simultaneously (2 h at 37  C).	('D702A', 'Mutation', 'p.D702A', (50, 55))	('L1.3', 'Gene', '28929', (26, 30))	('L1.3 WT', 'Gene', (26, 33))	('L1.3', 'Gene', (20, 24))	('L1.3', 'Gene', '28929', (20, 24))	('L1.3', 'Gene', '28929', (39, 43))	('L1.3 WT', 'Gene', '6137', (26, 33))	('D205A', 'SUBSTITUTION', 'None', (44, 49))	('mutations', 'Var', (127, 136))	('L1.3', 'Gene', (39, 43))	('L1.3', 'Gene', (26, 30))	('D205A', 'Var', (44, 49))
188566	27843499	We identified four putative tumour-specific L1 mutations in four different GBM patients (Additional file 1: Table S2).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (47, 56))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', (28, 34))	('patients', 'Species', '9606', (79, 87))	('L1', 'Gene', '6137', (44, 46))
188567	27843499	Three of these mutations were located within genes known to be active in the brain (MeCP2, EGFR and CEP112) while the other was intergenic and was not associated with a known regulatory element, such as a promoter region or annotated enhancer (Additional file 1: Table S2).	('MeCP2', 'Gene', (84, 89))	('EGFR', 'Gene', (91, 95))	('mutations', 'Var', (15, 24))	('CEP112', 'Gene', '201134', (100, 106))	('EGFR', 'Gene', '1956', (91, 95))	('CEP112', 'Gene', (100, 106))	('MeCP2', 'Gene', '4204', (84, 89))
188568	27843499	The putative tumour-specific L1 mutations in MeCP2 and EGFR were validated via PCR (see below).	('EGFR', 'Gene', '1956', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('EGFR', 'Gene', (55, 59))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('L1', 'Gene', '6137', (29, 31))	('MeCP2', 'Gene', '4204', (45, 50))	('mutations', 'Var', (32, 41))	('tumour', 'Disease', (13, 19))	('MeCP2', 'Gene', (45, 50))
188569	27843499	RC-seq read information however indicated that the putative L1 insertion in CEP112 involved an L1-Ta donor sequence, a long (102 nt) poly-A tail and a degenerate L1 EN recognition motif, suggesting potential TPRT-mediated L1 mobilisation, albeit without corroboration via PCR.	('donor', 'Species', '9606', (101, 106))	('involved', 'Reg', (83, 91))	('L1', 'Gene', '6137', (162, 164))	('insertion', 'Var', (63, 72))	('CEP112', 'Gene', '201134', (76, 82))	('L1', 'Gene', '6137', (222, 224))	('L1', 'Gene', '6137', (95, 97))	('TPRT', 'Chemical', '-', (208, 212))	('L1', 'Gene', '6137', (60, 62))	('CEP112', 'Gene', (76, 82))
188570	27843499	The remaining putative L1 mutation was annotated as an older L1PA2 element, which are usually not capable of autonomous retrotransposition in humans, and also lacked an L1 EN motif.	('mutation', 'Var', (26, 34))	('L1', 'Gene', '6137', (169, 171))	('L1', 'Gene', '6137', (61, 63))	('lacked', 'NegReg', (159, 165))	('L1', 'Gene', '6137', (23, 25))	('humans', 'Species', '9606', (142, 148))
188572	27843499	In patient #2, a female, we identified a putative intronic L1 mutation in the methyl CpG binding protein 2 (MeCP2) gene by RC-seq that was confirmed by PCR (Fig.	('methyl CpG binding protein 2', 'Gene', (78, 106))	('L1', 'Gene', '6137', (59, 61))	('patient', 'Species', '9606', (3, 10))	('mutation', 'Var', (62, 70))	('MeCP2', 'Gene', '4204', (108, 113))	('MeCP2', 'Gene', (108, 113))	('methyl CpG binding protein 2', 'Gene', '4204', (78, 106))
188583	27843499	WGS applied to patient #2 tumour and adjacent brain revealed tumour-specific copy number gain at the MeCP2 locus and an absence of single nucleotide variants or DNA rearrangements, other than the L1 mutation.	('patient', 'Species', '9606', (15, 22))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('L1', 'Gene', '6137', (196, 198))	('gain', 'PosReg', (89, 93))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('single nucleotide variants', 'Var', (131, 157))	('tumour', 'Disease', (26, 32))	('tumour', 'Disease', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('MeCP2', 'Gene', '4204', (101, 106))	('copy', 'MPA', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('MeCP2', 'Gene', (101, 106))
188584	27843499	Quantitative PCR measuring copy number of the genomic region deleted 3' of the L1 mutation confirmed that the L1-mutant MeCP2 allele was amplified in the tumour as, despite overall amplification of the MeCP2 locus as detected by WGS, we identified copy number loss of this deleted 3' sequence in the tumour.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('MeCP2', 'Gene', '4204', (120, 125))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('mutation', 'Var', (82, 90))	('MeCP2', 'Gene', (120, 125))	('MeCP2', 'Gene', (202, 207))	('L1', 'Gene', '6137', (79, 81))	('L1', 'Gene', '6137', (110, 112))	('tumour', 'Phenotype', 'HP:0002664', (300, 306))	('tumour', 'Disease', (154, 160))	('MeCP2', 'Gene', '4204', (202, 207))	('tumour', 'Disease', 'MESH:D009369', (300, 306))	('tumour', 'Disease', (300, 306))	('loss', 'NegReg', (260, 264))
188588	27843499	Replicate PCR performed on seven spatially disparate tumour foci detected the L1 mutation in all locations (Additional file 2: Figure S1C).	('tumour foci', 'Disease', 'MESH:C565785', (53, 64))	('detected', 'Reg', (65, 73))	('tumour foci', 'Disease', (53, 64))	('mutation', 'Var', (81, 89))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('L1', 'Gene', '6137', (78, 80))
188589	27843499	These data suggest that the MeCP2 L1 mutation underwent copy number gain, was present in clonally amplified cells, and may have impacted MeCP2 expression and function throughout the tumour mass.	('L1', 'Gene', '6137', (34, 36))	('tumour mass', 'Disease', (182, 193))	('expression', 'MPA', (143, 153))	('mutation', 'Var', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('function', 'MPA', (158, 166))	('MeCP2', 'Gene', '4204', (137, 142))	('MeCP2', 'Gene', (137, 142))	('impacted', 'Reg', (128, 136))	('MeCP2', 'Gene', '4204', (28, 33))	('MeCP2', 'Gene', (28, 33))	('gain', 'PosReg', (68, 72))	('tumour mass', 'Disease', 'MESH:C536030', (182, 193))	('copy number', 'MPA', (56, 67))
188590	27843499	Given these results, we propose transcriptional disruption by the L1 as a plausible cause for reduced MeCP2 expression, although we cannot rule out the involvement of another mechanism.	('L1', 'Gene', '6137', (66, 68))	('MeCP2', 'Gene', '4204', (102, 107))	('reduced', 'NegReg', (94, 101))	('MeCP2', 'Gene', (102, 107))	('transcriptional disruption', 'Var', (32, 58))	('expression', 'MPA', (108, 118))
188591	27843499	In patient #8, RC-seq detected a putative tumour-specific L1 mutation in the first intron of the epidermal growth factor receptor gene (EGFR) (Fig.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('L1', 'Gene', '6137', (58, 60))	('patient', 'Species', '9606', (3, 10))	('mutation in', 'Var', (61, 72))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
188594	27843499	PCR upon multiple tumour foci suggested that the L1 mutation was clonally amplified (Additional file 2: Figure S1E).	('L1', 'Gene', '6137', (49, 51))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('mutation', 'Var', (52, 60))	('tumour foci', 'Disease', (18, 29))	('tumour foci', 'Disease', 'MESH:C565785', (18, 29))
188595	27843499	Unlike the MeCP2 L1 mutation, the EGFR L1 mutation did not appear to impact host gene expression.	('L1', 'Gene', '6137', (17, 19))	('EGFR', 'Gene', (34, 38))	('MeCP2', 'Gene', '4204', (11, 16))	('mutation', 'Var', (42, 50))	('L1', 'Gene', '6137', (39, 41))	('MeCP2', 'Gene', (11, 16))	('impact', 'Reg', (69, 75))	('EGFR', 'Gene', '1956', (34, 38))
188597	27843499	As EGFR structural and copy number variation is a common feature of GBM, we performed WGS on patient #8 tumour and blood samples, elucidating major (>50x) copy number amplification of EGFR and the surrounding genomic locus (Fig.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('EGFR', 'Gene', '1956', (184, 188))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('copy number amplification', 'Var', (155, 180))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('EGFR', 'Gene', (184, 188))	('patient', 'Species', '9606', (93, 100))	('tumour', 'Disease', (104, 110))
188599	27843499	Further WGS data analysis suggested that the majority of additional EGFR alleles did not incorporate the L1 mutation, indicating that copy number amplification primarily drove EGFR induction.	('EGFR', 'Gene', '1956', (176, 180))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (176, 180))	('L1', 'Gene', '6137', (105, 107))	('EGFR', 'Gene', (68, 72))	('copy number amplification', 'Var', (134, 159))
188600	27843499	To place the PCR validated L1-associated mutations in MeCP2 and EGFR into a broader context of genomic abnormality, we analysed WGS data from patients #2 and #8 (Additional file 1: Table S5).	('mutations', 'Var', (41, 50))	('MeCP2', 'Gene', '4204', (54, 59))	('L1', 'Gene', '6137', (27, 29))	('MeCP2', 'Gene', (54, 59))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('patients', 'Species', '9606', (142, 150))
188602	27843499	Here we found that a significant portion of cells from the normal tissue did in fact contain tumour cells based on the presence of mutations at low variant allele fraction (VAF) in the normal tissue and at an increased VAF in the tumour tissue.	('mutations', 'Var', (131, 140))	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('VAF', 'MPA', (219, 222))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('VAF', 'Chemical', '-', (219, 222))	('tumour', 'Disease', (230, 236))	('increased', 'PosReg', (209, 218))	('VAF', 'Chemical', '-', (173, 176))	('contain', 'Reg', (85, 92))
188603	27843499	For example, we identified a TP53 mutation (c.421C > T/p.Arg141Cys) present in 18.5 % of sequencing reads from adjacent tissue and 90.9 % of tumour reads.	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('p.Arg141Cys', 'Mutation', 'rs121913343', (55, 66))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('c.421C > T/p.Arg141Cys', 'Var', (44, 66))	('tumour', 'Disease', (141, 147))	('c.421C > T', 'Mutation', 'rs121913343', (44, 54))
188604	27843499	This mutation corresponded to rs121913343/COSM3719990 (dbSNP/COSMIC) but may have been somatic in this instance given the low VAF in normal tissue.	('VAF', 'CPA', (126, 129))	('rs121913343', 'DBSNP_MENTION', 'None', (30, 41))	('VAF', 'Chemical', '-', (126, 129))	('rs121913343', 'Var', (30, 41))
188605	27843499	Other potentially pathogenic point mutations in patient #2 included an established GBM mutation in the IDH1 gene at p.Arg132His.	('pathogenic', 'Reg', (18, 28))	('IDH1', 'Gene', '3417', (103, 107))	('p.Arg132His', 'Mutation', 'rs121913500', (116, 127))	('p.Arg132His', 'Var', (116, 127))	('patient', 'Species', '9606', (48, 55))	('IDH1', 'Gene', (103, 107))
188606	27843499	We observe LOH over APC leading to at least two non-synonymous changes increasing in VAF to >95 % (rs139196838, rs459552).	('rs459552', 'Var', (112, 120))	('increasing', 'PosReg', (71, 81))	('rs459552', 'Mutation', 'rs459552', (112, 120))	('rs139196838', 'Mutation', 'rs139196838', (99, 110))	('VAF', 'Chemical', '-', (85, 88))	('APC', 'Disease', 'MESH:D011125', (20, 23))	('VAF', 'Protein', (85, 88))	('rs139196838', 'Var', (99, 110))	('APC', 'Disease', (20, 23))
188608	27843499	We also detected a focal ~2.7kbp deletion removing both copies of CDKN2A exon 2 inside of a larger single-copy region encompassing CDKN2A/B (Additional file 4: Figure S4).	('CDKN2A/B', 'Gene', '1029;1030', (131, 139))	('CDKN2A', 'Gene', '1029', (131, 137))	('deletion', 'Var', (33, 41))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDKN2A/B', 'Gene', (131, 139))	('removing', 'NegReg', (42, 50))	('CDKN2A', 'Gene', (66, 72))	('CDKN2A', 'Gene', (131, 137))
188609	27843499	Finally, we detected copy number amplifications at the end of the q arm on chromosome X, which indicated one additional copy in two regions, one of which included MeCP2 (Additional file 5: Figure S5).	('MeCP2', 'Gene', '4204', (163, 168))	('copy number amplifications', 'Var', (21, 47))	('MeCP2', 'Gene', (163, 168))
188610	27843499	This copy number increase provides a reasonable explanation for the 50 % decrease in MeCP2 expression in this tumour relative to the adjacent tissue, due to the aforementioned intronic L1 mutation in the amplified MeCP2 allele (Fig.	('expression', 'MPA', (91, 101))	('MeCP2', 'Gene', '4204', (214, 219))	('L1', 'Gene', '6137', (185, 187))	('MeCP2', 'Gene', '4204', (85, 90))	('mutation', 'Var', (188, 196))	('MeCP2', 'Gene', (214, 219))	('MeCP2', 'Gene', (85, 90))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('intronic', 'Var', (176, 184))	('decrease', 'NegReg', (73, 81))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
188612	27843499	Additionally this tumour contained a deletion surrounding CDKN2A/B, and an amplification of the RAS-related oncogene RAB14 on chr9q33.2 (Additional file 6: Figure S6B).	('deletion', 'Var', (37, 45))	('CDKN2A/B', 'Gene', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('RAB14', 'Gene', '51552', (117, 122))	('RAB14', 'Gene', (117, 122))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('CDKN2A/B', 'Gene', '1029;1030', (58, 66))	('tumour', 'Disease', (18, 24))
188613	27843499	There were few point mutations affecting known cancer or GBM-associated genes detected in this sample at appreciable (>10 %) VAF.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('point mutations', 'Var', (15, 30))	('VAF', 'Chemical', '-', (125, 128))
188614	27843499	The detected examples include a frameshift mutation of the histone methyltransferase and known tumour suppressor SETD2 (p.Asp14fs) that can activate TP53 and is necessary for DSB repair via homologous recombination, and a putative splice donor site mutation affecting CIITA (class II MHC transactivator).	('class II MHC transactivator', 'Gene', (275, 302))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('activate', 'PosReg', (140, 148))	('SETD2', 'Gene', '29072', (113, 118))	('class II MHC transactivator', 'Gene', '4261', (275, 302))	('TP53', 'Gene', '7157', (149, 153))	('donor', 'Species', '9606', (238, 243))	('SETD2', 'Gene', (113, 118))	('CIITA', 'Gene', (268, 273))	('frameshift mutation', 'Var', (32, 51))	('tumour', 'Disease', (95, 101))	('CIITA', 'Gene', '4261', (268, 273))	('TP53', 'Gene', (149, 153))	('p.Asp14fs', 'Mutation', 'p.D14fsX', (120, 129))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
188615	27843499	Thus, the L1 mutation observed here in EGFR was likely a passenger to the main oncogenic transformation enabling tumorigenesis in patient #8 and occurred in an environment of impinged DNA repair.	('patient', 'Species', '9606', (130, 137))	('mutation', 'Var', (13, 21))	('L1', 'Gene', '6137', (10, 12))	('tumorigenesis', 'CPA', (113, 126))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
188624	27843499	These experiments reveal rare L1-associated mutations caused by recombination or L1 ENi retrotransposition in GBM tumours, accompanied by an absence of TPRT-driven L1 insertions.	('L1', 'Gene', '6137', (164, 166))	('retrotransposition', 'Var', (88, 106))	('caused by', 'Reg', (54, 63))	('GBM tumours', 'Disease', 'MESH:D005910', (110, 121))	('recombination', 'Var', (64, 77))	('GBM tumours', 'Disease', (110, 121))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (44, 53))	('ENi', 'Chemical', '-', (84, 87))	('TPRT', 'Chemical', '-', (152, 156))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('L1', 'Gene', '6137', (30, 32))	('L1', 'Gene', '6137', (81, 83))
188625	27843499	Endonuclease-independent L1 insertions have been reported by several prior studies employing engineered L1 reporter constructs in cultured cancer cells or cells otherwise deficient for DNA damage repair factors, or through bioinformatic analysis of the human reference genome.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('L1', 'Gene', '6137', (25, 27))	('L1', 'Gene', '6137', (104, 106))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('insertions', 'Var', (28, 38))	('human', 'Species', '9606', (253, 258))	('cancer', 'Disease', (139, 145))
188626	27843499	Unusual L1 integration sites identified by these studies incorporated, amongst other features, genomic deletions, deletions of the L1 3' end and poly-A tail, absence of TSDs and absence of an L1 EN recognition motif.	('TSDs', 'Disease', 'None', (169, 173))	('L1', 'Gene', '6137', (192, 194))	('TSDs', 'Disease', (169, 173))	('L1', 'Gene', '6137', (131, 133))	('absence', 'NegReg', (178, 185))	('deletions', 'Var', (103, 112))	('L1', 'Gene', '6137', (8, 10))	('deletions', 'Var', (114, 123))
188627	27843499	Here, by fully resolving the structures of GBM tumour-specific L1 mutations through RC-seq and capillary sequencing, we confirmed they lacked a recognisable L1 poly-A tail or TSDs, and incorporated genomic deletions.	('mutations', 'Var', (66, 75))	('incorporated', 'Reg', (185, 197))	('GBM tumour', 'Disease', 'MESH:D005910', (43, 53))	('L1', 'Gene', '6137', (63, 65))	('TSDs', 'Disease', (175, 179))	('TSDs', 'Disease', 'None', (175, 179))	('GBM tumour', 'Disease', (43, 53))	('lacked', 'NegReg', (135, 141))	('L1', 'Gene', '6137', (157, 159))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
188628	27843499	In the case of the EGFR L1 mutation, these features are suggestive of L1 ENi mobilisation, as primarily reported by others using engineered L1 systems in vitro or, potentially, DNA recombination.	('L1', 'Gene', '6137', (24, 26))	('ENi', 'Chemical', '-', (73, 76))	('L1', 'Gene', '6137', (70, 72))	('EGFR', 'Gene', '1956', (19, 23))	('mutation', 'Var', (27, 35))	('EGFR', 'Gene', (19, 23))	('L1', 'Gene', '6137', (140, 142))
188629	27843499	Genomic abnormality at L1 mutation sites may also explain failure to PCR validate 2/4 observed putative tumour-specific L1 mutations.	('mutations', 'Var', (123, 132))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('L1', 'Gene', '6137', (120, 122))	('L1', 'Gene', '6137', (23, 25))	('tumour', 'Disease', (104, 110))
188630	27843499	Notably, our WGS analyses elucidated mutations in key DSB repair factors, such as SETD2 in patient #8, as well as TP53 deficiency in patient #2.	('SETD2', 'Gene', '29072', (82, 87))	('deficiency', 'Disease', 'MESH:D007153', (119, 129))	('SETD2', 'Gene', (82, 87))	('patient', 'Species', '9606', (133, 140))	('TP53', 'Gene', '7157', (114, 118))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (114, 118))	('patient', 'Species', '9606', (91, 98))	('deficiency', 'Disease', (119, 129))
188631	27843499	Thus, rare tumour-specific L1-associated mutations occur in GBM in a milieu of deficient DSB repair previously encountered for similar events in vitro.	('mutations', 'Var', (41, 50))	('L1', 'Gene', '6137', (27, 29))	('GBM', 'Gene', (60, 63))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('tumour', 'Disease', (11, 17))
188632	27843499	Although identified at first by RC-seq as a potential L1 mobilisation event, further characterisation of the MeCP2 L1 mutation indicated a probable DNA rearrangement event mediated by Alu:Alu recombination.	('MeCP2', 'Gene', '4204', (109, 114))	('MeCP2', 'Gene', (109, 114))	('Alu', 'Chemical', '-', (184, 187))	('L1', 'Gene', '6137', (115, 117))	('mutation', 'Var', (118, 126))	('L1', 'Gene', '6137', (54, 56))	('Alu', 'Chemical', '-', (188, 191))
188634	27843499	The involvement of an older L1 family in a tumour-specific DNA rearrangement event is reminiscent of one of the earliest L1 mutations detected in cancer, in that case affecting the myc locus in breast tumour.	('tumour', 'Disease', (201, 207))	('affecting', 'Reg', (167, 176))	('cancer', 'Disease', (146, 152))	('myc', 'Gene', (181, 184))	('mutations', 'Var', (124, 133))	('L1', 'Gene', '6137', (28, 30))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('L1', 'Gene', '6137', (121, 123))	('tumour', 'Disease', (43, 49))	('myc', 'Gene', '4609', (181, 184))	('breast tumour', 'Disease', (194, 207))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('breast tumour', 'Phenotype', 'HP:0100013', (194, 207))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('breast tumour', 'Disease', 'MESH:D001943', (194, 207))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
188636	27843499	The tumour-specific L1 mutation in MeCP2 appeared to reduce the expression of this gene concomitant with copy number gain for the L1 mutant MeCP2 allele and, as suggested by increased L1 expression and reduced L1 5'UTR methylation, may have reduced MeCP2 function throughout the tumour mass, causing a molecular phenotype.	('reduced', 'NegReg', (202, 209))	('reduced', 'NegReg', (241, 248))	('tumour mass', 'Disease', 'MESH:C536030', (279, 290))	('function', 'MPA', (255, 263))	('MeCP2', 'Gene', (140, 145))	('tumour mass', 'Disease', (279, 290))	('MeCP2', 'Gene', '4204', (35, 40))	('copy', 'MPA', (105, 109))	('reduce', 'NegReg', (53, 59))	('MeCP2', 'Gene', (249, 254))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('MeCP2', 'Gene', (35, 40))	('L1', 'Gene', '6137', (20, 22))	('expression', 'MPA', (64, 74))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('L1', 'Gene', '6137', (130, 132))	('mutant', 'Var', (133, 139))	('tumour', 'Disease', (279, 285))	('MeCP2', 'Gene', '4204', (140, 145))	('mutation', 'Var', (23, 31))	('L1', 'Gene', '6137', (210, 212))	('gain', 'PosReg', (117, 121))	('L1', 'Gene', '6137', (184, 186))	('expression', 'MPA', (187, 197))	('increased', 'PosReg', (174, 183))	('MeCP2', 'Gene', '4204', (249, 254))
188637	27843499	Notably, the EGFR L1 mutation provides an interesting example because, despite not having a direct effect on gene activity, it is one of very few tumour-specific L1 mutations noted in a major oncogene or tumour suppressor since the first such example was discovered more than 20 years ago by Miki et al..	('tumour', 'Disease', (204, 210))	('tumour', 'Disease', (146, 152))	('L1', 'Gene', '6137', (18, 20))	('L1', 'Gene', '6137', (162, 164))	('mutation', 'Var', (21, 29))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
188638	27843499	Previous studies employing high-throughput sequencing reported no tumour-specific L1 insertions in brain tumours.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('insertions', 'Var', (85, 95))	('brain tumour', 'Phenotype', 'HP:0030692', (99, 111))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('brain tumours', 'Phenotype', 'HP:0030692', (99, 112))	('tumour', 'Disease', (105, 111))	('L1', 'Gene', '6137', (82, 84))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('brain tumours', 'Disease', 'MESH:D001932', (99, 112))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('brain tumours', 'Disease', (99, 112))
188639	27843499	did observe putative tumour-specific L1 insertions, though subsequent PCR validation experiments were unsuccessful.	('insertions', 'Var', (40, 50))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('L1', 'Gene', '6137', (37, 39))	('tumour', 'Disease', (21, 27))
188640	27843499	Thus, although the atypical L1-associated mutations reported here represent the first PCR validated variants of this type in in GBM, our in vivo and in vitro results agree with prior reports of a lack of TPRT-driven L1 insertions in brain cancers (Table 1).	('brain cancers', 'Disease', 'MESH:D001932', (233, 246))	('L1', 'Gene', '6137', (216, 218))	('brain cancers', 'Disease', (233, 246))	('L1', 'Gene', '6137', (28, 30))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('TPRT', 'Chemical', '-', (204, 208))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
188644	27843499	Although we conclusively find that L1 mobilisation is a rare event in GBM, our discovery of atypical L1-associated mutations in MeCP2 and EGFR demonstrates that L1 can otherwise contribute to GBM genome abnormality in key loci regulating neural cell differentiation and proliferation.	('MeCP2', 'Gene', (128, 133))	('mutations', 'Var', (115, 124))	('L1', 'Gene', '6137', (35, 37))	('L1', 'Gene', '6137', (161, 163))	('EGFR', 'Gene', '1956', (138, 142))	('L1', 'Gene', '6137', (101, 103))	('EGFR', 'Gene', (138, 142))	('contribute', 'Reg', (178, 188))	('MeCP2', 'Gene', '4204', (128, 133))
188669	33647051	IVIM imaging fits the signal decay to a bi-exponential model by manipulating multiple b-values and segregates pseudo-diffusivity (D*) from the capillary perfusion fraction (f), allowing diffusion and perfusion markers to be calculated separately from the same imaging sequence.	('fits', 'Disease', (13, 17))	('D*', 'Gene', '294258', (130, 132))	('manipulating', 'Var', (64, 76))	('pseudo-diffusivity', 'MPA', (110, 128))	('fits', 'Disease', 'MESH:D012640', (13, 17))	('b-values', 'MPA', (86, 94))
188772	33659067	Deactivation of DMN regions is therefore often interpreted as a necessary inhibition of brain processes that may interfere with cognitive task performance, whereas CEN activation is typically associated with execution of the task itself.	('DMN', 'Chemical', '-', (16, 19))	('CEN', 'Chemical', '-', (164, 167))	('Deactivation', 'Var', (0, 12))	('cognitive task performance', 'CPA', (128, 154))	('brain processes', 'CPA', (88, 103))
188773	33659067	Conversely, abnormal functioning of either of these 2 networks may underlie cognitive impairments in brain tumor patients.	('cognitive impairments', 'Disease', 'MESH:D003072', (76, 97))	('brain tumor', 'Phenotype', 'HP:0030692', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('patients', 'Species', '9606', (113, 121))	('underlie', 'Reg', (67, 75))	('cognitive impairment', 'Phenotype', 'HP:0100543', (76, 96))	('cognitive impairments', 'Disease', (76, 97))	('abnormal', 'Var', (12, 20))	('brain tumor', 'Disease', (101, 112))	('brain tumor', 'Disease', 'MESH:D001932', (101, 112))	('cognitive impairments', 'Phenotype', 'HP:0100543', (76, 97))
188780	33659067	Patients with a World Health Organization (WHO) grade II tumor with an isocitrate dehydrogenase (IDH)1 mutation (IDH1+, astrocytoma as well as oligodendroglioma [with 1p19q codeletion]) were classified as LGG.	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('oligodendroglioma', 'Disease', 'MESH:D009837', (143, 160))	('IDH1', 'Gene', (113, 117))	('IDH)1', 'Gene', '3417', (97, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('II tumor', 'Disease', (54, 62))	('IDH1', 'Gene', '3417', (113, 117))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutation', 'Var', (103, 111))	('astrocytoma', 'Disease', 'MESH:D001254', (120, 131))	('oligodendroglioma', 'Disease', (143, 160))	('II tumor', 'Disease', 'MESH:D009369', (54, 62))	('astrocytoma', 'Disease', (120, 131))
188850	33659067	The DMN has previously been associated with processes that are performed during rest, but interfere with goal-oriented behavior, such as "mind wandering."	('DMN', 'Chemical', '-', (4, 7))	('goal-oriented behavior', 'CPA', (105, 127))	('interfere', 'NegReg', (90, 99))	('DMN', 'Var', (4, 7))
188855	33659067	Since deactivation of the DMN is generally understood to be a prerequisite for goal-oriented behavior, one may speculate that it could potentially indicate cognitive impairment and therefore serve as a cognitive biomarker in glioma patients.	('cognitive impairment', 'Disease', 'MESH:D003072', (156, 176))	('DMN', 'Chemical', '-', (26, 29))	('patients', 'Species', '9606', (232, 240))	('glioma', 'Disease', (225, 231))	('indicate', 'Reg', (147, 155))	('deactivation', 'Var', (6, 18))	('cognitive impairment', 'Phenotype', 'HP:0100543', (156, 176))	('cognitive impairment', 'Disease', (156, 176))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioma', 'Disease', 'MESH:D005910', (225, 231))
188897	32752094	Abnormalities in CNTN1 expression associate with cancer progression and poor prognosis.	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CNTN1', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('associate', 'Reg', (34, 43))	('cancer', 'Disease', (49, 55))
188904	32752094	Aberrant expression of CAMs has been shown to associate with invasive phenotype of tumour cells.	('tumour', 'Disease', (83, 89))	('Aberrant expression', 'Var', (0, 19))	('CAMs', 'Gene', (23, 27))	('associate', 'Reg', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))
188921	32752094	Specifically, the CNTN1 mutants show an overt ataxia phenotype by day 10 which subsequently progresses to pronounced smaller size, emaciated appearance and uncontrolled movement by day 15.	('uncontrolled movement', 'Phenotype', 'HP:0007738', (156, 177))	('mutants', 'Var', (24, 31))	('CNTN1', 'Gene', (18, 23))	('ataxia', 'Phenotype', 'HP:0001251', (46, 52))	('ataxia', 'Disease', 'MESH:D001259', (46, 52))	('ataxia', 'Disease', (46, 52))
188928	32752094	The knockdown of CNTN1 via in utero electroporation resulted in significantly delayed radical migration mediated by RhoA activation, a Rho-GTPase critical for actin cytoskeletal reorganization.	('delayed', 'NegReg', (78, 85))	('RhoA', 'Gene', '387', (116, 120))	('CNTN1', 'Gene', (17, 22))	('RhoA', 'Gene', (116, 120))	('radical migration', 'CPA', (86, 103))	('knockdown', 'Var', (4, 13))
188930	32752094	A previous report also described a lethal form of congenital myopathy possibly caused by the loss of CNTN1 in the neuromuscular junction due to a familial mutation.	('myopathy', 'Phenotype', 'HP:0003198', (61, 69))	('congenital myopathy', 'Disease', 'MESH:D009224', (50, 69))	('loss', 'Var', (93, 97))	('caused by', 'Reg', (79, 88))	('CNTN1', 'Gene', (101, 106))	('congenital myopathy', 'Disease', (50, 69))
188938	32752094	Furthermore, NCAM localized in membrane compartments binds and stimulates fibroblast growth factor receptor 1 (FGFR1) through its fibronectin type III (F3) domains and activates MAPK-mediated cell migration in non-neural cells.	('NCAM', 'Var', (13, 17))	('FGFR1', 'Gene', '2260', (111, 116))	('fibronectin', 'Gene', '2335', (130, 141))	('fibroblast growth factor receptor 1', 'Gene', (74, 109))	('stimulates', 'PosReg', (63, 73))	('fibroblast growth factor receptor 1', 'Gene', '2260', (74, 109))	('fibronectin', 'Gene', (130, 141))	('FGFR1', 'Gene', (111, 116))	('MAPK-mediated cell migration in non-neural cells', 'CPA', (178, 226))	('activates', 'PosReg', (168, 177))
188940	32752094	Indeed, the correlation between deregulated NCAM expression and poor prognosis has been found in different cancer types including neuroblastoma, myeloma, acute myeloid leukemia, pancreatic cancer, and small cell lung cancer.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (130, 143))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('myeloma', 'Disease', 'MESH:D009101', (145, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('NCAM', 'Gene', (44, 48))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('myeloma', 'Disease', (145, 152))	('deregulated', 'Var', (32, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (178, 195))	('acute myeloid leukemia', 'Disease', (154, 176))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (189, 195))	('pancreatic cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('small cell lung cancer', 'Disease', 'MESH:D055752', (201, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('neuroblastoma', 'Disease', (130, 143))	('cancer', 'Disease', (217, 223))	('neuroblastoma', 'Phenotype', 'HP:0003006', (130, 143))	('small cell lung cancer', 'Disease', (201, 223))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
188941	32752094	However, as the central nervous system was the only defective organ in CNTN1 deficient mice, the protein is not a major contributor to the development of other organs at least in mice.	('CNTN1', 'Gene', (71, 76))	('mice', 'Species', '10090', (87, 91))	('deficient', 'Var', (77, 86))	('mice', 'Species', '10090', (179, 183))
188946	32752094	Amplifications and gains of genomic materials are frequent in this region for malignant gliomas and astrocytoma.	('malignant gliomas', 'Disease', 'MESH:D005910', (78, 95))	('astrocytoma', 'Disease', 'MESH:D001254', (100, 111))	('gains', 'PosReg', (19, 24))	('astrocytoma', 'Disease', (100, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('Amplifications', 'Var', (0, 14))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('malignant gliomas', 'Disease', (78, 95))
188964	32752094	discovered that while the knockdown of CNTN1 did not influence lung cancer cell proliferation, it significantly reduced cancer cell's invasive abilities both in vitro and in xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('invasive abilities', 'CPA', (134, 152))	('lung cancer', 'Disease', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('knockdown', 'Var', (26, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('cancer', 'Disease', (68, 74))	('reduced', 'NegReg', (112, 119))	('CNTN1', 'Gene', (39, 44))
188971	32752094	Similarly, CNTN1 expression was elevated in multidrug resistance (MDR) A549/cisplatin (A549/DDP) cells compared to its progenitor A549 lung cancer cells, and the silencing of CNTN1 rendered both cells higher cisplatin sensitivity and upregulated cisplatin-induced apoptosis, leading to inhibition of tumor invasion and metastasis.	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('lung cancer', 'Disease', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('expression', 'MPA', (17, 27))	('upregulated', 'PosReg', (234, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (246, 255))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('silencing', 'Var', (162, 171))	('elevated', 'PosReg', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CNTN1', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('higher', 'PosReg', (201, 207))	('cisplatin sensitivity', 'MPA', (208, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('tumor', 'Disease', (300, 305))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('CNTN1', 'Gene', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('inhibition', 'NegReg', (286, 296))
188972	32752094	This enhanced chemoresistance of lung cancer cells induced by CNTN1 overexpression was also found to be attributable to PI3K/AKT activated EMT enhancement (Figure 4).	('AKT', 'Gene', '207', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('chemoresistance', 'CPA', (14, 29))	('AKT', 'Gene', (125, 128))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('CNTN1', 'Gene', (62, 67))	('enhanced', 'PosReg', (5, 13))	('enhancement', 'PosReg', (143, 154))	('overexpression', 'Var', (68, 82))	('lung cancer', 'Disease', (33, 44))
188982	32752094	Recent study has shown that a reduction in CNTN1 expression alone was sufficient to reverse the enhanced migration ability of esophageal cancer cells attributable to ectopic VEFGC expression in vitro.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('VEFGC', 'Gene', (174, 179))	('enhanced', 'PosReg', (96, 104))	('CNTN1', 'Gene', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('reduction', 'NegReg', (30, 39))	('cancer', 'Disease', (137, 143))	('migration ability', 'CPA', (105, 122))	('ectopic', 'Var', (166, 173))	('expression', 'Var', (180, 190))
188986	32752094	demonstrated that CNTN1 expression was directly regulated by Flt4 stimulation or inhibition, and this alteration was robustly associated with enhanced or reduced OSCC cell proliferation and migration correspondingly.	('OSCC cell proliferation', 'CPA', (162, 185))	('migration', 'CPA', (190, 199))	('inhibition', 'Var', (81, 91))	('expression', 'MPA', (24, 34))	('Flt4', 'Gene', (61, 65))	('CNTN1', 'Gene', (18, 23))	('stimulation', 'PosReg', (66, 77))	('Flt4', 'Gene', '2324', (61, 65))	('enhanced', 'PosReg', (142, 150))	('reduced', 'NegReg', (154, 161))	('regulated', 'Reg', (48, 57))
188989	32752094	The OSCC cells with CNTN1 knocked-down exhibits significant reduction in invasion but not proliferative properties, which is in line with previous findings demonstrating that CNTN1 may promote progression of cancer cells through exclusive activation of metastatic pathways.	('cancer', 'Disease', (208, 214))	('CNTN1', 'Gene', (175, 180))	('CNTN1', 'Gene', (20, 25))	('knocked-down', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('reduction', 'NegReg', (60, 69))	('proliferative properties', 'CPA', (90, 114))	('activation', 'PosReg', (239, 249))	('promote', 'PosReg', (185, 192))	('invasion', 'CPA', (73, 81))	('metastatic', 'CPA', (253, 263))	('progression', 'CPA', (193, 204))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
189000	32752094	Further analysis showed that silencing or knockdown of CNTN1 expression resulted in suppression of proliferation, invasion and migration capabilities in PC cells concurrent with a reduced PI3K/AKT signaling.	('AKT', 'Gene', '207', (193, 196))	('migration capabilities', 'CPA', (127, 149))	('silencing', 'Var', (29, 38))	('PC', 'CellLine', 'CVCL:0152', (153, 155))	('reduced', 'NegReg', (180, 187))	('AKT', 'Gene', (193, 196))	('suppression', 'NegReg', (84, 95))	('CNTN1', 'Gene', (55, 60))	('invasion', 'CPA', (114, 122))	('proliferation', 'CPA', (99, 112))	('knockdown', 'Var', (42, 51))
189001	32752094	CNTN1 inhibition also increased expression of E-cadherin while reduced N-cadherin and Vimentin, suggesting an inhibition of the EMT process pivotal in cancer metastases (Figure 4).	('inhibition', 'NegReg', (110, 120))	('Vimentin', 'Gene', (86, 94))	('reduced', 'NegReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('N-cadherin', 'Gene', '1000', (71, 81))	('cancer metastases', 'Disease', (151, 168))	('CNTN1', 'Gene', (0, 5))	('E-cadherin', 'Protein', (46, 56))	('Vimentin', 'Gene', '7431', (86, 94))	('increased', 'PosReg', (22, 31))	('EMT process', 'CPA', (128, 139))	('inhibition', 'Var', (6, 16))	('expression', 'MPA', (32, 42))	('N-cadherin', 'Gene', (71, 81))	('cancer metastases', 'Disease', 'MESH:D009362', (151, 168))
189003	32752094	Silencing of CNTN1 with short hairpin RNA (shRNA) inhibited cellular malignant phenotype and reduced expression of pluripotent markers such as CD44, octamer-binding transcription factor 4 (OCT-4), and Nanog.	('octamer-binding transcription factor 4', 'Gene', (149, 187))	('CD44', 'Gene', '960', (143, 147))	('Nanog', 'Gene', '79923', (201, 206))	('reduced', 'NegReg', (93, 100))	('CNTN1', 'Gene', (13, 18))	('OCT-4', 'Gene', '5460', (189, 194))	('CD44', 'Gene', (143, 147))	('OCT-4', 'Gene', (189, 194))	('cellular malignant phenotype', 'CPA', (60, 88))	('Nanog', 'Gene', (201, 206))	('octamer-binding transcription factor 4', 'Gene', '5460', (149, 187))	('expression', 'MPA', (101, 111))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (50, 59))
189004	32752094	CNTN1 silencing sensitized Dox-resistant PC cells and inhibited PI3K/AKT signaling in vivo.	('inhibited', 'NegReg', (54, 63))	('PC', 'CellLine', 'CVCL:0152', (41, 43))	('AKT', 'Gene', (69, 72))	('Dox-resistant PC', 'Disease', (27, 43))	('CNTN1', 'Gene', (0, 5))	('Dox', 'Chemical', 'MESH:D000077143', (27, 30))	('AKT', 'Gene', '207', (69, 72))	('silencing', 'Var', (6, 15))
189006	32752094	In a study investigating breast cancer (BC), ectopic CNTN1 overexpression enhanced cell proliferation, invasion, migration as well as cell cycle progression from G1 to S phase in breast cancer cells in vitro.	('cell cycle progression from G1 to S phase', 'CPA', (134, 175))	('BC', 'Phenotype', 'HP:0003002', (40, 42))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cell proliferation', 'CPA', (83, 101))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer', 'Disease', (25, 38))	('overexpression enhanced', 'PosReg', (59, 82))	('ectopic', 'Var', (45, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('migration', 'CPA', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('invasion', 'CPA', (103, 111))	('CNTN1', 'Gene', (53, 58))
189007	32752094	Notably, CNTN1 overexpression also enhanced breast cancer xenograft tumor growth in vivo in nude mice.	('tumor', 'Disease', (68, 73))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('nude mice', 'Species', '10090', (92, 101))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('enhanced', 'PosReg', (35, 43))	('overexpression', 'Var', (15, 29))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CNTN1', 'Gene', (9, 14))
189010	32752094	Among the 5 subtypes, we noticed a significant higher level of CNTN1 in HER2-E in a population consisting of 50 DNA microarray studies (n = 9254) and in the population of three RNA-seq investigation (n = 4712) (Figure 5).	('HER2', 'Gene', (72, 76))	('CNTN1', 'Var', (63, 68))	('higher', 'PosReg', (47, 53))	('HER2', 'Gene', '2064', (72, 76))
189015	32752094	In both positively correlated gene populations, enrichment in the terms of extracellular matrix organization (GO:0030198) and cell adhesion (GO:0007155) in Biological Process (BP) was observed in BC (All patients, Table 2).	('patients', 'Species', '9606', (204, 212))	('cell adhesion', 'CPA', (126, 139))	('GO:0007155', 'Var', (141, 151))	('BC', 'Phenotype', 'HP:0003002', (196, 198))	('extracellular matrix organization', 'CPA', (75, 108))
189018	32752094	As well, CNTN1 expression was found to be an independent prognostic factor for OS (hazard ratio 2.383, 95% confidence interval 1.262-4.503; p = 0.007) and DFS (disease free survival) (hazard ratio 2.356, 95% confidence interval 1.370-4.049; p = 0.002) in HCC patients.	('expression', 'Var', (15, 25))	('patients', 'Species', '9606', (259, 267))	('HCC', 'Disease', (255, 258))	('DFS', 'Disease', (155, 158))	('HCC', 'Phenotype', 'HP:0001402', (255, 258))	('CNTN1', 'Gene', (9, 14))	('DFS', 'Disease', 'None', (155, 158))
189019	32752094	RET/PTC3 (Ret proto-oncogene and Ret-activating protein ELE1) rearrangement is the most frequent genetic alteration in thyroid cancer and most functions of RET are mediated through pathways including ERK, JNK, and PI3K/AKT.	('thyroid cancer', 'Disease', 'MESH:D013964', (119, 133))	('Ret', 'Gene', (10, 13))	('mediated', 'Reg', (164, 172))	('thyroid cancer', 'Phenotype', 'HP:0002890', (119, 133))	('Ret', 'Gene', (33, 36))	('RET', 'Gene', '5979', (0, 3))	('ERK', 'Gene', '5594', (200, 203))	('ELE1', 'Gene', '8031', (56, 60))	('JNK', 'Gene', (205, 208))	('Ret', 'Gene', '5979', (10, 13))	('JNK', 'Gene', '5599', (205, 208))	('PTC3', 'Gene', '8031', (4, 8))	('Ret', 'Gene', '5979', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('AKT', 'Gene', (219, 222))	('ERK', 'Gene', (200, 203))	('PTC3', 'Gene', (4, 8))	('RET', 'Gene', (0, 3))	('RET', 'Gene', '5979', (156, 159))	('thyroid cancer', 'Disease', (119, 133))	('functions', 'MPA', (143, 152))	('rearrangement', 'Var', (62, 75))	('ELE1', 'Gene', (56, 60))	('AKT', 'Gene', '207', (219, 222))	('RET', 'Gene', (156, 159))
189025	32752094	Functionally, CNTN1 silencing in vitro restrained thyroid cancer cell migration and invasion abilities.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('thyroid cancer', 'Phenotype', 'HP:0002890', (50, 64))	('thyroid cancer', 'Disease', (50, 64))	('restrained', 'NegReg', (39, 49))	('CNTN1', 'Gene', (14, 19))	('invasion abilities', 'CPA', (84, 102))	('silencing', 'Var', (20, 29))	('thyroid cancer', 'Disease', 'MESH:D013964', (50, 64))
189030	32752094	The Notch signaling pathway is highly conserved, and its dysregulation is associated with many cancers.	('dysregulation', 'Var', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Notch signaling pathway', 'Pathway', (4, 27))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (74, 84))
189037	32752094	While these analyses support a positive association between high CNTN1 expression and poor OS in cancers, this association might be cancer-type specific at least at the level of mRNA; high CNTN1 expression displays a reverse association with poor OS in LGG (Figure 6c).	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('expression', 'MPA', (71, 81))	('cancer', 'Disease', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('CNTN1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CNTN1', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('high CNTN1', 'Gene', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('high', 'Var', (184, 188))	('poor OS in LGG', 'Disease', (242, 256))
189045	32752094	For example, a Cre-LoxP system can be explored in which mice carrying the transgene insertion of a strong translational and transcriptional termination (STOP) sequence flanked by loxP or FRT sites between the promoter sequence and CNTN1 which can be crossed with mice carrying tissue-specific promoters.	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (263, 267))	('transgene insertion', 'Var', (74, 93))	('CNTN1', 'Gene', (231, 236))	('insertion', 'Var', (84, 93))
189050	32752094	High CNTN1 expression was associated with biochemical recurrence following radical proctectomy in PC.	('CNTN1', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('biochemical recurrence', 'Disease', (42, 64))	('PC', 'CellLine', 'CVCL:0152', (98, 100))	('associated with', 'Reg', (26, 41))
189056	32752094	In view of the critical aspect of communications between cancer and stroma, proper adhesion is critical for cancer evolution or progression, targeting CNTN1 might thus be a useful option.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CNTN1', 'Gene', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('targeting', 'Var', (141, 150))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
189078	32752094	Indeed, silencing or inhibition of CNTN1 in experimental models have already highlighted its suitability as a potential target in lung, gastric, prostate, thyroid cancers, and oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (176, 204))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('thyroid cancer', 'Phenotype', 'HP:0002890', (155, 169))	('prostate', 'Disease', (145, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('silencing', 'Var', (8, 17))	('thyroid cancers', 'Disease', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('thyroid cancers', 'Disease', 'MESH:D013964', (155, 170))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 204))	('CNTN1', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('gastric', 'Disease', (136, 143))	('inhibition', 'NegReg', (21, 31))	('lung', 'Disease', (130, 134))
189082	32806529	Germline mutations in more than ten genes involved in RAS-MAPK signal pathway have been demonstrated to cause the disease.	('Germline mutations', 'Var', (0, 18))	('RA', 'Disease', 'MESH:D001172', (54, 56))	('cause', 'Reg', (104, 109))
189085	32806529	We described also a 13-year-old girl with NS associated with a recurrent mutation in PTPN11, who developed three different types of brain tumors, i.e., an optic pathway glioma, a glioneuronal neoplasm of the left temporal lobe and a cerebellar pilocytic astrocytoma.	('brain tumors', 'Disease', (132, 144))	('cerebellar pilocytic astrocytoma', 'Disease', (233, 265))	('optic pathway glioma', 'Phenotype', 'HP:0009734', (155, 175))	('cerebellar pilocytic astrocytoma', 'Disease', 'MESH:D001254', (233, 265))	('PTPN11', 'Gene', (85, 91))	('mutation', 'Var', (73, 81))	('PTPN11', 'Gene', '5781', (85, 91))	('glioneuronal neoplasm', 'Disease', 'MESH:D009369', (179, 200))	('neoplasm', 'Phenotype', 'HP:0002664', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('girl', 'Species', '9606', (32, 36))	('associated', 'Reg', (45, 55))	('NS', 'Disease', 'MESH:D009404', (42, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (254, 265))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('developed', 'Reg', (97, 106))	('glioneuronal neoplasm', 'Phenotype', 'HP:0025170', (179, 200))	('brain tumors', 'Phenotype', 'HP:0030692', (132, 144))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioneuronal neoplasm', 'Disease', (179, 200))	('brain tumors', 'Disease', 'MESH:D001932', (132, 144))	('brain tumor', 'Phenotype', 'HP:0030692', (132, 143))	('optic pathway glioma', 'Disease', 'MESH:D020339', (155, 175))	('optic pathway glioma', 'Disease', (155, 175))
189092	32806529	These disorders are related to germline mutations in the genes encoding proteins within the RAS-mitogen-activated protein kinase (MAPK) signaling pathway and have therefore been referred to as RASopathies.	('RA', 'Disease', 'MESH:D001172', (193, 195))	('RASopathies', 'Disease', (193, 204))	('RA', 'Disease', 'MESH:D001172', (92, 94))	('germline mutations', 'Var', (31, 49))	('related', 'Reg', (20, 27))	('RASopathies', 'Disease', 'None', (193, 204))
189100	32806529	At one month, based on these clinical features, the patient was suspected to have NS and a genetic analysis performed using a dedicated gene panel (BRAF, CBL, CDC42, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RIT1, RRAS, SHOC2, SOS1, SOS2 and SPRED1) revealed the pathogenic PTPN11 variant NM_002834.3 (c.922A>G, p.Asn308Asp), one of the most common mutations associated with NS.	('MAP2K2', 'Gene', '5605', (186, 192))	('SPRED1', 'Gene', (253, 259))	('KRAS', 'Gene', '3845', (172, 176))	('c.922A>G', 'Var', (313, 321))	('RAF1', 'Gene', (213, 217))	('PTPN11', 'Gene', (285, 291))	('RIT1', 'Gene', (219, 223))	('PTPN11', 'Gene', (205, 211))	('KRAS', 'Gene', (172, 176))	('RRAS', 'Gene', (225, 229))	('PTPN11', 'Gene', '5781', (285, 291))	('pathogenic', 'Reg', (274, 284))	('SOS1', 'Gene', '6654', (238, 242))	('SHOC2', 'Gene', (231, 236))	('SOS2', 'Gene', (244, 248))	('p.Asn308Asp', 'Var', (323, 334))	('PTPN11', 'Gene', '5781', (205, 211))	('NRAS', 'Gene', (199, 203))	('CDC42', 'Gene', (159, 164))	('BRAF', 'Gene', '673', (148, 152))	('c.922A>G', 'Mutation', 'rs28933386', (313, 321))	('RRAS', 'Gene', '6237', (225, 229))	('BRAF', 'Gene', (148, 152))	('NS', 'Disease', 'MESH:D009404', (386, 388))	('p.Asn308Asp', 'Mutation', 'rs28933386', (323, 334))	('SOS2', 'Gene', '6655', (244, 248))	('NF1', 'Gene', '4763', (194, 197))	('CDC42', 'Gene', '998', (159, 164))	('MAP2K2', 'Gene', (186, 192))	('MAP2K1', 'Gene', '5604', (178, 184))	('RIT1', 'Gene', '6016', (219, 223))	('MAP2K1', 'Gene', (178, 184))	('CBL', 'Gene', (154, 157))	('SHOC2', 'Gene', '8036', (231, 236))	('SPRED1', 'Gene', '161742', (253, 259))	('SOS1', 'Gene', (238, 242))	('NS', 'Disease', 'MESH:D009404', (82, 84))	('NF1', 'Gene', (194, 197))	('HRAS', 'Gene', '3265', (166, 170))	('RAF1', 'Gene', '5894', (213, 217))	('HRAS', 'Gene', (166, 170))	('patient', 'Species', '9606', (52, 59))	('NRAS', 'Gene', '4893', (199, 203))	('CBL', 'Gene', '867', (154, 157))
189101	32806529	In addition, a maternally transmitted missense variant in SPRED1 (c.182G>A, p.Arg61His; NM_152594.3) was identified.	('SPRED1', 'Gene', (58, 64))	('c.182G>A', 'Mutation', 'rs750686148', (66, 74))	('p.Arg61His', 'Var', (76, 86))	('SPRED1', 'Gene', '161742', (58, 64))	('c.182G>A', 'Var', (66, 74))	('p.Arg61His', 'Mutation', 'rs750686148', (76, 86))
189102	32806529	This missense change was classified as "likely benign", based on the American College of Medical Genetics criteria (PM1, BS2, BP1, BP4).	('PM1', 'Gene', (116, 119))	('PM1', 'Gene', '8834', (116, 119))	('BP4', 'Gene', (131, 134))	('BP4', 'Gene', '474258', (131, 134))	('missense change', 'Var', (5, 20))	('BP1', 'Gene', (126, 129))	('BP1', 'Gene', '474256', (126, 129))
189121	32806529	Immunohistochemistry (ICH) was negative for the BRAF V600E point mutation and positive for phosphorylated MTOR (Ser2448), indicating the activation of the MTOR pathway (Figure 3A).	('MTOR', 'Gene', (155, 159))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('ICH', 'Disease', 'MESH:D002543', (22, 25))	('MTOR', 'Gene', '2475', (155, 159))	('Ser2448', 'Chemical', '-', (112, 119))	('V600E', 'Var', (53, 58))	('MTOR', 'Gene', (106, 110))	('activation', 'PosReg', (137, 147))	('ICH', 'Disease', (22, 25))	('BRAF', 'Gene', '673', (48, 52))	('BRAF', 'Gene', (48, 52))	('MTOR', 'Gene', '2475', (106, 110))
189126	32806529	Similar to other RASopathies, certain mutations causing NS may predispose to cancer.	('RASopathies', 'Disease', (17, 28))	('RASopathies', 'Disease', 'None', (17, 28))	('predispose', 'Reg', (63, 73))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('NS', 'Disease', 'MESH:D009404', (56, 58))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (38, 47))
189130	32806529	Similarly, somatic PTPN11 mutations have been detected with variable prevalence in some solid tumors, such as lung, liver and colorectal cancer, thyroid carcinoma, bladder carcinoma, neuroblastoma, rhabdomyosarcoma, melanoma and brain tumors.	('bladder carcinoma', 'Disease', (164, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('mutations', 'Var', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung', 'Disease', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('neuroblastoma', 'Disease', (183, 196))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('liver', 'Disease', (116, 121))	('neuroblastoma', 'Phenotype', 'HP:0003006', (183, 196))	('tumors', 'Disease', (94, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (145, 162))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('neuroblastoma', 'Disease', 'MESH:D009447', (183, 196))	('brain tumors', 'Disease', 'MESH:D001932', (229, 241))	('rhabdomyosarcoma', 'Disease', (198, 214))	('brain tumors', 'Phenotype', 'HP:0030692', (229, 241))	('colorectal cancer', 'Disease', (126, 143))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (198, 214))	('thyroid carcinoma', 'Disease', (145, 162))	('brain tumor', 'Phenotype', 'HP:0030692', (229, 240))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (164, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('tumors', 'Disease', (235, 241))	('PTPN11', 'Gene', (19, 25))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (145, 162))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (198, 214))	('bladder carcinoma', 'Disease', 'MESH:D001749', (164, 181))	('brain tumors', 'Disease', (229, 241))	('detected', 'Reg', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('PTPN11', 'Gene', '5781', (19, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
189131	32806529	NS can be caused by germline mutations in several genes related to the RAS-MAPK pathway cascade (i.e., PTPN11, SOS1, SOS2, RAF1, KRAS, NRAS, RIT1, MRAS, RRAS2 and LZTR1).	('RRAS2', 'Gene', '22800', (153, 158))	('PTPN11', 'Gene', '5781', (103, 109))	('RAF1', 'Gene', '5894', (123, 127))	('NRAS', 'Gene', '4893', (135, 139))	('LZTR1', 'Gene', '8216', (163, 168))	('NS', 'Disease', 'MESH:D009404', (0, 2))	('MRAS', 'Gene', (147, 151))	('RA', 'Disease', 'MESH:D001172', (136, 138))	('caused by', 'Reg', (10, 19))	('KRAS', 'Gene', '3845', (129, 133))	('MRAS', 'Gene', '22808', (147, 151))	('RAF1', 'Gene', (123, 127))	('SOS1', 'Gene', '6654', (111, 115))	('RA', 'Disease', 'MESH:D001172', (71, 73))	('KRAS', 'Gene', (129, 133))	('germline mutations', 'Var', (20, 38))	('RIT1', 'Gene', '6016', (141, 145))	('SOS2', 'Gene', (117, 121))	('NRAS', 'Gene', (135, 139))	('SOS2', 'Gene', '6655', (117, 121))	('SOS1', 'Gene', (111, 115))	('RA', 'Disease', 'MESH:D001172', (148, 150))	('LZTR1', 'Gene', (163, 168))	('RA', 'Disease', 'MESH:D001172', (130, 132))	('RA', 'Disease', 'MESH:D001172', (154, 156))	('PTPN11', 'Gene', (103, 109))	('RRAS2', 'Gene', (153, 158))	('RA', 'Disease', 'MESH:D001172', (123, 125))	('RIT1', 'Gene', (141, 145))
189132	32806529	A gain-of-function mutations in PTPN11, which encodes the SHP2 protein, causes 50% of cases of NS.	('NS', 'Disease', 'MESH:D009404', (95, 97))	('SHP2', 'Gene', '5781', (58, 62))	('gain-of-function', 'PosReg', (2, 18))	('SHP2', 'Gene', (58, 62))	('mutations', 'Var', (19, 28))	('PTPN11', 'Gene', '5781', (32, 38))	('PTPN11', 'Gene', (32, 38))
189134	32806529	Both germline and somatic PTPN11 mutations are activating and enhance SHP2 function by destabilizing the catalytically inactive conformation of the phosphatase, resulting in increased signal flow through the RAS-MAPK pathway.	('signal flow', 'MPA', (184, 195))	('PTPN11', 'Gene', (26, 32))	('function', 'MPA', (75, 83))	('SHP2', 'Gene', (70, 74))	('RA', 'Disease', 'MESH:D001172', (208, 210))	('enhance', 'PosReg', (62, 69))	('SHP2', 'Gene', '5781', (70, 74))	('mutations', 'Var', (33, 42))	('PTPN11', 'Gene', '5781', (26, 32))	('increased', 'PosReg', (174, 183))	('activating', 'PosReg', (47, 57))	('destabilizing', 'NegReg', (87, 100))
189137	32806529	A recent study conducted in France showed the correlation between JMML and NS in a cohort of 641 patients with germline PTPN11 mutations.	('NS', 'Disease', 'MESH:D009404', (75, 77))	('PTPN11', 'Gene', '5781', (120, 126))	('PTPN11', 'Gene', (120, 126))	('JMML', 'Disease', (66, 70))	('JMML', 'Disease', 'MESH:D054429', (66, 70))	('mutations', 'Var', (127, 136))	('JMML', 'Phenotype', 'HP:0012209', (66, 70))	('correlation', 'Interaction', (46, 57))	('patients', 'Species', '9606', (97, 105))
189138	32806529	Somatic mutations in those genes are related to up to 20% of all sporadic hematologic and solid malignancies.	('Somatic mutations', 'Var', (0, 17))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('related', 'Reg', (37, 44))	('malignancies', 'Disease', (96, 108))
189139	32806529	Germline mutations in those genes underlying tumor formation seams to determine enhanced signaling activity, although in a less consistent way than seen in corresponding somatic mutations.	('Germline mutations', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('signaling activity', 'MPA', (89, 107))	('enhanced', 'PosReg', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
189140	32806529	It is hypothesized that those activating somatic gene mutations causing cancer are not seen in the germline because they may cause embryonal lethality.	('embryonal lethality', 'Disease', 'MESH:D020964', (131, 150))	('activating', 'PosReg', (30, 40))	('embryonal lethality', 'Disease', (131, 150))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cause', 'Reg', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
189143	32806529	We analyzed 30 cases of patients with NS and brain tumors carrying PTPN11 mutation (Table 1).	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('NS', 'Disease', 'MESH:D009404', (38, 40))	('brain tumors', 'Disease', 'MESH:D001932', (45, 57))	('brain tumors', 'Phenotype', 'HP:0030692', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PTPN11', 'Gene', '5781', (67, 73))	('patients', 'Species', '9606', (24, 32))	('PTPN11', 'Gene', (67, 73))	('brain tumors', 'Disease', (45, 57))	('brain tumor', 'Phenotype', 'HP:0030692', (45, 56))
189164	32806529	While the functional link between the identified PTPN11 mutation and MTOR hyperactivation needs further study, the present finding suggests a possible molecular target for a new therapeutic strategy and that assessment of MTOR activation should be evaluated in brain tumors of patients with NS or a related RASopathy.	('RASopathy', 'Disease', (307, 316))	('MTOR', 'Gene', '2475', (69, 73))	('brain tumor', 'Phenotype', 'HP:0030692', (261, 272))	('PTPN11', 'Gene', '5781', (49, 55))	('RASopathy', 'Disease', 'None', (307, 316))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('patients', 'Species', '9606', (277, 285))	('PTPN11', 'Gene', (49, 55))	('MTOR', 'Gene', (222, 226))	('brain tumors', 'Disease', 'MESH:D001932', (261, 273))	('brain tumors', 'Phenotype', 'HP:0030692', (261, 273))	('MTOR', 'Gene', '2475', (222, 226))	('brain tumors', 'Disease', (261, 273))	('mutation', 'Var', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('MTOR', 'Gene', (69, 73))	('NS', 'Disease', 'MESH:D009404', (291, 293))
189172	32806529	We acknowledge that supplemental considerations may stem from further characterizations of LGGs in patients with NS and PTPN11 variants, however, we feel that the frequency of these tumors in NS is still too low to allow solid conclusions.	('variants', 'Var', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('NS', 'Disease', 'MESH:D009404', (113, 115))	('PTPN11', 'Gene', (120, 126))	('NS', 'Disease', 'MESH:D009404', (192, 194))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('patients', 'Species', '9606', (99, 107))	('LGGs', 'Disease', (91, 95))	('PTPN11', 'Gene', '5781', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
189173	32806529	The positive response to everolimus observed in our patient may provide an ex adiuvantibus piece of evidence for a pathogenic link between the RAS-MAPK and PI3K/mTOR pathways, activated by PTPN11 variants, but, as we stated in our Discussion, the functional link between the identified PTPN11 mutation and MTOR hyperactivation needs further study.	('MTOR', 'Gene', (306, 310))	('PTPN11', 'Gene', '5781', (286, 292))	('MTOR', 'Gene', '2475', (306, 310))	('PTPN11', 'Gene', '5781', (189, 195))	('PTPN11', 'Gene', (286, 292))	('PTPN11', 'Gene', (189, 195))	('RA', 'Disease', 'MESH:D001172', (143, 145))	('patient', 'Species', '9606', (52, 59))	('everolimus', 'Chemical', 'MESH:D000068338', (25, 35))	('mTOR', 'Gene', '2475', (161, 165))	('mutation', 'Var', (293, 301))	('mTOR', 'Gene', (161, 165))	('variants', 'Var', (196, 204))
189192	28789345	Overexpression of survivin has been reported in cancer and is associated with a poor prognosis for a number of human malignancies, including non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('survivin', 'Gene', (18, 26))	('human', 'Species', '9606', (111, 116))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (48, 54))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('cancer', 'Disease', (161, 167))	('malignancies', 'Disease', (117, 129))	('survivin', 'Gene', '11799', (18, 26))	('non-small cell lung cancer', 'Disease', (141, 167))
189228	28789345	A log-rank test indicated that survival time for those positive for COX-2 was significantly lower compared with those negative for COX-2 (chi2=10.113; P<0.01; Fig.	('COX-2', 'Gene', (131, 136))	('COX-2', 'Gene', '5743', (131, 136))	('survival time', 'CPA', (31, 44))	('COX-2', 'Gene', '5743', (68, 73))	('positive', 'Var', (55, 63))	('COX-2', 'Gene', (68, 73))	('lower', 'NegReg', (92, 97))
189240	28789345	Abnormal expression levels of apoptotic genes perturbs apoptosis, allowing cells to escape normal control mechanisms, and inducing cell cycle disorders and tumorigenesis.	('apoptotic genes', 'Gene', (30, 45))	('inducing', 'Reg', (122, 130))	('cell cycle disorders', 'CPA', (131, 151))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('expression levels', 'MPA', (9, 26))	('Abnormal', 'Var', (0, 8))	('perturbs', 'NegReg', (46, 54))	('cell cycle disorders', 'Phenotype', 'HP:0011018', (131, 151))	('tumor', 'Disease', (156, 161))	('apoptosis', 'CPA', (55, 64))
189246	28789345	Previous studies have suggested that positive staining for COX-2 is associated with cancer, thus it is used as a diagnostic and therapeutic target for breast, colon, gastric and esophageal cancer.	('esophageal cancer', 'Disease', (178, 195))	('positive', 'Var', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('COX-2', 'Gene', '5743', (59, 64))	('breast', 'Disease', (151, 157))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (84, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('gastric', 'Disease', 'MESH:D013274', (166, 173))	('gastric', 'Disease', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colon', 'Disease', (159, 164))	('COX-2', 'Gene', (59, 64))	('cancer', 'Disease', (189, 195))
189252	28789345	El-Sayed and Taha revealed that COX-2 expression was significantly associated with poor survival (r=0.58; P<0.001).	('COX-2', 'Gene', (32, 37))	('COX-2', 'Gene', '5743', (32, 37))	('poor survival', 'CPA', (83, 96))	('expression', 'Var', (38, 48))	('associated', 'Reg', (67, 77))
189262	28789345	While cytoplasmic survivin did not modify prognosis, nuclear survivin localization was correlated with a significantly lower survival rate compared with patients with low nuclear survivin levels.	('nuclear', 'Var', (53, 60))	('survival', 'MPA', (125, 133))	('survivin', 'Gene', (179, 187))	('survivin', 'Gene', (18, 26))	('lower', 'NegReg', (119, 124))	('patients', 'Species', '9606', (153, 161))	('survivin', 'Gene', '11799', (61, 69))	('survivin', 'Gene', '11799', (179, 187))	('survivin', 'Gene', '11799', (18, 26))	('survivin', 'Gene', (61, 69))
189267	28789345	In addition, the median survival time of patients with high survivin expression was significantly shorter compared with that for patients with low expression (322 vs. 1,084 days).	('patients', 'Species', '9606', (129, 137))	('survivin', 'Gene', '11799', (60, 68))	('expression', 'MPA', (69, 79))	('patients', 'Species', '9606', (41, 49))	('high', 'Var', (55, 59))	('survivin', 'Gene', (60, 68))	('shorter', 'NegReg', (98, 105))
189273	28789345	A study by Mehar et al indicated that survivin expression could be induced by celecoxib and that it was dependent on COX-2 expression.	('induced', 'Reg', (67, 74))	('celecoxib', 'Var', (78, 87))	('COX-2', 'Gene', '5743', (117, 122))	('survivin', 'Gene', (38, 46))	('celecoxib', 'Chemical', 'MESH:D000068579', (78, 87))	('survivin', 'Gene', '11799', (38, 46))	('expression', 'MPA', (47, 57))	('COX-2', 'Gene', (117, 122))
189278	28789345	The two proteins were potent indicators of glioma survival, and follow-up data revealed that the survival time for patients who were positive for the two proteins was significantly lower compared with patients who were negative for the two proteins.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (115, 123))	('positive', 'Var', (133, 141))	('lower', 'NegReg', (181, 186))	('glioma', 'Disease', (43, 49))	('survival time', 'CPA', (97, 110))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
189281	28789345	Ren et al confirmed that inhibition of proliferation and promotion of apoptosis in U251 glioma cells could be induced by celecoxib in a dose- and time-dependent manner, and that this may occur by downregulation of survivin expression.	('Ren', 'Gene', (0, 3))	('U251', 'CellLine', 'CVCL:0021', (83, 87))	('survivin', 'Gene', '11799', (214, 222))	('Ren', 'Gene', '5972', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (88, 94))	('promotion', 'PosReg', (57, 66))	('downregulation', 'NegReg', (196, 210))	('proliferation', 'CPA', (39, 52))	('celecoxib', 'Chemical', 'MESH:D000068579', (121, 130))	('survivin', 'Gene', (214, 222))	('apoptosis', 'CPA', (70, 79))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('celecoxib', 'Var', (121, 130))
189284	28789345	Furthermore, these proteins may have potential value for glioma therapy, as COX-2 inhibitors are effective for reducing the risk of malignancies and inhibiting tumorigenesis.	('COX-2', 'Gene', (76, 81))	('COX-2', 'Gene', '5743', (76, 81))	('glioma', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('inhibitors', 'Var', (82, 92))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('inhibiting', 'NegReg', (149, 159))	('reducing', 'NegReg', (111, 119))	('tumor', 'Disease', (160, 165))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('malignancies', 'Disease', (132, 144))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
189343	27587949	Previous studies showed that MVA correlates more strongly with patient survival compared with MVD.	('patient survival', 'CPA', (63, 79))	('patient', 'Species', '9606', (63, 70))	('MVA', 'Var', (29, 32))
189373	27587949	With SWI, the internal architecture of a tumor can be better defined compared with to that seen on conventional, contrast-enhanced, T1-weighted images.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('SWI', 'Var', (5, 8))
189390	27587949	Early changes in the ADC have been shown to be predictive of the long-term patient response to radiation and chemotherapies for brain tumors.	('brain tumors', 'Disease', (128, 140))	('brain tumor', 'Phenotype', 'HP:0030692', (128, 139))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('changes', 'Var', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ADC', 'Gene', (21, 24))	('brain tumors', 'Phenotype', 'HP:0030692', (128, 140))	('brain tumors', 'Disease', 'MESH:D001932', (128, 140))	('patient', 'Species', '9606', (75, 82))
189418	27587949	Antiangiogenic treatment would prune some abnormal vessels and remodel the remaining vessels by blocking vascular endothelial growth factor signaling and thus resulting in a normalized vasculature.	('blocking', 'NegReg', (96, 104))	('vascular endothelial growth factor', 'Gene', (105, 139))	('abnormal vessels', 'Phenotype', 'HP:0002597', (42, 58))	('vascular endothelial growth factor', 'Gene', '7422', (105, 139))	('resulting in', 'Reg', (159, 171))	('normalized vasculature', 'MPA', (174, 196))	('prune', 'Var', (31, 36))
189521	25121771	D-SEG analysis of these data show that combined tumor and edema VOIs determined by D-SEG correspond visually with the extent of tumor on standard MRI; however, their complex margins are indistinct on conventional MRI or within p and q maps.	('D-SEG', 'Var', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (48, 53))	('edema VOIs', 'Disease', 'MESH:D004487', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('edema VOIs', 'Disease', (58, 68))	('edema', 'Phenotype', 'HP:0000969', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
189558	25353163	In oligodendroglioma, LRIG2 expression is associated with poor survival, suggesting that LRIG2 might have different functions compared with LRIG1.	('oligodendroglioma', 'Disease', (3, 20))	('LRIG1', 'Gene', '26018', (140, 145))	('expression', 'Species', '29278', (28, 38))	('oligodendroglioma', 'Disease', 'MESH:D009837', (3, 20))	('expression', 'Var', (28, 38))	('LRIG1', 'Gene', (140, 145))	('LRIG2', 'Gene', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('poor', 'NegReg', (58, 62))
189581	25353163	In addition, LRIG2 expression is associated with poor survival in oligodendroglioma and squamous cell carcinoma of the uterine cervix.	('LRIG2', 'Gene', (13, 18))	('oligodendroglioma', 'Disease', (66, 83))	('carcinoma of the uterine', 'Phenotype', 'HP:0010784', (102, 126))	('expression', 'Var', (19, 29))	('oligodendroglioma', 'Disease', 'MESH:D009837', (66, 83))	('uterine cervix', 'Phenotype', 'HP:0030160', (119, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('poor', 'NegReg', (49, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('squamous cell carcinoma', 'Disease', (88, 111))	('expression', 'Species', '29278', (19, 29))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
189605	25353163	Paraffin sections with a thickness of 4 microm were incubated with anti-LRIG2 (1:100), anti-Ki-67 (1:200), anti-PCNA (1:200), and anti-caspase3 (1:100) antibodies at 4 C overnight as previously described.	('1:200', 'Var', (118, 123))	('PCNA', 'Gene', (112, 116))	('Ki-67', 'Chemical', '-', (92, 97))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('caspase3', 'Gene', (135, 143))	('anti-Ki-67', 'Var', (87, 97))	('PCNA', 'Gene', '5111', (112, 116))	('caspase3', 'Gene', '836', (135, 143))	('anti-LRIG2', 'Var', (67, 77))
189641	25353163	In line with the results of U87 cells, the percentages of Ki-67 positive cells of LRIG2 and LRIG2ecto overexpressing U251 cells were also significantly increased compared to the U251 control cells (Figure 4B).	('U251', 'Var', (117, 121))	('U87', 'Gene', '641648', (28, 31))	('Ki-67', 'Gene', (58, 63))	('increased', 'PosReg', (152, 161))	('Ki-67', 'Chemical', '-', (58, 63))	('U87', 'Gene', (28, 31))
189642	25353163	Further, we investigated whether LRIG2 or LRIG2ecto altered glioblastoma anchorage-independent growth, a property that mimics tumorigenesis in vivo.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('LRIG2ecto', 'Var', (42, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('altered', 'Reg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
189655	25353163	Similar to the results obtained from in vitro studies, the expression levels of Ki-67 and PCNA, two markers of cell proliferation activity, in LRIG2 and LRIG2ecto groups were both significantly increased and the levels of caspase3, a marker of apoptosis, were both markedly inhibited compared to the control group (Figure 6C).	('PCNA', 'Gene', '5111', (90, 94))	('expression levels', 'MPA', (59, 76))	('LRIG2', 'Var', (143, 148))	('Ki-67', 'Gene', (80, 85))	('expression', 'Species', '29278', (59, 69))	('inhibited', 'NegReg', (274, 283))	('increased', 'PosReg', (194, 203))	('caspase3', 'Gene', (222, 230))	('PCNA', 'Gene', (90, 94))	('caspase3', 'Gene', '836', (222, 230))	('Ki-67', 'Chemical', '-', (80, 85))
189665	25353163	U87 cells overexpressing LRIG2 or LRIG2ecto exhibited not only increased levels of total and phosphorylated EGFR but also enhanced Akt activation with or without EGF stimulation (Figure 9A).	('U87', 'Gene', '641648', (0, 3))	('enhanced', 'PosReg', (122, 130))	('increased', 'PosReg', (63, 72))	('activation', 'PosReg', (135, 145))	('levels', 'MPA', (73, 79))	('Akt', 'Gene', (131, 134))	('EGF', 'Gene', (108, 111))	('EGF', 'Gene', '1950', (108, 111))	('LRIG2', 'Var', (25, 30))	('EGF', 'Gene', '1950', (162, 165))	('phosphorylated', 'MPA', (93, 107))	('Akt', 'Gene', '207', (131, 134))	('U87', 'Gene', (0, 3))	('EGF', 'Gene', (162, 165))	('LRIG2ecto', 'Var', (34, 43))
189666	25353163	U251 cells overexpressing LRIG2 or LRIG2ecto revealed strikingly increased levels of total EGFR with or without EGF stimulation, modestly increased phosphorylated EGFR and Akt activation with EGF stimulation for 5 minutes (Figure 9A).	('LRIG2', 'Var', (26, 31))	('increased', 'PosReg', (65, 74))	('EGF', 'Gene', (91, 94))	('increased', 'PosReg', (138, 147))	('EGF', 'Gene', '1950', (163, 166))	('EGF', 'Gene', (112, 115))	('LRIG2ecto', 'Var', (35, 44))	('EGF', 'Gene', (192, 195))	('Akt', 'Gene', '207', (172, 175))	('EGF', 'Gene', '1950', (91, 94))	('levels', 'MPA', (75, 81))	('EGF', 'Gene', '1950', (112, 115))	('EGF', 'Gene', '1950', (192, 195))	('Akt', 'Gene', (172, 175))	('activation', 'PosReg', (176, 186))	('EGF', 'Gene', (163, 166))
189667	25353163	Next, we used gefitinib (10 microM) to inhibit the phosphorylation of EGFR followed by detecting the downstream PI3 K/Akt pathway and results revealed that inhibition of phosphorylation of EGFR abrogated the effects of LRIG2 and LRIG2ecto overexpressions on the Akt activation (Figure 9B), which further demonstrated that LRIG2 or LRIG2ecto overexpression enhanced the activation of PI3 K/Akt pathway through stabilizing the EGFR and enhancing the EGFR phosphorylation.	('expression', 'Species', '29278', (243, 253))	('Akt', 'Gene', (262, 265))	('LRIG2', 'Var', (322, 327))	('enhanced', 'PosReg', (356, 364))	('LRIG2ecto', 'Var', (331, 340))	('expression', 'Species', '29278', (345, 355))	('Akt', 'Gene', (118, 121))	('EGFR', 'Protein', (448, 452))	('Akt', 'Gene', '207', (389, 392))	('Akt', 'Gene', '207', (118, 121))	('enhancing', 'PosReg', (434, 443))	('Akt', 'Gene', (389, 392))	('EGFR', 'Protein', (425, 429))	('Akt', 'Gene', '207', (262, 265))	('stabilizing', 'MPA', (409, 420))
189668	25353163	Combining the forementioned results, we suggest that upregulation of LRIG2 or LRIG2ecto lead to stabilization of EGFR and activation of EGFR, thereby enhancing the downstream PI3K/AKT pathway.	('enhancing', 'PosReg', (150, 159))	('LRIG2', 'Var', (69, 74))	('EGFR', 'Protein', (113, 117))	('upregulation', 'PosReg', (53, 65))	('AKT', 'Gene', (180, 183))	('activation', 'PosReg', (122, 132))	('LRIG2ecto', 'Var', (78, 87))	('EGFR', 'Protein', (136, 140))	('stabilization', 'MPA', (96, 109))	('AKT', 'Gene', '207', (180, 183))
189701	25353163	Going forward, it will be important to determine how LRIG2 ectodomain is released from glioblastoma cells, whether this kind of release is universal, and how LRIG2 ectodomain interact with EGFR and enhance the activation of EGFR.	('EGFR', 'Protein', (224, 228))	('EGFR', 'Protein', (189, 193))	('LRIG2 ectodomain', 'Var', (158, 174))	('ectodomain', 'Var', (164, 174))	('activation', 'MPA', (210, 220))	('glioblastoma', 'Disease', (87, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('interact', 'Interaction', (175, 183))	('enhance', 'PosReg', (198, 205))
189717	24602166	Aberrant PAX gene expression is present in multiple cancer types, including cancers of the lymphoid tissue, thyroid, kidney, breast, and endometrium.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('PAX gene', 'Gene', (9, 17))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (76, 83))	('breast', 'Disease', (125, 131))	('PAX', 'Chemical', '-', (9, 12))	('thyroid', 'Disease', (108, 115))	('kidney', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('expression', 'MPA', (18, 28))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('endometrium', 'Disease', (137, 148))
189743	24602166	Two additional siRNA for p53 sc29435 (siTP53 2 in this study) and sc44218 (siTP53 3 in this study) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('sc44218', 'Var', (66, 73))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
189745	24602166	Two additional siRNA for BCL2 214532 (siBCL2 2 in this study) and 214533 (siBCL2 3 in this study) purchased from Life Technologies (Carlsbad, CA).	('214533', 'Var', (66, 72))	('BCL2', 'Gene', '596', (76, 80))	('BCL2', 'Gene', (25, 29))	('BCL2', 'Gene', '596', (40, 44))	('BCL2', 'Gene', (76, 80))	('BCL2', 'Gene', (40, 44))	('BCL2', 'Gene', '596', (25, 29))
189756	24602166	PAX8-positive glioblastomas were present in all the telomere maintenance mechanism groups, but a higher prevalence was observed in the telomerase-positive (80%) and NDTMM-positive (73%) tumours compared with the ALT-positive tumours (44%; P = 0.007 and P = 0.043, respectively).	('ALT-positive tumours', 'Disease', 'MESH:D009369', (212, 232))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumours', 'Disease', (225, 232))	('tumours', 'Disease', (186, 193))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('NDTMM-positive', 'Gene', (165, 179))	('glioblastomas', 'Phenotype', 'HP:0012174', (14, 27))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('PAX8-positive', 'Gene', (0, 13))	('glioblastomas', 'Disease', 'MESH:D005909', (14, 27))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('telomerase-positive', 'Var', (135, 154))	('glioblastomas', 'Disease', (14, 27))	('ALT-positive tumours', 'Disease', (212, 232))
189783	24602166	Western blots assessing the relative levels of BCL2 with PAX8 knockdown revealed a reduction in the BCL2 expression (Figure 3A), whereas in the controls (mock transfection, transfection with non-targeting siRNAs or the scrambled siRNA [sc8-1]) no reduction in PAX8 or BCL2 expression was observed (Figure 3A).	('PAX8', 'Gene', (57, 61))	('BCL2', 'Gene', (47, 51))	('BCL2', 'Gene', '596', (268, 272))	('BCL2', 'Gene', (100, 104))	('BCL2', 'Gene', (268, 272))	('BCL2', 'Gene', '596', (47, 51))	('reduction', 'NegReg', (83, 92))	('expression', 'MPA', (105, 115))	('BCL2', 'Gene', '596', (100, 104))	('knockdown', 'Var', (62, 71))
189784	24602166	A similar result was found for WT1, in which reduced WT1 was specific to lysates with PAX8 knockdown (Figure 3B).	('WT1', 'Gene', (53, 56))	('WT1', 'Gene', '7490', (31, 34))	('knockdown', 'Var', (91, 100))	('WT1', 'Gene', (31, 34))	('PAX8', 'Gene', (86, 90))	('WT1', 'Gene', '7490', (53, 56))
189785	24602166	These data suggest that PAX8 silencing leads to downregulation of BCL2 and WT1 expression.	('WT1', 'Gene', (75, 78))	('BCL2', 'Gene', '596', (66, 70))	('silencing', 'Var', (29, 38))	('PAX8', 'Gene', (24, 28))	('BCL2', 'Gene', (66, 70))	('downregulation', 'NegReg', (48, 62))	('WT1', 'Gene', '7490', (75, 78))
189786	24602166	To investigate whether this reduction in BCL2 expression could explain the growth reduction associated with the PAX8-knockdown, BCL2 was knocked down using a BCL2 siRNA in A172 cells, and cell growth monitored for 24-96 hours after transfection.	('BCL2', 'Gene', '596', (158, 162))	('growth', 'MPA', (75, 81))	('BCL2', 'Gene', '596', (128, 132))	('BCL2', 'Gene', (41, 45))	('reduction', 'NegReg', (82, 91))	('BCL2', 'Gene', (158, 162))	('A172', 'CellLine', 'CVCL:0131', (172, 176))	('knocked', 'Var', (137, 144))	('BCL2', 'Gene', (128, 132))	('reduction', 'NegReg', (28, 37))	('BCL2', 'Gene', '596', (41, 45))
189787	24602166	BCL2 silencing resulted in a reduction in glioma cell growth similar to the reduction observed with PAX8 silencing (Figure 3C) at 48-96 hours post-transfection (P < 0.01, BCL2 siRNA compared with controls).	('glioma cell growth', 'Disease', (42, 60))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('BCL2', 'Gene', (171, 175))	('reduction', 'NegReg', (29, 38))	('silencing', 'Var', (5, 14))	('BCL2', 'Gene', (0, 4))	('glioma cell growth', 'Disease', 'MESH:D005910', (42, 60))	('BCL2', 'Gene', '596', (171, 175))	('BCL2', 'Gene', '596', (0, 4))
189802	24602166	Hypomethylation, for example, produces an increase in PAX2 expression in endometrioid carcinoma.	('PAX2', 'Gene', '5076', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Hypomethylation', 'Var', (0, 15))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (73, 95))	('expression', 'MPA', (59, 69))	('PAX2', 'Gene', (54, 58))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (73, 95))	('endometrioid carcinoma', 'Disease', (73, 95))	('increase', 'PosReg', (42, 50))
189815	24602166	The silencing PAX8 in several glioma cell lines caused a marked reduction in cell number, which is partly explained by an increase in apoptosis.	('cell number', 'CPA', (77, 88))	('PAX8', 'Gene', (14, 18))	('increase', 'PosReg', (122, 130))	('reduction', 'NegReg', (64, 73))	('glioma', 'Disease', (30, 36))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('silencing', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
189817	24602166	These findings are consistent with previous reports that demonstrate PAX expression enhances cell growth and survival, and upregulated BCL2 is found in gliomagenesis.	('expression', 'Var', (73, 83))	('cell growth', 'CPA', (93, 104))	('enhances', 'PosReg', (84, 92))	('PAX', 'Gene', (69, 72))	('upregulated', 'PosReg', (123, 134))	('glioma', 'Disease', (152, 158))	('BCL2', 'Gene', '596', (135, 139))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('BCL2', 'Gene', (135, 139))	('survival', 'CPA', (109, 117))	('PAX', 'Chemical', '-', (69, 72))
189818	24602166	In other studies BCL2 silencing induced cell death in vitro, led to an arrest of cell cycle progression, and was associated with the downregulation of multiple developmental genes.	('BCL2', 'Gene', '596', (17, 21))	('BCL2', 'Gene', (17, 21))	('downregulation', 'NegReg', (133, 147))	('silencing', 'Var', (22, 31))	('death', 'Disease', 'MESH:D003643', (45, 50))	('death', 'Disease', (45, 50))	('cell cycle progression', 'CPA', (81, 103))
189841	33085656	Similarly, GPX1 overexpression was also found to promote tumor growth and metastasis in a skin cancer mouse model.	('GPX1', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (90, 101))	('metastasis', 'CPA', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('overexpression', 'Var', (16, 30))	('skin cancer', 'Disease', (90, 101))	('promote', 'PosReg', (49, 56))	('skin cancer', 'Disease', 'MESH:D012878', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (57, 62))	('mouse', 'Species', '10090', (102, 107))
189842	33085656	However, there is evidence indicating that high expression of GPX1 could inhibit pancreatic cancer cell proliferation.	('high expression', 'Var', (43, 58))	('GPX1', 'Gene', (62, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))	('inhibit', 'NegReg', (73, 80))
189872	33085656	GPX1 expression was sharply higher in high-grade, 1p/19q non-codel status, and IDH-wild-type status gliomas and in older patients; there was no statistically significant sex-based differences based on the TCGA (Figure 2E-2I) and CGGA (Figure 2J-2N) datasets.	('expression', 'MPA', (5, 15))	('GPX1', 'Gene', (0, 4))	('IDH', 'Gene', (79, 82))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH', 'Gene', '3417', (79, 82))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('1p/19q non-codel status', 'Var', (50, 73))	('status gliomas', 'Disease', (93, 107))	('higher', 'PosReg', (28, 34))	('status gliomas', 'Disease', 'MESH:D005910', (93, 107))	('patients', 'Species', '9606', (121, 129))	('high-grade', 'Var', (38, 48))
189874	33085656	Univariate Cox regression analysis based on the TCGA dataset showed that the WHO grade, age, IDH status, 1p/19q status, and GPX1 expression were strongly associated with OS of patients.	('patients', 'Species', '9606', (176, 184))	('1p/19q status', 'Var', (105, 118))	('associated with', 'Reg', (154, 169))	('IDH', 'Gene', (93, 96))	('GPX1', 'Gene', (124, 128))	('IDH', 'Gene', '3417', (93, 96))	('OS of patients', 'Disease', (170, 184))
189877	33085656	The nomogram integrated age, grade, 1p19q status, IDH status, and GPX1 expression for gliomas in the TCGA dataset (Figure 3A), and the C-index was 0.861.	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('GPX1', 'Gene', (66, 70))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))	('1p19q status', 'Var', (36, 48))
189885	33085656	These analyses revealed that high expression levels of GPX1 could critically increase immune infiltrating levels of B cells (R=0.242, P=5.55e-07), CD4+ cells (R=0.158, P=1.21e-03), macrophages (R=0.236, P=1.09e-06), neutrophils (R=0.286, P=2.54e-09), and dendritic cells (R=0.343, P=5.65-13), while negative associations were found for levels of CD8+ T cells (R=-0.1777, P=2.83e-04) in GBM (Figure 5A).	('CD4', 'Gene', '920', (147, 150))	('GPX1', 'Gene', (55, 59))	('CD8', 'Gene', (346, 349))	('CD8', 'Gene', '925', (346, 349))	('immune infiltrating levels of B', 'MPA', (86, 117))	('increase', 'PosReg', (77, 85))	('high expression levels', 'Var', (29, 51))	('GBM', 'Phenotype', 'HP:0012174', (386, 389))	('CD4', 'Gene', (147, 150))
189906	33085656	The GPX1 expression level was positively correlated with older patients, and high-grade, 1p19q non-codel, and IDH-wild-type status glioma; this correlation may imply a previously unidentified molecular mechanism of GPX1 in glioma malignancies.	('status glioma', 'Disease', 'MESH:D005910', (124, 137))	('glioma malignancies', 'Disease', 'MESH:D005910', (223, 242))	('1p19q non-codel', 'Var', (89, 104))	('correlated', 'Interaction', (41, 51))	('GPX1', 'Gene', (4, 8))	('IDH', 'Gene', (110, 113))	('high-grade', 'Disease', (77, 87))	('expression level', 'MPA', (9, 25))	('status glioma', 'Disease', (124, 137))	('IDH', 'Gene', '3417', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('glioma malignancies', 'Disease', (223, 242))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('patients', 'Species', '9606', (63, 71))	('imply', 'Reg', (160, 165))
189908	33085656	In addition, some clinical characteristics also had a positive correlation with worse OS; these included patient age, glioma grade, and 1p/19q codel and IDH status.	('patient', 'Species', '9606', (105, 112))	('glioma', 'Disease', (118, 124))	('1p/19q codel', 'Var', (136, 148))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('IDH', 'Gene', (153, 156))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('IDH', 'Gene', '3417', (153, 156))
189913	33085656	We hypothesized that these signaling pathways have a critical role in malignancy progression of gliomas, and high GPX1 expression is correlated with these critical inflammatory signal pathways.	('expression', 'MPA', (119, 129))	('high', 'Var', (109, 113))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('malignancy', 'Disease', (70, 80))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('correlated', 'Reg', (133, 143))	('GPX1', 'Gene', (114, 118))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
189930	33085656	Moreover, we also found that high GPX1 expression increases immune infiltration levels in GBM and LGG, which means that GPX1 is involved in the activation of immune infiltration in gliomas.	('high', 'Var', (29, 33))	('GPX1', 'Gene', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('expression', 'Var', (39, 49))	('immune infiltration levels', 'MPA', (60, 86))	('increases', 'PosReg', (50, 59))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('gliomas', 'Disease', (181, 188))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
189936	31027305	Additionally, siRNA-mediated knockdown of integrin alpha10 in GBM cells led to decreased migration and increased cell death.	('knockdown', 'Var', (29, 38))	('decreased', 'NegReg', (79, 88))	('cell death', 'CPA', (113, 123))	('rat', 'Species', '10116', (92, 95))	('migration', 'CPA', (89, 98))	('integrin alpha10', 'Protein', (42, 58))
189961	31027305	Furthermore, integrin alpha10beta1 has been shown to be an important receptor on alpha-smooth muscle actin (alpha-SMA)-expressing stromal cells in human ovarian tumors by binding to the HU177 cryptic collagen epitope.	('alpha-SMA', 'Gene', (108, 117))	('binding', 'Interaction', (171, 178))	('ovarian tumors', 'Disease', (153, 167))	('ovarian tumor', 'Phenotype', 'HP:0100615', (153, 166))	('human', 'Species', '9606', (147, 152))	('HU177', 'Var', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('alpha-SMA', 'Gene', '11475', (108, 117))	('ovarian tumors', 'Phenotype', 'HP:0100615', (153, 167))	('ovarian tumors', 'Disease', 'MESH:D010051', (153, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))
189974	31027305	We further examined five cell lines (U3071MG, U3078MG, U3046MG, U3054MG, and U3073MG) with high or low ITGA10 expression using flow cytometry (Figure 2B) and immunofluorescence analysis (Figure 2C).	('U3046MG', 'CellLine', 'CVCL:C677', (55, 62))	('U3046MG', 'Var', (55, 62))	('U3054MG', 'CellLine', 'CVCL:0022', (64, 71))	('U3078MG', 'Var', (46, 53))	('low', 'NegReg', (99, 102))	('U3071MG', 'CellLine', 'CVCL:1W52', (37, 44))	('ITGA10', 'Gene', (103, 109))	('U3071MG', 'Var', (37, 44))	('U3073MG', 'CellLine', 'CVCL:9M09', (77, 84))	('U3054MG', 'Var', (64, 71))	('expression', 'MPA', (110, 120))	('U3073MG', 'Var', (77, 84))	('U3078MG', 'CellLine', 'CVCL:9M13', (46, 53))
189975	31027305	Cell line U3071MG, with the highest gene expression level of ITGA10, also expressed the integrin alpha10 protein to a high degree, whereas the other cell lines showed lower expression levels as determined by flow cytometry (Figure 2B).	('integrin alpha10 protein', 'Protein', (88, 112))	('expressed', 'MPA', (74, 83))	('U3071MG', 'CellLine', 'CVCL:1W52', (10, 17))	('U3071MG', 'Var', (10, 17))	('ITGA10', 'Gene', (61, 67))
189977	31027305	Cell line U3071MG appeared to have the highest expression level of integrin alpha10 protein (Figure 2B,C).	('U3071MG', 'CellLine', 'CVCL:1W52', (10, 17))	('U3071MG', 'Var', (10, 17))	('expression level', 'MPA', (47, 63))
189979	31027305	Immunofluorescence analysis of cell lines U3078MG and U3054MG demonstrated cellular co-expression between integrin alpha10beta1 and the intracellular markers Sox2 and Nestin (Figure 3A).	('U3054MG', 'CellLine', 'CVCL:0022', (54, 61))	('U3078MG', 'CellLine', 'CVCL:9M13', (42, 49))	('U3054MG', 'Var', (54, 61))	('Nestin', 'Gene', '18008', (167, 173))	('Nestin', 'Gene', (167, 173))	('U3078MG', 'Var', (42, 49))	('co-expression', 'Interaction', (84, 97))	('rat', 'Species', '10116', (69, 72))	('integrin', 'Protein', (106, 114))
189985	31027305	We found that mRNA expression of ITGA3 and ITGA6 were all higher in the population of U3054MG cells with low intensity of integrin alpha10 (Figure 3E).	('ITGA6', 'Gene', '16403', (43, 48))	('ITGA6', 'Gene', (43, 48))	('ITGA3', 'Gene', (33, 38))	('U3054MG', 'CellLine', 'CVCL:0022', (86, 93))	('ITGA3', 'Gene', '16400', (33, 38))	('higher', 'PosReg', (58, 64))	('mRNA expression', 'MPA', (14, 29))	('U3054MG', 'Var', (86, 93))
189987	31027305	For a better understanding of the phenotype of this subpopulation of GBM cells, gene expression analysis was performed on U3071MG, U3078MG, and U3054MG cells sorted into integrin alpha10high and alpha10low populations.	('U3078MG', 'Var', (131, 138))	('U3071MG', 'CellLine', 'CVCL:1W52', (122, 129))	('U3054MG', 'CellLine', 'CVCL:0022', (144, 151))	('U3071MG', 'Var', (122, 129))	('U3078MG', 'CellLine', 'CVCL:9M13', (131, 138))	('U3054MG', 'Var', (144, 151))
189990	31027305	The expression of CAPN6 was very low in U3078MG cells, which may reflect the heterogeneity of the cell lines.	('low', 'NegReg', (33, 36))	('U3078MG', 'Var', (40, 47))	('CAPN6', 'Gene', (18, 23))	('expression', 'MPA', (4, 14))	('U3078MG', 'CellLine', 'CVCL:9M13', (40, 47))	('CAPN6', 'Gene', '12338', (18, 23))
189996	31027305	We then sorted U3054MG cells into integrin alpha10high and alpha10low populations and cultured the cells as spheres or in a monolayer on laminin-111 coated plates.	('U3054MG', 'CellLine', 'CVCL:0022', (15, 22))	('laminin-111', 'Gene', (137, 148))	('U3054MG', 'Var', (15, 22))	('laminin-111', 'Gene', '16777', (137, 148))	('alpha10low', 'Var', (59, 69))
189997	31027305	We found that the expression of integrin alpha10beta1 was drastically increased when the cells were cultured as spheres compared with cells grown in a monolayer, on both alpha10high- and alpha10low- U3054MG cells (Figure 4C).	('alpha10high-', 'Var', (170, 182))	('alpha10low- U3054MG', 'Var', (187, 206))	('increased', 'PosReg', (70, 79))	('U3054MG', 'CellLine', 'CVCL:0022', (199, 206))	('integrin alpha10beta1', 'Protein', (32, 53))	('expression', 'MPA', (18, 28))
189999	31027305	ITGA10 expression was knocked down in two GBM cell lines with high integrin alpha10 levels, U3078MG and U3046MG, using siRNA.	('U3046MG', 'Var', (104, 111))	('U3078MG', 'Var', (92, 99))	('ITGA10', 'Gene', (0, 6))	('U3078MG', 'CellLine', 'CVCL:9M13', (92, 99))	('U3046MG', 'CellLine', 'CVCL:C677', (104, 111))
190000	31027305	After 96 h, a specific knockdown of ITGA10 was demonstrated both on mRNA and the cell surface protein level (Figure 5A,B).	('ITGA10', 'Gene', (36, 42))	('rat', 'Species', '10116', (54, 57))	('knockdown', 'Var', (23, 32))
190001	31027305	As demonstrated in Figure 5C, we found that cell migration on gelatin-coated transwell filters was significantly diminished in ITGA10 knockdown cells.	('rat', 'Species', '10116', (52, 55))	('ITGA10', 'Gene', (127, 133))	('diminished', 'NegReg', (113, 123))	('knockdown', 'Var', (134, 143))	('rat', 'Species', '10116', (10, 13))	('cell migration on', 'CPA', (44, 61))
190002	31027305	Moreover, by knocking down ITGA10, the viability was reduced, seen as an increased number of dead cells (7-Aminoactinomycin D (7-AAD) positive cells) compared with the control transfected cells (Figure 5D,E).	('increased', 'PosReg', (73, 82))	('knocking down', 'Var', (13, 26))	('7-Aminoactinomycin D', 'Chemical', 'MESH:C025942', (105, 125))	('ITGA10', 'Gene', (27, 33))	('reduced', 'NegReg', (53, 60))	('7-AAD', 'Chemical', 'MESH:C025942', (127, 132))	('viability', 'CPA', (39, 48))
190008	31027305	When the U3046MG and U3054MG GBM cells were treated with anti-alpha10-SAP, the number of viable cells was strongly reduced with the increasing concentration of anti-alpha10-SAP (Figure 6C,D).	('U3046MG', 'Var', (9, 16))	('U3054MG', 'CellLine', 'CVCL:0022', (21, 28))	('U3046MG', 'CellLine', 'CVCL:C677', (9, 16))	('reduced', 'NegReg', (115, 122))	('rat', 'Species', '10116', (150, 153))	('SAP', 'Gene', (173, 176))	('U3054MG', 'Var', (21, 28))	('SAP', 'Gene', (70, 73))	('SAP', 'Gene', '20219', (173, 176))	('SAP', 'Gene', '20219', (70, 73))
190009	31027305	The best effect was shown with the U3054MG cells, where viability and sphere formation capacity was decreased by 50% and 70%, respectively, compared with anti-ctrl-SAP-treated cells at a concentration of 69 nM (Figure 6D,E).	('SAP', 'Gene', (164, 167))	('sphere formation capacity', 'CPA', (70, 95))	('rat', 'Species', '10116', (194, 197))	('SAP', 'Gene', '20219', (164, 167))	('U3054MG', 'CellLine', 'CVCL:0022', (35, 42))	('decreased', 'NegReg', (100, 109))	('U3054MG', 'Var', (35, 42))
190038	31027305	Moreover, we show that high ITGA10 expression correlates with a worse overall survival probability in glioma patients and may play a critical role in tumor progression in glioma.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('worse', 'NegReg', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('overall survival', 'MPA', (70, 86))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('high', 'Var', (23, 27))	('ITGA10', 'Gene', (28, 34))	('patients', 'Species', '9606', (109, 117))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('expression', 'MPA', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('glioma', 'Disease', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('play', 'Reg', (126, 130))	('glioma', 'Disease', (102, 108))	('tumor', 'Disease', (150, 155))
190047	31027305	A number of integrins have been demonstrated to be expressed by GBM cells and the integrin subunits alpha3, alpha6, and alpha7 are not only up-regulated in glioma stem-like cells, but increase their tumorigenicity.	('tumor', 'Disease', (199, 204))	('alpha3', 'Protein', (100, 106))	('glioma', 'Disease', (156, 162))	('alpha6', 'Protein', (108, 114))	('increase', 'PosReg', (184, 192))	('rat', 'Species', '10116', (39, 42))	('alpha7', 'Var', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('up-regulated', 'PosReg', (140, 152))
190087	31027305	After a 30-min incubation with a primary antibody, cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS, SH3002802, Hyclone, Logan, UT, USA) containing 1% FBS and 0.1% sodium azide and incubated with a secondary antibody (Table S3) for 20 min in the dark at 4  C. For co-staining integrin alpha3 and alpha7 with integrin alpha10, cells were then incubated with integrin alpha10 Alexa Fluor 647 antibody for 30 min in the dark at 4  C before subsequent analysis using flow cytometry.	('integrin alpha3', 'Gene', '16400', (299, 314))	('PBS', 'Chemical', 'MESH:D007854', (119, 122))	('integrin alpha3', 'Gene', (299, 314))	('FBS', 'Disease', 'MESH:D005198', (174, 177))	('co-staining', 'Var', (287, 298))	('Alexa Fluor 647', 'Chemical', 'MESH:C569686', (397, 412))	('FBS', 'Disease', (174, 177))
190093	31027305	The U3078MG and U3046MG GBM cells were seeded in antibiotic-free medium in 60 mm plates 24 h before transfection.	('U3078MG', 'Var', (4, 11))	('U3046MG', 'Var', (16, 23))	('U3078MG', 'CellLine', 'CVCL:9M13', (4, 11))	('U3046MG', 'CellLine', 'CVCL:C677', (16, 23))
190099	31027305	The trans-well inserts (CytoSelect Cell Migration Assay kit, Cell Biolabs, San Diego, CA, USA) were coated with gelatin (Sigma Aldrich, Saint Louis, MO, USA) for approximately 2-4 h at 37  C. The ITGA10-knocked-down U3078MG and U3046MG cells were seeded to the upper compartment of the CytoSelect Insert.	('U3046MG', 'Var', (228, 235))	('U3078MG', 'CellLine', 'CVCL:9M13', (216, 223))	('U3046MG', 'CellLine', 'CVCL:C677', (228, 235))	('rat', 'Species', '10116', (43, 46))	('ITGA10-knocked-down', 'Gene', (196, 215))	('U3078MG', 'Var', (216, 223))
190106	31027305	The isotype control IgG2a antibody (401504, Biolegend) and blocking monoclonal integrin alpha10 antibody were used at a concentration of 3-5 microg/mL.	('IgG2a', 'Gene', (20, 25))	('rat', 'Species', '10116', (127, 130))	('IgG2a', 'Gene', '668478', (20, 25))	('401504', 'Var', (36, 42))
190107	31027305	The C2C12alpha10 and C2C12alpha11 cells were added to the wells at a concentration of 65,000/well and U3054MG cells at a concentration of 100,000/well, and cells were allowed to adhere for 1 h at 37  C. After incubation, cells were gently rinsed with PBS (+Ca/Mg) to remove non-adherent cells.	('rat', 'Species', '10116', (76, 79))	('U3054MG', 'CellLine', 'CVCL:0022', (102, 109))	('C2C12alpha11', 'Var', (21, 33))	('PBS', 'Chemical', 'MESH:D007854', (251, 254))	('U3054MG', 'Var', (102, 109))	('rat', 'Species', '10116', (128, 131))	('C2C12alpha10', 'Var', (4, 16))
190131	31027305	The U3071MG, U3078MG, U3046MG, U3054MG, and U3073MG cells were seeded on 8-well, glass bottom, microscope chamber slides (ibiTreat, Ibidi, Germany).	('U3073MG', 'Var', (44, 51))	('U3046MG', 'Var', (22, 29))	('U3046MG', 'CellLine', 'CVCL:C677', (22, 29))	('U3071MG', 'CellLine', 'CVCL:1W52', (4, 11))	('U3054MG', 'CellLine', 'CVCL:0022', (31, 38))	('U3078MG', 'Var', (13, 20))	('U3073MG', 'CellLine', 'CVCL:9M09', (44, 51))	('U3071MG', 'Var', (4, 11))	('U3054MG', 'Var', (31, 38))	('U3078MG', 'CellLine', 'CVCL:9M13', (13, 20))
190167	31027305	Data Curation: M.M.T., K.C.M., C.K., X.H., S.K., L.S., E.E., and B.H.	('C.K.', 'Var', (31, 35))	('K.C.M.', 'Var', (23, 29))	('rat', 'Species', '10116', (7, 10))	('S.K.', 'Var', (43, 47))
190172	31032260	A meta-analysis evidenced that gross total resection improves progression free survival and overall survival (OS) in glioblastomas.	('gross', 'Var', (31, 36))	('improves', 'PosReg', (53, 61))	('overall survival', 'MPA', (92, 108))	('progression', 'MPA', (62, 73))	('glioblastomas', 'Phenotype', 'HP:0012174', (117, 130))	('glioblastomas', 'Disease', 'MESH:D005909', (117, 130))	('glioblastomas', 'Disease', (117, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
190173	31032260	In a consecutive cohort with 500 newly diagnosed glioblastomas, a significant survival benefit was noted with as little as 78% EOR, and stepwise improvement in OS was observed even in the 95-100% EOR range.	('glioblastomas', 'Disease', (49, 62))	('benefit', 'PosReg', (87, 94))	('EOR', 'Var', (127, 130))	('glioblastomas', 'Phenotype', 'HP:0012174', (49, 62))	('survival', 'MPA', (78, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('glioblastomas', 'Disease', 'MESH:D005909', (49, 62))
190213	29590109	The important role of vasculitropin in the process of solid tumors' neoangiogenesis is associated with its increased concentration in body fluids:high expression of VEGF is associated with increased tumor aggressiveness (rapid growth, metastasis) and the same:poor prognosis.	('increased tumor aggressiveness', 'Disease', (189, 219))	('VEGF', 'Gene', '7422', (165, 169))	('aggressiveness', 'Phenotype', 'HP:0000718', (205, 219))	('neoangiogenesis', 'CPA', (68, 83))	('increased tumor aggressiveness', 'Disease', 'MESH:D009369', (189, 219))	('solid tumors', 'Disease', 'MESH:D009369', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('VEGF', 'Gene', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('solid tumors', 'Disease', (54, 66))	('high expression', 'Var', (146, 161))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
190222	29590109	The control group consisted of 50 adults (Mp = 59.16) volunteers of both sexes (24 women and 26 men), without tumor diagnosis, who did not underwent surgery in less than 30 days, negating occurrence of diabetes, hypertension and coronary heart disease, and do not taking any medicines on a regular basis.	('men', 'Species', '9606', (96, 99))	('diabetes', 'Disease', (202, 210))	('hypertension', 'Disease', 'MESH:D006973', (212, 224))	('occurrence', 'Reg', (188, 198))	('diabetes', 'Disease', 'MESH:D003920', (202, 210))	('coronary heart disease', 'Disease', (229, 251))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('hypertension', 'Disease', (212, 224))	('coronary heart disease', 'Phenotype', 'HP:0001677', (229, 251))	('coronary heart disease', 'Disease', 'MESH:D003324', (229, 251))	('hypertension', 'Phenotype', 'HP:0000822', (212, 224))	('men', 'Species', '9606', (85, 88))	('negating', 'Var', (179, 187))	('women', 'Species', '9606', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
190297	27346749	Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene.	('mutations', 'Var', (21, 30))	('MGMT', 'Gene', '4255', (172, 176))	('methylguanine DNA methyltransferase', 'Gene', (135, 170))	('MGMT', 'Gene', (172, 176))	('epigenetic silencing', 'Var', (107, 127))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('methylguanine DNA methyltransferase', 'Gene', '4255', (135, 170))	('associated', 'Reg', (91, 101))
190298	27346749	However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus.	('MGMT', 'Gene', '4255', (49, 53))	('deletion', 'Var', (152, 160))	('MGMT', 'Gene', (49, 53))	('MGMT', 'Gene', '4255', (131, 135))	('IDH', 'Gene', (76, 79))	('MGMT', 'Gene', (131, 135))	('association', 'Interaction', (111, 122))	('IDH', 'Gene', '3417', (76, 79))	('MGMT', 'Gene', '4255', (202, 206))	('MGMT', 'Gene', (202, 206))
190299	27346749	Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype.	('glioma', 'Disease', (83, 89))	('IDH1', 'Gene', (54, 58))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (33, 37))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('IDH', 'Gene', (54, 57))	('mutation', 'Var', (59, 67))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IDH', 'Gene', (150, 153))	('IDH1', 'Gene', '3417', (54, 58))	('IDH', 'Gene', '3417', (54, 57))	('IDH', 'Gene', '3417', (150, 153))
190303	27346749	MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.	('MGMT', 'Gene', (0, 4))	('contributing', 'Reg', (196, 208))	('loss', 'Var', (87, 91))	('inactivation', 'NegReg', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('10q deletion', 'Var', (57, 69))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('MGMT', 'Gene', (179, 183))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('MGMT', 'Gene', '4255', (0, 4))	('tumor', 'Disease', (212, 217))	('MGMT', 'Gene', '4255', (179, 183))
190309	27346749	Among them, mutations in the IDH1 and IDH2 genes, which encode isocitrate dehydrogenases, are considered valuable diagnostic and prognostic markers.	('IDH1', 'Gene', (29, 33))	('mutations', 'Var', (12, 21))	('IDH1', 'Gene', '3417', (29, 33))	('IDH2', 'Gene', (38, 42))	('IDH2', 'Gene', '3418', (38, 42))
190310	27346749	IDH1 is mutated in 50%-80% of astrocytomas, oligodendrogliomas, oligoastrocytomas, and secondary glioblastomas, with R132H the most common mutation (90%).	('oligoastrocytomas', 'Disease', 'MESH:D001254', (64, 81))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (44, 62))	('R132H', 'Var', (117, 122))	('glioblastomas', 'Disease', (97, 110))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('R132H', 'Mutation', 'rs121913500', (117, 122))	('astrocytomas', 'Disease', (30, 42))	('astrocytomas', 'Disease', 'MESH:D001254', (69, 81))	('IDH1', 'Gene', (0, 4))	('oligodendrogliomas', 'Disease', (44, 62))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('astrocytomas', 'Disease', 'MESH:D001254', (30, 42))	('glioblastomas', 'Phenotype', 'HP:0012174', (97, 110))	('astrocytomas', 'Disease', (69, 81))	('oligoastrocytomas', 'Disease', (64, 81))	('glioblastomas', 'Disease', 'MESH:D005909', (97, 110))	('IDH1', 'Gene', '3417', (0, 4))
190311	27346749	IDH2 is mutated in approximately 3% of gliomas.	('mutated', 'Var', (8, 15))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Disease', (39, 46))	('IDH2', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH2', 'Gene', '3418', (0, 4))
190312	27346749	It is likely that mutations in the IDHs represent an early event in tumor development, and it has been suggested that they may occur in the neoplastic cell of origin.	('tumor', 'Disease', (68, 73))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutations', 'Var', (18, 27))
190313	27346749	Indeed, IDH1 mutations are strongly associated with other driver alterations, namely, TP53 mutations and the 1p/19q co-deletion, in diffuse gliomas.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('TP53', 'Gene', '7157', (86, 90))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', (8, 12))	('TP53', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (8, 12))	('mutations', 'Var', (91, 100))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))	('associated', 'Reg', (36, 46))
190314	27346749	Mutations of the IDH genes confer an enzymatic gain-of-function phenotype, associated with production of the alternative metabolite, 2-hydroxyglutarate.	('production of the alternative metabolite', 'MPA', (91, 131))	('IDH', 'Gene', '3417', (17, 20))	('gain-of-function', 'PosReg', (47, 63))	('2-hydroxyglutarate', 'MPA', (133, 151))	('Mutations', 'Var', (0, 9))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (133, 151))	('IDH', 'Gene', (17, 20))
190316	27346749	Among methylated genes, the O6-methylguanine DNA methyltransferase (MGMT) promoter frequently undergoes methylation in the presence of IDH mutations, suggesting a possible molecular link between the two events.	('mutations', 'Var', (139, 148))	('methylation', 'MPA', (104, 115))	('O6-methylguanine DNA methyltransferase', 'Gene', (28, 66))	('undergoes', 'Reg', (94, 103))	('IDH', 'Gene', (135, 138))	('IDH', 'Gene', '3417', (135, 138))	('MGMT', 'Gene', '4255', (68, 72))	('MGMT', 'Gene', (68, 72))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (28, 66))
190317	27346749	MGMT acts as a tumor suppressor gene that functions in DNA repair and plays a fundamental role in maintaining genome integrity by removing O6-alkylguanine DNA adducts induced by radiotherapy or alkylating agents (i.e.	('MGMT', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('genome', 'MPA', (110, 116))	('O6-alkylguanine', 'Var', (139, 154))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('removing', 'NegReg', (130, 138))	('O6-alkylguanine', 'Chemical', '-', (139, 154))	('MGMT', 'Gene', '4255', (0, 4))
190324	27346749	Loss of heterozygosity (LOH) of 10q is frequent in gliomas and is classically associated with HGGs, where it is a negative prognostic marker.	('gliomas', 'Disease', (51, 58))	('associated', 'Reg', (78, 88))	('Loss of heterozygosity', 'Var', (0, 22))	('HGGs', 'Disease', (94, 98))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
190328	27346749	In this study, we used a quantitative approach to evaluate IDH1 mutations and MGMT promoter methylation in 208 primitive gliomas.	('IDH1', 'Gene', '3417', (59, 63))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('MGMT', 'Gene', '4255', (78, 82))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('MGMT', 'Gene', (78, 82))	('mutations', 'Var', (64, 73))	('IDH1', 'Gene', (59, 63))
190329	27346749	We also analyzed MGMT deletion in the same cases to explore the distribution of these biomarkers and possible associations between them, considering potential additive effects and their clinical significance.	('MGMT', 'Gene', (17, 21))	('deletion', 'Var', (22, 30))	('MGMT', 'Gene', '4255', (17, 21))
190347	27346749	Considering that mutations of IDH genes are usually heterozygous, a value of 50% for the mutated allele indicates that the alteration is present in virtually 100% of cells.	('IDH', 'Gene', '3417', (30, 33))	('mutations', 'Var', (17, 26))	('IDH', 'Gene', (30, 33))
190352	27346749	We investigated chromosome 10q deletions in 84 of 208 glioma samples, depending on DNA availability.	('glioma', 'Disease', (54, 60))	('deletions', 'Var', (31, 40))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('glioma', 'Disease', 'MESH:D005910', (54, 60))
190353	27346749	We used 2 different approaches as follows: when PBLs were available (76 cases), we compared the genotypes of short tandem repeats (STRs) in PBLs and tumor DNAs, whereas in the absence of normal tissue for comparison, array-comparative genomic hybridization (CGH) was performed (8 cases).	('short tandem repeats', 'Var', (109, 129))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('PBLs', 'Disease', (140, 144))
190355	27346749	Seven STRs spanning 11 Mb (D10S1483, D10S587, D10S1727, D10S1676, D10S169, D10S1770, and D10S212) were used to investigate the region neighboring MGMT (10q26.3).	('MGMT', 'Gene', '4255', (146, 150))	('D10S587', 'Var', (37, 44))	('D10S1770', 'Var', (75, 83))	('MGMT', 'Gene', (146, 150))	('D10S1727', 'Var', (46, 54))	('D10S1483', 'Var', (27, 35))	('D10S1676', 'Var', (56, 64))	('D10S212', 'Var', (89, 96))	('S212', 'CellLine', 'CVCL:E512', (92, 96))	('D10S169', 'Var', (66, 73))
190360	27346749	IDH1 R132H was the only mutation present in the samples.	('IDH1', 'Gene', (0, 4))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('R132H', 'Var', (5, 10))	('IDH1', 'Gene', '3417', (0, 4))
190369	27346749	In grade II and grade III gliomas, the IDH1 mutation was predominantly observed in MGMT-methylated tumors: 16 of 19 (84%) grade II tumors (p = 0.0012, Fisher exact test) and 7 of 27 (26%) grade III tumors (p = 0.0216, Fisher exact test).	('mutation', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('MGMT', 'Gene', (83, 87))	('IDH1', 'Gene', (39, 43))	('observed', 'Reg', (71, 79))	('gliomas', 'Disease', (26, 33))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('III tumors', 'Disease', (194, 204))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('II tumors', 'Disease', 'MESH:D009369', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('IDH1', 'Gene', '3417', (39, 43))	('tumors', 'Disease', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('tumors', 'Disease', (99, 105))	('MGMT', 'Gene', '4255', (83, 87))	('II tumors', 'Disease', (128, 137))	('III tumors', 'Disease', 'MESH:D009369', (194, 204))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('II tumors', 'Disease', 'MESH:D009369', (195, 204))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
190371	27346749	Specifically, of the 126 grade IV gliomas, 4 were positive for IDH1 mutation and MGMT methylation, 3 were IDH1-mutated and MGMT-unmethylated, 55 were IDH wild-type and MGMT unmethylated, and 66 were IDH wild-type and MGMT methylated (Fig.	('MGMT', 'Gene', '4255', (217, 221))	('mutation', 'Var', (68, 76))	('MGMT', 'Gene', (123, 127))	('IDH', 'Gene', (150, 153))	('MGMT', 'Gene', '4255', (81, 85))	('IDH1', 'Gene', '3417', (106, 110))	('positive', 'Reg', (50, 58))	('IDH1', 'Gene', (63, 67))	('IDH', 'Gene', (199, 202))	('MGMT', 'Gene', '4255', (168, 172))	('IDH', 'Gene', '3417', (106, 109))	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', '3417', (150, 153))	('MGMT', 'Gene', (217, 221))	('gliomas', 'Disease', (34, 41))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('IDH1', 'Gene', '3417', (63, 67))	('IDH', 'Gene', '3417', (199, 202))	('IDH', 'Gene', '3417', (63, 66))	('MGMT', 'Gene', '4255', (123, 127))	('MGMT', 'Gene', (81, 85))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('MGMT', 'Gene', (168, 172))	('IDH1', 'Gene', (106, 110))	('IDH', 'Gene', (106, 109))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
190377	27346749	Quantitative IDH1 genotyping showed that the R132H mutation was present in 21-53% of alleles (mean: 46%) (Fig.	('R132H', 'Var', (45, 50))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('IDH1', 'Gene', '3417', (13, 17))	('IDH1', 'Gene', (13, 17))
190379	27346749	In samples with IDH1 mutations, the percentage of MGMT methylation ranged from 5% to 70% (mean 32%; Fig.	('MGMT', 'Gene', (50, 54))	('IDH1', 'Gene', (16, 20))	('MGMT', 'Gene', '4255', (50, 54))	('IDH1', 'Gene', '3417', (16, 20))	('mutations', 'Var', (21, 30))
190382	27346749	The nonoverlapping distribution of IDH1-mutated and MGMT-methylated alleles in a tumor sample indicates that while the IDH1 mutation is present in virtually all cancer cells, MGMT is methylated in a variable subgroup (Figs.	('cancer', 'Disease', (161, 167))	('IDH1', 'Gene', (35, 39))	('MGMT', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MGMT', 'Gene', '4255', (52, 56))	('IDH1', 'Gene', '3417', (35, 39))	('IDH1', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutation', 'Var', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('IDH1', 'Gene', '3417', (119, 123))	('MGMT', 'Gene', (175, 179))	('MGMT', 'Gene', '4255', (175, 179))	('tumor', 'Disease', (81, 86))
190388	27346749	Univariate analysis of molecular markers highlighted that IDH1 mutation correlated positively with OS in both LGGs and HGGs (p < 0.0001 and p = 0.0116, respectively, Log-rank test) (Fig.	('LGGs', 'Disease', (110, 114))	('IDH1', 'Gene', '3417', (58, 62))	('mutation', 'Var', (63, 71))	('HGGs', 'Disease', (119, 123))	('OS', 'Chemical', '-', (99, 101))	('IDH1', 'Gene', (58, 62))
190389	27346749	The median OS for patients with IDH1 mutations was 31 months for LGGs and 34 months for HGGs.	('LGGs', 'Disease', (65, 69))	('OS', 'Chemical', '-', (11, 13))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('mutations', 'Var', (37, 46))	('HGGs', 'Disease', (88, 92))	('patients', 'Species', '9606', (18, 26))
190391	27346749	MGMT methylation conferred a survival advantage on both LGGs and HGGs (p < 0.0001, Log-rank test).	('MGMT', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('advantage', 'PosReg', (38, 47))	('MGMT', 'Gene', '4255', (0, 4))	('survival', 'CPA', (29, 37))
190393	27346749	Similarly, the median OS for HGGs patients was 24 months in methylated versus 14 months in nonmethylated cases (Fig.	('HGGs', 'Disease', (29, 33))	('OS', 'Chemical', '-', (22, 24))	('patients', 'Species', '9606', (34, 42))	('methylated', 'Var', (60, 70))
190398	27346749	Moreover, patients with MGMT-methylated HGGs had longer OS, independent of IDH1 mutation status (p =0.0337 and p = 0.0020 for IDH1 mutated and wild-type, respectively, Log-rank test) (Supplementary Data Fig.	('IDH1', 'Gene', '3417', (126, 130))	('MGMT', 'Gene', '4255', (24, 28))	('HGGs', 'Gene', (40, 44))	('OS', 'Chemical', '-', (56, 58))	('mutated', 'Var', (131, 138))	('IDH1', 'Gene', (75, 79))	('IDH1', 'Gene', (126, 130))	('longer', 'PosReg', (49, 55))	('patients', 'Species', '9606', (10, 18))	('IDH1', 'Gene', '3417', (75, 79))	('MGMT', 'Gene', (24, 28))
190399	27346749	Multivariate analysis suggested that both IDH1 mutation and MGMT methylation significantly affected OS (p = 0.0162 and p = 0.0037, respectively), but MGMT methylation shows a more positive correlation with OS (e = -0.01476, hazard ratio = 0.9853) compared to IDH1 mutation (e = -0.8057, hazard ratio = 0.4468), emphasizing its role as a strong marker of positive prognosis.	('affected', 'Reg', (91, 99))	('IDH1', 'Gene', (259, 263))	('OS', 'Chemical', '-', (206, 208))	('IDH1', 'Gene', '3417', (42, 46))	('OS', 'Chemical', '-', (100, 102))	('mutation', 'Var', (47, 55))	('MGMT', 'Gene', (60, 64))	('IDH1', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (259, 263))	('MGMT', 'Gene', '4255', (60, 64))	('MGMT', 'Gene', (150, 154))	('positive', 'PosReg', (180, 188))	('MGMT', 'Gene', '4255', (150, 154))
190401	27346749	This study demonstrates that, whatever the underlying mechanism, MGMT promoter methylation is not homogeneously distributed in glioma samples, suggesting that only a fraction of cells in the tumor bulk is sensitive to MGMT epigenetic silencing.	('MGMT', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('MGMT', 'Gene', '4255', (65, 69))	('epigenetic silencing', 'Var', (223, 243))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('MGMT', 'Gene', (218, 222))	('MGMT', 'Gene', '4255', (218, 222))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('glioma', 'Disease', (127, 133))
190402	27346749	Overall, our data on grade II and grade III gliomas indicate that IDH1 mutation and MGMT methylation are often found concomitantly, as previously reported.	('found', 'Reg', (111, 116))	('IDH1', 'Gene', '3417', (66, 70))	('mutation', 'Var', (71, 79))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('MGMT', 'Gene', '4255', (84, 88))	('MGMT', 'Gene', (84, 88))	('IDH1', 'Gene', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
190404	27346749	In particular, the distribution of IDH1-mutated alleles confirmed, as expected for a heterozygous mutation, that the gene was mutated in virtually all cancer cells and that the IDH1 mutation is an early event in gliomagenesis.	('IDH1', 'Gene', (35, 39))	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('IDH1', 'Gene', (177, 181))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('cancer', 'Disease', (151, 157))	('mutation', 'Var', (182, 190))	('IDH1', 'Gene', '3417', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('glioma', 'Disease', (212, 218))
190405	27346749	This result supports the hypothesis that IDH1 mutation triggers G-CIMP and confers only an increased likelihood of MGMT methylation in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('MGMT', 'Gene', '4255', (115, 119))	('tumor', 'Disease', (135, 140))	('MGMT', 'Gene', (115, 119))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('triggers', 'Reg', (55, 63))	('G-CIMP', 'Chemical', '-', (64, 70))	('mutation', 'Var', (46, 54))	('G-CIMP', 'MPA', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
190407	27346749	Similar to IDH1-mutated gliomas, wild-type tumors showed a heterogeneous distribution of MGMT-methylated alleles, suggesting that, whatever the underlying mechanism, MGMT epigenetic silencing occurs in only a subset of tumor cells.	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('MGMT', 'Gene', '4255', (89, 93))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('IDH1', 'Gene', '3417', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('MGMT', 'Gene', '4255', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('epigenetic silencing', 'Var', (171, 191))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('gliomas', 'Disease', (24, 31))	('MGMT', 'Gene', (89, 93))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('MGMT', 'Gene', (166, 170))	('IDH1', 'Gene', (11, 15))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
190408	27346749	Our data suggest that IDH1 mutation (or other unknown mechanisms) may predispose to MGMT methylation in a variable percentage of tumor cells.	('predispose', 'Reg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mutation', 'Var', (27, 35))	('IDH1', 'Gene', (22, 26))	('MGMT', 'Gene', '4255', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MGMT', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (22, 26))	('tumor', 'Disease', (129, 134))
190410	27346749	It is conceivable that, given the crucial role of MGMT in the maintenance of genome integrity, its epigenetic silencing may lead to mutation acquisition and thus contribute to promotion or maintenance of neoplastic transformation.	('mutation', 'MPA', (132, 140))	('promotion', 'PosReg', (176, 185))	('MGMT', 'Gene', (50, 54))	('neoplastic transformation', 'CPA', (204, 229))	('MGMT', 'Gene', '4255', (50, 54))	('contribute', 'Reg', (162, 172))	('epigenetic silencing', 'Var', (99, 119))	('lead to', 'Reg', (124, 131))
190412	27346749	We also observed that in approximately 50% of HGGs with LOH at the MGMT locus, the second allele was methylated, suggesting that in advanced stages of gliomagenesis, MGMT could be completely inactivated by methylation of one allele and deletion of the other.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('MGMT', 'Gene', (166, 170))	('deletion', 'Var', (236, 244))	('MGMT', 'Gene', '4255', (166, 170))	('MGMT', 'Gene', '4255', (67, 71))	('methylation', 'Var', (206, 217))	('MGMT', 'Gene', (67, 71))	('glioma', 'Disease', (151, 157))
190416	27346749	PTEN, ERCC6 and DMBT1) mapping to the same region of chromosome 10q and associated with reduced OS.	('ERCC6', 'Gene', '2074', (6, 11))	('DMBT1', 'Gene', (16, 21))	('reduced', 'NegReg', (88, 95))	('ERCC6', 'Gene', (6, 11))	('DMBT1', 'Gene', '1755', (16, 21))	('OS', 'Chemical', '-', (96, 98))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('mapping', 'Var', (23, 30))
190449	33381460	In the train set, covariables included risk score, age, gender, race, grade, radiotherapy, isocitrate dehydrogenase (IDH) mutant, motor function change, sensor function change, seizer, headache.	('seizer', 'Disease', (177, 183))	('sensor function change', 'Disease', (153, 175))	('headache', 'Disease', (185, 193))	('isocitrate dehydrogenase', 'Gene', (91, 115))	('IDH', 'Gene', (117, 120))	('isocitrate dehydrogenase', 'Gene', '3417', (91, 115))	('headache', 'Phenotype', 'HP:0002315', (185, 193))	('IDH', 'Gene', '3417', (117, 120))	('motor function change', 'Disease', (130, 151))	('headache', 'Disease', 'MESH:D006261', (185, 193))	('mutant', 'Var', (122, 128))
190450	33381460	In the external validation set, covariables included risk score, age, gender, grade, radiotherapy, chemotherapy, IDH mutant, O6-methylguanine-DNA methyltransferase (MGMT) methylation.	('IDH', 'Gene', '3417', (113, 116))	('O6-methylguanine-DNA methyltransferase', 'Gene', (125, 163))	('methylation', 'Var', (171, 182))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (125, 163))	('IDH', 'Gene', (113, 116))	('MGMT', 'Gene', (165, 169))	('MGMT', 'Gene', '4255', (165, 169))
190456	33381460	Therefore, we were able to divide the LGG cohort from the CGGA database into three groups, which were listed as follows: LGG with IDH wild type, LGG with IDH mutant and 1p/19q non-codeletion (intact), and LGG with IDH mutant and 1p/19q codeletion.	('IDH', 'Gene', '3417', (130, 133))	('non-codeletion', 'Var', (176, 190))	('1p/19q codeletion', 'Var', (229, 246))	('IDH', 'Gene', (214, 217))	('IDH', 'Gene', (154, 157))	('IDH', 'Gene', (130, 133))	('IDH', 'Gene', '3417', (214, 217))	('1p/19q non-codeletion', 'Var', (169, 190))	('IDH', 'Gene', '3417', (154, 157))
190473	33381460	Overall, the risk score and status of IDH had shown great independent prognostic value predicting OS in LGG patients; the high-risk score is an independent predictor of unfavorable OS (HR > 1), while IDH mutation status is an independent predictor of favorable OS in LGG (HR < 1).	('IDH', 'Gene', (38, 41))	('LGG', 'Disease', (104, 107))	('IDH', 'Gene', (200, 203))	('IDH', 'Gene', '3417', (38, 41))	('IDH', 'Gene', '3417', (200, 203))	('high-risk', 'Var', (122, 131))	('patients', 'Species', '9606', (108, 116))
190474	33381460	In one previous multivariate analysis conducted by Sanson et al., IDH mutation was also identified as an independent favorable predictor of glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('IDH', 'Gene', (66, 69))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('IDH', 'Gene', '3417', (66, 69))	('glioma', 'Disease', (140, 146))	('mutation', 'Var', (70, 78))
190476	33381460	Among these three LGG subgroups, the subgroup with IDH wild type had the highest gene expression level and risk score, and the subgroup with IDH mutant and 1p/19q codeletion had the lowest gene expression level and risk score among the three groups.	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', (141, 144))	('IDH', 'Gene', '3417', (51, 54))	('1p/19q codeletion', 'Var', (156, 173))	('IDH', 'Gene', '3417', (141, 144))	('highest', 'Reg', (73, 80))	('gene expression level', 'MPA', (81, 102))
190477	33381460	In LGG patients, high-expression level of these four genes indicates poor prognosis (Figure 4), and high-risk score also indicates poor prognosis (Figure 5); it is reasonable to infer that subgroup with IDH wild type may have the worst prognosis, which further reflected distinct biological pattern between these three LGG subgroups.	('IDH', 'Gene', (203, 206))	('LGG', 'Disease', (3, 6))	('IDH', 'Gene', '3417', (203, 206))	('high-expression', 'Var', (17, 32))	('patients', 'Species', '9606', (7, 15))
190478	33381460	Among these three LGG subgroups, we found that the LGG subgroup with IDH mutant and 1P /19q codeletion group had the best prognosis, while the LGG subgroup with IDH wild type had the worst prognosis (Figure 6B, log rank p < 0.05); this conclusion is consistent with previous studies.	('IDH', 'Gene', '3417', (161, 164))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (69, 72))	('IDH', 'Gene', (161, 164))	('1P /19q codeletion', 'Var', (84, 102))
190488	33381460	Three studies suggested that high expression of the CD44 gene was significantly associated with poor prognosis in glioma patients, and two studies suggested that CD44 gene expression was not significantly associated with prognosis.	('high', 'Var', (29, 33))	('CD44', 'Gene', (52, 56))	('poor prognosis', 'CPA', (96, 110))	('glioma', 'Disease', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('associated', 'Reg', (80, 90))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('patients', 'Species', '9606', (121, 129))
190491	33381460	The expression level of CD44 is related to the histopathological grade of gliomas, and the monoclonal anti-CD44 antibody is capable of inhibiting the migration of glioma cells.	('expression level', 'MPA', (4, 20))	('related', 'Reg', (32, 39))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Disease', (163, 169))	('anti-CD44', 'Gene', (102, 111))	('monoclonal', 'Var', (91, 101))	('gliomas', 'Disease', (74, 81))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Disease', (74, 80))	('inhibiting', 'NegReg', (135, 145))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
190500	33381460	In colorectal cancer, high expression of HYAL1 and HYAL2 can inhibit tumor metastasis, but in triple-negative breast cancer, high expression of HYAL2 genes is associated with shorter disease-free survival, higher tumor recurrence rate, and higher tumor metastasis rate.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor metastasis', 'Disease', (69, 85))	('HYAL1', 'Gene', (41, 46))	('colorectal cancer', 'Disease', (3, 20))	('higher', 'PosReg', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('disease-free survival', 'CPA', (183, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor metastasis', 'Disease', 'MESH:D009362', (247, 263))	('HYAL2', 'Gene', '8692', (51, 56))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (247, 252))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('HYAL2', 'Gene', '8692', (144, 149))	('HYAL1', 'Gene', '3373', (41, 46))	('tumor metastasis', 'Disease', (247, 263))	('inhibit', 'NegReg', (61, 68))	('high expression', 'Var', (125, 140))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (213, 218))	('HYAL2', 'Gene', (51, 56))	('shorter', 'NegReg', (175, 182))	('tumor', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor metastasis', 'Disease', 'MESH:D009362', (69, 85))	('HYAL2', 'Gene', (144, 149))	('higher', 'PosReg', (240, 246))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
190507	33381460	The present study also identified IDH mutation as an independent predictor of favorable OS, and this finding is consistent with previous research.	('favorable OS', 'Disease', (78, 90))	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))	('mutation', 'Var', (38, 46))
190508	33381460	The updated classification of tumors of CNS divides the LGG into three subgroups based on IDH mutation status and 1p/19q codeletion status, and these three types of LGG vary in genetic characteristics and prognosis.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('IDH', 'Gene', (90, 93))	('tumors of CNS', 'Phenotype', 'HP:0100006', (30, 43))	('IDH', 'Gene', '3417', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutation', 'Var', (94, 102))
190509	33381460	The function of the IDH enzyme is to catalyze the transformation from isocitrate into alpha-keto-beta-carboxy glutamic acid, and the mutant IDH consumes alpha-keto-beta-carboxy glutamic acid for D-2-hydroxyglutarate synthesis in an NADPH-dependent manner.	('IDH', 'Gene', (140, 143))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (195, 215))	('IDH', 'Gene', (20, 23))	('transformation', 'MPA', (50, 64))	('IDH', 'Gene', '3417', (140, 143))	('IDH', 'Gene', '3417', (20, 23))	('isocitrate', 'Chemical', 'MESH:C034219', (70, 80))	('NADPH', 'Gene', '1666', (232, 237))	('mutant', 'Var', (133, 139))	('NADPH', 'Gene', (232, 237))
190510	33381460	Numerous studies have shown that mutations in IDH affect many biological processes, including cellular metabolism, epigenetic shift, genomic instability, and redox Q[CE] homeostasis.	('genomic', 'MPA', (133, 140))	('redox Q[CE] homeostasis', 'MPA', (158, 181))	('cellular metabolism', 'MPA', (94, 113))	('IDH', 'Gene', (46, 49))	('mutations', 'Var', (33, 42))	('epigenetic shift', 'MPA', (115, 131))	('affect', 'Reg', (50, 56))	('IDH', 'Gene', '3417', (46, 49))	('biological processes', 'CPA', (62, 82))
190511	33381460	IDH mutation has become the essential molecular in the diagnosis of gliomas.	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))
190512	33381460	In the present study, we divided the LGG cohort from the CGGA database into three groups, including IDH-wild type LGG, IDH-mutant and 1p/19q non-codeletion LGG, and IDH-mutant and 1p/19q codeletion LGG, and then we explored the relationship between gene signature and these three subgroups.	('IDH', 'Gene', (100, 103))	('IDH', 'Gene', '3417', (119, 122))	('IDH', 'Gene', (165, 168))	('IDH', 'Gene', '3417', (165, 168))	('1p/19q non-codeletion', 'Var', (134, 155))	('IDH', 'Gene', '3417', (100, 103))	('non-codeletion', 'Var', (141, 155))	('IDH', 'Gene', (119, 122))
190514	33381460	The Kaplan-Meier curve suggested an unfavorable prognosis in IDH-wild type LGG patients; IDH-mutant gliomas have a favorable prognosis, especially the IDH-mutant glioma combined with 1p/19q codeletion; this conclusion is consistent with previous research.	('glioma', 'Disease', (100, 106))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('IDH', 'Gene', '3417', (61, 64))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH', 'Gene', '3417', (151, 154))	('glioma', 'Disease', (162, 168))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('IDH', 'Gene', '3417', (89, 92))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('1p/19q codeletion', 'Var', (183, 200))	('patients', 'Species', '9606', (79, 87))	('IDH', 'Gene', (89, 92))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('IDH', 'Gene', (61, 64))	('gliomas', 'Disease', (100, 107))	('IDH', 'Gene', (151, 154))
190518	33381460	There is growing evidence that IDH mutation could suppress tumor-infiltrating lymphocytes' activation and create an immunosuppressive tumor microenvironment.	('create', 'Reg', (106, 112))	('IDH', 'Gene', (31, 34))	('tumor', 'Disease', (59, 64))	('IDH', 'Gene', '3417', (31, 34))	('suppress', 'NegReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('immunosuppressive', 'MPA', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (134, 139))
190521	33381460	The combination of PD-L1 expressed in tumor cells and PD-1 expressed in immune cells can inhibit T cells' activation, inhibit the monitoring function of immune cells, and contribute to the immune escape of tumor cells.	('inhibit', 'NegReg', (118, 125))	('tumor', 'Disease', (38, 43))	('PD-L1', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('contribute', 'Reg', (171, 181))	('tumor', 'Disease', (206, 211))	('combination', 'Var', (4, 15))	('inhibit', 'NegReg', (89, 96))	('monitoring function of immune cells', 'MPA', (130, 165))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	("T cells' activation", 'CPA', (97, 116))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('PD-1', 'Gene', (54, 58))
190524	33381460	The patients with high-risk scores had higher immune checkpoint expression, suggesting that these patients may be more sensitive to immunotherapy.	('immune checkpoint expression', 'MPA', (46, 74))	('higher', 'PosReg', (39, 45))	('scores', 'Var', (28, 34))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (4, 12))
190542	26515590	The results of in vitro angiogenesis assay showed that GMF-beta knockdown significantly inhibited tubulogenesis of human U87 glioblastoma cells.	('inhibited', 'NegReg', (88, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('GMF-beta', 'Gene', (55, 63))	('human', 'Species', '9606', (115, 120))	('glioblastoma', 'Disease', (125, 137))	('knockdown', 'Var', (64, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
190543	26515590	Furthermore, GMF-beta knockdown suppressed tumor growth and the formation of human-CD31 positive (glioma cell-derived) microvessels in a mouse orthotopic U87 glioma model.	('formation', 'CPA', (64, 73))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('GMF-beta', 'Gene', (13, 21))	('mouse', 'Species', '10090', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('knockdown', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('glioma', 'Disease', (158, 164))	('glioma', 'Disease', (98, 104))	('tumor', 'Disease', (43, 48))	('human', 'Species', '9606', (77, 82))	('suppressed', 'NegReg', (32, 42))
190565	26515590	Furthermore, we founded that GMF-beta plays an important role in inducing the tubulogenesis of glioma cells in vitro, as well as the formation of human CD31-positive vessels in a mouse glioma model.	('mouse', 'Species', '10090', (179, 184))	('inducing', 'PosReg', (65, 73))	('tubulogenesis', 'CPA', (78, 91))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('human', 'Species', '9606', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('glioma', 'Disease', (185, 191))	('GMF-beta', 'Var', (29, 37))
190594	26515590	We found that GMF-beta knockdown inhibited U87 cell proliferation (P < 0.05; Supplementary Figure S1).	('U87 cell proliferation', 'CPA', (43, 65))	('knockdown', 'Var', (23, 32))	('GMF-beta', 'Gene', (14, 22))	('rat', 'Species', '10116', (59, 62))	('inhibited', 'NegReg', (33, 42))
190596	26515590	The severe combined immunodeficient (SCID) mice were intracranially implanted with U87-shGMF-beta cells, or U87-mock cells, respectively.	('mice', 'Species', '10090', (43, 47))	('SCID', 'Disease', 'MESH:D053632', (37, 41))	('SCID', 'Disease', (37, 41))	('U87-shGMF-beta', 'Var', (83, 97))	('immunodeficient', 'Disease', 'MESH:D007153', (20, 35))	('immunodeficient', 'Disease', (20, 35))
190597	26515590	No weight loss and neurological signs were observed in SCID mice of U87-shGMF-beta group up to week 5.	('mice', 'Species', '10090', (60, 64))	('weight loss', 'Disease', (3, 14))	('U87-shGMF-beta', 'Var', (68, 82))	('neurological signs', 'Phenotype', 'HP:0000707', (19, 37))	('weight loss', 'Phenotype', 'HP:0001824', (3, 14))	('SCID', 'Disease', 'MESH:D053632', (55, 59))	('SCID', 'Disease', (55, 59))	('weight loss', 'Disease', 'MESH:D015431', (3, 14))
190605	26515590	The xenograft tumor volumes in U87-shGMF-beta group were significantly smaller than those in U87-mock group (P < 0.001; Figure 5E).	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('U87-shGMF-beta', 'Var', (31, 45))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('smaller', 'NegReg', (71, 78))
190616	26515590	These phenomena imply that GMF-beta can promote glioma progression, probably due to its pro-vasculogenic potential.	('promote', 'PosReg', (40, 47))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('GMF-beta', 'Var', (27, 35))	('glioma', 'Disease', (48, 54))
190622	26515590	We further verified that GMF-beta is an inducer for vasculogenic activity of glioma cells, not merely a glial lineage marker.	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('GMF-beta', 'Var', (25, 33))	('vasculogenic activity', 'MPA', (52, 73))	('glioma', 'Disease', (77, 83))	('inducer', 'Reg', (40, 47))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
190637	26515590	Lim et al found that GMF-beta could promote the initial growth, but also restore contact inhibition of rat C6 glioma cells and human HG-1 glioma cells in vitro.	('rat', 'Species', '10116', (103, 106))	('glioma', 'Disease', (110, 116))	('glioma', 'Disease', (138, 144))	('promote', 'PosReg', (36, 43))	('HG-1', 'CellLine', 'CVCL:Y547', (133, 137))	('human', 'Species', '9606', (127, 132))	('C6', 'CellLine', 'CVCL:X905', (107, 109))	('GMF-beta', 'Var', (21, 29))	('contact inhibition', 'MPA', (81, 99))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('restore', 'NegReg', (73, 80))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('growth', 'MPA', (56, 62))
190662	26515590	Multiplication of category A and B resulted in an IRS ranging from 0 to 12 for each tumor.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('IRS', 'MPA', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Multiplication', 'Var', (0, 14))	('tumor', 'Disease', (84, 89))	('resulted in', 'Reg', (35, 46))
190670	26515590	The primary antibodies included rabbit anti-human GMF-beta (NBP1-89755, dilution 1:200; Novus Biologicals, Littleton, CO, USA) and rabbit anti-human beta-actin (#5125, dilution 1:1000; Cell Signaling, Boston, MA, USA).	('human', 'Species', '9606', (44, 49))	('beta-actin', 'Gene', (149, 159))	('human', 'Species', '9606', (143, 148))	('rabbit', 'Species', '9986', (131, 137))	('rabbit', 'Species', '9986', (32, 38))	('NBP1', 'Gene', '4682', (60, 64))	('NBP1', 'Gene', (60, 64))	('#5125', 'Var', (161, 166))	('beta-actin', 'Gene', '728378', (149, 159))
190687	33954192	Studies have shown that gross total resection (GTR) can positively influence quality of life, as well as progression-free survival (PFS) and overall survival (OS).	('influence', 'Reg', (67, 76))	('overall survival', 'CPA', (141, 157))	('quality of life', 'CPA', (77, 92))	('progression-free survival', 'CPA', (105, 130))	('GTR', 'Chemical', '-', (47, 50))	('gross', 'Var', (24, 29))
190724	33954192	Most of the tumor boundaries displayed using CEUS are larger than those displayed using conventional ultrasound.	('CEUS', 'Var', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CEUS', 'Chemical', '-', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
190880	33954192	Glioma resection may also create ultrasound image noise when the resection cavity is filled with isotonic saline water.	('resection', 'Var', (7, 16))	('ultrasound image noise', 'MPA', (33, 55))	('water', 'Chemical', 'MESH:D014867', (113, 118))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('create', 'Reg', (26, 32))	('Glioma', 'Disease', (0, 6))
190949	29124520	The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('isocitrate dehydrogenase', 'Gene', (170, 194))	('IDH', 'Gene', '3417', (196, 199))	('isocitrate dehydrogenase', 'Gene', '3417', (170, 194))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutation', 'Var', (201, 209))	('1p/19p codeletion', 'Var', (214, 231))	('tumors', 'Disease', (92, 98))	('IDH', 'Gene', (196, 199))
190969	29124520	The traditional histologic separation between astrocytomas and oligodendrogliomas is complemented by recent evidence for two molecularly and virtually exclusive subtypes, characterized by IDH, ATRX and TP53 mutation in the absence of 1p/19q codeletion (astrocytic) versus IDH mutation, 1p/19q codeletion, and TERT promoter mutation (oligodendroglial).	('IDH', 'Gene', '3417', (188, 191))	('TP53', 'Gene', (202, 206))	('astrocytomas', 'Disease', (46, 58))	('ATRX', 'Gene', '546', (193, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (46, 57))	('IDH', 'Gene', (272, 275))	('TERT', 'Gene', (309, 313))	('IDH', 'Gene', '3417', (272, 275))	('TP53', 'Gene', '7157', (202, 206))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (63, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('ATRX', 'Gene', (193, 197))	('astrocytomas', 'Disease', 'MESH:D001254', (46, 58))	('IDH', 'Gene', (188, 191))	('mutation', 'Var', (207, 215))	('oligodendrogliomas', 'Disease', (63, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('TERT', 'Gene', '7015', (309, 313))
190972	29124520	Demonstration of the ATRX mutation or loss of ATRX nuclear expression is recommended for the diagnosis of astrocytoma.	('ATRX', 'Gene', '546', (46, 50))	('mutation', 'Var', (26, 34))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('ATRX', 'Gene', (46, 50))	('astrocytoma', 'Disease', 'MESH:D001254', (106, 117))	('loss', 'NegReg', (38, 42))	('astrocytoma', 'Disease', (106, 117))
190975	29124520	The diagnosis of oligodendroglioma requires the demonstration of both an IDH gene mutation and combined whole-arm 1p/19q codeletion.	('arm 1p', 'Gene', '9622', (110, 116))	('oligodendroglioma', 'Disease', (17, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('mutation', 'Var', (82, 90))	('oligodendroglioma', 'Disease', 'MESH:D009837', (17, 34))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (73, 76))	('arm 1p', 'Gene', (110, 116))
190976	29124520	A stepwise diagnosis algorithm is recommended, starting with immunochemistry for ATRX and R132H-mutant IDH1 (representing about 90% of all IDH mutations), followed by testing for 1p/19q codeletion, and then followed by IDH sequencing of the tumors that were negative for IDH1 immunochemistry.	('IDH', 'Gene', '3417', (219, 222))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('IDH', 'Gene', '3417', (139, 142))	('IDH1', 'Gene', (103, 107))	('IDH1', 'Gene', '3417', (271, 275))	('IDH', 'Gene', '3417', (271, 274))	('IDH', 'Gene', (103, 106))	('R132H-mutant', 'Var', (90, 102))	('IDH1', 'Gene', '3417', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('IDH', 'Gene', '3417', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('IDH', 'Gene', (219, 222))	('ATRX', 'Gene', (81, 85))	('tumors', 'Disease', (241, 247))	('ATRX', 'Gene', '546', (81, 85))	('IDH1', 'Gene', (271, 275))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', (271, 274))
190992	29124520	DTI data and further application using fiber-tracking techniques (tractography) can reveal the microstructural integrity of brain tissue and the relationship between the tumor and adjacent white matter tracts: LGG tend to deviate, rather than destruct or infiltrate the adjacent white matter.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('LGG', 'Chemical', '-', (210, 213))	('tumor', 'Disease', (170, 175))	('LGG', 'Var', (210, 213))	('deviate', 'CPA', (222, 229))
191002	29124520	A retrospective multicentric study analyzing 1097 patients (in which the assessed population was divided into three subgroups depending on the extent of resection: 100%, 50-99% and less than 50%) showed that the amount of residual lesion impacted on the course of the disease (OS was 10.5 and 14 years for patients with a less than 50 and 50-99% Extent of resection, being unreached instead after 15 years for patients with no residual tumor).	('course', 'MPA', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (436, 441))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', (436, 441))	('less than 50', 'Var', (322, 334))	('patients', 'Species', '9606', (410, 418))	('impacted', 'Reg', (238, 246))	('tumor', 'Disease', 'MESH:D009369', (436, 441))	('patients', 'Species', '9606', (306, 314))
191013	29124520	Factors to consider when selecting patients for immediate postoperative therapy include the presence of tumour-related symptoms and risk factors for worse outcome, which comprise age >= 40 years, large preoperative tumour size (>= 4 cm), incomplete resection, astrocytic histology, and absence of 1p/19q-codeletion.	('absence', 'Var', (286, 293))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('astrocytic', 'Disease', (260, 270))	('tumour', 'Disease', (215, 221))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('1p/19q-codeletion', 'Var', (297, 314))	('patients', 'Species', '9606', (35, 43))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('tumour', 'Disease', (104, 110))
191018	29124520	If all three favorable prognostic factors were present (< 1 cm residual tumour, tumour diameter < 4 cm, and oligodendroglioma histological type), the 2- and 5-year PFS rates were 100 and 70%, respectively.	('tumour', 'Disease', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('< 1', 'Var', (56, 59))	('oligodendroglioma', 'Disease', (108, 125))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('oligodendroglioma', 'Disease', 'MESH:D009837', (108, 125))	('tumour', 'Disease', (72, 78))
191019	29124520	Therefore, a "wait and see" approach following initial surgery may be followed in young patients (<= 40 years) with a favorable prognosis who have undergone an extensive resection for an IDH-mutant low-grade glioma, especially if molecular studies show the presence of a 1p/19q-codeletion (Level II-B).	('glioma', 'Disease', (208, 214))	('IDH', 'Gene', (187, 190))	('patients', 'Species', '9606', (88, 96))	('IDH', 'Gene', '3417', (187, 190))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('1p/19q-codeletion', 'Var', (271, 288))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))
191044	29124520	Median progression-free survival was also prolonged in patients who received PCV (10.4 versus 4.0 years; HR: 0.50; 95% CI 0.36-0.68; p < 0.001).	('prolonged', 'PosReg', (42, 51))	('progression-free survival', 'CPA', (7, 32))	('PCV', 'Var', (77, 80))	('patients', 'Species', '9606', (55, 63))
191049	29124520	IDH1 R132H mutation was present in 61% (35/57) of patients treated with RT + PCV and in 64% (36/56) of those treated with RT.	('patients', 'Species', '9606', (50, 58))	('R132H', 'Var', (5, 10))	('RT + PCV', 'Chemical', '-', (72, 80))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
191050	29124520	Patients with tumoral IDH1 R132H mutations had significantly longer overall survival than did those without the mutation, regardless of treatment (p = 0.02).	('R132H', 'Var', (27, 32))	('longer', 'PosReg', (61, 67))	('R132H', 'Mutation', 'rs121913500', (27, 32))	('IDH1', 'Gene', (22, 26))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (68, 84))	('tumoral', 'Disease', (14, 21))	('tumoral', 'Disease', 'MESH:D009369', (14, 21))	('IDH1', 'Gene', '3417', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
191052	29124520	Among patients with tumoral IDH1 R132H mutations, those who received radiation therapy plus chemotherapy had longer overall survival than did those who received radiation therapy alone (HR: 0.42; 95% CI 0.20-0.86; p = 0.02).	('longer', 'PosReg', (109, 115))	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (39, 48))	('tumoral', 'Disease', (20, 27))	('tumoral', 'Disease', 'MESH:D009369', (20, 27))	('R132H mutations', 'Var', (33, 48))	('overall survival', 'MPA', (116, 132))	('patients', 'Species', '9606', (6, 14))	('R132H', 'Mutation', 'rs121913500', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IDH1', 'Gene', (28, 32))
191053	29124520	The number of events among patients without the IDH1 R132H mutation was too small to determine the association of treatment effect in this subgroup.	('IDH1', 'Gene', '3417', (48, 52))	('R132H', 'Var', (53, 58))	('patients', 'Species', '9606', (27, 35))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('IDH1', 'Gene', (48, 52))
191055	29124520	Eligible patients were either age 18-39 years with subtotal resection or biopsy, or age >= 40 years with any extent of resection.	('biopsy', 'Var', (73, 79))	('subtotal resection', 'Var', (51, 69))	('patients', 'Species', '9606', (9, 17))
191058	29124520	Moreover, analogous randomized trials in patients with anaplastic gliomas (i.e., RT with or without adjuvant PCV) found that the survival advantage of PCV was largely driven by patients with oligodendroglial tumors with 1p/19q-codeletion, and possibly others (e.g., 1p/19q-non-codeleted tumors with MGMT methylation or an IDH1 mutation).	('MGMT', 'Gene', (299, 303))	('anaplastic gliomas', 'Disease', 'MESH:D005910', (55, 73))	('anaplastic gliomas', 'Disease', (55, 73))	('1p/19q-codeletion', 'Var', (220, 237))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('oligodendroglial tumors', 'Disease', (191, 214))	('1p/19q-non-codeleted', 'Var', (266, 286))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (191, 214))	('MGMT', 'Gene', '4255', (299, 303))	('IDH1', 'Gene', (322, 326))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('patients', 'Species', '9606', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('PCV', 'Var', (151, 154))	('IDH1', 'Gene', '3417', (322, 326))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
191064	29124520	An interim analysis of the CATNON study of patients with 1p/19q-non-codeleted anaplastic glioma found that 12 cycles of adjuvant temozolomide improved survival over radiation alone (HR 0.67; 95% CI 0.51-0.88; 5-year OS 56 versus 44%).	('temozolomide', 'Chemical', 'MESH:D000077204', (129, 141))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('patients', 'Species', '9606', (43, 51))	('improved', 'PosReg', (142, 150))	('glioma', 'Disease', (89, 95))	('survival', 'MPA', (151, 159))	('1p/19q-non-codeleted', 'Var', (57, 77))
191076	29124520	Loss of 1p and 19q seems limited to patients with pure oligodendroglioma (p = 0.009) and were not associated with response to PCV (possibly because of the small sample size).	('patients', 'Species', '9606', (36, 44))	('oligodendroglioma', 'Disease', (55, 72))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('oligodendroglioma', 'Disease', 'MESH:D009837', (55, 72))	('Loss', 'Var', (0, 4))
191080	29124520	In the subgroup of patients with IDH-mutant, 1p/19q-non-codeleted tumors, progression-free survival was longer in patients randomized to receive radiation (55 versus 36 months; HR 1.86; 95% CI 1.21-2.87; p = 0.0043) (Level II-B).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (19, 27))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('1p/19q-non-codeleted', 'Var', (45, 65))	('longer', 'PosReg', (104, 110))	('IDH', 'Gene', (33, 36))	('progression-free survival', 'CPA', (74, 99))	('patients', 'Species', '9606', (114, 122))	('IDH', 'Gene', '3417', (33, 36))
191081	29124520	In contrast, progression-free survival was similar for radiation versus temozolomide in patients with 1p/19q-codeleted tumors (62 versus 55 months) and in patients with IDH-wildtype tumors (19 versus 24 months).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('patients', 'Species', '9606', (88, 96))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('patients', 'Species', '9606', (155, 163))	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (169, 188))	('temozolomide', 'Chemical', 'MESH:D000077204', (72, 84))	('1p/19q-codeleted', 'Var', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('IDH-wildtype tumors', 'Disease', (169, 188))
191084	29124520	For patients with available tissue, molecular subtype was assessed based upon 1p/19q codeletion and IDH-1 R132H mutation status.	('IDH-1', 'Gene', '3417', (100, 105))	('IDH-1', 'Gene', (100, 105))	('patients', 'Species', '9606', (4, 12))	('R132H', 'Var', (106, 111))	('R132H', 'Mutation', 'rs121913500', (106, 111))
191085	29124520	Patients with 1p/19q codeletion demonstrated a 0% risk of progression during treatment.	('Patients', 'Species', '9606', (0, 8))	('codeletion', 'Var', (21, 31))	('1p/19q codeletion', 'Var', (14, 31))
191087	29124520	It is important to note, however, that even a median progression-free survival of 4-5 years in 1p/19q-codeleted tumors with adjuvant temozolomide, is far inferior to the approximately 10-year progression-free survival achieved by RT plus PCV in the RTOG 9802 study.	('1p/19q-codeleted', 'Var', (95, 111))	('tumors', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('temozolomide', 'Chemical', 'MESH:D000077204', (133, 145))
191089	29124520	Therefore, postoperative chemotherapy with delayed radiation can be considered in patients with 1p/19q-codeleted oligodendrogliomas for whom postoperative therapy is indicated, although long-term outcome data are more limited for this approach compared with early RT with or without chemotherapy (level II).	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (113, 131))	('patients', 'Species', '9606', (82, 90))	('oligodendrogliomas', 'Disease', (113, 131))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('1p/19q-codeleted', 'Var', (96, 112))
191090	29124520	Low-grade gliomas that lack a mutation in IDH make up a relatively small proportion of all low-grade gliomas and carry a significantly worse prognosis compared with IDH-mutant tumors.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('IDH', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('IDH', 'Gene', (165, 168))	('gliomas', 'Disease', (101, 108))	('IDH', 'Gene', '3417', (165, 168))	('mutation', 'Var', (30, 38))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('IDH', 'Gene', '3417', (42, 45))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('gliomas', 'Disease', (10, 17))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
191092	29124520	Some of these tumors bear molecular similarity to glioblastoma (e.g., TERT mutations, loss of heterozygosity of chromosome 10).	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('loss of heterozygosity', 'Var', (86, 108))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('TERT', 'Gene', (70, 74))	('glioblastoma', 'Disease', (50, 62))	('TERT', 'Gene', '7015', (70, 74))
191104	29124520	The main molecular factors for subdividing LGG are IDH mutations, 1p19q codeletions, ATXR and TERT mutations.	('LGG', 'Chemical', '-', (43, 46))	('IDH', 'Gene', (51, 54))	('ATXR', 'Disease', (85, 89))	('IDH', 'Gene', '3417', (51, 54))	('LGG', 'Disease', (43, 46))	('TERT', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (94, 98))	('1p19q codeletions', 'Var', (66, 83))
191204	28450707	Finally, the accuracies of the four patients without treatment were 0.673, 0.802, 0.740, 0.778 and 0.805, 0.890, 0.851, 0.875 for JS and DC, respectively.	('0.740', 'Var', (82, 87))	('patients', 'Species', '9606', (36, 44))	('0.778', 'Var', (89, 94))	('0.802', 'Var', (75, 80))
191218	28450707	Our model accuracy is investigated using different experiments on both synthetic and clinical MR images of 9 LGG patients who underwent surgery and different treatment regimens with ranges of [0.673 0.822] for JS and [0.805 0.902] for DC, respectively.	('patients', 'Species', '9606', (113, 121))	('LGG', 'Disease', (109, 112))	('[0.805 0.902]', 'Var', (217, 230))
191223	26699864	Of these, IDH1 or IDH2 mutations are associated with lowest hazard ratio, which confirms IDH as the most important prognostic marker in diffuse gliomas.	('IDH', 'Gene', (10, 13))	('IDH2', 'Gene', '3418', (18, 22))	('IDH1', 'Gene', '3417', (10, 14))	('hazard ratio', 'MPA', (60, 72))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH', 'Gene', (18, 21))	('IDH', 'Gene', '3417', (10, 13))	('IDH', 'Gene', '3417', (18, 21))	('mutations', 'Var', (23, 32))	('IDH1', 'Gene', (10, 14))	('IDH', 'Gene', (89, 92))	('IDH2', 'Gene', (18, 22))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('IDH', 'Gene', '3417', (89, 92))	('lowest', 'NegReg', (53, 59))
191224	26699864	Subsequent subgroup analysis largely confirms many of the currently used molecular classification schemes for diffuse gliomas (ATRX or TP53 mutations, 1p19q codeletion).	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('ATRX', 'Gene', (127, 131))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('TP53', 'Gene', '7157', (135, 139))	('ATRX', 'Gene', '546', (127, 131))	('1p19q codeletion', 'Var', (151, 167))	('TP53', 'Gene', (135, 139))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
191225	26699864	Our analysis also identified PI3-kinase mutations as markers of poor prognosis in IDH-mutated + ATRX/TP53 mutated diffuse gliomas, median survival 3.7 v. 6.3 years (P = 0.02, Hazard rate (HR) 2.93, 95 % confidence interval (CI) 1.16 - 7.38).	('IDH', 'Gene', '3417', (82, 85))	('PI3', 'Gene', '5266', (29, 32))	('ATRX', 'Gene', (96, 100))	('PI3', 'Gene', (29, 32))	('TP53', 'Gene', '7157', (101, 105))	('mutations', 'Var', (40, 49))	('TP53', 'Gene', (101, 105))	('gliomas', 'Disease', (122, 129))	('ATRX', 'Gene', '546', (96, 100))	('IDH', 'Gene', (82, 85))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
191226	26699864	PI3-kinase mutations were also prognostic in two independent datasets.	('mutations', 'Var', (11, 20))	('PI3', 'Gene', (0, 3))	('PI3', 'Gene', '5266', (0, 3))
191231	26699864	ATRX mutated diffuse gliomas).	('ATRX', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('ATRX', 'Gene', '546', (0, 4))	('gliomas', 'Disease', (21, 28))	('mutated', 'Var', (5, 12))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))
191232	26699864	We have identified PI3K mutations as novel prognostic markers in gliomas.	('gliomas', 'Disease', (65, 72))	('PI3', 'Gene', '5266', (19, 22))	('PI3', 'Gene', (19, 22))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mutations', 'Var', (24, 33))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
191233	26699864	We also demonstrate that the mutational load is associated with tumor grade.	('tumor', 'Disease', (64, 69))	('associated', 'Reg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutational load', 'Var', (29, 44))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
191234	26699864	The increase in mutational load may partially explain the increased aggressiveness of higher grade diffuse gliomas when a subset of the affected genes actively contributes to gliomagenesis and/or progression.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('aggressiveness', 'Disease', (68, 82))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('aggressiveness', 'Phenotype', 'HP:0000718', (68, 82))	('glioma', 'Disease', (175, 181))	('mutational load', 'Var', (16, 31))	('aggressiveness', 'Disease', 'MESH:D001523', (68, 82))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Disease', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
191239	26699864	For example, IDH1 mutations are frequent events in all grade II and III gliomas and in secondary glioblastomas (sGBM, glioblastomas that progress from lower grade gliomas) whereas primary GBMs (pGBM) are usually IDHwt and frequently have genetic changes involving the EGFR locus, PTEN deletions and TERT promoter mutations.	('gliomas', 'Disease', (163, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('TERT', 'Gene', (299, 303))	('grade II', 'Disease', (55, 63))	('TERT', 'Gene', '7015', (299, 303))	('EGFR', 'Gene', '1956', (268, 272))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('glioblastomas', 'Disease', (118, 131))	('PTEN', 'Gene', (280, 284))	('IDH1', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioblastomas', 'Phenotype', 'HP:0012174', (97, 110))	('IDH', 'Gene', (13, 16))	('gliomas', 'Disease', (72, 79))	('IDH', 'Gene', (212, 215))	('glioblastomas', 'Disease', 'MESH:D005909', (118, 131))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('PTEN', 'Gene', '5728', (280, 284))	('IDH1', 'Gene', '3417', (13, 17))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('primary GBMs', 'Disease', (180, 192))	('IDH', 'Gene', '3417', (13, 16))	('glioblastomas', 'Disease', (97, 110))	('IDH', 'Gene', '3417', (212, 215))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('EGFR', 'Gene', (268, 272))	('deletions', 'Var', (285, 294))	('glioblastomas', 'Disease', 'MESH:D005909', (97, 110))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('glioblastomas', 'Phenotype', 'HP:0012174', (118, 131))	('mutations', 'Var', (18, 27))
191240	26699864	In addition, CIC, FUBP1, TERT promoter mutations and 1p/19q codeletion are observed more frequently in oligodendrogliomas than in astrocytic tumors whereas ATRX and TP53 mutations are seen more frequently in grade II/III astrocytic tumors.	('astrocytic tumors', 'Disease', 'MESH:D001254', (130, 147))	('TP53', 'Gene', (165, 169))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (103, 121))	('FUBP1', 'Gene', (18, 23))	('ATRX', 'Gene', (156, 160))	('CIC', 'Gene', (13, 16))	('ATRX', 'Gene', '546', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('III astrocytic tumors', 'Disease', 'MESH:D001254', (217, 238))	('astrocytic tumors', 'Disease', 'MESH:D001254', (221, 238))	('TP53', 'Gene', '7157', (165, 169))	('oligodendrogliomas', 'Disease', (103, 121))	('FUBP1', 'Gene', '8880', (18, 23))	('TERT', 'Gene', (25, 29))	('CIC', 'Gene', '23152', (13, 16))	('TERT', 'Gene', '7015', (25, 29))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('III astrocytic tumors', 'Disease', (217, 238))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('observed', 'Reg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('1p/19q codeletion', 'Var', (53, 70))	('astrocytic tumors', 'Disease', (130, 147))
191248	26699864	Our analysis confirms many of the currently used molecular classification schemes for diffuse gliomas: gliomas are first separated based on IDH-mutation status and a further stratification is based on ATRX/TP53 mutation status or 1p19q codeletion.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('TP53', 'Gene', '7157', (206, 210))	('gliomas', 'Disease', (94, 101))	('gliomas', 'Disease', (103, 110))	('TP53', 'Gene', (206, 210))	('IDH', 'Gene', '3417', (140, 143))	('ATRX', 'Gene', '546', (201, 205))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('1p19q codeletion', 'Var', (230, 246))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('ATRX', 'Gene', (201, 205))	('IDH', 'Gene', (140, 143))
191249	26699864	We show that PI3-kinase mutations are associated with poor prognosis in molecular astrocytomas (i.e.	('PI3', 'Gene', '5266', (13, 16))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('molecular astrocytomas', 'Disease', (72, 94))	('PI3', 'Gene', (13, 16))	('molecular astrocytomas', 'Disease', 'MESH:D001254', (72, 94))	('mutations', 'Var', (24, 33))
191250	26699864	diffuse gliomas that are IDH-mutated and 1p19q intact (or ATRX/TP53 mutated)) and that no other marker investigated in this study appears to further refine this molecular/prognostic classification of diffuse gliomas.	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('gliomas', 'Disease', (8, 15))	('IDH', 'Gene', (25, 28))	('diffuse', 'Disease', (200, 207))	('TP53', 'Gene', '7157', (63, 67))	('IDH', 'Gene', '3417', (25, 28))	('TP53', 'Gene', (63, 67))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('ATRX', 'Gene', (58, 62))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('gliomas', 'Disease', (208, 215))	('1p19q', 'Var', (41, 46))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('ATRX', 'Gene', '546', (58, 62))
191254	26699864	ATRX mutated gliomas).	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('ATRX', 'Gene', (0, 4))	('ATRX', 'Gene', '546', (0, 4))	('gliomas', 'Disease', (13, 20))	('mutated', 'Var', (5, 12))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
191255	26699864	The increased mutational load may partially explain the increased aggressiveness of higher grade gliomas when a subset of the affected genes actively contribute to gliomagenesis and/or progression.	('aggressiveness', 'Disease', 'MESH:D001523', (66, 80))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('glioma', 'Disease', (97, 103))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('contribute', 'Reg', (150, 160))	('mutational load', 'Var', (14, 29))	('aggressiveness', 'Disease', (66, 80))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (66, 80))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('glioma', 'Disease', (164, 170))
191258	26699864	EGFR amplification status and CDKN2A deletions data were downloaded from the cbioportal site.	('deletions', 'Var', (37, 46))	('EGFR', 'Gene', (0, 4))	('CDKN2A', 'Gene', (30, 36))	('CDKN2A', 'Gene', '1029', (30, 36))	('EGFR', 'Gene', '1956', (0, 4))
191259	26699864	When values were disconcordant between 1p and 19q or values were between 0 and -0.3 (which can occur in tumors with a high content of non-neoplastic tissue), we determined 1p19q codeletion based on visualization of the copynumber plot.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('1p19q', 'Var', (172, 177))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (138, 155))
191262	26699864	Because IDH1 and IDH2 mutations are mutually exclusive and play an identical role in tumor pathogenesis, we have combined mutation data into an additional single IDH-mutations variable.	('tumor', 'Disease', (85, 90))	('IDH', 'Gene', '3417', (17, 20))	('IDH', 'Gene', (8, 11))	('IDH1', 'Gene', (8, 12))	('IDH', 'Gene', (162, 165))	('IDH2', 'Gene', (17, 21))	('IDH', 'Gene', '3417', (8, 11))	('IDH1', 'Gene', '3417', (8, 12))	('IDH', 'Gene', '3417', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutations', 'Var', (22, 31))	('IDH2', 'Gene', '3418', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('IDH', 'Gene', (17, 20))
191267	26699864	We analyzed the combined GBM and LGG (low grade glioma) datasets from the TCGA (n = 542 samples) and identified 128 genes that are mutated (non-silent mutations only) in ten or more samples, consistent with a population frequency >1.7 % (i.e.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('mutated', 'Var', (131, 138))	('LGG', 'Gene', (33, 36))	('glioma', 'Disease', (48, 54))
191268	26699864	Of these, 57 genes were significantly associated with survival and the list included the well-known favourable prognostic markers IDH1/2, 1p19q codeletion, CIC, FUBP1 and NOTCH1.	('associated', 'Reg', (38, 48))	('FUBP1', 'Gene', (161, 166))	('CIC', 'Gene', (156, 159))	('IDH1/2', 'Gene', (130, 136))	('NOTCH1', 'Gene', '4851', (171, 177))	('NOTCH1', 'Gene', (171, 177))	('IDH1/2', 'Gene', '3417;3418', (130, 136))	('CIC', 'Gene', '23152', (156, 159))	('FUBP1', 'Gene', '8880', (161, 166))	('1p19q codeletion', 'Var', (138, 154))
191269	26699864	Poor prognostic markers included genetic changes in the EGFR locus, PTEN-mutations and alt 7/10 (Additional file 1 Table S1).	('EGFR', 'Gene', '1956', (56, 60))	('PTEN', 'Gene', (68, 72))	('EGFR', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (68, 72))	('genetic changes', 'Var', (33, 48))
191278	26699864	In a dataset of anaplastic astrocytomas, mutations in two of these four genes (PKHD1 and MUC16) were identified and in a set of GBMs, mutations in three genes (MUC16, F5 and PKHD1) were identified.	('mutations', 'Var', (41, 50))	('MUC16', 'Gene', '94025', (160, 165))	('PKHD1', 'Gene', '5314', (174, 179))	('MUC16', 'Gene', '94025', (89, 94))	('PKHD1', 'Gene', (79, 84))	('PKHD1', 'Gene', (174, 179))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (16, 39))	('PKHD1', 'Gene', '5314', (79, 84))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('MUC16', 'Gene', (160, 165))	('mutations', 'Var', (134, 143))	('anaplastic astrocytomas', 'Disease', (16, 39))	('MUC16', 'Gene', (89, 94))
191280	26699864	IDH-wt diffuse gliomas are often further subdivided into those with trisomy on chromosome 7 combined with LOH of chromosome 10 (alt 7/10) and those without (7/10 wt).	('IDH', 'Gene', (0, 3))	('LOH of chromosome 10', 'Var', (106, 126))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('trisomy on chromosome', 'Var', (68, 89))
191285	26699864	It is interesting to note that TP53 mutations are associated with a more favourable prognosis in the molecular classical gliomas and PIK3CA (or combined PIK3CA and PIK3R1) mutations with poor prognosis in the molecular mesenchymal gliomas.	('PIK3CA', 'Gene', '5290', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('PIK3R1', 'Gene', '5295', (164, 170))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('PIK3R1', 'Gene', (164, 170))	('gliomas', 'Disease', (121, 128))	('PIK3CA', 'Gene', (133, 139))	('TP53', 'Gene', '7157', (31, 35))	('gliomas', 'Disease', (231, 238))	('TP53', 'Gene', (31, 35))	('PIK3CA', 'Gene', '5290', (133, 139))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('mutations', 'Var', (36, 45))	('gliomas', 'Disease', 'MESH:D005910', (231, 238))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('PIK3CA', 'Gene', (153, 159))
191290	26699864	Mutations in three and two genes of these were also identified in validation datasets of anaplastic astrocytomas and GBMs respectively.	('identified', 'Reg', (52, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('Mutations', 'Var', (0, 9))	('GBMs', 'Disease', (117, 121))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (89, 112))	('anaplastic astrocytomas', 'Disease', (89, 112))
191293	26699864	those with mutations in ATRX and/or TP53) and molecular oligodendrogliomas (i.e.	('mutations', 'Var', (11, 20))	('molecular oligodendrogliomas', 'Disease', 'MESH:D009837', (46, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('ATRX', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('ATRX', 'Gene', '546', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('molecular oligodendrogliomas', 'Disease', (46, 74))
191296	26699864	We therefore separated IDH-mutated samples into those with TP53 or ATRX mutations (n = 151) and those with 1p19q codeletion (n = 74).	('ATRX', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('TP53', 'Gene', (59, 63))	('ATRX', 'Gene', '546', (67, 71))	('IDH', 'Gene', (23, 26))	('TP53', 'Gene', '7157', (59, 63))	('IDH', 'Gene', '3417', (23, 26))
191302	26699864	The median survival in molecular astrocytomas with PI3-kinase mutations was 3.7 years v. 6.3 years for PI3-kinase wt molecular astrocytomas (P = 0.02, HR 2.93, 95 % CI 1.16 - 7.38, Fig.	('PI3', 'Gene', (103, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (127, 138))	('molecular astrocytomas', 'Disease', (117, 139))	('molecular astrocytomas', 'Disease', 'MESH:D001254', (117, 139))	('PI3', 'Gene', '5266', (51, 54))	('molecular astrocytomas', 'Disease', 'MESH:D001254', (23, 45))	('PI3', 'Gene', '5266', (103, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('molecular astrocytomas', 'Disease', (23, 45))	('mutations', 'Var', (62, 71))	('PI3', 'Gene', (51, 54))
191303	26699864	Individual PI3-kinase mutations are listed in Additional file 1: Table S10.	('PI3', 'Gene', '5266', (11, 14))	('PI3', 'Gene', (11, 14))	('mutations', 'Var', (22, 31))
191304	26699864	PIK3CA mutations are missense mutations or in-frame deletions and often affect the known hotspots of the protein (E542, E545 or the C-terminal domain, see).	('affect', 'Reg', (72, 78))	('missense', 'Var', (21, 29))	('C-terminal domain', 'MPA', (132, 149))	('PIK3CA', 'Gene', (0, 6))	('E545', 'MPA', (120, 124))	('PIK3CA', 'Gene', '5290', (0, 6))	('hotspots of the protein', 'MPA', (89, 112))	('mutations', 'Var', (7, 16))
191305	26699864	PIK3R1 mutations are more heterogeneous (in-frame deletions, nonsense, frame-shifts, splice site or missence) not confined to specific hotspots.	('missence', 'Var', (100, 108))	('PIK3R1', 'Gene', '5295', (0, 6))	('PIK3R1', 'Gene', (0, 6))	('nonsense', 'Var', (61, 69))	('frame-shifts', 'Var', (71, 83))	('mutations', 'Var', (7, 16))
191307	26699864	Within the IDH-mutated and TP53 or ATRX mutated tumors, mutations in four genes out of the 15 identified in the TCGA dataset (PIK3R1, PKHD1, NEB1, and NOTCH2) were identified.	('IDH', 'Gene', '3417', (11, 14))	('NOTCH2', 'Gene', (151, 157))	('NEB1', 'Gene', (141, 145))	('tumors', 'Disease', (48, 54))	('PIK3R1', 'Gene', '5295', (126, 132))	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('NEB1', 'Gene', '10898', (141, 145))	('NOTCH2', 'Gene', '4853', (151, 157))	('ATRX', 'Gene', (35, 39))	('ATRX', 'Gene', '546', (35, 39))	('PKHD1', 'Gene', '5314', (134, 139))	('TP53', 'Gene', '7157', (27, 31))	('PKHD1', 'Gene', (134, 139))	('PIK3R1', 'Gene', (126, 132))	('IDH', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
191308	26699864	Of these, tumors with PIK3R1 mutations (n = 4) had poorer prognosis than PIK3R1 wt tumors (n = 20), median survival 2.4 and 5.4 years respectively (Additional file 2: Figure S1a).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', (83, 89))	('poorer', 'NegReg', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('PIK3R1', 'Gene', '5295', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('PIK3R1', 'Gene', (73, 79))	('PIK3R1', 'Gene', '5295', (22, 28))	('PIK3R1', 'Gene', (22, 28))
191309	26699864	Also in this dataset, we observed a similar poor prognostic trend for PIK3R1 mutations in IDH-mutated and TP53 or ATRX mutated GBMs: Tumors with PIK3R1 mutations (n = 2) had poorer prognosis than PIK3R1 wt tumors (n = 2), median survival 1.4 and 5.5 years respectively (Additional file 2: Figure S1b).	('mutations', 'Var', (152, 161))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('PIK3R1', 'Gene', (196, 202))	('IDH', 'Gene', '3417', (90, 93))	('Tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('PIK3R1', 'Gene', '5295', (70, 76))	('Tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (206, 212))	('PIK3R1', 'Gene', (145, 151))	('TP53', 'Gene', (106, 110))	('PIK3R1', 'Gene', '5295', (196, 202))	('Tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('ATRX', 'Gene', (114, 118))	('IDH', 'Gene', (90, 93))	('ATRX', 'Gene', '546', (114, 118))	('Tumors', 'Disease', 'MESH:D009369', (133, 139))	('PIK3R1', 'Gene', (70, 76))	('PIK3R1', 'Gene', '5295', (145, 151))	('TP53', 'Gene', '7157', (106, 110))
191310	26699864	When this is performed, a median survival of 1.9 v. 5.4 years was observed for PIK3R1 mut and PIK3R1 wt tumors respectively, HR 17.0, 95 % CI (2.40-121), P = 0.0046 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PIK3R1', 'Gene', '5295', (79, 85))	('PIK3R1', 'Gene', '5295', (94, 100))	('PIK3R1', 'Gene', (79, 85))	('tumors', 'Disease', (104, 110))	('PIK3R1', 'Gene', (94, 100))	('mut', 'Var', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
191311	26699864	The fact that PI3-kinase mutations showed similar trends in prognosis in three independent datasets, strongly suggests they are prognostic markers for molecular astrocytomas.	('mutations', 'Var', (25, 34))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('molecular astrocytomas', 'Disease', (151, 173))	('molecular astrocytomas', 'Disease', 'MESH:D001254', (151, 173))	('PI3', 'Gene', '5266', (14, 17))	('PI3', 'Gene', (14, 17))
191314	26699864	all tumors that harbour mutations in one of the lineage specific genes IDH, CIC, FUBP1, ATRX, TP53, PTEN, EGFR, 1p19q codeletion or alt 7/10, frequency listed in Table 2) tumor grade often remained inversely correlated with survival (Additional file 2: Figure S3, Table 3).	('PTEN', 'Gene', (100, 104))	('tumor', 'Disease', (4, 9))	('CIC', 'Gene', '23152', (76, 79))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('TP53', 'Gene', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('IDH', 'Gene', (71, 74))	('mutations', 'Var', (24, 33))	('survival', 'MPA', (224, 232))	('EGFR', 'Gene', (106, 110))	('PTEN', 'Gene', '5728', (100, 104))	('correlated', 'Reg', (208, 218))	('FUBP1', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('IDH', 'Gene', '3417', (71, 74))	('CIC', 'Gene', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (94, 98))	('EGFR', 'Gene', '1956', (106, 110))	('FUBP1', 'Gene', '8880', (81, 86))	('ATRX', 'Gene', (88, 92))	('inversely', 'NegReg', (198, 207))	('tumors', 'Disease', (4, 10))	('ATRX', 'Gene', '546', (88, 92))	('tumor', 'Disease', (171, 176))
191318	26699864	When screening for mutations that occur at different frequencies between grade II and III diffuse gliomas, the only genes identified were the lineage specific genetic changes (IDH, CIC, 1p19q co-deletion, ATRX, EGFR, and alt 7/10).	('CIC', 'Gene', (181, 184))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('IDH', 'Gene', (176, 179))	('EGFR', 'Gene', '1956', (211, 215))	('CIC', 'Gene', '23152', (181, 184))	('IDH', 'Gene', '3417', (176, 179))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('1p19q co-deletion', 'Var', (186, 203))	('ATRX', 'Gene', (205, 209))	('EGFR', 'Gene', (211, 215))	('ATRX', 'Gene', '546', (205, 209))
191320	26699864	those that result in a change in the primary protein sequence) genetic changes in grade II astrocytomas was 18.8 +- 13.1 (n = 30), in grade III astrocytomas it was 36.8 +- 47.6 (n = 68), P = 0.0050 (Table 4).	('II astrocytomas', 'Disease', (88, 103))	('change', 'Reg', (23, 29))	('changes', 'Var', (71, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('genetic changes', 'Var', (63, 78))	('primary protein sequence', 'MPA', (37, 61))	('II astrocytomas', 'Disease', 'MESH:D001254', (141, 156))	('II astrocytomas', 'Disease', (141, 156))	('II astrocytomas', 'Disease', 'MESH:D001254', (88, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
191322	26699864	For example, the mutational load of ATRX mutated gliomas increased from 21.6 +- 10.3 and 26.0 +- 11.2 to 65.4 +- 40.1 mutations per sample (P < 0.0001) for grade II, III and IV gliomas respectively.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('mutated', 'Var', (41, 48))	('ATRX', 'Gene', '546', (36, 40))	('gliomas', 'Disease', (177, 184))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('III', 'Disease', (166, 169))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('ATRX', 'Gene', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('increased', 'PosReg', (57, 66))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('grade II', 'Disease', (156, 164))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
191325	26699864	As patient age and tumor grade were correlated, and tumor grade was correlated to the mutational load, it is not surprizing that age was also correlated with the mutational load of the tumor (Fig.	('tumor', 'Disease', (185, 190))	('mutational', 'Var', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('patient', 'Species', '9606', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
191329	26699864	Similar results were obtained when performing multivariate analysis within defined molecular subtypes (mutations in IDH, CIC or FUBP1, TP53, EGFR, PTEN, NF1 or trisomy of Chr7 combined with LOH of Chr 10 or 1p19q codeletion), data not shown.	('IDH', 'Gene', (116, 119))	('mutations', 'Var', (103, 112))	('FUBP1', 'Gene', (128, 133))	('IDH', 'Gene', '3417', (116, 119))	('CIC', 'Gene', (121, 124))	('EGFR', 'Gene', '1956', (141, 145))	('NF1', 'Gene', (153, 156))	('TP53', 'Gene', '7157', (135, 139))	('NF1', 'Gene', '4763', (153, 156))	('EGFR', 'Gene', (141, 145))	('FUBP1', 'Gene', '8880', (128, 133))	('Chr7', 'Gene', (171, 175))	('TP53', 'Gene', (135, 139))	('trisomy', 'Var', (160, 167))	('PTEN', 'Gene', (147, 151))	('CIC', 'Gene', '23152', (121, 124))	('PTEN', 'Gene', '5728', (147, 151))
191333	26699864	Further stratification into molecular oligodendrogliomas and molecular astrocytomas involves determining the ATRX and/or TP53 mutation status or determining 1p19q codeletion (these changes are mutually exclusive).	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('molecular astrocytomas', 'Disease', 'MESH:D001254', (61, 83))	('ATRX', 'Gene', '546', (109, 113))	('molecular oligodendrogliomas', 'Disease', (28, 56))	('TP53', 'Gene', '7157', (121, 125))	('mutation', 'Var', (126, 134))	('TP53', 'Gene', (121, 125))	('1p19q codeletion', 'Var', (157, 173))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('ATRX', 'Gene', (109, 113))	('molecular oligodendrogliomas', 'Disease', 'MESH:D009837', (28, 56))	('molecular astrocytomas', 'Disease', (61, 83))
191334	26699864	Within molecular astrocytomas, mutations in PI3 kinase genes PIK3CA and PIK3R1 are likely to be associated with poor prognosis.	('PIK3CA', 'Gene', (61, 67))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', '5290', (61, 67))	('astrocytoma', 'Phenotype', 'HP:0009592', (17, 28))	('molecular astrocytomas', 'Disease', (7, 29))	('associated', 'Reg', (96, 106))	('PIK3R1', 'Gene', (72, 78))	('PI3', 'Gene', (44, 47))	('PIK3R1', 'Gene', '5295', (72, 78))	('molecular astrocytomas', 'Disease', 'MESH:D001254', (7, 29))	('PI3', 'Gene', '5266', (44, 47))
191337	26699864	Such mutations are frequently observed in various cancer types including diffuse gliomas.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('observed', 'Reg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
191338	26699864	It has been speculated that, as PI3 kinase mutations are frequently observed in diffuse gliomas, specific inhibitors may provide clinical benefit for PI3 kinase mutated diffuse glioma patients.	('PI3', 'Gene', '5266', (150, 153))	('patients', 'Species', '9606', (184, 192))	('glioma', 'Disease', (88, 94))	('observed', 'Reg', (68, 76))	('gliomas', 'Disease', (88, 95))	('PI3', 'Gene', (150, 153))	('glioma', 'Disease', (177, 183))	('PI3', 'Gene', (32, 35))	('mutations', 'Var', (43, 52))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('PI3', 'Gene', '5266', (32, 35))
191339	26699864	Here we show that PI3 kinase mutations also act as prognostic markers for molecular astrocytoma patients, providing the first evidence to demonstrate they are associated with poor outcome within a defined glioma subtype.	('molecular astrocytoma', 'Disease', 'MESH:D001254', (74, 95))	('glioma subtype', 'Disease', 'MESH:D005910', (205, 219))	('mutations', 'Var', (29, 38))	('associated with', 'Reg', (159, 174))	('glioma subtype', 'Disease', (205, 219))	('patients', 'Species', '9606', (96, 104))	('molecular astrocytoma', 'Disease', (74, 95))	('PI3', 'Gene', '5266', (18, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (84, 95))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('PI3', 'Gene', (18, 21))
191340	26699864	Our analysis also shows that grade is associated with mutational load of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutational load', 'Var', (54, 69))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
191341	26699864	This is an interesting observation as the mutational load may provide a biological explanation for tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mutational load', 'Var', (42, 57))
191342	26699864	Even if only a subset of the affected genes contributes to gliomagenesis and/or progression, an increase in mutational load would increase tumor aggressiveness.	('glioma', 'Disease', (59, 65))	('aggressiveness', 'Phenotype', 'HP:0000718', (145, 159))	('mutational', 'Var', (108, 118))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (139, 159))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor aggressiveness', 'Disease', (139, 159))	('increase', 'PosReg', (130, 138))	('increase', 'PosReg', (96, 104))
191347	26699864	The mutational load therefore cannot fully explain the increased aggressiveness of tumors of higher grade.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('aggressiveness of tumors', 'Disease', (65, 89))	('mutational load', 'Var', (4, 19))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('aggressiveness of tumors', 'Disease', 'MESH:D001523', (65, 89))
191373	33076453	Accordingly, deregulation of NOTCH signaling occurs in several human diseases, including cancer.	('NOTCH', 'Gene', '31293', (29, 34))	('human', 'Species', '9606', (63, 68))	('NOTCH', 'Gene', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('occurs', 'Reg', (45, 51))	('cancer', 'Disease', (89, 95))	('deregulation', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
191376	33076453	Genetic alterations in the genes of different NOTCH pathway components that can lead to either enhanced or decreased NOTCH signaling have been identified in multiple cancers.	('Genetic alterations', 'Var', (0, 19))	('NOTCH', 'Gene', (117, 122))	('multiple cancers', 'Disease', 'MESH:D009369', (157, 173))	('NOTCH', 'Gene', (46, 51))	('decreased', 'NegReg', (107, 116))	('multiple cancers', 'Disease', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('enhanced', 'PosReg', (95, 103))	('NOTCH', 'Gene', '31293', (117, 122))	('NOTCH', 'Gene', '31293', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
191377	33076453	Mutations that directly occur in NOTCH receptor genes can alter different portions of the protein.	('NOTCH', 'Gene', '31293', (33, 38))	('NOTCH', 'Gene', (33, 38))	('Mutations', 'Var', (0, 9))	('portions of the protein', 'MPA', (74, 97))	('alter', 'Reg', (58, 63))
191378	33076453	NOTCH activating mutations often occur in the negative regulatory region (NRR), which regulates receptor cleavage, or in the PEST domain, which is involved in NICD degradation, thus leading to ligand-independent or prolonged receptor activation.	('ligand-independent', 'MPA', (193, 211))	('activating', 'PosReg', (6, 16))	('NICD degradation', 'Disease', 'MESH:D055959', (159, 175))	('NOTCH', 'Gene', (0, 5))	('NOTCH', 'Gene', '31293', (0, 5))	('leading to', 'Reg', (182, 192))	('activation', 'PosReg', (234, 244))	('NICD degradation', 'Disease', (159, 175))	('mutations', 'Var', (17, 26))	('receptor', 'MPA', (225, 233))	('cleavage', 'MPA', (105, 113))
191380	33076453	These mutations, including point mutations, focal deletions, and nonsense and missense mutations, are predicted to prevent ligand binding or generate a truncated protein and are often associated with downregulated expression of NOTCH target genes.	('missense mutations', 'Var', (78, 96))	('NOTCH', 'Gene', '31293', (228, 233))	('NOTCH', 'Gene', (228, 233))	('point mutations', 'Var', (27, 42))	('protein', 'Protein', (162, 169))	('focal deletions', 'Var', (44, 59))	('truncated', 'MPA', (152, 161))	('downregulated', 'NegReg', (200, 213))	('prevent', 'NegReg', (115, 122))	('nonsense', 'Var', (65, 73))	('expression', 'MPA', (214, 224))	('ligand binding', 'Interaction', (123, 137))
191381	33076453	Historically, NOTCH signaling in cancer has been extensively studied in the context of T-ALL, where NOTCH acts as an oncogene and NOTCH-activating mutations are present in more than 50% of patients.	('NOTCH', 'Gene', (100, 105))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('NOTCH', 'Gene', '31293', (130, 135))	('T-ALL', 'Phenotype', 'HP:0006727', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('NOTCH', 'Gene', (130, 135))	('NOTCH', 'Gene', '31293', (14, 19))	('NOTCH', 'Gene', '31293', (100, 105))	('patients', 'Species', '9606', (189, 197))	('NOTCH', 'Gene', (14, 19))
191382	33076453	Different laboratories have identified translocations or mutation clusters within the NOTCH1 receptor gene that significantly favor tumor progression by causing a ligand-independent constitutive activation of the pathway.	('mutation clusters', 'Var', (57, 74))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('constitutive activation', 'MPA', (182, 205))	('translocations', 'Var', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('causing', 'Reg', (153, 160))	('tumor', 'Disease', (132, 137))	('favor', 'PosReg', (126, 131))	('NOTCH1 receptor', 'Gene', (86, 101))
191384	33076453	It has been demonstrated that integration of the mouse mammary tumor virus (MMTV) causes rearrangement and activation of a particular locus containing the Notch4 sequence and this ultimately results in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('results in', 'Reg', (191, 201))	('mouse mammary tumor virus', 'Species', '11757', (49, 74))	('MMTV', 'Species', '11757', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('activation', 'PosReg', (107, 117))	('cancer', 'Disease', (202, 208))	('Notch4', 'Gene', '4855', (155, 161))	('integration', 'Var', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('rearrangement', 'MPA', (89, 102))	('Notch4', 'Gene', (155, 161))
191401	33076453	As a consequence, NOTCH mutant tumor cells show increased ERK1/2 phosphorylation that can be reverted by NOTCH activation.	('mutant', 'Var', (24, 30))	('increased', 'PosReg', (48, 57))	('ERK1/2', 'Gene', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('ERK1/2', 'Gene', '5595;5594', (58, 64))	('tumor', 'Disease', (31, 36))	('NOTCH', 'Gene', '31293', (105, 110))	('NOTCH', 'Gene', (105, 110))	('phosphorylation', 'MPA', (65, 80))	('NOTCH', 'Gene', '31293', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('NOTCH', 'Gene', (18, 23))
191403	33076453	For instance, although the growth of HNSCC is largely driven by NOTCH inactivation, occasional Notch gain-of-function mutations have been reported in oral squamous cell carcinoma (OSCC).	('oral squamous cell carcinoma', 'Disease', (150, 178))	('Notch', 'Gene', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('mutations', 'Var', (118, 127))	('Notch', 'Gene', '31293', (95, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('NOTCH', 'Gene', (64, 69))	('NOTCH', 'Gene', '31293', (64, 69))	('gain-of-function', 'PosReg', (101, 117))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
191407	33076453	Consequently, NOTCH gain-of-function mutations lead to a rapid and abnormal expansion of T cells at the expense of other cell lineages, whereas NOTCH inactivation, particularly in the stromal compartment, causes an increase in myeloid progenitors and granulocyte/macrophage descendants, resulting in myeloid hyperplasia and myeloproliferative-like disease.	('myeloproliferative-like disease', 'Phenotype', 'HP:0005547', (324, 355))	('myeloproliferative-like disease', 'Disease', (324, 355))	('increase', 'PosReg', (215, 223))	('T cells', 'CPA', (89, 96))	('expansion of T cells', 'Phenotype', 'HP:0100828', (76, 96))	('mutations', 'Var', (37, 46))	('myeloid hyperplasia', 'Disease', (300, 319))	('NOTCH', 'Gene', '31293', (144, 149))	('NOTCH', 'Gene', '31293', (14, 19))	('gain-of-function', 'PosReg', (20, 36))	('myeloid hyperplasia', 'Disease', 'MESH:D006965', (300, 319))	('NOTCH', 'Gene', (144, 149))	('NOTCH', 'Gene', (14, 19))
191428	33076453	Indeed, both quiescent and actively proliferating NSCs express Hes5, indicating NOTCH pathway activation, and simultaneous Notch1 and Notch2 or Rbpj gene deletion in mice causes NSC proliferation, differentiation, and exhaustion.	('causes', 'Reg', (171, 177))	('Notch1', 'Gene', '18128', (123, 129))	('NOTCH', 'Gene', (80, 85))	('Notch2', 'Gene', (134, 140))	('NOTCH', 'Gene', '31293', (80, 85))	('Rbpj', 'Gene', '19664', (144, 148))	('Notch2', 'Gene', '18129', (134, 140))	('differentiation', 'CPA', (197, 212))	('NSC', 'Disease', (178, 181))	('deletion', 'Var', (154, 162))	('Rbpj', 'Gene', (144, 148))	('mice', 'Species', '10090', (166, 170))	('exhaustion', 'Disease', (218, 228))	('Hes5', 'Protein', (63, 67))	('Notch1', 'Gene', (123, 129))	('activation', 'PosReg', (94, 104))
191429	33076453	Interestingly, however, and in contrast to global NOTCH pathway inhibition, blocking the function of individual NOTCH receptors differentially affects active versus quiescent NSC populations, which seem to preferentially rely on NOTCH1 and NOTCH2/3, respectively.	('NOTCH2/3', 'Gene', '4853;4854', (240, 248))	('NOTCH', 'Gene', '31293', (112, 117))	('NOTCH', 'Gene', (229, 234))	('NOTCH', 'Gene', '31293', (229, 234))	('function', 'MPA', (89, 97))	('affects', 'Reg', (143, 150))	('NOTCH', 'Gene', (50, 55))	('NOTCH', 'Gene', '31293', (50, 55))	('NOTCH', 'Gene', (112, 117))	('blocking', 'Var', (76, 84))	('NOTCH', 'Gene', '31293', (240, 245))	('NOTCH', 'Gene', (240, 245))	('NOTCH2/3', 'Gene', (240, 248))
191449	33076453	In agreement with this, in vitro and xenotransplantation studies with glioma cell lines have indicated that CD133-positive GSCs are particularly sensitive to gamma-secretase inhibitors (GSI) or NOTCH1/2 knockdown compared to CD133-negative glioma cells.	('glioma', 'Disease', (70, 76))	('NOTCH1/2', 'Gene', (194, 202))	('CD133', 'Gene', (225, 230))	('CD133', 'Gene', (108, 113))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('CD133', 'Gene', '8842', (225, 230))	('CD133', 'Gene', '8842', (108, 113))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('sensitive', 'Reg', (145, 154))	('NOTCH1/2', 'Gene', '4851;4853', (194, 202))	('glioma', 'Disease', (240, 246))	('knockdown', 'Var', (203, 212))
191454	33076453	Reports have shown that knocking down the NOTCH ligands Jagged1 or Dll1 by RNA interference reduced survival and growth of tumor cells in multiple glioma cell lines and high Jagged1 expression correlates with poor prognosis of glioma patients.	('high', 'Var', (169, 173))	('Dll1', 'Gene', (67, 71))	('Jagged1', 'Gene', '182', (174, 181))	('Dll1', 'Gene', '28514', (67, 71))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('RNA interference', 'MPA', (75, 91))	('Jagged1', 'Gene', (174, 181))	('Jagged1', 'Gene', '182', (56, 63))	('glioma', 'Disease', (147, 153))	('Jagged1', 'Gene', (56, 63))	('tumor', 'Disease', (123, 128))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('survival', 'CPA', (100, 108))	('patients', 'Species', '9606', (234, 242))	('NOTCH', 'Gene', '31293', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('knocking', 'Var', (24, 32))	('expression', 'MPA', (182, 192))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('NOTCH', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('reduced', 'NegReg', (92, 99))	('glioma', 'Disease', (227, 233))
191467	33076453	Genome-wide analyses in patients with LGG identified mutations in NOTCH signaling components in a significant proportion of isocitrate dehydrogenase (IDH) mutant tumors.	('isocitrate dehydrogenase', 'Gene', '3417', (124, 148))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutant', 'Var', (155, 161))	('mutations', 'Var', (53, 62))	('IDH', 'Gene', (150, 153))	('tumors', 'Disease', (162, 168))	('patients', 'Species', '9606', (24, 32))	('NOTCH', 'Gene', '31293', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('isocitrate dehydrogenase', 'Gene', (124, 148))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('IDH', 'Gene', '3417', (150, 153))	('NOTCH', 'Gene', (66, 71))
191468	33076453	These mutations are particularly frequent in the genes encoding the NOTCH1 and NOTCH2 receptors but less common in NOTCH3/4, and occur at similar positions to those demonstrated experimentally to inactivate NOTCH1 function in epithelial cancers.	('NOTCH1', 'Gene', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('inactivate', 'Var', (196, 206))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('epithelial cancers', 'Disease', (226, 244))	('NOTCH3/4', 'Gene', (115, 123))	('NOTCH1', 'Gene', (68, 74))	('NOTCH3/4', 'Gene', '4854;4855', (115, 123))	('mutations', 'Var', (6, 15))	('epithelial cancers', 'Disease', 'MESH:D009369', (226, 244))
191470	33076453	Accordingly, the expression of some NOTCH target genes is downregulated in NOTCH/RBPJ mutant gliomas, indicating pathway inactivation.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('mutant', 'Var', (86, 92))	('expression', 'MPA', (17, 27))	('NOTCH', 'Gene', (75, 80))	('NOTCH', 'Gene', '31293', (75, 80))	('NOTCH', 'Gene', '31293', (36, 41))	('downregulated', 'NegReg', (58, 71))	('NOTCH', 'Gene', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('RBPJ', 'Gene', (81, 85))	('RBPJ', 'Gene', '3516', (81, 85))
191471	33076453	Expression of the proliferation marker MKI67 was found to be augmented in NOTCH1/RBPJ mutant brain tumors with low HES/HEY expression levels, and NOTCH mutations were a high-risk factor associated with shorter patient survival, suggesting that NOTCH signaling inhibition contributes to increased glioma aggressiveness.	('brain tumors', 'Disease', (93, 105))	('MKI67', 'Gene', '4288', (39, 44))	('glioma aggressiveness', 'Disease', 'MESH:D005910', (296, 317))	('HEY', 'Gene', (119, 122))	('HEY', 'Gene', '100188776', (119, 122))	('NOTCH', 'Gene', (244, 249))	('RBPJ', 'Gene', (81, 85))	('NOTCH', 'Gene', '31293', (146, 151))	('NOTCH', 'Gene', '31293', (74, 79))	('shorter', 'NegReg', (202, 209))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('aggressiveness', 'Phenotype', 'HP:0000718', (303, 317))	('NOTCH', 'Gene', (146, 151))	('mutant', 'Var', (86, 92))	('Expression', 'MPA', (0, 10))	('NOTCH', 'Gene', (74, 79))	('HES', 'Gene', (115, 118))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('augmented', 'PosReg', (61, 70))	('brain tumors', 'Disease', 'MESH:D001932', (93, 105))	('brain tumors', 'Phenotype', 'HP:0030692', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('glioma aggressiveness', 'Disease', (296, 317))	('HES', 'Gene', '3280;15205;54626;390992;388585;15208', (115, 118))	('brain tumor', 'Phenotype', 'HP:0030692', (93, 104))	('increased', 'PosReg', (286, 295))	('patient', 'Species', '9606', (210, 217))	('NOTCH', 'Gene', '31293', (244, 249))	('MKI67', 'Gene', (39, 44))	('RBPJ', 'Gene', '3516', (81, 85))
191473	33076453	Although occasional NOTCH1/2 mutations could also be detected in IDH mutant astrocytomas with TP53 inactivation, genetic inactivation of NOTCH pathway components mainly occurs in oligodendrogliomas with co-deletion of chromosome arms 1p and 19q.	('IDH', 'Gene', (65, 68))	('NOTCH1/2', 'Gene', '4851;4853', (20, 28))	('arms 1p', 'Gene', '3075', (229, 236))	('TP53', 'Gene', (94, 98))	('NOTCH1/2', 'Gene', (20, 28))	('astrocytomas', 'Disease', 'MESH:D001254', (76, 88))	('NOTCH', 'Gene', '31293', (20, 25))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('inactivation', 'NegReg', (121, 133))	('IDH', 'Gene', '3417', (65, 68))	('NOTCH', 'Gene', (20, 25))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (179, 197))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (94, 98))	('arms 1p', 'Gene', (229, 236))	('NOTCH', 'Gene', '31293', (137, 142))	('astrocytomas', 'Disease', (76, 88))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('oligodendrogliomas', 'Disease', (179, 197))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('NOTCH', 'Gene', (137, 142))	('occurs', 'Reg', (169, 175))
191475	33076453	Interestingly, genetic inhibition of NOTCH can promote OPC proliferation and expansion in mouse models, and excessive activation of quiescent OPC populations leads to malignant transformation.	('OPC proliferation', 'CPA', (55, 72))	('leads to', 'Reg', (158, 166))	('NOTCH', 'Gene', (37, 42))	('NOTCH', 'Gene', '31293', (37, 42))	('promote', 'PosReg', (47, 54))	('mouse', 'Species', '10090', (90, 95))	('expansion', 'CPA', (77, 86))	('genetic inhibition', 'Var', (15, 33))	('malignant transformation', 'CPA', (167, 191))
191477	33076453	However, it is worth noting that levels of NOTCH signaling activation substantially vary among GBM samples and subtypes, and hemizygous or homozygous deletions of the 1p36 locus, which could affect the MIB2 and HES2-5 genes, occur in a proportion of GBMs.	('deletions', 'Var', (150, 159))	('1p36', 'Gene', (167, 171))	('MIB2', 'Gene', (202, 206))	('HES2-5', 'Gene', '54626;390992;57801;388585', (211, 217))	('affect', 'Reg', (191, 197))	('MIB2', 'Gene', '142678', (202, 206))	('NOTCH', 'Gene', '31293', (43, 48))	('NOTCH', 'Gene', (43, 48))	('HES2-5', 'Gene', (211, 217))
191480	33076453	Lineage tracing experiments in mice have shown that ASCL1+ neural progenitors can be cells of origin of GBM and upregulation of ASCL1 and inhibition of NOTCH signaling characterize astrocytoma progression.	('astrocytoma', 'Disease', (181, 192))	('NOTCH', 'Gene', (152, 157))	('astrocytoma', 'Phenotype', 'HP:0009592', (181, 192))	('ASCL1', 'Gene', (128, 133))	('mice', 'Species', '10090', (31, 35))	('upregulation', 'PosReg', (112, 124))	('inhibition', 'Var', (138, 148))	('NOTCH', 'Gene', '31293', (152, 157))	('astrocytoma', 'Disease', 'MESH:D001254', (181, 192))
191481	33076453	ASCL1 expression is maintained in both xenografts from human proneural GBM samples and GBM mouse models, and ASCL1 can induce cell cycle genes and oncogenes, thereby promoting glioma cell proliferation in some contexts.	('glioma', 'Disease', (176, 182))	('oncogenes', 'CPA', (147, 156))	('induce', 'PosReg', (119, 125))	('promoting', 'PosReg', (166, 175))	('human', 'Species', '9606', (55, 60))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('mouse', 'Species', '10090', (91, 96))	('cell cycle genes', 'Gene', (126, 142))	('ASCL1', 'Var', (109, 114))
191482	33076453	Accordingly, ASCL1 knockdown or conditional gene knockout prolong survival of glioma-bearing mice.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('conditional gene knockout', 'Var', (32, 57))	('mice', 'Species', '10090', (93, 97))	('survival', 'CPA', (66, 74))	('glioma', 'Disease', (78, 84))	('prolong', 'PosReg', (58, 65))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
191485	33076453	More direct evidence that NOTCH signaling could restrict glioma formation in some contexts comes from studies taking advantage of genetic conditional gene deletion or overexpression approaches in vivo.	('conditional gene deletion', 'Var', (138, 163))	('restrict', 'NegReg', (48, 56))	('glioma', 'Disease', (57, 63))	('NOTCH', 'Gene', (26, 31))	('NOTCH', 'Gene', '31293', (26, 31))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
191489	33076453	Moreover, inactivation of the Rbpj gene together with the tumor suppressor gene Trp53 induces aggressive, de novo forebrain tumors with primitive neuroectodermal features.	('forebrain tumors', 'Disease', (114, 130))	('forebrain tumors', 'Disease', 'MESH:C566067', (114, 130))	('induces', 'Reg', (86, 93))	('Rbpj', 'Gene', '19664', (30, 34))	('tumor', 'Disease', (124, 129))	('primitive neuroectodermal', 'Disease', (136, 161))	('Trp53', 'Gene', (80, 85))	('Trp53', 'Gene', '7157', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('brain tumors', 'Phenotype', 'HP:0030692', (118, 130))	('primitive neuroectodermal features', 'Phenotype', 'HP:0030065', (136, 170))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('brain tumor', 'Phenotype', 'HP:0030692', (118, 129))	('aggressive', 'CPA', (94, 104))	('inactivation', 'Var', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Rbpj', 'Gene', (30, 34))
191504	33076453	NOTCH inhibition can contribute to the initiation of epithelial cancers by favoring the expansion of NOTCH mutant clones at the expense of wild-type cells.	('NOTCH', 'Gene', (101, 106))	('NOTCH', 'Gene', '31293', (101, 106))	('mutant', 'Var', (107, 113))	('epithelial cancers', 'Disease', (53, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('NOTCH', 'Gene', (0, 5))	('favoring', 'PosReg', (75, 83))	('NOTCH', 'Gene', '31293', (0, 5))	('epithelial cancers', 'Disease', 'MESH:D009369', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
191505	33076453	Since analogous cell competition mechanisms play important roles during cancer progression, it would be interesting to determine if NOTCH-regulated competitive interactions occur between adjacent neural progenitors and if NOTCH mutations can contribute to glioma formation in this context.	('NOTCH', 'Gene', '31293', (132, 137))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('contribute', 'Reg', (242, 252))	('NOTCH', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NOTCH', 'Gene', (222, 227))	('NOTCH', 'Gene', '31293', (222, 227))	('glioma', 'Disease', (256, 262))	('mutations', 'Var', (228, 237))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('interactions', 'Interaction', (160, 172))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('cancer', 'Disease', (72, 78))
191508	33076453	Finally, indication for a tumor-suppressive activity of the NOTCH pathway in glioma predominantly comes from an in vivo immunocompetent setting, and a recent CRISPR screen identified frequent co-mutation of the NOTCH1 receptor and B2m, an essential component of the MHC-I antigen presentation complex.	('co-mutation', 'Var', (192, 203))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('B2m', 'Gene', (231, 234))	('NOTCH', 'Gene', (211, 216))	('NOTCH', 'Gene', '31293', (211, 216))	('NOTCH', 'Gene', (60, 65))	('NOTCH', 'Gene', '31293', (60, 65))	('glioma', 'Disease', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
191515	33076453	In addition, differences in the outcome of NOTCH modulation likely relate to the stage of disease progression, crosstalk with other signaling pathways, and intratumoral (stem) cell heterogeneity.	('modulation', 'Var', (49, 59))	('NOTCH', 'Gene', '31293', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('NOTCH', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
191521	31801484	EGFR mutation: novel prognostic factor associated with immune infiltration in lower-grade glioma; an exploratory study Glioma is one of the most common type of primary central nervous system tumors.	('glioma', 'Disease', (90, 96))	('EGFR', 'Gene', (0, 4))	('Glioma', 'Phenotype', 'HP:0009733', (119, 125))	('nervous system tumors', 'Phenotype', 'HP:0004375', (176, 197))	('Glioma', 'Disease', 'MESH:D005910', (119, 125))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (168, 197))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('Glioma', 'Disease', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('associated', 'Reg', (39, 49))	('central nervous system tumors', 'Disease', 'MESH:D016543', (168, 197))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('central nervous system tumors', 'Disease', (168, 197))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
191522	31801484	EGFR mutation, a common alteration occurs in various tumors, is not brought to the forefront in understanding and treating glioma at present.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('EGFR', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('glioma', 'Disease', (123, 129))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))	('tumors', 'Disease', (53, 59))
191523	31801484	In the present study, we demonstrated an immune infiltration related pattern of EGFR mutation in lower-grade glioma.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('EGFR', 'Gene', '1956', (80, 84))	('mutation', 'Var', (85, 93))	('EGFR', 'Gene', (80, 84))	('glioma', 'Disease', (109, 115))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
191524	31801484	In silico analyses were performed to investigate EGFR mutation and its biological effects and clinical values.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('mutation', 'Var', (54, 62))
191527	31801484	Here we revealed that EGFR mutation leads to an up-regulation of immune response related pathways and dismal prognosis in lower-grade glioma.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('EGFR', 'Gene', (22, 26))	('mutation', 'Var', (27, 35))	('immune response related pathways', 'Pathway', (65, 97))	('EGFR', 'Gene', '1956', (22, 26))	('glioma', 'Disease', (134, 140))	('up-regulation', 'PosReg', (48, 61))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
191530	31801484	EGFR mutation indicates increasing infiltration of specific types of immune cells and poor prognosis in lower-grade glioma.	('EGFR', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Disease', (116, 122))	('increasing', 'PosReg', (24, 34))	('infiltration', 'CPA', (35, 47))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
191531	31801484	Alteration of immune microenvironment since the EGFR mutation might influence the survival of glioma.	('EGFR', 'Gene', '1956', (48, 52))	('mutation', 'Var', (53, 61))	('survival', 'CPA', (82, 90))	('glioma', 'Disease', (94, 100))	('influence', 'Reg', (68, 77))	('EGFR', 'Gene', (48, 52))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
191538	31801484	TP53 mutation is considered to be early event during the genesis of an astrocytoma, while the amplification of EGFR and loss of function or mutation of PTEN are features of higher grade glioma.	('glioma', 'Disease', (186, 192))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('loss of function', 'NegReg', (120, 136))	('EGFR', 'Gene', '1956', (111, 115))	('PTEN', 'Gene', (152, 156))	('mutation', 'Var', (140, 148))	('PTEN', 'Gene', '5728', (152, 156))	('astrocytoma', 'Disease', 'MESH:D001254', (71, 82))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('EGFR', 'Gene', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('astrocytoma', 'Disease', (71, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('mutation', 'Var', (5, 13))
191539	31801484	Based on the TCGA data, the most frequently mutated genes in lower-grade glioma (WHO grade II- grade III) were IDH1 (77.25%), TP53 (48.04%), ATRX (39.22%), CIC (22.75%), TTN (17.06%), PIK3CA (8.43%) and EGFR (6.86%), and the most prevalent mutations in glioblastoma (GBM) were PTEN (34.86%), TTN (32.57%), TP53 (31.55%), EGFR (26.97%), MUC16 (18.07%) and NF1 (12.98%).	('glioblastoma', 'Disease', (253, 265))	('MUC16', 'Gene', '94025', (336, 341))	('TP53', 'Gene', (126, 130))	('EGFR', 'Gene', (203, 207))	('glioblastoma', 'Phenotype', 'HP:0012174', (253, 265))	('ATRX', 'Gene', (141, 145))	('PTEN', 'Gene', '5728', (277, 281))	('TTN', 'Gene', '7273', (292, 295))	('IDH1', 'Gene', (111, 115))	('ATRX', 'Gene', '546', (141, 145))	('EGFR', 'Gene', (321, 325))	('NF1', 'Gene', '4763', (355, 358))	('GBM', 'Phenotype', 'HP:0012174', (267, 270))	('TTN', 'Gene', (292, 295))	('TP53', 'Gene', (306, 310))	('PIK3CA', 'Gene', (184, 190))	('MUC16', 'Gene', (336, 341))	('TP53', 'Gene', '7157', (126, 130))	('NF1', 'Gene', (355, 358))	('EGFR', 'Gene', '1956', (203, 207))	('glioma', 'Disease', (73, 79))	('IDH1', 'Gene', '3417', (111, 115))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('EGFR', 'Gene', '1956', (321, 325))	('TTN', 'Gene', '7273', (170, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (253, 265))	('TP53', 'Gene', '7157', (306, 310))	('PTEN', 'Gene', (277, 281))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('PIK3CA', 'Gene', '5290', (184, 190))	('mutations', 'Var', (240, 249))	('TTN', 'Gene', (170, 173))
191542	31801484	Previous studies have revealed several deletions and point mutations that were characterized by enhancing the activity of the EGFR.	('EGFR', 'Gene', (126, 130))	('activity', 'MPA', (110, 118))	('enhancing', 'PosReg', (96, 105))	('point mutations', 'Var', (53, 68))	('EGFR', 'Gene', '1956', (126, 130))
191544	31801484	In contrast to the EGFR mutation residing in the intracellular kinase domain in lung cancer, gliomas harbor EGFR mutations in the extracellular domain, and this signature of EGFR alteration gave the explanation to the dismal effect on the treatment with Tyrosine kinase inhibitors (TKIs) such as erlotinib.	('gliomas', 'Disease', (93, 100))	('EGFR', 'Gene', (174, 178))	('erlotinib', 'Chemical', 'MESH:D000069347', (296, 305))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', '1956', (174, 178))	('lung cancer', 'Disease', (80, 91))	('mutations', 'Var', (113, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('Tyrosine kinase', 'Gene', (254, 269))	('EGFR', 'Gene', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Tyrosine kinase', 'Gene', '7294', (254, 269))
191545	31801484	Further research proved that EGFRvIII mutation in glioma lead to activation of multiple RTKs, and these coactivation effects could initiate the downstream signaling cascade, resulting in erlotinib resistance.	('resulting in', 'Reg', (174, 186))	('initiate', 'Reg', (131, 139))	('activation', 'PosReg', (65, 75))	('erlotinib', 'Chemical', 'MESH:D000069347', (187, 196))	('erlotinib resistance', 'MPA', (187, 207))	('glioma', 'Disease', (50, 56))	('RTKs', 'Gene', '5979', (88, 92))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('mutation', 'Var', (38, 46))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('RTKs', 'Gene', (88, 92))
191548	31801484	EGFR mutation was confirmed to play significant role in modifying tumor microenvironment in lung cancer.	('lung cancer', 'Disease', (92, 103))	('modifying', 'Reg', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
191549	31801484	We hypothesize that EGFR mutation in glioma shares the similar characteristics in modifying immune microenvironment.	('EGFR', 'Gene', (20, 24))	('glioma', 'Disease', (37, 43))	('mutation', 'Var', (25, 33))	('modifying', 'Reg', (82, 91))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('EGFR', 'Gene', '1956', (20, 24))
191550	31801484	Therefore, we analyzed the RNA-sequencing data combined with clinical traits of patient from TCGA database to explore the immune related features of EGFR mutation in glioma, and a prospect on inferior overall survival in EGFR mutated gliomas was obtained.	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('gliomas', 'Disease', (234, 241))	('EGFR', 'Gene', '1956', (221, 225))	('glioma', 'Disease', (166, 172))	('mutation', 'Var', (154, 162))	('EGFR', 'Gene', '1956', (149, 153))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('EGFR', 'Gene', (221, 225))	('EGFR', 'Gene', (149, 153))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('glioma', 'Disease', (234, 240))	('patient', 'Species', '9606', (80, 87))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('mutated', 'Var', (226, 233))
191553	31801484	1.An EGFR mutation were identified using the MAF files.	('EGFR', 'Gene', (5, 9))	('EGFR', 'Gene', '1956', (5, 9))	('mutation', 'Var', (10, 18))
191554	31801484	29 LGG cases with EGFR mutations were identified, one with synonymous mutation was excluded.	('mutations', 'Var', (23, 32))	('LGG', 'Disease', (3, 6))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
191555	31801484	28 identified EGFR mutation were predicted to have high or moderate impact on EGFR function.	('EGFR', 'Gene', '1956', (14, 18))	('mutation', 'Var', (19, 27))	('EGFR', 'Gene', (14, 18))	('function', 'MPA', (83, 91))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))
191565	31801484	The following log-rank test was performed using Survival and Survminer packages in R, and Kaplan-Meier curves were plotted in R. To explore the characteristics of EGFR mutations in lower grade glioma, we performed differential analysis of gene expression using RNA-seq data from TCGA-LGG cases with and without EGFR mutations.	('EGFR', 'Gene', (311, 315))	('mutations', 'Var', (316, 325))	('glioma', 'Disease', (193, 199))	('EGFR', 'Gene', '1956', (163, 167))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('TCGA-LGG', 'Gene', (279, 287))	('EGFR', 'Gene', (163, 167))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('EGFR', 'Gene', '1956', (311, 315))
191567	31801484	In the TCGA cohort, the SNP frequency of EGFR is about 6.86%, and the rates of EGFR amplification and deletion in the whole cohort are 5.2% and 0.6% respectively (Fig.	('EGFR', 'Gene', (41, 45))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('deletion', 'Var', (102, 110))	('EGFR', 'Gene', '1956', (41, 45))
191582	31801484	To further explore the relationship between EGFR mutation and TIIC, the infiltration levels were analyzed according to EGFR copy number variations, by using data available at TIMER.	('copy number variations', 'Var', (124, 146))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', (119, 123))
191583	31801484	Infiltration levels of subsets of CD4+ T cells, neutrophils, macrophages, and dendritic cells were significantly increased with EGFR level amplification cases compared to diploid cases (Fig.	('CD4', 'Gene', (34, 37))	('amplification', 'Var', (139, 152))	('EGFR', 'Gene', '1956', (128, 132))	('CD4', 'Gene', '920', (34, 37))	('EGFR', 'Gene', (128, 132))	('increased', 'PosReg', (113, 122))
191584	31801484	For neutrophils and macrophages subsets, infiltration levels in EGFR amplification (Copy-number > 2) cases were significantly higher than those in EGFR level-gain (2 > Copy-number > 0) cases.	('EGFR', 'Gene', (147, 151))	('higher', 'PosReg', (126, 132))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (147, 151))	('infiltration levels', 'MPA', (41, 60))	('amplification', 'Var', (69, 82))
191586	31801484	Remarkable correlation of increasing copy-number and mRNA level of EGFR was observed in those EGFR copy-number gained or lost cases (Additional file 8: Fig.	('EGFR', 'Gene', '1956', (94, 98))	('increasing', 'PosReg', (26, 36))	('gained', 'PosReg', (111, 117))	('EGFR', 'Gene', (94, 98))	('lost', 'NegReg', (121, 125))	('mRNA level', 'MPA', (53, 63))	('copy-number', 'Var', (99, 110))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', '1956', (67, 71))
191587	31801484	On the other hand, relationships were analyzed between EGFR mutation and genes from enriched immune response pathways.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (55, 59))	('mutation', 'Var', (60, 68))
191588	31801484	To extracted genes which actively participate in the immune response changes triggered by EGFR mutation, we chose the genes that were significantly associated with clinical outcomes both in EGFR-MUT and EGFR-WT cases (FDR < 0.05).	('EGFR', 'Gene', '1956', (203, 207))	('EGFR', 'Gene', '1956', (190, 194))	('EGFR', 'Gene', (203, 207))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (190, 194))	('EGFR', 'Gene', (90, 94))	('associated', 'Reg', (148, 158))	('mutation', 'Var', (95, 103))
191592	31801484	A hypothesis was consequently emerged that: The increasement of both EGFR copy number and mRNA level might cause a series of biological changes including a PD-L1 elevation and rise the TIICs level, eventually change the immune microenvironment.	('EGFR', 'Gene', '1956', (69, 73))	('TIICs level', 'MPA', (185, 196))	('change', 'Reg', (209, 215))	('copy number', 'Var', (74, 85))	('PD-L1', 'Gene', (156, 161))	('EGFR', 'Gene', (69, 73))	('mRNA level', 'MPA', (90, 100))	('rise', 'PosReg', (176, 180))	('cause', 'Reg', (107, 112))	('increasement', 'PosReg', (48, 60))	('PD-L1', 'Gene', '29126', (156, 161))	('elevation', 'PosReg', (162, 171))
191593	31801484	Similar immune signature was previously reported in EGFR mutation-positive non-small-cell lung cancer (NSCLC), in which, elevated PD-L1 in EGFR mutant tumor was consider to be an indicator of better overall response rate to PD-1 inhibitors.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('NSCLC', 'Disease', (103, 108))	('EGFR', 'Gene', (52, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('EGFR', 'Gene', (139, 143))	('mutant', 'Var', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PD-1', 'Gene', (224, 228))	('PD-1', 'Gene', '5133', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('elevated', 'PosReg', (121, 129))	('EGFR', 'Gene', '1956', (52, 56))	('lung cancer', 'Disease', (90, 101))	('EGFR', 'Gene', '1956', (139, 143))	('tumor', 'Disease', (151, 156))	('PD-L1', 'Gene', (130, 135))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('PD-L1', 'Gene', '29126', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
191595	31801484	We inspected whether there was a resembling effect in the survival of LGG patients with or without EGFR mutation.	('EGFR', 'Gene', (99, 103))	('patients', 'Species', '9606', (74, 82))	('LGG', 'Disease', (70, 73))	('mutation', 'Var', (104, 112))	('EGFR', 'Gene', '1956', (99, 103))
191596	31801484	Survival analysis was performed based on the grouping of EGFR mutant and infiltration levels of different types of immune cells respectively.	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (57, 61))	('mutant', 'Var', (62, 68))
191597	31801484	We found a significant difference in the survival of patients with and without EGFR mutation (p < 0.0001), displaying an inferior prognosis associated with EGFR mutation.	('EGFR', 'Gene', '1956', (79, 83))	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (156, 160))	('mutation', 'Var', (161, 169))	('EGFR', 'Gene', (156, 160))
191613	31801484	However, opposite effects were observed for EGFR-MUT cases, highly expressed SOCS2 or PLSCR1 significantly reduced the survival risks at FDR < 0.05 and associated with better outcomes (Fig.	('SOCS2', 'Gene', '8835', (77, 82))	('PLSCR1', 'Gene', (86, 92))	('reduced', 'NegReg', (107, 114))	('outcomes', 'MPA', (175, 183))	('better', 'PosReg', (168, 174))	('survival', 'MPA', (119, 127))	('PLSCR1', 'Gene', '5359', (86, 92))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('SOCS2', 'Gene', (77, 82))	('highly expressed', 'Var', (60, 76))
191618	31801484	So far TP53 and IDH1 are the most highlighted and studied alteration in LGG, nevertheless EGFR mutation in LGG is a potential underestimated factor on monitoring glioma biological characteristics.	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('glioma', 'Disease', (162, 168))	('EGFR', 'Gene', '1956', (90, 94))	('IDH1', 'Gene', (16, 20))	('EGFR', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (16, 20))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('mutation', 'Var', (95, 103))
191619	31801484	According to TCGA data, frequency of EGFR mutation in GBM and LGG is 26.97 and 6.86% respectively.	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('mutation', 'Var', (42, 50))
191620	31801484	However, recent research has revealed a higher EGFR mutation frequency of 23% in LGGs, attributing to the different population of patients and deeper sequencing depth.	('patients', 'Species', '9606', (130, 138))	('EGFR', 'Gene', '1956', (47, 51))	('mutation', 'Var', (52, 60))	('LGGs', 'Disease', (81, 85))	('EGFR', 'Gene', (47, 51))
191621	31801484	It gave us one hint that frequency of EGFR mutation might be notably underestimated, and it also might be the potential explanation of some rapid progressed lower-grade glioma (histopathological diagnosis) which might essentially be higher-grade glioma in molecular level.	('EGFR', 'Gene', '1956', (38, 42))	('glioma', 'Disease', (169, 175))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('glioma', 'Disease', (246, 252))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
191622	31801484	EGFR-MUT LGGs were observed to harbor worse overall survival due to the characteristics of amplification of EGFR and elevated level of EGFR mRNA with higher probability, and the following initiation of cascaded downstream effects such as RTK related pathways.	('initiation', 'Reg', (188, 198))	('EGFR', 'Gene', (0, 4))	('level', 'MPA', (126, 131))	('worse', 'NegReg', (38, 43))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('EGFR', 'Gene', '1956', (135, 139))	('amplification', 'Var', (91, 104))	('RTK related pathways', 'Pathway', (238, 258))	('EGFR', 'Gene', (135, 139))	('overall survival', 'CPA', (44, 60))	('elevated', 'PosReg', (117, 125))	('EGFR', 'Gene', '1956', (0, 4))
191623	31801484	GSEA and layered GO analyses revealed that an enrichment of immune response-related gene sets in EGFR mutant cases.	('mutant', 'Var', (102, 108))	('EGFR', 'Gene', (97, 101))	('GSEA', 'Chemical', '-', (0, 4))	('EGFR', 'Gene', '1956', (97, 101))
191625	31801484	were found to more significantly enriched in EGFR-MUT LGGs, indicating the different patterns of histopathology, tumor microenvironment (TME) and metabolism process in EGFR mutant positive and negative LGGs.	('tumor', 'Disease', (113, 118))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', (168, 172))	('mutant positive', 'Var', (173, 188))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('EGFR', 'Gene', '1956', (45, 49))
191638	31801484	EGFRvIII is the most prevalent ligand-independent phenotype of EGFR alterations, and might causes a tumor-promoting chronic inflammation.	('EGFR', 'Gene', '1956', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('causes', 'Reg', (91, 97))	('inflammation', 'Disease', (124, 136))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (100, 105))	('EGFR', 'Gene', (63, 67))	('alterations', 'Var', (68, 79))	('EGFR', 'Gene', '1956', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('inflammation', 'Disease', 'MESH:D007249', (124, 136))
191650	31801484	Comprehensively, the alteration of EGFR in LGG might changes the TME and triggers a tumor-associated chronic inflammation, which eventually affect the functions of tumor infiltrated immune cells.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('changes', 'Reg', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('functions', 'MPA', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('alteration', 'Var', (21, 31))	('tumor', 'Disease', (84, 89))	('affect', 'Reg', (140, 146))	('inflammation', 'Disease', (109, 121))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('triggers', 'Reg', (73, 81))	('TME', 'MPA', (65, 68))
191651	31801484	There's also one exciting clue obtained that PD-1 and PD-L1 were observed elevated in EGFR mutant LGGs and correlated with higher level of infiltrative immune cells.	('PD-1', 'Gene', (45, 49))	('EGFR', 'Gene', '1956', (86, 90))	('elevated', 'PosReg', (74, 82))	('PD-L1', 'Gene', (54, 59))	('higher', 'PosReg', (123, 129))	('PD-1', 'Gene', '5133', (45, 49))	('level of infiltrative immune cells', 'MPA', (130, 164))	('EGFR', 'Gene', (86, 90))	('PD-L1', 'Gene', '29126', (54, 59))	('mutant', 'Var', (91, 97))
191652	31801484	Unlike the strategy of targeted therapy in EGFR mutant NSCLC, neither TKIs nor immune checkpoint inhibitors were widely used in glioma at present.	('mutant', 'Var', (48, 54))	('NSCLC', 'Disease', (55, 60))	('glioma', 'Disease', (128, 134))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('EGFR', 'Gene', '1956', (43, 47))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('EGFR', 'Gene', (43, 47))
191653	31801484	But the pattern of EGFR mutation along with higher expression level of PD-L1 was identified correlate with better response rate of PD-1 inhibitor, indicating EGFR-mutation might be a novel biomarker monitoring a better outcome of PD-1 inhibitor treatment.	('EGFR', 'Gene', (158, 162))	('PD-1', 'Gene', (230, 234))	('better', 'PosReg', (107, 113))	('PD-L1', 'Gene', (71, 76))	('EGFR', 'Gene', '1956', (19, 23))	('PD-1', 'Gene', '5133', (230, 234))	('PD-L1', 'Gene', '29126', (71, 76))	('expression', 'MPA', (51, 61))	('mutation', 'Var', (24, 32))	('EGFR', 'Gene', (19, 23))	('response rate', 'MPA', (114, 127))	('EGFR', 'Gene', '1956', (158, 162))	('PD-1', 'Gene', (131, 135))	('PD-1', 'Gene', '5133', (131, 135))
191658	31801484	We therefore performed further investigation and found that SOCS2 expression was higher in EGFR mutant LGGs than that in EGFR wild-type LGGs.	('EGFR', 'Gene', (91, 95))	('mutant', 'Var', (96, 102))	('EGFR', 'Gene', '1956', (121, 125))	('SOCS2', 'Gene', '8835', (60, 65))	('higher', 'PosReg', (81, 87))	('EGFR', 'Gene', (121, 125))	('expression', 'MPA', (66, 76))	('EGFR', 'Gene', '1956', (91, 95))	('SOCS2', 'Gene', (60, 65))
191667	31801484	According to TCGA data, EGFR mutated GBMs showed no significant difference on survival times (Fig.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutated', 'Var', (29, 36))	('GBM', 'Phenotype', 'HP:0012174', (37, 40))
191669	31801484	So far, numerous further experimental corroborations were necessary to fully understand the different impacts of EGFR mutation signature on GBM and LGG.	('EGFR', 'Gene', '1956', (113, 117))	('mutation', 'Var', (118, 126))	('EGFR', 'Gene', (113, 117))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))
191670	31801484	We described a novel hallmark of EGFR mutation in Lower grade gliomas (WHO grade II-III), and established a connection between noted tumor-related gene phenotype, tumor immune microenvironment and clinical prognosis in LGG.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('LGG', 'Disease', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'Gene', '1956', (33, 37))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (133, 138))	('mutation', 'Var', (38, 46))	('EGFR', 'Gene', (33, 37))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
191671	31801484	From another point of view, we provide a new scenario on explaining that EGFR mutated LGG cases always harboring worse prognosis, and raise a new potential marker of indicating the prognosis and immune microenvironment status.	('LGG', 'Disease', (86, 89))	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (73, 77))	('mutated', 'Var', (78, 85))
191690	31620163	Surgery resection is the primary therapeutic method for low-grade gliomas, but the outcomes are less than satisfactory because of the highly infiltrative nature of glioma, and the presence of residual tumor tissue results in recurrence and malignant progression.	('glioma', 'Disease', (66, 72))	('recurrence', 'CPA', (225, 235))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('presence', 'Var', (180, 188))	('results in', 'Reg', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('malignant progression', 'CPA', (240, 261))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('tumor', 'Disease', (201, 206))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('glioma', 'Disease', (164, 170))	('gliomas', 'Disease', (66, 73))
191694	31620163	Dysregulation of metabolism-related genes leads to cellular transformation and tumor progression.	('tumor', 'Disease', (79, 84))	('Dysregulation', 'Var', (0, 13))	('leads to', 'Reg', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cellular transformation', 'CPA', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
191731	31620163	In contrast, patients with high expression levels of TIGAR, ERBB2, EGFR, and FGFR1 had a higher HR for death than that of patients with low expression levels of those genes (P < 0.0001) (Table 6).	('FGFR1', 'Gene', (77, 82))	('ERBB2', 'Gene', '2064', (60, 65))	('TIGAR', 'Gene', '57103', (53, 58))	('ERBB2', 'Gene', (60, 65))	('patients', 'Species', '9606', (13, 21))	('FGFR1', 'Gene', '2260', (77, 82))	('higher', 'PosReg', (89, 95))	('high expression levels', 'Var', (27, 49))	('patients', 'Species', '9606', (122, 130))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('TIGAR', 'Gene', (53, 58))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
191752	31620163	It has been reported that the mRNA levels of RET are elevated in astrocytoma patients with IDH mutations, who are known to have prolonged survival.	('RET', 'Gene', '5979', (45, 48))	('elevated', 'PosReg', (53, 61))	('astrocytoma', 'Disease', 'MESH:D001254', (65, 76))	('astrocytoma', 'Disease', (65, 76))	('RET', 'Gene', (45, 48))	('patients', 'Species', '9606', (77, 85))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('IDH', 'Gene', (91, 94))	('mutations', 'Var', (95, 104))	('IDH', 'Gene', '3417', (91, 94))
191795	30806082	Some studies suggest that this occurs more frequently in tumors in which there is methylation of the DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT), although other studies have not confirmed this.	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (120, 158))	('methylation', 'Var', (82, 93))	('MGMT', 'Gene', (160, 164))	('MGMT', 'Gene', '4255', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('O6-methylguanine-DNA methyltransferase', 'Gene', (120, 158))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
191818	30806082	Once BM is developed, management typically entails local therapies, such as surgical resection or radiation, whereas several driver mutations have been identified in systemic malignancies, resulting in development of targeted drugs, notably in non-small-cell lung cancer, melanoma and breast cancers, the reach of these agents on associated BM has been modest, attributable to multiple factors including access of agents cross the blood-brain and blood-tumor barrier, and tumor heterogeneity).	('tumor', 'Phenotype', 'HP:0002664', (453, 458))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (244, 270))	('breast cancers', 'Phenotype', 'HP:0003002', (285, 299))	('tumor', 'Disease', (472, 477))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('tumor', 'Disease', 'MESH:D009369', (472, 477))	('malignancies', 'Disease', 'MESH:D009369', (175, 187))	('blood-brain and blood-tumor', 'Disease', 'MESH:D006402', (431, 458))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('malignancies', 'Disease', (175, 187))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('lung cancer', 'Disease', (259, 270))	('melanoma', 'Disease', 'MESH:D008545', (272, 280))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumor', 'Disease', (453, 458))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('tumor', 'Disease', 'MESH:D009369', (453, 458))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (248, 270))	('mutations', 'Var', (132, 141))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('breast cancers', 'Disease', 'MESH:D001943', (285, 299))	('breast cancers', 'Disease', (285, 299))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('melanoma', 'Disease', (272, 280))
191906	28002790	It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS).	('leads to', 'Reg', (59, 67))	('fusions', 'Var', (46, 53))	('oncogene', 'Gene', (68, 76))	('BRAF', 'Gene', '673', (41, 45))	('caused', 'Reg', (22, 28))	('BRAF', 'Gene', (41, 45))	('KIAA1549', 'Gene', '57670', (32, 40))	('KIAA1549', 'Gene', (32, 40))
191907	28002790	OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures.	('preventing', 'NegReg', (88, 98))	('growth arrest', 'Disease', (40, 53))	('establishment of PA cultures', 'CPA', (99, 127))	('OIS', 'Var', (0, 3))	('growth arrest', 'Disease', 'MESH:D006323', (40, 53))	('growth arrest', 'Phenotype', 'HP:0001510', (40, 53))
191929	28002790	The most frequent alteration found in PA is the activating fusion of KIAA1549 with the BRAF kinase domain (>60%), followed by typically mutually exclusive BRAFV600E point mutation, FGFR1 mutations, NTRK-family fusions, NF1 mutations, or KRAS mutations.	('KRAS', 'Gene', (237, 241))	('BRAF', 'Gene', (155, 159))	('KRAS', 'Gene', '3845', (237, 241))	('BRAFV600E', 'Mutation', 'rs113488022', (155, 164))	('NTRK', 'Gene', (198, 202))	('point mutation', 'Var', (165, 179))	('activating', 'PosReg', (48, 58))	('FGFR1', 'Gene', (181, 186))	('KIAA1549', 'Gene', '57670', (69, 77))	('KIAA1549', 'Gene', (69, 77))	('FGFR1', 'Gene', '2260', (181, 186))	('NTRK', 'Gene', '4915', (198, 202))	('BRAF', 'Gene', (87, 91))	('NF1', 'Gene', (219, 222))	('BRAF', 'Gene', '673', (155, 159))	('BRAF', 'Gene', '673', (87, 91))	('NF1', 'Gene', '4763', (219, 222))
191938	28002790	published a PA model, where transduction of BRAFV600E into human neural stem cells caused transformation and subsequent growth arrest.	('human', 'Species', '9606', (59, 64))	('caused', 'Reg', (83, 89))	('transformation', 'CPA', (90, 104))	('transduction', 'Var', (28, 40))	('growth arrest', 'Disease', 'MESH:D006323', (120, 133))	('growth arrest', 'Disease', (120, 133))	('growth arrest', 'Phenotype', 'HP:0001510', (120, 133))	('BRAFV600E', 'Var', (44, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))
191939	28002790	These models replicate BRAFV600E positive PAs, however they are difficult to expand and therefore only of limited use for medium- to high-throughput preclinical testing.	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('PAs', 'Chemical', 'MESH:D011478', (42, 45))	('BRAFV600E', 'Var', (23, 32))	('PAs', 'Disease', (42, 45))
191941	28002790	This model was established from a juvenile pleomorphic xanthoastrocytoma patient and is characterized by a BRAFV600E mutation and homozygous CDKN2A/B deletion, thereby molecularly resembling a WHO grade II-III glioma rather than a PA. To date, there are no reported patient-derived PA cell lines, and consequently no model with endogenous expression of the prototypical KIAA1549:BRAF fusion on a human genetic background.	('CDKN2A', 'Gene', '1029', (141, 147))	('patient', 'Species', '9606', (73, 80))	('juvenile pleomorphic xanthoastrocytoma', 'Disease', (34, 72))	('glioma', 'Disease', (210, 216))	('KIAA1549', 'Gene', '57670', (370, 378))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('human', 'Species', '9606', (396, 401))	('BRAF', 'Gene', '673', (379, 383))	('BRAF', 'Gene', (379, 383))	('BRAFV600E', 'Mutation', 'rs113488022', (107, 116))	('KIAA1549', 'Gene', (370, 378))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('BRAF', 'Gene', '673', (107, 111))	('CDKN2A', 'Gene', (141, 147))	('BRAF', 'Gene', (107, 111))	('patient', 'Species', '9606', (266, 273))	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('juvenile pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (34, 72))	('mutation', 'Var', (117, 125))
191965	28002790	DKFZ-BT66 cells demonstrated steady proliferation with a calculated mean doubling time of 43.8h (SD 3.8; n=3, passage 11 - 13) in the presence of doxycycline and hence SV40-TAg expression (Figure 1e).	('TAg', 'Gene', '404663', (173, 176))	('doxycycline', 'Chemical', 'MESH:D004318', (146, 157))	('BT', 'Chemical', 'MESH:C005465', (5, 7))	('doxycycline', 'MPA', (146, 157))	('TAg', 'Gene', (173, 176))	('DKFZ-BT66', 'Var', (0, 9))
191977	28002790	The presence of the KIAA1549:BRAF-fusion (KEX16BEX9) was additionally confirmed by gene-panel sequencing with detected breakpoints within BRAF intron 8 (position 140488009 on chromosome 7) and KIAA1549 intron 16 (position 138538359 on chromosome 7) (not shown).	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('KIAA1549', 'Gene', '57670', (20, 28))	('BRAF', 'Gene', '673', (138, 142))	('KIAA1549', 'Gene', (20, 28))	('position 140488009', 'Var', (153, 171))	('position 138538359', 'Var', (213, 231))	('KIAA1549', 'Gene', (193, 201))	('KIAA1549', 'Gene', '57670', (193, 201))	('BRAF', 'Gene', (138, 142))
191980	28002790	DKFZ-BT66 cells showed higher levels of phosphorylated MEK (pMEK; Ser217/ Ser221) and ERK (pERK; Thr202/ Tyr204) compared to the BRAF wild type cell line HEK293T constitutively expressing SV40-TAg, and an ERK activation comparable to the BRAFV600E-expressing cell line BT-40 (Figure 1i).	('MEK', 'Gene', (55, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (238, 247))	('ERK', 'Gene', (92, 95))	('Ser221', 'Chemical', '-', (74, 80))	('BT', 'Chemical', 'MESH:C005465', (269, 271))	('pERK', 'Gene', (91, 95))	('BRAF', 'Gene', '673', (238, 242))	('MEK', 'Gene', '5609', (61, 64))	('pERK', 'Gene', '9451', (91, 95))	('BRAF', 'Gene', (238, 242))	('Ser217', 'Chemical', '-', (66, 72))	('higher', 'PosReg', (23, 29))	('TAg', 'Gene', (193, 196))	('phosphorylated', 'MPA', (40, 54))	('ERK', 'Gene', '5594', (86, 89))	('DKFZ-BT66', 'Var', (0, 9))	('TAg', 'Gene', '404663', (193, 196))	('MEK', 'Gene', (61, 64))	('ERK', 'Gene', '5594', (205, 208))	('BT', 'Chemical', 'MESH:C005465', (5, 7))	('HEK293T', 'CellLine', 'CVCL:0063', (154, 161))	('Tyr204', 'Chemical', '-', (105, 111))	('ERK', 'Gene', (86, 89))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('ERK', 'Gene', (205, 208))	('ERK', 'Gene', '5594', (92, 95))	('MEK', 'Gene', '5609', (55, 58))	('Thr202', 'Chemical', '-', (97, 103))
191981	28002790	Although we could clearly demonstrated the PA origin of DKFZ-BT66 cells, some additional copy number aberrations not present in the primary tumor and rather atypical for PA (e.g.	('DKFZ-BT66', 'Var', (56, 65))	('BT', 'Chemical', 'MESH:C005465', (61, 63))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
191982	28002790	In summary, DKFZ-BT66 displayed a methylation profile similar to primary infratentorial PAs as well as to the primary tumor of origin, expressed and maintained the prototypical KIAA1549:BRAF fusion, and showed the expected MAPK activity.	('BRAF', 'Gene', (186, 190))	('primary infratentorial PAs', 'Disease', (65, 91))	('MAPK', 'Enzyme', (223, 227))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('primary infratentorial PAs', 'Disease', 'MESH:D015192', (65, 91))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BT', 'Chemical', 'MESH:C005465', (17, 19))	('DKFZ-BT66', 'Var', (12, 21))	('maintained', 'PosReg', (149, 159))	('tumor', 'Disease', (118, 123))	('methylation', 'MPA', (34, 45))	('BRAF', 'Gene', '673', (186, 190))	('KIAA1549', 'Gene', (177, 185))	('KIAA1549', 'Gene', '57670', (177, 185))
191986	28002790	It was accompanied by several senescence-associated phenotypic changes of DKFZ-BT66 cells, comparable to primary PA cultures in OIS: withdrawal of doxycycline led to a distinct change in cell morphology with rounded, enlarged and flattened cells (Figure 2a), a phenotype typical for senescent cells.	('doxycycline', 'Chemical', 'MESH:D004318', (147, 158))	('withdrawal', 'Var', (133, 143))	('cell morphology', 'CPA', (187, 202))	('change', 'Reg', (177, 183))	('BT', 'Chemical', 'MESH:C005465', (79, 81))
191999	28002790	Taken together, the observed growth arrest of DKFZ-BT66 in the absence of SV40-TAg was accompanied by distinct morphological as well as cell biological changes indicative of induction of a senescent phenotype comparable to OIS.	('growth arrest', 'Disease', 'MESH:D006323', (29, 42))	('growth arrest', 'Phenotype', 'HP:0001510', (29, 42))	('DKFZ-BT66', 'Var', (46, 55))	('TAg', 'Gene', (79, 82))	('senescent', 'CPA', (189, 198))	('BT', 'Chemical', 'MESH:C005465', (51, 53))	('TAg', 'Gene', '404663', (79, 82))	('growth arrest', 'Disease', (29, 42))
192010	28002790	In summary, these data demonstrate that DKFZ-BT66 cells carry a dominant senescence program that differs from replicative senescence and is in line with OIS driven by the KIAA:BRAF1549 fusion.	('dominant senescence program', 'MPA', (64, 91))	('BT', 'Chemical', 'MESH:C005465', (45, 47))	('DKFZ-BT66', 'Var', (40, 49))	('BRAF', 'Gene', (176, 180))	('BRAF', 'Gene', '673', (176, 180))
192021	28002790	MLN2480 and TAK-632, two potent class II RAFi, also caused paradoxical activation of the pathway in our model (Figure 5a).	('TAK-632', 'Var', (12, 19))	('activation', 'PosReg', (71, 81))	('TAK-632', 'Chemical', 'MESH:C586564', (12, 19))	('MLN2480', 'Chemical', 'MESH:C000626538', (0, 7))	('MLN2480', 'Var', (0, 7))
192038	28002790	Circumvention of senescence in DKFZ-BT66 abrogates this limitation and allows for expansion of the cell line.	('DKFZ-BT66', 'Var', (31, 40))	('BT', 'Chemical', 'MESH:C005465', (36, 38))	('abrogates', 'NegReg', (41, 50))
192051	28002790	Growth arrest observed in TERT-overexpressing DKFZ-BT66 after SV40-TAg withdrawal was therefore strongly suggestive for OIS being present in DKFZ-BT66.	('TAg', 'Gene', '404663', (67, 70))	('TERT', 'Gene', (26, 30))	('DKFZ-BT66', 'Var', (46, 55))	('Growth arrest', 'Disease', (0, 13))	('TERT', 'Gene', '7015', (26, 30))	('TAg', 'Gene', (67, 70))	('BT', 'Chemical', 'MESH:C005465', (51, 53))	('Growth arrest', 'Disease', 'MESH:D006323', (0, 13))	('BT', 'Chemical', 'MESH:C005465', (146, 148))	('Growth arrest', 'Phenotype', 'HP:0001510', (0, 13))
192054	28002790	This was not unexpected, since SV40-Large T inhibits the CDKN2A/RB1 pathway at the level of RB1, which is downstream of CDKN2A and therefore does not influence the expression level of CDKN2A.	('RB1', 'Gene', '5925', (64, 67))	('RB1', 'Gene', '5925', (92, 95))	('CDKN2A', 'Gene', '1029', (184, 190))	('CDKN2A', 'Gene', (57, 63))	('CDKN2A', 'Gene', (120, 126))	('CDKN2A', 'Gene', '1029', (57, 63))	('CDKN2A', 'Gene', '1029', (120, 126))	('RB1', 'Gene', (92, 95))	('RB1', 'Gene', (64, 67))	('SV40-Large', 'Var', (31, 41))	('inhibits', 'NegReg', (44, 52))	('CDKN2A', 'Gene', (184, 190))
192071	28002790	DKFZ-BT66 was able to detect paradoxical activation after treatment with sorafenib, recapitulating the results of the phase II trial, and the same was observed for vemurafenib.	('paradoxical activation', 'MPA', (29, 51))	('BT', 'Chemical', 'MESH:C005465', (5, 7))	('sorafenib', 'Chemical', 'MESH:D000077157', (73, 82))	('DKFZ-BT66', 'Var', (0, 9))	('vemurafenib', 'Chemical', 'MESH:D000077484', (164, 175))
192072	28002790	Since KIAA1549:BRAF fusions signal as homodimers, we tested MLN2480 and TAK-632, two potent inhibitors of dimeric RAF, for their activity in DKFZ-BT66.	('BRAF', 'Gene', '673', (15, 19))	('tested', 'Reg', (53, 59))	('TAK-632', 'Chemical', 'MESH:C586564', (72, 79))	('BRAF', 'Gene', (15, 19))	('KIAA1549', 'Gene', '57670', (6, 14))	('MLN2480', 'Chemical', 'MESH:C000626538', (60, 67))	('KIAA1549', 'Gene', (6, 14))	('MLN2480', 'Var', (60, 67))	('BT', 'Chemical', 'MESH:C005465', (146, 148))	('TAK-632', 'Gene', (72, 79))
192073	28002790	However, both MLN2480 and TAK-632 caused unexpected paradoxical activation of pERK in our model system, similar to sorafenib and vemurafenib.	('MLN2480', 'Var', (14, 21))	('vemurafenib', 'Chemical', 'MESH:D000077484', (129, 140))	('pERK', 'Gene', '9451', (78, 82))	('sorafenib', 'Chemical', 'MESH:D000077157', (115, 124))	('TAK-632', 'Var', (26, 33))	('TAK-632', 'Chemical', 'MESH:C586564', (26, 33))	('activation', 'PosReg', (64, 74))	('MLN2480', 'Chemical', 'MESH:C000626538', (14, 21))	('pERK', 'Gene', (78, 82))
192074	28002790	Other groups have reported MAPK inhibition upon RAFi treatment in RAS and BRAF mutated as well as BRAF fusion backgrounds.	('mutated', 'Var', (79, 86))	('inhibition', 'NegReg', (32, 42))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('MAPK', 'Protein', (27, 31))
192075	28002790	MLN2480 inhibited MAPK pathway signaling in preclinical BRAF and RAS mutant melanoma and colorectal carcinoma models.	('melanoma', 'Disease', (76, 84))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (89, 109))	('inhibited', 'NegReg', (8, 17))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('RAS', 'Gene', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('BRAF', 'Gene', '673', (56, 60))	('MLN2480', 'Chemical', 'MESH:C000626538', (0, 7))	('colorectal carcinoma', 'Disease', (89, 109))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('MAPK pathway signaling', 'Pathway', (18, 40))	('MLN2480', 'Var', (0, 7))	('BRAF', 'Gene', (56, 60))
192076	28002790	In addition, MLN2480 has recently been shown to suppress pERK and cell proliferation in short term cultures of primary pilocytic astrocytoma cells that were confirmed as positive for the KIAA1549:BRAF fusion gene.	('suppress', 'NegReg', (48, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (129, 140))	('cell proliferation', 'CPA', (66, 84))	('pilocytic astrocytoma', 'Disease', (119, 140))	('BRAF', 'Gene', '673', (196, 200))	('MLN2480', 'Chemical', 'MESH:C000626538', (13, 20))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (119, 140))	('BRAF', 'Gene', (196, 200))	('KIAA1549', 'Gene', (187, 195))	('KIAA1549', 'Gene', '57670', (187, 195))	('MLN2480', 'Var', (13, 20))	('pERK', 'Gene', '9451', (57, 61))	('pERK', 'Gene', (57, 61))
192078	28002790	TAK-632 was shown to induce minimal paradoxical activation and potent antiproliferative effects in preclinical NRAS- and BRAF-mutated melanoma models.	('BRAF', 'Gene', (121, 125))	('antiproliferative effects', 'CPA', (70, 95))	('NRAS-', 'Gene', '4893', (111, 116))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('TAK-632', 'Var', (0, 7))	('NRAS-', 'Gene', (111, 116))	('paradoxical', 'MPA', (36, 47))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('BRAF', 'Gene', '673', (121, 125))	('TAK-632', 'Chemical', 'MESH:C586564', (0, 7))
192090	28002790	Other mechanisms could include the reconfiguration of chromatin leading to sustained up-regulation of mechanisms activating RAS signaling through PI3K, as has been shown in IDH mutant gliomas, with subsequent stimulation of metabolism.	('metabolism', 'MPA', (224, 234))	('gliomas', 'Disease', 'MESH:D005910', (184, 191))	('stimulation', 'PosReg', (209, 220))	('gliomas', 'Disease', (184, 191))	('IDH', 'Gene', (173, 176))	('PI3K', 'Var', (146, 150))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('IDH', 'Gene', '3417', (173, 176))	('mutant', 'Var', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('up-regulation', 'PosReg', (85, 98))	('RAS signaling', 'MPA', (124, 137))
192093	28002790	However, preclinical drug screens using this model will have to take the limitation into account, that signaling effects such as changes in pMEK and pERK are readily detectable, but effects on cell proliferation or cell death are limited.	('changes', 'Var', (129, 136))	('MEK', 'Gene', (141, 144))	('MEK', 'Gene', '5609', (141, 144))	('pERK', 'Gene', '9451', (149, 153))	('pERK', 'Gene', (149, 153))
192096	28002790	It will be also very useful to understand the biochemistry of BRAF fusion proteins that significantly differ in their regulatory requirements from BRAF point mutants such as V600E.	('V600E', 'Var', (174, 179))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('V600E', 'Mutation', 'rs113488022', (174, 179))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))
192224	24894847	Alterations in glutamate neurotransmission form a core part of the pathophysiology of epileptogenesis.	('glutamate neurotransmission', 'MPA', (15, 42))	('Alterations', 'Var', (0, 11))	('epileptogenesis', 'Disease', (86, 101))	('glutamate', 'Chemical', 'MESH:D018698', (15, 24))	('rat', 'Species', '10116', (4, 7))
192252	24894847	Thus, for human focal epilepsies, alterations in chloride homeostasis can switch GABA neurotransmission from hyperpolarizing to depolarizing and, therefore, decrease the threshold for seizure genesis.	('switch', 'Reg', (74, 80))	('chloride', 'Chemical', 'MESH:D002712', (49, 57))	('human', 'Species', '9606', (10, 15))	('threshold', 'MPA', (170, 179))	('GABA', 'Chemical', 'MESH:D005680', (81, 85))	('GABA neurotransmission', 'MPA', (81, 103))	('decrease', 'NegReg', (157, 165))	('seizure', 'Phenotype', 'HP:0001250', (184, 191))	('hyperpolarizing', 'MPA', (109, 124))	('chloride homeostasis', 'MPA', (49, 69))	('epilepsies', 'Phenotype', 'HP:0001250', (22, 32))	('seizure', 'Disease', (184, 191))	('seizure', 'Disease', 'MESH:D012640', (184, 191))	('alterations', 'Var', (34, 45))	('rat', 'Species', '10116', (38, 41))	('epilepsies', 'Disease', 'MESH:D004827', (22, 32))	('epilepsies', 'Disease', (22, 32))
192268	24894847	Polymorphisms or mutations of murine and human KCNJ10, which encodes the astroglial Kir4.1 K+ channel, are associated with epilepsy.	('KCNJ10', 'Gene', '3766', (47, 53))	('epilepsy', 'Disease', (123, 131))	('associated', 'Reg', (107, 117))	('Polymorphisms', 'Var', (0, 13))	('human', 'Species', '9606', (41, 46))	('murine', 'Species', '10090', (30, 36))	('epilepsy', 'Disease', 'MESH:D004827', (123, 131))	('Kir4.1', 'Gene', (84, 90))	('KCNJ10', 'Gene', (47, 53))	('Kir4.1', 'Gene', '3766', (84, 90))	('mutations', 'Var', (17, 26))	('epilepsy', 'Phenotype', 'HP:0001250', (123, 131))
192271	24894847	In addition to changes in the balance of neurotransmitters, alterations in peritumoral zone pH have also been put forward as a hypothesis for increased epileptogenicity.	('changes', 'Reg', (15, 22))	('tumor', 'Disease', (79, 84))	('balance of neurotransmitters', 'MPA', (30, 58))	('rat', 'Species', '10116', (64, 67))	('alterations', 'Var', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('epileptogenicity', 'MPA', (152, 168))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
192281	24894847	In lower grade tumors, localized acidity causes astrocytoma cells and malignant glial cells to demonstrate an increased Na+ influx and may lead to increased cellular excitability.	('cellular excitability', 'MPA', (157, 178))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('increased', 'PosReg', (147, 156))	('astrocytoma', 'Disease', 'MESH:D001254', (48, 59))	('increased', 'PosReg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('astrocytoma', 'Disease', (48, 59))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('Na+ influx', 'MPA', (120, 130))	('acidity', 'Var', (33, 40))	('rat', 'Species', '10116', (102, 105))	('tumors', 'Disease', (15, 21))
192282	24894847	However, if this were the only mechanism coupling changes in pH to epileptogenicity, then it ought to be the case that the high-grade tumors most susceptible to hypoxia and ischemia would be those most likely to exhibit seizures, and this is clearly not the case.	('exhibit', 'Reg', (212, 219))	('tumors', 'Disease', (134, 140))	('changes', 'Var', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('ischemia', 'Disease', (173, 181))	('seizures', 'Disease', 'MESH:D012640', (220, 228))	('hypoxia', 'Disease', 'MESH:D000860', (161, 168))	('ischemia', 'Disease', 'MESH:D007511', (173, 181))	('seizures', 'Disease', (220, 228))	('hypoxia', 'Disease', (161, 168))	('seizures', 'Phenotype', 'HP:0001250', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('seizure', 'Phenotype', 'HP:0001250', (220, 227))
192309	24894847	demonstrated that disruption of the BBB caused foci of epileptiform discharges in rat cortex.	('epileptiform discharges', 'Disease', (55, 78))	('epileptiform discharges', 'Phenotype', 'HP:0011182', (55, 78))	('epileptiform discharges', 'Disease', 'MESH:D019522', (55, 78))	('rat', 'Species', '10116', (82, 85))	('rat', 'Species', '10116', (7, 10))	('disruption', 'Var', (18, 28))	('BBB', 'Gene', (36, 39))
192312	24894847	As discussed above, shifts in pH are associated with increased seizure activity, and this mechanism may further implicate BBB disruption in epileptogenesis in the peritumoral zone.	('implicate', 'Reg', (112, 121))	('seizure', 'Phenotype', 'HP:0001250', (63, 70))	('seizure', 'Disease', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('shifts', 'Var', (20, 26))	('seizure', 'Disease', 'MESH:D012640', (63, 70))	('increased', 'PosReg', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
192348	24894847	It seems that the most likely reason for partial resection resulting in poorer control of TAE postoperatively is that the epileptogenic focus has not been removed.	('TAE', 'Chemical', '-', (90, 93))	('rat', 'Species', '10116', (101, 104))	('control', 'MPA', (79, 86))	('poorer', 'NegReg', (72, 78))	('partial resection', 'Var', (41, 58))
192359	24894847	Neurosurgery for tumor excision where a cure cannot be affected is a balance; in high-grade tumors a greater extent of resection increases time to tumor progression and median survival, and a similar trend suggests that the same may be true of low-grade gliomas.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('increases', 'PosReg', (129, 138))	('time to', 'MPA', (139, 146))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('gliomas', 'Phenotype', 'HP:0009733', (254, 261))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('gliomas', 'Disease', 'MESH:D005910', (254, 261))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('gliomas', 'Disease', (254, 261))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('median survival', 'CPA', (169, 184))	('high-grade', 'Var', (81, 91))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
192380	32351547	Several biomarkers, including the isocitrate dehydrogenase (IDH) mutation, co-deletion of chromosome arms 1p and 19q (1p/19q codeletion), and O-6-methylguanine-DNA methyltransferase (MGMT) methylation have been integrated to the 2016 WHO classification, to illustrate the histological features and guide the therapeutic strategy.	('MGMT', 'Gene', (183, 187))	('MGMT', 'Gene', '4255', (183, 187))	('isocitrate dehydrogenase', 'Gene', (34, 58))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (142, 181))	('IDH', 'Gene', (60, 63))	('mutation', 'Var', (65, 73))	('co-deletion', 'Var', (75, 86))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (142, 181))	('IDH', 'Gene', '3417', (60, 63))	('isocitrate dehydrogenase', 'Gene', '3417', (34, 58))
192405	32351547	The Cancer Cell Line Encyclopedia (CCLE) was generated to provide a compilation of mRNA expression, copy number variation, and preclinical datasets for mutations in various cancer types.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('mutations', 'Var', (152, 161))	('cancer', 'Disease', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
192418	32351547	The comprehensive risk score was imputed as follows: (0.38625 x expression level of CANX) + (0.18073 x expression level of HSPA1B) + (-0.27702 x expression level of KLRC2) + (-0.71285 x expression level of PSMC6) + (-0.68077 x expression level of RFXAP) + (0.34100 x expression level of TAP1).	('PSMC6', 'Gene', '5706', (206, 211))	('KLRC2', 'Gene', '3822', (165, 170))	('RFXAP', 'Gene', (247, 252))	('0.38625', 'Var', (54, 61))	('HSPA1B', 'Gene', (123, 129))	('0.18073', 'Var', (93, 100))	('KLRC2', 'Gene', (165, 170))	('CANX', 'Gene', '821', (84, 88))	('RFXAP', 'Gene', '5994', (247, 252))	('HSPA1B', 'Gene', '3304', (123, 129))	('CANX', 'Gene', (84, 88))	('PSMC6', 'Gene', (206, 211))	('TAP1', 'Gene', (287, 291))	('TAP1', 'Gene', '6890', (287, 291))
192437	32351547	However, no significant difference was observed between the IDH wild and mutant groups in recurrent LGG (Supplementary Figures S6A,C).	('LGG', 'Disease', (100, 103))	('IDH', 'Gene', '3417', (60, 63))	('IDH', 'Gene', (60, 63))	('mutant', 'Var', (73, 79))
192655	21153680	Although not ascertained in the current study, it is known that the frequency of co-deletion in mixed oligoastrocytoma (26%) and pure astrocytoma (8%) is lower than with pure oligodendroglioma (44%).	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('oligoastrocytoma', 'Disease', (102, 118))	('oligodendroglioma', 'Disease', 'MESH:D009837', (175, 192))	('astrocytoma', 'Disease', 'MESH:D001254', (107, 118))	('astrocytoma', 'Disease', (107, 118))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('co-deletion', 'Var', (81, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (107, 118))	('astrocytoma', 'Disease', 'MESH:D001254', (134, 145))	('oligodendroglioma', 'Disease', (175, 192))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (102, 118))	('astrocytoma', 'Disease', (134, 145))
192657	21153680	In a prior report, the frequency of 1p19q co-deletion did not appear to differ between newly diagnosed and recurrent patients (for those with oligodendroglioma, 39 vs 56%; those with mixed glioma, 21 vs 33%; and those with pure astrocytoma 8 vs 6%, respectively).	('glioma', 'Disease', (189, 195))	('oligodendroglioma', 'Disease', (142, 159))	('1p19q co-deletion', 'Var', (36, 53))	('glioma', 'Disease', (153, 159))	('astrocytoma', 'Disease', 'MESH:D001254', (228, 239))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('astrocytoma', 'Disease', (228, 239))	('glioma', 'Disease', 'MESH:D005910', (189, 195))	('oligodendroglioma', 'Disease', 'MESH:D009837', (142, 159))	('astrocytoma', 'Phenotype', 'HP:0009592', (228, 239))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('patients', 'Species', '9606', (117, 125))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))
192672	21153680	During this time, not only has the conventional histologic classifications of glioma evolved, but the field has also seen early implementation of prognostic molecular markers (such as 1p/19q co-deletion status, and the presence of IDH1 mutations) in clinical trials and practice.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH1', 'Gene', (231, 235))	('IDH1', 'Gene', '3417', (231, 235))	('mutations', 'Var', (236, 245))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
192675	21153680	Other factors are likely important, including amplification of EGFR, and gene promotor hypermethylation profile.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('amplification', 'Var', (46, 59))
192678	21153680	De novo GBMs typically have mutations in EGFR, PTEN and INK4A/ARF/CDKN2A, while secondary GBMs usually display PDGF and TP53 alterations.	('TP53', 'Gene', '7157', (120, 124))	('EGFR', 'Gene', (41, 45))	('INK4A', 'Gene', (56, 61))	('CDKN2A', 'Gene', '1029', (66, 72))	('ARF', 'Disease', 'MESH:D058186', (62, 65))	('PTEN', 'Gene', (47, 51))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('PTEN', 'Gene', '5728', (47, 51))	('ARF', 'Disease', (62, 65))	('GBM', 'Phenotype', 'HP:0012174', (8, 11))	('EGFR', 'Gene', '1956', (41, 45))	('CDKN2A', 'Gene', (66, 72))	('INK4A', 'Gene', '1029', (56, 61))	('TP53', 'Gene', (120, 124))	('mutations', 'Var', (28, 37))
192683	21153680	Recently, the presence of an IDH-1 mutation was reported to correlate with longer survival (27.1 vs 11.3 mos., p<0.0001) and was more frequent in secondary GBM than de novo GBM (73% vs 3.7%, p < 0.0001).	('presence', 'Var', (14, 22))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('secondary GBM', 'Disease', (146, 159))	('frequent', 'Reg', (134, 142))	('IDH-1', 'Gene', '3417', (29, 34))	('mutation', 'Var', (35, 43))	('IDH-1', 'Gene', (29, 34))	('GBM', 'Phenotype', 'HP:0012174', (173, 176))
192697	33692846	Results revealed that Rap2B was highly expressed in human glioma compared with that in adjacent normal tissues and normal human astrocytes, and that silenced Rap2B led to a reduction of cell proliferation and migration ability in glioma cells.	('human', 'Species', '9606', (122, 127))	('reduction', 'NegReg', (173, 182))	('Rap2B', 'Gene', (22, 27))	('migration ability', 'CPA', (209, 226))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('human', 'Species', '9606', (52, 57))	('Rap2B', 'Gene', '5912', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('Rap2B', 'Gene', '5912', (158, 163))	('cell proliferation', 'CPA', (186, 204))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('silenced', 'Var', (149, 157))	('Rap2B', 'Gene', (158, 163))	('glioma', 'Disease', (58, 64))	('glioma', 'Disease', (230, 236))
192701	33692846	Furthermore, silencing the ERK pathway by SCH772984 led to the inhibition of Rap2B-mediated proliferation, migration and the reduction of MMP2 and MMP9 expression.	('reduction', 'NegReg', (125, 134))	('MMP9', 'Gene', (147, 151))	('migration', 'CPA', (107, 116))	('SCH772984', 'Chemical', 'MESH:C587178', (42, 51))	('Rap2B', 'Gene', '5912', (77, 82))	('MMP2', 'Gene', (138, 142))	('SCH772984', 'Var', (42, 51))	('Rap2B', 'Gene', (77, 82))	('ERK', 'Gene', '5594', (27, 30))	('silencing', 'NegReg', (13, 22))	('expression', 'MPA', (152, 162))	('inhibition', 'NegReg', (63, 73))	('MMP2', 'Gene', '4313', (138, 142))	('ERK', 'Gene', (27, 30))	('MMP9', 'Gene', '4318', (147, 151))
192730	33692846	The following sequences were used to knockdown Rap2B: siRNA, 5'-CGACCAUCGAAGACUUUUATT-3' (Sense) and 5'-UAAAAGUCUUCGAUGGUCGTT-3' (antisense).	('Rap2B', 'Gene', (47, 52))	('Rap2B', 'Gene', '5912', (47, 52))	('knockdown', 'Var', (37, 46))
192731	33692846	Glioma cells were transfected with 50 nM si-Rap2B or 50 nM si-NC until cell density reached ~50% confluence by riboFECT CP reagent (Guangzhou RiboBio Co., Ltd.) based on the manufacturer's indication.	('si-Rap2B', 'Gene', '5912', (41, 49))	('si-NC', 'Var', (59, 64))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('si-Rap2B', 'Gene', (41, 49))
192739	33692846	After transfection, 2x104 glioma cells were placed into the upper chambers with serum-free medium, and 500 microl of DMEM (HyClone; Cytiva) containing 20% FBS (HyClone; Cytiva) was added to the lower chambers.	('transfection', 'Var', (6, 18))	('DMEM', 'Chemical', '-', (117, 121))	('glioma', 'Disease', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
192771	33692846	Relative to the respective NC group, mRNA and protein expression of Rap2B in both U87 and U251 cells was decreased in the silenced Rap2B group (Fig.	('Rap2B', 'Gene', (131, 136))	('silenced', 'Var', (122, 130))	('U251', 'CellLine', 'CVCL:0021', (90, 94))	('Rap2B', 'Gene', '5912', (68, 73))	('Rap2B', 'Gene', (68, 73))	('U87', 'Gene', (82, 85))	('U87', 'Gene', '641648', (82, 85))	('decreased', 'NegReg', (105, 114))	('Rap2B', 'Gene', '5912', (131, 136))
192779	33692846	The inhibitor SCH772984 weakened this promotive effect of proliferation elicited by overexpressed Rap2B in both U87 and U251 cells (P<0.05; Fig.	('U251', 'CellLine', 'CVCL:0021', (120, 124))	('proliferation', 'CPA', (58, 71))	('SCH772984', 'Var', (14, 23))	('Rap2B', 'Gene', '5912', (98, 103))	('Rap2B', 'Gene', (98, 103))	('U87', 'Gene', (112, 115))	('weakened', 'NegReg', (24, 32))	('overexpressed', 'PosReg', (84, 97))	('SCH772984', 'Chemical', 'MESH:C587178', (14, 23))	('U87', 'Gene', '641648', (112, 115))
192781	33692846	The aforementioned results demonstrated that the alterations of Rap2B were closely associated with the proliferation of glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('alterations', 'Var', (49, 60))	('proliferation', 'CPA', (103, 116))	('Rap2B', 'Gene', '5912', (64, 69))	('associated', 'Reg', (83, 93))	('glioma', 'Disease', (120, 126))	('Rap2B', 'Gene', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
192796	33692846	However, SCH772984 (an ERK pathway inhibitor) reversed the promotion in the phosphorylation of ERK mediated by Rap2B-overexpression in U87 and U251 cells (P<0.05).	('SCH772984', 'Chemical', 'MESH:C587178', (9, 18))	('Rap2B', 'Gene', (111, 116))	('Rap2B', 'Gene', '5912', (111, 116))	('ERK', 'Gene', '5594', (95, 98))	('U87', 'Gene', (135, 138))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'Gene', (95, 98))	('ERK', 'Gene', (23, 26))	('phosphorylation', 'MPA', (76, 91))	('U87', 'Gene', '641648', (135, 138))	('SCH772984', 'Var', (9, 18))	('U251', 'CellLine', 'CVCL:0021', (143, 147))	('promotion', 'PosReg', (59, 68))
192800	33692846	2B-D and 3B, it was observed that SCH772984 significantly weakened Rap2B-induced promotion of proliferation and migration of glioma cells (P<0.05), indicating that ERK signaling was required for proliferation and migration induced by Rap2B.	('glioma', 'Disease', (125, 131))	('SCH772984', 'Var', (34, 43))	('Rap2B', 'Gene', (67, 72))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('Rap2B', 'Gene', '5912', (67, 72))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('Rap2B', 'Gene', (234, 239))	('ERK', 'Gene', '5594', (164, 167))	('proliferation', 'CPA', (94, 107))	('Rap2B', 'Gene', '5912', (234, 239))	('weakened', 'NegReg', (58, 66))	('SCH772984', 'Chemical', 'MESH:C587178', (34, 43))	('promotion', 'PosReg', (81, 90))	('ERK', 'Gene', (164, 167))
192801	33692846	Moreover, the results of the ELISA assays and western blotting showed that MMP2 and MMP9 expression was significantly reduced following co-treatment with Rap2B and SCH772984 compared with that in the overexpressed Rap2B group (all P<0.05, P<0.01 or P<0.001; Fig.	('MMP2', 'Gene', (75, 79))	('expression', 'MPA', (89, 99))	('SCH772984', 'Var', (164, 173))	('Rap2B', 'Gene', '5912', (214, 219))	('Rap2B', 'Gene', (214, 219))	('reduced', 'NegReg', (118, 125))	('Rap2B', 'Gene', '5912', (154, 159))	('MMP2', 'Gene', '4313', (75, 79))	('Rap2B', 'Gene', (154, 159))	('SCH772984', 'Chemical', 'MESH:C587178', (164, 173))	('MMP9', 'Gene', '4318', (84, 88))	('MMP9', 'Gene', (84, 88))
192802	33692846	Hence, inhibition of ERK pathway using SCH772984 treatment could restrain Rap2B-mediated production of MMP2 and MMP9 (Fig.	('restrain', 'NegReg', (65, 73))	('Rap2B', 'Gene', '5912', (74, 79))	('Rap2B', 'Gene', (74, 79))	('MMP2', 'Gene', (103, 107))	('SCH772984', 'Chemical', 'MESH:C587178', (39, 48))	('MMP2', 'Gene', '4313', (103, 107))	('MMP9', 'Gene', (112, 116))	('ERK', 'Gene', '5594', (21, 24))	('SCH772984', 'Var', (39, 48))	('MMP9', 'Gene', '4318', (112, 116))	('inhibition', 'NegReg', (7, 17))	('ERK', 'Gene', (21, 24))
192804	33692846	As Rap2B expression promoted the proliferation and migration of glioma cells, the association between Rap2B expression and clinical features in GBM and LGG was further analyzed using TCGA database.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('expression', 'Var', (9, 19))	('migration', 'CPA', (51, 60))	('Rap2B', 'Gene', (102, 107))	('Rap2B', 'Gene', '5912', (102, 107))	('promoted', 'PosReg', (20, 28))	('proliferation', 'CPA', (33, 46))	('glioma', 'Disease', (64, 70))	('Rap2B', 'Gene', (3, 8))	('Rap2B', 'Gene', '5912', (3, 8))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
192807	33692846	Kaplan-Meier survival analysis indicated that patients with GBM with high expression of Rap2B showed a shorter survival time compared with those in the low expression group, but there was no significant difference between two groups (Fig.	('patients', 'Species', '9606', (46, 54))	('Rap2B', 'Gene', '5912', (88, 93))	('Rap2B', 'Gene', (88, 93))	('shorter', 'NegReg', (103, 110))	('high expression', 'Var', (69, 84))	('survival time', 'CPA', (111, 124))
192810	33692846	Moreover, high expression of Rap2B was found to be associated with poor prognosis of patients with tumor grade 3 (Fig.	('tumor', 'Disease', (99, 104))	('Rap2B', 'Gene', '5912', (29, 34))	('Rap2B', 'Gene', (29, 34))	('associated', 'Reg', (51, 61))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('high', 'Var', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
192814	33692846	A previous study reported that mutations or overexpression of Ras genes are implicated in tumorigenesis and predicted poor prognostic survival in numerous types of tumors, such as thyroid, lung and colorectal cancer.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', (90, 95))	('overexpression', 'PosReg', (44, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (198, 215))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('colorectal cancer', 'Disease', (198, 215))	('mutations', 'Var', (31, 40))	('tumors', 'Disease', (164, 170))	('lung', 'Disease', (189, 193))	('thyroid', 'Disease', (180, 187))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Ras genes', 'Gene', (62, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (198, 215))	('implicated', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
192824	33692846	Consistent with the results of aforementioned studies, the present study demonstrated that Rap2B enhanced the proliferation and migration of U87 and U251 cells, whereas silencing Rap2B restrained this effect, further indicating the biological function of Rap2B.	('restrained', 'NegReg', (185, 195))	('U87', 'Gene', '641648', (141, 144))	('Rap2B', 'Gene', '5912', (91, 96))	('silencing', 'Var', (169, 178))	('migration', 'CPA', (128, 137))	('Rap2B', 'Gene', (91, 96))	('U251', 'CellLine', 'CVCL:0021', (149, 153))	('proliferation', 'CPA', (110, 123))	('enhanced', 'PosReg', (97, 105))	('Rap2B', 'Gene', (179, 184))	('Rap2B', 'Gene', '5912', (179, 184))	('Rap2B', 'Gene', (255, 260))	('U87', 'Gene', (141, 144))	('Rap2B', 'Gene', '5912', (255, 260))
192829	33692846	A recent study showed that Rap2B silencing inhibits the development of hepatocellular carcinoma via inhibition of the PTEN/PI3K/Akt and ERK pathways.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Akt', 'Gene', (128, 131))	('silencing', 'Var', (33, 42))	('PTEN', 'Gene', '5728', (118, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('ERK', 'Gene', '5594', (136, 139))	('PTEN', 'Gene', (118, 122))	('hepatocellular carcinoma', 'Disease', (71, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('Rap2B', 'Gene', '5912', (27, 32))	('Akt', 'Gene', '207', (128, 131))	('ERK', 'Gene', (136, 139))	('Rap2B', 'Gene', (27, 32))	('inhibits', 'NegReg', (43, 51))	('inhibition', 'NegReg', (100, 110))
192833	33692846	MMP2 and MMP9 drive cell motility and tumor growth by digesting the ECM, basal lamina and adhesion proteins.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('MMP2', 'Gene', (0, 4))	('cell motility', 'CPA', (20, 33))	('MMP9', 'Gene', (9, 13))	('drive', 'PosReg', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('MMP2', 'Gene', '4313', (0, 4))	('digesting', 'Var', (54, 63))	('MMP9', 'Gene', '4318', (9, 13))
192837	33692846	Kaplan-Meier analysis showed that high expression of Rap2B was associated with overall survival time of patients with LGG, indicating a risk factor in LGG.	('Rap2B', 'Gene', '5912', (53, 58))	('high expression', 'Var', (34, 49))	('Rap2B', 'Gene', (53, 58))	('associated', 'Reg', (63, 73))	('LGG', 'Disease', (118, 121))	('patients', 'Species', '9606', (104, 112))
192935	30271043	In our study, we observed that high-grade astrocytomas were associated with subtotal and partial resections yielding poor OS rates, while low-grade astrocytomas were associated with total resection and better survival rates, in concordance with the literature.	('astrocytomas', 'Disease', 'MESH:D001254', (42, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (42, 53))	('astrocytomas', 'Disease', (42, 54))	('partial resections', 'CPA', (89, 107))	('astrocytomas', 'Disease', 'MESH:D001254', (148, 160))	('subtotal', 'Var', (76, 84))	('OS', 'Chemical', '-', (122, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (148, 159))	('astrocytomas', 'Disease', (148, 160))
192948	24029126	Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion.	('pure', 'Disease', (164, 168))	('anaplastic oligodendroglioma', 'Disease', (178, 206))	('1p/19q codeletion', 'Var', (221, 238))	('patients', 'Species', '9606', (150, 158))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (178, 206))
193011	24029126	In a randomized trial conducted by the EORTC in patients with low-grade astrocytomas, no survival difference was observed when 45.0 Gy was compared with 59.4 Gy.	('45.0 Gy', 'Var', (127, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('astrocytomas', 'Disease', 'MESH:D001254', (72, 84))	('patients', 'Species', '9606', (48, 56))	('astrocytomas', 'Disease', (72, 84))
193020	24029126	Patients with low-grade oligodendrogliomas, especially those with 1p/19q deletions, may represent favorable candidates for chemotherapy in light of good response rates reported in literature; however, this has never been prospectively determined.	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (24, 42))	('1p/19q deletions', 'Var', (66, 82))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('oligodendrogliomas', 'Disease', (24, 42))
193022	24029126	If the tumor is found to have components of oligodendroglioma, 1p/19q deletion testing should be considered because it is a favorable prognostic factor.	('1p/19q deletion testing', 'Var', (63, 86))	('oligodendroglioma', 'Disease', 'MESH:D009837', (44, 61))	('tumor', 'Disease', (7, 12))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('oligodendroglioma', 'Disease', (44, 61))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
193025	24029126	Mutations in the IDH genes are common and are reported to be a significant marker of positive prognosis.	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', '3417', (17, 20))	('IDH', 'Gene', (17, 20))
193027	24029126	The following are considered low-risk features for low-grade gliomas: age of 40 years or younger; Karnofsky performance status (KPS) of 70 or greater; minor or no neurologic deficit; oligodendroglioma or mixed oligoastrocytoma; tumor dimension less than 6 cm; 1p and 19q codeletion; and IDH1 or IDH2 mutation.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('IDH1', 'Gene', (287, 291))	('neurologic deficit', 'Phenotype', 'HP:0000707', (163, 181))	('gliomas', 'Disease', (61, 68))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (210, 226))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('IDH1', 'Gene', '3417', (287, 291))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('oligodendroglioma', 'Disease', 'MESH:D009837', (183, 200))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('neurologic deficit', 'Disease', 'MESH:D009461', (163, 181))	('oligoastrocytoma', 'Disease', (210, 226))	('oligodendroglioma', 'Disease', (183, 200))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('neurologic deficit', 'Disease', (163, 181))	('IDH2', 'Gene', (295, 299))	('mutation', 'Var', (300, 308))	('IDH2', 'Gene', '3418', (295, 299))	('tumor', 'Disease', (228, 233))
193028	24029126	Patients are categorized as being high risk if they have 3 or more of the following: age older than 40 years, KPS less than 70, tumor larger than 6 cm, tumor crossing midline, or preoperative neurologic deficit of more than minor degree.	('neurologic deficit', 'Disease', (192, 210))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('neurologic deficit', 'Phenotype', 'HP:0000707', (192, 210))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Patients', 'Species', '9606', (0, 8))	('KPS less than 70', 'Var', (110, 126))	('tumor', 'Disease', (128, 133))	('neurologic deficit', 'Disease', 'MESH:D009461', (192, 210))
193029	24029126	Other adverse factors to consider include increased perfusion on imaging; one or no deletion on 1p and 19q; and wild-type IDH1 or IDH2.	('increased', 'PosReg', (42, 51))	('deletion', 'Var', (84, 92))	('IDH2', 'Gene', (130, 134))	('IDH1', 'Gene', (122, 126))	('IDH2', 'Gene', '3418', (130, 134))	('IDH1', 'Gene', '3417', (122, 126))	('perfusion', 'MPA', (52, 61))
193054	24029126	Retrospective analyses also suggest that gross total resection lengthens survival and is especially effective in patients with good PS.	('patients', 'Species', '9606', (113, 121))	('survival', 'MPA', (73, 81))	('gross', 'Var', (41, 46))	('lengthens', 'PosReg', (63, 72))
193067	24029126	In particular, combined chemoradiation has emerged as a new standard of care for patients with 1p/19q codeleted anaplastic oligodendroglioma or oligoastrocytoma and good PS nonelderly glioblastoma.	('oligodendroglioma or oligoastrocytoma', 'Disease', (123, 160))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (184, 196))	('patients', 'Species', '9606', (81, 89))	('anaplastic oligodendroglioma', 'Disease', (112, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('oligodendroglioma or oligoastrocytoma', 'Disease', 'MESH:D001254', (123, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (184, 196))	('1p/19q codeleted', 'Var', (95, 111))	('glioblastoma', 'Disease', (184, 196))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (112, 140))
193107	24029126	Improved survival observed in 2 randomized clinical trials established combined PCV chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion.	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (172, 200))	('1p/19q codeletion', 'Var', (215, 232))	('patients', 'Species', '9606', (144, 152))	('anaplastic oligodendroglioma', 'Disease', (172, 200))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('pure', 'Disease', (158, 162))
193112	24029126	Median survival was not reached in patients with codeleted tumors who received PCV/RT compared with 112 months for those in the RT group.	('PCV/RT', 'Var', (79, 85))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
193134	24029126	For patients with 1p/19q codeleted anaplastic oligodendroglioma or oligoastrocytoma, fractionated EBRT plus PCV given before or after RT is a category 1 recommendation.	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (35, 63))	('oligodendroglioma or oligoastrocytoma', 'Disease', 'MESH:D001254', (46, 83))	('EBRT', 'Chemical', '-', (98, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('1p/19q', 'Var', (18, 24))	('anaplastic oligodendroglioma', 'Disease', (35, 63))	('patients', 'Species', '9606', (4, 12))	('oligodendroglioma or oligoastrocytoma', 'Disease', (46, 83))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
193262	24029126	In patients with systemic cancers and druggable targets (eg, epidermal growth factor receptor mutations in non-small cell lung cancer and BRAF mutations in metastatic melanoma), targeted therapy in neurologically asymptomatic patients with brain metastases is considered reasonable before administration of RT.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('non-small cell lung cancer', 'Disease', (107, 133))	('brain metastases', 'Disease', 'MESH:D009362', (240, 256))	('brain metastases', 'Disease', (240, 256))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('systemic cancers', 'Disease', (17, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('systemic cancers', 'Disease', 'MESH:D009369', (17, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('patients', 'Species', '9606', (226, 234))	('mutations', 'Var', (143, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('epidermal growth factor receptor', 'Gene', (61, 93))	('mutations', 'Var', (94, 103))	('epidermal growth factor receptor', 'Gene', '1956', (61, 93))	('patients', 'Species', '9606', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))
193280	24029126	Palliative neurosurgery should be considered if a lesion is causing a life-threatening mass effect, hemorrhage, or hydrocephalus.	('hydrocephalus', 'Phenotype', 'HP:0000238', (115, 128))	('hemorrhage', 'Disease', (100, 110))	('hemorrhage', 'Disease', 'MESH:D006470', (100, 110))	('mass effect', 'Disease', (87, 98))	('hydrocephalus', 'Disease', 'MESH:D006849', (115, 128))	('lesion', 'Var', (50, 56))	('hydrocephalus', 'Disease', (115, 128))
193320	24571613	Panel 1 consists of five lung cancer cDNA arrays (HLRT101, HLRT102, HLRT103, HLRT104, and HLRT105) purchased from OriGene Technologies (Rockville, MD).	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('HLRT103', 'Var', (68, 75))	('HLRT104', 'Var', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
193327	24571613	The reference genes ACTB (Hs99999903_m1), GAPDH (Hs99999905_m1) and GUSB (AssyID: Hs99999908_m1) were purchased from Life Technologies.	('GAPDH', 'Gene', '2597', (42, 47))	('Hs99999903_m1', 'Var', (26, 39))	('GAPDH', 'Gene', (42, 47))	('GUSB', 'Gene', '2990', (68, 72))	('ACTB', 'Gene', (20, 24))	('ACTB', 'Gene', '60', (20, 24))	('Hs99999905_m1', 'Var', (49, 62))	('GUSB', 'Gene', (68, 72))
193404	23888189	FOXP3 silencing in one GB-NS expressing measurable levels of the gene caused a significant increase in proliferation and migration as well as highly aggressive growth in xenografts.	('rat', 'Species', '10116', (124, 127))	('rat', 'Species', '10116', (110, 113))	('migration', 'CPA', (121, 130))	('proliferation', 'CPA', (103, 116))	('GB', 'Phenotype', 'HP:0012174', (23, 25))	('increase', 'PosReg', (91, 99))	('GB-NS', 'Chemical', '-', (23, 28))	('highly aggressive growth in xenografts', 'CPA', (142, 180))	('silencing', 'Var', (6, 15))	('FOXP3', 'Gene', (0, 5))
193418	23888189	The identification of mutations of isocytrate dehydrogenase 1 (IDH1) has been particularly relevant, contributing to novel efforts aimed at therapeutic targeting of the GB genome.	('IDH1', 'Gene', '3417', (63, 67))	('GB', 'Phenotype', 'HP:0012174', (169, 171))	('rat', 'Species', '10116', (41, 44))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', (63, 67))
193419	23888189	Another example is provided by the identification of increased copy number of TACC3, an Aurora-A kinase substrate: we have recently collaborated to the identification of a fusion protein of TACC3 with fibroblast growth factor receptor with constitutive kinase activity, triggering aneuploidy in GB cells.	('TACC3', 'Gene', (78, 83))	('triggering', 'Reg', (270, 280))	('fusion', 'Var', (172, 178))	('rat', 'Species', '10116', (139, 142))	('TACC3', 'Gene', '10460', (190, 195))	('rat', 'Species', '10116', (109, 112))	('TACC3', 'Gene', '10460', (78, 83))	('TACC3', 'Gene', (190, 195))	('GB', 'Phenotype', 'HP:0012174', (295, 297))	('aneuploidy', 'CPA', (281, 291))
193421	23888189	In the initial experiments shown in Figure S1, we found Foxp3+ cells in murine malignant gliomas derived from the GL261 cells.	('Foxp3+', 'Var', (56, 62))	('malignant gliomas', 'Disease', (79, 96))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('malignant gliomas', 'Disease', 'MESH:D005910', (79, 96))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('GL261', 'CellLine', 'CVCL:Y003', (114, 119))	('murine', 'Species', '10090', (72, 78))
193427	23888189	FOXP3+ tumor cells were identified by GFAP expression and negativity for the CD3 marker (Figure 1B central and right panel).	('CD3', 'Gene', '12501', (77, 80))	('tumor', 'Disease', (7, 12))	('GFAP expression', 'Protein', (38, 53))	('negativity', 'Var', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('CD3', 'Gene', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
193429	23888189	GB may or may not give rise to NS (GB-NS-Yes and GB-NS-No, respectively): 58% of these tumors (34/59) were GB-NS-Yes and had lower FOXP3 expression compared to GB-NS-No (mean +- SD: 0.3 +- 0.3 vs. 0.6 +- 0.5, respectively, P = 0.03).	('GB-NS-No', 'Chemical', '-', (49, 57))	('GB-NS-Yes', 'Chemical', '-', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('expression', 'MPA', (137, 147))	('GB', 'Phenotype', 'HP:0012174', (0, 2))	('GB', 'Phenotype', 'HP:0012174', (107, 109))	('GB', 'Phenotype', 'HP:0012174', (49, 51))	('GB-NS-No', 'Chemical', '-', (160, 168))	('GB', 'Phenotype', 'HP:0012174', (35, 37))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('FOXP3', 'Protein', (131, 136))	('lower', 'NegReg', (125, 130))	('GB-NS-Yes', 'Chemical', '-', (107, 116))	('tumors', 'Disease', (87, 93))	('GB', 'Phenotype', 'HP:0012174', (160, 162))	('GB-NS-Yes', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
193430	23888189	The overall survival (OS) of patients with GB-NS-Yes and lower FOXP3 expression was significantly shorter than the OS of patients with GB-NS-No and higher FOXP3 expression (P = 0.03 by Kaplan Meier analysis; Figure 1D).	('FOXP3', 'Gene', (63, 68))	('patients', 'Species', '9606', (29, 37))	('GB-NS-Yes', 'Var', (43, 52))	('GB-NS-Yes', 'Chemical', '-', (43, 52))	('GB-NS-No', 'Chemical', '-', (135, 143))	('expression', 'MPA', (69, 79))	('GB', 'Phenotype', 'HP:0012174', (135, 137))	('GB', 'Phenotype', 'HP:0012174', (43, 45))	('overall survival', 'MPA', (4, 20))	('patients', 'Species', '9606', (121, 129))	('shorter', 'NegReg', (98, 105))	('lower', 'NegReg', (57, 62))
193434	23888189	An analysis with the microarray GSE4290 dataset of two probe sets corresponding to the FOXP3 gene (221334_s _at and 224211_s_at) confirmed that the expression of FOXP3 is significantly down-regulated in 73 glioblastomas compared to 15 normal brains (P = 0.003 for 221334_s _at; P = 0.008 for 224211_s_at; Figure 2A).	('FOXP3', 'Gene', (87, 92))	('down-regulated', 'NegReg', (185, 199))	('FOXP3', 'Gene', (162, 167))	('GSE4290', 'Chemical', '-', (32, 39))	('221334_s _at', 'Var', (99, 111))	('glioblastomas', 'Phenotype', 'HP:0012174', (206, 219))	('expression', 'MPA', (148, 158))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('glioblastomas', 'Disease', 'MESH:D005909', (206, 219))	('glioblastomas', 'Disease', (206, 219))	('221334_s _at', 'Var', (264, 276))
193443	23888189	Over-expression of FOXP3 b but not a was associated with a significant reduction of migration compared to the empty vector (P = 0.003) (Figure 3F and Figure S3B, respectively).	('reduction', 'NegReg', (71, 80))	('migration', 'CPA', (84, 93))	('FOXP3 b', 'Gene', (19, 26))	('Over-expression', 'Var', (0, 15))	('rat', 'Species', '10116', (87, 90))
193446	23888189	The effects of FOXP3 inhibition on proliferation and migration were then evaluated in shFOXP3-NS and in scrambled-NS as the control (Figure 4B, upper panel).	('rat', 'Species', '10116', (56, 59))	('rat', 'Species', '10116', (42, 45))	('migration', 'CPA', (53, 62))	('FOXP3', 'Gene', (15, 20))	('inhibition', 'NegReg', (21, 31))	('shFOXP3-NS', 'Var', (86, 96))
193447	23888189	Proliferation assays performed at 24 h, 48 h and 72 h showed that shFOXP3-NS proliferate significantly more than scrambled-NS (24 h P <0.01; 48 h P =0.02, 72 h P = 0.04).	('rat', 'Species', '10116', (84, 87))	('more', 'PosReg', (103, 107))	('proliferate', 'CPA', (77, 88))	('rat', 'Species', '10116', (7, 10))	('shFOXP3-NS', 'Var', (66, 76))
193448	23888189	shFOXP3-NS also had a significantly higher migration capacity compared to scrambled cells (2.8 fold vs. scrambled cells, P = 0.003; Figure 4B, lower panel).	('migration capacity', 'CPA', (43, 61))	('higher', 'PosReg', (36, 42))	('rat', 'Species', '10116', (46, 49))	('shFOXP3-NS', 'Var', (0, 10))
193449	23888189	In vivo, we found that mice injected with shFOXP3-NS survived significantly less than mice injected with scrambled-NS (mean +- SD: 41.6 +- 1.1 vs. 65.6 +- 2.2 days, P = 0.002; Figure 4C).	('less', 'NegReg', (76, 80))	('survived', 'CPA', (53, 61))	('mice', 'Species', '10090', (86, 90))	('shFOXP3-NS', 'Var', (42, 52))	('mice', 'Species', '10090', (23, 27))
193460	23888189	We found a significant reduction of p21 and an increase of c-MYC expression in shFOXP3 cells (P < 0.001 and P < 0.0001 compared to scrambled cells, respectively; Figure 5B).	('c-MYC', 'Gene', (59, 64))	('c-MYC', 'Gene', '4609', (59, 64))	('p21', 'Gene', '1026', (36, 39))	('reduction', 'NegReg', (23, 32))	('p21', 'Gene', (36, 39))	('increase', 'PosReg', (47, 55))	('shFOXP3', 'Var', (79, 86))
193478	23888189	This scenario and our results, in particular the presence of periventricular FOXP3/GFAP+ cells in normal fetal brains, support the hypothesis that during astrocytic development, and possibly during astrocytic proliferation in reactive gliosis, FOXP3 orchestrates the induction of astroglial terminal differentiation by preventing c-myc activation and proliferation in glial cell precursors.	('rat', 'Species', '10116', (358, 361))	('gliosis', 'Disease', (235, 242))	('proliferation', 'CPA', (351, 364))	('glial cell precursors', 'CPA', (368, 389))	('FOXP3', 'Var', (244, 249))	('c-myc', 'Gene', '4609', (330, 335))	('rat', 'Species', '10116', (257, 260))	('gliosis', 'Phenotype', 'HP:0002171', (235, 242))	('c-myc', 'Gene', (330, 335))	('preventing', 'NegReg', (319, 329))	('gliosis', 'Disease', 'MESH:D005911', (235, 242))	('activation', 'PosReg', (336, 346))	('rat', 'Species', '10116', (216, 219))
193489	23888189	Beta-2-microglobulin (Hs99999907_m1, Applied Biosystems) was chosen as the reference gene, and commercial RNA from a normal human brain (Life Technologies) was used as the calibrator for the calculation of fold expression levels with the DeltaDeltaCt method.	('Hs99999907_m1', 'Var', (22, 35))	('rat', 'Species', '10116', (177, 180))	('Beta-2-microglobulin', 'Gene', '567', (0, 20))	('human', 'Species', '9606', (124, 129))	('Beta-2-microglobulin', 'Gene', (0, 20))
193491	23888189	Membranes with transferred proteins were incubated with a primary antibody; either anti-FOXP3 antibody (1:250; eBioscience, Science Center Drive, San Diego, USA) or anti-alpha-tubulin antibody (1:5000).	('alpha-tubulin', 'Gene', '10376', (170, 183))	('alpha-tubulin', 'Gene', (170, 183))	('anti-FOXP3', 'Var', (83, 93))
193492	23888189	The primary antibody interaction was followed by incubation with peroxidase conjugated to the secondary antibody [anti-rat (1:10000), anti-mouse (1:10000) or anti-rabbit (1:10000)].	('rabbit', 'Species', '9986', (163, 169))	('anti-mouse (1:10000', 'Var', (134, 153))	('rat', 'Species', '10116', (119, 122))	('mouse', 'Species', '10090', (139, 144))	('1:10000', 'Var', (146, 153))	('1:10000', 'Var', (124, 131))
193530	33086616	ESCRT-III, the most ancient and preserved of the ESCRTs, consists of a core complex that contains the subunits Vps20, Vps32, Vps24, and Vps2, assembled in a highly ordered manner.	('Vps2', 'Gene', '27243', (136, 140))	('Vps2', 'Gene', (111, 115))	('Vps2', 'Gene', (125, 129))	('Vps24', 'Gene', (125, 130))	('Vps32', 'Var', (118, 123))	('Vps2', 'Gene', '27243', (111, 115))	('Vps2', 'Gene', '27243', (125, 129))	('Vps20', 'Gene', (111, 116))	('Vps2', 'Gene', (136, 140))	('Vps20', 'Gene', '79643', (111, 116))	('Vps24', 'Gene', '51652', (125, 130))
193533	33086616	Conversely, a recent study of mammalian cells showed, through the depletion of all four ESCRT key subunits, that, despite a dramatic alteration in the morphology of cellular components, early and late endosomes remain unaffected.	('ESCRT', 'Gene', (88, 93))	('rat', 'Species', '10116', (137, 140))	('alteration', 'Reg', (133, 143))	('depletion', 'Var', (66, 75))	('mammalian', 'Species', '9606', (30, 39))
193560	33086616	PEG chains can form reticular structures that allow the entrapping of proteins, aggregates, and impurities in the holes of MNP.	('PEG chains', 'Var', (0, 10))	('proteins', 'Protein', (70, 78))	('entrapping', 'MPA', (56, 66))	('PEG', 'Chemical', 'MESH:D011092', (0, 3))	('aggregates', 'MPA', (80, 90))
193611	33086616	For example, microglia-derived EVs can alleviate acute inflammatory responses by converting immature IL-1b into a biologically active molecule; regulate the excitation inhibition balance via the endocannabinoids content; and reduce the levels of amyloid-beta, a neurotoxic peptide linked to Alzheimer's disease.	('converting', 'Reg', (81, 91))	('endocannabinoids', 'Chemical', 'MESH:D063388', (195, 211))	('reduce', 'NegReg', (225, 231))	('amyloid-beta', 'Gene', (246, 258))	('amyloid-beta', 'Gene', '351', (246, 258))	('immature', 'Var', (92, 100))	('neurotoxic', 'Disease', 'MESH:D020258', (262, 272))	('alleviate', 'PosReg', (39, 48))	('excitation inhibition balance', 'MPA', (157, 186))	('regulate', 'Reg', (144, 152))	('IL-1b', 'Gene', (101, 106))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (291, 310))	('endocannabinoids content', 'MPA', (195, 219))	('neurotoxic', 'Disease', (262, 272))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (291, 310))	('acute inflammatory responses', 'MPA', (49, 77))	('IL-1b', 'Gene', '3553', (101, 106))	("Alzheimer's disease", 'Disease', (291, 310))
193614	33086616	The phosphatidylserine enrichment of oligodendrocyte-derived exosomes activated pinocytosis in a subset of microglia macrophages without antigen-presenting capability.	('phosphatidylserine', 'Var', (4, 22))	('activated', 'PosReg', (70, 79))	('pinocytosis', 'MPA', (80, 91))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (4, 22))
193660	33086616	However, the modulation of CLIC1 protein expression in GBM cells induces phenotypic changes only on molecular cargo, since no relevant modification was observed on the EV secretion or uptake mechanism.	('expression', 'Species', '29278', (41, 51))	('CLIC1', 'Gene', '1192', (27, 32))	('modulation', 'Var', (13, 23))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('CLIC1', 'Gene', (27, 32))	('protein', 'Protein', (33, 40))
193670	33086616	showed that EGFRvIII overexpression increased the polymerase I and transcript release factor (PTRF) expression.	('transcript', 'MPA', (67, 77))	('expression', 'Species', '29278', (25, 35))	('overexpression', 'Var', (21, 35))	('expression', 'Species', '29278', (100, 110))	('expression', 'MPA', (100, 110))	('polymerase I', 'Enzyme', (50, 62))	('increased', 'PosReg', (36, 45))	('EGFR', 'Gene', '1956', (12, 16))	('PTRF', 'Gene', (94, 98))	('EGFR', 'Gene', (12, 16))	('polymer', 'Chemical', 'MESH:D011108', (50, 57))	('PTRF', 'Gene', '284119', (94, 98))
193682	33086616	miRNA-584 acts as a tumor suppressor in some cancers and inhibits specifically glioma cells activity by binding to the 3'-UTR of CYP2J2.	('CYP2J2', 'Gene', (129, 135))	('glioma', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('miRNA-584', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('binding', 'Interaction', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('miRNA-584', 'Chemical', '-', (0, 9))	('CYP2J2', 'Gene', '1573', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancers', 'Disease', (45, 52))	('U', 'Chemical', 'MESH:D014501', (122, 123))	('inhibits', 'NegReg', (57, 65))	('tumor', 'Disease', (20, 25))
193683	33086616	Interestingly, they demonstrated that MSCs exosomal miRNA-584 affects invasive ability of U-87 MG cells in vitro and decrease tumor mass weights in U87 MG xenograft nude mouse model.	('invasive ability of U-87 MG cells', 'CPA', (70, 103))	('miRNA-584', 'Chemical', '-', (52, 61))	('U', 'Chemical', 'MESH:D014501', (90, 91))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('U', 'Chemical', 'MESH:D014501', (148, 149))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('affects', 'Reg', (62, 69))	('mouse', 'Species', '10090', (170, 175))	('rat', 'Species', '10116', (27, 30))	('miRNA-584', 'Var', (52, 61))	('decrease', 'NegReg', (117, 125))	('U87 MG', 'CellLine', 'CVCL:0022', (148, 154))	('tumor', 'Disease', (126, 131))
193688	33086616	Finally, to determine if M146-Exo had an anti-tumor effect in vivo, they administered M146-exo or M67-exo to Fischer rats bearing 9L gliosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('gliosarcoma', 'Disease', (133, 144))	('tumor', 'Disease', (46, 51))	('M146-Exo', 'Var', (25, 33))	('M67-exo', 'Var', (98, 105))	('rats', 'Species', '10116', (117, 121))	('gliosarcoma', 'Disease', 'MESH:D018316', (133, 144))	('M146-exo', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
193689	33086616	One intra-tumor injection of M146-exo, 5 days after intracranial tumor xenograft implantation, led to a significant reduction in tumor volume at 10 days post-implant compared to control.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('intracranial tumor', 'Disease', (52, 70))	('intra-tumor', 'Disease', (4, 15))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('reduction', 'NegReg', (116, 125))	('intracranial tumor', 'Disease', 'MESH:D001932', (52, 70))	('intra-tumor', 'Disease', 'MESH:D009369', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('M146-exo', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
193697	33086616	Indeed, deregulation of microRNA expression has been observed in several cancers' progression mechanisms, including GBM.	('cancers', 'Disease', (73, 80))	('observed', 'Reg', (53, 61))	('microRNA', 'Protein', (24, 32))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('expression', 'Species', '29278', (33, 43))	('deregulation', 'Var', (8, 20))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('GBM', 'Disease', (116, 119))
193708	33086616	Reinforcing this point, they reported the use of both U-87 MG and bEND.3 exosomes to deliver paclitaxel (PTX) or doxorubicin (DXR) across the BBB in a zebrafish model of brain tumor employing U-87 MG glioma.	('MG glioma', 'Disease', (197, 206))	('U', 'Chemical', 'MESH:D014501', (192, 193))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PTX', 'Chemical', 'MESH:D017239', (105, 108))	('zebrafish', 'Species', '7955', (151, 160))	('U', 'Chemical', 'MESH:D014501', (54, 55))	('brain tumor', 'Phenotype', 'HP:0030692', (170, 181))	('doxorubicin', 'Chemical', 'MESH:D004317', (113, 124))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('U-87', 'Var', (192, 196))	('DXR', 'Chemical', 'MESH:D004317', (126, 129))	('doxorubicin', 'MPA', (113, 124))	('brain tumor', 'Disease', 'MESH:D001932', (170, 181))	('MG glioma', 'Disease', 'MESH:D000080343', (197, 206))	('brain tumor', 'Disease', (170, 181))
193715	33086616	Furthermore, ex vivo fluorescence studies of the brain performed after intravenous injections of DiR-labeled EVs or EVs-KLA-LDL confirmed that EVs-KLA-LDL crosses the BBB and penetrates the brain more efficiently than blank-EVs, which might be attributed to the interaction between the LDL peptide and the LDLR over-expressed at the BBB.	('DiR', 'Gene', (97, 100))	('rat', 'Species', '10116', (180, 183))	('DiR', 'Gene', '554', (97, 100))	('interaction', 'Interaction', (262, 273))	('LDLR', 'Gene', (306, 310))	('penetrates', 'CPA', (175, 185))	('KLA', 'Chemical', '-', (120, 123))	('EVs-KLA-LDL', 'Var', (143, 154))	('LDLR', 'Gene', '3949', (306, 310))	('KLA', 'Chemical', '-', (147, 150))
193809	31456678	In addition, in our cascaded segmentation framework, segmentation of whole tumor (tumor core) was used as a crisp mask for tumor core (enhancing tumor core), this may lead mis-segmentations in an early stage to cause mis-segmentations in a later stage.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (123, 128))	('lead', 'Reg', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mis-segmentations', 'Var', (172, 189))	('tumor', 'Disease', (82, 87))	('mis-segmentations', 'MPA', (217, 234))	('tumor', 'Disease', (75, 80))	('cause', 'Reg', (211, 216))
193813	31456678	Table 3 also shows that TTA reduces the standard deviation (improves the robustness) of the networks in most cases, especially for 3D UNet.	('improves', 'PosReg', (60, 68))	('TTA', 'Chemical', '-', (24, 27))	('reduces', 'NegReg', (28, 35))	('TTA', 'Var', (24, 27))	('standard deviation', 'MPA', (40, 58))	('robustness', 'MPA', (73, 83))
193826	30276676	Rmean, Rmax, VDmin, VDmax, and MVA were higher in grade-III than in grade-II LGGs (p < 0.05) in each type except the isocitrate dehydrogenase (IDH) mutant with 1p/19q-intact type.	('MVA', 'MPA', (31, 34))	('Rmean', 'MPA', (0, 5))	('isocitrate dehydrogenase', 'Gene', '3417', (117, 141))	('higher', 'PosReg', (40, 46))	('IDH', 'Gene', '3417', (143, 146))	('VDmin', 'MPA', (13, 18))	('mutant', 'Var', (148, 154))	('VDmax', 'MPA', (20, 25))	('isocitrate dehydrogenase', 'Gene', (117, 141))	('Rmax', 'MPA', (7, 11))	('IDH', 'Gene', (143, 146))
193827	30276676	For grade II, the IDH mutant with 1p/19q co-deleted and IDH wildtype possessed more dominant angiogenesis than IDH mutant with 1p/19q-intact type, revealed by lower Rmean, Rmax and VDmin while higher MVD for the former (p < 0.05), the same as oligodendroglioma versus astrocytoma.	('Rmax', 'MPA', (172, 176))	('1p/19q co-deleted', 'Var', (34, 51))	('IDH', 'Gene', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('higher', 'PosReg', (193, 199))	('IDH', 'Gene', (56, 59))	('VDmin', 'MPA', (181, 186))	('IDH', 'Gene', '3417', (18, 21))	('lower', 'NegReg', (159, 164))	('IDH', 'Gene', (111, 114))	('IDH', 'Gene', '3417', (56, 59))	('oligodendroglioma versus astrocytoma', 'Disease', 'MESH:D009837', (243, 279))	('astrocytoma', 'Phenotype', 'HP:0009592', (268, 279))	('MVD', 'MPA', (200, 203))	('angiogenesis', 'CPA', (93, 105))	('IDH', 'Gene', '3417', (111, 114))	('oligodendroglioma versus astrocytoma', 'Disease', (243, 279))	('Rmean', 'MPA', (165, 170))
193833	30276676	The classification of LGGs, based on the mutational status of isocitrate dehydrogenase (IDH) and deletion of the 1p/19q chromosome, could reflect the genetic information of subtypes and predict prognosis.	('isocitrate dehydrogenase', 'Gene', '3417', (62, 86))	('isocitrate dehydrogenase', 'Gene', (62, 86))	('IDH', 'Gene', (88, 91))	('LGGs', 'Disease', (22, 26))	('IDH', 'Gene', '3417', (88, 91))	('deletion', 'Var', (97, 105))
193836	30276676	The IDHMUT/1p/19q- type is sensitive to radiotherapy and chemotherapy for the 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (78, 96))	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (4, 7))
193838	30276676	Patients with IDH wildtype (IDHWT), which presents telomerase reverse transcriptase mutation and epidermal growth factor receptor amplification, experience poor prognosis with a median survival time of only 1.23 years.	('IDH', 'Gene', (14, 17))	('IDH', 'Gene', (28, 31))	('mutation', 'Var', (84, 92))	('IDH', 'Gene', '3417', (14, 17))	('IDH', 'Gene', '3417', (28, 31))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))	('epidermal growth factor receptor', 'Gene', (97, 129))	('Patients', 'Species', '9606', (0, 8))	('telomerase', 'MPA', (51, 61))
193844	30276676	The rCBV of the 1p/19q co-deleted type was higher than 1p/19q intact type in oligodendroglioma.	('oligodendroglioma', 'Disease', 'MESH:D009837', (77, 94))	('rCBV', 'MPA', (4, 8))	('higher', 'PosReg', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('rCBV', 'Chemical', '-', (4, 8))	('oligodendroglioma', 'Disease', (77, 94))	('1p/19q co-deleted', 'Var', (16, 33))
193864	30276676	IDH1 and IDH2 alterations of the mutational hot-spot codons R132 and R172 were determined via polymerase chain reaction.	('IDH2', 'Gene', (9, 13))	('IDH2', 'Gene', '3418', (9, 13))	('R172', 'Var', (69, 73))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
193870	30276676	There were 40 cases of IDH mutant (grade II/III, 28/12), 17 cases of IDH wildtype (grade II/III, 8/9), 25 cases of 1p/19q intact (grade II/III, 16/9) and 32 cases of 1p/19q co-deleted (grade II/III, 20/12).	('1p/19q intact', 'Var', (115, 128))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (69, 72))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (23, 26))
193908	30276676	The mutation of the IDH gene results in the conversion of alpha-ketoglutarate into 2-hydroxyglutaric acid, which inhibits tumour angiogenesis by inhibiting hypoxia inducible factor 1alpha.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('IDH', 'Gene', (20, 23))	('results in', 'Reg', (29, 39))	('IDH', 'Gene', '3417', (20, 23))	('2-hydroxyglutaric acid', 'Chemical', 'MESH:C019417', (83, 105))	('tumour', 'Disease', (122, 128))	('mutation', 'Var', (4, 12))	('conversion', 'MPA', (44, 54))	('hypoxia inducible factor 1alpha', 'Gene', '3091', (156, 187))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (58, 77))	('inhibiting', 'NegReg', (145, 155))	('hypoxia inducible factor 1alpha', 'Gene', (156, 187))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('inhibits', 'NegReg', (113, 121))
193910	30276676	IDH mutation affects an early event in gliomagenesis that may influence the early stage of angiogenesis.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (39, 45))	('IDH', 'Gene', '3417', (0, 3))	('affects', 'Reg', (13, 20))	('mutation', 'Var', (4, 12))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('influence', 'Reg', (62, 71))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
193912	30276676	The 1p/19q co-deletion in the IDHMUT/1p/19q- type was considered to be correlated with the "chicken-wire" vasculature.	('chicken', 'Species', '9031', (92, 99))	('IDH', 'Gene', '3417', (30, 33))	('IDH', 'Gene', (30, 33))	('1p/19q co-deletion', 'Var', (4, 22))
193918	30276676	The patients having telomerase reverse transcriptase mutation, epidermal growth factor receptor amplification which are similar to glioblastoma, experience poor prognosis.	('mutation', 'Var', (53, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('telomerase reverse', 'Gene', (20, 38))	('epidermal growth factor receptor', 'Gene', (63, 95))	('patients', 'Species', '9606', (4, 12))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
193922	30276676	When the genotype is IDH wildtype with 1p/19q co-deletion, the tumour is classified as "not otherwise specified".	('IDH', 'Gene', (21, 24))	('IDH', 'Gene', '3417', (21, 24))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('1p/19q co-deletion', 'Var', (39, 57))	('tumour', 'Disease', (63, 69))
193936	27853494	According to the ROC analysis, the cutoff values of 0.843 x 10-3 mm2/s, 2.117 x 10-3 mm2/s and 165.2 for the minimum ADC, maximum ADC and maximum DWI respectively, obtained the best combination of sensitivity and specificity for distinguishing low-grade and high-grade astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (269, 281))	('0.843 x 10-3 mm2/s', 'Var', (52, 70))	('astrocytoma', 'Phenotype', 'HP:0009592', (269, 280))	('ADC', 'MPA', (130, 133))	('2.117 x 10-3 mm2/s', 'Var', (72, 90))	('astrocytomas', 'Disease', (269, 281))	('low-grade', 'Disease', (244, 253))	('165.2', 'Var', (95, 100))
194042	26708035	Two further biomarkers provided by DT-MRI include the axial (lambdaAX) and radial (lambdaRAD) diffusivities which represent water diffusion parallel and perpendicular to the axonal fibers and may be used to infer axonal and/or myelin injury.	('perpendicular to the axonal fibers', 'Disease', (153, 187))	('myelin injury', 'Disease', 'MESH:D003711', (227, 240))	('myelin injury', 'Disease', (227, 240))	('axial', 'MPA', (54, 59))	('axonal and/or', 'CPA', (213, 226))	('radial', 'MPA', (75, 81))	('DT', 'Chemical', 'MESH:D013936', (35, 37))	('DT-MRI', 'Var', (35, 41))	('water', 'Chemical', 'MESH:D014867', (124, 129))	('perpendicular to the axonal fibers', 'Disease', 'MESH:D000071075', (153, 187))
194266	17760992	Preliminary data from Japan have shown effectivity of C12 in patients with GBM, however, in this series, no concomitant chemotherapy was applied which is considered the standard for the treatment of primary GBM.	('effectivity', 'MPA', (39, 50))	('GBM', 'Disease', (75, 78))	('patients', 'Species', '9606', (61, 69))	('C12', 'Var', (54, 57))
194304	33673070	DNA methylation-based classification for CNS tumors is reported to be a reproducible and valuable approach, and is expected to reduce the substantial inter-observer variability that occurs in conventional morphology-based classification.	('methylation-based', 'Var', (4, 21))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('CNS tumors', 'Disease', 'MESH:D016543', (41, 51))	('CNS tumor', 'Phenotype', 'HP:0100006', (41, 50))	('CNS tumors', 'Disease', (41, 51))
194306	33673070	Methylation profiling for pediatric CNS tumors is a useful tool to identify specific subtypes with different clinical outcomes, and is expected to be a robust tool for diagnosis.	('CNS tumor', 'Phenotype', 'HP:0100006', (36, 45))	('CNS tumors', 'Disease', 'MESH:D016543', (36, 46))	('Methylation', 'Var', (0, 11))	('CNS tumors', 'Disease', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
194313	33673070	Recent efforts including ours have developed digital PCR-based liquid biopsy targeting cell-free tumor DNA in CSF for detecting glioma-specific diagnostic mutations.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (155, 164))	('glioma', 'Disease', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))
194314	33673070	used NGS to analyze CSF samples from patients with diffuse gliomas, and identified glioma-related genetic alterations in 42 (49.2%) of 85 tumors.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', (59, 65))	('patients', 'Species', '9606', (37, 45))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('genetic alterations', 'Var', (98, 117))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
194333	33673070	Compared to adult LGGs, isocitrate dehydrogenase (IDH) mutations are less observed in children, and malignant progression is extremely rare.	('children', 'Species', '9606', (86, 94))	('mutations', 'Var', (55, 64))	('IDH', 'Gene', (50, 53))	('isocitrate dehydrogenase', 'Gene', '3417', (24, 48))	('isocitrate dehydrogenase', 'Gene', (24, 48))	('IDH', 'Gene', '3417', (50, 53))
194339	33673070	In particular, radiation is associated with increased mortality.	('mortality', 'Disease', (54, 63))	('mortality', 'Disease', 'MESH:D003643', (54, 63))	('radiation', 'Var', (15, 24))
194344	33673070	reported that the 10-year PFS is 27% and 60.2% for the BRAF V600E mutant and wild-type pLGG, respectively (p < 0.001).	('V600E', 'Mutation', 'rs113488022', (60, 65))	('V600E', 'Var', (60, 65))	('BRAF', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (55, 59))
194346	33673070	The BRAF V600E mutation is commonly observed in pleomorphic xanthoastrocytomas (78%), followed by gangliogliomas (49%), and also in diffuse astrocytomas (43%).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('observed', 'Reg', (36, 44))	('gangliogliomas', 'Disease', (98, 112))	('gangliogliomas', 'Disease', 'MESH:D018303', (98, 112))	('astrocytomas', 'Disease', 'MESH:D001254', (140, 152))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (140, 151))	('V600E', 'Var', (9, 14))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (48, 78))	('astrocytomas', 'Disease', (140, 152))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (66, 77))	('astrocytomas', 'Disease', 'MESH:D001254', (66, 78))	('BRAF', 'Gene', (4, 8))	('pleomorphic xanthoastrocytomas', 'Disease', (48, 78))	('BRAF', 'Gene', '673', (4, 8))	('astrocytomas', 'Disease', (66, 78))
194352	33673070	FGFR1 aberrations include FGFR1 mutations, FGFR1-TACC1 fusions, and FGFR1-TKD duplications.	('FGFR1', 'Gene', (43, 48))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (26, 31))	('TACC1', 'Gene', '6867', (49, 54))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', '2260', (43, 48))	('FGFR1', 'Gene', '2260', (68, 73))	('mutations', 'Var', (32, 41))	('TACC1', 'Gene', (49, 54))	('fusions', 'Var', (55, 62))
194353	33673070	These aberrations cause FGFR1 autophosphorylation, resulting in upregulation of the RAS/MAPK pathway (Table 1).	('aberrations', 'Var', (6, 17))	('autophosphorylation', 'MPA', (30, 49))	('RAS/MAPK pathway', 'Pathway', (84, 100))	('upregulation', 'PosReg', (64, 76))	('cause', 'Reg', (18, 23))	('FGFR1', 'Gene', (24, 29))	('FGFR1', 'Gene', '2260', (24, 29))
194354	33673070	NF-1: neurofibromatosis type 1 (NF-1) is a well-known inherited tumor predisposition syndrome caused by a germline mutation in the NF-1 tumor suppressor gene.	('NF-1', 'Gene', '4763', (0, 4))	('inherited tumor predisposition syndrome', 'Disease', 'OMIM:614327', (54, 93))	('caused by', 'Reg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('NF-1', 'Gene', (0, 4))	('NF-1', 'Gene', '4763', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('neurofibromatosis type 1 (NF-1', 'Gene', '4763', (6, 36))	('NF-1', 'Gene', '4763', (32, 36))	('germline mutation', 'Var', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('NF-1', 'Gene', (32, 36))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (6, 23))	('NF-1', 'Gene', (131, 135))	('tumor', 'Disease', (136, 141))	('inherited tumor predisposition syndrome', 'Disease', (54, 93))
194359	33673070	MYB and MYBL1 alterations: MYB alteration influences on control of proliferation and differentiation of hematopoietic and other progenitor cells, and is associated with proto-oncogenic functions in both human leukemia and solid tumors.	('leukemia', 'Disease', 'MESH:D007938', (209, 217))	('leukemia', 'Disease', (209, 217))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('MYB', 'Gene', '4602', (8, 11))	('control', 'CPA', (56, 63))	('MYB', 'Gene', (8, 11))	('solid tumors', 'Disease', 'MESH:D009369', (222, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('MYB', 'Gene', '4602', (0, 3))	('MYB', 'Gene', (0, 3))	('MYBL1', 'Gene', (8, 13))	('MYBL1', 'Gene', '4603', (8, 13))	('MYB', 'Gene', (27, 30))	('influences', 'Reg', (42, 52))	('leukemia', 'Phenotype', 'HP:0001909', (209, 217))	('human', 'Species', '9606', (203, 208))	('alteration', 'Var', (31, 41))	('MYB', 'Gene', '4602', (27, 30))	('differentiation', 'CPA', (85, 100))	('solid tumors', 'Disease', (222, 234))
194363	33673070	MYBL1 alterations are rare and are detected in diffuse astrocytomas.	('alterations', 'Var', (6, 17))	('detected', 'Reg', (35, 43))	('astrocytomas', 'Disease', 'MESH:D001254', (55, 67))	('MYBL1', 'Gene', (0, 5))	('diffuse', 'Disease', (47, 54))	('MYBL1', 'Gene', '4603', (0, 5))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('astrocytomas', 'Disease', (55, 67))
194366	33673070	The clinical course is generally indolent in glioma patients with MYB and MYBL1 alterations, and Chiang et al.	('MYB', 'Gene', (66, 69))	('alterations', 'Var', (80, 91))	('MYBL1', 'Gene', (74, 79))	('MYBL1', 'Gene', '4603', (74, 79))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('MYB', 'Gene', '4602', (74, 77))	('MYB', 'Gene', (74, 77))	('glioma', 'Disease', (45, 51))	('MYB', 'Gene', '4602', (66, 69))	('patients', 'Species', '9606', (52, 60))
194368	33673070	Homozygous deletion of CDKN2A can contribute to uncontrolled tumor cell proliferation, and has been reported as a poor prognostic marker in adult glioma.	('uncontrolled', 'MPA', (48, 60))	('glioma', 'Disease', (146, 152))	('CDKN2A', 'Gene', (23, 29))	('contribute', 'Reg', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CDKN2A', 'Gene', '1029', (23, 29))	('Homozygous', 'Var', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
194370	33673070	CDKN2A homozygous deletion co-occurs with the BRAF V600E mutation, demonstrating poor clinical outcomes.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('V600E', 'Var', (51, 56))	('CDKN2A', 'Gene', (0, 6))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('CDKN2A', 'Gene', '1029', (0, 6))
194373	33673070	In this report, pediatric diffuse gliomas were classified by MYB, MYBL1, or FGFR1 alterations or BRAF V600E mutations.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('MYB', 'Gene', (66, 69))	('V600E mutations', 'Var', (102, 117))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('MYB', 'Gene', '4602', (61, 64))	('MYB', 'Gene', '4602', (66, 69))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('alterations', 'Var', (82, 93))	('BRAF', 'Gene', '673', (97, 101))	('MYBL1', 'Gene', '4603', (66, 71))	('MYB', 'Gene', (61, 64))	('MYBL1', 'Gene', (66, 71))	('FGFR1', 'Gene', '2260', (76, 81))	('FGFR1', 'Gene', (76, 81))	('BRAF', 'Gene', (97, 101))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
194374	33673070	reported that a BRAF V600E mutation, FGFR alteration, or rearrangement of MYB or MYBL1 were detected in 84% of IDH-wild type/H3-wild type diffuse gliomas in a large pediatric cohort.	('MYB', 'Gene', '4602', (81, 84))	('MYB', 'Gene', '4602', (74, 77))	('MYB', 'Gene', (81, 84))	('V600E', 'Mutation', 'rs113488022', (21, 26))	('MYB', 'Gene', (74, 77))	('detected', 'Reg', (92, 100))	('gliomas', 'Disease', (146, 153))	('BRAF', 'Gene', (16, 20))	('MYBL1', 'Gene', (81, 86))	('BRAF', 'Gene', '673', (16, 20))	('MYBL1', 'Gene', '4603', (81, 86))	('IDH', 'Gene', (111, 114))	('rearrangement', 'Var', (57, 70))	('FGFR', 'Gene', (37, 41))	('V600E', 'Var', (21, 26))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('IDH', 'Gene', '3417', (111, 114))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))
194379	33673070	However, an additional MEK inhibitor that inhibits the MAPK pathway to BRAF inhibitors, trametinib, overcame BRAF inhibitor resistance, and demonstrated superiority over a BRAF inhibitor alone in phase III clinical trials in patients with BRAF mutant metastatic melanoma.	('BRAF', 'Gene', (239, 243))	('BRAF', 'Gene', '673', (239, 243))	('MEK', 'Gene', (23, 26))	('resistance', 'MPA', (124, 134))	('melanoma', 'Phenotype', 'HP:0002861', (262, 270))	('melanoma', 'Disease', (262, 270))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', (71, 75))	('MAPK pathway', 'Pathway', (55, 67))	('patients', 'Species', '9606', (225, 233))	('BRAF', 'Gene', '673', (172, 176))	('trametinib', 'Chemical', 'MESH:C560077', (88, 98))	('melanoma', 'Disease', 'MESH:D008545', (262, 270))	('BRAF', 'Gene', (172, 176))	('inhibits', 'NegReg', (42, 50))	('mutant', 'Var', (244, 250))	('overcame', 'PosReg', (100, 108))	('MEK', 'Gene', '5609', (23, 26))
194383	33673070	In this study, children with PA harboring either one of the two most common BRAF aberrations, KIAA1549-BRAF fusion or the BRAF V600E mutation, and NF-1 associated LGG, participated.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('NF-1', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (103, 107))	('BRAF', 'Gene', '673', (122, 126))	('children', 'Species', '9606', (15, 23))	('BRAF', 'Gene', (122, 126))	('V600E mutation', 'Var', (127, 141))	('V600E', 'Mutation', 'rs113488022', (127, 132))	('KIAA1549', 'Gene', (94, 102))	('KIAA1549', 'Gene', '57670', (94, 102))	('BRAF', 'Gene', (103, 107))	('NF-1', 'Gene', '4763', (147, 151))
194389	33673070	AZD4547 is an orally bioavailable FGFR1-3 inhibitor.	('FGFR1', 'Gene', '2260', (34, 39))	('AZD4547', 'Var', (0, 7))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR1', 'Gene', (34, 39))
194390	33673070	In the NCI-MATCH trial, AZD4547 was administered to patients with tumors harboring FGFR1-3 mutations or fusions.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('AZD4547', 'Chemical', 'MESH:C572463', (24, 31))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('FGFR1', 'Gene', (83, 88))	('mutations', 'Var', (91, 100))	('FGFR1', 'Gene', '2260', (83, 88))	('fusions', 'Var', (104, 111))	('patients', 'Species', '9606', (52, 60))
194392	33673070	However, this trial showed modest activity of AZD4547 in patients with FGFR mutations and fusions, suggesting the possibility of clinical use in the future.	('activity', 'MPA', (34, 42))	('mutations', 'Var', (76, 85))	('patients', 'Species', '9606', (57, 65))	('AZD4547', 'Var', (46, 53))	('AZD4547', 'Chemical', 'MESH:C572463', (46, 53))	('fusions', 'Var', (90, 97))	('FGFR', 'Gene', (71, 75))
194397	33673070	This feature is reflected in the 2016 WHO classification:diffuse midline gliomas with K27M histone mutations, including most DIPGs, are classified as WHO grade 4, regardless of histological findings.	('DIPGs', 'Chemical', 'MESH:C060938', (125, 130))	('midline gliomas', 'Disease', 'MESH:D005910', (65, 80))	('K27M', 'Var', (86, 90))	('histone', 'Protein', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('K27M', 'Mutation', 'p.K27M', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('midline gliomas', 'Disease', (65, 80))
194398	33673070	G34R/V and K27M mutations are well-known mutations in pHGG.	('pHGG', 'Gene', (54, 58))	('G34R', 'SUBSTITUTION', 'None', (0, 4))	('G34R', 'Var', (0, 4))	('K27M mutations', 'Var', (11, 25))	('K27M', 'Mutation', 'p.K27M', (11, 15))	('pHGG', 'Chemical', '-', (54, 58))
194399	33673070	In an integrated molecular meta-analysis of pHGG, the distribution of recurrently mutated genes was 47% TP53, 36% H3.3, 24% ATRX, and 7% BRAF V600E.	('V600E', 'Mutation', 'rs113488022', (142, 147))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('ATRX', 'Gene', (124, 128))	('pHGG', 'Chemical', '-', (44, 48))	('H3.3', 'Var', (114, 118))	('ATRX', 'Gene', '546', (124, 128))
194400	33673070	These tumors included presence of mutually exclusive G34 and K27M mutations, and co-occurring mutations of ATRX with G34R of NF1.	('K27M mutations', 'Var', (61, 75))	('NF1', 'Gene', (125, 128))	('K27M', 'Mutation', 'p.K27M', (61, 65))	('G34', 'Var', (53, 56))	('G34R', 'Mutation', 'rs1057519902', (117, 121))	('mutations', 'Var', (94, 103))	('NF1', 'Gene', '4763', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('ATRX', 'Gene', (107, 111))	('G34R', 'Var', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('ATRX', 'Gene', '546', (107, 111))
194401	33673070	H3K27M mutation: histone H3 (H3F3A and HIST1H3B) pK27M mutations are frequently observed in DIPGs, which arise in the brainstem almost exclusively in children, and in pHGGs in midline structures such as the thalamus and spinal cord.	('K27M', 'Mutation', 'p.K27M', (2, 6))	('DIPGs', 'Disease', (92, 97))	('mutations', 'Var', (55, 64))	('pK27M', 'Gene', (49, 54))	('DIPGs', 'Chemical', 'MESH:C060938', (92, 97))	('K27M', 'Mutation', 'p.K27M', (50, 54))	('H3F3A', 'Gene', '3020', (29, 34))	('pHGG', 'Chemical', '-', (167, 171))	('children', 'Species', '9606', (150, 158))	('HIST1H3B', 'Gene', (39, 47))	('HIST1H3B', 'Gene', '8358', (39, 47))	('H3F3A', 'Gene', (29, 34))
194402	33673070	This tumor type was classified as a separate entity, "diffuse midline glioma, H3K27M-mutant" (WHO grade 4), in the 2016 WHO classification.	('midline glioma', 'Disease', (62, 76))	('H3K27M-mutant', 'Var', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('K27M', 'Mutation', 'p.K27M', (80, 84))	('tumor', 'Disease', (5, 10))	('midline glioma', 'Disease', 'MESH:D005910', (62, 76))
194403	33673070	H3K27M mutation results in a global H3K27me3 reduction by multiple mechanisms, such as aberrant polycomb repressive complex 2 (PRC2) interactions and hampered H3K27me3 spreading.	('K27M', 'Mutation', 'p.K27M', (2, 6))	('H3K27me3', 'CPA', (159, 167))	('reduction', 'NegReg', (45, 54))	('H3K27me3', 'Protein', (36, 44))	('H3K27M mutation', 'Var', (0, 15))	('interactions', 'Interaction', (133, 145))
194404	33673070	Although additional mechanisms have not been revealed to date, the H3K27M mutation is an important key for pHGG treatment.	('pHGG', 'Chemical', '-', (107, 111))	('H3K27M', 'Var', (67, 73))	('K27M', 'Mutation', 'p.K27M', (69, 73))	('pHGG', 'Disease', (107, 111))
194405	33673070	H3G34R/V mutation: in cIMPACT-NOW update 6, diffuse glioma, H3.3 G34-mutant was reported as a novel tumor type separated from the established gliomas as well as from diffuse midline glioma, H3K27M-mutant.	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('tumor', 'Disease', (100, 105))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('K27M', 'Mutation', 'p.K27M', (192, 196))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('H3.3', 'Gene', (60, 64))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('midline glioma', 'Disease', (174, 188))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('G34-mutant', 'Var', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('G34R/V', 'Mutation', 'rs1057519902', (2, 8))	('midline glioma', 'Disease', 'MESH:D005910', (174, 188))	('glioma', 'Disease', (182, 188))	('gliomas', 'Disease', (142, 149))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('glioma', 'Disease', (142, 148))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Disease', (52, 58))
194406	33673070	When compared with the K27M mutation, how the G34 mutation affects the epigenome remains unclear.	('K27M', 'Mutation', 'p.K27M', (23, 27))	('G34', 'Gene', (46, 49))	('affects', 'Reg', (59, 66))	('mutation', 'Var', (50, 58))
194407	33673070	G34R/V in H3F3A, which encodes non-canonical histone H3.3, occurs in pHGGs of the cerebral cortex, whereas the G34W mutation is prevalent in bone tumors.	('G34R', 'SUBSTITUTION', 'None', (0, 4))	('G34R', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('H3F3A', 'Gene', '3020', (10, 15))	('bone tumors', 'Disease', (141, 152))	('histone H3.3', 'Gene', '3020', (45, 57))	('bone tumors', 'Disease', 'MESH:D001859', (141, 152))	('G34W', 'Mutation', 'rs765285880', (111, 115))	('pHGG', 'Chemical', '-', (69, 73))	('bone tumors', 'Phenotype', 'HP:0010622', (141, 152))	('H3F3A', 'Gene', (10, 15))	('occurs', 'Reg', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('histone H3.3', 'Gene', (45, 57))	('G34W', 'Var', (111, 115))
194408	33673070	analyzed data from 77 patients with GBM under the age of 30, and found that the frequency of G34R/V and K27M mutations was 16% and 32%, respectively.	('age', 'Gene', (50, 53))	('age', 'Gene', '5973', (50, 53))	('G34R', 'SUBSTITUTION', 'None', (93, 97))	('K27M', 'Mutation', 'p.K27M', (104, 108))	('patients', 'Species', '9606', (22, 30))	('G34R', 'Var', (93, 97))	('K27M', 'Var', (104, 108))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
194409	33673070	Among our 411 consecutive glioma patients, 14 (3.4%) harbored H3F3A mutations, of which 4 had G34R mutations and 10 K27M mutations.	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('patients', 'Species', '9606', (33, 41))	('K27M', 'Mutation', 'p.K27M', (116, 120))	('G34R', 'Mutation', 'rs1057519902', (94, 98))	('H3F3A', 'Gene', '3020', (62, 67))	('glioma', 'Disease', (26, 32))	('mutations', 'Var', (68, 77))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('G34R mutations', 'Var', (94, 108))	('H3F3A', 'Gene', (62, 67))
194410	33673070	We recently reported that G34 mutations exerted characteristic methylomic effects, regardless of the tumor tissue of origin, and this mutation could affect chromosome instability.	('chromosome instability', 'Phenotype', 'HP:0040012', (156, 178))	('affect', 'Reg', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('chromosome instability', 'MPA', (156, 178))	('methylomic', 'MPA', (63, 73))	('mutations', 'Var', (30, 39))	('G34', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
194411	33673070	Although G34R/V mutations are relatively rare in pHGG, this genotype is likely to have specific methylomic signals and show extensive infiltration and various histological phenotypes.	('G34R', 'Var', (9, 13))	('pHGG', 'Chemical', '-', (49, 53))	('methylomic', 'MPA', (96, 106))	('G34R', 'SUBSTITUTION', 'None', (9, 13))
194413	33673070	H3K27M has been shown to inhibit PRC2, a multiprotein complex responsible for the methylation of H3 at lysin 27, by binding to its catalytic subunit, EZH2.	('K27M', 'Mutation', 'p.K27M', (2, 6))	('EZH2', 'Gene', '2146', (150, 154))	('binding', 'Interaction', (116, 123))	('EZH2', 'Gene', (150, 154))	('PRC2', 'Gene', (33, 37))	('inhibit', 'NegReg', (25, 32))	('H3K27M', 'Var', (0, 6))
194414	33673070	demonstrated that H3K27M mutated tumors require PRC2 for proliferation, and EZH2 inhibitors cease tumor cell growth.	('H3K27M', 'Protein', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cease', 'NegReg', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('K27M', 'Mutation', 'p.K27M', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EZH2', 'Gene', '2146', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (98, 103))	('EZH2', 'Gene', (76, 80))	('tumors', 'Disease', (33, 39))	('mutated', 'Var', (25, 32))
194415	33673070	EZH2 is a potential therapeutic target for the treatment of H3K27M mutated tumors, and the pediatric MATCH study included this targeted therapy.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('H3K27M mutated', 'Var', (60, 74))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('K27M', 'Mutation', 'p.K27M', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
194424	33673070	However, as the other targeted therapy for DIPG, phase II studies of ONC201, a dopamine receptor D2 antagonist for patients with newly diagnosed DIPG harboring the H3K27M mutation, demonstrated clinical efficacy.	('dopamine receptor D2', 'Gene', '1813', (79, 99))	('patients', 'Species', '9606', (115, 123))	('ONC201', 'Gene', (69, 75))	('H3K27M mutation', 'Var', (164, 179))	('DIPG', 'Disease', (145, 149))	('dopamine receptor D2', 'Gene', (79, 99))	('K27M', 'Mutation', 'p.K27M', (166, 170))
194426	33673070	In gliomas harboring the H3K27M mutation, dopamine receptor D2 is overexpressed and dopamine receptor D5 is suppressed, resulting in enhancement of sensitivity to a dopamine receptor D2 antagonist.	('dopamine receptor D2', 'Gene', '1813', (165, 185))	('dopamine receptor D5', 'Gene', '1816', (84, 104))	('K27M', 'Mutation', 'p.K27M', (27, 31))	('dopamine receptor D5', 'Gene', (84, 104))	('overexpressed', 'PosReg', (66, 79))	('dopamine receptor D2', 'Gene', '1813', (42, 62))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('dopamine receptor D2', 'Gene', (165, 185))	('dopamine receptor D2', 'Gene', (42, 62))	('suppressed', 'NegReg', (108, 118))	('enhancement', 'PosReg', (133, 144))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('H3K27M', 'Var', (25, 31))
194439	33673070	NTRK fusions affect both the RAS/MAPK and PI3K/AKT/mTOR pathways, and are considered to be associated with tumorigenesis.	('mTOR', 'Gene', (51, 55))	('AKT', 'Gene', (47, 50))	('RAS/MAPK', 'Pathway', (29, 37))	('tumor', 'Disease', (107, 112))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (1, 4))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('fusions', 'Var', (5, 12))	('AKT', 'Gene', '207', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mTOR', 'Gene', '2475', (51, 55))	('affect', 'Reg', (13, 19))	('associated', 'Reg', (91, 101))
194440	33673070	reported that 40% (4/10) of non-brainstem high-grade gliomas in children under 3 years of age contained NTRK1-3 fusion genes.	('fusion genes', 'Var', (112, 124))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('NTRK1-3', 'Gene', (104, 111))	('age', 'Gene', (90, 93))	('children', 'Species', '9606', (64, 72))	('NTRK1-3', 'Gene', '4914;4915;4916', (104, 111))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('contained', 'Reg', (94, 103))	('age', 'Gene', '5973', (90, 93))
194442	33673070	However, NTRK fusions can be detected in histologically diagnosed glioneuronal tumors, and cancer multi-gene panel tests should be widely and frequently performed.	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (66, 85))	('glioneuronal tumors', 'Disease', (66, 85))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (66, 85))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('detected', 'Reg', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('TRK', 'Gene', (10, 13))	('TRK', 'Gene', '4914', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('fusions', 'Var', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
194444	33673070	ALK fusion is reported to cause ectopic expression of the ALK fusion protein, resulting in upregulation of the RAS/MAPK and PI3K/AKT/mTOR pathways.	('ectopic expression', 'MPA', (32, 50))	('upregulation', 'PosReg', (91, 103))	('AKT', 'Gene', '207', (129, 132))	('ALK', 'Gene', (58, 61))	('fusion', 'Var', (4, 10))	('mTOR', 'Gene', '2475', (133, 137))	('ALK', 'Gene', (0, 3))	('mTOR', 'Gene', (133, 137))	('AKT', 'Gene', (129, 132))	('ALK', 'Gene', '238', (58, 61))	('ALK', 'Gene', '238', (0, 3))
194448	33673070	Although ROS1 fusion in glioma is quite rare, several reports have highlighted it as a targetable genetic alteration.	('ROS1', 'Gene', '6098', (9, 13))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('fusion', 'Var', (14, 20))	('glioma', 'Disease', (24, 30))	('ROS1', 'Gene', (9, 13))
194449	33673070	GOPC-ROS1 was reported as the most common ROS1 alteration in glioma.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('alteration', 'Var', (47, 57))	('ROS1', 'Gene', (42, 46))	('glioma', 'Disease', (61, 67))	('ROS1', 'Gene', '6098', (5, 9))	('ROS1', 'Gene', '6098', (42, 46))	('ROS1', 'Gene', (5, 9))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
194454	33673070	Group 1 tumors: group 1 tumors harbored ALK/ROS1/NTRK/MET alterations, and 5-year OS was 53.8, 25.0, and 42.9% for tumors with ALK, ROS1, and NTRK fusions, respectively.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('ROS1', 'Gene', '6098', (44, 48))	('tumors', 'Disease', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors harbored ALK', 'Disease', (24, 43))	('tumors', 'Disease', (8, 14))	('alterations', 'Var', (58, 69))	('TRK', 'Gene', (50, 53))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('ROS1', 'Gene', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors harbored ALK', 'Disease', 'MESH:C537062', (24, 43))	('MET', 'Gene', (54, 57))	('ROS1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TRK', 'Gene', '4914', (50, 53))	('TRK', 'Gene', (143, 146))	('tumors', 'Disease', (115, 121))	('ALK', 'Gene', '238', (40, 43))	('ALK', 'Gene', '238', (127, 130))	('ALK', 'Gene', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('TRK', 'Gene', '4914', (143, 146))	('ALK', 'Gene', (127, 130))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('ROS1', 'Gene', '6098', (132, 136))	('MET', 'Gene', '79811', (54, 57))
194456	33673070	Only reversible grade 1/2 adverse events and active against gene fusions of NTRK1-3, ROS1, and ALK were found in adult patients with solid tumors, including CNS tumors.	('ROS1', 'Gene', (85, 89))	('CNS tumor', 'Phenotype', 'HP:0100006', (157, 166))	('ALK', 'Gene', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('ROS1', 'Gene', '6098', (85, 89))	('CNS tumors', 'Disease', 'MESH:D016543', (157, 167))	('patients', 'Species', '9606', (119, 127))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ALK', 'Gene', '238', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('gene fusions', 'Var', (60, 72))	('CNS tumors', 'Disease', (157, 167))	('NTRK1-3', 'Gene', (76, 83))	('NTRK1-3', 'Gene', '4914;4915;4916', (76, 83))	('solid tumors', 'Disease', (133, 145))
194508	33373375	Conventional MR sequences included: T1-MPRAGE; TR/TE 1900/2.54 milliseconds, FOV 256x256 mm2, acq.	('MPRAGE', 'Gene', (39, 45))	('MPRAGE', 'Gene', '177', (39, 45))	('FOV 256x256 mm2', 'Var', (77, 92))	('TR', 'Gene', '2149', (47, 49))
194528	33373375	Status of promoter region methylation of O6-methylguanine DNA methyltransferase (MGMT) and Isocitrate dehydrogenase 1 and 2 (IDH 1/2) mutations were also assessed.	('O6-methylguanine DNA methyltransferase', 'Gene', (41, 79))	('IDH 1/2', 'Gene', '3417;3418', (125, 132))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (41, 79))	('MGMT', 'Gene', '4255', (81, 85))	('IDH 1/2', 'Gene', (125, 132))	('mutations', 'Var', (134, 143))	('MGMT', 'Gene', (81, 85))
194531	33373375	Summarized in Table 5, there was only mixed iso and hypointense signal on Gd-enhanced T1-MPRAGE (Table 5), hypointensity on T1-MPRAGE, and hyperintensity on FLAIR overlapped with increasing APTw signal (Fig 4).	('hyperintensity', 'Var', (139, 153))	('MPRAGE', 'Gene', (89, 95))	('iso', 'MPA', (44, 47))	('hypointense', 'MPA', (52, 63))	('MPRAGE', 'Gene', (127, 133))	('MPRAGE', 'Gene', '177', (89, 95))	('MPRAGE', 'Gene', '177', (127, 133))	('hypointensity', 'Var', (107, 120))	('APTw signal', 'MPA', (190, 201))
194552	33373375	Histopathological diagnosis confirmed that four of the radiologically diagnosed LGGs during the initial radiological classification would have been diagnosed as glioblastoma by utilization of either mean APTw > 2.0% or max APTw signal of > 2.48% (see Tables 1 and 5).	('glioblastoma', 'Disease', (161, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (161, 173))	('LGGs', 'Disease', (80, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (161, 173))	('max APTw signal', 'MPA', (219, 234))	('> 2.0', 'Var', (209, 214))
194560	33373375	IDH status in terms of IDH 1 or 2 mutation for LGG (3 LGGs with mutation vs. 2 LGGs without) was, due to an individual group size < 4, not enough for statistical analysis.	('IDH', 'Gene', (0, 3))	('IDH 1', 'Gene', (23, 28))	('mutation', 'Var', (64, 72))	('IDH', 'Gene', '3417', (0, 3))	('IDH 1', 'Gene', '3417', (23, 28))	('LGG', 'Gene', (47, 50))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (23, 26))
194581	33373375	This is in conjunction with a previous study that has shown the APTw signal values (mean, variance, 50th percentile, 90th percentile and width (10-90)) to be higher in glioblastomas with a methylated MGMT promoter than in those without.	('MGMT', 'Gene', '4255', (200, 204))	('MGMT', 'Gene', (200, 204))	('methylated', 'Var', (189, 199))	('higher', 'PosReg', (158, 164))	('glioblastomas', 'Phenotype', 'HP:0012174', (168, 181))	('glioblastomas', 'Disease', (168, 181))	('glioblastomas', 'Disease', 'MESH:D005909', (168, 181))	('APTw', 'MPA', (64, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (168, 180))
194583	33373375	The evaluation of APTw images between IDH 1/2 mutated LGG and wildtype LGG (n = 3 with mutation and 2 without) could not be performed in our cohort due to lack of statistical power (individual group size < 4).	('IDH 1/2', 'Gene', '3417;3418', (38, 45))	('LGG', 'Gene', (54, 57))	('mutated', 'Var', (46, 53))	('IDH 1/2', 'Gene', (38, 45))
194606	33238942	Higher IL1RN expression was significantly associated with shorter progression-free survival (PFS), advanced tumor stage, tumor metastasis, increased incidence of BRAF mutations, and decreased incidence of N-RAS and H-RAS mutations.	('H-RAS', 'Gene', '3265', (215, 220))	('IL1RN', 'Gene', '3557', (7, 12))	('mutations', 'Var', (167, 176))	('tumor', 'Disease', (108, 113))	('N-RAS', 'Gene', '4893', (205, 210))	('shorter', 'NegReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('decreased', 'NegReg', (182, 191))	('N-RAS', 'Gene', (205, 210))	('progression-free survival', 'CPA', (66, 91))	('BRAF', 'Gene', '673', (162, 166))	('BRAF', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('expression', 'MPA', (13, 23))	('H-RAS', 'Gene', (215, 220))	('Higher', 'PosReg', (0, 6))	('IL1RN', 'Gene', (7, 12))
194611	33238942	Methylation may act as an upstream regulator of IL1RN expression and biological function.	('IL1RN', 'Gene', '3557', (48, 53))	('Methylation', 'Var', (0, 11))	('IL1RN', 'Gene', (48, 53))
194631	33238942	The gene expression profiles of four independent datasets (GSE3467, GSE33630, GSE58545, and GSE60542) were downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/).	('GSE3467', 'Chemical', '-', (59, 66))	('GSE58545', 'Var', (78, 86))	('GSE60542', 'Var', (92, 100))	('GSE3467', 'Var', (59, 66))	('GSE33630', 'Var', (68, 76))
194640	33238942	Spearman correlation analysis was conducted to examine the associations between the methylation density and gene expression and between the methylation density and tumor purity.	('tumor', 'Disease', (164, 169))	('associations', 'Interaction', (59, 71))	('methylation', 'Var', (84, 95))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('gene expression', 'MPA', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
194646	33238942	The IL1RN expression level was further compared between the groups with wild-type and mutant versions of BRAF, NRAS and HRAS.	('expression level', 'MPA', (10, 26))	('NRAS', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (105, 109))	('mutant', 'Var', (86, 92))	('BRAF', 'Gene', (105, 109))	('NRAS', 'Gene', '4893', (111, 115))	('IL1RN', 'Gene', '3557', (4, 9))	('IL1RN', 'Gene', (4, 9))	('HRAS', 'Gene', '3265', (120, 124))	('HRAS', 'Gene', (120, 124))
194649	33238942	Furthermore, expression data from four independent PTC cohorts obtained from the Gene Expression Omnibus (GEO) (GSE3467, GSE33630, GSE58545, and GSE60542) were employed for validation (Fig.	('GSE60542', 'Var', (145, 153))	('GSE3467', 'Var', (112, 119))	('GSE33630', 'Var', (121, 129))	('PTC', 'Gene', '8030', (51, 54))	('GSE3467', 'Chemical', '-', (112, 119))	('PTC', 'Gene', (51, 54))	('GSE58545', 'Var', (131, 139))	('PTC', 'Phenotype', 'HP:0002895', (51, 54))
194654	33238942	The results showed that patients with high IL1RN expression had significantly shorter PFS than those with low expression (P = 0.0034).	('IL1RN', 'Gene', '3557', (43, 48))	('IL1RN', 'Gene', (43, 48))	('high', 'Var', (38, 42))	('PFS', 'MPA', (86, 89))	('patients', 'Species', '9606', (24, 32))	('shorter', 'NegReg', (78, 85))
194685	33238942	These results illustrate that methylated IL1RN may inhibit immune-related pathways by downregulating IL1RN expression.	('methylated', 'Var', (30, 40))	('immune-related pathways', 'Pathway', (59, 82))	('downregulating', 'NegReg', (86, 100))	('expression', 'MPA', (107, 117))	('IL1RN', 'Gene', '3557', (41, 46))	('IL1RN', 'Gene', (41, 46))	('IL1RN', 'Gene', '3557', (101, 106))	('inhibit', 'NegReg', (51, 58))	('IL1RN', 'Gene', (101, 106))
194687	33238942	The IL1RN expression level was further compared between the groups with wild-type and mutant variants of BRAF, NRAS and HRAS (Fig.	('mutant variants', 'Var', (86, 101))	('expression level', 'MPA', (10, 26))	('NRAS', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (105, 109))	('NRAS', 'Gene', '4893', (111, 115))	('BRAF', 'Gene', (105, 109))	('IL1RN', 'Gene', '3557', (4, 9))	('variants', 'Var', (93, 101))	('IL1RN', 'Gene', (4, 9))	('HRAS', 'Gene', '3265', (120, 124))	('HRAS', 'Gene', (120, 124))
194688	33238942	The expression of IL1RN was significantly higher in PTC with the BRAF mutant than in PTC with the wild type (Fig.	('PTC', 'Gene', '8030', (85, 88))	('PTC', 'Phenotype', 'HP:0002895', (52, 55))	('mutant', 'Var', (70, 76))	('IL1RN', 'Gene', '3557', (18, 23))	('PTC', 'Gene', (85, 88))	('expression', 'MPA', (4, 14))	('IL1RN', 'Gene', (18, 23))	('higher', 'PosReg', (42, 48))	('PTC', 'Phenotype', 'HP:0002895', (85, 88))	('BRAF', 'Gene', '673', (65, 69))	('PTC', 'Gene', '8030', (52, 55))	('PTC', 'Gene', (52, 55))	('BRAF', 'Gene', (65, 69))
194689	33238942	However, mutated NRAS (Fig.	('mutated', 'Var', (9, 16))	('NRAS', 'Gene', '4893', (17, 21))	('NRAS', 'Gene', (17, 21))
194690	33238942	S2C) and mutated HRAS (Fig.	('mutated', 'Var', (9, 16))	('HRAS', 'Gene', (17, 21))	('HRAS', 'Gene', '3265', (17, 21))
194706	33238942	In addition, the analysis of the relationship between IL1RN expression and PTC mutations showed that high IL1RN expression was associated with mutated BRAF, wild-type NRAS and wild-type HRAS.	('PTC', 'Gene', '8030', (75, 78))	('PTC', 'Gene', (75, 78))	('IL1RN', 'Gene', '3557', (54, 59))	('IL1RN', 'Gene', (54, 59))	('IL1RN', 'Gene', '3557', (106, 111))	('BRAF', 'Gene', '673', (151, 155))	('IL1RN', 'Gene', (106, 111))	('NRAS', 'Gene', (167, 171))	('HRAS', 'Gene', '3265', (186, 190))	('PTC', 'Phenotype', 'HP:0002895', (75, 78))	('BRAF', 'Gene', (151, 155))	('HRAS', 'Gene', (186, 190))	('NRAS', 'Gene', '4893', (167, 171))	('mutated', 'Var', (143, 150))	('high', 'PosReg', (101, 105))	('expression', 'MPA', (112, 122))
194715	33238942	PTC patients with high IL1RN expression had decreased PFS compared to those with low IL1RN expression.	('IL1RN', 'Gene', (23, 28))	('IL1RN', 'Gene', '3557', (85, 90))	('IL1RN', 'Gene', (85, 90))	('PTC', 'Gene', '8030', (0, 3))	('PTC', 'Gene', (0, 3))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))	('PTC', 'Phenotype', 'HP:0002895', (0, 3))	('IL1RN', 'Gene', '3557', (23, 28))	('decreased', 'NegReg', (44, 53))	('PFS', 'MPA', (54, 57))
194719	33238942	In contrast, low levels of IL1RN have been associated with increased disease severity in myeloma, colorectal cancer and prostate cancer.	('colorectal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('low levels', 'Var', (13, 23))	('myeloma', 'Disease', (89, 96))	('IL1RN', 'Gene', '3557', (27, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('IL1RN', 'Gene', (27, 32))	('prostate cancer', 'Disease', (120, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('associated', 'Reg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('myeloma', 'Disease', 'MESH:D009101', (89, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))
194755	32372386	The proposed deep learning architectures have been successfully tested and evaluated on-line based on MRI datasets of brain tumor segmentation (BraTS 2019) challenge, including s336 cases as training data and 125 cases for validation data.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('brain tumor', 'Phenotype', 'HP:0030692', (118, 129))	('s336', 'Var', (177, 181))	('brain tumor', 'Disease', 'MESH:D001932', (118, 129))	('brain tumor', 'Disease', (118, 129))
194801	32372386	Each patient has four multimodal scans: native T1-weighted, post-contrasted T1-weighted, T2-weighted, and T2-FLAIR.	('T2-FLAIR', 'Var', (106, 114))	('patient', 'Species', '9606', (5, 12))	('T2-weighted', 'Var', (89, 100))
194814	32372386	The main reason is the internal building architecture of MobileNet variants which is developed for smartphone devices.	('Net', 'Gene', '2004', (63, 66))	('variants', 'Var', (67, 75))	('Net', 'Gene', (63, 66))
194818	32372386	Although the Xception encoder showed the best value for the sensitivity of 0.856 with approximately 7% better than the original U-Net model, it achieved the same value of the specificity.	('Net', 'Gene', '2004', (130, 133))	('0.856', 'Var', (75, 80))	('Net', 'Gene', (130, 133))
194823	32372386	For instance, a small-sized tumor in case TCIA12_470_1 was accurately segmented by proposed methods; however, when the heterogeneity of malignant cells increases, the performance varied remarkably.	('tumor', 'Disease', (28, 33))	('varied', 'Reg', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('TCIA12_470_1', 'Var', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
194835	29091765	Low-grade astrocytoma mutations in IDH1, P53 and ATRX cooperate to block differentiation of human neural stem cells via repression of SOX2 Low-grade astrocytomas (LGA) carry neomorphic mutations in Isocitrate Dehydrogenase (IDH), concurrently with P53 and ATRX loss.	('IDH1', 'Gene', (35, 39))	('IDH', 'Gene', (224, 227))	('astrocytoma', 'Disease', 'MESH:D001254', (149, 160))	('astrocytoma', 'Disease', (149, 160))	('IDH', 'Gene', '3417', (35, 38))	('P53', 'Gene', '7157', (41, 44))	('differentiation of human neural stem cells', 'CPA', (73, 115))	('P53', 'Gene', '7157', (248, 251))	('IDH1', 'Gene', '3417', (35, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('IDH', 'Gene', '3417', (224, 227))	('astrocytomas', 'Disease', (149, 161))	('ATRX', 'Gene', (49, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('mutations', 'Var', (22, 31))	('ATRX', 'Gene', '546', (49, 53))	('human', 'Species', '9606', (92, 97))	('ATRX', 'Gene', (256, 260))	('astrocytoma', 'Disease', 'MESH:D001254', (10, 21))	('IDH', 'Gene', (35, 38))	('astrocytoma', 'Disease', (10, 21))	('ATRX', 'Gene', '546', (256, 260))	('P53', 'Gene', (41, 44))	('P53', 'Gene', (248, 251))	('astrocytomas', 'Disease', 'MESH:D001254', (149, 161))	('mutations', 'Var', (185, 194))
194836	29091765	To model LGA formation, we introduced R132H IDH1, P53 shRNA and ATRX shRNA in human neural stem cells (NSCs).	('R132H', 'Var', (38, 43))	('ATRX', 'Gene', (64, 68))	('P53', 'Gene', (50, 53))	('ATRX', 'Gene', '546', (64, 68))	('R132H', 'Mutation', 'rs121913500', (38, 43))	('P53', 'Gene', '7157', (50, 53))	('IDH1', 'Gene', (44, 48))	('human', 'Species', '9606', (78, 83))
194843	29091765	The single most prevalent genetic change in either type is mutation in the Isocitrate Dehydrogenase (IDH) gene family.	('prevalent', 'Reg', (16, 25))	('IDH', 'Gene', '3417', (101, 104))	('IDH', 'Gene', (101, 104))	('mutation', 'Var', (59, 67))
194844	29091765	Among IDH-mutated LGGs, astrocytomas carry concurrent P53 and chromatin remodeler ATRX loss-of-function mutations, while oligodendrogliomas carry 1p/19q co-deletion and TERT promoter mutations.	('P53', 'Gene', (54, 57))	('1p/19q co-deletion', 'Var', (146, 164))	('TERT', 'Gene', '7015', (169, 173))	('ATRX', 'Gene', (82, 86))	('IDH', 'Gene', (6, 9))	('mutations', 'Var', (104, 113))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('ATRX', 'Gene', '546', (82, 86))	('IDH', 'Gene', '3417', (6, 9))	('P53', 'Gene', '7157', (54, 57))	('loss-of-function', 'NegReg', (87, 103))	('astrocytomas', 'Disease', 'MESH:D001254', (24, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (121, 139))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('astrocytomas', 'Disease', (24, 36))	('TERT', 'Gene', (169, 173))	('oligodendrogliomas', 'Disease', (121, 139))
194845	29091765	The presence of mutant IDH in two divergent tumor lineages suggests it is a common genetic driver that occurs early in a multipotent progenitor cell.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutant', 'Var', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('IDH', 'Gene', (23, 26))	('tumor', 'Disease', (44, 49))	('IDH', 'Gene', '3417', (23, 26))
194847	29091765	Heterozygous neomorphic mutations in the catalytic site of IDH (R132H in the cytosolic isoform IDH1) result in production of the oncometabolite 2-hydroxyglutarate (2HG).	('R132H', 'Mutation', 'rs121913500', (64, 69))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', (95, 98))	('production', 'MPA', (111, 121))	('IDH', 'Gene', '3417', (95, 98))	('R132H', 'Var', (64, 69))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (144, 162))	('result in', 'Reg', (101, 110))
194848	29091765	Inhibition of DNA and histone demethylation by 2HG leads to a hypermethylated epigenetic state, which may cause dysregulation of oncogenes and tumor suppressors.	('histone', 'Protein', (22, 29))	('tumor', 'Disease', (143, 148))	('cause', 'Reg', (106, 111))	('Inhibition', 'NegReg', (0, 10))	('DNA', 'Protein', (14, 17))	('dysregulation', 'MPA', (112, 125))	('2HG', 'Var', (47, 50))	('oncogenes', 'Protein', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('hypermethylated epigenetic state', 'MPA', (62, 94))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
194849	29091765	postulated that hypermethylation may disrupt the binding of methylation-sensitive chromatin organizer CTCF, leading to chromatin disorganization and aberrant expression of oncogenes in IDH-mutated high-grade gliomas.	('CTCF', 'Gene', '10664', (102, 106))	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', '3417', (185, 188))	('expression', 'MPA', (158, 168))	('disrupt', 'NegReg', (37, 44))	('binding', 'Interaction', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('hypermethylation', 'Var', (16, 32))	('gliomas', 'Disease', (208, 215))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('oncogenes', 'Gene', (172, 181))	('chromatin disorganization', 'MPA', (119, 144))	('CTCF', 'Gene', (102, 106))	('leading to', 'Reg', (108, 118))
194850	29091765	Recent mouse models have suggested that expression of mutant IDH1 in progenitors of the subventricular zone (SVZ) may induce a pre-tumorigenic state.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mouse', 'Species', '10090', (7, 12))	('expression', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('induce', 'Reg', (118, 124))	('IDH1', 'Gene', (61, 65))	('tumor', 'Disease', (131, 136))	('mutant', 'Var', (54, 60))
194851	29091765	The mechanism whereby the IDH1 mutation cooperates with loss of P53 and ATRX to promote LGA formation remains unknown.	('ATRX', 'Gene', '546', (72, 76))	('P53', 'Gene', (64, 67))	('LGA formation', 'CPA', (88, 101))	('mutation', 'Var', (31, 39))	('IDH1', 'Gene', (26, 30))	('P53', 'Gene', '7157', (64, 67))	('ATRX', 'Gene', (72, 76))	('promote', 'PosReg', (80, 87))
194852	29091765	We modeled mutant IDH1 LGA formation in neural stem cells (NSCs) derived from human embryonic stem cells (hESCs).	('human', 'Species', '9606', (78, 83))	('mutant', 'Var', (11, 17))	('IDH1', 'Gene', (18, 22))
194853	29091765	We systematically introduced the 3 core genetic changes found in LGA via lentiviral expression of R132H mutant IDH1, and short hairpin RNA (shRNA)-mediated knockdown of P53 and ATRX, in order to study progression of gliomagenesis on an oncogenic hit-by-hit basis.	('P53', 'Gene', '7157', (169, 172))	('R132H', 'Mutation', 'rs121913500', (98, 103))	('P53', 'Gene', (169, 172))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('ATRX', 'Gene', '546', (177, 181))	('R132H', 'Var', (98, 103))	('IDH1', 'Gene', (111, 115))	('ATRX', 'Gene', (177, 181))	('glioma', 'Disease', (216, 222))
194856	29091765	The etiology of this transcriptional silencing is disrupted chromatin looping due to hypermethylation of DNA binding sites for chromatin insulator CTCF, leading to disassociation of the SOX2 promoter from critical enhancer elements.	('hypermethylation', 'Var', (85, 101))	('CTCF', 'Gene', (147, 151))	('silencing', 'NegReg', (37, 46))	('CTCF', 'Gene', '10664', (147, 151))	('disassociation', 'MPA', (164, 178))
194861	29091765	To test how mutant IDH1 and loss of P53 and ATRX work together to promote gliomagenesis, we serially introduced an IDH1-mCherry fusion gene (R132H or wild-type or mCherry alone) into NSCs via lentivirus (Figure 1B,C), generated a pure population by FACS isolation, and added lentiviral shRNA against P53, followed by shRNA against ATRX (Figure 1B,C).	('ATRX', 'Gene', (44, 48))	('ATRX', 'Gene', '546', (331, 335))	('P53', 'Gene', '7157', (36, 39))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('P53', 'Gene', '7157', (300, 303))	('R132H', 'Var', (141, 146))	('ATRX', 'Gene', '546', (44, 48))	('R132H', 'Mutation', 'rs121913500', (141, 146))	('mutant', 'Var', (12, 18))	('glioma', 'Disease', (74, 80))	('ATRX', 'Gene', (331, 335))	('P53', 'Gene', (300, 303))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('P53', 'Gene', (36, 39))
194862	29091765	We focused on conditions that are most biologically relevant: vector only ("vector"), mutant IDH1 alone ("1-hit"), mutant IDH1 with P53 knock-down ("2-hits") and mutant IDH1 with P53 and ATRX knockdown ("3-hits").	('IDH1', 'Gene', (93, 97))	('ATRX', 'Gene', '546', (187, 191))	('knock-down', 'Var', (136, 146))	('mutant', 'Var', (86, 92))	('P53', 'Gene', (179, 182))	('mutant', 'Var', (162, 168))	('ATRX', 'Gene', (187, 191))	('P53', 'Gene', '7157', (179, 182))	('P53', 'Gene', (132, 135))	('P53', 'Gene', '7157', (132, 135))
194863	29091765	Mutant-IDH1 NSCs with ATRX knockdown in a wild-type P53 background resulted in poor cell viability (Figure 1C), which precluded subsequent P53 knockdown.	('ATRX', 'Gene', (22, 26))	('P53', 'Gene', '7157', (52, 55))	('P53', 'Gene', (139, 142))	('P53', 'Gene', '7157', (139, 142))	('Mutant-IDH1', 'Var', (0, 11))	('ATRX', 'Gene', '546', (22, 26))	('cell viability', 'CPA', (84, 98))	('P53', 'Gene', (52, 55))	('poor', 'NegReg', (79, 83))
194864	29091765	Immunofluorescent microscopy, qPCR and immunoblot verified our lines were expressing IDH1-mCherry and knocking down P53 and ATRX (Figure 1D-G).	('IDH1-mCherry', 'Var', (85, 97))	('P53', 'Gene', (116, 119))	('ATRX', 'Gene', (124, 128))	('P53', 'Gene', '7157', (116, 119))	('knocking down', 'Var', (102, 115))	('ATRX', 'Gene', '546', (124, 128))
194866	29091765	To understand the roles of mutant IDH1, P53 and ATRX in our NSCs, we profiled their DNA methylomes and transcriptomes using Illumina 450k methylation arrays and RNA-seq, respectively.	('P53', 'Gene', (40, 43))	('mutant', 'Var', (27, 33))	('P53', 'Gene', '7157', (40, 43))	('ATRX', 'Gene', (48, 52))	('IDH1', 'Gene', (34, 38))	('ATRX', 'Gene', '546', (48, 52))
194869	29091765	Mutant-IDH1 NSCs clustered with mutant-IDH1 gliomas (violet dendrogram in Figure 2C), suggesting epigenetic similarity.	('Mutant-IDH1', 'Var', (0, 11))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
194871	29091765	Supervised hierarchical clustering using the top 500 most variable TCGA genes resulted in four groups that closely resembled clusters identified by the TCGA: wild-type IDH gliomas; IDH mutant 1p/19q co-deleted gliomas (oligodendrogliomas); IDH mutant 1p/19q intact gliomas (astrocytomas); and a mixed group of IDH mutated gliomas (Figure 2D).	('IDH gliomas', 'Disease', (168, 179))	('IDH', 'Gene', (240, 243))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('gliomas', 'Disease', (322, 329))	('co-deleted', 'Var', (199, 209))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('glioma', 'Phenotype', 'HP:0009733', (322, 328))	('gliomas', 'Disease', (265, 272))	('gliomas', 'Disease', (210, 217))	('IDH', 'Gene', '3417', (168, 171))	('IDH', 'Gene', '3417', (240, 243))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('IDH', 'Gene', (310, 313))	('gliomas', 'Disease', 'MESH:D005910', (322, 329))	('IDH gliomas', 'Disease', 'MESH:D005910', (168, 179))	('gliomas', 'Disease', 'MESH:D005910', (265, 272))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))	('astrocytoma', 'Phenotype', 'HP:0009592', (274, 285))	('astrocytomas', 'Disease', (274, 286))	('IDH', 'Gene', (181, 184))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (219, 237))	('glioma', 'Phenotype', 'HP:0009733', (265, 271))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('gliomas', 'Phenotype', 'HP:0009733', (322, 329))	('IDH', 'Gene', '3417', (310, 313))	('gliomas', 'Disease', (230, 237))	('gliomas', 'Phenotype', 'HP:0009733', (265, 272))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('TCGA', 'Gene', (67, 71))	('IDH', 'Gene', '3417', (181, 184))	('oligodendrogliomas', 'Disease', (219, 237))	('gliomas', 'Disease', (172, 179))	('gliomas', 'Disease', 'MESH:D005910', (230, 237))	('astrocytomas', 'Disease', 'MESH:D001254', (274, 286))	('IDH', 'Gene', (168, 171))
194872	29091765	1-hit NSCs grouped with mutant-IDH1 1p/19q intact astrocytomas, while 3-hit NSCs clustered with the mixed group of mutant-IDH1 gliomas.	('astrocytomas', 'Disease', (50, 62))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('1p/19q', 'Var', (36, 42))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('astrocytomas', 'Disease', 'MESH:D001254', (50, 62))	('mutant-IDH1 1p/19q', 'Var', (24, 42))
194878	29091765	Using in vitro growth assays, we found that two conditions, 1-hit and mutant IDH1 with ATRX knockdown, grew more slowly than the others (Figure 3A).	('grew', 'MPA', (103, 107))	('mutant', 'Var', (70, 76))	('slowly', 'NegReg', (113, 119))	('ATRX', 'Gene', (87, 91))	('IDH1', 'Gene', (77, 81))	('ATRX', 'Gene', '546', (87, 91))
194879	29091765	1-hit and mutant IDH with ATRX knockdown NSCs had significantly elevated levels of TUNEL+ cells.	('ATRX', 'Gene', (26, 30))	('IDH', 'Gene', '3417', (17, 20))	('mutant', 'Var', (10, 16))	('elevated', 'PosReg', (64, 72))	('ATRX', 'Gene', '546', (26, 30))	('IDH', 'Gene', (17, 20))	('levels of TUNEL+ cells', 'MPA', (73, 95))
194880	29091765	P53 knockdown in the 2-hit and 3-hit conditions decreased TUNEL staining to control levels.	('decreased', 'NegReg', (48, 57))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('TUNEL staining', 'MPA', (58, 72))	('knockdown', 'Var', (4, 13))
194882	29091765	These findings indicated that decreased cellular proliferation and increased cell death caused by R132H IDH1 were rescued by P53 knockdown in the 2-hit and 3-hit conditions.	('P53', 'Gene', '7157', (125, 128))	('cell death', 'CPA', (77, 87))	('R132H', 'Mutation', 'rs121913500', (98, 103))	('cellular proliferation', 'CPA', (40, 62))	('decreased', 'NegReg', (30, 39))	('R132H', 'Var', (98, 103))	('IDH1', 'Gene', (104, 108))	('P53', 'Gene', (125, 128))
194883	29091765	Furthermore, these experiments indicated that loss of ATRX as the second hit leads to non-viable cells.	('non-viable cells', 'CPA', (86, 102))	('ATRX', 'Gene', '546', (54, 58))	('loss', 'Var', (46, 50))	('ATRX', 'Gene', (54, 58))	('leads to', 'Reg', (77, 85))
194885	29091765	However, the effect of combined IDH mutation and P53/ATRX loss on NSC self-renewal and differentiation is not known.	('ATRX', 'Gene', (53, 57))	('loss', 'NegReg', (58, 62))	('ATRX', 'Gene', '546', (53, 57))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('P53', 'Gene', (49, 52))	('NSC', 'Disease', (66, 69))	('P53', 'Gene', '7157', (49, 52))	('mutation', 'Var', (36, 44))
194889	29091765	The 1-hit line had mildly diminished ability to form spheres, but the addition of P53 and ATRX knockdown rescued this deficit.	('diminished', 'NegReg', (26, 36))	('P53', 'Gene', (82, 85))	('P53', 'Gene', '7157', (82, 85))	('knockdown', 'Var', (95, 104))	('ATRX', 'Gene', (90, 94))	('ATRX', 'Gene', '546', (90, 94))
194897	29091765	We confirmed this finding by comparing wild-type IDH (n=53) and mutant IDH (n=157) LGGs from the TCGA.	('IDH', 'Gene', (49, 52))	('IDH', 'Gene', '3417', (49, 52))	('IDH', 'Gene', (71, 74))	('IDH', 'Gene', '3417', (71, 74))	('mutant', 'Var', (64, 70))
194898	29091765	When we examined a 1.2 Mb-wide genomic region surrounding the SOX2 locus, we observed increased DNA methylation in specific areas upstream and downstream of SOX2 in 3-hit vs. vector NSCs, and a similar trend when comparing mutant to wild-type IDH gliomas in the TCGA (Figure 5B).	('mutant', 'Var', (223, 229))	('IDH gliomas', 'Disease', (243, 254))	('SOX2', 'Gene', (62, 66))	('increased', 'PosReg', (86, 95))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('DNA methylation', 'MPA', (96, 111))	('IDH gliomas', 'Disease', 'MESH:D005910', (243, 254))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))
194901	29091765	showed that DNA hypermethylation in IDH-mutated high-grade gliomas causes the promoter of an oncogene (PDGFRA) to ectopically associate with an enhancer in a neighboring TAD due to disruption of CTCF binding and loss of inter-TAD insulation.	('loss', 'NegReg', (212, 216))	('PDGFRA', 'Gene', (103, 109))	('PDGFRA', 'Gene', '5156', (103, 109))	('associate', 'Interaction', (126, 135))	('hypermethylation', 'Var', (16, 32))	('binding', 'Interaction', (200, 207))	('IDH', 'Gene', (36, 39))	('CTCF', 'Gene', '10664', (195, 199))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('promoter', 'MPA', (78, 86))	('IDH', 'Gene', '3417', (36, 39))	('gliomas', 'Disease', (59, 66))	('disruption', 'NegReg', (181, 191))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('CTCF', 'Gene', (195, 199))
194904	29091765	All four CTCF motifs upstream of the SOX2 promoter, and a single site ~1Mb downstream, had CpGs directly in the motif, suggesting sensitivity to methylation.	('CpGs', 'Var', (91, 95))	('CTCF', 'Gene', (9, 13))	('CTCF', 'Gene', '10664', (9, 13))
194905	29091765	To understand if direct hypermethylation of CTCF sites could lead to decreased CTCF occupancy at these CTCF sites, we performed targeted bisulfite sequencing of vector and 3-hit NSCs (n=10/motif) (Figure 5E).	('hypermethylation', 'Var', (24, 40))	('CTCF', 'Gene', '10664', (44, 48))	('CTCF', 'Gene', (79, 83))	('bisulfite', 'Chemical', 'MESH:C042345', (137, 146))	('CTCF', 'Gene', (103, 107))	('decreased', 'NegReg', (69, 78))	('CTCF', 'Gene', '10664', (79, 83))	('CTCF', 'Gene', '10664', (103, 107))	('CTCF', 'Gene', (44, 48))
194908	29091765	Every site assayed had a ~2-fold decrease in CTCF occupancy, supporting the hypothesis that DNA hypermethylation in 3-hit NSCs leads to reduced CTCF occupancy around the SOX2 locus.	('CTCF', 'Gene', (144, 148))	('decrease', 'NegReg', (33, 41))	('CTCF', 'Gene', (45, 49))	('CTCF', 'Gene', '10664', (144, 148))	('CTCF', 'Gene', '10664', (45, 49))	('reduced', 'NegReg', (136, 143))	('hypermethylation', 'Var', (96, 112))
194915	29091765	To validate the critical role of SOX2 in gliomagenesis, we ectopically expressed SOX2 in all conditions studied and subjected them to astrocytic and neuronal differentiation.	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('ectopically', 'Var', (59, 70))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('SOX2', 'Gene', (81, 85))	('glioma', 'Disease', (41, 47))
194917	29091765	Mutant IDH1 is a shared core mutation in both LGA and oligodendroglioma, suggesting the cell of origin is a shared neuroglial progenitor.	('LGA', 'Disease', (46, 49))	('oligodendroglioma', 'Disease', (54, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('Mutant', 'Var', (0, 6))	('oligodendroglioma', 'Disease', 'MESH:D009837', (54, 71))	('IDH1', 'Gene', (7, 11))
194920	29091765	Second, expression of mutant IDH1 alone in progenitor cells leads to pre-tumorigenic changes.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('IDH1', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('mutant', 'Var', (22, 28))	('leads to', 'Reg', (60, 68))
194921	29091765	Third, germline mosaicism for neomorphic IDH mutations in Ollier disease can result in brain astrocytomas.	('IDH', 'Gene', (41, 44))	('mutations', 'Var', (45, 54))	('IDH', 'Gene', '3417', (41, 44))	('result in', 'Reg', (77, 86))	('Ollier disease', 'Disease', (58, 72))	('Ollier disease', 'Phenotype', 'HP:0500045', (58, 72))	('brain astrocytomas', 'Disease', (87, 105))	('germline mosaicism', 'Var', (7, 25))	('brain astrocytomas', 'Disease', 'MESH:D001254', (87, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('brain astrocytomas', 'Phenotype', 'HP:0009592', (87, 105))	('Ollier disease', 'Disease', 'MESH:D004687', (58, 72))
194922	29091765	In contrast, loss of ATRX by itself in a wild-type P53 background does not lead to brain tumor formation.	('brain tumor', 'Phenotype', 'HP:0030692', (83, 94))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('P53', 'Gene', (51, 54))	('brain tumor', 'Disease', 'MESH:D001932', (83, 94))	('brain tumor', 'Disease', (83, 94))	('P53', 'Gene', '7157', (51, 54))	('loss', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
194924	29091765	We therefore propose that the most likely order of the 3 oncogenic hits is IDH mutation, followed by loss of P53 and finally loss of ATRX.	('P53', 'Gene', (109, 112))	('P53', 'Gene', '7157', (109, 112))	('loss', 'Var', (101, 105))	('ATRX', 'Gene', '546', (133, 137))	('mutation', 'Var', (79, 87))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('ATRX', 'Gene', (133, 137))
194929	29091765	This chromatin loop is disrupted in 3-hit NSCs due to hypermethylation of CTCF motifs flanking the SOX2 locus, leading to decreased SOX2 expression and differentiation block.	('expression', 'MPA', (137, 147))	('SOX2', 'Gene', (132, 136))	('CTCF', 'Gene', '10664', (74, 78))	('differentiation block', 'CPA', (152, 173))	('hypermethylation', 'Var', (54, 70))	('CTCF', 'Gene', (74, 78))	('SOX2', 'Gene', (99, 103))	('decreased', 'NegReg', (122, 131))
194937	29091765	CTCF ChIP-seq data from 2 grade III mutant IDH and 2 grade IV wild-type IDH datasets (GSE70991), as in, were used to identify CTCF binding sites near the SOX2 locus.	('CTCF', 'Gene', (126, 130))	('IDH', 'Gene', '3417', (43, 46))	('CTCF', 'Gene', (0, 4))	('IDH and 2', 'Gene', '3417', (43, 52))	('CTCF', 'Gene', '10664', (0, 4))	('IDH', 'Gene', (72, 75))	('CTCF', 'Gene', '10664', (126, 130))	('IDH', 'Gene', '3417', (72, 75))	('binding', 'Interaction', (131, 138))	('mutant', 'Var', (36, 42))	('IDH', 'Gene', (43, 46))
194938	29091765	For HiC data (GSE35156 and GSE52457), publicly available datasets from lung fibroblasts (IMR90), H1 hESCs and NSCs were used.	('HiC', 'Gene', '29969', (4, 7))	('IMR90', 'CellLine', 'CVCL:0347', (89, 94))	('GSE35156', 'Var', (14, 22))	('HiC', 'Gene', (4, 7))
195015	28851312	Increased PFS gap between the low N-cadherin expression group and high-expression group compared to OS curves are shown in Fig.	('N-cadherin', 'Gene', (34, 44))	('OS', 'Chemical', '-', (100, 102))	('low', 'Var', (30, 33))	('PFS gap', 'MPA', (10, 17))	('N-cadherin', 'Gene', '1000', (34, 44))
195032	28851312	As supported by important experimental findings in epithelial malignancies including colon, pancreatic and breast cancer, induction of EMT can co-induce stem cell properties, thereby connecting cell motility and stem cell-like programs.	('induction', 'Var', (122, 131))	('colon', 'Disease', (85, 90))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('epithelial malignancies', 'Disease', (51, 74))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('stem cell properties', 'CPA', (153, 173))	('pancreatic', 'Disease', (92, 102))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (51, 74))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('EMT', 'Gene', (135, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('epithelial malignancies', 'Disease', 'MESH:D002277', (51, 74))
195049	28851312	However, further investigation needs be performed to reveal the relation between N-cadherin or other EMT markers/inducers and key parameters for new 2016 WHO glioma classification, such as IDH1 mutation, 1p/19q co-deletion or MGMT promoter methylation.	('mutation', 'Var', (194, 202))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('IDH1', 'Gene', '3417', (189, 193))	('N-cadherin', 'Gene', '1000', (81, 91))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('MGMT', 'Gene', '4255', (226, 230))	('glioma', 'Disease', (158, 164))	('IDH1', 'Gene', (189, 193))	('1p/19q co-deletion', 'Var', (204, 222))	('MGMT', 'Gene', (226, 230))	('N-cadherin', 'Gene', (81, 91))
195069	21843312	Germline mutations, somatic mutation, disruption, copy number variation of genes and loci contribute to the pathogenesis of glioma.	('glioma', 'Disease', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('disruption', 'Var', (38, 48))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('contribute', 'Reg', (90, 100))	('copy number variation', 'Var', (50, 71))
195070	21843312	Genetic alterations frequently involved, include amplification of genes encoding for receptor tyrosine kinases (EGFR, PDGFRA), onocogens (PDGF, PDGFR, CDK4) and deletions/mutations in tumor suppressor genes (IDH1, IDH2, TP53, CDKN2A, PTEN).	('TP53', 'Gene', (220, 224))	('IDH2', 'Gene', (214, 218))	('IDH1', 'Gene', (208, 212))	('PDGFRA', 'Gene', (118, 124))	('IDH2', 'Gene', '3418', (214, 218))	('CDKN2A', 'Gene', (226, 232))	('PDGFRA', 'Gene', '5156', (118, 124))	('PDGFR', 'Gene', (144, 149))	('PTEN', 'Gene', (234, 238))	('PDGFR', 'Gene', '5159', (144, 149))	('IDH1', 'Gene', '3417', (208, 212))	('tumor', 'Disease', (184, 189))	('CDKN2A', 'Gene', '1029', (226, 232))	('PTEN', 'Gene', '5728', (234, 238))	('EGFR', 'Gene', (112, 116))	('TP53', 'Gene', '7157', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('PDGFR', 'Gene', (118, 123))	('PDGFR', 'Gene', '5159', (118, 123))	('CDK4', 'Gene', (151, 155))	('deletions/mutations', 'Var', (161, 180))	('amplification', 'Var', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('CDK4', 'Gene', '1019', (151, 155))	('EGFR', 'Gene', '1956', (112, 116))
195078	21843312	Glioma cells (T98G, U251-MG, U87-MG, A172, SW1736, U118-MG, U138-MG, H4 and HS-683) were purchased from ATCC and were cultured in Dulbecco's modified Eagle's medium (GIBCO) supplemented with 10% fetal bovine serum (GIBCO) and 4 mM glutamine.	('U138-MG', 'CellLine', 'CVCL:0020', (60, 67))	('glutamine', 'Chemical', 'MESH:D005973', (231, 240))	('U138-MG', 'Var', (60, 67))	('U251-MG', 'Var', (20, 27))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('SW1736', 'CellLine', 'CVCL:3883', (43, 49))	('Glioma', 'Disease', (0, 6))	('bovine', 'Species', '9913', (201, 207))	('U118-MG', 'Var', (51, 58))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (130, 164))	('U87-MG', 'Var', (29, 35))
195089	21843312	The efficiency of CDKN2A knockdown was detected by western blot 48 h after transfection.	('CDKN2A', 'Gene', '1029', (18, 24))	('CDKN2A', 'Gene', (18, 24))	('knockdown', 'Var', (25, 34))
195104	21843312	We also detected the expression of CDKN2A in high (T98G, U251-MG, U87-MG, A172, SW1736, U118-MG and U138-MG) and low grade glioma cells (H4 and HS-683).	('U251-MG', 'Var', (57, 64))	('U138-MG', 'Var', (100, 107))	('CDKN2A', 'Gene', '1029', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('U118-MG', 'Var', (88, 95))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('SW1736', 'CellLine', 'CVCL:3883', (80, 86))	('detected', 'Reg', (8, 16))	('U138-MG', 'CellLine', 'CVCL:0020', (100, 107))	('U87-MG', 'Var', (66, 72))	('glioma', 'Disease', (123, 129))	('CDKN2A', 'Gene', (35, 41))	('SW1736', 'Var', (80, 86))
195109	21843312	Meanwhile, Transfection of CDKN2A into glioma cells resulted in a reduction in the rate of cell growth (Figure 3).	('glioma', 'Disease', (39, 45))	('rate', 'MPA', (83, 87))	('CDKN2A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('Transfection', 'Var', (11, 23))	('reduction', 'NegReg', (66, 75))
195117	21843312	In contrast, we observed elevated levels of cyclin D1 and pRb when CDKN2A was knockdown.	('CDKN2A', 'Gene', (67, 73))	('elevated levels of cyclin', 'Phenotype', 'HP:0003236', (25, 50))	('knockdown', 'Var', (78, 87))	('CDKN2A', 'Gene', '1029', (67, 73))	('cyclin D1', 'Gene', '595', (44, 53))	('elevated', 'PosReg', (25, 33))	('pRb', 'Gene', (58, 61))	('cyclin D1', 'Gene', (44, 53))	('pRb', 'Gene', '5925', (58, 61))	('levels', 'MPA', (34, 40))
195118	21843312	However, flavopiridola, an available cyclin D1 inhibitor reserved the accelerated cell growth and the increased phosphorylation of pBb induced by CDKN2A knockdown in low-grade glioma cells (Figure 4B, C and Figure 5B).	('CDKN2A', 'Gene', (146, 152))	('glioma', 'Disease', (176, 182))	('knockdown', 'Var', (153, 162))	('increased', 'PosReg', (102, 111))	('phosphorylation', 'MPA', (112, 127))	('cyclin D1', 'Gene', '595', (37, 46))	('CDKN2A', 'Gene', '1029', (146, 152))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('cyclin D1', 'Gene', (37, 46))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cell growth', 'CPA', (82, 93))	('accelerated', 'PosReg', (70, 81))	('pBb', 'Protein', (131, 134))
195122	21843312	It was reported that CDKN2A be mutated and deleted in various human tumors, including more than 70% of human glioma cell lines and glioblastoma.	('deleted', 'Var', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('human', 'Species', '9606', (103, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('human', 'Species', '9606', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (109, 115))	('glioma', 'Disease', (109, 115))	('CDKN2A', 'Gene', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDKN2A', 'Gene', '1029', (21, 27))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
195129	21843312	However, knockdown of CDKN2A promotes the low grade gliomas to high grade gliomas.	('gliomas', 'Disease', (52, 59))	('knockdown', 'Var', (9, 18))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('gliomas', 'Disease', (74, 81))	('low', 'Disease', (42, 45))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('promotes', 'PosReg', (29, 37))
195138	21843312	Cyclin D1 overexpression, CDKN2A loss, and pRb inactivation play a key role in glioma tumorigenesis.	('inactivation', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('glioma', 'Disease', (79, 85))	('CDKN2A', 'Gene', (26, 32))	('tumor', 'Disease', (86, 91))	('loss', 'NegReg', (33, 37))	('Cyclin D1', 'Gene', '595', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('CDKN2A', 'Gene', '1029', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('pRb', 'Gene', '5925', (43, 46))	('pRb', 'Gene', (43, 46))	('overexpression', 'PosReg', (10, 24))	('Cyclin D1', 'Gene', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
195150	30554344	It has been shown that the level of PpIX in gliomas correlates with tumor cell density and a number of proliferative biomarkers such as Ki-67, mitochondrial activity, etc.	('tumor', 'Disease', (68, 73))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('PpIX', 'Var', (36, 40))	('gliomas', 'Disease', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('PpIX', 'Chemical', 'MESH:C028025', (36, 40))	('mitochondrial', 'MPA', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
195204	30835699	During the last several years, however, remarkable advances in our understanding of the molecular underpinnings of these tumors have occurred as a result of high-resolution genomic, epigenetic, and transcriptomic profiling, which have provided insights for improved tumor categorization and molecularly directed therapies.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('epigenetic', 'Var', (182, 192))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
195208	30835699	Conversely, the majority of pilocytic astrocytomas appear to result from genetic changes that alter a single, therapeutically targetable molecular pathway.	('result from', 'Reg', (61, 72))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (28, 50))	('changes', 'Var', (81, 88))	('Co', 'Chemical', 'MESH:C065987', (0, 2))	('pilocytic astrocytomas', 'Disease', (28, 50))
195230	30835699	While the above studies were in progress, a series of molecular analyses demonstrated that many pilocytic astrocytomas exhibit translocations or, less commonly, activating mutations of the BRAF gene, which may promote tumor development (Fig.	('BRAF', 'Gene', '673', (189, 193))	('pilocytic astrocytomas', 'Disease', (96, 118))	('activating', 'PosReg', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (96, 118))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('promote', 'PosReg', (210, 217))	('BRAF', 'Gene', (189, 193))	('tumor', 'Disease', (218, 223))	('translocations', 'Var', (127, 141))
195231	30835699	BRAF-KIAA fusions are common in cerebellar and optic pathway pilocytic tumors and lead to constitutive activation of the BRAF protein, whereas BRAF mutations are more common in gangliogliomas, pleomorphic xanthoastrocytomas, and cerebral pilocytic astrocytomas (Fig.	('BRAF', 'Gene', (121, 125))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('common', 'Reg', (22, 28))	('BRAF', 'Gene', (0, 4))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (193, 223))	('optic pathway', 'Disease', (47, 60))	('pilocytic tumors', 'Disease', 'MESH:D001254', (61, 77))	('gangliogliomas', 'Disease', 'MESH:D018303', (177, 191))	('activation', 'PosReg', (103, 113))	('gangliogliomas', 'Disease', (177, 191))	('pleomorphic xanthoastrocytomas', 'Disease', (193, 223))	('cerebral pilocytic astrocytomas', 'Disease', (229, 260))	('cerebellar', 'Disease', (32, 42))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('pilocytic tumors', 'Disease', (61, 77))	('fusions', 'Var', (10, 17))	('cerebral pilocytic astrocytomas', 'Disease', 'MESH:D001254', (229, 260))	('constitutive', 'MPA', (90, 102))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('BRAF', 'Gene', '673', (121, 125))
195232	30835699	Tumors lacking BRAF fusions or mutations often have alterations in other components of the mitogen-activated protein kinase (MAPK) signaling pathway, including NF1 mutations and RAF fusions.	('BRAF', 'Gene', '673', (15, 19))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (31, 40))	('alterations', 'Reg', (52, 63))	('NF1', 'Gene', (160, 163))	('BRAF', 'Gene', (15, 19))	('NF1', 'Gene', '4763', (160, 163))	('RAF', 'Gene', '22882', (16, 19))	('RAF', 'Gene', (16, 19))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('RAF', 'Gene', '22882', (178, 181))	('mutations', 'Var', (164, 173))	('RAF', 'Gene', (178, 181))
195233	30835699	This convergence of mutations on a single downstream pathway prompted interest in the targeted inhibition of MAPK signaling as a therapy for these tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('mutations', 'Var', (20, 29))
195236	30835699	Based on these results, a phase II study of this agent was launched, which stratified patients by MAPK pathway mutation status (e.g., BRAF translocations or mutations), histological diagnosis, and presence of NF1.	('MAPK', 'Gene', (98, 102))	('translocations', 'Var', (139, 153))	('BRAF', 'Gene', '673', (134, 138))	('NF1', 'Gene', (209, 212))	('mutations', 'Var', (157, 166))	('BRAF', 'Gene', (134, 138))	('NF1', 'Gene', '4763', (209, 212))	('patients', 'Species', '9606', (86, 94))
195239	30835699	Given promising preliminary results, one ongoing phase II randomized clinical trial is already testing the activity of dabrafenib and trametinib (MEK inhibitor) against the combination of carboplatin and vincristine in children with newly diagnosed BRAFV600E-mutated LGGs .	('carboplatin', 'Chemical', 'MESH:D016190', (188, 199))	('trametinib', 'Chemical', 'MESH:C560077', (134, 144))	('activity', 'MPA', (107, 115))	('BRAFV600E', 'Mutation', 'rs113488022', (249, 258))	('MEK', 'Gene', (146, 149))	('LGGs', 'Disease', (267, 271))	('MEK', 'Gene', '5609', (146, 149))	('BRAFV600E-mutated', 'Var', (249, 266))	('dabrafenib', 'Chemical', 'MESH:C561627', (119, 129))	('vincristine', 'Chemical', 'MESH:D014750', (204, 215))	('children', 'Species', '9606', (219, 227))
195250	30835699	The majority of WNT-activated medulloblastomas can be readily identified by nuclear expression of beta-catenin by immunohistochemistry combined with the detection of monosomy 6 and/or CTNNB1 mutations.	('medulloblastomas', 'Disease', 'MESH:D008527', (30, 46))	('medulloblastoma', 'Phenotype', 'HP:0002885', (30, 45))	('monosomy', 'Gene', (166, 174))	('CTNNB1', 'Gene', '1499', (184, 190))	('mutations', 'Var', (191, 200))	('medulloblastomas', 'Disease', (30, 46))	('CTNNB1', 'Gene', (184, 190))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))
195274	30835699	Maximal safe surgery with the intent of achieving near-total resection (NTR; maximum longest diameter of residual tumor < 5 mm) or gross-total resection (GTR) followed by local fractionated RT is considered standard therapy for children with newly diagnosed non-metastatic ependymoma, except for extremely young infants.	('gross-total', 'Var', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('infants', 'Species', '9606', (312, 319))	('ependymoma', 'Phenotype', 'HP:0002888', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('ependymoma', 'Disease', (273, 283))	('children', 'Species', '9606', (228, 236))	('ependymoma', 'Disease', 'MESH:D004806', (273, 283))
195318	30835699	One landmark observation was the detection of novel mutations in histones H3F3A (positions K27 and G34) and HIST1H3B (position K27).	('H3F3A', 'Gene', (74, 79))	('K27', 'Gene', (91, 94))	('G34', 'Var', (99, 102))	('K27', 'Gene', '342574', (127, 130))	('HIST1H3B', 'Gene', (108, 116))	('HIST1H3B', 'Gene', '8358', (108, 116))	('K27', 'Gene', (127, 130))	('H3F3A', 'Gene', '3020', (74, 79))	('K27', 'Gene', '342574', (91, 94))
195319	30835699	It was also recognized that a subset of tumors, particularly from older children, have mutations in the IDH1 or IDH2 genes, whereas another subset has frequent BRAFV600E mutations, similar to pleomorphic xanthoastrocytomas.	('IDH1', 'Gene', '3417', (104, 108))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (192, 222))	('children', 'Species', '9606', (72, 80))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('IDH2', 'Gene', (112, 116))	('mutations', 'Var', (170, 179))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('BRAFV600E', 'Mutation', 'rs113488022', (160, 169))	('IDH2', 'Gene', '3418', (112, 116))	('pleomorphic xanthoastrocytomas', 'Disease', (192, 222))	('BRAFV600E mutations', 'Var', (160, 179))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('IDH1', 'Gene', (104, 108))	('mutations', 'Var', (87, 96))	('tumors', 'Disease', (40, 46))
195321	30835699	The K27 subgroup is characterized by a midline location, typified by DIPGs and thalamic HGGs, and a predilection for affecting young children, whereas the G34, IDH, and BRAF subgroups most commonly arise in the cerebral hemispheres of older children, along with a subset of tumors (RTK-I) that exhibit amplification of the PDGFRA gene and a subset of so-called mesenchymal tumors.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('K27', 'Gene', '342574', (4, 7))	('IDH', 'Gene', (160, 163))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (361, 379))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('children', 'Species', '9606', (241, 249))	('tumors', 'Disease', (373, 379))	('PDGFRA', 'Gene', '5156', (323, 329))	('PDGFRA', 'Gene', (323, 329))	('mesenchymal tumors', 'Disease', (361, 379))	('K27', 'Gene', (4, 7))	('IDH', 'Gene', '3417', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (373, 379))	('children', 'Species', '9606', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Disease', (274, 280))	('amplification', 'Var', (302, 315))
195325	30835699	COG studies of BRAFV600E and MAPK inhibition with dabrafenib and trametinib are also under development for the subset of HGGs with BRAF mutations.	('BRAF', 'Gene', '673', (15, 19))	('HGGs', 'Disease', (121, 125))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', (15, 19))	('BRAFV600E', 'Mutation', 'rs113488022', (15, 24))	('dabrafenib', 'Chemical', 'MESH:C561627', (50, 60))	('trametinib', 'Chemical', 'MESH:C560077', (65, 75))	('mutations', 'Var', (136, 145))	('BRAF', 'Gene', '673', (131, 135))
195326	30835699	For the subsets of tumors lacking IDH, K27, or BRAF mutations, a protocol is under development using ABT888, a poly (ADP-ribose) (PARP) inhibitor, as a radiosensitizer.	('mutations', 'Var', (52, 61))	('K27', 'Gene', '342574', (39, 42))	('tumors lacking IDH', 'Disease', 'MESH:D001259', (19, 37))	('PARP', 'Gene', (130, 134))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('K27', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ABT888', 'Chemical', 'MESH:C521013', (101, 107))	('PARP', 'Gene', '142', (130, 134))	('tumors lacking IDH', 'Disease', (19, 37))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('poly (ADP-ribose)', 'Chemical', 'MESH:D011064', (111, 128))
195333	30835699	Whereas an LGG is likely to have prolonged sensitivity to MAPK inhibitor therapy, an SHH-activated medulloblastoma may rapidly develop mutations that render it resistant to a promising inhibitor.	('medulloblastoma', 'Disease', 'MESH:D008527', (99, 114))	('develop', 'Reg', (127, 134))	('medulloblastoma', 'Phenotype', 'HP:0002885', (99, 114))	('resistant', 'MPA', (160, 169))	('mutations', 'Var', (135, 144))	('medulloblastoma', 'Disease', (99, 114))	('SHH', 'Gene', '6469', (85, 88))	('SHH', 'Gene', (85, 88))
195336	30857299	Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins Isocitrate dehydrogenases (IDH) 1 and 2 are key metabolic enzymes that generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain a pool of reduced glutathione and peroxiredoxin, and produce alpha-ketoglutarate, a co-factor of numerous enzymes.	('peroxiredoxin', 'MPA', (293, 306))	('NADPH', 'Chemical', 'MESH:D009249', (240, 245))	('Gliomas', 'Disease', 'MESH:D005910', (36, 43))	('IDH', 'Gene', (16, 19))	('Gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('alpha-ketoglutarate', 'MPA', (320, 339))	('IDH', 'Gene', (94, 97))	('IDH1', 'Gene', (16, 20))	('IDH', 'Gene', '3417', (16, 19))	('pool of reduced glutathione', 'MPA', (261, 288))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (320, 339))	('IDH', 'Gene', (134, 137))	('Isocitrate dehydrogenases (IDH) 1 and 2', 'Gene', '3417;3418', (107, 146))	('Mutations', 'Var', (23, 32))	('Gliomas', 'Disease', (36, 43))	('IDH', 'Gene', '3417', (94, 97))	('IDH1', 'Gene', '3417', (16, 20))	('glutathione', 'Chemical', 'MESH:D005978', (277, 288))	('IDH', 'Gene', '3417', (134, 137))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (195, 238))
195337	30857299	IDH1/2 is mutated in ~70-80% of lower-grade gliomas and the majority of secondary glioblastomas.	('mutated', 'Var', (10, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('glioblastomas', 'Disease', 'MESH:D005909', (82, 95))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('glioblastomas', 'Disease', (82, 95))	('IDH1/2', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
195338	30857299	The mutant IDH1 (R132H), in addition to losing its normal catalytic activity, gains the function of producing the d-(R)-2-hydroxyglutarate (2-HG).	('R132H', 'Var', (17, 22))	('losing', 'NegReg', (40, 46))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('d-(R)-2-hydroxyglutarate', 'Chemical', '-', (114, 138))	('gains', 'PosReg', (78, 83))	('producing', 'PosReg', (100, 109))	('catalytic activity', 'MPA', (58, 76))	('IDH1', 'Gene', (11, 15))
195340	30857299	We summarize recent findings characterizing molecular mechanisms underlying oncogenic alterations associated with mutated IDH1/2, and their impact on tumor microenvironment and antitumor immunity.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutated', 'Var', (114, 121))	('IDH1/2', 'Gene', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('impact', 'Reg', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', (150, 155))
195341	30857299	Isoform-selective IDH inhibitors which suppress 2-HG production and induce antitumor responses in cells with IDH1 and IDH2 mutations were developed and validated in preclinical settings.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('IDH2', 'Gene', (118, 122))	('tumor', 'Disease', (79, 84))	('induce', 'PosReg', (68, 74))	('IDH', 'Gene', (18, 21))	('IDH', 'Gene', (109, 112))	('IDH', 'Gene', (118, 121))	('IDH2', 'Gene', '3418', (118, 122))	('IDH', 'Gene', '3417', (18, 21))	('suppress', 'NegReg', (39, 47))	('IDH', 'Gene', '3417', (118, 121))	('2-HG production', 'MPA', (48, 63))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mutations', 'Var', (123, 132))	('IDH', 'Gene', '3417', (109, 112))	('clinical', 'Species', '191496', (168, 176))
195342	30857299	Inhibitors of mutated IDH1/2 enzymes entered clinical trials and represent a novel drug class for targeted therapy of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('mutated', 'Var', (14, 21))	('IDH1/2', 'Gene', (22, 28))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('Inhibitors', 'Var', (0, 10))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('clinical', 'Species', '191496', (45, 53))
195344	30857299	All those results support the translational potential of strategies targeting gliomas carrying IDH1 mutations.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('mutations', 'Var', (100, 109))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('IDH1', 'Gene', (95, 99))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))
195345	30857299	Since the initial discovery of mutations in the isocitrate dehydrogenase 1 (IDH1) gene by whole-genome sequencing in a large subset of human gliomas, and in acute myelogenous leukemia (AML), much interest was focused on understanding consequences of mutations in IDH genes and their roles in tumor progression.	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (157, 183))	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('IDH', 'Gene', (263, 266))	('IDH', 'Gene', '3417', (76, 79))	('AML', 'Disease', 'MESH:D015470', (185, 188))	('AML', 'Phenotype', 'HP:0004808', (185, 188))	('AML', 'Disease', (185, 188))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('isocitrate', 'Chemical', 'MESH:C034219', (48, 58))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (163, 183))	('human', 'Species', '9606', (135, 140))	('IDH', 'Gene', '3417', (263, 266))	('mutations', 'Var', (31, 40))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (157, 183))	('gliomas', 'Disease', (141, 148))	('acute myelogenous leukemia', 'Disease', (157, 183))	('tumor', 'Disease', (292, 297))	('IDH', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
195358	30857299	High-density oligonucleotide arrays and next-generation sequencing of glioma samples of grades II and III (according to classification of the World Health Organization, WHO) revealed an unexpected spectrum of mutations, among which somatic, recurrent mutations in the IDH1 gene were found in 12% of glioma samples.	('IDH1', 'Gene', (268, 272))	('oligonucleotide', 'Chemical', 'MESH:D009841', (13, 28))	('mutations', 'Var', (251, 260))	('glioma', 'Disease', (299, 305))	('found', 'Reg', (283, 288))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (299, 305))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (299, 305))	('mutations', 'Var', (209, 218))
195359	30857299	IDH mutations occur early in pathogenesis of gliomas and persist throughout progression of a glioma from a neural stem or progenitor cell.	('IDH', 'Gene', (0, 3))	('glioma', 'Disease', (93, 99))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('mutations', 'Var', (4, 13))	('glioma', 'Disease', (45, 51))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('gliomas', 'Disease', (45, 52))
195360	30857299	All known IDH mutations are invariably monoallelic.	('IDH', 'Gene', (10, 13))	('mutations', 'Var', (14, 23))	('IDH', 'Gene', '3417', (10, 13))
195361	30857299	Mutations in IDH1 and IDH2 genes are mostly missense variants leading to a single amino-acid substitution of arginine residues at codon 132 in exon 4 of the IDH1 gene or codons 140 or 172 of the IDH2 gene (IDH1-R132, IDH2-R140, or IDH2-R172).	('IDH2', 'Gene', (231, 235))	('arginine residues', 'MPA', (109, 126))	('IDH2', 'Gene', (22, 26))	('IDH2', 'Gene', (195, 199))	('IDH1', 'Gene', (13, 17))	('IDH2', 'Gene', '3418', (195, 199))	('IDH2', 'Gene', '3418', (231, 235))	('Mutations', 'Var', (0, 9))	('IDH2', 'Gene', (217, 221))	('IDH1', 'Gene', (157, 161))	('IDH2', 'Gene', '3418', (22, 26))	('substitution', 'Var', (93, 105))	('leading to', 'Reg', (62, 72))	('IDH2', 'Gene', '3418', (217, 221))	('arginine', 'Chemical', 'MESH:D001120', (109, 117))
195362	30857299	In addition to losing its catalytic activity, mutant IDH1 and IDH2 enzymes gain the function of catalyzing the reduction of alpha-ketoglutarate (KG) to its (R)-enantiomer of 2-hydroxyglutarate (2-HG).	('gain', 'PosReg', (75, 79))	('losing', 'NegReg', (15, 21))	('catalytic activity', 'MPA', (26, 44))	('IDH1', 'Gene', (53, 57))	('alpha-ketoglutarate', 'MPA', (124, 143))	('mutant', 'Var', (46, 52))	('catalyzing', 'MPA', (96, 106))	('IDH2', 'Gene', '3418', (62, 66))	('IDH2', 'Gene', (62, 66))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (174, 192))	('reduction', 'MPA', (111, 120))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (124, 143))
195369	30857299	Changes in histone methylation profiles (especially H3K9 methylation) are associated with IDH mutations and result in inhibition of cell differentiation.	('IDH', 'Gene', (90, 93))	('mutations', 'Var', (94, 103))	('inhibition', 'NegReg', (118, 128))	('cell differentiation', 'CPA', (132, 152))	('histone methylation profiles', 'MPA', (11, 39))	('IDH', 'Gene', '3417', (90, 93))	('H3K9', 'Protein', (52, 56))	('Changes', 'Reg', (0, 7))	('associated', 'Reg', (74, 84))
195372	30857299	More detailed studies revealed that IDH mutation status is associated with a distinct angiogenesis transcriptome signature, decreased expression of HIF1alpha targets, and impairment of downstream biological functions such as angio- and vasculogenesis that are critical for tumor growth.	('mutation', 'Var', (40, 48))	('expression', 'MPA', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('HIF1alpha', 'Gene', (148, 157))	('decreased', 'NegReg', (124, 133))	('IDH', 'Gene', (36, 39))	('IDH', 'Gene', '3417', (36, 39))	('tumor', 'Disease', (273, 278))	('impairment', 'NegReg', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('HIF1alpha', 'Gene', '3091', (148, 157))	('angiogenesis transcriptome signature', 'MPA', (86, 122))
195373	30857299	IDH mutations cause profound changes in global cellular metabolism.	('global cellular metabolism', 'MPA', (40, 66))	('IDH', 'Gene', (0, 3))	('changes', 'Reg', (29, 36))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))
195374	30857299	Initial studies of the effect of IDH mutations on the tricarboxylic acid (TCA) cycle function failed to demonstrate significant alterations in TCA cycle metabolites.	('TCA', 'Chemical', 'MESH:D014233', (143, 146))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('mutations', 'Var', (37, 46))	('IDH', 'Gene', (33, 36))	('tricarboxylic acid', 'MPA', (54, 72))	('IDH', 'Gene', '3417', (33, 36))	('TCA', 'Chemical', 'MESH:D014233', (74, 77))
195376	30857299	N-Acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in IDH1-mut expressing cells and 8.3-fold reduced in IDH2-mut expressing cells.	('IDH2', 'Gene', '3418', (138, 142))	('dipeptide', 'Chemical', 'MESH:D004151', (45, 54))	('N-Acetyl-aspartyl-glutamate', 'Chemical', 'MESH:C027172', (0, 27))	('N-Acetyl-aspartyl-glutamate', 'MPA', (0, 27))	('reduced', 'NegReg', (77, 84))	('IDH2', 'Gene', (138, 142))	('NAAG', 'Chemical', 'MESH:C027172', (29, 33))	('IDH1-mut', 'Var', (88, 96))
195383	30857299	Genetic and pharmacological inactivation of IDH1 decreased GBM cell growth, promoted more differentiated phenotype, increased apoptosis in response to targeted therapies, and prolonged survival of animals with patient-derived xenografts.	('prolonged', 'PosReg', (175, 184))	('IDH1', 'Gene', (44, 48))	('survival', 'CPA', (185, 193))	('more differentiated phenotype', 'CPA', (85, 114))	('inactivation', 'Var', (28, 40))	('apoptosis', 'CPA', (126, 135))	('decreased', 'NegReg', (49, 58))	('patient', 'Species', '9606', (210, 217))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('increased', 'PosReg', (116, 125))	('promoted', 'PosReg', (76, 84))	('GBM cell growth', 'CPA', (59, 74))
195390	30857299	LGGs are further divided into IDH wild type or mutant, which is further classified into either an oligodendroglioma that harbors 1p/19q co-deletion or a diffuse astrocytoma that has an intact 1p/19q loci, but is enriched for ATRX and TP53 mutations.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('TP53', 'Gene', '7157', (234, 238))	('astrocytoma', 'Disease', (161, 172))	('TP53', 'Gene', (234, 238))	('1p/19q co-deletion', 'Var', (129, 147))	('ATRX', 'Gene', '546', (225, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('oligodendroglioma', 'Disease', (98, 115))	('IDH', 'Gene', (30, 33))	('ATRX', 'Gene', (225, 229))	('IDH', 'Gene', '3417', (30, 33))	('oligodendroglioma', 'Disease', 'MESH:D009837', (98, 115))	('astrocytoma', 'Disease', 'MESH:D001254', (161, 172))
195392	30857299	A mutation in IDH1 is sufficient to induce genome-wide changes in DNA methylation patterns, including the glioma cytosine phosphate guanine (CpG) island methylator phenotype (G-CIMP) found in a subset of gliomas, which is associated with diverse transcriptional changes.	('mutation', 'Var', (2, 10))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('G-CIMP', 'Chemical', '-', (175, 181))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('glioma', 'Disease', (204, 210))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('DNA methylation patterns', 'MPA', (66, 90))	('cytosine phosphate guanine', 'Chemical', '-', (113, 139))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('glioma', 'Disease', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('IDH1', 'Gene', (14, 18))	('changes', 'Reg', (55, 62))
195399	30857299	Clinical statistics show that a median overall survival (OS) is 31 months for secondary GBM patients with IDH mutations compared to 15 months for those without the mutations.	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('IDH', 'Gene', '3417', (106, 109))	('Clinical', 'Species', '191496', (0, 8))	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (92, 100))	('secondary GBM', 'Disease', (78, 91))	('IDH', 'Gene', (106, 109))
195401	30857299	The presence of IDH1 mutations in anaplastic oligodendroglioma patients is a very strong prognostic factor for OS, but has no a predictive significance for outcome to PCV chemotherapy (adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine).	('mutations', 'Var', (21, 30))	('PCV', 'Species', '28355', (167, 170))	('procarbazine', 'Chemical', 'MESH:D011344', (194, 206))	('1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea', 'Chemical', '-', (208, 252))	('oligodendroglioma', 'Disease', 'MESH:D009837', (45, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH1', 'Gene', (16, 20))	('vincristine', 'Chemical', 'MESH:D014750', (258, 269))	('patients', 'Species', '9606', (63, 71))	('oligodendroglioma', 'Disease', (45, 62))
195402	30857299	All reasons for which glioma patients with IDH1 mutations show better therapeutic responses and longer survival remain unclear.	('patients', 'Species', '9606', (29, 37))	('IDH1', 'Gene', (43, 47))	('glioma', 'Disease', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('mutations', 'Var', (48, 57))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
195403	30857299	Almost 100% of tumors of oligoastrocytic and oligodendrocytic origin harbor IDH1/2 mutations; up to now, there is no evidence of any mutations in IDH3 in glial tumors.	('mutations', 'Var', (83, 92))	('glial tumors', 'Disease', 'MESH:D005910', (154, 166))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('glial tumors', 'Disease', (154, 166))	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', '3417', (146, 149))	('tumors of oligoastrocytic and oligodendrocytic', 'Disease', 'MESH:D009369', (15, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
195404	30857299	IDH1/2 mutations were found in a majority of secondary GBMs (derived from lower-grade tumors), but only 2-3% were found in primary GBMs or pediatric gliomas.	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('GBMs', 'Phenotype', 'HP:0012174', (131, 135))	('pediatric gliomas', 'Disease', (139, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('secondary GBMs', 'Disease', (45, 59))	('tumors', 'Disease', (86, 92))	('found', 'Reg', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('GBMs', 'Phenotype', 'HP:0012174', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('pediatric gliomas', 'Disease', 'MESH:D005910', (139, 156))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
195405	30857299	IDH mutations are considered to be the primary initiating event in WHO grade II/III gliomas and secondary GBMs.	('IDH', 'Gene', (0, 3))	('III gliomas', 'Disease', (80, 91))	('IDH', 'Gene', '3417', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('GBMs', 'Phenotype', 'HP:0012174', (106, 110))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('mutations', 'Var', (4, 13))	('III gliomas', 'Disease', 'MESH:D005910', (80, 91))
195406	30857299	Several concepts were conceived to explain how IDH mutations influence patient outcome.	('IDH', 'Gene', '3417', (47, 50))	('mutations', 'Var', (51, 60))	('influence', 'Reg', (61, 70))	('patient', 'Species', '9606', (71, 78))	('IDH', 'Gene', (47, 50))
195407	30857299	It is believed that decreased MGMT expression, caused by the MGMT gene promoter methylation, has a major influence on GBMs responsiveness to alkylating agent therapy (i.e., temozolomide, TMZ).	('GBM', 'Phenotype', 'HP:0012174', (118, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (187, 190))	('decreased', 'NegReg', (20, 29))	('influence', 'Reg', (105, 114))	('GBMs', 'Phenotype', 'HP:0012174', (118, 122))	('MGMT', 'Gene', '4255', (61, 65))	('methylation', 'Var', (80, 91))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', (61, 65))	('temozolomide', 'Chemical', 'MESH:D000077204', (173, 185))	('MGMT', 'Gene', '4255', (30, 34))	('responsiveness', 'MPA', (123, 137))
195408	30857299	IDH mutations occur more frequently in young patients (younger age of diagnosis) with WHO grade II/III gliomas, who have generally better prognosis.	('IDH', 'Gene', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('III gliomas', 'Disease', 'MESH:D005910', (99, 110))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('III gliomas', 'Disease', (99, 110))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (4, 13))
195409	30857299	However, the IDH1 mutation does not directly or always correlate with patient survival.	('patient', 'Species', '9606', (70, 77))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', (13, 17))
195411	30857299	However, the presence of IDH1 mutation was a weak prognostic factor in GBM patients with a long-term survival.	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('mutation', 'Var', (30, 38))	('patients', 'Species', '9606', (75, 83))	('GBM', 'Disease', (71, 74))	('IDH1', 'Gene', (25, 29))
195412	30857299	Also, in the case of low-grade oligodendroglial tumors, the mutation in IDH1 was not a prognostic factor.	('mutation', 'Var', (60, 68))	('IDH1', 'Gene', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (31, 54))	('oligodendroglial tumors', 'Disease', (31, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
195413	30857299	While 91% of oligodendrogliomas harbored the IDH1 mutation, the survival times of patients with IDH1-mut tumors were not different compared to patients with IDH1-wt tumors.	('tumors', 'Disease', (105, 111))	('IDH1-wt tumors', 'Disease', 'MESH:D009369', (157, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('harbored', 'Reg', (32, 40))	('mutation', 'Var', (50, 58))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('IDH1', 'Gene', (45, 49))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (13, 31))	('patients', 'Species', '9606', (82, 90))	('tumors', 'Disease', (165, 171))	('IDH1-wt tumors', 'Disease', (157, 171))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('oligodendrogliomas', 'Disease', (13, 31))
195414	30857299	Patients with IDH1-mut diffuse astrocytomas lived significantly longer.	('longer', 'PosReg', (64, 70))	('astrocytomas', 'Disease', 'MESH:D001254', (31, 43))	('astrocytoma', 'Phenotype', 'HP:0009592', (31, 42))	('IDH1-mut', 'Var', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('astrocytomas', 'Disease', (31, 43))
195415	30857299	This suggests that IDH mutations could be a prognostic factor for diffuse astrocytoma, but not for oligodendroglioma.	('oligodendroglioma', 'Disease', 'MESH:D009837', (99, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('mutations', 'Var', (23, 32))	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', (19, 22))	('astrocytoma', 'Disease', 'MESH:D001254', (74, 85))	('astrocytoma', 'Disease', (74, 85))	('oligodendroglioma', 'Disease', (99, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))
195416	30857299	Several reports pointed out that prognosis for glioma patients with the IDH1 mutation is associated with DNA methylation patterns.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('associated', 'Reg', (89, 99))	('DNA methylation', 'MPA', (105, 120))	('IDH1', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('patients', 'Species', '9606', (54, 62))	('glioma', 'Disease', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
195417	30857299	There is a subtype of glioma characterized by the presence of the IDH mutation and a low level of DNA methylation (G-CIMP-low) which was associated with a poor outcome.	('IDH', 'Gene', (66, 69))	('G-CIMP', 'Chemical', '-', (115, 121))	('IDH', 'Gene', '3417', (66, 69))	('DNA methylation', 'MPA', (98, 113))	('subtype of glioma', 'Disease', 'MESH:D005910', (11, 28))	('presence', 'Var', (50, 58))	('subtype of glioma', 'Disease', (11, 28))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('mutation', 'Var', (70, 78))
195418	30857299	Additionally, the impact of IDH1 mutations for patient survival may depend on other factors, such as alterations in 1p/19q, ATRX, PTEN, or MGMT methylation status.	('patient', 'Species', '9606', (47, 54))	('alterations', 'Var', (101, 112))	('MGMT', 'Gene', (139, 143))	('1p/19q', 'Protein', (116, 122))	('mutations', 'Var', (33, 42))	('MGMT', 'Gene', '4255', (139, 143))	('ATRX', 'Gene', (124, 128))	('PTEN', 'Gene', (130, 134))	('PTEN', 'Gene', '5728', (130, 134))	('ATRX', 'Gene', '546', (124, 128))	('IDH1', 'Gene', (28, 32))
195420	30857299	Patients with IDH1/2-mut and a low level of Ki-67 expression had a relatively good prognosis, while patients with IDH1/2-mut and a high level of Ki-67 expression had significantly worse prognosis and shorter times of survival.	('IDH1/2-mut', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (100, 108))	('shorter', 'NegReg', (200, 207))	('low', 'NegReg', (31, 34))	('Ki-67', 'Gene', (44, 49))
195421	30857299	Outcome of patients with IDH mutation was also associated with the occurrence of copy number alterations (CNAs).	('patients', 'Species', '9606', (11, 19))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('copy number alterations', 'Var', (81, 104))
195422	30857299	Patients characterized by the presence of one of the CNAs, +7q, +8q, -9p, or -11p, were associated with worse prognosis and worse overall survival when compared to other patients with the IDH mutation.	('patients', 'Species', '9606', (170, 178))	('IDH', 'Gene', '3417', (188, 191))	('+7q', 'Var', (59, 62))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', (188, 191))
195423	30857299	Additionally, prognosis and time of survival of patients with the IDH mutation may be gender-dependent; the presence of the IDH1 mutation was associated with a longer time of survival in male, but not in female patients.	('longer', 'PosReg', (160, 166))	('presence', 'Var', (108, 116))	('IDH', 'Gene', (66, 69))	('patients', 'Species', '9606', (211, 219))	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', '3417', (66, 69))	('IDH', 'Gene', '3417', (124, 127))	('patients', 'Species', '9606', (48, 56))
195424	30857299	While the presence of IDH mutations commonly correlates with better outcome of glioma patients, some studies showed the connection between the presence of IDH mutation and seizure risk in glioma patients.	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('connection', 'Reg', (120, 130))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('mutations', 'Var', (26, 35))	('presence', 'Var', (143, 151))	('patients', 'Species', '9606', (86, 94))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('IDH', 'Gene', (22, 25))	('patients', 'Species', '9606', (195, 203))	('IDH', 'Gene', (155, 158))	('seizure', 'Disease', 'MESH:D012640', (172, 179))	('IDH', 'Gene', '3417', (22, 25))	('seizure', 'Phenotype', 'HP:0001250', (172, 179))	('glioma', 'Disease', (79, 85))	('seizure', 'Disease', (172, 179))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('IDH', 'Gene', '3417', (155, 158))	('glioma', 'Disease', (188, 194))	('presence', 'Var', (10, 18))
195425	30857299	A majority of patients with WHO grade II astrocytoma (but not GBM) suffered pre-operative seizures related to the presence of IDH mutation.	('presence', 'Var', (114, 122))	('IDH', 'Gene', '3417', (126, 129))	('mutation', 'Var', (130, 138))	('II astrocytoma', 'Disease', (38, 52))	('suffered', 'Reg', (67, 75))	('II astrocytoma', 'Disease', 'MESH:D001254', (38, 52))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('seizures', 'Disease', 'MESH:D012640', (90, 98))	('seizures', 'Disease', (90, 98))	('seizure', 'Phenotype', 'HP:0001250', (90, 97))	('seizures', 'Phenotype', 'HP:0001250', (90, 98))	('IDH', 'Gene', (126, 129))	('patients', 'Species', '9606', (14, 22))
195426	30857299	A recent meta-analysis confirmed that the presence of IDH1 mutation is correlated with the higher number of preoperative seizures in LGG.	('seizure', 'Phenotype', 'HP:0001250', (121, 128))	('IDH1', 'Gene', (54, 58))	('LGG', 'Disease', (133, 136))	('seizures', 'Phenotype', 'HP:0001250', (121, 129))	('seizures', 'Disease', 'MESH:D012640', (121, 129))	('mutation', 'Var', (59, 67))	('seizures', 'Disease', (121, 129))	('presence', 'Var', (42, 50))
195429	30857299	Recent studies provided emerging insights into how IDH mutations affect the glioma microenvironment.	('affect', 'Reg', (65, 71))	('glioma', 'Disease', (76, 82))	('IDH', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))	('IDH', 'Gene', '3417', (51, 54))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))
195437	30857299	The impact of IDH mutations on immune microenvironment is under debate.	('IDH', 'Gene', '3417', (14, 17))	('IDH', 'Gene', (14, 17))	('mutations', 'Var', (18, 27))
195439	30857299	Introduction of mutant IDH1 or treatment with 2-HG reduced levels of a chemokine CXCL (C-X-C motif) 10, which was associated with decreased expression of a transcription factor STAT1 (signal transducer and activator of transcription 1), an inducer of inflammation.	('reduced', 'NegReg', (51, 58))	('expression', 'MPA', (140, 150))	('IDH1', 'Gene', (23, 27))	('inflammation', 'Disease', 'MESH:D007249', (251, 263))	('mutant', 'Var', (16, 22))	('STAT1', 'Gene', (177, 182))	('signal transducer and activator of transcription 1', 'Gene', '6772', (184, 234))	('inflammation', 'Disease', (251, 263))	('decreased', 'NegReg', (130, 139))	('STAT1', 'Gene', '6772', (177, 182))
195440	30857299	Forced expression of a mutant IDH1 also suppressed the accumulation of T cells at tumor sites.	('suppressed', 'NegReg', (40, 50))	('accumulation of T cells', 'Phenotype', 'HP:0100828', (55, 78))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('IDH1', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('mutant', 'Var', (23, 29))
195441	30857299	Those events were reversed by IDH-C35, a specific inhibitor of a mutant IDH1.	('mutant', 'Var', (65, 71))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (30, 33))
195442	30857299	A single study showed that IDH1 mutation did not associate with increased intratumoral expression of either PD-1+ TIL or PD-L1 in GBMs.	('PD-L1', 'Gene', (121, 126))	('PD-L1', 'Gene', '29126', (121, 126))	('tumor', 'Disease', (79, 84))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('GBMs', 'Phenotype', 'HP:0012174', (130, 134))	('IDH1', 'Gene', (27, 31))	('PD-1+', 'Protein', (108, 113))	('mutation', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
195449	30857299	A flow cytometry analysis of immune composition of human gliomas with a different IDH1 status demonstrated that human IDH1-mut gliomas have significantly lower infiltration of CD45+ immune cells, including microglia, macrophages, dendritic cells, B cells, and T cells, compared with IDH1-wt gliomas.	('lower infiltration of CD45+ immune cells', 'Phenotype', 'HP:0410378', (154, 194))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('human', 'Species', '9606', (51, 56))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (291, 298))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('human', 'Species', '9606', (112, 117))	('glioma', 'Phenotype', 'HP:0009733', (291, 297))	('lower', 'NegReg', (154, 159))	('CD45', 'Gene', (176, 180))	('infiltration', 'CPA', (160, 172))	('IDH1-wt gliomas', 'Disease', (283, 298))	('gliomas', 'Disease', 'MESH:D005910', (291, 298))	('CD45', 'Gene', '5788', (176, 180))	('IDH1-wt gliomas', 'Disease', 'MESH:D005910', (283, 298))	('gliomas', 'Phenotype', 'HP:0009733', (291, 298))	('gliomas', 'Disease', (57, 64))	('gliomas', 'Disease', (127, 134))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('IDH1-mut', 'Var', (118, 126))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
195451	30857299	Introduction of IDH1-mut into transgenic mouse gliomas with different genetic background, expressing platelet-derived growth factor alpha (PDGFalpha), shp53, or Ink4a/Arf+/+ and Ink4a/Arf+/-, demonstrated significantly shorter survival compared to mice with IDH1-wt tumors.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('shorter', 'NegReg', (219, 226))	('mouse', 'Species', '10090', (41, 46))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('platelet-derived growth factor alpha', 'Gene', '18590', (101, 137))	('IDH1-wt tumors', 'Disease', 'MESH:D009369', (258, 272))	('Ink4a', 'Gene', '12578', (161, 166))	('Ink4a', 'Gene', '12578', (178, 183))	('Ink4a', 'Gene', (161, 166))	('Ink4a', 'Gene', (178, 183))	('PDGFalpha', 'Gene', '18590', (139, 148))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('platelet-derived growth factor alpha', 'Gene', (101, 137))	('PDGFalpha', 'Gene', (139, 148))	('mice', 'Species', '10090', (248, 252))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('IDH1-wt tumors', 'Disease', (258, 272))	('survival', 'CPA', (227, 235))	('shp53', 'Var', (151, 156))	('gliomas', 'Disease', (47, 54))
195452	30857299	Similar to human IDH1-mut gliomas, reductions in CD45+ cells, including microglia, macrophages, monocytes, and polymorphonuclear leukocytes, were reported in the IDH1-mut murine tumors.	('reductions', 'NegReg', (35, 45))	('CD45', 'Gene', (49, 53))	('human', 'Species', '9606', (11, 16))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('murine', 'Species', '10090', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('CD45', 'Gene', '5788', (49, 53))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('IDH1-mut', 'Var', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
195453	30857299	Gene expression in IDH1-mut mouse gliomas was negatively associated with leukocyte and neutrophil migration.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('associated', 'Interaction', (57, 67))	('mouse', 'Species', '10090', (28, 33))	('negatively', 'NegReg', (46, 56))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('IDH1-mut', 'Var', (19, 27))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('gliomas', 'Disease', (34, 41))
195454	30857299	All G-CIMP and IDH1-mut GBMs were characterized by negative immune responses and lower human leukocyte antigen (HLA) expression.	('G-CIMP', 'Chemical', '-', (4, 10))	('lower', 'NegReg', (81, 86))	('G-CIMP', 'Var', (4, 10))	('human', 'Species', '9606', (87, 92))	('negative', 'NegReg', (51, 59))	('GBM', 'Phenotype', 'HP:0012174', (24, 27))	('GBMs', 'Phenotype', 'HP:0012174', (24, 28))	('IDH1-mut', 'Var', (15, 23))	('immune responses', 'CPA', (60, 76))
195455	30857299	The analyses of complement activation and CD4+, CD8+, or FoxP3+ T-cell infiltration in sections from 72 gliomas of WHO grade III and IV with or without IDH mutations showed significantly reduced complement activation and decreased numbers of tumor-infiltrating CD4+ and CD8+ T cells with comparable FoxP3+/CD4+ ratios.	('CD4', 'Gene', (261, 264))	('CD8', 'Gene', '925', (270, 273))	('IDH', 'Gene', (152, 155))	('tumor', 'Disease', (242, 247))	('CD8', 'Gene', '925', (48, 51))	('FoxP3', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('decreased', 'NegReg', (221, 230))	('FoxP3', 'Gene', '50943', (57, 62))	('CD4', 'Gene', '920', (306, 309))	('IDH', 'Gene', '3417', (152, 155))	('gliomas', 'Disease', (104, 111))	('CD8', 'Gene', (270, 273))	('mutations', 'Var', (156, 165))	('complement', 'CPA', (195, 205))	('CD4', 'Gene', (306, 309))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('FoxP3', 'Gene', (299, 304))	('CD8', 'Gene', (48, 51))	('CD4', 'Gene', '920', (42, 45))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('CD4', 'Gene', (42, 45))	('FoxP3', 'Gene', '50943', (299, 304))	('CD4', 'Gene', '920', (261, 264))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('reduced', 'NegReg', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
195458	30857299	A direct link between an IDH mutation and T-cell functions was recently demonstrated.	('mutation', 'Var', (29, 37))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('T-cell functions', 'CPA', (42, 58))
195460	30857299	IDH1-mut gliomas showed reduced T-cell numbers and altered calcium signaling.	('altered', 'Reg', (51, 58))	('IDH1-mut', 'Var', (0, 8))	('gliomas', 'Disease', (9, 16))	('reduced', 'NegReg', (24, 31))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('calcium signaling', 'MPA', (59, 76))	('T-cell numbers', 'CPA', (32, 46))	('reduced T-cell numbers', 'Phenotype', 'HP:0005403', (24, 46))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('calcium', 'Chemical', 'MESH:D002118', (59, 66))
195461	30857299	Consistently, antitumor immunity to experimental syngeneic IDH1-mut gliomas induced by an IDH1-specific vaccine or checkpoint inhibition was significantly improved by inhibition of the enzymatic function of mutant IDH1.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Disease', (18, 23))	('IDH1', 'Gene', (214, 218))	('inhibition', 'NegReg', (167, 177))	('improved', 'PosReg', (155, 163))	('IDH1-mut', 'Gene', (59, 67))	('mutant', 'Var', (207, 213))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('enzymatic', 'MPA', (185, 194))
195470	30857299	In principle, small molecules are designed to bind within the active catalytic site of a mutant IDH1/2 and block the conformational change required for the enzyme to convert alpha-KG to 2-HG.	('block', 'NegReg', (107, 112))	('conformational change', 'MPA', (117, 138))	('bind', 'Interaction', (46, 50))	('alpha-KG', 'Chemical', 'MESH:D007656', (174, 182))	('IDH1/2', 'Gene', (96, 102))	('mutant', 'Var', (89, 95))	('convert alpha-KG to 2-HG', 'MPA', (166, 190))
195471	30857299	Current targeted inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221), and pan-IDH1/2 (AG881) selectively inhibit the mutant IDH activity and induce cell differentiation in in vitro and in vivo models.	('IDH', 'Gene', (31, 34))	('IDH2', 'Gene', (53, 57))	('activity', 'MPA', (125, 133))	('IDH', 'Gene', (121, 124))	('IDH', 'Gene', '3417', (31, 34))	('IDH305', 'Chemical', '-', (44, 50))	('mutant', 'Var', (114, 120))	('induce', 'Reg', (138, 144))	('cell differentiation', 'CPA', (145, 165))	('IDH2', 'Gene', '3418', (53, 57))	('IDH', 'Gene', '3417', (121, 124))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (53, 56))	('inhibit', 'NegReg', (102, 109))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', '3417', (53, 56))
195473	30857299	AG-120 is a first-in-class, orally administered, reversible, and highly selective small-molecule inhibitor of mutant IDH1/R132H with half maximal inhibitory concentration (IC50) = 40-50 nM.	('IDH1/R132H', 'Gene', (117, 127))	('R132H', 'Mutation', 'rs121913500', (122, 127))	('mutant', 'Var', (110, 116))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))
195475	30857299	AG-120 is currently being evaluated in several clinical trials for the therapy of patients with relapsed or refractory AML, myelodysplastic syndrome, and advanced solid tumors including glioma, chondrosarcoma, and cholangiocarcinoma with a mutant IDH1/R132H (Table 1).	('glioma', 'Disease', (186, 192))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (124, 148))	('solid tumors', 'Disease', (163, 175))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('IDH1/R132H', 'Gene', (247, 257))	('mutant', 'Var', (240, 246))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('AML', 'Phenotype', 'HP:0004808', (119, 122))	('AML', 'Disease', (119, 122))	('clinical', 'Species', '191496', (47, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (214, 232))	('solid tumors', 'Disease', 'MESH:D009369', (163, 175))	('patients', 'Species', '9606', (82, 90))	('myelodysplastic syndrome', 'Disease', (124, 148))	('chondrosarcoma', 'Disease', 'MESH:D002813', (194, 208))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('cholangiocarcinoma', 'Disease', (214, 232))	('chondrosarcoma', 'Disease', (194, 208))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (214, 232))	('R132H', 'Mutation', 'rs121913500', (252, 257))	('AG-120', 'Chemical', 'MESH:C000627630', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (194, 208))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (124, 148))
195478	30857299	The plasma 2-HG level in patients with IDH1-mutant AML was reduced almost completely after AG-120 treatment.	('AML', 'Disease', (51, 54))	('reduced', 'NegReg', (59, 66))	('AML', 'Phenotype', 'HP:0004808', (51, 54))	('IDH1-mutant', 'Var', (39, 50))	('patients', 'Species', '9606', (25, 33))	('AML', 'Disease', 'MESH:D015470', (51, 54))	('plasma 2-HG level', 'MPA', (4, 21))	('AG-120', 'Chemical', 'MESH:C000627630', (91, 97))
195482	30857299	AGI-5198 also reduced growth of human IDH1/R132H glioma xenografts in mice and did not impair glioma expressing wild type IDH1, without significant toxicity.	('reduced', 'NegReg', (14, 21))	('glioma', 'Disease', (94, 100))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('mice', 'Species', '10090', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('growth', 'CPA', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1/R132H', 'Var', (38, 48))	('human', 'Species', '9606', (32, 37))	('AGI-5198', 'Chemical', 'MESH:C581156', (0, 8))	('toxicity', 'Disease', (148, 156))	('R132H', 'Mutation', 'rs121913500', (43, 48))	('glioma', 'Disease', (49, 55))
195484	30857299	AGI-5198 also reduced 2-HG levels in human chondrosarcoma cells that harbor IDH1/R132G and IDH1/R132C mutations in a dose-dependent manner.	('R132G', 'Mutation', 'rs121913499', (81, 86))	('reduced', 'NegReg', (14, 21))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (43, 57))	('R132C', 'Mutation', 'rs121913499', (96, 101))	('2-HG levels', 'MPA', (22, 33))	('chondrosarcoma', 'Disease', (43, 57))	('IDH1/R132G', 'Gene', (76, 86))	('human', 'Species', '9606', (37, 42))	('chondrosarcoma', 'Disease', 'MESH:D002813', (43, 57))	('AGI-5198', 'Chemical', 'MESH:C581156', (0, 8))	('IDH1/R132C mutations', 'Var', (91, 111))
195485	30857299	Moreover, AGI-5198 significantly inhibited colony formation and migration of chondrosarcoma cells, without influence on IDH1-wt human normal chondrocytes, and induced an apoptotic cell death and G2/M cell-cycle arrest in human chondrosarcoma cells in vitro.	('chondrosarcoma', 'Disease', 'MESH:D002813', (227, 241))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (77, 91))	('inhibited', 'NegReg', (33, 42))	('chondrosarcoma', 'Disease', (227, 241))	('colony formation', 'CPA', (43, 59))	('human', 'Species', '9606', (221, 226))	('arrest', 'Disease', 'MESH:D006323', (211, 217))	('AGI-5198', 'Var', (10, 18))	('human', 'Species', '9606', (128, 133))	('chondrosarcoma', 'Disease', (77, 91))	('chondrosarcoma', 'Disease', 'MESH:D002813', (77, 91))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (227, 241))	('arrest', 'Disease', (211, 217))	('AGI-5198', 'Chemical', 'MESH:C581156', (10, 18))	('induced', 'Reg', (159, 166))	('apoptotic cell death', 'CPA', (170, 190))
195487	30857299	BAY-1436032 is a small-molecule, oral inhibitor of pan-mutant IDH1 with IC50 = 3-16 nM.	('pan-mutant', 'Var', (51, 61))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (0, 11))	('BAY-1436032', 'Var', (0, 11))	('IDH1', 'Gene', (62, 66))
195489	30857299	In mice with implanted AML xenografts, BAY-1436032 decreased the level of 2-HG in serum nearly to the level found in normal tissues, and promoted differentiation of leukemic blast cells which correlated with the prolonged survival.	('BAY-1436032', 'Chemical', 'MESH:C000622445', (39, 50))	('leukemic', 'Disease', 'MESH:D007938', (165, 173))	('promoted', 'PosReg', (137, 145))	('BAY-1436032', 'Var', (39, 50))	('AML', 'Disease', 'MESH:D015470', (23, 26))	('mice', 'Species', '10090', (3, 7))	('decreased', 'NegReg', (51, 60))	('AML', 'Phenotype', 'HP:0004808', (23, 26))	('level of 2-HG in serum', 'MPA', (65, 87))	('differentiation', 'CPA', (146, 161))	('AML', 'Disease', (23, 26))	('leukemic', 'Disease', (165, 173))
195491	30857299	Similarly to other IDH-mutant inhibitors, BAY-1436032 affected global histone and DNA methylation levels.	('affected', 'Reg', (54, 62))	('global histone', 'MPA', (63, 77))	('BAY-1436032', 'Chemical', 'MESH:C000622445', (42, 53))	('BAY-1436032', 'Var', (42, 53))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (19, 22))
195493	30857299	FT-2102 is a small-molecule, oral allosteric inhibitor of mutant IDH1 (IC50 = 10 nM) currently undergoing a clinical study for the treatment of patients with IDH1-mut AML or higher-risk myelodysplastic syndrome, who relapsed or are refractory to a prior therapy or were disqualified for standard treatment.	('mutant', 'Var', (58, 64))	('clinical', 'Species', '191496', (108, 116))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (186, 210))	('AML', 'Disease', 'MESH:D015470', (167, 170))	('FT-2102', 'Chemical', '-', (0, 7))	('patients', 'Species', '9606', (144, 152))	('myelodysplastic syndrome', 'Disease', (186, 210))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (186, 210))	('AML', 'Disease', (167, 170))	('IDH1', 'Gene', (65, 69))	('AML', 'Phenotype', 'HP:0004808', (167, 170))
195495	30857299	HMS-101 is a small-molecule inhibitor of mutant IDH1 which reduced 2-HG level, affected proliferation and the ERK (extracellular signal-regulated kinase) signaling pathway, and inhibited colony formation of IDH1-mut murine cells and primary AML cells cultured ex vivo without affecting normal bone marrow cells.	('inhibited', 'NegReg', (177, 186))	('ERK', 'Gene', (110, 113))	('reduced', 'NegReg', (59, 66))	('murine', 'Species', '10090', (216, 222))	('colony formation', 'CPA', (187, 203))	('mutant', 'Var', (41, 47))	('ERK', 'Gene', '26413', (110, 113))	('2-HG level', 'MPA', (67, 77))	('extracellular signal-regulated kinase', 'Gene', (115, 152))	('AML', 'Disease', 'MESH:D015470', (241, 244))	('HMS', 'Disease', 'MESH:C537627', (0, 3))	('affected', 'Reg', (79, 87))	('extracellular signal-regulated kinase', 'Gene', '26413', (115, 152))	('proliferation', 'CPA', (88, 101))	('IDH1', 'Gene', (48, 52))	('HMS', 'Disease', (0, 3))	('AML', 'Disease', (241, 244))	('AML', 'Phenotype', 'HP:0004808', (241, 244))
195499	30857299	IDH305 is a small-molecule, oral, highly selective, allosteric inhibitor of the mutant IDH1/R132H.	('IDH1/R132H', 'Gene', (87, 97))	('IDH305', 'Chemical', '-', (0, 6))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('mutant', 'Var', (80, 86))
195500	30857299	IDH305 inhibited 2-HG production and tumor cell proliferation with an IC50 = 24 nM, and showed an anticancer activity in IDH1/132H-mut cells in preclinical studies.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('IDH305', 'Var', (0, 6))	('cancer', 'Disease', (102, 108))	('2-HG production', 'MPA', (17, 32))	('tumor', 'Disease', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('inhibited', 'NegReg', (7, 16))	('IDH305', 'Chemical', '-', (0, 6))	('clinical', 'Species', '191496', (147, 155))
195501	30857299	IDH305 is under clinical evaluation as a single agent or in combination with standard treatments for the therapy of patients with progressive II or III gliomas, low-grade gliomas with measurable 2-HG levels, AML, and other advanced malignancies harboring IDH1/R132H mutations (see summary in Table 1).	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (171, 178))	('malignancies', 'Disease', 'MESH:D009369', (232, 244))	('2-HG levels', 'MPA', (195, 206))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('IDH305', 'Var', (0, 6))	('AML', 'Disease', 'MESH:D015470', (208, 211))	('malignancies', 'Disease', (232, 244))	('III gliomas', 'Disease', (148, 159))	('patients', 'Species', '9606', (116, 124))	('IDH1/R132H', 'Gene', (255, 265))	('AML', 'Phenotype', 'HP:0004808', (208, 211))	('AML', 'Disease', (208, 211))	('clinical', 'Species', '191496', (16, 24))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('gliomas', 'Disease', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('R132H', 'Mutation', 'rs121913500', (260, 265))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('IDH305', 'Chemical', '-', (0, 6))	('III gliomas', 'Disease', 'MESH:D005910', (148, 159))
195502	30857299	Early results from clinical studies demonstrated an encouraging anticancer potential of IDH305 and a favorable safety profile in patients with AML harboring mutant IDH1/132H.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('IDH305', 'Chemical', '-', (88, 94))	('mutant', 'Var', (157, 163))	('patients', 'Species', '9606', (129, 137))	('clinical', 'Species', '191496', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('IDH1/132H', 'Gene', (164, 173))	('cancer', 'Disease', (68, 74))	('AML', 'Disease', (143, 146))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
195507	30857299	AG-221 (enasidenib, CC-90007) is an orally available, reversible, and highly selective inhibitor of the mutant IDH2/R140Q with IC50 = 12 nM.	('IDH2', 'Gene', '3418', (111, 115))	('mutant', 'Var', (104, 110))	('R140Q', 'Mutation', 'rs121913502', (116, 121))	('enasidenib', 'Chemical', 'MESH:C000605269', (8, 18))	('CC-90007', 'Chemical', 'MESH:C000605269', (20, 28))	('IDH2', 'Gene', (111, 115))	('AG-221', 'Chemical', 'MESH:C000605269', (0, 6))
195509	30857299	AG-221 is currently being evaluated in several clinical trials for the use in advanced hematologic malignancies positive for a mutated IDH2.	('IDH2', 'Gene', (135, 139))	('hematologic malignancies', 'Disease', (87, 111))	('mutated', 'Var', (127, 134))	('IDH2', 'Gene', '3418', (135, 139))	('clinical', 'Species', '191496', (47, 55))	('hematologic malignancies', 'Disease', 'MESH:D019337', (87, 111))	('AG-221', 'Chemical', 'MESH:C000605269', (0, 6))
195517	30857299	Recently, the inhibitor entered clinical trials for the treatment of patients with advanced solid tumors including glioma, chondrosarcoma, and cholangiocarcinoma with a mutated IDH2 (Table 1).	('solid tumors', 'Disease', (92, 104))	('chondrosarcoma', 'Disease', 'MESH:D002813', (123, 137))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('IDH2', 'Gene', (177, 181))	('glioma', 'Disease', (115, 121))	('mutated', 'Var', (169, 176))	('clinical', 'Species', '191496', (32, 40))	('IDH2', 'Gene', '3418', (177, 181))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (143, 161))	('solid tumors', 'Disease', 'MESH:D009369', (92, 104))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (123, 137))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('patients', 'Species', '9606', (69, 77))	('cholangiocarcinoma', 'Disease', (143, 161))	('chondrosarcoma', 'Disease', (123, 137))
195519	30857299	Preclinical studies indicated that AG-881 blocks both mutated IDH1 and IDH2 proteins with IC50 = 0.04-22 nM, decreases the level of 2-HG, and crosses the blood-brain barrier.	('AG-881', 'Var', (35, 41))	('level of 2-HG', 'MPA', (123, 136))	('mutated', 'MPA', (54, 61))	('IDH2', 'Gene', (71, 75))	('blocks', 'NegReg', (42, 48))	('IDH2', 'Gene', '3418', (71, 75))	('clinical', 'Species', '191496', (3, 11))	('crosses', 'Reg', (142, 149))	('IDH1', 'Gene', (62, 66))	('AG-881', 'Chemical', '-', (35, 41))	('decreases', 'NegReg', (109, 118))
195520	30857299	AG-881 was shown as a full brain-penetrant and, thus, may possibly represent a more effective agent for the therapy of patients with IDH1/2-mut gliomas.	('IDH1/2-mut', 'Var', (133, 143))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('AG-881', 'Gene', (0, 6))	('patients', 'Species', '9606', (119, 127))	('AG-881', 'Chemical', '-', (0, 6))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))
195522	30857299	AG-881 is currently being investigated in clinical trials for patients with solid tumors, including gliomas and advanced hematologic malignancies harboring mutated IDH1 and/or IDH2 that progressed prior to treatment with the use of mutant IDH inhibitors.	('hematologic malignancies', 'Disease', 'MESH:D019337', (121, 145))	('clinical', 'Species', '191496', (42, 50))	('IDH', 'Gene', (176, 179))	('IDH', 'Gene', (239, 242))	('patients', 'Species', '9606', (62, 70))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('mutated', 'Var', (156, 163))	('IDH', 'Gene', '3417', (176, 179))	('solid tumors', 'Disease', (76, 88))	('AG-881', 'Chemical', '-', (0, 6))	('IDH', 'Gene', (164, 167))	('IDH', 'Gene', '3417', (239, 242))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IDH2', 'Gene', (176, 180))	('IDH', 'Gene', '3417', (164, 167))	('IDH2', 'Gene', '3418', (176, 180))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('hematologic malignancies', 'Disease', (121, 145))	('gliomas', 'Disease', (100, 107))
195525	30857299	A fraction of IDH1-mut glioma patients have isoform-specific antibodies and displayed an IFN-gamma T-cell response against a mutant IDH1 (mutIDH1) protein.	('protein', 'Protein', (147, 154))	('IDH1', 'Gene', (132, 136))	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('mutant', 'Var', (125, 131))	('IDH1-mut', 'Gene', (14, 22))	('glioma', 'Disease', (23, 29))	('patients', 'Species', '9606', (30, 38))	('isoform-specific', 'MPA', (44, 60))	('antibodies', 'Protein', (61, 71))	('IFN-gamma', 'Gene', '3458', (89, 98))	('IFN-gamma', 'Gene', (89, 98))
195529	30857299	Peptide vaccination of humanized mice (transgenic for human MHCI and II molecules) with IDH1-R132H tumors resulted in induction of specific antitumor immune responses and restriction of growth of syngeneic IDH1-R132H-expressing tumors.	('R132H', 'Var', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('growth', 'MPA', (186, 192))	('tumor', 'Disease', (99, 104))	('R132H', 'SUBSTITUTION', 'None', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumors', 'Disease', (228, 234))	('R132H', 'Var', (211, 216))	('human', 'Species', '9606', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (144, 149))	('R132H', 'Mutation', 'rs121913500', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mice', 'Species', '10090', (33, 37))	('R132H', 'SUBSTITUTION', 'None', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('induction', 'PosReg', (118, 127))	('human', 'Species', '9606', (54, 59))	('tumors', 'Disease', (99, 105))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('R132H', 'Mutation', 'rs121913500', (211, 216))	('restriction', 'NegReg', (171, 182))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
195531	30857299	A similar good efficacy of mutIDH1 vaccine was demonstrated in a murine GL261 model, in which immunization of mice bearing mutIDH1/R132H GL261 gliomas was carried out.	('mutIDH1/R132H', 'Var', (123, 136))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('mice', 'Species', '10090', (110, 114))	('R132H', 'Mutation', 'rs121913500', (131, 136))	('gliomas', 'Disease', (143, 150))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('murine', 'Species', '10090', (65, 71))
195535	30857299	It was followed by a clinical trial (NOA-16) of the IDH1 peptide vaccine targeting the IDH1-R132H to evaluate the safety and tolerability, as well as immune responses to the vaccine in patients having IDH1-R132H malignant gliomas .	('IDH1-R132H', 'Var', (201, 211))	('malignant gliomas', 'Disease', 'MESH:D005910', (212, 229))	('R132H', 'Mutation', 'rs121913500', (206, 211))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('patients', 'Species', '9606', (185, 193))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))	('clinical', 'Species', '191496', (21, 29))	('malignant gliomas', 'Disease', (212, 229))
195536	30857299	First reported results showed that NOA-16 demonstrated safety and immunogenicity of a mutant IDH1-R132H peptide vaccine in patients with newly diagnosed IDH1-R132H malignant astrocytomas.	('R132H', 'Var', (158, 163))	('R132H', 'Mutation', 'rs121913500', (158, 163))	('astrocytoma', 'Phenotype', 'HP:0009592', (174, 185))	('R132H', 'SUBSTITUTION', 'None', (158, 163))	('mutant', 'Var', (86, 92))	('patients', 'Species', '9606', (123, 131))	('R132H', 'Var', (98, 103))	('R132H', 'SUBSTITUTION', 'None', (98, 103))	('R132H', 'Mutation', 'rs121913500', (98, 103))
195537	30857299	These encouraging results provided a strong evidence that a mutation-specific IDH1-R132H vaccine may represent a viable novel therapeutic strategy for IDH1-R132H-mutant tumors.	('R132H', 'Mutation', 'rs121913500', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('IDH1-R132H-mutant', 'Var', (151, 168))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('R132H', 'Mutation', 'rs121913500', (156, 161))
195538	30857299	Several studies provided strong evidence for the oncogenic potential of IDH1/2 mutations, leading to the production of an oncometabolite 2-HG, which alters epigenetic regulation, cancer cell differentiation, and cell metabolism.	('leading to', 'Reg', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('IDH1/2', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cell metabolism', 'CPA', (212, 227))	('alters', 'Reg', (149, 155))	('epigenetic regulation', 'MPA', (156, 177))	('cancer', 'Disease', (179, 185))	('mutations', 'Var', (79, 88))
195539	30857299	Depending on associated genomic aberrations and a cellular context, the oncogenic potential of IDH1/2 mutations ranges from an initiating event, which promotes transformation, to a secondary oncogenic event conferring selective advantage to cancer cells.	('IDH1/2', 'Gene', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('promotes', 'PosReg', (151, 159))	('transformation', 'CPA', (160, 174))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))
195540	30857299	In vitro and in vivo preclinical studies demonstrated that inhibition of mutated IDH1/2 enzymes reduces intracellular 2-HG levels, reverses epigenetic deregulation, and releases the differentiation block in cancer cells.	('clinical', 'Species', '191496', (24, 32))	('intracellular 2-HG levels', 'MPA', (104, 129))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('mutated', 'Var', (73, 80))	('reduces', 'NegReg', (96, 103))	('cancer', 'Disease', (207, 213))	('IDH1/2', 'Gene', (81, 87))	('reverses', 'NegReg', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('inhibition', 'Var', (59, 69))	('releases', 'PosReg', (169, 177))	('epigenetic deregulation', 'MPA', (140, 163))
195541	30857299	These findings provided a rationale for initiation of preclinical and a few clinical trials evaluating novel, isoform-specific, mutated IDH1/2 inhibitors in cancers with such genomic alteration.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutated', 'Var', (128, 135))	('clinical', 'Species', '191496', (76, 84))	('IDH1/2', 'Gene', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('clinical', 'Species', '191496', (57, 65))	('cancers', 'Disease', (157, 164))
195542	30857299	Novel inhibitors of mutant IDH1 (AG120, IDH305), IDH2 (AG221), and pan-IDH1/2 (AG881) were developed that selectively inhibit mutant IDH proteins and induce cell differentiation in in vitro and in vivo models.	('inhibit', 'NegReg', (118, 125))	('IDH', 'Gene', (27, 30))	('cell differentiation', 'CPA', (157, 177))	('IDH', 'Gene', '3417', (133, 136))	('IDH2', 'Gene', '3418', (49, 53))	('IDH', 'Gene', (49, 52))	('IDH', 'Gene', '3417', (27, 30))	('IDH', 'Gene', '3417', (49, 52))	('IDH305', 'Chemical', '-', (40, 46))	('IDH', 'Gene', (40, 43))	('IDH', 'Gene', (71, 74))	('IDH2', 'Gene', (49, 53))	('IDH', 'Gene', '3417', (40, 43))	('IDH', 'Gene', '3417', (71, 74))	('IDH', 'Gene', (133, 136))	('mutant', 'Var', (20, 26))	('mutant', 'Var', (126, 132))	('induce', 'Reg', (150, 156))
195543	30857299	Preliminary results from phase I clinical trials with those inhibitors demonstrated a response rate ranging from 31% to 40% with durable responses (>1 year) in patients with advanced hematologic malignancies and a positive activity in solid tumors with IDH mutations, such as cholangiocarcinomas and low-grade gliomas.	('mutations', 'Var', (257, 266))	('gliomas', 'Disease', 'MESH:D005910', (310, 317))	('clinical', 'Species', '191496', (33, 41))	('solid tumors', 'Disease', (235, 247))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (276, 295))	('activity', 'MPA', (223, 231))	('cholangiocarcinomas', 'Disease', (276, 295))	('gliomas', 'Phenotype', 'HP:0009733', (310, 317))	('IDH', 'Gene', (253, 256))	('solid tumors', 'Disease', 'MESH:D009369', (235, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('IDH', 'Gene', '3417', (253, 256))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('patients', 'Species', '9606', (160, 168))	('gliomas', 'Disease', (310, 317))	('hematologic malignancies', 'Disease', (183, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (276, 294))	('glioma', 'Phenotype', 'HP:0009733', (310, 316))	('hematologic malignancies', 'Disease', 'MESH:D019337', (183, 207))
195544	30857299	The mutated IDH1-R132H vaccines were developed and proven to be effective in launching antitumor immunity in preclinical models, which led to initiation of a clinical trial in glioma patients.	('mutated', 'Var', (4, 11))	('clinical', 'Species', '191496', (158, 166))	('glioma', 'Disease', (176, 182))	('IDH1-R132H', 'Gene', (12, 22))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('clinical', 'Species', '191496', (112, 120))	('tumor', 'Disease', (91, 96))	('patients', 'Species', '9606', (183, 191))
195545	30857299	Current clinical trials evaluating potential inhibitors in cancers with mutant IDH1/2 are aimed at confirming their safety and tolerability profiles, and clinical activity as a single agent or in combination with standard treatment strategies.	('mutant', 'Var', (72, 78))	('clinical', 'Species', '191496', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('clinical', 'Species', '191496', (154, 162))	('cancers', 'Disease', (59, 66))	('IDH1/2', 'Gene', (79, 85))
195547	30857299	Preliminary results from ongoing clinical trials indicate that pharmacological, small-molecule inhibitors of mutant IDH1/2 have promising activity and efficacy in patients with relapsed and/or refractory cancer disease, as discussed in an elegant recent review.	('activity', 'MPA', (138, 146))	('cancer disease', 'Disease', 'MESH:D009369', (204, 218))	('patients', 'Species', '9606', (163, 171))	('IDH1/2', 'Gene', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer disease', 'Disease', (204, 218))	('clinical', 'Species', '191496', (33, 41))	('relapsed and/or', 'Disease', (177, 192))	('mutant', 'Var', (109, 115))
195604	27549193	TAM numbers have been reported to be a predictor of worse outcome in many cancers.	('TAM numbers', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('TAM', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
195610	27549193	Non-synonymous somatic mutations in the tumor genome can generate immunogenic neoantigens that trigger antitumor response through T-cell activation.	('T-cell', 'CPA', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Non-synonymous somatic mutations', 'Var', (0, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (40, 45))	('immunogenic neoantigens', 'MPA', (66, 89))	('trigger', 'PosReg', (95, 102))
195614	27549193	In addition, we observed that dendritic cell infiltration is correlated with the total mutation load in breast cancer (Spearman's rho = 0.11, q = 0.037), as is B-cell infiltration (rho = 0.13, q = 0.018), suggesting cancer-specific roles for these cell types in antitumor immunity.	('dendritic cell', 'CPA', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('breast cancer', 'Disease', (104, 117))	('mutation load', 'Var', (87, 100))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (266, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
195617	27549193	MSI typically generates small indels across the genome, producing non-self antigens that may be recognized by the host immune system.	('MSI', 'Disease', 'None', (0, 3))	('non-self antigens', 'MPA', (66, 83))	('indels', 'Var', (30, 36))	('MSI', 'Disease', (0, 3))	('producing', 'Reg', (56, 65))
195658	27549193	More importantly, we found that tumors with high TIM3 expression can be divided into two distinct groups with different levels of infiltrating CD8 T cells (Fig.	('TIM3', 'Gene', '84868', (49, 53))	('high', 'Var', (44, 48))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('TIM3', 'Gene', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
195674	27549193	Systematic exploration of tumor-immune interactions revealed cancer genetic alterations and chemokine/receptor expression networks are potential regulators of immune cell infiltration heterogeneity.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('genetic alterations', 'Var', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (26, 31))
195728	27549193	We investigated the expression levels of the B-cell markers CD19 and CD20 in OV and discovered that tumor purity is not negatively correlated with gene expression levels for both genes, indicating that aneuploid cells in ovarian cancer may also express B-cell markers.	('aneuploid', 'Var', (202, 211))	('express', 'Reg', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CD19', 'Gene', (60, 64))	('tumor', 'Disease', (100, 105))	('ovarian cancer', 'Disease', (221, 235))	('CD20', 'Gene', '54474', (69, 73))	('CD19', 'Gene', '930', (60, 64))	('CD20', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('OV', 'Phenotype', 'HP:0012887', (77, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))
195758	25955030	The Proneural subtype is associated with PDGFRA abnormalities, IDH1 and TP53 mutations, and is usually found in younger patients.	('PDGFRA', 'Gene', (41, 47))	('IDH1', 'Gene', '3417', (63, 67))	('associated', 'Reg', (25, 35))	('PDGFRA', 'Gene', '5156', (41, 47))	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (120, 128))	('IDH1', 'Gene', (63, 67))	('Proneural subtype', 'Disease', (4, 21))
195761	25955030	The Classical glioma subtype has an astrocytic signature; EGFR amplification is commonly observed in this tumor type as well as high expression of Nestin (a neural precursor and stem cell marker), and Notch and Sonic hedgehog signaling pathways.	('EGFR', 'Gene', '1956', (58, 62))	('expression', 'MPA', (133, 143))	('Classical glioma', 'Disease', (4, 20))	('glioma subtype', 'Disease', (14, 28))	('EGFR', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Nestin', 'Gene', '10763', (147, 153))	('glioma subtype', 'Disease', 'MESH:D005910', (14, 28))	('Classical glioma', 'Disease', 'MESH:D005910', (4, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('amplification', 'Var', (63, 76))	('tumor', 'Disease', (106, 111))	('Nestin', 'Gene', (147, 153))
195762	25955030	Gliomas classified as Mesenchymal exhibit higher expression of mesenchymal markers, MET and CHI3L1, and genes in the NF-kappaB pathway, such as TRADD, RELB and TNFSF1A, as well as deletion of NF1.	('deletion', 'Var', (180, 188))	('CHI3L1', 'Gene', '1116', (92, 98))	('NF-kappaB', 'Gene', (117, 126))	('RELB', 'Gene', '5971', (151, 155))	('expression', 'MPA', (49, 59))	('NF1', 'Gene', (192, 195))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('higher', 'PosReg', (42, 48))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('NF-kappaB', 'Gene', '4790', (117, 126))	('TNF', 'Gene', (160, 163))	('NF1', 'Gene', '4763', (192, 195))	('TNF', 'Gene', '7124', (160, 163))	('Gliomas', 'Disease', (0, 7))	('CHI3L1', 'Gene', (92, 98))	('TRADD', 'Gene', '8717', (144, 149))	('RELB', 'Gene', (151, 155))	('TRADD', 'Gene', (144, 149))
195771	25955030	When injected subcutaneously into the flanks or orthotopically into the brains of immunocompromised mice, Ad-GSCs and Sp-GSCs were found to have markedly enhanced tumor-initiating activity (TIA) as compared to bulk tumor cells, and form tumors that display identical histological features.	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('enhanced', 'PosReg', (154, 162))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('mice', 'Species', '10090', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Ad-GSCs', 'Var', (106, 113))	('Sp-GSCs', 'Var', (118, 125))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('Sp', 'Chemical', 'MESH:C000604007', (118, 120))
195830	25955030	Fig 2B shows that expression of Mesenchymal markers CHI3L1, TRADD and RelB is significantly elevated in Ad-GSCs xenografts as compared to tumor xenografts of bulk tumor cells and Sp-GSCs.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (138, 143))	('CHI3L1', 'Gene', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('RelB', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('elevated', 'PosReg', (92, 100))	('Sp', 'Chemical', 'MESH:C000604007', (179, 181))	('RelB', 'Gene', '5971', (70, 74))	('expression', 'MPA', (18, 28))	('tumor', 'Disease', (163, 168))	('CHI3L1', 'Gene', '1116', (52, 58))	('TRADD', 'Gene', (60, 65))	('TRADD', 'Gene', '8717', (60, 65))	('Ad-GSCs', 'Var', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
195836	25955030	Significant EGFR amplification is observed in 97% of Classical glioblastomas in the TCGA database but infrequently in other subtypes.	('Classical glioblastomas', 'Disease', (53, 76))	('Classical glioblastomas', 'Disease', 'MESH:D005909', (53, 76))	('glioblastomas', 'Phenotype', 'HP:0012174', (63, 76))	('EGFR', 'Gene', '1956', (12, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('amplification', 'Var', (17, 30))	('EGFR', 'Gene', (12, 16))
195837	25955030	The GBM6 xenograft is derived from a patient with overexpression of the VIII mutant of EGFR, and our finding of high EGFR expression in bulk tumor cells and in tumors derived from them is consistent with EGFR overexpression.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('expression', 'MPA', (122, 132))	('EGFR', 'Gene', '1956', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('EGFR', 'Gene', '1956', (117, 121))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('EGFR', 'Gene', '1956', (204, 208))	('VIII', 'Gene', '1351', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('EGFR', 'Gene', (87, 91))	('mutant', 'Var', (77, 83))	('tumor', 'Disease', (160, 165))	('EGFR', 'Gene', (204, 208))	('patient', 'Species', '9606', (37, 44))	('EGFR', 'Gene', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('VIII', 'Gene', (72, 76))
195860	25955030	This finding is consistent with our previous studies that revealed Ad-GSCs were more potent in inducing subcutaneous tumors when compared to bulk GBM tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Ad-GSCs', 'Var', (67, 74))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('subcutaneous tumors', 'Disease', (104, 123))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('inducing', 'Reg', (95, 103))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (104, 123))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (104, 123))	('tumor', 'Disease', (150, 155))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (104, 122))
195867	25955030	As shown in Fig 4C, expression of the Mesenchymal markers CHI3L1, TRADD and RelB was significantly elevated in intracranial tumors derived from Ad-GSCs compared to the other xenografts, while NF1 was decreased.	('TRADD', 'Gene', (66, 71))	('expression', 'MPA', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('intracranial tumors', 'Disease', (111, 130))	('CHI3L1', 'Gene', (58, 64))	('RelB', 'Gene', (76, 80))	('NF1', 'Gene', (192, 195))	('elevated', 'PosReg', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('NF1', 'Gene', '4763', (192, 195))	('Ad-GSCs', 'Var', (144, 151))	('RelB', 'Gene', '5971', (76, 80))	('CHI3L1', 'Gene', '1116', (58, 64))	('intracranial tumors', 'Disease', 'MESH:D001932', (111, 130))	('TRADD', 'Gene', '8717', (66, 71))
195896	25955030	As shown in Fig 8A, treatment with WP1066 decreased the expression of angiogenic genes (ANGPTL4, VEGFR-1 and VEGFR-2), as well as expression of stem cell marker genes (CD133, SOX2 and Nestin).	('VEGFR-1', 'Gene', '2321', (97, 104))	('expression', 'MPA', (130, 140))	('ANGPTL4', 'Gene', (88, 95))	('VEGFR-2', 'Gene', (109, 116))	('CD133', 'Gene', '8842', (168, 173))	('decreased', 'NegReg', (42, 51))	('Nestin', 'Gene', (184, 190))	('WP1066', 'Chemical', 'MESH:C519885', (35, 41))	('ANGPTL4', 'Gene', '51129', (88, 95))	('WP1066', 'Var', (35, 41))	('expression', 'MPA', (56, 66))	('VEGFR-2', 'Gene', '3791', (109, 116))	('SOX2', 'Gene', '6657', (175, 179))	('Nestin', 'Gene', '10763', (184, 190))	('CD133', 'Gene', (168, 173))	('VEGFR-1', 'Gene', (97, 104))	('SOX2', 'Gene', (175, 179))
195900	25955030	In addition, the STAT3 inhibitor WP1066 decreased STAT3 binding to ANGPTL4 in Ad-GSCs.	('STAT3 binding', 'MPA', (50, 63))	('WP1066', 'Chemical', 'MESH:C519885', (33, 39))	('WP1066', 'Var', (33, 39))	('ANGPTL4', 'Gene', (67, 74))	('decreased', 'NegReg', (40, 49))	('ANGPTL4', 'Gene', '51129', (67, 74))
195907	25955030	As shown in Fig 9A, the tumorigenicity of Ad-GSCs was markedly suppressed by treatment with WP1066.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('suppressed', 'NegReg', (63, 73))	('WP1066', 'Var', (92, 98))	('WP1066', 'Chemical', 'MESH:C519885', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
195908	25955030	The apparent increase in tumor size upon treatment with WP1066 at 24 and 28 days is apparently due to tumor necrosis, because live animal imaging showed a marked decrease in bioluminescence during this time after treatment (Fig 9B).	('tumor necrosis', 'Disease', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('WP1066', 'Var', (56, 62))	('bioluminescence', 'MPA', (174, 189))	('tumor', 'Disease', (25, 30))	('WP1066', 'Chemical', 'MESH:C519885', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('increase', 'PosReg', (13, 21))	('tumor necrosis', 'Disease', 'MESH:D009336', (102, 116))	('decrease', 'NegReg', (162, 170))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
195909	25955030	In addition, immunoblotting of tumor tissue showed that high STAT3 activity in Ad-GSC xenografts was evident by virtue of Y705-STAT3 phosphorylation, and that WP1066 treatment of mice nearly abolished STAT3 activity (Fig 9C).	('Y705-STAT3', 'Var', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (179, 183))	('WP1066', 'Var', (159, 165))	('WP1066', 'Chemical', 'MESH:C519885', (159, 165))	('tumor', 'Disease', (31, 36))	('abolished', 'NegReg', (191, 200))	('STAT3 activity', 'MPA', (201, 215))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('STAT3 activity', 'MPA', (61, 75))
195925	25955030	For example, the GBM6 xenograft is derived from a patient with overexpression of the EGFRVIII mutant, and our finding of high EGFR expression in bulk tumor cells, and in tumors derived from them is consistent with EGFR overexpression.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (214, 218))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('EGFR', 'Gene', '1956', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('EGFR', 'Gene', '1956', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('mutant', 'Var', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('EGFR', 'Gene', (214, 218))	('tumor', 'Disease', (150, 155))	('EGFR', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('expression', 'MPA', (131, 141))	('tumors', 'Disease', (170, 176))	('patient', 'Species', '9606', (50, 57))
195926	25955030	EGFR amplification is observed in 97% of Classical glioblastomas in the TCGA database but infrequently in other subtypes.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('Classical glioblastomas', 'Disease', (41, 64))	('Classical glioblastomas', 'Disease', 'MESH:D005909', (41, 64))	('glioblastomas', 'Phenotype', 'HP:0012174', (51, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('EGFR', 'Gene', '1956', (0, 4))
195951	25955030	We then examined the anticancer effects of the STAT3 inhibitor WP1066 on GSCs in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('WP1066', 'Chemical', 'MESH:C519885', (63, 69))	('WP1066', 'Var', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
195952	25955030	WP1066 is a JAK-2 kinase inhibitor that blocks STAT3 tyrosine phosphorylation, and has proapoptotic and antiproliferative activity in a variety of cancers, including glioma.	('antiproliferative activity', 'CPA', (104, 130))	('blocks', 'NegReg', (40, 46))	('WP1066', 'Chemical', 'MESH:C519885', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('proapoptotic', 'CPA', (87, 99))	('WP1066', 'Var', (0, 6))	('glioma', 'Disease', (166, 172))	('JAK-2', 'Gene', '3717', (12, 17))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('cancers', 'Disease', (147, 154))	('STAT3 tyrosine phosphorylation', 'MPA', (47, 77))	('JAK-2', 'Gene', (12, 17))
195953	25955030	We found that WP1066 decreased the expression of pro-angiogenic genes, including ANGPTL4, and ablated STAT3 binding to the ANGPTL4 promoter.	('ANGPTL4', 'Gene', (81, 88))	('ANGPTL4', 'Gene', '51129', (123, 130))	('ANGPTL4', 'Gene', (123, 130))	('WP1066', 'Var', (14, 20))	('decreased', 'NegReg', (21, 30))	('ANGPTL4', 'Gene', '51129', (81, 88))	('binding', 'Interaction', (108, 115))	('WP1066', 'Chemical', 'MESH:C519885', (14, 20))	('ablated', 'NegReg', (94, 101))	('expression', 'MPA', (35, 45))	('STAT3', 'Protein', (102, 107))
195954	25955030	WP1066 also inhibited the expression of stem cell marker genes.	('expression', 'MPA', (26, 36))	('WP1066', 'Chemical', 'MESH:C519885', (0, 6))	('WP1066', 'Var', (0, 6))	('inhibited', 'NegReg', (12, 21))
195955	25955030	Most importantly, WP1066 decreased the tumorigenicity of Ad-GSCs and led to marked tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('WP1066', 'Var', (18, 24))	('decreased', 'NegReg', (25, 34))	('WP1066', 'Chemical', 'MESH:C519885', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
195956	25955030	WP1066 has been shown to significantly inhibit growth of malignant glioma xenografts by blocking STAT3 activation and the subsequent induction of proliferation-related genes.	('WP1066', 'Chemical', 'MESH:C519885', (0, 6))	('STAT3 activation', 'MPA', (97, 113))	('proliferation-related genes', 'Gene', (146, 173))	('WP1066', 'Var', (0, 6))	('inhibit', 'NegReg', (39, 46))	('malignant glioma', 'Disease', (57, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('malignant glioma', 'Disease', 'MESH:D005910', (57, 73))	('blocking', 'NegReg', (88, 96))	('induction', 'Reg', (133, 142))	('growth', 'CPA', (47, 53))
196040	20212231	In contrast, patients with low-grade tumors were more likely to present with seizures if their tumors were located in the temporal lobe.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('low-grade', 'Var', (27, 36))	('seizures', 'Disease', (77, 85))	('patients', 'Species', '9606', (13, 21))	('seizures', 'Phenotype', 'HP:0001250', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('seizure', 'Phenotype', 'HP:0001250', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('seizures', 'Disease', 'MESH:D012640', (77, 85))
196082	26689994	In astrocytic chemical models of hypoxia, exposure to CoCl2 increases HIF-1alpha, NF-kappaB and GFAP levels.	('GFAP', 'Gene', '2670', (96, 100))	('hypoxia', 'Disease', (33, 40))	('HIF-1alpha', 'Gene', (70, 80))	('NF-kappaB', 'Gene', (82, 91))	('CoCl2', 'Gene', (54, 59))	('CoCl2', 'Chemical', 'MESH:C018021', (54, 59))	('HIF-1alpha', 'Gene', '3091', (70, 80))	('hypoxia', 'Disease', 'MESH:D000860', (33, 40))	('GFAP', 'Gene', (96, 100))	('exposure', 'Var', (42, 50))	('increases', 'PosReg', (60, 69))	('NF-kappaB', 'Gene', '4790', (82, 91))
196085	26689994	Control of MAOB transcription by Sp1 and Sp3 has been investigated by Wong and co-workers, and generally, Sp1 upregulates and Sp3 inhibits MAOB synthesis.	('Sp', 'Chemical', '-', (33, 35))	('MAOB', 'Gene', (11, 15))	('upregulates', 'PosReg', (110, 121))	('Sp', 'Chemical', '-', (41, 43))	('MAOB', 'Gene', '4129', (11, 15))	('Sp', 'Chemical', '-', (126, 128))	('MAOB', 'Gene', '4129', (139, 143))	('Sp3', 'Gene', '6670', (41, 44))	('MAOB', 'Gene', (139, 143))	('Sp3', 'Gene', '6670', (126, 129))	('Sp', 'Chemical', '-', (106, 108))	('Sp3', 'Gene', (41, 44))	('Sp1', 'Var', (106, 109))	('inhibits', 'NegReg', (130, 138))	('Sp3', 'Gene', (126, 129))
196101	26689994	The high concentrations of P+-MUS damage the mitochondria, including its DNA, and mitochondrial dysfunction leads to gliomal cell death, Figure 1C.	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('leads to', 'Reg', (108, 116))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mitochondria', 'MPA', (45, 57))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (82, 107))	('P+-MUS', 'Var', (27, 33))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (82, 107))	('glioma', 'Disease', (117, 123))	('mitochondrial dysfunction', 'Disease', (82, 107))
196140	26689994	After deesterification, the internalized H2-DCF probe is oxidized by oxidants, principally peroxide, to the fluorophore DCF.	('peroxide', 'Chemical', 'MESH:D010545', (91, 99))	('DCF', 'Chemical', 'MESH:D015649', (120, 123))	('deesterification', 'Var', (6, 22))	('oxidized', 'MPA', (57, 65))	('H2-DCF', 'Chemical', '-', (41, 47))	('DCF', 'Chemical', 'MESH:D015649', (44, 47))	('H2-DCF', 'Protein', (41, 47))
196184	26689994	Therefore, the upregulation of MAOB appears to be tied to a positive feedback signaling loop, where MAOB increases peroxide levels, peroxide facilitates Sp3 repression and upregulation HiF-1alpha and Sp1, and these events ultimately increase MAOB expression.	('peroxide', 'Chemical', 'MESH:D010545', (132, 140))	('Sp3', 'Gene', '6670', (153, 156))	('MAOB', 'Gene', '4129', (242, 246))	('peroxide', 'Chemical', 'MESH:D010545', (115, 123))	('MAOB', 'Gene', (100, 104))	('MAOB', 'Gene', (31, 35))	('peroxide levels', 'MPA', (115, 130))	('expression', 'MPA', (247, 257))	('increases', 'PosReg', (105, 114))	('Sp1', 'Protein', (200, 203))	('Sp', 'Chemical', '-', (200, 202))	('Sp', 'Chemical', '-', (153, 155))	('Sp3', 'Gene', (153, 156))	('MAOB', 'Gene', (242, 246))	('increase', 'PosReg', (233, 241))	('MAOB', 'Gene', '4129', (100, 104))	('upregulation', 'PosReg', (172, 184))	('HiF-1alpha', 'Gene', (185, 195))	('peroxide', 'Var', (132, 140))	('MAOB', 'Gene', '4129', (31, 35))	('facilitates', 'PosReg', (141, 152))	('HiF-1alpha', 'Gene', '3091', (185, 195))
196186	26689994	They find that MAOA generated H2O2 to induce epithelial-to-mesenchymal transition via stabilization of HIF-1alpha.	('epithelial-to-mesenchymal transition', 'CPA', (45, 81))	('HIF-1alpha', 'Gene', (103, 113))	('induce', 'PosReg', (38, 44))	('MAOA', 'Gene', '4128', (15, 19))	('HIF-1alpha', 'Gene', '3091', (103, 113))	('H2O2', 'Chemical', 'MESH:D006861', (30, 34))	('H2O2', 'Var', (30, 34))	('stabilization', 'MPA', (86, 99))	('MAOA', 'Gene', (15, 19))
196187	26689994	This peroxide-induced stabilization of HIF-1alpha increases proliferation, invasiveness, and metastasis of prostate cancer cells.	('peroxide', 'Chemical', 'MESH:D010545', (5, 13))	('stabilization', 'Var', (22, 35))	('metastasis of prostate cancer', 'Disease', (93, 122))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('invasiveness', 'CPA', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HIF-1alpha increases proliferation', 'Disease', (39, 73))	('metastasis of prostate cancer', 'Disease', 'MESH:D009362', (93, 122))	('HIF-1alpha increases proliferation', 'Disease', 'MESH:D065703', (39, 73))
196189	26689994	However, the Sp3 gene has four start codons that allow the generation of four different protein products, with different properties, and these variants are all subject to functional sculpting via post-transcriptional modifications that include, phosphorylation, acylation and SUMOation.	('Sp3', 'Gene', '6670', (13, 16))	('acylation', 'MPA', (262, 271))	('subject', 'Reg', (160, 167))	('Sp3', 'Gene', (13, 16))	('SUMOation', 'MPA', (276, 285))	('phosphorylation', 'MPA', (245, 260))	('variants', 'Var', (143, 151))
196191	26689994	Sp3 activity has been shown to be regulated by SUMO-1 modification, and such modification can flip its activity from being a repressor to activator, and vice versa.	('activity', 'MPA', (103, 111))	('modification', 'Var', (54, 66))	('modification', 'Var', (77, 89))	('Sp3', 'Gene', '6670', (0, 3))	('SUMO-1', 'Gene', (47, 53))	('activity', 'MPA', (4, 12))	('Sp3', 'Gene', (0, 3))	('SUMO-1', 'Gene', '7341', (47, 53))
196193	26689994	Following SUMOylation the SUMO-Sp3 is found bound to DNA at the nuclear periphery and inside the nucleus in small clusters and inversion occurs and much Sp3-dependent transcription is repressed.	('Sp3', 'Gene', '6670', (153, 156))	('Sp3', 'Gene', (31, 34))	('SUMOylation', 'Var', (10, 21))	('Sp3', 'Gene', (153, 156))	('Sp3', 'Gene', '6670', (31, 34))
196197	26689994	Figure 6 shows a graphical representation of how we believe that elevated MAOB drive increased cellular peroxide levels in GBM and initiates the 'Warburg' phenotype.	('elevated', 'Var', (65, 73))	('initiates', 'Reg', (131, 140))	('cellular peroxide levels', 'MPA', (95, 119))	('increased cellular peroxide', 'Phenotype', 'HP:0025464', (85, 112))	('increased', 'PosReg', (85, 94))	("'Warburg'", 'CPA', (145, 154))	('MAOB', 'Gene', (74, 78))	('peroxide', 'Chemical', 'MESH:D010545', (104, 112))	('MAOB', 'Gene', '4129', (74, 78))
196199	26689994	Firstly, FIH, which irreversibly modifies and inactivates HIF-1alpha is highly sensitive to peroxide inhibition and modest increases in ROS will extend the life of active HIF-1a (B).	('HIF-1a', 'Gene', '3091', (58, 64))	('HIF-1a', 'Gene', (58, 64))	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('ROS', 'Protein', (136, 139))	('peroxide', 'Chemical', 'MESH:D010545', (92, 100))	('HIF-1alpha', 'Gene', '3091', (58, 68))	('life', 'MPA', (156, 160))	('extend', 'PosReg', (145, 151))	('inactivates', 'Var', (46, 57))	('HIF-1a', 'Gene', '3091', (171, 177))	('HIF-1a', 'Gene', (171, 177))	('HIF-1alpha', 'Gene', (58, 68))	('increases', 'PosReg', (123, 132))
196205	26689994	In GBM this alteration in Sp3 resulting in an upregulation of MAOB, and so leads to a further increase in peroxide levels.	('alteration', 'Var', (12, 22))	('MAOB', 'Gene', (62, 66))	('upregulation', 'PosReg', (46, 58))	('increase', 'PosReg', (94, 102))	('Sp3', 'Gene', '6670', (26, 29))	('MAOB', 'Gene', '4129', (62, 66))	('peroxide', 'Chemical', 'MESH:D010545', (106, 114))	('peroxide levels', 'MPA', (106, 121))	('Sp3', 'Gene', (26, 29))
196325	19698149	This made it possible to compute the ratios between the C and L for each subject and the average of 50 random networks C/<C-s> and L/<L-s> (<> denoting ensemble averages).	('s', 'Chemical', 'MESH:D013455', (42, 43))	('C', 'Chemical', '-', (56, 57))	('s', 'Chemical', 'MESH:D013455', (117, 118))	('L-s', 'Chemical', '-', (134, 137))	('C/<C-s>', 'Var', (119, 126))	('s', 'Chemical', 'MESH:D013455', (168, 169))	('L/<L-s>', 'Var', (131, 138))	('s', 'Chemical', 'MESH:D013455', (15, 16))	('s', 'Chemical', 'MESH:D013455', (124, 125))	('s', 'Chemical', 'MESH:D013455', (73, 74))	('s', 'Chemical', 'MESH:D013455', (16, 17))	('s', 'Chemical', 'MESH:D013455', (136, 137))	('s', 'Chemical', 'MESH:D013455', (154, 155))	('C', 'Chemical', '-', (119, 120))	('C', 'Chemical', '-', (122, 123))	('s', 'Chemical', 'MESH:D013455', (3, 4))	('C-s', 'Chemical', '-', (122, 125))
196328	19698149	A network can be defined as a small-world network if C/<C-s> >> 1 and L/<L-s> ~ 1, which means that a value of S greater than 1 is called a small-world network.	('s', 'Chemical', 'MESH:D013455', (58, 59))	('C', 'Chemical', '-', (56, 57))	('s', 'Chemical', 'MESH:D013455', (140, 141))	('s', 'Chemical', 'MESH:D013455', (93, 94))	('L/<L-s> ~ 1', 'Var', (70, 81))	('C-s', 'Chemical', '-', (56, 59))	('C', 'Chemical', '-', (53, 54))	('L-s', 'Chemical', '-', (73, 76))	('s', 'Chemical', 'MESH:D013455', (30, 31))	('s', 'Chemical', 'MESH:D013455', (75, 76))	('s', 'Chemical', 'MESH:D013455', (129, 130))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('C/<C-s> >> 1', 'Var', (53, 65))
196341	19698149	For the graph analysis we calculated C/<C-s> and L/<L-s>, small world-ness (S), and degree correlation (R).	('s', 'Chemical', 'MESH:D013455', (21, 22))	('L/<L-s>', 'Var', (49, 56))	('s', 'Chemical', 'MESH:D013455', (58, 59))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('C/<C-s>', 'Var', (37, 44))	('s', 'Chemical', 'MESH:D013455', (73, 74))	('s', 'Chemical', 'MESH:D013455', (19, 20))	('C', 'Chemical', '-', (37, 38))	('L-s', 'Chemical', '-', (52, 55))	('C-s', 'Chemical', '-', (40, 43))	('C', 'Chemical', '-', (40, 41))	('s', 'Chemical', 'MESH:D013455', (54, 55))	('s', 'Chemical', 'MESH:D013455', (42, 43))
196383	19698149	Post hoc regression analysis showed that an increase in the L/<L-s> ratio was associated with poorer executive and attentional functioning as shown in table 3 (p = 0.007 and p = 0.000 respectively).	('s', 'Chemical', 'MESH:D013455', (76, 77))	('s', 'Chemical', 'MESH:D013455', (186, 187))	('s', 'Chemical', 'MESH:D013455', (27, 28))	('poorer executive', 'Phenotype', 'HP:0001249', (94, 110))	('attentional functioning', 'CPA', (115, 138))	('s', 'Chemical', 'MESH:D013455', (50, 51))	('increase', 'PosReg', (44, 52))	('s', 'Chemical', 'MESH:D013455', (2, 3))	('s', 'Chemical', 'MESH:D013455', (79, 80))	('s', 'Chemical', 'MESH:D013455', (142, 143))	('s', 'Chemical', 'MESH:D013455', (25, 26))	('s', 'Chemical', 'MESH:D013455', (65, 66))	('s', 'Chemical', 'MESH:D013455', (80, 81))	('s', 'Chemical', 'MESH:D013455', (15, 16))	('L/<L-s>', 'Var', (60, 67))	('L-s', 'Chemical', '-', (63, 66))	('s', 'Chemical', 'MESH:D013455', (14, 15))	('s', 'Chemical', 'MESH:D013455', (29, 30))	('poorer', 'NegReg', (94, 100))	('s', 'Chemical', 'MESH:D013455', (140, 141))
196386	19698149	Post hoc regression analysis showed that increases in C/<C-s> and L/<L-s> were associated with decreasing verbal memory (p = 0.036 and p = 0.007 respectively).	('C', 'Chemical', '-', (57, 58))	('s', 'Chemical', 'MESH:D013455', (27, 28))	('s', 'Chemical', 'MESH:D013455', (147, 148))	('C/<C-s>', 'Var', (54, 61))	('s', 'Chemical', 'MESH:D013455', (2, 3))	('s', 'Chemical', 'MESH:D013455', (81, 82))	('C-s', 'Chemical', '-', (57, 60))	('s', 'Chemical', 'MESH:D013455', (25, 26))	('s', 'Chemical', 'MESH:D013455', (49, 50))	('s', 'Chemical', 'MESH:D013455', (80, 81))	('increases', 'PosReg', (41, 50))	('s', 'Chemical', 'MESH:D013455', (15, 16))	('s', 'Chemical', 'MESH:D013455', (71, 72))	('s', 'Chemical', 'MESH:D013455', (47, 48))	('C', 'Chemical', '-', (54, 55))	('L/<L-s>', 'Var', (66, 73))	('s', 'Chemical', 'MESH:D013455', (14, 15))	('verbal memory', 'CPA', (106, 119))	('decreasing', 'NegReg', (95, 105))	('s', 'Chemical', 'MESH:D013455', (101, 102))	('s', 'Chemical', 'MESH:D013455', (29, 30))	('L-s', 'Chemical', '-', (69, 72))	('s', 'Chemical', 'MESH:D013455', (59, 60))
196425	19698149	Increased path length was associated with poorer executive functioning and attentional task performance in the delta band, and was associated with decreasing verbal memory within the lower alpha band.	('s', 'Chemical', 'MESH:D013455', (27, 28))	('executive functioning', 'CPA', (49, 70))	('verbal memory', 'CPA', (158, 171))	('s', 'Chemical', 'MESH:D013455', (28, 29))	('man', 'Species', '9606', (98, 101))	('poorer executive', 'Phenotype', 'HP:0001249', (42, 58))	('poorer', 'NegReg', (42, 48))	('s', 'Chemical', 'MESH:D013455', (132, 133))	('s', 'Chemical', 'MESH:D013455', (153, 154))	('decreasing', 'NegReg', (147, 157))	('attentional task performance', 'CPA', (75, 103))	('path length', 'Var', (10, 21))	('s', 'Chemical', 'MESH:D013455', (129, 130))	('s', 'Chemical', 'MESH:D013455', (24, 25))	('s', 'Chemical', 'MESH:D013455', (133, 134))	('s', 'Chemical', 'MESH:D013455', (89, 90))	('s', 'Chemical', 'MESH:D013455', (6, 7))
196500	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
196514	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
196522	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
196532	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('hallmark characteristics', 'MPA', (70, 94))	('change', 'Reg', (60, 66))	('cancers', 'Disease', (111, 118))	('TRIM44', 'Gene', '54765', (18, 24))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
196534	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('TRIM44', 'Gene', '54765', (0, 6))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
196536	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
196537	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', '5111', (125, 131))	('cyclin', 'Gene', '5111', (111, 117))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('cyclin', 'Gene', (125, 131))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', (111, 117))
196539	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('TRIM44', 'Gene', '54765', (14, 20))	('p27', 'Gene', '10671', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('TRIM44', 'Gene', (14, 20))	('inhibited', 'NegReg', (91, 100))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
196540	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('p21', 'Gene', (22, 25))	('glioma', 'Disease', (112, 118))	('activated', 'PosReg', (99, 108))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
196541	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('cancer', 'Disease', (118, 124))	('TRIM44', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
196542	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
196553	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('NUPR1', 'Gene', (89, 94))	('knockdown', 'Var', (39, 48))	('activate', 'PosReg', (158, 166))	('CADM1', 'Gene', (103, 108))	('DDIT4', 'Gene', (130, 135))	('TRIM44', 'Gene', '54765', (32, 38))	('TNFSF10', 'Gene', '8743', (117, 124))	('CADM1', 'Gene', '23705', (103, 108))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('CDK19', 'Gene', '23097', (96, 101))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('dysregulation', 'MPA', (72, 85))
196562	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', (84, 90))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
196569	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
196595	32335823	IDH1 mutation was significantly associated with high-SST2 status.	('SST', 'Gene', '6750', (53, 56))	('associated', 'Reg', (32, 42))	('IDH1', 'Gene', (0, 4))	('SST', 'Gene', (53, 56))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
196603	32335823	In particular, several radioligands targeting SST have been developed, such as 68Ga-DOTATOC and 68Ga-DOTATATE, which are now commonly used in the diagnosis of neuroendocrine tumors (NETs) via positron emission tomography (PET).	('neuroendocrine tumors', 'Disease', (159, 180))	('SST', 'Gene', '6750', (46, 49))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (159, 180))	('68Ga-DOTATATE', 'Var', (96, 109))	('DOTATOC', 'Chemical', '-', (84, 91))	('NETs', 'Phenotype', 'HP:0100634', (182, 186))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (159, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('SST', 'Gene', (46, 49))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
196645	32335823	Mutational profiles were significantly associated with high-SST2 status in LGG, which showed the highest proportion of high-SST tumors, including isocitrate dehydrogenase 1 (IDH1), capicua transcriptional repressor (CIC), and far upstream element binding protein 1 (FUBP1) mutations.	('FUBP1', 'Gene', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('associated', 'Reg', (39, 49))	('tumors', 'Disease', (128, 134))	('CIC', 'Gene', '23152', (216, 219))	('isocitrate dehydrogenase 1', 'Gene', (146, 172))	('isocitrate dehydrogenase 1', 'Gene', '3417', (146, 172))	('SST', 'Gene', (124, 127))	('IDH1', 'Gene', (174, 178))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('capicua transcriptional repressor', 'Gene', '23152', (181, 214))	('FUBP1', 'Gene', '8880', (266, 271))	('far upstream element binding protein 1', 'Gene', '8880', (226, 264))	('SST', 'Gene', (60, 63))	('IDH1', 'Gene', '3417', (174, 178))	('CIC', 'Gene', (216, 219))	('SST', 'Gene', '6750', (124, 127))	('SST', 'Gene', '6750', (60, 63))	('mutations', 'Var', (273, 282))	('capicua transcriptional repressor', 'Gene', (181, 214))	('far upstream element binding protein 1', 'Gene', (226, 264))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
196646	32335823	In contrast, epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and tumor protein 53 (TP53) mutations were more common in low-SST2 tumors than in high-SST2 tumors (Fig.	('common', 'Reg', (141, 147))	('PTEN', 'Gene', (86, 90))	('mutations', 'Var', (121, 130))	('tumor protein 53', 'Gene', (97, 113))	('tumors', 'Disease', (185, 191))	('tumor protein 53', 'Gene', '7157', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', '1956', (47, 51))	('tumors', 'Disease', (160, 166))	('epidermal growth factor receptor', 'Gene', (13, 45))	('PTEN', 'Gene', '5728', (86, 90))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('SST', 'Gene', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('TP53', 'Gene', (115, 119))	('SST', 'Gene', (180, 183))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('SST', 'Gene', '6750', (155, 158))	('EGFR', 'Gene', (47, 51))	('phosphatase and tensin homolog', 'Gene', '5728', (54, 84))	('SST', 'Gene', '6750', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
196647	32335823	In pancreatic adenocarcinoma (PAAD), Kirsten rat sarcoma (KRAS) and TP53 mutations were associated with low-SST2 status.	('KRAS', 'Gene', (58, 62))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('SST', 'Gene', '6750', (108, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('KRAS', 'Gene', '24525', (58, 62))	('pancreatic adenocarcinoma', 'Disease', (3, 28))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('PAAD', 'Phenotype', 'HP:0006725', (30, 34))	('SST', 'Gene', (108, 111))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 28))	('associated', 'Reg', (88, 98))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('rat', 'Species', '10116', (45, 48))	('sarcoma', 'Disease', (49, 56))
196648	32335823	In uterine corpus endometrial carcinoma (UCEC), catenin beta 1 (CTNNB1) mutation showed an association with low-SST2 status.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (18, 39))	('SST', 'Gene', (112, 115))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (18, 39))	('CTNNB1', 'Gene', (64, 70))	('catenin beta 1', 'Gene', (48, 62))	('endometrial carcinoma', 'Disease', (18, 39))	('SST', 'Gene', '6750', (112, 115))	('CTNNB1', 'Gene', '1499', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('mutation', 'Var', (72, 80))	('catenin beta 1', 'Gene', '1499', (48, 62))	('association', 'Interaction', (91, 102))
196649	32335823	When high-SST2 tumors were defined with the expression level in PCPG as a reference value, SST2-based tumor subtypes were not significantly associated with gene alterations in other cancer subtypes, including BRCA, PCPG, and KIRC.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SST', 'Gene', '6750', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('BRCA', 'Phenotype', 'HP:0003002', (209, 213))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('KIRC', 'Disease', (225, 229))	('cancer', 'Disease', (182, 188))	('rat', 'Species', '10116', (165, 168))	('SST', 'Gene', (91, 94))	('tumors', 'Disease', (15, 21))	('BRCA', 'Gene', '672', (209, 213))	('alterations', 'Var', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('associated', 'Reg', (140, 150))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('BRCA', 'Gene', (209, 213))	('SST', 'Gene', '6750', (91, 94))	('SST', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('PCPG', 'Disease', (215, 219))
196652	32335823	The SST2 level in G2 grade tumors was significantly higher than that in G3 grade tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('G2 grade', 'Var', (18, 26))	('SST', 'Gene', (4, 7))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SST', 'Gene', '6750', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
196666	32335823	Additionally, we revealed that fourteen of the 32 cancer subtypes had more than 5% of tumors with high-SST2 expression when SST2 expression in normal kidney tissue was used as the reference.	('SST', 'Gene', '6750', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SST', 'Gene', '6750', (103, 106))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', (86, 92))	('SST', 'Gene', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SST', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('expression', 'Var', (108, 118))
196679	32335823	Several gene mutations were noted to have a correlation with SST2 expression in LGG.	('SST', 'Gene', (61, 64))	('SST', 'Gene', '6750', (61, 64))	('expression', 'MPA', (66, 76))	('correlation', 'Reg', (44, 55))	('mutations', 'Var', (13, 22))
196680	32335823	In particular, the IDH1 mutation was revealed to be associated with SST2 expression, which is supported by a previous study.	('IDH1', 'Gene', (19, 23))	('associated', 'Reg', (52, 62))	('IDH1', 'Gene', '3417', (19, 23))	('expression', 'MPA', (73, 83))	('SST', 'Gene', '6750', (68, 71))	('mutation', 'Var', (24, 32))	('SST', 'Gene', (68, 71))
196681	32335823	The close association between IDH1 mutation and SST2 expression was also verified by the association of high-SST2 with good prognosis in LGG.	('IDH1', 'Gene', '3417', (30, 34))	('IDH1', 'Gene', (30, 34))	('SST', 'Gene', (48, 51))	('SST', 'Gene', '6750', (109, 112))	('mutation', 'Var', (35, 43))	('SST', 'Gene', '6750', (48, 51))	('SST', 'Gene', (109, 112))	('LGG', 'Disease', (137, 140))	('association', 'Interaction', (89, 100))
196682	32335823	The presence of IDH1 mutation is the most common factor used to classify tumor subtypes in terms of disparate molecular pathogenesis and favorable prognosis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('rat', 'Species', '10116', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutation', 'Var', (21, 29))	('IDH1', 'Gene', (16, 20))	('tumor', 'Disease', (73, 78))	('IDH1', 'Gene', '3417', (16, 20))
196683	32335823	Additionally, not only IDH1 but also CIC and FUBP1 mutations demonstrated a positive association with SST2 expression.	('SST', 'Gene', (102, 105))	('mutations', 'Var', (51, 60))	('CIC', 'Gene', '23152', (37, 40))	('FUBP1', 'Gene', '8880', (45, 50))	('expression', 'MPA', (107, 117))	('IDH1', 'Gene', (23, 27))	('CIC', 'Gene', (37, 40))	('rat', 'Species', '10116', (68, 71))	('SST', 'Gene', '6750', (102, 105))	('FUBP1', 'Gene', (45, 50))	('IDH1', 'Gene', '3417', (23, 27))	('positive', 'PosReg', (76, 84))
196684	32335823	This finding is also consistent with previous studies that showed an association between IDH1, CIC, and FUBP1 mutations and a favorable prognosis.	('mutations', 'Var', (110, 119))	('CIC', 'Gene', '23152', (95, 98))	('FUBP1', 'Gene', '8880', (104, 109))	('CIC', 'Gene', (95, 98))	('IDH1', 'Gene', (89, 93))	('FUBP1', 'Gene', (104, 109))	('IDH1', 'Gene', '3417', (89, 93))
196685	32335823	In contrast, EGFR, PTEN, and TP53 mutations showed a negative association with SST2 expression.	('EGFR', 'Gene', (13, 17))	('SST', 'Gene', '6750', (79, 82))	('SST', 'Gene', (79, 82))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('TP53', 'Gene', (29, 33))	('expression', 'MPA', (84, 94))	('EGFR', 'Gene', '1956', (13, 17))	('negative', 'NegReg', (53, 61))	('mutations', 'Var', (34, 43))
196690	32335823	Considering the association between gene mutations and SST2 expression, a high level of SST2 expression can be deemed a strong alternative to favorable prognostic markers, such as IDH1 mutation or tumor grade.	('mutations', 'Var', (41, 50))	('SST', 'Gene', (88, 91))	('IDH1', 'Gene', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('IDH1', 'Gene', '3417', (180, 184))	('SST', 'Gene', '6750', (88, 91))	('mutation', 'Var', (185, 193))	('SST', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SST', 'Gene', '6750', (55, 58))	('tumor', 'Disease', (197, 202))
196705	32335823	Despite IDH1 mutations and hormone receptor expression being good prognostic factors, recurrence of brain tumor patients with IDH1 mutations and breast cancer patients with hormone receptor expression is frequently observed in the clinical setting.	('IDH1', 'Gene', '3417', (126, 130))	('mutations', 'Var', (131, 140))	('IDH1', 'Gene', (8, 12))	('patients', 'Species', '9606', (112, 120))	('brain tumor', 'Disease', (100, 111))	('IDH1', 'Gene', '3417', (8, 12))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('IDH1', 'Gene', (126, 130))	('brain tumor', 'Disease', 'MESH:D001932', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('breast cancer', 'Disease', (145, 158))	('patients', 'Species', '9606', (159, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('brain tumor', 'Phenotype', 'HP:0030692', (100, 111))
196725	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
196727	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
196735	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
196754	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
196755	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
196756	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
196758	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
196759	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('E59K', 'Var', (0, 4))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
196760	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
196761	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('R238C', 'Var', (117, 122))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('NTNG1', 'Gene', '22854', (33, 38))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
196762	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
196763	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('NTN3', 'Gene', '4917', (224, 228))	('patients', 'Species', '9606', (76, 84))	('NTN1', 'Gene', (138, 142))	('NTN3', 'Gene', (224, 228))	('NTN4', 'Gene', '59277', (301, 305))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
196764	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('NTNG1', 'Gene', '22854', (104, 109))	('NTN5', 'Gene', (65, 69))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))	('patient', 'Species', '9606', (75, 82))	('NTNG1', 'Gene', (104, 109))
196765	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('NTNG2', 'Gene', '84628', (204, 209))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('patient', 'Species', '9606', (84, 91))	('NTN1', 'Gene', '9423', (195, 199))
196766	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
196767	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
196768	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
196769	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
196770	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
196771	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
196772	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('NTN4', 'Gene', (42, 46))	('NTN5', 'Gene', '126147', (52, 56))	('NTN3', 'Gene', '4917', (36, 40))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
196773	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('NTNG1', 'Gene', (7, 12))
196774	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
196784	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('cancer', 'Disease', (118, 124))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MLK1', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('epigenetic activation', 'Var', (66, 87))	('transcription', 'MPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MMP9', 'Gene', '4318', (91, 95))	('enhanced', 'PosReg', (19, 27))
196819	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTN1', 'Gene', '9423', (57, 61))	('NTNG1', 'Gene', '22854', (255, 260))	('NTN1', 'Gene', (57, 61))	('NTN1', 'Gene', '9423', (238, 242))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
196822	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
196824	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('methylation', 'Var', (31, 42))	('associated', 'Reg', (55, 65))	('NTN4', 'Gene', '59277', (46, 50))	('NTN4', 'Gene', (46, 50))
196825	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
196827	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('radiation therapy', 'Disease', (49, 66))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
196828	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', (15, 19))	('associated', 'Reg', (24, 34))	('NTN3', 'Gene', '4917', (15, 19))
196829	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (104, 114))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
196830	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
196834	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('EZH2', 'Gene', '2146', (102, 106))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
196849	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
196855	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('affected', 'Reg', (27, 35))	('eQTL', 'Var', (39, 43))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
196858	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('non-obstructive azoospermia', 'Disease', (96, 123))	('AIDS', 'Disease', (55, 59))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
196861	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('MYC', 'Gene', (96, 99))	('EBF1', 'Gene', '1879', (108, 112))	('TCF12', 'Gene', '6938', (101, 106))	('rs9894790', 'Var', (22, 31))	('TCF12', 'Gene', (101, 106))	('EGR1', 'Gene', (114, 118))	('MYC', 'Gene', '4609', (96, 99))	('NR2F2', 'Gene', '7026', (124, 129))	('affect', 'Reg', (74, 80))	('EGR1', 'Gene', '1958', (114, 118))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('NR2F2', 'Gene', (124, 129))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs9901637', 'Var', (33, 42))	('EBF1', 'Gene', (108, 112))	('binding', 'Interaction', (85, 92))
196862	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('high', 'Var', (14, 18))	('NTN1', 'Gene', '9423', (33, 37))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
196870	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
196882	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('GPX4', 'Gene', '2879', (99, 103))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
196891	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
196894	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Netrin', 'Gene', (112, 118))
196895	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
196896	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('NTR', 'Gene', (215, 218))
196899	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
196907	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
196915	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('NTNG1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (150, 156))	('NTNG2', 'Gene', (61, 66))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('methylation', 'Var', (36, 47))
196916	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
196918	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
196919	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
196923	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
197071	30663162	The most recent 2016 WHO classification of CNS tumors, in addition to histology, uses molecular markers such as isocitrate dehydrogenase (IDH1/2) mutation and 1p/19q codeletion to define tumor entities.	('IDH1/2', 'Gene', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CNS tumors', 'Disease', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('IDH1/2', 'Gene', '3417;3418', (138, 144))	('tumor', 'Disease', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutation', 'Var', (146, 154))	('tumor', 'Disease', (47, 52))	('CNS tumors', 'Disease', 'MESH:D016543', (43, 53))
197075	30663162	have shown that the APTw signal has potential as an imaging biomarker for identifying IDH mutation status in low-grade gliomas and MGMT methylation status in high-grade gliomas.	('gliomas', 'Disease', (169, 176))	('IDH', 'Gene', (86, 89))	('APT', 'Gene', (20, 23))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('IDH', 'Gene', '3417', (86, 89))	('MGMT', 'Gene', '4255', (131, 135))	('MGMT', 'Gene', (131, 135))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('mutation', 'Var', (90, 98))	('APT', 'Gene', '653639', (20, 23))
197076	30663162	These preliminary APTw MRI results showed that IDH-wildtype lesions were typically associated with relatively high APTw intensities, compared to IDH-mutant lesions.	('IDH', 'Gene', '3417', (47, 50))	('APT', 'Gene', '653639', (18, 21))	('APT', 'Gene', '653639', (115, 118))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('APT', 'Gene', (18, 21))	('APT', 'Gene', (115, 118))	('IDH', 'Gene', (47, 50))	('lesions', 'Var', (60, 67))
197077	30663162	This is consistent with lab research results, showing global downregulation of protein expression in mutant IDH1-driven glioma cells, compared to oncogenic HRAS IDH1-wild type glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('glioma', 'Disease', (176, 182))	('downregulation', 'NegReg', (61, 75))	('IDH1', 'Gene', '3417', (108, 112))	('protein expression', 'MPA', (79, 97))	('HRAS', 'Gene', '3265', (156, 160))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('IDH1', 'Gene', (161, 165))	('mutant', 'Var', (101, 107))	('glioma', 'Disease', (120, 126))	('HRAS', 'Gene', (156, 160))	('IDH1', 'Gene', (108, 112))	('IDH1', 'Gene', '3417', (161, 165))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
197105	30663162	It is expected that the pH/diffusion mismatch will be better than the current standard of care criteria (perfusion/diffusion mismatch) at identifying the true viable tissue area at risk of infarction, i.e., the ischemic penumbra.	('mismatch', 'Var', (37, 45))	('infarction', 'Disease', (189, 199))	('infarction', 'Disease', 'MESH:D007238', (189, 199))
197186	30663162	This means that the effect of the increasing T1w on the measured APTw signals was mostly canceled out by the effect of the increasing water content in the tumor, as pointed out in the early APTw study.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('APT', 'Gene', '653639', (190, 193))	('water', 'Chemical', 'MESH:D014867', (134, 139))	('water', 'MPA', (134, 139))	('APT', 'Gene', (65, 68))	('tumor', 'Disease', (155, 160))	('APT', 'Gene', '653639', (65, 68))	('APT', 'Gene', (190, 193))	('T1w', 'Var', (45, 48))
197187	30663162	Further, two recent numerical simulation studies have clearly demonstrated that the MTRasym(3.5ppm) signal increase with T1w at low B1 (<1 muT), is roughly insensitive to T1w at intermediate B1 (1.5-2.5 muT), and even slightly decreases with T1w at high B1 (>3 muT), a complicated non-linear relationship because of complicated differential equations.	('T1w', 'Var', (121, 124))	('decreases', 'NegReg', (227, 236))	('increase', 'PosReg', (107, 115))	('low', 'NegReg', (128, 131))	('rat', 'Species', '10116', (69, 72))
197211	30663162	Fortunately, the areas of large liquefactive necrosis, hemorrhages, or large vessels are often evident on standard structural MRI sequences (such as T2w, FLAIR, and T1w).	('liquefactive necrosis', 'Disease', 'MESH:D009336', (32, 53))	('liquefactive necrosis', 'Disease', (32, 53))	('hemorrhages', 'Disease', 'MESH:D006470', (55, 66))	('hemorrhages', 'Disease', (55, 66))	('T1w', 'Var', (165, 168))
197220	30663162	For brain tumors, we recommend the use of B1 = 2 muT and a total saturation time (with interpulse delays if needed) of 0.8-2 sec followed by B0 correction and asymmetry analysis.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('brain tumors', 'Phenotype', 'HP:0030692', (4, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('B1 =', 'Var', (42, 46))	('brain tumors', 'Disease', 'MESH:D001932', (4, 16))	('brain tumors', 'Disease', (4, 16))	('brain tumor', 'Phenotype', 'HP:0030692', (4, 15))	('rat', 'Species', '10116', (69, 72))
197284	30867254	performed DNA methylation analyses in oral squamous cell carcinoma tissues, high-grade squamous intraepithelial lesions and corresponding normal contralateral mucosae, and found oral squamous cell carcinoma tissues and high-grade squamous intraepithelial lesions exhibited hypermethylation of LINC00599 in comparison with corresponding normal contralateral mucosae.	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (230, 262))	('LINC00599', 'Gene', '157627', (293, 302))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('squamous intraepithelial lesions', 'Disease', (230, 262))	('LINC00599', 'Gene', (293, 302))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('squamous intraepithelial lesions', 'Disease', (87, 119))	('oral squamous cell carcinoma', 'Disease', (178, 206))	('exhibited', 'Reg', (263, 272))	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (87, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('hypermethylation', 'Var', (273, 289))	('oral squamous cell carcinoma', 'Disease', (38, 66))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 206))
197294	30867254	We analyzed the expression difference of LINC00599 in glioma cases, which were grouped according to age, gender, tumor size, and WHO grade, and found glioma tissues with WHO III-IV grade exhibited lower levels of LINC00599 expression than glioma tissues with I-II grade.	('lower', 'NegReg', (197, 202))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('III-IV grade', 'Var', (174, 186))	('expression', 'MPA', (223, 233))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('glioma', 'Disease', (239, 245))	('glioma', 'Disease', (150, 156))	('LINC00599', 'Gene', (41, 50))	('LINC00599', 'Gene', '157627', (41, 50))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('glioma', 'Disease', (54, 60))	('LINC00599', 'Gene', '157627', (213, 222))	('LINC00599', 'Gene', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
197308	27270613	NIK promotes dramatic alterations in glioma cell morphology that are characterized by extensive membrane branching and elongated pseudopodial protrusions.	('NIK', 'Var', (0, 3))	('glioma', 'Disease', (37, 43))	('alterations', 'Reg', (22, 33))	('membrane branching', 'CPA', (96, 114))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
197309	27270613	Correspondingly, NIK increases the phosphorylation, enzymatic activity and pseudopodial localization of membrane type-1 matrix metalloproteinase (MT1-MMP/MMP14), which is associated with enhanced tumor cell invasion of three-dimensional collagen matrices.	('increases', 'PosReg', (21, 30))	('enzymatic activity', 'MPA', (52, 70))	('MMP14', 'Gene', '4323', (154, 159))	('tumor', 'Disease', (196, 201))	('membrane type-1 matrix metalloproteinase', 'Gene', (104, 144))	('NIK', 'Var', (17, 20))	('membrane type-1 matrix metalloproteinase', 'Gene', '4323', (104, 144))	('MMP14', 'Gene', (154, 159))	('MT1-MMP', 'Gene', '4323', (146, 153))	('pseudopodial localization', 'MPA', (75, 100))	('enhanced', 'PosReg', (187, 195))	('phosphorylation', 'MPA', (35, 50))	('MT1-MMP', 'Gene', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
197333	27270613	To address the role of NIK, a key upstream regulator of noncanonical NF-kappaB signaling, in glioma invasion and pathogenesis, we first sought to determine whether NIK was sufficient to promote cell invasion in BT114 glioma cells, which exhibit low invasive activity.	('promote', 'PosReg', (186, 193))	('glioma', 'Disease', (93, 99))	('glioma invasion', 'Disease', 'MESH:D005910', (93, 108))	('glioma', 'Disease', 'MESH:D005910', (217, 223))	('NIK', 'Var', (164, 167))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('glioma', 'Disease', (217, 223))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('cell invasion', 'CPA', (194, 207))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioma invasion', 'Disease', (93, 108))
197334	27270613	Specifically, a S867A substitution at the conserved TBK1 phosphorylation site renders human NIK resistant to degradation, and immunoblot analysis of BT114 glioma cells confirmed that NIK(S867A) is expressed at higher levels than NIK(WT) (Figure 1a).	('S867A', 'Mutation', 'p.S867A', (187, 192))	('TBK1', 'Gene', '29110', (52, 56))	('S867A', 'Mutation', 'p.S867A', (16, 21))	('S867A', 'Var', (16, 21))	('human', 'Species', '9606', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('TBK1', 'Gene', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('glioma', 'Disease', (155, 161))
197335	27270613	Using 3D collagen type I invasion assays, we observed that NIK-transfected cells were more invasive than controls cells, and NIK(S867A) exerted a significantly stronger effect than NIK(WT) (Figures 1b and c).	('S867A', 'Mutation', 'p.S867A', (129, 134))	('NIK-transfected', 'Var', (59, 74))	('invasive', 'CPA', (91, 99))	('NIK(S867A', 'Var', (125, 134))	('stronger', 'PosReg', (160, 168))
197336	27270613	Furthermore, ectopic expression of NIK in several additional glioma lines, including BT116, U87 and BT25 cells, promoted cell invasion in this assay (Supplementary Figure 1).	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma lines', 'Disease', (61, 73))	('promoted', 'PosReg', (112, 120))	('glioma lines', 'Disease', 'MESH:D005910', (61, 73))	('cell invasion in this assay', 'CPA', (121, 148))	('ectopic expression', 'Var', (13, 31))	('NIK', 'Gene', (35, 38))
197338	27270613	NIK protein was no longer detectable in both untreated and TWEAK-treated BT25-sgNIK cells, indicating efficient sgRNA-mediated deletion of NIK (Figure 1d).	('deletion', 'Var', (127, 135))	('NIK', 'Gene', (139, 142))	('TWEAK-', 'Gene', (59, 65))	('TWEAK-', 'Gene', '8742', (59, 65))
197344	27270613	Examination of BT114 cells in 2D culture revealed that both NIK(WT) and NIK(S867A) significantly altered cell morphology, specifically by inducing the formation of F-actin- and cortactin-dense, branched cellular processes resembling the pseudopodia of invasive cells (Figure 2a).	('cell morphology', 'CPA', (105, 120))	('cortactin', 'Gene', (177, 186))	('altered', 'Reg', (97, 104))	('inducing', 'Reg', (138, 146))	('F-actin- and', 'Protein', (164, 176))	('cortactin', 'Gene', '2017', (177, 186))	('NIK(S867A', 'Var', (72, 81))	('S867A', 'Mutation', 'p.S867A', (76, 81))	('NIK', 'Var', (60, 63))
197345	27270613	Quantification of these features (Supplementary 3A) revealed that total cell area as well as the length of extended pseudopodial cell processes were increased in both NIK(WT) and NIK(S867A) cells, compared with vector control cells (Figures 2b and c).	('NIK', 'Var', (167, 170))	('increased', 'PosReg', (149, 158))	('NIK(S867A', 'Var', (179, 188))	('length of extended pseudopodial cell processes', 'CPA', (97, 143))	('S867A', 'Mutation', 'p.S867A', (183, 188))
197353	27270613	The increase of MT1-MMP in BT114-NIK(S867A) cells compared with BT114-NIK(WT) cells is likely due to higher expression levels of transfected NIK in the former compared with the latter cells (Figures 3a and b).	('S867A', 'Mutation', 'p.S867A', (37, 42))	('higher', 'PosReg', (101, 107))	('expression levels', 'MPA', (108, 125))	('MT1-MMP', 'Gene', (16, 23))	('MT1-MMP', 'Gene', '4323', (16, 23))	('increase', 'PosReg', (4, 12))	('BT114-NIK(S867A', 'Var', (27, 42))
197355	27270613	However, BT114 cells overexpressing NIK(WT) and NIK(S867A) exhibited increased levels of pMT1-MMP (Figure 3a), suggesting that NIK may regulate MT1-MMP intracellular localization.	('regulate', 'Reg', (135, 143))	('levels', 'MPA', (79, 85))	('increased', 'PosReg', (69, 78))	('MT1-MMP', 'Gene', (144, 151))	('MT1-MMP', 'Gene', '4323', (144, 151))	('MT1-MMP', 'Gene', (90, 97))	('MT1-MMP', 'Gene', '4323', (90, 97))	('S867A', 'Mutation', 'p.S867A', (52, 57))	('NIK', 'Var', (36, 39))
197358	27270613	When compared with these controls, BT114 cells expressing NIK(WT) or NIK(S867A) showed an increase in pMT1-MMP pseudopodial staining, with NIK(S867A) having a stronger effect than NIK(WT) (Figure 3c).	('increase', 'PosReg', (90, 98))	('S867A', 'Mutation', 'p.S867A', (73, 78))	('MT1-MMP', 'Gene', '4323', (103, 110))	('S867A', 'Mutation', 'p.S867A', (143, 148))	('MT1-MMP', 'Gene', (103, 110))	('NIK(S867A', 'Var', (69, 78))	('NIK(S867A', 'Var', (139, 148))
197359	27270613	Quantification of pMT1-MMP staining demonstrated that the percent of pMT1-MMP at the pseudopodia was significantly increased in NIK(WT)- and NIK(S867A)-expressing cells, and correlated with levels of NIK expression (Figure 3d and Supplementary Figure 3).	('MT1-MMP', 'Gene', '4323', (19, 26))	('increased', 'PosReg', (115, 124))	('MT1-MMP', 'Gene', '4323', (70, 77))	('MT1-MMP', 'Gene', (70, 77))	('NIK(S867A)-expressing', 'Var', (141, 162))	('NIK', 'Var', (128, 131))	('S867A', 'Mutation', 'p.S867A', (145, 150))	('MT1-MMP', 'Gene', (19, 26))
197361	27270613	Consistent with these observations, we observed that MT1-MMP enzymatic activity was increased in cells expressing NIK(WT) or NIK(S867A) (Figure 3e).	('S867A', 'Mutation', 'p.S867A', (129, 134))	('NIK(S867A', 'Var', (125, 134))	('increased', 'PosReg', (84, 93))	('NIK', 'Var', (114, 117))	('MT1-MMP', 'Gene', (53, 60))	('MT1-MMP', 'Gene', '4323', (53, 60))
197362	27270613	Loss of NIK in BT25-sgNIK cells did not affect the expression of MT1-MMP mRNA or total protein, but did diminish levels of pMT1-MMP (Figures 4a and b).	('NIK', 'Gene', (8, 11))	('MT1-MMP', 'Gene', '4323', (65, 72))	('MT1-MMP', 'Gene', (65, 72))	('MT1-MMP', 'Gene', (124, 131))	('MT1-MMP', 'Gene', '4323', (124, 131))	('Loss', 'Var', (0, 4))	('diminish', 'NegReg', (104, 112))
197365	27270613	To test the hypothesis that NIK enhances MT1-MMP activity post-transcriptionally, we used a heterologous assay involving ectopic co-expression of NIK(S867A) and MT1-MMP in HEK293FT cells.	('enhances', 'PosReg', (32, 40))	('MT1-MMP', 'Gene', '4323', (161, 168))	('MT1-MMP', 'Gene', (41, 48))	('MT1-MMP', 'Gene', (161, 168))	('MT1-MMP', 'Gene', '4323', (41, 48))	('S867A', 'Var', (150, 155))	('S867A', 'Mutation', 'p.S867A', (150, 155))	('HEK293FT', 'CellLine', 'CVCL:6911', (172, 180))
197369	27270613	Consistent with increased cell invasion, we observed that HEK293FT cells co-expressing NIK and MT1-MMP exhibited increased MT1-MMP enzymatic activity compared with expression of MT1-MMP alone (Supplementary Figure 5B).	('MT1-MMP', 'Gene', (95, 102))	('MT1-MMP', 'Gene', '4323', (178, 185))	('MT1-MMP', 'Gene', '4323', (123, 130))	('MT1-MMP', 'Gene', (178, 185))	('MT1-MMP', 'Gene', (123, 130))	('NIK', 'Var', (87, 90))	('increased', 'PosReg', (16, 25))	('increased', 'PosReg', (113, 122))	('HEK293FT', 'CellLine', 'CVCL:6911', (58, 66))	('cell invasion', 'CPA', (26, 39))	('MT1-MMP', 'Gene', '4323', (95, 102))
197372	27270613	We first noted that neither NIK(WT) or NIK(S867A) affected p65 phosphorylation (pS536), a marker of p65 transcriptional activation (see Figure 3a).	('S867A', 'Var', (43, 48))	('p65 phosphorylation', 'MPA', (59, 78))	('S867A', 'Mutation', 'p.S867A', (43, 48))
197374	27270613	MEFs derived from homozygous p65-/- or p65-/-;cRel-/- mice showed significantly reduced invasion compared with their corresponding pooled wild-type MEFs, while RelB-/-MEF invasion was almost completely abrogated (Figure 5a).	('p65-/-', 'Var', (29, 35))	('MEF', 'Disease', 'None', (0, 3))	('MEF', 'Disease', (167, 170))	('MEF', 'Disease', (148, 151))	('invasion', 'CPA', (88, 96))	('p65-/-', 'Var', (39, 45))	('MEFs', 'CellLine', 'CVCL:9115', (0, 4))	('reduced', 'NegReg', (80, 87))	('MEF', 'Disease', 'None', (148, 151))	('MEF', 'Disease', (0, 3))	('mice', 'Species', '10090', (54, 58))	('MEFs', 'CellLine', 'CVCL:9115', (148, 152))	('MEF', 'Disease', 'None', (167, 170))
197376	27270613	Notably, TWEAK-enhanced invasion of p65-/- MEFs was accompanied by a significant increase of pMT1-MMP located within pseudopodia (Figure 5b and Supplementary Figure 7F).	('p65-/- MEFs', 'Var', (36, 47))	('MEFs', 'CellLine', 'CVCL:9115', (43, 47))	('TWEAK-', 'Gene', (9, 15))	('MT1-MMP', 'Gene', '4323', (94, 101))	('TWEAK-', 'Gene', '8742', (9, 15))	('MT1-MMP', 'Gene', (94, 101))	('invasion', 'CPA', (24, 32))	('increase', 'PosReg', (81, 89))
197380	27270613	Regardless, the NIK+/+ MEFs exhibited robust TWEAK-induced invasion, which was significantly impaired in NIK-/- MEFs (Supplementary Figure 8A).	('TWEAK-', 'Gene', '8742', (45, 51))	('impaired', 'NegReg', (93, 101))	('MEFs', 'CellLine', 'CVCL:9115', (23, 27))	('MEFs', 'CellLine', 'CVCL:9115', (112, 116))	('NIK+/+ MEFs', 'Var', (16, 27))	('NIK-/-', 'Var', (105, 111))	('TWEAK-', 'Gene', (45, 51))
197381	27270613	Moreover, we also observed decreased pseudopodial localization of pMT1-MMP in NIK-/- MEFs compared with NIK+/+ MEFs (Supplementary Figures 8B and C).	('NIK-/- MEFs', 'Var', (78, 89))	('MEFs', 'CellLine', 'CVCL:9115', (85, 89))	('decreased', 'NegReg', (27, 36))	('pseudopodial localization', 'MPA', (37, 62))	('MEFs', 'CellLine', 'CVCL:9115', (111, 115))	('MT1-MMP', 'Gene', (67, 74))	('MT1-MMP', 'Gene', '4323', (67, 74))
197383	27270613	Expression of NIK(WT) in p65-/-;cRel-/- MEFs increased invasion (Figure 5c) and pseudopodial localization of pMT1-MMP (Figure 5d).	('pseudopodial', 'CPA', (80, 92))	('increased', 'PosReg', (45, 54))	('cRel-/-', 'Gene', (32, 39))	('MT1-MMP', 'Gene', (110, 117))	('p65-/-', 'Var', (25, 31))	('MT1-MMP', 'Gene', '4323', (110, 117))	('invasion', 'CPA', (55, 63))	('MEFs', 'CellLine', 'CVCL:9115', (40, 44))
197385	27270613	Together, these results demonstrate that TWEAK and NIK promote invasion and pMT1-MMP localization within pseudopodia, independently of the canonical NF-kappaB pathway.	('TWEAK', 'Var', (41, 46))	('NIK', 'Var', (51, 54))	('invasion', 'CPA', (63, 71))	('promote', 'PosReg', (55, 62))	('MT1-MMP', 'Gene', '4323', (77, 84))	('MT1-MMP', 'Gene', (77, 84))
197386	27270613	We previously demonstrated that BT114-NIK cells formed larger tumors in vivo, compared with BT114-Control cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BT114-NIK cells', 'Var', (32, 47))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))
197388	27270613	Immunofluorescence staining verified increased NIK expression in BT114-NIK tumors compared with BT114-Control tumors (Figures 6a and b).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('BT114-NIK', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('increased', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NIK', 'Protein', (47, 50))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))
197389	27270613	Adjacent tumor sections were used for immunohistochemical staining, which revealed increased expression of pMT1-MMP in BT114-NIK tumors, compared with BT114-Control tumors (Figures 6c-e).	('BT114-NIK', 'Var', (119, 128))	('tumors', 'Disease', (129, 135))	('MT1-MMP', 'Gene', '4323', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('increased', 'PosReg', (83, 92))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumors', 'Disease', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('MT1-MMP', 'Gene', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('expression', 'MPA', (93, 103))
197396	27270613	The mean survival of GBM patients with increased NIK and MT1-MMP expression (5% of cases) is 10.6 months compared with 14.1 months for patients with unaltered expression (Figure 7c).	('MT1-MMP', 'Gene', (57, 64))	('patients', 'Species', '9606', (135, 143))	('MT1-MMP', 'Gene', '4323', (57, 64))	('NIK', 'Var', (49, 52))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('increased', 'PosReg', (39, 48))	('patients', 'Species', '9606', (25, 33))
197397	27270613	In lower grade glioma (LGG), the correlation between high NIK and MT1-MMP expression (12% of cases) and poor patient survival was even higher (Figure 7d), suggesting that high NIK and MT1-MMP expression is a prognostic indicator for LGGs that are likely to progress to more aggressive tumors.	('LGGs', 'Disease', (233, 237))	('high', 'Var', (53, 57))	('patient', 'Species', '9606', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('MT1-MMP', 'Gene', (66, 73))	('MT1-MMP', 'Gene', '4323', (66, 73))	('aggressive tumors', 'Disease', 'MESH:D001523', (274, 291))	('high NIK', 'Var', (171, 179))	('glioma', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('aggressive tumors', 'Disease', (274, 291))	('MT1-MMP', 'Gene', (184, 191))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('MT1-MMP', 'Gene', '4323', (184, 191))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
197398	27270613	Furthermore, the time to disease progression for LGG patients with high NIK and MT1-MMP expression is significantly shorter and is reflected by a higher rate of relapse (Figure 7e).	('higher', 'PosReg', (146, 152))	('shorter', 'NegReg', (116, 123))	('high NIK', 'Var', (67, 75))	('LGG', 'Disease', (49, 52))	('patients', 'Species', '9606', (53, 61))	('MT1-MMP', 'Gene', (80, 87))	('MT1-MMP', 'Gene', '4323', (80, 87))
197400	27270613	Aberrant activation of NIK has been shown to have oncogenic roles in several cancers, including melanoma, ovarian cancer and multiple myeloma, primarily through regulation of proliferation and cell survival.	('regulation', 'Reg', (161, 171))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('multiple myeloma', 'Phenotype', 'HP:0006775', (125, 141))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('multiple myeloma', 'Disease', 'MESH:D009101', (125, 141))	('NIK', 'Gene', (23, 26))	('ovarian cancer', 'Disease', (106, 120))	('cell survival', 'CPA', (193, 206))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('multiple myeloma', 'Disease', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
197404	27270613	A post-transcriptional process is indicated because we observed that NIK increases MT1-MMP phosphorylation and activity, but does not affect MT1-MMP mRNA expression (Figures 3b and 4a).	('increases', 'PosReg', (73, 82))	('activity', 'MPA', (111, 119))	('MT1-MMP', 'Gene', '4323', (141, 148))	('NIK', 'Var', (69, 72))	('MT1-MMP', 'Gene', '4323', (83, 90))	('MT1-MMP', 'Gene', (141, 148))	('MT1-MMP', 'Gene', (83, 90))
197405	27270613	As phosphorylation of Y573 is the critical step in enhancing movement of MT1-MMP to the cell surface, and NIK is a serine-threonine kinase, we speculate that NIK-induced MT1-MMP phosphorylation is indirect.	('Y573', 'Var', (22, 26))	('MT1-MMP', 'Gene', '4323', (73, 80))	('MT1-MMP', 'Gene', (73, 80))	('enhancing', 'PosReg', (51, 60))	('Y573', 'Chemical', '-', (22, 26))	('MT1-MMP', 'Gene', (170, 177))	('MT1-MMP', 'Gene', '4323', (170, 177))
197406	27270613	However, we cannot rule out the possibility that NIK phosphorylates MT1-MMP at either the T567 or S577 residues within the cytoplasmic tail, which may, in turn, regulate Y573 phosphorylation.	('T567', 'Var', (90, 94))	('MT1-MMP', 'Gene', (68, 75))	('MT1-MMP', 'Gene', '4323', (68, 75))	('Y573', 'Chemical', '-', (170, 174))	('regulate', 'Reg', (161, 169))	('S577', 'Var', (98, 102))	('Y573 phosphorylation', 'MPA', (170, 190))
197417	27270613	Indeed, because invadopodia and pseudopodia formation drive dissemination and metastasis of several cancers, inhibition of NIK may be an efficacious therapeutic approach in many invasive tumor types.	('pseudopodia', 'Disease', (32, 43))	('invasive tumor', 'Disease', 'MESH:D009369', (178, 192))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('inhibition', 'Var', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NIK', 'Gene', (123, 126))	('metastasis', 'CPA', (78, 88))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('invasive tumor', 'Disease', (178, 192))	('cancers', 'Disease', (100, 107))
197418	27270613	rhTNFalpha (#G5241) was obtained from Promega, Madison, WI, USA; rhTWEAK (#310-06) was purchased from PeproTech, Rocky Hill, NJ, USA; TAPI-2 was obtained from Calbiochem, San Diego, CA, USA.	('TAPI-2', 'Chemical', 'MESH:C099410', (134, 140))	('TNF', 'Gene', '7124', (2, 5))	('#G5241', 'Var', (12, 18))	('TNF', 'Gene', (2, 5))
197446	27270613	To detect NIK protein expression, cells were pre-treated with MG132 (5 muM) +-TWEAK (10 ng/ml), as indicated.	('muM', 'Gene', (71, 74))	('MG132', 'Var', (62, 67))	('MG132', 'Chemical', 'MESH:C072553', (62, 67))	('NIK protein', 'Protein', (10, 21))	('muM', 'Gene', '56925', (71, 74))
197452	27270613	Kaplan-Meier plots were generated from GBM and LGG patients with increased NIK (MAP3K14) and MT1-MMP (MMP14) mRNA expression with a z-score of 1.5.	('increased', 'PosReg', (65, 74))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('MMP14', 'Gene', '4323', (102, 107))	('MAP3K14', 'Gene', '9020', (80, 87))	('MT1-MMP', 'Gene', '4323', (93, 100))	('MMP14', 'Gene', (102, 107))	('MT1-MMP', 'Gene', (93, 100))	('patients', 'Species', '9606', (51, 59))	('MAP3K14', 'Gene', (80, 87))	('NIK', 'Var', (75, 78))
197456	26045167	IDH1 mutation induces reprogramming of pyruvate metabolism Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2-hydroxyglutarate but also elicits additional metabolic changes.	('metabolic changes', 'MPA', (175, 192))	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', '3417', (0, 4))	('IDH1', 'Gene', '3417', (94, 98))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (128, 146))	('isocitrate', 'Chemical', 'MESH:C034219', (66, 76))	('induces', 'Reg', (14, 21))	('elicits', 'Reg', (156, 163))	('reprogramming of pyruvate metabolism Mutant', 'MPA', (22, 65))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('pyruvate', 'Chemical', 'MESH:D019289', (39, 47))
197457	26045167	Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared to cells expressing wild-type IDH1.	('Levels of', 'MPA', (0, 9))	('U87 glioblastoma', 'Disease', 'MESH:D005909', (101, 117))	('IDH1', 'Gene', (180, 184))	('human', 'Species', '9606', (134, 139))	('activity', 'MPA', (58, 66))	('pyruvate dehydrogenase', 'Gene', '54704', (29, 51))	('glutamate', 'MPA', (15, 24))	('PDH', 'Gene', (53, 56))	('U87 glioblastoma', 'Disease', (101, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('affected', 'Reg', (89, 97))	('pyruvate dehydrogenase', 'Gene', (29, 51))	('PDH', 'Gene', '54704', (53, 56))	('mutant', 'Var', (173, 179))	('glutamate', 'Chemical', 'MESH:D018698', (15, 24))
197458	26045167	In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism.	('mutation', 'Var', (82, 90))	('reprograms', 'Reg', (103, 113))	('pyruvate', 'Chemical', 'MESH:D019289', (114, 122))	('IDH1', 'Gene', (77, 81))
197459	26045167	Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3 and levels of hypoxia inducible factor-1alpha.	('levels', 'MPA', (191, 197))	('NHA IDH1', 'Gene', (45, 53))	('inhibitory phosphorylation', 'MPA', (113, 139))	('PDH', 'Gene', (109, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('increases', 'PosReg', (96, 105))	('PDH', 'Gene', '54704', (8, 11))	('hypoxia inducible factor-1alpha', 'Gene', '3091', (201, 232))	('pyruvate dehydrogenase kinase-3', 'Gene', '5165', (155, 186))	('Reduced', 'NegReg', (0, 7))	('activity', 'MPA', (12, 20))	('hypoxia inducible factor-1alpha', 'Gene', (201, 232))	('expression', 'MPA', (141, 151))	('U87 glioblastoma', 'Disease', 'MESH:D005909', (24, 40))	('mutant', 'Var', (54, 60))	('Reduced PDH activity', 'Phenotype', 'HP:0002928', (0, 20))	('pyruvate dehydrogenase kinase-3', 'Gene', (155, 186))	('PDH', 'Gene', '54704', (109, 112))	('PDH', 'Gene', (8, 11))	('U87 glioblastoma', 'Disease', (24, 40))
197461	26045167	13C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells.	('13C', 'Chemical', '-', (0, 3))	('glucose flux to glutamate', 'MPA', (37, 62))	('mutant', 'Var', (71, 77))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('reduction', 'NegReg', (24, 33))	('glutamate', 'Chemical', 'MESH:D018698', (53, 62))	('IDH1', 'Gene', (66, 70))
197462	26045167	Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-13C-glutamate in IDH1 mutant cells.	('production of hyperpolarized 5-13C-glutamate', 'MPA', (95, 139))	('PDH', 'Gene', (39, 42))	('IDH1', 'Gene', (143, 147))	('PDH', 'Gene', '54704', (39, 42))	('mutant', 'Var', (148, 154))	('dichloroacetate', 'Chemical', 'MESH:D003999', (63, 78))	('increased', 'PosReg', (85, 94))	('activation', 'PosReg', (25, 35))	('DCA', 'Chemical', 'MESH:D003999', (80, 83))	('5-13C-glutamate', 'Chemical', '-', (124, 139))
197463	26045167	Further, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation.	('IDH1', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))	('clonogenic advantage', 'CPA', (42, 62))	('abrogated', 'NegReg', (28, 37))	('DCA', 'Chemical', 'MESH:D003999', (9, 12))
197464	26045167	Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation.	('PDH', 'Gene', '54704', (69, 72))	('patient', 'Species', '9606', (6, 13))	('rat', 'Species', '10116', (112, 115))	('PDH', 'Gene', (69, 72))	('mutant', 'Var', (22, 28))
197465	26045167	Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications.	('mutation', 'Var', (54, 62))	('pyruvate', 'Chemical', 'MESH:D019289', (106, 114))	('induces', 'Reg', (63, 70))	('rat', 'Species', '10116', (161, 164))	('IDH1', 'Gene', (49, 53))	('reprogramming of pyruvate metabolism', 'MPA', (89, 125))
197471	26045167	Beyond the metabolic reprogramming that occurs downstream of oncogenic signaling, a powerful illustration of the role of altered metabolism as a potential driver of tumorigenesis is the discovery of tumors with somatic mutations in the metabolic enzyme isocitrate dehydrogenase (IDH).	('tumor', 'Disease', (199, 204))	('isocitrate', 'Chemical', 'MESH:C034219', (253, 263))	('IDH', 'Gene', (279, 282))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('rat', 'Species', '10116', (259, 262))	('IDH', 'Gene', '3417', (279, 282))	('rat', 'Species', '10116', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (219, 228))	('tumor', 'Disease', (165, 170))
197472	26045167	Specifically, the cytosolic isoform of IDH, IDH1, is mutated in 70-90% of low-grade gliomas and secondary glioblastoma (GBM) and mitochondrial IDH2 is mutated in ~20% of acute myeloid leukemia cases.	('gliomas', 'Disease', (84, 91))	('mutated', 'Var', (53, 60))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('IDH', 'Gene', (143, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('IDH', 'Gene', (39, 42))	('acute myeloid leukemia', 'Disease', (170, 192))	('IDH', 'Gene', '3417', (143, 146))	('glioblastoma', 'Disease', (106, 118))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (39, 42))	('IDH2', 'Gene', (143, 147))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (170, 192))	('GBM', 'Phenotype', 'HP:0012174', (120, 123))	('IDH2', 'Gene', '3418', (143, 147))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (170, 192))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (176, 192))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	('IDH', 'Gene', '3417', (44, 47))
197474	26045167	The IDH1 mutation, which commonly occurs at the R132 residue in the active site, leads to a loss of wild-type enzyme activity and to a neomorphic activity that catalyzes the reduction of alpha-KG to 2-hydroxyglutarate (2-HG).	('wild-type', 'MPA', (100, 109))	('mutation', 'Var', (9, 17))	('alpha-KG', 'Chemical', 'MESH:D007656', (187, 195))	('activity', 'MPA', (117, 125))	('2-HG', 'Chemical', 'MESH:C019417', (219, 223))	('loss', 'NegReg', (92, 96))	('IDH1', 'Gene', (4, 8))	('reduction', 'MPA', (174, 183))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (199, 217))
197475	26045167	As a result, IDH1 mutant gliomas show significantly elevated levels of 2-HG.	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('mutant', 'Var', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('IDH1', 'Gene', (13, 17))	('2-HG', 'Chemical', 'MESH:C019417', (71, 75))	('levels of 2-HG', 'MPA', (61, 75))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))	('elevated', 'PosReg', (52, 60))
197481	26045167	Furthermore, a noninvasive 1H-MRS investigation of mutant IDH1-glioma patients reported that glutamate levels were lower compared to normal brain.	('glutamate levels', 'MPA', (93, 109))	('patients', 'Species', '9606', (70, 78))	('1H', 'Chemical', '-', (27, 29))	('mutant', 'Var', (51, 57))	('glutamate', 'Chemical', 'MESH:D018698', (93, 102))	('lower', 'NegReg', (115, 120))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1-glioma', 'Disease', (58, 69))	('IDH1-glioma', 'Disease', 'MESH:D005910', (58, 69))
197482	26045167	In line with these findings, the activity of three enzymes - branched chain amino acid transferase 1 (BCAT-1), aspartate transaminase (AST), and glutamate dehydrogenase (GDH) - that catalyze the conversion of alpha-KG to glutamate, was shown to be lower in IDH1 mutant cells.	('GDH', 'Gene', (170, 173))	('branched chain amino acid transferase 1', 'Gene', (61, 100))	('activity', 'MPA', (33, 41))	('glutamate dehydrogenase', 'Gene', (145, 168))	('glutamate', 'Chemical', 'MESH:D018698', (221, 230))	('glutamate dehydrogenase', 'Gene', '2746', (145, 168))	('AST', 'Gene', '26503', (135, 138))	('lower', 'NegReg', (248, 253))	('alpha-KG', 'Chemical', 'MESH:D007656', (209, 217))	('BCAT-1', 'Gene', '586', (102, 108))	('mutant', 'Var', (262, 268))	('BCAT-1', 'Gene', (102, 108))	('aspartate transaminase', 'Gene', (111, 133))	('AST', 'Gene', (135, 138))	('IDH1', 'Gene', (257, 261))	('aspartate transaminase', 'Gene', '26503', (111, 133))	('GDH', 'Gene', '2746', (170, 173))	('glutamate', 'Chemical', 'MESH:D018698', (145, 154))	('branched chain amino acid transferase 1', 'Gene', '586', (61, 100))
197483	26045167	also noted a drop in phosphocholine (PC) and an increase in glycerophosphocholine (GPC) in IDH1 mutant cells and analysis of ex vivo tumor samples and animal models by MRS confirmed the increase of GPC.	('PC', 'Chemical', 'MESH:D010767', (199, 201))	('glycerophosphocholine', 'MPA', (60, 81))	('mutant', 'Var', (96, 102))	('GPC', 'Chemical', 'MESH:D005997', (198, 201))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PC', 'Chemical', 'MESH:D010767', (84, 86))	('PC', 'Chemical', 'MESH:D010767', (37, 39))	('glycerophosphocholine', 'Chemical', 'MESH:D005997', (60, 81))	('phosphocholine', 'Chemical', 'MESH:D010767', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('IDH1', 'Gene', (91, 95))	('tumor', 'Disease', (133, 138))	('GPC', 'Chemical', 'MESH:D005997', (83, 86))	('phosphocholine', 'Chemical', 'MESH:D010767', (21, 35))	('drop', 'NegReg', (13, 17))	('increase', 'PosReg', (48, 56))
197484	26045167	This observation is counter to the increase in PC and drop in GPC typically observed in cancer and possibly points to metabolic alterations unique to mutant IDH1 tumors.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('rat', 'Species', '10116', (132, 135))	('IDH1 tumors', 'Disease', 'MESH:D009369', (157, 168))	('GPC', 'Chemical', 'MESH:D005997', (62, 65))	('GPC', 'MPA', (62, 65))	('PC', 'Chemical', 'MESH:D010767', (47, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('mutant', 'Var', (150, 156))	('IDH1 tumors', 'Disease', (157, 168))	('PC', 'Chemical', 'MESH:D010767', (63, 65))
197485	26045167	Consistent with this idea, the lactate dehydrogenase (LDHA) gene, responsible for lactate production and typically overexpressed in cancer, is silenced in IDH1 mutant gliomas and IDH1 mutant cells appear to have a greater dependence on the TCA cycle compared to wild-type cells.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('IDH1', 'Gene', (155, 159))	('lactate', 'Chemical', 'MESH:D019344', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lactate dehydrogenase', 'Gene', (31, 52))	('TCA', 'Chemical', 'MESH:D014233', (240, 243))	('lactate dehydrogenase', 'Gene', '3939', (31, 52))	('mutant', 'Var', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('LDHA', 'Gene', '3939', (54, 58))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('LDHA', 'Gene', (54, 58))	('silenced', 'NegReg', (143, 151))	('lactate', 'Chemical', 'MESH:D019344', (31, 38))
197486	26045167	In our laboratory, we have studied two genetically engineered cell models that overexpress either wild-type IDH1 or mutant IDH1: a U87 GBM-derived model and an immortalized normal human astrocyte (NHA)-derived model.	('U87', 'Gene', (131, 134))	('human', 'Species', '9606', (180, 185))	('IDH1', 'Gene', (123, 127))	('overexpress', 'PosReg', (79, 90))	('U87', 'Gene', '641648', (131, 134))	('rat', 'Species', '10116', (11, 14))	('mutant', 'Var', (116, 122))	('GBM', 'Phenotype', 'HP:0012174', (135, 138))
197487	26045167	We used 1H-MRS to analyze the metabolomic signature associated with the IDH1 mutation and, consistent with previous work, found that it was associated with an MRS-detectable increase in GPC and drop in PC, lactate and glutamate.	('IDH1', 'Gene', (72, 76))	('glutamate', 'MPA', (218, 227))	('GPC', 'Chemical', 'MESH:D005997', (186, 189))	('PC', 'Chemical', 'MESH:D010767', (187, 189))	('mutation', 'Var', (77, 85))	('GPC', 'MPA', (186, 189))	('1H', 'Chemical', '-', (8, 10))	('increase', 'PosReg', (174, 182))	('drop', 'NegReg', (194, 198))	('PC', 'Chemical', 'MESH:D010767', (202, 204))	('lactate', 'Chemical', 'MESH:D019344', (206, 213))	('glutamate', 'Chemical', 'MESH:D018698', (218, 227))
197488	26045167	We also used hyperpolarized 13C-MRS, a novel metabolic imaging approach that can rapidly monitor metabolic fluxes and showed that we could detect elevated flux from alpha-KG to 2-HG and reduced flux from alpha-KG to glutamate in mutant IDH1 tumors compared to wild-type.	('IDH1 tumors', 'Disease', 'MESH:D009369', (236, 247))	('glutamate', 'Chemical', 'MESH:D018698', (216, 225))	('flux', 'MPA', (155, 159))	('alpha-KG', 'Chemical', 'MESH:D007656', (165, 173))	('13C', 'Chemical', '-', (28, 31))	('alpha-KG', 'Chemical', 'MESH:D007656', (204, 212))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('reduced', 'NegReg', (186, 193))	('flux', 'MPA', (194, 198))	('IDH1 tumors', 'Disease', (236, 247))	('mutant', 'Var', (229, 235))	('2-HG', 'Chemical', 'MESH:C019417', (177, 181))	('elevated', 'PosReg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
197489	26045167	In a separate study, we observed that the activity of PDH, the enzyme that catalyzes the decarboxylation of pyruvate to acetyl CoA prior to entry into the TCA cycle, was also reduced in IDH1 mutant cells.	('reduced', 'NegReg', (175, 182))	('PDH', 'Gene', (54, 57))	('IDH1', 'Gene', (186, 190))	('rat', 'Species', '10116', (9, 12))	('activity', 'MPA', (42, 50))	('TCA', 'Chemical', 'MESH:D014233', (155, 158))	('PDH', 'Gene', '54704', (54, 57))	('pyruvate', 'Chemical', 'MESH:D019289', (108, 116))	('mutant', 'Var', (191, 197))	('acetyl CoA', 'Chemical', 'MESH:D000105', (120, 130))
197490	26045167	This led us to question the role of PDH in IDH1 mutant cells.	('PDH', 'Gene', (36, 39))	('PDH', 'Gene', '54704', (36, 39))	('mutant', 'Var', (48, 54))	('IDH1', 'Gene', (43, 47))
197492	26045167	Using 13C-MRS and hyperpolarized 13C-MRS we then confirmed that glucose flux via PDH was reduced in IDH1 mutant cells compared to wild-type.	('PDH', 'Gene', (81, 84))	('glucose flux', 'MPA', (64, 76))	('13C', 'Chemical', '-', (6, 9))	('PDH', 'Gene', '54704', (81, 84))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('13C', 'Chemical', '-', (33, 36))	('reduced', 'NegReg', (89, 96))	('IDH1', 'Gene', (100, 104))	('mutant', 'Var', (105, 111))
197493	26045167	Importantly, we found that pharmacological activation of PDH not only altered metabolism but also abrogated the mutant IDH1-mediated clonogenicity of our cells and inhibited proliferation of patient-derived mutant IDH1 neurospheres.	('altered', 'Reg', (70, 77))	('activation', 'PosReg', (43, 53))	('PDH', 'Gene', (57, 60))	('abrogated', 'NegReg', (98, 107))	('inhibited', 'NegReg', (164, 173))	('metabolism', 'MPA', (78, 88))	('IDH1-mediated', 'Gene', (119, 132))	('rat', 'Species', '10116', (181, 184))	('mutant', 'Var', (112, 118))	('PDH', 'Gene', '54704', (57, 60))	('patient', 'Species', '9606', (191, 198))	('proliferation', 'CPA', (174, 187))
197494	26045167	Our results thus suggest that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism via PDH that is essential for tumorigenesis and that could serve as a possible target for treatment of mutant IDH1 tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('mutation', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PDH', 'Gene', '54704', (115, 118))	('tumor', 'Disease', (141, 146))	('IDH1 tumors', 'Disease', (221, 232))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('induces', 'Reg', (48, 55))	('reprogramming of pyruvate metabolism', 'MPA', (74, 110))	('IDH1 tumors', 'Disease', 'MESH:D009369', (221, 232))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('IDH1', 'Gene', (34, 38))	('PDH', 'Gene', (115, 118))	('pyruvate', 'Chemical', 'MESH:D019289', (91, 99))	('tumor', 'Disease', (226, 231))
197495	26045167	U87 and NHA cell lines expressing wild-type IDH1 (U87IDHwt and NHAIDHwt) or IDH1 R132H mutant gene (U87IDHmut and NHAIDHmut) were generated and maintained as described previously.	('U87', 'Gene', '641648', (0, 3))	('IDH', 'Gene', '3417', (66, 69))	('U87', 'Gene', (50, 53))	('IDH', 'Gene', '3417', (76, 79))	('R132H', 'Mutation', 'rs121913500', (81, 86))	('U87', 'Gene', '641648', (100, 103))	('IDH', 'Gene', (103, 106))	('rat', 'Species', '10116', (134, 137))	('U87', 'Gene', (0, 3))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (103, 106))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', (53, 56))	('R132H', 'Var', (81, 86))	('U87', 'Gene', '641648', (50, 53))	('U87', 'Gene', (100, 103))	('IDH', 'Gene', (66, 69))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', '3417', (117, 120))	('IDH', 'Gene', '3417', (44, 47))	('IDH', 'Gene', '3417', (53, 56))
197511	26045167	U87 and NHA cells were grown in media containing 1-13C-glucose (5mM) or 3-13C-glutamine (2mM) for 24h.	('U87', 'Gene', '641648', (0, 3))	('3-13C-glutamine', 'Var', (72, 87))	('1-13C-glucose', 'Chemical', '-', (49, 62))	('U87', 'Gene', (0, 3))	('3-13C-glutamine', 'Chemical', '-', (72, 87))
197517	26045167	To assess the importance of PDH in IDH1 mutant cells, we first sought to confirm our findings in a second genetically engineered model.	('mutant', 'Var', (40, 46))	('IDH1', 'Gene', (35, 39))	('PDH', 'Gene', '54704', (28, 31))	('PDH', 'Gene', (28, 31))
197518	26045167	We found that PDH activity was significantly reduced in U87IDHmut cells compared to U87IDHwt (75+-6%, p<0.005; Fig.	('PDH', 'Gene', '54704', (14, 17))	('activity', 'MPA', (18, 26))	('reduced', 'NegReg', (45, 52))	('PDH', 'Gene', (14, 17))	('U87IDHmut', 'Var', (56, 65))
197519	26045167	Furthermore, and similar to the NHA model, this was associated with increased phosphorylation of Ser293 (93+-26%, p<0.05) and Ser300 (71+-19%, p<0.005) (Fig.	('phosphorylation', 'MPA', (78, 93))	('Ser293', 'Protein', (97, 103))	('Ser300', 'Var', (126, 132))	('increased', 'PosReg', (68, 77))	('Ser300', 'Chemical', '-', (126, 132))
197522	26045167	Again, similar to the NHA model, we found that PDK1 and PDK3 mRNA levels were significantly higher in U87IDHmut cells relative to U87IDHwt by 183+- 82% (p<0.05) for PDK1 and 100+-26% (p<0.05) for PDK3 (Fig.	('higher', 'PosReg', (92, 98))	('PDK1', 'Gene', '5163', (47, 51))	('PDK3', 'Gene', (196, 200))	('PDK1', 'Gene', (47, 51))	('PDK1', 'Gene', '5163', (165, 169))	('PDK3', 'Gene', '5165', (56, 60))	('U87IDHmut', 'Var', (102, 111))	('PDK1', 'Gene', (165, 169))	('PDK3', 'Gene', (56, 60))	('mRNA levels', 'MPA', (61, 72))	('PDK3', 'Gene', '5165', (196, 200))
197526	26045167	PDK3 expression was higher in IDH1 mutant cells compared to IDH1 wild-type for both U87 and NHA models (Fig.	('PDK3', 'Gene', '5165', (0, 4))	('expression', 'MPA', (5, 15))	('PDK3', 'Gene', (0, 4))	('U87', 'Gene', (84, 87))	('higher', 'PosReg', (20, 26))	('U87', 'Gene', '641648', (84, 87))	('IDH1 mutant', 'Var', (30, 41))
197527	26045167	2A and 2B; 56+-16%, p<0.01 for U87 and 71+-3%, p<0.001 for NHA), consistent with increased phosphorylation of Ser293 and Ser300, the targets of PDK3.	('Ser300', 'Var', (121, 127))	('phosphorylation', 'MPA', (91, 106))	('U87', 'Gene', '641648', (31, 34))	('Ser300', 'Chemical', '-', (121, 127))	('PDK3', 'Gene', '5165', (144, 148))	('PDK3', 'Gene', (144, 148))	('Ser293', 'Var', (110, 116))	('increased', 'PosReg', (81, 90))	('U87', 'Gene', (31, 34))
197529	26045167	In cancer, PDK3 expression is typically up-regulated by HIF-1alpha leading to a drop in PDH activity and contributing to the switch from oxidative phosphorylation to glycolysis.	('PDH', 'Gene', (88, 91))	('glycolysis', 'MPA', (166, 176))	('switch', 'MPA', (125, 131))	('HIF-1alpha', 'Var', (56, 66))	('PDK3', 'Gene', '5165', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('drop', 'NegReg', (80, 84))	('up-regulated', 'PosReg', (40, 52))	('PDK3', 'Gene', (11, 15))	('oxidative phosphorylation', 'MPA', (137, 162))	('cancer', 'Disease', (3, 9))	('PDH', 'Gene', '54704', (88, 91))	('expression', 'MPA', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
197530	26045167	2C and 2D) indicated that HIF-1alpha levels were higher in IDH1 mutant cells compared to wild-type for both U87 and NHA models (32+-4%, p<0.005 for U87 and 42+-21%, p<0.05 for NHA).	('U87', 'Gene', (148, 151))	('U87', 'Gene', '641648', (108, 111))	('U87', 'Gene', '641648', (148, 151))	('U87', 'Gene', (108, 111))	('IDH1', 'Gene', (59, 63))	('HIF-1alpha levels', 'MPA', (26, 43))	('higher', 'PosReg', (49, 55))	('mutant', 'Var', (64, 70))
197531	26045167	To confirm that increased HIF-1alpha and PDK3 levels and reduced PDH activity were associated with mutant IDH1-induced 2-HG production, we measured PDH activity in NHAIDHwt and U87IDHwt cells treated with exogenous 2-HG, previously shown to model the effect of the IDH1 mutation.	('PDK3', 'Gene', '5165', (41, 45))	('activity', 'MPA', (152, 160))	('PDH', 'Gene', '54704', (148, 151))	('IDH', 'Gene', '3417', (265, 268))	('IDH', 'Gene', (167, 170))	('IDH', 'Gene', '3417', (106, 109))	('PDK3', 'Gene', (41, 45))	('reduced', 'NegReg', (57, 64))	('PDH', 'Gene', (148, 151))	('PDH', 'Gene', '54704', (65, 68))	('HIF-1alpha', 'MPA', (26, 36))	('IDH', 'Gene', '3417', (167, 170))	('activity', 'MPA', (69, 77))	('IDH', 'Gene', (180, 183))	('reduced PDH activity', 'Phenotype', 'HP:0002928', (57, 77))	('2-HG', 'Chemical', 'MESH:C019417', (215, 219))	('2-HG', 'Chemical', 'MESH:C019417', (119, 123))	('IDH', 'Gene', (265, 268))	('increased', 'PosReg', (16, 25))	('IDH', 'Gene', '3417', (180, 183))	('PDH', 'Gene', (65, 68))	('mutant', 'Var', (99, 105))	('IDH', 'Gene', (106, 109))
197537	26045167	Taken together, our findings suggested that higher HIF-1alpha levels in IDH1 mutant cells lead to elevated expression of PDK3, likely resulting in reduced PDH activity.	('IDH1', 'Gene', (72, 76))	('activity', 'MPA', (159, 167))	('HIF-1alpha levels', 'MPA', (51, 68))	('higher', 'PosReg', (44, 50))	('expression', 'MPA', (107, 117))	('elevated', 'PosReg', (98, 106))	('PDK3', 'Gene', '5165', (121, 125))	('PDH', 'Gene', (155, 158))	('PDK3', 'Gene', (121, 125))	('reduced PDH activity', 'Phenotype', 'HP:0002928', (147, 167))	('mutant', 'Var', (77, 83))	('reduced', 'NegReg', (147, 154))	('PDH', 'Gene', '54704', (155, 158))
197544	26045167	Following 3-13C-glutamine perfusion, we detected build-up of 3-13C-glutamate (27.8 ppm) and 3-13C-2-HG (31.6 ppm) in U87IDHmut cells, whereas, as expected, only glutamate labeling was detected in U87IDHwt cells (Fig.	('3-13C', 'Chemical', '-', (10, 15))	('2-HG', 'Chemical', 'MESH:C019417', (98, 102))	('glutamate', 'Chemical', 'MESH:D018698', (161, 170))	('3-13C-2-HG', 'Var', (92, 102))	('3-13C-glutamate', 'Chemical', '-', (61, 76))	('3-13C', 'Chemical', '-', (61, 66))	('3-13C', 'Chemical', '-', (92, 97))	('3-13C-glutamine', 'Chemical', '-', (10, 25))	('glutamate', 'Chemical', 'MESH:D018698', (67, 76))	('build-up', 'PosReg', (49, 57))	('3-13C-glutamate', 'Var', (61, 76))
197545	26045167	Following 1-13C-glucose perfusion, we detected production of 3-13C-lactate (21.0 ppm) in both IDH1 wild-type and mutant cells, but no difference in 3-13C-lactate production was observed between U87IDHwt and U87IDHmut cells.	('3-13C-lactate', 'Chemical', '-', (61, 74))	('1-13C-glucose', 'Chemical', '-', (10, 23))	('mutant', 'Var', (113, 119))	('3-13C-lactate', 'MPA', (61, 74))	('3-13C-lactate', 'Chemical', '-', (148, 161))
197552	26045167	In U87IDHwt cells, 1.0+-0.2 fmol/cell of glutamate was derived from 1-13C-glucose and 4.9+-0.8 fmol/cell was derived from 3-13C-glutamine.	('3-13C-glutamine', 'Chemical', '-', (122, 137))	('1-13C-glucose', 'Var', (68, 81))	('glutamate', 'Chemical', 'MESH:D018698', (41, 50))	('glutamate', 'Protein', (41, 50))	('1-13C-glucose', 'Chemical', '-', (68, 81))
197558	26045167	When considering the contribution of labeled glutamine and glucose to the total pool of glutamate, we found that U87IDHmut cells displayed a significant drop in glutamine-derived glutamate compared to U87IDHwt cells (4.9+-0.8 versus 2.2+-0.4 fmol/cell, p<0.05, Fig.	('glutamate', 'Chemical', 'MESH:D018698', (179, 188))	('glutamine', 'Chemical', 'MESH:D005973', (45, 54))	('U87IDHmut', 'Var', (113, 122))	('glutamine-derived glutamate', 'MPA', (161, 188))	('drop', 'NegReg', (153, 157))	('glutamine', 'Chemical', 'MESH:D005973', (161, 170))	('glutamate', 'Chemical', 'MESH:D018698', (88, 97))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))
197561	26045167	For example, glutamate, which has been shown to enhance the growth of IDH1 mutant gliomas, could be imported into the cell via the excitatory amino acid transporter-2.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('glutamate', 'Protein', (13, 22))	('growth', 'MPA', (60, 66))	('glutamate', 'Chemical', 'MESH:D018698', (13, 22))	('enhance', 'PosReg', (48, 55))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('mutant', 'Var', (75, 81))	('IDH1', 'Gene', (70, 74))
197563	26045167	This points to a role for glucose-derived glutamate, and thus PDH, in explaining the drop in glutamate levels in IDH1 mutant cells.	('glutamate levels', 'MPA', (93, 109))	('drop', 'NegReg', (85, 89))	('IDH1', 'Gene', (113, 117))	('glucose', 'Chemical', 'MESH:D005947', (26, 33))	('glutamate', 'Chemical', 'MESH:D018698', (42, 51))	('PDH', 'Gene', (62, 65))	('glutamate', 'Chemical', 'MESH:D018698', (93, 102))	('mutant', 'Var', (118, 124))	('PDH', 'Gene', '54704', (62, 65))
197569	26045167	Next we wanted to assess whether the reduction in PDH activity in IDH1 mutant cells has any biological significance.	('PDH', 'Gene', (50, 53))	('reduction', 'NegReg', (37, 46))	('PDH', 'Gene', '54704', (50, 53))	('mutant', 'Var', (71, 77))	('activity', 'MPA', (54, 62))	('IDH1', 'Gene', (66, 70))
197574	26045167	6A and 6B) indicate that DCA induced activation of PDH most effectively in IDH1 mutant cells.	('mutant', 'Var', (80, 86))	('activation', 'PosReg', (37, 47))	('DCA', 'Chemical', 'MESH:D003999', (25, 28))	('IDH1', 'Gene', (75, 79))	('PDH', 'Gene', (51, 54))	('PDH', 'Gene', '54704', (51, 54))
197575	26045167	PDH activity increased by 730+-219% (p<0.005) in U87IDHmut, by 41+-26% (p<0.05) in U87IDHwt (Fig.	('U87IDHmut', 'Var', (49, 58))	('PDH', 'Gene', (0, 3))	('U87IDHwt', 'Var', (83, 91))	('PDH', 'Gene', '54704', (0, 3))	('activity', 'MPA', (4, 12))	('increased', 'PosReg', (13, 22))
197577	26045167	Next, we confirmed the effect of DCA on metabolism using hyperpolarized 13C-MRS. Hyperpolarized 5-13C-glutamate increased by 142+-76% (p<0.05) in U87IDHmut and by 43+-30% (p<0.05) in U87IDHwt (Fig.	('U87IDHmut', 'Var', (146, 155))	('DCA', 'Chemical', 'MESH:D003999', (33, 36))	('13C', 'Chemical', '-', (72, 75))	('increased', 'PosReg', (112, 121))	('glutamate increased', 'Phenotype', 'HP:0500149', (102, 121))	('Hyperpolarized 5-13C-glutamate', 'MPA', (81, 111))	('13C', 'Chemical', '-', (98, 101))	('5-13C-glutamate', 'Chemical', '-', (96, 111))
197580	26045167	In the U87 model, both IDH1 wild-type and mutant cells readily formed colonies on soft agar and DCA inhibited clonogenicity equally in U87IDHwt (46+-10%, p<0.01) and U87IDHmut (44+-8%, p<0.05), likely reflecting the GBM background of this model and pointing to a limited growth advantage associated with PDH down-regulation in these cells (Fig.	('PDH', 'Gene', (304, 307))	('U87', 'Gene', (166, 169))	('mutant', 'Var', (42, 48))	('limited growth', 'Phenotype', 'HP:0001510', (263, 277))	('U87', 'Gene', (135, 138))	('U87', 'Gene', '641648', (166, 169))	('DCA', 'Chemical', 'MESH:D003999', (96, 99))	('agar', 'Chemical', 'MESH:D000362', (87, 91))	('PDH', 'Gene', '54704', (304, 307))	('down-regulation', 'NegReg', (308, 323))	('GBM', 'Phenotype', 'HP:0012174', (216, 219))	('U87', 'Gene', '641648', (135, 138))	('U87', 'Gene', (7, 10))	('clonogenicity', 'CPA', (110, 123))	('inhibited', 'NegReg', (100, 109))	('U87', 'Gene', '641648', (7, 10))
197584	26045167	However, DCA completely abrogated the effect of the IDH1 mutation, resulting in equivalent colony numbers for untreated NHAIDHwt and DCA-treated NHAIDHmut cells (8+-2 versus 11+-3, p=0.2; Fig.	('mutation', 'Var', (57, 65))	('colony numbers', 'CPA', (91, 105))	('DCA', 'Chemical', 'MESH:D003999', (133, 136))	('IDH', 'Gene', (148, 151))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('IDH', 'Gene', '3417', (148, 151))	('IDH', 'Gene', (123, 126))	('abrogated', 'NegReg', (24, 33))	('IDH', 'Gene', '3417', (123, 126))	('DCA', 'Chemical', 'MESH:D003999', (9, 12))
197585	26045167	These results highlighted the importance of PDH down-regulation for IDH1 mutation-induced tumorigenesis in the NHA model.	('down-regulation', 'NegReg', (48, 63))	('PDH', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('PDH', 'Gene', '54704', (44, 47))	('IDH1', 'Gene', (68, 72))	('mutation-induced', 'Var', (73, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
197586	26045167	In order to confirm our findings in clinically relevant models, we extended our studies to the BT54 and BT142 patient-derived mutant IDH1 neurosphere models.	('IDH1', 'Gene', (133, 137))	('BT142', 'Chemical', '-', (104, 109))	('patient', 'Species', '9606', (110, 117))	('mutant', 'Var', (126, 132))
197597	26045167	Collectively, our findings in the patient-derived mutant IDH1 models confirmed our observations in genetically engineered IDH1 mutant cells.	('mutant', 'Var', (127, 133))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', (122, 126))	('patient', 'Species', '9606', (34, 41))	('mutant', 'Var', (50, 56))
197599	26045167	In the context of the IDH1 mutation, several studies have cataloged the metabolic changes associated with mutant IDH, but the biological significance and therapeutic potential of these changes is not fully understood.	('IDH', 'Gene', '3417', (113, 116))	('mutant', 'Var', (106, 112))	('metabolic changes', 'MPA', (72, 89))	('IDH', 'Gene', (22, 25))	('mutation', 'Var', (27, 35))	('IDH', 'Gene', '3417', (22, 25))	('IDH', 'Gene', (113, 116))
197600	26045167	Here, we focused on the enzyme PDH and found that PDH activity and glucose flux towards glutamate were reduced in genetically engineered IDH1 mutant cells compared to wild-type.	('PDH', 'Gene', (50, 53))	('reduced', 'NegReg', (103, 110))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('IDH1', 'Gene', (137, 141))	('glucose flux towards glutamate', 'MPA', (67, 97))	('PDH', 'Gene', '54704', (50, 53))	('mutant', 'Var', (142, 148))	('activity', 'MPA', (54, 62))	('PDH', 'Gene', (31, 34))	('PDH', 'Gene', '54704', (31, 34))	('glutamate', 'Chemical', 'MESH:D018698', (88, 97))
197601	26045167	Furthermore, we found that activation of PDH, both in our genetically engineered and in patient-derived mutant IDH1 models, significantly reduced proliferation and clonogenicity, pointing to an essential role for PDH.	('patient', 'Species', '9606', (88, 95))	('reduced', 'NegReg', (138, 145))	('rat', 'Species', '10116', (153, 156))	('PDH', 'Gene', (213, 216))	('PDH', 'Gene', (41, 44))	('mutant', 'Var', (104, 110))	('clonogenicity', 'CPA', (164, 177))	('PDH', 'Gene', '54704', (213, 216))	('activation', 'PosReg', (27, 37))	('PDH', 'Gene', '54704', (41, 44))	('IDH1', 'Gene', (111, 115))
197606	26045167	Previous work indicates that mutant IDH1 tumors reprogram their metabolism differently from wild-type IDH1 glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('reprogram', 'Reg', (48, 57))	('IDH1 tumors', 'Disease', 'MESH:D009369', (36, 47))	('mutant', 'Var', (29, 35))	('IDH1 tumors', 'Disease', (36, 47))	('IDH1 glioblastoma', 'Disease', (102, 119))	('metabolism', 'MPA', (64, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('IDH1 glioblastoma', 'Disease', 'MESH:D005909', (102, 119))
197608	26045167	Importantly, these can be directly linked to mutant IDH.	('linked', 'Reg', (35, 41))	('mutant', 'Var', (45, 51))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))
197609	26045167	Mutant IDH1 via 2-HG production can stabilize HIF-1alpha levels by inhibiting alpha-KG-dependent prolyl hydroxylases (PHD).	('2-HG', 'Chemical', 'MESH:C019417', (16, 20))	('PHD', 'Disease', (118, 121))	('alpha-KG', 'Chemical', 'MESH:D007656', (78, 86))	('PHD', 'Disease', 'MESH:D011547', (118, 121))	('Mutant', 'Var', (0, 6))	('alpha-KG-dependent prolyl hydroxylases', 'MPA', (78, 116))	('stabilize HIF-1alpha levels', 'MPA', (36, 63))	('IDH1', 'Gene', (7, 11))	('inhibiting', 'NegReg', (67, 77))
197610	26045167	showed that introduction of the IDH1 mutation or addition of 2-HG to cell lines resulted in diminished HIF-1alpha levels and reduced expression of HIF-1alpha target genes.	('expression of', 'MPA', (133, 146))	('2-HG', 'Chemical', 'MESH:C019417', (61, 65))	('diminished', 'NegReg', (92, 102))	('HIF-1alpha levels', 'MPA', (103, 120))	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('reduced', 'NegReg', (125, 132))
197611	26045167	However, in contrast, and in line with our findings, two other studies showed that expression of mutant IDH1 or 2-HG treatment in U87 cells elevated HIF-1alpha levels and increased expression of HIF-1alpha target genes, and this effect was abrogated by treatment with an IDH1 inhibitor.	('2-HG', 'Chemical', 'MESH:C019417', (112, 116))	('expression', 'MPA', (181, 191))	('mutant', 'Var', (97, 103))	('HIF-1alpha levels', 'MPA', (149, 166))	('U87', 'Gene', (130, 133))	('elevated', 'PosReg', (140, 148))	('U87', 'Gene', '641648', (130, 133))	('IDH1', 'Gene', (104, 108))	('increased', 'PosReg', (171, 180))
197614	26045167	Therefore, U87 and NHA IDH1 mutant cells might be expected to show increased LDHA expression relative to wild-type cells.	('LDHA', 'Gene', '3939', (77, 81))	('NHA IDH1', 'Gene', (19, 27))	('mutant', 'Var', (28, 34))	('U87', 'Gene', '641648', (11, 14))	('expression', 'MPA', (82, 92))	('increased', 'PosReg', (67, 76))	('U87', 'Gene', (11, 14))	('LDHA', 'Gene', (77, 81))
197615	26045167	demonstrated that the LDHA gene in IDH1 mutant glioma cells is silenced by methylation of CpG sites within the promoter.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH1', 'Gene', (35, 39))	('LDHA', 'Gene', '3939', (22, 26))	('methylation', 'Var', (75, 86))	('glioma', 'Disease', (47, 53))	('rat', 'Species', '10116', (7, 10))	('mutant', 'Var', (40, 46))	('silenced', 'NegReg', (63, 71))	('LDHA', 'Gene', (22, 26))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
197616	26045167	Therefore, elevated HIF-1alpha expression in IDH1 mutant cells might not translate to increased LDHA expression.	('LDHA', 'Gene', (96, 100))	('LDHA', 'Gene', '3939', (96, 100))	('expression', 'MPA', (31, 41))	('HIF-1alpha', 'Protein', (20, 30))	('mutant', 'Var', (50, 56))	('IDH1', 'Gene', (45, 49))	('elevated', 'PosReg', (11, 19))
197619	26045167	This is consistent with a recent study demonstrating a 10-fold reduction in spare respiratory capacity in high-grade GBMs compared to SV-40 immortalized human astrocytes, associated with modulation of PDH activity.	('rat', 'Species', '10116', (46, 49))	('spare respiratory capacity', 'MPA', (76, 102))	('PDH', 'Gene', '54704', (201, 204))	('activity', 'MPA', (205, 213))	('modulation', 'Var', (187, 197))	('human', 'Species', '9606', (153, 158))	('reduction', 'NegReg', (63, 72))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('PDH', 'Gene', (201, 204))	('rat', 'Species', '10116', (87, 90))
197620	26045167	Thus, while the IDH1 mutation leads to reduced PDH activity and flux to the TCA cycle, this flux remains higher in the NHA and BT models than in high-grade GBMs and points to a greater dependence on the TCA cycle in mutant IDH1 low-grade glioma compared to GBM.	('activity', 'MPA', (51, 59))	('glioma', 'Disease', (238, 244))	('mutant', 'Var', (216, 222))	('higher', 'PosReg', (105, 111))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('PDH', 'Gene', (47, 50))	('TCA', 'Chemical', 'MESH:D014233', (203, 206))	('mutation', 'Var', (21, 29))	('IDH1', 'Gene', (16, 20))	('reduced PDH activity', 'Phenotype', 'HP:0002928', (39, 59))	('GBM', 'Phenotype', 'HP:0012174', (257, 260))	('PDH', 'Gene', '54704', (47, 50))	('flux', 'MPA', (64, 68))	('reduced', 'NegReg', (39, 46))	('TCA', 'Chemical', 'MESH:D014233', (76, 79))	('IDH1', 'Gene', (223, 227))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))
197621	26045167	Our findings are thus consistent with observations showing that HIF-1alpha target genes are under-expressed in mutant IDH1 patient-derived models (including BT54 and BT142) compared to primary GBM models wild-type for IDH1 and concur with observations of reduced PDH activity in engineered IDH1 mutant colorectal cancer cells.	('BT142', 'Chemical', '-', (166, 171))	('under-expressed', 'NegReg', (92, 107))	('PDH', 'Gene', (263, 266))	('colorectal cancer', 'Disease', 'MESH:D015179', (302, 319))	('patient', 'Species', '9606', (123, 130))	('GBM', 'Phenotype', 'HP:0012174', (193, 196))	('IDH1', 'Gene', (118, 122))	('mutant', 'Var', (111, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (302, 319))	('IDH1', 'Gene', (290, 294))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('PDH', 'Gene', '54704', (263, 266))	('mutant', 'Var', (295, 301))	('colorectal cancer', 'Disease', (302, 319))	('reduced PDH activity', 'Phenotype', 'HP:0002928', (255, 275))
197622	26045167	Reduced flux through the TCA cycle would allow IDH1 mutant cells to divert carbon precursors towards macromolecular biosynthesis, even if these cells proliferate slower than GBM.	('mutant', 'Var', (52, 58))	('TCA', 'Chemical', 'MESH:D014233', (25, 28))	('GBM', 'Phenotype', 'HP:0012174', (174, 177))	('IDH1', 'Gene', (47, 51))	('Reduced', 'NegReg', (0, 7))	('flux', 'MPA', (8, 12))	('rat', 'Species', '10116', (157, 160))	('carbon', 'Chemical', 'MESH:D002244', (75, 81))
197623	26045167	In our studies we used the classic PDK inhibitor, DCA, to understand the biological significance of reduced PDH activity in IDH1 mutant cells.	('PDH', 'Gene', '54704', (108, 111))	('DCA', 'Chemical', 'MESH:D003999', (50, 53))	('reduced', 'NegReg', (100, 107))	('PDH', 'Gene', (108, 111))	('activity', 'MPA', (112, 120))	('IDH1', 'Gene', (124, 128))	('reduced PDH activity', 'Phenotype', 'HP:0002928', (100, 120))	('mutant', 'Var', (129, 135))
197627	26045167	Following DCA treatment, we found that clonogenicity was inhibited equally for U87IDHwt and U87IDHmut cells.	('inhibited', 'NegReg', (57, 66))	('U87IDHmut', 'Var', (92, 101))	('DCA', 'Chemical', 'MESH:D003999', (10, 13))	('U87IDHwt', 'Var', (79, 87))	('clonogenicity', 'CPA', (39, 52))
197629	26045167	It is also consistent with the fact that introduction of the IDH1 mutation did not increase the clonogenicity of the cells and thus a differential effect of DCA on clonogenicity would not be expected.	('DCA', 'Chemical', 'MESH:D003999', (157, 160))	('IDH1', 'Gene', (61, 65))	('clonogenicity of the cells', 'CPA', (96, 122))	('mutation', 'Var', (66, 74))
197630	26045167	In contrast, in the NHA model, introduction of the IDH1 mutation significantly increased clonogenicity, and, importantly, this effect was completely abrogated by DCA treatment.	('increased', 'PosReg', (79, 88))	('clonogenicity', 'CPA', (89, 102))	('DCA', 'Chemical', 'MESH:D003999', (162, 165))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))
197632	26045167	Our data thus suggest that the reprogramming of PDH activity by the IDH1 mutation is crucial for tumorigenesis and to the best of our knowledge, this is the first report of the efficacy of DCA against low-grade mutant IDH1 glioma cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PDH', 'Gene', '54704', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('IDH1', 'Gene', (218, 222))	('IDH1', 'Gene', (68, 72))	('DCA', 'Chemical', 'MESH:D003999', (189, 192))	('tumor', 'Disease', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('PDH', 'Gene', (48, 51))	('mutation', 'Var', (73, 81))	('glioma', 'Disease', (223, 229))
197633	26045167	Our studies also shed light on the different factors contributing to reduced glutamate levels in IDH1 mutant gliomas.	('mutant', 'Var', (102, 108))	('reduced glutamate levels', 'Phenotype', 'HP:0500150', (69, 93))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('IDH1', 'Gene', (97, 101))	('glutamate levels', 'MPA', (77, 93))	('reduced', 'NegReg', (69, 76))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('glutamate', 'Chemical', 'MESH:D018698', (77, 86))
197635	26045167	However, our studies show that the drop in PDH flux into the TCA cycle and reduced contribution of glucose to glutamate synthesis also contribute to the lower levels of glutamate in IDH1 mutant cells.	('PDH', 'Gene', (43, 46))	('contribution', 'MPA', (83, 95))	('glucose', 'MPA', (99, 106))	('TCA', 'Chemical', 'MESH:D014233', (61, 64))	('levels of glutamate', 'MPA', (159, 178))	('drop', 'NegReg', (35, 39))	('mutant', 'Var', (187, 193))	('reduced', 'NegReg', (75, 82))	('PDH', 'Gene', '54704', (43, 46))	('glucose', 'Chemical', 'MESH:D005947', (99, 106))	('lower', 'NegReg', (153, 158))	('glutamate', 'Chemical', 'MESH:D018698', (110, 119))	('glutamate', 'Chemical', 'MESH:D018698', (169, 178))	('IDH1', 'Gene', (182, 186))
197641	26045167	It was also used to detect reduced glutamate levels in patients with mutant IDH1 tumors, and our study mechanistically validates reduced glutamate as a potential complementary metabolic biomarker of mutant IDH1 tumors.	('IDH1 tumors', 'Disease', (206, 217))	('reduced', 'NegReg', (27, 34))	('glutamate', 'Chemical', 'MESH:D018698', (137, 146))	('mutant', 'Var', (69, 75))	('IDH1 tumors', 'Disease', (76, 87))	('glutamate', 'MPA', (137, 146))	('IDH1 tumors', 'Disease', 'MESH:D009369', (206, 217))	('IDH1 tumors', 'Disease', 'MESH:D009369', (76, 87))	('patients', 'Species', '9606', (55, 63))	('glutamate', 'Chemical', 'MESH:D018698', (35, 44))	('glutamate levels', 'MPA', (35, 51))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduced', 'NegReg', (129, 136))	('reduced glutamate levels', 'Phenotype', 'HP:0500150', (27, 51))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
197643	26045167	We have previously used hyperpolarized 13C-MRS to image 2-HG production in tumors expressing mutant IDH1.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('2-HG', 'Chemical', 'MESH:C019417', (56, 60))	('mutant', 'Var', (93, 99))	('13C', 'Chemical', '-', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('IDH1', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))	('2-HG production', 'MPA', (56, 71))
197644	26045167	We have also shown that we can detect a reduction in alpha-KG to glutamate conversion that occurs as part of the metabolic reprogramming of mutant IDH1 tumors.	('IDH1 tumors', 'Disease', (147, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('alpha-KG', 'Chemical', 'MESH:D007656', (53, 61))	('glutamate', 'Chemical', 'MESH:D018698', (65, 74))	('alpha-KG to glutamate conversion', 'MPA', (53, 85))	('IDH1 tumors', 'Disease', 'MESH:D009369', (147, 158))	('reduction', 'NegReg', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutant', 'Var', (140, 146))
197645	26045167	Our current findings point to the value of hyperpolarized 2-13C-pyruvate and its conversion to glutamate as another potential complementary imaging approach for mutant IDH1 tumors.	('glutamate', 'Chemical', 'MESH:D018698', (95, 104))	('mutant', 'Var', (161, 167))	('2-13C-pyruvate', 'Chemical', '-', (58, 72))	('IDH1 tumors', 'Disease', 'MESH:D009369', (168, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('IDH1 tumors', 'Disease', (168, 179))
197647	26045167	In summary, our study demonstrates that reprogramming of PDH activity is essential for mutant IDH1 cell proliferation, that MRS can be used to detect this reprogramming and that modulation of PDH activity could potentially serve as a therapeutic approach for mutant IDH1 tumors.	('rat', 'Species', '10116', (111, 114))	('IDH1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('PDH', 'Gene', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('rat', 'Species', '10116', (29, 32))	('PDH', 'Gene', (192, 195))	('IDH1 tumors', 'Disease', (266, 277))	('mutant', 'Var', (87, 93))	('PDH', 'Gene', '54704', (192, 195))	('PDH', 'Gene', '54704', (57, 60))	('modulation', 'Var', (178, 188))	('IDH1 tumors', 'Disease', 'MESH:D009369', (266, 277))
197652	33936779	The ADC values at tumor center and edema were higher than 1.12 x 10-3 mm2/s (sensitivity = 100% and specificity = 96.0%) and 1.15 x 10-3 mm2/s (sensitivity = 75.0% and specificity = 64.0%), respectively, could be classified as low-grade tumors.	('edema', 'Phenotype', 'HP:0000969', (35, 40))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (18, 23))	('higher', 'PosReg', (46, 52))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('ADC', 'MPA', (4, 7))	('edema', 'Disease', (35, 40))	('1.15 x 10-3 mm2/s', 'Var', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('ADC', 'Chemical', '-', (4, 7))	('edema', 'Disease', 'MESH:D004487', (35, 40))
197712	33936779	The ROIs of ADC1 and ADC2 were contoured inside the tumor regions, while the ROIs of other ADC values were defined outside the tumor.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (127, 132))	('ADC', 'Chemical', '-', (12, 15))	('ADC', 'Chemical', '-', (91, 94))	('ADC2', 'Var', (21, 25))	('ADC', 'Chemical', '-', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
197713	33936779	Therefore, it was expected that ADC1 and ADC2 values could have better differentiation between low- and high-grade tumors.	('low-', 'Disease', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ADC', 'Chemical', '-', (32, 35))	('ADC1', 'Var', (32, 36))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ADC', 'Chemical', '-', (41, 44))	('ADC2', 'Gene', (41, 45))
197746	33420056	In contrast, reactivation of telomerase enables malignant transformation and cancer cell immortality.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('malignant transformation', 'Disease', 'MESH:D009369', (48, 72))	('malignant transformation', 'Disease', (48, 72))	('telomerase', 'Protein', (29, 39))	('reactivation', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('enables', 'PosReg', (40, 47))
197753	33420056	Some cancer lineages (e.g., brain, liver, skin, and bladder) frequently acquire recurrent mutations in the TERT promoter (TERTp) region, predominantly at -124 and -146 loci upstream from TERT transcription start site.	('bladder', 'Disease', (52, 59))	('TERTp', 'Gene', '7015', (122, 127))	('liver', 'Disease', (35, 40))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('TERT', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (122, 126))	('cancer', 'Disease', (5, 11))	('TERT', 'Gene', (187, 191))	('brain', 'Disease', (28, 33))	('TERT', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('TERT', 'Gene', '7015', (107, 111))	('TERTp', 'Gene', (122, 127))	('TERT', 'Gene', '7015', (187, 191))
197754	33420056	These C > T mutations create consensus binding sites for GABP transcription factors, alter chromatin states, and enhance the transcriptional output of TERT.	('mutations', 'Var', (12, 21))	('GABP transcription factors', 'Protein', (57, 83))	('TERT', 'Gene', (151, 155))	('alter', 'Reg', (85, 90))	('chromatin states', 'MPA', (91, 107))	('TERT', 'Gene', '7015', (151, 155))	('binding', 'Interaction', (39, 46))	('C > T mutations', 'Var', (6, 21))	('enhance', 'PosReg', (113, 120))
197755	33420056	In bladder cancer, the promoter mutations correlate with increased TERT expression and telomerase enzymatic activity.	('telomerase', 'Enzyme', (87, 97))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('mutations', 'Var', (32, 41))	('enzymatic activity', 'MPA', (98, 116))	('increased', 'PosReg', (57, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))
197765	33420056	In addition, mutations in DKC1 and TERC both cause dyskeratosis congenita, a rare genetic syndrome related to impaired telomerase.	('TERC', 'Gene', '7012', (35, 39))	('DKC1', 'Gene', (26, 30))	('dyskeratosis congenita', 'Disease', (51, 73))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (51, 73))	('genetic syndrome', 'Disease', (82, 98))	('cause', 'Reg', (45, 50))	('DKC1', 'Gene', '1736', (26, 30))	('mutations', 'Var', (13, 22))	('genetic syndrome', 'Disease', 'MESH:D030342', (82, 98))	('TERC', 'Gene', (35, 39))
197775	33420056	However, mutations in ATRX and its interacting partner DAXX are nearly perfectly correlated with ALT.	('ATRX', 'Gene', (22, 26))	('ALT', 'Disease', (97, 100))	('mutations', 'Var', (9, 18))	('DAXX', 'Gene', (55, 59))	('ATRX', 'Gene', '546', (22, 26))	('correlated', 'Reg', (81, 91))	('DAXX', 'Gene', '1616', (55, 59))
197776	33420056	We thus searched the TCGA dataset for cancer types with both high frequencies of mutations in the TERTp and ATRX and DAXX.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('DAXX', 'Gene', '1616', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('ATRX', 'Gene', (108, 112))	('DAXX', 'Gene', (117, 121))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (38, 44))	('TERTp', 'Gene', (98, 103))	('ATRX', 'Gene', '546', (108, 112))	('TERTp', 'Gene', '7015', (98, 103))
197780	33420056	These genes were further intersected with genes upregulated in the TERTp mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutant', 'Var', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('TERTp', 'Gene', (67, 72))	('TERTp', 'Gene', '7015', (67, 72))
197783	33420056	Mutations in HELLS, a gene encoding a lymphoid-specific helicase, cause the centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder associated with short telomeres.	('facial anomalies', 'Phenotype', 'HP:0000271', (104, 120))	('HELLS', 'Gene', '3070', (13, 18))	('lymphoid-specific helicase', 'Gene', (38, 64))	('genetic disorder', 'Disease', 'MESH:D030342', (139, 155))	('lymphoid-specific helicase', 'Gene', '3070', (38, 64))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (66, 71))	('short telomeres', 'Phenotype', 'HP:0031413', (172, 187))	('facial anomalies (ICF) syndrome', 'Disease', 'MESH:C537362', (104, 135))	('genetic disorder', 'Disease', (139, 155))	('HELLS', 'Gene', (13, 18))
197799	33420056	In liposarcoma, telomerase-positive tumors had significantly higher EXTEND scores than ALT tumors (P < 0.01, Student t test; Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('higher', 'PosReg', (61, 67))	('EXTEND scores', 'MPA', (68, 81))	('liposarcoma', 'Disease', (3, 14))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('liposarcoma', 'Disease', 'MESH:D008080', (3, 14))	('liposarcoma', 'Phenotype', 'HP:0012034', (3, 14))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('telomerase-positive', 'Var', (16, 35))
197813	33420056	This patient carried loss-of-function mutations in poly(A)-specific ribonuclease (PARN), a gene required for TERC maturation.	('TERC', 'Gene', (109, 113))	('patient', 'Species', '9606', (5, 12))	('poly(A)-specific ribonuclease', 'Gene', '5073', (51, 80))	('PARN', 'Gene', (82, 86))	('loss-of-function', 'NegReg', (21, 37))	('TERC', 'Gene', '7012', (109, 113))	('PARN', 'Gene', '5073', (82, 86))	('mutations', 'Var', (38, 47))	('poly(A)-specific ribonuclease', 'Gene', (51, 80))
197814	33420056	Inhibition of poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) counteracts PARN mutations to increase TERC levels and telomerase activity.	('PARN', 'Gene', (88, 92))	('telomerase activity', 'MPA', (131, 150))	('mutations', 'Var', (93, 102))	('PAPD5', 'Gene', '64282', (69, 74))	('TERC', 'Gene', '7012', (115, 119))	('PARN', 'Gene', '5073', (88, 92))	('PAPD5', 'Gene', (69, 74))	('increase', 'PosReg', (106, 114))	('poly(A)', 'Chemical', 'MESH:D011061', (14, 21))	('TERC', 'Gene', (115, 119))
197815	33420056	EXTEND predicted higher telomerase activity in PARN mutant cells compared with wild-type controls upon PAPD5 knockdown, confirming the earlier finding (Fig.	('telomerase activity', 'MPA', (24, 43))	('PARN', 'Gene', (47, 51))	('mutant', 'Var', (52, 58))	('PAPD5', 'Gene', '64282', (103, 108))	('higher', 'PosReg', (17, 23))	('PAPD5', 'Gene', (103, 108))	('PARN', 'Gene', '5073', (47, 51))
197835	33420056	Five cancer types (adrenocortical carcinoma (ACC), kidney chromophobe (KICH), KIRP, LUAD, and SARC (sarcoma)) exhibited worse overall survival in the high score group, whereas STAD and thymoma (THYM) exhibited the opposite pattern (Fig.	('thymoma', 'Disease', 'MESH:D013945', (185, 192))	('KIRP', 'Disease', (78, 82))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (19, 43))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('KICH', 'Disease', (71, 75))	('THYM', 'Phenotype', 'HP:0100522', (194, 198))	('sarcoma', 'Disease', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('thymoma', 'Disease', (185, 192))	('kidney chromophobe', 'Disease', 'MESH:D000238', (51, 69))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (19, 43))	('overall survival', 'MPA', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('thymoma', 'Phenotype', 'HP:0100522', (185, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('kidney chromophobe', 'Disease', (51, 69))	('adrenocortical carcinoma', 'Disease', (19, 43))	('worse', 'NegReg', (120, 125))	('cancer', 'Disease', (5, 11))	('KICH', 'Disease', 'None', (71, 75))	('LUAD', 'Disease', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('high score', 'Var', (150, 160))
197878	33420056	Single-cell analysis confirmed the tight correlation between active telomerase and cancer stemness program, and further revealed that the high stemness, high telomerase cells were cycling cells.	('high telomerase', 'Var', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer stemness', 'Disease', 'MESH:D009369', (83, 98))	('high', 'PosReg', (138, 142))	('cancer stemness', 'Disease', (83, 98))
197880	33420056	In summary, our study demonstrates the feasibility of digitalizing telomerase enzymatic activity, a pathway fundamental to the cancer cell and stem cell survival.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('digitalizing', 'Var', (54, 66))	('cancer', 'Disease', (127, 133))	('telomerase', 'Protein', (67, 77))
197883	33420056	We used the TCGA LGG cohort consisting of 81 TERTp mutant samples and 123 ATRX altered cases (based on mutations, deletions, and structural events).	('ATRX', 'Gene', (74, 78))	('mutant', 'Var', (51, 57))	('TERTp', 'Gene', (45, 50))	('ATRX', 'Gene', '546', (74, 78))	('TERTp', 'Gene', '7015', (45, 50))	('deletions', 'Var', (114, 123))
197885	33420056	We first performed differential gene expression analysis using one-sided t test between TERTp mutant and ATRX altered groups.	('ATRX', 'Gene', '546', (105, 109))	('mutant', 'Var', (94, 100))	('TERTp', 'Gene', (88, 93))	('TERTp', 'Gene', '7015', (88, 93))	('ATRX', 'Gene', (105, 109))
197886	33420056	The upregulated genes in TERTp mutant group were shortlisted using P value threshold <=0.05 and log 2 FC >1.5.	('upregulated', 'PosReg', (4, 15))	('mutant', 'Var', (31, 37))	('TERTp', 'Gene', '7015', (25, 30))	('TERTp', 'Gene', (25, 30))
197887	33420056	Using Pearson's correlation, we identified TERT co-expressed genes using 81 TERTp mutant cases at thresholds ranging from 0.2 to 0.7 divided by the step of 0.5.	('TERT', 'Gene', '7015', (76, 80))	('TERT', 'Gene', (43, 47))	('TERT', 'Gene', '7015', (43, 47))	('TERTp', 'Gene', (76, 81))	('TERTp', 'Gene', '7015', (76, 81))	('TERT', 'Gene', (76, 80))	('mutant', 'Var', (82, 88))
197924	33420056	TERC dataset, Liposarcomas, and Neuroblastomas data were downloaded from Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) ("GSE81507," "GSE14533," and "GSE120572").	('Neuroblastomas', 'Disease', 'MESH:D009447', (32, 46))	('Neuroblastomas', 'Disease', (32, 46))	('Liposarcomas', 'Phenotype', 'HP:0012034', (14, 26))	('Neuroblastomas', 'Phenotype', 'HP:0003006', (32, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('TERC', 'Gene', (0, 4))	('Liposarcoma', 'Phenotype', 'HP:0012034', (14, 25))	('Liposarcomas', 'Disease', 'MESH:D008080', (14, 26))	('Liposarcomas', 'Disease', (14, 26))	('GSE14533', 'Var', (153, 161))	('TERC', 'Gene', '7012', (0, 4))
197946	32256589	The most common single tumor entity was meningioma (26.99%, ICD-O-3 histology codes 9530/0, 9539/1, and 9530/3) followed by glioblastoma (25.10%, ICD-O-3 histology codes 9440/3 and 9442/3) (Figure 4).	('meningioma', 'Disease', (40, 50))	('9539/1', 'Var', (92, 98))	('meningioma', 'Phenotype', 'HP:0002858', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('9530/3', 'Var', (104, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
197951	32256589	Pilocytic astrocytomas (36.76%, ICD-O-3 histology code 9421/1) were the predominant glioma tumor for pediatric populations followed by ependymomas (23.53%, ICD-O-3 histology codes 9392/3, 9391/3, and 9394/1) and high-grade gliomas (20.58%, ICD-O-3 histology codes 9440/3, 9380/3, 9401/3, and 9451/3) (Figure 9).	('Pilocytic astrocytomas', 'Disease', (0, 22))	('gliomas', 'Phenotype', 'HP:0009733', (223, 230))	('glioma tumor', 'Disease', (84, 96))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('glioma tumor', 'Disease', 'MESH:D005910', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('9451/3', 'Var', (292, 298))	('ependymomas', 'Disease', (135, 146))
197969	30810537	It has been reported in several forms, including N1-methyladenosine, N7-methyladenosine, 5-methylcytosine, pseudouridine, N6,2'-O-dimethyladenosine (m6A) and 2'-O-methylation.	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (49, 67))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (89, 105))	("2'-O", 'Chemical', 'MESH:C030514', (125, 129))	('N7-methyladenosine', 'Chemical', '-', (69, 87))	('m6A', 'Gene', '56339', (149, 152))	("2'-O-methylation", 'MPA', (158, 174))	('N1-methyladenosine', 'Var', (49, 67))	('pseudouridine', 'MPA', (107, 120))	("N6,2'-O-dimethyladenosine", 'Chemical', '-', (122, 147))	('pseudouridine', 'Chemical', 'MESH:D011560', (107, 120))	('N7-methyladenosine', 'Var', (69, 87))	('5-methylcytosine', 'MPA', (89, 105))	("2'-O", 'Chemical', 'MESH:C030514', (158, 162))	('m6A', 'Gene', (149, 152))
197973	30810537	m6A modification not only plays a vital role in oocyte and central nervous system development but also has various regulatory functions in tumor initiation, progression and radio-resistance.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('m6A', 'Gene', '56339', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('modification', 'Var', (4, 16))	('m6A', 'Gene', (0, 3))
197974	30810537	Moreover, increasing evidence indicates that genetic changes and dysregulated expression of m6A RNA methylation regulators are closely associated with malignant progression in various kinds of cancer.	('dysregulated', 'Var', (65, 77))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('expression', 'MPA', (78, 88))	('cancer', 'Disease', (193, 199))	('genetic changes', 'Var', (45, 60))	('malignant progression', 'CPA', (151, 172))	('m6A', 'Gene', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('associated with', 'Reg', (135, 150))	('m6A', 'Gene', '56339', (92, 95))
197982	30810537	Considering the important biological functions of each m6A RNA methylation regulator in tumorigenesis and development, we systematically investigated the relationships between each individual m6A RNA methylation regulator and the pathological features of gliomas, including WHO grade, IDH status, and 1p/19q codeletion status.	('1p/19q codeletion status', 'Var', (301, 325))	('m6A', 'Gene', (55, 58))	('IDH', 'Gene', (285, 288))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('m6A', 'Gene', '56339', (55, 58))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('IDH', 'Gene', '3417', (285, 288))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('m6A', 'Gene', (192, 195))	('tumor', 'Disease', (88, 93))	('gliomas', 'Phenotype', 'HP:0009733', (255, 262))	('gliomas', 'Disease', (255, 262))	('m6A', 'Gene', '56339', (192, 195))	('investigated', 'Reg', (137, 149))	('gliomas', 'Disease', 'MESH:D005910', (255, 262))
197990	30810537	FTO, YTHDC1 and METTL3 were also differentially expressed between GBM with and without IDH mutation in the CGGA dataset (Fig.	('mutation', 'Var', (91, 99))	('FTO', 'Gene', '79068', (0, 3))	('IDH', 'Gene', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('IDH', 'Gene', '3417', (87, 90))	('METTL3', 'Gene', '56339', (16, 22))	('FTO', 'Gene', (0, 3))	('YTHDC1', 'Gene', (5, 11))	('METTL3', 'Gene', (16, 22))	('differentially', 'Reg', (33, 47))	('YTHDC1', 'Gene', '91746', (5, 11))
197994	30810537	Considering METTL16 is also a putative m6A methyltransferase and knockdown of METTL16 could result in approximately 20% decrease of m6A, we also investigated the expression of METTL16 in gliomas with different malignancy status in the CGGA dataset (Figure S1).	('gliomas', 'Disease', (187, 194))	('METTL16', 'Gene', (176, 183))	('m6A', 'Gene', '56339', (39, 42))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('m6A', 'Gene', '56339', (132, 135))	('m6A', 'Gene', (39, 42))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('METTL16', 'Gene', '79066', (176, 183))	('knockdown', 'Var', (65, 74))	('METTL16', 'Gene', (78, 85))	('m6A', 'Gene', (132, 135))	('malignancy', 'Disease', 'MESH:D009369', (210, 220))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('METTL16', 'Gene', (12, 19))	('METTL16', 'Gene', '79066', (78, 85))	('malignancy', 'Disease', (210, 220))	('decrease', 'NegReg', (120, 128))	('investigated', 'Reg', (145, 157))	('METTL16', 'Gene', '79066', (12, 19))
198001	30810537	The RM1 subgroup is significantly correlated with younger age at diagnosis (P < 0.0001), lower grade (P < 0.0001), proneural or neural subtypes (P < 0.0001), IDH-mutational status (P < 0.0001) and 1p/19q codel status (P < 0.0001).	('lower grade', 'CPA', (89, 100))	('IDH', 'Gene', '3417', (158, 161))	('1p/19q codel status', 'Var', (197, 216))	('RM1', 'Var', (4, 7))	('IDH', 'Gene', (158, 161))	('proneural', 'Disease', (115, 124))
198002	30810537	The RM2 subgroup mainly contains gliomas with an older age at diagnosis, glioblastoma (GBM) phenotype, classic or mesenchymal subtypes, IDH-wildtype status and 1p/19q noncodel status (Table S2).	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('glioblastoma', 'Disease', (73, 85))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('1p/19q noncodel status', 'Var', (160, 182))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))
198017	30810537	Among these eleven genes, ALKBH5, YTHDF1, YTHDF2, HNRNPC, RBM15, KIAA1429, and WTAP are risky genes with HR > 1, while FTO, YTHDC1, ZC3H13, and METTL3 are protective genes with HR < 1.	('METTL3', 'Gene', '56339', (144, 150))	('HNRNPC', 'Gene', '3183', (50, 56))	('YTHDC1', 'Gene', (124, 130))	('ALKBH5', 'Gene', (26, 32))	('YTHDF1', 'Gene', (34, 40))	('ALKBH5', 'Gene', '54890', (26, 32))	('RBM15', 'Gene', '64783', (58, 63))	('YTHDF1', 'Gene', '54915', (34, 40))	('YTHDF2', 'Gene', (42, 48))	('KIAA1429', 'Gene', (65, 73))	('KIAA1429', 'Gene', '25962', (65, 73))	('FTO', 'Gene', '79068', (119, 122))	('WTAP', 'Gene', '9589', (79, 83))	('ZC3H13', 'Gene', (132, 138))	('HNRNPC', 'Gene', (50, 56))	('HR > 1', 'Var', (105, 111))	('FTO', 'Gene', (119, 122))	('ZC3H13', 'Gene', '23091', (132, 138))	('YTHDF2', 'Gene', '51441', (42, 48))	('WTAP', 'Gene', (79, 83))	('METTL3', 'Gene', (144, 150))	('YTHDC1', 'Gene', '91746', (124, 130))	('RBM15', 'Gene', (58, 63))
198019	30810537	For the genes with prognostic value in LGG, the expression levels of YTHDF2, WTAP, ALKBH5, RBM15, KIAA1429, HNRNPC, YTHDF1, and FTO are significantly correlated with the overall survival (OS) of patients with IDH-mutant and 1p/19q noncodel LGG.	('LGG', 'Disease', (240, 243))	('YTHDF1', 'Gene', '54915', (116, 122))	('HNRNPC', 'Gene', (108, 114))	('YTHDF2', 'Gene', (69, 75))	('WTAP', 'Gene', (77, 81))	('ALKBH5', 'Gene', '54890', (83, 89))	('RBM15', 'Gene', '64783', (91, 96))	('correlated with', 'Reg', (150, 165))	('KIAA1429', 'Gene', (98, 106))	('expression', 'MPA', (48, 58))	('KIAA1429', 'Gene', '25962', (98, 106))	('FTO', 'Gene', '79068', (128, 131))	('1p/19q noncodel', 'Var', (224, 239))	('patients', 'Species', '9606', (195, 203))	('FTO', 'Gene', (128, 131))	('YTHDF2', 'Gene', '51441', (69, 75))	('IDH', 'Gene', (209, 212))	('HNRNPC', 'Gene', '3183', (108, 114))	('RBM15', 'Gene', (91, 96))	('overall survival', 'MPA', (170, 186))	('YTHDF1', 'Gene', (116, 122))	('WTAP', 'Gene', '9589', (77, 81))	('IDH', 'Gene', '3417', (209, 212))	('ALKBH5', 'Gene', (83, 89))
198025	30810537	We observed significant differences between the high- and low-risk groups with respect to WHO grade (P < 0.001), age (P < 0.001), IDH status (P < 0.001), 1p/19q codel status (P < 0.001), TCGA subtypes (P < 0.001), and RM1/2 subgroups (P < 0.001).	('IDH', 'Gene', '3417', (130, 133))	('IDH', 'Gene', (130, 133))	('1p/19q codel status', 'Var', (154, 173))	('differences', 'Reg', (24, 35))
198026	30810537	We observed that risk scores are significantly different between patients stratified by WHO grade, TCGA subtype, age, IDH status, 1p/19q codel status, and RM1/2 subgroups, but not by gender, in both the CGGA (Fig.	('IDH', 'Gene', (118, 121))	('1p/19q codel status', 'Var', (130, 149))	('IDH', 'Gene', '3417', (118, 121))	('patients', 'Species', '9606', (65, 73))	('CGGA', 'Disease', (203, 207))	('different', 'Reg', (47, 56))
198030	30810537	By univariate analysis, the risk score, 1p/19q codel status, IDH status, age and WHO grade were all correlated with the OS.	('1p/19q codel status', 'Var', (40, 59))	('correlated', 'Reg', (100, 110))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))
198034	30810537	We found that patients with high risk scores had significantly shorter OS than those with low scores in WHO grade II and III gliomas (Fig.	('III gliomas', 'Disease', (121, 132))	('scores', 'Var', (38, 44))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('shorter', 'NegReg', (63, 70))	('III gliomas', 'Disease', 'MESH:D005910', (121, 132))	('patients', 'Species', '9606', (14, 22))
198038	30810537	Traditional epigenetics, limited to DNA or protein modification, has a variety of functions in glioma initiation, malignant progression, and prognosis.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma initiation', 'Disease', 'MESH:D005910', (95, 112))	('glioma initiation', 'Disease', (95, 112))	('malignant', 'CPA', (114, 123))	('epigenetics', 'Var', (12, 23))
198039	30810537	In this study, we demonstrated that the expression of regulators of another area of epigenetics:RNA m6A RNA methylation:is also closely associated with the malignancy and prognosis of gliomas.	('m6A', 'Gene', '56339', (100, 103))	('gliomas', 'Disease', 'MESH:D005910', (184, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('gliomas', 'Disease', (184, 191))	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('malignancy', 'Disease', (156, 166))	('methylation', 'Var', (108, 119))	('m6A', 'Gene', (100, 103))	('associated with', 'Reg', (136, 151))
198047	30810537	WTAP expression was significantly increased in high-grade, mesenchymal subtype, IDH-wildtype, 1p/19q noncodel and elderly glioma patients, indicating potential functions of WTAP in glioma malignancy.	('expression', 'MPA', (5, 15))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioma', 'Disease', (122, 128))	('mesenchymal subtype', 'CPA', (59, 78))	('WTAP', 'Gene', (173, 177))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('IDH', 'Gene', (80, 83))	('increased', 'PosReg', (34, 43))	('glioma malignancy', 'Disease', (181, 198))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('WTAP', 'Gene', '9589', (0, 4))	('patients', 'Species', '9606', (129, 137))	('glioma malignancy', 'Disease', 'MESH:D005910', (181, 198))	('1p/19q noncodel', 'Var', (94, 109))	('IDH', 'Gene', '3417', (80, 83))	('WTAP', 'Gene', (0, 4))	('WTAP', 'Gene', '9589', (173, 177))	('glioma', 'Disease', (181, 187))
198051	30810537	Interestingly, the expression of FTO was significantly deceased in gliomas with malignant clinicopathological features, such as higher WHO grade, mesenchymal subtype, IDH-wildtype status, 1p/19q noncodel and older ages at diagnosis.	('expression', 'MPA', (19, 29))	('deceased', 'NegReg', (55, 63))	('IDH', 'Gene', '3417', (167, 170))	('FTO', 'Gene', (33, 36))	('1p/19q noncodel', 'Var', (188, 203))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('gliomas', 'Disease', (67, 74))	('mesenchymal subtype', 'CPA', (146, 165))	('FTO', 'Gene', '79068', (33, 36))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH', 'Gene', (167, 170))	('higher WHO grade', 'CPA', (128, 144))
198065	30810537	As we observed, though the signature risk score can stratify the OS for IDH-mutant and 1p/19q noncodel lower grade gliomas, IDH-wildtype lower grade gliomas, and IDH-wildtype GBM in the CGGA dataset, it cannot distinguish the OS in the TCGA dataset (data not shown).	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('IDH', 'Gene', (124, 127))	('gliomas', 'Disease', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('IDH', 'Gene', (162, 165))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('GBM', 'Phenotype', 'HP:0012174', (175, 178))	('IDH', 'Gene', '3417', (124, 127))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('IDH', 'Gene', '3417', (162, 165))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('1p/19q', 'Var', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))
198093	30470401	In 2009, it was discovered that the vast majority of LGG harbored mutations in Isocitrate Dehydrogenase 1 (IDH1) and less frequently in the closely related enzyme IDH2.	('mutations', 'Var', (66, 75))	('IDH1', 'Gene', (107, 111))	('IDH1', 'Gene', '3417', (107, 111))	('IDH2', 'Gene', '3418', (163, 167))	('Isocitrate Dehydrogenase 1', 'Gene', (79, 105))	('LGG', 'Disease', (53, 56))	('IDH2', 'Gene', (163, 167))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (79, 105))
198095	30470401	In 2009, LGG and secondary glioblastoma, which originates from a preexisting LGG, were shown to harbor characteristic, neomorphic, heterozygous mutations in Isocitrate Dehydrogenase 1 (IDH1).	('IDH1', 'Gene', '3417', (185, 189))	('Isocitrate Dehydrogenase 1', 'Gene', (157, 183))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('LGG', 'Disease', (9, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (157, 183))	('mutations', 'Var', (144, 153))	('IDH1', 'Gene', (185, 189))
198097	30470401	Additionally, LGGs lacking a mutation in IDH1 may harbor an analogous mutation in IDH2, a mitochondrial enzyme that also produces alpha-KG, primarily for the TCA cycle.	('TCA', 'Chemical', 'MESH:C000589078', (158, 161))	('alpha-KG', 'Chemical', 'MESH:C029743', (130, 138))	('IDH2', 'Gene', (82, 86))	('IDH2', 'Gene', '3418', (82, 86))	('IDH1', 'Gene', (41, 45))	('mutation', 'Var', (70, 78))	('IDH1', 'Gene', '3417', (41, 45))
198098	30470401	Acute myeloid leukemia (AML), cholangiocarcinoma, and myelodysplastic syndromes have been found to exhibit the same class of mutations.	('mutations', 'Var', (125, 134))	('AML', 'Disease', (24, 27))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (0, 22))	('myelodysplastic syndromes', 'Disease', (54, 79))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (54, 79))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (6, 22))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (54, 79))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (0, 22))	('AML', 'Disease', 'MESH:D015470', (24, 27))	('Acute myeloid leukemia', 'Disease', (0, 22))	('cholangiocarcinoma', 'Disease', (30, 48))	('AML', 'Phenotype', 'HP:0004808', (24, 27))
198099	30470401	Interestingly, the genetic syndrome Ollier Disease, which results from somatic mosaicism for mutations in IDH, is associated with an increased rate of gliomas compared to the general population and an earlier age of diagnosis than seen in the broader LGG patient population.	('IDH', 'Gene', '3417', (106, 109))	('mutations', 'Var', (93, 102))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('Ollier Disease', 'Phenotype', 'HP:0500045', (36, 50))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('patient', 'Species', '9606', (255, 262))	('results from', 'Reg', (58, 70))	('genetic syndrome Ollier Disease', 'Disease', 'MESH:D004687', (19, 50))	('gliomas', 'Disease', (151, 158))	('IDH', 'Gene', (106, 109))	('genetic syndrome Ollier Disease', 'Disease', (19, 50))
198100	30470401	After their initial identification in LGG and secondary glioblastoma, IDH mutations were identified in >80% of tumors histologically classified as LGG.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('LGG', 'Disease', (147, 150))	('LGG', 'Disease', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('IDH', 'Gene', (70, 73))	('mutations', 'Var', (74, 83))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('IDH', 'Gene', '3417', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('glioblastoma', 'Disease', (56, 68))	('identified', 'Reg', (89, 99))
198101	30470401	The larger of these subclasses is characterized by inactivating mutations in the tumor suppressor TP53 and the chromatin remodeling enzyme ATRX (Fig.	('ATRX', 'Gene', '546', (139, 143))	('inactivating mutations', 'Var', (51, 73))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('TP53', 'Gene', '7157', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ATRX', 'Gene', (139, 143))	('tumor', 'Disease', (81, 86))	('TP53', 'Gene', (98, 102))
198102	30470401	Tumors containing this set of mutations correspond to astrocytoma, as identified by histopathology.	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (30, 39))	('astrocytoma', 'Disease', 'MESH:D001254', (54, 65))	('correspond', 'Reg', (40, 50))	('astrocytoma', 'Disease', (54, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))
198107	30470401	All of this classification so far neglects the small percentage of histopathologically graded LGGs which do not exhibit a mutation in IDH1/2.	('IDH1/2', 'Gene', '3417;3418', (134, 140))	('mutation', 'Var', (122, 130))	('LGGs', 'Disease', (94, 98))	('IDH1/2', 'Gene', (134, 140))
198111	30470401	However, the other half of IDH wildtype LGGs lack these mutations and have a clinical course resembling more closely that of LGG with average survival of greater than 7 years.	('IDH', 'Gene', (27, 30))	('mutations', 'Var', (56, 65))	('lack', 'NegReg', (45, 49))	('IDH', 'Gene', '3417', (27, 30))	('LGG', 'Disease', (125, 128))
198115	30470401	The presence of a mutation in IDH1/2 in combination with loss of ATRX and TP53 results in the diagnosis of a diffuse astrocytoma or anaplastic astrocytoma, grade II and grade III respectively.	('astrocytoma', 'Disease', (143, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('IDH1/2', 'Gene', '3417;3418', (30, 36))	('astrocytoma', 'Disease', (117, 128))	('IDH1/2', 'Gene', (30, 36))	('astrocytoma', 'Disease', 'MESH:D001254', (143, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (117, 128))	('ATRX', 'Gene', (65, 69))	('TP53', 'Gene', '7157', (74, 78))	('loss', 'NegReg', (57, 61))	('mutation', 'Var', (18, 26))	('ATRX', 'Gene', '546', (65, 69))	('presence', 'Var', (4, 12))	('TP53', 'Gene', (74, 78))	('astrocytoma', 'Disease', 'MESH:D001254', (117, 128))
198116	30470401	If IDH mutations are found in combination with chromosomal 1p/19q codeletion then the diagnosis of oligodendroglioma or anaplastic oligodendroglioma is made.	('IDH', 'Gene', '3417', (3, 6))	('oligodendroglioma', 'Disease', 'MESH:D009837', (99, 116))	('oligodendroglioma', 'Disease', (131, 148))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('oligodendroglioma', 'Disease', 'MESH:D009837', (131, 148))	('oligodendroglioma', 'Disease', (99, 116))	('IDH', 'Gene', (3, 6))	('mutations', 'Var', (7, 16))
198120	30470401	Patient genomic analysis established the mutations discussed previously as being nearly pathognomonic for low-grade astrocytoma (LGA) and oliodendroglioma (LGO), but studying how each individual mutation or combination of mutations contribute to tumorigenesis is important for making this information therapeutically actionable.	('mutations', 'Var', (41, 50))	('contribute', 'Reg', (232, 242))	('astrocytoma', 'Disease', (116, 127))	('astrocytoma', 'Phenotype', 'HP:0009592', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('oliodendroglioma', 'Disease', (138, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('astrocytoma', 'Disease', 'MESH:D001254', (116, 127))	('tumor', 'Disease', (246, 251))	('Patient', 'Species', '9606', (0, 7))	('oliodendroglioma', 'Disease', 'None', (138, 154))
198122	30470401	High levels of methylation have been linked to heightened mutagenesis in colorectal cancer, another malignancy where many tumors exhibit increased CpG island methylation.	('methylation', 'Var', (15, 26))	('tumors', 'Disease', (122, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('malignancy', 'Disease', 'MESH:D009369', (100, 110))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mutagenesis', 'MPA', (58, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('malignancy', 'Disease', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('heightened', 'PosReg', (47, 57))
198123	30470401	While the exact consequences of the G-CIMP phenotype are not clear, analysis of the actions of mutant IDH provided a mechanistic link to its establishment.	('IDH', 'Gene', '3417', (102, 105))	('IDH', 'Gene', (102, 105))	('mutant', 'Var', (95, 101))
198124	30470401	Evidence for IDH mutations as a driver of gliomagenesis was supported by their presence in a number of distinct glioma subtypes and other tumors, but the strongest evidence was seen in studies of IDH-mutant glioma recurrences after initial treatment.	('gliomagenesis', 'Disease', 'None', (42, 55))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('gliomagenesis', 'Disease', (42, 55))	('mutations', 'Var', (17, 26))	('glioma', 'Disease', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Disease', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glioma', 'Disease', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', '3417', (196, 199))	('tumors', 'Disease', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))
198125	30470401	It has been convincingly shown that if an initial tumor contains a mutant IDH then 100% of recurrences will also contain the same exact mutation.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('IDH', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutant', 'Var', (67, 73))	('tumor', 'Disease', (50, 55))	('IDH', 'Gene', '3417', (74, 77))	('contain', 'Reg', (113, 120))
198126	30470401	This strongly supports the hypothesis that mutations in IDH1/2 are the driving event behind the formation of an IDH mutant LGG and remain necessary for tumor progression.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('IDH', 'Gene', (56, 59))	('tumor', 'Disease', (152, 157))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('IDH', 'Gene', '3417', (56, 59))	('mutations', 'Var', (43, 52))	('IDH', 'Gene', (112, 115))	('mutant', 'Var', (116, 122))	('IDH1/2', 'Gene', (56, 62))	('IDH', 'Gene', '3417', (112, 115))
198129	30470401	In contrast, the neomorphic IDH mutations produce the unique metabolic product 2-hydroxyglutarate (2HG), which inhibits dioxygenase calalytic activity, resulting in DNA hypermethylation among other effects (Fig.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (79, 97))	('IDH', 'Gene', (28, 31))	('IDH', 'Gene', '3417', (28, 31))	('inhibits', 'NegReg', (111, 119))	('DNA hypermethylation', 'MPA', (165, 185))	('2HG', 'Chemical', 'MESH:C019417', (99, 102))	('mutations', 'Var', (32, 41))	('dioxygenase calalytic activity', 'MPA', (120, 150))
198130	30470401	Studies have confirmed that mutant IDH is sufficient to impart the G-CIMP DNA hypermethylation epigenotype seen in patients.	('patients', 'Species', '9606', (115, 123))	('mutant', 'Var', (28, 34))	('DNA hypermethylation', 'MPA', (74, 94))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (35, 38))
198131	30470401	Furthermore, mutant IDH increases histone methylation, and in particular repressive methylation modifications associated with transcriptionally silent chromatin.	('mutant', 'Var', (13, 19))	('repressive methylation modifications', 'MPA', (73, 109))	('increases', 'PosReg', (24, 33))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('histone methylation', 'MPA', (34, 53))
198132	30470401	Low-grade astrocytomas, as discussed previously, harbor inactivating mutations of TP53 and ATRX.	('TP53', 'Gene', (82, 86))	('ATRX', 'Gene', (91, 95))	('astrocytomas', 'Disease', 'MESH:D001254', (10, 22))	('inactivating mutations', 'Var', (56, 78))	('ATRX', 'Gene', '546', (91, 95))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('astrocytomas', 'Disease', (10, 22))	('TP53', 'Gene', '7157', (82, 86))
198133	30470401	P53 is a stereotypical tumor suppressor whose inactivation is observed in 50% of all human cancers.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('inactivation', 'Var', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (23, 28))	('human', 'Species', '9606', (85, 90))
198141	30470401	Inactivation of ATRX has also been observed to contribute to the invasive, migratory phenotype of glioma cells both by itself and in the presence of mutant IDH and loss of P53.	('loss', 'Var', (164, 168))	('glioma cells', 'Disease', 'MESH:D005910', (98, 110))	('contribute', 'Reg', (47, 57))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('mutant', 'Var', (149, 155))	('ATRX', 'Gene', '546', (16, 20))	('IDH', 'Gene', (156, 159))	('P53', 'Gene', (172, 175))	('glioma cells', 'Disease', (98, 110))	('P53', 'Gene', '7157', (172, 175))	('IDH', 'Gene', '3417', (156, 159))	('invasive', 'CPA', (65, 73))	('Inactivation', 'Var', (0, 12))	('ATRX', 'Gene', (16, 20))
198143	30470401	Despite these insights into mutant IDH1 gliomagenesis, the exact mechanism whereby the mutation transforms neural cells into glioma remains unclear.	('glioma', 'Disease', (125, 131))	('IDH1', 'Gene', (35, 39))	('mutant', 'Var', (28, 34))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('gliomagenesis', 'Disease', (40, 53))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('gliomagenesis', 'Disease', 'None', (40, 53))
198146	30470401	We derived these hNSCs from human embryonic stem cells (hESCs) and genetically engineered them to express mutant IDH1 (the R132H mutation), as well as short hairpin RNAs that specifically knockdown P53 and ATRX, to mimic the stereotypic genetic background of LGA.	('mutant', 'Var', (106, 112))	('R132H', 'Mutation', 'rs121913500', (123, 128))	('P53', 'Gene', (198, 201))	('ATRX', 'Gene', (206, 210))	('IDH1', 'Gene', (113, 117))	('human', 'Species', '9606', (28, 33))	('P53', 'Gene', '7157', (198, 201))	('IDH1', 'Gene', '3417', (113, 117))	('knockdown', 'Var', (188, 197))	('ATRX', 'Gene', '546', (206, 210))
198147	30470401	Our findings suggest that the oncogenic mechanism underlying low-grade gliomagenesis is the prevention of generation of post-mitotic neuroglial lineages from brain progenitor cells by the combination of mutant IDH and loss of P53 and ATRX, resulting in the slow growth of undifferentiated, proliferating stem-like tumor cells.	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('mutant', 'Var', (203, 209))	('gliomagenesis', 'Disease', (71, 84))	('IDH', 'Gene', '3417', (210, 213))	('ATRX', 'Gene', (234, 238))	('slow growth', 'Phenotype', 'HP:0001510', (257, 268))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('P53', 'Gene', (226, 229))	('tumor', 'Disease', (314, 319))	('loss', 'Var', (218, 222))	('ATRX', 'Gene', '546', (234, 238))	('slow growth', 'CPA', (257, 268))	('gliomagenesis', 'Disease', 'None', (71, 84))	('P53', 'Gene', '7157', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH', 'Gene', (210, 213))
198149	30470401	We found that SOX2 became transcriptionally downregulated in hNSCs bearing mutant IDH1 and loss of P53/ATRX (Fig.	('SOX2', 'Gene', '6657', (14, 18))	('SOX2', 'Gene', (14, 18))	('downregulated', 'NegReg', (44, 57))	('P53', 'Gene', (99, 102))	('ATRX', 'Gene', (103, 107))	('IDH1', 'Gene', (82, 86))	('P53', 'Gene', '7157', (99, 102))	('mutant', 'Var', (75, 81))	('IDH1', 'Gene', '3417', (82, 86))	('ATRX', 'Gene', '546', (103, 107))	('loss', 'Var', (91, 95))	('transcriptionally', 'MPA', (26, 43))
198151	30470401	We also confirmed the change in SOX2 expression between normal human brain tissue and IDH mutant LGA (Fig.	('IDH', 'Gene', (86, 89))	('human', 'Species', '9606', (63, 68))	('IDH', 'Gene', '3417', (86, 89))	('SOX2', 'Gene', '6657', (32, 36))	('mutant', 'Var', (90, 96))	('SOX2', 'Gene', (32, 36))	('LGA', 'Gene', (97, 100))	('expression', 'MPA', (37, 47))	('change', 'Reg', (22, 28))
198158	30470401	Mutations in IDH are near universal in LGO and the consequences of this change is much the same as it is in LGA.	('IDH', 'Gene', (13, 16))	('IDH', 'Gene', '3417', (13, 16))	('Mutations', 'Var', (0, 9))
198159	30470401	The pathognomonic molecular changes in LGO are the chromosomal deletion of 1p and 19q and mutations in the promoter of TERT.	('mutations', 'Var', (90, 99))	('TERT', 'Gene', (119, 123))	('TERT', 'Gene', '7015', (119, 123))	('LGO', 'Disease', (39, 42))	('pathognomonic', 'Reg', (4, 17))
198160	30470401	TERT promoter mutations, resulting in overexpression of TERT, provide a mechanism by which tumors can maintain telomere length and avoid replicative senescence.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('overexpression', 'PosReg', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TERT', 'Gene', (56, 60))	('telomere length', 'MPA', (111, 126))	('mutations', 'Var', (14, 23))	('replicative senescence', 'MPA', (137, 159))	('TERT', 'Gene', '7015', (56, 60))
198161	30470401	Beyond the two hallmark changes discussed above, LGO harbors inactivating mutations of the homolog of capicua (CIC) and far-upstream binding protein 1 (FUBP1) in 70% and 30% of cases, respectively.	('far-upstream binding protein 1', 'Gene', '8880', (120, 150))	('CIC', 'Gene', '23152', (111, 114))	('FUBP1', 'Gene', '8880', (152, 157))	('CIC', 'Gene', (111, 114))	('inactivating mutations', 'Var', (61, 83))	('FUBP1', 'Gene', (152, 157))	('far-upstream binding protein 1', 'Gene', (120, 150))
198163	30470401	Loss of CIC, a transcriptional repressor, was recently found to promote the proliferation and block the differentiation of neural progenitors, thus providing a mechanism for oligodendroglioma initiation and growth.	('promote', 'PosReg', (64, 71))	('CIC', 'Gene', (8, 11))	('differentiation', 'CPA', (104, 119))	('block', 'NegReg', (94, 99))	('oligodendroglioma initiation', 'Disease', 'MESH:D009837', (174, 202))	('proliferation', 'CPA', (76, 89))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('oligodendroglioma initiation', 'Disease', (174, 202))	('Loss', 'Var', (0, 4))	('CIC', 'Gene', '23152', (8, 11))
198164	30470401	FUBP1 mutations are less well characterized but seem to result in transcriptional activation of C-MYC, a transcription factor activated by growth factor signaling, and upregulation of ribosome biogenesis.	('transcriptional', 'MPA', (66, 81))	('ribosome biogenesis', 'MPA', (184, 203))	('FUBP1', 'Gene', (0, 5))	('activation', 'PosReg', (82, 92))	('FUBP1', 'Gene', '8880', (0, 5))	('C-MYC', 'Gene', (96, 101))	('upregulation', 'PosReg', (168, 180))	('mutations', 'Var', (6, 15))	('C-MYC', 'Gene', '4609', (96, 101))
198166	30470401	Mutant IDH LGA and LGO both inevitably progress to high-grade gliomas.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('progress', 'Reg', (39, 47))	('Mutant', 'Var', (0, 6))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
198168	30470401	The most common deletion associated with progression was that of tumor suppressor CDKN2A, while the most common amplification was that of MYC.	('tumor', 'Disease', (65, 70))	('associated', 'Reg', (25, 35))	('deletion', 'Var', (16, 24))	('MYC', 'Gene', (138, 141))	('CDKN2A', 'Gene', (82, 88))	('CDKN2A', 'Gene', '1029', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('MYC', 'Gene', '4609', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
198173	30470401	This increased mutational burden is associated with exacerbated malignancy.	('mutational', 'Var', (15, 25))	('malignancy', 'Disease', (64, 74))	('exacerbated', 'PosReg', (52, 63))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))
198175	30470401	Common genetic alterations in the acquisition of the hypermutant genotype include loss of CDKN2A and mutations to other components of the RB tumor suppressor pathway, as well as a number of the components of the MAPK signaling pathway.	('CDKN2A', 'Gene', '1029', (90, 96))	('mutations', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('RB tumor', 'Disease', (138, 146))	('RB tumor', 'Disease', 'MESH:D012175', (138, 146))	('loss', 'NegReg', (82, 86))	('CDKN2A', 'Gene', (90, 96))
198177	30470401	A number of inhibitors of mutant IDH have been produced and their use in treating several cancers is now under investigation.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IDH', 'Gene', (33, 36))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('mutant', 'Var', (26, 32))	('IDH', 'Gene', '3417', (33, 36))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
198181	30470401	Early preclinical evidence showed promise that inhibitors could slow tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibitors', 'Var', (47, 57))	('slow', 'NegReg', (64, 68))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
198183	30470401	Current evidence shows that the effects of mutant IDH are long-lasting and remain even following full inhibition of 2HG production.	('2HG', 'Chemical', 'MESH:C019417', (116, 119))	('mutant', 'Var', (43, 49))	('IDH', 'Gene', '3417', (50, 53))	('IDH', 'Gene', (50, 53))
198184	30470401	A number of genes, whose expression is changed by 2HG, remain aberrantly expressed following prolonged inhibition of mutant IDH.	('IDH', 'Gene', (124, 127))	('mutant', 'Var', (117, 123))	('IDH', 'Gene', '3417', (124, 127))	('2HG', 'Chemical', 'MESH:C019417', (50, 53))	('inhibition', 'NegReg', (103, 113))
198185	30470401	If such a pathway is found, targeted interference in its function can eliminate cancerous cells while sparing their healthy counterparts.	('cancerous', 'Disease', (80, 89))	('eliminate', 'NegReg', (70, 79))	('targeted interference', 'Var', (28, 49))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancerous', 'Disease', 'MESH:D009369', (80, 89))
198186	30470401	A different and somewhat less effective mechanism, non-homologous end joining (NHEJ), is theoretically available for repair throughout the cell cycle but acts primarily in G1 as a result of its suppression in S/G2 by proteins like CYREN.	('S/G2', 'SUBSTITUTION', 'None', (209, 213))	('suppression', 'NegReg', (194, 205))	('EJ', 'CellLine', 'CVCL:7039', (81, 83))	('S/G2', 'Var', (209, 213))
198191	30470401	Another effect of mutant IDH is to reduce cellular nicotinamide adenine dinucleotide (NAD+) levels by transcriptionally downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (NARPT1).	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('NAD', 'Chemical', 'MESH:D009243', (86, 89))	('mutant', 'Var', (18, 24))	('NAD+', 'Pathway', (139, 143))	('nicotinate phosphoribosyltransferase', 'Gene', (167, 203))	('reduce', 'NegReg', (35, 41))	('NAD', 'Chemical', 'MESH:D009243', (139, 142))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (51, 84))	('downregulating', 'NegReg', (120, 134))	('nicotinate phosphoribosyltransferase', 'Gene', '93100', (167, 203))
198192	30470401	Preclinical animal model testing has found strong sensitivity of mutant IDH glioma to NAD+ depletion via inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the sole enzyme that can support NAD+ biosynthesis in the absence of NARPT1.	('nicotinamide phosphoribosyltransferase', 'Gene', (119, 157))	('NAD', 'Chemical', 'MESH:D009243', (86, 89))	('IDH glioma', 'Disease', (72, 82))	('NAMPT', 'Gene', (159, 164))	('inhibition', 'NegReg', (105, 115))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (119, 157))	('mutant', 'Var', (65, 71))	('IDH glioma', 'Disease', 'MESH:D005910', (72, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('NAD', 'Chemical', 'MESH:D009243', (200, 203))	('NAD+ depletion', 'MPA', (86, 100))	('NAMPT', 'Gene', '10135', (159, 164))
198194	30470401	It was recently demonstrated that mutant IDH can change the balance of these factors.	('IDH', 'Gene', (41, 44))	('balance of these factors', 'MPA', (60, 84))	('IDH', 'Gene', '3417', (41, 44))	('change', 'Reg', (49, 55))	('mutant', 'Var', (34, 40))
198195	30470401	The presence of mutant IDH or exogenous 2HG activates the energy-sensing protein AMP-activated protein kinase (AMPK), which has the downstream effect of inhibiting production of MCL1, a member of the Bcl-2/Bcl-xL anti-apoptotic family of proteins.	('AMP', 'Chemical', 'MESH:D000249', (111, 114))	('AMP', 'Chemical', 'MESH:D000249', (81, 84))	('production', 'MPA', (164, 174))	('Bcl-2', 'Gene', (200, 205))	('Bcl-xL', 'Gene', '598', (206, 212))	('Bcl-2', 'Gene', '596', (200, 205))	('2HG', 'Gene', (40, 43))	('MCL1', 'Gene', '4170', (178, 182))	('2HG', 'Chemical', 'MESH:C019417', (40, 43))	('activates', 'PosReg', (44, 53))	('Bcl-xL', 'Gene', (206, 212))	('mutant', 'Var', (16, 22))	('MCL1', 'Gene', (178, 182))	('IDH', 'Gene', (23, 26))	('inhibiting', 'NegReg', (153, 163))	('IDH', 'Gene', '3417', (23, 26))
198196	30470401	Because of the low levels of MCL1, treatment of mutant IDH glioma with the compound ABT263, which is an inhibitor of Bcl-xL and Bcl-2, depletes IDH mutant tumor cells of anti-apoptotic activity and confers synthetic lethality with the IDH mutation both in vitro and in vivo.	('anti-apoptotic activity', 'CPA', (170, 193))	('IDH glioma', 'Disease', 'MESH:D005910', (55, 65))	('tumor', 'Disease', (155, 160))	('Bcl-2', 'Gene', '596', (128, 133))	('MCL1', 'Gene', '4170', (29, 33))	('IDH', 'Gene', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutant', 'Var', (48, 54))	('IDH', 'Gene', (55, 58))	('depletes', 'NegReg', (135, 143))	('ABT263', 'Chemical', 'MESH:C528561', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('IDH', 'Gene', '3417', (144, 147))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH', 'Gene', '3417', (55, 58))	('Bcl-xL', 'Gene', (117, 123))	('IDH', 'Gene', (235, 238))	('synthetic lethality', 'CPA', (206, 225))	('IDH glioma', 'Disease', (55, 65))	('Bcl-xL', 'Gene', '598', (117, 123))	('Bcl-2', 'Gene', (128, 133))	('mutant', 'Var', (148, 154))	('IDH', 'Gene', '3417', (235, 238))	('MCL1', 'Gene', (29, 33))
198198	30470401	The IDH mutation, a hallmark of LGG, is important to understand further in order to be therapeutically targeted.	('IDH', 'Gene', (4, 7))	('IDH', 'Gene', '3417', (4, 7))	('mutation', 'Var', (8, 16))
198200	30470401	Recent advances in genome sequencing have identified genetic alterations that define low-grade glioma The IDH mutation initiates metabolic, epigenetic and cellular changes that transform neural progenitors to glioma cells Laboratory findings are giving rise to novel therapeutic approaches in low-grade glioma Advances in genome sequencing have elucidated the genetics of low-grade glioma.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH', 'Gene', '3417', (106, 109))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('glioma', 'Disease', (303, 309))	('glioma cells', 'Disease', 'MESH:D005910', (209, 221))	('glioma', 'Disease', (382, 388))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (303, 309))	('glioma', 'Disease', (209, 215))	('mutation', 'Var', (110, 118))	('glioma', 'Disease', 'MESH:D005910', (303, 309))	('glioma', 'Disease', 'MESH:D005910', (382, 388))	('glioma', 'Phenotype', 'HP:0009733', (382, 388))	('IDH', 'Gene', (106, 109))	('glioma cells', 'Disease', (209, 221))
198202	30470401	Mutant IDH produces the oncometabolite 2-hydroxyglutarate, which inhibits enzymes that demethylate genomic DNA and histones.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('inhibits', 'NegReg', (65, 73))	('demethylate', 'MPA', (87, 98))	('genomic DNA', 'Protein', (99, 110))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (39, 57))	('Mutant', 'Var', (0, 6))	('enzymes', 'Enzyme', (74, 81))
198203	30470401	Recent findings by us and others suggest the ensuing hypermethylation alters chromatin conformation and the transcription factor landscape in brain progenitor cells, leading to a block in differentiation and tumor initiation.	('chromatin', 'MPA', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('hypermethylation', 'Var', (53, 69))	('alters', 'Reg', (70, 76))	('block', 'NegReg', (179, 184))	('differentiation', 'CPA', (188, 203))
198222	29040640	Recent molecular genetic studies have also shown high frequency of mutations in RAS-RAF-MAPK and PI3K-AKT-mTOR pathways linking this group of tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', (142, 148))	('RAF', 'Gene', '22882', (84, 87))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('mTOR', 'Gene', (106, 110))	('RAF', 'Gene', (84, 87))	('mTOR', 'Gene', '2475', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
198244	29040640	Molecular pathology in the dGNT confirmed that none had an IDH1 mutation, and in 6 cases where ATRX mutation had been evaluated, this was not present.	('IDH1', 'Gene', '3417', (59, 63))	('ATRX', 'Gene', (95, 99))	('mutation', 'Var', (64, 72))	('ATRX', 'Gene', '546', (95, 99))	('dGNT', 'Chemical', '-', (27, 31))	('IDH1', 'Gene', (59, 63))
198254	29040640	For simple DNTs, single well-defined lesions, cystic components, cortical expansion and high signal rim on FLAIR were all more common than in dGNT (Table 2).	('high signal', 'Var', (88, 99))	('DNTs', 'Chemical', 'MESH:C023514', (11, 15))	('cortical expansion', 'CPA', (65, 83))	('simple DNTs', 'Disease', (4, 15))	('cystic', 'Disease', (46, 52))	('dGNT', 'Chemical', '-', (142, 146))
198261	29040640	Subcortical white matter T2w hyper intensity correlated with a predominant histological diffuse growth pattern (p < 0.0001), CD34 expression (p < 0.0001; Figs.	('CD34', 'Gene', '947', (125, 129))	('T2w', 'Var', (25, 28))	('expression', 'MPA', (130, 140))	('CD34', 'Gene', (125, 129))
198285	29040640	There is more compelling evidence, however, grouping dGNT with ganglioglioma through the shared and predominant expression patterns of CD34, observation of foci of atypical ganglion cells (including cases in the present study) more frequent BRAF V600E gene mutations than DNT and methylation cluster analysis.	('glioma', 'Disease', (70, 76))	('CD34', 'Gene', (135, 139))	('DNT', 'Chemical', '-', (272, 275))	('dGNT', 'Chemical', '-', (53, 57))	('V600E', 'Mutation', 'rs113488022', (246, 251))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('V600E', 'Var', (246, 251))	('BRAF', 'Gene', '673', (241, 245))	('BRAF', 'Gene', (241, 245))	('CD34', 'Gene', '947', (135, 139))
198303	27270107	15% of tumors present hypermutations at relapse in highly expressed genes with a clear mutational signature.	('hypermutations', 'Var', (22, 36))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
198304	27270107	We find that 11% of recurrent tumors harbor mutations in LTBP4, a protein binding to TGF-beta.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('TGF-beta', 'Gene', (85, 93))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('LTBP4', 'Gene', (57, 62))	('LTBP4', 'Gene', '8425', (57, 62))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TGF-beta', 'Gene', '7040', (85, 93))	('binding', 'Interaction', (74, 81))
198305	27270107	Silencing LTBP4 in GBM cells leads to TGF-beta activity suppression and decreased proliferation.	('TGF-beta', 'Gene', (38, 46))	('decreased', 'NegReg', (72, 81))	('suppression', 'NegReg', (56, 67))	('TGF-beta', 'Gene', '7040', (38, 46))	('LTBP4', 'Gene', '8425', (10, 15))	('LTBP4', 'Gene', (10, 15))	('proliferation', 'CPA', (82, 95))	('activity', 'MPA', (47, 55))	('Silencing', 'Var', (0, 9))
198306	27270107	In IDH1-wild-type recurrent GBM, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-beta pathway as a potential therapeutic target in GBM.	('TGF-beta', 'Gene', '7040', (108, 116))	('high', 'Var', (33, 37))	('expression', 'MPA', (44, 54))	('TGF-beta', 'Gene', (108, 116))	('LTBP4', 'Gene', '8425', (38, 43))	('LTBP4', 'Gene', (38, 43))	('IDH1', 'Gene', (3, 7))	('IDH1', 'Gene', '3417', (3, 7))
198313	27270107	Mutations of TP53 gene were recently proposed to mark subclonal heterogeneity of GBM, but a clear pattern of tumor evolution remains elusive.	('TP53', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', (109, 114))
198317	27270107	Recurrent GBM patients (89 diagnosed with primary GBM) were collected from Istituto Neurologico C. Besta (INCB, R001-R019), MD Anderson Cancer Center (R020-R029), The Cancer Genome Atlas (TCGA, R030-R042), University of California San Francisco (UCSF, R043-R052), Kyoto University (KU, R053-R055), and Samsung Medical Center (SMC, R056-R114).	('R001-R019', 'Disease', (112, 121))	('Cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('R043-R052', 'Var', (252, 261))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (124, 142))	('Cancer Genome Atlas', 'Disease', (167, 186))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (167, 186))	('MD Anderson Cancer', 'Disease', (124, 142))	('R030-R042', 'Var', (194, 203))	('patients', 'Species', '9606', (14, 22))	('R001-R019', 'Disease', 'None', (112, 121))
198321	27270107	Sanger sequencing successfully validated 98% (39/40) of the mutational calls as well as changes in allele frequency between untreated and recurrent tumor (Supplementary Table 2 and Supplementary Data 1).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('changes', 'Reg', (88, 95))	('tumor', 'Disease', (148, 153))	('mutational calls', 'Var', (60, 76))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
198326	27270107	16 out of 17 hypermutated samples gained mutations in genes coding DNA mismatch repair proteins (MSH6, MSH2, MHS4, MSH5, PMS1, PMS2, MLH1, and MLH2) (Figure 1B).	('mutations', 'Var', (41, 50))	('PMS2', 'Gene', (127, 131))	('MLH2', 'Gene', '5378', (143, 147))	('MHS4', 'Gene', '4265', (109, 113))	('MSH5', 'Gene', (115, 119))	('MLH1', 'Gene', '4292', (133, 137))	('PMS2', 'Gene', '5395', (127, 131))	('PMS1', 'Gene', (121, 125))	('MLH1', 'Gene', (133, 137))	('MLH2', 'Gene', (143, 147))	('MSH6', 'Gene', (97, 101))	('MSH2', 'Gene', (103, 107))	('PMS1', 'Gene', '5378', (121, 125))	('MSH5', 'Gene', '4439', (115, 119))	('MSH2', 'Gene', '4436', (103, 107))	('MSH6', 'Gene', '2956', (97, 101))	('MHS4', 'Gene', (109, 113))
198331	27270107	These associations include co-occurrence of MGMT promoter methylation and hypermutation (p-value=4x10-3, Fisher's exact test, only TMZ treated patients), co-deletion of RB1 and PTEN (p-value<10-4, Fisher's exact test); and co-mutation of NF1 and TP53 (p-value=10-2, Fisher's exact test).	('NF1', 'Gene', '4763', (238, 241))	('hypermutation', 'MPA', (74, 87))	('co-mutation', 'Var', (223, 234))	('TMZ', 'Chemical', 'MESH:D000077204', (131, 134))	('RB1', 'Gene', (169, 172))	('patients', 'Species', '9606', (143, 151))	('PTEN', 'Gene', (177, 181))	('MGMT', 'Gene', (44, 48))	('RB1', 'Gene', '5925', (169, 172))	('PTEN', 'Gene', '5728', (177, 181))	('TP53', 'Gene', '7157', (246, 250))	('MGMT', 'Gene', '4255', (44, 48))	('co-deletion', 'Var', (154, 165))	('TP53', 'Gene', (246, 250))	('NF1', 'Gene', (238, 241))
198332	27270107	We observed mutations in known drivers of GBM including TP53, PTEN, EGFR, PIK3CA, ATRX, IDH1, PIK3R1, and PDGFRA with similar frequency in both untreated and recurrent tumors (Figure 1D).	('PTEN', 'Gene', (62, 66))	('IDH1', 'Gene', (88, 92))	('PIK3CA', 'Gene', '5290', (74, 80))	('tumors', 'Disease', (168, 174))	('PTEN', 'Gene', '5728', (62, 66))	('TP53', 'Gene', '7157', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('PIK3R1', 'Gene', '5295', (94, 100))	('EGFR', 'Gene', '1956', (68, 72))	('IDH1', 'Gene', '3417', (88, 92))	('PIK3CA', 'Gene', (74, 80))	('ATRX', 'Gene', (82, 86))	('ATRX', 'Gene', '546', (82, 86))	('PDGFRA', 'Gene', (106, 112))	('PDGFRA', 'Gene', '5156', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (12, 21))	('TP53', 'Gene', (56, 60))	('PIK3R1', 'Gene', (94, 100))	('EGFR', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
198335	27270107	Interestingly all eight cases with mutations in MSH6 occurred in hypermutated recurrences (p-value<10-4, Fisher's exact test), and three of these cases include nonsense mutations in the gene, indicating that loss of function of MSH6 is related to genomic hypermutation in GBM.	('MSH6', 'Gene', (48, 52))	('occurred', 'Reg', (53, 61))	('MSH6', 'Gene', (228, 232))	('MSH6', 'Gene', '2956', (48, 52))	('loss of function', 'NegReg', (208, 224))	('MSH6', 'Gene', '2956', (228, 232))	('mutations', 'Var', (35, 44))
198338	27270107	Disruption of this gene causes abnormal lung development, cardiomyopathy, and colorectal cancer in mouse.	('mouse', 'Species', '10090', (99, 104))	('causes', 'Reg', (24, 30))	('cardiomyopathy', 'Disease', (58, 72))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('abnormal lung', 'Phenotype', 'HP:0002088', (31, 44))	('colorectal cancer', 'Disease', (78, 95))	('lung', 'Disease', (40, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (58, 72))	('cardiomyopathy', 'Disease', 'MESH:D009202', (58, 72))	('Disruption', 'Var', (0, 10))
198339	27270107	EGFR amplification, which is frequently co-occurrent with EGFR SNVs and EGFRvIII, was observed in 42% of initial tumors (44/104) and 34% of recurrent tumors (35/102), whereas CDK4 amplification was detected in 19% of both initial and recurrent samples (20/104).	('tumors', 'Disease', (150, 156))	('observed', 'Reg', (86, 94))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (0, 4))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('EGFR', 'Gene', '1956', (72, 76))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('EGFR', 'Gene', (72, 76))	('CDK4', 'Gene', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CDK4', 'Gene', '1019', (175, 179))	('EGFR', 'Gene', '1956', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
198340	27270107	Deletions in CDKN2A were the most frequent copy deletion in 47% (49/104) of initial samples and 52% of recurrent tumors (53/102).	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('CDKN2A', 'Gene', (13, 19))	('CDKN2A', 'Gene', '1029', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Deletions', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
198342	27270107	To identify potential tumor suppressors associated to a two-hit mechanism, we analyzed genes with point mutations in regions with LOH in non-hypermutated recurrent tumors.	('tumor', 'Disease', (164, 169))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('point mutations', 'Var', (98, 113))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
198343	27270107	This analysis recapitulated known tumor suppressors in GBM, including TP53 (14/78 samples), PTEN (9/78), and NF1 (3/78), and LOH encompassing inactivating mutations in other genes not previously reported in GBM including APC (R876*) (Supplementary Table 5).	('APC', 'Disease', (221, 224))	('tumor', 'Disease', (34, 39))	('TP53', 'Gene', '7157', (70, 74))	('NF1', 'Gene', (109, 112))	('R876*', 'SUBSTITUTION', 'None', (226, 231))	('PTEN', 'Gene', (92, 96))	('NF1', 'Gene', '4763', (109, 112))	('PTEN', 'Gene', '5728', (92, 96))	('TP53', 'Gene', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('R876*', 'Var', (226, 231))	('APC', 'Disease', 'MESH:D011125', (221, 224))	('LOH', 'Var', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
198344	27270107	We found gene fusions reported as recurrent alterations in GBM, such as FGFR3-TACC3 and EGFR fusions with multiple partners.	('TACC3', 'Gene', (78, 83))	('fusions', 'Var', (93, 100))	('FGFR3', 'Gene', '2261', (72, 77))	('EGFR', 'Gene', '1956', (88, 92))	('TACC3', 'Gene', '10460', (78, 83))	('FGFR3', 'Gene', (72, 77))	('EGFR', 'Gene', (88, 92))
198345	27270107	FGFR3-TACC3 fusions were highly expressed in both the untreated and matched recurrent tumors, thus confirming the clonal nature of these fusion events.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('fusions', 'Var', (12, 19))	('TACC3', 'Gene', '10460', (6, 11))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR3', 'Gene', '2261', (0, 5))
198350	27270107	MGMT is a gene that encodes for an O6-methylguanine-DNA methyltransferase and epigenetic silencing of this gene has been associated with longer overall survival in GBM patients under therapy.	('MGMT', 'Gene', (0, 4))	('overall', 'MPA', (144, 151))	('associated', 'Reg', (121, 131))	('O6-methylguanine-DNA methyltransferase', 'Gene', (35, 73))	('longer', 'PosReg', (137, 143))	('patients', 'Species', '9606', (168, 176))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (35, 73))	('epigenetic silencing', 'Var', (78, 98))	('MGMT', 'Gene', '4255', (0, 4))
198356	27270107	The gain of mutations in the mismatch repair pathway as well as the accompanying hypermutations in glioma patients after treatment has been reported before but the pattern of the hypermutated genes and the mechanism causing the mutations remain unclear.	('gain', 'PosReg', (4, 8))	('mismatch repair pathway', 'Pathway', (29, 52))	('mutations', 'Var', (12, 21))	('glioma', 'Disease', (99, 105))	('patients', 'Species', '9606', (106, 114))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
198357	27270107	To better explain patient mutational variation, we grouped all mutations into four types: those identified in recurrent samples without TMZ, those in untreated tumors, those in TMZ-treated but non-hypermutated cases, and mutations in TMZ-treated hypermutated cases.	('mutations', 'Var', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('TMZ', 'Chemical', 'MESH:D000077204', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('patient', 'Species', '9606', (18, 25))	('untreated tumors', 'Disease', (150, 166))	('untreated tumors', 'Disease', 'MESH:D009369', (150, 166))	('TMZ', 'Chemical', 'MESH:D000077204', (136, 139))	('TMZ', 'Chemical', 'MESH:D000077204', (234, 237))
198358	27270107	Hypermutated recurrent tumors are highly enriched with C>T (G>A) transitions (Figure 2A).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('C>T (G>A', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
198360	27270107	By contrast, a pattern of mutations at CpR elements can be seen in all other tumor types tested.	('CpR', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CpR', 'Gene', '5447', (39, 42))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
198361	27270107	Although we found no significant association in ratios of silent/missense mutations in non-hypermutated tumors, recurrent hypermutated samples contained significantly greater numbers of silent mutations (Figure 2C).	('greater', 'PosReg', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('silent mutations', 'MPA', (186, 202))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('silent/missense mutations', 'Var', (58, 83))
198363	27270107	The number of mutations exclusive to untreated tumors, recurrent tumors, or those in common can be used to describe an evolutionary tree.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('untreated tumors', 'Disease', (37, 53))	('untreated tumors', 'Disease', 'MESH:D009369', (37, 53))	('mutations', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
198366	27270107	Consistent with epidemiological observations and classical models of tumor evolution of Armitage-Doll and Nordling, the number of mutations in the untreated tumor increases with the patient's age at diagnosis (Supplementary Figure 7D, average of 0.6 protein changing mutations per year or 0.02 per Mb-year).	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('patient', 'Species', '9606', (182, 189))	('mutations', 'Var', (267, 276))	('mutations', 'Var', (130, 139))	('protein', 'Protein', (250, 257))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
198380	27270107	As this analysis uses as input the fraction of cells harboring a particular mutation, we estimated the purity of the tumor using ABSOLUTE (Supplementary Table 7) and PyClone (Supplementary Table 8).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PyClone', 'Chemical', '-', (166, 173))	('tumor', 'Disease', (117, 122))	('mutation', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
198381	27270107	The resulting TEDG indicates that mutations in IDH1, PIK3CA and ATRX are early events, mutations in TP53, NF1, and PTEN occur later, and mutations in MSH6 and LTBP4 are relapse-specific events (Figure 3D).	('TP53', 'Gene', (100, 104))	('MSH6', 'Gene', (150, 154))	('LTBP4', 'Gene', '8425', (159, 164))	('mutations', 'Var', (87, 96))	('PTEN', 'Gene', (115, 119))	('IDH1', 'Gene', (47, 51))	('MSH6', 'Gene', '2956', (150, 154))	('TP53', 'Gene', '7157', (100, 104))	('PIK3CA', 'Gene', '5290', (53, 59))	('PTEN', 'Gene', '5728', (115, 119))	('NF1', 'Gene', '4763', (106, 109))	('IDH1', 'Gene', '3417', (47, 51))	('ATRX', 'Gene', (64, 68))	('ATRX', 'Gene', '546', (64, 68))	('mutations', 'Var', (137, 146))	('NF1', 'Gene', (106, 109))	('PIK3CA', 'Gene', (53, 59))	('mutations', 'Var', (34, 43))	('LTBP4', 'Gene', (159, 164))
198387	27270107	An example is patient R005 whose untreated tumor harbors EGFR amplification and the S645C mutation.	('S645C', 'Mutation', 'rs772046081', (84, 89))	('S645C', 'Var', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('patient', 'Species', '9606', (14, 21))	('EGFR', 'Gene', '1956', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('amplification', 'Var', (62, 75))	('tumor', 'Disease', (43, 48))	('EGFR', 'Gene', (57, 61))
198392	27270107	Mutational replacement also occurs in the tumor suppressor TP53 (G105R to R337C in Patient R038, Figure 4C) in EGFR (A1201T to G598V in Patient R065, Figure 4D).	('R337C', 'Mutation', 'rs587782529', (74, 79))	('Patient', 'Species', '9606', (83, 90))	('tumor', 'Disease', (42, 47))	('TP53', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('A1201T', 'Mutation', 'rs369585356', (117, 123))	('EGFR', 'Gene', '1956', (111, 115))	('Patient', 'Species', '9606', (136, 143))	('G598V', 'Mutation', 'rs139236063', (127, 132))	('EGFR', 'Gene', (111, 115))	('G105R', 'Mutation', 'rs1060501195', (65, 70))	('A1201T to G598V', 'Var', (117, 132))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('G105R to R337C', 'Var', (65, 79))	('TP53', 'Gene', '7157', (59, 63))
198394	27270107	The strong association between switching alterations and key driver genes (EGFR, TP53, PDGFRA) suggests (1) some of these genes contribute to a late expansion both with treated and untreated tumors and (2) converging evolution is associated to these genes.	('untreated tumors', 'Disease', (181, 197))	('untreated tumors', 'Disease', 'MESH:D009369', (181, 197))	('PDGFRA', 'Gene', (87, 93))	('TP53', 'Gene', (81, 85))	('PDGFRA', 'Gene', '5156', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('EGFR', 'Gene', '1956', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('EGFR', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (81, 85))	('alterations', 'Var', (41, 52))	('contribute', 'Reg', (128, 138))
198396	27270107	As expected, we found that IDH1 mutated patients are mostly classified as proneural gliomas; EGFR alterations are associated to classical subtype; and NF1 alterations to mesenchymal subtype (Figure 5B).	('EGFR', 'Gene', '1956', (93, 97))	('patients', 'Species', '9606', (40, 48))	('gliomas', 'Disease', (84, 91))	('mutated', 'Var', (32, 39))	('EGFR', 'Gene', (93, 97))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('NF1', 'Gene', (151, 154))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('IDH1', 'Gene', (27, 31))	('NF1', 'Gene', '4763', (151, 154))	('alterations', 'Var', (98, 109))	('IDH1', 'Gene', '3417', (27, 31))	('alterations', 'Reg', (155, 166))
198398	27270107	We found that the gene Latent transforming growth factor beta binding protein 4 (LTBP4) harbors significantly more mutations in recurrent than untreated GBM (Figure 1D, Supplementary Figure 14).	('mutations', 'Var', (115, 124))	('LTBP4', 'Gene', '8425', (81, 86))	('LTBP4', 'Gene', (81, 86))	('Latent transforming growth factor beta binding protein 4', 'Gene', '8425', (23, 79))
198400	27270107	Interestingly, activation of TGF-beta is known to drive aggressiveness of malignant glioma, and we found that high expression of LTBP4 in recurrent tumors is associated with worse prognosis in IDH1-wild-type primary GBM patients (p-value=7x10-3, Figure 6B).	('IDH1', 'Gene', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('LTBP4', 'Gene', '8425', (129, 134))	('LTBP4', 'Gene', (129, 134))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', (29, 37))	('IDH1', 'Gene', '3417', (193, 197))	('patients', 'Species', '9606', (220, 228))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('high expression', 'Var', (110, 125))	('aggressiveness of malignant glioma', 'Disease', 'MESH:D005910', (56, 90))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('aggressiveness', 'Phenotype', 'HP:0000718', (56, 70))	('aggressiveness of malignant glioma', 'Disease', (56, 90))
198401	27270107	Furthermore, mutations of LTBP4 are correlated with higher expression of this gene (p-value<0.05, Figure 6A).	('LTBP4', 'Gene', '8425', (26, 31))	('LTBP4', 'Gene', (26, 31))	('expression', 'MPA', (59, 69))	('higher', 'PosReg', (52, 58))	('mutations', 'Var', (13, 22))
198405	27270107	Conversely, LTBP4 silencing also led to the up-regulation of RhoB and GADD45a, two genes repressed by TGF-beta in glioma (Figures 6E and 6F).	('GADD45a', 'Gene', (70, 77))	('RhoB', 'Gene', (61, 65))	('silencing', 'Var', (18, 27))	('LTBP4', 'Gene', (12, 17))	('glioma', 'Disease', (114, 120))	('LTBP4', 'Gene', '8425', (12, 17))	('GADD45a', 'Gene', '1647', (70, 77))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('TGF-beta', 'Gene', '7040', (102, 110))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('up-regulation', 'PosReg', (44, 57))	('TGF-beta', 'Gene', (102, 110))	('RhoB', 'Gene', '388', (61, 65))
198406	27270107	Consistent with the pro-tumorigenic role of TGF-beta in GBM, LTBP4 silencing markedly impaired proliferation of U87 and U251 glioma cells (Figures 6G and 6H).	('U251', 'CellLine', 'CVCL:0021', (120, 124))	('glioma', 'Disease', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('impaired', 'NegReg', (86, 94))	('tumor', 'Disease', (24, 29))	('LTBP4', 'Gene', '8425', (61, 66))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('LTBP4', 'Gene', (61, 66))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('TGF-beta', 'Gene', '7040', (44, 52))	('silencing', 'Var', (67, 76))	('TGF-beta', 'Gene', (44, 52))	('proliferation', 'CPA', (95, 108))
198408	27270107	Our first observation from this analysis is that, despite 45% of mutations (in non-hypermutated tumors) being shared between diagnosis and relapse samples, the dominant clone at diagnosis is generally not a lineal ancestor of the dominant clone at relapse.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (65, 74))
198414	27270107	Evolutionary dynamics generally appear similar before and after treatment: our mathematical model estimates typical substitution rates of ~0.03 substitutions per Mb per year during both periods, except in the 16% of cases that recur with hypermutated tumors.	('tumors', 'Disease', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('substitutions', 'Var', (144, 157))
198415	27270107	Hypermutated tumors, which are highly enriched for mutations at CpC dinucleotides, harbor mutations in mismatch repair (MMR) genes, most commonly in MSH6, and can exhibit 100-fold higher substitution rates (~3 substitutions per Mb per year).	('mutations', 'Var', (90, 99))	('mutations', 'Var', (51, 60))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('MSH6', 'Gene', (149, 153))	('substitution', 'MPA', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('MMR', 'Gene', (120, 123))	('higher', 'PosReg', (180, 186))	('MSH6', 'Gene', '2956', (149, 153))
198417	27270107	In addition to previously reported mutations in MMR genes in 15% of patients (14/93), we found mutations in the LTBP4 gene in 11% of relapsed tumors (10/93).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('LTBP4', 'Gene', '8425', (112, 117))	('LTBP4', 'Gene', (112, 117))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Disease', (142, 148))	('mutations', 'Var', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
198420	27270107	We have provided both clinical and in vitro evidence that LTBP4 activates this signaling pathway to drive tumor growth: Higher expression of LTBP4 in IDH1 wild-type primary GBM associated to poorer survival (Figure 6B, p-value=7x10-3), and silencing LTBP4 in two different cell lines decreases both proliferation and activity of TGF-beta target genes.	('TGF-beta', 'Gene', '7040', (329, 337))	('LTBP4', 'Gene', (141, 146))	('survival', 'CPA', (198, 206))	('tumor', 'Disease', (106, 111))	('proliferation', 'CPA', (299, 312))	('activity', 'MPA', (317, 325))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('IDH1', 'Gene', (150, 154))	('LTBP4', 'Gene', '8425', (141, 146))	('TGF-beta', 'Gene', (329, 337))	('expression', 'MPA', (127, 137))	('Higher', 'PosReg', (120, 126))	('LTBP4', 'Gene', (250, 255))	('poorer', 'NegReg', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LTBP4', 'Gene', (58, 63))	('silencing', 'Var', (240, 249))	('IDH1', 'Gene', '3417', (150, 154))	('LTBP4', 'Gene', '8425', (250, 255))	('LTBP4', 'Gene', '8425', (58, 63))	('decreases', 'NegReg', (284, 293))
198421	27270107	These results are consistent with recent animal studies showing that TGF-beta inhibitors reduce viability and invasion of gliomas and advance the case for these molecules as potential anti-tumor therapeutics.	('tumor', 'Disease', (189, 194))	('TGF-beta', 'Gene', (69, 77))	('inhibitors', 'Var', (78, 88))	('viability', 'CPA', (96, 105))	('reduce', 'NegReg', (89, 95))	('TGF-beta', 'Gene', '7040', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('gliomas', 'Disease', (122, 129))	('invasion', 'CPA', (110, 118))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
198429	27270107	Three cases had a history of lower grade astrocytoma prior to the first GBM (R022/R027/R029).	('astrocytoma', 'Disease', (41, 52))	('R022/R027/R029', 'Var', (77, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('astrocytoma', 'Disease', 'MESH:D001254', (41, 52))
198437	27270107	Initial tumors from R076-R078/R098/R105/R114 were secondary GBM, with history of low-grade gliomas.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('low-grade', 'Disease', (81, 90))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('R076-R078/R098/R105/R114', 'Var', (20, 44))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
198438	27270107	Patient R103 had cervical cancer three years prior to the first diagnosis of GBM.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('R103', 'Var', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Patient', 'Species', '9606', (0, 7))
198439	27270107	Genomic DNA from initial tumor/recurrent tumor/matched normal blood of patients R001-R016, and recurrent tumor of patients R017-R019 were extracted purified, quantitated, fragmented, quality controlled and used to create a library of genomic DNA fragments.	('R017-R019', 'Var', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (41, 46))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('R001-R016', 'Var', (80, 89))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
198444	27270107	Total RNA depleted of ribosomal RNA of patients R001-R005, R007-R008, R010 and R012 were sequenced by TrueSeq3 stranded prep (Illumina).	('R010', 'Var', (70, 74))	('patients', 'Species', '9606', (39, 47))	('R012', 'Var', (79, 83))	('R007-R008', 'Var', (59, 68))	('R001-R005', 'Var', (48, 57))
198449	27270107	SAVI2 was able to assess mutations by simultaneously considering multiple tumor samples, as well their corresponding RNA samples if available.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
198452	27270107	Tumor DNA of Patient R083-R093, R102, R111-R114 were not complete.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('R083-R093', 'Var', (21, 30))	('R111-R114', 'Var', (38, 47))	('R102', 'Var', (32, 36))	('Patient', 'Species', '9606', (13, 20))
198469	27270107	In hypermutated cases, we only considered mutations of MSH6 and LTBP4.	('MSH6', 'Gene', (55, 59))	('LTBP4', 'Gene', '8425', (64, 69))	('MSH6', 'Gene', '2956', (55, 59))	('LTBP4', 'Gene', (64, 69))	('mutations', 'Var', (42, 51))
198470	27270107	A mutation that was predicted to be clonal (cellular fraction>0.8) in both initial tumor and recurrent tumor was defined as an early event, while a mutation that was only present (variant allele fraction>5%) in one sample was defined as a late event.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutation', 'Var', (2, 10))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
198472	27270107	Using CancerScan, we found that no read reported the variant in the sample where it was deemed absent by WES (Supplementary Table 12), median CancerScan depth 563 [217-1377].	('variant', 'Var', (53, 60))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cancer', 'Disease', (6, 12))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', (142, 148))	('Cancer', 'Disease', 'MESH:D009369', (6, 12))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))
198588	23026359	Furthermore, single-photon emission computed tomography (SPECT) has been applied using radioiodinated amino acids such as l-3[123I]iodo-alpha-methyl tyrosine (IMT) or p-[123I]iodo-l-phenylalanine.	('l-3[123I', 'Var', (122, 130))	('IMT', 'Chemical', 'MESH:C030855', (159, 162))	('l-3[123I]iodo-alpha-methyl tyrosine', 'Chemical', 'MESH:C030855', (122, 157))	('p-[123I]iodo-l-phenylalanine', 'Var', (167, 195))	('p-[123I]iodo-l-phenylalanine', 'Chemical', 'MESH:C049181', (167, 195))
198589	23026359	As it is beyond the scope of this review to consider all radiolabeled amino acids applied in brain tumors, this chapter is focused on the clinical experiences with 11C-MET, 18F-FET, and 123I-IMT, which are at present the best validated amino acid tracers for PET and SPECT.	('123I-IMT', 'Var', (186, 194))	('brain tumors', 'Disease', (93, 105))	('brain tumor', 'Phenotype', 'HP:0030692', (93, 104))	('11C-MET', 'Var', (164, 171))	('IMT', 'Chemical', 'MESH:C030855', (191, 194))	('11C-MET', 'Chemical', '-', (164, 171))	('brain tumors', 'Phenotype', 'HP:0030692', (93, 105))	('brain tumors', 'Disease', 'MESH:D001932', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
198590	23026359	The increased uptake of 11C-MET, 18F-FET, and 123I-IMT by cerebral glioma tissue appears to be caused almost entirely by increased transport via specific amino acid transporters, namely amino acid transport system L for large neutral amino acids.	('IMT', 'Chemical', 'MESH:C030855', (51, 54))	('123I-IMT', 'Var', (46, 54))	('cerebral glioma', 'Disease', 'MESH:C564230', (58, 73))	('increased', 'PosReg', (121, 130))	('11C-MET', 'Var', (24, 31))	('transport', 'MPA', (131, 140))	('11C-MET', 'Chemical', '-', (24, 31))	('18F-FET', 'Var', (33, 40))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('increased', 'PosReg', (4, 13))	('cerebral glioma', 'Disease', (58, 73))	('uptake', 'MPA', (14, 20))
198600	23026359	A recent study demonstrated that integrating 11C-MET-PET into the image-guided resection of HGG provided a final target contour different from that obtained with MRI alone in approximately 80% of the procedures.	('HGG', 'Disease', (92, 95))	('11C-MET', 'Chemical', '-', (45, 52))	('11C-MET-PET', 'Var', (45, 56))
198603	23026359	These data indicate that resection of malignant gliomas guided by amino acid PET may increase the amount of anaplastic tissue removed and thus the patient's survival.	('malignant gliomas', 'Disease', (38, 55))	('survival', 'CPA', (157, 165))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('patient', 'Species', '9606', (147, 154))	('malignant gliomas', 'Disease', 'MESH:D005910', (38, 55))	('amino acid PET', 'Var', (66, 80))	('increase', 'PosReg', (85, 93))
198618	23026359	The sensitivity of 11C-MET-PET for tumor recurrence is similar, whereas the specificity appears to be lower and has been reported to be in the range of 60%-80%.	('lower', 'NegReg', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('11C-MET-PET', 'Var', (19, 30))	('11C-MET', 'Chemical', '-', (19, 26))	('tumor', 'Disease', (35, 40))	('specificity', 'MPA', (76, 87))
198621	23026359	The feasibility and usefulness of 11C-MET and 18F-FET-PET for therapy assessment and follow-up after surgery, chemotherapy, and radiotherapy have been demonstrated in several studies.	('11C-MET', 'Var', (34, 41))	('11C-MET', 'Chemical', '-', (34, 41))	('18F-FET-PET', 'Gene', (46, 57))
198625	23026359	A reliable monitoring of chemotherapy could also be demonstrated with 11C-MET and 18F-FET-PET in recurrent glioblastoma during standard chemotherapy with TMZ, as well as in some experimental therapeutic approaches, such as radioimmunotherapy, convection-enhanced delivery of paclitaxel, and chemotherapy with bevacizumab and irinotecan.	('paclitaxel', 'Chemical', 'MESH:D017239', (275, 285))	('18F-FET-PET', 'Var', (82, 93))	('11C-MET', 'Var', (70, 77))	('irinotecan', 'Chemical', 'MESH:D000077146', (325, 335))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('glioblastoma', 'Disease', (107, 119))	('TMZ', 'Chemical', 'MESH:D000077204', (154, 157))	('11C-MET', 'Chemical', '-', (70, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('bevacizumab', 'Chemical', 'MESH:D000068258', (309, 320))
198644	23026359	Phosphorylated FLT strongly correlates with thymidine incorporation into DNA, as has been demonstrated in various tumor models, including 2 glioma cell lines.	('Phosphorylated', 'Var', (0, 14))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('thymidine incorporation into DNA', 'MPA', (44, 76))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('correlates', 'Reg', (28, 38))	('tumor', 'Disease', (114, 119))	('FLT', 'Gene', (15, 18))	('glioma', 'Disease', (140, 146))	('thymidine', 'Chemical', 'MESH:D013936', (44, 53))	('FLT', 'Chemical', 'MESH:C002854', (15, 18))
198661	23026359	The sensitivity for tumor detection was lower for FLT than 11C-MET, 78% versus 91%, respectively.	('FLT', 'Chemical', 'MESH:C002854', (50, 53))	('FLT', 'Var', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('11C-MET', 'Chemical', '-', (59, 66))	('tumor', 'Disease', (20, 25))	('lower', 'NegReg', (40, 45))
198691	23026359	In an extension of this pilot study, it was found that changes in FLT uptake are important in determining metabolic response, not the absolute value.	('FLT', 'Chemical', 'MESH:C002854', (66, 69))	('metabolic response', 'CPA', (106, 124))	('changes', 'Var', (55, 62))	('FLT uptake', 'MPA', (66, 76))
198693	23026359	There was excellent correlation between influx rate Ki and SUV75% (comprising all voxels in the tumor between 75% and 100% of the maximum).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('SUV75', 'Var', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('influx', 'MPA', (40, 46))
198716	23026359	The use of perfusion agents for diagnosis of brain tumors is based on early experience with 99mTc-hexametazime (Hm-PAO) and 99mTc-ethylcysteinate dimer (ECD), but impact has been limited by variability of results and poor relation to tumor grade.	('99mTc-ethylcysteinate', 'Var', (124, 145))	('tumor', 'Disease', (234, 239))	('Hm-PAO', 'Chemical', 'MESH:C068296', (112, 118))	('brain tumor', 'Phenotype', 'HP:0030692', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('brain tumors', 'Disease', 'MESH:D001932', (45, 57))	('hexametazime', 'Chemical', '-', (98, 110))	('brain tumors', 'Phenotype', 'HP:0030692', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('ethylcysteinate', 'Chemical', '-', (130, 145))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('ECD', 'Disease', 'MESH:C574275', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('brain tumors', 'Disease', (45, 57))	('ECD', 'Disease', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
198730	23026359	The tracer also appears to be useful for imaging of brain metastasis, where T/N ratios were, on average, higher for 11C-choline (6.6) compared with 11C-METhionine (1.5).	('11C-choline', 'Var', (116, 127))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('higher', 'PosReg', (105, 111))	('brain metastasis', 'Disease', (52, 68))	('11C-METhionine', 'Chemical', '-', (148, 162))	('T/N ratios', 'MPA', (76, 86))	('11C-choline', 'Chemical', '-', (116, 127))	('brain metastasis', 'Disease', 'MESH:D009362', (52, 68))
198739	23026359	Although FDG and most amino acids are transported across the intact BBB by transporter enzymes, the uptake of most other tracers in brain tumors depends on the disruption of the BBB, similar to contrast enhancement on CT and MRI.	('BBB', 'Protein', (178, 181))	('brain tumors', 'Disease', (132, 144))	('disruption', 'Var', (160, 170))	('brain tumor', 'Phenotype', 'HP:0030692', (132, 143))	('FDG', 'Chemical', 'MESH:D019788', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('brain tumors', 'Phenotype', 'HP:0030692', (132, 144))	('uptake', 'MPA', (100, 106))	('brain tumors', 'Disease', 'MESH:D001932', (132, 144))
198866	17047653	P1 promoter controls the TAp73 transcripts containing exons 1-3 that encode N-terminal sequences with transactivatory activity (TA), and DeltaEx2, DeltaEx2-3 and DeltaN' transcripts collectively designate DeltaTAp73 that lack a fully competent TA domain (Stiewe et al, 2002a, 2002b).	('p73', 'Gene', (27, 30))	('p73', 'Gene', (212, 215))	('DeltaEx2-3', 'Var', (147, 157))	('DeltaEx2', 'Var', (137, 145))	('p73', 'Gene', '7161', (27, 30))	('p73', 'Gene', '7161', (212, 215))
198897	17047653	The forward primers for DeltaEx2p73 as well as for DeltaEx2-3p73 were designed to specifically recognise on the exon-exon boundaries (exon1/exon3 for DeltaEx2p73 and exon1/exon4 for DeltaEx2-3p73).	('exon1/exon4', 'Var', (166, 177))	('p73', 'Gene', (61, 64))	('p73', 'Gene', '7161', (32, 35))	('p73', 'Gene', '7161', (192, 195))	('p73', 'Gene', (32, 35))	('p73', 'Gene', '7161', (158, 161))	('p73', 'Gene', '7161', (61, 64))	('p73', 'Gene', (158, 161))	('p73', 'Gene', (192, 195))
198912	17047653	Because no significant difference was found in P1-p73 transcript expression between high- and low-grade tumours, deregulation of the P1 promoter that generates the TAp73 and DeltaTAp73 isoforms was likely to occur early in the tumorigenic process.	('p73', 'Gene', (181, 184))	('p73', 'Gene', '7161', (166, 169))	('low-grade tumours', 'Disease', (94, 111))	('p73', 'Gene', (166, 169))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('low-grade tumours', 'Disease', 'MESH:D008228', (94, 111))	('p73', 'Gene', '7161', (50, 53))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('p73', 'Gene', (50, 53))	('deregulation', 'Var', (113, 125))	('p73', 'Gene', '7161', (181, 184))
198933	17047653	In multivariate analysis including age and DeltaEx2-3p7 expression, age is a significant prognostic factor (P=0.017) and a trend is observed for DeltaEx2-3p73 (P=0.070).	('p73', 'Gene', '7161', (155, 158))	('DeltaEx2-3p7 expression', 'Var', (43, 66))	('p73', 'Gene', (155, 158))
198945	17047653	Thus, deregulation of the P1 promoter and emergence of particular RNA populations are likely to be an early event as this deregulation is likewise observed in high-grade gliomas and could possibly influence cell evolution toward malignancy.	('deregulation', 'Var', (6, 18))	('influence', 'Reg', (197, 206))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('gliomas', 'Disease', (170, 177))	('malignancy', 'Disease', 'MESH:D009369', (229, 239))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('malignancy', 'Disease', (229, 239))
199045	32524393	A significantly lower extent of resection was achieved in bilingual patients in comparison to monolingual patients (64.8% vs 80.9%, respectively) (P = 0.04), with a significantly higher post-operative residual tumor volume in bilingual patients in comparison to the monolingual patients (13.5 vs 8.1 cm3, respectively) (P = 0.03) (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('patients', 'Species', '9606', (236, 244))	('tumor', 'Disease', (210, 215))	('patients', 'Species', '9606', (68, 76))	('bilingual', 'Var', (226, 235))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (278, 286))	('higher', 'PosReg', (179, 185))	('lower', 'NegReg', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
199137	19841428	Traditional karyotype analysis has been unrevealing in multiple studies, with chromosome 7 gain the only consistent finding, but present in a minority of tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('chromosome', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('gain', 'PosReg', (91, 95))
199140	19841428	The 7q34 duplication involves a known oncogene, BRAF, and appears to result in upregulation of the RAS/RAF/MEK pathway (Figure 5).	('RAF', 'Gene', '22882', (49, 52))	('upregulation', 'PosReg', (79, 91))	('RAF', 'Gene', '22882', (103, 106))	('RAF', 'Gene', (49, 52))	('RAF', 'Gene', (103, 106))	('MEK', 'Gene', (107, 110))	('7q34 duplication', 'Var', (4, 20))	('MEK', 'Gene', '5609', (107, 110))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
199144	19841428	For example, adult low-grade gliomas show frequent TP53 mutations, present in up to 88% of gemistocytic and 53% of diffuse fibrillary astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (134, 146))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('astrocytomas', 'Disease', (134, 146))	('gliomas', 'Disease', (29, 36))	('fibrillary astrocytoma', 'Disease', (123, 145))	('fibrillary astrocytoma', 'Disease', 'MESH:D001254', (123, 145))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('gemistocytic', 'Disease', (91, 103))	('TP53', 'Gene', '7157', (51, 55))
199145	19841428	TP53 mutations in children appear to be restricted to 5% to 10% of low-grade gliomas that undergo malignant transformation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('children', 'Species', '9606', (18, 26))	('gliomas', 'Disease', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('mutations', 'Var', (5, 14))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
199146	19841428	Loss of heterozygosity of chromosomes 1p36 and 19q13, and in particular codeletion at both loci, is a favorable prognostic factor in adults with oligodendrogliomas (WHO grade 2) but has not been replicated in pediatric tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('pediatric tumors', 'Disease', 'MESH:D063766', (209, 225))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (145, 163))	('pediatric tumors', 'Disease', (209, 225))	('Loss', 'Var', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('oligodendrogliomas', 'Disease', (145, 163))
199148	19841428	The neurofibromatosis type 1 model shows that inactivation of the tumor suppressor neurofibromin results in upregulation of the RAS family of proteins, involved in a number of oncogenic signal transduction pathways in astrocytes.	('neurofibromin', 'Gene', '4763', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('neurofibromatosis type 1', 'Gene', '4763', (4, 28))	('tumor', 'Disease', (66, 71))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (4, 21))	('neurofibromin', 'Gene', (83, 96))	('neurofibromatosis type 1', 'Gene', (4, 28))	('inactivation', 'Var', (46, 58))	('RAS family of proteins', 'Protein', (128, 150))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('upregulation', 'PosReg', (108, 120))
199149	19841428	Mutations in 1 of 2 tumor suppressor genes, TSC1 and TSC2, result in tuberous sclerosis syndrome.	('TSC1', 'Gene', '7248', (44, 48))	('tuberous sclerosis syndrome', 'Disease', (69, 96))	('TSC1', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Mutations', 'Var', (0, 9))	('TSC2', 'Gene', '7249', (53, 57))	('tuberous sclerosis syndrome', 'Disease', 'MESH:D014402', (69, 96))	('result in', 'Reg', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TSC2', 'Gene', (53, 57))	('tumor', 'Disease', (20, 25))
199233	19841428	Therefore, even in the absence of radiotherapy, parents of children with low-grade gliomas must be properly counseled not only on the risk of tumor progression or recurrence but also the risk of neurocognitive and behavioral impairments.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('low-grade', 'Var', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('behavioral impairments', 'Disease', (214, 236))	('behavioral impairments', 'Phenotype', 'HP:0000708', (214, 236))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('children', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('behavioral impairments', 'Disease', 'MESH:D001523', (214, 236))
199264	18949365	Specimens were pre-weighed and transferred to a ZrO2 rotor tube (4 mm diameter, 50 mul), containing an external standard [trimethylsilyl propionic-2,2,3,3-d4 acid (TSP), Mw=172, d=0.00 ppm] that functioned as a reference both for both resonance chemical shift and quantification.	('Mw=172', 'Var', (170, 176))	('trimethylsilyl propionic-2,2,3,3-d4 acid', 'Chemical', '-', (122, 162))	('TSP', 'Gene', '83592', (164, 167))	('ZrO2', 'Chemical', '-', (48, 52))	('TSP', 'Gene', (164, 167))
199278	18949365	Similarly, for sub-typing metastases, more features increased the sensitivity but did not necessarily improve the other metrics.	('increased', 'PosReg', (52, 61))	('sensitivity', 'MPA', (66, 77))	('metastases', 'Disease', (26, 36))	('sub-typing', 'Var', (15, 25))	('metastases', 'Disease', 'MESH:D009362', (26, 36))
199302	18949365	Gln and Asp were the most significant features of pilocytic astrocytomas (an often difficult to diagnose tumor) and metastases, respectively.	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Asp', 'Chemical', 'MESH:D001224', (8, 11))	('metastases', 'Disease', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Gln', 'Var', (0, 3))	('pilocytic astrocytomas', 'Disease', (50, 72))	('tumor', 'Disease', (105, 110))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (50, 72))
199321	31167546	Taken together, these findings propose the 4-gene signature as a novel panel of efficacy predictors of TMZ therapy, as well as potential downstream mechanisms, including homologous recombination, OR51F2, and DNA methylation independent of MGMT.	('TMZ', 'Chemical', 'MESH:D000077204', (103, 106))	('DNA methylation', 'Var', (208, 223))	('MGMT', 'Gene', (239, 243))	('OR51F2', 'Gene', (196, 202))	('MGMT', 'Gene', '4255', (239, 243))	('OR51F2', 'Gene', '119694', (196, 202))
199330	31167546	Molecular characterizations have enabled grouping LGGs into 3 subtypes based on mutation status of IDH1 and IDH2.	('IDH2', 'Gene', '3418', (108, 112))	('mutation status', 'Var', (80, 95))	('LGGs', 'Disease', (50, 54))	('IDH1', 'Gene', (99, 103))	('IDH2', 'Gene', (108, 112))	('IDH1', 'Gene', '3417', (99, 103))
199331	31167546	Low-grade gliomas with a mutated IDH1/2 can harbor 1p/19q codeletion, showing mutations in CIC, NOTCH1, FUBP1, and TERT promoter, and display the most favorable clinical outcome.	('TERT', 'Gene', '7015', (115, 119))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('IDH1/2', 'Gene', (33, 39))	('CIC', 'Gene', '23152', (91, 94))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('FUBP1', 'Gene', '8880', (104, 109))	('CIC', 'Gene', (91, 94))	('mutations', 'Var', (78, 87))	('NOTCH1', 'Gene', '4851', (96, 102))	('NOTCH1', 'Gene', (96, 102))	('gliomas', 'Disease', (10, 17))	('mutated', 'Var', (25, 32))	('FUBP1', 'Gene', (104, 109))	('TERT', 'Gene', (115, 119))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
199332	31167546	The IDH1/2-mutant LGGs lacking 1p/19q codeletion mostly harbor TP53 mutation (94%) and ATRX inactivation (86).	('TP53', 'Gene', '7157', (63, 67))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', (63, 67))	('ATRX', 'Gene', (87, 91))	('ATRX', 'Gene', '546', (87, 91))	('harbor', 'Reg', (56, 62))
199333	31167546	On the other hand, the majority of LGGs without an IDH1/2 mutation showed highly similar molecular and clinical behavior to those of primary glioblastoma, a major form of HGG, and therefore exhibit the least favorable outcome.	('primary glioblastoma', 'Disease', (133, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('LGGs', 'Disease', (35, 39))	('mutation', 'Var', (58, 66))	('primary glioblastoma', 'Disease', 'MESH:D005909', (133, 153))	('IDH1/2', 'Gene', (51, 57))
199338	31167546	First introduced as a radiosensitizer, to date TMZ is the most effective first-line chemotherapy option for glioblastomas, and has been shown to elicit response in other tumors such as melanomas, pituitary tumors, and lung cancers.	('lung cancers', 'Disease', 'MESH:D008175', (218, 230))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancers', 'Disease', (218, 230))	('elicit', 'Reg', (145, 151))	('glioblastomas', 'Phenotype', 'HP:0012174', (108, 121))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))	('pituitary tumors', 'Disease', 'MESH:D010911', (196, 212))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('lung cancers', 'Phenotype', 'HP:0100526', (218, 230))	('melanomas', 'Disease', (185, 194))	('TMZ', 'Var', (47, 50))	('tumors', 'Disease', (206, 212))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('glioblastomas', 'Disease', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('pituitary tumors', 'Disease', (196, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('glioblastomas', 'Disease', 'MESH:D005909', (108, 121))	('tumors', 'Disease', (170, 176))
199343	31167546	Notably, molecular markers supplementary to IDH1/2 status and 1p/19q codeletion have been reported, including intrinsic glioma subtyping based on gene expression profile and methylation on DNA damage response (DDR) genes MGMT, MLH3, RAD21, and SMC4.	('RAD21', 'Gene', '5885', (233, 238))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('SMC4', 'Gene', '10051', (244, 248))	('MGMT', 'Gene', (221, 225))	('methylation', 'Var', (174, 185))	('MGMT', 'Gene', '4255', (221, 225))	('DDR', 'Gene', (210, 213))	('SMC4', 'Gene', (244, 248))	('MLH3', 'Gene', '27030', (227, 231))	('glioma', 'Disease', (120, 126))	('RAD21', 'Gene', (233, 238))	('MLH3', 'Gene', (227, 231))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
199357	31167546	Instead, cases were screened based on the presence of DFS value, and whether there was new tumor event after initial treatment (new_tumor_event_after_initial_treatment = YES).	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('DFS', 'Var', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
199375	31167546	Starting from miRNA expression data from the same cases used in the previous section, we identified 100 miRNAs significantly associated with Response (through ordinal logistic regression, P < .05), 33 with DFS (through correlation analysis, P < .05), and 112 with OS (through univariate Cox regression, P < .05).	('Cox', 'Gene', '1351', (287, 290))	('Cox', 'Gene', (287, 290))	('OS', 'Chemical', '-', (264, 266))	('Response', 'Disease', (141, 149))	('associated with', 'Reg', (125, 140))	('DFS', 'Var', (206, 209))
199398	31167546	Accordingly, MGMT depletion, either through epigenetic silencing by promoter methylation or use of inhibitor.	('MGMT', 'Gene', '4255', (13, 17))	('epigenetic silencing', 'Var', (44, 64))	('promoter methylation', 'Var', (68, 88))	('MGMT', 'Gene', (13, 17))
199408	31167546	As TMZ induces DNA damage in tumor cells, it is conceivable that response to TMZ can be enhanced by defective DDR.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('DNA damage', 'MPA', (15, 25))	('induces', 'Reg', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (77, 80))	('enhanced', 'PosReg', (88, 96))	('defective', 'Var', (100, 109))	('tumor', 'Disease', (29, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (3, 6))	('response', 'MPA', (65, 73))
199412	31167546	Most of these genes play roles in homologous recombination, either through dissolution of Holliday junction, a key intermediate (eg, RMI1 and EME1), or through repairing DNA double strand breaks (eg, PALB2, BRCA2, and XRCC2).	('XRCC2', 'Gene', '7516', (218, 223))	('EME1', 'Gene', (142, 146))	('PALB2', 'Gene', (200, 205))	('XRCC2', 'Gene', (218, 223))	('repairing', 'Var', (160, 169))	('BRCA2', 'Gene', (207, 212))	('RMI1', 'Gene', '80010', (133, 137))	('RMI1', 'Gene', (133, 137))	('BRCA2', 'Gene', '675', (207, 212))	('EME1', 'Gene', '146956', (142, 146))	('DNA double strand breaks', 'MPA', (170, 194))	('PALB2', 'Gene', '79728', (200, 205))
199415	31167546	While its expression level increased in the high expression group, hypomethylation on OR51F2 was also observed, suggesting a potential role of this G-protein-coupled receptor in bridging the gap between the 4-gene signature and the clinical outcomes of TMZ treatment.	('expression level', 'MPA', (10, 26))	('increased', 'PosReg', (27, 36))	('TMZ', 'Chemical', 'MESH:D000077204', (253, 256))	('OR51F2', 'Gene', (86, 92))	('hypomethylation', 'Var', (67, 82))	('OR51F2', 'Gene', '119694', (86, 92))
199427	31167546	In vitro, cyclin B was reported to mediate cell proliferation inhibition by a number of interventions that target, downregulate, or degrade cyclin B, including microRNA-181, HIF-1alpha silencing, demethoxycurcumin, and flubendazole.	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (196, 213))	('flubendazole', 'Chemical', 'MESH:C018945', (219, 231))	('HIF-1alpha', 'Gene', '3091', (174, 184))	('microRNA-181', 'Var', (160, 172))	('silencing', 'NegReg', (185, 194))	('cell proliferation', 'CPA', (43, 61))	('cyclin', 'Protein', (140, 146))	('degrade', 'NegReg', (132, 139))	('HIF-1alpha', 'Gene', (174, 184))	('downregulate', 'NegReg', (115, 127))
199434	31167546	ASPM silencing led to inefficient repair of DSBs in irradiated glioblastoma cells in a DNA-PK-dependent pathway.	('DSBs', 'Var', (44, 48))	('ASPM', 'Gene', '259266', (0, 4))	('silencing', 'Var', (5, 14))	('glioblastoma', 'Disease', (63, 75))	('DSBs', 'Chemical', 'MESH:C007563', (44, 48))	('ASPM', 'Gene', (0, 4))	('repair', 'MPA', (34, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('inefficient', 'NegReg', (22, 33))
199437	31167546	Double-strand breaks repair through HR has been reported to contribute to TMZ resistance in glioblastoma cells, and was proposed as therapeutic targets in enhancing TMZ efficacy.	('TMZ resistance', 'MPA', (74, 88))	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('contribute', 'Reg', (60, 70))	('Double-strand breaks', 'Var', (0, 20))	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
199439	31167546	Also, silencing of Werner syndrome helicase, a DNA helicase/exonuclease, sensitized glioma cell lines to O-methylguanine adducts in the absence of MGMT activity.	('O-methylguanine', 'Chemical', '-', (105, 120))	('O-methylguanine adducts', 'MPA', (105, 128))	('Werner syndrome', 'Disease', 'MESH:D014898', (19, 34))	('Werner syndrome', 'Disease', (19, 34))	('glioma', 'Disease', (84, 90))	('sensitized', 'Reg', (73, 83))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('MGMT', 'Gene', (147, 151))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('silencing', 'Var', (6, 15))	('MGMT', 'Gene', '4255', (147, 151))
199443	31167546	Olfactory receptor OR51F2 was upregulated in the high expression group while harboring a lower of level of methylation (Figure 9).	('lower', 'NegReg', (89, 94))	('upregulated', 'PosReg', (30, 41))	('OR51F2', 'Gene', (19, 25))	('OR51F2', 'Gene', '119694', (19, 25))	('high expression', 'Var', (49, 64))
199452	31167546	Altogether, these findings propose the 4-gene signature as a novel panel of efficacy predictors of TMZ therapy, as well as potential downstream mechanisms, including homologous recombination, OR51F2, and DNA methylation independent of MGMT.	('DNA methylation', 'Var', (204, 219))	('MGMT', 'Gene', (235, 239))	('OR51F2', 'Gene', (192, 198))	('MGMT', 'Gene', '4255', (235, 239))	('TMZ', 'Chemical', 'MESH:D000077204', (99, 102))	('OR51F2', 'Gene', '119694', (192, 198))
199456	25147764	Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('brain tumors', 'Disease', 'MESH:D001932', (122, 134))	('brain tumors', 'Phenotype', 'HP:0030692', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (128, 133))	('brain tumors', 'Disease', (122, 134))	('focused', 'Reg', (15, 22))	('epigenetic regulation', 'Var', (62, 83))
199470	25147764	The RB and p53 pathways involved in regulation of the G1-to-S-phase transition, are major targets of inactivating mutations in GBM.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('inactivating mutations', 'Var', (101, 123))	('GBM', 'Gene', (127, 130))	('RB', 'Chemical', 'MESH:D012413', (4, 6))
199471	25147764	The Rb1 gene, which maps on chromosome 13q14, is mutated in 25% of HGG and the loss of 13q is characteristic of transition from low-grade to intermediate-grade gliomas.	('HGG', 'Disease', (67, 70))	('loss', 'Var', (79, 83))	('Rb1', 'Gene', '5925', (4, 7))	('low-grade', 'Disease', (128, 137))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('gliomas', 'Disease', (160, 167))	('13q', 'MPA', (87, 90))	('Rb1', 'Gene', (4, 7))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
199472	25147764	The importance of the inactivation of the RB pathway in glioma progression is evidenced by the near-universal and mutually exclusive alteration of RB pathway effectors and inhibitors in both primary and secondary GBM.	('inactivation', 'Var', (22, 34))	('glioma', 'Disease', (56, 62))	('RB pathway', 'Pathway', (42, 52))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('RB', 'Chemical', 'MESH:D012413', (42, 44))	('RB', 'Chemical', 'MESH:D012413', (147, 149))	('alteration', 'Reg', (133, 143))
199473	25147764	However, many in vitro and in vivo assays showed that the neutralization of this pathway alone is insufficient to subvert cell cycle control, thus not sufficient to cause cellular transformation.	('insufficient', 'Disease', 'MESH:D000309', (98, 110))	('subvert', 'NegReg', (114, 121))	('cell', 'MPA', (122, 126))	('insufficient', 'Disease', (98, 110))	('cause', 'Reg', (165, 170))	('neutralization', 'Var', (58, 72))
199475	25147764	The p53 pathway is nearly invariably altered in sporadic (ex novo) GBMs: loss of p53, through either point mutations that prevent DNA binding or loss of chromosome 17p, is a frequent and early event in the pathological progression of secondary GBM.	('p53', 'Gene', '7157', (4, 7))	('loss', 'Var', (73, 77))	('prevent', 'NegReg', (122, 129))	('loss', 'NegReg', (145, 149))	('p53', 'Gene', (81, 84))	('DNA binding', 'Interaction', (130, 141))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (4, 7))	('secondary GBM', 'Disease', (234, 247))	('point mutations', 'Var', (101, 116))
199476	25147764	The importance of p53 in gliomagenesis is also demonstrated by the increased incidence of gliomas in Li-Fraumeni syndrome, which is characterized by germline p53 mutations.	('gliomas', 'Disease', (90, 97))	('mutations', 'Var', (162, 171))	('p53', 'Gene', (18, 21))	('glioma', 'Disease', (90, 96))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (101, 121))	('p53', 'Gene', '7157', (18, 21))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('p53', 'Gene', '7157', (158, 161))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('Li-Fraumeni syndrome', 'Disease', (101, 121))	('p53', 'Gene', (158, 161))	('glioma', 'Disease', (25, 31))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
199477	25147764	Amplification of the p53 antagonists MDM2 and MDM4have also been found in distinct subsets of Tp53 intactGBMs, as well as mutations and/or deletions inthe CDKN2A second locus that encodes p14ARF which is a regulator of p53.	('MDM2', 'Gene', (37, 41))	('p53', 'Gene', '7157', (95, 98))	('found', 'Reg', (65, 70))	('deletions', 'Var', (139, 148))	('CDKN2A', 'Gene', '1029', (155, 161))	('MDM2', 'Gene', '4193', (37, 41))	('p14ARF', 'Gene', (188, 194))	('MDM4', 'Gene', '4194', (46, 50))	('p53', 'Gene', (95, 98))	('MDM4', 'Gene', (46, 50))	('p53', 'Gene', '7157', (21, 24))	('Tp53', 'Gene', (94, 98))	('p53', 'Gene', (21, 24))	('p53', 'Gene', '7157', (219, 222))	('p53', 'Gene', (219, 222))	('mutations', 'Var', (122, 131))	('p14ARF', 'Gene', '1029', (188, 194))	('CDKN2A', 'Gene', (155, 161))	('Tp53', 'Gene', '7157', (94, 98))
199482	25147764	Approximately 40% of GBMs shows EGFR gene amplification and overexpression.Amplification of the EGFR gene is often associated with a mutation that encodes for a truncated form of the receptor, known as EGFR variant vIII (EGFRvIII), lacking the extracellular binding domain and leading to constitutive activation of tyrosine kinases.	('EGFR', 'Gene', (202, 206))	('vIII', 'Gene', (225, 229))	('EGFR', 'Gene', '1956', (221, 225))	('vIII', 'Gene', (215, 219))	('EGFR', 'Gene', (96, 100))	('vIII', 'Gene', '1351', (225, 229))	('EGFR', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (202, 206))	('lacking', 'NegReg', (232, 239))	('extracellular', 'MPA', (244, 257))	('activation', 'PosReg', (301, 311))	('vIII', 'Gene', '1351', (215, 219))	('associated', 'Reg', (115, 125))	('overexpression.Amplification', 'Var', (60, 88))	('EGFR', 'Gene', (221, 225))	('EGFR', 'Gene', '1956', (96, 100))	('mutation', 'Var', (133, 141))	('EGFR', 'Gene', '1956', (32, 36))	('tyrosine kinases', 'MPA', (315, 331))
199490	25147764	In contrast to the pathway of EGFR; amplification or rearrangement of PDGFRalpha is a less common event.	('EGFR', 'Gene', (30, 34))	('PDGFRalpha', 'Gene', '5156', (70, 80))	('PDGFRalpha', 'Gene', (70, 80))	('amplification', 'Var', (36, 49))	('EGFR', 'Gene', '1956', (30, 34))	('rearrangement', 'Var', (53, 66))
199491	25147764	This justifies that oncogenic deletion mutation of PDGFRalpha (loss of exons 8 and 9) have been rarely described.	('PDGFRalpha', 'Gene', (51, 61))	('deletion', 'Var', (30, 38))	('loss', 'NegReg', (63, 67))	('PDGFRalpha', 'Gene', '5156', (51, 61))
199514	25147764	Moreover, anti-angiogenic therapy showed to produce a more invasive and aggressive tumor cell phenotype, including increased expression of other proangiogenic factors, upregulation of pro-invasion proteins such as matrix metalloproteinases, activation of proinvasive signaling pathway such as the phosphatidylinositol 3-kinase (PI3K)- and Wnt-signaling pathways.	('more', 'PosReg', (54, 58))	('proinvasive signaling pathway', 'Pathway', (255, 284))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('increased', 'PosReg', (115, 124))	('pro-invasion', 'CPA', (184, 196))	('aggressive tumor', 'Disease', 'MESH:D001523', (72, 88))	('expression', 'MPA', (125, 135))	('activation', 'PosReg', (241, 251))	('upregulation', 'PosReg', (168, 180))	('invasive', 'CPA', (59, 67))	('aggressive tumor', 'Disease', (72, 88))	('anti-angiogenic', 'Var', (10, 25))
199520	25147764	Conversely, patients with a methylated MGMT promoter do not generate the protein and, therefore, are more sensitive to TMZ therapy, particularly if combined with radiation.	('patients', 'Species', '9606', (12, 20))	('methylated', 'Var', (28, 38))	('not', 'NegReg', (56, 59))	('sensitive', 'MPA', (106, 115))	('MGMT', 'Gene', (39, 43))	('generate', 'MPA', (60, 68))	('MGMT', 'Gene', '4255', (39, 43))	('more', 'PosReg', (101, 105))	('TMZ', 'Chemical', '-', (119, 122))
199521	25147764	The recognition that this specific epigenetic modification dramatically alters the potency of a commonly used chemotherapeutic was an important assumption, as it allows a patient-tailored treatment.	('epigenetic modification', 'Var', (35, 58))	('alters', 'Reg', (72, 78))	('patient', 'Species', '9606', (171, 178))	('potency of', 'MPA', (83, 93))
199525	25147764	Recently, missense mutations in isocitrate dehydrogenase 1 (IDH1) were found in a significant number of GBMs that tend to occur mostly in younger patients with more protracted clinical courses.	('occur', 'Reg', (122, 127))	('isocitrate dehydrogenase 1', 'Gene', '3417', (32, 58))	('isocitrate dehydrogenase 1', 'Gene', (32, 58))	('IDH1', 'Gene', (60, 64))	('found', 'Reg', (71, 76))	('missense mutations', 'Var', (10, 28))	('GBMs', 'Disease', (104, 108))	('patients', 'Species', '9606', (146, 154))
199526	25147764	These point mutations are restricted exclusively to the R132 residue in the active site region of the protein in which they disrupt hydrogen binding with its substrate.	('disrupt', 'NegReg', (124, 131))	('hydrogen binding', 'MPA', (132, 148))	('hydrogen', 'Chemical', 'MESH:D006859', (132, 140))	('R132', 'Var', (56, 60))
199527	25147764	Curiously, a separate group of gliomas harbour mutations in the IDH1 homologue IDH2 at the analogous residue (R172).	('IDH2', 'Gene', '3418', (79, 83))	('mutations', 'Var', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH2', 'Gene', (79, 83))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
199528	25147764	Further investigations have shown that mutations in IDH1 and IDH2 are present in high proportions of grade II and III astrocytic and oligodendroglial tumours (72-100%) along with secondary GBMs (85%), but are largely absent in primary GBMs (5%).	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('grade II', 'Disease', (101, 109))	('IDH2', 'Gene', (61, 65))	('mutations', 'Var', (39, 48))	('astrocytic and oligodendroglial tumours', 'Disease', 'MESH:D001254', (118, 157))	('IDH2', 'Gene', '3418', (61, 65))	('IDH1', 'Gene', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
199529	25147764	Additionally, IDH mutations are associated with other genomic abnormalities that are typically seen in LGG, such as Tp53 mutation and 1p/19q deletion; they are also mutually exclusive with EGFR amplification and chromosome 10 loss, and multivariate analysis suggests that they are independent favourable prognostic markers.	('EGFR', 'Gene', '1956', (189, 193))	('IDH', 'Gene', (14, 17))	('LGG', 'Disease', (103, 106))	('IDH', 'Gene', '3417', (14, 17))	('EGFR', 'Gene', (189, 193))	('Tp53', 'Gene', '7157', (116, 120))	('mutation', 'Var', (121, 129))	('associated', 'Reg', (32, 42))	('loss', 'NegReg', (226, 230))	('Tp53', 'Gene', (116, 120))	('1p/19q deletion', 'Var', (134, 149))	('mutations', 'Var', (18, 27))
199530	25147764	These findings suggest that, although IDH mutations probably contribute to the early evolution of LGG (including those that subsequently progress to higher grade lesions), they seem to have no role in the underlying biology of ex novo GBM.	('contribute', 'Reg', (61, 71))	('IDH', 'Gene', (38, 41))	('IDH', 'Gene', '3417', (38, 41))	('mutations', 'Var', (42, 51))	('LGG', 'Disease', (98, 101))
199531	25147764	The mechanisms related to mutations in IDH genes and the induction of gliomagenesis are still largely unknown.	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('mutations', 'Var', (26, 35))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', '3417', (39, 42))
199532	25147764	However, a recent study demonstrated that loss of IDH1 function through point mutation induces hypoxia inducible factor 1alpha (HIF1alpha).	('hypoxia inducible factor 1alpha', 'Gene', (95, 126))	('IDH1', 'Gene', (50, 54))	('point mutation', 'Var', (72, 86))	('HIF1alpha', 'Gene', '3091', (128, 137))	('function', 'MPA', (55, 63))	('induces', 'Reg', (87, 94))	('hypoxia inducible factor 1alpha', 'Gene', '3091', (95, 126))	('HIF1alpha', 'Gene', (128, 137))	('loss', 'NegReg', (42, 46))
199534	25147764	By contrast, another recent report has shown that mutant IDH1 proteins exhibit a gain-of-function phenotype by generating R-2-hydroxyglutarate (2HG), a toxic metabolite associated with an increased risk of malignant brain tumours in patients with inherited errors of 2HG metabolism.	('proteins', 'Protein', (62, 70))	('tumours', 'Phenotype', 'HP:0002664', (222, 229))	('IDH1', 'Gene', (57, 61))	('gain-of-function', 'PosReg', (81, 97))	('R-2-hydroxyglutarate', 'Chemical', '-', (122, 142))	('mutant', 'Var', (50, 56))	('R-2-hydroxyglutarate', 'MPA', (122, 142))	('brain tumours', 'Phenotype', 'HP:0030692', (216, 229))	('malignant brain tumours', 'Disease', (206, 229))	('malignant brain tumours', 'Disease', 'MESH:D001932', (206, 229))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('patients', 'Species', '9606', (233, 241))
199535	25147764	Although much remains to be analyzed, the identification of IDH mutations in diffuse gliomas, and more recently in acute myeloid leukaemia, provided new potential therapeutic targets and emphasized the increasingly compelling link between cancer biology and basic metabolic processes.	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (115, 138))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (121, 138))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('gliomas', 'Disease', (85, 92))	('cancer', 'Disease', (239, 245))	('IDH', 'Gene', (60, 63))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('mutations', 'Var', (64, 73))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (115, 138))	('IDH', 'Gene', '3417', (60, 63))	('acute myeloid leukaemia', 'Disease', (115, 138))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
199541	25147764	More recently, the NADP+ -dependent enzyme IDH1 was found to be mutated in ~70% of grade II and grade III astrocytomas and oligodendrogliomas, and secondary GBMs.	('astrocytomas', 'Disease', 'MESH:D001254', (106, 118))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (123, 141))	('astrocytomas', 'Disease', (106, 118))	('IDH1', 'Gene', (43, 47))	('mutated', 'Var', (64, 71))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('oligodendrogliomas', 'Disease', (123, 141))	('NADP', 'Chemical', 'MESH:D009249', (19, 23))
199542	25147764	How mutations in IDH1 result in DNA methylation in gliomas is not entirely known.	('DNA methylation', 'MPA', (32, 47))	('gliomas', 'Disease', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('IDH1', 'Gene', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('mutations', 'Var', (4, 13))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('result', 'Reg', (22, 28))
199543	25147764	3) is that mutant IDH1 catalyzes the production of 2-hydroxyglutarate (2-HG) from a-ketoglutarate (a-KG).	('mutant', 'Var', (11, 17))	('a-ketoglutarate', 'Chemical', '-', (82, 97))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (51, 69))	('production of 2-hydroxyglutarate', 'MPA', (37, 69))	('IDH1', 'Gene', (18, 22))	('2-HG', 'Chemical', 'MESH:C019417', (71, 75))
199549	25147764	Treatment of an oligodendroglioma cell line harboring an endogenous IDH1-R132H mutation with this inhibitor reduced growth in soft agar by 40%-60% and impeded the growth of xenograft tumors derived from that cell line in mice.	('reduced', 'NegReg', (108, 115))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('xenograft tumors', 'Disease', 'MESH:D009369', (173, 189))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('impeded', 'NegReg', (151, 158))	('mice', 'Species', '10090', (221, 225))	('mutation', 'Var', (79, 87))	('IDH1-R132H', 'Gene', (68, 78))	('oligodendroglioma', 'Disease', (16, 33))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('growth in soft agar', 'MPA', (116, 135))	('agar', 'Chemical', 'MESH:D000362', (131, 135))	('oligodendroglioma', 'Disease', 'MESH:D009837', (16, 33))	('xenograft tumors', 'Disease', (173, 189))
199551	25147764	This study demonstrated that, in this model, targeting mutant IDH1 can impair glioma growth in vivo and this growth inhibition is linked to changes in differentiation.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioma', 'Disease', (78, 84))	('targeting mutant', 'Var', (45, 61))	('IDH1', 'Gene', (62, 66))	('impair', 'NegReg', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
199564	22390413	When examined by qMSP, 26% of low-grade and 37% of high-grade gliomas were found to be methylated, whereas 97% of low-grade and 55% of high-grade gliomas were found methylated by pyrosequencing.	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('methylated', 'Var', (87, 97))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
199565	22390413	The average MGMT gene expression level was significantly lower in the group of patients with a methylated promoter independent of method used for methylation detection.	('MGMT', 'Gene', (12, 16))	('methylated promoter', 'Var', (95, 114))	('MGMT', 'Gene', '4255', (12, 16))	('patients', 'Species', '9606', (79, 87))	('lower', 'NegReg', (57, 62))
199566	22390413	Primary glioblastoma patients with a methylated MGMT promoter (as evaluated by both methylation detection methods) had approximately 5 months longer median survival compared to patients with an unmethylated promoter (log-rank test; pyrosequencing P = .02, qMSP P = .06).	('MGMT', 'Gene', (48, 52))	('MGMT', 'Gene', '4255', (48, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('methylated', 'Var', (37, 47))	('Primary glioblastoma', 'Disease', 'MESH:D005909', (0, 20))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (21, 29))	('longer', 'PosReg', (142, 148))	('Primary glioblastoma', 'Disease', (0, 20))
199567	22390413	The overall survival analysis shows that these patients have an intermediate prognosis between the groups with concordant MGMT promoter methylation results when comparing the two methods.	('MGMT', 'Gene', (122, 126))	('patients', 'Species', '9606', (47, 55))	('MGMT', 'Gene', '4255', (122, 126))	('methylation', 'Var', (136, 147))
199570	22390413	Prognosis is highly variable depending on histopathology, grade, patient age, and genetic tumor factors such as the presence of a 1p/19q co-deletion, IDH1 and IDH2 mutations, and MGMT promoter methylation.	('IDH2', 'Gene', (159, 163))	('1p/19q', 'Gene', (130, 136))	('IDH2', 'Gene', '3418', (159, 163))	('MGMT', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('genetic tumor', 'Disease', 'MESH:D030342', (82, 95))	('patient', 'Species', '9606', (65, 72))	('mutations', 'Var', (164, 173))	('IDH1', 'Gene', (150, 154))	('genetic tumor', 'Disease', (82, 95))	('IDH1', 'Gene', '3417', (150, 154))	('MGMT', 'Gene', '4255', (179, 183))
199575	22390413	About 5% of the DNA methylation induced by TMZ is located at the O6-position of guanine and methylation in this position is considered to be the main contributor to the cytotoxic effect.	('DNA methylation', 'MPA', (16, 31))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('guanine', 'Chemical', 'MESH:D006147', (80, 87))	('TMZ', 'Var', (43, 46))
199576	22390413	The DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT) removes methyl groups from the O6-position of guanine and the expression of MGMT is therefore thought to inhibit the cytotoxic effect of TMZ.	('expression', 'Var', (131, 141))	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('MGMT', 'Gene', '4255', (145, 149))	('inhibit', 'NegReg', (174, 181))	('MGMT', 'Gene', (145, 149))	('guanine', 'Chemical', 'MESH:D006147', (32, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (206, 209))	('guanine', 'Chemical', 'MESH:D006147', (115, 122))	('cytotoxic effect', 'CPA', (186, 202))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (22, 61))	('methyl groups', 'MPA', (77, 90))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (22, 61))
199603	22390413	The PCR was run at 50 C for 2 min, 95 C for 10 min, and 40 cycles of 95 C for 15 s and 60 C for 60 s. Each sample was analyzed with two different TaqMan Gene Expression Assays for MGMT (Hs01037698_m1 and Hs00172470_m1; part number 4331182, Applied Biosystems, Life Technologies) as well as two endogenous controls (ACTB; part number 4352935E, and GUSB part number 4333767 F, Applied Biosystems, Life Technologies).	('Hs00172470_m1', 'Var', (204, 217))	('MGMT', 'Gene', '4255', (180, 184))	('Hs01037698_m1', 'Var', (186, 199))	('MGMT', 'Gene', (180, 184))	('ACTB', 'Gene', (315, 319))	('GUSB', 'Gene', (347, 351))	('ACTB', 'Gene', '60', (315, 319))	('GUSB', 'Gene', '2990', (347, 351))
199614	22390413	The methylation levels (amount of methylation) determined by pyrosequencing and the MGMT_1 qMSP assay were significantly lower in methylated low-grade gliomas compared to methylated high-grade gliomas, P = .003 and P = .018, respectively.	('gliomas', 'Disease', (193, 200))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('methylation levels', 'MPA', (4, 22))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('MGMT', 'Gene', '4255', (84, 88))	('lower', 'NegReg', (121, 126))	('MGMT', 'Gene', (84, 88))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('methylated', 'Var', (130, 140))
199623	22390413	In the present study, we report MGMT promoter methylation frequencies in gliomas determined by qMSP (low-grade gliomas 26% and high-grade gliomas 37%) as well as by pyrosequencing (low-grade gliomas 97% and high-grade gliomas 55%).	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('MGMT', 'Gene', '4255', (32, 36))	('gliomas', 'Disease', (138, 145))	('methylation', 'Var', (46, 57))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('gliomas', 'Disease', (218, 225))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('gliomas', 'Disease', (73, 80))	('gliomas', 'Disease', (191, 198))	('MGMT', 'Gene', (32, 36))	('gliomas', 'Disease', 'MESH:D005910', (218, 225))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))
199624	22390413	The MGMT promoter is typically reported methylated in 30-60% of glioblastomas and in 30-90% of low-grade gliomas.	('MGMT', 'Gene', '4255', (4, 8))	('glioblastomas', 'Phenotype', 'HP:0012174', (64, 77))	('methylated', 'Var', (40, 50))	('glioblastomas', 'Disease', 'MESH:D005909', (64, 77))	('glioblastomas', 'Disease', (64, 77))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('MGMT', 'Gene', (4, 8))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
199640	22390413	In accordance with previous reports, our results show that the overall survival for patients with a methylated MGMT promoter is better than for patients with an unmethylated promoter.	('MGMT', 'Gene', (111, 115))	('patients', 'Species', '9606', (84, 92))	('MGMT', 'Gene', '4255', (111, 115))	('methylated', 'Var', (100, 110))	('patients', 'Species', '9606', (144, 152))	('better', 'PosReg', (128, 134))
199642	22390413	These results are in line with the observation that the patients with non-concordant methylation findings (unmethylated by qMSP and methylated by pyrosequencing) showed a trend towards better survival than patients with unmethylated MGMT promoter by both methods (Figure 1C).	('MGMT', 'Gene', '4255', (233, 237))	('methylation', 'Var', (85, 96))	('patients', 'Species', '9606', (56, 64))	('better', 'PosReg', (185, 191))	('patients', 'Species', '9606', (206, 214))	('MGMT', 'Gene', (233, 237))
199646	22390413	It is also interesting that, independent of the method used, the methylation level (amount of methylation) observed in methylation positive low-grade gliomas is low compared to the level observed in methylation positive high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('methylation level', 'MPA', (65, 82))	('gliomas', 'Disease', (231, 238))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Disease', 'MESH:D005910', (231, 238))	('low', 'NegReg', (161, 164))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('methylation positive', 'Var', (119, 139))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
199652	22390413	However, two studies analyzing 68 and 185 low-grade gliomas report methylation frequencies of 93% and 81%, respectively, using the same MSP primers in a nested two-stage approach.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('methylation', 'Var', (67, 78))
199654	22390413	The most commonly analyzed region in the MGMT gene promoter covers 9 of the totally 97 CpG sites in the promoter, and it has been suggested that methylation in some specific CpG sites correlates better with reduction in gene expression level than analysis of the common MSP region (Additional file 1: Figure S1).	('gene expression level', 'MPA', (220, 241))	('reduction', 'NegReg', (207, 216))	('methylation', 'Var', (145, 156))	('MGMT', 'Gene', '4255', (41, 45))	('MGMT', 'Gene', (41, 45))
199663	22390413	There is currently no "gold standard" for which technique to use for assessing clinically meaningful MGMT promoter methylation.	('MGMT', 'Gene', (101, 105))	('methylation', 'Var', (115, 126))	('MGMT', 'Gene', '4255', (101, 105))	('clinical', 'Species', '191496', (79, 87))
199696	33166290	Other factors influence the clustering results (such as the copy-number aberrations and immune features), which led to partially mixed tumor groups in the clustering (including pan-kidney, pan-squamous, and immune-related mixture category).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('copy-number aberrations', 'Var', (60, 83))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('pan-squamous', 'Disease', (189, 201))	('pan-kidney', 'Disease', (177, 187))
199722	33166290	Simultaneously, there is a certain correlation between some of the clusters (such as C2 and C21, C3 and C19), which implies that some clusters are related while others are quite different.	('C19', 'Var', (104, 107))	('C21', 'Gene', '79718', (92, 95))	('C21', 'Gene', (92, 95))
199725	33166290	Most of the remaining clusters contain similar tissue or organ samples (C7, C13, C22: Squamous histology cancers; C21: gastrointestinal cancers).	('C22', 'Var', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('C13', 'Gene', '3229', (76, 79))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (119, 143))	('gastrointestinal cancers', 'Disease', (119, 143))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('C21', 'Gene', (114, 117))	('C13', 'Gene', (76, 79))	('C21', 'Gene', '79718', (114, 117))
199732	33166290	K-means and Spectral are the two most stable and effective clustering algorithms, while AE and VAE are two deep learning algorithms applied to omics data clustering.	('learning algorithms', 'Disease', 'MESH:D007859', (112, 131))	('learning algorithms', 'Disease', (112, 131))	('K-means', 'Var', (0, 7))
199741	33166290	To illustrate that ClusterATAC identified diverse patterns of the TCGA pan-cancers, we analyzed the clustering results of ClusterATAC (C1~C22) and DensityPeakCluster (D1~D18).	('C1~C22', 'Var', (135, 141))	('D', 'Chemical', 'MESH:D003903', (147, 148))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('D', 'Chemical', 'MESH:D003903', (170, 171))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('D', 'Chemical', 'MESH:D003903', (167, 168))
199747	33166290	Both KIRC and KIRP are histological clusters of renal cell carcinoma (RCC), but KIRP patients are more likely to experience significantly worse clinical outcomes.	('KIRP', 'Var', (80, 84))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (48, 68))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('renal cell carcinoma', 'Disease', (48, 68))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (48, 68))
199751	33166290	Patients with D17 are concentrated in C17 and C12 (S4 Fig).	('C17', 'Gene', '54360', (38, 41))	('D', 'Chemical', 'MESH:D003903', (14, 15))	('C12', 'Chemical', '-', (46, 49))	('Patients', 'Species', '9606', (0, 8))	('C17', 'Gene', (38, 41))	('D17', 'Var', (14, 17))
199755	33166290	Although the cancer cell types influence the clustering results of the two methods, most of the heterogeneous clusters of ClusterATAC (C7, C12, C13, C21, C22) are entirely different from the previous 28-cluster solution.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('C22', 'Var', (154, 157))	('C7', 'Var', (135, 137))	('ClusterATAC', 'Gene', (122, 133))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('C12', 'Var', (139, 142))	('C21', 'Gene', (149, 152))	('C12', 'Chemical', '-', (139, 142))	('C13', 'Gene', '3229', (144, 147))	('C13', 'Gene', (144, 147))	('C21', 'Gene', '79718', (149, 152))
199760	33166290	Firstly, we investigated the clusters that follow the "cell-of-origin patterns" (C1~ C6, C8~C11, C14~C18, C20).	('C1~ C6', 'Var', (81, 87))	('C18', 'Gene', (101, 104))	('C11', 'Gene', '1109', (92, 95))	('C18', 'Gene', '27241', (101, 104))	('C20', 'Var', (106, 109))	('C11', 'Gene', (92, 95))
199761	33166290	Copy number enhancement occurring in this locus is thought to increase the likelihood of metastatic recurrence of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Copy number enhancement', 'Var', (0, 23))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('metastatic recurrence', 'CPA', (89, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))	('increase', 'PosReg', (62, 70))
199765	33166290	The previous study showed that chromosomal alterations in this region could significantly affect the survival time of colorectal cancer patients.	('affect', 'Reg', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('chromosomal alterations', 'Var', (31, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('patients', 'Species', '9606', (136, 144))	('survival time', 'CPA', (101, 114))	('colorectal cancer', 'Disease', (118, 135))
199779	33166290	Experiments showed that knocking down the IRX5 gene in the breast cancer cell leads to a decrease in cell survival.	('knocking down', 'Var', (24, 37))	('IRX5', 'Gene', '10265', (42, 46))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('decrease', 'NegReg', (89, 97))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('IRX5', 'Gene', (42, 46))	('cell survival', 'CPA', (101, 114))
199782	33166290	The study found that Epigenetic alterations occurred in the BNC1 gene in the mesothelioma cell line and may be involved in mesothelioma progression.	('mesothelioma', 'Disease', (77, 89))	('BNC1', 'Gene', '646', (60, 64))	('involved in', 'Reg', (111, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('Epigenetic alterations', 'Var', (21, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('BNC1', 'Gene', (60, 64))	('mesothelioma', 'Disease', (123, 135))
199840	33166290	Next, the GAN process is combined with the reconstruction process:  Where lambda1 is the weight of LGAN, and lambda2 is the weight of LREC.	('GAN', 'Chemical', '-', (10, 13))	('GAN', 'Chemical', '-', (100, 103))	('lambda2', 'Var', (109, 116))	('lambda1', 'Var', (74, 81))
199866	32175193	Notably, previous research has reported that high expression of EMILIN3 was confirmed to predict poor survival in LGG.	('LGG', 'Disease', (114, 117))	('high expression', 'Var', (45, 60))	('EMILIN3', 'Gene', (64, 71))	('EMILIN3', 'Gene', '90187', (64, 71))	('poor', 'NegReg', (97, 101))
199881	32175193	Kaplan-Meier plots displayed the relationship between EMILIN/Multimerin genetic mutations, OS and DFS in patients with LGG.	('patients', 'Species', '9606', (105, 113))	('DFS', 'Disease', (98, 101))	('EMILIN', 'Gene', (54, 60))	('EMILIN', 'Gene', '11117', (54, 60))	('LGG', 'Disease', (119, 122))	('genetic mutations', 'Var', (72, 89))
199919	32175193	The alteration frequency of EMILIN/Multimerin mutations in LGG was analyzed using cBioPortal and the results indicated five categories based on filtering (Fig.	('mutations', 'Var', (46, 55))	('EMILIN', 'Gene', '11117', (28, 34))	('EMILIN', 'Gene', (28, 34))	('LGG', 'Gene', (59, 62))
199920	32175193	The ratios of genetic alterations in EMILIN/Multimerins range from 0.4% to 1.4% for each member (EMILIN1 0.4%, EMILIN2 1.4%, EMILIN3 0.4%, MMRN1 0.4% and MMRN2 1.4%; Fig.	('EMILIN', 'Gene', (97, 103))	('MMRN1', 'Gene', '22915', (139, 144))	('MMRN2', 'Gene', '79812', (154, 159))	('MMRN2', 'Gene', (154, 159))	('EMILIN3', 'Gene', (125, 132))	('EMILIN3', 'Gene', '90187', (125, 132))	('EMILIN', 'Gene', (125, 131))	('EMILIN', 'Gene', '11117', (111, 117))	('EMILIN', 'Gene', (37, 43))	('EMILIN', 'Gene', '11117', (97, 103))	('EMILIN2', 'Gene', (111, 118))	('MMRN1', 'Gene', (139, 144))	('EMILIN', 'Gene', '11117', (125, 131))	('EMILIN2', 'Gene', '84034', (111, 118))	('EMILIN', 'Gene', '11117', (37, 43))	('genetic alterations', 'Var', (14, 33))	('EMILIN1', 'Gene', (97, 104))	('EMILIN1', 'Gene', '11117', (97, 104))	('EMILIN', 'Gene', (111, 117))
199921	32175193	Additionally, we analyzed genetic alterations in EMILIN/Multimerins and their association with OS and DFS in patients with LGG.	('DFS', 'Disease', (102, 105))	('patients', 'Species', '9606', (109, 117))	('EMILIN', 'Gene', '11117', (49, 55))	('genetic alterations', 'Var', (26, 45))	('EMILIN', 'Gene', (49, 55))	('association', 'Interaction', (78, 89))
199949	32175193	Survival curve analysis indicated that patients with LGG with a high expression of EMILIN2 were linked to poor OS and DFS.	('EMILIN2', 'Gene', '84034', (83, 90))	('poor OS', 'Disease', (106, 113))	('EMILIN2', 'Gene', (83, 90))	('linked', 'Reg', (96, 102))	('high expression', 'Var', (64, 79))	('patients', 'Species', '9606', (39, 47))	('LGG', 'Disease', (53, 56))	('DFS', 'Disease', (118, 121))
199962	32175193	Overexpression of MMRN2 was related to lower OS in patients with LGG, but was not correlated to DFS.	('LGG', 'Disease', (65, 68))	('MMRN2', 'Gene', '79812', (18, 23))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (51, 59))	('lower', 'NegReg', (39, 44))	('MMRN2', 'Gene', (18, 23))
199970	32175193	We calculated the percentage of genetic alterations in EMILIN/Multimerin family members using the TCGA dataset and found they varied from 0.4% to 1.4%.	('EMILIN', 'Gene', '11117', (55, 61))	('EMILIN', 'Gene', (55, 61))	('genetic alterations', 'Var', (32, 51))
199980	30946477	review the origins of this signature in glioma: it may arise via the tumour stroma, via NF1-mutation in tumour cells and be influenced by the cell of origin, or arise in response to radiotherapy/chemotherapy/anti-angiogenic treatment.	('tumour', 'Disease', (69, 75))	('NF1-mutation', 'Gene', (88, 100))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('tumour stroma', 'Disease', 'MESH:D009369', (69, 82))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour stroma', 'Disease', (69, 82))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('glioma', 'Disease', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('NF1-mutation', 'Var', (88, 100))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('arise', 'Reg', (55, 60))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('tumour', 'Disease', (104, 110))
199988	30946477	Genetic abnormalities, mainly NF1 mutations, together with NF-kappaB transcriptional programs, are the main driver of acquiring mesenchymal-signature.	('NF-kappaB', 'Gene', '4790', (59, 68))	('NF1', 'Gene', (30, 33))	('Genetic abnormalities', 'Disease', 'MESH:D030342', (0, 21))	('NF-kappaB', 'Gene', (59, 68))	('Genetic abnormalities', 'Disease', (0, 21))	('mutations', 'Var', (34, 43))
199998	30946477	Major revision was needed to update the century-old diagnostic principle by incorporating the microscopy analysis with the molecular parameters such as IDH status, ATRX loss, H3K27M mutation, TP53 mutation, and 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (211, 229))	('ATRX', 'Gene', (164, 168))	('IDH', 'Gene', (152, 155))	('H3K27M mutation', 'Var', (175, 190))	('IDH', 'Gene', '3417', (152, 155))	('ATRX', 'Gene', '546', (164, 168))	('TP53', 'Gene', (192, 196))
200001	30946477	Now, these tumours are grouped together according to their growth pattern and IDH1/IDH2-drived genetic mutations.	('mutations', 'Var', (103, 112))	('IDH2', 'Gene', '3418', (83, 87))	('IDH1', 'Gene', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('IDH1', 'Gene', '3417', (78, 82))	('IDH2', 'Gene', (83, 87))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))
200007	30946477	The first TCGA pilot study identified new GBM genomic alterations such as homozygous deletions of NF1 and PARK2, and amplifications of AKT3, in addition to previously known amplifications and deletions.	('deletions', 'Var', (85, 94))	('amplifications', 'Var', (117, 131))	('AKT3', 'Gene', (135, 139))	('NF1', 'Gene', (98, 101))	('AKT3', 'Gene', '10000', (135, 139))	('PARK2', 'Gene', '5071', (106, 111))	('PARK2', 'Gene', (106, 111))
200009	30946477	The MGMT promoter methylation, a predictive marker for alkylating agent treatment, induced a hypermutated GBM phenotype.	('MGMT', 'Gene', '4255', (4, 8))	('hypermutated', 'MPA', (93, 105))	('methylation', 'Var', (18, 29))	('induced', 'Reg', (83, 90))	('MGMT', 'Gene', (4, 8))
200012	30946477	The proneural subtype was associated with IDH1 mutation, TP53, PDGFRA amplification and/or mutations.	('proneural subtype', 'Disease', (4, 21))	('IDH1', 'Gene', '3417', (42, 46))	('PDGFRA', 'Gene', (63, 69))	('mutation', 'Var', (47, 55))	('PDGFRA', 'Gene', '5156', (63, 69))	('mutations', 'Var', (91, 100))	('IDH1', 'Gene', (42, 46))	('TP53', 'Gene', (57, 61))	('associated', 'Reg', (26, 36))	('amplification', 'Var', (70, 83))
200016	30946477	Interestingly, chr7 amplification and chr10 deletion, the most common GBM abnormalities, were low in the proneural subtype (20-54%), high in mesenchymal samples (>75%), and highest in the classical subtype of (93%).	('chr10', 'Gene', (38, 43))	('GBM abnormalities', 'Disease', 'MESH:D005910', (70, 87))	('deletion', 'Var', (44, 52))	('GBM abnormalities', 'Disease', (70, 87))	('proneural', 'Disease', (105, 114))	('low', 'NegReg', (94, 97))	('chr7', 'Gene', (15, 19))
200032	30946477	Although DNA methylation of the MGMT gene promotor (a gene that encodes O-6-methylguanine-DNA methyltransferase) has been associated with longer survival after temozolomide therapy in primary GBM, DNA methylation of this gene was correlated with a treatment response only in the classical subtype, but not proneural or mesenchymal subtypes.	('methylation', 'Var', (13, 24))	('associated with', 'Reg', (122, 137))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (72, 111))	('longer survival', 'PosReg', (138, 153))	('MGMT', 'Gene', '4255', (32, 36))	('MGMT', 'Gene', (32, 36))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (72, 111))	('methylation', 'Var', (201, 212))	('temozolomide', 'Chemical', 'MESH:D000077204', (160, 172))
200033	30946477	The TCGA proteomic profiling showed that EGFR amplification or mutation and phosphorylation were prominent in the classical subtype.	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', (41, 45))	('mutation', 'Var', (63, 71))
200045	30946477	The 12 genes classified GBM into three subtypes: proneural, identified by P2RX7, STMN4, SOX10 and ERBB3; classical, by ACSBG1 and KCNF1; and mesenchymal, by S100A, DAB2, TGFB1, THBS1, COL1A2 and COL1A1.	('ACSBG1', 'Gene', '23205', (119, 125))	('THBS1', 'Gene', (177, 182))	('COL1A1', 'Gene', '1277', (195, 201))	('mesenchymal', 'CPA', (141, 152))	('P2RX7', 'Gene', '5027', (74, 79))	('STMN4', 'Gene', (81, 86))	('THBS1', 'Gene', '7057', (177, 182))	('S100A', 'SUBSTITUTION', 'None', (157, 162))	('SOX10', 'Gene', '6663', (88, 93))	('COL1A2', 'Gene', '1278', (184, 190))	('STMN4', 'Gene', '81551', (81, 86))	('COL1A1', 'Gene', (195, 201))	('TGFB1', 'Gene', '7040', (170, 175))	('ERBB3', 'Gene', '2065', (98, 103))	('TGFB1', 'Gene', (170, 175))	('COL1A2', 'Gene', (184, 190))	('SOX10', 'Gene', (88, 93))	('KCNF1', 'Gene', (130, 135))	('KCNF1', 'Gene', '3754', (130, 135))	('P2RX7', 'Gene', (74, 79))	('DAB2', 'Gene', '1601', (164, 168))	('DAB2', 'Gene', (164, 168))	('ACSBG1', 'Gene', (119, 125))	('ERBB3', 'Gene', (98, 103))	('S100A', 'Var', (157, 162))
200054	30946477	Mesenchymal tumours are predominantly IDH wild-type and G-CIMP-, contrary to the proneural subtype.	('G-CIMP-', 'Var', (56, 63))	('G-CIMP', 'Chemical', '-', (56, 62))	('IDH', 'Gene', (38, 41))	('Mesenchymal tumours', 'Disease', 'MESH:D008637', (0, 19))	('Mesenchymal tumours', 'Disease', (0, 19))	('IDH', 'Gene', '3417', (38, 41))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))
200058	30946477	Furthermore, the epigenetic chromatin modifiers EZH2 and BMI1 were shown to have differential expression between the mesenchymal and proneural subtypes, keeping in mind that 40% of GBMs harbour mutations in BMI1 and EZH2.	('EZH2', 'Gene', '2146', (216, 220))	('EZH2', 'Gene', (216, 220))	('BMI1', 'Gene', (57, 61))	('EZH2', 'Gene', '2146', (48, 52))	('mutations', 'Var', (194, 203))	('EZH2', 'Gene', (48, 52))	('BMI1', 'Gene', '648', (207, 211))	('BMI1', 'Gene', '648', (57, 61))	('BMI1', 'Gene', (207, 211))
200102	30946477	However, the most well-known genetic alterations of GBM, gain of chr7 and loss of chr10, were expressed in all single cells from different patients.	('patients', 'Species', '9606', (139, 147))	('chr7', 'Gene', (65, 69))	('chr10', 'Gene', (82, 87))	('loss', 'Var', (74, 78))	('gain', 'PosReg', (57, 61))
200121	30946477	Furthermore, PDGFRB mutation increased from 3.5% in primary GBM to 50% in all metastatic lesions.	('PDGFRB', 'Gene', (13, 19))	('mutation', 'Var', (20, 28))	('primary GBM', 'Disease', (52, 63))	('increased', 'PosReg', (29, 38))	('PDGFRB', 'Gene', '5159', (13, 19))
200122	30946477	Also, the metastatic lesions acquired mutations in EGFR, RB1, and SETD2 that were not detected in the primary tumour.	('RB1', 'Gene', '5925', (57, 60))	('metastatic lesions', 'CPA', (10, 28))	('EGFR', 'Gene', (51, 55))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'Gene', '1956', (51, 55))	('SETD2', 'Gene', '29072', (66, 71))	('RB1', 'Gene', (57, 60))	('mutations', 'Var', (38, 47))	('SETD2', 'Gene', (66, 71))	('tumour', 'Disease', (110, 116))
200137	30946477	The PMT could be induced in proneural mouse model (PDGFA/shP53) and GBM cell lines with PDGFRA amplification through subsequent knockdown of NF1.	('mouse', 'Species', '10090', (38, 43))	('knockdown', 'Var', (128, 137))	('P53', 'Gene', (59, 62))	('PDGFRA', 'Gene', '5156', (88, 94))	('PDGFRA', 'Gene', (88, 94))	('P53', 'Gene', '7157', (59, 62))	('NF1', 'Gene', (141, 144))
200138	30946477	The NF1 deletion resulted in significantly shorter survival in the triple infected mice with mesenchymal-like subtype compared to the double infected proneural-like subtype.	('mice', 'Species', '10090', (83, 87))	('NF1', 'Gene', (4, 7))	('survival', 'CPA', (51, 59))	('mesenchymal-like subtype', 'CPA', (93, 117))	('deletion', 'Var', (8, 16))	('shorter', 'NegReg', (43, 50))
200150	30946477	The metagene was strongly associated with CD44 expression.	('metagene', 'Var', (4, 12))	('expression', 'MPA', (47, 57))	('CD44', 'Gene', '960', (42, 46))	('CD44', 'Gene', (42, 46))	('associated', 'Reg', (26, 36))
200155	30946477	The primary tumours had 60 mutations on average, whereas the hypermutated recurrent tumours (six primary GBM and 11 secondary GBM) were all temozolomide-treated and harboured >500 mutant genes per tumour, whereas none of temozolomide-untreated tumours were hypermutants (0/14).	('mutations', 'Var', (27, 36))	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('tumour', 'Disease', (84, 90))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumour', 'Disease', (197, 203))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))	('tumour', 'Disease', (244, 250))	('tumour', 'Disease', (12, 18))	('temozolomide', 'Chemical', 'MESH:D000077204', (221, 233))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('tumours', 'Disease', (244, 251))	('temozolomide', 'Chemical', 'MESH:D000077204', (140, 152))	('tumours', 'Disease', (84, 91))	('tumours', 'Disease', (12, 19))	('primary tumours', 'Disease', 'MESH:D009369', (4, 19))	('primary tumours', 'Disease', (4, 19))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Disease', 'MESH:D009369', (244, 251))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
200158	30946477	The tumour evolution mutational dynamic seems to have a similar alteration rate for a given time, for both primary and recurrent tumours after treatment (~0.03 substitutions/megabase/year), except for those with a hypermutated profile.	('substitutions/megabase/year', 'Var', (160, 187))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('tumours', 'Disease', (129, 136))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))
200161	30946477	Also, significant associations were observed between co-deletion of RB1 and PTEN, co-mutation of NF1 and TP53, and MGMT promoter methylation and hypermutation.	('NF1', 'Gene', (97, 100))	('RB1', 'Gene', '5925', (68, 71))	('co-mutation', 'Var', (82, 93))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (76, 80))	('MGMT', 'Gene', '4255', (115, 119))	('co-deletion', 'Var', (53, 64))	('MGMT', 'Gene', (115, 119))	('TP53', 'Gene', (105, 109))	('RB1', 'Gene', (68, 71))	('hypermutation', 'Var', (145, 158))
200196	30946477	The glioma subtype driving mutations can be explained in glioma transgenic mouse models.	('mutations', 'Var', (27, 36))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Disease', (57, 63))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('transgenic', 'Species', '10090', (64, 74))	('mouse', 'Species', '10090', (75, 80))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('glioma', 'Disease', (4, 10))
200197	30946477	While RCAS-PDGFB-amplification can drive a proneural-like transcriptome pattern, RCAS-NF1 silencing in a paediatric or adult glioma mouse model drive a mesenchymal-like subtype.	('PDGFB', 'Gene', (11, 16))	('glioma', 'Disease', (125, 131))	('RCAS', 'Chemical', '-', (81, 85))	('mesenchymal-like subtype', 'CPA', (152, 176))	('drive', 'Reg', (144, 149))	('silencing', 'Var', (90, 99))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('RCAS', 'Chemical', '-', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('proneural-like transcriptome pattern', 'MPA', (43, 79))	('RCAS-NF1', 'Gene', (81, 89))	('drive', 'Reg', (35, 40))	('mouse', 'Species', '10090', (132, 137))	('PDGFB', 'Gene', '5155', (11, 16))
200200	30946477	Interestingly, the NF1 model had significantly longer survival than the proneural PDGFB model.	('longer', 'PosReg', (47, 53))	('NF1', 'Var', (19, 22))	('PDGFB', 'Gene', '5155', (82, 87))	('PDGFB', 'Gene', (82, 87))	('survival', 'CPA', (54, 62))
200201	30946477	All these together suggest that genetic driver mutations may impact tumour vasculature and structure.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('impact', 'Reg', (61, 67))	('mutations', 'Var', (47, 56))	('tumour vasculature', 'Disease', (68, 86))	('tumour vasculature', 'Disease', 'MESH:C565633', (68, 86))
200206	30946477	showed that two populations of adult CNS progenitors, with different cell of origin, gave rise to molecularly and biological distinct gliomas despite being hit with the same tumour suppressor mutation in Nf1, Trp53, and Pten.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('gliomas', 'Disease', (134, 141))	('mutation', 'Var', (192, 200))	('Trp53', 'Gene', '7157', (209, 214))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('tumour', 'Disease', (174, 180))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('Pten', 'Gene', (220, 224))	('Nf1', 'Gene', (204, 207))	('gave rise to', 'Reg', (85, 97))	('Trp53', 'Gene', (209, 214))
200218	30946477	TIL infiltration was associated with NF1 and RB1 mutations, a common alteration in the mesenchymal subtype.	('RB1', 'Gene', (45, 48))	('TIL', 'Gene', '7096', (0, 3))	('mutations', 'Var', (49, 58))	('associated', 'Reg', (21, 31))	('NF1', 'Gene', (37, 40))	('RB1', 'Gene', '5925', (45, 48))	('TIL', 'Gene', (0, 3))
200220	30946477	Further, NF1 knockdown increased the in vitro recruitment of human macrophages isolated from GBM patients.	('NF1', 'Gene', (9, 12))	('GBM', 'Disease', (93, 96))	('in vitro recruitment of human macrophages', 'CPA', (37, 78))	('increased', 'PosReg', (23, 32))	('human', 'Species', '9606', (61, 66))	('knockdown', 'Var', (13, 22))	('patients', 'Species', '9606', (97, 105))
200221	30946477	Additionally, TILs were strongly associated with NF1 deletion or mutation, and absent in both EGFR-amplified tumours and those with homozygous PTEN deletion.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('EGFR', 'Gene', '1956', (94, 98))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('deletion', 'Var', (53, 61))	('TIL', 'Gene', '7096', (14, 17))	('tumours', 'Disease', (109, 116))	('EGFR', 'Gene', (94, 98))	('associated', 'Reg', (33, 43))	('mutation', 'Var', (65, 73))	('PTEN', 'Gene', (143, 147))	('PTEN', 'Gene', '5728', (143, 147))	('TIL', 'Gene', (14, 17))	('NF1', 'Gene', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
200225	30946477	While tumour cells with NF1 deletion exert their effect by recruiting macrophages/microglial cells to the tumour, the macrophage/microglia cells also affect the tumour and create a micro-environment that shapes mesenchymal subtype tumour cells.	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', (231, 237))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('tumour', 'Disease', (161, 167))	('tumour', 'Disease', (106, 112))	('affect', 'Reg', (150, 156))	('deletion', 'Var', (28, 36))	('NF1', 'Gene', (24, 27))	('tumour', 'Disease', (6, 12))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))
200250	30946477	All these together highlight the complexity of GBM heterogeneity and subtypes and suggest that NF1 abnormality and tumour micro-environment with its recruited cells, vasculature and anatomic location induce the mesenchymal criteria.	('NF1', 'Gene', (95, 98))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('induce', 'PosReg', (200, 206))	('mesenchymal criteria', 'CPA', (211, 231))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))	('abnormality', 'Var', (99, 110))
200268	30946477	showed that knockout of VEGF enhanced MET activation (phospho-MET), which induced highly aggressive and invasive mesenchymal-like GBM.	('knockout', 'Var', (12, 20))	('induced', 'Reg', (74, 81))	('VEGF', 'Gene', '7422', (24, 28))	('highly', 'PosReg', (82, 88))	('VEGF', 'Gene', (24, 28))	('enhanced', 'PosReg', (29, 37))
200269	30946477	Importantly, combining the ablation of VEGF with knocking down MET expression reduced vascularity and invasion, converted cell phenotype into epithelial-like cells, and extended animal survival 3-fold compared to the control group.	('knocking down', 'Var', (49, 62))	('extended', 'PosReg', (169, 177))	('vascularity', 'CPA', (86, 97))	('invasion', 'CPA', (102, 110))	('VEGF', 'Gene', (39, 43))	('MET expression', 'Gene', (63, 77))	('ablation', 'Var', (27, 35))	('reduced', 'NegReg', (78, 85))	('converted', 'Reg', (112, 121))	('VEGF', 'Gene', '7422', (39, 43))	('animal survival', 'CPA', (178, 193))
200278	30946477	Clinical data showed that GBM patients with high CD44 expression and NF-kappaB activation were associated with poor response rate to radiation treatment and have lower survival than those with low mesenchymal metagene expression.	('expression', 'MPA', (54, 64))	('high', 'Var', (44, 48))	('NF-kappaB', 'Gene', '4790', (69, 78))	('lower', 'NegReg', (162, 167))	('CD44', 'Gene', '960', (49, 53))	('patients', 'Species', '9606', (30, 38))	('activation', 'PosReg', (79, 89))	('NF-kappaB', 'Gene', (69, 78))	('CD44', 'Gene', (49, 53))	('survival', 'MPA', (168, 176))
200281	30946477	In fact, it has been recommended to avoid temozolomide in elderly GBM patients, and retain it for patients harbouring a methylated MGMT promoter gene that has a good response to this treatment.	('patients', 'Species', '9606', (70, 78))	('methylated', 'Var', (120, 130))	('MGMT', 'Gene', '4255', (131, 135))	('MGMT', 'Gene', (131, 135))	('patients', 'Species', '9606', (98, 106))	('temozolomide', 'Chemical', 'MESH:D000077204', (42, 54))	('temozolomide', 'MPA', (42, 54))
200289	30946477	Inhibition of CDC20 abolished the EMT features and enhanced temozolomide sensitivity.	('abolished', 'NegReg', (20, 29))	('temozolomide', 'Chemical', 'MESH:D000077204', (60, 72))	('temozolomide sensitivity', 'MPA', (60, 84))	('enhanced', 'PosReg', (51, 59))	('Inhibition', 'Var', (0, 10))	('EMT features', 'CPA', (34, 46))	('CDC20', 'Gene', (14, 19))	('CDC20', 'Gene', '991', (14, 19))
200293	30946477	ZEB1 knock-down not only decreased GSC marker expression (SOX2, OLIG2 and CD133), it also reduced tumour invasion and chemo-resistance.	('SOX2', 'Gene', (58, 62))	('chemo-resistance', 'CPA', (118, 134))	('reduced', 'NegReg', (90, 97))	('knock-down', 'Var', (5, 15))	('SOX2', 'Gene', '6657', (58, 62))	('GSC', 'Gene', '145258', (35, 38))	('GSC', 'Gene', (35, 38))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('decreased', 'NegReg', (25, 34))	('OLIG2', 'Gene', (64, 69))	('CD133', 'Gene', (74, 79))	('tumour', 'Disease', (98, 104))	('CD133', 'Gene', '8842', (74, 79))	('ZEB1', 'Gene', (0, 4))	('OLIG2', 'Gene', '10215', (64, 69))	('ZEB1', 'Gene', '6935', (0, 4))
200301	30946477	suggested that all non-G-CIMP GBMs, including both proneural and mesenchymal subtypes, arise from common proneural-like precursors and that disease lethality is increased by accumulated mutations such as TP53, PTEN, or CDKN2A in PDGFA-driven gliomas.	('PTEN', 'Gene', '5728', (210, 214))	('mutations', 'Var', (186, 195))	('gliomas', 'Disease', 'MESH:D005910', (242, 249))	('gliomas', 'Phenotype', 'HP:0009733', (242, 249))	('gliomas', 'Disease', (242, 249))	('CDKN2A', 'Gene', (219, 225))	('disease lethality', 'CPA', (140, 157))	('G-CIMP', 'Chemical', '-', (23, 29))	('CDKN2A', 'Gene', '1029', (219, 225))	('increased', 'PosReg', (161, 170))	('TP53', 'Gene', (204, 208))	('PTEN', 'Gene', (210, 214))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))
200302	30946477	Their computational model identified cells harbouring both chr7-gain, driven by PDGFA amplification, and chr10-loss, driven by PTEN loss, as the most likely cells of origin for gliomas.	('amplification', 'Var', (86, 99))	('chr10-loss', 'Gene', (105, 115))	('loss', 'NegReg', (132, 136))	('gliomas', 'Disease', (177, 184))	('PDGFA', 'Protein', (80, 85))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('chr7-gain', 'Gene', (59, 68))	('chr7-gain', 'PosReg', (59, 68))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', '5728', (127, 131))
200303	30946477	The mesenchymal subtype might evolve from the proneural subtype and be driven by accumulated mutations (NF1 loss in this case) in tumour cells that overexpress PDGFA.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('loss', 'NegReg', (108, 112))	('mutations', 'Var', (93, 102))	('tumour', 'Disease', (130, 136))	('mesenchymal subtype', 'CPA', (4, 23))	('overexpress', 'PosReg', (148, 159))	('PDGFA', 'Protein', (160, 165))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('NF1', 'Gene', (104, 107))
200308	30946477	Also, simultaneous deletion of NF1 and Tp53 without PDGFA amplification background induced GBM with the mesenchymal profile in an RCAS/tv-a model.	('RCAS', 'Chemical', '-', (130, 134))	('GBM with the mesenchymal profile', 'CPA', (91, 123))	('tv-a', 'Chemical', 'MESH:C050413', (135, 139))	('deletion', 'Var', (19, 27))	('NF1', 'Gene', (31, 34))	('Tp53', 'Gene', (39, 43))	('induced', 'Reg', (83, 90))
200311	30946477	have suggested that mutations in EGFR and CDKN2A/B/p14ARF are early event drivers, while PDGFRA and PTEN mutations are later events.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('PDGFRA', 'Gene', '5156', (89, 95))	('p14ARF', 'Gene', '1029', (51, 57))	('CDKN2A/B', 'Gene', (42, 50))	('EGFR', 'Gene', '1956', (33, 37))	('CDKN2A/B', 'Gene', '1029;1030', (42, 50))	('p14ARF', 'Gene', (51, 57))	('EGFR', 'Gene', (33, 37))	('mutations', 'Var', (20, 29))	('PDGFRA', 'Gene', (89, 95))
200312	30946477	A study by described mutations in IDH1, PIK3CA, and ATRX as early events while mutations in TP53, NF1, and PTEN occur later during tumour evolution.	('IDH1', 'Gene', '3417', (34, 38))	('tumour', 'Disease', (131, 137))	('PTEN', 'Gene', (107, 111))	('PIK3CA', 'Gene', (40, 46))	('PTEN', 'Gene', '5728', (107, 111))	('PIK3CA', 'Gene', '5290', (40, 46))	('NF1', 'Gene', (98, 101))	('ATRX', 'Gene', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('TP53', 'Gene', (92, 96))	('ATRX', 'Gene', '546', (52, 56))	('IDH1', 'Gene', (34, 38))	('mutations', 'Var', (79, 88))	('mutations', 'Var', (21, 30))
200313	30946477	suggested that PDGFA amplification and PTEN deletion are the common and leading events in all subtypes of non-GCIMP GBMs.	('CIMP', 'Chemical', '-', (111, 115))	('deletion', 'Var', (44, 52))	('PDGFA', 'Protein', (15, 20))	('PTEN', 'Gene', (39, 43))	('PTEN', 'Gene', '5728', (39, 43))	('amplification', 'Var', (21, 34))
200314	30946477	NF1 loss is a late event based on the subsequent targeting of NF1 in the proneural (PDGFA/shP53) mouse model that results in mesenchymal-like tumour formation.	('tumour', 'Disease', (142, 148))	('results in', 'Reg', (114, 124))	('P53', 'Gene', (92, 95))	('P53', 'Gene', '7157', (92, 95))	('NF1', 'Gene', (62, 65))	('mouse', 'Species', '10090', (97, 102))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('NF1', 'Gene', (0, 3))	('targeting', 'Var', (49, 58))	('loss', 'NegReg', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
200315	30946477	First, IDH1 mutation, which is a common mutation in the proneural subtype, is detected in fewer than 10% of GBM patients.	('mutation', 'Var', (12, 20))	('IDH1', 'Gene', (7, 11))	('IDH1', 'Gene', '3417', (7, 11))	('patients', 'Species', '9606', (112, 120))
200325	30946477	The multiple cell of origin hypothesis was suggested a long time ago in hereditary neurofibromas, a disease related to NF1 mutation/deletion.	('hereditary neurofibromas', 'Disease', (72, 96))	('NF1', 'Gene', (119, 122))	('mutation/deletion', 'Var', (123, 140))	('hereditary neurofibromas', 'Phenotype', 'HP:0001067', (72, 96))	('hereditary neurofibromas', 'Disease', 'MESH:D009455', (72, 96))
200330	30946477	Our hypothesis is that specific genetic mutations that hit specific cell types give rise either to proneural, classical or mesenchymal subtypes, and the polyclonal evolution of GBM, which is influenced by accumulated genetic and epigenetic changes, the cell of origin, recruited stromal cells with their secreted factors, and the dynamic interactions between these variable clones, in addition to their interaction with micro-environment, drive molecular subtype heterogeneity that leads to intra- and inter-tumoural heterogeneity.	('tumour', 'Phenotype', 'HP:0002664', (508, 514))	('mutations', 'Var', (40, 49))	('stroma', 'Disease', (279, 285))	('tumour', 'Disease', 'MESH:D009369', (508, 514))	('tumour', 'Disease', (508, 514))	('leads to', 'Reg', (482, 490))	('stroma', 'Disease', 'None', (279, 285))
200457	33391355	Five immune gene-related lncRNAs (AP001007.1, LBX-AS1, MIR155HG, MAPT-AS1, and LINC00515) were screened to construct risk models.	('AS1', 'Gene', '5729', (70, 73))	('AS1', 'Gene', (70, 73))	('MIR155HG', 'Gene', '114614', (55, 63))	('MAPT-AS1', 'Gene', (65, 73))	('AS1', 'Gene', (50, 53))	('MIR155HG', 'Gene', (55, 63))	('AS1', 'Gene', '5729', (50, 53))	('LINC00515', 'Gene', '282566', (79, 88))	('MAPT-AS1', 'Gene', '100128977', (65, 73))	('LINC00515', 'Gene', (79, 88))	('AP001007.1', 'Var', (34, 44))
200514	33391355	The nine lncRNAs we screened were AC084018.1, AP001007.1, DICER1-AS1, HCP5, LBX2-AS1, LINC00515, MAPT-AS1, USP30-AS1, and MIR155HG.	('HCP5', 'Gene', (70, 74))	('MAPT-AS1', 'Gene', '100128977', (97, 105))	('AC084018.1', 'Var', (34, 44))	('AS1', 'Gene', '5729', (81, 84))	('AS1', 'Gene', '5729', (113, 116))	('AS1', 'Gene', (102, 105))	('MAPT-AS1', 'Gene', (97, 105))	('LINC00515', 'Gene', '282566', (86, 95))	('AS1', 'Gene', '5729', (65, 68))	('DICER1', 'Gene', '23405', (58, 64))	('MIR155HG', 'Gene', '114614', (122, 130))	('MIR155HG', 'Gene', (122, 130))	('HCP5', 'Gene', '10866', (70, 74))	('LINC00515', 'Gene', (86, 95))	('DICER1', 'Gene', (58, 64))	('AS1', 'Gene', (81, 84))	('AS1', 'Gene', '5729', (102, 105))	('AS1', 'Gene', (113, 116))	('AS1', 'Gene', (65, 68))	('USP30', 'Gene', (107, 112))	('USP30', 'Gene', '84749', (107, 112))	('LBX2', 'Gene', '85474', (76, 80))	('LBX2', 'Gene', (76, 80))
200515	33391355	After univariate (Figure 5A) and multivariate (Figure 5B) analyses, AP001007.1, MIR155HG, and LBX2-AS1 were identified as independent risk factors [hazard ratio (HR) > 1, P < 0.05], and LINC00515 and MAPT-AS1 were identified as independent protective factors (HR < 1, P < 0.001).	('AP001007.1', 'Var', (68, 78))	('AS1', 'Gene', (205, 208))	('LINC00515', 'Gene', (186, 195))	('MAPT-AS1', 'Gene', '100128977', (200, 208))	('AS1', 'Gene', '5729', (205, 208))	('AS1', 'Gene', '5729', (99, 102))	('AS1', 'Gene', (99, 102))	('LBX2', 'Gene', '85474', (94, 98))	('LBX2', 'Gene', (94, 98))	('LINC00515', 'Gene', '282566', (186, 195))	('MIR155HG', 'Gene', '114614', (80, 88))	('MIR155HG', 'Gene', (80, 88))	('MAPT-AS1', 'Gene', (200, 208))
200518	33391355	Finally, correlation analysis showed that the primary, recurrent, and secondary (PRS) type, World Health Organization (WHO) grade, isocitrate dehydrogenase (IDH)-mutant, 1p/19q co-deleted, age, and risk score were independent prognostic factors (Figures 5E,F, p < 0.05).	('isocitrate dehydrogenase', 'Gene', (131, 155))	('isocitrate dehydrogenase', 'Gene', '3417', (131, 155))	('IDH', 'Gene', '3417', (157, 160))	('PRS', 'Gene', '5640', (81, 84))	('1p/19q co-deleted', 'Var', (170, 187))	('PRS', 'Gene', (81, 84))	('IDH', 'Gene', (157, 160))
200519	33391355	The results indicated that as the WHO level increased, AP001007.1, LBX-AS1, and MIR155HG expression also increased, while MAPT-AS1 and LINC00515 expression decreased (Figure 6B, p < 0.001).	('expression', 'MPA', (89, 99))	('LINC00515', 'Gene', (135, 144))	('MIR155HG', 'Gene', '114614', (80, 88))	('MAPT-AS1', 'Gene', (122, 130))	('AS1', 'Gene', (71, 74))	('AS1', 'Gene', '5729', (71, 74))	('AP001007.1', 'Var', (55, 65))	('MAPT-AS1', 'Gene', '100128977', (122, 130))	('increased', 'PosReg', (105, 114))	('AS1', 'Gene', (127, 130))	('AS1', 'Gene', '5729', (127, 130))	('LINC00515', 'Gene', '282566', (135, 144))	('MIR155HG', 'Gene', (80, 88))
200520	33391355	In addition, 1p19q no-codeletion (Figure 6C), IDH1 wildtype (Figure 6D), MGMT un-methylated (Figure 6E), and recurrent glioma (Figure 6F) compared with 1p19q deletion (Figure 6C), IDH1 mutant (Figure 6D), MGMT methylated (Figure 6E), and primary glioma (Figure 6F), AP001007.1, LBX-AS1, and MIR155HG also was high expression, while MAPT-AS1 and LINC00515 were also low in CGGA (except for LINC00515 in Figure 6E and MAPT-AS1 in Figure 6F, p > 0.05).	('AS1', 'Gene', '5729', (282, 285))	('MIR155HG', 'Gene', '114614', (291, 299))	('MGMT', 'Gene', '4255', (73, 77))	('MIR155HG', 'Gene', (291, 299))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('MAPT-AS1', 'Gene', (416, 424))	('LINC00515', 'Gene', (389, 398))	('MGMT', 'Gene', '4255', (205, 209))	('IDH1', 'Gene', (46, 50))	('AS1', 'Gene', '5729', (421, 424))	('MAPT-AS1', 'Gene', '100128977', (332, 340))	('LINC00515', 'Gene', '282566', (345, 354))	('AS1', 'Gene', (337, 340))	('MGMT', 'Gene', (73, 77))	('IDH1', 'Gene', (180, 184))	('AS1', 'Gene', (282, 285))	('MAPT-AS1', 'Gene', (332, 340))	('glioma', 'Disease', (246, 252))	('1p19q', 'Var', (13, 18))	('IDH1', 'Gene', '3417', (46, 50))	('glioma', 'Disease', (119, 125))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('AS1', 'Gene', (421, 424))	('LINC00515', 'Gene', (345, 354))	('MGMT', 'Gene', (205, 209))	('IDH1', 'Gene', '3417', (180, 184))	('1p19q', 'Var', (152, 157))	('LINC00515', 'Gene', '282566', (389, 398))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))	('MAPT-AS1', 'Gene', '100128977', (416, 424))	('AS1', 'Gene', '5729', (337, 340))
200522	33391355	In addition, we found that AP001007.1, LBX2-AS1, and MIR155HG had the highest expression, while MAPT-AS1 and LINC00515 expression was the lowest in the immune_H group.	('expression', 'MPA', (78, 88))	('LINC00515', 'Gene', '282566', (109, 118))	('LBX2', 'Gene', '85474', (39, 43))	('AS1', 'Gene', '5729', (101, 104))	('AP001007.1', 'Var', (27, 37))	('AS1', 'Gene', (101, 104))	('AS1', 'Gene', '5729', (44, 47))	('AS1', 'Gene', (44, 47))	('MAPT-AS1', 'Gene', (96, 104))	('LINC00515', 'Gene', (109, 118))	('MAPT-AS1', 'Gene', '100128977', (96, 104))	('MIR155HG', 'Gene', (53, 61))	('LBX2', 'Gene', (39, 43))	('MIR155HG', 'Gene', '114614', (53, 61))
200523	33391355	In contrast, the expression of AP001007.1, LBX-AS1, and MIR155HG were relatively low, while the expressions of MAPT-AS1 and LINC00515 were relatively high in the immune_L group (Figure 6H).	('MAPT-AS1', 'Gene', '100128977', (111, 119))	('low', 'NegReg', (81, 84))	('LINC00515', 'Gene', (124, 133))	('expression', 'MPA', (17, 27))	('AP001007.1', 'Var', (31, 41))	('expressions', 'MPA', (96, 107))	('AS1', 'Gene', '5729', (116, 119))	('AS1', 'Gene', '5729', (47, 50))	('AS1', 'Gene', (47, 50))	('LINC00515', 'Gene', '282566', (124, 133))	('high', 'PosReg', (150, 154))	('MAPT-AS1', 'Gene', (111, 119))	('MIR155HG', 'Gene', (56, 64))	('AS1', 'Gene', (116, 119))	('MIR155HG', 'Gene', '114614', (56, 64))
200531	33391355	Through qRT-PCR, we confirmed that AP001007.1, MIR155HG, and LBX2-AS1 are highly expressed, while LINC00515 and MAPT-AS1 are low expressed in gliomas compared to the control group (Figure 9A).	('AS1', 'Gene', (117, 120))	('MIR155HG', 'Gene', (47, 55))	('LBX2', 'Gene', (61, 65))	('gliomas', 'Disease', (142, 149))	('MAPT-AS1', 'Gene', (112, 120))	('MIR155HG', 'Gene', '114614', (47, 55))	('LBX2', 'Gene', '85474', (61, 65))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('AP001007.1', 'Var', (35, 45))	('LINC00515', 'Gene', (98, 107))	('MAPT-AS1', 'Gene', '100128977', (112, 120))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('AS1', 'Gene', '5729', (66, 69))	('AS1', 'Gene', (66, 69))	('LINC00515', 'Gene', '282566', (98, 107))	('AS1', 'Gene', '5729', (117, 120))
200546	33391355	We also observed that among all the glioma samples, the immune_H group had the worst prognosis, followed by the immune_M group, and the immune_L group had the best prognosis.	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('immune_H', 'Var', (56, 64))	('glioma', 'Disease', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (36, 42))
200553	33391355	We further observed that five lncRNAs interact and are closely related to the clinical symptoms of glioma patients (WHO grade, IDH1 status, 1q19q status, and MGMT).	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('MGMT', 'Gene', '4255', (158, 162))	('1q19q status', 'Var', (140, 152))	('IDH1', 'Gene', (127, 131))	('glioma', 'Disease', (99, 105))	('patients', 'Species', '9606', (106, 114))	('IDH1', 'Gene', '3417', (127, 131))	('related', 'Reg', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('MGMT', 'Gene', (158, 162))
200555	33391355	In the immune_H group, we found that AP001007.1, LBX2-AS1, and MIR155HG were highly expressed, while LINC00515 and MAPT-AS1 expression was low.	('LINC00515', 'Gene', (101, 110))	('MAPT-AS1', 'Gene', '100128977', (115, 123))	('AS1', 'Gene', '5729', (54, 57))	('AS1', 'Gene', (54, 57))	('MIR155HG', 'Gene', '114614', (63, 71))	('MIR155HG', 'Gene', (63, 71))	('LBX2', 'Gene', (49, 53))	('LBX2', 'Gene', '85474', (49, 53))	('LINC00515', 'Gene', '282566', (101, 110))	('AS1', 'Gene', '5729', (120, 123))	('AS1', 'Gene', (120, 123))	('MAPT-AS1', 'Gene', (115, 123))	('AP001007.1', 'Var', (37, 47))
200556	33391355	Survival analysis showed that AP001007.1, LBX2-AS1, and MIR155HG were risk factors, and their high expression predicted poor patient outcomes.	('LBX2', 'Gene', '85474', (42, 46))	('LBX2', 'Gene', (42, 46))	('AS1', 'Gene', '5729', (47, 50))	('AS1', 'Gene', (47, 50))	('MIR155HG', 'Gene', '114614', (56, 64))	('patient', 'Species', '9606', (125, 132))	('MIR155HG', 'Gene', (56, 64))	('AP001007.1', 'Var', (30, 40))
200566	33391355	To reveal the mechanism of partial resistance or treatment resistance within a new risk model, five immune-related lncRNAs were analyzed and shown to have good stability and feasibility (AP001007.1, LBX-AS1, MIR155HG, MAPT-AS1, and LINC00515).	('AS1', 'Gene', '5729', (223, 226))	('AS1', 'Gene', (223, 226))	('LINC00515', 'Gene', '282566', (232, 241))	('LINC00515', 'Gene', (232, 241))	('AP001007.1', 'Var', (187, 197))	('MAPT-AS1', 'Gene', '100128977', (218, 226))	('MIR155HG', 'Gene', '114614', (208, 216))	('AS1', 'Gene', '5729', (203, 206))	('AS1', 'Gene', (203, 206))	('MIR155HG', 'Gene', (208, 216))	('MAPT-AS1', 'Gene', (218, 226))
200573	32257943	Overexpressed TNFRSF1A was strongly related to clinical features such as WHO grade, and functioned as an independent poor prognostic predictor of glioma patients.	('related', 'Reg', (36, 43))	('Overexpressed', 'Var', (0, 13))	('patients', 'Species', '9606', (153, 161))	('glioma', 'Disease', (146, 152))	('TNFRSF1A', 'Gene', (14, 22))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))
200582	32257943	In 2016, molecular characteristics, including isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion, are included into the revised the classification of the CNS Tumors.	('isocitrate dehydrogenase', 'Gene', (46, 70))	('isocitrate dehydrogenase', 'Gene', '3417', (46, 70))	('mutation', 'Var', (77, 85))	('CNS Tumors', 'Disease', 'MESH:D009369', (165, 175))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('Tumor', 'Phenotype', 'HP:0002664', (169, 174))	('CNS Tumors', 'Disease', (165, 175))	('Tumors', 'Phenotype', 'HP:0002664', (169, 175))
200583	32257943	Based on a study of The Cancer Genome Atlas (TCGA), glioblastoma multiforme (GBM) were divided into four molecular subtypes: Proneural, Neural, Classical and Mesenchymal by using by abnormalities in PDGFRA, IDH1, EGFR, and NF1.	('IDH1', 'Gene', (207, 211))	('PDGFRA', 'Gene', (199, 205))	('NF1', 'Gene', '4763', (223, 226))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('EGFR', 'Gene', (213, 217))	('EGFR', 'Gene', '1956', (213, 217))	('NF1', 'Gene', (223, 226))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('IDH1', 'Gene', '3417', (207, 211))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (24, 43))	('glioblastoma multiforme', 'Disease', (52, 75))	('Cancer Genome Atlas', 'Disease', (24, 43))	('Mes', 'Chemical', 'MESH:C004550', (158, 161))	('abnormalities', 'Var', (182, 195))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (52, 75))	('PDGFRA', 'Gene', '5156', (199, 205))
200593	32257943	TNFRSF1A polymorphism rs4149584 was found to alleviate the severity of multiple sclerosis patients by decreasing age at disease onset and retarding disease progression.	('multiple sclerosis', 'Disease', (71, 89))	('TNFRSF1A', 'Gene', (0, 8))	('rs4149584', 'Var', (22, 31))	('retarding disease', 'Disease', (138, 155))	('multiple sclerosis', 'Disease', 'MESH:D009103', (71, 89))	('age', 'MPA', (113, 116))	('decreasing', 'NegReg', (102, 112))	('alleviate', 'NegReg', (45, 54))	('rs4149584', 'Mutation', 'rs4149584', (22, 31))	('retarding disease', 'Disease', 'MESH:D008607', (138, 155))	('patients', 'Species', '9606', (90, 98))
200601	32257943	The glioma expression profiles with clinical information were downloaded from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) database, including GSE4271, GSE4290, GSE4412, GSE13041, and GSE68848.	('GSE4290', 'Var', (175, 182))	('GSE68848', 'Var', (207, 215))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('GSE4271', 'Chemical', '-', (166, 173))	('glioma', 'Disease', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('GSE4271', 'Var', (166, 173))	('GSE13041', 'Var', (193, 201))	('GSE4290', 'Chemical', '-', (175, 182))	('GSE4412', 'Chemical', '-', (184, 191))	('GSE4412', 'Var', (184, 191))
200602	32257943	The GSE4271 and GSE4412 datasets were originated from GPL96, and the dataset GSE13041 with 267 samples included three platforms GPL96, GPL570, and GPL8300.	('GSE4271', 'Chemical', '-', (4, 11))	('GPL8300', 'Var', (147, 154))	('GPL570', 'Var', (135, 141))	('GSE4412', 'Chemical', '-', (16, 23))	('GPL96', 'Var', (128, 133))
200630	32257943	More importantly, the expression level of TNFRSF1A was positively associated with WHO grade in the eight datasets, including GSE4290, GSE68848, CGGA (mRNA-array_301, mRNAseq_325 and mRNAseq_693), TCGA_glioma, GSE4271 and GSE4412, respectively (Figures 3I-P).	('WHO grade', 'Disease', (82, 91))	('GSE4290', 'Chemical', '-', (125, 132))	('glioma', 'Disease', (201, 207))	('associated', 'Reg', (66, 76))	('TNFRSF1A', 'Gene', (42, 50))	('expression level', 'MPA', (22, 38))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('mRNAseq_693', 'Var', (182, 193))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('GSE4271', 'Chemical', '-', (209, 216))	('GSE4412', 'Chemical', '-', (221, 228))
200639	32257943	TCGA group classified HGGs into four subtypes: Classical, Mesenchymal, Neural and Proneural based on the molecular biomarkers such as 1p/19q codeletion and IDH mutation.	('IDH', 'Gene', (156, 159))	('Mes', 'Chemical', 'MESH:C004550', (58, 61))	('1p/19q codeletion', 'Var', (134, 151))	('IDH', 'Gene', '3417', (156, 159))
200641	32257943	Likewise, TNFRSF1A expression of gliomas carrying 1p/19q codeletion or IDH mutation was lower than the corresponding glioma samples (Figures 4Q-V; Supplementary Tables 1-3).	('expression', 'MPA', (19, 29))	('glioma', 'Disease', (33, 39))	('TNFRSF1A', 'Gene', (10, 18))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('1p/19q codeletion', 'Var', (50, 67))	('IDH', 'Gene', (71, 74))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('lower', 'NegReg', (88, 93))	('IDH', 'Gene', '3417', (71, 74))	('glioma', 'Disease', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
200645	32257943	Likewise, the high TNFRSF1A expression group (n = 156, 310, 39, 43, 142, 347, and 263 respectively) had a poor prognosis compared with the corresponding low group (n = 155, 309, 38, 42, 142, 346, and 263 respectively) in the other seven datasets, including CGGA (mRNAseq_325 and mRNAseq_693), GSE4271, GSE4412, GSE68848, TCGA_glioma, and TCGA_LGG, respectively (Figures 5B-H).	('mRNAseq_693', 'Var', (279, 290))	('glioma', 'Disease', 'MESH:D005910', (326, 332))	('glioma', 'Phenotype', 'HP:0009733', (326, 332))	('GSE4271', 'Chemical', '-', (293, 300))	('mRNAseq_325', 'Var', (263, 274))	('GSE4271', 'Var', (293, 300))	('high', 'Var', (14, 18))	('GSE4412', 'Chemical', '-', (302, 309))	('GSE4412', 'Var', (302, 309))	('glioma', 'Disease', (326, 332))	('GSE68848', 'Var', (311, 319))	('CGGA', 'Disease', (257, 261))	('TNFRSF1A', 'Gene', (19, 27))
200646	32257943	Furthermore, glioma or LGG patients with high TNFRSF1A expression had a shorter disease-free survival (DFS) than the low expression group using GEPIA2 (Figures 5I,J).	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('shorter', 'NegReg', (72, 79))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('TNFRSF1A', 'Gene', (46, 54))	('disease-free survival', 'CPA', (80, 101))	('LGG', 'Disease', (23, 26))	('glioma', 'Disease', (13, 19))
200649	32257943	In the dataset CGGA mRNA-array_301, univariate Cox regression analysis result revealed that a total of 10 factors were associated with OS of gliomas, including TNFRSF1A expression, age, WHO grade, PRS_type, histology, TCGA_subtypes, Radio_status, Chemo_status, IDH_mutation_status and 1p19q_codeletion_status (Table 1).	('IDH', 'Gene', (261, 264))	('Cox', 'Gene', '1351', (47, 50))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('IDH', 'Gene', '3417', (261, 264))	('Cox', 'Gene', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))	('1p19q_codeletion_status', 'Var', (285, 308))	('gliomas', 'Disease', (141, 148))	('TNFRSF1A', 'Gene', (160, 168))	('associated', 'Reg', (119, 129))
200650	32257943	Similarly in the another dataset CGGA mRNAseq_325, univariate analysis revealed that a total of 9 factors were associated with OS of gliomas, including TNFRSF1A expression, age, WHO grade, PRS_type, histology, Radio_status, Chemo_status, IDH_mutation_status and 1p19q_codeletion_status (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('IDH', 'Gene', (238, 241))	('associated', 'Reg', (111, 121))	('1p19q_codeletion_status', 'Var', (262, 285))	('IDH', 'Gene', '3417', (238, 241))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('TNFRSF1A', 'Gene', (152, 160))
200651	32257943	Taken together, these results from the two datasets revealed that TNFRSF1A expression and WHO grade as well as 1p19q_codeletion_status were independent prognostic indicators of OS in gliomas.	('gliomas', 'Disease', (183, 190))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('TNFRSF1A', 'Gene', (66, 74))	('1p19q_codeletion_status', 'Var', (111, 134))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))
200653	32257943	To investigate the role of TNFRSF1A in glioma, TNFRSF1A was knocked down in U251 and U87.	('knocked down', 'Var', (60, 72))	('TNFRSF1A', 'Gene', (47, 55))	('glioma', 'Disease', (39, 45))	('U87', 'Gene', (85, 88))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('U87', 'Gene', '641648', (85, 88))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
200654	32257943	After transfection of glioma cells with si-NC or TNFRSF1A siRNAs, knockdown efficiency of TNFRSF1A siRNA2 was most obvious in both U251 and U87 (Figure 7A).	('si-NC', 'Var', (40, 45))	('TNFRSF1A', 'Gene', (49, 57))	('glioma', 'Disease', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('U87', 'Gene', (140, 143))	('U87', 'Gene', '641648', (140, 143))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
200657	32257943	As shown in Figure 7F, transwell assay showed that TNFRSF1A knockdown significantly reduced the migration of glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('TNFRSF1A', 'Gene', (51, 59))	('glioma', 'Disease', (109, 115))	('reduced', 'NegReg', (84, 91))	('knockdown', 'Var', (60, 69))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
200671	32257943	Furthermore, consistent with the above results, survival analyses and Cox regression analyses demonstrated that human patients with gliomas carrying high TNFRSF1A expression had a shorter OS or DFS than the low expression patients, and TNFRSF1A functioned as an independent prognostic indicator of OS.	('high', 'Var', (149, 153))	('DFS', 'MPA', (194, 197))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('TNFRSF1A', 'Gene', (154, 162))	('patients', 'Species', '9606', (222, 230))	('Cox', 'Gene', '1351', (70, 73))	('shorter', 'NegReg', (180, 187))	('human', 'Species', '9606', (112, 117))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('Cox', 'Gene', (70, 73))	('patients', 'Species', '9606', (118, 126))
200674	32257943	And glioma patients with molecular characteristics such as IDH mutation or 1p/19q codeletion had a lower expression level of TNFRSF1A than the glioma samples without these characteristics.	('patients', 'Species', '9606', (11, 19))	('IDH', 'Gene', (59, 62))	('lower', 'NegReg', (99, 104))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('IDH', 'Gene', '3417', (59, 62))	('expression level', 'MPA', (105, 121))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('glioma', 'Disease', (143, 149))	('TNFRSF1A', 'Gene', (125, 133))	('1p/19q codeletion', 'Var', (75, 92))	('glioma', 'Disease', (4, 10))
200675	32257943	From the above results that TNFRSF1A expression was an independent prognostic indicator related to poor prognosis in gliomas, therefore, gliomas with IDH mutation or 1p/19q codeletion had a longer survival time, which was consistent with the conclusions of the previous studies.	('survival time', 'CPA', (197, 210))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('1p/19q codeletion', 'Var', (166, 183))	('TNFRSF1A', 'Gene', (28, 36))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('gliomas', 'Disease', (137, 144))	('IDH', 'Gene', (150, 153))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('longer', 'PosReg', (190, 196))	('IDH', 'Gene', '3417', (150, 153))
200678	32257943	Some previous studies found that IDH mutation was associated with 1p/19q codeletion, and glioma patients with IDH mutation had a longer median overall survival time than samples with IDH wildtype (25).	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('IDH', 'Gene', (110, 113))	('longer', 'PosReg', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('1p/19q', 'Var', (66, 72))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', (183, 186))	('overall survival', 'MPA', (143, 159))	('IDH', 'Gene', (33, 36))	('glioma', 'Disease', (89, 95))	('patients', 'Species', '9606', (96, 104))	('IDH', 'Gene', '3417', (183, 186))	('associated', 'Reg', (50, 60))	('IDH', 'Gene', '3417', (33, 36))
200693	31968687	Recently, Next Generation Sequencing was set-up as an all-in-one diagnostic tool aimed at detecting both DNA copy number variations and mutations in gliomas.	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('mutations', 'Var', (136, 145))
200712	31968687	For instance, the diagnosis of oligodendroglioma requires that tumor harbors both an IDH1/2 mutation and a 1p/19q codeletion.	('tumor', 'Disease', (63, 68))	('mutation', 'Var', (92, 100))	('oligodendroglioma', 'Disease', (31, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH1/2', 'Gene', (85, 91))	('oligodendroglioma', 'Disease', 'MESH:D009837', (31, 48))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('IDH1/2', 'Gene', '3417;3418', (85, 91))
200713	31968687	Moreover, astrocytomas are featured by the IDH1/2 mutation in the absence of 1p/19q codeletion, while often harboring inactivating mutations in alpha-thalassemia mental retardation X-linked (ATRX) and tumor protein p53 (TP53) genes.	('TP53', 'Gene', '7157', (220, 224))	('IDH1/2', 'Gene', (43, 49))	('TP53', 'Gene', (220, 224))	('alpha-thalassemia mental retardation X-linked', 'Disease', (144, 189))	('alpha-thalassemia mental retardation X-linked', 'Disease', 'MESH:C538258', (144, 189))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('astrocytomas', 'Disease', 'MESH:D001254', (10, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('ATRX', 'Gene', '546', (191, 195))	('p53', 'Gene', (215, 218))	('tumor', 'Disease', (201, 206))	('p53', 'Gene', '7157', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('IDH1/2', 'Gene', '3417;3418', (43, 49))	('astrocytomas', 'Disease', (10, 22))	('ATRX', 'Gene', (191, 195))	('mental retardation', 'Phenotype', 'HP:0001249', (162, 180))	('mutation', 'Var', (50, 58))
200722	31968687	In fact, as demonstrated in other cancer diseases, much of the inherited risk is likely to be the result of the co-inheritance of common multiple low-risk variants.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer diseases', 'Disease', 'MESH:D009369', (34, 49))	('cancer diseases', 'Disease', (34, 49))	('variants', 'Var', (155, 163))
200723	31968687	To this aim, genome-wide association studies (GWAS) and additional fine-mapping identified some common germline genetic variants associated with an increased risk of glioma.	('associated with', 'Reg', (129, 144))	('variants', 'Var', (120, 128))	('glioma', 'Disease', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))
200725	31968687	Most genes located within these loci are affected by somatic mutations occurring in gliomas, namely cyclin-dependent kinase inhibitor 2A and B (CDKN2A, CDKN2B), epidermal growth factor receptor (EGFR), telomerase reverse transcriptase (TERT), TP53, pleckstrin homology-like domain family B member 1 (PHLDB1), and regulator of telomere elongation helicase 1 (RTEL1).	('cyclin-dependent kinase inhibitor 2A and B', 'Gene', '1029', (100, 142))	('CDKN2B', 'Gene', (152, 158))	('EGFR', 'Gene', (195, 199))	('RTEL1', 'Gene', (358, 363))	('gliomas', 'Disease', (84, 91))	('pleckstrin homology-like domain family B member 1', 'Gene', (249, 298))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('TP53', 'Gene', (243, 247))	('PHLDB1', 'Gene', (300, 306))	('telomerase reverse transcriptase', 'Gene', '7015', (202, 234))	('TERT', 'Gene', (236, 240))	('TERT', 'Gene', '7015', (236, 240))	('PHLDB1', 'Gene', '23187', (300, 306))	('pleckstrin homology-like domain family B member 1', 'Gene', '23187', (249, 298))	('CDKN2A', 'Gene', (144, 150))	('CDKN2B', 'Gene', '1030', (152, 158))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('EGFR', 'Gene', '1956', (195, 199))	('regulator of telomere elongation helicase 1', 'Gene', '51750', (313, 356))	('RTEL1', 'Gene', '51750', (358, 363))	('mutations', 'Var', (61, 70))	('regulator of telomere elongation helicase 1', 'Gene', (313, 356))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('CDKN2A', 'Gene', '1029', (144, 150))	('TP53', 'Gene', '7157', (243, 247))	('epidermal growth factor receptor', 'Gene', (161, 193))	('affected', 'Reg', (41, 49))	('epidermal growth factor receptor', 'Gene', '1956', (161, 193))	('telomerase reverse transcriptase', 'Gene', (202, 234))
200726	31968687	The first germline studies identified a locus on chromosome 9p21, encompassing the CDKN2A (MIM number 600160) and CDKN2B (MIM number 600431) tumor suppressor genes, which have an established role in glioma development.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CDKN2B', 'Gene', (114, 120))	('CDKN2A', 'Gene', '1029', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('MIM number 600160', 'Var', (91, 108))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('CDKN2B', 'Gene', '1030', (114, 120))	('tumor', 'Disease', (141, 146))	('MIM number 600431', 'Var', (122, 139))	('glioma', 'Disease', (199, 205))	('CDKN2A', 'Gene', (83, 89))
200727	31968687	In keeping with this, homozygous deletion in CDKN2A is detectable in approximately 50% of tumors, and the loss of CDKN2A expression is linked to poor prognosis.	('CDKN2A', 'Gene', '1029', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('expression', 'MPA', (121, 131))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CDKN2A', 'Gene', (45, 51))	('loss', 'NegReg', (106, 110))	('CDKN2A', 'Gene', (114, 120))	('homozygous deletion', 'Var', (22, 41))	('CDKN2A', 'Gene', '1029', (45, 51))
200728	31968687	Furthermore, CDKN2A germline mutations are responsible for the melanoma-astrocytoma syndrome (MIM number 155755), and genetic variants close to both CDKN2A and CDKN2B genes (on the chromosomal locus 9p21) are known to increase the risk for glioma, basal cell carcinoma, and melanoma.	('CDKN2A', 'Gene', '1029', (149, 155))	('basal cell carcinoma', 'Disease', (248, 268))	('CDKN2B', 'Gene', (160, 166))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('CDKN2A', 'Gene', '1029', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('CDKN2B', 'Gene', '1030', (160, 166))	('melanoma-astrocytoma syndrome', 'Disease', 'MESH:C536149', (63, 92))	('glioma', 'Disease', (240, 246))	('melanoma-astrocytoma syndrome', 'Disease', (63, 92))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (248, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('mutations', 'Var', (29, 38))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('responsible', 'Reg', (43, 54))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('CDKN2A', 'Gene', (149, 155))	('increase', 'Reg', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('variants', 'Var', (126, 134))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (248, 268))	('CDKN2A', 'Gene', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))
200730	31968687	This is consistent with germline variants at 8q24.21, which are associated with IDH1- IDH2 mutated astrocytoma and oligodendroglial tumors.	('IDH2', 'Gene', (86, 90))	('associated', 'Reg', (64, 74))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('IDH2', 'Gene', '3418', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('astrocytoma and oligodendroglial tumors', 'Disease', 'MESH:D001254', (99, 138))	('variants', 'Var', (33, 41))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
200732	31968687	For example, high-grade gliomas are associated with risk variants in RTEL1, CDKN2B, and TERT, while low-grade gliomas with IDH mutation-1p/19q codeletion are associated with risk variants in CCDC26 and PHLDB1 regions.	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('RTEL1', 'Gene', (69, 74))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('variants', 'Var', (57, 65))	('CDKN2B', 'Gene', (76, 82))	('IDH', 'Gene', (123, 126))	('RTEL1', 'Gene', '51750', (69, 74))	('gliomas', 'Disease', (24, 31))	('CCDC26', 'Gene', '137196', (191, 197))	('TERT', 'Gene', (88, 92))	('gliomas', 'Disease', (110, 117))	('PHLDB1', 'Gene', '23187', (202, 208))	('PHLDB1', 'Gene', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('CDKN2B', 'Gene', '1030', (76, 82))	('TERT', 'Gene', '7015', (88, 92))	('CCDC26', 'Gene', (191, 197))	('IDH', 'Gene', '3417', (123, 126))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
200733	31968687	Diffuse gliomas (DGs) of the astrocytic and oligodendroglial lineages (grade II and III) are characterized by frequent IDH mutations (Figure 2A).	('IDH', 'Gene', '3417', (119, 122))	('gliomas', 'Disease', (8, 15))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('IDH', 'Gene', (119, 122))	('mutations', 'Var', (123, 132))
200735	31968687	Mutations in IDH1 or its homolog 2 (IDH2) have been identified as early molecular events in the development of astrocytomas and oligodendrogliomas, and they occur in various types of malignancies, including IDH-mutant glioblastoma (grade IV) (Figure 2A).	('IDH2', 'Gene', (36, 40))	('IDH2', 'Gene', '3418', (36, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('IDH1', 'Gene', (13, 17))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Mutations', 'Var', (0, 9))	('IDH-mutant glioblastoma', 'Disease', (207, 230))	('malignancies', 'Disease', (183, 195))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (111, 146))	('IDH1', 'Gene', '3417', (13, 17))	('IDH-mutant glioblastoma', 'Disease', 'MESH:D005909', (207, 230))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('occur', 'Reg', (157, 162))
200736	31968687	These mutations affect the R132 codon of IDH1 or the corresponding R172 codon in its homolog IDH2 (p.R172K, p.R172W, and p.R172M), which fall in catalytically-active sites of these enzymes.	('fall', 'Phenotype', 'HP:0002527', (137, 141))	('IDH2', 'Gene', '3418', (93, 97))	('p.R172K', 'Var', (99, 106))	('affect', 'Reg', (16, 22))	('p.R172M', 'Var', (121, 128))	('p.R172M', 'Mutation', 'rs121913503', (121, 128))	('p.R172K', 'Mutation', 'rs121913503', (99, 106))	('IDH1', 'Gene', (41, 45))	('p.R172W', 'Var', (108, 115))	('IDH1', 'Gene', '3417', (41, 45))	('p.R172W', 'Mutation', 'rs1057519906', (108, 115))	('IDH2', 'Gene', (93, 97))
200737	31968687	Although both types of gliomas contain IDH1/2 mutations, in astrocytic gliomas, IDH mutations are typically associated with mutations in TP53 and ATRX genes (Figure 2A).	('IDH1/2', 'Gene', (39, 45))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('mutations', 'Var', (46, 55))	('IDH', 'Gene', (80, 83))	('ATRX', 'Gene', (146, 150))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('IDH', 'Gene', (39, 42))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (60, 78))	('astrocytic gliomas', 'Disease', (60, 78))	('ATRX', 'Gene', '546', (146, 150))	('TP53', 'Gene', (137, 141))	('gliomas', 'Disease', (71, 78))	('mutations', 'Var', (84, 93))	('associated', 'Reg', (108, 118))	('IDH', 'Gene', '3417', (80, 83))	('IDH', 'Gene', '3417', (39, 42))	('mutations', 'Var', (124, 133))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Disease', (23, 30))	('TP53', 'Gene', '7157', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH1/2', 'Gene', '3417;3418', (39, 45))
200740	31968687	Later on, sequence analysis was focused on hotspot mutations located in exons 5-8, although recent studies suggest that TP53 carries mutations also outside its mutational hotspots.	('TP53', 'Gene', '7157', (120, 124))	('mutations', 'Var', (133, 142))	('TP53', 'Gene', (120, 124))
200741	31968687	Loss-of-function mutations in ATRX (SWI/SNF chromatin re-modeler gene) co-occur with mutations in TP53 and IDH1/IDH2 genes in adults or H3.3 histone monomers genes (H3F3A and HIST1H3B) in children.	('IDH1', 'Gene', (107, 111))	('Loss-of-function', 'NegReg', (0, 16))	('ATRX', 'Gene', (30, 34))	('H3F3A', 'Gene', '3020', (165, 170))	('HIST1H3B', 'Gene', (175, 183))	('IDH2', 'Gene', (112, 116))	('IDH1', 'Gene', '3417', (107, 111))	('H3F3A', 'Gene', (165, 170))	('HIST1H3B', 'Gene', '8358', (175, 183))	('mutations', 'Var', (85, 94))	('IDH2', 'Gene', '3418', (112, 116))	('ATRX', 'Gene', '546', (30, 34))	('TP53', 'Gene', '7157', (98, 102))	('children', 'Species', '9606', (188, 196))	('mutations', 'Var', (17, 26))	('TP53', 'Gene', (98, 102))
200742	31968687	Recent papers suggest that ATRX deficiency produces deleterious effects on genomic integrity through an alternative lengthening of telomeres (ALT) that impairs the physiological arrest of cell division.	('ATRX', 'Gene', (27, 31))	('ATRX', 'Gene', '546', (27, 31))	('genomic integrity', 'CPA', (75, 92))	('effects', 'Reg', (64, 71))	('deficiency', 'Var', (32, 42))	('impairs', 'NegReg', (152, 159))	('physiological arrest of cell division', 'CPA', (164, 201))
200743	31968687	Similarly to astrocytomas, oligodendrogliomas have IDH mutations associated with co-deletion of chromosomal arms 1p and 19q (Figure 2A).	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('astrocytomas', 'Disease', 'MESH:D001254', (13, 25))	('astrocytoma', 'Phenotype', 'HP:0009592', (13, 24))	('mutations', 'Var', (55, 64))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('oligodendrogliomas have IDH', 'Disease', 'MESH:D009837', (27, 54))	('associated', 'Reg', (65, 75))	('astrocytomas', 'Disease', (13, 25))	('oligodendrogliomas have IDH', 'Disease', (27, 54))
200744	31968687	According to the 2007 WHO classification, oligodendrogliomas could be diagnosed only when typical histological features are associated with the recently defined "oligodendroglioma, IDH-mutant and 1p/19q codeleted", a molecular condition that requires the concomitancy of both IDH1 or IDH2 mutations and 1p/19q co-deletion.	('oligodendroglioma', 'Disease', (162, 179))	('mutations', 'Var', (289, 298))	('IDH2', 'Gene', (284, 288))	('oligodendroglioma', 'Disease', 'MESH:D009837', (42, 59))	('IDH2', 'Gene', '3418', (284, 288))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('oligodendrogliomas', 'Disease', (42, 60))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('oligodendroglioma', 'Disease', (42, 59))	('IDH1', 'Gene', (276, 280))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('IDH', 'Gene', (276, 279))	('IDH', 'Gene', (284, 287))	('IDH', 'Gene', (181, 184))	('IDH1', 'Gene', '3417', (276, 280))	('IDH', 'Gene', '3417', (276, 279))	('IDH', 'Gene', '3417', (284, 287))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (42, 60))	('IDH', 'Gene', '3417', (181, 184))	('oligodendroglioma', 'Disease', 'MESH:D009837', (162, 179))
200745	31968687	Oligodendrogliomas often feature mutations in the Drosophila homolog of capicua transcriptional repressor (CIC) gene and the TERT promoter, which encodes for the catalytic subunit of telomerase.	('CIC', 'Gene', (107, 110))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('feature', 'Reg', (25, 32))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('mutations', 'Var', (33, 42))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('capicua transcriptional repressor', 'Gene', '53560', (72, 105))	('capicua transcriptional repressor', 'Gene', (72, 105))	('TERT', 'Gene', (125, 129))	('TERT', 'Gene', '7015', (125, 129))
200746	31968687	The two most common mutations in the TERTp are p.C228T and p.C250T, which are located upstream of the TERT ATG start site.	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', (102, 106))	('p.C228T', 'Var', (47, 54))	('TERT', 'Gene', '7015', (102, 106))	('TERT', 'Gene', '7015', (37, 41))	('p.C250T', 'Var', (59, 66))	('p.C228T', 'Mutation', 'p.C228T', (47, 54))	('p.C250T', 'Mutation', 'p.C250T', (59, 66))
200747	31968687	These mutations produce TERT activation, which is responsible for the growth properties of the tumor cells, indicating the importance of its role in cancer development (Figure 2A).	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('produce', 'Reg', (16, 23))	('TERT', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('TERT', 'Gene', '7015', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', (95, 100))
200751	31968687	It is known that the effect of pTERT mutations is inversely related to mutations found in the IDH1 gene, and this is strongly related to a favorable prognosis.	('TERT', 'Gene', '7015', (32, 36))	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', '3417', (94, 98))	('mutations found', 'Var', (71, 86))	('related to', 'Reg', (126, 136))	('TERT', 'Gene', (32, 36))
200753	31968687	Primary glioblastomas typically lack IDH mutations, while possessing severe dysregulations of specific signaling pathways (Figure 2B).	('mutations', 'Var', (41, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('Primary glioblastomas', 'Disease', (0, 21))	('lack', 'NegReg', (32, 36))	('specific signaling pathways', 'Pathway', (94, 121))	('IDH', 'Gene', (37, 40))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('Primary glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('IDH', 'Gene', '3417', (37, 40))
200754	31968687	This is best exemplified by alterations in tyrosine kinase receptor (RTK)/RAS/PI(3)K signaling leading to EGFR amplification.	('alterations', 'Var', (28, 39))	('tyrosine kinase receptor', 'MPA', (43, 67))	('amplification', 'MPA', (111, 124))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (106, 110))
200756	31968687	A quite common activating EGFR mutation consists of exons 2-7 deletion leading to a truncated EGFR variant III (EGFRvIII), which is often described in glioblastoma.	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', '1956', (94, 98))	('glioblastoma', 'Disease', (151, 163))	('mutation', 'Var', (31, 39))	('variant III', 'Var', (99, 110))	('EGFR', 'Gene', (94, 98))	('activating', 'PosReg', (15, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', '1956', (26, 30))
200758	31968687	Among EGFR mutants, EGFRvIII represents a late event following wild type EGFR amplification.	('mutants', 'Var', (11, 18))	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (6, 10))	('EGFR', 'Gene', (20, 24))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (20, 24))	('EGFR', 'Gene', '1956', (6, 10))
200760	31968687	In addition, 24% of glioblastoma samples have point mutations in the extracellular region of EGFR which keep EGFR in active conformation.	('EGFR', 'Gene', '1956', (93, 97))	('glioblastoma', 'Disease', (20, 32))	('active conformation', 'MPA', (117, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (109, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('EGFR', 'Gene', (109, 113))	('keep', 'Reg', (104, 108))	('point mutations', 'Var', (46, 61))
200761	31968687	Primary glioblastomas also carry mutations in the phosphatase and tensin homolog (PTEN) gene and in the TERT promoter.	('Primary glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('mutations', 'Var', (33, 42))	('Primary glioblastomas', 'Disease', (0, 21))	('TERT', 'Gene', (104, 108))	('TERT', 'Gene', '7015', (104, 108))	('PTEN', 'Gene', (82, 86))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('PTEN', 'Gene', '5728', (82, 86))
200762	31968687	In addition, monosomy of chromosome 10, gain of chromosome 7 or 7q, and loss of 9p involving the CDKN2A/B loci often occur.	('CDKN2A/B', 'Gene', '1029;1030', (97, 105))	('loss', 'NegReg', (72, 76))	('monosomy', 'Var', (13, 21))	('CDKN2A/B', 'Gene', (97, 105))	('gain', 'PosReg', (40, 44))
200763	31968687	Over the last decade, mutations in epigenetic regulator genes have been identified as key drivers for specific subtypes of glioma with distinct clinical features.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('mutations', 'Var', (22, 31))	('glioma', 'Disease', (123, 129))
200764	31968687	This is the case of mutations in IDH1 or IDH2 in lower-grade gliomas, and histone 3 (H3F3A and HIST1H3B) mutations in pediatric high-grade gliomas that are also associated with specific patterns of DNA methylation.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('H3F3A', 'Gene', '3020', (85, 90))	('IDH2', 'Gene', '3418', (41, 45))	('IDH1', 'Gene', (33, 37))	('gliomas', 'Disease', (139, 146))	('H3F3A', 'Gene', (85, 90))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Disease', (61, 68))	('IDH1', 'Gene', '3417', (33, 37))	('IDH2', 'Gene', (41, 45))	('mutations', 'Var', (105, 114))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('mutations', 'Var', (20, 29))	('HIST1H3B', 'Gene', (95, 103))	('HIST1H3B', 'Gene', '8358', (95, 103))
200768	31968687	MGMT silencing may blunt therapeutic efficacy by hampering the repairs of O6-methylguanine, a toxic damage induced by alkylating agents.	('repairs', 'MPA', (63, 70))	('MGMT', 'Gene', (0, 4))	('hampering', 'NegReg', (49, 58))	('therapeutic', 'MPA', (25, 36))	('blunt', 'NegReg', (19, 24))	('O6-methylguanine', 'MPA', (74, 90))	('toxic damage', 'Disease', 'MESH:D064420', (94, 106))	('silencing', 'Var', (5, 14))	('toxic damage', 'Disease', (94, 106))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (74, 90))	('MGMT', 'Gene', '4255', (0, 4))
200769	31968687	Therefore, GMB patients with unmethylated MGMT do not profit much from the addition of temozolomide either as a concomitant drug or as an adjuvant to radiotherapy.	('MGMT', 'Gene', (42, 46))	('patients', 'Species', '9606', (15, 23))	('MGMT', 'Gene', '4255', (42, 46))	('temozolomide', 'Chemical', 'MESH:D000077204', (87, 99))	('unmethylated', 'Var', (29, 41))	('GMB', 'Chemical', 'MESH:C032138', (11, 14))
200771	31968687	Correlations between IDH1 mutation, MGMT promoter methylation and survival outcomes have been analyzed.	('mutation', 'Var', (26, 34))	('MGMT', 'Gene', (36, 40))	('MGMT', 'Gene', '4255', (36, 40))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (21, 25))
200772	31968687	The role of the MGMT methylation status on benefit from temozolomide in IDH mutant (IDHmt) lower-grade gliomas is less clear, although most cases (>80%) show methylation at the MGMT promoter.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('methylation', 'Var', (158, 169))	('mutant', 'Var', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('IDH', 'Gene', (72, 75))	('MGMT', 'Gene', (177, 181))	('MGMT', 'Gene', (16, 20))	('IDH', 'Gene', '3417', (84, 87))	('IDH', 'Gene', '3417', (72, 75))	('MGMT', 'Gene', '4255', (177, 181))	('MGMT', 'Gene', '4255', (16, 20))	('temozolomide', 'Chemical', 'MESH:D000077204', (56, 68))	('IDH', 'Gene', (84, 87))
200777	31968687	Recurrent Copy Number Variations (CNVs) have been reported in gliomas, where various chromosome regions are involved following several combinations, suggesting a strong genomic instability.	('Copy Number Variations', 'Var', (10, 32))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('reported', 'Reg', (50, 58))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
200786	31968687	Virtually, 1p/19q co-deleted tumors harbor an accompanying IDH1/IDH2 mutation.	('IDH1', 'Gene', '3417', (59, 63))	('tumors', 'Disease', (29, 35))	('IDH2', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutation', 'Var', (69, 77))	('IDH2', 'Gene', '3418', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('IDH1', 'Gene', (59, 63))
200787	31968687	Other common molecular alterations co-occurring with 1p/19q co-deletion include variants in TERT, CIC, (far upstream element-binding protein 1) FUBP1 as well as MGMT promoter methylation.	('TERT', 'Gene', (92, 96))	('far upstream element-binding protein 1', 'Gene', '8880', (104, 142))	('TERT', 'Gene', '7015', (92, 96))	('FUBP1', 'Gene', '8880', (144, 149))	('FUBP1', 'Gene', (144, 149))	('variants', 'Var', (80, 88))	('CIC', 'Gene', (98, 101))	('MGMT', 'Gene', (161, 165))	('MGMT', 'Gene', '4255', (161, 165))	('far upstream element-binding protein 1', 'Gene', (104, 142))
200789	31968687	IH has been widely used for the detection of EGFRvIII in tumors with EGFR rearrangements, as well as for ATRX, TP53, and IDHR132.	('EGFR', 'Gene', '1956', (69, 73))	('ATRX', 'Gene', '546', (105, 109))	('EGFR', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (111, 115))	('EGFR', 'Gene', (69, 73))	('IDH', 'Gene', (121, 124))	('ATRX', 'Gene', (105, 109))	('TP53', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IDH', 'Gene', '3417', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('rearrangements', 'Var', (74, 88))	('EGFR', 'Gene', '1956', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
200790	31968687	Array comparative genomic hybridization (aCGH), a technique enabling high-resolution, genome-wide screening of CNVs, has been fundamental to detect complex genomic alterations that involve gliomagenesis, including sequence changes, CNVs, and epigenetic modifications.	('gliomagenesis', 'Disease', 'None', (189, 202))	('CNVs', 'Disease', (232, 236))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('gliomagenesis', 'Disease', (189, 202))	('epigenetic modifications', 'Var', (242, 266))	('sequence changes', 'Var', (214, 230))
200794	31968687	When applying NGS assay for the routine diagnosis of CNS tumours, several issues need to be considered: (i) The assay should identify single nucleotide variations, insertions and deletions, complex genetic alterations (gene fusions, CNVs) in a set of genes, and mutational hotspots.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('insertions', 'Var', (164, 174))	('single nucleotide variations', 'Var', (134, 162))	('deletions', 'Var', (179, 188))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('complex genetic alterations', 'Var', (190, 217))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
200799	31968687	used a 20-gene panel for an integrated histological and molecular diagnosis of 111 diffuse gliomas, allowing a re-classification of oligoastrocytoma and glioblastoma by IDH-status and identification of tumours with H3F3A mutations.	('gliomas', 'Disease', (91, 98))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (132, 148))	('IDH', 'Gene', '3417', (169, 172))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('H3F3A', 'Gene', '3020', (215, 220))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('mutations', 'Var', (221, 230))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('oligoastrocytoma', 'Disease', (132, 148))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('H3F3A', 'Gene', (215, 220))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('glioblastoma', 'Disease', (153, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('IDH', 'Gene', (169, 172))	('tumours', 'Disease', (202, 209))
200801	31968687	This is the case of tuberous sclerosis 1/hamartin (TSC1) or tuberous sclerosis 2/tuberin (TSC2) mutations occurring in subependymal giant cell astrocytomas, as well as H3 histone family member A/B (HIST1H3A/B) and activin receptor type 1 (ACVR1) mutations in diffuse intrinsic pontine gliomas.	('subependymal giant cell astrocytomas', 'Disease', 'MESH:D001254', (119, 155))	('ACVR1', 'Gene', '90', (239, 244))	('gliomas', 'Disease', 'MESH:D005910', (285, 292))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (20, 38))	('tuberin', 'Gene', '7249', (81, 88))	('activin receptor type 1', 'Gene', '90', (214, 237))	('glioma', 'Phenotype', 'HP:0009733', (285, 291))	('tuberin', 'Gene', (81, 88))	('TSC1', 'Gene', (51, 55))	('H3 histone family member A/B', 'Gene', '8350;8351', (168, 196))	('tuberous sclerosis', 'Disease', (20, 38))	('mutations', 'Var', (96, 105))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (60, 78))	('gliomas', 'Phenotype', 'HP:0009733', (285, 292))	('H3 histone family member A/B', 'Gene', (168, 196))	('mutations', 'Var', (246, 255))	('TSC1', 'Gene', '7248', (51, 55))	('tuberous sclerosis', 'Disease', (60, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('hamartin', 'Gene', '7248', (41, 49))	('TSC2', 'Gene', '7249', (90, 94))	('hamartin', 'Gene', (41, 49))	('subependymal giant cell astrocytomas', 'Disease', (119, 155))	('activin receptor type 1', 'Gene', (214, 237))	('gliomas', 'Disease', (285, 292))	('ACVR1', 'Gene', (239, 244))	('HIST1H3A/B', 'Gene', (198, 208))	('TSC2', 'Gene', (90, 94))	('subependymal giant cell astrocytomas', 'Phenotype', 'HP:0009718', (119, 155))
200803	31968687	These approaches, considering targeted or extended genes panel, reliably assess key mutations such as CNVs, including 1p/19q codeletion and EGFR gene amplification, CDKN2A homozygous deletion, and PTEN loss.	('EGFR', 'Gene', (140, 144))	('CDKN2A', 'Gene', (165, 171))	('PTEN', 'Gene', (197, 201))	('PTEN', 'Gene', '5728', (197, 201))	('CNVs', 'Gene', (102, 106))	('amplification', 'Var', (150, 163))	('CDKN2A', 'Gene', '1029', (165, 171))	('loss', 'NegReg', (202, 206))	('homozygous', 'Var', (172, 182))	('EGFR', 'Gene', '1956', (140, 144))
200808	31968687	Tagged-amplicon deep sequencing (TAm-Seq) allowed detecting blood-ctDNA mutations in about 2% of gliomas.	('detecting', 'Reg', (50, 59))	('mutations', 'Var', (72, 81))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('blood-ctDNA', 'Gene', (60, 71))
200814	31968687	found mutations in IDH1/2, EGFR, PTEN, FGFR2, and ERBB2 genes, and they showed that CSF-ctDNA undergoes dynamic changes that are correlated with the treatment course of patients with glioblastoma.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (169, 177))	('ERBB2', 'Gene', (50, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (183, 195))	('ERBB2', 'Gene', '2064', (50, 55))	('IDH1/2', 'Gene', (19, 25))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('correlated', 'Reg', (129, 139))	('FGFR2', 'Gene', (39, 44))	('glioblastoma', 'Disease', (183, 195))	('FGFR2', 'Gene', '2263', (39, 44))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (183, 195))	('mutations', 'Var', (6, 15))
200822	31968687	This is the case of CSF-isolated EVs which allowed the detection of IDH1 mutations in five out of eight patients using beads, emulsion, amplification, magnetics (BEAMing) and Droplet Digital PCR (ddPCR) techniques.	('detection', 'Reg', (55, 64))	('Droplet Digital', 'Disease', 'MESH:D058066', (175, 190))	('IDH1', 'Gene', (68, 72))	('IDH1', 'Gene', '3417', (68, 72))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (73, 82))	('Droplet Digital', 'Disease', (175, 190))
200828	31968687	Recently, 41 immune prognostic genes were identified in glioma patients based on the IDH1 mutation status.	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH1', 'Gene', (85, 89))	('patients', 'Species', '9606', (63, 71))	('IDH1', 'Gene', '3417', (85, 89))	('mutation status', 'Var', (90, 105))
200833	31968687	In glioma patients, a correlation has also been identified among EGFR mutation, shorter survival time and increased infiltration of immune cells along with PD-L1 expression.	('EGFR', 'Gene', '1956', (65, 69))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('EGFR', 'Gene', (65, 69))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('mutation', 'Var', (70, 78))	('shorter', 'NegReg', (80, 87))	('glioma', 'Disease', (3, 9))	('patients', 'Species', '9606', (10, 18))	('infiltration of immune cells', 'CPA', (116, 144))	('increased', 'PosReg', (106, 115))	('survival time', 'CPA', (88, 101))
200841	31968687	On the contrary, somatic mutations identified within the tissue define tumor genotype as well as glioma subtypes, focusing on dysregulated pathways that can be either common or specific to a subset of cancers.	('mutations', 'Var', (25, 34))	('dysregulated', 'MPA', (126, 138))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('glioma', 'Disease', (97, 103))	('cancers', 'Disease', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('tumor', 'Disease', (71, 76))
200844	31968687	This technique is now under evaluation as an all-in-one diagnostic tool aimed at detecting both DNA copy number variations and mutations in glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('mutations', 'Var', (127, 136))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('glioma', 'Disease', (140, 146))
200949	32692766	This study aims to evaluate epigenetic age acceleration as a prognostic biomarker for gliomas.	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('epigenetic age acceleration', 'Var', (28, 55))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))
200951	32692766	We used multivariate linear regression to assess the association of epigenetic age acceleration with tumor molecular subtypes, including Codel, Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like.	('Codel', 'Disease', (137, 142))	('Mesenchymal-like', 'CPA', (183, 199))	('G-CIMP-low', 'Chemical', '-', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('G-CIMP-low', 'Var', (171, 181))	('Classic-like', 'Disease', (144, 156))	('epigenetic age', 'Var', (68, 82))	('PA-like', 'Disease', (204, 211))	('G-CIMP-high', 'Var', (158, 169))	('G-CIMP', 'Chemical', '-', (171, 177))	('G-CIMP', 'Chemical', '-', (158, 164))	('association', 'Interaction', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
200954	32692766	Our results show epigenetic age acceleration is positively associated with patient overall survival (per 10-year age acceleration, HR = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03) in multivariate analysis.	('epigenetic age acceleration', 'Var', (17, 44))	('patient overall survival', 'CPA', (75, 99))	('patient', 'Species', '9606', (75, 82))	('associated', 'Reg', (59, 69))
200955	32692766	When stratified by molecular subtypes, epigenetic age acceleration remains positively associated with patient survival after adjusting age and tumor grade.	('epigenetic age acceleration', 'Var', (39, 66))	('tumor', 'Disease', (143, 148))	('patient', 'Species', '9606', (102, 109))	('associated', 'Reg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('patient survival', 'CPA', (102, 118))
200956	32692766	In conclusion, epigenetic age acceleration is significantly associated with molecular subtypes and patient overall survival in gliomas, indication that epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.	('patient', 'Species', '9606', (99, 106))	('epigenetic age acceleration', 'Var', (15, 42))	('epigenetic', 'Var', (152, 162))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('gliomas', 'Disease', (237, 244))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('associated', 'Reg', (60, 70))
200959	32692766	In addition, epigenetic age acceleration shows predictive power for morbidity and mortality.	('mortality', 'Disease', 'MESH:D003643', (82, 91))	('epigenetic age acceleration', 'Var', (13, 40))	('mortality', 'Disease', (82, 91))
200960	32692766	Though epigenetic age acceleration was observed in many cancers, it remains unclear whether epigenetic age can be used as biomarkers for cancer prognosis.	('cancers', 'Disease', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (137, 143))	('epigenetic age', 'Var', (7, 21))	('acceleration', 'PosReg', (22, 34))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
200963	32692766	For example, mutations in IDH1 is associated with better survival in younger patients of GBM; 1p/19q deletion is strongly associated with oligodendroglia differentiation and better response to chemical therapies in oligodendroglioma patients.	('IDH1', 'Gene', '3417', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('oligodendroglioma', 'Disease', (215, 232))	('associated with', 'Reg', (122, 137))	('IDH1', 'Gene', (26, 30))	('patients', 'Species', '9606', (77, 85))	('oligodendroglia differentiation', 'Disease', (138, 169))	('oligodendroglioma', 'Disease', 'MESH:D009837', (215, 232))	('mutations', 'Var', (13, 22))	('oligodendroglia differentiation', 'Disease', 'MESH:D012734', (138, 169))	('patients', 'Species', '9606', (233, 241))
200966	32692766	For example, mutations in IDH1 only occur in 12% of GBM patients and 1p/19q deletion are mostly found in oigodendrogliomas, but not GBM.	('patients', 'Species', '9606', (56, 64))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('IDH1', 'Gene', (26, 30))	('oigodendrogliomas', 'Disease', (105, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('oigodendrogliomas', 'Disease', 'None', (105, 122))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', '3417', (26, 30))	('found', 'Reg', (96, 101))
200968	32692766	Here we evaluate the potential of epigenetic age acceleration as quantitative prognostic biomarkers for broad types of gliomas, including both GBM and LGG.	('LGG', 'Disease', (151, 154))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('epigenetic age', 'Var', (34, 48))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('GBM', 'Disease', (143, 146))
200969	32692766	A recent study suggested that epigenetic aging can serve as a potential prognostic biomarker for gliomas and showed that epigenetic age was correlated with molecular subtype of gliomas and significantly associated with patient survival.	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Disease', (177, 184))	('patient', 'Species', '9606', (219, 226))	('gliomas', 'Disease', (97, 104))	('epigenetic aging', 'Var', (30, 46))	('associated with', 'Reg', (203, 218))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('correlated', 'Reg', (140, 150))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('epigenetic age', 'Var', (121, 135))
200971	32692766	In this study, we aim to evaluate the potential of epigenetic age acceleration (epigenetic aging after controlling the effects of biological aging) as a prognostic biomarker for gliomas.	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('acceleration', 'PosReg', (66, 78))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('gliomas', 'Disease', (178, 185))	('epigenetic age', 'Var', (51, 65))
200972	32692766	The association of epigenetic age acceleration with cancer patient outcomes has been investigated in several studies.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('epigenetic age', 'Var', (19, 33))	('patient', 'Species', '9606', (59, 66))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
200973	32692766	A pan-cancer study using DNA methylation data from The Cancer Genome Atlas (TCGA) reported that the association of epigenetic age acceleration with patient survival varies with cancer types.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient survival', 'CPA', (148, 164))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('Cancer', 'Disease', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patient', 'Species', '9606', (148, 155))	('epigenetic age', 'Var', (115, 129))	('cancer', 'Disease', (6, 12))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('acceleration', 'PosReg', (130, 142))
200980	32692766	In this study, we examined the association of epigenetic age acceleration and clinical outcomes of gliomas using tumor tissue samples.	('epigenetic age acceleration', 'Var', (46, 73))	('tumor', 'Disease', (113, 118))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
200981	32692766	We recently reported that epigenetic age acceleration is significantly associated with consensus molecular subtypes (CMS) of colorectal cancer in the TCGA patients.	('CMS', 'Disease', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('epigenetic age acceleration', 'Var', (26, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('patients', 'Species', '9606', (155, 163))	('colorectal cancer', 'Disease', (125, 142))	('CMS', 'Disease', 'MESH:C536089', (117, 120))	('associated', 'Reg', (71, 81))
200982	32692766	Compared with CMS2, epigenetic age acceleration for CMS1, CMS3, and CMS4 was 23.90 years, 9.16 years, and 6.05 years, respectively.	('acceleration', 'PosReg', (35, 47))	('CMS', 'Disease', (14, 17))	('CMS', 'Disease', (52, 55))	('CMS', 'Disease', 'MESH:C536089', (68, 71))	('CMS', 'Disease', 'MESH:C536089', (58, 61))	('epigenetic age', 'Var', (20, 34))	('CMS', 'Disease', (68, 71))	('CMS', 'Disease', 'MESH:C536089', (14, 17))	('CMS', 'Disease', (58, 61))	('CMS', 'Disease', 'MESH:C536089', (52, 55))
200983	32692766	Furthermore, epigenetic age acceleration is positively associated with total mortality (HR = 1.97; 95%CI: 1.14-3.39; P = 0.014).	('mortality', 'Disease', (77, 86))	('mortality', 'Disease', 'MESH:D003643', (77, 86))	('acceleration', 'PosReg', (28, 40))	('epigenetic age', 'Var', (13, 27))
200985	32692766	Leveraging multiple robust molecular subtyping platforms and extensive DNA methylation data for gliomas available in TCGA, we here evaluated epigenetic age acceleration as a potential biomarker for glioma patient survival, with an emphasis on its association with molecular subtypes and tumor grade.	('patient', 'Species', '9606', (205, 212))	('glioma', 'Disease', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('acceleration', 'PosReg', (156, 168))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('gliomas', 'Disease', (96, 103))	('epigenetic age', 'Var', (141, 155))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('glioma', 'Disease', (96, 102))
200986	32692766	We found that accelerated epigenetic age is significantly associated with better patient survival of gliomas, which is opposite to that observed in colorectal cancer.	('better', 'PosReg', (74, 80))	('patient survival', 'CPA', (81, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('patient', 'Species', '9606', (81, 88))	('epigenetic age', 'Var', (26, 40))	('gliomas', 'Disease', (101, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('colorectal cancer', 'Disease', (148, 165))	('accelerated', 'PosReg', (14, 25))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
200991	32692766	In this study, we used the Supervised DNA methylation (SDM) system based on its better clinical relevance, which classified brain tumors patients into six types: Codel (IDH mutant-codel LGGs), G-CIMP-high (IDH mutant-non-codel glioma with higher global levels of DNA methylation), G-CIMP-low (IDH mutant-non-codel glioma with relatively low genome-wide DNA methylation), Classic-like (IDH wild type with classical gene expression signature) and Mesenchymal-like and PA-like (pilocytic astrocytoma).	('glioma', 'Disease', (314, 320))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('IDH', 'Gene', '3417', (385, 388))	('glioma', 'Disease', 'MESH:D005910', (314, 320))	('IDH', 'Gene', '3417', (169, 172))	('IDH', 'Gene', (206, 209))	('astrocytoma', 'Phenotype', 'HP:0009592', (485, 496))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('IDH', 'Gene', (293, 296))	('glioma', 'Phenotype', 'HP:0009733', (314, 320))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('G-CIMP-low', 'Chemical', '-', (281, 291))	('IDH', 'Gene', '3417', (206, 209))	('patients', 'Species', '9606', (137, 145))	('IDH', 'Gene', '3417', (293, 296))	('G-CIMP', 'Chemical', '-', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('brain tumors', 'Disease', 'MESH:D001932', (124, 136))	('brain tumors', 'Phenotype', 'HP:0030692', (124, 136))	('astrocytoma', 'Disease', 'MESH:D001254', (485, 496))	('G-CIMP-high', 'Var', (193, 204))	('IDH', 'Gene', (385, 388))	('astrocytoma', 'Disease', (485, 496))	('IDH', 'Gene', (169, 172))	('G-CIMP', 'Chemical', '-', (193, 199))	('Mesenchymal-like and', 'CPA', (445, 465))	('brain tumors', 'Disease', (124, 136))	('glioma', 'Disease', (227, 233))
200996	32692766	Multivariable linear regression model was used to assess the association of epigenetic age acceleration with tumor molecular subtype and tumor grade.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('epigenetic age acceleration', 'Var', (76, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (109, 114))
201003	32692766	Based on univariate analysis, epigenetic age acceleration was significantly associated with race, histology type, tumor grade and SDM subtypes, but not with gender (Table 1).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('epigenetic age acceleration', 'Var', (30, 57))	('tumor', 'Disease', (114, 119))	('associated', 'Interaction', (76, 86))	('SDM', 'Disease', (130, 133))
201005	32692766	After adjusting age group, race and tumor grade, epigenetic age acceleration remains significantly associated with molecular subtypes.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('epigenetic age acceleration', 'Var', (49, 76))	('tumor', 'Disease', (36, 41))	('associated', 'Reg', (99, 109))
201007	32692766	Furthermore, the age deceleration showed bigger in the order of Class-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like, which is also concordant with that in the discovery dataset.	('G-CIMP-low', 'Chemical', '-', (89, 99))	('Mesenchymal-like', 'CPA', (101, 117))	('G-CIMP', 'Chemical', '-', (76, 82))	('G-CIMP-low', 'Var', (89, 99))	('age deceleration', 'CPA', (17, 33))	('G-CIMP', 'Chemical', '-', (89, 95))	('G-CIMP-high', 'Var', (76, 87))
201008	32692766	We used two methods to investigate the relationship of epigenetic age acceleration with patient overall survival in gliomas: Kaplan-Meier estimator and Cox proportional hazards regression.	('patient', 'Species', '9606', (88, 95))	('gliomas', 'Disease', (116, 123))	('epigenetic age acceleration', 'Var', (55, 82))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
201011	32692766	We show that patients with epigenetic age acceleration have improved survival for both Grade 2 (S2 Fig) and oligoastrocytoma (S3 Fig).	('Grade', 'Disease', (87, 92))	('improved', 'PosReg', (60, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('patients', 'Species', '9606', (13, 21))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (108, 124))	('oligoastrocytoma', 'Disease', (108, 124))	('epigenetic age acceleration', 'Var', (27, 54))
201016	32692766	We show that epigenetic age acceleration is significantly associated with patient survival (per 10-year age acceleration, HR = 0.86, CI: 0.80-0.91, p = 1.20E-06).	('patient survival', 'CPA', (74, 90))	('patient', 'Species', '9606', (74, 81))	('associated', 'Reg', (58, 68))	('epigenetic age acceleration', 'Var', (13, 40))
201017	32692766	To assess whether epigenetic age acceleration can provide independently prognostic information besides survival predictors mentioned above, such as age, tumor grade, histology and molecular subtype, we performed survival analysis using multivariate Cox proportional hazards regression.	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('epigenetic age acceleration', 'Var', (18, 45))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
201018	32692766	Our analysis shows that epigenetic age acceleration is positively associated with patient survival (per 10-year age acceleration, HR = 0.89, CI: 0.82-0.97, p = 9.04E-03) after adjusting age, race, tumor grade and SDM molecular subtype (Table 4), indicating that epigenetic age acceleration is an independent prognostic factor for glioma patients.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('patient', 'Species', '9606', (82, 89))	('epigenetic age', 'Var', (24, 38))	('glioma', 'Disease', 'MESH:D005910', (330, 336))	('patient', 'Species', '9606', (337, 344))	('glioma', 'Phenotype', 'HP:0009733', (330, 336))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('patient survival', 'CPA', (82, 98))	('epigenetic', 'Var', (262, 272))	('patients', 'Species', '9606', (337, 345))	('tumor', 'Disease', (197, 202))	('glioma', 'Disease', (330, 336))
201020	32692766	The epigenetic age acceleration shows similar positive associations with patient survival both in younger and older groups (Fig 2A).	('patient survival', 'CPA', (73, 89))	('patient', 'Species', '9606', (73, 80))	('epigenetic age acceleration', 'Var', (4, 31))
201021	32692766	The epigenetic age acceleration shows similar but distinctive positive associations in each tumor grade group (Fig 2B).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('epigenetic age acceleration', 'Var', (4, 31))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
201022	32692766	When patients were stratified by SDM subtype, epigenetic age acceleration shows positive association with patient survival in Classic-like and Mesenchymal-like subtypes, but negative association with patient survival in Codel subtype.	('patient survival', 'CPA', (106, 122))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('epigenetic age', 'Var', (46, 60))	('patient', 'Species', '9606', (106, 113))	('Mesenchymal-like', 'CPA', (143, 159))	('patient', 'Species', '9606', (200, 207))	('acceleration', 'PosReg', (61, 73))	('positive', 'PosReg', (80, 88))
201024	32692766	Since age and tumor grade are two key predictors for patient survival, we evaluated the epigenetic age acceleration with glioma patient survival after adjusting age and tumor grade.	('epigenetic age', 'Var', (88, 102))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('patient', 'Species', '9606', (53, 60))	('acceleration', 'PosReg', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('patient', 'Species', '9606', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('glioma', 'Disease', (121, 127))
201025	32692766	Suggestive positive associations of epigenetic age acceleration with patient survival were observed in G-CIMP-high and G-CIMP-low subtypes.	('acceleration', 'PosReg', (51, 63))	('epigenetic age', 'Var', (36, 50))	('G-CIMP-low', 'Chemical', '-', (119, 129))	('patient survival', 'CPA', (69, 85))	('G-CIMP-high', 'Disease', (103, 114))	('patient', 'Species', '9606', (69, 76))	('G-CIMP', 'Chemical', '-', (119, 125))	('G-CIMP', 'Chemical', '-', (103, 109))
201031	32692766	Interestingly, we observed the trends that epigenetic age acceleration has benefit for glioma patients similar to the findings in the discover dataset.	('epigenetic age acceleration', 'Var', (43, 70))	('glioma', 'Disease', (87, 93))	('patients', 'Species', '9606', (94, 102))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))
201033	32692766	Similarly, the hazard ratios in G2, G3 and G4 are 0.77 (95% CI: 0.47-1.28, p = 0.317), 0.87 (95% CI: 0.71-1.11, p = 0.299) and 0.97 (95% CI: 0.85-1.10, p = 0.640) respectively For the hazard ratios in different molecular subtypes, epigenetic age acceleration shows marginally positive association with patient survival in Mesenchymal-like subtype (HR: 0.85, 95% CI: 0.70-1.13, p = 0.094) (S5 Table and Fig 4).	('G4', 'Chemical', 'MESH:D004003', (43, 45))	('epigenetic age acceleration', 'Var', (231, 258))	('patient', 'Species', '9606', (302, 309))	('Mesenchymal-like subtype', 'Disease', (322, 346))	('G3', 'Chemical', '-', (36, 38))
201035	32692766	In this study, we evaluated the associations of epigenetic age acceleration with patient survival in gliomas.	('patient', 'Species', '9606', (81, 88))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('epigenetic age acceleration', 'Var', (48, 75))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
201036	32692766	Our results show that epigenetic age acceleration is significantly associated with DNA methylation-based molecular subtypes in gliomas.	('epigenetic age acceleration', 'Var', (22, 49))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('associated', 'Reg', (67, 77))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
201037	32692766	By incorporation of molecular subtype in our survival analysis, epigenetic age acceleration was shown to be significantly associated with patient overall survival.	('associated', 'Reg', (122, 132))	('epigenetic age acceleration', 'Var', (64, 91))	('patient', 'Species', '9606', (138, 145))
201039	32692766	Taken together, the evidence suggests that epigenetic age acceleration has potential as promising prognostic biomarker for glioma patients.	('epigenetic age acceleration', 'Var', (43, 70))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('patients', 'Species', '9606', (130, 138))	('glioma', 'Disease', (123, 129))
201041	32692766	Several molecular biomarkers for gliomas have been identified in recent decades, including IDH1 mutation, 1p/19q deletion, MGCT promoter methylation and EGFRvIII, among others.	('1p/19q deletion', 'Var', (106, 121))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))	('gliomas', 'Disease', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('IDH1', 'Gene', '3417', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('MGCT', 'Gene', (123, 127))
201044	32692766	In this study, we show that epigenetic age acceleration is significantly associated with patient overall survival in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('patient', 'Species', '9606', (89, 96))	('gliomas', 'Disease', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('associated', 'Reg', (73, 83))	('epigenetic age acceleration', 'Var', (28, 55))
201048	32692766	The association of epigenetic age acceleration with patient survival in gliomas is strong and independent (per 10-year age acceleration, HR = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03), further supporting its potential as a prognostic biomarker in clinical settings.	('epigenetic age', 'Var', (19, 33))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('patient', 'Species', '9606', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))	('acceleration', 'PosReg', (34, 46))
201050	32692766	In our previous study, we showed a weak association of epigenetic age acceleration with patient survival in colorectal cancer, where the association is only observed when categorizing patients into epigenetic age acceleration and epigenetic age deceleration groups.	('patient', 'Species', '9606', (88, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('patients', 'Species', '9606', (184, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('colorectal cancer', 'Disease', (108, 125))	('epigenetic age', 'Var', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patient', 'Species', '9606', (184, 191))
201051	32692766	The mechanisms underlying this observed cancer-type specific association between epigenetic age acceleration and patient survival remains unknown and warrant further investigation.	('patient', 'Species', '9606', (113, 120))	('epigenetic age acceleration', 'Var', (81, 108))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
201052	32692766	One explanation is that epigenetic age in specific cancer types is correlated with cancer-specific gene mutations.	('mutations', 'Var', (104, 113))	('correlated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('epigenetic age', 'Var', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (83, 89))
201053	32692766	Thus, in gliomas, the epigenetic age may be associated with gene mutations that have strong predictive power for patient survival.	('patient', 'Species', '9606', (113, 120))	('epigenetic age', 'Var', (22, 36))	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))
201054	32692766	The direction of the association between epigenetic age acceleration and cancer patient survival is also cancer-type specific.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('acceleration', 'PosReg', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('epigenetic age', 'Var', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patient', 'Species', '9606', (80, 87))
201055	32692766	In this study, we showed that epigenetic age acceleration is positively associated with patient survival in gliomas, suggesting cancer patients with older epigenetic age have better survival.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('patient', 'Species', '9606', (135, 142))	('better', 'PosReg', (175, 181))	('gliomas', 'Disease', (108, 115))	('patient', 'Species', '9606', (88, 95))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('epigenetic age acceleration', 'Var', (30, 57))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('patient survival', 'CPA', (88, 104))	('cancer', 'Disease', (128, 134))
201056	32692766	On the other hand, negative associations of epigenetic age acceleration with patient survival were observed in other cancers, including colorectal cancer in our previous study and thyroid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('thyroid carcinoma', 'Disease', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('epigenetic age', 'Var', (44, 58))	('acceleration', 'PosReg', (59, 71))	('colorectal cancer', 'Disease', (136, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('patient', 'Species', '9606', (77, 84))	('cancers', 'Disease', (117, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('negative', 'NegReg', (19, 27))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (180, 197))	('patient survival', 'CPA', (77, 93))
201057	32692766	It remains unclear what causes this intriguing cancer-type specific relationship between epigenetic age acceleration and patient survival.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('epigenetic age acceleration', 'Var', (89, 116))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patient', 'Species', '9606', (121, 128))
201059	32692766	Age-related CpGs, especially hypermethylated CpGs, are coordinately regulated in cancer and strongly enriched in CpG islands and enhancer-related loci.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('hypermethylated', 'Var', (29, 44))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
201060	32692766	Horvath and Lin observed that epigenetic age is often associated with mutation patterns in cancer.	('epigenetic age', 'Var', (30, 44))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (54, 64))
201061	32692766	For example, mutations in TP53 have higher incidence with younger epigenetic age.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', '7157', (26, 30))
201062	32692766	High prevalence of TP53 mutations was found in gliomas and correlated with worse prognosis, which may partially explain younger epigenetic age is detrimental to glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('glioma', 'Disease', (47, 53))	('gliomas', 'Disease', (47, 54))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('patients', 'Species', '9606', (168, 176))	('TP53', 'Gene', (19, 23))	('TP53', 'Gene', '7157', (19, 23))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('mutations', 'Var', (24, 33))	('glioma', 'Disease', (161, 167))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
201063	32692766	Overall, the observed cancer-type specific association of epigenetic age acceleration with patient survival is likely related to underlying disease mechanisms in cancer-specific ways.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (22, 28))	('epigenetic age acceleration', 'Var', (58, 85))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('patient survival', 'CPA', (91, 107))	('patient', 'Species', '9606', (91, 98))
201064	32692766	8 May 2020  PONE-D-20-06616 Epigenetic age acceleration and clinical outcomes in gliomas PLOS ONE Dear Dr Xu, Thank you for submitting your manuscript to PLOS ONE.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('PONE-D-20-06616', 'Chemical', '-', (12, 27))	('Epigenetic age', 'Var', (28, 42))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))
201065	32692766	reported that epigenetic age acceleration is significantly associated with molecular subtypes and overall survival in glioma patients, indicating of epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('glioma', 'Disease', (118, 124))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('associated', 'Reg', (59, 69))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('epigenetic age acceleration', 'Var', (14, 41))	('glioma', 'Disease', (234, 240))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('gliomas', 'Disease', (234, 241))	('patients', 'Species', '9606', (125, 133))
201067	32692766	Although some notions has been implied in the previous study "Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence, Neuro-Oncology, Volume 20, Issue 7, July 2018 (ref.21)", this study provide more comprehensive investigation.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('Oncology', 'Phenotype', 'HP:0002664', (200, 208))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('glioma', 'Disease', (126, 132))	('methylation', 'Var', (111, 122))	('associated', 'Reg', (133, 143))
201072	32692766	To validate our results, we compiled a validation cohort from three published studies including 229 patients under GEO (GSE36278, GSE61160 and GSE44684, see S2 Table for the details).	('GSE61160', 'Var', (130, 138))	('GSE44684', 'Var', (143, 151))	('GSE36278', 'Var', (120, 128))	('patients', 'Species', '9606', (100, 108))
201074	32692766	G1 34.28 20.08 48.47 3.56E-06 ***  G3 23.49 9.06 37.92 1.54E-03 **  G4 22.53 10.51 34.55 2.78E-04 *** a Multivariate linear regression was used to study the association of epigenetic age acceleration with SDM, adjusting  age and tumor grade.	('SDM', 'Disease', (205, 208))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('G4', 'Chemical', 'MESH:D004003', (68, 70))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('G3', 'Chemical', '-', (35, 37))	('epigenetic age acceleration', 'Var', (172, 199))	('tumor', 'Disease', (229, 234))
201075	32692766	* p < 0.05, ** p < 0.01, *** p < 0.001 2) The positive association of epigenetic age acceleration with patient overall survival  We are unable to validate this association, which may be due to data heterogeneity and small sample sizes.	('epigenetic age', 'Var', (70, 84))	('acceleration', 'PosReg', (85, 97))	('patient', 'Species', '9606', (103, 110))
201076	32692766	However, in stratified analyses, we observed the trend that epigenetic age acceleration is positively correlated with patient overall survival.	('epigenetic age acceleration', 'Var', (60, 87))	('patient', 'Species', '9606', (118, 125))	('correlated', 'Reg', (102, 112))
201079	32692766	For the hazard ratios in different molecular subtypes, epigenetic age acceleration shows marginally positive association with patient survival in Mesenchymal-like subtype (HR: 0.85, 95% CI: 0.70-1.13, p=0.094).	('patient', 'Species', '9606', (126, 133))	('Mesenchymal-like subtype', 'Disease', (146, 170))	('epigenetic age acceleration', 'Var', (55, 82))
201080	32692766	29 Jun 2020  Epigenetic age acceleration and clinical outcomes in gliomas PONE-D-20-06616R1 Dear Dr. Xu, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('Epigenetic', 'Var', (13, 23))	('PONE-D-20-06616', 'Chemical', '-', (74, 89))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))
201090	27739434	Traditionally, anatomic imaging sequences such as T1 and T2 weighted (T1w, T2w) images have been used to differentiate high-grade from low-grade gliomas or to identify defined genomic aberrations such as combined 1p/19q loss in oligodendroglial tumors.	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('oligodendroglial tumors', 'Disease', (228, 251))	('combined 1p/19q', 'Var', (204, 219))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (228, 251))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('gliomas', 'Disease', (145, 152))	('loss', 'NegReg', (220, 224))
201104	27739434	Isocitrate dehydrogenase (IDH) mutation status was available for 35/37 patients: 31 patients were IDH wild type, while four patients (two WHO grade II glioma, two WHO grade III glioma) carried a mutant IDH allele.	('IDH', 'Gene', '3417', (202, 205))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('patients', 'Species', '9606', (71, 79))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('IDH', 'Gene', '3417', (26, 29))	('patients', 'Species', '9606', (124, 132))	('IDH', 'Gene', '3417', (98, 101))	('patients', 'Species', '9606', (84, 92))	('glioma', 'Disease', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('III glioma', 'Disease', (173, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('mutant', 'Var', (195, 201))	('glioma', 'Disease', (151, 157))	('IDH', 'Gene', (202, 205))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('IDH', 'Gene', (26, 29))	('III glioma', 'Disease', 'MESH:D005910', (173, 183))	('IDH', 'Gene', (98, 101))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
201131	27739434	Only four of the ten WHO grade II and III patients in our cohort carried a mutant IDH allele, while large-scale population-bases studies suggest that between 60-80% of these tumors should be IDH mutant.	('IDH', 'Gene', '3417', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('IDH', 'Gene', (191, 194))	('IDH', 'Gene', '3417', (191, 194))	('mutant', 'Var', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('IDH', 'Gene', (82, 85))	('patients', 'Species', '9606', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
201152	33664747	Patients with high PDIA5 high-expression benefited from immunotherapies.	('PDIA5', 'Gene', '10954', (19, 24))	('immunotherapies', 'CPA', (56, 71))	('PDIA5', 'Gene', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('high-expression', 'Var', (25, 40))
201175	33664747	Other research has found that PDI inhibition could impair tumorigenic T cells and enhance normal T cell function.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inhibition', 'Var', (34, 44))	('PDI', 'Gene', (30, 33))	('PDI', 'Gene', '5034', (30, 33))	('impair', 'NegReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('enhance', 'PosReg', (82, 89))
201198	33664747	After antigen retrieval and blocking endogenous HRP activity, the slides were blocked with 10% normal goat serum and incubated with primary antibody (anti-PDIA5 antibody human reactivity (D225376, 1:200, Sangon Biotech, China), anti-CD68 E11 human reactivity (SC-17832, 1:400, Santa Cruz, US) at 4 C overnight.	('PDIA5', 'Gene', '10954', (155, 160))	('PDIA5', 'Gene', (155, 160))	('anti-CD68', 'Var', (228, 237))	('human', 'Species', '9606', (170, 175))	('human', 'Species', '9606', (242, 247))
201207	33664747	It is well-known that several molecular biomarkers, such as isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are related to the malignancy of gliomas.	('IDH', 'Gene', (86, 89))	('mutation', 'Var', (91, 99))	('O6-methylguanine DNA methyltransferase', 'Gene', (130, 168))	('isocitrate dehydrogenase', 'Gene', (60, 84))	('malignancy of gliomas', 'Disease', (216, 237))	('IDH', 'Gene', '3417', (86, 89))	('MGMT', 'Gene', '4255', (170, 174))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (130, 168))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('MGMT', 'Gene', (170, 174))	('isocitrate dehydrogenase', 'Gene', '3417', (60, 84))	('malignancy of gliomas', 'Disease', 'MESH:D005910', (216, 237))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('related', 'Reg', (201, 208))
201217	33664747	Furthermore, in the IVY GBM dataset, high PDIA5 level was enriched in hyperplastic blood vessels, microvascular proliferation, and peri-necrotic zones compared with other areas (Figure 1F).	('PDIA5', 'Gene', '10954', (42, 47))	('high', 'Var', (37, 41))	('microvascular proliferation', 'CPA', (98, 125))	('hyperplastic blood vessels', 'CPA', (70, 96))	('PDIA5', 'Gene', (42, 47))	('peri-necrotic zones', 'CPA', (131, 150))
201222	33664747	These results suggest that PDIA5 is significantly increased in gliomas and high PDIA5 expression may play an important role in invasive processes of gliomas.	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', (63, 70))	('play', 'Reg', (101, 105))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('PDIA5', 'Gene', (80, 85))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('high', 'Var', (75, 79))	('PDIA5', 'Gene', '10954', (80, 85))	('increased', 'PosReg', (50, 59))	('expression', 'MPA', (86, 96))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
201225	33664747	These findings revealed that high PDIA5 expression predicts poor clinical outcomes in multiple cancers.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PDIA5', 'Gene', '10954', (34, 39))	('PDIA5', 'Gene', (34, 39))
201228	33664747	Similarly, high PDIA5 expression was significantly associated with poor prognosis in the CGGA dataset (Supplementary Figure S2I).	('PDIA5', 'Gene', '10954', (16, 21))	('PDIA5', 'Gene', (16, 21))	('expression', 'MPA', (22, 32))	('high', 'Var', (11, 15))
201230	33664747	Regardless of whether IDH was mutated, 1p19q was co-deleted, and MGMT promoter was methylated, low PDIA5 expression was related to a favorable outcome (Supplementary Figures S3A-F), and the same results were obtained in the analysis of chemotherapy and radiotherapy (Supplementary Figures S3G-I).	('MGMT', 'Gene', (65, 69))	('low', 'NegReg', (95, 98))	('MGMT', 'Gene', '4255', (65, 69))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', '3417', (22, 25))	('PDIA5', 'Gene', (99, 104))	('PDIA5', 'Gene', '10954', (99, 104))	('1p19q', 'Var', (39, 44))	('expression', 'MPA', (105, 115))
201234	33664747	Amplification of chr7 and deletion of chr10 consistently appeared in gliomas with high PDIA5 expression.	('chr10', 'Gene', (38, 43))	('PDIA5', 'Gene', '10954', (87, 92))	('chr7', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('gliomas', 'Disease', (69, 76))	('appeared', 'Reg', (57, 65))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('deletion', 'Var', (26, 34))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('PDIA5', 'Gene', (87, 92))
201235	33664747	Additionally, 1p/19q codeletion more frequently occurred in gliomas with low PDIA5 expression (Supplementary Figure S4A), and 63 and 30 significant genomic events were discovered in the high and low PDIA5 groups respectively (Supplementary Figure S4B).	('occurred', 'Reg', (48, 56))	('1p/19q codeletion', 'Var', (14, 31))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('PDIA5', 'Gene', (77, 82))	('PDIA5', 'Gene', (199, 204))	('PDIA5', 'Gene', '10954', (77, 82))	('low', 'NegReg', (73, 76))	('PDIA5', 'Gene', '10954', (199, 204))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
201236	33664747	In the high PDIA5 group, focal amplification peaks, including driver oncogenes such as PIK3C2B (1q32.1), PDGFRA (4q12), EGFR (7p11.2), and CDK4 (12q14.1) were found accompanied by focal deletion peaks for tumor suppressor genes such as CHD5 (1p36.31), CDKN2A/CDKN2B (9p21.3), and PTEN (10q23.31).	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('CDKN2A', 'Gene', '1029', (252, 258))	('PDIA5', 'Gene', '10954', (12, 17))	('CHD5', 'Gene', (236, 240))	('PIK3C2B', 'Gene', '5287', (87, 94))	('CDKN2B', 'Gene', (259, 265))	('10q23.31', 'Var', (286, 294))	('CDK4', 'Gene', (139, 143))	('PTEN', 'Gene', (280, 284))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('EGFR', 'Gene', (120, 124))	('CDK4', 'Gene', '1019', (139, 143))	('CDKN2B', 'Gene', '1030', (259, 265))	('PTEN', 'Gene', '5728', (280, 284))	('PDGFRA', 'Gene', (105, 111))	('CHD5', 'Gene', '26038', (236, 240))	('deletion', 'Var', (186, 194))	('CDKN2A', 'Gene', (252, 258))	('PDIA5', 'Gene', (12, 17))	('tumor', 'Disease', (205, 210))	('EGFR', 'Gene', '1956', (120, 124))	('PIK3C2B', 'Gene', (87, 94))
201238	33664747	In regards to somatic mutations, mutation in TP53 (41%), TTN (25%), PTEN (23%), and EGFR (22%) were identified in the high PDIA5 group, while IDH1 (89%), CIC (45%), and FUBP1 (22%) were detected in the low PDIA5 group (Supplementary Figure S4C).	('TP53', 'Gene', (45, 49))	('TTN', 'Gene', '7273', (57, 60))	('PTEN', 'Gene', (68, 72))	('PDIA5', 'Gene', '10954', (123, 128))	('CIC', 'Disease', (154, 157))	('FUBP1', 'Gene', (169, 174))	('TTN', 'Gene', (57, 60))	('IDH', 'Gene', (142, 145))	('EGFR', 'Gene', '1956', (84, 88))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', '7157', (45, 49))	('PDIA5', 'Gene', (206, 211))	('mutation', 'Var', (33, 41))	('CIC', 'Disease', 'None', (154, 157))	('FUBP1', 'Gene', '8880', (169, 174))	('IDH', 'Gene', '3417', (142, 145))	('PDIA5', 'Gene', '10954', (206, 211))	('EGFR', 'Gene', (84, 88))	('PDIA5', 'Gene', (123, 128))
201240	33664747	Moreover, in combination analysis of LGG and GBM, we observed PDIA5 expression was higher in the PDIA5 copy number gain group relative to the other two groups (Supplementary Figure S5B).	('PDIA5', 'Gene', '10954', (62, 67))	('PDIA5', 'Gene', (62, 67))	('PDIA5', 'Gene', '10954', (97, 102))	('PDIA5', 'Gene', (97, 102))	('expression', 'MPA', (68, 78))	('S5B', 'Gene', '5711', (181, 184))	('S5B', 'Gene', (181, 184))	('gain', 'PosReg', (115, 119))	('higher', 'PosReg', (83, 89))	('copy number', 'Var', (103, 114))
201262	33664747	Finally, patients with high PDIA5 and CD68, high combined expression of PDIA5 and CD68 group, and high ratio of PDIA5 to CD68 group experienced shorter OS (Supplementary Figures S8B-D).	('PDIA5', 'Gene', '10954', (28, 33))	('patients', 'Species', '9606', (9, 17))	('combined', 'Interaction', (49, 57))	('high', 'Var', (23, 27))	('shorter', 'NegReg', (144, 151))	('PDIA5', 'Gene', '10954', (72, 77))	('PDIA5', 'Gene', (112, 117))	('CD68', 'Var', (38, 42))	('PDIA5', 'Gene', '10954', (112, 117))	('CD68', 'Gene', (82, 86))	('PDIA5', 'Gene', (28, 33))	('PDIA5', 'Gene', (72, 77))
201277	33664747	Finally, the results of GO enrichment analysis (Supplementary Table S3, S4, S5) and KEGG pathway analysis (Supplementary Table S6, S7, S8) in regards to PDIA5 in neoplastic cells and macrophages is shown in Supplementary Figures S9D-F and S10D-F.	('KEGG pathway', 'Pathway', (84, 96))	('PDIA5', 'Gene', (153, 158))	('S10D', 'Mutation', 'p.S10D', (239, 243))	('S9D-F', 'Var', (229, 234))	('PDIA5', 'Gene', '10954', (153, 158))	('S10D-F', 'Var', (239, 245))
201285	33664747	Furthermore, knock-down PDIA5 presented the malignant behavior decreasing of glioma cells in immune cells exhausting.	('knock-down', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('malignant behavior', 'CPA', (44, 62))	('glioma', 'Disease', (77, 83))	('decreasing', 'NegReg', (63, 73))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('PDIA5', 'Gene', '10954', (24, 29))	('PDIA5', 'Gene', (24, 29))
201297	33664747	In the anti-PD-L1 cohort (IMvigor210), we observed that patients with high PDIA5 experienced significant clinical survival benefits (Figure 8A).	('patients', 'Species', '9606', (56, 64))	('PD-L1', 'Gene', (12, 17))	('clinical survival', 'CPA', (105, 122))	('benefits', 'PosReg', (123, 131))	('PD-L1', 'Gene', '29126', (12, 17))	('PDIA5', 'Gene', '10954', (75, 80))	('PDIA5', 'Gene', (75, 80))	('high', 'Var', (70, 74))
201299	33664747	In the anti-PD-L1 cohort, the percentages of complete response (CR) and progressive disease (PD) were 19.35 and 39.44% in the high PDIA5 group, respectively, and 6.7 and 58.64% in the low PDIA5 group, respectively.	('PD-L1', 'Gene', (12, 17))	('progressive disease', 'Disease', 'MESH:D018450', (72, 91))	('progressive disease', 'Disease', (72, 91))	('PDIA5', 'Gene', (131, 136))	('PDIA5', 'Gene', '10954', (131, 136))	('PD-L1', 'Gene', '29126', (12, 17))	('high', 'Var', (126, 130))	('PDIA5', 'Gene', (188, 193))	('PDIA5', 'Gene', '10954', (188, 193))	('complete', 'Disease', (45, 53))
201300	33664747	And the proportion of high PDIA5 expression in CR group and PD group were 35.93 and 11.56%, respectively.	('high', 'Var', (22, 26))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))
201304	33664747	And the proportion of high PDIA5 expression in CR group, PD group, and PR group were 100, 84.35, and 94.84%, respectively (Figure 8I).	('high', 'Var', (22, 26))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))
201310	33664747	Genomic alterations in gliomas are able to predict disease classification and prognosis.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('Genomic alterations', 'Var', (0, 19))	('predict', 'Reg', (43, 50))
201313	33664747	These results suggest that high PDIA5 expression plays an important role in glioma infiltration.	('expression', 'MPA', (38, 48))	('glioma infiltration', 'Disease', 'MESH:D005910', (76, 95))	('high', 'Var', (27, 31))	('PDIA5', 'Gene', (32, 37))	('PDIA5', 'Gene', '10954', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('glioma infiltration', 'Disease', (76, 95))
201337	33664747	Therefore, we deduced that high expression of PDIA5 may induce macrophage associated immunity, and contribute to M2 polarization of macrophage in gliomas.	('PDIA5', 'Gene', (46, 51))	('macrophage associated immunity', 'CPA', (63, 93))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('contribute', 'Reg', (99, 109))	('PDIA5', 'Gene', '10954', (46, 51))	('induce', 'PosReg', (56, 62))	('high expression', 'Var', (27, 42))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('M2 polarization', 'MPA', (113, 128))
201357	33664747	Further predictive analysis based on the existing databases showed that patients with high PDIA5 had high anti-tumor immune activity and were more likely to benefit from immunotherapies in gliomas as well as other tumor types, indicating that inhibition of combined PDIA5 and these immune checkpoints could improve the clinical management of gliomas.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PDIA5', 'Gene', '10954', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (342, 349))	('PDIA5', 'Gene', '10954', (266, 271))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('high', 'Var', (86, 90))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('tumor', 'Disease', (111, 116))	('gliomas', 'Disease', (342, 349))	('tumor', 'Disease', (214, 219))	('benefit', 'PosReg', (157, 164))	('high', 'PosReg', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PDIA5', 'Gene', (266, 271))	('PDIA5', 'Gene', (91, 96))	('gliomas', 'Disease', 'MESH:D005910', (342, 349))	('gliomas', 'Disease', (189, 196))	('patients', 'Species', '9606', (72, 80))
201361	33664747	Prior evidence implicated that high PD-L1 contributed to immunosuppression but enhanced the response rate to anti-PD-1 therapy in metastatic melanomas and breast cancer.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('PD-1', 'Gene', '5133', (114, 118))	('immunosuppression', 'MPA', (57, 74))	('PD-L1', 'Gene', (36, 41))	('melanomas and breast cancer', 'Disease', 'MESH:D001943', (141, 168))	('enhanced', 'PosReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PD-L1', 'Gene', '29126', (36, 41))	('high', 'Var', (31, 35))	('PD-1', 'Gene', (114, 118))	('response rate', 'MPA', (92, 105))
201388	33665000	Besides, it was found that glioblastoma with isocitrate dehydrogenase (IDH) mutations indicated a relatively favorable survival.	('mutations', 'Var', (76, 85))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('IDH', 'Gene', (71, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('isocitrate dehydrogenase', 'Gene', (45, 69))	('IDH', 'Gene', '3417', (71, 74))	('isocitrate dehydrogenase', 'Gene', '3417', (45, 69))
201423	33665000	Enrichment analysis revealed that the seven IRGs were significantly associated with the co-occurrence of ATRX, TP53, and IDH1 mutations (Figure 5E).	('IDH1', 'Gene', (121, 125))	('associated', 'Reg', (68, 78))	('ATRX', 'Gene', '546', (105, 109))	('TP53', 'Gene', '7157', (111, 115))	('IDH1', 'Gene', '3417', (121, 125))	('TP53', 'Gene', (111, 115))	('mutations', 'Var', (126, 135))	('ATRX', 'Gene', (105, 109))
201445	33665000	The identification of IDH mutation, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion was found to be closely related to glioma prognosis.	('related', 'Reg', (152, 159))	('glioma', 'Disease', (163, 169))	('mutation', 'Var', (26, 34))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('IDH', 'Gene', (22, 25))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('MGMT', 'Gene', '4255', (77, 81))	('IDH', 'Gene', '3417', (22, 25))	('MGMT', 'Gene', (77, 81))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (36, 75))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (36, 75))
201450	33665000	Notably, the mutation of IDH was found to be a protective factor for patients with glioblastoma, whereas its prognostic value was not validated in LGG.	('IDH', 'Gene', '3417', (25, 28))	('IDH', 'Gene', (25, 28))	('mutation', 'Var', (13, 21))	('LGG', 'Chemical', '-', (147, 150))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('patients', 'Species', '9606', (69, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
201451	33665000	Based on our extracted data, we found that the IDH mutation indicated a relatively favorable prognosis in LGG patients (Figure S5).	('IDH', 'Gene', '3417', (47, 50))	('LGG', 'Disease', (106, 109))	('LGG', 'Chemical', '-', (106, 109))	('mutation', 'Var', (51, 59))	('IDH', 'Gene', (47, 50))	('patients', 'Species', '9606', (110, 118))
201452	33665000	Besides, the IDH mutation was identified as an independent risk factor in multivariate Cox analysis.	('IDH', 'Gene', '3417', (13, 16))	('IDH', 'Gene', (13, 16))	('mutation', 'Var', (17, 25))
201461	33665000	Besides, IRGs with APA events were associated with disease-free survival and gene mutations, such as IDH1 and TP53 mutation in LGG patients.	('IDH1', 'Gene', (101, 105))	('LGG', 'Disease', (127, 130))	('patients', 'Species', '9606', (131, 139))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('IDH1', 'Gene', '3417', (101, 105))	('LGG', 'Chemical', '-', (127, 130))	('associated', 'Reg', (35, 45))	('disease-free survival', 'CPA', (51, 72))	('mutation', 'Var', (115, 123))	('APA', 'Chemical', '-', (19, 22))
201484	33665000	Given that patients in the low-risk group did not significantly benefit from radiotherapy, and radiotherapy might increase the body stress and cause adverse events for those in the low-risk group, the risk stratification could provide a reference for the treatment of grade III glioma.	('increase', 'PosReg', (114, 122))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('radiotherapy', 'Var', (95, 107))	('stress', 'Disease', (132, 138))	('cause', 'Reg', (143, 148))	('stress', 'Disease', 'MESH:D000079225', (132, 138))	('patients', 'Species', '9606', (11, 19))	('III glioma', 'Disease', 'MESH:D005910', (274, 284))	('III glioma', 'Disease', (274, 284))
201524	33553434	The results showed that IL31RA, PODNL1, KRT8, and other genes were positively correlated with the risk score of the model (p < 0.05), with IL31RA showing the strongest correlation, while JAZF1-ASI, FREM3, RHBG, and the rest of the genes were negatively correlated with the risk score of the model (p < 0.05) (Figure 5(a)).	('ASI', 'Gene', (193, 196))	('PODNL1', 'Gene', (32, 38))	('IL31RA', 'Gene', (24, 30))	('JAZF1', 'Gene', (187, 192))	('IL31RA', 'Var', (139, 145))	('PODNL1', 'Gene', '79883', (32, 38))	('ASI', 'Gene', '340075', (193, 196))	('JAZF1', 'Gene', '221895', (187, 192))	('RHBG', 'Gene', '57127', (205, 209))	('KRT8', 'Gene', '3856', (40, 44))	('FREM3', 'Gene', '166752', (198, 203))	('KRT8', 'Gene', (40, 44))	('FREM3', 'Gene', (198, 203))	('RHBG', 'Gene', (205, 209))
201531	33553434	Jing Han and his colleagues showed that high IL-13Ralpha1 with or without IL-13Ralpha2 expression was associated with poor prognosis in patients with high-grade gliomas.	('high', 'Var', (40, 44))	('IL-13Ralpha1', 'Gene', (45, 57))	('IL-13Ralpha1', 'Gene', '3597', (45, 57))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('IL-13Ralpha2', 'Gene', (74, 86))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('high-grade gliomas', 'Disease', (150, 168))	('IL-13Ralpha2', 'Gene', '3598', (74, 86))
201566	30786040	In addition, we assume that muk, Sigmak are mutually independent over K response groups with conjugate priors of normal-inverse Wishart and hyperparameters (mu0k, Lambda0k/k0k;nu0k, Lambda0k).	('muk', 'Gene', '7786', (28, 31))	('mu0k', 'Var', (157, 161))	('muk', 'Gene', (28, 31))
201634	30786040	Specifically, 79 pairs of patients were produced using the R package of MatchIt (default settings); the resultant standardized mean differences were 0.000, -0.050, 0.051, and 0.162 for tumor grade, gender, age and IYPD, respectively.	('tumor', 'Disease', (185, 190))	('IYPD', 'Disease', 'None', (214, 218))	('0.162', 'Var', (175, 180))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('IYPD', 'Disease', (214, 218))
201670	32309604	ZEB1 even under normal conditions can be very complex with opposing functional activities so it is not unreasonable to believe that in cancer the complexity of ZEB1 would remain, and in fact be greater due to ZEB1 dysregulation.	('dysregulation', 'Var', (214, 227))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ZEB1', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
201679	32309604	A study done in MDA MB-231 breast cancer cells revealed that knocking down ZEB1 produced downregulation of more than 30 genes and upregulation of more than 200, many of which affected epithelial cell adhesion genes including the classic cadherin superfamily, components of tight junctions (e.g.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('epithelial cell adhesion genes', 'Gene', (184, 214))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('affected', 'Reg', (175, 183))	('downregulation', 'NegReg', (89, 103))	('MDA MB-231', 'CellLine', 'CVCL:0062', (16, 26))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('ZEB1', 'Gene', (75, 79))	('upregulation', 'PosReg', (130, 142))	('knocking down', 'Var', (61, 74))	('cadherin', 'Gene', (237, 245))	('cadherin', 'Gene', '999', (237, 245))
201682	32309604	ZEB1 represses collagen in osteoblasts and has also been shown to inhibit muscle differentiation by blocking the transcriptional activity of the myogenic factor MEF2C.	('blocking', 'NegReg', (100, 108))	('muscle differentiation', 'CPA', (74, 96))	('ZEB1', 'Var', (0, 4))	('inhibit', 'NegReg', (66, 73))	('MEF2C', 'Gene', (161, 166))	('represses', 'NegReg', (5, 14))	('MEF2C', 'Gene', '4208', (161, 166))	('transcriptional activity', 'MPA', (113, 137))	('collagen in osteoblasts', 'CPA', (15, 38))
201690	32309604	It has been well established that E-Cadherin functions as a tumor suppressor gene that, when lost, causes cancer cells to increase metastasis, migration and invasion in addition, migration, invasion, and metastasis negatively impact patient survival.	('lost', 'Var', (93, 97))	('E-Cadherin', 'Gene', (34, 44))	('cancer', 'Disease', (106, 112))	('impact', 'Reg', (226, 232))	('tumor', 'Disease', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('metastasis', 'CPA', (204, 214))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('migration', 'CPA', (179, 188))	('metastasis', 'CPA', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('E-Cadherin', 'Gene', '999', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('negatively', 'NegReg', (215, 225))	('increase', 'PosReg', (122, 130))	('invasion', 'CPA', (190, 198))	('patient', 'Species', '9606', (233, 240))	('invasion', 'CPA', (157, 165))	('patient survival', 'CPA', (233, 249))
201700	32309604	Likewise, ZEB1 causes loss of cell polarity and increased metastasis in colorectal cancer by suppressing polarity genes, in particular Lgl2 (lethal giant larvae homolog 2), which leads to reduced cell-cell adhesion and increased invasion in cancer cell lines.	('Lgl2', 'Gene', '3993', (135, 139))	('reduced cell-cell adhesion', 'Phenotype', 'HP:0008352', (188, 214))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('loss', 'NegReg', (22, 26))	('suppressing', 'NegReg', (93, 104))	('increased', 'PosReg', (219, 228))	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('colorectal cancer', 'Disease', (72, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('polarity genes', 'Gene', (105, 119))	('lethal giant larvae homolog 2', 'Gene', (141, 170))	('lethal giant larvae homolog 2', 'Gene', '3993', (141, 170))	('reduced', 'NegReg', (188, 195))	('cell polarity', 'CPA', (30, 43))	('metastasis', 'CPA', (58, 68))	('increased', 'PosReg', (48, 57))	('invasion', 'CPA', (229, 237))	('cell-cell adhesion', 'CPA', (196, 214))	('ZEB1', 'Var', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('Lgl2', 'Gene', (135, 139))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (83, 89))
201701	32309604	A study in Mantle Cell lymphoma (MCL) indicated that ZEB1 knockdown in MCL cells resulted in decreased proliferation in vitro and tumor growth in xenograft mouse models.	('Mantle Cell lymphoma', 'Disease', (11, 31))	('Cell lymphoma', 'Phenotype', 'HP:0012191', (18, 31))	('proliferation', 'CPA', (103, 116))	('lymphoma', 'Phenotype', 'HP:0002665', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('decreased', 'NegReg', (93, 102))	('ZEB1', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mouse', 'Species', '10090', (156, 161))	('tumor', 'Disease', (130, 135))	('knockdown', 'Var', (58, 67))	('Mantle Cell lymphoma', 'Disease', 'MESH:D020522', (11, 31))
201706	32309604	This family of microRNAs has received much of the focus in regard to ZEB1 as studies in various cancer lines have shown that this family is the most upregulated when ZEB1 is knocked down.	('ZEB1', 'Gene', (166, 170))	('knocked down', 'Var', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('upregulated', 'PosReg', (149, 160))	('cancer', 'Disease', (96, 102))
201711	32309604	In an attempt to delineate the molecular mechanism underlying leukemogenesis after viral infection, genetic and expression analyses revealed that the TCF8 gene (ZEB1) was frequently altered by epigenetic dysregulation.	('altered', 'Reg', (182, 189))	('viral infection', 'Disease', 'MESH:D001102', (83, 98))	('leukemogenesis', 'Disease', (62, 76))	('TCF8', 'Gene', '6935', (150, 154))	('ZEB1', 'Gene', (161, 165))	('viral infection', 'Disease', (83, 98))	('TCF8', 'Gene', (150, 154))	('leukemogenesis', 'Disease', 'None', (62, 76))	('epigenetic dysregulation', 'Var', (193, 217))
201712	32309604	ZEB1 mutant mice confirmed the importance of this alteration by frequently developing invasive CD4+ T-cell lymphomas; additional in vitro studies showed the loss of ZEB1 expression in ATLL cells resulted in an escape from growth inhibition by TGF-beta.	('ATLL', 'Disease', (184, 188))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (100, 116))	('lymphomas', 'Disease', (107, 116))	('developing', 'Reg', (75, 85))	('ATLL', 'Disease', 'MESH:D015459', (184, 188))	('lymphomas', 'Disease', 'MESH:D008223', (107, 116))	('escape', 'MPA', (210, 216))	('growth', 'CPA', (222, 228))	('ZEB1', 'Gene', (165, 169))	('mice', 'Species', '10090', (12, 16))	('lymphoma', 'Phenotype', 'HP:0002665', (107, 115))	('expression', 'MPA', (170, 180))	('loss', 'Var', (157, 161))
201719	32309604	In a subpopulation of PC-3 prostate cancer cells, a study found that the knockdown of ZEB1 increased expression of laminin-332, a pro-migratory molecule.	('ZEB1', 'Gene', (86, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (27, 42))	('laminin-332', 'Protein', (115, 126))	('PC-3 prostate cancer', 'Disease', 'MESH:D011471', (22, 42))	('increased', 'PosReg', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('expression', 'MPA', (101, 111))	('PC-3 prostate cancer', 'Disease', (22, 42))	('knockdown', 'Var', (73, 82))
201728	32309604	In glioblastoma stem cells they found that targeting ZEB1 blocked the invasion of glioblastoma cells in a hypoxia setting and slowed them in normoxia suggesting a key role for ZEB1 in promoting invasion in the tumor core.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('targeting', 'Var', (43, 52))	('glioblastoma', 'Disease', (82, 94))	('slowed', 'NegReg', (126, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('promoting', 'PosReg', (184, 193))	('tumor', 'Disease', (210, 215))	('hypoxia', 'Disease', (106, 113))	('ZEB1', 'Gene', (53, 57))	('blocked', 'NegReg', (58, 65))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('invasion', 'CPA', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
201743	32309604	Genetic subtype analysis showed that Isocitrate Dehydrogenase 1/2 (IDH1/2)-mutant gliomas, which are gliomas with the best overall prognosis, had a significantly higher expression of ZEB1 and lowered levels of ZEB1 transcriptional target genes.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('higher', 'PosReg', (162, 168))	('gliomas', 'Disease', (101, 108))	('lowered', 'NegReg', (192, 199))	('-mutant', 'Var', (74, 81))	('IDH1/2', 'Gene', (67, 73))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('expression', 'MPA', (169, 179))	('IDH1/2', 'Gene', '3417;3418', (67, 73))	('ZEB1', 'Protein', (183, 187))	('levels of', 'MPA', (200, 209))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
201754	32309604	Genomic analysis of over 4000 brain cancers showed that there was a ZEB1 deletion in ~15% (grade II and III) and were significantly higher loss in glioblastomas.	('brain cancers', 'Disease', (30, 43))	('glioblastomas', 'Phenotype', 'HP:0012174', (147, 160))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('brain cancer', 'Phenotype', 'HP:0030692', (30, 42))	('ZEB1', 'Gene', (68, 72))	('glioblastomas', 'Disease', 'MESH:D005909', (147, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('glioblastomas', 'Disease', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('deletion', 'Var', (73, 81))	('brain cancers', 'Disease', 'MESH:D001932', (30, 43))
201761	32309604	The cellular impact of the loss of ZEB1 appeared to be an impairment of stemness.	('loss', 'Var', (27, 31))	('impairment of stemness', 'Disease', (58, 80))	('ZEB1', 'Gene', (35, 39))	('impairment of stemness', 'Disease', 'MESH:D020295', (58, 80))
201769	32309604	They also discovered a trend of longer overall survival in tumors with a high ZEB1 labeling index.	('longer', 'PosReg', (32, 38))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('overall', 'MPA', (39, 46))	('high', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
201778	27812792	Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway Epileptogenic tumors affecting children and young adults are a morphologically diverse collection of neuroepithelial neoplasms that, as a group, exhibit varying levels of glial and/or neuronal differentiation.	('neuroepithelial tumor', 'Disease', (23, 44))	('neoplasm', 'Phenotype', 'HP:0002664', (333, 341))	('epileptogenic neoplasm', 'Disease', (70, 92))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('oligodendroglioma', 'Disease', (98, 115))	('neuroepithelial neoplasms', 'Disease', 'MESH:D018302', (317, 342))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (23, 44))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))	('children', 'Species', '9606', (247, 255))	('Epileptogenic tumors', 'Disease', 'MESH:D009369', (216, 236))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('CD34', 'Gene', (142, 146))	('aberrant', 'Var', (133, 141))	('Epileptogenic tumors', 'Disease', (216, 236))	('genetic alterations', 'Var', (163, 182))	('neuroepithelial neoplasms', 'Phenotype', 'HP:0030063', (317, 342))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (23, 44))	('neoplasms', 'Phenotype', 'HP:0002664', (333, 342))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('neuroepithelial neoplasms', 'Disease', (317, 342))	('epileptogenic neoplasm', 'Disease', 'MESH:D009369', (70, 92))	('CD34', 'Gene', '947', (142, 146))	('oligodendroglioma', 'Disease', 'MESH:D009837', (98, 115))
201786	27812792	In particular, genome-wide DNA methylation profiling and the identification of recurrent genomic aberrations (e.g., mutations, rearrangements, and copy number abnormalities) have been crucial in the delineation of biologically distinct disease entities and in refining tumor classification.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('rearrangements', 'Var', (127, 141))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (269, 274))	('copy number abnormalities', 'Disease', 'MESH:D007674', (147, 172))	('copy number abnormalities', 'Disease', (147, 172))	('mutations', 'Var', (116, 125))
201787	27812792	Here, we describe a unique epileptogenic LGNT variant affecting children and young adults, which we call polymorphous low-grade neuroepithelial tumor of the young (PLNTY).	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (128, 149))	('variant', 'Var', (46, 53))	('children', 'Species', '9606', (64, 72))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (128, 149))	('neuroepithelial tumor', 'Disease', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('LGNT', 'Gene', (41, 45))
201789	27812792	Moreover, we demonstrate that PLNTYs exhibit a distinct DNA methylation signature, most closely related to that of ganglioglioma, and harbor molecular abnormalities involving mitogen-activated protein kinase (MAPK) pathway constituents.	('ganglioglioma', 'Disease', 'MESH:D018303', (115, 128))	('PLNTYs', 'Var', (30, 36))	('harbor molecular abnormalities', 'Disease', (134, 164))	('ganglioglioma', 'Disease', (115, 128))	('harbor molecular abnormalities', 'Disease', 'MESH:C537062', (134, 164))	('DNA methylation', 'MPA', (56, 71))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
201793	27812792	BRAF V600E mutations were detected using the Sequenom Mass ARRAY system as previously described.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (5, 10))	('V600E', 'Mutation', 'rs113488022', (5, 10))
201794	27812792	Filtering of probes included removal of probes targeting the X and Y chromosomes (n = 11,551), removal of probes containing a single-nucleotide polymorphism (dbSNP132 Common) within five base pairs of and including the targeted CpG-site (n = 24,536), and probes not mapping uniquely to the human reference genome (hg19) allowing for one mismatch (n = 9993).	('oval', 'Disease', 'MESH:D054092', (32, 36))	('oval', 'Disease', 'MESH:D054092', (98, 102))	('oval', 'Disease', (32, 36))	('single-nucleotide polymorphism', 'Var', (126, 156))	('oval', 'Disease', (98, 102))	('human', 'Species', '9606', (290, 295))
201811	27812792	Of the five other patients with refractory epilepsy who had gross total excisions, four were rendered seizure-free and one had a marked reduction in seizure frequency.	('seizure', 'Phenotype', 'HP:0001250', (149, 156))	('epilepsy', 'Disease', (43, 51))	('seizure', 'Disease', 'MESH:D012640', (102, 109))	('seizure', 'Disease', (102, 109))	('seizure', 'Disease', 'MESH:D012640', (149, 156))	('seizure', 'Phenotype', 'HP:0001250', (102, 109))	('excisions', 'Var', (72, 81))	('reduction', 'NegReg', (136, 145))	('seizure', 'Disease', (149, 156))	('patients', 'Species', '9606', (18, 26))	('epilepsy', 'Disease', 'MESH:D004827', (43, 51))	('epilepsy', 'Phenotype', 'HP:0001250', (43, 51))
201834	27812792	First, we employed validated Sequenom-based genotyping for BRAF V600E, the most common cancer-associated BRAF mutation.	('cancer', 'Disease', (87, 93))	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('V600E', 'Var', (64, 69))
201837	27812792	While we were unable to demonstrate KIAA1549-BRAF transcripts in any profiled tumors, we identified fusions involving fibroblast growth factor receptors, FGFR2 and FGFR3, in three cases (Fig.	('fusions', 'Var', (100, 107))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('KIAA1549', 'Gene', '57670', (36, 44))	('FGFR3', 'Gene', (164, 169))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('KIAA1549', 'Gene', (36, 44))	('FGFR2', 'Gene', (154, 159))	('FGFR2', 'Gene', '2263', (154, 159))	('FGFR3', 'Gene', '2261', (164, 169))
201838	27812792	Notably, FGFR fusions were mutually exclusive with BRAF V600E mutations across our sample set.	('V600E', 'Var', (56, 61))	('BRAF', 'Gene', '673', (51, 55))	('fusions', 'Var', (14, 21))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('BRAF', 'Gene', (51, 55))	('FGFR', 'Gene', (9, 13))
201841	27812792	FGFR fusions are thought to drive enhanced downstream signaling through MAP kinase pathway effectors by way of homodimerization and autophosphorylation, a process mediated by coiled coil domains resident in their respective fusion partners (e.g., TACC3, KIAA1598).	('TACC3', 'Gene', '10460', (247, 252))	('enhanced', 'PosReg', (34, 42))	('FGFR', 'Gene', (0, 4))	('TACC3', 'Gene', (247, 252))	('KIAA1598', 'Gene', (254, 262))	('fusions', 'Var', (5, 12))	('MAP kinase pathway', 'Pathway', (72, 90))	('homodimerization', 'MPA', (111, 127))	('KIAA1598', 'Gene', '57698', (254, 262))	('downstream signaling', 'MPA', (43, 63))	('autophosphorylation', 'MPA', (132, 151))
201845	27812792	Finally, copy number profiling derived from Infinium methylation analysis (see below) demonstrated that FGFR3 and FGFR2 fusions derived from tandem duplication and deletion events, respectively, consistent with prior reports (Fig.	('tandem duplication', 'Var', (141, 159))	('derived', 'Reg', (128, 135))	('FGFR2', 'Gene', (114, 119))	('FGFR2', 'Gene', '2263', (114, 119))	('FGFR3', 'Gene', '2261', (104, 109))	('fusions', 'Var', (120, 127))	('deletion', 'Var', (164, 172))	('FGFR3', 'Gene', (104, 109))
201846	27812792	Moreover, these data revealed an additional likely FGFR2-KIAA1598 fusion event in a tumor that had not undergone ArcherDX analysis (Table 1, case 6).	('KIAA1598', 'Gene', (57, 65))	('KIAA1598', 'Gene', '57698', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('FGFR2', 'Gene', (51, 56))	('FGFR2', 'Gene', '2263', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('fusion', 'Var', (66, 72))	('tumor', 'Disease', (84, 89))
201849	27812792	Importantly, BRAF alterations (V600E mutations and KIAA1549-BRAF fusions) were distributed across multiple diagnostic groups:PLNTY, ganglioglioma, and pilocytic astrocytoma:each of which exhibited a distinct methylation signature.	('ganglioglioma', 'Disease', 'MESH:D018303', (132, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('BRAF', 'Gene', (60, 64))	('KIAA1549-BRAF fusions', 'Disease', (51, 72))	('pilocytic astrocytoma', 'Disease', (151, 172))	('BRAF', 'Gene', '673', (60, 64))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('PLNTY', 'Disease', (125, 130))	('V600E', 'Mutation', 'rs113488022', (31, 36))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('V600E mutations', 'Var', (31, 46))	('ganglioglioma', 'Disease', (132, 145))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (151, 172))	('KIAA1549-BRAF fusions', 'Disease', 'MESH:D000069337', (51, 72))
201850	27812792	More distant associations with other neuroepithelial tumor entities, including PXA, IDH-mutant diffuse astrocytoma and oligodendroglioma, and pediatric low-grade glioma with MYB/MYBL1 alterations were revealed by t-sne scatterplotting (FIG.	('glioma', 'Disease', (130, 136))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (37, 58))	('MYBL1', 'Gene', (178, 183))	('MYBL1', 'Gene', '4603', (178, 183))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('neuroepithelial tumor', 'Disease', (37, 58))	('glioma', 'Disease', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (37, 58))	('MYB', 'Gene', '4602', (174, 177))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (103, 136))	('MYB', 'Gene', (174, 177))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('alterations', 'Var', (184, 195))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('IDH', 'Gene', (84, 87))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('PXA', 'Disease', (79, 82))	('IDH', 'Gene', '3417', (84, 87))	('MYB', 'Gene', '4602', (178, 181))	('MYB', 'Gene', (178, 181))
201852	27812792	Interestingly, these tumors harbored likely FGFR2 fusions by copy number analysis (Fig.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('fusions', 'Var', (50, 57))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
201866	27812792	In fact, it was this immunohistochemical observation, along with the consistent failure of the tumors in this series to manifest labeling for IDH1 R132H or chromosome 1p/19q codeletion, despite their oligodendrogliomatous appearances, that prompted us to consider these as distinct from the infiltrating gliomas of later life and to initiate additional molecular studies.	('R132H', 'Var', (147, 152))	('oligodendrogliomatous', 'Disease', 'None', (200, 221))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (304, 310))	('IDH1', 'Gene', '3417', (142, 146))	('R132H', 'Mutation', 'rs121913500', (147, 152))	('oligodendrogliomatous', 'Disease', (200, 221))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('gliomas', 'Disease', 'MESH:D005910', (304, 311))	('gliomas', 'Phenotype', 'HP:0009733', (304, 311))	('gliomas', 'Disease', (304, 311))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('IDH1', 'Gene', (142, 146))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))
201878	27812792	Using focused molecular profiling, we found that nearly all of the PLNTYs harbored either BRAF V600E mutations or fusion events involving FGFR2/FGFR3.	('BRAF', 'Gene', (90, 94))	('FGFR2', 'Gene', (138, 143))	('mutations', 'Var', (101, 110))	('FGFR3', 'Gene', '2261', (144, 149))	('FGFR2', 'Gene', '2263', (138, 143))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('FGFR3', 'Gene', (144, 149))	('fusion', 'MPA', (114, 120))	('BRAF', 'Gene', '673', (90, 94))
201879	27812792	Indeed, both V600E-mutant BRAF monomers and FGFR fusion chimeras have been shown to activate MAPK signaling, the latter by way of constitutive receptor dimerization, a mechanism likely operative in all such cases in our sample set (see above).	('FGFR', 'Gene', (44, 48))	('MAPK signaling', 'MPA', (93, 107))	('BRAF', 'Gene', '673', (26, 30))	('V600E-mutant', 'Var', (13, 25))	('BRAF', 'Gene', (26, 30))	('V600E', 'Mutation', 'rs113488022', (13, 18))	('activate', 'PosReg', (84, 92))
201880	27812792	That being said, abnormal MAPK pathway activation, by either BRAF V600E or FGFR fusion, is hardly specific to PLNTYs as a transforming molecular event.	('activation', 'PosReg', (39, 49))	('FGFR', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (61, 65))	('MAPK pathway', 'Pathway', (26, 38))	('fusion', 'Var', (80, 86))	('V600E', 'Mutation', 'rs113488022', (66, 71))
201881	27812792	BRAF V600E has been widely implicated in the pathogenesis of LGNTs, with particularly high rates of incidence in gangliogliomas and PXAs.	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('gangliogliomas', 'Disease', (113, 127))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('gangliogliomas', 'Disease', 'MESH:D018303', (113, 127))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('LGNTs', 'Disease', (61, 66))	('PXAs', 'Disease', (132, 136))	('implicated', 'Reg', (27, 37))	('BRAF', 'Gene', (0, 4))
201882	27812792	Similarly, recent work has identified frequent FGFR fusion events in DNETs, and diffusely infiltrating pediatric gliomas exhibiting either astrocytic or oligodendroglial histopathology.	('FGFR', 'Gene', (47, 51))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('fusion events', 'Var', (52, 65))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('DNETs', 'Disease', (69, 74))
201883	27812792	BRAF V600E mutations and FGFR fusions are even found in a small minority of glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('V600E mutations', 'Var', (5, 20))	('glioblastomas', 'Disease', (76, 89))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('FGFR', 'Gene', (25, 29))	('fusions', 'Var', (30, 37))	('found', 'Reg', (47, 52))	('BRAF', 'Gene', '673', (0, 4))	('glioblastomas', 'Phenotype', 'HP:0012174', (76, 89))	('BRAF', 'Gene', (0, 4))	('glioblastomas', 'Disease', 'MESH:D005909', (76, 89))
201888	27812792	Methylation profiling has also facilitated more appropriate tumor classification within poorly defined histopathologic groupings.	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))
201890	27812792	Interestingly, the PLNTY methylation signature was most closely related to those of other, morphologically diverse LGNTs:gangliogliomas, pilocytic astrocytomas, and DNETs:characterized by MAPK pathway activation.	('pilocytic astrocytomas', 'Disease', (137, 159))	('PLNTY methylation', 'Var', (19, 36))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (137, 159))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('gangliogliomas', 'Disease', (121, 135))	('gangliogliomas', 'Disease', 'MESH:D018303', (121, 135))
201891	27812792	While the demonstration of aberrant CD34 expression by neoplastic and ramified neural elements certainly suggests PLNTY in the appropriate context, calling into serious question the diagnosis of any conventional glioma of infiltrating type, it would be premature to conclude that this finding obviates the need for assessments of IDH1/2 mutation and chromosome 1p/19q codeletion status in the evaluation of neurosurgical specimens.	('CD34', 'Gene', (36, 40))	('IDH1', 'Gene', '3417', (330, 334))	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('aberrant', 'Var', (27, 35))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('suggests', 'Reg', (105, 113))	('IDH1', 'Gene', (330, 334))	('glioma', 'Disease', (212, 218))
201892	27812792	Candidate cases should be studied for BRAF and FGFR2/3 abnormalities and an integrated diagnosis rendered on the basis of the histologic, immunophenotypic, and molecular genetic features.	('abnormalities', 'Var', (55, 68))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))
201895	27812792	In summary, we report the characterization of PLNTY, a molecularly distinct LGNT that likely represents a significant subset of oligodendroglioma-like tumors arising in pediatric populations.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('oligodendroglioma-like tumors', 'Disease', 'MESH:D009837', (128, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('PLNTY', 'Var', (46, 51))	('oligodendroglioma-like tumors', 'Disease', (128, 157))
201974	32024817	One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('telomeric sequences', 'Var', (65, 84))	('tumor', 'Disease', (19, 24))
201980	32024817	Telomerase is upregulated in ~85% of human cancers by different genetic aberrations, including TERT amplifications, rearrangements, or mutations in the TERT promoter.	('Telomerase', 'Enzyme', (0, 10))	('TERT', 'Gene', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('mutations', 'Var', (135, 144))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('upregulated', 'PosReg', (14, 25))	('human', 'Species', '9606', (37, 42))	('rearrangements', 'Var', (116, 130))
201982	32024817	Details on the ALT mechanism remain elusive, but it has been associated with loss-of-function mutations in the chromatin remodeling genes ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death domain-associated protein).	('loss-of-function', 'NegReg', (77, 93))	('mental retardation', 'Phenotype', 'HP:0001249', (163, 181))	('mutations', 'Var', (94, 103))	('DAXX', 'Gene', '1616', (205, 209))	('ATRX', 'Gene', (138, 142))	('DAXX', 'Gene', (205, 209))	('alpha-thalassaemia/mental retardation syndrome X-linked', 'Disease', 'MESH:D038901', (144, 199))	('ATRX', 'Gene', '546', (138, 142))
201988	32024817	Besides determining telomere content and searching for mutations associated with different telomere maintenance mechanisms (TMMs), we systematically detect 2683 somatic telomere insertions and show that different TMMs are associated with the enrichment of previously undescribed singleton TVRs.	('associated', 'Reg', (222, 232))	('insertions', 'Var', (178, 188))	('TMM', 'Chemical', 'MESH:C068303', (124, 127))	('TMM', 'Chemical', 'MESH:C068303', (213, 216))
202003	32024817	Different types of mutations in ATRX or DAXX, and at the TERT locus have been associated with ALT and telomerase activation, respectively.	('associated', 'Reg', (78, 88))	('ATRX', 'Gene', '546', (32, 36))	('telomerase activation', 'MPA', (102, 123))	('ALT', 'MPA', (94, 97))	('mutations', 'Var', (19, 28))	('DAXX', 'Gene', '1616', (40, 44))	('ATRX', 'Gene', (32, 36))	('DAXX', 'Gene', (40, 44))
202007	32024817	Of note, 10 of the 11 DAXX alterations were found in pancreatic endocrine tumors, while ATRX mutations were seen in a wider variety of entities.	('DAXX', 'Gene', (22, 26))	('ATRX', 'Gene', '546', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('found', 'Reg', (44, 49))	('pancreatic endocrine tumors', 'Disease', 'MESH:D010190', (53, 80))	('pancreatic endocrine tumors', 'Phenotype', 'HP:0030405', (53, 80))	('DAXX', 'Gene', '1616', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('pancreatic endocrine tumors', 'Disease', (53, 80))	('ATRX', 'Gene', (88, 92))	('alterations', 'Var', (27, 38))
202008	32024817	An additional 46 samples had nontruncating ATRX/DAXX simple nucleotide variants.	('DAXX', 'Gene', '1616', (48, 52))	('ATRX', 'Gene', '546', (43, 47))	('DAXX', 'Gene', (48, 52))	('nontruncating', 'MPA', (29, 42))	('simple nucleotide variants', 'Var', (53, 79))	('ATRX', 'Gene', (43, 47))
202010	32024817	The latter group comprised 198 activating C228T or C250T promoter mutations (of which 132 were obtained from the PCAWG simple nucleotide variant consensus calls and the remaining were detected with a targeted approach), 11 amplifications leading to at least six additional TERT copies, 55 structural variations within 20 kb upstream of TERT (TERTpSV), and 6 samples with more than one of these modifications.	('C250T', 'Mutation', 'rs1470227348', (51, 56))	('C228T', 'Mutation', 'rs750893877', (42, 47))	('activating', 'PosReg', (31, 41))	('C250T', 'Var', (51, 56))	('C228T', 'Var', (42, 47))
202011	32024817	Additionally, 18 tumor samples had both ATRX/DAXX truncating or other missense mutations and TERT alterations.	('ATRX', 'Gene', '546', (40, 44))	('tumor', 'Disease', (17, 22))	('DAXX', 'Gene', (45, 49))	('missense mutations', 'Var', (70, 88))	('ATRX', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('DAXX', 'Gene', '1616', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
202014	32024817	Moreover, the subtype-specific histological classification available in this study showed that TERTpSV were more frequent in liposarcoma (32%) than in leiomyosarcoma (7%).	('leiomyosarcoma', 'Disease', 'MESH:D007890', (151, 165))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('frequent', 'Reg', (113, 121))	('leiomyosarcoma', 'Disease', (151, 165))	('TERTpSV', 'Var', (95, 102))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (151, 165))	('liposarcoma', 'Disease', (125, 136))
202019	32024817	Samples with nontruncating ATRX/DAXX simple nucleotide variants had a similar telomere content as TERTmod samples (p > 0.05, Wilcoxon rank-sum test), suggesting that most of the nontruncating ATRX/DAXX mutations are passenger events.	('nontruncating', 'MPA', (178, 191))	('DAXX', 'Gene', (197, 201))	('ATRX', 'Gene', (192, 196))	('DAXX', 'Gene', '1616', (32, 36))	('ATRX', 'Gene', (27, 31))	('ATRX', 'Gene', '546', (192, 196))	('DAXX', 'Gene', '1616', (197, 201))	('ATRX', 'Gene', '546', (27, 31))	('DAXX', 'Gene', (32, 36))	('mutations', 'Var', (202, 211))
202023	32024817	Telomere insertions were found in 27% of the tumor samples, with counts ranging between 1 and 228 telomere insertion events.	('Telomere insertions', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('found', 'Reg', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
202024	32024817	The tumor types with the highest amount of telomere insertions per tumor sample were liposarcoma, leiomyosarcoma, and osteosarcoma, all of which also had a relatively high mean telomere content.	('tumor', 'Disease', (4, 9))	('liposarcoma', 'Disease', (85, 96))	('tumor', 'Disease', (67, 72))	('leiomyosarcoma', 'Disease', (98, 112))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (98, 112))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('osteosarcoma', 'Disease', (118, 130))	('liposarcoma', 'Disease', 'MESH:D008080', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (98, 112))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('telomere', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('osteosarcoma', 'Disease', 'MESH:D012516', (118, 130))
202025	32024817	To test for a synergistic effect, linear models that predict telomere insertions from telomere content and breakpoint abundance with and without an interaction term were computed.	('syn', 'Gene', (14, 17))	('telomere', 'Var', (61, 69))	('syn', 'Gene', '23336', (14, 17))
202026	32024817	There was clearly a higher percentage of samples with telomere insertions in ATRX/DAXXtrunc tumors (80%) than TERTmod tumors (28%; Fig.	('telomere insertions', 'Var', (54, 73))	('ATRX', 'Gene', '546', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('DAXXtrunc tumors', 'Disease', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('TERTmod tumors', 'Disease', 'MESH:D009369', (110, 124))	('TERTmod tumors', 'Disease', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('ATRX', 'Gene', (77, 81))	('DAXXtrunc tumors', 'Disease', 'MESH:D009369', (82, 98))
202031	32024817	In ATRX/DAXXtrunc samples, autosomal chromosome arms that showed evidence for BFB cycles and chromothripsis had the highest incidence of telomere insertions (Supplementary Fig.	('telomere insertions', 'MPA', (137, 156))	('DAXX', 'Gene', '1616', (8, 12))	('ATRX', 'Gene', (3, 7))	('autosomal', 'Var', (27, 36))	('ATRX', 'Gene', '546', (3, 7))	('DAXX', 'Gene', (8, 12))
202032	32024817	Correlation analysis of telomere insertions and mutations in telomere maintenance-associated genes from the TelNet database [http://www.cancertelsys.org/telnet] revealed significant association with TP53 (q = 1.9 x 10-42), ATRX (q = 2.6 x 10-6), PLCB2 (q = 7.8 x 10-4), MEN1 (q = 0.017), TSSC4 (q = 0.017), RB1 (q = 0.018), DAXX (q = 0.019), and ABCC8 mutations (q = 0.04, Wilcoxon rank-sum tests after Benjamini-Hochberg correction).	('mutations', 'Var', (352, 361))	('MEN1', 'Gene', (270, 274))	('cancer', 'Disease', (136, 142))	('ABCC8', 'Gene', (346, 351))	('DAXX', 'Gene', (324, 328))	('mutations', 'Var', (48, 57))	('TP53', 'Gene', '7157', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('PLCB2', 'Gene', '5330', (246, 251))	('DAXX', 'Gene', '1616', (324, 328))	('TSSC4', 'Gene', '10078', (288, 293))	('RB1', 'Gene', (307, 310))	('ABCC8', 'Gene', '6833', (346, 351))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('RB1', 'Gene', '5925', (307, 310))	('PLCB2', 'Gene', (246, 251))	('TP53', 'Gene', (199, 203))	('ATRX', 'Gene', (223, 227))	('ATRX', 'Gene', '546', (223, 227))	('MEN1', 'Gene', '4221', (270, 274))	('TSSC4', 'Gene', (288, 293))
202056	32024817	A total of 17 samples without ATRX/DAXXtrunc mutations had an ALT probability of over 0.9, of which three had nontruncating ATRX/DAXX mutations and one sample had a frameshift insertion in ATRX and a TERT amplification (11 TERT copies, triploid).	('ALT', 'MPA', (62, 65))	('ATRX', 'Gene', (30, 34))	('DAXX', 'Gene', '1616', (35, 39))	('ATRX', 'Gene', (189, 193))	('DAXX', 'Gene', '1616', (129, 133))	('ATRX', 'Gene', (124, 128))	('ATRX', 'Gene', '546', (30, 34))	('nontruncating', 'MPA', (110, 123))	('mutations', 'Var', (134, 143))	('DAXX', 'Gene', (35, 39))	('ATRX', 'Gene', '546', (189, 193))	('ATRX', 'Gene', '546', (124, 128))	('DAXX', 'Gene', (129, 133))	('frameshift', 'Var', (165, 175))
202058	32024817	This included some samples with ATRX/DAXX missense mutations, suggesting that the mutations in those samples may be more of a passenger event than functionally relevant.	('ATRX', 'Gene', '546', (32, 36))	('DAXX', 'Gene', '1616', (37, 41))	('missense mutations', 'Var', (42, 60))	('ATRX', 'Gene', (32, 36))	('DAXX', 'Gene', (37, 41))
202060	32024817	In this study, we have shown that the presence of ALT-associated mutations in tumors correlates with increased telomere content, enrichment of isolated TVRs in t-type context (singletons), a higher number of genomic breakpoints, and intrachromosomal telomere insertions (Fig.	('higher', 'PosReg', (191, 197))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('increased', 'PosReg', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ALT-associated', 'Gene', (50, 64))	('telomere content', 'MPA', (111, 127))	('mutations', 'Var', (65, 74))
202061	32024817	In contrast, tumors with mutations associated with a possible telomerase activation showed moderate decrease of telomere content and increased TERT expression.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('telomere content', 'MPA', (112, 128))	('TERT expression', 'MPA', (143, 158))	('decrease', 'NegReg', (100, 108))	('increased', 'PosReg', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('decrease of telomere content', 'Phenotype', 'HP:0031413', (100, 128))
202064	32024817	In addition to telomere elongation, the increase of telomere content in ALT-positive tumors detected by sequencing-based methods may partly stem from aberrant intrachromosomal telomere insertions or extrachromosomal telomeric DNA.	('ALT-positive', 'Disease', (72, 84))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('aberrant', 'Var', (150, 158))	('increase', 'PosReg', (40, 48))	('extrachromosomal telomeric DNA', 'CPA', (199, 229))	('stem from', 'Reg', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('telomere content', 'MPA', (52, 68))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
202065	32024817	Although almost all tumors must maintain their telomeres, we only detected somatic mutations highly associated with ALT or telomerase activation in a subset of the samples.	('ALT', 'MPA', (116, 119))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('telomeres', 'MPA', (47, 56))	('activation', 'PosReg', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('telomerase', 'MPA', (123, 133))
202067	32024817	Thus, telomere maintenance activating mutations occur more frequently in tumors derived from slowly replicating cells.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (38, 47))	('telomere maintenance', 'Gene', (6, 26))
202068	32024817	In line with this assumption, we observed high rates of TMM-associated mutations in brain, liver, bladder, and kidney tumors and TERT expression despite lack of TMM-associated mutations in lymphomas, tumors of the gastrointestinal tract, and female reproductive system.	('lymphomas', 'Disease', 'MESH:D008223', (189, 198))	('brain', 'Disease', (84, 89))	('liver', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('TMM', 'Chemical', 'MESH:C068303', (161, 164))	('tumors of the gastrointestinal tract', 'Disease', 'MESH:D005770', (200, 236))	('lymphomas', 'Phenotype', 'HP:0002665', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TMM-associated', 'Gene', (56, 70))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('TMM', 'Chemical', 'MESH:C068303', (56, 59))	('kidney tumors', 'Disease', (111, 124))	('mutations', 'Var', (71, 80))	('tumors of the gastrointestinal tract', 'Disease', (200, 236))	('bladder', 'Disease', (98, 105))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('kidney tumors', 'Disease', 'MESH:D007680', (111, 124))	('lymphomas', 'Disease', (189, 198))
202077	32024817	In agreement with data suggesting that TERT expression is higher in TERTpmut than in TERT promoter methylated medulloblastomas, we found that the telomere content was significantly higher in medulloblastomas with TERTmod than in those without (p = 0.0045, Wilcoxon rank-sum test).	('medulloblastoma', 'Phenotype', 'HP:0002885', (191, 206))	('medulloblastomas', 'Disease', 'MESH:D008527', (110, 126))	('higher', 'PosReg', (181, 187))	('medulloblastomas', 'Disease', (110, 126))	('TERTmod', 'Var', (213, 220))	('medulloblastomas', 'Disease', 'MESH:D008527', (191, 207))	('medulloblastoma', 'Phenotype', 'HP:0002885', (110, 125))	('telomere content', 'MPA', (146, 162))	('medulloblastomas', 'Disease', (191, 207))
202078	32024817	Telomere insertions were particularly frequent in ATRX/DAXXtrunc tumors, in which the abundant extrachromosomal telomeric DNA expands the telomere template pool for microhomology-mediated double-strand repair.	('Telomere insertions', 'Var', (0, 19))	('ATRX', 'Gene', '546', (50, 54))	('telomere template pool', 'MPA', (138, 160))	('DAXXtrunc tumors', 'Disease', 'MESH:D009369', (55, 71))	('microhomology-mediated double-strand repair', 'MPA', (165, 208))	('ATRX', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('expands', 'PosReg', (126, 133))	('DAXXtrunc tumors', 'Disease', (55, 71))	('frequent', 'Reg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
202080	32024817	Together with the correlation of telomere insertions and mutations in TP53, RB1, MEN1, ATRX, and DAXX, these findings suggest that genome instability and the ALT phenotype are prerequisites for a high number of telomere insertions.	('DAXX', 'Gene', '1616', (97, 101))	('RB1', 'Gene', (76, 79))	('TP53', 'Gene', '7157', (70, 74))	('ATRX', 'Gene', '546', (87, 91))	('ATRX', 'Gene', (87, 91))	('ALT', 'CPA', (158, 161))	('mutations', 'Var', (57, 66))	('DAXX', 'Gene', (97, 101))	('TP53', 'Gene', (70, 74))	('RB1', 'Gene', '5925', (76, 79))	('MEN1', 'Gene', (81, 85))	('MEN1', 'Gene', '4221', (81, 85))	('genome instability', 'CPA', (131, 149))
202081	32024817	Mutations in TP53, RB1, and MEN1 have been associated with impaired DNA damage response and repair.	('TP53', 'Gene', (13, 17))	('MEN1', 'Gene', (28, 32))	('MEN1', 'Gene', '4221', (28, 32))	('TP53', 'Gene', '7157', (13, 17))	('DNA damage response', 'MPA', (68, 87))	('repair', 'MPA', (92, 98))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', (19, 22))	('associated', 'Reg', (43, 53))	('impaired', 'NegReg', (59, 67))	('RB1', 'Gene', '5925', (19, 22))
202083	32024817	Here, we report a stronger association of singleton TVRs with ATRX/DAXXtrunc mutations than TVRs in an arbitrary context.	('DAXX', 'Gene', (67, 71))	('association', 'Interaction', (27, 38))	('ATRX', 'Gene', (62, 66))	('singleton', 'Var', (42, 51))	('DAXX', 'Gene', '1616', (67, 71))	('ATRX', 'Gene', '546', (62, 66))
202085	32024817	Notably, we report for the first time that TTTGGG singletons but not TTTGGG in arbitrary context were depleted in ATRX/DAXXtrunc samples.	('singletons', 'Var', (50, 60))	('ATRX', 'Gene', '546', (114, 118))	('TTTGGG', 'Gene', (43, 49))	('DAXX', 'Gene', '1616', (119, 123))	('ATRX', 'Gene', (114, 118))	('DAXX', 'Gene', (119, 123))
202094	32024817	Somatic simple nucleotide, structural variations, and copy numbers were obtained from the PCAWG consensus calls (Synapse IDs syn7364923, syn7596712, and syn8042992, respectively).	('syn7596712', 'Chemical', 'MESH:C525256', (137, 147))	('syn7596712', 'Var', (137, 147))	('syn8042992', 'Var', (153, 163))	('syn7364923', 'Chemical', 'MESH:C525256', (125, 135))	('syn8042992', 'Chemical', 'MESH:C525256', (153, 163))
202096	32024817	Samples with a truncating ATRX or DAXX alteration (frame-shift insertion/deletion, stop-codon gain, or structural variation breakpoint within the gene) were defined as ATRX/DAXXtrunc, samples with other simple nucleotide variants were defined as ATRX/DAXXnon-trunc.	('ATRX', 'Gene', (246, 250))	('ATRX', 'Gene', (26, 30))	('DAXX', 'Gene', '1616', (34, 38))	('frame-shift insertion/deletion', 'Var', (51, 81))	('DAXX', 'Gene', (251, 255))	('DAXX', 'Gene', (34, 38))	('ATRX', 'Gene', '546', (246, 250))	('DAXX', 'Gene', '1616', (173, 177))	('ATRX', 'Gene', (168, 172))	('ATRX', 'Gene', '546', (26, 30))	('ATRX', 'Gene', '546', (168, 172))	('structural variation breakpoint', 'Var', (103, 134))	('DAXX', 'Gene', (173, 177))	('DAXX', 'Gene', '1616', (251, 255))
202098	32024817	Of note, a frame-shift deletion called in the tumor sample of donor SP112201 was excluded as a false positive after visual inspection in the Integrative Genomics Viewer (IGV).	('frame-shift deletion', 'Var', (11, 31))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('donor', 'Species', '9606', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
202099	32024817	Tumor samples with a C228T or C250T TERT promoter mutation were defined as TERTpmut.	('C228T', 'Var', (21, 26))	('TERT promoter', 'Gene', (36, 49))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('C250T', 'Var', (30, 35))	('C228T', 'Mutation', 'rs750893877', (21, 26))	('C250T', 'SUBSTITUTION', 'None', (30, 35))
202118	32024817	Data access is possible via the ICGC data portal (DCC), were the original files are split into ICGC and TCGA subsets due to different access regulations: somatic simple nucleotide calls (syn7364923): and [https://dcc.icgc.org/releases/PCAWG/consensus_snv_indel], structural variation calls (syn7596712): and [https://dcc.icgc.org/releases/PCAWG/consensus_sv], copy number calls (syn8042992): and [https://dcc.icgc.org/releases/PCAWG/consensus_cnv].	('dcc', 'Gene', '1630', (405, 408))	('syn8042992', 'Chemical', 'MESH:C525256', (379, 389))	('DCC', 'Gene', (50, 53))	('dcc', 'Gene', (213, 216))	('dcc', 'Gene', '1630', (317, 320))	('syn8042992):', 'Var', (379, 391))	('DCC', 'Gene', '1630', (50, 53))	('dcc', 'Gene', (405, 408))	('dcc', 'Gene', (317, 320))	('syn7364923', 'Chemical', 'MESH:C525256', (187, 197))	('syn7596712', 'Chemical', 'MESH:C525256', (291, 301))	('dcc', 'Gene', '1630', (213, 216))
202120	30023167	Quantitative analysis of neurite orientation dispersion and density imaging in grading gliomas and detecting IDH-1 gene mutation status Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique that has rarely been applied for glioma grading.	('glioma', 'Disease', (261, 267))	('glioma', 'Disease', (87, 93))	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('glioma', 'Disease', 'MESH:D005910', (261, 267))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('mutation', 'Var', (120, 128))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('IDH-1', 'Gene', '3417', (109, 114))	('IDH-1', 'Gene', (109, 114))	('gliomas', 'Disease', (87, 94))
202121	30023167	The purpose of this study was to quantitatively evaluate the diagnostic efficiency of NODDI in tumour parenchyma (TP) and peritumoural area (PT) for grading gliomas and detecting isocitrate dehydrogenase-1 (IDH-1) mutation status.	('tumour parenchyma', 'Disease', 'MESH:D010195', (95, 112))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('mutation', 'Var', (214, 222))	('isocitrate dehydrogenase-1', 'Gene', (179, 205))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (95, 101))	('tumour', 'Disease', (126, 132))	('gliomas', 'Disease', (157, 164))	('tumour parenchyma', 'Disease', (95, 112))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('IDH-1', 'Gene', (207, 212))	('IDH-1', 'Gene', '3417', (207, 212))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('detecting', 'Reg', (169, 178))	('isocitrate dehydrogenase-1', 'Gene', '3417', (179, 205))
202125	30023167	Tumours with high icvfTP (>=0.306) and low icvfPT (<=0.331) were more likely to be high-grade gliomas (HGGs), while lesions with low icvfTP (<0.306) and high icvfPT (>0.331) were prone to be low-grade gliomas (LGGs) (P < 0.001).	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('<=0.331', 'Var', (51, 58))	('gliomas', 'Disease', (201, 208))	('>=0.306', 'Var', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('low icvfPT (<=0.331', 'Var', (39, 58))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('high icvfTP (>=0.306', 'Var', (13, 33))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
202127	30023167	However, no significant differences were found in NODDI metrics for differentiating IDH-1 mutation status.	('mutation', 'Var', (90, 98))	('IDH-1', 'Gene', '3417', (84, 89))	('IDH-1', 'Gene', (84, 89))
202130	30023167	However, the utility of NODDI metrics for detecting IDH-1 mutation status has not been fully explored, as a larger sample size may be necessary to uncover benefits.	('mutation', 'Var', (58, 66))	('IDH-1', 'Gene', (52, 57))	('IDH-1', 'Gene', '3417', (52, 57))
202131	30023167	Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique Quantitative NOODI metrics in TP and PT area could help grading gliomas Age, icvf in TP and PT area were significantly associated with glioma grading The utility of NODDI in detecting IDH-1 mutation status has not been fully explored  Gliomas account for approximately 30% of all brain and central nervous system tumours and 80% of all malignant brain tumours.	('glioma', 'Disease', (156, 162))	('Gliomas', 'Disease', (327, 334))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('gliomas', 'Disease', (156, 163))	('brain tumours', 'Phenotype', 'HP:0030692', (438, 451))	('malignant brain tumours', 'Disease', 'MESH:D001932', (428, 451))	('IDH-1', 'Gene', (276, 281))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('mutation', 'Var', (282, 290))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('nervous system tumours', 'Disease', 'MESH:D009423', (390, 412))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('Gliomas', 'Disease', 'MESH:D005910', (327, 334))	('tumour', 'Phenotype', 'HP:0002664', (405, 411))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('tumours', 'Phenotype', 'HP:0002664', (405, 412))	('nervous system tumours', 'Disease', (390, 412))	('IDH-1', 'Gene', '3417', (276, 281))	('tumour', 'Phenotype', 'HP:0002664', (444, 450))	('associated', 'Reg', (211, 221))	('Glioma', 'Phenotype', 'HP:0009733', (327, 333))	('Gliomas', 'Phenotype', 'HP:0009733', (327, 334))	('tumours', 'Phenotype', 'HP:0002664', (444, 451))	('central nervous system tumours', 'Phenotype', 'HP:0100006', (382, 412))	('ODI', 'Chemical', '-', (107, 110))	('malignant brain tumours', 'Disease', (428, 451))	('glioma', 'Disease', (227, 233))
202142	30023167	The most prominent change is that the new edition incorporates the status of isocitrate dehydrogenase (IDH) into glioma diagnosis, with the majority of IDH mutations being IDH-1 positive.	('IDH', 'Gene', (172, 175))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH-1', 'Gene', '3417', (172, 177))	('IDH-1', 'Gene', (172, 177))	('IDH', 'Gene', (103, 106))	('mutations', 'Var', (156, 165))	('IDH', 'Gene', '3417', (172, 175))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', '3417', (103, 106))	('glioma', 'Disease', (113, 119))	('IDH', 'Gene', '3417', (152, 155))
202143	30023167	Regardless of glioma grade, patients with IDH-1 positive mutations have a better chance of survival.	('better', 'PosReg', (74, 80))	('survival', 'CPA', (91, 99))	('IDH-1', 'Gene', '3417', (42, 47))	('IDH-1', 'Gene', (42, 47))	('Regardless of glioma', 'Disease', 'MESH:D005910', (0, 20))	('Regardless of glioma', 'Disease', (0, 20))	('mutations', 'Var', (57, 66))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('patients', 'Species', '9606', (28, 36))
202146	30023167	Their results showed that patients with IDH-1 mutations have higher apparent diffusion coefficient (ADC) values but lower mean kurtosis (MK), fractional anisotropy (FA) and relative cerebral blood volumes.	('lower', 'NegReg', (116, 121))	('mutations', 'Var', (46, 55))	('higher', 'PosReg', (61, 67))	('fractional anisotropy', 'MPA', (142, 163))	('patients', 'Species', '9606', (26, 34))	('apparent diffusion coefficient', 'MPA', (68, 98))	('kurtosis', 'Disease', (127, 135))	('kurtosis', 'Disease', 'None', (127, 135))	('IDH-1', 'Gene', '3417', (40, 45))	('IDH-1', 'Gene', (40, 45))
202147	30023167	However, the utility of NODDI for detecting IDH-1 mutation status is unknown.	('IDH-1', 'Gene', '3417', (44, 49))	('IDH-1', 'Gene', (44, 49))	('mutation', 'Var', (50, 58))
202148	30023167	Therefore, the purpose of this study was to assess the value of NODDI metrics (icvf and ODI) in grading gliomas and detecting IDH-1 mutation status.	('gliomas', 'Disease', (104, 111))	('detecting', 'Reg', (116, 125))	('mutation status', 'Var', (132, 147))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('ODI', 'Chemical', '-', (88, 91))	('IDH-1', 'Gene', '3417', (126, 131))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('IDH-1', 'Gene', (126, 131))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
202173	30023167	However, the incidence of IDH-1 mutation decreased as glioma grade increased.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('decreased', 'NegReg', (41, 50))	('glioma', 'Disease', (54, 60))	('IDH-1', 'Gene', '3417', (26, 31))	('mutation', 'Var', (32, 40))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH-1', 'Gene', (26, 31))
202188	30023167	Furthermore, the correlations between IDH-1 mutation status and NODDI metrics were sub-analysed within each grade of glioma.	('NODDI', 'MPA', (64, 69))	('IDH-1', 'Gene', (38, 43))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mutation status', 'Var', (44, 59))	('glioma', 'Disease', (117, 123))	('IDH-1', 'Gene', '3417', (38, 43))
202189	30023167	For grade IV gliomas, the mean value of ricvf was significantly higher in patients with IDH-1 mutations (ricvfIDH-1(+) vs. ricvf IDH-1(-): 0.971 +- 0.106 vs. 0.751 +- 0.238; P = 0.029).	('IV gliomas', 'Disease', (10, 20))	('IV gliomas', 'Disease', 'MESH:D005910', (10, 20))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('mutations', 'Var', (94, 103))	('grade', 'Disease', (4, 9))	('higher', 'PosReg', (64, 70))	('IDH-1', 'Gene', '3417', (110, 115))	('patients', 'Species', '9606', (74, 82))	('IDH-1', 'Gene', '3417', (88, 93))	('IDH-1', 'Gene', (110, 115))	('IDH-1', 'Gene', '3417', (129, 134))	('IDH-1', 'Gene', (129, 134))	('IDH-1', 'Gene', (88, 93))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
202190	30023167	For grade II gliomas, the NODDI and DTI parameters were not statistically significant for the detection of IDH mutations.	('mutations', 'Var', (111, 120))	('II gliomas', 'Disease', 'MESH:D005910', (10, 20))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', '3417', (107, 110))	('II gliomas', 'Disease', (10, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
202213	30023167	Furthermore, recent studies on the identification of IDH-1 mutation status by DTI and DKI have shown that IDH-1-mutated gliomas have lower maximum FA and mean MK values.	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('MK values', 'MPA', (159, 168))	('mutation', 'Var', (59, 67))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('IDH-1', 'Gene', (53, 58))	('IDH-1', 'Gene', '3417', (53, 58))	('gliomas', 'Disease', (120, 127))	('lower', 'NegReg', (133, 138))	('IDH-1', 'Gene', '3417', (106, 111))	('IDH-1', 'Gene', (106, 111))
202216	30023167	First, our results show that the utility of NODDI metrics in detecting IDH-1 mutation status has not been fully established, as a larger group size may demonstrate benefits.	('IDH-1', 'Gene', '3417', (71, 76))	('IDH-1', 'Gene', (71, 76))	('mutation', 'Var', (77, 85))
202220	30023167	However, the utility of NODDI in detecting IDH-1 mutation status has not been established due to small group size.	('IDH-1', 'Gene', '3417', (43, 48))	('IDH-1', 'Gene', (43, 48))	('mutation', 'Var', (49, 57))
202227	28969023	Patients with high-grade brain tumors had significantly higher pretreatment serum lactate levels (p = 0.011).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('serum lactate levels', 'MPA', (76, 96))	('high-grade', 'Var', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('lactate', 'Chemical', 'MESH:D019344', (82, 89))	('men', 'Species', '9606', (71, 74))	('brain tumors', 'Phenotype', 'HP:0030692', (25, 37))	('Patients', 'Species', '9606', (0, 8))	('brain tumors', 'Disease', 'MESH:D001932', (25, 37))	('higher', 'PosReg', (56, 62))	('brain tumors', 'Disease', (25, 37))	('brain tumor', 'Phenotype', 'HP:0030692', (25, 36))
202251	28969023	In addition, the patients with high-grade brain tumors tended to have lower serum GFAP than those with low-grade tumors (0.145 +- 0.354 vs. 0.281 +- 0.522 ng/mL; p = 0.097; Table 1).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Disease', (113, 119))	('high-grade', 'Var', (31, 41))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('GFAP', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('lower', 'NegReg', (70, 75))	('patients', 'Species', '9606', (17, 25))	('brain tumors', 'Disease', 'MESH:D001932', (42, 54))	('brain tumors', 'Phenotype', 'HP:0030692', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('brain tumors', 'Disease', (42, 54))	('GFAP', 'Gene', '2670', (82, 86))	('brain tumor', 'Phenotype', 'HP:0030692', (42, 53))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
202330	28714279	This corresponded to the areas under the receiver-operator-characteristic curves of 0.89, 0.76, 0.75, and 0.75, respectively, for the prediction of the IDH mutation status.	('mutation status', 'Var', (156, 171))	('IDH', 'Gene', '3417', (152, 155))	('IDH', 'Gene', (152, 155))
202331	28714279	IDH-wildtype lesions were typically associated with relatively high APTw signal intensities, compared with IDH-mutant lesions.	('IDH', 'Gene', (0, 3))	('lesions', 'Var', (13, 20))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', '3417', (107, 110))	('APTw signal intensities', 'MPA', (68, 91))
202332	28714279	The APTw signal could be a valuable imaging biomarker by which to identify IDH1 mutation status in grade-II gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('APTw signal', 'MPA', (4, 15))	('IDH1', 'Gene', (75, 79))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1', 'Gene', '3417', (75, 79))	('mutation', 'Var', (80, 88))
202334	28714279	The recent breakthrough in the understanding of isocitrate dehydrogenase (IDH) mutations in glioma has resulted in a prompt reappraisal of the molecular oncogenesis of this group of diseases.	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma', 'Disease', (92, 98))	('IDH', 'Gene', (74, 77))	('isocitrate dehydrogenase', 'Gene', (48, 72))	('IDH', 'Gene', '3417', (74, 77))	('mutations', 'Var', (79, 88))	('isocitrate dehydrogenase', 'Gene', '3417', (48, 72))
202337	28714279	Mutations in IDH genes, which occur in the majority of WHO grade-II and -III gliomas and secondary glioblastomas, have been postulated to indicate a favorable clinical prognosis.	('IDH', 'Gene', '3417', (13, 16))	('gliomas', 'Disease', (77, 84))	('glioblastomas', 'Phenotype', 'HP:0012174', (99, 112))	('glioblastomas', 'Disease', 'MESH:D005909', (99, 112))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('Mutations', 'Var', (0, 9))	('glioblastomas', 'Disease', (99, 112))	('IDH', 'Gene', (13, 16))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
202338	28714279	Since IDH-gene-encoded enzymes are closely involved in the energy-producing Krebs cycle as catalytic isozymes, mutations in IDH genes may cause widespread disturbances of cellular metabolism, including alteration of amino acid concentrations and enzymatic activity, and raise global DNA hypermethylation and global downregulation of protein expression as well.	('amino acid concentrations', 'MPA', (216, 241))	('alteration', 'Reg', (202, 212))	('cellular metabolism', 'MPA', (171, 190))	('mutations', 'Var', (111, 120))	('IDH', 'Gene', (6, 9))	('protein expression', 'MPA', (333, 351))	('IDH', 'Gene', (124, 127))	('disturbances', 'MPA', (155, 167))	('IDH', 'Gene', '3417', (6, 9))	('global DNA hypermethylation', 'MPA', (276, 303))	('downregulation', 'NegReg', (315, 329))	('IDH', 'Gene', '3417', (124, 127))	('raise', 'PosReg', (270, 275))	('cause', 'Reg', (138, 143))	('Krebs', 'Chemical', '-', (76, 81))	('enzymatic activity', 'MPA', (246, 264))
202340	28714279	As popularly applied in clinical practice, IDH mutation screening is generally performed with an immunohistochemical (IHC) assay on surgical samples using antibodies which detect IDH1-R132H.	('IDH', 'Gene', '3417', (43, 46))	('IDH', 'Gene', '3417', (179, 182))	('IDH', 'Gene', (179, 182))	('R132H', 'Var', (184, 189))	('IDH1', 'Gene', (179, 183))	('R132H', 'SUBSTITUTION', 'None', (184, 189))	('IDH', 'Gene', (43, 46))	('IDH1', 'Gene', '3417', (179, 183))
202341	28714279	More than 85% of all genetic alterations in IDH1 in gliomas are heterozygous missense mutations of arginine to histidine (R132H); thus, this immunohistochemical approach will detect the majority of cases.	('R132H', 'SUBSTITUTION', 'None', (122, 127))	('histidine', 'Chemical', 'MESH:D006639', (111, 120))	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH1', 'Gene', (44, 48))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('IDH1', 'Gene', '3417', (44, 48))	('genetic alterations', 'Var', (21, 40))	('R132H', 'Var', (122, 127))
202346	28714279	Notably, since lab studies have proven that the oncometabolite 2-hydroxyglutarate (2-HG) holds a 100-fold increase in IDH-mutant cells compared to IDH-wildtype type cells, recent studies have also shown that significantly higher 2-HG detected by single-voxel MRS can identify patients with IDH-1 mutant gliomas, with high sensitivity.	('patients', 'Species', '9606', (276, 284))	('gliomas', 'Disease', 'MESH:D005910', (303, 310))	('IDH', 'Gene', '3417', (147, 150))	('gliomas', 'Disease', (303, 310))	('mutant', 'Var', (296, 302))	('gliomas', 'Phenotype', 'HP:0009733', (303, 310))	('higher', 'PosReg', (222, 228))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (63, 81))	('IDH', 'Gene', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (303, 309))	('IDH', 'Gene', '3417', (118, 121))	('IDH', 'Gene', (290, 293))	('increase', 'PosReg', (106, 114))	('IDH', 'Gene', (147, 150))	('IDH-1', 'Gene', '3417', (290, 295))	('IDH-1', 'Gene', (290, 295))	('IDH', 'Gene', '3417', (290, 293))
202351	28714279	For glial neoplasms, in particular, consistent APTw MRI results have been produced across various labs, showing promise for the grading of gliomas (distinct hyperintensity in grades-III and -IV gliomas vs. iso-intensity to minimal hyperintensity in grade-II gliomas), which demonstrate increasing protein concentrations with grade, as revealed by proteomics and in vivo MR spectroscopy.	('gliomas', 'Phenotype', 'HP:0009733', (258, 265))	('grades-III', 'Var', (175, 185))	('gliomas', 'Disease', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('glial neoplasms', 'Disease', (4, 19))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Disease', (194, 201))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('glial neoplasms', 'Disease', 'MESH:D005910', (4, 19))	('neoplasms', 'Phenotype', 'HP:0002664', (10, 19))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('gliomas', 'Disease', (258, 265))	('gliomas', 'Disease', 'MESH:D005910', (258, 265))
202353	28714279	Enrollment criteria were as follows: >=18 years old; APTw and routine MRI scanning occurred within 7 days preoperatively; histopathologically confirmed as a WHO grade-II astrocytoma, oligoastrocytoma, or oligodendroglioma (according to their medical records; originally based on the 2007 WHO criteria); IDH1 mutation status and 1p/19q co-deletion status available from operative sample; and received no radiotherapy or chemotherapy before imaging.	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('astrocytoma', 'Disease', (188, 199))	('IDH1', 'Gene', '3417', (303, 307))	('astrocytoma', 'Phenotype', 'HP:0009592', (188, 199))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (183, 199))	('oligodendroglioma', 'Disease', (204, 221))	('astrocytoma', 'Disease', 'MESH:D001254', (170, 181))	('astrocytoma', 'Disease', (170, 181))	('mutation status', 'Var', (308, 323))	('oligoastrocytoma', 'Disease', (183, 199))	('astrocytoma', 'Disease', 'MESH:D001254', (188, 199))	('oligodendroglioma', 'Disease', 'MESH:D009837', (204, 221))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('IDH1', 'Gene', (303, 307))
202361	28714279	IDH1-R132H evaluation was performed by IHC and DNA sequencing, as described previously.	('IDH1', 'Gene', (0, 4))	('R132H', 'SUBSTITUTION', 'None', (5, 10))	('R132H', 'Var', (5, 10))	('IDH1', 'Gene', '3417', (0, 4))
202362	28714279	Paraffin-embedded slices of operative specimens were stained with IDH1-R132H-specific antibody (1:50; H09 clone, Dianova; Hamburg, Germany).	('IDH1', 'Gene', '3417', (66, 70))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('R132H', 'Var', (71, 76))	('IDH1', 'Gene', (66, 70))	('R132H', 'SUBSTITUTION', 'None', (71, 76))
202372	28714279	IDH mutations were found in 20 cases (74.1%), 15 of which were histopathologically classified as oligodendrogliomas, IDH mutant and 1p/19q codeleted, and five as diffuse astrocytomas, IDH mutant.	('astrocytomas', 'Disease', (170, 182))	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('IDH', 'Gene', (0, 3))	('oligodendrogliomas', 'Disease', (97, 115))	('found', 'Reg', (19, 24))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (184, 187))	('IDH', 'Gene', '3417', (117, 120))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('astrocytomas', 'Disease', 'MESH:D001254', (170, 182))	('IDH', 'Gene', '3417', (184, 187))	('mutations', 'Var', (4, 13))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (97, 115))
202382	28714279	The APTw images showed mildly increased hyperintensity in T2w-hyperintense areas (at least some portions), compared to the CNAWM, demonstrating the IDH-wildtype lesions as relatively heterogeneous masses with scattered punctate or pitchy high APTw signals.	('increased hyperintensity', 'Phenotype', 'HP:0030890', (30, 54))	('T2w-hyperintense', 'Var', (58, 74))	('IDH', 'Gene', (148, 151))	('hyperintensity', 'MPA', (40, 54))	('punctate', 'MPA', (219, 227))	('IDH', 'Gene', '3417', (148, 151))	('increased', 'PosReg', (30, 39))
202398	28714279	The modernized understanding of the somatic mutations of the IDH 1 and 2 genes in gliomas allows us to better sub-classify this group of entities which have distinguished prognosis, opening up a new era in the treatment of brain tumors.	('brain tumors', 'Disease', (223, 235))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('mutations', 'Var', (44, 53))	('gliomas', 'Disease', (82, 89))	('brain tumors', 'Disease', 'MESH:D001932', (223, 235))	('IDH 1 and 2', 'Gene', '3417;3418', (61, 72))	('brain tumors', 'Phenotype', 'HP:0030692', (223, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))
202409	28714279	Therefore, the APTw signal could be a valuable imaging biomarker by which to identify IDH1 mutation status in grade-II gliomas.	('mutation', 'Var', (91, 99))	('IDH1', 'Gene', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('IDH1', 'Gene', '3417', (86, 90))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))
202415	28714279	Notably, lab research results have shown global downregulation of protein expression in mutant IDH1-driven glioma cells, compared to oncogenic HRAS IDH1-wild type glioma cells, which is consistent with our findings that significantly lower APTw signal intensities were observed in IDH-mutant grade-II gliomas.	('glioma', 'Disease', (163, 169))	('APTw signal intensities', 'MPA', (240, 263))	('lower', 'NegReg', (234, 239))	('gliomas', 'Phenotype', 'HP:0009733', (301, 308))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('mutant', 'Var', (88, 94))	('IDH', 'Gene', (95, 98))	('type glioma', 'Disease', (158, 169))	('IDH', 'Gene', '3417', (281, 284))	('type glioma', 'Disease', 'MESH:D005910', (158, 169))	('protein expression', 'MPA', (66, 84))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1', 'Gene', (95, 99))	('IDH', 'Gene', '3417', (95, 98))	('IDH1', 'Gene', (148, 152))	('IDH', 'Gene', (148, 151))	('gliomas', 'Disease', (301, 308))	('glioma', 'Disease', (301, 307))	('HRAS', 'Gene', '3265', (143, 147))	('IDH1', 'Gene', '3417', (95, 99))	('HRAS', 'Gene', (143, 147))	('glioma', 'Disease', 'MESH:D005910', (301, 307))	('IDH1', 'Gene', '3417', (148, 152))	('gliomas', 'Disease', 'MESH:D005910', (301, 308))	('IDH', 'Gene', '3417', (148, 151))	('downregulation', 'NegReg', (48, 62))	('glioma', 'Phenotype', 'HP:0009733', (301, 307))	('IDH', 'Gene', (281, 284))	('glioma', 'Disease', (107, 113))
202417	28714279	In addition, our results in this study are consistent with a recent study by Xiong et al., who reported that IDH mutations significantly correlated with a lower cell proliferation in grade-II oligodendroglial tumors, thus leading to a lower APTw signal.	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('APTw signal', 'MPA', (241, 252))	('cell proliferation', 'CPA', (161, 179))	('mutations', 'Var', (113, 122))	('lower', 'NegReg', (155, 160))	('oligodendroglial tumors', 'Disease', (192, 215))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (192, 215))	('IDH', 'Gene', (109, 112))	('lower', 'NegReg', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('IDH', 'Gene', '3417', (109, 112))
202423	28714279	Non-invasive prediction of IDH1 mutation status could provide more valuable supplementary information about the prognosis of grade-II gliomas before surgery.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('gliomas', 'Disease', (134, 141))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('IDH1', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('IDH1', 'Gene', '3417', (27, 31))
202425	28603776	The most widely validated markers in neuro-oncology presently are: 1) MGMT promoter methylation as a prognostic and predictive marker in glioblastoma, 2) co-deletion of 1p and 19q differentiating oligodendrogliomas from astrocytomas, 3) IDH1/2 mutations, and 4) select pathway-associated mutations.	('oncology', 'Phenotype', 'HP:0002664', (43, 51))	('glioblastoma', 'Disease', (137, 149))	('MGMT', 'Gene', (70, 74))	('astrocytomas', 'Disease', 'MESH:D001254', (220, 232))	('IDH1/2 mutations, and 4', 'Gene', '3417', (237, 260))	('MGMT', 'Gene', '4255', (70, 74))	('pathway-associated mutations', 'Reg', (269, 297))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (196, 214))	('glioblastoma', 'Disease', 'MESH:D005909', (137, 149))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('astrocytoma', 'Phenotype', 'HP:0009592', (220, 231))	('astrocytomas', 'Disease', (220, 232))	('oligodendrogliomas', 'Disease', (196, 214))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('co-deletion', 'Var', (154, 165))	('differentiating', 'Reg', (180, 195))
202428	28603776	Some of these key alterations inferred the development of novel biomarkers that have been incorporated into the newly released World Health Organization (WHO) Classification of Tumors of the Central Nervous System, which for the first time classifies brain tumors not only based on their histological appearance but also on molecular parameters.	('Tumors of the Central Nervous', 'Disease', 'MESH:D016543', (177, 206))	('alterations', 'Var', (18, 29))	('brain tumors', 'Phenotype', 'HP:0030692', (251, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('Tumors of the Central Nervous', 'Disease', (177, 206))	('brain tumors', 'Disease', 'MESH:D001932', (251, 263))	('brain tumors', 'Disease', (251, 263))	('brain tumor', 'Phenotype', 'HP:0030692', (251, 262))	('Tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('Tumors of the Central Nervous System', 'Phenotype', 'HP:0100006', (177, 213))
202439	28603776	Mutations in the genes coding for isocitrate dehydrogenase 1 (IDH1) or less frequently 2 (IDH2) occur in approximately 80% of grade II and III astrocytoma and oligodendrogliomas (see below), as well as secondary GBM, i.e.	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('astrocytoma and oligodendrogliomas', 'Disease', 'MESH:D009837', (143, 177))	('IDH2', 'Gene', '3418', (90, 94))	('IDH1', 'Gene', '3417', (62, 66))	('II astrocytoma', 'Disease', (140, 154))	('II astrocytoma', 'Disease', 'MESH:D001254', (140, 154))	('occur', 'Reg', (96, 101))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (62, 66))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('IDH2', 'Gene', (90, 94))
202441	28603776	Studies have demonstrated that an isolated amino acid missense mutation in IDH1/2 at arginine 132 (R132) or the analogous residue 172 (R172) results in metabolic reprogramming with the ability to convert alpha-ketoglutarate (alpha-KG) to the R(-)-2-hydroxyglutarate (2-HG).	('results in', 'Reg', (141, 151))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (204, 223))	('2-HG', 'Chemical', '-', (267, 271))	('IDH1/2', 'Gene', (75, 81))	('arginine', 'Chemical', 'MESH:D001120', (85, 93))	('missense mutation', 'Var', (54, 71))	('R(-)-2-hydroxyglutarate', 'Chemical', '-', (242, 265))	('convert', 'MPA', (196, 203))	('IDH1/2', 'Gene', '3417;3418', (75, 81))	('metabolic reprogramming', 'CPA', (152, 175))
202443	28603776	Significant prognostic differences have been identified between IDH1/2 mutant and wildtype astrocytomas that have started to impact clinical treatment decisions, even outside of clinical trials.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('astrocytomas', 'Disease', (91, 103))	('IDH1/2', 'Gene', (64, 70))	('mutant', 'Var', (71, 77))	('astrocytomas', 'Disease', 'MESH:D001254', (91, 103))	('impact', 'Reg', (125, 131))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
202450	28603776	Methylation of the MGMT promoter region leads to epigenetic silencing of MGMT, thereby inhibiting DNA repair.	('DNA repair', 'MPA', (98, 108))	('MGMT', 'Gene', (73, 77))	('MGMT', 'Gene', '4255', (73, 77))	('Methylation', 'Var', (0, 11))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('inhibiting', 'NegReg', (87, 97))	('epigenetic silencing', 'MPA', (49, 69))
202451	28603776	Thus, MGMT promoter methylation is a strong predictor of prolonged survival, independent of other clinical factors or treatment and is associated with prolonged progression-free and overall survival in patients with GBM treated with chemotherapy and radiation therapy.	('MGMT', 'Gene', (6, 10))	('prolonged', 'PosReg', (151, 160))	('patients', 'Species', '9606', (202, 210))	('methylation', 'Var', (20, 31))	('associated with', 'Reg', (135, 150))	('MGMT', 'Gene', '4255', (6, 10))
202452	28603776	Of the 206 cases available of the original EORTC/NCIC study, 45% showed MGMT promoter methylation, which was associated with an independently favorable median overall survival (OS) of 21.7 months after radiochemotherapy, yet a smaller survival advantage of 15.3 months was also observed in patients with unmethylated MGMT.	('CIC', 'Gene', '23152', (50, 53))	('MGMT', 'Gene', (317, 321))	('patients', 'Species', '9606', (290, 298))	('MGMT', 'Gene', '4255', (72, 76))	('MGMT', 'Gene', '4255', (317, 321))	('MGMT', 'Gene', (72, 76))	('CIC', 'Gene', (50, 53))	('promoter methylation', 'Var', (77, 97))
202455	28603776	Multiple recent randomized trials have confirmed the important prognostic and predictive roles of MGMT promoter methylation in patients with newly diagnosed GBM, including 'elderly patients'.	('methylation', 'Var', (112, 123))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (181, 189))	('MGMT', 'Gene', (98, 102))	('MGMT', 'Gene', '4255', (98, 102))
202464	28603776	However, due to the lack of alternative treatment options for patients with unmethylated GBM, MGMT's role in clinical decision-making remains limited and the direction-changing impact of routine MGMT analysis is restricted to only a few clinical scenarios.	('MGMT', 'Gene', '4255', (94, 98))	('MGMT', 'Gene', (94, 98))	('GBM', 'Gene', (89, 92))	('unmethylated', 'Var', (76, 88))	('MGMT', 'Gene', (195, 199))	('patients', 'Species', '9606', (62, 70))	('MGMT', 'Gene', '4255', (195, 199))
202467	28603776	Recently, alterations of TERT, ATRX and TP53 have been implicated in differential pathways in gliomagenesis (see also separate sections below), but so far neither of these markers has directly impacted clinical decision-making in astrocytomas (Table 1).	('alterations', 'Var', (10, 21))	('astrocytomas', 'Disease', 'MESH:D001254', (230, 242))	('glioma', 'Disease', (94, 100))	('TERT', 'Gene', (25, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (230, 241))	('ATRX', 'Gene', (31, 35))	('astrocytomas', 'Disease', (230, 242))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('impacted', 'Reg', (193, 201))	('TP53', 'Gene', (40, 44))	('TP53', 'Gene', '7157', (40, 44))	('TERT', 'Gene', '7015', (25, 29))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('ATRX', 'Gene', '546', (31, 35))	('implicated', 'Reg', (55, 65))
202470	28603776	Fluorescence in situ (FISH) studies performed on patients enrolled in the two landmark anaplastic oligodendroglioma (AO) studies, RTOG 9402 and EORTC 26951, showed that patients whose tumors harbored a completed co-deletion of chromosomes 1p and 19q (co-deletion of 1p/19q) had significantly longer survival than patients without this marker, proving its prognostic relevance.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('patients', 'Species', '9606', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('survival', 'MPA', (299, 307))	('longer', 'PosReg', (292, 298))	('tumors', 'Disease', (184, 190))	('oligodendroglioma', 'Disease', (98, 115))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('patients', 'Species', '9606', (313, 321))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('patients', 'Species', '9606', (49, 57))	('co-deletion', 'Var', (212, 223))	('oligodendroglioma', 'Disease', 'MESH:D009837', (98, 115))
202472	28603776	These studies demonstrated that co-deletion of 1p/19q was not only a prognostic but also a predictive biomarker in these cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('1p/19q', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('co-deletion', 'Var', (32, 43))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
202478	28603776	The question of appropriate molecular testing has been addressed because presence of co-deletion of 1p/19q (whole arm losses of 1p and 19q) as well as a mutation in IDH1/2 are now a prerequisite for the diagnosis of oligodendrogliomas, based on the 2016 WHO classification.	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('losses', 'NegReg', (118, 124))	('IDH1/2', 'Gene', '3417;3418', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (216, 234))	('IDH1/2', 'Gene', (165, 171))	('co-deletion', 'Var', (85, 96))	('oligodendrogliomas', 'Disease', (216, 234))	('mutation', 'Var', (153, 161))
202479	28603776	A potentially predictive role for IDH mutations in AO had also been suggested as part of a subgroup analysis of study RTOG 9402 in AO, in which IDH mutation status was found to be predictive of response to chemotherapy.	('IDH', 'Gene', (144, 147))	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (144, 147))	('predictive', 'Reg', (14, 24))	('mutations', 'Var', (38, 47))
202480	28603776	Mutational analysis of the breakpoint region in 1p/19q co-deleted oligodendrogliomas revealed frequent mutations of the CIC gene on chromosome 19q and of FUBP1 on chromosome 1p.	('mutations', 'Var', (103, 112))	('oligodendrogliomas', 'Disease', (66, 84))	('FUBP1', 'Gene', (154, 159))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (66, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('CIC', 'Gene', '23152', (120, 123))	('FUBP1', 'Gene', '8880', (154, 159))	('CIC', 'Gene', (120, 123))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
202481	28603776	In addition, new data, integrating 1p/19q co-deletion status, mutations of IDH, TP53, ATRX and TERT have emerged.	('ATRX', 'Gene', '546', (86, 90))	('TERT', 'Gene', (95, 99))	('TERT', 'Gene', '7015', (95, 99))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('ATRX', 'Gene', (86, 90))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('mutations', 'Var', (62, 71))
202490	28603776	More than 90% of WNT-MB harbor mutations in CTNNB1, a key gene that encodes beta-catenin and renders the protein resistant to degradation, leading to its accumulation in the cell nucleus.	('mutations', 'Var', (31, 40))	('accumulation', 'PosReg', (154, 166))	('CTNNB1', 'Gene', (44, 50))	('beta-catenin', 'Gene', (76, 88))	('CTNNB1', 'Gene', '1499', (44, 50))	('beta-catenin', 'Gene', '1499', (76, 88))
202491	28603776	beta-catenin gene expression profiling or beta-catenin nucleopositivity on immunohistochemistry along with CTNNB1 mutations and monosomy 6 characterize this molecular subgroup.	('beta-catenin', 'Gene', (42, 54))	('CTNNB1', 'Gene', '1499', (107, 113))	('mutations', 'Var', (114, 123))	('beta-catenin', 'Gene', '1499', (42, 54))	('beta-catenin', 'Gene', '1499', (0, 12))	('CTNNB1', 'Gene', (107, 113))	('beta-catenin', 'Gene', (0, 12))
202495	28603776	Patients with SHH/TP53 mutant MBs have profoundly worse outcome than those with SHH/TP53 wild-type tumors because mutant TP53 has been associated with catastrophic cellular events, a high rate of anaplasia and MYCN amplification.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', '7157', (121, 125))	('mutant', 'Var', (114, 120))	('TP53', 'Gene', (84, 88))	('SHH', 'Gene', '6469', (80, 83))	('MYCN', 'Gene', (210, 214))	('Patients', 'Species', '9606', (0, 8))	('SHH', 'Gene', '6469', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('TP53', 'Gene', (121, 125))	('TP53', 'Gene', (18, 22))	('SHH', 'Gene', (80, 83))	('TP53', 'Gene', '7157', (84, 88))	('associated with', 'Reg', (135, 150))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutant', 'Var', (23, 29))	('tumors', 'Disease', (99, 105))	('anaplasia', 'Disease', 'MESH:D000708', (196, 205))	('SHH', 'Gene', (14, 17))	('anaplasia', 'Disease', (196, 205))	('MYCN', 'Gene', '4613', (210, 214))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
202496	28603776	Given its clinical impact, TP53 mutation status has been incorporated into the 2016 WHO classification for CNS tumors and is now routinely assessed in all SHH activated MBs.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('SHH', 'Gene', '6469', (155, 158))	('SHH', 'Gene', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('CNS tumors', 'Disease', 'MESH:D009369', (107, 117))	('mutation', 'Var', (32, 40))	('CNS tumors', 'Disease', (107, 117))
202501	28603776	They frequently show amplification of MYC or MYCN and chromosome 17 imbalance, which prospectively predict a poor prognosis.	('MYCN', 'Gene', (45, 49))	('MYC', 'Gene', (38, 41))	('MYC', 'Gene', '4609', (38, 41))	('MYC', 'Gene', (45, 48))	('MYCN', 'Gene', '4613', (45, 49))	('chromosome', 'Gene', (54, 64))	('MYC', 'Gene', '4609', (45, 48))	('amplification', 'Var', (21, 34))	('imbalance', 'Phenotype', 'HP:0002172', (68, 77))
202506	28603776	Chromatin-remodeling defects are key in the pathogenesis of pediatric HGG, especially in diffuse midline glioma, but are virtually absent in adult tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('HGG', 'Disease', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('midline glioma', 'Disease', 'MESH:D005910', (97, 111))	('midline glioma', 'Disease', (97, 111))	('adult tumors', 'Disease', 'MESH:C538052', (141, 153))	('defects', 'Var', (21, 28))	('adult tumors', 'Disease', (141, 153))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
202507	28603776	Of particular clinical relevance are mutations in histone H3F3A, with 78% of DIPG harboring the amino acid substitution lysine 27 to methionine (K27M) and up to approximately one-third of non-brainstem HGGs carrying glycine 34 to valine or arginine (G34V/R) or K27M mutations.	('K27M', 'Var', (261, 265))	('glycine 34 to valine or arginine', 'SUBSTITUTION', 'None', (216, 248))	('glycine 34 to valine or arginine', 'Var', (216, 248))	('G34V', 'Var', (250, 254))	('H3F3A', 'Gene', '3020', (58, 63))	('H3F3A', 'Gene', (58, 63))	('lysine 27 to methionine', 'Mutation', 'p.K27M', (120, 143))	('mutations', 'Var', (37, 46))	('DIPG', 'Chemical', '-', (77, 81))	('K27M', 'Mutation', 'p.K27M', (261, 265))	('K27M', 'Mutation', 'p.K27M', (145, 149))	('glycine 34 to valine', 'Mutation', 'p.G34V', (216, 236))	('G34V', 'SUBSTITUTION', 'None', (250, 254))
202508	28603776	Tumors harboring these mutations carry a grim prognosis.	('mutations', 'Var', (23, 32))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
202512	28603776	Tandem duplication at 7q34 creates the fusion gene KIAA1549:BRAF and results in abnormal activation of MAPK/ERK pathway and deregulation of cell growth, differentiation and apoptosis.	('deregulation', 'MPA', (124, 136))	('apoptosis', 'CPA', (173, 182))	('ERK', 'Gene', (108, 111))	('Tandem duplication', 'Var', (0, 18))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('differentiation', 'CPA', (153, 168))	('cell growth', 'CPA', (140, 151))	('KIAA1549', 'Gene', (51, 59))	('KIAA1549', 'Gene', '57670', (51, 59))	('activation', 'PosReg', (89, 99))	('ERK', 'Gene', '5594', (108, 111))
202515	28603776	The prognostic significance of the KIAA1549:BRAF fusion remains uncertain, although a few studies have found slight improvements in survival between tumors with and without BRAF duplication/fusion while others found no difference.	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', '673', (173, 177))	('BRAF', 'Gene', (44, 48))	('survival', 'MPA', (132, 140))	('BRAF', 'Gene', (173, 177))	('KIAA1549', 'Gene', '57670', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('duplication/fusion', 'Var', (178, 196))	('KIAA1549', 'Gene', (35, 43))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('improvements', 'PosReg', (116, 128))
202516	28603776	Regardless, the high frequency of this BRAF alteration in PA may serve as a diagnostic tool for differentiating between PA and grade II astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('BRAF', 'Gene', '673', (39, 43))	('II astrocytoma', 'Disease', 'MESH:D001254', (133, 147))	('alteration', 'Var', (44, 54))	('BRAF', 'Gene', (39, 43))	('II astrocytoma', 'Disease', (133, 147))
202518	28603776	Preclinical studies showed that BRAF influences the proliferative potential of cells and silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition with various MEK inhibitors, such as U0126, PD0325901 and AZD6244 blocked proliferation and arrested growth of glioma cells, whereas wild-type xenografts were insensitive to MEK inhibition.	('AZD6244', 'Chemical', 'MESH:C517975', (234, 241))	('BRAF', 'Gene', '673', (32, 36))	('MEK', 'Gene', (350, 353))	('BRAF', 'Gene', (32, 36))	('MEK', 'Gene', '5609', (189, 192))	('U0126', 'Var', (213, 218))	('arrested growth', 'Phenotype', 'HP:0001510', (268, 283))	('blocked', 'NegReg', (242, 249))	('MEK', 'Gene', (189, 192))	('glioma', 'Disease', (287, 293))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('proliferative potential of cells', 'CPA', (52, 84))	('glioma', 'Disease', 'MESH:D005910', (287, 293))	('influences', 'Reg', (37, 47))	('PD0325901', 'Var', (220, 229))	('proliferation', 'CPA', (250, 263))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('arrested growth', 'CPA', (268, 283))	('MEK', 'Gene', '5609', (350, 353))	('PD0325901', 'Chemical', 'MESH:C506614', (220, 229))	('silencing', 'Var', (89, 98))	('AZD6244', 'Var', (234, 241))	('U0126', 'Chemical', 'MESH:C113580', (213, 218))
202521	28603776	Apart from the already mentioned ones, additional biomarkers, including BRAFV600E, EGFRvIII, TERT, ATRX, TP53 and micro-satellite instability (MSI)/mismatch repair deficiency genes have also gained attention in the neuro-oncological field but their ability to predict clinical behavior, response to therapy and outcome appears limited or unclear.	('EGFR', 'Gene', '1956', (83, 87))	('BRAFV600E', 'Var', (72, 81))	('ATRX', 'Gene', (99, 103))	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('EGFR', 'Gene', (83, 87))	('ATRX', 'Gene', '546', (99, 103))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))
202522	28603776	BRAFV600E mutations were found in a variety of tumors including PAs, pediatric diffusely infiltrating gliomas (WHO grades II-IV), gangliogliomas as well as pleomorphic xanthoastrocytomas (PXA).	('pleomorphic xanthoastrocytomas', 'Disease', (156, 186))	('PAs', 'Disease', (64, 67))	('gangliogliomas', 'Disease', 'MESH:D018303', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('tumors', 'Disease', (47, 53))	('BRAFV600E', 'Gene', (0, 9))	('gangliogliomas', 'Disease', (130, 144))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('gliomas', 'Disease', (137, 144))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('found', 'Reg', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (174, 185))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (156, 186))	('gliomas', 'Disease', 'MESH:D005910', (137, 144))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('PAs', 'Chemical', 'MESH:D011478', (64, 67))	('gliomas', 'Disease', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('mutations', 'Var', (10, 19))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))
202525	28603776	EGFRvIII is the most common mutated receptor tyrosine kinase receptor in approximately 20-30% of GBM cases leading to constitutive activation of the EGFR-PI3K pathway.	('mutated', 'Var', (28, 35))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (149, 153))	('constitutive', 'MPA', (118, 130))	('EGFR', 'Gene', (149, 153))	('EGFR', 'Gene', '1956', (0, 4))
202530	28603776	TERT promoter mutations, which result in enhanced telomerase activity and lengthened telomeres are strongly associated with 1p19q and IDH.	('telomeres', 'CPA', (85, 94))	('IDH', 'Gene', '3417', (134, 137))	('enhanced', 'PosReg', (41, 49))	('1p19q', 'Disease', (124, 129))	('telomerase', 'Enzyme', (50, 60))	('lengthened telomeres', 'Phenotype', 'HP:0031413', (74, 94))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('associated', 'Reg', (108, 118))	('activity', 'MPA', (61, 69))	('mutations', 'Var', (14, 23))	('IDH', 'Gene', (134, 137))
202533	28603776	Mutations in ATRX and TP53 are frequent in adult diffuse gliomas (WHO grade II and III) and are strongly associated with astrocytic tumors carrying IDH1/2 mutations.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('IDH1/2', 'Gene', (148, 154))	('astrocytic tumors', 'Disease', (121, 138))	('ATRX', 'Gene', (13, 17))	('ATRX', 'Gene', '546', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('astrocytic tumors', 'Disease', 'MESH:D001254', (121, 138))	('frequent', 'Reg', (31, 39))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('gliomas', 'Disease', (57, 64))	('IDH1/2', 'Gene', '3417;3418', (148, 154))	('TP53', 'Gene', '7157', (22, 26))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('associated', 'Reg', (105, 115))	('TP53', 'Gene', (22, 26))
202534	28603776	Mismatch repair-deficiency has been observed in a small fraction of brain neoplasms leading to a higher mutational load.	('brain neoplasms', 'Disease', 'MESH:D001932', (68, 83))	('higher', 'PosReg', (97, 103))	('brain neoplasms', 'Phenotype', 'HP:0030692', (68, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (74, 83))	('mutational load', 'MPA', (104, 119))	('Mismatch', 'Var', (0, 8))	('brain neoplasms', 'Disease', (68, 83))
202535	28603776	Recently, it was shown that tumors with a high number of somatic mutations secondary to mismatch-repair defects are more susceptible to immune checkpoint blockade.	('defects', 'Var', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mismatch-repair', 'Gene', (88, 103))
202543	28603776	An example is magnet resonance spectroscopy to detect 2-hydroxybutyrate, the onco-metabolite of IDH1/2 mutations.	('2-hydroxybutyrate', 'MPA', (54, 71))	('mutations', 'Var', (103, 112))	('IDH1/2', 'Gene', '3417;3418', (96, 102))	('IDH1/2', 'Gene', (96, 102))	('2-hydroxybutyrate', 'Chemical', 'MESH:C031570', (54, 71))
202544	28603776	Novel clinical trial designs that aim at selecting patients based on presence of targetable molecular alterations rather than tumor type, such as the so-called "basket trials" and large marker driven studies such as the NIH MATCH trial, are expected to significantly expedite the development of new targeted drugs and propel biomarker-driven clinical research, as highlighted in BRAFV600E mutated non-melanomatous cancers treated with vemurafenib.	('BRAFV600E mutated', 'Var', (379, 396))	('cancers', 'Phenotype', 'HP:0002664', (414, 421))	('non-melanomatous cancers', 'Disease', 'MESH:D009369', (397, 421))	('BRAFV600E', 'Mutation', 'rs113488022', (379, 388))	('cancer', 'Phenotype', 'HP:0002664', (414, 420))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('vemurafenib', 'Chemical', 'MESH:D000077484', (435, 446))	('non-melanomatous cancers', 'Disease', (397, 421))	('tumor', 'Disease', (126, 131))
202547	28603776	In addition, the presence or absence of aberrations in the WNT and SHH pathway in MB can clarify the underlying mechanism and guide treatment decisions while testing of TP53, MYC, MYCN and GLI2 could identify certain high-risk subpopulations in the future.	('MYC', 'Gene', (175, 178))	('GLI2', 'Gene', (189, 193))	('MYC', 'Gene', '4609', (180, 183))	('GLI2', 'Gene', '2736', (189, 193))	('TP53', 'Gene', '7157', (169, 173))	('WNT', 'Pathway', (59, 62))	('MYC', 'Gene', '4609', (175, 178))	('aberrations', 'Var', (40, 51))	('SHH', 'Gene', (67, 70))	('MYC', 'Gene', (180, 183))	('MYCN', 'Gene', (180, 184))	('MYCN', 'Gene', '4613', (180, 184))	('TP53', 'Gene', (169, 173))	('SHH', 'Gene', '6469', (67, 70))
202549	28603776	Basket trial Biomarker-driven trials that include patients whose tumors have a specific molecular feature (e.g., BRAF mutation), testing targeted therapies in diverse populations of cancers.	('BRAF', 'Gene', '673', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (50, 58))	('BRAF', 'Gene', (113, 117))	('testing', 'Reg', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutation', 'Var', (118, 126))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
202554	28603776	The key question that needs to be addressed for each individual marker: Does the presence of the respective marker truly change the clinical outcome for patients?	('change', 'Reg', (121, 127))	('patients', 'Species', '9606', (153, 161))	('presence', 'Var', (81, 89))
202558	28603776	MGMT promoter methylation in high-grade astrocytomas and co-deletion of 1p/19q in oligodendrogliomas are proven prognostic and predictive markers that play a role in standard practice, and mutations of IDH1 or IDH2 are of strong prognostic value in gliomas.	('gliomas', 'Disease', (93, 100))	('astrocytomas', 'Disease', (40, 52))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (82, 100))	('co-deletion', 'Var', (57, 68))	('MGMT', 'Gene', '4255', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Disease', (249, 256))	('oligodendrogliomas', 'Disease', (82, 100))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH2', 'Gene', (210, 214))	('mutations', 'Var', (189, 198))	('astrocytomas', 'Disease', 'MESH:D001254', (40, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (40, 51))	('IDH2', 'Gene', '3418', (210, 214))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (249, 256))	('IDH1', 'Gene', (202, 206))	('1p/19q', 'Gene', (72, 78))	('MGMT', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('gliomas', 'Phenotype', 'HP:0009733', (249, 256))	('IDH1', 'Gene', '3417', (202, 206))
202561	28603776	Some of these markers enable us to pair available targeted drugs with subpopulations of tumors based on a biological rationale and a true drug target (e.g., BRAF inhibitors in V600E mutated tumors, 'basket trials').	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('BRAF', 'Gene', '673', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BRAF', 'Gene', (157, 161))	('V600E mutated', 'Var', (176, 189))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (190, 196))	('tumors', 'Disease', (88, 94))	('V600E', 'Mutation', 'rs113488022', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
202572	28124178	As molecular characteristics based upon isocitrate dehydrogenase (IDH) mutation and 1p19q deletion status can provide important prognostic information, diffuse gliomas are now classified using both histologic and molecular characteristics.	('IDH', 'Gene', (66, 69))	('isocitrate dehydrogenase', 'Gene', (40, 64))	('mutation', 'Var', (71, 79))	('IDH', 'Gene', '3417', (66, 69))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('isocitrate dehydrogenase', 'Gene', '3417', (40, 64))	('gliomas', 'Disease', (160, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
202602	28124178	Mouse monoclonal anti-IDH1R132H (DIA H09) antibody was used to screen samples for the presence of IDH1 mutation.	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', (98, 102))	('IDH1', 'Gene', '3417', (22, 26))	('Mouse', 'Species', '10090', (0, 5))	('mutation', 'Var', (103, 111))	('IDH1', 'Gene', '3417', (98, 102))
202605	28124178	Tumors were classified as IDH1 mutant or wildtype based on immunostaining.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutant', 'Var', (31, 37))	('IDH1', 'Gene', (26, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('IDH1', 'Gene', '3417', (26, 30))
202606	28124178	IDH wildtype status was not confirmed with IDH1 and IDH2 codon sequencing, so some of these tumors may harbor rarer IDH1 or IDH2 mutations.	('IDH', 'Gene', '3417', (116, 119))	('IDH', 'Gene', '3417', (52, 55))	('IDH1', 'Gene', '3417', (43, 47))	('IDH2', 'Gene', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('IDH', 'Gene', '3417', (43, 46))	('IDH2', 'Gene', '3418', (124, 128))	('IDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('IDH2', 'Gene', (52, 56))	('tumors', 'Disease', (92, 98))	('IDH2', 'Gene', '3418', (52, 56))	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', '3417', (0, 3))	('IDH1', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('IDH', 'Gene', (116, 119))	('mutations', 'Var', (129, 138))	('IDH', 'Gene', '3417', (124, 127))	('IDH1', 'Gene', (43, 47))	('IDH', 'Gene', (52, 55))	('IDH1', 'Gene', '3417', (116, 120))	('IDH', 'Gene', (43, 46))
202615	28124178	LGG gliomas with astrocytoma or oligodendroglioma histology were classified accordingly, while gliomas with oligoastrocytoma histology were classified as oligodendrogliomas if they were 1p19q codeleted, and as astrocytomas if they were 1p19q intact.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('oligodendroglioma', 'Disease', 'MESH:D009837', (154, 171))	('astrocytomas', 'Disease', 'MESH:D001254', (210, 222))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (108, 124))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('oligodendrogliomas', 'Disease', (154, 172))	('oligodendroglioma', 'Disease', (154, 171))	('gliomas', 'Disease', (4, 11))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('astrocytoma', 'Phenotype', 'HP:0009592', (17, 28))	('1p19q codeleted', 'Var', (186, 201))	('oligoastrocytoma', 'Disease', (108, 124))	('oligodendroglioma', 'Disease', 'MESH:D009837', (32, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('gliomas', 'Disease', 'MESH:D005910', (4, 11))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('astrocytoma', 'Disease', 'MESH:D001254', (210, 221))	('astrocytoma', 'Disease', (210, 221))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('gliomas', 'Disease', (95, 102))	('oligodendroglioma', 'Disease', (32, 49))	('astrocytomas', 'Disease', (210, 222))	('astrocytoma', 'Disease', 'MESH:D001254', (113, 124))	('astrocytoma', 'Disease', 'MESH:D001254', (17, 28))	('astrocytoma', 'Disease', (113, 124))	('astrocytoma', 'Disease', (17, 28))	('gliomas', 'Phenotype', 'HP:0009733', (4, 11))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (154, 172))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Disease', (165, 172))
202653	28124178	Within the IDH mutant astrocytomas, T2ALL vol, Fvol(nADC>1.5), 10%, median, and 90% nFA, sum(CNI) and the CNI>2 volume were significantly associated with PFS.	('astrocytomas', 'Disease', 'MESH:D001254', (22, 34))	('nFA', 'Chemical', 'MESH:D009544', (84, 87))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('T2ALL', 'Var', (36, 41))	('astrocytomas', 'Disease', (22, 34))	('associated with', 'Reg', (138, 153))	('astrocytoma', 'Phenotype', 'HP:0009592', (22, 33))	('nADC', 'Chemical', '-', (52, 56))
202674	33946049	Knock-down of CTSC, an aging-related gene, can inhibit cell cycle progression, colony formation, cell proliferation and increase cell senescence in glioma cell lines in vitro.	('CTSC', 'Gene', (14, 18))	('glioma', 'Disease', (148, 154))	('cell cycle progression', 'CPA', (55, 77))	('Knock-down', 'Var', (0, 10))	('increase', 'PosReg', (120, 128))	('inhibit', 'NegReg', (47, 54))	('cell senescence', 'CPA', (129, 144))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('cell proliferation', 'CPA', (97, 115))	('colony formation', 'CPA', (79, 95))	('CTSC', 'Gene', '1075', (14, 18))
202675	33946049	Indeed, high expression of CTSC was associated with poor prognosis in glioma cases.	('high', 'Var', (8, 12))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('CTSC', 'Gene', '1075', (27, 31))	('CTSC', 'Gene', (27, 31))
202684	33946049	Cancer and aging share some hallmarks such as epigenetic alteration, reprogrammed metabolism, immune and inflammation injury and aberrant telomeres.	('epigenetic alteration', 'Var', (46, 67))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('aberrant telomeres', 'CPA', (129, 147))	('inflammation injury', 'Disease', (105, 124))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('reprogrammed metabolism', 'CPA', (69, 92))	('inflammation injury', 'Disease', 'MESH:D007249', (105, 124))
202695	33946049	The clinical information (age, gender, mutational status, isocitrate dehydrogenase (IDH), 1p/19q codelet, giloma grade, type and survival information) and mRNA expression profiles derived from TCGA (The Cancer Genome Atlas) (http://cancergenome.nih.gov) and the CGGA (Chinese Glioma Genome Atlas) (http://www.cgga.org.cn).	('Glioma', 'Phenotype', 'HP:0009733', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('Glioma', 'Disease', (276, 282))	('giloma', 'Disease', (106, 112))	('cancer', 'Disease', (232, 238))	('Cancer', 'Disease', (203, 209))	('mutational', 'Var', (39, 49))	('giloma', 'Disease', 'None', (106, 112))	('isocitrate dehydrogenase', 'Gene', (58, 82))	('Cancer', 'Disease', 'MESH:D009369', (203, 209))	('IDH', 'Gene', '3417', (84, 87))	('Cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('isocitrate dehydrogenase', 'Gene', '3417', (58, 82))	('IDH', 'Gene', (84, 87))	('Glioma', 'Disease', 'MESH:D005910', (276, 282))
202701	33946049	The prediction value of clusters, risk score, grade and age was compared using ROC in some respects, including 5-year OS, 5-year PFI, 5-year DSS, IDH status, MGMT status, 1p19q codel status, subtypes.	('IDH', 'Gene', (146, 149))	('IDH', 'Gene', '3417', (146, 149))	('1p19q codel', 'Var', (171, 182))	('MGMT', 'Gene', '4255', (158, 162))	('MGMT', 'Gene', (158, 162))
202732	33946049	There were no obvious differences in expression levels of these genes between mutant IDH group and wildtype IDH group in the GBM cohort (Figure 2D-2I).	('IDH', 'Gene', '3417', (85, 88))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (108, 111))	('expression', 'MPA', (37, 47))	('IDH', 'Gene', (85, 88))	('mutant', 'Var', (78, 84))	('GBM', 'Phenotype', 'HP:0012174', (125, 128))
202733	33946049	Moreover CHEK2, CTSC, MBD2 were down-regulated in LGG with 1p19q non-codeletion and mutant IDH (Figure 2G).	('MBD2', 'Gene', '8932', (22, 26))	('1p19q non-codeletion', 'Var', (59, 79))	('CHEK2', 'Gene', '11200', (9, 14))	('mutant', 'Var', (84, 90))	('CTSC', 'Gene', '1075', (16, 20))	('IDH', 'Gene', (91, 94))	('CHEK2', 'Gene', (9, 14))	('MBD2', 'Gene', (22, 26))	('CTSC', 'Gene', (16, 20))	('down-regulated', 'NegReg', (32, 46))	('IDH', 'Gene', '3417', (91, 94))
202734	33946049	In addition, survival analysis was also performed in several glioma data sets, including GSE4271, GSE4412, GSE13041, GSE16011, GSE43289, GSE43378, GSE61335, GSE68838, GSE74187, GSE83300, GSE108474 (Supplementary Figure 3I-3Q).	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('GSE43378', 'Var', (137, 145))	('GSE4412', 'Var', (98, 105))	('GSE68838', 'Var', (157, 165))	('GSE74187', 'Var', (167, 175))	('GSE4412', 'Chemical', '-', (98, 105))	('glioma', 'Disease', (61, 67))	('GSE16011', 'Var', (117, 125))	('GSE4271', 'Chemical', '-', (89, 96))	('GSE61335', 'Var', (147, 155))	('GSE13041', 'Var', (107, 115))	('GSE108474', 'Var', (187, 196))	('GSE43289', 'Var', (127, 135))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
202737	33946049	In TCGA LGGGBM datasets, we found that a high risk score was associated with IDH wildtype, 1p19q noncodel, unmethylated MGMT promoter, subtype, progressive disease, GBM groups, higher grades, age>=45, and cluster1.	('progressive disease', 'Disease', (144, 163))	('1p19q noncodel', 'Var', (91, 105))	('GBM', 'Phenotype', 'HP:0012174', (11, 14))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('IDH', 'Gene', (77, 80))	('MGMT', 'Gene', '4255', (120, 124))	('progressive disease', 'Disease', 'MESH:D018450', (144, 163))	('MGMT', 'Gene', (120, 124))	('IDH', 'Gene', '3417', (77, 80))
202744	33946049	The frequency of mutations for PIK3CA, MUC16 and TTN was significantly higher in high risk glioma cases (TTN, 26% vs. 7%; MUC16, 16% vs. 8%; PIK3CA, 10% vs. 3%).	('PIK3CA', 'Gene', '5290', (141, 147))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('MUC16', 'Gene', '94025', (122, 127))	('TTN', 'Gene', '7273', (105, 108))	('MUC16', 'Gene', (39, 44))	('glioma', 'Disease', (91, 97))	('higher', 'Reg', (71, 77))	('TTN', 'Gene', (49, 52))	('MUC16', 'Gene', '94025', (39, 44))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', (141, 147))	('PIK3CA', 'Gene', '5290', (31, 37))	('TTN', 'Gene', '7273', (49, 52))	('MUC16', 'Gene', (122, 127))	('TTN', 'Gene', (105, 108))	('mutations', 'Var', (17, 26))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
202745	33946049	The mutation frequency of ATRX and TP53 was lower in high risk glioma cases (TP53, 26% vs 46%; ATRX, 7% vs 33%).	('lower', 'NegReg', (44, 49))	('ATRX', 'Gene', (95, 99))	('ATRX', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('mutation', 'Var', (4, 12))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('ATRX', 'Gene', '546', (95, 99))	('ATRX', 'Gene', '546', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('glioma', 'Disease', (63, 69))
202746	33946049	We also identified mutations in EGFR (30%), PTEN (26%) and NF1 (15%) in high risk group, and IDH1 (93%), CIC (30%) and FUBP1 (12%) in low risk group (Figure 5A, 5B).	('IDH1', 'Gene', (93, 97))	('IDH1', 'Gene', '3417', (93, 97))	('FUBP1', 'Gene', (119, 124))	('CIC', 'Gene', (105, 108))	('mutations', 'Var', (19, 28))	('EGFR', 'Gene', '1956', (32, 36))	('PTEN', 'Gene', (44, 48))	('EGFR', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (44, 48))	('NF1', 'Gene', (59, 62))	('FUBP1', 'Gene', '8880', (119, 124))	('NF1', 'Gene', '4763', (59, 62))
202747	33946049	GISTIC 2.0 analysis also showed that many regions harboring multiple oncogenes such as 12q14.1(CDK4), 7p11.2(EGFR), 4q12 (PDGFRA), and 1q23.1 (PIK3C2B) were amplified in the high risk group.	('4q12', 'Var', (116, 120))	('7p11.2', 'Var', (102, 108))	('PIK3C2B', 'Gene', (143, 150))	('CDK4', 'Gene', (95, 99))	('EGFR', 'Gene', '1956', (109, 113))	('PIK3C2B', 'Gene', '5287', (143, 150))	('CDK4', 'Gene', '1019', (95, 99))	('PDGFRA', 'Gene', (122, 128))	('1q23.1', 'Var', (135, 141))	('EGFR', 'Gene', (109, 113))	('PDGFRA', 'Gene', '5156', (122, 128))
202748	33946049	Focal deletion peaks including 1p36.23 (TNFRSF9, ERRFI1), 1p32.3 (CDKN2C), 10q23.31 (PTEN, KLLN), and 9p21.3 (CDKN2A) were also discovered in high-risk group.	('1p36.23', 'Var', (31, 38))	('CDKN2A', 'Gene', (110, 116))	('KLLN', 'Gene', '100144748', (91, 95))	('KLLN', 'Gene', (91, 95))	('CDKN2C', 'Gene', '1031', (66, 72))	('9p21.3', 'Var', (102, 108))	('ERRFI1', 'Gene', (49, 55))	('CDKN2A', 'Gene', '1029', (110, 116))	('1p32.3', 'Var', (58, 64))	('10q23.31', 'Var', (75, 83))	('TNFRSF9', 'Gene', (40, 47))	('CDKN2C', 'Gene', (66, 72))	('ERRFI1', 'Gene', '54206', (49, 55))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (85, 89))	('TNFRSF9', 'Gene', '3604', (40, 47))
202749	33946049	The genes found in the regions with focal deletions can inhibit the occurrence and development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('deletions', 'Var', (42, 51))	('cancer', 'Disease', (98, 104))	('inhibit', 'NegReg', (56, 63))
202751	33946049	Cluster 1 was associated with 1p19q noncodel, unmethylated MGMT promoter, higher grade, IDH wildtype, and GBM and higher risk score (Supplementary Figure 1A, 1B).	('1p19q noncodel', 'Var', (30, 44))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('unmethylated', 'Var', (46, 58))	('IDH', 'Gene', (88, 91))	('MGMT', 'Gene', (59, 63))	('IDH', 'Gene', '3417', (88, 91))	('MGMT', 'Gene', '4255', (59, 63))
202762	33946049	To study the effect of the CTSC gene on cell senescence in glioma cells, we knocked-down the CTSC gene in SHG-44 cells and U251 cells using siRNA-623, siRNA-837 and siRNA-963.	('knocked-down', 'Var', (76, 88))	('glioma', 'Disease', (59, 65))	('CTSC', 'Gene', '1075', (93, 97))	('CTSC', 'Gene', (93, 97))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('SHG-44', 'CellLine', 'CVCL:6728', (106, 112))	('U251', 'CellLine', 'CVCL:0021', (123, 127))	('CTSC', 'Gene', '1075', (27, 31))	('CTSC', 'Gene', (27, 31))
202764	33946049	All the transfected cells showed a decrease in CTSC expression (P<0.001), with the cells transfected with siRNA-623 and siRNA-963 showing more significant decrease in expression than those transfected with siRNA-837.	('decrease', 'NegReg', (35, 43))	('decrease', 'NegReg', (155, 163))	('CTSC', 'Gene', '1075', (47, 51))	('siRNA-963', 'Var', (120, 129))	('CTSC', 'Gene', (47, 51))	('expression', 'MPA', (167, 177))	('siRNA-623', 'Var', (106, 115))
202767	33946049	In addition, CTSC inhibition increased beta-gal staining but decreased colony formation in both U251 and SHG-44 cells (Figure 8D).	('U251', 'CellLine', 'CVCL:0021', (96, 100))	('beta-gal', 'Protein', (39, 47))	('beta-gal', 'Chemical', '-', (39, 47))	('SHG-44', 'CellLine', 'CVCL:6728', (105, 111))	('inhibition', 'Var', (18, 28))	('colony formation', 'CPA', (71, 87))	('increased', 'PosReg', (29, 38))	('CTSC', 'Gene', '1075', (13, 17))	('CTSC', 'Gene', (13, 17))	('decreased', 'NegReg', (61, 70))
202773	33946049	Similarly, high CTSC expression was also associated with shorter OS in the CGGA datasets (Supplementary Figure 6J-6L).	('CTSC', 'Gene', (16, 20))	('CTSC', 'Gene', '1075', (16, 20))	('high', 'Var', (11, 15))
202774	33946049	These findings indicated that high expression of CTSC might affect prognosis of glioma patients.	('glioma', 'Disease', (80, 86))	('CTSC', 'Gene', '1075', (49, 53))	('CTSC', 'Gene', (49, 53))	('high', 'Var', (30, 34))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('affect', 'Reg', (60, 66))	('patients', 'Species', '9606', (87, 95))
202780	33946049	In addition, CHEK2*1100delC heterozygosity is related to increased risk for several neoplasms such as breast cancer.	('breast cancer', 'Disease', (102, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('CHEK2*1100delC', 'DELETION', 'None', (13, 27))	('CHEK2*1100delC', 'Var', (13, 27))	('neoplasms', 'Disease', 'MESH:D009369', (84, 93))	('neoplasms', 'Disease', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
202783	33946049	Somatic alterations analysis showed that high risk score was associated with mutations of oncogenes (PIK3CA, MUC16, TTN), but had less mutations of ATRX and TP53.	('TP53', 'Gene', (157, 161))	('oncogenes', 'Gene', (90, 99))	('PIK3CA', 'Gene', '5290', (101, 107))	('MUC16', 'Gene', '94025', (109, 114))	('TTN', 'Gene', (116, 119))	('TTN', 'Gene', '7273', (116, 119))	('TP53', 'Gene', '7157', (157, 161))	('MUC16', 'Gene', (109, 114))	('mutations', 'Var', (77, 86))	('ATRX', 'Gene', (148, 152))	('ATRX', 'Gene', '546', (148, 152))	('PIK3CA', 'Gene', (101, 107))
202784	33946049	The genes found in the regions with focal deletions can inhibit the occurrence and development of cancer in high-risk group.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('deletions', 'Var', (42, 51))	('cancer', 'Disease', (98, 104))	('inhibit', 'NegReg', (56, 63))
202801	33946049	The results from this study indicated that aging-related genes may affect the tumor microenvironment by regulating immune cells and stromal cells, thus contributing to the development of tumors.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('genes', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('affect', 'Reg', (67, 73))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (187, 192))	('contributing', 'Reg', (152, 164))	('immune cells', 'CPA', (115, 127))	('tumors', 'Disease', (187, 193))	('regulating', 'Reg', (104, 114))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
202809	33946049	This study found that the inhibition of CTSC increases cell senescence and the expression of CTSC is associated with poor prognosis of glioma patients.	('cell senescence', 'CPA', (55, 70))	('glioma', 'Disease', (135, 141))	('increases', 'PosReg', (45, 54))	('expression', 'MPA', (79, 89))	('CTSC', 'Gene', '1075', (93, 97))	('CTSC', 'Gene', (93, 97))	('inhibition', 'Var', (26, 36))	('CTSC', 'Gene', '1075', (40, 44))	('CTSC', 'Gene', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('associated', 'Reg', (101, 111))	('patients', 'Species', '9606', (142, 150))
202812	33946049	We found that inhibition of CTSC increases cell senescence, and previous studies have reported that high state of senescence inhibits the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('CTSC', 'Gene', (28, 32))	('increases', 'PosReg', (33, 42))	('inhibits', 'NegReg', (125, 133))	('cell senescence', 'CPA', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('inhibition', 'Var', (14, 24))	('CTSC', 'Gene', '1075', (28, 32))
202833	33611848	In the revised classification of central nervous system (CNS) tumours proposed by the World Health Organization (WHO) in 2016, gliomas were classified based on a combination of histological findings and molecular findings, namely isocitrate dehydrogenase (IDH) mutations, 1p19q codeletion, H3 Lys27Met and RELA-fusion.	('mutations', 'Var', (261, 270))	('isocitrate dehydrogenase', 'Gene', '3417', (230, 254))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('central nervous system (CNS) tumours', 'Disease', 'MESH:D016543', (33, 69))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('isocitrate dehydrogenase', 'Gene', (230, 254))	('gliomas', 'Disease', (127, 134))	('IDH', 'Gene', (256, 259))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('1p19q codeletion', 'Var', (272, 288))	('RELA', 'Gene', (306, 310))	('RELA', 'Gene', '5970', (306, 310))	('H3 Lys27Met', 'Var', (290, 301))	('IDH', 'Gene', '3417', (256, 259))	('Lys27Met', 'Mutation', 'p.K27M', (293, 301))
202852	33611848	22  Therefore, aberrant expression of ER stress-related genes may have prognostic value for glioma patients and can be exploited as potential therapeutic targets.	('aberrant expression', 'Var', (15, 34))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('ER', 'Gene', '2069', (38, 40))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
202879	33611848	Age, gender, tumour grade, IDH mutation status, 1p19q codeletion status, MGMT promoter methylation status and ER stress-related risk scores were combined to develop a nomogram using the R packages survival and rms.	('MGMT', 'Gene', (73, 77))	('IDH', 'Gene', (27, 30))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('MGMT', 'Gene', '4255', (73, 77))	('IDH', 'Gene', '3417', (27, 30))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('1p19q', 'Var', (48, 53))	('tumour', 'Disease', (13, 19))	('ER', 'Gene', '2069', (110, 112))
202889	33611848	A data set (http://www.cbioportal.org) comprising a merged cohort of low-grade glioma (LGG) and GBM containing 794 patients/samples harbouring both mutations and CAN data was queried.	('patients', 'Species', '9606', (115, 123))	('mutations', 'Var', (148, 157))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))
202890	33611848	Genetic alterations were found in 108 (13.60%) of the queried patients/samples (Figure S1D).	('patients', 'Species', '9606', (62, 70))	('Genetic alterations', 'Var', (0, 19))	('found', 'Reg', (25, 30))
202900	33611848	Additionally, the risk scores were notably different among stratified patients, with high-risk scores in high-grade glioma, wild-type IDH, 1p19q non-codeletion, mesenchymal subtype and MGMT promoter unmethylated patients (Figure 3G-N, Figure S4A-D).	('MGMT', 'Gene', '4255', (185, 189))	('patients', 'Species', '9606', (70, 78))	('MGMT', 'Gene', (185, 189))	('IDH', 'Gene', '3417', (134, 137))	('glioma', 'Disease', (116, 122))	('patients', 'Species', '9606', (212, 220))	('1p19q non-codeletion', 'Var', (139, 159))	('non-codeletion', 'Var', (145, 159))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('IDH', 'Gene', (134, 137))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
202914	33611848	TGFB1, VEGFA, ARG1, FGL2 and IL10 are secreted immunosuppressive factors in glioma, 41 ,  42 ,  43 ,  44 ,  45 ,  46  while CD95L and CD70 are glioma cell-surface immunosuppressive factors.	('glioma', 'Disease', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('ARG1', 'Gene', '383', (14, 18))	('FGL2', 'Gene', '10875', (20, 24))	('IL10', 'Gene', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('VEGFA', 'Gene', (7, 12))	('CD70', 'Var', (134, 138))	('IL10', 'Gene', '3586', (29, 33))	('glioma', 'Disease', (143, 149))	('TGFB1', 'Gene', '7040', (0, 5))	('ARG1', 'Gene', (14, 18))	('FGL2', 'Gene', (20, 24))	('TGFB1', 'Gene', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('VEGFA', 'Gene', '7422', (7, 12))	('CD95L', 'Gene', '356', (124, 129))	('CD95L', 'Gene', (124, 129))
202925	33611848	In addition to the ER stress risk score, there are numerous known prognostic factors for glioma, such as age, gender, WHO grade, IDH mutation status, 1p19q codeletion status and MGMT promoter methylation status.	('mutation', 'Var', (133, 141))	('MGMT', 'Gene', '4255', (178, 182))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('1p19q codeletion status', 'Var', (150, 173))	('ER', 'Gene', '2069', (19, 21))	('IDH', 'Gene', '3417', (129, 132))	('glioma', 'Disease', (89, 95))	('IDH', 'Gene', (129, 132))	('MGMT', 'Gene', (178, 182))
202928	33611848	Moreover, age, grade, IDH mutation status, 1p19q codeletion status and MGMT promoter status were also significantly related to OS (Figure 7A).	('1p19q codeletion status', 'Var', (43, 66))	('related', 'Reg', (116, 123))	('IDH', 'Gene', (22, 25))	('MGMT', 'Gene', '4255', (71, 75))	('MGMT', 'Gene', (71, 75))	('IDH', 'Gene', '3417', (22, 25))
202931	33611848	We established a nomogram to predict 1-, 3- and 5-year OS in the TCGA data set, by integrating ER stress risk signature, age, gender, WHO grade, IDH mutation status, 1p19q codeletion status and MGMT promoter methylation status.	('mutation status', 'Var', (149, 164))	('ER', 'Gene', '2069', (95, 97))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (145, 148))	('MGMT', 'Gene', '4255', (194, 198))	('MGMT', 'Gene', (194, 198))	('1p19q', 'Var', (166, 171))
202952	33611848	BRCA1 mutations are closely related to the tumorigenesis and progression of female breast and ovarian tumours.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('BRCA1', 'Gene', (0, 5))	('progression', 'CPA', (61, 72))	('tumorigenesis', 'CPA', (43, 56))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('breast and ovarian tumours', 'Disease', 'MESH:D009369', (83, 109))	('related', 'Reg', (28, 35))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (6, 15))
202967	33611848	To fully utilize the potential of the risk model, we developed a nomogram combining the ER stress signature, age, gender, WHO grade, IDH mutation status, 1p19q codeletion status and MGMT promoter methylation status.	('MGMT', 'Gene', (182, 186))	('IDH', 'Gene', '3417', (133, 136))	('mutation', 'Var', (137, 145))	('ER', 'Gene', '2069', (88, 90))	('IDH', 'Gene', (133, 136))	('MGMT', 'Gene', '4255', (182, 186))
202983	33072586	The role of nonimaging biomarkers in gliomas and GBMs is well known, i.e., IDH1 mutation and methylguanine-DNA methyltransferase (MGMT) promoter methylation.	('methylguanine-DNA methyltransferase', 'Gene', '4255', (93, 128))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('IDH1', 'Gene', (75, 79))	('methylguanine-DNA methyltransferase', 'Gene', (93, 128))	('gliomas', 'Disease', (37, 44))	('MGMT', 'Gene', '4255', (130, 134))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('MGMT', 'Gene', (130, 134))	('IDH1', 'Gene', '3417', (75, 79))	('mutation', 'Var', (80, 88))
202998	33072586	alpha-[11C]Methyl-L-tryptophan PET has also been shown to predict longer overall survival.	('overall survival', 'CPA', (73, 89))	('alpha-[11C]Methyl-L-tryptophan PET', 'Var', (0, 34))	('longer', 'PosReg', (66, 72))	('alpha-[11C]Methyl-L-tryptophan', 'Chemical', 'MESH:C020774', (0, 30))
203005	33072586	Disease prognostication and prediction modeling:There are multiple prognostic determinants for brain tumors, including the histologic subtype, specific genetic mutations, degree of anaplasia, degree of necrosis of fibrosis, degree of de-differentiation, local infiltration, vasculogenesis and resulting vascular scavenging, and hypoxia.	('anaplasia', 'Disease', 'MESH:D000708', (181, 190))	('anaplasia', 'Disease', (181, 190))	('brain tumors', 'Phenotype', 'HP:0030692', (95, 107))	('mutations', 'Var', (160, 169))	('vasculogenesis', 'CPA', (274, 288))	('local infiltration', 'CPA', (254, 272))	('hypoxia', 'Disease', 'MESH:D000860', (328, 335))	('brain tumors', 'Disease', 'MESH:D001932', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('hypoxia', 'Disease', (328, 335))	('necrosis', 'Disease', 'MESH:D009336', (202, 210))	('brain tumors', 'Disease', (95, 107))	('vascular scavenging', 'CPA', (303, 322))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('fibrosis', 'Disease', 'MESH:D005355', (214, 222))	('fibrosis', 'Disease', (214, 222))	('necrosis', 'Disease', (202, 210))
203015	33072586	Genetic markers that are implicated in the prognostication and therapy guidance of GBM include gene amplification of epidermal growth factor receptor (EGFR), TP53, and PTEN mutation, among others.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('PTEN', 'Gene', (168, 172))	('epidermal growth factor receptor', 'Gene', (117, 149))	('EGFR', 'Gene', '1956', (151, 155))	('EGFR', 'Gene', (151, 155))	('PTEN', 'Gene', '5728', (168, 172))	('epidermal growth factor receptor', 'Gene', '1956', (117, 149))	('gene amplification', 'Var', (95, 113))	('mutation', 'Var', (173, 181))
203021	32316617	The main focus of this review is on the roles of m6A modification in glioblastoma, the most aggressive and invariably lethal brain tumour.	('brain tumour', 'Disease', 'MESH:D001932', (125, 137))	('brain tumour', 'Disease', (125, 137))	('m6A modification', 'Var', (49, 65))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('brain tumour', 'Phenotype', 'HP:0030692', (125, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
203022	32316617	Although the study of m6A in glioblastoma is a young one, and papers in this field can yield divergent conclusions, the results collected so far clearly demonstrate that modulation of mRNA m6A levels impacts multiple aspects of this tumour, including growth, glioma stem cells self-renewal, and tumorigenesis, suggesting that mRNA m6A modification may serve as a promising target for glioblastoma therapy.	('growth', 'CPA', (251, 257))	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('impacts', 'Reg', (200, 207))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('glioma', 'Disease', (259, 265))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('tumour', 'Disease', 'MESH:D009369', (233, 239))	('glioblastoma', 'Disease', (384, 396))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('glioma', 'Disease', 'MESH:D005910', (259, 265))	('tumour', 'Disease', (233, 239))	('glioblastoma', 'Disease', 'MESH:D005909', (384, 396))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('modulation', 'Var', (170, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (384, 396))	('tumor', 'Disease', (295, 300))	('glioblastoma', 'Disease', (29, 41))
203030	32316617	H3K36me3, a marker for transcription elongation usually enriched in the CDS and near the 3' end, is recognized and bound directly by METTL14 which recruits other components of the m6A MTC and mediates deposition of m6A on the newly synthesized RNAs when encountering RNA Pol II.	('METTL14', 'Gene', '57721', (133, 140))	('H3K36me3', 'Var', (0, 8))	('recruits', 'PosReg', (147, 155))	('H3K36me3', 'Chemical', '-', (0, 8))	('METTL14', 'Gene', (133, 140))
203041	32316617	This, together with the difficulty of specifically detecting m6A vs. m6Am, might explain some apparently contrasting results about the effects of FTO depletion or reduction in several contexts.	('m6Am', 'Gene', '56339', (69, 73))	('reduction', 'NegReg', (163, 172))	('m6Am', 'Gene', (69, 73))	('m6A', 'Var', (61, 64))
203043	32316617	Incorporation of the methyl group on the N6 position of adenosine impairs the stability of Watson-Crick A:U base-pairing, leading to further global conformational rearrangement of the RNAsubstrate.	('adenosine', 'Chemical', 'MESH:D000241', (56, 65))	('Incorporation', 'Var', (0, 13))	('global conformational rearrangement', 'MPA', (141, 176))	('impairs', 'NegReg', (66, 73))	('stability', 'MPA', (78, 87))
203048	32316617	YTHDC1, the only known m6A reader in the nucleus, has been reported to be involved in exon selection during splicing, epigenetic silencing mediated by the noncoding RNA XIST, and the nuclear export of mRNA.	('XIST', 'Gene', '7503', (169, 173))	('YTHDC1', 'Gene', (0, 6))	('XIST', 'Gene', (169, 173))	('YTHDC1', 'Gene', '91746', (0, 6))	('mRNA', 'Protein', (201, 205))	('epigenetic silencing', 'Var', (118, 138))	('nuclear export', 'MPA', (183, 197))	('involved', 'Reg', (74, 82))
203051	32316617	For instance, the m6A reader heterogeneous nuclear ribonucleoprotein C (HNRNPC), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing including splicing, was shown to bind m6A-modified RNA through a "m6A-switch" mechanism, in which the m6A-mediated destabilization of an RNA hairpin exposes a single-stranded HNRNPC binding motif.	('m6A-modified', 'Var', (195, 207))	('bind', 'Interaction', (190, 194))	('HNRNPC', 'Gene', '3183', (332, 338))	('HNRNPC', 'Gene', (332, 338))	('HNRNPC', 'Gene', '3183', (72, 78))	('HNRNPC', 'Gene', (72, 78))
203055	32316617	Thus, the presence of m6A bypasses the normal requirement for eIF4E and may be a mode of translation that is important when eIF4E (the 7-methylguanosine-containing mRNA cap-binding protein) function is impaired.	('eIF4E', 'Gene', (62, 67))	('eIF4E', 'Gene', (124, 129))	('m6A', 'Var', (22, 25))	('eIF4E', 'Gene', '1977', (62, 67))	('eIF4E', 'Gene', '1977', (124, 129))
203056	32316617	Studies using single-molecule ribosome translocation assays showed that mammalian ribosomes have a tendency to stall on mRNA at m6A-containing codons.	('stall', 'MPA', (111, 116))	('mRNA at m6A-containing', 'Var', (120, 142))	('mammalian', 'Species', '9606', (72, 81))
203057	32316617	RasGTPase-activating protein-binding protein 1 (G3BP1) and 2 (G3BP2), that function in the assembly of stress granules and are known to be important for embryonic development, are repelled by the presence of m6A.	('G3BP1', 'Gene', (48, 53))	('m6A', 'Var', (208, 211))	('G3BP1', 'Gene', '10146', (48, 53))	('G3BP2', 'Gene', '9908', (62, 67))	('repelled', 'NegReg', (180, 188))	('RasGTPase-activating protein-binding protein 1', 'Gene', '10146', (0, 46))	('RasGTPase-activating protein-binding protein 1', 'Gene', (0, 46))	('G3BP2', 'Gene', (62, 67))
203059	32316617	Emerging evidence suggests that m6A modification is involved in human carcinogenesis.	('human', 'Species', '9606', (64, 69))	('involved', 'Reg', (52, 60))	('m6A', 'Var', (32, 35))
203061	32316617	These alterations have been implicated to play a role in different cancer functions, including cancer stem cell formation, epithelial-mesenchymal transition (EMT), cancer metabolism, apoptosisand signal transduction, by regulating the mRNA stability or protein translation of different downstream targets.	('epithelial-mesenchymal transition', 'CPA', (123, 156))	('alterations', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('protein translation', 'MPA', (253, 272))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('apoptosisand', 'CPA', (183, 195))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('regulating', 'Reg', (220, 230))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mRNA stability', 'MPA', (235, 249))
203065	32316617	Consequently, METTL3 inhibits hematopoietic stem/progenitor cell differentiation and increases leukemia cell growth, and METTL3 depletion induces cell-cycle arrest, cell differentiation, and apoptosis and delays leukemia progression in mice.	('leukemia', 'Phenotype', 'HP:0001909', (212, 220))	('apoptosis', 'CPA', (191, 200))	('mice', 'Species', '10090', (236, 240))	('inhibits', 'NegReg', (21, 29))	('hematopoietic stem/progenitor cell differentiation', 'CPA', (30, 80))	('arrest', 'Disease', (157, 163))	('METTL3', 'Gene', (121, 127))	('induces', 'Reg', (138, 145))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('delays leukemia', 'Disease', (205, 220))	('increases leukemia', 'Disease', 'MESH:D007938', (85, 103))	('delays leukemia', 'Disease', 'MESH:D007938', (205, 220))	('METTL3', 'Var', (14, 20))	('arrest', 'Disease', 'MESH:D006323', (157, 163))	('increases leukemia', 'Disease', (85, 103))	('depletion', 'Var', (128, 137))	('cell differentiation', 'CPA', (165, 185))
203067	32316617	m6A in Snail CDS, but not 3'UTR, triggers polysome-mediated translation of Snail mRNA in cancer cells.	('triggers', 'Reg', (33, 41))	('Snail', 'Gene', (75, 80))	('Snail', 'Gene', '6615', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Snail', 'Gene', '6615', (7, 12))	('Snail', 'Gene', (7, 12))	('cancer', 'Disease', (89, 95))	('polysome-mediated translation', 'MPA', (42, 71))	('m6A', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
203068	32316617	Loss and gain functional studies confirmed that the reader YTHDF1 mediates m6A-increased translation of Snail mRNA.	('m6A-increased', 'PosReg', (75, 88))	('m6A-increased', 'Var', (75, 88))	('translation', 'MPA', (89, 100))	('Snail', 'Gene', (104, 109))	('Snail', 'Gene', '6615', (104, 109))	('YTHDF1', 'Gene', '54915', (59, 65))	('YTHDF1', 'Gene', (59, 65))
203071	32316617	Global translation rates are generally enhanced in cancer cells and altered translational control is a fundamental response to oncogenic stimulation.m6A methylome analysis also identified that multiple translation initiation factors were modulated by m6A, indicating that m6A modification could directly regulate the expression of translation associated factors, thereby facilitating tumorigenesis and metastasis of ovarian cancer.	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (402, 430))	('m6A', 'Var', (272, 275))	('translation', 'MPA', (331, 342))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (424, 430))	('tumor', 'Disease', (384, 389))	('tumor', 'Disease', 'MESH:D009369', (384, 389))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('regulate', 'Reg', (304, 312))	('ovarian cancer', 'Phenotype', 'HP:0100615', (416, 430))	('modulated', 'Reg', (238, 247))	('expression', 'MPA', (317, 327))	('metastasis of ovarian cancer', 'Disease', (402, 430))	('tumor', 'Phenotype', 'HP:0002664', (384, 389))	('cancer', 'Disease', (424, 430))	('modification', 'Var', (276, 288))	('facilitating', 'PosReg', (371, 383))	('cancer', 'Phenotype', 'HP:0002664', (424, 430))	('cancer', 'Disease', (51, 57))
203073	32316617	Another reader, YTHDF2, was found to bind c-Myc and CEBPA mRNAs to enable m6A modification in the 5'-UTR and CDS, promoting c-Myc and CEBPA mRNA stabilization and leukemia cell proliferation.	('YTHDF2', 'Gene', (16, 22))	('c-Myc', 'Gene', (42, 47))	('c-Myc', 'Gene', '4609', (124, 129))	('modification', 'Var', (78, 90))	('m6A', 'Var', (74, 77))	('c-Myc', 'Gene', (124, 129))	('CEBPA', 'Gene', (134, 139))	('YTHDF2', 'Gene', '51441', (16, 22))	('promoting', 'PosReg', (114, 123))	('CEBPA', 'Gene', '1050', (134, 139))	('leukemia', 'Disease', (163, 171))	('leukemia', 'Phenotype', 'HP:0001909', (163, 171))	('leukemia', 'Disease', 'MESH:D007938', (163, 171))	('CEBPA', 'Gene', (52, 57))	('c-Myc', 'Gene', '4609', (42, 47))	('CEBPA', 'Gene', '1050', (52, 57))
203081	32316617	In parallel, the knock-down of two key m6A "writers", METTL3 and METTL14, while reducing general m6A methylation, enhanced the GSC proliferation and self-renewal ability, and in turn METTL3 overexpression reduced the same tumorigenic properties of GSCs.	('METTL3', 'Gene', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('general m6A methylation', 'MPA', (89, 112))	('GSC proliferation', 'CPA', (127, 144))	('METTL14', 'Gene', (65, 72))	('reduced', 'NegReg', (205, 212))	('self-renewal ability', 'CPA', (149, 169))	('knock-down', 'Var', (17, 27))	('METTL14', 'Gene', '57721', (65, 72))	('enhanced', 'PosReg', (114, 122))	('METTL3', 'Gene', (183, 189))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('reducing', 'NegReg', (80, 88))	('overexpression', 'PosReg', (190, 204))
203082	32316617	These results, suggesting an inverse correlation between GSC tumorigenicity and the general levels of m6A RNA methylation, were further corroborated by in vivo data, showing that the knock-down of METTL3 or METTL14, or both, significantly enhanced the growth of GSC-generated tumours.	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('tumours', 'Disease', 'MESH:D009369', (276, 283))	('tumours', 'Phenotype', 'HP:0002664', (276, 283))	('tumours', 'Disease', (276, 283))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('METTL14', 'Gene', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('growth', 'CPA', (252, 258))	('knock-down', 'Var', (183, 193))	('METTL14', 'Gene', '57721', (207, 214))	('METTL3', 'Gene', (197, 203))	('tumor', 'Disease', (61, 66))	('enhanced', 'PosReg', (239, 247))
203084	32316617	Mechanistically, by combining m6A-seq analysis in GSCs, and RNA-seq in GSCs depleted of METTL3 or METTL14, the authors revealed key mediators of the functional effects of m6A RNA methylation perturbation in glioblastoma initiating cells.	('METTL14', 'Gene', (98, 105))	('glioblastoma', 'Disease', 'MESH:D005909', (207, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (207, 219))	('methylation', 'Var', (179, 190))	('METTL14', 'Gene', '57721', (98, 105))	('glioblastoma', 'Disease', (207, 219))	('perturbation', 'NegReg', (191, 203))	('m6A', 'Gene', (171, 174))
203085	32316617	Among them, several oncogenes, whose expression increased upon METTL3 or METTL14 depletion, and was reduced by MA2 treatment, in an inverse correlation with the levels of specific m6A methylation of their mRNAs.	('increased', 'PosReg', (48, 57))	('MA2', 'Chemical', 'MESH:C029090', (111, 114))	('reduced', 'NegReg', (100, 107))	('depletion', 'Var', (81, 90))	('METTL14', 'Gene', (73, 80))	('METTL14', 'Gene', '57721', (73, 80))	('METTL3', 'Gene', (63, 69))	('expression', 'MPA', (37, 47))
203091	32316617	In fact, the depletion of ALKBH5 in GSCs reduced their self-renewal and proliferation, and impaired their ability to form a tumour.	('reduced', 'NegReg', (41, 48))	('impaired', 'NegReg', (91, 99))	('proliferation', 'CPA', (72, 85))	('depletion', 'Var', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('ALKBH5', 'Gene', (26, 32))	('self-renewal', 'CPA', (55, 67))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Disease', (124, 130))
203093	32316617	Among them, the authors focused on FOXM1, a pivotal transcription factor in cell-cycle regulation, self-renewal and tumorigenesis of GSCs, as its mRNA was hypermethylated upon depletion of ALKBH5, and its expression, at both mRNA and protein levels, was reduced by ALKBH5 knock-down.	('ALKBH5', 'Gene', (189, 195))	('FOXM1', 'Gene', (35, 40))	('ALKBH5', 'Gene', (265, 271))	('depletion', 'MPA', (176, 185))	('reduced', 'NegReg', (254, 261))	('FOXM1', 'Gene', '2305', (35, 40))	('expression', 'MPA', (205, 215))	('knock-down', 'Var', (272, 282))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hypermethylated', 'Var', (155, 170))	('tumor', 'Disease', (116, 121))
203094	32316617	They went much deeper in the mechanism, by demonstrating that a unique methylation site in FOXM1 mRNA 3'UTR affected by ALKBH5 is responsible for ALKBH5 effects on FOXM1 expression, as the methylation at that site impairs binding of the nuclear RNA binding protein HuR to FOXM1 nascent mRNA.	('binding', 'Interaction', (222, 229))	('impairs', 'NegReg', (214, 221))	('HuR', 'Gene', (265, 268))	('HuR', 'Gene', '1994', (265, 268))	('FOXM1', 'Gene', (91, 96))	('methylation', 'Var', (189, 200))	('FOXM1', 'Gene', '2305', (91, 96))	('FOXM1', 'Gene', (164, 169))	('FOXM1', 'Gene', '2305', (272, 277))	('nuclear', 'Protein', (237, 244))	('FOXM1', 'Gene', '2305', (164, 169))	('FOXM1', 'Gene', (272, 277))	('expression', 'MPA', (170, 180))
203095	32316617	As HuR interaction with FOXM1 mRNA promotes its expression, the site-specific hypermethylation of FOXM1 3'UTR upon ALKBH5 depletion results in FOXM1 reduction.	('HuR', 'Gene', '1994', (3, 6))	('reduction', 'NegReg', (149, 158))	('depletion', 'Var', (122, 131))	('FOXM1', 'Gene', (98, 103))	('expression', 'MPA', (48, 58))	('promotes', 'PosReg', (35, 43))	('FOXM1', 'Gene', '2305', (98, 103))	('hypermethylation', 'Var', (78, 94))	('FOXM1', 'Gene', '2305', (24, 29))	('FOXM1', 'Gene', (143, 148))	('FOXM1', 'Gene', (24, 29))	('FOXM1', 'Gene', '2305', (143, 148))	('HuR', 'Gene', (3, 6))
203098	32316617	While our manuscript was in preparation, a paper was published reporting the possibility of impairing the in vitro migration and invasiveness of the U87MG glioblastoma cell line, by the supplementation of MV1035, an inhibitor of ALKBH5.	('invasiveness', 'Disease', (129, 141))	('U87MG', 'CellLine', 'CVCL:0022', (149, 154))	('MV1035', 'Var', (205, 211))	('supplementation', 'Var', (186, 201))	('MV1035', 'Chemical', '-', (205, 211))	('glioblastoma', 'Disease', (155, 167))	('impairing', 'NegReg', (92, 101))	('invasiveness', 'Disease', 'MESH:D009361', (129, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
203101	32316617	In fact, IDH1 and IDH2 mutations correlate with a better overall survival of glioma patients.	('IDH2', 'Gene', '3418', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH1', 'Gene', (9, 13))	('patients', 'Species', '9606', (84, 92))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('IDH1', 'Gene', '3417', (9, 13))	('mutations', 'Var', (23, 32))	('glioma', 'Disease', (77, 83))	('IDH2', 'Gene', (18, 22))	('better', 'PosReg', (50, 56))	('overall', 'MPA', (57, 64))
203103	32316617	The somatic mutations frequently present in low-grade gliomas induce a neomorphic enzymatic function able to catalyze the conversion of alpha-KG to R-hydroxyglutarate (R-2HG).	('induce', 'Reg', (62, 68))	('mutations', 'Var', (12, 21))	('neomorphic', 'MPA', (71, 81))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Disease', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('conversion', 'MPA', (122, 132))	('alpha-KG', 'Chemical', 'MESH:D007656', (136, 144))	('R-hydroxyglutarate', 'Chemical', '-', (148, 166))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
203104	32316617	The apparent conundrum of mutations specifically arising in tumours but representing good prognostic factors compared to the wild type forms of the same genes was addressed by Su R. and collaborators in a huge work essentially devoted to leukemia oncogenesis, but with important implications for glioma too [36.	('Su R', 'Gene', (176, 180))	('Su R', 'Gene', '6833', (176, 180))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('leukemia', 'Phenotype', 'HP:0001909', (238, 246))	('leukemia oncogenesis', 'Disease', 'MESH:D063646', (238, 258))	('mutations', 'Var', (26, 35))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('leukemia oncogenesis', 'Disease', (238, 258))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('glioma', 'Disease', (296, 302))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
203105	32316617	One of the key mRNA targets whose methylation changed upon R-2HG administration in IDH1 or 2 wild type leukemia cells was the MYC one, thus made less stable, with a consequent reduction of Myc expression and signalling.	('IDH1', 'Gene', (83, 87))	('reduction', 'NegReg', (176, 185))	('R-2HG', 'Var', (59, 64))	('MYC', 'Gene', (126, 129))	('IDH1', 'Gene', '3417', (83, 87))	('signalling', 'MPA', (208, 218))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('changed', 'Reg', (46, 53))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('Myc', 'Gene', (189, 192))	('Myc', 'Gene', '4609', (189, 192))	('MYC', 'Gene', '4609', (126, 129))	('leukemia', 'Disease', (103, 111))	('methylation', 'MPA', (34, 45))
203107	32316617	Even if this work was mostly performed in leukemia cells, and all mechanistic demonstrations were made in that context, the authors also showed that R-2HG can inhibit the proliferation of a panel of glioma cell lines, all IDH1/2 wild type.	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('IDH1/2', 'Gene', (222, 228))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('IDH1/2', 'Gene', '3417;3418', (222, 228))	('leukemia', 'Disease', (42, 50))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('leukemia', 'Disease', 'MESH:D007938', (42, 50))	('R-2HG', 'Var', (149, 154))	('glioma', 'Disease', (199, 205))	('proliferation', 'CPA', (171, 184))	('inhibit', 'NegReg', (159, 166))
203108	32316617	They suggested that the endogenous production of R-2HG typical of low-grade gliomas may prevent the progression of such tumours toward higher grade glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('endogenous', 'MPA', (24, 34))	('gliomas', 'Disease', (76, 83))	('prevent', 'NegReg', (88, 95))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('R-2HG', 'Var', (49, 54))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (148, 161))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('glioblastomas', 'Disease', 'MESH:D005909', (148, 161))	('glioblastomas', 'Disease', (148, 161))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
203109	32316617	Of course, a corollary of their observation should be that, in low grade, IDH1/2 mutant gliomas, the levels of FTO, kept low by R-2HG, result in an overall high level of m6A (or likely m6Am) RNA methylation, particularly relevant on MYC transcripts.	('m6Am', 'Gene', '56339', (185, 189))	('IDH1/2', 'Gene', (74, 80))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('m6Am', 'Gene', (185, 189))	('MYC', 'Gene', '4609', (233, 236))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('mutant', 'Var', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('IDH1/2', 'Gene', '3417;3418', (74, 80))	('MYC', 'Gene', (233, 236))
203113	32316617	As WTAP is a crucial interactor of the methyltransferase complex, this and other observational works suggested that m6A inducing enzymes, and, as a consequence, m6A RNA methylation, may play an oncogenic role in glioma.	('WTAP', 'Gene', '9589', (3, 7))	('glioma', 'Disease', 'MESH:D005910', (212, 218))	('play', 'Reg', (186, 190))	('WTAP', 'Gene', (3, 7))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('glioma', 'Disease', (212, 218))	('m6A', 'Gene', (116, 119))	('m6A', 'Var', (161, 164))
203116	32316617	SOX2 mRNA, in fact, was directly bound by METTL3, and its m6A methylation levels were diminished upon silencing of METTL3.	('SOX2', 'Gene', '6657', (0, 4))	('silencing', 'Var', (102, 111))	('METTL3', 'Gene', (42, 48))	('m6A methylation levels', 'MPA', (58, 80))	('METTL3', 'Gene', (115, 121))	('diminished', 'NegReg', (86, 96))	('bound', 'Interaction', (33, 38))	('SOX2', 'Gene', (0, 4))
203126	32316617	Of clinical relevance is also the result about the reduced in vivotumorigenicity of U87 stem-like cells depleted of METTL3, together with the evidence of METTL3 mRNA and protein higher abundance in glioblastoma tissues compared to normal brain.	('METTL3', 'Protein', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('METTL3', 'Gene', (116, 122))	('glioblastoma', 'Disease', (198, 210))	('reduced', 'NegReg', (51, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (198, 210))	('tumor', 'Disease', (66, 71))	('depleted', 'Var', (104, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('higher', 'PosReg', (178, 184))	('U87', 'CellLine', 'CVCL:0022', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
203127	32316617	The same group went further in its study of METTL3 role in glioblastoma stem cells by performing an integrated analysis of m6A-RIP (RNA immunoprecipitation) and total RNA-Seq of METTL3-silenced GSCs.	('glioblastoma', 'Disease', (59, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('m6A-RIP', 'Var', (123, 130))
203128	32316617	One key example of a transcript which is a direct target of METTL3 and whose abundance is reduced in METTL3 knock-down cells is SOX2, as previously demonstrated by the same group.	('METTL3', 'Gene', (101, 107))	('reduced', 'NegReg', (90, 97))	('SOX2', 'Gene', '6657', (128, 132))	('SOX2', 'Gene', (128, 132))	('abundance', 'MPA', (77, 86))	('knock-down', 'Var', (108, 118))
203129	32316617	In addition, a number of other GSC transcription factors were repressed upon METTL3 deprivation, even if their mRNAs were not affected by m6A methylation, indicating, again, that the METTL3 tumoral role in GSCs may go beyond the pool of mRNAs directly affected by its enzymatic activity.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('deprivation', 'Var', (84, 95))	('METTL3', 'Gene', (183, 189))
203134	32316617	In both established glioblastoma cell lines and in three different primary cell lines derived from patients, the CRISPR/Cas9-mediated depletion of METTL3 as well as the overexpression of a catalytically inactive dominant negative form of METTL3 in vitrostrongly reduced the proliferation, migration and invasiveness, while increasing the apoptotic index of U87 cells, and in vivo reduced the tumour formation rate.	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('U87', 'CellLine', 'CVCL:0022', (357, 360))	('glioblastoma', 'Disease', (20, 32))	('apoptotic index', 'CPA', (338, 353))	('reduced', 'NegReg', (380, 387))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('tumour', 'Phenotype', 'HP:0002664', (392, 398))	('tumour', 'Disease', 'MESH:D009369', (392, 398))	('increasing', 'PosReg', (323, 333))	('overexpression', 'PosReg', (169, 183))	('tumour', 'Disease', (392, 398))	('METTL3', 'Gene', (147, 153))	('reduced', 'NegReg', (262, 269))	('patients', 'Species', '9606', (99, 107))	('invasiveness', 'Disease', (303, 315))	('proliferation', 'CPA', (274, 287))	('invasiveness', 'Disease', 'MESH:D009361', (303, 315))	('migration', 'CPA', (289, 298))	('depletion', 'Var', (134, 143))	('METTL3', 'Gene', (238, 244))
203136	32316617	The mechanism explaining this phenotype was investigated by Li and colleagues, who found, in partial agreement with Visvanathan and colleagues, that METTL3 depletion in the U87 cell line induced the downregulation of the splicing factors SRSF3, SRSF6, and SRSF11.	('SRSF3', 'Gene', (238, 243))	('SRSF11', 'Gene', (256, 262))	('downregulation', 'NegReg', (199, 213))	('SRSF3', 'Gene', '6428', (238, 243))	('U87', 'CellLine', 'CVCL:0022', (173, 176))	('METTL3', 'Gene', (149, 155))	('SRSF6', 'Gene', '6431', (245, 250))	('SRSF11', 'Gene', '9295', (256, 262))	('SRSF6', 'Gene', (245, 250))	('splicing', 'MPA', (221, 229))	('depletion', 'Var', (156, 165))
203138	32316617	The link to m6A RNA methylation was found in the specific m6A methylation sites around the start codons of SRSF mRNAs: by combining a sophisticated reporter system and different single point mutations at the methylated adenosines of SRSF6 and SRSF3, the METTL3-mediated m6A RNA methylation was shown to be necessary for inhibiting the NMD of SRSF mRNAs.	('adenosines', 'Chemical', 'MESH:D000241', (219, 229))	('NMD of', 'CPA', (335, 341))	('SRSF6', 'Gene', '6431', (233, 238))	('mutations', 'Var', (191, 200))	('SRSF6', 'Gene', (233, 238))	('SRSF3', 'Gene', (243, 248))	('inhibiting', 'NegReg', (320, 330))	('SRSF3', 'Gene', '6428', (243, 248))
203139	32316617	A step forward was taken by this group, which identified also the m6A reader responsible for this mechanism: YTHDC1 was shown to bind the m6A residues around SRSF start codons, and YTHDC1 knock-down induced the NMD, together with the reduction of in vitro tumorigenic properties of U87 cells.	('NMD', 'CPA', (211, 214))	('induced', 'PosReg', (199, 206))	('YTHDC1', 'Gene', (181, 187))	('YTHDC1', 'Gene', '91746', (181, 187))	('knock-down', 'Var', (188, 198))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('U87', 'CellLine', 'CVCL:0022', (282, 285))	('reduction', 'NegReg', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('YTHDC1', 'Gene', (109, 115))	('YTHDC1', 'Gene', '91746', (109, 115))	('tumor', 'Disease', (256, 261))
203141	32316617	This work holds an undeniable value sustaining the protumoral role of METTL3-mediated mRNA methylation in glioblastoma.	('methylation', 'Var', (91, 102))	('glioblastoma', 'Disease', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('tumor', 'Disease', (54, 59))
203147	32316617	As for the prognostic value of these results, by performing a univariate Cox regression analysis on the expression levels in the CGGA dataset, these authors found that eleven out of thirteen tested genes were significantly correlated with OS, with in particular FTO behaving always as a protective gene in all types of glioma, including low-grade gliomas and glioblastomas, both IDH wild-type and IDH mutant.	('gliomas', 'Disease', (347, 354))	('glioma', 'Phenotype', 'HP:0009733', (347, 353))	('IDH', 'Gene', (397, 400))	('gliomas', 'Disease', 'MESH:D005910', (347, 354))	('IDH', 'Gene', (379, 382))	('glioma', 'Disease', (319, 325))	('glioblastomas', 'Phenotype', 'HP:0012174', (359, 372))	('IDH', 'Gene', '3417', (397, 400))	('correlated', 'Reg', (223, 233))	('gliomas', 'Phenotype', 'HP:0009733', (347, 354))	('glioma', 'Disease', 'MESH:D005910', (319, 325))	('IDH', 'Gene', '3417', (379, 382))	('FTO', 'Gene', (262, 265))	('mutant', 'Var', (401, 407))	('glioma', 'Disease', (347, 353))	('glioblastomas', 'Disease', (359, 372))	('glioma', 'Phenotype', 'HP:0009733', (319, 325))	('glioblastoma', 'Phenotype', 'HP:0012174', (359, 371))	('glioma', 'Disease', 'MESH:D005910', (347, 353))	('glioblastomas', 'Disease', 'MESH:D005909', (359, 372))
203151	32316617	Furthermore, and of clinical importance, the highrisk score patients were more sensitive to temozolomide, suggesting the possibility of using this signature to set-up the treatment protocol.	('temozolomide', 'Chemical', 'MESH:D000077204', (92, 104))	('patients', 'Species', '9606', (60, 68))	('sensitive to temozolomide', 'MPA', (79, 104))	('highrisk', 'Var', (45, 53))
203154	32316617	Only one relevant paper was recently published about the involvement of this type of modification hitting 28S rRNA in glioma, and the findings described therein hold very interesting aspects with potential clinical implications for glioma patients.	('glioma', 'Disease', (118, 124))	('glioma', 'Disease', (232, 238))	('patients', 'Species', '9606', (239, 247))	('modification', 'Var', (85, 97))	('28S rRNA', 'Protein', (106, 114))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))
203155	32316617	Starting from the evidence of the epigenetic silencing of the promoter of the NSUN5 gene through the hypermethylation of a CpG island in several glioma cell lines, correlating with NSUN5 transcriptional silencing, this group showed that NSUN5 behaves as a tumour suppressor in several in vivo mouse models of glioma growth.	('glioma', 'Disease', (309, 315))	('glioma', 'Disease', (145, 151))	('epigenetic silencing', 'Var', (34, 54))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('tumour', 'Disease', (256, 262))	('hypermethylation', 'Var', (101, 117))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('glioma', 'Disease', 'MESH:D005910', (309, 315))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('NSUN5', 'Gene', (78, 83))	('mouse', 'Species', '10090', (293, 298))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('silencing', 'NegReg', (203, 212))
203157	32316617	The ultimate result of their work showed thatin glioma cells, the epigenetic loss of NSUN5, in a frame of general restriction of the protein synthesis, induces the selective synthesis of specific proteins.	('restriction', 'NegReg', (114, 125))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('protein synthesis', 'MPA', (133, 150))	('selective synthesis of specific proteins', 'MPA', (164, 204))	('induces', 'Reg', (152, 159))	('epigenetic loss', 'Var', (66, 81))	('NSUN5', 'Gene', (85, 90))	('glioma', 'Disease', (48, 54))
203158	32316617	Interestingly, they showed that NSUN5-silenced glioma cells are far more sensitive to drugs targeting NQO1 than cell lines where NSUN5 is expressed, and this was reflected also in vivo, where specific anti-NQO1 drugs could increase the survival of mice orthotopically injected with NSUN5-deficient glioma cells, but did not influence the fate of animals injected with NSUN5 proficient cells.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('survival', 'CPA', (236, 244))	('increase', 'PosReg', (223, 231))	('glioma', 'Disease', 'MESH:D005910', (298, 304))	('glioma', 'Phenotype', 'HP:0009733', (298, 304))	('anti-NQO1', 'Var', (201, 210))	('glioma', 'Disease', (47, 53))	('mice', 'Species', '10090', (248, 252))	('NSUN5-deficient glioma', 'Disease', 'MESH:D005910', (282, 304))	('glioma', 'Disease', (298, 304))	('NSUN5-deficient glioma', 'Disease', (282, 304))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
203159	32316617	The analysis of the data present in the TCGA database led to discover that: (i) 28% of the annotated gliomas shows CpG island hypermethylation in NSUN5 promoter, correlating with transcript downregulation, (ii) this condition is particularly enriched in low-grade gliomas compared to GBM, (iii) NSUN5 hypermethylation and low levels of expression positively correlate with longer overall survival in all glioma grades.	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('gliomas', 'Disease', (101, 108))	('glioma', 'Disease', 'MESH:D005910', (404, 410))	('glioma', 'Disease', (101, 107))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (404, 410))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('hypermethylation', 'Var', (301, 317))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('hypermethylation', 'Var', (126, 142))	('glioma', 'Disease', (264, 270))	('NSUN5', 'Gene', (146, 151))	('gliomas', 'Disease', (264, 271))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('transcript', 'MPA', (179, 189))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('longer', 'PosReg', (373, 379))	('glioma', 'Disease', (404, 410))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('NSUN5', 'Gene', (295, 300))	('downregulation', 'NegReg', (190, 204))	('GBM', 'Phenotype', 'HP:0012174', (284, 287))
203160	32316617	Moreover, by studying a different validation cohort, the authors could confirm and extend these results, by calculating a positive correlation between NSUN5 hypermethylation and progression-free survival in both low grade gliomas and in glioblastomas.	('NSUN5', 'Gene', (151, 156))	('progression-free survival', 'CPA', (178, 203))	('glioblastomas', 'Phenotype', 'HP:0012174', (237, 250))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('gliomas', 'Disease', (222, 229))	('glioblastomas', 'Disease', 'MESH:D005909', (237, 250))	('hypermethylation', 'Var', (157, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('glioblastomas', 'Disease', (237, 250))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
203161	32316617	Moreover, and specifically for glioma, this apparent paradox is tightly linked to another seemingly controversial observation of a condition:NSUN5 depletion via promoter hypermethylation:which favours tumour growth but at the same time is a good prognostic factor.	('tumour', 'Disease', (201, 207))	('NSUN5', 'Gene', (141, 146))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('depletion', 'NegReg', (147, 156))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('promoter hypermethylation', 'Var', (161, 186))	('glioma', 'Disease', (31, 37))	('favours', 'PosReg', (193, 200))	('tumour', 'Disease', 'MESH:D009369', (201, 207))
203162	32316617	As mentioned by the authors, this is true for IDH1/2 mutations too, and likely depicts a state where tumour cells struggle to deal with metabolic and hypoxic stress: by silencing NSUN5, they try their last choice for survival, reducing global protein synthesis but switching on emergency translational programs which include NQO1.	('IDH1/2', 'Gene', (46, 52))	('global protein synthesis', 'MPA', (236, 260))	('tumour', 'Disease', (101, 107))	('silencing', 'Var', (169, 178))	('mutations', 'Var', (53, 62))	('reducing', 'NegReg', (227, 235))	('hypoxic stress', 'Disease', (150, 164))	('IDH1/2', 'Gene', '3417;3418', (46, 52))	('hypoxic stress', 'Disease', 'MESH:D000079225', (150, 164))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('NSUN5', 'Gene', (179, 184))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
203164	32316617	It is striking that, among such a limited number of papers published so far about epitranscriptomic modifications in glioma, roughly one half indicate a protumoral role of m6A RNA methylation, whereas the remaining half sustain the opposite (Table 1).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('glioma', 'Disease', (117, 123))	('m6A', 'Var', (172, 175))
203168	32316617	This might explain, at least in part, the contrasting results obtained by different groups in this field, as for example the correlation of m6A RNA methylation extent with differentiation of glioblastoma stem cells, or the effects of METTL3 knock-down on the in vitro self-renewal and in vivotumorigenicity of these cells (compare with).	('differentiation', 'CPA', (172, 187))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('tumor', 'Disease', (292, 297))	('knock-down', 'Var', (241, 251))	('METTL3', 'Gene', (234, 240))	('m6A', 'Gene', (140, 143))	('glioblastoma', 'Disease', (191, 203))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('glioblastoma', 'Disease', 'MESH:D005909', (191, 203))
203184	32316617	Moreover, one should never overlook that a crosstalk may exist between different epitranscriptomic modifiers affecting the same transcripts, as shown, for example, between the A to I RNA editing enzyme ADAR1 and m6A methylation.	('ADAR1', 'Gene', '103', (202, 207))	('ADAR1', 'Gene', (202, 207))	('m6A', 'Var', (212, 215))
203185	32316617	In specific transcripts, in fact, the association of ADAR1 was shown to be impaired by m6A methylation.	('association', 'Interaction', (38, 49))	('methylation', 'Var', (91, 102))	('m6A methylation', 'Var', (87, 102))	('impaired', 'NegReg', (75, 83))	('ADAR1', 'Gene', (53, 58))	('ADAR1', 'Gene', '103', (53, 58))
203190	20714900	This article provides an overview and critical appraisal of the types of genetic and epigenetic aberrations that have gained significance in the molecular diagnostics of gliomas, namely deletions of chromosome arms 1p and 19q, promoter hypermethylation of the O6-methylguanine-methyl-transferase (MGMT) gene, and the mutation status of the IDH1 and IDH2 genes.	('arms 1p', 'Gene', (210, 217))	('IDH1', 'Gene', '3417', (340, 344))	('arms 1p', 'Gene', '3075', (210, 217))	('promoter', 'MPA', (227, 235))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('IDH2', 'Gene', (349, 353))	('guanine', 'Chemical', 'MESH:D006147', (269, 276))	('gliomas', 'Disease', (170, 177))	('genetic aberrations', 'Disease', (88, 107))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('MGMT', 'Gene', (297, 301))	('IDH1', 'Gene', (340, 344))	('IDH2', 'Gene', '3418', (349, 353))	('MGMT', 'Gene', '4255', (297, 301))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('genetic aberrations', 'Disease', 'MESH:D030342', (88, 107))	('deletions', 'Var', (186, 195))
203209	20714900	Like cancer in general, gliomas develop as a result of genetic alterations that accumulate with tumor progression.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('genetic alterations', 'Var', (55, 74))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (5, 11))	('tumor', 'Disease', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('gliomas', 'Disease', (24, 31))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
203211	20714900	Briefly, mutation of the tumor suppressor gene TP53 (located at 17p13.1) and loss of heterozygosity on chromosome arm 17p are found in more than half of the WHO grade II diffuse astrocytomas.	('mutation', 'Var', (9, 17))	('astrocytomas', 'Disease', 'MESH:D001254', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('tumor', 'Disease', (25, 30))	('astrocytomas', 'Disease', (178, 190))	('found', 'Reg', (126, 131))	('TP53', 'Gene', '7157', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('TP53', 'Gene', (47, 51))
203214	20714900	Only recently, mutation of the isocitrate dehydrogenase 1 (IDH1) gene, or less commonly of the related IDH2 gene, have been identified in the vast majority of WHO grades II and III astrocytic, oligodendroglial, and oligoastrocytic gliomas suggesting a common initiating event in these histologically and biologically diverse glioma types.	('IDH1', 'Gene', '3417', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('IDH2', 'Gene', '3418', (103, 107))	('astrocytic', 'Disease', (181, 191))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('oligoastrocytic gliomas', 'Disease', (215, 238))	('oligoastrocytic gliomas', 'Disease', 'MESH:D005910', (215, 238))	('oligodendroglial', 'Disease', (193, 209))	('glioma', 'Disease', (231, 237))	('glioma', 'Disease', (325, 331))	('IDH1', 'Gene', (59, 63))	('IDH2', 'Gene', (103, 107))	('glioma', 'Disease', 'MESH:D005910', (325, 331))	('glioma', 'Disease', 'MESH:D005910', (231, 237))	('mutation', 'Var', (15, 23))	('identified', 'Reg', (124, 134))	('isocitrate dehydrogenase 1', 'Gene', (31, 57))	('isocitrate dehydrogenase 1', 'Gene', '3417', (31, 57))	('glioma', 'Phenotype', 'HP:0009733', (325, 331))
203215	20714900	Anaplastic (WHO grade III) astrocytomas often carry additional, progression-associated genetic changes, such as losses of the tumor suppressor genes CDKN2A, CDKN2B, and p14ARF on 9p21 and deletions on chromosomes 6, 11p, 22q, and others.	('CDKN2B', 'Gene', '1030', (157, 163))	('CDKN2A', 'Gene', '1029', (149, 155))	('astrocytomas', 'Disease', 'MESH:D001254', (27, 39))	('Anaplastic', 'Disease', (0, 10))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('deletions', 'Var', (188, 197))	('p14ARF', 'Gene', '1029', (169, 175))	('losses', 'NegReg', (112, 118))	('astrocytomas', 'Disease', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('CDKN2B', 'Gene', (157, 163))	('CDKN2A', 'Gene', (149, 155))	('p14ARF', 'Gene', (169, 175))	('tumor', 'Disease', (126, 131))
203216	20714900	Moreover, CDK4 or CDK6 amplification or inactivating alterations of RB1 are detectable in a subset of anaplastic gliomas, mainly anaplastic astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (140, 152))	('RB1', 'Gene', '5925', (68, 71))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('detectable', 'Reg', (76, 86))	('inactivating', 'NegReg', (40, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (140, 151))	('CDK6', 'Gene', (18, 22))	('amplification', 'Var', (23, 36))	('astrocytomas', 'Disease', (140, 152))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('RB1', 'Gene', (68, 71))	('CDK4', 'Gene', (10, 14))	('CDK6', 'Gene', '1021', (18, 22))	('CDK4', 'Gene', '1019', (10, 14))
203220	20714900	In particular, primary glioblastomas show frequent EGFR amplification and PTEN mutation but lack IDH1 mutation, while secondary glioblastomas are characterized by frequent mutations in the TP53 and IDH1 genes, but lack EGFR amplification (Fig.	('IDH1', 'Gene', (97, 101))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (219, 223))	('TP53', 'Gene', (189, 193))	('glioblastomas', 'Disease', (128, 141))	('glioblastomas', 'Disease', (23, 36))	('primary glioblastomas', 'Disease', 'MESH:D005909', (15, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('glioblastomas', 'Disease', 'MESH:D005909', (128, 141))	('glioblastomas', 'Disease', 'MESH:D005909', (23, 36))	('IDH1', 'Gene', '3417', (97, 101))	('IDH1', 'Gene', (198, 202))	('PTEN', 'Gene', (74, 78))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', '1956', (219, 223))	('TP53', 'Gene', '7157', (189, 193))	('IDH1', 'Gene', '3417', (198, 202))	('mutation', 'Var', (79, 87))	('PTEN', 'Gene', '5728', (74, 78))	('glioblastomas', 'Phenotype', 'HP:0012174', (128, 141))	('glioblastomas', 'Phenotype', 'HP:0012174', (23, 36))	('amplification', 'Var', (56, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('mutations', 'Var', (172, 181))	('primary glioblastomas', 'Disease', (15, 36))	('lack', 'NegReg', (92, 96))
203221	20714900	At the chromosomal level, primary glioblastomas are distinct from secondary glioblastomas by the frequent trisomy of chromosome 7 and monosomy of 10, as well as frequent gains of chromosome arms 12p, 19q, and 20q.	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('gains', 'PosReg', (170, 175))	('19q', 'CPA', (200, 203))	('glioblastomas', 'Disease', (76, 89))	('glioblastomas', 'Phenotype', 'HP:0012174', (34, 47))	('monosomy', 'Var', (134, 142))	('glioblastomas', 'Disease', 'MESH:D005909', (34, 47))	('primary glioblastomas', 'Disease', 'MESH:D005909', (26, 47))	('primary glioblastomas', 'Disease', (26, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (76, 89))	('glioblastomas', 'Disease', (34, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('glioblastomas', 'Disease', 'MESH:D005909', (76, 89))	('trisomy', 'Var', (106, 113))
203222	20714900	Despite these differences, however, most of the genetic alterations in primary and secondary glioblastomas can be assigned to a common set of functional pathways (Fig.	('glioblastomas', 'Disease', (93, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('primary', 'Disease', (71, 78))	('glioblastomas', 'Phenotype', 'HP:0012174', (93, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (93, 106))	('genetic alterations', 'Var', (48, 67))
203223	20714900	Several of the molecular alterations detected in gliomas may have diagnostic and/or prognostic implications, as they are associated with histologically defined tumor types or malignancy grades.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('malignancy', 'Disease', (175, 185))	('molecular alterations', 'Var', (15, 36))	('associated', 'Reg', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('malignancy', 'Disease', 'MESH:D009369', (175, 185))	('tumor', 'Disease', (160, 165))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
203228	20714900	In this regard, the number of molecular biomarkers in neurooncology to date is limited to a few alterations, namely combined deletions of the chromosome arms 1p and 19q in oligodendroglial tumors, MGMT hypermethylation in glioblastomas and anaplastic gliomas, IDH1 and IDH2 mutations in diffuse gliomas, as well as BRAF aberrations in pilocytic astrocytomas (Table 1).	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (335, 357))	('arms 1p', 'Gene', (153, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (222, 234))	('glioblastomas', 'Disease', (222, 235))	('MGMT', 'Gene', (197, 201))	('gliomas', 'Disease', 'MESH:D005910', (251, 258))	('gliomas', 'Phenotype', 'HP:0009733', (295, 302))	('astrocytoma', 'Phenotype', 'HP:0009592', (345, 356))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutations', 'Var', (274, 283))	('IDH2', 'Gene', (269, 273))	('glioblastomas', 'Disease', 'MESH:D005909', (222, 235))	('IDH2', 'Gene', '3418', (269, 273))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('arms 1p', 'Gene', '3075', (153, 160))	('BRAF', 'Gene', '673', (315, 319))	('BRAF', 'Gene', (315, 319))	('IDH1', 'Gene', (260, 264))	('MGMT', 'Gene', '4255', (197, 201))	('gliomas', 'Disease', (295, 302))	('oligodendroglial tumors', 'Disease', (172, 195))	('pilocytic astrocytomas', 'Disease', (335, 357))	('glioblastomas', 'Phenotype', 'HP:0012174', (222, 235))	('hypermethylation', 'Var', (202, 218))	('glioma', 'Phenotype', 'HP:0009733', (295, 301))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (172, 195))	('deletions', 'Var', (125, 134))	('gliomas', 'Disease', (251, 258))	('gliomas', 'Disease', 'MESH:D005910', (295, 302))	('IDH1', 'Gene', '3417', (260, 264))
203235	20714900	There is a strong association between 1p/19q codeletion and classical oligodendroglial features on histology (e.g., perinuclear halo and chicken-wire vascular pattern).	('1p/19q codeletion', 'Var', (38, 55))	('chicken', 'Species', '9031', (137, 144))	('classical oligodendroglial', 'Disease', (60, 86))	('perinuclear halo', 'CPA', (116, 132))	('oligodendroglial features', 'Phenotype', 'HP:0100709', (70, 95))
203238	20714900	Since then, many subsequent studies have been performed, including three prospective randomized phase III trials that corroborated 1p/19q deletion as a powerful prognostic marker in patients with WHO grade III gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (210, 217))	('1p/19q deletion', 'Var', (131, 146))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('patients', 'Species', '9606', (182, 190))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
203242	20714900	However, while 1p/19q loss is associated with more favorable prognosis of patients receiving adjuvant treatment, it needs to be emphasized that this marker is of limited help for making treatment decisions, such as radio- versus chemotherapy.	('loss', 'NegReg', (22, 26))	('1p/19q', 'Var', (15, 21))	('patients', 'Species', '9606', (74, 82))
203247	20714900	In addition, one should be aware that "pseudo-LOH" may be detected in some tumors displaying allelic imbalances due to copy number gain rather than loss of one allele, e.g.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('copy number', 'Var', (119, 130))	('gain', 'PosReg', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('imbalances', 'Phenotype', 'HP:0002172', (101, 111))	('tumors', 'Disease', (75, 81))
203251	20714900	The MGMT (O6-methylguanine-DNA methyltransferase) gene at 10q26 is frequently silenced by promoter hypermethylation in diffuse gliomas and this has been pinpointed as an epigenetic mechanism reducing MGMT expression levels.	('promoter hypermethylation', 'Var', (90, 115))	('MGMT', 'Gene', '4255', (4, 8))	('O6-methylguanine-DNA methyltransferase', 'Gene', (10, 48))	('MGMT', 'Gene', '4255', (200, 204))	('MGMT', 'Gene', (200, 204))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (10, 48))	('silenced', 'NegReg', (78, 86))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))	('MGMT', 'Gene', (4, 8))
203252	20714900	Importantly, an association between MGMT promoter methylation and the response of malignant gliomas to alkylating chemotherapy using nitrosourea compounds, temozolomide, or a combination of both has been observed.	('response', 'MPA', (70, 78))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('MGMT', 'Gene', (36, 40))	('MGMT', 'Gene', '4255', (36, 40))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('nitrosourea compounds', 'Chemical', 'MESH:D009607', (133, 154))	('alkylating chemotherapy', 'MPA', (103, 126))	('association', 'Interaction', (16, 27))	('temozolomide', 'Chemical', 'MESH:D000077204', (156, 168))	('malignant gliomas', 'Disease', (82, 99))	('malignant gliomas', 'Disease', 'MESH:D005910', (82, 99))	('methylation', 'Var', (50, 61))
203254	20714900	reported that patients treated with radiotherapy and temozolomide, and whose tumors had a methylated MGMT promoter (which is seen in approximately 40% of primary glioblastomas) survive significantly longer when compared with patients whose tumors lacked MGMT promoter methylation.	('MGMT', 'Gene', (101, 105))	('tumors', 'Disease', (240, 246))	('glioblastomas', 'Phenotype', 'HP:0012174', (162, 175))	('patients', 'Species', '9606', (14, 22))	('MGMT', 'Gene', '4255', (254, 258))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('primary glioblastomas', 'Disease', (154, 175))	('tumors', 'Disease', (77, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('patients', 'Species', '9606', (225, 233))	('longer', 'PosReg', (199, 205))	('MGMT', 'Gene', '4255', (101, 105))	('primary glioblastomas', 'Disease', 'MESH:D005909', (154, 175))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('temozolomide', 'Chemical', 'MESH:D000077204', (53, 65))	('MGMT', 'Gene', (254, 258))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('methylated', 'Var', (90, 100))
203255	20714900	In this land-mark paper, MGMT promoter methylation did not significantly influence survival in patients treated with radiotherapy alone, suggesting that the MGMT hypermethylation is predictive for favorable response to chemotherapy.	('patients', 'Species', '9606', (95, 103))	('MGMT', 'Gene', '4255', (157, 161))	('hypermethylation', 'Var', (162, 178))	('MGMT', 'Gene', (25, 29))	('MGMT', 'Gene', (157, 161))	('MGMT', 'Gene', '4255', (25, 29))
203258	20714900	MGMT promoter methylation, however, impedes the transcription of the gene resulting in a lack of MGMT mRNA and protein expression.	('MGMT', 'Gene', (0, 4))	('impedes', 'NegReg', (36, 43))	('lack', 'NegReg', (89, 93))	('MGMT', 'Gene', (97, 101))	('MGMT', 'Gene', '4255', (97, 101))	('transcription', 'MPA', (48, 61))	('methylation', 'Var', (14, 25))	('MGMT', 'Gene', '4255', (0, 4))
203259	20714900	Glioblastoma cells with MGMT promoter hypermethylation thus respond better to temozolomide, as they lack the ability to repair the therapy-induced DNA damage.	('temozolomide', 'Chemical', 'MESH:D000077204', (78, 90))	('MGMT', 'Gene', '4255', (24, 28))	('Glioblastoma', 'Disease', (0, 12))	('better', 'PosReg', (68, 74))	('promoter hypermethylation', 'Var', (29, 54))	('lack', 'NegReg', (100, 104))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('respond', 'MPA', (60, 67))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('MGMT', 'Gene', (24, 28))
203266	20714900	The reason for a prognostic role of MGMT promoter methylation in patients just receiving radiotherapy remains unclear, and is rather unexpected from a functional point of view.	('MGMT', 'Gene', '4255', (36, 40))	('MGMT', 'Gene', (36, 40))	('patients', 'Species', '9606', (65, 73))	('methylation', 'Var', (50, 61))
203267	20714900	One may speculate that the strong association of MGMT hypermethylation with 1p/19q codeletion and IDH1 mutation (Fig.	('association', 'Interaction', (34, 45))	('MGMT', 'Gene', '4255', (49, 53))	('MGMT', 'Gene', (49, 53))	('IDH1', 'Gene', (98, 102))	('mutation', 'Var', (103, 111))	('IDH1', 'Gene', '3417', (98, 102))
203284	20714900	Mutations in the gene encoding the human cytosolic NADPH-dependent isocitrate dehydrogenase (IDH1), an enzyme that participates in the citric acid cycle, were originally identified in 2008 employing large scale sequencing analysis of 22 glioblastomas.	('IDH1', 'Gene', (93, 97))	('IDH1', 'Gene', '3417', (93, 97))	('citric acid', 'Chemical', 'MESH:D019343', (135, 146))	('human', 'Species', '9606', (35, 40))	('NADPH', 'Chemical', 'MESH:D009249', (51, 56))	('glioblastomas', 'Phenotype', 'HP:0012174', (237, 250))	('Mutations', 'Var', (0, 9))	('isocitrate', 'Chemical', 'MESH:C034219', (67, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (237, 250))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('glioblastomas', 'Disease', (237, 250))
203285	20714900	All mutations were found in the evolutionarily conserved residue R132 that is located in the substrate-binding site of IDH1.	('IDH1', 'Gene', (119, 123))	('R132', 'Var', (65, 69))	('IDH1', 'Gene', '3417', (119, 123))
203286	20714900	The mutations were detected preferentially in glioblastomas of young patients and in secondary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (95, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('glioblastomas', 'Disease', (46, 59))	('glioblastomas', 'Disease', 'MESH:D005909', (95, 108))	('patients', 'Species', '9606', (69, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('glioblastomas', 'Disease', (95, 108))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('mutations', 'Var', (4, 13))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))
203287	20714900	Soon after, multiple studies corroborated these findings and additionally revealed that somatic IDH1 mutations are present in the vast majority of low-grade diffuse (WHO grade II) and anaplastic (WHO grade III) astrocytic, oligodendroglial, and mixed oligodendroglial neoplasms.	('oligodendroglial', 'Disease', (223, 239))	('IDH1', 'Gene', '3417', (96, 100))	('oligodendroglial neoplasms', 'Disease', 'MESH:D009369', (251, 277))	('mutations', 'Var', (101, 110))	('astrocytic', 'Disease', (211, 221))	('oligodendroglial neoplasms', 'Disease', (251, 277))	('low-grade diffuse', 'Disease', (147, 164))	('neoplasm', 'Phenotype', 'HP:0002664', (268, 276))	('present', 'Reg', (115, 122))	('anaplastic', 'Disease', (184, 194))	('neoplasms', 'Phenotype', 'HP:0002664', (268, 277))	('IDH1', 'Gene', (96, 100))
203288	20714900	In a small subset of WHO grade II and III, diffuse gliomas and secondary glioblastomas that lack IDH1 mutations, the gene of the mitochondrial isoform IDH2 was found to harbor mutations affecting the analogous amino acid (R172).	('gliomas', 'Disease', (51, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('mutations', 'Var', (176, 185))	('IDH1', 'Gene', (97, 101))	('R172', 'Var', (222, 226))	('IDH1', 'Gene', '3417', (97, 101))	('IDH2', 'Gene', (151, 155))	('glioblastomas', 'Phenotype', 'HP:0012174', (73, 86))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('glioblastomas', 'Disease', 'MESH:D005909', (73, 86))	('IDH2', 'Gene', '3418', (151, 155))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('glioblastomas', 'Disease', (73, 86))
203289	20714900	In contrast, IDH1 or IDH2 mutations are rare in primary glioblastomas and restricted to only individual cases of other primary brain tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('primary glioblastomas', 'Disease', (48, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('brain tumors', 'Disease', 'MESH:D001932', (127, 139))	('brain tumors', 'Phenotype', 'HP:0030692', (127, 139))	('IDH1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('IDH2', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('brain tumors', 'Disease', (127, 139))	('brain tumor', 'Phenotype', 'HP:0030692', (127, 138))	('glioblastomas', 'Phenotype', 'HP:0012174', (56, 69))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (21, 25))	('primary glioblastomas', 'Disease', 'MESH:D005909', (48, 69))
203290	20714900	recognized that IDH1 mutations were associated with prolonged overall survival in glioblastoma patients.	('glioblastoma', 'Disease', (82, 94))	('patients', 'Species', '9606', (95, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('IDH1', 'Gene', (16, 20))	('prolonged', 'PosReg', (52, 61))	('IDH1', 'Gene', '3417', (16, 20))	('overall survival', 'MPA', (62, 78))	('mutations', 'Var', (21, 30))
203291	20714900	Subsequent studies analyzing the whole spectrum of diffuse gliomas underscored the association between IDH1 mutation and better outcome, multivariate analyses often revealing IDH1 mutation as a strong and independent favorable prognostic marker.	('IDH1', 'Gene', '3417', (175, 179))	('IDH1', 'Gene', '3417', (103, 107))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH1', 'Gene', (175, 179))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('mutation', 'Var', (108, 116))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('mutation', 'Var', (180, 188))	('IDH1', 'Gene', (103, 107))
203292	20714900	So far, there is no evidence that the type of IDH1 mutation (R132H vs. non-R132H) affects patient survival.	('R132H', 'Mutation', 'rs121913500', (61, 66))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('patient', 'Species', '9606', (90, 97))	('R132H', 'Var', (61, 66))	('R132H', 'Mutation', 'rs121913500', (75, 80))
203293	20714900	In contrast to the strong prognostic significance, several studies reported a lack of predictive significance of IDH1 mutations in gliomas for response to (chemo)therapy.	('gliomas', 'Disease', (131, 138))	('IDH1', 'Gene', (113, 117))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('mutations', 'Var', (118, 127))	('IDH1', 'Gene', '3417', (113, 117))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))
203294	20714900	At the genetic level, the presence of IDH1 mutations in diffuse gliomas is strongly correlated with TP53 mutation or 1p/19q deletions.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('TP53', 'Gene', '7157', (100, 104))	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (38, 42))	('TP53', 'Gene', (100, 104))	('correlated', 'Reg', (84, 94))	('1p/19q deletions', 'Var', (117, 133))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('mutations', 'Var', (43, 52))	('IDH1', 'Gene', (38, 42))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))
203295	20714900	Analysis of multiple glioma biopsies from the same patient revealed that IDH1 mutations do not occur after the acquisition of either a TP53 mutation or loss of 1p/19q.	('IDH1', 'Gene', '3417', (73, 77))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('TP53', 'Gene', '7157', (135, 139))	('loss', 'Var', (152, 156))	('mutation', 'Var', (140, 148))	('mutations', 'Var', (78, 87))	('patient', 'Species', '9606', (51, 58))	('TP53', 'Gene', (135, 139))	('glioma', 'Disease', (21, 27))	('IDH1', 'Gene', (73, 77))
203297	20714900	These mutations thus seem to represent a very early event, affecting a common glial precursor cell, and may in fact form a prerequisite for the t(1;19) translocation leading to 1p/19q co-deletion and oligodendroglial tumor development.	('1p/19q co-deletion', 'Var', (177, 195))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('leading to', 'Reg', (166, 176))	('affecting', 'Reg', (59, 68))	('oligodendroglial tumor', 'Disease', (200, 222))	('oligodendroglial tumor', 'Disease', 'MESH:D009369', (200, 222))	('mutations', 'Var', (6, 15))
203298	20714900	The presence of IDH1 mutations in gliomas was also reported to be tightly associated with MGMT promoter methylation and inversely correlated with the loss of chromosome 10 and EGFR amplification.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('mutations', 'Var', (21, 30))	('MGMT', 'Gene', (90, 94))	('EGFR', 'Gene', '1956', (176, 180))	('MGMT', 'Gene', '4255', (90, 94))	('IDH1', 'Gene', (16, 20))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('EGFR', 'Gene', (176, 180))	('loss', 'NegReg', (150, 154))	('IDH1', 'Gene', '3417', (16, 20))	('gliomas', 'Disease', 'MESH:D005910', (34, 41))	('associated', 'Reg', (74, 84))	('gliomas', 'Disease', (34, 41))
203300	20714900	In up to 90% of the diffuse gliomas with mutated IDH1, the mutation is of the R132H (G395A) type.	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('mutated', 'Var', (41, 48))	('IDH1', 'Gene', '3417', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('G395A', 'Mutation', 'rs121913500', (85, 90))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('IDH1', 'Gene', (49, 53))	('R132H', 'Mutation', 'rs121913500', (78, 83))	('gliomas', 'Disease', (28, 35))
203301	20714900	One study of more than 1,000 diffuse WHO grade II and III gliomas showed that R132C IDH1 mutations are associated with astrocytic neoplasms, while IDH2 mutations predominantly occur in oligodendroglial tumors.	('associated', 'Reg', (103, 113))	('mutations', 'Var', (89, 98))	('gliomas', 'Disease', (58, 65))	('R132C', 'Mutation', 'rs121913499', (78, 83))	('oligodendroglial tumors', 'Disease', (185, 208))	('R132C', 'Var', (78, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (130, 139))	('astrocytic neoplasms', 'Phenotype', 'HP:0009592', (119, 139))	('IDH2', 'Gene', (147, 151))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (185, 208))	('IDH2', 'Gene', '3418', (147, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('IDH1', 'Gene', (84, 88))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('astrocytic neoplasms', 'Disease', (119, 139))	('IDH1', 'Gene', '3417', (84, 88))	('astrocytic neoplasms', 'Disease', 'MESH:D001254', (119, 139))
203302	20714900	Another study revealed that non-R132H IDH1 mutations are rare in classic oligodendrogliomas with 1p/19q loss and occur at significantly higher frequency in other grade II and III gliomas, including those with TP53 mutations.	('loss', 'NegReg', (104, 108))	('IDH1', 'Gene', '3417', (38, 42))	('TP53', 'Gene', (209, 213))	('classic oligodendrogliomas', 'Disease', 'MESH:D009837', (65, 91))	('gliomas', 'Disease', (84, 91))	('non-R132H', 'Var', (28, 37))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('mutations', 'Var', (43, 52))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('IDH1', 'Gene', (38, 42))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('gliomas', 'Disease', (179, 186))	('TP53', 'Gene', '7157', (209, 213))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))	('classic oligodendrogliomas', 'Disease', (65, 91))	('R132H', 'Mutation', 'rs121913500', (32, 37))
203303	20714900	Interestingly, all five examined astrocytomas of patients with Li-Fraumeni syndrome carried R132C IDH1 mutations, indicating that glial/glioma precursor cells with a germline TP53 mutation carry an increased risk to acquire such a non-R132H mutation.	('astrocytomas', 'Disease', (33, 45))	('Li-Fraumeni syndrome', 'Disease', (63, 83))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (63, 83))	('IDH1', 'Gene', '3417', (98, 102))	('TP53', 'Gene', '7157', (175, 179))	('mutations', 'Var', (103, 112))	('glioma', 'Disease', (136, 142))	('germline', 'Var', (166, 174))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('astrocytomas', 'Disease', 'MESH:D001254', (33, 45))	('R132C', 'Mutation', 'rs121913499', (92, 97))	('R132C', 'Var', (92, 97))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('patients', 'Species', '9606', (49, 57))	('R132H', 'Mutation', 'rs121913500', (235, 240))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('TP53', 'Gene', (175, 179))	('IDH1', 'Gene', (98, 102))	('mutation', 'Var', (180, 188))
203304	20714900	IDH1 mutations have now also been reported in a subset of (anaplastic) gangliogliomas, supratentorial primitive neuroectodermal tumors and in gliomatosis cerebri.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('reported', 'Reg', (34, 42))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('gliomatosis cerebri', 'Disease', (142, 161))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (102, 134))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (112, 134))	('IDH1', 'Gene', (0, 4))	('gliomatosis cerebri', 'Disease', 'MESH:D018302', (142, 161))	('neuroectodermal tumors', 'Disease', (112, 134))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (112, 134))	('IDH1', 'Gene', '3417', (0, 4))
203305	20714900	IDH mutations are rare or absent in other glial tumors, such as pilocytic astrocytomas and ependymomas.	('IDH', 'Gene', (0, 3))	('glial tumors', 'Disease', 'MESH:D005910', (42, 54))	('IDH', 'Gene', '3417', (0, 3))	('ependymoma', 'Phenotype', 'HP:0002888', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))	('ependymomas', 'Disease', 'MESH:D004806', (91, 102))	('glial tumors', 'Disease', (42, 54))	('pilocytic astrocytomas', 'Disease', (64, 86))	('mutations', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('ependymomas', 'Disease', (91, 102))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (64, 86))
203306	20714900	Importantly, the vast majority of high-grade (WHO grade III and IV) gliomas in the pediatric age group lacks IDH1 mutation as well, corroborating the notion that these pediatric neoplasms are fundamentally different from their adult counterparts.	('neoplasms', 'Disease', (178, 187))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH1', 'Gene', (109, 113))	('high-grade', 'Disease', (34, 44))	('neoplasms', 'Phenotype', 'HP:0002664', (178, 187))	('lacks', 'NegReg', (103, 108))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('IDH1', 'Gene', '3417', (109, 113))	('gliomas', 'Disease', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('mutation', 'Var', (114, 122))	('neoplasm', 'Phenotype', 'HP:0002664', (178, 186))	('neoplasms', 'Disease', 'MESH:D009369', (178, 187))
203307	20714900	IDH1 mutations are reported to occur in some non-central nervous system tumors, e.g., a subset of acute myeloid leukemias with a normal karyotype, and occasionally in prostate cancer, B-ALL, and paraganglioma.	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (98, 120))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('paraganglioma', 'Disease', (195, 208))	('IDH1', 'Gene', (0, 4))	('paraganglioma', 'Disease', 'MESH:D010235', (195, 208))	('non-central nervous system tumors', 'Disease', 'MESH:D016543', (45, 78))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (98, 121))	('non-central nervous system tumors', 'Disease', (45, 78))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (98, 121))	('acute myeloid leukemias', 'Disease', (98, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))	('IDH1', 'Gene', '3417', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (104, 121))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('paraganglioma', 'Phenotype', 'HP:0002668', (195, 208))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (31, 36))	('prostate cancer', 'Disease', (167, 182))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (49, 78))	('leukemias', 'Phenotype', 'HP:0001909', (112, 121))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('nervous system tumors', 'Phenotype', 'HP:0004375', (57, 78))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (104, 120))
203310	20714900	There are different hypotheses on the role of IDH1 and IDH2 mutations in gliomagenesis, including an effect on the stabilization of hypoxia inducible factor 1 (HIF-1), upregulation of (other) genes involved in angiogenesis, glucose transport and glycolysis, and inhibition of developmental apoptosis.	('stabilization', 'MPA', (115, 128))	('glucose', 'Chemical', 'MESH:D005947', (224, 231))	('glioma', 'Disease', (73, 79))	('hypoxia inducible factor 1', 'Gene', (132, 158))	('IDH2', 'Gene', '3418', (55, 59))	('IDH1', 'Gene', (46, 50))	('IDH2', 'Gene', (55, 59))	('developmental apoptosis', 'CPA', (276, 299))	('HIF-1', 'Gene', '3091', (160, 165))	('IDH1', 'Gene', '3417', (46, 50))	('upregulation', 'PosReg', (168, 180))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('HIF-1', 'Gene', (160, 165))	('mutations', 'Var', (60, 69))	('hypoxia inducible factor 1', 'Gene', '3091', (132, 158))
203311	20714900	However, recent studies suggest that the heterozygous IDH1 and IDH2 mutations in gliomas do not just result in a loss of function, that is a reduced ability to catalyze conversion of isocitrate to alpha-ketoglutarate, but also confer an enzymatic gain of function, in particular the ability to catalyze the NADPH-dependent reduction of alpha-ketoglutarate to 2-hydroxyglutarate (2HG).	('IDH2', 'Gene', '3418', (63, 67))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (197, 216))	('mutations', 'Var', (68, 77))	('reduction', 'MPA', (323, 332))	('IDH1', 'Gene', (54, 58))	('conversion', 'MPA', (169, 179))	('gain of function', 'PosReg', (247, 263))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (359, 377))	('gliomas', 'Disease', (81, 88))	('isocitrate', 'Chemical', 'MESH:C034219', (183, 193))	('reduced', 'NegReg', (141, 148))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (336, 355))	('IDH1', 'Gene', '3417', (54, 58))	('ability', 'MPA', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('NADPH', 'Chemical', 'MESH:D009249', (307, 312))	('IDH2', 'Gene', (63, 67))
203312	20714900	Indeed, gliomas harboring IDH1 mutations demonstrate markedly elevated levels of 2HG, and this 'onco-metabolite' may contribute to the oncogenesis of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('gliomas', 'Disease', (8, 15))	('mutations', 'Var', (31, 40))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('IDH1', 'Gene', (26, 30))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('levels', 'MPA', (71, 77))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('2HG', 'MPA', (81, 84))	('contribute', 'Reg', (117, 127))	('IDH1', 'Gene', '3417', (26, 30))	('elevated', 'PosReg', (62, 70))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
203313	20714900	Similarly, IDH1 and IDH2 mutations dramatically increase 2HG in acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (78, 86))	('2HG', 'MPA', (57, 60))	('mutations', 'Var', (25, 34))	('IDH1', 'Gene', '3417', (11, 15))	('IDH2', 'Gene', '3418', (20, 24))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (64, 86))	('acute myeloid leukemia', 'Disease', (64, 86))	('IDH2', 'Gene', (20, 24))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (64, 86))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (70, 86))	('IDH1', 'Gene', (11, 15))	('increase', 'PosReg', (48, 56))
203314	20714900	Because of the specificity of the IDH1 and IDH2 mutations in gliomas and of their metabolic effects, there is hope that these aberrations provide new avenues for anti-cancer therapies.	('IDH1', 'Gene', '3417', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('IDH2', 'Gene', (43, 47))	('cancer', 'Disease', (167, 173))	('gliomas', 'Disease', (61, 68))	('IDH2', 'Gene', '3418', (43, 47))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('IDH1', 'Gene', (34, 38))	('mutations', 'Var', (48, 57))
203315	20714900	However, further study of the (exact effect of) IDH1 and IDH2 mutations is needed to seize this opportunity.	('IDH1', 'Gene', '3417', (48, 52))	('IDH2', 'Gene', (57, 61))	('IDH2', 'Gene', '3418', (57, 61))	('IDH1', 'Gene', (48, 52))	('mutations', 'Var', (62, 71))
203316	20714900	Various methods are applied for the detection of IDH1 and/or IDH2 mutations in clinical glioma specimens (Table 2), including single-strand conformation polymorphism analysis, direct sequencing, PCR-restriction fragment length polymorphism-based assays, DNA pyrosequencing and real-time PCR with post-PCR fluorescence melting curve analysis assays.	('mutations', 'Var', (66, 75))	('IDH1', 'Gene', '3417', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (88, 94))	('IDH2', 'Gene', (61, 65))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('IDH2', 'Gene', '3418', (61, 65))	('IDH1', 'Gene', (49, 53))
203317	20714900	Especially, these latter assays allow for rapid, inexpensive, and sensitive analysis of IDH1 and IDH2 mutations in routinely processed (i.e.	('IDH2', 'Gene', (97, 101))	('IDH1', 'Gene', (88, 92))	('IDH2', 'Gene', '3418', (97, 101))	('mutations', 'Var', (102, 111))	('IDH1', 'Gene', '3417', (88, 92))
203319	20714900	Only recently, specific, and robust monoclonal antibodies were established that can be used for immunohistochemical analysis of gliomas bearing the IDH1 R132H mutation.	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Disease', (128, 135))	('IDH1', 'Gene', '3417', (148, 152))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('R132H', 'Var', (153, 158))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('R132H', 'Mutation', 'rs121913500', (153, 158))	('IDH1', 'Gene', (148, 152))
203320	20714900	Testing for mutations in IDH1 or IDH2 can now easily and effectively be performed in a clinical setting and thereby enhance the diagnostic accuracy, especially, in cases where traditional methods are insufficient to reach a definitive diagnosis.	('enhance', 'PosReg', (116, 123))	('IDH2', 'Gene', (33, 37))	('mutations', 'Var', (12, 21))	('IDH2', 'Gene', '3418', (33, 37))	('diagnostic accuracy', 'MPA', (128, 147))	('IDH1', 'Gene', (25, 29))	('insufficient', 'Disease', 'MESH:D000309', (200, 212))	('insufficient', 'Disease', (200, 212))	('IDH1', 'Gene', '3417', (25, 29))
203321	20714900	For example, IDH1 and IDH2 mutation analysis might be helpful in case of a differential diagnosis of diffuse glioma versus pilocytic astrocytoma or ependymoma, and for discrimination between primary and secondary glioblastoma.	('ependymoma', 'Phenotype', 'HP:0002888', (148, 158))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('ependymoma', 'Disease', (148, 158))	('glioblastoma', 'Disease', (213, 225))	('IDH2', 'Gene', (22, 26))	('ependymoma', 'Disease', 'MESH:D004806', (148, 158))	('IDH1', 'Gene', (13, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (213, 225))	('glioma versus pilocytic astrocytoma', 'Disease', (109, 144))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('mutation analysis', 'Var', (27, 44))	('glioma versus pilocytic astrocytoma', 'Disease', 'MESH:D001254', (109, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (213, 225))
203322	20714900	Using immunohistochemistry with the anti-IDH1R132H antibody, even individual cells of gliomas with the IDH1 R132H mutation (e.g.	('IDH1', 'Gene', '3417', (103, 107))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('R132H', 'Var', (108, 113))	('R132H', 'Mutation', 'rs121913500', (108, 113))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))	('IDH1', 'Gene', (103, 107))
203324	20714900	Of note, lack of staining with this antibody does not rule out the presence of an IDH1 mutation (about 10% of the IDH1 mutated gliomas carry a non-R132H mutation) nor of an IDH2 mutation.	('IDH1', 'Gene', (114, 118))	('IDH2', 'Gene', (173, 177))	('R132H', 'Mutation', 'rs121913500', (147, 152))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('IDH1', 'Gene', (82, 86))	('carry', 'Reg', (135, 140))	('non-R132H mutation', 'Var', (143, 161))	('IDH1', 'Gene', '3417', (114, 118))	('IDH2', 'Gene', '3418', (173, 177))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('mutated', 'Var', (119, 126))	('IDH1', 'Gene', '3417', (82, 86))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
203325	20714900	Given the diagnostic and prognostic importance as well as the robustness and relative ease of IDH1 and IDH2 mutation testing, it is very likely that determination of these mutations will soon become a part of the routine diagnostic assessment of gliomas.	('IDH1', 'Gene', (94, 98))	('IDH2', 'Gene', '3418', (103, 107))	('gliomas', 'Disease', 'MESH:D005910', (246, 253))	('IDH1', 'Gene', '3417', (94, 98))	('gliomas', 'Phenotype', 'HP:0009733', (246, 253))	('gliomas', 'Disease', (246, 253))	('mutation', 'Var', (108, 116))	('IDH2', 'Gene', (103, 107))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
203327	20714900	For example, one may address interesting questions like (1) should IDH1 and IDH2 wild-type anaplastic gliomas be biologically considered as glioblastomas that consequently would require more aggressive treatment when compared with IDH1 or IDH2 mutant anaplastic gliomas, or (2) should the rare, prognostically favorable IDH1 mutant primary glioblastoma be regarded as a separate entity distinct from the "ordinary" IDH1 wild-type primary glioblastoma.	('gliomas', 'Disease', 'MESH:D005910', (262, 269))	('primary glioblastoma', 'Disease', (332, 352))	('IDH1', 'Gene', (231, 235))	('IDH1', 'Gene', (320, 324))	('glioblastomas', 'Phenotype', 'HP:0012174', (140, 153))	('IDH1', 'Gene', '3417', (67, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (340, 352))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('primary glioblastoma', 'Disease', 'MESH:D005909', (332, 352))	('IDH1', 'Gene', '3417', (415, 419))	('gliomas', 'Phenotype', 'HP:0009733', (262, 269))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('IDH1', 'Gene', '3417', (320, 324))	('IDH1', 'Gene', '3417', (231, 235))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('glioblastomas', 'Disease', (140, 153))	('mutant', 'Var', (325, 331))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('IDH2', 'Gene', (76, 80))	('primary glioblastoma', 'Disease', (430, 450))	('IDH2', 'Gene', '3418', (76, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (140, 153))	('gliomas', 'Disease', (262, 269))	('IDH2', 'Gene', (239, 243))	('primary glioblastoma', 'Disease', 'MESH:D005909', (430, 450))	('glioblastoma', 'Phenotype', 'HP:0012174', (438, 450))	('IDH1', 'Gene', (67, 71))	('IDH2', 'Gene', '3418', (239, 243))	('gliomas', 'Disease', (102, 109))	('IDH1', 'Gene', (415, 419))
203331	20714900	Identification of EGFR amplification and rearrangements, such as EGFRvIII, are highly indicative for high-grade malignancy and, therefore, may provide diagnostic as well as prognostic information.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (65, 69))	('rearrangements', 'Var', (41, 55))	('amplification', 'Var', (23, 36))	('provide', 'Reg', (143, 150))	('EGFR', 'Gene', (18, 22))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('malignancy', 'Disease', (112, 122))
203334	20714900	Detection of EGFR aberrations also may be relevant from a therapeutic point of view as inhibition of the EGFR pathway bears the potential of restoring apoptosis, thereby increasing the sensitivity to adjuvant therapies.	('inhibition', 'Var', (87, 97))	('aberrations', 'Var', (18, 29))	('restoring', 'PosReg', (141, 150))	('increasing', 'PosReg', (170, 180))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (105, 109))	('apoptosis', 'CPA', (151, 160))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
203337	20714900	Attempts to identify additional biomarkers predictive of response to EGFR-related therapies suggested that tumors with EGFRvIII and intact PTEN or with EGFR amplification (but not EGFRvIII) and low levels of phosphorylated AKT were more likely to respond to the small molecule tyrosine kinase inhibitors erlotinib or gefitinib.	('gefitinib', 'Chemical', 'MESH:D000077156', (317, 326))	('AKT', 'Gene', (223, 226))	('erlotinib', 'Chemical', 'MESH:D000069347', (304, 313))	('EGFR', 'Gene', '1956', (69, 73))	('low', 'Var', (194, 197))	('more', 'PosReg', (232, 236))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('PTEN', 'Gene', (139, 143))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (152, 156))	('AKT', 'Gene', '207', (223, 226))	('EGFR', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('PTEN', 'Gene', '5728', (139, 143))	('respond to', 'MPA', (247, 257))	('EGFR', 'Gene', (69, 73))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', (180, 184))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('EGFR', 'Gene', '1956', (119, 123))
203338	20714900	The EGFRvIII mutant, as not being present in non-neoplastic tissues, also may serve as an attractive target for immunotherapy.	('mutant', 'Var', (13, 19))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', '1956', (4, 8))
203342	20714900	Furthermore, MLPA analysis allows for the detection of EGFR rearrangements by the simultaneous and semi-quantitative copy number analysis of multiple small DNA fragments encompassing different EGFR exons, with available assays detecting EGFRvIII and different other types of rearrangements and being applicable to routinely processed formalin-fixed and paraffin-embedded tissue samples.	('EGFR', 'Gene', '1956', (55, 59))	('rearrangements', 'Var', (60, 74))	('EGFR', 'Gene', '1956', (237, 241))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (193, 197))	('EGFR', 'Gene', (237, 241))	('EGFR', 'Gene', (193, 197))	('paraffin', 'Chemical', 'MESH:D010232', (353, 361))	('formalin', 'Chemical', 'MESH:D005557', (334, 342))
203343	20714900	Aberrant activation of the BRAF proto-oncogene at 7q34, most commonly by gene duplication and fusion or less frequently by point mutation, has only recently been identified as the characteristic genetic aberration in pilocytic astrocytomas.	('activation', 'PosReg', (9, 19))	('pilocytic astrocytomas', 'Disease', (217, 239))	('gene duplication', 'Var', (73, 89))	('Aberrant', 'Var', (0, 8))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (217, 239))	('astrocytoma', 'Phenotype', 'HP:0009592', (227, 238))	('BRAF', 'Gene', '673', (27, 31))	('fusion', 'Var', (94, 100))	('BRAF', 'Gene', (27, 31))
203344	20714900	BRAF gene alterations are detectable in 60-80% of pilocytic astrocytomas, but are infrequent in diffusely infiltrating astrocytic gliomas.	('astrocytic gliomas', 'Disease', (119, 137))	('alterations', 'Var', (10, 21))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('pilocytic astrocytomas', 'Disease', (50, 72))	('detectable', 'Reg', (26, 36))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (119, 137))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (50, 72))
203345	20714900	Thus, testing for BRAF gene alterations might be helpful in the sometimes difficult differential diagnosis between pilocytic astrocytomas and low-grade diffuse astrocytomas.	('astrocytomas', 'Disease', (160, 172))	('alterations', 'Var', (28, 39))	('pilocytic astrocytomas', 'Disease', (115, 137))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (115, 137))	('astrocytomas', 'Disease', 'MESH:D001254', (125, 137))	('BRAF', 'Gene', '673', (18, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (125, 136))	('astrocytomas', 'Disease', 'MESH:D001254', (160, 172))	('astrocytoma', 'Phenotype', 'HP:0009592', (160, 171))	('BRAF', 'Gene', (18, 22))	('astrocytomas', 'Disease', (125, 137))
203347	20714900	As mentioned above, low-grade diffuse astrocytoma:in contrast to pilocytic astrocytoma:would contain frequent mutations in the IDH1 gene and as such testing for both markers in combination could finally turn the scales for one of the two entities.	('astrocytoma', 'Disease', (38, 49))	('turn', 'Reg', (203, 207))	('mutations', 'Var', (110, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (38, 49))	('IDH1', 'Gene', (127, 131))	('pilocytic astrocytoma', 'Disease', (65, 86))	('astrocytoma', 'Disease', 'MESH:D001254', (75, 86))	('IDH1', 'Gene', '3417', (127, 131))	('astrocytoma', 'Disease', (75, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (65, 86))	('astrocytoma', 'Disease', 'MESH:D001254', (38, 49))
203348	20714900	However, IDH1 and IDH2 mutations are generally rare in pediatric astrocytomas, including the diffusely infiltrating tumors, which implies that the significance of diagnostic testing for these mutations may be lower in pediatric glioma patients.	('tumors', 'Disease', (116, 122))	('IDH2', 'Gene', '3418', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('pediatric glioma', 'Disease', (218, 234))	('IDH1', 'Gene', (9, 13))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('patients', 'Species', '9606', (235, 243))	('IDH1', 'Gene', '3417', (9, 13))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('mutations', 'Var', (23, 32))	('pediatric astrocytomas', 'Phenotype', 'HP:0009592', (55, 77))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('astrocytomas', 'Disease', (65, 77))	('pediatric glioma', 'Disease', 'MESH:D005910', (218, 234))	('IDH2', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
203349	20714900	The frequent BRAF alterations in pilocytic astrocytomas may have additional clinical implications as a novel therapeutic target.	('alterations', 'Var', (18, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('pilocytic astrocytomas', 'Disease', (33, 55))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (33, 55))
203350	20714900	Tumors with BRAF duplication or activating mutation show aberrant signaling via the BRAF pathway.	('activating mutation', 'Var', (32, 51))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('duplication', 'Var', (17, 28))	('BRAF', 'Gene', (84, 88))	('signaling', 'MPA', (66, 75))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
203352	20714900	Thus, pharmacological inhibition of the MAPK pathway may serve as a potential treatment option in pediatric astrocytoma patients, as exemplified in a recent case report.	('astrocytoma', 'Disease', 'MESH:D001254', (108, 119))	('pharmacological', 'Var', (6, 21))	('MAPK pathway', 'Pathway', (40, 52))	('astrocytoma', 'Disease', (108, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('patients', 'Species', '9606', (120, 128))
203355	20714900	However, recent data suggest that in addition to age at diagnosis, gain of 1q and homozygous CDKN2A deletion are independent indicators of unfavorable prognosis, whereas gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 are associated with excellent survival for pediatric and adult patients with intracranial ependymomas.	('CDKN2A', 'Gene', (93, 99))	('CDKN2A', 'Gene', '1029', (93, 99))	('ependymoma', 'Phenotype', 'HP:0002888', (321, 331))	('patients', 'Species', '9606', (294, 302))	('intracranial ependymomas', 'Disease', (308, 332))	('deletion', 'Var', (100, 108))	('gain', 'PosReg', (67, 71))	('intracranial ependymomas', 'Disease', 'MESH:C531673', (308, 332))
203358	20714900	The success of large scale profiling approaches is exemplified by the first detection of IDH1 mutations in a study that sequenced 20,661 genes in 22 human glioblastoma samples.	('mutations', 'Var', (94, 103))	('glioblastoma', 'Disease', (155, 167))	('human', 'Species', '9606', (149, 154))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('IDH1', 'Gene', (89, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('IDH1', 'Gene', '3417', (89, 93))
203362	20714900	Sequencing of glioblastomas for mutations in 601 selected genes additionally revealed three previously unrecognized mutations that occurred with significant frequency, namely NF1 gene mutations in 14%, ERBB2 gene mutations in 8% and PIK3R1 mutations in nearly 10% of glioblastomas.	('PIK3R1', 'Gene', '5295', (233, 239))	('glioblastomas', 'Phenotype', 'HP:0012174', (267, 280))	('PIK3R1', 'Gene', (233, 239))	('glioblastomas', 'Disease', 'MESH:D005909', (267, 280))	('mutations', 'Var', (184, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (267, 279))	('glioblastomas', 'Phenotype', 'HP:0012174', (14, 27))	('glioblastomas', 'Disease', (267, 280))	('ERBB2', 'Gene', '2064', (202, 207))	('NF1', 'Gene', '4763', (175, 178))	('NF1', 'Gene', (175, 178))	('ERBB2', 'Gene', (202, 207))	('glioblastomas', 'Disease', 'MESH:D005909', (14, 27))	('mutations', 'Var', (213, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('mutations', 'Var', (240, 249))	('glioblastomas', 'Disease', (14, 27))
203363	20714900	As an example, PIK3R1 encodes the regulatory protein p85a subunit of Pi3k and the response to Pi3k inhibitors may depend on whether the tumors bear mutations in this specific gene or not.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('mutations', 'Var', (148, 157))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PIK3R1', 'Gene', '5295', (15, 21))	('PIK3R1', 'Gene', (15, 21))
203371	20714900	Interestingly, promoter DNA methylation profiling in 272 TCGA glioblastomas revealed that a subset of patients had concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP).	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('hypermethylation', 'Var', (125, 141))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('patients', 'Species', '9606', (102, 110))	('G-CIMP', 'Chemical', '-', (239, 245))	('glioblastomas', 'Phenotype', 'HP:0012174', (62, 75))	('glioblastomas', 'Disease', 'MESH:D005909', (62, 75))	('glioma', 'Disease', (199, 205))	('glioblastomas', 'Disease', (62, 75))
203372	20714900	Further investigations showed that G-CIMP tumors were more common among low-grade gliomas, displayed a proneural expression signature, frequently carried IDH1 mutations and were associated with significantly longer survival.	('proneural expression signature', 'MPA', (103, 133))	('G-CIMP', 'Chemical', '-', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('mutations', 'Var', (159, 168))	('carried', 'Reg', (146, 153))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('IDH1', 'Gene', (154, 158))	('gliomas', 'Disease', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('IDH1', 'Gene', '3417', (154, 158))	('longer', 'PosReg', (208, 214))
203373	20714900	Other authors also found a tight association between the IDH1 mutation status and gene expression profiles, suggesting two major pathomechanisms in diffuse astrocytic gliomas characterized either by IDH1 mutation and a proneural expression profile, found mostly in diffuse and anaplastic astrocytomas as well as secondary glioblastomas, or by lack of IDH1 mutation and a mesenchymal/proliferative expression profile.	('mutation', 'Var', (204, 212))	('IDH1', 'Gene', (57, 61))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('diffuse', 'Disease', (265, 272))	('IDH1', 'Gene', (199, 203))	('astrocytomas', 'Disease', 'MESH:D001254', (288, 300))	('astrocytoma', 'Phenotype', 'HP:0009592', (288, 299))	('IDH1', 'Gene', '3417', (351, 355))	('glioblastomas', 'Disease', (322, 335))	('glioblastoma', 'Phenotype', 'HP:0012174', (322, 334))	('IDH1', 'Gene', (351, 355))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (156, 174))	('IDH1', 'Gene', '3417', (57, 61))	('astrocytic gliomas', 'Disease', (156, 174))	('IDH1', 'Gene', '3417', (199, 203))	('glioblastomas', 'Disease', 'MESH:D005909', (322, 335))	('proneural expression profile', 'MPA', (219, 247))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('astrocytomas', 'Disease', (288, 300))	('glioblastomas', 'Phenotype', 'HP:0012174', (322, 335))
203374	20714900	In addition, IDH1 mutant glioblastomas have been reported to be frequently accompanied by telomerase-independent alternative lengthening of telomeres (ALTs), suggesting that such ALT + tumors belong to the less aggressive, 'proneural' glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (235, 248))	('glioblastomas', 'Disease', (235, 248))	('glioblastoma', 'Phenotype', 'HP:0012174', (235, 247))	('tumors', 'Disease', (185, 191))	('mutant', 'Var', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('glioblastomas', 'Phenotype', 'HP:0012174', (25, 38))	('IDH1', 'Gene', (13, 17))	('accompanied', 'Reg', (75, 86))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('glioblastomas', 'Disease', 'MESH:D005909', (25, 38))	('IDH1', 'Gene', '3417', (13, 17))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('glioblastomas', 'Phenotype', 'HP:0012174', (235, 248))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('glioblastomas', 'Disease', (25, 38))
203377	20714900	Nevertheless, it remains to be proven that any of these prognostic gene signatures yields clinically relevant data beyond the information provided by the analysis of IDH1 mutation, MGMT promoter methylation and 1p/19q deletion.	('IDH1', 'Gene', (166, 170))	('mutation', 'Var', (171, 179))	('IDH1', 'Gene', '3417', (166, 170))	('1p/19q deletion', 'Var', (211, 226))	('MGMT', 'Gene', (181, 185))	('MGMT', 'Gene', '4255', (181, 185))
203389	20714900	identified somatic mutations of the mismatch repair gene MSH6 in a large-scale sequencing approach of the functional domains of 518 protein kinases.	('MSH6', 'Gene', (57, 61))	('mutations', 'Var', (19, 28))	('MSH6', 'Gene', '2956', (57, 61))
203391	20714900	Indeed, in recurrent glioblastomas, the rate of MSH6 mutations was significantly increased adding further evidence to a potential causal link between MSH6 deficiency and treatment resistance.	('glioblastomas', 'Disease', (21, 34))	('MSH6', 'Gene', (48, 52))	('MSH6', 'Gene', '2956', (150, 154))	('mutations', 'Var', (53, 62))	('MSH6 deficiency', 'Disease', 'MESH:D007153', (150, 165))	('glioblastomas', 'Phenotype', 'HP:0012174', (21, 34))	('MSH6', 'Gene', '2956', (48, 52))	('MSH6 deficiency', 'Disease', (150, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('glioblastomas', 'Disease', 'MESH:D005909', (21, 34))	('increased', 'PosReg', (81, 90))	('MSH6', 'Gene', (150, 154))
203392	20714900	Interestingly, a subsequent publication reported that MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance.	('glioblastomas', 'Disease', 'MESH:D005909', (78, 91))	('glioblastomas', 'Disease', (78, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('mediate', 'Reg', (124, 131))	('glioblastomas', 'Phenotype', 'HP:0012174', (78, 91))	('MSH6', 'Gene', (54, 58))	('arise in', 'Reg', (69, 77))	('mutations', 'Var', (59, 68))	('temozolomide', 'Chemical', 'MESH:D000077204', (132, 144))	('temozolomide resistance', 'MPA', (132, 155))	('MSH6', 'Gene', '2956', (54, 58))	('temozolomide', 'Chemical', 'MESH:D000077204', (99, 111))
203394	20714900	Moreover, knockdown of MSH6 in the glioblastoma cell line U251 increased resistance to temozolomide cytotoxicity and reconstitution restored cytotoxicity in MSH6-null glioma cells.	('MSH6', 'Gene', (23, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('MSH6', 'Gene', (157, 161))	('MSH6', 'Gene', '2956', (23, 27))	('MSH6', 'Gene', '2956', (157, 161))	('U251', 'CellLine', 'CVCL:0021', (58, 62))	('glioblastoma', 'Disease', (35, 47))	('glioma', 'Disease', (167, 173))	('temozolomide', 'Chemical', 'MESH:D000077204', (87, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('knockdown', 'Var', (10, 19))	('glioma', 'Disease', 'MESH:D005910', (167, 173))	('restored', 'PosReg', (132, 140))	('cytotoxicity', 'Disease', (100, 112))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('cytotoxicity', 'Disease', (141, 153))	('cytotoxicity', 'Disease', 'MESH:D064420', (100, 112))	('increased', 'PosReg', (63, 72))	('cytotoxicity', 'Disease', 'MESH:D064420', (141, 153))
203395	20714900	These findings indicate that MSH6 mutations and/or mutations in other DNA mismatch repair genes are selected in glioblastomas during temozolomide therapy and that patients who initially responded to a frontline therapy, i.e., particularly patients with MGMT-hypermethylated tumors, may develop treatment resistance by acquiring a hypermutator phenotype involving frequent mutations in DNA mismatch repair genes.	('mutations', 'Var', (51, 60))	('glioblastomas', 'Disease', 'MESH:D005909', (112, 125))	('mutations', 'Var', (372, 381))	('MSH6', 'Gene', (29, 33))	('treatment resistance', 'CPA', (294, 314))	('develop', 'PosReg', (286, 293))	('DNA mismatch repair genes', 'Gene', (385, 410))	('MSH6', 'Gene', '2956', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('temozolomide', 'Chemical', 'MESH:D000077204', (133, 145))	('glioblastomas', 'Phenotype', 'HP:0012174', (112, 125))	('patients', 'Species', '9606', (163, 171))	('MGMT-hypermethylated tumors', 'Disease', (253, 280))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('patients', 'Species', '9606', (239, 247))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('glioblastomas', 'Disease', (112, 125))	('MGMT-hypermethylated tumors', 'Disease', 'MESH:D009369', (253, 280))	('mutations', 'Var', (34, 43))
203397	20714900	Although undoubtedly representing a relevant novel discovery, MSH6 mutations may be just the tip of an iceberg of molecular changes that are associated with treatment response.	('MSH6', 'Gene', (62, 66))	('MSH6', 'Gene', '2956', (62, 66))	('mutations', 'Var', (67, 76))
203398	20714900	Furthermore, these mutations appear not be linked to high-level microsatellite instability in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('mutations', 'Var', (19, 28))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
203399	20714900	Other studies have reported that alteration of the base excision repair pathway may sensitize glioma cells to temozolomide treatment and suggested inhibition of poly(ADP-ribose)polymerase as a promising therapeutic approach.	('alteration', 'Var', (33, 43))	('glioma', 'Disease', (94, 100))	('poly(ADP-ribose)polymerase', 'Gene', '142', (161, 187))	('sensitize', 'Reg', (84, 93))	('temozolomide', 'Chemical', 'MESH:D000077204', (110, 122))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('inhibition', 'Var', (147, 157))	('base excision repair pathway', 'Pathway', (51, 79))	('poly(ADP-ribose)polymerase', 'Gene', (161, 187))
203400	20714900	Furthermore, large-scale heterochromatin reorganization has been observed in glioma cells following treatment with temozolomide and carmustine, suggesting that treatment efficacy may implicate a first event characterized by changes in heterochromatin organization and, conversely, treatment failure may be associated with the aberrant euchromatinization of novel, yet to be identified chemotherapy resistance genes.	('aberrant', 'Var', (326, 334))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('changes', 'Reg', (224, 231))	('glioma', 'Disease', (77, 83))	('temozolomide', 'Chemical', 'MESH:D000077204', (115, 127))	('carmustine', 'Chemical', 'MESH:D002330', (132, 142))	('heterochromatin organization', 'MPA', (235, 263))	('treatment failure', 'Disease', 'MESH:D016609', (281, 298))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('treatment failure', 'Disease', (281, 298))
203405	20714900	In fact, the antibody against the IDH1 R132H mutation is already used in many neuropathology laboratories, e.g.	('IDH1', 'Gene', '3417', (34, 38))	('R132H', 'Var', (39, 44))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('neuropathology laboratories', 'Disease', (78, 105))	('IDH1', 'Gene', (34, 38))	('neuropathology laboratories', 'Disease', 'MESH:D007757', (78, 105))
203420	32081833	It was found that H19 could affect the immune infiltration level of glioma through copy number variations, thus affecting the prognosis of glioma patients.	('affect', 'Reg', (28, 34))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('affecting', 'Reg', (112, 121))	('H19', 'Gene', '283120', (18, 21))	('glioma', 'Disease', (139, 145))	('H19', 'Gene', (18, 21))	('immune infiltration level', 'MPA', (39, 64))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Disease', (68, 74))	('copy number variations', 'Var', (83, 105))	('patients', 'Species', '9606', (146, 154))
203472	32081833	Analysis of 667 samples from TCGA exhibited that H19 differential expression was noticeably associated with primary disease, histological type, histologic grade, new tumor event, tumor tissue site, cancer status, primary therapy outcome, radiation therapy, sample type, targeted molecular therapy and age (Figure 10B).	('H19', 'Gene', '283120', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('H19', 'Gene', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (198, 204))	('primary disease', 'Disease', 'MESH:D009202', (108, 123))	('tumor', 'Disease', (166, 171))	('primary disease', 'Disease', (108, 123))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('differential expression', 'Var', (53, 76))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('new', 'Disease', (162, 165))	('associated', 'Reg', (92, 102))	('tumor', 'Disease', (179, 184))
203474	32081833	Survival analysis exhibited that low expression of H19 had a better prognosis (Figure 11), which was in line with the result from GEPIA analysis.	('low expression', 'Var', (33, 47))	('H19', 'Gene', (51, 54))	('H19', 'Gene', '283120', (51, 54))
203475	32081833	These results demonstrated that H19 could be used as an indicator of progression and prognosis in patients with glioma, and high H19 expression indicated poor therapeutic effect.	('expression', 'MPA', (133, 143))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('poor therapeutic effect', 'Phenotype', 'HP:0020173', (154, 177))	('H19', 'Gene', '283120', (32, 35))	('patients', 'Species', '9606', (98, 106))	('glioma', 'Disease', (112, 118))	('H19', 'Gene', (32, 35))	('poor', 'NegReg', (154, 158))	('H19', 'Gene', '283120', (129, 132))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('high', 'Var', (124, 128))	('H19', 'Gene', (129, 132))
203488	32081833	These results illustrated that patients with high expression of H19 tended to have a worse prognosis than those with low expression of H19.	('H19', 'Gene', '283120', (135, 138))	('H19', 'Gene', (135, 138))	('patients', 'Species', '9606', (31, 39))	('H19', 'Gene', '283120', (64, 67))	('high expression', 'Var', (45, 60))	('H19', 'Gene', (64, 67))
203496	32081833	Meanwhile, we found that the expression level of H19 in patients who received radiotherapy in LGG was higher than those who did not (Figure 12L, P<0.05), and the opposite result was found in GBM, but not statistically significant (Figure 12M, P>0.05).	('H19', 'Gene', '283120', (49, 52))	('patients', 'Species', '9606', (56, 64))	('H19', 'Gene', (49, 52))	('expression level', 'MPA', (29, 45))	('radiotherapy', 'Var', (78, 90))	('higher', 'PosReg', (102, 108))	('GBM', 'Disease', (191, 194))	('GBM', 'Disease', 'MESH:D005909', (191, 194))
203505	32081833	Besides, it was found that the copy number variations of H19 could notably affect the infiltration level of glioma immune cells (Supplementary Figure 2), but could not affect the mRNA level of H19 (Supplementary Figure 3).	('copy number variations', 'Var', (31, 53))	('glioma', 'Disease', (108, 114))	('H19', 'Gene', '283120', (193, 196))	('men', 'Species', '9606', (135, 138))	('H19', 'Gene', (193, 196))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('affect', 'Reg', (75, 81))	('men', 'Species', '9606', (204, 207))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('H19', 'Gene', '283120', (57, 60))	('H19', 'Gene', (57, 60))
203506	32081833	These results indicated that H19 could affect the immune infiltration level by copy number variations, thereby influencing the prognosis of patients with glioma.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('immune infiltration level', 'MPA', (50, 75))	('H19', 'Gene', (29, 32))	('affect', 'Reg', (39, 45))	('glioma', 'Disease', (154, 160))	('influencing', 'Reg', (111, 122))	('H19', 'Gene', '283120', (29, 32))	('patients', 'Species', '9606', (140, 148))	('copy number variations', 'Var', (79, 101))
203522	32081833	TGF-beta signaling pathway also plays a key role in metazoan biology, and its misregulation can lead to tumor development.	('TGF-beta signaling pathway', 'Pathway', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('men', 'Species', '9606', (117, 120))	('tumor', 'Disease', (104, 109))	('lead to', 'Reg', (96, 103))	('misregulation', 'Var', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
203550	32081833	GSEA was then used to elucidate the significant survival difference observed between high- and low-H19 groups.	('H19', 'Gene', (99, 102))	('high-', 'Var', (85, 90))	('GSEA', 'Chemical', '-', (0, 4))	('H19', 'Gene', '283120', (99, 102))
203558	32081833	Finally, SCNA module was used to analyze the relationship between H19 copy number variations in different somatic cells and infiltration level of glioma.	('H19', 'Gene', '283120', (66, 69))	('H19', 'Gene', (66, 69))	('glioma', 'Disease', (146, 152))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('copy number variations', 'Var', (70, 92))
203584	31413876	The aim of this review is to summarize the data on certain genetic mutations associated with the development and progression of astrocytas and gliomas of various degrees of malignancy, as well as the potential of using them for predicting and diagnosing this type of tumors, including SCA.	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('astrocytas', 'Disease', (128, 138))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('mutations', 'Var', (67, 76))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Disease', (143, 150))	('glioma', 'Disease', (143, 149))	('SCA', 'Disease', (285, 288))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('associated', 'Reg', (77, 87))
203585	31413876	Genetic markers associated with astrocytomas    There is abundant evidence of the leading role played by genetic aberrations in the development and progression of primary malignant tumors of the CNS.	('astrocytomas', 'Disease', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('malignant tumors', 'Disease', (171, 187))	('malignant tumors', 'Disease', 'MESH:D018198', (171, 187))	('genetic aberrations', 'Var', (105, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
203587	31413876	For instance, duplication and activation of BRAF are found in juvenile PA, which is localized in the cerebellum (80%) and the hypothalamic/chiasmal region (62%).	('BRAF', 'Gene', (44, 48))	('hypothalamic', 'Disease', 'MESH:D007027', (126, 138))	('activation', 'PosReg', (30, 40))	('juvenile PA', 'Phenotype', 'HP:0005681', (62, 73))	('duplication', 'Var', (14, 25))	('hypothalamic', 'Disease', (126, 138))
203591	31413876	However, it should be noted that, in some cases, mutations in BRAF can be found in diffuse gliomas and malignant astrocytomas, in combination with mutations in other genes, such as CDKN2A or IDH .	('found', 'Reg', (74, 79))	('mutations', 'Var', (49, 58))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('CDKN2', 'Gene', '1029', (181, 186))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('CDKN2', 'Gene', (181, 186))	('IDH', 'Gene', (191, 194))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('malignant astrocytomas', 'Disease', 'MESH:D020339', (103, 125))	('IDH', 'Gene', '3417', (191, 194))	('malignant astrocytomas', 'Disease', (103, 125))	('CDKN2A', 'Gene', (181, 187))	('BRAF', 'Gene', (62, 66))	('CDKN2A', 'Gene', '1029', (181, 187))	('diffuse gliomas', 'Disease', (83, 98))
203592	31413876	According to the multicenter study on SCA, more than 80% of PAs contain mutations in BRAF, with 40% of these cases being presented with a BRAF-KIAA1549 mutation and the remaining 60% being presented with BRAF duplication variants.	('BRAF-KIAA1549', 'Disease', 'None', (138, 151))	('mutations', 'Var', (72, 81))	('BRAF-KIAA1549', 'Disease', (138, 151))	('PAs', 'Disease', (60, 63))	('PAs', 'Chemical', 'MESH:D011478', (60, 63))	('BRAF', 'Gene', (85, 89))
203593	31413876	In addition to PA, deletions in CDKN2A are quite often detected in glioblastomas in adult patients.	('glioblastomas', 'Phenotype', 'HP:0012174', (67, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (67, 80))	('detected', 'Reg', (55, 63))	('CDKN2A', 'Gene', (32, 38))	('glioblastomas', 'Disease', (67, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('deletions', 'Var', (19, 28))
203595	31413876	One of the most important discoveries in the study of gliomas (including astrocytomas) was the identification of mutations in the IDH1 and IDH2 genes encoding NADP+-dependent homodimers of isocitrate dehydrogenases 1 and 2, which are localized in the cytoplasm and mitochondria, respectively, and catalyze oxidative decarboxylation of isocitrate with the formation of alpha-ketoglutarate (alpha-KG).	('IDH2', 'Gene', (139, 143))	('isocitrate', 'Chemical', 'MESH:C034219', (335, 345))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('isocitrate', 'Chemical', 'MESH:C034219', (189, 199))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', (130, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('mutations', 'Var', (113, 122))	('NADP', 'Chemical', 'MESH:D009249', (159, 163))	('alpha-KG', 'Chemical', 'MESH:D007656', (389, 397))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (368, 387))
203598	31413876	In the overwhelming majority of cases (> 90%), the IDH1 mutation is presented with a substitution of arginine to histidine at position 132 (the enzyme active center).	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))	('substitution', 'Var', (85, 97))	('arginine to histidine at position 132', 'Mutation', 'rs121913500', (101, 138))
203599	31413876	The mutant enzyme variant catalyzes the reduction of alpha-KG to 2-hydroxyglutarate (2-HG), a competitive inhibitor of alpha-KG-dependent dioxygenases, thus resulting in genome hypermethylation, which presumably occurs due to inhibition of the TET methylcytosine hydroxylase.	('resulting in', 'Reg', (157, 169))	('2-HG', 'Chemical', 'MESH:C019417', (85, 89))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (65, 83))	('genome', 'MPA', (170, 176))	('variant', 'Var', (18, 25))
203600	31413876	In addition, these mutations can alter the histone methylation level by suppressing cell differentiation and also contribute to the accumulation of the hypoxia-induced factor HIF-1alpha, which affects a number of processes, such as angiogenesis, cell metabolism, growth, differentiation, and apoptosis.	('alter', 'Reg', (33, 38))	('differentiation', 'CPA', (271, 286))	('histone methylation level', 'MPA', (43, 68))	('HIF-1alpha', 'Gene', '3091', (175, 185))	('cell metabolism', 'CPA', (246, 261))	('angiogenesis', 'CPA', (232, 244))	('mutations', 'Var', (19, 28))	('growth', 'CPA', (263, 269))	('suppressing', 'NegReg', (72, 83))	('accumulation', 'PosReg', (132, 144))	('cell differentiation', 'CPA', (84, 104))	('HIF-1alpha', 'Gene', (175, 185))	('apoptosis', 'CPA', (292, 301))	('hypoxia', 'Disease', 'MESH:D000860', (152, 159))	('hypoxia', 'Disease', (152, 159))	('affects', 'Reg', (193, 200))
203601	31413876	Tumors with mutations in IDH also typically carry a mutation in the TP53 gene or 1p/19q codeletion.	('IDH', 'Gene', (25, 28))	('1p/19q', 'Gene', (81, 87))	('mutations', 'Var', (12, 21))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutation', 'Var', (52, 60))	('P53', 'Gene', (69, 72))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('P53', 'Gene', '7157', (69, 72))
203603	31413876	Only a few percents of cases with mutations in IDH1 or IDH2 were also characterized by changes in the PTEN, EGFR, CDKN2A, and CDKN2B genes.	('changes', 'Reg', (87, 94))	('CDKN2A', 'Gene', (114, 120))	('EGFR', 'Gene', '1956', (108, 112))	('IDH1', 'Gene', (47, 51))	('EGFR', 'Gene', (108, 112))	('CDKN2B', 'Gene', (126, 132))	('PTEN', 'Gene', (102, 106))	('IDH2', 'Gene', (55, 59))	('CDKN2B', 'Gene', '1030', (126, 132))	('PTEN', 'Gene', '5728', (102, 106))	('mutations', 'Var', (34, 43))
203604	31413876	For instance, the study focused on grades II and III SCA (n = 9) revealed no IDH1 R132H mutation, which is the most frequent mutation in intracranial astrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('R132H', 'Mutation', 'rs121913500', (82, 87))	('R132H', 'Var', (82, 87))	('IDH1', 'Gene', (77, 81))
203607	31413876	In addition to the accompanying TP53 and 1p/19q mutations, gliomas with mutations in IDH are distinguished by the presence of mutations in the TERT and ATRX genes, which are involved in telomere elongation.	('mutations', 'Var', (72, 81))	('gliomas', 'Disease', (59, 66))	('TERT', 'Gene', (143, 147))	('TERT', 'Gene', '7015', (143, 147))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('mutations', 'Var', (126, 135))	('ATRX', 'Gene', (152, 156))	('IDH', 'Gene', (85, 88))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
203608	31413876	The ATRX mutation is considered a hallmark of astrocytic tumors; it is closely associated with the IDH mutation in diffuse astrocytomas and secondary glioblastomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('associated', 'Reg', (79, 89))	('secondary glioblastomas', 'Disease', (140, 163))	('glioblastomas', 'Phenotype', 'HP:0012174', (150, 163))	('ATRX', 'Gene', (4, 8))	('hallmark of astrocytic tumors', 'Disease', 'MESH:D001254', (34, 63))	('hallmark of astrocytic tumors', 'Disease', (34, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('diffuse astrocytomas', 'Disease', (115, 135))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutation', 'Var', (103, 111))	('IDH', 'Gene', (99, 102))
203609	31413876	Mutations in ATRX lead to activity loss by its protein product, which causes typical developmental disorders, such as mental retardation, urogenital abnormalities and alpha-thalassemia.	('urogenital abnormalities', 'Disease', (138, 162))	('protein', 'Protein', (47, 54))	('developmental disorders', 'Disease', 'MESH:D002658', (85, 108))	('alpha-thalassemia', 'Disease', 'MESH:D017085', (167, 184))	('ATRX', 'Gene', (13, 17))	('mental retardation', 'Disease', (118, 136))	('mental retardation', 'Phenotype', 'HP:0001249', (118, 136))	('loss', 'NegReg', (35, 39))	('mental retardation', 'Disease', 'MESH:D008607', (118, 136))	('Mutations', 'Var', (0, 9))	('developmental disorders', 'Disease', (85, 108))	('causes', 'Reg', (70, 76))	('urogenital abnormalities', 'Disease', 'MESH:D014564', (138, 162))	('urogenital abnormalities', 'Phenotype', 'HP:0000119', (138, 162))	('alpha-thalassemia', 'Disease', (167, 184))	('activity', 'MPA', (26, 34))
203611	31413876	The ATRX mutation is found in pilocytic astrocytomas with anaplasia signs .	('mutation', 'Var', (9, 17))	('anaplasia', 'Disease', 'MESH:D000708', (58, 67))	('anaplasia', 'Disease', (58, 67))	('ATRX', 'Gene', (4, 8))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (30, 51))	('pilocytic astrocytomas', 'Disease', (30, 52))	('found', 'Reg', (21, 26))	('astrocytoma', 'Phenotype', 'HP:0009592', (40, 51))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (30, 52))
203616	31413876	Moreover, two mutually exclusive variants, namely substitution of lysine to methionine at position 27 (K27M) and substitution of glycine to arginine or valine at position 34 (G34R/V), are found in such cases .	('G34R', 'Var', (175, 179))	('substitution', 'Var', (50, 62))	('lysine to methionine at position 27', 'Mutation', 'p.K27M', (66, 101))	('K27M', 'Mutation', 'p.K27M', (103, 107))	('found', 'Reg', (188, 193))	('glycine', 'Chemical', 'MESH:D005998', (129, 136))	('G34R', 'SUBSTITUTION', 'None', (175, 179))
203617	31413876	Trimethylation of Lys27 is associated with decreased gene expression, while acetylation activates transcription.	('Lys27', 'Gene', (18, 23))	('Lys27', 'Chemical', '-', (18, 23))	('activates', 'PosReg', (88, 97))	('acetylation', 'MPA', (76, 87))	('Trimethylation', 'Var', (0, 14))	('decreased', 'NegReg', (43, 52))	('gene expression', 'MPA', (53, 68))	('transcription', 'MPA', (98, 111))
203618	31413876	Certain mutations in H3F3A are found in tumors of specific localization with a specific level of expression of OLIG1, OLIG2, and FOXG1 transcription factors.	('OLIG2', 'Gene', '10215', (118, 123))	('FOXG1', 'Gene', (129, 134))	('OLIG1', 'Gene', '116448', (111, 116))	('mutations', 'Var', (8, 17))	('FOXG1', 'Gene', '2290', (129, 134))	('H3F3A', 'Gene', (21, 26))	('OLIG1', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('found', 'Reg', (31, 36))	('OLIG2', 'Gene', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
203619	31413876	Gliomas with different mutations in H3F3A are believed to have different cellular origins.	('H3F3A', 'Gene', (36, 41))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('mutations', 'Var', (23, 32))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))
203620	31413876	The G34R/V mutation is mainly found in children diagnosed with intracranial non-midline glioblastomas; the frequency of this mutation is 20%-30%.	('G34R', 'SUBSTITUTION', 'None', (4, 8))	('G34R', 'Var', (4, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('intracranial non-midline glioblastomas', 'Disease', (63, 101))	('intracranial non-midline glioblastomas', 'Disease', 'MESH:D005909', (63, 101))	('glioblastomas', 'Phenotype', 'HP:0012174', (88, 101))
203621	31413876	The K27M mutation is mainly found in malignant astrocytomas of the thalamus, and brainstem and the spinal cord are prevalent in adolescents and children.	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('malignant astrocytomas of the thalamus', 'Disease', (37, 75))	('K27M', 'SUBSTITUTION', 'None', (4, 8))	('malignant astrocytomas of the thalamus', 'Disease', 'MESH:D020339', (37, 75))	('K27M', 'Var', (4, 8))
203622	31413876	The K27M mutation is associated with high tumor aggressivity, even if it is classified histologically as low-grade astrocytoma.	('K27M', 'SUBSTITUTION', 'None', (4, 8))	('high tumor aggressivity', 'Disease', (37, 60))	('high tumor aggressivity', 'Disease', 'MESH:D001523', (37, 60))	('K27M', 'Var', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('astrocytoma', 'Phenotype', 'HP:0009592', (115, 126))
203623	31413876	However, according to some data, the prognosis of thalamic gliomas in adults carrying this mutation may not appear worse than that in patients without the aberration, which suggests heterogeneity of this molecular subgroup of diffuse gliomas.	('mutation', 'Var', (91, 99))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('thalamic gliomas', 'Disease', 'MESH:D013786', (50, 66))	('thalamic gliomas', 'Disease', (50, 66))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
203624	31413876	The K27M mutation is often associated with mutations in TP53 (thalamic gliomas) and chromosome 10 monosomy, while it is rarely diagnosed together with mutations in BRAF (V600E) and ATRX and never found together with mutations in IDH1 and EGFR .	('K27M', 'SUBSTITUTION', 'None', (4, 8))	('associated', 'Reg', (27, 37))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('mutations', 'Var', (43, 52))	('V600E', 'Var', (170, 175))	('TP53', 'Gene', (56, 60))	('V600E', 'SUBSTITUTION', 'None', (170, 175))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('K27M', 'Var', (4, 8))
203625	31413876	demonstrated that the ATRX mutation is much more frequently associated with the G34R/V mutation than with the K27M mutation in H3F3A.	('ATRX', 'Gene', (22, 26))	('K27M', 'SUBSTITUTION', 'None', (110, 114))	('G34R', 'SUBSTITUTION', 'None', (80, 84))	('G34R', 'Var', (80, 84))	('K27M', 'Var', (110, 114))	('associated', 'Reg', (60, 70))
203626	31413876	The K27M mutation in H3F3A in patients with spinal cord astrocytomas is associated with grade III and IV tumors.	('K27M', 'SUBSTITUTION', 'None', (4, 8))	('IV tumors', 'Disease', 'MESH:D009369', (102, 111))	('associated', 'Reg', (72, 82))	('IV tumors', 'Disease', (102, 111))	('H3F3A', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('spinal cord astrocytomas', 'Disease', (44, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (56, 67))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('K27M', 'Var', (4, 8))	('grade III', 'Disease', (88, 97))
203627	31413876	revealed the K27M mutation in 77.8% of cases (n = 9) of spinal cord glioblastomas.	('K27M', 'SUBSTITUTION', 'None', (13, 17))	('spinal cord glioblastomas', 'Disease', 'MESH:D005909', (56, 81))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('K27M', 'Var', (13, 17))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('spinal cord glioblastomas', 'Disease', (56, 81))
203628	31413876	It should be noted that K27M is not present in other types of malignant tumors and, therefore, may be pathognomonic for the primary spinal glioblastoma and may also serve as an indicator of the worst prognosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('primary spinal glioblastoma', 'Disease', (124, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('K27M', 'SUBSTITUTION', 'None', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('pathognomonic', 'Reg', (102, 115))	('K27M', 'Var', (24, 28))
203629	31413876	Mutations in TP53 provoke a more aggressive growth of grade I-II astrocytomas: i.e., they are considered an unfavorable prognostic factor.	('TP53', 'Gene', (13, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('Mutations', 'Var', (0, 9))	('I-II astrocytomas', 'Disease', (60, 77))	('I-II astrocytomas', 'Disease', 'MESH:D001254', (60, 77))
203630	31413876	It is an interesting fact that, in contrast to intracranial glioblastomas, a TP53 mutation in spinal cord glioblastomas is often detected in the absence of a IDH1 mutation.	('glioblastomas', 'Phenotype', 'HP:0012174', (106, 119))	('mutation', 'Var', (82, 90))	('intracranial glioblastomas', 'Disease', 'MESH:D005909', (47, 73))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('detected', 'Reg', (129, 137))	('intracranial glioblastomas', 'Disease', (47, 73))	('TP53', 'Gene', (77, 81))	('spinal cord glioblastomas', 'Disease', (94, 119))
203632	31413876	Atypical migration of progenitor cells carrying a PTEN mutation can lead to cerebellar and hippocampal dysplasia, followed by gliomagenesis.	('cerebellar', 'Disease', (76, 86))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('Atypical migration', 'Phenotype', 'HP:0002269', (0, 18))	('hippocampal dysplasia', 'Disease', 'MESH:D004828', (91, 112))	('lead to', 'Reg', (68, 75))	('PTEN', 'Gene', (50, 54))	('gliomagenesis', 'Disease', (126, 139))	('hippocampal dysplasia', 'Disease', (91, 112))	('mutation', 'Var', (55, 63))	('hippocampal dysplasia', 'Phenotype', 'HP:0025101', (91, 112))
203633	31413876	In the latter case, PTEN mutations are extremely rarely found in PA but are present in 18% of anaplastic astrocytomas and up to 40% of glioblastomas, mainly the primary ones.	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (94, 117))	('mutations', 'Var', (25, 34))	('glioblastomas', 'Phenotype', 'HP:0012174', (135, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('glioblastomas', 'Disease', (135, 148))	('anaplastic astrocytomas', 'Disease', (94, 117))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (94, 116))	('present', 'Reg', (76, 83))	('PTEN', 'Gene', (20, 24))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
203636	31413876	Most EGFR mutations in gliomas, including EGFRvIII, affect the extracellular domain of the receptor, while being mainly associated with the intracellular domain in non-glioma tumors.	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('associated', 'Reg', (120, 130))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('non-glioma tumors', 'Disease', 'MESH:D005910', (164, 181))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('non-glioma tumors', 'Disease', (164, 181))	('EGFR', 'Gene', (5, 9))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('affect', 'Reg', (52, 58))	('extracellular domain of the', 'MPA', (63, 90))
203637	31413876	The product of EGFRvIII mutation is a constitutively active EGFR variant stimulating tumor angiogenesis in malignant gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('malignant gliomas', 'Disease', (107, 124))	('EGFRvIII', 'Gene', (15, 23))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('malignant gliomas', 'Disease', 'MESH:D005910', (107, 124))	('stimulating', 'PosReg', (73, 84))	('mutation', 'Var', (24, 32))	('variant', 'Var', (65, 72))	('tumor angiogenesis', 'CPA', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('EGFR', 'Gene', (60, 64))
203638	31413876	Amplification and overexpression of EGFR is considered to be associated with a high degree of glioma malignancy, aneuploidy, and proliferative index, while a mutation in EGFRvIII is potentially associated with an aggressive disease course, refractoriness to therapy, and poor prognosis.	('Amplification', 'Var', (0, 13))	('EGFRvIII', 'Gene', (170, 178))	('glioma malignancy', 'Disease', 'MESH:D005910', (94, 111))	('aneuploidy', 'Disease', 'MESH:D000782', (113, 123))	('overexpression', 'PosReg', (18, 32))	('glioma malignancy', 'Disease', (94, 111))	('aggressive disease', 'Disease', 'MESH:D001523', (213, 231))	('mutation', 'Var', (158, 166))	('proliferative', 'MPA', (129, 142))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('aggressive disease', 'Disease', (213, 231))	('aneuploidy', 'Disease', (113, 123))	('EGFR', 'Gene', (36, 40))	('associated', 'Reg', (61, 71))	('associated with', 'Reg', (194, 209))
203639	31413876	A vast number of studies conducted over the last 10-15 years have significantly improved our under standing of the mechanisms of the onset and progression of CNS glial tumors and revealed the key genes whose mutations or aberration can be considered potential prognostic and diagnostic factors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('CNS glial tumors', 'Disease', (158, 174))	('CNS glial tumors', 'Disease', 'MESH:D005910', (158, 174))	('mutations', 'Var', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('improved', 'PosReg', (80, 88))	('aberration', 'Var', (221, 231))
203641	31413876	For example:   - pilocytic astrocytomas mainly contain mutations in the BRAF, NF1 and CDKN2A genes;   - mutations in IDH1, ATRX and TP53 are mainly associated with primary glioblastomas and grade II-III astrocytomas (often found in combination with each other);   - mutations in H3F3A are mainly diagnosed in grades III-IV astrocytomas and, apparently, (in the case of a K27M mutation) are pathognomonic for the primary spinal glioblastomas;   - mutations in EGFR and PTEN are mostly associated with primary glioblastoma as well as anaplastic astrocytomas; and   - a mutation in PDGFRA is predominantly found in secondary but not primary glioblastomas.	('K27M', 'SUBSTITUTION', 'None', (371, 375))	('PDGFRA', 'Gene', '5156', (579, 585))	('glioblastomas', 'Phenotype', 'HP:0012174', (427, 440))	('associated', 'Reg', (484, 494))	('glioblastoma', 'Phenotype', 'HP:0012174', (427, 439))	('glioblastomas', 'Phenotype', 'HP:0012174', (172, 185))	('astrocytoma', 'Phenotype', 'HP:0009592', (543, 554))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (203, 214))	('NF1', 'Gene', '4763', (78, 81))	('glioblastomas', 'Phenotype', 'HP:0012174', (638, 651))	('NF1', 'Gene', (78, 81))	('PDGFR', 'Gene', (579, 584))	('K27M', 'Var', (371, 375))	('glioblastoma', 'Phenotype', 'HP:0012174', (638, 650))	('PDGFR', 'Gene', '5159', (579, 584))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))	('associated', 'Reg', (148, 158))	('EGFR', 'Gene', (459, 463))	('primary glioblastoma', 'Disease', (500, 520))	('PTEN', 'Gene', (468, 472))	('anaplastic astrocytomas', 'Disease', (532, 555))	('astrocytoma', 'Phenotype', 'HP:0009592', (323, 334))	('mutations', 'Var', (446, 455))	('glioblastoma', 'Phenotype', 'HP:0012174', (508, 520))	('PDGFRA', 'Gene', (579, 585))
203642	31413876	The mutation V600E in BRAF (in children and adolescents) serves as a positive prognostic marker of grades I and II astrocytomas.	('BRAF', 'Gene', (22, 26))	('V600E', 'Var', (13, 18))	('V600E', 'SUBSTITUTION', 'None', (13, 18))	('astrocytoma', 'Phenotype', 'HP:0009592', (115, 126))
203643	31413876	H3F3A K27M, TP53, EGFR, and PTEN are mutations that worsen the disease course and the overall prognosis.	('PTEN', 'Gene', (28, 32))	('K27M', 'SUBSTITUTION', 'None', (6, 10))	('H3F3A', 'Gene', (0, 5))	('EGFR', 'Gene', (18, 22))	('worsen', 'PosReg', (52, 58))	('K27M', 'Var', (6, 10))	('TP53', 'Gene', (12, 16))	('disease course', 'CPA', (63, 77))
203644	31413876	Such tumors are usually aggressive and similar to primary glioblastomas in their molecular characteristics (aberrations in EGFR, PTEN, NF1, CDKN2A/B).	('EGFR', 'Gene', (123, 127))	('aberrations', 'Var', (108, 119))	('NF1', 'Gene', (135, 138))	('glioblastomas', 'Phenotype', 'HP:0012174', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('PTEN', 'Gene', (129, 133))	('CDKN2A/B', 'Gene', '1029;1030', (140, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('CDKN2A/B', 'Gene', (140, 148))
203645	31413876	To date, there is no information on any identification of markers such as IDH1/2, H3F3A G34R/V, and FGFR2 in SCA.	('FGFR2', 'Gene', (100, 105))	('H3F3A', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (100, 105))	('IDH1/2', 'Gene', (74, 80))	('SCA', 'Disease', (109, 112))	('G34R', 'SUBSTITUTION', 'None', (88, 92))	('G34R', 'Var', (88, 92))	('IDH1/2', 'Gene', '3417;3418', (74, 80))
203646	31413876	Pilocytic astrocytomas of the spinal cord were shown to be associated with mutations in the BRAF, CDKN2, NF1, and PTEN genes, while malignant grades III-IV SCA variants are associated primarily with H3F3A K27M (mostly young patients and children), TP53, and PTEN [32].	('Pilocytic astrocytomas', 'Disease', (0, 22))	('K27M', 'Var', (205, 209))	('NF1', 'Gene', (105, 108))	('CDKN2', 'Gene', (98, 103))	('SCA', 'Gene', (156, 159))	('BRAF', 'Gene', (92, 96))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('PTEN', 'Gene', (114, 118))	('associated', 'Reg', (59, 69))	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (0, 22))	('mutations', 'Var', (75, 84))	('associated', 'Reg', (173, 183))	('K27M', 'SUBSTITUTION', 'None', (205, 209))	('variants', 'Var', (160, 168))
203647	31413876	For example, partial efficacy of selective inhibitors of isocitrate dehydrogenase with the IDH1 R132H mutation has been shown both in vitro and in glioma models.	('isocitrate dehydrogenase', 'Enzyme', (57, 81))	('R132H', 'Var', (96, 101))	('R132H', 'SUBSTITUTION', 'None', (96, 101))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('IDH1', 'Gene', (91, 95))
203651	30468298	Markers for DVL1,DVL2 and DVL3 were used to detect microsatellite instability (MSI) and gross deletions (LOH), while immunohistochemistry and immunoreactivity score were used to determine the signal strengths of the three DVL proteins and transcription factors of the pathway, TCF1 and LEF1.	('TCF1', 'Gene', '6932', (277, 281))	('LEF1', 'Gene', (286, 290))	('DVL3', 'Gene', (26, 30))	('DVL1', 'Gene', (12, 16))	('gross deletions', 'Var', (88, 103))	('microsatellite instability', 'MPA', (51, 77))	('DVL3', 'Gene', '1857', (26, 30))	('DVL1', 'Gene', '1855', (12, 16))	('LEF1', 'Gene', '51176', (286, 290))	('TCF1', 'Gene', (277, 281))	('MSI', 'Gene', '5928', (79, 82))	('MSI', 'Gene', (79, 82))
203654	30468298	LOHs of DVL3 gene were significantly associated with grade IV tumours (P = 0.007).	('DVL3', 'Gene', (8, 12))	('LOHs', 'Var', (0, 4))	('IV tumours', 'Disease', (59, 69))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('IV tumours', 'Disease', 'MESH:D009369', (59, 69))	('DVL3', 'Gene', '1857', (8, 12))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('associated', 'Reg', (37, 47))
203670	30468298	In the present investigation, we searched for changes of all three human DVL genes and proteins and tried to define their involvement in specific astrocytoma grade.	('changes', 'Var', (46, 53))	('astrocytoma', 'Disease', 'MESH:D001254', (146, 157))	('astrocytoma', 'Disease', (146, 157))	('DVL genes', 'Gene', (73, 82))	('astrocytoma', 'Phenotype', 'HP:0009592', (146, 157))	('human', 'Species', '9606', (67, 72))
203697	30468298	PP score was determined as follows: no immunopositivity in tumour cells = score 0; 1%-25% positive cells = score 1; >25%-50% = score 2; >50%-85% = score 3; >85% = score 4.	('>25%-50%', 'Var', (116, 124))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('>50%-85', 'Var', (136, 143))	('tumour', 'Disease', (59, 65))
203701	30468298	Genetic changes publicly reported on DVL genes were assessed from cBioPortal and COSMIC databases,24, 25 while survival plots were performed from GEPIA database.26  Our study explored DVL1, DVL2 and DVL3 gene alterations in association with tumour grade.	('DVL3', 'Gene', '1857', (199, 203))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('DVL2', 'Gene', (190, 194))	('DVL3', 'Gene', (199, 203))	('DVL1', 'Gene', '1855', (184, 188))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('alterations', 'Var', (209, 220))	('tumour', 'Disease', (241, 247))	('association', 'Reg', (224, 235))	('DVL1', 'Gene', (184, 188))
203704	30468298	Marker D1S468 showed a substantial rate of microsatellite instability (MSI) across all astrocytoma grades, pilocytic (grade I) showed 21.4%, diffuse (grade II) 53.8%, anaplastic (grade III) 36.4% and glioblastoma (grade IV) 17.1%.	('glioblastoma', 'Phenotype', 'HP:0012174', (200, 212))	('astrocytoma', 'Disease', 'MESH:D001254', (87, 98))	('glioblastoma', 'Disease', (200, 212))	('D1S468', 'Var', (7, 13))	('MSI', 'Gene', '5928', (71, 74))	('MSI', 'Gene', (71, 74))	('pilocytic', 'Disease', (107, 116))	('astrocytoma', 'Disease', (87, 98))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('anaplastic', 'Disease', (167, 177))	('microsatellite instability', 'MPA', (43, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (200, 212))	('diffuse', 'Disease', (141, 148))
203707	30468298	Genetic changes were significantly more distributed to glioblastoma group (P = 0.020).	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))	('Genetic changes', 'Var', (0, 15))	('glioblastoma', 'Disease', (55, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))
203711	30468298	For DVL2 gene analysis marker D17S960 was selected and it showed a lower rate of MSI in all tumour grades, 7.1% in grade I, 15.4% in grade II, 0% in grade III and 8.6% in grade VI.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('MSI', 'Gene', (81, 84))	('MSI', 'Gene', '5928', (81, 84))	('D17S960', 'Var', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('lower', 'NegReg', (67, 72))
203713	30468298	DVL3 gene was analysed with D3S1262 marker (Figure 1C).	('D3S1262 marker', 'Var', (28, 42))	('DVL3', 'Gene', '1857', (0, 4))	('DVL3', 'Gene', (0, 4))
203714	30468298	Microsatellite instability rate was again relatively constant across different grades (grade I with 21.4%; grade II with 15.4%; grade III with 14.3% and grade IV with 14.3%) while gross deletions were associated only to higher malignancy grades (grade III with 18.2% and grade IV with 31.2%) (Table 2).	('Microsatellite instability', 'MPA', (0, 26))	('gross deletions', 'Var', (180, 195))	('malignancy', 'Disease', 'MESH:D009369', (227, 237))	('malignancy', 'Disease', (227, 237))
203715	30468298	Statistical analysis revealed that LOH of DVL3 gene was significantly more frequent in glioblastomas as compared with astrocytomas of lower grades (P = 0.007).	('DVL3', 'Gene', '1857', (42, 46))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('DVL3', 'Gene', (42, 46))	('astrocytomas', 'Disease', 'MESH:D001254', (118, 130))	('glioblastomas', 'Phenotype', 'HP:0012174', (87, 100))	('LOH', 'Var', (35, 38))	('glioblastomas', 'Disease', 'MESH:D005909', (87, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('astrocytomas', 'Disease', (118, 130))	('glioblastomas', 'Disease', (87, 100))
203721	30468298	Nevertheless, low number of cases with amplified DVL1 (0.19%) were also reported.	('DVL1', 'Gene', '1855', (49, 53))	('DVL1', 'Gene', (49, 53))	('amplified', 'Var', (39, 48))
203722	30468298	Furthermore, deletions of DVL1 were found in seven glioblastomas and deletions of DVL2 in two glioblastomas, while deletions of DVL3 were not reported.	('glioblastomas', 'Disease', 'MESH:D005909', (94, 107))	('DVL3', 'Gene', '1857', (128, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('DVL1', 'Gene', (26, 30))	('glioblastomas', 'Disease', (51, 64))	('glioblastomas', 'Disease', (94, 107))	('found', 'Reg', (36, 41))	('deletions', 'Var', (13, 22))	('deletions', 'Var', (69, 78))	('DVL2', 'Gene', (82, 86))	('DVL3', 'Gene', (128, 132))	('glioblastomas', 'Phenotype', 'HP:0012174', (51, 64))	('glioblastomas', 'Phenotype', 'HP:0012174', (94, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('DVL1', 'Gene', '1855', (26, 30))	('glioblastomas', 'Disease', 'MESH:D005909', (51, 64))
203723	30468298	It is also obvious that mutational burden is much more frequent in glioblastomas than low-grade tumours and those amplifications are particularly associated to DVL3 gene and to glioblastomas.	('tumours', 'Disease', (96, 103))	('glioblastomas', 'Disease', 'MESH:D005909', (67, 80))	('glioblastomas', 'Phenotype', 'HP:0012174', (67, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (177, 190))	('glioblastomas', 'Disease', (67, 80))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('glioblastomas', 'Disease', (177, 190))	('DVL3', 'Gene', '1857', (160, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('mutational burden', 'Var', (24, 41))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('associated', 'Reg', (146, 156))	('DVL3', 'Gene', (160, 164))	('frequent', 'Reg', (55, 63))	('glioblastomas', 'Phenotype', 'HP:0012174', (177, 190))
203776	30468298	Especially rare are studies about the roles of DVL1, DVL2 and DVL3 in human astrocytic brain tumours.27, 28, 29 The results of the present study showed that genetic and protein changes of all three Dishevelleds have distinct roles in the process of astrocytoma formation and progression.	('changes', 'Var', (177, 184))	('astrocytic brain tumours', 'Disease', 'MESH:D001254', (76, 100))	('brain tumours', 'Phenotype', 'HP:0030692', (87, 100))	('DVL3', 'Gene', '1857', (62, 66))	('Dishevelled', 'Gene', (198, 209))	('DVL1', 'Gene', (47, 51))	('astrocytic brain tumours', 'Disease', (76, 100))	('Dishevelled', 'Gene', '32078', (198, 209))	('human', 'Species', '9606', (70, 75))	('DVL3', 'Gene', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('astrocytoma', 'Disease', 'MESH:D001254', (249, 260))	('brain tumour', 'Phenotype', 'HP:0030692', (87, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('DVL1', 'Gene', '1855', (47, 51))	('astrocytoma', 'Disease', (249, 260))	('astrocytoma', 'Phenotype', 'HP:0009592', (249, 260))	('roles', 'Reg', (225, 230))
203778	30468298	Microsatellite instability at DVL1 locus was detected in 28.6% of pilocytic, 61.5% diffuse, 45.5% anaplastic astrocytomas and 34.3% of glioblastomas.	('detected', 'Reg', (45, 53))	('glioblastomas', 'Phenotype', 'HP:0012174', (135, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('pilocytic', 'Disease', (66, 75))	('glioblastomas', 'Disease', (135, 148))	('DVL1', 'Gene', (30, 34))	('glioblastomas', 'Disease', 'MESH:D005909', (135, 148))	('DVL1', 'Gene', '1855', (30, 34))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (98, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('diffuse', 'Disease', (83, 90))	('Microsatellite instability', 'Var', (0, 26))	('anaplastic astrocytomas', 'Disease', (98, 121))
203785	30468298	It has been known that the increase of mutation accumulation results in an acceleration of the tumour cell evolution.30 But besides having effect on cell proliferation, the increased rate of mutations within tumour cells could also lead to cell death.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Disease', (208, 214))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (191, 200))	('tumour', 'Disease', (95, 101))	('cell death', 'CPA', (240, 250))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('lead to', 'Reg', (232, 239))
203786	30468298	The lower frequencies of MSI found in glioblastomas for all three DVL homologs could be explained by the inability of tumour cells to proceed into much desired apoptosis.31  As MSI results from impaired DNA mismatch repair (MMR), several groups32, 33, 34, 35, 36 analysed MMR genes in astrocytoma of different grades but reported low rate of mutations.	('MSI', 'Gene', '5928', (177, 180))	('MSI', 'Gene', (177, 180))	('MSI', 'Gene', '5928', (25, 28))	('astrocytoma', 'Disease', 'MESH:D001254', (285, 296))	('glioblastomas', 'Phenotype', 'HP:0012174', (38, 51))	('astrocytoma', 'Disease', (285, 296))	('astrocytoma', 'Phenotype', 'HP:0009592', (285, 296))	('inability of tumour', 'Disease', (105, 124))	('glioblastomas', 'Disease', 'MESH:D005909', (38, 51))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('MSI', 'Gene', (25, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('impaired DNA', 'Var', (194, 206))	('glioblastomas', 'Disease', (38, 51))	('MMR', 'Gene', (272, 275))	('inability of tumour', 'Disease', 'MESH:D016388', (105, 124))
203788	30468298	Microsatellites are generally found in non-coding regions and their role in various malignant diseases is still unexplained.37, 38 Establishing a pattern of characteristic microsatellite loci in tumours could have predictive potential for tumour behaviour.	('microsatellite loci', 'Var', (172, 191))	('malignant diseases', 'Disease', 'MESH:D009369', (84, 102))	('malignant diseases', 'Disease', (84, 102))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Disease', (239, 245))	('tumour', 'Disease', (195, 201))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
203789	30468298	The results on gross deletions of the three human DVL genes indicate that LOHs of DVL1 and DVL3 genes were confined only to the high-grade malignant group (grades III and IV) while LOHs of DVL2 were appearing across all grades.	('human', 'Species', '9606', (44, 49))	('DVL', 'Gene', (50, 53))	('DVL3', 'Gene', (91, 95))	('DVL1', 'Gene', (82, 86))	('deletions', 'Var', (21, 30))	('DVL3', 'Gene', '1857', (91, 95))	('DVL1', 'Gene', '1855', (82, 86))
203791	30468298	Statistical analysis pointed out that deletions of DVL3 gene were significantly associated to the highest grade (P = 0.007) and could be connected to tumour progression.	('DVL3', 'Gene', '1857', (51, 55))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('DVL3', 'Gene', (51, 55))	('tumour', 'Disease', (150, 156))	('highest grade', 'CPA', (98, 111))	('deletions', 'Var', (38, 47))	('associated', 'Reg', (80, 90))	('connected to', 'Reg', (137, 149))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
203794	30468298	Genetic changes of DVL3 gene suggest its involvement in the process of glioma progression.	('DVL3', 'Gene', (19, 23))	('Genetic changes', 'Var', (0, 15))	('glioma', 'Disease', (71, 77))	('DVL3', 'Gene', '1857', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('involvement', 'Reg', (41, 52))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
203796	30468298	Statistical analysis revealed that LOH of DVL3 was significantly more frequent in glioblastomas than in lower-grade tumours (P = 0.007).	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('DVL3', 'Gene', '1857', (42, 46))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('glioblastomas', 'Disease', 'MESH:D005909', (82, 95))	('DVL3', 'Gene', (42, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('LOH', 'Var', (35, 38))	('tumours', 'Disease', (116, 123))	('glioblastomas', 'Disease', (82, 95))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
203797	30468298	We also found the amplification of DVL3 gene in 8.6% of glioblastoma which could indicate different cellular roles for this gene.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('DVL3', 'Gene', '1857', (35, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('glioblastoma', 'Disease', (56, 68))	('DVL3', 'Gene', (35, 39))	('amplification', 'Var', (18, 31))
203798	30468298	Hu et al44 detected 30% of glioblastomas with LOH in the chromosomal region 3q where DVL3 is located.	('glioblastomas', 'Disease', (27, 40))	('DVL3', 'Gene', (85, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('glioblastomas', 'Phenotype', 'HP:0012174', (27, 40))	('LOH', 'Var', (46, 49))	('glioblastomas', 'Disease', 'MESH:D005909', (27, 40))	('DVL3', 'Gene', '1857', (85, 89))
203800	30468298	However, the mutations that have been found are much more frequent in glioblastomas than low-grade tumours.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastomas', 'Disease', (70, 83))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('tumours', 'Disease', (99, 106))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('mutations', 'Var', (13, 22))	('frequent', 'Reg', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))
203803	30468298	Loss of heterozygosity was found to be often present in anaplastic astrocytoma and glioblastoma and therefore could be involved in the process of tumour progression as a background mechanism for inactivation of tumour suppressor genes.	('involved', 'Reg', (119, 127))	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumour', 'Disease', (146, 152))	('Loss of heterozygosity', 'Var', (0, 22))	('tumour', 'Disease', (211, 217))	('anaplastic astrocytoma', 'Disease', (56, 78))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (56, 78))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('astrocytoma', 'Phenotype', 'HP:0009592', (67, 78))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
203812	30468298	We also noticed that in tumours with low DVL1 expression, the signal was predominantly localized in the cytoplasm or in the cytoplasm and cell membrane, while in those with moderate and strong expression, the signal was confined to cytoplasm and nucleus (P < 0.001).	('tumours', 'Disease', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('low', 'Var', (37, 40))	('DVL1', 'Gene', (41, 45))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('expression', 'MPA', (46, 56))	('DVL1', 'Gene', '1855', (41, 45))
203817	30468298	The authors confirmed the role of DVL2 in human glioblastoma by DVL2 gene attenuation using RNAi.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('human', 'Species', '9606', (42, 47))	('gene', 'Var', (69, 73))	('DVL2', 'Gene', (64, 68))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))
203827	30468298	As the correlation between the decreased protein expression of DVL3 and the presence of gross deletions has not been established, there is a possibility that the observed LOHs are the reflection of tumour heterogeneity occurring only in certain glioblastoma subtypes.	('tumour', 'Disease', (198, 204))	('glioblastoma', 'Disease', (245, 257))	('DVL3', 'Gene', '1857', (63, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (245, 257))	('protein expression', 'MPA', (41, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (245, 257))	('decreased', 'NegReg', (31, 40))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('DVL3', 'Gene', (63, 67))	('deletions', 'Var', (94, 103))	('tumour', 'Disease', 'MESH:D009369', (198, 204))
203843	30468298	Double knockout of DVL1 and DVL3 did not display neural tube defects which indicate that each DVL has a unique role to play.	('neural tube defects', 'Disease', 'MESH:D009436', (49, 68))	('DVL1', 'Gene', (19, 23))	('DVL3', 'Gene', '1857', (28, 32))	('DVL3', 'Gene', (28, 32))	('DVL1', 'Gene', '1855', (19, 23))	('Double knockout', 'Var', (0, 15))	('neural tube defects', 'Phenotype', 'HP:0045005', (49, 68))	('neural tube defects', 'Disease', (49, 68))
203844	30468298	Another point in favour of different roles is the aberrant expression of DVL genes linked to different human disorders.	('aberrant', 'Var', (50, 58))	('DVL genes', 'Gene', (73, 82))	('human', 'Species', '9606', (103, 108))
203912	29358915	By this procedure, ADC maps at low b-values (ADC0,200) and high b-values (ADC200,1000) were generated.	('rat', 'Species', '10116', (96, 99))	('b-values', 'MPA', (35, 43))	('ADC0,200', 'Var', (45, 53))	('ADC200,1000', 'Var', (74, 85))
204019	28096729	As in nephrogenic systemic fibrosis, the macrocyclic gadolinium chelates are more stable and, therefore, less accumulated in the brain than the linear chelates.	('less', 'NegReg', (105, 109))	('nephrogenic systemic fibrosis', 'Disease', (6, 35))	('nephrogenic systemic fibrosis', 'Disease', 'MESH:D054989', (6, 35))	('accumulated', 'MPA', (110, 121))	('macrocyclic', 'Var', (41, 52))	('gadolinium', 'Chemical', 'MESH:D005682', (53, 63))
204159	33546237	Low grade papillary urothelial carcinoma Ta, Hematoxylin and eosin, x100 Low grade papillary urothelial carcinoma Ta, Sema3A, x100 Cells in the basal layer of the mucosa show light Sema3A staining.	('Sema3A', 'Gene', (181, 187))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (83, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('Sema3A', 'Gene', (118, 124))	('x100', 'Var', (126, 130))	('papillary urothelial carcinoma Ta', 'Disease', (10, 43))	('papillary urothelial carcinoma Ta', 'Disease', (83, 116))	('Sema3A', 'Gene', '10371', (181, 187))	('papillary urothelial carcinoma Ta', 'Disease', 'MESH:D002291', (83, 116))	('Hematoxylin', 'Chemical', 'MESH:D006416', (45, 56))	('eosin', 'Chemical', 'MESH:D004801', (61, 66))	('papillary urothelial carcinoma Ta', 'Disease', 'MESH:D002291', (10, 43))	('papillary urothelial carcinoma', 'Phenotype', 'HP:0006766', (10, 40))	('Sema3A', 'Gene', '10371', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
204160	33546237	High grade urothelial carcinoma Ta, Hematoxylin and eosin, x200 High grade urothelial carcinoma Ta, Sema3A, x200 Sama3A staining is intense in the entire thickness of the mucosa without any change in stain intensity between the different urothelial layers.	('urothelial carcinoma Ta', 'Disease', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Hematoxylin', 'Chemical', 'MESH:D006416', (36, 47))	('eosin', 'Chemical', 'MESH:D004801', (52, 57))	('Sema3A', 'Gene', (100, 106))	('urothelial carcinoma Ta', 'Disease', 'MESH:D014523', (11, 34))	('urothelial carcinoma Ta', 'Disease', (11, 34))	('x200', 'Var', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('x200 Sama3A', 'Var', (108, 119))	('Sema3A', 'Gene', '10371', (100, 106))	('urothelial carcinoma Ta', 'Disease', 'MESH:D014523', (75, 98))
204161	33546237	Carcinoma in situ, Hematoxylin and eosin, x200 Carcinoma in situ, Sema3A, x200 The urothelial mucosa was roughly divided into three layers: basal, intermediate, and apical.	('Carcinoma', 'Disease', 'MESH:D009369', (0, 9))	('x200', 'Var', (74, 78))	('Carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('eosin', 'Chemical', 'MESH:D004801', (35, 40))	('Hematoxylin', 'Chemical', 'MESH:D006416', (19, 30))	('Sema3A', 'Gene', (66, 72))	('Carcinoma', 'Phenotype', 'HP:0030731', (0, 9))	('Carcinoma in situ', 'Phenotype', 'HP:0030075', (47, 64))	('Carcinoma', 'Disease', (47, 56))	('x200', 'Var', (42, 46))	('Carcinoma in situ', 'Phenotype', 'HP:0030075', (0, 17))	('Sema3A', 'Gene', '10371', (66, 72))	('Carcinoma', 'Disease', 'MESH:D009369', (47, 56))	('Carcinoma', 'Disease', (0, 9))
204184	33546237	A number of studies showed that low levels of Sema3A were associated with non-small cell lung carcinoma and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (78, 103))	('low', 'Var', (32, 35))	('Sema3A', 'Gene', '10371', (46, 52))	('associated', 'Reg', (58, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('low levels of Sema3A', 'Phenotype', 'HP:0032429', (32, 52))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (74, 103))	('Sema3A', 'Gene', (46, 52))	('lung carcinoma', 'Disease', (89, 103))	('lung carcinoma', 'Disease', 'MESH:D008175', (89, 103))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
204195	32906679	The 1p/19q codeletion is a prognostic marker of OD with an isocitrate dehydrogenase (IDH) mutation and is associated with a clinically favorable overall survival (OS).	('IDH', 'Gene', '3417', (85, 88))	('overall', 'MPA', (145, 152))	('1p', 'Chemical', '-', (4, 6))	('19q', 'Chemical', '-', (7, 10))	('isocitrate dehydrogenase', 'Gene', (59, 83))	('mutation', 'Var', (90, 98))	('IDH', 'Gene', (85, 88))	('isocitrate dehydrogenase', 'Gene', '3417', (59, 83))
204202	32906679	The 1p/19q codeletion is a prognostic marker of OD with an isocitrate dehydrogenase (IDH) mutation and is associated with a clinically favorable overall survival (OS); however, the exact underlying mechanism remains unclear.	('IDH', 'Gene', '3417', (85, 88))	('overall', 'MPA', (145, 152))	('1p', 'Chemical', '-', (4, 6))	('19q', 'Chemical', '-', (7, 10))	('isocitrate dehydrogenase', 'Gene', (59, 83))	('mutation', 'Var', (90, 98))	('IDH', 'Gene', (85, 88))	('isocitrate dehydrogenase', 'Gene', '3417', (59, 83))
204207	32906679	In conclusion, ceRNAs with a 1p/19q codeletion can create different tumor microenvironments via potassium ion channels and ECM composition changes; furthermore, differences in OS may occur.	('tumor', 'Disease', (68, 73))	('changes', 'Reg', (139, 146))	('19q', 'Chemical', '-', (32, 35))	('potassium', 'Chemical', 'MESH:D011188', (96, 105))	('differences', 'Reg', (161, 172))	('1p', 'Chemical', '-', (29, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('1p/19q codeletion', 'Var', (29, 46))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('potassium ion channels', 'MPA', (96, 118))
204212	32906679	IDH1 and IDH2 (collectively referred to as IDH hereafter), which encode isocitrate dehydrogenase and cause mutations and 1p/19q codeletion, were included as characteristic prognostic markers of ODs.	('IDH', 'Gene', '3417', (43, 46))	('IDH2', 'Gene', (9, 13))	('IDH', 'Gene', (0, 3))	('isocitrate dehydrogenase', 'Gene', '3417', (72, 96))	('mutations', 'Var', (107, 116))	('ODs', 'Disease', (194, 197))	('1p', 'Chemical', '-', (121, 123))	('IDH2', 'Gene', '3418', (9, 13))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', '3417', (9, 12))	('IDH1', 'Gene', (0, 4))	('IDH', 'Gene', (43, 46))	('isocitrate dehydrogenase', 'Gene', (72, 96))	('19q', 'Chemical', '-', (124, 127))	('IDH1', 'Gene', '3417', (0, 4))
204213	32906679	Although the 1p/19q codeletion is a prognostic marker of ODs with IDH1/2 mutations, 30-40% of all ODs are not codeleted at 1p/19q and have a worse prognosis.	('1p', 'Chemical', '-', (123, 125))	('19q', 'Chemical', '-', (16, 19))	('1p', 'Chemical', '-', (13, 15))	('IDH1/2', 'Gene', '3417;3418', (66, 72))	('ODs', 'Disease', (57, 60))	('19q', 'Chemical', '-', (126, 129))	('IDH1/2', 'Gene', (66, 72))	('mutations', 'Var', (73, 82))
204214	32906679	Hence, the 1p/19q codeletion is reportedly associated with diagnosis, prognosis, and clinically favorable overall survival (OS) in glioma; however, the exact underlying mechanism remains unclear.	('19q', 'Chemical', '-', (14, 17))	('glioma', 'Disease', (131, 137))	('1p/19q codeletion', 'Var', (11, 28))	('1p', 'Chemical', '-', (11, 13))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('associated', 'Reg', (43, 53))
204217	32906679	lncRNAs are regulatory RNA transcripts with a length >200 nucleotides and have recently been reported to play various important roles in the regulation of transcription and translation as well as in epigenetic modification.	('ncRNA', 'Gene', (1, 6))	('epigenetic modification', 'Var', (199, 222))	('transcription', 'MPA', (155, 168))	('ncRNA', 'Gene', '220202', (1, 6))
204231	32906679	We downloaded harmonized data from TCGA database as reference of hg38 (platform "Illumina HiSeq") for 189 patients with OD who had IDH mutation information and selected 168 patients with IDH mutation.	('hg38', 'Gene', (65, 69))	('hg38', 'Gene', '8549', (65, 69))	('patients', 'Species', '9606', (173, 181))	('IDH', 'Gene', (187, 190))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (187, 190))	('patients', 'Species', '9606', (106, 114))	('IDH', 'Gene', '3417', (131, 134))	('mutation', 'Var', (135, 143))
204243	32906679	We evaluated the profile of each module by comparing it to the correlation between the modules and the clinical traits of OD having an IDH mutation with a 1p/19q codeletion.	('mutation', 'Var', (139, 147))	('1p', 'Chemical', '-', (155, 157))	('19q', 'Chemical', '-', (158, 161))	('IDH', 'Gene', (135, 138))	('IDH', 'Gene', '3417', (135, 138))
204250	32906679	We evaluated the ceRNA network using adjusted rand index (ARI) with DEcodingRNAs belonging to each ceRNA network and selected it as the final ceRNA network having a high concordance with traits of IDH mutations with 1p/19q codeletion.	('mutations', 'Var', (201, 210))	('1p', 'Chemical', '-', (216, 218))	('IDH', 'Gene', '3417', (197, 200))	('IDH', 'Gene', (197, 200))	('19q', 'Chemical', '-', (219, 222))
204260	32906679	There were 342 upregulated DEcodingRNAs and 573 downregulated DEcodingRNAs in IDH mutations with 1p/19q codeletions than in those with non-codeletions (Figure 1A).	('DEcodingRNAs', 'MPA', (27, 39))	('upregulated', 'PosReg', (15, 26))	('downregulated', 'NegReg', (48, 61))	('DEcodingRNAs', 'MPA', (62, 74))	('mutations', 'Var', (82, 91))	('1p', 'Chemical', '-', (97, 99))	('IDH', 'Gene', (78, 81))	('19q', 'Chemical', '-', (100, 103))	('IDH', 'Gene', '3417', (78, 81))
204272	32906679	The results were that the blue module had the strongest positive relationship with the 1p/19q codeletion of IDH mutation in ODs, with a correlation value of 0.69 (left panel of Figure 3C); the turquoise module had the strongest negative relationship, with a value of -0.71 (right panel of Figure 3C).	('mutation', 'Var', (112, 120))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (108, 111))	('1p', 'Chemical', '-', (87, 89))	('positive', 'PosReg', (56, 64))	('19q', 'Chemical', '-', (90, 93))
204284	32906679	The evaluation was based on 1p/19q codeletion, 1p/19q non-codeletion, and wildtype, and the results surprisingly confirmed that all ceRNA networks distinguish well between the 1p/19q codeletion and wildtype in lower grade gliomas (Table 1).	('1p', 'Chemical', '-', (47, 49))	('1p', 'Chemical', '-', (28, 30))	('1p', 'Chemical', '-', (176, 178))	('19q', 'Chemical', '-', (50, 53))	('1p/19q codeletion', 'Var', (176, 193))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('gliomas', 'Disease', (222, 229))	('19q', 'Chemical', '-', (31, 34))	('19q', 'Chemical', '-', (179, 182))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
204288	32906679	As a result, patients with IDH mutations in OD had different survivals according to the expression levels of lncRNA INHBA-AS1 and LINC01551.	('IDH', 'Gene', (27, 30))	('LINC01551', 'Gene', (130, 139))	('mutations', 'Var', (31, 40))	('INHBA-AS1', 'Gene', (116, 125))	('IDH', 'Gene', '3417', (27, 30))	('ncRNA', 'Gene', '220202', (110, 115))	('patients', 'Species', '9606', (13, 21))	('INHBA-AS1', 'Gene', '285954', (116, 125))	('LINC01551', 'Gene', '387978', (130, 139))	('expression levels', 'MPA', (88, 105))	('ncRNA', 'Gene', (110, 115))
204290	32906679	In addition, in the data of patients extended to lower grade glioma, a higher number of non-coding RNAs in the ceRNA network showed a difference in OS rate according to the expression level.	('higher', 'PosReg', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('non-coding RNAs', 'Var', (88, 103))	('glioma', 'Disease', (61, 67))	('patients', 'Species', '9606', (28, 36))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
204291	32906679	In particular, the ceRNA network containing LINC01551 and hsa-miR-301a-3p similarly classified subgroups of 1p/19q from both OD and lower glioma including wildtype compared to the actual subgroup (Figure 5A,B and Figure S3A,B).	('LINC01551', 'Gene', (44, 53))	('glioma', 'Disease', (138, 144))	('19q', 'Chemical', '-', (111, 114))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('1p', 'Chemical', '-', (108, 110))	('1p/19q', 'Var', (108, 114))	('LINC01551', 'Gene', '387978', (44, 53))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))
204294	32906679	Some parts of genes related to the 1p/19q codeletion can promote tumor progression, but in many cases, this is a positive prognostic indicator not only for OD but also for glioma.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('promote', 'PosReg', (57, 64))	('1p/19q codeletion', 'Var', (35, 52))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('1p', 'Chemical', '-', (35, 37))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('glioma', 'Disease', (172, 178))	('19q', 'Chemical', '-', (38, 41))
204297	32906679	Therefore, a better understanding of the effect of 1p/19q codeletion on OD will be of great help to an improved understanding of treatment and cancer progression in OD as well as overall glioma.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('1p/19q codeletion', 'Var', (51, 68))	('glioma', 'Disease', (187, 193))	('19q', 'Chemical', '-', (54, 57))	('1p', 'Chemical', '-', (51, 53))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('glioma', 'Disease', 'MESH:D005910', (187, 193))
204308	32906679	The repression of Kir6.2/SUR1 channels stimulates the release of insulin, and it has been reported that mutations and deficiencies of ABCC8 and KCNJ11 induce hyperinsulinism.	('Kir6.2', 'Gene', '3767', (18, 24))	('stimulates', 'PosReg', (39, 49))	('insulin', 'Gene', '3630', (163, 170))	('mutations', 'Var', (104, 113))	('hyperinsulinism', 'Disease', (158, 173))	('induce', 'Reg', (151, 157))	('KCNJ11', 'Gene', '3767', (144, 150))	('KCNJ11', 'Gene', (144, 150))	('ABCC8', 'Gene', '6833', (134, 139))	('SUR1', 'Gene', (25, 29))	('SUR1', 'Gene', '6833', (25, 29))	('ABCC8', 'Gene', (134, 139))	('deficiencies', 'Var', (118, 130))	('insulin', 'Gene', (65, 72))	('hyperinsulinism', 'Disease', 'MESH:D006946', (158, 173))	('Kir6.2', 'Gene', (18, 24))	('insulin', 'Gene', '3630', (65, 72))	('insulin', 'Gene', (163, 170))
204310	32906679	These genes were relatively upregulated as per the results of our study, and these results suggest that potassium channels play important roles in the brain tumor microenvironments related to proliferation, apoptosis, and migration; this can be one of the survival advantages of the 1p/19q codeletion in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (304, 310))	('19q', 'Chemical', '-', (286, 289))	('brain tumor', 'Disease', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('gliomas', 'Disease', 'MESH:D005910', (304, 311))	('brain tumor', 'Disease', 'MESH:D001932', (151, 162))	('gliomas', 'Disease', (304, 311))	('gliomas', 'Phenotype', 'HP:0009733', (304, 311))	('1p/19q', 'Var', (283, 289))	('brain tumor', 'Phenotype', 'HP:0030692', (151, 162))	('1p', 'Chemical', '-', (283, 285))	('potassium', 'Chemical', 'MESH:D011188', (104, 113))
204315	32906679	Interestingly, the high expression of TNR gene has been observed in ODs with a high grade in this report, and the expression of TNR is upregulated in OD having a 1p/19q codeletion.	('TNR', 'Gene', (38, 41))	('TNR', 'Gene', (128, 131))	('TNR', 'Gene', '7143', (128, 131))	('expression', 'MPA', (24, 34))	('1p/19q codeletion', 'Var', (162, 179))	('1p', 'Chemical', '-', (162, 164))	('expression', 'MPA', (114, 124))	('19q', 'Chemical', '-', (165, 168))	('TNR', 'Gene', '7143', (38, 41))	('upregulated', 'PosReg', (135, 146))
204322	32906679	The expression of MMP24 was observed to be high in GBM and OD, similar to that reported in previous studies, but patients with a high level of MMP24 had better survival in OD (Figure S4A).	('survival', 'CPA', (160, 168))	('MMP24', 'Gene', '10893', (143, 148))	('MMP24', 'Gene', '10893', (18, 23))	('patients', 'Species', '9606', (113, 121))	('high level', 'Var', (129, 139))	('better', 'PosReg', (153, 159))	('MMP24', 'Gene', (143, 148))	('MMP24', 'Gene', (18, 23))
204326	32906679	The results were confirmed to be similar to the survival rate according to the clinical information of actual TCGA OD patients with IDH mutations.	('mutations', 'Var', (136, 145))	('IDH', 'Gene', '3417', (132, 135))	('patients', 'Species', '9606', (118, 126))	('IDH', 'Gene', (132, 135))
204344	32906679	Our study also demonstrates that subtypes of glioma have a high IDH mutation frequency and that these are known to improve survival and exhibit similar traits; however, different effects can be derived from the same gene, and this would result in survival differences in different subtypes such as ODs and astrocytomas.	('IDH', 'Gene', '3417', (64, 67))	('survival', 'CPA', (123, 131))	('mutation', 'Var', (68, 76))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('astrocytoma', 'Phenotype', 'HP:0009592', (306, 317))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('ODs', 'Disease', (298, 301))	('astrocytomas', 'Disease', 'MESH:D001254', (306, 318))	('result in', 'Reg', (237, 246))	('improve', 'PosReg', (115, 122))	('glioma', 'Disease', (45, 51))	('IDH', 'Gene', (64, 67))	('astrocytomas', 'Disease', (306, 318))
204351	31382920	Across 7 studies (219 patients) for glioma grading, 18F-FDOPA PET and PET/CT showed a pooled sensitivity of 0.88 (95%CI: 0.81-0.93) and a pooled specificity of 0.73 (95%CI: 0.64-0.81).	('18F-FDOPA', 'Chemical', 'MESH:C043437', (52, 61))	('patients', 'Species', '9606', (22, 30))	('18F-FDOPA', 'Var', (52, 61))	('glioma', 'Disease', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
204369	31382920	The inclusion criteria were: (1) Original studies investigating the diagnostic or grading capacity of 18F-FDOPA PET or PET/CT in patients with gliomas; (2) Studies with histopathology and/or clinical and imaging follow-up as reference standards; (3) Certain numbers of true-positive (TP), false-positive (FP), false-negative (FN) and true-negative (TN) results in diagnostic or grading tests can be derived from sufficient data.	('false-negative', 'Var', (310, 324))	('patients', 'Species', '9606', (129, 137))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('TP', 'Chemical', '-', (284, 286))	('gliomas', 'Disease', (143, 150))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (102, 111))
204392	31382920	This meta-analysis demonstrated a pooled sensitivity of 0.90 and specificity of 0.75 for 18F-FDOPA PET and PET/CT in diagnosing gliomas, and a pooled sensitivity of 0.88 and specificity of 0.73 in grading gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('gliomas', 'Disease', (205, 212))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('PET/CT', 'Var', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (89, 98))
204490	21216337	High-energy metabolism shown by FDG PET may also be related to the large neuronal cell population of gangliogliomas, which have higher metabolism than normal cells of WM.	('FDG', 'Var', (32, 35))	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('High-energy metabolism', 'MPA', (0, 22))	('FDG', 'Chemical', 'MESH:D019788', (32, 35))
204495	32453707	In various carcinomas, long non-coding RNAs (lncRNAs) contribute to pathogenic processes, including tumorigenesis, metastasis, chemoresistance, and radioresistance.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))	('metastasis', 'CPA', (115, 125))	('tumor', 'Disease', (100, 105))	('contribute', 'Reg', (54, 64))	('carcinomas', 'Disease', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('long non-coding RNAs', 'Var', (23, 43))	('chemoresistance', 'CPA', (127, 142))	('radioresistance', 'CPA', (148, 163))	('carcinomas', 'Disease', 'MESH:D009369', (11, 21))
204512	32453707	Among the 148 nodes, 8 central node genes with more than 10 connections each that might play crucial roles in radiosensitvity were identified: LINC01447, AC004832.1, AC020659.1, AC087241.4, AC092343.1, AL157831.2, DISC1FP1, and FAM30A.	('LINC01447', 'Gene', '101929086', (143, 152))	('AC087241.4', 'Var', (178, 188))	('DISC1FP1', 'Gene', '101929222', (214, 222))	('AC004832.1', 'Var', (154, 164))	('DISC1FP1', 'Gene', (214, 222))	('FAM30A', 'Gene', '9834', (228, 234))	('FAM30A', 'Gene', (228, 234))	('AL157831.2', 'Var', (202, 212))	('LINC01447', 'Gene', (143, 152))	('AC092343.1', 'Var', (190, 200))	('AC020659.1', 'Var', (166, 176))
204515	32453707	In total, 10 lncRNAs were significantly associated with OS: LINC01447, AC023796.1, AC000061.1, AL078605.1, LINC01163, LINC02237, AC073324.2, AC023905.1, AL133415.1, and AC106786.1 (Figure 2).	('AC106786.1', 'Var', (169, 179))	('LINC01447', 'Gene', '101929086', (60, 69))	('AL133415', 'Chemical', '-', (153, 161))	('AL133415.1', 'Var', (153, 163))	('LINC01163', 'Gene', (107, 116))	('LINC02237', 'Var', (118, 127))	('AL078605.1', 'Var', (95, 105))	('AC023905.1', 'Var', (141, 151))	('LINC01447', 'Gene', (60, 69))	('AC023796.1', 'Var', (71, 81))	('LINC01163', 'Gene', '101927381', (107, 116))	('AC073324.2', 'Var', (129, 139))	('associated', 'Reg', (40, 50))	('AC000061.1', 'Var', (83, 93))
204516	32453707	Ten lncRNAs were significantly associated with PFS: LINC01447, LINC02237, AC106786.1, KC6, GS1-24F4.2, LINC01163, AC000061.1, AL133415.1, AL137005.1, and AC046168.2 (Figure 3).	('AC000061.1', 'Var', (114, 124))	('AC046168.2', 'Var', (154, 164))	('LINC01163', 'Gene', (103, 112))	('KC6', 'Gene', (86, 89))	('AC106786.1', 'Var', (74, 84))	('associated', 'Reg', (31, 41))	('GS1-24F4.2', 'Gene', (91, 101))	('KC6', 'Gene', '641516', (86, 89))	('GS1-24F4.2', 'Gene', '100652791', (91, 101))	('LINC01163', 'Gene', '101927381', (103, 112))	('LINC01447', 'Gene', '101929086', (52, 61))	('AL133415', 'Chemical', '-', (126, 134))	('AL133415.1', 'Var', (126, 136))	('LINC01447', 'Gene', (52, 61))	('AL137005.1', 'Var', (138, 148))
204517	32453707	Notably, high expression of AL133415.1, LINC01447, and AC106786.1 predicted poor prognosis after radiotherapy as indicated by reduced OS and PFS; these lncRNAs might therefore be risk factors.	('LINC01447', 'Gene', '101929086', (40, 49))	('poor', 'NegReg', (76, 80))	('LINC01447', 'Gene', (40, 49))	('PFS', 'CPA', (141, 144))	('AL133415', 'Chemical', '-', (28, 36))	('AC106786.1', 'Var', (55, 65))	('AL133415.1', 'Var', (28, 38))	('reduced', 'NegReg', (126, 133))
204520	32453707	In the multivariate analysis, three lncRNAs with P<0.01 (AC106786.1, LINC02237, and LINC01447) were included in the predictive model (Figure 4A).	('LINC01447', 'Gene', '101929086', (84, 93))	('LINC01447', 'Gene', (84, 93))	('AC106786.1', 'Var', (57, 67))	('LINC02237', 'Var', (69, 78))
204522	32453707	As shown in the heatmap in Figure 1B, expression of LINC01447 and AC106786.1 were increased in patients with higher risk scores, while LINC02237 expression was increased in those with lower risk scores.	('patients', 'Species', '9606', (95, 103))	('expression', 'MPA', (38, 48))	('LINC02237', 'Var', (135, 144))	('LINC01447', 'Gene', '101929086', (52, 61))	('increased', 'PosReg', (82, 91))	('LINC01447', 'Gene', (52, 61))	('AC106786.1', 'Var', (66, 76))
204533	32453707	Here, as shown in Figure 7B, PD-L1 was overexpressed in the high-risk group and was positively correlated with risk score (r=0.20, P<0.01), suggesting that PD-L1 inhibitors might benefit high-risk LGG patients receiving radiation treatment.	('patients', 'Species', '9606', (201, 209))	('benefit', 'PosReg', (179, 186))	('PD-L1', 'Gene', (29, 34))	('PD-L1', 'Gene', (156, 161))	('correlated', 'Reg', (95, 105))	('PD-L1', 'Gene', '29126', (29, 34))	('LGG', 'Disease', (197, 200))	('PD-L1', 'Gene', '29126', (156, 161))	('overexpressed', 'PosReg', (39, 52))	('inhibitors', 'Var', (162, 172))
204536	32453707	The predictive model consisted of LINC02237, AC106786.1 and LINC01447, and overexpression of LINC01447 and AC106786.1 was associated with decreased OS and PFS times.	('LINC01447', 'Gene', '101929086', (60, 69))	('overexpression', 'PosReg', (75, 89))	('decreased', 'NegReg', (138, 147))	('LINC01447', 'Gene', (60, 69))	('PFS', 'CPA', (155, 158))	('LINC01447', 'Gene', '101929086', (93, 102))	('AC106786.1', 'Var', (107, 117))	('LINC02237', 'Var', (34, 43))	('AC106786.1', 'Var', (45, 55))	('LINC01447', 'Gene', (93, 102))
204537	32453707	To further validate the effects of these lncRNAs on radiation response, HS683 low-grade glioma cells were transfected with LINC01447-siRNA or AC106786.1-siRNA (Figure 8A, 8B), and then exposed to single radiation doses of 0, 2, 4, or 6 Gy.	('LINC01447', 'Gene', '101929086', (123, 132))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', (88, 94))	('HS683', 'CellLine', 'CVCL:0844', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('LINC01447', 'Gene', (123, 132))	('AC106786.1-siRNA', 'Var', (142, 158))
204538	32453707	The siRNAs successfully downregulated expression of LINC01447 and AC106786.1 (Figure 8C).	('expression', 'MPA', (38, 48))	('downregulated', 'NegReg', (24, 37))	('LINC01447', 'Gene', '101929086', (52, 61))	('LINC01447', 'Gene', (52, 61))	('AC106786.1', 'Var', (66, 76))
204539	32453707	The CCK-8 assay demonstrated that cell viability decreased 48, 72, and 96 hours after 6 Gy radiation in HS683 transfected with either LINC01447-siRNA or AC106786.1-siRNA (Figure 8D).	('AC106786.1-siRNA', 'Var', (153, 169))	('LINC01447', 'Gene', (134, 143))	('HS683', 'CellLine', 'CVCL:0844', (104, 109))	('decreased', 'NegReg', (49, 58))	('LINC01447', 'Gene', '101929086', (134, 143))	('cell viability', 'CPA', (34, 48))
204540	32453707	Apoptosis rates increased in both LINC01447-siRNA and AC106786.1-siRNA cells 48 h after treatment with 6 Gy radiation compared to control cells (Figure 8E, 8F).	('Apoptosis rates', 'CPA', (0, 15))	('AC106786.1-siRNA', 'Var', (54, 70))	('LINC01447', 'Gene', '101929086', (34, 43))	('increased', 'PosReg', (16, 25))	('LINC01447', 'Gene', (34, 43))
204541	32453707	Colony formation assays showed that downregulation of LINC01447 or AC106786.1 inhibited survival and foci formation in cells exposed to IR (Figure 8G).	('AC106786.1', 'Var', (67, 77))	('downregulation', 'NegReg', (36, 50))	('inhibited', 'NegReg', (78, 87))	('LINC01447', 'Gene', (54, 63))	('LINC01447', 'Gene', '101929086', (54, 63))
204542	32453707	Taken together, these results show that downregulation of LINC01447 or AC106786.1 enhanced the radiosensitivity of low-grade glioma cells.	('glioma', 'Disease', (125, 131))	('enhanced', 'PosReg', (82, 90))	('AC106786.1', 'Var', (71, 81))	('downregulation', 'NegReg', (40, 54))	('LINC01447', 'Gene', '101929086', (58, 67))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('radiosensitivity', 'CPA', (95, 111))	('LINC01447', 'Gene', (58, 67))
204560	32453707	Although there is no evidence of overlapping with existing 31-gene signature in our lncRNAs and report genes, the underlying pathway regulated by these lncRNAs, like PI3K-Akt signaling pathway, MAPK signaling pathway, activation of cell proliferation, inhibition of apoptotic processes and DNA damage response, are consistent with findings on resistance to radiotherapy in other tumors.	('inhibition', 'NegReg', (252, 262))	('lncRNAs', 'Var', (152, 159))	('activation', 'PosReg', (218, 228))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('MAPK signaling pathway', 'Pathway', (194, 216))	('Akt', 'Gene', '207', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('apoptotic processes', 'CPA', (266, 285))	('tumors', 'Disease', (379, 385))	('Akt', 'Gene', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (379, 385))	('cell proliferation', 'CPA', (232, 250))
204561	32453707	PD-L1 has been identified as a promising target for immune therapy and as a candidate biomarker of treatment failure following radiation in head and neck cancer; the radiotherapy failure rate in tumors with high PD-L1 expression was 60% compared to 20% in the low PD-L1 expression group.	('high', 'Var', (207, 211))	('PD-L1', 'Gene', '29126', (264, 269))	('neck cancer', 'Disease', 'MESH:D006258', (149, 160))	('neck cancer', 'Disease', (149, 160))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', '29126', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('head and neck cancer', 'Phenotype', 'HP:0012288', (140, 160))	('failure', 'Disease', 'MESH:D006333', (109, 116))	('PD-L1', 'Gene', (212, 217))	('failure', 'Disease', (109, 116))	('PD-L1', 'Gene', '29126', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (195, 201))	('failure', 'Disease', 'MESH:D006333', (179, 186))	('neck cancer', 'Phenotype', 'HP:0012288', (149, 160))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('failure', 'Disease', (179, 186))	('PD-L1', 'Gene', (264, 269))	('expression', 'MPA', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
204563	32453707	Next-generation sequencing has identified thousands of lncRNAs for which aberrant expression is associated with various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('associated', 'Reg', (96, 106))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('aberrant expression', 'Var', (73, 92))
204566	32453707	The development of multi-gene risk models may improve genetic cancer risk assessment and help to improve clinical decisions, especially in patients with high PD-L1 who often experience failures after radiotherapy.	('PD-L1', 'Gene', '29126', (158, 163))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('failure', 'Disease', (185, 192))	('failure', 'Disease', 'MESH:D006333', (185, 192))	('cancer', 'Disease', (62, 68))	('PD-L1', 'Gene', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('high', 'Var', (153, 157))	('improve', 'PosReg', (46, 53))
204575	32453707	Three siRNA sequences targeting LINC01447 or AC106786.1 were synthesized by Guangzhou Rui Bo Biological Technology.	('LINC01447', 'Gene', '101929086', (32, 41))	('LINC01447', 'Gene', (32, 41))	('AC106786.1', 'Var', (45, 55))
204637	31903354	Patients who received radiotherapy had a longer PFS as opposed to those who did not [Figure 1].	('PFS', 'MPA', (48, 51))	('radiotherapy', 'Var', (22, 34))	('Patients', 'Species', '9606', (0, 8))
204639	31903354	Statistically significant survival benefit was found in patients who received radiotherapy as opposed to those who did not [Figure 2].	('patients', 'Species', '9606', (56, 64))	('radiotherapy', 'Var', (78, 90))	('survival', 'CPA', (26, 34))
204699	31523056	In addition, COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.	('regulate', 'Reg', (94, 102))	('tumours', 'Disease', (159, 166))	('degradation', 'MPA', (56, 67))	('NF-kappaB', 'Gene', (71, 80))	('COMMD6', 'Var', (13, 19))	('NF-kappaB', 'Gene', '4790', (71, 80))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('ubiquitination', 'MPA', (37, 51))	('modulate', 'Reg', (24, 32))
204713	31523056	It is also found that nuclear expression of COMMD1 sensitises ovarian cancer to cisplatin, and downregulation COMMD1 promotes tumour development by modulating a positive feedback loop that amplifies inflammatory- and stemness-associated properties of cancer cells.	('positive feedback loop', 'MPA', (161, 183))	('sensitises ovarian cancer', 'Disease', (51, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('COMMD1', 'Gene', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('promotes', 'PosReg', (117, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('cancer', 'Disease', (70, 76))	('downregulation', 'Var', (95, 109))	('COMMD1', 'Gene', '150684', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('amplifies', 'PosReg', (189, 198))	('cancer', 'Disease', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('COMMD1', 'Gene', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('sensitises ovarian cancer', 'Disease', 'MESH:D010051', (51, 76))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('modulating', 'Reg', (148, 158))	('COMMD1', 'Gene', '150684', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
204714	31523056	In addition, COMMD5 inhibits renal cell carcinoma by promoting de-phosphorylation of ErbB2/HER2 and epigenetic gene silencing of EGFR and ErbB3 via promoter methylation.	('de-phosphorylation', 'MPA', (63, 81))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (29, 49))	('inhibits', 'NegReg', (20, 28))	('ErbB2', 'Gene', (85, 90))	('epigenetic gene silencing', 'Var', (100, 125))	('renal cell carcinoma', 'Disease', (29, 49))	('COMMD5', 'Gene', (13, 19))	('COMMD5', 'Gene', '28991', (13, 19))	('ErbB3', 'Gene', (138, 143))	('ErbB3', 'Gene', '2065', (138, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('EGFR', 'Gene', '1956', (129, 133))	('HER2', 'Gene', (91, 95))	('promoting', 'PosReg', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('ErbB2', 'Gene', '2064', (85, 90))	('HER2', 'Gene', '2064', (91, 95))	('EGFR', 'Gene', (129, 133))
204716	31523056	It has also been found that inhibition of COMMD7 suppresses invasion of pancreatic ductal adenocarcinoma by decreasing MMP2 secretion.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (72, 104))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (72, 104))	('invasion', 'CPA', (60, 68))	('MMP2', 'Gene', '4313', (119, 123))	('inhibition', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('COMMD7', 'Gene', '149951', (42, 48))	('COMMD7', 'Gene', (42, 48))	('pancreatic ductal adenocarcinoma', 'Disease', (72, 104))	('decreasing', 'NegReg', (108, 118))	('MMP2', 'Gene', (119, 123))	('suppresses', 'NegReg', (49, 59))
204720	31523056	Moreover, COMMD6 has also been reported to be involved in the inhibition of NF-kappaB pathway activity in HEK-293 cells.	('NF-kappaB', 'Gene', (76, 85))	('activity', 'MPA', (94, 102))	('NF-kappaB', 'Gene', '4790', (76, 85))	('COMMD6', 'Var', (10, 16))	('inhibition', 'NegReg', (62, 72))	('HEK-293', 'CellLine', 'CVCL:0045', (106, 113))
204721	31523056	The activation of NF-kappaB could be completely abolished by the mutation of the amino acid residues Trp24 and Pro41 in the COMM domain of COMMD6.	('Trp24', 'Gene', (101, 106))	('abolished', 'NegReg', (48, 57))	('NF-kappaB', 'Gene', '4790', (18, 27))	('mutation', 'Var', (65, 73))	('NF-kappaB', 'Gene', (18, 27))	('Trp24', 'Chemical', 'MESH:C509690', (101, 106))	('activation', 'PosReg', (4, 14))
204745	31523056	The mutation of COMMD6 in human tumour cell lines evaluated by COSMIC database (https://cancer.sanger.ac.uk/cosmic).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (32, 38))	('COMMD6', 'Gene', (16, 22))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('human', 'Species', '9606', (26, 31))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
204777	31523056	High expression of COMMD6 was associated with shorter overall survival (OS) and disease free survival (DFS) in patients with head and neck squamous cell carcinoma (HNSC, P = 0.0084 and HR = 1.7 for OS; P = 0.0056 and HR = 2.0 for DFS), cholangiocarcinoma (CHOL, P = 0.05 and HR = 2.7 for OS; P = 0.029 and HR = 2.8 for DFS) and adrenocortical carcinoma (ACC, P = 0.0077 and HR = 2.9 for OS; P = 0.0053 and HR = 2.6 for DFS) (Fig.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (125, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (236, 254))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (328, 352))	('High', 'Var', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (125, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (236, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('disease free survival', 'CPA', (80, 101))	('overall survival', 'CPA', (54, 70))	('adrenocortical carcinoma', 'Disease', (328, 352))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('COMMD6', 'Gene', (19, 25))	('shorter', 'NegReg', (46, 53))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (328, 352))	('cholangiocarcinoma', 'Disease', (236, 254))	('patients', 'Species', '9606', (111, 119))
204778	31523056	In contrast, high expression of COMMD6 was associated with longer OS and DFS in patients with brain lower grade glioma (LGG, P = 0.0016 and HR = 0.56 for OS; P = 0.0096 and HR = 0.66 for DFS) and uveal melanoma (UVM, P = 0.0085 and HR = 0.30 for OS; P = 0.028 and HR = 0.35 for DFS) (Fig.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('patients', 'Species', '9606', (80, 88))	('high expression', 'Var', (13, 28))	('COMMD6', 'Gene', (32, 38))	('glioma', 'Disease', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('uveal melanoma', 'Disease', 'MESH:C536494', (196, 210))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('DFS', 'MPA', (73, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('uveal melanoma', 'Disease', (196, 210))
204779	31523056	In addition, high expression of COMMD6 was associated with longer OS in patients with testicular germ cell tumours (TGCT, P = 0.05, HR = 1.7E-09), longer DFS in patients with thyroid carcinoma (THCA, P = 0.017, HR = 0.48) and uterine corpus endometrial carcinoma (UCEC, P = 0.029, HR = 0.47) (Fig.	('TGCT', 'Disease', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('THCA', 'Disease', 'MESH:D013964', (194, 198))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('THCA', 'Disease', (194, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('endometrial carcinoma', 'Disease', (241, 262))	('longer', 'PosReg', (147, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('DFS', 'MPA', (154, 157))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (175, 192))	('patients', 'Species', '9606', (161, 169))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (241, 262))	('thyroid carcinoma', 'Disease', (175, 192))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (241, 262))	('high expression', 'Var', (13, 28))	('TGCT', 'Disease', 'MESH:C563236', (116, 120))	('COMMD6', 'Gene', (32, 38))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (86, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (175, 192))	('testicular germ cell tumours', 'Disease', (86, 114))	('patients', 'Species', '9606', (72, 80))
204802	31523056	COMMD6 has been reported to completely abolish NF-kappaB pathway activity by the mutation of the amino acid residues Trp24 and Pro41 in the COMM domain in HEK293 cells, indicating that COMMD6 may also play a vital role in the tumorigenesis and malignant progression.	('Trp24', 'Gene', (117, 122))	('activity', 'MPA', (65, 73))	('NF-kappaB', 'Gene', (47, 56))	('mutation', 'Var', (81, 89))	('Trp24', 'Chemical', 'MESH:C509690', (117, 122))	('abolish', 'NegReg', (39, 46))	('HEK293', 'CellLine', 'CVCL:0045', (155, 161))	('NF-kappaB', 'Gene', '4790', (47, 56))
204806	31523056	Phylogenetic analysis results showed that COMMD6 was clustered with COMMD7, COMMD8 and COMMD10 rather than other COMMD family members, indicating that these four COMMD members might play familiar roles during evolution.	('COMMD10', 'Gene', '51397', (87, 94))	('COMMD7', 'Gene', '149951', (68, 74))	('COMMD7', 'Gene', (68, 74))	('COMMD8', 'Gene', (76, 82))	('COMMD6', 'Var', (42, 48))	('COMMD10', 'Gene', (87, 94))	('COMMD8', 'Gene', '54951', (76, 82))
204851	31523056	Mutations of ribosome genes have been detected in various tumours, such as endometrial cancer, colorectal cancer and glioma.	('detected', 'Reg', (38, 46))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('ribosome genes', 'Gene', (13, 27))	('Mutations', 'Var', (0, 9))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))	('colorectal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('endometrial cancer', 'Disease', (75, 93))	('glioma', 'Disease', (117, 123))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('rectal cancer', 'Phenotype', 'HP:0100743', (99, 112))	('tumours', 'Disease', (58, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))
204853	31523056	Inhibition of the spliceosome impairs survival, tumorigenicity and metastasis of MYC-dependent breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumorigenicity', 'CPA', (48, 62))	('breast cancer', 'Disease', (95, 108))	('impairs', 'NegReg', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('metastasis', 'CPA', (67, 77))	('survival', 'CPA', (38, 46))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
204855	31523056	More importantly, the expression of COMMD6 could predict the survival of cancer patients, indicating the significant role of COMMD6 in tumour development and progression.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('patients', 'Species', '9606', (80, 88))	('expression', 'Var', (22, 32))	('COMMD6', 'Gene', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))	('predict', 'Reg', (49, 56))
204857	31523056	In addition, we found that COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.	('degradation', 'MPA', (70, 81))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('NF-kappaB', 'Gene', '4790', (85, 94))	('ubiquitination', 'MPA', (51, 65))	('NF-kappaB', 'Gene', (85, 94))	('COMMD6', 'Var', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('regulate', 'Reg', (108, 116))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('modulate', 'Reg', (38, 46))
204862	31177992	Total copy number variation as a prognostic factor in adult astrocytoma subtypes Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations.	('astrocytoma', 'Disease', 'MESH:D001254', (166, 177))	('mutations', 'Var', (113, 122))	('astrocytoma', 'Disease', (166, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (280, 292))	('astrocytoma', 'Phenotype', 'HP:0009592', (280, 291))	('astrocytomas', 'Disease', (166, 178))	('glioblastomas', 'Phenotype', 'HP:0012174', (297, 310))	('astrocytoma', 'Disease', 'MESH:D001254', (60, 71))	('better', 'PosReg', (146, 152))	('astrocytoma', 'Disease', (60, 71))	('glioblastomas', 'Disease', (297, 310))	('astrocytoma', 'Disease', 'MESH:D001254', (280, 291))	('glioblastoma', 'Phenotype', 'HP:0012174', (297, 309))	('astrocytomas', 'Disease', 'MESH:D001254', (166, 178))	('astrocytoma', 'Disease', (280, 291))	('astrocytoma', 'Phenotype', 'HP:0009592', (166, 177))	('astrocytomas', 'Disease', (280, 292))	('glioblastomas', 'Disease', 'MESH:D005909', (297, 310))	('IDH1/2', 'Gene', (106, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))
204863	31177992	In the present study, we subclassify 135 astrocytomas (67 IDH-wildtype and 68 IDH-mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH-status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH-mutant groups.	('IDH', 'Gene', '3417', (58, 61))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CDKN2A/B', 'Gene', '1029;1030', (243, 251))	('CDK4', 'Gene', '1019', (220, 224))	('IDH', 'Gene', '3417', (273, 276))	('astrocytomas', 'Disease', 'MESH:D001254', (41, 53))	('amplification', 'Var', (225, 238))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('IDH', 'Gene', (78, 81))	('IDH', 'Gene', (157, 160))	('deletion', 'Var', (252, 260))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (99, 118))	('CDKN2A/B', 'Gene', (243, 251))	('IDH', 'Gene', (58, 61))	('IDH', 'Gene', '3417', (78, 81))	('Cancer Genome Atlas', 'Disease', (99, 118))	('IDH', 'Gene', '3417', (157, 160))	('astrocytomas', 'Disease', (41, 53))	('CDK4', 'Gene', (220, 224))	('IDH', 'Gene', (273, 276))
204866	31177992	While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH-mutant groups.	('higher', 'PosReg', (225, 231))	('IDH', 'Gene', (293, 296))	('mutations', 'Var', (135, 144))	('CNV', 'MPA', (237, 240))	('IDH', 'Gene', '3417', (293, 296))	('genes', 'Gene', (148, 153))
204867	31177992	Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome.	('astrocytomas', 'Disease', (90, 102))	('CNV level', 'MPA', (44, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (223, 234))	('astrocytomas', 'Disease', 'MESH:D001254', (223, 235))	('astrocytoma', 'Phenotype', 'HP:0009592', (90, 101))	('mutations', 'Var', (116, 125))	('astrocytomas', 'Disease', 'MESH:D001254', (90, 102))	('astrocytomas', 'Disease', (223, 235))
204872	31177992	Within the IDH-wildtype groups, these studies have suggested that lower-grade gliomas (LGG) with EGFR amplification, gain of chromosome 7 and loss of 10, or TERT promoter mutations will have aggressive clinical courses and outcomes similar to IDH-wildtype glioblastoma, regardless of histologic features.	('loss of', 'Var', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('EGFR', 'Gene', '1956', (97, 101))	('IDH-wildtype glioblastoma', 'Disease', 'MESH:D005909', (243, 268))	('TERT', 'Gene', (157, 161))	('gain', 'PosReg', (117, 121))	('TERT', 'Gene', '7015', (157, 161))	('amplification', 'Var', (102, 115))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('EGFR', 'Gene', (97, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (256, 268))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('IDH-wildtype glioblastoma', 'Disease', (243, 268))	('IDH', 'Gene', (243, 246))	('IDH', 'Gene', '3417', (243, 246))
204873	31177992	In IDH-mutant groups, lower-grade tumors with alterations in genes in the retinoblastoma pathway, including amplification of CDK4 and deletion of CDKN2A/B, demonstrate significantly worse clinical behavior and shorter patient survival.	('CDK4', 'Gene', (125, 129))	('clinical behavior', 'CPA', (188, 205))	('IDH', 'Gene', '3417', (3, 6))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('patient', 'Species', '9606', (218, 225))	('worse', 'NegReg', (182, 187))	('patient survival', 'CPA', (218, 234))	('CDKN2A/B', 'Gene', '1029;1030', (146, 154))	('amplification', 'Var', (108, 121))	('CDK4', 'Gene', '1019', (125, 129))	('shorter', 'NegReg', (210, 217))	('deletion', 'Var', (134, 142))	('retinoblastoma', 'Disease', 'MESH:D012175', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('IDH', 'Gene', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (34, 40))	('retinoblastoma', 'Phenotype', 'HP:0009919', (74, 88))	('CDKN2A/B', 'Gene', (146, 154))	('alterations', 'Var', (46, 57))	('retinoblastoma', 'Disease', (74, 88))
204877	31177992	To better understand the effect of CNV, we analyzed 135 astrocytic tumors from The Cancer Genome Atlas (TCGA) (67 IDH-wildtype and 68 IDH-mutant cases) with respect to clinical outcome, CNV levels, chromosomal and specific gene amplification and deletion events, chromothripsis, total mutation load, specific mutations in known glioma/GBM genes, and mutations in genes associated with overall genomic instability.	('glioma', 'Disease', 'MESH:D005910', (328, 334))	('IDH', 'Gene', '3417', (134, 137))	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('astrocytic tumors', 'Disease', (56, 73))	('IDH', 'Gene', (114, 117))	('astrocytic tumors', 'Disease', 'MESH:D001254', (56, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IDH', 'Gene', '3417', (114, 117))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (83, 102))	('mutations', 'Var', (350, 359))	('glioma', 'Disease', (328, 334))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer Genome Atlas', 'Disease', (83, 102))	('mutations', 'Var', (309, 318))	('IDH', 'Gene', (134, 137))
204878	31177992	Building on our previous results, we performed wide scale genomic analysis, on a framework of pre-established prognostic factors including grade, IDH1/2-status, and the presence of CDK4 amplifications or CDKN2A/B deletions.	('CDKN2A/B', 'Gene', '1029;1030', (204, 212))	('deletions', 'Var', (213, 222))	('CDKN2A/B', 'Gene', (204, 212))	('CDK4', 'Gene', (181, 185))	('amplifications', 'Var', (186, 200))	('presence', 'Reg', (169, 177))	('CDK4', 'Gene', '1019', (181, 185))
204879	31177992	With the exception of 2 IDH1/2-wildtype cases, CDK4 amplification and CDKN2A/B deletion were found to be mutually exclusive.	('CDKN2A/B', 'Gene', (70, 78))	('CDK4', 'Gene', (47, 51))	('CDK4', 'Gene', '1019', (47, 51))	('amplification', 'Var', (52, 65))	('CDKN2A/B', 'Gene', '1029;1030', (70, 78))
204880	31177992	We divided the cases into 5 groups: IDH1/2-mutant LGG without CDK4 amplification or CDKN2A/B deletion (Group 1), IDH1/2-mutant LGG with either CDK4 amplification or CDKN2A/B deletion LGG (Group 2), IDH1/2-mutant GBM (Group 3), IDH1/2-wildtype LGG (Group 4), and IDH1/2-wildtype GBM (Group 5).	('LGG', 'Gene', (183, 186))	('CDK4', 'Gene', '1019', (62, 66))	('CDKN2A/B', 'Gene', (165, 173))	('CDKN2A/B', 'Gene', '1029;1030', (84, 92))	('CDK4', 'Gene', '1019', (143, 147))	('CDK4', 'Gene', (143, 147))	('LGG', 'Disease', (50, 53))	('CDKN2A/B', 'Gene', (84, 92))	('CDKN2A/B', 'Gene', '1029;1030', (165, 173))	('CDK4', 'Gene', (62, 66))	('IDH1/2-mutant', 'Var', (113, 126))
204885	31177992	All cases were manually reclassified according the WHO 2016 criteria as diffuse astrocytomas (WHO grade II-IV) by histology, intact 1p/19q status, and IDH1/2, ATRX, and TP53 status.	('ATRX', 'Gene', '546', (159, 163))	('1p/19q', 'Protein', (132, 138))	('IDH1/2', 'Var', (151, 157))	('TP53', 'Gene', '7157', (169, 173))	('astrocytomas', 'Disease', (80, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (80, 91))	('ATRX', 'Gene', (159, 163))	('TP53', 'Gene', (169, 173))	('astrocytomas', 'Disease', 'MESH:D001254', (80, 92))	('intact', 'Var', (125, 131))
204886	31177992	Oligodendrogliomas were specifically excluded on the basis of 1p/19q co-deletion, as these tumors have been shown to have different underlying molecular drivers and a more favorable clinical outcome as a group.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('1p/19q co-deletion', 'Var', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
204894	31177992	As previously demonstrated, IDH-mutant LGGs (group 1) had a significantly longer progression-free survival (PFS; median 95 months) and overall survival (OS; > 172 months) than IDH-mutant LGGs with CDK4 amplifications or CDKN2A/B deletions (group 2) (PFS 32 months, p = 0.0224; OS 36 months, p = 0.0150) and a significantly longer PFS and OS than IDH-mutant GBM (group 3) (PFS 10 months, p = 0.0032; OS 33 months, p = 0.0081).	('progression-free survival', 'CPA', (81, 106))	('deletions', 'Var', (229, 238))	('IDH', 'Gene', (28, 31))	('CDKN2A/B', 'Gene', (220, 228))	('IDH', 'Gene', '3417', (346, 349))	('longer', 'PosReg', (74, 80))	('IDH', 'Gene', (176, 179))	('IDH', 'Gene', '3417', (28, 31))	('CDK4', 'Gene', '1019', (197, 201))	('CDK4', 'Gene', (197, 201))	('overall survival', 'CPA', (135, 151))	('IDH', 'Gene', '3417', (176, 179))	('PFS', 'CPA', (330, 333))	('longer', 'PosReg', (323, 329))	('CDKN2A/B', 'Gene', '1029;1030', (220, 228))	('IDH', 'Gene', (346, 349))
204895	31177992	A significant difference was not found between IDH-mutant LGGs with CDK4 amplifications or CDKN2A/B deletions (group 2) and IDH-mutant GBM (group 3) in terms of PFS (p = 0.0769) or OS (p = 0.2892) (Fig.	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', (124, 127))	('PFS', 'MPA', (161, 164))	('CDKN2A/B', 'Gene', '1029;1030', (91, 99))	('CDK4', 'Gene', (68, 72))	('IDH', 'Gene', '3417', (124, 127))	('CDK4', 'Gene', '1019', (68, 72))	('CDKN2A/B', 'Gene', (91, 99))	('deletions', 'Var', (100, 109))	('IDH', 'Gene', (47, 50))
204897	31177992	Amplifications in CDK4 and deletions in CDKN2A/B did not have prognostic significance within the IDH-mutant GBM group in terms of PFS (p = 0.8406) or OS (p = 0.1471) (Fig.	('IDH', 'Gene', (97, 100))	('CDKN2A/B', 'Gene', '1029;1030', (40, 48))	('IDH', 'Gene', '3417', (97, 100))	('deletions', 'Var', (27, 36))	('CDKN2A/B', 'Gene', (40, 48))	('CDK4', 'Gene', '1019', (18, 22))	('CDK4', 'Gene', (18, 22))
204904	31177992	No significant difference was noted when comparing IDH-mutant GBM cases with CDK4 amplification or CDKN2A/B deletion to those without (p = 0.5326) (Fig.	('CDKN2A/B', 'Gene', (99, 107))	('IDH', 'Gene', (51, 54))	('CDK4', 'Gene', (77, 81))	('amplification', 'Var', (82, 95))	('IDH', 'Gene', '3417', (51, 54))	('CDK4', 'Gene', '1019', (77, 81))	('CDKN2A/B', 'Gene', '1029;1030', (99, 107))
204906	31177992	In the IDH-mutant astrocytomas as a whole (groups 1-3), there was a statistically significant inverse correlation between the total copy number variation in each case and both the progression-free survival (r = - 0.3415; p = 0.0047) (Fig.	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('astrocytomas', 'Disease', 'MESH:D001254', (18, 30))	('progression-free survival', 'CPA', (180, 205))	('astrocytoma', 'Phenotype', 'HP:0009592', (18, 29))	('copy number variation', 'Var', (132, 153))	('astrocytomas', 'Disease', (18, 30))	('inverse', 'NegReg', (94, 101))
204908	31177992	Analysis of the IDH-mutant tumors (groups 1-3) revealed a heterogeneous assortment of genomic alterations with few consistent chromosomal regions with amplifications or deletions, although there is a clear increase in number of overall alterations between the group 1 IDH-mutant LGGs and the group 2 IDH-mutant LGGs with CDK4 amplification/CDKN2A/B deletion and group 3 IDH-mutant GBM (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('IDH', 'Gene', (370, 373))	('IDH', 'Gene', '3417', (370, 373))	('CDKN2A/B', 'Gene', (340, 348))	('IDH', 'Gene', (268, 271))	('tumors', 'Disease', (27, 33))	('IDH', 'Gene', (300, 303))	('deletion', 'Var', (349, 357))	('IDH', 'Gene', (16, 19))	('CDK4', 'Gene', (321, 325))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('IDH', 'Gene', '3417', (268, 271))	('IDH', 'Gene', '3417', (300, 303))	('IDH', 'Gene', '3417', (16, 19))	('CDK4', 'Gene', '1019', (321, 325))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('CDKN2A/B', 'Gene', '1029;1030', (340, 348))
204909	31177992	Conversely, IDH-wildtype LGGs and GBMs form a relatively homogeneous group with consistent amplifications, including large amplifications along chromosome 7, deletions on 9p, and deletions of chromosome 10 (Fig.	('IDH', 'Gene', (12, 15))	('deletions', 'Var', (179, 188))	('IDH', 'Gene', '3417', (12, 15))	('deletions on', 'Var', (158, 170))
204911	31177992	Similarly, 9p21.3 (a region containing CDKN2A) showed frequent deletions in groups 2, 3, 4, and 5 but not in group 1.	('9p21.3', 'Gene', (11, 17))	('CDKN2A', 'Gene', '1029', (39, 45))	('CDKN2A', 'Gene', (39, 45))	('deletions', 'Var', (63, 72))
204912	31177992	IDH-wildtype tumors had consistent amplifications of 7p11.2 (containing EGFR) and 1q32.1 and deletions of 1p32.3, but only IDH-wildtype GBM had consistent deletions at 10q23.31.	('IDH', 'Gene', (0, 3))	('1p32.3', 'Gene', (106, 112))	('amplifications', 'MPA', (35, 49))	('1q32.1', 'Gene', (82, 88))	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (0, 19))	('EGFR', 'Gene', '1956', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('IDH', 'Gene', '3417', (0, 3))	('EGFR', 'Gene', (72, 76))	('deletions', 'Var', (93, 102))	('IDH-wildtype tumors', 'Disease', (0, 19))	('IDH', 'Gene', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('7p11.2', 'Gene', (53, 59))	('IDH', 'Gene', '3417', (123, 126))
204913	31177992	Interestingly, IDH-mutant GBM and IDH-mutant LGGs with CDK4 amplification/CDKN2A/B deletion both had amplifications at 2p24.3 (a chromosomal region containing MYCN).	('CDK4', 'Gene', '1019', (55, 59))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('CDKN2A/B', 'Gene', '1029;1030', (74, 82))	('CDKN2A/B', 'Gene', (74, 82))	('amplifications', 'MPA', (101, 115))	('IDH', 'Gene', (15, 18))	('MYCN', 'Gene', (159, 163))	('MYCN', 'Gene', '4613', (159, 163))	('deletion', 'Var', (83, 91))	('IDH', 'Gene', '3417', (15, 18))	('CDK4', 'Gene', (55, 59))
204915	31177992	Group 1 IDH-mutant LGGs had significant consistent amplifications at 3p25.2, 5q31.1, 8q24.13, 11q24.2, 13q34, 19q13.12, Xp22.32, and Xq28, as well as consistent deletions at 3p14.1, 9p24.2, 11p12, 13q14.3, 14q24.3, and Xq21.1 that were not identified in any other tumor group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('IDH', 'Gene', (8, 11))	('tumor', 'Disease', (264, 269))	('deletions', 'Var', (161, 170))	('IDH', 'Gene', '3417', (8, 11))	('Xq28', 'Var', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
204916	31177992	Amplifications and deletions in specific genes of interest were rare in the group 1 IDH-mutant LGGs, per our study design (Additional file 1: Figure S1).	('IDH', 'Gene', '3417', (84, 87))	('deletions', 'Var', (19, 28))	('IDH', 'Gene', (84, 87))
204917	31177992	IDH-mutant astrocytomas with poor clinical outcomes (groups 2 and 3) also showed more frequent amplifications of GLI1, KIT, KDR, MYC, MYCN, GATA3, CCND2, and KRAS as well as more frequent deletions of PTEN, PTPRD, ATRX, and RB1 (Additional file 2: Figure S2 and Additional file 3: Figure S3).	('KRAS', 'Gene', (158, 162))	('MYCN', 'Gene', (134, 138))	('ATRX', 'Gene', '546', (214, 218))	('KDR', 'Gene', (124, 127))	('deletions', 'Var', (188, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('MYC', 'Gene', '4609', (134, 137))	('RB1', 'Gene', '5925', (224, 227))	('MYC', 'Gene', (129, 132))	('CCND2', 'Gene', (147, 152))	('PTPRD', 'Gene', (207, 212))	('CCND2', 'Gene', '894', (147, 152))	('IDH', 'Gene', (0, 3))	('PTEN', 'Gene', (201, 205))	('astrocytomas', 'Disease', 'MESH:D001254', (11, 23))	('GLI1', 'Gene', '2735', (113, 117))	('GATA3', 'Gene', '2625', (140, 145))	('PTPRD', 'Gene', '5789', (207, 212))	('KDR', 'Gene', '3791', (124, 127))	('IDH', 'Gene', '3417', (0, 3))	('MYC', 'Gene', '4609', (129, 132))	('PTEN', 'Gene', '5728', (201, 205))	('MYCN', 'Gene', '4613', (134, 138))	('ATRX', 'Gene', (214, 218))	('GATA3', 'Gene', (140, 145))	('KIT', 'Gene', (119, 122))	('MYC', 'Gene', (134, 137))	('RB1', 'Gene', (224, 227))	('KRAS', 'Gene', '3845', (158, 162))	('GLI1', 'Gene', (113, 117))	('amplifications', 'MPA', (95, 109))	('astrocytomas', 'Disease', (11, 23))
204918	31177992	IDH-wildtype groups frequently had amplifications in EGFR, PDGFRA, CDK4, MDM2, MDM4, KIT, and KDR, as well as deletions in CDKN2A/B, and PTEN.	('CDKN2A/B', 'Gene', '1029;1030', (123, 131))	('KDR', 'Gene', '3791', (94, 97))	('MDM4', 'Gene', '4194', (79, 83))	('IDH', 'Gene', (0, 3))	('CDK4', 'Gene', (67, 71))	('MDM4', 'Gene', (79, 83))	('PTEN', 'Gene', (137, 141))	('MDM2', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (53, 57))	('amplifications', 'MPA', (35, 49))	('IDH', 'Gene', '3417', (0, 3))	('PDGFRA', 'Gene', '5156', (59, 65))	('PDGFRA', 'Gene', (59, 65))	('CDK4', 'Gene', '1019', (67, 71))	('MDM2', 'Gene', '4193', (73, 77))	('PTEN', 'Gene', '5728', (137, 141))	('CDKN2A/B', 'Gene', (123, 131))	('KDR', 'Gene', (94, 97))	('KIT', 'Gene', (85, 88))	('EGFR', 'Gene', (53, 57))	('deletions', 'Var', (110, 119))
204919	31177992	CDK4 amplification and CDKN2A/B deletion appear to be almost mutually exclusive, as they only occur together in one IDH-wildtype LGG case and one IDH-wildtype GBM case (2.3% of cases with these alterations) (Additional file 4: Figure S4 and Additional file 5: Figure S5).	('IDH', 'Gene', (116, 119))	('deletion', 'Var', (32, 40))	('IDH', 'Gene', '3417', (116, 119))	('IDH', 'Gene', (146, 149))	('CDKN2A/B', 'Gene', '1029;1030', (23, 31))	('IDH', 'Gene', '3417', (146, 149))	('CDK4', 'Gene', (0, 4))	('CDKN2A/B', 'Gene', (23, 31))	('CDK4', 'Gene', '1019', (0, 4))
204920	31177992	Chromothripsis, defined here as 10 or more alternating bands of amplifications and deletions in a single chromosome, was identified in at least one tumor in each of the 5 groups analyzed (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('deletions', 'Var', (83, 92))	('Chromothripsis', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
204921	31177992	Comparing individual groups, there was a significant difference in the number of cases with chromothripsis between group 1 LGGs without CDK4 amplification or CDKN2A/B deletion and group 3 IDH-mutant glioblastomas (p = 0.0132) and a significant difference in group 1 LGGs compared to all IDH-mutant tumors with poor prognosis (groups 2 and 3 combined) (p = 0.0211).	('IDH', 'Gene', '3417', (188, 191))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('IDH', 'Gene', '3417', (287, 290))	('CDKN2A/B', 'Gene', (158, 166))	('tumors', 'Disease', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('glioblastomas', 'Phenotype', 'HP:0012174', (199, 212))	('CDK4', 'Gene', (136, 140))	('deletion', 'Var', (167, 175))	('glioblastomas', 'Disease', 'MESH:D005909', (199, 212))	('CDK4', 'Gene', '1019', (136, 140))	('CDKN2A/B', 'Gene', '1029;1030', (158, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (199, 211))	('IDH', 'Gene', (188, 191))	('glioblastomas', 'Disease', (199, 212))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('IDH', 'Gene', (287, 290))
204924	31177992	Analysis of individual genes in the IDH-mutant groups reveals consistently high rates of TP53 mutations in all 3 groups (91-100% of cases) and relatively high rates of ATRX mutations (68-77% of cases).	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('IDH', 'Gene', (36, 39))	('ATRX', 'Gene', (168, 172))	('ATRX', 'Gene', '546', (168, 172))	('IDH', 'Gene', '3417', (36, 39))
204925	31177992	There are other scattered pathogenic mutations, with elevated numbers of EGFR (14%) and PIK3R1 (27%) mutations in the IDH-mutant GBM group (Additional file 1: Figure S1, Additional file 2: Figure S2 and Additional file 3: Figure S3).	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', '1956', (73, 77))	('IDH', 'Gene', (118, 121))	('EGFR', 'Gene', (73, 77))	('IDH', 'Gene', '3417', (118, 121))	('PIK3R1', 'Gene', '5295', (88, 94))	('PIK3R1', 'Gene', (88, 94))
204926	31177992	The IDH-wildtype tumor groups have significantly lower rates of ATRX mutation in both the LGG group (4%) and GBM group (0%), as well as lower rates of TP53 mutations in the LGG group (20%) and GBM group (33%).	('lower', 'NegReg', (136, 141))	('ATRX', 'Gene', (64, 68))	('tumor', 'Disease', (17, 22))	('TP53', 'Gene', (151, 155))	('ATRX', 'Gene', '546', (64, 68))	('IDH', 'Gene', '3417', (4, 7))	('mutations', 'Var', (156, 165))	('mutation', 'Var', (69, 77))	('lower', 'NegReg', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TP53', 'Gene', '7157', (151, 155))	('IDH', 'Gene', (4, 7))
204927	31177992	Mutations in EGFR (32% in LGG; 24% in GBM), PTEN (28% in LGG; 31% in GBM), NF1 (32% in LGG; 7% in GBM), and RB1 (12% in LGG; 12% in GBM) were seen significantly more frequently in these tumors than in the IDH-mutant groups 1-3 (Additional file 4: Figure S4 and Additional file 5: Figure S5).	('RB1', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('NF1', 'Gene', (75, 78))	('IDH', 'Gene', (205, 208))	('NF1', 'Gene', '4763', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (44, 48))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('RB1', 'Gene', '5925', (108, 111))	('PTEN', 'Gene', '5728', (44, 48))	('IDH', 'Gene', '3417', (205, 208))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
204928	31177992	Using a 43-gene panel of genes known to be associated with chromosomal instability (excluding TP53 due to its relative frequency across all groups), we detected a significant difference in the number of mutations between group 1 IDH-mutant LGGs without CDK4 amplifications or CDKN2A/B deletions and group 2 IDH-mutant LGGs with either alteration (p = 0.0197) as well as between group 1 IDH-mutant LGGs and group 3 IDH-mutant GBMs (p = 0.0086) (Fig.	('CDKN2A/B', 'Gene', '1029;1030', (276, 284))	('IDH', 'Gene', (307, 310))	('chromosomal instability', 'Phenotype', 'HP:0040012', (59, 82))	('IDH', 'Gene', (386, 389))	('CDK4', 'Gene', (253, 257))	('TP53', 'Gene', (94, 98))	('CDKN2A/B', 'Gene', (276, 284))	('IDH', 'Gene', (229, 232))	('TP53', 'Gene', '7157', (94, 98))	('IDH', 'Gene', '3417', (307, 310))	('IDH', 'Gene', (414, 417))	('IDH', 'Gene', '3417', (386, 389))	('CDK4', 'Gene', '1019', (253, 257))	('IDH', 'Gene', '3417', (414, 417))	('IDH', 'Gene', '3417', (229, 232))	('deletions', 'Var', (285, 294))	('mutations', 'Var', (203, 212))
204930	31177992	No significant difference was identified between IDH-mutant tumors with poor outcomes (group 2 + 3) and IDH-wildtype tumors with poor prognosis (group 4 + 5) (p = 0.1297), although there was a trend toward fewer mutations in genes specifically associated with chromosomal instability in the IDH-wildtype groups (Tables 1 and 2).	('IDH', 'Gene', '3417', (291, 294))	('IDH', 'Gene', (104, 107))	('IDH', 'Gene', (49, 52))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('IDH-wildtype tumors', 'Disease', (104, 123))	('genes', 'Gene', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('IDH', 'Gene', '3417', (104, 107))	('IDH', 'Gene', '3417', (49, 52))	('tumors', 'Disease', (117, 123))	('fewer', 'NegReg', (206, 211))	('mutations', 'Var', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('chromosomal instability', 'Phenotype', 'HP:0040012', (260, 283))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('IDH', 'Gene', (291, 294))	('tumors', 'Disease', (60, 66))	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (104, 123))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
204935	31177992	In addition, new methods to analyze whole genome genetic and epigenetic signatures are leading to new definitions for many of these tumor groups with significant prognostic implications.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('epigenetic signatures', 'Var', (61, 82))	('tumor', 'Disease', 'MESH:D009369', (132, 137))
204939	31177992	The elevated CNV levels in IDH-mutant LGGs with CDK4 or CDKN2A/B alterations and IDH-mutant GBM represent a heterogenous assortment of genomic alterations within the IDH-mutant group with only a few consistent areas of gains and losses (Fig.	('IDH', 'Gene', (27, 30))	('alterations', 'Var', (65, 76))	('CDK4', 'Gene', '1019', (48, 52))	('IDH', 'Gene', '3417', (27, 30))	('IDH', 'Gene', (166, 169))	('CDKN2A/B', 'Gene', (56, 64))	('IDH', 'Gene', '3417', (166, 169))	('elevated', 'PosReg', (4, 12))	('CNV levels', 'MPA', (13, 23))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', '3417', (81, 84))	('CDK4', 'Gene', (48, 52))	('CDKN2A/B', 'Gene', '1029;1030', (56, 64))
204940	31177992	5b-c) whereas a large fraction of the CNV in IDH-wildtype tumors arose from consistent amplifications in chromosome 7p (containing EGFR), and deletions in chromosomes 9p and 10 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('arose from', 'Reg', (65, 75))	('CNV', 'Disease', (38, 41))	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (45, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('amplifications', 'Var', (87, 101))	('EGFR', 'Gene', '1956', (131, 135))	('deletions', 'Var', (142, 151))	('EGFR', 'Gene', (131, 135))	('IDH-wildtype tumors', 'Disease', (45, 64))
204941	31177992	Our data also agrees with the previously demonstrated data that CDK4 and CDKN2A/B alterations are prognostic factors within the IDH-mutant LGGs.	('CDK4', 'Gene', (64, 68))	('IDH', 'Gene', (128, 131))	('CDKN2A/B', 'Gene', (73, 81))	('CDK4', 'Gene', '1019', (64, 68))	('IDH', 'Gene', '3417', (128, 131))	('alterations', 'Var', (82, 93))	('CDKN2A/B', 'Gene', '1029;1030', (73, 81))
204942	31177992	While worse prognosis seems to correlate with CDK4 or CDKN2A/B status, our earlier study showed only a fraction of the rapidly progressing tumors had these specific alterations, yet all of them had high overall CNV, indicating that it may be an earlier event or a separate phenomenon altogether.	('CNV', 'MPA', (211, 214))	('CDK4', 'Gene', (46, 50))	('rapidly', 'Disease', (119, 126))	('CDK4', 'Gene', '1019', (46, 50))	('CDKN2A/B', 'Gene', '1029;1030', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CDKN2A/B', 'Gene', (54, 62))	('alterations', 'Var', (165, 176))
204947	31177992	CDK4 amplification and CDKN2A/B deletion also appear to be mutually exclusive, with only two total cases (2.3%) having both molecular alterations (Additional file 4: Figure S4 and Additional file 5: Figure S5).	('deletion', 'Var', (32, 40))	('CDKN2A/B', 'Gene', '1029;1030', (23, 31))	('CDK4', 'Gene', (0, 4))	('CDKN2A/B', 'Gene', (23, 31))	('CDK4', 'Gene', '1019', (0, 4))
204948	31177992	An additional finding in these tumor groups is the trend toward more frequent mutations in genes associated with overall chromosomal stability in groups with worse clinical outcomes (groups 2-5) compared to the group with relatively favorable outcomes (group 1) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('mutations', 'Var', (78, 87))
204949	31177992	The number of mutations in genes with chromosomal stability functions and cases with chromothripsis are somewhat lower in the IDH-wildtype cohorts compared to groups 2 and 3 in the IDH-mutant cohorts, despite having statistically identical CNV levels (Fig.	('CNV levels', 'MPA', (240, 250))	('IDH', 'Gene', (181, 184))	('IDH', 'Gene', '3417', (126, 129))	('lower', 'NegReg', (113, 118))	('IDH', 'Gene', '3417', (181, 184))	('chromosomal', 'Gene', (38, 49))	('chromothripsis', 'Disease', (85, 99))	('mutations', 'Var', (14, 23))	('IDH', 'Gene', (126, 129))
204951	31177992	Inactivating mutations in genes associated with maintenance of genetic and chromosomal integrity, and the resulting increase in CNV, allows for rapid and widespread changes to the genome, including chromothripsis, and has the potential to cause more frequent gains of oncogenes and loss of tumor suppressor genes and drive tumor formation and progression towards malignancy.	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('oncogenes', 'Protein', (268, 277))	('malignancy', 'Disease', (363, 373))	('loss of tumor', 'Disease', (282, 295))	('genes', 'Gene', (26, 31))	('gains', 'PosReg', (259, 264))	('tumor', 'Disease', (323, 328))	('Inactivating mutations', 'Var', (0, 22))	('drive', 'PosReg', (317, 322))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('changes', 'Reg', (165, 172))	('increase', 'PosReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('loss of tumor', 'Disease', 'MESH:D009369', (282, 295))	('malignancy', 'Disease', 'MESH:D009369', (363, 373))	('CNV', 'MPA', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('tumor', 'Disease', (290, 295))
204954	31177992	We demonstrate for the first time that higher CNV is associated with previously established prognostic factors within the IDH-mutant LGG subgroup, such as CDK4 amplification and CDKN2A/B deletion.	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('higher', 'PosReg', (39, 45))	('CDK4', 'Gene', '1019', (155, 159))	('amplification', 'Var', (160, 173))	('LGG', 'Gene', (133, 136))	('CDKN2A/B', 'Gene', '1029;1030', (178, 186))	('CDKN2A/B', 'Gene', (178, 186))	('CNV', 'MPA', (46, 49))	('CDK4', 'Gene', (155, 159))
204957	31177992	We also provide a possible mechanism for the overall CNV differences in these astrocytoma subgroups, as the CNV levels seem to correlate with numbers of mutations in genes with roles in maintaining genomic stability.	('mutations', 'Var', (153, 162))	('astrocytoma', 'Disease', 'MESH:D001254', (78, 89))	('astrocytoma', 'Disease', (78, 89))	('astrocytoma', 'Phenotype', 'HP:0009592', (78, 89))
204958	31177992	These results suggest that high overall CNV negate the beneficial effects of IDH1/2 mutation, and could potentially be used as a prognostic marker in IDH-mutant astrocytomas in the future.	('CNV', 'MPA', (40, 43))	('astrocytomas', 'Disease', 'MESH:D001254', (161, 173))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('astrocytomas', 'Disease', (161, 173))	('IDH', 'Gene', (77, 80))	('IDH', 'Gene', (150, 153))	('IDH', 'Gene', '3417', (77, 80))	('IDH', 'Gene', '3417', (150, 153))	('negate', 'NegReg', (44, 50))	('mutation', 'Var', (84, 92))
205072	29763623	In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV.	('POLD1', 'Gene', '5424', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('BRAF', 'Gene', (200, 204))	('V600E', 'Mutation', 'rs113488022', (205, 210))	('NF1', 'Gene', '4763', (214, 217))	('tumor', 'Disease', (44, 49))	('CD8', 'Gene', '925', (251, 254))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('NF1', 'Gene', (214, 217))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (147, 176))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (256, 261))	('BEV', 'Chemical', 'MESH:D000068258', (329, 332))	('POLD1', 'Gene', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('more', 'PosReg', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('pleomorphic xanthoastrocytoma', 'Disease', (147, 176))	('tumors', 'Disease', (44, 50))	('CD8', 'Gene', (251, 254))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('longer', 'PosReg', (292, 298))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('BRAF', 'Gene', '673', (200, 204))
205073	29763623	Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold.	('G34R', 'SUBSTITUTION', 'None', (34, 38))	('K27M', 'Mutation', 'p.K27M', (53, 57))	('G34R', 'Var', (34, 38))	('Histone H3', 'Protein', (0, 10))
205080	29763623	Histone wild-type (WT) tumors have widely differing mutational burdens, ranging from infant cases (<3 years) driven by single gene fusion events through to patients with biallelic mismatch repair deficiency harboring some of the highest mutational rates in human cancer.	('patients', 'Species', '9606', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('biallelic mismatch repair deficiency', 'Var', (170, 206))	('cancer', 'Disease', (263, 269))	('human', 'Species', '9606', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('infant', 'Species', '9606', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
205081	29763623	These include the Children's Oncology Group ACNS0126 (radiotherapy [RT]/temozolomide [TMZ]) and ACNS0423 (RT/TMZ followed by TMZ and lomustine) studies, which report on the frequency and clinical correlations of O6-methylguanine-DNA methyltransferase (MGMT) expression (ACNS0126), IDH1 mutation (ACNS0423), as well as phosphorylated Akt expression and microsatellite instability (both).	('lomustine', 'Chemical', 'MESH:D008130', (133, 142))	('Children', 'Species', '9606', (18, 26))	('Akt', 'Gene', '207', (333, 336))	('TMZ', 'Chemical', 'MESH:D000077204', (125, 128))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (212, 250))	('microsatellite instability', 'MPA', (352, 378))	('IDH1', 'Gene', (281, 285))	('Akt', 'Gene', (333, 336))	('temozolomide', 'Chemical', 'MESH:D000077204', (72, 84))	('MGMT', 'Gene', '4255', (252, 256))	('TMZ', 'Chemical', 'MESH:D000077204', (109, 112))	('MGMT', 'Gene', (252, 256))	('mutation', 'Var', (286, 294))	('IDH1', 'Gene', '3417', (281, 285))	('O6-methylguanine-DNA methyltransferase', 'Gene', (212, 250))	('TMZ', 'Chemical', 'MESH:D000077204', (86, 89))	('Oncology', 'Phenotype', 'HP:0002664', (29, 37))
205082	29763623	The CCG-945 study ("8 in 1" chemotherapy) reported on the prognostic significance of p53 expression/mutation, in addition to the presence/absence of 1p19q co-deletion.	('p53', 'Gene', '7157', (85, 88))	('expression/mutation', 'MPA', (89, 108))	('1p19q co-deletion', 'Var', (149, 166))	('p53', 'Gene', (85, 88))
205083	29763623	It has subsequently become clear that numerous histological subtypes of HGG can harbor distinct genetic drivers and have considerably better clinical outcomes, such as BRAF_V600E mutations in epithelioid glioblastoma (GBM), anaplastic ganglioglioma, and anaplastic pleomorphic xanthoastrocytoma (PXA); in the latter two categories, this mutation is also found in lower-grade entities lacking obvious anaplasia.	('better', 'PosReg', (134, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (283, 294))	('V600E', 'Mutation', 'rs113488022', (173, 178))	('anaplastic pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (254, 294))	('GBM', 'Phenotype', 'HP:0012174', (218, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('glioma', 'Disease', (242, 248))	('anaplastic pleomorphic xanthoastrocytoma', 'Disease', (254, 294))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('BRAF', 'Gene', '673', (168, 172))	('anaplasia', 'Disease', (400, 409))	('anaplasia', 'Disease', 'MESH:D000708', (400, 409))	('mutations', 'Var', (179, 188))	('epithelioid glioblastoma', 'Disease', (192, 216))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('BRAF', 'Gene', (168, 172))	('epithelioid glioblastoma', 'Disease', 'MESH:D005909', (192, 216))
205098	29763623	When IDH1, PXA-like, and LGG-like tumors were excluded from the analysis, the significant differences between histone mutant and HGG-WT groups were absent (H3K27M, p = 0.257 EFS and p = 0.0746 OS; H3G34R/V, p = 0.552 EFS and p = 0.116 OS, log rank test).	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('H3K27M', 'Var', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('K27M', 'Mutation', 'p.K27M', (158, 162))	('H3G34R/V', 'Var', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('IDH1', 'Gene', (5, 9))	('G34R/V', 'Mutation', 'rs569791806', (199, 205))	('IDH1', 'Gene', '3417', (5, 9))	('mutant', 'Var', (118, 124))	('histone', 'Protein', (110, 117))
205099	29763623	Twelve out of 78 (15%) samples harbored a methylated MGMT promoter, although this was largely restricted to the H3G34R/V (n = 3, p = 0.0249, Fishers exact test) and IDH1 (n = 3, p = 0.0062, Fisher's exact test) subgroups (Figure S1A), and was not significantly associated with survival (Figure S1B) in these uniformly TMZ-treated patients.	('Fishers', 'Species', '76720', (141, 148))	('methylated', 'Var', (42, 52))	('H3G34R/V', 'Var', (112, 120))	('TMZ', 'Chemical', 'MESH:D000077204', (318, 321))	('IDH1', 'Gene', (165, 169))	('MGMT', 'Gene', (53, 57))	('G34R/V', 'Mutation', 'rs569791806', (114, 120))	('patients', 'Species', '9606', (330, 338))	('MGMT', 'Gene', '4255', (53, 57))	('IDH1', 'Gene', '3417', (165, 169))
205100	29763623	The most common alteration was TP53 mutation (39/82, 48%), followed by ATRX deletion/mutation (25/82, 30%), PDGFRA amplification/mutation (17/82, 21%), and CDKN2A/B deletion (15/82, 18%).	('CDKN2A/B', 'Gene', '1029;1030', (156, 164))	('TP53', 'Gene', '7157', (31, 35))	('ATRX', 'Gene', '546', (71, 75))	('TP53', 'Gene', (31, 35))	('ATRX', 'Gene', (71, 75))	('PDGFRA', 'Gene', '5156', (108, 114))	('CDKN2A/B', 'Gene', (156, 164))	('PDGFRA', 'Gene', (108, 114))	('deletion/mutation', 'Var', (76, 93))	('mutation', 'Var', (36, 44))
205101	29763623	Additional recurrent alterations in receptor tyrosine kinases (EGFR, MET, ERBB3, IGF1R, and NTRK2), phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (PTEN, PIK3CA, TSC2, and PIK3R1), and MAP-kinase (NF1, BRAF, PTPN11, and PTPN12) pathways were common, as were amplifications/mutations in various genes associated with cell-cycle regulation (RB1, CDK4, MDM2, and CCND2).	('EGFR', 'Gene', '1956', (63, 67))	('TSC2', 'Gene', '7249', (182, 186))	('PIK3R1', 'Gene', '5295', (192, 198))	('PTEN', 'Gene', '5728', (168, 172))	('MDM2', 'Gene', (370, 374))	('RB1', 'Gene', '5925', (359, 362))	('IGF1R', 'Gene', '3480', (81, 86))	('PTPN12', 'Gene', '5782', (240, 246))	('PTPN11', 'Gene', (228, 234))	('CDK4', 'Gene', '1019', (364, 368))	('alterations', 'Reg', (21, 32))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (100, 129))	('NTRK2', 'Gene', (92, 97))	('IGF1R', 'Gene', (81, 86))	('MDM2', 'Gene', '4193', (370, 374))	('TSC2', 'Gene', (182, 186))	('BRAF', 'Gene', '673', (222, 226))	('BRAF', 'Gene', (222, 226))	('PIK3CA', 'Gene', '5290', (174, 180))	('PTPN11', 'Gene', '5781', (228, 234))	('ERBB3', 'Gene', '2065', (74, 79))	('phosphatidylinositol 3-kinase', 'Gene', (100, 129))	('amplifications/mutations', 'Var', (278, 302))	('PTPN12', 'Gene', (240, 246))	('PIK3R1', 'Gene', (192, 198))	('mammalian target of rapamycin', 'Gene', '2475', (137, 166))	('EGFR', 'Gene', (63, 67))	('CCND2', 'Gene', (380, 385))	('MAP-kinase', 'Pathway', (205, 215))	('receptor tyrosine kinases', 'Pathway', (36, 61))	('CCND2', 'Gene', '894', (380, 385))	('NF1', 'Gene', '4763', (217, 220))	('PTEN', 'Gene', (168, 172))	('PIK3CA', 'Gene', (174, 180))	('mammalian target of rapamycin', 'Gene', (137, 166))	('RB1', 'Gene', (359, 362))	('NTRK2', 'Gene', '4915', (92, 97))	('CDK4', 'Gene', (364, 368))	('ERBB3', 'Gene', (74, 79))	('NF1', 'Gene', (217, 220))
205104	29763623	A further case, a compact and necrotic tumor with perivascular radiating arrangements (Figure S2B), displayed a methylation classifier score strongly indicative of a high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1, methylation classifier score = 0.713) (Figure S2C).	('neuroepithelial tumor', 'Disease', (177, 198))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (177, 198))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('necrotic tumor', 'Disease', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (177, 198))	('necrotic tumor', 'Disease', 'MESH:D009369', (30, 44))	('MN1', 'Gene', (204, 207))	('alteration', 'Var', (208, 218))
205105	29763623	We identified a candidate alteration in this case fusing exon 1 of MN1 (22q12.1) to exon 3 of CARD6 (5p13.1) (Figure S2D), and thus appears most likely to fall into this categorization.	('fall', 'Reg', (155, 159))	('alteration', 'Var', (26, 36))	('MN1', 'Gene', (67, 70))	('CARD6', 'Gene', (94, 99))	('fall', 'Phenotype', 'HP:0002527', (155, 159))	('CARD6', 'Gene', '84674', (94, 99))	('fusing', 'NegReg', (50, 56))
205107	29763623	The first two harbored mitogen-activated protein kinase (MAPK) dysregulation in the form of either BRAF_V600E or intragenic FGFR1 duplication (Figure S2E).	('duplication', 'Var', (130, 141))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('dysregulation', 'Reg', (63, 76))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('FGFR1', 'Gene', (124, 129))	('FGFR1', 'Gene', '2260', (124, 129))
205110	29763623	There were four cases with IDH1 hotspot mutations (Figure S3A).	('mutations', 'Var', (40, 49))	('IDH1', 'Gene', '3417', (27, 31))	('IDH1', 'Gene', (27, 31))
205111	29763623	Three were classified as WHO-grade III anaplastic astrocytoma (AA), IDH1_R132-positive by immunohistochemistry, with concurrent TP53 and ATRX mutations.	('mutations', 'Var', (142, 151))	('ATRX', 'Gene', (137, 141))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('IDH1', 'Gene', (68, 72))	('ATRX', 'Gene', '546', (137, 141))	('astrocytoma', 'Disease', 'MESH:D001254', (50, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('IDH1', 'Gene', '3417', (68, 72))	('astrocytoma', 'Disease', (50, 61))	('AA', 'Phenotype', 'HP:0009592', (63, 65))
205112	29763623	The remaining case was originally classified as a mixed oligo-astrocytoma, which, by virtue of the presence of IDH1_R132 and TERT promoter mutation (C228T), as well as copy-number loss of chromosomes 1p and 19q, would be described as an oligodendroglioma according to WHO 2016 (Figure S3B).	('C228T', 'Mutation', 'c.228C>T', (149, 154))	('copy-number loss', 'Var', (168, 184))	('oligodendroglioma', 'Disease', (237, 254))	('oligo-astrocytoma', 'Disease', (56, 73))	('oligodendroglioma', 'Disease', 'MESH:D009837', (237, 254))	('oligo-astrocytoma', 'Disease', 'MESH:D001254', (56, 73))	('IDH1', 'Gene', '3417', (111, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('C228T', 'Var', (149, 154))	('TERT', 'Gene', (125, 129))	('mixed', 'Disease', (50, 55))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('TERT', 'Gene', '7015', (125, 129))	('IDH1', 'Gene', (111, 115))
205113	29763623	Across the whole cohort, IDH1 mutation conferred a significantly longer EFS (p = 0.0398, log rank test), although not OS (p = 0.110, log rank test) (Figure S3C), and were restricted to the frontal lobes (Figure S3D).	('EFS', 'MPA', (72, 75))	('mutation', 'Var', (30, 38))	('frontal lobes', 'Disease', 'MESH:D001927', (189, 202))	('longer', 'PosReg', (65, 71))	('frontal lobes', 'Disease', (189, 202))	('IDH1', 'Gene', (25, 29))	('IDH1', 'Gene', '3417', (25, 29))
205114	29763623	After excluding IDH1 mutant cases, the remaining H3F3A and BRAF WT cases (n = 38) represented a heterogeneous mix of genomic profiles, with recurrent deletions/mutations in the common pHGG tumor suppressor genes TP53 (n = 11), ATRX (n = 5), CDKN2A/B (n = 7), NF1 (n = 8), RB1 (n = 7), and PTEN (n = 5), but also with an enrichment of gene amplifications in PDGFRA (n = 5, with KIT and KDR, n = 4), CDK4 (n = 7, with MDM2, n = 4), EGFR (n = 4), MET (n = 2), CCND2 (n = 3), and MYCN (n = 3) (Figure S3E).	('CCND2', 'Gene', '894', (457, 462))	('CDK4', 'Gene', '1019', (398, 402))	('PDGFRA', 'Gene', '5156', (357, 363))	('PDGFRA', 'Gene', (357, 363))	('RB1', 'Gene', '5925', (272, 275))	('CDKN2A/B', 'Gene', (241, 249))	('H3F3A', 'Gene', '3020', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('PTEN', 'Gene', (289, 293))	('KDR', 'Gene', (385, 388))	('EGFR', 'Gene', (430, 434))	('NF1', 'Gene', '4763', (259, 262))	('IDH1', 'Gene', (16, 20))	('ATRX', 'Gene', (227, 231))	('MDM2', 'Gene', (416, 420))	('H3F3A', 'Gene', (49, 54))	('CDKN2A/B', 'Gene', '1029;1030', (241, 249))	('TP53', 'Gene', '7157', (212, 216))	('ATRX', 'Gene', '546', (227, 231))	('MET', 'Gene', (444, 447))	('PTEN', 'Gene', '5728', (289, 293))	('MYCN', 'Gene', '4613', (476, 480))	('NF1', 'Gene', (259, 262))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('MDM2', 'Gene', '4193', (416, 420))	('KDR', 'Gene', '3791', (385, 388))	('IDH1', 'Gene', '3417', (16, 20))	('CDK4', 'Gene', (398, 402))	('EGFR', 'Gene', '1956', (430, 434))	('tumor', 'Disease', (189, 194))	('RB1', 'Gene', (272, 275))	('deletions/mutations', 'Var', (150, 169))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CCND2', 'Gene', (457, 462))	('MYCN', 'Gene', (476, 480))	('TP53', 'Gene', (212, 216))
205116	29763623	Histone mutations have been shown to be present in approximately half of all pHGGs, with a clear negative impact on survival for K27M, although the situation is less clear for G34R/V mutations.	('Histone', 'Protein', (0, 7))	('K27M', 'Var', (129, 133))	('G34R', 'SUBSTITUTION', 'None', (176, 180))	('G34R', 'Var', (176, 180))	('survival', 'MPA', (116, 124))	('negative', 'NegReg', (97, 105))	('K27M', 'Mutation', 'p.K27M', (129, 133))
205118	29763623	There were seven cases with H3F3A_G34 substitutions (six G34R and one G34V), with six out of seven (86%) cases additionally harboring TP53 and/or ATRX mutations (five out of seven, 71% both), while five out of seven (71%) also contained PDGFRA amplification and/or mutation (Figure 4B).	('G34R', 'Var', (57, 61))	('PDGFRA', 'Gene', '5156', (237, 243))	('H3F3A', 'Gene', '3020', (28, 33))	('PDGFRA', 'Gene', (237, 243))	('TP53', 'Gene', (134, 138))	('mutation', 'Reg', (265, 273))	('harboring', 'Reg', (124, 133))	('ATRX', 'Gene', (146, 150))	('H3F3A', 'Gene', (28, 33))	('G34V', 'Mutation', 'p.G34V', (70, 74))	('G34R', 'Mutation', 'rs1057519902', (57, 61))	('TP53', 'Gene', '7157', (134, 138))	('ATRX', 'Gene', '546', (146, 150))
205119	29763623	There were no other recurrent mutations, although isolated instances of mutations in PI3K signaling (PIK3CA and PTEN) and DNA repair (ERCC1) were observed (Table S3).	('mutations', 'Var', (72, 81))	('PI3K signaling', 'Pathway', (85, 99))	('PIK3CA', 'Gene', '5290', (101, 107))	('ERCC1', 'Gene', '2067', (134, 139))	('DNA', 'MPA', (122, 125))	('PTEN', 'Gene', (112, 116))	('PTEN', 'Gene', '5728', (112, 116))	('ERCC1', 'Gene', (134, 139))	('PIK3CA', 'Gene', (101, 107))
205121	29763623	Across all tumors within this hemispheric subgroup, patients harboring these mutations trended toward a shorter EFS (median = 8.3 months; p = 0.0572, log rank test) and had a significantly shorter OS (median = 12.0 months; p = 0.00765, log rank test) (Figure 4D), although this association was lost when IDH1, PXA-like, and LGG-like tumors were excluded (p = 0.440 EFS and p = 0.139 OS, log rank test) (Figure S4A).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Disease', (333, 339))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('shorter', 'NegReg', (104, 111))	('IDH1', 'Gene', (304, 308))	('shorter', 'NegReg', (189, 196))	('tumors', 'Disease', (11, 17))	('EFS', 'MPA', (112, 115))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mutations', 'Var', (77, 86))	('IDH1', 'Gene', '3417', (304, 308))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('patients', 'Species', '9606', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
205123	29763623	Two patients had distinct, separate lesions in the thalamus and hypothalamus, while the remaining had central thalamic, midbrain, or cerebellar localization (Figure 4E).	('lesions', 'Var', (36, 43))	('separate lesions in the thalamus', 'Phenotype', 'HP:0010664', (27, 59))	('hypothalamus', 'Disease', (64, 76))	('hypothalamus', 'Disease', 'MESH:D007029', (64, 76))	('patients', 'Species', '9606', (4, 12))
205124	29763623	Fifteen out of 21 (71%) exome-sequenced cases carried additional amplifications/mutations in the receptor-tyrosine kinase (RTK)-PI3K pathway across a range of genes (PDGFRA, MET, IGF1R, FGFR1, PTEN, PIK3CA, and PIK3R1), with five out of six of the remaining tumors harboring ATRX mutation (Figure 4F; Table S3).	('receptor-tyrosine kinase', 'Gene', '5979', (97, 121))	('RTK', 'Gene', '5979', (123, 126))	('ATRX', 'Gene', (275, 279))	('PIK3CA', 'Gene', '5290', (199, 205))	('ATRX', 'Gene', '546', (275, 279))	('PDGFRA', 'Gene', '5156', (166, 172))	('PDGFRA', 'Gene', (166, 172))	('amplifications/mutations', 'Var', (65, 89))	('PIK3R1', 'Gene', (211, 217))	('FGFR1', 'Gene', '2260', (186, 191))	('MET', 'Gene', (174, 177))	('mutation', 'Var', (280, 288))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('amplifications/mutations', 'Reg', (65, 89))	('PTEN', 'Gene', (193, 197))	('receptor-tyrosine kinase', 'Gene', (97, 121))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('PIK3CA', 'Gene', (199, 205))	('tumors', 'Disease', (258, 264))	('PTEN', 'Gene', '5728', (193, 197))	('IGF1R', 'Gene', '3480', (179, 184))	('PIK3R1', 'Gene', '5295', (211, 217))	('FGFR1', 'Gene', (186, 191))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('IGF1R', 'Gene', (179, 184))	('RTK', 'Gene', (123, 126))
205126	29763623	Although conferring a worse prognosis across the whole cohort (above), within midline locations there was no association with either EFS (median = 7.9 months; p = 0.482, log rank test) or OS (median = 14.2 months; p = 0.839, log rank test) (Figure 4H), nor any prognostic value for WHO-grade in K27M tumors (p = 0.646 EFS and p = 0.762 OS, log rank test) (Figure S4B).	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('K27M', 'Mutation', 'p.K27M', (295, 299))	('tumors', 'Disease', (300, 306))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('K27M', 'Var', (295, 299))
205127	29763623	Mutation signature analysis showed predominantly C > T transitions and hotspot somatic POLE mutations in three cases, and a somatic POLD1 mutation in the fourth (Figure 5B).	('hotspot', 'PosReg', (71, 78))	('POLD1', 'Gene', '5424', (132, 137))	('POLD1', 'Gene', (132, 137))	('C > T transitions', 'Var', (49, 66))
205133	29763623	Histone mutant tumors were notably immune cold as defined by a lack of CD8 immunoreactivity and an absence of TILs.	('CD8', 'Gene', '925', (71, 74))	('Histone', 'Gene', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('lack', 'NegReg', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mutant', 'Var', (8, 14))	('lack of CD8 immunoreactivity', 'Phenotype', 'HP:0005422', (63, 91))	('tumors', 'Disease', (15, 21))	('CD8', 'Gene', (71, 74))
205134	29763623	Five out of nine (55%) harbored BRAF_V600E mutations, with three out of five (60%) also containing CDKN2A/B deletions and/or TERT amplification or promoter mutation (C250T) (Figure 6A).	('CDKN2A/B', 'Gene', (99, 107))	('BRAF', 'Gene', '673', (32, 36))	('BRAF', 'Gene', (32, 36))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('C250T', 'Var', (166, 171))	('TERT', 'Gene', (125, 129))	('C250T', 'Mutation', 'c.250C>T', (166, 171))	('deletions', 'Var', (108, 117))	('CDKN2A/B', 'Gene', '1029;1030', (99, 107))	('TERT', 'Gene', '7015', (125, 129))
205135	29763623	Three of four of the remaining cases were instead found with somatic NF1 mutation, often in concert with TP53 (three out of four) and/or ATRX mutation (two out of four).	('NF1', 'Gene', '4763', (69, 72))	('ATRX', 'Gene', (137, 141))	('ATRX', 'Gene', '546', (137, 141))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('mutation', 'Var', (73, 81))	('NF1', 'Gene', (69, 72))
205138	29763623	Gene expression data from RNA-seq were available for a subset of samples, in which a CD8 T effector/T cell signature was found to correlate with CD8 positivity by immunohistochemistry (r2 = 0.49138, p = 0.00523), with two hypermutator cases as outliers (Figure 7A).	('CD8', 'Gene', (85, 88))	('CD8', 'Gene', '925', (85, 88))	('CD8', 'Gene', (145, 148))	('positivity', 'Var', (149, 159))	('CD8', 'Gene', '925', (145, 148))
205139	29763623	Although no PXA-like or BRAF_V600E mutant cases were included in this subset, these signatures were particularly evident in cases with predicted MAPK pathway-activating alterations in NF1 (truncating frameshift/nonsense, disrupting translocation or predicted damaging missense), NTRK2 (translocation or tandem duplication of kinase domains), and FGFR1 (known activating hotspot mutation) (Figure 7B).	('V600E', 'Mutation', 'rs113488022', (29, 34))	('NF1', 'Gene', (184, 187))	('alterations', 'Var', (169, 180))	('translocation', 'MPA', (232, 245))	('NTRK2', 'Gene', '4915', (279, 284))	('truncating frameshift/nonsense', 'Var', (189, 219))	('FGFR1', 'Gene', (346, 351))	('NF1', 'Gene', '4763', (184, 187))	('FGFR1', 'Gene', '2260', (346, 351))	('MAPK pathway-activating', 'Pathway', (145, 168))	('BRAF', 'Gene', (24, 28))	('disrupting', 'Var', (221, 231))	('NTRK2', 'Gene', (279, 284))	('BRAF', 'Gene', '673', (24, 28))
205145	29763623	Although the presence of macrophage infiltration has previously been reported in diffuse intrinsic pontine glioma, we observed no association of the M2 gene expression signature with K27M midline tumors in our cohort (p = 0.965).	('K27M', 'Var', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('midline tumors', 'Disease', (188, 202))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('midline tumors', 'Disease', 'MESH:D009369', (188, 202))	('K27M', 'Mutation', 'p.K27M', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('glioma', 'Disease', (107, 113))
205148	29763623	Notably, however, while not predictive in the TMZ/RT arm (Figure 7D), the presence of high levels of CD8+ T cells within the central tumor area conferred a significantly better OS in children receiving the addition of BEV (p = 0.0404, log rank test) (Figure 7E).	('CD8', 'Gene', '925', (101, 104))	('children', 'Species', '9606', (183, 191))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('presence', 'Var', (74, 82))	('TMZ', 'Chemical', 'MESH:D000077204', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('better', 'PosReg', (170, 176))	('CD8', 'Gene', (101, 104))	('BEV', 'Chemical', 'MESH:D000068258', (218, 221))
205149	29763623	Fitting a Cox interaction model (with proportional hazards confirmed by calculating Schoenfeld residuals, p = 0.268), high CD8 levels trended toward predictivity of response to TMZ/RT + BEV, with a hazard ratio of 0.360 (p = 0.066).	('high', 'Var', (118, 122))	('CD8', 'Gene', (123, 126))	('TMZ', 'Chemical', 'MESH:D000077204', (177, 180))	('Cox', 'Gene', '1351', (10, 13))	('Cox', 'Gene', (10, 13))	('CD8', 'Gene', '925', (123, 126))	('BEV', 'Chemical', 'MESH:D000068258', (186, 189))
205151	29763623	Within hemispheric tumors only, there is a significant interaction between high CD8 and BEV (hazard ratio [HR] = 0.251, p = 0.024).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('CD8', 'Gene', '925', (80, 83))	('high', 'Var', (75, 79))	('interaction', 'Interaction', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BEV', 'Chemical', 'MESH:D000068258', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('CD8', 'Gene', (80, 83))	('BEV', 'Gene', (88, 91))
205153	29763623	An important example is the four adolescent patients with IDH1 mutation, who had a significantly better clinical outcome, and may now be thought of as the lower age limit of an adult subgroup rather than pHGGs.	('IDH1', 'Gene', '3417', (58, 62))	('patients', 'Species', '9606', (44, 52))	('mutation', 'Var', (63, 71))	('better', 'PosReg', (97, 103))	('IDH1', 'Gene', (58, 62))
205156	29763623	Notably, both hypermutator cases, and those biologically resembling PXAs, the latter of which harbored either BRAF- or NF1-driven MAP-kinase alterations, were found to be the most immunogenic in terms of CD8+ T cells/TILs, including a significantly elevated CD8 effector T cell gene expression signature.	('CD8', 'Gene', '925', (204, 207))	('alterations', 'Var', (141, 152))	('elevated', 'PosReg', (249, 257))	('NF1', 'Gene', (119, 122))	('CD8', 'Gene', (258, 261))	('BRAF', 'Gene', '673', (110, 114))	('NF1', 'Gene', '4763', (119, 122))	('CD8', 'Gene', '925', (258, 261))	('BRAF', 'Gene', (110, 114))	('CD8', 'Gene', (204, 207))
205161	29763623	Although involved in the regulation of T cell proliferation and survival, selective BRAF inhibitors have been shown to increase CD8+ lymphocytes in human metastatic melanoma models.	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('inhibitors', 'Var', (89, 99))	('human', 'Species', '9606', (148, 153))	('CD8', 'Gene', (128, 131))	('increase', 'PosReg', (119, 127))	('CD8', 'Gene', '925', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
205162	29763623	Crucially, although MEK inhibition has been demonstrated to block naive CD8+ T cell priming in a colon cancer model, the number of CD8+ effector T cells within the tumor were increased, and could potentiate immune checkpoint therapy.	('colon cancer', 'Disease', 'MESH:D015179', (97, 109))	('tumor', 'Disease', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MEK', 'Gene', (20, 23))	('colon cancer', 'Phenotype', 'HP:0003003', (97, 109))	('colon cancer', 'Disease', (97, 109))	('MEK', 'Gene', '5609', (20, 23))	('potentiate', 'PosReg', (196, 206))	('inhibition', 'Var', (24, 34))	('CD8', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('increased', 'PosReg', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('CD8', 'Gene', (131, 134))	('immune checkpoint therapy', 'CPA', (207, 232))	('CD8', 'Gene', '925', (72, 75))	('CD8', 'Gene', '925', (131, 134))
205164	29763623	This is a challenge given that these patients represent approximately 10%-15% of an already rare disease; however, international collaborative trials groups (such as those in HERBY represent), already recruit hypermutator and MAPK-altered HGGs in this population for appropriately targeted therapies (NCT02992964, NCT02684058).	('HGGs', 'Protein', (239, 243))	('MAPK-altered', 'Var', (226, 238))	('NCT02992964', 'Var', (301, 312))	('patients', 'Species', '9606', (37, 45))
205165	29763623	Equally importantly, the histone H3 mutant subgroups, which represent a substantial proportion of patients in this age group were found to be very poorly immunogenic, confirming a previous study in resectable malignant brainstem gliomas in children and adults with K27M mutations, and further negating the likelihood of clinical response to such therapies.	('brainstem gliomas', 'Phenotype', 'HP:0010796', (219, 236))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('brainstem glioma', 'Phenotype', 'HP:0010796', (219, 235))	('gliomas', 'Disease', (229, 236))	('patients', 'Species', '9606', (98, 106))	('K27M mutations', 'Var', (265, 279))	('gliomas', 'Disease', 'MESH:D005910', (229, 236))	('histone H3', 'Protein', (25, 35))	('gliomas', 'Phenotype', 'HP:0009733', (229, 236))	('mutant', 'Var', (36, 42))	('K27M', 'Mutation', 'p.K27M', (265, 269))	('children', 'Species', '9606', (240, 248))
205166	29763623	A key observation is the high prevalence of tumors occurring outside the cerebral hemispheres harboring histone mutations, included in the most recent 2016 WHO classification system as a separate entity called diffuse midline glioma with H3K27M mutation.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('H3K27M mutation', 'Var', (238, 253))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('K27M', 'Mutation', 'p.K27M', (240, 244))	('midline glioma', 'Disease', 'MESH:D005910', (218, 232))	('midline glioma', 'Disease', (218, 232))	('mutations', 'Var', (112, 121))	('histone', 'Gene', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
205168	29763623	Critically, midline K27M tumors classified histologically as either grade 3 or 4 according to the WHO 2007 classification had no difference in clinical outcome within the HERBY cohort, and with the caveat of small numbers, support the current 2016 guidelines to assign all such tumors as grade 4 on the basis of their location and molecular findings.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (278, 284))	('tumors', 'Disease', (25, 31))	('K27M', 'SUBSTITUTION', 'None', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('K27M', 'Var', (20, 24))
205170	29763623	A previous study reported G34R mutations to convey a better prognosis in respect of OS (HR = 0.49, p = 0.01), although this was not significant in multivariate analysis (p = 0.84), although the present study explores this in a consistently treated and well-annotated clinical trial setting.	('G34R', 'Mutation', 'rs1057519902', (26, 30))	('mutations', 'Var', (31, 40))	('G34R', 'Gene', (26, 30))
205186	29763623	Only three cases left insufficient DNA for exome sequencing, all of which were found to harbor K27M mutations, and thus additional Sanger sequencing for genes encoding H3.1 variants were not undertaken.	('K27M mutations', 'Var', (95, 109))	('K27M', 'Mutation', 'p.K27M', (95, 99))	('harbor', 'Reg', (88, 94))	('H3.1', 'Gene', (168, 172))	('H3.1', 'Gene', '8352', (168, 172))
205192	29763623	The panel capture a total of 22 genes recently implicated in brain tumors (ALK, BCOR, BRAF, c11orf95, C19MC, CIC, ETV6, FGFR1-3, FOXR2, KIAA1549, MET, MN1, MYB, MYBL1, NTRK1-3, RAF, RELA, TPM3 and YAP1).	('AA', 'Phenotype', 'HP:0009592', (138, 140))	('KIAA1549', 'Gene', (136, 144))	('FOXR2', 'Gene', '139628', (129, 134))	('FGFR1', 'Gene', (120, 125))	('MYBL1', 'Gene', (161, 166))	('RAF', 'Gene', (177, 180))	('ALK', 'Gene', '238', (75, 78))	('brain tumors', 'Disease', (61, 73))	('MYBL1', 'Gene', '4603', (161, 166))	('RELA', 'Gene', (182, 186))	('MYB', 'Gene', '4602', (161, 164))	('RELA', 'Gene', '5970', (182, 186))	('MYB', 'Gene', (161, 164))	('C19MC', 'Var', (102, 107))	('ALK', 'Gene', (75, 78))	('RAF', 'Gene', '22882', (87, 90))	('BCOR', 'Gene', '54880', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('NTRK1', 'Gene', '4914', (168, 173))	('TPM3', 'Gene', '7170', (188, 192))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (86, 90))	('ETV6', 'Gene', '2120', (114, 118))	('YAP1', 'Gene', '10413', (197, 201))	('NTRK1', 'Gene', (168, 173))	('MN1', 'Gene', (151, 154))	('BCOR', 'Gene', (80, 84))	('RAF', 'Gene', (87, 90))	('FGFR1', 'Gene', '2260', (120, 125))	('brain tumor', 'Phenotype', 'HP:0030692', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('YAP1', 'Gene', (197, 201))	('c11orf95', 'Gene', '65998', (92, 100))	('MYB', 'Gene', '4602', (156, 159))	('KIAA1549', 'Gene', '57670', (136, 144))	('brain tumors', 'Disease', 'MESH:D001932', (61, 73))	('brain tumors', 'Phenotype', 'HP:0030692', (61, 73))	('FOXR2', 'Gene', (129, 134))	('TPM3', 'Gene', (188, 192))	('MYB', 'Gene', (156, 159))	('RAF', 'Gene', '22882', (177, 180))	('ETV6', 'Gene', (114, 118))	('c11orf95', 'Gene', (92, 100))
205195	29763623	A standard pre-treatment protocol included CC1 buffer (or CC2 for H3G34R) and then a primary antibody incubation for 32 minutes (92 minutes for MLH1, PMS2, MSH2 and MSH6) at room temperature (37 C for H3K27M and MLH1).	('PMS2', 'Gene', (150, 154))	('H3K27M', 'Var', (201, 207))	('PMS2', 'Gene', '5395', (150, 154))	('MSH6', 'Gene', '2956', (165, 169))	('MLH1', 'Gene', '4292', (212, 216))	('MLH1', 'Gene', (212, 216))	('MLH1', 'Gene', '4292', (144, 148))	('CC1', 'Gene', '9821', (43, 46))	('MLH1', 'Gene', (144, 148))	('K27M', 'Mutation', 'p.K27M', (203, 207))	('G34R', 'Mutation', 'rs1057519902', (68, 72))	('MSH2', 'Gene', (156, 160))	('CC1', 'Gene', (43, 46))	('MSH6', 'Gene', (165, 169))	('MSH2', 'Gene', '4436', (156, 160))
205208	29763623	Variants were annotated using the Ensembl Variant Effect Predictor v74 (ensembl.org/info/docs/variation/vep) incorporating SIFT (sift.jcvi.org) and PolyPhen (genetics.bwh.harvard.edu/pph2) predictions, COSMIC v64 (sanger.ac.uk/ genetics/CGP/cosmic/) and dbSNP build 137 (ncbi.nlm.nih.gov/sites/SNP) annotations.	('SIFT', 'Disease', 'None', (123, 127))	('Variants', 'Var', (0, 8))	('SIFT', 'Disease', (123, 127))
89968	29763623	Simplified methylation subgroup assignments were then made to incorporate cases carrying G34R/V or K27M mutations in H3 histones, IDH1 mutation at R132, low grade glioma-like profiles (predominantly diffuse infantile ganglioglioma and pilocytic astrocytoma) and those similar to pleomorphic xanthoastrocytoma (PXA).	('G34R', 'SUBSTITUTION', 'None', (89, 93))	('glioma', 'Disease', (163, 169))	('K27M mutations', 'Var', (99, 113))	('H3 histones', 'Protein', (117, 128))	('K27M', 'Mutation', 'p.K27M', (99, 103))	('G34R', 'Var', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('IDH1', 'Gene', '3417', (130, 134))	('ganglioglioma and pilocytic astrocytoma', 'Disease', 'MESH:D001254', (217, 256))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('glioma', 'Disease', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('mutation at R132', 'Var', (135, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (245, 256))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (279, 308))	('IDH1', 'Gene', (130, 134))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('infant', 'Species', '9606', (207, 213))	('astrocytoma', 'Phenotype', 'HP:0009592', (297, 308))	('pleomorphic xanthoastrocytoma', 'Disease', (279, 308))
205213	29763623	The mean expression was also used to correlate with CD8 positivity by IHC.	('CD8', 'Gene', (52, 55))	('CD8', 'Gene', '925', (52, 55))	('positivity', 'Var', (56, 66))
205214	29763623	Gene Set enrichment analysis was performed using the GSEA java application based upon pairwise comparisons of MAPK altered versus wild-type for curated canonical gene sets.	('MAPK', 'Gene', (110, 114))	('altered', 'Var', (115, 122))	('GSEA', 'Chemical', '-', (53, 57))
205246	29184090	The effect of tetrac, triac and T1AM on cancer cell proliferation and viability was examined in vitro in two ovarian cancer cell lines, OVCAR3, with high alphavbeta3 integrin levels and A2780, with lower integrin expression.	('beta3', 'Gene', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('high', 'PosReg', (149, 153))	('ovarian cancer', 'Disease', 'MESH:D010051', (109, 123))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tetrac', 'Chemical', 'MESH:C011126', (14, 20))	('beta3', 'Gene', '1934', (160, 165))	('cancer', 'Disease', (40, 46))	('ovarian cancer', 'Disease', (109, 123))	('A2780', 'Var', (186, 191))	('A2780', 'CellLine', 'CVCL:0134', (186, 191))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('T1AM', 'Chemical', '-', (32, 36))	('amine', 'Chemical', 'MESH:D000588', (86, 91))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('triac', 'Chemical', 'MESH:C010642', (22, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
205265	29184090	The effect of T1AM on cyclin D1 induction was observed between 1-2 hours of treatment and was diminished after 4 hours.	('T1AM', 'Chemical', '-', (14, 18))	('induction', 'MPA', (32, 41))	('T1AM', 'Var', (14, 18))	('cyclin D1', 'Gene', '595', (22, 31))	('cyclin D1', 'Gene', (22, 31))
205268	29184090	3A), while triac and T1AM inhibited cell viability in OVCAR3 at 25 muM and at both concentrations in A2780.	('T1AM', 'Var', (21, 25))	('inhibited', 'NegReg', (26, 35))	('triac', 'Chemical', 'MESH:C010642', (11, 16))	('A2780', 'CellLine', 'CVCL:0134', (101, 106))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', (67, 70))	('cell viability', 'CPA', (36, 50))	('T1AM', 'Chemical', '-', (21, 25))
205269	29184090	Cell viability was increased by tetrac/triac/T1AM at 10 and 25 muM in the normal control cells, while in OVCAR3 and A2780 a similar increase was shown by tetrac at 10 muM.	('tetrac/triac/T1AM', 'Var', (32, 49))	('T1AM', 'Chemical', '-', (45, 49))	('muM', 'Gene', '56925', (63, 66))	('tetrac', 'Chemical', 'MESH:C011126', (32, 38))	('tetrac', 'Chemical', 'MESH:C011126', (154, 160))	('muM', 'Gene', (167, 170))	('Cell viability', 'CPA', (0, 14))	('muM', 'Gene', (63, 66))	('increased', 'PosReg', (19, 28))	('A2780', 'CellLine', 'CVCL:0134', (116, 121))	('triac', 'Chemical', 'MESH:C010642', (39, 44))	('muM', 'Gene', '56925', (167, 170))
205275	29184090	Triac and T1AM potently induced apoptosis in the two cell models at both examined concentrations.	('T1AM', 'Chemical', '-', (10, 14))	('apoptosis', 'CPA', (32, 41))	('amine', 'Chemical', 'MESH:D000588', (75, 80))	('T1AM', 'Var', (10, 14))	('Triac', 'Chemical', 'MESH:C010642', (0, 5))	('induced', 'Reg', (24, 31))
205276	29184090	Representative flow-cytometry analysis for OVCAR3 and A2780 are presented in Supplementary Fig.	('A2780', 'CellLine', 'CVCL:0134', (54, 59))	('A2780', 'Var', (54, 59))	('OVCAR3', 'Gene', (43, 49))
205282	29184090	For T1AM, apoptosis was observed in both ovarian cancer cell lines, mainly at 25 muM concentration.	('ovarian cancer', 'Disease', (41, 55))	('T1AM', 'Chemical', '-', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('T1AM', 'Var', (4, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('muM', 'Gene', '56925', (81, 84))	('muM', 'Gene', (81, 84))
205284	29184090	Using this cellular platform we were able to demonstrate that the effect of 25 muM triac and T1AM on apoptosis (annexin-PI, Fig.	('muM', 'Gene', '56925', (79, 82))	('T1AM', 'Chemical', '-', (93, 97))	('triac', 'Chemical', 'MESH:C010642', (83, 88))	('T1AM', 'Var', (93, 97))	('annexin-PI', 'Chemical', '-', (112, 122))	('muM', 'Gene', (79, 82))	('apoptosis', 'CPA', (101, 110))
205286	29184090	Next we examined whether the induction in apoptosis produced by tetrac, triac and T1AM, is caspase-mediated.	('caspase', 'Gene', (91, 98))	('T1AM', 'Var', (82, 86))	('tetrac', 'Chemical', 'MESH:C011126', (64, 70))	('caspase', 'Gene', '841;842;843', (91, 98))	('amine', 'Chemical', 'MESH:D000588', (10, 15))	('triac', 'Chemical', 'MESH:C010642', (72, 77))	('T1AM', 'Chemical', '-', (82, 86))
205288	29184090	The increase in apoptosis (annexin-V/PI, flow cytometry) by tetrac was completely abrogated in the presence of Z-VAD-FMK in the low-grade A2780 cells (Fig.	('A2780', 'CellLine', 'CVCL:0134', (138, 143))	('apoptosis', 'CPA', (16, 25))	('tetrac', 'Chemical', 'MESH:C011126', (60, 66))	('Z-VAD-FMK', 'Var', (111, 120))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (111, 120))	('abrogated', 'NegReg', (82, 91))	('annexin-V', 'Gene', '308', (27, 36))	('annexin-V', 'Gene', (27, 36))
205294	29184090	Overall, these collective results imply that tetrac, triac and T1AM induce apoptosis that is primarily caspase-mediated.	('caspase', 'Gene', '841;842;843', (103, 110))	('induce', 'Reg', (68, 74))	('triac', 'Var', (53, 58))	('T1AM', 'Chemical', '-', (63, 67))	('apoptosis', 'CPA', (75, 84))	('T1AM', 'Var', (63, 67))	('tetrac', 'Chemical', 'MESH:C011126', (45, 51))	('caspase', 'Gene', (103, 110))	('triac', 'Chemical', 'MESH:C010642', (53, 58))
205301	29184090	T1AM produced an elevation in caspase-3 activation (150%) after 2 hours of treatment (Fig.	('caspase-3', 'Gene', '836', (30, 39))	('T1AM', 'Chemical', '-', (0, 4))	('T1AM', 'Var', (0, 4))	('elevation', 'PosReg', (17, 26))	('caspase-3', 'Gene', (30, 39))	('activation', 'MPA', (40, 50))
205324	29184090	Similarly, the effect of T1AM on DNA damage/response markers was more pronounced in OVCAR3 cells peaking to 8-fold for ATM phosphorylation and 4.5-fold for PARP-1 (Fig.	('T1AM', 'Chemical', '-', (25, 29))	('T1AM', 'Var', (25, 29))	('ATM', 'Gene', (119, 122))	('PARP-1', 'Gene', (156, 162))	('PARP-1', 'Gene', '142', (156, 162))	('ATM', 'Gene', '472', (119, 122))	('DNA damage/response', 'MPA', (33, 52))
205336	29184090	There is no data available regarding integrin binding or blocking by T1AM and, to the best of our knowledge, this derivative has never been studied in cancer cells in general and ovarian cancer in particular.	('ovarian cancer', 'Phenotype', 'HP:0100615', (179, 193))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('T1AM', 'Chemical', '-', (69, 73))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Disease', 'MESH:D010051', (179, 193))	('T1AM', 'Var', (69, 73))	('ovarian cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
205346	29184090	For T1AM, no toxicity was observed at 50 mg/kg.	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('toxicity', 'Disease', (13, 21))	('T1AM', 'Var', (4, 8))	('T1AM', 'Chemical', '-', (4, 8))
205350	29184090	In contrast, triac and T1AM effectively induced cell death in both cell lines.	('induced', 'Reg', (40, 47))	('triac', 'Chemical', 'MESH:C010642', (13, 18))	('cell death', 'CPA', (48, 58))	('T1AM', 'Chemical', '-', (23, 27))	('T1AM', 'Var', (23, 27))
205364	29184090	OVCAR3 cells express the most common p53 mutation in high-grade disease (R248W).	('R248W', 'Mutation', 'rs121912651', (73, 78))	('R248W', 'Var', (73, 78))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (37, 40))	('high-grade disease', 'Disease', (53, 71))
205365	29184090	This R248W p53 mutation lacks normal p53 function and concomitantly gained novel oncogenic functions, often with deleterious effects.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('gained', 'PosReg', (68, 74))	('oncogenic functions', 'CPA', (81, 100))	('R248W', 'Mutation', 'rs121912651', (5, 10))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('R248W', 'Var', (5, 10))
205376	29184090	In conclusion, our results demonstrate cytotoxic effects of three thyroid hormone derivatives, tetrac, triac and T1AM in ovarian cancer cells, with effects on cell proliferation, viability, apoptosis and DNA damage.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('apoptosis', 'CPA', (190, 199))	('viability', 'CPA', (179, 188))	('tetrac', 'Chemical', 'MESH:C011126', (95, 101))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('effects', 'Reg', (148, 155))	('cytotoxic effects', 'CPA', (39, 56))	('triac', 'Chemical', 'MESH:C010642', (103, 108))	('T1AM', 'Var', (113, 117))	('cell proliferation', 'CPA', (159, 177))	('T1AM', 'Chemical', '-', (113, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (121, 135))	('ovarian cancer', 'Disease', (121, 135))	('DNA', 'MPA', (204, 207))
205388	29184090	Primary anti human antibodies against p21 (#2947), p27 (#3686), CycD1 (#2978), total/cleaved caspase 3 (#9665), PARP-1 (#9542) were from Cell Signaling technology (Leiden, The Netherlands).	('human', 'Species', '9606', (13, 18))	('caspase', 'Gene', '841;842;843', (93, 100))	('p21', 'Gene', (38, 41))	('p21', 'Gene', '644914', (38, 41))	('#3686', 'Var', (56, 61))	('p27', 'Gene', '3429', (51, 54))	('p27', 'Gene', (51, 54))	('#2978', 'Var', (71, 76))	('PARP-1', 'Gene', (112, 118))	('#2947', 'Var', (43, 48))	('#9542', 'Var', (120, 125))	('#9665', 'Var', (104, 109))	('PARP-1', 'Gene', '142', (112, 118))	('caspase', 'Gene', (93, 100))	('CycD1', 'Gene', (64, 69))
205390	29184090	phospho ATM antibodies (phospho-serine1981, #2152-1) were from Epitomics (Burlingame, CA, USA).	('serine1981', 'Chemical', '-', (32, 42))	('phospho-serine1981', 'Var', (24, 42))	('ATM', 'Gene', '472', (8, 11))	('ATM', 'Gene', (8, 11))
205392	29184090	Annexin-/PI-, surviving cell fraction; annexin +/PI-, early apoptosis; annexin +/PI+, late apoptosis and annexin-/PI+, late apoptosis/necrosis.	('necrosis', 'Disease', 'MESH:D009336', (134, 142))	('necrosis', 'Disease', (134, 142))	('annexin +/PI+', 'Var', (71, 84))
205412	22209148	An EQD2 to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043).	('impairment in Wechsler Memory', 'Disease', 'MESH:D008569', (71, 100))	('rat', 'Species', '10116', (151, 154))	('>7.3', 'Var', (43, 47))	('Word', 'Disease', 'MESH:D008569', (111, 115))	('impairment in Wechsler Memory', 'Disease', (71, 100))	('Word', 'Disease', (111, 115))
205413	22209148	EQD2 to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (173, 185))	('brain tumors', 'Phenotype', 'HP:0030692', (173, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('list-learning', 'CPA', (103, 116))	('brain tumors', 'Disease', (173, 185))	('EQD2', 'Var', (0, 4))	('impairment', 'NegReg', (89, 99))
205417	22209148	Preclinical models have demonstrated loss of hippocampal-dependent functions of spatial learning and memory, as tested by water maze tests, as a consequence of hippocampal irradiation.	('hippocampal', 'Var', (160, 171))	('loss', 'NegReg', (37, 41))	('rat', 'Species', '10116', (31, 34))	('hippocampal-dependent', 'MPA', (45, 66))
205455	22209148	With adjustment for age, binary logistic regression analysis of risk of impairment in WMS-III Word Lists Delayed Recall Test demonstrated a significant association with D40% to the bilateral hippocampi >7.3 Gy (odds ratio [OR] 19.3; p = 0.043) and an association that trended to significance with D100% to the bilateral hippocampi >0.0 Gy (OR 14.8; p = 0.068) (Table 4).	('WMS-III', 'Gene', (86, 93))	('Word', 'Disease', 'MESH:D008569', (94, 98))	('D40%', 'Var', (169, 173))	('rat', 'Species', '10116', (132, 135))	('D100%', 'Var', (297, 302))	('rat', 'Species', '10116', (216, 219))	('Word', 'Disease', (94, 98))
205456	22209148	In addition, the association between risk of impairment in WMS-III Word Lists Delayed Recall Test and D40% to the bilateral hippocampi >7.3 Gy remained significant when adjustment was made for both age and planning target volume (p = 0.013).	('D40%', 'Var', (102, 106))	('Word', 'Disease', 'MESH:D008569', (67, 71))	('Word', 'Disease', (67, 71))
205469	22209148	In addition to serving as a feasibility study, RTOG 0933 also seeks to make a statistical comparison of impairment in Hopkins Verbal Learning Test (HVLT)-delayed recall in patients receiving hippocampal avoidance during WBRT with a historical control of patients who received WBRT without hippocampal avoidance.	('hippocampal', 'Var', (191, 202))	('impairment in Hopkins Verbal Learning Test', 'Disease', (104, 146))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (254, 262))	('impairment in Hopkins Verbal Learning Test', 'Disease', 'MESH:D007859', (104, 146))
205488	33937022	High CHI3L2 expression was reported to be associated with poor prognosis in breast cancer and renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('CHI3L2', 'Gene', '1117', (5, 11))	('High', 'Var', (0, 4))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CHI3L2', 'Gene', (5, 11))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('expression', 'MPA', (12, 22))	('renal cell carcinoma', 'Disease', (94, 114))
205493	33937022	The overall survival time was higher in patients with dual-low CHI3L2 expression in TC and MC compared to those in patients with non-dual CHI3L2 expression and dual high expression in DIG and IDH wild-type gliomas.	('CHI3L2', 'Gene', (138, 144))	('patients', 'Species', '9606', (115, 123))	('IDH', 'Gene', '3417', (192, 195))	('CHI3L2', 'Gene', '1117', (138, 144))	('higher', 'PosReg', (30, 36))	('patients', 'Species', '9606', (40, 48))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('dual-low', 'Var', (54, 62))	('CHI3L2', 'Gene', '1117', (63, 69))	('gliomas', 'Disease', (206, 213))	('CHI3L2', 'Gene', (63, 69))	('gliomas', 'Disease', 'MESH:D005910', (206, 213))	('IDH', 'Gene', (192, 195))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('TC', 'Chemical', '-', (84, 86))
205494	33937022	By univariate and multivariate analysis, we found that high CHI3L2 expression in tumor cells was an independent unfavorable prognostic factor in glioma patients.	('glioma', 'Disease', (145, 151))	('CHI3L2', 'Gene', '1117', (60, 66))	('CHI3L2', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('high', 'Var', (55, 59))	('expression', 'MPA', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patients', 'Species', '9606', (152, 160))	('tumor', 'Disease', (81, 86))
205503	33937022	The 2016 World Health Organization (WHO) classification of adult diffuse glioma combines tumor histological morphology and molecular features, including the isocitrate dehydrogenase (IDH) mutation and the chromosomal arms 1p and 19q complete deletion (1p/19q co-deletion).	('glioma combines tumor', 'Disease', (73, 94))	('mutation', 'Var', (188, 196))	('IDH', 'Gene', (183, 186))	('glioma combines tumor', 'Disease', 'MESH:D005910', (73, 94))	('isocitrate dehydrogenase', 'Gene', (157, 181))	('isocitrate dehydrogenase', 'Gene', '3417', (157, 181))	('IDH', 'Gene', '3417', (183, 186))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('arms 1p', 'Gene', '3075', (217, 224))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('arms 1p', 'Gene', (217, 224))
205534	33937022	CD8+ T cell were separated by positive selection from PBMCs with CD8 magnetic beads and cultured in RPMI-1640 medium supplemented with 10% human serum, 5% L-glutamine-penicillin-streptomycin solution (Sigma-Aldrich, USA), CD3/CD28 antibody (Biolegend, USA) (25ul/ml) and IL-2 (100IU/ml) in 24-well plates.	('IL-2', 'Gene', '3558', (271, 275))	('penicillin', 'Chemical', 'MESH:D010406', (167, 177))	('IL-2', 'Gene', (271, 275))	('L-glutamine', 'Chemical', 'MESH:D005973', (155, 166))	('CD28', 'Gene', (226, 230))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', (65, 68))	('100IU/ml', 'Var', (277, 285))	('CD8', 'Gene', '925', (0, 3))	('human', 'Species', '9606', (139, 144))	('25ul/ml', 'Var', (258, 265))	('CD8', 'Gene', '925', (65, 68))	('RPMI-1640 medium', 'Chemical', '-', (100, 116))	('streptomycin', 'Chemical', 'MESH:D013307', (178, 190))	('CD28', 'Gene', '940', (226, 230))
205568	33937022	In tumor cells, we found significant correlations between CHI3L2 expression and WHO grade (P<0.001), age (P=0.001), Ki67 (P<0.001), P53 (P=0.034), PHH3 (mitotic figures) (P<0.001), ATRX protein expression (P=0.026), IDH (P<0.001) and 1p/19q codeleted (P=0.002).	('IDH', 'Gene', (216, 219))	('1p/19q', 'Var', (234, 240))	('tumor', 'Disease', (3, 8))	('ATRX', 'Gene', (181, 185))	('PHH3', 'Var', (147, 151))	('IDH', 'Gene', '3417', (216, 219))	('CHI3L2', 'Gene', '1117', (58, 64))	('ATRX', 'Gene', '546', (181, 185))	('CHI3L2', 'Gene', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('P53', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('P53', 'Gene', '7157', (132, 135))
205569	33937022	In macrophage cells, CHI3L2 is strongly correlated with WHO grade (P<0.001), gender (P=0.008), age (P=0.006), Ki67 (P<0.001), PHH3 (mitotic figures) (P<0.001), and IDH status (P<0.001).	('IDH', 'Gene', '3417', (164, 167))	('WHO grade', 'CPA', (56, 65))	('Ki67', 'Var', (110, 114))	('correlated', 'Reg', (40, 50))	('CHI3L2', 'Gene', '1117', (21, 27))	('CHI3L2', 'Gene', (21, 27))	('IDH', 'Gene', (164, 167))
205574	33937022	When considering the CHI3L2 expression of tumor cells and macrophages together, we found the overall survival time was higher in patients with dual-low CHI3L2 expression in TC and MC compared to those in patients with non-dual CHI3L2 expression and dual high expression in DIG ( Figure 3G ), but this difference is not statistically significant in LGG and GBM ( Figures 3H, I ).	('patients', 'Species', '9606', (204, 212))	('CHI3L2', 'Gene', '1117', (152, 158))	('tumor', 'Disease', (42, 47))	('CHI3L2', 'Gene', (152, 158))	('survival time', 'CPA', (101, 114))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('higher', 'PosReg', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CHI3L2', 'Gene', (21, 27))	('CHI3L2', 'Gene', '1117', (227, 233))	('CHI3L2', 'Gene', '1117', (21, 27))	('CHI3L2', 'Gene', (227, 233))	('dual-low', 'Var', (143, 151))	('TC', 'Chemical', '-', (173, 175))
205576	33937022	We found CHI3L2 expression in tumor cells is closely related to the prognosis of all new molecular classification of glioma, and high CHI3L2 expression in tumor cells, macrophages and TC + MC predicted poor outcome for IDH wild-type gliomas ( Figure S2 ).	('related', 'Reg', (53, 60))	('TC + MC', 'Chemical', '-', (184, 191))	('IDH', 'Gene', '3417', (219, 222))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('gliomas', 'Disease', (233, 240))	('glioma', 'Disease', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('glioma', 'Disease', 'MESH:D005910', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('CHI3L2', 'Gene', '1117', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('CHI3L2', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('expression', 'MPA', (141, 151))	('glioma', 'Disease', (117, 123))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('IDH', 'Gene', (219, 222))	('high', 'Var', (129, 133))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('CHI3L2', 'Gene', '1117', (134, 140))	('CHI3L2', 'Gene', (134, 140))	('tumor', 'Disease', (30, 35))
205577	33937022	Furthermore, we found regardless of whether patients with glioma have methylation of the MGMT promoter or have received adjuvant therapy, high CHI3L2 indicates a poor prognosis for glioma ( Figure S3 ).	('MGMT', 'Gene', (89, 93))	('patients', 'Species', '9606', (44, 52))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('methylation', 'Var', (70, 81))	('glioma', 'Disease', (181, 187))	('CHI3L2', 'Gene', '1117', (143, 149))	('CHI3L2', 'Gene', (143, 149))	('glioma', 'Disease', (58, 64))	('high', 'Var', (138, 142))	('MGMT', 'Gene', '4255', (89, 93))
205580	33937022	We found CHI3L2 expression in tumor cells, location, Ki67, IDH, 1p/19q codeleted were independent prognostic factors in gliomas ( Table 3 ).	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('CHI3L2', 'Gene', (9, 15))	('IDH, 1p/19q', 'Gene', '3417', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))	('CHI3L2', 'Gene', '1117', (9, 15))	('tumor', 'Disease', (30, 35))	('Ki67', 'Var', (53, 57))
205584	33937022	We further analyze the CHI3L2 mRNA expression levels in new molecular classification of diffusely infiltrating glioma, including IDH mutant without 1p/19q codeleted gliomas, IDH mutant with 1p/19q codeleted gliomas, and IDH wild-type gliomas, in TCGA and CGGA database ( Figure S4A  and  Figure S4B ).	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('CHI3L2', 'Gene', '1117', (23, 29))	('CHI3L2', 'Gene', (23, 29))	('IDH', 'Gene', (174, 177))	('glioma', 'Disease', (234, 240))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Disease', (234, 241))	('IDH', 'Gene', '3417', (129, 132))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('TC', 'Chemical', '-', (246, 248))	('glioma', 'Disease', (111, 117))	('IDH', 'Gene', '3417', (174, 177))	('IDH', 'Gene', (220, 223))	('gliomas', 'Disease', (207, 214))	('glioma', 'Disease', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('mutant', 'Var', (133, 139))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('gliomas', 'Disease', 'MESH:D005910', (207, 214))	('IDH', 'Gene', '3417', (220, 223))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('IDH', 'Gene', (129, 132))	('gliomas', 'Disease', (165, 172))	('glioma', 'Disease', (165, 171))
205586	33937022	Gliomas with IDH mutant and 1p/19q codeleted have higher CHI3L2 mRNA levels than gliomas with IDH mutant and non-1p/19q codeleted.	('IDH', 'Gene', '3417', (13, 16))	('CHI3L2', 'Gene', '1117', (57, 63))	('higher', 'PosReg', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('1p/19q', 'Var', (28, 34))	('CHI3L2', 'Gene', (57, 63))	('IDH', 'Gene', (94, 97))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH', 'Gene', '3417', (94, 97))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('gliomas', 'Disease', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))	('IDH', 'Gene', (13, 16))
205590	33937022	Except for gliomas with IDH mutant and non-1p/19q codeleted in the TCGA dataset, high levels of CHI3L2 mRNA in any other subgroup indicate a poor prognosis, whether in the TCGA or CGGA dataset.	('non-1p/19q', 'Var', (39, 49))	('gliomas', 'Disease', (11, 18))	('IDH', 'Gene', (24, 27))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('IDH', 'Gene', '3417', (24, 27))	('TC', 'Chemical', '-', (172, 174))	('CHI3L2', 'Gene', '1117', (96, 102))	('CHI3L2', 'Gene', (96, 102))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('TC', 'Chemical', '-', (67, 69))
205606	33937022	The proportion of apoptotic cells in the control group was 28.1%, the proportion of apoptotic cells in the 0.5ug/ml CHI3L2 group was 33.6%, and the proportion of apoptotic cells in the 2.5ug/ml CHI3L2 group was 35.9%.	('CHI3L2', 'Gene', (194, 200))	('0.5ug/ml', 'Var', (107, 115))	('CHI3L2', 'Gene', '1117', (116, 122))	('CHI3L2', 'Gene', (116, 122))	('CHI3L2', 'Gene', '1117', (194, 200))
205663	30536195	The molecular data collected included the status of IDH1/2, TP53, TERT promoter and ATRX mutations, in addition to 1p/19q co-deletions.	('TP53', 'Gene', (60, 64))	('ATRX', 'Gene', '546', (84, 88))	('IDH1/2', 'Gene', '3417;3418', (52, 58))	('TP53', 'Gene', '7157', (60, 64))	('TERT', 'Gene', (66, 70))	('mutations', 'Var', (89, 98))	('TERT', 'Gene', '7015', (66, 70))	('IDH1/2', 'Gene', (52, 58))	('ATRX', 'Gene', (84, 88))
205666	30536195	Consistent with previous reports, T2-FLAIR mismatch was preferentially found in Group A tumors (73.1%, 60 of 82), although its presence was not associated with survival, after controlling for molecular group.	('A tumors', 'Disease', (86, 94))	('found', 'Reg', (71, 76))	('A tumors', 'Disease', 'MESH:D009369', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('T2-FLAIR mismatch', 'Var', (34, 51))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
205684	30536195	The molecular data collected from the TCGA cohort included the status of IDH1/2, TP53 and ATRX mutations, in addition to 1p/19q co-deletions.	('IDH1/2', 'Gene', (73, 79))	('1p/19q', 'Var', (121, 127))	('ATRX', 'Gene', '546', (90, 94))	('IDH1/2', 'Gene', '3417;3418', (73, 79))	('ATRX', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
205685	30536195	In the remaining cohorts, IDH mutations were assessed using either Next Generation Sequencing (MGH Cohort) or Sanger sequencing (Dresden cohort) or Immunohistochemistry (MGH and Dresden).	('IDH', 'Gene', '3417', (26, 29))	('IDH', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))
205687	30536195	TERT promoter (TERTp) mutations were assessed either by amplification using Sanger sequencing performed with ABI Prism 3730 DNA Analyzer or using the fluorescence PCR technique, as previously described.	('TERT', 'Gene', '7015', (15, 19))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', (15, 20))	('mutations', 'Var', (22, 31))	('TERTp', 'Gene', '7015', (15, 20))	('TERT', 'Gene', (15, 19))
205701	30536195	The molecular astrocytic "Group A" is characterized by IDH mutation with concomitant TP53/ATRX inactivation, or the absence of lp/19q co-deletions and/or TERTp mutations.	('TP53', 'Gene', (85, 89))	('molecular astrocytic "Group A', 'Disease', (4, 33))	('TERTp', 'Gene', '7015', (154, 159))	('IDH', 'Gene', (55, 58))	('IDH', 'Gene', '3417', (55, 58))	('mutation', 'Var', (59, 67))	('ATRX', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (85, 89))	('TERTp', 'Gene', (154, 159))	('lp/19q', 'Gene', (127, 133))	('ATRX', 'Gene', '546', (90, 94))
205702	30536195	Group G ("glioblastoma-like") can then be defined by the absence of a mutation in an IDH gene.	('IDH', 'Gene', '3417', (85, 88))	('absence', 'NegReg', (57, 64))	('glioblastoma', 'Disease', (10, 22))	('glioblastoma', 'Disease', 'MESH:D005909', (10, 22))	('mutation', 'Var', (70, 78))	('IDH', 'Gene', (85, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (10, 22))
205713	30536195	We speculate that because IDH mutant tumors have a slower growth trajectory, they are able to achieve a larger size prior to becoming clinically symptomatic and then being diagnosed for the first time.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('growth trajectory', 'MPA', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('IDH', 'Gene', (26, 29))	('tumors', 'Disease', (37, 43))	('IDH', 'Gene', '3417', (26, 29))	('mutant', 'Var', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
205724	30536195	Consistent with the prior reports, T2-FLAIR mismatch was preferentially found in Group A tumors, 68.7% and 76% of WHO grades II and III, respectively.	('found', 'Reg', (72, 77))	('T2-FLAIR mismatch', 'Var', (35, 52))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('A tumors', 'Disease', (87, 95))	('A tumors', 'Disease', 'MESH:D009369', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
205746	30536195	We detected the presence of the mismatch sign in a considerably higher rate of gliomas than previously reported, potentially explained by inclusion of IDH-mutant WHO grade III and more contrast-enhancing gliomas in our series.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('IDH', 'Gene', '3417', (151, 154))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('gliomas', 'Disease', (204, 211))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('mismatch', 'Var', (32, 40))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('IDH', 'Gene', (151, 154))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
205749	30536195	Though useful for predicting which tumors are IDH-mutant, the presence of the mismatch sign in either oligodendrogliomas or astrocytomas was not associated with a difference in PFS, limiting its utility as a prognostic tool.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (102, 120))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('astrocytomas', 'Disease', 'MESH:D001254', (124, 136))	('IDH', 'Gene', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('oligodendrogliomas', 'Disease', (102, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (124, 135))	('tumors', 'Disease', (35, 41))	('IDH', 'Gene', '3417', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('astrocytomas', 'Disease', (124, 136))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('PFS', 'MPA', (177, 180))	('mismatch', 'Var', (78, 86))
205751	30536195	have recently demonstrated that ADC values obtained from DWI correlate with IDH mutation status and overall survival in adult diffuse gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('ADC', 'MPA', (32, 35))	('mutation status', 'Var', (80, 95))	('gliomas', 'Disease', (134, 141))	('IDH', 'Gene', (76, 79))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('IDH', 'Gene', '3417', (76, 79))	('DWI', 'Gene', (57, 60))
205783	30272346	U251MG and U87MG cells that were cultured with the COL1A1 siRNA used as the experimental group were named as 'COL1A1 siRNA' cells.	('U87MG', 'Var', (11, 16))	('U87MG', 'CellLine', 'CVCL:0022', (11, 16))	('U251MG', 'CellLine', 'CVCL:0021', (0, 6))	('COL1A1', 'Gene', (51, 57))
205784	30272346	U251MG and U87MG cells with the treatment of siControl served as the control group were designated as 'Non-targeted' or 'NT' cells.	('U87MG', 'Var', (11, 16))	('U251MG', 'Var', (0, 6))	('U251MG', 'CellLine', 'CVCL:0021', (0, 6))	('U87MG', 'CellLine', 'CVCL:0022', (11, 16))
205801	30272346	The effects of COL1A1 on U251MG or U87MG cell invasion were quantitatively determined by Transwell assay (Fig.	('U87MG', 'Var', (35, 40))	('COL1A1', 'Gene', (15, 21))	('U251MG', 'CellLine', 'CVCL:0021', (25, 31))	('U251MG', 'Var', (25, 31))	('U87MG', 'CellLine', 'CVCL:0022', (35, 40))
205815	30272346	Previous studies have revealed that the PI3K/Akt signaling pathway is abnormally expressed during malignant glioma progression and alterations in the PI3K/Akt signaling pathway lead to glioma formation.	('lead to', 'Reg', (177, 184))	('Akt', 'Gene', (45, 48))	('glioma', 'Disease', (108, 114))	('alterations', 'Var', (131, 142))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('malignant glioma', 'Disease', 'MESH:D005910', (98, 114))	('Akt', 'Gene', '207', (45, 48))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('malignant glioma', 'Disease', (98, 114))	('Akt', 'Gene', '207', (155, 158))	('glioma', 'Disease', (185, 191))	('Akt', 'Gene', (155, 158))
205820	30272346	It has been reported that a high expression of LAMC1 together with a large GBM tumor size may be associated with a shorter median OS.	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (33, 43))	('LAMC1', 'Gene', (47, 52))	('high', 'Var', (28, 32))	('associated', 'Reg', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))
205824	30272346	The expression of COL1A1 in the U251M cell line was associated with an increase in cell motility and invasiveness.	('U251M', 'CellLine', 'CVCL:0021', (32, 37))	('COL1A1', 'Gene', (18, 24))	('cell motility', 'CPA', (83, 96))	('invasiveness', 'CPA', (101, 113))	('increase', 'PosReg', (71, 79))	('expression', 'Var', (4, 14))
205825	30272346	A recent study performed by Balbous et al, which aimed to identify a mesenchymal glioma stem cell profile, reported that the silencing of COL1A1 resulted in a significant reduction in cell invasive capabilities.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('silencing', 'Var', (125, 134))	('COL1A1', 'Gene', (138, 144))	('cell invasive capabilities', 'CPA', (184, 210))	('glioma', 'Disease', (81, 87))	('reduction', 'NegReg', (171, 180))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
205834	30272346	The downregulation of COL1A1 in the U251MG or U87MG cells reduced the protein levels of the recognized invasion-related factors, such as p-STAT3, MMP-2, MMP-9 and NF-kappaB, suggesting that the JAK/STAT3, PI3K/AKT and NF-kappaB signaling path-ways may be involved in COL1A1-mediated invasion.	('protein levels', 'MPA', (70, 84))	('AKT', 'Gene', (210, 213))	('U87MG', 'Var', (46, 51))	('U251MG', 'CellLine', 'CVCL:0021', (36, 42))	('COL1A1', 'Gene', (22, 28))	('downregulation', 'NegReg', (4, 18))	('AKT', 'Gene', '207', (210, 213))	('reduced', 'NegReg', (58, 65))	('U87MG', 'CellLine', 'CVCL:0022', (46, 51))	('U251MG', 'Var', (36, 42))
205844	27170161	The current state of the latest therapeutic developments including tumor-specific targeted drug therapies, metabolic targeting, epigenetic modulation and immunotherapy are summarized and suggestions for future directions are offered.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('epigenetic modulation', 'Var', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
205856	27170161	The hallmark molecular abnormality that is now increasingly used to define oligodendroglioma is co-deletion of chromosomes 1p and 19q, which also predicts a better prognosis and responsiveness to radiation therapy and chemotherapy.	('hallmark molecular abnormality', 'Disease', 'MESH:C567116', (4, 34))	('co-deletion', 'Var', (96, 107))	('hallmark molecular abnormality', 'Disease', (4, 34))	('better', 'PosReg', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('oligodendroglioma', 'Disease', (75, 92))	('responsiveness to radiation', 'Phenotype', 'HP:0011133', (178, 205))	('oligodendroglioma', 'Disease', 'MESH:D009837', (75, 92))
205865	27170161	About 5% of gliomas are due to inherited germ-line mutations associated with known syndromes such as Cowden's disease (PTEN mutation), tuberous sclerosis (TSC1 9q34, TSC2 16p13), Li-Fraumeni syndrome (p53 mutation), neurofibromatosis types 1 and 2 (neurofibromin and merlin mutations) and Lynch Syndrome (miss-match DNA repair defect).	('neurofibromin', 'Gene', (249, 262))	('mutations', 'Var', (51, 60))	('gliomas', 'Disease', (12, 19))	('p53', 'Gene', (201, 204))	('TSC2', 'Gene', (166, 170))	("Cowden's disease", 'Disease', 'MESH:D006223', (101, 117))	('TSC1', 'Gene', (155, 159))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('merlin', 'Gene', '4771', (267, 273))	('neurofibromin', 'Gene', '4763', (249, 262))	('TSC1', 'Gene', '7248', (155, 159))	('associated', 'Reg', (61, 71))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	("Cowden's disease", 'Disease', (101, 117))	('Li-Fraumeni syndrome', 'Disease', (179, 199))	('neurofibromatosis types 1 and 2', 'Gene', '4763', (216, 247))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (289, 303))	('p13', 'Gene', (173, 176))	('PTEN', 'Gene', (119, 123))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (179, 199))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (135, 153))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (216, 233))	('tuberous sclerosis', 'Disease', (135, 153))	('TSC2', 'Gene', '7249', (166, 170))	('p53', 'Gene', '7157', (201, 204))	('PTEN', 'Gene', '5728', (119, 123))	('p13', 'Gene', '440926', (173, 176))	('Lynch Syndrome', 'Disease', (289, 303))	('merlin', 'Gene', (267, 273))
205870	27170161	These studies have all but established a new standard of care that combines radiation and PCV chemotherapy for patients with anaplastic 1p19q co-deleted oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('anaplastic 1p19q co-deleted', 'Var', (125, 152))	('oligodendroglioma', 'Disease', (153, 170))	('oligodendroglioma', 'Disease', 'MESH:D009837', (153, 170))	('patients', 'Species', '9606', (111, 119))
205878	27170161	The strongest predictive and prognostic factor for a therapeutic response and a longer survival is the epigenetic silencing of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT).	('MGMT', 'Gene', '4255', (190, 194))	('MGMT', 'Gene', (190, 194))	('epigenetic silencing', 'Var', (103, 123))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (149, 188))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (149, 188))
205883	27170161	Nearly all HGGs show genetic alterations in the receptor tyrosine kinase (RTK)-PI3K-RAS pathway, although specific aberrations and frequencies greatly differ between adults and children.	('receptor tyrosine kinase', 'Gene', (48, 72))	('receptor tyrosine kinase', 'Gene', '5979', (48, 72))	('RTK', 'Gene', (74, 77))	('children', 'Species', '9606', (177, 185))	('genetic alterations', 'Var', (21, 40))	('RTK', 'Gene', '5979', (74, 77))
205885	27170161	Oncogenic RTK hyperactivation is driven by multiple mechanisms such as RTK gene amplification and overexpression resulting in ligand-independent receptor oligomerization, receptor mutation resulting in constitutive activation and ligand over-expression.	('over-expression', 'PosReg', (237, 252))	('ligand', 'MPA', (230, 236))	('constitutive activation', 'MPA', (202, 225))	('RTK', 'Gene', (71, 74))	('RTK', 'Gene', '5979', (10, 13))	('RTK', 'Gene', (10, 13))	('RTK', 'Gene', '5979', (71, 74))	('mutation', 'Var', (180, 188))	('ligand-independent receptor oligomerization', 'MPA', (126, 169))
205886	27170161	Dysregulated RTK hyperactivation drives multiple oncogenic processes such as cell proliferation, aberrant survival and therapeutic resistance, migration/invasion, and tumor cell stemness that is closely linked to tumor propagating capacity.	('tumor', 'Disease', (213, 218))	('tumor cell stemness', 'Disease', 'MESH:D020295', (167, 186))	('RTK', 'Gene', '5979', (13, 16))	('aberrant survival', 'CPA', (97, 114))	('drives', 'Reg', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor cell stemness', 'Disease', (167, 186))	('Dysregulated', 'Var', (0, 12))	('migration/invasion', 'CPA', (143, 161))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('RTK', 'Gene', (13, 16))	('tumor', 'Disease', (167, 172))	('cell proliferation', 'CPA', (77, 95))
205888	27170161	The most common is EGFR variant III (EGFRvIII), a truncated 801 base pair in-frame deletion of the wild-type EGFR, which is tumor-specific and absent in healthy tissue.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('common', 'Reg', (9, 15))	('tumor', 'Disease', (124, 129))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (19, 23))	('EGFR', 'Gene', (109, 113))	('EGFR', 'Gene', (37, 41))	('variant III', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
205889	27170161	Despite this frequency and that fact that EGFR inhibitors are efficacious in other molecularly defined malignancies (e.g.	('EGFR', 'Gene', '1956', (42, 46))	('inhibitors', 'Var', (47, 57))	('EGFR', 'Gene', (42, 46))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('malignancies', 'Disease', (103, 115))
205890	27170161	EGFR mutated non-small cell lung cancer), multiple EGFR inhibitors (erlotinib, gefitinib, lapatinib and the chimeric EGFR monoclonal antibody cetuximab), alone or in combination, have been largely ineffective against HGG in multiple clinical trials, attributed to the absence of the kinase domain mutations required for durable therapeutic responses, insufficient CNS drug penetration or toxicity, particularly when used in combination.	('cell lung cancer', 'Disease', (23, 39))	('gefitinib', 'Chemical', 'MESH:D000077156', (79, 88))	('cetuximab', 'Chemical', 'MESH:D000068818', (142, 151))	('EGFR', 'Gene', (51, 55))	('ineffective', 'NegReg', (197, 208))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('insufficient', 'Disease', 'MESH:D000309', (351, 363))	('erlotinib', 'Chemical', 'MESH:D000069347', (68, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('HGG', 'Disease', (217, 220))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (13, 39))	('EGFR', 'Gene', '1956', (117, 121))	('toxicity', 'Disease', 'MESH:D064420', (388, 396))	('mutated', 'Var', (5, 12))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (17, 39))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (0, 4))	('toxicity', 'Disease', (388, 396))	('lapatinib', 'Chemical', 'MESH:D000077341', (90, 99))	('insufficient', 'Disease', (351, 363))	('cell lung cancer', 'Disease', 'MESH:D008175', (23, 39))	('EGFR', 'Gene', (117, 121))	('CNS drug penetration', 'CPA', (364, 384))	('EGFR', 'Gene', '1956', (0, 4))
205894	27170161	Despite such disappointing results to date, the development of new EGFR inhibitors continues to be of high interest due to its critical role in gliomagenesis, which is also underscored by the fact that the majority of agents evaluated in clinical trials for glioma patients have targeted one or multiple components of this signaling pathway.	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Disease', (258, 264))	('glioma', 'Disease', 'MESH:D005910', (258, 264))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('glioma', 'Disease', (144, 150))	('patients', 'Species', '9606', (265, 273))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('inhibitors', 'Var', (72, 82))
205895	27170161	The novel agent Dacomitinib (PF-299804), an irreversible pan-HER inhibitor, was found to have promising activity in preclinical EGFR mutated glioma models and is currently being evaluated in two Phase II studies for recurrent GBM patients with EGFR amplification or EGFRvIII expression (NCT01520870, NCT01112527).	('EGFR', 'Gene', '1956', (244, 248))	('GBM', 'Disease', (226, 229))	('Dacomitinib', 'Chemical', 'MESH:C525726', (16, 27))	('activity', 'MPA', (104, 112))	('EGFR', 'Gene', (244, 248))	('PF-299804', 'Chemical', 'MESH:C525726', (29, 38))	('EGFR', 'Gene', (128, 132))	('PF-299804', 'Var', (29, 38))	('amplification', 'Var', (249, 262))	('EGFR', 'Gene', '1956', (266, 270))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('patients', 'Species', '9606', (230, 238))	('EGFR', 'Gene', '1956', (128, 132))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('mutated', 'Var', (133, 140))	('EGFR', 'Gene', (266, 270))	('NCT01520870', 'Var', (287, 298))	('glioma', 'Disease', (141, 147))
205899	27170161	Although none of them have been able to demonstrate a significant survival advantage in patients with recurrent GBM, several new agents are currently undergoing clinical trial evaluations: AMG 595, a first-in-human mAb for patients with EGFRvIII recurrent HGG (NCT01475006); Sym004, a recombinant antibody that specifically binds to EGFR in patients with EGFR amplified GBM (NCT02540161); and ABT-414, an antibody-drug conjugate, with a toxic payload (monomethylauristatin F) targeted to EGFR or EGFRvIII amplified GBMs (Intellance 1; NCT02573324).	('human', 'Species', '9606', (209, 214))	('patients', 'Species', '9606', (341, 349))	('EGFR', 'Gene', (488, 492))	('GBMs', 'Disease', (515, 519))	('EGFR', 'Gene', '1956', (333, 337))	('EGFR', 'Gene', '1956', (237, 241))	('EGFR', 'Gene', '1956', (355, 359))	('amplified', 'PosReg', (505, 514))	('EGFR', 'Gene', '1956', (496, 500))	('NCT02540161', 'Var', (375, 386))	('AMG', 'Gene', (189, 192))	('EGFR', 'Gene', '1956', (488, 492))	('ABT-414', 'Chemical', 'MESH:C000620234', (393, 400))	('EGFR', 'Gene', (333, 337))	('AMG', 'Gene', '265', (189, 192))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', (237, 241))	('EGFR', 'Gene', (355, 359))	('EGFR', 'Gene', (496, 500))	('patients', 'Species', '9606', (223, 231))
205902	27170161	PDGFR inhibitors have also largely disappointed in the treatment of HGGs despite encouraging preclinical results.	('disappointed', 'Reg', (35, 47))	('HGGs', 'Disease', (68, 72))	('PDGFR', 'Gene', (0, 5))	('inhibitors', 'Var', (6, 16))	('PDGFR', 'Gene', '5159', (0, 5))
205908	27170161	The novel PDGFRalpha/beta and Flt3 inhibitor crenolanib is currently in Phase II for adult HGG (NCT01229644) and in a Phase I study for recurrent pediatric HGG (NCT01393912).	('NCT01229644', 'Var', (96, 107))	('Flt3', 'Gene', '2322', (30, 34))	('PDGFRalpha/beta', 'Gene', '5156;5159', (10, 25))	('crenolanib', 'Chemical', 'MESH:C577197', (45, 55))	('Flt3', 'Gene', (30, 34))	('PDGFRalpha/beta', 'Gene', (10, 25))
205924	27170161	Lenvatinib (E7080), a novel multitargeted tyrosine kinase inhibitor for all VEGFRs and PDGFR, did not warrant further testing in recurrent GBM patients beyond Phase II because the therapeutic effect was very limited with no objective responses (NCT01137604).	('patients', 'Species', '9606', (143, 151))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('E7080', 'Var', (12, 17))	('PDGFR', 'Gene', (87, 92))	('VEGFRs', 'Gene', (76, 82))	('PDGFR', 'Gene', '5159', (87, 92))	('VEGFRs', 'Gene', '2321;2324;3791', (76, 82))
205931	27170161	Almost 90% of patients with GBM show at least one alteration in the phosphatidylinositol 3-kinase (PI3K) signaling, which can either result from activating mutations in PI3K itself (25%), loss of the tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) (41%) or downstream activation of RTKs.	('phosphatidylinositol 3-kinase', 'Gene', '5293', (68, 97))	('PI3K', 'Gene', (169, 173))	('RTK', 'Gene', '5979', (294, 297))	('loss of the tumor', 'Disease', 'MESH:D009369', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutations', 'Var', (156, 165))	('activation', 'PosReg', (280, 290))	('loss of the tumor', 'Disease', (188, 205))	('alteration', 'Reg', (50, 60))	('activating', 'PosReg', (145, 155))	('RTK', 'Gene', (294, 297))	('phosphatidylinositol 3-kinase', 'Gene', (68, 97))	('patients', 'Species', '9606', (14, 22))	('PTEN', 'Gene', (254, 258))	('PTEN', 'Gene', '5728', (254, 258))
205932	27170161	The downstream effectors of PI3K include AKT and mammalian target of rapamycin (mTOR) consisting of mTOR complexes mTORC1 and 2, which play key roles in cell metabolism, survival, and protein translation.	('mTORC1 and 2', 'Gene', '74343;382056', (115, 127))	('mTOR', 'Gene', '2475', (115, 119))	('mTOR', 'Gene', (80, 84))	('PI3K', 'Var', (28, 32))	('mTOR', 'Gene', '2475', (80, 84))	('mTOR', 'Gene', (115, 119))	('mammalian target of rapamycin', 'Gene', '2475', (49, 78))	('mammalian target of rapamycin', 'Gene', (49, 78))	('AKT', 'Gene', '207', (41, 44))	('mTOR', 'Gene', (100, 104))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', '2475', (100, 104))
205936	27170161	Currently ongoing clinical trials focus on the evaluation of everolimus in the treatment of progressive LGGs in combination with TMZ (NCT02023905), as single agent in children with progressive LGGs (NCT01734512) and ependymoma (NCT02155920).	('ependymoma', 'Disease', (216, 226))	('LGGs', 'Disease', (193, 197))	('everolimus', 'Chemical', 'MESH:D000068338', (61, 71))	('TMZ', 'Chemical', 'MESH:D000077204', (129, 132))	('ependymoma', 'Phenotype', 'HP:0002888', (216, 226))	('NCT01734512', 'Var', (199, 210))	('children', 'Species', '9606', (167, 175))	('NCT02155920', 'Var', (228, 239))	('ependymoma', 'Disease', 'MESH:D004806', (216, 226))
205937	27170161	In addition, dual mTORC1/2 inhibitor sapanisertib (INK1280) is in early clinical investigation to assess CNS penetration and response in patients with recurrent GBM (NCT02133183).	('mTORC1/2', 'Gene', '74343;382056', (18, 26))	('sapanisertib', 'Chemical', 'MESH:C572449', (37, 49))	('INK1280', 'Chemical', '-', (51, 58))	('patients', 'Species', '9606', (137, 145))	('mTORC1/2', 'Gene', (18, 26))	('NCT02133183', 'Var', (166, 177))	('GBM', 'Disease', (161, 164))
205940	27170161	Ongoing studies with buparlisib include a Phase I/II dose-escalation trial with concurrent standard chemoradiation in newly diagnosed GBM (NCT01473901), a Phase II trial in recurrent GBM (NCT01339052) and combination trials for recurrent GBM with bevacizumab (NCT01349660), and carboplatin or lomustine (NCT01934361).	('NCT01339052', 'Var', (188, 199))	('buparlisib', 'Chemical', 'MESH:C571178', (21, 31))	('NCT01934361', 'Var', (304, 315))	('NCT01473901', 'Var', (139, 150))	('carboplatin', 'Chemical', 'MESH:D016190', (278, 289))	('NCT01349660', 'Var', (260, 271))	('bevacizumab', 'Chemical', 'MESH:D000068258', (247, 258))	('lomustine', 'Chemical', 'MESH:D008130', (293, 302))
205941	27170161	PX-886 (Oncothyreon) is a semi-synthetic derivative of wortmannin and irreversibly inhibits PI3K.	('PX-886', 'Chemical', '-', (0, 6))	('inhibits', 'NegReg', (83, 91))	('PX-886', 'Var', (0, 6))	('PI3K', 'Pathway', (92, 96))	('Oncothyreon', 'Chemical', '-', (8, 19))	('wortmannin', 'Chemical', 'MESH:D000077191', (55, 65))
205942	27170161	In glioma cells, PX-866 dramatically inhibited proliferation, autophagy and angiogenic potential in a variety of cell lines and U87 mouse xenograft models.	('PX-866', 'Var', (17, 23))	('autophagy', 'CPA', (62, 71))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('inhibited', 'NegReg', (37, 46))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('U87', 'CellLine', 'CVCL:0022', (128, 131))	('angiogenic potential', 'CPA', (76, 96))	('PX-866', 'Chemical', 'MESH:C496788', (17, 23))	('mouse', 'Species', '10090', (132, 137))	('glioma', 'Disease', (3, 9))	('proliferation', 'CPA', (47, 60))
205944	27170161	GBM with mutant PI3K alleles may also benefit from inhibition of AKT.	('inhibition', 'NegReg', (51, 61))	('benefit', 'PosReg', (38, 45))	('AKT', 'Gene', (65, 68))	('mutant PI3K', 'Var', (9, 20))	('AKT', 'Gene', '207', (65, 68))	('PI3K', 'Var', (16, 20))
205948	27170161	The presence of activating mutations in constituents of the mitogen activate protein kinase (MAPK) pathway has raised considerable interest in inhibiting this pathway in patients with HGGs and also in patients with unresectable or recurrent LGGs, which typically harbor oncogenic activation of BRAF resulting from a BRAFV600E point mutation or a KIAA1549:BRAF fusion.	('mutations', 'Var', (27, 36))	('KIAA1549', 'Gene', (346, 354))	('BRAFV600E point mutation', 'Var', (316, 340))	('LGGs', 'Disease', (241, 245))	('KIAA1549', 'Gene', '57670', (346, 354))	('patients', 'Species', '9606', (170, 178))	('patients', 'Species', '9606', (201, 209))	('HGGs', 'Disease', (184, 188))	('BRAFV600E', 'Mutation', 'rs113488022', (316, 325))	('activation', 'PosReg', (280, 290))	('MAPK', 'Gene', '5594', (93, 97))	('inhibiting', 'NegReg', (143, 153))	('MAPK', 'Gene', (93, 97))	('activating', 'PosReg', (16, 26))
205951	27170161	Vemurafenib (PLX4032), which has demonstrated remarkable activity against metastatic BRAFV600E mutated melanoma, is currently undergoing Phase I/II testing in patients with BRAFV600E positive recurrent or refractory pediatric glioma (NCT01748149).	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('BRAFV600E', 'Gene', (85, 94))	('PLX4032', 'Chemical', 'MESH:D000077484', (13, 20))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('pediatric glioma', 'Disease', (216, 232))	('recurrent', 'Disease', (192, 201))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('mutated', 'Var', (95, 102))	('BRAFV600E', 'Mutation', 'rs113488022', (173, 182))	('patients', 'Species', '9606', (159, 167))	('BRAFV600E', 'Mutation', 'rs113488022', (85, 94))	('pediatric glioma', 'Disease', 'MESH:D005910', (216, 232))	('melanoma', 'Disease', (103, 111))
205952	27170161	Additional agents currently in clinical trial for pediatric BRAFV600E mutated glioma are the BRAF inhibitor dabrafenib (GSK436) (NCT01677741) and the two MEK1/2 inhibitors trametanib (GSK212) (NCT02034110, NCT02124772) and MEK162 (NCT02285439).	('NCT02285439', 'Var', (231, 242))	('NCT02124772', 'Var', (206, 217))	('dabrafenib', 'Chemical', 'MESH:C561627', (108, 118))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('GSK436', 'Chemical', '-', (120, 126))	('BRAFV600E mutated', 'Var', (60, 77))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('NCT02034110', 'Var', (193, 204))	('trametanib', 'Chemical', '-', (172, 182))	('GSK212) (NCT02034110', 'Var', (184, 204))	('glioma', 'Disease', (78, 84))	('MEK1/2', 'Gene', '5604;5605', (154, 160))	('BRAFV600E', 'Mutation', 'rs113488022', (60, 69))	('MEK1/2', 'Gene', (154, 160))	('mutated', 'Var', (70, 77))
205954	27170161	Isolated case reports detailing complete clinical responses to dabrafenib in children with BRAFV600E-mutant GBMs have sparked excitement; however, responses are rarely durable due to MAPK reactivation.	('MAPK', 'Gene', '5594', (183, 187))	('MAPK', 'Gene', (183, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (91, 100))	('children', 'Species', '9606', (77, 85))	('dabrafenib', 'Chemical', 'MESH:C561627', (63, 73))	('BRAFV600E-mutant', 'Var', (91, 107))
205957	27170161	This limitation can potentially be overcome in appropriate patient subsets using MEK inhibitors that target wild-type MEK1/2 kinase that is hyperactivated downstream of oncogenic BRAF driver mutations.	('patient', 'Species', '9606', (59, 66))	('mutations', 'Var', (191, 200))	('MEK1/2', 'Gene', '5604;5605', (118, 124))	('MEK1/2', 'Gene', (118, 124))	('BRAF', 'Gene', (179, 183))	('hyperactivated', 'PosReg', (140, 154))
205959	27170161	The latter, selumetinib, a second-generation MEK1/2 inhibitor, is undergoing Phase II evaluation in LGGs and neurofibromatosis 1 (NF1)-associated tumors, including optic pathway gliomas as well as plexiform neurofibromas (NCT01386450, NCT01089101) that has resulted in some encouraging therapeutic responses, particularly in patients with NF1.	('selumetinib', 'Chemical', 'MESH:C517975', (12, 23))	('NCT01386450', 'Var', (222, 233))	('neurofibromatosis 1', 'Gene', '4763', (109, 128))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (109, 126))	('NF1', 'Gene', '4763', (339, 342))	('gliomas', 'Disease', (178, 185))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('neurofibromas', 'Disease', (207, 220))	('MEK1/2', 'Gene', '5604;5605', (45, 51))	('MEK1/2', 'Gene', (45, 51))	('NF1', 'Gene', (339, 342))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('neurofibromatosis 1', 'Gene', (109, 128))	('NCT01089101', 'Var', (235, 246))	('optic pathway gliomas', 'Phenotype', 'HP:0009734', (164, 185))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (197, 220))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('NF1', 'Gene', '4763', (130, 133))	('neurofibromas', 'Phenotype', 'HP:0001067', (207, 220))	('neurofibromas', 'Disease', 'MESH:D009455', (207, 220))	('patients', 'Species', '9606', (325, 333))	('NF1', 'Gene', (130, 133))	('tumors', 'Disease', (146, 152))	('LGGs', 'Disease', (100, 104))
205961	27170161	In diffuse gliomas, the premier oncogenic mutations that result in metabolic reprogramming are within the genes coding for isocitrate dehydrogenases, IDH1 and IDH2.	('IDH2', 'Gene', (159, 163))	('IDH2', 'Gene', '3418', (159, 163))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('IDH1', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (150, 154))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('mutations', 'Var', (42, 51))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
205962	27170161	Originally detected in primary GBMs (5-10%), IDH1 mutations occur in 50-80% of grade II and III astrocytoma and oligodendroglioma, as well as secondary GBM, while IDH2 mutations are less common and are mutually exclusive with mutations in IDH1.	('IDH1', 'Gene', '3417', (45, 49))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', (239, 243))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('IDH2', 'Gene', '3418', (163, 167))	('grade II', 'Disease', (79, 87))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (96, 129))	('IDH1', 'Gene', '3417', (239, 243))	('IDH1', 'Gene', (45, 49))	('IDH2', 'Gene', (163, 167))	('occur', 'Reg', (60, 65))
205963	27170161	The most common mutation in IDH1 is arginine 132 to histidine (R132H) that results in the ability to convert alpha-ketoglutarate (alpha-KG) to the R(-)-2-hydroxyglutarate (2-HG), a potential onco-metabolite, with the coincident conversion of NADPH to NADP+.	('R132H', 'Chemical', '-', (63, 68))	('arginine 132 to', 'Var', (36, 51))	('(-)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (148, 170))	('IDH1', 'Gene', '3417', (28, 32))	('NADP+', 'Chemical', 'MESH:D009249', (251, 256))	('convert', 'MPA', (101, 108))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (109, 128))	('NADPH', 'Chemical', 'MESH:D009249', (242, 247))	('ability', 'MPA', (90, 97))	('arginine 132 to histidine', 'Mutation', 'rs121913500', (36, 61))	('2-HG', 'Chemical', '-', (172, 176))	('IDH1', 'Gene', (28, 32))
205965	27170161	There are currently no therapies approved targeting mutant IDH; however, multiple therapeutic approaches targeting mutant IDH1/2 and the altered metabolic pathway are currently in clinical and preclinical development stages.	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', (59, 62))	('mutant', 'Var', (115, 121))	('IDH1/2', 'Gene', (122, 128))	('IDH', 'Gene', '3417', (59, 62))	('IDH1/2', 'Gene', '3417;3418', (122, 128))
205966	27170161	Because IDH1 mutation is involved in the inhibition of histone lysine demethylases, DNA methyltransferase (DNMT) inhibitors have been suggested as a potential therapeutic approach, including decitabine and 5-azacytidine that reverse cancer-promoting hypermethylation restoring cell differentiation and tumor suppressing functions.	('DNMT', 'Gene', '1786', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('DNA methyltransferase', 'Gene', '1786', (84, 105))	('DNMT', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('mutation', 'Var', (13, 21))	('IDH1', 'Gene', (8, 12))	('tumor', 'Disease', (302, 307))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('IDH1', 'Gene', '3417', (8, 12))	('decitabine', 'Chemical', 'MESH:D000077209', (191, 201))	('5-azacytidine', 'Chemical', 'MESH:D001374', (206, 219))	('cell differentiation', 'CPA', (277, 297))	('DNA methyltransferase', 'Gene', (84, 105))
205968	27170161	Similar compounds of mutant-selective inhibitors of IDH1 (AG-120), IDH2 (AG-221) or both IDH1/2 (AG-881) have entered the clinical trial Phase (NCT02073994, NCT02273739, NCT02481154) (Tab.	('IDH1/2', 'Gene', '3417;3418', (89, 95))	('IDH1', 'Gene', '3417', (52, 56))	('AG-120', 'Chemical', 'MESH:C000627630', (58, 64))	('IDH2', 'Gene', (67, 71))	('mutant-selective', 'Var', (21, 37))	('IDH1/2', 'Gene', (89, 95))	('NCT02073994', 'Var', (144, 155))	('IDH2', 'Gene', '3418', (67, 71))	('IDH1', 'Gene', (89, 93))	('NCT02273739', 'Var', (157, 168))	('IDH1', 'Gene', (52, 56))	('IDH1', 'Gene', '3417', (89, 93))
205970	27170161	Dichloroacetate (DCA) represents another strategy for targeting the oncogenic effects of IDH mutation.	('DCA', 'Chemical', 'MESH:D003999', (17, 20))	('Dichloroacetate', 'Chemical', 'MESH:D003999', (0, 15))	('IDH', 'Gene', (89, 92))	('mutation', 'Var', (93, 101))	('IDH', 'Gene', '3417', (89, 92))
205971	27170161	DCA is an inhibitor of mitochondrial pyruvate dehydrogenase kinase and thus, increases intracellular levels of pyruvate dehydrogenase, which is reduced in IDH1 mutated tumors.	('reduced', 'NegReg', (144, 151))	('IDH1', 'Gene', (155, 159))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('IDH1', 'Gene', '3417', (155, 159))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('mutated', 'Var', (160, 167))	('DCA', 'Chemical', 'MESH:D003999', (0, 3))	('increases', 'PosReg', (77, 86))	('intracellular levels of pyruvate dehydrogenase', 'MPA', (87, 133))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
205972	27170161	DCA has been shown to reduce GBM cell proliferation and clonogenicity in preclinical animal models.	('reduce', 'NegReg', (22, 28))	('DCA', 'Var', (0, 3))	('DCA', 'Chemical', 'MESH:D003999', (0, 3))	('clonogenicity', 'CPA', (56, 69))	('GBM cell proliferation', 'CPA', (29, 51))
205973	27170161	A small case series of 5 patients treated with oral DCA confirmed the inhibition of pyruvate dehydrogenase kinase along with p53 activation inducing apoptosis in human GBMs and gave rise to a Phase II trial for primary and recurrent GBM, albeit unselected for IDH1 status, which was recently completed (NCT00540176).	('apoptosis', 'CPA', (149, 158))	('inducing', 'Reg', (140, 148))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('activation', 'PosReg', (129, 139))	('human', 'Species', '9606', (162, 167))	('DCA', 'Chemical', 'MESH:D003999', (52, 55))	('pyruvate dehydrogenase kinase', 'Enzyme', (84, 113))	('IDH1', 'Gene', (260, 264))	('inhibition', 'Var', (70, 80))	('patients', 'Species', '9606', (25, 33))	('IDH1', 'Gene', '3417', (260, 264))
205981	27170161	Currently, there are multiple clinical trials under way investigating the feasibility of ketogenic dietary therapy as an adjunct to radiation and chemotherapy in adult patients with HGGs (NCT02046187, NCT02302235, NCT01754350, NCT01865162).	('NCT01865162', 'Var', (227, 238))	('NCT01754350', 'Var', (214, 225))	('patients', 'Species', '9606', (168, 176))	('NCT02302235', 'Var', (201, 212))	('NCT02046187', 'Var', (188, 199))	('HGGs', 'Disease', (182, 186))
205984	27170161	Regardless, these data highlight that energy metabolism reprogramming drugs or diets might be an attractive treatment option for GBM patients with mutated or wildtype IDH1.	('patients', 'Species', '9606', (133, 141))	('IDH1', 'Gene', (167, 171))	('GBM', 'Disease', (129, 132))	('IDH1', 'Gene', '3417', (167, 171))	('mutated', 'Var', (147, 154))
205990	27170161	Knockdown of ACSS2 expression was found to dramatically impair the incorporation of exogenously supplied acetate into lipids and histone protein and increased animal survival.	('acetate', 'Chemical', 'MESH:D000085', (105, 112))	('Knockdown', 'Var', (0, 9))	('histone', 'Protein', (129, 136))	('increased', 'PosReg', (149, 158))	('impair', 'NegReg', (56, 62))	('animal survival', 'CPA', (159, 174))	('ACSS2', 'Gene', (13, 18))	('lipids', 'Chemical', 'MESH:D008055', (118, 124))	('ACSS2', 'Gene', '55902', (13, 18))
205994	27170161	Histone deacetylases (HDAC), responsible for maintaining this balance are frequently overactivated in cancers and inhibition of HDAC in glioma cell lines and GBM animal models demonstrated anti-neoplastic activity.	('anti-neoplastic activity', 'CPA', (189, 213))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('Histone', 'Protein', (0, 7))	('HDAC', 'Gene', (128, 132))	('HDAC', 'Gene', '9734', (128, 132))	('overactivated', 'PosReg', (85, 98))	('HDAC', 'Gene', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('glioma', 'Disease', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('HDAC', 'Gene', '9734', (22, 26))	('cancers', 'Disease', (102, 109))	('inhibition', 'Var', (114, 124))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
206000	27170161	Of particular significance are mutations in histone H3.3, with 78% of DIPG carrying the amino acid substitution lysine 27 to methionine (K27M) and up to 31% of non-brainstem pediatric HGGs harboring glycine 34 to valine or arginine (G34V/R) or K27M mutations.	('DIPG', 'Chemical', '-', (70, 74))	('K27M', 'Mutation', 'p.K27M', (137, 141))	('glycine 34 to valine or arginine', 'Var', (199, 231))	('histone H3.3', 'Gene', '3021', (44, 56))	('histone H3.3', 'Gene', (44, 56))	('glycine 34 to valine or arginine', 'SUBSTITUTION', 'None', (199, 231))	('G34V', 'SUBSTITUTION', 'None', (233, 237))	('K27M', 'Mutation', 'p.K27M', (244, 248))	('G34V', 'Var', (233, 237))	('lysine 27 to methionine', 'Mutation', 'p.K27M', (112, 135))	('glycine 34 to valine', 'Mutation', 'rs1217358160', (199, 219))	('K27M', 'Var', (244, 248))
206001	27170161	It is thus not surprising that epigenetic modifier panobinostat demonstrated significant anti-tumor efficacy in a preclinical DIPG animal model, further substantiating the underlying mechanism, and has rapidly emerged as a promising therapeutic strategy for this devastating disease.	('panobinostat', 'Chemical', 'MESH:D000077767', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('epigenetic modifier', 'Var', (31, 50))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('DIPG', 'Chemical', '-', (126, 130))	('panobinostat', 'Gene', (51, 63))
206003	27170161	As H3K27M DIPG cells are transcriptionally more active with reduced di- and trimethylation, one potential strategy has focused on inhibiting the Jumonji-domain demethylase JMJD3, a key enzyme responsible for the demethylation.	('JMJD3', 'Gene', '23135', (172, 177))	('inhibiting', 'NegReg', (130, 140))	('H3K27M', 'Var', (3, 9))	('reduced', 'NegReg', (60, 67))	('K27M', 'Mutation', 'p.K27M', (5, 9))	('DIPG', 'Chemical', '-', (10, 14))	('JMJD3', 'Gene', (172, 177))
206004	27170161	The use of the GSKJ4, an inhibitor of JMJD3 demethylase, resulted in complete growth inhibition of H3K27M -expressing DIPG cells and brainstem glioma xenografts along with increased K27 methylation and a subsequent decrease in gene expression, an effect that could be further enhanced by panobinostat.	('decrease', 'NegReg', (215, 223))	('increased', 'PosReg', (172, 181))	('DIPG', 'Chemical', '-', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('glioma xenografts', 'Disease', (143, 160))	('growth inhibition', 'CPA', (78, 95))	('gene expression', 'MPA', (227, 242))	('H3K27M', 'Var', (99, 105))	('glioma xenografts', 'Disease', 'MESH:D005910', (143, 160))	('K27', 'Protein', (182, 185))	('methylation', 'MPA', (186, 197))	('panobinostat', 'Chemical', 'MESH:D000077767', (288, 300))	('JMJD3', 'Gene', (38, 43))	('GSKJ4', 'Gene', (15, 20))	('K27M', 'Mutation', 'p.K27M', (101, 105))	('brainstem glioma', 'Phenotype', 'HP:0010796', (133, 149))	('JMJD3', 'Gene', '23135', (38, 43))
206007	27170161	Rindopepimut (PEPvIII vaccine), the most extensively studied vaccine for CNS neoplasms, is targeted against the EGFRvIII peptide (H-Leu-Glu-Glu-Lys-Lys-Gln-Asn-Tyr-Val-Val-Thr-Asp-His-Cys-OH) conjugated to keyhole limpet hemocyanin (KLH).	('EGFR', 'Gene', (112, 116))	('limpet', 'Species', '6465', (214, 220))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('Cys', 'Chemical', 'MESH:D003545', (184, 187))	('Asp', 'Chemical', 'MESH:D001224', (176, 179))	('neoplasms', 'Disease', 'MESH:D009369', (77, 86))	('EGFR', 'Gene', '1956', (112, 116))	('neoplasms', 'Disease', (77, 86))	('CNS neoplasms', 'Phenotype', 'HP:0100006', (73, 86))	('H-Leu-Glu-Glu-Lys-Lys-Gln-Asn-Tyr-Val-Val-Thr-Asp-His-Cys-OH', 'Var', (130, 190))
206022	27170161	Another promising tumor-specific neoantigen with high uniformity and penetrance is IDH1R132H.	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('IDH1R132H', 'Var', (83, 92))
206023	27170161	The immunogenic epitope encircling this mutation is found on major histocompatibility complexes (MHC) class II and induces mutation-specific CD4+ T-helper-1 (TH1) responses.	('mutation', 'Var', (40, 48))	('CD4', 'Gene', (141, 144))	('CD4', 'Gene', '920', (141, 144))	('induces', 'Reg', (115, 122))
206024	27170161	Notably, peptide vaccination of mice that are transgenic for human MHC class I and II with IDH1R132H resulted in an effective MHC class II-restricted mutation-specific antitumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('IDH1R132H', 'Var', (91, 100))	('tumor', 'Disease', (172, 177))	('mice', 'Species', '10090', (32, 36))	('human', 'Species', '9606', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
206025	27170161	Based on these results two Phase I trials were initiated for patients with IDH1R132H-positive grade III and IV gliomas (NCT02454634) and for IDH1R132H-positive grade II gliomas (RESIST, NCT02193347).	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', (111, 118))	('IV gliomas', 'Disease', 'MESH:D005910', (108, 118))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('IDH1R132H-positive', 'Var', (75, 93))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('IV gliomas', 'Disease', (108, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('patients', 'Species', '9606', (61, 69))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('NCT02454634', 'Var', (120, 131))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))
206041	27170161	Clinical trials in other cancers have already convincingly demonstrated that inhibition of CTLA4, PD1, and PDL1 can activate anti-tumor immune responses, with significant and durable therapeutic benefits.	('tumor', 'Disease', (130, 135))	('activate', 'PosReg', (116, 124))	('inhibition', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PDL1', 'Gene', '29126', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('cancers', 'Disease', (25, 32))	('PDL1', 'Gene', (107, 111))	('PD1', 'Gene', (98, 101))	('CTLA4', 'Gene', (91, 96))
206044	27170161	bevacizumab, TMZ, radiation and vaccines): nivolumab, pidilizumab, and pembrolizumab, which inhibit the interaction of the PD1 receptor with its PDL1 ligand; MEDI4736 and MPDL3280A, which neutralize the PDL1-ligand; and ipilimumab, that targets CTLA4.	('nivolumab', 'Chemical', 'MESH:D000077594', (43, 52))	('ipilimumab', 'Chemical', 'MESH:D000074324', (220, 230))	('PDL1', 'Gene', '29126', (203, 207))	('MPDL3280A', 'Var', (171, 180))	('interaction', 'Interaction', (104, 115))	('PDL1', 'Gene', (203, 207))	('inhibit', 'NegReg', (92, 99))	('pembrolizumab', 'Chemical', 'MESH:C582435', (71, 84))	('neu', 'Gene', '2064', (188, 191))	('TMZ', 'Chemical', 'MESH:D000077204', (13, 16))	('pidilizumab', 'Chemical', 'MESH:C585832', (54, 65))	('PDL1', 'Gene', '29126', (145, 149))	('bevacizumab', 'Chemical', 'MESH:D000068258', (0, 11))	('neu', 'Gene', (188, 191))	('PD1', 'Gene', (123, 126))	('PDL1', 'Gene', (145, 149))
206056	27170161	Recent data suggests that tumors with mismatch repair deficiency, which is only present in a small fraction of brain cancers leading to a higher mutational load, may be more susceptible to immune checkpoint blockade and thus, providing a potential screening tool.	('deficiency', 'Var', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mismatch', 'Gene', (38, 46))	('brain cancers', 'Disease', 'MESH:D001932', (111, 124))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('brain cancers', 'Disease', (111, 124))	('mutational load', 'MPA', (145, 160))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('higher', 'PosReg', (138, 144))	('brain cancer', 'Phenotype', 'HP:0030692', (111, 123))	('tumors', 'Disease', (26, 32))
206068	27170161	p53 mutation, Retinoblastoma (Rb) mutation) to increase the tumor specificity and spare normal cells.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mutation', 'Var', (4, 12))	('Rb', 'Gene', '5925', (30, 32))	('Retinoblastoma', 'Gene', '5925', (14, 28))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increase', 'PosReg', (47, 55))	('tumor', 'Disease', (60, 65))	('Retinoblastoma', 'Gene', (14, 28))
206070	27170161	Likewise, tumor-selective adenovirus Delta24 carries a deletion in the E1A region responsible for binding Rb protein and can only replicate in Rb deficient glioma cells.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('binding', 'Interaction', (98, 105))	('tumor', 'Disease', (10, 15))	('adenovirus', 'Species', '28285', (26, 36))	('Rb', 'Gene', '5925', (143, 145))	('Rb deficient glioma', 'Disease', 'MESH:D005910', (143, 162))	('Rb', 'Gene', '5925', (106, 108))	('deletion', 'Var', (55, 63))	('Rb deficient glioma', 'Disease', (143, 162))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
206077	27170161	Furthermore G47 delta, derived from G207 with an additional deletion of nonessential alpha47 gene to enhance replication efficacy, and M032, an HSV-1 strain equipped with a human IL-12 transgene, have entered early clinical testing for recurrent or progressive HGGs (NCT02062827).	('HSV-1', 'Species', '10298', (144, 149))	('replication efficacy', 'MPA', (109, 129))	('HGGs', 'Disease', (261, 265))	('deletion', 'Var', (60, 68))	('alpha47', 'Gene', (85, 92))	('G47', 'Gene', (12, 15))	('human', 'Species', '9606', (173, 178))	('enhance', 'PosReg', (101, 108))
206086	27170161	Other oncolytic viruses in early stages of clinical development include parvovirus H1 (NCT01301430), and measles virus (NCT00390299).	('parvovirus H1', 'Species', '10799', (72, 85))	('parvovirus H1', 'Disease', (72, 85))	('measles virus', 'Disease', (105, 118))	('measles virus', 'Species', '11234', (105, 118))	('NCT01301430', 'Var', (87, 98))	('NCT00390299', 'Var', (120, 131))
206093	27170161	Furthermore, viral efficacy may be hampered by genetic modifications intended to limit toxicity that inadvertently affect the viral replication and spread.	('viral replication', 'CPA', (126, 143))	('genetic modifications', 'Var', (47, 68))	('affect', 'Reg', (115, 121))	('toxicity', 'Disease', 'MESH:D064420', (87, 95))	('toxicity', 'Disease', (87, 95))	('spread', 'CPA', (148, 154))
206127	31805879	Numerous cytokines derived from eosinophils could regulate the immune response and affect the tumor microenvironment; moreover, eosinophils may inhibit the tumorigenesis of glioma, which should be explored in the future and may enlighten some new paths for glioma therapy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('affect', 'Reg', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('glioma', 'Disease', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('eosinophils', 'Var', (128, 139))	('inhibit', 'NegReg', (144, 151))	('tumor', 'Disease', (156, 161))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', (257, 263))
206172	31805879	The ELR was decreased in the patients with GBM compared with the patients with non-GBM disease, and this difference almost reached statistical significance, with a p value of 0.06; similarly, the Ly was decreased but not significantly different.	('patients', 'Species', '9606', (29, 37))	('GBM', 'Var', (43, 46))	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('decreased', 'NegReg', (12, 21))	('patients', 'Species', '9606', (65, 73))	('ELR', 'MPA', (4, 7))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))
206191	31805879	reported that EPO, in cooperation with macrophages, can kill tumor cells and catalyze peroxidative oxidation, leading to either DNA mutations or effects on tumor cell aging and apoptosis, which may promote tumorigenesis.	('apoptosis', 'CPA', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('leading to', 'Reg', (110, 120))	('EPO', 'Gene', (14, 17))	('promote', 'PosReg', (198, 205))	('effects', 'Reg', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (206, 211))	('mutations', 'Var', (132, 141))	('DNA', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('EPO', 'Gene', '2056', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', (61, 66))
206203	31805879	This phenomenon might be because the expression of EGOT can arrest the cell cycle in the G0/G1 phase and reduce glioma cell proliferation.	('expression', 'Var', (37, 47))	('reduce', 'NegReg', (105, 111))	('arrest', 'PosReg', (60, 66))	('glioma', 'Disease', (112, 118))	('EGOT', 'Gene', '100126791', (51, 55))	('EGOT', 'Gene', (51, 55))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('cell cycle in the G0/G1 phase', 'CPA', (71, 100))
206206	31805879	Therefore, all of these findings suggest some latent relation between eosinophils and the grade of glioma, which we mainly support.	('eosinophils', 'Var', (70, 81))	('glioma', 'Disease', (99, 105))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
206250	31485480	More recent studies demonstrated the potent antitumor effects of B7-H3 CAR-T cells in several solid tumor preclinical models, including pancreatic ductal adenocarcinoma, ovarian cancer, neuroblastoma, and various pediatric cancers.	('B7-H3 CAR-T', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (100, 105))	('pediatric cancers', 'Disease', 'MESH:D009369', (213, 230))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (136, 168))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('neuroblastoma', 'Disease', 'MESH:D009447', (186, 199))	('ovarian cancer', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('pancreatic ductal adenocarcinoma', 'Disease', (136, 168))	('clinical', 'Species', '191496', (109, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (48, 53))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (65, 76))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (136, 168))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('neuroblastoma', 'Disease', (186, 199))	('neuroblastoma', 'Phenotype', 'HP:0003006', (186, 199))	('pediatric cancers', 'Disease', (213, 230))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
206260	31485480	As shown in Figure 1B, significantly higher expression of B7-H3 was found in high-grade glioma, while negative and lower expression levels were observed in normal cerebral tissues and low-grade glioma, respectively.	('expression', 'MPA', (44, 54))	('higher', 'PosReg', (37, 43))	('glioma', 'Disease', (194, 200))	('B7-H3', 'Var', (58, 63))	('glioma', 'Disease', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))
206273	31485480	As shown, strong specific lysis was observed in B7-H3 highly expressed A172, U87-B7-H3, and UPN1 cells, moderate cytotoxicity in UPN2, while no significant response was observed in B7-H3 negative or low cells, such as Raji and U87 wild-type cells.	('cytotoxicity', 'Disease', (113, 125))	('B7-H3', 'Var', (48, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (113, 125))	('Raji', 'CellLine', 'CVCL:0511', (218, 222))	('A172', 'Var', (71, 75))
206281	31485480	In this in vivo study, we used a cell line stably expressing B7-H3, so the antigen loss resulting from tumor heterogeneity may not occur.	('tumor', 'Disease', (103, 108))	('B7-H3', 'Var', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))
206287	31485480	It has been reported that B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels and anti-B7-H3 drug conjugates display potent antitumor and antimetastatic activity, suggesting it is a potentially ideal dual-compartment therapeutic target.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (69, 74))	('anti-B7-H3', 'Var', (143, 153))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('antimetastatic activity', 'CPA', (199, 222))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
206288	31485480	In murine systems, B7-H3 was reported to possess both co-stimulatory and co-inhibitory function in regulation of different T cell subsets.	('regulation', 'MPA', (99, 109))	('B7-H3', 'Var', (19, 24))	('murine', 'Species', '10090', (3, 9))
206289	31485480	With human T cells, it is reported that B7-H3 potently and consistently down-modulated human T cell responses in the presence of strong activating signals.	('human T cell responses', 'CPA', (87, 109))	('human', 'Species', '9606', (87, 92))	('down-modulated', 'NegReg', (72, 86))	('human', 'Species', '9606', (5, 10))	('B7-H3', 'Var', (40, 45))
206306	31485480	In conclusion, our results indicated that B7-H3 was expressed in 58% of clinical glioma samples, and its expression level was correlated to the malignancy grade of glioma and the poor survival of both LGG and GBM patients.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('GBM', 'Phenotype', 'HP:0012174', (209, 212))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('malignancy', 'Disease', (144, 154))	('B7-H3', 'Var', (42, 47))	('clinical', 'Species', '191496', (72, 80))	('expression level', 'MPA', (105, 121))	('glioma', 'Disease', (81, 87))	('correlated', 'Reg', (126, 136))	('patients', 'Species', '9606', (213, 221))	('glioma', 'Disease', (164, 170))	('malignancy', 'Disease', 'MESH:D009369', (144, 154))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
206336	31485480	On day 3, anti-CD3 (OKT3)/anti-CD28 activated T cells were transduced with lentivirus (MOI 3-10) over the recombinant fibronectin fragment (Novoprotein) in the presence of IL-2.	('/anti-CD28', 'Var', (25, 35))	('fibronectin', 'Gene', (118, 129))	('CD3', 'Gene', (15, 18))	('CD3', 'Gene', '12503', (15, 18))	('fibronectin', 'Gene', '14268', (118, 129))
206337	31485480	Vehicle control T cells were established in the same conditions, and NT cells were stimulated with CD3 and CD28 mAb but not transduced with lentivirus.	('CD3', 'Gene', (99, 102))	('CD3', 'Gene', '12503', (99, 102))	('CD28 mAb', 'Var', (107, 115))
206345	31485480	Mice were injected with B7-H3 CAR-T cells or equivalent number of vehicle control T cells on day 10 (as indicated in Figure 5) after tumor injection.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('Mice', 'Species', '10090', (0, 4))	('B7-H3 CAR-T cells', 'Var', (24, 41))
206347	31485480	A "survival analysis" experiment was used to compare B7-H3-specific CAR with vehicle T cells on their antitumor effect.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('B7-H3-specific CAR', 'Var', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
206353	29263839	Identification of potentially oncogenic alterations from tumor-only samples reveals Fanconi anemia pathway mutations in bladder carcinomas Cancer is caused by germline and somatic mutations, which can share biological features such as amino acid change.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder carcinomas', 'Disease', 'MESH:D001749', (120, 138))	('mutations', 'Var', (107, 116))	('Fanconi anemia', 'Disease', (84, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('caused', 'Reg', (149, 155))	('Fanconi anemia', 'Disease', 'MESH:D005199', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (120, 138))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (120, 137))	('anemia', 'Phenotype', 'HP:0001903', (92, 98))	('tumor', 'Disease', (57, 62))	('bladder carcinomas', 'Disease', (120, 138))
206354	29263839	We present a framework that uses machine learning to learn features of recurrent somatic mutations to (1) predict somatic variants from tumor-only samples and (2) identify somatic-like germline variants for integrated analysis of tumor-normal DNA.	('tumor', 'Disease', (230, 235))	('variants', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (136, 141))
206355	29263839	Using data from 1769 patients from seven cancer types (bladder, glioblastoma, low-grade glioma, lung, melanoma, stomach, and pediatric glioma), we show that "somatic-like" germline variants are enriched for autosomal-dominant cancer-predisposition genes (p < 4.35 x 10-15), including TP53.	('patients', 'Species', '9606', (21, 29))	('cancer', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('glioma', 'Disease', (88, 94))	('pediatric glioma', 'Disease', 'MESH:D005910', (125, 141))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('pediatric glioma', 'Disease', (125, 141))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('TP53', 'Gene', '7157', (284, 288))	('autosomal-dominant cancer', 'Disease', (207, 232))	('glioma', 'Disease', (135, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('autosomal-dominant cancer', 'Disease', 'MESH:D009369', (207, 232))	('glioblastoma', 'Disease', (64, 76))	('variants', 'Var', (181, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('cancer', 'Disease', (226, 232))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('TP53', 'Gene', (284, 288))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
206356	29263839	Our framework identifies germline and somatic nonsense variants in BRCA2 and other Fanconi anemia genes in 11% (11/100) of bladder cancer cases, suggesting a potential genetic predisposition in these patients.	('Fanconi anemia', 'Disease', 'MESH:D005199', (83, 97))	('patients', 'Species', '9606', (200, 208))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('nonsense variants', 'Var', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA2', 'Gene', (67, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('Fanconi anemia', 'Disease', (83, 97))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (83, 97))	('bladder cancer', 'Disease', (123, 137))	('anemia', 'Phenotype', 'HP:0001903', (91, 97))
206357	29263839	The bladder carcinoma patients with Fanconi anemia nonsense variants display a BRCA-deficiency somatic mutation signature, suggesting treatment targeted to DNA repair.	('bladder carcinoma', 'Disease', 'MESH:D001749', (4, 21))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (36, 50))	('nonsense variants', 'Var', (51, 68))	('bladder carcinoma', 'Disease', (4, 21))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (4, 21))	('Fanconi anemia', 'Disease', (36, 50))	('patients', 'Species', '9606', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('BRCA-deficiency', 'Disease', (79, 94))	('BRCA-deficiency', 'Disease', 'OMIM:604370', (79, 94))	('Fanconi anemia', 'Disease', 'MESH:D005199', (36, 50))	('anemia', 'Phenotype', 'HP:0001903', (44, 50))
206358	29263839	Bladder cancer cells often harbor DNA mutations that occur after tumor development, including some mutations that affect DNA repair.	('Bladder cancer', 'Disease', (0, 14))	('tumor', 'Disease', (65, 70))	('DNA', 'Gene', (34, 37))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (38, 47))	('harbor', 'Reg', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
206359	29263839	Raul Rabadan, Jiguang Wang, and colleagues from Columbia University in New York, USA, developed an analytic framework for identifying genetic variants, both inherited and newly arisen, that contribute to tumor development.	('contribute', 'Reg', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('variants', 'Var', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))
206360	29263839	The machine-learning tool:known as Tumor-Only Boosting Identification, or TOBI:learns what's a cancer-associated mutation from a small training set of tumor samples and matched healthy controls.	('mutation', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('TOBI', 'Chemical', '-', (74, 78))	('tumor', 'Disease', (151, 156))	('cancer', 'Disease', (95, 101))	('Tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
206362	29263839	They found that TOBI pinpointed many inherited and non-inherited mutations known to contribute to cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TOBI', 'Chemical', '-', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (65, 74))
206363	29263839	In bladder cancer samples, the tool also revealed a previously unknown role for inherited mutations in BRCA2 and other DNA repair genes in the so-called Fanconi anemia pathway.	('anemia', 'Phenotype', 'HP:0001903', (161, 167))	('mutations', 'Var', (90, 99))	('Fanconi anemia', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('Fanconi anemia', 'Disease', 'MESH:D005199', (153, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('so-called Fanconi anemia', 'Phenotype', 'HP:0001994', (143, 167))	('BRCA2', 'Gene', (103, 108))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (153, 167))
206364	29263839	Cancer often results from specific DNA alterations, and identification of cancer-causing mutations underlies genome-based precision cancer treatment.	('cancer', 'Disease', (132, 138))	('results from', 'Reg', (13, 25))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (74, 80))	('Cancer', 'Disease', (0, 6))	('alterations', 'Var', (39, 50))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
206368	29263839	Common attempts to identify somatic variants from tumor-only WES data involve removing dbSNP mutations common in the general population and focusing on genes in the Catalogue Of Somatic Mutations In Cancer (COSMIC).	('dbSNP', 'Gene', (87, 92))	('mutations', 'Var', (93, 102))	('Cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
206370	29263839	Certain strategies rely on a single patient's sequence alignment information, either predicting somatic deletions based on read-pair alignments and read depth or predicting somatic single nucleotide variants (SNV) using base quality, variant allele frequency (VAF), and sequencing error.	('deletions', 'Var', (104, 113))	('single nucleotide variants', 'Var', (181, 207))	('patient', 'Species', '9606', (36, 43))
206374	29263839	The tumor-normal cases would form a test set for identifying true somatic mutations, and the biological features of these confirmed somatic variants would be used to classify variants from the remaining tumor-only samples.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('variants', 'Var', (140, 148))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
206378	29263839	A machine learning framework built upon biological features of somatic variants would have high power to identify germline variants with somatic features that might influence tumor development.	('tumor', 'Disease', (175, 180))	('influence', 'Reg', (165, 174))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('variants', 'Var', (123, 131))
206380	29263839	Our Tumor-Only Boosting Identification framework (TOBI) learns from a small training set of tumor-normal pairs to generate a classification model that identifies variants with somatic characteristics from tumor-only samples.	('TOBI', 'Chemical', '-', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('variants', 'Var', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (92, 97))	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))
206383	29263839	Using 1769 patients across seven tumor types, we developed TOBI, evaluated TOBI's ability to identify somatic variants, and identified somatic-like germline variants (SLG variants), including variants with known or possible oncogenic potential.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('TOBI', 'Chemical', '-', (75, 79))	('variants', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SLG', 'Gene', '89858', (167, 170))	('TOBI', 'Chemical', '-', (59, 63))	('tumor', 'Disease', (33, 38))	('patients', 'Species', '9606', (11, 19))	('SLG', 'Gene', (167, 170))
206387	29263839	Ten biological features were used for gradient boosting (full features in Supplementary Text); features include database-derived features from COSMIC, cohort-associated features such as "Variants per Gene", and individual sequence features such as tumor VAF.	('Variants', 'Var', (187, 195))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
206404	29263839	", representing the number of cases in COSMIC with a specific variant; this may reflect both the lower mutation burden in pediatric glioma and the prevalence of hotspot mutations in H3F3A.	('mutations', 'Var', (169, 178))	('pediatric glioma', 'Disease', (122, 138))	('mutation burden', 'MPA', (103, 118))	('H3F3A', 'Gene', '3020', (182, 187))	('H3F3A', 'Gene', (182, 187))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('pediatric glioma', 'Disease', 'MESH:D005910', (122, 138))
206405	29263839	We compared TOBI's somatic classifications to published somatic calls from tumor-normal analysis of test set cases, Across all variants, TOBI had a sensitivity of 86.6%; for nonsynonymous variants, TOBI had a sensitivity of 87.2%.	('variants', 'Var', (127, 135))	('TOBI', 'Chemical', '-', (198, 202))	('TOBI', 'Chemical', '-', (12, 16))	('TOBI', 'Chemical', '-', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
206406	29263839	TOBI also has high sensitivity for variants with tumor VAF as low as 5% (Supplementary figure 5b,c).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('variants', 'Var', (35, 43))	('tumor', 'Disease', (49, 54))	('TOBI', 'Chemical', '-', (0, 4))
206409	29263839	While TOBI identifies variants with somatic characteristics, an important challenge in precision medicine involves finding genes that promote tumor development ("driver genes").	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('promote', 'PosReg', (134, 141))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TOBI', 'Chemical', '-', (6, 10))	('variants', 'Var', (22, 30))
206411	29263839	In six cancers, TOBI has a higher true positive rate of nonsynonymous variants in driver genes compared to all genes (Fig.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('TOBI', 'Chemical', '-', (16, 20))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('nonsynonymous variants', 'Var', (56, 78))
206415	29263839	All predicted BRAF and IDH1 variants occurred at known somatic hotspots (BRAF V600E, IDH1 R132H).	('BRAF', 'Gene', '673', (73, 77))	('variants', 'Var', (28, 36))	('R132H', 'Var', (90, 95))	('IDH1', 'Gene', (23, 27))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('occurred', 'Reg', (37, 45))	('BRAF', 'Gene', '673', (14, 18))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', (85, 89))	('V600E', 'Var', (78, 83))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', (73, 77))	('IDH1', 'Gene', '3417', (85, 89))
206424	29263839	TOBI's false positive (FP) variants could include germline variants that share features with true somatic variants, making them "somatic-like" germline (SLG) variants.	('variants', 'Var', (27, 35))	('TOBI', 'Chemical', '-', (0, 4))	('SLG', 'Gene', '89858', (153, 156))	('SLG', 'Gene', (153, 156))
206425	29263839	SLG variants could be benign or oncogenic.	('SLG', 'Gene', (0, 3))	('variants', 'Var', (4, 12))	('SLG', 'Gene', '89858', (0, 3))
206426	29263839	Alternatively, FP variants might be tumor-specific variants that were not previously published due to variability in somatic variant analysis.	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('variants', 'Var', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
206428	29263839	Since FP variants may include SLG variants, we also calculated the FPR from applying the Ped.Glioma classification model to a set of 100 non-tumor exomes from individuals without cancer sequenced by the 1000 Genomes Project.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Glioma', 'Disease', 'MESH:D005910', (93, 99))	('SLG', 'Gene', '89858', (30, 33))	('tumor', 'Disease', (141, 146))	('SLG', 'Gene', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('variants', 'Var', (9, 17))	('cancer', 'Disease', (179, 185))	('Glioma', 'Phenotype', 'HP:0009733', (93, 99))	('Glioma', 'Disease', (93, 99))
206431	29263839	To identify SLG variants, we analyzed germline VAF from 1327 test cases in six cancers excluding GBM.	('cancers', 'Disease', (79, 86))	('SLG', 'Gene', '89858', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SLG', 'Gene', (12, 15))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('variants', 'Var', (16, 24))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
206433	29263839	To be classified as an SLG variant, a FP variant needed a germline VAF of at least 30% to decrease the probability that the germline variant represented tumor contamination or artifacts.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('SLG', 'Gene', '89858', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('SLG', 'Gene', (23, 26))	('variant', 'Var', (41, 48))
206434	29263839	Since certain germline variants highly increase predisposition to cancer, we analyzed SLG variants for enrichment in 60 genes associated with autosomal dominant cancer-predisposition syndromes, or "AD genes" (listed in Supplementary Table 9), and found significant enrichment of AD genes in nonsynonymous SLG variants (p < 1.53 x 10-10; Fig.	('cancer', 'Disease', (161, 167))	('SLG', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('SLG', 'Gene', '89858', (305, 308))	('variants', 'Var', (309, 317))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('increase', 'PosReg', (39, 47))	('variants', 'Var', (90, 98))	('SLG', 'Gene', (305, 308))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('SLG', 'Gene', '89858', (86, 89))	('variants', 'Var', (23, 31))	('cancer', 'Disease', (66, 72))
206435	29263839	SLG nonsynonymous variants in TP53 occurred in seven cases (Fig.	('TP53', 'Gene', (30, 34))	('nonsynonymous variants', 'Var', (4, 26))	('SLG', 'Gene', '89858', (0, 3))	('TP53', 'Gene', '7157', (30, 34))	('SLG', 'Gene', (0, 3))	('occurred', 'Reg', (35, 43))
206436	29263839	Certain inactivating mutations in tumor suppressors are heterozygous germline variants, but show loss of heterozygosity in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (127, 132))	('inactivating mutations', 'Var', (8, 30))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
206437	29263839	Five of TP53 SLG variants exhibit evidence of loss of heterozygosity, with germline VAFs below 45% and tumor VAFs above 70%.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('variants', 'Var', (17, 25))	('tumor', 'Disease', (103, 108))	('SLG', 'Gene', '89858', (13, 16))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('heterozygosity', 'MPA', (54, 68))	('SLG', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
206438	29263839	Focusing on nonsynonymous FP variants in AD genes, we found 15 cases with TP53 mutations and at least seven cases with mutations in CDH1, RB1, RET or TSC2 (Fig.	('TSC2', 'Gene', (150, 154))	('RB1', 'Gene', (138, 141))	('CDH1', 'Gene', (132, 136))	('RET', 'Gene', (143, 146))	('RB1', 'Gene', '5925', (138, 141))	('TP53', 'Gene', '7157', (74, 78))	('CDH1', 'Gene', '999', (132, 136))	('TP53', 'Gene', (74, 78))	('RET', 'Gene', '5979', (143, 146))	('mutations', 'Var', (79, 88))	('TSC2', 'Gene', '7249', (150, 154))
206439	29263839	In three Ped.Glioma cases, TOBI predicted somatic TP53 variants with tumor VAF greater than 65% and germline VAF of 0% (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('variants', 'Var', (55, 63))	('tumor', 'Disease', (69, 74))	('Glioma', 'Disease', 'MESH:D005910', (13, 19))	('Glioma', 'Phenotype', 'HP:0009733', (13, 19))	('Glioma', 'Disease', (13, 19))	('TP53', 'Gene', '7157', (50, 54))	('TOBI', 'Chemical', '-', (27, 31))	('TP53', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
206440	29263839	3c; variants G105V, R175H, and R273C).	('R273C', 'Var', (31, 36))	('R273C', 'Mutation', 'rs121913343', (31, 36))	('G105V', 'Mutation', 'rs587781504', (13, 18))	('R175H', 'Mutation', 'rs28934578', (20, 25))	('G105V', 'Var', (13, 18))	('R175H', 'Var', (20, 25))
206442	29263839	Certain germline variants in cancer-associated genes correlate with earlier age of diagnosis, so we analyzed whether presence of nonsynonymous SLG variants in 565 cancer-associated genes (list in Supplementary Table 9) associated with earlier age of diagnosis in any cancer type.	('cancer', 'Disease', (29, 35))	('variants', 'Var', (147, 155))	('associated with', 'Reg', (219, 234))	('cancer', 'Disease', (267, 273))	('variants', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('SLG', 'Gene', '89858', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('SLG', 'Gene', (143, 146))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
206443	29263839	Supplementary table 10 provides the number of cases with SLG variants in these cancer-associated genes for each cancer type.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SLG', 'Gene', '89858', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SLG', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (79, 85))	('variants', 'Var', (61, 69))
206444	29263839	In LGG, patients with cancer-associated SLG variants had significantly earlier age at diagnosis (median 37 years vs. 41 years, p = 0.0013; Fig.	('LGG', 'Disease', (3, 6))	('SLG', 'Gene', '89858', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('SLG', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('variants', 'Var', (44, 52))	('patients', 'Species', '9606', (8, 16))
206445	29263839	The most LGG cases had SLG variants in TP53 (n = 4), followed by IDH1 (three cases: V71I [COSM96923], one case: R82K [COSM4169909]) and RET (Y791F [COSM1159820], I852M [COSM4573611], R982H [COSM1264016], T1038A [COSM4650197]).	('Y791F', 'Mutation', 'rs77724903', (141, 146))	('LGG', 'Disease', (9, 12))	('SLG', 'Gene', (23, 26))	('T1038A', 'Mutation', 'rs201740483', (204, 210))	('Y791F [COSM1159820]', 'Var', (141, 160))	('RET', 'Gene', '5979', (136, 139))	('R982H', 'Mutation', 'rs368550200', (183, 188))	('IDH1', 'Gene', '3417', (65, 69))	('SLG', 'Gene', '89858', (23, 26))	('V71I', 'Mutation', 'rs73070954', (84, 88))	('I852M [COSM4573611]', 'Var', (162, 181))	('TP53', 'Gene', '7157', (39, 43))	('RET', 'Gene', (136, 139))	('COSM1159820', 'Chemical', '-', (148, 159))	('T1038A [COSM4650197]', 'Var', (204, 224))	('COSM1264016', 'Chemical', '-', (190, 201))	('R82K', 'Mutation', 'rs775186249', (112, 116))	('I852M', 'Mutation', 'rs377767426', (162, 167))	('R982H [COSM1264016]', 'Var', (183, 202))	('IDH1', 'Gene', (65, 69))	('TP53', 'Gene', (39, 43))
206446	29263839	Many genes with SLG variants in LGG have also shown recurrent somatic mutations in prior analysis (e.g., TP53, IDH1, EGFR, and NF2; Fig.	('NF2', 'Gene', (127, 130))	('SLG', 'Gene', '89858', (16, 19))	('variants', 'Var', (20, 28))	('LGG', 'Gene', (32, 35))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('NF2', 'Gene', '4771', (127, 130))	('IDH1', 'Gene', '3417', (111, 115))	('SLG', 'Gene', (16, 19))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('IDH1', 'Gene', (111, 115))
206447	29263839	Truncating germline alterations in cancer predisposition genes have been reported in 4-19% of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('reported', 'Reg', (73, 81))	('Truncating germline alterations', 'Var', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
206448	29263839	Accordingly, we examined the exome-wide SLG nonsense variants in each cancer type.	('SLG', 'Gene', '89858', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SLG', 'Gene', (40, 43))	('nonsense variants', 'Var', (44, 61))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
206449	29263839	Bladder carcinoma cases showed significant enrichment of SLG nonsense variants in the FA pathway based on pathway assessment with g:Profiler (49 genes with SLG variants, 54 genes in FA pathway, 3 overlapping genes; p-value of 0.029 after multiple testing correction; Supplementary Fig.	('FA', 'Phenotype', 'HP:0001994', (182, 184))	('SLG', 'Gene', '89858', (156, 159))	('FA pathway', 'Pathway', (86, 96))	('carcinoma', 'Disease', 'MESH:D002277', (8, 17))	('SLG', 'Gene', (156, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('SLG', 'Gene', '89858', (57, 60))	('Bladder carcinoma', 'Phenotype', 'HP:0002862', (0, 17))	('FA', 'Phenotype', 'HP:0001994', (86, 88))	('carcinoma', 'Disease', (8, 17))	('SLG', 'Gene', (57, 60))	('variants', 'Var', (160, 168))
206451	29263839	In bladder cancer, TOBI predicted these variants in 11% (11/100) of patients.	('TOBI', 'Chemical', '-', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('patients', 'Species', '9606', (68, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('variants', 'Var', (40, 48))
206452	29263839	Less than 2.5% of patients in any other cancer type had predicted nonsense FA variants.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('patients', 'Species', '9606', (18, 26))	('FA', 'Phenotype', 'HP:0001994', (75, 77))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('nonsense', 'Var', (66, 74))
206453	29263839	True somatic nonsense variants occurred in 6% of BLCA cases, affecting genes BRCA2, FANCM, FANCE, REV3L, and SLX4.	('SLX4', 'Gene', (109, 113))	('affecting', 'Reg', (61, 70))	('REV3L', 'Gene', '5980', (98, 103))	('FANCM', 'Gene', '57697', (84, 89))	('FA', 'Phenotype', 'HP:0001994', (91, 93))	('BRCA2', 'Gene', (77, 82))	('FANCE', 'Gene', (91, 96))	('SLX4', 'Gene', '84464', (109, 113))	('FA', 'Phenotype', 'HP:0001994', (84, 86))	('FANCE', 'Gene', '2178', (91, 96))	('FANCM', 'Gene', (84, 89))	('REV3L', 'Gene', (98, 103))	('nonsense variants', 'Var', (13, 30))	('variants', 'Var', (22, 30))
206456	29263839	5b: FANCM R1931*, BRCA2 Y3308*).	('Y3308*', 'SUBSTITUTION', 'None', (24, 30))	('R1931*', 'Var', (10, 16))	('FA', 'Phenotype', 'HP:0001994', (4, 6))	('Y3308*', 'Var', (24, 30))	('R1931*', 'SUBSTITUTION', 'None', (10, 16))	('FANCM', 'Gene', '57697', (4, 9))	('FANCM', 'Gene', (4, 9))
206457	29263839	Of note, BRCA2 variant Y3308* has been associated with hereditary colorectal and breast cancer.	('Y3308*', 'SUBSTITUTION', 'None', (23, 29))	('BRCA2', 'Gene', (9, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('Y3308*', 'Var', (23, 29))	('hereditary colorectal and breast cancer', 'Disease', 'MESH:D015179', (55, 94))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
206458	29263839	Mice ES cells with BRCA2 Y3308* mutations showed hypersensitivity to ionizing radiation and crosslinking agents, as well as decreased homologous recombination efficiency.	('hypersensitivity', 'Disease', 'MESH:D004342', (49, 65))	('BRCA2', 'Gene', (19, 24))	('hypersensitivity', 'Disease', (49, 65))	('Y3308*', 'SUBSTITUTION', 'None', (25, 31))	('decreased', 'NegReg', (124, 133))	('Mice', 'Species', '10090', (0, 4))	('homologous recombination efficiency', 'CPA', (134, 169))	('Y3308*', 'Var', (25, 31))
206459	29263839	Additionally, FANCM R1931* was associated with increased breast cancer risk and deficient DNA repair.	('R1931*', 'Var', (20, 26))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('FANCM', 'Gene', (14, 19))	('R1931*', 'SUBSTITUTION', 'None', (20, 26))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('increased', 'PosReg', (47, 56))	('deficient', 'NegReg', (80, 89))	('FANCM', 'Gene', '57697', (14, 19))	('DNA repair', 'CPA', (90, 100))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
206462	29263839	Enrichment of this somatic mutation signature in bladder cancer cases with nonsense FA variants suggests that these FA nonsense variants, whether somatic or germline, affect the bladder cancer somatic mutation landscape.	('bladder cancer', 'Disease', (49, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('somatic mutation landscape', 'MPA', (193, 219))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('variants', 'Var', (87, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('variants', 'Var', (128, 136))	('affect', 'Reg', (167, 173))	('FA', 'Phenotype', 'HP:0001994', (84, 86))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('FA', 'Phenotype', 'HP:0001994', (116, 118))
206463	29263839	In this report, we present TOBI, a new unifying framework that uses the gradient boosting machine learning algorithm to identify somatic variants from tumor-only data or identify somatic-like germline variants in patients with tumor-normal DNA available.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('variants', 'Var', (137, 145))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (151, 156))	('TOBI', 'Chemical', '-', (27, 31))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
206465	29263839	In tumor-only analysis, TOBI successfully identified 87% of nonsynonymous somatic variants.	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('TOBI', 'Chemical', '-', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('nonsynonymous', 'Var', (60, 73))
206466	29263839	Higher true positive rates in driver genes suggest that TOBI enriches for cancer-causing variants.	('TOBI', 'Chemical', '-', (56, 60))	('variants', 'Var', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
206468	29263839	A TOBI modification trained on FFPE artifacts could potentially remove more FFPE sequencing artifacts, although this modification would need testing.	('remove', 'NegReg', (64, 70))	('modification', 'Var', (7, 19))	('TOBI', 'Chemical', '-', (2, 6))	('FFPE sequencing artifacts', 'MPA', (76, 101))
206474	29263839	These SLG variants include oncogenic germline variants validated by outside groups, such as the TP53 R248Q alteration confirmed as germline by tumor-normal analysis of a pediatric glioma case.	('tumor', 'Disease', (143, 148))	('variants', 'Var', (10, 18))	('TP53', 'Gene', (96, 100))	('R248Q alteration', 'Var', (101, 117))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('pediatric glioma', 'Disease', 'MESH:D005910', (170, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('SLG', 'Gene', '89858', (6, 9))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('R248Q', 'Mutation', 'rs11540652', (101, 106))	('pediatric glioma', 'Disease', (170, 186))	('SLG', 'Gene', (6, 9))	('TP53', 'Gene', '7157', (96, 100))
206475	29263839	SLG variants in cancer genes also associated with earlier age of diagnosis in patients with low-grade glioma (Fig.	('associated', 'Reg', (34, 44))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('variants', 'Var', (4, 12))	('cancer', 'Disease', (16, 22))	('patients', 'Species', '9606', (78, 86))	('SLG', 'Gene', '89858', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('glioma', 'Disease', (102, 108))	('SLG', 'Gene', (0, 3))
206476	29263839	4a), suggesting that TOBI's SLG variants are enriched for cancer-associated variants.	('SLG', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TOBI', 'Chemical', '-', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('variants', 'Var', (32, 40))	('SLG', 'Gene', '89858', (28, 31))	('cancer', 'Disease', (58, 64))
206477	29263839	Analysis of bladder carcinoma cases using TOBI revealed largely unreported germline inactivating mutations in the FA pathway, suggesting a potential genetic predisposition in 5% of patients.	('TOBI', 'Chemical', '-', (42, 46))	('germline', 'Var', (75, 83))	('FA pathway', 'Pathway', (114, 124))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (12, 29))	('patients', 'Species', '9606', (181, 189))	('FA', 'Phenotype', 'HP:0001994', (114, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('bladder carcinoma', 'Disease', (12, 29))	('bladder carcinoma', 'Disease', 'MESH:D001749', (12, 29))
206478	29263839	Outside analysis of a 14-patient bladder tumor cohort found a germline nonsense variant in BRCA2, but did not assess FA mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FA', 'Phenotype', 'HP:0001994', (117, 119))	('bladder tumor', 'Disease', 'MESH:D001749', (33, 46))	('BRCA2', 'Gene', (91, 96))	('bladder tumor', 'Phenotype', 'HP:0009725', (33, 46))	('patient', 'Species', '9606', (25, 32))	('bladder tumor', 'Disease', (33, 46))	('germline nonsense', 'Var', (62, 79))
206479	29263839	Germline BRCA2 nonsense mutations in bladder carcinoma may reflect the pan-cancer susceptibility attributed to germline BRCA2 mutations in analysis of other adult cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('BRCA2', 'Gene', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('nonsense mutations', 'Var', (15, 33))	('adult cancers', 'Disease', (157, 170))	('cancer', 'Disease', (75, 81))	('adult cancers', 'Disease', 'MESH:C535836', (157, 170))	('BRCA2', 'Gene', (120, 125))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('bladder carcinoma', 'Disease', (37, 54))	('bladder carcinoma', 'Disease', 'MESH:D001749', (37, 54))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
206480	29263839	Future assessment of a larger BLCA cohort may reveal associations between germline FA mutations and clinical outcomes, similar to how an expanded cohort of prostate cancer patients revealed significantly more deleterious germline mutations in DNA repair genes in patients with metastatic vs. localized prostate cancer.	('mutations', 'Var', (86, 95))	('localized prostate cancer', 'Disease', (292, 317))	('germline mutations', 'Var', (221, 239))	('prostate cancer', 'Disease', (156, 171))	('DNA repair genes', 'Gene', (243, 259))	('metastatic', 'Disease', (277, 287))	('prostate cancer', 'Disease', 'MESH:D011471', (302, 317))	('patients', 'Species', '9606', (263, 271))	('prostate cancer', 'Phenotype', 'HP:0012125', (302, 317))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('FA', 'Phenotype', 'HP:0001994', (83, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('associations', 'Interaction', (53, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('patients', 'Species', '9606', (172, 180))	('localized prostate cancer', 'Disease', 'MESH:D011471', (292, 317))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
206481	29263839	Our integrated somatic and germline analysis identified nonsense FA pathway mutations in 11% of BLCA cases, suggesting a role for aberrant interstrand crosslink repair in bladder tumor development.	('nonsense', 'Var', (56, 64))	('mutations', 'Var', (76, 85))	('bladder tumor', 'Disease', (171, 184))	('FA', 'Phenotype', 'HP:0001994', (65, 67))	('bladder tumor', 'Disease', 'MESH:D001749', (171, 184))	('BLCA', 'Disease', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('bladder tumor', 'Phenotype', 'HP:0009725', (171, 184))
206482	29263839	Enrichment for a BRCA-deficiency somatic signature in these patients indicates similarity between FA mutant bladder cancers and BRCA-mutant breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancers', 'Disease', 'MESH:D001943', (140, 154))	('breast cancers', 'Disease', (140, 154))	('BRCA-deficiency', 'Disease', 'OMIM:604370', (17, 32))	('BRCA-deficiency', 'Disease', (17, 32))	('bladder cancers', 'Disease', 'MESH:D001749', (108, 123))	('bladder cancers', 'Disease', (108, 123))	('breast cancers', 'Phenotype', 'HP:0003002', (140, 154))	('FA', 'Phenotype', 'HP:0001994', (98, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('patients', 'Species', '9606', (60, 68))	('BRCA', 'Gene', '672', (17, 21))	('BRCA', 'Gene', '672', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA', 'Gene', (17, 21))	('bladder cancers', 'Phenotype', 'HP:0009725', (108, 123))	('BRCA', 'Gene', (128, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('mutant', 'Var', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))
206485	29263839	Additionally, recent research found that the presence of tumor DNA alterations in FANCC (a member of the FA pathway), ATM, and RB1 predicted beneficial response to cisplatin neoadjuvant chemotherapy.	('ATM', 'Gene', (118, 121))	('FANCC', 'Gene', '2176', (82, 87))	('FA', 'Phenotype', 'HP:0001994', (105, 107))	('RB1', 'Gene', '5925', (127, 130))	('beneficial', 'PosReg', (141, 151))	('FANCC', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ATM', 'Gene', '472', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('RB1', 'Gene', (127, 130))	('tumor', 'Disease', (57, 62))	('FA', 'Phenotype', 'HP:0001994', (82, 84))	('response to cisplatin neoadjuvant chemotherapy', 'MPA', (152, 198))	('presence', 'Var', (45, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
206486	29263839	Future research could determine whether FA nonsense mutations also predict beneficial response to Cisplatin, particularly given the beneficial response to cisplatin in patients with BRCA1 mutant breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (195, 209))	('BRCA1', 'Gene', '672', (182, 187))	('breast cancers', 'Disease', 'MESH:D001943', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancers', 'Disease', (195, 209))	('Cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('BRCA1', 'Gene', (182, 187))	('beneficial', 'PosReg', (132, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('beneficial', 'PosReg', (75, 85))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('patients', 'Species', '9606', (168, 176))	('FA', 'Phenotype', 'HP:0001994', (40, 42))	('mutant', 'Var', (188, 194))
206493	29263839	Fourth, for germline variant analysis, TOBI's designation of SLG variants denotes "somatic-like" status, but does not differentiate oncogenic and benign germline variants.	('TOBI', 'Chemical', '-', (39, 43))	('variants', 'Var', (65, 73))	('SLG', 'Gene', (61, 64))	('SLG', 'Gene', '89858', (61, 64))
206494	29263839	Finally, fully understanding the role of FA variants in bladder cancer requires experimental validation.	('FA', 'Phenotype', 'HP:0001994', (41, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('bladder cancer', 'Disease', (56, 70))	('variants', 'Var', (44, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
206495	29263839	In sum, we propose a framework that analyzes either tumor-only samples or samples with matched tumor-normal DNA for variants with somatic features.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variants', 'Var', (116, 124))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (95, 100))
206499	29263839	Applying the TOBI framework to seven cancer types illustrated that TOBI recovers known oncogenic variants of somatic and germline origin, and suggests a previously unreported role for inactivating mutations in the FA pathway in bladder cancer.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('TOBI', 'Chemical', '-', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (37, 43))	('TOBI', 'Chemical', '-', (13, 17))	('bladder cancer', 'Disease', (228, 242))	('cancer', 'Disease', (236, 242))	('bladder cancer', 'Disease', 'MESH:D001749', (228, 242))	('bladder cancer', 'Phenotype', 'HP:0009725', (228, 242))	('inactivating mutations', 'Var', (184, 206))	('FA', 'Phenotype', 'HP:0001994', (214, 216))	('FA pathway', 'Pathway', (214, 224))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
206501	29263839	For the remaining five TCGA cancers (BLCA, LGG, LUAD, SKCM, STAD), we downloaded Protected Mutation vcf files with somatic and germline variants for entry into the TOBI.vcf pathway indicated in Fig.	('cancers', 'Disease', (28, 35))	('variants', 'Var', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('LUAD', 'Disease', (48, 52))	('SKCM', 'Disease', (54, 58))	('TOBI', 'Chemical', '-', (164, 168))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('LGG', 'Disease', (43, 46))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
206504	29263839	Bam files were available for datasets EGAD00001000807 (St. Jude Children's Research Hospital:Washington University Pediatric Cancer Genome Project Steering Committee) and EGAD00001000706 (ICR DIPG Data Access Committee).	('EGAD00001000706', 'Var', (171, 186))	('Children', 'Species', '9606', (64, 72))	('EGAD00001000807', 'Var', (38, 53))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))
206506	29263839	For 1000 Genomes Project samples, phase 3 bam files were downloaded from the public FTP site for the first 99 "mapped" samples listed in ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/alignment_indices/20130502.exome.alignment.index, as well as sample NA11994, which was previously reported to have a germline variant in TP53 (R273H).	('R273H', 'Var', (321, 326))	('R273H', 'Mutation', 'rs28934576', (321, 326))	('TP53', 'Gene', '7157', (315, 319))	('TP53', 'Gene', (315, 319))
206514	29263839	For each cancer, TOBI generates an optimum classification model by running a systematic grid search through gradient boosting's three parameters: number of trees (100, 150, 200), interaction depth (3-7 splits), and shrinkage (constant at 0.1).	('cancer', 'Disease', (9, 15))	('100', 'Var', (163, 166))	('TOBI', 'Chemical', '-', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
206524	29263839	For enrichment of gene sets in FP variants, the Poisson cumulative distribution was calculated for each gene set, with g total genes and n FP variants in those genes from a cancer dataset with N variants found in G genes, as the probability of a value greater than  with  using the R ppois function: ppois(n-1, g*N/G, lower.tail = FALSE).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('variants', 'Var', (34, 42))	('cancer', 'Disease', (173, 179))	('variants', 'Var', (142, 150))	('FA', 'Phenotype', 'HP:0001994', (331, 333))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))
206527	29263839	We compared the distribution of diagnosis age for cases with or without SLG variants using the Wilcoxon-Mann-Whitney test in R, wilcox.test.	('SLG', 'Gene', (72, 75))	('variants', 'Var', (76, 84))	('SLG', 'Gene', '89858', (72, 75))
206528	29263839	g:Profiler analysis of BLCA nonsense SLG variants was run using defaults (Significant only; Hierarchical sorting; Numeric IDs treated as: WIKIGENE_ACC; Significance threshold: g:SCS threshold; Statistical domain size: Only annotated genes.)	('SLG', 'Gene', (37, 40))	('variants', 'Var', (41, 49))	('SLG', 'Gene', '89858', (37, 40))
206538	25706986	Metabolic Reprogramming in Mutant IDH1 Glioma Cells Mutations in isocitrate dehydrogenase (IDH) 1 have been reported in over 70% of low-grade gliomas and secondary glioblastomas.	('Glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH1 Glioma', 'Disease', (34, 45))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('reported', 'Reg', (108, 116))	('Mutations', 'Var', (52, 61))	('glioblastomas', 'Phenotype', 'HP:0012174', (164, 177))	('IDH1 Glioma', 'Disease', 'MESH:D005910', (34, 45))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('glioblastomas', 'Disease', 'MESH:D005909', (164, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('glioblastomas', 'Disease', (164, 177))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (65, 97))
206539	25706986	IDH1 is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate while mutant IDH1 catalyzes the conversion of alpha-ketoglutarate into 2-hydroxyglutarate.	('oxidative', 'MPA', (38, 47))	('IDH1', 'Gene', (114, 118))	('mutant', 'Var', (107, 113))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (81, 100))	('IDH1', 'Gene', '3417', (114, 118))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (147, 166))	('isocitrate', 'Chemical', 'MESH:C034219', (67, 77))	('IDH1', 'Gene', (0, 4))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (172, 190))	('IDH1', 'Gene', '3417', (0, 4))
206540	25706986	These mutations are associated with the accumulation of 2-hydroxyglutarate within the tumor and are believed to be one of the earliest events in the development of low-grade gliomas.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('associated', 'Reg', (20, 30))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (56, 74))	('tumor', 'Disease', (86, 91))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('gliomas', 'Disease', (174, 181))	('2-hydroxyglutarate', 'MPA', (56, 74))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutations', 'Var', (6, 15))	('accumulation', 'MPA', (40, 52))
206541	25706986	The goal of this work was to determine whether the IDH1 mutation leads to additional magnetic resonance spectroscopy (MRS)-detectable changes in the cellular metabolome.	('IDH1', 'Gene', '3417', (51, 55))	('changes', 'Reg', (134, 141))	('cellular metabolome', 'MPA', (149, 168))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))
206543	25706986	For both models, wild-type IDH1 cells were generated by transduction with a lentiviral vector coding for the wild-type IDH1 gene while mutant IDH1 cells were generated by transduction with a lentiviral vector coding for the R132H IDH1 mutant gene.	('R132H', 'Var', (224, 229))	('IDH1', 'Gene', '3417', (142, 146))	('R132H', 'Mutation', 'rs121913500', (224, 229))	('IDH1', 'Gene', (119, 123))	('IDH1', 'Gene', (230, 234))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (119, 123))	('IDH1', 'Gene', '3417', (230, 234))	('IDH1', 'Gene', '3417', (27, 31))	('IDH1', 'Gene', (142, 146))
206545	25706986	Principal Component Analysis clearly discriminated between wild-type and mutant IDH1 cells.	('discriminated', 'Reg', (37, 50))	('IDH1', 'Gene', '3417', (80, 84))	('IDH1', 'Gene', (80, 84))	('mutant', 'Var', (73, 79))
206546	25706986	Analysis of the loading plots revealed significant metabolic changes associated with the IDH1 mutation.	('IDH1', 'Gene', (89, 93))	('metabolic changes', 'MPA', (51, 68))	('mutation', 'Var', (94, 102))	('IDH1', 'Gene', '3417', (89, 93))
206547	25706986	Specifically, a significant drop in the concentration of glutamate, lactate and phosphocholine as well as the expected elevation in 2-hydroxyglutarate were observed in mutant IDH1 cells when compared to their wild-type counterparts.	('phosphocholine', 'Chemical', 'MESH:D010767', (80, 94))	('mutant', 'Var', (168, 174))	('drop', 'NegReg', (28, 32))	('glutamate', 'Chemical', 'MESH:D018698', (57, 66))	('lactate', 'Chemical', 'MESH:D019344', (68, 75))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (132, 150))	('elevation', 'PosReg', (119, 128))	('IDH1', 'Gene', (175, 179))	('lactate', 'MPA', (68, 75))	('concentration of glutamate', 'MPA', (40, 66))	('IDH1', 'Gene', '3417', (175, 179))	('2-hydroxyglutarate', 'MPA', (132, 150))
206548	25706986	The IDH1 mutation leads to several, potentially translatable MRS-detectable metabolic changes beyond the production of 2-hydroxyglutarate.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('metabolic changes', 'MPA', (76, 93))	('leads to', 'Reg', (18, 26))	('IDH1', 'Gene', (4, 8))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (119, 137))
206554	25706986	A new diagnostic paradigm emerged in 2009 when mutations in the cytosolic isocitrate dehydrogenase 1 (IDH1) enzyme were detected in 70-80% of grade II, III and grade IV secondary (upgraded) GBMs, but rarely in primary GBM tumors.	('isocitrate dehydrogenase 1 ', 'Gene', (74, 101))	('isocitrate dehydrogenase 1 ', 'Gene', '3417', (74, 101))	('mutations', 'Var', (47, 56))	('IDH1', 'Gene', (102, 106))	('GBM tumors', 'Disease', (218, 228))	('GBM tumors', 'Disease', 'MESH:D005910', (218, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('IDH1', 'Gene', '3417', (102, 106))	('detected', 'Reg', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('secondary', 'Disease', (169, 178))
206555	25706986	Mutations in the mitochondrial isoform of IDH, namely IDH2, have also been reported but these occur more commonly in acute myeloid leukemia (AML).	('AML', 'Disease', (141, 144))	('IDH', 'Gene', (42, 45))	('IDH2', 'Gene', (54, 58))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (117, 139))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (123, 139))	('IDH', 'Gene', '3417', (42, 45))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (117, 139))	('IDH2', 'Gene', '3418', (54, 58))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (54, 57))	('occur', 'Reg', (94, 99))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('AML', 'Disease', 'MESH:D015470', (141, 144))	('IDH', 'Gene', '3417', (54, 57))	('acute myeloid leukemia', 'Disease', (117, 139))
206556	25706986	In addition to glioma and AML, IDH mutations have been confirmed in enchondroma and in some cases of thyroid carcinomas, cartilaginous tumors and intrahepatic cholangiocarcinomas.	('AML', 'Disease', 'MESH:D015470', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (146, 178))	('enchondroma', 'Disease', (68, 79))	('AML', 'Disease', (26, 29))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('IDH', 'Gene', (31, 34))	('cartilaginous tumors', 'Disease', (121, 141))	('confirmed', 'Reg', (55, 64))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (101, 119))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (121, 141))	('thyroid carcinomas', 'Disease', (101, 119))	('enchondroma', 'Disease', 'MESH:D002812', (68, 79))	('enchondroma', 'Phenotype', 'HP:0030038', (68, 79))	('IDH', 'Gene', '3417', (31, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('intrahepatic cholangiocarcinomas', 'Disease', (146, 178))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (101, 119))	('glioma', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('mutations', 'Var', (35, 44))
206557	25706986	Different studies have analyzed the role of IDH mutations in cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('IDH', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('IDH', 'Gene', '3417', (44, 47))	('mutations', 'Var', (48, 57))
206558	25706986	The main biochemical alteration associated with these mutations is the gain of a new enzymatic activity wherein mutant IDH reduces alpha-ketoglutarate (alpha-KG, also called 2-oxoglutarate) to 2-hydroxyglutarate (2-HG).	('IDH', 'Gene', '3417', (119, 122))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (174, 188))	('alpha-ketoglutarate', 'MPA', (131, 150))	('gain', 'PosReg', (71, 75))	('alpha-KG', 'Chemical', 'MESH:D007656', (152, 160))	('reduces alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (123, 150))	('mutations', 'Var', (54, 63))	('2-HG', 'Chemical', 'MESH:C019417', (213, 217))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (193, 211))	('mutant', 'Var', (112, 118))	('IDH', 'Gene', (119, 122))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (131, 150))	('reduces', 'NegReg', (123, 130))
206560	25706986	As a result, mutant IDH leads to elevated levels of 2-HG in tumor cells.	('mutant', 'Var', (13, 19))	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('elevated', 'PosReg', (33, 41))	('levels of 2-HG', 'MPA', (42, 56))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('2-HG', 'Chemical', 'MESH:C019417', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
206561	25706986	The exact mechanism through which mutant IDH and 2-HG induce oncogenesis continues to be investigated.	('oncogenesis', 'CPA', (61, 72))	('IDH', 'Gene', (41, 44))	('IDH', 'Gene', '3417', (41, 44))	('2-HG', 'Chemical', 'MESH:C019417', (49, 53))	('2-HG', 'Gene', (49, 53))	('induce', 'Reg', (54, 60))	('mutant', 'Var', (34, 40))
206564	25706986	A previous publication using mass spectrometric studies of cellular models suggests that the IDH1 mutation might also cause changes in global cellular metabolism.	('IDH1', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('IDH1', 'Gene', '3417', (93, 97))	('global cellular metabolism', 'MPA', (135, 161))	('changes', 'Reg', (124, 131))
206566	25706986	1H MRS has been applied to investigations of glioma patient biopsies and has confirmed that, in addition to elevated levels of 2-HG, other metabolic alterations occur in mutant IDH tumors.	('metabolic alterations', 'MPA', (139, 160))	('occur', 'Reg', (161, 166))	('1H', 'Chemical', '-', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('IDH tumors', 'Disease', (177, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('IDH tumors', 'Disease', 'MESH:D009369', (177, 187))	('patient', 'Species', '9606', (52, 59))	('mutant', 'Var', (170, 176))	('glioma', 'Disease', (45, 51))	('2-HG', 'Chemical', 'MESH:C019417', (127, 131))
206567	25706986	Studies of genetically-defined cell models combined with MRS-based metabolomics can be used to further investigate the broad-based metabolic alterations specifically associated with the IDH mutation and its distinct molecular phenotype.	('mutation', 'Var', (190, 198))	('IDH', 'Gene', '3417', (186, 189))	('IDH', 'Gene', (186, 189))	('associated', 'Reg', (166, 176))
206570	25706986	The aim of our study was to analyze the metabolic changes associated with the IDH1 mutation using a comprehensive and reproducible metabolomics platform.	('mutation', 'Var', (83, 91))	('IDH1', 'Gene', '3417', (78, 82))	('IDH1', 'Gene', (78, 82))
206571	25706986	To achieve this objective, we analyzed two genetically engineered IDH1 mutant cell models, a U87 glioblastoma cell line-based model and an E6/E7/hTERT immortalized Normal Human Astrocyte (NHA)-based model.	('U87', 'Gene', (93, 96))	('IDH1', 'Gene', '3417', (66, 70))	('Human', 'Species', '9606', (171, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('IDH1', 'Gene', (66, 70))	('U87', 'Gene', '641648', (93, 96))	('mutant', 'Var', (71, 77))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
206572	25706986	MRS data were analyzed by multivariate analysis techniques in order to identify the metabolic differences between wild-type and mutant IDH1 cells common to both cellular models.	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', '3417', (135, 139))	('mutant', 'Var', (128, 134))
206574	25706986	For both models, wild-type IDH1 cells (IDHwt) were generated by transduction with a lentiviral vector coding for the wild-type IDH1 gene and mutant IDH1 cells (IDHmut) were generated by transduction with a lentiviral vector coding for the mutant IDH1 gene (point mutation in R132H).	('IDH', 'Gene', '3417', (27, 30))	('IDH1', 'Gene', (127, 131))	('IDH', 'Gene', (246, 249))	('IDH', 'Gene', (160, 163))	('IDH', 'Gene', (127, 130))	('IDH1', 'Gene', (246, 250))	('IDH', 'Gene', (39, 42))	('IDH1', 'Gene', '3417', (127, 131))	('IDH', 'Gene', '3417', (246, 249))	('IDH', 'Gene', '3417', (160, 163))	('IDH1', 'Gene', (148, 152))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (148, 151))	('IDH1', 'Gene', '3417', (246, 250))	('IDH1', 'Gene', (27, 31))	('IDH', 'Gene', '3417', (39, 42))	('IDH', 'Gene', (27, 30))	('IDH1', 'Gene', '3417', (148, 152))	('point mutation', 'Var', (257, 271))	('R132H', 'Mutation', 'rs121913500', (275, 280))	('IDH', 'Gene', '3417', (148, 151))	('IDH1', 'Gene', '3417', (27, 31))
206578	25706986	Membranes were blocked overnight in 5% milk (Santa Cruz Biotechnology, TX, USA) in TBST (Tris-buffered Saline with 0.1% Tween 20, pH 7.5) at 4 C. Membranes were then washed 3 times for 5 min each in TBST and incubated with primary antibodies diluted in TBST [IDH1 wild-type (Cell Signaling, MA, USA), IDH1 R132H mutant (Dianova, Hamburg, Germany), beta- tubulin (Cell Signaling, MA, USA)] for 1 h at room temperature.	('IDH1', 'Gene', (259, 263))	('Tween 20', 'Chemical', 'MESH:D011136', (120, 128))	('TBST', 'Chemical', '-', (253, 257))	('R132H', 'Var', (306, 311))	('IDH1', 'Gene', (301, 305))	('Tris-buffered Saline', 'Chemical', '-', (89, 109))	('R132H', 'Mutation', 'rs121913500', (306, 311))	('IDH1', 'Gene', '3417', (259, 263))	('IDH1', 'Gene', '3417', (301, 305))	('TBST', 'Chemical', '-', (199, 203))	('TBST', 'Chemical', '-', (83, 87))	('beta- tubulin', 'Protein', (348, 361))
206579	25706986	Following 3 washes of 10 min each with TBST, HRP-conjugated secondary antibodies (IDH1 mutant (Abcam, MA, USA), IDH1 wild-type and beta- tubulin (Cell Signaling, MA, USA) were added for 1 h in TBST at room temperature.	('TBST', 'Chemical', '-', (193, 197))	('TBST', 'Chemical', '-', (39, 43))	('IDH1', 'Gene', (112, 116))	('IDH1', 'Gene', (82, 86))	('mutant', 'Var', (87, 93))	('IDH1', 'Gene', '3417', (82, 86))	('IDH1', 'Gene', '3417', (112, 116))
206596	25706986	First, we used Western blot analysis to assess the expression of IDH1 wild-type and R132H mutant proteins in our models (Fig.	('R132H', 'Var', (84, 89))	('IDH1', 'Gene', '3417', (65, 69))	('IDH1', 'Gene', (65, 69))	('R132H', 'Mutation', 'rs121913500', (84, 89))
206598	25706986	In addition, we confirmed that the IDHwt and IDHmut cells display comparable protein expression i.e., the expression of the IDH1 wild-type protein in U87IDHwt and NHAIDHwt cells was comparable to the expression of the IDH1 R132H mutant protein in their IDHmut counterparts (representative blots are shown in Fig.	('IDH', 'Gene', '3417', (35, 38))	('IDH1', 'Gene', '3417', (218, 222))	('IDH', 'Gene', (153, 156))	('IDH', 'Gene', '3417', (218, 221))	('R132H', 'Mutation', 'rs121913500', (223, 228))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', (253, 256))	('IDH1', 'Gene', (124, 128))	('IDH', 'Gene', '3417', (153, 156))	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', '3417', (166, 169))	('IDH', 'Gene', '3417', (253, 256))	('R132H', 'Var', (223, 228))	('IDH', 'Gene', (35, 38))	('IDH1', 'Gene', '3417', (124, 128))	('IDH', 'Gene', '3417', (45, 48))	('IDH1', 'Gene', (218, 222))	('IDH', 'Gene', '3417', (124, 127))	('IDH', 'Gene', (218, 221))
206599	25706986	We also confirmed that there was considerable expression of the IDH1 wild-type protein in the mutant cell lines, and that this expression was comparable to that of the IDH1 R132H protein.	('IDH1', 'Gene', '3417', (168, 172))	('IDH1', 'Gene', (64, 68))	('mutant', 'Var', (94, 100))	('IDH1', 'Gene', '3417', (64, 68))	('R132H', 'Mutation', 'rs121913500', (173, 178))	('expression', 'MPA', (46, 56))	('IDH1', 'Gene', (168, 172))
206600	25706986	We found that in the U87 model, presence of mutant IDH1 led to a slight drop in G1 content (from 77.8 +- 0.2% to 67.3 +- 0.3) with a concomitant increase in G2 plus S content.	('IDH1', 'Gene', '3417', (51, 55))	('G2 plus S content', 'MPA', (157, 174))	('increase', 'PosReg', (145, 153))	('G1 content', 'MPA', (80, 90))	('presence', 'Var', (32, 40))	('drop', 'NegReg', (72, 76))	('U87', 'Gene', (21, 24))	('IDH1', 'Gene', (51, 55))	('mutant', 'Var', (44, 50))	('U87', 'Gene', '641648', (21, 24))
206607	25706986	A significant decrease in glutamine, glutathione and myo-inositol was observed in U87IDHmut cells when compared to U87IDHwt cells, but was not observed in the NHA model.	('glutathione', 'Chemical', 'MESH:D005978', (37, 48))	('myo-inositol', 'MPA', (53, 65))	('U87IDHmut', 'Var', (82, 91))	('glutamine', 'Chemical', 'MESH:D005973', (26, 35))	('decrease', 'NegReg', (14, 22))	('glutathione', 'MPA', (37, 48))	('myo-inositol', 'Chemical', 'MESH:D007294', (53, 65))	('U87IDHmut', 'CellLine', 'CVCL:0022', (82, 91))	('glutamine', 'MPA', (26, 35))
206612	25706986	Specifically, we found that both IDH1 mutant cell models present significantly higher NMR intensities at the following chemical shift positions: 0.96-1.04ppm (assigned to 2-hydroxybutyrate), 1.11-1.19ppm (assigned to valine) and 1.71-1.78ppm, 2.08-2.16ppm and 4.10-4.17ppm (all assigned to 2-HG).	('mutant', 'Var', (38, 44))	('NMR intensities', 'MPA', (86, 101))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', '3417', (33, 37))	('valine', 'Chemical', 'MESH:D014633', (217, 223))	('higher', 'PosReg', (79, 85))	('2-HG', 'Chemical', 'MESH:C019417', (290, 294))	('2-hydroxybutyrate', 'Chemical', 'MESH:C031570', (171, 188))
206618	25706986	As expected, 2-HG was present at a concentration of 0.67 +- 0.19 fmol/cell and 6.34 +- 1.47 fmol/cell in the U87IDHmut and NHAIDHmut cells respectively (it is not possible to distinguish between the IDH1 mutant-derived D-2-HG and the IDH1-independent L-2-HG stereoisomers, and thus our measurements of 2-HG reflect the total of both stereoisomers).	('IDH1', 'Gene', '3417', (199, 203))	('IDH', 'Gene', (234, 237))	('IDH', 'Gene', '3417', (126, 129))	('IDH', 'Gene', '3417', (199, 202))	('2-HG', 'Chemical', 'MESH:C019417', (13, 17))	('IDH', 'Gene', '3417', (234, 237))	('IDH1', 'Gene', '3417', (234, 238))	('mutant-derived', 'Var', (204, 218))	('2-HG', 'Chemical', 'MESH:C019417', (221, 225))	('2-HG', 'Chemical', 'MESH:C019417', (302, 306))	('IDH', 'Gene', '3417', (112, 115))	('IDH', 'Gene', (112, 115))	('IDH1', 'Gene', (234, 238))	('2-HG', 'Chemical', 'MESH:C019417', (253, 257))	('IDH1', 'Gene', (199, 203))	('U87IDHmut', 'CellLine', 'CVCL:0022', (109, 118))	('IDH', 'Gene', (126, 129))	('IDH', 'Gene', (199, 202))
206625	25706986	Importantly, no significant differences were found in the cellular concentrations of the metabolites analyzed in this study when comparing the parental cell lines with the IDHwt cell lines for both U87 and NHA models, underscoring the fact that the metabolic changes reported here result from the IDH1 mutation.	('IDH', 'Gene', (172, 175))	('IDH1', 'Gene', (297, 301))	('IDH', 'Gene', '3417', (172, 175))	('U87', 'Gene', (198, 201))	('result from', 'Reg', (281, 292))	('IDH', 'Gene', (297, 300))	('IDH', 'Gene', '3417', (297, 300))	('IDH1', 'Gene', '3417', (297, 301))	('U87', 'Gene', '641648', (198, 201))	('metabolic changes', 'MPA', (249, 266))	('mutation', 'Var', (302, 310))
206626	25706986	In this study we have characterized the metabolic profile of two genetically engineered IDH1 mutant cell models using 1H-MRS and a completely untargeted multivariate statistical analysis.	('IDH1', 'Gene', (88, 92))	('mutant', 'Var', (93, 99))	('1H', 'Chemical', '-', (118, 120))	('IDH1', 'Gene', '3417', (88, 92))
206627	25706986	We chose to perform this study on genetically engineered cells because they provided a platform to compare stably transfected cells that differed only in the expression of mutant IDH1, and thus could serve to identify MR-detectable metabolic changes specifically associated with the IDH1 mutation.	('mutant', 'Var', (172, 178))	('mutation', 'Var', (288, 296))	('IDH1', 'Gene', (283, 287))	('IDH1', 'Gene', (179, 183))	('IDH1', 'Gene', '3417', (283, 287))	('associated', 'Reg', (263, 273))	('IDH1', 'Gene', '3417', (179, 183))
206628	25706986	We confirmed that expression of mutant IDH1 did not alter doubling time or cell cycle distribution in a common manner in both of our cell models, and thus ruled out those factors as explanations of our findings.	('IDH1', 'Gene', '3417', (39, 43))	('mutant', 'Var', (32, 38))	('IDH1', 'Gene', (39, 43))	('cell cycle distribution', 'CPA', (75, 98))
206629	25706986	We also confirmed that in both of our model systems IDHmut cells express both wild-type and mutant IDH1 enzymes, and that the expression of these two proteins was comparable.	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('IDH1', 'Gene', (99, 103))	('mutant', 'Var', (92, 98))	('IDH', 'Gene', (99, 102))	('IDH1', 'Gene', '3417', (99, 103))
206630	25706986	Thus our models are consistent with clinical data that shows heterozygous expression of the mutant IDH1 gene, and are consistent with previous studies.	('IDH1', 'Gene', '3417', (99, 103))	('IDH1', 'Gene', (99, 103))	('mutant', 'Var', (92, 98))
206633	25706986	report that trimethylation of histone H3 at lysine 9 was significantly elevated by passage 12 following transfection with the mutant IDH1 gene.	('histone H3', 'Protein', (30, 40))	('IDH1', 'Gene', (133, 137))	('elevated', 'PosReg', (71, 79))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('IDH1', 'Gene', '3417', (133, 137))	('trimethylation', 'MPA', (12, 26))	('mutant', 'Var', (126, 132))
206636	25706986	Therefore, we believe that the IDHmut cells we have used in our studies have had sufficient time to develop a hypermethylated phenotype, and thus our findings are associated with presence of the IDH1 mutation.	('IDH', 'Gene', (195, 198))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', '3417', (31, 34))	('IDH1', 'Gene', (195, 199))	('associated', 'Reg', (163, 173))	('IDH1', 'Gene', '3417', (195, 199))	('mutation', 'Var', (200, 208))	('presence', 'Var', (179, 187))
206640	25706986	Probing for additional metabolic alterations that are associated with the IDH1 mutation can enhance such clinical investigations.	('metabolic alterations', 'MPA', (23, 44))	('IDH1', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('IDH1', 'Gene', '3417', (74, 78))	('enhance', 'PosReg', (92, 99))
206641	25706986	Our studies, which provide high-resolution spectra of a homogenous population of IDHwt and IDHmut cells, can serve to identify such translational MR-detectable IDH1 mutation-specific metabolic alterations.	('IDH1', 'Gene', (160, 164))	('IDH1', 'Gene', '3417', (160, 164))	('IDH', 'Gene', (160, 163))	('mutation-specific', 'Var', (165, 182))	('IDH', 'Gene', (91, 94))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', '3417', (160, 163))	('IDH', 'Gene', '3417', (91, 94))	('IDH', 'Gene', '3417', (81, 84))
206643	25706986	The different genetic backgrounds could also explain why not all the metabolic alterations associated with the expression of the mutant IDH1 gene were identical in our two models.	('IDH1', 'Gene', (136, 140))	('mutant', 'Var', (129, 135))	('IDH1', 'Gene', '3417', (136, 140))
206645	25706986	Glutamate, lactate, and PC, all dropped significantly in the IDHmut cells compared to IDHwt, most likely reflecting metabolic reprogramming that results from the expression of the mutant IDH1 enzyme.	('lactate', 'MPA', (11, 18))	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', '3417', (86, 89))	('IDH', 'Gene', (187, 190))	('mutant', 'Var', (180, 186))	('Glutamate', 'MPA', (0, 9))	('IDH1', 'Gene', '3417', (187, 191))	('Glutamate', 'Chemical', 'MESH:D018698', (0, 9))	('IDH', 'Gene', '3417', (187, 190))	('lactate', 'Chemical', 'MESH:D019344', (11, 18))	('IDH', 'Gene', (61, 64))	('dropped', 'NegReg', (32, 39))	('PC', 'Chemical', 'MESH:D010767', (24, 26))	('IDH1', 'Gene', (187, 191))
206653	25706986	Alternatively, because the IDH1 mutation is known to be an early event in tumor development, it is possible that the biopsy findings reflect additional events that occur during tumor development subsequent to the IDH1 mutation and that are not reflected in our models.	('IDH1', 'Gene', '3417', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mutation', 'Var', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (74, 79))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('tumor', 'Disease', (177, 182))	('IDH1', 'Gene', (213, 217))
206658	25706986	These findings are also consistent with an earlier study demonstrating hypermethylation of BCAT1 in U87IDHmut cells with a concomitant reduction in glutamate secretion into the media.	('reduction', 'NegReg', (135, 144))	('BCAT1', 'Gene', (91, 96))	('glutamate secretion into the media', 'MPA', (148, 182))	('glutamate', 'Chemical', 'MESH:D018698', (148, 157))	('U87IDHmut', 'CellLine', 'CVCL:0022', (100, 109))	('BCAT1', 'Gene', '586', (91, 96))	('hypermethylation', 'Var', (71, 87))
206660	25706986	We looked at the dataset of 3141 genes that were found to be hypermethylated in mutant IDH1-expressing NHAs, and discovered that BCAT1, BCAT2, GOT1L1, GPT, GPT2 are all hypermethylated in the NHAIDHmut cells (5.8, 23.1, 14.8, 8.4 and 11.8 fold change in IDHmut vs. IDHwt respectively, see Table 1).	('GPT', 'Gene', (151, 154))	('IDH', 'Gene', '3417', (195, 198))	('IDH', 'Gene', '3417', (265, 268))	('GPT2', 'Gene', (156, 160))	('IDH1', 'Gene', (87, 91))	('BCAT2', 'Gene', (136, 141))	('GPT', 'Gene', '2875', (151, 154))	('IDH', 'Gene', (254, 257))	('mutant', 'Var', (80, 86))	('IDH', 'Gene', (87, 90))	('BCAT1', 'Gene', '586', (129, 134))	('GPT', 'Gene', (156, 159))	('BCAT1', 'Gene', (129, 134))	('IDH1', 'Gene', '3417', (87, 91))	('IDH', 'Gene', '3417', (254, 257))	('IDH', 'Gene', '3417', (87, 90))	('GPT', 'Gene', '2875', (156, 159))	('GPT2', 'Gene', '84706', (156, 160))	('BCAT2', 'Gene', '587', (136, 141))	('IDH', 'Gene', (195, 198))	('IDH', 'Gene', (265, 268))	('GOT1L1', 'Gene', '137362', (143, 149))	('GOT1L1', 'Gene', (143, 149))
206661	25706986	Taken together, these findings suggest that hypermethylation and repression of several genes likely contributes to the observed decrease in glutamate production in IDHmut cells.	('IDH', 'Gene', '3417', (164, 167))	('glutamate production', 'MPA', (140, 160))	('glutamate', 'Chemical', 'MESH:D018698', (140, 149))	('genes', 'Gene', (87, 92))	('hypermethylation', 'Var', (44, 60))	('repression', 'NegReg', (65, 75))	('decrease', 'NegReg', (128, 136))	('IDH', 'Gene', (164, 167))
206662	25706986	The decrease in lactate concentration in IDHmut cells is consistent with our previous study, which investigated the status of lactate dehydrogenase A (LDHA, the enzyme that catalyzes the production of lactate from pyruvate) in mutant IDH1 patient samples and in patient-derived cell lines, and which demonstrated silencing of the LDHA gene by methylation.	('IDH', 'Gene', (41, 44))	('lactate dehydrogenase A', 'Gene', (126, 149))	('lactate', 'Chemical', 'MESH:D019344', (16, 23))	('IDH', 'Gene', '3417', (234, 237))	('LDHA', 'Gene', '3939', (330, 334))	('silencing', 'NegReg', (313, 322))	('LDHA', 'Gene', (151, 155))	('patient', 'Species', '9606', (239, 246))	('IDH', 'Gene', '3417', (41, 44))	('decrease', 'NegReg', (4, 12))	('lactate', 'Chemical', 'MESH:D019344', (126, 133))	('patient', 'Species', '9606', (262, 269))	('LDHA', 'Gene', (330, 334))	('lactate concentration', 'MPA', (16, 37))	('IDH1', 'Gene', (234, 238))	('pyruvate', 'Chemical', 'MESH:D019289', (214, 222))	('IDH', 'Gene', (234, 237))	('lactate', 'Chemical', 'MESH:D019344', (201, 208))	('LDHA', 'Gene', '3939', (151, 155))	('mutant', 'Var', (227, 233))	('methylation', 'Var', (343, 354))	('lactate dehydrogenase A', 'Gene', '3939', (126, 149))	('IDH1', 'Gene', '3417', (234, 238))
206673	25706986	study, the methylome data indicates that CHKB, the gene coding for choline kinase beta, is hypermethylated in mutant IDH1 cells (1.5 fold IDHmut/IDHwt, Table 1) and thus its associated transcriptional repression could account for the reduction in PC levels in IDHmut cells.	('transcriptional', 'MPA', (185, 200))	('choline kinase beta', 'Gene', '1120', (67, 86))	('IDH', 'Gene', '3417', (145, 148))	('IDH', 'Gene', '3417', (138, 141))	('reduction', 'NegReg', (234, 243))	('IDH', 'Gene', (260, 263))	('PC', 'Chemical', 'MESH:D010767', (247, 249))	('IDH1', 'Gene', (117, 121))	('CHKB', 'Gene', '1120', (41, 45))	('choline kinase beta', 'Gene', (67, 86))	('IDH', 'Gene', (117, 120))	('PC levels', 'MPA', (247, 256))	('mutant', 'Var', (110, 116))	('IDH', 'Gene', '3417', (260, 263))	('IDH1', 'Gene', '3417', (117, 121))	('IDH', 'Gene', (138, 141))	('IDH', 'Gene', (145, 148))	('IDH', 'Gene', '3417', (117, 120))	('CHKB', 'Gene', (41, 45))
206675	25706986	Thus, further studies are needed to fully assess the mechanism through which presence of the mutant IDH1 gene changes the levels of choline containing metabolites.	('levels of choline containing metabolites', 'MPA', (122, 162))	('IDH1', 'Gene', '3417', (100, 104))	('mutant', 'Var', (93, 99))	('presence', 'Var', (77, 85))	('choline', 'Chemical', 'MESH:D002794', (132, 139))	('IDH1', 'Gene', (100, 104))	('changes', 'Reg', (110, 117))
206676	25706986	In summary, by investigating the snapshot of steady state cellular metabolite levels, our work identifies three different metabolites that, in addition to 2-HG, are consistently modulated by the IDH1 mutation in different cell models.	('metabolites', 'MPA', (122, 133))	('2-HG', 'MPA', (155, 159))	('IDH1', 'Gene', (195, 199))	('2-HG', 'Chemical', 'MESH:C019417', (155, 159))	('modulated', 'Reg', (178, 187))	('mutation', 'Var', (200, 208))	('IDH1', 'Gene', '3417', (195, 199))
206677	25706986	As such, these findings could serve to validate and enhance clinical in vivo findings, highlighting the metabolic changes specifically associated with the IDH1 mutation.	('metabolic changes', 'MPA', (104, 121))	('IDH1', 'Gene', (155, 159))	('mutation', 'Var', (160, 168))	('IDH1', 'Gene', '3417', (155, 159))
206678	25706986	Our study also paves the way for future research directions that could lead to a greater understanding of the metabolic reprogramming associated with the IDH1 mutation, allowing the development of new therapeutic approaches and associated metabolic imaging biomarkers.	('mutation', 'Var', (159, 167))	('IDH1', 'Gene', (154, 158))	('IDH1', 'Gene', '3417', (154, 158))
206691	21793074	Nuclear antigen, Ki-67, is present in proliferating cancer cells, and the presence of high Ki-67 staining has been associated with high pathologic grade and stage prostate tumors and metastases.	('Ki-67', 'Chemical', '-', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('high pathologic grade', 'CPA', (131, 152))	('metastases', 'Disease', (183, 193))	('stage prostate tumors', 'Disease', (157, 178))	('stage prostate tumors', 'Disease', 'MESH:C537243', (157, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('presence', 'Var', (74, 82))	('associated', 'Reg', (115, 125))	('Ki-67', 'Chemical', '-', (17, 22))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('cancer', 'Disease', (52, 58))	('Ki-67', 'Gene', (91, 96))
206743	21793074	Representative fully relaxed 1H HR-MAS spectra of a benign predominantly glandular prostate tissue (left), low Gleason score (3+3) prostate cancer (middle) and high Gleason score (4+4) prostate cancer (right) are shown in figure 1A.	('benign predominantly glandular prostate tissue', 'Phenotype', 'HP:0008711', (52, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('low Gleason score', 'Var', (107, 124))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prostate cancer', 'Disease', (185, 200))	('1H', 'Chemical', '-', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('prostate cancer', 'Disease', (131, 146))
206790	21793074	The low concentrations of PC relative to GPC observed in high grade human prostate cancer tissues is also consistent with 1H HR-MAS spectra of low grade glioma tissues in which GPC was the dominate phospholipid as compared to high grade gliomas where PC dominated.	('phospholipid', 'Chemical', 'MESH:D010743', (198, 210))	('human', 'Species', '9606', (68, 73))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PC', 'Chemical', 'MESH:D010767', (178, 180))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('PC', 'Chemical', 'MESH:D010767', (42, 44))	('glioma', 'Disease', (153, 159))	('prostate cancer', 'Disease', (74, 89))	('PC', 'Chemical', 'MESH:D010767', (26, 28))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('gliomas', 'Disease', (237, 244))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('GPC', 'Chemical', 'MESH:D005997', (177, 180))	('glioma', 'Disease', (237, 243))	('1H', 'Chemical', '-', (122, 124))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('GPC', 'Chemical', 'MESH:D005997', (41, 44))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('GPC', 'Var', (177, 180))	('PC', 'Chemical', 'MESH:D010767', (251, 253))
206802	21793074	For example, men with a Gleason pattern 4 in any of their biopsies, are assumed to be of higher risk for cancer spread, and are treated more aggressively.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Gleason pattern 4', 'Var', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('men', 'Species', '9606', (13, 16))
206834	21709698	The growing ability to analyze the genetic and epigenetic abnormalities in tumor cells is driving the discovery of somatic mutations and their role in the development and progression of cancer.	('genetic abnormalities', 'Disease', (50, 71))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('genetic abnormalities', 'Disease', 'MESH:D030342', (50, 71))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', (186, 192))	('mutations', 'Var', (123, 132))	('tumor', 'Disease', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
206835	21709698	Mutations of more than 1.6% of the approximately 22,000 protein-coding human genes have been implicated in carcinogenesis and, to date, the number of known cancer genes has grown to 437, many of which are involved in childhood cancer (www.sanger.ac.uk/genetics/CGP/Census).	('implicated', 'Reg', (93, 103))	('childhood cancer', 'Disease', (217, 233))	('childhood cancer', 'Disease', 'MESH:C536928', (217, 233))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (227, 233))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('involved', 'Reg', (205, 213))	('carcinogenesis', 'Disease', (107, 121))	('human', 'Species', '9606', (71, 76))
206865	21709698	IKZF1 (encoding the lymphoid transcription factor Ikaros) is deleted in approximately 80% of cases of BCR-ABL1 positive ALL.	('Ikaros', 'Gene', (50, 56))	('IKZF1', 'Gene', '10320', (0, 5))	('lymphoid', 'Disease', (20, 28))	('IKZF1', 'Gene', (0, 5))	('ALL', 'Phenotype', 'HP:0006721', (120, 123))	('BCR-ABL1', 'Gene', (102, 110))	('Ikaros', 'Gene', '10320', (50, 56))	('BCR-ABL1', 'Gene', '613;25', (102, 110))	('deleted', 'Var', (61, 68))	('lymphoid', 'Disease', 'MESH:D008223', (20, 28))
206866	21709698	Large-scale genome-wide analyses have identified a high-risk subgroup of BCR-ABL1 negative B-cell precursor ALL that is also characterized by IKZF1 deletion, and another high-risk subtype of B-cell precursor ALL with overexpression of CRLF2 (encoding for cytokine receptor-like factor 2 [CRLF-2]).	('deletion', 'Var', (148, 156))	('CRLF-2', 'Gene', '64109', (288, 294))	('ALL', 'Phenotype', 'HP:0006721', (208, 211))	('CRLF-2', 'Gene', (288, 294))	('BCR-ABL1', 'Gene', (73, 81))	('cytokine receptor-like factor 2', 'Gene', (255, 286))	('CRLF2', 'Gene', '64109', (235, 240))	('BCR-ABL1', 'Gene', '613;25', (73, 81))	('IKZF1', 'Gene', '10320', (142, 147))	('CRLF2', 'Gene', (235, 240))	('overexpression', 'PosReg', (217, 231))	('ALL', 'Phenotype', 'HP:0006721', (108, 111))	('cytokine receptor-like factor 2', 'Gene', '64109', (255, 286))	('IKZF1', 'Gene', (142, 147))	('negative', 'NegReg', (82, 90))
206867	21709698	In the study by Mullighan et al., the cumulative rates of relapse were 47.0% and 24.6% at 10 years in the original cohort of patients, and were 73.8% and 25.0% at 5 years in the validated cohort with or without IKZF1 deletion, respectively.	('deletion', 'Var', (217, 225))	('IKZF1', 'Gene', '10320', (211, 216))	('IKZF1', 'Gene', (211, 216))	('patients', 'Species', '9606', (125, 133))
206868	21709698	High levels of expression of CRLF-2 were associated with a significantly higher 6-year cumulative risk of relapse (23-39% versus 10-12% in patients with low expression) in a study by Cario et al.	('relapse', 'Disease', (106, 113))	('patients', 'Species', '9606', (139, 147))	('High levels of', 'Var', (0, 14))	('expression', 'MPA', (15, 25))	('CRLF-2', 'Gene', '64109', (29, 35))	('CRLF-2', 'Gene', (29, 35))
206869	21709698	The presence of activating mutations in the JAK family of protein kinases in both of these subtypes raises the possibility of treating these patients with JAK inhibitors.	('mutations', 'Var', (27, 36))	('JAK family of protein kinases', 'Enzyme', (44, 73))	('activating', 'PosReg', (16, 26))	('patients', 'Species', '9606', (141, 149))
206871	21709698	Promising novel therapeutics under investigation in this setting include natural killer-cell (NK-cell) transplantation using donor NK cells that express inhibitory killer-cell immunoglobulin-like receptors in the absence of cognate ligand in the recipient:that is, receptor-ligand mismatch:and immunotherapy with conjugated antibodies, bispecific T-cell-engager single-chain antibodies (for example, blinatumomab), and chimeric T-cell receptors.	('donor', 'Species', '9606', (125, 130))	('blinatumomab', 'Disease', 'None', (400, 412))	('bispecific', 'Var', (336, 346))	('chimeric', 'Var', (419, 427))	('blinatumomab', 'Disease', (400, 412))
206874	21709698	Subtypes of AML with t(8;21) ETO-AML1, inv(16) MYH11-CBFB, t(15;17) PML-RARalpha, or mutations of CEBPA (encoding for CCAAT/enhancer-binding protein alpha) or NPM (encoding for nucleophosmin) are highly curable without the use of allogeneic stem-cell transplantation.	('nucleophosmin', 'Gene', '4869', (177, 190))	('CEBPA', 'Gene', (98, 103))	('ETO', 'Gene', (29, 32))	('nucleophosmin', 'Gene', (177, 190))	('CBFB', 'Gene', (53, 57))	('AML', 'Disease', 'MESH:D015470', (33, 36))	('AML', 'Disease', (33, 36))	('MYH11', 'Gene', '4629', (47, 52))	('NPM', 'Gene', (159, 162))	('AML', 'Phenotype', 'HP:0004808', (33, 36))	('NPM', 'Gene', '4869', (159, 162))	('AML1', 'Gene', '861', (33, 37))	('MYH11', 'Gene', (47, 52))	('CBFB', 'Gene', '865', (53, 57))	('mutations', 'Var', (85, 94))	('CCAAT/enhancer-binding protein alpha', 'Gene', '1050', (118, 154))	('ETO', 'Gene', '862', (29, 32))	('CCAAT/enhancer-binding protein alpha', 'Gene', (118, 154))	('AML1', 'Gene', (33, 37))	('AML', 'Disease', 'MESH:D015470', (12, 15))	('AML', 'Phenotype', 'HP:0004808', (12, 15))	('AML', 'Disease', (12, 15))	('CEBPA', 'Gene', '1050', (98, 103))
206875	21709698	By contrast, monosomy 7, abnormalities in 5q or 12p, t(6;9)(p23;q34), and internal tandem duplications of FLT3:particularly when associated with a high mutant to wild-type allelic ratio:are associated with 5-year event-free survival below 40% despite the use of allogeneic stem-cell transplantation.	('associated', 'Reg', (129, 139))	('abnormalities in 5q', 'Var', (25, 44))	('monosomy 7', 'Var', (13, 23))	('internal tandem duplications', 'Var', (74, 102))	('FLT3', 'Gene', '2322', (106, 110))	('associated', 'Reg', (190, 200))	('t(6;9)(p23;q34)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 68))	('FLT3', 'Gene', (106, 110))
206876	21709698	Several clinical trials are testing various FLT-3 inhibitors with or without transplantation in 10-15% of the participating patients with internal tandem duplications of FLT3.	('internal tandem duplications', 'Var', (138, 166))	('FLT-3', 'Gene', '2322', (44, 49))	('FLT3', 'Gene', '2322', (170, 174))	('FLT3', 'Gene', (170, 174))	('FLT-3', 'Gene', (44, 49))	('patients', 'Species', '9606', (124, 132))
206894	21709698	The subgroup of adolescents with mutations in the components of the Wnt and beta-catenin signaling pathway constitute about 15% of the patients with an excellent prognosis and a 5-year event-free survival rate of more than 95% with conventional therapy.	('patients', 'Species', '9606', (135, 143))	('beta-catenin', 'Gene', (76, 88))	('mutations', 'Var', (33, 42))	('beta-catenin', 'Gene', '1499', (76, 88))
206895	21709698	The subgroup of patients with mutations in components of the hedgehog signaling pathway (HH):which comprise about 20-25% of the patients with medulloblastoma and who have mutations in PTCH, Smoothened (SMO) and SUFU:have an intermediate prognosis with 5-year event-free survival rate of 75-85% when treated with conventional therapy.	('SMO', 'Gene', '6608', (202, 205))	('Smoothened', 'Gene', '6608', (190, 200))	('SMO', 'Gene', (202, 205))	('medulloblastoma', 'Disease', (142, 157))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (128, 136))	('medulloblastoma', 'Disease', 'MESH:D008527', (142, 157))	('mutations', 'Var', (30, 39))	('SUFU', 'Gene', (211, 215))	('medulloblastoma', 'Phenotype', 'HP:0002885', (142, 157))	('mutations', 'Var', (171, 180))	('Smoothened', 'Gene', (190, 200))	('SUFU', 'Gene', '51684', (211, 215))	('PTCH', 'Gene', (184, 188))	('PTCH', 'Gene', '5727', (184, 188))
206899	21709698	Gain of chromosome 1q25 and homozygous deletion of CDKN2A (encoding for the tumor suppressor p16-INK4alpha) negatively impact the survival of these patients with overall survival of 30-82% and 10-76%, respectively, whereas gain of chromosomes 9q34, 15q22, 18q21 and loss of 6q23 are associated with excellent survival.	('CDKN2A', 'Gene', '1029', (51, 57))	('p16-INK4alpha', 'Gene', (93, 106))	('patients', 'Species', '9606', (148, 156))	('p16-INK4alpha', 'Gene', '1029', (93, 106))	('survival', 'CPA', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Gain', 'PosReg', (0, 4))	('homozygous deletion', 'Var', (28, 47))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CDKN2A', 'Gene', (51, 57))	('negatively impact', 'NegReg', (108, 125))
206902	21709698	No data are currently documented on approaches for patients with gain of 1q25 or loss of CDKN2A.	('gain', 'PosReg', (65, 69))	('CDKN2A', 'Gene', (89, 95))	('patients', 'Species', '9606', (51, 59))	('1q25', 'Var', (73, 77))	('CDKN2A', 'Gene', '1029', (89, 95))	('loss', 'NegReg', (81, 85))
206908	21709698	These include the absence of hot-spot mutations in IDH1 and the presence of focal amplification of PDGFRA in pediatric tumors that are not present in adults, and explain some of the different responses to chemotherapy.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('IDH1', 'Gene', '3417', (51, 55))	('pediatric tumors', 'Disease', 'MESH:D063766', (109, 125))	('pediatric tumors', 'Disease', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('hot-spot', 'MPA', (29, 37))	('absence', 'NegReg', (18, 25))	('mutations', 'Var', (38, 47))	('IDH1', 'Gene', (51, 55))	('PDGFRA', 'Gene', (99, 105))	('PDGFRA', 'Gene', '5156', (99, 105))
206913	21709698	The major main molecular alterations in low-grade gliomas include duplication, activating mutations and fusion transcripts of BRAF, implicating the MAPK pathway in the pathogenesis of these tumors.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('activating', 'PosReg', (79, 89))	('gliomas', 'Disease', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('duplication', 'Var', (66, 77))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('BRAF', 'Gene', (126, 130))	('fusion transcripts', 'Var', (104, 122))	('BRAF', 'Gene', '673', (126, 130))	('tumors', 'Disease', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
206917	21709698	Most of these tumors have mutations in the HH pathway and may be cured with targeted therapy in the future.	('HH pathway', 'Pathway', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('mutations', 'Var', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
206920	21709698	The molecular hallmark signature of ATRT is deletion of SMARCB1 (encoding the chromatin regulator BAF47), detected by presence of monosomy 22 and the absence of BAF47 staining on immunohistochemistry.	('BAF47', 'Gene', (161, 166))	('SMARCB1', 'Gene', (56, 63))	('SMARCB1', 'Gene', '6598', (56, 63))	('deletion', 'Var', (44, 52))	('ATRT', 'Disease', (36, 40))	('BAF47', 'Gene', '6598', (98, 103))	('BAF47', 'Gene', '6598', (161, 166))	('BAF47', 'Gene', (98, 103))
206926	21709698	By contrast, among patients with high-risk disease:defined by segmental chromosomal aberrations such as amplification of MYCN (also known as neuroblastoma MYC oncogene):the cure rate is much lower with induction chemotherapy, myeloblative consolidation therapy, and maintenance therapy with isotrenitoin.	('cure', 'CPA', (173, 177))	('patients', 'Species', '9606', (19, 27))	('neuroblastoma', 'Phenotype', 'HP:0003006', (141, 154))	('neuroblastoma MYC oncogene', 'Gene', '4613', (141, 167))	('isotrenitoin', 'Chemical', '-', (291, 303))	('MYCN', 'Gene', (121, 125))	('MYCN', 'Gene', '4613', (121, 125))	('neuroblastoma MYC oncogene', 'Gene', (141, 167))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (72, 95))	('lower', 'NegReg', (191, 196))	('amplification', 'Var', (104, 117))
206927	21709698	The addition of ch14.18, the anti-GD2 antibody, with alternating cycles of interleukin-2 or granulocyte macrophage-CSF (GM-CSF) in addition to isotretinoin, has been reported to improve the 2-year event-free survival of these patients to 66%, a 20% increase over the 2-year event-free survival of patients who received isotretinoin alone.	('ch14.18', 'Var', (16, 23))	('isotretinoin', 'Chemical', 'MESH:D015474', (143, 155))	('GM-CSF', 'Gene', (120, 126))	('event-free', 'MPA', (197, 207))	('improve', 'PosReg', (178, 185))	('GM-CSF', 'Gene', '1437', (120, 126))	('patients', 'Species', '9606', (297, 305))	('increase', 'PosReg', (249, 257))	('granulocyte macrophage-CSF', 'Gene', (92, 118))	('isotretinoin', 'Chemical', 'MESH:D015474', (319, 331))	('interleukin-2', 'Gene', '3558', (75, 88))	('anti-GD2', 'Var', (29, 37))	('granulocyte macrophage-CSF', 'Gene', '1437', (92, 118))	('patients', 'Species', '9606', (226, 234))	('interleukin-2', 'Gene', (75, 88))
206928	21709698	Promising results in the relapse setting suggested that radiolabeled I131-metaiodobenzylguanidine or I123-metaiodobenzylguanidine should also be explored as consolidation therapy in high-risk patients.	('I131-metaiodobenzylguanidine', 'Chemical', 'MESH:D019797', (69, 97))	('I123-metaiodobenzylguanidine', 'Var', (101, 129))	('patients', 'Species', '9606', (192, 200))	('I131-metaiodobenzylguanidine', 'Var', (69, 97))	('I123-metaiodobenzylguanidine', 'Chemical', '-', (101, 129))
206929	21709698	Moreover, the discovery of ALK mutations or amplifications in about 15% of newly diagnosed neuroblastoma cases has prompted the development of treatment to inhibit this target.	('amplifications', 'Var', (44, 58))	('mutations', 'Var', (31, 40))	('neuroblastoma', 'Disease', 'MESH:D009447', (91, 104))	('ALK', 'Gene', (27, 30))	('neuroblastoma', 'Disease', (91, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (91, 104))	('ALK', 'Gene', '238', (27, 30))
206930	21709698	Finally, the Pediatric Preclinical Testing Program has identified an aurora kinase A inhibitor (MLN8237) and the replication-competent RNA virus Seneca Valley virus as potential active agents.	('Seneca Valley virus', 'Species', '390157', (145, 164))	('aurora kinase A', 'Gene', '6790', (69, 84))	('aurora kinase A', 'Gene', (69, 84))	('MLN8237', 'Var', (96, 103))
206936	21709698	In rhabdomyosarcoma xenograft models, the anti-IGF-1R antibody h7C10 synergized with rapamycin causing a reduction in tumor growth and phosphorylated AKT levels.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (3, 19))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('IGF-1R', 'Gene', '3480', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('AKT', 'Gene', '207', (150, 153))	('IGF-1R', 'Gene', (47, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('rapamycin', 'Chemical', 'MESH:D020123', (85, 94))	('phosphorylated', 'MPA', (135, 149))	('reduction', 'NegReg', (105, 114))	('tumor', 'Disease', (118, 123))	('rhabdomyosarcoma', 'Disease', (3, 19))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (3, 19))	('AKT', 'Gene', (150, 153))	('h7C10', 'Var', (63, 68))
206939	21709698	Moreover, mutations in FGFR4 (encoding for fibroblast growth factor receptor 4) were found in 7% of primary rhabdomyosarcomas, providing a rationale for targeting this gene.	('fibroblast growth factor receptor 4', 'Gene', (43, 78))	('fibroblast growth factor receptor 4', 'Gene', '2264', (43, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (108, 124))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (108, 125))	('found', 'Reg', (85, 90))	('FGFR4', 'Gene', '2264', (23, 28))	('rhabdomyosarcomas', 'Disease', (108, 125))	('FGFR4', 'Gene', (23, 28))	('mutations', 'Var', (10, 19))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (108, 125))
206944	21709698	Effective treatment of adults with soft-tissue sarcoma has been achieved by the use of targeted therapies, including imatinib for KIT-mutated gastrointestinal stromal tumor (GIST) and crizotinib for ALK-rearranged inflammatory myofibroblastic tumor.	('GIST', 'Phenotype', 'HP:0100723', (174, 178))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('sarcoma', 'Disease', (47, 54))	('tumor', 'Disease', (243, 248))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (35, 54))	('KIT-mutated', 'Var', (130, 141))	('imatinib', 'Chemical', 'MESH:D000068877', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (142, 172))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (227, 248))	('crizotinib', 'Chemical', 'MESH:D000077547', (184, 194))	('tumor', 'Disease', (167, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (142, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('gastrointestinal stromal tumor', 'Disease', (142, 172))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('ALK', 'Gene', '238', (199, 202))	('ALK', 'Gene', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
206946	21709698	For example, activating mutations of KIT or PDGFRA are detected in over 90% of adult GISTs, but in only 11% of the childhood cases; thus, targeted therapies commonly used in adults:such as imatinib:are expected to be less effective in the pediatric population.	('imatinib', 'Chemical', 'MESH:D000068877', (189, 197))	('activating', 'PosReg', (13, 23))	('GIST', 'Phenotype', 'HP:0100723', (85, 89))	('KIT', 'Gene', (37, 40))	('mutations', 'Var', (24, 33))	('PDGFRA', 'Gene', '5156', (44, 50))	('PDGFRA', 'Gene', (44, 50))	('child', 'Species', '9606', (115, 120))
206948	21709698	The Ewing sarcoma family of tumors:a group of bone and soft-tissue tumors derived from mesenchymal progenitor cells characterized by rearrangements of EWS:includes classic Ewing sarcoma, Askin tumor, and peripheral primitive neuroectodermal tumor.	('soft-tissue tumors', 'Phenotype', 'HP:0031459', (55, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('Askin tumor', 'Disease', (187, 198))	('Ewing sarcoma', 'Disease', (172, 185))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (215, 246))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('EWS', 'Gene', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('peripheral primitive neuroectodermal tumor', 'Phenotype', 'HP:0030067', (204, 246))	('rearrangements', 'Var', (133, 147))	('Ewing sarcoma family of tumors', 'Disease', (4, 34))	('Ewing sarcoma family of tumors', 'Disease', 'MESH:C563168', (4, 34))	('tumors', 'Disease', (28, 34))	('Askin tumor', 'Disease', 'MESH:C563168', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (225, 246))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (4, 17))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (172, 185))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (225, 246))	('tumors', 'Disease', (67, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('neuroectodermal tumor', 'Disease', (225, 246))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
206951	21709698	The most attractive candidate agents are the IGF-1R inhibitors, which have produced responses as single agents in about 10% of patients with relapsed disease.	('inhibitors', 'Var', (52, 62))	('patients', 'Species', '9606', (127, 135))	('IGF-1R', 'Gene', (45, 51))	('IGF-1R', 'Gene', '3480', (45, 51))
206952	21709698	Other potential agents include inhibitors of PDGFR, mTOR (in combination with IGF-1R inhibitors), SRC, VEGF, and CD99, as well as the Seneca Valley virus and the kinesin spindle protein inhibitor ispinesib.	('PDGFR', 'Gene', (45, 50))	('mTOR', 'Gene', (52, 56))	('VEGF', 'Gene', (103, 107))	('mTOR', 'Gene', '2475', (52, 56))	('PDGFR', 'Gene', '5159', (45, 50))	('IGF-1R', 'Gene', (78, 84))	('VEGF', 'Gene', '7422', (103, 107))	('IGF-1R', 'Gene', '3480', (78, 84))	('Seneca Valley virus', 'Species', '390157', (134, 153))	('inhibitors', 'Var', (31, 41))
206955	21709698	Instead, the tumors are characterized by a complex karyotype, aneuploidy, and dysregulation of numerous pathways and genes including RB, TP53, CDKN2A, RECQL4, MET, FOS, mTOR, WNT, NOTCH, IGF1, EGFR, VEGFR, PDGFR, MYC, HER2, and Ezrin.	('MET', 'Gene', (159, 162))	('EGFR', 'Gene', (193, 197))	('Ezrin', 'Gene', (228, 233))	('NOTCH', 'Gene', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('HER2', 'Gene', (218, 222))	('IGF1', 'Gene', '3479', (187, 191))	('mTOR', 'Gene', (169, 173))	('EGFR', 'Gene', (200, 204))	('RECQL4', 'Gene', '9401', (151, 157))	('aneuploidy', 'Disease', 'MESH:D000782', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('MYC', 'Gene', (213, 216))	('TP53', 'Gene', (137, 141))	('PDGFR', 'Gene', (206, 211))	('RECQL4', 'Gene', (151, 157))	('FOS', 'Gene', (164, 167))	('PDGFR', 'Gene', '5159', (206, 211))	('tumors', 'Disease', (13, 19))	('mTOR', 'Gene', '2475', (169, 173))	('EGFR', 'Gene', '1956', (193, 197))	('FOS', 'Gene', '2353', (164, 167))	('CDKN2A', 'Gene', (143, 149))	('IGF1', 'Gene', (187, 191))	('aneuploidy', 'Disease', (62, 72))	('dysregulation', 'Var', (78, 91))	('VEGFR', 'Gene', '3791', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('MYC', 'Gene', '4609', (213, 216))	('EGFR', 'Gene', '1956', (200, 204))	('HER2', 'Gene', '2064', (218, 222))	('VEGFR', 'Gene', (199, 204))	('TP53', 'Gene', '7157', (137, 141))	('CDKN2A', 'Gene', '1029', (143, 149))
206956	21709698	Promising new therapeutic approaches include administration of the immunostimulant muramyl tripeptide phosphatidylethanolamine, the combination of an IGF-1R and mTOR inhibitors, SRC kinase inhibition, immune targeting of HER2, angiogenesis inhibition (inhibition of VEGF), and agents that target the MET, receptor activator of nuclear factor kappaB ligand (RANKL), and Notch pathways.	('HER2', 'Gene', (221, 225))	('VEGF', 'Gene', '7422', (266, 270))	('Notch pathways', 'Pathway', (369, 383))	('HER2', 'Gene', '2064', (221, 225))	('VEGF', 'Gene', (266, 270))	('RANKL', 'Gene', '8600', (357, 362))	('RANKL', 'Gene', (357, 362))	('IGF-1R', 'Gene', '3480', (150, 156))	('muramyl tripeptide phosphatidylethanolamine', 'Chemical', 'MESH:C037144', (83, 126))	('inhibition', 'Var', (189, 199))	('IGF-1R', 'Gene', (150, 156))	('receptor activator of nuclear factor kappaB ligand', 'Gene', '8600', (305, 355))	('receptor activator of nuclear factor kappaB ligand', 'Gene', (305, 355))	('mTOR', 'Gene', '2475', (161, 165))	('angiogenesis', 'CPA', (227, 239))	('MET', 'Pathway', (300, 303))	('mTOR', 'Gene', (161, 165))
206962	21709698	The discovery of inactivation of the p53 pathway via MDMX amplification in promoting human retinoblastoma suggests that MDMX inhibitors, such as nutlin-3, might be effective for the treatment of this disease.	('MDMX', 'Gene', (120, 124))	('retinoblastoma', 'Phenotype', 'HP:0009919', (91, 105))	('nutlin-3', 'Chemical', 'MESH:C482205', (145, 153))	('MDMX', 'Gene', '4194', (53, 57))	('MDMX', 'Gene', '4194', (120, 124))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('retinoblastoma', 'Gene', '5925', (91, 105))	('human', 'Species', '9606', (85, 90))	('MDMX', 'Gene', (53, 57))	('amplification', 'Var', (58, 71))	('inactivation', 'NegReg', (17, 29))	('retinoblastoma', 'Gene', (91, 105))
206965	21709698	However, a high incidence of this disease has been observed in children in southern Brazil, a finding that has led to the discovery of unique germline TP53 mutations that contribute to its pathogenesis.	('mutations', 'Var', (156, 165))	('children', 'Species', '9606', (63, 71))	('TP53', 'Gene', '7157', (151, 155))	('TP53', 'Gene', (151, 155))
206966	21709698	Most children with adrenocortical tumors:particularly those under 4 years of age:have inherited mutations in TP53.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('adrenocortical tumors', 'Disease', (19, 40))	('children', 'Species', '9606', (5, 13))	('TP53', 'Gene', '7157', (109, 113))	('inherited', 'Reg', (86, 95))	('TP53', 'Gene', (109, 113))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (19, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('mutations', 'Var', (96, 105))
206969	21709698	A family-based linkage study found that DICER1:a gene encoding ribonuclease III endonuclease that participates in the generation of small RNAs and small interfering RNAs:was mutated in this type of tumor.	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('small RNAs', 'MPA', (132, 142))	('DICER1', 'Gene', '23405', (40, 46))	('tumor', 'Disease', (198, 203))	('DICER1', 'Gene', (40, 46))	('mutated', 'Var', (174, 181))
206971	21709698	The parents of children with cancer report poorer quality of life compared with population norms; many parents experience distress from having to make difficult end-of-life care decisions, such as participating in phase I clinical trials, withholding or withdrawing life-sustaining treatments, foregoing cancer chemotherapy, talking to their children about death, or deciding on the location during the terminal phase.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('children', 'Species', '9606', (15, 23))	('cancer', 'Disease', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('children', 'Species', '9606', (342, 350))	('withdrawing', 'NegReg', (254, 265))	('foregoing', 'Var', (294, 303))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
206996	30198226	Recent characterizations of LGGs have shown that these tumors can be subclassified into three subtypes with distinct clinical behaviors based on the IDH1 and IDH2 mutations and the codeletion status of chromosomes 1p and 19q.	('mutations', 'Var', (163, 172))	('LGGs', 'Disease', (28, 32))	('IDH1', 'Gene', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('IDH1', 'Gene', '3417', (149, 153))	('IDH2', 'Gene', (158, 162))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('IDH2', 'Gene', '3418', (158, 162))
206997	30198226	LGGs with an IDH mutation either harbored a TP53 mutation or had 1p/19q codeletion.	('IDH', 'Gene', '3417', (13, 16))	('mutation', 'Var', (17, 25))	('mutation', 'Var', (49, 57))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('IDH', 'Gene', (13, 16))	('harbored', 'Reg', (33, 41))
206998	30198226	IDH-mutant LGGs with 1p/19q codeletion showed mutations in CIC, NOTCH1, FUBP1, and the TERT promoter, and had the most-favorable outcome clinically, whereas nearly all IDH mutants without 1p/19q codeletion had TP53 mutations (94%) and ATRX inactivation (86%).	('IDH', 'Gene', (0, 3))	('CIC', 'Gene', (59, 62))	('mutations', 'Var', (46, 55))	('IDH', 'Gene', '3417', (168, 171))	('TP53', 'Gene', (210, 214))	('ATRX', 'Gene', '546', (235, 239))	('NOTCH1', 'Gene', '4851', (64, 70))	('NOTCH1', 'Gene', (64, 70))	('IDH', 'Gene', '3417', (0, 3))	('FUBP1', 'Gene', '8880', (72, 77))	('mutations', 'Var', (215, 224))	('TERT', 'Gene', (87, 91))	('FUBP1', 'Gene', (72, 77))	('TERT', 'Gene', '7015', (87, 91))	('ATRX', 'Gene', (235, 239))	('TP53', 'Gene', '7157', (210, 214))	('IDH', 'Gene', (168, 171))
206999	30198226	LGGs without an IDH mutation were similar to glioblastomas clinically and molecularly, and thus have had the least-favorable outcome.	('mutation', 'Var', (20, 28))	('IDH', 'Gene', (16, 19))	('glioblastomas', 'Phenotype', 'HP:0012174', (45, 58))	('IDH', 'Gene', '3417', (16, 19))	('glioblastomas', 'Disease', 'MESH:D005909', (45, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('glioblastomas', 'Disease', (45, 58))
207015	30198226	In a large molecularly defined cohort study, in which molecular genetic examinations were applied to LGG tumors after resection (IDH1 mutation, 1p/19q codeletion, and p53 mutation), Cordier et al.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('1p/19q codeletion', 'Var', (144, 161))	('IDH1', 'Gene', (129, 133))	('mutation', 'Var', (171, 179))	('mutation', 'Var', (134, 142))	('p53', 'Gene', '7157', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IDH1', 'Gene', '3417', (129, 133))	('p53', 'Gene', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
207018	30198226	Therefore, a high EOR could benefit the prognosis even with LGGs lacking good prognostic genetic markers such as 1p/19q codeletion, and should always be attempted to increase OS.	('benefit', 'PosReg', (28, 35))	('OS', 'Chemical', '-', (175, 177))	('prognosis', 'MPA', (40, 49))	('1p/19q codeletion', 'Var', (113, 130))
207030	30198226	A particularly perplexing subgroup of LGG patients do not harbor the favorable IDH mutation (i.e., wild type) but are younger than 40 years and have undergone GTR.	('IDH', 'Gene', (79, 82))	('LGG', 'Disease', (38, 41))	('IDH', 'Gene', '3417', (79, 82))	('mutation', 'Var', (83, 91))	('patients', 'Species', '9606', (42, 50))
207043	30198226	One of these studies found that patients with an abnormal baseline MMSE score before radiotherapy were more likely to experience improvement in their cognitive capacities following radiation treatment, although a small proportion of the studied patients showed cognitive decline after treatment.	('men', 'Species', '9606', (196, 199))	('cognitive decline', 'Disease', (261, 278))	('patients', 'Species', '9606', (32, 40))	('MMSE', 'Gene', (67, 71))	('patients', 'Species', '9606', (245, 253))	('abnormal', 'Var', (49, 57))	('cognitive decline', 'Disease', 'MESH:D003072', (261, 278))	('men', 'Species', '9606', (290, 293))	('cognitive decline', 'Phenotype', 'HP:0001268', (261, 278))	('improvement', 'PosReg', (129, 140))	('cognitive capacities', 'CPA', (150, 170))	('men', 'Species', '9606', (136, 139))
207058	30198226	Although the response duration appears to be shorter in patients without 1p/19q codeletion, a response was nevertheless observed for both subtypes.	('1p/19q codeletion', 'Var', (73, 90))	('response', 'MPA', (13, 21))	('shorter', 'NegReg', (45, 52))	('patients', 'Species', '9606', (56, 64))
207064	30198226	TMZ works by depleting the DNA-repair enzyme O6-alkylguanine-DNA alkyltransferase and methylating guanine and adenine, which together result in a continuous cycle of DNA base-mismatch repair leading to apoptosis.	('DNA base-mismatch repair', 'MPA', (166, 190))	('O6-alkylguanine', 'Chemical', '-', (45, 60))	('adenine', 'Chemical', 'MESH:D000225', (110, 117))	('methylating', 'Var', (86, 97))	('O6-alkylguanine-DNA', 'Enzyme', (45, 64))	('result in', 'Reg', (134, 143))	('guanine', 'Chemical', 'MESH:D006147', (53, 60))	('apoptosis', 'CPA', (202, 211))	('guanine', 'Chemical', 'MESH:D006147', (98, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('depleting', 'NegReg', (13, 22))
207080	30198226	Potent MGMT inhibitors include O6-benzylguanine and O6-(4-bromothenyl) guanine (PaTrin-2).	('MGMT', 'Gene', '4255', (7, 11))	('MGMT', 'Gene', (7, 11))	('PaTrin-2', 'Chemical', '-', (80, 88))	('O6-benzylguanine', 'Var', (31, 47))	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (31, 47))	('O6-(4-bromothenyl) guanine', 'Chemical', 'MESH:C403290', (52, 78))
207081	30198226	More specifically, an increased TMZ response was also associated with 1p deletion and low MGMT expression.	('MGMT', 'Gene', (90, 94))	('1p deletion', 'Var', (70, 81))	('MGMT', 'Gene', '4255', (90, 94))	('TMZ', 'Chemical', 'MESH:D000077204', (32, 35))	('TMZ response', 'MPA', (32, 44))	('increased', 'PosReg', (22, 31))	('low', 'NegReg', (86, 89))
207084	30198226	That study demonstrated that patients with the highest MGMT levels had no deletion of 1p, while patients with 1p deletion tended to exhibit the lowest expressions of MGMT.	('MGMT', 'Gene', '4255', (55, 59))	('patients', 'Species', '9606', (29, 37))	('MGMT', 'Gene', (55, 59))	('deletion', 'Var', (74, 82))	('MGMT', 'Gene', (166, 170))	('MGMT', 'Gene', '4255', (166, 170))	('patients', 'Species', '9606', (96, 104))
207085	30198226	Moreover, significant correlations were found between the radiographic response to TMZ, 1p deletion, and low MGMT levels.	('1p deletion', 'Var', (88, 99))	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('MGMT', 'Gene', (109, 113))	('MGMT', 'Gene', '4255', (109, 113))
207093	30198226	That study also identified predictive molecular factors and confirmed that the PFS rates differed significantly between three subgroups: 1) IDH mutation with 1p/19q codeletion, 2) IDH mutation without 1p/19q codeletion, and 3) wild-type IDH.	('IDH', 'Gene', '3417', (237, 240))	('IDH', 'Gene', '3417', (140, 143))	('1p/19q codeletion', 'Var', (158, 175))	('differed', 'Reg', (89, 97))	('IDH', 'Gene', (180, 183))	('mutation', 'Var', (144, 152))	('IDH', 'Gene', '3417', (180, 183))	('IDH', 'Gene', (237, 240))	('IDH', 'Gene', (140, 143))
207095	30198226	However, there were no treatment-dependent differences for patients with combined IDH mutation and 1p/19q codeletion and IDH wild-type tumors.	('IDH', 'Gene', '3417', (82, 85))	('men', 'Species', '9606', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH', 'Gene', (121, 124))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('patients', 'Species', '9606', (59, 67))	('IDH', 'Gene', '3417', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('IDH', 'Gene', (82, 85))	('1p/19q codeletion', 'Var', (99, 116))
207109	30198226	In vivo studies of astrocytoma formation have shown that constitutively activated NTRK2 alleles, namely QKI-NTRK2 fusion, synergize with Ink4a/Arf loss to promote the formation of an astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('Ink4a/Arf', 'Gene', (137, 146))	('NTRK2', 'Gene', (82, 87))	('Ink4a/Arf', 'Gene', '1029', (137, 146))	('fusion', 'Var', (114, 120))	('NTRK2', 'Gene', '4915', (108, 113))	('astrocytoma', 'Disease', 'MESH:D001254', (183, 194))	('loss', 'NegReg', (147, 151))	('formation of', 'CPA', (167, 179))	('astrocytoma', 'Disease', (183, 194))	('astrocytoma', 'Disease', 'MESH:D001254', (19, 30))	('NTRK2', 'Gene', '4915', (82, 87))	('promote', 'PosReg', (155, 162))	('astrocytoma', 'Disease', (19, 30))	('QKI', 'Gene', (104, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (183, 194))	('NTRK2', 'Gene', (108, 113))	('QKI', 'Gene', '9444', (104, 107))
207110	30198226	This suggests that patients harboring astrocytomas with QKI-NTRK2 fusion could benefit from targeted therapies against NTRK2.	('QKI', 'Gene', '9444', (56, 59))	('patients', 'Species', '9606', (19, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (38, 49))	('astrocytomas', 'Disease', 'MESH:D001254', (38, 50))	('NTRK2', 'Gene', (60, 65))	('NTRK2', 'Gene', (119, 124))	('fusion', 'Var', (66, 72))	('NTRK2', 'Gene', '4915', (60, 65))	('NTRK2', 'Gene', '4915', (119, 124))	('astrocytomas', 'Disease', (38, 50))	('QKI', 'Gene', (56, 59))
207142	30622928	Biopsy of the neck mass revealed EMC staining positive for CK7, CKAE1/AE3, CK903, S100, and smooth muscle actin and negative for CK20, PAX8, GATA, CDX2, GFAP.	('CK903', 'Var', (75, 80))	('GFAP', 'Gene', (153, 157))	('CK7', 'Gene', '3855', (59, 62))	('GATA', 'Gene', '55278', (141, 145))	('AE3', 'Gene', (70, 73))	('PAX8', 'Gene', '7849', (135, 139))	('CDX2', 'Gene', (147, 151))	('GFAP', 'Gene', '2670', (153, 157))	('CK20', 'Gene', (129, 133))	('CK20', 'Gene', '54474', (129, 133))	('CK7', 'Gene', (59, 62))	('CDX2', 'Gene', '1045', (147, 151))	('PAX8', 'Gene', (135, 139))	('GATA', 'Gene', (141, 145))	('AE3', 'Gene', '6508', (70, 73))
207157	30622928	For adjuvant treatment of EMC, the patient's left hemineck received intensity-modulated radiation therapy consisting of 5040 cGy in 28 fractions, followed by a 3D-boost of 1620 cGy in 9 fractions to the left submandibular tumor bed and adjacent level IB lymph node region.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('patient', 'Species', '9606', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('5040 cGy', 'Var', (120, 128))
207173	30622928	A fall while hospitalized lead to altered mental status and hypoxic respiratory failure, prompting transfer to the intensive care unit and intubation.	('altered', 'Reg', (34, 41))	('fall', 'Phenotype', 'HP:0002527', (2, 6))	('respiratory failure', 'Phenotype', 'HP:0002878', (68, 87))	('fall', 'Var', (2, 6))	('hypoxic respiratory failure', 'Disease', (60, 87))	('hypoxic respiratory failure', 'Disease', 'MESH:D012131', (60, 87))
207192	30622928	To risk stratify EMC based on pathological features, a retrospective study evaluated 61 tumors and reported positive margin status, angiolymphatic invasion, tumor necrosis, and myoepithelial anaplasia as significantly associated with shortened disease free survival.	('myoepithelial anaplasia', 'Disease', (177, 200))	('angiolymphatic', 'Disease', (132, 146))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('shortened', 'NegReg', (234, 243))	('myoepithelial anaplasia', 'Disease', 'MESH:D000708', (177, 200))	('tumor necrosis', 'Disease', (157, 171))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('positive', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor necrosis', 'Disease', 'MESH:D009336', (157, 171))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('disease free survival', 'CPA', (244, 265))
207205	29884885	An increased resistance to temozolomide was observed in T98G cells co-cultured in GBM-EC conditioned media.	('increased', 'PosReg', (3, 12))	('T98G', 'Var', (56, 60))	('resistance to temozolomide', 'MPA', (13, 39))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('temozolomide', 'Chemical', 'MESH:D000077204', (27, 39))
207210	29884885	The ability of tumor mass to grow, progress and infiltrate into surrounding tissue, compromising cognitive and motor skills, is due to the intense and aberrant angiogenesis, responsible for the formation of new blood vessels, which support tumor development, providing nutrition, oxygen and energy, in a mechanism well known as neovascularization.	('aberrant', 'Var', (151, 159))	('tumor', 'Disease', (240, 245))	('compromising', 'NegReg', (84, 96))	('angiogenesis', 'CPA', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('oxygen', 'Chemical', 'MESH:D010100', (280, 286))
207243	29884885	Notably, the amount of FITC-70 kDa dextran that passed across GBM-ECs barrier was significantly higher compared to LGG-ECs and MNG-ECs samples, indicating that GBM-ECs form a weak and defenestrated barrier.	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('LGG-EC', 'Chemical', '-', (115, 121))	('FITC-70 kDa', 'Var', (23, 34))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('FITC-70 kDa dextran', 'Chemical', '-', (23, 42))	('higher', 'PosReg', (96, 102))
207252	29884885	4B,C, at 24 h, number of segments and meshes was approximately halved after treatment with BEV 200 microg/ml and TMZ 200 microM and also total tube length was significantly decreased.	('BEV 200 microg/ml', 'Var', (91, 108))	('halved', 'NegReg', (63, 69))	('TMZ 200 microM', 'Var', (113, 127))	('TMZ', 'Chemical', 'MESH:D000077204', (113, 116))	('decreased', 'NegReg', (173, 182))	('BEV', 'Chemical', 'MESH:D000068258', (91, 94))
207267	29884885	In this regard, MTT assay revealed that TMZ 200 microM, after 48 h, decreased cell viability of about 40%, suggesting a sensitive response to chemotherapy(Fig.	('decreased', 'NegReg', (68, 77))	('TMZ 200 microM', 'Var', (40, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (40, 43))	('cell viability', 'CPA', (78, 92))	('MTT', 'Chemical', 'MESH:C070243', (16, 19))
207268	29884885	Noteworthy, combined treatment of T98G cells with TMZ + GBM-CM, significantly increased cell viability of about 25% compared to TMZ alone.	('TMZ', 'Chemical', 'MESH:D000077204', (128, 131))	('TMZ', 'Chemical', 'MESH:D000077204', (50, 53))	('increased', 'PosReg', (78, 87))	('cell viability', 'CPA', (88, 102))	('TMZ + GBM-CM', 'Var', (50, 62))	('GBM', 'Phenotype', 'HP:0012174', (56, 59))
207273	29884885	A similar but not so strong effect, was observed when T98G cells were treated with TMZ + LGG-CM and TMZ + MNG-CM.	('TMZ + LGG-CM', 'Var', (83, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('TMZ', 'Chemical', 'MESH:D000077204', (100, 103))	('TMZ + MNG-CM', 'Var', (100, 112))
207292	29884885	Together with these findings, our results showed that mRNA expression of VEGF, and its receptor VEGFR-1, was significantly increased in GBM, compared to both healthy brain, LGG, and MNG.	('increased', 'PosReg', (123, 132))	('mRNA expression', 'MPA', (54, 69))	('VEGFR-1', 'Gene', (96, 103))	('GBM', 'Var', (136, 139))	('VEGF', 'Gene', '7422', (96, 100))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('VEGF', 'Gene', '7422', (73, 77))	('VEGFR-1', 'Gene', '2321', (96, 103))	('VEGF', 'Gene', (73, 77))	('VEGF', 'Gene', (96, 100))
207312	29884885	Anyway, the high percentage of LGG-ECs positive to CD105 and CD90 may reflect the propensity of LGGs to undergo malignant transformation, developing in secondary GBMs.	('positive', 'Reg', (39, 47))	('LGG-EC', 'Chemical', '-', (31, 37))	('CD105', 'Var', (51, 56))	('CD90', 'Gene', '7070', (61, 65))	('GBM', 'Phenotype', 'HP:0012174', (162, 165))	('CD90', 'Gene', (61, 65))	('developing', 'Reg', (138, 148))
207313	29884885	Moreover, a high percentage of GBM-ECs (about 70%), showed positivity to CD56, or NCAM, a cell-surface glycoprotein widely characterized in CNS, when it regulates intercellular adhesion and cell migration.	('CD56', 'Gene', '4684', (73, 77))	('positivity', 'Var', (59, 69))	('NCAM', 'Gene', '4684', (82, 86))	('CD56', 'Gene', (73, 77))	('cell migration', 'CPA', (190, 204))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('intercellular adhesion', 'CPA', (163, 185))	('regulates', 'Reg', (153, 162))	('NCAM', 'Gene', (82, 86))
207325	29884885	Indeed, gene expression analysis of GBM-ECs after pharmacological treatment, revealed that tumor suppressor p53 was down-regulation by BEV and TMZ, and up-regulated by SUN.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('up-regulated', 'PosReg', (152, 164))	('TMZ', 'Var', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('down-regulation', 'NegReg', (116, 131))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (143, 146))	('BEV', 'Chemical', 'MESH:D000068258', (135, 138))	('tumor', 'Disease', (91, 96))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
207327	29884885	Activation of p53 triggers different cellular programs such as cell cycle arrest, apoptosis, differentiation, DNA repair, autophagy, and senescence through complex network and signalling pathways.	('p53', 'Gene', (14, 17))	('cell cycle arrest', 'CPA', (63, 80))	('apoptosis', 'CPA', (82, 91))	('differentiation', 'CPA', (93, 108))	('p53', 'Gene', '7157', (14, 17))	('senescence', 'CPA', (137, 147))	('DNA repair', 'CPA', (110, 120))	('Activation', 'Var', (0, 10))	('autophagy', 'CPA', (122, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('triggers', 'Reg', (18, 26))	('cellular programs', 'CPA', (37, 54))
207339	29884885	Interestingly, T98G cultured with conditioned media from GBM-ECs, LGG-ECs and MNG-ECs changed their response profile, turning into resistant cells.	('changed', 'Reg', (86, 93))	('LGG-EC', 'Chemical', '-', (66, 72))	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('T98G', 'Var', (15, 19))	('turning', 'Reg', (118, 125))	('response profile', 'MPA', (100, 116))
207340	29884885	Indeed, T98G treated with TMZ in combination with GBM-CM had a percentage of viable cells higher than those treated with TMZ alone, as well as higher than those treated with TMZ in combination with LGG-CM and MNG-CM.	('TMZ', 'Chemical', 'MESH:D000077204', (121, 124))	('T98G', 'Var', (8, 12))	('higher', 'PosReg', (143, 149))	('GBM-CM', 'Gene', (50, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (174, 177))	('TMZ', 'Chemical', 'MESH:D000077204', (26, 29))	('higher', 'PosReg', (90, 96))	('GBM', 'Phenotype', 'HP:0012174', (50, 53))
207342	29884885	Notably, the effect produced by LGG-CM and MNG-CM in conferring drug resistance to TMZ was not the same as GBM-CM, confirming the aberrant pro-angiogenic microenvironment specific of GBM.	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('MNG-CM', 'Var', (43, 49))	('drug resistance', 'MPA', (64, 79))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))	('GBM', 'Phenotype', 'HP:0012174', (183, 186))	('LGG-CM', 'Var', (32, 38))	('drug resistance', 'Phenotype', 'HP:0020174', (64, 79))
207343	29884885	Overall, our results obtained from co-culture systems indicated that GBM-CM, but not LGG-CM and MNG-CM, induced a resistant behaviour to anticancer drug TMZ in T89G cells, suggesting that the difference in tumor microenvironment or tumor malignancy may affect tumor response to drugs.	('tumor', 'Disease', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('TMZ', 'Chemical', 'MESH:D000077204', (153, 156))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('T89G', 'Mutation', 'rs926559231', (160, 164))	('induced', 'Reg', (104, 111))	('affect', 'Reg', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor malignancy', 'Disease', 'MESH:D018198', (232, 248))	('GBM-CM', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumor', 'Disease', (232, 237))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor malignancy', 'Disease', (232, 248))	('tumor', 'Disease', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
207363	29884885	ECs (1 x 105/tube) were resuspended in 200 mul of D-PBS and stained with FITC-conjugated anti-human CD105 and PE- conjugated anti-human CD133, anti-human CD56, anti-human CD90 (all purchased by BD Biosciences), for 20 min at RT in the dark.	('anti-human', 'Var', (160, 170))	('human', 'Species', '9606', (165, 170))	('CD56', 'Gene', (154, 158))	('FITC', 'Chemical', 'MESH:D016650', (73, 77))	('human', 'Species', '9606', (148, 153))	('human', 'Species', '9606', (94, 99))	('CD133', 'Gene', (136, 141))	('D-PBS', 'Chemical', 'MESH:C012939', (50, 55))	('CD133', 'Gene', '8842', (136, 141))	('CD90', 'Gene', '7070', (171, 175))	('CD56', 'Gene', '4684', (154, 158))	('CD90', 'Gene', (171, 175))	('human', 'Species', '9606', (130, 135))
207381	29291003	Pseudogenes of annexin A2, novel prognosis biomarkers for diffuse gliomas Diffuse gliomas is a kind of common malignant primary brain tumor.	('brain tumor', 'Phenotype', 'HP:0030692', (128, 139))	('Pseudogenes', 'Var', (0, 11))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('annexin A2', 'Gene', '302', (15, 25))	('annexin A2', 'Gene', (15, 25))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('brain tumor', 'Disease', (128, 139))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('brain tumor', 'Disease', 'MESH:D001932', (128, 139))
207382	29291003	Pseudogenes have multilayered biological function in the progression of human cancers.	('Pseudogenes', 'Var', (0, 11))	('human', 'Species', '9606', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
207385	29291003	Meanwhile, Pearson's correlation analysis revealed that the expression level of ANXA2 was positively correlated with ANXA2 pseudogenes expression.	('pseudogenes', 'Var', (123, 134))	('ANXA2', 'Gene', '303', (80, 85))	('ANXA2', 'Gene', (117, 122))	('correlated', 'Reg', (101, 111))	('expression', 'MPA', (135, 145))	('ANXA2', 'Gene', (80, 85))	('expression level', 'MPA', (60, 76))	('ANXA2', 'Gene', '303', (117, 122))
207387	29291003	Additionally, Kaplan-Meier analysis revealed that highly expressed ANXA2 and annexin A2 pseudogenes were associated with the poor survival outcome of glioma patients.	('ANXA2', 'Gene', '303', (67, 72))	('highly', 'PosReg', (50, 56))	('patients', 'Species', '9606', (157, 165))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('annexin A2', 'Gene', '302', (77, 87))	('annexin A2', 'Gene', (77, 87))	('glioma', 'Disease', (150, 156))	('associated', 'Reg', (105, 115))	('pseudogenes', 'Var', (88, 99))	('ANXA2', 'Gene', (67, 72))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
207389	29291003	Furthermore, down-regulation of ANXA2 and ANXA2 pseudogenes might contribute to the improvement of patients' survival who received chemotherapy and radiotherapy.	('ANXA2', 'Gene', '303', (42, 47))	('ANXA2', 'Gene', '303', (32, 37))	('ANXA2', 'Gene', (42, 47))	('pseudogenes', 'Var', (48, 59))	('improvement', 'PosReg', (84, 95))	('down-regulation', 'NegReg', (13, 28))	('patients', 'Species', '9606', (99, 107))	('ANXA2', 'Gene', (32, 37))
207390	29291003	These results demonstrated that ANXA2 pseudogenes and ANXA2 could be used as the novel biomarkers for diagnosis, prognosis and target therapy of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('pseudogenes', 'Var', (38, 49))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('ANXA2', 'Gene', '303', (32, 37))	('ANXA2', 'Gene', '303', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('ANXA2', 'Gene', (32, 37))	('gliomas', 'Disease', (145, 152))	('ANXA2', 'Gene', (54, 59))
207396	29291003	Although the pseudogenes had been regarded as "genomic fossil" or "junk genes" early, recent studies have demonstrated that pseudogenes have multilayered biological function in processes of pathology and physiology, especially in human cancers progression.	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('cancers', 'Disease', (236, 243))	('pseudogenes', 'Var', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('human', 'Species', '9606', (230, 235))
207398	29291003	Particularly, pseudogenes may play regulatory roles in both transcription and post-transcription of tumor cells.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pseudogenes', 'Var', (14, 25))
207406	29291003	Using bioinformatics analysis, we identify differentially expressed pseudogenes (DEPs) between 77 glioblastoma samples and 23 normal controls within GSE4290 dataset.	('differentially', 'Reg', (43, 57))	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('GSE4290', 'Chemical', '-', (149, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('pseudogenes', 'Var', (68, 79))
207410	29291003	As shown in Figure 2A, ANXA2 and its pseudogenes expression were remarkably increased in glioma tissues compared with non-tumor controls (all P<0.001).	('pseudogenes', 'Var', (37, 48))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('ANXA2', 'Gene', '303', (23, 28))	('increased', 'PosReg', (76, 85))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('expression', 'MPA', (49, 59))	('non-tumor', 'Disease', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('glioma', 'Disease', (89, 95))	('ANXA2', 'Gene', (23, 28))	('non-tumor', 'Disease', 'MESH:D009369', (118, 127))
207416	29291003	We described the expression of ANXA2 and ANXA2 pseudogenes in GBM subtypes based on the classification criterion of above.	('ANXA2', 'Gene', '303', (31, 36))	('GBM', 'Disease', (62, 65))	('ANXA2', 'Gene', (41, 46))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('ANXA2', 'Gene', (31, 36))	('ANXA2', 'Gene', '303', (41, 46))	('pseudogenes', 'Var', (47, 58))
207431	29291003	As shown in Figure 5A, analysis of TCGA dataset, the OS of glioma patients with high expression of ANXA2 and its pseudogenes were significantly worse than that with low expression (all P<0.0001).	('ANXA2', 'Gene', (99, 104))	('glioma', 'Disease', (59, 65))	('worse', 'NegReg', (144, 149))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('ANXA2', 'Gene', '303', (99, 104))	('high expression', 'Var', (80, 95))	('patients', 'Species', '9606', (66, 74))
207433	29291003	Additionally, in GSE4412 dataset, the OS of glioma patients with high expression of ANXA2 and its pseudogenes were noticeably worse than that with low expression (P=0.0058, P=0.0347, P=0.0019, P=0.0088, respectively; Figure 5C), and even more significant results were obtained from GSE43378 datasets (P<0.0001, P=0.0120, P<0.0001, P=0.1323, Figure 5D).	('worse', 'NegReg', (126, 131))	('ANXA2', 'Gene', '303', (84, 89))	('ANXA2', 'Gene', (84, 89))	('GSE4412', 'Chemical', '-', (17, 24))	('glioma', 'Disease', (44, 50))	('patients', 'Species', '9606', (51, 59))	('high expression', 'Var', (65, 80))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
207440	29291003	As shown in Figure 6A, our analyses displayed that the therapeutic outcome of TCGA patients who have received chemotherapy or radiotherapy with low expression of ANXA2 and ANXA2 pseudogenes was remarkably better than that with high expression (P<=0.0007, P<=0.0023).	('ANXA2', 'Gene', '303', (162, 167))	('pseudogenes', 'Var', (178, 189))	('TCGA', 'Gene', (78, 82))	('therapeutic outcome', 'CPA', (55, 74))	('ANXA2', 'Gene', (172, 177))	('ANXA2', 'Gene', (162, 167))	('low', 'NegReg', (144, 147))	('patients', 'Species', '9606', (83, 91))	('better', 'PosReg', (205, 211))	('ANXA2', 'Gene', '303', (172, 177))
207446	29291003	In addition, Pearson's correlation analysis found that the expression level of ANXA2 was positively correlated with ANXA2 pseudogenes expression.	('ANXA2', 'Gene', (116, 121))	('expression', 'MPA', (134, 144))	('pseudogenes', 'Var', (122, 133))	('ANXA2', 'Gene', (79, 84))	('ANXA2', 'Gene', '303', (116, 121))	('ANXA2', 'Gene', '303', (79, 84))	('expression level', 'MPA', (59, 75))
207447	29291003	Furthermore, Kaplan-Meier curve and Cox regression analyses showed that the high expression of ANXA2 and its pseudogenes were correlated with the poor OS of glioma patients, and the aberrantly expressed ANXA2, ANXA2P1 and ANXA2P2 were the independent prognosis factors for gliomas.	('ANXA2', 'Gene', '303', (210, 215))	('ANXA2', 'Gene', (95, 100))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Disease', (273, 279))	('Cox', 'Gene', '1351', (36, 39))	('glioma', 'Disease', 'MESH:D005910', (273, 279))	('ANXA2P2', 'Gene', (222, 229))	('expression', 'MPA', (81, 91))	('ANXA2', 'Gene', (203, 208))	('ANXA2', 'Gene', '303', (222, 227))	('poor', 'Disease', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('gliomas', 'Disease', (273, 280))	('ANXA2', 'Gene', '303', (95, 100))	('patients', 'Species', '9606', (164, 172))	('glioma', 'Phenotype', 'HP:0009733', (273, 279))	('Cox', 'Gene', (36, 39))	('ANXA2P1', 'Gene', (210, 217))	('ANXA2P1', 'Gene', '303', (210, 217))	('aberrantly expressed', 'Var', (182, 202))	('ANXA2', 'Gene', (210, 215))	('ANXA2P2', 'Gene', '304', (222, 229))	('gliomas', 'Disease', 'MESH:D005910', (273, 280))	('ANXA2', 'Gene', '303', (203, 208))	('gliomas', 'Phenotype', 'HP:0009733', (273, 280))	('glioma', 'Disease', (157, 163))	('ANXA2', 'Gene', (222, 227))	('high', 'PosReg', (76, 80))
207448	29291003	Taken together, these results suggest that three pseudogenes of ANXA2 may be suitable biomarkers for diagnostic or therapeutic strategies for diffuse gliomas.	('ANXA2', 'Gene', (64, 69))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('diffuse glioma', 'Disease', (142, 156))	('gliomas', 'Disease', (150, 157))	('pseudogenes', 'Var', (49, 60))	('diffuse glioma', 'Disease', 'MESH:D005910', (142, 156))	('ANXA2', 'Gene', '303', (64, 69))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
207453	29291003	Tracing glioma progression in rodent brain, researchers found that the ANXA2 knockdown group were tumor size decreased and tumor progression slowed.	('decreased', 'NegReg', (109, 118))	('ANXA2', 'Gene', (71, 76))	('tumor', 'Disease', (123, 128))	('glioma', 'Disease', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('knockdown', 'Var', (77, 86))	('ANXA2', 'Gene', '303', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('slowed', 'NegReg', (141, 147))	('glioma', 'Disease', 'MESH:D005910', (8, 14))	('tumor', 'Disease', (98, 103))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
207456	29291003	Through integrated analysis of several ovarian cancer datasets, a 19-gene model which including ANAX2P1 and ANXA2P3 can serve as a reproducible predictor of survival.	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('ANXA2P3', 'Gene', '305', (108, 115))	('ovarian cancer', 'Disease', (39, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('ANAX2P1', 'Var', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ANXA2P3', 'Gene', (108, 115))
207460	29291003	Pseudogenes of ANXA2 might play important roles in diffuse gliomas progression.	('Pseudogenes', 'Var', (0, 11))	('diffuse glioma', 'Disease', 'MESH:D005910', (51, 65))	('ANXA2', 'Gene', '303', (15, 20))	('diffuse glioma', 'Disease', (51, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('roles', 'Reg', (42, 47))	('gliomas', 'Disease', (59, 66))	('play', 'Reg', (27, 31))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('ANXA2', 'Gene', (15, 20))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
207465	29291003	In this study, for the first time, we found that high expression of ANXA2 pseudogenes were correlated with the poor OS of glioma patients.	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('ANXA2', 'Gene', (68, 73))	('patients', 'Species', '9606', (129, 137))	('glioma', 'Disease', (122, 128))	('correlated', 'Reg', (91, 101))	('poor OS', 'Disease', (111, 118))	('ANXA2', 'Gene', '303', (68, 73))	('high', 'PosReg', (49, 53))	('pseudogenes', 'Var', (74, 85))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
207466	29291003	What is the underlying mechanism of pseudogenes play their roles in cancer progression?	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('pseudogenes', 'Var', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (68, 74))
207470	29291003	In present study, we first time clarified that the expression level of ANXA2 was positively correlated with ANXA2 pseudogenes expression.	('ANXA2', 'Gene', (71, 76))	('ANXA2', 'Gene', '303', (108, 113))	('expression', 'MPA', (126, 136))	('correlated', 'Reg', (92, 102))	('ANXA2', 'Gene', '303', (71, 76))	('pseudogenes', 'Var', (114, 125))	('ANXA2', 'Gene', (108, 113))	('expression level', 'MPA', (51, 67))
207473	29291003	Further researches to validate the prediction and mechanisms of ANXA2 pseudogenes are on the way.	('ANXA2', 'Gene', '303', (64, 69))	('ANXA2', 'Gene', (64, 69))	('pseudogenes', 'Var', (70, 81))
207475	29291003	Summarizing other studies, ANXA2 was upregulated in gastric cancer tissues and as a direct target of miR-101, miR-101 alleviated chemoresistance of cisplatin or vincristine in gastric cancer cells by targeting ANXA2.	('ANXA2', 'Gene', '303', (210, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('miR-101', 'Chemical', '-', (101, 108))	('miR-101', 'Var', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('upregulated', 'PosReg', (37, 48))	('alleviated', 'NegReg', (118, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('gastric cancer', 'Disease', (52, 66))	('targeting', 'Reg', (200, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('ANXA2', 'Gene', (27, 32))	('chemoresistance', 'CPA', (129, 144))	('ANXA2', 'Gene', (210, 215))	('gastric cancer', 'Disease', (176, 190))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))	('miR-101', 'Chemical', '-', (110, 117))	('miR-101', 'Var', (110, 117))	('vincristine', 'Chemical', 'MESH:D014750', (161, 172))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ANXA2', 'Gene', '303', (27, 32))
207486	29291003	The gene expression profiles of GSE4290, GSE4412, and GSE43378 was downloaded from the Gene Expression Omnibus database (GEO, http://www.ncbi.nlm.nih.gov/geo/).	('GSE4290', 'Chemical', '-', (32, 39))	('GSE4412', 'Chemical', '-', (41, 48))	('GSE4412', 'Var', (41, 48))	('GSE4290', 'Var', (32, 39))	('GSE43378', 'Var', (54, 62))
207496	29291003	In summary, this study demonstrated that ANXA2 pseudogenes and ANXA2 were up-regulated in diffuse gliomas tissue compared to normal brain tissue, and preferentially expressed in mesenchymal subtypes of glioblastoma.	('ANXA2', 'Gene', (63, 68))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('diffuse glioma', 'Disease', (90, 104))	('glioblastoma', 'Disease', (202, 214))	('ANXA2', 'Gene', (41, 46))	('diffuse glioma', 'Disease', 'MESH:D005910', (90, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('up-regulated', 'PosReg', (74, 86))	('gliomas', 'Disease', (98, 105))	('preferentially', 'PosReg', (150, 164))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('ANXA2', 'Gene', '303', (63, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('ANXA2', 'Gene', '303', (41, 46))	('pseudogenes', 'Var', (47, 58))
207497	29291003	Highly expressed ANXA2 and its pseudogenes were associated with poor survival, and could be the independent prognosis factors for glioma patients.	('pseudogenes', 'Var', (31, 42))	('ANXA2', 'Gene', (17, 22))	('glioma', 'Disease', (130, 136))	('poor', 'NegReg', (64, 68))	('patients', 'Species', '9606', (137, 145))	('ANXA2', 'Gene', '303', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
207499	29291003	These results implied that ANXA2 pseudogenes and ANXA2 could be potentially used as prognosis biomarkers and therapeutic targets for gliomas.	('ANXA2', 'Gene', '303', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('ANXA2', 'Gene', (49, 54))	('ANXA2', 'Gene', (27, 32))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('pseudogenes', 'Var', (33, 44))	('ANXA2', 'Gene', '303', (27, 32))
207502	33896271	The cBio Cancer Genomics Portal was used to analyze the mutations of DCTN genes and their effects on the prognosis of LGG.	('mutations', 'Var', (56, 65))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('effects', 'Reg', (90, 97))	('DCTN genes', 'Gene', (69, 79))	('LGG', 'Disease', (118, 121))	('Cancer', 'Disease', (9, 15))	('Cancer', 'Disease', 'MESH:D009369', (9, 15))
207507	33896271	Further research showed that the genetic alteration in DCTN genes was related to a poor OS and progression-free survival of LGG patients.	('progression-free survival', 'CPA', (95, 120))	('genetic alteration', 'Var', (33, 51))	('poor OS', 'CPA', (83, 90))	('LGG', 'Disease', (124, 127))	('DCTN genes', 'Gene', (55, 65))	('related', 'Reg', (70, 77))	('patients', 'Species', '9606', (128, 136))
207513	33896271	In previous studies, some biomarkers including Ki-67, CXCL12, SEMA3G, MIF, CD31, KAZALD1, and STC1 were found to be associated with the development of LGG.	('SEMA3G', 'Gene', (62, 68))	('SEMA3G', 'Gene', '56920', (62, 68))	('associated with', 'Reg', (116, 131))	('LGG', 'Disease', (151, 154))	('MIF', 'Gene', (70, 73))	('STC1', 'Gene', '6781', (94, 98))	('KAZALD1', 'Gene', (81, 88))	('CD31', 'Gene', (75, 79))	('CXCL12', 'Gene', (54, 60))	('STC1', 'Gene', (94, 98))	('KAZALD1', 'Gene', '81621', (81, 88))	('MIF', 'Gene', '4282', (70, 73))	('CD31', 'Gene', '5175', (75, 79))	('Ki-67', 'Var', (47, 52))	('CXCL12', 'Gene', '6387', (54, 60))
207514	33896271	To date, the subunits of DCTN are known to include p150Glued (DCTN1), p50 (DCTN2), p24 (DCTN3), p62 (DCTN4), p25 (DCTN5), p27 (DCTN6), Arp11 (ACTR10), Arp1 (ACTR1A), beta-actin, and CapZ alpha/beta.	('DCTN4', 'Gene', '51164', (101, 106))	('DCTN2', 'Gene', '10540', (75, 80))	('p150Glued', 'Var', (51, 60))	('p62', 'Gene', '51164', (96, 99))	('ACTR10', 'Gene', (142, 148))	('p25', 'Gene', (109, 112))	('DCTN3', 'Gene', (88, 93))	('p50', 'Gene', '4790', (70, 73))	('DCTN4', 'Gene', (101, 106))	('DCTN6', 'Gene', '10671', (127, 132))	('ACTR10', 'Gene', '55860', (142, 148))	('p24', 'Gene', (83, 86))	('p24', 'Gene', '140767', (83, 86))	('DCTN2', 'Gene', (75, 80))	('ACTR1A', 'Gene', (157, 163))	('DCTN3', 'Gene', '11258', (88, 93))	('p50', 'Gene', (70, 73))	('p27', 'Gene', '10671', (122, 125))	('Arp11', 'Gene', '55860', (135, 140))	('ACTR1A', 'Gene', '10121', (157, 163))	('Arp1', 'Gene', '10121', (151, 155))	('DCTN5', 'Gene', (114, 119))	('DCTN5', 'Gene', '84516', (114, 119))	('DCTN6', 'Gene', (127, 132))	('CapZ alpha/beta', 'Gene', '832', (182, 197))	('p25', 'Gene', '54732', (109, 112))	('CapZ alpha/beta', 'Gene', (182, 197))	('Arp1', 'Gene', '10121', (135, 139))	('beta-actin', 'Protein', (166, 176))	('p27', 'Gene', (122, 125))	('p62', 'Gene', (96, 99))	('Arp1', 'Gene', (151, 155))	('Arp11', 'Gene', (135, 140))	('Arp1', 'Gene', (135, 139))
207518	33896271	Another study showed that high expression of DCTN4 was significantly related to a favorable prognosis in colon adenocarcinoma (COAD) patients.	('COAD', 'Disease', (127, 131))	('high', 'Var', (26, 30))	('DCTN4', 'Gene', (45, 50))	('patients', 'Species', '9606', (133, 141))	('colon adenocarcinoma', 'Disease', (105, 125))	('DCTN4', 'Gene', '51164', (45, 50))	('COAD', 'Disease', 'MESH:D029424', (127, 131))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (105, 125))	('related', 'Reg', (69, 76))
207534	33896271	As demonstrated by the above-mentioned analyses, the DCTN genes were mainly enriched in the following parts: antigen processing and presentation of exogenous peptide antigen via major histocompatibility complex (MHC) class II (GO: 0019886), endoplasmic reticulum (ER) to Golgi vesicle-mediated transport (GO: 0006888), dynactin complex (GO: 0005869), the centrosome (GO: 0005813), motor activity (GO: 0003774), and vasopressin-regulated water reabsorption (hsa04962).	('ER', 'Gene', '2069', (264, 266))	('water', 'Chemical', 'MESH:D014867', (437, 442))	('GO: 0005813', 'Var', (367, 378))	('GO: 0005869', 'Var', (337, 348))	('GO: 0003774', 'Var', (397, 408))	('vasopressin', 'Gene', '551', (415, 426))	('vasopressin', 'Gene', (415, 426))	('GO: 0006888', 'Var', (305, 316))
207547	33896271	The mutant forms of DCTN1 and DCTN3 were both missense mutations.	('missense mutations', 'Var', (46, 64))	('DCTN3', 'Gene', '11258', (30, 35))	('DCTN1', 'Gene', (20, 25))	('DCTN3', 'Gene', (30, 35))
207548	33896271	Amplification accounted for most of the mutations in the DCTN2.	('mutations', 'Var', (40, 49))	('DCTN2', 'Gene', (57, 62))	('accounted', 'Reg', (14, 23))	('DCTN2', 'Gene', '10540', (57, 62))
207550	33896271	The gene mutation of DCTN5 included 2 forms of missense mutation and amplification, while the mutation of DCTN6 had only one form of amplification.	('mutation', 'Var', (9, 17))	('missense', 'Var', (47, 55))	('DCTN6', 'Gene', (106, 111))	('amplification', 'MPA', (69, 82))	('DCTN6', 'Gene', '10671', (106, 111))	('DCTN5', 'Gene', '84516', (21, 26))	('DCTN5', 'Gene', (21, 26))
207562	33896271	The transcriptional dysregulation of DCTN1 may disrupt retrograde axonal transport thereby leading to neuronal dysfunction.	('disrupt', 'NegReg', (47, 54))	('leading to', 'Reg', (91, 101))	('dysregulation', 'Var', (20, 33))	('retrograde axonal transport', 'MPA', (55, 82))	('neuronal dysfunction', 'Disease', 'MESH:D009410', (102, 122))	('DCTN1', 'Gene', (37, 42))	('neuronal dysfunction', 'Disease', (102, 122))
207564	33896271	Our results indicated that high expression of DCTN1 is related to a better prognosis in patients with LGG, but the specific mechanism of action is still unclear.	('better', 'PosReg', (68, 74))	('patients', 'Species', '9606', (88, 96))	('high expression', 'Var', (27, 42))	('DCTN1', 'Gene', (46, 51))	('LGG', 'Disease', (102, 105))
207573	33896271	Previous studies have already shown that high expression of DCTN4 was related to a satisfactory OS of COAD, which is consistent with our results and suggest that a similar mechanism may also exist in LGG.	('COAD', 'Disease', (102, 106))	('high expression', 'Var', (41, 56))	('COAD', 'Disease', 'MESH:D029424', (102, 106))	('DCTN4', 'Gene', '51164', (60, 65))	('LGG', 'Disease', (200, 203))	('related', 'Reg', (70, 77))	('DCTN4', 'Gene', (60, 65))
207576	33896271	SPRIGHTLY lncRNA is encoded in the Drosophila gene homolog Sprouty-4 intron, and its aberrant expression is associated with a variety of cancers, such as human melanoma.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (154, 159))	('aberrant expression', 'Var', (85, 104))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('associated', 'Reg', (108, 118))	('cancers', 'Disease', (137, 144))	('Drosophila', 'Species', '7227', (35, 45))
207578	33896271	Our Kaplan-Meier curves showed that high expression of DCTN6 was related to a favorable prognosis in LGG patients.	('high expression', 'Var', (36, 51))	('patients', 'Species', '9606', (105, 113))	('LGG', 'Disease', (101, 104))	('DCTN6', 'Gene', (55, 60))	('DCTN6', 'Gene', '10671', (55, 60))
207580	33896271	It was demonstrated that the combination of DCTN1, DCTN3, DCTN4, and DCTN6 improves the sensitivity for predicting OS in LGG patients.	('DCTN1', 'Var', (44, 49))	('DCTN4', 'Gene', (58, 63))	('LGG', 'Disease', (121, 124))	('DCTN3', 'Gene', '11258', (51, 56))	('improves', 'PosReg', (75, 83))	('DCTN6', 'Gene', (69, 74))	('DCTN3', 'Gene', (51, 56))	('DCTN6', 'Gene', '10671', (69, 74))	('DCTN4', 'Gene', '51164', (58, 63))	('patients', 'Species', '9606', (125, 133))
207582	33896271	On the contrary, low level co-expression of these genes was linked to poor OS in LGG patients.	('co-expression', 'MPA', (27, 40))	('poor OS', 'Disease', (70, 77))	('low level', 'Var', (17, 26))	('patients', 'Species', '9606', (85, 93))	('LGG', 'Disease', (81, 84))	('linked', 'Reg', (60, 66))
207584	33896271	A previous study showed that genetic atypical Parkinson's disease, a neurological disease, was associated with mutations in DCTN1.	("Parkinson's disease", 'Disease', (46, 65))	('mutations', 'Var', (111, 120))	('neurological disease', 'Phenotype', 'HP:0000707', (69, 89))	("Parkinson's disease", 'Disease', 'MESH:D010300', (46, 65))	('DCTN1', 'Gene', (124, 129))	('neurological disease', 'Disease', 'MESH:D020271', (69, 89))	('associated', 'Reg', (95, 105))	('neurological disease', 'Disease', (69, 89))
207585	33896271	However, relationships between DCTN genes mutations and tumors of the nervous system have rarely been reported.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('DCTN genes', 'Gene', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (42, 51))	('tumors of the nervous system', 'Phenotype', 'HP:0004375', (56, 84))
207586	33896271	Our research contributes to the understanding of the potential roles of DCTN genes mutations in tumor development.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('DCTN genes', 'Gene', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
207588	33896271	Studies had shown that some subsets of CD4+ T cells, especially regulatory T cells and T follicular helper (TFH) cells, can promote tumor growth by inhibiting tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('CD4+', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (132, 137))	('promote', 'PosReg', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('inhibiting', 'NegReg', (148, 158))
207593	33896271	This suggested that DCTN1 and DCTN3 may reduce the proliferation of LGGs by reducing TAM infiltration in tumors which allows patients to have a better prognosis.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('DCTN3', 'Gene', (30, 35))	('DCTN1', 'Var', (20, 25))	('reduce', 'NegReg', (40, 46))	('TAM', 'Chemical', '-', (85, 88))	('proliferation', 'CPA', (51, 64))	('LGGs', 'CPA', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TAM', 'CPA', (85, 88))	('reducing', 'NegReg', (76, 84))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('DCTN3', 'Gene', '11258', (30, 35))	('patients', 'Species', '9606', (125, 133))
207594	33896271	Macrophage and dendritic cell infiltration has been associated with poorer OS in glioma patients, which is similar to the findings of the present study.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('Macrophage', 'Var', (0, 10))	('patients', 'Species', '9606', (88, 96))	('glioma', 'Disease', (81, 87))	('poorer', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
207684	33734413	Of the GISTs, none carried c-kit or PDGFRA mutations, 13 tumors (65.0%) were located in the jejunum or ileum, and 6 tumors (30.0%) were located in the duodenum.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('GISTs', 'Phenotype', 'HP:0100723', (7, 12))	('c-kit', 'Gene', '3815', (27, 32))	('c-kit', 'Gene', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PDGFRA', 'Gene', '5156', (36, 42))	('PDGFRA', 'Gene', (36, 42))	('tumors', 'Disease', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
207712	33734413	Inactivating mutations in NF1 is associated with downstream activation of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling, and uncontrolled cellular growth, differentiation, and survival, which is associated with the disease origin of NF1, including NF1-associated neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (340, 348))	('uncontrolled cellular growth', 'CPA', (202, 230))	('NF1', 'Gene', (325, 328))	('NF1', 'Gene', '4763', (310, 313))	('activation', 'PosReg', (60, 70))	('neoplasms', 'Disease', 'MESH:D009369', (340, 349))	('survival', 'CPA', (253, 261))	('NF1', 'Gene', (310, 313))	('Inactivating mutations', 'Var', (0, 22))	('differentiation', 'CPA', (232, 247))	('protein kinase B', 'Gene', '2185', (138, 154))	('mechanistic target of rapamycin', 'Gene', (155, 186))	('mechanistic target of rapamycin', 'Gene', '2475', (155, 186))	('mitogen-activated', 'MPA', (74, 91))	('neoplasms', 'Disease', (340, 349))	('protein kinase B', 'Gene', (138, 154))	('NF1', 'Gene', '4763', (26, 29))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (325, 328))	('neoplasms', 'Phenotype', 'HP:0002664', (340, 349))
207721	33734413	A 2000 review found that NF1-associated LGGs undergo malignant transformation more frequently than comparable sporadic LGGs; thus, malignant transformation of NF1-associated LGGs may be associated with the increased prevalence and younger age of diagnosis for HGG among patients with NF1 in our study compared with the general population.	('NF1', 'Gene', '4763', (159, 162))	('patients', 'Species', '9606', (270, 278))	('malignant transformation', 'Var', (131, 155))	('NF1', 'Gene', (284, 287))	('HGG', 'Disease', (260, 263))	('NF1', 'Gene', '4763', (284, 287))	('NF1', 'Gene', (25, 28))	('NF1', 'Gene', '4763', (25, 28))	('NF1', 'Gene', (159, 162))
207791	33306121	In addition, with respect to the mutations of Fam20C gene lead to Raine syndrome, which is characterized by generalized osteosclerosis, periosteal bone formation, and a unique facial phenotype.	('Raine syndrome', 'Disease', 'MESH:C535282', (66, 80))	('osteosclerosis', 'Disease', 'MESH:D010026', (120, 134))	('osteosclerosis', 'Phenotype', 'HP:0011001', (120, 134))	('osteosclerosis', 'Disease', (120, 134))	('periosteal bone formation', 'Phenotype', 'HP:0031485', (136, 161))	('mutations', 'Var', (33, 42))	('lead to', 'Reg', (58, 65))	('Fam20C', 'Gene', '56975', (46, 52))	('Raine syndrome', 'Disease', (66, 80))	('Fam20C', 'Gene', (46, 52))	('generalized osteosclerosis', 'Phenotype', 'HP:0005789', (108, 134))
207855	33306121	Consequently, a strong association of the Fam20C high expression with worse OS, FP (first progression), and PPS (post-progression survival) in female and male patients was found.	('PPS', 'Disease', (108, 111))	('Fam20C', 'Gene', (42, 48))	('PPS', 'Disease', 'MESH:C562509', (108, 111))	('worse OS', 'Disease', (70, 78))	('high expression', 'Var', (49, 64))	('patients', 'Species', '9606', (159, 167))	('Fam20C', 'Gene', '56975', (42, 48))
207887	33306121	Macrophages secrete a large number of chemokines such as CC-like chemokines CCL22 and CCL20, which induce Tregs to recruit to the tumor site, similarly DCs also induce Treg generation, and then promote the metastasis of cancer cells.	('CCL20', 'Gene', '6364', (86, 91))	('promote', 'PosReg', (194, 201))	('induce', 'Reg', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Tregs', 'Chemical', '-', (106, 111))	('DCs', 'Var', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Treg', 'Chemical', '-', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('CCL22', 'Gene', '6367', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Treg', 'Chemical', '-', (168, 172))	('CCL20', 'Gene', (86, 91))	('cancer', 'Disease', (220, 226))	('tumor', 'Disease', (130, 135))	('Treg generation', 'CPA', (168, 183))	('CCL22', 'Gene', (76, 81))
207897	33306121	Therefore, it is desirable to speculate that the expression of Fam20C may affect the survival of patients through the progression of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('Fam20C', 'Gene', '56975', (63, 69))	('survival', 'CPA', (85, 93))	('Fam20C', 'Gene', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('affect', 'Reg', (74, 80))	('expression', 'Var', (49, 59))	('patients', 'Species', '9606', (97, 105))
207907	33306121	Here, we present an integrated study on the Fam20C expression levels in pan-cancer, the association of Fam20C variations with prognosis among different cancers and the potential mechanisms underlying different clinicopathological features.	('Fam20C', 'Gene', (44, 50))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (152, 159))	('Fam20C', 'Gene', '56975', (103, 109))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Fam20C', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('variations', 'Var', (110, 120))	('Fam20C', 'Gene', '56975', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('association', 'Interaction', (88, 99))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
207966	32687065	In gliomas with high PDIA3 expression, somatic mutations showed the correlation with loss of PTEN and amplification of EGFR; meanwhile, in PDIA3 low gliomas, mutations in isocitrate dehydrogenase (IDH) took 80%.	('PTEN', 'Gene', (93, 97))	('low gliomas', 'Disease', (145, 156))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('isocitrate dehydrogenase', 'Gene', '3417', (171, 195))	('gliomas', 'Disease', (3, 10))	('PTEN', 'Gene', '5728', (93, 97))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('IDH', 'Gene', (197, 200))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('mutations', 'Var', (158, 167))	('PDIA3', 'Gene', (139, 144))	('EGFR', 'Gene', (119, 123))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('isocitrate dehydrogenase', 'Gene', (171, 195))	('IDH', 'Gene', '3417', (197, 200))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (149, 156))	('EGFR', 'Gene', '1956', (119, 123))	('low gliomas', 'Disease', 'MESH:D005910', (145, 156))
207981	32687065	Besides, in diffuse gliomas, high expression of PDIA3 has an influence on glioma progression and predicts worse survival outcome and therapeutic response of glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('high expression', 'Var', (29, 44))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('influence', 'Reg', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioma', 'Disease', (74, 80))	('PDIA3', 'Gene', (48, 53))	('glioma', 'Disease', (20, 26))	('glioma', 'Disease', (157, 163))	('patients', 'Species', '9606', (164, 172))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
207986	32687065	PDIA3 expression was enriched in higher histopathologic malignancies (Supplementary Figure 1D) and 1p/19q non-codeletion cases (Figure 1B).	('PDIA3', 'Gene', (0, 5))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('histopathologic malignancies', 'Phenotype', 'HP:0002664', (40, 68))	('malignancies', 'Disease', (56, 68))	('1p/19q', 'Var', (99, 105))
207987	32687065	Furthermore, Some genetic alterations including IDH mutation and 1p/19q codeletion were significantly associated with heterogeneous tumor histology based on 2016 WHO classification.	('1p/19q codeletion', 'Var', (65, 82))	('IDH', 'Gene', (48, 51))	('associated', 'Reg', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('IDH', 'Gene', '3417', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))
207990	32687065	Except genetic alternations, epigenetic alterations including DNA methylation equally facilitate carcinogenesis.	('facilitate', 'PosReg', (86, 96))	('DNA methylation', 'Var', (62, 77))	('carcinogenesis', 'Disease', (97, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
208004	32687065	In pan-glioma analysis of both TCGA and CGGA datasets, the overall survival (OS) of patients with high PDIA3 expression was significantly lower than that of patients with low PDIA3 expression (Figure 2A, 2D).	('patients', 'Species', '9606', (84, 92))	('glioma', 'Disease', 'MESH:D005910', (7, 13))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('high', 'Var', (98, 102))	('lower', 'NegReg', (138, 143))	('patients', 'Species', '9606', (157, 165))	('PDIA3', 'Gene', (103, 108))	('overall survival', 'MPA', (59, 75))	('glioma', 'Disease', (7, 13))
208013	32687065	The high PDIA3 expression cluster frequently showed amplification of chr7 and deletion of chr10, both of which were typical genomic events in GBM (Figure 3A); while deletion of 1p and 19q, a genomic hallmark of oligodendroglioma, occurred more frequently in PDIA3 low cluster (Figure 3B).	('chr10', 'Gene', (90, 95))	('deletion', 'Var', (78, 86))	('chr7', 'Gene', (69, 73))	('amplification', 'MPA', (52, 65))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))	('hallmark of oligodendroglioma', 'Disease', 'MESH:D009837', (199, 228))	('hallmark of oligodendroglioma', 'Disease', (199, 228))	('PDIA3', 'Gene', (9, 14))
208014	32687065	In high PDIA3 expression samples, frequently amplified genomic regions, containing oncogenic driver genes such as PDGFRA (4q12), EGFR (7p11.2) and CDK4 (12q14.1), were accompanied by CDKN2A/CDKN2B (9p21.3) and PTEN (10q23.3) deletion peaks.	('PTEN', 'Gene', '5728', (210, 214))	('CDKN2A', 'Gene', (183, 189))	('CDKN2B', 'Gene', (190, 196))	('deletion', 'Var', (225, 233))	('PDIA3', 'Gene', (8, 13))	('CDKN2A', 'Gene', '1029', (183, 189))	('CDK4', 'Gene', '1019', (147, 151))	('CDKN2B', 'Gene', '1030', (190, 196))	('PDGFRA', 'Gene', '5156', (114, 120))	('PDGFRA', 'Gene', (114, 120))	('EGFR', 'Gene', '1956', (129, 133))	('CDK4', 'Gene', (147, 151))	('EGFR', 'Gene', (129, 133))	('PTEN', 'Gene', (210, 214))
208015	32687065	Furthermore, analysis of somatic mutation profiles indicated a high frequency of mutations in EGFR (28%), TTN (23%), PTEN (22%) and NF1 (16%) in the high PDIA3 expression cluster, while IDH1 (80%), ATRX (32%), CIC (18%) were more frequently mutated in the PDIA3 low expression cluster (Figure 3C).	('IDH1', 'Gene', (186, 190))	('NF1', 'Gene', '4763', (132, 135))	('PTEN', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (94, 98))	('ATRX', 'Gene', '546', (198, 202))	('IDH1', 'Gene', '3417', (186, 190))	('TTN', 'Gene', (106, 109))	('CIC', 'Disease', (210, 213))	('PTEN', 'Gene', '5728', (117, 121))	('EGFR', 'Gene', (94, 98))	('TTN', 'Gene', '7273', (106, 109))	('CIC', 'Disease', 'None', (210, 213))	('mutations', 'Var', (81, 90))	('ATRX', 'Gene', (198, 202))	('NF1', 'Gene', (132, 135))
208023	32687065	Additionally, in the 10-immune cell lineage analysis, high PDIA3 expression gliomas were highly correlated with several stromal cells, including epithelial cells, astrocytes and fibroblasts (Supplementary Figure 7A-7D).	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('high PDIA3 expression', 'Var', (54, 75))
208026	32687065	To confirm whether PDIA3 was involved in T cell immunity, we performed GSVA analysis in TCGA cohort and found that PDIA3 was correlated with negative regulation of T cell mediated cytotoxicity and negative regulation of T cell proliferation (Figure 6A).	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('GSVA', 'Chemical', '-', (71, 75))	('T cell proliferation', 'CPA', (220, 240))	('negative', 'NegReg', (141, 149))	('PDIA3', 'Var', (115, 120))	('negative', 'NegReg', (197, 205))	('cytotoxicity', 'Disease', (180, 192))
208039	32687065	And methylation at cg12737574 and cg17847446 might be the potential regulatory element at higher PDIA3 expression levels in GBM.	('cg17847446', 'Chemical', '-', (34, 44))	('cg12737574', 'Chemical', '-', (19, 29))	('cg17847446', 'Var', (34, 44))	('cg12737574', 'Var', (19, 29))
208042	32687065	Overexpression of PDIA3 is relevant to worse prognosis in cancers including laryngeal cancer, breast cancer, cervical cancer, and epithelial ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (130, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cervical cancer', 'Disease', 'MESH:D002583', (109, 124))	('cervical cancer', 'Disease', (109, 124))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (76, 92))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Disease', (94, 107))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (130, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('PDIA3', 'Gene', (18, 23))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('epithelial ovarian cancer', 'Disease', (130, 155))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
208043	32687065	Critically, our findings also showed that high expression of PDIA3 was correlated with worse survival in TCGA and CGGA database.	('Critically', 'Disease', (0, 10))	('PDIA3', 'Gene', (61, 66))	('worse', 'NegReg', (87, 92))	('high', 'Var', (42, 46))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('expression', 'MPA', (47, 57))
208058	32687065	PDIA3 was positively associated with high malignancy of gliomas and worse survival of glioma patients.	('malignancy of gliomas', 'Phenotype', 'HP:0012174', (42, 63))	('glioma', 'Disease', (86, 92))	('glioma', 'Disease', (56, 62))	('PDIA3', 'Var', (0, 5))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('malignancy of gliomas', 'Disease', (42, 63))	('patients', 'Species', '9606', (93, 101))	('malignancy of gliomas', 'Disease', 'MESH:D005910', (42, 63))
208075	31731729	To investigate the possible mechanisms by which IL18 expression increased patient survival, we then assessed the correlation between IL18 expression and immune cell infiltration levels.	('patient', 'Species', '9606', (74, 81))	('IL18', 'Gene', '3606', (48, 52))	('expression', 'Var', (53, 63))	('IL18', 'Gene', (133, 137))	('cor', 'Chemical', '-', (113, 116))	('IL18', 'Gene', '3606', (133, 137))	('increased', 'PosReg', (64, 73))	('IL18', 'Gene', (48, 52))
208076	31731729	Infiltration of various immune cells, especially CD8+ T and natural killer (NK) cells, which are cytolytic effector cells, was significantly increased by IL18 expression.	('increased', 'PosReg', (141, 150))	('IL18', 'Gene', (154, 158))	('Infiltration of', 'CPA', (0, 15))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (49, 52))	('expression', 'Var', (159, 169))	('IL18', 'Gene', '3606', (154, 158))
208091	31731729	Exogenous IL-18 directly enhances the migration and invasion of a melanoma cell line, B16F10, suggesting that IL-18 has critical roles in melanoma malignancy.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('Exogenous', 'Var', (0, 9))	('IL-18', 'Gene', (10, 15))	('melanoma', 'Disease', (138, 146))	('melanoma', 'Disease', (66, 74))	('B16F10', 'CellLine', 'CVCL:0159', (86, 92))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma malignancy', 'Disease', 'MESH:D008545', (138, 157))	('enhances', 'PosReg', (25, 33))	('invasion', 'CPA', (52, 60))	('melanoma malignancy', 'Disease', (138, 157))	('migration', 'CPA', (38, 47))
208120	31731729	IL18 expression was examined for each alteration status (deep deletion, shallow deletion, diploid, and gain) and plotted.	('shallow deletion', 'Var', (72, 88))	('gain', 'PosReg', (103, 107))	('deep deletion', 'Var', (57, 70))	('IL18', 'Gene', (0, 4))	('IL18', 'Gene', '3606', (0, 4))
208136	31731729	As shown in Figure 2a-c, high IL18 expression was associated with longer survival in SKCM, SARC, and BRCA, leading to a good prognosis (Log-rank P < 0.05).	('expression', 'MPA', (35, 45))	('BRCA', 'Gene', '672', (101, 105))	('high', 'Var', (25, 29))	('IL18', 'Gene', (30, 34))	('BRCA', 'Gene', (101, 105))	('SKCM', 'Disease', (85, 89))	('longer', 'PosReg', (66, 72))	('IL18', 'Gene', '3606', (30, 34))	('SARC', 'Disease', (91, 95))
208137	31731729	In contrast, poor prognosis in two types of cancer, LGG and PAAD, were correlated with high IL18 expression (Log-rank P < 0.05, Figure 2d,e).	('cor', 'Chemical', '-', (71, 74))	('IL18', 'Gene', (92, 96))	('cancer', 'Disease', (44, 50))	('PAAD', 'Disease', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('LGG', 'Disease', (52, 55))	('IL18', 'Gene', '3606', (92, 96))	('high', 'Var', (87, 91))	('expression', 'MPA', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
208146	31731729	In the Tumor Melanoma Metastatic-Bhardwaj-44 dataset, patients with high IL18 expression (n = 16) had significantly higher overall survival than patients with lower IL18 expression (n = 28) (Figure 3c).	('patients', 'Species', '9606', (145, 153))	('Tumor Melanoma', 'Phenotype', 'HP:0002861', (7, 21))	('IL18', 'Gene', '3606', (73, 77))	('Tumor', 'Phenotype', 'HP:0002664', (7, 12))	('high', 'Var', (68, 72))	('higher', 'PosReg', (116, 122))	('patients', 'Species', '9606', (54, 62))	('Melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('Tumor Melanoma', 'Disease', 'MESH:D008545', (7, 21))	('IL18', 'Gene', (165, 169))	('overall survival', 'MPA', (123, 139))	('Tumor Melanoma', 'Disease', (7, 21))	('IL18', 'Gene', (73, 77))	('IL18', 'Gene', '3606', (165, 169))
208149	31731729	Five missense mutations were found in the IL18 coding region.	('missense mutations', 'Var', (5, 23))	('IL18', 'Gene', (42, 46))	('IL18', 'Gene', '3606', (42, 46))
208151	31731729	In total, 4.69% of IL18 genes were altered, consisting of 1.38% mutations, 3.31% deep deletions, and 3.31% of mRNA high (Figure 3e).	('altered', 'Reg', (35, 42))	('IL18', 'Gene', (19, 23))	('IL18', 'Gene', '3606', (19, 23))	('deep deletions', 'Var', (81, 95))	('mutations', 'Var', (64, 73))	('mRNA high', 'Var', (110, 119))
208153	31731729	Figure 3f shows that IL18 expression was significantly lower in the deep-deletion samples than the shallow deletion and diploid samples.	('expression', 'MPA', (26, 36))	('IL18', 'Gene', (21, 25))	('lower', 'NegReg', (55, 60))	('IL18', 'Gene', '3606', (21, 25))	('deep-deletion', 'Var', (68, 81))
208155	31731729	These data implied deep deletion CNA status could partially contribute that lower expression of IL18 in melanoma.	('IL18', 'Gene', '3606', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('expression', 'MPA', (82, 92))	('deep deletion', 'Var', (19, 32))	('lower', 'NegReg', (76, 81))	('IL18', 'Gene', (96, 100))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
208188	31731729	Additionally, gammadelta T cells could be a better prognostic indicator in cancer than CD8+ T cells and NK cells.	('gammadelta', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('CD8', 'Gene', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CD8', 'Gene', '925', (87, 90))
208189	31731729	Here, infiltration of anti-tumor effector cells, CD8+ T cells, NK cells, and gammadelta T cells was markedly increased by IL18 expression (Table 1, Supplementary Table S6 and S7).	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('S7', 'Gene', '6264', (175, 177))	('tumor', 'Disease', (27, 32))	('IL18', 'Gene', (122, 126))	('gammadelta T cells', 'CPA', (77, 95))	('CD8', 'Gene', (49, 52))	('infiltration', 'CPA', (6, 18))	('CD8', 'Gene', '925', (49, 52))	('IL18', 'Gene', '3606', (122, 126))	('NK cells', 'CPA', (63, 71))	('increased', 'PosReg', (109, 118))	('expression', 'Var', (127, 137))
208213	31731729	In vitro studies show the direct effects of exogenous IL-18 on melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('exogenous', 'Var', (44, 53))
208214	31731729	Exogenous IL-18 increases cell migration in the melanoma cell line B16F10, and cell adhesion in both murine and human melanoma cell lines, implying that IL-18 enhances malignant properties in melanoma cell.	('cell adhesion', 'CPA', (79, 92))	('malignant properties in', 'CPA', (168, 191))	('enhances', 'PosReg', (159, 167))	('human', 'Species', '9606', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('cell migration', 'CPA', (26, 40))	('murine', 'Species', '10090', (101, 107))	('increases', 'PosReg', (16, 25))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('IL-18', 'Gene', (10, 15))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('B16F10', 'CellLine', 'CVCL:0159', (67, 73))	('melanoma', 'Disease', (192, 200))	('IL-18', 'Var', (153, 158))
208217	31731729	In addition to the direct effects of IL-18 on NK cells, the expression of UL16 binding protein 2, which is a ligand for the NK cell-activating receptor, on tumor cells is increased by exogenous IL-18, leading to the increased NK cell cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (234, 246))	('expression', 'MPA', (60, 70))	('NK cell-activating receptor', 'Gene', (124, 151))	('exogenous', 'Var', (184, 193))	('NK cell-activating receptor', 'Gene', '9437', (124, 151))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('UL16 binding protein 2', 'Gene', (74, 96))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cytotoxicity', 'Disease', (234, 246))	('tumor', 'Disease', (156, 161))	('UL16 binding protein 2', 'Gene', '80328', (74, 96))	('increased', 'PosReg', (171, 180))	('increased', 'PosReg', (216, 225))
208223	31731729	Also, overexpression of IL-18 in a mouse model of malignant melanoma has been shown to increase tumor cell apoptosis, inhibit tumor growth, reduce lung metastasis, and inhibit angiogenesis, implying that IL-18 shows systemically a significant anti-cancer effect in the body.	('IL-18', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('increase', 'PosReg', (87, 95))	('overexpression', 'Var', (6, 20))	('malignant melanoma', 'Phenotype', 'HP:0002861', (50, 68))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('angiogenesis', 'CPA', (176, 188))	('malignant melanoma', 'Disease', 'MESH:D008545', (50, 68))	('cancer', 'Disease', (248, 254))	('inhibit', 'NegReg', (118, 125))	('reduce', 'NegReg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung metastasis', 'CPA', (147, 162))	('tumor', 'Disease', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Disease', (126, 131))	('malignant melanoma', 'Disease', (50, 68))	('mouse', 'Species', '10090', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('inhibit', 'NegReg', (168, 175))
208245	31731729	As such, this study provided the first clinical significance that IL18 expression could be a good prognostic factor in patients with SKCM via inducing immune cell infiltration; however, there are some limitations.	('IL18', 'Gene', '3606', (66, 70))	('inducing', 'Reg', (142, 150))	('expression', 'Var', (71, 81))	('patients', 'Species', '9606', (119, 127))	('SKCM', 'Disease', (133, 137))	('immune cell infiltration', 'CPA', (151, 175))	('IL18', 'Gene', (66, 70))
208312	28918564	According to the literature we reviewed in this study, 18F-FDG PET-CT is superior in the diagnosis of gliomas to conventional MRI.	('18F-FDG', 'Chemical', '-', (55, 62))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('18F-FDG', 'Var', (55, 62))	('gliomas', 'Disease', (102, 109))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))
208332	28918564	In many situations, 11C-MET-PET can form a tumor range larger than Gd does.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('11C-MET-PET', 'Var', (20, 31))	('11C-MET', 'Chemical', '-', (20, 27))	('tumor', 'Disease', (43, 48))
208333	28918564	The larger of the actual tumor diameter, the bigger the discrepancy between 11C-MET-PET and enhanced MRI there will be.	('11C-MET', 'Chemical', '-', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('actual tumor', 'Disease', 'MESH:D009369', (18, 30))	('actual tumor', 'Disease', (18, 30))	('11C-MET-PET', 'Var', (76, 87))	('MRI', 'MPA', (101, 104))	('enhanced', 'PosReg', (92, 100))
208334	28918564	Existing studies have shown that (1) the tumor margin of 11C-MET-PET is larger than that of enhanced MRI and (2) there are scenarios where the conclusion of enhanced MRI is radiation necrosis but 11C-MET-PET concludes that there is a tumor.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (234, 239))	('11C-MET-PET', 'Var', (57, 68))	('tumor', 'Disease', (41, 46))	('11C-MET', 'Chemical', '-', (57, 64))	('radiation necrosis', 'Disease', 'MESH:D004194', (173, 191))	('radiation necrosis', 'Disease', (173, 191))	('11C-MET', 'Chemical', '-', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
208338	28918564	But there are some cases where tumor ranges of 11C-MET-PET displaying in some areas more than that of T2-high areas, indicating that the actual margin of GBM remains beyond T2-high area.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('11C-MET-PET', 'Var', (47, 58))	('11C-MET', 'Chemical', '-', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
208339	28918564	T2-high area exceeding 11C-MET-PET displaying range is considered as peritumoral edema.	('peritumoral edema', 'Disease', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('11C-MET', 'Chemical', '-', (23, 30))	('edema', 'Phenotype', 'HP:0000969', (81, 86))	('peritumoral edema', 'Disease', 'MESH:D004487', (69, 86))	('T2-high', 'Var', (0, 7))
208340	28918564	In low-grade gliomas, the tumor range depicted by T2-weighted MRI is larger than the display range of 11C-MET-PET.	('T2-weighted', 'Var', (50, 61))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('11C-MET', 'Chemical', '-', (102, 109))	('gliomas', 'Disease', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
208348	28918564	18F-FET-PET in conjunction with conventional MRI is often able to achieve higher diagnostic accuracy for glioma diagnosis, while MRI alone is difficult to achieve the same result.	('higher', 'PosReg', (74, 80))	('glioma', 'Disease', (105, 111))	('18F-FET-PET', 'Var', (0, 11))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
208378	28918564	But with the absence of contrast enhancement or in low-grade glioma patients, 11C-MET-PET can predict survival.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('survival', 'Disease', (102, 110))	('predict', 'Reg', (94, 101))	('11C-MET-PET', 'Var', (78, 89))	('11C-MET', 'Chemical', '-', (78, 85))	('glioma', 'Disease', (61, 67))	('patients', 'Species', '9606', (68, 76))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
208379	28918564	In our review of relevant studies, 11C-MET-PET has a greater advantage than 18F-FDG-PET and MRI for low-grade glioma survival prediction.	('18F-FDG', 'Chemical', '-', (76, 83))	('glioma', 'Disease', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('11C-MET', 'Chemical', '-', (35, 42))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('11C-MET-PET', 'Var', (35, 46))
208380	28918564	Moreover, 11C-MET-PET is not only stronger than conventional imaging in providing prognostic information, but also stronger than the histopathology.	('11C-MET-PET', 'Var', (10, 21))	('11C-MET', 'Chemical', '-', (10, 17))	('stronger', 'PosReg', (115, 123))
208382	28918564	Therefore, 11C-MET-PET for high-grade gliomas provides no prognostic value.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('11C-MET-PET', 'Var', (11, 22))	('11C-MET', 'Chemical', '-', (11, 18))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
208387	28918564	Furthermore, studies show that 18F-FET-PET has a higher detection rate of high-grade gliomas compared to 18F-FLT-PET.	('gliomas', 'Disease', (85, 92))	('FLT', 'Gene', '2321', (109, 112))	('18F-FET-PET', 'Var', (31, 42))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('FLT', 'Gene', (109, 112))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
208419	28918564	When concerning about the four different tracers of PET-CT, 18F-FDG PET-CT and 11C-MET PET-CT are two basic types of PET-CT scans.	('11C-MET', 'Var', (79, 86))	('18F-FDG', 'Var', (60, 67))	('18F-FDG', 'Chemical', '-', (60, 67))	('11C-MET', 'Chemical', '-', (79, 86))
208422	28918564	Both 18F-FDG PET-CT and 11C-MET PET-CT can give information on the grade prediction of gliomas based on the tracer uptake.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('11C-MET', 'Var', (24, 31))	('18F-FDG', 'Chemical', '-', (5, 12))	('11C-MET', 'Chemical', '-', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('gliomas', 'Disease', (87, 94))
208428	29751795	Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose Glutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements.	('GOT1', 'Gene', '2805', (179, 183))	('Glutamate oxaloacetate transaminase 1', 'Gene', '2805', (140, 177))	('glutamate oxaloacetate transaminase 1', 'Gene', (14, 51))	('glucose', 'Chemical', 'MESH:D005947', (132, 139))	('regulates', 'Reg', (185, 194))	('increased', 'PosReg', (108, 117))	('glutamate oxaloacetate transaminase 1', 'Gene', '2805', (14, 51))	('cancer', 'Disease', (55, 61))	('cellular metabolism', 'MPA', (195, 214))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('utilization', 'MPA', (240, 251))	('altered', 'Reg', (84, 91))	('Inhibition', 'Var', (0, 10))	('carbohydrates', 'Chemical', 'MESH:D002241', (255, 268))	('Glutamate oxaloacetate transaminase 1', 'Gene', (140, 177))	('metabolism', 'MPA', (92, 102))	('dependency', 'MPA', (118, 128))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('GOT1', 'Gene', (179, 183))
208436	29751795	Inhibition of GOT1 sensitized the cancer cells to glucose deprivation, which was partially counteracted by oxaloacetate and phosphoenol pyruvate, metabolic intermediates downstream of GOT1.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('GOT1', 'Gene', '2805', (184, 188))	('GOT1', 'Gene', (184, 188))	('oxaloacetate', 'Chemical', 'MESH:D062907', (107, 119))	('glucose deprivation', 'Disease', 'MESH:D012892', (50, 69))	('phosphoenol pyruvate', 'Chemical', 'MESH:D010728', (124, 144))	('glucose deprivation', 'Disease', (50, 69))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('Inhibition', 'Var', (0, 10))	('GOT1', 'Gene', '2805', (14, 18))	('sensitized', 'Reg', (19, 29))	('GOT1', 'Gene', (14, 18))
208440	29751795	Our study suggests an important role of GOT1 to coordinate the glycolytic and the oxidative phosphorylation pathways in KRAS mutated cancer cells.	('GOT1', 'Gene', '2805', (40, 44))	('glycolytic', 'MPA', (63, 73))	('mutated', 'Var', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('GOT1', 'Gene', (40, 44))	('cancer', 'Disease', (133, 139))	('KRAS', 'Gene', (120, 124))	('KRAS', 'Gene', '3845', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('oxidative phosphorylation pathways', 'Pathway', (82, 116))
208444	29751795	Evidence shows that cancer cells with a KRAS mutation or an electron transport chain defect depended on glutamate oxaloacetate transaminase 1 (GOT1) to support cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('glutamate oxaloacetate transaminase 1', 'Gene', (104, 141))	('electron', 'Enzyme', (60, 68))	('KRAS', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('GOT1', 'Gene', '2805', (143, 147))	('mutation', 'Var', (45, 53))	('cancer', 'Disease', (20, 26))	('GOT1', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (40, 44))	('cell proliferation', 'CPA', (160, 178))	('glutamate oxaloacetate transaminase 1', 'Gene', '2805', (104, 141))	('defect', 'NegReg', (85, 91))	('depended', 'Reg', (92, 100))
208449	29751795	Interestingly, in contrast to PDAC cells, where aspartate was converted to OAA by GOT1, cancer cells with defects in the electron transport chain reversibly used GOT1 to provide aspartate from OAA to maintain cell growth.	('aspartate', 'MPA', (178, 187))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('GOT1', 'Gene', (162, 166))	('GOT1', 'Gene', '2805', (82, 86))	('aspartate', 'Chemical', 'MESH:D001224', (178, 187))	('OAA', 'Chemical', 'MESH:D062907', (193, 196))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('GOT1', 'Gene', (82, 86))	('OAA', 'Chemical', 'MESH:D062907', (75, 78))	('GOT1', 'Gene', '2805', (162, 166))	('aspartate', 'Chemical', 'MESH:D001224', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('defects', 'Var', (106, 113))
208457	29751795	Inhibition of GOT1 leads to increased glucose consumption and lactate secretion rates.	('increased', 'PosReg', (28, 37))	('glucose', 'Chemical', 'MESH:D005947', (38, 45))	('glucose consumption', 'MPA', (38, 57))	('Inhibition', 'Var', (0, 10))	('GOT1', 'Gene', '2805', (14, 18))	('lactate', 'Chemical', 'MESH:D019344', (62, 69))	('increased glucose', 'Phenotype', 'HP:0003074', (28, 45))	('lactate secretion rates', 'MPA', (62, 85))	('GOT1', 'Gene', (14, 18))
208498	29751795	To study autophagy in GOT1-null cells, the primary antibody was anti-LC3 (Sigma, L8918), and the secondary antibody was donkey anti-rabbit (Santa Cruz).	('rabbit', 'Species', '9986', (132, 138))	('GOT1', 'Gene', '2805', (22, 26))	('GOT1', 'Gene', (22, 26))	('anti-LC3', 'Var', (64, 72))	('donkey', 'Species', '9793', (120, 126))
208505	29751795	For GOT1 siRNA knock-down A549 cells, the same number of non-template control (NTC) cells and siRNA-1 cells were seeded in 96-well plates in triplicate.	('GOT1', 'Gene', '2805', (4, 8))	('GOT1', 'Gene', (4, 8))	('A549', 'CellLine', 'CVCL:0023', (26, 30))	('knock-down', 'Var', (15, 25))
208529	29751795	A deletion was introduced into exon 1 of GOT1 in the 143B osteosarcoma cell line, which led to a reading frame-shift mutation (Fig.	('led to a', 'Reg', (88, 96))	('osteosarcoma', 'Disease', (58, 70))	('deletion', 'Var', (2, 10))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('GOT1', 'Gene', '2805', (41, 45))	('GOT1', 'Gene', (41, 45))
208531	29751795	The mutation also decreased the stability of the GOT1 mRNA with a transcript level almost undetectable as compared to the wild type control cells (Fig.	('stability', 'MPA', (32, 41))	('transcript level', 'MPA', (66, 82))	('decreased', 'NegReg', (18, 27))	('mutation', 'Var', (4, 12))	('GOT1', 'Gene', '2805', (49, 53))	('GOT1', 'Gene', (49, 53))
208532	29751795	Cells with mutated GOT1 showed slower growth, formation of fewer colonies in soft agar and impaired cell migration in soft agar as compared to wild type cells (Fig.	('agar', 'Chemical', 'MESH:D000362', (123, 127))	('agar', 'Chemical', 'MESH:D000362', (82, 86))	('GOT1', 'Gene', '2805', (19, 23))	('GOT1', 'Gene', (19, 23))	('impaired', 'NegReg', (91, 99))	('cell migration in soft agar', 'CPA', (100, 127))	('slower', 'NegReg', (31, 37))	('colonies in soft agar', 'CPA', (65, 86))	('fewer', 'NegReg', (59, 64))	('mutated', 'Var', (11, 18))	('growth', 'CPA', (38, 44))
208533	29751795	The growth inhibitory effect was confirmed with aminooxyacetate (AOA), a GOT1 inhibitor (Fig1g and h) and in siRNA knockdown of GOT1 in 143B and A549 cell lines (Additional file 1: Figure S1a-f).	('GOT1', 'Gene', (128, 132))	('aminooxyacetate', 'Chemical', 'MESH:D000625', (48, 63))	('GOT1', 'Gene', (73, 77))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('growth inhibitory', 'MPA', (4, 21))	('GOT1', 'Gene', '2805', (128, 132))	('GOT1', 'Gene', '2805', (73, 77))	('knockdown', 'Var', (115, 124))
208538	29751795	Western blot analysis showed that inhibition of GOT1 led to signs of autophagy with increased ratios between the activated and inactivated forms of the autophagosome protein LC3A upon glucose deprivation (Fig.	('glucose deprivation', 'Disease', 'MESH:D012892', (184, 203))	('autophagy', 'CPA', (69, 78))	('LC3A', 'Gene', (174, 178))	('inhibition', 'Var', (34, 44))	('glucose deprivation', 'Disease', (184, 203))	('LC3A', 'Gene', '84557', (174, 178))	('ratios', 'MPA', (94, 100))	('increased', 'PosReg', (84, 93))	('GOT1', 'Gene', '2805', (48, 52))	('GOT1', 'Gene', (48, 52))
208595	29751795	The analysis of overall survival rate also indicated that a high level of GOT1 expression was linked to poor survival rate in certain types of tumors, including thyroid carcinoma, breast invasive carcinoma and lung cancer (Fig.	('expression', 'Species', '29278', (79, 89))	('breast invasive carcinoma and lung cancer', 'Disease', 'MESH:D008175', (180, 221))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('high', 'Var', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumors', 'Disease', (143, 149))	('GOT1', 'Gene', '2805', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('GOT1', 'Gene', (74, 78))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (161, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (161, 178))	('poor', 'NegReg', (104, 108))	('expression', 'Var', (79, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('thyroid carcinoma', 'Disease', (161, 178))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
208600	29751795	Inhibition of GOT1 led to glucose dependency and increased vulnerability to low nutrient levels.	('vulnerability to low nutrient levels', 'MPA', (59, 95))	('increased', 'PosReg', (49, 58))	('glucose dependency', 'Disease', (26, 44))	('glucose dependency', 'Disease', 'MESH:D019966', (26, 44))	('Inhibition', 'Var', (0, 10))	('GOT1', 'Gene', '2805', (14, 18))	('GOT1', 'Gene', (14, 18))
208601	29751795	We found that knockout of GOT1 had neglectable effect on cell growth and survival when nutrients are sufficient.	('cell growth', 'CPA', (57, 68))	('GOT1', 'Gene', '2805', (26, 30))	('survival', 'CPA', (73, 81))	('GOT1', 'Gene', (26, 30))	('knockout', 'Var', (14, 22))
208603	29751795	Withdrawal of glucose led to rapid death of both GOT1-null 143B and GOT1 siRNA knockdown A549 cancer cells compared to their controls.	('GOT1', 'Gene', '2805', (49, 53))	('A549 cancer', 'Disease', 'MESH:D009369', (89, 100))	('GOT1', 'Gene', '2805', (68, 72))	('GOT1', 'Gene', (49, 53))	('GOT1', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('knockdown', 'Var', (79, 88))	('A549 cancer', 'Disease', (89, 100))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))
208611	29751795	Although gluconeogenesis has been thought to exclusively occur in certain organs, PEPCK, the mitochondrial isoform of PEPCK and fructose-1,6-bisphophatase, are key enzymes in the gluconeogenesis pathway that have been shown to be involved in cancer cell proliferation and inhibition of those enzymes significantly inhibited cancer growth.	('cancer', 'Disease', (324, 330))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('PEPCK', 'Gene', '5106', (82, 87))	('PEPCK', 'Gene', (118, 123))	('involved', 'Reg', (230, 238))	('PEPCK', 'Gene', (82, 87))	('PEPCK', 'Gene', '5106', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('inhibition', 'Var', (272, 282))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('inhibited', 'NegReg', (314, 323))
208631	29751795	Furthermore, inhibition of GOT1 led to rapid ischemic-like cell death upon glucose deprivation and only OAA and PEP were able to fully prevent, and NAD+ partially prevent such morphological changes.	('glucose deprivation', 'Disease', 'MESH:D012892', (75, 94))	('OAA', 'Chemical', 'MESH:D062907', (104, 107))	('inhibition', 'Var', (13, 23))	('ischemic', 'Disease', (45, 53))	('glucose deprivation', 'Disease', (75, 94))	('PEP', 'Chemical', 'MESH:D010728', (112, 115))	('GOT1', 'Gene', '2805', (27, 31))	('NAD+', 'Chemical', 'MESH:D009243', (148, 152))	('GOT1', 'Gene', (27, 31))	('ischemic', 'Disease', 'MESH:D007511', (45, 53))
208645	24212955	Aberrant Signaling Pathways in Glioma Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available.	('Glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('Aberrant', 'Var', (0, 8))	('brain tumor', 'Disease', (140, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('malignant glioma', 'Disease', 'MESH:D005910', (84, 100))	('brain tumor', 'Disease', 'MESH:D001932', (140, 151))	('Glioma', 'Disease', 'MESH:D005910', (31, 37))	('malignant glioma', 'Disease', (84, 100))	('Glioblastoma multiforme', 'Disease', (38, 61))	('Glioma', 'Phenotype', 'HP:0009733', (31, 37))	('brain tumor', 'Phenotype', 'HP:0030692', (140, 151))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('Glioma', 'Disease', (31, 37))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (38, 61))
208652	24212955	The pathogenesis of GBM is complex due to a highly deregulated tumor genome with opportunistic deletion of tumor suppressor genes, amplification, and/or mutational hyper-activation of oncogenes, which are involved in a network of interconnected signaling pathways.	('GBM', 'Disease', (20, 23))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('deletion', 'Var', (95, 103))	('mutational hyper-activation', 'Var', (153, 180))	('amplification', 'Gene', (131, 144))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('deregulated', 'PosReg', (51, 62))	('oncogenes', 'Gene', (184, 193))
208683	24212955	Alterations of at least one component of this pathway occur in many anaplastic astrocytomas and in the vast majority of GBMs.	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (68, 90))	('astrocytomas', 'Disease', 'MESH:D001254', (79, 91))	('Alterations', 'Var', (0, 11))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('astrocytomas', 'Disease', (79, 91))	('anaplastic astrocytoma', 'Disease', (68, 90))	('occur', 'Reg', (54, 59))
208685	24212955	It is likely as well that less profound defects in cell cycle regulation occur in low-grade gliomas; for instance, p53 gene mutations may affect both the G1-S and G2-M checkpoints.	('mutations', 'Var', (124, 133))	('G2-M checkpoints', 'CPA', (163, 179))	('affect', 'Reg', (138, 144))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('gliomas', 'Disease', (92, 99))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('G1-S', 'CPA', (154, 158))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
208697	24212955	p53 mutations disturb the normal glial apoptotic response that would follow growth factor overexpression in low-grade gliomas, allowing further progression.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('glial apoptotic response', 'CPA', (33, 57))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('allowing', 'Reg', (127, 135))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('mutations', 'Var', (4, 13))	('disturb', 'Reg', (14, 21))
208700	24212955	Mutations in p53, also known as "guardian of the genome", may therefore lead to tumor progression through genomic instability.	('genomic instability', 'CPA', (106, 125))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('Mutations', 'Var', (0, 9))	('lead to', 'Reg', (72, 79))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))
208706	24212955	RTK activation in glioma can be achieved through protein overexpression or genetic amplification of several RTKs, and through gene mutations that lead to constitutive activity.	('overexpression', 'PosReg', (57, 71))	('glioma', 'Disease', (18, 24))	('RTK', 'Gene', (108, 111))	('constitutive', 'MPA', (154, 166))	('RTK', 'Gene', '5979', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('genetic amplification', 'Var', (75, 96))	('RTK', 'Gene', '5979', (108, 111))	('gene mutations', 'Var', (126, 140))	('RTK', 'Gene', (0, 3))	('activation', 'PosReg', (4, 14))
208707	24212955	In GBM, EGFR is dysregulated through overexpression, which arises because of EGFR gene amplification or activating mutations such as EGFRvIII that lead to ligand-independent signaling; this is the case in half of all GBM patients.	('GBM', 'Disease', (3, 6))	('patients', 'Species', '9606', (221, 229))	('mutations', 'Var', (115, 124))	('ligand-independent signaling', 'MPA', (155, 183))	('lead to', 'Reg', (147, 154))	('activating', 'PosReg', (104, 114))	('EGFR', 'Gene', (77, 81))	('amplification', 'Var', (87, 100))
208720	24212955	Because these signals result in cell growth and division, dysregulated Ras signaling can lead to oncogenesis and cancer.	('dysregulated', 'Var', (58, 70))	('division', 'CPA', (48, 56))	('cell growth', 'CPA', (32, 43))	('lead to', 'Reg', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('result in', 'Reg', (22, 31))	('cancer', 'Disease', (113, 119))	('oncogenesis', 'CPA', (97, 108))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
208728	24212955	GBM frequently contains alterations in PTEN (Phosphatase and Tensin Homolog Deleted from Chromosome 10) that is a lipid phosphatase and lead to activation of the Akt/mTOR pathway.	('alterations', 'Var', (24, 35))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('activation', 'PosReg', (144, 154))	('PTEN', 'Gene', (39, 43))	('PTEN', 'Gene', '5728', (39, 43))
208729	24212955	BRAF, v-RAF murine sarcoma viral oncogene homolog B1, is also an STK and a member of the RAS/RAF/MEK (MAPK kinase)/MAPK pathway that is commonly activated by somatic point mutation V600E in pilocytic astrocytoma.	('activated', 'PosReg', (145, 154))	('v-RAF murine sarcoma viral oncogene homolog B1', 'Gene', '673', (6, 52))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (190, 211))	('STK', 'Gene', '19882', (65, 68))	('v-RAF murine sarcoma viral oncogene homolog B1', 'Gene', (6, 52))	('V600E', 'Mutation', 'rs113488022', (181, 186))	('astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('STK', 'Gene', (65, 68))	('pilocytic astrocytoma', 'Disease', (190, 211))	('V600E', 'Var', (181, 186))
208733	24212955	The PI3K pathway has been implicated in mediating the activation of NF-kappaB by PDGF, and inactivation of PTEN and PDGF expression may contribute to the high levels of NF-kappaB.	('PDGF', 'Gene', '5154', (81, 85))	('PTEN', 'Gene', (107, 111))	('NF-kappaB', 'Gene', (169, 178))	('PDGF', 'Gene', '5154', (116, 120))	('PTEN', 'Gene', '5728', (107, 111))	('NF-kappaB', 'Gene', '4790', (68, 77))	('NF-kappaB', 'Gene', (68, 77))	('activation', 'PosReg', (54, 64))	('PI3K pathway', 'Pathway', (4, 16))	('NF-kappaB', 'Gene', '4790', (169, 178))	('inactivation', 'Var', (91, 103))	('PDGF', 'Gene', (116, 120))	('PDGF', 'Gene', (81, 85))
208762	24212955	Overexpression of CD44 in glioma is related to invasion.	('related', 'Reg', (36, 43))	('invasion', 'Disease', (47, 55))	('glioma', 'Disease', (26, 32))	('Overexpression', 'Var', (0, 14))	('CD44', 'Gene', '960', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('CD44', 'Gene', (18, 22))
208771	24212955	In glioma cells, depletion of Rac1 expression by small interfering RNA reduces cell migration and invasion and strongly inhibits lamellipodia formation.	('RNA', 'Gene', (67, 70))	('inhibits', 'NegReg', (120, 128))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('cell migration', 'CPA', (79, 93))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('Rac1', 'Gene', '5879', (30, 34))	('small interfering', 'Var', (49, 66))	('Rac1', 'Gene', (30, 34))	('glioma', 'Disease', (3, 9))	('reduces', 'NegReg', (71, 78))	('depletion', 'MPA', (17, 26))	('lamellipodia formation', 'CPA', (129, 151))
208782	24212955	Inactivation of either Ras/Raf/MAPK or PI3K/Akt/mTOR triggered activation of the other, suggesting that there may be mutually inhibitory crosstalk between them (Figure 3).	('mTOR', 'Gene', '2475', (48, 52))	('Raf', 'Gene', '22882', (27, 30))	('mTOR', 'Gene', (48, 52))	('Raf', 'Gene', (27, 30))	('Inactivation', 'Var', (0, 12))	('activation', 'PosReg', (63, 73))
208788	24212955	Among all the RTK alterations, EGFR gene amplification is the most frequent alteration (approximately 40%) in GBM.	('RTK', 'Gene', (14, 17))	('alterations', 'Var', (18, 29))	('frequent', 'Reg', (67, 75))	('RTK', 'Gene', '5979', (14, 17))	('EGFR gene', 'Gene', (31, 40))
208789	24212955	Some reports have shown that GBM patients with EGFR overexpression or mutants have shorter survival, suggesting that alterations of EGFR may be correlated with increased aggressiveness of GBM.	('alterations', 'Var', (117, 128))	('aggressiveness', 'Phenotype', 'HP:0000718', (170, 184))	('mutants', 'Var', (70, 77))	('patients', 'Species', '9606', (33, 41))	('increased', 'PosReg', (160, 169))	('survival', 'MPA', (91, 99))	('aggressiveness', 'Disease', 'MESH:D001523', (170, 184))	('shorter', 'NegReg', (83, 90))	('EGFR', 'Gene', (132, 136))	('correlated', 'Reg', (144, 154))	('overexpression', 'PosReg', (52, 66))	('aggressiveness', 'Disease', (170, 184))	('EGFR', 'Gene', (47, 51))
208790	24212955	Despite the high frequency of amplification and rearrangement of the EGFR gene, EGFR inhibitors (e.g., Gefinitib, Erlotinib) have not elicited clinical responses in patients with GBMs in clinical trials.	('Gefinitib', 'Chemical', '-', (103, 112))	('EGFR', 'Gene', (69, 73))	('rearrangement', 'Var', (48, 61))	('amplification', 'Var', (30, 43))	('patients', 'Species', '9606', (165, 173))	('Erlotinib', 'Chemical', 'MESH:D000069347', (114, 123))
208792	24212955	PDGFRA amplification (14%), as well as IDH1 mutation, is a hallmark of the proneural subtype of GBM according to the TCGA consortium, suggesting the association of this subtype and secondary GBM.	('PDGFRA', 'Gene', (0, 6))	('mutation', 'Var', (44, 52))	('PDGFRA', 'Gene', '5156', (0, 6))	('IDH1', 'Gene', (39, 43))	('association', 'Interaction', (149, 160))	('IDH1', 'Gene', '3417', (39, 43))	('amplification', 'Var', (7, 20))	('secondary GBM', 'Disease', (181, 194))
208794	24212955	The binding of PI3Ks and RTKs results in activation of Akt through PiP3 and PDK1, which affects multiple cellular processes including cell survival, proliferation, and motility (Figure 6).	('cell survival', 'CPA', (134, 147))	('motility', 'CPA', (168, 176))	('PI3Ks', 'Var', (15, 20))	('PiP3', 'Gene', (67, 71))	('affects', 'Reg', (88, 95))	('RTK', 'Gene', '5979', (25, 28))	('binding', 'Interaction', (4, 11))	('Akt', 'Pathway', (55, 58))	('proliferation', 'CPA', (149, 162))	('activation', 'PosReg', (41, 51))	('RTK', 'Gene', (25, 28))	('PDK1', 'Gene', (76, 80))	('PDK1', 'Gene', '5163', (76, 80))
208796	24212955	Oncogenic mutations or gene amplification of PIK3CA has been reported in various neoplasms including human brain tumors.	('neoplasms', 'Disease', 'MESH:D009369', (81, 90))	('brain tumors', 'Disease', (107, 119))	('brain tumor', 'Phenotype', 'HP:0030692', (107, 118))	('neoplasms', 'Phenotype', 'HP:0002664', (81, 90))	('PIK3CA', 'Gene', (45, 51))	('human', 'Species', '9606', (101, 106))	('PIK3CA', 'Gene', '5290', (45, 51))	('brain tumors', 'Phenotype', 'HP:0030692', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('brain tumors', 'Disease', 'MESH:D001932', (107, 119))	('mutations', 'Var', (10, 19))	('gene amplification', 'Var', (23, 41))	('neoplasms', 'Disease', (81, 90))	('reported', 'Reg', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
208797	24212955	In primary GBM, PIK3CA mutations and amplification are observed in 5% and 13% of cases.	('primary GBM', 'Disease', (3, 14))	('PIK3CA', 'Gene', '5290', (16, 22))	('amplification', 'Var', (37, 50))	('mutations', 'Var', (23, 32))	('PIK3CA', 'Gene', (16, 22))	('observed', 'Reg', (55, 63))
208799	24212955	The TCGA analysis revealed that PIK3R1 mutations were found in 10% (9/91) of GBM cases.	('mutations', 'Var', (39, 48))	('GBM', 'Disease', (77, 80))	('found', 'Reg', (54, 59))	('PIK3R1', 'Gene', '5295', (32, 38))	('PIK3R1', 'Gene', (32, 38))
208800	24212955	First generation of the PI3K inhibitors, LY294002 and wortmannin were not applied for clinical trials because of problems in solubility, selectivity, and toxicity.	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('wortmannin', 'Chemical', 'MESH:D000077191', (54, 64))	('toxicity', 'Disease', (154, 162))	('LY294002', 'Chemical', 'MESH:C085911', (41, 49))	('LY294002', 'Var', (41, 49))
208801	24212955	To date, lots of PI3K inhibitors (many of them are PI3K/mTOR dual inhibitors) such as XL147, XL765 (Exelixis and Sanofi-Aventis), BKM120, BEZ235, BGT226 (Novartis), GDC0980 (Genentech), PKI587, PF04691502 (Pfizer), GSK2126458 (Glaxo-Smith-Kline) are currently undergoing Phase I/II trials for GBM patients.	('PF04691502', 'Var', (194, 204))	('Sanofi-Aventis', 'Disease', 'None', (113, 127))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('GBM', 'Disease', (293, 296))	('patients', 'Species', '9606', (297, 305))	('PKI587', 'Var', (186, 192))	('Sanofi-Aventis', 'Disease', (113, 127))	('BKM120', 'Var', (130, 136))	('GDC0980', 'Var', (165, 172))	('BGT226', 'Var', (146, 152))	('GSK2126458', 'Var', (215, 225))
208804	24212955	Homozygous deletion or mutation of PTEN is a common genetic feature in GBM (~40%), resulting in constitutive activation of the RTKs/PI3K/Akt pathway.	('RTK', 'Gene', '5979', (127, 130))	('mutation', 'Var', (23, 31))	('PTEN', 'Gene', (35, 39))	('activation', 'PosReg', (109, 119))	('PTEN', 'Gene', '5728', (35, 39))	('deletion', 'Var', (11, 19))	('RTK', 'Gene', (127, 130))
208805	24212955	Some reports implied that GBMs with EGFRvIII and intact PTEN are more likely to respond to EGFR inhibitors.	('EGFR', 'Gene', (91, 95))	('PTEN', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (56, 60))	('EGFRvIII', 'Var', (36, 44))	('respond to', 'MPA', (80, 90))
208821	24212955	Thus, inactivation of p14ARF/MDM2/p53 is caused by altered expression of any of the p53, MDM2, or p14ARF genes (Figure 7).	('p53', 'Gene', (34, 37))	('altered', 'Reg', (51, 58))	('p53', 'Gene', '7157', (34, 37))	('MDM2', 'Gene', (29, 33))	('MDM2', 'Gene', '4193', (29, 33))	('p14ARF', 'Gene', (98, 104))	('inactivation', 'Var', (6, 18))	('p14ARF', 'Gene', '1029', (22, 28))	('expression', 'MPA', (59, 69))	('MDM2', 'Gene', '4193', (89, 93))	('p53', 'Gene', (84, 87))	('MDM2', 'Gene', (89, 93))	('p53', 'Gene', '7157', (84, 87))	('p14ARF', 'Gene', '1029', (98, 104))	('p14ARF', 'Gene', (22, 28))
208823	24212955	IDH1 gene mutations at chromosome 2q33, which were identified in an analysis of 20,661 protein-coding genes in GBMs, are early events in the development of astrocytomas and constitute a remarkably reliable molecular signature of secondary GBMs as well as their precursor lesions.	('astrocytomas', 'Disease', (156, 168))	('astrocytomas', 'Disease', 'MESH:D001254', (156, 168))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('IDH1', 'Gene', '3417', (0, 4))
208824	24212955	The additional acquisition of a p53 mutation, which is a genetic event subsequent to the IDH1/2 mutations except in the case of Li-Fraumeni syndrome, may lead to astrocytic differentiation, while subsequent loss of 1p/19q favors the acquisition of an oligodendroglial phenotype.	('IDH1/2', 'Gene', '3417;3418', (89, 95))	('oligodendroglial', 'Disease', (251, 267))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (128, 148))	('astrocytic differentiation', 'CPA', (162, 188))	('mutation', 'Var', (36, 44))	('lead to', 'Reg', (154, 161))	('IDH1/2', 'Gene', (89, 95))	('p53', 'Gene', (32, 35))	('Li-Fraumeni syndrome', 'Disease', (128, 148))	('p53', 'Gene', '7157', (32, 35))	('oligodendroglial', 'Disease', 'None', (251, 267))	('mutations', 'Var', (96, 105))
208825	24212955	GBMs with IDH1/2 mutations frequently have p53 mutations, which are significantly associated.	('associated', 'Reg', (82, 92))	('IDH1/2', 'Gene', '3417;3418', (10, 16))	('mutations', 'Var', (47, 56))	('p53', 'Gene', (43, 46))	('IDH1/2', 'Gene', (10, 16))	('p53', 'Gene', '7157', (43, 46))	('mutations', 'Var', (17, 26))
208826	24212955	p53 mutations are also common in two-thirds of precursor low-grade diffuse astrocytomas; this frequency is similar to that in anaplastic astrocytomas and secondary GBMs.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('astrocytomas', 'Disease', 'MESH:D001254', (137, 149))	('astrocytomas', 'Disease', 'MESH:D001254', (75, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('anaplastic astrocytoma', 'Disease', (126, 148))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (126, 148))	('astrocytomas', 'Disease', (75, 87))	('astrocytomas', 'Disease', (137, 149))	('common', 'Reg', (23, 29))	('mutations', 'Var', (4, 13))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))
208827	24212955	p53 mutations also occur in primary GBMs, but at a significantly lower frequency (approx.	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('primary GBMs', 'Disease', (28, 40))	('mutations', 'Var', (4, 13))	('occur', 'Reg', (19, 24))
208828	24212955	In secondary GBMs, 57% of p53 mutations are located in the hotspot codons 248 and 273; however, in primary GBMs, mutations are more equally distributed through all exons, with only 17% occurring in codons 248 and 273.	('mutations', 'Var', (30, 39))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', (26, 29))
208829	24212955	The less-specific pattern of p53 mutations may constitute, at least in part, secondary events owing to increasing genomic instability during tumor development.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('genomic instability', 'CPA', (114, 133))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (141, 146))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (29, 32))
208833	24212955	p14ARF appears to be associated mostly with aberrant promoter methylation or hemizygous deletion, whereas mutational inactivation is rare.	('p14ARF', 'Gene', '1029', (0, 6))	('associated', 'Reg', (21, 31))	('hemizygous', 'Disease', (77, 87))	('p14ARF', 'Gene', (0, 6))	('aberrant', 'Var', (44, 52))
208836	24212955	reported that loss of the ATM/Chk2/p53 pathway components accelerates glioma development and contributes to radiation resistance.	('loss', 'Var', (14, 18))	('p53', 'Gene', (35, 38))	('glioma', 'Disease', (70, 76))	('p53', 'Gene', '7157', (35, 38))	('ATM', 'Gene', (26, 29))	('accelerates', 'PosReg', (58, 69))	('Chk2', 'Gene', '11200', (30, 34))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('Chk2', 'Gene', (30, 34))	('ATM', 'Gene', '472', (26, 29))	('contributes', 'Reg', (93, 104))	('radiation resistance', 'CPA', (108, 128))
208839	24212955	Although previous studies reported no or low frequency of Chk2 mutations (approx.	('mutations', 'Var', (63, 72))	('Chk2', 'Gene', (58, 62))	('Chk2', 'Gene', '11200', (58, 62))
208840	24212955	6%), 22% of glioma patients in the TCGA study presented single-copy loss of the chromosomal region containing Chk2, with a significant reduction of Chk2 mRNA, suggesting that it might represent an important tumor suppressor in a subset of glioma patients.	('Chk2', 'Gene', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('reduction', 'NegReg', (135, 144))	('mRNA', 'MPA', (153, 157))	('patients', 'Species', '9606', (19, 27))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('patients', 'Species', '9606', (246, 254))	('glioma', 'Disease', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('glioma', 'Disease', (239, 245))	('Chk2', 'Gene', '11200', (110, 114))	('tumor', 'Disease', (207, 212))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('single-copy loss', 'Var', (56, 72))	('Chk2', 'Gene', '11200', (148, 152))	('Chk2', 'Gene', (110, 114))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
208844	24212955	Thus, alteration of RB1, CDK4, or CDKN2A can cause dysregulation of the G1-S phase transition.	('RB1', 'Gene', '5925', (20, 23))	('CDKN2A', 'Gene', (34, 40))	('CDK4', 'Gene', '1019', (25, 29))	('CDKN2A', 'Gene', '1029', (34, 40))	('alteration', 'Var', (6, 16))	('CDK4', 'Gene', (25, 29))	('G1-S phase transition', 'CPA', (72, 93))	('cause', 'Reg', (45, 50))	('RB1', 'Gene', (20, 23))	('dysregulation', 'MPA', (51, 64))
208846	24212955	The TCGA pilot project revealed that the frequency of genetic alterations in the RB signaling pathway was 77%, containing CDKN2A homozygous deletion or mutations (52%), CDKN2B (p15INK4b) homozygous deletion (47%), CDKN2C (p18INK4c) homozygous deletion (2%), CDK4 amplification (18%), CCND2 (cyclin D2) amplification (2%), CDK6 amplification (1%), and RB1 mutation or homozygous deletion (11%).	('mutations', 'Var', (152, 161))	('CDKN2A', 'Gene', (122, 128))	('CDKN2B', 'Gene', '1030', (169, 175))	('RB1', 'Gene', '5925', (351, 354))	('p18INK4c', 'Gene', '1031', (222, 230))	('CDK4', 'Gene', (258, 262))	('p18INK4c', 'Gene', (222, 230))	('CDKN2C', 'Gene', (214, 220))	('CDKN2A', 'Gene', '1029', (122, 128))	('CDK4', 'Gene', '1019', (258, 262))	('RB signaling pathway', 'Pathway', (81, 101))	('cyclin D2', 'Gene', '894', (291, 300))	('CDK6', 'Gene', '1021', (322, 326))	('CDKN2C', 'Gene', '1031', (214, 220))	('p15INK4b', 'Gene', '1030', (177, 185))	('CDK6', 'Gene', (322, 326))	('CDKN2B', 'Gene', (169, 175))	('RB1', 'Gene', (351, 354))	('p15INK4b', 'Gene', (177, 185))	('CCND2', 'Gene', (284, 289))	('cyclin D2', 'Gene', (291, 300))	('amplification', 'PosReg', (302, 315))	('CCND2', 'Gene', '894', (284, 289))	('mutation', 'Var', (355, 363))	('alterations', 'Reg', (62, 73))
208847	24212955	Alteration of only the Rb pathway is insufficient to induce tumor formation.	('insufficient', 'Disease', (37, 49))	('Rb', 'Chemical', 'MESH:D012413', (23, 25))	('Rb pathway', 'Pathway', (23, 33))	('Alteration', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('insufficient', 'Disease', 'MESH:D000309', (37, 49))
208848	24212955	EGFR amplification enhances the PI3K pro-growth pathway and is typically associated with CDKN2A deletions.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('enhances', 'PosReg', (19, 27))	('CDKN2A', 'Gene', (89, 95))	('deletions', 'Var', (96, 105))	('PI3K pro-growth pathway', 'Pathway', (32, 55))	('CDKN2A', 'Gene', '1029', (89, 95))
208852	24212955	In the TCGA pilot study, NF-1 mutation/homozygous deletions were identified in 18% of GBM.	('NF-1', 'Gene', '4763', (25, 29))	('mutation/homozygous', 'Var', (30, 49))	('NF-1', 'Gene', (25, 29))
208857	24212955	Although activating RAS mutations are observed in approximately 30% of human cancers, the RAS mutations are rare in human GBM (2%, according to the TCGA study).	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('activating', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (24, 33))	('human', 'Species', '9606', (71, 76))	('human', 'Species', '9606', (116, 121))
208860	24212955	In pediatric low-grade glioma, consisting of pilocytic astrocytoma and fibrillary astrocytoma, chromosome 7q34 rearrangements result in an in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E).	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('fibrillary astrocytoma', 'Disease', (71, 93))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('rearrangements', 'Var', (111, 125))	('V600E', 'Mutation', 'rs113488022', (250, 255))	('pilocytic astrocytoma', 'Disease', (45, 66))	('glioma', 'Disease', (23, 29))	('result in', 'Reg', (126, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('BRAF', 'Gene', (157, 161))	('KIAA1549', 'Gene', (148, 156))	('KIAA1549', 'Gene', '57670', (148, 156))	('fibrillary astrocytoma', 'Disease', 'MESH:D001254', (71, 93))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (45, 66))
208861	24212955	In contrast, RAF mutations or rearrangements are rare in malignant gliomas in adults.	('malignant gliomas', 'Disease', 'MESH:D005910', (57, 74))	('RAF', 'Protein', (13, 16))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('malignant gliomas', 'Disease', (57, 74))	('mutations', 'Var', (17, 26))	('rearrangements', 'Var', (30, 44))
208864	24212955	Aberrant signaling through this pathway leads to cell transformation and resistance to apoptosis; thus, this pathway is an attractive target for malignant glioma therapy.	('cell transformation', 'CPA', (49, 68))	('resistance to apoptosis', 'CPA', (73, 96))	('Aberrant', 'Var', (0, 8))	('malignant glioma', 'Disease', (145, 161))	('malignant glioma', 'Disease', 'MESH:D005910', (145, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('leads to', 'Reg', (40, 48))	('signaling', 'MPA', (9, 18))
208870	24212955	Activated PI3K activates PDK1 which phosphorylates Akt, which transduces signals for cell survival, proliferation, motility, and angiogenesis as shown in Figure 6.	('PI3K', 'Var', (10, 14))	('activates', 'PosReg', (15, 24))	('angiogenesis', 'CPA', (129, 141))	('PDK1', 'Gene', '5163', (25, 29))	('PDK1', 'Gene', (25, 29))	('motility', 'CPA', (115, 123))
208871	24212955	PDGF signaling in neural stem cells is required for oligodendrogenesis, and amplification of this signal induces the aberrant proliferation of neural stem cells and the formation of large glioma-like lesions.	('oligodendrogenesis', 'Disease', (52, 70))	('induces', 'Reg', (105, 112))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('PDGF', 'Gene', (0, 4))	('oligodendrogenesis', 'Disease', 'None', (52, 70))	('aberrant proliferation', 'CPA', (117, 139))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('PDGF', 'Gene', '5154', (0, 4))	('formation', 'CPA', (169, 178))	('glioma', 'Disease', (188, 194))	('amplification', 'Var', (76, 89))
208872	24212955	Hereditary loss of function mutations in the SHH receptor, Patched (PTCH) lead to constitutive activation of the SHH pathway and predisposition to medulloblastoma in Gorlin syndrome.	('Gorlin syndrome', 'Disease', (166, 181))	('PTCH', 'Gene', (68, 72))	('SHH', 'Gene', (45, 48))	('SHH', 'Gene', '6469', (113, 116))	('PTCH', 'Gene', '5727', (68, 72))	('Patched', 'Gene', (59, 66))	('medulloblastoma', 'Disease', 'MESH:D008527', (147, 162))	('Patched', 'Gene', '5727', (59, 66))	('activation', 'PosReg', (95, 105))	('medulloblastoma', 'Phenotype', 'HP:0002885', (147, 162))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (166, 181))	('loss of function', 'NegReg', (11, 27))	('medulloblastoma', 'Disease', (147, 162))	('SHH', 'Gene', '6469', (45, 48))	('SHH', 'Gene', (113, 116))	('mutations', 'Var', (28, 37))
208881	24212955	Notch ligands (Delta-like1, Delta-like3, and Delta-like4, and Jagged1-2 in mammals) are also transmembrane proteins and, when bound to Notch, expose the receptor to proteolytic activation.	('bound', 'Interaction', (126, 131))	('Delta-like3', 'Gene', (28, 39))	('Jagged1', 'Gene', '182', (62, 69))	('proteolytic activation', 'MPA', (165, 187))	('Delta-like4', 'Var', (45, 56))	('Jagged1', 'Gene', (62, 69))	('Delta-like3', 'Gene', '10683', (28, 39))
208904	24212955	Because of their frequent activation or mutation in human GBM and their paramount role in the maintenance of proliferation signaling, both EGFR and PDGFR are plausible targets for molecular therapies.	('mutation', 'Var', (40, 48))	('proliferation signaling', 'MPA', (109, 132))	('PDGFR', 'Gene', (148, 153))	('PDGFR', 'Gene', '5159', (148, 153))	('human', 'Species', '9606', (52, 57))	('activation', 'PosReg', (26, 36))	('EGFR', 'Gene', (139, 143))
208906	24212955	However, according to the individual genetic analysis in this clinical trial, the carriers of variant EGFR (EGFRvIII) and wild-type PTEN showed good response to the inhibitors.	('response to the inhibitors', 'MPA', (149, 175))	('variant', 'Var', (94, 101))	('PTEN', 'Gene', (132, 136))	('PTEN', 'Gene', '5728', (132, 136))	('EGFR', 'Gene', (102, 106))
209021	32257553	The RT options available to elderly patients with a good status, low-grade gliomas, isocitrate dehydro-genase (IDH) mutations, epidermal growth factor receptor (EGFR) amplification, 1p/19q deficiencies or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation considerably vary if these patients are carefully monitored.	('isocitrate dehydro-genase', 'Gene', (84, 109))	('epidermal growth factor receptor', 'Gene', (127, 159))	('gliomas', 'Disease', (75, 82))	('epidermal growth factor receptor', 'Gene', '1956', (127, 159))	('patients', 'Species', '9606', (299, 307))	('EGFR', 'Gene', (161, 165))	('patients', 'Species', '9606', (36, 44))	('deficiencies', 'Var', (189, 201))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('IDH', 'Gene', (111, 114))	('MGMT', 'Gene', '4255', (245, 249))	('isocitrate dehydro-genase', 'Gene', '3417', (84, 109))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (205, 243))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('mutations', 'Var', (116, 125))	('IDH', 'Gene', '3417', (111, 114))	('EGFR', 'Gene', '1956', (161, 165))	('O6-methylguanine-DNA methyltransferase', 'Gene', (205, 243))	('MGMT', 'Gene', (245, 249))
209040	32257553	The patients with low CCI scores experienced longer survival times than the patients with higher CCI scores.	('scores', 'Var', (26, 32))	('patients', 'Species', '9606', (76, 84))	('survival times', 'CPA', (52, 66))	('longer', 'PosReg', (45, 51))	('patients', 'Species', '9606', (4, 12))
209043	32257553	The preoperative factors that were independently associated with reduced survival included a KPS<80 (P=0.001), chronic obstructive pulmonary disease (P=0.01), dyskinesia (P=0.01), speech impairment (P=0.005), recognition dysfunction (P=0.02), and tumor size>4 cm (P=0.002).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('survival', 'MPA', (73, 81))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (119, 148))	('dyskinesia', 'Phenotype', 'HP:0100660', (159, 169))	('reduced', 'NegReg', (65, 72))	('speech impairment', 'Disease', (180, 197))	('tumor', 'Disease', (247, 252))	('dyskinesia', 'Disease', 'MESH:D004409', (159, 169))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (111, 148))	('KPS<80', 'Var', (93, 99))	('chronic obstructive pulmonary disease', 'Disease', (111, 148))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (111, 148))	('speech impairment', 'Phenotype', 'HP:0002167', (180, 197))	('recognition dysfunction', 'Disease', (209, 232))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('dyskinesia', 'Disease', (159, 169))
209047	32257553	Compared with RT, the use of TMZ alone can prolong event-free survival in patients with MGMT promoter methylation.	('event-free', 'MPA', (51, 61))	('promoter methylation', 'Var', (93, 113))	('patients', 'Species', '9606', (74, 82))	('MGMT', 'Gene', (88, 92))	('TMZ', 'Chemical', 'MESH:D000077204', (29, 32))	('MGMT', 'Gene', '4255', (88, 92))	('prolong', 'PosReg', (43, 50))
209087	32257553	CAR-T-mediated therapies targeting GBM markers, such as EGFRvIII, IL-13Ralpha2, HER2, and EphA2, are also being tested in ongoing clinical trials (NCT01454596, NCT02664363, NCT02209376, NCT 02208362, NCT02442297, NCT01109095, and NCT02575261).	('NCT01109095', 'Var', (213, 224))	('HER2', 'Gene', '2064', (80, 84))	('EphA2', 'Gene', (90, 95))	('IL-13Ralpha2', 'Gene', (66, 78))	('HER2', 'Gene', (80, 84))	('NCT01454596', 'Var', (147, 158))	('NCT02575261', 'Var', (230, 241))	('EGFR', 'Gene', '1956', (56, 60))	('EphA2', 'Gene', '1969', (90, 95))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('EGFR', 'Gene', (56, 60))	('IL-13Ralpha2', 'Gene', '3598', (66, 78))	('NCT 02208362', 'Var', (186, 198))	('NCT02442297', 'Var', (200, 211))	('NCT02209376', 'Var', (173, 184))	('NCT02664363', 'Var', (160, 171))
209120	30107644	The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis.	('better', 'PosReg', (92, 98))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('associated', 'Reg', (76, 86))	('mutations', 'Var', (34, 43))
209121	30107644	Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated.	('RMGs', 'Chemical', '-', (21, 25))	('mutations', 'Var', (72, 81))	('RMGs', 'Gene', (21, 25))	('downregulated', 'NegReg', (104, 117))
209128	30107644	Mutations in cancer genome can influence molecular function of genes and signaling pathways, leading to cell differentiation, proliferation, and survival (Hanahan & Weinberg Robert, 2011; Watson, Takahashi, Futreal, & Chin, 2013).	('genes', 'Pathway', (63, 68))	('proliferation', 'CPA', (126, 139))	('leading to', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cell differentiation', 'CPA', (104, 124))	('influence', 'Reg', (31, 40))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))	('signaling pathways', 'Pathway', (73, 91))	('survival', 'CPA', (145, 153))	('molecular function', 'MPA', (41, 59))
209132	30107644	TP53 (OMIM *191170) was reported as the most frequently mutated gene in diverse cancers, and patients with TP53 mutation tend to have worse prognosis (Wang & Sun, 2017).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('patients', 'Species', '9606', (93, 101))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
209133	30107644	investigated 127 significantly mutated genes in 12 cancers and categorized them into 20 cellular processes, including Wnt/beta-catenin, MAPK, and PI3K signaling pathways (Kandoth et al., 2013).	('PI3K signaling pathways', 'Pathway', (146, 169))	('cancers', 'Disease', (51, 58))	('beta-catenin', 'Gene', '1499', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('MAPK', 'Pathway', (136, 140))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('beta-catenin', 'Gene', (122, 134))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('mutated', 'Var', (31, 38))
209135	30107644	For instance, 10 RMGs including KRAS (* 190070), TP53, CDKN2A (* 600160), and RREB1 (* 602209) were identified in Pancreatic Ductal Adenocarcinoma (PDAC), and it was revealed that the frequent disruptions in RAS-MAPK pathway played a pivotal role in this cancer (Network, 2014).	('CDKN2A', 'Gene', '1029', (55, 61))	('TP53', 'Gene', '7157', (49, 53))	('RMGs', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (255, 261))	('* 600160', 'Var', (63, 71))	('PDAC', 'Phenotype', 'HP:0006725', (148, 152))	('disruptions', 'Reg', (193, 204))	('Pancreatic Ductal Adenocarcinoma', 'Disease', (114, 146))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('KRAS', 'Gene', '3845', (32, 36))	('Pancreatic Ductal Adenocarcinoma', 'Phenotype', 'HP:0006725', (114, 146))	('TP53', 'Gene', (49, 53))	('KRAS', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('RREB1', 'Gene', '6239', (78, 83))	('Pancreatic Ductal Adenocarcinoma', 'Disease', 'MESH:D021441', (114, 146))	('CDKN2A', 'Gene', (55, 61))	('RAS-MAPK pathway', 'Pathway', (208, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('RREB1', 'Gene', (78, 83))	('* 602209', 'Var', (85, 93))
209136	30107644	Besides, dozens of significantly mutated genes in various canonical signaling pathways were identified in Muscle-Invasive Bladder Cancer (BLCA), which highlighted the importance of these pathways in the disease (Robertson et al., 2017).	('Muscle-Invasive Bladder Cancer', 'Disease', 'MESH:D001749', (106, 136))	('Invasive Bladder', 'Phenotype', 'HP:0100645', (113, 129))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (122, 136))	('mutated', 'Var', (33, 40))	('Muscle-Invasive Bladder Cancer', 'Disease', (106, 136))	('BLCA', 'Phenotype', 'HP:0009725', (138, 142))
209139	30107644	Besides, it was reported that the mutations of six RMGs including TP53, KDR (* 191306), PIK3CA (* 171834), ATM (* 607585), AKT1 (* 164730), and KIT (* 164920) were associated with a poor prognosis in sporadic triple negative breast cancer (Pop et al., 2018).	('PIK3CA', 'Gene', '5290', (88, 94))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('* 191306', 'Var', (77, 85))	('AKT1', 'Gene', '207', (123, 127))	('KDR', 'Gene', '3791', (72, 75))	('* 164730', 'Var', (129, 137))	('* 171834', 'Var', (96, 104))	('PIK3CA', 'Gene', (88, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('* 164920', 'Var', (149, 157))	('AKT1', 'Gene', (123, 127))	('associated', 'Reg', (164, 174))	('TP53', 'Gene', (66, 70))	('ATM', 'Gene', '472', (107, 110))	('* 607585', 'Var', (112, 120))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))	('KIT', 'Gene', (144, 147))	('KDR', 'Gene', (72, 75))	('RMGs', 'Chemical', '-', (51, 55))	('ATM', 'Gene', (107, 110))
209140	30107644	The diagnostic and prognostic impacts of RMGs (e.g., EZH2 (* 601573), ELP3 (* 612722), and IDH2 (* 147650)) in lymphoma were surveyed for better clinical decision making (Rosenquist et al., 2016).	('* 601573', 'Var', (59, 67))	('* 147650', 'Var', (97, 105))	('ELP3', 'Gene', '55140', (70, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('IDH2', 'Gene', (91, 95))	('lymphoma', 'Disease', 'MESH:D008223', (111, 119))	('lymphoma', 'Disease', (111, 119))	('RMGs', 'Chemical', '-', (41, 45))	('IDH2', 'Gene', '3418', (91, 95))	('ELP3', 'Gene', (70, 74))	('* 612722', 'Var', (76, 84))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
209141	30107644	Moreover, RMGs (e.g., TET2 (* 612839), DNMT3A (* 602769), BAP1 (* 603089), and ASXL1 (* 612990)) involved in histone modification, chromatin remodeling and DNA methylation were associated with adverse outcome in thymic carcinoma (Wang et al., 2014).	('DNMT3A', 'Gene', (39, 45))	('DNMT3A', 'Gene', '1788', (39, 45))	('* 612839', 'Var', (28, 36))	('BAP1', 'Gene', (58, 62))	('TET2', 'Gene', '54790', (22, 26))	('thymic carcinoma', 'Disease', 'MESH:D013945', (212, 228))	('thymic carcinoma', 'Disease', (212, 228))	('* 602769', 'Var', (47, 55))	('ASXL1', 'Gene', '171023', (79, 84))	('RMGs', 'Chemical', '-', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('associated', 'Reg', (177, 187))	('TET2', 'Gene', (22, 26))	('BAP1', 'Gene', '8314', (58, 62))	('* 603089', 'Var', (64, 72))	('ASXL1', 'Gene', (79, 84))	('* 612990', 'Var', (86, 94))
209157	30107644	The differences of overall survival time between RMG-mutation, RMG-MS or RMG-NS patients and RMG wild-type patients were shown by KM survival curves (log-rank test).	('RMG-NS', 'Disease', (73, 79))	('patients', 'Species', '9606', (80, 88))	('RMG-mutation', 'Var', (49, 61))	('RMG-NS', 'Disease', 'MESH:D009404', (73, 79))	('RMG-MS', 'Disease', (63, 69))	('patients', 'Species', '9606', (107, 115))
209160	30107644	As a result, we identified 897 unique RMGs across 31 cancer types (Supporting Information Table S1).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RMGs', 'Var', (38, 42))	('RMGs', 'Chemical', '-', (38, 42))
209162	30107644	There were more than 100 RMGs in SKCM, STAD, LUSC, LUAD, ACC, and DLBC (see the abbreviations of cancer types in method section), indicating that these cancers were closely related to gene recurrent mutations.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (152, 159))	('cancer', 'Disease', (97, 103))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RMGs', 'Chemical', '-', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (199, 208))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
209175	30107644	In addition, we identified 624 specifically mutated RMGs (smRMGs) that were only in a single cancer type (Figure 1d and Supporting Information Table S2).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('RMGs', 'Chemical', '-', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutated', 'Var', (44, 51))	('RMGs', 'Chemical', '-', (52, 56))
209179	30107644	We also detected another five smRMGs that mutated in nearly half of the samples in corresponding cancers, including PCDHAC2 in SKCM (53%), ZFPM1 in ACC (52%), VHL in KIRC (49%), GNAQ in UVM (49%), and ADAM6 in LUSC (45%).	('PCDHAC2', 'Gene', '56134', (116, 123))	('UVM', 'Phenotype', 'HP:0007716', (186, 189))	('ADAM6', 'Gene', '8755', (201, 206))	('PCDHAC2', 'Gene', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('RMGs', 'Chemical', '-', (32, 36))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('VHL', 'Disease', (159, 162))	('GNAQ', 'Gene', '2776', (178, 182))	('GNAQ', 'Gene', (178, 182))	('ZFPM1', 'Gene', '161882', (139, 144))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('LUSC', 'Phenotype', 'HP:0030359', (210, 214))	('ACC', 'Phenotype', 'HP:0006744', (148, 151))	('mutated', 'Var', (42, 49))	('ADAM6', 'Gene', (201, 206))	('VHL', 'Disease', 'MESH:D006623', (159, 162))	('ZFPM1', 'Gene', (139, 144))
209182	30107644	PI3K-Akt signaling pathway had the most number of RMGs (n = 47) and were disrupted in 23 cancer types.	('Akt', 'Gene', '207', (5, 8))	('RMGs', 'Var', (50, 54))	('RMGs', 'Chemical', '-', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Akt', 'Gene', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
209186	30107644	It was also shown that BLCA had the greatest proportion of RMGs in cell cycle.	('cell cycle', 'CPA', (67, 77))	('RMGs', 'Var', (59, 63))	('BLCA', 'Phenotype', 'HP:0009725', (23, 27))	('RMGs', 'Chemical', '-', (59, 63))
209192	30107644	For most cRMGs, missense mutation accounts for the largest proportion (>50%), especially for PIK3CA.	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (93, 99))	('RMGs', 'Chemical', '-', (10, 14))	('missense mutation', 'Var', (16, 33))
209193	30107644	Specially, KMT2C in LUSC and CHOL as well as DNAH5 in CHOL were more frequently disrupted by nonsense mutation.	('DNAH5', 'Gene', (45, 50))	('DNAH5', 'Gene', '1767', (45, 50))	('disrupted', 'Reg', (80, 89))	('CHOL', 'Phenotype', 'HP:0030153', (29, 33))	('KMT2C', 'Gene', (11, 16))	('nonsense mutation', 'Var', (93, 110))	('KMT2C', 'Gene', '58508', (11, 16))	('CHOL', 'Phenotype', 'HP:0030153', (54, 58))	('LUSC', 'Phenotype', 'HP:0030359', (20, 24))
209194	30107644	In addition, frame shift insertion was also found to be a key mutation for MUC5B in KICH, which occupied a relatively large proportion.	('MUC5B', 'Gene', '727897', (75, 80))	('frame shift insertion', 'Var', (13, 34))	('MUC5B', 'Gene', (75, 80))
209197	30107644	It was observed that TP53 was more frequently disrupted by nonsense mutations, frame-shift indels and splice site mutations compared with other cRMGs (Figure 3a), which results in the initiation and progression of cancers (Payne & Kemp, 2005; Wojnarowicz et al., 2012).	('TP53', 'Gene', (21, 25))	('RMGs', 'Chemical', '-', (145, 149))	('frame-shift indels', 'Var', (79, 97))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('results in', 'Reg', (169, 179))	('splice site mutations', 'Var', (102, 123))	('nonsense mutations', 'Var', (59, 77))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('progression', 'PosReg', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('disrupted', 'Reg', (46, 55))	('TP53', 'Gene', '7157', (21, 25))
209199	30107644	To assess the functional impacts of TP53 mutations, we identified 87 DEGs shared by more than one-quarter of the 21 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', '7157', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (36, 40))
209205	30107644	Surprisingly, patients with MUC3A, MUC4, MUC5B, MUC6, and MUC16 mutations had significantly better OS prognoses compared with those without mutations in several cancer types (Figure 4a).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('better', 'PosReg', (92, 98))	('MUC6', 'Gene', (48, 52))	('MUC4', 'Gene', '4585', (35, 39))	('MUC16', 'Gene', '94025', (58, 63))	('MUC4', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('MUC6', 'Gene', '4588', (48, 52))	('mutations', 'Var', (64, 73))	('MUC5B', 'Gene', (41, 46))	('OS prognoses', 'CPA', (99, 111))	('cancer', 'Disease', (161, 167))	('MUC3A', 'Gene', '4584', (28, 33))	('MUC3A', 'Gene', (28, 33))	('MUC5B', 'Gene', '727897', (41, 46))	('MUC16', 'Gene', (58, 63))	('patients', 'Species', '9606', (14, 22))
209207	30107644	Results showed that there was a greater proportion of in-frame deletion of MUC4 in KIPAN and KIRC (Figure 3a), where the mutations of MUC4 were significantly associated with prognosis.	('MUC4', 'Gene', (75, 79))	('MUC4', 'Gene', (134, 138))	('mutations', 'Var', (121, 130))	('associated with', 'Reg', (158, 173))	('MUC4', 'Gene', '4585', (134, 138))	('in-frame deletion', 'Var', (54, 71))	('MUC4', 'Gene', '4585', (75, 79))
209208	30107644	Similarly, we found a greater proportion of frame-shift deletion of MUC5B in STAD and STES.	('MUC5B', 'Gene', '727897', (68, 73))	('STES', 'Chemical', '-', (86, 90))	('MUC5B', 'Gene', (68, 73))	('STAD', 'Disease', (77, 81))	('frame-shift deletion', 'Var', (44, 64))	('STES', 'Disease', (86, 90))
209212	30107644	There were more recurrently mutated MUC family genes in SKCM, DLBC, CHOL, ACC, ESCA, KICH, and STAD compared with other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('STAD', 'Disease', (95, 99))	('KICH', 'Disease', (85, 89))	('mutated', 'Var', (28, 35))	('CHOL', 'Disease', (68, 72))	('SKCM', 'Disease', (56, 60))	('ESCA', 'Phenotype', 'HP:0011459', (79, 83))	('DLBC', 'Disease', (62, 66))	('ESCA', 'Disease', (79, 83))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('cancer', 'Disease', (120, 126))	('ACC', 'Disease', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('MUC', 'Gene', '100508689', (36, 39))	('CHOL', 'Phenotype', 'HP:0030153', (68, 72))	('MUC', 'Gene', (36, 39))
209214	30107644	As a result, the better OS prognosis were observed in SKCM and STAD (Supporting Information Figure S3), which further suggested that mutations of MUC family genes were frequently associated with better survival prognosis in cancers.	('better', 'PosReg', (195, 201))	('associated', 'Reg', (179, 189))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('MUC', 'Gene', (146, 149))	('mutations', 'Var', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('MUC', 'Gene', '100508689', (146, 149))	('cancers', 'Disease', (224, 231))
209215	30107644	To explore the impacts of mutation types on gene expression, we firstly identified 37 RMGs which were differentially expressed caused by their own mutations (Supporting Information Table S3).	('RMGs', 'Chemical', '-', (86, 90))	('mutations', 'Var', (147, 156))	('caused', 'Reg', (127, 133))
209218	30107644	We further categorized the mutations into two groups: MS (including missense and in-frame mutations) and NS (including nonsense, frame-shift, and splice site mutations).	('NS', 'Disease', 'MESH:D009404', (105, 107))	('frame-shift', 'Var', (129, 140))	('nonsense', 'Var', (119, 127))	('splice site mutations', 'Var', (146, 167))	('missense', 'Var', (68, 76))
209221	30107644	When comparing RMG-NS cancers to RMG wild-type cancers, we found all the 20 differentially expressed RMGs are downregulated (Supporting Information Figure S4), which may mainly due to nonsense-mediated mRNA decay (Noensie & Dietz, 2001).	('RMGs', 'Chemical', '-', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('RMG-NS cancers', 'Disease', 'MESH:D009369', (15, 29))	('cancers', 'Disease', (22, 29))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('RMG-NS cancers', 'Disease', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('downregulated', 'NegReg', (110, 123))	('nonsense-mediated mRNA decay', 'Var', (184, 212))	('RMGs', 'Gene', (101, 105))
209226	30107644	Similarly, to study the influences of mutation types on prognosis, we identified 13 cRMGs that mutated in sufficient samples (n >= 5) in each respective group (MS and NS) excluding TP53 that have been widely explored (Freed-Pastor & Prives, 2012).	('NS', 'Disease', 'MESH:D009404', (167, 169))	('TP53', 'Gene', (181, 185))	('mutated', 'Var', (95, 102))	('RMGs', 'Chemical', '-', (85, 89))	('TP53', 'Gene', '7157', (181, 185))
209228	30107644	The results showed that six cRMGs including OBSCN, CDKN2A, CSMD3, DMD, DNAH5, and KMT2Cwith MS or NS mutations have significant associations with prognosis in several cancer types (Figure 5c).	('DMD', 'Gene', '1756', (66, 69))	('CDKN2A', 'Gene', '1029', (51, 57))	('NS', 'Disease', 'MESH:D009404', (98, 100))	('mutations', 'Var', (101, 110))	('RMGs', 'Chemical', '-', (29, 33))	('OBSCN', 'Gene', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('OBSCN', 'Gene', '84033', (44, 49))	('cancer', 'Disease', (167, 173))	('KMT2C', 'Gene', (82, 87))	('KMT2C', 'Gene', '58508', (82, 87))	('DNAH5', 'Gene', '1767', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DNAH5', 'Gene', (71, 76))	('DMD', 'Gene', (66, 69))	('CDKN2A', 'Gene', (51, 57))	('CSMD3', 'Gene', (59, 64))	('CSMD3', 'Gene', '114788', (59, 64))
209229	30107644	Patients with NS mutations in CDKN2A (PAAD), CSMD3 (STAD), and DMD (STAD and STES) had worse survival.	('CSMD3', 'Gene', (45, 50))	('CSMD3', 'Gene', '114788', (45, 50))	('DMD', 'Gene', '1756', (63, 66))	('CDKN2A', 'Gene', (30, 36))	('NS', 'Disease', 'MESH:D009404', (14, 16))	('CDKN2A', 'Gene', '1029', (30, 36))	('Patients', 'Species', '9606', (0, 8))	('PAAD', 'Phenotype', 'HP:0006725', (38, 42))	('STES', 'Chemical', '-', (77, 81))	('DMD', 'Gene', (63, 66))	('mutations', 'Var', (17, 26))
209232	30107644	The NS mutations downregulated its mRNA expression, therefore, dysregulated transcription, chromatin architecture or cellular differentiation.	('downregulated', 'NegReg', (17, 30))	('cellular differentiation', 'CPA', (117, 141))	('NS', 'Disease', 'MESH:D009404', (4, 6))	('transcription', 'MPA', (76, 89))	('mRNA expression', 'MPA', (35, 50))	('dysregulated', 'Reg', (63, 75))	('chromatin architecture', 'CPA', (91, 113))	('mutations', 'Var', (7, 16))
209233	30107644	Whereas, both OBSCN (in STAD) and DNAH5 (in SKCM) with MS mutations had better survival.	('OBSCN', 'Gene', '84033', (14, 19))	('mutations', 'Var', (58, 67))	('DNAH5', 'Gene', '1767', (34, 39))	('OBSCN', 'Gene', (14, 19))	('better', 'PosReg', (72, 78))	('DNAH5', 'Gene', (34, 39))
209238	30107644	Of which, mutations in ARID1A and PIK3CA were co-occurred (p-value < 0.01), which was consistent with the previous study (Liang et al., 2012).	('PIK3CA', 'Gene', (34, 40))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (34, 40))	('mutations', 'Var', (10, 19))
209241	30107644	Mutations in ARID1A could activate the PI3K pathway activity, and the concordance of mutations in ARID1A and PI3K pathway contributed to tumorigenesis (Liang et al., 2012).	('ARID1A', 'Gene', '8289', (98, 104))	('tumor', 'Disease', (137, 142))	('ARID1A', 'Gene', (98, 104))	('activate', 'PosReg', (26, 34))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1A', 'Gene', (13, 19))	('activity', 'MPA', (52, 60))	('PI3K pathway', 'Pathway', (39, 51))	('PI3K pathway', 'Pathway', (109, 121))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('contributed', 'Reg', (122, 133))
209244	30107644	The co-occurred mutations in RNF43 and FAT3/FAT4 disrupted the Wnt signaling and thus promoted the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RNF43', 'Gene', (29, 34))	('FAT3', 'Gene', (39, 43))	('RNF43', 'Gene', '54894', (29, 34))	('FAT3', 'Gene', '120114', (39, 43))	('mutations', 'Var', (16, 25))	('FAT4', 'Gene', (44, 48))	('Wnt signaling', 'Pathway', (63, 76))	('FAT4', 'Gene', '79633', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('disrupted', 'NegReg', (49, 58))	('promoted', 'PosReg', (86, 94))	('cancer', 'Disease', (114, 120))
209249	30107644	Moreover, we found MUC family genes were enriched in RMGs, and mutations of five MUC family genes were associated with better OS prognosis.	('MUC', 'Gene', (81, 84))	('mutations', 'Var', (63, 72))	('MUC', 'Gene', '100508689', (19, 22))	('MUC', 'Gene', '100508689', (81, 84))	('MUC', 'Gene', (19, 22))	('associated', 'Reg', (103, 113))	('RMGs', 'Chemical', '-', (53, 57))	('RMGs', 'Disease', (53, 57))
209250	30107644	In addition, we assessed the impacts of mutations in RMGs on gene expression and survival, as well as the pairwise mutation patterns among RMGs.	('mutations', 'Var', (40, 49))	('gene expression', 'MPA', (61, 76))	('RMGs', 'Chemical', '-', (139, 143))	('RMGs', 'Chemical', '-', (53, 57))
209251	30107644	In this study, we showed that the RMGs with mutation rates greater than 25% were enriched in hydrolases.	('mutation', 'Var', (44, 52))	('RMGs', 'Chemical', '-', (34, 38))	('hydrolases', 'Enzyme', (93, 103))
209252	30107644	Among these genes, PTEN was a tumor suppressor gene encoding a phosphatase and its mutation may lead to decreased sensitivity to apoptosis stimulating thus promote tumorigenesis (Farrow & Mark Evers, 2003; Stambolic et al., 1998; Zhong et al., 2000).	('tumor', 'Disease', (164, 169))	('sensitivity to apoptosis stimulating', 'MPA', (114, 150))	('PTEN', 'Gene', (19, 23))	('decreased', 'NegReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutation', 'Var', (83, 91))	('PTEN', 'Gene', '5728', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (30, 35))	('promote', 'PosReg', (156, 163))
209254	30107644	Mutations in PTPRD abrogated its function to regulate STAT3 and promoted cancer progression (Funato, Yamazumi, Oda, & Akiyama, 2011; Zhao et al., 2010).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PTPRD', 'Gene', '5789', (13, 18))	('promoted', 'PosReg', (64, 72))	('PTPRD', 'Gene', (13, 18))	('STAT3', 'Gene', '6774', (54, 59))	('abrogated', 'NegReg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Mutations', 'Var', (0, 9))	('STAT3', 'Gene', (54, 59))	('function', 'MPA', (33, 41))
209255	30107644	In addition, the alterations in cathepsins may disrupt lysosomal trafficking and autophagy, thus led to tumor invasion (Dielschneider, Henson, & Gibson, 2017; White, Mehnert, & Chan, 2015).	('disrupt', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('led to', 'Reg', (97, 103))	('cathepsins', 'Protein', (32, 42))	('tumor', 'Disease', (104, 109))	('autophagy', 'CPA', (81, 90))	('lysosomal trafficking', 'CPA', (55, 76))	('alterations', 'Var', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
209256	30107644	Recurrent mutations in hydrolases may cause uncontrolled proliferation, differentiation and metastasis, so target tumor cell hydrolases is a good way to treat cancer.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('differentiation', 'CPA', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cause', 'Reg', (38, 43))	('metastasis', 'CPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (114, 119))	('uncontrolled', 'MPA', (44, 56))	('hydrolases', 'Gene', (23, 33))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
209260	30107644	The recurrent mutations of MUC4 were detected only in ESCA (16%), whereas not in STAD.	('MUC4', 'Gene', (27, 31))	('detected', 'Reg', (37, 45))	('ESCA', 'Phenotype', 'HP:0011459', (54, 58))	('ESCA', 'Disease', (54, 58))	('MUC4', 'Gene', '4585', (27, 31))	('mutations', 'Var', (14, 23))
209263	30107644	Our results suggested recurrent mutations of MUC family genes are closely associated with survival in diverse cancers, so the mutations of MUC4 may cause the increase in mRNA expression and further protect epithelial surfaces in ESCA and STAD.	('ESCA', 'Disease', (229, 233))	('cancers', 'Disease', (110, 117))	('MUC', 'Gene', '100508689', (139, 142))	('MUC4', 'Gene', '4585', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MUC', 'Gene', '100508689', (45, 48))	('MUC4', 'Gene', (139, 143))	('MUC', 'Gene', (45, 48))	('STAD', 'Disease', (238, 242))	('mutations', 'Var', (126, 135))	('protect', 'PosReg', (198, 205))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('ESCA', 'Phenotype', 'HP:0011459', (229, 233))	('increase', 'PosReg', (158, 166))	('mRNA expression', 'MPA', (170, 185))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('MUC', 'Gene', (139, 142))
209264	30107644	Similarly, PTEN was frequently mutated in GBM and the combined data, GBMLGG, which could also indicate the mutated PTEN lost its cancer suppressing property thus promote tumorigenesis in GBM.	('PTEN', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lost', 'NegReg', (120, 124))	('PTEN', 'Gene', '5728', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PTEN', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PTEN', 'Gene', '5728', (115, 119))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (170, 175))	('promote', 'PosReg', (162, 169))
209266	30107644	Mutant p53 protein encoded by TP53 with MS mutations could inactivate p53-related proteins and acquire new oncogenic functions (Freed-Pastor & Prives, 2012), so the upregulation of TP53 helped the tumor cells evade apoptosis and senescence.	('oncogenic functions', 'CPA', (107, 126))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', (181, 185))	('inactivate', 'NegReg', (59, 69))	('TP53', 'Gene', '7157', (181, 185))	('p53', 'Gene', (70, 73))	('protein', 'Protein', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('p53', 'Gene', '7157', (70, 73))	('cells evade apoptosis and', 'CPA', (203, 228))	('p53', 'Gene', '7157', (7, 10))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Mutant', 'Var', (0, 6))	('TP53', 'Gene', '7157', (30, 34))	('the', 'PosReg', (161, 164))	('tumor', 'Disease', (197, 202))	('p53', 'Gene', (7, 10))
209268	30107644	The mutated CDKN2A proteins failed to bind to cdk4, which promoted the development of cancer (Lilischkis, Sarcevic, Kennedy, Warlters, & Sutherland, 1996; Liu et al., 1995; Ranade et al., 1995).	('mutated', 'Var', (4, 11))	('CDKN2A', 'Gene', (12, 18))	('cdk4', 'Gene', '1019', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDKN2A', 'Gene', '1029', (12, 18))	('cdk4', 'Gene', (46, 50))	('promoted', 'PosReg', (58, 66))	('proteins', 'Protein', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
209271	30107644	Whereas NS mutations could only downregulate gene expression (Supporting Information Figure S4).	('downregulate', 'NegReg', (32, 44))	('gene expression', 'MPA', (45, 60))	('mutations', 'Var', (11, 20))	('NS', 'Disease', 'MESH:D009404', (8, 10))
209277	30107644	Strong correlation between recurrently mutated MUC family genes and human survival were revealed.	('human survival', 'CPA', (68, 82))	('human', 'Species', '9606', (68, 73))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('mutated', 'Var', (39, 46))
209304	21188132	The combination of RT and TMZ as compared with RT alone, increased the median survival (14.6 months vs 12.1 months, P < 0.001).	('TMZ', 'Var', (26, 29))	('as', 'Chemical', 'MESH:D001151', (30, 32))	('TMZ', 'Chemical', 'MESH:D000077204', (26, 29))	('as', 'Chemical', 'MESH:D001151', (62, 64))	('increased', 'PosReg', (57, 66))
209305	21188132	In addition, the survival rate at 2 years among the patients who received RT and TMZ was significantly greater than the rate among the patients who received RT alone (26.5% vs 10.4%).	('patients', 'Species', '9606', (135, 143))	('TMZ', 'Var', (81, 84))	('survival', 'CPA', (17, 25))	('greater', 'PosReg', (103, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('as', 'Chemical', 'MESH:D001151', (86, 88))	('patients', 'Species', '9606', (52, 60))
209311	21188132	On the basis of the results of these studies, TMZ 150 to 200 mg/m2 per day for 5 days every 28 days rapidly became the standard therapy for relapsed malignant gliomas in adult patients.	('patients', 'Species', '9606', (176, 184))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('TMZ 150 to 200 mg/m2', 'Var', (46, 66))	('as', 'Chemical', 'MESH:D001151', (164, 166))	('TMZ', 'Chemical', 'MESH:D000077204', (46, 49))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('malignant gliomas', 'Disease', (149, 166))	('malignant gliomas', 'Disease', 'MESH:D005910', (149, 166))	('as', 'Chemical', 'MESH:D001151', (8, 10))
209375	21188132	The combination of 1p/19q chromosome deletion and the hypermethylation of the MGMT gene promoter bear a large risk reduction for TTF and MPFS irrespective of histology and treatment.	('reduction', 'NegReg', (115, 124))	('MPFS', 'Disease', (137, 141))	('TTF', 'Disease', (129, 132))	('MGMT', 'Gene', '4255', (78, 82))	('hypermethylation', 'Var', (54, 70))	('MGMT', 'Gene', (78, 82))
209384	21188132	Survival was significantly greater in the TMZ group than in the RT alone group throughout follow-up.	('greater', 'PosReg', (27, 34))	('Survival', 'CPA', (0, 8))	('TMZ', 'Var', (42, 45))	('as', 'Chemical', 'MESH:D001151', (10, 12))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))
209387	21188132	Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was the strongest predictor for outcome and benefit from TMZ chemotherapy.	('as', 'Chemical', 'MESH:D001151', (54, 56))	('as', 'Chemical', 'MESH:D001151', (75, 77))	('Methylation', 'Var', (0, 11))	('TMZ', 'Chemical', 'MESH:D000077204', (131, 134))	('MGMT', 'Gene', '4255', (59, 63))	('O6-methylguanine-DNA methyltransferase', 'Gene', (19, 57))	('MGMT', 'Gene', (59, 63))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (19, 57))
209397	21188132	One-year PFS rate was 36.6% in the TMZ group and 7.7% in the RT alone group.	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('PFS', 'Disease', (9, 12))	('as', 'Chemical', 'MESH:D001151', (19, 21))	('TMZ', 'Var', (35, 38))
209398	21188132	Median OS time was also significantly better in TMZ group vs the RT alone group (13.4 vs 7.7 months, respectively; P < 0.0001), as was the 1-year OS at 56.3% vs 15.7% (P < 0.0001), respectively.	('as', 'Chemical', 'MESH:D001151', (16, 18))	('TMZ', 'Chemical', 'MESH:D000077204', (48, 51))	('better', 'PosReg', (38, 44))	('Median OS time', 'MPA', (0, 14))	('as', 'Chemical', 'MESH:D001151', (132, 134))	('TMZ group', 'Var', (48, 57))	('as', 'Chemical', 'MESH:D001151', (128, 130))
209403	21188132	A total of 447 patients were randomized 2:1:1 to PCV, TMZ 200 mg/m2 for 5 days (TMZ-5), and TMZ 100 mg/m2 for 21 days (TMZ-21).	('patients', 'Species', '9606', (15, 23))	('TMZ 200 mg/m2', 'Var', (54, 67))	('TMZ-5', 'Chemical', '-', (80, 85))	('TMZ 100 mg/m2', 'Var', (92, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('TMZ-21', 'Chemical', '-', (119, 125))	('TMZ', 'Chemical', 'MESH:D000077204', (119, 122))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))
209449	21188132	Overall survival was promising, notably in the patients with a methylated MGMT gene promoter.	('patients', 'Species', '9606', (47, 55))	('MGMT', 'Gene', (74, 78))	('methylated', 'Var', (63, 73))	('MGMT', 'Gene', '4255', (74, 78))	('as', 'Chemical', 'MESH:D001151', (18, 20))
209487	21188132	Studies have shown that treatment of human tumor cells with TMZ induced an increase in the activity of poly (ADP-ribose) polymerase (PARP), and the inhibition of PARP has been reported to enhance the cytotoxicity of methylating agents.	('PARP', 'Gene', (133, 137))	('poly (ADP-ribose) polymerase', 'Gene', (103, 131))	('tumor', 'Disease', (43, 48))	('cytotoxicity', 'Disease', (200, 212))	('enhance', 'PosReg', (188, 195))	('PARP', 'Gene', '142', (162, 166))	('cytotoxicity', 'Disease', 'MESH:D064420', (200, 212))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('PARP', 'Gene', (162, 166))	('TMZ', 'Var', (60, 63))	('inhibition', 'NegReg', (148, 158))	('TMZ', 'Chemical', 'MESH:D000077204', (60, 63))	('activity', 'MPA', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('human', 'Species', '9606', (37, 42))	('increase', 'PosReg', (75, 83))	('as', 'Chemical', 'MESH:D001151', (168, 170))	('PARP', 'Gene', '142', (133, 137))	('as', 'Chemical', 'MESH:D001151', (80, 82))	('poly (ADP-ribose) polymerase', 'Gene', '142', (103, 131))	('as', 'Chemical', 'MESH:D001151', (128, 130))
209488	21188132	A phase I trial evaluated the safety and pharmacokinetic-pharmacodynamic profile of AGO14699, a PARP inhibitor, in combination with TMZ.	('AGO14699', 'Var', (84, 92))	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('PARP', 'Gene', (96, 100))	('AGO14699', 'Chemical', '-', (84, 92))	('as', 'Chemical', 'MESH:D001151', (4, 6))	('PARP', 'Gene', '142', (96, 100))
209492	21188132	MGMT plays a key role in reverting lethal DNA damage induced by TMZ, and thus neutralizing the cytotoxic effect.	('MGMT', 'Gene', (0, 4))	('TMZ', 'Var', (64, 67))	('lethal DNA damage', 'MPA', (35, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (64, 67))	('MGMT', 'Gene', '4255', (0, 4))	('reverting', 'NegReg', (25, 34))
209502	21188132	The presence of a methylated MGMT allele is only due to tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('MGMT', 'Gene', '4255', (29, 33))	('MGMT', 'Gene', (29, 33))	('methylated', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
209505	21188132	Epigenetic silencing of MGMT by promoter hypermethylation is present in approximately 40% of primary GBM and represents the main mechanism to reduce MGMT expression and diminish the DNA repair activity.	('MGMT', 'Gene', '4255', (24, 28))	('promoter hypermethylation', 'Var', (32, 57))	('MGMT', 'Gene', (149, 153))	('diminish', 'NegReg', (169, 177))	('MGMT', 'Gene', '4255', (149, 153))	('DNA repair activity', 'MPA', (182, 201))	('Epigenetic silencing', 'Var', (0, 20))	('reduce', 'NegReg', (142, 148))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('MGMT', 'Gene', (24, 28))	('expression', 'MPA', (154, 164))
209507	21188132	In this study TMZ only benefited patients with a methylated MGMT gene promoter.	('TMZ', 'Chemical', 'MESH:D000077204', (14, 17))	('patients', 'Species', '9606', (33, 41))	('MGMT', 'Gene', (60, 64))	('methylated', 'Var', (49, 59))	('MGMT', 'Gene', '4255', (60, 64))
209508	21188132	TMZ treated patients with a nonsilenced MGMT gene had an OS and PFS similar to patients who initially received radiotherapy alone.	('patients', 'Species', '9606', (12, 20))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('patients', 'Species', '9606', (79, 87))	('nonsilenced', 'Var', (28, 39))	('PFS', 'Disease', (64, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
209513	21188132	In this study patients with newly diagnosed GBM are stratified by MGMT methylation status before randomization to a TMZ schedule (standard daily dose for 5/28 days or a 21/28 days dose-dense regimen).	('methylation', 'Var', (71, 82))	('MGMT', 'Gene', (66, 70))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('MGMT', 'Gene', '4255', (66, 70))	('GBM', 'Disease', (44, 47))	('patients', 'Species', '9606', (14, 22))	('TMZ', 'Chemical', 'MESH:D000077204', (116, 119))
209525	21188132	This work showed that before disease progression, patients treated with TMZ had an improvement in most of preselected HRQOL domains analyzed compared with their pretreatment scores.	('improvement', 'PosReg', (83, 94))	('HRQOL', 'Gene', (118, 123))	('patients', 'Species', '9606', (50, 58))	('TMZ', 'Chemical', 'MESH:D000077204', (72, 75))	('TMZ', 'Var', (72, 75))	('as', 'Chemical', 'MESH:D001151', (33, 35))
209544	21188132	Nonadherence can have multiple consequences such as inducing the physician to attribute progression of the disease to a lack of activity of the drug, and increasing the consumption of healthcare resources.	('activity', 'MPA', (128, 136))	('consumption of', 'MPA', (169, 183))	('increasing', 'PosReg', (154, 164))	('Nonadherence', 'Var', (0, 12))	('inducing', 'Reg', (52, 60))	('as', 'Chemical', 'MESH:D001151', (49, 51))	('as', 'Chemical', 'MESH:D001151', (159, 161))	('as', 'Chemical', 'MESH:D001151', (111, 113))
209597	31512439	In 2016, the WHO majorly restructured the classification of CNS tumors, such as diffuse gliomas, medulloblastomas, and glioblastomas, and included new entities that are diagnosed with combined histopathological and molecular characteristics and genetic features, such as diffuse midline glioma H3 K27M-mutant and others.	('K27M', 'Mutation', 'p.K27M', (297, 301))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('midline glioma', 'Disease', (279, 293))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioblastomas', 'Disease', (119, 132))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CNS tumors', 'Disease', 'MESH:D016543', (60, 70))	('glioblastomas', 'Disease', 'MESH:D005909', (119, 132))	('medulloblastomas', 'Disease', (97, 113))	('midline glioma', 'Disease', 'MESH:D005910', (279, 293))	('CNS tumor', 'Phenotype', 'HP:0100006', (60, 69))	('gliomas', 'Disease', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('H3 K27M-mutant', 'Var', (294, 308))	('glioma', 'Phenotype', 'HP:0009733', (287, 293))	('glioblastomas', 'Phenotype', 'HP:0012174', (119, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('medulloblastomas', 'Disease', 'MESH:D008527', (97, 113))	('CNS tumors', 'Disease', (60, 70))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))
209606	31512439	The VRR system also uses less power and a shorter integration time to collect signals; thus, VRR provides a safer and more suitable method for in vivo and real-time in situ brain cancer diagnosis compared with NIR or FT-Raman methods.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('brain cancer', 'Disease', (173, 185))	('VRR', 'Var', (93, 96))	('brain cancer', 'Disease', 'MESH:D001932', (173, 185))	('brain cancer', 'Phenotype', 'HP:0030692', (173, 185))
209625	31512439	For example, the strength of the saturated fatty acid bond (1441 and ) is weaker, and the RR molecular fingerprints of amide I , amide II , amide III , tryptophan and mitochondrion (1587 and ), and the RR peak at  (higher than ), which reflects  saturation status and oxygen delivery at the cellular level, all show a tendency of either growing or weakening, respectively.	('1441', 'Var', (60, 64))	('amide I', 'Chemical', 'MESH:D000577', (129, 136))	('amide I', 'Chemical', 'MESH:D000577', (119, 126))	('amide I', 'Chemical', 'MESH:D000577', (140, 147))	('tryptophan', 'Chemical', 'None', (152, 162))	('weaker', 'NegReg', (74, 80))	('strength', 'MPA', (17, 25))	('weakening', 'NegReg', (348, 357))	('fatty acid', 'Chemical', 'MESH:D005227', (43, 53))	('amide III', 'Chemical', 'MESH:D000577', (140, 149))	('1587', 'Var', (182, 186))	('amide II', 'Chemical', 'MESH:D000577', (129, 137))	('oxygen', 'Chemical', 'MESH:D010100', (268, 274))	('saturated fatty acid bond', 'MPA', (33, 58))	('amide II', 'Chemical', 'MESH:D000577', (140, 148))
209636	31512439	For example, the peak  drastically decreases with the decreasing concentration of saturated fatty acid lipids reflected by the peaks at 1442 and .	('1442', 'Var', (136, 140))	('concentration', 'MPA', (65, 78))	('decreases', 'NegReg', (35, 44))	('fatty acid', 'Chemical', 'MESH:D005227', (92, 102))	('saturated fatty acid lipids', 'MPA', (82, 109))
209639	31512439	RR modes of 1157 and  could be a significant marker to diagnose glioma and other CNS cancers.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('glioma', 'Disease', (64, 70))	('RR modes', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
209640	31512439	The peak at  observed in the RR spectra is considered to be the main vibrational mode  of the fingerprint of tryptophan.- It was enhanced due to resonance, especially in the malignant gliomas of high grades (III and IV).	('malignant gliomas', 'Disease', (174, 191))	('enhanced', 'PosReg', (129, 137))	('malignant gliomas', 'Disease', 'MESH:D005910', (174, 191))	('gliomas', 'Phenotype', 'HP:0009733', (184, 191))	('tryptophan', 'Chemical', 'None', (109, 119))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('resonance', 'Var', (145, 154))
209656	31512439	Both fluorescence quantum yield and differential Raman cross section of phenylalanine and tyrosine are much smaller than tryptophan.	('phenylalanine', 'Chemical', 'MESH:C119108', (72, 85))	('tyrosine', 'Var', (90, 98))	('smaller', 'NegReg', (108, 115))	('differential Raman cross section', 'MPA', (36, 68))	('fluorescence quantum yield', 'MPA', (5, 31))	('tryptophan', 'Chemical', 'None', (121, 131))	('tyrosine', 'Chemical', 'None', (90, 98))	('phenylalanine', 'Var', (72, 85))
209658	31512439	The Raman modes 2934 and  are both symmetric stretches that correspond to methyl  and methylene , respectively.	('2934', 'Var', (16, 20))	('methyl', 'Chemical', 'MESH:C031105', (86, 92))	('methylene', 'MPA', (86, 95))	('methylene', 'Chemical', 'MESH:D008752', (86, 95))	('methyl', 'Chemical', 'MESH:C031105', (74, 80))	('methyl', 'MPA', (74, 80))	('correspond', 'Reg', (60, 70))
209716	31357584	High FREM2 Gene and Protein Expression Are Associated with Favorable Prognosis of IDH-WT Glioblastomas World Health Organization grade IV diffuse gliomas, known as glioblastomas, are the most common malignant brain tumors, and they show poor prognosis.	('Glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('glioblastomas', 'Phenotype', 'HP:0012174', (164, 177))	('brain tumors', 'Phenotype', 'HP:0030692', (209, 221))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('brain tumor', 'Phenotype', 'HP:0030692', (209, 220))	('High', 'Var', (0, 4))	('gliomas', 'Disease', (146, 153))	('IDH-WT Glioblastomas', 'Disease', 'MESH:D005909', (82, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('IDH-WT Glioblastomas', 'Disease', (82, 102))	('glioblastomas', 'Disease', (164, 177))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('malignant brain tumors', 'Disease', (199, 221))	('glioblastomas', 'Disease', 'MESH:D005909', (164, 177))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('FREM2', 'Gene', (5, 10))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('FREM2', 'Gene', '341640', (5, 10))	('malignant brain tumors', 'Disease', 'MESH:D001932', (199, 221))	('Glioblastomas', 'Phenotype', 'HP:0012174', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
209742	31357584	Based on isocitrate dehydrogenase (IDH) 1 and 2 mutation status, glioblastomas are defined as primary (IDH-wild-type (WT)), which arise de novo, and secondary (IDH-mutant), which evolve from lower grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', (103, 106))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (9, 47))	('IDH', 'Gene', '3417', (35, 38))	('IDH', 'Gene', '3417', (103, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('IDH', 'Gene', (160, 163))	('mutation', 'Var', (48, 56))	('glioblastomas', 'Disease', (65, 78))	('IDH', 'Gene', '3417', (160, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('gliomas', 'Disease', (203, 210))
209762	31357584	Quantification of the bands from the immunoblots defined higher FREM2 expression levels in glioblastomas for GBM versus REF (****, p < 0.0001) and GBM versus LGG (***, p = 0.0009), as shown in Figure 1C.	('glioblastomas', 'Phenotype', 'HP:0012174', (91, 104))	('higher', 'PosReg', (57, 63))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('expression levels', 'MPA', (70, 87))	('GBM', 'Var', (147, 150))	('glioblastomas', 'Disease', 'MESH:D005909', (91, 104))	('GBM', 'Phenotype', 'HP:0012174', (147, 150))	('glioblastomas', 'Disease', (91, 104))	('FREM2', 'Gene', '341640', (64, 69))	('FREM2', 'Gene', (64, 69))
209793	31357584	who reported amplification of the FREM2 gene and overexpression of the FREM2 protein in 64 gliosarcomas.	('FREM2', 'Gene', (34, 39))	('gliosarcomas', 'Disease', (91, 103))	('gliosarcomas', 'Disease', 'MESH:D018316', (91, 103))	('protein', 'Protein', (77, 84))	('amplification', 'Var', (13, 26))	('FREM2', 'Gene', '341640', (71, 76))	('overexpression', 'PosReg', (49, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('FREM2', 'Gene', (71, 76))	('FREM2', 'Gene', '341640', (34, 39))
209794	31357584	They further investigated different areas of the analyzed gliosarcomas, and found amplification of the FREM2 gene and overexpression of the FREM2 protein in the mesenchymal areas, and not in the glial tumor areas, of the gliosarcomas.	('FREM2', 'Gene', (140, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('overexpression', 'PosReg', (118, 132))	('FREM2', 'Gene', '341640', (103, 108))	('gliosarcomas', 'Disease', 'MESH:D018316', (58, 70))	('gliosarcomas', 'Disease', (221, 233))	('glial tumor', 'Disease', 'MESH:D005910', (195, 206))	('FREM2', 'Gene', (103, 108))	('amplification', 'Var', (82, 95))	('gliosarcomas', 'Disease', 'MESH:D018316', (221, 233))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('mesenchymal areas', 'CPA', (161, 178))	('FREM2', 'Gene', '341640', (140, 145))	('gliosarcomas', 'Disease', (58, 70))	('glial tumor', 'Disease', (195, 206))
209800	31357584	These findings are not so unexpected, because some clinically relevant mutations, such as TERT, have provided controversial predictions for glioblastoma due to various confounding factors.	('TERT', 'Gene', '7015', (90, 94))	('glioblastoma', 'Disease', (140, 152))	('glioblastoma', 'Disease', 'MESH:D005909', (140, 152))	('mutations', 'Var', (71, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('TERT', 'Gene', (90, 94))
209803	31357584	The therapeutic benefit here is a result of the formation of O6-guanine residues that cause mispairing with thymine, and the consequent DNA damage that triggers apoptosis.	('O6-guanine residues', 'Var', (61, 80))	('apoptosis', 'CPA', (161, 170))	('mispairing with thymine', 'MPA', (92, 115))	('DNA', 'MPA', (136, 139))	('O6-guanine', 'Chemical', '-', (61, 71))	('thymine', 'Chemical', 'MESH:D013941', (108, 115))	('triggers', 'Reg', (152, 160))
209804	31357584	In addition to this, temozolomide has undesired genotoxic properties that can cause the onset of genetic mutations upon relapse that were not present at diagnosis.	('cause', 'Reg', (78, 83))	('temozolomide', 'Chemical', 'MESH:D000077204', (21, 33))	('genetic mutations', 'Var', (97, 114))
209806	31357584	In addition, variant allele frequency enrichment of FREM2 in temozolomide-resistant glioblastoma cells has been reported previously.	('temozolomide', 'Chemical', 'MESH:D000077204', (61, 73))	('FREM2', 'Gene', '341640', (52, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('FREM2', 'Gene', (52, 57))	('variant', 'Var', (13, 20))	('glioblastoma', 'Disease', (84, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))
209807	31357584	The authors of this study performed whole exome deep sequencing of in-vitro temozolomide-treated residual cell cultures, and reported a 76% variant allele frequency enrichment of FREM2 in their aggressive glioblastoma-derived neurospheres.	('FREM2', 'Gene', (179, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('temozolomide', 'Chemical', 'MESH:D000077204', (76, 88))	('variant', 'Var', (140, 147))	('FREM2', 'Gene', '341640', (179, 184))	('glioblastoma', 'Disease', (205, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))
209808	31357584	It is now a challenge for the research community to determine whether the FREM2 changes detected are a cause for or a consequence of glioblastoma formation.	('glioblastoma', 'Disease', (133, 145))	('changes', 'Var', (80, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('FREM2', 'Gene', '341640', (74, 79))	('FREM2', 'Gene', (74, 79))
209815	31357584	The role of SPRY1 in glioblastoma cell lines was also examined and it was shown that SPRY1 knock-down reduced expression of mesenchymal markers and impaired invasiveness of U251 cells.	('SPRY1', 'Gene', (85, 90))	('glioblastoma', 'Disease', (21, 33))	('impaired invasiveness', 'Disease', 'MESH:D009422', (148, 169))	('SPRY1', 'Gene', '10252', (12, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('SPRY1', 'Gene', (12, 17))	('impaired invasiveness', 'Disease', (148, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('SPRY1', 'Gene', '10252', (85, 90))	('expression of', 'MPA', (110, 123))	('reduced', 'NegReg', (102, 109))	('knock-down', 'Var', (91, 101))	('U251', 'CellLine', 'CVCL:0021', (173, 177))
209834	31357584	Incubations with antibodies for the loading controls and secondary anti-mouse (A4416; Sigma Aldrich) and anti-rabbit (A0545; Sigma Aldrich) IgG whole molecule horseradish peroxidase antibodies produced in goat were for 1 h at 4  C, while shaking at 60 rpm.	('horseradish', 'Species', '3704', (159, 170))	('rabbit', 'Species', '9986', (110, 116))	('mouse', 'Species', '10090', (72, 77))	('A4416', 'Var', (79, 84))	('A0545', 'Var', (118, 123))	('goat', 'Species', '9925', (205, 209))
209839	31357584	After 1 h incubation at room temperature, the wells were washed again and secondary anti-mouse (A3562, Sigma Aldrich) and anti-rabbit (A3687, Sigma Aldrich) IgG whole molecule alkaline phosphatase antibodies produced in goat were prepared at 1:2000 dilution in 1% PBS-milk, and were applied (100 microL/well).	('alkaline phosphatase antibodies', 'Phenotype', 'HP:0003155', (176, 207))	('A3562', 'CellLine', 'CVCL:6479', (96, 101))	('phosphatase antibodies', 'Phenotype', 'HP:0003148', (185, 207))	('rabbit', 'Species', '9986', (127, 133))	('goat', 'Species', '9925', (220, 224))	('A3562', 'Var', (96, 101))	('rat', 'Species', '10116', (34, 37))	('PBS-milk', 'Disease', (264, 272))	('PBS-milk', 'Disease', 'MESH:D011535', (264, 272))	('A3687', 'Var', (135, 140))	('mouse', 'Species', '10090', (89, 94))
209874	27144334	Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas.	('Mutations', 'Var', (90, 99))	('gliomas', 'Disease', (169, 176))	('IDH1', 'Gene', '3417', (7, 11))	('IDH1', 'Gene', (131, 135))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('IDH1', 'Gene', '3417', (131, 135))	('down-regulation', 'NegReg', (42, 57))	('monocarboxylate transporters', 'MPA', (61, 89))	('isocitrate dehydrogenase 1', 'Gene', (103, 129))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('isocitrate dehydrogenase 1', 'Gene', '3417', (103, 129))	('IDH1', 'Gene', (7, 11))
209875	27144334	We recently showed that mutant IDH1 cells reprogram cellular metabolism by down-regulating pyruvate dehydrogenase (PDH) activity.	('mutant', 'Var', (24, 30))	('IDH1', 'Gene', '3417', (31, 35))	('reprogram', 'Reg', (42, 51))	('PDH', 'Gene', '54704', (115, 118))	('pyruvate dehydrogenase', 'Gene', '54704', (91, 113))	('down-regulating', 'NegReg', (75, 90))	('pyruvate dehydrogenase', 'Gene', (91, 113))	('activity', 'MPA', (120, 128))	('PDH', 'Gene', (115, 118))	('IDH1', 'Gene', (31, 35))
209878	27144334	We used 13C magnetic resonance spectroscopy and compared the conversion of hyperpolarized [1-13C]-pyruvate to [1-13C]-lactate in immortalized normal human astrocytes expressing mutant or wild-type IDH1 (NHAIDHmut and NHAIDHwt).	('13C', 'Chemical', 'MESH:C000615229', (93, 96))	('IDH', 'Gene', (206, 209))	('IDH', 'Gene', (220, 223))	('IDH1', 'Gene', (197, 201))	('IDH', 'Gene', '3417', (220, 223))	('IDH', 'Gene', '3417', (206, 209))	('13C', 'Chemical', 'MESH:C000615229', (113, 116))	('[1-13C]-lactate', 'Chemical', '-', (110, 125))	('human', 'Species', '9606', (149, 154))	('hyperpolarized [1-13C]-pyruvate', 'MPA', (75, 106))	('mutant', 'Var', (177, 183))	('[1-13C]-pyruvate', 'Chemical', '-', (90, 106))	('IDH', 'Gene', (197, 200))	('IDH', 'Gene', '3417', (197, 200))	('IDH1', 'Gene', '3417', (197, 201))	('13C', 'Chemical', 'MESH:C000615229', (8, 11))
209884	27144334	Finally analysis of low-grade glioma patient biopsy data from The Cancer Genome Atlas revealed that MCT1 and MCT4 expression was significantly reduced in mutant IDH1 tumors compared to wild-type.	('IDH1 tumors', 'Disease', (161, 172))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('patient', 'Species', '9606', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('MCT4 expression', 'MPA', (109, 124))	('MCT1', 'Gene', (100, 104))	('IDH1 tumors', 'Disease', 'MESH:D009369', (161, 172))	('Cancer Genome Atlas', 'Disease', (66, 85))	('MCT1', 'Gene', '6566', (100, 104))	('glioma', 'Disease', (30, 36))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (66, 85))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('mutant', 'Var', (154, 160))	('reduced', 'NegReg', (143, 150))
209885	27144334	Taken together, our study shows that reduced MCT expression is part of the metabolic reprogramming of mutant IDH1 gliomas.	('mutant', 'Var', (102, 108))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (109, 121))	('MCT', 'Gene', '6566', (45, 48))	('reduced MCT', 'Phenotype', 'HP:0031851', (37, 48))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('MCT', 'Gene', (45, 48))	('reduced', 'NegReg', (37, 44))	('IDH1 gliomas', 'Disease', (109, 121))
209886	27144334	This finding could impact treatment and has important implications for metabolic imaging of mutant IDH1 gliomas.	('impact', 'Reg', (19, 25))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))	('treatment', 'CPA', (26, 35))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (99, 111))	('mutant', 'Var', (92, 98))	('IDH1 gliomas', 'Disease', (99, 111))
209894	27144334	The recent discovery that mutations in metabolic enzymes such as succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase (IDH) can facilitate malignancy further emphasizes the connection between altered metabolism and cancer.	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('malignancy', 'Disease', 'MESH:D009369', (159, 169))	('malignancy', 'Disease', (159, 169))	('mutations', 'Var', (26, 35))	('facilitate', 'PosReg', (148, 158))	('IDH', 'Gene', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('IDH', 'Gene', '3417', (139, 142))	('isocitrate', 'Chemical', 'MESH:C034219', (113, 123))
209897	27144334	In contrast, mutations in the enzyme lead to its neomorphic ability to convert alpha-KG to 2-hydroxyglutarate (2-HG).	('2-HG', 'Chemical', 'MESH:C019417', (111, 115))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (91, 109))	('alpha-KG', 'Chemical', 'MESH:D007656', (79, 87))	('mutations', 'Var', (13, 22))	('convert alpha-KG to 2-hydroxyglutarate', 'MPA', (71, 109))
209899	27144334	The resulting hypermethylator phenotype is thought to lead to a block in differentiation and the initiation of tumorigenesis in mutant IDH1 cells.	('block', 'NegReg', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('hypermethylator', 'Var', (14, 29))	('IDH1', 'Gene', (135, 139))	('differentiation', 'CPA', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutant', 'Var', (128, 134))	('tumor', 'Disease', (111, 116))	('IDH1', 'Gene', '3417', (135, 139))
209900	27144334	Several studies have demonstrated that mutant IDH1 cells also undergo extensive metabolic reprogramming that extends beyond 2-HG production.	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('2-HG', 'Chemical', 'MESH:C019417', (124, 128))	('mutant', 'Var', (39, 45))	('metabolic reprogramming', 'CPA', (80, 103))
209901	27144334	were the first to perform a metabolomic analysis of wild-type and mutant IDH1 glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH1 glioma', 'Disease', 'MESH:D005910', (73, 84))	('mutant', 'Var', (66, 72))	('IDH1 glioma', 'Disease', (73, 84))
209902	27144334	They showed that levels of several amino acids and TCA cycle intermediates were reduced in mutant IDH1 cells relative to wild-type and similar results were obtained in a subsequent study of patient-derived mutant IDH1 tumor samples.	('levels of several amino acids', 'MPA', (17, 46))	('IDH1', 'Gene', '3417', (213, 217))	('IDH1', 'Gene', '3417', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('reduced', 'NegReg', (80, 87))	('TCA', 'Chemical', 'MESH:D014233', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('IDH1', 'Gene', (98, 102))	('TCA cycle intermediates', 'MPA', (51, 74))	('tumor', 'Disease', (218, 223))	('mutant', 'Var', (91, 97))	('IDH1', 'Gene', (213, 217))	('patient', 'Species', '9606', (190, 197))
209903	27144334	also found reduced levels of phosphocholine (PC) and increased levels of glycerophosphocholine (GPC) in mutant IDH1 glioma cells relative to wild-type cells and these results were in line with a subsequent study by Esmaeili et al.	('reduced', 'NegReg', (11, 18))	('PC', 'Chemical', 'MESH:D010767', (45, 47))	('phosphocholine', 'Chemical', 'MESH:D010767', (80, 94))	('PC', 'Chemical', 'MESH:D010767', (97, 99))	('phosphocholine', 'Chemical', 'MESH:D010767', (29, 43))	('levels of phosphocholine', 'MPA', (19, 43))	('mutant', 'Var', (104, 110))	('IDH1 glioma', 'Disease', 'MESH:D005910', (111, 122))	('increased', 'PosReg', (53, 62))	('IDH1 glioma', 'Disease', (111, 122))	('glycerophosphocholine', 'Chemical', 'MESH:D005997', (73, 94))	('levels of glycerophosphocholine', 'MPA', (63, 94))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
209904	27144334	that showed increased GPC levels in mutant IDH1 gliomas relative to wild-type tumors.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('increased', 'PosReg', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutant', 'Var', (36, 42))	('PC', 'Chemical', 'MESH:D010767', (23, 25))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (43, 55))	('GPC levels', 'MPA', (22, 32))	('IDH1 gliomas', 'Disease', (43, 55))
209905	27144334	These findings run counter to the increase in PC and drop in GPC typically observed in cancer and suggest that mutant IDH1 cells reprogram their metabolism differently.	('cancer', 'Disease', (87, 93))	('IDH1', 'Gene', (118, 122))	('mutant', 'Var', (111, 117))	('metabolism', 'MPA', (145, 155))	('PC', 'Chemical', 'MESH:D010767', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('IDH1', 'Gene', '3417', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('PC', 'Chemical', 'MESH:D010767', (62, 64))
209906	27144334	Another indicator of unusual metabolic reprogramming in mutant IDH1 gliomas is their silencing of LDHA expression shown by Chesnelong et al.	('IDH1 gliomas', 'Disease', 'MESH:D005910', (63, 75))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('LDHA', 'Gene', '3939', (98, 102))	('mutant', 'Var', (56, 62))	('IDH1 gliomas', 'Disease', (63, 75))	('silencing', 'NegReg', (85, 94))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('LDHA', 'Gene', (98, 102))
209907	27144334	to occur via promoter hypermethylation in patient-derived mutant IDH1 glioma models and patient samples.	('mutant', 'Var', (58, 64))	('patient', 'Species', '9606', (88, 95))	('IDH1 glioma', 'Disease', 'MESH:D005910', (65, 76))	('occur', 'Reg', (3, 8))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1 glioma', 'Disease', (65, 76))	('patient', 'Species', '9606', (42, 49))	('promoter', 'MPA', (13, 21))
209911	27144334	In particular, [1-13C]-pyruvate is readily hyperpolarized and has been widely used to probe the Warburg effect in cancer cells, animals, and recently in prostate cancer patients.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('[1-13C]-pyruvate', 'Var', (15, 31))	('patients', 'Species', '9606', (169, 177))	('cancer', 'Disease', (162, 168))	('prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('[1-13C]-pyruvate', 'Chemical', '-', (15, 31))	('prostate cancer', 'Disease', (153, 168))	('cancer', 'Disease', (114, 120))
209912	27144334	Our laboratory has used MRS to investigate the metabolic reprogramming of mutant IDH1 glioma cells.	('mutant', 'Var', (74, 80))	('IDH1 glioma', 'Disease', (81, 92))	('IDH1 glioma', 'Disease', 'MESH:D005910', (81, 92))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))
209913	27144334	We carried out an unbiased 1H MRS-based metabolomic analysis of glioma cells genetically engineered to express either the wild-type or mutant IDH1 enzyme and found that steady-state levels of glutamate, lactate and PC were reduced in mutant IDH1 cells.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('mutant', 'Var', (234, 240))	('IDH1', 'Gene', '3417', (142, 146))	('lactate', 'MPA', (203, 210))	('1H', 'Chemical', '-', (27, 29))	('reduced', 'NegReg', (223, 230))	('IDH1', 'Gene', '3417', (241, 245))	('mutant', 'Var', (135, 141))	('glutamate', 'Chemical', 'MESH:D018698', (192, 201))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('PC', 'Chemical', 'MESH:D010767', (215, 217))	('glioma', 'Disease', (64, 70))	('IDH1', 'Gene', (241, 245))	('lactate', 'Chemical', 'MESH:D019344', (203, 210))	('IDH1', 'Gene', (142, 146))
209914	27144334	In a separate study, we linked the reduction in glutamate levels to down-regulation of pyruvate dehydrogenase (PDH) activity in mutant IDH1 cells.	('pyruvate dehydrogenase', 'Gene', (87, 109))	('PDH', 'Gene', '54704', (111, 114))	('IDH1', 'Gene', (135, 139))	('glutamate', 'Chemical', 'MESH:D018698', (48, 57))	('mutant', 'Var', (128, 134))	('IDH1', 'Gene', '3417', (135, 139))	('reduction in glutamate levels', 'Phenotype', 'HP:0500150', (35, 64))	('down-regulation', 'NegReg', (68, 83))	('activity', 'MPA', (116, 124))	('glutamate levels', 'MPA', (48, 64))	('PDH', 'Gene', (111, 114))	('pyruvate dehydrogenase', 'Gene', '54704', (87, 109))	('reduction', 'NegReg', (35, 44))
209916	27144334	The down-regulation of PDH activity in mutant IDH1 cells might, therefore, be expected to result in increased lactate production from pyruvate in these cells.	('PDH', 'Gene', (23, 26))	('increased', 'PosReg', (100, 109))	('pyruvate', 'Chemical', 'MESH:D019289', (134, 142))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('lactate production from pyruvate', 'MPA', (110, 142))	('PDH', 'Gene', '54704', (23, 26))	('increased lactate production', 'Phenotype', 'HP:0003128', (100, 128))	('mutant', 'Var', (39, 45))	('lactate', 'Chemical', 'MESH:D019344', (110, 117))	('down-regulation', 'NegReg', (4, 19))	('activity', 'MPA', (27, 35))
209917	27144334	However, LDHA expression is typically silenced in mutant IDH1 gliomas, suggesting that pyruvate conversion to lactate could be reduced.	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('pyruvate conversion to lactate', 'MPA', (87, 117))	('LDHA', 'Gene', (9, 13))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (57, 69))	('pyruvate', 'Chemical', 'MESH:D019289', (87, 95))	('mutant', 'Var', (50, 56))	('LDHA', 'Gene', '3939', (9, 13))	('lactate', 'Chemical', 'MESH:D019344', (110, 117))	('reduced', 'NegReg', (127, 134))	('silenced', 'NegReg', (38, 46))	('IDH1 gliomas', 'Disease', (57, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
209918	27144334	The goal of this study was therefore to investigate the flux of pyruvate to lactate in mutant IDH1 glioma cells using hyperpolarized 13C MRS. We performed our studies on an immortalized normal human astrocyte (NHA) cell line genetically engineered to express either wild-type or mutant IDH1.	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', (286, 290))	('IDH1 glioma', 'Disease', 'MESH:D005910', (94, 105))	('lactate', 'Chemical', 'MESH:D019344', (76, 83))	('mutant', 'Var', (279, 285))	('IDH1', 'Gene', '3417', (94, 98))	('IDH1', 'Gene', '3417', (286, 290))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('13C', 'Chemical', 'MESH:C000615229', (133, 136))	('IDH1 glioma', 'Disease', (94, 105))	('human', 'Species', '9606', (193, 198))	('pyruvate', 'Chemical', 'MESH:D019289', (64, 72))
209919	27144334	Our results indicate that the flux of hyperpolarized [1-13C]-pyruvate to hyperpolarized [1-13C]-lactate is significantly reduced in mutant IDH1 cells compared to wild-type and this could be linked, at least in part, to reduced MCT1 and MCT4 expression in our mutant IDH1 cells.	('reduced', 'NegReg', (219, 226))	('[1-13C]-pyruvate', 'Chemical', '-', (53, 69))	('IDH1', 'Gene', (139, 143))	('IDH1', 'Gene', (266, 270))	('MCT4', 'Gene', (236, 240))	('[1-13C]-lactate', 'Chemical', '-', (88, 103))	('mutant', 'Var', (132, 138))	('reduced', 'NegReg', (121, 128))	('expression', 'MPA', (241, 251))	('mutant', 'Var', (259, 265))	('MCT1', 'Gene', (227, 231))	('IDH1', 'Gene', '3417', (266, 270))	('IDH1', 'Gene', '3417', (139, 143))	('MCT1', 'Gene', '6566', (227, 231))	('reduced MCT', 'Phenotype', 'HP:0031851', (219, 230))
209921	27144334	Our findings contribute to the understanding of mutant IDH1 cell metabolism and have important implications for the treatment and imaging of mutant IDH1 gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1', 'Gene', '3417', (148, 152))	('mutant', 'Var', (141, 147))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (148, 160))	('IDH1 gliomas', 'Disease', (148, 160))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('IDH1', 'Gene', (55, 59))	('IDH1', 'Gene', (148, 152))
209923	27144334	Following injection of hyperpolarized [1-13C]-pyruvate (delta=171.1 ppm) into the medium of perfused cells, production of hyperpolarized [1-13C]-lactate (delta=183.2 ppm) could be observed (Figure 1A).	('hyperpolarized [1-13C]-lactate', 'MPA', (122, 152))	('hyperpolarized [1-13C]-pyruvate', 'Var', (23, 54))	('[1-13C]-pyruvate', 'Chemical', '-', (38, 54))	('[1-13C]-lactate', 'Chemical', '-', (137, 152))
209933	27144334	As mentioned earlier, LDHA expression is silenced by hypermethylation in patient-derived mutant IDH1 glioma models.	('IDH1 glioma', 'Disease', 'MESH:D005910', (96, 107))	('LDHA', 'Gene', '3939', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH1 glioma', 'Disease', (96, 107))	('patient', 'Species', '9606', (73, 80))	('mutant', 'Var', (89, 95))	('hypermethylation', 'Var', (53, 69))	('silenced', 'NegReg', (41, 49))	('LDHA', 'Gene', (22, 26))
209951	27144334	2-HG produced by the IDH1 mutation is known to induce DNA hypermethylation resulting in reduced expression of several genes.	('DNA hypermethylation', 'MPA', (54, 74))	('mutation', 'Var', (26, 34))	('expression of several genes', 'MPA', (96, 123))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('IDH1', 'Gene', (21, 25))	('induce', 'Reg', (47, 53))	('reduced', 'NegReg', (88, 95))	('IDH1', 'Gene', '3417', (21, 25))
209952	27144334	Examination of the methylome of NHAIDHwt and NHAIDHmut cells indicated that the SLC16A3 gene coding for MCT4 was hypermethylated in NHAIDHmut cells relative to NHAIDHwt (Deltabeta = 0.39, p<0.0001, probe cg09147131).	('IDH', 'Gene', (48, 51))	('IDH', 'Gene', (35, 38))	('IDH', 'Gene', '3417', (48, 51))	('hypermethylated', 'Var', (113, 128))	('IDH', 'Gene', (163, 166))	('IDH', 'Gene', '3417', (35, 38))	('IDH', 'Gene', (135, 138))	('SLC16A3', 'Gene', (80, 87))	('IDH', 'Gene', '3417', (163, 166))	('IDH', 'Gene', '3417', (135, 138))	('MCT4', 'Gene', (104, 108))	('SLC16A3', 'Gene', '9123', (80, 87))
209960	27144334	We found that the mean normalized z-scores of mRNA expression were significantly reduced for both MCT1 (Figure 6A, 0.22 vs. -0.21, p<0.05) and MCT4 (Figure 6B, 0.25 vs. -0.15, p<0.005) in mutant IDH1 glioma samples (n=218) compared to wild-type IDH1 low-grade glioma (n=68).	('glioma', 'Disease', (200, 206))	('mRNA expression', 'MPA', (46, 61))	('MCT1', 'Gene', (98, 102))	('glioma', 'Disease', 'MESH:D005910', (260, 266))	('IDH1', 'Gene', (245, 249))	('glioma', 'Phenotype', 'HP:0009733', (260, 266))	('MCT4', 'MPA', (143, 147))	('IDH1 glioma', 'Disease', (195, 206))	('MCT1', 'Gene', '6566', (98, 102))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('IDH1', 'Gene', (195, 199))	('glioma', 'Disease', (260, 266))	('IDH1', 'Gene', '3417', (245, 249))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('reduced', 'NegReg', (81, 88))	('IDH1 glioma', 'Disease', 'MESH:D005910', (195, 206))	('IDH1', 'Gene', '3417', (195, 199))	('mutant', 'Var', (188, 194))
209961	27144334	This confirmed that our findings in the NHA model reflected the behavior of mutant IDH1 tumors in patients.	('IDH1 tumors', 'Disease', (83, 94))	('mutant', 'Var', (76, 82))	('patients', 'Species', '9606', (98, 106))	('IDH1 tumors', 'Disease', 'MESH:D009369', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
209962	27144334	Using a combination of MRS, cell and molecular biological assays, our study found that the expression of the monocarboxylate transporters MCT1 and MCT4 was reduced in our genetically engineered mutant IDH1 cells when compared to their wild-type IDH1 counterparts.	('expression', 'MPA', (91, 101))	('IDH1', 'Gene', (245, 249))	('mutant', 'Var', (194, 200))	('IDH1', 'Gene', '3417', (201, 205))	('MCT4', 'Gene', (147, 151))	('monocarboxylate transporters', 'MPA', (109, 137))	('MCT1', 'Gene', (138, 142))	('reduced', 'NegReg', (156, 163))	('IDH1', 'Gene', '3417', (245, 249))	('monocarboxylate', 'Chemical', '-', (109, 124))	('MCT1', 'Gene', '6566', (138, 142))	('IDH1', 'Gene', (201, 205))
209963	27144334	Whereas recently isolated patient-derived mutant IDH1 models are clinically more relevant, they do not provide a matched comparison between IDH1 wild-type and mutant cells.	('patient', 'Species', '9606', (26, 33))	('IDH1', 'Gene', '3417', (140, 144))	('mutant', 'Var', (42, 48))	('IDH1', 'Gene', '3417', (49, 53))	('IDH1', 'Gene', (140, 144))	('IDH1', 'Gene', (49, 53))
209964	27144334	In the current study we therefore used immortalized NHAs genetically engineered to express either the wild-type or mutant IDH1 enzyme in order to obtain a paired comparison of the effect of the IDH1 mutation on MCT expression.	('MCT', 'Gene', (211, 214))	('MCT', 'Gene', '6566', (211, 214))	('IDH1', 'Gene', (194, 198))	('mutant', 'Var', (115, 121))	('mutation', 'Var', (199, 207))	('IDH1', 'Gene', (122, 126))	('IDH1', 'Gene', '3417', (194, 198))	('IDH1', 'Gene', '3417', (122, 126))
209967	27144334	This could be due to their relatively low passage number (~P20) following mutant IDH1 transfection, considering that remodeling of the methylome has been shown to occur progressively.	('IDH1', 'Gene', '3417', (81, 85))	('~P20', 'Gene', '51673', (58, 62))	('~P20', 'Gene', (58, 62))	('IDH1', 'Gene', (81, 85))	('mutant', 'Var', (74, 80))
209970	27144334	By comparing hyperpolarized pyruvate to lactate conversion in lysates and in intact cells, we have identified the role of down-regulated MCT1 and MCT4 expression in reducing hyperpolarized lactate production in mutant IDH1 cells.	('MCT1', 'Gene', (137, 141))	('down-regulated', 'NegReg', (122, 136))	('lactate', 'Chemical', 'MESH:D019344', (40, 47))	('MCT1', 'Gene', '6566', (137, 141))	('reducing', 'NegReg', (165, 173))	('expression', 'MPA', (151, 161))	('IDH1', 'Gene', (218, 222))	('pyruvate', 'Chemical', 'MESH:D019289', (28, 36))	('hyperpolarized lactate production', 'MPA', (174, 207))	('mutant', 'Var', (211, 217))	('IDH1', 'Gene', '3417', (218, 222))	('reducing hyperpolarized lactate production', 'Phenotype', 'HP:0030086', (165, 207))	('MCT4', 'Gene', (146, 150))	('lactate', 'Chemical', 'MESH:D019344', (189, 196))
209971	27144334	However, it should be noted that lysing cells not only removes the cell membrane (and therefore the MCTs), but also dilutes the intracellular lactate.	('lysing', 'Var', (33, 39))	('cell membrane', 'MPA', (67, 80))	('intracellular lactate', 'MPA', (128, 149))	('dilutes', 'NegReg', (116, 123))	('MCTs', 'Chemical', '-', (100, 104))	('removes', 'NegReg', (55, 62))	('lactate', 'Chemical', 'MESH:D019344', (142, 149))
209972	27144334	We have previously shown that intracellular lactate levels are lower by 28+-14.8% (p<0.05) in mutant IDH1 cells and others have demonstrated that a reduction in intracellular lactate levels can reduce hyperpolarized lactate production.	('IDH1', 'Gene', (101, 105))	('hyperpolarized lactate production', 'MPA', (201, 234))	('reduction', 'NegReg', (148, 157))	('intracellular lactate levels', 'MPA', (161, 189))	('lower', 'NegReg', (63, 68))	('IDH1', 'Gene', '3417', (101, 105))	('lactate', 'Chemical', 'MESH:D019344', (44, 51))	('mutant', 'Var', (94, 100))	('lactate', 'Chemical', 'MESH:D019344', (216, 223))	('lactate', 'Chemical', 'MESH:D019344', (175, 182))	('intracellular lactate levels', 'MPA', (30, 58))	('reduce hyperpolarized lactate production', 'Phenotype', 'HP:0030086', (194, 234))	('reduce', 'NegReg', (194, 200))
209973	27144334	We therefore cannot rule out that lower intracellular lactate levels in mutant IDH1 cells also play a role in reduced hyperpolarized lactate production.	('IDH1', 'Gene', '3417', (79, 83))	('lower intracellular lactate', 'Phenotype', 'HP:0030086', (34, 61))	('hyperpolarized lactate production', 'MPA', (118, 151))	('lactate', 'Chemical', 'MESH:D019344', (54, 61))	('reduced', 'NegReg', (110, 117))	('mutant', 'Var', (72, 78))	('lower', 'NegReg', (34, 39))	('lactate', 'Chemical', 'MESH:D019344', (133, 140))	('IDH1', 'Gene', (79, 83))	('reduced hyperpolarized lactate production', 'Phenotype', 'HP:0030086', (110, 151))	('intracellular lactate levels', 'MPA', (40, 68))
209977	27144334	Further functional studies with MCT1/4 inhibitors and genetic knockdowns are needed to unravel the relative contributions of MCT1 and MCT4 towards hyperpolarized pyruvate transport in mutant IDH1 gliomas.	('mutant', 'Var', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (191, 203))	('IDH1 gliomas', 'Disease', (191, 203))	('MCT1', 'Gene', (125, 129))	('pyruvate', 'Chemical', 'MESH:D019289', (162, 170))	('hyperpolarized pyruvate transport', 'MPA', (147, 180))	('MCT1', 'Gene', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('MCT1', 'Gene', '6566', (125, 129))	('MCT1', 'Gene', '6566', (32, 36))
209980	27144334	who, using NHAs of similar origin as our study, found that the SLC16A3 (MCT4) gene was hypermethylated in mutant IDH1 cells (22.9 fold, p<0.05) relative to wild-type cells.	('mutant', 'Var', (106, 112))	('IDH1', 'Gene', (113, 117))	('SLC16A3', 'Gene', (63, 70))	('SLC16A3', 'Gene', '9123', (63, 70))	('IDH1', 'Gene', '3417', (113, 117))
209981	27144334	Our findings are also in agreement with a previous study showing that SLC16A3 (MCT4) mRNA levels were lower in patient-derived mutant IDH1 models compared to wild-type IDH1 glioblastoma models.	('mutant', 'Var', (127, 133))	('lower', 'NegReg', (102, 107))	('IDH1', 'Gene', '3417', (168, 172))	('IDH1 glioblastoma', 'Disease', (168, 185))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('IDH1 glioblastoma', 'Disease', 'MESH:D005909', (168, 185))	('SLC16A3', 'Gene', (70, 77))	('SLC16A3', 'Gene', '9123', (70, 77))	('mRNA levels', 'MPA', (85, 96))	('IDH1', 'Gene', (134, 138))	('patient', 'Species', '9606', (111, 118))	('IDH1', 'Gene', '3417', (134, 138))	('IDH1', 'Gene', (168, 172))
209982	27144334	Most importantly, our results are in line with the TCGA data wherein a reduction in SLC16A3 (MCT4) mRNA levels was observed in mutant IDH1 patient biopsy samples relative to wild-type.	('mutant', 'Var', (127, 133))	('reduction', 'NegReg', (71, 80))	('patient', 'Species', '9606', (139, 146))	('mRNA levels', 'MPA', (99, 110))	('IDH1', 'Gene', (134, 138))	('IDH1', 'Gene', '3417', (134, 138))	('SLC16A3', 'Gene', (84, 91))	('SLC16A3', 'Gene', '9123', (84, 91))
209983	27144334	Taken together, these findings suggest that MCT4 expression is likely down-regulated in mutant IDH1 cells via promoter hypermethylation.	('MCT4', 'Gene', (44, 48))	('expression', 'MPA', (49, 59))	('down-regulated', 'NegReg', (70, 84))	('IDH1', 'Gene', (95, 99))	('mutant', 'Var', (88, 94))	('IDH1', 'Gene', '3417', (95, 99))
209985	27144334	who found that the SLC16A1 (MCT1) gene is significantly methylated (1.7 fold, p<0.05) in mutant IDH1 cells compared to wild-type.	('IDH1', 'Gene', '3417', (96, 100))	('SLC16A1', 'Gene', (19, 26))	('SLC16A1', 'Gene', '6566', (19, 26))	('MCT1', 'Gene', (28, 32))	('MCT1', 'Gene', '6566', (28, 32))	('IDH1', 'Gene', (96, 100))	('mutant', 'Var', (89, 95))
209986	27144334	However, it should be noted that the cells used in that study were at a higher passage number (P40), possibly indicating that, ultimately, mutant IDH1 cells reduce MCT1 expression via more than one mechanism.	('IDH1', 'Gene', (146, 150))	('MCT1', 'Gene', (164, 168))	('P40', 'Gene', '3578', (95, 98))	('IDH1', 'Gene', '3417', (146, 150))	('MCT1', 'Gene', '6566', (164, 168))	('reduce', 'NegReg', (157, 163))	('mutant', 'Var', (139, 145))	('expression', 'MPA', (169, 179))	('P40', 'Gene', (95, 98))
209987	27144334	Indeed, a recent paper identified methylation-independent modulation of gene expression via insulator function modification in mutant IDH1 cells.	('mutant', 'Var', (127, 133))	('IDH1', 'Gene', (134, 138))	('modulation', 'Reg', (58, 68))	('gene expression', 'MPA', (72, 87))	('insulator', 'Protein', (92, 101))	('IDH1', 'Gene', '3417', (134, 138))	('modification', 'Var', (111, 123))
209988	27144334	Further studies are needed to fully understand the mechanisms by which MCT1 and MCT4 expression and function are modulated in mutant IDH1 cells.	('expression', 'MPA', (85, 95))	('MCT4', 'Gene', (80, 84))	('MCT1', 'Gene', '6566', (71, 75))	('function', 'MPA', (100, 108))	('IDH1', 'Gene', (133, 137))	('modulated', 'Reg', (113, 122))	('IDH1', 'Gene', '3417', (133, 137))	('MCT1', 'Gene', (71, 75))	('mutant', 'Var', (126, 132))
209989	27144334	Independent of mechanism, our findings highlight another aspect of the unusual metabolic reprogramming of mutant IDH1 cancer cells.	('cancer', 'Disease', (118, 124))	('mutant', 'Var', (106, 112))	('IDH1', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IDH1', 'Gene', '3417', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
209991	27144334	Mutant IDH1 glioma cells, however, display reduced PC levels indicating that they reprogram choline metabolism differently.	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('IDH1 glioma', 'Disease', (7, 18))	('PC levels', 'MPA', (51, 60))	('Mutant', 'Var', (0, 6))	('reduced', 'NegReg', (43, 50))	('PC', 'Chemical', 'MESH:D010767', (51, 53))	('IDH1 glioma', 'Disease', 'MESH:D005910', (7, 18))	('choline', 'Chemical', 'MESH:D002794', (92, 99))
209993	27144334	Our results indicate that mutant IDH1 cells, on the other hand, reduce glucose uptake and concomitant lactate production, in addition to silencing LDHA expression, making their metabolic phenotype different from non-IDH mutated cancer cells.	('IDH', 'Gene', (216, 219))	('reduce', 'NegReg', (64, 70))	('IDH1', 'Gene', (33, 37))	('IDH', 'Gene', (33, 36))	('mutant', 'Var', (26, 32))	('IDH', 'Gene', '3417', (216, 219))	('LDHA', 'Gene', '3939', (147, 151))	('silencing', 'NegReg', (137, 146))	('IDH1', 'Gene', '3417', (33, 37))	('lactate', 'Chemical', 'MESH:D019344', (102, 109))	('expression', 'MPA', (152, 162))	('IDH', 'Gene', '3417', (33, 36))	('cancer', 'Disease', (228, 234))	('lactate production', 'MPA', (102, 120))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('LDHA', 'Gene', (147, 151))	('glucose uptake', 'MPA', (71, 85))	('glucose', 'Chemical', 'MESH:D005947', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
209995	27144334	Our finding that expression of MCTs is reduced in mutant IDH1 gliomas is therefore also unusual.	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('expression', 'MPA', (17, 27))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (57, 69))	('MCTs', 'Chemical', '-', (31, 35))	('mutant', 'Var', (50, 56))	('reduced', 'NegReg', (39, 46))	('MCTs', 'Protein', (31, 35))	('IDH1 gliomas', 'Disease', (57, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
209996	27144334	However, it is in line with a study showing that NHE-1, another transporter involved in maintenance of intracellular pH and cell survival in glycolytic tumors, is silenced in 1p/19q co-deleted mutant IDH1 gliomas.	('NHE-1', 'Gene', '6548', (49, 54))	('glycolytic tumors', 'Disease', 'MESH:D009369', (141, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('silenced', 'NegReg', (163, 171))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('glycolytic tumors', 'Disease', (141, 158))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (200, 212))	('mutant', 'Var', (193, 199))	('IDH1 gliomas', 'Disease', (200, 212))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('NHE-1', 'Gene', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
209997	27144334	Silencing of NHE-1 and reduced MCT expression are consistent with reduced glycolytic production of lactate as well as silencing of LDHA expression; cells that produce less lactate do not require an increase in its export and are, therefore, less dependent on MCT and NHE-1 expression.	('reduced', 'NegReg', (66, 73))	('NHE-1', 'Gene', (267, 272))	('MCT', 'Gene', '6566', (259, 262))	('NHE-1', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('export', 'MPA', (214, 220))	('reduced MCT', 'Phenotype', 'HP:0031851', (23, 34))	('NHE-1', 'Gene', '6548', (267, 272))	('silencing', 'Var', (118, 127))	('lactate', 'Chemical', 'MESH:D019344', (172, 179))	('LDHA', 'Gene', '3939', (131, 135))	('MCT', 'Gene', (31, 34))	('NHE-1', 'Gene', '6548', (13, 18))	('glycolytic production of lactate', 'MPA', (74, 106))	('lactate', 'Chemical', 'MESH:D019344', (99, 106))	('MCT', 'Gene', '6566', (31, 34))	('reduced', 'NegReg', (23, 30))	('MCT', 'Gene', (259, 262))	('LDHA', 'Gene', (131, 135))
209998	27144334	Reduced MCT1 and MCT4 expression in mutant IDH1 gliomas could also have important implications for chemotherapy.	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('Reduced', 'NegReg', (0, 7))	('MCT4', 'Protein', (17, 21))	('mutant', 'Var', (36, 42))	('MCT1', 'Gene', (8, 12))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (43, 55))	('expression', 'MPA', (22, 32))	('IDH1 gliomas', 'Disease', (43, 55))	('MCT1', 'Gene', '6566', (8, 12))
210000	27144334	Additionally, the MCTs have been shown to impact the effects of chemotherapeutic agents such as 3-bromopyruvate and dichloroacetate by modulating their delivery to the cell.	('dichloroacetate', 'MPA', (116, 131))	('delivery to the cell', 'MPA', (152, 172))	('modulating', 'Reg', (135, 145))	('3-bromopyruvate', 'MPA', (96, 111))	('MCTs', 'Var', (18, 22))	('3-bromopyruvate', 'Chemical', 'MESH:C017092', (96, 111))	('impact', 'Reg', (42, 48))	('dichloroacetate', 'Chemical', 'MESH:D003999', (116, 131))	('MCTs', 'Chemical', '-', (18, 22))	('effects', 'MPA', (53, 60))
210003	27144334	However, in the current study, we show that expression of MCT1 and MCT4 is significantly reduced in mutant IDH1 gliomas.	('expression', 'MPA', (44, 54))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (107, 119))	('mutant', 'Var', (100, 106))	('MCT1', 'Gene', (58, 62))	('MCT4', 'Gene', (67, 71))	('IDH1 gliomas', 'Disease', (107, 119))	('MCT1', 'Gene', '6566', (58, 62))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('reduced', 'NegReg', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
210004	27144334	Further studies are needed to assess the utility of MCT inhibition as a treatment strategy for mutant IDH1 gliomas, but considering that the effectiveness of MCT inhibitors has been linked to MCT expression, inhibition of MCT expression and/or function likely would not provide a therapeutic opportunity for mutant IDH1 gliomas and this point should be considered in the planning of treatment for mutant IDH1 glioma patients.	('IDH1 gliomas', 'Disease', (315, 327))	('MCT', 'Gene', (192, 195))	('MCT', 'Gene', '6566', (52, 55))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (315, 327))	('MCT', 'Gene', '6566', (192, 195))	('IDH1 glioma', 'Disease', 'MESH:D005910', (404, 415))	('MCT', 'Gene', (158, 161))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('IDH1 glioma', 'Disease', 'MESH:D005910', (315, 326))	('IDH1 glioma', 'Disease', 'MESH:D005910', (102, 113))	('MCT', 'Gene', '6566', (158, 161))	('glioma', 'Phenotype', 'HP:0009733', (409, 415))	('glioma', 'Phenotype', 'HP:0009733', (320, 326))	('MCT', 'Gene', (222, 225))	('mutant', 'Var', (308, 314))	('IDH1 glioma', 'Disease', (404, 415))	('patients', 'Species', '9606', (416, 424))	('gliomas', 'Phenotype', 'HP:0009733', (320, 327))	('IDH1 gliomas', 'Disease', (102, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('MCT', 'Gene', '6566', (222, 225))	('MCT', 'Gene', (52, 55))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (102, 114))
210005	27144334	Nonetheless other metabolic targets such as mutant IDH and PDH may provide potential therapeutic opportunities.	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', '3417', (51, 54))	('PDH', 'Gene', (59, 62))	('mutant', 'Var', (44, 50))	('PDH', 'Gene', '54704', (59, 62))
210010	27144334	Hyperpolarized 13C MRS of pyruvate therefore has clear potential as an imaging method for brain tumors.	('Hyperpolarized 13C MRS', 'Var', (0, 22))	('13C', 'Chemical', 'MESH:C000615229', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('pyruvate', 'Chemical', 'MESH:D019289', (26, 34))	('brain tumors', 'Disease', (90, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('brain tumors', 'Phenotype', 'HP:0030692', (90, 102))	('brain tumors', 'Disease', 'MESH:D001932', (90, 102))
210012	27144334	Our finding regarding reduced expression of the MCTs, taken together with reduced intracellular lactate levels and the silencing of LDHA expression, indicate that in mutant IDH1 gliomas in vivo the production of hyperpolarized lactate is likely to be very limited.	('reduced intracellular lactate', 'Phenotype', 'HP:0030086', (74, 103))	('expression', 'MPA', (30, 40))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('LDHA', 'Gene', (132, 136))	('reduced', 'NegReg', (74, 81))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (173, 185))	('lactate', 'Chemical', 'MESH:D019344', (96, 103))	('mutant', 'Var', (166, 172))	('LDHA', 'Gene', '3939', (132, 136))	('MCTs', 'Chemical', '-', (48, 52))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('lactate', 'Chemical', 'MESH:D019344', (227, 234))	('intracellular lactate levels', 'MPA', (82, 110))	('IDH1 gliomas', 'Disease', (173, 185))
210013	27144334	While a head-to-head comparison of NHAIDHwt and NHAIDHmut tumors is not possible in vivo due to the lack of tumorigenicity of the NHAIDHwt cells, a comparison of patient-derived mutant IDH1 models, such as BT142, with wild-type IDH1 glioblastoma models, such as the U87 model, is feasible and provides a clinically relevant comparison.	('mutant', 'Var', (178, 184))	('IDH', 'Gene', (185, 188))	('IDH', 'Gene', '3417', (51, 54))	('tumor', 'Disease', (108, 113))	('IDH1 glioblastoma', 'Disease', 'MESH:D005909', (228, 245))	('IDH1 glioblastoma', 'Disease', (228, 245))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (58, 63))	('IDH1', 'Gene', '3417', (185, 189))	('IDH', 'Gene', '3417', (185, 188))	('IDH', 'Gene', (228, 231))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('IDH', 'Gene', (133, 136))	('NHAIDHmut tumors', 'Disease', 'MESH:D009369', (48, 64))	('IDH', 'Gene', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('IDH1', 'Gene', (228, 232))	('NHAIDHmut tumors', 'Disease', (48, 64))	('IDH', 'Gene', '3417', (228, 231))	('BT142', 'Chemical', '-', (206, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (233, 245))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('IDH', 'Gene', '3417', (133, 136))	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', '3417', (38, 41))	('IDH1', 'Gene', '3417', (228, 232))	('patient', 'Species', '9606', (162, 169))	('IDH1', 'Gene', (185, 189))
210015	27144334	While this could preclude the use of hyperpolarized lactate production as an indicator of response to therapy it could provide a method of confirming mutant IDH1 status.	('lactate', 'Chemical', 'MESH:D019344', (52, 59))	('hyperpolarized lactate production', 'MPA', (37, 70))	('IDH1', 'Gene', (157, 161))	('confirming', 'Reg', (139, 149))	('IDH1', 'Gene', '3417', (157, 161))	('mutant', 'Var', (150, 156))
210016	27144334	In summary, our finding that the expression of MCT1 and MCT4 is reduced in mutant IDH1 gliomas highlights the unusual metabolic reprogramming that occurs in mutant IDH1 tumors and has important implications for our understanding of these tumors and their treatment.	('MCT1', 'Gene', '6566', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('expression', 'MPA', (33, 43))	('tumors', 'Disease', (238, 244))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('IDH1 gliomas', 'Disease', (82, 94))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (82, 94))	('reduced', 'NegReg', (64, 71))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (169, 175))	('IDH1 tumors', 'Disease', 'MESH:D009369', (164, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('MCT1', 'Gene', (47, 51))	('mutant', 'Var', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('mutant', 'Var', (75, 81))	('MCT4', 'MPA', (56, 60))	('IDH1 tumors', 'Disease', (164, 175))
210018	27144334	Normal human astrocytes (Clonetics) were immortalized as described previously and transfected with lentiviral vectors expressing the wild-type IDH1 gene (NHAIDHwt) or mutant IDH1 R132H gene (NHAIDHmut).	('IDH', 'Gene', '3417', (174, 177))	('R132H', 'Mutation', 'rs121913500', (179, 184))	('IDH', 'Gene', '3417', (157, 160))	('IDH', 'Gene', '3417', (143, 146))	('IDH', 'Gene', (143, 146))	('IDH1', 'Gene', '3417', (174, 178))	('human', 'Species', '9606', (7, 12))	('IDH', 'Gene', '3417', (194, 197))	('IDH1', 'Gene', (143, 147))	('IDH', 'Gene', (194, 197))	('IDH1', 'Gene', (174, 178))	('mutant', 'Var', (167, 173))	('IDH', 'Gene', (174, 177))	('IDH1', 'Gene', '3417', (143, 147))	('IDH', 'Gene', (157, 160))
210044	27144334	Finally, Deltabeta values (difference in beta value between NHAIDHwt and NHAIDHmut cells) and p-values were assigned to the most significant probe difference within a gene.	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', '3417', (63, 66))	('Deltabeta', 'Var', (9, 18))	('IDH', 'Gene', '3417', (76, 79))
210046	27144334	Mean normalized z-scores for mRNA levels were determined for mutant and wild-type IDH1 glioma datasets.	('IDH1 glioma', 'Disease', (82, 93))	('mRNA levels', 'MPA', (29, 40))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('IDH1 glioma', 'Disease', 'MESH:D005910', (82, 93))	('mutant', 'Var', (61, 67))
210066	20614029	Application during surgery of 5-aminolevulinic acid (5-ALA), which is metabolized to fluorescent protoporphyrin IX, was shown to increase "total resections" from 36% to 65% as defined by loss of post-operative MRI contrast-enhancing tissue.	('protoporphyrin IX', 'Chemical', 'MESH:C028025', (97, 114))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (30, 51))	('increase', 'PosReg', (129, 137))	('5-aminolevulinic acid', 'Var', (30, 51))	('5-ALA', 'Chemical', 'MESH:C000614854', (53, 58))
210074	20614029	In a survey of 15 established human glioma tissue cell lines we observed that binding of QD-EGF varied considerably, consistent with the known variability of wildtype and mutant EGFR expression in gliomas.	('binding', 'Interaction', (78, 85))	('human', 'Species', '9606', (30, 35))	('EGFR', 'Gene', '1956', (178, 182))	('gliomas', 'Phenotype', 'HP:0009733', (197, 204))	('gliomas', 'Disease', (197, 204))	('EGFR', 'Gene', (178, 182))	('glioma', 'Disease', (197, 203))	('glioma', 'Disease', (36, 42))	('gliomas', 'Disease', 'MESH:D005910', (197, 204))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('mutant', 'Var', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
210075	20614029	The EGFR mutant vIII lacks the EGF binding site but is constituitively active and is expressed in ~60% of high-grade gliomas EGFR.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('EGFR', 'Gene', (4, 8))	('vIII', 'Gene', (16, 20))	('mutant', 'Var', (9, 15))	('EGFR', 'Gene', '1956', (125, 129))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('EGFR', 'Gene', (125, 129))	('vIII', 'Gene', '1351', (16, 20))	('EGF', 'Protein', (31, 34))	('EGFR', 'Gene', '1956', (4, 8))
210082	20614029	As in the cell cultures, G-28 cell line derived tumors in mouse brain showed extensive uptake of QD-EGF (Fig.	('QD-EGF', 'Var', (97, 103))	('mouse', 'Species', '10090', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('uptake', 'MPA', (87, 93))
210126	20614029	The data presented here show highly specific labeling of native human glioma biopsies that can be distinguished from normal brain tissue down to the single cell level by staining with QD-EGF and/or QD-MAb anti-EGFR.	('human', 'Species', '9606', (64, 69))	('glioma', 'Disease', (70, 76))	('EGFR', 'Gene', (210, 214))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('QD-EGF', 'Var', (184, 190))	('EGFR', 'Gene', '1956', (210, 214))
210129	20614029	A survey of 15 human glioma cell lines showed that MAbs against the ectodomain of EGFR could positively identify lines that were negative for EGF binding due to mutations in the EGF binding site or lines with low receptor density.	('EGFR', 'Gene', (82, 86))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('binding', 'Interaction', (182, 189))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('EGF', 'Protein', (178, 181))	('mutations', 'Var', (161, 170))	('human', 'Species', '9606', (15, 20))	('glioma', 'Disease', (21, 27))	('EGFR', 'Gene', '1956', (82, 86))	('negative', 'NegReg', (129, 137))
210161	20614029	Mouse monoclonal antibodies (MAb) 528 (IgG2a), H-11 (IgG1) and H199.12 (IgG2a), specific for the extracellular portion of human EGFR (Her1), were obtained from Dianova or purified from monoclonal cell culture supernatant by Protein G Sepharose chromatography.	('human', 'Species', '9606', (122, 127))	('Sepharose', 'Chemical', 'MESH:D012685', (234, 243))	('H199.12', 'CellLine', 'CVCL:B620', (63, 70))	('H-11', 'Gene', (47, 51))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('Her1', 'Gene', '1956', (134, 138))	('H199.12', 'Var', (63, 70))	('Her1', 'Gene', (134, 138))	('H-11', 'Gene', '3024', (47, 51))	('Mouse', 'Species', '10090', (0, 5))
210165	20614029	MAbs were either directly conjugated to amino-QDs (Invitrogen) or QDStAv (for biotinylated 528 and PDGFRalpha) or staining was carried out in 2 steps using MAb followed by QD-coupled goat anti-mouse (Fab)2 (GAMIG) (Q11021MP or A10195) (invitrogen).	('GAMIG', 'Chemical', '-', (207, 212))	('Q11021MP', 'Var', (215, 223))	('biotin', 'Chemical', 'MESH:D001710', (78, 84))	('A10195', 'Var', (227, 233))	('amino-QDs', 'Chemical', '-', (40, 49))	('goat', 'Species', '9925', (183, 187))	('mouse', 'Species', '10090', (193, 198))	('PDGFRalpha', 'Gene', '5156', (99, 109))	('PDGFRalpha', 'Gene', (99, 109))
210234	33291423	Our studies in various gliomas, glioneuronal tumors, and meningiomas demonstrated that high tumoral IDO1 expression on immunohistochemistry (and, in the case of meningiomas, high TDO2 expression) was associated with altered AMT metabolic rates estimated by tracer kinetic analysis from dynamic PET scanning.	('IDO1', 'Gene', (100, 104))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('TDO2', 'Gene', (179, 183))	('expression', 'MPA', (184, 194))	('AMT metabolic rates', 'MPA', (224, 243))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('meningioma', 'Phenotype', 'HP:0002858', (57, 67))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('high', 'Var', (174, 178))	('meningiomas', 'Disease', 'MESH:D008577', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('AMT', 'Chemical', 'MESH:C020774', (224, 227))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('meningioma', 'Phenotype', 'HP:0002858', (161, 171))	('meningiomas', 'Phenotype', 'HP:0002858', (57, 68))	('meningiomas', 'Disease', 'MESH:D008577', (161, 172))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumoral', 'Disease', (92, 99))	('tumoral', 'Disease', 'MESH:D009369', (92, 99))	('meningiomas', 'Disease', (57, 68))	('meningiomas', 'Phenotype', 'HP:0002858', (161, 172))	('meningiomas', 'Disease', (161, 172))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (32, 51))	('IDO1', 'Gene', '3620', (100, 104))	('TDO2', 'Gene', '6999', (179, 183))	('gliomas', 'Disease', (23, 30))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (32, 51))	('glioneuronal tumors', 'Disease', (32, 51))	('altered', 'Reg', (216, 223))
210245	33291423	The high uptake area included the sensorimotor cortex, and removal of the lesion has led to cessation of the seizures.	('seizures', 'Phenotype', 'HP:0001250', (109, 117))	('removal', 'Var', (59, 66))	('seizures', 'Disease', (109, 117))	('seizure', 'Phenotype', 'HP:0001250', (109, 116))	('seizures', 'Disease', 'MESH:D012640', (109, 117))
210271	33291423	In contrast, there was an inverse correlation between SUVs (and SUV ratios) and age at seizure onset (r = -0.51, p < 0.01 for the latter in Pearson's correlation): i.e., patients with FET-enhancing lesions were significantly younger at epilepsy onset than those with low FET uptake (14 vs. 27 years, respectively).	('patients', 'Species', '9606', (170, 178))	('FET-enhancing', 'Protein', (184, 197))	('FET', 'Chemical', 'MESH:C117289', (271, 274))	('lesions', 'Var', (198, 205))	('seizure', 'Phenotype', 'HP:0001250', (87, 94))	('epilepsy', 'Disease', (236, 244))	('seizure', 'Disease', (87, 94))	('epilepsy', 'Disease', 'MESH:D004827', (236, 244))	('FET', 'Chemical', 'MESH:C117289', (184, 187))	('seizure', 'Disease', 'MESH:D012640', (87, 94))	('epilepsy', 'Phenotype', 'HP:0001250', (236, 244))
210313	33291423	A more recent study used proton high-resolution magic angle spinning spectroscopy to measure multiple metabolites in gliomas and found both GABA and glutamate concentrations to be reduced in isocitrate dehydrogenase (IDH)-mutated lesions; however, these data were not studied from the prospect of epileptogenicity.	('isocitrate dehydrogenase', 'Gene', (191, 215))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('GABA', 'Chemical', 'MESH:D005680', (140, 144))	('isocitrate dehydrogenase', 'Gene', '3417', (191, 215))	('IDH', 'Gene', (217, 220))	('glutamate concentrations', 'MPA', (149, 173))	('reduced', 'NegReg', (180, 187))	('lesions', 'Var', (230, 237))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('IDH', 'Gene', '3417', (217, 220))	('glutamate', 'Chemical', 'MESH:D018698', (149, 158))
210347	30131308	Finally, high CMTM6 expression was associated with reduced survival time and may serve as a strong indicator of poor prognosis in gliomas.	('reduced', 'NegReg', (51, 58))	('survival time', 'CPA', (59, 72))	('high CMTM6 expression', 'Var', (9, 30))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
210352	30131308	Somatic mutations and copy number alterations of the tumor-associated genes are prevalent in gliomas with high CMTM6 expression.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('prevalent', 'Reg', (80, 89))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CMTM6', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('tumor', 'Disease', (53, 58))	('copy number alterations', 'Var', (22, 45))
210354	30131308	CMTM6 is a potential predictor of poor prognosis in glioma patients.	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('CMTM6', 'Var', (0, 5))	('patients', 'Species', '9606', (59, 67))	('glioma', 'Disease', (52, 58))
210359	30131308	Furthermore, patients with high CMTM6 expression had shorter median survival.	('high CMTM6 expression', 'Var', (27, 48))	('median survival', 'MPA', (61, 76))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (53, 60))
210362	30131308	Patients have been observed to benefit upon blockage of the interaction between programmed death-1 (PD-1) and ligand-1 (PD-L1) to inhibit the suppression of T cell immune responses.	('benefit', 'PosReg', (31, 38))	('inhibit', 'NegReg', (130, 137))	('T cell immune responses', 'CPA', (157, 180))	('Patients', 'Species', '9606', (0, 8))	('suppression', 'MPA', (142, 153))	('blockage', 'Var', (44, 52))	('interaction', 'Interaction', (60, 71))
210365	30131308	CMTM6 promotes PD-L1 expression in tumor cells against T cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PD-L1', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('promotes', 'PosReg', (6, 14))	('expression', 'MPA', (21, 31))	('tumor', 'Disease', (35, 40))	('CMTM6', 'Var', (0, 5))
210367	30131308	Previous studies published that CMTM6 suppresses T cell activation and the anti-tumor responses in vitro and in mouse melanoma models.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CMTM6', 'Var', (32, 37))	('tumor', 'Disease', (80, 85))	('suppresses', 'NegReg', (38, 48))	('mouse', 'Species', '10090', (112, 117))	('T cell activation', 'CPA', (49, 66))
210384	30131308	Meanwhile, according to 2016 WHO classification of tumors in the central nervous system, we divided gliomas into five group including lower-grade glioma (LGG) oligodendroglioma (LGG-Oligo, IDH-mutant LGG with TERT promoter mutation or 1p/19q codeletion), LGG astrocytoma (LGG-Astro, IDH-mutant LGG without TERT promoter mutation or 1p/19q codeletion and with ATRX mutation), LGG with wild-type IDH status (LGG IDH-wildtype), GBM with mutant IDH status (GBM IDH-mutant), and GBM with wild-type IDH status (GBM IDH-wildtype).	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('glioma (LGG) oligodendroglioma', 'Disease', 'MESH:D005910', (146, 176))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('LGG astrocytoma', 'Disease', 'MESH:D001254', (255, 270))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('LGG astrocytoma', 'Disease', (255, 270))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('mutant', 'Var', (434, 440))	('lower-grade', 'Disease', (134, 145))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('astrocytoma', 'Phenotype', 'HP:0009592', (259, 270))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('gliomas', 'Disease', (100, 107))
210385	30131308	Additionally, the higher expression level of CMTM6 was detected in the gliomas with a wild-type IDH gene (Fig.	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('CMTM6', 'Var', (45, 50))	('expression level', 'MPA', (25, 41))
210394	30131308	These results suggested that CMTM6 may play an important role in the progression of glioma.	('CMTM6', 'Var', (29, 34))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('glioma', 'Disease', (84, 90))
210396	30131308	Meanwhile, high frequency of mutations in EGFR, PTEN, and NF1 was observed in gliomas with high CMTM6 expression (Fig.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('observed', 'Reg', (66, 74))	('PTEN', 'Gene', (48, 52))	('mutations', 'Var', (29, 38))	('EGFR', 'Gene', (42, 46))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('NF1', 'Gene', (58, 61))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))
210397	30131308	2B, an amplification of Chr 7 accompanied with a deletion of Chr 10 was enriched in gliomas with high CMTM6 expression.	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('Chr 10', 'Gene', (61, 67))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('deletion', 'Var', (49, 57))
210398	30131308	Whereas, the incidence of the 1p/19q codeletion, which is a genomic hallmark in oligodendroglioma, reduced along with increasing of CMTM6 expression in gliomas (Fig.	('increasing', 'PosReg', (118, 128))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('oligodendroglioma', 'Disease', (80, 97))	('CMTM6', 'Gene', (132, 137))	('expression', 'MPA', (138, 148))	('oligodendroglioma', 'Disease', 'MESH:D009837', (80, 97))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('reduced', 'NegReg', (99, 106))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('1p/19q codeletion', 'Var', (30, 47))
210400	30131308	Although a 4q12 peak was also detected in the cases with low CMTM6 expression, the G score was obviously lower than the gliomas with high CMTM6 expression.	('lower', 'NegReg', (105, 110))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('G score', 'MPA', (83, 90))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('low CMTM6 expression', 'Var', (57, 77))	('gliomas', 'Disease', (120, 127))
210401	30131308	According to the aforementioned results, CMTM6 may play an essential role in the biological functions of glioma.	('glioma', 'Disease', (105, 111))	('CMTM6', 'Var', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
210405	30131308	Thus, in glioma CMTM6 is positively correlated with most relevant immune responses while negatively correlated with few relevant immune responses.	('glioma', 'Disease', (9, 15))	('CMTM6', 'Var', (16, 21))	('correlated', 'Reg', (36, 46))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('positively', 'PosReg', (25, 35))
210419	30131308	6, patients with high CMTM6 expression tumors experienced significantly shorter survival in whole gliomas.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('shorter', 'NegReg', (72, 79))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('high', 'Var', (17, 21))	('survival', 'MPA', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CMTM6', 'Gene', (22, 27))	('gliomas', 'Disease', (98, 105))	('patients', 'Species', '9606', (3, 11))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('tumors', 'Disease', (39, 45))
210421	30131308	Patients with gliomas in a high level of CMTM6 expression show inferior outcome, although some subgroups failed to acquire the statistical significance.	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('CMTM6 expression', 'Var', (41, 57))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('gliomas', 'Disease', (14, 21))
210423	30131308	These results revealed that CMTM6 may facilitate to serve as an indicator for the poor prognosis in glioma due to suppression of T cell immune response to antitumor.	('glioma', 'Disease', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('suppression', 'NegReg', (114, 125))	('tumor', 'Disease', (159, 164))	('CMTM6', 'Var', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
210425	30131308	As a novel therapeutic approach in the last decade, immunotherapy, especially the targeting PD-1/PD-L1, has achieved marked success in preclinical or clinical trials of many malignant tumors, such as those of lung cancer, breast cancer, renal cancer, melanoma, and head and neck cancer.	('targeting', 'Var', (82, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('renal cancer', 'Disease', (237, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('renal cancer', 'Phenotype', 'HP:0009726', (237, 249))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('breast cancer', 'Disease', (222, 235))	('head and neck cancer', 'Phenotype', 'HP:0012288', (265, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('neck cancer', 'Disease', 'MESH:D006258', (274, 285))	('neck cancer', 'Disease', (274, 285))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('PD-1/PD-L1', 'Gene', (92, 102))	('renal cancer', 'Disease', 'MESH:D007680', (237, 249))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('clinical', 'Species', '191496', (150, 158))	('lung cancer', 'Disease', (209, 220))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('malignant tumors', 'Disease', 'MESH:D018198', (174, 190))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('malignant tumors', 'Disease', (174, 190))	('clinical', 'Species', '191496', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
210432	30131308	Besides, CMTM6 was highly enriched in mesenchymal subtype gliomas.	('CMTM6', 'Var', (9, 14))	('mesenchymal subtype gliomas', 'Disease', (38, 65))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('mesenchymal subtype gliomas', 'Disease', 'MESH:D005910', (38, 65))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))
210433	30131308	Mesenchymal subtype is characterized by mesenchymal differentiation with NF1 mutations, presenting immunosuppression and aggression.	('aggression', 'Disease', 'MESH:D001523', (121, 131))	('aggression', 'Disease', (121, 131))	('Mesenchymal', 'Disease', (0, 11))	('mesenchymal differentiation', 'CPA', (40, 67))	('mutations', 'Var', (77, 86))	('aggression', 'Phenotype', 'HP:0000718', (121, 131))	('NF1', 'Gene', (73, 76))
210437	30131308	Meanwhile, a deletion peak of CDKN2A and CDKN2B, tumor suppressor genes, was also observed in the gliomas with high CMTM6 expression.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('CDKN2A', 'Gene', (30, 36))	('tumor', 'Disease', (49, 54))	('deletion', 'Var', (13, 21))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('CDKN2B', 'Gene', (41, 47))
210441	30131308	The correlation between CMTM6 and other immune checkpoints also suggested that CMTM6 may play a suppressive role in the anti-tumor immune responses.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('CMTM6', 'Var', (79, 84))	('suppressive', 'NegReg', (96, 107))
210446	30131308	Collectively, the special effect of CMTM6 demonstrate that CMTM6 functions as an important immune checkpoint inhibitor by modulating T-lymphocyte-mediated anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CMTM6', 'Var', (59, 64))	('tumor', 'Disease', (160, 165))	('modulating', 'Reg', (122, 132))
210447	30131308	In addition, CMTM6 was also involved in inflammatory reaction to promote the progression in gliomas, via activation of tumor-associated macrophage and dysfunctional T cells.	('tumor', 'Disease', (119, 124))	('dysfunctional', 'Disease', (151, 164))	('dysfunctional', 'Disease', 'MESH:D006331', (151, 164))	('activation', 'PosReg', (105, 115))	('CMTM6', 'Var', (13, 18))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('promote', 'PosReg', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
210451	30131308	As a result, CMTM6 may serve as a potential prognostic predictor for glioma patients.	('glioma', 'Disease', (69, 75))	('patients', 'Species', '9606', (76, 84))	('CMTM6', 'Var', (13, 18))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))
210455	30131308	In addition, the clinical trials of immune checkpoint blockades for gliomas, such as anti-PD-1 (NCT02359565), anti-PD-L1 (NCT02794883), anti-CTLA-4 (NCT03233152), and anti-lymphocyte activation gene 3 protein (LAG3, NCT02658981), are ongoing.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('anti-PD-1', 'Var', (85, 94))	('NCT03233152', 'Var', (149, 160))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('NCT02359565', 'Var', (96, 107))	('NCT02794883', 'Var', (122, 133))	('clinical', 'Species', '191496', (17, 25))
210457	30131308	Thus, it is suggested that combined anti-CMTM6 with other immune checkpoint blockades may be a novel approach for glioma treatments.	('glioma', 'Disease', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('anti-CMTM6', 'Var', (36, 46))
210458	30131308	Future studies are necessary to demonstrate that inhibiting CMTM6 can reduce the tumor growth and extend the survival of gliomas.	('extend', 'PosReg', (98, 104))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('inhibiting', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('reduce', 'NegReg', (70, 76))	('CMTM6', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('survival', 'CPA', (109, 117))	('tumor', 'Disease', (81, 86))
210459	30131308	Our findings indicated that CMTM6 may serve as an important biomarker in gliomas including the tumor mutational profile, genomic, histologic and clinical features.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('clinical', 'Species', '191496', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CMTM6', 'Var', (28, 33))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('gliomas', 'Disease', (73, 80))
210468	30069164	Expression profile analysis of antisense long non-coding RNA identifies WDFY3-AS2 as a prognostic biomarker in diffuse glioma Increasing evidence has shown that long non-coding RNAs (lncRNAs) are important prognostic biomarkers and epigenetic regulators with critical roles in cancer initiation and progression.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('long non-coding', 'Var', (161, 176))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('WDFY3', 'Gene', (72, 77))	('WDFY3', 'Gene', '23001', (72, 77))	('cancer initiation', 'Disease', 'MESH:D009369', (277, 294))	('glioma', 'Disease', (119, 125))	('cancer initiation', 'Disease', (277, 294))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
210469	30069164	However, the expression and clinical prognostic value of antisense lncRNAs in diffuse glioma patients remain unknown.	('glioma', 'Disease', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('antisense', 'Var', (57, 66))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('patients', 'Species', '9606', (93, 101))
210473	30069164	Expression profiling identified 169 aberrantly expressed antisense lncRNAs between lower grade glioma (LGG) (grade II and III) and glioblastoma multiforme (GBM), 113 antisense lncRNAs between LGG IDH-wt and IDH-mut samples, and 70 antisense lncRNAs between GBM IDH-wt and IDH-mut samples, respectively.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (131, 154))	('IDH', 'Gene', (261, 264))	('antisense', 'Reg', (166, 175))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('IDH', 'Gene', '3417', (196, 199))	('IDH', 'Gene', (272, 275))	('IDH', 'Gene', '3417', (261, 264))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('antisense', 'Var', (57, 66))	('IDH', 'Gene', '3417', (272, 275))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('IDH', 'Gene', (207, 210))	('glioblastoma multiforme', 'Disease', (131, 154))	('IDH', 'Gene', '3417', (207, 210))	('IDH', 'Gene', (196, 199))
210478	30069164	Kaplan-Meier analysis found that patients with high WDFY3-AS2 expression had longer OS than the low expression ones in the stratified cohorts.	('longer', 'PosReg', (77, 83))	('patients', 'Species', '9606', (33, 41))	('WDFY3-AS2', 'Gene', '404201', (52, 61))	('WDFY3-AS2', 'Gene', (52, 61))	('high', 'Var', (47, 51))
210484	30069164	Although recent studies have found several genetic mutations and deregulated signaling pathways, these findings are still insufficient to uncover the molecular basis of gliomagenesis.	('mutations', 'Var', (51, 60))	('deregulated', 'Reg', (65, 76))	('signaling pathways', 'Pathway', (77, 95))	('glioma', 'Disease', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))
210486	30069164	Moreover, accumulating reports found that dysregulated expression of antisense lncRNAs plays a crucial role in development and progression of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('antisense', 'Protein', (69, 78))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('expression', 'MPA', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('dysregulated', 'Var', (42, 54))
210494	30069164	In this study, we profiled differentially expressed antisense lncRNAs in diffuse glioma.	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('antisense', 'Var', (52, 61))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Disease', (81, 87))
210495	30069164	Combined with prognosis and tumor progression, we identified a new antisense lncRNA WDFY3-AS2 with length of 3383 nt which is located in chromosome 4q21.23.	('tumor', 'Disease', (28, 33))	('antisense', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('WDFY3-AS2', 'Gene', '404201', (84, 93))	('WDFY3-AS2', 'Gene', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
210512	30069164	Based on the Wald P values, 248 antisense lncRNAs were correlated with patients' overall survival.	('patients', 'Species', '9606', (71, 79))	('correlated', 'Reg', (55, 65))	('antisense', 'Var', (32, 41))
210516	30069164	The Venn diagram presented the workflow used to identify antisense lncRNAs associated with prognosis and tumor progression (Fig.	('antisense', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('associated', 'Reg', (75, 85))	('tumor', 'Disease', (105, 110))
210526	30069164	4, the AUC of WDFY3-AS2 (0.796) was much higher than that of age (0.611), grade (0.764), subtype (0.676), IDH status (0.706) and MGMT promoter status (0.629).	('0.796', 'Var', (25, 30))	('IDH', 'Gene', '3417', (106, 109))	('WDFY3-AS2', 'Gene', '404201', (14, 23))	('WDFY3-AS2', 'Gene', (14, 23))	('MGMT', 'Gene', (129, 133))	('MGMT', 'Gene', '4255', (129, 133))	('higher', 'PosReg', (41, 47))	('AUC', 'MPA', (7, 10))	('IDH', 'Gene', (106, 109))
210532	30069164	Our results indicated that low level of WDFY3-AS2 was significantly associated with unfavorable prognosis in patients with diffuse glioma.	('glioma', 'Disease', (131, 137))	('associated', 'Reg', (68, 78))	('patients', 'Species', '9606', (109, 117))	('low level', 'Var', (27, 36))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('WDFY3-AS2', 'Gene', '404201', (40, 49))	('WDFY3-AS2', 'Gene', (40, 49))
210557	30069164	mir-221, mir-26a, mir-135a, mir-9 and mir-139 showed the potential interaction with WDFY3-AS2.	('mir-135a', 'Var', (18, 26))	('mir-9', 'Gene', (28, 33))	('mir-221', 'Gene', (0, 7))	('mir-139', 'Gene', '406931', (38, 45))	('mir-26a', 'Gene', '407015', (9, 16))	('mir-139', 'Gene', (38, 45))	('interaction', 'Interaction', (67, 78))	('mir-221', 'Gene', '407006', (0, 7))	('WDFY3-AS2', 'Gene', '404201', (84, 93))	('mir-26a', 'Gene', (9, 16))	('WDFY3-AS2', 'Gene', (84, 93))
210570	29434027	Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma Gangliogliomas (WHO grade I) are rare tumors affecting the central nervous system and are most frequently observed in children.	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('ganglioglioma', 'Disease', 'MESH:D018303', (120, 133))	('patient', 'Species', '9606', (97, 104))	('rare tumors', 'Disease', 'MESH:D035583', (167, 178))	('c.1794_1796dupTAC;p.Thr599dup', 'Var', (54, 83))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('rare tumors', 'Disease', (167, 178))	('tumors affecting the central nervous system', 'Phenotype', 'HP:0100006', (172, 215))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('p.Thr599dup', 'Mutation', 'p.599dup', (72, 83))	('duplication c.1794_1796dupTAC;p.Thr599dup', 'Var', (42, 83))	('c.1794_1796dupTAC', 'Mutation', 'rs727502902', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('ganglioglioma', 'Disease', (120, 133))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('gliomas', 'Disease', (141, 148))	('children', 'Species', '9606', (252, 260))	('p.Thr599dup', 'Var', (72, 83))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
210572	29434027	Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13.	('c.1794_1796dupTAC; p.Thr599dup', 'Var', (58, 88))	('NM_004333.4', 'Var', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('BRAF', 'Gene', '673', (23, 27))	('patient', 'Species', '9606', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('p.Thr599dup', 'Var', (77, 88))	('ganglioglioma', 'Disease', 'MESH:D018303', (197, 210))	('BRAF', 'Gene', (23, 27))	('tumor', 'Disease', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('p.Thr599dup', 'Mutation', 'p.599dup', (77, 88))	('ganglioglioma', 'Disease', (197, 210))	('NM_004333.4:c.1794_1796dupTAC', 'Mutation', 'rs727502902', (46, 75))
210574	29434027	Based on previous studies, this variant is likely to increase kinase activity, similar to the well-characterized BRAF p.Val600Glu (V600E) pathogenic variant.	('V600E', 'Mutation', 'rs113488022', (131, 136))	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('increase', 'PosReg', (53, 61))	('p.Val600Glu', 'Mutation', 'rs113488022', (118, 129))	('kinase activity', 'MPA', (62, 77))	('p.Val600Glu', 'Var', (118, 129))
210575	29434027	In addition, although the p.T599dup somatic mutation has been documented rarely in human cancers, the variant has not been previously reported in ganglioglioma.	('p.T599dup', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('human', 'Species', '9606', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('p.T599dup', 'Mutation', 'p.599dupT', (26, 35))	('ganglioglioma', 'Disease', (146, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('ganglioglioma', 'Disease', 'MESH:D018303', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
210590	29434027	DNA derived from peripheral blood and tumor was independently used as template to PCR amplify BRAF exon 15 using the following primer sequences: exon 15F 5'-GTAAAACGACGGCCAGACTCTTCATAATGCTTGCTCTGA-3' and exon 15R 5'-CAGGAAACAGCTATGACAGTAACTCAGCAGCATCTCAGG-3'.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('BRAF', 'Gene', (94, 98))	('exon 15R', 'Var', (204, 212))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('exon 15F', 'Var', (145, 153))	('BRAF', 'Gene', '673', (94, 98))
210593	29434027	Potential variants were screened for cancer relevance based on previous reports in ClinVar, COSMIC, dbSNP, ICGC, and TCGA databases.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('variants', 'Var', (10, 18))
210595	29434027	Our somatic analysis detected a pathogenic variant c.1794_1796dupTAC;p.Thr599dup in the BRAF gene (Table 1).	('BRAF', 'Gene', (88, 92))	('pathogenic', 'Reg', (32, 42))	('BRAF', 'Gene', '673', (88, 92))	('p.Thr599dup', 'Mutation', 'p.599dup', (69, 80))	('c.1794_1796dupTAC', 'Mutation', 'rs727502902', (51, 68))	('c.1794_1796dupTAC;p.Thr599dup', 'Var', (51, 80))	('p.Thr599dup', 'Var', (69, 80))
210596	29434027	The duplication of three nucleotides results in an in-frame introduction of a threonine residue at amino acid 599 (Fig.	('introduction', 'PosReg', (60, 72))	('duplication', 'Var', (4, 15))	('results in', 'Reg', (37, 47))	('threonine', 'Chemical', 'MESH:D013912', (78, 87))
210597	29434027	Histology reports indicated a 70% tumor cellularity; however, the variant allele frequency (VAF) of somatic mutations suggests a much lower actual tumor cellularity.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('lower', 'NegReg', (134, 139))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (108, 117))	('actual tumor', 'Disease', 'MESH:D009369', (140, 152))	('actual tumor', 'Disease', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('variant', 'Var', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
210605	29434027	Previous in vitro studies of the p.T599dup variant demonstrated kinase activity and cellular MEK/ERK activation potential comparable to that of BRAF p.V600E, suggesting that a similar therapeutic approach as for V600E may be effective.	('ERK', 'Gene', (97, 100))	('activation', 'PosReg', (101, 111))	('p.T599dup', 'Mutation', 'p.599dupT', (33, 42))	('BRAF', 'Gene', '673', (144, 148))	('MEK', 'Gene', (93, 96))	('kinase activity', 'MPA', (64, 79))	('MEK', 'Gene', '5609', (93, 96))	('V600E', 'Mutation', 'rs113488022', (212, 217))	('BRAF', 'Gene', (144, 148))	('p.V600E', 'Mutation', 'rs113488022', (149, 156))	('V600E', 'Mutation', 'rs113488022', (151, 156))	('ERK', 'Gene', '5594', (97, 100))	('p.T599dup', 'Var', (33, 42))
210606	29434027	Presumably, the duplication of the threonine residue destabilizes the inactive conformation of the kinase domain.	('duplication', 'Var', (16, 27))	('inactive conformation of the kinase domain', 'MPA', (70, 112))	('destabilizes', 'NegReg', (53, 65))	('threonine', 'Chemical', 'MESH:D013912', (35, 44))
210607	29434027	The c.1794_1796TACdup variant was classified as Tier II, Level C variant in accordance with the AMP/ASCO Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer.	('Cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ASCO', 'Chemical', '-', (100, 104))	('c.1794_1796TACdup', 'Var', (4, 21))	('AMP', 'Chemical', 'MESH:D000249', (96, 99))	('Cancer', 'Disease', (191, 197))
210608	29434027	The variant has a potential clinical actionability based on reports demonstrating therapeutic and diagnostic/prognostic utility of BRAF p.V600 substitution mutations.	('p.V600 substitution mutations', 'Var', (136, 165))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', '673', (131, 135))
210609	29434027	Although the c.1794_1796dupTAC somatic variant has been observed in other cancers, notably in thyroid cancer, melanoma, and pilocytic astrocytoma, it has not been previously described in low-grade ganglioglioma.	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('thyroid cancer', 'Disease', 'MESH:D013964', (94, 108))	('cancers', 'Disease', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (124, 145))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('observed', 'Reg', (56, 64))	('thyroid cancer', 'Phenotype', 'HP:0002890', (94, 108))	('pilocytic astrocytoma', 'Disease', (124, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('ganglioglioma', 'Disease', 'MESH:D018303', (197, 210))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('thyroid cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('c.1794_1796dupTAC', 'Mutation', 'rs727502902', (13, 30))	('ganglioglioma', 'Disease', (197, 210))	('c.1794_1796dupTAC', 'Var', (13, 30))
210611	29434027	The mutation duplicates the threonine residue at amino acid 599.	('mutation duplicates', 'Var', (4, 23))	('threonine', 'Chemical', 'MESH:D013912', (28, 37))	('duplicates', 'Var', (13, 23))
210613	29434027	Specifically, the p.V600E variant accounts for >70% of reported somatic pathogenic mutations in BRAF.	('BRAF', 'Gene', '673', (96, 100))	('p.V600E', 'Mutation', 'rs113488022', (18, 25))	('BRAF', 'Gene', (96, 100))	('p.V600E', 'Var', (18, 25))
210614	29434027	Specific to gangliogliomas, BRAF substitutions are quite common.	('BRAF', 'Gene', '673', (28, 32))	('ganglioglioma', 'Disease', 'MESH:D018303', (12, 25))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('substitutions', 'Var', (33, 46))	('BRAF', 'Gene', (28, 32))	('ganglioglioma', 'Disease', (12, 25))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
210615	29434027	For example, BRAF p.V600E has been observed in 25%-35% of adult and pediatric gangliogliomas, whereas other BRAF genetic alterations and KIAA1549-BRAF and FAM131B-BRAF fusions have also been observed in low-grade gliomas, the former fusion having been identified in gangliogliomas.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('observed', 'Reg', (191, 199))	('KIAA1549-BRAF', 'Disease', 'None', (137, 150))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('ganglioglioma', 'Disease', (266, 279))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('ganglioglioma', 'Disease', 'MESH:D018303', (78, 91))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('gliomas', 'Disease', (273, 280))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('BRAF', 'Gene', '673', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (273, 279))	('BRAF', 'Gene', (108, 112))	('gliomas', 'Disease', (213, 220))	('gliomas', 'Disease', 'MESH:D005910', (273, 280))	('BRAF', 'Gene', '673', (146, 150))	('p.V600E', 'Mutation', 'rs113488022', (18, 25))	('KIAA1549-BRAF', 'Disease', (137, 150))	('ganglioglioma', 'Disease', (78, 91))	('BRAF', 'Gene', (146, 150))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('p.V600E', 'Var', (18, 25))	('ganglioglioma', 'Disease', 'MESH:D018303', (266, 279))	('gliomas', 'Disease', (85, 92))	('FAM131B', 'Gene', (155, 162))	('FAM131B', 'Gene', '9715', (155, 162))	('gliomas', 'Phenotype', 'HP:0009733', (273, 280))	('gliomas', 'Disease', 'MESH:D005910', (213, 220))
210616	29434027	All of the above BRAF alterations cause increased activation of BRAF and therefore constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.	('BRAF', 'Gene', '673', (64, 68))	('MAPK', 'Gene', '5594', (148, 152))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', '673', (17, 21))	('activation', 'PosReg', (50, 60))	('MAPK', 'Gene', (148, 152))	('BRAF', 'Gene', (17, 21))	('alterations', 'Var', (22, 33))	('activation', 'PosReg', (96, 106))
210617	29434027	Previous studies have indicated that the c.1794_1796dupTAC mutation described here is pathogenic and mimics the increased oncogenic kinase activity associated with BRAF p.V600E.	('p.V600E', 'Var', (169, 176))	('c.1794_1796dupTAC', 'Mutation', 'rs727502902', (41, 58))	('BRAF', 'Gene', '673', (164, 168))	('BRAF', 'Gene', (164, 168))	('oncogenic kinase activity', 'MPA', (122, 147))	('p.V600E', 'Mutation', 'rs113488022', (169, 176))	('c.1794_1796dupTAC', 'Var', (41, 58))
210618	29434027	Inhibitors that can target aberrant BRAF expression (e.g., vemurafenib, dabrafenib) have been shown to positively impact disease outcomes and treatment responses in patients with BRAF V600 substitutions.	('impact', 'Reg', (114, 120))	('BRAF', 'Gene', (36, 40))	('vemurafenib', 'Chemical', 'MESH:D000077484', (59, 70))	('treatment responses', 'CPA', (142, 161))	('BRAF', 'Gene', '673', (179, 183))	('V600 substitutions', 'Var', (184, 202))	('BRAF', 'Gene', (179, 183))	('patients', 'Species', '9606', (165, 173))	('disease outcomes', 'CPA', (121, 137))	('dabrafenib', 'Chemical', 'MESH:C561627', (72, 82))	('BRAF', 'Gene', '673', (36, 40))
210622	29434027	In conclusion, we suggest that screening for somatic BRAF alterations should extend beyond the well-documented hotspot variant BRAF p.V600E, as the pathogenic variant p.T599dup described here mimics the increased oncogenic kinase activity associated with p.V600E.	('p.V600E', 'Var', (132, 139))	('BRAF', 'Gene', '673', (53, 57))	('p.T599dup', 'Var', (167, 176))	('BRAF', 'Gene', '673', (127, 131))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', (127, 131))	('p.T599dup', 'Mutation', 'p.599dupT', (167, 176))	('p.V600E', 'Mutation', 'rs113488022', (255, 262))	('p.V600E', 'Var', (255, 262))	('p.V600E', 'Mutation', 'rs113488022', (132, 139))	('oncogenic kinase activity', 'MPA', (213, 238))
210623	29434027	It is critical that genetic assays, particularly for BRAF mutations, are capable of detecting a full range of genotypes, as the identification of pathogenic variants can lead to targeted treatment approaches for patients, as discussed here.	('mutations', 'Var', (58, 67))	('lead to', 'Reg', (170, 177))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('patients', 'Species', '9606', (212, 220))	('variants', 'Var', (157, 165))
210641	28475680	1p19q codeletion in combination with IDH mutation now define oligodendroglioma, a diagnosis that used to be associated with considerable uncertainty based on morphological classification alone.	('oligodendroglioma', 'Disease', 'MESH:D009837', (61, 78))	('1p19q', 'Var', (0, 5))	('oligodendroglioma', 'Disease', (61, 78))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3417', (37, 40))
210647	28475680	The assessment of molecular markers aimed at assigning patients to one of three molecular groups: (i) the low-risk group being IDH mutated, 1p19q codeleted, (ii) the intermediate-risk group being IDH mutated and 1p19q non-codeleted, and (iii) the high-risk group being IDH wild-type.	('IDH', 'Gene', (127, 130))	('1p19q', 'Var', (140, 145))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', '3417', (196, 199))	('IDH', 'Gene', (269, 272))	('1p19q', 'Var', (212, 217))	('IDH', 'Gene', '3417', (269, 272))	('patients', 'Species', '9606', (55, 63))	('IDH', 'Gene', (196, 199))
133214	28475680	Samples classified as IDH wild-type after MLPA assessment were subject to PCR and DNA sequencing for IDH1 and IDH2 mutations.	('IDH1', 'Gene', (101, 105))	('IDH2', 'Gene', '3418', (110, 114))	('mutations', 'Var', (115, 124))	('IDH', 'Gene', (110, 113))	('IDH1', 'Gene', '3417', (101, 105))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (22, 25))	('IDH2', 'Gene', (110, 114))	('IDH', 'Gene', '3417', (101, 104))
210649	28475680	At hospital in region B an integrated approach was used, with immunohistochemistry for IDH1 R132H and alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein expression.	('ATRX', 'Gene', (158, 162))	('IDH1', 'Gene', '3417', (87, 91))	('ATRX', 'Gene', '546', (158, 162))	('R132H', 'Var', (92, 97))	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (102, 156))	('R132H', 'Mutation', 'rs121913500', (92, 97))	('IDH1', 'Gene', (87, 91))	('mental retardation', 'Phenotype', 'HP:0001249', (120, 138))
210651	28475680	Samples classified as IDH wild-type after immunohistochemistry were subject to PCR and DNA sequencing for IDH1 and IDH2 mutations.	('IDH2', 'Gene', (115, 119))	('IDH', 'Gene', '3417', (106, 109))	('IDH2', 'Gene', '3418', (115, 119))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', (115, 118))	('IDH1', 'Gene', (106, 110))	('IDH', 'Gene', '3417', (115, 118))	('mutations', 'Var', (120, 129))	('IDH', 'Gene', '3417', (22, 25))	('IDH1', 'Gene', '3417', (106, 110))	('IDH', 'Gene', (106, 109))
210652	28475680	In samples with IDH mutation and ATRX presence, we carried out fluorescence insitu hybridization (FISH) to confirm the 1p19q codeletion.	('1p19q', 'Var', (119, 124))	('ATRX', 'Gene', '546', (33, 37))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', '3417', (16, 19))	('ATRX', 'Gene', (33, 37))
210653	28475680	However, in three cases we assumed 1p19q codeletion based on IDH and ATRX presence, but without FISH confirmation since no additional tissue was available.	('IDH', 'Gene', '3417', (61, 64))	('ATRX', 'Gene', (69, 73))	('1p19q codeletion', 'Var', (35, 51))	('ATRX', 'Gene', '546', (69, 73))	('IDH', 'Gene', (61, 64))
210671	28475680	The fraction of patients harboring LGGs with IDH mutations is comparable or slightly lower than recently published clinical studies, including a large Chinese population-based study.	('IDH', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('LGGs', 'Disease', (35, 39))	('IDH', 'Gene', '3417', (45, 48))	('patients', 'Species', '9606', (16, 24))
210676	28475680	However, the molecular markers were assessed differently between regions and due to the approach in region B there could be a slight underestimation of 1p19q codeleted tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('1p19q codeleted', 'Var', (152, 167))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
210815	25165570	Depression may also be more frequent in patients with left-hemisphere tumor high-grade gliomas, while right-hemisphere primary brain tumor patients may have higher anxiety.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('anxiety', 'Disease', 'MESH:D001008', (164, 171))	('left-hemisphere', 'Var', (54, 69))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('brain tumor', 'Phenotype', 'HP:0030692', (127, 138))	('anxiety', 'Phenotype', 'HP:0000739', (164, 171))	('Depression', 'Disease', 'MESH:D000275', (0, 10))	('Depression', 'Disease', (0, 10))	('patients', 'Species', '9606', (139, 147))	('brain tumor', 'Disease', (127, 138))	('brain tumor', 'Disease', 'MESH:D001932', (127, 138))	('tumor', 'Disease', (133, 138))	('gliomas', 'Disease', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Disease', (70, 75))	('frequent', 'Reg', (28, 36))	('anxiety', 'Disease', (164, 171))	('Depression', 'Phenotype', 'HP:0000716', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
210885	32151273	BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('FGFR1', 'Gene', '2260', (61, 66))	('tumor', 'Disease', (211, 216))	('BRAF', 'Gene', (0, 4))	('PGNT', 'Disease', (141, 145))	('PRKCA', 'Gene', '5578', (124, 129))	('AG', 'Disease', 'MESH:D005910', (104, 106))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('CD34', 'Gene', '947', (44, 48))	('alterations', 'Var', (89, 100))	('DNT', 'Disease', 'MESH:D018302', (80, 83))	('FGFR1', 'Gene', (61, 66))	('MYB', 'Gene', '4602', (85, 88))	('GG', 'Disease', 'MESH:D018303', (36, 38))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('PGNT', 'Disease', 'MESH:D009410', (141, 145))	('MYB', 'Gene', (85, 88))	('PRKCA', 'Gene', (124, 129))	('CD34', 'Gene', (44, 48))	('mutations', 'Var', (67, 76))	('DNT', 'Disease', (80, 83))
210905	32151273	Hence, BRAF V600E, FGFR1, FGFR2, MYB/L1 and PRKCA gene alterations have been recognized in common LEAT entities and likely translate into specific subgroups.	('alterations', 'Var', (55, 66))	('FGFR1', 'Gene', '2260', (19, 24))	('V600E', 'Mutation', 'rs113488022', (12, 17))	('PRKCA', 'Gene', '5578', (44, 49))	('MYB', 'Gene', '4602', (33, 36))	('MYB', 'Gene', (33, 36))	('FGFR2', 'Gene', (26, 31))	('PRKCA', 'Gene', (44, 49))	('BRAF', 'Gene', (7, 11))	('FGFR2', 'Gene', '2263', (26, 31))	('FGFR1', 'Gene', (19, 24))
210911	32151273	One class was predominated by astrocytic differentiation patterns and BRAF V600E mutations whereas another class was enriched in FGFR1 alterations and oligodendroglial differentiation patterns.	('FGFR1', 'Gene', (129, 134))	('BRAF V600E mutations', 'Var', (70, 90))	('FGFR1', 'Gene', '2260', (129, 134))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('astrocytic differentiation patterns', 'CPA', (30, 65))	('oligodendroglial differentiation patterns', 'CPA', (151, 192))
210913	32151273	Similar results were found by Qaddoumi and coworkers forming three molecular subgroups: a ganglioglioma-like group driven by BRAF alterations, secondly a FGFR1 group predominated by oligodendrocyte-like cells and lastly a MYB group with astrocytic and angiocentric patterns.	('FGFR1', 'Gene', (154, 159))	('FGFR1', 'Gene', '2260', (154, 159))	('alterations', 'Var', (130, 141))	('MYB', 'Gene', '4602', (222, 225))	('ganglioglioma', 'Disease', (90, 103))	('MYB', 'Gene', (222, 225))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('ganglioglioma', 'Disease', 'MESH:D018303', (90, 103))	('BRAF', 'Gene', (125, 129))
210916	32151273	Later BRAF alterations were also found in low-grade (pilocytic) astrocytoma and ganglioglioma.	('alterations', 'Var', (11, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (64, 75))	('found', 'Reg', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('ganglioglioma', 'Disease', (80, 93))	('astrocytoma', 'Disease', 'MESH:D001254', (64, 75))	('ganglioglioma', 'Disease', 'MESH:D018303', (80, 93))	('astrocytoma', 'Disease', (64, 75))
210917	32151273	A study from 2009 included 11 ganglioglioma and detected a BRAF V600E mutation in 3 of them.	('ganglioglioma', 'Disease', (30, 43))	('ganglioglioma', 'Disease', 'MESH:D018303', (30, 43))	('BRAF', 'Gene', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('V600E', 'Var', (64, 69))
210918	32151273	This was confirmed in a larger cohort of 18 ganglioglioma of which 9 showed the BRAF V600E mutation.	('BRAF', 'Gene', (80, 84))	('ganglioglioma', 'Disease', (44, 57))	('ganglioglioma', 'Disease', 'MESH:D018303', (44, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('V600E', 'Var', (85, 90))
210919	32151273	Furthermore, the BRAF V600E mutation was screened in a cohort of 1320 nervous system tumors and detected in 18% of histopathologically diagnosed ganglioglioma (14/77), 21% of adults (11/53) and 13% of children (3/24).	('detected', 'Reg', (96, 104))	('nervous system tumors', 'Disease', (70, 91))	('nervous system tumors', 'Phenotype', 'HP:0004375', (70, 91))	('children', 'Species', '9606', (201, 209))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('ganglioglioma', 'Disease', (145, 158))	('BRAF', 'Gene', (17, 21))	('nervous system tumors', 'Disease', 'MESH:D009423', (70, 91))	('V600E', 'Var', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('ganglioglioma', 'Disease', 'MESH:D018303', (145, 158))
210921	32151273	The first BRAF V600E specific antibody was reported in 2011 (clone VE1;) and is used nowadays to histopathologically screen for BRAF V600E mutations in the diagnostic work-up of formalin-fixed and paraffin-embedded tissue specimens.	('V600E', 'Mutation', 'rs113488022', (15, 20))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('formalin', 'Chemical', 'MESH:D005557', (178, 186))	('paraffin', 'Chemical', 'MESH:D010232', (197, 205))	('V600E', 'Var', (133, 138))	('BRAF', 'Gene', (128, 132))
210922	32151273	The VE1 antibody was scientifically explored in 71 ganglioglioma by Koelsche and coworkers in 2013, detecting the mutation in 58% of these tumors (41/71).	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ganglioglioma', 'Disease', (51, 64))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('mutation', 'Var', (114, 122))	('detecting', 'Reg', (100, 109))	('ganglioglioma', 'Disease', 'MESH:D018303', (51, 64))
210923	32151273	Interestingly, a BRAF V600E mutation was associated with younger patient age (compared to their previous report) and not with proliferation.	('BRAF', 'Gene', (17, 21))	('patient', 'Species', '9606', (65, 72))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('V600E', 'Var', (22, 27))
210925	32151273	In many cases mutant BRAF was also expressed by glial cells, indicating that cells carrying a BRAF mutation remain capable to differentiate into both, neuronal and glial cell lineages, and both of which represent the major cellular composition of the tumor.	('BRAF', 'Gene', (94, 98))	('tumor', 'Disease', (251, 256))	('mutation', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
210927	32151273	These studies of human tumor tissue were recently confirmed and further corroborated by Koh and coworkers in an animal model expressing the BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (145, 150))	('human', 'Species', '9606', (17, 22))	('V600E', 'Var', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('Koh', 'Chemical', 'MESH:C029943', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BRAF', 'Gene', (140, 144))	('tumor', 'Disease', (23, 28))
210929	32151273	When the mutation was successfully integrated into neuronal cell progenies 90% of the mice showed spontaneous epileptic seizures after 4 weeks postnatally, averaging five generalized, tonic-clonic seizures per day, and which could be rescued with the FDA-approved BRAF V600E inhibitor vemurafenib.	('mutation', 'Var', (9, 17))	('V600E', 'Mutation', 'rs113488022', (269, 274))	('tonic-clonic seizures', 'Disease', 'MESH:D004830', (184, 205))	('seizure', 'Phenotype', 'HP:0001250', (197, 204))	('tonic-clonic seizures', 'Phenotype', 'HP:0002069', (184, 205))	('vemurafenib', 'Chemical', 'MESH:D000077484', (285, 296))	('seizures', 'Phenotype', 'HP:0001250', (120, 128))	('mice', 'Species', '10090', (86, 90))	('epileptic seizures', 'Disease', (110, 128))	('seizure', 'Phenotype', 'HP:0001250', (120, 127))	('epileptic seizures', 'Disease', 'MESH:D004827', (110, 128))	('tonic-clonic seizures', 'Disease', (184, 205))	('seizures', 'Phenotype', 'HP:0001250', (197, 205))
210930	32151273	The tumorigenic properties were, however, mostly due to BRAF V600E integration into the glial cell lineage.	('tumor', 'Disease', (4, 9))	('BRAF V600E', 'Var', (56, 66))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('due', 'Reg', (49, 52))
210932	32151273	Interestingly, and important for any future genetically driven classification scheme of LEAT, the BRAF V600E mutation was correlated with a worse recurrence-free survival in a cohort 47 GG tested, of which 18 (38%) were immunohistochemically positive.	('GG', 'Disease', 'MESH:D018303', (186, 188))	('V600E', 'Var', (103, 108))	('BRAF', 'Gene', (98, 102))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('worse', 'NegReg', (140, 145))
210935	32151273	Notwithstanding, many other genetic alterations have been described in GG amongst which genetic alterations of the MAP kinase signaling pathway were most prominent.	('genetic alterations', 'Var', (88, 107))	('GG', 'Disease', 'MESH:D018303', (71, 73))	('MAP kinase signaling pathway', 'Pathway', (115, 143))
210938	32151273	FGFR1 gene alterations were first reported by Jones et al.	('alterations', 'Var', (11, 22))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))
210941	32151273	A more comprehensive study revealed FGFR1 alterations in 18 of 22 DNTs studied (82%), including 9 tyrosine kinase domain duplications, eight missense single nucleotide variants and 8 FGFR1-TACC fusions.	('DNTs', 'Chemical', 'MESH:C023514', (66, 70))	('missense single nucleotide variants', 'Var', (141, 176))	('FGFR1', 'Gene', (36, 41))	('alterations', 'Var', (42, 53))	('FGFR1', 'Gene', '2260', (183, 188))	('FGFR1', 'Gene', '2260', (36, 41))	('tyrosine kinase domain duplications', 'MPA', (98, 133))	('FGFR1', 'Gene', (183, 188))
210942	32151273	The group also noted that similar mutations were present in tumors with an oligodendroglial phenotype.	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('mutations', 'Var', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
210943	32151273	confirmed the above findings and showed 12 FGFR1 tyrosine kinase domain duplications, 10 point mutations and 3 breakpoints in a series of 25 of 43 DNTs (58,1%).	('FGFR1', 'Gene', (43, 48))	('point mutations', 'Var', (89, 104))	('FGFR1', 'Gene', '2260', (43, 48))	('tyrosine kinase domain', 'MPA', (49, 71))	('DNTs', 'Chemical', 'MESH:C023514', (147, 151))
210944	32151273	Thus, FGFR1 alterations have an approximate prevalence in DNT of 58.1-82%.	('DNT', 'Disease', (58, 61))	('alterations', 'Var', (12, 23))	('FGFR1', 'Gene', (6, 11))	('FGFR1', 'Gene', '2260', (6, 11))	('DNT', 'Disease', 'MESH:D018302', (58, 61))
210952	32151273	Interestingly, 77% of IDGs also had alterations in the MYBL1- or MYB-loci, mostly representing copy number alterations or MYBL1- and MYB-fusions as shown by RNA sequencing.	('MYB', 'Gene', '4602', (65, 68))	('MYB', 'Gene', (65, 68))	('MYB', 'Gene', (55, 58))	('alterations', 'Reg', (36, 47))	('MYBL1', 'Gene', (122, 127))	('MYBL1', 'Gene', '4603', (55, 60))	('MYB', 'Gene', '4602', (133, 136))	('MYBL1', 'Gene', '4603', (122, 127))	('IDGs', 'Disease', (22, 26))	('MYB', 'Gene', '4602', (122, 125))	('MYB', 'Gene', (133, 136))	('MYBL1', 'Gene', (55, 60))	('MYB', 'Gene', (122, 125))	('MYB', 'Gene', '4602', (55, 58))	('copy number alterations', 'Var', (95, 118))
210960	32151273	All of the latter group were histopathologically confirmed as PGNT, and 9/18 examined by RNA sequencing or FISH revealed a fusion with the PRKCA gene.	('PRKCA', 'Gene', '5578', (139, 144))	('fusion', 'Var', (123, 129))	('PRKCA', 'Gene', (139, 144))	('PGNT', 'Disease', 'MESH:D009410', (62, 66))	('PGNT', 'Disease', (62, 66))
210978	32151273	Three out of eight tested tumors showed a BRAF V600E mutation, one showed a FGFR3 fusion and three had a FGFR2 fusion.	('BRAF V600E', 'Var', (42, 52))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('FGFR2', 'Gene', '2263', (105, 110))	('FGFR3', 'Gene', '2261', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('FGFR2', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('FGFR3', 'Gene', (76, 81))	('tumors', 'Disease', (26, 32))
210979	32151273	Such FGFR2 fusions have not yet been detected in any other LEAT category and might qualify as a distinctive feature in the near future.	('FGFR2', 'Gene', (5, 10))	('FGFR2', 'Gene', '2263', (5, 10))	('fusions', 'Var', (11, 18))
210987	32151273	In a series of seven MVNTs no BRAF V600E mutations were found but one case showed a FGFR2 fusion.	('V600E', 'Var', (35, 40))	('FGFR2', 'Gene', (84, 89))	('FGFR2', 'Gene', '2263', (84, 89))	('V600E', 'Mutation', 'rs113488022', (35, 40))
210988	32151273	In another series of eight MVNTs genetic alterations were found in BRAF other than V600E, MAP2K1 and FGFR2 (2/8, 5/8 and 1/8, respectively).	('V600E', 'Var', (83, 88))	('MAP2K1', 'Gene', (90, 96))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('MAP2K1', 'Gene', '5604', (90, 96))
210997	32151273	in neurons transfected with the BRAF V600E mutation in vivo.	('BRAF', 'Gene', (32, 36))	('V600E', 'Var', (37, 42))	('V600E', 'Mutation', 'rs113488022', (37, 42))
211018	32151273	They also looked at molecular alterations and found BRAF V600E in 39%, hTERT promotor mutations in 61%, p53 accumulation in 39%, ATRX loss in 17% and p.K27M H3F3A mutations in 17% of the cohort.	('H3F3A', 'Gene', '3020', (157, 162))	('mutations', 'Var', (86, 95))	('p53', 'Gene', (104, 107))	('BRAF V600E', 'Var', (52, 62))	('ATRX', 'Gene', '546', (129, 133))	('accumulation', 'PosReg', (108, 120))	('p53', 'Gene', '7157', (104, 107))	('H3F3A', 'Gene', (157, 162))	('V600E', 'Mutation', 'rs113488022', (57, 62))	('hTERT', 'Gene', '7015', (71, 76))	('p.K27M', 'Var', (150, 156))	('loss', 'NegReg', (134, 138))	('hTERT', 'Gene', (71, 76))	('ATRX', 'Gene', (129, 133))	('p.K27M', 'Mutation', 'p.K27M', (150, 156))
211032	32151273	A homozygous deletion of CDKN2A/B, corresponding to loss of 9q21.3, is a rather distinctive molecular feature of PXA.	('9q21.3', 'Protein', (60, 66))	('loss', 'NegReg', (52, 56))	('PXA', 'Disease', (113, 116))	('deletion', 'Var', (13, 21))	('PXA', 'Disease', 'MESH:D008228', (113, 116))	('CDKN2A', 'Gene', (25, 31))	('CDKN2A', 'Gene', '1029', (25, 31))
211033	32151273	In a study of 24 PXA and 14 anaplastic PXA, CDKN2A/B deletions were identified in 83 and 93%, respectively.	('deletions', 'Var', (53, 62))	('CDKN2A', 'Gene', (44, 50))	('PXA', 'Disease', (39, 42))	('CDKN2A', 'Gene', '1029', (44, 50))	('PXA', 'Disease', 'MESH:D008228', (39, 42))	('PXA', 'Disease', (17, 20))	('PXA', 'Disease', 'MESH:D008228', (17, 20))
211035	32151273	Even with currently available molecular genetic markers such as BRAF V600E and FGFR1 and immunohistochemical surrogate markers, such as CD34 and p16, there is still a poor inter-rater agreement in the histopathological diagnosis.	('p16', 'Gene', '1029', (145, 148))	('CD34', 'Gene', (136, 140))	('FGFR1', 'Gene', (79, 84))	('CD34', 'Gene', '947', (136, 140))	('p16', 'Gene', (145, 148))	('FGFR1', 'Gene', '2260', (79, 84))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('BRAF V600E', 'Var', (64, 74))
211045	31419958	Gene set enrichment analysis suggests that these molecules are enriched in extracellular region, sequence-specific DNA binding, neuropeptide signaling pathway, transcriptional misregulation in cancer, cytokine-cytokine receptor interaction, protein digestion and absorption, chemokine signaling pathway, etc.	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('misregulation', 'Var', (176, 189))
211051	31419958	Among them, blockers for the PD-1/PD-L1 pathway have achieved great success in melanoma.	('PD-1', 'Gene', '5133', (29, 33))	('blockers', 'Var', (12, 20))	('PD-L1', 'Gene', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('PD-L1', 'Gene', '29126', (34, 39))	('PD-1', 'Gene', (29, 33))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
211085	31419958	In bladder cancer, SCHLAP1 acts as a pro-oncogene, and silencing SCHLAP1 induces proliferation of bladder cancer cells, promotes apoptosis, and inhibits cell migration.	('inhibits', 'NegReg', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('induces', 'PosReg', (73, 80))	('SCHLAP1', 'Gene', '101669767', (19, 26))	('SCHLAP1', 'Gene', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('SCHLAP1', 'Gene', '101669767', (65, 72))	('silencing', 'Var', (55, 64))	('SCHLAP1', 'Gene', (65, 72))	('cell migration', 'CPA', (153, 167))	('apoptosis', 'CPA', (129, 138))	('promotes', 'PosReg', (120, 128))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('proliferation', 'CPA', (81, 94))
211089	31419958	Gene set enrichment analysis revealed that these immune-related lncRNAs may be involved in functions such as extracellular region, sequence-specific DNA binding, neuropeptide signaling pathway, transcriptional misregulation in cancer, cytokine-cytokine receptor interaction, protein digestion and absorption, chemokine signaling pathway, etc.	('chemokine signaling pathway', 'Pathway', (309, 336))	('neuropeptide signaling pathway', 'Pathway', (162, 192))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('misregulation', 'Var', (210, 223))	('involved', 'Reg', (79, 87))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))
211121	31097430	For DSC-MRI, a total of 0.1 mmol/kg dose of gadopentate dimeglumine (Gd-DTPA; Magnevist, Bayer Schering Pharma, Leverkusen,Germany) was administered, 0.025 mmol/kg for preload dosage to mitigate T1-based leakage contamination and the remaining 0.075 mmol/kg for dynamic bolus administration.	('0.025 mmol/kg', 'Var', (150, 163))	('T1-based leakage contamination', 'MPA', (195, 225))	('gadopentate dimeglumine', 'Chemical', 'MESH:D019786', (44, 67))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (69, 76))
211137	31097430	Consistent with the patient-wise observation that T2 hyperintense lesions exhibit a more significant median CBV - median MTRasym correlation than contrast enhancing lesions, the voxel-wise analysis in difference ROIs across all patients showed that the p-value of Pearson's correlation is lower in T2 hyperintense lesions (median 5.55x10-122) compared to in contrast enhancing lesions (median 3.68x10-26, P=0.0003).	('patients', 'Species', '9606', (228, 236))	('patient', 'Species', '9606', (20, 27))	('lower', 'NegReg', (289, 294))	('T2 hyperintense', 'Var', (298, 313))	('patient', 'Species', '9606', (228, 235))
211156	31097430	Acidification of the tumor microenvironment can result in vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PDGF) expression, resulting in further angiogenesis and altered blood flow.	('Acidification', 'Var', (0, 13))	('tumor', 'Disease', (21, 26))	('vascular endothelial growth factor', 'Gene', (58, 92))	('VEGF', 'Gene', (94, 98))	('angiogenesis', 'CPA', (192, 204))	('blood flow', 'CPA', (217, 227))	('expression', 'MPA', (159, 169))	('vascular endothelial growth factor', 'Gene', '7422', (58, 92))	('VEGF', 'Gene', '7422', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('altered', 'Reg', (209, 216))	('result in', 'Reg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
211183	31097430	However, we contest the mixture of both treated and untreated tumors allowed us to better generalize across all patient populations in a way that is consistent with clinical practice, suggesting amine CEST EPI may be useful as a clinical tool under a variety of treatment conditions.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patient', 'Species', '9606', (112, 119))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('amine', 'Chemical', 'MESH:D000588', (195, 200))	('amine', 'Var', (195, 200))
211185	31097430	Examination of median measurements within tumor regions across a large number of patients demonstrated a positive linear association between blood volume and tumor acidity in areas of T2 hyperintense, non-enhancing tumor; however, areas of contrast enhancement were more complex and did not show a strong relationship.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (42, 47))	('tumor acidity', 'Disease', 'MESH:D009369', (158, 171))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor acidity', 'Disease', (158, 171))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('blood volume', 'MPA', (141, 153))	('T2 hyperintense', 'Var', (184, 199))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
211188	30713788	ISG20 promotes local tumor immunity and contributes to poor survival in human glioma Recent evidence has confirmed that a mutation of the isocitrate dehydrogenase (IDH) gene occurs early in gliomagenesis and contributes to suppressed immunity.	('suppressed immunity', 'CPA', (223, 242))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('isocitrate dehydrogenase', 'Gene', '3417', (138, 162))	('mutation', 'Var', (122, 130))	('ISG20', 'Gene', (0, 5))	('human', 'Species', '9606', (72, 77))	('IDH', 'Gene', (164, 167))	('contributes', 'Reg', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('glioma', 'Disease', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('isocitrate dehydrogenase', 'Gene', (138, 162))	('IDH', 'Gene', '3417', (164, 167))	('ISG20', 'Gene', '3669', (0, 5))	('glioma', 'Disease', (78, 84))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
211199	30713788	Recent analyses demonstrated that an IDH1/2 mutation, encoding isocitrate dehydrogenase (IDH) gene, occurs early in gliomagenesis, affecting a common glial precursor cell population.	('IDH1/2', 'Gene', (37, 43))	('mutation', 'Var', (44, 52))	('glioma', 'Disease', (116, 122))	('isocitrate dehydrogenase', 'Gene', (63, 87))	('IDH1/2', 'Gene', '3417;3418', (37, 43))	('IDH', 'Gene', (89, 92))	('affecting', 'Reg', (131, 140))	('IDH', 'Gene', (37, 40))	('isocitrate dehydrogenase', 'Gene', '3417', (63, 87))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('IDH', 'Gene', '3417', (89, 92))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('IDH', 'Gene', '3417', (37, 40))
211200	30713788	Patients with tumors harboring an IDH1/2 mutation (IDHmut) show significantly longer survival than those expressing wild-type IDH1/2 (IDHwt).	('IDH1/2', 'Gene', '3417;3418', (126, 132))	('IDH', 'Gene', (34, 37))	('longer', 'PosReg', (78, 84))	('IDH', 'Gene', '3417', (51, 54))	('IDH1/2', 'Gene', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('IDH', 'Gene', '3417', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (41, 49))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', (134, 137))	('IDH', 'Gene', (126, 129))	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('IDH1/2', 'Gene', (34, 40))	('tumors', 'Disease', (14, 20))	('IDH', 'Gene', '3417', (134, 137))	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', '3417', (126, 129))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('survival', 'MPA', (85, 93))
211201	30713788	IDH mutation leads to a CpG island methylator phenotype (CIMP) by modulating the methylation patterns on a genome-wide scale, changing transcriptional programs and altering the differentiation state.	('transcriptional programs', 'MPA', (135, 159))	('IDH', 'Gene', (0, 3))	('differentiation state', 'CPA', (177, 198))	('altering', 'Reg', (164, 172))	('modulating', 'Reg', (66, 76))	('IDH', 'Gene', '3417', (0, 3))	('methylation patterns', 'MPA', (81, 101))	('CIMP', 'Chemical', '-', (57, 61))	('mutation', 'Var', (4, 12))	('changing', 'Reg', (126, 134))	('CpG island methylator phenotype', 'Disease', (24, 55))	('leads to', 'Reg', (13, 21))
211211	30713788	We then determined the differentially expressed immune-related genes according to IDH mutation status, analyzed separately for LGG and GBM cases, and performed pathway enrichment analysis for functional annotation.	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', (82, 85))	('mutation', 'Var', (86, 94))
211218	30713788	Moreover, ISG20 expression was up-regulated in 1p/19q-non-co-deleted gliomas compared with those with 1p/19q-co-deletion (Figure 2(c); Fig.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('up-regulated', 'PosReg', (31, 43))	('gliomas', 'Disease', (69, 76))	('1p/19q-non-co-deleted', 'Var', (47, 68))	('ISG20', 'Gene', '3669', (10, 15))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('ISG20', 'Gene', (10, 15))	('expression', 'MPA', (16, 26))
211220	30713788	Overall, these results suggest that ISG20 expression is suppressed in IDH mutant tumors and is associated with higher tumor malignancy.	('tumor malignancy', 'Disease', (118, 134))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('ISG20', 'Gene', '3669', (36, 41))	('IDH', 'Gene', (70, 73))	('expression', 'MPA', (42, 52))	('ISG20', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('suppressed', 'NegReg', (56, 66))	('tumor malignancy', 'Disease', 'MESH:D018198', (118, 134))	('IDH', 'Gene', '3417', (70, 73))	('higher', 'PosReg', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutant', 'Var', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
211227	30713788	In line with the results from the bioinformatics analyses, protein expression of ISG20 showed the same results, with increased expression in higher tumor grade and decreased expression in IDH mutant tumors.	('tumor', 'Disease', (199, 204))	('IDH', 'Gene', '3417', (188, 191))	('mutant', 'Var', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('decreased', 'NegReg', (164, 173))	('tumors', 'Disease', (199, 205))	('expression', 'MPA', (174, 184))	('expression', 'MPA', (127, 137))	('increased', 'PosReg', (117, 126))	('ISG20', 'Gene', '3669', (81, 86))	('tumor', 'Disease', (148, 153))	('ISG20', 'Gene', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('IDH', 'Gene', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
211243	30713788	In line with the bioinformatic findings, the composition of the immune infiltrates differed between the low ISG20 expression group and the high ISG20 expression group, with a more substantial number of macrophages and lower number of the T cell subsets (T cells, Tfh cells, memory T cells) in high ISG20 expression tumors.	('T cell subsets', 'CPA', (238, 252))	('tumors', 'Disease', (315, 321))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('ISG20', 'Gene', '3669', (144, 149))	('ISG20', 'Gene', '3669', (298, 303))	('ISG20', 'Gene', (144, 149))	('ISG20', 'Gene', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('ISG20', 'Gene', '3669', (108, 113))	('high', 'Var', (293, 297))	('Tfh cells', 'CPA', (263, 272))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('ISG20', 'Gene', (108, 113))	('lower', 'NegReg', (218, 223))
211249	30713788	Mounting evidence suggests that glioma with an IDH mutation has suppressed immunity.	('IDH', 'Gene', '3417', (47, 50))	('suppressed', 'NegReg', (64, 74))	('glioma', 'Disease', (32, 38))	('mutation', 'Var', (51, 59))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('IDH', 'Gene', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('immunity', 'CPA', (75, 83))
211259	30713788	In this study, we found that ISG20 expression is associated with many chemokines, leading to tumor infiltration of a variety of immune cells.	('ISG20', 'Gene', (29, 34))	('ISG20', 'Gene', '3669', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('associated', 'Reg', (49, 59))	('tumor', 'Disease', (93, 98))	('leading to', 'Reg', (82, 92))	('expression', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
211297	33795525	Evaluation of gliomas peritumoral diffusion and prediction of IDH1 mutation by IVIM-DWI Glioma characterized by high morbidity and mortality, is one of the most common brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('brain tumor', 'Phenotype', 'HP:0030692', (168, 179))	('gliomas peritumoral', 'Disease', (14, 33))	('Glioma', 'Disease', 'MESH:D005910', (88, 94))	('mortality', 'Disease', (131, 140))	('mutation', 'Var', (67, 75))	('brain tumors', 'Disease', 'MESH:D001932', (168, 180))	('brain tumors', 'Phenotype', 'HP:0030692', (168, 180))	('gliomas peritumoral', 'Disease', 'MESH:D005910', (14, 33))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('IDH1', 'Gene', (62, 66))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('Glioma', 'Phenotype', 'HP:0009733', (88, 94))	('mortality', 'Disease', 'MESH:D003643', (131, 140))	('brain tumors', 'Disease', (168, 180))	('Glioma', 'Disease', (88, 94))	('IDH1', 'Gene', '3417', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
211306	33795525	IVIM-DWI presented efficacy in differentiating glioma grading and IDH1 mutation status.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH1', 'Gene', '3417', (66, 70))	('mutation', 'Var', (71, 79))	('glioma', 'Disease', (47, 53))	('IDH1', 'Gene', (66, 70))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
211326	33795525	IDH1 mutation (IDH1mut) may lead to the increase of oxidative stress level].	('IDH1', 'Gene', (15, 19))	('increase', 'PosReg', (40, 48))	('oxidative stress level]', 'MPA', (52, 75))	('IDH1', 'Gene', '3417', (15, 19))	('increase of oxidative stress', 'Phenotype', 'HP:0025464', (40, 68))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
211351	33795525	Therefore, IVIM-DWI might be a promising method to predict IDH1 gene mutation and evaluation of gliomas peritumoral diffusion.	('IDH1', 'Gene', '3417', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutation', 'Var', (69, 77))	('gliomas peritumoral', 'Disease', 'MESH:D005910', (96, 115))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('gliomas peritumoral', 'Disease', (96, 115))	('IDH1', 'Gene', (59, 63))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))
211356	33795525	The AUC value of rCBF1-2 was the highest, 0.861 (P<0.001) with specificity 94.1% and sensitivity 92.3%.	('AUC', 'MPA', (4, 7))	('0.861', 'Var', (42, 47))	('CBF1', 'Gene', '3516', (18, 22))	('CBF1', 'Gene', (18, 22))
211364	33795525	Perfusion has been proved to increase the diagnose sensitivity of many diseases including glioma.	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('increase', 'PosReg', (29, 37))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('Perfusion', 'Var', (0, 9))
211371	33795525	Meanwhile, IDH1 mutations were also found in the anaplastic thyroid cancer, melanoma, acute myeloid leukemia patients.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (92, 108))	('melanoma', 'Disease', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (86, 108))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('IDH1', 'Gene', '3417', (11, 15))	('patients', 'Species', '9606', (109, 117))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (49, 74))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('mutations', 'Var', (16, 25))	('found', 'Reg', (36, 41))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (86, 108))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (49, 74))	('acute myeloid leukemia', 'Disease', (86, 108))	('anaplastic thyroid cancer', 'Disease', (49, 74))	('IDH1', 'Gene', (11, 15))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
211382	33795525	10 cases were identified with IDH1 wild type and 16 cases were mutation type.	('IDH1', 'Gene', (30, 34))	('wild type', 'Var', (35, 44))	('IDH1', 'Gene', '3417', (30, 34))
211384	33795525	Among them, 41 cases were IDH1 wild type and 11 cases were mutant type.	('mutant type', 'Var', (59, 70))	('IDH1', 'Gene', '3417', (26, 30))	('IDH1', 'Gene', (26, 30))
211401	33879792	Age-associated SCNAs and mutations are identified in several cancer-driver genes across different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Age', 'Gene', '5973', (0, 3))	('SCNAs', 'Disease', (15, 20))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Age', 'Gene', (0, 3))
211418	33879792	We show that, in general, GI and mutations frequency increase with age.	('age', 'Gene', '5973', (67, 70))	('mutations', 'Var', (33, 42))	('increase', 'PosReg', (53, 61))	('GI', 'Gene', '2770', (26, 28))	('age', 'Gene', (67, 70))
211458	33879792	The only exception was sarcoma, with a significant association between age and chromosome/arm-level but not with focal-level and overall SCNA scores.	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('age', 'Gene', '5973', (71, 74))	('chromosome/arm-level', 'Var', (79, 99))	('sarcoma', 'Disease', (23, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('age', 'Gene', (71, 74))
211461	33879792	The significant associations between age and chromosomal arm gains and losses are shown in Fig.	('age', 'Gene', (37, 40))	('losses', 'NegReg', (71, 77))	('age', 'Gene', '5973', (37, 40))	('gains', 'PosReg', (61, 66))	('chromosomal', 'Var', (45, 56))
211472	33879792	For instance, we found an increased incidence in the loss of chromosome 13q (harbouring RB1) with age in thyroid cancer.	('thyroid cancer', 'Disease', 'MESH:D013964', (105, 119))	('age', 'Gene', (98, 101))	('thyroid cancer', 'Disease', (105, 119))	('RB1', 'Gene', (88, 91))	('age', 'Gene', '5973', (98, 101))	('thyroid cancer', 'Phenotype', 'HP:0002890', (105, 119))	('loss', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('RB1', 'Gene', '5925', (88, 91))
211495	33879792	This age-related mutation accumulation is in part explained by a clock-like mutational process, spontaneous deamination of 5-methylcytosine to thymine.	('age', 'Gene', (5, 8))	('clock', 'Gene', (65, 70))	('mutation', 'Var', (17, 25))	('thymine', 'Chemical', 'MESH:D013941', (143, 150))	('age', 'Gene', '5973', (5, 8))	('clock', 'Gene', '9575', (65, 70))	('deamination of 5-methylcytosine to thymine', 'MPA', (108, 150))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (123, 139))
211496	33879792	As expected, we confirmed the positive association between age and mutation load (somatic non-silent SNVs and indels) in the pan-cancer cohort using multiple linear regression adjusting for gender, race, and cancer type (adj.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (208, 214))	('age', 'Gene', '5973', (59, 62))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('age', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('mutation load', 'Var', (67, 80))
211497	33879792	In cancer-specific analyses, 18 cancer types exhibited a significant relationship between age and mutation load using linear regression (adj.	('age', 'Gene', '5973', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('age', 'Gene', (90, 93))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('mutation load', 'Var', (98, 111))
211498	33879792	This increase in mutation load was mainly contributed by C>T mutations, as we found a positive association between the fraction of C>T mutations and age (regression coefficient = 0.058, p value = 8.57 x 10-7) in a pan-cancer analysis.	('C>T', 'Var', (57, 60))	('age', 'Gene', '5973', (149, 152))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('increase', 'PosReg', (5, 13))	('age', 'Gene', (149, 152))	('mutation load', 'MPA', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('C>T mutations', 'Var', (131, 144))
211499	33879792	Conversely, the fraction of C>A mutations was negatively associated with age (regression coefficient = -0.065, p value = 8.84 x 10-10) (Supplementary Data 10), concordant with a previous report.	('negatively', 'NegReg', (46, 56))	('age', 'Gene', '5973', (73, 76))	('C>A mutations', 'Var', (28, 41))	('age', 'Gene', (73, 76))
211501	33879792	Consistent with the pan-cancer analysis, C>T mutations showed a significant positive association with age in six cancer types, whereas C>A mutations had a significant negative association with age in three cancer types.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('age', 'Gene', '5973', (193, 196))	('age', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('C>T mutations', 'Var', (41, 54))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', (206, 212))	('age', 'Gene', '5973', (102, 105))	('age', 'Gene', (193, 196))	('positive', 'PosReg', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('C>A', 'Var', (135, 138))
211505	33879792	Microsatellite instability (MSI) is a unique molecular alteration caused by defects in DNA mismatch repair.	('Microsatellite instability', 'Disease', (0, 26))	('defects', 'Var', (76, 83))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))
211509	33879792	Another source of hypermutation in cancer is defective DNA polymerase proofreading due to mutations in polymerase epsilon (POLE) or polymerase delta (POLD1) genes.	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('POLD1', 'Gene', '5424', (150, 155))	('DNA polymerase', 'Enzyme', (55, 69))	('POLD1', 'Gene', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('defective', 'NegReg', (45, 54))	('POLE', 'Gene', (123, 127))	('cancer', 'Disease', (35, 41))
211510	33879792	We showed that mutations in POLE (OR = 0.9690, 95% CI = 0.9422-0.9959, p value = 0.0243) and POLD1 (OR = 0.9573, 95% CI = 0.9223-0.9925, p value = 0.0177) were both more prevalent in younger endometrial cancer patients (Fig.	('POLD1', 'Gene', (93, 98))	('POLD1', 'Gene', '5424', (93, 98))	('POLE', 'Gene', (28, 32))	('prevalent', 'Reg', (170, 179))	('mutations', 'Var', (15, 24))	('endometrial cancer', 'Disease', (191, 209))	('patients', 'Species', '9606', (210, 218))	('endometrial cancer', 'Phenotype', 'HP:0012114', (191, 209))	('endometrial cancer', 'Disease', 'MESH:D016889', (191, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
211511	33879792	Indeed, when we excluded tumours with MSI-H and tumours containing POLE/POLD1 mutations from the analysis, we found a significant positive association between mutation burden and age in endometrial cancer (adj.	('tumours', 'Disease', (25, 32))	('positive', 'PosReg', (130, 138))	('age', 'Gene', (179, 182))	('mutations', 'Var', (78, 87))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('endometrial cancer', 'Phenotype', 'HP:0012114', (186, 204))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('POLD1', 'Gene', (72, 77))	('tumours', 'Disease', (48, 55))	('endometrial cancer', 'Disease', (186, 204))	('MSI-H and tumours', 'Disease', 'MESH:D009369', (38, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (186, 204))	('age', 'Gene', '5973', (179, 182))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('mutation burden', 'Var', (159, 174))	('POLD1', 'Gene', '5424', (72, 77))
211512	33879792	Therefore, the negative correlation between age and mutation loads in endometrial cancer could be explained by the presence of hypermutated tumours in younger patients, which are associated with MSI-H and POLE/POLD1 mutations.	('POLD1', 'Gene', (210, 215))	('age', 'Gene', (44, 47))	('MSI-H', 'Gene', (195, 200))	('associated', 'Reg', (179, 189))	('POLD1', 'Gene', '5424', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('endometrial cancer', 'Disease', (70, 88))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('endometrial cancer', 'Phenotype', 'HP:0012114', (70, 88))	('age', 'Gene', '5973', (44, 47))	('endometrial cancer', 'Disease', 'MESH:D016889', (70, 88))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', (140, 147))	('mutations', 'Var', (216, 225))	('patients', 'Species', '9606', (159, 167))
211514	33879792	Together with our SCNA results, younger endometrial cancer patients are likely to associate with a POLE and MSI-H subtypes, high mutation rate and better survival, whilst tumours from older patients are characterised by many SCNAs and are generally associated with a worse prognosis, indicating differences between age-related subtypes in endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (40, 58))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('age', 'Gene', (315, 318))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('endometrial cancer', 'Phenotype', 'HP:0012114', (339, 357))	('mutation', 'Var', (129, 137))	('better', 'PosReg', (147, 153))	('patients', 'Species', '9606', (190, 198))	('endometrial cancer', 'Disease', 'MESH:D016889', (339, 357))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('endometrial cancer', 'Disease', (40, 58))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('age', 'Gene', '5973', (315, 318))	('patients', 'Species', '9606', (59, 67))	('endometrial cancer', 'Disease', (339, 357))	('endometrial cancer', 'Phenotype', 'HP:0012114', (40, 58))	('tumours', 'Disease', (171, 178))
211517	33879792	When we further examined associations between age and mutations in POLE and POLD1 in other cancers apart from endometrial cancer, no significant associations were observed (Supplementary Fig.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('POLD1', 'Gene', (76, 81))	('POLD1', 'Gene', '5424', (76, 81))	('age', 'Gene', '5973', (46, 49))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('endometrial cancer', 'Disease', (110, 128))	('mutations', 'Var', (54, 63))	('POLE', 'Gene', (67, 71))	('endometrial cancer', 'Disease', 'MESH:D016889', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('age', 'Gene', (46, 49))	('endometrial cancer', 'Phenotype', 'HP:0012114', (110, 128))
211521	33879792	We first investigated associations between age and pan-cancer gene-level mutations.	('age', 'Gene', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('age', 'Gene', '5973', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('associations', 'Interaction', (22, 34))	('mutations', 'Var', (73, 82))	('cancer', 'Disease', (55, 61))
211522	33879792	Using multiple logistic regression correcting for gender, race, and cancer type, mutations in IDH1 (OR = 0.9608, 95% CI = 0.9497-0.9719, adj.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', '3417', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (81, 90))
211525	33879792	On the other hand, mutations in PIK3CA were more common in older individuals (OR = 1.0096, 95% CI = 1.0035-1.0158, adj.	('PIK3CA', 'Gene', '5290', (32, 38))	('common', 'Reg', (49, 55))	('mutations', 'Var', (19, 28))	('PIK3CA', 'Gene', (32, 38))
211527	33879792	Using logistic regression, we identified 31 mutations in 12 cancer types that increased or decreased as a function of the patients' age (adj.	('age', 'Gene', '5973', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('patients', 'Species', '9606', (122, 130))	('mutations', 'Var', (44, 53))	('age', 'Gene', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('decreased', 'NegReg', (91, 100))
211528	33879792	The most striking negative associations between mutations and age in low-grade glioma and glioblastoma were found in IDH1 (OR = 0.9509 and 0.8962, 95% CI = 0.9328-0.9686 and 0.8598-0.9291, adj.	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('glioma', 'Disease', (79, 85))	('IDH1', 'Gene', '3417', (117, 121))	('age', 'Gene', '5973', (62, 65))	('age', 'Gene', (62, 65))	('negative', 'NegReg', (18, 26))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('glioblastoma', 'Disease', (90, 102))	('mutations', 'Var', (48, 57))	('IDH1', 'Gene', (117, 121))
211529	33879792	p value = 4.12 x 10-7 and 1.78 x 10-9, respectively), ATRX (OR = 0.9471 and 0.9120, 95% CI = 0.9310-0.9628 and 0.8913-0.9466, adj.	('ATRX', 'Gene', '546', (54, 58))	('0.9120', 'Var', (76, 82))	('ATRX', 'Gene', (54, 58))
211530	33879792	p value = 1.67 x 10-10 and 2.33 x 10-8, respectively), and TP53 (OR = 0.9431 and 0.9736, 95% CI = 0.9274-0.9582 and 0.9564-0.9905, adj.	('0.9736', 'Var', (81, 87))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (59, 63))
211532	33879792	Patients carrying IDH1 mutations generally had a longer survival than IDH-WT patients.	('IDH', 'Gene', (18, 21))	('IDH1', 'Gene', '3417', (18, 22))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (18, 21))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (77, 85))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', '3417', (70, 73))	('longer', 'PosReg', (49, 55))	('IDH1', 'Gene', (18, 22))
211533	33879792	Previous studies also reported that IDH1 mutations often co-occurred with ATRX and TP53 mutations, and mutations in these three genes were more prevalent in gliomas without EGFR mutations.	('co-occurred', 'Reg', (57, 68))	('mutations', 'Var', (41, 50))	('mutations', 'Var', (103, 112))	('TP53', 'Gene', '7157', (83, 87))	('IDH1', 'Gene', (36, 40))	('TP53', 'Gene', (83, 87))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('ATRX', 'Gene', '546', (74, 78))	('mutations', 'Var', (88, 97))	('EGFR', 'Gene', '1956', (173, 177))	('IDH1', 'Gene', '3417', (36, 40))	('gliomas', 'Disease', (157, 164))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('prevalent', 'Reg', (144, 153))	('EGFR', 'Gene', (173, 177))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('ATRX', 'Gene', (74, 78))
211534	33879792	Indeed, we found that EGFR mutations were more common in older low-grade glioma patients (OR = 1.0865, 95% CI = 1.0525-1.1258, adj.	('mutations', 'Var', (27, 36))	('glioma', 'Disease', (73, 79))	('patients', 'Species', '9606', (80, 88))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('common', 'Reg', (47, 53))	('EGFR', 'Gene', '1956', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('EGFR', 'Gene', (22, 26))
211537	33879792	Together with the SCNA results, gliomas from younger patients are associated with IDH1, ATRX, and TP53 mutations, lower SCNAs, and longer survival.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (53, 61))	('gliomas', 'Disease', (32, 39))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('ATRX', 'Gene', '546', (88, 92))	('IDH1', 'Gene', (82, 86))	('SCNAs', 'MPA', (120, 125))	('lower', 'NegReg', (114, 119))	('IDH1', 'Gene', '3417', (82, 86))	('TP53', 'Gene', '7157', (98, 102))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('ATRX', 'Gene', (88, 92))	('TP53', 'Gene', (98, 102))
211538	33879792	In contrast, gliomas from older patients were more likely to be IDH-WT with EGFR mutations, chromosome 7 gain and 10 loss, CDKN2A deletion and worse prognosis.	('IDH', 'Gene', '3417', (64, 67))	('patients', 'Species', '9606', (32, 40))	('loss', 'NegReg', (117, 121))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('EGFR', 'Gene', '1956', (76, 80))	('deletion', 'Var', (130, 138))	('CDKN2A', 'Gene', (123, 129))	('EGFR', 'Gene', (76, 80))	('gliomas', 'Disease', (13, 20))	('mutations', 'Var', (81, 90))	('gain', 'PosReg', (105, 109))	('CDKN2A', 'Gene', '1029', (123, 129))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('IDH', 'Gene', (64, 67))
211540	33879792	Mutations in CDH1 were more frequent in younger stomach cancer patients (OR = 0.9414, 95% CI = 0.9027-0.9800, adj.	('stomach cancer', 'Disease', 'MESH:D013274', (48, 62))	('CDH1', 'Gene', '999', (13, 17))	('stomach cancer', 'Phenotype', 'HP:0012126', (48, 62))	('stomach cancer', 'Disease', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (28, 36))	('patients', 'Species', '9606', (63, 71))	('CDH1', 'Gene', (13, 17))
211544	33879792	Using subtype information from a previous TCGA study, CDH1 mutations were found more often in the genomically stable (GS) subtype of stomach cancer (two-sided Fisher's exact, p value = 2.0 x 10-5), which was presented more frequently in younger patients (two-sided Wilcoxon rank sum test, p value = 0.0058) (Supplementary Fig.	('stomach cancer', 'Disease', (133, 147))	('found', 'Reg', (74, 79))	('patients', 'Species', '9606', (245, 253))	('GS', 'Disease', 'MESH:D011125', (118, 120))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CDH1', 'Gene', (54, 58))	('mutations', 'Var', (59, 68))	('stomach cancer', 'Disease', 'MESH:D013274', (133, 147))	('CDH1', 'Gene', '999', (54, 58))	('stomach cancer', 'Phenotype', 'HP:0012126', (133, 147))
211545	33879792	As expected, CDH1 mutations were highly enriched in the invasive lobular carcinoma (ILC) subtype of breast cancer (two-sided Fisher's exact, p value = 4.4 x 10-38), which was more prevalent in older patients (two-sided Wilcoxon rank sum test, p value = 0.00081) (Supplementary Fig.	('CDH1', 'Gene', '999', (13, 17))	('invasive lobular carcinoma', 'Disease', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (56, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (65, 82))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('patients', 'Species', '9606', (199, 207))	('breast cancer', 'Disease', (100, 113))	('CDH1', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
211552	33879792	p value < 0.05), indicating that the genes in these pathways are altered more frequently in older patients, concordant with the increase in overall mutations and SCNAs with age (Fig.	('altered', 'Reg', (65, 72))	('mutations', 'Var', (148, 157))	('increase', 'PosReg', (128, 136))	('age', 'Gene', '5973', (173, 176))	('patients', 'Species', '9606', (98, 106))	('age', 'Gene', (173, 176))
211555	33879792	Alterations in Hippo and TP53 signalling pathways significantly associated with age, both positively and negatively, in five cancer types.	('associated', 'Reg', (64, 74))	('TP53', 'Gene', (25, 29))	('age', 'Gene', '5973', (80, 83))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('age', 'Gene', (80, 83))	('TP53', 'Gene', '7157', (25, 29))
211558	33879792	This was largely explained by the increase in CDKN2A and CDKN2B deletions with age as well as epigenetic silencing of CDKN2A in older patients (Fig.	('CDKN2A', 'Gene', (118, 124))	('CDKN2A', 'Gene', (46, 52))	('CDKN2A', 'Gene', '1029', (118, 124))	('CDKN2B', 'Gene', (57, 63))	('deletions', 'Var', (64, 73))	('patients', 'Species', '9606', (134, 142))	('epigenetic silencing', 'Var', (94, 114))	('CDKN2A', 'Gene', '1029', (46, 52))	('CDKN2B', 'Gene', '1030', (57, 63))	('age', 'Gene', (79, 82))	('increase', 'PosReg', (34, 42))	('age', 'Gene', '5973', (79, 82))
211560	33879792	p value = 2.63 x 10-8), due to mutations in the TP53 gene (Fig.	('TP53', 'Gene', '7157', (48, 52))	('mutations', 'Var', (31, 40))	('TP53', 'Gene', (48, 52))	('due to', 'Reg', (24, 30))
211574	33879792	To exclude the possibility that germline predisposition mutations in some patients may cause such a high number of age-DEGs and age-DMGs in cancers of the female reproductive system, we excluded samples harbouring germline mutations in BRCA1, BRCA2 and TP53 as previously identified from the breast, ovarian and endometrial cancer cohorts and repeated the multiple linear regression analysis.	('BRCA1', 'Gene', (236, 241))	('age', 'Gene', '5973', (128, 131))	('ovarian and endometrial cancer', 'Disease', 'MESH:D004714', (300, 330))	('cause', 'Reg', (87, 92))	('BRCA2', 'Gene', '675', (243, 248))	('mutations', 'Var', (56, 65))	('DEGs', 'Gene', '8560', (119, 123))	('TP53', 'Gene', '7157', (253, 257))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('age', 'Gene', (115, 118))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('age', 'Gene', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('age', 'Gene', '5973', (115, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (312, 330))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('BRCA2', 'Gene', (243, 248))	('BRCA1', 'Gene', '672', (236, 241))	('TP53', 'Gene', (253, 257))	('DEGs', 'Gene', (119, 123))
211600	33879792	We confirmed the known increase in mutation load, that can be in part explained by an increase in C>T mutations, and found an increase in GI, LOH and WGD with age in several cancer types.	('C>T mutations', 'Var', (98, 111))	('increase', 'PosReg', (86, 94))	('WGD', 'Disease', (150, 153))	('GI', 'Gene', '2770', (138, 140))	('age', 'Gene', (159, 162))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('increase', 'PosReg', (23, 31))	('LOH', 'Disease', (142, 145))	('increase', 'PosReg', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('age', 'Gene', '5973', (159, 162))	('mutation load', 'MPA', (35, 48))
211601	33879792	We identified several age-related pan-cancer and cancer-specific alterations.	('alterations', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('age', 'Gene', '5973', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('age', 'Gene', (22, 25))	('cancer', 'Disease', (49, 55))
211603	33879792	Cancer develops through the accumulation of genetic and epigenetic alterations.	('genetic', 'Var', (44, 51))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic alterations', 'Var', (56, 78))
211604	33879792	Mutation accumulation with age is thought to be a cause of cancer and a substantial portion of mutations arise before cancer initiation.	('cancer', 'Disease', (118, 124))	('cancer initiation', 'Disease', 'MESH:D009369', (118, 135))	('Mutation', 'Var', (0, 8))	('cancer initiation', 'Disease', (118, 135))	('age', 'Gene', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('age', 'Gene', '5973', (27, 30))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
211605	33879792	The age-associated mutation accumulation has been demonstrated in both cancer and normal tissues, providing a better understanding of early carcinogenic events.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mutation', 'Var', (19, 27))	('cancer', 'Disease', (71, 77))	('carcinogenic', 'Disease', 'MESH:D063646', (140, 152))	('age', 'Gene', (4, 7))	('carcinogenic', 'Disease', (140, 152))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('age', 'Gene', '5973', (4, 7))
211608	33879792	The negative association between age and mutation in IDH1, ATRX and TP53 in glioma points towards the difference of patient age at diagnosis between the IDH-mutant and IDH-WT subtypes.	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('age', 'Gene', '5973', (33, 36))	('age', 'Gene', (124, 127))	('IDH', 'Gene', (153, 156))	('TP53', 'Gene', (68, 72))	('IDH', 'Gene', '3417', (168, 171))	('ATRX', 'Gene', (59, 63))	('negative', 'NegReg', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('mutation', 'Var', (41, 49))	('ATRX', 'Gene', '546', (59, 63))	('IDH', 'Gene', '3417', (153, 156))	('age', 'Gene', '5973', (124, 127))	('IDH1', 'Gene', (53, 57))	('IDH', 'Gene', (53, 56))	('TP53', 'Gene', '7157', (68, 72))	('age', 'Gene', (33, 36))	('patient', 'Species', '9606', (116, 123))	('IDH1', 'Gene', '3417', (53, 57))	('IDH', 'Gene', '3417', (53, 56))	('IDH', 'Gene', (168, 171))
211612	33879792	A recent functional study in neural stem cells (NSCs) showed that the combination of IDH1, ATRX and TP53 alterations blocks NSC differentiation by causing hypermethylation of CTCF motifs flanking the SOX2 locus, disrupting chromatin looping and dysregulation of SOX2, an important transcription factor in self-renewal and differentiation of NSCs.	('TP53', 'Gene', (100, 104))	('CTCF', 'Gene', '10664', (175, 179))	('chromatin looping', 'MPA', (223, 240))	('SOX2', 'Gene', '6657', (200, 204))	('SOX2', 'Gene', (200, 204))	('alterations', 'Var', (105, 116))	('CTCF', 'Gene', (175, 179))	('SOX2', 'Gene', '6657', (262, 266))	('TP53', 'Gene', '7157', (100, 104))	('causing', 'Reg', (147, 154))	('dysregulation', 'MPA', (245, 258))	('SOX2', 'Gene', (262, 266))	('ATRX', 'Gene', (91, 95))	('ATRX', 'Gene', '546', (91, 95))	('disrupting', 'NegReg', (212, 222))	('IDH1', 'Gene', (85, 89))	('NSC differentiation', 'CPA', (124, 143))	('meth', 'Disease', 'None', (160, 164))	('meth', 'Disease', (160, 164))	('blocks', 'NegReg', (117, 123))	('IDH1', 'Gene', '3417', (85, 89))
211613	33879792	Impaired differentiation, growth arrest evasion by mutations in TP53, and alternative lengthening of telomeres by ATRX inactivation thus cooperatively promote gliomas in younger patients.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('mutations', 'Var', (51, 60))	('gliomas', 'Disease', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('growth arrest', 'Disease', 'MESH:D006323', (26, 39))	('ATRX', 'Gene', '546', (114, 118))	('growth arrest', 'Disease', (26, 39))	('patients', 'Species', '9606', (178, 186))	('Impaired differentiation', 'CPA', (0, 24))	('promote', 'PosReg', (151, 158))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('growth arrest', 'Phenotype', 'HP:0001510', (26, 39))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('ATRX', 'Gene', (114, 118))	('inactivation', 'Var', (119, 131))
211618	33879792	Previous studies have classified endometrial cancer into four subtypes: POLE, MSI-H, copy-number low and copy-number high subtypes.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('copy-number high', 'Var', (105, 121))	('endometrial cancer', 'Disease', (33, 51))	('copy-number low', 'Var', (85, 100))	('endometrial cancer', 'Phenotype', 'HP:0012114', (33, 51))	('endometrial cancer', 'Disease', 'MESH:D016889', (33, 51))
211619	33879792	Conversely, the copy-number low and copy-number high subtypes had a dominant ageing-related mutational signature.	('age', 'Gene', (77, 80))	('copy-number high', 'Var', (36, 52))	('age', 'Gene', '5973', (77, 80))	('copy-number low', 'Var', (16, 31))
211620	33879792	Therefore, endometrial cancer from younger patients is associated with POLE mutations, mismatch repair defects, high mutation load and better survival outcomes.	('endometrial cancer', 'Disease', (11, 29))	('patients', 'Species', '9606', (43, 51))	('endometrial cancer', 'Phenotype', 'HP:0012114', (11, 29))	('POLE mutations', 'Var', (71, 85))	('mismatch repair', 'CPA', (87, 102))	('endometrial cancer', 'Disease', 'MESH:D016889', (11, 29))	('high mutation load', 'Var', (112, 130))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
211623	33879792	Indeed, some of these age-related differences might be explained by age-related subtypes, such as the high prevalence of CDH1 mutation in invasive lobular breast carcinoma and GS stomach cancer, that are presented more often in older and younger patients, respectively.	('age', 'Gene', (68, 71))	('CDH1', 'Gene', (121, 125))	('patients', 'Species', '9606', (246, 254))	('age', 'Gene', '5973', (22, 25))	('mutation', 'Var', (126, 134))	('CDH1', 'Gene', '999', (121, 125))	('age', 'Gene', '5973', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('stomach cancer', 'Phenotype', 'HP:0012126', (179, 193))	('age', 'Gene', (22, 25))	('invasive lobular breast carcinoma and GS stomach cancer', 'Disease', 'MESH:D001943', (138, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('breast carcinoma', 'Phenotype', 'HP:0003002', (155, 171))
211630	33879792	We reason that tissue environment changes during ageing might provide different selective advantages for tumours harbouring different molecular alterations, in turn directing tumours to different evolutionary routes.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('age', 'Gene', (96, 99))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumours', 'Disease', 'MESH:D009369', (175, 182))	('age', 'Gene', (49, 52))	('alterations', 'Var', (144, 155))	('age', 'Gene', '5973', (96, 99))	('age', 'Gene', '5973', (49, 52))	('tumours', 'Disease', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
211632	33879792	Gene expression and epigenetic changes related to ageing have been studied and linked to cancer.	('age', 'Gene', (50, 53))	('linked', 'Reg', (79, 85))	('age', 'Gene', '5973', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('epigenetic', 'Var', (20, 30))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
211640	33879792	Other probes might also have an impact on gene expression as well as might cause noise in our GSEA analysis from methylation data.	('cause', 'Reg', (75, 80))	('meth', 'Disease', 'None', (113, 117))	('impact', 'Reg', (32, 38))	('GSEA', 'Chemical', '-', (94, 98))	('meth', 'Disease', (113, 117))	('gene expression', 'MPA', (42, 57))	('probes', 'Var', (6, 12))
211645	33879792	In addition, despite using slightly different statistical cutoffs and models, several age-associated genomic features are identified by both studies, for example, the higher frequency of IDH1 and ATRX mutations in younger glioma patients.	('patients', 'Species', '9606', (229, 237))	('higher', 'PosReg', (167, 173))	('ATRX', 'Gene', (196, 200))	('mutations', 'Var', (201, 210))	('glioma', 'Disease', (222, 228))	('age', 'Gene', (86, 89))	('IDH1', 'Gene', '3417', (187, 191))	('ATRX', 'Gene', '546', (196, 200))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))	('age', 'Gene', '5973', (86, 89))	('glioma', 'Disease', 'MESH:D005910', (222, 228))	('IDH1', 'Gene', (187, 191))
211658	33879792	mutation as 1 and wild-type as 0) and multiple logistic regression adjusting for covariates were carried out using the glm function in R. In pan-cancer analyses, gender, race and cancer type were variables included in the linear model.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (179, 185))
211699	33879792	For pan-cancer analysis, multiple logistic regression accounting for gender, race and cancer type was performed to investigate the association between age and mutations in 20 cancer genes that are mutated in >5% of samples (Supplementary Data 11).	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (159, 168))	('age', 'Gene', (151, 154))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('age', 'Gene', '5973', (151, 154))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', (86, 92))
211700	33879792	For cancer-specific analysis, simple logistic regression was used to identify cancer genes that the mutations in these genes are associated with the patient's age.	('mutations', 'Var', (100, 109))	('associated', 'Reg', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('age', 'Gene', (159, 162))	('patient', 'Species', '9606', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (4, 10))	('age', 'Gene', '5973', (159, 162))
211711	33879792	Similarly, POLE and POLD1 mutation status were in a binary outcome (mutated and not mutated).	('POLD1', 'Gene', (20, 25))	('POLD1', 'Gene', '5424', (20, 25))	('mutation', 'Var', (26, 34))
211712	33879792	Multiple logistic regression was used to investigate the association between age and POLE/POLD1 mutations in cancer types that contained POLE/POLD1 mutations in >5% of samples.	('age', 'Gene', (77, 80))	('POLD1', 'Gene', '5424', (142, 147))	('mutations', 'Var', (148, 157))	('POLD1', 'Gene', (142, 147))	('POLD1', 'Gene', (90, 95))	('POLD1', 'Gene', '5424', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('age', 'Gene', '5973', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (96, 105))
211714	33879792	Member genes in the pathways were accessed for SCNAs, mutations, epigenetic silencing through promoter DNA hypermethylation and gene fusions.	('meth', 'Disease', 'None', (112, 116))	('epigenetic silencing', 'Var', (65, 85))	('gene fusions', 'Var', (128, 140))	('mutations', 'Var', (54, 63))	('meth', 'Disease', (112, 116))	('SCNAs', 'Disease', (47, 52))
211715	33879792	For the pan-cancer analysis, we employed multiple logistic regression adjusting for the patient's gender, race and cancer type to demonstrate the relationship between pathway-level alteration and age.	('patient', 'Species', '9606', (88, 95))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('age', 'Gene', (196, 199))	('alteration', 'Var', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('age', 'Gene', '5973', (196, 199))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
211726	33879792	To exclude the possibility that germline predisposition mutations in some patients may cause this high number of age-DEGs and age-DMGs in female reproductive cancers, we excluded samples harbouring germline mutations in BRCA1, BRCA2 and TP53 as previously identified from breast, ovarian and endometrial cancer cohorts.	('BRCA1', 'Gene', '672', (220, 225))	('age', 'Gene', (126, 129))	('TP53', 'Gene', (237, 241))	('BRCA2', 'Gene', '675', (227, 232))	('endometrial cancer', 'Phenotype', 'HP:0012114', (292, 310))	('cause', 'Reg', (87, 92))	('BRCA1', 'Gene', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('mutations', 'Var', (56, 65))	('ovarian and endometrial cancer', 'Disease', 'MESH:D004714', (280, 310))	('DEGs', 'Gene', (117, 121))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('age', 'Gene', '5973', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('TP53', 'Gene', '7157', (237, 241))	('age', 'Gene', (113, 116))	('patients', 'Species', '9606', (74, 82))	('DEGs', 'Gene', '8560', (117, 121))	('BRCA2', 'Gene', (227, 232))	('age', 'Gene', '5973', (113, 116))	('cancers', 'Disease', 'MESH:D009369', (158, 165))
211749	33066121	When active HGF binds the extracellular portion of the beta domain of MET, it causes receptor dimerization followed by the downstream auto-phosphorylation of two tyrosines located on the intracellular portion of the beta domain (Y1349 and Y1356).	('causes', 'Reg', (78, 84))	('tyrosines', 'Chemical', 'MESH:D014443', (162, 171))	('Y1349', 'Var', (229, 234))	('binds', 'Interaction', (16, 21))	('Y1356', 'Var', (239, 244))	('MET', 'Gene', (70, 73))	('auto-phosphorylation', 'MPA', (134, 154))	('receptor dimerization', 'MPA', (85, 106))
211760	33066121	In the mouse embryo, HGF is highly expressed in the limb bud, and mutant mice are not able to form the skeletal muscles of the limb and diaphragm.	('mouse', 'Species', '10090', (7, 12))	('mice', 'Species', '10090', (73, 77))	('HGF', 'Gene', (21, 24))	('mutant', 'Var', (66, 72))
211811	33066121	In 2011, research from John Laterra's group showed that MET is activated and functional in glioblastoma neurospheres that harbor a large population of glioblastoma stem cells, and in fact, MET expression correlates with and induces the expression of stem cell markers and reprogramming transcription factors.	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('glioblastoma neurospheres', 'Disease', (91, 116))	('MET', 'Var', (189, 192))	('stem cell', 'CPA', (250, 259))	('induces', 'PosReg', (224, 231))	('glioblastoma', 'Disease', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('glioblastoma', 'Disease', (91, 103))	('expression', 'MPA', (236, 246))	('glioblastoma neurospheres', 'Disease', 'MESH:D005909', (91, 116))
211827	33066121	When dysregulated, HGF/MET signaling promotes tumor progression and angiogenesis in many cancers including brain tumors (Figure 2).	('HGF/MET', 'Gene', '3082;79811', (19, 26))	('brain tumor', 'Phenotype', 'HP:0030692', (107, 118))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('dysregulated', 'Var', (5, 17))	('cancers', 'Disease', (89, 96))	('promotes', 'PosReg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('brain tumors', 'Disease', (107, 119))	('brain tumors', 'Disease', 'MESH:D001932', (107, 119))	('HGF/MET', 'Gene', (19, 26))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (46, 51))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('angiogenesis', 'CPA', (68, 80))	('brain tumors', 'Phenotype', 'HP:0030692', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
211832	33066121	Mutations in the MET gene also induce tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('MET', 'Gene', (17, 20))	('induce', 'Reg', (31, 37))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
211833	33066121	These mutations include missense mutations that cause either inherited or sporadic carcinomas.	('carcinomas', 'Disease', 'MESH:D009369', (83, 93))	('missense mutations', 'Var', (24, 42))	('inherited', 'Disease', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('carcinomas', 'Disease', (83, 93))	('cause', 'Reg', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
211860	33066121	Genetic alterations in gliomas occur frequently.	('Genetic alterations', 'Var', (0, 19))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('rat', 'Species', '10116', (12, 15))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))
211861	33066121	Approximately 80% of low-grade gliomas harbor recurrent mutations in the isocitrate dehydrogenase genes 1 and 2 (commonly referred to as IDH1 and IDH2, respectively).	('mutations', 'Var', (56, 65))	('IDH2', 'Gene', '3418', (146, 150))	('IDH1', 'Gene', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('rat', 'Species', '10116', (79, 82))	('IDH1', 'Gene', '3417', (137, 141))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('IDH2', 'Gene', (146, 150))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
211862	33066121	Because these genetic alterations are so common, current classifications of gliomas, spearheaded by scientific discovery and adopted by the World Health Organization (WHO), have taken into account the IDH mutation status and have come up with three distinct categories of classification based on this genetic property: (1) IDH mutated with chromosome 1p/19q co-deleted; (2) IDH mutated without chromosome 1p/19q co-deleted; and (3) IDH wild-type.	('IDH', 'Gene', (432, 435))	('IDH', 'Gene', (374, 377))	('gliomas', 'Disease', (76, 83))	('IDH', 'Gene', '3417', (432, 435))	('IDH', 'Gene', (323, 326))	('IDH', 'Gene', (201, 204))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('rat', 'Species', '10116', (26, 29))	('mutated', 'Var', (327, 334))	('IDH', 'Gene', '3417', (374, 377))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('IDH', 'Gene', '3417', (323, 326))	('IDH', 'Gene', '3417', (201, 204))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))
211863	33066121	Other gene amplifications or mutations have included RTK/RAS/PI3K, TP53, ATRX loss, and RB signaling pathways.	('RTK', 'Gene', '5979', (53, 56))	('RB', 'Phenotype', 'HP:0009919', (88, 90))	('mutations', 'Var', (29, 38))	('ATRX', 'Gene', (73, 77))	('RTK', 'Gene', (53, 56))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('RB', 'Gene', '5925', (88, 90))	('ATRX', 'Gene', '546', (73, 77))
211864	33066121	IDH mutations are seen in gliomas such as astrocytomas and oligodendrogliomas whereas IDH wild-type is present 90% of the time in glioblastomas.	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', (0, 3))	('glioblastomas', 'Phenotype', 'HP:0012174', (130, 143))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (42, 77))	('gliomas', 'Disease', (26, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (42, 53))	('seen', 'Reg', (18, 22))	('IDH', 'Gene', '3417', (86, 89))	('IDH', 'Gene', '3417', (0, 3))	('glioblastomas', 'Disease', (130, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('gliomas', 'Disease', (70, 77))	('mutations', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('glioblastomas', 'Disease', 'MESH:D005909', (130, 143))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
211867	33066121	The aberrant expression of MET in high-grade gliomas and embryonal brain tumors is associated with poor clinical outcomes.	('brain tumors', 'Phenotype', 'HP:0030692', (67, 79))	('MET', 'Gene', (27, 30))	('brain tumor', 'Phenotype', 'HP:0030692', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('gliomas and embryonal brain tumors', 'Disease', 'MESH:C564230', (45, 79))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('aberrant expression', 'Var', (4, 23))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))
211880	33066121	In this context, the most commonly mutated one is the RTK/PI3K pathway, and there is approximately 88% of glioblastoma samples that harbor at least one genetic event in this core pathway.	('mutated', 'Var', (35, 42))	('glioblastoma', 'Disease', (106, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('RTK', 'Gene', (54, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('RTK', 'Gene', '5979', (54, 57))
211890	33066121	Anaplastic oligodendroglioma, differing from oligodendroglioma for histological reasons, with IDH mutations and chromosome 1p/19q co-deletion is classified as a grade III.	('oligodendroglioma', 'Disease', (11, 28))	('IDH', 'Gene', (94, 97))	('Anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (0, 28))	('oligodendroglioma', 'Disease', 'MESH:D009837', (45, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH', 'Gene', '3417', (94, 97))	('mutations', 'Var', (98, 107))	('oligodendroglioma', 'Disease', 'MESH:D009837', (11, 28))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('Anaplastic oligodendroglioma', 'Disease', (0, 28))	('oligodendroglioma', 'Disease', (45, 62))
211892	33066121	showed that MET expression was correlated with progression-free survival in oligodendroglial tumors with IDH mutations.	('IDH', 'Gene', '3417', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MET expression', 'MPA', (12, 26))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('IDH', 'Gene', (105, 108))	('mutations', 'Var', (109, 118))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (76, 99))	('oligodendroglial tumors', 'Disease', (76, 99))	('correlated', 'Reg', (31, 41))
211901	33066121	Deregulated expression of RTKs and related growth factors such as VEGF, HGF, and PDGF can result in specific signaling that enhances tumor growth.	('VEGF', 'Gene', (66, 70))	('Deregulated', 'Var', (0, 11))	('PDGF', 'Gene', '5156', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('VEGF', 'Gene', '7422', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('RTK', 'Gene', (26, 29))	('HGF', 'Gene', (72, 75))	('tumor', 'Disease', (133, 138))	('RTK', 'Gene', '5979', (26, 29))	('expression', 'MPA', (12, 22))	('enhances', 'PosReg', (124, 132))	('specific signaling', 'MPA', (100, 118))	('result in', 'Reg', (90, 99))	('PDGF', 'Gene', (81, 85))
211925	33066121	Similarly, LY2875358/Emibetuzumab is another anti-MET antibody developed by Eli Lilly and Company that has recently completed testing in a phase I clinical trial in human patients with non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (185, 211))	('human', 'Species', '9606', (165, 170))	('non-small cell lung cancer', 'Disease', (185, 211))	('patients', 'Species', '9606', (171, 179))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (185, 211))	('LY2875358/Emibetuzumab', 'Var', (11, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('LY2875358', 'Chemical', 'MESH:C000599789', (11, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (189, 211))	('Emibetuzumab', 'Chemical', 'MESH:C000599789', (21, 33))
211929	33066121	While antibodies are large and therefore cannot easily penetrate the BBB, small-molecules overcome the drug delivery obstacle by being small and often hydrophobic.	('small-molecules', 'Var', (74, 89))	('drug delivery obstacle', 'MPA', (103, 125))	('rat', 'Species', '10116', (60, 63))
211933	33066121	Another common type I inhibitor is PF-02341066 developed by Pfizer, Inc.. PF-02341066 was shown to be effective against MET-dependent growth, invasion, and survival and has been tested in phase II clinical trials for CNS and solid brain tumors.	('PF-02341066', 'Chemical', 'MESH:D000077547', (74, 85))	('brain tumors', 'Disease', 'MESH:D001932', (231, 243))	('brain tumors', 'Phenotype', 'HP:0030692', (231, 243))	('MET-dependent', 'MPA', (120, 133))	('brain tumors', 'Disease', (231, 243))	('PF-02341066', 'Chemical', 'MESH:D000077547', (35, 46))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('effective', 'Reg', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PF-02341066', 'Var', (74, 85))	('brain tumor', 'Phenotype', 'HP:0030692', (231, 242))	('survival', 'CPA', (156, 164))	('invasion', 'CPA', (142, 150))	('CNS', 'Disease', (217, 220))
211940	33066121	This is advantageous for the reason that certain cancers can have high levels of MET mutations and each MET mutant will need to be inhibited for the therapy to be most effective.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('MET mutations', 'Var', (81, 94))
212070	30343559	Using intraoperative n3DUS, we were better able to delineate many of these tumors (almost 3 times the number that could be well-defined on MRI), enabling GTR in 51% of all such non-enhancing tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('GTR', 'MPA', (154, 157))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('n3DUS', 'Var', (21, 26))	('enabling', 'PosReg', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('GTR', 'Chemical', '-', (154, 157))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', (75, 81))
212134	29453678	Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer.	('Fn14', 'Gene', (124, 128))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('overexpressed', 'PosReg', (132, 145))	('IDH1', 'Gene', (54, 58))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('Fn14', 'Gene', '51330', (46, 50))	('mutant', 'Var', (73, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (183, 195))	('adult brain cancer', 'Disease', (238, 256))	('TWEAK receptor', 'Gene', (31, 45))	('Fn14', 'Gene', '51330', (124, 128))	('adult brain cancer', 'Disease', 'MESH:D001932', (238, 256))	('TWEAK receptor', 'Gene', '51330', (31, 45))	('glioblastoma', 'Disease', (183, 195))	('IDH1', 'Gene', '3417', (54, 58))	('tumor', 'Disease', (160, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (183, 195))	('gliomas', 'Disease', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('Fn14', 'Gene', (46, 50))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('brain cancer', 'Phenotype', 'HP:0030692', (244, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('GBM', 'Phenotype', 'HP:0012174', (197, 200))
212135	29453678	GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('expression levels', 'MPA', (104, 121))	('tumor', 'Disease', (135, 140))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('Fn14', 'Gene', '51330', (99, 103))	('increase', 'PosReg', (126, 134))	('high', 'Var', (94, 98))	('Fn14', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
212137	29453678	Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme.	('IDH1', 'Gene', '3417', (140, 144))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH1', 'Gene', '3417', (227, 231))	('R132H', 'Mutation', 'rs121913500', (327, 332))	('gliomas', 'Disease', (266, 273))	('R132H', 'Var', (259, 264))	('comparing', 'Reg', (193, 202))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('Fn14', 'Gene', (203, 207))	('gliomas', 'Disease', 'MESH:D005910', (266, 273))	('human', 'Species', '9606', (56, 61))	('glioma', 'Phenotype', 'HP:0009733', (266, 272))	('isocitrate dehydrogenase 1', 'Gene', (112, 138))	('isocitrate dehydrogenase 1', 'Gene', '3417', (112, 138))	('IDH1', 'Gene', (322, 326))	('gliomas', 'Phenotype', 'HP:0009733', (266, 273))	('IDH1', 'Gene', (140, 144))	('R132H', 'Mutation', 'rs121913500', (259, 264))	('gliomas', 'Disease', (62, 69))	('IDH1', 'Gene', (227, 231))	('Fn14', 'Gene', '51330', (203, 207))	('IDH1', 'Gene', '3417', (322, 326))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))
212146	29453678	Recently, the histopathological classification of GBM has been modified based on genetic mutations in the isocitrate dehydrogenase (IDH) gene.	('genetic mutations', 'Var', (81, 98))	('IDH', 'Gene', (132, 135))	('isocitrate dehydrogenase', 'Gene', (106, 130))	('IDH', 'Gene', '3417', (132, 135))	('isocitrate dehydrogenase', 'Gene', '3417', (106, 130))	('GBM', 'Phenotype', 'HP:0012174', (50, 53))
212147	29453678	IDH mutations were first identified in GBM tumors in 2008 during an analysis of 20,661 protein-coding genes in 22 GBM samples.	('IDH', 'Gene', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('IDH', 'Gene', '3417', (0, 3))	('GBM tumors', 'Disease', (39, 49))	('GBM tumors', 'Disease', 'MESH:D005910', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (4, 13))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))
212148	29453678	This work laid the foundation for more extensive genomic analyses, which identified mutations in the IDH1 or IDH2 isoforms in 60-80% of grade II and III gliomas.	('IDH1', 'Gene', (101, 105))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('IDH1', 'Gene', '3417', (101, 105))	('IDH2', 'Gene', (109, 113))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('mutations', 'Var', (84, 93))	('IDH2', 'Gene', '3418', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))
212149	29453678	These mutations are also found in 80% of secondary GBMs, which are tumors that have developed from low grade gliomas (LGGs), but only 3-7% of primary GBMs (i.e.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('secondary GBMs', 'Disease', (41, 55))	('gliomas', 'Disease', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (6, 15))
212150	29453678	The most commonly identified mutation is the IDH1 R132H gain-of-function mutation, which catalyzes the NADPH dependent reduction of alpha-ketoglutarate (alpha-KG) to produce the R enantiomer of 2-hydroxyglutarate (2-HG).	('IDH1', 'Gene', '3417', (45, 49))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (132, 151))	('alpha-KG', 'Chemical', 'MESH:D007656', (153, 161))	('NADPH', 'Chemical', 'MESH:D009249', (103, 108))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (194, 212))	('R132H', 'Var', (50, 55))	('IDH1', 'Gene', (45, 49))	('2-HG', 'Chemical', 'MESH:C019417', (214, 218))	('gain-of-function', 'PosReg', (56, 72))	('R132H', 'Mutation', 'rs121913500', (50, 55))
212151	29453678	In turn, 2-HG inhibits alpha-KG-dependent dioxygenases, with resultant downstream effects that mediate tumor cell interactions with the environment, collagen modification, responses to hypoxia, and immune evasion.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('2-HG', 'Var', (9, 13))	('inhibits', 'NegReg', (14, 22))	('tumor', 'Disease', (103, 108))	('alpha-KG', 'Chemical', 'MESH:D007656', (23, 31))	('collagen', 'MPA', (149, 157))	('hypoxia', 'Disease', (185, 192))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('interactions', 'Interaction', (114, 126))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('2-HG', 'Chemical', 'MESH:C019417', (9, 13))	('immune evasion', 'MPA', (198, 212))	('alpha-KG-dependent dioxygenases', 'Enzyme', (23, 54))
212152	29453678	IDH1 mutant GBMs are more likely to involve the frontal lobes, demonstrate less contrast enhancement, and produce less peritumoral changes on MRI.	('frontal lobes', 'Disease', (48, 61))	('tumor', 'Disease', (123, 128))	('less', 'NegReg', (114, 118))	('involve', 'Reg', (36, 43))	('contrast', 'CPA', (80, 88))	('less', 'NegReg', (75, 79))	('mutant', 'Var', (5, 11))	('frontal lobes', 'Disease', 'MESH:D001927', (48, 61))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('IDH1', 'Gene', (0, 4))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('IDH1', 'Gene', '3417', (0, 4))
212153	29453678	Patients with IDH1 mutant tumors are, on average, younger (33 vs. 53 years) and survive significantly longer than those with IDH1 WT tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('IDH1', 'Gene', '3417', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('IDH1 WT tumors', 'Disease', 'MESH:C536751', (125, 139))	('Patients', 'Species', '9606', (0, 8))	('mutant', 'Var', (19, 25))	('IDH1 WT tumors', 'Disease', (125, 139))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', (125, 129))	('tumors', 'Disease', (26, 32))	('IDH1', 'Gene', '3417', (14, 18))
212154	29453678	Gliomas with the IDH1 mutation are found to have a specific cellular phenotype, characterized by global DNA hypermethylation at CpG islands.	('mutation', 'Var', (22, 30))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('IDH1', 'Gene', (17, 21))	('Gliomas', 'Disease', (0, 7))	('IDH1', 'Gene', '3417', (17, 21))
212155	29453678	Evidence suggests that these IDH mutation-related epigenetic changes impact a variety of biological processes, including metabolic pathways and transcriptional programs linked to tumor growth and development.	('transcriptional programs', 'CPA', (144, 168))	('metabolic', 'CPA', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('mutation-related', 'Reg', (33, 49))	('epigenetic changes', 'Var', (50, 68))	('IDH', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('impact', 'Reg', (69, 75))	('IDH', 'Gene', '3417', (29, 32))	('tumor', 'Disease', (179, 184))
212156	29453678	Although the TWEAK-Fn14 axis and the IDH1 mutation have both been shown to have important effects on glioma cell biology and patient outcome, the inter-relationship between these patho-biological systems has not been studied.	('TWEAK', 'Gene', (13, 18))	('TWEAK', 'Gene', '8742', (13, 18))	('effects', 'Reg', (90, 97))	('glioma', 'Disease', (101, 107))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('Fn14', 'Gene', (19, 23))	('IDH1', 'Gene', '3417', (37, 41))	('Fn14', 'Gene', '51330', (19, 23))	('patient', 'Species', '9606', (125, 132))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
212157	29453678	Recent work has shown that forced overexpression of the IDH1 R132H protein in glioma cells reduces migration and invasion in vitro.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('IDH1', 'Gene', '3417', (56, 60))	('overexpression', 'PosReg', (34, 48))	('reduces', 'NegReg', (91, 98))	('R132H', 'Var', (61, 66))	('protein', 'Protein', (67, 74))	('glioma', 'Disease', (78, 84))	('R132H', 'Mutation', 'rs121913500', (61, 66))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('IDH1', 'Gene', (56, 60))
212158	29453678	Given the role that Fn14 may play in promoting glioma cell invasion, we investigated Fn14 gene expression levels in IDH1 WT and R132H mutant low-grade gliomas (LGGs) and GBM tumors as well as IDH1 R132H-overexpressing glioma cell lines.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioma', 'Disease', (218, 224))	('GBM tumors', 'Disease', (170, 180))	('IDH1', 'Gene', '3417', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('Fn14', 'Gene', (85, 89))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('Fn14', 'Gene', (20, 24))	('GBM tumors', 'Disease', 'MESH:D005910', (170, 180))	('R132H', 'Mutation', 'rs121913500', (128, 133))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('GBM', 'Phenotype', 'HP:0012174', (170, 173))	('glioma', 'Disease', (47, 53))	('IDH1', 'Gene', (116, 120))	('Fn14', 'Gene', '51330', (85, 89))	('gliomas', 'Disease', (151, 158))	('R132H', 'Mutation', 'rs121913500', (197, 202))	('glioma', 'Disease', (151, 157))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('Fn14', 'Gene', '51330', (20, 24))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('R132H', 'Var', (128, 133))	('IDH1', 'Gene', (192, 196))	('IDH1', 'Gene', '3417', (116, 120))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
212159	29453678	We report that resected gliomas and glioma cell lines carrying an IDH1 R132H mutation express Fn14 at relatively low levels compared to their IDH1 WT counterparts, supporting a possible link between low Fn14 levels, reduced cell invasion, and improved patient prognosis associated with the IDH1 mutation.	('glioma', 'Disease', (36, 42))	('Fn14', 'Gene', (94, 98))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('IDH1', 'Gene', (142, 146))	('reduced', 'NegReg', (216, 223))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('IDH1', 'Gene', '3417', (66, 70))	('Fn14', 'Gene', (203, 207))	('cell invasion', 'CPA', (224, 237))	('glioma', 'Disease', (24, 30))	('R132H', 'Mutation', 'rs121913500', (71, 76))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('patient', 'Species', '9606', (252, 259))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('IDH1', 'Gene', '3417', (142, 146))	('IDH1', 'Gene', (290, 294))	('Fn14', 'Gene', '51330', (94, 98))	('gliomas', 'Disease', (24, 31))	('improved', 'PosReg', (243, 251))	('Fn14', 'Gene', '51330', (203, 207))	('patient prognosis', 'CPA', (252, 269))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('R132H mutation', 'Var', (71, 85))	('IDH1', 'Gene', '3417', (290, 294))	('IDH1', 'Gene', (66, 70))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
212162	29453678	Among the LGG dataset, 65 IDH1 WT tumors and 221 IDH1 mutant tumors were identified, while among the GBM dataset, 227 IDH1 WT and 13 IDH1 mutant tumors were identified (12 containing the R132H point mutation, and 1 with an R132G mutation).	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('IDH1', 'Gene', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('R132H point', 'Var', (187, 198))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('IDH1', 'Gene', '3417', (49, 53))	('IDH1 WT tumors', 'Disease', (26, 40))	('IDH1', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('IDH1', 'Gene', '3417', (26, 30))	('IDH1 WT tumors', 'Disease', 'MESH:C536751', (26, 40))	('tumors', 'Disease', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('IDH1', 'Gene', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('IDH1', 'Gene', '3417', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('IDH1', 'Gene', '3417', (118, 122))	('tumors', 'Disease', (145, 151))	('R132G', 'Mutation', 'rs121913499', (223, 228))	('R132H', 'Mutation', 'rs121913500', (187, 192))	('IDH1', 'Gene', (49, 53))
212165	29453678	All 13 IDH1 mutant GBM samples were of the proneural subtype; these were analyzed as a distinct subset relative to the 125 proneural tumors with either WT (n = 45) or unknown (n = 80) IDH1 status.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('IDH1', 'Gene', '3417', (7, 11))	('IDH1', 'Gene', (184, 188))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('IDH1', 'Gene', '3417', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutant', 'Var', (12, 18))	('IDH1', 'Gene', (7, 11))
212168	29453678	Samples were categorized into 4 groups: (1) IDH1 WT LGG, (2) IDH1 mutant LGG, (3) IDH1 WT GBM and (4) IDH1 mutant GBM.	('mutant', 'Var', (66, 72))	('IDH1', 'Gene', (44, 48))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', (102, 106))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (44, 48))	('IDH1', 'Gene', '3417', (82, 86))	('IDH1', 'Gene', '3417', (102, 106))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('IDH1', 'Gene', '3417', (61, 65))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))
212170	29453678	Six IDH1 WT LGGs, five IDH1 mutant LGGs, five IDH1 WT GBMs, and three IDH1 mutant GBM samples were retrieved.	('IDH1', 'Gene', '3417', (4, 8))	('mutant', 'Var', (28, 34))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('IDH1', 'Gene', (46, 50))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (70, 74))	('IDH1', 'Gene', '3417', (46, 50))	('IDH1', 'Gene', (4, 8))	('IDH1', 'Gene', '3417', (23, 27))	('IDH1', 'Gene', (70, 74))
212183	29453678	Immunoblotting was performed as previously described using the following primary antibodies: IDH1 R132H (Dianova GmbH; Hamburg, Germany), Fn14 (Cell Signaling Technology (CST); Danvers, MA), PAR-4 (CST), MLH1 (CST), and GAPDH (CST).	('IDH1', 'Gene', (93, 97))	('MLH1', 'Gene', '4292', (204, 208))	('GAPDH', 'Gene', '2597', (220, 225))	('MLH1', 'Gene', (204, 208))	('Fn14', 'Gene', '51330', (138, 142))	('PAR-4', 'Gene', '5074', (191, 196))	('IDH1', 'Gene', '3417', (93, 97))	('Fn14', 'Gene', (138, 142))	('GAPDH', 'Gene', (220, 225))	('PAR-4', 'Gene', (191, 196))	('R132H', 'Var', (98, 103))	('R132H', 'Mutation', 'rs121913500', (98, 103))
212189	29453678	However, this prior analysis utilized a relatively small GBM subtype sample size and did not distinguish between IDH1 WT and R132H mutant tumors.	('R132H', 'Var', (125, 130))	('IDH1', 'Gene', (113, 117))	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('IDH1', 'Gene', '3417', (113, 117))	('R132H', 'Mutation', 'rs121913500', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
212192	29453678	We also identified 13 IDH1 mutant GBM samples in the proneural group, which were analyzed as a distinct subset relative to the 125 proneural tumors with either WT (n = 45) or unknown (n = 80) IDH1 gene status.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mutant', 'Var', (27, 33))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('IDH1', 'Gene', (192, 196))	('IDH1', 'Gene', (22, 26))	('IDH1', 'Gene', '3417', (22, 26))	('IDH1', 'Gene', '3417', (192, 196))
212196	29453678	Similarly, IDH1 mutant GBMs demonstrated lower Fn14 expression than GBMs of the classical (p < 0.0001), mesenchymal (p < 0.0001), and neural subtypes (p = 0.0016).	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('IDH1', 'Gene', '3417', (11, 15))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('lower', 'NegReg', (41, 46))	('expression', 'MPA', (52, 62))	('mutant', 'Var', (16, 22))	('Fn14', 'Gene', '51330', (47, 51))	('Fn14', 'Gene', (47, 51))	('IDH1', 'Gene', (11, 15))
212197	29453678	Fn14 mRNA in the 13 proneural, IDH1 mutant GBMs showed a trend toward lower expression when compared to the other 125 proneural GBM subtype tumors, but this difference was not statistically significant (p = 0.2234).	('Fn14', 'Gene', (0, 4))	('Fn14', 'Gene', '51330', (0, 4))	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('IDH1', 'Gene', '3417', (31, 35))	('lower', 'NegReg', (70, 75))	('expression', 'MPA', (76, 86))	('mutant', 'Var', (36, 42))	('GBM subtype tumors', 'Disease', 'MESH:D005910', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('GBM subtype tumors', 'Disease', (128, 146))	('IDH1', 'Gene', (31, 35))
212198	29453678	Since IDH1 mutations are most frequently found in secondary GBMs (defined as those that develop from LGGs), we next examined the relative levels of Fn14 expression in IDH1 WT and mutant LGGs.	('IDH1', 'Gene', '3417', (6, 10))	('mutations', 'Var', (11, 20))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('mutant', 'Var', (179, 185))	('Fn14', 'Gene', '51330', (148, 152))	('Fn14', 'Gene', (148, 152))	('IDH1', 'Gene', (167, 171))	('IDH1', 'Gene', '3417', (167, 171))	('IDH1', 'Gene', (6, 10))
212199	29453678	Of the 286 LGGs with sequencing data in the TCGA database, 221 samples (77.3%) exhibited an IDH1 mutation.	('IDH1', 'Gene', '3417', (92, 96))	('IDH1', 'Gene', (92, 96))	('mutation', 'Var', (97, 105))	('exhibited', 'Reg', (79, 88))
212200	29453678	Fn14 mRNA expression was significantly lower in LGGs with mutant IDH1 relative to those with WT IDH1 (p < 0.0001) (Fig.	('Fn14', 'Gene', (0, 4))	('mutant', 'Var', (58, 64))	('Fn14', 'Gene', '51330', (0, 4))	('IDH1', 'Gene', '3417', (65, 69))	('IDH1', 'Gene', '3417', (96, 100))	('mRNA expression', 'MPA', (5, 20))	('IDH1', 'Gene', (65, 69))	('IDH1', 'Gene', (96, 100))	('lower', 'NegReg', (39, 44))
212202	29453678	GBM tumors with the IDH1 mutation had, on average, significantly lower Fn14 mRNA levels than those with WT IDH1 (p < 0.0001) (Fig.	('GBM tumors', 'Disease', (0, 10))	('IDH1', 'Gene', (107, 111))	('GBM tumors', 'Disease', 'MESH:D005910', (0, 10))	('IDH1', 'Gene', '3417', (20, 24))	('IDH1', 'Gene', '3417', (107, 111))	('mutation', 'Var', (25, 33))	('lower', 'NegReg', (65, 70))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Fn14', 'Gene', (71, 75))	('Fn14', 'Gene', '51330', (71, 75))	('IDH1', 'Gene', (20, 24))
212203	29453678	As our Fn14 gene expression profiling analysis identified relatively low Fn14 mRNA levels in IDH1 mutant low and high-grade gliomas, we next studied whether this relationship was also present at the protein level in 19 resected glioma specimens.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('IDH1', 'Gene', (93, 97))	('Fn14', 'Gene', '51330', (73, 77))	('Fn14', 'Gene', (7, 11))	('glioma', 'Disease', (124, 130))	('Fn14', 'Gene', '51330', (7, 11))	('glioma', 'Disease', (228, 234))	('IDH1', 'Gene', '3417', (93, 97))	('Fn14', 'Gene', (73, 77))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('low', 'NegReg', (69, 72))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('mutant', 'Var', (98, 104))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
212204	29453678	Immunohistochemistry revealed moderate Fn14 levels in IDH1 WT LGGs, low Fn14 levels in IDH1 mutant LGGs, moderate-to-high Fn14 levels in IDH1 WT GBMs, and perhaps most strikingly, low-to-moderate Fn14 levels in IDH1 mutant GBM samples.	('IDH1', 'Gene', (87, 91))	('IDH1', 'Gene', '3417', (137, 141))	('IDH1', 'Gene', (54, 58))	('Fn14', 'Gene', '51330', (72, 76))	('GBM', 'Phenotype', 'HP:0012174', (145, 148))	('Fn14', 'Gene', '51330', (39, 43))	('Fn14', 'Gene', '51330', (196, 200))	('Fn14', 'Gene', (122, 126))	('IDH1', 'Gene', '3417', (87, 91))	('IDH1', 'Gene', (211, 215))	('IDH1', 'Gene', '3417', (54, 58))	('mutant', 'Var', (92, 98))	('IDH1', 'Gene', (137, 141))	('Fn14', 'Gene', (72, 76))	('IDH1', 'Gene', '3417', (211, 215))	('GBM', 'Phenotype', 'HP:0012174', (223, 226))	('Fn14', 'Gene', '51330', (122, 126))	('Fn14', 'Gene', (39, 43))	('Fn14', 'Gene', (196, 200))
212206	29453678	We next investigated whether IDH1 R132H overexpression in human glioma cells altered Fn14 levels using U138 and LN18 cells engineered to overexpress this protein.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('R132H', 'Mutation', 'rs121913500', (34, 39))	('human', 'Species', '9606', (58, 63))	('IDH1', 'Gene', (29, 33))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('IDH1', 'Gene', '3417', (29, 33))	('altered', 'Reg', (77, 84))	('glioma', 'Disease', (64, 70))	('Fn14', 'Gene', '51330', (85, 89))	('R132H', 'Var', (34, 39))	('Fn14', 'Gene', (85, 89))
212218	29453678	We found that drug treatment increased Fn14 levels, with the maximal increase in Fn14 expression (~ 2.3-fold) detected using 5-aza-dC at a concentration of 10 mug/ml (Fig.	('Fn14', 'Gene', (81, 85))	('increase', 'PosReg', (69, 77))	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (86, 96))	('5-aza-dC', 'Var', (125, 133))	('Fn14', 'Gene', '51330', (39, 43))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (125, 133))	('Fn14', 'Gene', (39, 43))	('Fn14', 'Gene', '51330', (81, 85))
212228	29453678	We then focused on the analysis of Fn14 gene expression levels in IDH1 WT and mutant (R132H) gliomas.	('gliomas', 'Disease', (93, 100))	('IDH1', 'Gene', '3417', (66, 70))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('R132H', 'Var', (86, 91))	('Fn14', 'Gene', '51330', (35, 39))	('R132H', 'Mutation', 'rs121913500', (86, 91))	('Fn14', 'Gene', (35, 39))	('mutant (R132H', 'Var', (78, 91))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH1', 'Gene', (66, 70))
212233	29453678	We report here that expression of the pro-invasive receptor Fn14 is lower in GBM tumors carrying the IDH1 gene mutation compared to those with an IDH1 WT gene.	('IDH1', 'Gene', (101, 105))	('IDH1', 'Gene', (146, 150))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('lower', 'NegReg', (68, 73))	('expression', 'MPA', (20, 30))	('IDH1', 'Gene', '3417', (101, 105))	('IDH1', 'Gene', '3417', (146, 150))	('GBM tumors', 'Disease', (77, 87))	('Fn14', 'Gene', '51330', (60, 64))	('GBM tumors', 'Disease', 'MESH:D005910', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutation', 'Var', (111, 119))	('Fn14', 'Gene', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
212235	29453678	2), proneural, IDH1 mutant GBMs showed a trend toward lower expression when compared to the other proneural GBM subtype tumors, but this difference was not statistically significant (p = 0.2234).	('expression', 'MPA', (60, 70))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('IDH1', 'Gene', (15, 19))	('IDH1', 'Gene', '3417', (15, 19))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('GBM subtype tumors', 'Disease', 'MESH:D005910', (108, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('GBM subtype tumors', 'Disease', (108, 126))	('mutant', 'Var', (20, 26))	('lower', 'NegReg', (54, 59))
212236	29453678	This most likely reflects the fact that this proneural group contained 80 tumors of unknown IDH1 gene status, and if some of these were IDH1 mutant tumors, then we predict that the difference between the two groups would be masked.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutant', 'Var', (141, 147))	('IDH1', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('IDH1', 'Gene', (136, 140))	('IDH1', 'Gene', '3417', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', (148, 154))	('IDH1', 'Gene', '3417', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
212237	29453678	In any case, in the second analysis where we examined Fn14 mRNA expression in IDH1 WT and mutant GBMs using data from the cBioPortal (Fig.	('mutant', 'Var', (90, 96))	('IDH1', 'Gene', (78, 82))	('Fn14', 'Gene', '51330', (54, 58))	('IDH1', 'Gene', '3417', (78, 82))	('Fn14', 'Gene', (54, 58))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))
212238	29453678	3), the difference between Fn14 mRNA levels in IDH1 WT and mutant GBM tumors was highly significant (p < 0.0001).	('Fn14', 'Gene', '51330', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('GBM tumors', 'Disease', (66, 76))	('GBM tumors', 'Disease', 'MESH:D005910', (66, 76))	('Fn14', 'Gene', (27, 31))	('IDH1', 'Gene', (47, 51))	('mutant', 'Var', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('IDH1', 'Gene', '3417', (47, 51))
212239	29453678	Of note, in this analysis we found a 5.4% incidence of the IDH1 mutation in GBMs and we did not classify GBMs as primary or secondary.	('IDH1', 'Gene', '3417', (59, 63))	('mutation', 'Var', (64, 72))	('GBMs', 'Disease', (76, 80))	('IDH1', 'Gene', (59, 63))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))
212240	29453678	The difference between Fn14 mRNA levels in IDH1 WT and mutant LGGs was also highly significant (p < 0.0001) (Fig.	('mRNA levels', 'MPA', (28, 39))	('mutant', 'Var', (55, 61))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))	('Fn14', 'Gene', '51330', (23, 27))	('LGGs', 'Gene', (62, 66))	('Fn14', 'Gene', (23, 27))
212241	29453678	We identified a 77.3% incidence of the IDH1 mutation in LGGs, which agrees with the incidence cited by prior studies.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
212242	29453678	We then examined Fn14 gene expression levels in cell lines engineered to overexpress the IDH1 R132H enzyme.	('Fn14', 'Gene', (17, 21))	('R132H', 'Var', (94, 99))	('R132H', 'Mutation', 'rs121913500', (94, 99))	('IDH1', 'Gene', (89, 93))	('Fn14', 'Gene', '51330', (17, 21))	('IDH1', 'Gene', '3417', (89, 93))
212244	29453678	This finding, in combination with the prior data linking elevated Fn14 signaling with glioma cell invasive capacity, suggests that there may be a link between the IDH1 gene mutation, low Fn14 levels, and decreased tumor invasiveness.	('glioma', 'Disease', (86, 92))	('IDH1', 'Gene', (163, 167))	('Fn14', 'Gene', '51330', (66, 70))	('Fn14', 'Gene', '51330', (187, 191))	('elevated', 'PosReg', (57, 65))	('Fn14', 'Gene', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Fn14', 'Gene', (187, 191))	('IDH1', 'Gene', '3417', (163, 167))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('decreased tumor invasiveness', 'Disease', (204, 232))	('decreased tumor invasiveness', 'Disease', 'MESH:D009369', (204, 232))	('low', 'NegReg', (183, 186))	('mutation', 'Var', (173, 181))
212245	29453678	This would be consistent with recent studies demonstrating that IDH1 R132H overexpression in human glioma cells decreases migration, invasion, and matrix metalloproteinase expression in vitro.	('R132H', 'Var', (69, 74))	('invasion', 'CPA', (133, 141))	('overexpression', 'PosReg', (75, 89))	('R132H', 'Mutation', 'rs121913500', (69, 74))	('human', 'Species', '9606', (93, 98))	('IDH1', 'Gene', (64, 68))	('glioma', 'Disease', (99, 105))	('IDH1', 'Gene', '3417', (64, 68))	('migration', 'CPA', (122, 131))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('decreases', 'NegReg', (112, 121))	('matrix metalloproteinase expression', 'MPA', (147, 182))
212246	29453678	used mathematical modeling to study the invasiveness of contrast-enhancing gliomas on MR imaging, and found no difference in the net rate of invasion or velocity of radial expansion in IDH1 WT and IDH1 mutant tumors.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('tumors', 'Disease', (209, 215))	('IDH1', 'Gene', '3417', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('IDH1', 'Gene', (197, 201))	('gliomas', 'Disease', (75, 82))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('IDH1', 'Gene', '3417', (197, 201))	('IDH1', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('mutant', 'Var', (202, 208))
212252	29453678	We observed that Fn14 expression was up-regulated after 5-aza-dC treatment, but the effect was not strictly dose-dependent, consistent with a previous report examining 5-aza-dC activity on antigen presentation in breast cancer cells.	('Fn14', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('breast cancer', 'Disease', (213, 226))	('5-aza-dC', 'Var', (56, 64))	('up-regulated', 'PosReg', (37, 49))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (168, 176))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (56, 64))	('Fn14', 'Gene', '51330', (17, 21))	('expression', 'MPA', (22, 32))
212253	29453678	Our results suggest that the low level of Fn14 protein expression noted in both IDH1 mutant-overexpressing cells and IDH1 mutant tumors may be due, at least in part, to transcriptional repression by an epigenetic mechanism.	('protein', 'Protein', (47, 54))	('Fn14', 'Gene', '51330', (42, 46))	('IDH1', 'Gene', (80, 84))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('IDH1', 'Gene', '3417', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('transcriptional', 'MPA', (169, 184))	('Fn14', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (80, 84))	('mutant-overexpressing', 'Var', (85, 106))	('expression', 'MPA', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutant', 'Var', (122, 128))	('IDH1', 'Gene', (117, 121))
212254	29453678	Given the recent efforts to develop TWEAK- or Fn14-targeted therapeutic agents for the treatment of cancer patients, including GBM patients, our findings also suggest that the IDH1 mutation status might serve as an important eligibility criterion in GBM clinical trials involving Fn14-targeted agents.	('patients', 'Species', '9606', (131, 139))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('Fn14', 'Gene', '51330', (46, 50))	('TWEAK', 'Gene', '8742', (36, 41))	('IDH1', 'Gene', '3417', (176, 180))	('Fn14', 'Gene', '51330', (280, 284))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Fn14', 'Gene', (280, 284))	('mutation', 'Var', (181, 189))	('Fn14', 'Gene', (46, 50))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (107, 115))	('TWEAK', 'Gene', (36, 41))	('GBM', 'Phenotype', 'HP:0012174', (250, 253))	('IDH1', 'Gene', (176, 180))
212256	29453678	Additional work will be needed to further elucidate the connections between the IDH1 R132H mutation and Fn14 gene expression, Fn14 signaling and glioma cell invasion.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('glioma', 'Disease', (145, 151))	('Fn14', 'Gene', (126, 130))	('IDH1', 'Gene', (80, 84))	('Fn14', 'Gene', '51330', (104, 108))	('Fn14', 'Gene', (104, 108))	('IDH1', 'Gene', '3417', (80, 84))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('R132H', 'Var', (85, 90))	('Fn14', 'Gene', '51330', (126, 130))
212284	29876257	RS-fMRI was performed using axial slice orientation (3.0 T magnet: 200 volumes, 39 slices, no interslice gap, voxel size 2.39 x 2.39 x 3 mm3, TR 2400 ms, TE 30 ms, flip angle 90 , BW 1875 Hz/pixel, PAT factor 2, acquisition time 8 min//1.5 T magnet: 200 volumes, 28 slices, no interslice gap, voxel size 3 x 3 x 5.5 mm3, TR 2400 ms, TE 50 ms, flip angle 90 , BW 2003 Hz/pixel, PAT factor 2, acquisition time 8 min).	('RS', 'Chemical', '-', (0, 2))	('BW 2003 Hz/pixel', 'Var', (359, 375))	('flip angle', 'Var', (343, 353))
212308	29876257	From MRI-1 to MRI-2 a significant functional connectivity decrease was found between the orbital portion of the right middle frontal gyrus and the dorsolateral part of the right frontal superior gyrus, as well as between the medial part of left superior frontal gyrus and the left medial orbital part of the superior frontal gyrus.	('MRI-2', 'Var', (14, 19))	('MRI-1', 'Gene', (5, 10))	('decrease', 'NegReg', (58, 66))	('right middle frontal gyrus', 'Disease', (112, 138))	('right middle frontal gyrus', 'Disease', 'MESH:D020244', (112, 138))	('functional connectivity', 'MPA', (34, 57))	('MRI-1', 'Gene', '84245', (5, 10))
212310	29876257	From MRI-1 to MRI-2 a significant decrease in functional homotopic connectivity was found (P < 0.05, FWE-corrected), for supratentorial cortex (frontal, parietal, occipital lobes, insula, temporal poles, cingulum), and to a lesser extent in subcortical grey matter (thalamus), and between the cerebellar hemispheres.	('MRI-2', 'Var', (14, 19))	('decrease', 'NegReg', (34, 42))	('MRI-1', 'Gene', (5, 10))	('functional homotopic connectivity', 'MPA', (46, 79))	('occipital lobes, insula', 'Disease', 'MESH:D004828', (163, 186))	('MRI-1', 'Gene', '84245', (5, 10))
212311	29876257	From MRI-2 to MRI-3 this connectivity increased in the frontal and parietal lobes, as well as between the thalami, and no difference was observed between MRI-1 and MRI-3.	('parietal lobes', 'Disease', (67, 81))	('MRI-1', 'Gene', '84245', (154, 159))	('MRI-1', 'Gene', (154, 159))	('MRI-3', 'Gene', (14, 19))	('MRI-2', 'Var', (5, 10))	('connectivity', 'MPA', (25, 37))	('increased', 'PosReg', (38, 47))	('parietal lobes', 'Disease', 'MESH:C566826', (67, 81))
212319	29876257	From MRI-1 to MRI-2 first a decrease in FA for the splenium was observed (P < 0.05).	('MRI-2', 'Var', (14, 19))	('MRI-1', 'Gene', (5, 10))	('decrease', 'NegReg', (28, 36))	('FA for the splenium', 'CPA', (40, 59))	('MRI-1', 'Gene', '84245', (5, 10))
212404	34040895	The results showed that the expression level of PLOD1 was higher in gliomas than normal tissues, and high expression of PLOD1 was related to poor survival which can serve as an oncogenic factor and an independent prognostic indicator for glioma patients.	('patients', 'Species', '9606', (245, 253))	('gliomas', 'Disease', (68, 75))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('related', 'Reg', (130, 137))	('expression', 'MPA', (106, 116))	('PLOD1', 'Gene', (120, 125))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('PLOD1', 'Gene', (48, 53))	('high', 'Var', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('glioma', 'Disease', (238, 244))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('PLOD1', 'Gene', '5351', (120, 125))	('higher', 'PosReg', (58, 64))	('PLOD1', 'Gene', '5351', (48, 53))	('expression level', 'MPA', (28, 44))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('poor', 'NegReg', (141, 145))
212406	34040895	The results showed that high expression of PLOD1 leads to poor prognosis, and PLOD1 is an independent prognostic factor and a novel biomarker for the treatment of glioma.	('glioma', 'Disease', (163, 169))	('PLOD1', 'Gene', (78, 83))	('PLOD1', 'Gene', (43, 48))	('PLOD1', 'Gene', '5351', (78, 83))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('PLOD1', 'Gene', '5351', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('high', 'Var', (24, 28))
212407	34040895	Furthermore, targeting PLOD1 is most likely a potential therapeutic strategy for glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('PLOD1', 'Gene', (23, 28))	('patients', 'Species', '9606', (88, 96))	('PLOD1', 'Gene', '5351', (23, 28))	('glioma', 'Disease', (81, 87))	('targeting', 'Var', (13, 22))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
212448	34040895	Both CGGA and TCGA datasets contained grading data, age, gender, IDH mutation status and 1p19 codeletion status.	('mutation', 'Var', (69, 77))	('IDH', 'Gene', '3417', (65, 68))	('IDH', 'Gene', (65, 68))
212456	34040895	The results showed that patients with IDH mutation had a longer survival regardless of the level of PLOD1 expression (AUC = p < 0.001, Fig.	('longer', 'PosReg', (57, 63))	('IDH', 'Gene', (38, 41))	('IDH', 'Gene', '3417', (38, 41))	('mutation', 'Var', (42, 50))	('patients', 'Species', '9606', (24, 32))	('PLOD1', 'Gene', (100, 105))	('PLOD1', 'Gene', '5351', (100, 105))
212460	34040895	Univariate analysis showed that PLOD1 expression (HR = 1.986; 95% CI [1.796-2.198]; P < 0.001), PRS type, grade, age, IDH mutation, and 1p19q codeletion were significantly associated with OS (Fig.	('PLOD1', 'Gene', (32, 37))	('1p19q codeletion', 'Var', (136, 152))	('associated', 'Reg', (172, 182))	('IDH', 'Gene', (118, 121))	('PLOD1', 'Gene', '5351', (32, 37))	('IDH', 'Gene', '3417', (118, 121))
212461	34040895	Furthermore, multivariate Cox regression analysis revealed that PLOD1 expression (HR = 1.283; 95% CI [1.128-1.460]; P < 0.001), PRS type, grade, chemotherapy after resection, IDH mutation, and 1p19q codeletion remained significantly correlated with OS (Fig.	('IDH', 'Gene', '3417', (175, 178))	('1p19q codeletion', 'Var', (193, 209))	('PLOD1', 'Gene', (64, 69))	('IDH', 'Gene', (175, 178))	('PLOD1', 'Gene', '5351', (64, 69))	('correlated', 'Reg', (233, 243))
212463	34040895	Furthermore, to quantitatively predict the prognosis of glioma patients, we constructed a nomogram using grade, IDH mutation status, MGMT promoter methylation status, 1p19q codeletion status and PLOD1 expression level.	('glioma', 'Disease', (56, 62))	('mutation', 'Var', (116, 124))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('PLOD1', 'Gene', (195, 200))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('patients', 'Species', '9606', (63, 71))	('MGMT', 'Gene', '4255', (133, 137))	('IDH', 'Gene', (112, 115))	('MGMT', 'Gene', (133, 137))	('PLOD1', 'Gene', '5351', (195, 200))	('IDH', 'Gene', '3417', (112, 115))
212468	34040895	For molecular type, PLOD1 expressed lower in patients with 1p19q codeletion and IDH1 mutants (p < 0.001, Figs.	('lower', 'NegReg', (36, 41))	('IDH1', 'Gene', (80, 84))	('IDH1', 'Gene', '3417', (80, 84))	('PLOD1', 'Gene', (20, 25))	('PLOD1', 'Gene', '5351', (20, 25))	('1p19q codeletion', 'Var', (59, 75))	('patients', 'Species', '9606', (45, 53))	('mutants', 'Var', (85, 92))
212473	34040895	The PLOD1 was positively associated with HSPG2, COL6A2, COL4A2, FN1, COL1A1, COL4A1, CD44, COL3A1, COL1A2, SPP1 (Figs.	('COL3A1', 'Gene', (91, 97))	('FN1', 'Gene', '2335', (64, 67))	('HSPG2', 'Gene', '3339', (41, 46))	('CD44', 'Var', (85, 89))	('COL6A2', 'Gene', '1292', (48, 54))	('COL4A2', 'Gene', '1284', (56, 62))	('COL4A1', 'Gene', '1282', (77, 83))	('COL6A2', 'Gene', (48, 54))	('PLOD1', 'Gene', '5351', (4, 9))	('COL1A2', 'Gene', '1278', (99, 105))	('COL1A1', 'Gene', '1277', (69, 75))	('FN1', 'Gene', (64, 67))	('SPP1', 'Gene', (107, 111))	('COL1A2', 'Gene', (99, 105))	('COL1A1', 'Gene', (69, 75))	('COL4A1', 'Gene', (77, 83))	('COL3A1', 'Gene', '1281', (91, 97))	('SPP1', 'Gene', '6696', (107, 111))	('COL4A2', 'Gene', (56, 62))	('PLOD1', 'Gene', (4, 9))	('HSPG2', 'Gene', (41, 46))
212509	33228171	The Role of the T2-FLAIR Mismatch Sign as an Imaging Marker of IDH Status in a Mixed Population of Low- and High-Grade Gliomas Our study evaluated the role of the T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign in detecting isocitrate dehydrogenase (IDH) mutations based on a mixed sample of 24 patients with low- and high- grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (343, 349))	('mutations', 'Var', (268, 277))	('Glioma', 'Phenotype', 'HP:0009733', (119, 125))	('IDH', 'Gene', (63, 66))	('Gliomas', 'Disease', 'MESH:D005910', (119, 126))	('Gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('patients', 'Species', '9606', (308, 316))	('IDH', 'Gene', '3417', (63, 66))	('gliomas', 'Disease', 'MESH:D005910', (343, 350))	('Gliomas', 'Disease', (119, 126))	('isocitrate dehydrogenase', 'Gene', (237, 261))	('gliomas', 'Disease', (343, 350))	('IDH', 'Gene', (263, 266))	('gliomas', 'Phenotype', 'HP:0009733', (343, 350))	('mixed sample', 'Species', '1427524', (289, 301))	('isocitrate dehydrogenase', 'Gene', '3417', (237, 261))	('IDH', 'Gene', '3417', (263, 266))
212512	33228171	The sensitivity and specificity of T2-FLAIR mismatch sign in the detection of the IDH mutation was 88.9% and 86.7%, respectively.	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', (82, 85))	('T2-FLAIR mismatch sign', 'MPA', (35, 57))	('mutation', 'Var', (86, 94))
212521	33228171	A histopathological study showed that the T2-FLAIR mismatch sign might reflect microcyst formation in IDH mutant astrocytomas and could be common in IDH mutant protoplasmic astrocytomas.	('IDH', 'Gene', '3417', (102, 105))	('mutant', 'Var', (106, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('IDH', 'Gene', (149, 152))	('astrocytomas', 'Disease', (173, 185))	('astrocytomas', 'Disease', (113, 125))	('microcyst', 'Disease', (79, 88))	('T2-FLAIR mismatch', 'MPA', (42, 59))	('IDH', 'Gene', '3417', (149, 152))	('astrocytoma', 'Phenotype', 'HP:0009592', (173, 184))	('reflect', 'Reg', (71, 78))	('IDH', 'Gene', (102, 105))	('astrocytomas', 'Disease', 'MESH:D001254', (173, 185))	('astrocytomas', 'Disease', 'MESH:D001254', (113, 125))
212534	33228171	Testing for IDH1/2 mutation by real-time PCR had been performed on samples received during the enrollment period.	('IDH1/2', 'Gene', (12, 18))	('mutation', 'Var', (19, 27))	('IDH1/2', 'Gene', '3417;3418', (12, 18))
212536	33228171	All patients underwent 3D T1 weighted images (WI) pre- and post-contrast, axial T2 WI, axial T2 WI, FLAIR, diffusion WI, and T2* WI.	('T2* WI', 'Var', (125, 131))	('FLAIR', 'Var', (100, 105))	('patients', 'Species', '9606', (4, 12))
212545	33228171	Accordingly, the highest probabilities of distinguishing between mutant and wild-type IDH variants with the use of MRI were achieved when considering the T2-FLAIR mismatch sign.	('IDH', 'Gene', '3417', (86, 89))	('T2-FLAIR mismatch', 'MPA', (154, 171))	('IDH', 'Gene', (86, 89))	('mutant', 'Var', (65, 71))
212548	33228171	The sensitivity and specificity of the T2-FLAIR mismatch sign in the detection of the IDH mutation was 88.9% and 86.7%, respectively.	('IDH', 'Gene', (86, 89))	('T2-FLAIR mismatch', 'MPA', (39, 56))	('mutation', 'Var', (90, 98))	('IDH', 'Gene', '3417', (86, 89))
212552	33228171	Until recently, the T2-FLAIR mismatch sign has been used and validated for the prediction of 1p/19q status in IDH mutant LGGs.	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', (110, 113))	('mutant', 'Var', (114, 120))
212553	33228171	described a positive correlation between the T2-FLAIR mismatch sign and the absence of 1p/19q codeletion in IDH mutant LGGs, with estimated positive (PPV) and negative predictive (NPV) values as high as 100% and 54%, respectively.	('absence', 'NegReg', (76, 83))	('1p/19q', 'Protein', (87, 93))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (108, 111))	('mutant', 'Var', (112, 118))	('mismatch', 'Var', (54, 62))
212555	33228171	found that the presence of T2-FLAIR mismatch over 50% was highly predictive of a non-codeleted tumor.	('T2-FLAIR', 'MPA', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mismatch', 'Var', (36, 44))	('tumor', 'Disease', (95, 100))
212557	33228171	proposed a two-step classification algorithm based on neuroimaging metrics and the patient's age, which demonstrated a moderate prediction accuracy of 1p/19q status in IDH mutant LGGs.	('IDH', 'Gene', '3417', (168, 171))	('1p/19q status', 'Var', (151, 164))	('patient', 'Species', '9606', (83, 90))	('IDH', 'Gene', (168, 171))
212561	33228171	The authors classified 133 patients from two tumor databases in three groups, according to the molecular characteristics of the tumors: Group O (IDH mutant, 1p/19q codeleted oligodendrogliomas), Group A (IDH mutant, ATRX inactivated astrocytomas), and Group G (IDH wild-type, GBM-like).	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('astrocytoma', 'Phenotype', 'HP:0009592', (233, 244))	('IDH', 'Gene', '3417', (145, 148))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('IDH', 'Gene', (261, 264))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (174, 192))	('1p/19q', 'Var', (157, 163))	('astrocytomas', 'Disease', 'MESH:D001254', (233, 245))	('patients', 'Species', '9606', (27, 35))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ATRX', 'Gene', (216, 220))	('IDH', 'Gene', '3417', (261, 264))	('IDH', 'Gene', (204, 207))	('ATRX', 'Gene', '546', (216, 220))	('oligodendrogliomas', 'Disease', (174, 192))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('IDH', 'Gene', (145, 148))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('astrocytomas', 'Disease', (233, 245))	('IDH', 'Gene', '3417', (204, 207))
212564	33228171	recognized the T2-FLAIR mismatch sign in 12 of 113 cases (10.6%) (Grade II and III gliomas) and in none of the 295 glioblastoma cases.	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('III gliomas', 'Disease', 'MESH:D005910', (79, 90))	('III gliomas', 'Disease', (79, 90))	('T2-FLAIR mismatch', 'Var', (15, 32))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioblastoma', 'Disease', (115, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))
212565	33228171	estimated the pooled accuracy of the T2-FLAIR mismatch sign in predicting IDH mutation based on data extracted from three studies focusing on the prediction of 1p/19q status in patients with LGG.	('patients', 'Species', '9606', (177, 185))	('IDH', 'Gene', '3417', (74, 77))	('IDH', 'Gene', (74, 77))	('mutation', 'Var', (78, 86))
212567	33228171	According to a population-based study focusing on LGGs by Correl et al., the sensitivity and specificity of the mismatch sign for IDH mutation detection were 26.4% and 97.6%, respectively.	('IDH', 'Gene', '3417', (130, 133))	('IDH', 'Gene', (130, 133))	('mutation', 'Var', (134, 142))
212570	33228171	Thus, it seems that the T2-FLAIR mismatch sign is characterized by a high predictive value for the presence of an IDH1/2 mutation.	('IDH1/2', 'Gene', (114, 120))	('T2-FLAIR mismatch', 'MPA', (24, 41))	('mutation', 'Var', (121, 129))	('IDH1/2', 'Gene', '3417;3418', (114, 120))
212577	33228171	Among them, there was a case of a 44-year-old adult with an IDH mutant and 1p/19q codeleted oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('oligodendroglioma', 'Disease', (92, 109))	('IDH', 'Gene', (60, 63))	('1p/19q', 'Var', (75, 81))	('IDH', 'Gene', '3417', (60, 63))	('mutant', 'Var', (64, 70))	('oligodendroglioma', 'Disease', 'MESH:D009837', (92, 109))
212634	31611978	Overexpression of PPIA was associated with poor relapse free survival of lung adenocarcinoma in datasets GSE32210 and GSE8894 using various primers, and poor OS in datasets GSE32210, GSE13213, jacob-00182-UM and GSE13213.	('lung adenocarcinoma', 'Disease', (73, 92))	('PPIA', 'Gene', (18, 22))	('poor', 'NegReg', (43, 47))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (73, 92))	('Overexpression', 'Var', (0, 14))	('PPIA', 'Gene', '5478', (18, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('relapse free survival', 'CPA', (48, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
212636	31611978	In breast cancer, there was a certain level of contradiction, although the OS was revealed to be positively correlated with PPIA expression level (HR, 0.83) in dataset GSE9893, the other survival values of breast cancer were negatively correlated with PPIA expression, such as disease free survival in GSE4922-GPL96 (HR, 6.99 and 6.07 with different primers), relapse free survival in GSE1456-GPL96 (HR, 7.41 and 7.12 with different primers), distant metastasis free survival in GSE11121, GSE9195 and GSE2990, and disease specific survival in GSE3494-GPL96 and GSE1456-GPL96.	('GSE2990', 'Var', (501, 508))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('distant metastasis free survival', 'CPA', (443, 475))	('PPIA', 'Gene', (124, 128))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('disease specific survival', 'CPA', (514, 539))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('PPIA', 'Gene', '5478', (252, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('negatively', 'NegReg', (225, 235))	('breast cancer', 'Disease', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('relapse free survival', 'CPA', (360, 381))	('PPIA', 'Gene', (252, 256))	('PPIA', 'Gene', '5478', (124, 128))	('GSE9195', 'Var', (489, 496))
212637	31611978	These results indicated that overexpression of PPIA was a risk factor for breast cancer progression and metastasis, and may be harnessed as a therapeutic target.	('breast cancer', 'Disease', (74, 87))	('PPIA', 'Gene', (47, 51))	('metastasis', 'CPA', (104, 114))	('PPIA', 'Gene', '5478', (47, 51))	('overexpression', 'Var', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
212647	31611978	The prognoses of tumor grade 1, 2, 3 and 4 in those with high PPIA expression levels were all poorer than the prognoses of respective tumor grades with low or median PPIA expression levels in LIHC.	('PPIA', 'Gene', '5478', (166, 170))	('tumor', 'Disease', (17, 22))	('PPIA', 'Gene', (62, 66))	('high', 'Var', (57, 61))	('PPIA', 'Gene', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('LIHC', 'Disease', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PPIA', 'Gene', '5478', (62, 66))	('LIHC', 'Disease', 'MESH:D006528', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (134, 139))
212648	31611978	The prognosis of low or median PPIA expression in every tumor grade was better than the prognosis of high PPIA expression in every tumor grade, as presented in Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PPIA', 'Gene', (31, 35))	('tumor', 'Disease', (56, 61))	('PPIA', 'Gene', '5478', (106, 110))	('tumor', 'Disease', (131, 136))	('low', 'Var', (17, 20))	('PPIA', 'Gene', (106, 110))	('PPIA', 'Gene', '5478', (31, 35))	('expression', 'MPA', (36, 46))
212668	31611978	The OS of patients with high PPIA expression levels was significantly decreased compared with patients with low PPIA expression levels in the sorafenib-administered group.	('patients', 'Species', '9606', (94, 102))	('PPIA', 'Gene', '5478', (29, 33))	('sorafenib', 'Chemical', 'MESH:C471405', (142, 151))	('PPIA', 'Gene', '5478', (112, 116))	('decreased', 'NegReg', (70, 79))	('PPIA', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('PPIA', 'Gene', (112, 116))
212669	31611978	This indicated that PPIA played a specific role in the progression of LIHC in the poorer OS subgroup of the sorafenib-administered group and that inhibition of PPIA expression or PPIA inhibitor ciclosporin A may be beneficial for sorafenib-administered patients.	('PPIA', 'Gene', '5478', (160, 164))	('PPIA', 'Gene', (20, 24))	('LIHC', 'Disease', (70, 74))	('LIHC', 'Disease', 'MESH:D006528', (70, 74))	('patients', 'Species', '9606', (253, 261))	('sorafenib', 'Chemical', 'MESH:C471405', (108, 117))	('PPIA', 'Gene', '5478', (20, 24))	('PPIA', 'Gene', (160, 164))	('PPIA', 'Gene', '5478', (179, 183))	('ciclosporin A', 'Chemical', 'MESH:D016572', (194, 207))	('inhibition', 'Var', (146, 156))	('PPIA', 'Gene', (179, 183))	('sorafenib', 'Chemical', 'MESH:C471405', (230, 239))
212678	31611978	Lu et al revealed that basolateral CD147 induced hepatocyte polarity loss by E-cadherin ubiquitination and degradation in the progression of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('loss', 'NegReg', (69, 73))	('hepatocellular carcinoma', 'Disease', (141, 165))	('hepatocyte polarity', 'MPA', (49, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('degradation', 'MPA', (107, 118))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('basolateral', 'Var', (23, 34))	('ubiquitination', 'MPA', (88, 102))	('CD147', 'Gene', (35, 40))
212690	31611978	CD4+ T cells expressing more CD147 migrated more readily to PPIA.	('migrated', 'CPA', (35, 43))	('CD147', 'Var', (29, 34))	('PPIA', 'Gene', '5478', (60, 64))	('CD4', 'Gene', '920', (0, 3))	('PPIA', 'Gene', (60, 64))	('CD4', 'Gene', (0, 3))
212699	31288858	Clustered protocadherins methylation alterations in cancer Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: alpha-, beta- and gamma-PCDH.	('human', 'Species', '9606', (109, 114))	('cadherin', 'Gene', '8641', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cadherin', 'Gene', (15, 23))	('cadherin', 'Gene', (74, 82))	('alterations', 'Var', (37, 48))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cadherin', 'Gene', '8641', (74, 82))	('methylation alterations', 'Var', (25, 48))
212701	31288858	In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation.	('hypermethylation', 'Var', (85, 101))	('PCDHs', 'Gene', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
212702	31288858	In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia.	('pilocytic astrocytoma', 'Disease', (193, 214))	('colorectal', 'Disease', (146, 156))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (255, 283))	('solid tumours', 'Disease', 'MESH:D009369', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('methylation alterations', 'Var', (36, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (203, 214))	('chronic lymphocytic leukemia', 'Disease', (255, 283))	('gastric and biliary tract cancers', 'Disease', 'MESH:D001661', (158, 191))	('hematologic neoplasms', 'Disease', 'MESH:D019337', (225, 246))	('hematologic neoplasms', 'Phenotype', 'HP:0004377', (225, 246))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (255, 283))	('leukemia', 'Phenotype', 'HP:0001909', (275, 283))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('hematologic neoplasms', 'Disease', (225, 246))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('solid tumours', 'Disease', (122, 135))	('associated', 'Reg', (75, 85))	('CpG', 'Gene', (63, 66))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (193, 214))	('neoplasms', 'Phenotype', 'HP:0002664', (237, 246))
212704	31288858	Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer.	('pilocytic astrocytoma', 'Disease', (64, 85))	('hypomethylated', 'Var', (176, 190))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (64, 85))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('PCDHs', 'Gene', (129, 134))
212705	31288858	In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('hypermethylated', 'Var', (46, 61))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('PCDH-associated', 'Disease', (9, 24))	('gastrointestinal tumour', 'Phenotype', 'HP:0007378', (65, 88))	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (65, 89))	('gastrointestinal tumours', 'Disease', (65, 89))
212706	31288858	Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers.	('solid cancers', 'Disease', (101, 114))	('alteration', 'Reg', (31, 41))	('solid cancers', 'Disease', 'MESH:D009369', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PCDH genes', 'Gene', (194, 204))	('PCDHs', 'Gene', (59, 64))	('methylation', 'Var', (65, 76))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
212722	31288858	In cancer pathogenesis, clustered PCDHs undergo a mechanism of long-range epigenetic silencing (LRES) by hypermethylation.	('PCDHs', 'Gene', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('hypermethylation', 'Var', (105, 121))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
212724	31288858	detected hypermethylation and transcription downregulation in the three clustered PCDHs in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('transcription', 'MPA', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('downregulation', 'NegReg', (44, 58))	('hypermethylation', 'Var', (9, 25))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('PCDHs', 'Gene', (82, 87))
212725	31288858	Other breast cancer studies showed that the abnormal DNA methylation of these gene families could be the consequence of the reduction of CTCF interaction with DNA due to CTCF aberrant expression or mutations in its binding domain.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('reduction', 'NegReg', (124, 133))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('aberrant', 'Var', (175, 183))	('CTCF', 'Gene', '10664', (137, 141))	('breast cancer', 'Disease', (6, 19))	('interaction', 'Interaction', (142, 153))	('CTCF', 'Gene', '10664', (170, 174))	('mutations', 'Var', (198, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('CTCF', 'Gene', (170, 174))	('CTCF', 'Gene', (137, 141))	('binding', 'Interaction', (215, 222))
212727	31288858	also found hypermethylation of the majority of PCDHA, PCDHB and PCDHG in both adenomas and colorectal carcinomas, relative to normal tissue.	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('PCDHG', 'Gene', (64, 69))	('hypermethylation', 'Var', (11, 27))	('colorectal carcinomas', 'Disease', (91, 112))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (91, 112))	('adenomas', 'Disease', 'MESH:D000236', (78, 86))	('PCDHB', 'Gene', (54, 59))	('adenomas', 'Disease', (78, 86))	('PCDHB', 'Gene', '56116', (54, 59))	('PCDHG', 'Gene', '56115', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('PCDHA', 'Gene', (47, 52))	('PCDHA', 'Gene', '56117', (47, 52))
212729	31288858	Interestingly, PCDHGC3 has been found highly methylated only in carcinomas and not in previous stages and has been proposed as a driver for the progression from adenoma to carcinoma.	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (161, 181))	('carcinomas', 'Disease', (64, 74))	('PCDHGC3', 'Gene', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('adenoma to carcinoma', 'Disease', (161, 181))	('methylated', 'Var', (45, 55))	('PCDHGC3', 'Gene', '5098', (15, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('carcinomas', 'Disease', 'MESH:D002277', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
212732	31288858	detected hypermethylation in PCDHGA11 in astrocytoma, glioblastoma and glioma cell lines.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('astrocytoma', 'Disease', (41, 52))	('glioma', 'Disease', (71, 77))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('PCDHGA11', 'Gene', '56105', (29, 37))	('hypermethylation', 'Var', (9, 25))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('PCDHGA11', 'Gene', (29, 37))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('astrocytoma', 'Disease', 'MESH:D001254', (41, 52))	('glioblastoma', 'Disease', (54, 66))
212733	31288858	Moreover, these authors found a significant correlation between PCDHGA11 hypermethylation and downregulation in astrocytomas and glioma cell lines.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('PCDHGA11', 'Gene', (64, 72))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (112, 123))	('hypermethylation', 'Var', (73, 89))	('astrocytomas', 'Disease', (112, 124))	('PCDHGA11', 'Gene', '56105', (64, 72))	('glioma', 'Disease', (129, 135))	('astrocytomas', 'Disease', 'MESH:D001254', (112, 124))	('downregulation', 'NegReg', (94, 108))
212734	31288858	reported mosaic methylation and hypomethylation of the CpG islands (CGIs) associated with Pcdha cluster in mouse neuroblastoma cell lines.	('mouse', 'Species', '10090', (107, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (113, 126))	('associated', 'Reg', (74, 84))	('hypomethylation', 'Var', (32, 47))	('neuroblastoma', 'Disease', (113, 126))	('neuroblastoma', 'Phenotype', 'HP:0003006', (113, 126))	('Pcdha cluster', 'Disease', (90, 103))
212735	31288858	Other PCDHA@ genes, PCDHA4 and PCDHA13, have been found frequently hypermethylated in severe cervical neoplasia.	('hypermethylated', 'Var', (67, 82))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (93, 111))	('PCDHA@', 'Gene', '56117', (6, 12))	('PCDHA13', 'Gene', (31, 38))	('PCDHA4', 'Gene', (20, 26))	('PCDHA@', 'Gene', (6, 12))	('PCDHA13', 'Gene', '56136', (31, 38))	('neoplasia', 'Disease', (102, 111))	('PCDHA4', 'Gene', '56144', (20, 26))	('neoplasia', 'Phenotype', 'HP:0002664', (102, 111))	('neoplasia', 'Disease', 'MESH:D009369', (102, 111))
212761	31288858	In silico methylation data from The Cancer Genome Atlas (TCGA), the NCBI GEO Portal and the International Cancer Genome Consortium (IGCG) Data Portal were used to validate the methylation alterations detected in the different cancer types analysed (Fig.	('Cancer Genome Atlas', 'Disease', (36, 55))	('methylation', 'Var', (176, 187))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('Cancer', 'Disease', (36, 42))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (36, 55))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Cancer', 'Disease', (106, 112))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
212767	31288858	In fact, hypermethylation of CGIs associated with PCDH genes was among the most significant methylation alterations detected, even in BTC where methylation differences between tumour and normal samples were fewer and less pronounced than in the other cancers analysed.	('CGIs', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('PCDH genes', 'Gene', (50, 60))	('hypermethylation', 'Var', (9, 25))	('cancers', 'Disease', (251, 258))	('BTC', 'Disease', (134, 137))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', (176, 182))
212770	31288858	Interestingly, we detected a hypomethylation event in PCDHG cluster although we did not find any hypermethylated CGIs associated with PCDH in pilocytic astrocytoma.	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (142, 163))	('pilocytic astrocytoma', 'Disease', (142, 163))	('PCDHG', 'Gene', '56115', (54, 59))	('PCDHG', 'Gene', (54, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (152, 163))	('hypomethylation', 'Var', (29, 44))
212784	31288858	Deltabeta value = 0.435 and 0.277, in CRC and CRA, respectively.	('CRA', 'Gene', (46, 49))	('0.277', 'Var', (28, 33))	('CRA', 'Gene', '10903', (46, 49))	('Deltabeta', 'Chemical', '-', (0, 9))	('CRC', 'Disease', (38, 41))
212786	31288858	We observed that one CGI (chr5:140855386-140856620, CpG 95) was hypermethylated in COAD but not READ samples, with the exception of the most telomeric part of the CGI (cg04453180, cg07445963) (Fig.	('cg07445963', 'Var', (180, 190))	('chr5:140855386-140856620', 'STRUCTURAL_ABNORMALITY', 'None', (26, 50))	('cg04453180', 'Var', (168, 178))
212792	31288858	Thus, MSI was significantly more frequent in the group of tumours with high methylation values (p value = 2.0E- 02).	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('frequent', 'Reg', (33, 41))	('MSI', 'Disease', 'None', (6, 9))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('MSI', 'Disease', (6, 9))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))	('high methylation values', 'Var', (71, 94))
212797	31288858	7), implying that EBV infection was significantly more frequent in the group of highly methylated samples (p value = 1.4E- 04).	('highly methylated', 'Var', (80, 97))	('EBV infection', 'Disease', 'MESH:D020031', (18, 31))	('frequent', 'Reg', (55, 63))	('EBV infection', 'Disease', (18, 31))
212807	31288858	To note, the normal samples of our discovery dataset included nine gallbladder and one extrahepatic tissues with average beta values of 0.185 (CpG 45) and 0.227 (CpG 41), while in silico normal samples included eight intrahepatic and one extrahepatic tissues with average methylation values of 0.078 (CpG 45) and 0.160 (CpG 41).	('intrahepatic', 'Disease', (217, 229))	('intrahepatic', 'Disease', 'MESH:D002780', (217, 229))	('0.227', 'Var', (155, 160))
212811	31288858	Differently, PCDHGC4 and PCDHGC5 were commonly hypermethylated in a large variety of tumours (Fig.	('PCDHGC5', 'Gene', '56097', (25, 32))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('hypermethylated', 'Var', (47, 62))	('PCDHGC4', 'Gene', '56098', (13, 20))	('tumours', 'Disease', (85, 92))	('PCDHGC5', 'Gene', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('PCDHGC4', 'Gene', (13, 20))
212812	31288858	We tested whether the methylation alteration status of N-shelf region or CGIs annotated in promoter regions (Tables 1, 2, 3 and 4) could be associated with change in the expression pattern of the respective gene using TCGA-LGG, TCGA-COADREAD, TCGA-STAD and TCGA-CHOL data.	('alteration', 'Var', (34, 44))	('change', 'Reg', (156, 162))	('CHOL', 'Chemical', '-', (262, 266))	('expression pattern', 'MPA', (170, 188))
212813	31288858	We found a statistically significant negative correlation between methylation and gene expression (Additional file 3: Figure S2, Additional file 4: Figure S3, Additional file 5: Figure S4 and Additional file 6: Figure S5) except for CpG16 methylation and PCDHGB3 gene expression in TCGA-COAD (Additional file 4: Figure S3).	('methylation', 'Var', (239, 250))	('PCDHGB3', 'Gene', (255, 262))	('CpG16', 'Gene', (233, 238))	('PCDHGB3', 'Gene', '56102', (255, 262))	('expression', 'MPA', (268, 278))	('negative', 'NegReg', (37, 45))
212815	31288858	Therefore, the survival curves were focused on the chromosome region, chr5:140750050-140893189 altered in CRC; chr5:140762401-140864748 in gastric cancer; chr5:140787447-140788044 in BTC; and chr5:140865433-140870165 in low grade glioma (LGG) (Fig.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('chr5:140787447-140788044', 'STRUCTURAL_ABNORMALITY', 'None', (155, 179))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('chr5:140865433-140870165', 'STRUCTURAL_ABNORMALITY', 'None', (192, 216))	('chr5:140762401-140864748', 'STRUCTURAL_ABNORMALITY', 'None', (111, 135))	('chr5:140787447-140788044', 'Var', (155, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('CRC', 'Disease', (106, 109))	('chr5:140750050-140893189', 'STRUCTURAL_ABNORMALITY', 'None', (70, 94))	('glioma', 'Disease', (230, 236))
212820	31288858	Secondly, the methylation level of each of the three isoforms, PCDHGC3, PCDHGC4 and PCDHGC5, tended to negatively correlate with their expression levels, suggesting that aberrant methylation may be essential for their transcript regulation in LGG (Fig.	('methylation', 'MPA', (179, 190))	('methylation level', 'MPA', (14, 31))	('PCDHGC4', 'Gene', (72, 79))	('PCDHGC3', 'Gene', '5098', (63, 70))	('PCDHGC5', 'Gene', (84, 91))	('expression levels', 'MPA', (135, 152))	('aberrant', 'Var', (170, 178))	('PCDHGC5', 'Gene', '56097', (84, 91))	('PCDHGC4', 'Gene', '56098', (72, 79))	('LGG', 'Disease', (243, 246))	('PCDHGC3', 'Gene', (63, 70))
212821	31288858	The epigenetic dysregulation of clustered PCDHs has been associated with brain disorders and with cancer as well.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PCDHs', 'Gene', (42, 47))	('brain disorders', 'Disease', (73, 88))	('epigenetic dysregulation', 'Var', (4, 28))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('brain disorders', 'Disease', 'MESH:D001927', (73, 88))	('associated', 'Reg', (57, 67))	('clustered', 'Protein', (32, 41))
212831	31288858	Thus, our results confirmed that hypermethylated genes in cancer are already lowly expressed in the respective normal tissues, while a tumour in a tissue with high expression, as in this case of gliomas, can undergo hypomethylation in this gene cluster.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('undergo', 'Reg', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('hypomethylation', 'Var', (216, 231))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('gliomas', 'Disease', (195, 202))	('cancer', 'Disease', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('gliomas', 'Disease', 'MESH:D005910', (195, 202))	('expressed', 'MPA', (83, 92))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('tumour', 'Disease', (135, 141))
212837	31288858	This survival curve indicated that in the low-beta values group of patients (blue line), the survival probability had an early reduction compared to the high-beta values group (Fig.	('reduction', 'NegReg', (127, 136))	('survival', 'MPA', (93, 101))	('patients', 'Species', '9606', (67, 75))	('low-beta values', 'Var', (42, 57))
212838	31288858	Moreover, at the expression level, PCDHGs are essential during neuronal development and their knockdown or deficiency leads to loss of different neuronal cell types, synapse decrease or dendritic arborisation decline.	('knockdown', 'Var', (94, 103))	('PCDHG', 'Gene', '56115', (35, 40))	('decrease', 'NegReg', (174, 182))	('PCDHG', 'Gene', (35, 40))	('dendritic arborisation decline', 'Disease', 'MESH:D007635', (186, 216))	('synapse', 'CPA', (166, 173))	('deficiency', 'Var', (107, 117))	('loss', 'NegReg', (127, 131))	('dendritic arborisation decline', 'Disease', (186, 216))
212839	31288858	Therefore, the hypomethylation event could lead to the upregulation of this group of PCDHGs, suggesting that tumour cells need to behave as progenitor cells, i.e.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumour', 'Disease', (109, 115))	('PCDHG', 'Gene', '56115', (85, 90))	('hypomethylation', 'Var', (15, 30))	('upregulation', 'PosReg', (55, 67))	('PCDHG', 'Gene', (85, 90))
212843	31288858	Our experimental data showed that the CGIs of clustered PCDHs in CRC are the most highly hypermethylated among the gastrointestinal tumours analysed (Tables 2, 3 and 4).	('hypermethylated', 'MPA', (89, 104))	('CRC', 'Gene', (65, 68))	('gastrointestinal tumours', 'Disease', (115, 139))	('PCDHs', 'Var', (56, 61))	('gastrointestinal tumour', 'Phenotype', 'HP:0007378', (115, 138))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (115, 139))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))
212844	31288858	Moreover, the hypermethylation of these CGIs could be early events during carcinogenesis because they are frequently found in our adenoma samples although some of them did not present methylation alterations.	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('hypermethylation', 'Var', (14, 30))	('adenoma', 'Disease', (130, 137))	('carcinogenesis', 'Disease', (74, 88))	('adenoma', 'Disease', 'MESH:D000236', (130, 137))
212846	31288858	As the values we are referring to, were average values, the differences observed between the two data sets could be due either to increased degree of methylation of each involved island in carcinomas compared to adenomas or to hypermethylation presence in more CRC samples than in adenomas.	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('hypermethylation', 'Var', (227, 243))	('carcinomas', 'Disease', (189, 199))	('carcinomas', 'Disease', 'MESH:D002277', (189, 199))	('adenomas', 'Disease', 'MESH:D000236', (281, 289))	('adenomas', 'Disease', 'MESH:D000236', (212, 220))	('adenomas', 'Disease', (281, 289))	('adenomas', 'Disease', (212, 220))	('increased', 'PosReg', (130, 139))	('methylation', 'MPA', (150, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
212847	31288858	In fact, when we analysed adenomas, we found that while few of them branched nearby normal mucosa samples (CTE1279, CTE1434 and CTE1620), the remaining ones grouped on separated branches and some of them more closely resembled the methylation pattern of carcinomas (Fig.	('carcinomas', 'Phenotype', 'HP:0030731', (254, 264))	('carcinomas', 'Disease', (254, 264))	('carcinomas', 'Disease', 'MESH:D002277', (254, 264))	('resembled', 'Reg', (217, 226))	('CTE1279', 'Var', (107, 114))	('CTE1620', 'Var', (128, 135))	('CTE1434', 'Var', (116, 123))	('adenomas', 'Disease', 'MESH:D000236', (26, 34))	('adenomas', 'Disease', (26, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))
212848	31288858	To complement the analysis, we did not find any correlation between PCDHs methylation alterations and the grade of carcinogenesis in adenoma.	('adenoma', 'Disease', (133, 140))	('PCDHs', 'Gene', (68, 73))	('methylation alterations', 'Var', (74, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('adenoma', 'Disease', 'MESH:D000236', (133, 140))	('carcinogenesis', 'Disease', (115, 129))	('alterations', 'Var', (86, 97))
212850	31288858	Interestingly, our experimental methylation studies showed that some CGI alterations were common in different cancers (gastric, biliary tract and colorectal cancer) and others were specific for each cancer-type but they were all associated with the PCDHG cluster (Table 5).	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('PCDHG', 'Gene', '56115', (249, 254))	('rectal cancer', 'Phenotype', 'HP:0100743', (150, 163))	('CGI', 'Gene', (69, 72))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('associated', 'Reg', (229, 239))	('gastric', 'Disease', (119, 126))	('common', 'Reg', (90, 96))	('cancer', 'Disease', (110, 116))	('cancers', 'Disease', (110, 117))	('alterations', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('PCDHG', 'Gene', (249, 254))	('biliary tract', 'Disease', (128, 141))	('colorectal cancer', 'Disease', (146, 163))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
212851	31288858	Since this CGI was also hypermethylated in CRA indicating that it is an early event in CRC tumorigenic, it is likely that this event can occur early also during GC tumorigenesis.	('CRC', 'Disease', (87, 90))	('hypermethylated', 'Var', (24, 39))	('CRA', 'Gene', '10903', (43, 46))	('CRA', 'Gene', (43, 46))
212852	31288858	Other studies have previously found methylation alterations of PCDHG cluster in gastrointestinal tumours, including colon cancer.	('gastrointestinal tumours', 'Disease', (80, 104))	('PCDHG', 'Gene', (63, 68))	('gastrointestinal tumour', 'Phenotype', 'HP:0007378', (80, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('found', 'Reg', (30, 35))	('methylation alterations', 'Var', (36, 59))	('colon cancer', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (80, 104))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('PCDHG', 'Gene', '56115', (63, 68))
212854	31288858	Furthermore, the detected methylation aberrations seem to be frequent events in gastrointestinal tumours, some involved in tissue-specific mechanisms and others in common mechanisms.	('gastrointestinal tumours', 'Disease', (80, 104))	('gastrointestinal tumour', 'Phenotype', 'HP:0007378', (80, 103))	('methylation aberrations', 'Var', (26, 49))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (80, 104))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))
212858	31288858	BTC results showed differences in Deltabeta values of two CGIs between localizations suggesting that the detected methylation alterations might reach higher beta values in gallbladder/extrahepatic.	('methylation alterations', 'Var', (114, 137))	('gallbladder/extrahepatic', 'Disease', (172, 196))	('higher', 'PosReg', (150, 156))	('beta values', 'MPA', (157, 168))	('alterations', 'Var', (126, 137))	('Deltabeta', 'Chemical', '-', (34, 43))
212862	31288858	We investigated whether other clinical characteristics were associated with methylation alterations in the different cancers analysed, finding an association between hypermethylation and MSI status only in GC as reported by other authors.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hypermethylation', 'Var', (166, 182))	('MSI', 'Disease', 'None', (187, 190))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('MSI', 'Disease', (187, 190))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
212866	31288858	The association between molecular subtypes and methylation values could be also observed in the other gastrointestinal tumours.	('gastrointestinal tumour', 'Phenotype', 'HP:0007378', (102, 125))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (102, 126))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('methylation', 'Var', (47, 58))	('gastrointestinal tumours', 'Disease', (102, 126))
212871	31288858	Since methylation regulates CTCF binding, the methylation abnormalities detected in our experimental results could avoid or modify the hub formation by blocking the interaction between the CTCF protein and the neighbouring binding sites, consequently regulating PCDHG cluster transcription.	('abnormalities', 'Var', (58, 71))	('PCDHG', 'Gene', '56115', (262, 267))	('modify', 'Reg', (124, 130))	('avoid', 'NegReg', (115, 120))	('interaction', 'Interaction', (165, 176))	('CTCF', 'Gene', (189, 193))	('hub formation', 'MPA', (135, 148))	('PCDHG', 'Gene', (262, 267))	('CTCF', 'Gene', (28, 32))	('regulating', 'Reg', (251, 261))	('blocking', 'NegReg', (152, 160))	('transcription', 'MPA', (276, 289))	('CTCF', 'Gene', '10664', (189, 193))	('CTCF', 'Gene', '10664', (28, 32))	('binding', 'Interaction', (33, 40))
212872	31288858	Previous functional studies have already shown that DNA methylation aberrations are associated to alteration of CTCF binding to DNA.	('methylation aberrations', 'Var', (56, 79))	('CTCF', 'Gene', '10664', (112, 116))	('binding', 'Interaction', (117, 124))	('alteration', 'Reg', (98, 108))	('DNA', 'Gene', (52, 55))	('aberrations', 'Var', (68, 79))	('CTCF', 'Gene', (112, 116))
212876	31288858	Furthermore, an aspect that is certainly worth investigating is the lack of an experimental expression analysis and further functional analyses aimed to understand if and how the identified methylation alterations play a role in the tumorigenesis of the different tumours analysed.	('tumours', 'Disease', (264, 271))	('methylation alterations', 'Var', (190, 213))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('tumorigenesis', 'CPA', (233, 246))	('tumours', 'Phenotype', 'HP:0002664', (264, 271))	('tumours', 'Disease', 'MESH:D009369', (264, 271))
212879	31288858	These epigenetic aberrations in the CGIs associated to PCDHG@ genes could be useful to consider specific members of this cluster as possible biomarkers.	('PCDHG@', 'Gene', (55, 61))	('epigenetic aberrations', 'Var', (6, 28))	('PCDHG@', 'Gene', '56115', (55, 61))
212945	30930834	There were no significant differences between PROMIS and Neuro-QOL PRO scores between HGG and LGG groups, with the following exceptions: PROMIS pain intensity, in which patients with LGG experienced greater pain-related intensity relative to patients with HGG (t-score: HGG 1.76 +- 2, LGG 3.29 +- 3; P = 0.01) and greater distress from declining physical function among patients with HGG (t-score: HGG 41.83 +- 12.59, LGG 47.74 +- 12.16; P = 0.05) (Table 3).	('pain', 'Disease', 'MESH:D010146', (144, 148))	('pain', 'Disease', (144, 148))	('greater', 'PosReg', (199, 206))	('patients', 'Species', '9606', (169, 177))	('pain', 'Phenotype', 'HP:0012531', (207, 211))	('pain', 'Disease', 'MESH:D010146', (207, 211))	('pain', 'Disease', (207, 211))	('patients', 'Species', '9606', (370, 378))	('pain', 'Phenotype', 'HP:0012531', (144, 148))	('LGG', 'Var', (183, 186))	('patients', 'Species', '9606', (242, 250))
213006	25398846	These studies have unmasked a common theme in pediatric brain tumors in which molecular discrete subtypes of each tumor likely arise from topographically discrete neural progenitor cells that are selectively susceptible to specific transforming mutations.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('brain tumor', 'Phenotype', 'HP:0030692', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (245, 254))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (62, 67))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (46, 68))	('tumor', 'Disease', (114, 119))	('brain tumors', 'Phenotype', 'HP:0030692', (56, 68))	('pediatric brain tumors', 'Disease', (46, 68))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
213010	25398846	The discovery of hSNF5/INI1 mutations in atypical teratoid/rhabdoid tumors (ATRT), provided the first firm evidence that not all tumors treated as 'medulloblastoma' were the same disease.	('hSNF5', 'Gene', (17, 22))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', (68, 74))	('INI1', 'Gene', (23, 27))	('INI1', 'Gene', '6598', (23, 27))	("'medulloblastoma", 'Disease', 'MESH:D008527', (147, 163))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('hSNF5', 'Gene', '6598', (17, 22))	('rhabdoid tumors', 'Disease', (59, 74))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (59, 74))	("'medulloblastoma", 'Disease', (147, 163))	('mutations', 'Var', (28, 37))	('medulloblastoma', 'Phenotype', 'HP:0002885', (148, 163))
213018	25398846	About 80% of WNT medulloblastomas have mutations in the gene encoding beta-catenin, and about 80% have a deletion of one copy of chromosome 6 (monosomy 6).	('deletion', 'Var', (105, 113))	('beta-catenin', 'Gene', (70, 82))	('medulloblastoma', 'Phenotype', 'HP:0002885', (17, 32))	('WNT medulloblastomas', 'Disease', 'MESH:D008527', (13, 33))	('beta-catenin', 'Gene', '1499', (70, 82))	('mutations', 'Var', (39, 48))	('WNT medulloblastomas', 'Disease', (13, 33))
213027	25398846	SHH medulloblastomas also appear to arise in patients with germline mutations in TP53, and evidence of shattering of the chromosomes (chromothripsis) in their tumors.	('arise', 'Reg', (36, 41))	('germline mutations', 'Var', (59, 77))	('SHH medulloblastomas', 'Disease', 'MESH:D008527', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('medulloblastoma', 'Phenotype', 'HP:0002885', (4, 19))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('SHH medulloblastomas', 'Disease', (0, 20))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
213031	25398846	Developing molecular-based therapies of Group 3 medulloblastoma will be more challenging since these tumors contain genetic alterations that are difficult to target e.g., amplification of MYC, or the associated fusion gene PVT1-MYC.	('MYC', 'Gene', '4609', (228, 231))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MYC', 'Gene', '4609', (188, 191))	('PVT1', 'Gene', (223, 227))	('medulloblastoma', 'Phenotype', 'HP:0002885', (48, 63))	('amplification', 'Var', (171, 184))	('MYC', 'Gene', (228, 231))	('medulloblastoma', 'Disease', 'MESH:D008527', (48, 63))	('PVT1', 'Gene', '5820', (223, 227))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('MYC', 'Gene', (188, 191))	('medulloblastoma', 'Disease', (48, 63))
213033	25398846	The only subgroup specific genetic event identified to date in this subgroup are tandem duplications of the Parkinson's disease associated gene SNCAIP on chromosome 5.	('SNCAIP', 'Gene', (144, 150))	("Parkinson's disease", 'Disease', 'MESH:D010300', (108, 127))	('tandem duplications', 'Var', (81, 100))	('SNCAIP', 'Gene', '9627', (144, 150))	("Parkinson's disease", 'Disease', (108, 127))
213037	25398846	As epigenetic events are by definition reversible, this may offer a therapeutic window for the treatment of medulloblastoma patients.	('medulloblastoma', 'Disease', (108, 123))	('medulloblastoma', 'Disease', 'MESH:D008527', (108, 123))	('medulloblastoma', 'Phenotype', 'HP:0002885', (108, 123))	('epigenetic events', 'Var', (3, 20))	('patients', 'Species', '9606', (124, 132))
213046	25398846	Histologic similarities among ependymomas have led investigators to treat these tumors as a single entity; however, recent genomic studies of gene expression and DNA copy number alterations have shown that ependymomas from different regions of the central nervous system (CNS) include discrete subtypes that display disparate prognoses, transcriptional profiles and genetic alterations, suggesting they are different diseases.	('ependymomas', 'Disease', 'MESH:D004806', (206, 217))	('ependymomas', 'Disease', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ependymoma', 'Phenotype', 'HP:0002888', (30, 40))	('ependymomas', 'Disease', (206, 217))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('ependymomas', 'Disease', 'MESH:D004806', (30, 41))	('alterations', 'Var', (178, 189))	('ependymoma', 'Phenotype', 'HP:0002888', (206, 216))
213055	25398846	Both studies found very few single nucleotide variations, insertion/deletions, or focal (<5 genes) copy number variations in ependymomas.	('ependymoma', 'Phenotype', 'HP:0002888', (125, 135))	('insertion/deletions', 'Var', (58, 77))	('ependymomas', 'Disease', 'MESH:D004806', (125, 136))	('single nucleotide variations', 'Var', (28, 56))	('copy number variations', 'Var', (99, 121))	('ependymomas', 'Disease', (125, 136))
213056	25398846	This genomic disruption resulted in a novel translocation that fused a poorly characterized gene, C11orf95, to RELA, the principal effector of canonical NF-kappaB signaling in 70% of supratentorial, but no posterior fossa or spinal ependymomas, making it the most recurrent genetic alteration in ependymoma.	('C11orf95', 'Gene', (98, 106))	('ependymoma', 'Disease', 'MESH:D004806', (296, 306))	('spinal ependymomas', 'Disease', (225, 243))	('ependymoma', 'Phenotype', 'HP:0002888', (232, 242))	('supratentorial', 'Disease', (183, 197))	('disruption', 'Var', (13, 23))	('ependymoma', 'Disease', (232, 242))	('spinal ependymomas', 'Disease', 'MESH:D004806', (225, 243))	('C11orf95', 'Gene', '65998', (98, 106))	('ependymoma', 'Disease', 'MESH:D004806', (232, 242))	('resulted in', 'Reg', (24, 35))	('ependymoma', 'Phenotype', 'HP:0002888', (296, 306))	('fused', 'Reg', (63, 68))	('ependymoma', 'Disease', (296, 306))
213064	25398846	Studying DNA methylation patterns this group identified two distinct groups of posterior ependymomas: group A posterior fossa ependymomas that a much higher extent of CpG island methylation and exhibit a 'CpG island methylator' or 'CIMP' phenotype (PFA-CIMP+) ependymomas, and PFB CIMP-negative tumors.	('tumors', 'Disease', (295, 301))	('higher', 'PosReg', (150, 156))	('fossa ependymomas', 'Disease', (120, 137))	('CIMP', 'Chemical', '-', (253, 257))	('ependymoma', 'Phenotype', 'HP:0002888', (126, 136))	('posterior ependymomas', 'Disease', (79, 100))	('PFA', 'Chemical', 'MESH:D017245', (249, 252))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('PFB CIMP', 'Chemical', '-', (277, 285))	('ependymomas', 'Disease', (89, 100))	('ependymoma', 'Phenotype', 'HP:0002888', (260, 270))	('posterior ependymomas', 'Disease', 'MESH:D004806', (79, 100))	('ependymomas', 'Disease', 'MESH:D004806', (260, 271))	('CpG island methylation', 'Var', (167, 189))	('ependymomas', 'Disease', 'MESH:D004806', (126, 137))	('methylation', 'Var', (178, 189))	('CIMP+', 'Chemical', '-', (253, 258))	('fossa ependymomas', 'Disease', 'MESH:D004806', (120, 137))	('CIMP', 'Chemical', '-', (281, 285))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('ependymomas', 'Disease', (260, 271))	("'CIMP'", 'PosReg', (231, 237))	('CIMP', 'Chemical', '-', (232, 236))	('ependymoma', 'Phenotype', 'HP:0002888', (89, 99))	('ependymomas', 'Disease', (126, 137))	("'CpG", 'PosReg', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('ependymomas', 'Disease', 'MESH:D004806', (89, 100))
213079	25398846	Mutations in the IDH1 gene are a hallmark genetic lesion in adult AA and AO, but they are exceedingly rare in children.	('children', 'Species', '9606', (110, 118))	('genetic lesion', 'Disease', (42, 56))	('genetic lesion', 'Disease', 'MESH:D020022', (42, 56))	('IDH1', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('AA', 'Phenotype', 'HP:0009592', (66, 68))	('IDH1', 'Gene', '3417', (17, 21))
213080	25398846	The same holds true for 1p/19q deletion, the quasidiagnostic cytogenetic lesion in adult oligodendroglioma.	('adult oligodendroglioma', 'Disease', 'MESH:D009837', (83, 106))	('adult oligodendroglioma', 'Disease', (83, 106))	('1p/19q deletion', 'Var', (24, 39))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('genetic lesion', 'Disease', (65, 79))	('genetic lesion', 'Disease', 'MESH:D020022', (65, 79))
213085	25398846	However, some genetic alterations, such as PDGFRA or MET amplification and TP53 mutation, are found in both pediatric and adult HGGs.	('found', 'Reg', (94, 99))	('PDGFRA', 'Gene', (43, 49))	('TP53', 'Gene', (75, 79))	('PDGFRA', 'Gene', '5156', (43, 49))	('TP53', 'Gene', '7157', (75, 79))	('mutation', 'Var', (80, 88))	('MET', 'Gene', (53, 56))
213086	25398846	PDGFRA amplification, a potentially druggable lesion, is more common in pediatric HGG cohorts, and it appears to be more frequently observed in secondary GBM after CNS radiotherapy for another indication (or in post-treatment primary HGG samples obtained at postmortem).	('PDGFRA', 'Gene', (0, 6))	('PDGFRA', 'Gene', '5156', (0, 6))	('amplification', 'Var', (7, 20))	('secondary GBM', 'Disease', (144, 157))	('observed', 'Reg', (132, 140))
213087	25398846	The most intriguing finding, so far, has been highly recurrent hotspot mutations affecting two distinct residues (K27 and G34) of the noncanonical histone gene H3F3A, as well as the canonical histone genes HIST1H3B and HIST1H3C.	('K27', 'Var', (114, 117))	('H3F3A', 'Gene', (160, 165))	('HIST1H3B', 'Gene', (206, 214))	('HIST1H3B', 'Gene', '8358', (206, 214))	('G34', 'Var', (122, 125))	('mutations', 'Var', (71, 80))	('HIST1H3C', 'Gene', '8352', (219, 227))	('HIST1H3C', 'Gene', (219, 227))	('H3F3A', 'Gene', '3020', (160, 165))
213088	25398846	These studies have demonstrated a striking pattern of spatial heterogeneity, with K27M substitutions almost exclusively occurring in midline tumors (i.e., those in the thalamus, brainstem.	('K27M', 'Mutation', 'p.K27M', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('midline tumors', 'Disease', (133, 147))	('occurring', 'Reg', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('midline tumors', 'Disease', 'MESH:D009369', (133, 147))	('K27M', 'Var', (82, 86))
213090	25398846	Although G34 mutations typically co-occur with ATRX mutations and alternative lengthening of telomeres (a potential point of targeted interference), those mutations are less frequently coexpressed in tumors carrying K27M substitutions.	('ATRX', 'Gene', (47, 51))	('mutations', 'Var', (52, 61))	('K27M', 'Mutation', 'p.K27M', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ATRX', 'Gene', '546', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('G34', 'Gene', (9, 12))	('K27M', 'Var', (216, 220))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('mutations', 'Var', (13, 22))	('co-occur', 'Reg', (33, 41))
213091	25398846	Several groups have shown that K27M mutations functionally inactivate the polycomb repressor complex 2 by entrapping EZH2, the main enzyme required to establish the repressive chromatin mark K27me3, thus conferring a dominant effect at the level of H3K27me on histones H3 and H3.3.	('polycomb repressor complex', 'Pathway', (74, 100))	('K27me3', 'Var', (191, 197))	('K27M mutations', 'Var', (31, 45))	('EZH2', 'Gene', (117, 121))	('K27M', 'Mutation', 'p.K27M', (31, 35))	('EZH2', 'Gene', '2146', (117, 121))	('entrapping', 'Reg', (106, 116))	('inactivate', 'NegReg', (59, 69))
213092	25398846	Both histone mutations are thought to arrest the respective cells of origin in a primitive progenitor state and may require additional genetic hits (e.g., TP53 mutation) to drive tumorigenesis and proliferation (Fig.	('mutation', 'Var', (160, 168))	('TP53', 'Gene', '7157', (155, 159))	('drive', 'PosReg', (173, 178))	('TP53', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('proliferation', 'CPA', (197, 210))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (179, 184))
213093	25398846	How to molecularly target these constellations of H3, TP53, and ATRX mutations remains to be determined and is the focus of several ongoing HTDS.	('mutations', 'Var', (69, 78))	('ATRX', 'Gene', (64, 68))	('ATRX', 'Gene', '546', (64, 68))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))
213094	25398846	Four recent DIPG studies have independently identified driver mutations in the ACVR1 gene, mostly in combination with HIST1H3B/C mutations.	('DIPG', 'Chemical', '-', (12, 16))	('HIST1H3B', 'Gene', (118, 126))	('HIST1H3B', 'Gene', '8358', (118, 126))	('ACVR1', 'Gene', (79, 84))	('ACVR1', 'Gene', '90', (79, 84))	('mutations', 'Var', (62, 71))
213096	25398846	In a distinct subgroup of midline tumors that mostly occur in the thalamus, investigators have identified recurrent FGFR1 hotspot mutations for which targeted compounds are in clinical trials in other disease entities.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('midline tumors', 'Disease', (26, 40))	('midline tumors', 'Disease', 'MESH:D009369', (26, 40))	('FGFR1', 'Gene', (116, 121))	('FGFR1', 'Gene', '2260', (116, 121))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
213097	25398846	Finally, recurrent fusions involving NTRK1, NTRK2, or NTRK3 described in one recent study in a relevant subset of infant (non-brainstem) HGGs might also provide a promising drug target.	('NTRK1', 'Gene', '4914', (37, 42))	('NTRK2', 'Gene', (44, 49))	('fusions', 'Var', (19, 26))	('NTRK3', 'Gene', '4916', (54, 59))	('infant', 'Species', '9606', (114, 120))	('NTRK1', 'Gene', (37, 42))	('NTRK2', 'Gene', '4915', (44, 49))	('NTRK3', 'Gene', (54, 59))
213098	25398846	In the pediatric setting, the four major methylation subgroups are highly enriched for the following: H3K27 mutation, H3G34 mutation, PDGFRA amplification (receptor tyrosine kinase subgroup 1), or none of the previous (mesenchymal subgroup) (Table 1; Fig.	('H3G34', 'Gene', (118, 123))	('mutation', 'Var', (124, 132))	('H3K27', 'Gene', (102, 107))	('mutation', 'Var', (108, 116))	('PDGFRA', 'Gene', '5156', (134, 140))	('PDGFRA', 'Gene', (134, 140))
213104	25398846	Although genetic mosaicism (i.e., different amplifications in different cells within the same tumor) and intratumoral heterogeneity in general appear to be more common in pediatric HGGs than in other pediatric malignancies, molecularly targeted therapies are worth further exploration.	('common', 'Reg', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('pediatric HGGs', 'Disease', (171, 185))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('malignancies', 'Disease', 'MESH:D009369', (210, 222))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (94, 99))	('malignancies', 'Disease', (210, 222))	('genetic mosaicism', 'Var', (9, 26))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
213106	25398846	H3F3A- and HIST1H3B/C-mutation status and molecular subgrouping should be considered standard diagnostic assays for pediatric HGG; PDGFRA and MET amplifications, ATRX status (by immunohistochemical analysis), FGFR1 and ACVR1 mutations, and NTRK2 fusions would be the first candidates to be routinely assessed as potential molecular drug targets.	('NTRK2', 'Gene', '4915', (240, 245))	('H3F3A', 'Gene', '3020', (0, 5))	('mutations', 'Var', (225, 234))	('fusions', 'Var', (246, 253))	('H3F3A', 'Gene', (0, 5))	('PDGFRA', 'Gene', (131, 137))	('FGFR1', 'Gene', (209, 214))	('FGFR1', 'Gene', '2260', (209, 214))	('HIST1H3B', 'Gene', (11, 19))	('NTRK2', 'Gene', (240, 245))	('PDGFRA', 'Gene', '5156', (131, 137))	('HIST1H3B', 'Gene', '8358', (11, 19))	('ACVR1', 'Gene', (219, 224))	('ATRX', 'Gene', (162, 166))	('ACVR1', 'Gene', '90', (219, 224))	('ATRX', 'Gene', '546', (162, 166))
213116	25398846	Duplication of BRAF is a common copy-number variation that occurs in tumors that originate in the cerebellum, hypothalamus, or optic chiasm.	('hypothalamus', 'Disease', (110, 122))	('BRAF', 'Gene', '673', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BRAF', 'Gene', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('Duplication', 'Var', (0, 11))	('hypothalamus', 'Disease', 'MESH:D007029', (110, 122))
213117	25398846	The 7q34 gain has been characterized as a BRAF duplication with a tandem insertion in the KIAA1549 gene.	('7q34', 'Var', (4, 8))	('BRAF', 'Gene', '673', (42, 46))	('AA', 'Phenotype', 'HP:0009592', (92, 94))	('gain', 'PosReg', (9, 13))	('KIAA1549', 'Gene', (90, 98))	('KIAA1549', 'Gene', '57670', (90, 98))	('BRAF', 'Gene', (42, 46))
213118	25398846	Fusion genes containing BRAF variants activate the MAPK signaling pathway; therefore, this pathway holds promise as a potential therapeutic option for pediatric LGGs.	('MAPK signaling pathway', 'Pathway', (51, 73))	('activate', 'PosReg', (38, 46))	('variants', 'Var', (29, 37))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))
213121	25398846	Tuberous sclerosis, which is a hereditary disorder in which benign tumors form in many organs, including the brain, is caused by mutations in two tumor-suppressor genes, TSC1 and TSC2.	('tumor', 'Disease', (146, 151))	('benign tumors', 'Disease', (60, 73))	('tumor', 'Disease', (67, 72))	('TSC2', 'Gene', '7249', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('TSC1', 'Gene', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('TSC1', 'Gene', '7248', (170, 174))	('TSC2', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('hereditary disorder', 'Disease', (31, 50))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('caused by', 'Reg', (119, 128))	('hereditary disorder', 'Disease', 'MESH:D030342', (31, 50))	('Tuberous sclerosis', 'Disease', (0, 18))	('benign tumors', 'Disease', 'MESH:D009369', (60, 73))	('mutations', 'Var', (129, 138))
213123	25398846	TSC1 and TSC2 are negative regulators of the mTOR pathway, which mediates cell proliferation; thus, mutations in TSC1 and TSC2 activate mTOR, thereby increasing a child's predisposition to LGGs.	('TSC2', 'Gene', (122, 126))	('LGGs', 'Disease', (189, 193))	('activate', 'PosReg', (127, 135))	('mutations', 'Var', (100, 109))	('TSC2', 'Gene', '7249', (122, 126))	('child', 'Species', '9606', (163, 168))	('TSC1', 'Gene', '7248', (113, 117))	('increasing', 'PosReg', (150, 160))	('TSC1', 'Gene', (113, 117))	('TSC2', 'Gene', '7249', (9, 13))	('mTOR', 'Gene', '2475', (136, 140))	('TSC1', 'Gene', '7248', (0, 4))	('TSC1', 'Gene', (0, 4))	('TSC2', 'Gene', (9, 13))	('mTOR', 'Gene', (136, 140))	('mTOR', 'Gene', '2475', (45, 49))	('mTOR', 'Gene', (45, 49))
213125	25398846	MYB gene mutations also occur in multiple types of LGG.	('MYB', 'Gene', (0, 3))	('LGG', 'Disease', (51, 54))	('occur', 'Reg', (24, 29))	('mutations', 'Var', (9, 18))	('MYB', 'Gene', '4602', (0, 3))
213128	25398846	MYBL1, another member of the MYB family of proteins, is mutated in diffuse astrocytomas and angiocentric gliomas.	('MYB', 'Gene', (0, 3))	('astrocytomas', 'Disease', 'MESH:D001254', (75, 87))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (92, 112))	('angiocentric gliomas', 'Disease', (92, 112))	('mutated', 'Var', (56, 63))	('astrocytomas', 'Disease', (75, 87))	('MYB', 'Gene', '4602', (29, 32))	('MYBL1', 'Gene', (0, 5))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('MYBL1', 'Gene', '4603', (0, 5))	('MYB', 'Gene', (29, 32))	('MYB', 'Gene', '4602', (0, 3))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
213130	25398846	FGFR1 N546K and K656E mutations occur in 5% of the supratentorial pilocytic astrocytomas.	('K656E', 'Mutation', 'rs869320694', (16, 21))	('N546K', 'Var', (6, 11))	('pilocytic astrocytomas', 'Disease', (66, 88))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (66, 88))	('K656E', 'Var', (16, 21))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('occur', 'Reg', (32, 37))	('N546K', 'Mutation', 'rs779707422', (6, 11))
213133	25398846	Additionally, FGFR1 mutations and duplication of its tyrosine kinase domain have been described in pilocytic astrocytomas, diffuse astrocytomas, and dysembryoplastic neuroepithelial tumors.	('astrocytomas', 'Disease', (131, 143))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (99, 121))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('astrocytomas', 'Disease', (109, 121))	('described', 'Reg', (86, 95))	('duplication', 'Var', (34, 45))	('FGFR1', 'Gene', (14, 19))	('astrocytomas', 'Disease', 'MESH:D001254', (131, 143))	('FGFR1', 'Gene', '2260', (14, 19))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (149, 188))	('dysembryoplastic neuroepithelial tumors', 'Disease', (149, 188))	('astrocytomas', 'Disease', 'MESH:D001254', (109, 121))	('pilocytic astrocytomas', 'Disease', (99, 121))	('mutations', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (166, 188))
213134	25398846	These include genomic alterations affecting the kinase domain of neurotrophic tyrosine kinase type 2 (NTRK2), which have been described in pediatric pilocytic astrocytomas.	('kinase domain', 'MPA', (48, 61))	('pediatric pilocytic astrocytomas', 'Disease', (139, 171))	('affecting', 'Reg', (34, 43))	('genomic alterations', 'Var', (14, 33))	('NTRK2', 'Gene', (102, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (159, 170))	('pediatric pilocytic astrocytomas', 'Disease', 'MESH:D001254', (139, 171))	('neurotrophic tyrosine kinase type 2', 'Gene', '4915', (65, 100))	('NTRK2', 'Gene', '4915', (102, 107))	('neurotrophic tyrosine kinase type 2', 'Gene', (65, 100))	('described', 'Reg', (126, 135))
213150	32287174	A data-mining study also revealed that TLR10 levels were positively correlated with WHO grade in glioma, and patients with high TLR10 levels showed shorter overall survival (OS) and disease-free survival (DFS) times than patients with low TLR10 levels.	('TLR10', 'Gene', (128, 133))	('patients', 'Species', '9606', (221, 229))	('glioma', 'Disease', (97, 103))	('TLR10', 'Gene', (239, 244))	('TLR10', 'Gene', (39, 44))	('patients', 'Species', '9606', (109, 117))	('overall survival', 'CPA', (156, 172))	('high', 'Var', (123, 127))	('disease-free survival', 'CPA', (182, 203))	('TLR10', 'Gene', '81793', (128, 133))	('shorter', 'NegReg', (148, 155))	('TLR10', 'Gene', '81793', (239, 244))	('TLR10', 'Gene', '81793', (39, 44))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('correlated', 'Reg', (68, 78))
213183	32287174	The GEPIA results (Figure 2D) showed that a high TLR10 expression level was associated with poor overall survival (OS, P=6.8e-08) and poor disease-free survival (DFS, P=7.2e-06) in glioma patients.	('TLR10', 'Gene', (49, 54))	('expression level', 'MPA', (55, 71))	('high', 'Var', (44, 48))	('TLR10', 'Gene', '81793', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('overall survival', 'CPA', (97, 113))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('poor', 'NegReg', (92, 96))	('patients', 'Species', '9606', (188, 196))	('poor', 'NegReg', (134, 138))	('disease-free survival', 'CPA', (139, 160))	('glioma', 'Disease', (181, 187))
213186	32287174	Taken together, these findings show that TLR10 was highly expressed in both LGG and GBM, and high TLR10 expression was associated with a poor prognosis in glioma patients.	('associated', 'Reg', (119, 129))	('patients', 'Species', '9606', (162, 170))	('hes', 'Gene', (17, 20))	('TLR10', 'Gene', '81793', (41, 46))	('TLR10', 'Gene', (98, 103))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('expression', 'MPA', (104, 114))	('TLR10', 'Gene', (41, 46))	('TLR10', 'Gene', '81793', (98, 103))	('high', 'Var', (93, 97))	('hes', 'Gene', '6238', (17, 20))	('glioma', 'Disease', (155, 161))
213188	32287174	Figure 3A shows that TLR10 was remarkably increased in DLBC and LAML tissues compared with normal tissues and had a significant relationship with FAB classification/FLT3 mutation in LAML (Figure 3C, 3D) but not with DLBL tumor grade (Figure 3B).	('increased', 'PosReg', (42, 51))	('mal', 'Gene', (94, 97))	('TLR10', 'Gene', '81793', (21, 26))	('relationship', 'Interaction', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('DLBL tumor', 'Disease', 'MESH:D009369', (216, 226))	('mal', 'Gene', '4118', (94, 97))	('TLR10', 'Gene', (21, 26))	('DLBL tumor', 'Disease', (216, 226))	('FAB classification/FLT3', 'Gene', (146, 169))	('mutation', 'Var', (170, 178))
213206	32287174	A similar effect was observed in the macrophage cell line THP-1, wherein the levels of the chemokines CCL20, CCL1, and IL-8 were decreased following TLR10 knockdown.	('knockdown', 'Var', (155, 164))	('TLR10', 'Gene', (149, 154))	('TLR10', 'Gene', '81793', (149, 154))	('CCL1', 'MPA', (109, 113))	('THP-1', 'CellLine', 'CVCL:0006', (58, 63))	('decreased', 'NegReg', (129, 138))	('levels of the chemokines CCL20', 'MPA', (77, 107))
213210	32287174	We found that TLR10 levels were positively correlated with WHO grade in glioma, and patients with high TLR10 levels showed shorter overall survival and disease-free survival times than patients with low TLR10 levels.	('TLR10', 'Gene', '81793', (203, 208))	('glioma', 'Disease', (72, 78))	('TLR10', 'Gene', '81793', (14, 19))	('shorter', 'NegReg', (123, 130))	('TLR10', 'Gene', '81793', (103, 108))	('patients', 'Species', '9606', (84, 92))	('overall survival', 'CPA', (131, 147))	('high', 'Var', (98, 102))	('correlated', 'Reg', (43, 53))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('TLR10', 'Gene', (203, 208))	('TLR10', 'Gene', (14, 19))	('disease-free survival times', 'CPA', (152, 179))	('patients', 'Species', '9606', (185, 193))	('TLR10', 'Gene', (103, 108))
213268	31389669	Specifically, DCE-MRI has high diagnostic performance in stratifying gliomas in high- or low-grade, and moderate diagnostic accuracy in differentiating recurrence from treatment-related changes, and PCNSLs from HGGs.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('DCE', 'Gene', '1718', (14, 17))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('DCE', 'Gene', (14, 17))	('gliomas', 'Disease', (69, 76))	('PCNSL', 'Phenotype', 'HP:0030069', (199, 204))	('PCNSLs', 'Phenotype', 'HP:0030069', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('PCNSLs', 'Var', (199, 205))
213337	30669406	As discussed in the last section, mutations in certain types of genes define the cancer.	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
213340	30669406	Tp53 level is found to be quite abnormal in high-grade gliomas and mutations have been found in more than 80% of tumors.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('Tp53', 'Gene', (0, 4))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Tp53', 'Gene', '7157', (0, 4))	('mutations', 'Var', (67, 76))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
213342	30669406	RB1 mutation is found in approximately 75% of brain tumors and it is more relevant to glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('brain tumors', 'Disease', (46, 58))	('RB1', 'Gene', '5925', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('brain tumors', 'Phenotype', 'HP:0030692', (46, 58))	('mutation', 'Var', (4, 12))	('brain tumor', 'Phenotype', 'HP:0030692', (46, 57))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('RB1', 'Gene', (0, 3))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('brain tumors', 'Disease', 'MESH:D001932', (46, 58))
213344	30669406	Mutation in EGFR will lead to increased cell cycle proliferation and increased tumor cell survival.	('increased', 'PosReg', (69, 78))	('tumor', 'Disease', (79, 84))	('Mutation', 'Var', (0, 8))	('EGFR', 'Gene', '1956', (12, 16))	('cell cycle proliferation', 'CPA', (40, 64))	('increased', 'PosReg', (30, 39))	('EGFR', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
213345	30669406	It is generally associated with primary glioblastomas and approximately 40% of the mutations that caused them are found within it.	('mutations', 'Var', (83, 92))	('glioblastomas', 'Phenotype', 'HP:0012174', (40, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('glioblastomas', 'Disease', 'MESH:D005909', (40, 53))	('glioblastomas', 'Disease', (40, 53))	('primary glioblastoma', 'Disease', 'MESH:D005909', (32, 52))	('primary glioblastoma', 'Disease', (32, 52))	('associated', 'Reg', (16, 26))
213346	30669406	PTEN is a tumor suppressor gene and are responsible for about 15-40% of mutations found in primary glioblastomas.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (72, 81))	('tumor', 'Disease', (10, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('glioblastomas', 'Phenotype', 'HP:0012174', (99, 112))	('glioblastomas', 'Disease', 'MESH:D005909', (99, 112))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('glioblastomas', 'Disease', (99, 112))	('primary glioblastoma', 'Disease', 'MESH:D005909', (91, 111))	('primary glioblastoma', 'Disease', (91, 111))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
213349	30669406	Generally, IDH1 mutation is found less in primary glioblastoma patients (5%), but more in high grade glioblastomas (70-80%).	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('glioblastomas', 'Disease', (101, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('primary glioblastoma', 'Disease', (42, 62))	('primary glioblastoma', 'Disease', 'MESH:D005909', (42, 62))	('glioblastomas', 'Phenotype', 'HP:0012174', (101, 114))	('patients', 'Species', '9606', (63, 71))	('glioblastomas', 'Disease', 'MESH:D005909', (101, 114))	('IDH1', 'Gene', (11, 15))
213350	30669406	IDH2 mutations are generally seen in oligodendroglial tumors.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (37, 60))	('oligodendroglial tumors', 'Disease', (37, 60))	('mutations', 'Var', (5, 14))	('seen', 'Reg', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IDH2', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('IDH2', 'Gene', '3418', (0, 4))
213351	30669406	Co-deletion of chromosomes 1p and 19q is indicative of oligodendroglial lineage and mainly seen in anaplastic oligoastrocytomas (20-30%), oligoastrocytomas (30-50%), anaplastic oligodendrogliomas (60%) and oligodendrogliomas (80%).	('anaplastic oligoastrocytomas', 'Disease', (99, 127))	('oligodendroglial lineage', 'Disease', (55, 79))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('oligodendrogliomas', 'Disease', (177, 195))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (206, 224))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('oligoastrocytomas', 'Disease', (110, 127))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (110, 127))	('seen', 'Reg', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('oligoastrocytomas', 'Disease', (138, 155))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (138, 155))	('gliomas', 'Phenotype', 'HP:0009733', (217, 224))	('anaplastic oligoastrocytomas', 'Disease', 'MESH:D001254', (99, 127))	('oligodendrogliomas', 'Disease', (206, 224))	('Co-deletion', 'Var', (0, 11))	('anaplastic oligodendrogliomas', 'Disease', 'MESH:D009837', (166, 195))	('anaplastic oligodendrogliomas', 'Disease', (166, 195))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (177, 195))	('oligodendroglial lineage', 'Disease', 'MESH:D015456', (55, 79))
213354	30669406	BRAF mutations are generally found in pilocyticastrocytomas (65-80%), pleomorphic xanthoastrocytomas (about 80%) and gangliogliomas (25%).	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('pilocyticastrocytomas', 'Disease', 'None', (38, 59))	('found', 'Reg', (29, 34))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (70, 100))	('mutations', 'Var', (5, 14))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('BRAF', 'Gene', '673', (0, 4))	('pilocyticastrocytomas', 'Disease', (38, 59))	('gangliogliomas', 'Disease', (117, 131))	('gangliogliomas', 'Disease', 'MESH:D018303', (117, 131))	('BRAF', 'Gene', (0, 4))	('pleomorphic xanthoastrocytomas', 'Disease', (70, 100))
213355	30669406	A-Thalassemia-mental retardation syndrome X-linked (ATRX) is a gene that encodes a protein and is associated with TP53 and IDH1 mutations.	('mutations', 'Var', (128, 137))	('A-Thalassemia-mental retardation syndrome X-linked', 'Disease', (0, 50))	('IDH1', 'Gene', (123, 127))	('TP53', 'Gene', '7157', (114, 118))	('ATRX', 'Gene', (52, 56))	('TP53', 'Gene', (114, 118))	('ATRX', 'Gene', '546', (52, 56))	('A-Thalassemia-mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (0, 50))	('IDH1', 'Gene', '3417', (123, 127))	('associated', 'Reg', (98, 108))	('-mental retardation', 'Phenotype', 'HP:0001249', (13, 32))
213356	30669406	It is use as a prognostic indicator when tumors have anIDH1 mutation and it distinguishes between the tumors of oligodendroglial origin.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutation', 'Var', (60, 68))	('IDH1', 'Gene', '3417', (55, 59))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors of oligodendroglial', 'Disease', 'MESH:D009369', (102, 128))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors of oligodendroglial', 'Disease', (102, 128))	('IDH1', 'Gene', (55, 59))
213416	30669406	Mutation in the genes is the root cause of cancer and the degree of this mutation in specific genes can be measured through biomarker tests.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('Mutation', 'Var', (0, 8))	('cause', 'Reg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
213464	30669406	The tumor images were further divided into five classes based on patient data i.e, class-0: normal, class-2: enhancing region, class-3: necrotic region, class-4: T1-abnormality, class-5: FLAIR abnormality, class-1: ground truth region based on combination of classes 2-5.	('tumor', 'Disease', (4, 9))	('necrotic', 'Disease', 'MESH:D009336', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('patient', 'Species', '9606', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('T1-abnormality', 'Var', (162, 176))	('necrotic', 'Disease', (136, 144))
213553	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
213559	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
213628	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('LAG3', 'Gene', '3902', (128, 132))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
213632	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
213649	28448514	A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g.	('KIAA1549-BRAF', 'Disease', (116, 129))	('BRAF-', 'Gene', (156, 161))	('deregulation', 'Reg', (29, 41))	('KIAA1549-BRAF', 'Disease', 'None', (116, 129))	('RAF1', 'Gene', (165, 169))	('point', 'Var', (187, 192))	('RAF1', 'Gene', '5894', (165, 169))	('BRAF-', 'Gene', '673', (156, 161))
213652	28448514	Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5' gene fusion partner GTF2I (7q11.23), not previously described in PA.	('BRAF', 'Gene', '673', (95, 99))	('fusion', 'Var', (100, 106))	('BRAF', 'Gene', (95, 99))	('GTF2I', 'Gene', (144, 149))	('GTF2I', 'Gene', '2969', (144, 149))
213653	28448514	The new GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene.	('KIAA1549-BRAF', 'Disease', 'None', (104, 117))	('fusion', 'Var', (25, 31))	('GTF2I-BRAF 19-10', 'Gene', '2969', (8, 24))	('KIAA1549-BRAF', 'Disease', (104, 117))	('GTF2I-BRAF 19-10', 'Gene', (8, 24))
213657	28448514	Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types.	('fusion', 'Var', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('B-Raf', 'Gene', (78, 83))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (110, 115))	('B-Raf', 'Gene', '673', (78, 83))	('BRAF', 'Gene', '673', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('BRAF', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
213658	28448514	Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('RAF', 'Gene', '22882', (51, 54))	('RAF', 'Gene', (51, 54))	('fusions', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('RAF', 'Gene', '22882', (47, 50))	('tumor', 'Disease', (116, 121))	('RAF', 'Gene', (47, 50))
213670	28448514	These fusions are formed by tandem duplications or deletions on chromosome arms 7q.34 (involving BRAF) and 3p (involving the less common RAF1 gene).	('RAF1', 'Gene', (137, 141))	('RAF1', 'Gene', '5894', (137, 141))	('deletions', 'Var', (51, 60))	('BRAF', 'Gene', '673', (97, 101))	('tandem duplications', 'Var', (28, 47))	('BRAF', 'Gene', (97, 101))
213674	28448514	The common feature for all reported BRAF/RAF fusions is the absence of inhibitory N-domain leading to constitutive active RAF kinase.	('RAF', 'Gene', '22882', (122, 125))	('absence', 'NegReg', (60, 67))	('RAF', 'Gene', (41, 44))	('BRAF', 'Gene', (36, 40))	('RAF', 'Gene', (122, 125))	('RAF', 'Gene', '22882', (37, 40))	('inhibitory N-domain', 'MPA', (71, 90))	('RAF', 'Gene', (37, 40))	('fusions', 'Var', (45, 52))	('BRAF', 'Gene', '673', (36, 40))	('RAF', 'Gene', '22882', (41, 44))
213676	28448514	Point mutations and rearrangements are reported to be mutually exclusive in this tumor type, which highlight a central role of the MAPK pathway in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Point mutations', 'Var', (0, 15))	('tumor', 'Disease', (81, 86))
213677	28448514	The presence of the KIAA1549-BRAF fusion is associated with improved outcome in PA, and has been suggested as a prognostic marker.	('presence', 'Var', (4, 12))	('KIAA1549-BRAF', 'Disease', (20, 33))	('KIAA1549-BRAF', 'Disease', 'None', (20, 33))	('improved', 'PosReg', (60, 68))
213679	28448514	Since the KIAA1549-BRAF fusions are highly prevalent in pediatric PA, this feature can be used as a supportive diagnostic marker in cases where neuropathological distinction from other gliomas is difficult.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('fusions', 'Var', (24, 31))	('KIAA1549-BRAF', 'Disease', (10, 23))	('KIAA1549-BRAF', 'Disease', 'None', (10, 23))	('gliomas', 'Disease', (185, 192))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))
213680	28448514	The diagnostic and prognostic potential of KIAA1549-BRAF fusion in addition to ongoing development and evaluation of MAPK pathway targeted therapy requires reliable detection of all BRAF rearrangements for correct molecular subgrouping of tumors and patients treatment groups.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('patients', 'Species', '9606', (250, 258))	('KIAA1549-BRAF', 'Disease', 'None', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('rearrangements', 'Var', (187, 201))	('BRAF', 'Gene', '673', (182, 186))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (182, 186))	('BRAF', 'Gene', (52, 56))	('KIAA1549-BRAF', 'Disease', (43, 56))
213685	28448514	The four fusion-detection methods evaluated in this paper suggest the FISH break apart probe for BRAF to be the most suitable method for detection of different kinds BRAF rearrangement, irrespectively of its exon junction or fusion partner.	('rearrangement', 'Var', (171, 184))	('break apart', 'Phenotype', 'HP:0001061', (75, 86))	('BRAF', 'Gene', (166, 170))	('BRAF', 'Gene', (97, 101))	('BRAF', 'Gene', '673', (166, 170))	('BRAF', 'Gene', '673', (97, 101))
213694	28448514	Competitive Allele-Specific TaqMan PCR (castPCR) was performed to detect and measure somatic mutation of BRAFV600E using the TaqMan Mutation Detection Assay (Hs00000111_mu, Applied Biosystems) for c.1799T>A in BRAF (RefSeq accession no: NM_004333.4).	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', (105, 109))	('c.1799T>A', 'Mutation', 'rs113488022', (197, 206))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('BRAFV600E', 'Mutation', 'rs113488022', (105, 114))	('c.1799T>A', 'Var', (197, 206))
213730	28448514	Each sample was investigated with RT-qPCR for presence of the three most common KIAA1549-BRAF mRNA fusion junctions (16-9, 15-9, and 16-11) and BRAFV600E point mutation status (Table 2).	('KIAA1549-BRAF', 'Disease', 'None', (80, 93))	('KIAA1549-BRAF', 'Disease', (80, 93))	('BRAFV600E', 'Mutation', 'rs113488022', (144, 153))	('BRAFV600E', 'Var', (144, 153))
213733	28448514	Hence, a causative BRAF alteration could be identified in five out of six cases, whereas in case PA3 the genetic background was unknown.	('alteration', 'Var', (24, 34))	('BRAF', 'Gene', '673', (19, 23))	('PA3', 'Chemical', '-', (97, 100))	('BRAF', 'Gene', (19, 23))
213745	28448514	These CNV duplications verified the novel DENND2A-GTF2IRD1 14-2 fusion junction detected by RNA-seq, but also indicated a BRAF fusion formed by the same rearrangement event; BRAF-GTF2I.	('BRAF', 'Gene', '673', (122, 126))	('DENND2A-GTF2IRD1', 'Gene', '27147;9569', (42, 58))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (122, 126))	('duplications', 'Var', (10, 22))	('BRAF', 'Gene', (174, 178))	('DENND2A-GTF2IRD1', 'Gene', (42, 58))
213775	28448514	BRAF, a downstream target of RAS proteins, is a common target for activating mutations and fusions in diverse cancer forms including PA.	('cancer', 'Disease', (110, 116))	('fusions', 'Var', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('BRAF', 'Gene', '673', (0, 4))	('mutations', 'Var', (77, 86))	('BRAF', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
213776	28448514	The most frequent event in tumorigenesis of PA is BRAF gene rearrangements formed by duplication or deletions on chromosomal region 7q34, and KIAA1549-BRAF 16-9 is found in the majority (~60%) of PA cases.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('rearrangements', 'Var', (60, 74))	('BRAF', 'Gene', (50, 54))	('duplication', 'Var', (85, 96))	('tumor', 'Disease', (27, 32))	('BRAF', 'Gene', '673', (151, 155))	('KIAA1549-BRAF', 'Disease', (142, 155))	('BRAF', 'Gene', (151, 155))	('deletions', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('BRAF', 'Gene', '673', (50, 54))	('KIAA1549-BRAF', 'Disease', 'None', (142, 155))
213778	28448514	BRAF, KIAA1549) are transcribed in the telomere to centromere direction, and linear duplications/translocations may simply form fusions.	('KIAA1549', 'Gene', '57670', (6, 14))	('linear duplications/translocations', 'Var', (77, 111))	('KIAA1549', 'Gene', (6, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
213808	28448514	who demonstrated that KIAA1549-BRAF fusions is expressed at lower levels than BRAF, but at only slightly lower levels than the KIAA1549 promoter.	('KIAA1549', 'Gene', '57670', (22, 30))	('KIAA1549-BRAF', 'Disease', (22, 35))	('KIAA1549', 'Gene', (127, 135))	('BRAF', 'Gene', '673', (78, 82))	('KIAA1549', 'Gene', '57670', (127, 135))	('BRAF', 'Gene', (78, 82))	('fusions', 'Var', (36, 43))	('KIAA1549-BRAF', 'Disease', 'None', (22, 35))	('BRAF', 'Gene', '673', (31, 35))	('KIAA1549', 'Gene', (22, 30))	('BRAF', 'Gene', (31, 35))
213809	28448514	Due to the high prevalence of BRAF rearrangements in pediatric PA and the documented better clinical outcome of KIAA1549-BRAF positive cases, the BRAF fusions have been suggested as a prognostic marker and supplement tool for better diagnostics.	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', (146, 150))	('BRAF', 'Gene', '673', (121, 125))	('rearrangements', 'Var', (35, 49))	('KIAA1549-BRAF', 'Disease', 'None', (112, 125))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('BRAF', 'Gene', '673', (146, 150))	('KIAA1549-BRAF', 'Disease', (112, 125))
213810	28448514	This emphasizes the need for reliable detection of variant BRAF rearrangements in clinical routine irrespectively of its fusion partner or exon-exon junction.	('rearrangements', 'Var', (64, 78))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('variant', 'Var', (51, 58))
213812	28448514	The advantage of FISH method compared to qPCR, CNV analysis and RNA sequencing is that this method is a robust and informative diagnostic tool to indicate BRAF rearrangements independent of the fusion partner, fusion junction, size of duplication, or expression of the fusion gene.	('BRAF', 'Gene', (155, 159))	('indicate', 'Reg', (146, 154))	('rearrangements', 'Var', (160, 174))	('BRAF', 'Gene', '673', (155, 159))
213814	28448514	But complementary qPCR can be used to detect the most common KIAA1549-BRAF fusions in PA.	('KIAA1549-BRAF', 'Disease', 'None', (61, 74))	('KIAA1549-BRAF', 'Disease', (61, 74))	('fusions', 'Var', (75, 82))
213815	28448514	The high occurrence and impact of BRAF rearrangements in pediatric gliomas, essentially PA, not only open the possibility for better diagnostics but also provides an opportunity for targeted therapy.	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('pediatric gliomas', 'Disease', (57, 74))	('rearrangements', 'Var', (39, 53))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))	('pediatric gliomas', 'Disease', 'MESH:D005910', (57, 74))
213818	28448514	However, Raf inhibitors have been reported to generate a paradoxal activation of the MAPK pathway in the cells expressing wild type BRAF and BRAF fusions.	('BRAF', 'Gene', (132, 136))	('BRAF', 'Gene', (141, 145))	('fusions', 'Var', (146, 153))	('activation', 'PosReg', (67, 77))	('inhibitors', 'Var', (13, 23))	('Raf', 'Gene', '22882', (9, 12))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', '673', (141, 145))	('MAPK pathway', 'Pathway', (85, 97))	('Raf', 'Gene', (9, 12))
213822	28448514	Moreover, the occurrence of an increasing number of BRAF fusion variants and possibility for MAPK pathway targeted therapy highlights the importance of a robust method for fast and cost-effective detection of BRAF deregulations to guide diagnosis, prognosis, and accurate targeted therapy.	('MAPK', 'Pathway', (93, 97))	('fusion variants', 'Var', (57, 72))	('deregulations', 'Var', (214, 227))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))	('variants', 'Var', (64, 72))
213943	33229627	DZIP3 was an independent predictive factor of good prognosis in all grade and lower grade gliomas (p < 0.0001).	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('DZIP3', 'Var', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
213946	33229627	Conclusion: In conclusion, the loss of DZIP3 may be involved in the mechanism of angiogenesis in the invasive biological process of glioma.	('glioma', 'Disease', (132, 138))	('DZIP3', 'Gene', (39, 44))	('loss', 'Var', (31, 35))	('angiogenesis', 'CPA', (81, 93))	('involved', 'Reg', (52, 60))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
213956	33229627	Isocitrate dehydrogenase 1 (IDH1) mutation, which occurs early in gliomagenesis, especially for WHO grade II and III gliomas, is an acknowledged molecular alteration.	('glioma', 'Disease', (66, 72))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('IDH1', 'Gene', '3417', (28, 32))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('mutation', 'Var', (34, 42))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('III gliomas', 'Disease', 'MESH:D005910', (113, 124))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('III gliomas', 'Disease', (113, 124))	('glioma', 'Disease', (117, 123))	('IDH1', 'Gene', (28, 32))
213957	33229627	Mutation in IDH1 is a stable marker indicating prognosis in both LGGs and GBM with the incidence of 75% and 12%, respectively.	('LGGs', 'Disease', (65, 69))	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('IDH1', 'Gene', (12, 16))	('Mutation', 'Var', (0, 8))	('IDH1', 'Gene', '3417', (12, 16))	('GBM', 'Disease', (74, 77))
213958	33229627	However, previous studies have established gene signatures to divide the IDH1 mutation glioma patients with different clinical features into various groups.	('glioma', 'Disease', (87, 93))	('mutation', 'Var', (78, 86))	('patients', 'Species', '9606', (94, 102))	('IDH1', 'Gene', '3417', (73, 77))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('IDH1', 'Gene', (73, 77))
213963	33229627	indicated that DZIP3 affects the developmental genes in mouse embryonic stem cells by reorganizing the 3D chromatin conformation, and knockdown of DZIP3 could result in an expansion of the mouse embryonic stem cells.	('result in', 'Reg', (159, 168))	('developmental genes', 'Gene', (33, 52))	('mouse', 'Species', '10090', (189, 194))	('mouse', 'Species', '10090', (56, 61))	('affects', 'Reg', (21, 28))	('knockdown', 'Var', (134, 143))	('DZIP3', 'Gene', (147, 152))	('mouse embryonic stem cells', 'CPA', (189, 215))	('expansion', 'PosReg', (172, 181))
213976	33229627	Based on the aforementioned results, DZIP3 affected the key biological functions to change the malignancy of glioma.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('change', 'Reg', (84, 90))	('malignancy of glioma', 'Phenotype', 'HP:0012174', (95, 115))	('malignancy of glioma', 'Disease', 'MESH:D005910', (95, 115))	('DZIP3', 'Var', (37, 42))	('malignancy of glioma', 'Disease', (95, 115))
213987	33229627	In lower-grade glioma, DZIP3 expression could predict the survival time in IDH1 mutant and IDH1 wild-type subgroups (Figure 5A-5D).	('mutant', 'Var', (80, 86))	('survival', 'CPA', (58, 66))	('IDH1', 'Gene', (91, 95))	('IDH1', 'Gene', (75, 79))	('glioma', 'Disease', (15, 21))	('predict', 'Reg', (46, 53))	('IDH1', 'Gene', '3417', (91, 95))	('IDH1', 'Gene', '3417', (75, 79))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
213988	33229627	IDH1 mutation was a key genetic event that mainly occurs in lower grade gliomas, while the IDH1 wild-type phenotype constituted the GBM group.	('occurs', 'Reg', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('IDH1', 'Gene', (91, 95))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (91, 95))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('GBM', 'Phenotype', 'HP:0012174', (132, 135))	('gliomas', 'Disease', (72, 79))	('IDH1', 'Gene', '3417', (0, 4))
213990	33229627	As shown in Figure 6A, DZIP3 classified IDH1 wild-type lower-grade glioma into GBM-like and IDH1 mutation lower grade-like groups with similar survival tendencies.	('lower', 'NegReg', (106, 111))	('IDH1', 'Gene', (40, 44))	('glioma', 'Disease', (67, 73))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (40, 44))	('IDH1', 'Gene', '3417', (92, 96))	('GBM', 'Phenotype', 'HP:0012174', (79, 82))	('mutation', 'Var', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
213991	33229627	Also, these results could be validated in GSE 16011 array cohort (Figure 6B), indicating that the introduction of DZIP3 could provide the basis for accurate diagnosis and treatment of glioma, especially lower-grade glioma.	('DZIP3', 'Gene', (114, 119))	('glioma', 'Disease', (184, 190))	('glioma', 'Disease', (215, 221))	('introduction', 'Var', (98, 110))	('glioma', 'Disease', 'MESH:D005910', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))
213997	33229627	The glioma patients with tumors carrying a mutation in IDH1 and chromosome 1p/19q co-deletion could have a prolonged survival.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('IDH1', 'Gene', '3417', (55, 59))	('mutation', 'Var', (43, 51))	('tumors', 'Disease', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('patients', 'Species', '9606', (11, 19))	('IDH1', 'Gene', (55, 59))	('glioma', 'Disease', (4, 10))
213998	33229627	indicated that IDH-mutated astrocytomas with 19q-loss constitute a subgroup with improved prognosis.	('19q-loss', 'Var', (45, 53))	('astrocytomas', 'Disease', 'MESH:D001254', (27, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (27, 38))	('astrocytomas', 'Disease', (27, 39))	('IDH', 'Gene', (15, 18))	('IDH', 'Gene', '3417', (15, 18))
214057	32922550	The disruption of CA4 may be associated with the perturbation of pH homeostasis in retina and correlated with retinitis pigmentosa.	('retinitis pigmentosa', 'Disease', (110, 130))	('correlated', 'Reg', (94, 104))	('pH homeostasis', 'MPA', (65, 79))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (110, 130))	('perturbation', 'MPA', (49, 61))	('retinitis', 'Phenotype', 'HP:0032118', (110, 119))	('associated', 'Reg', (29, 39))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (110, 130))	('disruption', 'Var', (4, 14))	('CA4', 'Gene', (18, 21))	('CA4', 'Gene', '762', (18, 21))
214088	32922550	Formalin-fixed, paraffin-embedded KIRC tissues and human renal tissues were stained for anti-CA4 using ab236315 (Abcam, USA) at 1/3000 dilution in Fudan University Shanghai Cancer Center (FUSCC) cohort, and then independently evaluated by two experienced pathologists.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', (173, 179))	('human', 'Species', '9606', (51, 56))	('ab236315', 'Var', (103, 111))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('CA4', 'Gene', (93, 96))	('CA4', 'Gene', '762', (93, 96))
214107	32922550	Remarkably, CA4 amplification was obviously related to better PFS (KIRC: hazard ratio [HR] = 0.661, p < 0.001; LGG: HR = 0.552, p = 0.002; LUAD: HR = 0.922, p = 0.020; UVM: HR = 0.454, p = 0.001) and better OS (KIRC: HR = 0.847, p < 0.001; LGG: HR = 0.552, p < 0.001; LUAD: HR = 0.918, p = 0.007; UVM: HR = 0.454, p < 0.001) in all of these four cancers.	('CA4', 'Gene', (12, 15))	('CA4', 'Gene', '762', (12, 15))	('UVM', 'Phenotype', 'HP:0007716', (297, 300))	('LUAD', 'Phenotype', 'HP:0030078', (268, 272))	('PFS', 'MPA', (62, 65))	('amplification', 'Var', (16, 29))	('cancers', 'Disease', 'MESH:D009369', (346, 353))	('cancers', 'Phenotype', 'HP:0002664', (346, 353))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('cancers', 'Disease', (346, 353))	('better', 'PosReg', (55, 61))	('UVM', 'Phenotype', 'HP:0007716', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))
214114	32922550	Notably, CA4 amplification obviously correlated with better PFS in KIRC, LGG and LUAD (KIRC: HR = 0.749, p = 0.003; LGG: HR = 0.585, p = 0.005; LUAD: HR = 0.927, p = 0.029) and better OS in KIRC, LGG and UVM (KIRC: HR = 0.900, p = 0.022; LGG: HR = 0.655, p = 0.029; UVM: HR = 0.689, p = 0.005).	('PFS', 'MPA', (60, 63))	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('CA4', 'Gene', (9, 12))	('CA4', 'Gene', '762', (9, 12))	('UVM', 'Phenotype', 'HP:0007716', (266, 269))	('UVM', 'Phenotype', 'HP:0007716', (204, 207))	('amplification', 'Var', (13, 26))	('better', 'PosReg', (53, 59))
214138	32922550	Compared with low or no protein expression, high expression of CA2 is related to better survival outcomes, suggesting that CA2 can be a potential marker for this interstitial tumor diagnosis.	('survival', 'CPA', (88, 96))	('tumor', 'Disease', (175, 180))	('high', 'Var', (44, 48))	('better', 'PosReg', (81, 87))	('CA2', 'Gene', (123, 126))	('CA2', 'Gene', '760', (123, 126))	('CA2', 'Gene', (63, 66))	('CA2', 'Gene', '760', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
214189	31924170	In terms of biological validation, 74.5% of studies related radiomics features to biological correlates, such as the molecular subtype of IDH mutation or MGMT methylation status, while 62.7% of studies performed multivariate analysis using both radiomics and non-radiomic features.	('mutation', 'Var', (142, 150))	('MGMT', 'Gene', (154, 158))	('IDH', 'Gene', (138, 141))	('MGMT', 'Gene', '4255', (154, 158))
214228	29725063	Kaplan-Meier survival analysis revealed that glioma patients with higher ACTL6A expression had worse outcome (median survival, 17 months vs. 11 months; high ACTL6A expression and those with low; Fig.	('ACTL6A', 'Gene', (73, 79))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('ACTL6A', 'Gene', (157, 163))	('higher', 'PosReg', (66, 72))	('expression', 'MPA', (80, 90))	('high', 'Var', (152, 156))	('glioma', 'Disease', (45, 51))	('patients', 'Species', '9606', (52, 60))
214232	29725063	2a,b), and the expression construct led to significant increases in ACTL6A protein and RNA levels in U87MG (Fig.	('U87MG', 'Var', (101, 106))	('ACTL6A protein', 'Protein', (68, 82))	('increases', 'PosReg', (55, 64))	('RNA levels', 'MPA', (87, 97))	('U87MG', 'CellLine', 'CVCL:0022', (101, 106))
214233	29725063	Growth curves based on the Cell Counting Kit-8 (CCK-8) assay demonstrated that ACTL6A knockdown significantly decreased cell growth in A172 and U251 cells, whereas ACTL6A overexpression enhanced cell growth in U87MG cells (Figs.	('ACTL6A', 'Gene', (79, 85))	('knockdown', 'Var', (86, 95))	('decreased', 'NegReg', (110, 119))	('cell growth', 'CPA', (120, 131))	('U87MG', 'CellLine', 'CVCL:0022', (210, 215))
214234	29725063	Interestingly, ACTL6A knockdown also markedly decreased migration and invasion in A172 and U251 cells, whereas U87MG-ACTL6A exhibited enhanced migration and invasion (Figs.	('migration', 'CPA', (56, 65))	('enhanced', 'PosReg', (134, 142))	('invasion', 'CPA', (157, 165))	('ACTL6A', 'Gene', (15, 21))	('knockdown', 'Var', (22, 31))	('decreased', 'NegReg', (46, 55))	('migration', 'CPA', (143, 152))	('invasion', 'CPA', (70, 78))	('U87MG-ACTL6A', 'Var', (111, 123))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (111, 123))
214237	29725063	Xenografts from animals implanted with U251-sh-ACTL6A appeared to be more circumscribed and less invasive than tumors that developed from control U251-NC cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('U251-sh-ACTL6A', 'Var', (39, 53))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))
214238	29725063	In addition, xenografts from animals implanted with U87MG-ACTL6A appeared to be more invasive than tumors that developed from control U87MG-NC cells (Fig.	('U87MG-NC', 'CellLine', 'CVCL:0022', (134, 142))	('invasive', 'CPA', (85, 93))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('U87MG-ACTL6A', 'Var', (52, 64))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (52, 64))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
214239	29725063	Overall survival of animals implanted with U87MG-ACTL6A was decreased (median survival, 30 days vs. 24 days; U87MG-NC and U87MG-ACTL6A, respectively; Fig.	('U87MG-NC', 'CellLine', 'CVCL:0022', (109, 117))	('decreased', 'NegReg', (60, 69))	('U87MG-ACTL6A', 'Var', (43, 55))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (43, 55))	('U87MG-ACTL6A', 'Var', (122, 134))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (122, 134))	('U87MG-NC', 'Var', (109, 117))
214245	29725063	YAP/TAZ and downstream genes were reduced in A172- and U251-sh-ACTL6A cells, and increased in U87MG-ACTL6A cells (Fig.	('U251-sh-ACTL6A', 'Var', (55, 69))	('reduced', 'NegReg', (34, 41))	('U87MG-ACTL6A', 'Var', (94, 106))	('YAP', 'Gene', (0, 3))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (94, 106))	('YAP', 'Gene', '10413', (0, 3))	('increased', 'PosReg', (81, 90))	('A172-', 'Var', (45, 50))
214247	29725063	Based on qRT-PCR, mRNA levels of CTGF and CYR61 correlated with knockdown or overexpression of ACTL6A in these glioma cell lines (Fig.	('glioma', 'Disease', (111, 117))	('mRNA levels', 'MPA', (18, 29))	('overexpression', 'PosReg', (77, 91))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('CTGF', 'Gene', '1490', (33, 37))	('ACTL6A', 'Gene', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('CTGF', 'Gene', (33, 37))	('knockdown', 'Var', (64, 73))	('CYR61', 'Gene', (42, 47))	('CYR61', 'Gene', '3491', (42, 47))
214251	29725063	Interestingly, we found that phosphorylation of YAP on Ser-127 was reduced in A172- and U251- sh-ACTL6A cells, but relatively unchanged from controls in U87MG-ACTL6A cells (Fig.	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (153, 165))	('Ser', 'Chemical', 'MESH:D012694', (55, 58))	('YAP', 'Gene', (48, 51))	('A172-', 'Var', (78, 83))	('reduced', 'NegReg', (67, 74))	('U251- sh-ACTL6A', 'Var', (88, 103))	('YAP', 'Gene', '10413', (48, 51))	('phosphorylation', 'MPA', (29, 44))
214252	29725063	However, the ratio of p-YAP(S127) to total YAP was increased in A172- and U251- sh-ACTL6A cells, while decreased in U87MG-ACTL6A cells (Supplementary Figure S1b).	('YAP', 'Gene', (24, 27))	('increased', 'PosReg', (51, 60))	('YAP', 'Gene', '10413', (43, 46))	('decreased', 'NegReg', (103, 112))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (116, 128))	('YAP', 'Gene', '10413', (24, 27))	('YAP', 'Gene', (43, 46))	('U251- sh-ACTL6A', 'Var', (74, 89))
214254	29725063	In A172- and U251-sh-ACTL6A cells, YAP/TAZ levels were decreased in both the cytoplasm and nucleus compared with controls, but were significantly upregulated in both cellular locations in U87MG-ACTL6A.	('U251-sh-ACTL6A', 'Var', (13, 27))	('YAP', 'Gene', (35, 38))	('YAP', 'Gene', '10413', (35, 38))	('U87MG-ACTL6A', 'Var', (188, 200))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (188, 200))	('decreased', 'NegReg', (55, 64))	('upregulated', 'PosReg', (146, 157))	('A172-', 'Var', (3, 8))
214258	29725063	However, YAP/TAZ mRNA levels was not significantly different in A172- and U251-shACTL6A or U87MG-ACTL6A cells compared with control cells (Fig.	('U87MG-ACTL6A', 'Var', (91, 103))	('U251-shACTL6A', 'Var', (74, 87))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (91, 103))	('YAP', 'Gene', '10413', (9, 12))	('YAP', 'Gene', (9, 12))	('A172-', 'Var', (64, 69))
214261	29725063	We found that MG132 partially reversed the downregulation of YAP/TAZ protein in A172- and U251-shACTL6A (Fig.	('downregulation', 'NegReg', (43, 57))	('MG132', 'Var', (14, 19))	('MG132', 'Chemical', 'MESH:C072553', (14, 19))	('U251-shACTL6A', 'Var', (90, 103))	('YAP', 'Gene', '10413', (61, 64))	('YAP', 'Gene', (61, 64))
214264	29725063	Under ectopic expression of ACTL6A, the half-life of YAP/TAZ was extended from ~ 5 h in control cells to > 6 h in U87MG-ACTL6A (Fig.	('extended', 'PosReg', (65, 73))	('YAP', 'Gene', '10413', (53, 56))	('half-life', 'MPA', (40, 49))	('YAP', 'Gene', (53, 56))	('U87MG-ACTL6A', 'Var', (114, 126))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (114, 126))	('ACTL6A', 'Gene', (28, 34))
214265	29725063	Finally, endogenous YAP/TAZ ubiquitination was increased in U251-sh-ACTL6A cells, whereas decreased in U87MG-ACTL6A and HEK293 cells when co-transfected with ACTL6A (Fig.	('YAP', 'Gene', (20, 23))	('HEK293', 'CellLine', 'CVCL:0045', (120, 126))	('decreased', 'NegReg', (90, 99))	('increased', 'PosReg', (47, 56))	('U251-sh-ACTL6A', 'Var', (60, 74))	('YAP', 'Gene', '10413', (20, 23))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (103, 115))
214266	29725063	To rule out potential nonspecific immunoprecipitated smears, we used short hairpin RNAs (shRNAs) to knock down YAP/TAZ in U87MG cells and polyubiquitination levels of YAP/TAZ were evaluated (Supplementary Figure S6).	('YAP', 'Gene', '10413', (111, 114))	('U87MG', 'CellLine', 'CVCL:0022', (122, 127))	('YAP', 'Gene', (111, 114))	('YAP', 'Gene', '10413', (167, 170))	('YAP', 'Gene', (167, 170))	('polyubiquitination', 'MPA', (138, 156))	('knock down', 'Var', (100, 110))
214275	29725063	Meanwhile, beta-TrCP recognizes two different sites on the N-terminal (serine 58) or C-terminal (serine 314) region of TAZ when they are phosphorylated by glycogen synthase kinase 3 (GSK3) or CK1/LATS, respectively.	('CK1', 'Species', '2498238', (192, 195))	('beta-TrCP', 'Gene', (11, 20))	('beta-TrCP', 'Gene', '8945', (11, 20))	('serine 314', 'Var', (97, 107))	('serine', 'Chemical', 'MESH:D012694', (97, 103))	('serine', 'Chemical', 'MESH:D012694', (71, 77))
214284	29725063	To determine the functional role of YAP/TAZ proteins in the ACTL6A pathway in glioma, shRNAs targeting YAP/TAZ were co-transfected into U87MG-ACTL6A cells, and active forms of YAP (YAP-5SA) and TAZ (TAZ-4SA) were co-transfected into U251-sh-ACTL6A cells, which are constitutively active due to mutations in the inhibitory Lats phosphorylation sites.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('YAP', 'Gene', '10413', (103, 106))	('YAP', 'Gene', '10413', (176, 179))	('YAP', 'Gene', (181, 184))	('YAP', 'Gene', '10413', (36, 39))	('YAP', 'Gene', (103, 106))	('YAP', 'Gene', (36, 39))	('YAP', 'Gene', (176, 179))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (136, 148))	('glioma', 'Disease', (78, 84))	('mutations', 'Var', (294, 303))	('YAP', 'Gene', '10413', (181, 184))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
214286	29725063	Knockdown of YAP/TAZ decreased CTGF and CYR61 expression, and had no significant effect on ACTL6A expression, whereas ectopic expression of YAP-5SA/TAZ-4SA in U251-sh-ACTL6A cells restored the poor CTGF and CYR61 expression due to ACTL6A knockdown (Fig.	('knockdown', 'Var', (238, 247))	('CYR61', 'Gene', '3491', (40, 45))	('CTGF', 'Gene', '1490', (31, 35))	('decreased', 'NegReg', (21, 30))	('CYR61', 'Gene', (207, 212))	('CTGF', 'Gene', (31, 35))	('ACTL6A', 'Gene', (231, 237))	('CTGF', 'Gene', '1490', (198, 202))	('CYR61', 'Gene', (40, 45))	('YAP', 'Gene', '10413', (13, 16))	('CYR61', 'Gene', '3491', (207, 212))	('YAP', 'Gene', '10413', (140, 143))	('CTGF', 'Gene', (198, 202))	('YAP', 'Gene', (13, 16))	('YAP', 'Gene', (140, 143))
214287	29725063	Besides, the effects of ACTL6A knockdown on U251 cells could also be rescued by knockdown of beta-TrCP (Supplementary Figure S7).	('beta-TrCP', 'Gene', '8945', (93, 102))	('knockdown', 'Var', (80, 89))	('beta-TrCP', 'Gene', (93, 102))	('ACTL6A', 'Gene', (24, 30))
214288	29725063	Furthermore, ACTL6A-enhanced YAP/TAZ reporter activity was abrogated by YAP/TAZ knockdown, whereas YAP-5SA/TAZ-4SA rescued the effect of ACTL6A depletion (Supplementary Figure S4b).	('YAP', 'Gene', '10413', (72, 75))	('knockdown', 'Var', (80, 89))	('YAP', 'Gene', '10413', (29, 32))	('YAP', 'Gene', '10413', (99, 102))	('YAP', 'Gene', (72, 75))	('YAP', 'Gene', (29, 32))	('YAP', 'Gene', (99, 102))	('abrogated', 'NegReg', (59, 68))	('ACTL6A-enhanced', 'PosReg', (13, 28))	('ACTL6A-enhanced', 'Gene', (13, 28))
214311	29725063	In contrast, depletion of ACTL6A significantly decreased YAP/TAZ levels and expression of their target genes.	('depletion', 'Var', (13, 22))	('ACTL6A', 'Gene', (26, 32))	('YAP', 'Gene', '10413', (57, 60))	('expression', 'MPA', (76, 86))	('YAP', 'Gene', (57, 60))	('decreased', 'NegReg', (47, 56))
214315	29725063	Here we demonstrated that ACTL6A prevents YAP/TAZ from ubiquitination and prolongs the protein's half-life.	('ACTL6A', 'Var', (26, 32))	('prevents', 'NegReg', (33, 41))	('prolongs', 'NegReg', (74, 82))	('YAP', 'Gene', (42, 45))	('half-life', 'MPA', (97, 106))	('ubiquitination', 'MPA', (55, 69))	('YAP', 'Gene', '10413', (42, 45))
214321	29725063	However, we also demonstrated that ACTL6A-mediated glioma cell proliferation, migration, and invasion could be partially reversed by YAP/TAZ knockdown or ectopic expression, indicating that YAP/TAZ is not a unique downstream effector of ACTL6A in glioma cells.	('knockdown', 'Var', (141, 150))	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('glioma', 'Disease', (51, 57))	('invasion', 'CPA', (93, 101))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('YAP', 'Gene', '10413', (190, 193))	('YAP', 'Gene', '10413', (133, 136))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('ectopic expression', 'Var', (154, 172))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('YAP', 'Gene', (190, 193))	('migration', 'CPA', (78, 87))	('ACTL6A-mediated', 'Gene', (35, 50))	('glioma', 'Disease', (247, 253))	('YAP', 'Gene', (133, 136))
214325	29725063	Functional studies demonstrated that ACTL6A overexpression promotes cellular proliferation, migration, and invasion in vitro and in vivo, possibly through the direct interaction and stabilization of transcriptional regulator YAP/TAZ.	('YAP', 'Gene', '10413', (225, 228))	('ACTL6A', 'Gene', (37, 43))	('cellular proliferation', 'CPA', (68, 90))	('interaction', 'Interaction', (166, 177))	('promotes', 'PosReg', (59, 67))	('migration', 'CPA', (92, 101))	('YAP', 'Gene', (225, 228))	('invasion', 'CPA', (107, 115))	('overexpression', 'Var', (44, 58))
214332	29725063	The plasmids used were: pcDNA3.1-ACTL6A-3xFlag, pcDNA3.1-HA-UBB, pcDNA3.1-HA-YAP-wt, pcDNA3.1-HA-YAP-NT, pcDNA3.1-HA-YAP-CT, pcDNA3.1-HA-YAP-S127A, pcDNA3.1-HA-YAP-S400/403A, pcDNA3.1-HA-YAP-3SA, pcDNA3.1-HA-YAP-5SA (S61A, S109A, S127A, S164A, S397A), and pcDNA3.1-HA-TAZ-4SA (S66A, S89A, S117A, S311A) (OBiO Technology, Shanghai, China), pGL3-Control Vector (Promega, Madison, WI, USA), pGL4-SV40 Driven Renilla Luciferase Vector (Promega), and 8xGTIIC-luciferase (Addgene, Cambridge, MA, USA).	('pGL3', 'Gene', '6391', (339, 343))	('pGL4', 'Gene', '6390', (388, 392))	('YAP', 'Gene', '10413', (137, 140))	('YAP', 'Gene', (77, 80))	('S164A', 'Mutation', 'p.S164A', (237, 242))	('YAP', 'Gene', '10413', (97, 100))	('YAP', 'Gene', '10413', (208, 211))	('pGL4', 'Gene', (388, 392))	('YAP', 'Gene', (117, 120))	('YAP', 'Gene', '10413', (160, 163))	('S66A', 'Var', (277, 281))	('YAP', 'Gene', (187, 190))	('S127A', 'Mutation', 'rs762471803', (230, 235))	('S117A', 'Mutation', 'rs142405250', (289, 294))	('YAP', 'Gene', '10413', (77, 80))	('S109A', 'Mutation', 'p.S109A', (223, 228))	('YAP', 'Gene', (137, 140))	('S89A', 'Mutation', 'p.S89A', (283, 287))	('YAP', 'Gene', '10413', (117, 120))	('YAP', 'Gene', '10413', (187, 190))	('S397A', 'Mutation', 'p.S397A', (244, 249))	('S61A', 'Mutation', 'p.S61A', (217, 221))	('YAP', 'Gene', (97, 100))	('YAP', 'Gene', (160, 163))	('YAP', 'Gene', (208, 211))	('S66A', 'Mutation', 'p.S66A', (277, 281))	('S127A', 'Mutation', 'rs762471803', (141, 146))	('pGL3', 'Gene', (339, 343))	('S311A', 'Mutation', 'p.S311A', (296, 301))
214356	29725063	Animals were divided into four groups (eight mice per group) and inoculated into the frontal lobe using a stereotactic apparatus (KDS310, KD Scientific, Holliston, MA, USA) with one of the following cell populations (1 x 106 cells): U251-NC, U251-shACTL6A, U87MG-NC, and U87MG-ACTL6A.	('U87MG-NC', 'Var', (257, 265))	('mice', 'Species', '10090', (45, 49))	('U251-shACTL6A', 'Var', (242, 255))	('U87MG-NC', 'CellLine', 'CVCL:0022', (257, 265))	('U251-NC', 'Var', (233, 240))	('U87MG-ACTL6A', 'Var', (271, 283))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (271, 283))
214358	29725063	Excised tumor tissues were further examined through hemtoxylin and eosin, and IHC staining For subcutaneous glioma model, nude mice (n = 40) were divided into eight groups (U87MG-NC, U87MG-ACTL6A, U87MG-ACTL6A + shcontrol, U87MG-ACTL6A + shYAP/TAZ, U251-NC, U251-sh-ACTL6A, U251-sh-ACTL6A + control, and U251-sh-ACTL6A + YAP-5SA/TAZ-4SA, five mice per group).	('glioma', 'Disease', (108, 114))	('hemtoxylin', 'Chemical', '-', (52, 62))	('U87MG-ACTL6A +', 'Var', (223, 237))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('YAP', 'Gene', '10413', (240, 243))	('U87MG-ACTL6A', 'Var', (183, 195))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (183, 195))	('U251-sh-ACTL6A +', 'Var', (304, 320))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('YAP', 'Gene', (321, 324))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (223, 235))	('mice', 'Species', '10090', (343, 347))	('U87MG-ACTL6A', 'CellLine', 'CVCL:0022', (197, 209))	('tumor', 'Disease', (8, 13))	('eosin', 'Chemical', 'MESH:D004801', (67, 72))	('U87MG-ACTL6A + shcontrol', 'Var', (197, 221))	('mice', 'Species', '10090', (127, 131))	('U87MG-NC', 'CellLine', 'CVCL:0022', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('YAP', 'Gene', '10413', (321, 324))	('YAP', 'Gene', (240, 243))	('nude mice', 'Species', '10090', (122, 131))
214364	28392842	LGGs are further divided into isocitrate dehydrogenase (IDH) wild type or mutant, which is further classified into either oligodendroglioma that harbors 1p/19q codeletion or diffuse astrocytoma that has an intact 1p/19q loci but enriched for ATRX loss and TP53 mutation.	('oligodendroglioma', 'Disease', 'MESH:D009837', (122, 139))	('diffuse astrocytoma', 'Disease', (174, 193))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('ATRX', 'Gene', '546', (242, 246))	('isocitrate dehydrogenase', 'Gene', (30, 54))	('IDH', 'Gene', (56, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (182, 193))	('TP53', 'Gene', (256, 260))	('mutation', 'Var', (261, 269))	('IDH', 'Gene', '3417', (56, 59))	('isocitrate dehydrogenase', 'Gene', '3417', (30, 54))	('1p/19q codeletion', 'Var', (153, 170))	('TP53', 'Gene', '7157', (256, 260))	('loss', 'NegReg', (247, 251))	('ATRX', 'Gene', (242, 246))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (174, 193))	('oligodendroglioma', 'Disease', (122, 139))
214367	28392842	In this study, we applied PAM on a training set of diffuse gliomas derived from The Cancer Genome Atlas (TCGA) and identified DNA methylation signatures to classify LGG IDH wild type from LGG IDH mutant, LGG IDH mutant with 1p/19q codeletion from LGG IDH mutant with intact 1p/19q loci and GBM IDH wild type from GBM IDH mutant with an accuracy of 99-100%.	('IDH', 'Gene', (208, 211))	('IDH', 'Gene', '3417', (169, 172))	('gliomas', 'Disease', (59, 66))	('IDH', 'Gene', (294, 297))	('GBM', 'Phenotype', 'HP:0012174', (290, 293))	('1p/19q codeletion', 'Var', (224, 241))	('IDH', 'Gene', '3417', (192, 195))	('IDH', 'Gene', (317, 320))	('PAM', 'Chemical', '-', (26, 29))	('GBM', 'Phenotype', 'HP:0012174', (313, 316))	('IDH', 'Gene', '3417', (208, 211))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('IDH', 'Gene', (251, 254))	('IDH', 'Gene', '3417', (294, 297))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (84, 103))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('IDH', 'Gene', '3417', (317, 320))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutant', 'Var', (196, 202))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('Cancer Genome Atlas', 'Disease', (84, 103))	('IDH', 'Gene', '3417', (251, 254))	('IDH', 'Gene', (169, 172))	('IDH', 'Gene', (192, 195))
214378	28392842	One of the most exciting and clinically relevant observations was the discovery that a high percentage of grade II/III and grade IV secondary glioblastoma harbor mutations in the genes isocitrate dehydrogenase 1 and 2.	('mutations', 'Var', (162, 171))	('isocitrate dehydrogenase 1', 'Gene', (185, 211))	('isocitrate dehydrogenase 1', 'Gene', '3417', (185, 211))	('glioblastoma', 'Disease', (142, 154))	('glioblastoma', 'Disease', 'MESH:D005909', (142, 154))	('grade II/III', 'Disease', (106, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
214379	28392842	Growing data indicate that these mutations play a causal role in gliomagenesis, have a major impact on tumor biology, and also have clinical and prognostic importance.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('glioma', 'Disease', (65, 71))	('causal role', 'Reg', (50, 61))	('tumor', 'Disease', (103, 108))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('mutations', 'Var', (33, 42))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('impact', 'Reg', (93, 99))
214380	28392842	Nearly 12% of GBM patients have been identified to have point mutation in codon 132 (R132H) of the isocitrate dehydrogenase 1 (IDH1) gene located in the chromosome locus 2q33.	('point mutation in', 'Var', (56, 73))	('R132H', 'Mutation', 'rs121913500', (85, 90))	('GBM', 'Disease', (14, 17))	('isocitrate dehydrogenase 1', 'Gene', (99, 125))	('IDH1', 'Gene', (127, 131))	('isocitrate dehydrogenase 1', 'Gene', '3417', (99, 125))	('GBM', 'Phenotype', 'HP:0012174', (14, 17))	('IDH1', 'Gene', '3417', (127, 131))	('patients', 'Species', '9606', (18, 26))	('R132H', 'Var', (85, 90))
214382	28392842	Several studies showed that the IDH1 mutation is inversely associated with grade in diffuse glial tumors, affecting 71% of grade II, 64% of grade III, and 6% of primary glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (169, 182))	('glioblastomas', 'Phenotype', 'HP:0012174', (169, 182))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('affecting', 'Reg', (106, 115))	('mutation', 'Var', (37, 45))	('glioblastomas', 'Disease', (169, 182))	('IDH1', 'Gene', (32, 36))	('glial tumors', 'Disease', (92, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('IDH1', 'Gene', '3417', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glial tumors', 'Disease', 'MESH:D005910', (92, 104))	('grade', 'Disease', (75, 80))
214383	28392842	Interestingly, IDH mutation is found to be present in the secondary glioblastoma (76%) probably because these tumors have been derived from the lower grade gliomas.	('mutation', 'Var', (19, 27))	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('IDH', 'Gene', (15, 18))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('IDH', 'Gene', '3417', (15, 18))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
214385	28392842	IDH mutation has been shown to be associated with alterations in the methylome thus being sufficient to establish glioma hypermethylator phenotype.	('IDH', 'Gene', (0, 3))	('methylome', 'MPA', (69, 78))	('glioma', 'Disease', (114, 120))	('IDH', 'Gene', '3417', (0, 3))	('mutation', 'Var', (4, 12))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))
214388	28392842	The LGG IDH mutant subtype is further classified based on the codeletion of 1p/19q where LGG IDH mutant patients harboring 1p/19q codeletion is termed as oligodendrogliomas (ODG) while LGG IDH mutant patients having intact 1p/19q loci are termed as diffuse astrocytoma which may be enriched in TP53 mutation/ATRX loss.	('IDH', 'Gene', (8, 11))	('astrocytoma', 'Phenotype', 'HP:0009592', (257, 268))	('ATRX', 'Gene', '546', (308, 312))	('TP53', 'Gene', '7157', (294, 298))	('oligodendrogliomas', 'Disease', (154, 172))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('mutant', 'Var', (97, 103))	('IDH', 'Gene', '3417', (8, 11))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('IDH', 'Gene', (189, 192))	('IDH', 'Gene', (93, 96))	('TP53', 'Gene', (294, 298))	('patients', 'Species', '9606', (104, 112))	('diffuse astrocytoma', 'Disease', (249, 268))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (154, 172))	('patients', 'Species', '9606', (200, 208))	('IDH', 'Gene', '3417', (189, 192))	('IDH', 'Gene', '3417', (93, 96))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (249, 268))	('ATRX', 'Gene', (308, 312))
214396	28392842	The methylation signatures were developed to distinguish LGG IDH mutant from LGG IDH WT, LGG IDH mutant with 1p/19q codeletion (oligodendroglioma) from LGG IDH mutant with intact 1p/19q loci (diffuse astrocytoma) and GBM IDH mutant (progressive GBM) from GBM IDH WT (de novo GBM).	('IDH', 'Gene', '3417', (61, 64))	('oligodendroglioma', 'Disease', 'MESH:D009837', (128, 145))	('GBM', 'Phenotype', 'HP:0012174', (275, 278))	('astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('IDH', 'Gene', '3417', (81, 84))	('1p/19q', 'Var', (109, 115))	('oligodendroglioma', 'Disease', (128, 145))	('mutant', 'Var', (65, 71))	('mutant', 'Var', (97, 103))	('IDH', 'Gene', (221, 224))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IDH', 'Gene', '3417', (156, 159))	('GBM', 'Phenotype', 'HP:0012174', (245, 248))	('IDH', 'Gene', (93, 96))	('IDH', 'Gene', (156, 159))	('GBM', 'Phenotype', 'HP:0012174', (255, 258))	('GBM', 'Phenotype', 'HP:0012174', (217, 220))	('IDH', 'Gene', (259, 262))	('IDH', 'Gene', '3417', (221, 224))	('IDH', 'Gene', (61, 64))	('diffuse astrocytoma', 'Disease', (192, 211))	('IDH', 'Gene', '3417', (93, 96))	('IDH', 'Gene', (81, 84))	('IDH', 'Gene', '3417', (259, 262))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (192, 211))
214403	28392842	Prediction accuracy estimation by 10-fold cross-validation using PAM showed that the 14 CpG probe methylation signatures predicted all LGG IDH mutant samples accurately with no error (Fig.	('mutant', 'Var', (143, 149))	('LGG', 'Gene', (135, 138))	('PAM', 'Chemical', '-', (65, 68))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (139, 142))
214405	28392842	Thus, the 14 CpG DNA methylation signatures were able to discriminate LGG IDH mutant from LGG IDH WT with an overall classification accuracy of 100%.	('IDH', 'Gene', (94, 97))	('IDH', 'Gene', '3417', (94, 97))	('IDH', 'Gene', (74, 77))	('IDH', 'Gene', '3417', (74, 77))	('discriminate', 'Reg', (57, 69))	('mutant', 'Var', (78, 84))
214407	28392842	The 14 discriminatory probes were observed to be differentially methylated between LGG IDH mutant and LGG IDH WT in the test set also (Additional file 2: Figure S3A and Additional file 1: Table S3A).	('IDH', 'Gene', '3417', (106, 109))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (87, 90))	('mutant', 'Var', (91, 97))	('IDH', 'Gene', (106, 109))
214409	28392842	Prediction accuracy estimation by 10-fold cross-validation using PAM showed that the 14 CpG probe methylation signatures predicted all IDH mutant LGG samples accurately except one with an error rate of 0.004 (Additional file 2: Figure S3C).	('IDH', 'Gene', (135, 138))	('PAM', 'Chemical', '-', (65, 68))	('IDH', 'Gene', '3417', (135, 138))	('mutant', 'Var', (139, 145))
214411	28392842	Thus, the 14 CpG methylation signatures were able to discriminate between IDH mutant and WT LGG samples with an overall diagnostic accuracy of 99.62% in the test set.	('IDH', 'Gene', '3417', (74, 77))	('IDH', 'Gene', (74, 77))	('mutant', 'Var', (78, 84))
214414	28392842	Similarly, the 14 CpG methylation signatures were able to discriminate IDH mutant from WT LGG samples with an overall diagnostic accuracy of 85.8% in GSE48462 (Table 2; Additional file 1: Table S3A; Additional file 2: Figure S5A, B, and C).	('discriminate', 'Reg', (58, 70))	('GSE48462', 'Var', (150, 158))	('IDH', 'Gene', (71, 74))	('mutant', 'Var', (75, 81))	('IDH', 'Gene', '3417', (71, 74))
214415	28392842	Thus, from these experiments, we conclude that the 14 CpG methylation signatures developed as above distinguished LGG IDH mutant from WT samples with high accuracy.	('mutant', 'Var', (122, 128))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (118, 121))
214416	28392842	PAM analysis of differentially methylated CpGs (Additional file 1: Table S4) on the training (TCGA) set (Additional file 1: Table S1) identified a set of 14 CpGs to distinguish IDH mutant with 1p/19q codeletion (designated as oligodendroglioma) from LGG IDH mutant with intact 1p/19q loci (designated as diffuse astrocytoma) at a threshold value of 9.491 with minimal error (Fig.	('diffuse astrocytoma', 'Disease', (304, 323))	('astrocytoma', 'Phenotype', 'HP:0009592', (312, 323))	('IDH', 'Gene', (254, 257))	('oligodendroglioma', 'Disease', 'MESH:D009837', (226, 243))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('IDH', 'Gene', '3417', (254, 257))	('IDH', 'Gene', (177, 180))	('PAM', 'Chemical', '-', (0, 3))	('IDH', 'Gene', '3417', (177, 180))	('1p/19q codeletion', 'Var', (193, 210))	('oligodendroglioma', 'Disease', (226, 243))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (304, 323))
214420	28392842	Thus, the 14 CpG DNA methylation signatures were able to discriminate oligodendroglioma from diffuse astrocytoma with an overall diagnostic accuracy of 99.07%.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('oligodendroglioma', 'Disease', (70, 87))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (93, 112))	('diffuse astrocytoma', 'Disease', (93, 112))	('oligodendroglioma', 'Disease', 'MESH:D009837', (70, 87))	('methylation', 'Var', (21, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))
214422	28392842	The 14 discriminatory probes were observed to be differentially methylated between oligodendrogliomas and diffused astrocytoma similar to as seen in the training set (Additional file 2: Figure S6A and Additional file 1: Table S3B).	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('methylated', 'Var', (64, 74))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (83, 101))	('astrocytoma', 'Disease', 'MESH:D001254', (115, 126))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('astrocytoma', 'Disease', (115, 126))	('oligodendrogliomas', 'Disease', (83, 101))	('astrocytoma', 'Phenotype', 'HP:0009592', (115, 126))
214426	28392842	Thus, the 14 CpG methylation signatures were able to discriminate between oligodendroglioma and diffused astrocytoma samples with an overall diagnostic accuracy of 96.29% in the test set.	('methylation', 'Var', (17, 28))	('oligodendroglioma', 'Disease', (74, 91))	('astrocytoma', 'Disease', 'MESH:D001254', (105, 116))	('discriminate', 'Reg', (53, 65))	('oligodendroglioma', 'Disease', 'MESH:D009837', (74, 91))	('astrocytoma', 'Disease', (105, 116))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
214428	28392842	The 14 CpG methylation signatures, as identified in the training set and validated in the test set, were also used to classify the entire TCGA LGG IDH mutant samples into oligodendroglioma and diffuse astrocytoma samples.	('IDH', 'Gene', '3417', (147, 150))	('mutant', 'Var', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('diffuse astrocytoma', 'Disease', (193, 212))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (193, 212))	('astrocytoma', 'Phenotype', 'HP:0009592', (201, 212))	('oligodendroglioma', 'Disease', (171, 188))	('IDH', 'Gene', (147, 150))	('oligodendroglioma', 'Disease', 'MESH:D009837', (171, 188))
214429	28392842	In addition, we have also carried out additional validation of 14 CpG methylation signatures to distinguish oligodenroglioma from diffuse astrocytoma using two independent external LGG cohorts (GSE58218 and GSE48462).	('GSE58218', 'Var', (194, 202))	('GSE48462', 'Var', (207, 215))	('oligodenroglioma', 'Disease', (108, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (138, 149))	('oligodenroglioma', 'Disease', 'None', (108, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (130, 149))	('diffuse astrocytoma', 'Disease', (130, 149))
214431	28392842	Similarly, the 14 CpG methylation signatures were also able to discriminate oligodenroglioma from diffuse astrocytoma samples with an overall diagnostic accuracy of 78.57% in GSE48462 (Table 2; Additional file 1: Table S3B; Additional file 2: Figure S8A, B and C).	('diffuse astrocytoma', 'Disease', (98, 117))	('discriminate', 'Reg', (63, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (106, 117))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('GSE48462', 'Var', (175, 183))	('oligodenroglioma', 'Disease', (76, 92))	('oligodenroglioma', 'Disease', 'None', (76, 92))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (98, 117))
214433	28392842	PAM analysis of differentially methylated CpGs (Additional file 1: Table S5) in the training (TCGA) set (Additional file 1: Table S1) identified a set of 13 CpGs to distinguish GBM IDH mutant from IDH WT samples at a threshold value of 2.694 with no error (Fig.	('IDH', 'Gene', (181, 184))	('mutant', 'Var', (185, 191))	('IDH', 'Gene', '3417', (181, 184))	('PAM', 'Chemical', '-', (0, 3))	('IDH', 'Gene', (197, 200))	('IDH', 'Gene', '3417', (197, 200))	('GBM', 'Phenotype', 'HP:0012174', (177, 180))
214434	28392842	The CpG probes of the signature were found to be hypermethylated in IDH mutant GBMs compared to IDH WT GBMs (Fig.	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', '3417', (96, 99))	('mutant', 'Var', (72, 78))	('hypermethylated', 'PosReg', (49, 64))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('GBM', 'Phenotype', 'HP:0012174', (79, 82))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', (96, 99))
214438	28392842	Thus, the 13 CpG DNA methylation signatures were able to discriminate GBM IDH mutant from GBM IDH WT with an overall classification accuracy of 100%.	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('IDH', 'Gene', (94, 97))	('IDH', 'Gene', '3417', (94, 97))	('IDH', 'Gene', (74, 77))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('IDH', 'Gene', '3417', (74, 77))	('discriminate', 'Reg', (57, 69))	('mutant', 'Var', (78, 84))
214440	28392842	The 13 discriminatory probes were observed to be differentially methylated between GBM IDH mutant and GBM IDH WT in the test set also (Additional file 2: Figure S9A and Additional file 1: Table S3C).	('IDH', 'Gene', '3417', (106, 109))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('mutant', 'Var', (91, 97))	('IDH', 'Gene', (106, 109))
214444	28392842	Thus, the 13 CpG methylation signatures were able to discriminate IDH mutant from WT GBM samples with an overall diagnostic accuracy of 98.36% in the test set.	('IDH', 'Gene', (66, 69))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('IDH', 'Gene', '3417', (66, 69))	('mutant', 'Var', (70, 76))	('discriminate', 'Reg', (53, 65))
214448	28392842	Further, we have also carried out additional validation of 13 CpG methylation signatures to distinguish GBM IDH mutant from WT samples using an independent external GBM cohort (GSE36278).	('IDH', 'Gene', (108, 111))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('IDH', 'Gene', '3417', (108, 111))	('GBM', 'Phenotype', 'HP:0012174', (104, 107))	('mutant', 'Var', (112, 118))
214449	28392842	Analysis revealed that the 13 CpG methylation signatures were able to discriminate GBM IDH mutant from WT samples with an overall diagnostic accuracy of 96.10% (Tables 2 and 4; Fig.	('discriminate', 'Reg', (70, 82))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', '3417', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('mutant', 'Var', (91, 97))
214450	28392842	Thus, from these experiments, we conclude that the 13 CpG methylation signatures developed as above distinguished GBM IDH mutant from WT samples with high accuracy.	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('mutant', 'Var', (122, 128))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (118, 121))
214454	28392842	As per 2016 WHO CNS tumor classification, all LGG IDH mutant samples that have 1p/19q codeletion are designated as oligodendroglioma and those with intact 1p/19q loci and enriched for TP53 mutation/ATRX loss are designated as diffuse astrocytoma.	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (226, 245))	('CNS tumor', 'Phenotype', 'HP:0100006', (16, 25))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('diffuse astrocytoma', 'Disease', (226, 245))	('ATRX', 'Gene', '546', (198, 202))	('oligodendroglioma', 'Disease', (115, 132))	('astrocytoma', 'Phenotype', 'HP:0009592', (234, 245))	('TP53', 'Gene', '7157', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('TP53', 'Gene', (184, 188))	('oligodendroglioma', 'Disease', 'MESH:D009837', (115, 132))	('IDH', 'Gene', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutant', 'Var', (54, 60))	('ATRX', 'Gene', (198, 202))	('IDH', 'Gene', '3417', (50, 53))	('tumor', 'Disease', (20, 25))
214455	28392842	The LGG IDH mutant discordant sample had intact 1p/19q, WT TP53, and ATRX genes indicating that this sample is not an oligodendroglioma.	('ATRX', 'Gene', '546', (69, 73))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('TP53', 'Gene', (59, 63))	('IDH', 'Gene', (8, 11))	('ATRX', 'Gene', (69, 73))	('IDH', 'Gene', '3417', (8, 11))	('mutant', 'Var', (12, 18))	('oligodendroglioma', 'Disease', (118, 135))	('oligodendroglioma', 'Disease', 'MESH:D009837', (118, 135))	('TP53', 'Gene', '7157', (59, 63))	('1p/19q', 'Protein', (48, 54))
214461	28392842	Based on the WHO 2016 CNS tumor classification, IDH mutant LGGs having intact 1p/19q with an enrichment of TP53 mutation and ATRX loss are classified as diffuse astrocytoma.	('ATRX', 'Gene', '546', (125, 129))	('CNS tumor', 'Phenotype', 'HP:0100006', (22, 31))	('IDH', 'Gene', (48, 51))	('mutation', 'Var', (112, 120))	('astrocytoma', 'Phenotype', 'HP:0009592', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('IDH', 'Gene', '3417', (48, 51))	('TP53', 'Gene', (107, 111))	('TP53', 'Gene', '7157', (107, 111))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (153, 172))	('ATRX', 'Gene', (125, 129))	('diffuse astrocytoma', 'Disease', (153, 172))	('loss', 'NegReg', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
214463	28392842	While the single ODG discordant sample had 1p/19q codeletion and WT TP53/ATRX genes, this sample was identified as oligoastrocytoma as per histology.	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('ATRX', 'Gene', (73, 77))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (115, 131))	('1p/19q codeletion', 'Var', (43, 60))	('TP53', 'Gene', '7157', (68, 72))	('oligoastrocytoma', 'Disease', (115, 131))	('TP53', 'Gene', (68, 72))	('ATRX', 'Gene', '546', (73, 77))
214475	28392842	By using PAM, we have successfully developed and validated DNA methylation signatures to distinguish LGG IDH mutant from LGG IDH wild-type samples, LGG IDH mutant samples into diffuse astrocytoma and IDH mutant GBM from the IDH WT GBMs.	('IDH', 'Gene', (224, 227))	('IDH', 'Gene', (152, 155))	('IDH', 'Gene', (200, 203))	('IDH', 'Gene', '3417', (105, 108))	('GBM', 'Phenotype', 'HP:0012174', (211, 214))	('IDH', 'Gene', '3417', (224, 227))	('IDH', 'Gene', '3417', (152, 155))	('IDH', 'Gene', '3417', (200, 203))	('astrocytoma', 'Phenotype', 'HP:0009592', (184, 195))	('PAM', 'Chemical', '-', (9, 12))	('diffuse astrocytoma', 'Disease', (176, 195))	('IDH', 'Gene', (125, 128))	('mutant', 'Var', (109, 115))	('GBM', 'Phenotype', 'HP:0012174', (231, 234))	('LGG', 'Gene', (148, 151))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (176, 195))	('IDH', 'Gene', (105, 108))	('mutant', 'Var', (156, 162))	('IDH', 'Gene', '3417', (125, 128))
214477	28392842	Thus, the present study enabled us to identify DNA methylation fingerprint for each of the groups in comparison (LGG IDH1 WT versus mutant, ODG versus DA, and GBM IDH mutant versus WT).	('IDH1', 'Gene', '3417', (117, 121))	('IDH', 'Gene', (117, 120))	('mutant', 'Var', (132, 138))	('IDH', 'Gene', (163, 166))	('IDH', 'Gene', '3417', (117, 120))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('IDH', 'Gene', '3417', (163, 166))	('IDH1', 'Gene', (117, 121))
214485	28392842	Samples were then segregated according to the WHO 2016 CNS tumor IHC-based grading classification into three distinct groups, namely 1. lower grade glioma IDH wild-type and mutant (LGG IDH WT and mutant), 2. lower grade glioma IDH mutant with intact 1p/19q termed as diffuse astrocytoma and with 1p/19q codeletion termed as oligodendroglioma (DA and ODG), and 3. glioblastoma IDH mutant and wild type (GBM IDH WT and mutant).	('tumor', 'Disease', (59, 64))	('IDH', 'Gene', (185, 188))	('glioblastoma IDH', 'Disease', 'MESH:D005909', (363, 379))	('IDH', 'Gene', '3417', (227, 230))	('glioblastoma', 'Phenotype', 'HP:0012174', (363, 375))	('GBM', 'Phenotype', 'HP:0012174', (402, 405))	('IDH', 'Gene', '3417', (376, 379))	('IDH', 'Gene', (406, 409))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('CNS tumor', 'Phenotype', 'HP:0100006', (55, 64))	('glioma IDH', 'Disease', 'MESH:D005910', (220, 230))	('IDH', 'Gene', '3417', (185, 188))	('1p/19q codeletion', 'Var', (296, 313))	('glioma IDH', 'Disease', 'MESH:D005910', (148, 158))	('glioblastoma IDH', 'Disease', (363, 379))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('glioma IDH', 'Disease', (220, 230))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('mutant', 'Var', (231, 237))	('IDH', 'Gene', '3417', (406, 409))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('glioma IDH', 'Disease', (148, 158))	('diffuse astrocytoma', 'Disease', (267, 286))	('IDH', 'Gene', (155, 158))	('oligodendroglioma', 'Disease', 'MESH:D009837', (324, 341))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (267, 286))	('glioma', 'Phenotype', 'HP:0009733', (335, 341))	('IDH', 'Gene', (227, 230))	('IDH', 'Gene', (376, 379))	('astrocytoma', 'Phenotype', 'HP:0009592', (275, 286))	('oligodendroglioma', 'Disease', (324, 341))	('IDH', 'Gene', '3417', (155, 158))
214487	28392842	For this purpose, the first step was to identify significantly differentially methylated CpG probes between lower grade glioma IDH WT and mutant, between DA and ODG, and between GBM IDH mutant and WT which are described in details below.	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH', 'Gene', '3417', (182, 185))	('glioma IDH WT', 'Disease', 'MESH:D005910', (120, 133))	('mutant', 'Var', (138, 144))	('GBM', 'Phenotype', 'HP:0012174', (178, 181))	('glioma IDH WT', 'Disease', (120, 133))	('CpG', 'Gene', (89, 92))	('differentially', 'Reg', (63, 77))	('IDH', 'Gene', (182, 185))
214489	28392842	LGG IDH mutant: 1p/19q codel (ODG) versus non-codel (DA), and 3.	('1p/19q codel', 'Var', (16, 28))	('IDH', 'Gene', '3417', (4, 7))	('IDH', 'Gene', (4, 7))
214491	28392842	For the first comparison between LGG IDH mutant and WT, we have performed a Wilcoxon-rank sum test between IDH mutant and WT which yielded 269,442 CpG probes significantly (FDR <=0.0001) differentially methylated in mutant versus WT.	('mutant', 'Var', (216, 222))	('mutant', 'Var', (111, 117))	('IDH', 'Gene', (107, 110))	('IDH', 'Gene', '3417', (107, 110))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', '3417', (37, 40))	('differentially', 'Reg', (187, 201))
214492	28392842	Next, a stringent cutoff of 0.4 absolute Deltabeta value was applied that showed 9,554 significantly differentially methylated (26 CpGs were hypomethylated and 9528 CpGs were hypermethylated in IDH mutant LGG; Additional file 1: Table S2) CpG probes in mutant as compared to WT IDH LGG patients.	('mutant', 'Var', (253, 259))	('IDH', 'Gene', (278, 281))	('IDH', 'Gene', '3417', (278, 281))	('LGG', 'Disease', (205, 208))	('IDH', 'Gene', (194, 197))	('IDH', 'Gene', '3417', (194, 197))	('patients', 'Species', '9606', (286, 294))
214496	28392842	For this comparison, between LGG IDH mutant 1p/19q codel (ODG) and non-codel (DA), we have performed a Wilcoxon-rank sum test which yielded 160,288 CpG probes significantly differentially methylated in ODG versus DA.	('mutant 1p/19q', 'Var', (37, 50))	('methylated', 'MPA', (188, 198))	('IDH', 'Gene', (33, 36))	('differentially', 'Reg', (173, 187))	('IDH', 'Gene', '3417', (33, 36))
214497	28392842	Next, a stringent cutoff of 0.2 absolute Deltabeta value was applied that showed 2817 significantly differentially methylated (627 CpGs were hypomethylated and 2190 CpGs were hypermethylated in ODG; Additional file 1: Table S4) CpG probes in mutant as compared to WT IDH LGG patients.	('patients', 'Species', '9606', (275, 283))	('mutant', 'Var', (242, 248))	('IDH', 'Gene', '3417', (267, 270))	('IDH', 'Gene', (267, 270))
214498	28392842	The TCGA 450K human methylation dataset for LGG patients with 1p/19q codel (n = 172) and non-codel (n = 261) was randomized and 50% of each of the two classes formed the training set, and the remaining 50% was used as the test set.	('human', 'Species', '9606', (14, 19))	('1p/19q codel', 'Var', (62, 74))	('patients', 'Species', '9606', (48, 56))	('LGG', 'Disease', (44, 47))
214499	28392842	Likewise, the same work flow was followed to identify a methylation-based signature that could distinguish the GBM IDH WT from mutant samples (Fig.	('mutant', 'Var', (127, 133))	('IDH', 'Gene', (115, 118))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))	('IDH', 'Gene', '3417', (115, 118))
214500	28392842	In this comparison, between GBM IDH mutant and WT patient samples, we have performed a Wilcoxon-rank sum test which yielded 69,669 CpG probes significantly differentially methylated in mutant versus WT.	('mutant', 'Var', (185, 191))	('CpG', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (32, 35))	('IDH', 'Gene', (32, 35))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('patient', 'Species', '9606', (50, 57))	('differentially', 'Reg', (156, 170))
214501	28392842	Next, a stringent cutoff of 0.2 absolute Deltabeta value was applied that showed 259 significantly differentially methylated (33 CpGs were hypomethylated and 226 CpGs were hypermethylated in mutant; Additional file 1: Table S5) CpG probes in mutant as compared to WT IDH GBM patients.	('GBM', 'Phenotype', 'HP:0012174', (271, 274))	('mutant', 'Var', (191, 197))	('mutant', 'Var', (242, 248))	('IDH', 'Gene', (267, 270))	('patients', 'Species', '9606', (275, 283))	('IDH', 'Gene', '3417', (267, 270))
214502	28392842	The TCGA 450K human methylation dataset for GBM patients with IDH mutation (n = 7) and WT (n = 117) was randomized and 50% of each of the two classes formed the training set, and the remaining 50% was used as the test set.	('IDH', 'Gene', '3417', (62, 65))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('human', 'Species', '9606', (14, 19))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (48, 56))	('IDH', 'Gene', (62, 65))
214505	28392842	For preparing input files for PAM analysis, the list of significantly methylated probes between each compared groups across all the tumor samples was randomized and 50% of each of the two classes formed the training set, and the remaining 50% was used as the test set.	('PAM', 'Chemical', '-', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('methylated', 'Var', (70, 80))	('tumor', 'Disease', (132, 137))
214509	28392842	LGG IDH mutant versus WT, 2. diffuse astrocytoma versus oligodendroglioma, and 3.	('astrocytoma', 'Phenotype', 'HP:0009592', (37, 48))	('IDH', 'Gene', '3417', (4, 7))	('astrocytoma versus oligodendroglioma', 'Disease', (37, 73))	('mutant', 'Var', (8, 14))	('diffuse astrocytoma', 'Disease', (29, 48))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (29, 48))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('astrocytoma versus oligodendroglioma', 'Disease', 'MESH:D009837', (37, 73))	('IDH', 'Gene', (4, 7))
214510	28392842	GBM IDH mutant versus WT.	('IDH', 'Gene', '3417', (4, 7))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('mutant', 'Var', (8, 14))	('GBM', 'Gene', (0, 3))	('IDH', 'Gene', (4, 7))
214512	28392842	Consequently, one group of LGG IDH WT plus LGG IDH mutant was considered as a test set while the rest four groups were considered as training set and this is referred to as a "fold."	('IDH', 'Gene', '3417', (47, 50))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (31, 34))	('mutant', 'Var', (51, 57))	('IDH', 'Gene', (47, 50))
214513	28392842	LGG IDH mutant (217) versus WT (n = 49), 2. diffuse astrocytoma (n = 131) versus oligodendroglioma (n = 86), and 3.	('oligodendroglioma', 'Disease', 'MESH:D009837', (81, 98))	('IDH', 'Gene', '3417', (4, 7))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('mutant', 'Var', (8, 14))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (44, 63))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('oligodendroglioma', 'Disease', (81, 98))	('diffuse astrocytoma', 'Disease', (44, 63))	('IDH', 'Gene', (4, 7))
214514	28392842	GBM IDH mutant (n = 4) versus WT (n = 59) by random subset sampling.	('IDH', 'Gene', '3417', (4, 7))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('mutant', 'Var', (8, 14))	('IDH', 'Gene', (4, 7))
214516	28392842	PCA was performed using R package (version 3.1.0), on the training and test sets to know how well the identified methylation signature classifies LGG IDH mutant and WT.	('IDH', 'Gene', '3417', (150, 153))	('IDH', 'Gene', (150, 153))	('mutant', 'Var', (154, 160))
214517	28392842	This process was repeated for identifying a methylation signature between IDH mutant DA and ODG and between GBM IDH mutant and WT (a cutoff of 0.2 absolute  beta was used here to identify significantly differently methylated probes between the two classes).	('IDH', 'Gene', (74, 77))	('IDH', 'Gene', (112, 115))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('IDH', 'Gene', '3417', (74, 77))	('methylation', 'MPA', (44, 55))	('mutant', 'Var', (78, 84))	('IDH', 'Gene', '3417', (112, 115))	('GBM', 'Gene', (108, 111))
214529	27311729	The more limited literature that examines the overarching population of low-grade gliomas has shown an increased risk across several cognitive domains including intellectual functioning, academic achievement, and adaptive behaviors.	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('low-grade', 'Var', (72, 81))	('academic achievement', 'CPA', (187, 207))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('adaptive behaviors', 'CPA', (213, 231))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('gliomas', 'Disease', (82, 89))	('intellectual functioning', 'CPA', (161, 185))
214569	27311729	Damage to specific neural pathways connected to higher cortical regions has shown an impact on specific cognitive late effects in brain tumor survivors.	('brain tumor', 'Disease', 'MESH:D001932', (130, 141))	('brain tumor', 'Disease', (130, 141))	('impact', 'Reg', (85, 91))	('brain tumor', 'Phenotype', 'HP:0030692', (130, 141))	('Damage', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
214571	27311729	Thus, cognitive deficits identified in this study can result from direct tumor and surgical effects such as visual-motor and processing speed deficits secondary to encroachment of the pyramidal tracts, indirect tumor and surgical effects such as attention and executive dysfunction due to disruption of subcortical-cortical transmission, or late effects of adjuvant therapy such as deficits in attention, executive function and processing speed due to white matter changes associated with adjuvant therapies.	('cognitive deficits', 'Disease', 'MESH:D003072', (6, 24))	('attention', 'Disease', (246, 255))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cognitive deficits', 'Disease', (6, 24))	('tumor', 'Disease', (211, 216))	('speed deficits', 'Disease', 'MESH:D008569', (136, 150))	('executive dysfunction', 'Disease', (260, 281))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('speed deficits', 'Disease', (136, 150))	('visual-motor', 'CPA', (108, 120))	('result', 'Reg', (54, 60))	('white matter changes', 'Phenotype', 'HP:0002500', (452, 472))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('disruption', 'Var', (289, 299))	('executive function', 'CPA', (405, 423))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('attention', 'CPA', (394, 403))	('cognitive deficits', 'Phenotype', 'HP:0100543', (6, 24))	('processing speed', 'CPA', (428, 444))
214572	27311729	Core deficits in attention and executive functions can subsequently affect rate of learning such that declines are found over time in global indices such as intellectual, academic and adaptive functioning.	('adaptive functioning', 'CPA', (184, 204))	('rate of', 'MPA', (75, 82))	('declines', 'Disease', 'MESH:D060825', (102, 110))	('attention', 'CPA', (17, 26))	('intellectual', 'CPA', (157, 169))	('deficits', 'Var', (5, 13))	('declines', 'Disease', (102, 110))	('affect', 'Reg', (68, 74))
214595	27124395	Using these techniques, MGMT hypermethylation and mutations in isocitrate dehydrogenase (IDH1) have been the most frequently identified genomic marker of improved patient response to chemotherapy and therefore longer patient survival.	('MGMT', 'Gene', '4255', (24, 28))	('improved', 'PosReg', (154, 162))	('mutations', 'Var', (50, 59))	('patient', 'Species', '9606', (217, 224))	('longer', 'PosReg', (210, 216))	('patient', 'Species', '9606', (163, 170))	('IDH1', 'Gene', (89, 93))	('MGMT', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (89, 93))
214599	27124395	have identified correlations between genomic alterations and GBM patient survival times, the analysis and markers were not specific to LTS patients.	('LTS', 'Chemical', '-', (135, 138))	('patients', 'Species', '9606', (139, 147))	('correlations', 'Interaction', (16, 28))	('patient', 'Species', '9606', (65, 72))	('genomic alterations', 'Var', (37, 56))	('patient', 'Species', '9606', (139, 146))
214603	27124395	Second, the best-known genomic predictors of improved responses to temozolomide (TMZ) chemotherapy are mutations in IDH1 and methylation of the MGMT promoter, which are themselves frequently associated with secondary GBM (those that have progressed from LGG, as opposed to de novo GBM).	('temozolomide', 'Chemical', 'MESH:D000077204', (67, 79))	('mutations', 'Var', (103, 112))	('secondary GBM', 'Disease', (207, 220))	('IDH1', 'Gene', (116, 120))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('MGMT', 'Gene', (144, 148))	('IDH1', 'Gene', '3417', (116, 120))	('associated', 'Reg', (191, 201))	('MGMT', 'Gene', '4255', (144, 148))	('methylation', 'Var', (125, 136))
214617	27124395	Non-silent somatic mutations that were identified in more than one tumor were retained as candidate predictors of survival time for subsequent inclusion in our models.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Non-silent', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
214625	27124395	Consequently, separate regression analyses were performed with clinical information and point mutation genotypes as predictors of LTS.	('LTS', 'Chemical', '-', (130, 133))	('point mutation', 'Var', (88, 102))	('LTS', 'Disease', (130, 133))
214649	27124395	ULR identified 10 somatic mutations as predictors of LTS with p < 0.05 (none of which are statistically significant after Bonferroni or Benjamini-Hochberg adjustment of p-values), among these are mutations in genes whose somatic variants are well-known to correlate with GBM survival time such as IDH1 and PRSS1 (S2 Table).	('GBM survival time', 'CPA', (271, 288))	('LTS', 'Chemical', '-', (53, 56))	('IDH1', 'Gene', (297, 301))	('correlate', 'Reg', (256, 265))	('PRSS1', 'Gene', '5644', (306, 311))	('IDH1', 'Gene', '3417', (297, 301))	('PRSS1', 'Gene', (306, 311))	('variants', 'Var', (229, 237))	('mutations', 'Var', (196, 205))
214650	27124395	Most of the significant LLR mutations are located in different genes from those identified from ULR, except for mutations in IDH1 and the mRNA splicing gene DHX16.	('LLR', 'Gene', (24, 27))	('IDH1', 'Gene', '3417', (125, 129))	('DHX16', 'Gene', (157, 162))	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', (125, 129))	('DHX16', 'Gene', '8449', (157, 162))
214652	27124395	This is consistent with the occurrence of non-synonymous mutations in IDH1 in 16.67% of the LTS patients versus 1.19% of the non-LTS patients in the TCGA sample set, corresponding to an odds ratio of 16.03 (p = 6.8E-3).	('LTS', 'Chemical', '-', (129, 132))	('non-synonymous mutations', 'Var', (42, 66))	('patients', 'Species', '9606', (133, 141))	('LTS', 'Chemical', '-', (92, 95))	('IDH1', 'Gene', '3417', (70, 74))	('patients', 'Species', '9606', (96, 104))	('LTS', 'Disease', (92, 95))	('IDH1', 'Gene', (70, 74))
214653	27124395	The strongest associations are for mutations in the B3GALT5 (a Beta-galactosyltransferase gene) gene and the TGS1 (trimethyguanosine synthase), with beta = -0.28, -0.18, respectively, indicating that the wild type genotypes at these loci are weakly predictive of LTS (AUC = 0.52, 95% CI: 0.44-0.60, Table 5).	('B3GALT5', 'Gene', '10317', (52, 59))	('LTS', 'Chemical', '-', (263, 266))	('TGS1', 'Gene', (109, 113))	('TGS1', 'Gene', '96764', (109, 113))	('LTS', 'Disease', (263, 266))	('B3GALT5', 'Gene', (52, 59))	('mutations', 'Var', (35, 44))
214656	27124395	Among the 4 classes of genomic data, DNA methylation is the strongest predictor of LTS with the highest mean AUC (AUC = 0.84, CI: 0.78-0.90) in LLR models (Table 5), which was confirmed through 100 replicates of 10-fold cross validation.	('methylation', 'Var', (41, 52))	('AUC', 'MPA', (109, 112))	('LTS', 'Disease', (83, 86))	('LTS', 'Chemical', '-', (83, 86))
214657	27124395	Indeed, methylation is an even stronger predictor of LTS than age (i.e.	('LTS', 'Disease', (53, 56))	('LTS', 'Chemical', '-', (53, 56))	('methylation', 'Var', (8, 19))
214658	27124395	We found 38 methylation probes that are significant predictors of LTS in adjusted ULR models (S2 Table) vs. 43 in the LLR model (Table 4 and S3 Table).	('methylation', 'Var', (12, 23))	('LTS', 'Disease', (66, 69))	('LTS', 'Chemical', '-', (66, 69))
214659	27124395	Genes with Lasso regression coefficients  beta  > 10 include LETMD1, a known oncogene, the known tumor suppressor CDKN1B, as well as several other genes whose variants have been linked with other cancers, such as RSPO3.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CDKN1B', 'Gene', '1027', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('variants', 'Var', (159, 167))	('LETMD1', 'Gene', '25875', (61, 67))	('tumor', 'Disease', (97, 102))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('CDKN1B', 'Gene', (114, 120))	('cancers', 'Disease', (196, 203))	('LETMD1', 'Gene', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('linked', 'Reg', (178, 184))	('RSPO3', 'Gene', '84870', (213, 218))	('RSPO3', 'Gene', (213, 218))
214660	27124395	All of these genes are positively associated with LTS, indicating that their hypermethylation is predictive of improved patient outcomes.	('LTS', 'Chemical', '-', (50, 53))	('patient', 'Species', '9606', (120, 127))	('associated', 'Interaction', (34, 44))	('hypermethylation', 'Var', (77, 93))	('LTS', 'Disease', (50, 53))
214661	27124395	TNS4, whose oncogenic role has been documented for colorectal and other cancers, has the strongest negative association with LTS, suggesting that hypomethylation of this gene is predicts LTS (see Table 4 and S3 Table for a summary of genes that significantly predict LTS in LLR models).	('LTS', 'Chemical', '-', (187, 190))	('colorectal and other cancers', 'Disease', 'MESH:D015179', (51, 79))	('TNS4', 'Gene', (0, 4))	('LTS', 'Chemical', '-', (267, 270))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('LTS', 'Disease', (187, 190))	('TNS4', 'Gene', '84951', (0, 4))	('hypomethylation', 'Var', (146, 161))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('predicts', 'Reg', (178, 186))	('LTS', 'Chemical', '-', (125, 128))
214662	27124395	We remark that there is no significant association of MGMT promoter region methylation with LTS in LLR models, nor is methylation of this region a significant LTS predictor in a ULR model following FDR correction.	('methylation', 'Var', (75, 86))	('LTS', 'Chemical', '-', (92, 95))	('MGMT', 'Gene', (54, 58))	('MGMT', 'Gene', '4255', (54, 58))	('LTS', 'Chemical', '-', (159, 162))	('LTS', 'Disease', (92, 95))	('association', 'Interaction', (39, 50))
214663	27124395	However, the association between MGMT hypermethylation and LTS is significant in a ULR model (p = 0.036) without adjustment.	('hypermethylation', 'Var', (38, 54))	('LTS', 'Disease', (59, 62))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (33, 37))	('LTS', 'Chemical', '-', (59, 62))
214668	27124395	The strongest association of CNVs with LTS ( beta  > 1) in the LLR data included the oncogene DUSP28 (a negative association, indicating that deletion in this gene is predictive of LTS), as well as a positive association with HPR CNVs (i.e.	('DUSP28', 'Gene', '285193', (94, 100))	('HPR', 'Gene', (226, 229))	('LTS', 'Chemical', '-', (39, 42))	('LTS', 'Chemical', '-', (181, 184))	('HPR', 'Gene', '3250', (226, 229))	('deletion', 'Var', (142, 150))	('DUSP28', 'Gene', (94, 100))	('LTS', 'Disease', (39, 42))
214669	27124395	duplication at this locus is correlated with LTS).	('duplication', 'Var', (0, 11))	('LTS', 'Chemical', '-', (45, 48))	('correlated', 'Reg', (29, 39))
214670	27124395	Mutations in HPR have been documented in the literature as predictors of recurrent breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('HPR', 'Gene', '3250', (13, 16))	('breast cancer', 'Disease', (83, 96))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('HPR', 'Gene', (13, 16))
214672	27124395	Higher expression and amplification of this gene was associated with LTS (S3 Table), suggesting that the genomic amplification of STAM might lead to the upregulation of gene expression.	('amplification', 'MPA', (22, 35))	('upregulation', 'PosReg', (153, 165))	('LTS', 'Disease', (69, 72))	('expression', 'MPA', (7, 17))	('STAM', 'Gene', '8027', (130, 134))	('amplification', 'Var', (113, 126))	('LTS', 'Chemical', '-', (69, 72))	('gene expression', 'MPA', (169, 184))	('STAM', 'Gene', (130, 134))
214681	27124395	For example, in LLR analysis of methylation probes alone, methylation of the oncogene BRAF does not appear as a significant predictor, whereas in the integrative model it has beta = 4.62.	('methylation', 'Var', (58, 69))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (86, 90))
214686	27124395	This result is consistent with methylation being the strongest individual predictor of LTS in both integrative models and in models that only incorporate a single class of data.	('LTS', 'Disease', (87, 90))	('LTS', 'Chemical', '-', (87, 90))	('methylation', 'Var', (31, 42))
214700	27124395	A closer examination of IDH1 mutation status in showed that all 5 IDH1+ GBMs (including 3 LTSs and 2 non-LTSs) cluster with LGGs when the dendrogram was partitioned into two clusters (Fig 4, row-side color bar on the right), indicating a similarity in gene expression and methylation profiles between IDH1+ genotypes and LGGs.	('mutation', 'Var', (29, 37))	('LTS', 'Chemical', '-', (105, 108))	('IDH1', 'Gene', '3417', (24, 28))	('IDH1', 'Gene', '3417', (66, 70))	('IDH1', 'Gene', (301, 305))	('IDH1', 'Gene', '3417', (301, 305))	('IDH1', 'Gene', (24, 28))	('LTS', 'Chemical', '-', (90, 93))	('IDH1', 'Gene', (66, 70))
214711	27124395	The Moran's I autocorrelation measures are statistically insignificant for LTS methylation scores with respect to non-LTS GBM (Table 9), even when the LLR subset of genes are considered separately.	('methylation scores', 'Var', (79, 97))	('LTS', 'Chemical', '-', (118, 121))	('LTS', 'Disease', (75, 78))	('LTS', 'Chemical', '-', (75, 78))
214712	27124395	These results were unexpected in view of the fact that methylation is a stronger predictor of LTS in LLR models than expression profiles, which is probably a consequence a relatively small subset of the LTS samples with very similar expression profiles (high autocorrelation) in the LLR-selected genes.	('LTS', 'Chemical', '-', (94, 97))	('LTS', 'Chemical', '-', (203, 206))	('LTS', 'Disease', (94, 97))	('methylation', 'Var', (55, 66))
214716	27124395	For example, among the somatic point mutations, non-synonymous mutations in IDH1 were the strongest predictors of LTS in ULR and LLR models (Table 4), consistent with the significantly higher proportion of IDH1 mutated patients observed in the LTS vs. non-LTS data sets.	('IDH1', 'Gene', (76, 80))	('LTS', 'Chemical', '-', (256, 259))	('LTS', 'Chemical', '-', (114, 117))	('non-synonymous mutations', 'Var', (48, 72))	('LTS', 'Disease', (114, 117))	('mutated', 'Var', (211, 218))	('IDH1', 'Gene', '3417', (76, 80))	('LTS', 'Chemical', '-', (244, 247))	('patients', 'Species', '9606', (219, 227))	('IDH1', 'Gene', (206, 210))	('IDH1', 'Gene', '3417', (206, 210))
214717	27124395	However, even the association of LTS with IDH1 mutations is weak, i.e.	('LTS', 'Chemical', '-', (33, 36))	('IDH1', 'Gene', '3417', (42, 46))	('mutations', 'Var', (47, 56))	('IDH1', 'Gene', (42, 46))	('LTS', 'Disease', (33, 36))
214719	27124395	The low predictive performance of both somatic and germline mutations generally is in agreement with emerging clinical data suggesting that IDH1 is a only weak predictor of LTS in GBM, as survival beyond the fourth year can occur in patients without IDH1 mutations.	('LTS', 'Chemical', '-', (173, 176))	('IDH1', 'Gene', '3417', (140, 144))	('LTS in GBM', 'Disease', (173, 183))	('IDH1', 'Gene', (250, 254))	('IDH1', 'Gene', (140, 144))	('IDH1', 'Gene', '3417', (250, 254))	('patients', 'Species', '9606', (233, 241))	('mutations', 'Var', (255, 264))
214725	27124395	These results suggest that there are few if any inherited (familial) mutations that predict LTS in GBM patients, or that their effects are comparatively weak against the much stronger signal of variation among GBM types and the contribution of clinical variables such as age to patient survival.	('mutations', 'Var', (69, 78))	('LTS', 'Chemical', '-', (92, 95))	('patient', 'Species', '9606', (278, 285))	('patient', 'Species', '9606', (103, 110))	('patients', 'Species', '9606', (103, 111))	('LTS', 'Disease', (92, 95))
214726	27124395	Although mutational genotypic markers for LTS are limited, we did identify gene expression phenotypes, epigenetic markers, and copy number variant genotypes that are significantly predictive of LTS, with the exception of DNA methylation.	('variant', 'Var', (139, 146))	('LTS', 'Disease', (194, 197))	('LTS', 'Chemical', '-', (42, 45))	('LTS', 'Chemical', '-', (194, 197))
214734	27124395	Such results suggest that there are many patterns of gene expression and methylation that lead to LTS phenotypes.	('lead to', 'Reg', (90, 97))	('methylation', 'Var', (73, 84))	('LTS', 'Disease', (98, 101))	('LTS', 'Chemical', '-', (98, 101))
214738	27124395	Our finding that only IDH1+ GBMs have expression profiles resembling LGG may indicate that IDH1 mutated GBMs are either misidentified LGGs or represent a unique, LGG-like pathology among high-grade gliomas, this observation does not account the majority of LTS cases.	('mutated', 'Var', (96, 103))	('IDH1', 'Gene', (91, 95))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('IDH1', 'Gene', (22, 26))	('gliomas', 'Disease', (198, 205))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('LTS', 'Chemical', '-', (257, 260))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('IDH1', 'Gene', '3417', (91, 95))	('IDH1', 'Gene', '3417', (22, 26))
214741	27124395	GBM Glioblastoma multiforme LTS Long-term survival LGG Low grade glioma CNV Copy number variation TCGA the Cancer Genome Atlas PCA Principal component analysis LLR Lasso logistic regression ULR Univariate logistic regression	('Copy number variation', 'Var', (76, 97))	('glioma', 'Disease', (65, 71))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (4, 27))	('LGG Low', 'Phenotype', 'HP:0004315', (51, 58))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Glioblastoma multiforme', 'Disease', (4, 27))	('Cancer Genome Atlas', 'Disease', (107, 126))	('LTS', 'Chemical', '-', (28, 31))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (107, 126))	('Glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))
214744	24312143	The expression levels of SRPK1 protein in glioma cell lines transfected with siSRPK1 or not were examined using immunofluorescence, RT-PCR and Western blot analysis, respectively.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('SRPK1', 'Gene', (25, 30))	('siSRPK1', 'Var', (77, 84))	('glioma', 'Disease', (42, 48))
214746	24312143	The results showed that knockdown of SRPK1 inhibited tumor cells growth, invasion and migration in normoxic condition, but portion of the effect could be reversed in hypoxia.	('migration', 'CPA', (86, 95))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('invasion', 'CPA', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('SRPK1', 'Gene', (37, 42))	('tumor', 'Disease', (53, 58))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('knockdown', 'Var', (24, 33))	('hypoxia', 'Disease', (166, 173))
214747	24312143	SRPK1 expression was induced in glioma cells by DDP treated, but not TMZ, in both normoxia and hypoxia conditions.	('SRPK1', 'Gene', (0, 5))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('glioma', 'Disease', (32, 38))	('expression', 'MPA', (6, 16))	('DDP treated', 'Var', (48, 59))	('DDP', 'Chemical', 'MESH:D002945', (48, 51))	('hypoxia conditions', 'Disease', (95, 113))	('induced', 'Reg', (21, 28))	('hypoxia conditions', 'Disease', 'MESH:D000860', (95, 113))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
214758	24312143	Phosphorylated SRSF1 is indicative of an angiogenic phenotype as it results in proximal splicing and production of angiogenic VEGF isoforms (VEGF-A165).	('Phosphorylated', 'Var', (0, 14))	('VEGF', 'Gene', (141, 145))	('SRSF1', 'Gene', (15, 20))	('VEGF', 'Gene', '7422', (126, 130))	('results in', 'Reg', (68, 78))	('VEGF', 'Gene', '7422', (141, 145))	('VEGF', 'Gene', (126, 130))	('proximal splicing', 'MPA', (79, 96))
214765	24312143	More interesting SRPK1 and SRSF1 expression in hypoxic condition can be inhibited and knockdown SRPK1 can inhibit cells invasion, migration and sensitivity to chemotherapy drugs.	('knockdown', 'Var', (86, 95))	('migration', 'CPA', (130, 139))	('SRPK1', 'Gene', (17, 22))	('sensitivity', 'CPA', (144, 155))	('SRPK1', 'Gene', (96, 101))	('cells invasion', 'CPA', (114, 128))	('hypoxic condition', 'Disease', 'MESH:D009135', (47, 64))	('hypoxic condition', 'Disease', (47, 64))	('inhibit', 'NegReg', (106, 113))	('expression', 'MPA', (33, 43))	('inhibited', 'NegReg', (72, 81))	('SRSF1', 'Gene', (27, 32))
214773	24312143	For immunohistochemical detection of SRPK1 (1:100, Santa Cruz) and CD31 (1:50, Boster), tissue sections were routinely processed and subjected to antigen retrieval.	('CD31', 'Gene', '5175', (67, 71))	('CD31', 'Gene', (67, 71))	('SRPK1', 'Gene', (37, 42))	('1:100', 'Var', (44, 49))
214786	24312143	A549, U87 and U251 cells were transfected with siRNA targeting SRPK1 (siRNA438, siRNA716, siRNA1132, Shanghai GenePharma Co.,Ltd) and silencer siRNAs for SRPK1 were selected.	('U87', 'Gene', '641648', (6, 9))	('SRPK1', 'Gene', (63, 68))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('U251', 'CellLine', 'CVCL:0021', (14, 18))	('siRNA716', 'Var', (80, 88))	('siRNA1132', 'Var', (90, 99))	('U87', 'Gene', (6, 9))
214791	24312143	We designed and synthetized siRNA to target SRPK1 (Fig.2A and 2B) and studied whether knockdown SRPK1 influences the growth of glioma cells by flow cytometry.	('influences', 'Reg', (102, 112))	('knockdown', 'Var', (86, 95))	('SRPK1', 'Gene', (96, 101))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma', 'Disease', (127, 133))	('SRPK1', 'Gene', (44, 49))
214792	24312143	Cell cycle showed the rate of U251 and U87 cells in G1 and G2 phase were significantly higher in the siSRPK1 transfected group than that in the control group (P<0.01) in normoxia and hypoxia (Fig.2D).	('Cell cycle', 'CPA', (0, 10))	('higher', 'PosReg', (87, 93))	('U87', 'Gene', (39, 42))	('siSRPK1', 'Gene', (101, 108))	('U87', 'Gene', '641648', (39, 42))	('transfected', 'Var', (109, 120))	('hypoxia', 'Disease', 'MESH:D000860', (183, 190))	('U251', 'CellLine', 'CVCL:0021', (30, 34))	('hypoxia', 'Disease', (183, 190))
214794	24312143	These results suggest that inhibition of SRPK1 expression can reduce the activity of glioma cells proliferation by causing G0-G1 and G2/M phase arrest either in normoxia or in hypoxia.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('hypoxia', 'Disease', 'MESH:D000860', (176, 183))	('SRPK1', 'Gene', (41, 46))	('reduce', 'NegReg', (62, 68))	('causing', 'Reg', (115, 122))	('glioma', 'Disease', (85, 91))	('inhibition', 'Var', (27, 37))	('hypoxia', 'Disease', (176, 183))	('G2/M phase arrest', 'CPA', (133, 150))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
214798	24312143	Compared with non-transfected cells, SRPK1 silencing cells decreased invasion significantly in normoxia (20+-4.3 vs. 62.8+-9.1, P < 0.01, Fig.3C and 3D) and in hypoxia (44+-6.1 vs. 85.3+-6.4, P<0.01, Fig.3C and 3D).	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('decreased', 'NegReg', (59, 68))	('silencing', 'Var', (43, 52))	('invasion', 'CPA', (69, 77))	('SRPK1', 'Gene', (37, 42))
214801	24312143	These results implicate that inhibition of SRPK1 expression can bring down the migration and invasion capacity of glioma cells in normoxia and hypoxia, but the invasion can be restored in hypoxic condition.	('migration', 'CPA', (79, 88))	('glioma', 'Disease', (114, 120))	('hypoxia', 'Disease', 'MESH:D000860', (143, 150))	('hypoxic condition', 'Disease', 'MESH:D009135', (188, 205))	('hypoxic condition', 'Disease', (188, 205))	('invasion capacity', 'CPA', (93, 110))	('hypoxia', 'Disease', (143, 150))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('SRPK1', 'Gene', (43, 48))	('inhibition', 'Var', (29, 39))
214808	24312143	Furthermore, siSRPK1 was added 24h prior to addition of the chemotherapeutics, and the results showed that the inhibited SRPK1 expression could decrease the cells apoposis caused by DDP and TMZ in normoxic condition (P<0.05, Fig.4C and 4D).	('expression', 'MPA', (127, 137))	('decrease', 'NegReg', (144, 152))	('TMZ', 'Chemical', 'MESH:D000077204', (190, 193))	('DDP', 'Chemical', 'MESH:D002945', (182, 185))	('SRPK1', 'Gene', (121, 126))	('inhibited', 'NegReg', (111, 120))	('cells apoposis', 'CPA', (157, 171))	('DDP', 'Var', (182, 185))
214812	24312143	SRSF1 mRNA was increased by TMZ treatment more than DDP treatment in normoxic condition (Fig.5A).	('TMZ', 'Chemical', 'MESH:D000077204', (28, 31))	('increased', 'PosReg', (15, 24))	('TMZ', 'Var', (28, 31))	('SRSF1', 'Gene', (0, 5))	('DDP', 'Chemical', 'MESH:D002945', (52, 55))	('mRNA', 'MPA', (6, 10))
214824	24312143	In this study, we the first time describe the knockdown SRPK efficiently can inhibit the growth, migration invasion and chemosensitivity of glioma cells in normoxic and hypoxic condition.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('hypoxic condition', 'Disease', 'MESH:D009135', (169, 186))	('knockdown', 'Var', (46, 55))	('hypoxic condition', 'Disease', (169, 186))	('inhibit', 'NegReg', (77, 84))	('SRPK', 'Gene', (56, 60))	('glioma', 'Disease', (140, 146))	('growth', 'CPA', (89, 95))
214826	24312143	Maybe siSRPK1 affects the activity of SRPK2 (one of SR/RS protein kinases family) which can bind and phosphorylate acinus, low expression SRPK2 arrests cells at the G1 phase.	('SRPK2', 'Gene', (138, 143))	('SRPK2', 'Gene', (38, 43))	('low expression', 'Var', (123, 137))	('activity', 'MPA', (26, 34))	('SRPK2', 'Gene', '6733', (138, 143))	('SRPK2', 'Gene', '6733', (38, 43))	('affects', 'Reg', (14, 21))	('arrests', 'NegReg', (144, 151))	('cells at the G1 phase', 'CPA', (152, 173))
214828	24312143	And there is no significant different after transfected siSRPK1 between at normoxic or hypoxic condition, even if in hypoxic conditions can promote the synthesis of HIF-1alpha which contributes to tumor cell survival and activation of oncogenic pathways (PI3K/Akt) in cancer cells could result in an increased expression of HIF-1alpha.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('HIF-1alpha', 'Gene', (324, 334))	('increased', 'PosReg', (300, 309))	('Akt', 'Gene', (260, 263))	('siSRPK1', 'Gene', (56, 63))	('hypoxic condition', 'Disease', (87, 104))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('hypoxic condition', 'Disease', 'MESH:D009135', (87, 104))	('HIF-1alpha', 'Gene', (165, 175))	('Akt', 'Gene', '207', (260, 263))	('expression', 'MPA', (310, 320))	('hypoxic conditions', 'Disease', 'MESH:D009135', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('hypoxic condition', 'Disease', 'MESH:D009135', (117, 134))	('tumor', 'Disease', (197, 202))	('HIF-1alpha', 'Gene', '3091', (324, 334))	('cancer', 'Disease', (268, 274))	('activation', 'PosReg', (221, 231))	('hypoxic conditions', 'Disease', (117, 135))	('synthesis', 'MPA', (152, 161))	('promote', 'PosReg', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('HIF-1alpha', 'Gene', '3091', (165, 175))	('transfected', 'Var', (44, 55))
214831	24312143	It is interesting that hypoxia can reduce SRPK1 knockdown-induced tumor cell migration and invasion ability.	('knockdown-induced', 'Var', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))	('SRPK1', 'Gene', (42, 47))	('tumor', 'Disease', (66, 71))	('hypoxia', 'Disease', (23, 30))	('reduce', 'NegReg', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('invasion ability', 'CPA', (91, 107))
214899	21538632	Recent studies of data from patients with glioma have suggested that variations in ADC within the anatomic lesion are able to distinguish between different histological subtypes for grade II glioma, as well as differentiating between upgraded and nonupgraded recurrent low-grade glioma and predicting clinical outcome for patients with grade IV glioma.	('glioma', 'Disease', (345, 351))	('ADC', 'Gene', (83, 86))	('glioma', 'Disease', 'MESH:D005910', (345, 351))	('glioma', 'Disease', (42, 48))	('II glioma', 'Disease', 'MESH:D005910', (188, 197))	('II glioma', 'Disease', (188, 197))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('patients', 'Species', '9606', (322, 330))	('glioma', 'Phenotype', 'HP:0009733', (345, 351))	('patients', 'Species', '9606', (28, 36))	('glioma', 'Disease', (279, 285))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glioma', 'Disease', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('distinguish', 'Reg', (126, 137))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('variations', 'Var', (69, 79))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('differentiating', 'Reg', (210, 225))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))
214901	21538632	In some cases, there are also regions of hypointensity on T1-weighted images that are thought to correspond to necrosis (NEC).	('necrosis', 'Disease', (111, 119))	('hypointensity', 'Var', (41, 54))	('necrosis', 'Disease', 'MESH:D009336', (111, 119))
215021	21538632	This is of particular interest for the management of patients with glioma because the presence of Lac is a characteristic of high-grade glioma and is a prognostic factor for poor overall survival.	('Lac', 'Chemical', 'MESH:D019344', (98, 101))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('patients', 'Species', '9606', (53, 61))	('glioma', 'Disease', (67, 73))	('presence', 'Var', (86, 94))	('glioma', 'Disease', (136, 142))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('Lac', 'Gene', (98, 101))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
215033	31616182	We used multiple methods, including Western blot analysis, soft agar colony-formation assay, CCK8 assay, and flow cytometry, to evaluate the changes in multiple cellular functions after BHLHE41 knockdown or overexpression in U87 and U251 cell lines.	('overexpression', 'PosReg', (207, 221))	('knockdown', 'Var', (194, 203))	('U87', 'Gene', (225, 228))	('U87', 'Gene', '641648', (225, 228))	('changes', 'Reg', (141, 148))	('BHLHE41', 'Gene', (186, 193))
215039	31616182	Furthermore, the median OS of low-grade glioma (LGG) patients with low to median level of BHLHE41 was 22.6 months, longer than that of the patients with high level of BHLHE41 (21.0 months).	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('low to median level', 'Var', (67, 86))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (139, 147))	('BHLHE41', 'Var', (90, 97))	('glioma', 'Disease', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
215049	31616182	ERK phosphorylation results in a cascade activation and leads to numerous downstream target phosphorylations involved in cell proliferation regulation.	('phospho', 'Chemical', 'MESH:C033601', (92, 99))	('leads to', 'Reg', (56, 64))	('phospho', 'Chemical', 'MESH:C033601', (4, 11))	('cascade', 'MPA', (33, 40))	('ERK', 'Gene', '5594', (0, 3))	('activation', 'PosReg', (41, 51))	('ERK', 'Gene', (0, 3))	('phosphorylation', 'Var', (4, 19))
215057	31616182	Adding SCH772984 reversed BHLHE41-induced cyclinD1 upregulation as well as ERK phosphorylation.	('upregulation', 'PosReg', (51, 63))	('ERK', 'Gene', '5594', (75, 78))	('cyclinD1', 'Gene', '595', (42, 50))	('SCH772984', 'Var', (7, 16))	('ERK', 'Gene', (75, 78))	('SCH772984', 'Chemical', 'MESH:C587178', (7, 16))	('phospho', 'Chemical', 'MESH:C033601', (79, 86))	('BHLHE41-induced', 'Gene', (26, 41))	('cyclinD1', 'Gene', (42, 50))
215065	31616182	ERK (1:1000, #4695, CST), phospho (p)-ERK (1:1000, #4370, CST).	('CST', 'Gene', '106478911', (20, 23))	('CST', 'Gene', (58, 61))	('phospho', 'Chemical', 'MESH:C033601', (26, 33))	('CST', 'Gene', (20, 23))	('1:1000', 'Var', (43, 49))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))	('ERK', 'Gene', '5594', (38, 41))	('ERK', 'Gene', (38, 41))	('CST', 'Gene', '106478911', (58, 61))
215068	31616182	I-kappaB (1:1000, #4812, CST), NF-kappaB (1:1000, #8242S CST), Bax (1:1000, 50599-2-lg Proteintech), Bcl-2(1:1000, 12789-1-AP Proteintech).	('1:1000', 'Var', (42, 48))	('CST', 'Gene', (57, 60))	('CST', 'Gene', (25, 28))	('Bcl-2', 'Gene', (101, 106))	('Bax', 'Gene', '581', (63, 66))	('Bcl-2', 'Gene', '596', (101, 106))	('NF-kappaB', 'Gene', '4790', (31, 40))	('CST', 'Gene', '106478911', (57, 60))	('Bax', 'Gene', (63, 66))	('CST', 'Gene', '106478911', (25, 28))	('NF-kappaB', 'Gene', (31, 40))
215071	31616182	The above glioma cells were transfected with pcDNA or BHLHE41, or glioma cells transfected with NC-siRNA or BHLHE41-siRNA, and plated into 96-well plates (2x103 cells per well) containing media.	('glioma', 'Disease', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('BHLHE41-siRNA', 'Var', (108, 121))	('glioma', 'Disease', (10, 16))
215075	31616182	For DNA content analysis, U87 and U251 cells transfected with NC-siRNA or BHLHE41- siRNA, or U87 and U251 cells transfected with either pcDNA or Myc-His-BHLHE41.	('U87', 'Gene', (93, 96))	('U87', 'Gene', '641648', (93, 96))	('U87', 'Gene', (26, 29))	('Myc', 'Gene', '4609', (145, 148))	('Myc', 'Gene', (145, 148))	('U87', 'Gene', '641648', (26, 29))	('BHLHE41- siRNA', 'Var', (74, 88))
215084	31616182	U87 and U251 cells transfected with NC-siRNA, BHLHE41-siRNA, pcDNA, and Myc-His-BHLHE41 (800 cells/plate) were cultured in 5 mL of DMEM supplemented with 10% FBS in a 6-cm plate.	('U87', 'Gene', '641648', (0, 3))	('men', 'Species', '9606', (142, 145))	('Myc', 'Gene', '4609', (72, 75))	('Myc', 'Gene', (72, 75))	('U87', 'Gene', (0, 3))	('BHLHE41-siRNA', 'Var', (46, 59))
215098	31616182	S and G2 phase cell percentages increased from 35.11+-1.31% to 45.26+-0.30% (U251), and 66.01+-2.98% to 74.30+-4.21% (U87) in the BHLHE41 transfected group compared to control group (Figure 1D and E).	('U87', 'Gene', (118, 121))	('U87', 'Gene', '641648', (118, 121))	('transfected', 'Var', (138, 149))	('increased', 'PosReg', (32, 41))	('BHLHE41', 'Gene', (130, 137))
215100	31616182	CCK8 assays showed that BHLHE41 knockdown inhibits U87 and U251 cell growth.	('U87', 'Gene', '641648', (51, 54))	('inhibits', 'NegReg', (42, 50))	('BHLHE41', 'Gene', (24, 31))	('knockdown', 'Var', (32, 41))	('U87', 'Gene', (51, 54))
215101	31616182	Colony-formation assays showed that BHLHE41 silencing attenuates U87 and U251 cell proliferation, colony formation, and foci number (U87: pcDNA vs BHLHE41, 34.3+-7.0 vs 4.5+-2.5, p<0.01; U251: pcDNA vs BHLHE41, 73.7+-11.2 vs 28.3+-7.0, p<0.05) (Figure 2B and C).	('U87', 'Gene', '641648', (65, 68))	('silencing', 'Var', (44, 53))	('U87', 'Gene', (133, 136))	('colony formation', 'CPA', (98, 114))	('BHLHE41', 'Gene', (36, 43))	('U87', 'Gene', (65, 68))	('U87', 'Gene', '641648', (133, 136))	('attenuates', 'NegReg', (54, 64))	('foci number', 'CPA', (120, 131))
215102	31616182	Flow cytometry revealed that siRNA-induced BHLHE41 silence had higher cell proportions in the G1 phase (U251: 59.06+-7.90% vs 69.94+-11.60%; U87: 29.74+-1.17% vs 34.48+-1.83%) and a lower proportion in the S and G2 phase (U251: 40.94+-7.90% vs 30.06+-11.60%; U87: 70.26+-1.17% vs 65.52+-1.83%) compared with the control group (Figure 2D and E).	('BHLHE41', 'Gene', (43, 50))	('U87', 'Gene', '641648', (141, 144))	('cell proportions', 'CPA', (70, 86))	('silence', 'Var', (51, 58))	('U87', 'Gene', (259, 262))	('U87', 'Gene', '641648', (259, 262))	('U87', 'Gene', (141, 144))	('higher', 'PosReg', (63, 69))	('G1 phase', 'CPA', (94, 102))
215105	31616182	CyclinD1 and cyclinE1 were significantly upregulated after BHLHE41 transfection in U251 cells.	('cyclinE1', 'Gene', '898', (13, 21))	('transfection', 'Var', (67, 79))	('CyclinD1', 'Gene', '595', (0, 8))	('BHLHE41', 'Gene', (59, 66))	('upregulated', 'PosReg', (41, 52))	('CyclinD1', 'Gene', (0, 8))	('cyclinE1', 'Gene', (13, 21))
215115	31616182	SCH772984 significantly reduced p-ERK expression (Figure 4G-I).	('reduced', 'NegReg', (24, 31))	('SCH772984', 'Chemical', 'MESH:C587178', (0, 9))	('p-ERK', 'Gene', '9451', (32, 37))	('p-ERK', 'Gene', (32, 37))	('SCH772984', 'Var', (0, 9))
215121	31616182	However, compared with the control group, the number of apoptosis cells in U87 and U251 cells was only slightly changed after transfected with BHLHE41.	('U87', 'Gene', (75, 78))	('transfected', 'Var', (126, 137))	('U87', 'Gene', '641648', (75, 78))	('BHLHE41', 'Gene', (143, 150))
215125	31616182	Since we found that BHLHE41 expression enhanced cell proliferation in glioblastoma cells, we further investigated the association of BHLHE41 expression with clinical and pathological characteristics in LGG and GBM patients by TCGA analysis.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('GBM', 'Disease', (210, 213))	('patients', 'Species', '9606', (214, 222))	('LGG', 'Disease', (202, 205))	('GBM', 'Disease', 'MESH:D005909', (210, 213))	('BHLHE41', 'Gene', (20, 27))	('expression', 'Var', (28, 38))	('glioblastoma', 'Disease', (70, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('enhanced', 'PosReg', (39, 47))
215127	31616182	As shown in Figure 7A, the overall survival of LGG patients with the high level of BHLHE41 was much lower than that of group with the low to median level of BHLHE41 (Figure 7A, p=0.0019).	('high level', 'Var', (69, 79))	('lower', 'NegReg', (100, 105))	('BHLHE41', 'Var', (83, 90))	('patients', 'Species', '9606', (51, 59))	('LGG', 'Disease', (47, 50))
215129	31616182	As shown in Figure 7B, the overall survival of GBM patients with the high level of BHLHE41 was also lower than that of the patients with the low to median level of BHLHE41 (Figure 7B), but without a statistical difference (p=0.17).	('high level', 'Var', (69, 79))	('GBM', 'Disease', 'MESH:D005909', (47, 50))	('lower', 'NegReg', (100, 105))	('patients', 'Species', '9606', (123, 131))	('BHLHE41', 'Var', (83, 90))	('patients', 'Species', '9606', (51, 59))	('GBM', 'Disease', (47, 50))
215134	31616182	Recent studies have shown that the deregulation of their expression is associated with tumor progression.	('expression', 'MPA', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('deregulation', 'Var', (35, 47))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('associated', 'Reg', (71, 81))
215149	31616182	Consistent with this is the fact that silencing endogenous BHLHE41 led to significant cyclin (cyclinD1 and cyclinE1) decreases in both U251 and U87 cells.	('U87', 'Gene', '641648', (144, 147))	('U87', 'Gene', (144, 147))	('cyclin', 'Gene', (94, 100))	('cyclinD1', 'Gene', (94, 102))	('decreases', 'NegReg', (117, 126))	('BHLHE41', 'Gene', (59, 66))	('cyclinE1', 'Gene', (107, 115))	('cyclin', 'Gene', '5111', (107, 113))	('cyclinE1', 'Gene', '898', (107, 115))	('cyclinD1', 'Gene', '595', (94, 102))	('cyclin', 'Gene', '5111', (86, 92))	('cyclin', 'Gene', '5111', (94, 100))	('cyclin', 'Gene', (107, 113))	('silencing', 'Var', (38, 47))	('cyclin', 'Gene', (86, 92))
215150	31616182	Since we have found the effect of BHLHE41 on cell proliferation, next we performed Annexin V and PI double staining by flow cytometry to measure whether BHLHE41 may suppress apoptosis, and therefore promoted cell growth.	('Annexin V', 'Gene', '308', (83, 92))	('Annexin V', 'Gene', (83, 92))	('cell growth', 'CPA', (208, 219))	('apoptosis', 'CPA', (174, 183))	('BHLHE41', 'Var', (153, 160))	('promoted', 'PosReg', (199, 207))	('suppress', 'NegReg', (165, 173))
215163	31616182	In conclusion, this study is believed to be the first to demonstrate that BHLHE41 enhances U251 and U87 cell proliferation and colony formation abilities.	('U87', 'Gene', '641648', (100, 103))	('BHLHE41', 'Var', (74, 81))	('enhances', 'PosReg', (82, 90))	('U87', 'Gene', (100, 103))	('colony formation abilities', 'CPA', (127, 153))
215172	29246166	EGR1 expression levels in human gliomas are decreased compared with normal brain tissues, however, the patients with low EGR1 expression level showed significantly enhanced patient survival in all glioma patients.	('low', 'Var', (117, 120))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('human', 'Species', '9606', (26, 31))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('patients', 'Species', '9606', (204, 212))	('expression levels', 'MPA', (5, 22))	('patient', 'Species', '9606', (103, 110))	('patient', 'Species', '9606', (173, 180))	('expression', 'MPA', (126, 136))	('gliomas', 'Disease', (32, 39))	('glioma', 'Disease', (32, 38))	('patient survival', 'CPA', (173, 189))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('patient', 'Species', '9606', (204, 211))	('EGR1', 'Gene', (121, 125))	('enhanced', 'PosReg', (164, 172))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('glioma', 'Disease', (197, 203))	('patients', 'Species', '9606', (103, 111))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
215173	29246166	EGR1 silencing inhibited proliferation and induced G1 phase arrest in glioma cells.	('inhibited', 'NegReg', (15, 24))	('arrest', 'Disease', (60, 66))	('proliferation', 'CPA', (25, 38))	('glioma cells', 'Disease', (70, 82))	('induced', 'Reg', (43, 50))	('silencing', 'Var', (5, 14))	('glioma cells', 'Disease', 'MESH:D005910', (70, 82))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('arrest', 'Disease', 'MESH:D006323', (60, 66))	('EGR1', 'Gene', (0, 4))
215175	29246166	Our results show that stable knockdown EGR1 would inhibit glioma proliferation.	('glioma proliferation', 'Disease', (58, 78))	('glioma proliferation', 'Disease', 'MESH:D005910', (58, 78))	('knockdown', 'Var', (29, 38))	('inhibit', 'NegReg', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('EGR1', 'Gene', (39, 43))
215191	29246166	showed that EGR1 expression was significantly associated with enhanced patient survival and was an independent prognostic factor in multivariate analysis in high grade astrocytomas.	('astrocytomas', 'Disease', 'MESH:D001254', (168, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (168, 179))	('enhanced', 'PosReg', (62, 70))	('EGR1', 'Gene', (12, 16))	('expression', 'Var', (17, 27))	('astrocytomas', 'Disease', (168, 180))	('patient', 'Species', '9606', (71, 78))	('patient survival', 'CPA', (71, 87))
215195	29246166	But, stable knockdown of EGR1 in GSCs and normal glioma cells inhibited growth in cellular level and xenografted tumor.	('tumor', 'Disease', (113, 118))	('glioma cells', 'Disease', (49, 61))	('EGR1', 'Gene', (25, 29))	('glioma cells', 'Disease', 'MESH:D005910', (49, 61))	('knockdown', 'Var', (12, 21))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('inhibited', 'NegReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('growth in', 'CPA', (72, 81))
215255	29246166	In addition, EDU-positive cell rates were significantly decreased in siEGR1 group compared to the negative control (NC) group (Fig.	('EDU-positive cell rates', 'CPA', (13, 36))	('siEGR1', 'Var', (69, 75))	('EDU', 'Chemical', 'MESH:C031086', (13, 16))	('decreased', 'NegReg', (56, 65))
215256	29246166	These results identified the EGR1 knockdown by RNAi inhibited the proliferation of U251, U87 and U251SLC cells.	('proliferation', 'CPA', (66, 79))	('EGR1', 'Gene', (29, 33))	('inhibited', 'NegReg', (52, 61))	('knockdown', 'Var', (34, 43))	('U87', 'CellLine', 'CVCL:0022', (89, 92))
215257	29246166	A significant decreases in S phase was observed in siEGR1 group (12.69% in U87, 31.44% in U251, 17.09% in U251SLC), compared with the NC group (34.60% in U87, 54.92% in U251, 29.20% in U251SLC) (Fig.	('siEGR1', 'Var', (51, 57))	('U251', 'Var', (90, 94))	('decreases', 'NegReg', (14, 23))	('U251SLC', 'Var', (106, 113))	('U87', 'Var', (75, 78))	('S phase', 'MPA', (27, 34))	('U87', 'CellLine', 'CVCL:0022', (75, 78))	('U87', 'CellLine', 'CVCL:0022', (154, 157))
215258	29246166	At the same time, A significant increase in S phase was observed in siEGR1 group (72.45% in U87, 35.03% in U251, 74.91% in U251SLC), compared with the NC group (55.43% in U87, 14.69% in U251, 65.00% in U251SLC) (Fig.	('S phase', 'MPA', (44, 51))	('U251', 'Var', (107, 111))	('U87', 'CellLine', 'CVCL:0022', (171, 174))	('increase', 'PosReg', (32, 40))	('U251SLC', 'Var', (123, 130))	('U87', 'Var', (92, 95))	('siEGR1', 'Var', (68, 74))	('U87', 'CellLine', 'CVCL:0022', (92, 95))
215259	29246166	These data demonstrated that knockdown of EGR1 lead to G1 phase arrest and inhibited glioma cell proliferation.	('arrest', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('EGR1', 'Gene', (42, 46))	('knockdown', 'Var', (29, 38))	('inhibited', 'NegReg', (75, 84))	('glioma', 'Disease', (85, 91))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
215267	29246166	The GAPDH promotor region was analyzed and we also found an EGR1 binding site (-432 to -419) near to site of TATA-box (-681 to -656) in GAPDH gene which was able to bind by RNA polymerase II antibody (data not given).	('GAPDH', 'Gene', (4, 9))	('-681 to -656', 'Var', (119, 131))	('binding', 'Interaction', (65, 72))	('GAPDH', 'Gene', '2597', (136, 141))	('EGR1', 'Gene', (60, 64))	('bind', 'Interaction', (165, 169))	('-432', 'Var', (79, 83))	('GAPDH', 'Gene', (136, 141))	('GAPDH', 'Gene', '2597', (4, 9))
215274	29246166	The mice of siEGR1-U251 and NC-U251 group developed tumors at the 50th day (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('siEGR1-U251', 'Var', (12, 23))	('mice', 'Species', '10090', (4, 8))	('developed', 'PosReg', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))
215276	29246166	In contrast, only 3 mice developed xenograft tumors at Day 40 in siEGR1-U251SCL group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('mice', 'Species', '10090', (20, 24))	('xenograft tumors', 'Disease', (35, 51))	('siEGR1-U251SCL', 'Var', (65, 79))	('xenograft tumors', 'Disease', 'MESH:D009369', (35, 51))
215277	29246166	In addition, the average volumes of siEGR1-U251 tumors were approximately 1/10 of the average volumes of control (Fig.	('siEGR1-U251', 'Var', (36, 47))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
215278	29246166	Volumes of siEGR1-U251SLC tumors also were almost 1/10 of those of control (Fig.	('siEGR1-U251SLC', 'Var', (11, 25))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
215280	29246166	Ki-67 staining showed that tumors of siEGR1-U251 group had fewer proliferative cells than NC-U251 group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('proliferative cells', 'CPA', (65, 84))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('siEGR1-U251', 'Var', (37, 48))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('fewer', 'NegReg', (59, 64))
215281	29246166	As shown above, knockdown of EGR1 by RNAi was able to inhibit the growth of glioma cells.	('inhibit', 'NegReg', (54, 61))	('EGR1', 'Gene', (29, 33))	('glioma cells', 'Disease', (76, 88))	('knockdown', 'Var', (16, 25))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('glioma cells', 'Disease', 'MESH:D005910', (76, 88))
215290	29246166	The western-blot showed that proteins of EGR1 and CCND1 increased significantly in U251 cells and U251SLCs by EGF with or without EGR1 knock-down (Fig.	('EGF', 'Gene', '1950', (110, 113))	('increased', 'PosReg', (56, 65))	('CCND1', 'Gene', (50, 55))	('proteins', 'Protein', (29, 37))	('EGF', 'Gene', (110, 113))	('knock-down', 'Var', (135, 145))	('EGR1', 'Gene', (41, 45))
215301	29246166	found that EGR1 expression was associated with enhanced patient survival in high grade astrocytomas.	('EGR1', 'Gene', (11, 15))	('enhanced', 'PosReg', (47, 55))	('expression', 'Var', (16, 26))	('patient survival', 'CPA', (56, 72))	('astrocytomas', 'Disease', 'MESH:D001254', (87, 99))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('patient', 'Species', '9606', (56, 63))	('astrocytomas', 'Disease', (87, 99))
215309	29246166	However, Choi reported that the proliferation of U87 cells was not affected by EGR1 knockdown.	('knockdown', 'Var', (84, 93))	('U87', 'CellLine', 'CVCL:0022', (49, 52))	('EGR1', 'Gene', (79, 83))
215312	29246166	To our surprise, the proliferation of normal U251 cells and U87 cells was also reduced after knockdown EGR1 expression.	('knockdown', 'Var', (93, 102))	('proliferation', 'CPA', (21, 34))	('EGR1', 'Gene', (103, 107))	('reduced', 'NegReg', (79, 86))	('U87', 'CellLine', 'CVCL:0022', (60, 63))
215317	29246166	Our results of xenografts further verified the inhibition of proliferation by stable knockdown EGR1 in glioma cells.	('glioma cells', 'Disease', (103, 115))	('inhibition', 'NegReg', (47, 57))	('glioma cells', 'Disease', 'MESH:D005910', (103, 115))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('knockdown', 'Var', (85, 94))	('EGR1', 'Gene', (95, 99))	('proliferation', 'CPA', (61, 74))
215319	29246166	Moreover, we found that EGR1 knockdown inhibited glioma proliferation on account of G1 phase arrest, which was consistent with the study reported by Han et al..	('EGR1', 'Gene', (24, 28))	('glioma proliferation', 'Disease', (49, 69))	('glioma proliferation', 'Disease', 'MESH:D005910', (49, 69))	('inhibited', 'NegReg', (39, 48))	('knockdown', 'Var', (29, 38))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('arrest', 'Disease', (93, 99))
215329	29246166	We also found that high expression EGF can promote the proliferation of glioma cells.	('high expression', 'Var', (19, 34))	('promote', 'PosReg', (43, 50))	('proliferation', 'CPA', (55, 68))	('glioma cells', 'Disease', (72, 84))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma cells', 'Disease', 'MESH:D005910', (72, 84))	('EGF', 'Gene', (35, 38))	('EGF', 'Gene', '1950', (35, 38))
215340	29246166	In our assays, the proliferation inhibited by EGR1 interference was associated with the G1 phase arrest.	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('EGR1', 'Gene', (46, 50))	('proliferation', 'CPA', (19, 32))	('arrest', 'Disease', (97, 103))	('interference', 'Var', (51, 63))	('inhibited', 'NegReg', (33, 42))
215341	29246166	In conclusion, our study clarified that stable knockdown EGR1 would inhibit glioma cell growth in vitro and in vivo.	('glioma', 'Disease', (76, 82))	('inhibit', 'NegReg', (68, 75))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('knockdown', 'Var', (47, 56))	('EGR1', 'Gene', (57, 61))
215342	29246166	The results confirmed that the basal level of high EGR1 expression will promote glioma proliferation and partly explained the reason why the patients with higher EGR1 expression showed shorter survival.	('high', 'Var', (46, 50))	('shorter', 'NegReg', (185, 192))	('glioma proliferation', 'Disease', (80, 100))	('glioma proliferation', 'Disease', 'MESH:D005910', (80, 100))	('promote', 'PosReg', (72, 79))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('patients', 'Species', '9606', (141, 149))	('EGR1', 'Gene', (51, 55))
215345	29246166	And further knockdown of the expression of these genes may better control the progression of cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('progression', 'CPA', (78, 89))	('knockdown', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('control', 'Reg', (66, 73))
215354	26346755	Furthermore, both LGG and HGG are characterized by a wide clinical and histological heterogeneity; this is particularly true for HGG, because 35-40% of them have epigenetic modifications as the underlying mechanism driving malignancy.	('epigenetic modifications', 'Var', (162, 186))	('malignancy', 'Disease', (223, 233))	('malignancy', 'Disease', 'MESH:D009369', (223, 233))	('HGG', 'Disease', (129, 132))
215395	26346755	showed how the dominant uncinate fasciculus contributes to semantic memory and naming performance by outlining that during IOM direct electrostimulation of this fasciculus may disrupt its crosstalk with the memory circuit resulting in naming difficulty, verbal paraphasia, and recurrent and continuous perseveration.	('fasciculus', 'Disease', (161, 171))	('electrostimulation', 'Var', (134, 152))	('verbal paraphasia', 'Phenotype', 'HP:0002427', (254, 271))	('fasciculus', 'Disease', 'None', (161, 171))	('verbal paraphasia', 'Disease', 'MESH:D001039', (254, 271))	('memory', 'Pathway', (207, 213))	('disrupt', 'NegReg', (176, 183))	('naming', 'Disease', (235, 241))	('fasciculus', 'Disease', (33, 43))	('verbal paraphasia', 'Disease', (254, 271))	('perseveration', 'Phenotype', 'HP:0030223', (302, 315))	('fasciculus', 'Disease', 'None', (33, 43))	('crosstalk', 'MPA', (188, 197))
215435	21533525	Interestingly, in high-grade gliomas, the level of microvascular density was lower in VM positive tumors than those VM negative tumors (P = 0.039).	('lower', 'NegReg', (77, 82))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('level of microvascular density', 'MPA', (42, 72))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('tumors', 'Disease', (128, 134))	('VM positive', 'Var', (86, 97))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
215444	21533525	The presence of VM is associated with more aggressive tumor biology and increased tumor-related mortality.	('aggressive tumor', 'Disease', (43, 59))	('increased', 'PosReg', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('more', 'PosReg', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('presence', 'Var', (4, 12))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (82, 87))	('aggressive tumor', 'Disease', 'MESH:D001523', (43, 59))
215481	21533525	In patients with VM-positive gliomas, the median survival time was 15 months (95% CI, 2-28 months), compared with a median survival time of 38 months (95% CI, 25-50 months) for patients with VM-negative tumors (P = 0.027) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('patients', 'Species', '9606', (177, 185))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('VM-positive', 'Var', (17, 28))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('patients', 'Species', '9606', (3, 11))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
215514	21533525	To our knowledge, there have been no reports on whether the presence of VM channels would have an impact on the outcome of glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('presence', 'Var', (60, 68))	('impact', 'Reg', (98, 104))	('patients', 'Species', '9606', (130, 138))	('glioma', 'Disease', (123, 129))
215543	21533525	In conclusion, the presence of VM is associated with higher grade in gliomas, and may correlate with the aggressive and invasive nature of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gliomas', 'Disease', (69, 76))	('gliomas', 'Disease', (139, 146))	('correlate with', 'Reg', (86, 100))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('presence', 'Var', (19, 27))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('associated', 'Reg', (37, 47))
215559	28591697	In the past five years, anti-PD-1 or anti-PD-L1 antibodies blocking the binding between PD-1 and PD-L1 have been reported to promote marked antitumor immunity, and have risen to the forefront of immunotherapy due to their notable clinical efficacy in melanoma and non-small cell lung cancer clinical trials.	('PD-1', 'Gene', '5133', (29, 33))	('non-small cell lung cancer', 'Disease', (264, 290))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('antibodies', 'Var', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('PD-1', 'Gene', (88, 92))	('PD-1', 'Gene', '5133', (88, 92))	('tumor', 'Disease', (144, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (264, 290))	('binding', 'Interaction', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('anti-PD-L1', 'Gene', (37, 47))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (268, 290))	('promote', 'PosReg', (125, 132))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (264, 290))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PD-L1', 'Gene', (97, 102))	('PD-1', 'Gene', (29, 33))	('blocking', 'NegReg', (59, 67))
215561	28591697	Aberrant PD-L1 expression has been reported to occur in glioma and to contribute to immunoresistance.	('glioma', 'Disease', (56, 62))	('Aberrant', 'Var', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('contribute', 'Reg', (70, 80))	('occur', 'Reg', (47, 52))	('PD-L1', 'Gene', (9, 14))
215583	28591697	The mean MODs for VEGF, MMP-9 and KI-67 staining were also significantly higher in HGG (0.09598 +- 0.01981, 0.07884 +- 0.01191, and 0.08850 +- 0.01914, respectively) than in LGG (0.02248 +- 0.004159, 0.04203 +- 0.009844, and 0.01151 +- 0.003914, respectively) (p = 0.0078, 0.0401, and 0.0041, respectively; Table 1 and Figure 2).	('0.09598 +- 0.01981', 'Var', (88, 106))	('MMP-9', 'Gene', (24, 29))	('0.07884 +- 0.01191', 'Var', (108, 126))	('VEGF', 'Gene', '7422', (18, 22))	('MODs', 'MPA', (9, 13))	('VEGF', 'Gene', (18, 22))	('MMP-9', 'Gene', '4318', (24, 29))	('higher', 'PosReg', (73, 79))
215587	28591697	Positive VEGF and KI-67 expression were more significant frequently observed in the PD-L1 positive group (85.19% and 86.27%) than in the PD-L1 negative group (14.81% and 13.73%), respectively.	('PD-L1', 'Gene', (84, 89))	('expression', 'MPA', (24, 34))	('VEGF', 'Gene', (9, 13))	('positive', 'Var', (90, 98))	('VEGF', 'Gene', '7422', (9, 13))	('KI-67', 'Gene', (18, 23))
215589	28591697	Because VEGF and KI-67 were more significant frequently observed in the PD-L1 positive group than in the PD-L1 negative group, we decided to analyze the relationships among PD-L1, VEGF and KI-67 levels by treating the MOD as a continuous variable.	('observed', 'Reg', (56, 64))	('positive', 'Var', (78, 86))	('VEGF', 'Gene', (180, 184))	('VEGF', 'Gene', (8, 12))	('VEGF', 'Gene', '7422', (180, 184))	('VEGF', 'Gene', '7422', (8, 12))	('PD-L1', 'Gene', (72, 77))
215605	28591697	We found that PD-L1 immunoreactivity varied considerably among the 64 patients, and that the mean MOD was higher in HGG than in LGG (0.1144 +- 0.02754 vs. 0.005129 +- 0.001441, p = 0.0044).	('PD-L1', 'Protein', (14, 19))	('patients', 'Species', '9606', (70, 78))	('higher', 'PosReg', (106, 112))	('HGG', 'Disease', (116, 119))	('0.1144 +- 0.02754', 'Var', (133, 150))	('MOD', 'MPA', (98, 101))
215625	28591697	MEDI4736, a human anti-PD-L1 antibody, is now being tested in combination with radiotherapy and bevacizumab for the treatment of GBM (NCT02336165).	('NCT02336165', 'Var', (134, 145))	('men', 'Species', '9606', (121, 124))	('GBM', 'Disease', (129, 132))	('human', 'Species', '9606', (12, 17))	('bevacizumab', 'Chemical', 'MESH:D000068258', (96, 107))
215632	28591697	demonstrated that MMP-9 can proteolytically cleave PD-L1 and thus suppress T cell apoptosis.	('PD-L1', 'Protein', (51, 56))	('cleave', 'Var', (44, 50))	('MMP-9', 'Gene', '4318', (18, 23))	('suppress', 'NegReg', (66, 74))	('MMP-9', 'Gene', (18, 23))	('T cell apoptosis', 'CPA', (75, 91))
215635	28591697	Thus, MMP-9 expression is likely to be one of several complex mechanisms that may impact the glioma immune microenvironment.	('MMP-9', 'Gene', (6, 11))	('glioma', 'Disease', (93, 99))	('expression', 'Var', (12, 22))	('impact', 'Reg', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('men', 'Species', '9606', (119, 122))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('MMP-9', 'Gene', '4318', (6, 11))
215680	27339696	Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma.	('liver tumors', 'Disease', (74, 86))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (298, 328))	('liver hepatocellular carcinoma', 'Disease', (298, 328))	('KMT2B', 'Gene', '9757', (42, 47))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('integration', 'Var', (23, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (304, 328))	('KMT2B', 'Gene', (42, 47))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('HBV', 'Gene', (19, 22))
215681	27339696	Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer.	('cervical cancer', 'Disease', (110, 125))	('found', 'Reg', (33, 38))	('HPV', 'Species', '10566', (80, 83))	('PTPN13', 'Gene', '5783', (100, 106))	('HPV integrations', 'Var', (80, 96))	('PTPN13', 'Gene', (100, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
215682	27339696	Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences.	('HBV', 'Gene', (39, 42))	('HHV4', 'Species', '10376', (30, 34))	('HHV4', 'Gene', (30, 34))	('variants', 'Var', (43, 51))	('associated', 'Reg', (61, 71))
215685	27339696	The Cancer Genome Atlas (TCGA) Pan-Cancer project has discovered numerous somatic mutations in key cancer genes.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
215687	27339696	Also, mutational signatures related to endogenous and exogenous DNA damage have been found in different cancer types, such as the APOBEC-associated cytosine deaminase mutational signature and smoking-related cytosine-to-adenine signatures.	('adenine', 'Chemical', 'MESH:D000225', (220, 227))	('cytosine', 'Chemical', 'MESH:D003596', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('APOBEC-associated', 'Gene', (130, 147))	('mutational', 'Var', (167, 177))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cytosine', 'Chemical', 'MESH:D003596', (148, 156))
215697	27339696	Three important issues are explicitly addressed in the present study: 1) differential viral expression and integration patterns between tumors and adjacent normal samples, 2) the discovery and implications of novel rare viral insertions and 3) differences among ethnicities that may point to environmental influences on viral sequence evolution.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('viral', 'MPA', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('insertions', 'Var', (226, 236))	('integration', 'MPA', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('differences', 'Reg', (244, 255))
215717	27339696	However, we did observe some exceptional cases that were positive for two different viruses, for example, one STAD case having HHV4 and HHV5, one LIHC case having HBV and HPV16 (Fig.	('HHV5', 'Var', (136, 140))	('HPV16', 'Species', '333760', (171, 176))	('HHV4', 'Species', '10376', (127, 131))	('HHV5', 'Species', '10359', (136, 140))	('HHV4', 'Var', (127, 131))
215718	27339696	S3A) and one BLCA with having HPV6 and HPV11 (Fig.	('HPV11', 'Var', (39, 44))	('HPV6', 'Var', (30, 34))	('HPV11', 'Species', '10580', (39, 44))	('HPV', 'Species', '10566', (30, 33))	('HPV', 'Species', '10566', (39, 42))
215724	27339696	The clinical-pathological information shows that patient DD-A1EH with only HBV in adjacent normal has a family history of cancer, and sample DD-A11A with HBV in tumor has no family history of cancer, which may indicate different cancer etiologies, i.e., inherited mutations and HBV infection, respectively.	('DD-A1EH', 'Var', (57, 64))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patient', 'Species', '9606', (49, 56))	('HBV infection', 'Disease', (278, 291))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HBV infection', 'Disease', 'MESH:D006509', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
215742	27339696	Importantly, in these six tumors, we found three samples with HBV virus integration in KMT2B (MLL4), suggesting the integration sites in this gene are important for the development of liver cancer, consistent with other studies.	('important', 'Reg', (151, 160))	('integration', 'Var', (72, 83))	('KMT2B', 'Gene', '9757', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('MLL4', 'Gene', '9757', (94, 98))	('MLL4', 'Gene', (94, 98))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('KMT2B', 'Gene', (87, 92))	('liver cancer', 'Disease', (184, 196))	('tumors', 'Disease', (26, 32))
215753	27339696	For instance, we found that EBER-1 is highly expressed in BR-8676.	('EBER-1', 'Gene', (28, 34))	('BR-8676', 'Var', (58, 65))	('BR', 'Chemical', 'MESH:D001966', (58, 60))
215757	27339696	Because disruption of apoptosis can lead to tumor initiation, progression, or metastasis, RNA2.7 can be regarded as a viral oncogene.	('disruption', 'Var', (8, 18))	('lead to', 'Reg', (36, 43))	('progression', 'CPA', (62, 73))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('metastasis', 'CPA', (78, 88))	('apoptosis', 'Protein', (22, 31))	('tumor initiation', 'Disease', (44, 60))
215763	27339696	E6/E7 were involved in binding and degrading p53/Rb proteins and their expression suggests that HPV16 may also play a role in the tumorgenesis in these LGG samples.	('play', 'Reg', (111, 115))	('expression', 'MPA', (71, 81))	('E6/E7', 'Var', (0, 5))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('binding', 'Interaction', (23, 30))	('HPV16', 'Species', '333760', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('LGG', 'Disease', (152, 155))	('HPV16', 'Gene', (96, 101))	('tumor', 'Disease', (130, 135))	('degrading', 'NegReg', (35, 44))
215764	27339696	Discordant read pair analysis using Pindel (see Methods) revealed a battery of genes having recurrent HPV integrations in several cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('integrations', 'Var', (106, 118))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HPV', 'Species', '10566', (102, 105))
215772	27339696	The second hotpot of recurrent virus integration is at the RAD51B locus in 8 CESC samples, which include 3 samples with HPV16, 2 samples with HPV39, one with HPV18 and one with HPV45; interestingly, two HNSC tumors also harbor HPV16 integration at RAD51B.	('RAD51B', 'Gene', (59, 65))	('RAD51B', 'Gene', '5890', (248, 254))	('RAD51B', 'Gene', '5890', (59, 65))	('HNSC tumors', 'Disease', (203, 214))	('RAD51B', 'Gene', (248, 254))	('HPV', 'Species', '10566', (227, 230))	('HPV16', 'Species', '333760', (120, 125))	('HPV', 'Species', '10566', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('HPV', 'Species', '10566', (177, 180))	('HPV16 integration', 'Var', (227, 244))	('HPV16', 'Species', '333760', (227, 232))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('HNSC tumors', 'Disease', 'MESH:D009369', (203, 214))	('HPV', 'Species', '10566', (158, 161))	('HPV', 'Species', '10566', (120, 123))
215773	27339696	Whole-genome sequencing analysis reveals that HPV integration amplifies the somatic copy number of this region.	('HPV', 'Species', '10566', (46, 49))	('integration', 'Var', (50, 61))	('amplifies', 'PosReg', (62, 71))	('HPV', 'Gene', (46, 49))
215778	27339696	Three samples (C5-A1M9, DS-A7WF, LP-A5U3) with viral integration at ERBB2 locus showed significantly increased expression across all exons (P-value < 0.05) (Fig.	('increased', 'PosReg', (101, 110))	('viral integration', 'Var', (47, 64))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))	('expression', 'MPA', (111, 121))
215787	27339696	4C, HPV18 integrates at intron 1 of PTPN13 in sample EK-A2PK, while HPV16 integrates at exons 2 and 14 for samples WL-A834 and VS-A8QC, respectively.	('HPV', 'Species', '10566', (4, 7))	('integrates', 'Reg', (10, 20))	('PTPN13', 'Gene', (36, 42))	('HPV16', 'Species', '333760', (68, 73))	('VS-A8QC', 'Var', (127, 134))	('HPV18', 'Gene', (4, 9))	('integrates', 'Reg', (74, 84))	('HPV16', 'Gene', (68, 73))	('HPV', 'Species', '10566', (68, 71))	('PTPN13', 'Gene', '5783', (36, 42))
215788	27339696	The distinct virus integration sites and the consistent increase of the expression of the integrated or nearby exons provide strong evidence of novel recurrent HPV integrations within PTPN13.	('increase', 'PosReg', (56, 64))	('integrations', 'Var', (164, 176))	('expression', 'MPA', (72, 82))	('PTPN13', 'Gene', '5783', (184, 190))	('HPV', 'Species', '10566', (160, 163))	('HPV', 'Gene', (160, 163))	('PTPN13', 'Gene', (184, 190))
215793	27339696	For example, TERT was recently implicated by somatic events or viral integration in hepatocarcinogensis.	('TERT', 'Gene', (13, 17))	('hepatocarcinogensis', 'Disease', (84, 103))	('TERT', 'Gene', '7015', (13, 17))	('hepatocarcinogensis', 'Disease', 'None', (84, 103))	('viral integration', 'Var', (63, 80))
215794	27339696	Figure 4D and Table S2 show that the integration sites on KMT2B are between exon 3 and exon 8 and integrations often lead to increased expression of exons following these sites; this holds true for TERT, as well (Fig.	('increased', 'PosReg', (125, 134))	('KMT2B', 'Gene', '9757', (58, 63))	('TERT', 'Gene', '7015', (198, 202))	('integrations', 'Var', (98, 110))	('KMT2B', 'Gene', (58, 63))	('TERT', 'Gene', (198, 202))	('expression of exons', 'MPA', (135, 154))
215798	27339696	The average number of variants for HHV4, HBV and HPV16 are 121, 52 and 22, respectively.	('HBV', 'Gene', (41, 44))	('HHV4', 'Species', '10376', (35, 39))	('HHV4', 'Gene', (35, 39))	('HPV16', 'Gene', (49, 54))	('variants', 'Var', (22, 30))	('HPV16', 'Species', '333760', (49, 54))
215800	27339696	Using RPHM >= 1000 and sites with coverage >10X, we selected 50 variant sites for HBV across 50 HBV-positive LIHC samples, 101 variants across 24 HHV4-positive STAD samples, 17 variants across 60 HPV16-postive HNSC samples and 22 variants across 142 HPV16-positive CESC samples.	('variants', 'Var', (127, 135))	('HBV', 'Gene', (82, 85))	('HPV16', 'Species', '333760', (250, 255))	('HHV4', 'Species', '10376', (146, 150))	('variant', 'Var', (64, 71))	('HPV16', 'Species', '333760', (196, 201))
215801	27339696	Figure 5A shows the unsupervised clustering results for HHV4 variants across HHV4-positive samples with Caucasian and Asian cohorts separated in distinct groups.	('HHV4', 'Species', '10376', (56, 60))	('HHV4', 'Gene', (56, 60))	('HHV4-positive', 'Gene', (77, 90))	('HHV4', 'Species', '10376', (77, 81))	('variants', 'Var', (61, 69))
215802	27339696	Three variants, C   T at sites 343 and 454 and G   A at site 633, result in amino acid substitutions, L418F and P455S in HBV polymerase protein and R160K in S protein, respectively.	('R160K', 'Mutation', 'rs1222267645', (148, 153))	('R160K', 'Var', (148, 153))	('P455S', 'Var', (112, 117))	('HBV', 'Gene', (121, 124))	('P455S', 'Mutation', 'p.P455S', (112, 117))	('L418F', 'Mutation', 'p.L418F', (102, 107))	('L418F', 'Var', (102, 107))
215803	27339696	Variants C   T at sites 505 and 586 and A   G at site 616 are missense mutations, which lead to the respective amino acid substitutions H472Y, R499W and I509 V in HBV polymerase.	('R499W', 'Var', (143, 148))	('I509 V', 'Mutation', 'p.I509V', (153, 159))	('R499W', 'Mutation', 'rs199530208', (143, 148))	('H472Y', 'Mutation', 'p.H472Y', (136, 141))	('H472Y', 'Var', (136, 141))	('I509 V', 'Var', (153, 159))	('HBV polymerase', 'Enzyme', (163, 177))
215804	27339696	Finally, the tumor and adjacent normal pairs have the same variants for the sites observed in Fig.	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (13, 18))	('variants', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
215805	27339696	5B, except for sample DD-A116, in which HBV found in the tumor has an additional variant (A   G) at site 1034, leading to an amino acid substitution Q648R in the HBV polymerase.	('Q648R', 'Var', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Q648R', 'Mutation', 'rs1057519862', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('HBV polymerase', 'Enzyme', (162, 176))	('tumor', 'Disease', (57, 62))
215806	27339696	We also examined viral variation by cancer type by comparing HPV16 variants between CESC and HNSC samples.	('comparing', 'Reg', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('HPV16', 'Gene', (61, 66))	('HPV16', 'Species', '333760', (61, 66))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('examined', 'Reg', (8, 16))	('variants', 'Var', (67, 75))
215808	27339696	Most HPV16 variants overlap between the two cancer types, which suggests they reflect population diversity rather than tissue origin.	('HPV16', 'Gene', (5, 10))	('HPV16', 'Species', '333760', (5, 10))	('variants', 'Var', (11, 19))	('overlap', 'Reg', (20, 27))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
215811	27339696	We did not observe any strong correlation between HPV16 variants and ethnic group.	('HPV16', 'Species', '333760', (50, 55))	('HPV16', 'Gene', (50, 55))	('variants', 'Var', (56, 64))
215814	27339696	HPV subtypes in BLCA are HPV45, HPV51, HPV56 and HPV6 and virus abundance in four samples is especially high (RPHM > 104).	('HPV45', 'Var', (25, 30))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (25, 28))	('HPV', 'Species', '10566', (49, 52))	('HPV51', 'Var', (32, 37))	('HPV6', 'Var', (49, 53))	('HPV', 'Species', '10566', (32, 35))	('HPV', 'Species', '10566', (39, 42))	('HPV56', 'Var', (39, 44))
215824	27339696	For instance, recurrent HBV integrations in the KMT2B (MLL4) were observed in tumors, but none in adjacent normal samples.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('KMT2B', 'Gene', '9757', (48, 53))	('HBV', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLL4', 'Gene', '9757', (55, 59))	('MLL4', 'Gene', (55, 59))	('integrations', 'Var', (28, 40))	('KMT2B', 'Gene', (48, 53))
215832	27339696	In addition, the analyses of virus variants in tumor samples reveal the association of virus variants and ethnicity groups for HBV in LIHC and HHV4 in STAD.	('HBV', 'Gene', (127, 130))	('HHV4', 'Gene', (143, 147))	('association', 'Interaction', (72, 83))	('variants', 'Var', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LIHC', 'Disease', (134, 138))	('tumor', 'Disease', (47, 52))	('HHV4', 'Species', '10376', (143, 147))
215852	27339696	We used the contml tool from the PHYLIP toolkit (http://evolution.genetics.washington.edu/phylip.html) to construct phylogenetic trees based on variant allele fraction for HBV and HHV4.	('HHV4', 'Gene', (180, 184))	('HBV', 'Gene', (172, 175))	('HHV4', 'Species', '10376', (180, 184))	('variant', 'Var', (144, 151))
215875	25945328	The DWI imaging was calculated by at two-segment monoexponential algorithm as shown in IVIM equation (1), where D and D * are the diffusion parameters related to molecular diffusion and to the perfusion-related diffusion, respectively, S/S0 is the normalized signal attenuation, and f is the perfusion fraction.	('D *', 'Var', (118, 121))	('S/S0', 'MPA', (236, 240))	('men', 'Species', '9606', (44, 47))
215893	25945328	Compared to previously recent published works in gliomas, in this research more and greater b values were used, as more b values in segment of low b values can get more acute perfusion-related diffusion, while higher b values can better eliminate the perfusion-related diffusion; thus it can in turn generate a more realistic molecular diffusion coefficient value and perfusion-related diffusion.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('low b values', 'Var', (143, 155))	('more', 'PosReg', (311, 315))	('perfusion-related diffusion', 'MPA', (251, 278))	('men', 'Species', '9606', (135, 138))	('acute perfusion-related diffusion', 'MPA', (169, 202))	('perfusion-related diffusion', 'MPA', (368, 395))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('molecular diffusion coefficient value', 'MPA', (326, 363))	('gliomas', 'Disease', (49, 56))	('eliminate', 'NegReg', (237, 246))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
215973	33465115	The evaluation of CKMT1B expression as an independent parameter was conducted by integrating the following clinical parameters into the univariate and multivariable Cox regression analysis: age, gender, grade, radiotherapy-status, chemotherapy-status, IDH-mutation status, MGMT-promoter methylated, 1p19q-codeletion, and CKMT1B expression.	('CKMT1B', 'Gene', '1159', (18, 24))	('CKMT1B', 'Gene', (18, 24))	('1p19q-codeletion', 'Var', (299, 315))	('IDH', 'Gene', (252, 255))	('CKMT1B', 'Gene', '1159', (321, 327))	('CKMT1B', 'Gene', (321, 327))	('IDH', 'Gene', '3417', (252, 255))
215983	33465115	LGG patients with low expression of CKMT1B were more likely to present a more advanced tumor grade (II vs III, odds ratio = 0.52, p-value<0.001, Fig 1C).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CKMT1B', 'Gene', '1159', (36, 42))	('patients', 'Species', '9606', (4, 12))	('low expression', 'Var', (18, 32))	('CKMT1B', 'Gene', (36, 42))
215995	33465115	As shown in Fig 4, CKMT1B expression affects the infiltration level of M2 macrophages, activated mast cells and resting mast cells, among which M2 macrophages and activated mast cells are significantly different.	('infiltration level of M2 macrophages', 'MPA', (49, 85))	('expression', 'Var', (26, 36))	('affects', 'Reg', (37, 44))	('CKMT1B', 'Gene', '1159', (19, 25))	('CKMT1B', 'Gene', (19, 25))
216003	33465115	Consistent with our original data, high expression of CKMT1B predicts favorable prognosis in validation set (P = 4.957e-05, Fig 1D).	('CKMT1B', 'Gene', (54, 60))	('high expression', 'Var', (35, 50))	('CKMT1B', 'Gene', '1159', (54, 60))	('favorable', 'PosReg', (70, 79))
216004	33465115	As shown in S1 Fig, multivariate Cox analysis uncovered that overall survival was significantly associated with grade (HR = 3.76, p-value<0.001), 1p19q_codeletion_status (HR = 0.23, p-value<0.001), CKMT1B (HR = 0.75, p-value<0.001).	('overall', 'CPA', (61, 68))	('CKMT1B', 'Gene', '1159', (198, 204))	('CKMT1B', 'Gene', (198, 204))	('1p19q_codeletion_status', 'Var', (146, 169))	('associated', 'Interaction', (96, 106))
216015	33465115	LGG patients with low expression of CKMT1B were more likely to present a more advanced tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CKMT1B', 'Gene', '1159', (36, 42))	('patients', 'Species', '9606', (4, 12))	('low expression', 'Var', (18, 32))	('CKMT1B', 'Gene', (36, 42))
216027	33465115	The K-M survival curve analyses of 128 patients with prostate cancer showed that high-CKMT1B expression slightly reduced the PSA recurrence-free survival rate compared with patients with weak to moderate CKMT1B expression.	('expression', 'Var', (93, 103))	('prostate cancer', 'Disease', (53, 68))	('PSA', 'Disease', (125, 128))	('patients', 'Species', '9606', (39, 47))	('CKMT1B', 'Gene', '1159', (86, 92))	('patients', 'Species', '9606', (173, 181))	('CKMT1B', 'Gene', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('CKMT1B', 'Gene', '1159', (204, 210))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('CKMT1B', 'Gene', (204, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('reduced', 'NegReg', (113, 120))
216071	33465115	Finally, the results further suggest that an independent prognostic factor, high expression of CKMT1B mRNA, could be used to improve clinical outcomes in LGG patients.	('high expression', 'Var', (76, 91))	('LGG', 'Disease', (154, 157))	('patients', 'Species', '9606', (158, 166))	('improve', 'PosReg', (125, 132))	('CKMT1B', 'Gene', '1159', (95, 101))	('CKMT1B', 'Gene', (95, 101))
216128	31522214	In addition, photons-CSA was associated with significantly higher rates of grade 2 emesis, dysphagia, and myelo-suppression.	('CSA', 'Chemical', '-', (21, 24))	('myelo-suppression', 'Disease', 'MESH:D011596', (106, 123))	('dysphagia', 'Phenotype', 'HP:0002015', (91, 100))	('dysphagia', 'Disease', 'MESH:D003680', (91, 100))	('emesis', 'Phenotype', 'HP:0002013', (83, 89))	('dysphagia', 'Disease', (91, 100))	('myelo-suppression', 'Disease', (106, 123))	('photons-CSA', 'Var', (13, 24))	('higher', 'PosReg', (59, 65))	('grade', 'Disease', (75, 80))
216188	31522214	A small study from Sweden, compromising seven patients with locally advanced rectal cancers (sacrum or pelvic sidewall invasion) with IMRT and PBT (45 Gy to elective lymph nodes, 50 Gy to the primary tumor and 62.5 Gy to boost areas in 25 fractions).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('rectal cancer', 'Phenotype', 'HP:0100743', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('compromising', 'NegReg', (27, 39))	('tumor', 'Disease', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('45 Gy', 'Var', (148, 153))
216331	30216655	Recent studies have reported that the genetic alteration of some lncRNAs conferred a selective growth advantage to the cancer cells in which it occurs, playing an important role in the initiation and progression of cancer (Schmitt and Chang, 2016; Yan et al., 2015).	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('growth advantage', 'CPA', (95, 111))	('genetic alteration', 'Var', (38, 56))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
216336	30216655	Therefore, comprehensive identification of genetically altered driver lncRNAs across distinct tumor types is not only urgently needed, but also may promote new diagnostic and therapeutic strategies for cancer (Yan et al., 2015).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('genetically', 'Var', (43, 54))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('promote', 'PosReg', (148, 155))
216338	30216655	Some passenger lncRNAs also show random or hitchhiking somatic mutations, which can confound the analysis of cancer drivers (Garraway and Lander, 2013; Marx, 2014; Pon and Marra, 2015).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('hitchhiking', 'Var', (43, 54))	('Pon', 'Gene', (164, 167))	('cancer', 'Disease', (109, 115))	('Pon', 'Gene', '5444', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
216341	30216655	Interestingly, such genetically altered lncRNAs were found to be mutually exclusive with well-known cancer driver genes.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('genetically altered', 'Var', (20, 39))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
216351	30216655	Next, we screened for PCGs/lncRNAs whose copy number significantly affected their expression levels using a one-tailed Wilcoxon signed rank test with P < 0.05.	('expression levels', 'MPA', (82, 99))	('PCGs', 'Chemical', 'MESH:D010400', (22, 26))	('affected', 'Reg', (67, 75))	('copy number', 'Var', (41, 52))
216352	30216655	On average, 231 lncRNAs and 1425 PCGs per cancer type were found to be altered (with amplifications or deletions) (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('altered', 'Reg', (71, 78))	('deletions', 'Var', (103, 112))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('PCGs', 'Chemical', 'MESH:D010400', (33, 37))
216375	30216655	In detail, for each cancer type, only copy number affected PCGs that were recorded in the known driver PCG category downloaded from Cancer Gene Census (CGC) (Futreal et al., 2004) were regarded as driver PCGs according to the following criteria: (i) the copy number alteration of drivers occurred in more than 2.5% of samples; (ii) the copy number alteration showed detectable RNA expression (RPKM > 0.3 in at least 30% of the samples); and (iii) the copy number alteration significantly affected RNA expression levels by one-tailed Wilcoxon signed rank test with P < 0.05.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PCG', 'Chemical', '-', (204, 207))	('PCGs', 'Chemical', 'MESH:D010400', (204, 208))	('PCGs', 'Chemical', 'MESH:D010400', (59, 63))	('copy number alteration', 'Var', (451, 473))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('affected', 'Reg', (488, 496))	('cancer', 'Disease', (20, 26))	('RNA expression levels', 'MPA', (497, 518))	('PCG', 'Chemical', '-', (59, 62))	('PCG', 'Chemical', '-', (103, 106))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Disease', (132, 138))	('copy number alteration', 'Var', (336, 358))	('RNA expression', 'MPA', (377, 391))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
216397	30216655	Patients were stratified based on continuous copy number alteration or expression above or below the median.	('expression', 'MPA', (71, 81))	('continuous copy number alteration', 'Var', (34, 67))	('Patients', 'Species', '9606', (0, 8))
216405	30216655	(ii) lncRNAs were amplified in corresponding cells at log2 ratio > 0 (i.e., A549 for LUAD and MCF-7 for BRCA).	('BRCA', 'Gene', '672', (104, 108))	('BRCA', 'Gene', (104, 108))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('MCF-7', 'CellLine', 'CVCL:0031', (94, 99))	('A549', 'Var', (76, 80))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('BRCA', 'Phenotype', 'HP:0003002', (104, 108))
216406	30216655	Here, copy number alterations of lncRNAs in cell lines were obtained from the Cancer Cell Line Encyclopedia (Barretina et al., 2012) (https://portals.broadinstitute.org/ccle/home).	('Cancer Cell Line Encyclopedia', 'Disease', (78, 107))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (78, 107))	('copy number alterations', 'Var', (6, 29))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))
216420	30216655	Copy number alterations affected a large fraction of cancer genomes, activating oncogenes and inactivating tumor suppressors, and consequently contributed to tumorigenesis.	('inactivating', 'NegReg', (94, 106))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oncogenes', 'Protein', (80, 89))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Copy number alterations', 'Var', (0, 23))	('activating', 'PosReg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('affected', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('contributed to', 'Reg', (143, 157))
216423	30216655	An average of 3080 lncRNAs (and 4038 PCGs) per cancer type showed copy number alterations.	('PCGs', 'Chemical', 'MESH:D010400', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('copy number alterations', 'Var', (66, 89))	('cancer', 'Disease', (47, 53))	('showed', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
216432	30216655	1D), implying that copy number alteration was a potent contributor to lncRNA dysregulation in cancer.	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('copy number alteration', 'Var', (19, 41))
216433	30216655	For example, lncRNA RP11-745C15.2 was amplified in 39.1% of samples in GBM, resulting in an almost 50-fold increase in the expression compared to wild-type (Fig.	('RP11', 'Gene', '26121', (20, 24))	('expression', 'MPA', (123, 133))	('increase', 'PosReg', (107, 115))	('lncRNA', 'Var', (13, 19))	('RP11', 'Gene', (20, 24))
216462	30216655	Although CRISPRd identified functional lncRNAs in the liver cancer cell line Huh7.5OC, we only found two candidates identified in our results (amplification of lncRNA LINC00885 and AC084809.2 in HNSC and BRCA, respectively; P = 0.30, hypergeometric test), which may be a result of the tissue specificity of lncRNAs.	('LINC00885', 'Gene', '401109', (167, 176))	('LINC00885', 'Gene', (167, 176))	('BRCA', 'Phenotype', 'HP:0003002', (204, 208))	('AC084809.2', 'Var', (181, 191))	('Huh7.5OC', 'CellLine', 'CVCL:7927', (77, 85))	('HNSC', 'Phenotype', 'HP:0012288', (195, 199))	('BRCA', 'Gene', '672', (204, 208))	('liver cancer', 'Phenotype', 'HP:0002896', (54, 66))	('liver cancer', 'Disease', 'MESH:D006528', (54, 66))	('BRCA', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('liver cancer', 'Disease', (54, 66))
216464	30216655	For example, deletion of lncRNA ANRIL and CDK4 constituted a mutually exclusive module associated with the hallmark 'Self Sufficiency in Growth Signals' in GBM (Fig.	('CDK4', 'Gene', '1019', (42, 46))	('lncRNA', 'Gene', (25, 31))	("hallmark 'Self Sufficiency", 'Disease', (107, 133))	('ANRIL', 'Gene', (32, 37))	('associated', 'Reg', (87, 97))	('deletion', 'Var', (13, 21))	('Sufficiency in Growth', 'Phenotype', 'HP:0001510', (122, 143))	("hallmark 'Self Sufficiency", 'Disease', 'MESH:D012652', (107, 133))	('ANRIL', 'Gene', '100048912', (32, 37))	('CDK4', 'Gene', (42, 46))
216469	30216655	The inactivation of NORAD was sufficient to produce a chromosomal instability phenotype (Lee et al., 2016).	('inactivation', 'Var', (4, 16))	('produce', 'Reg', (44, 51))	('chromosomal instability phenotype', 'MPA', (54, 87))	('NORAD', 'Gene', '647979', (20, 25))	('chromosomal instability', 'Phenotype', 'HP:0040012', (54, 77))	('NORAD', 'Gene', (20, 25))
216470	30216655	In LUSC, deletion of lncRNA MIR31HG was identified to form a mutually exclusive module affecting hallmark 'Genome Instability and Mutation' (Fig.	('MIR31HG', 'Gene', (28, 35))	('deletion', 'Var', (9, 17))	("'Genome Instability", 'MPA', (106, 125))	('affecting', 'Reg', (87, 96))	("Mutation'", 'MPA', (130, 139))	('MIR31HG', 'Gene', '554202', (28, 35))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
216477	30216655	Similarly, these lncRNAs and cancer driver PCGs were both significantly enriched in sensitive/ultra-sensitive regions, which exhibit depletion of common polymorphisms and strong enrichment in disease-causing mutations (Khurana et al., 2013) (P < 0.001, hypergeometric test) (Fig.	('PCGs', 'Chemical', 'MESH:D010400', (43, 47))	('cancer', 'Disease', (29, 35))	('mutations', 'Var', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('disease-causing', 'Reg', (192, 207))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
216495	30216655	For example, in GBM, amplification of RP11-745C15.2 and deletion of CDKN2B-AS1 were both associated with the hallmark pathway of 'ceramide biosynthetic process', which was reported to promote apoptosis in glioblastoma (Sordillo et al., 2016), whereas, in PRAD, deletion of lncRNA AC003102.3, RGMB-AS1, and DLG5-AS1 was all related to the hallmark pathway of 'Urogenital System Development', during which the dysfunction in cell lineage specification predisposed prostate epithelia to hyperplasia and cancer (Brechka et al., 2016).	('deletion', 'Var', (56, 64))	('associated', 'Reg', (89, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('RGMB-AS1', 'Gene', '503569', (292, 300))	('RP11', 'Gene', '26121', (38, 42))	('CDKN2B-AS1', 'Gene', '100048912', (68, 78))	('prostate epithelia to hyperplasia and cancer', 'Disease', 'MESH:D011470', (462, 506))	('cancer', 'Phenotype', 'HP:0002664', (500, 506))	('glioblastoma', 'Disease', (205, 217))	('RGMB-AS1', 'Gene', (292, 300))	('CDKN2B-AS1', 'Gene', (68, 78))	('DLG5-AS1', 'Gene', '100128292;9231;5729', (306, 314))	('RP11', 'Gene', (38, 42))	('amplification', 'Var', (21, 34))	('DLG5-AS1', 'Gene', (306, 314))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	("'Urogenital System", 'Phenotype', 'HP:0000119', (358, 376))	('promote', 'PosReg', (184, 191))
216502	30216655	6E,F) and deregulation of CCNE1 expression led to genomic instability via mitotic delay (Caldon et al., 2013).	('mitotic delay', 'CPA', (74, 87))	('CCNE1', 'Gene', '898', (26, 31))	('deregulation', 'Var', (10, 22))	('CCNE1', 'Gene', (26, 31))	('genomic instability', 'CPA', (50, 69))	('led to', 'Reg', (43, 49))
216509	30216655	Specifically, in LGG, amplification of candidate driver lncRNA AC000123.4 conferred a poor prognosis to patients with glioma (P < 0.001 for DFS, log-rank test) (Fig.	('glioma', 'Disease', (118, 124))	('amplification', 'Var', (22, 35))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('AC000123.4', 'Gene', (63, 73))	('patients', 'Species', '9606', (104, 112))	('poor', 'NegReg', (86, 90))
216510	30216655	The median recurrence-free interval of AC000123.4 amplification patients was 39.6 months [95% confidence interval (CI) = 35.6-63.8], whereas that of AC000123.4 diploid patients was 68.9 months (95% CI = 44.5-100.9).	('amplification', 'Var', (50, 63))	('AC000123.4 amplification', 'Var', (39, 63))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (64, 72))
216511	30216655	Multivariate Cox proportional hazards models further showed that AC000123.4 amplification had a poor effect on DFS (hazard ratio (HR), 1.99, 95% CI = 1.38-2.88) (Table S7) independent of the patient's age, gender and pathologic stages.	('AC000123.4 amplification', 'Var', (65, 89))	('Cox', 'Gene', (13, 16))	('DFS', 'Disease', (111, 114))	('patient', 'Species', '9606', (191, 198))	('Cox', 'Gene', '1351', (13, 16))
216512	30216655	Moreover, its expression was significantly up-regulated in tumors with AC000123.4 amplification (P = 0.002, Student's t test) (Fig.	('AC000123.4 amplification', 'Var', (71, 95))	('expression', 'MPA', (14, 24))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('up-regulated', 'PosReg', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
216513	30216655	Likewise, we observed that up-expression of AC000123.4 in LGG was also significantly associated with decreased survival in patients (P < 0.001 for DFS, log-rank test) (Fig.	('AC000123.4', 'Var', (44, 54))	('survival', 'MPA', (111, 119))	('up-expression', 'PosReg', (27, 40))	('patients', 'Species', '9606', (123, 131))	('decreased', 'NegReg', (101, 110))
216516	30216655	Activated EGFR increased the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis (Larsen et al., 2011) and amplification of EGFR also indicated poor prognosis in glioma (Sun et al., 2014) (Fig.	('EGFR', 'Gene', '1956', (10, 14))	('promote', 'PosReg', (118, 125))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('EGFR', 'Gene', (10, 14))	('production', 'MPA', (29, 39))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('angiogenesis', 'CPA', (126, 138))	('VEGF', 'Gene', (57, 61))	('amplification', 'Var', (165, 178))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('glioma', 'Disease', (220, 226))	('VEGF', 'Gene', '7422', (57, 61))
216517	30216655	Interestingly, in EGFR wild-type samples, amplification of AC000123.4 is associated with a worse prognosis (DFS: HR = 1.86, 95% CI = 1.26-2.76, P = 0.0018) (Fig.	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('AC000123.4', 'Gene', (59, 69))	('amplification', 'Var', (42, 55))
216519	30216655	The median recurrence-free interval of AC000123.4 amplification patients without EGFR amplification was 42.9 months (95% CI = 38.90-74.8), whereas that of AC000123.4 diploid patients without EGFR amplification was 72.0 months (95% CI = 44.55-not reached), suggesting a complementary prognostic role of AC000123.4 to EGFR.	('amplification', 'Var', (50, 63))	('patients', 'Species', '9606', (64, 72))	('EGFR', 'Gene', '1956', (316, 320))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (316, 320))	('EGFR', 'Gene', (191, 195))	('patients', 'Species', '9606', (174, 182))	('AC000123.4 amplification', 'Var', (39, 63))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
216520	30216655	Our above observations indicated that these genetically altered lncRNAs may substantially contribute to tumorigenesis by inducing similar functional effects with known cancer driver PCGs in a mutually exclusive manner, suggesting their cancer-driving roles.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('inducing', 'Reg', (121, 129))	('tumor', 'Disease', (104, 109))	('genetically altered', 'Var', (44, 63))	('PCGs', 'Chemical', 'MESH:D010400', (182, 186))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('contribute', 'Reg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
216525	30216655	As a result, cell migration was significantly reduced by depletion of five of these lncRNAs in lung adenocarcinoma and breast cancer cell lines, as shown by a Transwell migration assay (P < 0.05, unpaired Student's test) (Fig.	('cell migration', 'CPA', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('depletion', 'Var', (57, 66))	('Transwell migration assay', 'CPA', (159, 184))	('breast cancer', 'Disease', (119, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('lung adenocarcinoma', 'Disease', (95, 114))	('reduced', 'NegReg', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))
216535	30216655	For example, lncRNA FAL1 amplified in ovarian cancers could promote cell proliferation by recruiting the chromatin repressor protein BMI-1 and inhibiting the expression of CDKN1A (Hu et al., 2014).	('promote', 'PosReg', (60, 67))	('amplified', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('expression', 'MPA', (158, 168))	('cell proliferation', 'CPA', (68, 86))	('FAL1', 'Gene', (20, 24))	('inhibiting', 'NegReg', (143, 153))	('ovarian cancers', 'Disease', (38, 53))	('BMI-1', 'Gene', (133, 138))	('FAL1', 'Gene', '100874054', (20, 24))	('CDKN1A', 'Gene', (172, 178))	('ovarian cancers', 'Phenotype', 'HP:0100615', (38, 53))	('ovarian cancers', 'Disease', 'MESH:D010051', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CDKN1A', 'Gene', '1026', (172, 178))	('recruiting', 'PosReg', (90, 100))	('BMI-1', 'Gene', '648', (133, 138))
216539	30216655	Recurrence is considered as one potential sign of positive selection among tumors (Dees et al., 2012; Fu et al., 2014); therefore, functional lncRNAs with recurrent genetic alterations are more likely to be driver lncRNAs, instead of non-driver cancer lncRNAs.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (75, 81))	('genetic alterations', 'Var', (165, 184))
216540	30216655	With the aim of identifying driver lncRNAs, our method considers lncRNAs that show recurrent copy number alteration, exhibit mutually exclusive patterns with known cancer drivers, and affect various cancer hallmarks.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('copy number alteration', 'Var', (93, 115))	('affect', 'Reg', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer hallmarks', 'Disease', (199, 215))	('cancer hallmarks', 'Disease', 'MESH:D009369', (199, 215))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (199, 205))
216550	30216655	When damage of a driver gene is sufficient to disturb the activity of certain key pathways, other gene alterations with similar functional consequences will offer no further selective advantage on that clone; that is the selection pressure on these other alterations could be diminished or even nullified during tumor evolution (Ciriello et al., 2012; Remy et al., 2015).	('activity', 'MPA', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('disturb', 'Reg', (46, 53))	('key pathways', 'Pathway', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', (312, 317))	('damage', 'Var', (5, 11))
216561	30216655	For example, in the hallmark 'Evading Immune Detection', we found that GO term 'regulation of defense response to virus' was only affected by mutually exclusive modules in HNSC, which is consistent with the prevalence and the roles of human papillomavirus in directly inhibiting innate immune system for this cancer type (Bodily and Laimins, 2011; Maxwell et al., 2016).	('human papillomavirus', 'Species', '10566', (235, 255))	('affected', 'Reg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('inhibiting', 'NegReg', (268, 278))	('HNSC', 'Gene', (172, 176))	('modules', 'Var', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('HNSC', 'Phenotype', 'HP:0012288', (172, 176))	('cancer', 'Disease', (309, 315))
216567	30216655	A previous study has demonstrated that PVT1 epigenetically repressed the expression of CDKN2A by binding to the EZH2 (Kong et al., 2015); therefore, amplification of PVT1 and deletion of CDKN2A could consistently trigger the expression abnormality of CDKN2A and in turn lead to genomic instability.	('PVT1', 'Gene', (39, 43))	('lead to', 'Reg', (270, 277))	('EZH2', 'Gene', '2146', (112, 116))	('CDKN2A', 'Gene', (187, 193))	('EZH2', 'Gene', (112, 116))	('amplification', 'Var', (149, 162))	('CDKN2A', 'Gene', '1029', (251, 257))	('PVT1', 'Gene', '5820', (166, 170))	('CDKN2A', 'Gene', '1029', (87, 93))	('CDKN2A', 'Gene', '1029', (187, 193))	('PVT1', 'Gene', '5820', (39, 43))	('trigger', 'Reg', (213, 220))	('expression abnormality', 'MPA', (225, 247))	('deletion', 'Var', (175, 183))	('genomic', 'MPA', (278, 285))	('CDKN2A', 'Gene', (251, 257))	('PVT1', 'Gene', (166, 170))	('CDKN2A', 'Gene', (87, 93))
216570	30216655	Interestingly, CCNE1 suffered much more frequent CNA (24.6%) than CDKN2A (4.5%) in OV, whereas the opposite trend was observed in LUAD (5.8% and 19.0% for CCNE1 and CDKN2A, respectively), indicating that amplification of PVT1 may dysregulate different downstream genes, which in turn contribute to cancer development.	('PVT1', 'Gene', '5820', (221, 225))	('CCNE1', 'Gene', (15, 20))	('amplification', 'Var', (204, 217))	('contribute', 'Reg', (284, 294))	('dysregulate', 'Reg', (230, 241))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDKN2A', 'Gene', (165, 171))	('cancer', 'Disease', (298, 304))	('OV', 'Phenotype', 'HP:0012887', (83, 85))	('CDKN2A', 'Gene', '1029', (165, 171))	('CCNE1', 'Gene', (155, 160))	('CCNE1', 'Gene', '898', (155, 160))	('PVT1', 'Gene', (221, 225))	('CCNE1', 'Gene', '898', (15, 20))	('CDKN2A', 'Gene', (66, 72))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
216573	30216655	These findings suggest that both of these lncRNAs and derived miRNAs contribute to tumorigenesis, although, for lncRNAs LINC00969, U47924.29 and LINC00669, we did not find evidence of oncogenic roles recorded in literature.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LINC00969', 'Gene', '440993', (120, 129))	('tumor', 'Disease', (83, 88))	('LINC00969', 'Gene', (120, 129))	('LINC00669', 'Gene', '647946', (145, 154))	('LINC00669', 'Gene', (145, 154))	('U47924.29', 'Var', (131, 140))	('contribute', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
216578	30216655	XXZ performed copy number analysis and pan-cancer analysis.	('cancer', 'Disease', (43, 49))	('copy number analysis', 'Var', (14, 34))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
216635	27402152	To assess whether we were missing viral infections because of a lack of detecting non-polyadenylated viral transcripts, we wanted to test whether sequencing of ribodepleted RNAs (versus polyA selected RNAs as per the TCGA cohort) might yield the detection of viral reads.	('ribodepleted', 'Var', (160, 172))	('viral infections', 'Disease', 'MESH:D001102', (34, 50))	('viral infections', 'Disease', (34, 50))
216648	27402152	MuLV reads were also detected in 33 out of the 36 glioma samples (0.03 - 5.74 RPMH) taken from the non-enhancing FLAIR portion of the tumor, 35 out of the 39 glioma samples (0.03 - 12.72 RPMH) taken from the contrast enhancing portion of the tumor, and 15 out of the 17 non-neoplastic samples (0.03 - 3.33 RPMH) (Additional file 6: File S3).	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('MuLV', 'Species', '11786', (0, 4))	('glioma', 'Disease', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('glioma', 'Disease', (158, 164))	('0.03', 'Var', (66, 70))	('tumor', 'Disease', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('tumor', 'Disease', (134, 139))
216666	27402152	The lack of any coverage of the right half of the HPV-16 genome is consistent with deletion of this region which is frequently observed in oncogenic HPV genome integrations (where viral integration and the concomitant deletion of these negative regulatory genes results in increased expression of the oncogenic E6 and E7 genes while at the same time preventing productive viral infection and host cell destruction).	('oncogenic', 'MPA', (301, 310))	('HPV-16', 'Species', '333760', (50, 56))	('HPV', 'Species', '10566', (149, 152))	('viral infection', 'Disease', 'MESH:D001102', (372, 387))	('deletion', 'Var', (218, 226))	('increased', 'PosReg', (273, 282))	('deletion', 'Var', (83, 91))	('preventing', 'NegReg', (350, 360))	('viral infection', 'Disease', (372, 387))	('expression', 'MPA', (283, 293))	('HPV', 'Species', '10566', (50, 53))	('E7 genes', 'Gene', (318, 326))
216712	27402152	Both HPV-16 and HPV-58 are considered high-risk HPV types, which are causative agents in the development of cervical carcinoma.	('HPV-16', 'Var', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('HPV', 'Species', '10566', (48, 51))	('HPV-58', 'Gene', (16, 22))	('HPV-16', 'Species', '333760', (5, 11))	('HPV', 'Species', '10566', (16, 19))	('HPV', 'Species', '10566', (5, 8))	('cervical carcinoma', 'Disease', 'MESH:D002575', (108, 126))	('cervical carcinoma', 'Disease', (108, 126))
216737	26971411	The classic MRI findings include pontine enlargement with tumor centered in and involving more than 50-70% of the cross sectional area of the pons, hypointense signal on T1-, and hyperintense signal on T2-weighted images.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('hyperintense', 'MPA', (179, 191))	('pontine enlargement', 'Disease', (33, 52))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('hypointense signal', 'Var', (148, 166))
216774	26971411	In children with DIPG we found a decrease in FA in the left and right PLIC compared to age-matched controls (p = 0.001 and p < 0.001, respectively), while no difference was observed in FA in the PCSO.	('children', 'Species', '9606', (3, 11))	('DIPG', 'Chemical', '-', (17, 21))	('decrease', 'NegReg', (33, 41))	('DIPG', 'Var', (17, 21))
216780	26971411	AD values were significantly lower in the left and right PLIC for children with DIPG compared to LGBG patients (p = 0.049 and p = 0.03, respectively), while in all regions, no differences were observed in FA, MD, and RD.	('AD values', 'MPA', (0, 9))	('children', 'Species', '9606', (66, 74))	('DIPG', 'Chemical', '-', (80, 84))	('DIPG', 'Var', (80, 84))	('patients', 'Species', '9606', (102, 110))	('AD', 'Chemical', '-', (0, 2))	('lower', 'NegReg', (29, 34))
216814	26971411	LGBG are expected to locally injure the white matter tracts and cause secondary Wallerian degeneration, but not invade and remotely injure the white matter tracts by tumor cells due to the low-grade of malignancy.	('white matter tracts', 'CPA', (40, 59))	('malignancy', 'Disease', 'MESH:D009369', (202, 212))	('LGBG', 'Var', (0, 4))	('injure', 'NegReg', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cause', 'Reg', (64, 69))	('malignancy', 'Disease', (202, 212))	('tumor', 'Disease', (166, 171))	('Wallerian degeneration', 'Disease', (80, 102))	('Wallerian degeneration', 'Disease', 'MESH:D014855', (80, 102))
216861	26519663	In this generalized case, the mean-square displacement (MSD), < x2 (t) <, can be represented by a power law, (x2(t)) ~ t2alpha/beta'   tgamma, where t is the diffusion time, and alpha and beta' are the fractional powers on the waiting time and jump length probability distributions, respectively.	('mean-square displacement', 'MPA', (30, 54))	('MSD', 'Disease', 'MESH:D052517', (56, 59))	('MSD', 'Disease', (56, 59))	('x2(t', 'Var', (110, 114))
216864	26519663	(1) yields a characteristic decay process that is represented by a Mittag-Leffler function (MLF), By defining beta = beta'/2, b = q2(Delta - delta/3), and Delta = (Delta - delta/3), where delta and Delta are the Stejskal-Tanner diffusion gradient pulse width and gradient lobe separation, respectively, and q is the q-space variable, the solution to Eq.	('Delta =', 'Var', (155, 162))	("beta'/2", 'Gene', '10242', (117, 124))	("beta'/2", 'Gene', (117, 124))	('rat', 'Species', '10116', (281, 284))
216889	26519663	Secondly, the receiver operating characteristic (ROC) curves were constructed by performing a multivariate logistic regression analysis for different combinations of the CTRW parameters: (Dm, alpha), (Dm, beta), (alpha, beta), and (Dm, alpha, beta).	('Dm', 'Var', (201, 203))	('(Dm, alpha', 'Gene', '3108', (187, 197))	('rat', 'Species', '10116', (26, 29))	('Dm, alpha', 'Gene', (232, 241))	('Dm, alpha', 'Gene', (188, 197))	('(Dm, alpha', 'Gene', '3108', (231, 241))
216899	26519663	The same trend was preserved when combining all patient data in each group, as summarized in Table 1 where mean Dm, alpha, and beta parameters in high-grade tumor group were lower by 66%, 4%, and 13%, respectively, as compared with the low-grade group.	('tumor', 'Disease', (157, 162))	('lower', 'NegReg', (174, 179))	('alpha', 'MPA', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('beta parameters', 'MPA', (127, 142))	('high-grade', 'Var', (146, 156))	('patient', 'Species', '9606', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
216916	26519663	Using a k-means clustering analysis, we have further demonstrated that combinations of the CTRW parameters can improve the specificity (83% vs. 54%) and accuracy (85% vs. 75%) for differentiating low- and high-grade groups compared to the approach relying on ADC values.	('specificity', 'MPA', (123, 134))	('improve', 'PosReg', (111, 118))	('rat', 'Species', '10116', (60, 63))	('combinations', 'Var', (71, 83))
216923	26519663	In contrast, intra-tumor heterogeneity is less developed in low-grade tumors compared to their high-grade counterparts.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('intra-tumor', 'Disease', 'MESH:D009369', (13, 24))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('intra-tumor', 'Disease', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('low-grade', 'Var', (60, 69))
216932	26519663	Although the spatial heterogeneity (represented by beta) and the temporal heterogeneity (represented by alpha) both originate from the underlying tissue structural heterogeneity, they reflect two independent and complementary aspects of diffusion heterogeneities; water molecules can take a variable time to make a move, or can produce a variable displacement in each move.	('water', 'Chemical', 'MESH:D014867', (264, 269))	('displacement', 'MPA', (347, 359))	('produce', 'Reg', (328, 335))	('water molecules', 'Var', (264, 279))
216996	32085654	As expected, VEGF-A overexpression frequently correlates not only with enhanced cancer invasiveness, but also with a high risk of tumor recurrence and unfavorable prognosis.	('enhanced', 'PosReg', (71, 79))	('overexpression', 'Var', (20, 34))	('cancer invasiveness', 'Disease', 'MESH:D009362', (80, 99))	('cancer invasiveness', 'Disease', (80, 99))	('VEGF-A', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
216997	32085654	On this basis, inhibition of the VEGF-A/VEGFRs signaling represents a widely used approach for cancer treatment through the use of the anti-VEGF-A and anti-VEGFR-2 monoclonal antibodies (mAbs) bevacizumab and ramucirumab, respectively; the chimeric molecule ziv-aflibercept; or a number of multi-targeted small-molecule TK inhibitors.	('bevacizumab', 'Chemical', 'MESH:D000068258', (193, 204))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('men', 'Species', '9606', (107, 110))	('ramucirumab', 'Chemical', 'MESH:C543333', (209, 220))	('VEGFR', 'Gene', (156, 161))	('anti-VEGF-A', 'Var', (135, 146))	('cancer', 'Disease', (95, 101))	('VEGFR', 'Gene', (40, 45))	(')', 'Gene', '7424', (191, 192))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('VEGFR', 'Gene', '3791', (156, 161))	('VEGFR', 'Gene', '3791', (40, 45))
217002	32085654	In regard to VEGF-B, ectopic expression of the growth factor in pancreatic beta-cells of transgenic mice prevented the formation of neuroendocrine tumors likely displacing VEGF-A or PlGF from VEGFR-1.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('displacing', 'NegReg', (161, 171))	('prevented', 'NegReg', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('formation', 'CPA', (119, 128))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('transgenic mice', 'Species', '10090', (89, 104))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (132, 153))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (132, 153))	('pancreatic', 'Disease', (64, 74))	('ectopic expression', 'Var', (21, 39))	('neuroendocrine tumors', 'Disease', (132, 153))
217015	32085654	The anti-VEGF-A bevacizumab is the standard regimen for advanced/metastatic non-squamous NSCLC in the first-line setting, in combination with platinum-based chemotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('men', 'Species', '9606', (48, 51))	('bevacizumab', 'Chemical', 'MESH:D000068258', (16, 27))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))	('anti-VEGF-A', 'Var', (4, 15))
217018	32085654	NSCLC is often associated with a hypoxic environment leading to HIF-1alpha overexpression, and HIF-1alpha knockdown in the NCI-H157 lung carcinoma cell line has been shown to reduce VEGF-A expression and cell invasiveness.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('HIF-1alpha', 'Gene', '3091', (95, 105))	('men', 'Species', '9606', (48, 51))	('overexpression', 'PosReg', (75, 89))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('reduce', 'NegReg', (175, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('VEGF-A', 'Protein', (182, 188))	('expression', 'MPA', (189, 199))	('knockdown', 'Var', (106, 115))	('HIF-1alpha', 'Gene', (95, 105))	('NCI-H157 lung carcinoma', 'Disease', (123, 146))	('NCI-H157 lung carcinoma', 'Disease', 'MESH:D008175', (123, 146))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('HIF-1alpha', 'Gene', (64, 74))	('cell invasiveness', 'CPA', (204, 221))	('NSCLC', 'Disease', (0, 5))
217025	32085654	The sVEGFR-1-i13 splice variant was reported to increase during treatment with antiangiogenic therapies and to contribute to the progression of squamous lung carcinoma.	('splice variant', 'Var', (17, 31))	('men', 'Species', '9606', (69, 72))	('squamous lung carcinoma', 'Disease', (144, 167))	('sVEGFR-1-i13', 'Gene', (4, 16))	('squamous lung carcinoma', 'Phenotype', 'HP:0030359', (144, 167))	('squamous lung carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('contribute', 'Reg', (111, 121))	('increase', 'PosReg', (48, 56))
217026	32085654	In fact, besides acting as inhibitor of angiogenesis, this sVEGFR-1 variant is a component of the ECM that binds to the alpha5beta1 integrin and stimulates the adhesion and migration of endothelial cells.	('binds', 'Interaction', (107, 112))	('rat', 'Species', '10116', (176, 179))	('sVEGFR-1', 'Gene', (59, 67))	('variant', 'Var', (68, 75))	('adhesion', 'CPA', (160, 168))	('beta1 integrin', 'Gene', '3688', (126, 140))	('stimulates', 'PosReg', (145, 155))	('beta1 integrin', 'Gene', (126, 140))
217036	32085654	Furthermore, the VEGFR-1 relevance to NSCLC aggressiveness was confirmed by the observation that patients with squamous cell carcinoma and high VEGF-B expression showed poorer survival compared to those with low VEGF-B expression.	('NSCLC', 'Disease', (38, 43))	('aggressiveness', 'Disease', 'MESH:D001523', (44, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('aggressiveness', 'Disease', (44, 58))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('survival', 'MPA', (176, 184))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('VEGF-B', 'Gene', (144, 150))	('squamous cell carcinoma', 'Disease', (111, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('poorer', 'NegReg', (169, 175))	('SCLC', 'Phenotype', 'HP:0030357', (39, 43))	('high', 'Var', (139, 143))	('patients', 'Species', '9606', (97, 105))
217050	32085654	Nevertheless, after metastatic nodule formation, VEGFR-1 blockade led to a decrease of BMDCs infiltration inside and around the metastatic nodules.	('decrease', 'NegReg', (75, 83))	('blockade', 'Var', (57, 65))	('VEGFR-1', 'Gene', (49, 56))	('rat', 'Species', '10116', (99, 102))	('BMDCs infiltration', 'CPA', (87, 105))
217055	32085654	Hepatocellular carcinoma is a hypervascularized cancer type, and dysregulation of several angiogenic pathways, including those activated by the VEGF family members, has been involved in the development and progression of this tumor.	('involved', 'Reg', (174, 182))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('VEGF', 'Gene', '7422', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('dysregulation', 'Var', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('men', 'Species', '9606', (197, 200))	('hypervascularized cancer', 'Disease', 'MESH:D009369', (30, 54))	('hypervascularized cancer', 'Disease', (30, 54))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('VEGF', 'Gene', (144, 148))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('angiogenic pathways', 'Pathway', (90, 109))	('tumor', 'Disease', (226, 231))
217062	32085654	PlGF blockade resulted in normalization of tumor-associated vessels, reduced tumor nodule formation in the liver, and increased animal survival.	('blockade', 'Var', (5, 13))	('reduced', 'NegReg', (69, 76))	('animal survival', 'CPA', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PlGF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))	('normalization', 'NegReg', (26, 39))
217063	32085654	Similar findings were obtained in chemically-induced hepatocellular and cholangiocarcinoma in vivo models, where treatment with the 5D11D4 mAb decreased tumor burden and infiltration by protumoral M2 cells.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (189, 194))	('rat', 'Species', '10116', (176, 179))	('cholangiocarcinoma', 'Disease', (72, 90))	('decreased', 'NegReg', (143, 152))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('men', 'Species', '9606', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumoral', 'Disease', (189, 196))	('tumoral', 'Disease', 'MESH:D009369', (189, 196))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('5D11D4', 'Var', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hepatocellular', 'Disease', (53, 67))
217072	32085654	Consistently, patients with high PlGF and miR-19a levels in the tumor showed a shorter overall survival (OS) than patients with low expression.	('tumor', 'Disease', (64, 69))	('miR-19a', 'Gene', (42, 49))	(')', 'Gene', '7424', (107, 108))	('shorter', 'NegReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('miR-19a', 'Gene', '406979', (42, 49))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('overall survival', 'MPA', (87, 103))
217075	32085654	In fact, blockade of VEGFR-1 by the MF-1 mAb in syngeneic murine RCC models induced 31% reduction in the growth of liver metastases, whereas blockade of VEGFR-2 had minimal effects.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('RCC', 'Disease', (65, 68))	('MF-1', 'Gene', (36, 40))	('reduction', 'NegReg', (88, 97))	('VEGFR-1', 'Gene', (21, 28))	('liver metastases', 'Disease', (115, 131))	('murine', 'Species', '10090', (58, 64))	('MF-1', 'Gene', '17300', (36, 40))	('liver metastases', 'Disease', 'MESH:D009362', (115, 131))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('blockade', 'Var', (9, 17))
217076	32085654	In the case of metastases from colon carcinoma, only the neutralization of both VEGFR-1 and VEGFR-2 was able to decrease the size of liver metastasis.	('liver metastasis', 'Disease', (133, 149))	('VEGFR-2', 'Gene', (92, 99))	('metastases', 'Disease', (15, 25))	('decrease', 'NegReg', (112, 120))	('neutralization', 'Var', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('colon carcinoma', 'Disease', 'MESH:D015179', (31, 46))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('size of liver', 'Phenotype', 'HP:0002240', (125, 138))	('colon carcinoma', 'Disease', (31, 46))	('VEGFR-1', 'Gene', (80, 87))	('liver metastasis', 'Disease', 'MESH:D009362', (133, 149))
217085	32085654	The ccRCC is characterized by mutations or epigenetic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which are considered to play a key role in VEGF-A overexpression.	('epigenetic inactivation', 'Var', (43, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (74, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ccRCC', 'Disease', (4, 9))	('ccRCC', 'Disease', 'MESH:C538614', (4, 9))	('mutations', 'Var', (30, 39))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))
217088	32085654	Thus, in the presence of low expression or dysfunctional VHL, the HIF-1alpha accumulates and activates a number of hypoxia-driven genes, including VEGF-A.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('dysfunctional', 'Var', (43, 56))	('activates', 'PosReg', (93, 102))	('HIF-1alpha', 'Gene', (66, 76))	('low expression', 'Var', (25, 39))	('accumulates', 'PosReg', (77, 88))	('VHL', 'Gene', (57, 60))	('HIF-1alpha', 'Gene', '3091', (66, 76))	('VHL', 'Gene', '7428', (57, 60))	('hypoxia', 'Disease', (115, 122))
217089	32085654	Several single nucleotide polymorphisms identified in the VEGF gene have been reported to be associated with RCC risk, tumor growth, and metastases.	('VEGF', 'Gene', (58, 62))	('tumor', 'Disease', (119, 124))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('VEGF', 'Gene', '7422', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('associated', 'Reg', (93, 103))	('RCC', 'Disease', (109, 112))	('single nucleotide polymorphisms', 'Var', (8, 39))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('metastases', 'Disease', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
217090	32085654	In particular, two meta-analysis studies indicated that the VEGF -2578C/A, +936C/T, and +405G/C polymorphisms correlated with elevated risk of RCC, especially in the Asian populations.	('VEGF', 'Gene', '7422', (60, 64))	('+405G/C', 'Mutation', 'rs2010963', (88, 95))	('VEGF', 'Gene', (60, 64))	('-2578C/A', 'Mutation', 'rs699947', (65, 73))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('+936C/T', 'Mutation', 'rs3025039', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('+405G/C', 'Var', (88, 95))
217105	32085654	However, PlGF neutralization by the TB403 mAb did not inhibit the growth of sunitinib-resistant ccRCC xenografts, which did not express VEGFR-1.	('TB403', 'Var', (36, 41))	('TB', 'Chemical', 'MESH:D013725', (36, 38))	('inhibit', 'NegReg', (54, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('ccRCC', 'Disease', 'MESH:C538614', (96, 101))
217112	32085654	demonstrated that VEGFR-1 overexpression increases in vitro and in vivo glioma growth via modulation of the Sonic Hedgehog Homolog (SHH) signaling pathway.	('glioma', 'Disease', (72, 78))	('increases', 'PosReg', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('VEGFR-1', 'Gene', (18, 25))	('rat', 'Species', '10116', (7, 10))	('overexpression', 'Var', (26, 40))	('Sonic Hedgehog Homolog', 'Gene', '6469', (108, 130))	('Sonic Hedgehog Homolog', 'Gene', (108, 130))	('modulation', 'Reg', (90, 100))
217115	32085654	In vitro treatment with the anti-VEGFR-1 D16F7 mAb markedly inhibited receptor autophosphorylation and ERK1/2 activation and reduced glioblastoma cell invasive behavior.	('glioblastoma', 'Disease', (133, 145))	('anti-VEGFR-1', 'Gene', (28, 40))	('men', 'Species', '9606', (14, 17))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('receptor autophosphorylation', 'MPA', (70, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('inhibited', 'NegReg', (60, 69))	('activation', 'MPA', (110, 120))	('reduced', 'NegReg', (125, 132))	('D16F7', 'Var', (41, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (41, 46))
217116	32085654	In vivo studies in glioblastoma murine models indicated that D16F7 was well-tolerated and confirmed its promising therapeutic potential, as the mAb induced a decrease in glioma growth and angiogenesis, as well as an increase in mice survival.	('glioblastoma', 'Disease', (19, 31))	('D16F7', 'Var', (61, 66))	('decrease in glioma growth', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('rat', 'Species', '10116', (80, 83))	('D16F7', 'Chemical', 'MESH:C000627505', (61, 66))	('murine', 'Species', '10090', (32, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('angiogenesis', 'CPA', (188, 200))	('decrease in glioma growth', 'Disease', 'MESH:D005910', (158, 183))	('mice survival', 'CPA', (228, 241))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('increase', 'PosReg', (216, 224))	('mice', 'Species', '10090', (228, 232))
217117	32085654	In particular, the efficacy of D16F7 mAb was tested in heterotopic (intramuscular) and orthotopic (intracranial) models using rat C6 glioma sublines, transfected to overexpress VEGFR-1.	('C6 glioma sublines', 'Disease', 'MESH:C567307', (130, 148))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('overexpress', 'PosReg', (165, 176))	(')', 'Gene', '7424', (111, 112))	('rat', 'Species', '10116', (126, 129))	('tested', 'Reg', (45, 51))	('C6 glioma sublines', 'Disease', (130, 148))	('D16F7', 'Var', (31, 36))	('VEGFR-1', 'Gene', (177, 184))	(')', 'Gene', '7424', (81, 82))	('D16F7', 'Chemical', 'MESH:C000627505', (31, 36))
217118	32085654	In the heterotopic intramuscular model, treatment with D16F7 reduced tumor growth and in the orthotopic intracranial model the mAb increased animal survival by 40% and 65% at 10 and 20 mg/kg, respectively, with a remarkable percentage (46%) of long-term survivors at the higher dose.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('increased', 'PosReg', (131, 140))	('men', 'Species', '9606', (45, 48))	('tumor', 'Disease', (69, 74))	('animal survival', 'CPA', (141, 156))	('D16F7', 'Chemical', 'MESH:C000627505', (55, 60))	('D16F7', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('reduced', 'NegReg', (61, 68))	(')', 'Gene', '7424', (239, 240))
217119	32085654	Additionally, immunohistochemical analysis of tumor sections from D16F7-treated animals showed a higher number of apoptotic cells and fewer blood vessels compared to untreated mice.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('apoptotic cells', 'CPA', (114, 129))	('mice', 'Species', '10090', (176, 180))	('fewer', 'NegReg', (134, 139))	('D16F7', 'Chemical', 'MESH:C000627505', (66, 71))	('D16F7-treated', 'Var', (66, 79))	('blood vessels', 'CPA', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
217141	32085654	Treatment of human (CR-Mel) and murine (B16F10) melanoma cells with the anti-VEGFR-1 D16F7 mAb strongly down-modulated the migration triggered by PlGF.	('melanoma cells', 'Disease', (48, 62))	('human', 'Species', '9606', (13, 18))	('melanoma cells', 'Disease', 'MESH:D008545', (48, 62))	('anti-VEGFR-1', 'Var', (72, 84))	('murine', 'Species', '10090', (32, 38))	('D16F7', 'Chemical', 'MESH:C000627505', (85, 90))	(')', 'Gene', '7424', (46, 47))	('men', 'Species', '9606', (5, 8))	('rat', 'Species', '10116', (126, 129))	('down-modulated', 'NegReg', (104, 118))	(')', 'Gene', '7424', (26, 27))	('migration', 'CPA', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
217142	32085654	Moreover, D16F7 inhibited vasculogenic mimicry (i.e., the formation of tube-like structures, resembling blood vessels) by melanoma cells in response to VEGF-A.	('inhibited', 'NegReg', (16, 25))	(')', 'Gene', '7424', (117, 118))	('D16F7', 'Var', (10, 15))	('melanoma cells', 'Disease', 'MESH:D008545', (122, 136))	('melanoma cells', 'Disease', (122, 136))	('vasculogenic mimicry', 'CPA', (26, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('formation of tube-like structures', 'CPA', (58, 91))
217143	32085654	In vivo studies performed in a syngeneic murine melanoma model (B16F10 cells injected in B6D2F1 mice) confirmed the efficacy of VEGFR-1 blockade by D16F7 and the good tolerability of the treatment.	('melanoma', 'Disease', (48, 56))	('blockade', 'NegReg', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('murine', 'Species', '10090', (41, 47))	('VEGFR-1', 'Gene', (128, 135))	('men', 'Species', '9606', (192, 195))	('D16F7', 'Var', (148, 153))	('D16F7', 'Chemical', 'MESH:C000627505', (148, 153))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
217145	32085654	Furthermore, immunohistochemical analysis of melanoma sections from D16F7-treated animals showed a reduction of tumor infiltration by monocytes/macrophages and a marked decrease of bone invasion by melanoma cells.	('rat', 'Species', '10116', (124, 127))	('decrease', 'NegReg', (169, 177))	('melanoma cells', 'Disease', 'MESH:D008545', (198, 212))	('melanoma cells', 'Disease', (198, 212))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('D16F7-treated', 'Var', (68, 81))	('reduction', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('D16F7', 'Chemical', 'MESH:C000627505', (68, 73))	('tumor', 'Disease', (112, 117))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
217147	32085654	In fact, the expression of VEGFR-1 in melanoma cells resistant to the BRAFi vemurafenib was higher than in their BRAFi-sensitive counterparts, whereas the transient silencing of VEGFR-1 in resistant cells increased BRAFi sensitivity and in susceptible cells delayed resistance development.	('BRAF', 'Gene', (215, 219))	('VEGFR-1', 'Gene', (178, 185))	('delayed', 'NegReg', (258, 265))	('VEGFR-1', 'Gene', (27, 34))	('increased', 'PosReg', (205, 214))	('BRAFi vemurafenib', 'Chemical', '-', (70, 87))	('silencing', 'Var', (165, 174))	('higher', 'PosReg', (92, 98))	('melanoma cells', 'Disease', 'MESH:D008545', (38, 52))	('BRAF', 'Gene', '673', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (70, 74))	('men', 'Species', '9606', (284, 287))	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('expression', 'MPA', (13, 23))	('melanoma cells', 'Disease', (38, 52))	('resistance development', 'CPA', (266, 288))	('BRAF', 'Gene', '673', (215, 219))
217148	32085654	Furthermore, vemurafenib-resistant melanoma cells expressing VEGFR-1 showed a higher invasive behavior, compared to melanoma cells susceptible to the BRAFi.	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('VEGFR-1', 'Var', (61, 68))	('higher', 'PosReg', (78, 84))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('BRAF', 'Gene', (150, 154))	('melanoma cells', 'Disease', 'MESH:D008545', (116, 130))	('melanoma cells', 'Disease', (116, 130))	('BRAF', 'Gene', '673', (150, 154))	('invasive behavior', 'CPA', (85, 102))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma cells', 'Disease', 'MESH:D008545', (35, 49))	('melanoma cells', 'Disease', (35, 49))
217149	32085654	Accordingly, treatment with D16F7 markedly reduced ECM invasion by resistant cells in response to VEGF-A and PlGF, suggesting that VEGFR-1 blockade in combination with the BRAFi might delay the acquisition of a resistance phenotype.	('D16F7', 'Chemical', 'MESH:C000627505', (28, 33))	('resistance phenotype', 'CPA', (211, 231))	('men', 'Species', '9606', (18, 21))	('D16F7', 'Var', (28, 33))	('delay', 'NegReg', (184, 189))	('ECM invasion', 'CPA', (51, 63))	('BRAF', 'Gene', '673', (172, 176))	('reduced', 'NegReg', (43, 50))	('VEGFR-1', 'Gene', (131, 138))	('BRAF', 'Gene', (172, 176))
217152	32085654	Indeed, PlGF silencing or inhibition of NF-kappaB restored melanoma cell sensitivity to the chemotherapeutic agent Finally, VEGF-B transcript levels in the tumor measured in a large cohort of melanoma patients inversely correlated with survival.	('patients', 'Species', '9606', (201, 209))	('PlGF', 'Gene', (8, 12))	('transcript levels', 'MPA', (131, 148))	('NF-kappaB', 'Gene', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('inhibition', 'NegReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('tumor', 'Disease', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('VEGF-B', 'Gene', (124, 130))	('restored', 'PosReg', (50, 58))	('correlated', 'Reg', (220, 230))	('silencing', 'Var', (13, 22))
217163	32085654	Moreover, a meta-analysis study performed in a Chinese population reported a link between VEGF-A gene polymorphisms (VEGF +936C/T and -634 G/C) and the risk of developing osteosarcoma.	('+936C/T', 'Mutation', 'rs3025039', (122, 129))	('VEGF', 'Gene', (117, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('VEGF', 'Gene', (90, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('-634 G/C', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('VEGF', 'Gene', '7422', (117, 121))	('-634 G/C', 'SUBSTITUTION', 'None', (134, 142))	('VEGF', 'Gene', '7422', (90, 94))	('osteosarcoma', 'Disease', (171, 183))
217165	32085654	Indeed, HIF-1alpha and VEGF-A knockdown decreased the invasive potential of Saos-2 and U2-OS osteosarcoma cell lines.	('VEGF-A', 'Gene', (23, 29))	('HIF-1alpha', 'Gene', '3091', (8, 18))	('HIF-1alpha', 'Gene', (8, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('invasive potential of Saos-2', 'CPA', (54, 82))	('osteosarcoma', 'Disease', (93, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('knockdown', 'Var', (30, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('decreased', 'NegReg', (40, 49))
217172	32085654	Consistently with the in vitro data, tumors originated from high-VEGFR-1 K7M3 cells produced more VEGF-A than low-VEGFR-1 cells.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high-VEGFR-1 K7M3', 'Var', (60, 77))	('K7M3', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('VEGF-A', 'MPA', (98, 104))
217196	32085654	Increased levels of PlGF were reported in obesity-associated pancreatic cancer patients and ablation of the VEGFR-1 signaling in pancreatic ductal adenocarcinoma murine models prevented obesity-induced tumor progression.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ablation', 'Var', (92, 100))	('obesity', 'Phenotype', 'HP:0001513', (42, 49))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('obesity', 'Disease', (186, 193))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic ductal adenocarcinoma', 'Disease', (129, 161))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('obesity', 'Disease', (42, 49))	('pancreatic cancer', 'Disease', (61, 78))	('obesity', 'Disease', 'MESH:D009765', (186, 193))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (129, 161))	('obesity', 'Disease', 'MESH:D009765', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('murine', 'Species', '10090', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('prevented', 'NegReg', (176, 185))	('VEGFR-1', 'Gene', (108, 115))	('patients', 'Species', '9606', (79, 87))	('obesity', 'Phenotype', 'HP:0001513', (186, 193))
217202	32085654	Moreover, triple VEGFRs downregulation synergized with standard chemotherapy (5-fluorouracil and cisplatin combination) in vivo.	('triple', 'Var', (10, 16))	('VEGFR', 'Gene', '3791', (17, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (78, 92))	(')', 'Gene', '7424', (118, 119))	('downregulation', 'NegReg', (24, 38))	('VEGFR', 'Gene', (17, 22))
217213	32085654	Patients with VEGF-A overexpression have a significantly increased risk (2-fold) of disease progression, with the development of distant metastases and shorter OS.	(')', 'Gene', '7424', (79, 80))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('overexpression', 'Var', (21, 35))	('men', 'Species', '9606', (121, 124))	('Patients', 'Species', '9606', (0, 8))	('disease', 'Disease', (84, 91))	('VEGF-A', 'Gene', (14, 20))	('metastases', 'Disease', (137, 147))
217215	32085654	Furthermore, a clinical study enrolling 334 patients with advanced esophageal squamous cell carcinoma revealed that the genetic polymorphism rs2010963 in VEGF-A gene independently correlated with worse OS, although this genotype was not associated with high pretreatment VEGF-A levels in the serum.	('patients', 'Species', '9606', (44, 52))	('VEGF-A', 'Gene', (154, 160))	('rs2010963', 'Mutation', 'rs2010963', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('rs2010963', 'Var', (141, 150))	('men', 'Species', '9606', (266, 269))	('worse OS', 'Disease', (196, 204))	('correlated with', 'Reg', (180, 195))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))
217258	32085654	Overexpression of CSE also increased the levels of MMP2 and MMP9 in early metastatic breast cancer cells, allowing the degradation of the ECM and consequently the entering of tumor cells into the blood circulation.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumor', 'Disease', (175, 180))	('increased', 'PosReg', (27, 36))	('MMP2', 'Gene', (51, 55))	('entering', 'MPA', (163, 171))	('breast cancer', 'Disease', (85, 98))	('CSE', 'Gene', '1491', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('MMP2', 'Gene', '4313', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('degradation', 'MPA', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MMP9', 'Var', (60, 64))	('CSE', 'Gene', (18, 21))	('levels', 'MPA', (41, 47))	('allowing', 'Reg', (106, 114))
217264	32085654	The addition of the anti-VEGFR-1 KM1732 mAb and a VEGFR-1 trap (sFlt-1-Fc) to CD34+ cultures, pretreated with the MDA-MB-231-conditioned medium or PlGF, prevented the generation of CD11b+ cells with sprouting-inducing ability.	('CD11b', 'Gene', (181, 186))	('CD34', 'Gene', (78, 82))	('CD34', 'Gene', '947', (78, 82))	('Flt-1', 'Gene', '2321', (65, 70))	('rat', 'Species', '10116', (171, 174))	(')', 'Gene', '7424', (73, 74))	('prevented', 'NegReg', (153, 162))	('Flt-1', 'Gene', (65, 70))	('CD11b', 'Gene', '3684', (181, 186))	('anti-VEGFR-1', 'Var', (20, 32))
217265	32085654	Furthermore, CD11b+ cells induced a significant angiogenic response in the murine corneal angiogenesis in vivo assay and PlGF silencing reduced the proangiogenic activity of circulating CD11b+ myelomonocytic cells in a breast cancer murine model.	('CD11b', 'Gene', (13, 18))	('corneal angiogenesis', 'Phenotype', 'HP:0011496', (82, 102))	('CD11b', 'Gene', '3684', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('murine', 'Species', '10090', (75, 81))	('CD11b', 'Gene', (186, 191))	('breast cancer', 'Disease', (219, 232))	('angiogenic response', 'CPA', (48, 67))	('CD11b', 'Gene', '3684', (186, 191))	('murine', 'Species', '10090', (233, 239))	('reduced', 'NegReg', (136, 143))	('silencing', 'Var', (126, 135))	('proangiogenic activity', 'CPA', (148, 170))	('PlGF', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
217269	32085654	Furthermore, while obesity promoted IL-6 and MMP9 expression in tumors, deletion of VEGFR-1 TK domain decreased the expression of these pro-M2 markers only in obese mice.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (116, 126))	('tumors', 'Disease', (64, 70))	('obese', 'Disease', (159, 164))	('IL-6', 'Gene', (36, 40))	('IL-6', 'Gene', '16193', (36, 40))	('obesity', 'Disease', 'MESH:D009765', (19, 26))	('mice', 'Species', '10090', (165, 169))	('obese', 'Disease', 'MESH:D009765', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('obesity', 'Disease', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('promoted', 'PosReg', (27, 35))	('MMP9 expression', 'MPA', (45, 60))	('obesity', 'Phenotype', 'HP:0001513', (19, 26))	('VEGFR-1', 'Gene', (84, 91))	('decreased', 'NegReg', (102, 111))	('deletion', 'Var', (72, 80))
217270	32085654	PlGF was identified as the VEGFR-1 ligand responsible for such effects since its plasma levels were elevated in diet-induced obese mice, and its deletion induced similar effects to those observed in VEGFR-1-TK-null obese mice.	('obese', 'Disease', (125, 130))	('obese', 'Disease', 'MESH:D009765', (215, 220))	('obese', 'Disease', (215, 220))	('mice', 'Species', '10090', (221, 225))	('PlGF', 'Gene', (0, 4))	('plasma levels', 'MPA', (81, 94))	('obese', 'Disease', 'MESH:D009765', (125, 130))	('mice', 'Species', '10090', (131, 135))	('elevated', 'PosReg', (100, 108))	('deletion', 'Var', (145, 153))
217281	32085654	Mice transplanted with human ovarian adenocarcinoma SKOV3 cells transfected with pLV-sFLT1 or exogenously (intraperitoneally) treated with recombinant sVEGFR-1, confirmed the antitumor effect of sVEGFR-1 also in vivo, in terms of reduced tumor size compared to control animals.	('reduced', 'NegReg', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('sVEGFR-1', 'Var', (195, 203))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (29, 51))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('ovarian adenocarcinoma', 'Disease', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	(')', 'Gene', '7424', (124, 125))	('tumor', 'Disease', (238, 243))	('human', 'Species', '9606', (23, 28))	('Mice', 'Species', '10090', (0, 4))	('SKOV3', 'CellLine', 'CVCL:0532;0.04086655203281981', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('tumor', 'Disease', (179, 184))
217283	32085654	VEGFR-1 as well VEGFR-2 expression levels in biopsy specimens have been recognized as prognostic factors for patients with cervical cancer: high VEGFR-1 expression was linked to distant metastases, together with poor OS and PFS, whereas high VEGFR-2 expression correlated with increased tumor size and reduced OS.	('metastases', 'Disease', (186, 196))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cervical cancer', 'Disease', (123, 138))	('high', 'Var', (140, 144))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('cervical cancer', 'Disease', 'MESH:D002583', (123, 138))	('VEGFR-1', 'Gene', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('increased', 'PosReg', (277, 286))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('men', 'Species', '9606', (57, 60))	('linked to', 'Reg', (168, 177))
217285	32085654	On the other hand, a recent study reported that patients with high serum levels of both VEGF-A and VEGFR-2 presented bulky tumors, pelvic lymph node involvement, parametrial infiltration, and significantly lower OS than patients with low VEGF-A and VEGFR-2 expression.	('VEGFR-2', 'Gene', (99, 106))	('parametrial infiltration', 'CPA', (162, 186))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('rat', 'Species', '10116', (180, 183))	('pelvic lymph node involvement', 'CPA', (131, 160))	('men', 'Species', '9606', (156, 159))	('lower', 'NegReg', (206, 211))	('serum levels', 'MPA', (67, 79))	('patients', 'Species', '9606', (220, 228))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('VEGF-A', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
217289	32085654	Deregulation of cellular energetic metabolism has been recognized as another feature of cancer, aimed at increasing the production of lactate, whose efflux in the ECM induces angiogenesis.	('cellular energetic metabolism', 'MPA', (16, 45))	('cancer', 'Disease', (88, 94))	('induces', 'Reg', (167, 174))	('increasing', 'PosReg', (105, 115))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Deregulation', 'Var', (0, 12))	('lactate', 'Chemical', 'MESH:D019344', (134, 141))	('angiogenesis', 'CPA', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('efflux', 'MPA', (149, 155))	('production of lactate', 'MPA', (120, 141))
217311	32085654	Consistently, ectopic VEGF-A expression decreased miR-130b level and abrogated its antiangiogenic effect, thus promoting the angiogenic response.	('abrogated', 'NegReg', (69, 78))	('antiangiogenic effect', 'CPA', (83, 104))	('promoting', 'PosReg', (111, 120))	('miR-130b', 'Gene', '406920', (50, 58))	('miR-130b', 'Gene', (50, 58))	('ectopic', 'Var', (14, 21))	('angiogenic response', 'CPA', (125, 144))	('decreased', 'NegReg', (40, 49))	('VEGF-A', 'Gene', (22, 28))
217334	32085654	Thus, the authors suggested that blockade of VEGFR-1 by a selective therapeutic agent might counteract leukemia cell movement within the bone marrow, delaying the extra-medullary tumor growth.	('blockade', 'Var', (33, 41))	('men', 'Species', '9606', (121, 124))	('delaying', 'NegReg', (150, 158))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('VEGFR-1', 'Gene', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('leukemia', 'Disease', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
217340	32085654	Other approved agents that are endowed with antiangiogenic effects but do not directly target the VEGFRs or their ligands include (i) the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (approved for RCC and mantle cell lymphoma) and everolimus (approved for advanced kidney and breast cancers, subependymal giant cell astrocytoma, pancreatic neuroendocrine tumors, neuroendocrine tumors of gastrointestinal or lung origin), and the (ii) the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide, approved for the treatment of multiple myeloma (lenalidomide also for relapsed or refractory mantle cell lymphoma and myelodysplastic syndromes with deletion of the long arm of chromosome 5).	('men', 'Species', '9606', (552, 555))	('multiple myeloma', 'Phenotype', 'HP:0006775', (560, 576))	('breast cancers', 'Phenotype', 'HP:0003002', (292, 306))	(')', 'Gene', '7424', (484, 485))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (356, 377))	('subependymal giant cell astrocytoma', 'Disease', (308, 343))	('pancreatic neuroendocrine tumors', 'Disease', (345, 377))	('cell lymphoma', 'Phenotype', 'HP:0012191', (228, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('lymphoma', 'Phenotype', 'HP:0002665', (233, 241))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (379, 400))	('mantle cell lymphoma', 'Disease', (623, 643))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (623, 643))	('multiple myeloma', 'Disease', 'MESH:D009101', (560, 576))	('tumors', 'Phenotype', 'HP:0002664', (394, 400))	('subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (308, 343))	('myelodysplastic syndromes', 'Disease', (648, 673))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (648, 673))	('cell lymphoma', 'Phenotype', 'HP:0012191', (630, 643))	('lymphoma', 'Phenotype', 'HP:0002665', (635, 643))	(')', 'Gene', '7424', (173, 174))	('subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (308, 343))	('mammalian target of rapamycin', 'Gene', '2475', (138, 167))	('everolimus', 'Chemical', 'MESH:D000068338', (247, 257))	('VEGFR', 'Gene', '3791', (98, 103))	(')', 'Gene', '7424', (435, 436))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('multiple myeloma', 'Disease', (560, 576))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (648, 673))	('deletion', 'Var', (679, 687))	('VEGFR', 'Gene', (98, 103))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (221, 241))	(')', 'Gene', '7424', (719, 720))	(')', 'Gene', '7424', (132, 133))	('mammalian target of rapamycin', 'Gene', (138, 167))	('mantle cell lymphoma', 'Disease', (221, 241))	(')', 'Gene', '7424', (449, 450))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (332, 343))	(')', 'Gene', '7424', (241, 242))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancers', 'Disease', 'MESH:D001943', (292, 306))	('breast cancers', 'Disease', (292, 306))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('neuroendocrine tumors of gastrointestinal', 'Disease', (379, 420))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (345, 377))	('tumors of gastrointestinal', 'Phenotype', 'HP:0007378', (394, 420))	('neuroendocrine tumors of gastrointestinal', 'Disease', 'MESH:D018358', (379, 420))
217344	32085654	Most of these mAbs prevent the interaction of VEGFR-1 ligands with the receptor (competitive inhibitors), whereas only D16F7 blocks receptor signal transduction without inhibiting ligand binding (non-competitive inhibitor).	('prevent', 'NegReg', (19, 26))	('D16F7', 'Var', (119, 124))	('interaction', 'Interaction', (31, 42))	(')', 'Gene', '7424', (103, 104))	('D16F7', 'Chemical', 'MESH:C000627505', (119, 124))	(')', 'Gene', '7424', (221, 222))	('receptor signal transduction', 'MPA', (132, 160))	('blocks', 'NegReg', (125, 131))	('VEGFR-1', 'Gene', (46, 53))
217347	32085654	This mAb has shown antitumor activity in human breast carcinoma xenograft models (i.e., DU4475, MDA-MB-231, and MDA-MB-435).	('DU4475', 'CellLine', 'CVCL:1183;-0.001036928386686134', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('breast carcinoma xenograft', 'Disease', (47, 73))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('human', 'Species', '9606', (41, 46))	('breast carcinoma xenograft', 'Disease', 'MESH:D001943', (47, 73))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('breast carcinoma', 'Phenotype', 'HP:0003002', (47, 63))	('tumor', 'Disease', (23, 28))	('DU4475', 'Var', (88, 94))
217349	32085654	Moreover, immunohistochemical analysis of tumor xenografts collected from treated mice showed an increase of tumor cell apoptosis and a decrease in MAPK and AKT activation and cell proliferation; (ii) The murine anti-human VEGFR-1 D16F7 mAb (mouse IgG1), which has a novel mechanism of action, as it interacts with a receptor site distinct from that involved in VEGF-A or PlGF binding and downregulates the signaling through the membrane receptor without affecting ligand binding.	(')', 'Gene', '7424', (199, 200))	('human', 'Species', '9606', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (42, 47))	('murine', 'Species', '10090', (205, 211))	('rat', 'Species', '10116', (188, 191))	('signaling through the membrane receptor', 'MPA', (407, 446))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	(')', 'Gene', '7424', (252, 253))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('D16F7', 'Var', (231, 236))	('mice', 'Species', '10090', (82, 86))	('MAPK', 'Pathway', (148, 152))	('mouse', 'Species', '10090', (242, 247))	('downregulates', 'NegReg', (389, 402))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('interacts', 'Interaction', (300, 309))	('D16F7', 'Chemical', 'MESH:C000627505', (231, 236))	('decrease', 'NegReg', (136, 144))	('tumor', 'Disease', (109, 114))
217351	32085654	Moreover, D16F7 leaves unaffected the sVEGFR-1 decoy function, as it neither affects sVEGFR-1 interaction with its ligands nor hampers the sVEGFR-1/VEGFR-2 inhibitory heterodimer formation.	('interaction', 'Interaction', (94, 105))	('D16F7', 'Var', (10, 15))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('hampers', 'NegReg', (127, 134))	('sVEGFR-1/VEGFR-2 inhibitory heterodimer formation', 'MPA', (139, 188))
217352	32085654	D16F7 has shown antitumor efficacy in preclinical in vivo models against highly aggressive tumor types, such as glioblastoma and melanoma (see also Section 2.4 and Section 2.5).	('D16F7', 'Var', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aggressive tumor', 'Disease', 'MESH:D001523', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (112, 137))	('aggressive tumor', 'Disease', (80, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (20, 25))	(')', 'Gene', '7424', (175, 176))
217353	32085654	Its ability to recognize not only the human form of the VEGFR-1 but also the murine receptor has allowed the analysis of the effects of VEGFR-1 inhibition on tumor-associated microenvironment; (iii) The anti-human VEGFR-1 KM1730 and KM1732 mAbs (mouse IgG1), which recognize different epitopes of the second Ig-like domain.	(')', 'Gene', '7424', (256, 257))	('tumor', 'Disease', (158, 163))	('human', 'Species', '9606', (38, 43))	('murine', 'Species', '10090', (77, 83))	('KM1732', 'Var', (233, 239))	('men', 'Species', '9606', (187, 190))	('mouse', 'Species', '10090', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	(')', 'Gene', '7424', (197, 198))	('human', 'Species', '9606', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('KM1730', 'Var', (222, 228))
217355	32085654	Moreover, treatment with KM1732 mAb of primary cell cultures derived from bone marrow samples collected from patients with AML resulted in significant inhibition of cell growth.	('patients', 'Species', '9606', (109, 117))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('men', 'Species', '9606', (15, 18))	('AML', 'Phenotype', 'HP:0004808', (123, 126))	('KM1732 mAb', 'Var', (25, 35))	('inhibition', 'NegReg', (151, 161))	('cell growth', 'CPA', (165, 176))	('AML', 'Disease', (123, 126))
217362	32085654	The anti-PlGF mAb 5D11D4 is directed against the murine PlGF of which inhibits the interaction with VEGFR-1 and with NRP-1.	('VEGFR-1', 'Protein', (100, 107))	('interaction', 'Interaction', (83, 94))	('inhibits', 'NegReg', (70, 78))	('5D11D4', 'Var', (18, 24))	('murine', 'Species', '10090', (49, 55))
217363	32085654	The 5D11D4 mAb inhibited tumor growth and metastasis formation in melanoma, cholangiocarcinoma, pancreatic, hepatocellular, and colon cancer in vivo models.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('melanoma', 'Disease', (66, 74))	('cholangiocarcinoma', 'Disease', (76, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('hepatocellular', 'Disease', (108, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('5D11D4', 'Var', (4, 10))	('pancreatic', 'Disease', 'MESH:D010195', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('tumor', 'Disease', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('pancreatic', 'Disease', (96, 106))	('inhibited', 'NegReg', (15, 24))	('colon cancer', 'Disease', (128, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
217380	32085654	AEE788 is instead a dual inhibitor of epidermal growth factor and VEGF receptors and is currently under investigation in patients with recurrent glioblastoma, as single agent or in combination with everolimus.	('VEGF', 'Gene', (66, 70))	('AEE788', 'Var', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('everolimus', 'Chemical', 'MESH:D000068338', (198, 208))	('AEE788', 'Chemical', 'MESH:C489254', (0, 6))	('VEGF', 'Gene', '7422', (66, 70))	('epidermal', 'Protein', (38, 47))	('glioblastoma', 'Disease', (145, 157))	('patients', 'Species', '9606', (121, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
217382	32085654	A total of thirty-two trials can be found in  where lucitanib is tested for solid tumors, breast cancer, NSCLC, SCLC, gastroesophageal reflux disease, and functional dyspepsia, with two of them including tumors with genetic alterations of the FGF receptor.	('gastroesophageal reflux disease', 'Disease', (118, 149))	('tumors', 'Disease', (82, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (118, 149))	('SCLC', 'Disease', 'MESH:D055752', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('genetic alterations', 'Var', (216, 235))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('rat', 'Species', '10116', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SCLC', 'Disease', 'MESH:D055752', (112, 116))	('SCLC', 'Disease', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('solid tumors', 'Disease', (76, 88))	('dyspepsia', 'Phenotype', 'HP:0410281', (166, 175))	('tumors', 'Disease', (204, 210))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('FGF receptor', 'Gene', (243, 255))	('SCLC', 'Disease', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('functional dyspepsia', 'Disease', 'MESH:D004415', (155, 175))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (118, 141))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('functional dyspepsia', 'Disease', (155, 175))	('breast cancer', 'Disease', (90, 103))	('lucitanib', 'Chemical', 'MESH:C000595232', (52, 61))	('NSCLC', 'Disease', (105, 110))	('tested', 'Reg', (65, 71))
217390	32085654	Inhibition of VEGF-A and its signaling through VEGFR-2, a receptor also involved in physiological angiogenesis, causes important adverse effects such as hypertension, proteinuria, bleeding, thromboembolism, delay in wound healing, and gastrointestinal perforation.	('bleeding', 'Disease', (180, 188))	('gastrointestinal', 'Disease', (235, 251))	('thromboembolism', 'Disease', 'MESH:D013923', (190, 205))	('thromboembolism', 'Phenotype', 'HP:0001907', (190, 205))	('VEGFR-2', 'Gene', (47, 54))	('hypertension', 'Disease', 'MESH:D006973', (153, 165))	('delay', 'CPA', (207, 212))	('proteinuria', 'Disease', (167, 178))	('hypertension', 'Disease', (153, 165))	('proteinuria', 'Disease', 'MESH:D011507', (167, 178))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (257, 260))	('thromboembolism', 'Disease', (190, 205))	('bleeding', 'Disease', 'MESH:D006470', (180, 188))	('proteinuria', 'Phenotype', 'HP:0000093', (167, 178))	('wound healing', 'CPA', (216, 229))	('hypertension', 'Phenotype', 'HP:0000822', (153, 165))	('VEGF-A', 'Gene', (14, 20))	('delay in wound healing', 'Phenotype', 'HP:0001058', (207, 229))
217393	32085654	Conversely, the neutralization of VEGFR-1 specific ligands, i.e., VEGF-B and PlGF, and the selective blockade of VEGFR-1 activation, represents a promising strategy to specifically counteract tumor-associated angiogenesis as well as malignant processes not directly related to new blood vessels formation.	('tumor', 'Disease', (192, 197))	('neutralization', 'Var', (16, 30))	('VEGFR-1', 'Gene', (34, 41))	('rat', 'Species', '10116', (158, 161))	('VEGF-B', 'Gene', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('VEGFR-1', 'Gene', (113, 120))
217394	32085654	Indeed, inhibition of VEGFR-1 signaling also reduces tumor cell survival and invasiveness, counteracts the mobilization of myeloid progenitors and prevents tumor infiltration by M2 protumoral macrophages.	('VEGFR-1', 'Gene', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumoral', 'Disease', 'MESH:D009369', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('reduces', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prevents', 'NegReg', (147, 155))	('tumor', 'Disease', (184, 189))	('invasiveness', 'CPA', (77, 89))	('tumor', 'Disease', (53, 58))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('inhibition', 'Var', (8, 18))	('tumoral', 'Disease', (184, 191))
217395	32085654	In this context, the D16F7 mAb is a promising tool to specifically and non-competitively interfere with VEGFR-1 signaling in the tumor.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('interfere', 'NegReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('D16F7', 'Chemical', 'MESH:C000627505', (21, 26))	('D16F7', 'Var', (21, 26))	('tumor', 'Disease', (129, 134))	('VEGFR-1 signaling', 'MPA', (104, 121))
217396	32085654	Conversely, other experimental mAbs designed to inhibit human VEGFR-1 signaling, like IMC-18F1/icrucumab, KM1730, or KM1732, possess a competitive mechanism of action, by inhibiting VEGF-A, VEGF-B, or PlGF binding to VEGFR-1.	('men', 'Species', '9606', (24, 27))	('PlGF', 'Protein', (201, 205))	('binding', 'Interaction', (206, 213))	('inhibiting', 'NegReg', (171, 181))	('icrucumab', 'Chemical', 'MESH:C000626257', (95, 104))	('IMC-18F1', 'Chemical', 'MESH:C548516', (86, 94))	('KM1730', 'Var', (106, 112))	('human', 'Species', '9606', (56, 61))	('VEGF-A', 'Protein', (182, 188))	('KM1732', 'Var', (117, 123))	('VEGF-B', 'Protein', (190, 196))	('inhibit', 'NegReg', (48, 55))
217397	32085654	Competitive VEGFR-1 inhibitors, by antagonizing ligand binding, may increase in the ECM the free VEGF-A available for VEGFR-2 activation and this may reduce the overall efficacy of the treatment.	('free VEGF-A', 'MPA', (92, 103))	('ligand binding', 'Interaction', (48, 62))	('reduce', 'NegReg', (150, 156))	('inhibitors', 'Var', (20, 30))	('antagonizing', 'Reg', (35, 47))	('men', 'Species', '9606', (190, 193))	('ECM', 'MPA', (84, 87))	('increase', 'PosReg', (68, 76))	('VEGFR-1', 'Gene', (12, 19))	('efficacy of the treatment', 'CPA', (169, 194))
217399	32085654	D16F7 mAb efficacy in monotherapy has already been demonstrated in in vivo preclinical models of highly aggressive tumors, showing significant inhibition of glioblastoma and melanoma growth, invasiveness and migration, impairment of endothelial cells chemotaxis and tumor-associated angiogenesis, as well as reduced myeloid progenitor mobilization and tumor infiltration by monocytes/macrophages.	('impairment', 'NegReg', (219, 229))	('aggressive tumors', 'Disease', 'MESH:D001523', (104, 121))	('tumor', 'Disease', (115, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('men', 'Species', '9606', (225, 228))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('tumor', 'Disease', (266, 271))	('inhibition', 'NegReg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('invasiveness', 'CPA', (191, 203))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('melanoma growth', 'Disease', 'MESH:D008545', (174, 189))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (352, 357))	('myeloid progenitor mobilization', 'CPA', (316, 347))	('rat', 'Species', '10116', (364, 367))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (157, 182))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('endothelial cells chemotaxis', 'CPA', (233, 261))	('rat', 'Species', '10116', (211, 214))	('D16F7', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('rat', 'Species', '10116', (58, 61))	('reduced', 'NegReg', (308, 315))	('melanoma growth', 'Disease', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('aggressive tumors', 'Disease', (104, 121))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('migration', 'CPA', (208, 217))
217435	31771237	Of note, as regards brain tumors, the profile of uptake for both [18F] FCH and [11C] choline was investigated in glioma cell culture: the authors found that the metabolism of (18F) FCH was very close to that of choline, although some minor differences were registered between the two compounds.	('choline', 'Chemical', 'MESH:D002794', (85, 92))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('FCH', 'Chemical', 'MESH:C419185', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('[18F] FCH', 'Chemical', 'MESH:C514960', (65, 74))	('brain tumors', 'Disease', 'MESH:D001932', (20, 32))	('brain tumors', 'Phenotype', 'HP:0030692', (20, 32))	('glioma', 'Disease', (113, 119))	('18F) FCH', 'Var', (176, 184))	('[11C] choline', 'Chemical', 'MESH:C447081', (79, 92))	('choline', 'Chemical', 'MESH:D002794', (211, 218))	('metabolism', 'MPA', (161, 171))	('brain tumors', 'Disease', (20, 32))	('brain tumor', 'Phenotype', 'HP:0030692', (20, 31))	('FCH', 'Chemical', 'MESH:C419185', (181, 184))
217440	31771237	The first studies in humans demonstrated that [11C] choline presents a very rapid blood clearance, with stable distribution in tissues and organs after the first 5 min p.i.	('[11C] choline', 'Chemical', 'MESH:C447081', (46, 59))	('[11C]', 'Var', (46, 51))	('blood clearance', 'MPA', (82, 97))	('humans', 'Species', '9606', (21, 27))
217472	31771237	The three compounds, labeled with the radionuclide gallium-68 ([68Ga]) and commonly used for PET imaging in clnical practice, are: [68Ga] DOTAPhe1-Tyr3-Octreotide (DOTATOC), [68Ga] DOTA-NaI3-Octreotide (DOTANOC), and [68Ga] DOTA-Tyr3-octreotate (DOTATATE).	('[68Ga] DOTA-Tyr3-octreotate', 'Var', (217, 244))	('DOTA', 'Chemical', 'MESH:C071349', (164, 168))	('DOTA', 'Chemical', 'MESH:C071349', (181, 185))	('DOTA', 'Chemical', 'MESH:C071349', (224, 228))	('[68Ga] DOTAPhe1-Tyr3-Octreotide', 'Chemical', 'MESH:C550726', (131, 162))	('DOTA', 'Chemical', 'MESH:C071349', (203, 207))	('DOTANOC', 'Chemical', 'MESH:C504894', (203, 210))	('radionuclide gallium-68 ([68Ga])', 'Chemical', 'MESH:C103850', (38, 70))	('DOTA', 'Chemical', 'MESH:C071349', (138, 142))	('DOTA', 'Chemical', 'MESH:C071349', (246, 250))	('[68Ga] DOTA-NaI3-Octreotide', 'Chemical', 'MESH:C587879', (174, 201))	('[68Ga] DOTA-Tyr3-octreotate', 'Chemical', 'MESH:C000594971', (217, 244))	('[68Ga] DOTA-NaI3-Octreotide', 'Var', (174, 201))
217475	31771237	Although they are characterized by minimal differences in affinity for sstr, the three aforementioned [68Ga] DOTA-peptides have been demonstrated to be highly sensitive and specific in detecting well differentiated NET, with a higher detection rate when compared to conventional radiological imaging (i.e., CT/MRI).	('[68Ga]', 'Var', (102, 108))	('[68Ga] DOTA', 'Chemical', 'MESH:C587879', (102, 113))	('detection', 'MPA', (234, 243))	('higher', 'PosReg', (227, 233))
217476	31771237	As concerns the applications in pediatric imaging, promising results were reported for the use of [68Ga] DOTATATE for the imaging of neuroblastoma, especially in the case of relapsed tumors.	('[68Ga', 'Var', (98, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (133, 146))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('[68Ga] DOTATATE', 'Chemical', 'MESH:C000594971', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('neuroblastoma', 'Disease', (133, 146))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('neuroblastoma', 'Phenotype', 'HP:0003006', (133, 146))	('tumors', 'Disease', (183, 189))
217486	31771237	[68Ga] DOTA-peptides present several advantages for SRI, when compared to [111In] pentetreotide.	('[68Ga] DOTA-peptides', 'Var', (0, 20))	('advantages', 'PosReg', (37, 47))	('[111In] pentetreotide', 'Chemical', 'MESH:C081788', (74, 95))	('SRI', 'Disease', (52, 55))	('[68Ga] DOTA', 'Chemical', 'MESH:C587879', (0, 11))
217489	31771237	Nevertheless, the scientific data regarding the application of PET/CT with [68Ga] DOTA-peptides for the imaging of PBT is still scant.	('[68Ga] DOTA', 'Chemical', 'MESH:C587879', (75, 86))	('PBT', 'Disease', 'MESH:D001932', (115, 118))	('[68Ga]', 'Var', (75, 81))	('PBT', 'Disease', (115, 118))
217491	31771237	In the overall examined population, which included histotypes of others than cerebral malignancies, the sensitivity and specificity of [68Ga] DOTATOC PET resulted in 88% and 100%, respectively.	('cerebral malignancies', 'Disease', (77, 98))	('[68Ga] DOTATOC', 'Chemical', 'MESH:C550726', (135, 149))	('cerebral malignancies', 'Disease', 'MESH:D001932', (77, 98))	('cerebral malignancies', 'Phenotype', 'HP:0030692', (77, 98))	('[68Ga]', 'Var', (135, 141))
217519	31771237	Reconstruction is usually performed by adding an adequate activity of [99mTc] O4- to the kit and warming the mixture in boiling water according to the manufacturer's recommendations.	('[99mTc] O4-', 'Var', (70, 81))	('[99mTc] O4', 'Chemical', 'MESH:D013670', (70, 80))	('activity', 'MPA', (58, 66))	('boiling', 'Phenotype', 'HP:0020083', (120, 127))
217528	31771237	The main drawback of [99mTc] MIBI resulted in its intense physiological uptake in the choroid plexus, which might hamper the detection of lesions located in the deep para-ventricular spaces.	('[99mTc] MIBI', 'Chemical', 'MESH:D017256', (21, 33))	('[99mTc] MIBI', 'Var', (21, 33))	('hamper', 'NegReg', (114, 120))	('physiological uptake', 'MPA', (58, 78))
217551	31771237	[18F] FDOPA may enter various pathways (e.g., peptide, protein, purine, pyrimidine, or hormone synthesis; act as methyl group donors, etc.).	('purine', 'Chemical', 'MESH:D011687', (64, 70))	('hormone synthesis', 'MPA', (87, 104))	('purine', 'MPA', (64, 70))	('peptide', 'MPA', (46, 53))	('methyl', 'Chemical', 'MESH:C031105', (113, 119))	('enter', 'Reg', (16, 21))	('pyrimidine', 'MPA', (72, 82))	('pyrimidine', 'Chemical', 'MESH:C030986', (72, 82))	('[18F]', 'Var', (0, 5))	('[18F] FDOPA', 'Chemical', 'MESH:C043437', (0, 11))	('protein', 'MPA', (55, 62))
217553	31771237	[11C] MET and [18F] FET are two radiopharmaceuticals that can easily cross the blood-brain barrier and they are taken up in the brain by L-type amino acid transporter system and Na+-dependent system B0 and are then mainly incorporated into proteins, but also into lipid, RNA, and DNA.	('[18F] FET', 'Chemical', 'MESH:C543201', (14, 23))	('[18F] FET', 'Var', (14, 23))	('[11C] MET', 'Var', (0, 9))	('[11C] MET', 'Chemical', 'MESH:C098756', (0, 9))
217568	31771237	demonstrated that PET imaging with [18F] FDG and [11C] MET was helpful in the surgical management of 126 children with PBT, surgical, and post-operative steps.	('[18F] FDG', 'Chemical', 'MESH:D019788', (35, 44))	('PBT', 'Disease', (119, 122))	('children', 'Species', '9606', (105, 113))	('[18F] FDG', 'Var', (35, 44))	('[11C] MET', 'Chemical', 'MESH:C098756', (49, 58))	('PBT', 'Disease', 'MESH:D001932', (119, 122))	('[11C] MET', 'Var', (49, 58))
217572	31771237	Lastly, [11C] MET improved the detection of tumor residues in the operative cavity at the early postoperative stage, thus facilitating the decision of early second-look surgery for optimizing the radical resection.	('[11C] MET', 'Chemical', 'MESH:C098756', (8, 17))	('[11C] MET', 'Var', (8, 17))	('improved', 'PosReg', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('detection', 'MPA', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
217576	31771237	Figure 5 and Figure 6 provide examples of [18F] FDOPA PETscan in a patient with PBT.	('PBT', 'Disease', (80, 83))	('[18F] FDOPA PETscan', 'Chemical', 'MESH:C043437', (42, 61))	('PBT', 'Disease', 'MESH:D001932', (80, 83))	('[18F] FDOPA', 'Var', (42, 53))	('patient', 'Species', '9606', (67, 74))
217590	31771237	[18F] FET showed promising results in biopsy guidance and treatment planning of cerebral tumors, especially when compared to [18F] FDG.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cerebral tumors', 'Disease', 'MESH:D001932', (80, 95))	('cerebral tumors', 'Phenotype', 'HP:0030692', (80, 95))	('[18F] FET', 'Var', (0, 9))	('treatment planning', 'CPA', (58, 76))	('cerebral tumors', 'Disease', (80, 95))	('[18F] FDG', 'Chemical', 'MESH:D019788', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('[18F] FET', 'Chemical', 'MESH:C543201', (0, 9))
217593	31771237	It has been recently noticed that [18F] FET uptake is significantly increased in IDH1/2 mutant-1p/19q non-codel gliomas.	('[18F] FET', 'Chemical', 'MESH:C543201', (34, 43))	('IDH1/2', 'Gene', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('[18F] FET uptake', 'MPA', (34, 50))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('increased', 'PosReg', (68, 77))	('mutant-1p/19q', 'Var', (88, 101))
217625	26093898	In this study, we employed multiple integrated bioinformatic approaches to identify the probable epigenetic factors, molecular pathways, and functionalities associated with mda-9 dysregulation during cancer progression.	('dysregulation', 'Var', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('mda-9', 'Gene', '6386', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('mda-9', 'Gene', (173, 178))	('cancer', 'Disease', (200, 206))
217643	26093898	One area that has not yet been investigated is how genetic and epigenetic factors contribute to its elevated expression during cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('expression', 'MPA', (109, 119))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('elevated', 'PosReg', (100, 108))	('epigenetic factors', 'Var', (63, 81))
217689	26093898	Except for two ( and cg10129404), the CpG sites were mostly unmethylated across all the cancer datasets.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cg10129404', 'Chemical', '-', (21, 31))	('cg10129404', 'Var', (21, 31))
217691	26093898	The CpG site is exactly 1105 bases from the 3' edge of the CpG island, while cg10129404 is part of the 3' UTR, making it less likely for the latter to be a factor in transcription of mda-9 (this will be clarified in the next subsection).	('mda-9', 'Gene', (183, 188))	('cg10129404', 'Var', (77, 87))	('cg10129404', 'Chemical', '-', (77, 87))	('mda-9', 'Gene', '6386', (183, 188))
217695	26093898	As mentioned above, it is unlikely that the 3' UTR CpG site cg10129404 influences mda-9 transcript levels.	('transcript levels', 'MPA', (88, 105))	('cg10129404', 'Chemical', '-', (60, 70))	('cg10129404', 'Var', (60, 70))	('mda-9', 'Gene', '6386', (82, 87))	('mda-9', 'Gene', (82, 87))
217696	26093898	A simple analysis was conducted by plotting mda-9 expression vs the beta value for or cg10129404 for two select TCGA datasets (glioma and KIRP) (Figure 7).	('cg10129404', 'Var', (86, 96))	('mda-9', 'Gene', (44, 49))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma', 'Disease', (127, 133))	('cg10129404', 'Chemical', '-', (86, 96))	('mda-9', 'Gene', '6386', (44, 49))
217697	26093898	In glioma, it is clear that the methylation at may influence mda-9 expression (R2 = 0.38; linear regression).	('mda-9', 'Gene', (61, 66))	('methylation', 'Var', (32, 43))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('glioma', 'Disease', (3, 9))	('mda-9', 'Gene', '6386', (61, 66))	('expression', 'MPA', (67, 77))	('influence', 'Reg', (51, 60))
217698	26093898	In contrast, cg10129404 appears to have a negligible effect on mda-9 expression (R2 = 0.051).	('mda-9', 'Gene', '6386', (63, 68))	('mda-9', 'Gene', (63, 68))	('expression', 'MPA', (69, 79))	('cg10129404', 'Chemical', '-', (13, 23))	('cg10129404', 'Var', (13, 23))
217700	26093898	Overall, these analyses indicate that cg10129404's influence on mda-9 expression is unlikely.	('cg10129404', 'Var', (38, 48))	('mda-9', 'Gene', (64, 69))	('expression', 'MPA', (70, 80))	('cg10129404', 'Chemical', '-', (38, 48))	('mda-9', 'Gene', '6386', (64, 69))
217704	26093898	However, it is also clear that among the samples with only two copies of mda-9, those with low degree of methylation at the cg17197774 tend to have a higher mda-9 expression level (R = -0.61; expression vs. cg17197774 beta value).	('mda-9', 'Gene', (157, 162))	('cg17197774', 'Var', (124, 134))	('expression level', 'MPA', (163, 179))	('cg17197774', 'Chemical', '-', (124, 134))	('higher', 'PosReg', (150, 156))	('mda-9', 'Gene', '6386', (73, 78))	('cg17197774', 'Chemical', '-', (207, 217))	('mda-9', 'Gene', (73, 78))	('mda-9', 'Gene', '6386', (157, 162))
217705	26093898	By itself, it appears that cg17197774 methylation status may be a reliable marker of survival in glioma (Figure 9).	('cg17197774', 'Var', (27, 37))	('cg17197774', 'Chemical', '-', (27, 37))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
217706	26093898	On average, SKCM samples have the lowest beta values for cg17197774, at -0.295 (Table 3).	('cg17197774', 'Var', (57, 67))	('cg17197774', 'Chemical', '-', (57, 67))	('lowest', 'NegReg', (34, 40))
217709	26093898	For the TCGA COAD dataset, both copy number and cg17197774 methylation appear to factor in mda-9 expression, with the former (R = 0.47) having greater influence than the latter (-0.22).	('copy number', 'Var', (32, 43))	('factor', 'Reg', (81, 87))	('cg17197774 methylation', 'Var', (48, 70))	('methylation', 'Var', (59, 70))	('mda-9', 'Gene', '6386', (91, 96))	('expression', 'MPA', (97, 107))	('mda-9', 'Gene', (91, 96))	('cg17197774', 'Chemical', '-', (48, 58))
217710	26093898	A great majority of KIRP samples have a neutral copy number (CN =2) at the mda-9 locus.	('mda-9', 'Gene', (75, 80))	('neutral copy number', 'Var', (40, 59))	('mda-9', 'Gene', '6386', (75, 80))
217711	26093898	Not surprisingly, the elevated mda-9 expression is primarily due to hypomethylation at cg17197774 (mda-9 expression vs. cg17197774 methylation correlation coefficient = -0.5).	('hypomethylation', 'Var', (68, 83))	('mda-9', 'Gene', (99, 104))	('cg17197774', 'Var', (87, 97))	('mda-9', 'Gene', '6386', (31, 36))	('elevated', 'PosReg', (22, 30))	('cg17197774', 'Chemical', '-', (87, 97))	('mda-9', 'Gene', (31, 36))	('cg17197774', 'Chemical', '-', (120, 130))	('expression', 'MPA', (37, 47))	('mda-9', 'Gene', '6386', (99, 104))
217712	26093898	In contrast to KIRP, the mode of mda-9 dysregulation in prostate cancer samples is primarily through copy number gain (R= 0.67), with cg17197774 methylation apparently lacking any effect on the gene's expression level.	('cg17197774 methylation', 'Var', (134, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('copy', 'MPA', (101, 105))	('gain', 'PosReg', (113, 117))	('mda-9', 'Gene', '6386', (33, 38))	('cg17197774', 'Chemical', '-', (134, 144))	('methylation', 'Var', (145, 156))	('mda-9', 'Gene', (33, 38))	('dysregulation', 'NegReg', (39, 52))	('prostate cancer', 'Disease', (56, 71))
217713	26093898	Among LIHC primary tumors, it is clear that both copy number (R = 0.55) and cg17197774 methylation (R = -0.45) are factors influencing mda-9 RNA levels.	('LIHC primary tumors', 'Disease', (6, 25))	('influencing', 'Reg', (123, 134))	('cg17197774', 'Chemical', '-', (76, 86))	('mda-9', 'Gene', '6386', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LIHC primary tumors', 'Disease', 'MESH:D009369', (6, 25))	('mda-9', 'Gene', (135, 140))	('cg17197774 methylation', 'Var', (76, 98))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('methylation', 'Var', (87, 98))
217714	26093898	For a unified view on the effects of both copy number and cg17197774 methylation on mda-9 expression, we used the PANCAN-normalized expression value for mda-9.	('mda-9', 'Gene', '6386', (153, 158))	('mda-9', 'Gene', '6386', (84, 89))	('cg17197774', 'Var', (58, 68))	('mda-9', 'Gene', (153, 158))	('mda-9', 'Gene', (84, 89))	('cg17197774', 'Chemical', '-', (58, 68))
217715	26093898	Figures 10 A-B show the same Cartesian plot (i.e., PANCAN-normalized mda-9 expression value vs. methylation at cg17197774) with varying information for each data point.	('cg17197774', 'Var', (111, 121))	('mda-9', 'Gene', '6386', (69, 74))	('cg17197774', 'Chemical', '-', (111, 121))	('mda-9', 'Gene', (69, 74))	('expression', 'MPA', (75, 85))
217716	26093898	As discussed previously, the highest mda-9 expression levels were those of SKCM samples, owing to the low beta values for cg17197774.	('mda-9', 'Gene', '6386', (37, 42))	('cg17197774', 'Var', (122, 132))	('cg17197774', 'Chemical', '-', (122, 132))	('expression levels', 'MPA', (43, 60))	('mda-9', 'Gene', (37, 42))
217718	26093898	This indicates that copy number can elevate mda-9 expression levels irrespective of the methylation status of cg17197774.	('mda-9', 'Gene', (44, 49))	('cg17197774', 'Chemical', '-', (110, 120))	('expression levels', 'MPA', (50, 67))	('copy number', 'Var', (20, 31))	('cg17197774', 'Gene', (110, 120))	('elevate', 'PosReg', (36, 43))	('mda-9', 'Gene', '6386', (44, 49))
217719	26093898	This shows that the methylation status of cg17197774 has greater influence (compared to mda-9 copy number) towards the gene's expression level.	('methylation', 'MPA', (20, 31))	('influence', 'Reg', (65, 74))	('cg17197774', 'Chemical', '-', (42, 52))	('mda-9', 'Gene', '6386', (88, 93))	('cg17197774', 'Var', (42, 52))	('mda-9', 'Gene', (88, 93))	('expression level', 'MPA', (126, 142))
217720	26093898	Figure 10C shows a superimposed exponential regression model (JMP Pro 10) relating mda-9 expression and cg17197774.	('expression', 'MPA', (89, 99))	('cg17197774', 'Var', (104, 114))	('cg17197774', 'Chemical', '-', (104, 114))	('mda-9', 'Gene', '6386', (83, 88))	('mda-9', 'Gene', (83, 88))
217722	26093898	At this point, we already know that tumor samples with neutral copy number for mda-9 can have an elevated expression of the gene if it is hypomethylated at cg17197774.	('elevated', 'PosReg', (97, 105))	('mda-9', 'Gene', (79, 84))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cg17197774', 'Var', (156, 166))	('neutral copy number', 'Var', (55, 74))	('cg17197774', 'Chemical', '-', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('mda-9', 'Gene', '6386', (79, 84))
217730	26093898	For MDA-9, two different antibodies were used: HPA023840 from Sigma-Aldrich and CAB012245 from Abcam.	('HPA023840', 'Var', (47, 56))	('CAB012245', 'Var', (80, 89))	('MDA-9', 'Gene', '6386', (4, 9))	('MDA-9', 'Gene', (4, 9))
217732	26093898	As shown in the figure (bottom right), the HPA023840 signal was much stronger in melanoma compared to glioma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('stronger', 'PosReg', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('glioma', 'Disease', (102, 108))	('HPA023840', 'Var', (43, 52))
217736	26093898	Since we have already established (from TCGA analysis) that the methylation at the CpG site cg17197774 correlates with decreased mda-9 expression, it would be of interest to investigate how this CpG site may also affect the constitution of chromatin covering the mda-9 locus.	('decreased', 'NegReg', (119, 128))	('methylation', 'Var', (64, 75))	('cg17197774', 'Var', (92, 102))	('affect', 'Reg', (213, 219))	('mda-9', 'Gene', '6386', (129, 134))	('mda-9', 'Gene', '6386', (263, 268))	('expression', 'MPA', (135, 145))	('cg17197774', 'Chemical', '-', (92, 102))	('mda-9', 'Gene', (129, 134))	('mda-9', 'Gene', (263, 268))
217738	26093898	As indicated in Figure 13A, the MDA-9 promoter region of HUVEC (hypomethylated at cg17197774; beta value = -0.353) exhibits greater affinity (darker bands) for Histone H3 mono-, di-, or tri-methylated at K4 (H3K4me1, H3K4me2, H3K4me3), and acetylated at K9 (H3K9ac), compared to that of H1-hESC (highly methylated at cg17197774; beta value = 0.230).	('ES', 'Chemical', '-', (291, 293))	('H3', 'Chemical', 'MESH:C012616', (208, 210))	('Histone H3', 'Protein', (160, 170))	('tri-methylated', 'Var', (186, 200))	('cg17197774', 'Chemical', '-', (317, 327))	('greater', 'PosReg', (124, 131))	('H3', 'Chemical', 'MESH:C012616', (258, 260))	('di-', 'Var', (178, 181))	('H3', 'Chemical', 'MESH:C012616', (217, 219))	('H3', 'Chemical', 'MESH:C012616', (226, 228))	('H3', 'Chemical', 'MESH:C012616', (168, 170))	('MDA-9', 'Gene', (32, 37))	('cg17197774', 'Var', (82, 92))	('cg17197774', 'Chemical', '-', (82, 92))	('MDA-9', 'Gene', '6386', (32, 37))	('affinity', 'MPA', (132, 140))
217739	26093898	Those histone modifications, just like hypomethylation at cg17197774, are associated with more active transcription.	('modifications', 'Var', (14, 27))	('more', 'PosReg', (90, 94))	('cg17197774', 'Chemical', '-', (58, 68))	('active transcription', 'MPA', (95, 115))	('associated', 'Reg', (74, 84))
217740	26093898	Four other markers (H4K20me1 which is associated with transcriptional activity; H3K36me3 which is associated with RNAPII elongation; H3K27me3 which is associated with promoter silencing; and the transcriptional repressor CTCF) were not significantly different between the two cell lines.	('H3K27me3', 'Var', (133, 141))	('CTCF', 'Gene', (221, 225))	('K20', 'Gene', (22, 25))	('H3K36me3', 'Var', (80, 88))	('CTCF', 'Gene', '10664', (221, 225))	('K20', 'Gene', '54474', (22, 25))
217744	26093898	As shown in Figure 13B, H1-hESC, HepG2 and HMEC, which are all highly methylated at cg17197774, are predicted to exhibit less active MDA-9 promoter and transcriptional activity (interpretations for segmental colors are listed in Figure 13C).	('less', 'NegReg', (121, 125))	('HepG2', 'CellLine', 'CVCL:0027', (33, 38))	('cg17197774', 'Var', (84, 94))	('cg17197774', 'Chemical', '-', (84, 94))	('HMEC', 'CellLine', 'CVCL:0307', (43, 47))	('ES', 'Chemical', '-', (28, 30))	('transcriptional activity', 'MPA', (152, 176))	('active', 'MPA', (126, 132))	('MDA-9', 'Gene', '6386', (133, 138))	('MDA-9', 'Gene', (133, 138))
217745	26093898	In contrast, MDA-9 expression is expected to be higher for cell lines GM12878, K562 and HUVEC, which are all weakly methylated at cg17197774.	('MDA-9', 'Gene', '6386', (13, 18))	('expression', 'MPA', (19, 29))	('K562', 'CellLine', 'CVCL:0004', (79, 83))	('higher', 'PosReg', (48, 54))	('cg17197774', 'Var', (130, 140))	('cg17197774', 'Chemical', '-', (130, 140))	('MDA-9', 'Gene', (13, 18))
217782	26093898	Its down-regulation among mda-9 high glioma is consistent with recent observations that relatively low expression of the gene correlates with the absence of 1p/19q co-deletion (which are established markers of good prognosis).	('mda-9', 'Gene', (26, 31))	('low', 'NegReg', (99, 102))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('expression', 'MPA', (103, 113))	('1p/19q co-deletion', 'Var', (157, 175))	('high glioma', 'Disease', 'MESH:D005910', (32, 43))	('high glioma', 'Disease', (32, 43))	('mda-9', 'Gene', '6386', (26, 31))	('absence', 'NegReg', (146, 153))	('down-regulation', 'NegReg', (4, 19))
217874	26093898	In glioma, both mda-9 expression level and methylation at cg17197774 can provide prognostic markers, with elevated expression and hypomethylation, respectively, correlating with poor survival.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('cg17197774', 'Gene', (58, 68))	('expression', 'MPA', (115, 125))	('elevated', 'PosReg', (106, 114))	('glioma', 'Disease', (3, 9))	('mda-9', 'Gene', '6386', (16, 21))	('hypomethylation', 'Var', (130, 145))	('cg17197774', 'Chemical', '-', (58, 68))	('expression', 'MPA', (22, 32))	('mda-9', 'Gene', (16, 21))
217875	26093898	Among the cancer types included in the TCGA Pan Cancer (PANCAN) dataset, melanoma exhibits the highest level of mda-9 (which is consistent with information downloaded from the Human Protein Atlas), which may be explained by its generally low methylation level at the cg17197774 CpG site (which has the lowest among the 6 TCGA datasets analyzed for CpG methylation).	('melanoma', 'Disease', (73, 81))	('mda-9', 'Gene', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cg17197774', 'Var', (267, 277))	('cg17197774', 'Chemical', '-', (267, 277))	('Human', 'Species', '9606', (176, 181))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('methylation level', 'MPA', (242, 259))	('low', 'NegReg', (238, 241))	('mda-9', 'Gene', '6386', (112, 117))	('cancer', 'Disease', (10, 16))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
217876	26093898	Hypomethylation at cg17197774 is associated with higher intensity of modified histones such as H3K4 di- and tri-methylation and H3K9 acetylation in the promoter area.	('H3', 'Chemical', 'MESH:C012616', (128, 130))	('tri-methylation', 'MPA', (108, 123))	('H3K4', 'Protein', (95, 99))	('Hypomethylation', 'Var', (0, 15))	('acetylation', 'MPA', (133, 144))	('H3', 'Chemical', 'MESH:C012616', (95, 97))	('intensity', 'MPA', (56, 65))	('cg17197774', 'Var', (19, 29))	('cg17197774', 'Chemical', '-', (19, 29))	('H3K9', 'Protein', (128, 132))	('di-', 'MPA', (100, 103))
217877	26093898	H3K4 methylations are characteristics of active (or poised to be activated) promoters, while H3K9 acetylation describes a likely active transcription.	('methylations', 'Var', (5, 17))	('H3', 'Chemical', 'MESH:C012616', (93, 95))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('H3K4', 'Protein', (0, 4))
217881	26093898	Among the top gene groups and molecular pathways identified using the scheme described above are those previously linked with both mda-9 dysregulation and glioma progression (e.g., matrix metalloproteinases, interleukins, IGFBP2 signaling, NF-kappaB activation).	('dysregulation', 'Var', (137, 150))	('NF-kappaB', 'Gene', '4790', (240, 249))	('IGFBP2', 'Gene', '3485', (222, 228))	('mda-9', 'Gene', '6386', (131, 136))	('activation', 'PosReg', (250, 260))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('IGFBP2', 'Gene', (222, 228))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('NF-kappaB', 'Gene', (240, 249))	('mda-9', 'Gene', (131, 136))	('glioma', 'Disease', (155, 161))
217883	26093898	Through the integrated bioinformatic analyses of publicly available cancer genomic datasets, we were able to comprehensively analyze the various epigenetic and molecular factors associated with the dysregulation of mda-9 in various types of cancer.	('mda-9', 'Gene', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (68, 74))	('mda-9', 'Gene', '6386', (215, 220))	('dysregulation', 'Var', (198, 211))
217884	26093898	The following is a list of the most important conclusions obtained from this exercise:  The driving forces behind a gene's dysregulated expression in cancer (either upregulation or downregulation) involve a multitude of factors including gene copy number variations, epigenetic regulation and transcription factors.	('expression', 'MPA', (136, 146))	('downregulation', 'NegReg', (181, 195))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('epigenetic regulation', 'Var', (267, 288))	('gene copy number variations', 'Var', (238, 265))	('cancer', 'Disease', (150, 156))	('upregulation', 'PosReg', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('dysregulated', 'PosReg', (123, 135))
217890	26093898	In contrast, the copy number influence is most pronounced in PRAD samples, which are mostly highly methylated at cg17197774.	('cg17197774', 'Var', (113, 123))	('cg17197774', 'Chemical', '-', (113, 123))	('PRAD', 'Disease', (61, 65))
217891	26093898	The influence of cg17197774 methylation towards mda-9 levels is readily observed in the 5 other tumor types.	('mda-9', 'Gene', '6386', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('mda-9', 'Gene', (48, 53))	('cg17197774 methylation', 'Var', (17, 39))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('methylation', 'Var', (28, 39))	('cg17197774', 'Chemical', '-', (17, 27))
217892	26093898	Our identification of cg17197774 as the most differentially methylated (and most highly associated with mda-9 transcript levels) is consistent with recent observations by Irizarry and colleagues.	('mda-9', 'Gene', '6386', (104, 109))	('cg17197774', 'Var', (22, 32))	('cg17197774', 'Chemical', '-', (22, 32))	('mda-9', 'Gene', (104, 109))	('associated', 'Reg', (88, 98))
217896	26093898	For example, an H3 histone di- or tri-methylated at K4 is indicative of a poised or active promoter.	('H3 histone', 'Protein', (16, 26))	('H3', 'Chemical', 'MESH:C012616', (16, 18))	('tri-methylated', 'Var', (34, 48))	('di-', 'Var', (27, 30))
217897	26093898	A mono-methylated H3 histone is often associated with enhancer downstream of a start site.	('enhancer', 'PosReg', (54, 62))	('H3 histone', 'Protein', (18, 28))	('mono-methylated', 'Var', (2, 17))	('H3', 'Chemical', 'MESH:C012616', (18, 20))
217899	26093898	Active transcription may also be characterized by an H4 histone methylated at K20.	('K20', 'Gene', '54474', (78, 81))	('methylated', 'Var', (64, 74))	('Active', 'MPA', (0, 6))	('K20', 'Gene', (78, 81))	('H4 histone', 'Protein', (53, 63))
217901	26093898	What we observed is that cell lines weakly methylated at cg17197774 (such as GM12878, K562 and HUVEC) tend to have more intense binding by H3 methylated at K4 or acetylated at K9, and H4 methylated at K20.	('intense', 'PosReg', (120, 127))	('H3', 'Chemical', 'MESH:C012616', (139, 141))	('K20', 'Gene', '54474', (201, 204))	('K562', 'CellLine', 'CVCL:0004', (86, 90))	('cg17197774', 'Var', (57, 67))	('binding', 'Interaction', (128, 135))	('K20', 'Gene', (201, 204))	('cg17197774', 'Chemical', '-', (57, 67))	('acetylated', 'MPA', (162, 172))
217903	26093898	For now, we can just assume that the methylation at cg17197774 may be detrimental to the binding affinity of these modified histones.	('cg17197774', 'Var', (52, 62))	('cg17197774', 'Chemical', '-', (52, 62))	('binding affinity', 'Interaction', (89, 105))	('methylation', 'MPA', (37, 48))
217918	26093898	CTLA4 (expressed in Helper T cells and a negative regulator of T lymphocytes) increased ~ 3-fold in mda-9 High relative to mda-9 Low glioma.	('High', 'Var', (106, 110))	('CTLA4', 'Gene', '1493', (0, 5))	('Low glioma', 'Disease', (129, 139))	('mda-9', 'Gene', '6386', (123, 128))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('CTLA4', 'Gene', (0, 5))	('mda-9', 'Gene', (123, 128))	('mda-9', 'Gene', '6386', (100, 105))	('Helper T', 'CellLine', 'CVCL:3174', (20, 28))	('mda-9', 'Gene', (100, 105))	('increased', 'PosReg', (78, 87))	('Low glioma', 'Disease', 'MESH:D005910', (129, 139))
217928	27036230	Characteristics of gliomas in patients with somatic IDH mosaicism IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors.	('IDH', 'Gene', '3417', (66, 69))	('IDH', 'Gene', '3417', (52, 55))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('cartilaginous tumors', 'Disease', (191, 211))	('gliomas', 'Disease', (19, 26))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('low-grade', 'Disease', (125, 134))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (191, 211))	('mutations', 'Var', (70, 79))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Disease', (150, 157))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('IDH', 'Gene', (66, 69))	('adult', 'Disease', (109, 114))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('IDH', 'Gene', (52, 55))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
217929	27036230	Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations.	('multiple benign cartilaginous tumors', 'Disease', 'MESH:D005097', (108, 144))	('Ollier disease', 'Phenotype', 'HP:0500045', (0, 14))	('mutations', 'Var', (184, 193))	('multiple benign cartilaginous tumors', 'Disease', (108, 144))	('Ollier disease', 'Disease', (0, 14))	('IDH', 'Gene', (180, 183))	('Maffucci syndrome', 'Disease', (19, 36))	('enchondromatosis syndromes', 'Disease', 'MESH:D004687', (45, 71))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('IDH', 'Gene', '3417', (180, 183))	('enchondroma', 'Phenotype', 'HP:0030038', (45, 56))	('Ollier disease', 'Disease', 'MESH:D004687', (0, 14))	('two enchondromatosis', 'Phenotype', 'HP:0005701', (41, 61))	('enchondromatosis syndromes', 'Disease', (45, 71))
217935	27036230	Their molecular profile was characterized by IDH mutations and loss of ATRX expression.	('IDH', 'Gene', (45, 48))	('mutations', 'Var', (49, 58))	('ATRX', 'Gene', '546', (71, 75))	('IDH', 'Gene', '3417', (45, 48))	('expression', 'MPA', (76, 86))	('loss', 'NegReg', (63, 67))	('ATRX', 'Gene', (71, 75))
217936	27036230	In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cartilaginous tumor', 'Disease', (79, 98))	('mutation', 'Var', (30, 38))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH', 'Gene', (26, 29))	('IDH', 'Gene', '3417', (26, 29))	('patients', 'Species', '9606', (7, 15))	('cartilaginous tumor', 'Disease', 'MESH:D015831', (79, 98))	('glioma', 'Disease', (63, 69))
217939	27036230	Early acquisition of IDH mutations could shift gliomagenesis towards the brainstem thereby mimicking the regional preference of histone mutated gliomas.	('IDH', 'Gene', (21, 24))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('mutations', 'Var', (25, 34))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('IDH', 'Gene', '3417', (21, 24))	('glioma', 'Disease', (47, 53))	('glioma', 'Disease', (144, 150))	('shift', 'Reg', (41, 46))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
217940	27036230	Mutations in the IDH1 or IDH2 genes are found in the majority of adult diffuse grade II and grade III gliomas and are considered as the earliest oncogenic event in these tumors.	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('found', 'Reg', (40, 45))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (17, 21))	('IDH2', 'Gene', (25, 29))	('gliomas', 'Disease', (102, 109))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('IDH1', 'Gene', '3417', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('tumors', 'Disease', (170, 176))	('IDH2', 'Gene', '3418', (25, 29))
217941	27036230	These mutations result in the abnormal production of 2-hydroxyglutarate (2-HG) which is structurally similar to alpha-ketoglutarate.	('2-HG', 'Chemical', 'MESH:C019417', (73, 77))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (112, 131))	('result in', 'Reg', (16, 25))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (53, 71))	('mutations', 'Var', (6, 15))	('production', 'MPA', (39, 49))
217943	27036230	In addition to gliomas, IDH mutations are particularly frequent in cartilaginous tumors.	('cartilaginous tumors', 'Disease', 'MESH:D015831', (67, 87))	('IDH', 'Gene', (24, 27))	('cartilaginous tumors', 'Disease', (67, 87))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('IDH', 'Gene', '3417', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('frequent', 'Reg', (55, 63))	('mutations', 'Var', (28, 37))
217947	27036230	The analysis of IDH mutations in multiple cartilaginous tumors and non-neoplastic tissues from enchondromatosis patients led to the conclusion that these pathologies are due to early post-zygotic acquisition of IDH mutations, resulting in somatic mosaic mutations of IDH1 or IDH2.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('enchondromatosis', 'Disease', (95, 111))	('enchondroma', 'Phenotype', 'HP:0030038', (95, 106))	('IDH', 'Gene', (16, 19))	('IDH2', 'Gene', (275, 279))	('enchondromatosis', 'Disease', 'MESH:D004687', (95, 111))	('IDH2', 'Gene', '3418', (275, 279))	('cartilaginous tumors', 'Disease', (42, 62))	('mutations', 'Var', (215, 224))	('IDH', 'Gene', '3417', (16, 19))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (42, 62))	('IDH', 'Gene', (275, 278))	('IDH1', 'Gene', (267, 271))	('IDH', 'Gene', (211, 214))	('IDH', 'Gene', (267, 270))	('mutations', 'Var', (20, 29))	('mosaic mutations', 'Var', (247, 263))	('IDH', 'Gene', '3417', (275, 278))	('patients', 'Species', '9606', (112, 120))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('IDH1', 'Gene', '3417', (267, 271))	('IDH', 'Gene', '3417', (211, 214))	('IDH', 'Gene', '3417', (267, 270))
217957	27036230	The following antibodies were used after antigen retrieval to assess the expression of ATRX (anti-ATRX, Sigma, polyclonal, dilution 1/400), IDH1R132H (anti-IDH1R132H, Dianova, clone H09, dilution 1/50) and TP53 (clone DO.7, Dako, dilution 1/200).	('ATRX', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('ATRX', 'Gene', (87, 91))	('ATRX', 'Gene', '546', (98, 102))	('anti-IDH1R132H', 'Var', (151, 165))	('IDH1R132H', 'Gene', (140, 149))	('ATRX', 'Gene', '546', (87, 91))
217976	27036230	In the negative case, no expression of IDH1 R132H was detected on immunohistochemistry, but other IDH mutations were not assessed.	('R132H', 'Var', (44, 49))	('IDH1', 'Gene', (39, 43))	('IDH1', 'Gene', '3417', (39, 43))	('IDH', 'Gene', (39, 42))	('IDH', 'Gene', (98, 101))	('R132H', 'Mutation', 'rs121913500', (44, 49))	('IDH', 'Gene', '3417', (39, 42))	('IDH', 'Gene', '3417', (98, 101))
217981	27036230	In an additional patient, sequencing demonstrated missenses TP53 mutations.	('missenses', 'Var', (50, 59))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('patient', 'Species', '9606', (17, 24))
217984	27036230	Genomic profiles of the tumors were obtained for 2 patients; one patient had an isolated LOH of the 17p region covering the TP53 locus (patient 3), and the other patient had a LOH of chromosome 9 associated with partial losses of chromosomes 14q and 15q and a partial gain of chromosome 11q (patient 5).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('patient', 'Species', '9606', (136, 143))	('chromosome', 'Gene', (276, 286))	('tumors', 'Disease', (24, 30))	('TP53', 'Gene', '7157', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('gain', 'PosReg', (268, 272))	('TP53', 'Gene', (124, 128))	('patient', 'Species', '9606', (292, 299))	('patient', 'Species', '9606', (51, 58))	('patient', 'Species', '9606', (65, 72))	('LOH', 'Var', (176, 179))	('patients', 'Species', '9606', (51, 59))	('patient', 'Species', '9606', (162, 169))	('losses', 'NegReg', (220, 226))
217993	27036230	IDH mutations are considered to be the earliest oncogenic events in the majority of lower grade gliomas.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('mutations', 'Var', (4, 13))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
217994	27036230	In animal models, IDH mutations have been shown to be sufficient to induce enchondromas and chondrosarcomas.	('chondrosarcomas', 'Disease', 'MESH:D002813', (92, 107))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (92, 106))	('induce', 'Reg', (68, 74))	('IDH', 'Gene', (18, 21))	('enchondromas', 'Disease', 'MESH:D002812', (75, 87))	('chondrosarcomas', 'Disease', (92, 107))	('enchondroma', 'Phenotype', 'HP:0030038', (75, 86))	('IDH', 'Gene', '3417', (18, 21))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (92, 107))	('enchondromas', 'Disease', (75, 87))	('mutations', 'Var', (22, 31))	('enchondromas', 'Phenotype', 'HP:0030038', (75, 87))
217995	27036230	To our knowledge, this demonstration has not been previously reported for gliomas, but the occurrence of gliomas in enchondromatosis patients, in whom IDH mutations are thought to occur as an early post-zygotic event suggests that IDH mutations can initiate gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (258, 264))	('patients', 'Species', '9606', (133, 141))	('IDH', 'Gene', (231, 234))	('IDH', 'Gene', (151, 154))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('glioma', 'Disease', (105, 111))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', (105, 112))	('glioma', 'Disease', (74, 80))	('IDH', 'Gene', '3417', (231, 234))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('IDH', 'Gene', '3417', (151, 154))	('enchondromatosis', 'Disease', (116, 132))	('enchondroma', 'Phenotype', 'HP:0030038', (116, 127))	('mutations', 'Var', (235, 244))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('enchondromatosis', 'Disease', 'MESH:D004687', (116, 132))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('glioma', 'Disease', (258, 264))
217997	27036230	In contrast to enchondromas, however, IDH mutation alone is probably not sufficient to induce gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('enchondroma', 'Phenotype', 'HP:0030038', (15, 26))	('IDH', 'Gene', (38, 41))	('induce', 'Reg', (87, 93))	('IDH', 'Gene', '3417', (38, 41))	('enchondromas', 'Disease', (15, 27))	('mutation', 'Var', (42, 50))	('enchondromas', 'Phenotype', 'HP:0030038', (15, 27))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('enchondromas', 'Disease', 'MESH:D002812', (15, 27))
217998	27036230	Additional alterations, such as ATRX and TP53 mutations, are necessary.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('ATRX', 'Gene', '546', (32, 36))	('mutations', 'Var', (46, 55))	('ATRX', 'Gene', (32, 36))
217999	27036230	identified a TP53 mutation in the glioma but not in an enchondroma of their patient, though both lesions shared the same IDH2 mutation.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('TP53', 'Gene', (13, 17))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('IDH2', 'Gene', '3418', (121, 125))	('enchondroma', 'Phenotype', 'HP:0030038', (55, 66))	('patient', 'Species', '9606', (76, 83))	('mutation', 'Var', (18, 26))	('glioma', 'Disease', (34, 40))	('enchondroma', 'Disease', 'MESH:D002812', (55, 66))	('enchondroma', 'Disease', (55, 66))	('TP53', 'Gene', '7157', (13, 17))	('IDH2', 'Gene', (121, 125))
218003	27036230	In cartilaginous tumors of enchondromatosis patients the IDH1 R132C mutation is more frequent than the IDH1 R132H mutation (70 and 15 %, respectively), while the IDH1 R132H mutation is the most frequent mutation (90 %) in sporadic IDH mutated gliomas.	('IDH1', 'Gene', '3417', (162, 166))	('IDH1', 'Gene', (57, 61))	('IDH', 'Gene', (231, 234))	('IDH', 'Gene', '3417', (162, 165))	('gliomas', 'Disease', (243, 250))	('IDH', 'Gene', (57, 60))	('R132H', 'Mutation', 'rs121913500', (167, 172))	('IDH1', 'Gene', (103, 107))	('patients', 'Species', '9606', (44, 52))	('IDH', 'Gene', (103, 106))	('R132C', 'Var', (62, 67))	('R132C', 'Mutation', 'rs121913499', (62, 67))	('IDH1', 'Gene', '3417', (57, 61))	('IDH', 'Gene', '3417', (231, 234))	('gliomas', 'Disease', 'MESH:D005910', (243, 250))	('IDH', 'Gene', '3417', (57, 60))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('IDH1', 'Gene', '3417', (103, 107))	('cartilaginous tumors of enchondromatosis', 'Disease', 'MESH:D004687', (3, 43))	('IDH', 'Gene', '3417', (103, 106))	('enchondroma', 'Phenotype', 'HP:0030038', (27, 38))	('gliomas', 'Phenotype', 'HP:0009733', (243, 250))	('IDH1', 'Gene', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('cartilaginous tumors of enchondromatosis', 'Disease', (3, 43))	('IDH', 'Gene', (162, 165))	('R132H', 'Mutation', 'rs121913500', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
218004	27036230	Enchondromatosis patients with an IDH1 R132H mutation could have a higher risk of developing gliomas than patients with an IDH1 R132C mutation.	('gliomas', 'Disease', (93, 100))	('IDH1', 'Gene', '3417', (34, 38))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH1', 'Gene', (123, 127))	('Enchondromatosis', 'Disease', 'MESH:D004687', (0, 16))	('R132H', 'Var', (39, 44))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (17, 25))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('R132C', 'Mutation', 'rs121913499', (128, 133))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH1', 'Gene', (34, 38))	('IDH1', 'Gene', '3417', (123, 127))	('Enchondromatosis', 'Disease', (0, 16))
218005	27036230	In our series, an IDH1 R132H mutation was present in 5 out of the 7 enchondromatosis patients who developed diffuse glioma.	('enchondromatosis', 'Disease', (68, 84))	('IDH1', 'Gene', '3417', (18, 22))	('enchondroma', 'Phenotype', 'HP:0030038', (68, 79))	('glioma', 'Disease', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('patients', 'Species', '9606', (85, 93))	('R132H', 'Var', (23, 28))	('R132H', 'Mutation', 'rs121913500', (23, 28))	('IDH1', 'Gene', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('enchondromatosis', 'Disease', 'MESH:D004687', (68, 84))
218010	27036230	Since both H3-K27M mutations (which are present in most cases of children brainstem gliomas) and IDH mutations alter histone methylation, brainstem gliomas may therefore require histone modification of precursor cells at an early stage of development.	('gliomas', 'Disease', (148, 155))	('IDH', 'Gene', (97, 100))	('brainstem glioma', 'Phenotype', 'HP:0010796', (138, 154))	('gliomas', 'Disease', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('brainstem glioma', 'Phenotype', 'HP:0010796', (74, 90))	('children', 'Species', '9606', (65, 73))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (138, 155))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('IDH', 'Gene', '3417', (97, 100))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (74, 91))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('alter', 'Reg', (111, 116))	('mutations', 'Var', (101, 110))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('K27M', 'Mutation', 'p.K27M', (14, 18))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('H3-K27M mutations', 'Var', (11, 28))	('histone methylation', 'MPA', (117, 136))
218011	27036230	This particularity could help explaining why early acquisition of IDH mutations mimics the regional preference of H3-K27M mutated gliomas and why gliomas in that location are rare in adults.	('IDH', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('H3-K27M', 'Protein', (114, 121))	('IDH', 'Gene', '3417', (66, 69))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('K27M', 'Mutation', 'p.K27M', (117, 121))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
218012	27036230	At last, none of the 6 enchondromatosis gliomas that could be tested were associated with a 1p/19q co-deletion.	('enchondroma', 'Phenotype', 'HP:0030038', (23, 34))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('associated', 'Reg', (74, 84))	('1p/19q co-deletion', 'Var', (92, 110))	('enchondromatosis gliomas', 'Disease', (23, 47))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('enchondromatosis gliomas', 'Disease', 'MESH:D004687', (23, 47))
218013	27036230	This observation needs confirmation in a larger series, however, again it could be related to a different timing of oncogenesis because the 1p/19q co-deletion is virtually absent in pediatric gliomas.	('1p/19q', 'Var', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('pediatric gliomas', 'Disease', 'MESH:D005910', (182, 199))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('pediatric gliomas', 'Disease', (182, 199))
218014	27036230	Consistently, in the present series, as in previously reported series, patients with 1p/19q co-deleted gliomas were older at diagnosis than those with IDH mutated non 1p/19q co-deleted gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('1p/19q co-deleted', 'Var', (85, 102))	('gliomas', 'Disease', (103, 110))	('IDH', 'Gene', '3417', (151, 154))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('patients', 'Species', '9606', (71, 79))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('gliomas', 'Disease', (185, 192))	('IDH', 'Gene', (151, 154))
218019	27036230	Our study shows that somatic mosaicism might be another mechanism leading to the development of multicentric gliomas.	('multicentric gliomas', 'Disease', (96, 116))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('multicentric gliomas', 'Disease', 'MESH:D005910', (96, 116))	('somatic mosaicism', 'Var', (21, 38))	('leading', 'Reg', (66, 73))
218021	27036230	In addition to its retrospective design and its small sample-size, limitations of the present study include the limited number of patients in whom molecular characterization was possible, the absence of comprehensive molecular analysis and the absence of IDH mutation assessment in several gliomas from the same patient.	('IDH', 'Gene', (255, 258))	('glioma', 'Phenotype', 'HP:0009733', (290, 296))	('patient', 'Species', '9606', (130, 137))	('patient', 'Species', '9606', (312, 319))	('IDH', 'Gene', '3417', (255, 258))	('gliomas', 'Disease', 'MESH:D005910', (290, 297))	('patients', 'Species', '9606', (130, 138))	('gliomas', 'Disease', (290, 297))	('gliomas', 'Phenotype', 'HP:0009733', (290, 297))	('absence', 'NegReg', (244, 251))	('mutation', 'Var', (259, 267))
218023	27036230	It provides evidence that the IDH mutation can initiate gliomagenesis and that the timing of IDH mutation acquisition might influence the location and molecular characteristics of gliomas.	('glioma', 'Disease', (56, 62))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', (180, 187))	('IDH', 'Gene', (93, 96))	('mutation', 'Var', (34, 42))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH', 'Gene', '3417', (93, 96))	('IDH', 'Gene', (30, 33))	('influence', 'Reg', (124, 133))	('IDH', 'Gene', '3417', (30, 33))	('glioma', 'Disease', (180, 186))
218031	31697921	With the advent of molecular diagnostics, the nosology of adult glioma has changed, now incorporating the presence or absence of specific genetic (e.g., IDH1 and IDH2 mutations) and genomic (e.g., chromosome 1p/19q co-deletions) alterations.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('mole', 'Phenotype', 'HP:0003764', (19, 23))	('IDH1', 'Gene', (153, 157))	('IDH2', 'Gene', '3418', (162, 166))	('mutations', 'Var', (167, 176))	('glioma', 'Disease', (64, 70))	('IDH2', 'Gene', (162, 166))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
218032	31697921	Similarly, pediatric diffuse gliomas are molecularly defined by mutations in histone H3 genes (H3-K27M-mutant diffuse midline gliomas).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('K27M', 'Mutation', 'p.K27M', (98, 102))	('H3-K27M-mutant', 'Var', (95, 109))	('midline gliomas', 'Disease', 'MESH:D005910', (118, 133))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('mole', 'Phenotype', 'HP:0003764', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('mutations', 'Var', (64, 73))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('midline gliomas', 'Disease', (118, 133))
218038	31697921	In one study, there was a positive association between the numbers of CD68-, CD163- and CD206-positive GAM in the vital tumor core and prolonged overall survival of patients with IDH1R132H-non-mutant GBM.	('CD163', 'Gene', (77, 82))	('CD68', 'Gene', (70, 74))	('overall survival', 'CPA', (145, 161))	('GAM', 'Gene', '2744', (103, 106))	('CD68', 'Gene', '968', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CD206', 'Gene', (88, 93))	('CD163', 'Gene', '9332', (77, 82))	('CD206', 'Gene', '4360', (88, 93))	('prolonged', 'PosReg', (135, 144))	('patients', 'Species', '9606', (165, 173))	('IDH1R132H-non-mutant', 'Var', (179, 199))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('GAM', 'Gene', (103, 106))	('tumor', 'Disease', (120, 125))
218043	31697921	In experimental malignant (high-grade) glioma models, microglia depletion reduces glioma growth (Figure 1).	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma growth', 'Disease', 'MESH:D005910', (82, 95))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('glioma', 'Disease', (39, 45))	('depletion', 'Var', (64, 73))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Disease', (82, 88))	('microglia', 'CPA', (54, 63))	('reduces', 'NegReg', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma growth', 'Disease', (82, 95))
218047	31697921	This receptor expression stimulates the migratory capacity of glioma cells, which accelerates tumor progression.	('expression', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('accelerates', 'PosReg', (82, 93))	('stimulates', 'PosReg', (25, 35))	('tumor', 'Disease', (94, 99))	('glioma', 'Disease', (62, 68))
218050	31697921	These tumors arise either sporadically, caused frequently by genomic alterations involving the BRAF kinase gene (KIAA1549:BRAF fusion), or in the setting of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (161, 178))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('Neurofibromatosis type 1 (NF1) cancer', 'Disease', 'MESH:C537392', (161, 198))	('genomic alterations', 'Var', (61, 80))	('caused', 'Reg', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
218052	31697921	In this regard, Nf1 loss or KIAA1549:BRAF expression in numerous cell types induces cellular senescence, which requires stromal signals to overcome and lead to neoplasia.	('cellular senescence', 'CPA', (84, 103))	('neoplasia', 'Disease', (160, 169))	('BRAF', 'Gene', (37, 41))	('neoplasia', 'Phenotype', 'HP:0002664', (160, 169))	('expression', 'Var', (42, 52))	('lead to', 'Reg', (152, 159))	('neoplasia', 'Disease', 'MESH:D009369', (160, 169))	('Nf1', 'Gene', (16, 19))	('loss', 'NegReg', (20, 24))	('induces', 'Reg', (76, 83))
218058	31697921	Consistent with the idea that high-grade gliomas gain some measure of stromal independence, malignant gliomas harboring NF1 mutations express CCL5, establishing an autocrine loop for mesenchymal glioblastoma survival.	('malignant gliomas', 'Disease', 'MESH:D005910', (92, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (195, 207))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('mutations', 'Var', (124, 133))	('CCL5', 'Gene', (142, 146))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('CCL5', 'Gene', '20304', (142, 146))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('mesenchymal glioblastoma', 'Disease', (183, 207))	('NF1', 'Gene', (120, 123))	('gliomas', 'Disease', (102, 109))	('malignant gliomas', 'Disease', (92, 109))	('mesenchymal glioblastoma', 'Disease', 'MESH:D005909', (183, 207))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))
218065	31697921	In this regard, Ccl2 is produced by low-grade glioma stem cells expressing the KIAA1549:BRAF genomic alteration, leading to monocyte attraction, whereas NF1 mutation in both low-grade and high-grade gliomas attracts microglia through Cx3cl1.	('Ccl2', 'Gene', (16, 20))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('NF1', 'Gene', (153, 156))	('glioma', 'Disease', (46, 52))	('mutation', 'Var', (157, 165))	('Ccl2', 'Gene', '20296', (16, 20))	('Cx3cl1', 'Gene', '20312', (234, 240))	('leading to', 'Reg', (113, 123))	('monocyte attraction', 'CPA', (124, 143))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))	('glioma', 'Disease', (199, 205))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', (199, 206))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('Cx3cl1', 'Gene', (234, 240))
218071	31697921	Support for potential mutation-specific effects on GAM recruitment comes from two studies: First, murine high-grade gliomas harboring a mutant IDH1 allele exhibited reduced macrophage and microglia infiltration, which correlated with lower levels of chemokine expression (e.g., CCL2, CXCL2).	('CXCL2', 'Gene', (284, 289))	('GAM', 'Gene', '2744', (51, 54))	('lower', 'NegReg', (234, 239))	('levels of chemokine expression', 'MPA', (240, 270))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('IDH1', 'Gene', (143, 147))	('murine', 'Species', '10090', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('CXCL2', 'Gene', '20310', (284, 289))	('gliomas', 'Disease', (116, 123))	('GAM', 'Gene', (51, 54))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('mutant', 'Var', (136, 142))	('reduced', 'NegReg', (165, 172))
218073	31697921	Second, differences in microglia recruitment were observed in mice genetically engineered to develop low-grade gliomas with distinct patient-derived germline NF1 gene mutations and cooperating genetic alterations (e.g., heterozygous Pten loss) through the elaboration of chemokines.	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('patient', 'Species', '9606', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('develop', 'PosReg', (93, 100))	('mice', 'Species', '10090', (62, 66))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('loss', 'NegReg', (238, 242))	('NF1', 'Gene', (158, 161))	('mutations', 'Var', (167, 176))	('Pten', 'Gene', '5728', (233, 237))	('Pten', 'Gene', (233, 237))
218074	31697921	These findings suggest that variations in the GAM composition of gliomas could be dictated by types of immune chemoattractant molecules produced by cancer cells with different mutations.	('cancer', 'Disease', (148, 154))	('gliomas', 'Disease', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('mutations', 'Var', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GAM', 'Gene', '2744', (46, 49))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('mole', 'Phenotype', 'HP:0003764', (126, 130))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('GAM', 'Gene', (46, 49))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
218083	31697921	Moreover, in glioma patients, CD47 expression inversely correlated with histopathologic grading (low-grade versus high-grade glioma), and high levels of CD47 were associated with lower overall survival rates.	('inversely', 'NegReg', (46, 55))	('glioma', 'Disease', (125, 131))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('lower', 'NegReg', (179, 184))	('CD47', 'Gene', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('overall survival rates', 'CPA', (185, 207))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('high levels', 'Var', (138, 149))	('expression', 'MPA', (35, 45))	('CD47', 'Gene', (153, 157))	('CD47', 'Gene', '961', (153, 157))	('patients', 'Species', '9606', (20, 28))	('glioma', 'Disease', (13, 19))	('CD47', 'Gene', '961', (30, 34))
218086	31697921	TLR2 expression is increased in GAM, such that mouse GL261 glioma cells implanted into the brains of Tlr2 knockout mice have smaller tumors and enhanced survival.	('survival', 'CPA', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mouse', 'Species', '10090', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('glioma', 'Disease', (59, 65))	('enhanced', 'PosReg', (144, 152))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('GAM', 'Gene', '2744', (32, 35))	('knockout', 'Var', (106, 114))	('Tlr2', 'Gene', (101, 105))	('smaller', 'NegReg', (125, 132))	('mice', 'Species', '10090', (115, 119))	('Tlr2', 'Gene', '24088', (101, 105))	('tumors', 'Disease', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TLR2', 'Gene', (0, 4))	('GAM', 'Gene', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('GL261', 'CellLine', 'CVCL:Y003', (53, 58))
218094	31697921	One of the endogenous ligands for TLR4 is the cell adhesion molecule, tenascin C. In tumors with genetically reduced tenascin C expression, microglia acquire a more amoeboid morphology and increased expression of MHCII molecules, similar to that observed with TLR2 silencing.	('TLR4', 'Gene', (34, 38))	('amoeboid morphology', 'CPA', (165, 184))	('more', 'PosReg', (160, 164))	('genetically', 'Var', (97, 108))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('expression', 'MPA', (199, 209))	('expression', 'MPA', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('microglia', 'CPA', (140, 149))	('tenascin C', 'Gene', '3371', (117, 127))	('tenascin C', 'Gene', '3371', (70, 80))	('reduced', 'NegReg', (109, 116))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tenascin C', 'Gene', (117, 127))	('tenascin C', 'Gene', (70, 80))	('mole', 'Phenotype', 'HP:0003764', (60, 64))	('mole', 'Phenotype', 'HP:0003764', (219, 223))	('TLR4', 'Gene', '7099', (34, 38))	('increased', 'PosReg', (189, 198))
218096	31697921	These T cells, found in small abundance in both human and mouse NF1-mutant tumors, secrete paracrine factors important for inducing microglia to express CCL5 and drive glioma growth.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mouse', 'Species', '10090', (58, 63))	('glioma growth', 'Disease', (168, 181))	('human', 'Species', '9606', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('CCL5', 'Gene', (153, 157))	('glioma growth', 'Disease', 'MESH:D005910', (168, 181))	('CCL5', 'Gene', '20304', (153, 157))	('inducing', 'PosReg', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('NF1-mutant', 'Gene', (64, 74))	('NF1-mutant', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('drive', 'PosReg', (162, 167))	('tumors', 'Disease', (75, 81))
218101	31697921	Similarly, swine engineered with a patient germline NF1 gene mutation develop low-grade optic gliomas, as observed in their human counterparts; however, little is known about the role of GAM populations in these tumors [Isakson et al., 2018].	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('mutation', 'Var', (61, 69))	('optic glioma', 'Disease', (88, 100))	('develop', 'Reg', (70, 77))	('NF1 gene', 'Gene', (52, 60))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('GAM', 'Gene', (187, 190))	('optic glioma', 'Disease', 'MESH:D020339', (88, 100))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('optic glioma', 'Phenotype', 'HP:0009734', (88, 100))	('tumors', 'Disease', (212, 218))	('swine', 'Species', '9823', (11, 16))	('gliomas', 'Disease', (94, 101))	('optic gliomas', 'Phenotype', 'HP:0009734', (88, 101))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('GAM', 'Gene', '2744', (187, 190))	('patient', 'Species', '9606', (35, 42))	('human', 'Species', '9606', (124, 129))
218111	31697921	While the current xenotransplantation models have employed established human glioblastoma cell lines, future modifications may incorporate reporter fish in which gliomas are induced by specific cancer-causing genetic alterations, thus providing a more physiologic context in which to examine the glioma ecosystem.	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('alterations', 'Var', (217, 228))	('glioma', 'Disease', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('gliomas', 'Disease', (162, 169))	('glioblastoma', 'Disease', (77, 89))	('glioma', 'Disease', (162, 168))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('human', 'Species', '9606', (71, 76))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('induced by', 'Reg', (174, 184))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('cancer', 'Disease', (194, 200))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('genetic alterations', 'Var', (209, 228))
218116	31697921	For example, CRISPR/CAS9 insertion of an oncogenic RAS allele into the TP53 locus in human iPSCs was used to generate high-grade gliomas following transplantation into immunodeficient animals.	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('generate', 'Reg', (109, 117))	('immunodeficient', 'Disease', 'MESH:D007153', (168, 183))	('immunodeficient', 'Disease', (168, 183))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('insertion', 'Var', (25, 34))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('human', 'Species', '9606', (85, 90))
218119	31697921	For example, the tetracycline analog, minocycline, which blocks microglia activation and reduces glioma expansion in experimental glioma mouse models of both high-grade and low-grade glioma, has led to three clinical trials with no clear clinical benefit (NCT01580969, NCT02272270, NCT02770378).	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Disease', (183, 189))	('glioma', 'Disease', (97, 103))	('mouse', 'Species', '10090', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Disease', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('minocycline', 'Chemical', 'MESH:D008911', (38, 49))	('NCT01580969', 'Var', (256, 267))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('blocks', 'NegReg', (57, 63))	('reduces', 'NegReg', (89, 96))	('microglia activation', 'CPA', (64, 84))	('tetracycline', 'Chemical', 'MESH:D013752', (17, 29))
218120	31697921	Similarly, PLX3397-induced depletion of microglia attenuates malignant glioma growth in mice; however, no efficacy was observed in human clinical trials [NCT01349036], despite good patient tolerability and adequate blood-brain-barrier penetration.	('PLX3397-induced', 'Var', (11, 26))	('patient', 'Species', '9606', (181, 188))	('malignant glioma growth', 'Disease', 'MESH:D005910', (61, 84))	('malignant glioma growth', 'Disease', (61, 84))	('human', 'Species', '9606', (131, 136))	('microglia', 'Protein', (40, 49))	('depletion', 'Var', (27, 36))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('attenuates', 'NegReg', (50, 60))	('mice', 'Species', '10090', (88, 92))
218121	31697921	Finally, antibody targeting of microglial TLRs reduces high-grade glioma growth in a mouse brain tumor slice model and exhibits good safety and tolerability profiles in healthy subjects, but has not progressed further in clinical trials for glioma.	('glioma', 'Disease', (66, 72))	('brain tumor', 'Disease', (91, 102))	('TLR', 'Gene', (42, 45))	('reduces', 'NegReg', (47, 54))	('mouse', 'Species', '10090', (85, 90))	('brain tumor', 'Disease', 'MESH:D001932', (91, 102))	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (91, 102))	('glioma growth', 'Disease', 'MESH:D005910', (66, 79))	('antibody targeting', 'Var', (9, 27))	('glioma growth', 'Disease', (66, 79))	('microglial', 'Gene', (31, 41))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('TLR', 'Gene', '7097;24088;7099', (42, 45))	('glioma', 'Disease', (241, 247))
218243	29742884	Generally, patients who have undergone total or subtotal resections of thalamic tumors experience improved outcomes and survival prognoses compared to those who do not undergo surgery.	('survival prognoses', 'CPA', (120, 138))	('resections', 'Var', (57, 67))	('thalamic tumors', 'Disease', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('subtotal resections', 'Var', (48, 67))	('outcomes', 'CPA', (107, 115))	('thalamic tumors', 'Disease', 'MESH:D013786', (71, 86))	('patients', 'Species', '9606', (11, 19))	('improved', 'PosReg', (98, 106))
218271	29742884	Accordingly, this approach distinguishes diffuse gliomas from astrocytomas that have a more circumscribed growth pattern, lack IDH gene family alterations, and frequently harbor BRAF alterations (pilocytic astrocytoma, pleomorphic xanthastrocytoma) or TSC1/TSC2 mutations (subependymal giant cell astrocytoma).	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('TSC1', 'Gene', (252, 256))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (196, 217))	('mutations', 'Var', (262, 271))	('IDH', 'Gene', (127, 130))	('TSC2', 'Gene', '7249', (257, 261))	('subependymal giant cell astrocytoma', 'Disease', (273, 308))	('TSC1', 'Gene', '7248', (252, 256))	('pilocytic astrocytoma', 'Disease', (196, 217))	('diffuse', 'Disease', (41, 48))	('BRAF', 'Gene', '673', (178, 182))	('astrocytomas', 'Disease', (62, 74))	('gliomas', 'Disease', (49, 56))	('subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (273, 308))	('IDH', 'Gene', '3417', (127, 130))	('TSC2', 'Gene', (257, 261))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('alterations', 'Var', (183, 194))	('subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (273, 308))	('astrocytoma', 'Phenotype', 'HP:0009592', (206, 217))	('astrocytoma', 'Phenotype', 'HP:0009592', (236, 247))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))	('pleomorphic xanthastrocytoma', 'Disease', 'MESH:D008228', (219, 247))	('astrocytomas', 'Disease', 'MESH:D001254', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('BRAF', 'Gene', (178, 182))	('astrocytoma', 'Phenotype', 'HP:0009592', (297, 308))	('pleomorphic xanthastrocytoma', 'Disease', (219, 247))
218274	29742884	These discoveries include the identification of recurrent mutations, fusion, and duplication events in the BRAF, FGFR1, MYB, and MYBL1 genes in pediatric low-grade gliomas, as well as mutations affecting histone components (H3F3A p.K27M or p. G34R/V) in pediatric high-grade gliomas.	('mutations', 'Var', (58, 67))	('MYBL1', 'Gene', (129, 134))	('duplication', 'Var', (81, 92))	('MYBL1', 'Gene', '4603', (129, 134))	('FGFR1', 'Gene', (113, 118))	('MYB', 'Gene', '4602', (129, 132))	('H3F3A', 'Gene', '3020', (224, 229))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('MYB', 'Gene', (129, 132))	('fusion', 'Var', (69, 75))	('gliomas', 'Disease', 'MESH:D005910', (275, 282))	('p.K27M', 'Var', (230, 236))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('G34R', 'SUBSTITUTION', 'None', (243, 247))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('H3F3A', 'Gene', (224, 229))	('MYB', 'Gene', (120, 123))	('MYB', 'Gene', '4602', (120, 123))	('gliomas', 'Phenotype', 'HP:0009733', (275, 282))	('G34R', 'Var', (243, 247))	('FGFR1', 'Gene', '2260', (113, 118))	('BRAF', 'Gene', '673', (107, 111))	('BRAF', 'Gene', (107, 111))	('p.K27M', 'Mutation', 'p.K27M', (230, 236))	('gliomas', 'Disease', (164, 171))	('gliomas', 'Disease', (275, 282))
218275	29742884	Adult low-grade gliomas are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('IDH1/2', 'Gene', '3417;3418', (45, 51))	('mutations', 'Var', (71, 80))	('IDH1/2', 'Gene', (45, 51))	('oligodendroglial tumors', 'Disease', (149, 172))	('gliomas', 'Disease', (16, 23))	('astrocytic tumors', 'Disease', (84, 101))	('ATRX', 'Gene', (66, 70))	('astrocytic tumors', 'Disease', 'MESH:D001254', (84, 101))	('ATRX', 'Gene', '546', (66, 70))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (149, 172))	('mutations', 'Var', (52, 61))	('gliomas', 'Disease', 'MESH:D005910', (16, 23))	('IDH1/2', 'Gene', '3417;3418', (106, 112))	('IDH1/2', 'Gene', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
218276	29742884	TERT promoter mutations are also noted in low-grade gliomas and are mainly associated with oligodendrogliomas.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (91, 109))	('gliomas', 'Disease', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('TERT', 'Gene', (0, 4))	('oligodendrogliomas', 'Disease', (91, 109))	('TERT', 'Gene', '7015', (0, 4))	('gliomas', 'Disease', (102, 109))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('associated', 'Reg', (75, 85))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('mutations', 'Var', (14, 23))
218279	29742884	The group of tumors that primarily occur in children can be genetically characterized by K27M mutations in the histone H3 gene H3F3A (approximately 75% of cases) or, less commonly, in the related HIST1H3B gene (approximately 25%) and exhibit clinically similar diffuse growth patterns and midline locations (e.g., thalamus, brain stem, and spinal cord).	('HIST1H3B', 'Gene', (196, 204))	('tumors', 'Disease', (13, 19))	('HIST1H3B', 'Gene', '8358', (196, 204))	('K27M mutations', 'Var', (89, 103))	('K27M', 'Mutation', 'p.K27M', (89, 93))	('H3F3A', 'Gene', '3020', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('children', 'Species', '9606', (44, 52))	('H3F3A', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
218280	29742884	This newly defined entity is termed diffuse midline glioma, H3 K27M-mutant, and includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('diffuse', 'Disease', (36, 43))	('DIPG', 'Chemical', '-', (156, 160))	('glioma', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('K27M', 'Mutation', 'p.K27M', (63, 67))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('midline glioma', 'Disease', 'MESH:D005910', (44, 58))	('midline glioma', 'Disease', (44, 58))	('H3 K27M-mutant', 'Var', (60, 74))	('glioma', 'Disease', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
218291	29742884	Another interesting discovery is the anatomic distribution of histone mutations in pediatric high-grade gliomas.	('gliomas', 'Disease', (104, 111))	('mutations', 'Var', (70, 79))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('histone', 'Protein', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
218292	29742884	K27M mutations are predominantly found in tumors arising in midline locations such as the thalamus, pons, and medulla oblongata.	('found', 'Reg', (33, 38))	('K27M mutations', 'Var', (0, 14))	('tumors', 'Disease', (42, 48))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
218293	29742884	Histone H3.3 G34R or G34V mutations and BRAFV600E mutations are predominantly found in hemispheric tumors.	('BRAFV600E', 'Gene', (40, 49))	('G34R', 'Var', (13, 17))	('Histone H3.3', 'Gene', '3020', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('found', 'Reg', (78, 83))	('Histone H3.3', 'Gene', (0, 12))	('G34V', 'Mutation', 'rs1217358160', (21, 25))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('G34V mutations', 'Var', (21, 35))	('G34R', 'SUBSTITUTION', 'None', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
218294	29742884	For example, ATRX/DAXX mutations are associated with cortical G34R/V tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('DAXX', 'Gene', '1616', (18, 22))	('ATRX', 'Gene', (13, 17))	('G34R', 'SUBSTITUTION', 'None', (62, 66))	('G34R', 'Var', (62, 66))	('ATRX', 'Gene', '546', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('V tumors', 'Disease', 'MESH:D009369', (67, 75))	('DAXX', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('associated', 'Reg', (37, 47))	('V tumors', 'Disease', (67, 75))
218295	29742884	Furthermore, diffuse midline gliomas, H3 K27M-mutant (WHO grade IV) are a distinct group that was introduced in the recent revision of the WHO classification.	('K27M', 'Mutation', 'p.K27M', (41, 45))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('diffuse', 'Disease', (13, 20))	('midline gliomas', 'Disease', (21, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('H3 K27M-mutant', 'Var', (38, 52))	('midline gliomas', 'Disease', 'MESH:D005910', (21, 36))
218303	29742884	Dysfunction of the NF-1 gene has been found to affect the mTOR pathway promoting cell survival, growth, and proliferation.	('mTOR', 'Gene', (58, 62))	('Dysfunction', 'Var', (0, 11))	('growth', 'CPA', (96, 102))	('affect', 'Reg', (47, 53))	('proliferation', 'CPA', (108, 121))	('NF-1', 'Gene', '4763', (19, 23))	('promoting', 'PosReg', (71, 80))	('NF-1', 'Gene', (19, 23))	('cell survival', 'CPA', (81, 94))	('mTOR', 'Gene', '2475', (58, 62))
218304	29742884	In the case of sporadic OPGs, it demonstrates a rearrangement in the kinase portion of the serine/threonin-protein kinase BRAF gene caused by fusion with KIAA1549 because of a duplication at 7q34 resulting in activation of BRAF.	('OPGs', 'Phenotype', 'HP:0009734', (24, 28))	('duplication at 7q34', 'Var', (176, 195))	('KIAA1549', 'Gene', (154, 162))	('OPGs', 'Chemical', '-', (24, 28))	('BRAF', 'Gene', '673', (122, 126))	('KIAA1549', 'Gene', '57670', (154, 162))	('rearrangement', 'Var', (48, 61))	('BRAF', 'Gene', (122, 126))	('BRAF', 'Gene', '673', (223, 227))	('activation', 'PosReg', (209, 219))	('BRAF', 'Gene', (223, 227))
218309	29108264	Long non-coding RNAs (lncRNAs), a type of RNA transcript with more than 200 nucleotides, involve in tumorigenesis and development of various cancers.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Long non-coding', 'Var', (0, 15))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('development', 'CPA', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancers', 'Disease', (141, 148))	('involve in', 'Reg', (89, 99))
218313	29108264	High expression of PVT1 and CYTOR as well as low HAR1A and MIAT expression were associated with high Ki-67 level and more TP53 mutation.	('PVT1', 'Gene', (19, 23))	('Ki-67 level', 'MPA', (101, 112))	('TP53', 'Gene', (122, 126))	('CYTOR', 'Gene', '112597', (28, 33))	('mutation', 'Var', (127, 135))	('PVT1', 'Gene', '5820', (19, 23))	('CYTOR', 'Gene', (28, 33))	('low', 'NegReg', (45, 48))	('MIAT', 'Gene', '440823', (59, 63))	('HAR1A', 'Gene', (49, 54))	('HAR1A', 'Gene', '768096', (49, 54))	('MIAT', 'Gene', (59, 63))	('TP53', 'Gene', '7157', (122, 126))
218314	29108264	Kaplan-Meier survival curve and Cox regression analyses showed that glioma patients with high PVT1 expression or low HAR1A expression had poor survival outcome, aberrantly expressed PVT1 and HAR1A could be the independent prognosis biomarkers for glioma patients.	('HAR1A', 'Gene', (191, 196))	('expression', 'MPA', (99, 109))	('expression', 'MPA', (123, 133))	('low', 'NegReg', (113, 116))	('HAR1A', 'Gene', (117, 122))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('PVT1', 'Gene', (182, 186))	('high', 'PosReg', (89, 93))	('glioma', 'Disease', (247, 253))	('PVT1', 'Gene', (94, 98))	('PVT1', 'Gene', '5820', (182, 186))	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('PVT1', 'Gene', '5820', (94, 98))	('patients', 'Species', '9606', (75, 83))	('aberrantly', 'Var', (161, 171))	('Cox', 'Gene', '1351', (32, 35))	('HAR1A', 'Gene', '768096', (191, 196))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('HAR1A', 'Gene', '768096', (117, 122))	('Cox', 'Gene', (32, 35))	('patients', 'Species', '9606', (254, 262))
218322	29108264	Dysregulation of lncRNAs has been linked to different diseases including cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('linked', 'Reg', (34, 40))
218340	29108264	HAR1A and MIAT expression were significantly lower in GBM samples than in LGGs (all P <0.001).	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('GBM', 'Var', (54, 57))	('HAR1A', 'Gene', '768096', (0, 5))	('HAR1A', 'Gene', (0, 5))	('MIAT', 'Gene', '440823', (10, 14))	('lower', 'NegReg', (45, 50))	('MIAT', 'Gene', (10, 14))
218346	29108264	By definition, the proneural subtype is associated with higher amplification of PDGFRA and more IDH1 mutations; neural subtype is closely related with the expression of neuron markers such as NEFL, GABRA1, SYT1 and SLC12A5.	('NEFL', 'Gene', (192, 196))	('IDH1', 'Gene', '3417', (96, 100))	('NEFL', 'Gene', '4747', (192, 196))	('mutations', 'Var', (101, 110))	('SLC12A5', 'Gene', (215, 222))	('PDGFRA', 'Gene', (80, 86))	('SYT1', 'Gene', '6857', (206, 210))	('amplification', 'MPA', (63, 76))	('SLC12A5', 'Gene', '57468', (215, 222))	('PDGFRA', 'Gene', '5156', (80, 86))	('GABRA1', 'Gene', '2554', (198, 204))	('GABRA1', 'Gene', (198, 204))	('SYT1', 'Gene', (206, 210))	('higher', 'PosReg', (56, 62))	('proneural subtype', 'Disease', (19, 36))	('IDH1', 'Gene', (96, 100))
218347	29108264	The results implied that CYTOR and MIAT may be associated with amplification of PDGFRA and IDH1 mutations, HAR1A may be related with neuron markers in glioblastomas.	('MIAT', 'Gene', '440823', (35, 39))	('MIAT', 'Gene', (35, 39))	('CYTOR', 'Gene', '112597', (25, 30))	('PDGFRA', 'Gene', (80, 86))	('HAR1A', 'Gene', '768096', (107, 112))	('PDGFRA', 'Gene', '5156', (80, 86))	('IDH1', 'Gene', (91, 95))	('glioblastomas', 'Phenotype', 'HP:0012174', (151, 164))	('related', 'Reg', (120, 127))	('HAR1A', 'Gene', (107, 112))	('CYTOR', 'Gene', (25, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('IDH1', 'Gene', '3417', (91, 95))	('glioblastomas', 'Disease', 'MESH:D005909', (151, 164))	('associated', 'Reg', (47, 57))	('amplification', 'Var', (63, 76))	('mutations', 'Var', (96, 105))	('glioblastomas', 'Disease', (151, 164))
218350	29108264	As shown in Figure 4A-4B, within glioma samples of TCGA along with LGG subtypes, the overall survival of glioma patients with high PVT1 expression was remarkably worse than that of the low expression patients (both P <0.0001).	('patients', 'Species', '9606', (200, 208))	('PVT1', 'Gene', '5820', (131, 135))	('glioma', 'Disease', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('glioma', 'Disease', (105, 111))	('expression', 'Var', (136, 146))	('patients', 'Species', '9606', (112, 120))	('worse', 'NegReg', (162, 167))	('high', 'Var', (126, 130))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('PVT1', 'Gene', (131, 135))	('glioma', 'Disease', 'MESH:D005910', (105, 111))
218351	29108264	Survival of glioma patients with low HAR1A expression was significantly worse than that with high expression (both P <0.0001).	('patients', 'Species', '9606', (19, 27))	('glioma', 'Disease', (12, 18))	('low', 'Var', (33, 36))	('worse', 'NegReg', (72, 77))	('HAR1A', 'Gene', '768096', (37, 42))	('expression', 'MPA', (43, 53))	('glioma', 'Disease', 'MESH:D005910', (12, 18))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('HAR1A', 'Gene', (37, 42))
218355	29108264	Furthermore, univariate Cox regression analysis of overall survival of glioma samples within TCGA showed that high PVT1 expression (P <0.001), low HAR1A expression (P <0.001), increased age (both P <0.001), high karnofsky performance score (KPS; both P <0.001) and WHO grade (all P <0.001 for II/IV and III/IV), and advanced histological types (all P <0.001 for OD/GBM, OA/GBM and A/GBM) were the risk factors associated with prognosis (Table 1).	('GBM', 'Phenotype', 'HP:0012174', (365, 368))	('GBM', 'Phenotype', 'HP:0012174', (383, 386))	('expression', 'MPA', (120, 130))	('PVT1', 'Gene', '5820', (115, 119))	('HAR1A', 'Gene', '768096', (147, 152))	('glioma', 'Disease', (71, 77))	('Cox', 'Gene', '1351', (24, 27))	('GBM', 'Phenotype', 'HP:0012174', (373, 376))	('HAR1A', 'Gene', (147, 152))	('low', 'Var', (143, 146))	('Cox', 'Gene', (24, 27))	('expression', 'MPA', (153, 163))	('high', 'Var', (110, 114))	('PVT1', 'Gene', (115, 119))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
218368	29108264	Low HAR1A and MIAT expressions were significantly correlated with high Ki-67 (P =0.008 and P =0.001).	('HAR1A', 'Gene', (4, 9))	('HAR1A', 'Gene', '768096', (4, 9))	('MIAT', 'Gene', '440823', (14, 18))	('high', 'Var', (66, 70))	('Ki-67', 'Gene', (71, 76))	('Low', 'NegReg', (0, 3))	('MIAT', 'Gene', (14, 18))
218371	29108264	Meanwhile, high CYTOR expression (P =0.005) and low HAR1A expression (P =0.032) were correlated with IDH mutation in diffuse glioma specimens.	('glioma', 'Disease', (125, 131))	('mutation', 'Var', (105, 113))	('CYTOR', 'Gene', (16, 21))	('expression', 'MPA', (58, 68))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('HAR1A', 'Gene', '768096', (52, 57))	('IDH', 'Gene', (101, 104))	('CYTOR', 'Gene', '112597', (16, 21))	('HAR1A', 'Gene', (52, 57))	('low', 'NegReg', (48, 51))	('IDH', 'Gene', '3417', (101, 104))
218374	29108264	Mutations in TP53 gene are associated with a variety of human cancers including gliomas.	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('associated', 'Reg', (27, 37))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('human', 'Species', '9606', (56, 61))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Disease', (62, 69))
218377	29108264	As shown in Figure 6A-6B, within glioma samples of TCGA along with LGG subtypes, the overall survival of low PVT1 expression group was significantly better than that of high expression group in glioma patients who received chemotherapy (P <0.0001 and P =0.0004) or radiotherapy (P <0.0001 and P =0.0005).	('patients', 'Species', '9606', (201, 209))	('low', 'Var', (105, 108))	('glioma', 'Disease', (194, 200))	('glioma', 'Disease', (33, 39))	('PVT1', 'Gene', '5820', (109, 113))	('better', 'PosReg', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('PVT1', 'Gene', (109, 113))
218378	29108264	Moreover, survival of high HAR1A expression patients was noticeably better than that of low expression patients who received chemotherapy (both P <0.0001) or radiotherapy (P <0.0001 and P =0.0003).	('patients', 'Species', '9606', (44, 52))	('better', 'PosReg', (68, 74))	('high', 'Var', (22, 26))	('HAR1A', 'Gene', (27, 32))	('survival', 'CPA', (10, 18))	('HAR1A', 'Gene', '768096', (27, 32))	('patients', 'Species', '9606', (103, 111))
218380	29108264	These results suggested that glioma patients with low PVT1 expression and high HAR1A expression could benefit more from chemotherapy and radiotherapy; up-regulated PVT1 and down-regulated HAR1A might be the indicators of poor response to adjuvant chemoradiotherapy.	('low', 'NegReg', (50, 53))	('HAR1A', 'Gene', '768096', (188, 193))	('expression', 'MPA', (59, 69))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('PVT1', 'Gene', (54, 58))	('patients', 'Species', '9606', (36, 44))	('PVT1', 'Gene', '5820', (54, 58))	('HAR1A', 'Gene', (188, 193))	('down-regulated', 'NegReg', (173, 187))	('HAR1A', 'Gene', '768096', (79, 84))	('PVT1', 'Gene', (164, 168))	('PVT1', 'Gene', '5820', (164, 168))	('benefit', 'PosReg', (102, 109))	('expression', 'MPA', (85, 95))	('glioma', 'Disease', (29, 35))	('high', 'Var', (74, 78))	('HAR1A', 'Gene', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('up-regulated', 'PosReg', (151, 163))
218384	29108264	High PVT1 and CYTOR expression as well as low HAR1A and MIAT expression were associated with high Ki-67 and more TP53 mutation in diffuse glioma specimens.	('PVT1', 'Gene', (5, 9))	('CYTOR', 'Gene', '112597', (14, 19))	('MIAT', 'Gene', (56, 60))	('glioma', 'Disease', (138, 144))	('PVT1', 'Gene', '5820', (5, 9))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('TP53', 'Gene', '7157', (113, 117))	('CYTOR', 'Gene', (14, 19))	('Ki-67', 'Gene', (98, 103))	('mutation', 'Var', (118, 126))	('low', 'NegReg', (42, 45))	('MIAT', 'Gene', '440823', (56, 60))	('HAR1A', 'Gene', (46, 51))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('TP53', 'Gene', (113, 117))	('HAR1A', 'Gene', '768096', (46, 51))
218386	29108264	Furthermore, survival curve and Cox regression analyses showed that glioma patients with high PVT1 expression or low HAR1A expression had poor survival outcome, aberrantly expressed PVT1 and HAR1A could be the independent prognosis biomarkers for diffuse glioma patients.	('HAR1A', 'Gene', (191, 196))	('expression', 'MPA', (99, 109))	('expression', 'MPA', (123, 133))	('low', 'NegReg', (113, 116))	('HAR1A', 'Gene', (117, 122))	('glioma', 'Disease', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('PVT1', 'Gene', (182, 186))	('aberrantly expressed', 'Var', (161, 181))	('high', 'PosReg', (89, 93))	('PVT1', 'Gene', (94, 98))	('PVT1', 'Gene', '5820', (182, 186))	('glioma', 'Disease', (255, 261))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('PVT1', 'Gene', '5820', (94, 98))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('patients', 'Species', '9606', (75, 83))	('Cox', 'Gene', '1351', (32, 35))	('HAR1A', 'Gene', '768096', (191, 196))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('HAR1A', 'Gene', '768096', (117, 122))	('Cox', 'Gene', (32, 35))	('patients', 'Species', '9606', (262, 270))
218388	29108264	Amplification of PVT1 correlated with short survival duration of ovarian and breast cancer.	('Amplification', 'Var', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('PVT1', 'Gene', (17, 21))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (65, 90))	('PVT1', 'Gene', '5820', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
218392	29108264	Knockdown of PVT1 inhibited cell proliferation and arrested cell cycle at G1 stage via recruiting EZH2 (zeste homolog 2) and regulating p15 and p16 epigenetically.	('EZH2', 'Gene', (98, 102))	('PVT1', 'Gene', (13, 17))	('arrested cell cycle at G1 stage', 'CPA', (51, 82))	('p15', 'Gene', (136, 139))	('p15', 'Gene', '1030', (136, 139))	('cell proliferation', 'CPA', (28, 46))	('p16', 'Gene', (144, 147))	('PVT1', 'Gene', '5820', (13, 17))	('regulating', 'Reg', (125, 135))	('inhibited', 'NegReg', (18, 27))	('recruiting', 'PosReg', (87, 97))	('epigenetically', 'Var', (148, 162))	('p16', 'Gene', '1029', (144, 147))	('EZH2', 'Gene', '2146', (98, 102))
218395	29108264	In pancreatic cancer cells, knockdown of PVT1 inhibited cell proliferation, migration and epithelial-mesenchymal transition (EMT) by regulating p21 expression.	('pancreatic cancer', 'Disease', (3, 20))	('PVT1', 'Gene', '5820', (41, 45))	('migration', 'CPA', (76, 85))	('p21', 'Gene', (144, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('regulating', 'Reg', (133, 143))	('PVT1', 'Gene', (41, 45))	('p21', 'Gene', '644914', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('epithelial-mesenchymal transition', 'CPA', (90, 123))	('cell proliferation', 'CPA', (56, 74))	('knockdown', 'Var', (28, 37))	('expression', 'MPA', (148, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('inhibited', 'NegReg', (46, 55))
218418	29108264	Aberrant of MIAT also involved in the progression of neuroendocrine prostate cancer and chronic lymphocytic leukemias (CLL).	('chronic lymphocytic leukemias', 'Phenotype', 'HP:0005550', (88, 117))	('leukemias', 'Phenotype', 'HP:0001909', (108, 117))	('Aberrant', 'Var', (0, 8))	('lymphocytic leukemias', 'Phenotype', 'HP:0005526', (96, 117))	('neuroendocrine prostate cancer', 'Disease', (53, 83))	('MIAT', 'Gene', (12, 16))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (53, 83))	('involved in', 'Reg', (22, 33))	('chronic lymphocytic leukemias', 'Disease', 'MESH:D015451', (88, 117))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CLL', 'Phenotype', 'HP:0005550', (119, 122))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))	('chronic lymphocytic leukemias', 'Disease', (88, 117))	('MIAT', 'Gene', '440823', (12, 16))
218421	29108264	Survival analyses indicated that glioma patients with low PVT1 expression and high HAR1A expression could benefit more from chemotherapy and radiotherapy.	('benefit', 'PosReg', (106, 113))	('high', 'Var', (78, 82))	('expression', 'MPA', (89, 99))	('low', 'NegReg', (54, 57))	('glioma', 'Disease', (33, 39))	('patients', 'Species', '9606', (40, 48))	('HAR1A', 'Gene', (83, 88))	('expression', 'MPA', (63, 73))	('HAR1A', 'Gene', '768096', (83, 88))	('PVT1', 'Gene', (58, 62))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('PVT1', 'Gene', '5820', (58, 62))
218428	29108264	The glioma gene expression profiling of GSE4290 and GSE43378 was downloaded from the Gene Expression Omnibus database (GEO, http://www.ncbi.nlm.nih.gov/geo/).	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('GSE4290', 'Chemical', '-', (40, 47))	('GSE4290', 'Var', (40, 47))	('glioma', 'Disease', (4, 10))
218449	27677590	Receiver operating characteristic (ROC) was performed to show that the three-gene signature was more sensitive and specific than histology, grade, age, IDH1 mutation and 1p/19q co-deletion.	('1p/19q co-deletion', 'Var', (170, 188))	('IDH1', 'Gene', '3417', (152, 156))	('IDH1', 'Gene', (152, 156))	('mutation', 'Var', (157, 165))
218465	27677590	Many genes such as isocitrate dehydrogenase1 mutation (IDH1mut), epidermal growth factor receptor (EGFR) amplification, and Ki67expression have been included in gliomas to predict prognosis.	('EGFR', 'Gene', (99, 103))	('IDH1', 'Gene', '3417', (55, 59))	('amplification', 'Var', (105, 118))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('epidermal growth factor receptor', 'Gene', (65, 97))	('epidermal growth factor receptor', 'Gene', '1956', (65, 97))	('gliomas', 'Disease', (161, 168))	('EGFR', 'Gene', '1956', (99, 103))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('Ki67expression', 'Var', (124, 138))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('IDH1', 'Gene', (55, 59))
218466	27677590	With deeper understanding of gliomas, it is acknowledged that polygenic abnormity, rather than single gene alterations, causes gliomas.	('polygenic abnormity', 'Var', (62, 81))	('causes', 'Reg', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('gliomas', 'Disease', (127, 134))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
218483	27677590	Receiver operating characteristic (ROC) assessment was performed to evaluate sensitivity and specificity of two year survival prediction for the three-gene signature, histology, grade, age, IDH1 mutation and 1p/19q co-deletion in the CGGA array dataset (training cohort) and TCGA RNA-seq dataset (the largest validation cohort).	('mutation', 'Var', (195, 203))	('1p/19q co-deletion', 'Var', (208, 226))	('IDH1', 'Gene', '3417', (190, 194))	('IDH1', 'Gene', (190, 194))
218487	27677590	A normal translocation in meningiomas could cause abnormal MN1expression.	('meningiomas', 'Phenotype', 'HP:0002858', (26, 37))	('cause', 'Reg', (44, 49))	('MN1', 'Gene', (59, 62))	('MN1', 'Gene', '4330', (59, 62))	('meningiomas', 'Disease', 'MESH:D008577', (26, 37))	('meningioma', 'Phenotype', 'HP:0002858', (26, 36))	('meningiomas', 'Disease', (26, 37))	('translocation', 'MPA', (9, 22))	('normal', 'Var', (2, 8))
218488	27677590	Meanwhile, MN1 inactivation could induce meningioma formation.	('induce', 'Reg', (34, 40))	('MN1', 'Gene', (11, 14))	('MN1', 'Gene', '4330', (11, 14))	('meningioma', 'Disease', (41, 51))	('meningioma', 'Phenotype', 'HP:0002858', (41, 51))	('inactivation', 'Var', (15, 27))	('meningioma', 'Disease', 'MESH:D008577', (41, 51))
218589	33725839	These authors also suggested that textural analyses of MRI data could predict IDH1 mutation, 1p/19q codeletion, histological grade, and tumor progression, emphasizing the importance of MRI.	('predict', 'Reg', (70, 77))	('1p/19q codeletion', 'Var', (93, 110))	('IDH1', 'Gene', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mutation', 'Var', (83, 91))	('IDH1', 'Gene', '3417', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
218596	33725839	The different molecular subtypes of low-grade glioma have been shown to have distinct prognoses based on IDH1 and IDH2 gene mutational and 1p/19q codeletion statuses.	('IDH2', 'Gene', (114, 118))	('and 1p', 'Gene', '11169', (135, 141))	('IDH1', 'Gene', (105, 109))	('and 1p', 'Gene', (135, 141))	('glioma', 'Disease', (46, 52))	('mutational', 'Var', (124, 134))	('IDH2', 'Gene', '3418', (114, 118))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
218623	29459741	1); (2) the ambiguous tumour border may deteriorate in the image with decreased resolution, especially in diffusion and perfusion parameter image such as ADC, FA and rCBV; (3) the partial volume effects and the inherent noise in imaging system could produce negative influence to the segmentation results.	('tumour border', 'Disease', (22, 35))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('perfusion parameter image', 'MPA', (120, 145))	('tumour border', 'Disease', 'MESH:D001882', (22, 35))	('decreased', 'NegReg', (70, 79))	('rCBV', 'Disease', (166, 170))	('rCBV', 'Chemical', '-', (166, 170))	('deteriorate', 'NegReg', (40, 51))	('partial', 'Var', (180, 187))	('ADC', 'Disease', (154, 157))
218644	29459741	The ADC values in hyperintense region such as solid enhancing tumour mass, tumour margin, infiltrating tumour, tumour-infiltrated oedema and infiltrated tissue are considered as reasonable representation of tumour.	('ADC', 'Var', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('oedema', 'Phenotype', 'HP:0000969', (130, 136))	('tumour', 'Disease', (75, 81))	('tumour-infiltrated oedema', 'Disease', 'MESH:D004487', (111, 136))	('tumour-infiltrated oedema', 'Disease', (111, 136))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))	('tumour', 'Disease', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('tumour', 'Disease', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))
218721	26222501	BRAF Fusion Analysis in Pilocytic Astrocytomas: KIAA1549-BRAF 15-9 Fusions Are More Frequent in the Midline Than Within the Cerebellum Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions.	('Pilocytic astrocytomas', 'Disease', 'MESH:D001254', (135, 157))	('Pilocytic Astrocytomas', 'Disease', (24, 46))	('BRAF', 'Gene', '673', (201, 205))	('BRAF', 'Gene', '673', (57, 61))	('KIAA1549-BRAF', 'Disease', (192, 205))	('Pilocytic Astrocytomas', 'Disease', 'MESH:D001254', (24, 46))	('KIAA1549-BRAF', 'Disease', (48, 61))	('Fusions', 'Var', (67, 74))	('BRAF', 'Gene', (57, 61))	('Pilocytic astrocytomas', 'Disease', (135, 157))	('BRAF', 'Gene', '673', (0, 4))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('KIAA1549-BRAF', 'Disease', 'None', (192, 205))	('BRAF', 'Gene', (0, 4))	('KIAA1549-BRAF', 'Disease', 'None', (48, 61))	('BRAF', 'Gene', (201, 205))
218722	26222501	We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients.	('K27M', 'Mutation', 'p.K27M', (143, 147))	('KIAA1549-BRAF', 'Disease', 'None', (78, 91))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('V600E', 'Var', (120, 125))	('patients', 'Species', '9606', (262, 270))	('KIAA1549-BRAF', 'Disease', (78, 91))
218733	26222501	Jones et al described a novel fusion oncogene comprising KIAA1549 and BRAF formed through the tandem duplication at the 7q34 locus in 66% of PAs but not in high-grade gliomas.	('KIAA1549', 'Gene', (57, 65))	('tandem duplication', 'Var', (94, 112))	('PAs', 'Disease', (141, 144))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('KIAA1549', 'Gene', '57670', (57, 65))
218734	26222501	The most common fusion is between exon 16 of KIAA1549 and exon 9 of BRAF (63%), with less common fusion variants including exon 15-exon 9 (23%) and exon 16-exon 11 (10%).	('exon 16-exon 11', 'Var', (148, 163))	('BRAF', 'Gene', (68, 72))	('KIAA1549', 'Gene', (45, 53))	('exon 15-exon 9', 'Var', (123, 137))	('KIAA1549', 'Gene', '57670', (45, 53))
218737	26222501	Forshew et al found KIAA1549-BRAF fusion variants in both diffuse fibrillary astrocytomas and pilomyxoid astrocytomas, albeit at lower frequency than that observed in PAs.	('pilomyxoid astrocytomas', 'Disease', (94, 117))	('variants', 'Var', (41, 49))	('pilomyxoid astrocytomas', 'Disease', 'MESH:D001254', (94, 117))	('KIAA1549-BRAF', 'Disease', (20, 33))	('fibrillary astrocytomas', 'Disease', (66, 89))	('astrocytoma', 'Phenotype', 'HP:0009592', (77, 88))	('fibrillary astrocytomas', 'Disease', 'MESH:D001254', (66, 89))	('KIAA1549-BRAF', 'Disease', 'None', (20, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
218739	26222501	Subsequent research has unveiled several other rare novel BRAF fusion genes and fusion genes involving RAF1, another RAF kinase involved in the mitogen-activated protein kinase (MAPK) pathway, accounting for approximately 4% of all reported gene fusions in PAs.	('RAF', 'Gene', '22882', (59, 62))	('RAF', 'Gene', (59, 62))	('RAF', 'Gene', '22882', (117, 120))	('RAF', 'Gene', '22882', (103, 106))	('RAF', 'Gene', (103, 106))	('RAF', 'Gene', (117, 120))	('RAF1', 'Gene', (103, 107))	('fusion', 'Var', (63, 69))	('RAF1', 'Gene', '5894', (103, 107))
218740	26222501	For example, Cin et al identified the known KIAA1549-BRAF fusions, the SRGAP3-RAF1 fusion, and described a novel fusion between FAM131B and BRAF in a large cohort of PAs.	('KIAA1549-BRAF', 'Disease', (44, 57))	('RAF1', 'Gene', (78, 82))	('fusion', 'Var', (113, 119))	('RAF1', 'Gene', '5894', (78, 82))	('SRGAP3', 'Gene', (71, 77))	('Cin', 'Gene', '57026', (13, 16))	('KIAA1549-BRAF', 'Disease', 'None', (44, 57))	('FAM131B', 'Gene', (128, 135))	('BRAF', 'Gene', (140, 144))	('fusions', 'Var', (58, 65))	('SRGAP3', 'Gene', '9901', (71, 77))	('Cin', 'Gene', (13, 16))	('FAM131B', 'Gene', '9715', (128, 135))
218741	26222501	Constitutive activation of BRAF in PAs can also occur through a point mutation in the BRAF kinase domain, c.1799T>A p.Val600Glu (commonly referred to as V600E).	('V600E', 'Mutation', 'rs113488022', (153, 158))	('p.Val600Glu', 'Mutation', 'rs113488022', (116, 127))	('p.Val600Glu', 'Var', (116, 127))	('c.1799T>A', 'Mutation', 'rs113488022', (106, 115))	('activation', 'PosReg', (13, 23))	('c.1799T>', 'Var', (106, 114))	('BRAF', 'Gene', (86, 90))
218744	26222501	By exploring the significance of the fusion in a clinically relevant cohort of subtotally resected tumors outside the cerebellum, Hawkins et al subsequently found that the KIAA1549-BRAF fusion was an independent prognostic marker for significantly improved 5-year progression-free survival for PAs, as well as grade II diffuse and pilomyxoid astrocytomas.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('PAs', 'Disease', (294, 297))	('astrocytoma', 'Phenotype', 'HP:0009592', (342, 353))	('improved', 'PosReg', (248, 256))	('pilomyxoid astrocytomas', 'Disease', (331, 354))	('KIAA1549-BRAF', 'Disease', (172, 185))	('pilomyxoid astrocytomas', 'Disease', 'MESH:D001254', (331, 354))	('grade', 'Disease', (310, 315))	('fusion', 'Var', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('KIAA1549-BRAF', 'Disease', 'None', (172, 185))	('tumors', 'Disease', (99, 105))
218748	26222501	The differential neuropathologic diagnosis for PAs includes pediatric high-grade gliomas, most of which have recently been associated with histone mutations (H3.3 K27M).	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('associated', 'Reg', (123, 133))	('PAs', 'Disease', (47, 50))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('H3.3 K27M', 'Var', (158, 167))	('K27M', 'Mutation', 'p.K27M', (163, 167))
218750	26222501	Here, we tested for the BRAF fusion, BRAFV600E, and histone H3K27me3 biomarkers and attempted to correlate them with the clinical outcome in a cohort of pediatric PA patients.	('BRAFV600E', 'Var', (37, 46))	('tested', 'Reg', (9, 15))	('patients', 'Species', '9606', (166, 174))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))
218760	26222501	A cohort composed of 32 PA patients was successfully tested using the BRAF fusion RT-PCR assay, BRAF V600E, and histone H3.3 K27M.	('V600E', 'Mutation', 'rs113488022', (101, 106))	('BRAF V600E', 'Var', (96, 106))	('V600E', 'Var', (101, 106))	('patients', 'Species', '9606', (27, 35))	('K27M', 'Mutation', 'p.K27M', (125, 129))
218763	26222501	All tumors were also negative for BRAF V600E (Table 1).	('V600E', 'Mutation', 'rs113488022', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('BRAF V600E', 'Var', (34, 44))
218781	26222501	Interestingly, the 15-9 fusion was significantly associated with tumor location in the midline outside of the cerebellum (p = 0.014) (Tables 2, 3).	('15-9 fusion', 'Var', (19, 30))	('tumor', 'Disease', (65, 70))	('associated', 'Reg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
218784	26222501	Age (p = 0.300), sex (p = 0.261), tumor location (p = 0.177), 16-9 fusion (p = 0.208), and 15-9 fusion (p = 0.208) were not significantly associated with overall survival.	('15-9 fusion', 'Var', (91, 102))	('tumor', 'Disease', (34, 39))	('16-9 fusion', 'Var', (62, 73))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
218786	26222501	The BRAF V600E mutation and H3K27me3 histone methylation were not detected in the cohort.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('BRAF', 'Gene', (4, 8))	('V600E', 'Var', (9, 14))
218793	26222501	In our cohort, the KIAA1549-BRAF 15-9 fusion was significantly associated with tumor location in the midline (p = 0.014) and PAs located within the cerebellum were negatively associated with fusion 15-9 (p = 0.008).	('fusion', 'Var', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('fusion', 'Var', (38, 44))	('KIAA1549-BRAF', 'Disease', 'None', (19, 32))	('associated', 'Reg', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('PAs', 'Disease', (125, 128))	('KIAA1549-BRAF', 'Disease', (19, 32))	('negatively', 'NegReg', (164, 174))
218794	26222501	There is some evidence of tumors in the cerebellum being associated with fusion 16-9, but this does not achieve significance (p = 0.080).	('tumors', 'Disease', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('fusion 16-9', 'Var', (73, 84))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('associated', 'Reg', (57, 67))
218798	26222501	The KIAA1549-BRAF fusions are more common in posterior fossa PAs, whereas supratentorial PAs are less frequently fusion positive but have an increased frequency of the oncogenic BRAFV600E mutation.	('fusions', 'Var', (18, 25))	('common', 'Reg', (35, 41))	('KIAA1549-BRAF', 'Disease', (4, 17))	('posterior fossa PAs', 'Disease', (45, 64))	('KIAA1549-BRAF', 'Disease', 'None', (4, 17))	('BRAFV600E', 'Var', (178, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (178, 187))
218804	26222501	Combination therapy may therefore be a useful approach in molecularly targeting BRAF alterations in pediatric gliomas and should be the focus of clinical trials in this area, particularly in patients with tumors that are difficult to resect.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('BRAF', 'Gene', (80, 84))	('patients', 'Species', '9606', (191, 199))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('pediatric gliomas', 'Disease', 'MESH:D005910', (100, 117))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('alterations', 'Var', (85, 96))	('tumors', 'Disease', (205, 211))	('pediatric gliomas', 'Disease', (100, 117))
218805	26222501	The BRAF fusions are a useful diagnostic biomarker and a potential prognostic biomarker in pediatric low-grade glioma.	('glioma', 'Disease', (111, 117))	('fusions', 'Var', (9, 16))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('BRAF', 'Gene', (4, 8))
218813	26222501	Moreover, analysis may also be complicated by amplification of the 7q34 region in some tumors without gene fusion.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('amplification', 'Var', (46, 59))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('7q34', 'Gene', (67, 71))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
218814	26222501	In conclusion, we have identified KIAA1549-BRAF fusions in 75% of patients with PA using an RT-PCR assay from FFPE tissue.	('KIAA1549-BRAF', 'Disease', 'None', (34, 47))	('KIAA1549-BRAF', 'Disease', (34, 47))	('patients', 'Species', '9606', (66, 74))	('fusions', 'Var', (48, 55))
218882	25937354	Therefore, these same factors significantly challenge the internal and external validities of our estimates due to absence of data on many important aspects of the analysis including 1p19q codeletion (available only in 43% of cases), IDH mutation status and other oncopanel parameters, as well as pre- and post-operative Karnofsky performance score, which might provide better insight on the factors that inform the clinical outcome of patients with primary intracranial gliomas.	('IDH', 'Gene', (234, 237))	('glioma', 'Phenotype', 'HP:0009733', (471, 477))	('IDH', 'Gene', '3417', (234, 237))	('intracranial gliomas', 'Disease', (458, 478))	('patients', 'Species', '9606', (436, 444))	('mutation', 'Var', (238, 246))	('intracranial gliomas', 'Disease', 'MESH:D005910', (458, 478))	('gliomas', 'Phenotype', 'HP:0009733', (471, 478))
218883	25937354	1p/19q tumor status is a known powerful predictor of patient survival and a clinically useful marker of prognosis.	('1p/19q', 'Var', (0, 6))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('patient', 'Species', '9606', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
218885	25937354	Another limitation is that tumor volumes of the patients of the IoMRI group were segmented on MR images obtained from a 0.5T midfield strength scanner, while the tumor volumes of the patients of the no-IoMRI group were segmented from MR images obtained from a high field 1.5T scanner.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('IoMRI', 'Var', (64, 69))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('patients', 'Species', '9606', (183, 191))
218923	25124385	In a review on AED management after epilepsy surgery, AED withdrawal was associated with a lower rate of seizure recurrence compared to AED continuation.	('lower', 'NegReg', (91, 96))	('AED', 'Var', (54, 57))	('seizure', 'Phenotype', 'HP:0001250', (105, 112))	('epilepsy', 'Disease', 'MESH:D004827', (36, 44))	('epilepsy', 'Phenotype', 'HP:0001250', (36, 44))	('seizure', 'Disease', (105, 112))	('epilepsy', 'Disease', (36, 44))	('seizure', 'Disease', 'MESH:D012640', (105, 112))
219011	33493139	Moreover, BCAT1 is an independent prognostic factor for glioma patients, high BCAT1 expression is related to unfavorable clinical parameters including older age, IDH wildtype, no 1p/19q codeletion, ATRX wildtype and MGMT unmethylated.	('BCAT1', 'Gene', (78, 83))	('glioma', 'Disease', (56, 62))	('no 1p/19q codeletion', 'Var', (176, 196))	('ATRX', 'Gene', '546', (198, 202))	('IDH', 'Gene', (162, 165))	('related', 'Reg', (98, 105))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH', 'Gene', '3417', (162, 165))	('BCAT1', 'Gene', (10, 15))	('patients', 'Species', '9606', (63, 71))	('BCAT1', 'Gene', '586', (78, 83))	('high', 'PosReg', (73, 77))	('expression', 'MPA', (84, 94))	('MGMT', 'Gene', '4255', (216, 220))	('ATRX', 'Gene', (198, 202))	('MGMT', 'Gene', (216, 220))	('BCAT1', 'Gene', '586', (10, 15))
219012	33493139	Additionally, BCAT1 correlated with apoptosis, hypoxia and angiogenesis processes in gliomas and high expression of BCAT1 revealed higher glycolysis level and increased immunosuppressive status in tumor progression.	('BCAT1', 'Gene', '586', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('BCAT1', 'Gene', (14, 19))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('BCAT1', 'Gene', '586', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('immunosuppressive status', 'MPA', (169, 193))	('BCAT1', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('high expression', 'Var', (97, 112))	('glycolysis level', 'MPA', (138, 154))	('higher', 'PosReg', (131, 137))	('hypoxia', 'Disease', (47, 54))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('increased', 'PosReg', (159, 168))	('gliomas', 'Disease', (85, 92))	('angiogenesis', 'CPA', (59, 71))	('correlated', 'Reg', (20, 30))	('tumor', 'Disease', (197, 202))
219017	33493139	In 2016, the revision of the WHO classification of CNS tumors has highlighted the importance of the IDH1 or IDH2 mutation and co-deletion of chromosomal arms 1p and 19q for the diagnosis of gliomas.	('mutation', 'Var', (113, 121))	('CNS tumors', 'Disease', (51, 61))	('co-deletion', 'Var', (126, 137))	('IDH', 'Gene', (100, 103))	('arms 1p', 'Gene', '3075', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (100, 103))	('arms 1p', 'Gene', (153, 160))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('gliomas', 'Disease', (190, 197))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('IDH', 'Gene', '3417', (108, 111))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('CNS tumors', 'Disease', 'MESH:D016543', (51, 61))
219018	33493139	Based on isocitrate dehydrogenase (IDH) 1/2 mutation status, glioblastomas can also be defined as primary (IDH1/2 wildtype), which originate de novo and secondary (IDH1/2 mutant), which evolve from lower grade gliomas (accounting for 80% IDH1/2 mutant cases).	('glioblastomas', 'Phenotype', 'HP:0012174', (61, 74))	('gliomas', 'Disease', (210, 217))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('IDH1/2', 'Gene', (238, 244))	('mutation', 'Var', (44, 52))	('IDH1/2', 'Gene', '3417;3418', (164, 170))	('glioblastomas', 'Disease', 'MESH:D005909', (61, 74))	('IDH1/2', 'Gene', '3417;3418', (107, 113))	('glioblastomas', 'Disease', (61, 74))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('IDH1/2', 'Gene', (164, 170))	('IDH1/2', 'Gene', (107, 113))	('IDH1/2', 'Gene', '3417;3418', (238, 244))	('isocitrate dehydrogenase (IDH) 1/2', 'Gene', '3417;3418', (9, 43))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
219021	33493139	Branched-chain amino acid transaminase 1 (BCAT1) is a cytosolic enzyme that catalyzes the transformation of branched-chain L-amino acids (BCAA) into branched-chain alpha-ketoacids (BCKA), with concomitant conversion of alpha-KG to glutamate.	('BCAT1', 'Gene', '586', (42, 47))	('Branched-chain amino acid transaminase 1', 'Gene', (0, 40))	('Branched-chain amino acid transaminase 1', 'Gene', '586', (0, 40))	('branched-chain alpha-ketoacids', 'Chemical', '-', (149, 179))	('branched-chain L-amino acids', 'Chemical', '-', (108, 136))	('conversion', 'MPA', (205, 215))	('BCAT1', 'Gene', (42, 47))	('BCAA', 'Chemical', '-', (138, 142))	('alpha-KG', 'Chemical', 'MESH:D007656', (219, 227))	('branched-chain', 'Var', (108, 122))	('glutamate', 'Chemical', 'MESH:D018698', (231, 240))	('alpha-KG', 'Protein', (219, 227))
219022	33493139	Emerging evidence suggests that BCAT1 plays a vital role in the progression of many cancers, especially highlighting the tight connection between BCAT1 level and IDH1 mutation status.	('BCAT1', 'Gene', (32, 37))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('IDH', 'Gene', (162, 165))	('mutation', 'Var', (167, 175))	('BCAT1', 'Gene', '586', (146, 151))	('cancers', 'Disease', (84, 91))	('IDH', 'Gene', '3417', (162, 165))	('BCAT1', 'Gene', '586', (32, 37))	('BCAT1', 'Gene', (146, 151))
219023	33493139	For glioma, it is indicated that loss of BCAT1 is a sensitive marker for IDH-mutant diffuse gliomas and that decreased expression of BCAT1 correlates with improved patient survival in IDH wild-type gliomas.	('BCAT1', 'Gene', (133, 138))	('patient survival', 'CPA', (164, 180))	('IDH', 'Gene', (73, 76))	('gliomas', 'Disease', 'MESH:D005910', (198, 205))	('IDH', 'Gene', (184, 187))	('gliomas', 'Disease', (92, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma', 'Disease', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('IDH', 'Gene', '3417', (73, 76))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('IDH', 'Gene', '3417', (184, 187))	('expression', 'MPA', (119, 129))	('glioma', 'Disease', (198, 204))	('patient', 'Species', '9606', (164, 171))	('improved', 'PosReg', (155, 163))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('decreased', 'NegReg', (109, 118))	('BCAT1', 'Gene', '586', (41, 46))	('glioma', 'Disease', (92, 98))	('gliomas', 'Disease', (198, 205))	('BCAT1', 'Gene', (41, 46))	('BCAT1', 'Gene', '586', (133, 138))	('loss', 'Var', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (92, 98))
219024	33493139	-2-hydroxyglutarate, produced by IDH1/2 mutants, can inhibit the BCAT transaminases thus increases tumoral reliance on glutaminase for glutamate and glutathione synthesis.	('inhibit', 'NegReg', (53, 60))	('tumoral', 'Disease', (99, 106))	('IDH1/2', 'Gene', (33, 39))	('tumoral', 'Disease', 'MESH:D009369', (99, 106))	('-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (0, 19))	('BCAT transaminases', 'Enzyme', (65, 83))	('glutathione', 'Chemical', 'MESH:D005978', (149, 160))	('mutants', 'Var', (40, 47))	('glutamate', 'Chemical', 'MESH:D018698', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('IDH1/2', 'Gene', '3417;3418', (33, 39))	('increases', 'PosReg', (89, 98))
219038	33493139	Furthermore, we took advantage of clinical human glioma samples to detect the protein pattern of BCAT1 and IDH1 R132H in glioma tissues (Figure 1E, 1F).	('R132H', 'Mutation', 'rs121913500', (112, 117))	('human', 'Species', '9606', (43, 48))	('IDH', 'Gene', (107, 110))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('BCAT1', 'Gene', '586', (97, 102))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH', 'Gene', '3417', (107, 110))	('R132H', 'Var', (112, 117))	('BCAT1', 'Gene', (97, 102))	('glioma', 'Disease', (121, 127))	('glioma', 'Disease', (49, 55))
219039	33493139	The results showed that BCAT1 is increasingly expressed in glioma tissues corresponding to increasing tumor grade (Figure 1G), and compared to IDH1 wild-type diffuse glioma patients (Figure 1H), the patients that had gained IDH1 R132H mutation showed a lower percentage of tumor cells with detectable BCAT1 expression.	('BCAT1', 'Gene', (301, 306))	('IDH', 'Gene', (224, 227))	('tumor', 'Disease', (273, 278))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('increasingly', 'PosReg', (33, 45))	('IDH', 'Gene', (143, 146))	('glioma', 'Disease', (59, 65))	('patients', 'Species', '9606', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('IDH', 'Gene', '3417', (224, 227))	('R132H', 'Mutation', 'rs121913500', (229, 234))	('IDH', 'Gene', '3417', (143, 146))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (102, 107))	('BCAT1', 'Gene', '586', (24, 29))	('glioma', 'Disease', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('R132H', 'Var', (229, 234))	('BCAT1', 'Gene', (24, 29))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('patients', 'Species', '9606', (199, 207))	('BCAT1', 'Gene', '586', (301, 306))	('expression', 'MPA', (307, 317))
219044	33493139	Moreover, we found that IDH1 wild-type gliomas showed a higher expression of BCAT1 than mutant types in both TCGA and CGGA datasets (Figure 2G, 2H), and further internal comparison of IDH1 mutant gliomas showed that 1p19q codeleted IDH1 mutant gliomas owns a lower expression than non codeleted 1p19q forms with a significant difference in the CGGA dataset (Figure 2I, 2J).	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('IDH', 'Gene', (184, 187))	('expression', 'MPA', (265, 275))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('BCAT1', 'Gene', '586', (77, 82))	('IDH', 'Gene', '3417', (232, 235))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))	('BCAT1', 'Gene', (77, 82))	('IDH', 'Gene', (24, 27))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('IDH', 'Gene', '3417', (184, 187))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('expression', 'MPA', (63, 73))	('IDH', 'Gene', '3417', (24, 27))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('1p19q', 'Var', (216, 221))	('gliomas', 'Disease', (39, 46))	('IDH', 'Gene', (232, 235))	('higher', 'PosReg', (56, 62))	('gliomas', 'Disease', (196, 203))	('gliomas', 'Disease', (244, 251))	('lower', 'NegReg', (259, 264))
219047	33493139	In the TCGA dataset, patient groups of younger age, IDH mutation, 1p/19q deletion, ATRX mutation and MGMT methylation, are associated with lower BCAT1 expression (P < 0.05).	('mutation', 'Var', (88, 96))	('1p/19q deletion', 'Var', (66, 81))	('MGMT', 'Gene', (101, 105))	('BCAT1', 'Gene', '586', (145, 150))	('patient', 'Species', '9606', (21, 28))	('ATRX', 'Gene', (83, 87))	('MGMT', 'Gene', '4255', (101, 105))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('lower', 'NegReg', (139, 144))	('ATRX', 'Gene', '546', (83, 87))	('BCAT1', 'Gene', (145, 150))
219049	33493139	The results are consistent with CGGA dataset (Table 2), in which low expression of BCAT1 is related with younger age, IDH mutation, 1p/19q codeletion and chemoradiotherapy.	('BCAT1', 'Gene', '586', (83, 88))	('1p/19q codeletion', 'Var', (132, 149))	('IDH', 'Gene', (118, 121))	('expression', 'MPA', (69, 79))	('low', 'NegReg', (65, 68))	('IDH', 'Gene', '3417', (118, 121))	('BCAT1', 'Gene', (83, 88))
219050	33493139	Besides, patients with high BCAT1 expression are also more likely to develop tumor recurrence.	('patients', 'Species', '9606', (9, 17))	('BCAT1', 'Gene', '586', (28, 33))	('high', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('develop', 'PosReg', (69, 76))	('BCAT1', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
219051	33493139	The result of COX regression analysis (Table 3) in the CGGA cohort indicates IDH mutation status, 1p/19q codeletion status and the expression of BCAT1 can be considered as independent clinical prognostic factors.	('BCAT1', 'Gene', '586', (145, 150))	('mutation', 'Var', (81, 89))	('IDH', 'Gene', (77, 80))	('IDH', 'Gene', '3417', (77, 80))	('BCAT1', 'Gene', (145, 150))
219052	33493139	According to all of the above evidences, high BCAT1 expression is associated with several clinicopathological parameters and could serve as an independent prognostic predictor for glioma patients.	('patients', 'Species', '9606', (187, 195))	('BCAT1', 'Gene', '586', (46, 51))	('associated', 'Reg', (66, 76))	('high', 'Var', (41, 45))	('expression', 'MPA', (52, 62))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('BCAT1', 'Gene', (46, 51))	('glioma', 'Disease', (180, 186))
219060	33493139	The tumor metabolic phenotype is characterized by preferential dependence on glycolysis, and glycolytic enzymes are also known to be associated with the worse or better prognosis in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('glycolytic', 'Var', (93, 103))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('glycolysis', 'MPA', (77, 87))	('tumor metabolic', 'Disease', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor metabolic', 'Disease', 'MESH:D008659', (4, 19))	('associated', 'Reg', (133, 143))
219078	33493139	It was indicated that IDH1 mutation is associated with changes in cellular metabolism, which includes decreased branched-chain amino acid transaminase 1 (BCAT1) activity.	('branched-chain amino acid transaminase 1', 'Gene', (112, 152))	('cellular metabolism', 'MPA', (66, 85))	('BCAT1', 'Gene', (154, 159))	('IDH', 'Gene', (22, 25))	('mutation', 'Var', (27, 35))	('BCAT1', 'Gene', '586', (154, 159))	('branched-chain amino acid transaminase 1', 'Gene', '586', (112, 152))	('IDH', 'Gene', '3417', (22, 25))	('changes', 'Reg', (55, 62))	('decreased', 'NegReg', (102, 111))	('activity', 'MPA', (161, 169))
219079	33493139	Specifically, BCAT1 expression is dependent on the concentration of alpha-ketoglutarate (alpha-KG) substrate and could be suppressed by downregulation of IDH1 in glioblastoma cell lines or overexpression of mutant IDH1 in immortalized human astrocytes.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('BCAT1', 'Gene', '586', (14, 19))	('expression', 'MPA', (20, 30))	('suppressed', 'NegReg', (122, 132))	('downregulation', 'NegReg', (136, 150))	('BCAT1', 'Gene', (14, 19))	('mutant', 'Var', (207, 213))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (68, 87))	('human', 'Species', '9606', (235, 240))	('overexpression', 'PosReg', (189, 203))	('IDH', 'Gene', (214, 217))	('alpha-KG', 'Chemical', 'MESH:D007656', (89, 97))	('glioblastoma', 'Disease', (162, 174))	('IDH', 'Gene', (154, 157))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('IDH', 'Gene', '3417', (214, 217))	('IDH', 'Gene', '3417', (154, 157))
219080	33493139	In addition, BCAT1 knockdown can strongly restrict tumor growth and progression in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('restrict', 'NegReg', (42, 50))	('knockdown', 'Var', (19, 28))	('progression', 'CPA', (68, 79))	('BCAT1', 'Gene', (13, 18))	('tumor', 'Disease', (51, 56))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('BCAT1', 'Gene', '586', (13, 18))
219085	33493139	Moreover, the association between BCAT1 and IDH1 status was also confirmed, as previously reported, high expression of BCAT1 is observed in IDH1 wild-type gliomas but is also preferentially expressed in non 1p19q co-deleted gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('IDH', 'Gene', '3417', (140, 143))	('non 1p19q co-deleted', 'Var', (203, 223))	('BCAT1', 'Gene', (119, 124))	('preferentially', 'PosReg', (175, 189))	('expression', 'MPA', (105, 115))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('gliomas', 'Disease', (224, 231))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('BCAT1', 'Gene', '586', (34, 39))	('BCAT1', 'Gene', (34, 39))	('IDH', 'Gene', (44, 47))	('gliomas', 'Disease', 'MESH:D005910', (224, 231))	('IDH', 'Gene', (140, 143))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('BCAT1', 'Gene', '586', (119, 124))	('gliomas', 'Disease', (155, 162))	('IDH', 'Gene', '3417', (44, 47))
219086	33493139	Besides, high BCAT1 expression represents poor survival of IDH1 wild-type gliomas.	('BCAT1', 'Gene', '586', (14, 19))	('IDH', 'Gene', (59, 62))	('expression', 'MPA', (20, 30))	('IDH', 'Gene', '3417', (59, 62))	('gliomas', 'Disease', (74, 81))	('BCAT1', 'Gene', (14, 19))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('high', 'Var', (9, 13))
219097	33493139	Meanwhile, high expression of BCAT1 is also linked with a high percentage of M2 and Treg cell infiltration, which are more frequently occurring in IDH wild-type gliomas.	('IDH', 'Gene', '3417', (147, 150))	('Treg cell infiltration', 'CPA', (84, 106))	('BCAT1', 'Gene', (30, 35))	('high', 'Var', (11, 15))	('Treg', 'Chemical', '-', (84, 88))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('gliomas', 'Disease', (161, 168))	('linked', 'Reg', (44, 50))	('BCAT1', 'Gene', '586', (30, 35))	('IDH', 'Gene', (147, 150))	('expression', 'MPA', (16, 26))
219099	33493139	To conclude, our work highlights that high expression of BCAT1 is a sensitive marker for predicting poor prognosis of IDH1 wild-type glioma patients.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('BCAT1', 'Gene', (57, 62))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('high expression', 'Var', (38, 53))	('IDH', 'Gene', (118, 121))	('glioma', 'Disease', (133, 139))	('IDH', 'Gene', '3417', (118, 121))	('patients', 'Species', '9606', (140, 148))	('BCAT1', 'Gene', '586', (57, 62))
219116	33493139	Chi-square test and rank sum test were used to verify if the expression of BCAT1 is distinct in different groups of age, gender, grade, IDH status, 1p19q, MGMT, ATRX, radiotherapy and chemotherapy.	('IDH', 'Gene', (136, 139))	('IDH', 'Gene', '3417', (136, 139))	('ATRX', 'Gene', (161, 165))	('MGMT', 'Gene', '4255', (155, 159))	('BCAT1', 'Gene', (75, 80))	('MGMT', 'Gene', (155, 159))	('ATRX', 'Gene', '546', (161, 165))	('BCAT1', 'Gene', '586', (75, 80))	('1p19q', 'Var', (148, 153))
219134	32500034	Currently, predictive biomarkers for immunotherapy mainly include programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden, but often ignore the problem of "poor soil".	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PD-L1', 'Gene', '29126', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('programmed death-ligand 1', 'Gene', (66, 91))	('programmed death-ligand 1', 'Gene', '29126', (66, 91))	('microsatellite', 'Var', (101, 115))	('tumor', 'Disease', (170, 175))	('PD-L1', 'Gene', (93, 98))
219156	32500034	As shown in Figure 2C, high hypoxia risk score was associated with poor OS in the CGGA cohort, which was further validated by the TCGA cohort (Figure 2D).	('poor OS', 'Disease', (67, 74))	('hypoxia', 'Disease', (28, 35))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('high', 'Var', (23, 27))
219158	32500034	We found that patients with high risk scores had significantly shorter OS than those with low scores in LGG in the CGGA and TCGA cohorts (Figures 2E,F).	('scores', 'Var', (38, 44))	('patients', 'Species', '9606', (14, 22))	('shorter', 'NegReg', (63, 70))	('LGG', 'Gene', (104, 107))
219160	32500034	We then studied the relationship of gene expression with 1p/19q codeletion status and IDH status, respectively.	('IDH', 'Gene', '3417', (86, 89))	('IDH', 'Gene', (86, 89))	('1p/19q codeletion', 'Var', (57, 74))
219161	32500034	The results showed that expression levels of VEGFA, HK2, JUN, LDHA, and GAPDH were significantly high in glioma with wildtype-IDH (Figure 3E) and wildtype-1p/19q codeletion (Figure 3F).	('high', 'PosReg', (97, 101))	('HK2', 'Gene', (52, 55))	('VEGFA', 'Gene', (45, 50))	('HK2', 'Gene', '3099', (52, 55))	('IDH', 'Gene', '3417', (126, 129))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('JUN', 'MPA', (57, 60))	('wildtype-1p/19q codeletion', 'Var', (146, 172))	('expression levels', 'MPA', (24, 41))	('GAPDH', 'Gene', (72, 77))	('glioma', 'Disease', (105, 111))	('LDHA', 'Gene', (62, 66))	('GAPDH', 'Gene', '2597', (72, 77))	('LDHA', 'Gene', '3939', (62, 66))	('VEGFA', 'Gene', '7422', (45, 50))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('IDH', 'Gene', (126, 129))
219168	32500034	Other variables related with poor survival included age, WHO grade, IDH status, and 1p19q status.	('1p19q status', 'Var', (84, 96))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3417', (68, 71))
219169	32500034	Multivariate analysis showed that high hypoxia risk score was independently associated with significantly poorer OS of glioma patients (Figure 4D), which could serve as an independent prognostic factor for glioma.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('poorer', 'NegReg', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('hypoxia', 'Disease', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('high', 'Var', (34, 38))	('glioma', 'Disease', (119, 125))	('patients', 'Species', '9606', (126, 134))	('glioma', 'Disease', (206, 212))
219233	31908895	Numerous studies have shown that genetic alterations in ATRX play a significant role in gliomas.	('ATRX', 'Gene', '546', (56, 60))	('role', 'Reg', (80, 84))	('gliomas', 'Disease', (88, 95))	('genetic alterations', 'Var', (33, 52))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('ATRX', 'Gene', (56, 60))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
219235	31908895	We used The Cancer Genome Atlas (TCGA) database and 130 immunohistochemical results to confirm the difference in ATRX mutations in high- and low-grade gliomas.	('ATRX', 'Gene', '546', (113, 117))	('high-', 'Disease', (131, 136))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('Cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (118, 127))	('gliomas', 'Disease', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('ATRX', 'Gene', (113, 117))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
219236	31908895	An online analysis of the TCGA glioma datasets using the cBioPortal platform was performed to study the relationship between ATRX mutations and IDH1, TP53, CDKN2A and CDKN2B mutations in the corresponding TCGA glioma dataset.	('ATRX', 'Gene', '546', (125, 129))	('TP53', 'Gene', (150, 154))	('CDKN2A', 'Gene', (156, 162))	('CDKN2B', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (156, 162))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('CDKN2B', 'Gene', '1030', (167, 173))	('mutations', 'Var', (130, 139))	('ATRX', 'Gene', (125, 129))	('IDH1', 'Gene', (144, 148))	('mutations', 'Var', (174, 183))	('TP53', 'Gene', '7157', (150, 154))	('glioma', 'Disease', (31, 37))	('IDH1', 'Gene', '3417', (144, 148))	('glioma', 'Disease', (210, 216))
219237	31908895	In the selected TCGA glioma datasets, a total of 2,228 patients were queried, 21% of whom had ATRX alterations, which co-occurred frequently with TP53 and IDH1 mutations.	('IDH1', 'Gene', (155, 159))	('TP53', 'Gene', '7157', (146, 150))	('mutations', 'Var', (160, 169))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('IDH1', 'Gene', '3417', (155, 159))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('TP53', 'Gene', (146, 150))	('alterations', 'Var', (99, 110))	('patients', 'Species', '9606', (55, 63))	('ATRX', 'Gene', (94, 98))	('glioma', 'Disease', (21, 27))	('ATRX', 'Gene', '546', (94, 98))
219238	31908895	ATRX alterations are associated with multiple critical molecular events, which results in a significantly improved overall survival (OS) rate.	('improved', 'PosReg', (106, 114))	('overall survival', 'MPA', (115, 131))	('ATRX', 'Gene', (0, 4))	('alterations', 'Var', (5, 16))	('ATRX', 'Gene', '546', (0, 4))
219239	31908895	In low-grade gliomas, ATRX mutations are significantly associated with multiple important molecular events, such as ZNF274 and FDXR at mRNA and protein levels.	('ATRX', 'Gene', (22, 26))	('mutations', 'Var', (27, 36))	('ZNF274', 'Gene', '10782', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('ATRX', 'Gene', '546', (22, 26))	('ZNF274', 'Gene', (116, 122))	('FDXR', 'Gene', (127, 131))	('associated with', 'Reg', (55, 70))	('FDXR', 'Gene', '2232', (127, 131))	('gliomas', 'Disease', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
219242	31908895	ATRX mutations have clinical implications for the molecular diagnosis of gliomas and can provide diagnostic and prognostic information for gliomas.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('ATRX', 'Gene', (0, 4))	('gliomas', 'Disease', (139, 146))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('implications', 'Reg', (29, 41))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('ATRX', 'Gene', '546', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', (73, 80))
219248	31908895	Genetic alterations play an important role in the development and progression of tumors.	('Genetic alterations', 'Var', (0, 19))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
219250	31908895	In 2016, the WHO used molecular diagnosis at the center of a new classification of CNS tumors and introduced the ATRX mutation while exploring the diagnostic significance of mutant/wild-type IDH1 for glioma classification.	('glioma', 'Disease', (200, 206))	('IDH1', 'Gene', (191, 195))	('ATRX', 'Gene', '546', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('IDH1', 'Gene', '3417', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('CNS tumor', 'Phenotype', 'HP:0100006', (83, 92))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('mutation', 'Var', (118, 126))	('tumors', 'Disease', (87, 93))	('ATRX', 'Gene', (113, 117))
219252	31908895	Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome.	('X-linked syndromes', 'Disease', (43, 61))	('alpha-thalassemia (ATRX) syndrome', 'Disease', 'MESH:C538258', (107, 140))	('associated', 'Reg', (27, 37))	('cognitive disabilities', 'Disease', (73, 95))	('Mutations', 'Var', (0, 9))	('cognitive disabilities', 'Disease', 'MESH:D003072', (73, 95))	('cognitive disabilities', 'Phenotype', 'HP:0100543', (73, 95))
219254	31908895	This gene is involved in a wide range of biological processes, and the occurrence of ATRX mutations can cause changes in the molecular and clinical aspects of tumor characteristics.	('ATRX', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('molecular and', 'CPA', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('ATRX', 'Gene', '546', (85, 89))	('changes', 'Reg', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
219255	31908895	Mutations in regulatory factors occur frequently in gliomas, suggesting that epigenetic rearrangement is an essential event in glioma development.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('Mutations', 'Var', (0, 9))	('glioma', 'Disease', (127, 133))	('glioma', 'Disease', (52, 58))
219256	31908895	Studies have found that ATRX deletions/mutations are associated with a number of conventional molecular events, including IDH1 mutations and TP53 mutations.	('mutations', 'Var', (146, 155))	('deletions/mutations', 'Var', (29, 48))	('ATRX', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('IDH1', 'Gene', (122, 126))	('associated', 'Reg', (53, 63))	('IDH1', 'Gene', '3417', (122, 126))	('ATRX', 'Gene', '546', (24, 28))	('mutations', 'Var', (127, 136))
219257	31908895	showed that the deletion of ATRX and the expression of mutant IDH1 are sufficient to produce tumorigenic cells with alternative lengthening of telomeres (ALT) characteristics.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1', 'Gene', '3417', (62, 66))	('deletion', 'Var', (16, 24))	('tumor', 'Disease', (93, 98))	('ATRX', 'Gene', (28, 32))	('mutant', 'Var', (55, 61))	('lengthening', 'NegReg', (128, 139))	('IDH1', 'Gene', (62, 66))	('ATRX', 'Gene', '546', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
219258	31908895	In addition, some studies have noted that ATRX mutation and CDKN2A deletion are closely related to the OS rate of patients with astrocytoma.	('related', 'Reg', (88, 95))	('mutation', 'Var', (47, 55))	('deletion', 'Var', (67, 75))	('astrocytoma', 'Disease', 'MESH:D001254', (128, 139))	('ATRX', 'Gene', (42, 46))	('CDKN2A', 'Gene', (60, 66))	('astrocytoma', 'Disease', (128, 139))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))	('CDKN2A', 'Gene', '1029', (60, 66))	('OS rate', 'Disease', (103, 110))	('patients', 'Species', '9606', (114, 122))	('ATRX', 'Gene', '546', (42, 46))
219261	31908895	In this study, we used The Cancer Genome Atlas (TCGA) database and the online analysis tool cBioPortal to explore the biological significance of ATRX deletions/mutations in gliomas and their correlation with other eminent molecular events.	('ATRX', 'Gene', '546', (145, 149))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('gliomas', 'Disease', (173, 180))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('deletions/mutations', 'Var', (150, 169))	('ATRX', 'Gene', (145, 149))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))
219263	31908895	There were 2,228 samples with available mutations and copy number variation (CNV) data in the corresponding TCGA glioma datasets.	('copy number variation', 'Var', (54, 75))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('mutations', 'Var', (40, 49))	('glioma', 'Disease', (113, 119))
219264	31908895	Cases with ATRX, IDH1, TP53, CDKN2A and CDKN2B mutations were selected, and the mutation query was performed by OncoPrint function.	('CDKN2A', 'Gene', (29, 35))	('CDKN2A', 'Gene', '1029', (29, 35))	('CDKN2B', 'Gene', (40, 46))	('ATRX', 'Gene', (11, 15))	('mutations', 'Var', (47, 56))	('IDH1', 'Gene', (17, 21))	('CDKN2B', 'Gene', '1030', (40, 46))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('ATRX', 'Gene', '546', (11, 15))	('IDH1', 'Gene', '3417', (17, 21))
219268	31908895	According to the 2016 WHO classification criteria for CNS tumors, immunohistochemistry IDH1 was performed, which was split into IDH1 mutant-type 47 cases and IDH l wild-type 83 cases.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('IDH', 'Gene', '3417', (158, 161))	('IDH1', 'Gene', '3417', (128, 132))	('tumors', 'Disease', (58, 64))	('IDH1', 'Gene', '3417', (87, 91))	('IDH', 'Gene', (128, 131))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('IDH', 'Gene', (87, 90))	('CNS', 'Disease', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('IDH', 'Gene', '3417', (128, 131))	('IDH', 'Gene', '3417', (87, 90))	('mutant-type', 'Var', (133, 144))	('IDH1', 'Gene', (87, 91))	('CNS tumor', 'Phenotype', 'HP:0100006', (54, 63))	('IDH', 'Gene', (158, 161))	('IDH1', 'Gene', (128, 132))
219276	31908895	There were 1,721 (77%) samples with ATRX, IDH1, TP53, CDKN2A, and CDKN2B mutations and CNV data in the corresponding TCGA glioma datasets.	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('TP53', 'Gene', '7157', (48, 52))	('CDKN2B', 'Gene', '1030', (66, 72))	('IDH1', 'Gene', '3417', (42, 46))	('ATRX', 'Gene', '546', (36, 40))	('TP53', 'Gene', (48, 52))	('CDKN2A', 'Gene', (54, 60))	('glioma', 'Disease', (122, 128))	('CDKN2A', 'Gene', '1029', (54, 60))	('IDH1', 'Gene', (42, 46))	('CDKN2B', 'Gene', (66, 72))	('ATRX', 'Gene', (36, 40))	('mutations', 'Var', (73, 82))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
219277	31908895	ATRX mutations were found in approximately 21% of the samples, with truncating mutations and deletions being the major type of alteration.	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('truncating', 'MPA', (68, 78))	('ATRX', 'Gene', '546', (0, 4))	('deletions', 'Var', (93, 102))
219278	31908895	The IDH1 mutation accounted for 38%, the TP53 mutation accounted for 32%, and the CDKN2A and CDKN2B depth deletions were approximately 35% and 34%, respectively (Figure 1A).	('mutation', 'Var', (9, 17))	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (4, 8))	('CDKN2B', 'Gene', (93, 99))	('CDKN2B', 'Gene', '1030', (93, 99))	('CDKN2A', 'Gene', (82, 88))	('IDH1', 'Gene', (4, 8))	('CDKN2A', 'Gene', '1029', (82, 88))
219279	31908895	We found that the co-occurrence of IDH1, TP53 and ATRX mutations mainly occurred in LGG (TCGA, Pan-Cancer).	('TP53', 'Gene', '7157', (41, 45))	('ATRX', 'Gene', '546', (50, 54))	('IDH1', 'Gene', (35, 39))	('TP53', 'Gene', (41, 45))	('LGG', 'Disease', 'MESH:D008228', (84, 87))	('occurred', 'Reg', (72, 80))	('mutations', 'Var', (55, 64))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('IDH1', 'Gene', '3417', (35, 39))	('LGG', 'Disease', (84, 87))	('ATRX', 'Gene', (50, 54))
219281	31908895	The analysis of the LGG (TCGA, Pan-Cancer) and GBM (TCGA, Pan-Cancer) datasets showed that the mutation frequency of the three genes in the LGG group was significantly higher than that in the GBM group (Figure 1B).	('LGG', 'Disease', (20, 23))	('LGG', 'Disease', (140, 143))	('GBM', 'Disease', 'MESH:D005909', (47, 50))	('GBM', 'Disease', 'MESH:D005909', (192, 195))	('LGG', 'Disease', 'MESH:D008228', (140, 143))	('LGG', 'Disease', 'MESH:D008228', (20, 23))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('higher', 'PosReg', (168, 174))	('GBM', 'Disease', (47, 50))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('GBM', 'Disease', (192, 195))	('mutation', 'Var', (95, 103))
219282	31908895	The plot function illustrated the corresponding mRNA levels associated with the CNVs/mutations of ATRX, TP53 and IDH1.	('ATRX', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('mRNA levels', 'MPA', (48, 59))	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (113, 117))	('ATRX', 'Gene', '546', (98, 102))	('CNVs/mutations', 'Var', (80, 94))
219283	31908895	The results show that deep deletions and truncation mutations of ATRX in LGGs are associated with low mRNA expression levels.	('mRNA expression levels', 'MPA', (102, 124))	('LGG', 'Disease', (73, 76))	('low', 'NegReg', (98, 101))	('deep deletions', 'Var', (22, 36))	('ATRX', 'Gene', (65, 69))	('ATRX', 'Gene', '546', (65, 69))	('LGG', 'Disease', 'MESH:D008228', (73, 76))	('truncation mutations', 'Var', (41, 61))
219284	31908895	Deletion and amplification of TP53 are associated with expression levels, but the incidence of mutations is low, and amplification of IDH1 is associated with high mRNA expression levels (Figure 2A).	('TP53', 'Gene', (30, 34))	('expression levels', 'MPA', (55, 72))	('IDH1', 'Gene', (134, 138))	('associated', 'Reg', (142, 152))	('amplification', 'Var', (13, 26))	('IDH1', 'Gene', '3417', (134, 138))	('TP53', 'Gene', '7157', (30, 34))	('high mRNA expression levels', 'MPA', (158, 185))	('amplification', 'Var', (117, 130))	('Deletion', 'Var', (0, 8))
219289	31908895	In GBM (TCGA, provisional), the OS of the ATRX mutant group was higher than that of the unstated group (Figure 3C), but there was no significant difference in DFS (Figure 3D).	('GBM', 'Disease', (3, 6))	('GBM', 'Disease', 'MESH:D005909', (3, 6))	('higher', 'PosReg', (64, 70))	('ATRX', 'Gene', (42, 46))	('ATRX', 'Gene', '546', (42, 46))	('mutant', 'Var', (47, 53))
219290	31908895	Analysis of the integrated dataset of LGG (TCGA, Provisional) and GBM (TCGA, Provisional) cases showed more significant differences; the OS and DFS of cases with ATRX mutations were significantly higher than those of the without ATRX mutations group (Figure 3E and 3F).	('DFS', 'CPA', (144, 147))	('ATRX', 'Gene', '546', (229, 233))	('GBM', 'Disease', (66, 69))	('LGG', 'Disease', (38, 41))	('GBM', 'Disease', 'MESH:D005909', (66, 69))	('mutations', 'Var', (167, 176))	('higher', 'PosReg', (196, 202))	('LGG', 'Disease', 'MESH:D008228', (38, 41))	('ATRX', 'Gene', (162, 166))	('ATRX', 'Gene', '546', (162, 166))	('ATRX', 'Gene', (229, 233))
219291	31908895	We thought that the survival analysis of LGGs was not significantly different due to longer shelf-life and ubiquitous IDH1 mutations.	('LGG', 'Disease', (41, 44))	('IDH1', 'Gene', (118, 122))	('LGG', 'Disease', 'MESH:D008228', (41, 44))	('IDH1', 'Gene', '3417', (118, 122))	('mutations', 'Var', (123, 132))
219292	31908895	Survival analysis in the GBM group showed that patients with ATRX mutations had a relatively good prognosis, which is expected to be very valuable.	('mutations', 'Var', (66, 75))	('GBM', 'Disease', (25, 28))	('GBM', 'Disease', 'MESH:D005909', (25, 28))	('ATRX', 'Gene', (61, 65))	('patients', 'Species', '9606', (47, 55))	('ATRX', 'Gene', '546', (61, 65))
219293	31908895	Integration analysis of survival also suggests that ATRX mutations can be utilized to judge prognosis and even provide indications for clinical pathological grade.	('ATRX', 'Gene', '546', (52, 56))	('mutations', 'Var', (57, 66))	('ATRX', 'Gene', (52, 56))
219294	31908895	Immunohistochemical studies have shown that ATRX loss is more common in mutant IDH1 gliomas but is rare in wild-type IDH1 gliomas.	('ATRX', 'Gene', (44, 48))	('loss', 'NegReg', (49, 53))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (117, 129))	('ATRX', 'Gene', '546', (44, 48))	('mutant', 'Var', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('IDH1 gliomas', 'Disease', (79, 91))	('IDH1 gliomas', 'Disease', (117, 129))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (79, 91))
219296	31908895	The incidence of ATRX deletions was 42.6% (20/47) and 22.9% (19/83), respectively (P < 0.05), which was statistically significant.	('ATRX', 'Gene', (17, 21))	('deletions', 'Var', (22, 31))	('ATRX', 'Gene', '546', (17, 21))
219297	31908895	The incidence of P53 overexpression in IDH1 mutant and wild-type gliomas was 42.6% (20/47) and 36.1% (30/83), respectively, with no significant difference ( Table 1 and Figure 4).	('gliomas', 'Disease', (65, 72))	('IDH1', 'Gene', (39, 43))	('P53', 'Gene', (17, 20))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('P53', 'Gene', '7157', (17, 20))	('overexpression', 'PosReg', (21, 35))	('IDH1', 'Gene', '3417', (39, 43))	('mutant', 'Var', (44, 50))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
219300	31908895	Built on the above analysis, we found that ATRX deletion/mutation mainly occurs in LGG (TCGA, Pan-Cancer) and is associated with patient prognosis.	('ATRX', 'Gene', '546', (43, 47))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('LGG', 'Disease', (83, 86))	('LGG', 'Disease', 'MESH:D008228', (83, 86))	('deletion/mutation', 'Var', (48, 65))	('occurs', 'Reg', (73, 79))	('ATRX', 'Gene', (43, 47))	('associated', 'Reg', (113, 123))	('patient', 'Species', '9606', (129, 136))
219301	31908895	In addition, ATRX is often co-mutated with IDH1 and TP53, so we further explored the interaction of ATRX mutations with IDH1 and TP53 in LGGs.	('ATRX', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (52, 56))	('IDH1', 'Gene', '3417', (120, 124))	('LGG', 'Disease', 'MESH:D008228', (137, 140))	('ATRX', 'Gene', '546', (13, 17))	('ATRX', 'Gene', (100, 104))	('IDH1', 'Gene', (43, 47))	('TP53', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (129, 133))	('IDH1', 'Gene', (120, 124))	('mutations', 'Var', (105, 114))	('ATRX', 'Gene', '546', (100, 104))	('IDH1', 'Gene', '3417', (43, 47))	('TP53', 'Gene', (129, 133))	('LGG', 'Disease', (137, 140))
219303	31908895	Interestingly, we also found significant mutual exclusivity between CIC and EGFR mutations and ATRX mutations (Figure 5A).	('ATRX', 'Gene', (95, 99))	('EGFR', 'Gene', '1956', (76, 80))	('ATRX', 'Gene', '546', (95, 99))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('CIC', 'Gene', (68, 71))
219304	31908895	In the CNV, we suggest that EGFR mutations are primarily negatively correlated with ATRX amplification (Figure 5B).	('EGFR', 'Gene', '1956', (28, 32))	('ATRX', 'Gene', '546', (84, 88))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('negatively', 'NegReg', (57, 67))	('ATRX', 'Gene', (84, 88))
219305	31908895	There is a mutual exclusivity among CDKN2A, CDKN2B and ATRX deep deletion changes (Figure 5C).	('CDKN2A', 'Gene', (36, 42))	('CDKN2A', 'Gene', '1029', (36, 42))	('ATRX', 'Gene', (55, 59))	('CDKN2B', 'Gene', (44, 50))	('CDKN2B', 'Gene', '1030', (44, 50))	('ATRX', 'Gene', '546', (55, 59))	('deep deletion changes', 'Var', (60, 81))
219308	31908895	These genes were input into the OncoPrint function for mRNA cluster analysis, and the results showed that the deletion mutation of ATRX was associated with a decrease in mRNA expression.	('ATRX', 'Gene', '546', (131, 135))	('decrease', 'NegReg', (158, 166))	('deletion mutation', 'Var', (110, 127))	('ATRX', 'Gene', (131, 135))	('mRNA expression', 'MPA', (170, 185))
219309	31908895	However, the mRNA expression levels of IDH1 and TP53 were not significantly correlated with their mutations, which may be related to the different incidence of mutation types.	('TP53', 'Gene', '7157', (48, 52))	('IDH1', 'Gene', (39, 43))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (98, 107))	('mRNA expression levels', 'MPA', (13, 35))	('IDH1', 'Gene', '3417', (39, 43))
219311	31908895	ATRX changes were significantly positively correlated with mRNA expression (Figure 5D).	('mRNA expression', 'MPA', (59, 74))	('ATRX', 'Gene', '546', (0, 4))	('changes', 'Var', (5, 12))	('ATRX', 'Gene', (0, 4))
219314	31908895	All of the above results suggest that these genes may interact with ATRX mutations.	('mutations', 'Var', (73, 82))	('ATRX', 'Gene', '546', (68, 72))	('interact', 'Reg', (54, 62))	('ATRX', 'Gene', (68, 72))
219315	31908895	When we entered into the list of neighboring genes into DAVID, we noticed that ATP binding was the most abundant biological process in ATRX mutation-related genes and plays a role in DNA damage repair and P53 binding.	('binding', 'Interaction', (209, 216))	('ATRX', 'Gene', '546', (135, 139))	('P53', 'Gene', '7157', (205, 208))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('mutation-related', 'Var', (140, 156))	('ATP', 'MPA', (79, 82))	('ATRX', 'Gene', (135, 139))	('P53', 'Gene', (205, 208))
219321	31908895	In 2016, the WHO supplemented the classification of CNS tumors and proposed new classifications based on histological and molecular characteristics, such as glioblastoma-IDH wild-type and glioblastoma-IDH mutant.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutant', 'Var', (205, 211))	('CNS tumor', 'Phenotype', 'HP:0100006', (52, 61))	('glioblastoma-IDH wild-type and glioblastoma-IDH', 'Disease', 'MESH:D005909', (157, 204))
219325	31908895	noted that the ATRX mutation is linked to age and is more common in adult diffuse glioma.	('common', 'Reg', (58, 64))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('ATRX', 'Gene', '546', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('mutation', 'Var', (20, 28))	('glioma', 'Disease', (82, 88))	('ATRX', 'Gene', (15, 19))
219326	31908895	reported that patients with ATRX mutations have higher survival rates in wild-type IDH1 adult gliomas.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('gliomas', 'Disease', (94, 101))	('IDH1', 'Gene', '3417', (83, 87))	('survival rates', 'CPA', (55, 69))	('ATRX', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('higher', 'PosReg', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('patients', 'Species', '9606', (14, 22))	('ATRX', 'Gene', '546', (28, 32))	('IDH1', 'Gene', (83, 87))
219327	31908895	Although many studies have indicated that ATRX mutations can provide useful information for glioma prognosis, there remains a lack of systematic and clear understanding of ATRX research, and its molecular mechanism needs further exploration.	('ATRX', 'Gene', (172, 176))	('mutations', 'Var', (47, 56))	('ATRX', 'Gene', (42, 46))	('glioma', 'Disease', (92, 98))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('ATRX', 'Gene', '546', (172, 176))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('ATRX', 'Gene', '546', (42, 46))
219328	31908895	In this study, we used the TCGA (Pan-Cancer) database to analyze the correlation between ATRX mutations and IDH1 and TP53 mutations by integrating a large amount of data.	('IDH1', 'Gene', '3417', (108, 112))	('ATRX', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('ATRX', 'Gene', '546', (89, 93))	('IDH1', 'Gene', (108, 112))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))
219329	31908895	Combined with the immunohistochemical results of pathological samples and TCGA survival analysis, it was confirmed that ATRX mutation can be invoked as a reference for pathological grading and prognosis, and the role of ATRX mutation in the development of glioma is discussed.	('ATRX', 'Gene', (120, 124))	('ATRX', 'Gene', (220, 224))	('glioma', 'Disease', 'MESH:D005910', (256, 262))	('glioma', 'Disease', (256, 262))	('ATRX', 'Gene', '546', (120, 124))	('ATRX', 'Gene', '546', (220, 224))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))	('mutation', 'Var', (125, 133))
219330	31908895	We found that patients with ATRX mutations in the GBM group also had a better prognosis, suggesting that ATRX may be a novel therapeutic target, which is valuable.	('ATRX', 'Gene', '546', (105, 109))	('ATRX', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('GBM', 'Disease', (50, 53))	('ATRX', 'Gene', (105, 109))	('patients', 'Species', '9606', (14, 22))	('ATRX', 'Gene', '546', (28, 32))	('GBM', 'Disease', 'MESH:D005909', (50, 53))
219332	31908895	In past studies, ATRX mutations/deletions were associated with the development of multiple cancers and involved in multiple biological processes.	('ATRX', 'Gene', (17, 21))	('multiple cancers', 'Disease', 'MESH:D009369', (82, 98))	('mutations/deletions', 'Var', (22, 41))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('associated with', 'Reg', (47, 62))	('ATRX', 'Gene', '546', (17, 21))	('involved', 'Reg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('multiple cancers', 'Disease', (82, 98))
219333	31908895	We found that ATRX cooccurs with IDH1 and TP53 mutations in LGGs.	('TP53', 'Gene', '7157', (42, 46))	('LGG', 'Disease', 'MESH:D008228', (60, 63))	('IDH1', 'Gene', (33, 37))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('ATRX', 'Gene', (14, 18))	('IDH1', 'Gene', '3417', (33, 37))	('ATRX', 'Gene', '546', (14, 18))	('LGG', 'Disease', (60, 63))
219334	31908895	Additionally, there is a significant negative correlation with EGFR and (Capicua) CIC mutations.	('mutations', 'Var', (86, 95))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (63, 67))	('negative', 'NegReg', (37, 45))
219335	31908895	Studies have shown that EGFR mutations are mainly found on amplification, mostly in GBM.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('GBM', 'Disease', (84, 87))	('GBM', 'Disease', 'MESH:D005909', (84, 87))
219336	31908895	The Drosophila CIC gene is homologous to the 1p/19q codeletion, and CIC mutations occur more frequently in oligodendroglioma.	('mutations', 'Var', (72, 81))	('oligodendroglioma', 'Disease', (107, 124))	('Drosophila CIC', 'Disease', (4, 18))	('oligodendroglioma', 'Disease', 'MESH:D009837', (107, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('CIC', 'Gene', (68, 71))	('Drosophila CIC', 'Disease', 'None', (4, 18))	('occur', 'Reg', (82, 87))
219339	31908895	The 3' exon of the zinc finger (ZNF) gene is a target of ATRX, and the H3K9me3 level in the ZNF gene is particularly sensitive to the inactivation of ATRX, which has the function of recruiting SETDB1, TRIM28 and zinc finger protein 274 (ZNF274).	('inactivation', 'Var', (134, 146))	('ATRX', 'Gene', (150, 154))	('ATRX', 'Gene', '546', (150, 154))	('TRIM28', 'Gene', '10155', (201, 207))	('H3K9me3 level', 'MPA', (71, 84))	('zinc finger protein 274', 'Gene', '10782', (212, 235))	('zinc finger protein 274', 'Gene', (212, 235))	('ZNF', 'Gene', (92, 95))	('ZNF', 'Gene', '284390', (92, 95))	('ZNF274', 'Gene', '10782', (237, 243))	('SETDB1', 'Gene', (193, 199))	('ZNF274', 'Gene', (237, 243))	('ATRX', 'Gene', (57, 61))	('ZNF', 'Gene', (32, 35))	('recruiting', 'PosReg', (182, 192))	('ZNF', 'Gene', '284390', (32, 35))	('ATRX', 'Gene', '546', (57, 61))	('SETDB1', 'Gene', '9869', (193, 199))	('TRIM28', 'Gene', (201, 207))	('ZNF', 'Gene', (237, 240))	('ZNF', 'Gene', '284390', (237, 240))
219349	31908895	The effect of the ATRX mutation on glioma may also be related to blood oxygen transport.	('effect', 'Reg', (4, 10))	('related', 'Reg', (54, 61))	('mutation', 'Var', (23, 31))	('blood oxygen transport', 'MPA', (65, 87))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('ATRX', 'Gene', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('ATRX', 'Gene', '546', (18, 22))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))	('glioma', 'Disease', (35, 41))
219350	31908895	This information may provide an explanation for the phenomenon of ATRX, TP53, and IDH1 mutations, and furnish additional research ideas for blood oxygen imbalance with tumor progression.	('blood oxygen imbalance', 'Phenotype', 'HP:0500165', (140, 162))	('tumor', 'Disease', (168, 173))	('TP53', 'Gene', '7157', (72, 76))	('imbalance', 'Phenotype', 'HP:0002172', (153, 162))	('IDH1', 'Gene', (82, 86))	('TP53', 'Gene', (72, 76))	('ATRX', 'Gene', (66, 70))	('IDH1', 'Gene', '3417', (82, 86))	('oxygen', 'Chemical', 'MESH:D010100', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('ATRX', 'Gene', '546', (66, 70))	('mutations', 'Var', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
219351	31908895	In summary, this study identified the genetic alterations in ATRX, IDH1 and TP53 as symbiotic characteristics through TCGA glioma datasets, which initially reflected the relationship of these tumor genes in mutation.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('tumor', 'Disease', (192, 197))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('ATRX', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('TP53', 'Gene', '7157', (76, 80))	('IDH1', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (61, 65))	('IDH1', 'Gene', '3417', (67, 71))	('TP53', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('glioma', 'Disease', (123, 129))	('genetic alterations', 'Var', (38, 57))
219352	31908895	The value of the ATRX mutation in prognostic evaluation was upheld.	('ATRX', 'Gene', (17, 21))	('mutation', 'Var', (22, 30))	('ATRX', 'Gene', '546', (17, 21))
219354	31908895	These findings and speculations still require more experimental and data support, but at least our data systematically demonstrate the distribution and clinical significance of ATRX mutations in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('ATRX', 'Gene', '546', (177, 181))	('ATRX', 'Gene', (177, 181))	('gliomas', 'Disease', (195, 202))	('gliomas', 'Disease', 'MESH:D005910', (195, 202))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('mutations', 'Var', (182, 191))
219379	31780652	We use ParTI to (i) identify trade-offs between five universal tasks shared across cancer types, (ii) show that tumors that specialize in a task are differentially sensitive to drugs that disrupt that task, and (iii) demonstrate that each driver mutation moves gene expression towards specialization in specific tasks.	('mutation', 'Var', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer type', 'Disease', (83, 94))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('gene expression', 'MPA', (261, 276))	('moves', 'Reg', (255, 260))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('cancer type', 'Disease', 'MESH:D009369', (83, 94))	('tumors', 'Disease', (112, 118))
219422	31780652	We computed the mean effect of each genetic alteration, a vector that describes how this alteration shifts gene expression (the difference in gene expression between tumors with and without the alteration, schematically shown in Fig.	('shifts', 'Reg', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('alteration', 'Var', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('alteration', 'Var', (89, 99))	('tumors', 'Disease', (166, 172))	('gene expression', 'MPA', (107, 122))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
219425	31780652	Strikingly, for five cancer types, the effect vectors of driver single nucleotide variants (SNVs) align with the polyhedron much more closely than expected from shuffled data: glioma (p = 10-4, shuffling test, Fig.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('glioma', 'Disease', (176, 182))	('cancer type', 'Disease', (21, 32))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cancer type', 'Disease', 'MESH:D009369', (21, 32))	('single nucleotide variants', 'Var', (64, 90))
219430	31780652	In breast cancer, the common TP53 mutation is the most aligned with the front.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('mutation', 'Var', (34, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))
219431	31780652	It points directly towards one archetype, cell division (angle to archetype = 18 , mutation enriched 2.6-fold in the 5% of tumor closest to archetype, p < 10-16, hypergeometric test, Fig.	('mutation', 'Var', (83, 91))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))
219432	31780652	Mutations in TP53 in breast cancer and IDH1 in glioma thus coordinate gene expression towards specializing in the cell-division task.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('coordinate', 'Reg', (59, 69))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('IDH1', 'Gene', (39, 43))	('breast cancer', 'Disease', (21, 34))	('glioma', 'Disease', (47, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (39, 43))	('TP53', 'Gene', '7157', (13, 17))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
219434	31780652	For example, PTEN deletion in lower grade glioma points to the immune archetype; MYC amplification in breast cancer points to the cell division archetype (inferred tasks for 229 CNAs are listed in Supplementary Data 5, FDR < 10%).	('breast cancer', 'Disease', (102, 115))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('PTEN', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PTEN', 'Gene', '5728', (13, 17))	('glioma', 'Disease', (42, 48))	('deletion', 'Var', (18, 26))
219442	31780652	In connecting intratumor heterogeneity with intertumor diversity, one prediction based on concepts from ecology is called "evolution along lines of least genetic resistance":the finding that the main axes of variations between individuals in a given species is aligned with variation between species in the same taxon.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('variations', 'Var', (208, 218))	('tumor', 'Disease', (19, 24))
219466	31780652	Nevertheless, clarifying the origin of the observed association between driver mutations and cancer tasks could be the object of future research, perhaps by comparing gene expression in genetically engineered mouse models with different driver mutations.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutations', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mouse', 'Species', '10090', (209, 214))
219547	31780652	Increasing proteasome activity is thought to be a strategy used by cancer cells to cope with the increased translation of low-quality proteins due to misfolding-causing mutations and aberrant splicing.	('aberrant splicing', 'Var', (183, 200))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('translation', 'MPA', (107, 118))	('increased', 'PosReg', (97, 106))	('mutations', 'Var', (169, 178))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
219559	31780652	Second, in the hypoxic environment of tumors cells, lack of oxygen blocks respiration which leads to an excess of reducing power (too much NADPH).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('hypoxic', 'Disease', 'MESH:D000860', (15, 22))	('oxygen', 'Chemical', 'MESH:D010100', (60, 66))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('respiration', 'MPA', (74, 85))	('NADPH', 'Chemical', 'MESH:D009249', (139, 144))	('lack', 'Var', (52, 56))	('reducing power', 'MPA', (114, 128))	('hypoxic', 'Disease', (15, 22))	('excess', 'PosReg', (104, 110))	('blocks', 'NegReg', (67, 73))
219609	31780652	To test the hypothesis that driver SNVs and CNAs are knobs that tune tumor gene expression towards specific tasks, we first compiled lists of (1) drivers alterations, (2) passengers alterations, and (3) alterations commonly found in cancer although not thought to be drivers in the cancer type of interest.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer type', 'Disease', (282, 293))	('cancer type', 'Disease', 'MESH:D009369', (282, 293))	('alterations', 'Var', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (282, 288))	('alterations', 'Var', (182, 193))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('alterations', 'Var', (203, 214))
219610	31780652	Second, we quantified whether these alterations pushed tumor gene expression along the cancer front or away from it.	('cancer', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('alterations', 'Var', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('pushed', 'PosReg', (48, 54))
219614	31780652	We defined driver alterations from: (1) genes lying within minimal amplification regions, upregulated as a result of this amplification, and with significant experimental evidence of their involvement in cancer development by Santarius et al.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('amplification', 'Var', (122, 135))	('upregulated', 'PosReg', (90, 101))	('involvement', 'Reg', (189, 200))
219615	31780652	(2) genes with a high proportion of recurrent SNVs (for oncogenes) or a high proportion of inactivating mutations (for tumor suppressors) in the survey of 2433 primary breast tumors of Pereira et al.. (3) genes commonly amplified, or carrying mis-sense or inframe mutations (for oncogenes), and genes commonly deleted or carrying frameshifting or non-sense mutations (for tumor suppressors) in a survey of 560 breast tumors.	('amplified', 'PosReg', (220, 229))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('breast tumors', 'Disease', 'MESH:D061325', (410, 423))	('mis-sense', 'Var', (243, 252))	('tumor', 'Disease', (417, 422))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('breast tumors', 'Disease', (168, 181))	('tumor', 'Disease', 'MESH:D009369', (417, 422))	('breast tumors', 'Phenotype', 'HP:0100013', (168, 181))	('tumors', 'Phenotype', 'HP:0002664', (417, 423))	('tumor', 'Disease', (175, 180))	('breast tumors', 'Disease', (410, 423))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('tumor', 'Disease', (372, 377))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('breast tumors', 'Phenotype', 'HP:0100013', (410, 423))	('breast tumors', 'Disease', 'MESH:D061325', (168, 181))	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('tumor', 'Disease', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('frameshifting', 'Var', (330, 343))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
219617	31780652	Deletions (weak or strong) corresponding to genes identified as tumor suppressors were also defined as driver CNAs.	('driver CNAs', 'Disease', (103, 114))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('Deletions', 'Var', (0, 9))
219619	31780652	We represented the average effect of each alteration on gene expression as a vector, connecting the centroid of tumors having the alteration to the centroid of tumors without the alteration (Fig.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('alteration', 'Var', (130, 140))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
219620	31780652	To quantify whether an alteration pushes gene expression along the cancer front or away from it, we computed the angle between the alteration vector and the cancer front.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (67, 73))	('pushes', 'Reg', (34, 40))	('alteration', 'Var', (23, 33))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (157, 163))
219700	31132822	McNemar's test was performed to compare the sensitivity and specificity of the combination of 11C-MET PET and MRS as well as those of the individual techniques.	('N', 'Chemical', 'MESH:D009584', (2, 3))	('MRS', 'Disease', 'MESH:D008556', (110, 113))	('11C-MET PET', 'Var', (94, 105))	('MRS', 'Disease', (110, 113))	('11C-MET', 'Chemical', '-', (94, 101))
219715	31132822	Upon comparing 11C-MET PET and MRS, 11C-MET PET showed better sensitivity (p = 0.029), but equal specificity (p = 0.480) (Fig.	('11C-MET PET', 'Var', (15, 26))	('11C-MET', 'Chemical', '-', (36, 43))	('MRS', 'Disease', 'MESH:D008556', (31, 34))	('11C-MET', 'Chemical', '-', (15, 22))	('MRS', 'Disease', (31, 34))	('better', 'PosReg', (55, 61))	('11C-MET', 'Var', (36, 43))
219727	31132822	Previous research has established that 11C-MET PET is more accurate for glioma diagnosis than CT, and other studies have suggested that 11C-MET PET is superior to MRI and 18F-fluorodeoxyglucose PET.	('11C-MET', 'Var', (136, 143))	('glioma', 'Disease', (72, 78))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (171, 193))	('11C-MET', 'Chemical', '-', (136, 143))	('11C-MET', 'Chemical', '-', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))
219749	31132822	Thus, for lesions located in these areas, 11C-MET PET could yield a better diagnosis than that of MRS.	('11C-MET', 'Chemical', '-', (42, 49))	('MRS', 'Disease', 'MESH:D008556', (98, 101))	('11C-MET PET', 'Var', (42, 53))	('MRS', 'Disease', (98, 101))
219752	31132822	Compared with MRS, 11C-MET PET had enhanced sensitivity and equal specificity, which suggested its superiority to MRS.	('sensitivity', 'MPA', (44, 55))	('MRS', 'Disease', 'MESH:D008556', (14, 17))	('11C-MET PET', 'Var', (19, 30))	('11C-MET', 'Chemical', '-', (19, 26))	('MRS', 'Disease', 'MESH:D008556', (114, 117))	('enhanced', 'PosReg', (35, 43))	('MRS', 'Disease', (14, 17))	('MRS', 'Disease', (114, 117))
219756	31132822	As a result, a combination of MRS and 11C-MET PET can substantially increase radiological diagnostic sensitivity for non-enhancing supratentorial gliomas without greatly reducing specificity.	('radiological diagnostic sensitivity', 'MPA', (77, 112))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('MRS', 'Disease', (30, 33))	('11C-MET PET', 'Var', (38, 49))	('increase', 'PosReg', (68, 76))	('11C-MET', 'Chemical', '-', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('MRS', 'Disease', 'MESH:D008556', (30, 33))
219768	31132822	In conclusion, the combination of MRS and 11C-MET PET can considerably improve accurate diagnostic sensitivity for non-enhancing supratentorial gliomas without significantly lowering specificity.	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('MRS', 'Disease', (34, 37))	('11C-MET PET', 'Var', (42, 53))	('11C-MET', 'Chemical', '-', (42, 49))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('MRS', 'Disease', 'MESH:D008556', (34, 37))	('improve', 'PosReg', (71, 78))
219770	30967140	Diagnostic emphasis has shifted from the morphology of a tumor under the microscope to an integrated approach based on morphologic and molecular features, including gene mutations, chromosomal copy number alterations, and gene rearrangements.	('gene rearrangements', 'Var', (222, 241))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('chromosomal copy number alterations', 'Var', (181, 216))
219777	30967140	Particular attention is given to the histone H3 G34R/G34V mutant astrocytomas, an entity to consider when faced with an infiltrating glioma in the cerebral hemisphere of children and young adults, and to the group of histologically lower grade diffuse astrocytic gliomas with molecular features of glioblastoma, an important category of tumors to recognize due to their aggressive clinical behavior.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (298, 310))	('children', 'Species', '9606', (170, 178))	('gliomas', 'Phenotype', 'HP:0009733', (263, 270))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (252, 270))	('astrocytic gliomas', 'Disease', (252, 270))	('G34V', 'Mutation', 'p.G34V', (53, 57))	('glioblastoma', 'Disease', (298, 310))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (370, 398))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('glioma', 'Disease', (263, 269))	('glioblastoma', 'Phenotype', 'HP:0012174', (298, 310))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('G34R', 'Mutation', 'rs1057519902', (48, 52))	('tumors', 'Disease', (337, 343))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('glioma', 'Disease', (133, 139))	('astrocytomas', 'Disease', (65, 77))	('G34R/G34V', 'Var', (48, 57))
219795	30967140	From the 1998 identification of chromosome arm 1p and 19q loss as a favorable prognostic indicator in infiltrating gliomas and the recognition of the association with oligodendroglioma histology, to the 2008 identification of isocitrate dehydrogenase mutations as an early driver of gliomagenesis, molecular advances have provided critical information that now has implications for brain tumor treatment and prognosis.	('glioma', 'Disease', (115, 121))	('isocitrate', 'Chemical', 'MESH:C034219', (226, 236))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('glioma', 'Disease', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('oligodendroglioma', 'Disease', 'MESH:D009837', (167, 184))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('gliomas', 'Disease', (115, 122))	('brain tumor', 'Phenotype', 'HP:0030692', (382, 393))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('oligodendroglioma', 'Disease', (167, 184))	('brain tumor', 'Disease', 'MESH:D001932', (382, 393))	('brain tumor', 'Disease', (382, 393))	('loss', 'NegReg', (58, 62))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('mutations', 'Var', (251, 260))	('glioma', 'Disease', (283, 289))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Disease', 'MESH:D005910', (283, 289))
219811	30967140	The consortium has released guidelines on topics such as how to use the NOS and NEC qualifiers in diagnostic reports, requirements for 1p/19q testing in infiltrating gliomas with astrocytic morphology, and the criteria for the diagnosis of diffuse midline glioma, H3 K27M-mutant, WHO grade IV.	('H3 K27M-mutant', 'Var', (264, 278))	('K27M', 'Mutation', 'p.K27M', (267, 271))	('midline glioma', 'Disease', 'MESH:D005910', (248, 262))	('midline glioma', 'Disease', (248, 262))	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('gliomas', 'Disease', (166, 173))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (256, 262))
219823	30967140	These tumors may have a more aggressive course and frequently show copy number gain of chromosome arm 12p encompassing the cyclin D2 (CCND2) locus.	('copy number gain', 'Var', (67, 83))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CCND2', 'Gene', (134, 139))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('cyclin D2', 'Gene', '894', (123, 132))	('CCND2', 'Gene', '894', (134, 139))	('cyclin D2', 'Gene', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
219837	30967140	In 2008, next-generation sequencing identified recurrent mutations in isocitrate dehydrogenase 1 (encoded by IDH1) in a subset of glioblastoma cases, mostly from younger patients with a history of prior lower-grade astrocytoma (clinically referred to as secondary glioblastoma).	('patients', 'Species', '9606', (170, 178))	('glioblastoma', 'Disease', (130, 142))	('isocitrate', 'Chemical', 'MESH:C034219', (70, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('IDH1', 'Gene', (109, 113))	('glioblastoma', 'Disease', (264, 276))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('mutations', 'Var', (57, 66))	('IDH1', 'Gene', '3417', (109, 113))	('astrocytoma', 'Disease', 'MESH:D001254', (215, 226))	('glioblastoma', 'Disease', 'MESH:D005909', (264, 276))	('astrocytoma', 'Disease', (215, 226))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('glioblastoma', 'Phenotype', 'HP:0012174', (264, 276))
219838	30967140	Subsequent studies showed that recurrent missense mutations involve IDH1 at position arginine 132, and less commonly in the homologous arginine 172 of IDH2.	('arginine', 'Chemical', 'MESH:D001120', (85, 93))	('IDH1', 'Gene', (68, 72))	('IDH2', 'Gene', (151, 155))	('missense mutations', 'Var', (41, 59))	('IDH1', 'Gene', '3417', (68, 72))	('IDH2', 'Gene', '3418', (151, 155))	('arginine', 'Chemical', 'MESH:D001120', (135, 143))
219839	30967140	Overall, IDH1 R132 and IDH2 R172 alterations occur in about 80-90% of adult WHO grade II or III infiltrating astrocytomas, oligodendrogliomas, and secondary glioblastoma.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (109, 120))	('glioblastoma', 'Disease', (157, 169))	('IDH1', 'Gene', (9, 13))	('astrocytomas', 'Disease', (109, 121))	('IDH2', 'Gene', (23, 27))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (123, 141))	('IDH1', 'Gene', '3417', (9, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('occur', 'Reg', (45, 50))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('alterations', 'Var', (33, 44))	('oligodendrogliomas', 'Disease', (123, 141))	('IDH2', 'Gene', '3418', (23, 27))	('astrocytomas', 'Disease', 'MESH:D001254', (109, 121))
219841	30967140	The mutant forms of IDH acquire a neomorphic activity and instead convert isocitrate to D-2-hydroxyglutarate, a so-called "oncometabolite" that builds to a very high level in tumor cells and interferes with several cellular processes, ultimately resulting in changes to DNA and histone methylation patterns that alter gene expression by establishing a glioma CpG island methylator phenotype (G-CIMP).	('tumor', 'Disease', (175, 180))	('IDH', 'Gene', (20, 23))	('mutant', 'Var', (4, 10))	('neomorphic activity', 'CPA', (34, 53))	('changes', 'Reg', (259, 266))	('IDH', 'Gene', '3417', (20, 23))	('G-CIMP', 'Chemical', '-', (392, 398))	('glioma', 'Disease', (352, 358))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (88, 108))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (352, 358))	('glioma', 'Disease', 'MESH:D005910', (352, 358))	('isocitrate', 'Chemical', 'MESH:C034219', (74, 84))
219842	30967140	The most common form of mutant IDH is a missense mutation in IDH1 converting arginine at position 132 to histidine (IDH1 R132H).	('mutant', 'Var', (24, 30))	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (116, 119))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (31, 34))	('R132H', 'Mutation', 'rs121913500', (121, 126))	('IDH1', 'Gene', (116, 120))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (116, 120))	('IDH1', 'Gene', '3417', (61, 65))	('missense mutation', 'Var', (40, 57))	('IDH', 'Gene', (61, 64))	('arginine at position 132 to histidine', 'Mutation', 'rs121913500', (77, 114))
219843	30967140	Immunopositivity for IDH1 R132H is sufficient to classify a glioma as "IDH-mutant".	('IDH', 'Gene', (21, 24))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('IDH', 'Gene', '3417', (21, 24))	('glioma', 'Disease', (60, 66))	('IDH', 'Gene', (71, 74))	('IDH1', 'Gene', (21, 25))	('R132H', 'Var', (26, 31))	('IDH', 'Gene', '3417', (71, 74))	('IDH1', 'Gene', '3417', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('R132H', 'Mutation', 'rs121913500', (26, 31))
219844	30967140	If the immunostain is negative, sequencing of IDH1 and IDH2 can be performed to assess for less common IDH1 mutations, or mutations in IDH2.	('IDH2', 'Gene', '3418', (55, 59))	('IDH2', 'Gene', (135, 139))	('IDH1', 'Gene', '3417', (103, 107))	('mutations', 'Var', (108, 117))	('IDH1', 'Gene', (46, 50))	('IDH2', 'Gene', '3418', (135, 139))	('IDH1', 'Gene', '3417', (46, 50))	('mutations', 'Var', (122, 131))	('IDH2', 'Gene', (55, 59))	('IDH1', 'Gene', (103, 107))
219847	30967140	Oligodendrogliomas now have a strict molecular definition and must show an IDH alteration and evidence for deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) for an integrated diagnosis.	('short arm', 'Phenotype', 'HP:0009824', (128, 137))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('IDH', 'Gene', '3417', (75, 78))	('IDH', 'Gene', (75, 78))	('deletion', 'Var', (107, 115))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
219849	30967140	Recently, evidence has amassed that FISH is insufficient to fully distinguish oligodendrogliomas from other brain tumors (usually glioblastoma) that harbor focal deletions of 1p and 19q and thus give false positive results on FISH analysis.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (78, 96))	('brain tumor', 'Phenotype', 'HP:0030692', (108, 119))	('glioblastoma', 'Disease', (130, 142))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('deletions', 'Var', (162, 171))	('oligodendrogliomas', 'Disease', (78, 96))	('brain tumors', 'Disease', 'MESH:D001932', (108, 120))	('brain tumors', 'Phenotype', 'HP:0030692', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('brain tumors', 'Disease', (108, 120))
219851	30967140	Another advantage is that this platform assesses genome-wide copy number changes, and alterations such as EGFR amplification, focal deletions on 9p encompassing CDKN2A/B, and focal or whole chromosome gains/losses can be detected.	('CDKN2A/B', 'Gene', (161, 169))	('gains/losses', 'PosReg', (201, 213))	('CDKN2A/B', 'Gene', '1029;1030', (161, 169))	('EGFR', 'Gene', '1956', (106, 110))	('deletions', 'Var', (132, 141))	('EGFR', 'Gene', (106, 110))
219854	30967140	Recurrent, mutually exclusive point mutations in the TERT promoter were originally discovered in melanoma, and subsequently identified in other tumors, including at a high frequency in primary glioblastoma and oligodendroglioma.	('tumors', 'Disease', (144, 150))	('point mutations', 'Var', (30, 45))	('TERT', 'Gene', (53, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('TERT', 'Gene', '7015', (53, 57))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('oligodendroglioma', 'Disease', (210, 227))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('oligodendroglioma', 'Disease', 'MESH:D009837', (210, 227))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('glioblastoma', 'Disease', (193, 205))	('discovered', 'Reg', (83, 93))
219855	30967140	Mechanistic studies later showed that TERT promoter mutations generate a cryptic binding site for an E26 transformation-specific (ETS) family transcription factor called GA-binding protein, alpha subunit (GABPA), leading to telomerase re-expression and subsequent telomere elongation.	('mutations', 'Var', (52, 61))	('GA-binding protein, alpha subunit', 'Gene', '2551', (170, 203))	('ETS', 'Chemical', '-', (130, 133))	('TERT', 'Gene', (38, 42))	('telomere elongation', 'CPA', (264, 283))	('telomerase', 'Protein', (224, 234))	('GABPA', 'Gene', '2551', (205, 210))	('TERT', 'Gene', '7015', (38, 42))	('binding', 'Interaction', (81, 88))	('GABPA', 'Gene', (205, 210))
219857	30967140	Epigenetic mechanisms can also regulate TERT expression, and this may have prognosis in certain pediatric brain tumors, where TERT promoter mutations are rare.	('TERT', 'Gene', '7015', (40, 44))	('brain tumors', 'Phenotype', 'HP:0030692', (106, 118))	('TERT', 'Gene', (126, 130))	('brain tumors', 'Disease', 'MESH:D001932', (106, 118))	('regulate', 'Reg', (31, 39))	('Epigenetic', 'Var', (0, 10))	('TERT', 'Gene', '7015', (126, 130))	('brain tumors', 'Disease', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('brain tumor', 'Phenotype', 'HP:0030692', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('TERT', 'Gene', (40, 44))
219859	30967140	In contrast to oligodendrogliomas and IDH-wildtype glioblastoma, TERT promoter mutations are rare in IDH-mutant astrocytomas, which instead maintain telomere length through a mechanism involving mutations in the ATRX gene, usually accompanied by mutations in TP53.	('astrocytomas', 'Disease', (112, 124))	('ATRX', 'Gene', (212, 216))	('ATRX', 'Gene', '546', (212, 216))	('TP53', 'Gene', (259, 263))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (15, 33))	('mutations', 'Var', (79, 88))	('maintain', 'PosReg', (140, 148))	('astrocytomas', 'Disease', 'MESH:D001254', (112, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('astrocytoma', 'Phenotype', 'HP:0009592', (112, 123))	('IDH', 'Gene', (38, 41))	('oligodendrogliomas', 'Disease', (15, 33))	('TP53', 'Gene', '7157', (259, 263))	('IDH-wildtype glioblastoma', 'Disease', 'MESH:D005909', (38, 63))	('TERT', 'Gene', (65, 69))	('IDH', 'Gene', (101, 104))	('TERT', 'Gene', '7015', (65, 69))	('mutations', 'Var', (195, 204))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('IDH-wildtype glioblastoma', 'Disease', (38, 63))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('IDH', 'Gene', '3417', (38, 41))	('telomere length', 'MPA', (149, 164))	('IDH', 'Gene', '3417', (101, 104))
219861	30967140	ATRX alterations strongly correlate with a phenotype called alternative lengthening of telomeres (ALT), characterized by increased telomere homologous recombination and subsequent telomere elongation.	('ATRX', 'Gene', (0, 4))	('increased', 'PosReg', (121, 130))	('alterations', 'Var', (5, 16))	('ALT', 'Chemical', '-', (98, 101))	('telomere elongation', 'CPA', (180, 199))	('ATRX', 'Gene', '546', (0, 4))	('telomere homologous recombination', 'CPA', (131, 164))	('alternative lengthening', 'CPA', (60, 83))
219862	30967140	Within brain tumors, the ALT phenotype is frequent in IDH-mutant astrocytomas and histone H3 mutant gliomas.	('brain tumors', 'Disease', (7, 19))	('frequent', 'Reg', (42, 50))	('ALT', 'Disease', (25, 28))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('astrocytomas', 'Disease', 'MESH:D001254', (65, 77))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('IDH', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('brain tumor', 'Phenotype', 'HP:0030692', (7, 18))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('histone H3', 'Protein', (82, 92))	('brain tumors', 'Phenotype', 'HP:0030692', (7, 19))	('IDH', 'Gene', '3417', (54, 57))	('brain tumors', 'Disease', 'MESH:D001932', (7, 19))	('mutant', 'Var', (93, 99))	('astrocytomas', 'Disease', (65, 77))	('ALT', 'Chemical', '-', (25, 28))	('gliomas', 'Disease', (100, 107))
219866	30967140	In astrocytomas, ATRX mutations are usually accompanied by loss of nuclear staining for ATRX protein, and TP53 mutations result in stabilization of the p53 protein leading to strong nuclear staining in a significant proportion of tumor nuclei (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (3, 14))	('p53', 'Gene', '7157', (152, 155))	('loss', 'NegReg', (59, 63))	('mutations', 'Var', (111, 120))	('p53', 'Gene', (152, 155))	('astrocytomas', 'Disease', 'MESH:D001254', (3, 15))	('TP53', 'Gene', (106, 110))	('result in', 'Reg', (121, 130))	('tumor', 'Disease', (230, 235))	('ATRX', 'Gene', (17, 21))	('nuclear staining', 'MPA', (182, 198))	('ATRX', 'Gene', '546', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mutations', 'Var', (22, 31))	('stabilization', 'MPA', (131, 144))	('ATRX', 'Gene', (88, 92))	('ATRX', 'Gene', '546', (88, 92))	('nuclear staining', 'MPA', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('astrocytomas', 'Disease', (3, 15))	('TP53', 'Gene', '7157', (106, 110))
219868	30967140	Also, not all ATRX mutations are associated with loss of nuclear staining, so in a tumor with classic astrocytoma histology and a confirmed IDH1 or IDH2 mutation, positive nuclear staining for ATRX does not exclude the diagnosis of astrocytoma.	('IDH1', 'Gene', '3417', (140, 144))	('astrocytoma', 'Disease', (102, 113))	('ATRX', 'Gene', '546', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('IDH2', 'Gene', '3418', (148, 152))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('tumor', 'Disease', (83, 88))	('ATRX', 'Gene', (14, 18))	('astrocytoma', 'Disease', 'MESH:D001254', (232, 243))	('IDH1', 'Gene', (140, 144))	('astrocytoma', 'Disease', (232, 243))	('ATRX', 'Gene', '546', (14, 18))	('ATRX', 'Gene', (193, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (232, 243))	('IDH2', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('astrocytoma', 'Disease', 'MESH:D001254', (102, 113))	('mutation', 'Var', (153, 161))
219870	30967140	Most TP53 mutations are missense mutations that result in nuclear accumulation of the protein.	('nuclear accumulation of the protein', 'MPA', (58, 93))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('mutations', 'Var', (10, 19))	('result in', 'Reg', (48, 57))
219871	30967140	However, this immunostaining pattern is neither sensitive nor specific for a TP53 mutation and the result must be interpreted in context with morphology and other immunohistochemical and molecular findings.	('mutation', 'Var', (82, 90))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
219872	30967140	In one series of 157 diffuse gliomas, a cutoff of strong nuclear p53 reactivity in > 10% of tumor nuclei had a positive predictive value of 94.5% and negative predictive value of 86.3% for predicting TP53 mutation status.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('reactivity', 'MPA', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('diffuse gliomas', 'Disease', 'MESH:D005910', (21, 36))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('TP53', 'Gene', '7157', (200, 204))	('mutation status', 'Var', (205, 220))	('TP53', 'Gene', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('diffuse gliomas', 'Disease', (21, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('tumor', 'Disease', (92, 97))
219873	30967140	Within brain tumors, TP53 mutations can be seen in IDH-wildtype glioblastomas, occasional circumscribed gliomas, embryonal tumors including medulloblastoma, other rare primary brain tumors such as choroid plexus neoplasms, and in metastatic tumors.	('TP53', 'Gene', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('embryonal tumor', 'Phenotype', 'HP:0002898', (113, 128))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('mutations', 'Var', (26, 35))	('embryonal tumors', 'Disease', (113, 129))	('embryonal tumors', 'Phenotype', 'HP:0002898', (113, 129))	('brain tumors', 'Disease', 'MESH:D001932', (176, 188))	('brain tumors', 'Phenotype', 'HP:0030692', (176, 188))	('embryonal tumors', 'Disease', 'MESH:D009373', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('medulloblastoma', 'Disease', 'MESH:D008527', (140, 155))	('brain tumor', 'Phenotype', 'HP:0030692', (176, 187))	('medulloblastoma', 'Phenotype', 'HP:0002885', (140, 155))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', (182, 188))	('choroid plexus neoplasms', 'Disease', 'MESH:D020288', (197, 221))	('medulloblastoma', 'Disease', (140, 155))	('seen', 'Reg', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('brain tumor', 'Phenotype', 'HP:0030692', (7, 18))	('TP53', 'Gene', '7157', (21, 25))	('gliomas', 'Disease', (104, 111))	('brain tumors', 'Disease', (176, 188))	('IDH-wildtype glioblastomas', 'Disease', (51, 77))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('glioblastomas', 'Phenotype', 'HP:0012174', (64, 77))	('tumors', 'Disease', (13, 19))	('choroid plexus neoplasms', 'Disease', (197, 221))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('brain tumors', 'Phenotype', 'HP:0030692', (7, 19))	('brain tumors', 'Disease', 'MESH:D001932', (7, 19))	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (51, 77))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('neoplasms', 'Phenotype', 'HP:0002664', (212, 221))	('tumors', 'Disease', (241, 247))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('brain tumors', 'Disease', (7, 19))	('neoplasm', 'Phenotype', 'HP:0002664', (212, 220))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
219875	30967140	Finally, absence of nuclear p53 staining does not exclude a TP53 mutation since truncating or splice site TP53 mutations are a mechanism for loss of p53 function, and this leads to loss of nuclear immunoreactivity due to decreased or absent protein expression.	('p53', 'Gene', (28, 31))	('mutations', 'Var', (111, 120))	('truncating', 'MPA', (80, 90))	('p53', 'Gene', (149, 152))	('protein', 'Protein', (241, 248))	('absent', 'NegReg', (234, 240))	('p53', 'Gene', '7157', (28, 31))	('loss', 'NegReg', (141, 145))	('p53', 'Gene', '7157', (149, 152))	('TP53', 'Gene', (106, 110))	('TP53', 'Gene', '7157', (60, 64))	('nuclear immunoreactivity', 'MPA', (189, 213))	('loss', 'NegReg', (181, 185))	('TP53', 'Gene', (60, 64))	('TP53', 'Gene', '7157', (106, 110))	('function', 'MPA', (153, 161))
219882	30967140	Amplification of double minute chromosomes of the epidermal growth factor receptor gene (EGFR) is a frequent event in IDH-wildtype glioblastomas, while EGFR point mutations are comparatively rare.	('IDH-wildtype glioblastomas', 'Disease', 'MESH:D005909', (118, 144))	('Amplification', 'Var', (0, 13))	('EGFR', 'Gene', (89, 93))	('epidermal growth factor receptor', 'Gene', '1956', (50, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('IDH-wildtype glioblastomas', 'Disease', (118, 144))	('EGFR', 'Gene', '1956', (152, 156))	('glioblastomas', 'Phenotype', 'HP:0012174', (131, 144))	('EGFR', 'Gene', (152, 156))	('epidermal growth factor receptor', 'Gene', (50, 82))	('EGFR', 'Gene', '1956', (89, 93))
219883	30967140	The EGFR gene also commonly incurs an intragenic deletion of exons 2-7 producing a constitutively active variant protein called EGFR-vIII, occurring in a quarter to half of glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (173, 185))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('incurs', 'Reg', (28, 34))	('vIII', 'Gene', (133, 137))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', (128, 132))	('EGFR', 'Gene', '1956', (128, 132))	('deletion', 'Var', (49, 57))	('vIII', 'Gene', '1351', (133, 137))	('glioblastoma', 'Disease', (173, 185))	('EGFR', 'Gene', '1956', (4, 8))
219885	30967140	Concomitant chromosome 7p gain combined with chromosome 10q loss is the most frequent genetic alteration in glioblastoma, with almost half showing both alterations; a large fraction of EGFR amplification occurs on a background of chromosome 7 polysomy and chromosome 10 monosomy.	('amplification', 'Var', (190, 203))	('EGFR', 'Gene', (185, 189))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('loss', 'NegReg', (60, 64))	('glioblastoma', 'Disease', (108, 120))	('polysomy', 'Var', (243, 251))	('gain', 'PosReg', (26, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('EGFR', 'Gene', '1956', (185, 189))
219887	30967140	Methylation of the MGMT promoter region is associated with silencing of gene expression, and occurs in about 40-50% of glioblastoma cases.	('glioblastoma', 'Disease', (119, 131))	('silencing', 'MPA', (59, 68))	('Methylation', 'Var', (0, 11))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('associated', 'Reg', (43, 53))	('occurs', 'Reg', (93, 99))
219892	30967140	The deleted region for EGFR-vIII is small, at only 13 kilobases, and therefore not amenable to FISH, and furthermore mosaicism complicates microarray detection and interpretation, particularly against the background of an amplified gene.	('vIII', 'Gene', '1351', (28, 32))	('mosaicism', 'Var', (117, 126))	('EGFR', 'Gene', '1956', (23, 27))	('vIII', 'Gene', (28, 32))	('EGFR', 'Gene', (23, 27))	('complicates', 'Reg', (127, 138))
219896	30967140	Traditional FISH using a PTEN probe will not detect DMBT1 deletion; SNP microarray will.	('DMBT1', 'Gene', '1755', (52, 57))	('deletion', 'Var', (58, 66))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))	('DMBT1', 'Gene', (52, 57))
219897	30967140	Copy number neutral loss of heterozygosity (LOH) is another common event in glioblastoma and can be detected using SNP chromosomal microarray.	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('loss of', 'NegReg', (20, 27))	('Copy number neutral', 'Var', (0, 19))	('glioblastoma', 'Disease', (76, 88))
219898	30967140	LOH can uncover recessive mutations due to the transfer of one recessive allele onto both chromosome homologues via chromosomal crossover events, and LOH of 17p, including the TP53 gene, is a frequent event.	('LOH', 'Var', (150, 153))	('TP53', 'Gene', '7157', (176, 180))	('TP53', 'Gene', (176, 180))
219905	30967140	Two categories of histone mutations have been identified in brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('brain tumors', 'Disease', 'MESH:D001932', (60, 72))	('brain tumors', 'Phenotype', 'HP:0030692', (60, 72))	('brain tumors', 'Disease', (60, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (26, 35))	('identified', 'Reg', (46, 56))	('histone', 'Protein', (18, 25))
219906	30967140	Sequencing studies of pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas identified recurrent mutations causing a lysine to methionine substitution at position 27 -- hereafter K27M -- in H3F3A and HIST1H3B/C, which are hereafter grouped as H3 to encompass H3.3 and H3.1.	('gliomas', 'Disease', (58, 65))	('H3F3A', 'Gene', '3020', (212, 217))	('HIST1H3B', 'Gene', (222, 230))	('HIST1H3B', 'Gene', '8358', (222, 230))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('glioblastomas', 'Disease', (84, 97))	('lysine to methionine substitution at position 27', 'Mutation', 'p.K27M', (139, 187))	('brainstem glioblastomas', 'Phenotype', 'HP:0010796', (74, 97))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('mutations', 'Var', (119, 128))	('glioblastomas', 'Disease', 'MESH:D005909', (84, 97))	('H3F3A', 'Gene', (212, 217))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('causing', 'Reg', (129, 136))	('K27M --', 'Var', (201, 208))	('lysine', 'MPA', (139, 145))	('K27M', 'Mutation', 'p.K27M', (201, 205))	('glioblastomas', 'Phenotype', 'HP:0012174', (84, 97))
219907	30967140	Very rare alternative alterations include a lysine to isoleucine alteration in H3F3A, and a K27M alteration in histone H2 variant encoded by HIST2H3C.	('K27M alteration', 'Var', (92, 107))	('HIST2H3C', 'Gene', '126961', (141, 149))	('H3F3A', 'Gene', '3020', (79, 84))	('HIST2H3C', 'Gene', (141, 149))	('histone H2', 'Protein', (111, 121))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('H3F3A', 'Gene', (79, 84))	('isoleucine', 'Chemical', 'MESH:D007532', (54, 64))	('lysine to isoleucine alteration', 'Var', (44, 75))	('K27M', 'Mutation', 'p.K27M', (92, 96))
219908	30967140	The H3 K27M mutant protein has a dominant negative effect on the enhancer of zest 2 (EZH2) methyltransferase protein, which is a component of the polycomb repressive complex normally responsible for H3 K27 trimethylation.	('EZH2', 'Gene', '2146', (85, 89))	('enhancer', 'PosReg', (65, 73))	('EZH2', 'Gene', (85, 89))	('K27M', 'Mutation', 'p.K27M', (7, 11))	('negative', 'NegReg', (42, 50))	('H3 K27M', 'Var', (4, 11))	('protein', 'Protein', (19, 26))
219909	30967140	Since the methionine residue of H3 K27M cannot be methylated, and also inhibits EZH2, the result is global alterations histone methylation and consequent dysregulation of gene expression.	('H3 K27M', 'Var', (32, 39))	('histone methylation', 'MPA', (119, 138))	('dysregulation', 'Reg', (154, 167))	('alterations', 'Reg', (107, 118))	('gene expression', 'MPA', (171, 186))	('EZH2', 'Gene', (80, 84))	('EZH2', 'Gene', '2146', (80, 84))	('methionine', 'Chemical', 'MESH:D008715', (10, 20))	('K27M', 'Mutation', 'p.K27M', (35, 39))	('inhibits', 'NegReg', (71, 79))
219910	30967140	The H3 K27M alteration has since been identified in midline gliomas across a spectrum of ages and tumor locations, including the third ventricle, pineal region, cerebellum, and spinal cord.	('midline gliomas', 'Disease', (52, 67))	('identified', 'Reg', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('midline gliomas', 'Disease', 'MESH:D005910', (52, 67))	('K27M', 'Mutation', 'p.K27M', (7, 11))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('H3 K27M', 'Var', (4, 11))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
219911	30967140	The WHO 2016 recognizes H3 K27M-mutant diffuse gliomas as a distinct molecular entity, and importantly these tumors correspond to WHO grade IV regardless of their histologic grade.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('diffuse gliomas', 'Disease', 'MESH:D005910', (39, 54))	('K27M', 'Mutation', 'p.K27M', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('diffuse gliomas', 'Disease', (39, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('H3 K27M-mutant', 'Var', (24, 38))	('tumors', 'Disease', (109, 115))
219912	30967140	The integrated diagnosis for these tumors is "Diffuse midline glioma, H3 K27M-mutant, WHO grade IV".	('H3 K27M-mutant', 'Var', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('midline glioma', 'Disease', 'MESH:D005910', (54, 68))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('K27M', 'Mutation', 'p.K27M', (73, 77))	('tumors', 'Disease', (35, 41))	('midline glioma', 'Disease', (54, 68))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
219914	30967140	Three examples of histone H3 mutant glioma are presented in Fig.	('mutant', 'Var', (29, 35))	('glioma', 'Disease', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('histone H3', 'Protein', (18, 28))
219915	30967140	5, with H3 K27M-mutant tumors of the midbrain and thalamus presented in panels A-D and E-H, respectively.	('presented', 'Reg', (59, 68))	('H3 K27M-mutant', 'Var', (8, 22))	('K27M', 'Mutation', 'p.K27M', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors of the midbrain', 'Disease', 'MESH:D020295', (23, 45))	('tumors of the midbrain', 'Disease', (23, 45))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
219917	30967140	However, since the K27M epitope is in a highly conserved region of the histone H3 family, the antibody does not distinguish mutations in H3F3A (H3.3-mutant) from HIST1H3B/C (H3.1-mutant).	('H3F3A', 'Gene', '3020', (137, 142))	('mutations', 'Var', (124, 133))	('H3F3A', 'Gene', (137, 142))	('HIST1H3B', 'Gene', (162, 170))	('HIST1H3B', 'Gene', '8358', (162, 170))	('K27M', 'Mutation', 'p.K27M', (19, 23))
219919	30967140	Because the H3 K27M mutant protein suppresses histone H3 trimethylation by mechanisms described above, expression of H3 K27M is associated with global reduction of histone H3 lysine position 27 trimethylation (H3 K27me3).	('histone H3 lysine position 27 trimethylation', 'MPA', (164, 208))	('K27M', 'Mutation', 'p.K27M', (120, 124))	('H3 K27M', 'Var', (12, 19))	('protein', 'Protein', (27, 34))	('histone H3 trimethylation', 'MPA', (46, 71))	('lysine', 'Chemical', 'MESH:D008239', (175, 181))	('reduction', 'NegReg', (151, 160))	('suppresses', 'NegReg', (35, 45))	('H3 K27M', 'Var', (117, 124))	('K27M', 'Mutation', 'p.K27M', (15, 19))
219920	30967140	5d), which reveals global loss of nuclear H3 K27me3 reactivity in tumor cells, however this is less specific than expression of the mutant protein, with the most common pitfall being focal loss of H3 K27me3 in atypical teratoid/rhabdoid tumor.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('H3 K27me3', 'Var', (197, 206))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (66, 71))	('rhabdoid tumor', 'Disease', (228, 242))	('H3 K27me3', 'Protein', (42, 51))	('fall', 'Phenotype', 'HP:0002527', (172, 176))	('loss', 'NegReg', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('loss', 'NegReg', (189, 193))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (228, 242))
219923	30967140	In practice, most H3 K27M-mutant diffuse midline gliomas will show both positive nuclear staining for H3 K27M mutant protein, and a corresponding loss of nuclear staining for H3 K27me3.	('loss', 'NegReg', (146, 150))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('H3 K27M-mutant', 'Var', (18, 32))	('nuclear staining', 'MPA', (154, 170))	('K27M', 'Mutation', 'p.K27M', (21, 25))	('protein', 'Protein', (117, 124))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('H3 K27M mutant', 'Var', (102, 116))	('midline gliomas', 'Disease', (41, 56))	('K27M', 'Mutation', 'p.K27M', (105, 109))	('midline gliomas', 'Disease', 'MESH:D005910', (41, 56))
219925	30967140	For H3 K27me3, non-neoplastic cellular components should be nuclear positive, and the tumor nuclei should be negative (Fig.	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('H3 K27me3', 'Var', (4, 13))
219926	30967140	When the WHO 2016 was published, H3 K27M mutations were thought to be specific for diffuse midline gliomas.	('H3 K27M mutations', 'Var', (33, 50))	('midline gliomas', 'Disease', (91, 106))	('midline gliomas', 'Disease', 'MESH:D005910', (91, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('K27M', 'Mutation', 'p.K27M', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
219927	30967140	However, H3 K27M mutations have now been reported in midline circumscribed gliomas such as ganglioglioma, pilocytic astrocytoma, unspecified glioneuronal tumors, and ependymoma, and in some series the clinical behavior of these tumors is more aggressive than histologically comparable H3 K27-wildtype counterparts, although it is not as dismal as for diffuse gliomas.	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (116, 127))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (141, 160))	('gliomas', 'Phenotype', 'HP:0009733', (359, 366))	('glioneuronal tumors', 'Disease', (141, 160))	('ependymoma', 'Disease', (166, 176))	('glioma', 'Disease', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('neuronal tumor', 'Phenotype', 'HP:0025170', (145, 159))	('diffuse gliomas', 'Disease', (351, 366))	('mutations', 'Var', (17, 26))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('glioma', 'Disease', (359, 365))	('reported', 'Reg', (41, 49))	('ependymoma', 'Phenotype', 'HP:0002888', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('glioma', 'Disease', 'MESH:D005910', (359, 365))	('tumors', 'Disease', (228, 234))	('glioma', 'Disease', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('unspecified', 'Species', '32644', (129, 140))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('ependymoma', 'Disease', 'MESH:D004806', (166, 176))	('midline circumscribed gliomas', 'Disease', (53, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('glioma', 'Phenotype', 'HP:0009733', (359, 365))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (106, 127))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('tumors', 'Disease', (154, 160))	('pilocytic astrocytoma', 'Disease', (106, 127))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('diffuse gliomas', 'Disease', 'MESH:D005910', (351, 366))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (141, 160))	('K27M', 'Mutation', 'p.K27M', (12, 16))	('midline circumscribed gliomas', 'Disease', 'MESH:D005910', (53, 82))
219928	30967140	Intriguingly, H3 K27M mutations can co-occur with BRAF V600E, a common driver alteration in a variety of circumscribed gliomas and glioneuronal tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('K27M', 'Mutation', 'p.K27M', (17, 21))	('BRAF', 'Gene', (50, 54))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (131, 150))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glioneuronal tumors', 'Disease', (131, 150))	('gliomas', 'Disease', (119, 126))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (131, 150))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('neuronal tumor', 'Phenotype', 'HP:0025170', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('H3 K27M mutations', 'Var', (14, 31))	('BRAF', 'Gene', '673', (50, 54))	('V600E', 'Mutation', 'rs113488022', (55, 60))
219929	30967140	In practice, this means that evidence for a H3 K27M mutation does not necessarily define the integrated diagnosis of diffuse midline glioma, WHO grade IV.	('midline glioma', 'Disease', 'MESH:D005910', (125, 139))	('K27M', 'Mutation', 'p.K27M', (47, 51))	('midline glioma', 'Disease', (125, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('H3 K27M', 'Var', (44, 51))
219930	30967140	The histologic context still matters: tumors must be definitively midline, diffusely infiltrating gliomas with a K27M alteration to qualify for the integrated diagnosis.	('K27M alteration', 'Var', (113, 128))	('K27M', 'Mutation', 'p.K27M', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))
219932	30967140	H3F3A mutations also occur at guanine position 34, substituting arginine (G34R) or valine (G34V - hereafter G34R/V) in histone H3.3, and an example of this is provided in Fig.	('valine', 'Chemical', 'MESH:D014633', (83, 89))	('G34R', 'Mutation', 'rs1057519902', (108, 112))	('substituting', 'Reg', (51, 63))	('arginine', 'Chemical', 'MESH:D001120', (64, 72))	('H3F3A', 'Gene', '3020', (0, 5))	('G34R', 'SUBSTITUTION', 'None', (108, 112))	('histone H3.3', 'Gene', '3021', (119, 131))	('H3F3A', 'Gene', (0, 5))	('G34V', 'Mutation', 'p.G34V', (91, 95))	('G34R', 'Var', (108, 112))	('histone H3.3', 'Gene', (119, 131))	('G34R', 'Mutation', 'rs1057519902', (74, 78))	('guanine', 'Chemical', 'MESH:D006147', (30, 37))	('G34R', 'SUBSTITUTION', 'None', (74, 78))	('G34V -', 'Var', (91, 97))	('G34R', 'Var', (74, 78))	('mutations', 'Var', (6, 15))
219933	30967140	5, panels I through M. Unlike H3 K27M, the H3.3 G34R/V alteration has not been identified in the histone H3.1 isoforms encoded by HIST1H3B/C.	('HIST1H3B', 'Gene', (130, 138))	('HIST1H3B', 'Gene', '8358', (130, 138))	('G34R', 'SUBSTITUTION', 'None', (48, 52))	('G34R', 'Var', (48, 52))	('histone H3.1', 'Gene', (97, 109))	('histone H3.1', 'Gene', '8352', (97, 109))	('K27M', 'Mutation', 'p.K27M', (33, 37))
219934	30967140	The H3.3 G34R/V mutant tumors typically occur in the cerebral hemispheres in adolescents and young adults, and in a series of 81 cases almost always show loss of ATRX by immunohistochemistry (95%), as well as TP53 mutation (88%).	('tumors', 'Disease', (23, 29))	('TP53', 'Gene', (209, 213))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('ATRX', 'Gene', '546', (162, 166))	('G34R', 'SUBSTITUTION', 'None', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ATRX', 'Gene', (162, 166))	('G34R', 'Var', (9, 13))	('H3.3', 'Gene', (4, 8))	('loss', 'NegReg', (154, 158))	('TP53', 'Gene', '7157', (209, 213))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
219935	30967140	Since the H3.3 G34R/V alteration is mutually exclusive with IDH mutations, H3.3 G34R/V should be considered in a hemispheric diffuse glioma that shows loss of ATRX but is proven by sequencing to be IDH1 and IDH2 wildtype.	('ATRX', 'Gene', '546', (159, 163))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('G34R', 'SUBSTITUTION', 'None', (80, 84))	('G34R', 'SUBSTITUTION', 'None', (15, 19))	('IDH', 'Gene', (207, 210))	('G34R', 'Var', (80, 84))	('G34R', 'Var', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('IDH1', 'Gene', (198, 202))	('IDH', 'Gene', (198, 201))	('IDH', 'Gene', '3417', (207, 210))	('IDH', 'Gene', (60, 63))	('IDH1', 'Gene', '3417', (198, 202))	('IDH2', 'Gene', (207, 211))	('IDH', 'Gene', '3417', (198, 201))	('IDH2', 'Gene', '3418', (207, 211))	('glioma', 'Disease', (133, 139))	('ATRX', 'Gene', (159, 163))	('IDH', 'Gene', '3417', (60, 63))
219936	30967140	About one third of the H3.3 G34R/V mutant tumors show primitive neuronal features, with monomorphic cells showing a high nuclear to cytoplasmic ratio and largely lacking vascular proliferation or necrosis, and regardless of their histologic pattern (i.e.	('necrosis', 'Disease', 'MESH:D009336', (196, 204))	('G34R', 'SUBSTITUTION', 'None', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('G34R', 'Var', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutant', 'Var', (35, 41))	('primitive neuronal features', 'CPA', (54, 81))	('necrosis', 'Disease', (196, 204))
219938	30967140	An H3.3 G34R/V mutant tumor should also be considered in the differential diagnosis of a central nervous system primitive neuronal tumor, even if the typical glial markers are negative or focal/patchy.	('neuronal tumor', 'Disease', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('neuronal tumor', 'Phenotype', 'HP:0025170', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (131, 136))	('G34R', 'SUBSTITUTION', 'None', (8, 12))	('neuronal tumor', 'Disease', 'MESH:D009410', (122, 136))	('G34R', 'Var', (8, 12))	('tumor', 'Disease', (22, 27))	('H3.3', 'Gene', (3, 7))
219939	30967140	Most H3.3 G34R/V mutant tumors are MGMT promoter hypermethylated, which may contribute to a slightly better outcome in this group of tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('G34R', 'SUBSTITUTION', 'None', (10, 14))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', (133, 139))	('H3.3', 'Gene', (5, 9))	('G34R', 'Var', (10, 14))	('MGMT', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('MGMT', 'Gene', '4255', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('better', 'PosReg', (101, 107))
219940	30967140	Since the H3.3 G34R/V is not currently a separate integrated diagnostic entity, these cases would be reported as astrocytomas of the appropriate histologic grade along with the "not elsewhere classified" modifier, and the molecular result of H3F3A G34R/V status should be reported.	('H3F3A', 'Gene', (242, 247))	('astrocytoma', 'Phenotype', 'HP:0009592', (113, 124))	('G34R', 'SUBSTITUTION', 'None', (248, 252))	('astrocytomas', 'Disease', (113, 125))	('G34R', 'Var', (248, 252))	('G34R', 'SUBSTITUTION', 'None', (15, 19))	('H3F3A', 'Gene', '3020', (242, 247))	('G34R', 'Var', (15, 19))	('astrocytomas', 'Disease', 'MESH:D001254', (113, 125))
219941	30967140	The more general designation of astrocytic glioma, IDH-wildtype is not applicable since proven H3 G34R/V-mutant diffuse gliomas have another disease-defining molecular alteration and distinct clinical features.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH', 'Gene', (51, 54))	('diffuse gliomas', 'Disease', 'MESH:D005910', (112, 127))	('IDH', 'Gene', '3417', (51, 54))	('astrocytic glioma', 'Disease', 'MESH:D001254', (32, 49))	('astrocytic glioma', 'Disease', (32, 49))	('diffuse gliomas', 'Disease', (112, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('G34R', 'SUBSTITUTION', 'None', (98, 102))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('G34R', 'Var', (98, 102))
219942	30967140	Mutation-specific antibodies to detect H3.3 G34R or G34V mutant protein are in use at a few academic centers.	('G34R', 'Mutation', 'rs1057519902', (44, 48))	('G34V', 'Mutation', 'p.G34V', (52, 56))	('G34V', 'Var', (52, 56))	('H3.3', 'Protein', (39, 43))	('G34R', 'Var', (44, 48))
219950	30967140	Per these recommendations, diffuse astrocytic gliomas qualify for this designation with evidence of one or more of the following molecular alterations: (1) EGFR amplification, (2) TERT promoter mutation, and (3) whole-chromosome 7 gain combined with whole chromosome 10 loss (hereafter + 7/- 10).	('EGFR', 'Gene', '1956', (156, 160))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (35, 53))	('loss', 'NegReg', (270, 274))	('astrocytic gliomas', 'Disease', (35, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gain', 'PosReg', (231, 235))	('EGFR', 'Gene', (156, 160))	('amplification', 'Var', (161, 174))	('TERT', 'Gene', (180, 184))	('TERT', 'Gene', '7015', (180, 184))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
219954	30967140	As a molecular signature of glioblastoma in that series, EGFR amplification is the most specific but least sensitive marker, with 99.8% specificity and 36.0% sensitivity.	('glioblastoma', 'Disease', (28, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('EGFR', 'Gene', '1956', (57, 61))	('amplification', 'Var', (62, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('EGFR', 'Gene', (57, 61))
219955	30967140	In this context, EGFR amplification refers to high level copy number gains; low level copy number gains and immunohistochemical expression of EGFR are not sufficiently specific for this purpose.	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('amplification', 'Var', (22, 35))	('EGFR', 'Gene', '1956', (17, 21))	('copy', 'MPA', (57, 61))	('EGFR', 'Gene', (17, 21))
219956	30967140	The + 7/- 10 chromosomal alteration is also relatively specific (98.0%) and was more sensitive that EGFR amplification (59.4%).	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))	('+ 7/- 10 chromosomal alteration', 'Var', (4, 35))
219957	30967140	Although partial arm deletions and various combinations of chromosomes 7 gain and 10 loss may be seen in glioblastoma, partial arm alterations are not considered sufficient by cIMPACT-NOW criteria at this time.	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('gain', 'PosReg', (73, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('partial arm deletions', 'Var', (9, 30))	('loss', 'NegReg', (85, 89))	('glioblastoma', 'Disease', (105, 117))
219958	30967140	Finally, TERT promoter mutations have a clear association with aggressive behavior in the setting of glioblastoma, and this is the most sensitive (66.7%) but least specific (89.4%) parameter, largely since TERT promoter mutations can be seen in other gliomas or systemic cancers.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('association', 'Interaction', (46, 57))	('aggressive behavior', 'CPA', (63, 82))	('gliomas', 'Disease', 'MESH:D005910', (251, 258))	('glioblastoma', 'Disease', (101, 113))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('mutations', 'Var', (23, 32))	('gliomas', 'Phenotype', 'HP:0009733', (251, 258))	('systemic cancers', 'Disease', (262, 278))	('systemic cancers', 'Disease', 'MESH:D009369', (262, 278))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))	('TERT', 'Gene', (206, 210))	('TERT', 'Gene', '7015', (206, 210))	('gliomas', 'Disease', (251, 258))	('aggressive behavior', 'Phenotype', 'HP:0000718', (63, 82))
219962	30967140	The presence of H3 K27M in an infiltrative astrocytoma is diagnostic of diffuse midline glioma, H3 K27-mutant, a separate molecularly defined entity.	('astrocytoma', 'Disease', (43, 54))	('midline glioma', 'Disease', 'MESH:D005910', (80, 94))	('astrocytoma', 'Phenotype', 'HP:0009592', (43, 54))	('H3 K27M', 'Var', (16, 23))	('midline glioma', 'Disease', (80, 94))	('H3 K27-mutant', 'Var', (96, 109))	('astrocytoma', 'Disease', 'MESH:D001254', (43, 54))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('K27M', 'Mutation', 'p.K27M', (19, 23))
219963	30967140	Similarly, the IDH-wildtype gliomas with histone H3.3 G34R/V mutation should be considered, especially in younger patients.	('IDH-wildtype gliomas', 'Disease', (15, 35))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH-wildtype gliomas', 'Disease', 'MESH:D005910', (15, 35))	('histone H3.3', 'Gene', '3021', (41, 53))	('G34R', 'SUBSTITUTION', 'None', (54, 58))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('G34R', 'Var', (54, 58))	('histone H3.3', 'Gene', (41, 53))	('patients', 'Species', '9606', (114, 122))
219964	30967140	Emerging molecular entities such as diffuse astrocytomas with MYB/MYBL fusion, FGFR1 or FGFR3 alterations, or BRAF alterations are associated with a more indolent clinical course, but do not yet have their own diagnostic categorization and would appear as IDH-wildtype.	('astrocytoma', 'Phenotype', 'HP:0009592', (44, 55))	('FGFR3', 'Gene', (88, 93))	('IDH', 'Gene', '3417', (256, 259))	('MYB', 'Gene', (66, 69))	('alterations', 'Var', (94, 105))	('astrocytomas', 'Disease', (44, 56))	('FGFR1', 'Gene', (79, 84))	('alterations', 'Var', (115, 126))	('BRAF', 'Gene', '673', (110, 114))	('IDH', 'Gene', (256, 259))	('FGFR1', 'Gene', '2260', (79, 84))	('FGFR3', 'Gene', '2261', (88, 93))	('astrocytomas', 'Disease', 'MESH:D001254', (44, 56))	('MYB', 'Gene', '4602', (62, 65))	('MYB', 'Gene', (62, 65))	('BRAF', 'Gene', (110, 114))	('MYB', 'Gene', '4602', (66, 69))
219965	30967140	Recently, through DNA methylation profiling of histologically defined anaplastic pilocytic astrocytoma, Reinhardt et al defined the entity of anaplastic astrocytoma with piloid features, a category of IDH-wildtype astrocytoma with piloid morphology and frequent MAPK pathway alterations, loss of CDKN2A/B, and loss of ATRX.	('astrocytoma', 'Phenotype', 'HP:0009592', (214, 225))	('IDH-wildtype astrocytoma', 'Disease', 'MESH:D001254', (201, 225))	('IDH-wildtype astrocytoma', 'Disease', (201, 225))	('CDKN2A/B', 'Gene', '1029;1030', (296, 304))	('loss', 'NegReg', (310, 314))	('pilocytic astrocytoma', 'Disease', (81, 102))	('MAPK pathway', 'Pathway', (262, 274))	('ATRX', 'Gene', '546', (318, 322))	('CDKN2A/B', 'Gene', (296, 304))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (142, 164))	('loss', 'Var', (288, 292))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (81, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (153, 164))	('ATRX', 'Gene', (318, 322))	('anaplastic astrocytoma', 'Disease', (142, 164))	('alterations', 'Reg', (275, 286))
219969	30967140	Within the context of a diffuse astrocytic neoplasm, based on the tumor age and location, H3-mutant tumors (either H3 K27M or H3.3 G34R/V) can be considered, along with molecular features of glioblastoma which, if identified, should be taken in the proper clinical, radiographic, and histologic context.	('H3-mutant', 'Gene', (90, 99))	('tumor', 'Disease', (100, 105))	('astrocytic neoplasm', 'Disease', (32, 51))	('astrocytic neoplasm', 'Phenotype', 'HP:0009592', (32, 51))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('H3 K27M', 'Var', (115, 122))	('G34R', 'SUBSTITUTION', 'None', (131, 135))	('tumors', 'Disease', (100, 106))	('astrocytic neoplasm', 'Disease', 'MESH:D001254', (32, 51))	('G34R', 'Var', (131, 135))	('glioblastoma', 'Disease', (191, 203))	('K27M', 'Mutation', 'p.K27M', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('tumors', 'Disease', 'MESH:D009369', (100, 106))
219978	30647847	Oncogenic transgelin-2 is differentially regulated in isocitrate dehydrogenase wild-type vs. mutant gliomas The presence of an isocitrate dehydrogenase (IDH1/2) mutation in gliomas is associated with favorable outcomes compared to gliomas without the mutation (IDH1/2 wild-type, WT).	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('presence', 'Var', (112, 120))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('mutation', 'Var', (161, 169))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('hydrogen', 'Chemical', 'MESH:D006859', (140, 148))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('isocitrate', 'Chemical', 'MESH:C034219', (127, 137))	('hydrogen', 'Chemical', 'MESH:D006859', (67, 75))	('gliomas', 'Disease', (231, 238))	('transgelin-2', 'Gene', (10, 22))	('isocitrate', 'Chemical', 'MESH:C034219', (54, 64))	('IDH1/2', 'Gene', (153, 159))	('gliomas', 'Disease', (173, 180))	('gliomas', 'Disease', 'MESH:D005910', (231, 238))	('transgelin-2', 'Gene', '8407', (10, 22))	('gliomas', 'Disease', (100, 107))
219979	30647847	The underlying biological mechanisms accounting for improved clinical outcomes in IDH1/2 mutant gliomas remain poorly understood, but may, in part, be due to the glioma CpG island methylator phenotype (G-CIMP) and epigenetic silencing of genes.	('glioma', 'Disease', (162, 168))	('improved', 'PosReg', (52, 60))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('IDH1/2', 'Gene', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('G-CIMP', 'Chemical', '-', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('gliomas', 'Disease', (96, 103))	('epigenetic silencing', 'Var', (214, 234))	('mutant', 'Var', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('glioma', 'Disease', (96, 102))
219980	30647847	We performed profiling of IDH1/2 WT versus IDH1/2 mutant Grade II and III gliomas and identified transgelin-2 (TAGLN2), an oncogene and actin-polymerizing protein, to be expressed at significantly higher levels in IDH1/2 WT gliomas compared to IDH1/2 mutant gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (224, 231))	('transgelin-2', 'Gene', '8407', (97, 109))	('IDH1/2 WT', 'Gene', '3417', (214, 223))	('higher levels', 'PosReg', (197, 210))	('mutant', 'Var', (50, 56))	('gliomas', 'Disease', (258, 265))	('TAGLN2', 'Gene', '8407', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', (224, 231))	('gliomas', 'Disease', 'MESH:D005910', (258, 265))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('IDH1/2 WT', 'Gene', (26, 35))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('gliomas', 'Disease', 'MESH:D005910', (224, 231))	('gliomas', 'Phenotype', 'HP:0009733', (258, 265))	('transgelin-2', 'Gene', (97, 109))	('WT gliomas', 'Disease', 'MESH:D005910', (221, 231))	('TAGLN2', 'Gene', (111, 117))	('WT gliomas', 'Disease', (221, 231))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('IDH1/2 WT', 'Gene', '3417', (26, 35))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('IDH1/2 WT', 'Gene', (214, 223))
219981	30647847	This differential expression of TAGLN2 was primarily due to promoter hypermethylation in IDH1/2 mutant gliomas, suggesting involvement of TAGLN2 in the G-CIMP.	('promoter hypermethylation', 'MPA', (60, 85))	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('gliomas', 'Disease', (103, 110))	('mutant', 'Var', (96, 102))	('TAGLN2', 'Gene', '8407', (138, 144))	('TAGLN2', 'Gene', (138, 144))	('IDH1/2', 'Gene', (89, 95))	('TAGLN2', 'Gene', '8407', (32, 38))	('G-CIMP', 'Chemical', '-', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('involvement', 'Reg', (123, 134))	('TAGLN2', 'Gene', (32, 38))
219987	30647847	In 2008, the IDH1/2 mutation was discovered in gliomas and has been associated with improved prognoses in gliomas independent of tumor grade (Grade II-IV) or histologic subtype (astrocytoma, oligodendroglioma, oligoastrocytoma).	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('mutation', 'Var', (20, 28))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('tumor', 'Disease', (129, 134))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (210, 226))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('IDH1/2', 'Gene', (13, 19))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('gliomas', 'Disease', (106, 113))	('oligodendroglioma', 'Disease', 'MESH:D009837', (191, 208))	('astrocytoma', 'Phenotype', 'HP:0009592', (215, 226))	('astrocytoma', 'Disease', 'MESH:D001254', (178, 189))	('astrocytoma', 'Disease', (178, 189))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('oligoastrocytoma', 'Disease', (210, 226))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('improved', 'PosReg', (84, 92))	('oligodendroglioma', 'Disease', (191, 208))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('gliomas', 'Disease', (47, 54))	('astrocytoma', 'Disease', 'MESH:D001254', (215, 226))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('astrocytoma', 'Disease', (215, 226))
219988	30647847	The World Health Organization (WHO) revised the low(er) grade glioma (LGG) classification system in 2016 to include isocitrate dehydrogenase (IDH1/2) mutations and 1p/19q co-deletion status in addition to glioma grade and histology.	('IDH1/2', 'Gene', (142, 148))	('1p/19q', 'Var', (164, 170))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('hydrogen', 'Chemical', 'MESH:D006859', (129, 137))	('glioma', 'Disease', (205, 211))	('mutations', 'Var', (150, 159))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('glioma', 'Disease', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('isocitrate', 'Chemical', 'MESH:C034219', (116, 126))
219989	30647847	As a result, IDH1/2 mutation status is routinely being utilized in the clinic to help predict tumor prognosis and guide management decisions for glioma patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glioma', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (20, 28))	('tumor', 'Disease', (94, 99))	('IDH1/2', 'Gene', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('patients', 'Species', '9606', (152, 160))
219990	30647847	While IDH1/2 mutations most commonly occur in Grade II and III gliomas, they are also present in approximately 5% of GBM that have progressed from lower grade gliomas, known as secondary GBM.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('Grade II', 'Disease', (46, 54))	('gliomas', 'Disease', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('occur', 'Reg', (37, 42))	('mutations', 'Var', (13, 22))	('GBM', 'Phenotype', 'HP:0012174', (187, 190))	('IDH1/2', 'Gene', (6, 12))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
219991	30647847	Regardless of the grade, IDH1/2 mutations are a favorable prognostic factor amongst all gliomas.	('gliomas', 'Disease', (88, 95))	('mutations', 'Var', (32, 41))	('IDH1/2', 'Gene', (25, 31))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
219992	30647847	In fact, secondary GBM patients harboring an IDH1/2 mutation (median survival of 2.1 years) often have improved survival compared to LGG without the mutation, referred to as IDH1/2 wild-type (IDH1/2 WT) (median survival of 1.7 years).	('IDH1/2 wild-type (IDH1/2 WT)', 'Gene', '3417', (174, 202))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('IDH1/2 wild-type (IDH1/2 WT', 'Gene', (174, 201))	('patients', 'Species', '9606', (23, 31))	('improved', 'PosReg', (103, 111))	('IDH1/2', 'Gene', (45, 51))	('survival', 'MPA', (112, 120))	('mutation', 'Var', (52, 60))
219995	30647847	The heterozygous R132H mutation in IDH1 accounts for 95% of IDH1/2 mutations in gliomas, however heterozygous mutations also occur in the analogous amino acid of IDH2 (R172), including R172G, R172K, and R172M.	('IDH1', 'Gene', (35, 39))	('R172G', 'Mutation', 'rs1057519906', (185, 190))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('IDH1', 'Gene', '3417', (35, 39))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('R172K', 'Var', (192, 197))	('IDH2', 'Gene', (162, 166))	('IDH2', 'Gene', '3418', (162, 166))	('R172M', 'Var', (203, 208))	('IDH1', 'Gene', (60, 64))	('R172M', 'Mutation', 'rs121913503', (203, 208))	('R132H', 'Var', (17, 22))	('gliomas', 'Disease', (80, 87))	('R172K', 'Mutation', 'rs121913503', (192, 197))	('mutations', 'Var', (67, 76))	('R172G', 'Var', (185, 190))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('IDH1', 'Gene', '3417', (60, 64))
219996	30647847	Both the R132 and R172 residues are located at the active site of IDH1/2 and form hydrogen bonds with the isocitrate substrate, therefore decreasing its binding affinity.	('isocitrate substrate', 'MPA', (106, 126))	('isocitrate', 'Chemical', 'MESH:C034219', (106, 116))	('hydrogen', 'Chemical', 'MESH:D006859', (82, 90))	('hydrogen bonds', 'Interaction', (82, 96))	('R132', 'Var', (9, 13))	('R172', 'Var', (18, 22))	('binding', 'Interaction', (153, 160))	('form', 'Reg', (77, 81))	('decreasing', 'NegReg', (138, 148))
219997	30647847	As a result, IDH1 and IDH2 mutations compromise alpha-KG production, but at the same time result in neomorphic enzymatic activity that reduces alpha-KG to 2-hydroxyglutarate (2-HG).	('mutations', 'Var', (27, 36))	('compromise', 'NegReg', (37, 47))	('neomorphic enzymatic activity', 'MPA', (100, 129))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (155, 173))	('IDH2', 'Gene', (22, 26))	('alpha-KG production', 'MPA', (48, 67))	('IDH1', 'Gene', (13, 17))	('alpha-KG', 'Chemical', 'MESH:D007656', (143, 151))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('reduces', 'NegReg', (135, 142))	('alpha-KG', 'Chemical', 'MESH:D007656', (48, 56))	('result in', 'Reg', (90, 99))
219999	30647847	The specific gene expression changes associated with this glioma hypermethylated phenotype in IDH1/2 mutant gliomas are yet to be elucidated.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('glioma', 'Disease', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('mutant', 'Var', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma', 'Disease', (58, 64))	('IDH1/2', 'Gene', (94, 100))
220000	30647847	In this study, we performed molecular profiling of IDH1/2 WT versus mutant low(er) grade II and III gliomas to identify key molecular pathways that may contribute to differences in survival outcomes.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH1/2 WT', 'Gene', '3417', (51, 60))	('IDH1/2 WT', 'Gene', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('gliomas', 'Disease', (100, 107))	('mutant', 'Var', (68, 74))
220001	30647847	To this end, by employing an mRNA and proteomics profiling approach, we identified transgelin-2 (TAGLN2) to be differentially expressed between IDH1/2 WT and mutant gliomas.	('IDH1/2 WT', 'Gene', (144, 153))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('TAGLN2', 'Gene', '8407', (97, 103))	('TAGLN2', 'Gene', (97, 103))	('IDH1/2 WT', 'Gene', '3417', (144, 153))	('gliomas', 'Disease', (165, 172))	('mutant', 'Var', (158, 164))	('transgelin-2', 'Gene', (83, 95))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('transgelin-2', 'Gene', '8407', (83, 95))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
220007	30647847	recently reported that silencing of TAGLN2 decreases proliferation and invasion in gliomas and that TAGLN2 may be a prognostic biomarker in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('gliomas', 'Disease', (83, 90))	('TAGLN2', 'Gene', '8407', (100, 106))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('TAGLN2', 'Gene', (100, 106))	('invasion', 'CPA', (71, 79))	('silencing', 'Var', (23, 32))	('TAGLN2', 'Gene', '8407', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('proliferation', 'CPA', (53, 66))	('gliomas', 'Disease', (140, 147))	('TAGLN2', 'Gene', (36, 42))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('decreases', 'NegReg', (43, 52))
220009	30647847	Here, we have shown that TAGLN2 functions as an oncogene in IDH1/2 WT gliomas and is expressed at significantly higher levels in IDH1/2 WT gliomas due to TAGLN2 promoter hypermethylation and subsequent gene silencing in IDH1/2 mutant gliomas.	('WT gliomas', 'Disease', 'MESH:D005910', (67, 77))	('WT gliomas', 'Disease', (67, 77))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('hypermethylation', 'PosReg', (170, 186))	('TAGLN2', 'Gene', '8407', (25, 31))	('gliomas', 'Disease', (234, 241))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('WT gliomas', 'Disease', 'MESH:D005910', (136, 146))	('gliomas', 'Disease', (139, 146))	('IDH1/2 WT', 'Gene', (129, 138))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('WT gliomas', 'Disease', (136, 146))	('IDH1/2', 'Gene', (220, 226))	('gliomas', 'Disease', 'MESH:D005910', (234, 241))	('TAGLN2', 'Gene', (154, 160))	('IDH1/2 WT', 'Gene', (60, 69))	('IDH1/2 WT', 'Gene', '3417', (129, 138))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('higher levels', 'PosReg', (112, 125))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('IDH1/2 WT', 'Gene', '3417', (60, 69))	('gene', 'MPA', (202, 206))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (234, 241))	('mutant', 'Var', (227, 233))	('TAGLN2', 'Gene', (25, 31))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('TAGLN2', 'Gene', '8407', (154, 160))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
220010	30647847	We also found higher mRNA expression of TAGLN2 in GBM compared to IDH1/2 WT gliomas of lower grades.	('GBM', 'Var', (50, 53))	('TAGLN2', 'Gene', (40, 46))	('IDH1/2 WT', 'Gene', '3417', (66, 75))	('WT gliomas', 'Disease', (73, 83))	('IDH1/2 WT', 'Gene', (66, 75))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('TAGLN2', 'Gene', '8407', (40, 46))	('mRNA expression', 'MPA', (21, 36))	('WT gliomas', 'Disease', 'MESH:D005910', (73, 83))	('higher', 'PosReg', (14, 20))	('GBM', 'Phenotype', 'HP:0012174', (50, 53))
220012	30647847	In order to better understand the biological mechanisms responsible for differences in clinical outcomes between patients harboring IDH1/2 WT and IDH1/2 mutant gliomas, we performed mRNA profiling to compare gene expression between IDH1/2 WT (n=7) and IDH1/2 mutant (n=51) grade II and III gliomas from our institutional cohort.	('glioma', 'Phenotype', 'HP:0009733', (290, 296))	('grade II', 'Disease', (273, 281))	('IDH1/2', 'Gene', (252, 258))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('IDH1/2 WT', 'Gene', '3417', (132, 141))	('patients', 'Species', '9606', (113, 121))	('gliomas', 'Disease', (160, 167))	('compare', 'Reg', (200, 207))	('mutant', 'Var', (259, 265))	('gliomas', 'Disease', 'MESH:D005910', (290, 297))	('gliomas', 'Disease', (290, 297))	('IDH1/2 WT', 'Gene', (132, 141))	('IDH1/2 WT', 'Gene', '3417', (232, 241))	('gliomas', 'Phenotype', 'HP:0009733', (290, 297))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('IDH1/2 WT', 'Gene', (232, 241))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
220015	30647847	In addition, we performed proteomic profiling of an institutional discovery cohort of 40 LGGs (7 IDH1/2 WT and 33 IDH1/2 mutant) that identified 120 differentially expressed peptides in IDH1/2 WT vs. IDH1/2 mutant tumors that mapped to 65 proteins (FDR p value <0.10).	('IDH1/2 WT', 'Gene', '3417', (97, 106))	('IDH1/2 WT', 'Gene', '3417', (186, 195))	('IDH1/2 WT', 'Gene', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('IDH1/2 WT', 'Gene', (186, 195))	('mutant', 'Var', (207, 213))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (214, 220))
220018	30647847	We validated these findings in an additional institutional cohort of IDH1/2 WT (n=7) versus IDH1/2 mutant (n=23) grade II and III gliomas.	('IDH1/2 WT', 'Gene', '3417', (69, 78))	('grade II', 'Disease', (113, 121))	('IDH1/2 WT', 'Gene', (69, 78))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('mutant', 'Var', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
220027	30647847	While the association between the hypermethylator phenotype and IDH1/2 mutation in gliomas has been well-established, the majority of individual genes involved remain to be identified.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('mutation', 'Var', (71, 79))	('IDH1/2', 'Gene', (64, 70))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('hypermethylator', 'Var', (34, 49))
220028	30647847	Since TAGLN2 was down-regulated in IDH1/2 mutant gliomas, we examined our global methylation data to determine whether increased promoter methylation may account for decreased TAGLN2 expression in these tumors.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('mutant', 'Var', (42, 48))	('TAGLN2', 'Gene', '8407', (176, 182))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('down-regulated', 'NegReg', (17, 31))	('TAGLN2', 'Gene', (176, 182))	('TAGLN2', 'Gene', (6, 12))	('TAGLN2', 'Gene', '8407', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('decreased', 'NegReg', (166, 175))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('expression', 'MPA', (183, 193))	('gliomas', 'Disease', (49, 56))	('IDH1/2', 'Gene', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
220029	30647847	Indeed, 60% (n=9/15) of the 15 CpG sites predicted to correspond to the TAGLN2 promoter showed significantly higher levels of methylation (FDR<0.05) in IDH1/2 mutant tumors.	('TAGLN2', 'Gene', '8407', (72, 78))	('methylation', 'MPA', (126, 137))	('IDH1/2', 'Gene', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TAGLN2', 'Gene', (72, 78))	('mutant', 'Var', (159, 165))	('higher', 'PosReg', (109, 115))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
220032	30647847	As shown in the Kaplan-Meier curve in Figure 3A, patients with high TAGLN2 mRNA levels (median split) trended toward worse OS in our institutional cohort of 58 grade II/III patients (HR 3.74, 0.77-18.09, p=0.079).	('TAGLN2', 'Gene', (68, 74))	('patients', 'Species', '9606', (173, 181))	('worse', 'NegReg', (117, 122))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('TAGLN2', 'Gene', '8407', (68, 74))
220056	30647847	The ability of GBM30 neurospheres to invade through an extracellular matrix after shRNA-mediated stable knock-down of TAGLN2 was compared to each respective cell type stably transfected with scrambled shRNA control.	('invade through an extracellular matrix', 'CPA', (37, 75))	('GBM', 'Phenotype', 'HP:0012174', (15, 18))	('TAGLN2', 'Gene', '8407', (118, 124))	('TAGLN2', 'Gene', (118, 124))	('knock-down', 'Var', (104, 114))
220057	30647847	Figure 5A shows a decreased average number of cells invading through the matrix after knock-down of TAGLN2 in GBM30 cells, respectively.	('TAGLN2', 'Gene', '8407', (100, 106))	('decreased', 'NegReg', (18, 27))	('GBM30', 'Gene', (110, 115))	('TAGLN2', 'Gene', (100, 106))	('knock-down', 'Var', (86, 96))	('GBM', 'Phenotype', 'HP:0012174', (110, 113))
220058	30647847	These experiments were also performed with siRNA-mediated transient knock-down of TAGLN2 in U87 MG and LN18 cells and similar results were obtained (Supplemental Figure 2).	('TAGLN2', 'Gene', (82, 88))	('LN18', 'CellLine', 'CVCL:0392', (103, 107))	('knock-down', 'Var', (68, 78))	('U87 MG', 'CellLine', 'CVCL:0022', (92, 98))	('TAGLN2', 'Gene', '8407', (82, 88))
220062	30647847	Since TAGLN2 was found to be expressed at significantly lower mRNA and protein levels in IDH1/2 mutant gliomas from both institutional and TCGA patient cohorts, we confirmed these findings in vitro by evaluating TAGLN2 protein levels in a commercially available U87 MG isogenic cell line overexpressing IDH1R132H mutant protein (ATCC, Manassas, VA), which will be referred to as IDH1 mutant U87 MG cells.	('gliomas', 'Disease', 'MESH:D005910', (103, 110))	('IDH1', 'Gene', (89, 93))	('gliomas', 'Phenotype', 'HP:0009733', (103, 110))	('TAGLN2', 'Gene', (212, 218))	('mutant', 'Var', (96, 102))	('IDH1', 'Gene', '3417', (303, 307))	('TAGLN2', 'Gene', (6, 12))	('patient', 'Species', '9606', (144, 151))	('IDH1', 'Gene', '3417', (89, 93))	('IDH1', 'Gene', (379, 383))	('lower', 'NegReg', (56, 61))	('U87 MG', 'CellLine', 'CVCL:0022', (391, 397))	('TAGLN2', 'Gene', '8407', (6, 12))	('TAGLN2', 'Gene', '8407', (212, 218))	('gliomas', 'Disease', (103, 110))	('protein', 'Protein', (320, 327))	('IDH1', 'Gene', '3417', (379, 383))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('overexpressing', 'PosReg', (288, 302))	('IDH1', 'Gene', (303, 307))	('U87 MG', 'CellLine', 'CVCL:0022', (262, 268))
220063	30647847	We compared levels of TAGLN2 protein in U87 MG cells overexpressing mutant IDH1 to U87 IDH1/2 WT MG parental cells by Western blot.	('U87', 'Gene', (83, 86))	('IDH1/2 WT', 'Gene', (87, 96))	('U87', 'Gene', '641648', (83, 86))	('IDH1', 'Gene', '3417', (87, 91))	('U87', 'Gene', (40, 43))	('U87 MG', 'CellLine', 'CVCL:0022', (40, 46))	('TAGLN2', 'Gene', '8407', (22, 28))	('IDH1', 'Gene', (75, 79))	('U87', 'Gene', '641648', (40, 43))	('TAGLN2', 'Gene', (22, 28))	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', (87, 91))	('IDH1/2 WT', 'Gene', '3417', (87, 96))	('mutant', 'Var', (68, 74))
220064	30647847	Similar to our patient-derived glioma tissues, cell lines expressing mutant IDH1 had decreased TAGLN2 protein levels compared to U87 MG IDH1/2 WT glioma cells (Figure 6A).	('IDH1', 'Gene', '3417', (76, 80))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('IDH1', 'Gene', (136, 140))	('WT glioma', 'Disease', (143, 152))	('glioma', 'Disease', (146, 152))	('TAGLN2', 'Gene', '8407', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('IDH1', 'Gene', '3417', (136, 140))	('patient', 'Species', '9606', (15, 22))	('U87 MG', 'CellLine', 'CVCL:0022', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('IDH1/2 WT', 'Gene', (136, 145))	('glioma', 'Disease', (31, 37))	('IDH1', 'Gene', (76, 80))	('decreased', 'NegReg', (85, 94))	('mutant', 'Var', (69, 75))	('WT glioma', 'Disease', 'MESH:D005910', (143, 152))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('IDH1/2 WT', 'Gene', '3417', (136, 145))	('TAGLN2', 'Gene', (95, 101))
220065	30647847	Since our methylation data in glioma patients suggested that TAGLN2 expression might be silenced in IDH1/2 mutant LGGs by promoter hypermethylation, we confirmed these results in vitro by treating IDH1 mutant U87 MG cells with 5-aza-2'-deoxycytidine (5-AZA), an inhibitor of DNA methyltransferase that results in DNA demethylation.	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('mutant', 'Var', (107, 113))	('IDH1', 'Gene', '3417', (100, 104))	('expression', 'MPA', (68, 78))	('patients', 'Species', '9606', (37, 45))	('IDH1', 'Gene', (197, 201))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (227, 249))	('5-AZA', 'Chemical', 'MESH:D001374', (251, 256))	('silenced', 'NegReg', (88, 96))	('IDH1', 'Gene', '3417', (197, 201))	('TAGLN2', 'Gene', '8407', (61, 67))	('U87 MG', 'CellLine', 'CVCL:0022', (209, 215))	('glioma', 'Disease', (30, 36))	('IDH1', 'Gene', (100, 104))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('TAGLN2', 'Gene', (61, 67))	('mutant', 'Var', (202, 208))
220067	30647847	As shown in Figure 6B, treatment with 5-AZA resulted in increased TAGLN2 protein expression in an almost dose-dependent manner in IDH1 mutant U87 MG cells.	('TAGLN2', 'Gene', '8407', (66, 72))	('increased', 'PosReg', (56, 65))	('TAGLN2', 'Gene', (66, 72))	('5-AZA', 'Chemical', 'MESH:D001374', (38, 43))	('mutant', 'Var', (135, 141))	('IDH1', 'Gene', (130, 134))	('IDH1', 'Gene', '3417', (130, 134))	('U87 MG', 'CellLine', 'CVCL:0022', (142, 148))
220069	30647847	These results suggest that TAGLN2 expression may be decreased due to its promoter hypermethylation-mediated transcriptional downregulation in IDH1/2 mutant gliomas.	('IDH1/2', 'Gene', (142, 148))	('transcriptional', 'MPA', (108, 123))	('TAGLN2', 'Gene', '8407', (27, 33))	('expression', 'MPA', (34, 44))	('TAGLN2', 'Gene', (27, 33))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('decreased', 'NegReg', (52, 61))	('gliomas', 'Disease', (156, 163))	('mutant', 'Var', (149, 155))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('promoter hypermethylation-mediated', 'MPA', (73, 107))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('downregulation', 'NegReg', (124, 138))
220071	30647847	In this study, we performed mRNA and proteomic profiling of IDH1/2 WT versus IDH1/2 mutant Grade II and III gliomas in order to better understand gene expression differences contributing to worse overall survival in IDH1/2 WT gliomas.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('IDH1/2 WT', 'Gene', (60, 69))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('WT gliomas', 'Disease', 'MESH:D005910', (223, 233))	('mutant', 'Var', (84, 90))	('IDH1/2 WT', 'Gene', '3417', (60, 69))	('IDH1/2 WT', 'Gene', '3417', (216, 225))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', (226, 233))	('IDH1/2 WT', 'Gene', (216, 225))	('WT gliomas', 'Disease', (223, 233))
220075	30647847	Previous studies have demonstrated that reorganization of the methylome and the resulting hypermethylator phenotype in gliomas is established by the presence of mutant IDH1/2.	('mutant', 'Var', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('presence', 'Reg', (149, 157))	('IDH1/2', 'Gene', (168, 174))	('hypermethylator', 'MPA', (90, 105))
220077	30647847	We are the first to identify TAGLN2 as a gene likely to be involved in the hypermethylator phenotype and further show that TAGLN2 undergoes epigenetic regulation in IDH1/2 mutant gliomas.	('mutant', 'Var', (172, 178))	('TAGLN2', 'Gene', '8407', (29, 35))	('epigenetic regulation', 'MPA', (140, 161))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('TAGLN2', 'Gene', (29, 35))	('IDH1/2', 'Gene', (165, 171))	('TAGLN2', 'Gene', '8407', (123, 129))	('gliomas', 'Disease', (179, 186))	('undergoes', 'Reg', (130, 139))	('TAGLN2', 'Gene', (123, 129))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))
220078	30647847	Our global methylation analysis of low(er) grade gliomas from our institutional cohort showed that CpG sites corresponding to the TAGLN2 promoter are more highly methylated in IDH1/2 mutant compared to IDH1/2 WT gliomas.	('TAGLN2', 'Gene', (130, 136))	('IDH1/2 WT', 'Gene', '3417', (202, 211))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('IDH1/2 WT', 'Gene', (202, 211))	('WT gliomas', 'Disease', 'MESH:D005910', (209, 219))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('mutant', 'Var', (183, 189))	('TAGLN2', 'Gene', '8407', (130, 136))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('gliomas', 'Disease', (49, 56))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('WT gliomas', 'Disease', (209, 219))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('methylated', 'MPA', (162, 172))	('IDH1/2', 'Gene', (176, 182))	('gliomas', 'Disease', (212, 219))	('highly', 'PosReg', (155, 161))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
220079	30647847	Therefore, our data suggest that epigenetic silencing by promoter hypermethylation likely accounts for decreased TAGLN2 mRNA and protein levels observed in IDH1/2 mutant gliomas.	('TAGLN2', 'Gene', (113, 119))	('IDH1/2', 'Gene', (156, 162))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('gliomas', 'Disease', (170, 177))	('decreased', 'NegReg', (103, 112))	('epigenetic silencing', 'MPA', (33, 53))	('mutant', 'Var', (163, 169))	('TAGLN2', 'Gene', '8407', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))
220081	30647847	Such an association between the IDH1/2 mutation and TAGLN2 expression is also demonstrated by our multivariate analysis that showed TAGLN2 as a negative prognostic factor, though highly dependent on IDH1/2 mutation status.	('mutation', 'Var', (39, 47))	('TAGLN2', 'Gene', '8407', (132, 138))	('negative', 'NegReg', (144, 152))	('TAGLN2', 'Gene', (52, 58))	('IDH1/2', 'Gene', (32, 38))	('expression', 'MPA', (59, 69))	('TAGLN2', 'Gene', (132, 138))	('TAGLN2', 'Gene', '8407', (52, 58))
220082	30647847	While our study is limited by the availability of only one established heterozygous IDH1 mutant glioma cell line, the epigenetic regulation of transgelin, a homologue of TAGLN2, has been reported in multiple other cancer types.	('cancer', 'Disease', (214, 220))	('transgelin', 'Gene', (143, 153))	('TAGLN2', 'Gene', '8407', (170, 176))	('IDH1', 'Gene', (84, 88))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('reported', 'Reg', (187, 195))	('IDH1', 'Gene', '3417', (84, 88))	('transgelin', 'Gene', '6876', (143, 153))	('TAGLN2', 'Gene', (170, 176))	('epigenetic regulation', 'MPA', (118, 139))	('mutant', 'Var', (89, 95))	('glioma', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
220084	30647847	Transgelin has been reported to be regulated by promoter hypermethylation in breast, colorectal, malignant peripheral nerve sheath tumors and hepatocellular carcinomas.	('promoter hypermethylation', 'Var', (48, 73))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (142, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('Transgelin', 'Gene', '6876', (0, 10))	('colorectal', 'Disease', 'MESH:D015179', (85, 95))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (97, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (142, 167))	('malignant peripheral nerve sheath tumors', 'Disease', (97, 137))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (97, 137))	('hepatocellular carcinomas', 'Disease', (142, 167))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('colorectal', 'Disease', (85, 95))	('breast', 'Disease', (77, 83))	('Transgelin', 'Gene', (0, 10))
220085	30647847	Moreover, promoter methylation has also been shown to regulate transgelin expression during normal physiologic processes, including epigenetic silencing of transgelin in endometrial stroma during reorganization of the actin cytoskeleton in preparation for pregnancy.	('expression', 'MPA', (74, 84))	('regulate', 'Reg', (54, 62))	('transgelin', 'Gene', '6876', (156, 166))	('epigenetic silencing', 'Var', (132, 152))	('transgelin', 'Gene', (63, 73))	('transgelin', 'Gene', (156, 166))	('endometrial stroma', 'Disease', 'MESH:D014591', (170, 188))	('transgelin', 'Gene', '6876', (63, 73))	('endometrial stroma', 'Disease', (170, 188))
220087	30647847	While TAGLN2 expression appears to be regulated at the epigenetic level in IDH mutant gliomas, we also found significant differences in TAGLN2 mRNA expression among different grades of IDH WT gliomas, suggesting that TAGLN2 expression may also be regulated during glioma progression in a 2HG-independent fashion.	('IDH', 'Gene', (185, 188))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('TAGLN2', 'Gene', '8407', (136, 142))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('IDH', 'Gene', '3417', (185, 188))	('TAGLN2', 'Gene', (6, 12))	('IDH WT gliomas', 'Disease', 'MESH:D005910', (185, 199))	('gliomas', 'Disease', (192, 199))	('glioma', 'Disease', (192, 198))	('glioma', 'Disease', (264, 270))	('TAGLN2', 'Gene', (217, 223))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('IDH WT gliomas', 'Disease', (185, 199))	('mutant', 'Var', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('mRNA expression', 'MPA', (143, 158))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('regulated', 'Reg', (38, 47))	('IDH', 'Gene', (75, 78))	('TAGLN2', 'Gene', (136, 142))	('gliomas', 'Disease', (86, 93))	('TAGLN2', 'Gene', '8407', (6, 12))	('glioma', 'Disease', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('differences', 'Reg', (121, 132))	('IDH', 'Gene', '3417', (75, 78))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('TAGLN2', 'Gene', '8407', (217, 223))
220094	30647847	found that IDH mutant GBMs were less invasive than IDH WT GBMs based on MRI diffusor-tensor imaging, a technique believed to delineate tumor margins more accurately than conventional MRI.	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('IDH', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('IDH', 'Gene', '3417', (51, 54))	('tumor', 'Disease', (135, 140))	('GBM', 'Phenotype', 'HP:0012174', (22, 25))	('mutant', 'Var', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
220095	30647847	Another study further showed IDH mutant cells to have a less invasive phenotype than IDH WT cells in vivo and in vitro.	('IDH', 'Gene', '3417', (85, 88))	('IDH', 'Gene', (29, 32))	('mutant', 'Var', (33, 39))	('IDH', 'Gene', '3417', (29, 32))	('IDH', 'Gene', (85, 88))	('less', 'MPA', (56, 60))
220105	30647847	In summary, we have shown that TAGLN2 expression is silenced by promoter hypermethylation and therefore likely involved in the glioma hypermethylator phenotype of IDH1/2 mutant gliomas.	('silenced', 'NegReg', (52, 60))	('expression', 'MPA', (38, 48))	('gliomas', 'Disease', (177, 184))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('TAGLN2', 'Gene', (31, 37))	('glioma', 'Disease', (177, 183))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('involved', 'Reg', (111, 119))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('mutant', 'Var', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioma', 'Disease', (127, 133))	('IDH1/2', 'Gene', (163, 169))	('TAGLN2', 'Gene', '8407', (31, 37))
220107	30647847	This differential regulation of TAGLN2 provides further insight into the genetic, epigenetic and oncogenic differences between IDH1/2 WT and mutant gliomas.	('IDH1/2 WT', 'Gene', (127, 136))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('mutant', 'Var', (141, 147))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('TAGLN2', 'Gene', '8407', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('IDH1/2 WT', 'Gene', '3417', (127, 136))	('TAGLN2', 'Gene', (32, 38))
220113	30647847	Patients were deemed IDH1/2 mutant if mutations were present at IDH1R132 or IDH2R172 positions.	('IDH2', 'Gene', '3418', (76, 80))	('IDH1', 'Gene', (64, 68))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', '3417', (64, 68))	('IDH1', 'Gene', (21, 25))	('mutations', 'Var', (38, 47))	('IDH2', 'Gene', (76, 80))	('IDH1', 'Gene', '3417', (21, 25))
220117	30647847	Differential gene expression between IDH1/2 WT and IDH1/2 mutant gliomas was determined by LIMMA analysis.	('gliomas', 'Disease', (65, 72))	('mutant', 'Var', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH1/2 WT', 'Gene', '3417', (37, 46))	('IDH1/2 WT', 'Gene', (37, 46))	('IDH1/2', 'Gene', (51, 57))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
220119	30647847	Proteins were comparatively evaluated between IDH1/2 mutant and WT tumors by mass spectrometry as previously described in Bassett et al..	('IDH1/2', 'Gene', (46, 52))	('WT tumors', 'Disease', 'MESH:C536751', (64, 73))	('WT tumors', 'Disease', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutant', 'Var', (53, 59))
220122	30647847	An isogenic line derived from overexpression of IDH1R132H in U87 MG parental cells was purchased from ATCC (Manassas, VA, USA).	('IDH1R132H', 'Var', (48, 57))	('overexpression', 'PosReg', (30, 44))	('U87 MG', 'CellLine', 'CVCL:0022', (61, 67))
220123	30647847	This cell line has a heterozygous C395G>A knock-in mutation encoding IDH1R132H protein expression generated by using the CRISPR/Cas9 gene editing technology.	('C395G>A', 'Mutation', 'c.395C>G,A', (34, 41))	('C395G>A', 'Var', (34, 41))	('IDH1R132H', 'Gene', (69, 78))
220133	30647847	Human TAGLN2 (Myc-DDK-tagged) in pCMV6-entry vector (Origene, Rockville, MD) was transfected into GBM30, U87 MG IDH1/2 WT and U87 MG glioma cells overexpressing mutant IDH1R132H using Lipofectamine 2000 (Thermo Scientific, Waltham, MA) according to the manufacturer's protocol.	('IDH1R132H', 'Gene', (168, 177))	('mutant', 'Var', (161, 167))	('Human', 'Species', '9606', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('MG glioma', 'Disease', (130, 139))	('U87 MG', 'CellLine', 'CVCL:0022', (105, 111))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('overexpressing', 'PosReg', (146, 160))	('TAGLN2', 'Gene', (6, 12))	('U87 MG', 'CellLine', 'CVCL:0022', (126, 132))	('Myc', 'Gene', '4609', (14, 17))	('Myc', 'Gene', (14, 17))	('IDH1/2 WT', 'Gene', '3417', (112, 121))	('MG glioma', 'Disease', 'MESH:D005910', (130, 139))	('IDH1/2 WT', 'Gene', (112, 121))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (184, 202))	('TAGLN2', 'Gene', '8407', (6, 12))
220145	30647847	Cell count (absorbance) at each time point was compared between stable cell lines with TAGLN2 knock-down/overexpression relative to their respective control cells using t-test (p<0.05).	('knock-down/overexpression', 'Var', (94, 119))	('TAGLN2', 'Gene', (87, 93))	('TAGLN2', 'Gene', '8407', (87, 93))	('knock-down/overexpression', 'PosReg', (94, 119))
220149	30647847	Average number of invading cells in each quadrant was averaged and compared between stable cell lines with TAGLN2 knock-down/overexpression relative to their respective control cells using t-test (p<0.05).	('knock-down/overexpression', 'PosReg', (114, 139))	('knock-down/overexpression', 'Var', (114, 139))	('TAGLN2', 'Gene', '8407', (107, 113))	('TAGLN2', 'Gene', (107, 113))
220157	33061437	Grade II patients (88%) and patients bearing 1p/19q co-deletion in their tumors (23%) were more likely to be diagnosed as iLGGs.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('iLGGs', 'Disease', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('1p/19q co-deletion', 'Var', (45, 63))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('patients', 'Species', '9606', (28, 36))
220178	33061437	It was common to employ a pyrosequencing technique to detect IDH mutation in CGGA.	('mutation', 'Var', (65, 73))	('IDH', 'Gene', '3417', (61, 64))	('IDH', 'Gene', (61, 64))
220201	33061437	Compared with niLGGs, there were more Grade II patients (88%, p<0.001) and 1p/19q co-deletion (23%, p<0.05) in iLGGs, and only a small percentage of patients (21%, p<0.001) received postoperative chemotherapy.	('age', 'Gene', '5973', (142, 145))	('1p/19q co-deletion', 'Var', (75, 93))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (47, 55))	('Grade II', 'Var', (38, 46))	('age', 'Gene', (142, 145))	('iLGGs', 'Disease', (111, 116))
220208	33061437	Considering the effect of molecular characteristics and surgery on the prognosis of patients, we divided LGG into groups according to IDH (mutant and intact, Figure S2A), 1p/19q (co-deletion and intact, Figure S2B) and extent of resection (total and subtotal, Figure S2C), and found that the survival trend of the iLGGs was better in all groups.	('IDH', 'Gene', '3417', (134, 137))	('co-deletion', 'Var', (179, 190))	('patients', 'Species', '9606', (84, 92))	('mutant', 'Var', (139, 145))	('IDH', 'Gene', (134, 137))
220234	33061437	Mutations in Arg132 of IDH1 or Arg172 appear in over 80% of Grade II/III gliomas and secondary GBMs.	('secondary GBMs', 'Disease', (85, 99))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('III gliomas', 'Disease', (69, 80))	('Arg172', 'Chemical', '-', (31, 37))	('Arg132', 'Chemical', '-', (13, 19))	('Arg172', 'Var', (31, 37))	('Mutations in Arg132', 'Var', (0, 19))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH', 'Gene', (23, 26))	('III gliomas', 'Disease', 'MESH:D005910', (69, 80))	('IDH', 'Gene', '3417', (23, 26))
220236	33061437	The coexistence of IDH mutation and aerobic respiration in iLGGs seem to be contradictory.	('IDH', 'Gene', '3417', (19, 22))	('IDH', 'Gene', (19, 22))	('mutation', 'Var', (23, 31))
220237	33061437	But simultaneous mutations of IDH1 and IDH2 are rare in glioma cells and the common genotype is IDH1 mutation and IDH2 wild-type.	('glioma', 'Disease', (56, 62))	('IDH', 'Gene', '3417', (96, 99))	('IDH', 'Gene', (114, 117))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('IDH', 'Gene', '3417', (114, 117))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', (39, 42))	('mutation', 'Var', (101, 109))	('IDH', 'Gene', '3417', (30, 33))	('mutations', 'Var', (17, 26))	('IDH', 'Gene', '3417', (39, 42))	('IDH', 'Gene', (96, 99))
220238	33061437	Wild-type IDH2 could catalyze the oxidative decarboxylation of isocitrate in IDH1 mutant iLGGs as well.	('IDH', 'Gene', (10, 13))	('IDH', 'Gene', '3417', (10, 13))	('isocitrate', 'Chemical', 'MESH:C034219', (63, 73))	('oxidative decarboxylation of isocitrate', 'MPA', (34, 73))	('IDH', 'Gene', (77, 80))	('IDH', 'Gene', '3417', (77, 80))	('mutant', 'Var', (82, 88))
220239	33061437	On the other hand, the main effect of IDH mutation is causing genome-wide methylation and globally increases the methylation of histones H3 and H4.	('methylation', 'MPA', (74, 85))	('IDH', 'Gene', (38, 41))	('histones H3', 'Protein', (128, 139))	('IDH', 'Gene', '3417', (38, 41))	('causing', 'Reg', (54, 61))	('mutation', 'Var', (42, 50))	('methylation', 'MPA', (113, 124))	('increases', 'PosReg', (99, 108))
220241	33061437	In conclusion, glioma glycolysis or aerobic respiration is not determined by IDH mutation status.	('glioma glycolysis', 'Disease', 'MESH:D005910', (15, 32))	('glioma glycolysis', 'Disease', (15, 32))	('mutation', 'Var', (81, 89))	('IDH', 'Gene', (77, 80))	('aerobic respiration', 'MPA', (36, 55))	('IDH', 'Gene', '3417', (77, 80))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
220242	33061437	Despite numerous IDH mutations in iLGGs, mitochondrial aerobic respiration is not affected.	('IDH', 'Gene', (17, 20))	('IDH', 'Gene', '3417', (17, 20))	('mitochondrial aerobic respiration', 'MPA', (41, 74))	('iLGGs', 'Gene', (34, 39))	('mutations', 'Var', (21, 30))
220302	31370107	Assortativity of the contralesional hemisphere was associated with complex attention scores (p < .05; all p's > .11 for all other graph metrics, FDR corrected): Higher contralesional assortativity was associated with higher performance on the complex attention domain (beta = 8.24, SE = 2.79; See Figure 5b).	('higher', 'PosReg', (217, 223))	('SE', 'Disease', 'None', (282, 284))	('contralesional', 'Var', (168, 182))	('complex attention domain', 'MPA', (243, 267))
220331	31370107	Furthermore, we found that contralesional assortativity, in combination with tumour type, is predictive of complex attention and cognitive flexibility scores.	('tumour type', 'Disease', 'MESH:D009369', (77, 88))	('tumour type', 'Disease', (77, 88))	('complex', 'MPA', (107, 114))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('contralesional', 'Var', (27, 41))
220333	30701024	Pan-cancer analysis of intratumor heterogeneity associated with patient prognosis using multidimensional measures Human cancers accumulate various mutations during development and consist of highly heterogeneous cell populations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (147, 156))	('patient', 'Species', '9606', (64, 71))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('cancers', 'Disease', (120, 127))	('Human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
220341	30701024	Cancer is indicated via dysregulated cell growth, proliferation, and cell cycle progression.	('dysregulated', 'Var', (24, 36))	('cell cycle progression', 'CPA', (69, 91))	('proliferation', 'CPA', (50, 63))	('cell growth', 'CPA', (37, 48))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
220342	30701024	Cancer cells often consist of heterogeneous populations with various mutations rather than composed of homogeneous populations.	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (69, 78))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
220343	30701024	Previous studies demonstrated that cancer develops from mutations in certain driver genes and eventually accumulates various genetic mutations through cell growth, leading to intratumor heterogeneity (ITH).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (180, 185))	('leading to', 'Reg', (164, 174))	('mutations', 'Var', (133, 142))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
220347	30701024	VAFs are able to estimate the fraction of tumor populations containing mutations in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (71, 80))	('VAF', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
220350	30701024	Moreover, mutant-allele tumor heterogeneity (MATH) scores represent the variance of VAFs, and the entropy-based mutation allele fraction (EMAF) represents uncertainty of somatic mutation patterns.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutant-allele', 'Var', (10, 23))	('VAF', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
220359	30701024	Since correlation coefficients were -0.44, 0.03, and 0.00, which were observed between m_Peaks vs. m_MATH, m_Peak vs. m_Count, and m_Count vs. m_MATH, respectively, we considered the parameters could be used as independent variables representing the characteristics of VAF distributions.	('VAF', 'Chemical', '-', (269, 272))	('m_Peak', 'Var', (107, 113))	('m_Peaks', 'Var', (87, 94))
220365	30701024	We drew histograms of VAFs assembled from all mutations in samples belonging to each cluster and created trunk-branch models of mutations in tumors (Figure 2A).	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('trunk-branch', 'Disease', (105, 117))	('trunk-branch', 'Disease', 'MESH:D016750', (105, 117))	('VAF', 'Chemical', '-', (22, 25))
220367	30701024	Since the VAF distributions showed that samples in cluster 1 had more MF mutations with higher VAF than lower VAF, while the samples in cluster 2 had more MF mutations with lower VAF than higher VAF, they were predicted to have accumulated clonal mutations in cluster 1 and subclonal mutations in cluster 2, respectively.	('VAF', 'Chemical', '-', (95, 98))	('VAF', 'Chemical', '-', (10, 13))	('VAF', 'Chemical', '-', (195, 198))	('VAF', 'Chemical', '-', (179, 182))	('lower', 'NegReg', (173, 178))	('VAF', 'Chemical', '-', (110, 113))	('mutations', 'Var', (73, 82))
220368	30701024	This observation was consistent with a recent study by McGranahan and colleagues, which indicated that, in some cancer types, including melanoma and lung cancer, mutations accumulated prior to carcinogenesis.	('mutations', 'Var', (162, 171))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('carcinogenesis', 'Disease', (193, 207))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (136, 160))
220371	30701024	This trend can be interpreted as MF mutations occurring in the early stages of cancer development and maintained through cancer progression, without further accumulating a large number of MF mutations among samples in cluster 3.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
220372	30701024	In cluster 4, expansion of some subclones with certain MF mutations might occur during cancer progression under strong positive selection.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
220373	30701024	In contrast, samples in cluster 5 had MF mutations that possibly occurred under neutral cancer evolution.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
220374	30701024	To evaluate the clusters' genetic characteristics, we calculated MF mutation frequencies of each gene for 16 cancer types and examined the 10 genes with the highest frequency of mutations in each cluster (Supplementary Figure 2).	('mutation', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
220375	30701024	In BRCA, the frequencies of MF mutation in PIK3CA in clusters 3, 4, and 5 (35.5%, 40.5%, and 32.5%, respectively), in which the m_Count was small, were relatively high.	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('mutation', 'Var', (31, 39))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))	('PIK3CA', 'Gene', (43, 49))
220376	30701024	Once mutations in PIK3CA occurred, without a striking increase in the number of other mutations, cells may remain genetically stable.	('PIK3CA', 'Gene', (18, 24))	('PIK3CA', 'Gene', '5290', (18, 24))	('mutations', 'Var', (5, 14))
220378	30701024	This result suggests that liver cancer cells with mutations in the driver gene CTNNB1, which have been generated in the earlier stage of cancer development, occupied in the cancer cell population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CTNNB1', 'Gene', '1499', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('liver cancer', 'Disease', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CTNNB1', 'Gene', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (26, 38))	('liver cancer', 'Disease', 'MESH:D006528', (26, 38))
220381	30701024	In our study, the samples in cluster 2 was predicted to have the highest ITH level due to a large number of mutations with lower VAF.	('VAF', 'Chemical', '-', (129, 132))	('ITH level', 'MPA', (73, 82))	('lower', 'NegReg', (123, 128))	('mutations', 'Var', (108, 117))
220383	30701024	In melanoma, the frequency of C>T transitions decreases, and the frequency of T>G transversions increases among branch mutations compared to trunk mutations.	('T>G transversions', 'Var', (78, 95))	('increases', 'PosReg', (96, 105))	('C>T transitions', 'Var', (30, 45))	('decreases', 'NegReg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
220384	30701024	Therefore, most mutations in samples with fewer mutations were proposed to occur in later, rather than earlier, stages of cancer development.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
220388	30701024	As mentioned above, samples in clusters 1 and 2 supposedly accumulated a large number of MF mutations during cancer development.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (92, 101))
220407	30701024	This suggested more mutations are associated with worse prognosis in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
220408	30701024	Cancer cells occupied by a lower number of mutations occurring early in cancer development might be associated with worse prognosis in BLCA and UCEC.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BLCA', 'Disease', (135, 139))	('Cancer', 'Disease', (0, 6))	('UCEC', 'Disease', (144, 148))	('mutations', 'Var', (43, 52))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
220409	30701024	Thus, samples were associated with poor prognosis when fewer mutations occurred at carcinogenesis and survived during cancer development.	('cancer', 'Disease', (118, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinogenesis', 'Disease', (83, 97))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
220410	30701024	Since frequencies of MF mutations in IDH1, which is one of the driver genes in LGG, were higher among samples in clusters 3, 4, and 5 (69.5%, 54.5%, and 59.5%, respectively), it was expected that other factors that increase the number of mutations from the early to mid-stage of cancer development may affect patient prognosis.	('affect', 'Reg', (302, 308))	('patient prognosis', 'CPA', (309, 326))	('IDH1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('patient', 'Species', '9606', (309, 316))	('higher', 'PosReg', (89, 95))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
220423	30701024	Previous studies have shown that melanoma is a highly malignant cancer and harbors various mutations in the early stages of cancer development.	('cancer', 'Disease', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
220425	30701024	Our results consistently showed that most samples have a large number of mutations accumulated prior to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))	('mutations', 'Var', (73, 82))
220426	30701024	Taking the mutation spectrum into consideration, most mutations in the samples with fewer mutations were considered to occur in the later rather than earlier stages of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
220428	30701024	From these results, we proposed the following hypothesis of the genetic evolution of melanoma: melanoma is generated by a large number of genetic mutations, including those in BRAF (clusters 1 and 2), and only those cells with certain mutations are selected under selective pressure.	('mutations', 'Var', (146, 155))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('generated by', 'Reg', (107, 119))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('BRAF', 'Gene', '673', (176, 180))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (176, 180))
220430	30701024	Other mutated genes may be involved in evolutionary process of melanoma because of the low frequency of driver gene mutations in samples with few mutations.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('involved', 'Reg', (27, 35))	('mutations', 'Var', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
220433	30701024	Previous studies showed that high TMB in NSCLC was associated with worse prognosis.	('high', 'Var', (29, 33))	('NSCLC', 'Disease', (41, 46))	('TMB', 'Chemical', '-', (34, 37))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('TMB', 'MPA', (34, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
220434	30701024	In LUAD, the mutations partially attributable to smoking may gradually accumulate in cells during cancer progression, leading to more aggressive cancer cells.	('more', 'PosReg', (129, 133))	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('leading to', 'Reg', (118, 128))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('aggressive cancer', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('aggressive cancer', 'Disease', (134, 151))
220435	30701024	Conversely, in LUSC, once mutations are occupied in cancer cells under selective pressure (cluster 4), those samples were predicted to have a worse prognosis than cancer cells with a large number of clonal mutations (cluster 1).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('LUSC', 'Phenotype', 'HP:0030359', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
220440	30701024	In this study, we analyzed 16 cancer types using only single nucleotide substitutions in genes.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('single nucleotide substitutions', 'Var', (54, 85))
220446	30701024	The MF mutations of amino acid substitution may have an impact on protein structures and/or functions, suggesting their possible involvement in cancer development or progression.	('mutations of amino acid substitution', 'Var', (7, 43))	('protein', 'Protein', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('involvement', 'Reg', (129, 140))	('cancer', 'Disease', (144, 150))	('functions', 'MPA', (92, 101))	('impact', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
220455	28698530	The dysregulation of miRNA plays a pivotal role in cancer tumorigenesis, including the development and progression of gliomas.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('dysregulation', 'Var', (4, 17))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
220465	28698530	The mutations in epigenetic modifiers, such as isocitrate dehydrogenase (IDH1/2), telomerase reverse transcriptase (TERT), and alpha-thalassemia/mental retardation syndrome X-linked (ATRX), which lead to global changes in the epigenome, are common drivers of gliomagenesis.	('IDH1/2', 'Gene', (73, 79))	('changes', 'Reg', (211, 218))	('alpha-thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (127, 181))	('mental retardation', 'Phenotype', 'HP:0001249', (145, 163))	('TERT', 'Gene', (116, 120))	('glioma', 'Disease', (259, 265))	('TERT', 'Gene', '7015', (116, 120))	('glioma', 'Disease', 'MESH:D005910', (259, 265))	('ATRX', 'Gene', (183, 187))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('IDH1/2', 'Gene', '3417;3418', (73, 79))	('mutations', 'Var', (4, 13))	('isocitrate', 'Chemical', 'MESH:C034219', (47, 57))	('telomerase reverse transcriptase', 'Gene', (82, 114))	('telomerase reverse transcriptase', 'Gene', '7015', (82, 114))	('ATRX', 'Gene', '546', (183, 187))
220466	28698530	The roles that these mutations play in miRNA dysregulation and glioma development are poorly understood.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Disease', (63, 69))	('mutations', 'Var', (21, 30))
220467	28698530	In this review, we discuss dysregulated miRNAs and their involvement in glioma development and progression.	('glioma', 'Disease', (72, 78))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('involvement', 'Reg', (57, 68))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('dysregulated', 'Var', (27, 39))
220487	28698530	The transcription and splicing of miRNAs are regulated by DNA methylation and histone modifications.	('modifications', 'Var', (86, 99))	('splicing', 'MPA', (22, 30))	('transcription', 'MPA', (4, 17))	('histone', 'Protein', (78, 85))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('DNA', 'Var', (58, 61))	('regulated', 'Reg', (45, 54))
220490	28698530	Hypermethylation of DNA and methylation of lysines 9 and 20 of histone H3 form condensed and inactive chromatin, resulting in gene silencing, whereas histone acetylation promotes active transcription of miRNAs.	('silencing', 'NegReg', (131, 140))	('Hypermethylation', 'Var', (0, 16))	('miR', 'Gene', '220972', (203, 206))	('miR', 'Gene', (203, 206))	('methylation', 'Var', (28, 39))	('lysines', 'Chemical', 'MESH:D008239', (43, 50))	('gene', 'MPA', (126, 130))
220496	28698530	To overcome this limitation, the WHO recently reclassified malignant gliomas by integrating molecular biomarkers, including IDH1/2, ATRX, TERT, TP53, CI, and FUBP1 genes, and co-deletion of 1p and 19q chromosome arms.	('TP53', 'Gene', '7157', (144, 148))	('co-deletion', 'Var', (175, 186))	('TP53', 'Gene', (144, 148))	('FUBP1', 'Gene', '8880', (158, 163))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('malignant gliomas', 'Disease', (59, 76))	('malignant gliomas', 'Disease', 'MESH:D005910', (59, 76))	('FUBP1', 'Gene', (158, 163))	('ATRX', 'Gene', (132, 136))	('IDH1/2', 'Gene', '3417;3418', (124, 130))	('TERT', 'Gene', (138, 142))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('TERT', 'Gene', '7015', (138, 142))	('IDH1/2', 'Gene', (124, 130))	('ATRX', 'Gene', '546', (132, 136))
220497	28698530	Lower-grade gliomas (LGGs, grades II and III) and glioblastomas (grade IV) have been redefined by the presence or absence of the IDH1/2 mutation.	('IDH1/2', 'Gene', '3417;3418', (129, 135))	('glioblastomas', 'Disease', 'MESH:D005909', (50, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('gliomas', 'Disease', (12, 19))	('mutation', 'Var', (136, 144))	('glioblastomas', 'Disease', (50, 63))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('IDH1/2', 'Gene', (129, 135))	('glioblastomas', 'Phenotype', 'HP:0012174', (50, 63))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('absence', 'NegReg', (114, 121))
220498	28698530	Notably, patients with gliomas harboring IDH1/2 mutations have an overall survival (OS) benefit over patients without an IDH1/2 mutation.	('overall survival', 'MPA', (66, 82))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (101, 109))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('IDH1/2', 'Gene', '3417;3418', (121, 127))	('IDH1/2', 'Gene', '3417;3418', (41, 47))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('IDH1/2', 'Gene', (121, 127))	('benefit', 'PosReg', (88, 95))	('IDH1/2', 'Gene', (41, 47))	('mutations', 'Var', (48, 57))
220499	28698530	Mutations in IDH1 are shown to induce the accumulation of methylated DNA via inhibition of DNA demethylation which, in turn, causes global promoter methylation and gene silencing.	('global promoter methylation', 'MPA', (132, 159))	('accumulation', 'PosReg', (42, 54))	('IDH1', 'Gene', (13, 17))	('inhibition', 'NegReg', (77, 87))	('methylated DNA', 'MPA', (58, 72))	('Mutations', 'Var', (0, 9))	('causes', 'Reg', (125, 131))	('DNA', 'Protein', (91, 94))	('IDH1', 'Gene', '3417', (13, 17))	('gene', 'MPA', (164, 168))
220501	28698530	found that IDH1/2 mutation status in lower grade gliomas has more impact on miRNA expression profiles than other genomic changes.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('mutation', 'Var', (18, 26))	('miR', 'Gene', '220972', (76, 79))	('impact', 'Reg', (66, 72))	('IDH1/2', 'Gene', (11, 17))	('gliomas', 'Disease', (49, 56))	('miR', 'Gene', (76, 79))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
220502	28698530	Moreover, miRNA profiles play a more significant prognostic role in IDH mutant tumors than IDH WT tumors, as evident from the identification of a four-miRNA risk classifier (miR-10b, miR-130b, miR-1304, and miR-302b) in IDH mutant patients.	('IDH', 'Gene', '3417', (68, 71))	('miR-10b', 'Gene', '406903', (174, 181))	('tumors than IDH WT tumors', 'Disease', 'MESH:D009369', (79, 104))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('miR-302b', 'Gene', (207, 215))	('miR', 'Gene', '220972', (193, 196))	('miR-130b', 'Gene', '406920', (183, 191))	('mutant', 'Var', (72, 78))	('miR-130b', 'Gene', (183, 191))	('miR', 'Gene', '220972', (10, 13))	('miR-302b', 'Gene', '442894', (207, 215))	('miR', 'Gene', '220972', (183, 186))	('miR', 'Gene', '220972', (207, 210))	('miR', 'Gene', (193, 196))	('IDH', 'Gene', (220, 223))	('miR-1304', 'Gene', (193, 201))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', '220972', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH', 'Gene', (91, 94))	('miR', 'Gene', (10, 13))	('IDH', 'Gene', (68, 71))	('miR', 'Gene', (183, 186))	('miR-1304', 'Gene', '100302240', (193, 201))	('miR', 'Gene', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (231, 239))	('tumors than IDH WT tumors', 'Disease', (79, 104))	('IDH', 'Gene', '3417', (220, 223))	('miR', 'Gene', (151, 154))	('miR', 'Gene', (174, 177))	('miR-10b', 'Gene', (174, 181))	('IDH', 'Gene', '3417', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
220519	28698530	miR-7-mediated silencing of OGT leads to degradation of transcription factors involved in VEGFR2 expression which, in turn, down-regulates VEGFR2 and angiogenesis.	('miR-7', 'Gene', '10859', (0, 5))	('VEGFR2', 'Gene', '3791', (90, 96))	('VEGFR2', 'Gene', '3791', (139, 145))	('angiogenesis', 'CPA', (150, 162))	('silencing', 'Var', (15, 24))	('VEGFR2', 'Gene', (90, 96))	('down-regulates', 'NegReg', (124, 138))	('OGT', 'Gene', (28, 31))	('VEGFR2', 'Gene', (139, 145))	('OGT', 'Gene', '8473', (28, 31))	('miR-7', 'Gene', (0, 5))	('degradation', 'MPA', (41, 52))
220532	28698530	have shown that inhibition of miR-21 leads to elevation of RECK and TIMP3 expression, and therefore decreases MMPs and invasion in glioma cells lines in vitro as well as a U87 glioma xenograft model in vivo.	('elevation', 'PosReg', (46, 55))	('expression', 'MPA', (74, 84))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', (131, 137))	('RECK', 'Gene', (59, 63))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('miR-21', 'Gene', '406991', (30, 36))	('decreases', 'NegReg', (100, 109))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('TIMP3', 'Gene', (68, 73))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('TIMP3', 'Gene', '7078', (68, 73))	('RECK', 'Gene', '8434', (59, 63))	('miR-21', 'Gene', (30, 36))	('inhibition', 'Var', (16, 26))
220534	28698530	Among other cellular functions, such as cell proliferation and survival, miR-34a decreases invasion in glioblastoma cell lines, in part by targeting HGF/c-Met and Notch1/2 signaling.	('decreases', 'NegReg', (81, 90))	('Notch1', 'Gene', (163, 169))	('miR-34a', 'Var', (73, 80))	('c-Met', 'Gene', (153, 158))	('HGF', 'Gene', (149, 152))	('Notch1', 'Gene', '4851', (163, 169))	('c-Met', 'Gene', '4233', (153, 158))	('glioblastoma', 'Disease', (103, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('HGF', 'Gene', '3082', (149, 152))	('targeting', 'Reg', (139, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
220556	28698530	Mutations in IDH and receptor tyrosine kinase pathways, both common genetic mutations in gliomas, are also believed to play a role in metabolic reprogramming.	('IDH', 'Gene', '3417', (13, 16))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('IDH', 'Gene', (13, 16))	('receptor tyrosine kinase pathways', 'Pathway', (21, 54))
220558	28698530	The IDH mutant protein then converts alpha-KG to 2-hydroxyglutarate.	('converts', 'Reg', (28, 36))	('IDH', 'Gene', '3417', (4, 7))	('alpha-KG to 2-hydroxyglutarate', 'MPA', (37, 67))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (49, 67))	('alpha-KG', 'Chemical', 'MESH:D007656', (37, 45))	('mutant', 'Var', (8, 14))	('protein', 'Protein', (15, 22))	('IDH', 'Gene', (4, 7))
220559	28698530	The accumulation of 2-hydroxyglutarate in IDH mutant gliomas inhibits DNA and histone demethylation enzymes, referred to as dioxygenases, and leads to the development of the hypermethylated glioma CpG island phenotype.	('oxygen', 'Chemical', 'MESH:D010100', (126, 132))	('IDH', 'Gene', (42, 45))	('accumulation', 'PosReg', (4, 16))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('hypermethylated', 'MPA', (174, 189))	('IDH', 'Gene', '3417', (42, 45))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('leads to', 'Reg', (142, 150))	('development', 'Reg', (155, 166))	('inhibits', 'NegReg', (61, 69))	('glioma', 'Disease', (190, 196))	('mutant', 'Var', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Disease', (53, 59))	('gliomas', 'Disease', (53, 60))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (20, 38))
220561	28698530	In presence of an IDH mutation, levels of alpha-ketoglutarate are reduced, which therefore results in decreased degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) by alpha-KG-dependent prolylhydroxylases.	('reduced', 'NegReg', (66, 73))	('mutation', 'Var', (22, 30))	('IDH', 'Gene', (18, 21))	('HIF-1alpha', 'Gene', '3091', (160, 170))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (127, 158))	('levels of alpha-ketoglutarate', 'MPA', (32, 61))	('IDH', 'Gene', '3417', (18, 21))	('hypoxia-inducible factor 1alpha', 'Gene', (127, 158))	('alpha-KG', 'Chemical', 'MESH:D007656', (175, 183))	('HIF-1alpha', 'Gene', (160, 170))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (42, 61))	('degradation', 'MPA', (112, 123))	('decreased', 'NegReg', (102, 111))
220623	28698530	Tumor suppressor miRNAs can also be replenished to restore anti-tumor functions by approaches including small molecule modulators, reversal of epigenetic silencing, or introducing miRNA mimics.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (64, 69))	('epigenetic silencing', 'Var', (143, 163))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
220624	28698530	Small molecule modulators of miRNA function are considered to be potential therapeutic candidates, since they are easily delivered and relatively stable.	('modulators', 'Var', (15, 25))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))
220625	28698530	Epigenetic silencing of miRNA can be reversed by hypomethylating agents such as decitabine or 5-azacytidine.	('decitabine', 'Chemical', 'MESH:D000077209', (80, 90))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('Epigenetic silencing', 'Var', (0, 20))	('5-azacytidine', 'Chemical', 'MESH:D001374', (94, 107))
220688	28698530	Given that the targets of miRNAs may involve multiple pathways via imperfect matching with 3'-UTRs, off-target gene silencing of tumor suppressor genes may lead to toxicities and/or reduced therapeutic effects.	('lead to', 'Reg', (156, 163))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('toxicities', 'Disease', 'MESH:D064420', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('gene silencing', 'Var', (111, 125))	('therapeutic effects', 'CPA', (190, 209))	('tumor', 'Disease', (129, 134))	('toxicities', 'Disease', (164, 174))	('reduced', 'NegReg', (182, 189))
220709	26849038	Tumours with the 1p/19q codeletion more commonly show heterogeneous signal intensity, particularly on T2 weighted imaging; calcifications; an indistinct margin; and mildly increased perfusion and metabolism than 1p/19q intact tumours.	('metabolism', 'CPA', (196, 206))	('increased', 'PosReg', (172, 181))	('calcification', 'Disease', (123, 136))	('T2 weighted imaging', 'MPA', (102, 121))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('perfusion', 'MPA', (182, 191))	('heterogeneous signal intensity', 'MPA', (54, 84))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumours', 'Disease', (226, 233))	('calcification', 'Disease', 'MESH:D002114', (123, 136))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('1p/19q', 'Var', (17, 23))
220716	26849038	The molecular hallmark feature of oligodendroglioma is codeletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), which is present in about 60-90% of histopathologically diagnosed oligodendroglioma.	('oligodendroglioma', 'Disease', 'MESH:D009837', (34, 51))	('codeletion', 'Var', (55, 65))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('oligodendroglioma', 'Disease', (211, 228))	('oligodendroglioma', 'Disease', 'MESH:D009837', (211, 228))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))	('short arm', 'Phenotype', 'HP:0009824', (73, 82))	('oligodendroglioma', 'Disease', (34, 51))
220717	26849038	Mixed oligoastrocytoma also commonly harbours the 1p/19q co-deletion, although less frequently (30-50%) than oligodendroglioma.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('harbours', 'Reg', (37, 45))	('1p/19q co-deletion', 'Var', (50, 68))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (6, 22))	('oligoastrocytoma', 'Disease', (6, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('oligodendroglioma', 'Disease', (109, 126))	('oligodendroglioma', 'Disease', 'MESH:D009837', (109, 126))
220724	26849038	This treatment regime is now the standard of care for patients with 1p/19q codeleted anaplastic oligodendroglioma.	('1p/19q', 'Var', (68, 74))	('patients', 'Species', '9606', (54, 62))	('anaplastic oligodendroglioma', 'Disease', (85, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (85, 113))
220814	26849038	Correlation of Ktrans with tumour grade is lower than that of rCBV, and it is more commonly used in the assessment of treatment effects.	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('Correlation', 'MPA', (0, 11))	('rCBV', 'Chemical', '-', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('Ktrans', 'Var', (15, 21))	('tumour', 'Disease', (27, 33))	('lower', 'NegReg', (43, 48))
220839	26849038	In the context of treatment monitoring, several studies have shown that 11C-MET accurately detects tumour recurrence.	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('detects', 'Reg', (91, 98))	('tumour', 'Disease', (99, 105))	('11C-MET', 'Var', (72, 79))	('11C-MET', 'Chemical', '-', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
220841	26849038	Several imaging features are more commonly seen in 1p/19q codeleted tumours, which may be used to distinguish these from 1p/19q intact tumours (Table 1).	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('1p/19q', 'Var', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (68, 75))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
220849	26849038	A sharp tumour border, however, is only rarely seen in codeleted tumours and therefore makes a 1p/19q intact tumour more likely.	('tumour', 'Disease', (8, 14))	('tumour border', 'Disease', 'MESH:D001882', (8, 21))	('tumour border', 'Disease', (8, 21))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('1p/19q intact', 'Var', (95, 108))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('tumour', 'Disease', (65, 71))	('tumours', 'Disease', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
220864	26849038	In an unselected patient population, fluorine-18 fluoro-ethyl-tyrosine PET also failed to reliably predict the 1p/19q codeletion in the individual patient, mostly because of overlapping findings between oligodendroglial and high-grade astrocytic tumours.	('astrocytic tumours', 'Disease', 'MESH:D001254', (235, 253))	('oligodendroglial', 'Disease', (203, 219))	('patient', 'Species', '9606', (147, 154))	('fluorine-18 fluoro-ethyl-tyrosine', 'Chemical', '-', (37, 70))	('1p/19q codeletion', 'Var', (111, 128))	('astrocytic tumours', 'Disease', (235, 253))	('patient', 'Species', '9606', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('tumours', 'Phenotype', 'HP:0002664', (246, 253))
220874	26849038	With metabolic PET imaging, 11C-MET seems to outperform 18F-FDG both for tumour grading and detection of tumour recurrence.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumour', 'Disease', (73, 79))	('tumour', 'Disease', (105, 111))	('11C-MET', 'Var', (28, 35))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('11C-MET', 'Chemical', '-', (28, 35))	('18F-FDG', 'Chemical', 'MESH:D019788', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
220875	26849038	The imaging features of the 1p/19q codeleted genotype are those traditionally considered typical of oligodendroglioma: indistinct tumour margin, heterogeneous signal intensity and calcifications.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('oligodendroglioma', 'Disease', (100, 117))	('1p/19q', 'Var', (28, 34))	('calcification', 'Disease', 'MESH:D002114', (180, 193))	('heterogeneous signal intensity', 'MPA', (145, 175))	('tumour', 'Disease', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('calcification', 'Disease', (180, 193))	('oligodendroglioma', 'Disease', 'MESH:D009837', (100, 117))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
220928	31001524	Our method (MDRANBL+DRANBD) achieved 0.862 DICE_1, 0.703 DICE_2, and the average score of 0.783.	('DICE_1', 'Gene', (43, 49))	('0.862', 'Var', (37, 42))	('DICE_1', 'Gene', '26512', (43, 49))	('0.703', 'Var', (51, 56))
220929	31001524	Using a single scale nuclei segmentation method (DRANBL+DRANBD), we obtained 0.853 DICE_1, 0.701 DICE_2, and the average score of 0.777, worse than those of the multiscale aggregation.	('DICE_1', 'Gene', '26512', (83, 89))	('DICE_1', 'Gene', (83, 89))	('0.701', 'Var', (91, 96))
220956	30412573	Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood.	('mutations', 'Var', (118, 127))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
220957	30412573	Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer.	('mutated trinucleotides', 'Var', (51, 73))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (197, 203))	('trinucleotides', 'Var', (59, 73))	('trinucleotides', 'Chemical', '-', (59, 73))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
220959	30412573	We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Cancer', 'Disease', (190, 196))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('Cancer', 'Disease', 'MESH:D009369', (190, 196))
220960	30412573	We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types.	('mutations', 'Var', (145, 154))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))
220961	30412573	We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair.	('AID', 'Gene', '57379', (84, 87))	('AID', 'Gene', (84, 87))	('mutations', 'Var', (44, 53))	('activity', 'MPA', (102, 110))	('deficient', 'Var', (115, 124))	('mismatch repair', 'MPA', (125, 140))
220962	30412573	We also identify negative associations (odds ratio < 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively.	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('mutations', 'Var', (206, 215))	('IDH1', 'Gene', '3417', (219, 223))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (254, 274))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (254, 274))	('brain cancers', 'Disease', 'MESH:D001932', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('KRAS', 'Gene', (228, 232))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (254, 273))	('IDH1', 'Gene', (219, 223))	('KRAS', 'Gene', '3845', (228, 232))	('brain cancers', 'Disease', (236, 249))	('lung adenocarcinomas', 'Disease', (254, 274))
220965	30412573	Cancer develops when cells acquire somatic driver mutations that confer a growth advantage.	('mutations', 'Var', (50, 59))	('growth advantage', 'CPA', (74, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
220968	30412573	In other cases, the altered trinucleotide preferences arising from a signature would have increased the likelihood of the associated driver mutation arising.	('driver mutation', 'MPA', (133, 148))	('trinucleotide preferences', 'Var', (28, 53))	('increased', 'PosReg', (90, 99))	('altered', 'Reg', (20, 27))	('trinucleotide', 'Chemical', '-', (28, 41))
220971	30412573	We examine known and novel associations between driver mutations and mutational signatures arising from processes such as defective proofreading during DNA replication, AID/APOBEC enzyme-associated mutagenesis and deficient mismatch repair.	('AID', 'Gene', '57379', (169, 172))	('AID', 'Gene', (169, 172))	('proofreading', 'MPA', (132, 144))	('mutagenesis', 'Var', (198, 209))	('mismatch repair', 'MPA', (224, 239))	('defective', 'Var', (122, 131))	('deficient', 'Var', (214, 223))
220974	30412573	Driver mutations typically affect certain cancer-associated genes by, for example, activating an oncogene or inactivating a tumour suppressor gene.	('mutations', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('inactivating', 'NegReg', (109, 121))	('activating', 'Reg', (83, 93))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('affect', 'Reg', (27, 33))	('tumour', 'Disease', (124, 130))	('oncogene', 'Protein', (97, 105))
220975	30412573	Research in recent years has led to the identification of hundreds of driver mutations in cancer-associated genes, but only a handful of driver mutations are sufficient for oncogenesis in a single cancer sample.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (197, 203))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
220979	30412573	Mutational signatures are displayed according to six substitution types (C>A, C>G, C>T, T>A, T>C and T>G) in the context of all trinucleotide combinations, thus representing each of the 96 possible mutation frequencies.	('C>G', 'Var', (78, 81))	('T>C and T>G', 'Var', (93, 104))	('C>T', 'Var', (83, 86))	('T>A', 'Var', (88, 91))	('T>G', 'Var', (101, 104))	('trinucleotide', 'Chemical', '-', (128, 141))	('C>A', 'Var', (73, 76))
220983	30412573	A recent study suggested that approximately two-thirds of mutations in human cancers arise due to errors in DNA replication occurring over time.	('errors', 'Var', (98, 104))	('mutations', 'Var', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (71, 76))
220984	30412573	Even cancers that have a strong environmental component therefore still harbour mutations incurred by unavoidable DNA replication errors.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('mutations', 'Var', (80, 89))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('harbour', 'Reg', (72, 79))
220985	30412573	We therefore undertook this study to determine the association between common driver mutations and distinct mutational processes in human cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (85, 94))	('human', 'Species', '9606', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
220986	30412573	Many mutational processes operating in cellular DNA alter the frequencies of mutation accumulation at certain trinucleotide contexts, thus resulting in these definable mutational signatures.	('definable', 'MPA', (158, 167))	('mutation', 'Var', (77, 85))	('alter', 'Reg', (52, 57))	('trinucleotide', 'Chemical', '-', (110, 123))	('resulting in', 'Reg', (139, 151))	('mutational signatures', 'MPA', (168, 189))
220992	30412573	For example, Signature 1 exhibits clock-like properties, and the number of mutations in this signature correlates with age across a majority of cancer types.	('correlates', 'Reg', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (75, 84))	('clock-like', 'MPA', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
220994	30412573	By investigating recurrence of mutations in known cancer driver genes (see Methods and S1 Fig), we selected 50 driver mutations for potential association with mutational signatures (S2 Table).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (118, 127))	('association', 'Interaction', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
220995	30412573	These mutations alter 21 different genes, with TP53 (n = 10), KRAS (n = 7), PIK3CA (n = 4) and PTEN (n = 4) harbouring at total of 50% of all of the driver mutations selected.	('alter', 'Reg', (16, 21))	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (62, 66))	('TP53', 'Gene', (47, 51))	('mutations', 'Var', (156, 165))	('PIK3CA', 'Gene', (76, 82))	('PTEN', 'Gene', (95, 99))	('TP53', 'Gene', '7157', (47, 51))	('PTEN', 'Gene', '5728', (95, 99))	('PIK3CA', 'Gene', '5290', (76, 82))	('mutations', 'Var', (6, 15))
220996	30412573	We next defined the landscape of somatic driver mutations across the cancer samples in our cohort (Fig 1).	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (69, 75))
220998	30412573	These mutations include BRAF p.V600E, which was also the most common driver mutation in our cohort (n = 287).	('p.V600E', 'Var', (29, 36))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('p.V600E', 'Mutation', 'rs113488022', (29, 36))
220999	30412573	The BRAF p.V600E mutation was most frequent in skin cutaneous melanoma and thyroid carcinoma, affecting 43% (n = 193) and 56% (n = 29) of samples respectively.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (47, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('skin cutaneous melanoma', 'Disease', (47, 70))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (75, 92))	('p.V600E', 'Var', (9, 16))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (75, 92))	('BRAF', 'Gene', (4, 8))	('thyroid carcinoma', 'Disease', (75, 92))	('BRAF', 'Gene', '673', (4, 8))	('frequent', 'Reg', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
221000	30412573	Of the other frequent mutations, four mutations altered KRAS amino acid G12, primarily affecting colorectal, lung and pancreatic adenocarcinomas.	('colorectal', 'Disease', 'MESH:D015179', (97, 107))	('KRAS', 'Gene', (56, 60))	('colorectal', 'Disease', (97, 107))	('KRAS', 'Gene', '3845', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('affecting', 'Reg', (87, 96))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (118, 144))	('pancreatic adenocarcinomas', 'Disease', (118, 144))	('mutations', 'Var', (22, 31))	('lung', 'Disease', (109, 113))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (118, 144))
221001	30412573	PIK3CA (p.E545K and p.H1047R) and TP53 (p.R248Q and p.R273C) harboured two highly frequent mutations each, and IDH1 p.R132H was most frequent in brain lower grade glioma (57%, n = 116).	('glioma', 'Disease', (163, 169))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('IDH1', 'Gene', (111, 115))	('p.R132H', 'Mutation', 'rs121913500', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('PIK3CA', 'Gene', '5290', (0, 6))	('p.R248Q', 'Mutation', 'rs11540652', (40, 47))	('p.R132H', 'Var', (116, 123))	('TP53', 'Gene', (34, 38))	('p.H1047R', 'Var', (20, 28))	('frequent', 'Reg', (133, 141))	('IDH1', 'Gene', '3417', (111, 115))	('p.E545K', 'Var', (8, 15))	('p.R273C', 'Var', (52, 59))	('p.R248Q', 'Var', (40, 47))	('PIK3CA', 'Gene', (0, 6))	('p.H1047R', 'Mutation', 'rs121913279', (20, 28))	('p.E545K', 'Mutation', 'rs104886003', (8, 15))	('TP53', 'Gene', '7157', (34, 38))	('p.R273C', 'Mutation', 'rs121913343', (52, 59))
221002	30412573	Taken together, we found these driver mutations to generally represent known frequencies in other cancer cohorts.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
221004	30412573	To exclude potentially spurious associations, we only examined associations in which >= 10 samples in a given cancer type harboured the driver mutation of interest, and >= 10 samples in that same cancer type harboured the signature of interest at a frequency of >= 20%.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (110, 116))	('harboured', 'Reg', (122, 131))	('mutation', 'Var', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
221006	30412573	These associations arose across 11 cancer types, affecting 9 mutational signatures and 18 driver mutations from 11 different genes (Table 2).	('arose', 'Reg', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutational', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('affecting', 'Reg', (49, 58))	('cancer', 'Disease', (35, 41))
221008	30412573	These negative associations arose between signature 1 and IDH1 p.R132H in brain lower grade glioma and glioblastoma multiforme (Table 2).	('IDH1', 'Gene', '3417', (58, 62))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (103, 126))	('negative', 'NegReg', (6, 14))	('glioma', 'Disease', (92, 98))	('p.R132H', 'Var', (63, 70))	('glioblastoma multiforme', 'Disease', (103, 126))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('p.R132H', 'Mutation', 'rs121913500', (63, 70))	('IDH1', 'Gene', (58, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
221012	30412573	To validate our methodology, we first investigated the six significant associations that we observed between driver mutations and signature 10 across uterine corpus endometrial carcinoma and colorectal adenocarcinoma (Table 2).	('endometrial carcinoma and colorectal adenocarcinoma', 'Disease', 'MESH:D016889', (165, 216))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (165, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('signature 10', 'Gene', (130, 142))	('mutations', 'Var', (116, 125))
221013	30412573	Signature 10 arises in cancers which harbour Polymerase Epsilon (POLE) exonuclease domain mutations.	('domain mutations', 'Var', (83, 99))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
221014	30412573	In our study, we found the POLE p.P286R (c.857C>G) mutation to be significantly associated with signature 10 in uterine corpus endometrial carcinoma (Table 2).	('c.857C>G', 'Mutation', 'c.857C>G', (41, 49))	('p.P286R (c.857C>G', 'Var', (32, 49))	('endometrial carcinoma', 'Disease', (127, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (127, 148))	('associated', 'Reg', (80, 90))	('p.P286R', 'Mutation', 'p.P286R', (32, 39))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (127, 148))
221015	30412573	The trinucleotide context of this mutation (C[C>G]T) is not frequently observed in signature 10 (Fig 3A), supporting existing literature that demonstrates the POLE p.P286R mutation to underlie many instances of the presence of signature 10 in cancer.	('p.P286R', 'Mutation', 'p.P286R', (164, 171))	('trinucleotide', 'Chemical', '-', (4, 17))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('p.P286R', 'Var', (164, 171))
221016	30412573	The remaining driver mutations that we found to be significantly associated with signature 10 (PIK3CA p.R88Q, PTEN p.R130Q, ARID1A p.R1989* and TP53 p.R213*) all occur in a T[C>T]G context (Table 2).	('TP53', 'Gene', '7157', (144, 148))	('p.R130Q', 'Var', (115, 122))	('TP53', 'Gene', (144, 148))	('PIK3CA', 'Gene', (95, 101))	('PTEN', 'Gene', '5728', (110, 114))	('p.R130Q', 'Mutation', 'rs121909229', (115, 122))	('p.R1989*', 'Var', (131, 139))	('PIK3CA', 'Gene', '5290', (95, 101))	('p.R213*', 'Var', (149, 156))	('p.R88Q', 'Var', (102, 108))	('p.R88Q', 'Mutation', 'rs121913287', (102, 108))	('p.R213*', 'Mutation', 'p.R213*', (149, 156))	('ARID1A', 'Gene', '8289', (124, 130))	('ARID1A', 'Gene', (124, 130))	('p.R1989*', 'SUBSTITUTION', 'None', (131, 139))	('PTEN', 'Gene', (110, 114))
221018	30412573	In fact, in colorectal cancer, TP53 p.R213* mutations have been suggested to arise in response to POLE exonuclease domain mutation, where DNA methylation at this CpG trinucleotide may further enhance the likelihood of mutation occurrence.	('colorectal cancer', 'Disease', (12, 29))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('trinucleotide', 'Chemical', '-', (166, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('p.R213*', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('p.R213*', 'Mutation', 'p.R213*', (36, 43))
221020	30412573	We found that a striking 36% (n = 14) of the associations that we identified arose between driver mutations in PIK3CA and signatures 2 or 13 across six different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('associations', 'Interaction', (45, 57))	('cancer', 'Disease', (162, 168))	('arose', 'Reg', (77, 82))	('PIK3CA', 'Gene', (111, 117))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PIK3CA', 'Gene', '5290', (111, 117))
221022	30412573	APOBEC activity has been implicated in the generation of specific PIK3CA mutations at p.E542K (c.1624G>A) and p.E545K (c.1633G>A), and we identified associations with both mutations in our study.	('c.1633G>A', 'Var', (119, 128))	('c.1624G>A', 'Var', (95, 104))	('c.1633G>A', 'Mutation', 'rs104886003', (119, 128))	('PIK3CA', 'Gene', (66, 72))	('p.E545K (c.1633G>A', 'Var', (110, 128))	('c.1624G>A', 'Mutation', 'rs121913273', (95, 104))	('p.E542K (c.1624G>A', 'Var', (86, 104))	('p.E542K', 'Mutation', 'rs121913273', (86, 93))	('p.E545K', 'Mutation', 'rs104886003', (110, 117))	('PIK3CA', 'Gene', '5290', (66, 72))	('implicated', 'Reg', (25, 35))
221023	30412573	In fact, both of these mutations match the extended context of the [T/C]TC[A/G] motif which has been established for APOBEC3A binding in single-stranded DNA (ssDNA).	('binding', 'Interaction', (126, 133))	('mutations', 'Var', (23, 32))	('APOBEC3A', 'Gene', (117, 125))	('APOBEC3A', 'Gene', '200315', (117, 125))
221024	30412573	In addition to the PIK3CA mutations, we found signatures 2 and 13 to be associated with ERBB2 p.S310F (c.929C>T) mutation in bladder cancer, and signature 13 to be associated with PPP2R1A p.P179R (c.536C>G) mutation in uterine corpus endometrial carcinoma (Table 2).	('ERBB2', 'Gene', (88, 93))	('PIK3CA', 'Gene', '5290', (19, 25))	('endometrial carcinoma', 'Disease', (234, 255))	('associated', 'Reg', (72, 82))	('c.929C>T', 'Mutation', 'rs1057519816', (103, 111))	('ERBB2', 'Gene', '2064', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (234, 255))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('PIK3CA', 'Gene', (19, 25))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (234, 255))	('associated', 'Reg', (164, 174))	('p.S310F (c.929C>T) mutation', 'Var', (94, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('PPP2R1A', 'Gene', '5518', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('c.536C>G', 'Mutation', 'rs786205228', (197, 205))	('p.S310F', 'Mutation', 'rs1057519816', (94, 101))	('PPP2R1A', 'Gene', (180, 187))	('p.P179R', 'Mutation', 'rs786205228', (188, 195))	('p.P179R (c.536C>G', 'Var', (188, 205))
221025	30412573	The broader contexts of these mutations, T[C>T]C and C[C>G]C respectively, do not match well with the typical APOBEC3A/B mutational context.	('C[C>G]', 'Var', (53, 59))	('T[C>T]C', 'Var', (41, 48))	('APOBEC3A/B', 'Gene', (110, 120))	('APOBEC3A/B', 'Gene', '100913187;200315;9582', (110, 120))
221026	30412573	Using ssDNA folding predictions (see Methods), we find that both of the cytosines mutated in the ERBB2 and PPP2R1A drivers are predicted to be located at stem-loops, and that these loops are greater than three bases in size (S4 Fig).	('PPP2R1A', 'Gene', (107, 114))	('PPP2R1A', 'Gene', '5518', (107, 114))	('mutated', 'Var', (82, 89))	('ERBB2', 'Gene', (97, 102))	('ERBB2', 'Gene', '2064', (97, 102))
221028	30412573	Confirmation of whether and how APOBEC3A/B binds and mutates these DNA sequences will need to be experimentally validated.	('binds', 'Interaction', (43, 48))	('mutates', 'Var', (53, 60))	('APOBEC3A/B', 'Gene', '100913187;200315;9582', (32, 42))	('APOBEC3A/B', 'Gene', (32, 42))
221031	30412573	Among the remaining five mutations is BRAF p.V600E, which is significantly associated with signatures 6 and 26 in colorectal adenocarcinoma (Table 2).	('p.V600E', 'Mutation', 'rs113488022', (43, 50))	('BRAF', 'Gene', '673', (38, 42))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (114, 139))	('p.V600E', 'Var', (43, 50))	('BRAF', 'Gene', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('colorectal adenocarcinoma', 'Disease', (114, 139))	('associated', 'Reg', (75, 85))
221032	30412573	The mechanism underlying the association between BRAF p.V600E and mismatch repair deficiency has not yet been established to our knowledge.	('p.V600E', 'Var', (54, 61))	('BRAF', 'Gene', '673', (49, 53))	('mismatch', 'MPA', (66, 74))	('BRAF', 'Gene', (49, 53))	('p.V600E', 'Mutation', 'rs113488022', (54, 61))
221033	30412573	It is possible that this association arises because acquisition of a BRAF p.V600E mutation predisposes otherwise normal cells to developing mismatch repair deficiency, though this hypothesis requires further investigation.	('p.V600E', 'Mutation', 'rs113488022', (74, 81))	('p.V600E', 'Var', (74, 81))	('developing mismatch repair deficiency', 'MPA', (129, 166))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))
221034	30412573	In support of this hypothesis, BRAF p.V600E mutations do occur much less commonly in hereditary nonpolyposis colorectal cancers -cancers which frequently arise due to germline mismatch repair defects.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p.V600E', 'Mutation', 'rs113488022', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('p.V600E', 'Var', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('BRAF', 'Gene', '673', (31, 35))	('hereditary nonpolyposis colorectal cancers -cancers', 'Disease', 'MESH:D003123', (85, 136))	('BRAF', 'Gene', (31, 35))
221035	30412573	Our results suggest that many driver mutations in cancers with mismatch repair deficiencies may arise independently from, or prior to, loss of mismatch repair.	('deficiencies', 'Var', (79, 91))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('mismatch repair', 'Protein', (63, 78))	('mutations', 'Var', (37, 46))	('arise', 'Reg', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
221038	30412573	These negative associations arose between the IDH1 p.R132H driver mutation and signature 1, occurring in brain lower grade glioma and in glioblastoma multiforme (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('IDH1', 'Gene', (46, 50))	('glioblastoma multiforme', 'Disease', (137, 160))	('p.R132H', 'Var', (51, 58))	('IDH1', 'Gene', '3417', (46, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('glioma', 'Disease', (123, 129))	('p.R132H', 'Mutation', 'rs121913500', (51, 58))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (137, 160))
221039	30412573	Demonstrating this negative association, we observed a significantly lower proportion of signature 1 mutations in IDH1 p.R132H mutant rather than wild-type brain lower grade glioma (P < 0.0001) and glioblastoma multiforme (P < 0.001; Fig 4A) by two-sided Mann Whitney U-Test.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('IDH1', 'Gene', (114, 118))	('glioblastoma multiforme', 'Disease', (198, 221))	('mutations', 'Var', (101, 110))	('p.R132H', 'Mutation', 'rs121913500', (119, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('lower', 'NegReg', (69, 74))	('glioma', 'Disease', (174, 180))	('IDH1', 'Gene', '3417', (114, 118))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (198, 221))	('p.R132H', 'Var', (119, 126))
221041	30412573	Consistent with our observed association, we found that patients with IDH1 p.R132H mutated tumours in our cohort were generally younger than patients with IDH1 p.R132H wild-type tumours.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('patients', 'Species', '9606', (56, 64))	('IDH1', 'Gene', (155, 159))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('p.R132H', 'Mutation', 'rs121913500', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('p.R132H', 'Mutation', 'rs121913500', (160, 167))	('IDH1', 'Gene', '3417', (155, 159))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('tumours', 'Disease', (91, 98))	('IDH1', 'Gene', '3417', (70, 74))	('tumours', 'Disease', (178, 185))	('p.R132H', 'Var', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (141, 149))	('IDH1', 'Gene', (70, 74))
221043	30412573	IDH1 mutations have been found to less commonly occur in older people with glioblastoma, and the results of our mutational signature analyses provide molecular support for this finding in glioblastoma multiforme and brain lower grade glioma.	('glioblastoma', 'Disease', (75, 87))	('people', 'Species', '9606', (63, 69))	('glioblastoma', 'Disease', (188, 200))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('mutations', 'Var', (5, 14))	('glioblastoma multiforme', 'Disease', (188, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (188, 211))	('IDH1', 'Gene', (0, 4))	('glioma', 'Disease', (234, 240))	('IDH1', 'Gene', '3417', (0, 4))
221044	30412573	While age would increase the likelihood of any mutation arising by chance alone, our results suggest that age might disproportionately favour the occurrence of mutations other than IDH1 p.R132H in these brain cancers, or that this mutation confers a greater selective advantage in younger people.	('brain cancers', 'Disease', (203, 216))	('p.R132H', 'Mutation', 'rs121913500', (186, 193))	('favour', 'PosReg', (135, 141))	('mutations', 'Var', (160, 169))	('brain cancers', 'Disease', 'MESH:D001932', (203, 216))	('people', 'Species', '9606', (289, 295))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('IDH1', 'Gene', (181, 185))	('p.R132H', 'Var', (186, 193))	('IDH1', 'Gene', '3417', (181, 185))
221047	30412573	KRAS p.G12D transition mutations are the most common KRAS somatic mutation arising in the lung adenocarcinomas of people who have never smoked.	('p.G12D transition', 'Var', (5, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (90, 110))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (90, 110))	('people', 'Species', '9606', (114, 120))	('KRAS', 'Gene', (53, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('p.G12D', 'Mutation', 'rs121913529', (5, 11))	('KRAS', 'Gene', '3845', (53, 57))	('KRAS', 'Gene', (0, 4))	('lung adenocarcinomas', 'Disease', (90, 110))	('KRAS', 'Gene', '3845', (0, 4))
221051	30412573	It has been suggested that approximately two-thirds of mutations in cancer arise from DNA replication errors.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('arise from', 'Reg', (75, 85))
221053	30412573	24 of the 36 associations (66%) arising across cancer types occur in cases where the trinucleotide context of the driver mutation frequently arises in the associated signature, implying a possibly direct causal relationship between defective DNA replication and occurrence of that driver mutation.	('trinucleotide', 'Chemical', '-', (85, 98))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
221055	30412573	Similarly, it is possible that somatic events that are causal in generating a replication-associated mutational signature arise as a result of exogenous environmental mutagens (for example, APOBEC enzyme activity could be altered following viral infection).	('viral infection', 'Disease', 'MESH:D001102', (240, 255))	('activity', 'MPA', (204, 212))	('mutational', 'Var', (101, 111))	('viral infection', 'Disease', (240, 255))	('APOBEC', 'Gene', (190, 196))	('altered', 'Reg', (222, 229))
221057	30412573	We observed a significant association in our study between BRAF p.V600M (c.1798G>A) and signature 7 in skin cutaneous melanoma (Table 2).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('c.1798G>A', 'Mutation', 'rs121913378', (73, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (108, 126))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 126))	('p.V600M', 'Mutation', 'rs121913378', (64, 71))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('skin cutaneous melanoma', 'Disease', (103, 126))	('p.V600M (c.1798G>A', 'Var', (64, 82))
221058	30412573	While the A[C>T]T trinucleotide context of the BRAF p.V600M mutation is infrequent (0.4%) within signature 7, C>T transition mutations within a pyrimidine dimer context do generally characterise this signature.	('p.V600M', 'Mutation', 'rs121913378', (52, 59))	('pyrimidine', 'Chemical', 'MESH:C030986', (144, 154))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('C>T', 'Var', (110, 113))	('trinucleotide', 'Chemical', '-', (18, 31))	('p.V600M', 'Var', (52, 59))
221059	30412573	Of note, BRAF p.V600E mutations more commonly arise than p.V600M mutations in melanomas.	('melanomas', 'Disease', (78, 87))	('p.V600E', 'Var', (14, 21))	('BRAF', 'Gene', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('p.V600M', 'Mutation', 'rs121913378', (57, 64))	('p.V600E', 'Mutation', 'rs113488022', (14, 21))	('arise', 'Reg', (46, 51))	('BRAF', 'Gene', '673', (9, 13))
221060	30412573	The BRAF p.V600E (c.1799T>A) mutation is not a characteristic C>T transition and various models have been proposed for how such mutations may result from exposure to UV radiation.	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('c.1799T>A', 'Mutation', 'rs113488022', (18, 27))	('p.V600E (c.1799T>A', 'Var', (9, 27))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))
221061	30412573	Interestingly, we did not find a significant association between signature 7 and BRAF p.V600E in our study (P = 0.7086, S3 Table).	('p.V600E', 'Var', (86, 93))	('BRAF', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (81, 85))	('p.V600E', 'Mutation', 'rs113488022', (86, 93))
221062	30412573	Melanomas arising on skin without chronic sun-induced damage often harbour BRAF p.V600E mutations, while those arising on skin with chronic sun-induced damage typically harbour other BRAF mutations.	('p.V600E', 'Mutation', 'rs113488022', (80, 87))	('p.V600E', 'Var', (80, 87))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('BRAF', 'Gene', '673', (75, 79))	('Melanomas', 'Disease', (0, 9))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (183, 187))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAF', 'Gene', (183, 187))
221063	30412573	Additionally, BRAF p.V600E mutations are commonly found in tumours from non-sun-exposed tissues such as thyroid and colorectal cancers, demonstrating that this mutation can arise following mutagenic processes other than UV radiation exposure.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('p.V600E', 'Mutation', 'rs113488022', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancers', 'Disease', (116, 134))	('p.V600E', 'Var', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('thyroid', 'Disease', (104, 111))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('BRAF', 'Gene', '673', (14, 18))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('BRAF', 'Gene', (14, 18))	('colorectal cancers', 'Disease', 'MESH:D015179', (116, 134))	('thyroid', 'Disease', 'MESH:D013959', (104, 111))	('tumours', 'Disease', (59, 66))
221064	30412573	In some melanomas, and particularly those with a low contribution from signature 7, we suggest that BRAF p.V600E mutations may also arise independently from UV radiation-associated mutagenesis.	('p.V600E', 'Mutation', 'rs113488022', (105, 112))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Disease', 'MESH:D008545', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('p.V600E', 'Var', (105, 112))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('melanomas', 'Disease', (8, 17))
221065	30412573	We note the possibility though, that some BRAF p.V600E mutations do arise as a result of mutagenesis following UV radiation exposure, and that this mutation could then confer a particularly strong selective advantage over other pyrimidine dimer-associated mutations, accounting for its observed recurrence in melanoma.	('pyrimidine', 'Chemical', 'MESH:C030986', (228, 238))	('advantage', 'PosReg', (207, 216))	('BRAF', 'Gene', '673', (42, 46))	('p.V600E', 'Mutation', 'rs113488022', (47, 54))	('p.V600E', 'Var', (47, 54))	('BRAF', 'Gene', (42, 46))	('melanoma', 'Disease', 'MESH:D008545', (309, 317))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('melanoma', 'Disease', (309, 317))
221067	30412573	In summary, we performed binary univariate logistic regression analyses to establish a statistical relationship between driver mutations and mutational signatures in 7,815 cancer samples across 26 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('15 cancer', 'Disease', (169, 178))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('15 cancer', 'Disease', 'MESH:C567447', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (172, 178))	('mutations', 'Var', (127, 136))
221069	30412573	These associations provide new insights into how some cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into mutational processes and cancer development.	('mutations', 'Var', (83, 92))	('advantageous', 'PosReg', (70, 82))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
221074	30412573	To select which samples to include in regression analyses, we excluded any mutations that were annotated by MuTect as present in a 'panel of normals', and then kept only cancer samples that harboured >= 30 single nucleotide somatic variants in cancer types with >= 40 samples.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('single nucleotide somatic variants', 'Var', (206, 240))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
221077	30412573	We then applied Sigfit (version 1.2.0) R package to determine the proportion of mutations attributable to each of the 30 mutational signatures from the COSMIC 'Signatures of Mutational Processes in Human Cancer' database.	('mutations', 'Var', (80, 89))	('Cancer', 'Disease', 'MESH:D009369', (204, 210))	('Cancer', 'Disease', (204, 210))	('Human', 'Species', '9606', (198, 203))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))
221078	30412573	We first selected only missense and stop-gain variants that were present in > 3.5% of samples in at least one cancer type (where TCGA-COAD and TCGA-READ were considered collectively as CRC).	('cancer', 'Disease', (110, 116))	('stop-gain', 'PosReg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('variants', 'Var', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('missense', 'Var', (23, 31))
221079	30412573	Next, we retained only mutations that altered genes listed in the COSMIC 'Cancer Gene Census' (Tier 1; retrieved 24 November 2017).	('mutations', 'Var', (23, 32))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))
221080	30412573	Using only the 7,815 samples described above, we then selected mutations that were present in > 10 samples in at least one cancer type, resulting in a list of 34 driver mutations.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (169, 178))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
221082	30412573	We then selected only mutations present in >= 5 samples within the IntOGen database, and > 10 samples from at least one cancer type from our TCGA cohort.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
221083	30412573	We merged these two lists of mutations and analysed each using the Cancer Genome Interpreter.	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (29, 38))	('Cancer', 'Disease', (67, 73))
221084	30412573	We removed any mutations that were not designated as being a tumour driver by the Cancer Genome Interpreter.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (15, 24))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('tumour', 'Disease', (61, 67))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
221087	30412573	The regression model used the following formula, where  represents the proportion of mutations attributed to a given mutational signature in a sample,  represents the probability that a given driver mutation is present or absent in that sample and beta values denote estimates from logistic regression:  The odds ratio was calculated by exponentiating the beta1 coefficient estimated from the logistic regression model.	('beta1', 'Gene', '10678', (356, 361))	('mutations', 'Var', (85, 94))	('beta1', 'Gene', (356, 361))
221091	30412573	For validation of a subset of our findings, we obtained single nucleotide somatic mutations for an independent cohort of 619 whole-exome sequenced colorectal cancers from a previously published study.	('single nucleotide somatic', 'Var', (56, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancers', 'Disease', 'MESH:D015179', (147, 165))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('colorectal cancers', 'Disease', (147, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
221092	30412573	DNA sequences +- 20 bp of the mutation site in ERBB2 p.S310F and PPP2R1A p.P179R were obtained from the UCSC genome browser.	('p.P179R', 'Var', (73, 80))	('PPP2R1A', 'Gene', (65, 72))	('ERBB2', 'Gene', (47, 52))	('p.P179R', 'Mutation', 'rs786205228', (73, 80))	('ERBB2', 'Gene', '2064', (47, 52))	('PPP2R1A', 'Gene', '5518', (65, 72))	('p.S310F', 'Mutation', 'rs1057519816', (53, 60))	('p.S310F', 'Var', (53, 60))
221115	28579810	The founding member of LGI family, LGI1, was shown to be deficient in malignant gliomas due to gene rearrangements and was postulated to be a tumor suppressor gene.	('gene rearrangements', 'Var', (95, 114))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('malignant gliomas', 'Disease', (70, 87))	('malignant gliomas', 'Disease', 'MESH:D005910', (70, 87))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('LGI1', 'Gene', '9211', (35, 39))	('LGI1', 'Gene', (35, 39))	('deficient', 'NegReg', (57, 66))
221163	28579810	All these gene products except CYBA were found in the previous reports on glioma that described the association of expression, function or genetic variation of these genes with glioma.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('association', 'Interaction', (100, 111))	('CYBA', 'Gene', (31, 35))	('glioma', 'Disease', (177, 183))	('genetic variation', 'Var', (139, 156))	('glioma', 'Disease', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('CYBA', 'Gene', '1535', (31, 35))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
221194	32189197	It was also reported that HCMV potentially induces a functional mesenchymal-to-epithelial (MET) transition without affecting their viability in transformed breast carcinoma and glioma stem cells, which might encourage tumor colonization (Oberstein and Shenk).	('induces', 'Reg', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('breast carcinoma', 'Phenotype', 'HP:0003002', (156, 172))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('glioma', 'Disease', (177, 183))	('encourage', 'PosReg', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('tumor', 'Disease', (218, 223))	('HCMV', 'Var', (26, 30))	('HCMV', 'Species', '10359', (26, 30))	('breast carcinoma', 'Disease', (156, 172))	('breast carcinoma', 'Disease', 'MESH:D001943', (156, 172))
221197	32189197	HCMV proteins US28, pp71, and glycoprotein B (gB) are also involved in gliomagenesis (Dziurzynski et al.,).	('glioma', 'Disease', (71, 77))	('US28', 'Gene', (14, 18))	('involved', 'Reg', (59, 67))	('glycoprotein B (gB', 'Protein', (30, 48))	('US28', 'Gene', '3077536', (14, 18))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('gB', 'Chemical', '-', (46, 48))	('pp71', 'Var', (20, 24))	('HCMV', 'Species', '10359', (0, 4))
221216	32189197	Quantification of HCMV protein levels based on integral optical density (IOD) and IHC scoring (See Supplementary Materials) confirmed that the levels of IE1/2, pp65 and gB were higher in glioma tissues compared to NG, while IE1/2 levels were higher in both HGG vs. LGG and LGG vs. NG (Fig.	('higher', 'PosReg', (177, 183))	('IE1/2', 'Gene', (153, 158))	('glioma', 'Disease', (187, 193))	('HCMV', 'Species', '10359', (18, 22))	('IE1/2', 'Gene', '258962', (224, 229))	('pp65', 'Var', (160, 164))	('IE1/2', 'Gene', '258962', (153, 158))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('gB', 'Chemical', '-', (169, 171))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('IE1/2', 'Gene', (224, 229))
221217	32189197	Odds ratio (OR) estimates obtained from logistic regression revealed only HCMV proteins, including IE1/2, pp65, and gB expression, but not age, sex, or tumor location, are potential risk factors associated with tumor grade (Table S1).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('associated', 'Reg', (195, 205))	('IE1/2', 'Gene', '258962', (99, 104))	('gB', 'Chemical', '-', (116, 118))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', (152, 157))	('IE1/2', 'Gene', (99, 104))	('risk', 'Reg', (182, 186))	('tumor', 'Disease', (211, 216))	('HCMV', 'Species', '10359', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('pp65', 'Var', (106, 110))
221225	32189197	Cox regression was performed to analyze correlative factors, including age, sex, and tumor grade, and protein levels of IE1/2, pp65, and gB.	('tumor', 'Disease', (85, 90))	('gB', 'Chemical', '-', (137, 139))	('IE1/2', 'Gene', (120, 125))	('protein levels', 'MPA', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('pp65', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('IE1/2', 'Gene', '258962', (120, 125))
221228	32189197	There was also a significant difference between the HGG/IE1/2high and the other three groups (Table S4), indicating that HGG patients with high IE1/2 levels had significantly shorter survival compared to the other groups.	('patients', 'Species', '9606', (125, 133))	('IE1/2', 'Gene', '258962', (144, 149))	('survival', 'MPA', (183, 191))	('shorter', 'NegReg', (175, 182))	('IE1/2', 'Gene', '258962', (56, 61))	('IE1/2', 'Gene', (144, 149))	('IE1/2', 'Gene', (56, 61))	('high', 'Var', (139, 143))	('HGG', 'Disease', (121, 124))
221235	32189197	Ki67 and IE1/2 were significant prognostic markers for glioma patients.	('glioma', 'Disease', (55, 61))	('IE1/2', 'Gene', (9, 14))	('Ki67', 'Chemical', '-', (0, 4))	('Ki67', 'Var', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('IE1/2', 'Gene', '258962', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('patients', 'Species', '9606', (62, 70))
221246	32189197	S1C and S1D), which contrasts with the exclusively nuclear localization of IE1/2 in infected fibroblasts (Fig.	('infected', 'Disease', (84, 92))	('IE1/2', 'Gene', (75, 80))	('S1D', 'Var', (8, 11))	('IE1/2', 'Gene', '258962', (75, 80))	('infected', 'Disease', 'MESH:D007239', (84, 92))
221247	32189197	One possible explanation is that in some glioma cells differential splicing of the IE gene locus could result in expression of IE protein isoforms that localize to the cytoplasm while retaining the epitope that is recognized by the IE1/2-specific antibody.	('expression', 'MPA', (113, 123))	('IE1/2', 'Gene', (232, 237))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('IE1/2', 'Gene', '258962', (232, 237))	('epitope', 'MPA', (198, 205))	('differential splicing', 'Var', (54, 75))	('localize', 'MPA', (152, 160))	('glioma', 'Disease', (41, 47))	('result in', 'Reg', (103, 112))
221248	32189197	Indeed, minor IE isoforms, including IE38, IE55, and IE18, have been observed during fibroblast infection and a similar isoform may be involved with genome maintenance during latency (Tarrant-Elorza et al.,).	('IE38', 'Var', (37, 41))	('infection', 'Disease', (96, 105))	('infection', 'Disease', 'MESH:D007239', (96, 105))	('IE55', 'Var', (43, 47))	('IE18', 'Var', (53, 57))	('involved', 'Reg', (135, 143))
221252	32189197	In contrast, the cells transduced with LV-IE1 or LV-IE2 had much higher levels of IE1 or IE2 and levels were consistent across all IE1- or IE2-transduced cultures (Fig.	('LV-IE2', 'Var', (49, 55))	('IE2', 'Chemical', '-', (52, 55))	('IE2', 'MPA', (89, 92))	('IE1', 'MPA', (82, 85))	('IE2', 'Chemical', '-', (139, 142))	('IE2', 'Chemical', '-', (89, 92))	('higher', 'PosReg', (65, 71))	('LV-IE1', 'Var', (39, 45))
221254	32189197	In contrast, IE2 decreased proliferation of all three primary glioma cells and two glioma cell lines but had no effect on the other two (Fig.	('glioma', 'Disease', (83, 89))	('decreased', 'NegReg', (17, 26))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('proliferation', 'CPA', (27, 40))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('IE2', 'Var', (13, 16))	('IE2', 'Chemical', '-', (13, 16))	('glioma', 'Disease', (62, 68))
221255	32189197	This differential response of GBM cell lines to IE1 might result from prevalent genetic lesions in signaling and cell cycle regulatory proteins, which could influence induction of cytoplasmic mitogenic signaling pathways through regulation of AKT and MAPK activity (Cobbs et al.,).	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('lesions', 'Var', (88, 95))	('AKT', 'Gene', (243, 246))	('genetic lesions', 'Var', (80, 95))	('AKT', 'Gene', '207', (243, 246))	('influence', 'Reg', (157, 166))	('result from', 'Reg', (58, 69))	('signaling', 'Protein', (99, 108))	('activity', 'MPA', (256, 264))	('regulation', 'Reg', (229, 239))	('MAPK', 'Pathway', (251, 255))	('cytoplasmic mitogenic signaling pathways', 'Pathway', (180, 220))
221260	32189197	IE1 enhanced migration of all three primary glioma cells and one glioma cell line (A172), but did not significantly alter migration of the other three glioma cell lines.	('glioma', 'Disease', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('enhanced', 'PosReg', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('IE1', 'Var', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('migration', 'CPA', (13, 22))	('glioma', 'Disease', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
221261	32189197	Similarly, IE2 enhanced the migration of two primary glioma cells (#251 and #256) and two glioma cell lines (A172 and LN229), but had no significant effect on the third primary glioma cells or the other two glioma cell lines (Fig.	('migration', 'CPA', (28, 37))	('IE2', 'Var', (11, 14))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', (207, 213))	('glioma', 'Disease', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('IE2', 'Chemical', '-', (11, 14))	('LN229', 'CellLine', 'CVCL:0393', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('enhanced', 'PosReg', (15, 23))
221262	32189197	IE1 and IE2 are also reported to promote degradation of connexin-43 and disruption of gap junction communication in U373MG (Dziurzynski et al.,) and inhibit apoptosis and to cooperate with E1A to sponsor "hit-and-run" transformation.	('inhibit', 'NegReg', (149, 156))	('gap junction communication', 'MPA', (86, 112))	('promote', 'PosReg', (33, 40))	('apoptosis', 'CPA', (157, 166))	('U373MG', 'CellLine', 'CVCL:2219', (116, 122))	('connexin-43', 'Gene', '2697', (56, 67))	('IE2', 'Chemical', '-', (8, 11))	('disruption', 'MPA', (72, 82))	('connexin-43', 'Gene', (56, 67))	('U373MG', 'Var', (116, 122))	('degradation', 'MPA', (41, 52))
221263	32189197	Our data suggest that IE1 more than IE2 may contribute to glioma malignant progression and may be involved in clinical outcome, as suggested by the survival analysis.	('IE1', 'Var', (22, 25))	('involved', 'Reg', (98, 106))	('glioma malignant', 'Disease', (58, 74))	('contribute', 'Reg', (44, 54))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('IE2', 'Chemical', '-', (36, 39))	('glioma malignant', 'Disease', 'MESH:D005910', (58, 74))
221269	31179415	Rare Pediatric Invasive Gliofibroma Has BRAFV600E Mutation and Transiently Responds to Targeted Therapy Before Progressive Clonal Evolution A previously healthy 20-month-old boy presented with three weeks of difficulty walking, emesis, headaches, and asymmetric smile following a viral illness.	('BRAFV600E Mutation', 'Var', (40, 58))	('emesis', 'Disease', (228, 234))	('asymmetric', 'Disease', (251, 261))	('viral illness', 'Disease', 'MESH:D001102', (280, 293))	('asymmetric smile', 'Phenotype', 'HP:0000324', (251, 267))	('boy', 'Species', '9606', (174, 177))	('headaches', 'Disease', 'MESH:D006261', (236, 245))	('headaches', 'Disease', (236, 245))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('headaches', 'Phenotype', 'HP:0002315', (236, 245))	('Invasive Gliofibroma', 'Disease', (15, 35))	('viral illness', 'Disease', (280, 293))	('emesis', 'Disease', 'MESH:D014839', (228, 234))	('difficulty walking', 'Phenotype', 'HP:0002355', (208, 226))	('emesis', 'Phenotype', 'HP:0002013', (228, 234))
221276	31179415	Significant clinical improvement followed initiation of dexamethasone, partial resection, and relief of the hydrocephalus.	('improvement', 'PosReg', (21, 32))	('hydrocephalus', 'Phenotype', 'HP:0000238', (108, 121))	('partial resection', 'Var', (71, 88))	('hydrocephalus', 'Disease', 'MESH:D006849', (108, 121))	('dexamethasone', 'Chemical', 'MESH:D003907', (56, 69))	('hydrocephalus', 'Disease', (108, 121))
221280	31179415	Molecular studies using the OncoScan (Thermo Fisher Scientific, Waltham, MA) chromosomal microarray (CMA) platform that has been validated for BRAFV600E revealed BRAFV600E mutation and homozygous deletion of CDKN2A (Table 1).	('BRAFV600E', 'Mutation', 'rs113488022', (143, 152))	('CDKN2A', 'Gene', (208, 214))	('BRAFV600E', 'Var', (162, 171))	('BRAFV600E', 'Mutation', 'rs113488022', (162, 171))	('deletion', 'Var', (196, 204))
221282	31179415	Immunohistochemistry revealed mutant BRAFV600E in the glial elements of the tumor, and absence of p16 (CDKN2A) in both glial and mesenchymal components (Figure 2), consistent with the molecular analysis showing BRAFV600E mutation and biallelic deletion of CDKN2A/B (Table 1).	('BRAFV600E', 'Gene', (37, 46))	('p16', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CDKN2A/B', 'Gene', '1029;1030', (256, 264))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))	('p16', 'Gene', '1029', (98, 101))	('BRAFV600E', 'Var', (211, 220))	('BRAFV600E', 'Mutation', 'rs113488022', (211, 220))	('absence', 'NegReg', (87, 94))	('mutant', 'Var', (30, 36))	('CDKN2A/B', 'Gene', (256, 264))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
221283	31179415	The infiltrative nature of the tumor, the inability to wean the patient off dexamethasone, the molecular studies showing a BRAFV600E mutation and deletion of CDKN2A that portend a worse prognosis in pediatric glioma patients and the high-grade features on MR spectroscopy raised concern for presence of high-grade infiltrative components in the residual tumor despite the low grade appearance of its resected portions.	('BRAFV600E', 'Mutation', 'rs113488022', (123, 132))	('deletion', 'Var', (146, 154))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('pediatric glioma', 'Disease', 'MESH:D005910', (199, 215))	('patient', 'Species', '9606', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Disease', (31, 36))	('patient', 'Species', '9606', (216, 223))	('CDKN2A', 'Gene', (158, 164))	('patients', 'Species', '9606', (216, 224))	('tumor', 'Disease', (354, 359))	('pediatric glioma', 'Disease', (199, 215))	('dexamethasone', 'Chemical', 'MESH:D003907', (76, 89))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('BRAFV600E', 'Var', (123, 132))
221298	31179415	Molecular studies of the recurrent tumor again revealed the BRAFV600E mutation (OncoKids  Next Generation Sequencing panel and OncoScan CMA) and the CDKN2A bi-allelic deletion (OncoScan).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('bi-allelic', 'Var', (156, 166))	('tumor', 'Disease', (35, 40))	('CDKN2A', 'Gene', (149, 155))	('BRAFV600E', 'Var', (60, 69))	('BRAFV600E', 'Mutation', 'rs113488022', (60, 69))
221299	31179415	Similar to the original tumor, IHC for BRAFV600E again showed areas with the mutant protein and areas without it (Figure 2).	('original tumor', 'Disease', 'MESH:D009369', (15, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('protein', 'Protein', (84, 91))	('BRAFV600E', 'Var', (39, 48))	('original tumor', 'Disease', (15, 29))
221300	31179415	The regions with high-grade features did express the mutant BRAF.	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
221301	31179415	Importantly, using OncoKids , two new mutations, not present in the original tumor, were revealed in the recurrence: PDGFRA (c.2524G>T NM_006206.4, p.Asp842Tyr, D842Y) and PTPN11 (c.215C>T NM_002834.3, p.Ala72Val).	('p.Ala72Val', 'Mutation', 'rs121918454', (202, 212))	('p.Asp842Tyr', 'Var', (148, 159))	('c.2524G>T NM_006206.4', 'Var', (125, 146))	('c.215C>T NM_002834.3', 'Var', (180, 200))	('original tumor', 'Disease', (68, 82))	('c.2524G>T', 'Mutation', 'rs121913265', (125, 134))	('original tumor', 'Disease', 'MESH:D009369', (68, 82))	('p.Asp842Tyr', 'Mutation', 'rs121913265', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('D842Y', 'Var', (161, 166))	('c.215C>T', 'Mutation', 'rs121918454', (180, 188))	('D842Y', 'SUBSTITUTION', 'None', (161, 166))
221304	31179415	OncoKids  on this tumor, obtained just two months after the first recurrence, demonstrated the prior mutations along with two new mutations: in TP53 (c.587G>A NM_000546.5, p.Arg196Gln) and PIK3CA (c.3140A>G NM_006218.3, p.His1047Arg), both of which are variants of strong clinical significance (Table 2).	('c.587G>A NM_000546.5', 'Var', (150, 170))	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('tumor', 'Disease', (18, 23))	('c.3140A>G NM_006218.3', 'Var', (197, 218))	('PIK3CA', 'Gene', (189, 195))	('p.His1047Arg', 'Var', (220, 232))	('p.His1047Arg', 'Mutation', 'rs121913279', (220, 232))	('p.Arg196Gln', 'Mutation', 'rs483352697', (172, 183))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('c.3140A>G', 'Mutation', 'rs121913279', (197, 206))	('PIK3CA', 'Gene', '5290', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('p.Arg196Gln', 'Var', (172, 183))	('c.587G>A', 'Mutation', 'rs483352697', (150, 158))
221315	31179415	Our patient provides four novel findings with regard to gliofibroma: 1) the first report on gliofibroma with a molecularly-proven BRAFV600E mutation and CDKN2A homozygous deletion, 2) the first gliofibroma patient reported to receive targeted therapy and to respond to BRAF+MEK inhibition, albeit only for limited time, 3) the first gliofibroma described to acquire PDGFRA and PTPN11 mutations upon recurrence as a high grade glioma resistant to BRAF and MEK inhibition, and 4) a rare opportunity to view the rapid molecular evolution of this tumor, with (1st recurrence) and without (2nd recurrence) therapy with BRAF+MEK inhibition.	('glioma', 'Disease', 'MESH:D005910', (426, 432))	('tumor', 'Disease', (543, 548))	('tumor', 'Disease', 'MESH:D009369', (543, 548))	('MEK', 'Gene', (619, 622))	('MEK', 'Gene', '5609', (274, 277))	('glioma', 'Phenotype', 'HP:0009733', (426, 432))	('patient', 'Species', '9606', (206, 213))	('MEK', 'Gene', '5609', (455, 458))	('BRAF', 'Gene', '673', (269, 273))	('MEK', 'Gene', (274, 277))	('BRAF', 'Gene', (269, 273))	('tumor', 'Phenotype', 'HP:0002664', (543, 548))	('PTPN11', 'Gene', (377, 383))	('BRAFV600E', 'Mutation', 'rs113488022', (130, 139))	('MEK', 'Gene', (455, 458))	('PDGFRA', 'Gene', (366, 372))	('BRAF', 'Gene', '673', (130, 134))	('BRAF', 'Gene', '673', (614, 618))	('patient', 'Species', '9606', (4, 11))	('BRAF', 'Gene', (130, 134))	('BRAF', 'Gene', (446, 450))	('BRAF', 'Gene', '673', (446, 450))	('mutations', 'Var', (384, 393))	('BRAF', 'Gene', (614, 618))	('glioma', 'Disease', (426, 432))	('MEK', 'Gene', '5609', (619, 622))
221317	31179415	While p16 (CDKN2A) immunohistochemistry was negative in both glial and mesenchymal components, it is not known if this is due to deletion of CDKN2A in both compartments, or if CDKN2A is deleted in one compartment and its expression is merely low in the other.	('CDKN2A', 'Gene', (141, 147))	('p16', 'Gene', '1029', (6, 9))	('p16', 'Gene', (6, 9))	('deletion', 'Var', (129, 137))
221318	31179415	It is interesting that in another glial tumor, ganglioglioma, the BRAFV600E-expressing cells were mostly those with neuronal capacity or both neuronal and glial capacity.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('BRAFV600E', 'Mutation', 'rs113488022', (66, 75))	('glial tumor', 'Disease', 'MESH:D005910', (34, 45))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('glioma', 'Disease', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('glial tumor', 'Disease', (34, 45))	('BRAFV600E-expressing', 'Var', (66, 86))
221320	31179415	The BRAFV600E oncogenic mutation is reported in 17% of pediatric low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))
221321	31179415	To date, BRAFV600E mutation has not been reported in gliofibromas.	('gliofibromas', 'Disease', (53, 65))	('BRAFV600E', 'Var', (9, 18))	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))
221322	31179415	One case report stated that BRAF mutations are present in "around 50%" of gliofibromas.	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('gliofibromas', 'Disease', (74, 86))	('mutations', 'Var', (33, 42))
221324	31179415	In pediatric patients with low-grade gliomas who received chemotherapy and irradiation, BRAFV600E was associated with worse outcome: whereas 10-year progression free survival (PFS) in patients with non-BRAFV600E gliomas was 60.2%, in those with mutant BRAFV600E it was only 27% (p<0.001).	('BRAFV600E', 'Mutation', 'rs113488022', (202, 211))	('patients', 'Species', '9606', (184, 192))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('patients', 'Species', '9606', (13, 21))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('non-BRAFV600E', 'Var', (198, 211))	('BRAFV600E', 'Mutation', 'rs113488022', (252, 261))	('BRAFV600E', 'Var', (88, 97))	('BRAFV600E', 'Mutation', 'rs113488022', (88, 97))	('gliomas', 'Disease', (212, 219))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))
221325	31179415	Moreover, incomplete resection or CDKN2A deletion independently contributed to poor outcome among children with BRAFV600E mutant low-grade gliomas.	('gliomas', 'Disease', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('deletion', 'Var', (41, 49))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('CDKN2A', 'Gene', (34, 40))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('BRAFV600E mutant', 'Var', (112, 128))	('children', 'Species', '9606', (98, 106))	('BRAFV600E', 'Mutation', 'rs113488022', (112, 121))
221328	31179415	KIAA1549-BRAF fusions also activate the MAPK pathway and are seen in over 50% of incompletely-resected pediatric low grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('KIAA1549-BRAF', 'Disease', (0, 13))	('activate', 'PosReg', (27, 35))	('KIAA1549-BRAF', 'Disease', 'None', (0, 13))	('MAPK', 'Gene', '5594', (40, 44))	('gliomas', 'Disease', (123, 130))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('MAPK', 'Gene', (40, 44))	('fusions', 'Var', (14, 21))
221329	31179415	Their prognosis is better than fusion-negative tumors: five-year PFS is 61% +/-8% for fusion-positive tumors versus 18% +/-8% for fusion-negative.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('fusion-positive', 'Var', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
221330	31179415	Compared to the KIAA1549-BRAF fusion-positive pediatric low grade gliomas, BRAFV600E mutant tumors have significantly worse survival.	('KIAA1549-BRAF', 'Disease', (16, 29))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('BRAFV600E', 'Gene', (75, 84))	('survival', 'MPA', (124, 132))	('BRAFV600E', 'Mutation', 'rs113488022', (75, 84))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('KIAA1549-BRAF', 'Disease', 'None', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('worse', 'NegReg', (118, 123))	('mutant', 'Var', (85, 91))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))
221332	31179415	Considering the poor response of incompletely resected BRAFV600E-mutated and CDKN2A- deleted pediatric low grade gliomas to chemotherapy and irradiation and the aggressive behavior of our patient's tumor at presentation we elected to treat him with the BRAFV600E inhibitor, vemurafenib combined with a MAPK kinase (MEK) inhibitor, trametinib.	('CDKN2A-', 'Gene', (77, 84))	('MEK', 'Gene', '5609', (315, 318))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('BRAFV600E', 'Mutation', 'rs113488022', (253, 262))	('MEK', 'Gene', (315, 318))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('gliomas', 'Disease', (113, 120))	('trametinib', 'Chemical', 'MESH:C560077', (331, 341))	('patient', 'Species', '9606', (188, 195))	('BRAFV600E-mutated', 'Gene', (55, 72))	('MAPK', 'Gene', (302, 306))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('BRAFV600E', 'Var', (253, 262))	('tumor', 'Disease', (198, 203))	('aggressive behavior', 'Phenotype', 'HP:0000718', (161, 180))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('MAPK', 'Gene', '5594', (302, 306))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('vemurafenib', 'Chemical', 'MESH:D000077484', (274, 285))
221334	31179415	Mechanisms responsible for resistance of BRAFV600E tumors to BRAF inhibitor monotherapy include increase in BRAF dimers, BRAF splice variants, NRAS and KRAS mutations, BRAF amplifications, MEK mutations, and others.	('BRAF', 'Gene', (121, 125))	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('MEK', 'Gene', '5609', (189, 192))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('BRAF', 'Gene', '673', (168, 172))	('BRAF', 'Gene', (168, 172))	('MEK', 'Gene', (189, 192))	('KRAS', 'Gene', '3845', (152, 156))	('mutations', 'Var', (157, 166))	('NRAS', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (108, 112))	('amplifications', 'Var', (173, 187))	('splice variants', 'MPA', (126, 141))	('BRAF', 'Gene', (108, 112))	('BRAF', 'Gene', '673', (61, 65))	('KRAS', 'Gene', (152, 156))	('BRAF', 'Gene', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('increase', 'PosReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('BRAF', 'Gene', '673', (41, 45))	('tumors', 'Disease', (51, 57))	('BRAF', 'Gene', (41, 45))	('NRAS', 'Gene', '4893', (143, 147))	('BRAF', 'Gene', '673', (121, 125))
221340	31179415	While pre-clinical research suggested benefit to combining a BRAF inhibitor and/or MEK inhibitor with a CDK4/6 inhibitor in tumors with both BRAFV600E and CDKN2A deletion, peer-reviewed clinical data on safety and efficacy of such combination was not available when the patient presented.	('deletion', 'Var', (162, 170))	('BRAF', 'Gene', (141, 145))	('benefit', 'PosReg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BRAFV600E', 'Mutation', 'rs113488022', (141, 150))	('BRAF', 'Gene', '673', (61, 65))	('MEK', 'Gene', (83, 86))	('patient', 'Species', '9606', (270, 277))	('MEK', 'Gene', '5609', (83, 86))	('CDK4/6', 'Gene', '1019;1021', (104, 110))	('BRAF', 'Gene', (61, 65))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('CDKN2A', 'Gene', (155, 161))	('CDK4/6', 'Gene', (104, 110))	('BRAF', 'Gene', '673', (141, 145))
221342	31179415	Molecular studies of the recurrent tumor revealed persistence of mutant BRAF, indicating emergence of resistance to BRAF inhibition.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('BRAF', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('BRAF', 'Gene', '673', (116, 120))	('mutant', 'Var', (65, 71))	('tumor', 'Disease', (35, 40))	('BRAF', 'Gene', (116, 120))	('BRAF', 'Gene', '673', (72, 76))
221343	31179415	Two mutations (PDGFRA-D842Y, PTPN11-A72V) in the recurrent tumor had not been detected in the original tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (103, 108))	('A72V', 'Mutation', 'rs121918454', (36, 40))	('D842Y', 'Var', (22, 27))	('D842Y', 'SUBSTITUTION', 'None', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PTPN11-A72V', 'Var', (29, 40))	('original tumor', 'Disease', (94, 108))	('original tumor', 'Disease', 'MESH:D009369', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
221344	31179415	While it is possible that intra-tumor heterogeneity was the basis for their absence in the sample tested from the original tumor, their co-existence with the BRAFV600E mutation and CDKN2A deletion in the recurrent sample suggest that they are newly acquired and may have played a role in the recurrence.	('intra-tumor', 'Disease', 'MESH:D009369', (26, 37))	('BRAFV600E', 'Gene', (158, 167))	('original tumor', 'Disease', 'MESH:D009369', (114, 128))	('deletion', 'Var', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('intra-tumor', 'Disease', (26, 37))	('CDKN2A', 'Gene', (181, 187))	('original tumor', 'Disease', (114, 128))	('BRAFV600E', 'Mutation', 'rs113488022', (158, 167))
221345	31179415	It is not known if these new mutations are in tumor cells that express the mutant BRAF protein or in those that stain negative for it (Fig 2r).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BRAF', 'Gene', '673', (82, 86))	('protein', 'Protein', (87, 94))	('tumor', 'Disease', (46, 51))	('BRAF', 'Gene', (82, 86))	('mutant', 'Var', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
221346	31179415	Overexpression and mutations in PDGFRA are frequent in pediatric gliomas and in other cancers, with mutations occurring in over 20% of high grade gliomas, but only rarely in low grade ones.	('gliomas', 'Disease', (65, 72))	('pediatric gliomas', 'Disease', (55, 72))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('frequent', 'Reg', (43, 51))	('mutations', 'Var', (19, 28))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('pediatric gliomas', 'Disease', 'MESH:D005910', (55, 72))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('PDGFRA', 'Gene', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
221347	31179415	The PDGFRA mutation, in addition to the aggressive nature of our patient's recurrent glioma, supported the use of radiation therapy for the recurrence.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('PDGFRA', 'Gene', (4, 10))	('glioma', 'Disease', (85, 91))	('patient', 'Species', '9606', (65, 72))	('mutation', 'Var', (11, 19))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
221348	31179415	Mutations in D842, located in the activation loop of PDGFRA, comprise over one third of PDGFRA substitution mutations reported to date in the COSMIC Catalogue (610 of 1705), with the majority (95%) being D842V.	('mutations', 'Var', (108, 117))	('D842V', 'Mutation', 'rs121908585', (204, 209))	('substitution mutations', 'Var', (95, 117))	('D842', 'Var', (13, 17))	('D842V', 'Var', (204, 209))	('Mutations', 'Var', (0, 9))	('PDGFRA', 'Gene', (88, 94))
221349	31179415	PDGFRA-D842V renders PDGFRA resistant to imatinib in vitro,  but it remains sensitive to crenolanib, a newer PDGFRA inhibitor currently in clinical trials.	('PDGFRA-D842V', 'Var', (0, 12))	('resistant to imatinib', 'MPA', (28, 49))	('crenolanib', 'Chemical', 'MESH:C577197', (89, 99))	('imatinib', 'Chemical', 'MESH:D000068877', (41, 49))	('D842V', 'Mutation', 'rs121908585', (7, 12))
221350	31179415	However, PDGFRA-D842Y (the mutation in our patient's tumor) is moderately resistant to imatinib in vitro, and is not as sensitive to crenolanib as the D842V mutant or the wildtype receptor.	('imatinib', 'Chemical', 'MESH:D000068877', (87, 95))	('D842V', 'Mutation', 'rs121908585', (151, 156))	('patient', 'Species', '9606', (43, 50))	('resistant to imatinib', 'MPA', (74, 95))	('D842V', 'Var', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('D842Y', 'Var', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('D842Y', 'SUBSTITUTION', 'None', (16, 21))	('crenolanib', 'Chemical', 'MESH:C577197', (133, 143))	('tumor', 'Disease', (53, 58))
221352	31179415	Across cancers, PTPN11 is mutated in 1,320 (1.9%) of the 70,712 cancer samples reported in COSMIC.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('mutated', 'Var', (26, 33))	('cancers', 'Disease', (7, 14))	('cancer', 'Disease', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('PTPN11', 'Gene', (16, 22))
221353	31179415	PTPN11 mutations are seen in both low-grade and high-grade pediatric gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('pediatric gliomas', 'Disease', 'MESH:D005910', (59, 76))	('PTPN11', 'Gene', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('low-grade', 'Disease', (34, 43))	('pediatric gliomas', 'Disease', (59, 76))	('seen', 'Reg', (21, 25))	('mutations', 'Var', (7, 16))
221354	31179415	The PTPN11 Ala72Val (A72V) mutation in our patient's recurrent tumor is located in the N-terminal SH2 domain of PTPN11 and is predicted to be a gain-of-function mutation.	('tumor', 'Disease', (63, 68))	('PTPN11', 'Gene', (112, 118))	('Ala72Val', 'Var', (11, 19))	('Ala72Val', 'SUBSTITUTION', 'None', (11, 19))	('patient', 'Species', '9606', (43, 50))	('PTPN11', 'Gene', (4, 10))	('gain-of-function', 'PosReg', (144, 160))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('A72V', 'Mutation', 'rs121918454', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
221355	31179415	Of the total 1,285 PTPN11 substitution mutations reported in COSMIC 180 are in alanine 72, the second most mutated amino acid after glutamine 76.	('alanine 72', 'MPA', (79, 89))	('alanine', 'Chemical', 'MESH:D000409', (79, 86))	('glutamine', 'Chemical', 'MESH:D005973', (132, 141))	('substitution mutations', 'Var', (26, 48))	('PTPN11', 'Gene', (19, 25))
221356	31179415	Seventy eight of the reported 180 Ala72 mutations are A72V.	('mutations', 'Var', (40, 49))	('A72V', 'Mutation', 'rs121918454', (54, 58))	('Ala72', 'Gene', (34, 39))
221357	31179415	Several PTPN11 inhibitors are now beginning clinical trials in cancer in adults.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('PTPN11', 'Gene', (8, 14))	('inhibitors', 'Var', (15, 25))	('cancer', 'Disease', (63, 69))
221359	31179415	It is therefore conceivable that with this gliofibroma's PDGFRA-D842Y and PTPN11-A72V activating mutations and the biallelic deletion in CDKN2A, this pathway may have contributed to the recurrent tumor in our patient.	('patient', 'Species', '9606', (209, 216))	('tumor', 'Disease', (196, 201))	('gliofibroma', 'Disease', (43, 54))	('biallelic deletion', 'Var', (115, 133))	('activating', 'PosReg', (86, 96))	('CDKN2A', 'Gene', (137, 143))	('A72V', 'Mutation', 'rs121918454', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('D842Y', 'Var', (64, 69))	('contributed', 'Reg', (167, 178))	('D842Y', 'SUBSTITUTION', 'None', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
221360	31179415	who describe BRAFV600E and CDKN2A deletion as early alterations in pediatric LGG that are undergoing transformation.	('BRAFV600E', 'Var', (13, 22))	('deletion', 'Var', (34, 42))	('CDKN2A', 'Gene', (27, 33))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))
221363	31179415	PIK3CA mutations are found in 21% of pediatric gliomas compared to 17% in adult glioblastomas (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioblastomas', 'Disease', (80, 93))	('pediatric gliomas', 'Disease', (37, 54))	('PIK3CA', 'Gene', (0, 6))	('glioblastomas', 'Phenotype', 'HP:0012174', (80, 93))	('PIK3CA', 'Gene', '5290', (0, 6))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('glioblastomas', 'Disease', 'MESH:D005909', (80, 93))	('found', 'Reg', (21, 26))	('pediatric gliomas', 'Disease', 'MESH:D005910', (37, 54))	('mutations', 'Var', (7, 16))
221365	31179415	While this suggests that molecular screening may benefit patients with gliofibroma, especially those with incompletely resected and/or infiltrative or clinically-aggressive tumors, it also indicates that broader drug combinations may need to be explored.	('gliofibroma', 'Disease', (71, 82))	('benefit', 'PosReg', (49, 56))	('patients', 'Species', '9606', (57, 65))	('aggressive tumor', 'Disease', 'MESH:D001523', (162, 178))	('molecular', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('aggressive tumor', 'Disease', (162, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
221382	27246838	Among them, the methylation of H3K4, H3K36, H3K79 is associated with transcriptional activation, and the methylation of H3K9 and H3K27 plays a role transcriptional repression.	('transcriptional', 'MPA', (69, 84))	('methylation', 'Var', (105, 116))	('H3', 'Chemical', 'MESH:C012616', (37, 39))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('H3', 'Chemical', 'MESH:C012616', (129, 131))	('activation', 'PosReg', (85, 95))	('H3K79', 'Var', (44, 49))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('H3K4', 'Protein', (31, 35))	('H3K36', 'Var', (37, 42))	('H3', 'Chemical', 'MESH:C012616', (31, 33))	('methylation', 'Var', (16, 27))
221390	27246838	Moreover, JARID1B increased the protein levels of phosphorylated (p-)Smad2.	('increased', 'PosReg', (18, 27))	('protein levels', 'MPA', (32, 46))	('JARID1B', 'Var', (10, 17))	('phosphorylated', 'MPA', (50, 64))	('Smad2', 'Gene', '4087', (69, 74))	('Smad2', 'Gene', (69, 74))
221392	27246838	Conversely, JARID1B knockdown by short hairpin RNA (shRNA) inhibited the proliferation and migration of glioma cells as well as sphere formation.	('inhibited', 'NegReg', (59, 68))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('knockdown', 'Var', (20, 29))	('JARID1B', 'Gene', (12, 19))	('glioma', 'Disease', (104, 110))	('sphere formation', 'CPA', (128, 144))
221394	27246838	These findings suggest that high JARID1B expression is involved in the pathogenesis of glioma.	('glioma', 'Disease', (87, 93))	('JARID1B', 'Gene', (33, 40))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (55, 63))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('high', 'Var', (28, 32))
221398	27246838	The human glioma cell lines, U251 (#09063001) and U373 (#08061901) were obtained from Sigma (St. Louis, MO, USA).	('human', 'Species', '9606', (4, 9))	('U373', 'CellLine', 'CVCL:2219', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('#08061901', 'Var', (56, 65))	('#09063001', 'Var', (35, 44))	('glioma', 'Disease', (10, 16))
221402	27246838	LY364947, an inhibitor of TGF-betaRI, was obtained from Selleckchem (Houston, TX, USA).	('TGF-beta', 'Gene', '7040', (26, 34))	('LY364947', 'Var', (0, 8))	('TGF-beta', 'Gene', (26, 34))	('LY364947', 'Chemical', 'MESH:C520284', (0, 8))
221415	27246838	An MTT assay was performed in order to determine the effect of overexpression or knockdown of JARID1B on the proliferation of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('glioma', 'Disease', (126, 132))	('knockdown', 'Var', (81, 90))	('JARID1B', 'Gene', (94, 101))
221448	27246838	An MTT assay was performed to detect proliferation and the results revealed that U251-pBabe-JARID1B displayed higher proliferation rates than the control cells (Fig.	('proliferation rates', 'CPA', (117, 136))	('higher', 'PosReg', (110, 116))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('U251-pBabe-JARID1B', 'Var', (81, 99))
221449	27246838	The results showed that U251-pBabe-JARID1B cells exhibited marked increases in cell migratory activity compared to the control U251-pBabe cells and the parent cells, suggesting that JARID1B may also enhance the rate of migration of glioma cells (Fig.	('U251-pBabe-JARID1B', 'Var', (24, 42))	('increases', 'PosReg', (66, 75))	('glioma', 'Disease', (232, 238))	('enhance', 'PosReg', (199, 206))	('JARID1B', 'Var', (182, 189))	('cell migratory activity', 'CPA', (79, 102))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))
221450	27246838	To examine the effect of JARID1B knockdown on the proliferation, migration and invasiveness of glioma cells as well as sphere formation, the SW1783 human glioma cell line, a highly tumorigenic cell line commonly used in glioma research, was transfected with pSuper-shJARID1B or the control (pSuper).	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('tumor', 'Disease', (181, 186))	('invasiveness of glioma', 'Disease', (79, 101))	('SW1783', 'CellLine', 'CVCL:1722', (141, 147))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', (154, 160))	('human', 'Species', '9606', (148, 153))	('invasiveness of glioma', 'Disease', 'MESH:D005910', (79, 101))	('pSuper-shJARID1B', 'Var', (258, 274))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('glioma', 'Disease', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
221452	27246838	As indicated by the Transwell assay and Matrigel assay, knockdown of JARID1B expression significantly inhibited the migration and invasiveness of glioma cell (Fig.	('invasiveness of glioma', 'Disease', (130, 152))	('inhibited', 'NegReg', (102, 111))	('invasiveness of glioma', 'Disease', 'MESH:D005910', (130, 152))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('JARID1B', 'Gene', (69, 76))	('knockdown', 'Var', (56, 65))
221454	27246838	To examine the function of JARID1B in vivo in glioma carcinogenesis, a xenograft model of glioma was established by implanting U251-pBabe and U251-pBabe-JARID1B cells subcutaneously into the right flanks of nude mice.	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', (46, 52))	('nude mice', 'Species', '10090', (207, 216))	('U251-pBabe', 'Var', (127, 137))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('U251-pBabe-JARID1B', 'Var', (142, 160))	('glioma carcinogenesis', 'Disease', 'MESH:D063646', (46, 67))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma carcinogenesis', 'Disease', (46, 67))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
221456	27246838	The tumors of the mice injected with U251-pBabe-JARID1B cells were significantly larger than those of the control mice injected with U251-pBabe cells 2 weeks after tumor cell injection (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (164, 169))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('mice', 'Species', '10090', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('larger', 'PosReg', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('U251-pBabe-JARID1B', 'Var', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
221457	27246838	The average weight of tumors from the mice injected with U251-pBabe-JARID1B cells was 5 g while that of the control mice injected with U251-pBabe cells was 2 g (Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mice', 'Species', '10090', (116, 120))	('mice', 'Species', '10090', (38, 42))	('U251-pBabe-JARID1B cells', 'Var', (57, 81))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
221458	27246838	Apparently, the tumor growth rate in the mice injected with U251-pBabe-JARID1B cells was greater than that in the control mice and this was confirmed by measuring the mean tumor volume 42 days after injection (Fig.	('U251-pBabe-JARID1B', 'Var', (60, 78))	('mice', 'Species', '10090', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('greater', 'PosReg', (89, 96))
221462	27246838	Inversely, the knockdown of JARID1B in the SW1783 cells significantly decreased the expression of p-Smad2, CD133, Oct4, nestin and Bmi-1 (Fig.	('Bmi-1', 'Gene', (131, 136))	('CD133', 'Gene', (107, 112))	('CD133', 'Gene', '8842', (107, 112))	('Oct4', 'Gene', '5460', (114, 118))	('knockdown', 'Var', (15, 24))	('decreased', 'NegReg', (70, 79))	('JARID1B', 'Gene', (28, 35))	('Bmi-1', 'Gene', '648', (131, 136))	('Smad2', 'Gene', '4087', (100, 105))	('SW1783', 'CellLine', 'CVCL:1722', (43, 49))	('Oct4', 'Gene', (114, 118))	('expression', 'MPA', (84, 94))	('Smad2', 'Gene', (100, 105))	('nestin', 'Protein', (120, 126))
221465	27246838	The suppression of p-Smad2 receptor signaling using the inhibitor LY364947 suppressed Smad2 phosphorylation, without affecting the expression of Smad2 in the U251-pBabe-JARID1B cells (Fig.	('Smad2', 'Gene', '4087', (145, 150))	('suppressed', 'NegReg', (75, 85))	('suppression', 'NegReg', (4, 15))	('phosphorylation', 'MPA', (92, 107))	('LY364947', 'Chemical', 'MESH:C520284', (66, 74))	('Smad2', 'Gene', '4087', (21, 26))	('Smad2', 'Gene', '4087', (86, 91))	('Smad2', 'Gene', (21, 26))	('Smad2', 'Gene', (86, 91))	('Smad2', 'Gene', (145, 150))	('LY364947', 'Var', (66, 74))
221466	27246838	Treatment with LY364947, an inhibitor of p-Smad2 receptor signaling, suppressed the expression of CD133, Oct4, nestin and Bmi-1 in the U251-pBabe-JARID1B cells (Fig.	('Smad2', 'Gene', '4087', (43, 48))	('LY364947', 'Var', (15, 23))	('Oct4', 'Gene', '5460', (105, 109))	('Smad2', 'Gene', (43, 48))	('Bmi-1', 'Gene', '648', (122, 127))	('LY364947', 'Chemical', 'MESH:C520284', (15, 23))	('Bmi-1', 'Gene', (122, 127))	('CD133', 'Gene', (98, 103))	('suppressed', 'NegReg', (69, 79))	('Oct4', 'Gene', (105, 109))	('CD133', 'Gene', '8842', (98, 103))	('expression', 'MPA', (84, 94))	('nestin', 'Gene', (111, 117))
221472	27246838	Conversely, the knockdown of JARID1B suppressed the proliferation, migration and invasiveness of glioma cells as well as sphere formation.	('invasiveness of glioma', 'Disease', (81, 103))	('JARID1B', 'Gene', (29, 36))	('sphere formation', 'CPA', (121, 137))	('proliferation', 'CPA', (52, 65))	('invasiveness of glioma', 'Disease', 'MESH:D005910', (81, 103))	('knockdown', 'Var', (16, 25))	('migration', 'CPA', (67, 76))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('suppressed', 'NegReg', (37, 47))
221492	27246838	Suppression of the p-Smad2 signaling pathway by LY364947 inhibited the inductive effect of JARID1B on the expression of the cancer stem cell-related markers.	('cancer', 'Disease', (124, 130))	('LY364947', 'Chemical', 'MESH:C520284', (48, 56))	('inhibited', 'NegReg', (57, 66))	('expression', 'MPA', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Smad2', 'Gene', '4087', (21, 26))	('Suppression', 'NegReg', (0, 11))	('Smad2', 'Gene', (21, 26))	('JARID1B', 'Gene', (91, 98))	('inductive effect', 'CPA', (71, 87))	('LY364947', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
221494	27246838	Thus, aberrant JARID1B expression in gliomas may enhance the oncogenic effects of the activated p-Smad2 signaling pathway.	('JARID1B', 'Gene', (15, 22))	('Smad2', 'Gene', '4087', (98, 103))	('aberrant', 'Var', (6, 14))	('oncogenic effects', 'CPA', (61, 78))	('enhance', 'PosReg', (49, 56))	('Smad2', 'Gene', (98, 103))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('expression', 'MPA', (23, 33))
221495	27246838	In conclusion, we have demonstrated for the first time, to the best of our knowledge, that JARID1B is overexpressed in glioma tissues, and the overexpression of JARID1B increased the growth and migration of glioma cells in vitro and enhanced glioma tumorigenesis in vivo.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('overexpression', 'Var', (143, 157))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('enhanced', 'PosReg', (233, 241))	('increased', 'PosReg', (169, 178))	('JARID1B', 'Gene', (161, 168))	('glioma', 'Disease', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('glioma', 'Disease', (242, 248))	('growth', 'CPA', (183, 189))	('tumor', 'Disease', (249, 254))	('glioma', 'Disease', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('glioma', 'Disease', 'MESH:D005910', (207, 213))
221525	26926066	Fluorescein has the potential to be a highly nonspecific biomarker that will accumulate in any areas with BBB disruption or blood leakage, and as such it will accumulate irrespective of tumor cell presence, e.g., in normal neuraxis regions without a BBB, such as choroid plexus, or in abnormal tissues such as edema, necrosis, leaking vessels, and bleeding vessels without hemostasis intraoperatively.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('edema', 'Disease', 'MESH:D004487', (310, 315))	('necrosis', 'Disease', (317, 325))	('Fluorescein', 'Chemical', 'MESH:D019793', (0, 11))	('edema', 'Phenotype', 'HP:0000969', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('edema', 'Disease', (310, 315))	('choroid plexus', 'Disease', (263, 277))	('necrosis', 'Disease', 'MESH:D009336', (317, 325))	('disruption', 'Var', (110, 120))	('choroid plexus', 'Disease', 'MESH:D020288', (263, 277))
221529	26926066	Tables 3 and 4 provide a general overview of key studies using PpIX and fluorescein, respectively, and the associated derived diagnostic capabilities of these agents.	('fluorescein', 'MPA', (72, 83))	('PpIX', 'Chemical', 'MESH:C028025', (63, 67))	('fluorescein', 'Chemical', 'MESH:D019793', (72, 83))	('PpIX', 'Var', (63, 67))
221607	26926066	In their study, the authors sampled the range from 381 to 1653 cm-1, noting differences in the lipid bands (700-1142 cm-1), nucleic acid bands (1540-1645 cm-1), and the breathing mode of phenylalanine in proteins (1005 cm-1).	('lipid', 'Chemical', 'MESH:D008055', (95, 100))	('nucleic acid bands', 'MPA', (124, 142))	('lipid bands', 'MPA', (95, 106))	('700-1142', 'Var', (108, 116))	('phenylalanine', 'Chemical', 'MESH:D010649', (187, 200))	('1540-1645 cm-1', 'Var', (144, 158))
221630	26617336	Aberrant Ras signalling resulting in downstream Mek/Erk pathway activation is found in many cancers.	('Ras signalling', 'Pathway', (9, 23))	('Aberrant', 'Var', (0, 8))	('Erk', 'Gene', (52, 55))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('Erk', 'Gene', '5594', (52, 55))	('cancers', 'Disease', (92, 99))	('Mek', 'Gene', (48, 51))	('activation', 'PosReg', (64, 74))	('Ras', 'Chemical', 'MESH:D011883', (9, 12))	('Mek', 'Gene', '5609', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
221635	26617336	Ras is turned 'ON' by the exchange of GDP with GTP, catalysed by guanine-nucleotide exchange factors.	('Ras', 'Chemical', 'MESH:D011883', (0, 3))	('GTP', 'Chemical', 'MESH:D006160', (47, 50))	('exchange', 'Var', (26, 34))	('GDP', 'Chemical', 'MESH:D006153', (38, 41))	('GDP', 'Gene', (38, 41))	('guanine-nucleotide', 'Chemical', 'MESH:D006150', (65, 83))
221638	26617336	Cancer-associated mutations in Ras, frequently in condons 12, 13 and 61, convert Ras into an active oncoprotein by impairing its GTPase activity.	('GTPase', 'Enzyme', (129, 135))	('impairing', 'NegReg', (115, 124))	('Ras', 'Gene', (31, 34))	('GTP', 'Chemical', 'MESH:D006160', (129, 132))	('Ras', 'Chemical', 'MESH:D011883', (31, 34))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Ras', 'Gene', (81, 84))	('Ras', 'Chemical', 'MESH:D011883', (81, 84))	('convert', 'Reg', (73, 80))	('mutations', 'Var', (18, 27))
221640	26617336	For example, loss of or mutation in neurofibromin 1 (NF1 that encodes GAP) in neurofibromatosis type 1 (ref.	('neurofibromatosis type', 'Disease', (78, 100))	('neurofibromin 1', 'Gene', '4763', (36, 51))	('NF1', 'Gene', (53, 56))	('NF1', 'Gene', '4763', (53, 56))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (78, 95))	('mutation', 'Var', (24, 32))	('neurofibromin 1', 'Gene', (36, 51))	('loss of', 'NegReg', (13, 20))	('neurofibromatosis type', 'Disease', 'MESH:C537392', (78, 100))
221641	26617336	), mutation in SHP2 (also known as PTPN11 that encodes protein tyrosine phosphatase) in juvenile myelomonocytic leukaemia, and the overexpression of growth factor receptors in breast cancer and glioblastoma multiforme (GBM) have been associated with the hyperactivation of wild-type (WT) Ras.	('protein tyrosine phosphatase', 'Gene', (55, 83))	('juvenile myelomonocytic leukaemia', 'Disease', 'MESH:D054429', (88, 121))	('juvenile myelomonocytic leukaemia', 'Phenotype', 'HP:0012209', (88, 121))	('breast cancer', 'Disease', (176, 189))	('glioblastoma multiforme', 'Disease', (194, 217))	('PTPN11', 'Gene', '5781', (35, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (194, 206))	('protein tyrosine phosphatase', 'Gene', '26191', (55, 83))	('Ras', 'Chemical', 'MESH:D011883', (288, 291))	('SHP2', 'Gene', (15, 19))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (194, 217))	('mutation', 'Var', (3, 11))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('PTPN11', 'Gene', (35, 41))	('juvenile myelomonocytic leukaemia', 'Disease', (88, 121))	('overexpression', 'PosReg', (131, 145))
221643	26617336	Primary GBM, which comprises ~90% of all GBMs, develops rapidly de novo, whereas secondary GBM progresses from a low-grade astrocytoma to a high-grade glioma through the acquisition of additional genetic alterations.	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('rat', 'Species', '10116', (208, 211))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('genetic alterations', 'Var', (196, 215))	('astrocytoma', 'Disease', 'MESH:D001254', (123, 134))	('glioma', 'Disease', (151, 157))	('astrocytoma', 'Disease', (123, 134))
221647	26617336	Germline-activating mutations in SHP2 cause Noonan syndrome, whereas somatic gain of function SHP2 mutations have been identified in several haematologic malignancies, most notably juvenile myelomonocytic leukaemia.	('juvenile myelomonocytic leukaemia', 'Disease', (181, 214))	('malignancies', 'Disease', 'MESH:D009369', (154, 166))	('juvenile myelomonocytic leukaemia', 'Disease', 'MESH:D054429', (181, 214))	('gain of function', 'PosReg', (77, 93))	('SHP2', 'Gene', (94, 98))	('cause', 'Reg', (38, 43))	('Noonan syndrome', 'Disease', 'MESH:D009634', (44, 59))	('mutations', 'Var', (99, 108))	('SHP2', 'Gene', (33, 37))	('juvenile myelomonocytic leukaemia', 'Phenotype', 'HP:0012209', (181, 214))	('malignancies', 'Disease', (154, 166))	('Noonan syndrome', 'Disease', (44, 59))
221651	26617336	Notably, molecular or pharmacologic SHP2 inhibition attenuated the Ras activation and downstream MAPK signalling, and suppressed the progression of tumours in mouse models of GBM.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('attenuated', 'NegReg', (52, 62))	('activation', 'PosReg', (71, 81))	('mouse', 'Species', '10090', (159, 164))	('SHP2', 'Gene', (36, 40))	('inhibition', 'Var', (41, 51))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('Ras', 'Protein', (67, 70))	('Ras', 'Chemical', 'MESH:D011883', (67, 70))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('suppressed', 'NegReg', (118, 128))
221664	26617336	1c), a catalytically dead SHP2(C459S) dominant-negative mutant allele or short hairpin RNA-mediated knockdown of endogenous SHP2 increased the level of tyrosyl phosphorylated HA-N-Ras(WT or 12D; Fig.	('SHP2', 'Gene', (124, 128))	('C459S', 'Mutation', 'p.C459S', (31, 36))	('increased', 'PosReg', (129, 138))	('level of tyrosyl phosphorylated', 'MPA', (143, 174))	('N-Ras', 'Gene', '4893', (178, 183))	('C459S', 'Var', (31, 36))	('SHP2', 'Gene', (26, 30))	('tyrosyl', 'Chemical', '-', (152, 159))	('N-Ras', 'Gene', (178, 183))
221665	26617336	Notably, tyrosyl phosphorylation of HA-N-Ras was not observed in the presence of catalytically dead c-Src(K295R Y527F) mutant irrespective of the expression of WT or dominant-negative SHP2 (Fig.	('c-Src', 'Gene', '6714', (100, 105))	('K295R', 'SUBSTITUTION', 'None', (106, 111))	('Y527F', 'SUBSTITUTION', 'None', (112, 117))	('N-Ras', 'Gene', '4893', (39, 44))	('SHP2', 'Gene', (184, 188))	('N-Ras', 'Gene', (39, 44))	('Y527F', 'Var', (112, 117))	('tyrosyl', 'Chemical', '-', (9, 16))	('K295R', 'Var', (106, 111))	('c-Src', 'Gene', (100, 105))
221670	26617336	Consistent with this observation, HA-H-Ras(12V) in RasB8p3 astrocytes had increased binding to Raf:RBD (Ras-binding domain) compared with RasB8p0 astrocytes (Supplementary Fig.	('RasB8p3', 'Var', (51, 58))	('Raf', 'Gene', (95, 98))	('Ras', 'Chemical', 'MESH:D011883', (39, 42))	('Ras', 'Chemical', 'MESH:D011883', (104, 107))	('Ras', 'Chemical', 'MESH:D011883', (138, 141))	('Ras', 'Chemical', 'MESH:D011883', (51, 54))	('increased', 'PosReg', (74, 83))	('Raf', 'Gene', '22882', (95, 98))	('binding', 'Interaction', (84, 91))	('HA-H-Ras(12V', 'Var', (34, 46))
221674	26617336	U87-viii astrocytes associated with aggressive glioma cell proliferation express in addition a hyperactive EGFR variant III.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('aggressive glioma', 'Disease', 'MESH:D005910', (36, 53))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('aggressive glioma', 'Disease', (36, 53))	('variant III', 'Var', (112, 123))	('hyperactive', 'PosReg', (95, 106))	('rat', 'Species', '10116', (66, 69))
221681	26617336	Elevated SHP2 phosphorylation status was also evident in four additional human GBM cell lines, U251, U118, A172 and T98G (Supplementary Fig.	('phosphorylation', 'MPA', (14, 29))	('T98G', 'Var', (116, 120))	('human', 'Species', '9606', (73, 78))	('SHP2', 'Gene', (9, 13))
221686	26617336	Importantly, HA-N-Ras(WT) binding to Flag-SHP2 markedly increased when co-expressed with c-Src, but not in the presence of kinase-dead c-Src(K295R Y527F) (Fig.	('c-Src', 'Gene', (135, 140))	('N-Ras', 'Gene', '4893', (16, 21))	('c-Src', 'Gene', '6714', (135, 140))	('increased', 'PosReg', (56, 65))	('K295R', 'Var', (141, 146))	('Y527F', 'SUBSTITUTION', 'None', (147, 152))	('c-Src', 'Gene', (89, 94))	('K295R', 'SUBSTITUTION', 'None', (141, 146))	('c-Src', 'Gene', '6714', (89, 94))	('N-Ras', 'Gene', (16, 21))	('Y527F', 'Var', (147, 152))	('binding', 'Interaction', (26, 33))	('Flag-SHP2', 'Gene', (37, 46))
221687	26617336	In comparison to Flag-N-Ras(WT), Flag-N-Ras(Y32F) mutant that escapes tyrosyl phosphorylation by c-Src bound considerably less to Flag-SHP2(WT) (Supplementary Fig.	('N-Ras', 'Gene', (38, 43))	('N-Ras', 'Gene', '4893', (22, 27))	('c-Src', 'Gene', (97, 102))	('c-Src', 'Gene', '6714', (97, 102))	('escapes', 'NegReg', (62, 69))	('bound', 'Interaction', (103, 108))	('N-Ras', 'Gene', '4893', (38, 43))	('tyrosyl', 'Chemical', '-', (70, 77))	('less', 'NegReg', (122, 126))	('mutant', 'Var', (50, 56))	('tyrosyl phosphorylation', 'MPA', (70, 93))	('N-Ras', 'Gene', (22, 27))	('Y32F', 'Mutation', 'p.Y32F', (44, 48))
221691	26617336	Notably, we have shown previously that EGF treatment fails to promote tyrosyl phosphorylation of Ras in SYF-/- MEFs.	('SYF-/- MEFs', 'Var', (104, 115))	('tyrosyl', 'Chemical', '-', (70, 77))	('Ras', 'Chemical', 'MESH:D011883', (97, 100))	('Ras', 'Protein', (97, 100))	('tyrosyl phosphorylation', 'MPA', (70, 93))	('MEFs', 'CellLine', 'CVCL:9115', (111, 115))
221695	26617336	Compared with the WT SHP2, constitutively active disease-causing Flag-SHP2(E76K) mutant markedly reduced the level of tyrosyl phosphorylated N-Ras and increased the binding of N-Ras to effector Raf:RBD and GTP-conjugated agarose beads in HEK293 cells (Fig.	('Raf', 'Gene', (194, 197))	('increased', 'PosReg', (151, 160))	('N-Ras', 'Gene', '4893', (141, 146))	('N-Ras', 'Gene', (176, 181))	('N-Ras', 'Gene', (141, 146))	('binding', 'Interaction', (165, 172))	('GTP', 'Chemical', 'MESH:D006160', (206, 209))	('Flag-SHP2', 'Gene', (65, 74))	('reduced', 'NegReg', (97, 104))	('Raf', 'Gene', '22882', (194, 197))	('mutant', 'Var', (81, 87))	('tyrosyl', 'Chemical', '-', (118, 125))	('N-Ras', 'Gene', '4893', (176, 181))	('E76K', 'Mutation', 'rs121918464', (75, 79))	('HEK293', 'CellLine', 'CVCL:0045', (238, 244))	('agarose', 'Chemical', 'MESH:D012685', (221, 228))
221696	26617336	Conversely, the expression of catalytically inactive Flag-SHP2(C459S) mutant as well as endogenous SHP2 knockdown in HEK293 cells was associated with hyper-phosphorylation of N-Ras and reduced the binding of N-Ras to Raf:RBD and GTP-conjugated beads (Fig.	('C459S', 'Mutation', 'p.C459S', (63, 68))	('N-Ras', 'Gene', '4893', (208, 213))	('Raf', 'Gene', '22882', (217, 220))	('mutant', 'Var', (70, 76))	('N-Ras', 'Gene', (175, 180))	('C459S) mutant', 'Var', (63, 76))	('N-Ras', 'Gene', (208, 213))	('N-Ras', 'Gene', '4893', (175, 180))	('HEK293', 'CellLine', 'CVCL:0045', (117, 123))	('GTP', 'Chemical', 'MESH:D006160', (229, 232))	('hyper-phosphorylation of N-Ras', 'Disease', 'MESH:D028361', (150, 180))	('Raf', 'Gene', (217, 220))	('GTP-conjugated', 'Protein', (229, 243))	('hyper-phosphorylation of N-Ras', 'Disease', (150, 180))	('binding', 'Interaction', (197, 204))	('Flag-SHP2', 'Gene', (53, 62))	('SHP2', 'Gene', (99, 103))	('reduced', 'NegReg', (185, 192))
221697	26617336	The enhanced level of tyrosyl phosphorylated ectopic or endogenous Ras in the presence of catalytically inactive Flag-SHP2(C459S) was also associated with reduced level of phosphorylated ERK, whereas the reduced level of tyrosyl phosphorylated Ras in the presence of constitutively active Flag-SHP2(E76K) was associated with increased level of phosphorylated ERK (Fig.	('E76K', 'Var', (299, 303))	('phosphorylated', 'MPA', (172, 186))	('Flag-SHP2', 'Gene', (113, 122))	('enhanced', 'PosReg', (4, 12))	('reduced', 'NegReg', (155, 162))	('level', 'MPA', (13, 18))	('Ras', 'Chemical', 'MESH:D011883', (244, 247))	('tyrosyl phosphorylated ectopic', 'MPA', (22, 52))	('level', 'MPA', (163, 168))	('tyrosyl', 'Chemical', '-', (221, 228))	('Ras', 'Chemical', 'MESH:D011883', (67, 70))	('E76K', 'Mutation', 'rs121918464', (299, 303))	('tyrosyl', 'Chemical', '-', (22, 29))	('C459S', 'Mutation', 'p.C459S', (123, 128))
221698	26617336	Notably, the effect of SHP2(WT or E76K or C459S) on N-Ras binding to Raf:RBD was markedly muted in the presence of kinase-dead c-Src(K295R Y527F) mutant (Fig.	('K295R', 'SUBSTITUTION', 'None', (133, 138))	('E76K', 'Mutation', 'rs121918464', (34, 38))	('binding', 'Interaction', (58, 65))	('N-Ras', 'Gene', (52, 57))	('Y527F', 'Var', (139, 144))	('muted', 'NegReg', (90, 95))	('Raf', 'Gene', '22882', (69, 72))	('c-Src', 'Gene', '6714', (127, 132))	('C459S', 'Var', (42, 47))	('c-Src', 'Gene', (127, 132))	('Raf', 'Gene', (69, 72))	('SHP2', 'Gene', (23, 27))	('N-Ras', 'Gene', '4893', (52, 57))	('K295R', 'Var', (133, 138))	('Y527F', 'SUBSTITUTION', 'None', (139, 144))	('C459S', 'Mutation', 'p.C459S', (42, 47))	('E76K', 'Var', (34, 38))
221700	26617336	Notably, SHP2 inhibitor II-B08 treatment or ectopic expression of a dominant-negative Flag-SHP2(C459S) markedly enhanced phosphorylation of oncogenic HA-N-Ras(12D) mutant, concomitant with reduced binding to Raf:RBD and GTP-loaded beads and attenuated induction of EGF-induced phosphorylated ERK level (Fig.	('enhanced', 'PosReg', (112, 120))	('Raf', 'Gene', (208, 211))	('mutant', 'Var', (164, 170))	('II-B08', 'Chemical', '-', (24, 30))	('induction', 'MPA', (252, 261))	('attenuated', 'NegReg', (241, 251))	('reduced', 'NegReg', (189, 196))	('C459S', 'Mutation', 'p.C459S', (96, 101))	('GTP', 'Chemical', 'MESH:D006160', (220, 223))	('phosphorylation', 'MPA', (121, 136))	('N-Ras', 'Gene', (153, 158))	('Raf', 'Gene', '22882', (208, 211))	('Flag-SHP2', 'Gene', (86, 95))	('binding', 'Interaction', (197, 204))	('N-Ras', 'Gene', '4893', (153, 158))	('EGF-induced phosphorylated ERK level', 'MPA', (265, 301))
221701	26617336	These results suggest that pharmacologic manipulation of SHP2 activity could influence the oncogenic potential of cancer-causing Ras mutants.	('Ras', 'Disease', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('influence', 'Reg', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('SHP2', 'Gene', (57, 61))	('mutants', 'Var', (133, 140))	('oncogenic potential', 'CPA', (91, 110))	('Ras', 'Chemical', 'MESH:D011883', (129, 132))	('cancer', 'Disease', (114, 120))
221709	26617336	Furthermore, ectopic expression of a dominant-negative Flag-SHP2(C459S) mutant markedly reduced Ras binding to Raf:RBD beads and attenuated phosphorylated ERK levels in Flag-N-Ras(WT)-expressing HEK293 cells, but had negligible effect on HEK293 cells expressing Flag-N-Ras(Y32F) mutant (Supplementary Fig.	('N-Ras', 'Gene', '4893', (267, 272))	('binding', 'Interaction', (100, 107))	('Ras', 'Chemical', 'MESH:D011883', (269, 272))	('Y32F', 'Mutation', 'p.Y32F', (273, 277))	('HEK293', 'CellLine', 'CVCL:0045', (238, 244))	('attenuated', 'NegReg', (129, 139))	('C459S', 'Mutation', 'p.C459S', (65, 70))	('mutant', 'Var', (72, 78))	('Flag-SHP2', 'Gene', (55, 64))	('reduced', 'NegReg', (88, 95))	('Raf', 'Gene', (111, 114))	('phosphorylated ERK levels', 'MPA', (140, 165))	('HEK293', 'CellLine', 'CVCL:0045', (195, 201))	('N-Ras', 'Gene', (174, 179))	('Ras', 'Chemical', 'MESH:D011883', (96, 99))	('N-Ras', 'Gene', '4893', (174, 179))	('N-Ras', 'Gene', (267, 272))	('Raf', 'Gene', '22882', (111, 114))	('Ras', 'Chemical', 'MESH:D011883', (176, 179))	('Ras', 'MPA', (96, 99))
221712	26617336	U87-bearing xenograft mice when exposed to II-B08 demonstrated a significant reduction in overall tumour size 7 days after therapy was started when compared with those treated with placebo.	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('reduction', 'NegReg', (77, 86))	('tumour', 'Disease', (98, 104))	('rat', 'Species', '10116', (57, 60))	('II-B08', 'Var', (43, 49))	('II-B08', 'Chemical', '-', (43, 49))	('mice', 'Species', '10090', (22, 26))
221731	26617336	For example, it is well established that tyrosyl phosphorylated SHP2 binds to the adapter Grb2 (ref.).	('binds', 'Interaction', (69, 74))	('tyrosyl phosphorylated', 'Var', (41, 63))	('tyrosyl', 'Chemical', '-', (41, 48))	('Grb2', 'Gene', (90, 94))	('SHP2', 'Gene', (64, 68))	('Grb2', 'Gene', '2885', (90, 94))
221736	26617336	We recently showed that tyrosyl phosphorylation of Ras promotes binding to RasGAP and GTP hydrolysis.	('binding', 'Interaction', (64, 71))	('tyrosyl phosphorylation', 'Var', (24, 47))	('RasGAP', 'Gene', (75, 81))	('RasGAP', 'Gene', '5921', (75, 81))	('GTP', 'Chemical', 'MESH:D006160', (86, 89))	('tyrosyl', 'Chemical', '-', (24, 31))	('Ras', 'Chemical', 'MESH:D011883', (51, 54))	('promotes', 'PosReg', (55, 63))	('Ras', 'Protein', (51, 54))	('Ras', 'Chemical', 'MESH:D011883', (75, 78))	('GTP hydrolysis', 'CPA', (86, 100))
221739	26617336	However, we show here that the catalytically inactive SHP2 mutant attenuates oncogenic Ras activation, which questions the involvement of Sprouty in SHP2-mediated regulation of Ras.	('attenuates', 'NegReg', (66, 76))	('mutant', 'Var', (59, 65))	('SHP2', 'Gene', (54, 58))	('Ras', 'Chemical', 'MESH:D011883', (87, 90))	('Ras', 'Chemical', 'MESH:D011883', (177, 180))	('oncogenic Ras', 'CPA', (77, 90))
221743	26617336	Gain-of-function mutations in the SHP2 gene, PTPN11, have been identified in Noonan Syndrome, haematological malignancies and other types of cancers, including breast cancer, lung cancer, neuroblastoma, pilocytic astrocytoma and medulloblastoma.	('haematological malignancies', 'Disease', 'MESH:D019337', (94, 121))	('lung cancer', 'Disease', (175, 186))	('Gain-of-function', 'PosReg', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('medulloblastoma', 'Disease', 'MESH:D008527', (229, 244))	('mutations', 'Var', (17, 26))	('medulloblastoma', 'Phenotype', 'HP:0002885', (229, 244))	('Noonan Syndrome', 'Disease', 'MESH:D009634', (77, 92))	('medulloblastoma', 'Disease', (229, 244))	('PTPN11', 'Gene', (45, 51))	('neuroblastoma', 'Disease', (188, 201))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', (141, 148))	('neuroblastoma', 'Phenotype', 'HP:0003006', (188, 201))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (203, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (213, 224))	('PTPN11', 'Gene', '5781', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('haematological malignancies', 'Disease', (94, 121))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pilocytic astrocytoma', 'Disease', (203, 224))	('neuroblastoma', 'Disease', 'MESH:D009447', (188, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('Noonan Syndrome', 'Disease', (77, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('breast cancer', 'Disease', (160, 173))
221744	26617336	According to the Cancer Genome Atlas database, ~2% of GBM patients harbour PTPN11 mutations.	('PTPN11', 'Gene', (75, 81))	('patients', 'Species', '9606', (58, 66))	('harbour', 'Reg', (67, 74))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (82, 91))	('PTPN11', 'Gene', '5781', (75, 81))
221745	26617336	Despite the rarity of PTPN11 mutations in gliomas, other components of the Ras signalling pathway, such EGFR, NF-1 and Ras, are genetically altered or deregulated in the majority of GBM.	('PTPN11', 'Gene', (22, 28))	('Ras', 'Chemical', 'MESH:D011883', (119, 122))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('mutations', 'Var', (29, 38))	('Ras signalling pathway', 'Pathway', (75, 97))	('NF-1', 'Gene', (110, 114))	('Ras', 'Chemical', 'MESH:D011883', (75, 78))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('PTPN11', 'Gene', '5781', (22, 28))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('deregulated', 'Reg', (151, 162))	('gliomas', 'Disease', (42, 49))
221748	26617336	As Ras transduces signals from many different receptor tyrosine kinases that are known to be overexpressed in GBM, including EGFR, FGFR and PDGFR, targeting SHP2 may prove more effective in GBM, which respond poorly to kinase inhibitor monotherapy.	('Ras', 'Chemical', 'MESH:D011883', (3, 6))	('tyrosine', 'Chemical', 'MESH:D014443', (55, 63))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (125, 129))	('GBM', 'Disease', (190, 193))	('PDGFR', 'Gene', (140, 145))	('targeting', 'Var', (147, 156))	('PDGFR', 'Gene', '5159', (140, 145))	('SHP2', 'Gene', (157, 161))
221752	26617336	In addition, there were reduced levels of Ki67 proliferation and an overall reduction in tumour cell density as determined by nuclei in the haematoxylin and eosin-stained tissues.	('reduction', 'NegReg', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('reduced', 'NegReg', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('Ki67', 'Var', (42, 46))	('rat', 'Species', '10116', (54, 57))	('tumour', 'Disease', (89, 95))	('haematoxylin', 'Chemical', 'MESH:D006416', (140, 152))	('eosin', 'Chemical', 'MESH:D004801', (157, 162))
221754	26617336	To determine whether SHP2 inhibition results in decrease tumour growth, we used an orthotopic model of malignant glioma by injecting malignant human glioma U87 cells intracranially in NOD/SCID mice.	('SCID', 'Disease', (188, 192))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('malignant glioma', 'Disease', 'MESH:D005910', (103, 119))	('decrease tumour', 'Disease', 'MESH:D009369', (48, 63))	('malignant glioma', 'Disease', (103, 119))	('inhibition', 'Var', (26, 36))	('glioma', 'Disease', (113, 119))	('mice', 'Species', '10090', (193, 197))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('human', 'Species', '9606', (143, 148))	('tumour growth', 'Disease', 'MESH:D006130', (57, 70))	('SHP2', 'Gene', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('glioma', 'Disease', (149, 155))	('SCID', 'Disease', 'MESH:D053632', (188, 192))	('decrease tumour', 'Disease', (48, 63))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('tumour growth', 'Disease', (57, 70))
221756	26617336	As confirmed by the in vitro work, the inhibition of SHP2 is able to perturb the RasB8 signalling pathways resulting in elevated levels of Ras in its phosphorylated state.	('inhibition', 'Var', (39, 49))	('levels of Ras in its phosphorylated state', 'MPA', (129, 170))	('SHP2', 'Gene', (53, 57))	('elevated', 'PosReg', (120, 128))	('perturb', 'Reg', (69, 76))	('RasB8 signalling pathways', 'Pathway', (81, 106))	('Ras', 'Chemical', 'MESH:D011883', (81, 84))	('Ras', 'Chemical', 'MESH:D011883', (139, 142))
221762	26617336	HEK293, MEF, MEF-SYF(-/-) and U87, U251, U118, A172 and T98G were obtained from American Type Culture Collection.	('T98G', 'Var', (56, 60))	('U251', 'Var', (35, 39))	('MEF', 'Gene', '2000', (13, 16))	('MEF', 'Gene', (13, 16))	('U87', 'Var', (30, 33))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('U118', 'Var', (41, 45))	('MEF-SYF', 'CellLine', 'CVCL:6461', (13, 20))	('MEF', 'Gene', '2000', (8, 11))	('A172', 'Var', (47, 51))	('MEF', 'Gene', (8, 11))
221778	26617336	GBM transgenic mouse model, RasB8, was generated through integration of a V12 RasB8 mutation under the control of GFAP-promoter leaving mice predisposed to sporadic GBM-like astrocytoma.	('RasB8', 'Gene', (78, 83))	('astrocytoma', 'Disease', (174, 185))	('mice', 'Species', '10090', (136, 140))	('astrocytoma', 'Phenotype', 'HP:0009592', (174, 185))	('Ras', 'Chemical', 'MESH:D011883', (28, 31))	('rat', 'Species', '10116', (43, 46))	('mouse', 'Species', '10090', (15, 20))	('astrocytoma', 'Disease', 'MESH:D001254', (174, 185))	('rat', 'Species', '10116', (62, 65))	('Ras', 'Chemical', 'MESH:D011883', (78, 81))	('mutation', 'Var', (84, 92))
221779	26617336	Embryonic stem cell complementation methodology was used to integrate a V12 RasB8 mutation (IRES LACz) under the control of GFAP-promoter into an ICR background strain mouse.	('mouse', 'Species', '10090', (168, 173))	('mutation', 'Var', (82, 90))	('V12 RasB8', 'Gene', (72, 81))	('Ras', 'Chemical', 'MESH:D011883', (76, 79))	('RasB8', 'Gene', (76, 81))	('rat', 'Species', '10116', (65, 68))
221781	26617336	Genotyping is carried out for both the RasB8 mutation and the LACz reporter construct; in addition, LACz immunohistochemistry (IHC) is carried out to ensure full protein translation.	('RasB8', 'Gene', (39, 44))	('mutation', 'Var', (45, 53))	('Ras', 'Chemical', 'MESH:D011883', (39, 42))
221787	26617336	Rabbit polyclonal antibodies against Src, phosphorylated (p)Src(Y416), pAKT, AKT, glutathione S-transferase (GST), pSHP2(Y542), SHP2 and HA (polyclonal) were obtained from Cell Signaling Technologies.	('glutathione S-transferase', 'Gene', '373156', (82, 107))	('glutathione S-transferase', 'Gene', (82, 107))	('GST', 'Gene', (109, 112))	('Y416', 'Var', (64, 68))	('Rabbit', 'Species', '9986', (0, 6))	('Y542', 'Var', (121, 125))	('GST', 'Gene', '373156', (109, 112))
221789	26617336	p-c-Raf(Y340) (#44506G) was obtained from Invitrogen.	('#44506G', 'Var', (15, 22))	('c-Raf', 'Gene', '5894', (2, 7))	('c-Raf', 'Gene', (2, 7))
221821	26617336	Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis.	('SHP2-mediated', 'Gene', (14, 27))	('suppresses', 'NegReg', (53, 63))	('dephosphorylation', 'MPA', (28, 45))	('oncogenesis', 'CPA', (64, 75))	('Ras', 'Protein', (49, 52))	('Ras', 'Chemical', 'MESH:D011883', (49, 52))	('Inhibition', 'Var', (0, 10))
221843	33634092	Recent studies have found that aberrant expression of RBPs could affect cellular functions, leading to the occurrence and progression of various cancers, including gliomas.	('cancers', 'Disease', (145, 152))	('affect', 'Reg', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('leading to', 'Reg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('RBP', 'Gene', '5950', (54, 57))	('aberrant expression', 'Var', (31, 50))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cellular', 'MPA', (72, 80))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))	('RBP', 'Gene', (54, 57))
221844	33634092	Further, growing evidence has associated RBP dysregulation to oncogenesis and cancer progression.	('RBP', 'Gene', (41, 44))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('oncogenesis', 'CPA', (62, 73))	('dysregulation', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('RBP', 'Gene', '5950', (41, 44))
221875	33634092	Subsequently, proteins were transferred onto polyvinylidene difluoride-membranes (PVDF membranes, Millipore, MA, USA) and membranes were blocked in 10% bull serum albumin (BSA) at room-temperature for 1 h. Blocked PVDF membranes were incubated with primary antibodies overnight at 4 C. The antibodies used in present study were rabbit anti-GNL1 (1:500, 14078-1-AP, Proteintech, China), rabbit anti-RDM1 (1:500, 20156-1-AP, Proteintech), rabbit anti-FBXO17 (1:500, 12844-1-AP, Proteintech), rabbit anti-SPATS2L (1:500, 16938-1-AP, Proteintech, China), rabbit anti-GAPDH (1:5000, 10494-1-AP, Proteintech) and rabbit anti-bTubulin (1:1,000, 10068-1-AP, Proteintech).	('GAPDH', 'Gene', (563, 568))	('serum albumin', 'Gene', '213', (157, 170))	('serum albumin', 'Gene', (157, 170))	('1:500', 'Var', (511, 516))	('GAPDH', 'Gene', '2597', (563, 568))
221908	33634092	Western blotting results showed that protein level of GNL1 was significantly lower in U251 and LN229 cells compared with SW1088 cells (Supplementary Figure 2A), while SPATS2L, RDM1, and FBXO17 protein expression levels were significantly higher in U251 and LN229 compared with SW1088 cells (Supplementary Figures 2B-D).	('higher', 'PosReg', (238, 244))	('lower', 'NegReg', (77, 82))	('U251', 'Var', (86, 90))	('LN229', 'Var', (95, 100))	('SW1088', 'CellLine', 'CVCL:1715', (277, 283))	('LN229', 'CellLine', 'CVCL:0393', (257, 262))	('U251', 'CellLine', 'CVCL:0021', (248, 252))	('U251', 'CellLine', 'CVCL:0021', (86, 90))	('SW1088', 'CellLine', 'CVCL:1715', (121, 127))	('GNL1', 'Gene', (54, 58))	('protein level', 'MPA', (37, 50))	('LN229', 'CellLine', 'CVCL:0393', (95, 100))
221921	33634092	Finally, biases have been reported when a risk model is constructed based on a cohort of a limited number of patients a training cohort with fewer samples may lead a labile model which may not be successfully validated in other independent cohorts.	('biases', 'Var', (9, 15))	('labile', 'MPA', (166, 172))	('patients', 'Species', '9606', (109, 117))
221937	33634092	RDM1 is reported to be involved in the cell response to cisplatin (Hamimes et al.,) and acts as an oncogene in several cancers; however, loss of RDM1 could promote liver cancer progression by the Ras/Raf/ERK and p53 pathways (Chen et al.,).	('RDM1', 'Gene', (145, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('liver cancer', 'Disease', 'MESH:D006528', (164, 176))	('liver cancer', 'Phenotype', 'HP:0002896', (164, 176))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('liver cancer', 'Disease', (164, 176))	('ERK', 'Gene', (204, 207))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ERK', 'Gene', '26413', (204, 207))	('loss', 'Var', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('promote', 'PosReg', (156, 163))
221953	32075753	The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs.	('post-transcriptional gene', 'MPA', (45, 70))	('GSC-EVs', 'Chemical', '-', (16, 23))	('miRNAs', 'Var', (95, 101))
221998	32075753	However, knockdown of miR-9-5p severely reduced the metabolic activity of the GBM8 neurosphere cultures as measured by the WST assay (Figures 4A and 4B), ending this line of investigation.	('miR-9-5p', 'Gene', (22, 30))	('miR-9-5p', 'Gene', '407052', (22, 30))	('knockdown', 'Var', (9, 18))	('metabolic activity', 'CPA', (52, 70))	('reduced', 'NegReg', (40, 47))	('GBM8', 'Gene', (78, 82))
222006	32075753	We provide multiple lines of evidence from both in vitro experiments on cell lines and computational deconvolution of tumors in vivo that EV-mediated transfer of RNAs from GBM cells to brain ECs induces angiogenesis.	('induces', 'PosReg', (195, 202))	('RNAs', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('transfer', 'Var', (150, 158))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('angiogenesis', 'CPA', (203, 215))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
222009	32075753	Moreover, 28 of 29 genes downregulated by GSC-EVs in vitro were also downregulated in vivo without observable gains in promoter methylation, which is consistent with post-transcriptional downregulation by miRNAs delivered from GSCs to ECs.	('genes', 'Gene', (19, 24))	('GSC', 'Chemical', '-', (42, 45))	('GSC-EVs', 'Var', (42, 49))	('GSC', 'Chemical', '-', (227, 230))	('downregulated', 'NegReg', (69, 82))	('downregulated', 'NegReg', (25, 38))	('GSC-EVs', 'Chemical', '-', (42, 49))	('downregulation', 'NegReg', (187, 201))
222010	32075753	The set includes miR-148a and miR-9-5p, both previously associated with glioma angiogenesis and poor survival.	('miR-148a', 'Var', (17, 25))	('glioma', 'Disease', (72, 78))	('miR-9-5p', 'Gene', (30, 38))	('miR-9-5p', 'Gene', '407052', (30, 38))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('associated with', 'Reg', (56, 71))
222012	32075753	Our results are also concordant with previous studies reporting that the silencing of miR-148a normalizes the aberrant tumor vasculature in mouse models of GBM.	('mouse', 'Species', '10090', (140, 145))	('tumor', 'Disease', (119, 124))	('silencing', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('miR-148a', 'Gene', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('normalizes', 'NegReg', (95, 105))
222014	32075753	RGS5 plays a central role in vascular growth; it has been shown to reduce endothelial growth; and small interfering RNA (siRNA)-mediated knockdown of RGS5 stimulates endothelial growth.	('reduce', 'NegReg', (67, 73))	('RGS5', 'Gene', (150, 154))	('endothelial growth', 'CPA', (74, 92))	('RGS5', 'Gene', (0, 4))	('RGS5', 'Gene', '8490', (150, 154))	('knockdown', 'Var', (137, 146))	('RGS5', 'Gene', '8490', (0, 4))	('endothelial growth', 'CPA', (166, 184))	('stimulates', 'PosReg', (155, 165))
222021	32075753	Moreover, reduction of the metabolic activity of GBM8 GSCs induced by the knockdown of miR-9-5p is consistent with previous reports of decreased proliferation in other GBM cell lines, suggesting that removal of miR-9-5p may also confer chemotherapy resistance by reducing proliferation.	('proliferation', 'CPA', (272, 285))	('metabolic activity', 'MPA', (27, 45))	('GSC', 'Chemical', '-', (54, 57))	('knockdown', 'Var', (74, 83))	('miR-9-5p', 'Gene', (87, 95))	('miR-9-5p', 'Gene', '407052', (87, 95))	('reduction', 'NegReg', (10, 19))	('miR-9-5p', 'Gene', (211, 219))	('miR-9-5p', 'Gene', '407052', (211, 219))	('chemotherapy resistance', 'CPA', (236, 259))	('reducing', 'NegReg', (263, 271))
222052	31583167	Temporal lobe, particularly mesial temporal area, is the most epileptogenic lobe in the brain and any lesion in the temporal lobe may cause seizure because mainly of lower seizure threshold and if uncontrolled by medication, diagnosis of epilepsy becomes inevitable.	('lesion', 'Var', (102, 108))	('seizure', 'Disease', (140, 147))	('seizure', 'Disease', (172, 179))	('cause', 'Reg', (134, 139))	('epileptogenic lobe', 'Disease', 'MESH:D008878', (62, 80))	('seizure', 'Disease', 'MESH:D012640', (140, 147))	('seizure', 'Disease', 'MESH:D012640', (172, 179))	('epilepsy', 'Disease', 'MESH:D004827', (238, 246))	('epilepsy', 'Phenotype', 'HP:0001250', (238, 246))	('seizure', 'Phenotype', 'HP:0001250', (172, 179))	('lower', 'NegReg', (166, 171))	('seizure', 'Phenotype', 'HP:0001250', (140, 147))	('epilepsy', 'Disease', (238, 246))	('epileptogenic lobe', 'Disease', (62, 80))
222120	31583167	The common notion is that lesionectomy alone is inadequate to obtain optimal seizure control in mesial temporal LGGs and resection of epileptogenic zone (or tailored temporal resection) under the guidance of neurophysiological and neuropsychological tests appears to offer the best results with respect to seizure control.	('seizure', 'Phenotype', 'HP:0001250', (306, 313))	('resection', 'Var', (121, 130))	('seizure', 'Phenotype', 'HP:0001250', (77, 84))	('GG', 'Disease', 'MESH:D018303', (113, 115))	('seizure', 'Disease', (306, 313))	('seizure', 'Disease', 'MESH:D012640', (306, 313))	('seizure', 'Disease', (77, 84))	('seizure', 'Disease', 'MESH:D012640', (77, 84))
222142	30393513	Blocking PD1/PDL1 Interactions Together with MLN4924 Therapy is a Potential Strategy for Glioma Treatment MLN4924, a pharmacological inhibitor of cullin neddylation, resulted in glioma cell apoptosis, deregulation of the S-phase of DNA synthesis and thus, offers great potential for the treatment of brain tumours.	('resulted in', 'Reg', (166, 177))	('PDL1', 'Gene', (13, 17))	('tumour', 'Phenotype', 'HP:0002664', (306, 312))	('brain tumours', 'Disease', (300, 313))	('S-phase of DNA synthesis', 'MPA', (221, 245))	('MLN4924', 'Chemical', 'MESH:C539933', (45, 52))	('glioma', 'Disease', (178, 184))	('tumours', 'Phenotype', 'HP:0002664', (306, 313))	('MLN4924', 'Var', (106, 113))	('PDL1', 'Gene', '29126', (13, 17))	('deregulation', 'MPA', (201, 213))	('Glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('PD1', 'Gene', '5133', (9, 12))	('brain tumours', 'Phenotype', 'HP:0030692', (300, 313))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('Glioma', 'Phenotype', 'HP:0009733', (89, 95))	('brain tumours', 'Disease', 'MESH:D001932', (300, 313))	('MLN4924', 'Chemical', 'MESH:C539933', (106, 113))	('Glioma', 'Disease', (89, 95))	('PD1', 'Gene', (9, 12))	('brain tumour', 'Phenotype', 'HP:0030692', (300, 312))
222143	30393513	However, targeting the neddylation pathway with an MLN4924 treatment stabilized the hypoxia-inducible factor 1A (HIF1A), which is one of the main transcriptional enhancers of the immune checkpoint molecule PDL1 (programmid death ligand-1) in cancer cells.	('HIF1A', 'Gene', '3091', (113, 118))	('MLN4924', 'Var', (51, 58))	('cancer', 'Disease', (242, 248))	('stabilized', 'NegReg', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('HIF1A', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('neddylation pathway', 'Pathway', (23, 42))	('hypoxia-inducible factor 1A', 'Gene', (84, 111))	('hypoxia-inducible factor 1A', 'Gene', '3091', (84, 111))	('MLN4924', 'Chemical', 'MESH:C539933', (51, 58))
222145	30393513	We hypothesize that i) PDL1 is up-regulated in gliomas after treatment with MLN4924 and induces T-cell energy; ii) co-utilization of the PD1/PDL1 blockage with MLN4924 therapy may reduce T-cell energy and may engage MLN4924-induced tumour disruption with the immune response.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('up-regulated', 'PosReg', (31, 43))	('tumour disruption', 'Disease', 'MESH:D019958', (232, 249))	('PDL1', 'Gene', (23, 27))	('PD1/PDL1', 'Gene', (137, 145))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('induces', 'PosReg', (88, 95))	('reduce', 'NegReg', (180, 186))	('reduce T-cell', 'Phenotype', 'HP:0005403', (180, 193))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('T-cell energy', 'MPA', (187, 200))	('MLN4924', 'Chemical', 'MESH:C539933', (76, 83))	('blockage', 'Var', (146, 154))	('MLN4924', 'Chemical', 'MESH:C539933', (216, 223))	('MLN4924', 'Chemical', 'MESH:C539933', (160, 167))	('gliomas', 'Disease', (47, 54))	('T-cell energy', 'MPA', (96, 109))	('tumour disruption', 'Disease', (232, 249))
222146	30393513	PDL1 expression and its immunosuppressive role in gliomas, glioma microenvironments, and after treatments with MLN4924 were assessed by utilizing methods of immunohistochemistry, molecular biology, and biochemistry.	('glioma', 'Disease', (59, 65))	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('gliomas', 'Disease', (50, 57))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('MLN4924', 'Var', (111, 118))	('glioma', 'Disease', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('PDL1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
222149	30393513	We found that a pharmacological inhibitor of cullin neddylation, MLN4924, exhibited strong cytotoxicity towards PDGx and established glioma cell lines, in vitro, with an IC50's range from 0.2 to 3 uM.	("50's", 'Species', '1214577', (172, 176))	('MLN4924', 'Var', (65, 72))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('glioma', 'Disease', (133, 139))	('MLN4924', 'Chemical', 'MESH:C539933', (65, 72))	('cytotoxicity', 'Disease', (91, 103))
222150	30393513	However, we observed a significant increase of HIF1A and PDL1 in mRNA and protein levels in all glioma cell lines after treatment with MLN4924.	('increase', 'PosReg', (35, 43))	('HIF1A', 'Gene', (47, 52))	('HIF1A', 'Gene', '3091', (47, 52))	('PDL1', 'Gene', (57, 61))	('MLN4924', 'Chemical', 'MESH:C539933', (135, 142))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('MLN4924', 'Var', (135, 142))	('glioma', 'Disease', (96, 102))
222151	30393513	The MLN4924-dependent induction of PDL1 in gliomas resulted in T-cell energy, which was blocked by a blockage of the PD1/PDL1 interaction.	('MLN4924-dependent', 'Var', (4, 21))	('interaction', 'Interaction', (126, 137))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('T-cell energy', 'CPA', (63, 76))	('gliomas', 'Disease', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('MLN4924', 'Chemical', 'MESH:C539933', (4, 11))	('PDL1', 'Gene', (35, 39))	('resulted in', 'Reg', (51, 62))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('induction', 'PosReg', (22, 31))
222152	30393513	We conclude that i) PDL1 up-regulation in gliomas and the glioma microenvironment is an important chemotherapeutic target; ii) MLN4924 therapy, combined with a blockage of the PD1/PDL1 pathway, should be considered as a potential strategy for glioma treatment.	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('up-regulation', 'PosReg', (25, 38))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('MLN4924 therapy', 'Var', (127, 142))	('PD1/PDL1 pathway', 'Pathway', (176, 192))	('PDL1', 'Gene', (20, 24))	('MLN4924', 'Chemical', 'MESH:C539933', (127, 134))	('glioma', 'Disease', (243, 249))	('glioma', 'Disease', (58, 64))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('glioma', 'Disease', (42, 48))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
222155	30393513	At least twenty-seven clinical trials were initiated to evaluate PDL1/PD1 inhibitors alone or in combination with other drugs for the treatment of brain tumors (including gliomas and GBM) during 2014-2017 period: NCT02550249 (2015), NCT02423343 (2015), NCT02017717 (2014), NCT02311920 (2015), NCT02337491 (2015), NCT023311582 (2015), NCT01952769 (2014), NCT02336165 (2015), NCT01375842 (2011), NCT02829931 (2016), NCT02313272 (2014), NCT02798406 (2016), NCT03058289 (2017), NCT02335918 (2015), NCT02852655 (2016), NCT02526017 (2015), NCT03233152 (2017), NCT02968940 (2016), NCT02327078 (2014), NCT02794883 (2016), NCT02311582 (2014), NCT02937844 (2016), NCT02866747 (2016), NCT02336165 (2015), NCT02337491 (2015), NCT03014804 (2017), NCT02550249 (2015).The preclinical data generated in the orthotopic glioma mice models suggests that combination treatment with PD1/PDL1 inhibitors and radiotherapy, natural killer cells, bevacizumab, and small-molecule inhibitors of apoptosis antagonists (SMCs) can successfully inhibit the tumors.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('tumors', 'Disease', (1026, 1032))	('brain tumors', 'Disease', (147, 159))	('gliomas', 'Disease', (171, 178))	('NCT02968940', 'Var', (554, 565))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('inhibit', 'NegReg', (1014, 1021))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (1026, 1032))	('gliomas', 'Disease', 'MESH:D005910', (171, 178))	('glioma', 'Disease', (802, 808))	('clinical', 'Species', '191496', (760, 768))	('glioma', 'Disease', 'MESH:D005910', (802, 808))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('clinical', 'Species', '191496', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (1026, 1031))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('tumors', 'Phenotype', 'HP:0002664', (1026, 1032))	('brain tumors', 'Disease', 'MESH:D001932', (147, 159))	('brain tumors', 'Phenotype', 'HP:0030692', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('glioma', 'Disease', (171, 177))	('mice', 'Species', '10090', (809, 813))	('glioma', 'Phenotype', 'HP:0009733', (802, 808))	('tumors', 'Disease', (153, 159))	('PD1/PDL1', 'Gene', (862, 870))	('brain tumor', 'Phenotype', 'HP:0030692', (147, 158))
222157	30393513	MLN4924, a pharmacological inhibitor of the NEDD8 E1 activation enzyme, is currently considered as a promising treatment for brain tumors.	('NEDD8', 'Gene', '18002', (44, 49))	('MLN4924', 'Var', (0, 7))	('brain tumor', 'Phenotype', 'HP:0030692', (125, 136))	('NEDD8', 'Gene', (44, 49))	('brain tumors', 'Disease', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('brain tumors', 'Phenotype', 'HP:0030692', (125, 137))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('brain tumors', 'Disease', 'MESH:D001932', (125, 137))
222158	30393513	MLN4924 can cross the blood-brain barrier and exhibits strong effectiveness towards tumors with an overactivated protein neddylation pathway, in vitro and in vivo.	('MLN4924', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('overactivated', 'PosReg', (99, 112))	('effectiveness', 'MPA', (62, 75))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('protein neddylation pathway', 'Pathway', (113, 140))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))
222160	30393513	Treatment with MLN4924 results in tumor-specific cell cycle arrest, apoptosis and induction of the DNA damage response in the preclinical mouse glioma model.	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('cell cycle arrest', 'CPA', (49, 66))	('mouse', 'Species', '10090', (138, 143))	('DNA damage response', 'MPA', (99, 118))	('apoptosis', 'CPA', (68, 77))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('clinical', 'Species', '191496', (129, 137))	('glioma', 'Disease', (144, 150))	('MLN4924', 'Var', (15, 22))	('induction', 'Reg', (82, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
222161	30393513	The engagement of MLN4924 treatment with an anti-tumor immune axis is currently unexplored.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MLN4924', 'Chemical', 'MESH:C539933', (18, 25))	('MLN4924 treatment', 'Var', (18, 35))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
222162	30393513	Our work seeks to evaluate the impact of MLN4924 treatment on PDL1 expression on gliomas and on glioma cell immune evasion, in vitro.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('MLN4924', 'Var', (41, 48))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Disease', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('PDL1', 'Gene', (62, 66))	('MLN4924', 'Chemical', 'MESH:C539933', (41, 48))	('glioma', 'Disease', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
222163	30393513	It was reported that treatment with MLN4924 is accompanied by a significant accumulation of the HIF1A transcriptional factor, which is a strong up-regulator of PDL1 expression.	('MLN4924', 'Chemical', 'MESH:C539933', (36, 43))	('HIF1A', 'Gene', (96, 101))	('HIF1A', 'Gene', '3091', (96, 101))	('MLN4924', 'Var', (36, 43))	('accumulation', 'PosReg', (76, 88))
222169	30393513	We found that MLN4924 exhibited strong cytotoxicity against established and PDGx glioma cell lines, in vitro, and therefore, is a promising candidate for the treatment of brain tumors.	('PDGx glioma', 'Disease', (76, 87))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('cytotoxicity', 'Disease', (39, 51))	('MLN4924', 'Var', (14, 21))	('brain tumors', 'Disease', 'MESH:D001932', (171, 183))	('brain tumors', 'Phenotype', 'HP:0030692', (171, 183))	('cytotoxicity', 'Disease', 'MESH:D064420', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('brain tumor', 'Phenotype', 'HP:0030692', (171, 182))	('brain tumors', 'Disease', (171, 183))	('PDGx glioma', 'Disease', 'MESH:D005910', (76, 87))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))
222170	30393513	However, we also observed a significant increase of HIF1A and PDL1 levels in all cell lines after treatment with MLN4924, which may lead to suppression of the immune response development, in vivo.	('PDL1 levels', 'MPA', (62, 73))	('immune response development', 'CPA', (159, 186))	('increase', 'PosReg', (40, 48))	('MLN4924', 'Chemical', 'MESH:C539933', (113, 120))	('HIF1A', 'Gene', (52, 57))	('HIF1A', 'Gene', '3091', (52, 57))	('suppression', 'NegReg', (140, 151))	('MLN4924', 'Var', (113, 120))
222171	30393513	We found that PDL1 up-regulation in glioma cells after MLN4924 treatment induced T-cell energy, which could be blocked by a PD1/PDL1 blockage.	('T-cell energy', 'CPA', (81, 94))	('MLN4924 treatment', 'Var', (55, 72))	('glioma', 'Disease', (36, 42))	('up-regulation', 'PosReg', (19, 32))	('PDL1', 'Gene', (14, 18))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('MLN4924', 'Chemical', 'MESH:C539933', (55, 62))	('induced', 'Reg', (73, 80))
222172	30393513	We conclude that using inhibitors of PDL1/ PD1 interaction with MLN4924 may improve the effectiveness of MLN4924 treatment, in vivo, via the reduction of immune-cell energy.	('interaction', 'Interaction', (47, 58))	('effectiveness', 'MPA', (88, 101))	('immune-cell energy', 'MPA', (154, 172))	('PDL1/ PD1', 'Gene', (37, 46))	('MLN4924', 'Chemical', 'MESH:C539933', (105, 112))	('MLN4924', 'Chemical', 'MESH:C539933', (64, 71))	('reduction', 'NegReg', (141, 150))	('MLN4924', 'Var', (105, 112))	('MLN4924', 'Var', (64, 71))	('improve', 'PosReg', (76, 83))
222173	30393513	We consider blocking the PD1/PDL1 pathway together with MLN4924 therapy as a potential strategy for glioma treatment; this strategy is in need of a detailed evaluation in preclinical orthotopic glioma mice models.	('MLN4924 therapy', 'Var', (56, 71))	('glioma', 'Disease', (100, 106))	('PD1/PDL1', 'Pathway', (25, 33))	('glioma', 'Disease', (194, 200))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('mice', 'Species', '10090', (201, 205))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('clinical', 'Species', '191496', (174, 182))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
222191	30393513	The following inventory TaqMan probes were used: Hs01125301_m1 CD274, Mm03048248_m1 CD274, Hs00266705_g1 GAPDH, Hs99999901_s1 18S.	('Mm03048248_m1 CD274', 'Var', (70, 89))	('Hs99999901_s1', 'Var', (112, 125))	('Hs01125301_m1', 'Var', (49, 62))	('Hs00266705_g1', 'Var', (91, 104))	('GAPDH', 'Gene', '2597', (105, 110))	('GAPDH', 'Gene', (105, 110))
222194	30393513	MLN4924 was purchased from Active Biochem (Kowloon Bay, Hong Kong); the PD1/PDL1-inhibitor-1 was purchased from Cayman Chemical (Ann Arbor, Michigan, USA).	('MLN4924', 'Var', (0, 7))	('inhibitor-1', 'Gene', (81, 92))	('inhibitor-1', 'Gene', '5502', (81, 92))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))
222221	30393513	HIF1A accumulation leads to PDL1 up-regulation in glioma cell lines.	('accumulation', 'Var', (6, 18))	('HIF1A', 'Gene', (0, 5))	('HIF1A', 'Gene', '3091', (0, 5))	('glioma', 'Disease', (50, 56))	('up-regulation', 'PosReg', (33, 46))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('PDL1', 'Gene', (28, 32))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
222228	30393513	The translation initiation complexes encoded by pAC154-dual-dCas9VP160 plasmids and guided by sgRNA to two HIF1A binding domains in the first intron of the PDL1 gene (Figure 2B-top) enhanced PDL1 protein expression by 1.5 +- 0.3, n=3 and 3.5 +- 0.6, n=3 fold for sites A and B, respectively, compared to PDL1 expression after cell transfection with translation initiated complexes guided by scrambled sgRNA (as a control) (Figure 2B).	('pAC154-dual-dCas9VP160', 'Var', (48, 70))	('protein', 'Protein', (196, 203))	('HIF1A', 'Gene', (107, 112))	('enhanced', 'PosReg', (182, 190))	('HIF1A', 'Gene', '3091', (107, 112))	('expression', 'MPA', (204, 214))	('PDL1', 'Gene', (191, 195))	('PDL1', 'Gene', (156, 160))
222231	30393513	MLN4924 treatment induces PDL1overexpression in glioma cell lines.	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('PDL1overexpression', 'MPA', (26, 44))	('PDL1overexpression', 'Protein', (26, 44))	('induces', 'Reg', (18, 25))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('glioma', 'Disease', (48, 54))	('MLN4924 treatment', 'Var', (0, 17))
222232	30393513	We predict that HIF1A/PDL1 axis may be overactivated in glioma cells after treatment with MLN4924.	('MLN4924', 'Chemical', 'MESH:C539933', (90, 97))	('glioma', 'Disease', (56, 62))	('MLN4924', 'Var', (90, 97))	('overactivated', 'PosReg', (39, 52))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('HIF1A', 'Gene', (16, 21))	('HIF1A', 'Gene', '3091', (16, 21))
222233	30393513	Figure 3A illustrates MLN4924 inhibitory dose response curves for PDGx, established, and PDGx-stem human glioma cell lines, in vitro.	('PDGx', 'Gene', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('MLN4924', 'Chemical', 'MESH:C539933', (22, 29))	('glioma', 'Disease', (105, 111))	('inhibitory', 'MPA', (30, 40))	('MLN4924', 'Var', (22, 29))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('human', 'Species', '9606', (99, 104))
222235	30393513	Note a remarkable loss of cell viability after treatment with MLN4924; however, we also confirmed a significant enhancement of HIF1A protein levels in all evaluated PDGx and established glioma cell lines after treatment with MLN4924, 1 uM for 5 days (Figure 3B).	('glioma', 'Disease', (186, 192))	('MLN4924', 'Var', (62, 69))	('HIF1A', 'Gene', (127, 132))	('MLN4924', 'Chemical', 'MESH:C539933', (225, 232))	('HIF1A', 'Gene', '3091', (127, 132))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('MLN4924', 'Chemical', 'MESH:C539933', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('MLN4924', 'Var', (225, 232))	('protein levels', 'MPA', (133, 147))	('enhancement', 'PosReg', (112, 123))
222237	30393513	The average enhancements of PDL1/18S mRNA ratio after MLN4924 treatment compared to untreated cells were 8 +- 3, 25 +- 5, 5 +- 1, 8 +- 3, 4.5+- 1 folds for U251, Ln229, U87, XD456, JX6 cell lines, respectively, based on three experiments (Figure 3C).	('enhancements', 'PosReg', (12, 24))	('MLN4924', 'Chemical', 'MESH:C539933', (54, 61))	('MLN4924', 'Var', (54, 61))	('PDL1/18S mRNA ratio', 'MPA', (28, 47))	('JX6', 'CellLine', 'CVCL:M085', (181, 184))
222238	30393513	We predict that MLN4924-dependent PDL1 up-regulation in glioma cells may enhance T-cell energy during a T-cell encounter with glioma cells treated with MLN4924.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('MLN4924', 'Chemical', 'MESH:C539933', (152, 159))	('MLN4924', 'Chemical', 'MESH:C539933', (16, 23))	('glioma', 'Disease', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('T-cell energy', 'MPA', (81, 94))	('MLN4924', 'Var', (152, 159))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('up-regulation', 'PosReg', (39, 52))	('enhance', 'PosReg', (73, 80))	('PDL1', 'Gene', (34, 38))	('MLN4924-dependent', 'Var', (16, 33))	('glioma', 'Disease', (126, 132))
222239	30393513	To evaluate our hypothesis, we performed a comparison of the interaction of allogenic T-cells preactivated by CD3/CD28 beads with: Glioma cells (U251 and XD456 cell lines) alone, Glioma cells plus a PD1/PDL1 blockage, Glioma cells treated with MLN4924, Glioma cells treated with MLN4924 plus a PD1/PDL1 blockage.	('MLN4924', 'Chemical', 'MESH:C539933', (244, 251))	('Glioma', 'Disease', 'MESH:D005910', (218, 224))	('Glioma', 'Phenotype', 'HP:0009733', (218, 224))	('Glioma', 'Disease', 'MESH:D005910', (253, 259))	('MLN4924', 'Var', (244, 251))	('Glioma', 'Disease', (218, 224))	('CD28', 'Gene', '940', (114, 118))	('Glioma', 'Disease', (253, 259))	('Glioma', 'Phenotype', 'HP:0009733', (253, 259))	('Glioma', 'Disease', 'MESH:D005910', (179, 185))	('Glioma', 'Phenotype', 'HP:0009733', (179, 185))	('Glioma', 'Phenotype', 'HP:0009733', (131, 137))	('MLN4924', 'Chemical', 'MESH:C539933', (279, 286))	('Glioma', 'Disease', (179, 185))	('Glioma', 'Disease', 'MESH:D005910', (131, 137))	('interaction', 'Interaction', (61, 72))	('Glioma', 'Disease', (131, 137))	('CD28', 'Gene', (114, 118))
222240	30393513	After MLN4924 treatment (1 uM, four days), glioma cells were washed and placed in the media with/and without an inhibitor of PD1/PDL1 interaction (4 uM).	('MLN4924', 'Var', (6, 13))	('glioma', 'Disease', (43, 49))	('MLN4924', 'Chemical', 'MESH:C539933', (6, 13))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
222242	30393513	The glioma cells after MLN4924 treatment have stronger potential to induce T-cell anergy compared to untreated glioma cells (the average decreases in T-cell proliferation were stronger by 24 +- 3% (n=4, P=0.0005) and 32 +- 3% (n=4, P=0.0003) after encounters with MLN4924 treated U251 and XD456 glioma cells, respectively, compared to T-cell proliferation after an encounter with untreated U251 and XD456 cells).	('glioma', 'Phenotype', 'HP:0009733', (295, 301))	('glioma', 'Disease', (111, 117))	('MLN4924', 'Chemical', 'MESH:C539933', (264, 271))	('glioma', 'Disease', 'MESH:D005910', (295, 301))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('MLN4924', 'Chemical', 'MESH:C539933', (23, 30))	('MLN4924', 'Var', (264, 271))	('glioma', 'Disease', (295, 301))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('T-cell anergy', 'CPA', (75, 88))	('MLN4924', 'Var', (23, 30))	('decreases', 'NegReg', (137, 146))	('stronger', 'PosReg', (176, 184))	('glioma', 'Disease', (4, 10))	('T-cell proliferation', 'CPA', (150, 170))
222243	30393513	Importantly, the enhancement of T-cell anergy induced by glioma cells treated with MLN4924 was inhibited in the presence of PD1/PDL1 inhibitor-#1 (Figure 4), suggesting that PD1/PDL1 interaction is the main signaling path involved in T-cell anergy after glioma cell treatment with MLN4924.	('involved', 'Reg', (222, 230))	('MLN4924', 'Var', (83, 90))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('glioma', 'Disease', (57, 63))	('inhibited', 'NegReg', (95, 104))	('inhibitor-#1', 'Gene', '5502', (133, 145))	('T-cell anergy', 'CPA', (32, 45))	('inhibitor-#1', 'Gene', (133, 145))	('glioma', 'Disease', (254, 260))	('MLN4924', 'Chemical', 'MESH:C539933', (281, 288))	('enhancement', 'PosReg', (17, 28))	('enhancement of T-cell anergy', 'Phenotype', 'HP:0031402', (17, 45))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('MLN4924', 'Chemical', 'MESH:C539933', (83, 90))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
222244	30393513	We conclude that the co-utilization of a PD1/PDL1 blockage with MLN4924 treatment reduces PD1/PDL1-dependent immune-cell energy associated with MLN4924-dependent PDL1 up-regulation.	('MLN4924-dependent', 'Var', (144, 161))	('PD1/PDL1-dependent immune-cell energy', 'MPA', (90, 127))	('MLN4924', 'Chemical', 'MESH:C539933', (64, 71))	('PD1/PDL1', 'Gene', (41, 49))	('up-regulation', 'PosReg', (167, 180))	('PDL1', 'Gene', (162, 166))	('MLN4924', 'Chemical', 'MESH:C539933', (144, 151))	('reduces', 'NegReg', (82, 89))
222245	30393513	Thus, we recommend using inhibitors of PDL1/PD1 interaction with MLN4924 treatment to improve anti-tumor immunity and to reduce glioma progression.	('MLN4924 treatment', 'Var', (65, 82))	('tumor', 'Disease', (99, 104))	('glioma', 'Disease', (128, 134))	('improve', 'PosReg', (86, 93))	('PDL1/PD1', 'Gene', (39, 47))	('interaction', 'Interaction', (48, 59))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('reduce', 'NegReg', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MLN4924', 'Chemical', 'MESH:C539933', (65, 72))
222251	30393513	Our manuscript emphasizes that MLN4924, in combination with the blockage of PD1/PD1 interaction, may be a potential strategy for glioma treatment.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('MLN4924', 'Var', (31, 38))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('PD1/PD1', 'Protein', (76, 83))	('glioma', 'Disease', (129, 135))	('MLN4924', 'Chemical', 'MESH:C539933', (31, 38))	('interaction', 'Interaction', (84, 95))
222252	30393513	First, MLN4924 exhibits strong cytotoxicity towards glioma cell lines and crosses the blood-brain barrier.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('MLN4924', 'Chemical', 'MESH:C539933', (7, 14))	('cytotoxicity', 'Disease', (31, 43))	('glioma', 'Disease', (52, 58))	('MLN4924', 'Var', (7, 14))
222253	30393513	Second, MLN4924 has a minimal impact on the intrinsic axis of immune cell growth compared to most of anti-cancer chemotherapeutics, which completely wipe out all types of proliferating cells, including immune cells.	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('MLN4924', 'Var', (8, 15))	('wipe out', 'NegReg', (149, 157))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
222254	30393513	The reported effects of MLN4924 on the immune system consist of: An increase of CD4-induced epitope exposure in cells infected with HIV-1 viruses, however, without significant alteration of host-initiated antibody-dependent cellular cytotoxicity, A partial suppression of graft-versus-host disease immunepathologies, A partial decrease of airway inflammatory responses.	('graft-versus-host disease immunepathologies', 'CPA', (272, 315))	('suppression', 'NegReg', (257, 268))	('cytotoxicity', 'Disease', 'MESH:D064420', (233, 245))	('MLN4924', 'Var', (24, 31))	('CD4', 'Gene', '920', (80, 83))	('cytotoxicity', 'Disease', (233, 245))	('CD4', 'Gene', (80, 83))	('HIV-1 viruses', 'Disease', 'MESH:D015658', (132, 145))	('increase', 'PosReg', (68, 76))	('decrease', 'NegReg', (327, 335))	('airway inflammatory responses', 'CPA', (339, 368))	('HIV-1 viruses', 'Disease', (132, 145))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))
222255	30393513	In our manuscript, we demonstrate significant up-regulation of the key immunosuppressive checkpoint molecule, PDL1, in glioma cells after treatment with MLN4924, and thus, PDL1-dependent T-cell energy after an encounter with glioma cells.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('MLN4924', 'Chemical', 'MESH:C539933', (153, 160))	('T-cell energy', 'MPA', (187, 200))	('up-regulation', 'PosReg', (46, 59))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('glioma', 'Disease', (225, 231))	('MLN4924', 'Var', (153, 160))	('glioma', 'Disease', (119, 125))	('PDL1', 'Gene', (110, 114))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioma', 'Disease', 'MESH:D005910', (225, 231))
222256	30393513	In agreement with our observation, the capacity of a PD1/PDL1-pathway blockage to enhance CD4 and CD8 T-cell responses and moreover, to improve anti-BTLA or anti-TIM3 therapy during allogeneic T and DC cell interactions have been recently confirmed.	('PD1/PDL1-pathway', 'Gene', (53, 69))	('improve', 'PosReg', (136, 143))	('CD8', 'Gene', (98, 101))	('blockage', 'Var', (70, 78))	('CD4', 'Gene', (90, 93))	('CD8', 'Gene', '925', (98, 101))	('CD4', 'Gene', '920', (90, 93))	('BTLA', 'Gene', (149, 153))	('enhance', 'PosReg', (82, 89))	('BTLA', 'Gene', '151888', (149, 153))
222257	30393513	This study extended our knowledge of PDL1 regulation in gliomas, the microenvironment of gliomas, and after glioma treatment with MLN4924.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('glioma', 'Disease', (56, 62))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('PDL1', 'Gene', (37, 41))	('glioma', 'Disease', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('MLN4924', 'Chemical', 'MESH:C539933', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('gliomas', 'Disease', (89, 96))	('MLN4924', 'Var', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma', 'Disease', (89, 95))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))
222258	30393513	Therefore, we suggest that a blockage of PD1/PDL1 interaction during/or after MLN4924 treatment may significantly improve the efficiency of MLN4924 therapy via the reduction of PD1/PDL- dependent immune cell energy and the promotion of anti-tumor immunity.	('promotion', 'PosReg', (223, 232))	('tumor', 'Disease', (241, 246))	('PDL', 'Gene', '5133', (181, 184))	('PDL', 'Gene', '5133', (45, 48))	('MLN4924', 'Chemical', 'MESH:C539933', (78, 85))	('MLN4924', 'Chemical', 'MESH:C539933', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('interaction', 'Interaction', (50, 61))	('improve', 'PosReg', (114, 121))	('PDL', 'Gene', (181, 184))	('PDL', 'Gene', (45, 48))	('reduction', 'NegReg', (164, 173))	('MLN4924', 'Var', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
222264	28966725	Antisense Praja morpholinos resulted in multiple embryonic defects including delayed neural development likely through increased apoptosis.	('morpholinos', 'Chemical', 'MESH:D060172', (16, 27))	('apoptosis', 'CPA', (129, 138))	('multiple embryonic defects', 'Disease', 'MESH:D000015', (40, 66))	('delayed neural development', 'CPA', (77, 103))	('Antisense', 'Var', (0, 9))	('multiple embryonic defects', 'Disease', (40, 66))
222266	28966725	In summary, these studies underscore Praja's role in mammalian brain development and Praja1 deregulation may lead to gliomas possibly through the regulation of cell cycle and/or apoptosis.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('lead to', 'Reg', (109, 116))	('gliomas', 'Disease', (117, 124))	('mammalian', 'Species', '9606', (53, 62))	('deregulation', 'Var', (92, 104))	('Praja1', 'Gene', (85, 91))
222272	28966725	Interestingly, Praja1 (PJA1) has been shown to be linked to human chromosome Xq12, between markers DXS983 and DXS1216, which is an area linked to X-linked mental retardation (MRX).	('X-linked mental retardation', 'Disease', (146, 173))	('DXS1216', 'Var', (110, 117))	('MRX', 'Gene', '1741', (175, 178))	('X-linked mental retardation', 'Disease', 'MESH:D038901', (146, 173))	('MRX', 'Gene', (175, 178))	('Praja1', 'Gene', (15, 21))	('DXS983', 'Var', (99, 105))	('human', 'Species', '9606', (60, 65))	('mental retardation', 'Phenotype', 'HP:0001249', (155, 173))
222278	28966725	Here we report the expression of PJA1 E3 ligase in embryonic brain development as well as in TGF-beta deficient Sptbn-/- mutant mice.	('PJA1', 'Gene', (33, 37))	('TGF-beta deficient', 'Disease', (93, 111))	('mutant', 'Var', (121, 127))	('TGF-beta deficient', 'Disease', 'MESH:D012497', (93, 111))	('mice', 'Species', '10090', (128, 132))	('E3 ligase', 'Protein', (38, 47))
222279	28966725	Loss of PJA1 in a zebrafish model leads to delayed neural development, apoptosis, as well as loss of dorsalization.	('PJA1', 'Gene', (8, 12))	('apoptosis', 'CPA', (71, 80))	('loss', 'NegReg', (93, 97))	('zebrafish', 'Species', '7955', (18, 27))	('delayed neural development', 'CPA', (43, 69))	('dorsalization', 'CPA', (101, 114))	('Loss', 'Var', (0, 4))
222283	28966725	We further analyzed genetic alterations of PJA1 and PJA2 that include copy number (CPN) gain, amplification, shallow deletion, deep deletion and mutations in 36 different cancer types.	('amplification', 'Var', (94, 107))	('mutations', 'Reg', (145, 154))	('PJA1', 'Gene', (43, 47))	('PJA2', 'Gene', (52, 56))	('shallow deletion', 'Var', (109, 125))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('gain', 'PosReg', (88, 92))	('copy number', 'MPA', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('deep deletion', 'Var', (127, 140))
222284	28966725	CPN gain and amplification are the most common alterations of these genes across all cancer types analyzed (Figure 1B), suggesting potential oncogenic roles of PJA in cancers.	('CPN gain', 'Disease', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancer', 'Disease', (85, 91))	('cancers', 'Disease', (167, 174))	('amplification', 'Var', (13, 26))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('CPN gain', 'Disease', 'MESH:D015430', (0, 8))
222287	28966725	While CPN gain or amplification is frequently observed in PJA1 and PJA2, Smad3 is more frequently downregulated or deleted (Figure 1C-1D).	('downregulated', 'NegReg', (98, 111))	('Smad3', 'Gene', (73, 78))	('CPN gain', 'Disease', (6, 14))	('amplification', 'MPA', (18, 31))	('deleted', 'Var', (115, 122))	('Smad3', 'Gene', '17127', (73, 78))	('CPN gain', 'Disease', 'MESH:D015430', (6, 14))
222288	28966725	Interestingly, genetic alterations of PJA1 but not PJA2 frequently co-occur with Smad3 alterations, which is consistent with our previous findings that PJA1 directly binds to TGF-beta signaling components, Smad3 and its adaptor SPTBN1 (Figure 1E).	('PJA1', 'Gene', (152, 156))	('co-occur', 'Reg', (67, 75))	('Smad3', 'Gene', '17127', (81, 86))	('alterations', 'Var', (87, 98))	('binds', 'Interaction', (166, 171))	('SPTBN1', 'Gene', (228, 234))	('Smad3', 'Gene', (81, 86))	('TGF-beta', 'Gene', '21803', (175, 183))	('PJA1', 'Gene', (38, 42))	('genetic alterations', 'Var', (15, 34))	('Smad3', 'Gene', '17127', (206, 211))	('Smad3', 'Gene', (206, 211))	('SPTBN1', 'Gene', '20742', (228, 234))	('TGF-beta', 'Gene', (175, 183))
222295	28966725	Interestingly, in contrast to that of wild type mice, PJA1 expression is more widely expressed in the developing brain of TGF-beta deficient (Sptbn1-/-) mutant mice.	('PJA1', 'Gene', (54, 58))	('mice', 'Species', '10090', (48, 52))	('mutant', 'Var', (153, 159))	('TGF-beta deficient', 'Disease', (122, 140))	('mice', 'Species', '10090', (160, 164))	('Sptbn1', 'Gene', (142, 148))	('TGF-beta deficient', 'Disease', 'MESH:D012497', (122, 140))	('Sptbn1', 'Gene', '20742', (142, 148))
222297	28966725	It is noteworthy that the mutant embryo brain exhibits multiple fore brain developmental defect including abnormal brain vesicles, further suggesting an important role of PJA1 in normal brain development (Figure 1E).	('brain developmental defect', 'Disease', 'MESH:D001927', (69, 95))	('developmental defect', 'Phenotype', 'HP:0001263', (75, 95))	('brain developmental defect', 'Disease', (69, 95))	('abnormal brain', 'Phenotype', 'HP:0012443', (106, 120))	('mutant', 'Var', (26, 32))
222299	28966725	To test our hypothesis that PJA1 is required for normal brain development, translation-blocking antisense PJA1 Morpholino oligonucleotides (MO) were injected into single-cell stage zebrafish embryos to knock down PJA1 that is normally expressed in zebrafish embryos (Figure 3A).	('zebrafish', 'Species', '7955', (248, 257))	('Morpholino oligonucleotides', 'Chemical', 'MESH:D060172', (111, 138))	('PJA1', 'Gene', (213, 217))	('knock down', 'Var', (202, 212))	('zebrafish', 'Species', '7955', (181, 190))
222300	28966725	As we expected, morpholino-mediated PJA1 knockdown results in multiple developmental defects throughout the embryo (Figure 3B) including reduced brain development, shortened and deformed tail, abnormal notochord, and loss of the chevron shape of the somites.	('PJA1', 'Gene', (36, 40))	('developmental defect', 'Phenotype', 'HP:0001263', (71, 91))	('chevron shape of the somites', 'CPA', (229, 257))	('reduced brain development', 'Phenotype', 'HP:0001263', (137, 162))	('brain development', 'CPA', (145, 162))	('reduced', 'NegReg', (137, 144))	('notochord', 'CPA', (202, 211))	('shortened and deformed tail', 'Phenotype', 'HP:0008436', (164, 191))	('developmental defects', 'Disease', (71, 92))	('developmental defects', 'Disease', 'MESH:D003147', (71, 92))	('knockdown', 'Var', (41, 50))	('loss', 'NegReg', (217, 221))
222301	28966725	Further, we found increased apoptosis visualized by acridine orange staining throughout the somitogenesis period in PJA1 MO injected embryos relative to control MO injected embryos.	('injected', 'Var', (124, 132))	('apoptosis', 'CPA', (28, 37))	('PJA1 MO injected', 'Var', (116, 132))	('acridine orange', 'Chemical', 'MESH:D000165', (52, 67))
222305	28966725	Through Annexin V staining, we found that expression of PJA1 mutant in cells results in three-fold increase of apoptosis (Figure 4A).	('Annexin V', 'Gene', '11747', (8, 17))	('mutant', 'Var', (61, 67))	('increase', 'PosReg', (99, 107))	('Annexin V', 'Gene', (8, 17))	('PJA1', 'Gene', (56, 60))	('apoptosis', 'CPA', (111, 120))
222306	28966725	In addition, knockdown of PJA1 by shRNA in HepG2 cells leads to increased cell apoptosis as determined by increased PARP expression as well as increased Caspase 3 and cleavage of Caspase3 (Figure 4B).	('Caspase3', 'Gene', (179, 187))	('increased', 'PosReg', (143, 152))	('Caspase 3', 'Gene', (153, 162))	('Caspase3', 'Gene', '836', (179, 187))	('PARP', 'Gene', (116, 120))	('cleavage', 'MPA', (167, 175))	('Caspase 3', 'Gene', '836', (153, 162))	('PJA1', 'Gene', (26, 30))	('HepG2', 'CellLine', 'CVCL:0027', (43, 48))	('expression', 'MPA', (121, 131))	('cell apoptosis', 'CPA', (74, 88))	('increased', 'PosReg', (64, 73))	('increased', 'PosReg', (106, 115))	('knockdown', 'Var', (13, 22))	('PARP', 'Gene', '1302', (116, 120))
222307	28966725	To examine whether kinases are required for apoptosis induced by PJA1 defect, we treated cell with Sorafenib, a tyrosine kinase inhibitor.	('PJA1', 'Gene', (65, 69))	('defect', 'Var', (70, 76))	('Sorafenib', 'Chemical', 'MESH:D000077157', (99, 108))
222311	28966725	We observed consistently a two-fold induction of Cdk1 phosphorylation at T14/Y15 in both TGF-beta and insulin treated cells transfected with PJA mut compared with cells transfected with PJA wild type (Figure 5, Supplementary Tables 1-4), indicating that Cdk1 activation is negatively regulated by PJA1.	('Cdk1', 'Gene', '12534', (254, 258))	('PJA mut', 'Var', (141, 148))	('Cdk1', 'Gene', '12534', (49, 53))	('TGF-beta', 'Gene', (89, 97))	('TGF-beta', 'Gene', '21803', (89, 97))	('phosphorylation', 'MPA', (54, 69))	('Cdk1', 'Gene', (254, 258))	('Cdk1', 'Gene', (49, 53))	('induction', 'PosReg', (36, 45))
222312	28966725	Our study is in line with previous findings showed that aberrant Cdk1 activation has been associated with neuronal cell apoptosis and Cdk1 is critical to brain development.	('Cdk1', 'Gene', '12534', (65, 69))	('Cdk1', 'Gene', (65, 69))	('aberrant', 'Var', (56, 64))	('associated', 'Reg', (90, 100))	('Cdk1', 'Gene', '12534', (134, 138))	('Cdk1', 'Gene', (134, 138))	('activation', 'PosReg', (70, 80))	('neuronal cell apoptosis', 'CPA', (106, 129))
222313	28966725	In addition to Cdk1 activation, insulin activating through insulin receptors induces activation of MEK/ERK and Akt signaling pathway in cells expressing PJA1 mutant, suggesting a negative regulation of these pathways by PJA1 as well.	('Akt', 'Gene', '11651', (111, 114))	('PJA1', 'Gene', (153, 157))	('ERK', 'Gene', (103, 106))	('Akt', 'Gene', (111, 114))	('ERK', 'Gene', '26413', (103, 106))	('Cdk1', 'Gene', '12534', (15, 19))	('Cdk1', 'Gene', (15, 19))	('activation', 'PosReg', (85, 95))	('MEK', 'Gene', '17242', (99, 102))	('mutant', 'Var', (158, 164))	('MEK', 'Gene', (99, 102))
222315	28966725	In addition, loss of PJA1 leads to hyper-activation of Cdk1 and thereby induces cell apoptosis during early embryogenesis possibly through cell cycle mitosis stress as Cdk1 is known to interact with cylin B1 to control the progression of cell cycle from G2- to M-phase.	('Cdk1', 'Gene', '12534', (168, 172))	('Cdk1', 'Gene', (168, 172))	('hyper-activation', 'PosReg', (35, 51))	('Cdk1', 'Gene', '12534', (55, 59))	('induces', 'Reg', (72, 79))	('mitosis stress', 'Disease', (150, 164))	('PJA1', 'Gene', (21, 25))	('mitosis stress', 'Disease', 'MESH:D004194', (150, 164))	('loss', 'Var', (13, 17))	('cell apoptosis', 'CPA', (80, 94))	('Cdk1', 'Gene', (55, 59))
222316	28966725	Aberrant Cdk1 activation has been associated with cell apoptosis.	('activation', 'PosReg', (14, 24))	('associated', 'Reg', (34, 44))	('cell apoptosis', 'CPA', (50, 64))	('Aberrant', 'Var', (0, 8))	('Cdk1', 'Gene', '12534', (9, 13))	('Cdk1', 'Gene', (9, 13))
222318	28966725	Interestingly, although we observed PJA2 mutations in brain cancer, we found no mutations in PJA1, only alterations leading to raised PJA1 expression.	('mutations', 'Var', (41, 50))	('brain cancer', 'Phenotype', 'HP:0030692', (54, 66))	('brain cancer', 'Disease', (54, 66))	('PJA2', 'Gene', (36, 40))	('expression', 'MPA', (139, 149))	('PJA1', 'Gene', (93, 97))	('brain cancer', 'Disease', 'MESH:D001932', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
222321	28966725	The upregulation of Cdk1 in loss of PJA1 function suggests a key role of loss of PJA1 expression in the irregularities of Cdk1/cyclin B mitotic cascade that instigates hyper-phosphorylation of neuronal proteins and neuronal apoptosis.	('neuronal apoptosis', 'CPA', (215, 233))	('Cdk1', 'Gene', '12534', (20, 24))	('PJA1', 'Gene', (36, 40))	('loss', 'Var', (73, 77))	('Cdk1', 'Gene', (20, 24))	('PJA1', 'Gene', (81, 85))	('hyper-phosphorylation', 'MPA', (168, 189))	('Cdk1', 'Gene', '12534', (122, 126))	('Cdk1', 'Gene', (122, 126))	('upregulation', 'PosReg', (4, 16))	('loss', 'NegReg', (28, 32))
222326	28966725	NRAGE deletion impedes BMP regulated neural developmental apoptosis of sympathetic neurons.	('NRAGE', 'Gene', (0, 5))	('NRAGE', 'Gene', '94275', (0, 5))	('impedes', 'NegReg', (15, 22))	('BMP', 'MPA', (23, 26))	('deletion', 'Var', (6, 14))
222334	28966725	Oncoquery language was utilized for the selection of samples with gain of function (GAIN), amplification (AMP), mRNA upregulation (EXP > = 1.5), or mutations in PJA1 or PJA2 (MUT), as well as deletion or loss (HETLOSS, HOMEDEL), mRNA downregulation (EXP < = -1.5), or mutation in Smad3 when observing TCGA Lower Grade Glioma.	('mutations', 'Var', (148, 157))	('mRNA', 'MPA', (229, 233))	('gain', 'PosReg', (66, 70))	('Smad3', 'Gene', (280, 285))	('Smad3', 'Gene', '17127', (280, 285))	('PJA2', 'Gene', (169, 173))	('loss', 'NegReg', (204, 208))	('PJA1', 'Gene', (161, 165))	('Glioma', 'Phenotype', 'HP:0009733', (318, 324))	('deletion', 'Var', (192, 200))	('mRNA', 'MPA', (112, 116))	('mutation', 'Var', (268, 276))	('downregulation', 'NegReg', (234, 248))	('Glioma', 'Disease', 'MESH:D005910', (318, 324))	('upregulation', 'PosReg', (117, 129))	('Glioma', 'Disease', (318, 324))
222335	28966725	Specifically, when examining the oncoprint results, the percentage of patient samples with alterations in the queried genes and whether those various samples increased expression of the genes (i.e.	('expression', 'MPA', (168, 178))	('alterations', 'Var', (91, 102))	('patient', 'Species', '9606', (70, 77))	('increased', 'PosReg', (158, 167))
222336	28966725	Subsequently, we attempted to identify mutations in PJA1 and PJA2 in these malignancies, thereby juxtaposing the results and structures of the two genes.	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('malignancies', 'Disease', (75, 87))	('mutations', 'Var', (39, 48))	('PJA1', 'Gene', (52, 56))	('PJA2', 'Gene', (61, 65))
222392	25969639	In ring-enhancing lesions (abscess n = 6, metastasis n = 3, TWT n = 7, and TOT n = 4), rCBF and rCBV of the capsule of metastases, abscess, and TOT showed significantly high perfusion compared to those of TWT (rCBF P < 0.013 and rCBV P < 0.002).	('rCBF', 'Gene', '362686', (210, 214))	('abscess', 'Phenotype', 'HP:0025615', (131, 138))	('high', 'PosReg', (169, 173))	('rCBF', 'Gene', '362686', (87, 91))	('rCBV', 'Chemical', '-', (96, 100))	('perfusion', 'MPA', (174, 183))	('rCBF', 'Gene', (210, 214))	('metastases', 'Disease', (119, 129))	('rCBV', 'Var', (96, 100))	('rCBF', 'Gene', (87, 91))	('rCBV', 'Chemical', '-', (229, 233))	('abscess', 'Phenotype', 'HP:0025615', (27, 34))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
222449	33000268	Glioblastoma multiforme (GBM), an incurable primary brain tumor with a poor prognosis, is characterized by various genetic alterations, such as mutation of isocitrate dehydrogenase (IDH)1/2, amplification of epidermal growth factor receptor (EGFR) and dysregulation of multiple signaling pathways, such as the PI3K/AKT/mTOR, Wnt/beta-catenin and NF/kappaB pathways.	('brain tumor', 'Phenotype', 'HP:0030692', (52, 63))	('epidermal growth factor receptor', 'Gene', '1956', (208, 240))	('isocitrate dehydrogenase (IDH)1/2', 'Gene', '3417;3418', (156, 189))	('amplification', 'Reg', (191, 204))	('brain tumor', 'Disease', (52, 63))	('EGFR', 'Gene', (242, 246))	('brain tumor', 'Disease', 'MESH:D001932', (52, 63))	('AKT', 'Gene', (315, 318))	('dysregulation', 'Reg', (252, 265))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('mTOR', 'Gene', (319, 323))	('EGFR', 'Gene', '1956', (242, 246))	('AKT', 'Gene', '207', (315, 318))	('mutation', 'Var', (144, 152))	('beta-catenin', 'Gene', (329, 341))	('epidermal growth factor receptor', 'Gene', (208, 240))	('beta-catenin', 'Gene', '1499', (329, 341))	('mTOR', 'Gene', '2475', (319, 323))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Glioblastoma multiforme', 'Disease', (0, 23))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('NF', 'Gene', '23114', (346, 348))
222459	33000268	Accumulating evidence has demonstrated that aberrant RPN2 overexpression is frequently associated with multiple clinical parameters, such as lymphatic metastasis, pathological grade and poor prognosis in a variety of tumors, including osteosarcoma, non-small cell lung cancer, advanced gastric cancer and colorectal cancer.	('colorectal cancer', 'Disease', (305, 322))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('non-small cell lung cancer', 'Disease', (249, 275))	('osteosarcoma', 'Disease', (235, 247))	('osteosarcoma', 'Disease', 'MESH:D012516', (235, 247))	('gastric cancer', 'Disease', 'MESH:D013274', (286, 300))	('lymphatic metastasis', 'Disease', (141, 161))	('associated', 'Reg', (87, 97))	('overexpression', 'PosReg', (58, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (249, 275))	('colorectal cancer', 'Phenotype', 'HP:0003003', (305, 322))	('RPN2', 'Gene', '6185', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('RPN2', 'Gene', (53, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (286, 300))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (253, 275))	('aberrant', 'Var', (44, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (249, 275))	('tumors', 'Disease', (217, 223))	('colorectal cancer', 'Disease', 'MESH:D015179', (305, 322))	('gastric cancer', 'Disease', (286, 300))
222489	33000268	LN229 and U87 cells (1x104/well) were cultured in 96-well plates, and co-transfected with wild-type or mutant luciferase reporters and the miR-422a mimic or miR-NC using the X-tremeGENE transfection reagent (Roche Diagnostics).	('LN229', 'CellLine', 'CVCL:0393', (0, 5))	('miR', 'Gene', '220972', (139, 142))	('luciferase', 'Enzyme', (110, 120))	('miR', 'Gene', (139, 142))	('mutant', 'Var', (103, 109))	('miR', 'Gene', '220972', (157, 160))	('miR', 'Gene', (157, 160))	('miR-422a', 'Gene', (139, 147))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('N', 'Chemical', 'MESH:D009584', (183, 184))	('miR-422a', 'Gene', '494334', (139, 147))
222491	33000268	TOP-FLASH (with repeats of the TCF binding site) or FOP-FLASH (with repeats of the mutant TCF binding site) plasmids (EMD Millipore) were transfected into LN229 and U87 cells transfected with miR-422a mimic.	('TCF', 'Gene', (31, 34))	('TCF', 'Gene', '3172', (31, 34))	('miR-422a', 'Gene', '494334', (192, 200))	('mutant', 'Var', (83, 89))	('TCF', 'Gene', (90, 93))	('LN229', 'CellLine', 'CVCL:0393', (155, 160))	('TCF', 'Gene', '3172', (90, 93))	('FOP-', 'Phenotype', 'HP:0500062', (52, 56))	('miR-422a', 'Gene', (192, 200))
222557	33000268	To confirm that RPN2 was a direct target of miR-422a, luciferase reporter constructs carrying the RPN2 3'UTR with wild-type or mutant miR-422a binding sites were constructed and co-transfected with miR-422a mimic and miR-NC.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (198, 201))	('miR', 'Gene', (134, 137))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('RPN2', 'Gene', '6185', (16, 20))	('miR', 'Gene', (44, 47))	('RPN2', 'Gene', (16, 20))	('miR-422a', 'Gene', (198, 206))	('miR-422a', 'Gene', (134, 142))	('miR', 'Gene', '220972', (217, 220))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('mutant', 'Var', (127, 133))	('miR-422a', 'Gene', '494334', (198, 206))	('miR-422a', 'Gene', (44, 52))	('miR-422a', 'Gene', '494334', (134, 142))	('miR', 'Gene', (217, 220))	('N', 'Chemical', 'MESH:D009584', (221, 222))	('miR', 'Gene', '220972', (198, 201))	('RPN2', 'Gene', '6185', (98, 102))	('miR-422a', 'Gene', '494334', (44, 52))	('miR', 'Gene', '220972', (134, 137))	('RPN2', 'Gene', (98, 102))
222577	33000268	Furthermore, the knockdown of RPN2 by shRPN2 significantly enhanced the caspase-3/7 activity (Fig.	('RPN2', 'Gene', '6185', (30, 34))	('caspase-3/7', 'Gene', (72, 83))	('RPN2', 'Gene', (40, 44))	('enhanced', 'PosReg', (59, 67))	('RPN2', 'Gene', (30, 34))	('RPN2', 'Gene', '6185', (40, 44))	('caspase-3/7', 'Gene', '836;840', (72, 83))	('knockdown', 'Var', (17, 26))
222579	33000268	These results indicate that miR-422 inhibits the GBM malignant phenotype, partially through the oncogene RPN2.	('miR-422', 'Var', (28, 35))	('RPN2', 'Gene', (105, 109))	('inhibits', 'NegReg', (36, 44))	('GBM malignant phenotype', 'CPA', (49, 72))	('miR-422', 'Chemical', '-', (28, 35))	('RPN2', 'Gene', '6185', (105, 109))
222591	33000268	Further analysis of RPN2 expression and relevant clinical characteristics indicated that RPN2 expression was significantly associated with IDH1 gene mutation status, age and 1p/19q codeletion status (Fig.	('associated', 'Reg', (123, 133))	('IDH1', 'Gene', (139, 143))	('mutation status', 'Var', (149, 164))	('RPN2', 'Gene', '6185', (89, 93))	('RPN2', 'Gene', '6185', (20, 24))	('RPN2', 'Gene', (89, 93))	('RPN2', 'Gene', (20, 24))	('IDH1', 'Gene', '3417', (139, 143))	('expression', 'MPA', (94, 104))
222594	33000268	Moreover, the data obtained from the 'Survival Map' module of GEPIA demonstrated that the high RPN2 expression group had a poorer overall survival and disease free survival compared with the low RPN2 expression group of patients with low-grade glioma (n=514) and gliomas, including low-grade and high-grade glioma (n=676) (Fig.	('glioma', 'Disease', (244, 250))	('glioma', 'Disease', (307, 313))	('gliomas', 'Phenotype', 'HP:0009733', (263, 270))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('patients', 'Species', '9606', (220, 228))	('glioma', 'Disease', 'MESH:D005910', (307, 313))	('RPN2', 'Gene', '6185', (95, 99))	('poorer', 'NegReg', (123, 129))	('glioma', 'Disease', (263, 269))	('RPN2', 'Gene', (95, 99))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('RPN2', 'Gene', '6185', (195, 199))	('gliomas', 'Disease', (263, 270))	('RPN2', 'Gene', (195, 199))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('overall survival', 'CPA', (130, 146))	('disease free survival', 'CPA', (151, 172))	('low-grade', 'Disease', (282, 291))	('gliomas', 'Disease', 'MESH:D005910', (263, 270))	('high', 'Var', (90, 94))
222615	33000268	Furthermore, in the present study, survival analysis from online public databases indicated that high RPN2 expression is associated with poor prognosis.	('expression', 'MPA', (107, 117))	('RPN2', 'Gene', (102, 106))	('high', 'Var', (97, 101))	('RPN2', 'Gene', '6185', (102, 106))
222634	33000268	A variety of miRNAs are regulated by other non-coding RNAs, such as circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs).	('long non-coding RNAs', 'Var', (97, 117))	('N', 'Chemical', 'MESH:D009584', (114, 115))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('circular RNAs', 'Disease', (68, 81))	('N', 'Chemical', 'MESH:D009584', (55, 56))
222636	33000268	Zhou et al, demonstrated that lncRNAD63785 acts as a ceRNA of miR-422a and enhances chemoresistance by retarding miR-422a-dependent suppression of MEF2D.	('miR-422a', 'Gene', (62, 70))	('MEF2D', 'Gene', '4209', (147, 152))	('miR-422a', 'Gene', '494334', (113, 121))	('MEF2D', 'Gene', (147, 152))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('retarding', 'NegReg', (103, 112))	('miR-422a', 'Gene', (113, 121))	('lncRNAD63785', 'Var', (30, 42))	('chemoresistance', 'CPA', (84, 99))	('enhances', 'PosReg', (75, 83))	('miR-422a', 'Gene', '494334', (62, 70))	('N', 'Chemical', 'MESH:D009584', (56, 57))
222638	33000268	In conclusion, the present study confirmed that ectopic miR-422a expression suppresses GBM tumorigenesis and promotes apoptosis by regulating the Wnt/beta-catenin signaling pathway, and that RPN2 plays significant roles in the miR-422a-mediated effect on tumor growth and Wnt pathway regulation as a direct functional target of miR-422a.	('RPN2', 'Gene', (191, 195))	('miR-422a', 'Gene', '494334', (328, 336))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (91, 96))	('apoptosis', 'CPA', (118, 127))	('miR-422a', 'Gene', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('miR-422a', 'Gene', '494334', (56, 64))	('ectopic', 'Var', (48, 55))	('regulating', 'Reg', (131, 141))	('beta-catenin', 'Gene', (150, 162))	('beta-catenin', 'Gene', '1499', (150, 162))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('miR-422a', 'Gene', (227, 235))	('miR-422a', 'Gene', (328, 336))	('RPN2', 'Gene', '6185', (191, 195))	('miR-422a', 'Gene', '494334', (227, 235))	('suppresses', 'NegReg', (76, 86))	('promotes', 'PosReg', (109, 117))
222681	30089500	There are ten cancer types that have a TP53 mutation rate greater than 50% in total (Fig.	('cancer', 'Disease', (14, 20))	('mutation', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', (39, 43))
222682	30089500	Moreover, we can find a summary of the variant classification of TP53 mutations in cancers, e.g., in pancreatic adenocarcinoma (PAAD), 64 and 12% of TP53 mutations being missense and frame-shift insertion, respectively (Fig.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 126))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', '7157', (149, 153))	('missense', 'Var', (170, 178))	('pancreatic adenocarcinoma', 'Disease', (101, 126))	('TP53', 'Gene', (149, 153))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (101, 126))	('mutations', 'Var', (154, 163))	('PAAD', 'Phenotype', 'HP:0006725', (128, 132))	('frame-shift insertion', 'Var', (183, 204))	('cancers', 'Disease', (83, 90))
222683	30089500	Importantly, we can find the associations of TP53 mutations with survival prognosis in cancers.	('cancers', 'Disease', (87, 94))	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('associations', 'Interaction', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('survival prognosis', 'CPA', (65, 83))	('TP53', 'Gene', '7157', (45, 49))
222684	30089500	For example, TP53 mutations are associated with worse survival (overall and disease free survival) prognosis in PAAD (Fig.	('TP53', 'Gene', (13, 17))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('PAAD', 'Disease', (112, 116))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
222686	30089500	In fact, previous studies have shown that PLK1 interacted with TP53, and that p53 dysfunction caused enhanced expression of PLK1 in cancers.	('PLK1', 'Gene', (124, 128))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('TP53', 'Gene', '7157', (63, 67))	('PLK1', 'Gene', '5347', (42, 46))	('TP53', 'Gene', (63, 67))	('PLK1', 'Gene', '5347', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('p53', 'Gene', (78, 81))	('enhanced', 'PosReg', (101, 109))	('expression', 'MPA', (110, 120))	('p53', 'Gene', '7157', (78, 81))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('PLK1', 'Gene', (42, 46))	('dysfunction', 'Var', (82, 93))
222711	30089500	In addition, TCOA shows that mir-1269, mir-10b, mir-224, and mir-183 are overexpressed in LIHC with more than 4-fold expression increase compared to normal tissue, while mir-1258, mir-675, mir-490, mir-424, mir-483, mir-1247, mir-199b, mir-199a-2, mir-139, mir-199a-1, mir-3607, and mir-451 are underexpressed in LIHC with more than 4-fold expression decrease compared to normal tissue (Fig.	('mir-183', 'Gene', '406959', (61, 68))	('mir-10b', 'Gene', '406903', (39, 46))	('mir-483', 'Gene', '619552', (207, 214))	('mir-675', 'Gene', '100033819', (180, 187))	('mir-199b', 'Gene', (226, 234))	('mir-451', 'Gene', '574411', (283, 290))	('TCOA', 'Chemical', '-', (13, 17))	('mir-139', 'Gene', '406931', (248, 255))	('mir-139', 'Gene', (248, 255))	('mir-199a-2', 'Gene', (236, 246))	('mir-10b', 'Gene', (39, 46))	('mir-451', 'Gene', (283, 290))	('mir-199a-2', 'Gene', '406977', (236, 246))	('mir-1269', 'Var', (29, 37))	('expression', 'MPA', (117, 127))	('mir-224', 'Gene', '407009', (48, 55))	('mir-483', 'Gene', (207, 214))	('mir-199b', 'Gene', '406978', (226, 234))	('mir-424', 'Gene', '494336', (198, 205))	('mir-424', 'Gene', (198, 205))	('decrease', 'NegReg', (351, 359))	('mir-183', 'Gene', (61, 68))	('mir-199a-1', 'Gene', (257, 267))	('increase', 'PosReg', (128, 136))	('mir-490', 'Gene', '574443', (189, 196))	('expression', 'MPA', (340, 350))	('mir-675', 'Gene', (180, 187))	('mir-490', 'Gene', (189, 196))	('mir-199a-1', 'Gene', '406976', (257, 267))	('mir-224', 'Gene', (48, 55))
222732	30089500	Kaplan-Meier survival curves were used to show the survival (OS or DFS) differences between gene-mutated cancer patients and gene-wildtype cancer patients, and between gene, miRNA or protein higher-expression-level patients and lower-expression-level patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (215, 223))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('protein', 'Protein', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (112, 120))	('gene-mutated', 'Var', (92, 104))	('higher-expression-level', 'PosReg', (191, 214))	('patients', 'Species', '9606', (251, 259))	('miRNA', 'Protein', (174, 179))	('OS', 'Chemical', '-', (61, 63))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
222755	28784180	And, the role of MYBL2 and FoxM1 in glioma cell progression and the underlying mechanisms were studied by using small interfering RNA (si-RNA) and pcDNA3.1 + HAvectors.	('glioma', 'Disease', (36, 42))	('FoxM1', 'Gene', '2305', (27, 32))	('small', 'Var', (112, 117))	('FoxM1', 'Gene', (27, 32))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
222758	28784180	In cohorts of TCGA, patients with high MYBL2 but without radio-chemotherapy had the highest hazard ratio (adjusted HR = 5.29, 95% CI = 1.475-18.969, P < 0.05).	('MYBL2', 'Gene', (39, 44))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (20, 28))
222761	28784180	Furthermore, inactivations of Akt/FoxM1 signaling by Akt inhibitor and siRNA-FoxM1 reduce the expression of MYBL2 in glioma cells.	('Akt', 'Gene', '207', (30, 33))	('Akt', 'Gene', '207', (53, 56))	('FoxM1', 'Gene', '2305', (77, 82))	('FoxM1', 'Gene', (77, 82))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('FoxM1', 'Gene', '2305', (34, 39))	('MYBL2', 'Gene', (108, 113))	('FoxM1', 'Gene', (34, 39))	('Akt', 'Gene', (30, 33))	('Akt', 'Gene', (53, 56))	('expression', 'MPA', (94, 104))	('reduce', 'NegReg', (83, 89))	('glioma', 'Disease', (117, 123))	('inactivations', 'Var', (13, 26))
222769	28784180	Transcription factors (TFs) play important roles in the transcriptional networks that regulate gene expression, and misregulation of these TFs can result in the acquisition of tumor-related properties.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('acquisition', 'PosReg', (161, 172))	('TFs', 'Gene', (139, 142))	('result in', 'Reg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('misregulation', 'Var', (116, 129))
222772	28784180	Meanwhile, MYBL2 amplification or overexpression has been observed in cancers such as myeloid leukemias (AML), hepatocellular carcinoma, breast cancer, and it is currently used as a marker for poor prognosis in colorectal carcinoma.	('MYBL2', 'Gene', (11, 16))	('AML', 'Disease', 'MESH:D015470', (105, 108))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (111, 135))	('AML', 'Disease', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('leukemias', 'Phenotype', 'HP:0001909', (94, 103))	('colorectal carcinoma', 'Disease', (211, 231))	('hepatocellular carcinoma', 'Disease', (111, 135))	('overexpression', 'PosReg', (34, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (211, 231))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cancers', 'Disease', (70, 77))	('myeloid leukemias', 'Disease', (86, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('myeloid leukemias', 'Disease', 'MESH:D007951', (86, 103))	('amplification', 'Var', (17, 30))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (86, 103))	('breast cancer', 'Disease', (137, 150))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('cancers', 'Disease', 'MESH:D009369', (70, 77))
222774	28784180	FoxM1 is a member of the Forkhead box (Fox) transcription factor family, which has been shown to be over-expressed in various cancers and studies have shown that alterations in FoxM1 signaling were associated with carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinogenesis', 'Disease', (214, 228))	('alterations', 'Var', (162, 173))	('FoxM1', 'Gene', '2305', (0, 5))	('FoxM1', 'Gene', (177, 182))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('FoxM1', 'Gene', (0, 5))	('cancers', 'Disease', (126, 133))	('associated', 'Reg', (198, 208))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('FoxM1', 'Gene', '2305', (177, 182))	('carcinogenesis', 'Disease', 'MESH:D063646', (214, 228))
222776	28784180	Aberrant FoxM1expression was found to be a common molecular alteration in malignant glioma.	('FoxM1', 'Gene', (9, 14))	('Aberrant', 'Var', (0, 8))	('malignant glioma', 'Disease', 'MESH:D005910', (74, 90))	('malignant glioma', 'Disease', (74, 90))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('FoxM1', 'Gene', '2305', (9, 14))
222809	28784180	Cells were seeded in six-well plates (5 x 105 cells/well) and 24 h later were transfected with the control siRNA, MYBL2 siRNA (50 nM) or FoxM1 siRNA (50 nM).	('50 nM', 'Var', (127, 132))	('FoxM1', 'Gene', (137, 142))	('FoxM1', 'Gene', '2305', (137, 142))
222856	28784180	Firstly, we transected GV230-MYBL2 (2 mug/mL) and pcDNA3.1 + HA-FOXM1 (2 mug/mL) to increase the genes expression in low grade glioma Hs683 cells, respectively.	('GV230-MYBL2', 'Var', (23, 34))	('genes expression', 'MPA', (97, 113))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('increase', 'PosReg', (84, 92))	('FOXM1', 'Gene', '2305', (64, 69))	('FOXM1', 'Gene', (64, 69))	('glioma', 'Disease', (127, 133))
222860	28784180	Conversely, in high-grade glioma U251 cells, the numbers of colonies were reduced by MYBL2 and FoxM1 knockdown (Fig.	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('FoxM1', 'Gene', '2305', (95, 100))	('FoxM1', 'Gene', (95, 100))	('glioma', 'Disease', (26, 32))	('U251', 'CellLine', 'CVCL:0021', (33, 37))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('reduced', 'NegReg', (74, 81))	('MYBL2', 'Gene', (85, 90))	('knockdown', 'Var', (101, 110))
222862	28784180	U251 cells generally manifest powerful growth ability and was greatly attenuated by knockdown of MYBL2 and FoxM1 in a time dependent manner, especially at 72 and 96 h (*P < 0.05) post transfection of the siRNAs (Fig.	('attenuated', 'NegReg', (70, 80))	('U251', 'CellLine', 'CVCL:0021', (0, 4))	('MYBL2', 'Gene', (97, 102))	('knockdown', 'Var', (84, 93))	('FoxM1', 'Gene', '2305', (107, 112))	('growth ability', 'CPA', (39, 53))	('FoxM1', 'Gene', (107, 112))
222866	28784180	4e, the number of cells that passed through a Matrigel coated membrane into the lower chamber was lower in U251cells in silenced groups than NC group (*p < 0.05).	('U251cells', 'Var', (107, 116))	('lower', 'NegReg', (98, 103))	('U251', 'CellLine', 'CVCL:0021', (107, 111))
222874	28784180	The possible effects of MYBL2 and FoxM1 knockdown on cell cycle progression were assessed by PI staining and flow cytometry.	('MYBL2', 'Gene', (24, 29))	('knockdown', 'Var', (40, 49))	('FoxM1', 'Gene', '2305', (34, 39))	('cell cycle progression', 'CPA', (53, 75))	('FoxM1', 'Gene', (34, 39))
222875	28784180	Depletion of MYBL2 and FoxM1 in U251 cells resulted in an increase in cells at the G2/M phase (Fig.	('increase', 'PosReg', (58, 66))	('MYBL2', 'Gene', (13, 18))	('FoxM1', 'Gene', (23, 28))	('cells at the G2/M phase', 'CPA', (70, 93))	('Depletion', 'Var', (0, 9))	('U251', 'CellLine', 'CVCL:0021', (32, 36))	('FoxM1', 'Gene', '2305', (23, 28))
222882	28784180	In addition, the protein levels of PTEN and P53 were increased in MYBL2 and FoxM1 siRNAs transfected cells (Fig.	('FoxM1', 'Gene', (76, 81))	('P53', 'Gene', (44, 47))	('P53', 'Gene', '7157', (44, 47))	('MYBL2', 'Gene', (66, 71))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))	('increased', 'PosReg', (53, 62))	('FoxM1', 'Gene', '2305', (76, 81))	('protein levels', 'MPA', (17, 31))	('transfected', 'Var', (89, 100))
222883	28784180	We also conducted caspase-3/9 activity assays and found that knockdown of MYBL2 and FoxM1 induced expression and activity of caspase-3/9 in a time-dependent manner (Fig.	('FoxM1', 'Gene', (84, 89))	('caspase-3/9', 'Gene', (18, 29))	('caspase-3/9', 'Gene', (125, 136))	('knockdown', 'Var', (61, 70))	('caspase-3/9', 'Gene', '836;842', (18, 29))	('caspase-3/9', 'Gene', '836;842', (125, 136))	('activity', 'MPA', (113, 121))	('MYBL2', 'Gene', (74, 79))	('FoxM1', 'Gene', '2305', (84, 89))	('expression', 'MPA', (98, 108))
222889	28784180	7c and d, down regulation of MYBL2 did a little change of FoxM1 expression, while MYBL2 expression was dramatically reduced by knockdown of FoxM1 (*p < 0.05).	('expression', 'MPA', (64, 74))	('down regulation', 'NegReg', (10, 25))	('knockdown', 'Var', (127, 136))	('FoxM1', 'Gene', '2305', (140, 145))	('FoxM1', 'Gene', '2305', (58, 63))	('FoxM1', 'Gene', (140, 145))	('FoxM1', 'Gene', (58, 63))	('reduced', 'NegReg', (116, 123))	('expression', 'MPA', (88, 98))	('MYBL2', 'Gene', (82, 87))
222914	28784180	GBM patients, those with MYBL2 high levels without radiotherapy had a significantly higher death risk than those with radiotherapy.	('MYBL2', 'Gene', (25, 30))	('high levels', 'Var', (31, 42))	('patients', 'Species', '9606', (4, 12))
222919	28784180	The results showed that knockout of MYBL2 and FoxM1 induced a G2/M phase arrest by down-regulation of cyclin B and cyclin D, but up-regulation of P21, P27 and CDK6.	('P21', 'Gene', (146, 149))	('P27', 'Gene', (151, 154))	('G2/M phase arrest', 'CPA', (62, 79))	('FoxM1', 'Gene', (46, 51))	('P27', 'Gene', '3429', (151, 154))	('cyclin D', 'MPA', (115, 123))	('up-regulation', 'PosReg', (129, 142))	('CDK6', 'Gene', (159, 163))	('P21', 'Gene', '644914', (146, 149))	('FoxM1', 'Gene', '2305', (46, 51))	('MYBL2', 'Gene', (36, 41))	('knockout', 'Var', (24, 32))	('induced', 'Reg', (52, 59))	('cyclin B', 'MPA', (102, 110))	('CDK6', 'Gene', '1021', (159, 163))	('down-regulation', 'NegReg', (83, 98))
222920	28784180	In addition, silencing of MYBL2 and FoxM1 down regulated the protein levels of N-cadherin and Vimentin but increased the levels of E-cadherin and ZEB1.	('FoxM1', 'Gene', '2305', (36, 41))	('ZEB1', 'Gene', '6935', (146, 150))	('E-cadherin', 'Gene', '999', (131, 141))	('down regulated', 'NegReg', (42, 56))	('N-cadherin', 'Gene', (79, 89))	('increased', 'PosReg', (107, 116))	('Vimentin', 'Gene', (94, 102))	('FoxM1', 'Gene', (36, 41))	('silencing', 'Var', (13, 22))	('N-cadherin', 'Gene', '1000', (79, 89))	('Vimentin', 'Gene', '7431', (94, 102))	('E-cadherin', 'Gene', (131, 141))	('MYBL2', 'Gene', (26, 31))	('ZEB1', 'Gene', (146, 150))
222951	27300198	Significantly higher mean SWI-LIV values were found in HGG compared to LGG (92.7 versus 30.8; p < 0.0001), IDH1-R132H negative compared to IDH1-R132H positive gliomas (109.9 versus 38.3; p < 0.0001) and tumours with significant CE compared to non-significant CE (120.1 versus 39.0; p < 0.0001).	('tumours', 'Disease', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('R132H', 'SUBSTITUTION', 'None', (144, 149))	('IDH1', 'Gene', '3417', (107, 111))	('IDH1', 'Gene', '3417', (139, 143))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('R132H', 'Mutation', 'rs121913500', (112, 117))	('tumours', 'Disease', 'MESH:D009369', (203, 210))	('SWI-LIV values', 'MPA', (26, 40))	('R132H', 'Mutation', 'rs121913500', (144, 149))	('HGG', 'Disease', (55, 58))	('higher', 'PosReg', (14, 20))	('gliomas', 'Disease', (159, 166))	('R132H', 'Var', (112, 117))	('IDH1', 'Gene', (107, 111))	('R132H', 'Var', (144, 149))	('IDH1', 'Gene', (139, 143))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('R132H', 'SUBSTITUTION', 'None', (112, 117))
222962	27300198	Most notably, presence of the isocitrate dehydrogenase 1 (IDH1) mutation was shown to be associated with WHO grade II/III gliomas and secondary GBM as well as a significantly longer progression-free and overall survival.	('associated', 'Reg', (89, 99))	('longer', 'PosReg', (175, 181))	('overall survival', 'CPA', (203, 219))	('presence', 'Var', (14, 22))	('mutation', 'Var', (64, 72))	('IDH1', 'Gene', '3417', (58, 62))	('isocitrate dehydrogenase 1', 'Gene', (30, 56))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('isocitrate dehydrogenase 1', 'Gene', '3417', (30, 56))	('progression-free', 'CPA', (182, 198))	('gliomas', 'Disease', (122, 129))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('IDH1', 'Gene', (58, 62))	('secondary GBM', 'Disease', (134, 147))
222963	27300198	By far the most common IDH1 mutation involves the amino acid 132 at exon 4 (IDH1-R132H).	('IDH1', 'Gene', (76, 80))	('amino acid 132', 'Var', (50, 64))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (76, 80))	('IDH1', 'Gene', '3417', (23, 27))	('R132H', 'Mutation', 'rs121913500', (81, 86))
222964	27300198	More and more, molecular markers such as the IDH1 mutational status are increasingly incorporated in clinical decision making in addition to the tumour grade.	('IDH1', 'Gene', '3417', (45, 49))	('tumour', 'Disease', (145, 151))	('mutational status', 'Var', (50, 67))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('IDH1', 'Gene', (45, 49))
222965	27300198	Furthermore, it has been recently demonstrated that IDH1 mutant gliomas particularly profit from aggressive tumour resections.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('aggressive tumour', 'Disease', 'MESH:D001523', (97, 114))	('IDH1', 'Gene', '3417', (52, 56))	('profit', 'PosReg', (85, 91))	('aggressive tumour', 'Disease', (97, 114))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('mutant', 'Var', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('IDH1', 'Gene', (52, 56))
222966	27300198	Similarly to different microvascular patterns in gliomas of various grades of malignancy, neo-angiogenesis, and thus formation of pathological microvessels was found to be associated with IDH1/2 mutational status with increased neo-angiogenesis in IDH1/2 wild-type gliomas and inhibition of neo-angiogenesis in IDH1/2 mutant tumours.	('IDH1/2', 'Gene', (248, 254))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('neo-angiogenesis', 'CPA', (228, 244))	('malignancy', 'Disease', 'MESH:D009369', (78, 88))	('gliomas', 'Disease', (265, 272))	('neo-angiogenesis', 'CPA', (291, 307))	('IDH1/2', 'Gene', '3417;3418', (188, 194))	('tumours', 'Disease', (325, 332))	('increased', 'PosReg', (218, 227))	('IDH1/2', 'Gene', (188, 194))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (265, 272))	('mutational status', 'Var', (195, 212))	('tumours', 'Phenotype', 'HP:0002664', (325, 332))	('malignancy', 'Disease', (78, 88))	('tumours', 'Disease', 'MESH:D009369', (325, 332))	('associated', 'Reg', (172, 182))	('glioma', 'Phenotype', 'HP:0009733', (265, 271))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))	('IDH1/2', 'Gene', '3417;3418', (311, 317))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))	('gliomas', 'Phenotype', 'HP:0009733', (265, 272))	('IDH1/2', 'Gene', (311, 317))	('IDH1/2', 'Gene', '3417;3418', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))
222974	27300198	Consequently, new reliable methods for direct visualization of pathological microvascularity in gliomas must be developed for preoperative estimation of the tumour grade and IDH1 mutational status.	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH1', 'Gene', (174, 178))	('tumour', 'Disease', (157, 163))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('IDH1', 'Gene', '3417', (174, 178))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('mutational status', 'Var', (179, 196))
223008	27300198	Consequently, all tumours with SWI-LIV <= 35 were classified as LGG and all gliomas with SWI-LIV > 35 as HGG in this comparative analysis.	('gliomas', 'Disease', (76, 83))	('tumours', 'Disease', (18, 25))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('SWI-LIV <= 35', 'Var', (31, 44))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('LGG', 'Disease', (64, 67))	('tumours', 'Disease', 'MESH:D009369', (18, 25))
223019	27300198	The mean SWI-LIV in IDH1-R132H negative gliomas (109.9; SD = 57.9) was significantly higher compared to IDH1-R132H positive gliomas (38.3; SD = 21.1; p < 0.0001).	('IDH1', 'Gene', '3417', (20, 24))	('gliomas', 'Disease', (124, 131))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('R132H', 'SUBSTITUTION', 'None', (25, 30))	('R132H', 'Var', (109, 114))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))	('IDH1', 'Gene', '3417', (104, 108))	('higher', 'PosReg', (85, 91))	('R132H', 'Mutation', 'rs121913500', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('SWI-LIV', 'MPA', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('R132H', 'SUBSTITUTION', 'None', (109, 114))	('gliomas', 'Disease', (40, 47))	('IDH1', 'Gene', (20, 24))	('R132H', 'Mutation', 'rs121913500', (109, 114))	('R132H', 'Var', (25, 30))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('IDH1', 'Gene', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
223023	27300198	Herein, we describe a new technique for quantitative analysis of hypointense SWI structures in diffusely infiltrating gliomas.	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('hypointense', 'Var', (65, 76))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
223024	27300198	In this prospective study using 7 Tesla MRI, we found significantly higher SWI-LIV values in HGG compared to LGG, IDH1-R132H negative compared to IDH1-R132H positive gliomas and tumours with significant CE compared to non-significant CE on MRI.	('IDH1', 'Gene', (146, 150))	('R132H', 'Mutation', 'rs121913500', (119, 124))	('IDH1', 'Gene', (114, 118))	('R132H', 'Var', (151, 156))	('HGG', 'Disease', (93, 96))	('R132H', 'SUBSTITUTION', 'None', (119, 124))	('IDH1', 'Gene', '3417', (146, 150))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('R132H', 'Mutation', 'rs121913500', (151, 156))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('higher', 'PosReg', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('R132H', 'SUBSTITUTION', 'None', (151, 156))	('IDH1', 'Gene', '3417', (114, 118))	('gliomas and tumours', 'Disease', 'MESH:D005910', (166, 185))	('SWI-LIV values', 'MPA', (75, 89))	('R132H', 'Var', (119, 124))
223037	27300198	The preoperative knowledge of the IDH1 status is of major interest for further patient management/surgical strategy since it was shown in a recent study that the IDH1 mutational status has a crucial impact on the surgical benefit: While patients with IDH1 wild-type malignant gliomas do not profit from further removal of the non-enhancing tumour in addition to the enhancing tumour, this surgical strategy results in a significantly prolonged overall survival in patients with IDH1 mutant tumours.	('tumour', 'Phenotype', 'HP:0002664', (340, 346))	('IDH1', 'Gene', '3417', (162, 166))	('tumour', 'Disease', 'MESH:D009369', (490, 496))	('tumour', 'Disease', (490, 496))	('tumour', 'Disease', 'MESH:D009369', (340, 346))	('tumour', 'Disease', (340, 346))	('patients', 'Species', '9606', (237, 245))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', '3417', (478, 482))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('patient', 'Species', '9606', (237, 244))	('overall survival', 'MPA', (444, 460))	('patients', 'Species', '9606', (464, 472))	('IDH1', 'Gene', (251, 255))	('patient', 'Species', '9606', (79, 86))	('prolonged', 'PosReg', (434, 443))	('tumour', 'Phenotype', 'HP:0002664', (376, 382))	('tumour', 'Disease', 'MESH:D009369', (376, 382))	('tumour', 'Disease', (376, 382))	('tumours', 'Disease', (490, 497))	('mutant', 'Var', (483, 489))	('IDH1', 'Gene', (162, 166))	('IDH1', 'Gene', '3417', (251, 255))	('tumours', 'Phenotype', 'HP:0002664', (490, 497))	('malignant gliomas', 'Disease', 'MESH:D005910', (266, 283))	('men', 'Species', '9606', (93, 96))	('tumours', 'Disease', 'MESH:D009369', (490, 497))	('patient', 'Species', '9606', (464, 471))	('IDH1', 'Gene', (34, 38))	('malignant gliomas', 'Disease', (266, 283))	('IDH1', 'Gene', (478, 482))	('tumour', 'Phenotype', 'HP:0002664', (490, 496))
223038	27300198	Interestingly, we observed a significantly higher mean SWI-LIV in IDH1-R132H negative compared to IDH1-R132H positive gliomas.	('R132H', 'Var', (103, 108))	('IDH1', 'Gene', '3417', (66, 70))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('higher', 'PosReg', (43, 49))	('R132H', 'Mutation', 'rs121913500', (103, 108))	('R132H', 'SUBSTITUTION', 'None', (103, 108))	('SWI-LIV', 'MPA', (55, 62))	('R132H', 'Var', (71, 76))	('IDH1', 'Gene', (98, 102))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('R132H', 'Mutation', 'rs121913500', (71, 76))	('IDH1', 'Gene', '3417', (98, 102))	('IDH1', 'Gene', (66, 70))	('R132H', 'SUBSTITUTION', 'None', (71, 76))
223043	27300198	observed a significantly increased absolute tumour blood flow measured by arterial spin-labelling/perfusion-MRI and tumour necrotic area on MRI in IDH1 wild-type compared to IDH1 mutant GBM.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('mutant', 'Var', (179, 185))	('increased', 'PosReg', (25, 34))	('tumour necrotic', 'Disease', 'MESH:D009369', (116, 131))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('IDH1', 'Gene', '3417', (174, 178))	('tumour', 'Disease', (116, 122))	('tumour', 'Disease', (44, 50))	('IDH1', 'Gene', (174, 178))	('IDH1', 'Gene', (147, 151))	('tumour necrotic', 'Disease', (116, 131))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('IDH1', 'Gene', '3417', (147, 151))
223044	27300198	These data including our own findings demonstrate that assessment of SWI and perfusion values is a promising method not only for preoperative determination of the correct WHO tumour grade, but also the IDH1 mutational status in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (228, 235))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('gliomas', 'Disease', (228, 235))	('mutational status', 'Var', (207, 224))	('tumour', 'Disease', (175, 181))	('IDH1', 'Gene', (202, 206))	('men', 'Species', '9606', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('IDH1', 'Gene', '3417', (202, 206))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
223164	25268588	Only a small number of low-grade gliomas (n = 8) was included; however, it is well known that low-grade gliomas account for 10-15% of all adult primary intracranial tumors, which is very similar to our study setting.	('gliomas', 'Disease', (104, 111))	('intracranial tumors', 'Disease', (152, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('low-grade', 'Var', (94, 103))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('intracranial tumors', 'Disease', 'MESH:D001932', (152, 171))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
223175	32668393	Homozygous deletion of six genes in 9p21.3 characterized an LGG subtype with poor prognosis and contributed to the dysfunction of cancer-associated pathways in a complementary way.	('contributed', 'Reg', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('Homozygous', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('dysfunction', 'MPA', (115, 126))	('LGG', 'Disease', (60, 63))
223184	32668393	Somatic copy-number alterations (SCNAs), one important type of somatic genetic alterations, have been reported to activate oncogenes and inactivate tumor suppressors, which further made contributions to cancer progression.	('alterations', 'Var', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('inactivate', 'NegReg', (137, 147))	('activate', 'PosReg', (114, 122))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('copy-number alterations', 'Var', (8, 31))	('oncogenes', 'Protein', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
223189	32668393	showed that the co-amplifications and co-deletions of cancer-causing genes and metabolic genes contributed to reprogram cancer cell metabolism.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('co-amplifications', 'Var', (16, 33))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('co-deletions', 'Var', (38, 50))	('contributed', 'Reg', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
223191	32668393	The driver genetic alterations could induce the dysregulation of multilayer factor-mediated regulatory networks of gene expression and further cause disorder of cancer-associated functions.	('cancer', 'Disease', (161, 167))	('disorder', 'MPA', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('multilayer factor-mediated regulatory networks of', 'Pathway', (65, 114))	('cause', 'Reg', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('induce', 'Reg', (37, 43))	('dysregulation', 'MPA', (48, 61))	('genetic alterations', 'Var', (11, 30))
223197	32668393	Copy number loss of both CNOT6LA and VAPA may downregulate PTEN in a miRNA-dependent manner.	('downregulate', 'NegReg', (46, 58))	('VAPA', 'Gene', '9218', (37, 41))	('VAPA', 'Gene', (37, 41))	('CNOT6LA', 'Gene', (25, 32))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))	('Copy number loss', 'Var', (0, 16))
223199	32668393	vIRF1 deletion increased miR-218-5p expression level and reduced the level of lnc-OIP5-AS1.	('OIP5-AS1', 'Gene', '729082;11339;5729', (82, 90))	('increased', 'PosReg', (15, 24))	('OIP5-AS1', 'Gene', (82, 90))	('deletion', 'Var', (6, 14))	('reduced', 'NegReg', (57, 64))	('vIRF1', 'Gene', (0, 5))	('miR-218-5p expression level', 'MPA', (25, 52))
223202	32668393	Homozygous deletion of six genes in 9p21.3 could characterize a LGG subtype with poor prognosis and contribute to the dysfunction of cancer-associated pathways in a complementary way.	('contribute', 'Reg', (100, 110))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('dysfunction', 'MPA', (118, 129))	('cancer', 'Disease', (133, 139))	('Homozygous deletion', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('LGG', 'Disease', (64, 67))
223212	32668393	The knocking down of COMMD9 was reported to inhibit cell proliferation and migration, and it arrested the cell cycle at the G1/S transition.	('knocking down', 'Var', (4, 17))	('cell cycle at the G1/S transition', 'CPA', (106, 139))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('inhibit', 'NegReg', (44, 51))	('cell proliferation', 'CPA', (52, 70))	('COMMD9', 'Gene', (21, 27))	('arrest', 'Disease', (93, 99))	('COMMD9', 'Gene', '29099', (21, 27))
223213	32668393	The depletion of CPSF1 suppressed cell viability and promoted cell apoptosis by inducing cell cycle arrest at the G0/G1 phase.	('promoted', 'PosReg', (53, 61))	('suppressed', 'NegReg', (23, 33))	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('arrest', 'Disease', (100, 106))	('depletion', 'Var', (4, 13))	('CPSF1', 'Gene', '29894', (17, 22))	('CPSF1', 'Gene', (17, 22))	('cell apoptosis', 'CPA', (62, 76))	('inducing', 'Reg', (80, 88))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('cell viability', 'CPA', (34, 48))
223215	32668393	HSF1 knockdown reduced cell migration and invasive ability, which were restored by HSF1 overexpression.	('invasive ability', 'CPA', (42, 58))	('knockdown', 'Var', (5, 14))	('HSF1', 'Gene', (0, 4))	('HSF1', 'Gene', '3297', (0, 4))	('HSF1', 'Gene', (83, 87))	('reduced', 'NegReg', (15, 22))	('cell migration', 'CPA', (23, 37))	('HSF1', 'Gene', '3297', (83, 87))
223220	32668393	To investigate whether dysregulated ceRNA networks were associated with cancer hallmarks, we downloaded 50 hallmark signatures from MSigDB and identified the significantly enriched hallmark signatures by the deregulated ceRNA networks using R package clusterProfiler at a false discovery rate (FDR) of 0.05.	('deregulated', 'Var', (208, 219))	('MSigDB', 'Gene', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer hallmarks', 'Disease', (72, 88))	('cancer hallmarks', 'Disease', 'MESH:D009369', (72, 88))
223221	32668393	For example, the dysregulated ceRNA networks caused by lncRNA ZNF252P-AS1 amplification were significantly enriched in a DNA damage signature (DNA_REPAIR), proliferation signatures (E2F_TARGETS, G2M_CHECKPOINT, MITOTIC_SPINDLE, MYC_TARGETS_V1, and MYC_TARGETS_V2), and a pathway signature (UNFOLDED_PROTEIN_RESPONSE).	('ZNF252P-AS1', 'Gene', (62, 73))	('MYC', 'Gene', '4609', (228, 231))	('amplification', 'Var', (74, 87))	('MYC', 'Gene', (248, 251))	('DNA damage signature', 'MPA', (121, 141))	('proliferation', 'MPA', (156, 169))	('ZNF252P-AS1', 'Gene', '286103', (62, 73))	('MYC', 'Gene', (228, 231))	('ceRNA', 'Gene', (30, 35))	('MYC', 'Gene', '4609', (248, 251))
223222	32668393	The most frequently enriched hallmark signatures across 37 dysregulated ceRNA networks were proliferation signatures, including E2F_TARGETS (30/37), G2M_CHECKPOINT (29/37), and MYC_TARGETS_V1 (25/37).	('MYC', 'Gene', '4609', (177, 180))	('E2F_TARGETS', 'Var', (128, 139))	('proliferation', 'CPA', (92, 105))	('MYC', 'Gene', (177, 180))
223227	32668393	To further analyze the association of 9p21.3 deletions with LGG poor prognosis in spite of alterations in the rest of the driver genes, we classified the LGG patients into three subgroups based on the SCNA status of the 44 driver genes as follows: subgroup I, including patients without any SCNAs of the 44 driver genes; subgroup II, including patients with homozygous deletions of at least one of the six genes in 9p21.3; and subgroup III, including patients without homozygous deletions of the six genes but with homozygous deletions or high-level amplifications of the rest of the 38 driver genes.	('patients', 'Species', '9606', (270, 278))	('deletions', 'Var', (45, 54))	('patients', 'Species', '9606', (158, 166))	('deletions', 'Var', (369, 378))	('patients', 'Species', '9606', (344, 352))	('patients', 'Species', '9606', (451, 459))
223228	32668393	By preforming function enrichment analysis, we found that these six dysregulated ceRNA networks were consistently and significantly enriched in the proliferation hallmark signatures, including E2F_TARGETS, G2M_CHECKPOINT and MYC_TARGETS_V1 (Figure 4F).	('MYC', 'Gene', '4609', (225, 228))	('MYC', 'Gene', (225, 228))	('E2F_TARGETS', 'Var', (193, 204))	('G2M_CHECKPOINT', 'Var', (206, 220))
223239	32668393	We found that amplification of lncRNA PVT1 could destroy its ceRNA networks in six cancer types, including OV, head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), BRCA, and bladder urothelial carcinoma (BLCA) (Figures S5-S10).	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('neck squamous cell carcinoma', 'Disease', (120, 148))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (120, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('PVT1', 'Gene', (38, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('ceRNA networks', 'CPA', (61, 75))	('PVT1', 'Gene', '5820', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BRCA', 'Gene', '672', (216, 220))	('destroy', 'NegReg', (49, 56))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (185, 207))	('OV', 'Phenotype', 'HP:0012887', (107, 109))	('stomach adenocarcinoma', 'Disease', (185, 207))	('bladder urothelial carcinoma', 'Disease', (226, 254))	('BRCA', 'Gene', (216, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Disease', (83, 89))	('lung adenocarcinoma', 'Disease', (157, 176))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (226, 254))	('amplification', 'Var', (14, 27))
223242	32668393	Amplification of PVT1 could contribute to the development ovarian and breast cancer.	('Amplification', 'Var', (0, 13))	('PVT1', 'Gene', (17, 21))	('ovarian and breast cancer', 'Disease', 'MESH:D001943', (58, 83))	('PVT1', 'Gene', '5820', (17, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('contribute to', 'Reg', (28, 41))
223243	32668393	Knockdown of PVT1 could inhibit cell migration and proliferation.	('Knockdown', 'Var', (0, 9))	('PVT1', 'Gene', '5820', (13, 17))	('inhibit', 'NegReg', (24, 31))	('PVT1', 'Gene', (13, 17))
223245	32668393	Compared with non-alteration status, amplification significantly elevated the expression levels of PVT1 (Figure 6B).	('PVT1', 'Gene', (99, 103))	('amplification', 'Var', (37, 50))	('PVT1', 'Gene', '5820', (99, 103))	('elevated', 'PosReg', (65, 73))	('expression levels', 'MPA', (78, 95))
223248	32668393	The amplification of PVT1 completely destroyed the active ceRNA networks, and the numbers of active ceRNA triples dropped to 0.	('active ceRNA networks', 'CPA', (51, 72))	('destroyed', 'NegReg', (37, 46))	('PVT1', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('PVT1', 'Gene', '5820', (21, 25))
223258	32668393	Comparative analysis showed that MTAP deletion also disturbed distinct ceRNA triples in different cancers (Figure S11).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MTAP', 'Gene', (33, 37))	('disturbed', 'Reg', (52, 61))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('ceRNA triples', 'MPA', (71, 84))	('MTAP', 'Gene', '4507', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('deletion', 'Var', (38, 46))
223263	32668393	However, the significant inverse relationships between hsa-miR-326 and both PVT1 and NEAT1 were destroyed by PVT1 amplification in HNSC.	('PVT1', 'Gene', '5820', (76, 80))	('amplification', 'Var', (114, 127))	('NEAT1', 'Gene', '283131', (85, 90))	('PVT1', 'Gene', '5820', (109, 113))	('NEAT1', 'Gene', (85, 90))	('hsa-miR-326', 'Gene', '442900', (55, 66))	('hsa-miR-326', 'Gene', (55, 66))	('PVT1', 'Gene', (76, 80))	('PVT1', 'Gene', (109, 113))
223274	32668393	EGFR amplification was associated with poor prognosis in both GBM and HNSC (p = 0.0242 for GBM, p = 0.0314 for HNSC; Figure S13).	('GBM', 'Disease', (62, 65))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('HNSC', 'Disease', (70, 74))	('EGFR', 'Gene', '1956', (0, 4))
223275	32668393	Compared with non-alteration, amplification significantly elevated EGFR expression levels in both GBM and HNSC (p = 3.6e-16 for GBM and p = 1.3e-9 for HNSC; Figure 8F).	('expression levels', 'MPA', (72, 89))	('amplification', 'Var', (30, 43))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('elevated', 'PosReg', (58, 66))
223276	32668393	However, EGFR did not participate in the ceRNA regulatory mechanism in spite of non-alteration or amplification in GBM (FDR = 0.05, PCC < 0; Figure 8G).	('GBM', 'Gene', (115, 118))	('EGFR', 'Gene', '1956', (9, 13))	('amplification', 'Var', (98, 111))	('EGFR', 'Gene', (9, 13))	('non-alteration', 'Var', (80, 94))
223277	32668393	Under non-alteration of EGFR in HNSC, four miRNAs showed significant inverse correlations with EGFR while no inverse correlations were identified between any miRNA and EGFR under EGFR amplifications (FDR = 0.05, PCC < 0; Figure 8H; Figure S14).	('EGFR', 'Gene', (179, 183))	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', (24, 28))	('non-alteration', 'Var', (6, 20))	('correlations', 'Interaction', (77, 89))	('EGFR', 'Gene', '1956', (95, 99))	('inverse', 'NegReg', (69, 76))	('EGFR', 'Gene', '1956', (179, 183))	('EGFR', 'Gene', (95, 99))
223281	32668393	Due to the less frequent SCNAs of known cancer genes, we re-identified the driver genes in LGG for the threshold of alteration frequencies at 0.08, 0.06, 0.04, and 0.02, which also could significantly capture known cancer genes.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('0.02', 'Var', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('LGG', 'Gene', (91, 94))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
223290	32668393	Analysis of ceRNA networks in previous studies explored ceRNA partners of PGs (PTEN) based on mRNA-mRNA ceRNA networks or predicted lncRNA functions based on lncRNA-mRNA ceRNA networks.	('PGs', 'Var', (74, 77))	('PTEN', 'Gene', '5728', (79, 83))	('lncRNA functions', 'MPA', (132, 148))	('PTEN', 'Gene', (79, 83))
223298	32668393	Amplification of EGFR could elevate EGFR expression levels in both HNSC and GBM.	('expression levels', 'MPA', (41, 58))	('Amplification', 'Var', (0, 13))	('elevate', 'PosReg', (28, 35))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', (17, 21))
223299	32668393	EGFR amplification dysregulated the EGFR-associated ceRNA network in HNSC, while EGFR did not participate in the ceRNA regulatory mechanism in GBM.	('dysregulated', 'Reg', (19, 31))	('EGFR', 'Gene', (0, 4))	('HNSC', 'Disease', (69, 73))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
223300	32668393	In other case, SCNAs of genes or lncRNAs could disturb their associated ceRNA networks through different miRNAs and different ceRNA partners in different cancer types.	('SCNAs', 'Var', (15, 20))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('miRNAs', 'MPA', (105, 111))	('disturb', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ceRNA networks', 'Pathway', (72, 86))
223305	32668393	The copy number profiles of 12 cancer types involved 5,814 cancer samples in TCGA.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('copy', 'Var', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
223321	32668393	According to copy number status of each candidate gene, we grouped cancer samples into subgroups and deleted the subgroups with fewer than five samples.	('copy', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
223322	32668393	For a given PG or lncRNA, three SCNA status levels may be present across cancer populations: heterozygous deletion (-2), high-level amplification (2), and non-alterations (0).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('non-alterations', 'Var', (155, 170))
223323	32668393	According to SCNA status of the PG or lncRNA, the cancer patients were divided into subgroups as follows: one subgroup of patients with heterozygous deletion (-2) of the PG or lncRNA, one subgroup of patients with high-level amplification (2) of the PG or lncRNA, and one subgroup of patients with non-alteration (0) of the PG or lncRNA.	('deletion', 'Var', (149, 157))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Disease', (50, 56))	('patients', 'Species', '9606', (284, 292))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
223331	31906320	NF1 is caused by pathogenic variants in the NF1 gene, located at chromosome 17q11.2.	('NF1', 'Gene', (44, 47))	('variants', 'Var', (28, 36))	('NF1', 'Gene', '4763', (44, 47))	('NF1', 'Gene', (0, 3))	('caused by', 'Reg', (7, 16))	('NF1', 'Gene', '4763', (0, 3))
223332	31906320	Such variants can be familial or occur de novo, with the latter occurring in ~50% of individuals with NF1.	('variants', 'Var', (5, 13))	('NF1', 'Gene', '4763', (102, 105))	('NF1', 'Gene', (102, 105))	('occurring', 'Reg', (64, 73))
223334	31906320	There are some genotype-phenotype correlations for specific NF1 variants, but much of the variability in phenotype has been attributed to stochastic events, environmental factors or modifier genes.	('NF1', 'Gene', '4763', (60, 63))	('NF1', 'Gene', (60, 63))	('variants', 'Var', (64, 72))
223340	31906320	Biallelic inactivation of NF1 gene function is required for tumor formation; i.e., the somatic inactivation of the unaffected NF1 allele is a "second hit," which leads to absence of neurofibromin within affected cells.	('NF1', 'Gene', (26, 29))	('neurofibromin', 'Gene', (182, 195))	('absence', 'NegReg', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NF1', 'Gene', (126, 129))	('NF1', 'Gene', '4763', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NF1', 'Gene', '4763', (126, 129))	('tumor', 'Disease', (60, 65))	('inactivation', 'Var', (95, 107))	('neurofibromin', 'Gene', '4763', (182, 195))
223346	31906320	The World Health Organization (WHO) classification of gliomas has been refined and incorporated molecular parameters, namely 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M, in addition to histology to define many tumor entities.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('mutation', 'Var', (151, 159))	('gliomas', 'Disease', (54, 61))	('IDH1/2', 'Gene', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('K27M', 'Mutation', 'p.K27M', (176, 180))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1/2', 'Gene', '3417;3418', (144, 150))
223353	31906320	The study included whole exome sequencing of tumor and matched blood germline DNA to identify germline and somatic single nucleotide variants, small insertions and deletions, and copy number variants.	('copy number variants', 'Var', (179, 199))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('single nucleotide variants', 'Var', (115, 141))	('deletions', 'Var', (164, 173))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
223354	31906320	The NF1 variants observed in germline DNA were typically truncating and led to frameshifts, which did not cluster into specific NF1 protein domains.	('NF1', 'Gene', '4763', (128, 131))	('led', 'Reg', (72, 75))	('frameshifts', 'Var', (79, 90))	('truncating', 'MPA', (57, 67))	('variants', 'Var', (8, 16))	('NF1', 'Gene', (4, 7))	('NF1', 'Gene', '4763', (4, 7))	('NF1', 'Gene', (128, 131))
223355	31906320	There was no association between particular patterns of NF1 genetic variants and the risk of developing glioma.	('genetic variants', 'Var', (60, 76))	('NF1', 'Gene', '4763', (56, 59))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('NF1', 'Gene', (56, 59))	('glioma', 'Disease', (104, 110))
223356	31906320	The data supported prior reports that a "second-hit" is required to develop tumors, as loss of heterozygosity in the NF1 region was detected in the majority of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('NF1', 'Gene', '4763', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('loss of heterozygosity', 'Var', (87, 109))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('NF1', 'Gene', (117, 120))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
223359	31906320	Indeed, individuals with gliomas harboring IDH mutations have better prognosis than those with IDH wild-type.	('IDH', 'Gene', '3417', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('mutations', 'Var', (47, 56))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', (43, 46))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
223362	31906320	Another example is that mutations in H3.3 histone genes, frequently found in sporadic pediatric gliomas, were absent in all samples regardless of age.	('H3.3', 'Gene', (37, 41))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('pediatric gliomas', 'Disease', 'MESH:D005910', (86, 103))	('mutations', 'Var', (24, 33))	('histone', 'Protein', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('pediatric gliomas', 'Disease', (86, 103))
223363	31906320	Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway, while high-grade tumors were characterized by a higher mutation burden and frequent mutations of ATRX, typically co-occurring with alterations of TP53 and cyclin-dependent kinase Inhibitor 2A (CDKN2).	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (10, 16))	('mutation', 'MPA', (161, 169))	('CDKN2', 'Gene', (299, 304))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', '1029', (261, 297))	('TP53', 'Gene', (252, 256))	('mutations', 'Var', (190, 199))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('ATRX', 'Gene', (203, 207))	('ATRX', 'Gene', '546', (203, 207))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('higher', 'PosReg', (154, 160))	('CDKN2', 'Gene', '1029', (299, 304))	('TP53', 'Gene', '7157', (252, 256))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', (261, 297))	('MAP kinase pathway', 'Pathway', (86, 104))
223364	31906320	DNA methylation assigned NF1-glioma to LGm6, a poorly defined IDH wild-type subgroup enriched with ATRX mutations, which may represent a point of therapeutic intervention, as previous studies have shown that loss of ATRX increases sensitivity to DNA-damaging agents.	('glioma', 'Disease', (29, 35))	('ATRX', 'Gene', (216, 220))	('ATRX', 'Gene', (99, 103))	('IDH', 'Gene', '3417', (62, 65))	('sensitivity to DNA-damaging agents', 'MPA', (231, 265))	('increases', 'PosReg', (221, 230))	('ATRX', 'Gene', '546', (216, 220))	('ATRX', 'Gene', '546', (99, 103))	('loss', 'Var', (208, 212))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('NF1', 'Gene', (25, 28))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('NF1', 'Gene', '4763', (25, 28))	('IDH', 'Gene', (62, 65))
223368	31906320	Summary table listing the frequencies (%) of mutations seen in NF1-glioma as studied by D'Angelo, et al.	('mutations', 'Var', (45, 54))	('glioma', 'Disease', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('NF1', 'Gene', (63, 66))	('NF1', 'Gene', '4763', (63, 66))
223370	31906320	Cell 2016), which is an IDH-WT group enriched with ATRX mutations.	('mutations', 'Var', (56, 65))	('IDH', 'Gene', (24, 27))	('ATRX', 'Gene', (51, 55))	('IDH', 'Gene', '3417', (24, 27))	('ATRX', 'Gene', '546', (51, 55))
223371	31906320	TERT = TERT copy number variant gain in NF1-Glioma and TERT promotor expression in LGm6 group.	('Glioma', 'Disease', 'MESH:D005910', (44, 50))	('Glioma', 'Phenotype', 'HP:0009733', (44, 50))	('Glioma', 'Disease', (44, 50))	('NF1', 'Gene', (40, 43))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (7, 11))	('NF1', 'Gene', '4763', (40, 43))	('TERT', 'Gene', (55, 59))	('gain', 'PosReg', (32, 36))	('TERT', 'Gene', '7015', (7, 11))	('TERT', 'Gene', '7015', (55, 59))	('variant', 'Var', (24, 31))
223372	31906320	ATRX = inactivation of ATRX from any mutation.	('inactivation', 'NegReg', (7, 19))	('ATRX', 'Gene', (0, 4))	('mutation', 'Var', (37, 45))	('ATRX', 'Gene', '546', (23, 27))	('ATRX', 'Gene', '546', (0, 4))	('ATRX', 'Gene', (23, 27))
223373	31906320	TP53 = frameshift or missense mutation in both groups.	('missense mutation', 'Var', (21, 38))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))
223374	31906320	PTEN = combination of missense and frameshift mutations in the NF-1 glioma group; missense and loss in LGm6 group.	('NF-1', 'Disease', 'MESH:D009456', (63, 67))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('frameshift mutations', 'Var', (35, 55))	('NF-1', 'Disease', (63, 67))	('LGm6', 'Gene', (103, 107))	('glioma', 'Disease', (68, 74))	('loss', 'NegReg', (95, 99))	('PTEN', 'Gene', (0, 4))	('missense', 'Var', (22, 30))	('PTEN', 'Gene', '5728', (0, 4))	('missense', 'Var', (82, 90))
223375	31906320	PIK3CA = missense and in-frame indel.	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('missense', 'Var', (9, 17))
223376	31906320	NF1 = frameshift/truncating.	('frameshift/truncating', 'Var', (6, 27))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (0, 3))
223377	31906320	BRAF = missense in NF1-glioma group, missense and frameshift in LGm6 group.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('NF1', 'Gene', (19, 22))	('missense', 'Var', (7, 15))	('NF1', 'Gene', '4763', (19, 22))	('frameshift', 'Var', (50, 60))	('glioma', 'Disease', (23, 29))	('BRAF', 'Gene', '673', (0, 4))	('missense', 'Var', (37, 45))	('BRAF', 'Gene', (0, 4))	('LGm6', 'Gene', (64, 68))
223383	31906320	Studies have suggested that individuals with mutations in the 5' tertile (exon 1-21) on NF1 gene have a greater risk of developing OPG, but this was not confirmed in a subsequent study.	('OPG', 'Gene', '690', (131, 134))	('NF1', 'Gene', (88, 91))	('NF1', 'Gene', '4763', (88, 91))	('OPG', 'Gene', (131, 134))	('mutations in', 'Var', (45, 57))
223384	31906320	A large cohort study that examined NF1 mutations in 215 NF1 patients (100 of them had OPGs) observed that those with variants in the cysteine/serine-rich domain of the NF1 gene (CSRD, residues 543-909), which is located in 5' tertile, had higher risk of developing OPGs.	('CSRD', 'Disease', (178, 182))	('NF1', 'Gene', '4763', (56, 59))	('CSRD', 'Disease', 'None', (178, 182))	('patients', 'Species', '9606', (60, 68))	('NF1', 'Gene', '4763', (35, 38))	('mutations', 'Var', (39, 48))	('OPGs', 'Phenotype', 'HP:0009734', (86, 90))	('OPGs', 'Chemical', '-', (86, 90))	('NF1', 'Gene', (168, 171))	('serine', 'Chemical', 'MESH:D012694', (142, 148))	('OPGs', 'Chemical', '-', (265, 269))	('cysteine', 'Chemical', 'MESH:D003545', (133, 141))	('OPGs', 'Phenotype', 'HP:0009734', (265, 269))	('NF1', 'Gene', '4763', (168, 171))	('NF1', 'Gene', (35, 38))	('NF1', 'Gene', (56, 59))	('OPGs', 'Disease', (265, 269))	('variants in', 'Var', (117, 128))
223385	31906320	A recent genotype-phenotype study reported a more severe phenotype in individuals with NF1 who carry missense mutations affecting one of five neighboring codons 844-848 located outside the GAP-related domain.	('missense mutations', 'Var', (101, 119))	('NF1', 'Gene', '4763', (87, 90))	('NF1', 'Gene', (87, 90))
223386	31906320	The study presented 162 individuals heterozygous for a constitutional NF1 missense mutation in one of the five neighboring codons 844-848.	('NF1', 'Gene', '4763', (70, 73))	('NF1', 'Gene', (70, 73))	('missense mutation', 'Var', (74, 91))
223387	31906320	The cluster of the recurrent missense mutations reported in this study involving aa 844-848 is located within the CSRD domain, which is likely functionally important, and was originally described by Fahsold et al..	('missense mutations', 'Var', (29, 47))	('CSRD', 'Disease', 'None', (114, 118))	('CSRD', 'Disease', (114, 118))
223442	31906320	In lung cancer models, reduced NF1 expression mediates resistance to EGFR therapy, and blocking MEK restores the response.	('resistance', 'MPA', (55, 65))	('EGFR', 'Gene', '1956', (69, 73))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('EGFR', 'Gene', (69, 73))	('MEK', 'Gene', (96, 99))	('response', 'MPA', (113, 121))	('MEK', 'Gene', '5609', (96, 99))	('expression', 'MPA', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('blocking', 'Var', (87, 95))	('NF1', 'Gene', (31, 34))	('reduced', 'NegReg', (23, 30))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('NF1', 'Gene', '4763', (31, 34))
223445	31906320	Loss of neurofibromin in glial cells leads to increased RAS activity and its downstream RAS effectors.	('increased', 'PosReg', (46, 55))	('neurofibromin', 'Gene', '4763', (8, 21))	('RAS', 'Protein', (56, 59))	('activity', 'MPA', (60, 68))	('Loss', 'Var', (0, 4))	('neurofibromin', 'Gene', (8, 21))
223447	31906320	Also, somatic NF1 mutation has been reported in 5-10% of sporadic tumors like glioblastoma, breast cancer, juvenile myelomonocytic leukemia, and lung adenocarcinoma.	('juvenile myelomonocytic leukemia', 'Phenotype', 'HP:0012209', (107, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (145, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('NF1', 'Gene', '4763', (14, 17))	('lung adenocarcinoma', 'Disease', (145, 164))	('juvenile myelomonocytic leukemia', 'Disease', (107, 139))	('mutation', 'Var', (18, 26))	('NF1', 'Gene', (14, 17))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('sporadic tumors like glioblastoma', 'Disease', (57, 90))	('breast cancer', 'Disease', (92, 105))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('juvenile myelomonocytic leukemia', 'Disease', 'MESH:D054429', (107, 139))	('sporadic tumors like glioblastoma', 'Disease', 'MESH:D005909', (57, 90))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('reported', 'Reg', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
223547	33385022	To explore genes and pathways associated with tumor progression phenotypes we analyzed gene expression in a panel of non-tumor and glioma cell lines, namely: ACBRI371, non-tumor human astrocytes; HDPC, fibroblasts derived from dental pulp; Res186, Res259, Res286 and UW467 that include grade I, II and III astrocytoma cell lines derived from pediatric tumors; and T98G, U343MG, U87MG, U138MG and U251MG, all derived from GBM (grade IV).	('glioma', 'Disease', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('U343MG', 'Var', (370, 376))	('U343MG', 'CellLine', 'CVCL:S471', (370, 376))	('human', 'Species', '9606', (178, 183))	('tumor', 'Disease', (172, 177))	('tumors', 'Disease', (352, 358))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('U87MG', 'Var', (378, 383))	('tumors', 'Disease', 'MESH:D009369', (352, 358))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('U138MG', 'CellLine', 'CVCL:0020', (385, 391))	('tumor', 'Disease', (121, 126))	('III astrocytoma', 'Disease', (302, 317))	('tumor', 'Disease', (352, 357))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('U251MG', 'Var', (396, 402))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('HDPC', 'Gene', '167227', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('GBM', 'Phenotype', 'HP:0012174', (421, 424))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('dental pulp', 'Phenotype', 'HP:0003771', (227, 238))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('astrocytoma', 'Phenotype', 'HP:0009592', (306, 317))	('HDPC', 'Gene', (196, 200))	('U87MG', 'CellLine', 'CVCL:0022', (378, 383))	('III astrocytoma', 'Disease', 'MESH:D001254', (302, 317))	('T98G', 'Var', (364, 368))	('U251MG', 'CellLine', 'CVCL:0021', (396, 402))
223560	33385022	We used two non-tumor cells and 9 cell lines representative of tumor progression, comprising: two non-tumor cells (HDPC and ACBRI371), two grade I (Res186, Res286), one grade II (Res259), one grade III (UW467) astrocytoma cells, and 5 GBM (T98G, U343MG, U87MG, U138MG and U251MG) cell lines.	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('GBM', 'Phenotype', 'HP:0012174', (235, 238))	('HDPC', 'Gene', (115, 119))	('U138MG', 'Var', (261, 267))	('U251MG', 'CellLine', 'CVCL:0021', (272, 278))	('U87MG', 'CellLine', 'CVCL:0022', (254, 259))	('tumor', 'Disease', (63, 68))	('astrocytoma', 'Disease', 'MESH:D001254', (210, 221))	('astrocytoma', 'Disease', (210, 221))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (102, 107))	('U343MG', 'CellLine', 'CVCL:S471', (246, 252))	('U87MG', 'Var', (254, 259))	('U343MG', 'Var', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('U138MG', 'CellLine', 'CVCL:0020', (261, 267))	('U251MG', 'Var', (272, 278))	('HDPC', 'Gene', '167227', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
223562	33385022	Additionally, we evaluated the impact of CPT-induced replication stress in the transcriptome of two GBM cells, the most resistant (U138MG) and the most sensitive (U251MG) (data not shown), along with non-tumor control cells.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('U138MG', 'Var', (131, 137))	('U138MG', 'CellLine', 'CVCL:0020', (131, 137))	('tumor', 'Disease', (204, 209))	('GBM', 'Phenotype', 'HP:0012174', (100, 103))	('U251MG', 'CellLine', 'CVCL:0021', (163, 169))	('CPT', 'Chemical', 'MESH:D002166', (41, 44))
223568	33385022	However, differences were more pronounced for U138MG (PCC=0.79) than for U251MG (PCC=0.97) cells (Fig.	('U251MG', 'CellLine', 'CVCL:0021', (73, 79))	('U138MG', 'Var', (46, 52))	('U251MG', 'Var', (73, 79))	('U138MG', 'CellLine', 'CVCL:0020', (46, 52))
223569	33385022	2D), 365 down regulated and 494 unregulated genes in U138MG (Fig.	('down regulated', 'NegReg', (9, 23))	('U138MG', 'Var', (53, 59))	('U138MG', 'CellLine', 'CVCL:0020', (53, 59))
223570	33385022	2E) and 21 down regulated and 172 up regulated genes in U251MG (Fig.	('U251MG', 'CellLine', 'CVCL:0021', (56, 62))	('down regulated', 'NegReg', (11, 25))	('up regulated', 'PosReg', (34, 46))	('U251MG', 'Var', (56, 62))
223579	33385022	T98G, U343MG, U87MG, U138MG and U251MG are commercially available GBM cell lines and were obtained from the American Type Culture Collection.	('U251MG', 'CellLine', 'CVCL:0021', (32, 38))	('U251MG', 'Var', (32, 38))	('U138MG', 'Var', (21, 27))	('U343MG', 'Var', (6, 12))	('U343MG', 'CellLine', 'CVCL:S471', (6, 12))	('U138MG', 'CellLine', 'CVCL:0020', (21, 27))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('U87MG', 'CellLine', 'CVCL:0022', (14, 19))	('T98G', 'Var', (0, 4))	('U87MG', 'Var', (14, 19))
223586	33385022	(2) H2AX phosphorylation was also accessed in 9 different time points of CPT-treatment at the IC50 for U251MG and U138MG.	('H2AX', 'Gene', (4, 8))	('CPT', 'Chemical', 'MESH:D002166', (73, 76))	('U251MG', 'CellLine', 'CVCL:0021', (103, 109))	('U251MG', 'Var', (103, 109))	('U138MG', 'CellLine', 'CVCL:0020', (114, 120))	('U138MG', 'Var', (114, 120))	('H2AX', 'Gene', '3014', (4, 8))
223649	29679199	The volume of CE (Fig 2A; 7.5+-6.3 cc vs. 0.2+-0.3 cc, Mann-Whitney, P < 0.00001) and 18F-FDOPA PET T/N SUVmax (Fig 2C; 2.7+-0.9 vs. 1.5+-0.5, P = 0.0002), but not the volume of T2 hyperintensity (Fig 2B; 47.0+-36.0 cc vs. 32.8+-50.7 cc, P = 0.04), were significantly higher in GBM (WHO IV) gliomas compared to lower grade gliomas (WHO I-III), respectively, after Bonferroni correction.	('gliomas', 'Disease', 'MESH:D005910', (323, 330))	('gliomas', 'Phenotype', 'HP:0009733', (323, 330))	('gliomas', 'Disease', (323, 330))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (86, 95))	('gliomas', 'Disease', 'MESH:D005910', (291, 298))	('GBM', 'Var', (278, 281))	('glioma', 'Phenotype', 'HP:0009733', (323, 329))	('gliomas', 'Disease', (291, 298))	('gliomas', 'Phenotype', 'HP:0009733', (291, 298))	('glioma', 'Phenotype', 'HP:0009733', (291, 297))	('higher', 'PosReg', (268, 274))
223655	29679199	Among the 39 patients with available IDH mutation status, the volume of CE was significantly higher (Fig 3A; 3.5+-4.9 cc vs. 0.1+-0.3 cc, Mann-Whitney, P = 0.0001) in IDH wild-type compared with IDH mutant gliomas, respectively; however, no difference in the volume of T2 hyperintensity (Fig 3B; 33.0+-30.8 cc vs. 47.7+-64.9 cc, P = 0.84) or 18F-FDOPA PET T/N SUVmax (Fig 3C; 2.2+-0.9 vs. 1.5+-0.5, P = 0.022) was observed after Bonferroni correction, respectively, although IDH wild-type tumors tended to have a higher 18F-FDOPA uptake.	('type tumors', 'Disease', (484, 495))	('patients', 'Species', '9606', (13, 21))	('IDH', 'Gene', '3417', (195, 198))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (489, 495))	('IDH', 'Gene', (167, 170))	('gliomas', 'Phenotype', 'HP:0009733', (206, 213))	('mutant', 'Var', (199, 205))	('IDH', 'Gene', (475, 478))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('mutation', 'Var', (41, 49))	('higher', 'PosReg', (513, 519))	('higher', 'PosReg', (93, 99))	('type tumors', 'Disease', 'MESH:D009369', (484, 495))	('IDH', 'Gene', '3417', (167, 170))	('IDH', 'Gene', '3417', (475, 478))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (520, 529))	('18F-FDOPA', 'MPA', (342, 351))	('gliomas', 'Disease', (206, 213))	('IDH', 'Gene', (37, 40))	('IDH', 'Gene', (195, 198))	('18F-FDOPA uptake', 'MPA', (520, 536))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (342, 351))	('gliomas', 'Disease', 'MESH:D005910', (206, 213))	('IDH', 'Gene', '3417', (37, 40))
223656	29679199	Among the 33 patients with available MGMT promoter methylation status, no detectable difference in CE volume (Fig 3D; 3.0+-5.0 cc vs. 1.7+-4.0 cc, Mann-Whitney, P = 0.37), volume of T2 hyperintensity (Fig 3E; 40.4+-62.2 cc vs. 45.6+-39.6 cc, P = 0.12), or 18F-FDOPA PET T/N SUVmax (Fig 3F; 2.0+-1.0 vs. 1.8+-0.9, P = 0.66) was observed between MGMT promoter methylated and unmethylated gliomas, respectively.	('gliomas', 'Disease', (386, 393))	('patients', 'Species', '9606', (13, 21))	('gliomas', 'Disease', 'MESH:D005910', (386, 393))	('MGMT', 'Gene', '4255', (344, 348))	('gliomas', 'Phenotype', 'HP:0009733', (386, 393))	('MGMT', 'Gene', (344, 348))	('MGMT', 'Gene', '4255', (37, 41))	('MGMT', 'Gene', (37, 41))	('promoter methylated', 'Var', (349, 368))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (256, 265))	('glioma', 'Phenotype', 'HP:0009733', (386, 392))	('18F-FDOPA PET T/N SUVmax', 'MPA', (256, 280))
223677	29679199	Further studies are needed to confirm these observations, as well as the exploration of 18F-FDOPA uptake among patients with other molecular markers including TP53 mutations and loss of heterozygosity of 1p and 19q.	('loss', 'Var', (178, 182))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (88, 97))	('mutations', 'Var', (164, 173))	('patients', 'Species', '9606', (111, 119))
223700	28912153	BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected.	('FGFR1', 'Gene', (52, 57))	('missense', 'Var', (58, 66))	('TP53', 'Gene', '7157', (125, 129))	('NF1', 'Gene', (84, 87))	('NF1', 'Gene', '4763', (84, 87))	('TP53', 'Gene', (125, 129))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('FGFR1', 'Gene', '2260', (52, 57))	('loss of function', 'NegReg', (88, 104))
223703	28912153	The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157).	('PDGFRA', 'Gene', (129, 135))	('ATRX', 'Gene', (82, 86))	('H3F3A', 'Gene', '3020', (59, 64))	('ATRX', 'Gene', '546', (82, 86))	('H3F3A', 'Gene', (59, 64))	('PDGFRA', 'Gene', '5156', (129, 135))	('mutated', 'Var', (26, 33))	('TP53', 'Gene', '7157', (39, 43))	('NF1', 'Gene', '4763', (104, 107))	('TP53', 'Gene', (39, 43))	('NF1', 'Gene', (104, 107))
223704	28912153	Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M.	('H3F3A', 'Gene', '3020', (20, 25))	('H3F3A', 'Gene', (20, 25))	('K28M', 'Mutation', 'rs1057519903', (68, 72))	('mutations', 'Var', (26, 35))	('K28M', 'Var', (68, 72))
223705	28912153	Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant.	('K28M', 'Mutation', 'rs1057519903', (86, 90))	('Midline tumor', 'Disease', (0, 13))	('H3F3A', 'Gene', (32, 37))	('consisted', 'Reg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('K28M', 'Var', (86, 90))	('Midline tumor', 'Disease', 'MESH:D009369', (0, 13))	('mutations', 'Var', (38, 47))	('H3F3A', 'Gene', '3020', (32, 37))
223707	28912153	Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases).	('POLD1', 'Gene', (190, 195))	('PMS2', 'Gene', (174, 178))	('POLD1', 'Gene', '5424', (190, 195))	('MSH6', 'Gene', (156, 160))	('MSH2', 'Gene', '4436', (162, 166))	('PMS2', 'Gene', '5395', (174, 178))	('TMB', 'Chemical', '-', (48, 51))	('MLH1', 'Gene', '4292', (168, 172))	('MLH1', 'Gene', (168, 172))	('mutations', 'Var', (116, 125))	('MSH2', 'Gene', (162, 166))	('MSH6', 'Gene', '2956', (156, 160))	('pHGG', 'Chemical', '-', (23, 27))
223712	28912153	Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations.	('patients', 'Species', '9606', (47, 55))	('oncogenic fusions', 'CPA', (116, 133))	('mutations', 'Var', (138, 147))
223713	28912153	Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes.	('glioblastomas', 'Phenotype', 'HP:0012174', (106, 119))	('tumor', 'Disease', (14, 19))	('DNA repair', 'Gene', (157, 167))	('glioblastomas', 'Disease', 'MESH:D005909', (106, 119))	('glioblastomas', 'Disease', (106, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutations', 'Var', (144, 153))	('TMB', 'Chemical', '-', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
223719	28912153	Among pLGGs, BRAF alterations are most commonly observed in pilocytic astrocytomas, pleomorphic xanthoastrocytomas (PXA), gangliogliomas, and other glioneuronal lineage tumors [2], [3], [4], [5].	('pleomorphic xanthoastrocytomas', 'Disease', (84, 114))	('gangliogliomas', 'Disease', 'MESH:D018303', (122, 136))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('observed', 'Reg', (48, 56))	('gangliogliomas', 'Disease', (122, 136))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('pilocytic astrocytomas', 'Disease', (60, 82))	('alterations', 'Var', (18, 29))	('astrocytoma', 'Phenotype', 'HP:0009592', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (84, 114))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (60, 82))	('glioneuronal lineage tumors', 'Phenotype', 'HP:0025170', (148, 175))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('tumors', 'Disease', (169, 175))
223720	28912153	Additionally, MYB alterations define subsets of pediatric diffuse gliomas, including MYB-QKI fusions for pediatric angiocentric gliomas [6], [7].	('alterations', 'Var', (18, 29))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('MYB', 'Gene', (14, 17))	('QKI', 'Gene', (89, 92))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('pediatric angiocentric gliomas', 'Disease', 'MESH:D005910', (105, 135))	('MYB', 'Gene', '4602', (85, 88))	('QKI', 'Gene', '9444', (89, 92))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('pediatric angiocentric gliomas', 'Disease', (105, 135))	('MYB', 'Gene', (85, 88))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('MYB', 'Gene', '4602', (14, 17))
223721	28912153	Mutations in histone proteins (H3F3A) reveal the importance and specificity of epigenome alterations in pHGGs [8], [9], [10].	('pHGG', 'Chemical', '-', (104, 108))	('pHGGs', 'Disease', (104, 109))	('H3F3A', 'Gene', '3020', (31, 36))	('Mutations', 'Var', (0, 9))	('H3F3A', 'Gene', (31, 36))
223725	28912153	The value of TMB as an objective biomarker in the setting of pediatric gliomas remains largely unexplored; however, there is increasing optimism that high TMB may be a biomarker to define a subset of pHGGs most likely to respond to checkpoint inhibitors [11], [17].	('TMB', 'MPA', (155, 158))	('TMB', 'Chemical', '-', (155, 158))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('high', 'Var', (150, 154))	('pHGG', 'Chemical', '-', (200, 204))	('pediatric gliomas', 'Disease', (61, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('pediatric gliomas', 'Disease', 'MESH:D005910', (61, 78))	('TMB', 'Chemical', '-', (13, 16))
223729	28912153	Although we recognize that there are differences for naming H3F3A mutations in the literature, in this study, H3F3A variants (H3F3A K28M or G35R/V) align with current Catalogue of Somatic Mutations in Cancer nomenclature, but are equivalent to K27M or G34R/V [18].	('variants', 'Var', (116, 124))	('H3F3A', 'Gene', '3020', (60, 65))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('H3F3A', 'Gene', (60, 65))	('H3F3A', 'Gene', (126, 131))	('K27M', 'SUBSTITUTION', 'None', (244, 248))	('G35R', 'SUBSTITUTION', 'None', (140, 144))	('K28M', 'Var', (132, 136))	('K28M', 'Mutation', 'rs1057519903', (132, 136))	('H3F3A', 'Gene', '3020', (110, 115))	('G34R', 'Mutation', 'rs1057519902', (252, 256))	('G35R', 'Var', (140, 144))	('H3F3A', 'Gene', (110, 115))	('K27M', 'Var', (244, 248))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('Cancer', 'Disease', (201, 207))	('H3F3A', 'Gene', '3020', (126, 131))
223738	28912153	BRAF was the most commonly altered gene, with variants detected in 48.0% (60/125) of cases including 26 base substitutions and 35 gene fusions.	('altered', 'Reg', (27, 34))	('BRAF', 'Gene', '673', (0, 4))	('variants', 'Var', (46, 54))	('BRAF', 'Gene', (0, 4))	('gene fusions', 'Var', (130, 142))	('base substitutions', 'Var', (104, 122))
223740	28912153	Among 46 pilocytic astrocytomas (PAs), 61% (n = 28) harbored KIAA1549-BRAF fusions, whereas 13% (n = 6) tumors harbored BRAF V600E mutations (supplemental online Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('KIAA1549-BRAF', 'Disease', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('V600E', 'Var', (125, 130))	('BRAF', 'Gene', '673', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('pilocytic astrocytomas', 'Disease', (9, 31))	('V600E', 'Mutation', 'rs113488022', (125, 130))	('tumors', 'Disease', (104, 110))	('BRAF', 'Gene', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('KIAA1549-BRAF', 'Disease', 'None', (61, 74))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (9, 31))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
223741	28912153	Interestingly, co-occurring alterations were detected in seven KIAA1549-BRAF PAs, including four with mutations in TP53, ARID1A, MDM4, or BRCA1, and three with CDKN2A/B deletions, and CDK4 or CDK6 amplifications.	('detected', 'Reg', (45, 53))	('CDK4', 'Gene', (184, 188))	('BRCA1', 'Gene', '672', (138, 143))	('CDKN2A/B', 'Gene', '1029;1030', (160, 168))	('KIAA1549-BRAF PAs', 'Disease', (63, 80))	('CDK6', 'Gene', '1021', (192, 196))	('CDK4', 'Gene', '1019', (184, 188))	('TP53', 'Gene', '7157', (115, 119))	('ARID1A', 'Gene', '8289', (121, 127))	('CDK6', 'Gene', (192, 196))	('ARID1A', 'Gene', (121, 127))	('BRCA1', 'Gene', (138, 143))	('mutations', 'Var', (102, 111))	('CDKN2A/B', 'Gene', (160, 168))	('TP53', 'Gene', (115, 119))	('MDM4', 'Gene', '4194', (129, 133))	('KIAA1549-BRAF PAs', 'Disease', 'MESH:D011471', (63, 80))	('MDM4', 'Gene', (129, 133))
223742	28912153	Of the 12 PAs in which BRAF alterations were not detected, 7 harbored FGFR1 alterations, including 1 with a duplication, three FGFR1 N546K, and three FGFR1 K656E variants (supplemental online Fig.	('alterations', 'Var', (76, 87))	('K656E', 'Mutation', 'rs869320694', (156, 161))	('FGFR1', 'Gene', (150, 155))	('N546K', 'Var', (133, 138))	('BRAF', 'Gene', '673', (23, 27))	('FGFR1', 'Gene', '2260', (70, 75))	('BRAF', 'Gene', (23, 27))	('FGFR1', 'Gene', '2260', (150, 155))	('K656E', 'Var', (156, 161))	('FGFR1', 'Gene', (127, 132))	('FGFR1', 'Gene', '2260', (127, 132))	('FGFR1', 'Gene', (70, 75))	('N546K', 'Mutation', 'rs779707422', (133, 138))	('duplication', 'Var', (108, 119))
223743	28912153	The correlation between anatomic location and BRAF or FGFR1 alterations is illustrated in supplemental online Table 4.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('alterations', 'Var', (60, 71))
223744	28912153	Five PAs without BRAF or FGFR1 alterations had mutations in other pediatric glioma-associated genes.	('alterations', 'Var', (31, 42))	('pediatric glioma', 'Disease', 'MESH:D005910', (66, 82))	('BRAF', 'Gene', '673', (17, 21))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('mutations', 'Reg', (47, 56))	('BRAF', 'Gene', (17, 21))	('FGFR1', 'Gene', (25, 30))	('pediatric glioma', 'Disease', (66, 82))	('FGFR1', 'Gene', '2260', (25, 30))
223745	28912153	One tumor harbored a previously reported QKI-RAF1 fusion co-occurring with a NOTCH1 V1575I mutation, whereas an uncharacterized EGFR R222C extracellular domain mutation was the only alteration detected in another PA [7].	('tumor', 'Disease', (4, 9))	('V1575I', 'Mutation', 'p.V1575I', (84, 90))	('NOTCH1', 'Gene', '4851', (77, 83))	('V1575I', 'Var', (84, 90))	('NOTCH1', 'Gene', (77, 83))	('EGFR', 'Gene', '1956', (128, 132))	('QKI', 'Gene', (41, 44))	('EGFR', 'Gene', (128, 132))	('RAF1', 'Gene', (45, 49))	('RAF1', 'Gene', '5894', (45, 49))	('QKI', 'Gene', '9444', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('R222C', 'Mutation', 'p.R222C', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
223746	28912153	NF1 loss-of-function mutations were detected in two PAs, with one tumor reporting a co-occurring PDGFRA A491T mutation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('loss-of-function', 'NegReg', (4, 20))	('A491T', 'Mutation', 'rs563016888', (104, 109))	('PDGFRA', 'Gene', (97, 103))	('PDGFRA', 'Gene', '5156', (97, 103))	('NF1', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('NF1', 'Gene', '4763', (0, 3))	('mutations', 'Var', (21, 30))
223747	28912153	One other PA harbored GLI1 P535S and XRCC2 R258H mutations.	('XRCC2', 'Gene', '7516', (37, 42))	('XRCC2', 'Gene', (37, 42))	('P535S', 'Mutation', 'rs144673003', (27, 32))	('R258H', 'Var', (43, 48))	('GLI1', 'Gene', '2735', (22, 26))	('GLI1', 'Gene', (22, 26))	('R258H', 'Mutation', 'rs149186933', (43, 48))
223748	28912153	Of the 12 diffuse astrocytomas, IDH1 and TP53 mutations were the most frequent alterations, co-occurring in 41.6% (5/12) of cases (supplemental online Fig.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('IDH1', 'Gene', (32, 36))	('astrocytomas', 'Disease', 'MESH:D001254', (18, 30))	('IDH1', 'Gene', '3417', (32, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (18, 29))	('astrocytomas', 'Disease', (18, 30))
223749	28912153	These five IDH1-mutated tumors were from mid-to-late adolescence (ages 15-17) patients with genetics similar to adult diffuse astrocytomas, which frequently harbor co-occurring TP53 and IDH1 mutations [19], [20].	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('astrocytomas', 'Disease', 'MESH:D001254', (126, 138))	('IDH1', 'Gene', (186, 190))	('IDH1', 'Gene', '3417', (11, 15))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('IDH1', 'Gene', '3417', (186, 190))	('mutations', 'Var', (191, 200))	('patients', 'Species', '9606', (78, 86))	('astrocytomas', 'Disease', (126, 138))	('TP53', 'Gene', '7157', (177, 181))	('TP53', 'Gene', (177, 181))	('IDH1', 'Gene', (11, 15))
223750	28912153	Three of these TP53/IDH1-mutated tumors also harbored other mutations, including one tumor with PIK3CA D350H, ACVR1B, and ATRX frameshift mutations, another tumor with a KRAS G13D, and the third tumor with FGFR1 K656E and ALK R1212H mutations.	('IDH1', 'Gene', '3417', (20, 24))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (195, 200))	('ALK', 'Gene', (222, 225))	('ACVR1B', 'Gene', '91', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('KRAS', 'Gene', '3845', (170, 174))	('PIK3CA', 'Gene', '5290', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('G13D', 'Mutation', 'rs112445441', (175, 179))	('KRAS', 'Gene', (170, 174))	('K656E', 'Mutation', 'rs869320694', (212, 217))	('D350H', 'Var', (103, 108))	('TP53', 'Gene', '7157', (15, 19))	('FGFR1', 'Gene', (206, 211))	('ACVR1B', 'Gene', (110, 116))	('tumor', 'Disease', (33, 38))	('R1212H', 'Mutation', 'rs143790259', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('D350H', 'Mutation', 'p.D350H', (103, 108))	('ATRX', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('harbored', 'Reg', (45, 53))	('ATRX', 'Gene', '546', (122, 126))	('PIK3CA', 'Gene', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('K656E', 'Var', (212, 217))	('IDH1', 'Gene', (20, 24))	('FGFR1', 'Gene', '2260', (206, 211))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TP53', 'Gene', (15, 19))	('ALK', 'Gene', '238', (222, 225))	('tumors', 'Disease', (33, 39))	('frameshift mutations', 'Var', (127, 147))
223751	28912153	Of the seven DA2s without IDH1 and TP53 lesions, we detected an FGFR3-TACC3 fusion co-occurring with a PIK3CG D238N mutation in one tumor and another tumor with a CEP85L-ROS1 fusion (supplemental online Fig.	('CEP85L-ROS1', 'Gene', (163, 174))	('FGFR3', 'Gene', (64, 69))	('TP53', 'Gene', '7157', (35, 39))	('IDH1', 'Gene', (26, 30))	('tumor', 'Disease', (132, 137))	('fusion', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('FGFR3', 'Gene', '2261', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PIK3CG', 'Gene', (103, 109))	('D238N', 'Var', (110, 115))	('PIK3CG', 'Gene', '5294', (103, 109))	('IDH1', 'Gene', '3417', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TP53', 'Gene', (35, 39))	('tumor', 'Disease', (150, 155))	('TACC3', 'Gene', '10460', (70, 75))	('TACC3', 'Gene', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('D238N', 'Mutation', 'rs149432307', (110, 115))	('CEP85L-ROS1', 'Gene', '387119;6098', (163, 174))
223752	28912153	Other tumors harbored KRAS Q61H and PIK3R2 Q494* mutations, a KDM5C R179H mutation co-occurring with homozygous TSC2 deletion, NF1 frameshift mutations, or EGFR A289V and PIK3CA H1047R mutations.	('PIK3CA', 'Gene', (171, 177))	('Q61H', 'Mutation', 'rs17851045', (27, 31))	('Q494*', 'Var', (43, 48))	('A289V', 'Mutation', 'rs149840192', (161, 166))	('NF1', 'Gene', (127, 130))	('KRAS', 'Gene', (22, 26))	('KDM5C', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('EGFR', 'Gene', '1956', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('H1047R', 'Var', (178, 184))	('deletion', 'Var', (117, 125))	('H1047R', 'Mutation', 'rs121913279', (178, 184))	('R179H', 'Mutation', 'rs201805773', (68, 73))	('PIK3CA', 'Gene', '5290', (171, 177))	('frameshift mutations', 'Var', (131, 151))	('tumors', 'Disease', (6, 12))	('PIK3R2', 'Gene', (36, 42))	('TSC2', 'Gene', '7249', (112, 116))	('Q494*', 'SUBSTITUTION', 'None', (43, 48))	('KDM5C', 'Gene', '8242', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('EGFR', 'Gene', (156, 160))	('PIK3R2', 'Gene', '5296', (36, 42))	('KRAS', 'Gene', '3845', (22, 26))	('NF1', 'Gene', '4763', (127, 130))	('TSC2', 'Gene', (112, 116))
223753	28912153	Furthermore, our cohort included a hypothalamic DA2 with an H3F3A K28M mutation, which raises the possibility that the tumor may follow a more aggressive clinical course as supported by recent studies.	('H3F3A', 'Gene', '3020', (60, 65))	('tumor', 'Disease', (119, 124))	('hypothalamic', 'Disease', (35, 47))	('H3F3A', 'Gene', (60, 65))	('K28M', 'Var', (66, 70))	('hypothalamic', 'Disease', 'MESH:D007027', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('K28M', 'Mutation', 'rs1057519903', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
223754	28912153	These showed that H3F3A K28M mutations are a negative prognostic factor among midline pLGGs.	('K28M', 'Mutation', 'rs1057519903', (24, 28))	('H3F3A', 'Gene', '3020', (18, 23))	('midline', 'Chemical', '-', (78, 85))	('K28M mutations', 'Var', (24, 38))	('H3F3A', 'Gene', (18, 23))	('midline pLGGs', 'Disease', (78, 91))
223755	28912153	Additionally, in light of this finding, midline infiltrating LGGs harboring H3F3A K28M mutations may be best classified as the newly recognized entity, diffuse midline glioma H3F3A-K28M mutant (WHO grade IV) [10], [21], [22].	('H3F3A', 'Gene', '3020', (175, 180))	('midline', 'Chemical', '-', (40, 47))	('midline', 'Chemical', '-', (160, 167))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('midline glioma', 'Disease', 'MESH:D005910', (160, 174))	('midline glioma', 'Disease', (160, 174))	('H3F3A', 'Gene', (175, 180))	('K28M mutations', 'Var', (82, 96))	('K28M', 'Mutation', 'rs1057519903', (82, 86))	('H3F3A', 'Gene', '3020', (76, 81))	('K28M', 'Mutation', 'rs1057519903', (181, 185))	('mutations', 'Var', (87, 96))	('H3F3A', 'Gene', (76, 81))
223757	28912153	In two cases, one GG and the PXA, the BRAF V600E mutation co-occurred with CDKN2A/B deletions.	('V600E', 'Mutation', 'rs113488022', (43, 48))	('BRAF', 'Gene', '673', (38, 42))	('co-occurred', 'Reg', (58, 69))	('CDKN2A/B', 'Gene', '1029;1030', (75, 83))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (43, 48))	('CDKN2A/B', 'Gene', (75, 83))
223759	28912153	We also identified a GG with an H3F3A K28M mutation co-occurring with an APC I307K and NF1 frameshift mutations.	('NF1', 'Gene', '4763', (87, 90))	('K28M', 'Var', (38, 42))	('H3F3A', 'Gene', (32, 37))	('I307K', 'Mutation', 'p.I307K', (77, 82))	('K28M', 'Mutation', 'rs1057519903', (38, 42))	('H3F3A', 'Gene', '3020', (32, 37))	('NF1', 'Gene', (87, 90))
223760	28912153	Both RFGNTs harbored PIK3CA H1047R mutations, with one tumor harboring co-occurring FGFR1 N546K and BRIP1 A453T mutations (supplemental online Fig.	('FGFR1', 'Gene', (84, 89))	('FGFR1', 'Gene', '2260', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('H1047R', 'Mutation', 'rs121913279', (28, 34))	('A453T', 'Mutation', 'rs587780227', (106, 111))	('BRIP1', 'Gene', '83990', (100, 105))	('N546K', 'Mutation', 'rs779707422', (90, 95))	('PIK3CA', 'Gene', (21, 27))	('tumor', 'Disease', (55, 60))	('H1047R mutations', 'Var', (28, 44))	('mutations', 'Var', (35, 44))	('PIK3CA', 'Gene', '5290', (21, 27))	('BRIP1', 'Gene', (100, 105))
223762	28912153	Of the 12 cases with BRAF lesions, 7 harbored BRAF V600E mutations, with 5 tumors harboring co-occurring mutations including CDKN2A/B deletions, RUNX1 deletion, KEL amplification, ARID1A Q1835* or PRKDC H1613R mutations.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('CDKN2A/B', 'Gene', '1029;1030', (125, 133))	('deletion', 'Var', (151, 159))	('KEL amplification', 'Var', (161, 178))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('Q1835*', 'SUBSTITUTION', 'None', (187, 193))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('RUNX1', 'Gene', (145, 150))	('PRKDC H1613R', 'Gene', (197, 209))	('H1613R', 'Mutation', 'p.H1613R', (203, 209))	('RUNX1', 'Gene', '861', (145, 150))	('Q1835*', 'Var', (187, 193))	('CDKN2A/B', 'Gene', (125, 133))	('BRAF lesions', 'Disease', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ARID1A', 'Gene', (180, 186))	('tumors', 'Disease', (75, 81))	('deletions', 'Var', (134, 143))	('V600E', 'Var', (51, 56))	('BRAF lesions', 'Disease', 'MESH:D051437', (21, 33))	('ARID1A', 'Gene', '8289', (180, 186))
223764	28912153	Two other tumors harbored a BRAF G466V mutation or T599_V600 insertion.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('T599_V600 insertion', 'Var', (51, 70))	('BRAF', 'Gene', '673', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('G466V', 'Mutation', 'rs121913351', (33, 38))	('BRAF', 'Gene', (28, 32))
223766	28912153	The other five tumors reported FGFR1 point mutations, including two with FGFR1 K656E variants and three with FGFR1 N546K variants; four of these tumors harbored co-occurring mutations including PIK3CA, NF1, or PTPN11 mutations.	('variants', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('FGFR1', 'Gene', '2260', (109, 114))	('K656E', 'Mutation', 'rs869320694', (79, 84))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('PIK3CA', 'Gene', (194, 200))	('FGFR1', 'Gene', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('N546K', 'Mutation', 'rs779707422', (115, 120))	('FGFR1', 'Gene', (31, 36))	('NF1', 'Gene', '4763', (202, 205))	('tumors', 'Disease', (15, 21))	('FGFR1', 'Gene', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('PTPN11', 'Gene', (210, 216))	('K656E variants', 'Var', (79, 93))	('NF1', 'Gene', (202, 205))	('PIK3CA', 'Gene', '5290', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('FGFR1', 'Gene', '2260', (73, 78))	('PTPN11', 'Gene', '5781', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('FGFR1', 'Gene', '2260', (31, 36))
223767	28912153	Of the six NF1 mutated pLGG NOS tumors, three harbored co-occurring FGFR1 mutations, and the other three tumors harbored co-occurring MLL3, PTPN11, or ARID1A and CCND2 mutations.	('tumors', 'Disease', (105, 111))	('CCND2', 'Gene', '894', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutated', 'Var', (15, 22))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('PTPN11', 'Gene', (140, 146))	('MLL3', 'Gene', (134, 138))	('FGFR1', 'Gene', '2260', (68, 73))	('PTPN11', 'Gene', '5781', (140, 146))	('NF1', 'Gene', '4763', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('LGG NOS tumors', 'Disease', (24, 38))	('ARID1A', 'Gene', (151, 157))	('NF1', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('FGFR1', 'Gene', (68, 73))	('ARID1A', 'Gene', '8289', (151, 157))	('LGG NOS tumors', 'Disease', 'MESH:D009369', (24, 38))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('MLL3', 'Gene', '58508', (134, 138))	('CCND2', 'Gene', (162, 167))
223769	28912153	For example, in one tumor, we identified a TPM3-NTRK1 fusion co-occurring with CDKN2A/B deletions.	('NTRK1', 'Gene', (48, 53))	('deletions', 'Var', (88, 97))	('CDKN2A/B', 'Gene', (79, 87))	('TPM3', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('NTRK1', 'Gene', '4914', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('CDKN2A/B', 'Gene', '1029;1030', (79, 87))	('TPM3', 'Gene', '7170', (43, 47))	('tumor', 'Disease', (20, 25))
223770	28912153	Another tumor harbored a GOPC-ROS1 fusion with TP53 and PTPN11 mutations.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('GOPC-ROS1', 'Gene', (25, 34))	('PTPN11', 'Gene', '5781', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TP53', 'Gene', '7157', (47, 51))	('PTPN11', 'Gene', (56, 62))	('tumor', 'Disease', (8, 13))	('GOPC-ROS1', 'Gene', '57120;6098', (25, 34))	('TP53', 'Gene', (47, 51))
223771	28912153	In the other seven tumors, we detected DNMT3A and KDM5C, PIK3R1, BRCA2, KRAS, SLIT2, VHL, or ATM and CTNNB1 mutations.	('tumors', 'Disease', (19, 25))	('VHL', 'Gene', (85, 88))	('detected', 'Reg', (30, 38))	('SLIT2', 'Gene', (78, 83))	('CTNNB1', 'Gene', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('BRCA2', 'Gene', '675', (65, 70))	('DNMT3A', 'Gene', '1788', (39, 45))	('ATM', 'Gene', '472', (93, 96))	('KDM5C', 'Gene', '8242', (50, 55))	('PIK3R1', 'Gene', (57, 63))	('VHL', 'Gene', '7428', (85, 88))	('SLIT2', 'Gene', '9353', (78, 83))	('KRAS', 'Gene', '3845', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ATM', 'Gene', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('DNMT3A', 'Gene', (39, 45))	('KRAS', 'Gene', (72, 76))	('mutations', 'Var', (108, 117))	('KDM5C', 'Gene', (50, 55))	('CTNNB1', 'Gene', '1499', (101, 107))	('BRCA2', 'Gene', (65, 70))	('PIK3R1', 'Gene', '5295', (57, 63))
223773	28912153	Of the nine PMAs in our cohort, five harbored FGFR1 alterations, including three with K656E mutations and two with duplications.	('K656E', 'Var', (86, 91))	('alterations', 'Reg', (52, 63))	('K656E', 'Mutation', 'rs869320694', (86, 91))	('FGFR1', 'Gene', (46, 51))	('FGFR1', 'Gene', '2260', (46, 51))
223774	28912153	The other four PMAs harbored BRAF alterations wherein three tumors were V600E positive and the other had a KIAA1549-BRAF fusion co-occurring with EPHB1 V322I mutation.	('BRAF', 'Gene', '673', (29, 33))	('KIAA1549-BRAF', 'Disease', 'None', (107, 120))	('EPHB1', 'Gene', '2047', (146, 151))	('BRAF', 'Gene', (29, 33))	('EPHB1', 'Gene', (146, 151))	('BRAF', 'Gene', '673', (116, 120))	('V600E positive', 'Var', (72, 86))	('BRAF', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('KIAA1549-BRAF', 'Disease', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('V600E', 'Mutation', 'rs113488022', (72, 77))	('V322I mutation', 'Var', (152, 166))	('V322I', 'Mutation', 'rs770155473', (152, 157))	('tumors', 'Disease', (60, 66))
223777	28912153	The fourth tumor harbored IDH1 R132H and CIC p1502fs*12 mutations, which is genomically similar to adult oligodendrogliomas [19].	('CIC p1502fs*12', 'Var', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('adult oligodendrogliomas', 'Disease', 'MESH:D009837', (99, 123))	('adult oligodendrogliomas', 'Disease', (99, 123))	('tumor', 'Disease', (11, 16))	('R132H', 'Mutation', 'rs121913500', (31, 36))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('IDH1', 'Gene', (26, 30))	('IDH1', 'Gene', '3417', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
223778	28912153	In the two DNETs, a DNMT3A splice site mutation was detected in one tumor and an FGFR1 K656E mutation with SOX2 amplification in the other.	('tumor', 'Disease', (68, 73))	('SOX2', 'Gene', (107, 111))	('FGFR1', 'Gene', (81, 86))	('SOX2', 'Gene', '6657', (107, 111))	('DNMT3A', 'Gene', (20, 26))	('FGFR1', 'Gene', '2260', (81, 86))	('DNMT3A', 'Gene', '1788', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('K656E', 'Mutation', 'rs869320694', (87, 92))	('K656E', 'Var', (87, 92))
223779	28912153	Both RFGNTs harbored PIK3CA H1047R mutations, with one of the tumors reporting co-occurring FGFR1 N546K and BRIP1 A453T mutations.	('FGFR1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BRIP1', 'Gene', (108, 113))	('H1047R', 'Mutation', 'rs121913279', (28, 34))	('FGFR1', 'Gene', '2260', (92, 97))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('PIK3CA', 'Gene', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('BRIP1', 'Gene', '83990', (108, 113))	('H1047R mutations', 'Var', (28, 44))	('A453T', 'Mutation', 'rs587780227', (114, 119))	('PIK3CA', 'Gene', '5290', (21, 27))	('A453T', 'Var', (114, 119))	('N546K', 'Mutation', 'rs779707422', (98, 103))	('N546K', 'Var', (98, 103))
223780	28912153	In the DIPG (G2), PGNT, PXA (G2), and DOLT a KIAA1549-BRAF fusion, FGFR1 N546K and PIK3R1 F456_Q457del, BRAF V600E, CDKN2A/B deletions, or KIAA1549-BRAF and SMAD4 P295I alterations, were identified, respectively (Fig.	('KIAA1549-BRAF', 'Disease', 'None', (139, 152))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('CDKN2A/B', 'Gene', '1029;1030', (116, 124))	('SMAD4', 'Gene', (157, 162))	('P295I', 'Mutation', 'p.P295I', (163, 168))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('FGFR1', 'Gene', '2260', (67, 72))	('Q457del', 'Mutation', 'p.457delQ', (95, 102))	('PGNT', 'Chemical', '-', (18, 22))	('PIK3R1', 'Gene', (83, 89))	('N546K', 'Var', (73, 78))	('BRAF', 'Gene', '673', (148, 152))	('V600E', 'Var', (109, 114))	('BRAF', 'Gene', (148, 152))	('DIPG', 'Chemical', 'MESH:C060938', (7, 11))	('P295I', 'Var', (163, 168))	('KIAA1549-BRAF', 'Disease', (45, 58))	('KIAA1549-BRAF', 'Disease', (139, 152))	('CDKN2A/B', 'Gene', (116, 124))	('FGFR1', 'Gene', (67, 72))	('F456_Q457del', 'Var', (90, 102))	('PIK3R1', 'Gene', '5295', (83, 89))	('N546K', 'Mutation', 'rs779707422', (73, 78))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))	('KIAA1549-BRAF', 'Disease', 'None', (45, 58))
223785	28912153	Other frequently altered genes included H3F3A mutations in 37.6% (59/157), NF1 loss of function mutations in 24.2% (38/157), ATRX loss of function mutations in 22.2% (35/157), and PDGFRA alterations in 21.7% (34/157) of pHGGs (Fig.	('H3F3A', 'Gene', '3020', (40, 45))	('mutations', 'Var', (147, 156))	('ATRX', 'Gene', '546', (125, 129))	('loss of function', 'NegReg', (130, 146))	('H3F3A', 'Gene', (40, 45))	('mutations', 'Var', (46, 55))	('pHGG', 'Chemical', '-', (220, 224))	('PDGFRA', 'Gene', (180, 186))	('NF1', 'Gene', (75, 78))	('PDGFRA', 'Gene', '5156', (180, 186))	('loss of function', 'NegReg', (79, 95))	('alterations', 'Var', (187, 198))	('NF1', 'Gene', '4763', (75, 78))	('ATRX', 'Gene', (125, 129))	('mutations', 'Var', (96, 105))
223786	28912153	In our cohort of 90 GBMs, TP53 was mutated in 62.2% (56/90) of cases, and H3F3A alterations were detected in 47.8% (43/90) of cases (Fig.	('TP53', 'Gene', (26, 30))	('mutated', 'Var', (35, 42))	('H3F3A', 'Gene', (74, 79))	('GBM', 'Phenotype', 'HP:0012174', (20, 23))	('H3F3A', 'Gene', '3020', (74, 79))	('TP53', 'Gene', '7157', (26, 30))
223787	28912153	Interestingly, the vast majority (81.4%, 35/43) of H3F3A mutations were the K28M variant, compared with 18.6% (8/43) being G35R variants.	('K28M', 'Mutation', 'rs1057519903', (76, 80))	('G35R', 'Mutation', 'p.G35R', (123, 127))	('H3F3A', 'Gene', '3020', (51, 56))	('K28M', 'Var', (76, 80))	('mutations', 'Var', (57, 66))	('H3F3A', 'Gene', (51, 56))
223788	28912153	Although frequent in pLGGs, only five pediatric glioblastoma (pGBM)s harbored BRAF V600E mutations, and of these tumors, four harbored co-occurring H3F3A K28M mutations.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('K28M', 'Var', (154, 158))	('BRAF', 'Gene', '673', (78, 82))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('BRAF', 'Gene', (78, 82))	('H3F3A', 'Gene', '3020', (148, 153))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('pediatric glioblastoma', 'Disease', (38, 60))	('K28M', 'Mutation', 'rs1057519903', (154, 158))	('H3F3A', 'Gene', (148, 153))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (38, 60))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
223789	28912153	Unlike adult GBM, alterations in EGFR, PTEN, CDKN2A, and CDNK2B were only observed in 7.8% (7/90), 15.6% (14/90), 20% (18/90), and 15.6% (14/90) of pediatric GBMs, respectively [23], [24].	('PTEN', 'Gene', '5728', (39, 43))	('alterations', 'Var', (18, 29))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('CDNK2B', 'Gene', (57, 63))	('EGFR', 'Gene', '1956', (33, 37))	('PTEN', 'Gene', (39, 43))	('EGFR', 'Gene', (33, 37))	('CDKN2A', 'Gene', (45, 51))	('CDKN2A', 'Gene', '1029', (45, 51))
223790	28912153	However, PDGFRA alterations, including point mutations and amplifications, were observed in 25.6% (23/90) of cases, which is nearly twice the rate observed in adult GBMs (15%; Fig.	('point mutations', 'Var', (39, 54))	('observed', 'Reg', (80, 88))	('alterations', 'Var', (16, 27))	('PDGFRA', 'Gene', (9, 15))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('amplifications', 'Var', (59, 73))	('PDGFRA', 'Gene', '5156', (9, 15))
223791	28912153	Anaplastic astrocytomas showed frequent EGFR alterations (mutations and amplifications), TP53 mutations, and PIK3CA mutations at rates of 40.7% (11/27), 33.3% (9/27), and 18.5% (5/27), respectively (Fig.	('alterations', 'Var', (45, 56))	('TP53', 'Gene', '7157', (89, 93))	('PIK3CA', 'Gene', (109, 115))	('TP53', 'Gene', (89, 93))	('Anaplastic astrocytomas', 'Disease', 'MESH:D001254', (0, 23))	('mutations', 'Var', (94, 103))	('PIK3CA', 'Gene', '5290', (109, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (11, 22))	('EGFR', 'Gene', '1956', (40, 44))	('mutations', 'Var', (116, 125))	('EGFR', 'Gene', (40, 44))	('Anaplastic astrocytomas', 'Disease', (0, 23))
223793	28912153	Four anaplastic astrocytomas (AAs) also harbored H3F3A K28M mutations that co-occurred with PIK3R1, FGFR1 and ATRX, PIK3CA and NF1, or TP53 mutations.	('PIK3CA', 'Gene', (116, 122))	('H3F3A', 'Gene', '3020', (49, 54))	('NF1', 'Gene', (127, 130))	('K28M', 'Mutation', 'rs1057519903', (55, 59))	('FGFR1', 'Gene', '2260', (100, 105))	('mutations', 'Var', (60, 69))	('TP53', 'Gene', '7157', (135, 139))	('astrocytomas', 'Disease', 'MESH:D001254', (16, 28))	('PIK3R1', 'Gene', '5295', (92, 98))	('astrocytoma', 'Phenotype', 'HP:0009592', (16, 27))	('H3F3A', 'Gene', (49, 54))	('co-occurred', 'Reg', (75, 86))	('PIK3CA', 'Gene', '5290', (116, 122))	('FGFR1', 'Gene', (100, 105))	('K28M mutations', 'Var', (55, 69))	('ATRX', 'Gene', (110, 114))	('TP53', 'Gene', (135, 139))	('ATRX', 'Gene', '546', (110, 114))	('NF1', 'Gene', '4763', (127, 130))	('PIK3R1', 'Gene', (92, 98))	('astrocytomas', 'Disease', (16, 28))
223794	28912153	In the pHGG NOS cohort, H3F3A was altered in 23.1% (6/26) of cases, all of which were the K28M variant (Fig.	('altered', 'Reg', (34, 41))	('K28M', 'Mutation', 'rs1057519903', (90, 94))	('H3F3A', 'Gene', '3020', (24, 29))	('pHGG', 'Chemical', '-', (7, 11))	('K28M', 'Var', (90, 94))	('H3F3A', 'Gene', (24, 29))
223795	28912153	NF1 and TP53 alterations were also frequent in pHGG NOS; they were detected in 23.1% (6/26) of tumors, co-occurring in five of the six cases.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('alterations', 'Var', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('detected', 'Reg', (67, 75))	('pHGG NOS', 'Disease', (47, 55))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('NF1', 'Gene', (0, 3))	('pHGG', 'Chemical', '-', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NF1', 'Gene', '4763', (0, 3))	('tumors', 'Disease', (95, 101))
223796	28912153	NF1 alterations were predominately loss of function mutations (5/6 cases), with one tumor harboring a homozygous NF1 deletion.	('mutations', 'Var', (52, 61))	('alterations', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('loss', 'NegReg', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NF1', 'Gene', (113, 116))	('tumor', 'Disease', (84, 89))	('NF1', 'Gene', '4763', (113, 116))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
223797	28912153	FGFR1 (19.2%, 5/26) and PDGFRA (19.2%, 5/26) alterations were also prevalent in pHGG NOS tumors.	('PDGFRA', 'Gene', '5156', (24, 30))	('alterations', 'Var', (45, 56))	('PDGFRA', 'Gene', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('NOS tumors', 'Disease', 'MESH:D009369', (85, 95))	('prevalent', 'Reg', (67, 76))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('pHGG', 'Chemical', '-', (80, 84))	('NOS tumors', 'Disease', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
223798	28912153	Three of five FGFR1 mutated tumors harbored N546K variants co-occurring with other mutations including CDKN2A/B deletions, PIK3CA H1047R or H3F3A K28M mutations.	('tumors', 'Disease', (28, 34))	('PIK3CA', 'Gene', (123, 129))	('H1047R', 'Var', (130, 136))	('H3F3A', 'Gene', (140, 145))	('FGFR1', 'Gene', (14, 19))	('CDKN2A/B', 'Gene', (103, 111))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('PIK3CA', 'Gene', '5290', (123, 129))	('K28M', 'Mutation', 'rs1057519903', (146, 150))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('FGFR1', 'Gene', '2260', (14, 19))	('H1047R', 'Mutation', 'rs121913279', (130, 136))	('N546K', 'Mutation', 'rs779707422', (44, 49))	('N546K', 'Var', (44, 49))	('CDKN2A/B', 'Gene', '1029;1030', (103, 111))	('H3F3A', 'Gene', '3020', (140, 145))
223799	28912153	Of the five PDGFRA altered tumors, four reported amplifications and three of these tumors harbored co-occurring CDKN2A/B deletions (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('altered tumors', 'Disease', 'MESH:D009369', (19, 33))	('tumors', 'Disease', (83, 89))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('CDKN2A/B', 'Gene', '1029;1030', (112, 120))	('PDGFRA', 'Gene', (12, 18))	('deletions', 'Var', (121, 130))	('altered tumors', 'Disease', (19, 33))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('PDGFRA', 'Gene', '5156', (12, 18))	('CDKN2A/B', 'Gene', (112, 120))
223800	28912153	Among high-grade DIPGs, H3F3A mutations were detected in 66.7% (6/9) of cases, with these cases reporting only the K28M variant (Fig.	('detected', 'Reg', (45, 53))	('K28M', 'Mutation', 'rs1057519903', (115, 119))	('H3F3A', 'Gene', '3020', (24, 29))	('mutations', 'Var', (30, 39))	('H3F3A', 'Gene', (24, 29))	('K28M', 'Var', (115, 119))	('DIPG', 'Chemical', 'MESH:C060938', (17, 21))
223801	28912153	In the H3F3A mutated DIPGs, four harbored co-occurring TP53 mutations and the other two tumors harbored PTPN11 and TERT mutations or CDKN2C deletion and PIK3R1 mutations.	('mutations', 'Var', (160, 169))	('PTPN11', 'Gene', '5781', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutated', 'Var', (13, 20))	('TP53', 'Gene', '7157', (55, 59))	('H3F3A', 'Gene', '3020', (7, 12))	('mutations', 'Var', (60, 69))	('PIK3R1', 'Gene', (153, 159))	('DIPG', 'Chemical', 'MESH:C060938', (21, 25))	('TERT', 'Gene', (115, 119))	('TERT', 'Gene', '7015', (115, 119))	('CDKN2C', 'Gene', (133, 139))	('H3F3A', 'Gene', (7, 12))	('deletion', 'Var', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('TP53', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('PTPN11', 'Gene', (104, 110))	('PIK3R1', 'Gene', '5295', (153, 159))	('CDKN2C', 'Gene', '1031', (133, 139))	('tumors', 'Disease', (88, 94))
223802	28912153	The three cases without H3F3A alterations reported only a TERT promoter -124C>T, PDGFRA D842del, or no reportable mutations, respectively.	('D842del', 'Mutation', 'p.842delD', (88, 95))	('H3F3A', 'Gene', '3020', (24, 29))	('H3F3A', 'Gene', (24, 29))	('TERT', 'Gene', (58, 62))	('TERT', 'Gene', '7015', (58, 62))	('PDGFRA', 'Gene', (81, 87))	('D842del', 'Var', (88, 95))	('PDGFRA', 'Gene', '5156', (81, 87))	('-124C>T', 'Mutation', 'rs1242535815', (72, 79))
223803	28912153	The six anaplastic PXAs in our cohort reported a spectrum of mutations: one tumor harbored a BRAF V600E mutation with CDKN2A/B deletions and a TERT promoter mutation, whereas in the other PXAs, only TP53 S183*, PIK3CA G118D, TSC2 Y1033fs*1, RB1 E672fs*5, or RB1 T140fs*5 and TP53 F109fs*14 mutations were detected.	('TP53', 'Gene', (275, 279))	('tumor', 'Disease', (76, 81))	('T140fs', 'Mutation', 'p.T140fsX', (262, 268))	('S183*', 'Var', (204, 209))	('TP53', 'Gene', '7157', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('PIK3CA', 'Gene', (211, 217))	('CDKN2A/B', 'Gene', (118, 126))	('S183*', 'SUBSTITUTION', 'None', (204, 209))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('TSC2', 'Gene', '7249', (225, 229))	('BRAF', 'Gene', '673', (93, 97))	('RB1', 'Gene', (241, 244))	('TP53', 'Gene', '7157', (275, 279))	('BRAF', 'Gene', (93, 97))	('RB1', 'Gene', (258, 261))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('G118D', 'Mutation', 'rs587777790', (218, 223))	('TSC2', 'Gene', (225, 229))	('E672fs', 'Mutation', 'rs1131690885', (245, 251))	('CDKN2A/B', 'Gene', '1029;1030', (118, 126))	('E672fs*5', 'Var', (245, 253))	('TERT', 'Gene', (143, 147))	('PIK3CA', 'Gene', '5290', (211, 217))	('TP53', 'Gene', (199, 203))	('RB1', 'Gene', '5925', (258, 261))	('RB1', 'Gene', '5925', (241, 244))	('TERT', 'Gene', '7015', (143, 147))	('deletions', 'Var', (127, 136))	('F109fs*14', 'Var', (280, 289))
223804	28912153	Contrary to adult oligodendrogliomas, the one anaplastic oligodendroglioma in our cohort did not harbor IDH1/2 mutations or 1p/19q co-deletion [19], [22], [26].	('adult oligodendrogliomas', 'Disease', 'MESH:D009837', (12, 36))	('adult oligodendrogliomas', 'Disease', (12, 36))	('mutations', 'Var', (111, 120))	('oligodendroglioma', 'Disease', (18, 35))	('oligodendroglioma', 'Disease', 'MESH:D009837', (57, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('oligodendroglioma', 'Disease', 'MESH:D009837', (18, 35))	('IDH1/2', 'Gene', '3417;3418', (104, 110))	('oligodendroglioma', 'Disease', (57, 74))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('IDH1/2', 'Gene', (104, 110))
223805	28912153	We detected KRAS G12V, EGFR R222C, and TERT promoter -124C>T mutations, a genomic signature that better aligns with an astrocytic lineage glioma.	('TERT', 'Gene', (39, 43))	('R222C', 'Mutation', 'p.R222C', (28, 33))	('astrocytic lineage glioma', 'Disease', (119, 144))	('G12V', 'SUBSTITUTION', 'None', (17, 21))	('TERT', 'Gene', '7015', (39, 43))	('-124C>T', 'Mutation', 'rs1242535815', (53, 60))	('G12V', 'Var', (17, 21))	('KRAS', 'Gene', (12, 16))	('EGFR', 'Gene', '1956', (23, 27))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('KRAS', 'Gene', '3845', (12, 16))	('EGFR', 'Gene', (23, 27))	('astrocytic lineage glioma', 'Disease', 'MESH:D001254', (119, 144))
223806	28912153	Of the less prevalent histologic subtypes, one anaplastic ganglioglioma harbored a BRAF V600E mutation with a co-occurring CDKN2A/B deletion.	('glioma', 'Disease', (65, 71))	('V600E', 'Mutation', 'rs113488022', (88, 93))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('CDKN2A/B', 'Gene', '1029;1030', (123, 131))	('V600E', 'Var', (88, 93))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('CDKN2A/B', 'Gene', (123, 131))
223812	28912153	Overall, H3F3A was the most commonly altered gene in midline tumors, altered in 40% of cases, with the K28M variant detected in all 40 mutated cases (supplemental online Figure 2A).	('midline tumors', 'Disease', (53, 67))	('midline tumors', 'Disease', 'MESH:D009369', (53, 67))	('altered', 'Reg', (69, 76))	('K28M', 'Var', (103, 107))	('H3F3A', 'Gene', '3020', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('K28M', 'Mutation', 'rs1057519903', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('altered', 'Reg', (37, 44))	('H3F3A', 'Gene', (9, 14))
223813	28912153	TP53 mutations were detected in 28% (28/100) of cases, and among these, 20 harbored co-occurring H3F3A K28M mutations.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('H3F3A', 'Gene', '3020', (97, 102))	('K28M mutations', 'Var', (103, 117))	('K28M', 'Mutation', 'rs1057519903', (103, 107))	('H3F3A', 'Gene', (97, 102))
223814	28912153	Interestingly, BRAF alterations occurred in 25% (25/100) of midline gliomas, with 12 tumors harboring KIAA1549-BRAF fusions and 11 tumors with BRAF V600E mutations.	('V600E', 'Mutation', 'rs113488022', (148, 153))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('KIAA1549-BRAF', 'Disease', (102, 115))	('alterations', 'Var', (20, 31))	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('V600E', 'Var', (148, 153))	('midline gliomas', 'Disease', (60, 75))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('KIAA1549-BRAF', 'Disease', 'None', (102, 115))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('midline gliomas', 'Disease', 'MESH:D005910', (60, 75))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
223818	28912153	Among 27 thalamic pHGGs, H3F3A mutations were detected in 66.7% (n = 18) of tumors and entirely consisted of the K28M variant (Fig.	('mutations', 'Var', (31, 40))	('consisted', 'Reg', (96, 105))	('pHGG', 'Chemical', '-', (18, 22))	('H3F3A', 'Gene', '3020', (25, 30))	('K28M', 'Mutation', 'rs1057519903', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('H3F3A', 'Gene', (25, 30))	('K28M', 'Var', (113, 117))
223821	28912153	Twenty-four of the BRAF-altered nonmidline gliomas harbored fusions, 24 others had BRAF V600E mutations, and 2 tumors had BRAF S605G or D594G mutations.	('midline gliomas', 'Disease', 'MESH:D005910', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('fusions', 'Var', (60, 67))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('midline gliomas', 'Disease', (35, 50))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('V600E mutations', 'Var', (88, 103))	('V600E', 'Mutation', 'rs113488022', (88, 93))	('BRAF', 'Gene', '673', (83, 87))	('D594G', 'Mutation', 'rs121913338', (136, 141))	('BRAF', 'Gene', (83, 87))	('S605G', 'Mutation', 'p.S605G', (127, 132))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (19, 23))	('D594G', 'Var', (136, 141))	('harbored', 'Reg', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('BRAF', 'Gene', (122, 126))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))
223822	28912153	In nonmidline tumors, H3F3A mutations were detected in 12.1% (22/182) of cases, including 14 K28M and 8 G35R/V variants.	('H3F3A', 'Gene', (22, 27))	('G35R', 'SUBSTITUTION', 'None', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('K28M', 'Var', (93, 97))	('detected', 'Reg', (43, 51))	('nonmidline tumors', 'Disease', (3, 20))	('nonmidline tumors', 'Disease', 'MESH:D009369', (3, 20))	('H3F3A', 'Gene', '3020', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('K28M', 'Mutation', 'rs1057519903', (93, 97))	('G35R', 'Var', (104, 108))
223823	28912153	Gene fusions were most common among pLGGs, with 35.2% (44/125) of tumors harboring an in-frame fusion.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Gene fusions', 'Var', (0, 12))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('common', 'Reg', (23, 29))	('pLGGs', 'Disease', (36, 41))
223826	28912153	Fourteen of these contained the first 15 exons of KIAA1549 fused to exons 9-18 of BRAF, 6 involved the first 16 exons of KIAA1549 fused to exons 9-18 of BRAF, 2 with exons 1-16 of KIAA1549 fused to exons 11-18 of BRAF, 9 consisted of exons 1-6 of KIAA1549 fused to exons 9-18 of BRAF, 1 consisted of exons 1-12 of KIAA1549 fused to exons 10-18 of BRAF, and 1 contained exons 1-13 of KIAA1549 fused to exons 11-18 of BRAF.	('BRAF', 'Gene', (153, 157))	('KIAA1549', 'Gene', '57670', (180, 188))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('KIAA1549', 'Gene', (180, 188))	('KIAA1549', 'Gene', '57670', (314, 322))	('BRAF', 'Gene', '673', (347, 351))	('BRAF', 'Gene', (347, 351))	('KIAA1549', 'Gene', '57670', (50, 58))	('KIAA1549', 'Gene', '57670', (247, 255))	('KIAA1549', 'Gene', '57670', (121, 129))	('KIAA1549', 'Gene', (383, 391))	('fused', 'Var', (130, 135))	('KIAA1549', 'Gene', (314, 322))	('KIAA1549', 'Gene', '57670', (383, 391))	('KIAA1549', 'Gene', (50, 58))	('BRAF', 'Gene', '673', (82, 86))	('KIAA1549', 'Gene', (247, 255))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', '673', (279, 283))	('BRAF', 'Gene', '673', (416, 420))	('KIAA1549', 'Gene', (121, 129))	('BRAF', 'Gene', (279, 283))	('BRAF', 'Gene', (416, 420))	('BRAF, 1', 'Gene', '673', (279, 286))	('BRAF', 'Gene', '673', (153, 157))
223829	28912153	Three FGFR3-TACC3 fusions were detected among pLGGs, including one diffuse astrocytoma, WHO grade II (DA), one oligodendroglioma, WHO Grade II (OG), and one pLGG NOS (Fig.	('detected', 'Reg', (31, 39))	('FGFR3', 'Gene', '2261', (6, 11))	('fusions', 'Var', (18, 25))	('oligodendroglioma', 'Disease', (111, 128))	('FGFR3', 'Gene', (6, 11))	('astrocytoma', 'Disease', 'MESH:D001254', (75, 86))	('TACC3', 'Gene', '10460', (12, 17))	('astrocytoma', 'Disease', (75, 86))	('oligodendroglioma', 'Disease', 'MESH:D009837', (111, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('TACC3', 'Gene', (12, 17))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
223832	28912153	The first was an FGFR2-PASD1 fusion detected in an OG that consisted of exons 1-17 of FGFR2 fused to exons 10-16 of PASD1, and the second was an FGFR2-INA fusion detected in a pLGG NOS that consisted of exons 1-17 of FGFR2 fused to exons 2-3 of INA.	('FGFR2', 'Gene', (17, 22))	('FGFR2', 'Gene', '2263', (17, 22))	('FGFR2', 'Gene', (86, 91))	('FGFR2', 'Gene', (145, 150))	('PASD1', 'Gene', (23, 28))	('FGFR2', 'Gene', '2263', (86, 91))	('PASD1', 'Gene', '139135', (23, 28))	('FGFR2', 'Gene', '2263', (217, 222))	('FGFR2', 'Gene', '2263', (145, 150))	('PASD1', 'Gene', (116, 121))	('fused', 'Var', (92, 97))	('PASD1', 'Gene', '139135', (116, 121))	('fusion', 'Var', (29, 35))	('FGFR2', 'Gene', (217, 222))
223833	28912153	Additionally, two in-frame QKI-RAF1 fusions were detected in one OG and a recurrent PA (Fig.	('QKI', 'Gene', (27, 30))	('fusions', 'Var', (36, 43))	('QKI', 'Gene', '9444', (27, 30))	('RAF1', 'Gene', '5894', (31, 35))	('RAF1', 'Gene', (31, 35))
223836	28912153	Although the fusion partner differed, both consisted of exons 35-43 of ROS1 (Fig.	('exons 35-43', 'Var', (56, 67))	('ROS1', 'Gene', '6098', (71, 75))	('consisted', 'Reg', (43, 52))	('ROS1', 'Gene', (71, 75))
223840	28912153	In the second case, an in-frame DGKB-ETV1 fusion was identified in a GBM and consisted of the first 22 DGKB exons fused to exons 7-14 of ETV1.	('ETV1', 'Gene', '2115', (37, 41))	('DGKB', 'Gene', (32, 36))	('DGKB', 'Gene', '1607', (32, 36))	('ETV1', 'Gene', '2115', (137, 141))	('fusion', 'Var', (42, 48))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('DGKB', 'Gene', (103, 107))	('DGKB', 'Gene', '1607', (103, 107))	('ETV1', 'Gene', (137, 141))	('ETV1', 'Gene', (37, 41))
223843	28912153	Lastly, an EWSR1-PATZ1 fusion was identified in a pHGG NOS, which comprised exons 1-9 of EWSR1 fused to exons 1-5 of PATZ1.	('EWSR1', 'Gene', (11, 16))	('fusion', 'Var', (23, 29))	('PATZ1', 'Gene', (17, 22))	('EWSR1', 'Gene', '2130', (89, 94))	('PATZ1', 'Gene', (117, 122))	('EWSR1', 'Gene', '2130', (11, 16))	('PATZ1', 'Gene', '23598', (117, 122))	('PATZ1', 'Gene', '23598', (17, 22))	('pHGG', 'Chemical', '-', (50, 54))	('EWSR1', 'Gene', (89, 94))
223845	28912153	In pLGGs, TMBs ranged from <1 to 758, with a median of 0.9 mutations per Mb (Fig.	('pLGGs', 'Gene', (3, 8))	('TMB', 'Chemical', '-', (10, 13))	('mutations', 'Var', (59, 68))
223849	28912153	Although TP53 mutations were the most frequent alteration across all pHGGs, H3F3A mutations were exclusive to tumors with low and intermediate TMBs (Fig.	('TMB', 'Chemical', '-', (143, 146))	('pHGG', 'Chemical', '-', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('TP53', 'Gene', '7157', (9, 13))	('tumors', 'Disease', (110, 116))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('H3F3A', 'Gene', '3020', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('frequent', 'Reg', (38, 46))	('mutations', 'Var', (14, 23))	('H3F3A', 'Gene', (76, 81))
223850	28912153	The average TMB of H3F3A mutated pHGGs was 1.8 mutations per Mb and ranged from <1 to 17.1, highlighting that these mutations are mutually exclusive from hypermutated pHGGs in our dataset.	('H3F3A', 'Gene', (19, 24))	('TMB', 'Chemical', '-', (12, 15))	('pHGG', 'Chemical', '-', (33, 37))	('pHGGs', 'Gene', (33, 38))	('H3F3A', 'Gene', '3020', (19, 24))	('pHGG', 'Chemical', '-', (167, 171))	('mutated', 'Var', (25, 32))
223851	28912153	The remaining 6% (9/157) of pHGGs were classified as hypermutated, with TMBs ranging from 43-575 mutations per Mb, and all harbored mutations in TP53 (100%, 9/9), NF1 (88.9%, 8/9), SETD2 (66.7%, 6/9), and ATRX (66.7%, 6/9; Fig.	('NF1', 'Gene', (163, 166))	('NF1', 'Gene', '4763', (163, 166))	('harbored', 'Reg', (123, 131))	('pHGG', 'Chemical', '-', (28, 32))	('mutations', 'Var', (132, 141))	('SETD2', 'Gene', '29072', (181, 186))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('SETD2', 'Gene', (181, 186))	('TMB', 'Chemical', '-', (72, 75))	('ATRX', 'Gene', (205, 209))	('ATRX', 'Gene', '546', (205, 209))
223852	28912153	Among the nine pHGGs (four newly diagnosed, five recurrent) with a high TMB, six harbored functional mutations in mismatch repair (MMR) or proofreading genes MSH2, MSH6, MLH1, POLE, PMS2, or POLD1 (Table 1), whereas the other three tumors harbored variants of unknown significance in these MMR genes.	('mutations', 'Var', (101, 110))	('MSH2', 'Gene', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('MSH6', 'Gene', '2956', (164, 168))	('PMS2', 'Gene', (182, 186))	('POLD1', 'Gene', (191, 196))	('POLD1', 'Gene', '5424', (191, 196))	('MSH2', 'Gene', '4436', (158, 162))	('PMS2', 'Gene', '5395', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('TMB', 'Chemical', '-', (72, 75))	('pHGG', 'Chemical', '-', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('MLH1', 'Gene', '4292', (170, 174))	('MSH6', 'Gene', (164, 168))	('MLH1', 'Gene', (170, 174))	('tumors', 'Disease', (232, 238))
223855	28912153	Among pLGGs, the most common alterations were BRAF alterations, followed by FGFR1 lesions, whereas in pHGGs, TP53 and H3F3A mutations dominated the genomic landscape.	('BRAF', 'Gene', (46, 50))	('alterations', 'Var', (51, 62))	('BRAF', 'Gene', '673', (46, 50))	('pHGG', 'Chemical', '-', (102, 106))	('TP53', 'Gene', '7157', (109, 113))	('H3F3A', 'Gene', '3020', (118, 123))	('TP53', 'Gene', (109, 113))	('FGFR1', 'Gene', (76, 81))	('FGFR1', 'Gene', '2260', (76, 81))	('H3F3A', 'Gene', (118, 123))
223856	28912153	Surprisingly, in our pHGG cohort, the H3F3A K28M variant (n = 51) was most prevalent, with only 8 of 59 pGBM cases with H3F3A mutations reporting a G35R variant; midline tumors also enriched for K28M variant.	('G35R', 'Var', (148, 152))	('pHGG', 'Chemical', '-', (21, 25))	('H3F3A', 'Gene', '3020', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('H3F3A', 'Gene', (120, 125))	('H3F3A', 'Gene', (38, 43))	('K28M', 'Mutation', 'rs1057519903', (44, 48))	('G35R', 'Mutation', 'p.G35R', (148, 152))	('midline tumors', 'Disease', (162, 176))	('K28M', 'Mutation', 'rs1057519903', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (126, 135))	('K28M', 'Var', (44, 48))	('midline tumors', 'Disease', 'MESH:D009369', (162, 176))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))	('H3F3A', 'Gene', '3020', (120, 125))
223857	28912153	Additionally, only the K28M variant was detected in pLGGs harboring H3F3A mutations.	('H3F3A', 'Gene', '3020', (68, 73))	('K28M', 'Mutation', 'rs1057519903', (23, 27))	('mutations', 'Var', (74, 83))	('H3F3A', 'Gene', (68, 73))	('K28M', 'Var', (23, 27))
223858	28912153	The presence of H3F3A mutations in pLGGs has significant clinical impact because previous reports demonstrated that the prognosis for K28M mutated gliomas is worse compared with G34R and wild-type H3F3A cases [10], [21], [22].	('H3F3A', 'Gene', (16, 21))	('G34R', 'Mutation', 'rs1057519902', (178, 182))	('H3F3A', 'Gene', (197, 202))	('K28M mutated', 'Var', (134, 146))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('pLGGs', 'Gene', (35, 40))	('K28M', 'Mutation', 'rs1057519903', (134, 138))	('gliomas', 'Disease', (147, 154))	('H3F3A', 'Gene', '3020', (16, 21))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('H3F3A', 'Gene', '3020', (197, 202))
223860	28912153	We report EML4-ALK, DGKB-ETV1, KIAA1549-BRAF, ATG7-RAF1, and EWSR1-PATZ1 rearrangements in pHGGs.	('ALK', 'Gene', (15, 18))	('PATZ1', 'Gene', '23598', (67, 72))	('rearrangements', 'Var', (73, 87))	('RAF1', 'Gene', '5894', (51, 55))	('DGKB', 'Gene', '1607', (20, 24))	('EWSR1', 'Gene', (61, 66))	('ATG7', 'Gene', '10533', (46, 50))	('PATZ1', 'Gene', (67, 72))	('ETV1', 'Gene', (25, 29))	('RAF1', 'Gene', (51, 55))	('KIAA1549-BRAF', 'Disease', (31, 44))	('ATG7', 'Gene', (46, 50))	('ETV1', 'Gene', '2115', (25, 29))	('EML4', 'Gene', (10, 14))	('DGKB', 'Gene', (20, 24))	('EML4', 'Gene', '27436', (10, 14))	('KIAA1549-BRAF', 'Disease', 'None', (31, 44))	('EWSR1', 'Gene', '2130', (61, 66))	('ALK', 'Gene', '238', (15, 18))	('pHGG', 'Chemical', '-', (91, 95))
223865	28912153	We report a multiply recurrent NF1 mutated PA previously treated with surgery alone that now shows a remarkable response to dual inhibitor therapy (everolimus and trametinib) following 3 months of treatment.	('mutated', 'Var', (35, 42))	('everolimus', 'Chemical', 'MESH:D000068338', (148, 158))	('NF1', 'Gene', (31, 34))	('trametinib', 'Chemical', 'MESH:C560077', (163, 173))	('NF1', 'Gene', '4763', (31, 34))
223934	28353668	In patients with gliomas and a gliomatosis cerebri growth pattern, IDH mutations are less frequent than in gliomas with a more solid phenotype, even in low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('gliomatosis cerebri growth', 'Disease', 'MESH:D018302', (31, 57))	('gliomas', 'Disease', (162, 169))	('gliomas', 'Disease', (107, 114))	('IDH', 'Gene', '3417', (67, 70))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('mutations', 'Var', (71, 80))	('gliomas', 'Disease', (17, 24))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('IDH', 'Gene', (67, 70))	('patients', 'Species', '9606', (3, 11))	('gliomas', 'Disease', 'MESH:D005910', (17, 24))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('gliomatosis cerebri growth', 'Disease', (31, 57))	('gliomas', 'Phenotype', 'HP:0009733', (17, 24))
223979	28353668	Deletions of 1p or 19q were defined by samples with over 50% of the tumor nuclei containing only one signal.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Deletions', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
223980	28353668	The immunostainings for mutated IDH1R132H were performed using standard diagnostic protocols and the DiscoveryXT immunohistochemistry system (Ventana, Strasbourg, France).	('IDH1', 'Gene', (32, 36))	('mutated', 'Var', (24, 31))	('IDH1', 'Gene', '3417', (32, 36))
223989	27655356	Further, malignant and atypical meningiomas are more prone to recurrence and aggressive growth, increasing patient morbidity and mortality.	('meningiomas', 'Phenotype', 'HP:0002858', (32, 43))	('meningioma', 'Phenotype', 'HP:0002858', (32, 42))	('meningiomas', 'Disease', (32, 43))	('malignant', 'Var', (9, 18))	('meningiomas', 'Disease', 'MESH:D008577', (32, 43))	('aggressive growth', 'CPA', (77, 94))	('patient', 'Species', '9606', (107, 114))
224058	27655356	By first calculating the difference between the ADCs before and after therapy, fDM was determined within the total tumor and was classified into three categories -- fDM+, fDM- and fDM0 -- indicating increased, decreased, and unchanged ADC, respectively.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('fDM+', 'Var', (165, 169))	('fDM0 --', 'Var', (180, 187))	('ADC', 'MPA', (235, 238))	('tumor', 'Disease', (115, 120))	('decreased', 'NegReg', (210, 219))	('fDM-', 'Var', (171, 175))	('increased', 'PosReg', (199, 208))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
224111	27655356	Moreover, pMRI-FTB is significantly correlated with the histologic tumor fraction (P < 0.0001) and overall survival (P < 0.02).	('pMRI-FTB', 'Var', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('correlated', 'Reg', (36, 46))	('overall survival', 'CPA', (99, 115))	('tumor', 'Disease', (67, 72))
224118	27655356	For prognosis, the alterations of rCBF in ASL and DSC imaging at the 6-week follow-up after stereotactic radiosurgery for brain metastases were highly predictive of treatment outcome.	('rCBF', 'Gene', (34, 38))	('alterations', 'Var', (19, 30))	('predictive of', 'Reg', (151, 164))	('brain metastases', 'Disease', (122, 138))	('brain metastases', 'Disease', 'MESH:D009362', (122, 138))	('rCBF', 'Gene', '362686', (34, 38))
224197	32825553	Human GBM-derived cell lines U87, U251, T98, and LN229 (American Type Culture Collection, ATCC, Manassas, VA, USA) were cultivated in Dulbecco's modified Eagle's medium (DMEM, L0107-500) high glucose supplemented with 10% fetal bovine serum (FBS; S1650), 1.0 mM pyruvate (L0642-100), 1.0 mM antibiotic (streptomycin 10 g/L; penicillin G 6.028 g/L; and amphotericin B 0.025 g/L, L0010), and 0.1 mM non-essential amino acids (X0557-100, Biowest, Nuaille, PDL, France).	('Human', 'Species', '9606', (0, 5))	('high glucose', 'Phenotype', 'HP:0003074', (187, 199))	('LN229', 'CellLine', 'CVCL:0393', (49, 54))	('pyruvate', 'Chemical', 'MESH:D019289', (262, 270))	('L0642-100', 'Var', (272, 281))	('U87', 'Gene', (29, 32))	('DMEM', 'Chemical', '-', (170, 174))	('GBM', 'Phenotype', 'HP:0012174', (6, 9))	('U87', 'Gene', '641648', (29, 32))	('glucose', 'Chemical', 'MESH:D005947', (192, 199))
224208	32825553	Gene expression relative to the 18S ribosomal RNA (rRNA) gene was quantified through the quantitative polymerase chain reaction (qPCR) using standardized primers for each gene: ESR1 (estrogen receptor 1/alpha) (FW-5'-agcaccctgaagtctctgga-3', RV-5'-gatgtgggagaggatgagga-3'); ESR2 (estrogen receptor 2/beta) (FW-5'-aagaagattcccggctttgt-3', RV-5'-tctacgcatttcccctcatc-3'); VIM (vimentin) (FW-5'-ggaccagctaaccaacgaca-3', RV-5'-aaggtcaagacgtgccagag-3'); CDH2 (cadherin-2/N-cadherin) (FW-5'-ctggagacattggggacttc-3', RV-5'-gagccactgccttcatagt-3'); TJP1 (tinght junction protein 1/zonula occludens 1 (ZO-1)) (FW-5'-gccattcccgaaggagttga-3', RV-5'-atcacagtgtggtaagcg-3'); rRNA18S (FW-5'-agtgaaactgcgaatggctc-3', RV-5'-ctgaccgggttggttttgat-3').	('CDH2', 'Gene', '1000', (449, 453))	('VIM', 'Gene', '7431', (370, 373))	('VIM', 'Gene', (370, 373))	('zonula occludens 1', 'Gene', (573, 591))	('zonula occludens 1', 'Gene', '7082', (573, 591))	('cadherin-2', 'Gene', (455, 465))	('estrogen receptor 1/alpha', 'Gene', '2099', (183, 208))	('ESR2', 'Gene', '2100', (274, 278))	('estrogen receptor 2/beta', 'Gene', '2100;2099', (280, 304))	('estrogen receptor 1/alpha', 'Gene', (183, 208))	('TJP1', 'Gene', '7082', (541, 545))	('estrogen receptor 2/beta', 'Gene', (280, 304))	('ESR2', 'Gene', (274, 278))	('ESR1', 'Gene', '2099', (177, 181))	("FW-5'-agtgaaactgcgaatggctc-3'", 'Var', (671, 700))	('ESR1', 'Gene', (177, 181))	('CDH2', 'Gene', (449, 453))	('cadherin-2', 'Gene', '1000', (455, 465))	('TJP1', 'Gene', (541, 545))
224233	32825553	In contrast, ESR2 expression levels were higher in GBM as compared with LGG and healthy tissue (Figure 1A).	('ESR2', 'Gene', '2100', (13, 17))	('expression levels', 'MPA', (18, 35))	('GBM', 'Var', (51, 54))	('ESR2', 'Gene', (13, 17))	('higher', 'PosReg', (41, 47))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))
224238	32825553	Analysis of expression in cell lines showed a similar trend to the TCGA data: the expression of both ESR1 and ESR2 in four cell lines derived from human GBM (U251, U87, T98G, and LN229) was found to be lower compared to the expression of normal human astrocytes (NHA).	('ESR1', 'Gene', '2099', (101, 105))	('human', 'Species', '9606', (147, 152))	('T98G', 'Var', (169, 173))	('expression', 'MPA', (82, 92))	('U87', 'Gene', '641648', (164, 167))	('lower', 'NegReg', (202, 207))	('ESR2', 'Gene', '2100', (110, 114))	('U87', 'Gene', (164, 167))	('ESR1', 'Gene', (101, 105))	('human', 'Species', '9606', (245, 250))	('LN229', 'CellLine', 'CVCL:0393', (179, 184))	('ESR2', 'Gene', (110, 114))	('GBM', 'Phenotype', 'HP:0012174', (153, 156))
224267	32825553	Overall, the fluorescence intensity of EMT markers significantly increased in E2-treated U251 and U87 cells (Figure 5C).	('increased', 'PosReg', (65, 74))	('E2-treated', 'Var', (78, 88))	('fluorescence intensity', 'MPA', (13, 35))	('E2', 'Chemical', 'MESH:D004958', (78, 80))	('U87', 'Gene', (98, 101))	('U87', 'Gene', '641648', (98, 101))
224282	32825553	Similarly, PPT increased the wound closure rate of U87 cells, and MPP blocked the agonist effect (Figure 8).	('MPP', 'Chemical', '-', (66, 69))	('U87', 'Gene', '641648', (51, 54))	('rat', 'Species', '10116', (43, 46))	('increased', 'PosReg', (15, 24))	('PPT', 'Var', (11, 14))	('U87', 'Gene', (51, 54))	('PPT', 'Chemical', 'MESH:C486184', (11, 14))
224302	32825553	However, NF-kB also improves the recruitment of ER-alpha to estrogen response elements (EREs) of its target promoters and increases its transcriptional activity.	('transcriptional activity', 'MPA', (136, 160))	('ER-alpha', 'Gene', '2099', (48, 56))	('ER', 'Gene', '2069', (88, 90))	('recruitment', 'MPA', (33, 44))	('improves', 'PosReg', (20, 28))	('ER', 'Gene', '2069', (48, 50))	('ER-alpha', 'Gene', (48, 56))	('increases', 'PosReg', (122, 131))	('NF-kB', 'Var', (9, 14))
224303	32825553	The change in ER-alpha functions may also be due to other factors, such as altered structural conformations that increase interaction with transcriptional coactivators, point mutations that promote active forms of the receptor in the absence of an agonist, or variations by alternative splicing that change receptor transactivation mechanisms.	('promote', 'PosReg', (190, 197))	('interaction', 'Interaction', (122, 133))	('transactivation', 'MPA', (316, 331))	('ER-alpha', 'Gene', '2099', (14, 22))	('structural conformations', 'MPA', (83, 107))	('change', 'Reg', (4, 10))	('altered', 'Reg', (75, 82))	('functions', 'MPA', (23, 32))	('increase', 'PosReg', (113, 121))	('ER-alpha', 'Gene', (14, 22))	('active forms', 'MPA', (198, 210))	('point mutations', 'Var', (169, 184))	('variations', 'Var', (260, 270))
224360	31723226	Tailoring treatments to specific groups of patients becomes very popular in recent years due to the confirmation that the fundamental biology of each patient is unique, such as DNA, RNA, protein and methylation.	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (43, 50))	('patients', 'Species', '9606', (43, 51))	('methylation', 'Var', (199, 210))	('RNA', 'Disease', (182, 185))	('DNA', 'Disease', (177, 180))
224379	31723226	However, most of these studies focused on genetics variants discovery or identifying biomarkers for subtypes of RCC.	('RCC', 'Disease', (112, 115))	('variants', 'Var', (51, 59))	('RCC', 'Disease', 'MESH:D002292', (112, 115))
224525	31091655	Presence of IDH1 mutation correlates with more favorable patient survival outcomes.	('IDH1', 'Gene', (12, 16))	('patient', 'Species', '9606', (57, 64))	('patient survival outcomes', 'CPA', (57, 82))	('mutation', 'Var', (17, 25))	('IDH1', 'Gene', '3417', (12, 16))
224527	31091655	Our findings indicate that PTPmicro high biomarker levels are predictive of longer survival time for all glioma subtypes.	('PTPmicro high', 'Var', (27, 40))	('glioma', 'Disease', (105, 111))	('survival time', 'CPA', (83, 96))	('longer', 'PosReg', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
224534	31091655	These PTPmicro high biomarker patients also had a significantly longer mean overall survival time of 48 months compared to the mean overall survival time of 22.4 months for the PTPmicro low patients (p < 0.001).	('high biomarker', 'Var', (15, 29))	('PTPmicro', 'Gene', (6, 14))	('longer', 'PosReg', (64, 70))	('patients', 'Species', '9606', (190, 198))	('overall', 'MPA', (76, 83))	('patients', 'Species', '9606', (30, 38))
224540	31091655	The TMAs were also stained for mutant IDH1, as shown in Figure 1b,f, and scored as positive or negative to replicate scoring by pathologists.	('IDH1', 'Gene', '3417', (38, 42))	('mutant', 'Var', (31, 37))	('IDH1', 'Gene', (38, 42))	('TMAs', 'Chemical', '-', (4, 8))
224541	31091655	A different TMA is shown in Figure 1f with samples illustrating the range of PTPmicro low and PTPmicro high as well as wild-type and mutant IDH1 samples.	('IDH1', 'Gene', '3417', (140, 144))	('TMA', 'Chemical', '-', (12, 15))	('IDH1', 'Gene', (140, 144))	('mutant', 'Var', (133, 139))	('PTPmicro', 'MPA', (94, 102))
224542	31091655	Kaplan Meier survival plots demonstrate that patients with PTPmicro high biomarker staining have significantly increased survival relative to patients with PTPmicro low biomarker staining.	('survival', 'MPA', (121, 129))	('PTPmicro high', 'Var', (59, 72))	('increased', 'PosReg', (111, 120))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (142, 150))
224544	31091655	The survival of all glioma patients with PTPmicro high and PTPmicro low is plotted either unadjusted (Figure 2a) or adjusted (Figure 2b) by gender, grade, age group, and IDH1 mutation status.	('PTPmicro high', 'Var', (41, 54))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('IDH1', 'Gene', (170, 174))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('PTPmicro', 'Var', (59, 67))	('IDH1', 'Gene', '3417', (170, 174))	('patients', 'Species', '9606', (27, 35))	('glioma', 'Disease', (20, 26))
224545	31091655	As shown in Figure 2a, the median survival of all glioma patients with PTPmicro low was 13.3 months compared to 57.8 months for those with PTPmicro high.	('patients', 'Species', '9606', (57, 65))	('PTPmicro low', 'Var', (71, 83))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
224546	31091655	After adjusting for sex, tumor grade, age group, and IDH1 mutation status, the median survival of all patients with PTPmicro low was about half as long, 18.6 months, as those with PTPmicro high staining, where the median survival was 38.2 months (Figure 2b).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('IDH1', 'Gene', (53, 57))	('patients', 'Species', '9606', (102, 110))	('PTPmicro low', 'Var', (116, 128))	('IDH1', 'Gene', '3417', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
224551	31091655	Consistent with previous studies, patients with mutant IDH1 had a significantly reduced hazard of death relative to wild-type IDH1 glioma patients (Figure 3).	('IDH1', 'Gene', '3417', (126, 130))	('patients', 'Species', '9606', (138, 146))	('mutant', 'Var', (48, 54))	('IDH1', 'Gene', '3417', (55, 59))	('IDH1 glioma', 'Disease', (126, 137))	('reduced', 'NegReg', (80, 87))	('IDH1', 'Gene', (126, 130))	('patients', 'Species', '9606', (34, 42))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('IDH1 glioma', 'Disease', 'MESH:D005910', (126, 137))	('IDH1', 'Gene', (55, 59))
224553	31091655	Unadjusted Kaplan Meier survival plots were calculated for glioma patients with PTPmicro low (Figure 4a) and PTPmicro high (Figure 4b).	('PTPmicro low', 'Var', (80, 92))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('PTPmicro high', 'Var', (109, 122))	('patients', 'Species', '9606', (66, 74))
224554	31091655	Too few patients were available in each category to make meaningful Kaplan Meier survival plots that adjusted for sex, grade, and IDH1 mutation.	('adjusted', 'Reg', (101, 109))	('IDH1', 'Gene', (130, 134))	('IDH1', 'Gene', '3417', (130, 134))	('mutation', 'Var', (135, 143))	('patients', 'Species', '9606', (8, 16))
224560	31091655	AYA patients with high levels of PTPmicro had longer survival compared to the other the age groups (Figure 4b), but median survival time could not be determined because only six deaths were recorded among the 19 AYA patients.	('longer', 'PosReg', (46, 52))	('survival', 'MPA', (53, 61))	('deaths', 'Disease', 'MESH:D003643', (178, 184))	('patients', 'Species', '9606', (216, 224))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))	('PTPmicro', 'Var', (33, 41))	('deaths', 'Disease', (178, 184))
224561	31091655	For instance, patients in the oldest age group with PTPmicro high staining had a significantly longer median overall survival of 18.9 months (Figure 4b) compared to 5.3 months for those patients 60 and over in the PTPmicro low group (Figure 4a; log rank p-value = 0.025).	('PTPmicro high staining', 'Var', (52, 74))	('longer', 'PosReg', (95, 101))	('overall survival', 'MPA', (109, 125))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (186, 194))
224566	31091655	Kaplan Meier survival plots for overall survival are shown unadjusted or adjusted for sex, age group, and IDH1 mutation status (Figure 5).	('IDH1', 'Gene', '3417', (106, 110))	('IDH1', 'Gene', (106, 110))	('mutation', 'Var', (111, 119))
224567	31091655	GBM patients with PTPmicro high staining showed significantly better survival compared to those with PTPmicro low staining in both unadjusted (Figure 5a) and adjusted plots (Figure 5b).	('high staining', 'Var', (27, 40))	('better', 'PosReg', (62, 68))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('patients', 'Species', '9606', (4, 12))	('survival', 'MPA', (69, 77))
224570	31091655	As with GBM patients, patients with lower grade tumors but PTPmicro high levels had longer overall survival than those with PTPmicro low levels, although this difference was only significant after adjusting for sex, age group, and IDH1 mutation status (Figure 6b).	('patients', 'Species', '9606', (12, 20))	('IDH1', 'Gene', (231, 235))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('patients', 'Species', '9606', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('overall survival', 'MPA', (91, 107))	('PTPmicro high levels', 'Var', (59, 79))	('IDH1', 'Gene', '3417', (231, 235))	('GBM', 'Phenotype', 'HP:0012174', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('longer', 'PosReg', (84, 90))
224572	31091655	However, after adjusting for sex, age group, and IDH1 mutation status, the PTPmicro high non-GBM glioma patients had significantly longer recurrence free survival times than the PTPmicro low non-GBM patients, 34.1 versus 11.8 months, respectively (Figure 6d).	('PTPmicro', 'Gene', (75, 83))	('IDH1', 'Gene', '3417', (49, 53))	('high', 'Var', (84, 88))	('glioma', 'Disease', (97, 103))	('recurrence free survival times', 'CPA', (138, 168))	('patients', 'Species', '9606', (104, 112))	('GBM', 'Phenotype', 'HP:0012174', (195, 198))	('GBM', 'Phenotype', 'HP:0012174', (93, 96))	('patients', 'Species', '9606', (199, 207))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('longer', 'PosReg', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('IDH1', 'Gene', (49, 53))
224573	31091655	The most recent WHO Classification of Tumors of the Central Nervous System recommendations combine basic histology with either immunohistochemical or genetic tests for mutated IDH1 status, transcriptional regulator (ATRX) loss, and TP53 mutation or 1p/19q chromosomal deletion status to differentiate tumors.	('Tumors of the Central Nervous', 'Disease', 'MESH:D016543', (38, 67))	('Tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('TP53', 'Gene', '7157', (232, 236))	('tumors', 'Disease', (301, 307))	('Tumor', 'Phenotype', 'HP:0002664', (38, 43))	('IDH1', 'Gene', '3417', (176, 180))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('ATRX', 'Gene', (216, 220))	('ATRX', 'Gene', '546', (216, 220))	('Tumors of the Central Nervous', 'Disease', (38, 67))	('TP53', 'Gene', (232, 236))	('mutated', 'Var', (168, 175))	('1p/19q chromosomal deletion status', 'Var', (249, 283))	('Tumors of the Central Nervous System', 'Phenotype', 'HP:0100006', (38, 74))	('mutation', 'Var', (237, 245))	('loss', 'NegReg', (222, 226))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('IDH1', 'Gene', (176, 180))
224575	31091655	Sequencing studies by The Cancer Genome Atlas (TCGA) identified the common mutation of IDH1 in GBM, with an observation that ~10% of GBM patients harbored IDH1 mutations.	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('IDH1', 'Gene', (155, 159))	('Cancer Genome Atlas', 'Disease', (26, 45))	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('mutations', 'Var', (160, 169))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (26, 45))	('IDH1', 'Gene', '3417', (87, 91))	('IDH1', 'Gene', '3417', (155, 159))	('patients', 'Species', '9606', (137, 145))	('GBM', 'Disease', (95, 98))	('IDH1', 'Gene', (87, 91))
224576	31091655	IDH1 mutations were associated with increased overall survival of GBM patients and occurred preferentially in young patients and those with secondary GBM, that is GBM progressing from a lower grade glioma as opposed to GBMs that arise de novo, i.e., primary GBM.	('patients', 'Species', '9606', (70, 78))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('glioma', 'Disease', (198, 204))	('patients', 'Species', '9606', (116, 124))	('mutations', 'Var', (5, 14))	('GBM', 'Phenotype', 'HP:0012174', (258, 261))	('overall', 'MPA', (46, 53))	('increased', 'PosReg', (36, 45))	('GBM', 'Phenotype', 'HP:0012174', (219, 222))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('IDH1', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('IDH1', 'Gene', '3417', (0, 4))
224577	31091655	A further refinement of glioma subtypes was accepted in the 2016 WHO guidelines by adding ATRX and TP53 mutational analysis alongside evaluation of 1p/19q chromosomal co-deletion.	('TP53', 'Gene', (99, 103))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('mutational', 'Var', (104, 114))	('ATRX', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (99, 103))	('glioma', 'Disease', (24, 30))	('ATRX', 'Gene', '546', (90, 94))	('1p/19q chromosomal', 'Var', (148, 166))
224579	31091655	Oligodendrogliomas can be distinguished from astrocytomas based on ATRX and TP53 mutations (observed in astrocytomas only) versus 1p/19q co-deletion (observed in oligodendrogliomas only along with IDH1 mutation).	('Oligodendrogliomas', 'Disease', (0, 18))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('mutations', 'Var', (81, 90))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('astrocytomas', 'Disease', 'MESH:D001254', (104, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (104, 115))	('TP53', 'Gene', (76, 80))	('astrocytomas', 'Disease', (45, 57))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (67, 71))	('IDH1', 'Gene', (197, 201))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (162, 180))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (45, 57))	('astrocytoma', 'Phenotype', 'HP:0009592', (45, 56))	('TP53', 'Gene', '7157', (76, 80))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('astrocytomas', 'Disease', (104, 116))	('IDH1', 'Gene', '3417', (197, 201))	('oligodendrogliomas', 'Disease', (162, 180))
224580	31091655	The use of immunohistochemistry for both IDH1 and ATRX mutation analysis should simplify the adoption of molecular diagnostics in the neurohistological setting.	('ATRX', 'Gene', '546', (50, 54))	('IDH1', 'Gene', (41, 45))	('ATRX', 'Gene', (50, 54))	('IDH1', 'Gene', '3417', (41, 45))	('mutation analysis', 'Var', (55, 72))
224581	31091655	For example, the presence of IDH1 mutations and 1p/19q co-deletions are associated with better survival outcomes for grade II, III, and IV gliomas, which may be relevant for determining treatment options for lower grade glioma patients with worse prognoses.	('III', 'Disease', (127, 130))	('1p/19q', 'Var', (48, 54))	('IDH1', 'Gene', (29, 33))	('glioma', 'Disease', (139, 145))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('IDH1', 'Gene', '3417', (29, 33))	('patients', 'Species', '9606', (227, 235))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('IV gliomas', 'Disease', (136, 146))	('IV gliomas', 'Disease', 'MESH:D005910', (136, 146))	('better', 'PosReg', (88, 94))	('glioma', 'Disease', (220, 226))	('grade II', 'Disease', (117, 125))	('mutations', 'Var', (34, 43))
224582	31091655	The data presented here suggest that high levels of PTPmicro staining correlate with longer overall survival (anywhere from one and a half to three times longer) for patients of similar age.	('longer', 'PosReg', (85, 91))	('high', 'Var', (37, 41))	('overall survival', 'MPA', (92, 108))	('PTPmicro', 'Var', (52, 60))	('patients', 'Species', '9606', (166, 174))
224585	31091655	The TCGA database indicates 13 mutations in the PTPmicro gene (PTPRM) coding region, most of them low impact mutations.	('PTPRM', 'Gene', (63, 68))	('mutations', 'Var', (31, 40))	('PTPRM', 'Gene', '5797', (63, 68))
224589	31091655	PTPmicro high biomarker staining and IDH1 mutation both substantially reduced the hazard ratio of death, as shown in Figure 3.	('reduced', 'NegReg', (70, 77))	('IDH1', 'Gene', (37, 41))	('hazard', 'MPA', (82, 88))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))
224591	31091655	Current practice is to utilize Clinical Laboratory Improvements Amendments (CLIA)-approved and commercially available monoclonal antibodies (mAbs) for the most common mutation of IDH1 and ATRX for routine grading of gliomas.	('ATRX', 'Gene', '546', (188, 192))	('mutation', 'Var', (167, 175))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('IDH1', 'Gene', (179, 183))	('CLIA', 'Disease', 'None', (76, 80))	('gliomas', 'Disease', 'MESH:D005910', (216, 223))	('CLIA', 'Disease', (76, 80))	('IDH1', 'Gene', '3417', (179, 183))	('gliomas', 'Disease', (216, 223))	('ATRX', 'Gene', (188, 192))
224605	31091655	In GBM, for example, TP53 and IDH1 mutations and phosphatase and tensin homolog (PTEN) deletion are frequently observed in patients under 40, as is hypermethylation of the CpG island methylator (C-GIMP) phenotype.	('TP53', 'Gene', (21, 25))	('observed', 'Reg', (111, 119))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('patients', 'Species', '9606', (123, 131))	('IDH1', 'Gene', (30, 34))	('PTEN', 'Gene', (81, 85))	('PTEN', 'Gene', '5728', (81, 85))	('TP53', 'Gene', '7157', (21, 25))	('deletion', 'Var', (87, 95))	('IDH1', 'Gene', '3417', (30, 34))	('mutations', 'Var', (35, 44))
224607	31091655	In older GBM patients, epidermal growth factor receptor (EGFR) amplification and PTEN deletions are observed in a majority of cases, and IDH1 mutations are rarely observed.	('epidermal growth factor receptor', 'Gene', (23, 55))	('GBM', 'Phenotype', 'HP:0012174', (9, 12))	('epidermal growth factor receptor', 'Gene', '1956', (23, 55))	('patients', 'Species', '9606', (13, 21))	('PTEN', 'Gene', '5728', (81, 85))	('IDH1', 'Gene', (137, 141))	('amplification', 'Var', (63, 76))	('EGFR', 'Gene', '1956', (57, 61))	('PTEN', 'Gene', (81, 85))	('deletions', 'Var', (86, 95))	('IDH1', 'Gene', '3417', (137, 141))	('EGFR', 'Gene', (57, 61))
224609	31091655	As with the IDH1 mutation, PTPmicro high staining correlates with improved survival.	('PTPmicro high staining', 'Var', (27, 49))	('survival', 'CPA', (75, 83))	('IDH1', 'Gene', (12, 16))	('improved', 'PosReg', (66, 74))	('IDH1', 'Gene', '3417', (12, 16))
224615	31091655	The remaining samples were stained for IDH1 mutation as described below.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
224618	31091655	Anti-IDH1 R132H Monoclonal Antibody clone H09 [American Research Products (Dianova GmbH), Waltham, MA, USA] reacts specifically with the isocitrate dehydrogenase 1 (IDH1) R132H point mutation in tissue sections from formalin-fixed brain tumor specimens.	('brain tumor', 'Disease', 'MESH:D001932', (231, 242))	('R132H', 'Mutation', 'rs121913500', (10, 15))	('IDH1', 'Gene', (5, 9))	('brain tumor', 'Phenotype', 'HP:0030692', (231, 242))	('IDH1', 'Gene', '3417', (5, 9))	('isocitrate dehydrogenase 1', 'Gene', (137, 163))	('IDH1', 'Gene', (165, 169))	('formalin', 'Chemical', 'MESH:D005557', (216, 224))	('isocitrate dehydrogenase 1', 'Gene', '3417', (137, 163))	('R132H', 'Var', (171, 176))	('IDH1', 'Gene', '3417', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('brain tumor', 'Disease', (231, 242))	('R132H', 'Mutation', 'rs121913500', (171, 176))
224627	31091655	Some samples were also stained for the IDH1 mutation.	('IDH1', 'Gene', '3417', (39, 43))	('IDH1', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
224632	31091655	For IDH1, samples were scored as either positive for the mutation or negative as it is done clinically.	('mutation', 'Var', (57, 65))	('positive', 'Reg', (40, 48))	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', (4, 8))
224633	31091655	The final model selected for all patient data adjusted for sex, age group, tumor grade, and IDH1 mutation.	('patient', 'Species', '9606', (33, 40))	('IDH1', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('IDH1', 'Gene', '3417', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (97, 105))	('tumor', 'Disease', (75, 80))
224635	31091655	Additional support was obtained from the National Institutes of Health sponsored Cancer Imaging Program of the Case Comprehensive Cancer Center and their cores (P30CA043703), the Visual Sciences Research Center (P30EY11373) as well as the Light Microscopy Imaging Core (S10OD024981).	('Visual Sciences', 'Disease', 'MESH:D014786', (179, 194))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('P30CA043703', 'Var', (161, 172))	('P30EY11373', 'Var', (212, 222))	('Visual Sciences', 'Disease', (179, 194))
224768	30962709	These interventions have been shown to enhance research delivery within England and have led to a 600% increase in the number of people taking part in research studies.	('increase', 'PosReg', (103, 111))	('interventions', 'Var', (6, 19))	('research delivery', 'MPA', (47, 64))	('enhance', 'PosReg', (39, 46))	('people', 'Species', '9606', (129, 135))
224778	30272052	IDH1, TP53, and ATRX mutations are present in 40% or more adult LGGs.	('mutations', 'Var', (21, 30))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('IDH1', 'Gene', '3417', (0, 4))	('ATRX', 'Gene', '546', (16, 20))	('IDH1', 'Gene', (0, 4))	('ATRX', 'Gene', (16, 20))
224783	30272052	However, a few studies have reported V detection in cancer cells of nonendothelial origin including osteosarcoma and glioma, and VWF is a prognostic factor in GBM.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (100, 112))	('osteosarcoma', 'Disease', (100, 112))	('GBM', 'Disease', (159, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (100, 112))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('VWF', 'Var', (129, 132))	('glioma', 'Disease', (117, 123))
224793	30272052	VWF was most often mutated and amplified in diffuse gliomas [Figure 2].	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('VWF', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('mutated', 'Var', (19, 26))	('amplified', 'Reg', (31, 40))
224796	30272052	IDHI, TP53, and ATRX mutations are present in 40% or more adult LGGs.	('mutations', 'Var', (21, 30))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('ATRX', 'Gene', '546', (16, 20))	('ATRX', 'Gene', (16, 20))
224797	30272052	When we analyzed the data with Cox regression, expression had a significant effect on survival (P = 0.02) that was unrelated to the effect of IDH1 expression (P = 0.062), TP53 expression (P = 0.135), independent of ATRX expression (P = 0.021), and histology (astrocytoma versus ohgoastrocytoma and oligodendroglioma, P = 0.002).	('TP53', 'Gene', (171, 175))	('ATRX', 'Gene', '546', (215, 219))	('IDH1', 'Gene', '3417', (142, 146))	('astrocytoma versus ohgoastrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (259, 315))	('Cox', 'Gene', '1351', (31, 34))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('expression', 'Var', (47, 57))	('TP53', 'Gene', '7157', (171, 175))	('astrocytoma', 'Phenotype', 'HP:0009592', (282, 293))	('Cox', 'Gene', (31, 34))	('astrocytoma', 'Phenotype', 'HP:0009592', (259, 270))	('survival', 'Disease', (86, 94))	('ATRX', 'Gene', (215, 219))	('IDH1', 'Gene', (142, 146))
80757	30272052	Recent findings suggest that genetic pathways within tumor cells might trigger thrombotic phenomena, worsening prognosis.	('trigger', 'Reg', (71, 78))	('thrombotic phenomena', 'Phenotype', 'HP:0001907', (79, 99))	('thrombotic', 'Disease', 'MESH:D013927', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('worsening', 'Reg', (101, 110))	('prognosis', 'MPA', (111, 120))	('thrombotic', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('genetic pathways', 'Var', (29, 45))
224817	27049832	Exclusively high PHH3 and Ki-67 values were predictor of poor prognosis (log rank test, P = 0.0281 for PHH3 and P = 0.032 for Ki-67), unlike standard mitotic count.	('Ki', 'Chemical', 'MESH:C066186', (126, 128))	('Ki', 'Chemical', 'MESH:C066186', (26, 28))	('high', 'Var', (12, 16))	('PHH3', 'Chemical', '-', (17, 21))	('PHH3', 'Gene', (17, 21))	('PHH3', 'Chemical', '-', (103, 107))	('Ki-67', 'Gene', (26, 31))
224819	27049832	In addition, stratifying by IDH expression status, high Ki-67 retained its prognostic relevance uniquely in the IDH negative patient (P = 0.029) doubling their risk of death (hazard ratio = 2.27).	('IDH', 'Gene', (28, 31))	('Ki-67', 'Gene', (56, 61))	('IDH', 'Gene', '3417', (28, 31))	('Ki', 'Chemical', 'MESH:C066186', (56, 58))	('death', 'Disease', 'MESH:D003643', (168, 173))	('doubling', 'PosReg', (145, 153))	('death', 'Disease', (168, 173))	('high', 'Var', (51, 55))	('patient', 'Species', '9606', (125, 132))	('IDH', 'Gene', (112, 115))	('IDH', 'Gene', '3417', (112, 115))
224825	27049832	Several molecular signatures have now been identified (IDH, 1p/19q co-deletion, ATRX, TERT, p53, MGMT promoter methylation), with important diagnostic, prognostic, and predictive roles.	('MGMT', 'Gene', (97, 101))	('1p/19q co-deletion', 'Var', (60, 78))	('IDH', 'Gene', (55, 58))	('MGMT', 'Gene', '4255', (97, 101))	('IDH', 'Gene', '3417', (55, 58))	('p53', 'Gene', (92, 95))	('TERT', 'Gene', (86, 90))	('ATRX', 'Gene', (80, 84))	('p53', 'Gene', '7157', (92, 95))	('TERT', 'Gene', '7015', (86, 90))	('ATRX', 'Gene', '546', (80, 84))
224840	27049832	Co-deletion of 1p19q was present in 37 of 79 tumor tested (47%), 34 of which were IDH mutated.	('IDH', 'Gene', '3417', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('Co-deletion', 'Var', (0, 11))	('IDH', 'Gene', (82, 85))	('1p19q', 'Var', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
224856	27049832	The significant association between high mitotic count and elevated histological grade (grade III) on H&E (Wilcoxon test, P= 0.018) was remarkably increased when using PHH3 (Wilcoxon test, P = 0.0002) and Ki-67 (Wilcoxon test, P < 0.0001).	('high mitotic count', 'CPA', (36, 54))	('H&E', 'Chemical', '-', (102, 105))	('using', 'Var', (162, 167))	('histological grade', 'CPA', (68, 86))	('PHH3', 'Chemical', '-', (168, 172))	('elevated', 'PosReg', (59, 67))	('Ki', 'Chemical', 'MESH:C066186', (205, 207))	('remarkably', 'PosReg', (136, 146))
224857	27049832	MGMT promoter methylation was related to high mitotic counts and PHH3 values (Wilcoxon test, P = 0.025 for H&E, P = 0.008 for PHH3, but not with Ki-67 values (Wilcoxon test, P = 0.279).	('MGMT', 'Gene', (0, 4))	('PHH3', 'Chemical', '-', (126, 130))	('PHH3', 'Chemical', '-', (65, 69))	('methylation', 'Var', (14, 25))	('Ki', 'Chemical', 'MESH:C066186', (145, 147))	('H&E', 'Chemical', '-', (107, 110))	('PHH3 values', 'MPA', (65, 76))	('MGMT', 'Gene', '4255', (0, 4))
224858	27049832	Conversely, IDH mutation was not found to be associated with mitotic counts (Wilcoxon test, P = 0.271 for H&E, P = 0.135 for PHH3) or with Ki-67 index (P = 0.782) and the same occurred for 1p/19q co-deletion (Wilcoxon test, P = 0.619 for H&E, P = 0.825 for PHH3 and P = 0.642 for Ki-67).	('mutation', 'Var', (16, 24))	('for 1p/19q', 'Var', (185, 195))	('PHH3', 'Chemical', '-', (257, 261))	('H&E', 'Chemical', '-', (106, 109))	('IDH', 'Gene', (12, 15))	('PHH3', 'Chemical', '-', (125, 129))	('IDH', 'Gene', '3417', (12, 15))	('H&E', 'Chemical', '-', (238, 241))	('Ki', 'Chemical', 'MESH:C066186', (139, 141))	('mitotic counts', 'CPA', (61, 75))	('Ki', 'Chemical', 'MESH:C066186', (280, 282))
224859	27049832	As expected, at univariate survival analysis, both IDH mutation, 1p/19q co-deletion and MGMT methylation were all related to an improved survival (univariate Cox regression, P < 0.001 for IDH mutated, P = 0.001 for 1p/19q co-deleted and 0.008 for MGMT methylated cases Table 2).	('Cox', 'Gene', '1351', (158, 161))	('IDH', 'Gene', '3417', (188, 191))	('IDH', 'Gene', (51, 54))	('Cox', 'Gene', (158, 161))	('IDH', 'Gene', '3417', (51, 54))	('improved', 'PosReg', (128, 136))	('MGMT', 'Gene', (88, 92))	('MGMT', 'Gene', (247, 251))	('MGMT', 'Gene', '4255', (88, 92))	('survival', 'MPA', (137, 145))	('mutation', 'Var', (55, 63))	('IDH', 'Gene', (188, 191))	('1p/19q co-deletion', 'Var', (65, 83))	('MGMT', 'Gene', '4255', (247, 251))
224860	27049832	With respect to the three methods for assessing proliferation, only high PHH3 and Ki-67 values were significantly associated with a poor outcome (univariate Cox regression, P = 0.0281 for PHH3 and P = 0.032 for Ki-67, Table 2).	('Ki', 'Chemical', 'MESH:C066186', (82, 84))	('Cox', 'Gene', '1351', (157, 160))	('PHH3', 'Chemical', '-', (188, 192))	('high', 'Var', (68, 72))	('Cox', 'Gene', (157, 160))	('PHH3', 'Chemical', '-', (73, 77))	('associated', 'Reg', (114, 124))	('Ki-67', 'Gene', (82, 87))	('Ki', 'Chemical', 'MESH:C066186', (211, 213))	('PHH3', 'Gene', (73, 77))
224866	27049832	As a matter of fact, IDH wild type patients with high Ki-67, had a doubled risk of death (hazard ratio = 2.27, 95% confidence interval 1.06-4.76) compared to those with low Ki-67 (Figure 4).	('IDH', 'Gene', (21, 24))	('Ki', 'Chemical', 'MESH:C066186', (54, 56))	('high Ki-67', 'Var', (49, 59))	('IDH', 'Gene', '3417', (21, 24))	('death', 'Disease', 'MESH:D003643', (83, 88))	('death', 'Disease', (83, 88))	('patients', 'Species', '9606', (35, 43))	('Ki', 'Chemical', 'MESH:C066186', (173, 175))
224878	27049832	A comparison between the prognostic performance of mitotic counting (either H&E or PHH3 based) and Ki-67 proliferation index proved that exclusively PHH3-based mitotic count and Ki-67 proliferation index were associated to a greater risk of death at univariate survival analysis.	('Ki', 'Chemical', 'MESH:C066186', (99, 101))	('Ki', 'Chemical', 'MESH:C066186', (178, 180))	('and', 'Var', (174, 177))	('death', 'Disease', 'MESH:D003643', (241, 246))	('PHH3-based mitotic', 'CPA', (149, 167))	('death', 'Disease', (241, 246))	('H&E', 'Chemical', '-', (76, 79))	('PHH3', 'Chemical', '-', (83, 87))	('exclusively', 'Var', (137, 148))	('PHH3', 'Chemical', '-', (149, 153))
224886	27049832	The discovery of the mutations in the IDH1 and 2 genes and the consistent deletion of chromosomal arms 1p and 19q represent to date the major diagnostic breakthrough in LGG classification, which bears prognostic impact.	('deletion', 'Var', (74, 82))	('IDH1 and 2', 'Gene', '3417;3418', (38, 48))	('LGG', 'Disease', (169, 172))	('mutations', 'Var', (21, 30))
224887	27049832	The integration of genome wide data by various groups has delineated different prognostic classes, which were more concordant with IDH and 1p/19q statuses than with histologic classifications.	('IDH', 'Gene', (131, 134))	('1p/19q', 'Var', (139, 145))	('IDH', 'Gene', '3417', (131, 134))
224913	27245697	The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas (sGBM).	('gliomas', 'Disease', (93, 100))	('isocitrate dehydrogenase', 'Gene', (152, 176))	('glioblastomas', 'Phenotype', 'HP:0012174', (234, 247))	('gliomas', 'Disease', 'MESH:D005910', (212, 219))	('IDH1', 'Gene', (142, 146))	('IDH2', 'Gene', (180, 184))	('IDH1', 'Gene', '3417', (66, 70))	('isocitrate dehydrogenase', 'Gene', '3417', (114, 138))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('IDH2', 'Gene', '3418', (180, 184))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioblastomas', 'Disease', (234, 247))	('gliomas', 'Phenotype', 'HP:0009733', (212, 219))	('frequent', 'Reg', (190, 198))	('IDH1', 'Gene', '3417', (142, 146))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('isocitrate dehydrogenase', 'Gene', '3417', (152, 176))	('IDH2', 'Gene', (75, 79))	('glioblastomas', 'Disease', 'MESH:D005909', (234, 247))	('IDH2', 'Gene', '3418', (75, 79))	('isocitrate dehydrogenase', 'Gene', (114, 138))	('Mutations', 'Var', (101, 110))	('gliomas', 'Disease', (212, 219))	('IDH1', 'Gene', (66, 70))
224915	27245697	The objective of this study was to provide insight into the differences between IDH1 and IDH2 mutant gliomas.	('IDH1', 'Gene', (80, 84))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('IDH1', 'Gene', '3417', (80, 84))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('mutant', 'Var', (94, 100))	('IDH2', 'Gene', (89, 93))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH2', 'Gene', '3418', (89, 93))
224916	27245697	To investigate the different clinical and molecular characterization between IDH1 mutant and IDH2 mutant gliomas, we studied 811 patients with IDH1 mutations, IDH2 mutations and IDH1/2 wild-type.	('IDH2', 'Gene', (159, 163))	('mutations', 'Var', (148, 157))	('IDH1', 'Gene', '3417', (178, 182))	('IDH1/2', 'Gene', '3417;3418', (178, 184))	('IDH2', 'Gene', '3418', (93, 97))	('patients', 'Species', '9606', (129, 137))	('IDH2', 'Gene', '3418', (159, 163))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('IDH1', 'Gene', (143, 147))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('IDH1', 'Gene', (77, 81))	('IDH1/2', 'Gene', (178, 184))	('IDH1', 'Gene', '3417', (77, 81))	('IDH1', 'Gene', (178, 182))	('IDH1', 'Gene', '3417', (143, 147))	('IDH2', 'Gene', (93, 97))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
224917	27245697	In addition, whole-transcriptome sequencing and DNA methylation data were used to assess the distribution of genetic changes in IDH1 and IDH2 mutant gliomas in a Chinese population-based cohort.	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('IDH1', 'Gene', '3417', (128, 132))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('IDH2', 'Gene', (137, 141))	('mutant', 'Var', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('IDH2', 'Gene', '3418', (137, 141))	('IDH1', 'Gene', (128, 132))
224918	27245697	Among 811 gliomas in our cohort, 448 cases (55.2 %) harbored an IDH1 mutation, 18 cases (2.2 %) harbored an IDH2 mutation and 345 cases (42.6 %) harbored an IDH1/2 wild-type.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('mutation', 'Var', (113, 121))	('IDH2', 'Gene', '3418', (108, 112))	('IDH1/2', 'Gene', '3417;3418', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('IDH1', 'Gene', (64, 68))	('mutation', 'Var', (69, 77))	('IDH1', 'Gene', '3417', (64, 68))	('IDH1', 'Gene', (157, 161))	('IDH1/2', 'Gene', (157, 163))	('harbored', 'Reg', (52, 60))	('IDH1', 'Gene', '3417', (157, 161))	('IDH2', 'Gene', (108, 112))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
224919	27245697	We found that IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN, P53 and ATRX mutations.	('PTEN', 'Gene', '5728', (110, 114))	('mutations', 'Var', (72, 81))	('IDH2', 'Gene', (67, 71))	('P53', 'Gene', (116, 119))	('IDH2', 'Gene', (23, 27))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('ATRX', 'Gene', (124, 128))	('IDH2', 'Gene', '3418', (67, 71))	('IDH2', 'Gene', '3418', (23, 27))	('P53', 'Gene', '7157', (116, 119))	('IDH1', 'Gene', (14, 18))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('PTEN', 'Gene', (110, 114))	('ATRX', 'Gene', '546', (124, 128))	('IDH1', 'Gene', '3417', (14, 18))
224920	27245697	Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion (p < 0.05) than IDH1 mutant patients.	('IDH1', 'Gene', (90, 94))	('IDH1', 'Gene', '3417', (90, 94))	('patients', 'Species', '9606', (102, 110))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('IDH2', 'Gene', (14, 18))	('1p/19q co-deletion', 'Var', (55, 73))	('IDH2', 'Gene', '3418', (14, 18))
224921	27245697	In addition, a Gene Set Enrichment Analysis (GSEA) showed that IDH2 mutant gliomas were associated with the oxidative phosphorylation gene set, and the four most representative biological processes for genes commonly altered by hypermethylation in IDH2 mutant gliomas were the regulation of cell proliferation, cell motion, cell migration and response to hypoxia.	('cell motion', 'CPA', (311, 322))	('IDH2', 'Gene', '3418', (63, 67))	('gliomas', 'Disease', (75, 82))	('gliomas', 'Disease', 'MESH:D005910', (260, 267))	('glioma', 'Phenotype', 'HP:0009733', (260, 266))	('gliomas', 'Phenotype', 'HP:0009733', (260, 267))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('oxidative phosphorylation gene set', 'MPA', (108, 142))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('hypermethylation', 'Var', (228, 244))	('mutant', 'Var', (253, 259))	('IDH2', 'Gene', (248, 252))	('hypoxia', 'Disease', (355, 362))	('GSEA', 'Chemical', '-', (45, 49))	('altered', 'Reg', (217, 224))	('cell proliferation', 'CPA', (291, 309))	('IDH2', 'Gene', '3418', (248, 252))	('cell migration', 'CPA', (324, 338))	('gliomas', 'Disease', (260, 267))	('associated', 'Reg', (88, 98))	('IDH2', 'Gene', (63, 67))	('hypoxia', 'Disease', 'MESH:D000860', (355, 362))	('mutant', 'Var', (68, 74))
224922	27245697	Patients with IDH2 mutant gliomas exhibited longer Overall survival (OS) (p < 0.05) and longer Progression-free survival (PFS) (p < 0.05) than patients with IDH1/2 wild-type gliomas.	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('Progression-free survival', 'CPA', (95, 120))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('mutant', 'Var', (19, 25))	('IDH2', 'Gene', (14, 18))	('IDH2', 'Gene', '3418', (14, 18))	('longer', 'PosReg', (44, 50))	('IDH1/2', 'Gene', '3417;3418', (157, 163))	('gliomas', 'Disease', (26, 33))	('Patients', 'Species', '9606', (0, 8))	('IDH1/2', 'Gene', (157, 163))	('longer', 'PosReg', (88, 94))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('gliomas', 'Disease', (174, 181))	('Overall survival', 'CPA', (51, 67))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('OS', 'Chemical', '-', (69, 71))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('patients', 'Species', '9606', (143, 151))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))
224923	27245697	However, their OS and PFS did not differ from that of IDH1 mutant patients.	('IDH1', 'Gene', (54, 58))	('mutant', 'Var', (59, 65))	('OS', 'Chemical', '-', (15, 17))	('IDH1', 'Gene', '3417', (54, 58))	('patients', 'Species', '9606', (66, 74))
224924	27245697	Our study revealed an intrinsic distinction between IDH1 and IDH2 mutant gliomas, and these mutations should be considered separately because their differences could have implications for the diagnosis and treatment of IDH1/2 mutant gliomas.	('IDH1', 'Gene', '3417', (219, 223))	('IDH1/2', 'Gene', '3417;3418', (219, 225))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('IDH1', 'Gene', '3417', (52, 56))	('mutant', 'Var', (66, 72))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('gliomas', 'Disease', (73, 80))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('IDH2', 'Gene', (61, 65))	('have implications', 'Reg', (166, 183))	('IDH1/2', 'Gene', (219, 225))	('gliomas', 'Disease', (233, 240))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('IDH2', 'Gene', '3418', (61, 65))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('IDH1', 'Gene', (219, 223))	('IDH1', 'Gene', (52, 56))
224927	27245697	Mutations in IDH1 and IDH2, which represent the most frequently mutated metabolic genes in human cancer, are implicated to be mutated in more than 50-80 % of low-grade gliomas and secondary glioblastomas (sGBM), 10 % of intrahepatic cholangiocarcinoma, 20 % of acute myeloid leukemia (AML), 56 % of chondrosarcomas, and over 10 % of melanoma cases.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (299, 314))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (220, 251))	('glioblastomas', 'Disease', (190, 203))	('intrahepatic cholangiocarcinoma', 'Disease', (220, 251))	('chondrosarcomas', 'Disease', 'MESH:D002813', (299, 314))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (233, 251))	('acute myeloid leukemia', 'Disease', (261, 283))	('mutated', 'Var', (126, 133))	('glioblastomas', 'Disease', 'MESH:D005909', (190, 203))	('cancer', 'Disease', (97, 103))	('leukemia', 'Phenotype', 'HP:0001909', (275, 283))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (333, 341))	('melanoma', 'Disease', (333, 341))	('IDH2', 'Gene', '3418', (22, 26))	('chondrosarcomas', 'Disease', (299, 314))	('AML', 'Disease', 'MESH:D015470', (285, 288))	('gliomas', 'Disease', (168, 175))	('AML', 'Disease', (285, 288))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (261, 283))	('AML', 'Phenotype', 'HP:0004808', (285, 288))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (267, 283))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (261, 283))	('IDH1', 'Gene', '3417', (13, 17))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('glioblastomas', 'Phenotype', 'HP:0012174', (190, 203))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('melanoma', 'Disease', 'MESH:D008545', (333, 341))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (299, 313))	('human', 'Species', '9606', (91, 96))
224930	27245697	For example, IDH1 mutations are predominant in gliomas, chondrosarcoma, and cholangiocarcinoma, whereas IDH1 mutations and IDH2 mutations are equally common in AML.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('chondrosarcoma', 'Disease', (56, 70))	('chondrosarcoma', 'Disease', 'MESH:D002813', (56, 70))	('cholangiocarcinoma', 'Disease', (76, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('IDH1', 'Gene', '3417', (104, 108))	('AML', 'Disease', 'MESH:D015470', (160, 163))	('IDH2', 'Gene', (123, 127))	('AML', 'Disease', (160, 163))	('IDH1', 'Gene', (13, 17))	('IDH2', 'Gene', '3418', (123, 127))	('AML', 'Phenotype', 'HP:0004808', (160, 163))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (56, 70))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))	('IDH1', 'Gene', '3417', (13, 17))	('gliomas', 'Disease', (47, 54))	('predominant', 'Reg', (32, 43))	('IDH1', 'Gene', (104, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))	('mutations', 'Var', (18, 27))
224931	27245697	Despite their different physiological characteristics, most genomic studies of the molecular landscapes in human cancer have frequently combined IDH1 mutations and IDH2 mutations as a single functional group.	('IDH1', 'Gene', (145, 149))	('mutations', 'Var', (169, 178))	('human', 'Species', '9606', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('IDH1', 'Gene', '3417', (145, 149))	('cancer', 'Disease', (113, 119))	('IDH2', 'Gene', (164, 168))	('mutations', 'Var', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('IDH2', 'Gene', '3418', (164, 168))
224935	27245697	In 2008, the genes encoding IDH1 were found to be mutated in low-grade gliomas and a subset of sGBM.	('IDH1', 'Gene', '3417', (28, 32))	('gliomas', 'Disease', (71, 78))	('gliomas', 'Disease', 'MESH:D005910', (71, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('mutated', 'Var', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('IDH1', 'Gene', (28, 32))
224936	27245697	In subsequent studies, IDH1 mutations were reported to occur in 70-80 % of WHO grade II or III astrocytomas, oligodendrogliomas, and oligoastrocytomas, whereas a small group (3-5 %) were found to harbor IDH2 mutations.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (109, 127))	('astrocytoma', 'Phenotype', 'HP:0009592', (95, 106))	('astrocytomas', 'Disease', (95, 107))	('astrocytomas', 'Disease', 'MESH:D001254', (138, 150))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (133, 150))	('oligodendrogliomas', 'Disease', (109, 127))	('occur', 'Reg', (55, 60))	('IDH1', 'Gene', (23, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (138, 149))	('IDH2', 'Gene', (203, 207))	('IDH1', 'Gene', '3417', (23, 27))	('astrocytomas', 'Disease', (138, 150))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('astrocytomas', 'Disease', 'MESH:D001254', (95, 107))	('mutations', 'Var', (28, 37))	('IDH2', 'Gene', '3418', (203, 207))	('oligoastrocytomas', 'Disease', (133, 150))
224937	27245697	This pattern contrasts that observed in AML, which features similar rates of IDH1 (6.6 %) and IDH2 mutations (10.8 %).	('AML', 'Disease', 'MESH:D015470', (40, 43))	('IDH2', 'Gene', '3418', (94, 98))	('IDH1', 'Gene', (77, 81))	('AML', 'Phenotype', 'HP:0004808', (40, 43))	('mutations', 'Var', (99, 108))	('AML', 'Disease', (40, 43))	('IDH1', 'Gene', '3417', (77, 81))	('IDH2', 'Gene', (94, 98))
224938	27245697	Moreover, mutations of IDH1 and IDH2 are mutually exclusive in gliomas, and biochemical investigations showed that IDH1 and IDH2 mutations differ in D-2-hydroxyglutarate (D-2HG) production in gliomas.	('differ', 'Reg', (139, 145))	('IDH1', 'Gene', '3417', (115, 119))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (149, 169))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH2', 'Gene', (124, 128))	('IDH2', 'Gene', '3418', (124, 128))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('IDH1', 'Gene', (23, 27))	('gliomas', 'Disease', (192, 199))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('IDH1', 'Gene', '3417', (23, 27))	('gliomas', 'Disease', (63, 70))	('IDH2', 'Gene', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('IDH1', 'Gene', (115, 119))	('mutations', 'Var', (129, 138))	('IDH2', 'Gene', '3418', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('mutations', 'Var', (10, 19))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
224939	27245697	This difference suggests that IDH1 and IDH2 mutations may impact different cellular pathways and exert different tumorigenic effects.	('tumor', 'Disease', (113, 118))	('IDH2', 'Gene', (39, 43))	('cellular pathways', 'Pathway', (75, 92))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', '3418', (39, 43))	('impact', 'Reg', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IDH1', 'Gene', '3417', (30, 34))
224940	27245697	To investigate the different clinical and molecular characterization between IDH1 mutant and IDH2 mutant gliomas, we studied a cohort of 811 patients consisting 448 IDH1 mutant, 18 IDH2 mutant and 345 IDH1/2 wild-type gliomas.	('IDH2', 'Gene', (181, 185))	('IDH1', 'Gene', '3417', (201, 205))	('mutant', 'Var', (170, 176))	('patients', 'Species', '9606', (141, 149))	('IDH2', 'Gene', (93, 97))	('IDH2', 'Gene', '3418', (181, 185))	('IDH2', 'Gene', '3418', (93, 97))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Disease', (218, 225))	('IDH1', 'Gene', (165, 169))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('IDH1', 'Gene', (77, 81))	('gliomas', 'Disease', 'MESH:D005910', (218, 225))	('IDH1/2', 'Gene', '3417;3418', (201, 207))	('IDH1', 'Gene', '3417', (165, 169))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('IDH1', 'Gene', (201, 205))	('IDH1/2', 'Gene', (201, 207))	('mutant', 'Var', (186, 192))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('IDH1', 'Gene', '3417', (77, 81))
224942	27245697	We compared the mutational landscapes of IDH1 and IDH2 mutant gliomas, their clinical associations, overall survival, and progression-free survival.	('IDH2', 'Gene', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('IDH2', 'Gene', '3418', (50, 54))	('mutant', 'Var', (55, 61))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('gliomas', 'Disease', (62, 69))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
224943	27245697	Our aim was to provide insight into the differences between IDH1 and IDH2 mutant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IDH2', 'Gene', '3418', (69, 73))	('IDH2', 'Gene', (69, 73))	('IDH1', 'Gene', (60, 64))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('IDH1', 'Gene', '3417', (60, 64))	('mutant', 'Var', (74, 80))
224944	27245697	Glioma samples were obtained from 811 patients with gliomas, including 448 IDH1 mutant, 18 IDH2 mutant and 345 IDH1/2 wild-type gliomas, which were composed of 577 low grade (II + III) gliomas, including 193 diffuse astrocytoma, 39 anaplastic astrocytomas, 49 low-grade oligodendrogliomas, 27 anaplastic oligodendrogliomas, 186 oligoastrocytomas, 83 anaplastic oligoastrocyotmas and 234 glioblastomas.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('astrocytoma', 'Disease', (333, 344))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (304, 322))	('astrocytomas', 'Disease', 'MESH:D001254', (243, 255))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (243, 254))	('astrocytomas', 'Disease', (333, 345))	('oligoastrocyotmas', 'Disease', (361, 378))	('gliomas', 'Disease', 'MESH:D005910', (315, 322))	('Glioma', 'Disease', (0, 6))	('glioblastomas', 'Disease', (387, 400))	('patients', 'Species', '9606', (38, 46))	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', (111, 115))	('glioma', 'Phenotype', 'HP:0009733', (315, 321))	('gliomas', 'Disease', (52, 59))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (270, 288))	('astrocytoma', 'Phenotype', 'HP:0009592', (216, 227))	('mutant', 'Var', (96, 102))	('mutant', 'Var', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('oligodendrogliomas', 'Disease', (304, 322))	('glioblastomas', 'Disease', 'MESH:D005909', (387, 400))	('gliomas', 'Phenotype', 'HP:0009733', (315, 322))	('gliomas', 'Disease', (281, 288))	('gliomas', 'Disease', (185, 192))	('astrocytoma', 'Disease', 'MESH:D001254', (243, 254))	('astrocytomas', 'Disease', 'MESH:D001254', (333, 345))	('astrocytoma', 'Disease', (243, 254))	('glioma', 'Phenotype', 'HP:0009733', (281, 287))	('gliomas', 'Disease', (128, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (333, 344))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('astrocytomas', 'Disease', (243, 255))	('IDH2', 'Gene', (91, 95))	('IDH1', 'Gene', '3417', (111, 115))	('oligodendrogliomas', 'Disease', (270, 288))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('IDH2', 'Gene', '3418', (91, 95))	('gliomas', 'Disease', 'MESH:D005910', (281, 288))	('astrocytoma', 'Disease', 'MESH:D001254', (216, 227))	('oligoastrocytomas', 'Disease', (328, 345))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('astrocytoma', 'Disease', (216, 227))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (328, 345))	('glioblastomas', 'Phenotype', 'HP:0012174', (387, 400))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH1/2', 'Gene', '3417;3418', (111, 117))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('IDH1', 'Gene', (75, 79))	('gliomas', 'Disease', (315, 322))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('astrocytoma', 'Disease', 'MESH:D001254', (333, 344))	('gliomas', 'Phenotype', 'HP:0009733', (281, 288))	('oligoastrocyotmas', 'Disease', 'None', (361, 378))	('IDH1/2', 'Gene', (111, 117))
224949	27245697	The pyrosequencing of IDH1/2 mutations was supported by Gene-tech (Shanghai, China) and performed on a Pyro-Mark Q96 ID System (Qiagen, Valencia, Calif).	('IDH1/2', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('Calif', 'Gene', (146, 151))	('Calif', 'Gene', '9337', (146, 151))
224952	27245697	The differences among patients in baseline clinical and molecular features according to IDH1 and IDH2 mutational status were tested using the Fisher's exact and Wilcoxon rank sum tests for categoric and continuous variables, respectively.	('IDH2', 'Gene', (97, 101))	('IDH1', 'Gene', (88, 92))	('IDH2', 'Gene', '3418', (97, 101))	('patients', 'Species', '9606', (22, 30))	('IDH1', 'Gene', '3417', (88, 92))	('mutational', 'Var', (102, 112))
224953	27245697	Gens that were differently methylated between IDH2 mutant and IDH1 mutant tumors were obtained using the standard two-sampled t-test with unequal variance and sample size.	('IDH2', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (62, 66))	('mutant', 'Var', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('IDH2', 'Gene', '3418', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('mutant', 'Var', (67, 73))	('IDH1', 'Gene', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
224954	27245697	We further filtered the list of significant genes by retaining those which exhibited at least 1.5-fold difference in gene expression between IDH2 mutant and IDH1 mutant in our final comparisons.	('IDH2', 'Gene', '3418', (141, 145))	('mutant', 'Var', (162, 168))	('mutant', 'Var', (146, 152))	('IDH1', 'Gene', (157, 161))	('IDH1', 'Gene', '3417', (157, 161))	('IDH2', 'Gene', (141, 145))
224955	27245697	Among a total of 811 gliomas, IDH2 mutations were identified in 18 cases (2.2 %) (Table 1).	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('IDH2', 'Gene', (30, 34))	('gliomas', 'Disease', (21, 28))	('IDH2', 'Gene', '3418', (30, 34))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('mutations', 'Var', (35, 44))
224956	27245697	IDH2 mutations were found in 0.5 % of pGBM (1/215), 3.4 % of sGBM (1/29) and 2.8 % (16/577) of low grade gliomas, while IDH1 mutations are found in 14.1 % (29/205) of pGBM, 55.2 % (16/29) of sGBM and 69.8 % (403/577) of low grade gliomas.	('pGBM', 'Disease', (38, 42))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('pGBM', 'Chemical', '-', (167, 171))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', (105, 112))	('pGBM', 'Chemical', '-', (38, 42))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('IDH1', 'Gene', (120, 124))	('IDH2', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('gliomas', 'Disease', 'MESH:D005910', (230, 237))	('IDH1', 'Gene', '3417', (120, 124))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('gliomas', 'Disease', (230, 237))	('IDH2', 'Gene', '3418', (0, 4))
224957	27245697	Combined IDH1 and IDH2 mutations were found in 14.6 % (30/205) of pGBM, 58.6 % (17/29) of sGBM and 72.6 % (419/577) of low grade gliomas.	('IDH2', 'Gene', '3418', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('IDH1', 'Gene', (9, 13))	('pGBM', 'Disease', (66, 70))	('gliomas', 'Disease', (129, 136))	('IDH1', 'Gene', '3417', (9, 13))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('mutations', 'Var', (23, 32))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('pGBM', 'Chemical', '-', (66, 70))	('IDH2', 'Gene', (18, 22))	('found', 'Reg', (38, 43))
224958	27245697	1 and Table 2, patients with mutations in IDH2 did not differ from IDH1-mutant patients in terms of age, gender, WHO grade, KPS, histologic type and laterality (Table 2).	('patients', 'Species', '9606', (15, 23))	('IDH1', 'Gene', (67, 71))	('mutations', 'Var', (29, 38))	('IDH1', 'Gene', '3417', (67, 71))	('IDH2', 'Gene', (42, 46))	('patients', 'Species', '9606', (79, 87))	('KPS', 'Disease', (124, 127))	('IDH2', 'Gene', '3418', (42, 46))
224959	27245697	To characterize the molecular features of IDH2 mutant gliomas, we analyzed associations between IDH2 mutations and other mutational events.	('IDH2', 'Gene', '3418', (96, 100))	('mutations', 'Var', (101, 110))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH2', 'Gene', (42, 46))	('IDH2', 'Gene', (96, 100))	('mutant', 'Var', (47, 53))	('IDH2', 'Gene', '3418', (42, 46))
224960	27245697	Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion (p < 0.05) and a lower frequency of P53 mutation (p < 0.05) than IDH1 mutant patients (Table 3).	('lower', 'NegReg', (91, 96))	('P53', 'Gene', '7157', (110, 113))	('IDH1', 'Gene', (139, 143))	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (151, 159))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', '3417', (139, 143))	('IDH2', 'Gene', (14, 18))	('P53', 'Gene', (110, 113))	('1p/19q co-deletion', 'Var', (55, 73))	('IDH2', 'Gene', '3418', (14, 18))
224961	27245697	Strikingly, the presence of IDH2 mutations and PTEN mutations, P53 mutation and ATRX mutation did not correlate (Fig.	('mutations', 'Var', (52, 61))	('IDH2', 'Gene', '3418', (28, 32))	('mutations', 'Var', (33, 42))	('PTEN', 'Gene', (47, 51))	('IDH2', 'Gene', (28, 32))	('P53', 'Gene', (63, 66))	('PTEN', 'Gene', '5728', (47, 51))	('ATRX', 'Gene', (80, 84))	('P53', 'Gene', '7157', (63, 66))	('ATRX', 'Gene', '546', (80, 84))
224962	27245697	To gain biologic insight into the potentially significance of IDH2 mutations, we compared the whole-transcriptome sequencing expression profiles of 5 IDH2 mutant patients with 109 IDH1 mutant patients and 47 IDH1/2 wild-type patients.	('patients', 'Species', '9606', (162, 170))	('IDH1', 'Gene', (180, 184))	('IDH1/2', 'Gene', (208, 214))	('patients', 'Species', '9606', (225, 233))	('IDH1', 'Gene', (208, 212))	('IDH1', 'Gene', '3417', (180, 184))	('patients', 'Species', '9606', (192, 200))	('mutant', 'Var', (155, 161))	('IDH1', 'Gene', '3417', (208, 212))	('IDH1/2', 'Gene', '3417;3418', (208, 214))	('IDH2', 'Gene', (150, 154))	('IDH2', 'Gene', (62, 66))	('IDH2', 'Gene', '3418', (150, 154))	('IDH2', 'Gene', '3418', (62, 66))
224963	27245697	First, we used a Gene Set Enrichment Analysis (GSEA) to compare the global gene expression profiles of the IDH2 mutant and IDH1 mutant gliomas.	('IDH2', 'Gene', '3418', (107, 111))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('IDH1', 'Gene', (123, 127))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('mutant', 'Var', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('GSEA', 'Chemical', '-', (47, 51))	('mutant', 'Var', (112, 118))	('IDH1', 'Gene', '3417', (123, 127))	('IDH2', 'Gene', (107, 111))
224964	27245697	We then compared the whole-transcriptome sequencing expression profiles of the IDH2 mutant and IDH1/2 wild-type gliomas (Fig.	('IDH2', 'Gene', '3418', (79, 83))	('IDH1/2', 'Gene', (95, 101))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('mutant', 'Var', (84, 90))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('IDH2', 'Gene', (79, 83))	('IDH1/2', 'Gene', '3417;3418', (95, 101))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
224965	27245697	Given the DNA methylation profiles of 3 IDH2 mutant gliomas and 41 IDH1 mutant gliomas, we used standard t-tests to identify differentially methylated regions.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', (52, 59))	('IDH2', 'Gene', (40, 44))	('mutant', 'Var', (45, 51))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('mutant', 'Var', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH1', 'Gene', (67, 71))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('IDH2', 'Gene', '3418', (40, 44))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', '3417', (67, 71))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
224966	27245697	The methylation patterns of genes that correlated with IDH2 mutant gliomas are shown in Fig.	('IDH2', 'Gene', '3418', (55, 59))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('IDH2', 'Gene', (55, 59))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('gliomas', 'Disease', (67, 74))	('mutant', 'Var', (60, 66))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
224967	27245697	The four most representative biological processes for genes commonly altered by hypermethylation were the regulation of cell proliferation, cell motion, cell migration and response to hypoxia (Fig.	('cell proliferation', 'CPA', (120, 138))	('hypoxia', 'Disease', (184, 191))	('hypoxia', 'Disease', 'MESH:D000860', (184, 191))	('cell motion', 'CPA', (140, 151))	('altered', 'Reg', (69, 76))	('hypermethylation', 'Var', (80, 96))	('cell migration', 'CPA', (153, 167))
224968	27245697	In our cohort, the presence of an IDH2 mutation was associated with a longer overall survival (p < 0.05) and longer progression-free survival (p < 0.05) (Fig.	('longer', 'PosReg', (109, 115))	('mutation', 'Var', (39, 47))	('presence', 'Var', (19, 27))	('overall', 'MPA', (77, 84))	('longer', 'PosReg', (70, 76))	('IDH2', 'Gene', (34, 38))	('progression-free survival', 'CPA', (116, 141))	('IDH2', 'Gene', '3418', (34, 38))
224970	27245697	However, when considering all patients with IDH2 mutations, the overall survival and time to recurrence did not differ from those of IDH1 mutant patients (Fig.	('patients', 'Species', '9606', (145, 153))	('mutations', 'Var', (49, 58))	('IDH2', 'Gene', (44, 48))	('IDH1', 'Gene', (133, 137))	('IDH2', 'Gene', '3418', (44, 48))	('patients', 'Species', '9606', (30, 38))	('IDH1', 'Gene', '3417', (133, 137))
224971	27245697	This result illustrates that the effects of IDH2 mutation and IDH1 mutation on clinical prognosis were similar.	('IDH2', 'Gene', (44, 48))	('IDH1', 'Gene', '3417', (62, 66))	('mutation', 'Var', (49, 57))	('IDH2', 'Gene', '3418', (44, 48))	('IDH1', 'Gene', (62, 66))
224972	27245697	Mutations in the IDH1 and IDH2 genes have been found in patients with gliomas and were initially identified in low-grade gliomas and secondary glioblastomas.	('patients', 'Species', '9606', (56, 64))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('glioblastomas', 'Disease', 'MESH:D005909', (143, 156))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1', 'Gene', '3417', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (97, 107))	('glioblastomas', 'Phenotype', 'HP:0012174', (143, 156))	('gliomas', 'Disease', (121, 128))	('found', 'Reg', (47, 52))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('IDH2', 'Gene', (26, 30))	('IDH1', 'Gene', (17, 21))	('glioblastomas', 'Disease', (143, 156))	('IDH2', 'Gene', '3418', (26, 30))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
224973	27245697	Strikingly, mutations in IDH1 and IDH2 are mutually exclusive in gliomas.	('gliomas', 'Disease', (65, 72))	('IDH2', 'Gene', '3418', (34, 38))	('mutations', 'Var', (12, 21))	('exclusive', 'Reg', (52, 61))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))	('IDH2', 'Gene', (34, 38))	('IDH1', 'Gene', (25, 29))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('IDH1', 'Gene', '3417', (25, 29))
224975	27245697	In this report, we compared the clinical and molecular characteristics of glioma patients harboring IDH1 and IDH2 mutations.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('IDH1', 'Gene', '3417', (100, 104))	('IDH2', 'Gene', (109, 113))	('mutations', 'Var', (114, 123))	('patients', 'Species', '9606', (81, 89))	('glioma', 'Disease', (74, 80))	('IDH2', 'Gene', '3418', (109, 113))	('IDH1', 'Gene', (100, 104))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
224976	27245697	Like mutations in IDH1, mutations in IDH2 affect a conserved arginine residue (R172) in the substrate-binding site of the IDH2 enzyme.	('affect', 'Reg', (42, 48))	('IDH2', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (18, 22))	('arginine', 'Chemical', 'MESH:D001120', (61, 69))	('IDH2', 'Gene', (122, 126))	('R172', 'Var', (79, 83))	('IDH2', 'Gene', '3418', (37, 41))	('IDH2', 'Gene', '3418', (122, 126))	('mutations', 'Var', (24, 33))	('IDH1', 'Gene', (18, 22))
224977	27245697	In our cohort, the presence of an IDH2 mutation did not correlate with the presence of PTEN, P53, and ATRX mutations, but a highly significant positive correlation was observed with the presence of a 1p/19q co-deletion: 44.4 % of IDH2 mutation patients harbored a 1p/19q co-deletion.	('mutation', 'Var', (235, 243))	('PTEN', 'Gene', (87, 91))	('ATRX', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (87, 91))	('P53', 'Gene', '7157', (93, 96))	('ATRX', 'Gene', '546', (102, 106))	('IDH2', 'Gene', '3418', (230, 234))	('IDH2', 'Gene', (230, 234))	('IDH2', 'Gene', (34, 38))	('patients', 'Species', '9606', (244, 252))	('P53', 'Gene', (93, 96))	('IDH2', 'Gene', '3418', (34, 38))
224978	27245697	In malignant glioma, IDH1 mutations are ubiquitous in tumor cells, and IDH1 mutations precede secondary and tertiary lesions, suggesting that IDH1 mutations are an early causative event in the genesis of gliomas.	('mutations', 'Var', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('gliomas', 'Disease', (204, 211))	('mutations', 'Var', (26, 35))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('IDH1', 'Gene', (142, 146))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('IDH1', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (142, 146))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('malignant glioma', 'Disease', (3, 19))	('IDH1', 'Gene', '3417', (71, 75))	('malignant glioma', 'Disease', 'MESH:D005910', (3, 19))	('IDH1', 'Gene', '3417', (21, 25))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (54, 59))
224979	27245697	A pathology study of multiple biopsies from the same patient found that IDH1 mutations occurred before the acquisition of P53 mutations and 1p/19q loss of heterozygosity (LOH), suggesting that IDH1 mutations may result in cellular stress that leads to the mutation of P53 and 1p/19q loss.	('IDH1', 'Gene', (193, 197))	('IDH1', 'Gene', (72, 76))	('loss of heterozygosity', 'NegReg', (147, 169))	('P53', 'Gene', (122, 125))	('mutation', 'Var', (256, 264))	('cellular stress', 'MPA', (222, 237))	('IDH1', 'Gene', '3417', (72, 76))	('IDH1', 'Gene', '3417', (193, 197))	('loss', 'NegReg', (283, 287))	('mutations', 'Var', (198, 207))	('result in', 'Reg', (212, 221))	('mutations', 'Var', (77, 86))	('P53', 'Gene', '7157', (122, 125))	('P53', 'Gene', '7157', (268, 271))	('1p/19q', 'Var', (276, 282))	('P53', 'Gene', (268, 271))	('patient', 'Species', '9606', (53, 60))
224980	27245697	However, IDH2 mutations and PTEN, P53 and ATRX mutations were mutually exclusive, suggesting that the microenvironment of IDH2 mutations may not create cellular stress that leads to the other mutations, which needs further research to fully elucidate.	('PTEN', 'Gene', (28, 32))	('IDH2', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (28, 32))	('P53', 'Gene', (34, 37))	('IDH2', 'Gene', (122, 126))	('ATRX', 'Gene', (42, 46))	('IDH2', 'Gene', '3418', (9, 13))	('IDH2', 'Gene', '3418', (122, 126))	('P53', 'Gene', '7157', (34, 37))	('mutations', 'Var', (127, 136))	('ATRX', 'Gene', '546', (42, 46))
224983	27245697	One study demonstrated that glioma cells harboring mutant IDH1 may maintain cell proliferation via the glutamate metabolism pathway.	('maintain', 'PosReg', (67, 75))	('IDH1', 'Gene', '3417', (58, 62))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glutamate metabolism pathway', 'Pathway', (103, 131))	('mutant', 'Var', (51, 57))	('glutamate', 'Chemical', 'MESH:D018698', (103, 112))	('cell proliferation', 'CPA', (76, 94))	('glioma', 'Disease', (28, 34))	('IDH1', 'Gene', (58, 62))
224984	27245697	In our study, GSEA was performed for IDH2 and IDH1 mutations, yielding enriched gene sets related to oxidative phosphorylation, which is critical to tricarboxylic acid (TCA) cycle, in the IDH2 mutation subset.	('mutations', 'Var', (51, 60))	('IDH1', 'Gene', (46, 50))	('IDH2', 'Gene', (37, 41))	('IDH2', 'Gene', (188, 192))	('oxidative', 'MPA', (101, 110))	('IDH1', 'Gene', '3417', (46, 50))	('IDH2', 'Gene', '3418', (37, 41))	('IDH2', 'Gene', '3418', (188, 192))	('TCA', 'Chemical', 'MESH:D014233', (169, 172))	('mutation', 'Var', (193, 201))	('GSEA', 'Chemical', '-', (14, 18))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (149, 167))
224989	27245697	In conclusion, our results describe the clinical and biological characteristics of IDH1 and IDH2 mutations in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('mutations', 'Var', (97, 106))	('IDH1', 'Gene', '3417', (83, 87))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('IDH2', 'Gene', (92, 96))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('IDH2', 'Gene', '3418', (92, 96))	('IDH1', 'Gene', (83, 87))
224990	27245697	Understanding the underlying biology of the differences in outcome observed for IDH1 and IDH2 mutant gliomas will be important for future studies and may lead to the development of novel approaches to therapy.	('IDH1', 'Gene', (80, 84))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('IDH1', 'Gene', '3417', (80, 84))	('lead to', 'Reg', (154, 161))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('mutant', 'Var', (94, 100))	('IDH2', 'Gene', (89, 93))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('IDH2', 'Gene', '3418', (89, 93))
225008	25815273	For example, in one study, few patients with low-grade gliomas showed cognitive deterioration when screened with the mini-mental state examination (MMSE), irrespective of radiation treatment.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('cognitive deterioration', 'Phenotype', 'HP:0001268', (70, 93))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('low-grade', 'Var', (45, 54))	('cognitive deterioration', 'Disease', (70, 93))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('patients', 'Species', '9606', (31, 39))	('cognitive deterioration', 'Disease', 'MESH:D003072', (70, 93))
225049	25815273	Apart from slightly higher self-reported symptoms of depression by the MoCA-Impaired group compared to the MoCA-Intact group, t(15) = 2.16, p < 0.05, the two groups were well matched for age, gender, education, pre-morbid intelligence, and chronicity (time since surgery; all p > 0.05).	('morbid intelligence', 'Phenotype', 'HP:0001249', (215, 234))	('MoCA-Impaired', 'Var', (71, 84))	('higher', 'PosReg', (20, 26))	('depression', 'Disease', 'MESH:D000275', (53, 63))	('depression', 'Phenotype', 'HP:0000716', (53, 63))	('depression', 'Disease', (53, 63))
225114	23050879	Autologous antibody to src-homology 3-domain GRB2-like 1 specifically increases in the sera of patients with low-grade gliomas Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable in spite of various therapeutic approaches.	('GRB2', 'Gene', '2885', (45, 49))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('patients', 'Species', '9606', (95, 103))	('Glioma', 'Disease', 'MESH:D005910', (127, 133))	('Glioma', 'Phenotype', 'HP:0009733', (127, 133))	('increases', 'PosReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('central nervous system tumor', 'Phenotype', 'HP:0100006', (171, 199))	('gliomas', 'Disease', (119, 126))	('nervous system tumor', 'Phenotype', 'HP:0004375', (179, 199))	('malignant central nervous system tumor', 'Disease', 'MESH:D016543', (161, 199))	('GRB2', 'Gene', (45, 49))	('Glioma', 'Disease', (127, 133))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('malignant central nervous system tumor', 'Disease', (161, 199))	('malignant central nervous system tumor in adult', 'Phenotype', 'HP:0100836', (161, 208))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('low-grade', 'Var', (109, 118))
225116	23050879	The levels of serum autoantibodies to the SEREX-identified glioma-related antigens were analyzed by ELISA, and the epitope site was identified using deletion mutants and overlap peptide array.	('deletion mutants', 'Var', (149, 165))	('glioma', 'Disease', (59, 65))	('SEREX', 'Chemical', '-', (42, 47))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))
225186	23050879	The level of anti-SH3GL1 autoantibody could be a novel low-grade glioma-specific serum marker.	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Disease', (65, 71))	('anti-SH3GL1', 'Var', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))
225191	23050879	To determine the accurate immuno-reactive site, an ELISA using 4 deletion mutants of SH3GL1 cDNA was performed.	('deletion mutants', 'Var', (65, 81))	('rat', 'Species', '10116', (21, 24))	('SH3GL1', 'Gene', (85, 91))
225194	23050879	Although these results indicated that the C-terminal of SH3GL1 contributed to the immune-response, the differences were disappeared in SH3GL1 mut-4, deleting only 15 amino acids at the 3' end of SH3GL1 mut-1 (Figure 4D).	('contributed', 'Reg', (63, 74))	('immune-response', 'CPA', (82, 97))	('SH3GL1 mut-1', 'Gene', '6455', (195, 207))	('SH3GL1 mut-1', 'Gene', (195, 207))	('deleting', 'Var', (149, 157))
225213	23050879	We have shown in this study that the SH3-domain of GRB2-like protein, which links the receptor tyrosine kinases activation to the ras pathway, had already overexpressed in low-grade gliomas and strongly induced a humoral immune response.	('GRB2-like protein', 'Gene', (51, 68))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('SH3-domain', 'Var', (37, 47))	('GRB2-like protein', 'Gene', '9402', (51, 68))	('overexpressed', 'PosReg', (155, 168))	('humoral immune response', 'CPA', (213, 236))	('induced', 'Reg', (203, 210))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('gliomas', 'Disease', (182, 189))	('ras pathway', 'Pathway', (130, 141))
225215	23050879	Although there are few reports describing overexpression of this protein in human cancers, SH3GL1 protein is related to the activation of MLL proto-oncogene by chromosomal translocation .	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('activation', 'PosReg', (124, 134))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('MLL', 'Gene', (138, 141))	('MLL', 'Gene', '4297', (138, 141))	('SH3GL1', 'Gene', (91, 97))	('chromosomal translocation', 'Var', (160, 185))	('protein', 'Protein', (98, 105))
225226	23050879	The major cause of the lower level of anti-SH3GL1 autoantibody in high-grade glioma patients would be the non-specific immunosuppression caused by increased immunosuppressive cytokines .	('patients', 'Species', '9606', (84, 92))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('anti-SH3GL1', 'Var', (38, 49))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('lower', 'NegReg', (23, 28))
225241	33063010	Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas The mitogen-activated protein kinases/extracelluar signal-regulated kinases pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer.	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('mutations', 'Var', (249, 258))	('BRAF', 'Gene', '673', (262, 266))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('BRAF', 'Gene', (262, 266))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
225242	33063010	Previous studies found that BRAF mutations as well as KIAA1549-BRAF fusions are common in intracranial low-grade gliomas (LGGs).	('KIAA1549', 'Gene', (54, 62))	('BRAF', 'Gene', '673', (28, 32))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('common', 'Reg', (80, 86))	('gliomas', 'Disease', (113, 120))	('mutations', 'Var', (33, 42))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', (63, 67))	('KIAA1549', 'Gene', '57670', (54, 62))
225250	33063010	Other mutations of interest were also identified in this patient cohort including BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion.	('FGFR1', 'Gene', '2260', (114, 119))	('deletion', 'Var', (132, 140))	('TP53', 'Gene', '7157', (108, 112))	('patient', 'Species', '9606', (57, 64))	('TP53', 'Gene', (108, 112))	('CDKN2A', 'Gene', '1029', (125, 131))	('PTPN11', 'Gene', '5781', (93, 99))	('H3F3A', 'Gene', '3020', (101, 106))	('BRAFV600E', 'Var', (82, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (82, 91))	('CDKN2A', 'Gene', (125, 131))	('H3F3A', 'Gene', (101, 106))	('FGFR1', 'Gene', (114, 119))	('PTPN11', 'Gene', (93, 99))
225256	33063010	They are known to have BRAF mutations as well as KIAA1549-BRAF fusions, which is helpful in predicting outcome and treatment responses in this group.	('BRAF', 'Gene', '673', (23, 27))	('KIAA1549', 'Gene', '57670', (49, 57))	('BRAF', 'Gene', (23, 27))	('KIAA1549', 'Gene', (49, 57))	('BRAF', 'Gene', '673', (58, 62))	('mutations', 'Var', (28, 37))	('BRAF', 'Gene', (58, 62))
225257	33063010	This study retrospectively investigated the genetic landscape of a cohort of pediatric spinal LGGs for the presence of BRAF aberrations as well as other genetic mutations of interest.	('BRAF', 'Gene', (119, 123))	('BRAF', 'Gene', '673', (119, 123))	('aberrations', 'Var', (124, 135))	('spinal LGGs', 'Disease', (87, 98))
225266	33063010	The most common genetic changes in intracranial LGGs or glioneuronal tumors involve the mitogen-activated protein kinases/extracelluar signal-regulated kinases (MAPK/ERK) pathway, which drives a number of processes including cellular proliferation, differentiation, mortality, stress response, apoptosis, and survival.	('cellular proliferation', 'CPA', (225, 247))	('drives', 'Reg', (186, 192))	('mortality', 'Disease', 'MESH:D003643', (266, 275))	('ERK', 'Gene', '5594', (166, 169))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (56, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ERK', 'Gene', (166, 169))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (56, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('apoptosis', 'CPA', (294, 303))	('mortality', 'Disease', (266, 275))	('differentiation', 'CPA', (249, 264))	('genetic', 'Var', (16, 23))	('intracranial LGGs or glioneuronal tumors', 'Disease', (35, 75))	('intracranial LGGs or glioneuronal tumors', 'Disease', 'MESH:D001932', (35, 75))
225267	33063010	There are a number of mutations and fusions in this pathway that result in constitutive over-activation of the MAP/ERK pathway.	('ERK', 'Gene', (115, 118))	('fusions', 'Var', (36, 43))	('mutations', 'Var', (22, 31))	('over-activation', 'PosReg', (88, 103))	('ERK', 'Gene', '5594', (115, 118))
225269	33063010	LGGs occurring elsewhere in the brain have a higher percentage of tumors with a point mutation in BRAF at codon 600 (BRAFV600E and variants such as BRAFV600D).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('BRAFV600E', 'Mutation', 'rs113488022', (117, 126))	('BRAF', 'Gene', (98, 102))	('tumors', 'Disease', (66, 72))	('point mutation', 'Var', (80, 94))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('BRAF', 'Gene', '673', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('BRAF', 'Gene', '673', (117, 121))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (117, 121))	('BRAF', 'Gene', (148, 152))
225270	33063010	This mutation is also seen in many CNS tumors including desmoplastic infantile gangliogliomas, diffuse astrocytomas, gangliogliomas, pleomorphic xanthoastrocytomas, and epitheloid glioblastomas.	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('astrocytomas', 'Disease', (151, 163))	('seen', 'Reg', (22, 26))	('astrocytomas', 'Disease', (103, 115))	('tumors', 'Disease', (39, 45))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('glioblastomas', 'Disease', (180, 193))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('desmoplastic infantile gangliogliomas', 'Disease', (56, 93))	('gangliogliomas', 'Disease', 'MESH:D018303', (79, 93))	('glioblastomas', 'Disease', 'MESH:D005909', (180, 193))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (133, 163))	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('desmoplastic infantile gangliogliomas', 'Disease', 'MESH:D018303', (56, 93))	('astrocytomas', 'Disease', 'MESH:D001254', (151, 163))	('astrocytoma', 'Phenotype', 'HP:0009592', (151, 162))	('astrocytomas', 'Disease', 'MESH:D001254', (103, 115))	('gangliogliomas', 'Disease', (79, 93))	('CNS tumor', 'Phenotype', 'HP:0100006', (35, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('gangliogliomas', 'Disease', 'MESH:D018303', (117, 131))	('pleomorphic xanthoastrocytomas', 'Disease', (133, 163))	('gangliogliomas', 'Disease', (117, 131))	('glioblastomas', 'Phenotype', 'HP:0012174', (180, 193))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('mutation', 'Var', (5, 13))
225273	33063010	BRAFV600E inhibitors like vemurafenib (NCT01748149) and dabrafenib (NCT01677741) and MEK inhibitors like trametinib (NCT03434262) are being explored to treat these tumors in phase 1 and 2 trials.	('MEK', 'Gene', '5609', (85, 88))	('trametinib', 'Chemical', 'MESH:C560077', (105, 115))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('NCT03434262', 'Var', (117, 128))	('NCT01677741', 'Var', (68, 79))	('NCT01748149', 'Var', (39, 50))	('vemurafenib', 'Chemical', 'MESH:D000077484', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('dabrafenib', 'Chemical', 'MESH:C561627', (56, 66))	('MEK', 'Gene', (85, 88))
225279	33063010	We evaluated clinical data and performed genetic testing on 46 spinal LGG (WHO grade 1 or 2) with available tumor samples and mapped PFS and OS of these patients to see if an association between aberrations in BRAF, treatment, and OS could be identified.	('aberrations', 'Var', (195, 206))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('BRAF', 'Gene', '673', (210, 214))	('BRAF', 'Gene', (210, 214))
225290	33063010	Cox proportional hazard models were fit for time to death and time to progression, and log-rank statistics were reported for differences between tumor grade and KIAA1549-BRAF positivity.	('positivity', 'Var', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('BRAF', 'Gene', (170, 174))	('KIAA1549', 'Gene', (161, 169))	('KIAA1549', 'Gene', '57670', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))	('BRAF', 'Gene', '673', (170, 174))
225307	33063010	Of those analyzed, there were 9 different genetic mutations and/or fusions identified in 21 patients including mutations in BRAF, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A (Table 2).	('mutations', 'Var', (111, 120))	('CDKN2A', 'Gene', (162, 168))	('H3F3A', 'Gene', '3020', (138, 143))	('CDKN2A', 'Gene', '1029', (162, 168))	('BRAF', 'Gene', '673', (124, 128))	('patients', 'Species', '9606', (92, 100))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('H3F3A', 'Gene', (138, 143))	('FGFR1', 'Gene', (151, 156))	('PTPN11', 'Gene', '5781', (130, 136))	('BRAF', 'Gene', (124, 128))	('FGFR1', 'Gene', '2260', (151, 156))	('PTPN11', 'Gene', (130, 136))
225317	33063010	Other studies have demonstrated that BRAFV600E mutations are common in grade 2 pleomorphic xanthoastrocytomas, pleomorphic xanthoastrocytomas with anaplasia, grade 1 gangliogliomas, grade 3 anaplastic gangliogliomas, and pilocytic astrocytomas in the brain.	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (221, 243))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('common', 'Reg', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('astrocytoma', 'Phenotype', 'HP:0009592', (129, 140))	('gangliogliomas', 'Disease', 'MESH:D018303', (201, 215))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (79, 109))	('mutations', 'Var', (47, 56))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (111, 141))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))	('gangliogliomas', 'Disease', 'MESH:D018303', (166, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (231, 242))	('gangliogliomas', 'Disease', (201, 215))	('pleomorphic xanthoastrocytomas', 'Disease', (79, 109))	('gangliogliomas', 'Disease', (166, 180))	('pleomorphic xanthoastrocytomas', 'Disease', (111, 141))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('BRAFV600E', 'Gene', (37, 46))	('pilocytic astrocytomas', 'Disease', (221, 243))
225318	33063010	More specifically, BRAF rearrangement has been found in 75%-80% of cerebellar pilocytic astrocytomas, and BRAFV600E mutations have been identified in non-cerebellar regions of the brain.	('BRAF', 'Gene', '673', (19, 23))	('rearrangement', 'Var', (24, 37))	('BRAF', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (106, 110))	('found', 'Reg', (47, 52))	('cerebellar pilocytic astrocytomas', 'Disease', (67, 100))	('BRAF', 'Gene', (106, 110))	('BRAFV600E', 'Mutation', 'rs113488022', (106, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('cerebellar pilocytic astrocytomas', 'Disease', 'MESH:D001254', (67, 100))
225321	33063010	found that spinal gangliogliomas do not harbor the BRAFV600E mutation in high frequency.	('spinal gangliogliomas', 'Disease', 'MESH:D018303', (11, 32))	('BRAFV600E', 'Var', (51, 60))	('BRAFV600E', 'Mutation', 'rs113488022', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('spinal gangliogliomas', 'Disease', (11, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))
225322	33063010	acknowledged that very little work has been done in regards to understanding the role of BRAF mutations in spinal cord tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('spinal cord tumors', 'Phenotype', 'HP:0010302', (107, 125))	('spinal cord tumors', 'Disease', 'MESH:D013120', (107, 125))	('mutations', 'Var', (94, 103))	('spinal cord tumor', 'Phenotype', 'HP:0010302', (107, 124))	('BRAF', 'Gene', '673', (89, 93))	('spinal cord tumors', 'Disease', (107, 125))	('BRAF', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
225323	33063010	reported the presence of both BRAFV660E, FGFR1 single nucleotide variants, as well as KIAA1549-BRAF and FGFR1-TACC1 fusions in spinal cord LGG.	('TACC1', 'Gene', (110, 115))	('TACC1', 'Gene', '6867', (110, 115))	('BRAF', 'Gene', '673', (95, 99))	('BRAF', 'Gene', (30, 34))	('fusions', 'Var', (116, 123))	('BRAF', 'Gene', (95, 99))	('KIAA1549', 'Gene', (86, 94))	('FGFR1', 'Gene', '2260', (104, 109))	('single nucleotide variants', 'Var', (47, 73))	('BRAF', 'Gene', '673', (30, 34))	('KIAA1549', 'Gene', '57670', (86, 94))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('FGFR1', 'Gene', (104, 109))	('presence', 'Reg', (13, 21))
225325	33063010	BRAF fusions are often correlated with a favorable prognosis in cerebellar LGG.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('cerebellar LGG', 'Disease', (64, 78))	('fusions', 'Var', (5, 12))
225331	33063010	The specific BRAF alteration is correlated to response to treatment; KIAA1549-BRAF fusions are RAF-independent and BRAFV600E mutations are responsive to autophagy and small molecule inhibitors.	('BRAF', 'Gene', '673', (115, 119))	('mutations', 'Var', (125, 134))	('RAF', 'Gene', '22882', (79, 82))	('BRAF', 'Gene', '673', (78, 82))	('RAF', 'Gene', (14, 17))	('RAF', 'Gene', (79, 82))	('BRAF', 'Gene', (115, 119))	('RAF', 'Gene', '22882', (14, 17))	('BRAFV600E', 'Mutation', 'rs113488022', (115, 124))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', '673', (13, 17))	('KIAA1549', 'Gene', '57670', (69, 77))	('BRAF', 'Gene', (13, 17))	('KIAA1549', 'Gene', (69, 77))	('RAF', 'Gene', (95, 98))	('RAF', 'Gene', '22882', (95, 98))	('RAF', 'Gene', (116, 119))	('RAF', 'Gene', '22882', (116, 119))
225333	33063010	Identification of KIAA1549-BRAF fusion mutations could help to inform treatment decisions to include MEK inhibition.	('fusion mutations', 'Var', (32, 48))	('BRAF', 'Gene', '673', (27, 31))	('KIAA1549', 'Gene', (18, 26))	('KIAA1549', 'Gene', '57670', (18, 26))	('BRAF', 'Gene', (27, 31))	('MEK', 'Gene', (101, 104))	('MEK', 'Gene', '5609', (101, 104))
225335	33063010	The primary aim of this study was to investigate the prevalence of BRAF mutations and fusions in low-grade spinal cord tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (72, 81))	('spinal cord tumors', 'Phenotype', 'HP:0010302', (107, 125))	('BRAF', 'Gene', '673', (67, 71))	('spinal cord tumors', 'Disease', 'MESH:D013120', (107, 125))	('BRAF', 'Gene', (67, 71))	('spinal cord tumor', 'Phenotype', 'HP:0010302', (107, 124))	('spinal cord tumors', 'Disease', (107, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
225336	33063010	Additional mutations were found in FGFR1, CDKN2A, H3F3A, TP53, and PTPN11.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (57, 61))	('H3F3A', 'Gene', (50, 55))	('PTPN11', 'Gene', (67, 73))	('CDKN2A', 'Gene', (42, 48))	('PTPN11', 'Gene', '5781', (67, 73))	('FGFR1', 'Gene', (35, 40))	('CDKN2A', 'Gene', '1029', (42, 48))	('TP53', 'Gene', (57, 61))	('H3F3A', 'Gene', '3020', (50, 55))	('FGFR1', 'Gene', '2260', (35, 40))
225337	33063010	Research has found that some low-grade intracranial tumors harbor alterations in FGFRs which involve fusions with TACC genes and FGFR1 tyrosine kinase domain duplication (FGFR1-TKDD) resulting in upregulation of MAPK/ERK and the PI3K pathway.	('FGFR', 'Gene', '2260', (129, 133))	('intracranial tumors', 'Disease', 'MESH:D001932', (39, 58))	('FGFR', 'Gene', (81, 85))	('PI3K pathway', 'Pathway', (229, 241))	('FGFR1', 'Gene', '2260', (171, 176))	('fusions', 'Interaction', (101, 108))	('ERK', 'Gene', '5594', (217, 220))	('alterations', 'Var', (66, 77))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('FGFR', 'Gene', '2260', (81, 85))	('FGFR1', 'Gene', '2260', (129, 134))	('upregulation', 'PosReg', (196, 208))	('ERK', 'Gene', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('FGFR', 'Gene', (171, 175))	('FGFR1', 'Gene', (171, 176))	('FGFR', 'Gene', (129, 133))	('FGFR1', 'Gene', (129, 134))	('FGFR', 'Gene', '2260', (171, 175))	('intracranial tumors', 'Disease', (39, 58))
225338	33063010	Similarly, our data found a FGFR1 mutation in a patient diagnosed with grade 2 astrocytoma NOS who experienced a relapse of this primary tumor 3 months from diagnosis but has survived to 60 months since diagnosis.	('tumor', 'Disease', (137, 142))	('mutation', 'Var', (34, 42))	('FGFR1', 'Gene', (28, 33))	('astrocytoma NOS', 'Disease', (79, 94))	('astrocytoma NOS', 'Disease', 'MESH:D001254', (79, 94))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('patient', 'Species', '9606', (48, 55))	('FGFR1', 'Gene', '2260', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
225339	33063010	Another patient with a pilocytic astrocytoma had a confirmed FGFR1 mutation.	('pilocytic astrocytoma', 'Disease', (23, 44))	('mutation', 'Var', (67, 75))	('FGFR1', 'Gene', (61, 66))	('FGFR1', 'Gene', '2260', (61, 66))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (23, 44))	('patient', 'Species', '9606', (8, 15))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))
225341	33063010	Recently, the Consortium to Inform Molecular and Practical Approaches to CNS tumor Taxonomy:Not Official WHO (cIMPACT-NOW) reported that diffuse gliomas characterized by FGFR1 alterations occur primarily in children and that these should be classified as diffuse glioma, FGFR1-mutant tumors.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('FGFR1', 'Gene', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('gliomas', 'Disease', (145, 152))	('glioma', 'Disease', (145, 151))	('FGFR1', 'Gene', '2260', (170, 175))	('children', 'Species', '9606', (207, 215))	('glioma', 'Disease', (263, 269))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('tumors', 'Disease', (284, 290))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('alterations', 'Var', (176, 187))	('CNS tumor', 'Phenotype', 'HP:0100006', (73, 82))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('FGFR1', 'Gene', (170, 175))	('FGFR1', 'Gene', '2260', (271, 276))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (284, 289))
225342	33063010	A comprehensive evaluation of LGG of the CNS found FGFR1 mutations in 1.5% of tumors analyzed and that these often co-occurred with other genetic alterations.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (57, 66))	('FGFR1', 'Gene', (51, 56))	('FGFR1', 'Gene', '2260', (51, 56))	('co-occurred', 'Reg', (115, 126))
225343	33063010	FGFR1-activating mutations and fusions have also been reported in pediatric spinal tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FGFR1', 'Gene', (0, 5))	('spinal tumors', 'Disease', (76, 89))	('FGFR1', 'Gene', '2260', (0, 5))	('spinal tumors', 'Disease', 'MESH:D013120', (76, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('spinal tumors', 'Phenotype', 'HP:0010302', (76, 89))	('fusions', 'Var', (31, 38))	('mutations', 'Var', (17, 26))
225345	33063010	In a previous study, 1.9% of patients with low-grade spinal cord tumors demonstrated mutations in H3F3A.	('patients', 'Species', '9606', (29, 37))	('H3F3A', 'Gene', (98, 103))	('spinal cord tumors', 'Phenotype', 'HP:0010302', (53, 71))	('spinal cord tumors', 'Disease', 'MESH:D013120', (53, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (85, 94))	('spinal cord tumor', 'Phenotype', 'HP:0010302', (53, 70))	('H3F3A', 'Gene', '3020', (98, 103))	('spinal cord tumors', 'Disease', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
225346	33063010	H3F3A K27M has proven to be a hallmark of many HG midline gliomas and occurs in about 20% of pediatric glioblastomas.	('H3F3A', 'Gene', '3020', (0, 5))	('midline gliomas', 'Disease', (50, 65))	('H3F3A', 'Gene', (0, 5))	('K27M', 'Mutation', 'p.K27M', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('midline gliomas', 'Disease', 'MESH:D005910', (50, 65))	('glioblastomas', 'Phenotype', 'HP:0012174', (103, 116))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('K27M', 'Var', (6, 10))	('glioblastomas', 'Disease', 'MESH:D005909', (103, 116))	('glioblastomas', 'Disease', (103, 116))
225354	33063010	and National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01NS107313 to J.M.M.L.	('R01NS107313', 'Var', (91, 102))	('Neurological Disorders', 'Disease', 'MESH:D009422', (56, 78))	('Stroke', 'Disease', (83, 89))	('Neurological Disorders', 'Disease', (56, 78))	('Stroke', 'Phenotype', 'HP:0001297', (83, 89))	('Stroke', 'Disease', 'MESH:D020521', (83, 89))
225355	33063010	), and University of Colorado Shared Resources Cancer Center Support Grant (P30CA046934; Molecular Pathology and Functional Genomics).	('P30CA046934', 'Var', (76, 87))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cancer', 'Disease', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))
225361	32793462	In the high-grade gliomas, the binary logistic regression revealed that the CHGMV can independently predict isocitrate dehydrogenase 1 (IDH1) and P53 mutations.	('gliomas', 'Disease', (18, 25))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('IDH1', 'Gene', (136, 140))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('mutations', 'Var', (150, 159))	('CHGMV', 'Gene', (76, 81))	('IDH1', 'Gene', '3417', (136, 140))	('CHGMV', 'Chemical', '-', (76, 81))	('P53', 'Gene', (146, 149))	('isocitrate dehydrogenase 1', 'Gene', (108, 134))	('isocitrate dehydrogenase 1', 'Gene', '3417', (108, 134))	('P53', 'Gene', '7157', (146, 149))
225374	32793462	In high-grade gliomas, immunohistochemical data based on the isocitrate-dehydrogenase (IDH) mutation status in a previous study revealed that glial tumor cells migrate into multiple brain regions, including the contralesional hemisphere, and redefined glioma as a whole-brain disease rather than a focal brain disease.	('glioma', 'Disease', (14, 20))	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('glial tumor', 'Disease', 'MESH:D005910', (142, 153))	('mutation', 'Var', (92, 100))	('glial tumor', 'Disease', (142, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('IDH', 'Gene', (87, 90))	('glioma', 'Disease', (252, 258))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('IDH', 'Gene', '3417', (87, 90))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('isocitrate-dehydrogenase', 'Gene', (61, 85))	('isocitrate-dehydrogenase', 'Gene', '3417', (61, 85))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('glioma', 'Disease', 'MESH:D005910', (252, 258))	('glioma', 'Phenotype', 'HP:0009733', (252, 258))	('gliomas', 'Disease', (14, 21))
225408	32793462	A binary logistic regression model was used to investigate predictors of IDH1/P53 mutation and ATRX loss and is presented using odds ratios (ORs) with its 95% confidence intervals (CIs).	('ATRX', 'Gene', (95, 99))	('P53', 'Gene', (78, 81))	('IDH1', 'Gene', '3417', (73, 77))	('mutation', 'Var', (82, 90))	('ATRX', 'Gene', '546', (95, 99))	('P53', 'Gene', '7157', (78, 81))	('IDH1', 'Gene', (73, 77))	('loss', 'NegReg', (100, 104))
225428	32793462	In this section, age, the CHGMV, the lesion volume, and the contrast-enhanced volume were used to predict IDH1 mutations, P53 mutations, and ATRX loss.	('loss', 'NegReg', (146, 150))	('mutations', 'Var', (111, 120))	('CHGMV', 'Chemical', '-', (26, 31))	('P53', 'Gene', (122, 125))	('ATRX', 'Gene', (141, 145))	('IDH1', 'Gene', (106, 110))	('P53', 'Gene', '7157', (122, 125))	('mutations', 'Var', (126, 135))	('IDH1', 'Gene', '3417', (106, 110))	('ATRX', 'Gene', '546', (141, 145))
225429	32793462	Both univariate and multivariate analyses were conducted to allow factors associated with the prediction of IDH1 mutations, P53 mutations, and ATRX loss to be identified.	('P53', 'Gene', '7157', (124, 127))	('ATRX', 'Gene', (143, 147))	('IDH1', 'Gene', '3417', (108, 112))	('mutations', 'Var', (128, 137))	('ATRX', 'Gene', '546', (143, 147))	('mutations', 'Var', (113, 122))	('P53', 'Gene', (124, 127))	('IDH1', 'Gene', (108, 112))
225430	32793462	The binary logistic regression modeling showed that the CHGMV was an independent predictor of IDH1 mutations (OR: 2.52E7, 95% CI: 6.361-1.00E14, p = 0.028, see Table 2) and P53 mutations (OR: 4.36E7, 95% CI: 10.753-1.77E14, p = 0.023, see Table 3).	('IDH1', 'Gene', (94, 98))	('P53', 'Gene', '7157', (173, 176))	('IDH1', 'Gene', '3417', (94, 98))	('mutations', 'Var', (177, 186))	('CHGMV', 'Chemical', '-', (56, 61))	('mutations', 'Var', (99, 108))	('P53', 'Gene', (173, 176))
225436	32793462	Second, all factors with a p < 0.1 were further evaluated by the forward stepwise multivariate Cox proportional hazards regression model, which suggested that a low CHGMV was an independent factor of poor OS (HR = 2.883, 95% CI: 1.075-7.735, p = 0.035) even after adjusting for the WHO grade (HR = 9.068, 95% CI: 2.629-31.282, p < 0.001), in the high-grade glioma patients (see Table 4).	('CHGMV', 'Gene', (165, 170))	('glioma', 'Disease', 'MESH:D005910', (357, 363))	('glioma', 'Phenotype', 'HP:0009733', (357, 363))	('CHGMV', 'Chemical', '-', (165, 170))	('low', 'Var', (161, 164))	('patients', 'Species', '9606', (364, 372))	('glioma', 'Disease', (357, 363))
225445	32793462	In recent years, immunohistochemical data using antibodies specific to IDH1 R132H mutant protein have revealed a more widespread tumor cell distribution than expected, including in the remote contrahemisphere, and have redefined high-grade glioma as a whole-brain disease.	('R132H', 'Var', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('IDH1', 'Gene', (71, 75))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('R132H', 'Mutation', 'rs121913500', (76, 81))	('IDH1', 'Gene', '3417', (71, 75))	('tumor', 'Disease', (129, 134))	('protein', 'Protein', (89, 96))	('glioma', 'Disease', (240, 246))
225457	32793462	Previously, clinical variables, such as a lower age, high KPS, lower histological grade, less infiltrating tumor, lower volumes of enhancing tumor, and lower edema volume, have been associated with a longer OS in patients with high-grade glioma.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('glioma', 'Disease', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('lower', 'NegReg', (63, 68))	('edema', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('high KPS', 'Var', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('lower', 'NegReg', (114, 119))	('patients', 'Species', '9606', (213, 221))	('histological grade', 'CPA', (69, 87))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('edema', 'Disease', 'MESH:D004487', (158, 163))	('edema', 'Phenotype', 'HP:0000969', (158, 163))
225459	32793462	Previous studies have suggested that IDH1 mutations, P53 mutations, MGMT promoter methylation, and ATRX loss indicated a good therapy response and longer OS in high-grade glioma.	('loss', 'NegReg', (104, 108))	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('ATRX', 'Gene', (99, 103))	('P53', 'Gene', (53, 56))	('P53', 'Gene', '7157', (53, 56))	('IDH1', 'Gene', (37, 41))	('glioma', 'Disease', (171, 177))	('mutations', 'Var', (57, 66))	('ATRX', 'Gene', '546', (99, 103))	('IDH1', 'Gene', '3417', (37, 41))	('MGMT', 'Gene', '4255', (68, 72))	('MGMT', 'Gene', (68, 72))	('mutations', 'Var', (42, 51))
225461	32793462	Interestingly, our results showed that patients with high CHGMV experience longer OS than those with low CHGMV.	('CHGMV', 'Chemical', '-', (105, 110))	('longer', 'PosReg', (75, 81))	('patients', 'Species', '9606', (39, 47))	('CHGMV', 'Chemical', '-', (58, 63))	('high CHGMV', 'Var', (53, 63))
225465	32793462	In addition to predicting OS, in our study, the CHGMV was also used to predict IDH1 mutation, P53 mutation, and ATRX loss using binary logistic regression analysis in high-grade glioma.	('IDH1', 'Gene', '3417', (79, 83))	('ATRX', 'Gene', (112, 116))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('loss', 'NegReg', (117, 121))	('mutation', 'Var', (98, 106))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('P53', 'Gene', '7157', (94, 97))	('CHGMV', 'Chemical', '-', (48, 53))	('ATRX', 'Gene', '546', (112, 116))	('P53', 'Gene', (94, 97))	('IDH1', 'Gene', (79, 83))	('glioma', 'Disease', (178, 184))	('mutation', 'Var', (84, 92))
225467	32793462	High CHGMV suggested an increased possibility of IDH and P53 mutations in high-grade gliomas.	('IDH', 'Gene', (49, 52))	('P53', 'Gene', (57, 60))	('P53', 'Gene', '7157', (57, 60))	('mutations', 'Var', (61, 70))	('gliomas', 'Disease', (85, 92))	('IDH', 'Gene', '3417', (49, 52))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('CHGMV', 'Chemical', '-', (5, 10))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
225479	30853980	Low GAS5 Levels as a Predictor of Poor Survival in Patients with Lower-Grade Gliomas Gliomas are infiltrative neoplasms of a highly invasive nature.	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('Glioma', 'Phenotype', 'HP:0009733', (85, 91))	('Glioma', 'Phenotype', 'HP:0009733', (77, 83))	('Gliomas', 'Disease', 'MESH:D005910', (77, 84))	('Gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('Gliomas', 'Disease', (77, 84))	('Gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('Gliomas', 'Disease', 'MESH:D005910', (85, 92))	('Gliomas', 'Disease', (85, 92))	('neoplasms', 'Disease', 'MESH:D009369', (110, 119))	('neoplasms', 'Disease', (110, 119))	('GAS5', 'Gene', (4, 8))	('Patients', 'Species', '9606', (51, 59))	('GAS5', 'Gene', '60674', (4, 8))	('Low', 'Var', (0, 3))
225499	30853980	Ectopic expression of GAS5 induces cell-cycle arrest in the G0-G1 phase by increasing the activity of the P27Kip1 promoter.	('increasing', 'PosReg', (75, 85))	('activity', 'MPA', (90, 98))	('GAS5', 'Gene', (22, 26))	('P27Kip1', 'Gene', '1027', (106, 113))	('Ectopic expression', 'Var', (0, 18))	('induces', 'Reg', (27, 34))	('P27Kip1', 'Gene', (106, 113))	('cell-cycle arrest in the G0-G1 phase', 'CPA', (35, 71))
225500	30853980	In addition, GAS5 interacts with E2F1 and enhances the binding of E2F1 to the P27Kip1 promoter in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('E2F1', 'Gene', (66, 70))	('GAS5', 'Var', (13, 17))	('E2F1', 'Gene', '1869', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('E2F1', 'Gene', (33, 37))	('prostate cancer', 'Disease', (98, 113))	('binding', 'Interaction', (55, 62))	('enhances', 'PosReg', (42, 50))	('E2F1', 'Gene', '1869', (66, 70))	('interacts', 'Interaction', (18, 27))
225510	30305794	A Visually Interpretable, Dictionary-Based Approach to Imaging-Genomic Modeling, With Low-Grade Glioma as a Case Study Radiomics is a rapidly growing field in which sophisticated imaging features are extracted from radiology images to predict clinical outcomes/responses, genetic alterations, and other outcomes relevant to a patient's prognosis or response to therapy.	('Low-Grade Glioma', 'Disease', (86, 102))	('patient', 'Species', '9606', (326, 333))	('Low-Grade Glioma', 'Disease', 'MESH:D005910', (86, 102))	('Glioma', 'Phenotype', 'HP:0009733', (96, 102))	('genetic alterations', 'Var', (272, 291))
225513	30305794	Using a publicly available data set of magnetic resonance imaging images from patients diagnosed with low-grade gliomas, we demonstrated that the dictionary-based model performs well in predicting 2 biomarkers of interest (1p/19q codeletion and IDH1 mutation).	('mutation', 'Var', (250, 258))	('IDH1', 'Gene', (245, 249))	('1p/19q codeletion', 'Var', (223, 240))	('patients', 'Species', '9606', (78, 86))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('IDH1', 'Gene', '3417', (245, 249))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
225539	30305794	The outcomes of interest to our study were 2 molecular biomarkers with prognostic value for individual patient outcome: (1) the mutation status of IDH1 gene and (2) the presence of codeletion of chromosome arms 1p and 19q.	('codeletion', 'Var', (181, 191))	('mutation status', 'Var', (128, 143))	('IDH1', 'Gene', (147, 151))	('patient', 'Species', '9606', (103, 110))	('IDH1', 'Gene', '3417', (147, 151))
225540	30305794	The IDH1 biomarker is determined by whether the gene is mutated or wild type, and this biomarker is of particular interest because it has been shown that patients with mutated IDH1 tend to have longer survival than patients with wild-type IDH1.	('mutated', 'Var', (168, 175))	('patients', 'Species', '9606', (215, 223))	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', (239, 243))	('IDH1', 'Gene', '3417', (176, 180))	('patients', 'Species', '9606', (154, 162))	('IDH1', 'Gene', (4, 8))	('survival', 'CPA', (201, 209))	('IDH1', 'Gene', '3417', (239, 243))	('longer', 'PosReg', (194, 200))	('IDH1', 'Gene', (176, 180))
225541	30305794	Similarly, patients with chromosomal 1p/19q codeletion have been shown to generally have better prognoses than patients lacking the codeletion; in particular, patients with the codeletion respond better to radiochemotherapy.	('better', 'PosReg', (196, 202))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (159, 167))	('chromosomal 1p/19q codeletion', 'Var', (25, 54))	('patients', 'Species', '9606', (111, 119))
225542	30305794	Furthermore, of the 108 patients in the data set, 85 had IDH1 mutation, and 26 had 1p/19q codeletion; thus, both classification tasks were notably unbalanced.	('mutation', 'Var', (62, 70))	('IDH1', 'Gene', '3417', (57, 61))	('IDH1', 'Gene', (57, 61))	('patients', 'Species', '9606', (24, 32))
225558	30305794	For prediction of IDH1 mutation, the strongest-performing model was the DLSI model trained on raw voxel intensity descriptors extracted from T2-weighted images.	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))
225559	30305794	Figure 1 compares IDH1 mutation prediction results between the dictionary-based (DLSI) models against BoW models trained with each of the 3 descriptors.	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))
225560	30305794	This figure considers only models trained on the T2-weighted images, as these imaging sequences proved to be the most predictive of IDH1 mutation.	('IDH1', 'Gene', '3417', (132, 136))	('IDH1', 'Gene', (132, 136))	('mutation', 'Var', (137, 145))
225563	30305794	At a significance level of alpha = .05, the dictionary-based model had a significantly higher mean AUC than the corresponding BoW model for every imaging sequence when predicting IDH1 mutation.	('AUC', 'MPA', (99, 102))	('IDH1', 'Gene', (179, 183))	('mutation', 'Var', (184, 192))	('IDH1', 'Gene', '3417', (179, 183))	('higher', 'PosReg', (87, 93))
225569	30305794	The PI plot corresponding to a patient with IDH1 mutation is shown in Figure 4.	('patient', 'Species', '9606', (31, 38))	('IDH1', 'Gene', '3417', (44, 48))	('IDH1', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))
225579	30305794	Both dictionary learning and BoW algorithms could predict IDH1 mutation status better than the remaining genomic information.	('IDH1', 'Gene', '3417', (58, 62))	('IDH1', 'Gene', (58, 62))	('predict', 'Reg', (50, 57))	('mutation', 'Var', (63, 71))
225580	30305794	This is probably because IDH1 mutation is shown to have oncogenic effects that can be identifiable from MRI scans.	('IDH1', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('IDH1', 'Gene', '3417', (25, 29))
225590	29752851	Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas [AA]), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas).	('1p/19q-codeletion', 'Var', (148, 165))	('IDH-mutated gliomas', 'Disease', (20, 39))	('astrocytoma', 'Phenotype', 'HP:0009592', (82, 93))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (178, 196))	('oligodendroglioma', 'Disease', 'MESH:D009837', (178, 195))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('1p-intact/19q-loss', 'Var', (109, 127))	('oligodendrogliomas', 'Disease', (178, 196))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('oligodendroglioma', 'Disease', (178, 195))
225591	29752851	Of the 88 IDH-wild type glioblastomas (GBMs), 14 showed 1p-intact/19q-loss status.	('1p-intact/19q-loss', 'Var', (56, 74))	('type glioblastomas', 'Disease', 'MESH:D005909', (19, 37))	('glioblastomas', 'Phenotype', 'HP:0012174', (24, 37))	('glioblastoma', 'Disease', (24, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (24, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (24, 36))	('type glioblastomas', 'Disease', (19, 37))
225592	29752851	All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation.	('harbored', 'Reg', (40, 48))	('mutation', 'Var', (54, 62))	('TERT', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (49, 53))	('TERT', 'Gene', '7015', (71, 75))	('TP53', 'Gene', (49, 53))
225597	29752851	Diffuse astrocytoma is defined as diffuse glioma with IDH1 or IDH2 mutation without 1p/19q codeletion, that most likely harbors TP53 and ATRX mutations.	('ATRX', 'Gene', (137, 141))	('Diffuse astrocytoma', 'Disease', (0, 19))	('mutation', 'Var', (67, 75))	('IDH1', 'Gene', (54, 58))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('ATRX', 'Gene', '546', (137, 141))	('astrocytoma', 'Phenotype', 'HP:0009592', (8, 19))	('IDH2', 'Gene', (62, 66))
225598	29752851	Difference in the clinical behavior has been confirmed in multiple studies showing that the 1p/19q codeleted gliomas show significantly better prognosis in both WHO grade II and III tumors.2, 3, 4 In general, morphological features and genetic alterations correlate well, with the majority of 1p/19q codeleted tumors presenting classic oligodendroglioma morphology with isomorphic round nuclei with artefactually swollen clear cytoplasm and delicate branching capillary network, whereas non-codeleted IDH-mutant tumors tend to show features of well-differentiated (grade II) or moderately anaplastic (grade III) fibrillary astrocytes.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (512, 517))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (347, 353))	('III tumors', 'Disease', (178, 188))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('II tumors', 'Disease', 'MESH:D009369', (179, 188))	('tumors', 'Phenotype', 'HP:0002664', (512, 518))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('1p/19q', 'Var', (293, 299))	('III tumors', 'Disease', 'MESH:D009369', (178, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
225607	29752851	The following microsatellite markers spanning the whole chromosome arms of 1p and 19q, as well as markers located at the commonly deleted 10q region, were used to detect loss of heterozygosity: D1S1166(1p11), D1S495(1p13), D1S207(1p21), D1S435(1p21), D1S2835(1p31.3), D1S2797(1p32), D1S2892(1p33), D1S2657(1p34), D1S2647(1p36.1), D1S402(1p36.1), and D1S244(1p36.22) for 1p; D19S919(19q12), D19S220(19q13.13), D19S420(19q13.2), D19S219(19q13.3), D19S112(19q13.3), D19S412(19q13.33), and D19S596(19q13.33) for 19q; and D10S1680(10q23), D10S185(10q23-24), and D10S587(10q26) for 10q.	('D1S435', 'Var', (237, 243))	('D19S219', 'Var', (427, 434))	('D19S112', 'CellLine', 'CVCL:H223', (445, 452))	('D1S244', 'Var', (350, 356))	('D1S2647', 'CellLine', 'CVCL:9K51', (313, 320))	('D1S2797', 'Var', (268, 275))	('p11', 'Gene', '6281', (203, 206))	('D1S2797', 'CellLine', 'CVCL:Z231', (268, 275))	('D1S2892', 'Var', (283, 290))	('p11', 'Gene', (203, 206))	('D19S412', 'CellLine', 'CVCL:1V29', (463, 470))	('D1S495', 'Var', (209, 215))	('D19S412', 'Var', (463, 470))	('D1S402', 'Var', (330, 336))	('D19S420', 'Var', (409, 416))	('D1S2835', 'Var', (251, 258))	('D10S587', 'Var', (557, 564))	('D1S207', 'Var', (223, 229))	('D1S2647', 'Var', (313, 320))	('D19S220', 'Var', (390, 397))	('D1S2657', 'Var', (298, 305))	('D19S219', 'CellLine', 'CVCL:G580', (427, 434))	('D19S112', 'Var', (445, 452))	('D1S1166', 'Var', (194, 201))	('D10S185', 'Var', (534, 541))
225608	29752851	Mutations in IDH1/2, TERT promoter, and TP53 were detected by direct Sanger sequencing.	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (40, 44))	('IDH1/2', 'Gene', '3417;3418', (13, 19))
225609	29752851	For TERT promoter, C228T and C250T mutations were surveyed by sequencing the PCR products.	('C250T', 'Mutation', 'c.250C>T', (29, 34))	('C228T', 'Var', (19, 24))	('C228T', 'Mutation', 'c.228C>T', (19, 24))	('C250T', 'Var', (29, 34))
225611	29752851	The mutational genes meeting the following conditions were listed: covered at least 250 times, mutant allele frequencies were >=30%, and registered as missense mutation in the COSMIC database (https://cancer.sanger.ac.uk/cosmic).	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('mutant', 'Var', (95, 101))	('cancer', 'Disease', (201, 207))
225615	29752851	No other genes commonly mutated in gliomas were detected, except that mutation of SMARCB1, MSH6, and LRP1B were detected in case 1, and mutation of PIK3CA was detected in case 7.	('PIK3CA', 'Gene', '5290', (148, 154))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('MSH6', 'Gene', '2956', (91, 95))	('LRP1B', 'Gene', '53353', (101, 106))	('SMARCB1', 'Gene', '6598', (82, 89))	('SMARCB1', 'Gene', (82, 89))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('detected', 'Reg', (112, 120))	('LRP1B', 'Gene', (101, 106))	('PIK3CA', 'Gene', (148, 154))	('mutation', 'Var', (70, 78))	('MSH6', 'Gene', (91, 95))
225617	29752851	Primary tumor was IDH-mutated, 1p-intact/19q-loss AA with oligodendroglioma-like regions and neuropil-like islands.	('Primary tumor', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('Primary tumor', 'Disease', 'MESH:D009369', (0, 13))	('1p-intact/19q-loss', 'Var', (31, 49))
225621	29752851	Cytogenetic studies revealed that unbalanced translocation between chromosome 1 and 19 resulting in the loss of der(1;19)(p10;q10) was the mechanism of the codeletion.10 However, despite extensive past efforts looking for specific genes primarily targeted by 1p-loss and 19q-loss in oligodendrogliomas, those genes have not been pinpointed.	('glioma', 'Phenotype', 'HP:0009733', (294, 300))	('oligodendrogliomas', 'Disease', (283, 301))	('gliomas', 'Phenotype', 'HP:0009733', (294, 301))	('p10', 'Gene', (122, 125))	('1p-loss', 'Var', (259, 266))	('p10', 'Gene', '6281', (122, 125))
225630	29188366	Pre-operative NC and NLCR were higher with increasing grade of tumour: grade 1 (NC 4.29 109/l, NLCR 2.26), grade 2 (NC 4.59 109/l, NLCR 2.38), grade 3 (NC 5.67 109/l, NLCR 2.72) and grade 4 (NC 6.59 109/l, NLCR 3.31).	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('NC', 'Var', (152, 154))	('tumour', 'Disease', (63, 69))
225635	29188366	Post-operative NC was significantly higher in the high-grade tumours (p = 0.034), but no difference was observed for NLCR (p = 0.28).	('higher', 'PosReg', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('high-grade', 'Var', (50, 60))	('tumours', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
225644	29188366	More recent work has shown tumour-associated neutrophils play little role in host defence, and modulating/down-regulating their activation can significantly restrict tumour growth in animal models.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('modulating/down-regulating', 'NegReg', (95, 121))	('tumour', 'Disease', (166, 172))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('modulating/down-regulating', 'Var', (95, 121))	('tumour growth', 'Disease', (166, 179))	('activation', 'MPA', (128, 138))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumour growth', 'Disease', 'MESH:D006130', (166, 179))	('tumour', 'Disease', (27, 33))	('restrict', 'NegReg', (157, 165))
225707	29188366	These findings seem to suggest that malignant or more aggressive tumours are more likely to elevate the systemic immune response, which potentially can be explained by increased destruction of the blood-brain barrier.	('aggressive tumours', 'Disease', (54, 72))	('elevate', 'PosReg', (92, 99))	('systemic immune', 'MPA', (104, 119))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('malignant', 'Var', (36, 45))	('aggressive tumours', 'Disease', 'MESH:D001523', (54, 72))
225745	31386677	For multiple clusters (C1, C6, C7, C19, C21, C28), as observed in Fig 5, the scatterplot clearly depicts different pairwise expression levels for LGG and GBM (brain cancer) samples than the other cancer sub-types which is detailed in the Discussion section.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('brain cancer', 'Disease', (159, 171))	('C19', 'Var', (35, 38))	('C1', 'Var', (23, 25))	('LGG', 'Gene', (146, 149))	('expression levels', 'MPA', (124, 141))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('C21', 'Gene', (40, 43))	('brain cancer', 'Disease', 'MESH:D001932', (159, 171))	('C21', 'Gene', '79718', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('brain cancer', 'Phenotype', 'HP:0030692', (159, 171))	('C28', 'Var', (45, 48))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('different', 'Reg', (105, 114))
225746	31386677	In order to further explore the phenomenon observed in the clusters with distinctly different expression level for brain (LGG and GBM) cancer samples in comparison to the other cancer sub-types, we isolated genes that are primarily classified into one of the 6 clusters of interest (C1, C6, C7, C19, C21, C28).	('C28', 'Var', (305, 308))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (177, 183))	('C21', 'Gene', '79718', (300, 303))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('C21', 'Gene', (300, 303))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('C19', 'Var', (295, 298))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('C1', 'Var', (283, 285))
225767	31386677	Similar bimodal clusters can also be observed in clusters C1, C7, C21, C19, and C28 with a distinct expression intensity shift for LGG and GBM indicating that there is a strong relationship between edges that were classified into these clusters and pathways that control brain and/or brain tumor function.	('brain tumor', 'Disease', 'MESH:D001932', (284, 295))	('brain tumor', 'Disease', (284, 295))	('C28', 'Var', (80, 83))	('LGG', 'Gene', (131, 134))	('C19', 'Var', (71, 74))	('brain tumor', 'Phenotype', 'HP:0030692', (284, 295))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('C21', 'Gene', '79718', (66, 69))	('C21', 'Gene', (66, 69))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
225768	31386677	In order to test if the edges classified within the bimodal clusters depicting the clear shift in LGG and GBM expression patterns may exhibit brain and/or brain tumor function, we examined the collective function of 5,352 genes in bimodal clusters (C1, C6, C7, C19, C21, C28) that involved a total of 1,048,575 edges.	('C21', 'Gene', (266, 269))	('C21', 'Gene', '79718', (266, 269))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('brain tumor', 'Disease', (155, 166))	('brain tumor', 'Disease', 'MESH:D001932', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('exhibit', 'Reg', (134, 141))	('brain', 'CPA', (142, 147))	('brain tumor', 'Phenotype', 'HP:0030692', (155, 166))	('C19', 'Var', (261, 264))
225785	31213913	Comprehensive analysis of genes based on chr1p/19q co-deletion reveals a robust 4-gene prognostic signature for lower grade glioma Purpose: The chr1p/19q co-deletion is a favorable prognostic factor in patients with lower grade glioma.	('glioma', 'Disease', (124, 130))	('glioma', 'Disease', (228, 234))	('patients', 'Species', '9606', (202, 210))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('chr1p/19q co-deletion', 'Var', (144, 165))
225791	31213913	The AUC of the 4-gene-signature for 5-year OS in TCGA and CGGA was 0.837 and 0.876, respectively, which was superior compared to other parameters such as chr1p/19q co-deletion, IDH mutant, WHO grade and histology type, especially in chr1p/19q non-co-deletion patients.	('IDH', 'Gene', '3417', (177, 180))	('patients', 'Species', '9606', (259, 267))	('IDH', 'Gene', (177, 180))	('chr1p/19q non-co-deletion', 'Var', (233, 258))
225794	31213913	More recently, molecular markers have received more and more attention Chromosomal 1p and 19q (chr1p/19q) co-deletion is considered to be a good prognostic factor in lower grade glioma.	('Chromosomal', 'Var', (71, 82))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('chr1p/19q', 'Gene', (95, 104))	('glioma', 'Disease', (178, 184))	('co-deletion', 'Var', (106, 117))
225798	31213913	It is welll known that chr1p and chr19q contain genes associated with DNA damage repairing, spindle checkpoint function, apoptosis, WNT signaling pathways, TGF-betasignaling pathways and tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('chr19q', 'Var', (33, 39))	('TGF-beta', 'Gene', '7040', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TGF-beta', 'Gene', (156, 164))	('tumor', 'Disease', (187, 192))	('WNT signaling pathways', 'Pathway', (132, 154))	('apoptosis', 'CPA', (121, 130))	('chr1p', 'Var', (23, 28))
225799	31213913	Chromosome 1p deletion is generally associated with the initiation of carcinogenesis However, in lower grade glioma, chr1p/19q co-deletion is a beneficial marker to the prognosis, which is contrary to previous knowledge We hypothesize that the co-deletion of chr1p/19q leads to the loss of important genes during tumor development.	('loss', 'NegReg', (282, 286))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('co-deletion', 'Var', (244, 255))	('tumor', 'Disease', (313, 318))	('glioma', 'Disease', (109, 115))	('carcinogenesis However', 'Disease', 'MESH:D063646', (70, 92))	('carcinogenesis However', 'Disease', (70, 92))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('deletion', 'Var', (14, 22))	('chr1p/19q', 'Gene', (259, 268))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
225803	31213913	Microarray dataset GSE16011 with 284 glioma (WHO grade II-III, 125; IV, 159) and eight normal brain samples measured by using Affymetrix U133 plus 2.0 array (GPL8542) were downloaded from Gene Expression Omnibus (GEO) database.	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('GSE16011', 'Var', (19, 27))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('glioma', 'Disease', (37, 43))
225815	31213913	These 76 genes were significantly higher in chr1p/19q non-co-deletion lower grade glioma compared to normal tissues and chr1p/19q co-deletion lower grade glioma, which suggests they may be associated with prolonged overall survival (OS) in patients with chr1p/19q co-deletion.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('chr1p/19q non-co-deletion', 'Var', (44, 69))	('higher', 'PosReg', (34, 40))	('lower', 'NegReg', (142, 147))	('glioma', 'Disease', (154, 160))	('patients', 'Species', '9606', (240, 248))	('overall', 'MPA', (215, 222))	('glioma', 'Disease', (82, 88))	('chr1p/19q co-deletion', 'Var', (120, 141))	('prolonged', 'PosReg', (205, 214))
225817	31213913	KEGG analysis showed that the up-regulated gene encoded by chr1p/19q was most significantly enriched in the "cell cycle," and were also associated with "breast cancer," "chronic myeloid leukemia," and "Notch signaling pathway" (Figure 2A).	('associated', 'Reg', (136, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('myeloid leukemia', 'Disease', (178, 194))	('chr1p/19q', 'Var', (59, 68))	('myeloid leukemia', 'Disease', 'MESH:D007951', (178, 194))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (178, 194))	('leukemia', 'Phenotype', 'HP:0001909', (186, 194))	('Notch signaling pathway', 'Pathway', (202, 225))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('up-regulated', 'PosReg', (30, 42))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (170, 194))	('breast cancer', 'Disease', (153, 166))
225830	31213913	Since IDH1 mutation status, histological type, and WHO classification are important for the prognosis of lower grade glioma, it was necessary to determine whether our risk score was an independent prognostic factor for OS.	('IDH1', 'Gene', '3417', (6, 10))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('mutation', 'Var', (11, 19))	('IDH1', 'Gene', (6, 10))	('glioma', 'Disease', (117, 123))
225833	31213913	The area under the receiver operating characteristic (ROC) curve (AUC) of 1-year, 3-year and 5-year survival rate were 0.858, 0.853 and 0.837 in TCGA, respectively, which was significantly higher compared to other clinical pathological parameters such as chr1p/19q deletion, histology type, WHO classification and IDH mutations (Figure 6A-C).	('higher', 'PosReg', (189, 195))	('IDH', 'Gene', (314, 317))	('IDH', 'Gene', '3417', (314, 317))	('0.837', 'Var', (136, 141))
225834	31213913	These results suggested that the signature is a more accurate and useful tool for the prediction of OS in lower grade glioma patients, especially for chr1p/19q non-co-deletion patients.	('patients', 'Species', '9606', (176, 184))	('glioma', 'Disease', (118, 124))	('chr1p/19q non-co-deletion', 'Var', (150, 175))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('non-co-deletion', 'Var', (160, 175))	('patients', 'Species', '9606', (125, 133))
225840	31213913	The prognosis of lower grade gliomas has traditionally been determined by histologic type and histologic grade, while over recent years the molecular markers have gained increasing attention According to Brat et al, patients with IDH mutations and 1p/19q co-deficiency have the best prognosis, while patients with only IDH mutations have the second highest prognosis, and IDH wild-type and 1p/19q wild type patients have the worst prognosis.	('IDH', 'Gene', (230, 233))	('IDH', 'Gene', '3417', (319, 322))	('1p/19q co-deficiency', 'Var', (248, 268))	('IDH', 'Gene', '3417', (230, 233))	('patients', 'Species', '9606', (407, 415))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('gliomas', 'Disease', (29, 36))	('IDH', 'Gene', (372, 375))	('patients', 'Species', '9606', (216, 224))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('IDH', 'Gene', '3417', (372, 375))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('IDH', 'Gene', (319, 322))	('patients', 'Species', '9606', (300, 308))
225841	31213913	Other prognostic factors include ATRX mutation, TERT promoter mutations, CIC loss, FUBP1 loss and PTEN loss The 1p/19q co-deletion is a well-recognized prognostic factor in glioma that often leads to high sensitivity to chemotherapy.	('CIC loss, FUBP1 loss', 'Disease', 'MESH:D015431', (73, 93))	('TERT', 'Gene', '7015', (48, 52))	('1p/19q co-deletion', 'Var', (112, 130))	('ATRX', 'Gene', '546', (33, 37))	('ATRX', 'Gene', (33, 37))	('glioma', 'Disease', (173, 179))	('PTEN', 'Gene', '5728', (98, 102))	('TERT', 'Gene', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('PTEN', 'Gene', (98, 102))	('high sensitivity to chemotherapy', 'MPA', (200, 232))	('mutation', 'Var', (38, 46))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('leads to', 'Reg', (191, 199))
225844	31213913	Chromosomal 1p contains genes associated with DNA damage repairing, spindle checkpoint function, apoptosis, Wnt signaling pathways, and tumor suppression Chromosome 19 has approximately 64 million base pairs, accounting for more than 2% of the human genome Chromosome 1p deletion is generally associated with the initiation of carcinogenesis Abnormal chromosome 19 may cause tumorigenesis through tumor suppressor gene deletion, DNA repair dysfunction, abnormal regulation of TGF-beta pathway and NF-kappaB pathway However, in lower grade glioma, chr1p/19q co-deletion is a beneficial prognosis marker, which is not consistent with existing research.	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', (375, 380))	('deletion', 'Var', (419, 427))	('initiation of carcinogenesis Abnormal chromosome 19', 'Disease', 'MESH:D063646', (313, 364))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('human', 'Species', '9606', (244, 249))	('NF-kappaB pathway', 'Pathway', (497, 514))	('DNA', 'Gene', (429, 432))	('TGF-beta', 'Gene', '7040', (476, 484))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('glioma', 'Disease', (539, 545))	('tumor', 'Disease', (397, 402))	('glioma', 'Disease', 'MESH:D005910', (539, 545))	('cause', 'Reg', (369, 374))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('Abnormal chromosome', 'Phenotype', 'HP:0031411', (342, 361))	('deletion', 'Var', (271, 279))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('regulation', 'Reg', (462, 472))	('TGF-beta', 'Gene', (476, 484))	('glioma', 'Phenotype', 'HP:0009733', (539, 545))
225846	31213913	Because chr1p/19q contains a large number of genes, a part of these genes may lead to tumorigenesis, while another part may be related to the prognosis of patients.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('lead to', 'Reg', (78, 85))	('related', 'Reg', (127, 134))	('genes', 'Var', (68, 73))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
225853	31213913	Recent studies have also reported that EMP3 may promote the development of glioblastoma by activating the transforming growth factor (TGF)-beta/Smad2/3 signaling pathway and is associated with poor prognosis of GBM G protein subunit gamma 12(GNG12, chr1p31.3) is a member of the G protein family that belongs to the G protein g subunit Previous studies have shown that it may be involved in processes such as cytoskeletal function and cell growth The reasons why the loss of chr1p/19q lead to an increase in overall survival in lower grade glioma patients still appear to be unclear.	('EMP3', 'Gene', '2014', (39, 43))	('TGF)-beta', 'Gene', '7040', (134, 143))	('overall survival', 'MPA', (508, 524))	('loss', 'Var', (467, 471))	('increase', 'PosReg', (496, 504))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('Smad2/3', 'Gene', (144, 151))	('promote', 'PosReg', (48, 55))	('GNG12', 'Gene', '55970', (242, 247))	('glioblastoma', 'Disease', (75, 87))	('glioma', 'Disease', (540, 546))	('glioma', 'Disease', 'MESH:D005910', (540, 546))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('EMP3', 'Gene', (39, 43))	('activating', 'Reg', (91, 101))	('Smad2/3', 'Gene', '4087;4088', (144, 151))	('GNG12', 'Gene', (242, 247))	('chr1p/19q', 'Gene', (475, 484))	('glioma', 'Phenotype', 'HP:0009733', (540, 546))	('patients', 'Species', '9606', (547, 555))
225854	31213913	In the current study, we aimed to reveal the molecular mechanism underlying chr1p/19q co-deletion leading to prolonged survival in patients with lower grade glioma from the bioinformatics perspective.	('patients', 'Species', '9606', (131, 139))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('co-deletion', 'Var', (86, 97))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('survival', 'MPA', (119, 127))	('glioma', 'Disease', (157, 163))	('chr1p/19q', 'Gene', (76, 85))	('prolonged', 'PosReg', (109, 118))
225859	31213913	Liu et al have found that the expression of Ki-67 protein (an indicator of cell proliferation) in 1p/19q co-deficient oligodendroglioma is down-regulated Palfi et al have found that glioma cell apoptosis is more pronounced in ch1p/19q co-deletion patients compared with non-co-deletion patients This is consistent with our functional analysis results.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('pronounced', 'PosReg', (212, 222))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('ch1p/19q co-deletion', 'Var', (226, 246))	('deficient oligodendroglioma', 'Disease', 'MESH:D009837', (108, 135))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('deficient oligodendroglioma', 'Disease', (108, 135))	('patients', 'Species', '9606', (247, 255))	('down-regulated', 'NegReg', (139, 153))	('glioma', 'Disease', (129, 135))	('co-deletion', 'Var', (235, 246))	('glioma', 'Disease', (182, 188))	('patients', 'Species', '9606', (286, 294))
225863	31213913	In addition, we found that the prolongation of survival in patients with chr1p/19q co-deletion might be related to the changes in pathways such as cell cycle and DNA mismatch repair.	('cell cycle', 'CPA', (147, 157))	('co-deletion', 'Var', (83, 94))	('changes', 'Reg', (119, 126))	('pathways', 'Pathway', (130, 138))	('DNA mismatch repair', 'MPA', (162, 181))	('chr1p/19q', 'Gene', (73, 82))	('survival', 'MPA', (47, 55))	('patients', 'Species', '9606', (59, 67))	('prolongation', 'PosReg', (31, 43))
225864	31213913	The four genes in this signature are promising molecular targets, especially for chr1p/19q non-co deletion patients.	('patients', 'Species', '9606', (107, 115))	('chr1p/19q', 'Var', (81, 90))	('non-co deletion', 'Disease', (91, 106))
225867	31143247	Many reports suggest the association of gross total resection with longer overall survival and progression-free survival in addition to better seizure control.	('progression-free survival', 'CPA', (95, 120))	('seizure', 'Disease', (143, 150))	('seizure', 'Disease', 'MESH:D012640', (143, 150))	('overall survival', 'CPA', (74, 90))	('seizure', 'Phenotype', 'HP:0001250', (143, 150))	('gross total', 'Var', (40, 51))	('longer', 'PosReg', (67, 73))
225906	31143247	The most valuable of these in practice are the mutation status of the genes regulating the Krebs cycle enzymes, isocitrate dehydrogenase 1 and 2 (IDH1/2), whole-arm co-deletion of chromosome arms 1p and 19q, alterations in tumor protein 53 (TP53), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and telomerase reverse transcriptase (TERT).	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (248, 302))	('tumor protein 53', 'Gene', (223, 239))	('IDH1/2', 'Gene', (146, 152))	('TERT', 'Gene', (349, 353))	('co-deletion', 'Var', (165, 176))	('Krebs', 'Chemical', '-', (91, 96))	('TP53', 'Gene', '7157', (241, 245))	('ATRX', 'Gene', '546', (304, 308))	('TERT', 'Gene', '7015', (349, 353))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('mental retardation', 'Phenotype', 'HP:0001249', (266, 284))	('tumor protein 53', 'Gene', '7157', (223, 239))	('TP53', 'Gene', (241, 245))	('alterations', 'Var', (208, 219))	('telomerase reverse transcriptase', 'Gene', (315, 347))	('IDH1/2', 'Gene', '3417;3418', (146, 152))	('ATRX', 'Gene', (304, 308))	('telomerase reverse transcriptase', 'Gene', '7015', (315, 347))
225907	31143247	Mutations of IDH1 are encountered more often than IDH2 and occur in 65%-80% of gliomas.	('IDH2', 'Gene', (50, 54))	('gliomas', 'Disease', (79, 86))	('occur', 'Reg', (59, 64))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('IDH2', 'Gene', '3418', (50, 54))	('IDH1', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
225908	31143247	Co-deletion of 1p and 19q is characteristic of oligodendroglial tumors.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Co-deletion', 'Var', (0, 11))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (47, 70))	('oligodendroglial tumors', 'Disease', (47, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
225909	31143247	Point mutations in IDH1/2 and co-deletion of 1p19q delineate subsets of dLGG with distinct biology and clinical behavior.	('IDH1/2', 'Gene', (19, 25))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('dLGG', 'Disease', (72, 76))	('Point mutations', 'Var', (0, 15))	('1p19q', 'Gene', (45, 50))
225910	31143247	IDH1 mutation at codon 132 is noted in >70% of WHO Grade II and III gliomas, whereas IDH2 mutation is noticed in up to 6% of them.	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('IDH2', 'Gene', (85, 89))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('IDH1', 'Gene', (0, 4))	('IDH2', 'Gene', '3418', (85, 89))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
225911	31143247	Deletion of 1p36 is reported in up to 18% of astrocytomas, and 73% of oligodendrogliomas, while the deletion of 19q13.3 is reported in 38% of astrocytomas and 73% of oligodendrogliomas.	('oligodendrogliomas', 'Disease', (70, 88))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('oligodendrogliomas', 'Disease', (166, 184))	('reported', 'Reg', (20, 28))	('astrocytomas', 'Disease', 'MESH:D001254', (45, 57))	('astrocytoma', 'Phenotype', 'HP:0009592', (45, 56))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (70, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('1p36', 'Gene', (12, 16))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (166, 184))	('astrocytomas', 'Disease', (45, 57))	('astrocytomas', 'Disease', 'MESH:D001254', (142, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (142, 153))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('astrocytomas', 'Disease', (142, 154))	('Deletion', 'Var', (0, 8))
225914	31143247	1p19q and IDH 1and 2 mutations are associated with prolonged survival and better response to chemotherapy (see below).	('IDH 1and 2', 'Gene', (10, 20))	('IDH 1and 2', 'Gene', '3417;3418', (10, 20))	('prolonged', 'PosReg', (51, 60))	('1p19q', 'Var', (0, 5))
225915	31143247	ATRX inactivation is also associated with astrocytic tumors, particularly IDH mutated gliomas (86%) and may represent a subset of astrocytomas with improved treatment outcomes.	('astrocytomas', 'Disease', 'MESH:D001254', (130, 142))	('ATRX', 'Gene', (0, 4))	('associated', 'Reg', (26, 36))	('astrocytic tumors', 'Disease', 'MESH:D001254', (42, 59))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('astrocytomas', 'Disease', (130, 142))	('IDH', 'Gene', (74, 77))	('ATRX', 'Gene', '546', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('astrocytoma', 'Phenotype', 'HP:0009592', (130, 141))	('inactivation', 'Var', (5, 17))	('gliomas', 'Disease', 'MESH:D005910', (86, 93))	('IDH', 'Gene', '3417', (74, 77))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))	('gliomas', 'Disease', (86, 93))	('astrocytic tumors', 'Disease', (42, 59))
225916	31143247	Mutations of the TERT promoter is one of the most common molecular markers in gliomas and is to be found in more than 90% of IDH mutant and 1p/19q co-deleted oligodendrogliomas.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (158, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('IDH', 'Gene', (125, 128))	('oligodendrogliomas', 'Disease', (158, 176))	('gliomas', 'Disease', (78, 85))	('Mutations', 'Var', (0, 9))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('IDH', 'Gene', '3417', (125, 128))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('mutant', 'Var', (129, 135))
225921	31143247	The first type was characterized by IDH mutations and 1p/19q co-deletion and showed a strong association with oligodendroglioma histology.	('1p/19q co-deletion', 'Var', (54, 72))	('oligodendroglioma', 'Disease', (110, 127))	('IDH', 'Gene', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('mutations', 'Var', (40, 49))	('oligodendroglioma', 'Disease', 'MESH:D009837', (110, 127))	('association', 'Interaction', (93, 104))	('IDH', 'Gene', '3417', (36, 39))
225922	31143247	Other findings in this type were activating mutations of TERT promoter in 96% of samples.	('mutations', 'Var', (44, 53))	('TERT', 'Gene', (57, 61))	('activating', 'PosReg', (33, 43))	('TERT', 'Gene', '7015', (57, 61))
225925	31143247	Rather, inactivation of ATRX and mutation of TP53 (86% and 94%, respectively) was found in most of this type, and these findings represent a strong association with astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (165, 176))	('mutation', 'Var', (33, 41))	('association', 'Reg', (148, 159))	('TP53', 'Gene', (45, 49))	('astrocytoma', 'Disease', (165, 176))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('ATRX', 'Gene', (24, 28))	('inactivation', 'Var', (8, 20))	('ATRX', 'Gene', '546', (24, 28))	('TP53', 'Gene', '7157', (45, 49))
225933	31143247	This advantage is sustained even after adjustment for the status of IDH mutation and 1p/19q co-deletion (Jakola 2017) Even when located in putatively eloquent regions of the cerebrum, dLGG rarely present with neurological deficits.	('IDH', 'Gene', '3417', (68, 71))	('neurological deficits', 'Disease', (209, 230))	('1p/19q co-deletion', 'Var', (85, 103))	('neurological deficits', 'Disease', 'MESH:D009461', (209, 230))	('IDH', 'Gene', (68, 71))	('neurological deficit', 'Phenotype', 'HP:0000707', (209, 229))	('neurological deficits', 'Phenotype', 'HP:0000707', (209, 230))
225939	31143247	Moreover, biopsy is not risk free and indeed may have mortality/morbidity risk equating those of modern series of surgical resections Gross or near GTR is associated with better seizure control and higher PFS and OS in addition to a lower risk of malignant transformation.	('OS', 'Chemical', '-', (213, 215))	('seizure', 'Disease', (178, 185))	('seizure', 'Disease', 'MESH:D012640', (178, 185))	('seizure', 'Phenotype', 'HP:0001250', (178, 185))	('Gross or near', 'Var', (134, 147))	('PFS', 'CPA', (205, 208))	('higher', 'PosReg', (198, 204))	('better', 'PosReg', (171, 177))
225943	31143247	GTR was associated with better seizure control compared to subtotal resection (STR) or biopsy alone (odds ratio: 16, P = 0.0064).	('seizure', 'Phenotype', 'HP:0001250', (31, 38))	('seizure', 'Disease', (31, 38))	('GTR', 'Var', (0, 3))	('seizure', 'Disease', 'MESH:D012640', (31, 38))
225972	31143247	The tumors' genetic profiles were obtained in majority of the cases for 1p, 19q deletion, and p53 overexpression.	('19q deletion', 'Var', (76, 88))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (94, 97))	('overexpression', 'PosReg', (98, 112))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
225975	31143247	The tumors with 1p-19q codeletion showed a significantly higher objective response to the therapy compared to the ones without this codeletion (73 vs. 50%, P = 0.03).	('objective response to', 'MPA', (64, 85))	('higher', 'PosReg', (57, 63))	('1p-19q codeletion', 'Var', (16, 33))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
225986	31143247	In tumors without IDH mutation or codeletion or those clinically at high risk of progression due to age, residual disease after surgery, and astrocytic histology, early RT may be beneficial, particularly those patients progressing after chemotherapy.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('mutation', 'Var', (22, 30))	('IDH', 'Gene', (18, 21))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('IDH', 'Gene', '3417', (18, 21))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
226038	29573042	Diffusivity metrics AD, MD and RD showed a significant (p < 0.001) increase in the lesion and pWM compared to cNAWM, whereas kurtosis metrics (AK, MK, and RK) showed a significant (p <0.001) decrease in both the lesion and pWM.	('RK', 'Disease', 'MESH:D020425', (155, 157))	('AD', 'Var', (20, 22))	('AK', 'Disease', 'MESH:C537792', (143, 145))	('increase', 'PosReg', (67, 75))	('Diffusivity', 'MPA', (0, 11))	('lesion', 'MPA', (83, 89))
226087	26575197	Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro.	('tumor', 'Disease', (144, 149))	('knockdown', 'Var', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('suppressed', 'NegReg', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ALDH1A3', 'Gene', (180, 187))
226092	26575197	Furthermore, high activity of ALDH was associated with poor prognosis in breast cancer, bladder cancer, and prostate cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (124, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('high', 'Var', (13, 17))	('ALDH', 'Protein', (30, 34))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('prostate cancer', 'Disease', (108, 123))
226096	26575197	In our previous study, we have found that hypermethylation status of ALDH1A3 promoter predicted a better prognosis with an accompanied low expression of ALDH1A3 protein in G-CIMP-negative primary GBMs.	('low', 'NegReg', (135, 138))	('CIMP', 'Chemical', '-', (174, 178))	('hypermethylation status', 'Var', (42, 65))	('expression', 'MPA', (139, 149))	('ALDH1A3', 'Gene', (69, 76))	('ALDH1A3', 'Gene', (153, 160))
226100	26575197	ALDH1A3 knockdown would inhibit PN-to-Mes transformation which is induced by radiation treatment.	('knockdown', 'Var', (8, 17))	('ALDH1A3', 'Gene', (0, 7))	('PN-to-Mes transformation', 'CPA', (32, 56))	('Mes', 'Chemical', '-', (38, 41))	('inhibit', 'NegReg', (24, 31))
226121	26575197	SDS-PAGE was performed on 40 mug of protein from each sample, gels were transferred to PVDF membranes (Millipore, USA) and incubated with the anti-GAPDH (Sigma, USA), anti-ALDH1A3 (Abcam, UK), anti-MMP2 (Abcam, UK), anti-snail and anti-slug (Cell Signaling Technology, USA).	('GAPDH', 'Gene', '2597', (147, 152))	('GAPDH', 'Gene', (147, 152))	('snail', 'Gene', (221, 226))	('MMP2', 'Gene', '4313', (198, 202))	('PVDF', 'Chemical', 'MESH:C024865', (87, 91))	('slug', 'Gene', (236, 240))	('anti-ALDH1A3', 'Var', (167, 179))	('slug', 'Gene', '6591', (236, 240))	('MMP2', 'Gene', (198, 202))	('SDS', 'Chemical', 'MESH:D012967', (0, 3))	('snail', 'Gene', '6615', (221, 226))
226152	26575197	In our study, we assessed whether the invasiveness of glioma cells could be inhibited by ALDH1A3 silencing in vitro.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('silencing', 'Var', (97, 106))	('ALDH1A3', 'Gene', (89, 96))	('glioma', 'Disease', (54, 60))	('inhibited', 'NegReg', (76, 85))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
226155	26575197	It indicated that the invasive abilities of the tumor cells were significantly suppressed by ALDH1A3 silencing.	('tumor', 'Disease', (48, 53))	('silencing', 'Var', (101, 110))	('suppressed', 'NegReg', (79, 89))	('ALDH1A3', 'Gene', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
226156	26575197	These results were also confirmed by ALDH1A3 knockdown in U87 and LN229 cells using shRNA, which resulted in the down-regulation of protein expression of invasion associated markers: SNAIL, SLUG and MMP2 (Fig 5D).	('LN229', 'CellLine', 'CVCL:0393', (66, 71))	('MMP2', 'Gene', (199, 203))	('ALDH1A3', 'Gene', (37, 44))	('SNAIL', 'Gene', (183, 188))	('SNAIL', 'Gene', '6615', (183, 188))	('knockdown', 'Var', (45, 54))	('down-regulation', 'NegReg', (113, 128))	('protein expression', 'MPA', (132, 150))	('MMP2', 'Gene', '4313', (199, 203))	('SLUG', 'Gene', '6591', (190, 194))	('SLUG', 'Gene', (190, 194))
226165	26575197	In our previously reported works, high ALDH1A3 mRNA expression had been proved to be related to poor clinical outcomes.	('mRNA expression', 'MPA', (47, 62))	('high', 'Var', (34, 38))	('clinical', 'Species', '191496', (101, 109))	('ALDH1A3', 'Gene', (39, 46))
226167	26575197	What's more, patients with high ALDH1A3 mRNA expression had worse overall survival than those with low ALDH1A3 mRNA expression in HGG.	('overall survival', 'MPA', (66, 82))	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (27, 31))	('ALDH1A3', 'Gene', (32, 39))	('worse', 'NegReg', (60, 65))
226172	26575197	But in another study, strong expression of ALDH1A1 was related to significantly better survival in GBM patients.	('survival', 'MPA', (87, 95))	('expression', 'Var', (29, 39))	('ALDH1A1', 'Gene', '216', (43, 50))	('better', 'PosReg', (80, 86))	('patients', 'Species', '9606', (103, 111))	('GBM', 'Disease', (99, 102))	('ALDH1A1', 'Gene', (43, 50))
226182	26575197	On the contrary, patients with ALDH1A3 mRNA low expression were more likely to be PN subtype.	('mRNA low expression', 'Var', (39, 58))	('patients', 'Species', '9606', (17, 25))	('PN subtype', 'Disease', (82, 92))	('ALDH1A3', 'Gene', (31, 38))
226188	26575197	Knockdown of ALDH1A3 by shRNA constructs could markedly down-regulate these tumor invasion associated genes (SNAIL, SLUG and MMP2), and the abilitie of cell invasion was also reduced in vitro.	('abilitie of cell invasion', 'CPA', (140, 165))	('reduced', 'NegReg', (175, 182))	('SLUG', 'Gene', '6591', (116, 120))	('Knockdown', 'Var', (0, 9))	('SLUG', 'Gene', (116, 120))	('ALDH1A3', 'Gene', (13, 20))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('MMP2', 'Gene', (125, 129))	('SNAIL', 'Gene', '6615', (109, 114))	('SNAIL', 'Gene', (109, 114))	('down-regulate', 'NegReg', (56, 69))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('MMP2', 'Gene', '4313', (125, 129))
226192	26575197	Thirdly, a recent study reported that inhibition of ALDH activity effectively eradicates drug-tolerant tumor cell subpopulations, which indicate a potential beneficial effect of combination therapy that includes ALDHs inhibition to delay gliomas relapse.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('inhibition', 'NegReg', (218, 228))	('ALDHs', 'Protein', (212, 217))	('gliomas', 'Disease', (238, 245))	('tumor', 'Disease', (103, 108))	('inhibition', 'Var', (38, 48))	('ALDH', 'Protein', (52, 56))	('eradicates', 'NegReg', (78, 88))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
226251	25793147	A cutoff value of Ktrans = 0.0848 for diagnosis of LGG provided the best good combination of sensitivity and specificity (0.88 and 1.0, respectively).	('LGG', 'Disease', (51, 54))	('Ktrans = 0.0848', 'Var', (18, 33))	('Ktrans', 'Chemical', '-', (18, 24))
226418	18952577	Very interesting data uncovered in this study showed a subgroup of patients with a mutation in the beta-catenin gene who had 100% survival.	('mutation', 'Var', (83, 91))	('beta-catenin', 'Gene', (99, 111))	('patients', 'Species', '9606', (67, 75))	('beta-catenin', 'Gene', '1499', (99, 111))
226442	18952577	Genetic polymorphisms for methotrexate metabolism, DNA repair genes, and other such genes could also influence late effects and could be analyzed for their predictive value.	('methotrexate metabolism', 'Gene', (26, 49))	('DNA repair genes', 'Gene', (51, 67))	('influence', 'Reg', (101, 110))	('late effects', 'MPA', (111, 123))	('methotrexate', 'Chemical', 'MESH:D008727', (26, 38))	('polymorphisms', 'Var', (8, 21))
226448	18952577	Does resection of a big part of the cerebellum without there being a tumor produce a syndrome?	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('produce', 'Reg', (75, 82))	('big part of the cerebellum', 'Phenotype', 'HP:0012081', (20, 46))	('resection', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('syndrome', 'Disease', (85, 93))
226496	18952577	A mutation in patched is found in about 15% of medulloblastomas.	('mutation', 'Var', (2, 10))	('medulloblastoma', 'Phenotype', 'HP:0002885', (47, 62))	('medulloblastomas', 'Disease', (47, 63))	('medulloblastomas', 'Disease', 'MESH:D008527', (47, 63))	('patched', 'Gene', (14, 21))
226497	18952577	Mice with heterozygous PTCH1 mutations develop tumors that resemble desmoplastic medulloblastomas.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('medulloblastoma', 'Phenotype', 'HP:0002885', (81, 96))	('mutations', 'Var', (29, 38))	('desmoplastic medulloblastomas', 'Disease', 'MESH:D008527', (68, 97))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Mice', 'Species', '10090', (0, 4))	('desmoplastic medulloblastomas', 'Disease', (68, 97))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('PTCH1', 'Gene', (23, 28))
226499	18952577	With conditional knockouts of PTCH1 in granule neuron precursor cells, most cells undergo transient aberrant proliferation, but not tumorigenesis at first.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PTCH1', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('rat', 'Species', '10116', (116, 119))	('knockouts', 'Var', (17, 26))
226508	18952577	Additionally, Jeremy Rich has shown that this CD133 population of tumor cells promotes angiogenesis and is more radioresistant than CD133- cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('promotes', 'PosReg', (78, 86))	('radioresistant', 'CPA', (112, 126))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CD133', 'Var', (46, 51))	('angiogenesis', 'CPA', (87, 99))
226520	18952577	A number of molecular alterations have been discovered, such as the infamous iso17q, gains of 1q, MYC amplification, ERBB2, mutations in beta-catenin, and deletions of 22q.	('beta-catenin', 'Gene', '1499', (137, 149))	('mutations', 'Var', (124, 133))	('MYC', 'Gene', '4609', (98, 101))	('rat', 'Species', '10116', (26, 29))	('deletions of', 'Var', (155, 167))	('ERBB2', 'Gene', (117, 122))	('gains', 'PosReg', (85, 90))	('ERBB2', 'Gene', '2064', (117, 122))	('beta-catenin', 'Gene', (137, 149))	('MYC', 'Gene', (98, 101))	('iso17q', 'Var', (77, 83))
226522	18952577	For example, MYC amplification is reported mainly in large cell anaplastic tumors, ERBB2 prognosticates poor survival, mutations in beta-catenin are found in classic morphological forms of medulloblastoma and portend a good prognosis, and 22q deletions are a feature of the poor prognosis atypical teratoid/rhabdoid tumors.	('anaplastic tumors', 'Disease', 'MESH:D002277', (64, 81))	('anaplastic tumors', 'Disease', (64, 81))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('MYC', 'Gene', '4609', (13, 16))	('rhabdoid tumors', 'Disease', (307, 322))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (307, 322))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('medulloblastoma', 'Disease', 'MESH:D008527', (189, 204))	('medulloblastoma', 'Phenotype', 'HP:0002885', (189, 204))	('mutations', 'Var', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('medulloblastoma', 'Disease', (189, 204))	('rat', 'Species', '10116', (300, 303))	('beta-catenin', 'Gene', (132, 144))	('ERBB2', 'Gene', (83, 88))	('beta-catenin', 'Gene', '1499', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MYC', 'Gene', (13, 16))	('22q deletions', 'Var', (239, 252))	('ERBB2', 'Gene', '2064', (83, 88))
226527	18952577	Drs David Ellison and Steve Clifford looked at a prospective population of medulloblastoma patients and found those with mutations of the beta-catenin pathway had a better prognosis.	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (121, 130))	('beta-catenin', 'Gene', (138, 150))	('medulloblastoma', 'Phenotype', 'HP:0002885', (75, 90))	('medulloblastoma', 'Disease', (75, 90))	('beta-catenin', 'Gene', '1499', (138, 150))	('medulloblastoma', 'Disease', 'MESH:D008527', (75, 90))
226530	18952577	Dr Wechsler-Reya and others have provided good evidence that medulloblastomas containing mutations in PTCH1 originate from granule neuron precursor cells.	('medulloblastoma', 'Phenotype', 'HP:0002885', (61, 76))	('PTCH1', 'Gene', (102, 107))	('medulloblastomas', 'Disease', (61, 77))	('mutations', 'Var', (89, 98))	('medulloblastomas', 'Disease', 'MESH:D008527', (61, 77))
226532	18952577	Mutations in PTCH1 lead to unbridled activation of Smoothened and transformation.	('activation', 'PosReg', (37, 47))	('PTCH1', 'Gene', (13, 18))	('Smoothened', 'Gene', (51, 61))	('Mutations', 'Var', (0, 9))	('Smoothened', 'Gene', '319757', (51, 61))
226533	18952577	With this knowledge, Tom Curran showed, in a mouse model, an inhibitor of Smoothened cured mice with PTCH1 mutation medulloblastomas.	('Smoothened', 'Gene', (74, 84))	('medulloblastomas', 'Disease', 'MESH:D008527', (116, 132))	('mice', 'Species', '10090', (91, 95))	('medulloblastomas', 'Disease', (116, 132))	('medulloblastoma', 'Phenotype', 'HP:0002885', (116, 131))	('Smoothened', 'Gene', '319757', (74, 84))	('mouse', 'Species', '10090', (45, 50))	('PTCH1', 'Gene', (101, 106))	('mutation', 'Var', (107, 115))
226534	18952577	Both Gilbertson and others showed that this population of cells was not susceptible to transformation through mutations in beta-catenin.	('beta-catenin', 'Gene', '1499', (123, 135))	('mutations', 'Var', (110, 119))	('beta-catenin', 'Gene', (123, 135))
226535	18952577	This suggests there is another population in the cerebellum that is susceptible to beta-catenin mutations, and the reason we see completely different morphologies, molecular markers, and prognoses in patients is because their tumors have distinct cells of origin which, not surprisingly, accrue different mutations during tumorigenesis.	('mutations', 'Var', (96, 105))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('patients', 'Species', '9606', (200, 208))	('beta-catenin', 'Gene', (83, 95))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('beta-catenin', 'Gene', '1499', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (322, 327))	('tumor', 'Disease', (226, 231))
226571	18952577	Epidermal growth factor receptor is overexpressed in both adult and pediatric malignant gliomas, however the mechanism of overexpression is different; it is often due to amplification of the EGFR gene in adults, which is rare in pediatrics.	('due', 'Reg', (163, 166))	('malignant gliomas', 'Disease', 'MESH:D005910', (78, 95))	('amplification', 'Var', (170, 183))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('overexpressed', 'PosReg', (36, 49))	('malignant gliomas', 'Disease', (78, 95))
226572	18952577	PTEN mutation, common in adult tumors, is exceedingly rare in pediatric tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('pediatric tumors', 'Disease', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('adult tumors', 'Disease', 'MESH:C538052', (25, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('PTEN', 'Gene', '5728', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('adult tumors', 'Disease', (25, 37))	('PTEN', 'Gene', (0, 4))	('pediatric tumors', 'Disease', 'MESH:D063766', (62, 78))	('mutation', 'Var', (5, 13))
226575	18952577	In the infant tumor protocols within the Children's Oncology Group, loss of chromosome 22 or mutations in the INI1 gene are used to identify and distinguish atypical teratoid/rhabdoid tumors from infant supratentorial primitive neuroectodermal tumors.	('infant', 'Species', '9606', (7, 13))	('rat', 'Species', '10116', (206, 209))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (218, 250))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (228, 250))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Children', 'Species', '9606', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('infant', 'Species', '9606', (196, 202))	('atypical', 'Disease', (157, 165))	('supratentorial primitive neuroectodermal tumor', 'Phenotype', 'HP:0030070', (203, 249))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (228, 250))	('tumor', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (228, 249))	('loss', 'Var', (68, 72))	('neuroectodermal tumors', 'Disease', (228, 250))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('mutations', 'Var', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('INI1', 'Gene', (110, 114))	('INI1', 'Gene', '6598', (110, 114))	('Oncology', 'Phenotype', 'HP:0002664', (52, 60))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (218, 249))	('rhabdoid tumors', 'Disease', (175, 190))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (175, 190))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
226580	18952577	Tumors with unmethylated promoters overexpress MGMT and carry a much worse prognosis than those that do not.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('overexpress', 'PosReg', (35, 46))	('MGMT', 'Gene', (47, 51))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MGMT', 'Gene', '4255', (47, 51))	('unmethylated promoters', 'Var', (12, 34))
226583	18952577	In response to this, new studies being conducted by the Pediatric Oncology Group and the Pediatric Brain Tumor Consortium are treating tumors that overexpress MGMT with O6-benzylguanine, which depletes MGMT.	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (169, 185))	('Tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('MGMT', 'Gene', '4255', (159, 163))	('overexpress', 'PosReg', (147, 158))	('MGMT', 'Gene', (159, 163))	('Brain Tumor', 'Phenotype', 'HP:0030692', (99, 110))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('O6-benzylguanine', 'Var', (169, 185))	('MGMT', 'Gene', '4255', (202, 206))	('MGMT', 'Gene', (202, 206))	('Oncology', 'Phenotype', 'HP:0002664', (66, 74))
226598	18952577	Audience Member: The histologic slides that you showed of the mouse in which you deleted PTCH1 in the granule cell precursors looked very much like the human disease Lhermitte-Duclos syndrome, which is part of Cowden disease, which is a PTEN mutation, except they don't develop medulloblastomas.	('PTEN', 'Gene', (237, 241))	('Lhermitte-Duclos syndrome', 'Disease', 'MESH:D006223', (166, 191))	('Lhermitte-Duclos syndrome', 'Phenotype', 'HP:0500009', (166, 191))	('PTEN', 'Gene', '5728', (237, 241))	('mouse', 'Species', '10090', (62, 67))	('PTCH1', 'Gene', (89, 94))	('medulloblastomas', 'Disease', 'MESH:D008527', (278, 294))	('Cowden disease', 'Disease', 'MESH:D006223', (210, 224))	('Lhermitte-Duclos', 'Phenotype', 'HP:0500009', (166, 182))	('Cowden disease', 'Disease', (210, 224))	('Lhermitte-Duclos syndrome', 'Disease', (166, 191))	('human', 'Species', '9606', (152, 157))	('medulloblastomas', 'Disease', (278, 294))	('medulloblastoma', 'Phenotype', 'HP:0002885', (278, 293))	('Lhermitte-', 'Phenotype', 'HP:0032504', (166, 176))	('deleted', 'Var', (81, 88))
226599	18952577	They do develop breast cancers and other things, and I am wondering whether there is something, maybe a PTEN mutation that could stop that particular thing from going further.	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('mutation', 'Var', (109, 117))	('develop', 'PosReg', (8, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancers', 'Disease', 'MESH:D001943', (16, 30))	('PTEN', 'Gene', (104, 108))	('breast cancers', 'Disease', (16, 30))	('PTEN', 'Gene', '5728', (104, 108))
226605	18952577	Suzy Baker made a model of Lhermitte-Duclos by deleting PTEN within a granule neuron precursor.	('Lhermitte-Duclos', 'Phenotype', 'HP:0500009', (27, 43))	('PTEN', 'Gene', (56, 60))	('deleting', 'Var', (47, 55))	('PTEN', 'Gene', '5728', (56, 60))	('Lhermitte-', 'Phenotype', 'HP:0032504', (27, 37))
226615	18952577	Methylated MGMT is a favorable prognostic factor, so I am not sure that is necessarily going to be applicable for that, but people are trying to use surrogate markers in the blood to assess disease status.	('people', 'Species', '9606', (124, 130))	('MGMT', 'Gene', '4255', (11, 15))	('MGMT', 'Gene', (11, 15))	('Methylated', 'Var', (0, 10))
226624	18952577	The reason we want to know the answer is because of therapeutics, so what is emerging in astrocytomas from David Gutmann and others, as well as our work in ependymomas, suggests that with a distinct cell of origin, the reason these cells develop into tumors that have distinct pathway mutations is because they inherently depend upon different pathways during development.	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('mutations', 'Var', (285, 294))	('astrocytomas', 'Disease', 'MESH:D001254', (89, 101))	('ependymoma', 'Phenotype', 'HP:0002888', (156, 166))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('pathway', 'Pathway', (277, 284))	('ependymomas', 'Disease', 'MESH:D004806', (156, 167))	('astrocytomas', 'Disease', (89, 101))	('develop', 'Reg', (238, 245))	('ependymomas', 'Disease', (156, 167))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
226629	18952577	Using wild-type and neurofibromin-deficient astrocytes, it was found that many of the proteins that were deregulated by a mutation in NF1 were in the ribosome biogenesis pathway and, thus, were involved in protein translation.	('involved', 'Reg', (194, 202))	('ribosome biogenesis pathway', 'Pathway', (150, 177))	('deregulated', 'PosReg', (105, 116))	('proteins', 'Protein', (86, 94))	('mutation', 'Var', (122, 130))	('neurofibromin', 'Gene', (20, 33))	('NF1', 'Gene', (134, 137))	('protein translation', 'MPA', (206, 225))	('neurofibromin', 'Gene', '4763', (20, 33))
226630	18952577	Loss of NF1 leads to high levels of activation of the mammalian target of rapamycin pathway and associated proteins, S6 kinase and ribosomal S6.	('NF1', 'Gene', (8, 11))	('mammalian target of rapamycin', 'Gene', '2475', (54, 83))	('mammalian target of rapamycin', 'Gene', (54, 83))	('proteins', 'Protein', (107, 115))	('ribosomal S6', 'MPA', (131, 143))	('activation', 'PosReg', (36, 46))	('Loss', 'Var', (0, 4))
226638	18952577	However, when every cell in the body contained one mutated NF1 allele and one wild-type and the astrocytes in the brain and spinal cord lacked NF1, the mice developed typical low-grade optic gliomas.	('optic glioma', 'Phenotype', 'HP:0009734', (185, 197))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('lacked', 'NegReg', (136, 142))	('mutated', 'Var', (51, 58))	('optic gliomas', 'Phenotype', 'HP:0009734', (185, 198))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('mice', 'Species', '10090', (152, 156))	('NF1', 'Gene', (59, 62))	('optic gliomas', 'Disease', (185, 198))	('optic gliomas', 'Disease', 'MESH:D020339', (185, 198))	('developed', 'Reg', (157, 166))
226643	18952577	Ablating the microglia resulted in a significant reduction of tumor cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('reduction', 'NegReg', (49, 58))	('microglia', 'CPA', (13, 22))	('rat', 'Species', '10116', (80, 83))	('tumor', 'Disease', (62, 67))	('Ablating', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
226691	18952577	As seen elsewhere in this journal issue, CD133+ stemlike glioma cells can be identified in human diffuse pontine gliomas, and it is likely they contribute to radiation and chemotherapy resistance.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('glioma', 'Disease', (57, 63))	('gliomas', 'Disease', (113, 120))	('contribute', 'Reg', (144, 154))	('glioma', 'Disease', (113, 119))	('CD133+', 'Var', (41, 47))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('human', 'Species', '9606', (91, 96))
226728	18952577	You postulated a different way to attack these tumors by antagonizing hyaluronan.	('tumors', 'Disease', (47, 53))	('antagonizing', 'Var', (57, 69))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('hyaluronan', 'Chemical', 'MESH:D006820', (70, 80))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('hyaluronan', 'Protein', (70, 80))
226816	32322670	Therefore, selectively opening of the BTB is considered one of the effective means to increase the efficacy of chemotherapy for glioma.	('BTB', 'Gene', (38, 41))	('increase', 'PosReg', (86, 94))	('glioma', 'Disease', (128, 134))	('efficacy', 'MPA', (99, 107))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('BTB', 'Chemical', '-', (38, 41))	('selectively opening', 'Var', (11, 30))
226852	32322670	To explore the functional role of endothelial RBFOX1 in BTB permeability, we established GEC lines with stable overexpression or silencing of RBFOX1 successfully.	('overexpression', 'PosReg', (111, 125))	('BTB', 'Chemical', '-', (56, 59))	('RBFOX1', 'Gene', (142, 148))	('silencing', 'Var', (129, 138))
226857	32322670	The western blot analysis showed that the expression of ZO-1, occludin, and claudin-5 was significantly decreased in the RBFOX1 OE group compared with vector group in GECs.	('claudin-5', 'Gene', '7122', (76, 85))	('occludin', 'Gene', (62, 70))	('ZO-1', 'Gene', '7082', (56, 60))	('expression', 'MPA', (42, 52))	('RBFOX1 OE', 'Var', (121, 130))	('decreased', 'NegReg', (104, 113))	('occludin', 'Gene', '100506658', (62, 70))	('ZO-1', 'Gene', (56, 60))	('claudin-5', 'Gene', (76, 85))
226858	32322670	However, the expression of ZO-1, occludin, and claudin-5 increased in the shRBFOX1 group compared with the shNC group (Figure 1H) in GECs.	('claudin-5', 'Gene', (47, 56))	('expression', 'MPA', (13, 23))	('occludin', 'Gene', '100506658', (33, 41))	('claudin-5', 'Gene', '7122', (47, 56))	('shRBFOX1', 'Var', (74, 82))	('ZO-1', 'Gene', (27, 31))	('increased', 'PosReg', (57, 66))	('occludin', 'Gene', (33, 41))	('ZO-1', 'Gene', '7082', (27, 31))
226875	32322670	These results suggest that LINC00673 knockdown could impair BTB integrity and increase BTB permeability.	('BTB permeability', 'MPA', (87, 103))	('LINC00673', 'Gene', (27, 36))	('BTB', 'Chemical', '-', (60, 63))	('knockdown', 'Var', (37, 46))	('BTB integrity', 'CPA', (60, 73))	('increase', 'PosReg', (78, 86))	('BTB', 'Chemical', '-', (87, 90))	('impair', 'NegReg', (53, 59))	('LINC00673', 'Gene', '100499467', (27, 36))
226881	32322670	Additionally, LINC00673 expression was increased in the shRBFOX1 group, compared with the shNC group (Figure 3A).	('shRBFOX1', 'Var', (56, 64))	('expression', 'MPA', (24, 34))	('increased', 'PosReg', (39, 48))	('LINC00673', 'Gene', '100499467', (14, 23))	('LINC00673', 'Gene', (14, 23))
226903	32322670	However, LINC00673 knockdown decreased the expression of LINC00673 and MAFF mRNA in STAU1 immunoprecipitates (Figure 4C).	('STAU1', 'Gene', (84, 89))	('STAU1', 'Gene', '6780', (84, 89))	('LINC00673', 'Gene', '100499467', (9, 18))	('LINC00673', 'Gene', '100499467', (57, 66))	('knockdown', 'Var', (19, 28))	('MAFF', 'Gene', '23764', (71, 75))	('LINC00673', 'Gene', (9, 18))	('MAFF', 'Gene', (71, 75))	('decreased', 'NegReg', (29, 38))	('LINC00673', 'Gene', (57, 66))	('expression', 'MPA', (43, 53))
226928	32322670	Wild-type and deletion constructs and putative MAFF binding sites were indicated.	('MAFF', 'Gene', '23764', (47, 51))	('binding', 'Interaction', (52, 59))	('deletion', 'Var', (14, 22))	('MAFF', 'Gene', (47, 51))
226929	32322670	Upon co-transfection with pEX3-MAFF, ZO-1 promoter activity was downregulated by the -683 site region (Figure 6A), occludin promoter activity was downregulated by the +100 site region (Figure 6B), and claudin-5 promoter activity was downregulated by the -462 site region, but there was no significant change by the -789 site region (Figure 6C).	('claudin-5', 'Gene', '7122', (201, 210))	('MAFF', 'Gene', (31, 35))	('pEX3', 'Gene', (26, 30))	('occludin', 'Gene', '100506658', (115, 123))	('ZO-1', 'Gene', (37, 41))	('downregulated', 'NegReg', (233, 246))	('+100 site', 'Var', (167, 176))	('occludin', 'Gene', (115, 123))	('ZO-1', 'Gene', '7082', (37, 41))	('pEX3', 'Gene', '8504', (26, 30))	('downregulated', 'NegReg', (146, 159))	('promoter activity', 'MPA', (42, 59))	('claudin-5', 'Gene', (201, 210))	('MAFF', 'Gene', '23764', (31, 35))	('downregulated', 'NegReg', (64, 77))
226954	32322670	Abnormal expression of RBFOX1 in the central nervous system promotes human neurodevelopmental disorders.	('promotes', 'PosReg', (60, 68))	('neurodevelopmental disorders', 'Disease', (75, 103))	('human', 'Species', '9606', (69, 74))	('Abnormal', 'Var', (0, 8))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (75, 103))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (75, 103))	('RBFOX1', 'Gene', (23, 29))
226959	32322670	The presence of RBFOX1 gene deletion mutations in colon cancer is positively related to the development of colon cancer.	('deletion mutations', 'Var', (28, 46))	('colon cancer', 'Disease', (107, 119))	('colon cancer', 'Disease', 'MESH:D015179', (50, 62))	('related', 'Reg', (77, 84))	('colon cancer', 'Disease', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('RBFOX1', 'Gene', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('colon cancer', 'Phenotype', 'HP:0003003', (50, 62))
226967	32322670	Our data demonstrated that the expression levels of tight junction proteins ZO-1, occludin, and claudin-5 were decreased following RBFOX1 overexpression, indicating that upregulated RBFOX1 increased BTB permeability by opening tight junctions through paracellular pathways.	('rat', 'Species', '10116', (16, 19))	('claudin-5', 'Gene', (96, 105))	('overexpression', 'Var', (138, 152))	('decreased', 'NegReg', (111, 120))	('paracellular pathways', 'Pathway', (251, 272))	('expression levels', 'MPA', (31, 48))	('tight', 'Pathway', (227, 232))	('occludin', 'Gene', '100506658', (82, 90))	('claudin-5', 'Gene', '7122', (96, 105))	('upregulated', 'PosReg', (170, 181))	('RBFOX1', 'Gene', (182, 188))	('opening', 'PosReg', (219, 226))	('BTB permeability', 'MPA', (199, 215))	('occludin', 'Gene', (82, 90))	('ZO-1', 'Gene', '7082', (76, 80))	('RBFOX1', 'Gene', (131, 137))	('BTB', 'Chemical', '-', (199, 202))	('ZO-1', 'Gene', (76, 80))	('increased', 'PosReg', (189, 198))
226968	32322670	Aberrantly expressed lncRNAs are vital regulatory factors in glioma blood vessels.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma blood vessels', 'Disease', 'MESH:D007022', (61, 81))	('Aberrantly', 'Var', (0, 10))	('glioma blood vessels', 'Disease', (61, 81))
226975	32322670	Our results indicated that knockdown of LINC00673 reduced ZO-1, occludin, and claudin-5 expression, destroyed the integrity of the BTB, and increased the permeability of the BTB.	('claudin-5', 'Gene', (78, 87))	('knockdown', 'Var', (27, 36))	('ZO-1', 'Gene', '7082', (58, 62))	('BTB', 'Chemical', '-', (131, 134))	('permeability of the BTB', 'MPA', (154, 177))	('LINC00673', 'Gene', (40, 49))	('expression', 'MPA', (88, 98))	('occludin', 'Gene', '100506658', (64, 72))	('claudin-5', 'Gene', '7122', (78, 87))	('LINC00673', 'Gene', '100499467', (40, 49))	('BTB', 'Chemical', '-', (174, 177))	('reduced', 'NegReg', (50, 57))	('occludin', 'Gene', (64, 72))	('integrity', 'MPA', (114, 123))	('ZO-1', 'Gene', (58, 62))	('destroyed', 'NegReg', (100, 109))	('increased', 'PosReg', (140, 149))
226976	32322670	Meanwhile, restoration of RBFOX1 dramatically reduced the LINC00673 expression and increased BTB permeability.	('restoration', 'Var', (11, 22))	('LINC00673', 'Gene', (58, 67))	('increased', 'PosReg', (83, 92))	('expression', 'MPA', (68, 78))	('rat', 'Species', '10116', (16, 19))	('BTB permeability', 'MPA', (93, 109))	('reduced', 'NegReg', (46, 53))	('LINC00673', 'Gene', '100499467', (58, 67))	('RBFOX1', 'Gene', (26, 32))	('BTB', 'Chemical', '-', (93, 96))
226989	32322670	Moreover, inhibition of LINC00673 markedly prolonged the half-life of MAFF mRNA.	('MAFF', 'Gene', (70, 74))	('LINC00673', 'Gene', (24, 33))	('LINC00673', 'Gene', '100499467', (24, 33))	('half-life', 'MPA', (57, 66))	('inhibition', 'Var', (10, 20))	('prolonged', 'PosReg', (43, 52))	('MAFF', 'Gene', '23764', (70, 74))
226990	32322670	Furthermore, the silencing of LINC00673 increased the permeability of the BTB by elevating MAFF mRNA stability.	('permeability of the BTB', 'MPA', (54, 77))	('BTB', 'Chemical', '-', (74, 77))	('MAFF', 'Gene', '23764', (91, 95))	('LINC00673', 'Gene', '100499467', (30, 39))	('MAFF', 'Gene', (91, 95))	('increased', 'PosReg', (40, 49))	('elevating', 'PosReg', (81, 90))	('silencing', 'Var', (17, 26))	('LINC00673', 'Gene', (30, 39))
226994	32322670	In this study, we found that LINC00673 overexpression destabilized MAFF mRNA, whereas STAU1 or UPF1 knockdown increased the stabilization of MAFF mRNA.	('MAFF', 'Gene', '23764', (141, 145))	('knockdown', 'Var', (100, 109))	('MAFF', 'Gene', (141, 145))	('destabilized', 'NegReg', (54, 66))	('LINC00673', 'Gene', '100499467', (29, 38))	('UPF1', 'Gene', (95, 99))	('increased', 'PosReg', (110, 119))	('MAFF', 'Gene', '23764', (67, 71))	('MAFF', 'Gene', (67, 71))	('LINC00673', 'Gene', (29, 38))	('UPF1', 'Gene', '5976', (95, 99))	('stabilization', 'MPA', (124, 137))	('STAU1', 'Gene', (86, 91))	('STAU1', 'Gene', '6780', (86, 91))
226996	32322670	MAFF and LINC00673 were co-transfected, and MAFF knockdown significantly reversed the effect of promoting BTB permeability by LINC006673 alone knockdown.	('knockdown', 'Var', (49, 58))	('LINC00673', 'Gene', '100499467', (9, 18))	('promoting', 'PosReg', (96, 105))	('MAFF', 'Gene', '23764', (44, 48))	('LINC006673', 'Chemical', '-', (126, 136))	('LINC00673', 'Gene', (9, 18))	('MAFF', 'Gene', (44, 48))	('BTB', 'Chemical', '-', (106, 109))	('MAFF', 'Gene', '23764', (0, 4))	('MAFF', 'Gene', (0, 4))	('BTB permeability', 'MPA', (106, 122))
226997	32322670	Thereby, LINC00673 knockdown increased the BTB permeability and decreased the expression of ZO-1, occludin, and claudin-5 by reducing MAFF mRNA degradation in an SMD manner.	('LINC00673', 'Gene', '100499467', (9, 18))	('SMD', 'Gene', (162, 165))	('increased', 'PosReg', (29, 38))	('knockdown', 'Var', (19, 28))	('occludin', 'Gene', '100506658', (98, 106))	('LINC00673', 'Gene', (9, 18))	('claudin-5', 'Gene', '7122', (112, 121))	('SMD', 'Gene', '6638', (162, 165))	('decreased', 'NegReg', (64, 73))	('BTB', 'Chemical', '-', (43, 46))	('ZO-1', 'Gene', '7082', (92, 96))	('MAFF', 'Gene', '23764', (134, 138))	('reducing', 'NegReg', (125, 133))	('MAFF', 'Gene', (134, 138))	('occludin', 'Gene', (98, 106))	('BTB permeability', 'MPA', (43, 59))	('expression', 'MPA', (78, 88))	('ZO-1', 'Gene', (92, 96))	('claudin-5', 'Gene', (112, 121))
227003	32322670	In the tumor microenvironment, the transcription inhibitor MAFF binds to mutP53, inhibits SIL-1Ra promoter activity, and facilitates the progression of malignancy.	('inhibits', 'NegReg', (81, 89))	('tumor', 'Disease', (7, 12))	('facilitates', 'PosReg', (121, 132))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('MAFF', 'Gene', '23764', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('mutP53', 'Var', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('malignancy', 'Disease', (152, 162))	('binds', 'Interaction', (64, 69))	('MAFF', 'Gene', (59, 63))	('SIL-1Ra promoter activity', 'MPA', (90, 115))
227008	32322670	In the present study, RBFOX1 overexpression increased BTB permeability, and LINC00673 knockdown increased BTB permeability, and these results revealed the methods of opening the BTB from the molecular level.	('LINC00673', 'Gene', '100499467', (76, 85))	('increased', 'PosReg', (96, 105))	('knockdown', 'Var', (86, 95))	('BTB', 'Chemical', '-', (54, 57))	('BTB', 'Chemical', '-', (178, 181))	('LINC00673', 'Gene', (76, 85))	('overexpression', 'Var', (29, 43))	('BTB permeability', 'MPA', (54, 70))	('BTB', 'Chemical', '-', (106, 109))	('increased', 'PosReg', (44, 53))	('RBFOX1', 'Gene', (22, 28))	('BTB permeability', 'MPA', (106, 122))
227009	32322670	Recent research reported that diphtheria toxin (DT)270-326 significantly increased the permeability of the BTB in vitro, and the combination of DT270-326 with Dox significantly enhanced the loss of cell viability and the apoptosis of glioma cells.	('increased', 'PosReg', (73, 82))	('Dox', 'Chemical', 'MESH:D004317', (159, 162))	('DT270-326', 'Var', (144, 153))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('combination', 'Interaction', (129, 140))	('loss', 'NegReg', (190, 194))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('cell viability', 'CPA', (198, 212))	('permeability of the BTB', 'MPA', (87, 110))	('apoptosis', 'CPA', (221, 230))	('glioma', 'Disease', (234, 240))	('enhanced', 'PosReg', (177, 185))	('BTB', 'Chemical', '-', (107, 110))
227031	32322670	A One-Step SYBR PrimeScript RT-PCR kit (Perfect Real Time, Takara Bio) was used to performed the following gene expression assays: RBFOX1 (NM_001308117.1), LINC00673 (NR_036488.1), MAFF (NM_001161572.1), ZO-1 (NM_001301025.3), occludin (NM_001205254.2), and claudin-5 (NM_001130861.1).	('NM_001308117.1', 'Var', (139, 153))	('ZO-1', 'Gene', (204, 208))	('NM_001130861.1', 'Var', (269, 283))	('LINC00673', 'Gene', '100499467', (156, 165))	('occludin', 'Gene', (227, 235))	('NM_001161572.1', 'Var', (187, 201))	('NR_036488.1', 'Var', (167, 178))	('LINC00673', 'Gene', (156, 165))	('occludin', 'Gene', '100506658', (227, 235))	('MAFF', 'Gene', '23764', (181, 185))	('ZO-1', 'Gene', '7082', (204, 208))	('claudin-5', 'Gene', (258, 267))	('NM_001205254.2', 'Var', (237, 251))	('MAFF', 'Gene', (181, 185))	('claudin-5', 'Gene', '7122', (258, 267))	('NM_001301025.3', 'Var', (210, 224))
227058	32322670	Wild-type pmirGLO-MAFF or MAFF mutant reporter plasmid and shLINC00673 or shNC were co-transfected into HEK293T cells.	('mutant', 'Var', (31, 37))	('LINC00673', 'Gene', '100499467', (61, 70))	('MAFF', 'Gene', '23764', (26, 30))	('MAFF', 'Gene', (26, 30))	('HEK293T', 'CellLine', 'CVCL:0063', (104, 111))	('LINC00673', 'Gene', (61, 70))	('MAFF', 'Gene', '23764', (18, 22))	('MAFF', 'Gene', (18, 22))
227070	32322670	Furthermore, we co-incubated biotin-labeled LINC00673 or antisense RNA with protein extract of GECs and magnetic beads.	('LINC00673', 'Gene', '100499467', (44, 53))	('antisense RNA', 'Var', (57, 70))	('biotin', 'Chemical', 'MESH:D001710', (29, 35))	('LINC00673', 'Gene', (44, 53))
227080	26206478	Whole arm 1p19q co-deletion was present in three cases from adolescent patients and 9p loss in 3, including one low-grade oligodendroglioma with CDKN2A homozygous deletion.	('loss', 'NegReg', (87, 91))	('oligodendroglioma', 'Disease', 'MESH:D009837', (122, 139))	('CDKN2A', 'Gene', '1029', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('patients', 'Species', '9606', (71, 79))	('1p19q co-deletion', 'Var', (10, 27))	('oligodendroglioma', 'Disease', (122, 139))	('CDKN2A', 'Gene', (145, 151))
227083	26206478	BRAF-KIAA1549 fusions and BRAF p.V600E mutations were absent (n = 13 and 8).	('BRAF', 'Gene', '673', (26, 30))	('BRAF-KIAA1549 fusions', 'Disease', 'MESH:D000069337', (0, 21))	('BRAF-KIAA1549 fusions', 'Disease', (0, 21))	('BRAF', 'Gene', (26, 30))	('p.V600E', 'Mutation', 'rs113488022', (31, 38))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('p.V600E', 'Var', (31, 38))
227084	26206478	In summary, cytogenetic alterations in pediatric oligodendrogliomas are characterized mostly by genomic losses, particularly in anaplastic tumors.	('alterations', 'Var', (24, 35))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('anaplastic tumors', 'Disease', 'MESH:D002277', (128, 145))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('anaplastic tumors', 'Disease', (128, 145))	('pediatric oligodendrogliomas', 'Disease', (39, 67))	('pediatric oligodendrogliomas', 'Disease', 'MESH:D009837', (39, 67))	('losses', 'NegReg', (104, 110))
227086	26206478	These tumors are characterized at the molecular level by the presence of whole-arm 1p19q co-deletion, a cytogenetic abnormality mediated by a t(1;19) translocation.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('1p19q co-deletion', 'Var', (83, 100))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
227087	26206478	Whole-exome sequencing studies have identified mutations in putative suppressor genes located in these regions, particularly FUBP1 and CIC in some, but not all, cases.	('CIC', 'Gene', '23152', (135, 138))	('FUBP1', 'Gene', '8880', (125, 130))	('CIC', 'Gene', (135, 138))	('mutations', 'Var', (47, 56))	('FUBP1', 'Gene', (125, 130))
227088	26206478	Like other diffuse gliomas, these tumors also have frequent mutations in IDH1 or IDH2.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('IDH1', 'Gene', '3417', (73, 77))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('IDH2', 'Gene', (81, 85))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('IDH1', 'Gene', (73, 77))	('IDH2', 'Gene', '3418', (81, 85))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
227089	26206478	Oligodendrogliomas with 1p19q co-deletion and IDH1 or IDH2 mutation demonstrate the best prognosis in the diffuse glioma category, and are particularly responsive to chemotherapy, as highlighted by long-term follow-up in clinical trials.	('IDH2', 'Gene', (54, 58))	('glioma', 'Disease', (114, 120))	('IDH1', 'Gene', (46, 50))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('IDH2', 'Gene', '3418', (54, 58))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('IDH1', 'Gene', '3417', (46, 50))	('1p19q co-deletion', 'Var', (24, 41))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('mutation', 'Var', (59, 67))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma', 'Disease', (11, 17))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
227092	26206478	They usually lack the molecular changes typical of adult oligodendroglioma, that is, 1p19q co-deletion and IDH1 or 2 mutations, particularly when developing in patients less than 15 years old.	('IDH1', 'Gene', (107, 111))	('mutations', 'Var', (117, 126))	('patients', 'Species', '9606', (160, 168))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('adult oligodendroglioma', 'Disease', 'MESH:D009837', (51, 74))	('IDH1', 'Gene', '3417', (107, 111))	('adult oligodendroglioma', 'Disease', (51, 74))	('1p19q', 'Gene', (85, 90))
227103	26206478	Briefly, in areas of increased spread of B-allele frequency (BAF) caused by LOH in the tumor, normal log-R ratio (LRR) would suggest copy-neutral change.	('BAF', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('BAF', 'Gene', '8815', (61, 64))	('LOH', 'Var', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('B-allele frequency', 'MPA', (41, 59))
227107	26206478	Formalin-fixed paraffin embedded sections were stained with a mouse monoclonal antibody specific for the human BRAF p.V600E mutant protein (Clone VE1, 1:100 dilution).	('human', 'Species', '9606', (105, 110))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('mouse', 'Species', '10090', (62, 67))	('p.V600E', 'Mutation', 'rs113488022', (116, 123))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('BRAF', 'Gene', '673', (111, 115))	('p.V600E', 'Var', (116, 123))	('BRAF', 'Gene', (111, 115))
227108	26206478	Other recurrent losses (involving two or more tumors) included 1q (n = 3), 3q (n = 3), 4q (n = 2), distal 6p (n = 2), 9p (n = 3), distal 11p (n = 3), 13q (n = 2), 17p (n = 3), 17q (n = 2), whole 18 (n = 2) and 19q (n = 4).	('distal 6p', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('19q', 'Var', (210, 213))	('distal 11p', 'Var', (130, 140))	('losses', 'NegReg', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('17q', 'Var', (176, 179))	('tumors', 'Disease', (46, 52))	('17p', 'Var', (163, 166))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
227111	26206478	This case also lacked BRAF alterations (BRAF : KIAA1549 and BRAF p.V600E).	('BRAF', 'Gene', '673', (40, 44))	('KIAA1549', 'Gene', '57670', (47, 55))	('KIAA1549', 'Gene', (47, 55))	('BRAF', 'Gene', (40, 44))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('BRAF', 'Gene', '673', (22, 26))	('BRAF', 'Gene', (22, 26))	('p.V600E', 'Mutation', 'rs113488022', (65, 72))	('p.V600E', 'Var', (65, 72))
227116	26206478	The third case was diagnosed as anaplastic and demonstrated numerous other abnormalities similar to those previously reported as common in anaplastic ODG, including hemizygosity of 9p and LOH on 14q and 15q, as well as gain of X.	('anaplastic ODG', 'Disease', (139, 153))	('gain of X', 'PosReg', (219, 228))	('LOH on 14q', 'Var', (188, 198))	('hemizygosity', 'Var', (165, 177))	('numerous other abnormalities', 'Disease', 'MESH:C535332', (60, 88))	('numerous other abnormalities', 'Disease', (60, 88))
227117	26206478	Two other cases with noteworthy alterations included one low-grade oligodendroglioma with whole-arm deletion of 1p but intact 19q, and one anaplastic oligodendroglioma with complex cytogenetic changes on 1p characterized by deletion of most of the arm, and gain of the portion from 1p36.23 to 1p36.11 along with complex changes in 19q (Figure 3C,D).	('gain', 'PosReg', (257, 261))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('oligodendroglioma', 'Disease', 'MESH:D009837', (150, 167))	('anaplastic oligodendroglioma', 'Disease', (139, 167))	('oligodendroglioma', 'Disease', 'MESH:D009837', (67, 84))	('low-grade', 'Disease', (57, 66))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (139, 167))	('oligodendroglioma', 'Disease', (67, 84))	('deletion', 'Var', (224, 232))	('deletion', 'Var', (100, 108))	('oligodendroglioma', 'Disease', (150, 167))
227121	26206478	Alterations in anaplastic tumors are outlined in Table 1 by case, but encompassed all common losses other than 1p and 19q, including 3q29 (n = 3), 4q (n = 2), 6p (n = 2), 11p(n = 3), 9p (n = 2), 13q (n = 2), 14q (n = 2), 17p(n = 2), 17q (n = 3) and chromosome 18 loss (n = 2).	('17q', 'Var', (233, 236))	('17p', 'Var', (221, 224))	('anaplastic tumors', 'Disease', (15, 32))	('loss', 'NegReg', (263, 267))	('chromosome', 'Var', (249, 259))	('14q', 'Var', (208, 211))	('3q29', 'Var', (133, 137))	('13q', 'Var', (195, 198))	('anaplastic tumors', 'Disease', 'MESH:D002277', (15, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('11p', 'Var', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
227122	26206478	One focal possible germ line LOH (or uniparental disomy) on 22q13.1-13.2 overlapped in two tumors (Figure 5), one anaplastic oligodendroglioma with whole arm 1p19q co-deletion in an 11-year-old girl and the second in a low-grade oligodendroglioma lacking 1p19q alterations in a 15-year-old boy.	('anaplastic oligodendroglioma', 'Disease', (114, 142))	('tumors', 'Disease', (91, 97))	('boy', 'Species', '9606', (290, 293))	('uniparental disomy', 'Disease', (37, 55))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('uniparental disomy', 'Disease', 'MESH:D024182', (37, 55))	('1p19q co-deletion', 'Var', (158, 175))	('oligodendroglioma', 'Disease', (125, 142))	('girl', 'Species', '9606', (194, 198))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (114, 142))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('oligodendroglioma', 'Disease', (229, 246))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('oligodendroglioma', 'Disease', 'MESH:D009837', (125, 142))	('oligodendroglioma', 'Disease', 'MESH:D009837', (229, 246))	('co-deletion', 'Var', (164, 175))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
227124	26206478	Fluorescence in situ hybridization studies were negative for BRAF-KIAA1549 fusion in all cases tested (n = 13).	('BRAF-KIAA1549', 'Disease', (61, 74))	('fusion', 'Var', (75, 81))	('BRAF-KIAA1549', 'Disease', 'None', (61, 74))
227125	26206478	BRAF p.V600E mutation tested by immunohistochemistry (n = 6) or sequencing (n = 2) was also absent.	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('p.V600E', 'Var', (5, 12))	('BRAF', 'Gene', '673', (0, 4))	('absent', 'NegReg', (92, 98))	('BRAF', 'Gene', (0, 4))
227127	26206478	Numerous studies have demonstrated a lack of 1p19q co-deletion in most pediatric oligodendrogliomas, and more recently, a lack of IDH1 (R132H) mutations.	('R132H', 'Mutation', 'rs121913500', (136, 141))	('1p19q co-deletion', 'Var', (45, 62))	('IDH1', 'Gene', (130, 134))	('pediatric oligodendrogliomas', 'Disease', (71, 99))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('IDH1', 'Gene', '3417', (130, 134))	('pediatric oligodendrogliomas', 'Disease', 'MESH:D009837', (71, 99))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('mutations', 'Var', (143, 152))
227128	26206478	In the largest clinicopathologic series to date focusing on pediatric oligodendrogliomas and critically excluding morphologic mimics as well as tumors with ambiguous histology, 1p19q co-deletion was present in 10 (25%), and isolated 1p loss in one (2%), while the majority lacked these alterations.	('tumors', 'Disease', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('1p19q co-deletion', 'Var', (177, 194))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('isolated', 'Var', (224, 232))	('loss', 'NegReg', (236, 240))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('pediatric oligodendrogliomas', 'Disease', (60, 88))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('pediatric oligodendrogliomas', 'Disease', 'MESH:D009837', (60, 88))
227132	26206478	In contrast, a prior study of 35 adult oligodendroglial tumors by Kitange et al using array comparative genomic hybridization in frozen tissue demonstrated genetic alterations in 18 of 20 (90%) grade II and 9 of 9 (100%) grade III oligodendrogliomas.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (39, 62))	('oligodendroglial tumors', 'Disease', (39, 62))	('gliomas', 'Phenotype', 'HP:0009733', (242, 249))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('genetic alterations', 'Var', (156, 175))	('II oligodendrogliomas', 'Disease', (228, 249))	('grade II', 'Disease', (194, 202))	('II oligodendrogliomas', 'Disease', 'MESH:D009837', (228, 249))
227134	26206478	This suggests that smaller genetic alterations are the genetic drivers in a significant subset of these tumors, as has been reported in other low-grade pediatric gliomas.	('pediatric gliomas', 'Disease', (152, 169))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('pediatric gliomas', 'Disease', 'MESH:D005910', (152, 169))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('smaller genetic alterations', 'Var', (19, 46))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))
227135	26206478	For example, in a recent whole-genome sequencing study, Zhang et al found FGFR1 tyrosine kinase duplications in three, combined 1p19q co-deletion, CIC and IDH1 mutation in one, and a MYB-MAML fusion in one of their five pediatric oligodendrogliomas.	('IDH1', 'Gene', (155, 159))	('mutation', 'Var', (160, 168))	('FGFR1', 'Gene', '2260', (74, 79))	('pediatric oligodendrogliomas', 'Disease', (220, 248))	('tyrosine kinase', 'Enzyme', (80, 95))	('pediatric oligodendrogliomas', 'Disease', 'MESH:D009837', (220, 248))	('IDH1', 'Gene', '3417', (155, 159))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('gliomas', 'Phenotype', 'HP:0009733', (241, 248))	('duplications', 'Var', (96, 108))	('CIC', 'Gene', '23152', (147, 150))	('1p19q', 'Var', (128, 133))	('CIC', 'Gene', (147, 150))	('FGFR1', 'Gene', (74, 79))
227137	26206478	The low-grade oligodendroglioma showed a homozygous CDKN2A deletion.	('oligodendroglioma', 'Disease', (14, 31))	('oligodendroglioma', 'Disease', 'MESH:D009837', (14, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('CDKN2A', 'Gene', (52, 58))	('deletion', 'Var', (59, 67))	('CDKN2A', 'Gene', '1029', (52, 58))
227138	26206478	In a recent study, CDKN2A deletions were frequent in a subset of pediatric low-grade gliomas that progressed to high grade over time and this appeared to be an early event.	('deletions', 'Var', (26, 35))	('CDKN2A', 'Gene', (19, 25))	('gliomas', 'Disease', (85, 92))	('CDKN2A', 'Gene', '1029', (19, 25))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('frequent', 'Reg', (41, 49))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
227140	26206478	RB1 pathway alterations, including RB1 and CDKN2A, have been associated with worse outcome in adult low-grade diffuse gliomas, and appear to be frequent in those tumors lacking more common diffuse glioma alterations (e.g.	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('CDKN2A', 'Gene', (43, 49))	('alterations', 'Var', (12, 23))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('RB1', 'Gene', '5925', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('CDKN2A', 'Gene', '1029', (43, 49))	('associated', 'Reg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RB1', 'Gene', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('glioma', 'Disease', (118, 124))	('gliomas', 'Disease', (118, 125))	('RB1', 'Gene', '5925', (35, 38))	('glioma', 'Disease', (197, 203))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('tumors', 'Disease', (162, 168))	('RB1', 'Gene', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
227141	26206478	1p19q co-deletion, IDH1/2 and TP53 mutations).	('TP53', 'Gene', (30, 34))	('1p19q co-deletion', 'Var', (0, 17))	('IDH1/2', 'Gene', (19, 25))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (35, 44))
227143	26206478	Loss of 10q is a frequent event in adult diffuse gliomas, may be associated with worse prognosis in oligodendrogliomas, and occurs in a subset of pediatric gliomas.	('Loss of 10q', 'Var', (0, 11))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('pediatric gliomas', 'Disease', (146, 163))	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (156, 163))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (156, 163))	('gliomas', 'Disease', (156, 163))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (100, 118))	('pediatric gliomas', 'Disease', 'MESH:D005910', (146, 163))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('gliomas', 'Disease', (49, 56))	('oligodendrogliomas', 'Disease', (100, 118))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
227146	26206478	Other studies of low-grade adult oligodendrogliomas have also found a predominance of deletions, with common gains in the study by Rossi et al involving mostly chromosome 7.	('adult oligodendrogliomas', 'Disease', 'MESH:D009837', (27, 51))	('adult oligodendrogliomas', 'Disease', (27, 51))	('gains', 'PosReg', (109, 114))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('deletions', 'Var', (86, 95))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
227148	26206478	Chromosome 12 gains were present in two cases, which has also been previously reported in adult gliomas, gains including the known oncogene MDM2.	('gains', 'Var', (105, 110))	('adult gliomas', 'Disease', (90, 103))	('MDM2', 'Gene', '4193', (140, 144))	('MDM2', 'Gene', (140, 144))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('adult gliomas', 'Disease', 'MESH:D005910', (90, 103))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))
227149	26206478	Additionally, 8q gains, previously associated with a subset of diffuse astrocytomas and oligodendroglial tumors with worse outcome, were absent.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (88, 111))	('astrocytomas', 'Disease', (71, 83))	('oligodendroglial tumors', 'Disease', (88, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('8q gains', 'Var', (14, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('astrocytomas', 'Disease', 'MESH:D001254', (71, 83))
227151	26206478	In adult patients, specific SNPs in 8q24.21 have been associated with an increased risk of IDH1 or 2 mutant glioma development, including oligodendroglioma, in genotyping studies.	('oligodendroglioma', 'Disease', (138, 155))	('patients', 'Species', '9606', (9, 17))	('glioma', 'Disease', (149, 155))	('SNPs in', 'Var', (28, 35))	('glioma', 'Disease', (108, 114))	('oligodendroglioma', 'Disease', 'MESH:D009837', (138, 155))	('IDH1', 'Gene', (91, 95))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('mutant', 'Var', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('IDH1', 'Gene', '3417', (91, 95))	('associated', 'Reg', (54, 64))
227154	26206478	LOH in these and nearby 22q regions are not uncommon in glial tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('LOH', 'Var', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('glial tumors', 'Disease', 'MESH:D005910', (56, 68))	('glial tumors', 'Disease', (56, 68))
227155	26206478	CYP2D6 abnormalities/polymorphisms been associated with the development of glial tumors, including oligodendrogliomas.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('glial tumors', 'Disease', 'MESH:D005910', (75, 87))	('CYP2D6', 'Gene', '1565', (0, 6))	('glial tumors', 'Disease', (75, 87))	('oligodendrogliomas', 'Disease', (99, 117))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('CYP2D6', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('abnormalities/polymorphisms', 'Var', (7, 34))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('associated', 'Reg', (40, 50))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (99, 117))
227157	26206478	Recurrent genetic alterations have not been described in these tumors, other than BRAF p.V600E in a subset.	('p.V600E', 'Var', (87, 94))	('BRAF', 'Gene', '673', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('p.V600E', 'Mutation', 'rs113488022', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
227161	26206478	These disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN) have been recently found to be characterized by a high frequency of combined 1p deletion and BRAF : KIAA1549 fusion, a molecular signature that separates them both from adult and pediatric oligodendrogliomas.	('pediatric oligodendrogliomas', 'Disease', 'MESH:D009837', (253, 281))	('oligodendroglioma-like leptomeningeal neoplasms', 'Disease', (19, 66))	('KIAA1549', 'Gene', (174, 182))	('KIAA1549', 'Gene', '57670', (174, 182))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('DOLN', 'Chemical', '-', (68, 72))	('neoplasms', 'Phenotype', 'HP:0002664', (57, 66))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('gliomas', 'Phenotype', 'HP:0009733', (274, 281))	('pediatric oligodendrogliomas', 'Disease', (253, 281))	('oligodendroglioma-like leptomeningeal neoplasms', 'Disease', 'MESH:D008577', (19, 66))	('fusion', 'Var', (183, 189))	('neoplasm', 'Phenotype', 'HP:0002664', (57, 65))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
227162	26206478	Our current data reinforce this molecular distinction in the pediatric setting, as isolated 1p loss was relatively rare and BRAF : KIAA1549 fusion was absent in all cases tested (n = 13).	('isolated', 'Var', (83, 91))	('BRAF', 'Gene', (124, 128))	('KIAA1549', 'Gene', '57670', (131, 139))	('KIAA1549', 'Gene', (131, 139))	('BRAF', 'Gene', '673', (124, 128))
227163	26206478	It must be noted, however, that rare case reports have also described BRAF : KIAA1549 fusions in pediatric oligodendroglioma.	('pediatric oligodendroglioma', 'Disease', 'MESH:D009837', (97, 124))	('KIAA1549', 'Gene', (77, 85))	('KIAA1549', 'Gene', '57670', (77, 85))	('fusions', 'Var', (86, 93))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('BRAF', 'Gene', '673', (70, 74))	('pediatric oligodendroglioma', 'Disease', (97, 124))	('BRAF', 'Gene', (70, 74))
227166	26206478	Deletion of 1p, usually combined with 19q deletion, is relatively rare in the group overall [5 of 20 (25%)], but represented the most common identifiable abnormality, with the caveat that these alterations are relatively rare compared with their adult counterparts and other pediatric low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (295, 301))	('gliomas', 'Phenotype', 'HP:0009733', (295, 302))	('gliomas', 'Disease', (295, 302))	('gliomas', 'Disease', 'MESH:D005910', (295, 302))	('Deletion', 'Var', (0, 8))
227167	26206478	BRAF alterations do not appear to play a prominent role in pediatric oligodendroglioma, and lack of BRAF fusions or BRAF p.V600E separate these tumors from several other pediatric low-grade gliomas.	('tumors', 'Disease', (144, 150))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('BRAF', 'Gene', '673', (0, 4))	('pediatric oligodendroglioma', 'Disease', (59, 86))	('BRAF', 'Gene', (0, 4))	('pediatric oligodendroglioma', 'Disease', 'MESH:D009837', (59, 86))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('BRAF', 'Gene', '673', (116, 120))	('fusions', 'Var', (105, 112))	('BRAF', 'Gene', (116, 120))	('p.V600E', 'Mutation', 'rs113488022', (121, 128))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('p.V600E', 'Var', (121, 128))	('gliomas', 'Disease', (190, 197))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
227168	23715902	[11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [11C]-(R)PK11195.	('Translocator protein', 'Gene', (112, 132))	('[11C]-(R)PK11195', 'Var', (208, 224))	('patients', 'Species', '9606', (56, 64))	('TSPO', 'Gene', '706', (134, 138))	('Translocator protein', 'Gene', '706', (112, 132))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('11C', 'Chemical', 'MESH:C000615233', (1, 4))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('TSPO', 'Gene', (134, 138))	('11C', 'Chemical', 'MESH:C000615233', (209, 212))	('glioma', 'Disease', (49, 55))
227184	23715902	[11C]-(R)PK11195 is a highly selective radioligand for TSPO and has been used extensively with PET for in vivo visualization of microglial activation in acute and chronic inflammatory as well as noninflammatory brain disorders.	('TSPO', 'Gene', (55, 59))	('[11C]-(R)PK11195', 'Var', (0, 16))	('11C', 'Chemical', 'MESH:C000615233', (1, 4))	('TSPO', 'Gene', '706', (55, 59))	('brain disorders', 'Disease', (211, 226))	('brain disorders', 'Disease', 'MESH:D001927', (211, 226))
227198	23715902	Only three PET studies using [11C]-PK11195 have so far been performed in a small number of patients with astrocytoma.	('patients', 'Species', '9606', (91, 99))	('[11C]-PK11195', 'Var', (29, 42))	('astrocytoma', 'Disease', 'MESH:D001254', (105, 116))	('11C', 'Chemical', 'MESH:C000615233', (30, 33))	('astrocytoma', 'Disease', (105, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
227240	23715902	Injection of [11C]-(R)PK11195 resulted in a rapid initial peak of activity in the TACs.	('[11C]-(R)PK11195', 'Var', (13, 29))	('activity', 'MPA', (66, 74))	('11C', 'Chemical', 'MESH:C000615233', (14, 17))
227281	23715902	TSPO is known to form homopolymers, predominantly dimers and trimers, that seem to increase during cell proliferation and to complex with other mitochondrial proteins present in the outer and inner mitochondrial membrane as part of the mitochondrial permeability transition pore.	('increase', 'PosReg', (83, 91))	('TSPO', 'Gene', '706', (0, 4))	('complex', 'Interaction', (125, 132))	('trimers', 'Var', (61, 68))	('TSPO', 'Gene', (0, 4))
227294	23715902	In the three patients with a mildly disturbed or relatively intact BBB, [11C]-(R)PK11195 accumulated in both the normal brain and tumour tissue rapidly, followed by a slightly slower washout from tumour tissue than from the GM.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('11C', 'Chemical', 'MESH:C000615233', (73, 76))	('patients', 'Species', '9606', (13, 21))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('tumour', 'Disease', (130, 136))	('slower', 'NegReg', (176, 182))	('tumour', 'Disease', (196, 202))	('accumulated', 'PosReg', (89, 100))	('washout', 'MPA', (183, 190))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('[11C]-(R)PK11195', 'Var', (72, 88))
227309	23715902	In addition, kinetic analysis revealed that the initial accumulation of [11C]-(R)PK11195 peaked at least to the level of the WM in all tumour TACs, indicating sufficient delivery of the radiotracer into the tumours.	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('tumour', 'Disease', (207, 213))	('delivery', 'MPA', (170, 178))	('11C', 'Chemical', 'MESH:C000615233', (73, 76))	('tumours', 'Disease', (207, 214))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('[11C]-(R)PK11195', 'Var', (72, 88))	('tumour', 'Disease', (135, 141))
227312	23715902	Overall, [11C]-(R)PK11195 proved to be a suitable radiotracer for glioma investigation, because it can be delivered sufficiently into the tumour, was not dependent on BBB leakage, and was taken up by the tumour within the framework of known kinetics.	('glioma', 'Disease', (66, 72))	('tumour', 'Disease', (204, 210))	('11C', 'Chemical', 'MESH:C000615233', (10, 13))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))	('[11C]-(R)PK11195', 'Var', (9, 25))
227331	23715902	On the other hand, overestimation of BPND using cerebellar GM as an input function could occur due to 'contamination' by small volumes of cerebellar WM because of imperfect segmentation or the partial volume effect.	('men', 'Species', '9606', (176, 179))	("'contamination'", 'PosReg', (102, 117))	('partial volume', 'Var', (193, 207))	('BPND', 'Chemical', '-', (37, 41))
227335	23715902	This effect is further increased by the presence of TSPO in blood vessel walls.	('TSPO', 'Gene', (52, 56))	('TSPO', 'Gene', '706', (52, 56))	('presence', 'Var', (40, 48))	('increased', 'PosReg', (23, 32))
227340	23715902	They also reflect the heterogeneous nature of gliomas, and confirm that [11C]-(R)PK11195 is a suitable radiotracer for glioma imaging because of its unimpeded delivery to tumour tissue and its well-characterized kinetics.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('11C', 'Chemical', 'MESH:C000615233', (73, 76))	('tumour', 'Disease', (171, 177))	('glioma', 'Disease', (46, 52))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('glioma', 'Disease', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('[11C]-(R)PK11195', 'Var', (72, 88))
227352	18952587	There is substantial evidence that the malignant progression of astrocytomas in adults results in part from perturbation of growth factor receptor tyrosine kinase signaling pathways that promote cell proliferation, survival, migration, invasion, and other crucial functions characteristic of malignant cell behavior.	('promote', 'PosReg', (187, 194))	('astrocytomas', 'Disease', 'MESH:D001254', (64, 76))	('astrocytoma', 'Phenotype', 'HP:0009592', (64, 75))	('cell proliferation', 'CPA', (195, 213))	('invasion', 'CPA', (236, 244))	('receptor tyrosine kinase', 'Gene', (138, 162))	('migration', 'CPA', (225, 234))	('receptor tyrosine kinase', 'Gene', '5979', (138, 162))	('astrocytomas', 'Disease', (64, 76))	('perturbation', 'Var', (108, 120))	('survival', 'CPA', (215, 223))
227356	18952587	For instance, TP53 mutations and EGFR amplification occur in ~50% of adult high-grade astrocytomas, but are much less frequently seen in pediatric high-grade astrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (158, 170))	('occur', 'Reg', (52, 57))	('mutations', 'Var', (19, 28))	('EGFR', 'Gene', '1956', (33, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('astrocytomas', 'Disease', (158, 170))	('astrocytomas', 'Disease', 'MESH:D001254', (86, 98))	('EGFR', 'Gene', (33, 37))	('amplification', 'Var', (38, 51))	('astrocytomas', 'Disease', (86, 98))
227382	18952587	The lower chambers contained 300 muL of serum-free Minimal Essential Medium with IGFBP2 (100 ng/mL) to establish a chemotactic gradient.	('IGFBP2', 'Gene', (81, 87))	('Essential Medium', 'Chemical', '-', (59, 75))	('100 ng/mL', 'Var', (89, 98))
227409	18952587	To elucidate whether IGFBP2 plays a functional role in modulating astrocytoma gene expression that may promote the high-grade phenotype independent of the IGF system, we performed serial microarray gene expression profiling, using the Affymetrix U133 array (~30,000 characterized gene sequences), of serum-depleted T98 and U87 cells stimulated with IGFBP2, IGF-I, or Minimal Essential Medium alone (negative baseline control).	('astrocytoma', 'Disease', (66, 77))	('U87', 'Gene', (323, 326))	('U87', 'Gene', '641648', (323, 326))	('Essential Medium', 'Chemical', '-', (375, 391))	('T98', 'CellLine', 'CVCL:B368', (315, 318))	('astrocytoma', 'Phenotype', 'HP:0009592', (66, 77))	('IGFBP2', 'Var', (349, 355))	('astrocytoma', 'Disease', 'MESH:D001254', (66, 77))
227446	18952587	Interestingly, a recent report demonstrated that blockade of radiation-induced import of EGFR to the nucleus abolished DNA-PK activation, suggesting that EGFR expression may also be crucial to DNA-PK repair function.	('EGFR', 'Gene', (154, 158))	('activation', 'MPA', (126, 136))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('DNA-PK', 'Gene', '5591', (119, 125))	('DNA-PK', 'Gene', (193, 199))	('blockade', 'Var', (49, 57))	('DNA-PK', 'Gene', '5591', (193, 199))	('DNA-PK', 'Gene', (119, 125))	('EGFR', 'Gene', '1956', (154, 158))	('abolished', 'NegReg', (109, 118))
227522	19222834	Therefore, it could be hypothesized that high expression of bcl-2 prevents cell proliferation, suppresses tumor growth and thereby is associated with a lower grade and pT-stage in RCCs, as previously stated.	('RCCs', 'Disease', (180, 184))	('suppresses', 'NegReg', (95, 105))	('high expression', 'Var', (41, 56))	('cell proliferation', 'CPA', (75, 93))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('prevents', 'NegReg', (66, 74))	('tumor', 'Disease', (106, 111))	('bcl-2', 'Gene', (60, 65))
227604	31814822	Comparing the two groups of patients, in the remapping group, the rate of stable motor eloquent sites was significantly lower than in the nonremapping group (65% vs. 97.1%).	('patients', 'Species', '9606', (28, 36))	('lower', 'NegReg', (120, 125))	('remapping', 'Var', (45, 54))
227694	31814822	However, the complexity of language system makes it difficult to delineate at which extent homologous areas in the nondominant hemisphere can take over for language compensation, when frontal or temporal language nodes are lesioned as well as when a language impairment occurred.	('language impairment', 'Phenotype', 'HP:0002463', (250, 269))	('lesioned', 'Var', (223, 231))	('language impairment', 'Disease', (250, 269))	('language impairment', 'Disease', 'MESH:D007806', (250, 269))
227736	30890735	Burden of unique and low prevalence somatic mutations correlates with cancer survival Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others.	('improved', 'PosReg', (126, 134))	('tumor aggressiveness', 'Disease', (202, 222))	('aggressiveness', 'Phenotype', 'HP:0000718', (208, 222))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('malignancies', 'Disease', (179, 191))	('Tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (202, 222))	('mutations', 'Var', (44, 53))	('survival', 'CPA', (135, 143))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
227739	30890735	High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60-0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70-0.93], p = 0.003.	('improved', 'PosReg', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('TEMMB', 'Chemical', '-', (5, 10))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial bladder carcinoma', 'Disease', (122, 150))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (133, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
227740	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00-1.74], p < 0.05.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
227742	30890735	In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02).	('high TEMMB', 'Var', (26, 36))	('survival outcomes', 'CPA', (64, 81))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('better', 'PosReg', (57, 63))	('TEMMB', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
227743	30890735	In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.	('tumor', 'Disease', (189, 194))	('TEMMB', 'Chemical', '-', (15, 20))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('survival', 'CPA', (149, 157))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('benefit', 'PosReg', (158, 165))
227746	30890735	Alternatively, highly mutated tumors may develop many novel peptides and thus display more neoantigens, rendering them more susceptible T-cell targets.	('tumors', 'Disease', (30, 36))	('peptides', 'MPA', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('develop', 'PosReg', (41, 48))	('neoantigens', 'MPA', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('more', 'PosReg', (86, 90))	('highly mutated', 'Var', (15, 29))
227747	30890735	For example, patients with melanomas with a high mutational load showed improved survival with ipilimumab and improved overall survival; patients with highly mutated ovarian cancer had improved postoperative chemotherapy response and higher overall survival.	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('improved', 'PosReg', (185, 193))	('overall', 'MPA', (241, 248))	('improved', 'PosReg', (110, 118))	('highly mutated', 'Var', (151, 165))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (137, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('melanomas', 'Disease', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('ipilimumab', 'Chemical', 'MESH:D000074324', (95, 105))	('higher', 'PosReg', (234, 240))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('overall', 'MPA', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('ovarian cancer', 'Disease', (166, 180))
227752	30890735	Furthermore, missense variants specifically have been suggested to be the most frequent class of alterations to carry the potential for neoepitope generation in chronic lymphocytic leukemia malignancy (as compared to frameshift or splice-site variants).	('neoepitope generation', 'MPA', (136, 157))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (161, 189))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('chronic lymphocytic leukemia malignancy', 'Disease', (161, 200))	('chronic lymphocytic leukemia malignancy', 'Disease', 'MESH:D015451', (161, 200))	('missense variants', 'Var', (13, 30))	('lymphocytic leukemia malignancy', 'Phenotype', 'HP:0005526', (169, 200))
227753	30890735	In multiple myeloma, missense mutational load was found to be highly correlated with predicted neoantigen loads.	('multiple myeloma', 'Disease', (3, 19))	('correlated', 'Reg', (69, 79))	('neoantigen loads', 'MPA', (95, 111))	('missense mutational load', 'Var', (21, 45))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
227754	30890735	Total missense mutational burden across all cohorts ranged from a low of 8 (median) missense mutations among acute myeloid leukemia (LAML) and thymoma (THYM), to 256 median mutations among the skin cutaneous melanoma (SKCM) cohort (Fig.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (109, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('thymoma', 'Disease', 'MESH:D013945', (143, 150))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('thymoma', 'Disease', (143, 150))	('acute myeloid leukemia', 'Disease', (109, 131))	('mutations', 'Var', (173, 182))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (193, 216))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('thymoma', 'Phenotype', 'HP:0100522', (143, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (109, 131))	('skin cutaneous melanoma', 'Disease', (193, 216))	('missense mutations', 'Var', (84, 102))
227756	30890735	Total (TEMB) and missense (TEMMB) tumor exonic mutational burden were found to be closely correlated among all cohorts: Pearson's r ranged from 0.95-1.00 for all cohorts other than uveal melanoma (UVM) which also revealed a strong positive correlation with r = 0.88 likely due to a small (N = 79) sample size (p < 2.2 x 10-16 for all cohorts) (Fig.	('missense', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('UVM', 'Phenotype', 'HP:0007716', (197, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TEMMB', 'Chemical', '-', (27, 32))	('uveal melanoma', 'Disease', (181, 195))
227758	30890735	Male sex was significantly associated with high TEMMB in renal papillary cell carcinoma (KIRP), sarcoma (SARC), and cutaneous melanoma (SKCM).	('high TEMMB', 'Var', (43, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('SARC', 'Phenotype', 'HP:0100242', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('associated', 'Reg', (27, 37))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (57, 87))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('cutaneous melanoma', 'Disease', (116, 134))	('TEMMB', 'Chemical', '-', (48, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('renal papillary cell carcinoma', 'Disease', (57, 87))	('sarcoma', 'Disease', (96, 103))
227759	30890735	Female sex was significantly associated with high TEMMB in colorectal adenocarcinoma (COAD) and glioblastoma multiforme (GBM).	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('colorectal adenocarcinoma', 'Disease', (59, 84))	('TEMMB', 'Chemical', '-', (50, 55))	('COAD', 'Disease', (86, 90))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (59, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('glioblastoma multiforme', 'Disease', (96, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('high TEMMB', 'Var', (45, 55))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (96, 119))
227762	30890735	High TEMMB correlated with improved survival in skin cutaneous melanoma (SKCM): HR = 0.71 [0.60-0.85], p = 0.0002, bladder urothelial carcinoma (BLCA): HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma (OV): HR = 0.80 [0.70-0.93], p = 0.003.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 71))	('improved', 'PosReg', (27, 35))	('OV', 'Phenotype', 'HP:0025318', (208, 210))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('TEMMB', 'Chemical', '-', (5, 10))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('survival', 'MPA', (36, 44))	('skin cutaneous melanoma', 'Disease', (48, 71))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))
227763	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma (COAD): HR = 1.32 [1.00-1.74], p < 0.05 (p = 0.0497).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('COAD', 'Disease', (80, 84))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('COAD', 'Disease', 'MESH:D029424', (80, 84))
227765	30890735	To characterize the somatic mutational profile of each cancer, we determined the relative burden of recurrent mutations to total mutations within each cohort, expressed as a recurrence score (RS).	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (55, 61))
227767	30890735	Several cohorts, notably adrenocortical carcinoma (ACC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), thyroid carcinoma (THCA), thymoma (THYM), and uveal melanoma (UVM), revealed mutations occurring at high prevalence among the sequenced population.	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('UVM', 'Phenotype', 'HP:0007716', (225, 228))	('glioma', 'Disease', (148, 154))	('THCA', 'Phenotype', 'HP:0002890', (182, 186))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (57, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (209, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (57, 79))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (163, 180))	('uveal melanoma', 'Disease', (209, 223))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (25, 49))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('mutations', 'Var', (240, 249))	('thyroid carcinoma', 'Disease', (163, 180))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (120, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', (106, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (209, 223))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (25, 49))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (163, 180))	('thymoma', 'Disease', 'MESH:D013945', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adrenocortical carcinoma', 'Disease', (25, 49))	('THYM', 'Phenotype', 'HP:0100522', (198, 202))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('acute myeloid leukemia', 'Disease', (57, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('thymoma', 'Disease', (189, 196))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('thymoma', 'Phenotype', 'HP:0100522', (189, 196))
227768	30890735	The recurrent mutations can be readily visualized as sharp peaks in the cancers' mutational profiles.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mutations', 'Var', (14, 23))
227771	30890735	In the adrenocortical carcinoma (ACC) cohort, 0.29% of all pooled missense mutations were in the ZNF517 gene (p.V349A), and 0.29% of missense mutations were recurrent GARS (p.P42A) mutations.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (7, 31))	('ZNF517', 'Gene', '340385', (97, 103))	('ZNF517', 'Gene', (97, 103))	('missense mutations', 'Var', (133, 151))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('missense mutations', 'Var', (66, 84))	('p.V349A', 'Mutation', 'rs2976653', (110, 117))	('p.P42A', 'Mutation', 'rs1049402', (173, 179))	('adrenocortical carcinoma', 'Disease', (7, 31))	('GARS', 'Gene', '2617', (167, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('GARS', 'Gene', (167, 171))	('p.P42A', 'Var', (173, 179))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (7, 31))
227772	30890735	In uveal melanoma (UVM) cohort, 2.54% were recurrent GNA11 (p.Q209P) mutations, 2.01% were recurrent GNAQ p.Q209P, and 0.75% GNAQ p.Q1209L.	('p.Q1209L', 'Var', (130, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('GNA11', 'Gene', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('p.Q1209L', 'Mutation', 'p.Q1209L', (130, 138))	('GNA11', 'Gene', '2767', (53, 58))	('UVM', 'Phenotype', 'HP:0007716', (19, 22))	('p.Q209P', 'Mutation', 'rs1057519742', (60, 67))	('p.Q209P', 'Mutation', 'rs1057519742', (106, 113))	('p.Q209P', 'Var', (106, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
227773	30890735	In thyroid carcinoma (THCA), 5.23% were BRAF p.V600E, 0.65% were NRAS p.Q61R, and 0.25% HRAS p.Q61R.	('p.Q61R', 'Mutation', 'rs755829919', (70, 76))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('thyroid carcinoma', 'Disease', (3, 20))	('THCA', 'Phenotype', 'HP:0002890', (22, 26))	('p.Q61R', 'Mutation', 'rs755829919', (93, 99))	('p.V600E', 'Mutation', 'p.V600E', (45, 52))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (3, 20))	('p.V600E', 'Var', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
227774	30890735	In the acute myeloid leukemia (LAML) cohort, 1.38% of missense mutations were in DNMT3A gene (p.R882H), 1.05% were IDH2 p.R140Q, and 0.79% were IDH1 p.R132C.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (7, 29))	('p.R882H', 'Mutation', 'rs147001633', (94, 101))	('leukemia', 'Phenotype', 'HP:0001909', (21, 29))	('missense mutations', 'Var', (54, 72))	('DNMT3A', 'Gene', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (7, 29))	('DNMT3A', 'Gene', '1788', (81, 87))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (13, 29))	('p.R140Q', 'Var', (120, 127))	('p.R132C', 'Mutation', 'rs121913499', (149, 156))	('p.R140Q', 'Mutation', 'rs121913502', (120, 127))	('acute myeloid leukemia', 'Disease', (7, 29))
227775	30890735	In pheochromocytoma and paraganglioma (PCPG), 0.64% of mutations were recurrent HRAS p.Q61R, and 0.36% were CHEK2 p.K152E.	('p.Q61R', 'Var', (85, 91))	('mutations', 'Var', (55, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('CHEK2', 'Gene', '11200', (108, 113))	('p.K152E', 'Mutation', 'rs74751600', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('p.Q61R', 'Mutation', 'rs755829919', (85, 91))	('CHEK2', 'Gene', (108, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (3, 19))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (3, 37))
227777	30890735	Cancers with low RS tended to exhibit survival benefit (HR < 1) with increased adjusted-TEMMB.	('adjusted-TEMMB', 'Var', (79, 93))	('increased', 'PosReg', (69, 78))	('TEMMB', 'Chemical', '-', (88, 93))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival benefit', 'CPA', (38, 54))
227778	30890735	Conversely, cancers with high RS were observed to have a decrease in survival (HR > 1) with increased adjusted-TEMMB.	('decrease', 'NegReg', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('high RS', 'Var', (25, 32))	('cancers', 'Disease', (12, 19))	('increased', 'PosReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('adjusted-TEMMB', 'Var', (102, 116))	('TEMMB', 'Chemical', '-', (111, 116))	('survival', 'MPA', (69, 77))
227779	30890735	Exonic missense mutation distribution displays considerable variability among cancers studied in TCGA.	('Exonic missense mutation', 'Var', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
227781	30890735	Somatic missense mutations strongly contribute to the generation of novel tumor epitopes.	('tumor epitopes', 'Disease', (74, 88))	('tumor epitopes', 'Disease', 'MESH:D009369', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('missense mutations', 'Var', (8, 26))
227786	30890735	Interestingly, low tumor stage was correlated (after Bonferroni adjustment) with high TEMMB in breast carcinoma, colon and rectal adenocarcinoma, and uveal melanoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (95, 111))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('high TEMMB', 'Var', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('low tumor', 'Disease', 'MESH:D009800', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('low tumor', 'Disease', (15, 24))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('colon and rectal adenocarcinoma', 'Disease', 'MESH:D012004', (113, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TEMMB', 'Chemical', '-', (86, 91))	('breast carcinoma', 'Disease', (95, 111))
227793	30890735	Given the high propensity for rapid metastasis in uveal melanoma, it is possible that intercepting such tumors at an early stage may partially be explained by a higher mutational load and thus more favorable immune response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutational load', 'Var', (168, 183))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('uveal melanoma', 'Disease', (50, 64))	('higher', 'PosReg', (161, 167))
227794	30890735	Driver mutations impart tumor growth advantage and are positively selected in cancer evolution, while biologically inert passengers accumulate without directional selection over the tumor growth timespan.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (7, 16))
227795	30890735	Many established bioinformatics methods to study drivers rely on techniques that identify recurrent mutations, and thus we quantified recurrent and non-recurrent mutations to serve as proxy for relative amounts of drivers and passengers within a cancer type.	('cancer', 'Disease', (246, 252))	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
227796	30890735	Our results suggest high TEMMB tends to confer survival benefit in cancers with more non-recurrent (likely passenger) mutations, and decreased survival in cancers with high recurrent (likely driver) fractions.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (118, 127))	('benefit', 'PosReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('survival', 'MPA', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('TEMMB', 'Chemical', '-', (25, 30))	('cancers', 'Disease', (155, 162))	('decreased', 'NegReg', (133, 142))
227797	30890735	We propose that in malignancies with large enrichments of non-recurrent mutations, high TEMMB marks a high passenger count, and increasing passenger mutation load increases neoantigen presentation without imparting additional growth advantage or aggressiveness.	('aggressiveness', 'Disease', (246, 260))	('malignancies', 'Disease', (19, 31))	('TEMMB', 'Chemical', '-', (88, 93))	('passenger mutation load', 'Var', (139, 162))	('aggressiveness', 'Phenotype', 'HP:0000718', (246, 260))	('increases', 'PosReg', (163, 172))	('aggressiveness', 'Disease', 'MESH:D001523', (246, 260))	('increasing', 'PosReg', (128, 138))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('neoantigen presentation', 'MPA', (173, 196))
227798	30890735	Our observed benefit with high TEMMB supports literature findings for melanoma and ovarian carcinoma.	('melanoma', 'Disease', (70, 78))	('ovarian carcinoma', 'Disease', (83, 100))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('high TEMMB', 'Var', (26, 36))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (83, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (83, 100))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('TEMMB', 'Chemical', '-', (31, 36))	('benefit', 'PosReg', (13, 20))
227801	30890735	Recent work has suggested a "double-edged" effect of increased DNA variants, noting that on the one hand, high DNA variation increases accumulation of drivers which are beneficial to tumor adaptation; conversely, high concurrent passenger loads may outweigh the driver effects.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('high', 'Var', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('accumulation', 'MPA', (135, 147))
227814	30890735	Cancers with higher proportions of non-recurrent and thus likely passenger mutations showed survival benefit with high TEMMB, while cancers with higher recurrent mutation fractions (likely drivers) revealed a decrease in survival.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('decrease', 'NegReg', (209, 217))	('TEMMB', 'Chemical', '-', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('benefit', 'PosReg', (101, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival', 'MPA', (92, 100))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('high TEMMB', 'Var', (114, 124))
227815	30890735	Mutational signatures for some cancers might contribute significantly to overall TEMMB (e.g.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TEMMB', 'Disease', (81, 86))	('TEMMB', 'Chemical', '-', (81, 86))	('cancers', 'Disease', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('Mutational signatures', 'Var', (0, 21))	('contribute', 'Reg', (45, 55))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
227834	30890735	We aggregated all nonsynonymous missense mutations among all individuals in each cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('nonsynonymous missense mutations', 'Var', (18, 50))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
227835	30890735	A somatic recurrence score (RS) was calculated as the fraction of total mutations in the cohort's pool comprised by recurrent mutations as defined above: A RS was assigned to each cancer type, and the correlation between log10-adjusted survival HR and log10-adjusted RS was computed with Pearson's correlation.	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('mutations', 'Var', (126, 135))
227840	22736199	On the same day within a few hours, rCBF was measured in ten adult patients with treatment-naive primary brain tumours, twice using 15O-H2O PET and once with PCT performed over the central part of the tumour.	('primary brain tumours', 'Disease', 'MESH:D001932', (97, 118))	('brain tumour', 'Phenotype', 'HP:0030692', (105, 117))	('primary brain tumours', 'Disease', (97, 118))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('tumour', 'Disease', (201, 207))	('men', 'Species', '9606', (86, 89))	('PCT', 'Gene', (158, 161))	('patients', 'Species', '9606', (67, 75))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('15O-H2O', 'Chemical', '-', (132, 139))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('rCBF', 'Gene', (36, 40))	('15O-H2O PET', 'Var', (132, 143))	('rCBF', 'Gene', '362686', (36, 40))	('brain tumours', 'Phenotype', 'HP:0030692', (105, 118))	('PCT', 'Gene', '796', (158, 161))
227940	22736199	Other research groups have quantified blood flow of different tumour types of the brain with 15O-H2O PET.	('15O-H2O', 'Chemical', '-', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('15O-H2O PET', 'Var', (93, 104))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))
227964	22736199	No significant difference was found between high- and low-grade gliomas using SE-EPI, while this was the case for GE-EPI.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('SE-EPI', 'Chemical', '-', (78, 84))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('GE', 'Chemical', 'MESH:D005857', (114, 116))	('SE-EPI', 'Var', (78, 84))
227980	22736199	An important factor to explain the quantitative and qualitative difference between PCT and 15O-H2O PET adheres to the fundamental differences between a CT non-diffusible intravascular iodinated medium and a PET freely diffusible tissue tracer.	('PCT', 'Gene', '796', (83, 86))	('15O-H2O', 'Chemical', '-', (91, 98))	('15O-H2O', 'Var', (91, 98))	('men', 'Species', '9606', (123, 126))	('PCT', 'Gene', (83, 86))
228014	33898320	Recent studies have shown that TLRs could reverse tumor differentiation and transform microglia into a glioma supportive phenotype in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma', 'Disease', (103, 109))	('gliomas', 'Disease', (134, 141))	('transform', 'Reg', (76, 85))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('microglia', 'CPA', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('glioma', 'Disease', (134, 140))	('TLRs', 'Var', (31, 35))	('tumor', 'Disease', (50, 55))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
228022	33898320	Moreover, the MYD88 expression was also related with IDH1 mutation status and methylation.	('expression', 'MPA', (20, 30))	('related', 'Reg', (40, 47))	('methylation', 'Var', (78, 89))	('MYD88', 'Gene', (14, 19))	('IDH1', 'Gene', (53, 57))	('IDH1', 'Gene', '3417', (53, 57))	('mutation status', 'Var', (58, 73))
228030	33898320	Then the slides were incubated with secondary antibodies (1:200, Servicebio, GB23303) for MYD88 and CD163 or secondary antibodies (1:200, Servicebio, GB23301) for CD68 50 min at room temperature.	('1:200', 'Var', (131, 136))	('CD163', 'Gene', (100, 105))	('1:200', 'Var', (58, 63))	('CD163', 'Gene', '9332', (100, 105))
228034	33898320	The IRS score of MYD88 was divided into groups based on IDH1 mutation status or WHO grades and compared separately.	('mutation', 'Var', (61, 69))	('IDH1', 'Gene', '3417', (56, 60))	('IDH1', 'Gene', (56, 60))
228064	33898320	We found that the macrophage M0 (p < 0.001,  Figure 6A  ), macrophage M1 (p < 0.001,  Figure 6A  ) and macrophage M2 (p = 0.002,  Figure 6A ) were significantly up-regulated in MYD88 high-expression group.	('age', 'Gene', '5973', (110, 113))	('high-expression', 'Var', (183, 198))	('age', 'Gene', (25, 28))	('age', 'Gene', (66, 69))	('age', 'Gene', (110, 113))	('MYD88', 'Gene', (177, 182))	('age', 'Gene', '5973', (25, 28))	('up-regulated', 'PosReg', (161, 173))	('age', 'Gene', '5973', (66, 69))
228066	33898320	IDH 1 mutant status was associated with lower MYD88 expression (p < 0.001,  Figure S2B ).	('IDH 1', 'Gene', '3417', (0, 5))	('IDH 1', 'Gene', (0, 5))	('expression', 'MPA', (52, 62))	('MYD88', 'Protein', (46, 51))	('mutant status', 'Var', (6, 19))	('lower', 'NegReg', (40, 45))
228067	33898320	MYD88 expression mainly manifested significantly lower in WHO III (p < 0.001,  Figure S2C ) and WHO IV (p < 0.001,  Figure S2C ) grade IDH 1 mutant patients.	('patients', 'Species', '9606', (148, 156))	('mutant', 'Var', (141, 147))	('expression', 'MPA', (6, 16))	('IDH 1', 'Gene', '3417', (135, 140))	('lower', 'NegReg', (49, 54))	('MYD88', 'Gene', (0, 5))	('IDH 1', 'Gene', (135, 140))
228071	33898320	And in the IDH1 mutant cases, the MYD88 was significantly lower as compared to the cases with IDH1 wild cases (p < 0.001,  Figures 7B-F ).	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', '3417', (11, 15))	('lower', 'NegReg', (58, 63))	('IDH1', 'Gene', '3417', (94, 98))	('mutant', 'Var', (16, 22))	('MYD88', 'MPA', (34, 39))	('IDH1', 'Gene', (11, 15))
228072	33898320	The CD163 was expressed lower in IDH1 mutant cases (p < 0.001,  Figures 8B, D, F, H, J ).	('mutant', 'Var', (38, 44))	('CD163', 'Gene', '9332', (4, 9))	('CD163', 'Gene', (4, 9))	('IDH1', 'Gene', (33, 37))	('lower', 'NegReg', (24, 29))	('IDH1', 'Gene', '3417', (33, 37))
228077	33898320	Besides that, MYD88 was also down regulated in the IDH1 mutant gliomas.	('IDH1', 'Gene', '3417', (51, 55))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('MYD88', 'Gene', (14, 19))	('mutant', 'Var', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('down regulated', 'NegReg', (29, 43))	('IDH1', 'Gene', (51, 55))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
228091	33898320	The MYD88 expression was significantly lower in normal tissues and high expression was associated with shorter survival time, older age, and higher WHO grade.	('MYD88', 'Gene', (4, 9))	('high', 'Var', (67, 71))	('age', 'Gene', '5973', (132, 135))	('WHO grade', 'CPA', (148, 157))	('expression', 'MPA', (10, 20))	('shorter', 'NegReg', (103, 110))	('survival time', 'CPA', (111, 124))	('age', 'Gene', (132, 135))	('lower', 'NegReg', (39, 44))
228117	33898320	IDH1 mutant status was associated with lower MYD88 expression.	('mutant status', 'Var', (5, 18))	('MYD88', 'Protein', (45, 50))	('expression', 'MPA', (51, 61))	('IDH1', 'Gene', (0, 4))	('lower', 'NegReg', (39, 44))	('IDH1', 'Gene', '3417', (0, 4))
228118	33898320	MYD88 expression mainly manifested significantly lower in WHO III and WHO IV grade IDH1 mutant patients compared with the IDH1 wild type group separately.	('IDH1', 'Gene', '3417', (83, 87))	('patients', 'Species', '9606', (95, 103))	('expression', 'MPA', (6, 16))	('IDH1', 'Gene', (122, 126))	('mutant', 'Var', (88, 94))	('lower', 'NegReg', (49, 54))	('IDH1', 'Gene', '3417', (122, 126))	('IDH1', 'Gene', (83, 87))	('MYD88', 'Gene', (0, 5))
228120	33898320	And in the WHO IV grade tissues, the MYD88 was significantly lower in IDH1 mutant cases.	('lower', 'NegReg', (61, 66))	('MYD88', 'MPA', (37, 42))	('IDH1', 'Gene', '3417', (70, 74))	('mutant', 'Var', (75, 81))	('IDH1', 'Gene', (70, 74))
228121	33898320	IDH1 and methylation of O -methylguanine DNA methyltransferase (MGMT) promoter are important biomarkers for GBM patients.	('methylation', 'Var', (9, 20))	('GBM', 'Disease', (108, 111))	('patients', 'Species', '9606', (112, 120))	('MGMT', 'Gene', (64, 68))	('O -methylguanine', 'Chemical', '-', (24, 40))	('MGMT', 'Gene', '4255', (64, 68))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
228122	33898320	The IDH1 mutation is common in lower grade gliomas.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('IDH1', 'Gene', (4, 8))	('gliomas', 'Disease', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('common', 'Reg', (21, 27))
228123	33898320	And 12% of GBM patients have IDH1 mutation.	('patients', 'Species', '9606', (15, 23))	('mutation', 'Var', (34, 42))	('IDH1', 'Gene', '3417', (29, 33))	('IDH1', 'Gene', (29, 33))
228124	33898320	The IDH1 mutation is associated with increased survival time of the patients.	('mutation', 'Var', (9, 17))	('survival time', 'CPA', (47, 60))	('IDH1', 'Gene', '3417', (4, 8))	('patients', 'Species', '9606', (68, 76))	('IDH1', 'Gene', (4, 8))	('increased', 'PosReg', (37, 46))
228126	33898320	These indicated that IDH1 mutant might be related with the downregulation of MYD88 expression and less inflammatory responses in glioma TME, which could benefit the prognostics of glioma patients.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('patients', 'Species', '9606', (187, 195))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('glioma TME', 'Disease', 'MESH:D005910', (129, 139))	('less', 'NegReg', (98, 102))	('benefit', 'PosReg', (153, 160))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('downregulation', 'NegReg', (59, 73))	('IDH1', 'Gene', (21, 25))	('MYD88', 'Gene', (77, 82))	('glioma', 'Disease', (129, 135))	('mutant', 'Var', (26, 32))	('glioma TME', 'Disease', (129, 139))	('expression', 'MPA', (83, 93))	('IDH1', 'Gene', '3417', (21, 25))	('glioma', 'Disease', (180, 186))	('inflammatory responses', 'CPA', (103, 125))
228145	30378290	Multivariable analysis showed that surgery +RT was independently associated with diminished OS and CSS for high risk group, which had no statistical significance for low-risk group.	('diminished', 'NegReg', (81, 91))	('CSS', 'Chemical', '-', (99, 102))	('surgery +RT', 'Var', (35, 46))	('OS', 'Chemical', '-', (92, 94))	('CSS', 'CPA', (99, 102))
228155	30378290	The European Organization for Research and Treatment of Cancer (EORTC 22844) conducted a randomized trial, which had shown no difference in CSS and OS for low-grade glioma patients who received PORT.6 Another trial from EORTC 22845 found that PORT improved CSS, but did not affect OS.11 The role of PORT for ALISA/O patients remained controversial.	('OS', 'Chemical', '-', (281, 283))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('PORT', 'Var', (243, 247))	('improved', 'PosReg', (248, 256))	('patients', 'Species', '9606', (316, 324))	('OS', 'Chemical', '-', (148, 150))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cancer', 'Disease', (56, 62))	('CSS', 'MPA', (257, 260))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('patients', 'Species', '9606', (172, 180))	('CSS', 'Chemical', '-', (257, 260))	('CSS', 'Chemical', '-', (140, 143))	('glioma', 'Disease', (165, 171))
228176	30378290	According to survival analysis by log-rank test, surgery +RT rather than surgery alone was significantly associated with worse OS (hazard ratio [HR], 2.32; 95% CI, 1.93-2.70; P < 0.001) and CSS (HR, 2.41; 95% CI, 1.97-2.83; P < 0.001) for patients with ALISA/O (Figure 1A,B).	('ALISA/O', 'Disease', (253, 260))	('CSS', 'Disease', (190, 193))	('patients', 'Species', '9606', (239, 247))	('CSS', 'Chemical', '-', (190, 193))	('surgery +RT', 'Var', (49, 60))	('OS', 'Chemical', '-', (127, 129))
228189	30378290	In the low risk group, the survival analysis showed that surgery +RT rather than surgery alone was significantly associated with worse OS (HR, 1.89; 95% CI, 1.29-3.25; P = 0.0024) and CSS (HR, 1.87; 95% CI, 1.23-3.30; P = 0.0054; Figure 3A,B).	('surgery +RT', 'Var', (57, 68))	('CSS', 'Disease', (184, 187))	('OS', 'Chemical', '-', (135, 137))	('CSS', 'Chemical', '-', (184, 187))
228200	30378290	Comparing tumor size >59 mm group with tumor size <=59 mm, multivariable analysis showed tumor size >59 mm was independently associated with diminished OS and CSS both in the low- and high risk groups.	('>59 mm', 'Var', (100, 106))	('CSS', 'Chemical', '-', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('CSS', 'CPA', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('OS', 'Chemical', '-', (152, 154))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('diminished', 'NegReg', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
228248	30588503	Especially difficult is the separation of ring or focal solid enhancing primary brain tumors from brain metastases (MET).	('brain tumors', 'Disease', 'MESH:D001932', (80, 92))	('brain tumors', 'Phenotype', 'HP:0030692', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('brain tumors', 'Disease', (80, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('focal', 'Var', (50, 55))	('brain metastases', 'Disease', (98, 114))	('brain metastases', 'Disease', 'MESH:D009362', (98, 114))
228300	30588503	The best AUC-values obtained with Cho/NAA and Cho/Cr were 0.9504 and 0.8959 with sensitivity 85% and specificity 0.93 for Cho/NAA and 86% and 86% for Cho/Cr respectively.	('Cho/NAA', 'Disease', (122, 129))	('NAA', 'Chemical', 'MESH:C000179', (126, 129))	('Cho', 'Chemical', 'MESH:C034482', (46, 49))	('Cr', 'Chemical', 'MESH:D002857', (50, 52))	('0.8959', 'Var', (69, 75))	('Cr', 'Chemical', 'MESH:D002857', (154, 156))	('NAA', 'Chemical', 'MESH:C000179', (38, 41))	('Cho', 'Chemical', 'MESH:C034482', (150, 153))	('0.9504', 'Var', (58, 64))	('Cho', 'Chemical', 'MESH:C034482', (122, 125))	('Cho', 'Chemical', 'MESH:C034482', (34, 37))
228309	30588503	Cho is also a source of the methyl group and can, through epigenetics, methylate the O6-methylguanine-DNA methyltransferase in glioblastoma.	('epigenetics', 'Var', (58, 69))	('methylate', 'Var', (71, 80))	('glioblastoma', 'Disease', (127, 139))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (85, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (127, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('Cho', 'Chemical', 'MESH:C034482', (0, 3))	('O6-methylguanine-DNA methyltransferase', 'Gene', (85, 123))
228317	30588503	An increase in tCho, tCr, Ins concentration may be because of a range of causes; gliosis, decreased intra- or extracellular H2O content with subsequent density rise, elevation in osmolarity in the brain, deviations in volume of the cortex, and lastly, increased synthesis or release of metabolites.	('gliosis', 'Disease', (81, 88))	('synthesis', 'MPA', (262, 271))	('decreased', 'NegReg', (90, 99))	('increased', 'PosReg', (252, 261))	('density', 'MPA', (152, 159))	('Ins', 'Chemical', 'MESH:D007294', (26, 29))	('tCr', 'Gene', (21, 24))	('tCr', 'Gene', '6962', (21, 24))	('rise', 'PosReg', (160, 164))	('H2O', 'Chemical', 'MESH:D014867', (124, 127))	('gliosis', 'Disease', 'MESH:D005911', (81, 88))	('osmolarity', 'MPA', (179, 189))	('volume of', 'CPA', (218, 227))	('elevation', 'PosReg', (166, 175))	('increase', 'PosReg', (3, 11))	('tCho', 'MPA', (15, 19))	('gliosis', 'Phenotype', 'HP:0002171', (81, 88))	('release of metabolites', 'MPA', (275, 297))	('intra- or extracellular H2O content', 'MPA', (100, 135))	('tCho', 'Chemical', '-', (15, 19))	('deviations', 'Var', (204, 214))
228320	30588503	With regards to malignant spread of gliomas, brain parenchyma with low tCho/tCr ratios have been observed to manifest reduced cluster size and reduced frequencies of tumor clusters in brain parenchyma, when compared to tissue with high tCho/tCr ratios that were observed to have tumor clusters with more rapid growth in size and with higher frequencies of these clusters.	('low', 'Var', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('gliomas', 'Disease', (36, 43))	('tCho', 'Chemical', '-', (236, 240))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('reduced', 'NegReg', (143, 150))	('tCr', 'Gene', (241, 244))	('tumor', 'Disease', (279, 284))	('reduced', 'NegReg', (118, 125))	('tCr', 'Gene', '6962', (241, 244))	('tumor', 'Disease', (166, 171))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('tCr', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tCr', 'Gene', '6962', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cluster size', 'CPA', (126, 138))	('tCho', 'Chemical', '-', (71, 75))
228341	26911151	To date, little is known regarding the nature of recurrent disease, and the most significant prognostic factors for patients diagnosed with LGG are the presence of somatic driver mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes and the codeletion of the 1p and 19q chromosomal arms, which have been associated with increased survival and sensitivity to the treatment given.	('LGG', 'Disease', (140, 143))	('increased', 'PosReg', (331, 340))	('IDH1/2', 'Gene', '3417;3418', (226, 232))	('patients', 'Species', '9606', (116, 124))	('IDH1/2', 'Gene', (226, 232))	('mutations', 'Var', (179, 188))
228342	26911151	IDH mutations have been implicated as an initiating event in gliomagenesis and are key to reprogramming the tumor epigenome and metabolome, largely through neomorphic production and accumulation of 2-hydroxyglutarate.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('2-hydroxyglutarate', 'MPA', (198, 216))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('IDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('accumulation', 'PosReg', (182, 194))	('IDH', 'Gene', '3417', (0, 3))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (198, 216))	('glioma', 'Disease', (61, 67))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (4, 13))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
228343	26911151	Given uncertainties regarding the effectiveness of options available for treating LGGs, IDH mutations have garnered significant attention as a targetable therapeutic pathway, and there are several novel therapies on the horizon.	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', (88, 91))	('LGGs', 'Disease', (82, 86))	('mutations', 'Var', (92, 101))
228395	26911151	Although there were several models that provided comparable results, the one with the highest overall accuracy included estimates of the 10th percentile of Cr in regions with CNI >2; the volume of ADC >1.5x that of NABT divided by the T2ALL volume; the median ADC in the T2ALL region; and the 10th percentile fast spin echo in the T2ALL.	('NABT', 'Chemical', '-', (215, 219))	('ADC', 'MPA', (260, 263))	('Cr', 'Chemical', 'MESH:D003401', (156, 158))	('ADC >1.5x', 'Var', (197, 206))	('fast spin echo', 'MPA', (309, 323))
228426	32165861	The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis.	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('increased', 'PosReg', (22, 31))	('cell sensitivity to TMZ', 'MPA', (32, 55))	('cell proliferation', 'CPA', (67, 85))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (57, 66))	('Skp2', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
228436	32165861	Skp2 targets cell cycle progression through the ubiquitin-mediated degradation of G1 checkpoint CDK inhibitors, p21Cip1/Waf1 and p27Kip1.	('p27Kip1', 'Gene', (129, 136))	('Skp2', 'Gene', (0, 4))	('p21Cip1/Waf1', 'Var', (112, 124))	('p27Kip1', 'Gene', '1027', (129, 136))	('ubiquitin-mediated degradation', 'MPA', (48, 78))	('cell cycle progression', 'CPA', (13, 35))
228443	32165861	We then modulated Skp2 level by knockdown or small molecule inhibition, and then examined the functions of Skp2 in the development of glioma through in vitro and in vivo assays.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('inhibition', 'Var', (60, 70))	('modulated', 'Reg', (8, 17))	('knockdown', 'Var', (32, 41))	('glioma', 'Disease', (134, 140))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
228458	32165861	The antibodies used were as follows: mouse anti-Skp2p45 (Thermo Fisher Scientific), anti-p21Cip1/Waf1 (Proteintech, Rosemont, IL, USA), anti-beta-catenin (Abcam, Cambridge, MA, USA), beta-tubulin (Proteintech), and beta-actin (CST, Danvers, MA, USA), and rabbit anti-p27Kip1 (Affinity, Cincinnati, OH, USA).	('p27Kip1', 'Gene', '1027', (267, 274))	('beta-tubulin', 'Protein', (183, 195))	('p27Kip1', 'Gene', (267, 274))	('beta-actin', 'Gene', (215, 225))	('anti-p21Cip1/Waf1', 'Var', (84, 101))	('beta-catenin', 'Gene', (141, 153))	('beta-actin', 'Gene', '11461', (215, 225))	('mouse', 'Species', '10090', (37, 42))	('beta-catenin', 'Gene', '12387', (141, 153))	('rabbit', 'Species', '9986', (255, 261))
228461	32165861	Lovastatin (C24H36O5, 404.54 g/mol, Merck Millipore, Darmstadt, Hessen, Germany) and SZL-P1-41 (C24H24N2O3S, 420.52 g/mol, Bio-Techne, Minneapolis, MN, USA) were used for combination treatment with TMZ (Selleck,Houston, TX, USA).	('C24H36O5', 'Var', (12, 20))	('C24H36O5', 'Chemical', '-', (12, 20))	('MN', 'CellLine', 'CVCL:U508', (148, 150))	('Bio-Techne', 'Chemical', '-', (123, 133))	('TMZ', 'Chemical', 'MESH:D000077204', (198, 201))	('C24H24N2O3S', 'Chemical', '-', (96, 107))	('C24H24N2O3S', 'Var', (96, 107))	('SZL-P1-41', 'Chemical', '-', (85, 94))	('Lovastatin', 'Chemical', 'MESH:D008148', (0, 10))
228478	32165861	IDH1 mutation was a favorable factor in the prognosis of diffuse glioma especially in LGG based on the 2016 WHO classification.	('LGG', 'Disease', (86, 89))	('glioma especially', 'Disease', (65, 82))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('glioma especially', 'Disease', 'MESH:D005910', (65, 82))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
228479	32165861	We then dissected cohort of LGG into IDH1 mutant (mut) and wild type (wt), and analyzed patient OS.	('patient', 'Species', '9606', (88, 95))	('mutant', 'Var', (42, 48))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))	('OS', 'Chemical', '-', (96, 98))
228480	32165861	The patients' prognoses were better with IDH1mut and Skp2low (Fig.	('Skp2low', 'Var', (53, 60))	('patients', 'Species', '9606', (4, 12))	('IDH1', 'Gene', (41, 45))	('better', 'PosReg', (29, 35))	('IDH1', 'Gene', '3417', (41, 45))
228485	32165861	We found that the combination of 1p19q non-co-deletion and Skp2high contributed to the poor prognoses in IDHmut LGG compared with other three groups, 1p19q co-deletion/Skp2low, 1p19q co-deletion/Skp2high and 1p19q non-co-deletion/Skp2low (Fig.	('IDH', 'Gene', '3417', (105, 108))	('Skp2high', 'Var', (59, 67))	('1p19q co-deletion/Skp2low', 'Var', (150, 175))	('1p19q co-deletion/Skp2high', 'Var', (177, 203))	('1p19q non-co-deletion/Skp2low', 'Var', (208, 237))	('IDH', 'Gene', (105, 108))	('1p19q non-co-deletion', 'Var', (33, 54))
228489	32165861	To determine the role of Skp2 in the proliferation of glioma cells, the expression level of Skp2 in 7 glioma cell lines (A172, U87, U118, U373, LNZ308, U138, and U343) was found stronger than in AST cells (Fig.	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('stronger', 'PosReg', (178, 186))	('expression level', 'MPA', (72, 88))	('U373', 'Var', (138, 142))	('glioma cell', 'Disease', 'MESH:D005910', (54, 65))	('glioma cell', 'Disease', (54, 65))	('LNZ308', 'CellLine', 'CVCL:0394', (144, 150))	('Skp2', 'Gene', (92, 96))	('glioma cell', 'Disease', 'MESH:D005910', (102, 113))	('glioma cell', 'Disease', (102, 113))	('LNZ308', 'Var', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('U138', 'Var', (152, 156))	('U118', 'Var', (132, 136))
228490	32165861	Three cell lines with low, moderate, and strong level of Skp2 were chosen for Skp2 knockdown, namely U87, U138, and LNZ308.	('LNZ308', 'CellLine', 'CVCL:0394', (116, 122))	('knockdown', 'Var', (83, 92))	('Skp2', 'Gene', (78, 82))
228491	32165861	The knockdown was successful in all three cell lines which were confirmed by the enhancement of p21Cip1/Waf1 and p27Kip1 (Fig.	('enhancement', 'PosReg', (81, 92))	('p27Kip1', 'Gene', '1027', (113, 120))	('p27Kip1', 'Gene', (113, 120))	('p21Cip1/Waf1', 'Var', (96, 108))
228492	32165861	In the xenograft mice model, both of the tumor size and weight were reduced upon Skp2 knockdown (***p < 0.001, Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('knockdown', 'Var', (86, 95))	('mice', 'Species', '10090', (17, 21))	('tumor', 'Disease', (41, 46))	('weight', 'CPA', (56, 62))	('reduced', 'NegReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Skp2', 'Gene', (81, 85))
228495	32165861	Upon Skp2 knockdown, the inhibition rate increased and the IC50 of TMZ decreased in all three cell lines (***p < 0.001, Fig.	('increased', 'PosReg', (41, 50))	('TMZ', 'Chemical', 'MESH:D000077204', (67, 70))	('IC50 of', 'MPA', (59, 66))	('Skp2', 'Gene', (5, 9))	('knockdown', 'Var', (10, 19))	('decreased', 'NegReg', (71, 80))	('inhibition rate', 'MPA', (25, 40))
228497	32165861	At the beginning, tumors were all suppressed by TMZ, but the tumors in shLuc group demonstrated faster growth than sh530 and sh532 groups after 15 days of treatment (Fig.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('faster', 'PosReg', (96, 102))	('TMZ', 'Chemical', 'MESH:D000077204', (48, 51))	('growth', 'CPA', (103, 109))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('shLuc', 'Var', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
228498	32165861	Similarly, the tumor weight was lower in the knockdown groups, compared with the control group (Fig.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('knockdown groups', 'Var', (45, 61))	('lower', 'NegReg', (32, 37))
228499	32165861	In this way, we demonstrated that the Skp2 knockdown sensitized glioma cells to TMZ both in vitro and in vivo.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('Skp2', 'Gene', (38, 42))	('knockdown', 'Var', (43, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('glioma cell', 'Disease', 'MESH:D005910', (64, 75))	('sensitized', 'Reg', (53, 63))	('glioma cell', 'Disease', (64, 75))
228501	32165861	We previously reported that Skp2 is involved in self-renewal ability of hematopoietic stem cells and cancer stem cells in nasopharyngeal carcinoma, therefore we speculated that Skp2 modulated glioma stem-like cells and thereafter regulated cell proliferation and drug sensitivity.	('nasopharyngeal carcinoma', 'Disease', (122, 146))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('cell proliferation', 'CPA', (240, 258))	('cancer', 'Disease', (101, 107))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (122, 146))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (122, 146))	('drug sensitivity', 'Phenotype', 'HP:0020174', (263, 279))	('regulated', 'Reg', (230, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('modulated', 'Reg', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Skp2', 'Var', (177, 181))	('glioma', 'Disease', (192, 198))	('drug sensitivity', 'CPA', (263, 279))
228504	32165861	Taken together, we showed that Skp2 was involved in the stemness maintenance of cell and that the knockdown of Skp2 attenuated cell proliferation by decreasing stemness and increasing cell senescence.	('increasing', 'PosReg', (173, 183))	('stemness', 'Disease', 'MESH:D020295', (56, 64))	('stemness', 'Disease', 'MESH:D020295', (160, 168))	('cell proliferation', 'CPA', (127, 145))	('knockdown', 'Var', (98, 107))	('cell senescence', 'CPA', (184, 199))	('Skp2', 'Gene', (111, 115))	('attenuated', 'NegReg', (116, 126))	('stemness', 'Disease', (56, 64))	('decreasing', 'NegReg', (149, 159))	('stemness', 'Disease', (160, 168))
228510	32165861	SZL-P1-41 prevents the assembly of Skp2-Skp1 complexes and inhibits Skp2 mediated ubiquitination of p27Kip1 and Akt, which therefore exhibits antitumor effects (Fig.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibits', 'NegReg', (59, 67))	('Akt', 'Gene', '207', (112, 115))	('tumor', 'Disease', (146, 151))	('p27Kip1', 'Gene', '1027', (100, 107))	('Skp1', 'Gene', '6500', (40, 44))	('p27Kip1', 'Gene', (100, 107))	('prevents', 'NegReg', (10, 18))	('Akt', 'Gene', (112, 115))	('SZL-P1-41', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('Skp1', 'Gene', (40, 44))	('assembly', 'MPA', (23, 31))	('SZL-P1-41', 'Var', (0, 9))
228515	32165861	At the same time, the level of Skp2 was reduced in all three cells upon lovastatin treatment and in U138 cells by SZL-P1-41 (right panels of Fig.	('SZL-P1-41', 'Var', (114, 123))	('reduced', 'NegReg', (40, 47))	('SZL-P1-41', 'Chemical', '-', (114, 123))	('lovastatin', 'Chemical', 'MESH:D008148', (72, 82))
228519	32165861	The suppression of Skp2 led to the accumulation of its substrates like p21Cip1/Waf1 and p27Kip1, and was therefore found to be involved in the regulation of quiescence and self-renewal of hematopoietic stem cells.	('suppression', 'NegReg', (4, 15))	('p27Kip1', 'Gene', (88, 95))	('involved', 'Reg', (127, 135))	('accumulation', 'PosReg', (35, 47))	('p21Cip1/Waf1', 'Var', (71, 83))	('self-renewal', 'CPA', (172, 184))	('Skp2', 'Gene', (19, 23))	('p27Kip1', 'Gene', '1027', (88, 95))
228522	32165861	In this study, Skp2 expression was found to be upregulated in glioma, and high-level of Skp2 predicted poor prognosis for patients with LGG.	('LGG', 'Disease', (136, 139))	('high-level', 'Var', (74, 84))	('expression', 'MPA', (20, 30))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('upregulated', 'PosReg', (47, 58))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('patients', 'Species', '9606', (122, 130))	('Skp2', 'Gene', (15, 19))	('Skp2', 'Gene', (88, 92))	('glioma', 'Disease', (62, 68))
228526	32165861	Selenonucleoside LJ-2618 was shown to be able to trigger G2/M cell cycle arrest in prostate cancer cells by promoting Skp2 degradation.	('Selenonucleoside LJ-2618', 'Chemical', '-', (0, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('promoting', 'PosReg', (108, 117))	('Skp2 degradation', 'MPA', (118, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('LJ-2618', 'Var', (17, 24))	('G2/M cell cycle arrest', 'CPA', (57, 79))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
228532	32165861	Our study provided the evidence that SPZ-P1-41 could successfully attenuate cell proliferation and sensitize cells to TMZ in both glioma cell and xenograft mice models.	('SPZ-P1-41', 'Var', (37, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (118, 121))	('glioma cell', 'Disease', 'MESH:D005910', (130, 141))	('attenuate', 'NegReg', (66, 75))	('glioma cell', 'Disease', (130, 141))	('cell proliferation', 'CPA', (76, 94))	('sensitize', 'Reg', (99, 108))	('SPZ-P1', 'Chemical', '-', (37, 43))	('mice', 'Species', '10090', (156, 160))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
228540	32165861	Our results therefore reveal the important role of Skp2 in glioma tumorigenesis, targeting Skp2 could potentially improve the therapeutic efficiency of glioma patients.	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Skp2', 'Var', (91, 95))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', (152, 158))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('glioma tumorigenesis', 'Disease', (59, 79))	('improve', 'PosReg', (114, 121))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('patients', 'Species', '9606', (159, 167))
228597	30765763	The diagnostic threshold of cross-scattering coefficient was 0.26 mm-1 for patients of all grades (sensitivity/specificity: 90.1%/87.5%, respectively) and 0.09 mm-1 for low-grade patients (sensitivity/specificity: 100%/100%, respectively).	('cross-scattering', 'MPA', (28, 44))	('patients', 'Species', '9606', (75, 83))	('0.09 mm-1', 'Var', (155, 164))	('patients', 'Species', '9606', (179, 187))
228622	30765763	Immunohistochemistry for the common IDH (isocitrate dehydrogenase) mutation in IDH mutated tumors and MIB-1 (monoclonal antibody to Ki67) staining in IDH wild-type tumors would be more sensitive to low levels of tumor infiltration.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', (164, 169))	('IDH', 'Gene', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (91, 96))	('IDH', 'Gene', (79, 82))	('mutation', 'Var', (67, 75))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('isocitrate dehydrogenase', 'Gene', '3417', (41, 65))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('IDH', 'Gene', '3417', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MIB-1', 'Gene', (102, 107))	('tumors', 'Disease', (164, 170))	('IDH', 'Gene', '3417', (79, 82))	('MIB-1', 'Gene', '57534', (102, 107))	('IDH', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (212, 217))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('isocitrate dehydrogenase', 'Gene', (41, 65))	('IDH', 'Gene', '3417', (36, 39))
228669	32218467	With regards to the mutational landscape, one recurrent DNA alteration found in 80% of patients is a missense mutation for the IDH1 gene (isocitrate dehydrogenase) involved in metabolism and epigenetic regulations.	('citrate', 'Chemical', 'MESH:D019343', (141, 148))	('missense mutation', 'Var', (101, 118))	('IDH1', 'Gene', (127, 131))	('IDH1', 'Gene', '3417', (127, 131))	('patients', 'Species', '9606', (87, 95))
228670	32218467	Astrocytomas have an additional mutation for the ATRX gene whereas oligodendrogliomas show a 1p19q co-deletion.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('ATRX', 'Gene', (49, 53))	('oligodendrogliomas', 'Disease', (67, 85))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('ATRX', 'Gene', '546', (49, 53))	('mutation', 'Var', (32, 40))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (67, 85))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('Astrocytomas', 'Disease', (0, 12))
228695	32218467	IDH1 mutation was established by immunohistochemistry against the IDH1 R132H epitope with at least 80% of positive cells in both DLGG and foci for each tumour.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('IDH1', 'Gene', '3417', (66, 70))	('tumour', 'Disease', (152, 158))	('R132H', 'Var', (71, 76))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('IDH1', 'Gene', (0, 4))	('R132H', 'Mutation', 'rs121913500', (71, 76))	('IDH1', 'Gene', (66, 70))	('IDH1', 'Gene', '3417', (0, 4))
228696	32218467	IDH1 mutation was then confirmed by sequencing of the IDH1 gene exon 4.	('IDH1', 'Gene', (54, 58))	('IDH1', 'Gene', '3417', (54, 58))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
228730	32218467	1A), we selected 8 tumours with mutations for IDH1 (IDH1 R132H) with and without 1p19q co-deletion (4 oligodendrogliomas and 4 astrocytomas respectively) (Table S1).	('oligodendrogliomas', 'Disease', 'MESH:D009837', (102, 120))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('IDH1', 'Gene', '3417', (52, 56))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('astrocytomas', 'Disease', 'MESH:D001254', (127, 139))	('astrocytoma', 'Phenotype', 'HP:0009592', (127, 138))	('IDH1', 'Gene', (46, 50))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('IDH1', 'Gene', '3417', (46, 50))	('oligodendrogliomas', 'Disease', (102, 120))	('astrocytomas', 'Disease', (127, 139))	('mutations', 'Var', (32, 41))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('R132H', 'Mutation', 'rs121913500', (57, 62))	('IDH1', 'Gene', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
228735	32218467	To ascertain that these cells were tumoral and not cells of the tumour environment, we performed double labelling for pSTAT3 and proteins which are frequently altered in DLGG, namely the mutated form of IDH1 (R132H) and loss of ATRX.	('R132H', 'Mutation', 'rs121913500', (209, 214))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('pSTAT3', 'Gene', (118, 124))	('altered', 'Reg', (159, 166))	('ATRX', 'Gene', '546', (228, 232))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('DLGG', 'Disease', (170, 174))	('tumour', 'Disease', (64, 70))	('IDH1', 'Gene', (203, 207))	('ATRX', 'Gene', (228, 232))	('R132H', 'Var', (209, 214))	('IDH1', 'Gene', '3417', (203, 207))
228737	32218467	1C), we found that >90% of pSTAT3+ cells in the foci or in the rest of the tumour also expressed the mutated form of IDH1 R132H.	('R132H', 'Mutation', 'rs121913500', (122, 127))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('IDH1', 'Gene', '3417', (117, 121))	('mutated', 'Var', (101, 108))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('IDH1', 'Gene', (117, 121))
228738	32218467	Expression of IDH1 R132H assessed by IF in the astrocytomas was too weak to perform reliable double pSTAT3/IDH1 R132H stainings so, as an alternative, pSTAT3/ATRX stainings were done.	('astrocytomas', 'Disease', 'MESH:D001254', (47, 59))	('IDH1', 'Gene', (107, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('ATRX', 'Gene', (158, 162))	('IDH1', 'Gene', '3417', (107, 111))	('astrocytomas', 'Disease', (47, 59))	('R132H', 'Var', (19, 24))	('ATRX', 'Gene', '546', (158, 162))	('R132H', 'Mutation', 'rs121913500', (19, 24))	('R132H', 'Mutation', 'rs121913500', (112, 117))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', '3417', (14, 18))
228778	32218467	This was addressed by performing double IF for ETNPPL and IDH1 R132H (1 oligodendroglioma) and ATRX (2 astrocytomas).	('R132H', 'Var', (63, 68))	('IDH1', 'Gene', '3417', (58, 62))	('R132H', 'SUBSTITUTION', 'None', (63, 68))	('astrocytomas', 'Disease', 'MESH:D001254', (103, 115))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('ETNPPL', 'Gene', '64850', (47, 53))	('astrocytomas', 'Disease', (103, 115))	('IDH1', 'Gene', (58, 62))	('ETNPPL', 'Gene', (47, 53))
228781	32218467	5A,C, S6A,B), we found that >95% of ETNPPL+ cells also expressed the mutated form of IDH1 R132H.	('R132H', 'Var', (90, 95))	('R132H', 'Mutation', 'rs121913500', (90, 95))	('IDH1', 'Gene', (85, 89))	('ETNPPL', 'Gene', '64850', (36, 42))	('ETNPPL', 'Gene', (36, 42))	('IDH1', 'Gene', '3417', (85, 89))
228803	32218467	In order to use cells bearing mutations typically found in DLGG, we derived a third culture named LGG85 from a patient affected by a secondary GBM and containing a mutated IDH1 gene.	('IDH1', 'Gene', '3417', (172, 176))	('LGG85', 'Gene', (98, 103))	('patient', 'Species', '9606', (111, 118))	('mutated', 'Var', (164, 171))	('IDH1', 'Gene', (172, 176))
228805	32218467	WB analysis and DNA sequencing show the expression of the IDH1 R132H protein in the cells and the IDH1 395 G > A mutation (Fig.	('R132H', 'Var', (63, 68))	('IDH1', 'Gene', '3417', (58, 62))	('R132H', 'Mutation', 'rs121913500', (63, 68))	('protein', 'Protein', (69, 76))	('395 G > A', 'Mutation', 'rs121913500', (103, 112))	('IDH1', 'Gene', (98, 102))	('IDH1', 'Gene', '3417', (98, 102))	('IDH1', 'Gene', (58, 62))
228818	32218467	As such, phosphorylation of STAT proteins, notably STAT3, is involved in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumour immune surveillance.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('phosphorylation', 'Var', (9, 24))	('involved', 'Reg', (61, 69))	('impairing tumour', 'Disease', 'MESH:D001523', (189, 205))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('promoting', 'PosReg', (125, 134))	('cell cycle progression', 'CPA', (135, 157))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('angiogenesis', 'CPA', (171, 183))	('stimulating', 'PosReg', (159, 170))	('cancers', 'Disease', (98, 105))	('STAT', 'Gene', '6774;20848', (51, 55))	('STAT', 'Gene', (51, 55))	('STAT', 'Gene', '6774;20848', (28, 32))	('impairing tumour', 'Disease', (189, 205))	('STAT', 'Gene', (28, 32))
228852	32218467	These glioblastoma-derived cultures have different types of mutations.	('glioblastoma', 'Phenotype', 'HP:0012174', (6, 18))	('mutations', 'Var', (60, 69))	('glioblastoma', 'Disease', (6, 18))	('glioblastoma', 'Disease', 'MESH:D005909', (6, 18))
228871	33810347	Transcriptional and epigenetic dysregulation is significantly associated with cancer stemness.	('cancer stemness', 'Disease', 'MESH:D009369', (78, 93))	('associated', 'Reg', (62, 72))	('epigenetic dysregulation', 'Var', (20, 44))	('cancer stemness', 'Disease', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
228874	33810347	Our results indicate that only TIF1beta (also known as Tripartite Motif protein 28, TRIM28) high expression is consequently associated with a "stemness high" phenotype, regardless of the tumor type, resulting in a worse prognosis for cancer patients.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('TIF1beta', 'Gene', (31, 39))	('high expression', 'Var', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TIF1beta', 'Gene', '8805', (31, 39))	('TRIM28', 'Gene', (84, 90))	('tumor', 'Disease', (187, 192))	('associated with', 'Reg', (124, 139))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('TRIM28', 'Gene', '10155', (84, 90))	('patients', 'Species', '9606', (241, 249))
228877	33810347	Our results demonstrate that the association between high TRIM28 expression and an enriched cancer stem cell-like phenotype is a common phenomenon across solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('TRIM28', 'Gene', (58, 64))	('high', 'Var', (53, 57))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('solid tumors', 'Disease', (154, 166))	('TRIM28', 'Gene', '10155', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('expression', 'MPA', (65, 75))	('solid tumors', 'Disease', 'MESH:D009369', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
228879	33810347	Cancer de-differentiation and the acquisition of stemness features are mediated by the transcriptional and epigenetic dysregulation of cancer cells.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic dysregulation', 'Var', (107, 131))	('stemness features', 'CPA', (49, 66))
228895	33810347	Reactivation of the ESC-like program in cancer strongly predicts metastatic potential and patient death.	('death', 'Disease', 'MESH:D003643', (98, 103))	('metastatic potential', 'CPA', (65, 85))	('predicts', 'Reg', (56, 64))	('death', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('Reactivation', 'Var', (0, 12))	('patient', 'Species', '9606', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ESC-like program', 'Gene', (20, 36))
228896	33810347	Cell de-differentiation and the acquisition of stemness features is mediated by the transcriptional and epigenetic dysregulation of cancer cells.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('epigenetic dysregulation', 'Var', (104, 128))	('stemness features', 'CPA', (47, 64))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Cell de-differentiation', 'CPA', (0, 23))
228903	33810347	TIF1 members are aberrantly expressed or mutated in multiple cancer types; however, their role in cancer stem cells is still not fully understood.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutated', 'Var', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('TIF1', 'Gene', '8805', (0, 4))	('TIF1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
228919	33810347	Among other TIF1 family members, only high TRIM28 expression might serve as a marker for stemness-associated traits of solid tumors.	('TIF1', 'Gene', '8805', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TIF1', 'Gene', (12, 16))	('high', 'Var', (38, 42))	('solid tumors', 'Disease', 'MESH:D009369', (119, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('TRIM28', 'Gene', (43, 49))	('TRIM28', 'Gene', '10155', (43, 49))	('solid tumors', 'Disease', (119, 131))
228925	33810347	The representative results of immunohistochemistry staining of Prostate Adenocarcinoma (PRAD) samples with anti-TRIM24 (antibody name: HPA043495), anti-TRIM28 (HPA064033), anti-TRIM33 (HPA004345), and anti-TRIM66 (HPA027420) antibodies were downloaded from the Human Protein Atlas database (, accessed on 10 October 2020).	('anti-TRIM24', 'Var', (107, 118))	('TRIM66', 'Gene', (206, 212))	('HPA004345', 'Var', (185, 194))	('TRIM28', 'Gene', (152, 158))	('TRIM33', 'Gene', '51592', (177, 183))	('Prostate Adenocarcinoma', 'Disease', (63, 86))	('TRIM33', 'Gene', (177, 183))	('Human', 'Species', '9606', (261, 266))	('TRIM66', 'Gene', '9866', (206, 212))	('TRIM28', 'Gene', '10155', (152, 158))	('Prostate Adenocarcinoma', 'Disease', 'MESH:D011471', (63, 86))
228931	33810347	All datasets were analyzed online using the R2 Platform (, accessed on 10 October 2020) to find genes that correlate with TRIM24, TRIM28, TRIM33, or TRIM66 expression.	('TRIM24', 'Var', (122, 128))	('TRIM33', 'Gene', '51592', (138, 144))	('TRIM28', 'Gene', (130, 136))	('TRIM33', 'Gene', (138, 144))	('TRIM66', 'Gene', (149, 155))	('TRIM66', 'Gene', '9866', (149, 155))	('TRIM28', 'Gene', '10155', (130, 136))
228938	33810347	Higher TRIM28 expression is significantly associated with worse survival for Kidney Renal Clear Cell Carcinoma (KIRC), Kidney Renal Papillary Cell Carcinoma (KIRP), LIHC, Lung Adenocarcinoma (LUAD), MESO, Adrenocortical Carcinoma (ACC), Skin Cutaneous Melanoma (SKCM), and Bladder Urothelial Carcinoma (BLCA), and with better survival for THYM, Uveal Melanoma (UVM), and Testicular Germ Cell Tumor (TGCT) patients (Figure 1B).	('UVM', 'Phenotype', 'HP:0007716', (361, 364))	('Bladder Urothelial Carcinoma', 'Disease', 'MESH:D001749', (273, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('THYM', 'Phenotype', 'HP:0100522', (339, 343))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (171, 190))	('Melanoma', 'Disease', (351, 359))	('Carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Kidney Renal Papillary Cell Carcinoma', 'Disease', 'MESH:C538614', (119, 156))	('MESO', 'Disease', (199, 203))	('TRIM28', 'Gene', (7, 13))	('expression', 'Var', (14, 24))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (77, 110))	('ACC', 'Phenotype', 'HP:0006744', (231, 234))	('Melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('Germ Cell Tumor', 'Phenotype', 'HP:0100728', (382, 397))	('Skin Cutaneous Melanoma', 'Disease', (237, 260))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (205, 229))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (77, 110))	('Lung Adenocarcinoma', 'Disease', (171, 190))	('Melanoma', 'Disease', 'MESH:D008545', (252, 260))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (242, 260))	('Tumor', 'Phenotype', 'HP:0002664', (392, 397))	('Bladder Urothelial Carcinoma', 'Disease', (273, 301))	('TRIM28', 'Gene', '10155', (7, 13))	('Carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (345, 359))	('Renal Papillary Cell Carcinoma', 'Phenotype', 'HP:0006766', (126, 156))	('LIHC', 'Disease', (165, 169))	('Melanoma', 'Disease', (252, 260))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (205, 229))	('Kidney Renal Papillary Cell Carcinoma', 'Disease', (119, 156))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (171, 190))	('patients', 'Species', '9606', (405, 413))	('Melanoma', 'Disease', 'MESH:D008545', (351, 359))	('Melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (237, 260))	('Adrenocortical Carcinoma', 'Disease', (205, 229))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
228942	33810347	Using the cBioportal data, we observed that across all tested tumor types (10,506 profiled samples in 27 solid TCGA tumor types), the frequencies of alterations (missense mutations, amplifications, deletions) in TIF1 member-encoding genes were relatively low (Figure S1A), with 2.6%, 2.2%, 1.8%, and 0.9% genetic alterations in profiled samples for TRIM24, TRIM28, TRIM33, and TRIM66, respectively.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TRIM28', 'Gene', '10155', (357, 363))	('TRIM66', 'Gene', (377, 383))	('TRIM24', 'Var', (349, 355))	('tumor', 'Disease', (62, 67))	('genetic alterations', 'Var', (305, 324))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TIF1', 'Gene', '8805', (212, 216))	('TRIM33', 'Gene', '51592', (365, 371))	('TRIM33', 'Gene', (365, 371))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TRIM66', 'Gene', '9866', (377, 383))	('TIF1', 'Gene', (212, 216))	('tumor', 'Disease', (116, 121))	('TRIM28', 'Gene', (357, 363))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
228943	33810347	In most cancer types, the frequency of alterations did not exceed 5% for each of the tested genes (Figure S1B-E), except for TRIM24 in Ovarian Serous Cystadenocarcinoma (OV) (10.98%) and SKCM (8.05%), and TRIM28 and TRIM33 in Esophageal Carcinoma (ESCA) (5.41% and 5.41% of altered samples, respectively), suggesting that genetic alterations in TIF1 members are not of great importance in cancer development.	('TIF1', 'Gene', (345, 349))	('Carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('Ovarian Serous Cystadenocarcinoma', 'Phenotype', 'HP:0012887', (135, 168))	('cancer', 'Disease', (389, 395))	('TIF1', 'Gene', '8805', (345, 349))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('Ovarian Serous Cystadenocarcinoma', 'Disease', (135, 168))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TRIM28', 'Gene', (205, 211))	('TRIM24', 'Var', (125, 131))	('Carcinoma', 'Disease', (237, 246))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (226, 246))	('Carcinoma', 'Disease', 'MESH:D009369', (237, 246))	('ESCA', 'Phenotype', 'HP:0011459', (248, 252))	('TRIM33', 'Gene', (216, 222))	('Ovarian Serous Cystadenocarcinoma', 'Disease', 'MESH:D018284', (135, 168))	('TRIM28', 'Gene', '10155', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('TRIM33', 'Gene', '51592', (216, 222))	('OV', 'Phenotype', 'HP:0012887', (170, 172))
228960	33810347	The number of genes that are significantly correlated with the expression of TRIM24, TRIM28, TRIM33, or TRIM66 are presented in Figure S2.	('TRIM28', 'Gene', '10155', (85, 91))	('TRIM24', 'Var', (77, 83))	('TRIM66', 'Gene', (104, 110))	('TRIM33', 'Gene', '51592', (93, 99))	('TRIM33', 'Gene', (93, 99))	('TRIM28', 'Gene', (85, 91))	('TRIM66', 'Gene', '9866', (104, 110))
228999	33810347	We have previously shown that high TRIM28 expression is strictly related to the stem cell-like phenotype of breast cancer and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('TRIM28', 'Gene', (35, 41))	('melanomas', 'Disease', (126, 135))	('expression', 'MPA', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high', 'Var', (30, 34))	('TRIM28', 'Gene', '10155', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('related', 'Reg', (65, 72))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
229002	33810347	Here, we reported for the first time that the association between high TRIM28 expression and an enriched stem cell-like phenotype is a common phenomenon across solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TRIM28', 'Gene', (71, 77))	('association', 'Interaction', (46, 57))	('high', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('TRIM28', 'Gene', '10155', (71, 77))	('solid tumors', 'Disease', (160, 172))
229025	33810347	As presented by Massague et al., the loss of TRIM33 expression does not affect stem cell self-renewal, but it impairs the differentiation process.	('differentiation process', 'CPA', (122, 145))	('TRIM33', 'Gene', '51592', (45, 51))	('TRIM33', 'Gene', (45, 51))	('impairs', 'NegReg', (110, 117))	('loss', 'Var', (37, 41))
229036	33810347	TRIM24 and TRIM28 are generally positively associated, while TRIM33 and TRIM66 are mostly negatively associated with cancer stemness in solid tumors.	('cancer stemness', 'Disease', (117, 132))	('associated', 'Interaction', (43, 53))	('TRIM28', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('solid tumors', 'Disease', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('negatively', 'NegReg', (90, 100))	('TRIM66', 'Gene', '9866', (72, 78))	('TRIM28', 'Gene', '10155', (11, 17))	('cancer stemness', 'Disease', 'MESH:D009369', (117, 132))	('TRIM24', 'Var', (0, 6))	('TRIM66', 'Gene', (72, 78))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('associated', 'Reg', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('TRIM33', 'Gene', '51592', (61, 67))	('TRIM33', 'Gene', (61, 67))
229103	33469081	Consistently, it was reported that TAF15 levels decrease during differentiation, TAF15 knockdown negatively affecting cell proliferation.	('TAF15', 'Gene', (81, 86))	('TAF15', 'Gene', '8148', (35, 40))	('negatively', 'NegReg', (97, 107))	('cell proliferation', 'CPA', (118, 136))	('TAF15', 'Gene', (35, 40))	('TAF15', 'Gene', '8148', (81, 86))	('knockdown', 'Var', (87, 96))
229190	32823572	The 2016 update of the WHO Classification of Tumours of the Central Nervous System highlighted molecular parameters as paramount features for the diagnosis, namely IDH1/2 mutations that distinguish primary and secondary GBM.	('IDH1/2', 'Gene', '3417;3418', (164, 170))	('Tumours of the Central Nervous System', 'Phenotype', 'HP:0100006', (45, 82))	('primary', 'Disease', (198, 205))	('GBM', 'Phenotype', 'HP:0012174', (220, 223))	('IDH1/2', 'Gene', (164, 170))	('mutations', 'Var', (171, 180))	('Tumours', 'Phenotype', 'HP:0002664', (45, 52))
229200	32823572	The revised 2016 World Health Organization (WHO) classification of tumors of the central nervous system recognizes the molecular evaluation as critical for the classification, since the mutation status of the IDH1 and IDH2 and the codeletion of 1p/19q are crucial for diagnosis, and the TERT promoter gene mutations and ATRX alterations are associated with prognosis.	('ATRX', 'Gene', '546', (320, 324))	('TERT', 'Gene', (287, 291))	('TERT', 'Gene', '7015', (287, 291))	('mutations', 'Var', (306, 315))	('IDH2', 'Gene', (218, 222))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (67, 103))	('associated', 'Reg', (341, 351))	('IDH1', 'Gene', (209, 213))	('ATRX', 'Gene', (320, 324))	('IDH2', 'Gene', '3418', (218, 222))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('mutation', 'Var', (186, 194))	('IDH1', 'Gene', '3417', (209, 213))
229201	32823572	However, other molecular alterations may be associated with diagnosis, prognosis, and glioma risk.	('alterations', 'Var', (25, 36))	('glioma', 'Disease', (86, 92))	('associated', 'Reg', (44, 54))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))
229205	32823572	Glioblastoma IDH-wildtype lacks IDH1/2 mutations and is considered primary glioblastoma.	('lacks', 'NegReg', (26, 31))	('glioblastoma', 'Disease', (75, 87))	('Glioblastoma IDH', 'Disease', (0, 16))	('IDH1/2', 'Gene', (32, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('Glioblastoma IDH', 'Disease', 'MESH:D005909', (0, 16))	('mutations', 'Var', (39, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))
229206	32823572	The typical genetic alterations of these tumors include TERT promoter mutations, homozygous deletion of CDKN2A/CDKN2B, loss of chromosomes 10p and 10q, EGFR alterations, PTEN, TP53 and PI3K mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TP53', 'Gene', '7157', (176, 180))	('tumors', 'Disease', (41, 47))	('PI3K', 'Gene', (185, 189))	('CDKN2B', 'Gene', '1030', (111, 117))	('PTEN', 'Gene', (170, 174))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('EGFR', 'Gene', (152, 156))	('CDKN2A', 'Gene', (104, 110))	('PTEN', 'Gene', '5728', (170, 174))	('TP53', 'Gene', (176, 180))	('CDKN2A', 'Gene', '1029', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('EGFR', 'Gene', '1956', (152, 156))	('TERT', 'Gene', (56, 60))	('CDKN2B', 'Gene', (111, 117))	('loss', 'Var', (119, 123))	('alterations', 'Var', (157, 168))	('TERT', 'Gene', '7015', (56, 60))
229207	32823572	Glioblastomas IDH-mutant show mutations in either the IDH1 or IDH2 gene and are characterized by frequent mutations in the TP53 and ATRX genes, loss of 10q, and lack EGFR amplification.	('loss', 'Var', (144, 148))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('IDH1', 'Gene', (54, 58))	('Glioblastomas IDH', 'Disease', 'MESH:D005909', (0, 17))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('ATRX', 'Gene', (132, 136))	('mutations', 'Var', (30, 39))	('IDH2', 'Gene', (62, 66))	('mutations', 'Var', (106, 115))	('IDH1', 'Gene', '3417', (54, 58))	('Glioblastomas IDH', 'Disease', (0, 17))	('IDH2', 'Gene', '3418', (62, 66))	('TP53', 'Gene', '7157', (123, 127))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('ATRX', 'Gene', '546', (132, 136))	('TP53', 'Gene', (123, 127))
229249	32823572	Aberrant EGFR signaling may ultimately affect major hallmarks of cancer, including tumor growth, invasion, malignancy, and prognosis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Aberrant', 'Var', (0, 8))	('malignancy', 'Disease', 'MESH:D009369', (107, 117))	('tumor', 'Disease', (83, 88))	('malignancy', 'Disease', (107, 117))	('affect', 'Reg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EGFR', 'Gene', '1956', (9, 13))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (52, 71))	('EGFR', 'Gene', (9, 13))	('hallmarks of cancer', 'Disease', (52, 71))	('invasion', 'CPA', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
229285	32823572	High cytoplasmic OPN expression in glioblastomas was associated with poor patients' survival.	('glioblastomas', 'Disease', 'MESH:D005909', (35, 48))	('glioblastomas', 'Disease', (35, 48))	('High', 'Var', (0, 4))	('OPN', 'Gene', (17, 20))	('patients', 'Species', '9606', (74, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))	('OPN', 'Gene', '6696', (17, 20))
229326	32823572	from the same group, and some years later, did not find any correlation with serum MMP-9 levels and tumor size, survival or chemotherapy response, concluding that serum MMP-9 showed no utility in determining glioma disease status in a cohort of 111 GBM patients, and was not a clinically relevant prognostic marker of survival.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('GBM', 'Phenotype', 'HP:0012174', (249, 252))	('MMP-9', 'Gene', '4318', (83, 88))	('tumor', 'Disease', (100, 105))	('MMP-9', 'Gene', (83, 88))	('serum', 'Var', (163, 168))	('patients', 'Species', '9606', (253, 261))	('MMP-9', 'Gene', '4318', (169, 174))	('MMP-9', 'Gene', (169, 174))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('glioma disease', 'Disease', 'MESH:D005910', (208, 222))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('glioma disease', 'Disease', (208, 222))
229422	32823572	Additionally, the characterization of a panel of genetic alterations in glioblastoma specimens that match peripheral blood markers, may increase the sensitivity of the screening biomarkers.	('genetic alterations', 'Var', (49, 68))	('sensitivity', 'MPA', (149, 160))	('glioblastoma', 'Disease', (72, 84))	('increase', 'PosReg', (136, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
229428	32328202	The hypo-methylations of EMP3 and SERPINE1 were contributing to the high expressions of EMP3 and SERPINE1 in old LGG patients.	('EMP3', 'Gene', (25, 29))	('SERPINE1', 'Gene', '5054', (97, 105))	('SERPINE1', 'Gene', (97, 105))	('EMP3', 'Gene', '2014', (25, 29))	('high', 'PosReg', (68, 72))	('expressions', 'MPA', (73, 84))	('hypo-methylations', 'Var', (4, 21))	('EMP3', 'Gene', (88, 92))	('patients', 'Species', '9606', (117, 125))	('LGG', 'Disease', (113, 116))	('SERPINE1', 'Gene', '5054', (34, 42))	('SERPINE1', 'Gene', (34, 42))	('EMP3', 'Gene', '2014', (88, 92))
229430	32328202	Moreover, high expressions of IGFBP2, EMP3, TIMP1 and SERPINE1 were associated with the worse prognosis of LGG patients.	('EMP3', 'Gene', (38, 42))	('associated', 'Reg', (68, 78))	('TIMP1', 'Gene', (44, 49))	('LGG', 'Disease', (107, 110))	('EMP3', 'Gene', '2014', (38, 42))	('IGFBP2', 'Gene', '3485', (30, 36))	('SERPINE1', 'Gene', '5054', (54, 62))	('SERPINE1', 'Gene', (54, 62))	('IGFBP2', 'Gene', (30, 36))	('TIMP1', 'Gene', '7076', (44, 49))	('high expressions', 'Var', (10, 26))	('patients', 'Species', '9606', (111, 119))
229431	32328202	Furthermore, we demonstrated that EMP3 and SERPINE1 were connected with each other and the combination of EMP3 and SERPINE1 had better prognostic effects in glioma patients.	('EMP3', 'Gene', '2014', (106, 110))	('EMP3', 'Gene', (34, 38))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('EMP3', 'Gene', '2014', (34, 38))	('SERPINE1', 'Gene', '5054', (115, 123))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('SERPINE1', 'Gene', (43, 51))	('SERPINE1', 'Gene', (115, 123))	('patients', 'Species', '9606', (164, 172))	('better', 'PosReg', (128, 134))	('glioma', 'Disease', (157, 163))	('SERPINE1', 'Gene', '5054', (43, 51))	('combination', 'Var', (91, 102))	('EMP3', 'Gene', (106, 110))
229454	32328202	At last, we demonstrate the prognostic effects of combination of EMP3 and SERPINE1 genes in glioma patients.	('EMP3', 'Gene', (65, 69))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('EMP3', 'Gene', '2014', (65, 69))	('SERPINE1', 'Gene', '5054', (74, 82))	('SERPINE1', 'Gene', (74, 82))	('combination', 'Var', (50, 61))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
229458	32328202	The gene expression series matrix of normal and cancerous brain tissues was downloaded from the Gene Expression Omnibus (GEO) website (www.ncbi.nlm.nih.gov/geo), and included the GEO datasets GSE4920, GSE16011 and GSE50161.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('GSE50161', 'Var', (214, 222))	('GSE16011', 'Var', (201, 209))	('cancerous brain', 'Phenotype', 'HP:0030692', (48, 63))	('GSE4920', 'Var', (192, 199))	('cancerous', 'Disease', (48, 57))
229513	32328202	Similarly, age related gene SERPINE1 was hypo-methylated in old LGG patients, compared with young LGG patients (P=5.35e-05) (Figure 4B).	('SERPINE1', 'Gene', '5054', (28, 36))	('SERPINE1', 'Gene', (28, 36))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (68, 76))	('hypo-methylated', 'Var', (41, 56))	('LGG', 'Disease', (64, 67))
229523	32328202	For example, high IGFBP2, EMP3, TIMP1 and SERPINE1 expressions were all positively associated with the overall survival of LGG patients, while, high SFRP2, IRX1, KLRC3 and LUZP2 expressions were all negatively associated with the overall survival of LGG patients (Table 2).	('IGFBP2', 'Gene', '3485', (18, 24))	('IRX1', 'Gene', '79192', (156, 160))	('TIMP1', 'Gene', (32, 37))	('LUZP2', 'Gene', '338645', (172, 177))	('SFRP2', 'Gene', (149, 154))	('positively', 'PosReg', (72, 82))	('SERPINE1', 'Gene', (42, 50))	('high', 'Var', (13, 17))	('IGFBP2', 'Gene', (18, 24))	('TIMP1', 'Gene', '7076', (32, 37))	('KLRC3', 'Gene', '3823', (162, 167))	('EMP3', 'Gene', (26, 30))	('KLRC3', 'Gene', (162, 167))	('SERPINE1', 'Gene', '5054', (42, 50))	('LGG', 'Disease', (250, 253))	('LGG', 'Disease', (123, 126))	('IRX1', 'Gene', (156, 160))	('EMP3', 'Gene', '2014', (26, 30))	('LUZP2', 'Gene', (172, 177))	('patients', 'Species', '9606', (127, 135))	('associated', 'Reg', (83, 93))	('SFRP2', 'Gene', '6423', (149, 154))	('patients', 'Species', '9606', (254, 262))
229534	32328202	We found that patients with both high EMP3 and SERPINE1 expressions were particular with lowest overall survival in glioma patients (Figure 7B).	('EMP3', 'Gene', (38, 42))	('high', 'Var', (33, 37))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Disease', (116, 122))	('lowest', 'NegReg', (89, 95))	('patients', 'Species', '9606', (123, 131))	('EMP3', 'Gene', '2014', (38, 42))	('overall survival', 'MPA', (96, 112))	('patients', 'Species', '9606', (14, 22))	('SERPINE1', 'Gene', '5054', (47, 55))	('SERPINE1', 'Gene', (47, 55))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
229535	32328202	Patients with the low expression of EMP3 or SERPINE1 had better clinical outcomes (Figure 7B).	('EMP3', 'Gene', (36, 40))	('Patients', 'Species', '9606', (0, 8))	('SERPINE1', 'Gene', '5054', (44, 52))	('SERPINE1', 'Gene', (44, 52))	('low expression', 'Var', (18, 32))	('EMP3', 'Gene', '2014', (36, 40))
229544	32328202	Moreover, EMP3 and SERPINE1 were highly correlated with each other (Figure 8D) and the combination of EMP3 and SERPINE1 genes had better survival prediction in Chinese patients with LGG (Figure 8E).	('EMP3', 'Gene', (10, 14))	('better', 'PosReg', (130, 136))	('survival', 'CPA', (137, 145))	('EMP3', 'Gene', '2014', (102, 106))	('SERPINE1', 'Gene', '5054', (111, 119))	('SERPINE1', 'Gene', (111, 119))	('EMP3', 'Gene', '2014', (10, 14))	('combination', 'Var', (87, 98))	('SERPINE1', 'Gene', '5054', (19, 27))	('SERPINE1', 'Gene', (19, 27))	('patients', 'Species', '9606', (168, 176))	('EMP3', 'Gene', (102, 106))	('LGG', 'Disease', (182, 185))
229563	32328202	Furthermore, high expressions of IGFBP2, EMP3, TIMP1 and SERPINE1 are associated with low overall survival of LGG patients (Figure 6).	('EMP3', 'Gene', (41, 45))	('patients', 'Species', '9606', (114, 122))	('high', 'Var', (13, 17))	('IGFBP2', 'Gene', '3485', (33, 39))	('LGG', 'Disease', (110, 113))	('TIMP1', 'Gene', (47, 52))	('EMP3', 'Gene', '2014', (41, 45))	('IGFBP2', 'Gene', (33, 39))	('TIMP1', 'Gene', '7076', (47, 52))	('SERPINE1', 'Gene', '5054', (57, 65))	('low', 'NegReg', (86, 89))	('SERPINE1', 'Gene', (57, 65))	('overall survival', 'MPA', (90, 106))
229564	32328202	Interestingly, EMP3 and SERPINE1 are connected with each other and the combination of EMP3 and SERPINE1 genes have better prognostic effects in glioma patients (Figure 7B and 7C).	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('SERPINE1', 'Gene', '5054', (24, 32))	('SERPINE1', 'Gene', (24, 32))	('patients', 'Species', '9606', (151, 159))	('EMP3', 'Gene', (86, 90))	('SERPINE1', 'Gene', (95, 103))	('SERPINE1', 'Gene', '5054', (95, 103))	('better', 'PosReg', (115, 121))	('glioma', 'Disease', (144, 150))	('EMP3', 'Gene', (15, 19))	('EMP3', 'Gene', '2014', (86, 90))	('combination', 'Var', (71, 82))	('EMP3', 'Gene', '2014', (15, 19))
229567	32328202	Although the expression of IGFBP2 is controlled by epigenetic DNA methylation in glioma patients, we find no significant different methylation intensity of IGFBP2 and TIMP1 genes between old and young LGG patients (Figure 4B).	('epigenetic', 'Var', (51, 61))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IGFBP2', 'Gene', (27, 33))	('patients', 'Species', '9606', (205, 213))	('IGFBP2', 'Gene', '3485', (156, 162))	('IGFBP2', 'Gene', (156, 162))	('patients', 'Species', '9606', (88, 96))	('TIMP1', 'Gene', (167, 172))	('glioma', 'Disease', (81, 87))	('LGG', 'Disease', (201, 204))	('TIMP1', 'Gene', '7076', (167, 172))	('IGFBP2', 'Gene', '3485', (27, 33))	('controlled', 'Reg', (37, 47))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
229577	32214825	MiR-138 overexpression in LGG cells was achieved by miR-138 mimics transfection.	('overexpression', 'PosReg', (8, 22))	('transfection', 'Var', (67, 79))	('MiR-138', 'Chemical', '-', (0, 7))	('miR-138', 'Chemical', '-', (52, 59))	('miR-138', 'Gene', (52, 59))	('MiR-138', 'Gene', (0, 7))
229582	32214825	Functional analysis indicated that ectopic miR-138 expression suppressed LGG cell growth and invasive phenotype in vitro, and inhibited tumor development in vivo.	('invasive phenotype', 'CPA', (93, 111))	('LGG cell growth', 'CPA', (73, 88))	('miR-138', 'Chemical', '-', (43, 50))	('miR-138', 'Gene', (43, 50))	('inhibited', 'NegReg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('suppressed', 'NegReg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('ectopic', 'Var', (35, 42))	('suppressed LGG cell', 'Phenotype', 'HP:0004315', (62, 81))	('tumor', 'Disease', (136, 141))
229585	32214825	miR-138 may function as a tumor inhibitor by directly inhibiting IGF2BP2 and suppressing EMT in the progression of LGG.	('suppressing', 'NegReg', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('miR-138', 'Chemical', '-', (0, 7))	('miR-138', 'Var', (0, 7))	('LGG', 'Disease', (115, 118))	('progression', 'CPA', (100, 111))	('IGF2BP2', 'Gene', '10644', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('EMT', 'CPA', (89, 92))	('IGF2BP2', 'Gene', (65, 72))	('inhibiting', 'NegReg', (54, 64))
229594	32214825	Gao et al found that miR-138-5p could reverse gefitinib resistance in NSCLC cells.	('reverse', 'NegReg', (38, 45))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('gefitinib resistance', 'MPA', (46, 66))	('miR-138-5p', 'Chemical', '-', (21, 31))	('miR-138-5p', 'Var', (21, 31))
229596	32214825	Li et al showed that miR-138 posttranscriptionally regulated LIMK1 to suppress the proliferation of breast cancer cells.	('proliferation', 'CPA', (83, 96))	('suppress', 'NegReg', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('miR-138', 'Var', (21, 28))	('miR-138', 'Chemical', '-', (21, 28))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('LIMK1', 'Gene', '3984', (61, 66))	('LIMK1', 'Gene', (61, 66))
229620	32214825	IGF2BP2 3'UTR containing the wild type or mutated binding sites was cloned into psi-CHECKTM-2 luciferase vector (Promega, USA), respectively.	('IGF2BP2', 'Gene', '10644', (0, 7))	('IGF2BP2', 'Gene', (0, 7))	('mutated', 'Var', (42, 49))
229625	32214825	After blocking in 5% BSA/PBST for 2 hrs, the PVDF membrane was probed with WTAP (60188-1-Ig, Proteintech, China), E-cadherin (20874-1-AP, Proteintech, China), N-cadherin (22018-1-AP, Proteintech, China), Slug (ab106077, Abcam, USA), Snail (ab53519, Abcam, USA), beta-catenin (51067-2-AP, Proteintech, China), GAPDH (60004-AP, Proteintech, China).	('E-cadherin', 'Gene', (114, 124))	('E-cadherin', 'Gene', '999', (114, 124))	('beta-catenin', 'Gene', (262, 274))	('GAPDH', 'Gene', '2597', (309, 314))	('GAPDH', 'Gene', (309, 314))	('PVDF', 'Chemical', 'MESH:C024865', (45, 49))	('beta-catenin', 'Gene', '1499', (262, 274))	('Snail', 'Gene', '6615', (233, 238))	('Snail', 'Gene', (233, 238))	('N-cadherin', 'Gene', (159, 169))	('51067-2-AP', 'Var', (276, 286))	('60004-AP', 'Var', (316, 324))	('22018-1-AP', 'Var', (171, 181))	('Slug', 'Gene', '6591', (204, 208))	('N-cadherin', 'Gene', '1000', (159, 169))	('Slug', 'Gene', (204, 208))	('WTAP', 'Gene', '9589', (75, 79))	('WTAP', 'Gene', (75, 79))
229636	32214825	LGG patients with low miR-138 expression had a higher rate of metastasis (Figure 1C, Supplementary Table 1).	('miR-138', 'Gene', (22, 29))	('metastasis', 'CPA', (62, 72))	('expression', 'MPA', (30, 40))	('miR-138', 'Chemical', '-', (22, 29))	('patients', 'Species', '9606', (4, 12))	('low', 'Var', (18, 21))
229643	32214825	Thus, we hypothesize that low level of miR-138 may promote LGG progression.	('miR-138', 'Gene', (39, 46))	('LGG', 'Disease', (59, 62))	('miR-138', 'Chemical', '-', (39, 46))	('promote', 'PosReg', (51, 58))	('low level', 'Var', (26, 35))
229644	32214825	To explore the function of miR-138 in LGG tumorigenesis, Res186 and Res259 cells were overexpressed miR-138 (Lenti-miR-138) or negative control (NC), as evaluated by RT-qPCR (Figure 2A).	('tumor', 'Disease', (42, 47))	('LGG', 'Disease', (38, 41))	('overexpressed', 'PosReg', (86, 99))	('miR-138', 'Chemical', '-', (27, 34))	('miR-138', 'Var', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('miR-138', 'Chemical', '-', (100, 107))	('miR-138', 'Chemical', '-', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
229648	32214825	As shown in Figure 2E and F, ectopic miR-139 expression markedly attenuated the metastasis ability of LGG cells.	('ectopic', 'Var', (29, 36))	('miR-139', 'Gene', '406931', (37, 44))	('attenuated', 'NegReg', (65, 75))	('metastasis ability of LGG cells', 'CPA', (80, 111))	('miR-139', 'Gene', (37, 44))
229649	32214825	Taken together, our results indicate that miR-138 suppresses LGG cell aggressiveness.	('suppresses', 'NegReg', (50, 60))	('aggressiveness', 'Disease', 'MESH:D001523', (70, 84))	('miR-138', 'Chemical', '-', (42, 49))	('aggressiveness', 'Disease', (70, 84))	('miR-138', 'Var', (42, 49))	('aggressiveness', 'Phenotype', 'HP:0000718', (70, 84))
229651	32214825	The results of tumor growth through in vivo image analysis indicated that the tumor volumes of Lenti-miR-138 group were markedly smaller than that in control group (Figure 3A).	('smaller', 'NegReg', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Lenti-miR-138', 'Var', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (78, 83))	('miR-138', 'Chemical', '-', (101, 108))
229652	32214825	Tumors from Lenti-miR-138 group had smaller tumor volume (Figure 3B), less photon flux (Figure 3C) and decreased tumor weight (Figure 3D) than those from NC group.	('less', 'NegReg', (70, 74))	('tumor', 'Disease', (113, 118))	('decreased tumor weight', 'Disease', 'MESH:D015431', (103, 125))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Lenti-miR-138', 'Var', (12, 25))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('decreased tumor weight', 'Disease', (103, 125))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('photon flux', 'MPA', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-138', 'Chemical', '-', (18, 25))	('tumor', 'Disease', (44, 49))	('smaller', 'NegReg', (36, 43))
229653	32214825	Consistently, Ki-67 IHC staining showed that the tumor tissues from Lenti-miR-138 group exhibited significantly reduced expression of Ki-67 compared with that in tumors from NC group (Figure 3E and F).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('expression', 'MPA', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('miR-138', 'Chemical', '-', (74, 81))	('tumor', 'Disease', (162, 167))	('Lenti-miR-138 group', 'Var', (68, 87))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (162, 168))	('reduced', 'NegReg', (112, 119))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Ki-67', 'Gene', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
229655	32214825	Given the findings that miR-138 inhibited the growth of LGG cells, we next investigated the potential underlying mechanism.	('inhibited', 'NegReg', (32, 41))	('miR-138', 'Var', (24, 31))	('growth of LGG cells', 'CPA', (46, 65))	('miR-138', 'Chemical', '-', (24, 31))
229659	32214825	Luciferase reporter vectors containing wild-type 3'-UTR of IGF2BP2 or mutated 3'-UTR of IGF2BP2 were constructed and luciferase reporter assay confirmed that miR-138 inhibited luciferase activity in HEK293 cells transfected with reporter plasmid containing WT IGF2BP2 3'-UTR, but not in HEK293 cells transfected with reporter plasmid containing mutant IGF2BP2 3'-UTR (Figure 4B).	('IGF2BP2', 'Gene', (352, 359))	('miR-138', 'Var', (158, 165))	('IGF2BP2', 'Gene', '10644', (88, 95))	('IGF2BP2', 'Gene', (260, 267))	('IGF2BP2', 'Gene', (88, 95))	('inhibited', 'NegReg', (166, 175))	('activity', 'MPA', (187, 195))	('miR-138', 'Chemical', '-', (158, 165))	('IGF2BP2', 'Gene', '10644', (352, 359))	('IGF2BP2', 'Gene', '10644', (59, 66))	('WT', 'Disease', 'MESH:C536751', (257, 259))	('luciferase', 'Enzyme', (176, 186))	('IGF2BP2', 'Gene', (59, 66))	('IGF2BP2', 'Gene', '10644', (260, 267))
229663	32214825	Together, these data validate that IGF2BP2 is a direct target of miR-138 and miR-138 negatively regulates IGF2BP2 in LGG.	('miR-138', 'Chemical', '-', (77, 84))	('IGF2BP2', 'Gene', '10644', (106, 113))	('miR-138', 'Chemical', '-', (65, 72))	('IGF2BP2', 'Gene', (106, 113))	('IGF2BP2', 'Gene', '10644', (35, 42))	('regulates', 'Reg', (96, 105))	('IGF2BP2', 'Gene', (35, 42))	('negatively', 'NegReg', (85, 95))	('miR-138', 'Var', (77, 84))
229665	32214825	Cell proliferation assessed by CCK-8 showed that ectopic IGF2BP2 partially reversed the suppressive effect of miR-138 in LGG cells (Figure 5B).	('IGF2BP2', 'Gene', '10644', (57, 64))	('miR-138', 'Gene', (110, 117))	('IGF2BP2', 'Gene', (57, 64))	('miR-138', 'Chemical', '-', (110, 117))	('ectopic', 'Var', (49, 56))
229668	32214825	The data confirm that miR-138 suppresses LGG cell growth and invasion by negatively regulating IGF2BP2 expression.	('miR-138', 'Var', (22, 29))	('IGF2BP2', 'Gene', '10644', (95, 102))	('miR-138', 'Chemical', '-', (22, 29))	('suppresses', 'NegReg', (30, 40))	('expression', 'MPA', (103, 113))	('negatively', 'NegReg', (73, 83))	('invasion', 'CPA', (61, 69))	('IGF2BP2', 'Gene', (95, 102))	('LGG cell growth', 'CPA', (41, 56))
229676	32214825	Gene Set Variation Analysis (GSVA) results showed that high level of IGF2BP2 expression was associated with the activation of EMT pathway (Figure 7A).	('IGF2BP2', 'Gene', (69, 76))	('high level', 'Var', (55, 65))	('EMT pathway', 'Pathway', (126, 137))	('GSVA', 'Chemical', '-', (29, 33))	('activation', 'PosReg', (112, 122))	('IGF2BP2', 'Gene', '10644', (69, 76))
229678	32214825	Moreover, the GSEA further confirmed the significant positive correlation between high IGF2BP2 expression and EMT-related gene signatures (Figure 7D and E).	('high', 'Var', (82, 86))	('IGF2BP2', 'Gene', '10644', (87, 94))	('EMT-related', 'CPA', (110, 121))	('IGF2BP2', 'Gene', (87, 94))	('expression', 'MPA', (95, 105))	('GSEA', 'Chemical', '-', (14, 18))
229684	32214825	For example, miR-128 could inhibit cell self-renewal by antagonizing Bmi-1.	('miR-128', 'Chemical', '-', (13, 20))	('antagonizing', 'NegReg', (56, 68))	('miR-128', 'Var', (13, 20))	('cell self-renewal', 'CPA', (35, 52))	('Bmi-1', 'Gene', '648', (69, 74))	('Bmi-1', 'Gene', (69, 74))	('inhibit', 'NegReg', (27, 34))
229686	32214825	Peng et al demonstrated that low miR-200b expression suppressed LGG cell growth and metastasis through targeting CREB1.	('miR-200b', 'Gene', '406984', (33, 41))	('suppressed LGG cell', 'Phenotype', 'HP:0004315', (53, 72))	('miR-200b', 'Gene', (33, 41))	('low', 'Var', (29, 32))	('expression', 'MPA', (42, 52))	('metastasis', 'CPA', (84, 94))	('targeting', 'Reg', (103, 112))	('LGG cell growth', 'CPA', (64, 79))	('CREB1', 'Gene', '1385', (113, 118))	('CREB1', 'Gene', (113, 118))	('suppressed', 'NegReg', (53, 63))
229691	32214825	However, other studies indicated that miR-138 might be an oncogenic miRNA as miR-138 was highly expressed in tumor-initiating glioma stem cell.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('miR-138', 'Chemical', '-', (77, 84))	('tumor-initiating glioma', 'Disease', 'MESH:D005910', (109, 132))	('tumor-initiating glioma', 'Disease', (109, 132))	('miR-138', 'Var', (38, 45))	('highly', 'PosReg', (89, 95))	('miR-138', 'Chemical', '-', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('miR-138', 'Gene', (77, 84))
229703	32214825	Aberrant expression of E-cadherin, Vimentin and Snail is correlated with tumor metastasis.	('Vimentin', 'Gene', (35, 43))	('Aberrant', 'Var', (0, 8))	('Vimentin', 'Gene', '7431', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('correlated', 'Reg', (57, 67))	('Snail', 'Gene', (48, 53))	('Snail', 'Gene', '6615', (48, 53))	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('expression', 'MPA', (9, 19))	('tumor metastasis', 'Disease', 'MESH:D009362', (73, 89))	('tumor metastasis', 'Disease', (73, 89))
229706	32214825	However, knockdown of IGF2BP2 could abolish these changes.	('IGF2BP2', 'Gene', '10644', (22, 29))	('knockdown', 'Var', (9, 18))	('IGF2BP2', 'Gene', (22, 29))
229724	30949502	Furthermore, the proliferation, invasion, and migration of U87MG and U251 glioblastoma stem-like cells (U87GS, U251GS) were significantly inhibited upon inhibition of ASB16-AS1, and the expression of key proteins in the EMT signaling pathway was affected by knocking down ASB16-AS1.	('AS1', 'Gene', (173, 176))	('ASB16', 'Gene', (167, 172))	('migration', 'CPA', (46, 55))	('inhibited', 'NegReg', (138, 147))	('affected', 'Reg', (246, 254))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('ASB16', 'Gene', '92591', (272, 277))	('AS1', 'Gene', '5729', (278, 281))	('invasion', 'CPA', (32, 40))	('glioblastoma', 'Disease', (74, 86))	('ASB16', 'Gene', '92591', (167, 172))	('AS1', 'Gene', '5729', (173, 176))	('U251GS', 'CellLine', 'CVCL:0021', (111, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('knocking down', 'Var', (258, 271))	('inhibition', 'NegReg', (153, 163))	('ASB16', 'Gene', (272, 277))	('EMT', 'Gene', (220, 223))	('EMT', 'Gene', '3702', (220, 223))	('expression', 'MPA', (186, 196))	('U87MG', 'CellLine', 'CVCL:0022', (59, 64))	('AS1', 'Gene', (278, 281))
229786	30949502	It was observed that the proliferation, invasion, and migration abilities of the cells were significantly suppressed upon knocking down ASB16-AS1 in U87GS and U251GS cells (Figure 4).	('AS1', 'Gene', (142, 145))	('ASB16', 'Gene', (136, 141))	('invasion', 'CPA', (40, 48))	('ASB16', 'Gene', '92591', (136, 141))	('migration abilities of the cells', 'CPA', (54, 86))	('U251GS', 'CellLine', 'CVCL:0021', (159, 165))	('suppressed', 'NegReg', (106, 116))	('knocking down', 'Var', (122, 135))	('AS1', 'Gene', '5729', (142, 145))
229807	30949502	As the results revealed, the function of glioma cells was suppressed by knocking down ASB16-AS1.	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('knocking down', 'Var', (72, 85))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('AS1', 'Gene', (92, 95))	('suppressed', 'NegReg', (58, 68))	('ASB16', 'Gene', (86, 91))	('AS1', 'Gene', '5729', (92, 95))	('ASB16', 'Gene', '92591', (86, 91))	('function', 'CPA', (29, 37))	('glioma', 'Disease', (41, 47))
229808	30949502	In addition, the EMT signaling pathway was affected by knocking down ASB16-AS1.	('EMT', 'Gene', (17, 20))	('affected', 'Reg', (43, 51))	('EMT', 'Gene', '3702', (17, 20))	('knocking down', 'Var', (55, 68))	('AS1', 'Gene', '5729', (75, 78))	('AS1', 'Gene', (75, 78))	('ASB16', 'Gene', (69, 74))	('ASB16', 'Gene', '92591', (69, 74))
229810	30949502	In the present study, knockdown of ASB16-AS1 inhibited cell proliferation and suppressed EMT in glioma cells.	('inhibited', 'NegReg', (45, 54))	('suppressed', 'NegReg', (78, 88))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('knockdown', 'Var', (22, 31))	('cell proliferation', 'CPA', (55, 73))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('ASB16', 'Gene', (35, 40))	('ASB16', 'Gene', '92591', (35, 40))	('AS1', 'Gene', '5729', (41, 44))	('AS1', 'Gene', (41, 44))	('EMT', 'Gene', (89, 92))	('EMT', 'Gene', '3702', (89, 92))	('glioma', 'Disease', (96, 102))
229839	30487391	Compared to healthy brain tissue, CNS tumors typically appear hypointense to myelinated white matter on T1-weighted images and hyperintense on T2.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('hyperintense', 'Var', (127, 139))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('CNS tumor', 'Phenotype', 'HP:0100006', (34, 43))	('hypointense to myelinated white matter', 'Disease', (62, 100))	('CNS tumors', 'Disease', 'MESH:D009369', (34, 44))	('CNS tumors', 'Disease', (34, 44))	('hypointense to myelinated white matter', 'Disease', 'MESH:D056784', (62, 100))
229887	30487391	11C-MET PET has been shown to be useful in delineating ependymomas, medulloblastoma, and astrocytomas in pediatric patients and can also effectively differentiate between radiation-induced brain tissue injury and tumor recurrence.	('brain tissue injury and tumor', 'Disease', 'MESH:D001932', (189, 218))	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('medulloblastoma', 'Disease', 'MESH:D008527', (68, 83))	('patients', 'Species', '9606', (115, 123))	('astrocytomas', 'Disease', 'MESH:D001254', (89, 101))	('medulloblastoma', 'Phenotype', 'HP:0002885', (68, 83))	('delineating ependymomas', 'Disease', (43, 66))	('11C-MET', 'Chemical', '-', (0, 7))	('astrocytomas', 'Disease', (89, 101))	('medulloblastoma', 'Disease', (68, 83))	('11C-MET PET', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('delineating ependymomas', 'Disease', 'MESH:D004806', (43, 66))
229921	30487391	Some case studies illustrate the advantages of amino acid PET over MRI in delineating tumor extent, informing on response to therapy, and detecting disease recurrence.	('tumor', 'Disease', (86, 91))	('amino acid PET', 'Var', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
229924	30487391	11C-MET PET was more diagnostically precise than contrast-enhanced MRI in delineating a broad and continuous tumor mass.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('11C-MET', 'Chemical', '-', (0, 7))	('11C-MET PET', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
229941	30487391	As summarized in Figure 3, these advantages offered by amino acid PET translate into precise tumor boundary delineation and early treatment response assessments that transcend MRI-based limitations of pseudoprogression and pseudoresponse.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('amino acid PET', 'Var', (55, 69))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
229944	29535603	Characterization of Hand Clenching in Human Sensorimotor Cortex Using High-, and Ultra-High Frequency Band Modulations of Electrocorticogram Functional mapping of eloquent cortex before the resection of a tumor is a critical procedure for optimizing survival and quality of life.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('Human', 'Species', '9606', (38, 43))	('Hand Clenching', 'Phenotype', 'HP:0001188', (20, 34))	('High Frequency Band Modulations', 'Phenotype', 'HP:0005101', (87, 118))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('Modulations', 'Var', (107, 118))
229948	29535603	Among all frequency bands we studied, the UFB modulations were closest to the central sulcus and direct cortical stimulation (DCS) positive site.	('UFB', 'Gene', (42, 45))	('DCS', 'Chemical', '-', (126, 129))	('UFB', 'Chemical', '-', (42, 45))	('modulations', 'Var', (46, 57))
229949	29535603	Both HFB and UFB modulations exhibited different timing characteristics at different locations.	('modulations', 'Var', (17, 28))	('HFB', 'Gene', (5, 8))	('UFB', 'Gene', (13, 16))	('HFB', 'Chemical', '-', (5, 8))	('UFB', 'Chemical', '-', (13, 16))
229958	29535603	However, some drawbacks of DCS are that it is time-consuming to adjust stimulation parameters, and test successively stimulation sites, and that it may induce spread of cortical activation that elicit seizures.	('seizures', 'Disease', (201, 209))	('seizure', 'Phenotype', 'HP:0001250', (201, 208))	('DCS', 'Var', (27, 30))	('DCS', 'Chemical', '-', (27, 30))	('spread', 'MPA', (159, 165))	('seizures', 'Disease', 'MESH:D012640', (201, 209))	('seizures', 'Phenotype', 'HP:0001250', (201, 209))	('induce', 'Reg', (152, 158))	('elicit', 'Reg', (194, 200))
230043	29535603	The UFB modulated channels were consistently closer to the central sulcus compared to LFB and HFB modulated channels.	('HFB', 'Chemical', '-', (94, 97))	('UFB', 'Chemical', '-', (4, 7))	('modulated', 'Var', (8, 17))	('closer', 'Reg', (45, 51))	('LFB', 'Chemical', '-', (86, 89))
230050	29535603	For P2, the peak of UFB-ERS was recorded in C31 while the peak of HFB-ERS was in C85.	('HFB-ERS', 'Disease', (66, 73))	('HFB-ERS', 'Disease', 'OMIM:204690', (66, 73))	('C31', 'Var', (44, 47))	('UFB', 'Chemical', '-', (20, 23))
230076	29535603	All groups revealed ERS (red) in HFB and ERD (blue) in LFB.	('HFB', 'Disease', (33, 36))	('ERS', 'Var', (20, 23))	('HFB', 'Chemical', '-', (33, 36))	('LFB', 'Disease', (55, 58))	('ERD', 'Var', (41, 44))	('LFB', 'Chemical', '-', (55, 58))
230082	29535603	Due to the delimited spatially localized feature of UFB modulations, the typical clinical grids with large inter-electrode spacing might fail to capture them consistently.	('UFB', 'Chemical', '-', (52, 55))	('UFB', 'Gene', (52, 55))	('modulations', 'Var', (56, 67))
230104	29535603	Although deemed as the gold standard of functional mapping, DCS does not map functional motor behavior, and might induce seizures by injecting current to the cortex (Boulogne et al.,).	('seizure', 'Phenotype', 'HP:0001250', (121, 128))	('DCS', 'Var', (60, 63))	('seizures', 'Disease', 'MESH:D012640', (121, 129))	('induce', 'Reg', (114, 120))	('injecting', 'Reg', (133, 142))	('seizures', 'Disease', (121, 129))	('DCS', 'Chemical', '-', (60, 63))	('seizures', 'Phenotype', 'HP:0001250', (121, 129))
230203	24189182	Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia.	('Loss-of-function', 'NegReg', (0, 16))	('KAL1', 'Gene', (30, 34))	('delayed puberty and anosmia', 'Disease', 'MESH:D011628', (69, 96))	('Kallmann syndrome', 'Disease', 'MESH:D017436', (46, 63))	('anosmia', 'Phenotype', 'HP:0000458', (89, 96))	('KAL1', 'Gene', '3730', (30, 34))	('mutations', 'Var', (17, 26))	('delayed puberty', 'Phenotype', 'HP:0000823', (69, 84))	('Kallmann syndrome', 'Disease', (46, 63))
230208	24189182	ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('anosmin-1', 'Gene', (28, 37))	('induced', 'Reg', (88, 95))	('knockdown', 'Var', (15, 24))	('tumor', 'Disease', (72, 77))	('anosmin-1', 'Gene', '3730', (28, 37))	('apoptosis', 'CPA', (96, 105))	('attenuated motility', 'Disease', (38, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('attenuated motility', 'Disease', 'MESH:C538265', (38, 57))
230214	24189182	Loss-of-function mutations of KAL1 underlie Kallmann syndrome (KS), a developmental disorder characterized by the association of hypogonadotrophic hypogonadism and anosmia.	('Loss-of-function', 'NegReg', (0, 16))	('developmental disorder', 'Disease', 'MESH:D002658', (70, 92))	('KAL1', 'Gene', (30, 34))	('Kallmann syndrome', 'Disease', (44, 61))	('developmental disorder', 'Disease', (70, 92))	('hypogonadism', 'Phenotype', 'HP:0000135', (147, 159))	('KAL1', 'Gene', '3730', (30, 34))	('hypogonadotrophic hypogonadism', 'Phenotype', 'HP:0000044', (129, 159))	('Kallmann syndrome', 'Disease', 'MESH:D017436', (44, 61))	('developmental disorder', 'Phenotype', 'HP:0001263', (70, 92))	('anosmia', 'Phenotype', 'HP:0000458', (164, 171))	('mutations', 'Var', (17, 26))	('hypogonadotrophic hypogonadism and anosmia', 'Disease', 'MESH:D017436', (129, 171))
230219	24189182	Anosmin-1 directly binds to FGFR1 and modulates its signaling, and mutations of FGFR1 and its ligand FGF8 have been found in KS.	('Anosmin-1', 'Gene', (0, 9))	('FGFR1', 'Gene', '2260', (80, 85))	('modulates', 'Reg', (38, 47))	('FGF8', 'Gene', (101, 105))	('FGFR1', 'Gene', (28, 33))	('signaling', 'MPA', (52, 61))	('mutations', 'Var', (67, 76))	('FGF8', 'Gene', '2253', (101, 105))	('found', 'Reg', (116, 121))	('binds', 'Interaction', (19, 24))	('FGFR1', 'Gene', '2260', (28, 33))	('FGFR1', 'Gene', (80, 85))	('Anosmin-1', 'Gene', '3730', (0, 9))
230223	24189182	Targeted knockout of beta1 integrin impaired GNRH neuronal migration in mouse, resulting in delayed puberty and reproductive dysfunctions, suggesting an important role of beta1 integrin in GNRH ontogeny.	('delayed', 'NegReg', (92, 99))	('knockout', 'Var', (9, 17))	('beta1 integrin', 'Gene', (21, 35))	('impaired GNRH neuronal migration', 'Disease', 'MESH:D054081', (36, 68))	('mouse', 'Species', '10090', (72, 77))	('puberty', 'Disease', 'MESH:D011628', (100, 107))	('beta1 integrin', 'Gene', '3688', (171, 185))	('puberty', 'Disease', (100, 107))	('impaired GNRH neuronal migration', 'Disease', (36, 68))	('delayed puberty', 'Phenotype', 'HP:0000823', (92, 107))	('reproductive dysfunctions', 'CPA', (112, 137))	('beta1 integrin', 'Gene', '3688', (21, 35))	('beta1 integrin', 'Gene', (171, 185))
230297	24189182	After stable infection of A172, the average knockdown of KAL1 assessed by qRT-PCR was 88% for shRNA676, 84% for shRNA675, and 67% for shRNA673, compared with nontargeting shRNA (Fig.	('KAL1', 'Gene', (57, 61))	('knockdown', 'MPA', (44, 53))	('shRNA673', 'Var', (134, 142))	('KAL1', 'Gene', '3730', (57, 61))	('shRNA676', 'Var', (94, 102))
230301	24189182	Thus, we asked whether these pathways are operational in tumor cells by examining the anosmin-1-induced motility in the presence of specific inhibitors of FGFR1 (SU5402, FGFR1 ectodomain antibody) or uPA (amiloride, uPA antibody).	('uPA', 'Gene', (200, 203))	('SU5402', 'Var', (162, 168))	('FGFR1', 'Gene', '2260', (170, 175))	('anosmin-1', 'Gene', '3730', (86, 95))	('uPA', 'Gene', '5328', (200, 203))	('anosmin-1', 'Gene', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('amiloride', 'Chemical', 'MESH:D000584', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('uPA', 'Gene', (216, 219))	('tumor', 'Disease', (57, 62))	('SU5402', 'Chemical', 'MESH:C105686', (162, 168))	('FGFR1', 'Gene', (155, 160))	('uPA', 'Gene', '5328', (216, 219))	('FGFR1', 'Gene', (170, 175))	('FGFR1', 'Gene', '2260', (155, 160))
230314	24189182	We also conducted a subcellular colocalization study in cells expressing GFP-tagged anosmin-1.	('anosmin-1', 'Gene', (84, 93))	('GFP-tagged', 'Var', (73, 83))	('anosmin-1', 'Gene', '3730', (84, 93))
230318	24189182	One of the earliest events upon integrin clustering and signaling is autophosphorylation of FAK at Y397, which leads to the recruitment of PI3K to focal adhesion, causing activation of AKT that regulates integrin-mediated cell survival.	('AKT', 'Gene', (185, 188))	('recruitment', 'MPA', (124, 135))	('FAK', 'Gene', (92, 95))	('focal', 'Protein', (147, 152))	('FAK', 'Gene', '5747', (92, 95))	('activation', 'PosReg', (171, 181))	('Y397', 'Var', (99, 103))	('AKT', 'Gene', '207', (185, 188))	('PI3K', 'Protein', (139, 143))
230322	24189182	It has been reported that PF-228 inhibits FAK phosphorylation (Tyr397) and FAK-mediated random motility in multiple cancer cell lines.	('FAK', 'Gene', '5747', (42, 45))	('FAK', 'Gene', (75, 78))	('FAK', 'Gene', '5747', (75, 78))	('Tyr397', 'Var', (63, 69))	('Tyr397', 'Chemical', '-', (63, 69))	('cancer', 'Disease', (116, 122))	('FAK', 'Gene', (42, 45))	('PF-228', 'Chemical', 'MESH:C521108', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PF-228', 'Gene', (26, 32))	('inhibits', 'NegReg', (33, 41))
230323	24189182	In LN229 cells, PF-228 reduced the basal level of motility about 20% in SFM.	('LN229', 'CellLine', 'CVCL:0393', (3, 8))	('PF-228', 'Var', (16, 22))	('PF-228', 'Chemical', 'MESH:C521108', (16, 22))	('reduced', 'NegReg', (23, 30))	('basal level of', 'MPA', (35, 49))
230333	24189182	4C), we speculate that loss of anosmin-1 may induce apoptosis.	('induce', 'Reg', (45, 51))	('anosmin-1', 'Gene', (31, 40))	('apoptosis', 'CPA', (52, 61))	('loss', 'Var', (23, 27))	('anosmin-1', 'Gene', '3730', (31, 40))
230339	24189182	We observed 80% decrease in AKT phosphorylation and 70% decrease in ERK phosphorylation by shRNA676 with 88% knockdown of KAL1.	('KAL1', 'Gene', (122, 126))	('decrease', 'NegReg', (16, 24))	('AKT', 'Gene', (28, 31))	('ERK', 'Gene', '5594', (68, 71))	('knockdown', 'Var', (109, 118))	('KAL1', 'Gene', '3730', (122, 126))	('ERK', 'Gene', (68, 71))	('decrease', 'NegReg', (56, 64))	('AKT', 'Gene', '207', (28, 31))	('shRNA676', 'Var', (91, 99))
230362	24189182	Reappearance of an embryonic pattern of ECM has been observed in pathological conditions in adulthood and aberrant expression of developmental genes results in malignant brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('malignant brain tumors', 'Disease', 'MESH:D001932', (160, 182))	('malignant brain tumors', 'Disease', (160, 182))	('brain tumor', 'Phenotype', 'HP:0030692', (170, 181))	('aberrant expression', 'Var', (106, 125))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('brain tumors', 'Phenotype', 'HP:0030692', (170, 182))	('results in', 'Reg', (149, 159))
230384	24189182	In summary, the loss-of-function mutations of anosmin-1 disrupt the normal GNRH neuronal development, thus causing KS, but inappropriate activation of anosmin-1-mediated signal pathways in the developed brain is the underlying mechanism of some malignant brain tumors.	('malignant brain tumors', 'Disease', (245, 267))	('malignant brain tumors', 'Disease', 'MESH:D001932', (245, 267))	('anosmin-1', 'Gene', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('anosmin-1', 'Gene', (46, 55))	('mutations', 'Var', (33, 42))	('disrupt', 'NegReg', (56, 63))	('anosmin-1', 'Gene', '3730', (151, 160))	('brain tumors', 'Phenotype', 'HP:0030692', (255, 267))	('loss-of-function', 'NegReg', (16, 32))	('brain tumor', 'Phenotype', 'HP:0030692', (255, 266))	('anosmin-1', 'Gene', '3730', (46, 55))	('GNRH neuronal development', 'CPA', (75, 100))
230413	18952588	Concurrently, our own investigations indicate that antagonists of constitutive hyaluronan interactions strongly inhibit invasiveness and anchorage-independent growth of several glioma cell lines.	('hyaluronan', 'Chemical', 'MESH:D006820', (79, 89))	('antagonists', 'Var', (51, 62))	('inhibit', 'NegReg', (112, 119))	('glioma', 'Disease', (177, 183))	('anchorage-independent growth', 'CPA', (137, 165))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))
230416	18952588	Taken together, these studies strongly suggest that hyaluronan signaling is "activated" during glioma progression and that hyaluronan may promote invasiveness and resistance to therapy in central nervous system gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('central nervous system gliomas', 'Disease', (188, 218))	('invasiveness', 'CPA', (146, 158))	('hyaluronan signaling', 'MPA', (52, 72))	('central nervous system gliomas', 'Disease', 'MESH:D005910', (188, 218))	('hyaluronan', 'Chemical', 'MESH:D006820', (52, 62))	('gliomas', 'Phenotype', 'HP:0009733', (211, 218))	('activated', 'PosReg', (77, 86))	('glioma', 'Disease', (211, 217))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('promote', 'PosReg', (138, 145))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('resistance to therapy', 'CPA', (163, 184))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('hyaluronan', 'Chemical', 'MESH:D006820', (123, 133))	('hyaluronan', 'Var', (123, 133))
230470	18952588	The fact that human intramedullary spinal astrocytoma and diffuse pontine glioma contain the targets for therapeutic hyaluronan antagonism with hyaluronan oligomers and that treatment-resistant CD133+ subpopulations of human glioma cells co-express membrane proteins that interact with CD44 suggest that antagonizing hyaluronan-CD44 interaction with oligomers may effectively abrogate malignant behaviors in these tumors.	('antagonizing', 'Var', (304, 316))	('CD44', 'Gene', '960', (328, 332))	('CD44', 'Gene', (328, 332))	('spinal astrocytoma', 'Disease', 'MESH:D001254', (35, 53))	('tumors', 'Disease', 'MESH:D009369', (414, 420))	('spinal astrocytoma', 'Disease', (35, 53))	('malignant behaviors', 'CPA', (385, 404))	('glioma', 'Disease', (225, 231))	('astrocytoma', 'Phenotype', 'HP:0009592', (42, 53))	('glioma', 'Disease', (74, 80))	('CD44', 'Gene', '960', (286, 290))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('CD44', 'Gene', (286, 290))	('hyaluronan', 'Chemical', 'MESH:D006820', (144, 154))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('human', 'Species', '9606', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (414, 420))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('abrogate', 'NegReg', (376, 384))	('human', 'Species', '9606', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('CD133', 'Gene', (194, 199))	('hyaluronan', 'Chemical', 'MESH:D006820', (117, 127))	('hyaluronan', 'Chemical', 'MESH:D006820', (317, 327))	('CD133', 'Gene', '8842', (194, 199))	('tumors', 'Disease', (414, 420))	('interaction', 'Interaction', (333, 344))
230471	30285995	VSTM2A Over-expression is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('VSTM2A', 'Gene', '222008', (0, 6))	('Spindle Cell Carcinoma', 'Disease', (86, 108))	('Carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mucinous tubular and spindle cell carcinoma', 'Disease', 'MESH:D002277', (241, 284))	('mutations', 'Var', (198, 207))	('VSTM2A', 'Gene', (0, 6))	('Hippo pathway', 'Pathway', (224, 237))	('Spindle Cell Carcinoma', 'Disease', 'MESH:D002277', (86, 108))	('chromosomal losses', 'Var', (167, 185))
230484	30285995	Our previous multi-institutional cohort sequencing study found MTSCC to be molecularly distinct from other RCC subtypes and typified by characteristic chromosomal losses, recurrent somatic mutations in Hippo signaling pathway genes, and the absence of chromosome 7 or 17 gains; our major findings have been independently confirmed by other groups.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('losses', 'NegReg', (163, 169))	('RCC', 'Disease', (107, 110))	('Hippo', 'Gene', (202, 207))	('MTSCC', 'Disease', (63, 68))	('mutations', 'Var', (189, 198))
230516	30285995	Trisomy of chromosomes 7 and/or 17 was considered as a characteristic genomic feature of PRCC.	('PRCC', 'Gene', '5546', (89, 93))	('PRCC', 'Gene', (89, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('Trisomy', 'Var', (0, 7))
230575	30285995	Our study of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and frequent biallelic alteration of Hippo pathway genes, resulting in increased YAP1 nuclear expression; however, YAP1 expression was not found to be of diagnostic use in differentiating MTSCC from PRCC in an independent study.	('RCC', 'Phenotype', 'HP:0005584', (286, 289))	('MTSCC', 'Disease', (274, 279))	('PRCC', 'Gene', '5546', (285, 289))	('Hippo pathway genes', 'Gene', (123, 142))	('biallelic alteration', 'Var', (99, 119))	('YAP1', 'Gene', (201, 205))	('YAP1', 'Gene', '10413', (201, 205))	('rat', 'Species', '10116', (113, 116))	('PRCC', 'Gene', (285, 289))	('YAP1', 'Gene', '10413', (167, 171))	('nuclear expression', 'MPA', (172, 190))	('increased', 'PosReg', (157, 166))	('chromosomal losses', 'Var', (67, 85))	('YAP1', 'Gene', (167, 171))
230592	30285995	Hence, our results indicate that for an individual tumor with morphologic features that can be observed in either MTSCC or PRCC, high VSTM2A expression above an ISH score cutoff of 200 will support an interpretation of MTSCC.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('PRCC', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (129, 133))	('tumor', 'Disease', (51, 56))	('VSTM2A', 'Gene', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('PRCC', 'Gene', '5546', (123, 127))	('VSTM2A', 'Gene', '222008', (134, 140))	('MTSCC', 'Disease', (114, 119))
230658	32493943	Another study using nrTMS demonstrated that lesions within the language-eloquent brain can induce plasticity as a shift of language function to the non-dominant hemisphere (right hemisphere).	('lesions', 'Var', (44, 51))	('plasticity', 'MPA', (98, 108))	('language', 'MPA', (123, 131))	('shift of language function', 'Phenotype', 'HP:0002463', (114, 140))	('TMS', 'Gene', (22, 25))	('shift', 'Reg', (114, 119))	('TMS', 'Gene', '29108', (22, 25))	('induce', 'Reg', (91, 97))
230700	32493943	Unlike high-grade gliomas, low-grade gliomas often contain several brain functions, such as motor, language, and cognitive functions, inside the tumor.	('gliomas', 'Disease', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('low-grade', 'Var', (27, 36))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('contain', 'Reg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('brain functions', 'CPA', (67, 82))	('language', 'CPA', (99, 107))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('tumor', 'Disease', (145, 150))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('cognitive functions', 'CPA', (113, 132))	('motor', 'CPA', (92, 97))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
230830	33889305	In conclusion, the P142 panel of metrics successfully predicted cancer progression status in patients with some, but not all cancer types analyzed.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('P142', 'Var', (19, 23))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('predicted', 'Reg', (54, 63))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
230837	33889305	However, many of the mechanisms driving cancer progression are still not fully understood, such as the causes, effects, and patterns of DNA mutation in oncogenesis.	('DNA', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
230838	33889305	As cancer develops, many mechanisms and endogenous cellular processes cause mutations in DNA.	('DNA', 'Gene', (89, 92))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cause', 'Reg', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
230840	33889305	For example, the binding motif for APOBEC3G is two consecutive cytosines ("CC") and deamination of the second cytosine results in another nucleotide being incorporated e.g., "CT".	('cytosines', 'Chemical', 'MESH:D003596', (63, 72))	('APOBEC3G', 'Gene', '60489', (35, 43))	('nucleotide', 'MPA', (138, 148))	('results in', 'Reg', (119, 129))	('cytosine', 'Chemical', 'MESH:D003596', (63, 71))	('cytosine', 'Chemical', 'MESH:D003596', (110, 118))	('APOBEC3G', 'Gene', (35, 43))	('deamination', 'Var', (84, 95))
230842	33889305	Furthermore, the accumulation of specific deaminase-associated mutations in a patient can provide valuable information on how the cancer has developed, and in specific cases provide information on the rate of progression of the disease and likely response to specific treatments.	('mutations', 'Var', (63, 72))	('deaminase-associated', 'Enzyme', (42, 62))	('patient', 'Species', '9606', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
230843	33889305	Despite clinical utility in a handful of examples, quantification of deaminase-associated DNA mutations currently does not provide actionable information for the majority of cancer types.	('mutations', 'Var', (94, 103))	('cancer', 'Disease', (174, 180))	('DNA', 'Gene', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('deaminase-associated', 'Var', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
230845	33889305	In this study, the proposed molecular model of AID/APOBEC and ADAR mutagenesis advances existing models by implicating the open transcription bubble and transcription elongation complex as illustrated by Lindley (Figure 1A).	('ADAR', 'Gene', '103', (62, 66))	('ADAR', 'Gene', (62, 66))	('mutagenesis', 'Var', (67, 78))	('implicating', 'Reg', (107, 118))	('AID', 'Gene', (47, 50))	('AID', 'Gene', '57379', (47, 50))
230851	33889305	The P142 panel is fundamentally different to these existing methods and may provide a new source of cancer progression biomarkers.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('P142', 'Var', (4, 8))
230854	33889305	We hypothesize that the P142 markers associated with AID/APOBEC and ADAR deamination and codon reading frame context can be used to predict cancer progression for patients with a range of different cancer types.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('patients', 'Species', '9606', (163, 171))	('cancer', 'Disease', (198, 204))	('predict', 'Reg', (132, 139))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('AID', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ADAR', 'Gene', '103', (68, 72))	('AID', 'Gene', '57379', (53, 56))	('P142', 'Var', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ADAR', 'Gene', (68, 72))
230865	33889305	However lower grade glioma (BLGG, Figure 2B), mesothelioma (MESO, Figure 2C) and adrenocortical carcinoma (ADCC, Figure 2D) had significantly more mutations in patients with "Low PFS" vs those with "High PFS" (p < 0.05).	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('mutations', 'Var', (147, 156))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('patients', 'Species', '9606', (160, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('adrenocortical carcinoma', 'Disease', (81, 105))	('mesothelioma', 'Disease', (46, 58))	('ADCC', 'Phenotype', 'HP:0006744', (107, 111))	('glioma', 'Disease', (20, 26))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (81, 105))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (81, 105))
230891	33889305	As this metric denotes a mutation of "G" within an APOBEC3B motif, the mutation occurred at C>T on the opposite strand, which is a measure of strand bias.	('mutation', 'Var', (25, 33))	('APOBEC3B', 'Gene', '9582', (51, 59))	('APOBEC3B', 'Gene', (51, 59))
230892	33889305	This mechanism is associated with many of the P142 metrics, for example #7: "cds:A3G_C-C- MC3%" (Supplementary Table 1), which calculates the proportion of mutations that occur within the APOBEC3G motif ("CC") at the 3rd position of a codon ("MC3").	('mutations', 'Var', (156, 165))	('cds', 'Chemical', 'MESH:D002104', (77, 80))	('APOBEC3G', 'Gene', '60489', (188, 196))	('APOBEC3G', 'Gene', (188, 196))
230894	33889305	Despite a clear correlation between the P142 metrics and patient outcome in the majority of cases, predictive accuracy was low for 8 of the 28 cancer types investigated.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patient', 'Species', '9606', (57, 64))	('P142', 'Var', (40, 44))	('low', 'NegReg', (123, 126))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
230897	33889305	Yet, in cells that are p53-compromised a significantly higher number of mutations with the expected APOBEC motif were observed when APOBEC3B was overexpressed.	('mutations', 'Var', (72, 81))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('APOBEC3B', 'Gene', (132, 140))	('APOBEC3B', 'Gene', '9582', (132, 140))
230898	33889305	This is another potential explanation for the low level of deaminase-associated mutations seen in some cancer types, such as TGCT and UVME, which do not typically have compromised DNA repair machinery.	('UVME', 'Chemical', '-', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (80, 89))	('UVME', 'Disease', (134, 138))	('TGCT', 'Disease', (125, 129))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
230901	33889305	High TMB is typically associated with positive response to immunotherapy (and subsequently higher PFS), yet in cancer types such as adrenocortical carcinoma and lower grade glioma (ADCC, BLGG) a lower mutation burden was associated with longer PFS (see Figures 3 and 4).	('ADCC', 'Phenotype', 'HP:0006744', (181, 185))	('High', 'Var', (0, 4))	('glioma', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (132, 156))	('TMB', 'MPA', (5, 8))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (132, 156))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('TMB', 'Chemical', '-', (5, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('adrenocortical carcinoma', 'Disease', (132, 156))
230909	33889305	We have previously speculated that the combinatorial association of different deaminase isoforms, homodimers and heterodimers may moderate deaminase targeting specificity and contribute to this accumulation of mutations as cancer progresses.	('mutations', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('moderate', 'NegReg', (130, 138))	('deaminase targeting specificity', 'MPA', (139, 170))	('contribute', 'Reg', (175, 185))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))
230915	33889305	This study provides a basis for further development of biomarker panels based on metrics associated with deaminase mutagenesis for predicting cancer progression and patient outcome.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patient', 'Species', '9606', (165, 172))	('mutagenesis', 'Var', (115, 126))	('cancer', 'Disease', (142, 148))
230925	33889305	Genomic metrics included in the P142 panel relate to mutational burden, deaminase binding motifs, incidence of tumor/normal single nucleotide mutations, and reading-frame context of the codon triplet (i.e., if a codon contains a mutation, what is the position of the mutated codon (MC): 1, 2 or 3 as read 5' to 3').	('mutation', 'Var', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (111, 116))
230945	32099409	Dysregulation of long non-coding RNA (lncRNA) is associated with initiation and development of various cancer types including glioma.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (49, 59))	('long non-coding RNA', 'Protein', (17, 36))	('glioma', 'Disease', (126, 132))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
230966	32099409	Dysregulation of lncRNAs is commonly observed in human diseases such as cancer.	('Dysregulation', 'Var', (0, 13))	('observed', 'Reg', (37, 45))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
230971	32099409	Loss of PTEN is a frequent event in glioblastoma and is associated with the prognosis of patients with GBM.	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('PTEN', 'Gene', (8, 12))	('GBM', 'Disease', (103, 106))	('associated', 'Reg', (56, 66))	('GBM', 'Disease', 'MESH:D005909', (103, 106))	('patients', 'Species', '9606', (89, 97))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('Loss', 'Var', (0, 4))	('glioblastoma', 'Disease', (36, 48))
230972	32099409	Recent studies have revealed that the downregulation of PTEN was the consequence of gene mutation, promoter methylation and deregulation of miRNA.	('promoter', 'MPA', (99, 107))	('deregulation', 'MPA', (124, 136))	('gene mutation', 'Var', (84, 97))	('PTEN', 'Gene', (56, 60))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('downregulation', 'NegReg', (38, 52))
230975	32099409	In addition, PART1 reduced cell proliferation and induced cell apoptosis in glioma cells via inactivation of PI3K/AKT signaling.	('AKT', 'Gene', '207', (114, 117))	('PART1', 'Var', (13, 18))	('glioma', 'Disease', (76, 82))	('cell proliferation', 'CPA', (27, 45))	('inactivation', 'NegReg', (93, 105))	('AKT', 'Gene', (114, 117))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('cell apoptosis', 'CPA', (58, 72))	('reduced', 'NegReg', (19, 26))
230989	32099409	pLNCX-Myr-AKT containing a constitutive activated mutant AKT was bought from Addgene (Watertown, MA).	('Myr-AKT', 'Gene', '207', (6, 13))	('AKT', 'Gene', (10, 13))	('activated', 'PosReg', (40, 49))	('Myr-AKT', 'Gene', (6, 13))	('AKT', 'Gene', '207', (57, 60))	('mutant', 'Var', (50, 56))	('AKT', 'Gene', '207', (10, 13))	('AKT', 'Gene', (57, 60))
230997	32099409	Primary antibodies against PI3K (#4255, 1:2000), p-PI3K (#17366, 1:2000), AKT (#2920, 1:2000), p-AKT (#4060, 1:2000) were bought from Cell Signaling Technology (Carlsbad, CA).	('AKT', 'Gene', '207', (97, 100))	('#4060', 'Var', (102, 107))	('#4255', 'Var', (33, 38))	('AKT', 'Gene', (97, 100))	('#2920', 'Var', (79, 84))	('AKT', 'Gene', '207', (74, 77))	('AKT', 'Gene', (74, 77))	('#17366', 'Var', (57, 63))
230998	32099409	Primary antibodies for PTEN (ab32199, 1:2000), Bax (ab32503, 1:2000), Bcl2 (ab32124, 1:2000) and GAPDH (ab8245, 1:5000) were obtained from Abcam (Cambridge, UK).	('Bcl2', 'Gene', '596', (70, 74))	('ab32199', 'Var', (29, 36))	('GAPDH', 'Gene', '2597', (97, 102))	('ab8245', 'Var', (104, 110))	('Bcl2', 'Gene', (70, 74))	('PTEN', 'Gene', (23, 27))	('GAPDH', 'Gene', (97, 102))	('Bax', 'Gene', (47, 50))	('ab32503', 'Var', (52, 59))	('Bax', 'Gene', '581', (47, 50))
230999	32099409	HRP-conjugated secondary antibodies against mouse (AP308P, 1:10,000) and rabbit (AP132, 1:10,000) were purchased from Sigma Aldrich (St. Louis, MI).	('AP308P', 'Var', (51, 57))	('mouse', 'Species', '10090', (44, 49))	('AP132', 'Var', (81, 86))	('rabbit', 'Species', '9986', (73, 79))
231012	32099409	Briefly, 2X105 U87MG or LN-18 cells were seeded in each well of 24-well plates and transfected with the indicated plasmids, pmirGLO-PART1-WT or pmirGLO-PART1-Mut or pmirGLO-PTEN 3'UTR-WT or pmirGLO-PTEN 3'UTR-Mut.	('LN-18', 'CellLine', 'CVCL:0392', (24, 29))	('pmirGLO-PART1-WT', 'Var', (124, 140))	('U87MG', 'CellLine', 'CVCL:0022', (15, 20))	("pmirGLO-PTEN 3'UTR-Mut", 'Var', (190, 212))	('pmirGLO-PART1-Mut', 'Var', (144, 161))	('pmirGLO-PTEN', 'Var', (165, 177))
231033	32099409	To support that PART1 repressed PI3K/AKT activity, a constitutively activated AKT (Myr-AKT) mutant was transfected into U87MG cells.	('Myr-AKT', 'Gene', '207', (83, 90))	('AKT', 'Gene', (87, 90))	('AKT', 'Gene', '207', (37, 40))	('AKT', 'Gene', '207', (87, 90))	('AKT', 'Gene', '207', (78, 81))	('U87MG', 'CellLine', 'CVCL:0022', (120, 125))	('AKT', 'Gene', (37, 40))	('mutant', 'Var', (92, 98))	('AKT', 'Gene', (78, 81))	('Myr-AKT', 'Gene', (83, 90))
231039	32099409	RT-qPCR suggested that PART1 was mainly localized in the cytoplasm (Figure 4A and B), which indicated that PART1 might function as a competing endogenous RNA (ceRNA) in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('PART1', 'Var', (107, 112))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Disease', (169, 175))
231061	32099409	In the cell proliferation assay, we observed that the cell proliferation inhibition induced by PART1 was partially reversed upon PTEN knockdown in U87MG cells and LN-18 cells (Figure 7B and C).	('PART1', 'Gene', (95, 100))	('cell proliferation', 'CPA', (54, 72))	('LN-18', 'CellLine', 'CVCL:0392', (163, 168))	('PTEN', 'Gene', (129, 133))	('knockdown', 'Var', (134, 143))	('U87MG', 'CellLine', 'CVCL:0022', (147, 152))
231062	32099409	In addition, the silencing of PTEN reduced percentage of apoptotic cells in U87MG cells and LN-18 cells transfected with PART1 (Figure 7D and E).	('reduced', 'NegReg', (35, 42))	('LN-18', 'CellLine', 'CVCL:0392', (92, 97))	('PTEN', 'Gene', (30, 34))	('silencing', 'Var', (17, 26))	('U87MG', 'CellLine', 'CVCL:0022', (76, 81))
231075	32099409	It was observed that overexpression of PART1 decreased phosphorylation levels of PI3K and AKT in glioma cells, suggesting that PART1 inactivated PI3K/AKT pathway in glioma.	('inactivated', 'NegReg', (133, 144))	('PART1', 'Var', (127, 132))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Disease', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('AKT', 'Gene', (90, 93))	('decreased', 'NegReg', (45, 54))	('AKT', 'Gene', '207', (150, 153))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('PI3K', 'Pathway', (81, 85))	('AKT', 'Gene', '207', (90, 93))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('AKT', 'Gene', (150, 153))	('phosphorylation levels', 'MPA', (55, 77))	('glioma', 'Disease', (165, 171))
231079	32099409	The downregulation of PTEN in glioma is the consequence of mutation and epigenetic regulation.	('epigenetic regulation', 'Var', (72, 93))	('mutation', 'Var', (59, 67))	('PTEN', 'Gene', (22, 26))	('glioma', 'Disease', (30, 36))	('downregulation', 'NegReg', (4, 18))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
231080	32099409	Dysregulation of miRNA was pivotal for the development of glioma.	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('miR', 'Gene', (17, 20))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('glioma', 'Disease', (58, 64))
231096	29541180	All patients with high MAGE-D4 expression in cancerous tissues experienced significantly reduced median overall survival (OS; 18.00 vs. 33.29 months; P<0.001) and recurrence-free survival (RFS; 12.7 vs. 28.3 months; P<0.001) times compared with those with low MAGE-D4 expression.	('overall survival', 'CPA', (104, 120))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MAGE-D4', 'Gene', '728239', (23, 30))	('MAGE-D4', 'Gene', (260, 267))	('cancerous', 'Disease', 'MESH:D009369', (45, 54))	('high', 'Var', (18, 22))	('MAGE-D4', 'Gene', (23, 30))	('reduced', 'NegReg', (89, 96))	('patients', 'Species', '9606', (4, 12))	('recurrence-free survival', 'CPA', (163, 187))	('cancerous', 'Disease', (45, 54))	('MAGE-D4', 'Gene', '728239', (260, 267))
231098	29541180	Multivariate analysis indicated that high MAGE-D4 protein expression was an important independent prognostic factor for patients with glioma (hazard ratio, 2.384; P=0.005), and was significantly associated with higher grade glioma (P<0.001).	('MAGE-D4', 'Gene', (42, 49))	('associated', 'Reg', (195, 205))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('high', 'Var', (37, 41))	('MAGE-D4', 'Gene', '728239', (42, 49))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('patients', 'Species', '9606', (120, 128))	('glioma', 'Disease', (134, 140))	('glioma', 'Disease', (224, 230))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
231182	29541180	All patients with high MAGE-D4 expression in cancerous tissues had a significantly reduced median OS (18.00 vs. 33.29 months; P<0.001) and RFS (12.7 vs. 28.3 months; P<0.001) time compared with those with low MAGE-D4 expression (Fig.	('MAGE-D4', 'Gene', '728239', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('reduced', 'NegReg', (83, 90))	('MAGE-D4', 'Gene', '728239', (23, 30))	('cancerous', 'Disease', 'MESH:D009369', (45, 54))	('RFS', 'MPA', (139, 142))	('high', 'Var', (18, 22))	('MAGE-D4', 'Gene', (23, 30))	('patients', 'Species', '9606', (4, 12))	('MAGE-D4', 'Gene', (209, 216))	('cancerous', 'Disease', (45, 54))
231183	29541180	In the patients with low-grade (WHO, I-II) glioma, the median OS (26.11 vs. 35.85 months; P=0.013) and RFS (22.7 vs. 37.3 months; P=0.010) times were significantly reduced in patients with high MAGE-D4 protein expression (Fig.	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('high', 'Var', (189, 193))	('MAGE-D4', 'Gene', (194, 201))	('patients', 'Species', '9606', (175, 183))	('I-II) glioma', 'Disease', 'MESH:D005910', (37, 49))	('MAGE-D4', 'Gene', '728239', (194, 201))	('reduced', 'NegReg', (164, 171))	('patients', 'Species', '9606', (7, 15))
231186	29541180	Among these variables, an age of >=38 years, WHO classification of III and IV, Ki-67 expression >=10%, p53 expression >=10% and high MAGE-D4protein expression were considered as significant prognostic parameters via univariate analysis.	('MAGE-D4', 'Gene', '728239', (133, 140))	('Ki-67', 'Gene', (79, 84))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('high', 'Var', (128, 132))	('expression', 'MPA', (148, 158))	('MAGE-D4', 'Gene', (133, 140))
231199	29541180	Finally, patients with high MAGE-D4 expression in cancerous tissues experienced significantly reduced median OS and RFS times compared with those with low MAGE-D4 expression.	('MAGE-D4', 'Gene', (28, 35))	('patients', 'Species', '9606', (9, 17))	('MAGE-D4', 'Gene', (155, 162))	('high', 'Var', (23, 27))	('reduced', 'NegReg', (94, 101))	('cancerous', 'Disease', (50, 59))	('MAGE-D4', 'Gene', '728239', (155, 162))	('MAGE-D4', 'Gene', '728239', (28, 35))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))	('RFS', 'CPA', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
231207	29541180	Patients with high MAGE-A1 and -A11 expression levels exhibited significantly reduced OS times compared with those with low expression levels.	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('MAGE-A1 and -A11', 'Gene', '4100;4110', (19, 35))	('reduced', 'NegReg', (78, 85))	('OS times', 'CPA', (86, 94))
231219	29541180	Secondly, according to the Human Protein Atlas (HPA) Database , as IHC showed Ki-67 staining in nucleus, nucleoli and nuclear , and p53 staining in nucleoplasm .	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('Human', 'Species', '9606', (27, 32))	('HPA', 'Disease', 'MESH:D010661', (48, 51))	('HPA', 'Disease', (48, 51))	('Ki-67', 'Var', (78, 83))
231220	29541180	Distribution of Ki-67 and p53 proteins was all located in the cell nucleus.	('Ki-67', 'Var', (16, 21))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', (26, 29))
231226	29541180	In the present study, there was no significantdifference between high and low MAGE-D4 expressionin high-grade gliomas (WHO, III-IV) for OS and RFS (P>0.05) time, possibly due to the relatively small patient number in the study; thus further studies should use an increased number of patients.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('MAGE-D4', 'Gene', '728239', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('patients', 'Species', '9606', (283, 291))	('low', 'Var', (74, 77))	('patient', 'Species', '9606', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('MAGE-D4', 'Gene', (78, 85))	('patient', 'Species', '9606', (283, 290))
231300	29300332	Changes in Ca2+: affect the cell movement because influencing the actin-myosin mediated contraction; regulate the cytoskeleton influencing the dynamics of tubulin; and control the focal adhesion kinases, thus altering the adhesion of cells to substrates.	('cell movement', 'CPA', (28, 41))	('altering', 'Reg', (209, 217))	('focal', 'Enzyme', (180, 185))	('Ca2+', 'Chemical', 'MESH:D000069285', (11, 15))	('influencing', 'Reg', (50, 61))	('cytoskeleton', 'MPA', (114, 126))	('myosin', 'Gene', (72, 78))	('Changes', 'Var', (0, 7))	('control', 'Reg', (168, 175))	('myosin', 'Gene', '79784', (72, 78))	('affect', 'Reg', (17, 23))	('dynamics of tubulin', 'MPA', (143, 162))	('adhesion', 'MPA', (222, 230))	('rat', 'Species', '10116', (248, 251))	('regulate', 'Reg', (101, 109))
231351	29300332	For example, it has been used to demonstrate that ionizing irradiation of PTEN null gliomas, U-251 MG and U-373 MG, determines an increased Matrigel  invasion in association with an enhanced MMP-2 secretion.	('U-373 MG', 'Var', (106, 114))	('gliomas', 'Disease', (84, 91))	('U-251 MG', 'Var', (93, 101))	('rat', 'Species', '10116', (40, 43))	('enhanced', 'PosReg', (182, 190))	('Matrigel  invasion', 'CPA', (140, 158))	('MMP-2', 'Gene', '4313', (191, 196))	('PTEN', 'Gene', (74, 78))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('PTEN', 'Gene', '5728', (74, 78))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('increased', 'PosReg', (130, 139))	('MMP-2', 'Gene', (191, 196))
231455	29300332	In this regard, continuous, commercially available, human tumour cell lines (e.g., A172, LN229, SF268, U87MG, U118MG and U138MG) have been widely used.	('U87MG', 'Var', (103, 108))	('LN229', 'CellLine', 'CVCL:0393', (89, 94))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('U138MG', 'Var', (121, 127))	('human', 'Species', '9606', (52, 57))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('U118MG', 'Var', (110, 116))	('tumour', 'Disease', (58, 64))	('U118MG', 'CellLine', 'CVCL:0633', (110, 116))	('U87MG', 'CellLine', 'CVCL:0022', (103, 108))	('SF268', 'CellLine', 'CVCL:1689', (96, 101))
231480	29300332	Additionally, using patient derived cells, it has been demonstrated that the adhesion strength of GSC on GASC appears to be dictated by the grade of the tumour of origin, being the strength significantly higher for GSC/GASC pairs derived from low-grade gliomas, with respect to the pairs derived from high-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (253, 259))	('tumour', 'Disease', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (312, 318))	('gliomas', 'Disease', 'MESH:D005910', (253, 260))	('gliomas', 'Phenotype', 'HP:0009733', (253, 260))	('gliomas', 'Disease', (253, 260))	('gliomas', 'Disease', (312, 319))	('patient', 'Species', '9606', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (312, 319))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('gliomas', 'Disease', 'MESH:D005910', (312, 319))	('low-grade', 'Var', (243, 252))	('rat', 'Species', '10116', (62, 65))	('adhesion', 'MPA', (77, 85))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('higher', 'PosReg', (204, 210))
231499	27780202	Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor Genome-wide association studies and candidate gene studies have identified several genetic variants that increase glioma risk.	('variants', 'Var', (174, 182))	('Variants', 'Var', (41, 49))	('increase glioma', 'Disease', (188, 203))	('Glioma', 'Phenotype', 'HP:0009733', (29, 35))	('increase glioma', 'Disease', 'MESH:D005910', (188, 203))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('Tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Glioma', 'Disease', 'MESH:D005910', (29, 35))	('Glioma', 'Disease', (29, 35))
231500	27780202	In this study, we hypothesize that some of the established glioma risk variants induce aberrant DNA methylation in the developing tumor, either locally (gene-specific) or globally (genome-wide).	('variants', 'Var', (71, 79))	('glioma', 'Disease', (59, 65))	('induce', 'Reg', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('DNA methylation', 'MPA', (96, 111))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
231504	27780202	In the pilot dataset, gCIMP was associated with two genetic variants in CDKN2B-AS1, rs1412829 and rs4977756 (9p21.3, p = 8.1 x 10-7 and 4.8 x 10-5, respectively).	('gCIMP', 'Chemical', '-', (22, 27))	('rs4977756', 'Var', (98, 107))	('CDKN2B-AS1', 'Gene', (72, 82))	('gCIMP', 'Disease', (22, 27))	('rs1412829', 'Var', (84, 93))	('CDKN2B-AS1', 'Gene', '100048912', (72, 82))	('associated', 'Reg', (32, 42))	('rs4977756', 'Mutation', 'rs4977756', (98, 107))	('rs1412829', 'Mutation', 'rs1412829', (84, 93))
231505	27780202	We also investigated the relation between glioma risk variants and DNA methylation in the promoter region of genes located within 30 kb of each variant.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('investigated', 'Reg', (8, 20))	('variants', 'Var', (54, 62))	('glioma', 'Disease', (42, 48))
231506	27780202	One association in the pilot dataset, between the TERT risk variant rs2736100 and lower methylation of cg23827991 (in TERT; p = 0.001), was confirmed in the TCGA dataset (p = 0.001).	('TERT', 'Gene', '7015', (118, 122))	('rs2736100', 'Var', (68, 77))	('TERT', 'Gene', '7015', (50, 54))	('cg23827991', 'Gene', (103, 113))	('rs2736100', 'Mutation', 'rs2736100', (68, 77))	('cg23827991', 'Chemical', '-', (103, 113))	('methylation', 'MPA', (88, 99))	('TERT', 'Gene', (50, 54))	('TERT', 'Gene', (118, 122))	('lower', 'NegReg', (82, 87))
231507	27780202	In conclusion, we found an association between rs1412829 and rs4977756 (9p21.3, CDKN2B-AS1) and global DNA methylation pattern in glioma, for which a trend was seen also in the TCGA glioblastoma dataset.	('rs1412829', 'Mutation', 'rs1412829', (47, 56))	('CDKN2B-AS1', 'Gene', (80, 90))	('rs4977756', 'Var', (61, 70))	('association', 'Interaction', (27, 38))	('glioma', 'Disease', (130, 136))	('glioblastoma', 'Disease', (182, 194))	('global DNA methylation pattern', 'MPA', (96, 126))	('glioblastoma', 'Disease', 'MESH:D005909', (182, 194))	('rs1412829', 'Var', (47, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('CDKN2B-AS1', 'Gene', '100048912', (80, 90))	('rs4977756', 'Mutation', 'rs4977756', (61, 70))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
231508	27780202	We also found an association between rs2736100 (in TERT) and levels of methylation at cg23827991 (localized in the same gene, 3.3 kbp downstream of the risk variant), which was validated in the TCGA dataset.	('rs2736100', 'Mutation', 'rs2736100', (37, 46))	('association', 'Interaction', (17, 28))	('TERT', 'Gene', (51, 55))	('cg23827991', 'Chemical', '-', (86, 96))	('cg23827991', 'Gene', (86, 96))	('methylation', 'MPA', (71, 82))	('TERT', 'Gene', '7015', (51, 55))	('rs2736100', 'Var', (37, 46))
231509	27780202	Except for this one association, we did not find strong evidence for gene-specific DNA methylation mediated by glioma risk variants.	('glioma', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('variants', 'Var', (123, 131))
231513	27780202	Some of these variants are located in or nearby genes that are frequently altered by mutations and/or aberrant expression in the tumor, such as EGFR, CDKN2A/B, TERT, and TP53.	('TERT', 'Gene', '7015', (160, 164))	('CDKN2A/B', 'Gene', (150, 158))	('EGFR', 'Gene', (144, 148))	('variants', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('TP53', 'Gene', '7157', (170, 174))	('expression', 'MPA', (111, 121))	('TP53', 'Gene', (170, 174))	('mutations', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CDKN2A/B', 'Gene', '1029;1030', (150, 158))	('TERT', 'Gene', (160, 164))	('tumor', 'Disease', (129, 134))	('EGFR', 'Gene', '1956', (144, 148))	('aberrant', 'Var', (102, 110))
231514	27780202	Aberrant DNA methylation is recognized as an important part of tumorigenesis in several malignancies.	('tumor', 'Disease', (63, 68))	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', (88, 100))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
231517	27780202	gCIMP has been associated with specific molecular and clinical features, such as mutations in IDH1 and TP53, lower grade, and a better outcome.	('TP53', 'Gene', '7157', (103, 107))	('IDH1', 'Gene', (94, 98))	('gCIMP', 'Chemical', '-', (0, 5))	('TP53', 'Gene', (103, 107))	('IDH1', 'Gene', '3417', (94, 98))	('mutations', 'Var', (81, 90))
231518	27780202	Turcan and collegues recently showed that a hypermethylated phenotype can be induced in primary human fibroblasts by expressing mutant IDH1, and suggested that this mutation is the molecular basis of gCIMP.	('IDH1', 'Gene', (135, 139))	('human', 'Species', '9606', (96, 101))	('IDH1', 'Gene', '3417', (135, 139))	('mutant', 'Var', (128, 134))	('Turcan', 'Chemical', '-', (0, 6))	('gCIMP', 'Chemical', '-', (200, 205))
231520	27780202	The aim of this study was to investigate if established glioma risk variants are associated with global DNA methylation pattern of the tumor or with gene-specific promoter DNA methylation.	('variants', 'Var', (68, 76))	('glioma', 'Disease', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('tumor', 'Disease', (135, 140))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('associated', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
231524	27780202	We selected 11 SNPs that have previously been associated with glioma risk in GWAS or candidate gene studies (including rs2736100, rs2252586, rs11979158, rs4295627, rs55705857, rs1412829, rs4977756, rs498872, rs78378222, rs6010620, and rs4809324; S1 Table).	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('rs11979158', 'Mutation', 'rs11979158', (141, 151))	('rs1412829', 'Mutation', 'rs1412829', (176, 185))	('rs4977756', 'Var', (187, 196))	('rs4295627', 'Mutation', 'rs4295627', (153, 162))	('rs4809324', 'Mutation', 'rs4809324', (235, 244))	('rs78378222', 'Var', (208, 218))	('associated', 'Reg', (46, 56))	('rs6010620', 'Mutation', 'rs6010620', (220, 229))	('rs4809324', 'Var', (235, 244))	('rs2252586', 'Var', (130, 139))	('rs2736100', 'Var', (119, 128))	('rs55705857', 'Mutation', 'rs55705857', (164, 174))	('rs11979158', 'Var', (141, 151))	('rs2252586', 'Mutation', 'rs2252586', (130, 139))	('rs78378222', 'Mutation', 'rs78378222', (208, 218))	('rs498872', 'Var', (198, 206))	('rs4977756', 'Mutation', 'rs4977756', (187, 196))	('glioma', 'Disease', (62, 68))	('rs498872', 'Mutation', 'rs498872', (198, 206))	('rs6010620', 'Var', (220, 229))	('rs4295627', 'Var', (153, 162))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('rs2736100', 'Mutation', 'rs2736100', (119, 128))	('rs55705857', 'Var', (164, 174))	('rs1412829', 'Var', (176, 185))
231528	27780202	Based on CNV profiles, we identified tumors that were homozygously deleted in the promoter regions of CDKN2A, CDKN2B, CDKN2B-AS1, and MTAP, and excluded these tumors in analyses of gene-specific methylation in the respective genes (n = 25-35).	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('CDKN2A', 'Gene', '1029', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('CDKN2B', 'Gene', (110, 116))	('CDKN2B', 'Gene', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Disease', (37, 43))	('CDKN2B', 'Gene', '1030', (118, 124))	('CDKN2B', 'Gene', '1030', (110, 116))	('MTAP', 'Gene', (134, 138))	('CDKN2B-AS1', 'Gene', '100048912', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('MTAP', 'Gene', '4507', (134, 138))	('CDKN2B-AS1', 'Gene', (118, 128))	('CDKN2A', 'Gene', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('deleted', 'Var', (67, 74))
231531	27780202	Five SNPs of interest (rs11979158, rs2252586, rs4295627, rs55705857, and rs78378222) were not represented on the chip and were therefore imputed using the software IMPUTE2 with data from the 1000 Genomes Project as the reference population.	('rs4295627', 'Var', (46, 55))	('rs4295627', 'Mutation', 'rs4295627', (46, 55))	('rs2252586', 'Mutation', 'rs2252586', (35, 44))	('rs78378222', 'Mutation', 'rs78378222', (73, 83))	('rs55705857', 'Var', (57, 67))	('rs55705857', 'Mutation', 'rs55705857', (57, 67))	('rs2252586', 'Var', (35, 44))	('rs78378222', 'Var', (73, 83))	('rs11979158', 'Mutation', 'rs11979158', (23, 33))	('rs11979158', 'Var', (23, 33))
231532	27780202	Due to the low imputation info score (<0.85), rs55705857 (8q24.21) and rs78378222 (in TP53, 17p13.1) were excluded from further analysis.	('rs78378222', 'Var', (71, 81))	('rs78378222', 'Mutation', 'rs78378222', (71, 81))	('rs55705857', 'Var', (46, 56))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('rs55705857', 'Mutation', 'rs55705857', (46, 56))
231543	27780202	Five SNPs of interest (rs4295627, rs1412829, rs4977756, rs6010620, and rs4809324) were not genotyped by the Affymetrix array.	('rs6010620', 'Mutation', 'rs6010620', (56, 65))	('rs4809324', 'Var', (71, 80))	('rs6010620', 'Var', (56, 65))	('rs4295627', 'Mutation', 'rs4295627', (23, 32))	('rs1412829', 'Mutation', 'rs1412829', (34, 43))	('rs4295627', 'Var', (23, 32))	('rs4977756', 'Mutation', 'rs4977756', (45, 54))	('rs4977756', 'Var', (45, 54))	('rs4809324', 'Mutation', 'rs4809324', (71, 80))	('rs1412829', 'Var', (34, 43))
231547	27780202	Association between germline genetic variants and genome-wide methylation pattern in the tumor was assessed using Chi-Square test or Fisher's exact test (when expected sample count in a table cell was <5).	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('variants', 'Var', (37, 45))	('Association', 'Interaction', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
231556	27780202	In the pilot dataset, gCIMP status was associated with IDH1 mutation (p = 1.6 x 10-7), oligodendroglial histopathology (p = 0.0015), and strong expression of p53 (indicative of mutation, p = 0.031), and was inversely associated with tumor grade (p = 1.53 x 10-5) and EGFR amplification (p = 0.0014) (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('gCIMP', 'Chemical', '-', (22, 27))	('mutation', 'Var', (60, 68))	('IDH1', 'Gene', '3417', (55, 59))	('p53', 'Gene', '7157', (158, 161))	('oligodendroglial', 'Disease', (87, 103))	('tumor', 'Disease', (233, 238))	('associated', 'Reg', (39, 49))	('EGFR', 'Gene', '1956', (267, 271))	('p53', 'Gene', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('IDH1', 'Gene', (55, 59))	('EGFR', 'Gene', (267, 271))
231558	27780202	Two variants, rs1412829 and rs4977756, both located on chromosome 9p21.3, were associated with the global DNA methylation pattern of the tumor (p = 8.07 x 10-7 and 4.81 x 10-5, respectively).	('global DNA methylation pattern', 'MPA', (99, 129))	('associated', 'Reg', (79, 89))	('tumor', 'Disease', (137, 142))	('rs4977756', 'Mutation', 'rs4977756', (28, 37))	('rs4977756', 'Var', (28, 37))	('rs1412829', 'Mutation', 'rs1412829', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('rs1412829', 'Var', (14, 23))
231559	27780202	An overrepresentation of gCIMP tumors was seen in patients with the rs1412829 AA (non-risk) genotype.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patients', 'Species', '9606', (50, 58))	('rs1412829', 'Mutation', 'rs1412829', (68, 77))	('rs1412829 AA', 'Var', (68, 80))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('overrepresentation', 'PosReg', (3, 21))	('gCIMP', 'Chemical', '-', (25, 30))
231560	27780202	50% of individuals with the AA genotype had a gCIMP tumor, compared to 2.5% and 4.3% of patients with rs1412829 AG and GG genotypes, respectively (Fig 2).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('rs1412829', 'Mutation', 'rs1412829', (102, 111))	('patients', 'Species', '9606', (88, 96))	('rs1412829 AG', 'Var', (102, 114))	('gCIMP', 'Chemical', '-', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
231561	27780202	rs1412829 and rs4977756 are in linkage disequilibrium (D' = 0.89; r2 = 0.74), and the relation between rs4977756 and global DNA methylation pattern was similar to that described for rs1412829 (S2 Fig).	('rs1412829', 'Var', (182, 191))	('rs1412829', 'Var', (0, 9))	('rs4977756', 'Mutation', 'rs4977756', (14, 23))	('global DNA methylation pattern', 'MPA', (117, 147))	('rs1412829', 'Mutation', 'rs1412829', (0, 9))	('rs1412829', 'Mutation', 'rs1412829', (182, 191))	('rs4977756', 'Mutation', 'rs4977756', (103, 112))	('rs4977756', 'Var', (14, 23))	('rs4977756', 'Var', (103, 112))
231562	27780202	An overrepresentation of gCIMP tumors among individuals with the rs1412829 AA genotype was seen also when restricting analyses to glioblastoma patients (n = 60; p = 4.18 x 10-4; S3 Fig) or non-glioblastoma patients (n = 17; p = 0.002; S3 Fig).	('rs1412829', 'Var', (65, 74))	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('glioblastoma', 'Disease', (130, 142))	('non-glioblastoma', 'Disease', (189, 205))	('tumors', 'Disease', (31, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('non-glioblastoma', 'Disease', 'MESH:D005909', (189, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (143, 151))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('overrepresentation', 'PosReg', (3, 21))	('patients', 'Species', '9606', (206, 214))	('rs1412829', 'Mutation', 'rs1412829', (65, 74))	('gCIMP', 'Chemical', '-', (25, 30))	('glioblastoma', 'Disease', (193, 205))
231563	27780202	None of the other seven investigated glioma risk variants were associated with the global DNA methylation pattern of the tumor (all p>0.05; S3 Table).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('variants', 'Var', (49, 57))	('global DNA methylation pattern', 'MPA', (83, 113))	('glioma', 'Disease', (37, 43))	('tumor', 'Disease', (121, 126))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
231565	27780202	The distribution of tumors with high, intermediate and low DNA methylation levels was not statistically significantly different between individuals with rs1412829 AA, AG and GG genotypes in the TCGA dataset (p = 0.137; S3 Table; Fig 2).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('rs1412829', 'Mutation', 'rs1412829', (153, 162))	('rs1412829 AA', 'Var', (153, 165))
231566	27780202	An overrepresentation of gCIMP tumors among individuals with the rs1412829 AA genotype was observed in the TCGA dataset when combining individuals with AG and GG genotypes (pAA vs. AG+GG = 0.048).	('rs1412829', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('overrepresentation', 'PosReg', (3, 21))	('rs1412829', 'Mutation', 'rs1412829', (65, 74))	('gCIMP', 'Chemical', '-', (25, 30))
231567	27780202	When combining the pilot and TCGA data sets, we observed a p-value of 4.35 x 10-4 for the difference in the distribution of tumors with high, intermediate and low DNA methylation between individuals with AA vs AG/GG genotypes.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('methylation', 'Var', (167, 178))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))
231569	27780202	The rs2736100 genotype was associated with methylation at cg23827991 in the pilot data set (p = 0.001) as well as the TCGA 450k dataset (p = 0.001) (Fig 3; Table 2; p-values not corrected for multiple testing).	('rs2736100', 'Var', (4, 13))	('cg23827991', 'Chemical', '-', (58, 68))	('cg23827991', 'Gene', (58, 68))	('rs2736100', 'Mutation', 'rs2736100', (4, 13))	('methylation', 'MPA', (43, 54))
231570	27780202	In general, carriers of the rs2736100 risk allele (C) had lower methylation at cg23827991.	('rs2736100', 'Var', (28, 37))	('lower', 'NegReg', (58, 63))	('cg23827991', 'Chemical', '-', (79, 89))	('rs2736100', 'Mutation', 'rs2736100', (28, 37))	('methylation', 'MPA', (64, 75))	('cg23827991', 'Var', (79, 89))
231572	27780202	The relation between methylation at cg23827991 and TERT mRNA expression was investigated in 67 TCGA subjects for whom these two data types were available.	('TERT', 'Gene', (51, 55))	('TERT', 'Gene', '7015', (51, 55))	('cg23827991', 'Var', (36, 46))	('cg23827991', 'Chemical', '-', (36, 46))
231581	27780202	In line with findings from previous studies, gCIMP status of the tumor was associated with IDH1 mutation, lower tumor grade, histopathology of the tumor, lack of EGFR amplification, and strong p53 staining (indicative of mutation).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('p53', 'Gene', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('mutation', 'Var', (96, 104))	('IDH1', 'Gene', (91, 95))	('p53', 'Gene', '7157', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('gCIMP', 'Chemical', '-', (45, 50))	('IDH1', 'Gene', '3417', (91, 95))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
231582	27780202	Of the nine SNPs we investigated, two were associated with the global DNA methylation pattern of the tumor, rs4977756 and rs1412829, located on chromosome 9p21.3.	('rs1412829', 'Mutation', 'rs1412829', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('global DNA methylation', 'MPA', (63, 85))	('rs4977756', 'Mutation', 'rs4977756', (108, 117))	('rs1412829', 'Var', (122, 131))	('associated', 'Reg', (43, 53))	('rs4977756', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
231586	27780202	Since our pilot data set is small, and differences were smaller in the TCGA data set, it is possible that the observation of overrepresentation of gCIMP tumors among patients carrying the rs1412829 and/or rs4977756 non-risk homozygous (AA) genotypes is a chance finding.	('rs4977756', 'Var', (205, 214))	('rs1412829', 'Mutation', 'rs1412829', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('gCIMP', 'Chemical', '-', (147, 152))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('overrepresentation', 'PosReg', (125, 143))	('rs4977756', 'Mutation', 'rs4977756', (205, 214))	('rs1412829', 'Var', (188, 197))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('patients', 'Species', '9606', (166, 174))
231587	27780202	The genetic variants rs1412829 and rs4977756 are both located on chromosome 9p21.3, within the long non-coding RNA CDKN2B-AS1 (a.k.a.	('CDKN2B-AS1', 'Gene', (115, 125))	('rs1412829', 'Mutation', 'rs1412829', (21, 30))	('rs4977756', 'Mutation', 'rs4977756', (35, 44))	('CDKN2B-AS1', 'Gene', '100048912', (115, 125))	('rs1412829', 'Var', (21, 30))	('rs4977756', 'Var', (35, 44))
231594	27780202	When investigating gene-specific methylation in these genes, we excluded data from 25-35 tumors with homozygous deletion of these genes.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('deletion', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
231595	27780202	When investigating the relation between glioma risk variants and DNA methylation in promoter regions of nearby genes, we found an association between a glioma risk variant localized in TERT, rs2736100, and lower methylation of cg23827991, a CpG probe localized close to the first exon of an alternative TERT transcript (uc003jbz.1).	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('methylation', 'MPA', (212, 223))	('cg23827991', 'Chemical', '-', (227, 237))	('glioma', 'Disease', (152, 158))	('lower', 'NegReg', (206, 211))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('glioma', 'Disease', (40, 46))	('TERT', 'Gene', (185, 189))	('TERT', 'Gene', (303, 307))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('TERT', 'Gene', '7015', (185, 189))	('rs2736100', 'Var', (191, 200))	('TERT', 'Gene', '7015', (303, 307))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('rs2736100', 'Mutation', 'rs2736100', (191, 200))	('cg23827991', 'Var', (227, 237))
231596	27780202	The association between rs2736100 and methylation at cg23827991 has previously been described in other tissue types, including breast, kidney, and both normal and tumor tissue from lung.	('methylation', 'MPA', (38, 49))	('rs2736100', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('breast', 'Disease', (127, 133))	('rs2736100', 'Mutation', 'rs2736100', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('cg23827991', 'Gene', (53, 63))	('kidney', 'Disease', (135, 141))	('cg23827991', 'Chemical', '-', (53, 63))
231598	27780202	Glioma risk SNP rs2736100, or SNPs in strong linkage disequlibrium with rs2736100, were however not investigated.	('rs2736100', 'Mutation', 'rs2736100', (16, 25))	('rs2736100', 'Var', (72, 81))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('rs2736100', 'Mutation', 'rs2736100', (72, 81))	('Glioma', 'Disease', (0, 6))	('rs2736100', 'Var', (16, 25))
231599	27780202	The rs2736100 C allele has been associated with a higher mRNA expression of TERT when measured in gastric cancer, lung cancer and esophageal squamous cell carcinoma as well as normal tissue adjacent to lung and esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (211, 245))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('esophageal squamous cell carcinoma', 'Disease', (130, 164))	('rs2736100', 'Mutation', 'rs2736100', (4, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('rs2736100 C', 'Var', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('mRNA expression', 'MPA', (57, 72))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (211, 245))	('TERT', 'Gene', (76, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (130, 164))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('TERT', 'Gene', '7015', (76, 80))	('gastric cancer', 'Disease', (98, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('lung cancer', 'Disease', (114, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('higher', 'PosReg', (50, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))
231601	27780202	In a limited set of TCGA subjects, we found a trend of a higher TERT mRNA expression in subjects with lower levels of cg23827991 methylation.	('TERT', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (64, 68))	('higher', 'PosReg', (57, 63))	('cg23827991', 'Var', (118, 128))	('cg23827991', 'Chemical', '-', (118, 128))
231604	27780202	A limitation of the present study was the relatively large number of tests performed to assess associations between genetic risk variants and nearby gene promotor methylation in our pilot data (199 SNP/CpG probe combinations), resulting in a large risk of type I errors (false positives).	('type I errors', 'Disease', 'MESH:D005776', (256, 269))	('type I errors', 'Disease', (256, 269))	('associations', 'Interaction', (95, 107))	('variants', 'Var', (129, 137))
231608	27780202	In conclusion, we observed an overrepresentation of gCIMP tumors in patients with the rs1412829 AA (non-risk) genotype (located in CDKN2B-AS1), which was present both in the pilot dataset and the TCGA dataset, although statistically significant in the latter only when combining individuals with AG and GG genotypes.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('CDKN2B-AS1', 'Gene', (131, 141))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('patients', 'Species', '9606', (68, 76))	('overrepresentation', 'PosReg', (30, 48))	('gCIMP', 'Chemical', '-', (52, 57))	('rs1412829', 'Mutation', 'rs1412829', (86, 95))	('rs1412829 AA', 'Var', (86, 98))	('gCIMP', 'Disease', (52, 57))	('CDKN2B-AS1', 'Gene', '100048912', (131, 141))
231609	27780202	We also found an association between glioma risk variant rs2736100 (TERT) and reduced methylation of CpG probe cg23827991 (TERT).	('TERT', 'Gene', (123, 127))	('rs2736100', 'Mutation', 'rs2736100', (57, 66))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('methylation', 'MPA', (86, 97))	('glioma', 'Disease', (37, 43))	('TERT', 'Gene', '7015', (123, 127))	('cg23827991', 'Gene', (111, 121))	('cg23827991', 'Chemical', '-', (111, 121))	('rs2736100', 'Var', (57, 66))	('reduced', 'NegReg', (78, 85))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
231610	27780202	Apart from this, we did not find strong support for our hypothesis that glioma risk variants affect DNA promoter methylation of adjacent genes.	('glioma', 'Disease', (72, 78))	('affect', 'Reg', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('DNA promoter methylation', 'MPA', (100, 124))	('variants', 'Var', (84, 92))
231765	28916782	Among the top-ranked features indicative of poor prognosis are: increased age at diagnosis (rank 3); histologic classification as de novo grade IV glioblastoma (rank 5); loss of chromosome arms 10p and 10q (ranks 2, 4); and deletions of tumor suppressor genes CDKN2A and PTEN (ranks 1, 8).	('tumor', 'Disease', (237, 242))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('CDKN2A', 'Gene', (260, 266))	('deletions', 'Var', (224, 233))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('grade', 'Disease', (138, 143))	('loss', 'Var', (170, 174))	('rank 5', 'Gene', '51479', (161, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('rank 5', 'Gene', (161, 167))	('CDKN2A', 'Gene', '1029', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('increased', 'PosReg', (64, 73))	('PTEN', 'Gene', (271, 275))	('PTEN', 'Gene', '5728', (271, 275))
231766	28916782	The top-ranked features associated with better prognosis included mutations in SMARCA4 (rank 6), IDH1/IDH2 (ranks 9, 10) and in CIC (rank 17).	('mutations', 'Var', (66, 75))	('IDH1', 'Gene', (97, 101))	('CIC', 'Gene', (128, 131))	('IDH2', 'Gene', (102, 106))	('SMARCA4', 'Gene', (79, 86))	('IDH1', 'Gene', '3417', (97, 101))	('SMARCA4', 'Gene', '6597', (79, 86))	('IDH2', 'Gene', '3418', (102, 106))
231797	28916782	Survival of patients diagnosed with infiltrating glioma depends largely on age, histologic grade and classification into three molecular subtypes defined by mutations in the Krebs cycle enzyme isocitrate dehydrogenase (IDH1/IDH2) and co-deletion of chromosome arms 1p and 19q: 1.	('IDH2', 'Gene', '3418', (224, 228))	('co-deletion', 'Var', (234, 245))	('patients', 'Species', '9606', (12, 20))	('IDH1', 'Gene', '3417', (219, 223))	('Krebs', 'Chemical', '-', (174, 179))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('IDH2', 'Gene', (224, 228))	('mutations', 'Var', (157, 166))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1', 'Gene', (219, 223))	('glioma', 'Disease', (49, 55))
231799	28916782	Gliomas with co-deletion of 1p and 19q and mutations in IDH (oligodendroglioma) have the best outcomes, with some patients surviving 10 years or more and 3.	('oligodendroglioma', 'Disease', 'MESH:D009837', (61, 78))	('IDH', 'Gene', (56, 59))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('IDH', 'Gene', '3417', (56, 59))	('mutations', 'Var', (43, 52))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('oligodendroglioma', 'Disease', (61, 78))	('Gliomas', 'Disease', (0, 7))	('co-deletion', 'Var', (13, 24))	('patients', 'Species', '9606', (114, 122))
231800	28916782	Gliomas with IDH mutations that lack co-deletions (IDH-mutant astrocytoma) have intermediate outcomes.	('IDH', 'Gene', '3417', (13, 16))	('astrocytoma', 'Disease', 'MESH:D001254', (62, 73))	('IDH', 'Gene', (51, 54))	('astrocytoma', 'Disease', (62, 73))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('IDH', 'Gene', '3417', (51, 54))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
231801	28916782	Risk backpropagation analysis of our model identified IDH1 and IDH2 mutations (ranks 9, 10) as strongly associated with better prognosis, consistent with the role of these mutations as the primary feature in classifying gliomas.	('IDH2', 'Gene', '3418', (63, 67))	('better', 'PosReg', (120, 126))	('IDH1', 'Gene', (54, 58))	('IDH2', 'Gene', (63, 67))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('IDH1', 'Gene', '3417', (54, 58))	('mutations', 'Var', (68, 77))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('gliomas', 'Disease', (220, 227))
231802	28916782	While our analysis did not explicitly identify 1p and 19q deletions as strongly associated with better prognosis (ranks 45, 233), it did identify CIC mutations, a signature of oligodendrogliomas (CIC mutations occur in more than 50% of oligodendrogliomas), and SMARCA4 mutations, that occur frequently in both the less aggressive oligodendroglioma and IDH-mutant astrocytoma subtypes.	('oligodendroglioma', 'Disease', (330, 347))	('oligodendroglioma', 'Disease', 'MESH:D009837', (176, 193))	('associated', 'Reg', (80, 90))	('IDH', 'Gene', '3417', (352, 355))	('astrocytoma', 'Disease', 'MESH:D001254', (363, 374))	('astrocytoma', 'Disease', (363, 374))	('oligodendrogliomas', 'Disease', (176, 194))	('oligodendroglioma', 'Disease', (176, 193))	('SMARCA4', 'Gene', (261, 268))	('deletions', 'Var', (58, 67))	('mutations', 'Var', (150, 159))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (236, 254))	('mutations', 'Var', (269, 278))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('CIC', 'Gene', (146, 149))	('oligodendroglioma', 'Disease', 'MESH:D009837', (236, 253))	('astrocytoma', 'Phenotype', 'HP:0009592', (363, 374))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('oligodendrogliomas', 'Disease', (236, 254))	('IDH', 'Gene', (352, 355))	('oligodendroglioma', 'Disease', 'MESH:D009837', (330, 347))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (176, 194))	('SMARCA4', 'Gene', '6597', (261, 268))	('glioma', 'Phenotype', 'HP:0009733', (341, 347))	('oligodendroglioma', 'Disease', (236, 253))	('gliomas', 'Phenotype', 'HP:0009733', (247, 254))
231803	28916782	The top-ranked feature associated with poor prognosis in our analysis was deletion of CDKN2A which is strongly associated with the aggressive astrocytomas, as well as with a subset of poor prognosis IDH-mutant astrocytomas that lack broad DNA hypermethylation (GCIMP-low).	('aggressive astrocytomas', 'Disease', 'MESH:D001254', (131, 154))	('CDKN2A', 'Gene', '1029', (86, 92))	('IDH', 'Gene', '3417', (199, 202))	('deletion', 'Var', (74, 82))	('astrocytomas', 'Disease', 'MESH:D001254', (210, 222))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('associated', 'Reg', (111, 121))	('aggressive astrocytomas', 'Disease', (131, 154))	('astrocytomas', 'Disease', 'MESH:D001254', (142, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (142, 153))	('astrocytomas', 'Disease', (210, 222))	('astrocytomas', 'Disease', (142, 154))	('CDKN2A', 'Gene', (86, 92))	('IDH', 'Gene', (199, 202))
231804	28916782	Loss of PTEN (rank 8) is also characteristic of astrocytomas, has been shown to be an early event in gliomagenesis, and related to the loss of its parent chromosome 10 (10q and 10p were ranked 2 and 4, respectively).	('loss', 'NegReg', (135, 139))	('glioma', 'Disease', (101, 107))	('PTEN', 'Gene', (8, 12))	('astrocytomas', 'Disease', 'MESH:D001254', (48, 60))	('PTEN', 'Gene', '5728', (8, 12))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('astrocytomas', 'Disease', (48, 60))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('Loss', 'Var', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
231811	28916782	Although genetic alterations and expression patterns are often strongly associated with primary disease site, common mechanisms of progression are likely shared by many cancers, and deep survival models can benefit from training with augmented datasets that provide additional evidence of these mechanisms.	('cancers', 'Disease', (169, 176))	('genetic alterations', 'Var', (9, 28))	('associated', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
231819	28916782	Significant mutations were identified for inclusion in each dataset (LGG/GBM, KIPAN, BRCA) using a MutSig2CV<= 0.1 q-value threshold.	('mutations', 'Var', (12, 21))	('BRCA', 'Gene', (85, 89))	('BRCA', 'Gene', '672', (85, 89))
231867	28599282	For each individual, conventional MRI images (T1ce/FLAIR), ASL parametric map (CBF), DWI parametric maps (fast ADC, fast f, slow ADC, slow f and Chi-square) and part of DCE parametric maps (9 out of 24 parameters, i.e.	('fast f', 'Var', (116, 122))	('DCE', 'Gene', '1718', (169, 172))	('slow ADC', 'Var', (124, 132))	('c', 'Gene', '3561', (6, 7))	('c', 'Gene', '3561', (182, 183))	('c', 'Gene', '3561', (21, 22))	('slow f', 'Var', (134, 140))	('c', 'Gene', '3561', (48, 49))	('DCE', 'Gene', (169, 172))	('c', 'Gene', '3561', (72, 73))	('c', 'Gene', '3561', (98, 99))	('ASL', 'Gene', (59, 62))	('ASL', 'Gene', '435', (59, 62))
231913	28599282	Compared to default models using PolyKernel and c=1, the classifying accuracy had a slight increase of 0.015 for both LGG and HGG classification as well as grade II, III and IV glioma discrimination by using RBFKernel and c=22/23.	('c', 'Gene', '3561', (75, 76))	('IV glioma', 'Disease', 'MESH:D005910', (174, 183))	('c', 'Gene', '3561', (48, 49))	('c', 'Gene', '3561', (138, 139))	('IV glioma', 'Disease', (174, 183))	('c', 'Gene', '3561', (70, 71))	('c', 'Gene', '3561', (93, 94))	('RBFKernel', 'Var', (208, 217))	('c', 'Gene', '3561', (57, 58))	('LGG', 'Disease', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('HGG', 'Disease', (126, 129))	('c', 'Gene', '3561', (187, 188))	('c', 'Gene', '3561', (71, 72))	('c', 'Gene', '3561', (130, 131))	('c', 'Gene', '3561', (222, 223))
231978	28599282	Advanced MRI scans included three dimensional ASL (3D-ASL), multi b-value DWI and DCE-MRI in transverse planes.	('ASL', 'Gene', (46, 49))	('ASL', 'Gene', (54, 57))	('c', 'Gene', '3561', (14, 15))	('c', 'Gene', '3561', (21, 22))	('ASL', 'Gene', '435', (46, 49))	('ASL', 'Gene', '435', (54, 57))	('DCE', 'Gene', '1718', (82, 85))	('multi b-value', 'Var', (60, 73))	('3D-ASL', 'Gene', (51, 57))	('DCE', 'Gene', (82, 85))	('3D-ASL', 'Gene', '435', (51, 57))	('c', 'Gene', '3561', (5, 6))
232130	27800481	Established correlation of gadolinium, a marker of BBB breakdown, with PpIX concentrations in glioma tissues, suggests that BBB disruption is the leading cause of increased 5-ALA accumulation in malignant cells.	('5-ALA accumulation', 'MPA', (173, 191))	('rat', 'Species', '10116', (83, 86))	('glioma', 'Disease', (94, 100))	('increased', 'PosReg', (163, 172))	('gadolinium', 'Chemical', 'MESH:D005682', (27, 37))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('BBB', 'Gene', (124, 127))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('5-ALA', 'Chemical', 'MESH:C000614854', (173, 178))	('disruption', 'Var', (128, 138))	('PpIX', 'Chemical', 'MESH:C028025', (71, 75))
232183	27800481	Variations in dose and timing of fluorescein administration may result in a variable degree of fluorescence in line with other factors such as fluorescein extravasation in surgically perturbed tissues, brain swelling, and unknown fluorescein distribution.	('fluorescein', 'Chemical', 'MESH:D019793', (143, 154))	('fluorescein', 'Chemical', 'MESH:D019793', (230, 241))	('result', 'Reg', (64, 70))	('brain swelling', 'Phenotype', 'HP:0002181', (202, 216))	('rat', 'Species', '10116', (53, 56))	('fluorescein extravasation', 'Phenotype', 'HP:0025320', (143, 168))	('Variations', 'Var', (0, 10))	('brain swelling', 'Disease', (202, 216))	('brain swelling', 'Disease', 'MESH:D001929', (202, 216))	('fluorescein', 'Chemical', 'MESH:D019793', (33, 44))	('fluorescence', 'MPA', (95, 107))
232196	27800481	Novel cancer-selective alkylphosphocholine analog fluorophores CLR1501 (green with excitation/emission peaks 500/517 nm) and CLR1502 (NIR with excitation/emission peaks 760/778 nm) were reported to have higher tumor-to-normal brain fluorescence than 5-ALA (7.23 +- 1.63 and 9.28 +- 1.08 vs. 4.81 +- 0.92, respectively) in a mouse xenograft glioblastoma model.	('alkylphosphocholine', 'Chemical', '-', (23, 42))	('5-ALA', 'Chemical', 'MESH:C000614854', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('glioblastoma', 'Disease', (340, 352))	('glioblastoma', 'Disease', 'MESH:D005909', (340, 352))	('tumor', 'Disease', (210, 215))	('NIR', 'Chemical', '-', (134, 137))	('mouse', 'Species', '10090', (324, 329))	('higher', 'PosReg', (203, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (340, 352))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('CLR1501', 'Var', (63, 70))	('CLR1502', 'Var', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
232216	27800481	Two clinical trials of IRD 800CW-labeled probes for visualization of breast cancer and familial adenomatous polyposis have been completed, and other trials are recruiting patients for the use of the Cy 5.5-labeled probe.	('800CW', 'Chemical', '-', (27, 32))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('familial adenomatous polyposis', 'Disease', (87, 117))	('patients', 'Species', '9606', (171, 179))	('breast cancer', 'Disease', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (87, 117))	('IRD', 'Var', (23, 26))	('Cy', 'Chemical', 'MESH:D003545', (199, 201))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (96, 117))
232219	27800481	ZW800-1 has great promise as it shows a higher tumor-to-background ratio than IRDye800-CW and Cy5.5 in vitro and in vivo (17.2 vs. 5.1 and 2.7, respectively).	('Cy5', 'Chemical', 'MESH:C085321', (94, 97))	('rat', 'Species', '10116', (67, 70))	('higher', 'PosReg', (40, 46))	('ZW800', 'Chemical', '-', (0, 5))	('ZW800-1', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
232230	27800481	This probe showed specific binding to tumor cells due to the AS1411 aptamer, which targets nucleolin.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('nucleolin', 'Gene', (91, 100))	('binding', 'Interaction', (27, 34))	('AS1411', 'Chemical', 'MESH:C513936', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('nucleolin', 'Gene', '4691', (91, 100))	('AS1411', 'Var', (61, 67))
232247	27800481	Magnetic NH2-cross-linked iron oxide nanoparticles labeled with Cy5.5 (32 nm in diameter) produced clear tumor border demarcation and co-localization on MRI imaging in a rat gliosarcoma model.	('iron oxide', 'Chemical', 'MESH:C000499', (26, 36))	('gliosarcoma', 'Disease', (174, 185))	('MR', 'Disease', 'MESH:C564570', (153, 155))	('rat', 'Species', '10116', (170, 173))	('tumor border demarcation', 'Disease', 'MESH:D001882', (105, 129))	('Cy5.5', 'Var', (64, 69))	('Cy5', 'Chemical', 'MESH:C085321', (64, 67))	('tumor border demarcation', 'Disease', (105, 129))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('gliosarcoma', 'Disease', 'MESH:D018316', (174, 185))
232288	27800481	Quantitative PpIX detection elevated the diagnostic sensitivity of low-grade gliomas (67% in 12 cases) to the level of qualitative wide-field detection of high-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (166, 173))	('PpIX', 'Chemical', 'MESH:C028025', (13, 17))	('PpIX', 'Gene', (13, 17))	('gliomas', 'Disease', (77, 84))	('gliomas', 'Disease', (166, 173))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('elevated', 'PosReg', (28, 36))	('detection', 'Var', (18, 27))
232349	32316566	Mutation of the isocitrate dehydrogenase 1/2 (IDH1/2-) gene was shown to correlate with seizures in low-grade gliomas due to the production of D-2-hydroxyglutarate which is similar to glutamate, an excitatory neurotransmitter that initiates NMDA-receptor related pathways.	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', (110, 117))	('seizures', 'Phenotype', 'HP:0001250', (88, 96))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('IDH1', 'Gene', (46, 50))	('seizures', 'Disease', (88, 96))	('Mutation', 'Var', (0, 8))	('IDH1', 'Gene', '3417', (46, 50))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('seizure', 'Phenotype', 'HP:0001250', (88, 95))	('correlate', 'Reg', (73, 82))	('glutamate', 'Chemical', 'MESH:D018698', (184, 193))	('seizures', 'Disease', 'MESH:D012640', (88, 96))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (143, 163))
232364	32316566	Isocitrate-dehydrogenase 1 (IDH1)-mutation status was assessed in 109/160 patients in the local department of neuropathology via immunostaining against the R132H mutation in all patients.	('IDH1', 'Gene', '3417', (28, 32))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (178, 186))	('Isocitrate-dehydrogenase 1', 'Gene', (0, 26))	('R132H', 'Var', (156, 161))	('Isocitrate-dehydrogenase 1', 'Gene', '3417', (0, 26))	('R132H', 'Mutation', 'rs121913500', (156, 161))	('IDH1', 'Gene', (28, 32))
232471	32161911	We did include 9421/3 (pilocytic astrocytoma) and 9400/3 (astrocytoma NOS low grade) in the group of LGG as they correspond to indolent glial tumors and behave as low grade in term of survival.	('astrocytoma', 'Disease', 'MESH:D001254', (58, 69))	('glial tumors', 'Disease', 'MESH:D005910', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('pilocytic astrocytoma', 'Disease', (23, 44))	('astrocytoma', 'Disease', (58, 69))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('glial tumors', 'Disease', (136, 148))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (23, 44))	('astrocytoma', 'Disease', 'MESH:D001254', (33, 44))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('astrocytoma', 'Disease', (33, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (33, 44))	('9400/3', 'Var', (50, 56))
232482	32161911	We observe that the Asian ethnicity was significantly in higher proportion (20.7%, 23/111) in the malignant germ cell tumors than the Asian ethnicity proportion (8.0%, 237/2964) in all other tumors (P < .001).	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('Asian ethnicity', 'Var', (20, 35))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('germ cell tumors', 'Phenotype', 'HP:0100728', (108, 124))	('germ cell tumor', 'Phenotype', 'HP:0100728', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
232518	32161911	However, we did find a significant increase in the proportion of Asian ethnicity patients into the malignant germ cell tumors group compared to other groups of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('increase', 'PosReg', (35, 43))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('germ cell tumor', 'Phenotype', 'HP:0100728', (109, 124))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('Asian', 'Var', (65, 70))	('germ cell tumors', 'Phenotype', 'HP:0100728', (109, 125))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
232542	32161911	Overall, 27.5% of all the children having cancer from CYP-C database in Canada had been enrolled in a therapeutic trial during the similar period 2001-2012, up to 48.8% for acute lymphoblastic leukemia in contrast to only 10.3% for the CNS tumors group.	('CYP-C database', 'Var', (54, 68))	('CNS tumors', 'Disease', 'MESH:D016543', (236, 246))	('CNS tumor', 'Phenotype', 'HP:0100006', (236, 245))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (173, 201))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('CNS tumors', 'Disease', (236, 246))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (173, 201))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('leukemia', 'Phenotype', 'HP:0001909', (193, 201))	('children', 'Species', '9606', (26, 34))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (179, 201))	('acute lymphoblastic leukemia', 'Disease', (173, 201))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
232570	31475440	It has reported that unsaturated fatty acid, cholesterol esters and phosphatidylcholine are only present in high-grade gliomas through magnetic resonance spectroscopy (NMR) analysis.6, 7 At present, more and more studies focus on revealing the biological phenotype and molecular mechanism that altered lipid component leads to in glioma.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('cholesterol esters', 'Chemical', 'MESH:D002788', (45, 63))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('altered', 'Var', (294, 301))	('phosphatidylcholine', 'Chemical', 'MESH:D010713', (68, 87))	('glioma', 'Disease', 'MESH:D005910', (330, 336))	('gliomas', 'Disease', (119, 126))	('glioma', 'Phenotype', 'HP:0009733', (330, 336))	('unsaturated fatty acid', 'Chemical', 'MESH:D005231', (21, 43))	('glioma', 'Disease', (119, 125))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('leads to', 'Reg', (318, 326))	('glioma', 'Disease', (330, 336))
232599	31475440	As shown in Figure 3, higher level of risk scores preferred to distribute in higher grade, classical, mesenchymal, IDH-wt, MGMT promoter unmethylated or 1p/19q non-codeleted patients.	('patients', 'Species', '9606', (174, 182))	('1p/19q', 'Var', (153, 159))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('MGMT', 'Gene', (123, 127))	('mesenchymal', 'CPA', (102, 113))	('MGMT', 'Gene', '4255', (123, 127))
232601	31475440	In both cohorts, Kaplan-Meier analysis showed that cases with high-risk score had shorter overall survival than the low-risk ones in most stratified patients (Figure 4, Figure S5).	('shorter', 'NegReg', (82, 89))	('patients', 'Species', '9606', (149, 157))	('high-risk score', 'Var', (62, 77))	('overall survival', 'MPA', (90, 106))
232602	31475440	The similar trend occurred in GBM or 1p/19q codeleted cases despite of no statistical difference (Figure 4B,G).	('GBM', 'Disease', (30, 33))	('1p/19q', 'Var', (37, 43))	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('GBM', 'Disease', 'MESH:D005909', (30, 33))
232650	29747434	Moreover, the HPV-E5, E6 or E7 proteins stimulate the cyclooxygenase (COX)-2 inflammatory pathway which, as for EGF, counteracts the apoptosis of epithelial cells and promotes their proliferation.	('proliferation', 'CPA', (182, 195))	('HPV', 'Species', '10566', (14, 17))	('EGF', 'Gene', (112, 115))	('stimulate', 'PosReg', (40, 49))	('promotes', 'PosReg', (167, 175))	('HPV-E5', 'Var', (14, 20))	('EGF', 'Gene', '1950', (112, 115))	('E7 proteins', 'Var', (28, 39))
232664	29747434	The probability of having persistent HR-HPV infection augments progressively with higher viral load and it is favored by E5, E6 or E7 activities permitting HR-HPV escape from host immune surveillance.	('HR-HPV', 'Disease', 'MESH:D030361', (156, 162))	('HR-HPV', 'Disease', 'MESH:D030361', (37, 43))	('viral load', 'MPA', (89, 99))	('augments', 'PosReg', (54, 62))	('HR-HPV infection', 'Disease', (37, 53))	('HR-HPV', 'Disease', (156, 162))	('HR-HPV', 'Disease', (37, 43))	('E7 activities', 'Var', (131, 144))	('HR-HPV infection', 'Disease', 'MESH:D030361', (37, 53))
232665	29747434	In particular, both the E5 and E7 proteins of HR-HPV can impair major histocompatibility complex (MHC)-restricted presentation of viral peptides to cytotoxic or helper T lymphocytes.	('HR-HPV', 'Disease', 'MESH:D030361', (46, 52))	('presentation of viral peptides', 'MPA', (114, 144))	('HR-HPV', 'Disease', (46, 52))	('E7 proteins', 'Var', (31, 42))	('impair', 'NegReg', (57, 63))
232668	29747434	HPV integration into cellular DNA causes the deletion of the HPV-E2 gene and the consequent overexpression of HPV-E6 or E7.	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (110, 113))	('overexpression', 'PosReg', (92, 106))	('HPV-E2', 'Gene', (61, 67))	('deletion', 'Var', (45, 53))	('HPV', 'Species', '10566', (61, 64))
232672	29747434	In fact, as a result of HPV-E6 or E7 overexpression caused by E2 gene deletion, the disturbance of cervical epithelial cell maturation and stratification is exacerbated.	('deletion', 'Var', (70, 78))	('overexpression', 'PosReg', (37, 51))	('HPV', 'Species', '10566', (24, 27))	('exacerbated', 'PosReg', (157, 168))
232680	29747434	In particular, following p53 degradation promoted by HPV-E6, p53-induced genes encoding for angiogenesis inhibitors, such as thrombospondin (TSP)-1, are no longer transcribed; whereas, the p53-repressed genes of angiogenic factors, including vascular endothelial growth factor (VEGF), are up-regulated (Figure 1).	('p53', 'Gene', (25, 28))	('VEGF', 'Gene', (278, 282))	('p53', 'Gene', '7157', (25, 28))	('thrombospondin (TSP)-1', 'Gene', '7057', (125, 147))	('HPV-E6', 'Var', (53, 59))	('p53', 'Gene', '7157', (189, 192))	('up-regulated', 'PosReg', (289, 301))	('vascular endothelial growth factor', 'Gene', '7422', (242, 276))	('HPV', 'Species', '10566', (53, 56))	('VEGF', 'Gene', '7422', (278, 282))	('thrombospondin (TSP)-1', 'Gene', (125, 147))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('vascular endothelial growth factor', 'Gene', (242, 276))	('p53', 'Gene', (189, 192))
232681	29747434	Of interest, also HPV-E5 can promote VEGF expression and this is due to E5 capability of triggering both EGF and COX-2 signaling.	('COX-2 signaling', 'MPA', (113, 128))	('promote', 'PosReg', (29, 36))	('EGF', 'Gene', (105, 108))	('HPV', 'Species', '10566', (18, 21))	('EGF', 'Gene', '1950', (105, 108))	('VEGF', 'Gene', (37, 41))	('EGF', 'Gene', (38, 41))	('HPV-E5', 'Var', (18, 24))	('EGF', 'Gene', '1950', (38, 41))	('VEGF', 'Gene', '7422', (37, 41))
232696	29747434	In addition, HIV-1 Tat may also favor the angiogenic switch of high-grade CIN, either because of its direct angiogenic effects or, again, via the up-regulation of HR-HPV E6 or E7 expression.	('up-regulation', 'PosReg', (146, 159))	('CIN', 'Disease', 'MESH:D007674', (74, 77))	('E7 expression', 'Var', (176, 189))	('HR-HPV E6', 'Disease', (163, 172))	('angiogenic switch', 'CPA', (42, 59))	('favor', 'PosReg', (32, 37))	('HIV-1', 'Species', '11676', (13, 18))	('HR-HPV E6', 'Disease', 'MESH:D030361', (163, 172))	('CIN', 'Phenotype', 'HP:0032242', (74, 77))	('angiogenic', 'CPA', (108, 118))	('CIN', 'Disease', (74, 77))
232724	29747434	In particular, cancer cells synthesize MMPs following the activation of oncogenes, the inactivation of onco-suppressor proteins, the stimulation by growth factors or inflammatory mediators, the generation of reactive oxygen species, and/or the presence of hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (256, 263))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (208, 231))	('MMPs', 'Gene', (39, 43))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;4319;4322;4323', (39, 43))	('hypoxia', 'Disease', (256, 263))	('stimulation', 'PosReg', (133, 144))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('inactivation', 'Var', (87, 99))	('onco-suppressor proteins', 'Protein', (103, 127))	('activation', 'PosReg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('oncogenes', 'Gene', (72, 81))
232737	29747434	In particular, the protective role of some MMPs in specific types and clinical stages of tumor is likely to result from MMP occasional/paradoxical capability of inhibiting tumor angiogenesis via the degradation of angiogenic growth factor receptors, and/or the generation of anti-angiogenesis molecules deriving from the cleavage of ECM components.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('degradation', 'MPA', (199, 210))	('MMP', 'Var', (120, 123))	('MMPs', 'Gene', (43, 47))	('tumor', 'Disease', (172, 177))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;4319;4322;4323', (43, 47))	('inhibiting', 'NegReg', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('angiogenic', 'Protein', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
232745	29747434	In fact, phosphorylated AKT activates transcription factors promoting mmp gene expression (Figure 1).	('AKT', 'Gene', (24, 27))	('mmp gene', 'Gene', (70, 78))	('AKT', 'Gene', '207', (24, 27))	('phosphorylated', 'Var', (9, 23))	('transcription', 'Protein', (38, 51))	('activates', 'PosReg', (28, 37))	('promoting', 'PosReg', (60, 69))
232760	29747434	One of the many consequences resulting from the functional impairment of the cellular proteasome promoted by the HIV-PI is the intracellular accumulation of the sterol regulatory element-binding protein (SREBP) 1 transcription factor.	('HIV-PI', 'Var', (113, 119))	('intracellular', 'MPA', (127, 140))	('HIV', 'Species', '12721', (113, 116))	('cellular', 'Protein', (77, 85))
232762	29747434	Another unexpected target of HIV-PI is the glucose transporter (GLUT)-4 (Figure 2), whose inhibition by HIV-PI halts glucose uptake by adipocytes, eventually causing insulin-resistance and diabetes.	('HIV', 'Species', '12721', (104, 107))	('HIV-PI', 'Gene', (104, 110))	('glucose', 'Chemical', 'MESH:D005947', (117, 124))	('insulin', 'Gene', '3630', (166, 173))	('diabetes', 'Disease', (189, 197))	('diabetes', 'Disease', 'MESH:D003920', (189, 197))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))	('insulin-resistance', 'Phenotype', 'HP:0000855', (166, 184))	('inhibition', 'Var', (90, 100))	('HIV', 'Species', '12721', (29, 32))	('halts', 'NegReg', (111, 116))	('causing', 'Reg', (158, 165))	('insulin', 'Gene', (166, 173))	('glucose uptake by adipocytes', 'MPA', (117, 145))
232776	29747434	In agreement with these findings, results from preclinical (in vitro and in vivo) and clinical studies indicate that HIV-PI can directly inhibit tumor cell survival, growth or invasion and angiogenesis in experimental models devoid of HIV and immune cells.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('HIV', 'Species', '12721', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('inhibit', 'NegReg', (137, 144))	('growth', 'CPA', (166, 172))	('HIV', 'Species', '12721', (235, 238))	('HIV-PI', 'Var', (117, 123))	('angiogenesis', 'CPA', (189, 201))	('invasion', 'CPA', (176, 184))
232777	29747434	In particular, due to their inhibitory effect on the function of the cellular proteasome, HIV-PI cause an increase in the intracellular amounts of cell cycle inhibitors or onco-suppressors, hence leading to the growth arrest and/or death of a variety of human tumor cells (Figure 2).	('tumor', 'Disease', (260, 265))	('growth arrest', 'Disease', 'MESH:D006323', (211, 224))	('HIV', 'Species', '12721', (90, 93))	('intracellular amounts of', 'MPA', (122, 146))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('human', 'Species', '9606', (254, 259))	('growth arrest', 'Phenotype', 'HP:0001510', (211, 224))	('death', 'CPA', (232, 237))	('leading to', 'Reg', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('increase', 'PosReg', (106, 114))	('HIV-PI', 'Var', (90, 96))	('growth arrest', 'Disease', (211, 224))
232779	29747434	As to the uterine cervix, the HIV-PI indinavir (IDV), ritonavir (RTV) or lopinavir have been shown to reduce the viability of HR-HPV-transformed epithelial cells.	('viability', 'CPA', (113, 122))	('RTV', 'Chemical', 'MESH:D019438', (65, 68))	('ritonavir', 'Chemical', 'MESH:D019438', (54, 63))	('reduce', 'NegReg', (102, 108))	('IDV', 'Chemical', 'MESH:D019469', (48, 51))	('HIV-PI', 'Var', (30, 36))	('HR-HPV', 'Disease', 'MESH:D030361', (126, 132))	('HIV', 'Species', '12721', (30, 33))	('HR-HPV', 'Disease', (126, 132))	('indinavir', 'Chemical', 'MESH:D019469', (37, 46))	('uterine cervix', 'Phenotype', 'HP:0030160', (10, 24))	('lopinavir', 'Chemical', 'MESH:D061466', (73, 82))
232795	29747434	These findings are consistent with results obtained in other experimental models, which indicate that inhibition of EGF-induced AKT phosphorylation, or Fra-1 silencing, reduces cellular invasion via the down-regulation of MMP-9 expression.	('cellular invasion', 'CPA', (177, 194))	('Fra-1', 'Gene', '8061', (152, 157))	('Fra-1', 'Gene', (152, 157))	('inhibition', 'Var', (102, 112))	('AKT', 'Gene', (128, 131))	('reduces', 'NegReg', (169, 176))	('EGF', 'Gene', (116, 119))	('MMP-9', 'Gene', '4318', (222, 227))	('silencing', 'NegReg', (158, 167))	('EGF', 'Gene', '1950', (116, 119))	('MMP-9', 'Gene', (222, 227))	('down-regulation', 'NegReg', (203, 218))	('AKT', 'Gene', '207', (128, 131))	('expression', 'MPA', (228, 238))
232819	29747434	Thus, HIV-PI could counteract the early stage of HPV infection, when cervical epithelial cells are not heavily transformed, HPV-DNA is episomic and the expression of E6, E7 and other HPV proteins is low.	('HIV', 'Species', '12721', (6, 9))	('HPV-DNA', 'Var', (124, 131))	('HPV', 'Species', '10566', (124, 127))	('HPV', 'Species', '10566', (49, 52))	('HPV infection', 'Disease', 'MESH:D030361', (49, 62))	('HPV proteins', 'Disease', 'MESH:D030361', (183, 195))	('HPV', 'Species', '10566', (183, 186))	('HPV proteins', 'Disease', (183, 195))	('low', 'NegReg', (199, 202))	('HPV infection', 'Disease', (49, 62))	('expression', 'MPA', (152, 162))	('E6, E7', 'Gene', '25479186', (166, 172))
232826	29747434	In fact, HIV-PI directly inhibit events leading to CIN onset and progression including the growth or invasion of HPV-positive epithelial cells and angiogenesis.	('CIN', 'Disease', 'MESH:D007674', (51, 54))	('HIV-PI', 'Var', (9, 15))	('CIN', 'Phenotype', 'HP:0032242', (51, 54))	('angiogenesis', 'CPA', (147, 159))	('HIV', 'Species', '12721', (9, 12))	('CIN', 'Disease', (51, 54))	('inhibit', 'NegReg', (25, 32))	('growth', 'CPA', (91, 97))	('HPV', 'Species', '10566', (113, 116))	('invasion', 'CPA', (101, 109))
232828	29747434	Consistently, as for HIV-positive patients, HIV-PI causes the regression or the complete remission of high-grade CIN lesions also in HIV-negative women.	('CIN lesions', 'Disease', (113, 124))	('HIV-PI', 'Var', (44, 50))	('HIV', 'Species', '12721', (44, 47))	('patients', 'Species', '9606', (34, 42))	('HIV', 'Species', '12721', (133, 136))	('CIN', 'Phenotype', 'HP:0032242', (113, 116))	('CIN lesions', 'Disease', 'MESH:D051437', (113, 124))	('HIV', 'Species', '12721', (21, 24))	('women', 'Species', '9606', (146, 151))
232836	29747434	Noteworthy, either SQV or RTV down-regulates MMP-9 expression, thereby blocking CIN cell invasiveness; whereas, IDV reduces MT1-MMP synthesis, thus impairing MMP-2 functional activation and angiogenesis.	('reduces', 'NegReg', (116, 123))	('MT1-MMP', 'Gene', '4323', (124, 131))	('expression', 'MPA', (51, 61))	('CIN cell invasiveness', 'Disease', 'MESH:D009362', (80, 101))	('down-regulates', 'NegReg', (30, 44))	('MMP-9', 'Gene', '4318', (45, 50))	('MMP-2', 'Gene', (158, 163))	('MMP-9', 'Gene', (45, 50))	('IDV', 'Var', (112, 115))	('CIN', 'Phenotype', 'HP:0032242', (80, 83))	('IDV', 'Chemical', 'MESH:D019469', (112, 115))	('impairing', 'NegReg', (148, 157))	('angiogenesis', 'CPA', (190, 202))	('blocking', 'NegReg', (71, 79))	('functional', 'MPA', (164, 174))	('MT1-MMP', 'Gene', (124, 131))	('RTV', 'Chemical', 'MESH:D019438', (26, 29))	('MMP-2', 'Gene', '4313', (158, 163))	('CIN cell invasiveness', 'Disease', (80, 101))
232844	29285249	In vitro, lentivirus-mediated shRNA knockdown of RDH10 suppressed glioma cell proliferation, survival, and invasiveness and cell cycle progression.	('glioma', 'Disease', (66, 72))	('RDH10', 'Gene', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('cell cycle progression', 'CPA', (124, 146))	('knockdown', 'Var', (36, 45))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('survival', 'CPA', (93, 101))	('suppressed', 'NegReg', (55, 65))
232845	29285249	In vivo, RDH10 knockdown reduced glioma growth in nude mice.	('nude mice', 'Species', '10090', (50, 59))	('reduced', 'NegReg', (25, 32))	('RDH10', 'Gene', (9, 14))	('knockdown', 'Var', (15, 24))	('glioma growth', 'Disease', (33, 46))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioma growth', 'Disease', 'MESH:D005910', (33, 46))
232846	29285249	Microarray analysis revealed that RDH10 silencing reduces expression of TNFRSF12A (Fn14), TNFSF12 (TWEAK), TRAF3, IKBKB (IKK-beta), and BMPR2, while it increases expression of TRAF1, NFKBIA (IkappaBalpha), NFKBIE (IkappaBepsilon), and TNFAIP3.	('IkappaBalpha', 'Gene', '4792', (191, 203))	('expression', 'MPA', (58, 68))	('NFKBIE', 'Gene', '4794', (206, 212))	('reduces', 'NegReg', (50, 57))	('silencing', 'Var', (40, 49))	('NFKBIE', 'Gene', (206, 212))	('BMPR2', 'Gene', (136, 141))	('TNFSF12', 'Gene', (90, 97))	('TRAF1', 'Gene', (176, 181))	('Fn14', 'Gene', (83, 87))	('TWEAK', 'Gene', (99, 104))	('increases', 'PosReg', (152, 161))	('TNFSF12', 'Gene', '8742', (90, 97))	('TRAF1', 'Gene', '7185', (176, 181))	('IkappaBepsilon', 'Gene', '4794', (214, 228))	('TRAF3', 'Gene', '7187', (107, 112))	('NFKBIA', 'Gene', (183, 189))	('IkappaBepsilon', 'Gene', (214, 228))	('IKBKB', 'Gene', (114, 119))	('NFKBIA', 'Gene', '4792', (183, 189))	('TNFRSF12A', 'Gene', '51330', (72, 81))	('RDH10', 'Gene', (34, 39))	('IKK-beta', 'Gene', '3551', (121, 129))	('IKBKB', 'Gene', '3551', (114, 119))	('TWEAK', 'Gene', '8742', (99, 104))	('TNFRSF12A', 'Gene', (72, 81))	('BMPR2', 'Gene', '659', (136, 141))	('Fn14', 'Gene', '51330', (83, 87))	('TNFAIP3', 'Gene', '7128', (235, 242))	('IKK-beta', 'Gene', (121, 129))	('IkappaBalpha', 'Gene', (191, 203))	('expression', 'MPA', (162, 172))	('TNFAIP3', 'Gene', (235, 242))	('TRAF3', 'Gene', (107, 112))
232872	29285249	These results showed that the cumulative survival rate was remarkably lower in glioma patients with higher RDH10 expression than in those with lower RDH10 expression (**P < 0.01) (Table 2, Figure 1D).	('glioma', 'Disease', (79, 85))	('patients', 'Species', '9606', (86, 94))	('cumulative survival rate', 'CPA', (30, 54))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('lower', 'NegReg', (70, 75))	('expression', 'Var', (113, 123))	('higher', 'PosReg', (100, 106))	('RDH10', 'Gene', (107, 112))
232879	29285249	To establish glioma cell lines with suppressed RDH10 expression, glioma cells were treated with RDH10-shRNA or scrambled (Scr)-shRNA viruses and RDH10 gene and protein levels were analyzed by real-time PCR (qPCR) and western blotting, respectively.	('suppressed', 'NegReg', (36, 46))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Disease', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('RDH10', 'Gene', (47, 52))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('RDH10-shRNA', 'Var', (96, 107))	('glioma', 'Disease', (13, 19))
232884	29285249	Therefore, we used flow cytometry and Annexin V-APC to assess apoptosis in U87 and U251 cells treated with RDH10-shRNA.	('Annexin V', 'Gene', (38, 47))	('U251', 'CellLine', 'CVCL:0021', (83, 87))	('RDH10-shRNA', 'Var', (107, 118))	('Annexin V', 'Gene', '308', (38, 47))
232885	29285249	The percentage of apoptotic U251 cells also significantly increased following RDH10-shRNA treatment compared with Scr-shRNA (12.04 +- 1.12 % vs 1.67 +- 0.12%, respectively; P = 0.0036) (Figure 3D), indicating that RDH10 may have an anti-apoptotic role in glioma cells.	('increased', 'PosReg', (58, 67))	('U251', 'CellLine', 'CVCL:0021', (28, 32))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('RDH10-shRNA', 'Var', (78, 89))	('apoptotic U251 cells', 'CPA', (18, 38))	('glioma', 'Disease', (255, 261))
232888	29285249	RDH10-shRNA significantly inhibited cell invasion ability of U87 and U251 cells.	('cell invasion ability of U87', 'CPA', (36, 64))	('U251', 'CellLine', 'CVCL:0021', (69, 73))	('RDH10-shRNA', 'Var', (0, 11))	('inhibited', 'NegReg', (26, 35))
232890	29285249	These results indicate that RDH10 knockdown inhibits cell invasion ability in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioma', 'Disease', (78, 84))	('RDH10', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))	('inhibits', 'NegReg', (44, 52))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
232891	29285249	To study whether RDH10 silencing affects the growth of glioma cells in vivo, U87 cells transfected with RDH10-shRNA or scrambled-shRNA were inoculated into nude mice to establish xenograft tumor model.	('glioma', 'Disease', (55, 61))	('nude mice', 'Species', '10090', (156, 165))	('xenograft tumor', 'Disease', 'MESH:D009369', (179, 194))	('silencing', 'NegReg', (23, 32))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('xenograft tumor', 'Disease', (179, 194))	('RDH10', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('RDH10-shRNA', 'Var', (104, 115))
232893	29285249	Furthermore, both tumor weight and fluorescence density were significantly lower in the RDH10-shRNA group than in the control Scr-shRNA group (Figure 4B-4C, n=10, P=0.0017 and 0.011, respectively).	('lower', 'NegReg', (75, 80))	('tumor', 'Disease', (18, 23))	('RDH10-shRNA', 'Var', (88, 99))	('fluorescence density', 'MPA', (35, 55))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
232895	29285249	To investigate the mechanisms of how RDH10 regulates glioma progression, we performed whole-genome expression microarray on U-87 cells expressing either Scr-shRNA or RDH10-shRNA.	('RDH10-shRNA', 'Var', (166, 177))	('glioma', 'Disease', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('U-87', 'CellLine', 'CVCL:0022', (124, 128))
232896	29285249	According to the Ingenuity Pathway Analysis (IPA) database, RDH10 knockdown affected expression of genes involved in cancer, apoptosis, growth and proliferation, motility and cell cycle (Figure 5B and 5C).	('expression of', 'MPA', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('RDH10', 'Gene', (60, 65))	('motility', 'CPA', (162, 170))	('growth', 'CPA', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('affected', 'Reg', (76, 84))	('knockdown', 'Var', (66, 75))	('cell cycle', 'CPA', (175, 185))
232897	29285249	Furthermore, RDH10 knockdown significantly repressed several key cancer pathways including TWEAK, TNFR1 and P53 (Figure 5D), indicating that RDH10 regulates malignant phenotypes in human glioma.	('TWEAK', 'Gene', '8742', (91, 96))	('human', 'Species', '9606', (181, 186))	('P53', 'Gene', '7157', (108, 111))	('knockdown', 'Var', (19, 28))	('glioma', 'Disease', (187, 193))	('TNFR1', 'Gene', '7132', (98, 103))	('TWEAK', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('RDH10', 'Gene', (13, 18))	('repressed', 'NegReg', (43, 52))	('regulates', 'Reg', (147, 156))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('P53', 'Gene', (108, 111))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('TNFR1', 'Gene', (98, 103))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
232899	29285249	Our microarray analysis indicated that the TWEAK-NF-kappaB pathway was inhibited after RDH10 knockdown (Figure 5D and 6A).	('knockdown', 'Var', (93, 102))	('TWEAK', 'Gene', '8742', (43, 48))	('inhibited', 'NegReg', (71, 80))	('NF-kappaB', 'Gene', '4790', (49, 58))	('TWEAK', 'Gene', (43, 48))	('NF-kappaB', 'Gene', (49, 58))	('RDH10', 'Gene', (87, 92))
232900	29285249	Further analysis of gene and protein levels by qPCR and western blotting validated the microarray data; compared with the control Scr-shRNA group, RDH10 silencing reduced expression of TNFRSF12A (TWEAKR, Fn14), TNFS12 (TWEAK), TRAF3, IKBKB (IKK-beta), TGFBR1, and BMPR2, while it increased expression of TRAF1, MAP3K14 (NIK), NFKBIA (IkBalpha), NFKBIE (IkBepsilon), TNFAIP3, GADD45A, and CDKN1A (Figures 6B-6D).	('TWEAKR', 'Gene', (196, 202))	('BMPR2', 'Gene', (264, 269))	('TNFAIP3', 'Gene', '7128', (366, 373))	('TRAF1', 'Gene', (304, 309))	('Fn14', 'Gene', (204, 208))	('TNFAIP3', 'Gene', (366, 373))	('IkBalpha', 'Gene', '4792', (334, 342))	('TRAF1', 'Gene', '7185', (304, 309))	('IKBKB', 'Gene', (234, 239))	('increased', 'PosReg', (280, 289))	('TGFBR1', 'Gene', '7046', (252, 258))	('TNFRSF12A', 'Gene', '51330', (185, 194))	('TGFBR1', 'Gene', (252, 258))	('NFKBIE', 'Gene', '4794', (345, 351))	('IKBKB', 'Gene', '3551', (234, 239))	('GADD45A', 'Gene', (375, 382))	('TNFRSF12A', 'Gene', (185, 194))	('NFKBIE', 'Gene', (345, 351))	('TRAF3', 'Gene', '7187', (227, 232))	('MAP3K14', 'Gene', (311, 318))	('TWEAK', 'Gene', '8742', (219, 224))	('CDKN1A', 'Gene', (388, 394))	('GADD45A', 'Gene', '1647', (375, 382))	('BMPR2', 'Gene', '659', (264, 269))	('Fn14', 'Gene', '51330', (204, 208))	('TWEAK', 'Gene', '8742', (196, 201))	('CDKN1A', 'Gene', '1026', (388, 394))	('IKK-beta', 'Gene', '3551', (241, 249))	('NIK', 'Gene', (320, 323))	('NFKBIA', 'Gene', (326, 332))	('RDH10', 'Gene', (147, 152))	('expression', 'MPA', (171, 181))	('IkBalpha', 'Gene', (334, 342))	('NFKBIA', 'Gene', '4792', (326, 332))	('TWEAK', 'Gene', (196, 201))	('TWEAK', 'Gene', (219, 224))	('reduced', 'NegReg', (163, 170))	('silencing', 'Var', (153, 162))	('MAP3K14', 'Gene', '9020', (311, 318))	('IKK-beta', 'Gene', (241, 249))	('NIK', 'Gene', '9020', (320, 323))	('TWEAKR', 'Gene', '51330', (196, 202))	('TRAF3', 'Gene', (227, 232))	('expression', 'MPA', (290, 300))
232904	29285249	We found that increased apoptosis (Figures 7A, 7B) and impaired cellular proliferation (Figure 7C) induced by RDH10 knockdown could be partially rescued by fusicoccin, thus supporting the direct link between RDH10 and NF-kappaB.	('increased', 'PosReg', (14, 23))	('fusicoccin', 'Chemical', 'MESH:C007808', (156, 166))	('NF-kappaB', 'Gene', (218, 227))	('knockdown', 'Var', (116, 125))	('cellular proliferation', 'CPA', (64, 86))	('apoptosis', 'CPA', (24, 33))	('NF-kappaB', 'Gene', '4790', (218, 227))	('impaired', 'NegReg', (55, 63))	('RDH10', 'Gene', (110, 115))
232908	29285249	Reports of lung cancer showed that RDH10 mutations were common in malignant non-small-cell lung cancer.	('RDH10', 'Gene', (35, 40))	('mutations', 'Var', (41, 50))	('common', 'Reg', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Disease', (91, 102))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
232917	29285249	In addition, high RDH10 expression was associated with malignant progression and poor prognosis in glioma patients, indicating that RDH10 may regulate human glioma development and progression.	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('human', 'Species', '9606', (151, 156))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioma', 'Disease', (99, 105))	('associated', 'Reg', (39, 49))	('patients', 'Species', '9606', (106, 114))	('regulate', 'Reg', (142, 150))	('glioma', 'Disease', (157, 163))	('malignant progression', 'CPA', (55, 76))	('RDH10', 'Gene', (18, 23))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('progression', 'CPA', (180, 191))
232927	29285249	Our data demonstrate that RDH10 silencing suppresses TNFRSF12A (TWEAKR, Fn14), TNFSF12 (TWEAK), TRAF3, IKBKB (IKKbeta), TGFBR1, and BMPR2 expression, while it increases TRAF1, MAP3K14 (NIK), NFKBIA (IkappaBalpha), NFKBIE (IkappaBepsilon), TNFAIP3, GADD45A, and CDKN1A expression (Figures 6A-6C).	('TNFRSF12A', 'Gene', '51330', (53, 62))	('NFKBIE', 'Gene', (214, 220))	('IkappaBalpha', 'Gene', (199, 211))	('MAP3K14', 'Gene', '9020', (176, 183))	('IKKbeta', 'Gene', (110, 117))	('TRAF3', 'Gene', '7187', (96, 101))	('NIK', 'Gene', '9020', (185, 188))	('silencing', 'Var', (32, 41))	('suppresses', 'NegReg', (42, 52))	('TNFRSF12A', 'Gene', (53, 62))	('TWEAK', 'Gene', (88, 93))	('expression', 'MPA', (138, 148))	('IkappaBalpha', 'Gene', '4792', (199, 211))	('TRAF1', 'Gene', (169, 174))	('TWEAK', 'Gene', '8742', (64, 69))	('TNFAIP3', 'Gene', '7128', (239, 246))	('Fn14', 'Gene', '51330', (72, 76))	('TNFAIP3', 'Gene', (239, 246))	('TRAF1', 'Gene', '7185', (169, 174))	('BMPR2', 'Gene', '659', (132, 137))	('TRAF3', 'Gene', (96, 101))	('TWEAK', 'Gene', (64, 69))	('IkappaBepsilon', 'Gene', '4794', (222, 236))	('increases', 'PosReg', (159, 168))	('expression', 'MPA', (268, 278))	('NFKBIA', 'Gene', (191, 197))	('TWEAKR', 'Gene', '51330', (64, 70))	('IKKbeta', 'Gene', '3551', (110, 117))	('NFKBIA', 'Gene', '4792', (191, 197))	('MAP3K14', 'Gene', (176, 183))	('CDKN1A', 'Gene', (261, 267))	('IkappaBepsilon', 'Gene', (222, 236))	('TWEAKR', 'Gene', (64, 70))	('CDKN1A', 'Gene', '1026', (261, 267))	('TNFSF12', 'Gene', (79, 86))	('GADD45A', 'Gene', (248, 255))	('RDH10', 'Gene', (26, 31))	('Fn14', 'Gene', (72, 76))	('IKBKB', 'Gene', (103, 108))	('TNFSF12', 'Gene', '8742', (79, 86))	('TGFBR1', 'Gene', (120, 126))	('BMPR2', 'Gene', (132, 137))	('GADD45A', 'Gene', '1647', (248, 255))	('TGFBR1', 'Gene', '7046', (120, 126))	('NFKBIE', 'Gene', '4794', (214, 220))	('NIK', 'Gene', (185, 188))	('TWEAK', 'Gene', '8742', (88, 93))	('IKBKB', 'Gene', '3551', (103, 108))
232933	29285249	Our results show that RDH10 knockdown inhibits glioma cell proliferation, survival, cell cycle, and invasion.	('survival', 'CPA', (74, 82))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('RDH10', 'Gene', (22, 27))	('inhibits', 'NegReg', (38, 46))	('glioma', 'Disease', (47, 53))	('cell cycle', 'CPA', (84, 94))	('invasion', 'CPA', (100, 108))	('knockdown', 'Var', (28, 37))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
232945	29285249	Antibodies were the following: RDH10 (ab174340, Abcam, Cambridge, UK), CDKN1A (ab7960, Abcam), BIRC3 (ab32059, Abcam), BMPR2 (ab130206, Abcam), NFKBIA (ab7217, Abcam), TGFBR1 (ab31013, Abcam), GADD45A (ab180768, Abcam) and GAPDH (sc-32233, Santa Cruz Biotechnology, Dallas, TX, USA).	('BMPR2', 'Gene', (119, 124))	('GADD45A', 'Gene', (193, 200))	('CDKN1A', 'Gene', (71, 77))	('NFKBIA', 'Gene', '4792', (144, 150))	('GAPDH', 'Gene', '2597', (223, 228))	('GAPDH', 'Gene', (223, 228))	('CDKN1A', 'Gene', '1026', (71, 77))	('BMPR2', 'Gene', '659', (119, 124))	('GADD45A', 'Gene', '1647', (193, 200))	('BIRC3', 'Gene', (95, 100))	('BIRC3', 'Gene', '330', (95, 100))	('ab31013', 'Var', (176, 183))	('TGFBR1', 'Gene', (168, 174))	('NFKBIA', 'Gene', (144, 150))	('TGFBR1', 'Gene', '7046', (168, 174))	('ab130206', 'Var', (126, 134))
232949	29285249	For NF-kappaB activation, agonist fusicoccin was added 24 hours after cells were treated with RDH10-shRNA or Scr-shRNA lentivirus at a final concentration of 20 muM.	('activation', 'PosReg', (14, 24))	('NF-kappaB', 'Gene', '4790', (4, 13))	('fusicoccin', 'Chemical', 'MESH:C007808', (34, 44))	('NF-kappaB', 'Gene', (4, 13))	('RDH10-shRNA', 'Var', (94, 105))
232971	28740449	Univariate analysis revealed a statistically significant association between 5-ALA fluorescence and the isocitrate dehydrogenase 1 (IDH1) status, 1p19q loss of heterozygosity (LOH), the MIB-1 labeling index, and the tumor margin, -heterogeneity, and -contrast enhancement on MRI scans (p < 0.001, p = 0.003, p = 0.007, p = 0.046, p = 0.021, and p = 0.002, respectively).	('MIB-1', 'Gene', '57534', (186, 191))	('tumor', 'Disease', (216, 221))	('5-ALA', 'Chemical', 'MESH:C000614854', (77, 82))	('5-ALA fluorescence', 'MPA', (77, 95))	('loss of', 'NegReg', (152, 159))	('1p19q', 'Var', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('MIB-1', 'Gene', (186, 191))	('men', 'Species', '9606', (267, 270))	('isocitrate dehydrogenase 1', 'Gene', (104, 130))	('isocitrate dehydrogenase 1', 'Gene', '3417', (104, 130))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
232977	28740449	The IDH1 mutation status is more prognostic for overall survival than are standard histological criteria that differentiate high-grade astrocytomas.	('mutation', 'Var', (9, 17))	('astrocytomas', 'Disease', (135, 147))	('prognostic', 'Reg', (33, 43))	('overall', 'MPA', (48, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (135, 146))	('IDH1', 'Gene', (4, 8))	('astrocytomas', 'Disease', 'MESH:D001254', (135, 147))
232978	28740449	Also, the prognosis of IDH1 mutant glioblastoma is considerably better than of IDH1 wild-type anaplastic astrocytoma and glioblastoma, and methylation of the O-6-methylguanine DNA methyltransferase (MGMT) promoter in diffuse gliomas is a predictive epigenetic marker of the responsiveness to alkylating agents such as temozolomide.	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('O-6-methylguanine DNA methyltransferase', 'Gene', '4255', (158, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))	('MGMT', 'Gene', '4255', (199, 203))	('temozolomide', 'Chemical', 'MESH:D000077204', (318, 330))	('gliomas', 'Disease', (225, 232))	('glioblastoma', 'Disease', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('O-6-methylguanine DNA methyltransferase', 'Gene', (158, 197))	('gliomas', 'Disease', 'MESH:D005910', (225, 232))	('astrocytoma', 'Disease', 'MESH:D001254', (105, 116))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('glioblastoma', 'Disease', (121, 133))	('MGMT', 'Gene', (199, 203))	('astrocytoma', 'Disease', (105, 116))	('methylation', 'Var', (139, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('mutant', 'Var', (28, 34))	('better', 'PosReg', (64, 70))	('gliomas', 'Phenotype', 'HP:0009733', (225, 232))	('IDH1 mutant', 'Var', (23, 34))
233011	28740449	IDH1 mutation was confirmed by immunohistochemical analysis using R132H antibody or by direct sequencing.	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('R132H', 'Mutation', 'rs121913500', (66, 71))	('R132H', 'Var', (66, 71))
233036	28740449	As shown in Table 3, among the 60 diffuse gliomas, 13 (22%) harbored IDH1 mutations.	('harbored', 'Reg', (60, 68))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('mutations', 'Var', (74, 83))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('IDH1', 'Gene', (69, 73))	('gliomas', 'Disease', (42, 49))
233038	28740449	Of the 13 tumors with IDH1 mutations, 2 (15%) manifested visible fluorescence, the other 11 did not.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('fluorescence', 'MPA', (65, 77))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('IDH1', 'Gene', (22, 26))
233039	28740449	Univariate analysis revealed a statistically significant association between 5-ALA fluorescence and the IDH1 status (mutated, non-mutated), 1p19q LOH, MIB-1, and the margin, heterogeneity, and contrast enhancement of the tumors (p < 0.001, p = 0.003, p = 0.007, p = 0.046, p = 0.021, and p = 0.002, respectively); neither the patient age nor the MGMT methylation status was significantly associated.	('5-ALA', 'Chemical', 'MESH:C000614854', (77, 82))	('patient', 'Species', '9606', (326, 333))	('tumors', 'Disease', (221, 227))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('men', 'Species', '9606', (209, 212))	('MIB-1', 'Gene', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('significant association', 'Reg', (45, 68))	('MGMT', 'Gene', (346, 350))	('1p19q LOH', 'Var', (140, 149))	('MGMT', 'Gene', '4255', (346, 350))	('5-ALA', 'MPA', (77, 82))	('MIB-1', 'Gene', '57534', (151, 156))
233050	28740449	showed that in tumor cells the IDH mutation may lead to the accumulation of tricarboxylic acid (TCA) cycle metabolites.	('IDH', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('IDH', 'Gene', '3417', (31, 34))	('TCA', 'Chemical', 'MESH:D014233', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mutation', 'Var', (35, 43))	('lead to', 'Reg', (48, 55))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (76, 94))
233053	28740449	A comparison of wild-type- and IDH1-mutant U87MG cell lines showed that mutated states of IDH1 are linked to enhance 5-ALA fluorescence.	('IDH1', 'Gene', (90, 94))	('mutated', 'Var', (72, 79))	('U87MG', 'CellLine', 'CVCL:0022', (43, 48))	('5-ALA', 'Chemical', 'MESH:C000614854', (117, 122))	('5-ALA fluorescence', 'MPA', (117, 135))	('enhance', 'PosReg', (109, 116))
233054	28740449	Paradoxically, glioma tissue harboring IDH1 mutations accumulated high levels of 2-hydroxyglutarate (2HG) while the level of other TCA cycle metabolites, including alpha-ketoglutarate, malate, fumarate, succinate, and isocitrate, was not significantly altered.	('succinate', 'Chemical', 'MESH:D019802', (203, 212))	('IDH1', 'Gene', (39, 43))	('glioma', 'Disease', (15, 21))	('malate', 'MPA', (185, 191))	('mutations', 'Var', (44, 53))	('accumulated', 'PosReg', (54, 65))	('isocitrate', 'Chemical', 'MESH:C034219', (218, 228))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (164, 183))	('fumarate', 'Chemical', 'MESH:D005650', (193, 201))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (81, 99))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('malate', 'Chemical', 'MESH:C030298', (185, 191))	('TCA', 'Chemical', 'MESH:D014233', (131, 134))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))
233055	28740449	These observations suggest that IDH1 mutant gliomas do not involve the activation of heme biosynthesis via activation of the TCA cycle.	('IDH1', 'Gene', (32, 36))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('heme', 'Chemical', 'MESH:D006418', (85, 89))	('mutant', 'Var', (37, 43))	('gliomas', 'Disease', (44, 51))	('TCA', 'Chemical', 'MESH:D014233', (125, 128))	('TCA cycle', 'Enzyme', (125, 134))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
233058	28740449	We hypothesize that the acquisition of IDH1 mutations by low-grade gliomas upgrades their cell protection from oxidative injury.	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('upgrades', 'PosReg', (75, 83))	('IDH1', 'Gene', (39, 43))	('gliomas', 'Disease', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('oxidative injury', 'Disease', 'MESH:D004194', (111, 127))	('mutations', 'Var', (44, 53))	('oxidative injury', 'Disease', (111, 127))	('cell protection', 'CPA', (90, 105))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
233063	28740449	reported that the messenger RNA level of HO-1 and of ATP-binding cassette transporter G2 (ABCG2), a transporter of porphyrins from the cytoplasm to the extracellular space across the plasma membrane, was markedly increased when HepG2 cells were exposed to PPIX and visible light.	('PPIX', 'Var', (256, 260))	('HO-1', 'Gene', '3162', (41, 45))	('HepG2', 'CellLine', 'CVCL:0027', (228, 233))	('ABCG2', 'Gene', (90, 95))	('ABCG2', 'Gene', '9429', (90, 95))	('ATP-binding cassette transporter G2', 'Gene', (53, 88))	('ATP-binding cassette transporter G2', 'Gene', '9429', (53, 88))	('HO-1', 'Gene', (41, 45))	('increased', 'PosReg', (213, 222))	('messenger RNA level', 'MPA', (18, 37))	('PPIX', 'Chemical', 'MESH:C028025', (256, 260))
233065	28740449	Although our study population was small, 22% of our 60 patients manifested IDH1 mutations.	('patients', 'Species', '9606', (55, 63))	('IDH1', 'Gene', (75, 79))	('manifested', 'Reg', (64, 74))	('mutations', 'Var', (80, 89))
233066	28740449	As in earlier studies, the incidence of the IDH1 mutation was highest in patients with WHO grade II gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('IDH1', 'Gene', (44, 48))	('II gliomas', 'Disease', 'MESH:D005910', (97, 107))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('patients', 'Species', '9606', (73, 81))	('mutation', 'Var', (49, 57))	('highest', 'Reg', (62, 69))	('II gliomas', 'Disease', (97, 107))
233067	28740449	While there might be a difference in the frequency of IDH1 mutations between the Japanese and other populations, of our 8 WHO grade II gliomas, 75% were 5-ALA fluorescence-negative, a finding similar to that reported by others.	('IDH1', 'Gene', (54, 58))	('II gliomas', 'Disease', 'MESH:D005910', (132, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('mutations', 'Var', (59, 68))	('5-ALA', 'Chemical', 'MESH:C000614854', (153, 158))	('II gliomas', 'Disease', (132, 142))
233072	28740449	They also stated that the molecular subclassification of brain tumors identified important glioma subgroups whose prognosis is favorable and that mutations in IDH1/2, TP53, ATRX, and a 1p19q co-deletion suffice for the accurate molecular classification of diffuse gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('glioma', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('TP53', 'Gene', '7157', (167, 171))	('ATRX', 'Gene', (173, 177))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('brain tumors', 'Phenotype', 'HP:0030692', (57, 69))	('diffuse', 'Disease', (256, 263))	('ATRX', 'Gene', '546', (173, 177))	('tumors', 'Disease', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('glioma', 'Disease', (264, 270))	('gliomas', 'Disease', (264, 271))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('TP53', 'Gene', (167, 171))	('mutations', 'Var', (146, 155))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('1p19q', 'Var', (185, 190))	('IDH1/2', 'Gene', '3417;3418', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('IDH1/2', 'Gene', (159, 165))
233083	28535583	While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp).	('CIC', 'Gene', '23152', (193, 196))	('glioblastomas', 'Disease', (46, 59))	('telomerase reverse transcriptase', 'Gene', (232, 264))	('mutations', 'Var', (175, 184))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))	('IDH', 'Gene', '3417', (106, 109))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (127, 145))	('TP53', 'Gene', '7157', (111, 115))	('astrocytomas', 'Disease', (6, 18))	('telomerase reverse transcriptase', 'Gene', '7015', (232, 264))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', (188, 191))	('TERTp', 'Gene', (266, 271))	('TERTp', 'Gene', '7015', (266, 271))	('FUBP1', 'Gene', (198, 203))	('CIC', 'Gene', (193, 196))	('ATRX', 'Gene', (121, 125))	('1p/19q', 'Var', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('oligodendrogliomas', 'Disease', (127, 145))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('ATRX', 'Gene', '546', (121, 125))	('IDH', 'Gene', '3417', (23, 26))	('IDH', 'Gene', '3417', (188, 191))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('astrocytomas', 'Disease', 'MESH:D001254', (6, 18))	('astrocytoma', 'Phenotype', 'HP:0009592', (6, 17))	('TP53', 'Gene', (111, 115))	('FUBP1', 'Gene', '8880', (198, 203))	('mutational', 'Var', (85, 95))	('IDH', 'Gene', (106, 109))
233084	28535583	IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp.	('PDGFRA', 'Gene', (143, 149))	('IDH', 'Gene', (65, 68))	('PDGFRA', 'Gene', '5156', (143, 149))	('glioblastomas', 'Disease', (23, 36))	('NF1', 'Gene', '4763', (155, 158))	('IDH', 'Gene', (0, 3))	('glioblastomas', 'Disease', 'MESH:D005909', (23, 36))	('IDH', 'Gene', '3417', (65, 68))	('EGFR', 'Gene', (121, 125))	('NF1', 'Gene', (155, 158))	('CDKN2A/B', 'Gene', (133, 141))	('IDH', 'Gene', '3417', (0, 3))	('PTEN', 'Gene', (127, 131))	('lack', 'NegReg', (47, 51))	('glioblastomas', 'Phenotype', 'HP:0012174', (23, 36))	('mutations', 'Var', (52, 61))	('mutations', 'Var', (170, 179))	('TERTp', 'Gene', (183, 188))	('CDKN2A/B', 'Gene', '1029;1030', (133, 141))	('TERTp', 'Gene', '7015', (183, 188))	('PTEN', 'Gene', '5728', (127, 131))
233085	28535583	High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('H3F3A', 'Gene', (92, 97))	('ATRX', 'Gene', (99, 103))	('gliomas', 'Disease', (56, 63))	('IDH', 'Gene', '3417', (126, 129))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('mutations', 'Var', (79, 88))	('DAXX', 'Gene', '1616', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('ATRX', 'Gene', '546', (99, 103))	('gliomas', 'Disease', (21, 28))	('H3F3A', 'Gene', '3020', (92, 97))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('DAXX', 'Gene', (109, 113))	('IDH', 'Gene', (126, 129))
233086	28535583	In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes.	('men', 'Species', '9606', (203, 206))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (109, 138))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('ganglioglioma', 'Disease', 'MESH:D018303', (144, 157))	('activating', 'PosReg', (183, 193))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (42, 64))	('FGFR1', 'Gene', (222, 227))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (86, 107))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('pleomorphic xanthoastrocytoma', 'Disease', (109, 138))	('pilocytic astrocytoma', 'Disease', (86, 107))	('ganglioglioma', 'Disease', (144, 157))	('astrocytoma', 'Phenotype', 'HP:0009592', (127, 138))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('neuroepithelial tumors', 'Disease', (42, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('FGFR1', 'Gene', '2260', (222, 227))	('mutations', 'Var', (170, 179))	('BRAF', 'Gene', '673', (216, 220))	('BRAF', 'Gene', (216, 220))	('MYB', 'Gene', '4602', (233, 236))	('children', 'Species', '9606', (68, 76))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (42, 64))	('MYB', 'Gene', (233, 236))
233087	28535583	Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', (10, 16))	('mesenchymal tumors', 'Disease', (117, 135))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('embryonal tumor', 'Phenotype', 'HP:0002898', (73, 88))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (52, 71))	('ependymomas', 'Disease', (26, 37))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('embryonal tumors', 'Phenotype', 'HP:0002898', (73, 89))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('embryonal tumors', 'Disease', (73, 89))	('embryonal tumors', 'Disease', 'MESH:D009373', (73, 89))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('genetic alterations', 'Var', (151, 170))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('neuronal', 'Disease', (39, 47))	('CNS tumors', 'Disease', (6, 16))	('CNS tumors', 'Disease', 'MESH:D009369', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (117, 135))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', (83, 89))	('meningothelial', 'Disease', (91, 105))	('men', 'Species', '9606', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('ependymomas', 'Disease', 'MESH:D004806', (26, 37))
233108	28535583	The signaling pathways that are mainly involved in GBM are RTK/RAS/phosphoinositide 3-kinase (PI3K) signaling, p53 signaling, and Rb signaling, which were identified through analyses of common mutations and copy number variations (CNV) in gliomas.	('copy number variations', 'Var', (207, 229))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('gliomas', 'Disease', (239, 246))	('RTK/RAS/phosphoinositide 3-kinase', 'Gene', (59, 92))	('RTK/RAS/phosphoinositide 3-kinase', 'Gene', '5290', (59, 92))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
233110	28535583	Mutations in IDH1 and IDH2 were discovered by whole exome sequencing (WES) of GBMs, thus altering the classification of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('altering', 'Reg', (89, 97))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('gliomas', 'Disease', (120, 127))
233111	28535583	IDH1 or IDH2 mutations are found in both astrocytic and oligodendroglial tumors since they act as a starting point for gliomagenesis.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('IDH2', 'Gene', (8, 12))	('astrocytic and oligodendroglial tumors', 'Disease', 'MESH:D001254', (41, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('IDH2', 'Gene', '3418', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('glioma', 'Disease', (119, 125))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', '3417', (0, 4))
233114	28535583	For example, oligodendrogliomas are characterized by a codeletion in 1p/19q, mutations in IDH, and the promoter region of the gene encoding telomerase reverse transcriptase (TERTp).	('TERTp', 'Gene', (174, 179))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('TERTp', 'Gene', '7015', (174, 179))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('IDH', 'Gene', (90, 93))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (13, 31))	('IDH', 'Gene', '3417', (90, 93))	('mutations', 'Var', (77, 86))	('oligodendrogliomas', 'Disease', (13, 31))	('telomerase reverse transcriptase', 'Gene', (140, 172))	('telomerase reverse transcriptase', 'Gene', '7015', (140, 172))
233115	28535583	Furthermore, grade 2 and grade 3 astrocytic tumors are characterized by ATRX and TP53 mutations, while IDH-wildtype (primary) GBMs are characterized by the CNV of EGFR, PTEN, CDKN2A/B, PDGFRA, and MET genes, in addition to a lack of mutations in IDH and a codeletion in 1p/19q.	('ATRX', 'Gene', '546', (72, 76))	('astrocytic tumors', 'Disease', (33, 50))	('IDH', 'Gene', (246, 249))	('EGFR', 'Gene', (163, 167))	('astrocytic tumors', 'Disease', 'MESH:D001254', (33, 50))	('TP53', 'Gene', '7157', (81, 85))	('CDKN2A/B', 'Gene', (175, 183))	('IDH', 'Gene', (103, 106))	('IDH', 'Gene', '3417', (246, 249))	('mutations', 'Var', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('PTEN', 'Gene', (169, 173))	('IDH', 'Gene', '3417', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CDKN2A/B', 'Gene', '1029;1030', (175, 183))	('TP53', 'Gene', (81, 85))	('PDGFRA', 'Gene', (185, 191))	('PDGFRA', 'Gene', '5156', (185, 191))	('PTEN', 'Gene', '5728', (169, 173))	('ATRX', 'Gene', (72, 76))
233116	28535583	Even in tumors that are morphologically similar, those with mutations in IDH and a codeletion in 1p/19q differ in the treatment response and prognosis compared with tumors without these two molecular alterations.	('prognosis', 'CPA', (141, 150))	('differ', 'Reg', (104, 110))	('tumors', 'Disease', (165, 171))	('IDH', 'Gene', (73, 76))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('men', 'Species', '9606', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('IDH', 'Gene', '3417', (73, 76))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutations', 'Var', (60, 69))	('treatment response', 'CPA', (118, 136))
233117	28535583	Since only gliomas with mutations in IDH and a codeletion in 1p/19q are considered oligodendrogliomas, the so-called pediatric-type oligodendroglioma lacking these two alterations is not considered an oligodendroglioma.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('oligodendroglioma', 'Disease', (83, 100))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('oligodendroglioma', 'Disease', (201, 218))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('mutations', 'Var', (24, 33))	('gliomas', 'Disease', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('glioma', 'Phenotype', 'HP:0009733', (212, 218))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (83, 101))	('oligodendroglioma', 'Disease', 'MESH:D009837', (132, 149))	('IDH', 'Gene', (37, 40))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (94, 101))	('oligodendroglioma', 'Disease', (132, 149))	('oligodendroglioma', 'Disease', 'MESH:D009837', (83, 100))	('oligodendroglioma', 'Disease', 'MESH:D009837', (201, 218))	('oligodendrogliomas', 'Disease', (83, 101))	('IDH', 'Gene', '3417', (37, 40))
233120	28535583	In other words, they more likely have mutations in IDH, ATRX, and TP53.	('ATRX', 'Gene', '546', (56, 60))	('IDH', 'Gene', (51, 54))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('IDH', 'Gene', '3417', (51, 54))	('ATRX', 'Gene', (56, 60))	('mutations', 'Var', (38, 47))
233121	28535583	Since the prognosis of each tumor depends on the mutational status of IDH1 and IDH2, astrocytic tumors are also classified according to this metric (Fig.	('IDH2', 'Gene', '3418', (79, 83))	('mutational status', 'Var', (49, 66))	('astrocytic tumors', 'Disease', 'MESH:D001254', (85, 102))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('IDH1', 'Gene', '3417', (70, 74))	('astrocytic tumors', 'Disease', (85, 102))	('IDH2', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('IDH1', 'Gene', (70, 74))
233123	28535583	No genetic abnormalities in IDH1 and IDH2 are found in pediatric GBMs, but mutations are generally found in H3F3A, ATRX and DAXX (Fig.	('DAXX', 'Gene', '1616', (124, 128))	('ATRX', 'Gene', '546', (115, 119))	('IDH1', 'Gene', '3417', (28, 32))	('IDH2', 'Gene', (37, 41))	('genetic abnormalities', 'Disease', 'MESH:D030342', (3, 24))	('H3F3A', 'Gene', '3020', (108, 113))	('DAXX', 'Gene', (124, 128))	('found', 'Reg', (99, 104))	('IDH2', 'Gene', '3418', (37, 41))	('mutations', 'Var', (75, 84))	('ATRX', 'Gene', (115, 119))	('genetic abnormalities', 'Disease', (3, 24))	('H3F3A', 'Gene', (108, 113))	('IDH1', 'Gene', (28, 32))
233124	28535583	The K27M in H3F3A is a major mutation found in diffuse midline gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('H3F3A', 'Gene', (12, 17))	('K27M', 'Mutation', 'p.K27M', (4, 8))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('diffuse midline gliomas', 'Disease', 'MESH:D005910', (47, 70))	('diffuse midline gliomas', 'Disease', (47, 70))	('H3F3A', 'Gene', '3020', (12, 17))	('K27M', 'Var', (4, 8))
233126	28535583	A V600E mutation in BRAF was found in circumscribed gliomas, such as pleomorphic xanthoastrocytoma (PXA) (66%), gangliogliomas (25%), and pilocytic astrocytomas (15%).	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (69, 98))	('gliomas', 'Disease', (52, 59))	('pilocytic astrocytomas', 'Disease', (138, 160))	('gangliogliomas', 'Disease', 'MESH:D018303', (112, 126))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('pleomorphic xanthoastrocytoma', 'Disease', (69, 98))	('gangliogliomas', 'Disease', (112, 126))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (138, 160))	('V600E', 'Mutation', 'rs113488022', (2, 7))	('gliomas', 'Disease', (119, 126))	('BRAF', 'Gene', '673', (20, 24))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('BRAF', 'Gene', (20, 24))	('found', 'Reg', (29, 34))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('astrocytoma', 'Phenotype', 'HP:0009592', (148, 159))	('V600E', 'Var', (2, 7))
233128	28535583	SMARCB1 (INI1) or SMARCA4 (BRG1) gene mutations or deletions were observed in atypical teratoid/rhabdoid tumors (AT/RT), and a NAB2-STAT6 fusion was present in solitary fibrous tumor/hemangiopericytomas.	('observed', 'Reg', (66, 74))	('fibrous tumor', 'Disease', 'MESH:D054364', (169, 182))	('SMARCA4', 'Gene', (18, 25))	('BRG1', 'Gene', (27, 31))	('fibrous tumor', 'Disease', (169, 182))	('AT', 'Disease', 'None', (113, 115))	('deletions', 'Var', (51, 60))	('NAB2', 'Gene', (127, 131))	('mutations', 'Var', (38, 47))	('INI1', 'Gene', '6598', (9, 13))	('INI1', 'Gene', (9, 13))	('NAB2', 'Gene', '4665', (127, 131))	('AT', 'Disease', 'None', (134, 136))	('STAT6', 'Gene', (132, 137))	('rhabdoid tumors', 'Disease', (96, 111))	('SMARCA4', 'Gene', '6597', (18, 25))	('SMARCB1', 'Gene', '6598', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (96, 111))	('SMARCB1', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('STAT6', 'Gene', '6778', (132, 137))	('BRG1', 'Gene', '6597', (27, 31))
233130	28535583	Sixty percent of the sporadic meningiomas have mutations in TRAF7, KLF4, AKT1, SMO, and PIK3CA.	('KLF4', 'Gene', (67, 71))	('KLF4', 'Gene', '9314', (67, 71))	('meningiomas', 'Phenotype', 'HP:0002858', (30, 41))	('PIK3CA', 'Gene', '5290', (88, 94))	('SMO', 'Gene', (79, 82))	('AKT1', 'Gene', '207', (73, 77))	('sporadic meningiomas', 'Disease', 'MESH:D008577', (21, 41))	('mutations', 'Var', (47, 56))	('TRAF7', 'Gene', (60, 65))	('AKT1', 'Gene', (73, 77))	('meningioma', 'Phenotype', 'HP:0002858', (30, 40))	('sporadic meningiomas', 'Disease', (21, 41))	('TRAF7', 'Gene', '84231', (60, 65))	('PIK3CA', 'Gene', (88, 94))	('SMO', 'Gene', '6608', (79, 82))
233131	28535583	Among them, mutations in TRAF7 and KLF4 are found in secretory-type meningiomas and mutations in TRAF7/AKT1/PIK3CA are found in meningothelial and transitional-type meningiomas.	('AKT1', 'Gene', (103, 107))	('found', 'Reg', (44, 49))	('meningiomas', 'Phenotype', 'HP:0002858', (165, 176))	('PIK3CA', 'Gene', (108, 114))	('meningiomas', 'Disease', 'MESH:D008577', (68, 79))	('meningioma', 'Phenotype', 'HP:0002858', (68, 78))	('secretory-type meningiomas', 'Disease', (53, 79))	('meningiomas', 'Disease', (165, 176))	('meningiomas', 'Phenotype', 'HP:0002858', (68, 79))	('meningothelial', 'Disease', (128, 142))	('men', 'Species', '9606', (128, 131))	('TRAF7', 'Gene', '84231', (97, 102))	('meningiomas', 'Disease', (68, 79))	('KLF4', 'Gene', '9314', (35, 39))	('TRAF7', 'Gene', '84231', (25, 30))	('mutations', 'Var', (84, 93))	('found', 'Reg', (119, 124))	('secretory-type meningiomas', 'Disease', 'MESH:D008577', (53, 79))	('TRAF7', 'Gene', (97, 102))	('PIK3CA', 'Gene', '5290', (108, 114))	('men', 'Species', '9606', (165, 168))	('AKT1', 'Gene', '207', (103, 107))	('mutations', 'Var', (12, 21))	('meningioma', 'Phenotype', 'HP:0002858', (165, 175))	('KLF4', 'Gene', (35, 39))	('meningiomas', 'Disease', 'MESH:D008577', (165, 176))	('men', 'Species', '9606', (68, 71))	('TRAF7', 'Gene', (25, 30))
233132	28535583	Mutations in TRAF7 are the most common genomic aberrations and are found in 12%-15% of sporadic meningiomas, preferentially fibrous and transitional subtype, which are found concurrently with mutations in KLF4, AKT1, or PIK3CA, but are mutually exclusive with mutations in SMO and neurofibromatosis type 2 (NF2).	('TRAF7', 'Gene', '84231', (13, 18))	('found', 'Reg', (67, 72))	('PIK3CA', 'Gene', (220, 226))	('AKT1', 'Gene', '207', (211, 215))	('KLF4', 'Gene', (205, 209))	('mutations', 'Var', (192, 201))	('sporadic meningiomas', 'Disease', (87, 107))	('Mutations', 'Var', (0, 9))	('TRAF7', 'Gene', (13, 18))	('SMO', 'Gene', '6608', (273, 276))	('NF2', 'Gene', '4771', (307, 310))	('AKT1', 'Gene', (211, 215))	('meningioma', 'Phenotype', 'HP:0002858', (96, 106))	('neurofibromatosis type 2', 'Gene', (281, 305))	('NF2', 'Gene', (307, 310))	('KLF4', 'Gene', '9314', (205, 209))	('PIK3CA', 'Gene', '5290', (220, 226))	('meningiomas', 'Phenotype', 'HP:0002858', (96, 107))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (281, 298))	('SMO', 'Gene', (273, 276))	('sporadic meningiomas', 'Disease', 'MESH:D008577', (87, 107))	('neurofibromatosis type 2', 'Gene', '4771', (281, 305))
233133	28535583	NF2-associated meningiomas have mutations in NF2.	('meningioma', 'Phenotype', 'HP:0002858', (15, 25))	('meningiomas', 'Phenotype', 'HP:0002858', (15, 26))	('NF2', 'Gene', (0, 3))	('NF2', 'Gene', (45, 48))	('meningiomas', 'Disease', 'MESH:D008577', (15, 26))	('NF2', 'Gene', '4771', (0, 3))	('NF2', 'Gene', '4771', (45, 48))	('meningiomas', 'Disease', (15, 26))	('mutations', 'Var', (32, 41))
233134	28535583	Atypical and anaplastic meningiomas usually have mutations in TERTp or marked copy number aberrations and loss of CDKN2A/2B.	('meningiomas', 'Disease', 'MESH:D008577', (24, 35))	('mutations', 'Var', (49, 58))	('TERTp', 'Gene', (62, 67))	('Atypical', 'Disease', (0, 8))	('meningiomas', 'Phenotype', 'HP:0002858', (24, 35))	('TERTp', 'Gene', '7015', (62, 67))	('CDKN2A/2B', 'Gene', '1029', (114, 123))	('meningioma', 'Phenotype', 'HP:0002858', (24, 34))	('meningiomas', 'Disease', (24, 35))	('loss', 'NegReg', (106, 110))	('copy', 'MPA', (78, 82))	('CDKN2A/2B', 'Gene', (114, 123))
233135	28535583	These findings demonstrate that tumors are genetic disorders and that certain mutations can represent different biological behaviors and result in different prognoses.	('mutations', 'Var', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('result in', 'Reg', (137, 146))	('genetic disorders', 'Disease', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('genetic disorders', 'Disease', 'MESH:D030342', (43, 60))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
233142	28535583	The discovery of mutations affecting the enzymatic function of IDH in gliomas provided a fundamentally new insight into the biology of gliomagenesis and triggered molecular classification of gliomas by a somatic mutation.	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('mutations', 'Var', (17, 26))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('IDH', 'Gene', (63, 66))	('glioma', 'Disease', (135, 141))	('gliomas', 'Disease', (191, 198))	('men', 'Species', '9606', (94, 97))	('glioma', 'Disease', (191, 197))	('IDH', 'Gene', '3417', (63, 66))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('gliomas', 'Disease', (70, 77))	('glioma', 'Disease', (70, 76))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
233143	28535583	IDH catalyzes the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (alpha-KG) and CO2, but mutant IDH1/2 has a preferential affinity for alpha-KG instead of isocitrate outside of the citric acid cycle, thus leading to the production and accumulation of the oncometabolite 2-hydroxyglutarate (2HG).	('affinity', 'Interaction', (146, 154))	('mutant', 'Var', (113, 119))	('IDH', 'Gene', (120, 123))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (69, 88))	('citric acid', 'Chemical', 'MESH:D019343', (205, 216))	('IDH', 'Gene', (0, 3))	('isocitrate', 'Chemical', 'MESH:C034219', (47, 57))	('alpha-KG', 'Chemical', 'MESH:D007656', (159, 167))	('CO2', 'Chemical', '-', (104, 107))	('IDH', 'Gene', '3417', (120, 123))	('alpha-KG', 'Chemical', 'MESH:D007656', (90, 98))	('IDH', 'Gene', '3417', (0, 3))	('leading to', 'Reg', (229, 239))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (294, 312))	('production', 'MPA', (244, 254))	('preferential', 'PosReg', (133, 145))	('IDH1/2', 'Gene', '3417;3418', (120, 126))	('isocitrate', 'Chemical', 'MESH:C034219', (179, 189))	('IDH1/2', 'Gene', (120, 126))	('accumulation', 'PosReg', (259, 271))
233144	28535583	hypothesized that 2HG induces redox stress due to damage to the respiratory chain, which subsequently promotes the mutagenesis and development of gliomas.	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('promotes', 'PosReg', (102, 110))	('gliomas', 'Disease', (146, 153))	('respiratory chain', 'Enzyme', (64, 81))	('redox stress', 'MPA', (30, 42))	('men', 'Species', '9606', (138, 141))	('mutagenesis', 'CPA', (115, 126))	('2HG', 'Var', (18, 21))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('development', 'CPA', (131, 142))	('induces', 'Reg', (22, 29))
233146	28535583	The glioma-CpG island methylator phenotype (G-CIMP) subset is distinctively and invariably found in the gliomas with mutant IDH, which is the proneural transcriptional group.	('gliomas', 'Disease', (104, 111))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('IDH', 'Gene', (124, 127))	('mutant', 'Var', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('IDH', 'Gene', '3417', (124, 127))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('G-CIMP', 'Chemical', '-', (44, 50))	('glioma', 'Disease', (104, 110))	('glioma', 'Disease', (4, 10))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
233147	28535583	2HG, the oncometabolite produced by mutant IDH1/2, inhibits alpha-KG-dependent dioxygenases including histone demethylases and the Ten-Eleven Translocation (TET) family of histone 5-methylcytosine hydroxylase, which directly induce the hypermethylated state.	('IDH1/2', 'Gene', (43, 49))	('inhibits', 'NegReg', (51, 59))	('TET', 'Chemical', '-', (157, 160))	('alpha-KG', 'Chemical', 'MESH:D007656', (60, 68))	('mutant', 'Var', (36, 42))	('IDH1/2', 'Gene', '3417;3418', (43, 49))	('alpha-KG-dependent dioxygenases', 'Enzyme', (60, 91))	('histone demethylases', 'Enzyme', (102, 122))
233149	28535583	All IDH1/2 mutations are common in 70%-80% of type II and III infiltrating gliomas and are found in 100% of oligoden-drogliomas and IDH-mutant GBMs.	('mutations', 'Var', (11, 20))	('IDH', 'Gene', '3417', (4, 7))	('gliomas', 'Disease', (75, 82))	('found', 'Reg', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('type II', 'Disease', (46, 53))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('oligoden-drogliomas', 'Disease', 'None', (108, 127))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('IDH', 'Gene', (132, 135))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('IDH1/2', 'Gene', (4, 10))	('gliomas', 'Disease', (120, 127))	('IDH', 'Gene', (4, 7))	('common', 'Reg', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('IDH', 'Gene', '3417', (132, 135))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('oligoden-drogliomas', 'Disease', (108, 127))
233152	28535583	Mutated TP53 genes and overexpressed abnormal p53 protein, which has a longer half-life than wild type p53, are associated with a variety of human cancers, including Li-Fraumeni syndrome and many hereditary gliomas.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('p53', 'Gene', (46, 49))	('gliomas', 'Phenotype', 'HP:0009733', (207, 214))	('Li-Fraumeni syndrome and many hereditary gliomas', 'Disease', 'MESH:D016864', (166, 214))	('p53', 'Gene', '7157', (46, 49))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('TP53', 'Gene', '7157', (8, 12))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('TP53', 'Gene', (8, 12))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('cancers', 'Disease', (147, 154))	('Mutated', 'Var', (0, 7))	('associated', 'Reg', (112, 122))
233154	28535583	WHO class II and III astrocytic tumors show high levels of TP53 mutations (94%) and/or p53 overexpression (Tables 3, 4).	('overexpression', 'PosReg', (91, 105))	('TP53', 'Gene', (59, 63))	('astrocytic tumors', 'Disease', 'MESH:D001254', (21, 38))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutations', 'Var', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('astrocytic tumors', 'Disease', (21, 38))	('TP53', 'Gene', '7157', (59, 63))
233159	28535583	Decreased nuclear expression of ATRX and ATRX mutations are observed in grade 2 and 3 astrocytic tumors including IDH mutant gliomas (86%), IDH-mutant GBMs (85%), and pediatric high grade gliomas such as diffuse midline gliomas (DMGs) (Figs.	('gliomas', 'Disease', (125, 132))	('IDH', 'Gene', '3417', (140, 143))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('IDH', 'Gene', '3417', (114, 117))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('gliomas', 'Disease', 'MESH:D005910', (220, 227))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('diffuse midline gliomas', 'Disease', 'MESH:D005910', (204, 227))	('mutations', 'Var', (46, 55))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('Decreased', 'NegReg', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('gliomas', 'Phenotype', 'HP:0009733', (220, 227))	('astrocytic tumors', 'Disease', (86, 103))	('ATRX', 'Gene', (41, 45))	('diffuse midline gliomas', 'Disease', (204, 227))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('astrocytic tumors', 'Disease', 'MESH:D001254', (86, 103))	('ATRX', 'Gene', '546', (41, 45))	('ATRX', 'Gene', (32, 36))	('IDH', 'Gene', (140, 143))	('DMGs', 'Chemical', '-', (229, 233))	('ATRX', 'Gene', '546', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('IDH', 'Gene', (114, 117))	('nuclear expression', 'MPA', (10, 28))	('gliomas', 'Disease', (188, 195))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gliomas', 'Disease', (220, 227))
233161	28535583	Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were first detected in the pediatric diffuse infiltrating pontine glioma (DIPG) by a comprehensive WES analysis.	('H3F3A', 'Gene', (23, 28))	('DIPG', 'Chemical', '-', (170, 174))	('glioma', 'Disease', (162, 168))	('H3F3A', 'Gene', '3020', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('mutations', 'Var', (10, 19))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))
233163	28535583	Eighty percent of pontine gliomas (DIPG) and 70% of other loci DMGs contain a mutation in one allele of the H3F3A gene, which is a mutation on the histone tail (K27M, K36, G34R/G34V), an important post-translational modification factor.	('G34V', 'Var', (177, 181))	('DIPG', 'Chemical', '-', (35, 39))	('G34R', 'SUBSTITUTION', 'None', (172, 176))	('G34R', 'Var', (172, 176))	('K27M', 'Mutation', 'p.K27M', (161, 165))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('DMGs', 'Chemical', '-', (63, 67))	('H3F3A', 'Gene', '3020', (108, 113))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('K36', 'Var', (167, 170))	('K27M', 'Var', (161, 165))	('H3F3A', 'Gene', (108, 113))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('G34V', 'SUBSTITUTION', 'None', (177, 181))
233164	28535583	The histone H3F3A mutant gliomas have a poor prognosis regardless of histopathological grade.	('H3F3A', 'Gene', (12, 17))	('mutant', 'Var', (18, 24))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('H3F3A', 'Gene', '3020', (12, 17))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
233165	28535583	K27M-H3.3 mutations occur mainy in young patients (median age, 11 years) and G34R/V-H3.3 mutations occur in older children and young adults (median age, 20 years.	('K27M-H3.3 mutations', 'Var', (0, 19))	('children', 'Species', '9606', (114, 122))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('patients', 'Species', '9606', (41, 49))	('G34R', 'SUBSTITUTION', 'None', (77, 81))	('mutations', 'Var', (10, 19))	('G34R', 'Var', (77, 81))
233166	28535583	All of the cases with G34-H3.3 mutations are in pediatric GBMs (13/13), and especially associated with mutations in ATRX and DAXX.	('mutations', 'Var', (103, 112))	('mutations', 'Var', (31, 40))	('DAXX', 'Gene', '1616', (125, 129))	('ATRX', 'Gene', (116, 120))	('ATRX', 'Gene', '546', (116, 120))	('associated', 'Reg', (87, 97))	('DAXX', 'Gene', (125, 129))	('G34-H3.3', 'Gene', (22, 30))
233167	28535583	Loss of ATRX is associated with the ALT phenotype; thus, ALT often coexists with mutations in ATRX/H3F3A/TP53.	('H3F3A', 'Gene', '3020', (99, 104))	('ATRX', 'Gene', '546', (8, 12))	('H3F3A', 'Gene', (99, 104))	('ATRX', 'Gene', (94, 98))	('ALT', 'Disease', (57, 60))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('mutations', 'Var', (81, 90))	('ATRX', 'Gene', (8, 12))	('ATRX', 'Gene', '546', (94, 98))
233168	28535583	Simultaneous deletion of chromosome 1p/19q is a characteristic and early genetic event in oligodendroglial tumors, which is associated with better prognosis and is also a good indicator of the patient response to specific combination chemotherapy of procarbazine, lomustine, and vincristine (PCV).	('Simultaneous deletion', 'Var', (0, 21))	('procarbazine', 'Chemical', 'MESH:D011344', (250, 262))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('lomustine', 'Chemical', 'MESH:D008130', (264, 273))	('vincristine', 'Chemical', 'MESH:D014750', (279, 290))	('patient', 'Species', '9606', (193, 200))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (90, 113))	('oligodendroglial tumors', 'Disease', (90, 113))
233169	28535583	Recurrent mutations in CIC and FUBP1 were found in 46%-53% and 15%-24% of oligodendrogliomas, respectively, in addition to a codeletion in 1p/19q and mutations in IDH1 or IDH2 (Fig.	('IDH1', 'Gene', (163, 167))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (74, 92))	('FUBP1', 'Gene', '8880', (31, 36))	('CIC', 'Gene', '23152', (23, 26))	('oligodendrogliomas', 'Disease', (74, 92))	('IDH2', 'Gene', (171, 175))	('CIC', 'Gene', (23, 26))	('IDH1', 'Gene', '3417', (163, 167))	('mutations', 'Var', (150, 159))	('FUBP1', 'Gene', (31, 36))	('found', 'Reg', (42, 47))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('mutations', 'Var', (10, 19))	('IDH2', 'Gene', '3418', (171, 175))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
233170	28535583	FUBP1 is located in 1p31.1, and mutations in FUBP1 are predicted to disrupt FUBP1 protein function (Table 1).	('disrupt', 'NegReg', (68, 75))	('FUBP1', 'Gene', '8880', (45, 50))	('FUBP1', 'Gene', '8880', (76, 81))	('FUBP1', 'Gene', (0, 5))	('FUBP1', 'Gene', '8880', (0, 5))	('mutations', 'Var', (32, 41))	('function', 'MPA', (90, 98))	('FUBP1', 'Gene', (45, 50))	('FUBP1', 'Gene', (76, 81))	('protein', 'Protein', (82, 89))
233171	28535583	FUBP1 acts as an RNA binding protein and alterations of its normal function can lead to tumorigenesis, which has been suggested to act either as a protooncogene or a tumor suppressor gene depending on the tumor type.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('lead to', 'Reg', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('FUBP1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('FUBP1', 'Gene', '8880', (0, 5))	('alterations', 'Var', (41, 52))
233175	28535583	CIC mutations promote the accumulation of 2HG and reduce clonogenicity in the setting of IDH1 mutations.	('CIC', 'Gene', (0, 3))	('reduce', 'NegReg', (50, 56))	('mutations', 'Var', (94, 103))	('CIC', 'Gene', '23152', (0, 3))	('promote', 'PosReg', (14, 21))	('IDH1', 'Gene', (89, 93))	('2HG', 'Protein', (42, 45))	('mutations', 'Var', (4, 13))	('clonogenicity', 'CPA', (57, 70))	('IDH1', 'Gene', '3417', (89, 93))
233176	28535583	Loss of 19q in oligodendroglial tumors unmasks mutations in the CIC gene.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (15, 38))	('oligodendroglial tumors', 'Disease', (15, 38))	('CIC', 'Gene', '23152', (64, 67))	('mutations', 'Var', (47, 56))	('Loss', 'NegReg', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CIC', 'Gene', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
233177	28535583	In this regard, the co-existence of IDH1 with CIC or FUBP1 mutations may partially explain the slower tumor growth and longer survival of oligodendrogliomas with mutations in IDH1 and a codeletion of 1p/19q when compared to other diffuse gliomas.	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (238, 245))	('CIC', 'Gene', (46, 49))	('IDH1', 'Gene', (175, 179))	('FUBP1', 'Gene', '8880', (53, 58))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('oligodendrogliomas', 'Disease', (138, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('IDH1', 'Gene', '3417', (175, 179))	('CIC', 'Gene', '23152', (46, 49))	('IDH1', 'Gene', (36, 40))	('gliomas', 'Disease', (238, 245))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', (102, 107))	('gliomas', 'Disease', (149, 156))	('FUBP1', 'Gene', (53, 58))	('mutations', 'Var', (162, 171))	('gliomas', 'Disease', 'MESH:D005910', (238, 245))	('slower', 'NegReg', (95, 101))	('longer', 'PosReg', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('IDH1', 'Gene', '3417', (36, 40))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (138, 156))
233178	28535583	The overall survival rate of patients with oligodendrogliomas with CIC mutations was lower than that of patients without CIC mutations, and the FUBP1 mutation was significantly associated with unfavorable progression-free survival.	('FUBP1', 'Gene', '8880', (144, 149))	('patients', 'Species', '9606', (29, 37))	('CIC', 'Gene', (121, 124))	('lower', 'NegReg', (85, 90))	('oligodendrogliomas', 'Disease', (43, 61))	('CIC', 'Gene', (67, 70))	('mutation', 'Var', (150, 158))	('FUBP1', 'Gene', (144, 149))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('mutations', 'Var', (71, 80))	('associated', 'Reg', (177, 187))	('CIC', 'Gene', '23152', (121, 124))	('patients', 'Species', '9606', (104, 112))	('CIC', 'Gene', '23152', (67, 70))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (43, 61))
233179	28535583	However, oligodendrogliomas cannot be diagnosed with CIC or FUBP1 mutations only.	('mutations', 'Var', (66, 75))	('oligodendrogliomas', 'Disease', (9, 27))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('FUBP1', 'Gene', (60, 65))	('CIC', 'Gene', '23152', (53, 56))	('CIC', 'Gene', (53, 56))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (9, 27))	('FUBP1', 'Gene', '8880', (60, 65))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))
233182	28535583	The EGFRvIII mutation is a 801 bp frame deletion from exons 2 to 7 of the EGFR gene, which is associated with EGFR amplification and the response to antibody therapy as well as poor prognosis.	('mutation', 'Var', (13, 21))	('EGFRvIII', 'Disease', (4, 12))	('to 7', 'Species', '1214577', (62, 66))	('associated', 'Reg', (94, 104))	('EGFR', 'Gene', (74, 78))
233186	28535583	Unlike EGFR point mutations, EGFR fusions with SEPT14, PSPH, or SEC61G has also been shown to play a role in GBMs, offering a unique opportunity to investigate fused oncogene dependencies.	('SEC61G', 'Gene', (64, 70))	('role', 'Reg', (101, 105))	('SEC61G', 'Gene', '23480', (64, 70))	('SEPT14', 'Gene', '346288', (47, 53))	('PSPH', 'Gene', (55, 59))	('fusions', 'Var', (34, 41))	('EGFR', 'Gene', (29, 33))	('SEPT14', 'Gene', (47, 53))	('GBMs', 'Disease', (109, 113))	('PSPH', 'Gene', '5723', (55, 59))	('play', 'Reg', (94, 98))
233188	28535583	In 60% of GBMs and 11% of low-grade gliomas including oligodendroglioma, pleomorphic xanthoastrocytoma, and pilocytic astrocytoma, the loss or inactivation of p16 protein as a result of a homozygous deletion or promoter methylation of CDKN2A/2B is observed (Fig.	('pleomorphic xanthoastrocytoma', 'Disease', (73, 102))	('gliomas', 'Disease', (36, 43))	('deletion', 'Var', (199, 207))	('CDKN2A/2B', 'Gene', '1029', (235, 244))	('promoter', 'MPA', (211, 219))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('p16', 'Gene', (159, 162))	('oligodendroglioma', 'Disease', 'MESH:D009837', (54, 71))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('inactivation', 'NegReg', (143, 155))	('p16', 'Gene', '1029', (159, 162))	('CDKN2A/2B', 'Gene', (235, 244))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (108, 129))	('protein', 'Protein', (163, 170))	('oligodendroglioma', 'Disease', (54, 71))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('pilocytic astrocytoma', 'Disease', (108, 129))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (73, 102))	('loss', 'NegReg', (135, 139))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
233190	28535583	After adjusting for the IDH mutational status, sex, and age, CDKN2A deletions were strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas.	('astrocytomas', 'Disease', (135, 147))	('overall survival', 'MPA', (115, 131))	('IDH', 'Gene', (24, 27))	('deletions', 'Var', (68, 77))	('CDKN2A', 'Gene', (61, 67))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('IDH', 'Gene', '3417', (24, 27))	('poorer', 'NegReg', (108, 114))	('CDKN2A', 'Gene', '1029', (61, 67))	('astrocytoma', 'Phenotype', 'HP:0009592', (135, 146))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (159, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (135, 147))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('oligodendrogliomas', 'Disease', (159, 177))
233191	28535583	BRAF V600E mutations and fusions of BRAF with KIAA1549 or FAM131B are characteristics of pilocytic astrocytomas.	('KIAA1549', 'Gene', '57670', (46, 54))	('BRAF', 'Gene', (36, 40))	('V600E mutations', 'Var', (5, 20))	('FAM131B', 'Gene', (58, 65))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('FAM131B', 'Gene', '9715', (58, 65))	('BRAF', 'Gene', '673', (0, 4))	('KIAA1549', 'Gene', (46, 54))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (89, 111))	('BRAF', 'Gene', (0, 4))	('fusions', 'Var', (25, 32))	('BRAF', 'Gene', '673', (36, 40))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))	('pilocytic astrocytomas', 'Disease', (89, 111))
233192	28535583	In 2008, a tandem duplication was confirmed in 7q34, and a new fusion gene was found to be generated by a fusion between the KIAA1549 gene and BRAF genes, which was previously uncharacterized in pilocytic astrocytomas.	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (195, 217))	('fusion', 'Var', (106, 112))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('KIAA1549', 'Gene', '57670', (125, 133))	('astrocytoma', 'Phenotype', 'HP:0009592', (205, 216))	('KIAA1549', 'Gene', (125, 133))	('pilocytic astrocytomas', 'Disease', (195, 217))
233194	28535583	The BRAF V600E mutation was found in two-thirds of all pleomorphic xanthoastrocytomas, one-fourth of gangliogliomas, and one-seventh of pilocytic astrocytomas.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gangliogliomas', 'Disease', 'MESH:D018303', (101, 115))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (136, 158))	('V600E', 'Var', (9, 14))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (55, 85))	('astrocytoma', 'Phenotype', 'HP:0009592', (146, 157))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('BRAF', 'Gene', (4, 8))	('found', 'Reg', (28, 33))	('BRAF', 'Gene', '673', (4, 8))	('gangliogliomas', 'Disease', (101, 115))	('pilocytic astrocytomas', 'Disease', (136, 158))	('pleomorphic xanthoastrocytomas', 'Disease', (55, 85))
233195	28535583	In children, CDKN2A deletions and BRAF mutations are early events in low-grade gliomas (pediatric low-grade glioma [PLGG]) undergoing malignant transformation (Fig.	('gliomas', 'Disease', (79, 86))	('children', 'Species', '9606', (3, 11))	('glioma', 'Disease', (79, 85))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('glioma', 'Disease', (108, 114))	('deletions', 'Var', (20, 29))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('CDKN2A', 'Gene', (13, 19))	('mutations', 'Var', (39, 48))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('BRAF', 'Gene', '673', (34, 38))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('CDKN2A', 'Gene', '1029', (13, 19))	('BRAF', 'Gene', (34, 38))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
233196	28535583	The BRAF V600E mutant PLGG has longer transformation latency periods than the BRAF wild type PLGG (median latency period, 6.65 years vs 1.59 years, respectively).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', (78, 82))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('transformation', 'CPA', (38, 52))
233197	28535583	As a result, all of the patients with secondary high-grade glioma (sHGGs) containing mutant BRAF were diagnosed at age 9 or older.	('glioma', 'Disease', (59, 65))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('patients', 'Species', '9606', (24, 32))	('mutant', 'Var', (85, 91))
233198	28535583	The sHGG in children showed recurrent changes of BRAF V600E mutations and CDKN2A deletions in 39% and 57%, respectively.	('deletions', 'Var', (81, 90))	('children', 'Species', '9606', (12, 20))	('CDKN2A', 'Gene', (74, 80))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('CDKN2A', 'Gene', '1029', (74, 80))	('changes', 'Reg', (38, 45))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
233200	28535583	Mutations in TERTp are molecular hallmarks of glioma, occurring in more than 80%-96% of IDH-wildtype GBMs and oligodendrogliomas, but less frequently present in grade II and III astrocytomas (38.5%) (Table 1, Fig.	('TERTp', 'Gene', (13, 18))	('oligodendrogliomas', 'Disease', (110, 128))	('TERTp', 'Gene', '7015', (13, 18))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('glioma', 'Disease', (46, 52))	('III astrocytomas', 'Disease', (174, 190))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Disease', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('Mutations', 'Var', (0, 9))	('IDH', 'Gene', (88, 91))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (110, 128))	('IDH', 'Gene', '3417', (88, 91))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('III astrocytomas', 'Disease', 'MESH:D001254', (174, 190))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('occurring', 'Reg', (54, 63))
233201	28535583	(2015) found that mutations in TERTp are present in 41 of 142 (28.9%) grade II gliomas and 20 of 72 (27.8%) grade III gliomas.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('present', 'Reg', (41, 48))	('gliomas', 'Disease', (118, 125))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('TERTp', 'Gene', (31, 36))	('TERTp', 'Gene', '7015', (31, 36))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('mutations', 'Var', (18, 27))
233202	28535583	The mutations were always found in two hotspots (chr5: 1 295 228 C > T and 1 295 250 C > T), resulting in a somatic gain-of-function mutation and an enhancement of TERTp activity.	('228 C > T', 'Var', (61, 70))	('mutation', 'Var', (133, 141))	('TERTp', 'Gene', (164, 169))	('TERTp', 'Gene', '7015', (164, 169))	('enhancement', 'PosReg', (149, 160))	('gain-of-function', 'PosReg', (116, 132))	('men', 'Species', '9606', (156, 159))	('250 C > T', 'Var', (81, 90))	('228 C > T', 'SUBSTITUTION', 'None', (61, 70))	('250 C > T', 'SUBSTITUTION', 'None', (81, 90))
233204	28535583	These two hot spot mutations are mutually exclusive in gliomas and TP53 mutations, but coincident with a 1p/19q codeletion.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('mutations', 'Var', (72, 81))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
233207	28535583	Other researchers have found that TERTp mutations are a predictor of a poorer response to temozolomide.	('TERTp', 'Gene', '7015', (34, 39))	('mutations', 'Var', (40, 49))	('temozolomide', 'Chemical', 'MESH:D000077204', (90, 102))	('poorer', 'NegReg', (71, 77))	('TERTp', 'Gene', (34, 39))
233208	28535583	TERTp mutations are associated with good outcome in gliomas with mutant IDH, but it is also related to poor outcome in gliomas with wild type IDH.	('TERTp', 'Gene', '7015', (0, 5))	('gliomas', 'Disease', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('IDH', 'Gene', (142, 145))	('mutant', 'Var', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('gliomas', 'Disease', (119, 126))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (142, 145))	('IDH', 'Gene', '3417', (72, 75))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('mutations', 'Var', (6, 15))	('TERTp', 'Gene', (0, 5))
233209	28535583	In gliomas with wildtype IDH or GBMs with hypomethylated MGMT, TERTp mutations were found to predict poor prognosis.	('TERTp', 'Gene', (63, 68))	('IDH', 'Gene', (25, 28))	('TERTp', 'Gene', '7015', (63, 68))	('IDH', 'Gene', '3417', (25, 28))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('MGMT', 'Gene', '4255', (57, 61))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('MGMT', 'Gene', (57, 61))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))	('hypomethylated', 'Var', (42, 56))
233210	28535583	Therefore, when using the TERTp mutational status as a prognostic factor, other factors such as mutations in IDH and tumor grade should be considered.	('IDH', 'Gene', '3417', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('IDH', 'Gene', (109, 112))	('TERTp', 'Gene', (26, 31))	('TERTp', 'Gene', '7015', (26, 31))	('mutations', 'Var', (96, 105))
233212	28535583	More than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA (the principle effector of canonical nuclear factor kappaB [NF-kappaB] signaling) and C11orf95 (an uncharacterized gene) (Table 2).	('C11orf95', 'Gene', '65998', (176, 184))	('supratentorial ependymomas', 'Disease', (24, 50))	('NF-kappaB', 'Gene', '4790', (150, 159))	('NF-kappaB', 'Gene', (150, 159))	('supratentorial ependymomas', 'Disease', 'MESH:D004806', (24, 50))	('C11orf95', 'Gene', (176, 184))	('fusions', 'Var', (69, 76))
233213	28535583	Ependymomas carrying the C11orf95-RELA fusion are characterized by a nuclear accumulation of p65RelA (NFkappaB) indicating a pathological activation of the NFkB signaling pathway.	('p65RelA', 'Var', (93, 100))	('Ependymomas', 'Disease', 'MESH:D004806', (0, 11))	('C11orf95', 'Gene', (25, 33))	('NFkappaB', 'Gene', '4790', (102, 110))	('NFkappaB', 'Gene', (102, 110))	('Ependymomas', 'Disease', (0, 11))	('NFkB signaling pathway', 'Pathway', (156, 178))	('C11orf95', 'Gene', '65998', (25, 33))	('activation', 'PosReg', (138, 148))	('nuclear accumulation', 'MPA', (69, 89))
233214	28535583	C11orf95-RELA fusions result from chromothripsis involving chromosome 11q13.1.	('C11orf95', 'Gene', (0, 8))	('result from', 'Reg', (22, 33))	('chromothripsis', 'Disease', 'MESH:D000072837', (34, 48))	('C11orf95', 'Gene', '65998', (0, 8))	('fusions', 'Var', (14, 21))	('chromothripsis', 'Disease', (34, 48))
233216	28535583	Mutations in CTNNB1 on chromosome 3p21, which encodes beta-catenin, promote the stabilization and nuclear translocation of itself, therefore activating the WNT signaling pathway (Table 2).	('CTNNB1', 'Gene', '1499', (13, 19))	('promote', 'PosReg', (68, 75))	('nuclear translocation', 'CPA', (98, 119))	('activating', 'Reg', (141, 151))	('CTNNB1', 'Gene', (13, 19))	('WNT signaling pathway', 'Pathway', (156, 177))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', '1499', (54, 66))	('stabilization', 'MPA', (80, 93))
233219	28535583	Overall, these mutations can act as future therapeutic targets in nuclear beta-catenin-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('beta-catenin', 'Gene', (74, 86))	('beta-catenin', 'Gene', '1499', (74, 86))
233222	28535583	MYC/MYCN amplification or overexpression is found not only in type-3 medulloblastomas, but also in other aggressive subtypes of medulloblastomas, which account for approximately 10% of medulloblastomas.	('MYC', 'Gene', (0, 3))	('medulloblastoma', 'Phenotype', 'HP:0002885', (128, 143))	('MYC', 'Gene', (4, 7))	('amplification', 'Var', (9, 22))	('MYCN', 'Gene', (4, 8))	('medulloblastomas', 'Disease', 'MESH:D008527', (185, 201))	('medulloblastomas', 'Disease', 'MESH:D008527', (69, 85))	('overexpression', 'PosReg', (26, 40))	('MYCN', 'Gene', '4613', (4, 8))	('medulloblastomas', 'Disease', (185, 201))	('medulloblastomas', 'Disease', 'MESH:D008527', (128, 144))	('MYC', 'Gene', '4609', (4, 7))	('medulloblastoma', 'Phenotype', 'HP:0002885', (185, 200))	('medulloblastomas', 'Disease', (69, 85))	('medulloblastomas', 'Disease', (128, 144))	('MYC', 'Gene', '4609', (0, 3))	('medulloblastoma', 'Phenotype', 'HP:0002885', (69, 84))
233223	28535583	AT/RT are highly malignant CNS embryonal tumors with rhabdoid morphology, where biallelic inactivation of SMARCB1 results in a loss of INI1 (BAF47) nuclear expression (Tables 2-4).	('INI1', 'Gene', (135, 139))	('CNS embryonal tumors', 'Disease', 'MESH:D009373', (27, 47))	('INI1', 'Gene', '6598', (135, 139))	('embryonal tumors', 'Phenotype', 'HP:0002898', (31, 47))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('rhabdoid', 'Disease', 'MESH:D018335', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('CNS embryonal tumors', 'Disease', (27, 47))	('BAF47', 'Gene', '6598', (141, 146))	('rhabdoid', 'Disease', (53, 61))	('BAF47', 'Gene', (141, 146))	('SMARCB1', 'Gene', (106, 113))	('loss', 'NegReg', (127, 131))	('SMARCB1', 'Gene', '6598', (106, 113))	('AT', 'Disease', 'None', (0, 2))	('embryonal tumor', 'Phenotype', 'HP:0002898', (31, 46))	('biallelic', 'Var', (80, 89))
233224	28535583	The loss of BRG1 nuclear expression in AT/RT with mutations in SMARCA4 is rarely reported.	('AT', 'Disease', 'None', (39, 41))	('BRG1', 'Gene', (12, 16))	('mutations', 'Var', (50, 59))	('SMARCA4', 'Gene', (63, 70))	('SMARCA4', 'Gene', '6597', (63, 70))	('BRG1', 'Gene', '6597', (12, 16))
233227	28535583	WES and RNA sequencing of AT/RT revealed few somatic mutations and several deregulated signaling pathways related to the SMARCB1 deficiency.	('SMARCB1', 'Gene', (121, 128))	('SMARCB1', 'Gene', '6598', (121, 128))	('deficiency', 'Var', (129, 139))	('AT', 'Disease', 'None', (26, 28))	('deregulated', 'Reg', (75, 86))
233229	28535583	C19MC amplification is a genetic feature of embryonal tumors with multilayer rosettes (ETMR), supratentorial ependymomas, and medulloepitheliomas (Table 2).	('embryonal tumors', 'Disease', 'MESH:D009373', (44, 60))	('medulloepitheliomas', 'Disease', (126, 145))	('supratentorial ependymomas', 'Disease', (94, 120))	('embryonal tumor', 'Phenotype', 'HP:0002898', (44, 59))	('rosettes', 'Phenotype', 'HP:0031925', (77, 85))	('medulloepitheliomas', 'Disease', 'MESH:D008527', (126, 145))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('C19MC amplification', 'Var', (0, 19))	('embryonal tumors', 'Disease', (44, 60))	('supratentorial ependymomas', 'Disease', 'MESH:D004806', (94, 120))	('embryonal tumors', 'Phenotype', 'HP:0002898', (44, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
233233	28535583	In cases of oligodendroglioma with promoter methylation of the MGMT gene, whether or not PCV chemotherapy is advantageous remains controversial.	('promoter methylation', 'Var', (35, 55))	('MGMT', 'Gene', '4255', (63, 67))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('MGMT', 'Gene', (63, 67))	('oligodendroglioma', 'Disease', (12, 29))	('oligodendroglioma', 'Disease', 'MESH:D009837', (12, 29))
233234	28535583	IDH R132H, H3 K27M, BRAF V600E, and EGFRvIII can be diagnosed using mutation-specific monoclonal antibodies (mAbs).	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('K27M', 'Mutation', 'p.K27M', (14, 18))	('BRAF', 'Gene', '673', (20, 24))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('V600E', 'Mutation', 'rs113488022', (25, 30))	('BRAF', 'Gene', (20, 24))	('H3 K27M', 'Var', (11, 18))	('EGFRvIII', 'Disease', (36, 44))
233235	28535583	IDH1 (H09), K27M, and BRAF VE1 antibodies have 100% sensitivity and specificity to detect gene mutations.	('BRAF', 'Gene', '673', (22, 26))	('K27M', 'Var', (12, 16))	('BRAF', 'Gene', (22, 26))	('IDH1', 'Gene', (0, 4))	('K27M', 'Mutation', 'p.K27M', (12, 16))	('IDH1', 'Gene', '3417', (0, 4))
233236	28535583	The INI-1 (SMARCB1), BRG1 (SMARCA4), p16 (CDKN2A), CIC, and FUBP1 mutations and MGMT methylation can be detected by the loss of expression.	('mutations', 'Var', (66, 75))	('INI-1', 'Gene', (4, 9))	('FUBP1', 'Gene', (60, 65))	('CDKN2A', 'Gene', (42, 48))	('p16', 'Gene', '1029', (37, 40))	('SMARCB1', 'Gene', '6598', (11, 18))	('SMARCB1', 'Gene', (11, 18))	('MGMT', 'Gene', '4255', (80, 84))	('SMARCA4', 'Gene', '6597', (27, 34))	('CDKN2A', 'Gene', '1029', (42, 48))	('FUBP1', 'Gene', '8880', (60, 65))	('CIC', 'Gene', (51, 54))	('BRG1', 'Gene', '6597', (21, 25))	('SMARCA4', 'Gene', (27, 34))	('MGMT', 'Gene', (80, 84))	('BRG1', 'Gene', (21, 25))	('CIC', 'Gene', '23152', (51, 54))	('INI-1', 'Gene', '6598', (4, 9))	('p16', 'Gene', (37, 40))
233237	28535583	TP53 mutations are detected by the complete loss of expression or overexpression via the stabilization of the mutant protein.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutant', 'Var', (110, 116))	('protein', 'Protein', (117, 124))	('expression', 'MPA', (52, 62))	('mutations', 'Var', (5, 14))	('stabilization', 'MPA', (89, 102))	('loss', 'NegReg', (44, 48))	('overexpression', 'PosReg', (66, 80))
233239	28535583	For example, p53 nuclear overexpression reflects a TP53 mutation, and p16 nuclear and cytoplasmic losses are associated with a CDKN2A homozygous deletion.	('associated', 'Reg', (109, 119))	('TP53', 'Gene', (51, 55))	('p16', 'Gene', '1029', (70, 73))	('p53', 'Gene', '7157', (13, 16))	('CDKN2A', 'Gene', (127, 133))	('p53', 'Gene', (13, 16))	('p16', 'Gene', (70, 73))	('mutation', 'Var', (56, 64))	('overexpression', 'PosReg', (25, 39))	('CDKN2A', 'Gene', '1029', (127, 133))	('TP53', 'Gene', '7157', (51, 55))
233240	28535583	Furthermore, the nuclear loss of ATRX is associated with an ATRX mutation, and MLH1, MSH2, and PMS nuclear losses are associated with methylation of these genes.	('associated', 'Reg', (41, 51))	('MSH2', 'Gene', (85, 89))	('ATRX', 'Gene', '546', (33, 37))	('nuclear', 'MPA', (17, 24))	('MSH2', 'Gene', '4436', (85, 89))	('ATRX', 'Gene', '546', (60, 64))	('MLH1', 'Gene', '4292', (79, 83))	('MLH1', 'Gene', (79, 83))	('mutation', 'Var', (65, 73))	('losses', 'NegReg', (107, 113))	('associated', 'Reg', (118, 128))	('loss', 'NegReg', (25, 29))	('ATRX', 'Gene', (33, 37))	('methylation', 'MPA', (134, 145))	('ATRX', 'Gene', (60, 64))
233243	28535583	This is because p53 immunoreactivity may have resulted from the prolongation of half-life either due to p53 mutations or the accumulation of wild type protein brought about by mechanisms other than those caused by mutations, such as a complex formation with MDM2 overexpression products, whereas p53 negativity can be observed by the methylation of the TP53 promoter.	('p53', 'Gene', (104, 107))	('p53', 'Gene', (296, 299))	('p53', 'Gene', '7157', (296, 299))	('mutations', 'Var', (108, 117))	('p53', 'Gene', '7157', (104, 107))	('prolongation', 'PosReg', (64, 76))	('p53', 'Gene', (16, 19))	('half-life', 'MPA', (80, 89))	('accumulation', 'PosReg', (125, 137))	('p53', 'Gene', '7157', (16, 19))	('MDM2', 'Gene', '4193', (258, 262))	('MDM2', 'Gene', (258, 262))	('TP53', 'Gene', '7157', (353, 357))	('TP53', 'Gene', (353, 357))
233244	28535583	Therefore, overexpression of p53 protein is not always associated with mutations in conserved exons of the p53 gene.	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('p53', 'Gene', (29, 32))	('mutations in', 'Var', (71, 83))	('p53', 'Gene', '7157', (29, 32))
233246	28535583	Therefore, the mutations of IDH 1/2, BRAF, CTNNB1, H3F3A (K27M, G34), TP53, ATRX, and TERTp are usually detected by direct sequencing.	('IDH 1/2', 'Gene', '3417;3418', (28, 35))	('ATRX', 'Gene', '546', (76, 80))	('BRAF', 'Gene', '673', (37, 41))	('TP53', 'Gene', '7157', (70, 74))	('TERTp', 'Gene', (86, 91))	('mutations', 'Var', (15, 24))	('H3F3A', 'Gene', '3020', (51, 56))	('BRAF', 'Gene', (37, 41))	('K27M', 'Mutation', 'p.K27M', (58, 62))	('TERTp', 'Gene', '7015', (86, 91))	('CTNNB1', 'Gene', '1499', (43, 49))	('IDH 1/2', 'Gene', (28, 35))	('TP53', 'Gene', (70, 74))	('ATRX', 'Gene', (76, 80))	('H3F3A', 'Gene', (51, 56))	('CTNNB1', 'Gene', (43, 49))
233248	28535583	In order to detect mutations in CIC (missense mutations or small in-frame deletions) and FUBP1 (indel, splicing alteration, and nonsense mutations) in the functional regions such as the HMG box and CI motif, NGS is required because the mutation sites of these two genes are widely distributed along the coding regions.	('CIC', 'Gene', '23152', (32, 35))	('CIC', 'Gene', (32, 35))	('mutations', 'Var', (19, 28))	('FUBP1', 'Gene', (89, 94))	('FUBP1', 'Gene', '8880', (89, 94))
233251	28535583	Various gene alterations can be detected by pyrosequencing, including IDH1/IDH2 mutations, TERTp mutation and MGMT methylation.	('MGMT', 'Gene', '4255', (110, 114))	('MGMT', 'Gene', (110, 114))	('mutations', 'Var', (80, 89))	('IDH2', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (70, 74))	('TERTp', 'Gene', (91, 96))	('IDH2', 'Gene', '3418', (75, 79))	('TERTp', 'Gene', '7015', (91, 96))	('IDH1', 'Gene', (70, 74))
233254	28535583	FISH studies can be easily used to identify chromosomal aberrations, such as a 1p/19q codeletion, EGFR amplification or high polysomy, PTEN and CDKN2A homozygous or hemizygous deletions, C-MYC and N-MYC amplifications, BRAF fusions or copy gains, C11orf95-RELA fusions, C11orf95-YAP1 fusions, YAP1-MAMLD1 fusions, and MYB-QKI fusions.	('QKI', 'Gene', (322, 325))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (44, 67))	('YAP1', 'Gene', (279, 283))	('C-MYC', 'Gene', '4609', (187, 192))	('PTEN', 'Gene', '5728', (135, 139))	('YAP1', 'Gene', '10413', (293, 297))	('C-MYC', 'Gene', (187, 192))	('MAMLD1', 'Gene', '10046', (298, 304))	('YAP1', 'Gene', (293, 297))	('CDKN2A', 'Gene', (144, 150))	('deletions', 'Var', (176, 185))	('MYB', 'Gene', '4602', (318, 321))	('MYB', 'Gene', (318, 321))	('copy gains', 'Var', (235, 245))	('C11orf95', 'Gene', (247, 255))	('C11orf95', 'Gene', '65998', (247, 255))	('BRAF', 'Gene', (219, 223))	('CDKN2A', 'Gene', '1029', (144, 150))	('BRAF', 'Gene', '673', (219, 223))	('C11orf95', 'Gene', (270, 278))	('N-MYC', 'Gene', (197, 202))	('MAMLD1', 'Gene', (298, 304))	('YAP1', 'Gene', '10413', (279, 283))	('PTEN', 'Gene', (135, 139))	('QKI', 'Gene', '9444', (322, 325))	('C11orf95', 'Gene', '65998', (270, 278))	('N-MYC', 'Gene', '4613', (197, 202))
233256	28535583	In cases of 1p/19q codeletion, the evaluation and interpretation of FISH results are based on International Society of Pediatric Oncology (SIOP) guidelines for neuroblastoma study.	('neuroblastoma', 'Disease', 'MESH:D009447', (160, 173))	('SIOP', 'Disease', 'None', (139, 143))	('Oncology', 'Phenotype', 'HP:0002664', (129, 137))	('neuroblastoma', 'Disease', (160, 173))	('SIOP', 'Disease', (139, 143))	('neuroblastoma', 'Phenotype', 'HP:0003006', (160, 173))	('1p/19q codeletion', 'Var', (12, 29))
233262	28535583	The most aggressive astrocytic tumors with a dismal prognosis are the GBMs with wild type IDH and DMG, histone-mutant (H3 K27, G34, and K36).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('IDH', 'Gene', (90, 93))	('G34', 'Var', (127, 130))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('aggressive astrocytic tumors', 'Disease', 'MESH:D001254', (9, 37))	('IDH', 'Gene', '3417', (90, 93))	('DMG', 'Chemical', '-', (98, 101))	('aggressive astrocytic tumors', 'Disease', (9, 37))	('H3 K27', 'Var', (119, 125))	('K36', 'Var', (136, 139))
233271	28535583	Diffuse astrocytic tumors and IDH-mutant GBMs are characterized by mutations in IDH1/2, TP53, and ATRX, whereas oligodendrogliomas are characterized by mutations in IDH1/2, CIC, FUBP1, and TERTp, and a codeletion in 1p/19q (whole chromosomal arm deletion) (Fig.	('TERTp', 'Gene', (189, 194))	('TERTp', 'Gene', '7015', (189, 194))	('FUBP1', 'Gene', (178, 183))	('TP53', 'Gene', '7157', (88, 92))	('IDH1/2', 'Gene', '3417;3418', (165, 171))	('oligodendrogliomas', 'Disease', (112, 130))	('IDH', 'Gene', (80, 83))	('astrocytic tumors', 'Disease', (8, 25))	('IDH1/2', 'Gene', (165, 171))	('IDH', 'Gene', (30, 33))	('astrocytic tumors', 'Disease', 'MESH:D001254', (8, 25))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('ATRX', 'Gene', (98, 102))	('FUBP1', 'Gene', '8880', (178, 183))	('IDH', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ATRX', 'Gene', '546', (98, 102))	('IDH', 'Gene', '3417', (80, 83))	('Diffuse', 'Disease', (0, 7))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('TP53', 'Gene', (88, 92))	('IDH', 'Gene', '3417', (30, 33))	('IDH', 'Gene', '3417', (165, 168))	('IDH1/2', 'Gene', '3417;3418', (80, 86))	('mutations', 'Var', (67, 76))	('IDH1/2, CIC', 'Gene', '23152;3417;3418', (165, 176))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (112, 130))	('IDH1/2', 'Gene', (80, 86))
233272	28535583	IDH-wildtype GBMs can be identified by demonstrating a dysregulation of several critical signaling pathways and a lack of the above-mentioned genetic alterations except TERTp mutations, which are common in IDH-wildtype GBM.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', (206, 209))	('critical signaling pathways', 'Pathway', (80, 107))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (206, 209))	('men', 'Species', '9606', (132, 135))	('TERTp', 'Gene', (169, 174))	('mutations', 'Var', (175, 184))	('lack', 'NegReg', (114, 118))	('TERTp', 'Gene', '7015', (169, 174))	('dysregulation', 'Reg', (55, 68))
233273	28535583	The main signaling pathways involved in IDH-wildtype GBMs are RTK/RAS/PI3K pathways (via amplification and mutations in EGFR [EGFRvIII], PIK3CA, RAS, NF1, and MET) and TP53 and RB1 suppressor pathways (via mutations in or loss of TP53, CDKN2A, and RB1 genes) (Fig.	('NF1', 'Gene', (150, 153))	('RB1', 'Gene', '5925', (248, 251))	('PIK3CA', 'Gene', '5290', (137, 143))	('CDKN2A', 'Gene', '1029', (236, 242))	('IDH', 'Gene', (40, 43))	('TP53', 'Gene', '7157', (230, 234))	('TP53', 'Gene', '7157', (168, 172))	('IDH', 'Gene', '3417', (40, 43))	('EGFR', 'Gene', (120, 124))	('PIK3CA', 'Gene', (137, 143))	('loss', 'NegReg', (222, 226))	('RB1', 'Gene', (177, 180))	('RB1', 'Gene', (248, 251))	('mutations', 'Var', (107, 116))	('TP53', 'Gene', (168, 172))	('TP53', 'Gene', (230, 234))	('CDKN2A', 'Gene', (236, 242))	('NF1', 'Gene', '4763', (150, 153))	('mutations in', 'Var', (206, 218))	('RB1', 'Gene', '5925', (177, 180))
233274	28535583	Mutations in IDH1/2 should be studied in diffuse gliomas for the WHO classification of CNS tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('CNS tumors', 'Disease', (87, 97))	('CNS tumors', 'Disease', 'MESH:D009369', (87, 97))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gliomas', 'Disease', (49, 56))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
233277	28535583	P53 and ATRX mutations are now the hallmark of WHO grade II and grade III astrocytic tumors.	('ATRX', 'Gene', (8, 12))	('ATRX', 'Gene', '546', (8, 12))	('astrocytic tumors', 'Disease', (74, 91))	('P53', 'Gene', (0, 3))	('astrocytic tumors', 'Disease', 'MESH:D001254', (74, 91))	('P53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
233278	28535583	TERTp mutations, such as C228T and C250T, are found in more than 90% of oligodendroglial tumors and in more than 80% of GBMs as well as about 30%-40% of lower grade gliomas.	('TERTp', 'Gene', '7015', (0, 5))	('GBMs', 'Disease', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('C228T', 'Var', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('C250T', 'Var', (35, 40))	('C250T', 'Mutation', 'c.250C>T', (35, 40))	('C228T', 'Mutation', 'c.228C>T', (25, 30))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (72, 95))	('gliomas', 'Disease', (165, 172))	('oligodendroglial tumors', 'Disease', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('TERTp', 'Gene', (0, 5))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
233279	28535583	Mutations in TERTp were associated with poor survival and resistance to radiotherapy in GBMs and in lower grade gliomas (grade II and III) without IDH mutation; however, TERTp mutations were associated with a favorable prognosis in lower grade gliomas with IDH mutations.	('gliomas', 'Phenotype', 'HP:0009733', (244, 251))	('TERTp', 'Gene', (13, 18))	('mutations', 'Var', (176, 185))	('IDH', 'Gene', '3417', (147, 150))	('IDH', 'Gene', '3417', (257, 260))	('TERTp', 'Gene', '7015', (13, 18))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('TERTp', 'Gene', (170, 175))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', (112, 119))	('TERTp', 'Gene', '7015', (170, 175))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('gliomas', 'Disease', (244, 251))	('IDH', 'Gene', (147, 150))	('IDH', 'Gene', (257, 260))	('gliomas', 'Disease', 'MESH:D005910', (244, 251))
233280	28535583	Pediatric high-grade gliomas are unique, featuring mutations in H3F3A, ATRX, and DAXX, whereas PLGGs contain mutations or rearrangements in BRAF, FGFR1, or MYB.	('mutations', 'Var', (51, 60))	('ATRX', 'Gene', '546', (71, 75))	('men', 'Species', '9606', (131, 134))	('gliomas', 'Disease', 'MESH:D005910', (21, 28))	('FGFR1', 'Gene', '2260', (146, 151))	('H3F3A', 'Gene', '3020', (64, 69))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('BRAF', 'Gene', '673', (140, 144))	('H3F3A', 'Gene', (64, 69))	('BRAF', 'Gene', (140, 144))	('FGFR1', 'Gene', (146, 151))	('mutations', 'Var', (109, 118))	('rearrangements', 'Var', (122, 136))	('MYB', 'Gene', '4602', (156, 159))	('DAXX', 'Gene', (81, 85))	('MYB', 'Gene', (156, 159))	('gliomas', 'Disease', (21, 28))	('DAXX', 'Gene', '1616', (81, 85))	('ATRX', 'Gene', (71, 75))
233281	28535583	Furthermore, mutations in IDH are rare unless the patient is an adolescent (Fig.	('mutations', 'Var', (13, 22))	('IDH', 'Gene', (26, 29))	('patient', 'Species', '9606', (50, 57))	('IDH', 'Gene', '3417', (26, 29))
233283	28535583	Histone H3 K27M, K36, and G34 mutations should be studied in pediatric glioma arising in the midline of CNS, i.e., the thalamus, pons, and spinal cord.	('G34 mutations', 'Var', (26, 39))	('glioma', 'Disease', (71, 77))	('K27M', 'Mutation', 'p.K27M', (11, 15))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('K36', 'Var', (17, 20))
233286	28535583	Medulloblastomas have been recently divided into several subtypes based on specific driver mutations including WNT, SHH, group 3, and group 4.	('Medulloblastomas', 'Disease', 'MESH:D008527', (0, 16))	('SHH', 'Gene', (116, 119))	('WNT', 'Disease', (111, 114))	('Medulloblastomas', 'Disease', (0, 16))	('SHH', 'Gene', '6469', (116, 119))	('mutations', 'Var', (91, 100))
233287	28535583	Mutations in CTNNB1, DDX3X or monosomy 6 in the Wnt pathway of medulloblastomas tend to lead to a much better prognosis.	('CTNNB1', 'Gene', '1499', (13, 19))	('lead', 'Reg', (88, 92))	('medulloblastomas', 'Disease', 'MESH:D008527', (63, 79))	('DDX3X', 'Gene', '1654', (21, 26))	('CTNNB1', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('medulloblastomas', 'Disease', (63, 79))	('DDX3X', 'Gene', (21, 26))	('Wnt pathway', 'Pathway', (48, 59))	('medulloblastoma', 'Phenotype', 'HP:0002885', (63, 78))	('monosomy 6', 'Var', (30, 40))
233290	28535583	CTNNB1 mutations can be present in classical-type medulloblastomas and adamantinomatous-type craniopharyngiomas.	('CTNNB1', 'Gene', '1499', (0, 6))	('medulloblastoma', 'Phenotype', 'HP:0002885', (50, 65))	('adamantinomatous-type craniopharyngiomas', 'Disease', (71, 111))	('present', 'Reg', (24, 31))	('CTNNB1', 'Gene', (0, 6))	('medulloblastomas', 'Disease', 'MESH:D008527', (50, 66))	('adamantinomatous-type craniopharyngiomas', 'Disease', 'MESH:D003397', (71, 111))	('medulloblastomas', 'Disease', (50, 66))	('mutations', 'Var', (7, 16))
233291	28535583	SMARCB1 (INI1) or SMARCA4 (BRG1) gene mutations or deletions are essential for the diagnosis of AT/RT, which show dismal prognosis.	('INI1', 'Gene', '6598', (9, 13))	('INI1', 'Gene', (9, 13))	('AT', 'Disease', 'None', (96, 98))	('SMARCA4', 'Gene', (18, 25))	('deletions', 'Var', (51, 60))	('SMARCB1', 'Gene', '6598', (0, 7))	('BRG1', 'Gene', (27, 31))	('SMARCA4', 'Gene', '6597', (18, 25))	('mutations', 'Var', (38, 47))	('SMARCB1', 'Gene', (0, 7))	('BRG1', 'Gene', '6597', (27, 31))
233294	28535583	Meningiomas often have mutations in the NF2, AKT1, SMO, and KLF4 genes.	('AKT1', 'Gene', '207', (45, 49))	('NF2', 'Gene', '4771', (40, 43))	('KLF4', 'Gene', (60, 64))	('SMO', 'Gene', '6608', (51, 54))	('AKT1', 'Gene', (45, 49))	('SMO', 'Gene', (51, 54))	('KLF4', 'Gene', '9314', (60, 64))	('mutations', 'Var', (23, 32))	('NF2', 'Gene', (40, 43))	('Meningiomas', 'Phenotype', 'HP:0002858', (0, 11))	('Meningiomas', 'Disease', 'MESH:D008577', (0, 11))	('Meningiomas', 'Disease', (0, 11))
233295	28535583	Furthermore, meningiomas with mutant NF2 are far more likely to exhibit atypical grade II features than the other subtypes.	('NF2', 'Gene', '4771', (37, 40))	('meningiomas', 'Phenotype', 'HP:0002858', (13, 24))	('meningioma', 'Phenotype', 'HP:0002858', (13, 23))	('meningiomas', 'Disease', 'MESH:D008577', (13, 24))	('NF2', 'Gene', (37, 40))	('meningiomas', 'Disease', (13, 24))	('mutant', 'Var', (30, 36))
233296	28535583	Recurrent mutations in KLF4, AKT1, and SMO genes are often present in NF2-negative sporadic meningiomas.	('KLF4', 'Gene', (23, 27))	('meningiomas', 'Phenotype', 'HP:0002858', (92, 103))	('present', 'Reg', (59, 66))	('SMO', 'Gene', (39, 42))	('NF2', 'Gene', (70, 73))	('meningioma', 'Phenotype', 'HP:0002858', (92, 102))	('AKT1', 'Gene', '207', (29, 33))	('sporadic meningiomas', 'Disease', 'MESH:D008577', (83, 103))	('NF2', 'Gene', '4771', (70, 73))	('SMO', 'Gene', '6608', (39, 42))	('sporadic meningiomas', 'Disease', (83, 103))	('mutations', 'Var', (10, 19))	('AKT1', 'Gene', (29, 33))	('KLF4', 'Gene', '9314', (23, 27))
233297	28535583	Clinical trials involving SMO/AKT/NF2 inhibitors are open for patients with progressive meningiomas with SMO/AKT/NF2 mutations.	('meningioma', 'Phenotype', 'HP:0002858', (88, 98))	('mutations', 'Var', (117, 126))	('meningiomas', 'Phenotype', 'HP:0002858', (88, 99))	('NF2', 'Gene', (34, 37))	('NF2', 'Gene', '4771', (113, 116))	('AKT', 'Gene', '207', (109, 112))	('AKT', 'Gene', '207', (30, 33))	('meningiomas', 'Disease', 'MESH:D008577', (88, 99))	('SMO', 'Gene', '6608', (105, 108))	('patients', 'Species', '9606', (62, 70))	('NF2', 'Gene', '4771', (34, 37))	('meningiomas', 'Disease', (88, 99))	('SMO', 'Gene', '6608', (26, 29))	('SMO', 'Gene', (26, 29))	('SMO', 'Gene', (105, 108))	('AKT', 'Gene', (30, 33))	('NF2', 'Gene', (113, 116))	('AKT', 'Gene', (109, 112))
233303	28535583	For example, clinical trials are now open for GBMs with EGFRvIII mutations, vemurafenib is being evaluated in BRAF V600E mutant gliomas, and clinical response has already been observed in FGFR3-TACC3-positive patients treated with an FGFR inhibitor.	('V600E', 'Mutation', 'rs113488022', (115, 120))	('FGFR3', 'Gene', '2261', (188, 193))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('EGFRvIII', 'Gene', (56, 64))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('vemurafenib', 'Chemical', 'MESH:D000077484', (76, 87))	('FGFR3', 'Gene', (188, 193))	('TACC3', 'Gene', '10460', (194, 199))	('patients', 'Species', '9606', (209, 217))	('BRAF', 'Gene', '673', (110, 114))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('TACC3', 'Gene', (194, 199))	('BRAF', 'Gene', (110, 114))	('mutations', 'Var', (65, 74))
233355	20838435	We reanalyzed the survival data excluding these two cases (HF1150 and HF0510), and none of the statistical findings were affected, except that the p-value for HR comparing classic and proneural oligodendrogliomas increased to 0.0595 (marginally significant) from 0.0100 (significant), which is not too surprising given that the sample size of the oligodendrogliomas was reduced by two.	('neural oligodendrogliomas', 'Disease', (187, 212))	('oligodendrogliomas', 'Disease', (194, 212))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Phenotype', 'HP:0009733', (358, 365))	('neural oligodendrogliomas', 'Disease', 'MESH:D009837', (187, 212))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (347, 365))	('HF0510', 'CellLine', 'CVCL:9A50', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (358, 364))	('HF0510', 'Var', (70, 76))	('HF1150', 'CellLine', 'CVCL:M656', (59, 65))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (194, 212))	('oligodendrogliomas', 'Disease', (347, 365))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
233359	20838435	While there were relatively few neural (n = 3) and classic (n = 5) oligodendrogliomas with SNP data, and no mesenchymal oligodendrogliomas, we did note that they generally contained either 1p deletion or 19q deletion, but not both deletions in any given tumor sample.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('19q deletion', 'Var', (204, 216))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (120, 138))	('tumor', 'Disease', (254, 259))	('1p deletion', 'Var', (189, 200))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('oligodendrogliomas', 'Disease', (67, 85))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('oligodendrogliomas', 'Disease', (120, 138))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
233373	20838435	Twelve of the 42 oligodendrogliomas showed co-deletion of at least 85% of chromosomes 1p and 19q, and eleven of those twelve samples were PN-oligos.	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (17, 35))	('oligodendrogliomas', 'Disease', (17, 35))	('co-deletion', 'Var', (43, 54))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))
233374	20838435	The other sample with co-deletion of 1p/19q was a classic oligodendroglioma.	('oligodendroglioma', 'Disease', 'MESH:D009837', (58, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('oligodendroglioma', 'Disease', (58, 75))	('co-deletion of', 'Var', (22, 36))
233383	20838435	Several components of the Notch pathway, including DLL3 and HEY2 are reduced in PN-GBM, while NOV/CCN3, which is associated with Notch inhibition was increased.	('DLL3', 'Gene', '10683', (51, 55))	('HEY2', 'Gene', (60, 64))	('reduced', 'NegReg', (69, 76))	('HEY2', 'Gene', '23493', (60, 64))	('Notch pathway', 'Pathway', (26, 39))	('PN-GBM', 'Var', (80, 86))	('CCN3', 'Gene', (98, 102))	('CCN3', 'Gene', '4856', (98, 102))	('DLL3', 'Gene', (51, 55))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))
233387	20838435	Finally, we observed reduced expression of the pro-apoptotic Bcl2 family member, BH3 interacting domain death agonist (BID) in high-grade proneural gliomas, suggesting that loss of BID expression promotes survival of these high-grade tumors.	('promotes', 'PosReg', (196, 204))	('gliomas', 'Disease', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('death', 'Disease', (104, 109))	('survival', 'CPA', (205, 213))	('BID', 'Gene', (119, 122))	('BH3', 'Chemical', 'MESH:C006008', (81, 84))	('Bcl2', 'Gene', (61, 65))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('BID', 'Gene', '637', (119, 122))	('Bcl2', 'Gene', '596', (61, 65))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('loss', 'Var', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('BID', 'Gene', (181, 184))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('death', 'Disease', 'MESH:D003643', (104, 109))	('BID', 'Gene', '637', (181, 184))	('expression', 'MPA', (29, 39))	('reduced', 'NegReg', (21, 28))	('tumors', 'Disease', (234, 240))
233398	32433577	Diffuse midline glioma, H3K27M-mutant is a new entity introduced to HGG in the latest WHO classification.	('K27M', 'Mutation', 'p.K27M', (26, 30))	('midline glioma', 'Disease', 'MESH:D005910', (8, 22))	('midline glioma', 'Disease', (8, 22))	('H3K27M-mutant', 'Var', (24, 37))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))
233400	32433577	Samples were screened for the mutation in histone H3.3 and H3.1 variants to examine its prevalence, prognostic impact, and assess its potential clinical value in limited resource settings.	('H3.1', 'Gene', (59, 63))	('histone H3.3', 'Gene', '3020', (42, 54))	('mutation', 'Var', (30, 38))	('H3.1', 'Gene', '8352', (59, 63))	('variants', 'Var', (64, 72))	('histone H3.3', 'Gene', (42, 54))
233401	32433577	H3K27M mutation was detected in 28 of 105 (26.7%) samples, and its distribution was significantly associated with midline locations (p-value < 0.0001) and HGG (p-value = 0.003).	('HGG', 'Disease', (155, 158))	('K27M', 'Mutation', 'p.K27M', (2, 6))	('midline', 'Disease', (114, 121))	('H3K27M', 'Var', (0, 6))	('associated', 'Reg', (98, 108))
233402	32433577	Overall and event- free survival (OS and EFS, respectively) of patients with mutant tumors did not differ significantly, neither according to histologic grade (OS p-value = 0.736, EFS p-value = 0.75) nor across anatomical sites (OS p-value = 0.068, EFS p-value = 0.153).	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patients', 'Species', '9606', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('mutant', 'Var', (77, 83))
233413	32433577	Recent studies have reported a high frequency of two point mutations in the genes of the histone variants H3.3 "H3F3A", and to a lesser extent H3.1 "HIST1H3B", which results in substitution of lysine amino acid at position 27 with methionine (K27M) or glycine at position 34 with arginine or valine (G34V/R).	('valine', 'Chemical', 'MESH:D014633', (292, 298))	('H3F3A', 'Gene', (112, 117))	('K27M', 'Mutation', 'p.K27M', (243, 247))	('G34V', 'Var', (300, 304))	('substitution', 'Reg', (177, 189))	('glycine at position 34 with arginine', 'Mutation', 'rs1057519902', (252, 288))	('H3.1', 'Gene', '8352', (143, 147))	('K27M', 'Var', (243, 247))	('G34V', 'SUBSTITUTION', 'None', (300, 304))	('lysine amino acid at position 27 with methionine', 'Mutation', 'p.LYSINEAMINO27M', (193, 241))	('H3.3', 'Gene', (106, 110))	('H3F3A', 'Gene', '3020', (112, 117))	('HIST1H3B', 'Gene', (149, 157))	('HIST1H3B', 'Gene', '8358', (149, 157))	('H3.1', 'Gene', (143, 147))
233414	32433577	Notably, these were the first reported histone mutations associated with human malignancies.	('histone', 'Protein', (39, 46))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('mutations', 'Var', (47, 56))	('human', 'Species', '9606', (73, 78))	('malignancies', 'Disease', (79, 91))	('associated', 'Reg', (57, 67))
233415	32433577	Further reports highlighted the association of K27M mutation with midline gliomas (MLG) and G34V/R mutation with gliomas of the cerebral hemispheres.	('G34V', 'SUBSTITUTION', 'None', (92, 96))	('K27M', 'Mutation', 'p.K27M', (47, 51))	('G34V', 'Var', (92, 96))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('association', 'Reg', (32, 43))	('K27M mutation', 'Var', (47, 60))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('midline gliomas', 'Disease', (66, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('midline gliomas', 'Disease', 'MESH:D005910', (66, 81))
233416	32433577	Mutation of the Lys 27 residue in the N-terminal tail of the H3 variants invokes disruption in post-translational modifications (methylation and acetylation) and could potentially alter the expression of oncogenes and tumor suppressor genes.	('oncogenes', 'Gene', (204, 213))	('Lys', 'Chemical', 'MESH:D008239', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Mutation', 'Var', (0, 8))	('expression', 'MPA', (190, 200))	('disruption', 'Reg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('invokes', 'Reg', (73, 80))	('tumor', 'Disease', (218, 223))	('alter', 'Reg', (180, 185))	('variants', 'Var', (64, 72))
233418	32433577	In its latest version of CNS tumors classification, the World Health Organization (WHO) included a novel entity called "diffuse midline glioma, H3 K27M-mutant".	('midline glioma', 'Disease', 'MESH:D005910', (128, 142))	('K27M', 'Mutation', 'p.K27M', (147, 151))	('midline glioma', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CNS tumors', 'Disease', 'MESH:D016543', (25, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('H3 K27M-mutant', 'Var', (144, 158))	('CNS tumors', 'Disease', (25, 35))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
233421	32433577	Radiologically confirmed diffuse intrinsic pontine gliomas (DIPGs) that harbor the mutation, which constitute 70 to 90% of DIPGs, are now included within this category.	('gliomas', 'Disease', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('mutation', 'Var', (83, 91))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
233423	32433577	In this study we screened for the K27M and G34V/R mutations in H3F3A and HIST1H3B variants in a cohort of histologically and anatomically diverse pediatric Egyptian glial brain tumor samples.	('G34V', 'SUBSTITUTION', 'None', (43, 47))	('G34V', 'Var', (43, 47))	('H3F3A', 'Gene', '3020', (63, 68))	('K27M', 'Mutation', 'p.K27M', (34, 38))	('H3F3A', 'Gene', (63, 68))	('HIST1H3B', 'Gene', (73, 81))	('HIST1H3B', 'Gene', '8358', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('K27M', 'Var', (34, 38))	('brain tumor', 'Phenotype', 'HP:0030692', (171, 182))	('glial brain tumor', 'Disease', (165, 182))	('glial brain tumor', 'Disease', 'MESH:D001927', (165, 182))
233428	32433577	None of the 105 tumor samples harbored H3G34V/R mutation (Table 1).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('H3G34V/R', 'Var', (39, 47))	('tumor', 'Disease', (16, 21))	('G34V/R', 'Mutation', 'rs1057519902', (41, 47))
233429	32433577	Among H3K27M mutant tumors, 82% (n = 23) were detected in the H3F3A gene and 17.8% (n = 5) in the HIST1H3B gene.	('mutant', 'Var', (13, 19))	('tumors', 'Disease', (20, 26))	('HIST1H3B', 'Gene', (98, 106))	('HIST1H3B', 'Gene', '8358', (98, 106))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('H3F3A', 'Gene', '3020', (62, 67))	('detected', 'Reg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('H3K27M', 'Gene', (6, 12))	('H3F3A', 'Gene', (62, 67))	('K27M', 'Mutation', 'p.K27M', (8, 12))
233430	32433577	H3F3A K27M mutant tumors were all MLG, and histologically classified as HGG (n = 18) and LGG (n = 5).	('HGG', 'Disease', (72, 75))	('H3F3A', 'Gene', '3020', (0, 5))	('H3F3A', 'Gene', (0, 5))	('K27M', 'Mutation', 'p.K27M', (6, 10))	('tumors', 'Disease', (18, 24))	('K27M mutant', 'Var', (6, 17))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('LGG', 'Disease', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
233431	32433577	On the other hand, HIST1H3B K27M mutant tumors were distributed as MLG (n = 4) and non-MLG (n = 1), and all of them were histologically classified as HGG.	('HIST1H3B', 'Gene', '8358', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('K27M', 'Mutation', 'p.K27M', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('HIST1H3B', 'Gene', (19, 27))	('K27M mutant', 'Var', (28, 39))	('tumors', 'Disease', (40, 46))
233432	32433577	Mean age at diagnosis for patients with H3F3A mutant tumors was 9.4 years, compared to 5.9 years for patients with HIST1H3B mutant tumors.	('H3F3A', 'Gene', '3020', (40, 45))	('patients', 'Species', '9606', (101, 109))	('H3F3A', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('patients', 'Species', '9606', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutant', 'Var', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('HIST1H3B', 'Gene', (115, 123))	('HIST1H3B', 'Gene', '8358', (115, 123))	('tumors', 'Disease', (53, 59))
233436	32433577	Thalamic gliomas represented 39.2% (n = 29) of MLG, including 13 cases with H3K27M mutation.	('K27M', 'Mutation', 'p.K27M', (78, 82))	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('H3K27M mutation', 'Var', (76, 91))
233442	32433577	Among histologically classified HGG (n = 60), 38.3% of cases had H3K27M mutation (n = 23).	('K27M', 'Mutation', 'p.K27M', (67, 71))	('H3K27M mutation', 'Var', (65, 80))	('HGG', 'Disease', (32, 35))
233446	32433577	H3K27M mutation was detected in midline AA (n = 11/15) and non-midline AA (n = 1/3).	('detected', 'Reg', (20, 28))	('K27M', 'Mutation', 'p.K27M', (2, 6))	('AA', 'Phenotype', 'HP:0009592', (40, 42))	('AA', 'Phenotype', 'HP:0009592', (71, 73))	('midline AA', 'Disease', (32, 42))	('H3K27M', 'Var', (0, 6))
233447	32433577	Two remaining cases of mutant HGG were a case of anaplastic ganglioglioma and another case of HGG, not otherwise specified (NOS) (Fig.	('HGG', 'Gene', (30, 33))	('anaplastic ganglioglioma', 'Disease', (49, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('mutant', 'Var', (23, 29))	('anaplastic ganglioglioma', 'Disease', 'MESH:D018303', (49, 73))
233448	32433577	In histologically classified LGG (n = 45), H3K27M mutation was detected in 11.1% (n = 5) cases.	('LGG', 'Disease', (29, 32))	('K27M', 'Mutation', 'p.K27M', (45, 49))	('detected', 'Reg', (63, 71))	('H3K27M mutation', 'Var', (43, 58))
233450	32433577	Univariate Cox proportional hazards analysis for age, tumor site, histological grade and H3K27M mutation identified histological grade and mutation status to have a significant impact on both overall survival (OS) and event-free survival (EFS) (p-value < 0.0001) (Table 2).	('impact', 'Reg', (177, 183))	('K27M', 'Mutation', 'p.K27M', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('event-free', 'MPA', (218, 228))	('mutation', 'Var', (96, 104))	('H3K27M', 'Gene', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('overall survival', 'MPA', (192, 208))	('tumor', 'Disease', (54, 59))
233452	32433577	The median OS for H3F3A mutant cases was 9.4 months compared to 12.6 months for HIST1H3B mutant cases (p-value = 0.435).	('mutant', 'Var', (24, 30))	('H3F3A', 'Gene', '3020', (18, 23))	('H3F3A', 'Gene', (18, 23))	('HIST1H3B', 'Gene', (80, 88))	('HIST1H3B', 'Gene', '8358', (80, 88))
233454	32433577	The mutation had a significant impact on the OS (p-value = 0.001) in LGG (Online resource 2a) while in HGG, the presence of H3K27M mutation was significantly correlated with inferior outcome in both OS (p-value = 0.035) and EFS (p-value = 0.012) (Online resource 2c and d respectively).	('H3K27M', 'Var', (124, 130))	('LGG', 'Disease', (69, 72))	('K27M', 'Mutation', 'p.K27M', (126, 130))	('presence', 'Var', (112, 120))	('impact', 'Reg', (31, 37))
233457	32433577	The mutation retained its impact on survival across different anatomical sites, with no significant difference between mutant DIPG, FBSG, and thalamic tumors (the median OS for DIPG = 6.5, FBSG = 32.5 and thalamic = 11.6 months, p-value = 0.068, median EFS of 4.6, 3.6 and 5.3 months, respectively, p-value = 0.153), (Fig.	('FBSG', 'Disease', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DIPG', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('thalamic tumors', 'Disease', 'MESH:D013786', (142, 157))	('mutant', 'Var', (119, 125))	('thalamic tumors', 'Disease', (142, 157))
233458	32433577	Patients with mutant MLG had inferior survival outcomes when compared to wild-type HGG; OS (p-value = 0.027) (Fig.	('inferior', 'NegReg', (29, 37))	('mutant', 'Var', (14, 20))	('survival', 'CPA', (38, 46))	('Patients', 'Species', '9606', (0, 8))	('MLG', 'Gene', (21, 24))
233459	32433577	The poor impact of H3K27M mutation on survival was evident in thalamic gliomas compared to wild type; OS (p-value = 0.006), (Online resource 2e) and EFS (p-value = 0.003), (Online resource 2 f), while it was not tested in DIPGs due to low number of wild-type cases.	('K27M', 'Mutation', 'p.K27M', (21, 25))	('mutation', 'Var', (26, 34))	('thalamic gliomas', 'Disease', 'MESH:D013786', (62, 78))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('H3K27M', 'Protein', (19, 25))	('thalamic gliomas', 'Disease', (62, 78))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))
233461	32433577	Accordingly, we evaluated 105 pediatric gliomas for point mutations in the most common H3 variants (H3F3A and HIST3H3B).	('H3F3A', 'Gene', '3020', (100, 105))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('H3F3A', 'Gene', (100, 105))	('point mutations', 'Var', (52, 67))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
233464	32433577	The mutation was significantly associated with high-grade histology and midline tumors.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutation', 'Var', (4, 12))	('associated', 'Reg', (31, 41))	('midline tumors', 'Disease', 'MESH:D009436', (72, 86))	('midline tumors', 'Disease', (72, 86))	('high-grade histology', 'CPA', (47, 67))
233465	32433577	The presence of mutation was correlated with inferior outcome compared to wild-type tumors, regardless of their histologic grading or anatomical location.	('mutation', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
233467	32433577	On the other hand, H3.3 K27M mutant tumors are seen in almost two-thirds of DIPG cases, as well as other midline HGG.	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('K27M', 'Mutation', 'p.K27M', (24, 28))	('DIPG', 'Disease', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('H3.3 K27M mutant', 'Var', (19, 35))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
233469	32433577	In contrast, G34V/R mutant tumors commonly arise in adolescents and young adults.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('G34V', 'SUBSTITUTION', 'None', (13, 17))	('G34V', 'Var', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))
233470	32433577	G34V/R mutant tumors are typically restricted to cerebral hemispheres and are not seen in midline locations.	('G34V', 'SUBSTITUTION', 'None', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('G34V', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
233471	32433577	This location specificity of histone-mutant tumors suggests that HGG harboring H3K27M and G34V/R mutations may arise from different cells of origin, or the same cell at different stages of differentiation, and are principally distinct diseases.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('K27M', 'Mutation', 'p.K27M', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('G34V', 'SUBSTITUTION', 'None', (90, 94))	('arise', 'Reg', (111, 116))	('G34V', 'Var', (90, 94))	('H3K27M', 'Var', (79, 85))	('HGG', 'Disease', (65, 68))
233472	32433577	Moreover, previous studies have highlighted the association of histone mutations with anatomical tumor location, age of patients, and overall prognosis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('association', 'Interaction', (48, 59))	('tumor', 'Disease', (97, 102))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (120, 128))	('histone', 'Protein', (63, 70))
233473	32433577	For instance, H3K27M mutant tumors are known to arise predominantly in midline structures such as the thalamus, pons, and spinal cord.	('K27M', 'Mutation', 'p.K27M', (16, 20))	('mutant', 'Var', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('H3K27M', 'Gene', (14, 20))
233474	32433577	While our GBM cases were equally distributed between midline and non-midline locations, H3K27M mutations were only detected in midline GBM and were coupled with a dismal prognosis.	('H3K27M', 'Gene', (88, 94))	('K27M', 'Mutation', 'p.K27M', (90, 94))	('mutations', 'Var', (95, 104))
233475	32433577	found that pediatric H3K27M mutant tumors in midline locations, including the brainstem and thalamus were associated with very poor survival.	('mutant', 'Var', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', (35, 41))	('H3K27M', 'Protein', (21, 27))	('K27M', 'Mutation', 'p.K27M', (23, 27))
233476	32433577	Our study illustrates the similarities in H3F3A and HIST1H3B genes mutations in MLG among populations with different socioeconomic environment and genetic background.	('MLG', 'Gene', (80, 83))	('H3F3A', 'Gene', '3020', (42, 47))	('mutations', 'Var', (67, 76))	('H3F3A', 'Gene', (42, 47))	('HIST1H3B', 'Gene', (52, 60))	('HIST1H3B', 'Gene', '8358', (52, 60))
233477	32433577	raised the possibility of different epigenetic histone methyltransferase mutations according to race and ethnicity.	('histone methyltransferase', 'Gene', (47, 72))	('histone methyltransferase', 'Gene', '56979', (47, 72))	('epigenetic', 'Var', (36, 46))
233478	32433577	were able to demonstrate different frequencies of genetic and epigenetic mutation in leukemogenesis in Arab Asian children when compared to Western, Taiwanese and Japanese children.	('genetic', 'Var', (50, 57))	('children', 'Species', '9606', (114, 122))	('epigenetic mutation', 'Var', (62, 81))	('leukemogenesis', 'Disease', (85, 99))	('children', 'Species', '9606', (172, 180))
233480	32433577	Moreover, there was no predictive power for the anatomical location (thalamic vs. DIPG vs. FBSG) on the survival outcome of mutant MLG, consistent with previous reports indicating the presence of H3K27M mutation as an independent negative prognostic marker in DIPG and thalamic gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (278, 285))	('MLG', 'Gene', (131, 134))	('thalamic gliomas', 'Disease', 'MESH:D013786', (269, 285))	('mutant', 'Var', (124, 130))	('thalamic gliomas', 'Disease', (269, 285))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('H3K27M', 'Var', (196, 202))	('K27M', 'Mutation', 'p.K27M', (198, 202))
233483	32433577	However, all LGG patients who were H3K27M mutant had significantly lower survival with a median OS of 17.1 months, compared to the median OS exceeding 3 years (median OS not reached) in the wild-type group.	('survival', 'MPA', (73, 81))	('patients', 'Species', '9606', (17, 25))	('H3K27M mutant', 'Var', (35, 48))	('LGG', 'Disease', (13, 16))	('lower', 'NegReg', (67, 72))	('K27M', 'Mutation', 'p.K27M', (37, 41))
233484	32433577	Thus, it is reasonable to suggest that in histologically classified LGG, H3K27M mutant tumors should be treated more aggressively.	('LGG', 'Disease', (68, 71))	('K27M', 'Mutation', 'p.K27M', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('H3K27M mutant', 'Var', (73, 86))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
233491	32433577	These histone mutations provide clinicians with better insights into patients' prognosis, and help prioritizing and tailoring the management of pediatric malignant gliomas.	('malignant gliomas', 'Disease', (154, 171))	('malignant gliomas', 'Disease', 'MESH:D005910', (154, 171))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('patients', 'Species', '9606', (69, 77))	('mutations', 'Var', (14, 23))
233495	32433577	This study is the first report on histone mutations in pediatric gliomas in Egypt - a LMIC - that coincides with those reported from international studies.	('gliomas', 'Disease', (65, 72))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('histone', 'Protein', (34, 41))	('mutations', 'Var', (42, 51))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
233497	32433577	Although the trend of poor prognosis was preserved in HGG compared to LGG, the presence of H3K27M mutation identified cases with worse outcome within each of these groups.	('presence', 'Var', (79, 87))	('K27M', 'Mutation', 'p.K27M', (93, 97))	('H3K27M', 'Gene', (91, 97))
233498	32433577	This highlights the fact that H3K27M status is a very important supplement to histological grading of gliomas for appropriate clinico-pathological diagnosis.	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('K27M', 'Mutation', 'p.K27M', (32, 36))	('gliomas', 'Disease', (102, 109))	('H3K27M status', 'Var', (30, 43))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))
233499	32433577	Testing for H3K27M mutations should be pursued in all pediatric midline gliomas independent of their histologic appearance or grade.	('midline gliomas', 'Disease', (64, 79))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('mutations', 'Var', (19, 28))	('H3K27M', 'Protein', (12, 18))	('K27M', 'Mutation', 'p.K27M', (14, 18))	('midline gliomas', 'Disease', 'MESH:D005910', (64, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))
233508	32433577	Template DNA was amplified using H3F3A primers which were designed to cover the region encoding Lys27 and Gly34 in Histone H3.3 (forward: TGGCTCGTACAAAGCAGACT, reverse: ATGGATACATACAAGAGAGACT).	('Lys27', 'Var', (96, 101))	('H3F3A', 'Gene', (33, 38))	('Gly34', 'Chemical', '-', (106, 111))	('Lys27', 'Chemical', '-', (96, 101))	('Gly34', 'Var', (106, 111))	('Histone H3.3', 'Gene', '3020', (115, 127))	('H3F3A', 'Gene', '3020', (33, 38))	('AA', 'Phenotype', 'HP:0009592', (181, 183))	('Histone H3.3', 'Gene', (115, 127))	('AA', 'Phenotype', 'HP:0009592', (148, 150))
233509	32433577	HIST1H3B primers amplified the region encoding Lys27 and Gly34 in Histone H3.1 (forward: GTTTTGCCATGGCTCGTACT, reverse: AAGCGAAGATCGGTCTTGAA).	('Gly34', 'Chemical', '-', (57, 62))	('AA', 'Phenotype', 'HP:0009592', (138, 140))	('Gly34', 'Var', (57, 62))	('HIST1H3B', 'Gene', (0, 8))	('HIST1H3B', 'Gene', '8358', (0, 8))	('AA', 'Phenotype', 'HP:0009592', (120, 122))	('Histone H3.1', 'Gene', (66, 78))	('Lys27', 'Var', (47, 52))	('AA', 'Phenotype', 'HP:0009592', (125, 127))	('Lys27', 'Chemical', '-', (47, 52))	('Histone H3.1', 'Gene', '8358', (66, 78))
233663	32373523	Reversible epigenetic modifications can influence gene expression without altering the DNA sequence, and thus determine cell differentiation and development.	('gene expression', 'MPA', (50, 65))	('influence', 'Reg', (40, 49))	('epigenetic modifications', 'Var', (11, 35))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('determine', 'Reg', (110, 119))	('development', 'CPA', (145, 156))	('cell differentiation', 'CPA', (120, 140))
233667	32373523	Aberant DNA hypermethylation of tumor suppressor gene promoter region results in gene silencing, which subsequently leads to dysregulation of diverse signaling pathways associated with human malignancies.	('dysregulation', 'MPA', (125, 138))	('human', 'Species', '9606', (185, 190))	('DNA', 'Var', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('gene', 'MPA', (81, 85))	('tumor', 'Disease', (32, 37))	('diverse signaling pathways', 'Pathway', (142, 168))	('malignancies', 'Disease', (191, 203))	('leads to', 'Reg', (116, 124))
233669	32373523	Patients with glioblastoma (GBM) containing a methylated MGMT promoter can benefited from TMZ therapy.	('TMZ', 'Chemical', 'MESH:D000077204', (90, 93))	('glioblastoma', 'Disease', (14, 26))	('Patients', 'Species', '9606', (0, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (14, 26))	('MGMT', 'Gene', '4255', (57, 61))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('MGMT', 'Gene', (57, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('methylated', 'Var', (46, 56))
233673	32373523	Among them, m6A is the most prevalent form of internal mRNA methylation.	('internal mRNA methylation', 'MPA', (46, 71))	('m6A', 'Var', (12, 15))	('m6A', 'Chemical', '-', (12, 15))	('prevalent', 'Reg', (28, 37))	('R', 'Chemical', 'MESH:D001120', (56, 57))
233674	32373523	RNA methylation has diverse effects on RNA metabolism, including RNA processing, RNA splicing, mRNA export, mRNA translation, and decay.	('RNA metabolism', 'MPA', (39, 53))	('R', 'Chemical', 'MESH:D001120', (109, 110))	('effects', 'Reg', (28, 35))	('R', 'Chemical', 'MESH:D001120', (39, 40))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('methylation', 'Var', (4, 15))	('RNA processing', 'MPA', (65, 79))	('decay', 'MPA', (130, 135))	('R', 'Chemical', 'MESH:D001120', (81, 82))	('RNA splicing', 'MPA', (81, 93))	('R', 'Chemical', 'MESH:D001120', (96, 97))	('mRNA export', 'MPA', (95, 106))	('R', 'Chemical', 'MESH:D001120', (65, 66))	('mRNA translation', 'MPA', (108, 124))
233675	32373523	The m6A mRNA modification is critical for glioblastoma stem cells (GSCs) self-renewal and tumorigenesis.	('R', 'Chemical', 'MESH:D001120', (9, 10))	('m6A', 'Chemical', '-', (4, 7))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('m6A', 'Var', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
233678	32373523	Moreover, the m6A demethylase ALKBH5 is highly expressed in GSCs, and silencing ALKBH5 suppresses the proliferation of patient-derived GSCs.	('ALKBH5', 'Gene', '54890', (80, 86))	('patient', 'Species', '9606', (119, 126))	('ALKBH5', 'Gene', (80, 86))	('silencing', 'Var', (70, 79))	('m6A', 'Chemical', '-', (14, 17))	('ALKBH5', 'Gene', '54890', (30, 36))	('ALKBH5', 'Gene', (30, 36))	('suppresses', 'NegReg', (87, 97))
233681	32373523	It is believed that methylation of K or R residues in the tail of histones largely decides the chromatin configurations, thus determining gene expression, cell fate and genomic stability.	('R', 'Chemical', 'MESH:D001120', (40, 41))	('cell fate', 'CPA', (155, 164))	('genomic stability', 'CPA', (169, 186))	('determining', 'Reg', (126, 137))	('methylation', 'Var', (20, 31))	('gene expression', 'MPA', (138, 153))	('decides', 'Reg', (83, 90))	('chromatin configurations', 'MPA', (95, 119))
233684	32373523	Meanwhile, methylation of several non-histone proteins participated in tumor-associated signaling pathways, including p53, RB1, NF-kappaB, STAT3, etc.	('RB1', 'Gene', '5925', (123, 126))	('STAT3', 'Gene', '6774', (139, 144))	('NF-kappaB', 'Gene', (128, 137))	('p53', 'Gene', (118, 121))	('STAT3', 'Gene', (139, 144))	('participated', 'Reg', (55, 67))	('non-histone proteins', 'Protein', (34, 54))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('p53', 'Gene', '7157', (118, 121))	('methylation', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('RB1', 'Gene', (123, 126))	('NF-kappaB', 'Gene', '4790', (128, 137))	('tumor', 'Disease', (71, 76))
233690	32373523	In 2016 WHO classification, mutations in the epigenetic modulator genes isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) and codeletion of chromosomal arms 1p/19q (1p/19q codel) have become key biomarkers for glioma classification.	('IDH2', 'Gene', (113, 117))	('IDH1', 'Gene', (105, 109))	('glioma', 'Disease', (207, 213))	('IDH2', 'Gene', '3418', (113, 117))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('mutations', 'Var', (28, 37))
233691	32373523	It emphasized the role of genetic and epigenetic alterations as a driving force for glioma evolution.	('epigenetic alterations', 'Var', (38, 60))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('glioma', 'Disease', (84, 90))
233706	32373523	Univariate and multivariate Cox regression analysis were used to determine independent prognostic factors, including gender, age at diagnosis, WHO grade, IDH status, 1p/19q status, MGMT promoter status, EGFR status, and risk score.	('EGFR', 'Gene', '1956', (203, 207))	('EGFR', 'Gene', (203, 207))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('IDH', 'Gene', (154, 157))	('MGMT', 'Gene', (181, 185))	('1p/19q status', 'Var', (166, 179))	('MGMT', 'Gene', '4255', (181, 185))	('IDH', 'Gene', '3417', (154, 157))
233717	32373523	Cluster 1 patients were strikingly correlated with older age at diagnosis (64.24%, P < 0.0001), high grade (49.01%, P < 0.0001), classical or mesenchymal subtypes (56.95%, P < 0.0001), IDH wildtype (68.87%, P < 0.0001), 1p/19q non-codel (91.40%, P < 0.0001), MGMT promoter unmethylation (44.07%, P < 0.0001), and EGFR amplification (34.34%, P < 0.0001) by Chi-square test.	('unmethylation', 'Var', (273, 286))	('EGFR', 'Gene', '1956', (313, 317))	('IDH', 'Gene', (185, 188))	('EGFR', 'Gene', (313, 317))	('IDH', 'Gene', '3417', (185, 188))	('amplification', 'Var', (318, 331))	('MGMT', 'Gene', (259, 263))	('MGMT', 'Gene', '4255', (259, 263))	('patients', 'Species', '9606', (10, 18))
233725	32373523	As shown in Figure 2C and Table 2, patients in high-risk group were mainly older, high grade, classical or mesenchymal subtype, IDH wildtype, 1p/19q non-codel, MGMT promoter unmethylated and EGFR amplification (P < 0.0001), while patients in low-risk group represented younger, lower grade, proneural or neural subtype, IDH mutant, 1p/19q codel, MGMT promoter methylated and without EGFR amplification (P < 0.0001).	('non-codel', 'Var', (149, 158))	('IDH', 'Gene', (320, 323))	('MGMT', 'Gene', (160, 164))	('IDH', 'Gene', (128, 131))	('EGFR', 'Gene', '1956', (383, 387))	('1p/19q codel', 'Var', (332, 344))	('1p/19q non-codel', 'Var', (142, 158))	('EGFR', 'Gene', (191, 195))	('MGMT', 'Gene', '4255', (160, 164))	('patients', 'Species', '9606', (230, 238))	('IDH', 'Gene', '3417', (320, 323))	('IDH', 'Gene', '3417', (128, 131))	('MGMT', 'Gene', (346, 350))	('EGFR', 'Gene', (383, 387))	('EGFR', 'Gene', '1956', (191, 195))	('patients', 'Species', '9606', (35, 43))	('MGMT', 'Gene', '4255', (346, 350))
233732	32373523	The risk score can perfectly predict Cluster 1/2 subgroups (AUC = 0.903 or 0.924), IDH mutant status (AUC = 0.979 or 0.925) and 1p/19q codel status (AUC = 0.816 or 0.723) in TCGA and CGGA datasets, which were higher than age and grade (Figures 3K-M, Figures S3K-M).	('IDH', 'Gene', (83, 86))	('1p/19q', 'Var', (128, 134))	('IDH', 'Gene', '3417', (83, 86))	('mutant status', 'Var', (87, 100))
233757	32373523	Protein-protein interaction analysis showed that five genes (EZH2, SUZ12, EED, PHF1 and SIRT1) are core components of PRC2 complex, which execute transcriptional inhibition via catalyzing H3K27me3 (Figure S2C).	('SIRT1', 'Gene', '23411', (88, 93))	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('EED', 'Gene', (74, 77))	('SIRT1', 'Gene', (88, 93))	('PHF1', 'Gene', (79, 83))	('transcriptional', 'MPA', (146, 161))	('PHF1', 'Gene', '5252', (79, 83))	('H3K27me3', 'Var', (188, 196))	('R', 'Chemical', 'MESH:D001120', (119, 120))	('SUZ12', 'Gene', '23512', (67, 72))	('EED', 'Gene', '8726', (74, 77))	('R', 'Chemical', 'MESH:D001120', (90, 91))	('SUZ12', 'Gene', (67, 72))
233761	32373523	miR-128, miR-105 and miR-767-5p are suppressors for glioma cell malignancy by targeting SUZ12.	('targeting', 'Reg', (78, 87))	('miR-105', 'Var', (9, 16))	('miR-105', 'Chemical', '-', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('miR-128', 'Chemical', '-', (0, 7))	('miR-767', 'Gene', (21, 28))	('miR-767', 'Gene', '768215', (21, 28))	('SUZ12', 'Gene', '23512', (88, 93))	('glioma cell malignancy', 'Disease', (52, 74))	('miR-128', 'Var', (0, 7))	('glioma cell malignancy', 'Phenotype', 'HP:0012174', (52, 74))	('glioma cell malignancy', 'Disease', 'MESH:D005910', (52, 74))	('SUZ12', 'Gene', (88, 93))
233763	32373523	On the one hand, SIRT1 knockdown significantly inhibited glioma cell proliferation, migration, invasion, promoted its apoptosis and potentiated TMZ toxicity.	('potentiated', 'PosReg', (132, 143))	('apoptosis', 'CPA', (118, 127))	('promoted', 'PosReg', (105, 113))	('invasion', 'CPA', (95, 103))	('inhibited', 'NegReg', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))	('glioma', 'Disease', (57, 63))	('knockdown', 'Var', (23, 32))	('migration', 'CPA', (84, 93))	('SIRT1', 'Gene', '23411', (17, 22))	('SIRT1', 'Gene', (17, 22))	('TMZ', 'MPA', (144, 147))	('toxicity', 'Disease', (148, 156))	('TMZ', 'Chemical', 'MESH:D000077204', (144, 147))	('glioma', 'Disease', 'MESH:D005910', (57, 63))
233765	32373523	Up-regulation of SIRT1 by genetic modification or treatment of melatonin significantly attenuated the adhesion molecular VCAM-1 and ICAM-1 expression in GBM, which modulated the monocytes interaction with GBM.	('VCAM-1', 'Gene', (121, 127))	('ICAM-1', 'Gene', '3383', (132, 138))	('VCAM-1', 'Gene', '7412', (121, 127))	('attenuated', 'NegReg', (87, 97))	('SIRT1', 'Gene', '23411', (17, 22))	('ICAM-1', 'Gene', (132, 138))	('Up-regulation', 'PosReg', (0, 13))	('melatonin', 'Chemical', 'MESH:D008550', (63, 72))	('SIRT1', 'Gene', (17, 22))	('genetic modification', 'Var', (26, 46))	('adhesion', 'MPA', (102, 110))	('expression', 'MPA', (139, 149))	('GBM', 'Phenotype', 'HP:0012174', (205, 208))	('GBM', 'Phenotype', 'HP:0012174', (153, 156))
233769	32373523	Importantly, MEN1 inhibitors significantly decreased the proliferation of adult glioma cells.	('glioma', 'Disease', (80, 86))	('inhibitors', 'Var', (18, 28))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('MEN1', 'Gene', '4221', (13, 17))	('decreased', 'NegReg', (43, 52))	('MEN1', 'Gene', (13, 17))
233772	32373523	CLNS1A knockdown increased sensitivity to PRMT5 inhibitor EPZ015666 in malignant glioma, which may due to the reducing of splicing capacity.	('increased', 'PosReg', (17, 26))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('sensitivity to', 'MPA', (27, 41))	('splicing capacity', 'MPA', (122, 139))	('EPZ015666', 'Chemical', 'MESH:C000599896', (58, 67))	('malignant glioma', 'Disease', (71, 87))	('reducing', 'NegReg', (110, 118))	('malignant glioma', 'Disease', 'MESH:D005910', (71, 87))	('CLNS1A', 'Gene', (0, 6))	('PRMT5', 'Gene', (42, 47))	('knockdown', 'Var', (7, 16))	('CLNS1A', 'Gene', '1207', (0, 6))	('PRMT5', 'Gene', '10419', (42, 47))
233775	32373523	METTL1 mediated tRNA and microRNA processing via N7-methylguanosine (m7G) methylation.	('N7-methylguanosine', 'Chemical', 'MESH:C016578', (49, 67))	('R', 'Chemical', 'MESH:D001120', (30, 31))	('METTL1', 'Gene', (0, 6))	('R', 'Chemical', 'MESH:D001120', (17, 18))	('N7-methylguanosine', 'Var', (49, 67))	('METTL1', 'Gene', '4234', (0, 6))
233780	32373523	Based on TCGA training set and CGGA validation set, we observed that the risk scores are much higher in WHO grade IV, IDH wildtype, 1p/19q non-codel, MGMT promoter unmethylated, EGFR amplification and worse TCGA subtypes (classical and mesenchymal).	('EGFR', 'Gene', '1956', (178, 182))	('non-codel', 'Var', (139, 148))	('TCGA', 'Gene', (207, 211))	('MGMT', 'Gene', '4255', (150, 154))	('EGFR', 'Gene', (178, 182))	('IDH', 'Gene', (118, 121))	('1p/19q non-codel', 'Var', (132, 148))	('IDH', 'Gene', '3417', (118, 121))	('MGMT', 'Gene', (150, 154))	('higher', 'PosReg', (94, 100))
233813	30072739	Emerging biomarkers for anti-PD-1 response include the expression level of its ligand PD-L1 , mutation burden or mismatch-repair deficiency , and tumor-infiltrating lymphocytes .	('PD-1', 'Gene', '5133', (29, 33))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('expression level', 'MPA', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PD-L1', 'Gene', '29126', (86, 91))	('tumor', 'Disease', (146, 151))	('mismatch-repair', 'MPA', (113, 128))	('mutation burden', 'Var', (94, 109))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', (86, 91))	('PD-1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
233815	30072739	Somatic mutations in oncogenes and tumor suppressors represent the most classic biomarkers as they are the main direct drivers of cancer progression .	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', (35, 40))	('oncogenes', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Somatic mutations', 'Var', (0, 17))
233818	30072739	Several other types of non-coding RNAs, such as long-noncoding RNAs (lncRNAs) , enhancer RNAs  and circular RNAs  have also been implicated in various cancer types .	('circular RNAs', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhancer', 'PosReg', (80, 88))	('implicated', 'Reg', (129, 139))	('cancer', 'Disease', (151, 157))	('long-noncoding', 'Var', (48, 62))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
233828	30072739	Here we performed a pan-cancer analysis of ~22 nt size-selected small RNA-seq (smRNA-seq) datasets from TCGA, exploring the expression of small RNAs mapping to annotated human snoRNAs in 10,262 patient samples across 32 cancer types.	('patient', 'Species', '9606', (194, 201))	('small', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('snoRNA', 'Gene', '85390', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (220, 226))	('snoRNA', 'Gene', (176, 182))
233842	30072739	This pan-cancer sdRNA transcriptome is derived from several subtypes of snoRNAs with distinct structures and motifs, such as canonical C/D box snoRNAs, H/ACA box snoRNAs, C/D box small Cajal body RNAs (scaRNAs), H/ACA box scaRNAs, hybrid snoRNAs, and several other subtypes (Figure 1b, Table S1, Table S2).	('snoRNA', 'Gene', '85390', (143, 149))	('cancer', 'Disease', (9, 15))	('snoRNA', 'Gene', (162, 168))	('snoRNA', 'Gene', '85390', (72, 78))	('snoRNA', 'Gene', '85390', (162, 168))	('snoRNA', 'Gene', '85390', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('snoRNA', 'Gene', (143, 149))	('C/D box', 'Var', (171, 178))	('snoRNA', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('snoRNA', 'Gene', (238, 244))
233847	30072739	In the case of C/D snoRNAs, these analyses revealed three classes of read distributions, corresponding to 5' sdRNAs, 3' sdRNAs, or mixed sdRNAs (Figure 1c).	('D snoRNAs', 'Phenotype', 'HP:0025267', (17, 26))	('C/D', 'Var', (15, 18))	('snoRNA', 'Gene', (19, 25))	('mixed', 'Disease', (131, 136))	('snoRNA', 'Gene', '85390', (19, 25))	('D snoRNA', 'Phenotype', 'HP:0025267', (17, 25))
233857	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('300.13 +- 4.21', 'Var', (112, 126))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
233939	30072739	For instance, high expression of sdRNAs derived from SNORA116, an H/ACA snoRNA, was connected to poorer survival in three independent cohorts: lower grade gliomas (LGG), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7b).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('expression', 'MPA', (19, 29))	('snoRNA', 'Gene', '85390', (72, 78))	('corpus endometrial carcinoma', 'Disease', (221, 249))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (221, 249))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 200))	('liver hepatocellular carcinoma', 'Disease', (170, 200))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('SNORA116', 'Var', (53, 61))	('poorer', 'NegReg', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('snoRNA', 'Gene', (72, 78))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
233940	30072739	As another example, high levels of sdRNAs from SNORD145, a CD snoRNA, were associated with shorter survival times in kidney clear cell carcinoma (KIRC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7c).	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (181, 209))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (188, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('sarcoma', 'Disease', (153, 160))	('SARC', 'Phenotype', 'HP:0100242', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 144))	('SNORD145', 'Var', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('snoRNA', 'Gene', (62, 68))	('survival times', 'CPA', (99, 113))	('corpus endometrial carcinoma', 'Disease', (181, 209))	('kidney clear cell carcinoma', 'Disease', (117, 144))	('sdRNAs', 'MPA', (35, 41))	('snoRNA', 'Gene', '85390', (62, 68))	('shorter', 'NegReg', (91, 98))
233941	30072739	SdRNAs from SNORA116 and SNORD145 thus appear to be indicators of cancers with a more aggressive course.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SNORA116', 'Var', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SNORD145', 'Var', (25, 33))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
233959	30072739	Because the ImmuneSurv score analyses were conducted in a cancer type-specific manner, we then sought a global assessment of sdRNAs and their relationships to cancer immunity regardless of cancer type (PANCAN32), by compiling all sdRNAs that were found to be significant in any of the 5 categories: PD-L1, CD8+ T cell abundance, GZMA, survival, or copy number variation (supplemental results, Figure S9) in any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer immunity regardless of cancer', 'Disease', 'MESH:D009369', (159, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CD8', 'Gene', (306, 309))	('GZMA', 'Gene', '3001', (329, 333))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('GZMA', 'Gene', (329, 333))	('PD-L1', 'Gene', (299, 304))	('PD-L1', 'Gene', '29126', (299, 304))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CD8', 'Gene', '925', (306, 309))	('copy number variation', 'Var', (348, 369))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer immunity regardless of cancer', 'Disease', (159, 195))	('cancer', 'Disease', (58, 64))
233970	30072739	Of note, SNORD115 has been demonstrated to act as a regulator of alternative splicing , and its deletion is sufficient to cause Prader-Willi syndrome.	('SNORD115', 'Gene', '692218', (9, 17))	('cause', 'Reg', (122, 127))	('deletion', 'Var', (96, 104))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (128, 149))	('Prader-Willi syndrome', 'Disease', (128, 149))	('alternative splicing', 'MPA', (65, 85))	('SNORD115', 'Gene', (9, 17))
233997	30072739	GISTIC 2.0 copy number variation calls were obtained from the GDAC Firehose (http://gdac.broadinstitute.org/) on September 2017.	('copy number variation', 'Var', (11, 32))	('DAC', 'Gene', (63, 66))	('DAC', 'Gene', '6468', (63, 66))
233999	30072739	Raw fastq files for independent smRNA-seq datasets (GSE33858, GSE46622, E-MTAB-3494) were accessed by NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) or EBI (https://www.ebi.ac.uk/).	('EBI', 'Gene', (150, 153))	('GSE46622', 'Var', (62, 70))	('GSE33858', 'Var', (52, 60))	('EBI', 'Gene', '6907', (150, 153))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
234025	30072739	As these tables report the precise genomic coordinates in which the amplification or deletion was identified, we utilized a q < 0.05 threshold and subsequently intersected the coordinates with the snoRNA annotations .	('snoRNA', 'Gene', (197, 203))	('deletion', 'Var', (85, 93))	('snoRNA', 'Gene', '85390', (197, 203))
234026	30072739	Amplification and deletion calls for individual snoRNAs were then compiled into separate tables.	('deletion', 'Var', (18, 26))	('snoRNA', 'Gene', (48, 54))	('snoRNA', 'Gene', '85390', (48, 54))
234029	30072739	For pan-cancer analysis, we considered all sdRNAs that were found to be significant in at least one cancer type across the following 5 analyses: CD274 correlation, GMZA correlation, CD8+ T cell abundance, copy number variation, and survival.	('cancer', 'Disease', (8, 14))	('CD8', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD8', 'Gene', '925', (182, 185))	('CD274', 'Gene', '29126', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('copy number variation', 'Var', (205, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CD274', 'Gene', (145, 150))
234035	30072739	Thus, for the example above (NNSNSN), sdRNAs from snoRNA X were found to be significantly associated with survival and significant for CNV in cancer type Y.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('snoRNA', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (90, 105))	('sdRNAs', 'Var', (38, 44))	('snoRNA', 'Gene', '85390', (50, 56))	('cancer', 'Disease', (142, 148))
234052	29189740	Mutations of IDH lead to hypermethylation of histones and DNA, altering gene expression, promoting the activation of oncogenes and blocking tumour suppressing mechanisms.	('DNA', 'Protein', (58, 61))	('oncogenes', 'Protein', (117, 126))	('IDH', 'Gene', '3417', (13, 16))	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('activation', 'PosReg', (103, 113))	('lead to', 'Reg', (17, 24))	('blocking', 'NegReg', (131, 139))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('altering', 'Reg', (63, 71))	('tumour', 'Disease', (140, 146))	('Mutations', 'Var', (0, 9))	('hypermethylation', 'MPA', (25, 41))	('gene expression', 'MPA', (72, 87))	('histones', 'Protein', (45, 53))	('IDH', 'Gene', (13, 16))	('promoting', 'PosReg', (89, 98))
234053	29189740	A variety of genetic mutations are implicated in glioblastoma development including the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor two (ERBB2), isocitrase dehydrogenase one (IDH1), neurofibromin one (NF1), phosphoinositide three-kinase (PI3K), phosphatase and tensin homolog (PTEN), retinoblastoma protein (RB1) and tumour suppressor p53 (TP53).	('isocitrase dehydrogenase', 'Gene', (181, 205))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('retinoblastoma', 'Gene', (320, 334))	('epidermal growth factor receptor', 'Gene', (135, 167))	('NF1', 'Gene', (237, 240))	('EGFR', 'Gene', (122, 126))	('PTEN', 'Gene', (313, 317))	('epidermal growth factor receptor', 'Gene', '1956', (135, 167))	('tumour', 'Phenotype', 'HP:0002664', (353, 359))	('tumour', 'Disease', 'MESH:D009369', (353, 359))	('neurofibromin', 'Gene', '4763', (218, 231))	('TP53', 'Gene', (376, 380))	('tumour', 'Disease', (353, 359))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('p53', 'Gene', '7157', (371, 374))	('isocitrase dehydrogenase', 'Gene', '3417', (181, 205))	('ERBB2', 'Gene', (173, 178))	('RB1', 'Gene', (344, 347))	('IDH1', 'Gene', (211, 215))	('retinoblastoma', 'Gene', '5925', (320, 334))	('glioblastoma', 'Disease', (49, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('retinoblastoma', 'Phenotype', 'HP:0009919', (320, 334))	('p53', 'Gene', (371, 374))	('ERBB2', 'Gene', '2064', (173, 178))	('EGFR', 'Gene', '1956', (122, 126))	('mutations', 'Var', (21, 30))	('TP53', 'Gene', '7157', (376, 380))	('RB1', 'Gene', '5925', (344, 347))	('IDH1', 'Gene', '3417', (211, 215))	('NF1', 'Gene', '4763', (237, 240))	('human', 'Species', '9606', (129, 134))	('epidermal growth factor receptor', 'Gene', (88, 120))	('neurofibromin', 'Gene', (218, 231))
234055	29189740	The classical subtype is associated with amplification of chromosome 7 teamed with loss of chromosome 10, EGFRoverexpression and mutations.	('associated', 'Reg', (25, 35))	('mutations', 'Var', (129, 138))	('amplification', 'Var', (41, 54))	('EGFR', 'Gene', '1956', (106, 110))	('loss', 'NegReg', (83, 87))	('EGFR', 'Gene', (106, 110))
234056	29189740	Mesenchymal glioblastomas maintain a high expression of CH13L1, MET, and genes associated with tumour necrosis factor and nuclear factor-kappaB pathways, along with mutations and deletions of NF1.	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('glioblastomas', 'Disease', 'MESH:D005909', (12, 25))	('tumour necrosis', 'Disease', (95, 110))	('MET', 'Gene', (64, 67))	('expression', 'MPA', (42, 52))	('glioblastomas', 'Disease', (12, 25))	('deletions', 'Var', (179, 188))	('NF1', 'Gene', (192, 195))	('CH13L1', 'Gene', (56, 62))	('NF1', 'Gene', '4763', (192, 195))	('tumour necrosis', 'Disease', 'MESH:D009336', (95, 110))	('glioblastomas', 'Phenotype', 'HP:0012174', (12, 25))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
234057	29189740	The proneural subclass parallels secondary glioblastoma and lower-grade glioma with mutations in IDH1 and TP53, and modification of platelet-derived growth factor receptor A (PDGFR-A).	('PDGFR-A', 'Gene', '5156', (175, 182))	('glioma', 'Disease', (72, 78))	('IDH1', 'Gene', (97, 101))	('glioblastoma', 'Disease', (43, 55))	('platelet-derived growth factor receptor A', 'Gene', '5156', (132, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (43, 55))	('IDH1', 'Gene', '3417', (97, 101))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('modification', 'Var', (116, 128))	('PDGFR-A', 'Gene', (175, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('mutations', 'Var', (84, 93))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('platelet-derived growth factor receptor A', 'Gene', (132, 173))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
234089	29189740	To date, a multitude of aptamers have been generated against cell membrane proteins expressed on glioblastoma cells (see Table 1 and Table 2).	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('cell membrane proteins', 'Protein', (61, 83))	('aptamers', 'Var', (24, 32))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
234108	29189740	This aptamer was generated with RNA containing 2'-F-pyrimidine to induce resistance to nucleases in the blood, and was truncated prior to further modifications to improve aptamer stability and half-life with the substitution of 2'-OCH3 purines, the addition of a thymidine cap at the 3' end, and a 5' amine as a conjugation site.	('stability', 'MPA', (179, 188))	('aptamer', 'Protein', (171, 178))	("2'-F-pyrimidine", 'Chemical', '-', (47, 62))	('substitution', 'Var', (212, 224))	('half-life', 'MPA', (193, 202))	('improve', 'PosReg', (163, 170))
234122	29189740	Overexpression and mutations of the platelet derived growth factor receptor (PDGFR) are associated with gliomagenesis and tumour progression.	('platelet derived growth factor receptor', 'Gene', '5159', (36, 75))	('gliomagenesis and tumour', 'Disease', 'MESH:D009369', (104, 128))	('mutations', 'Var', (19, 28))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('PDGFR', 'Gene', (77, 82))	('PDGFR', 'Gene', '5159', (77, 82))	('associated', 'Reg', (88, 98))	('platelet derived growth factor receptor', 'Gene', (36, 75))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
234134	29189740	Therefore, GL21.T should be used as a therapeutic delivery platform, and used in combination with other targeted therapies to ensure complete tumour eradication.	('GL21.T', 'Var', (11, 17))	('tumour eradication', 'Disease', 'MESH:D009369', (142, 160))	('tumour eradication', 'Disease', (142, 160))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))
234135	29189740	EGFR is involved with important cellular functions including cell growth, differentiation, survival, and migration, and deregulation of its signaling cascade is a driving force of glioblastoma tumorigenesis.	('glioblastoma', 'Phenotype', 'HP:0012174', (180, 192))	('EGFR', 'Gene', (0, 4))	('signaling cascade', 'MPA', (140, 157))	('EGFR', 'Gene', '1956', (0, 4))	('glioblastoma', 'Disease', (180, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (180, 192))	('deregulation', 'Var', (120, 132))
234137	29189740	An anti-EGFR RNA aptamer, CL4, capable of binding to both the wildtype and mutant variant has previously been generated via differential cell-SELEX with lung cancer cell lines.	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('CL4', 'Gene', (26, 29))	('binding', 'Interaction', (42, 49))	('EGFR', 'Gene', '1956', (8, 12))	('lung cancer', 'Disease', (153, 164))	('mutant', 'Var', (75, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('EGFR', 'Gene', (8, 12))	('CL4', 'Gene', '100862696', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
234144	29189740	There is little evidence to date that suggests U2 can penetrate the blood brain barrier in these mice, as such, conjugation with a transferrin receptor aptamer would ensure effective transport into the brain, though this would need to be extensively investigated both in vitro and in vivo.	('conjugation', 'Var', (112, 123))	('transport into the brain', 'MPA', (183, 207))	('mice', 'Species', '10090', (97, 101))	('transferrin', 'Gene', '7018', (131, 142))	('transferrin', 'Gene', (131, 142))	('ensure', 'Reg', (166, 172))
234154	29189740	This aptamer, E07, was determined to competitively bind to both the wildtype and mutant variant three of EGFR, hindering ligand binding and autophosphorylation of these receptors in vitro.	('autophosphorylation', 'MPA', (140, 159))	('mutant variant', 'Var', (81, 95))	('hindering', 'NegReg', (111, 120))	('variant', 'Var', (88, 95))	('ligand', 'MPA', (121, 127))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (105, 109))
234161	29189740	successfully delivered AS1411-conjugated paclitaxel nanoconjugates to U87MG-PMT48 orthotopic glioblastoma xenografts in BALB/c nude mice, significantly increasing the median survival time for the treated mice.	('paclitaxel', 'Chemical', 'MESH:D017239', (41, 51))	('increasing', 'PosReg', (152, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('AS1411', 'Chemical', 'MESH:C513936', (23, 29))	('glioblastoma', 'Disease', (93, 105))	('mice', 'Species', '10090', (132, 136))	('nude mice', 'Species', '10090', (127, 136))	('median survival time', 'CPA', (167, 187))	('mice', 'Species', '10090', (204, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('U87MG', 'CellLine', 'CVCL:0022', (70, 75))	('AS1411-conjugated', 'Var', (23, 40))
234163	29189740	Rigorous evaluation of AS1411 as a glioblastoma treatment in physiologically relevant in vitro and in vivo models is vital to ensure successful transition into clinical trials, and the potential off-target uptake must be evaluated if AS1411 is to be used for targeted drug delivery in the future.	('glioblastoma', 'Disease', (35, 47))	('AS1411', 'Chemical', 'MESH:C513936', (23, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('AS1411', 'Chemical', 'MESH:C513936', (234, 240))	('AS1411', 'Var', (23, 29))
234190	27430748	Non-invasive metabolic imaging of brain tumors in the era of precision medicine The genomic revolution in cancer has uncovered a variety of mutations in primary brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('brain tumors', 'Disease', 'MESH:D001932', (161, 173))	('brain tumors', 'Phenotype', 'HP:0030692', (161, 173))	('brain tumors', 'Phenotype', 'HP:0030692', (34, 46))	('brain tumor', 'Phenotype', 'HP:0030692', (34, 45))	('brain tumors', 'Disease', (161, 173))	('cancer', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('brain tumors', 'Disease', (34, 46))	('brain tumor', 'Phenotype', 'HP:0030692', (161, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
234196	27430748	Moreover, genetic alterations such as isocitrate dehydrogenase mutations produced unique metabolic signatures that can be detected using MR spectroscopy.	('mutations', 'Var', (63, 72))	('isocitrate dehydrogenase', 'Gene', (38, 62))	('metabolic signatures', 'MPA', (89, 109))	('isocitrate dehydrogenase', 'Gene', '3417', (38, 62))
234215	27430748	Additionally, histologic criteria are used to define tumor grade: low-grade (grade I and grade II) and high-grade (grade III and grade IV, or glioblastoma multiforme (GBM)).	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (142, 165))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('grade III', 'Var', (115, 124))	('glioblastoma multiforme', 'Disease', (142, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
234218	27430748	In adults, more than 90% of GBM show genetic alterations that converge on the PI3K-AKT/mTOR pathway.	('AKT', 'Gene', '207', (83, 86))	('mTOR', 'Gene', '2475', (87, 91))	('AKT', 'Gene', (83, 86))	('genetic alterations', 'Var', (37, 56))	('mTOR', 'Gene', (87, 91))
234220	27430748	Other genetic alterations in this pathway include PTEN deletion (~40%) and mutations in PI3K (~20%) (Table 1).	('PI3K', 'Gene', (88, 92))	('PTEN', 'Gene', (50, 54))	('PTEN', 'Gene', '5728', (50, 54))	('mutations', 'Var', (75, 84))	('deletion', 'Var', (55, 63))
234222	27430748	In contrast, high-grade gliomas in children are characterized by epigenetic mutations.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('epigenetic mutations', 'Var', (65, 85))	('gliomas', 'Disease', (24, 31))	('children', 'Species', '9606', (35, 43))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
234223	27430748	Histone H3 K27M and G34R/V mutations are noted in 60% of pediatric glioblastomas and H3K27M mutations occur in more than 80% of brain stem gliomas (termed diffuse intrinsic pontine gliomas) (Table 1).	('mutations', 'Var', (27, 36))	('brain stem gliomas', 'Disease', (128, 146))	('K27M', 'Mutation', 'p.K27M', (11, 15))	('brain stem gliomas', 'Disease', 'MESH:D020295', (128, 146))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('glioblastomas', 'Phenotype', 'HP:0012174', (67, 80))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('gliomas', 'Disease', (139, 146))	('Histone H3', 'Protein', (0, 10))	('H3K27M mutations', 'Var', (85, 101))	('K27M', 'Mutation', 'p.K27M', (87, 91))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('occur', 'Reg', (102, 107))	('G34R', 'SUBSTITUTION', 'None', (20, 24))	('G34R', 'Var', (20, 24))	('glioblastomas', 'Disease', (67, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('glioblastomas', 'Disease', 'MESH:D005909', (67, 80))	('brain stem gliomas', 'Phenotype', 'HP:0010796', (128, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('gliomas', 'Disease', (181, 188))
234225	27430748	More than 70% of intermediate-grade (grade II and III) gliomas (including astrocytomas and oligodendrogliomas) in adults bear mutations in isocitrate dehydrogenase (IDH) 1/2 (Table 1).	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (74, 109))	('IDH', 'Gene', (165, 168))	('IDH', 'Gene', '3417', (165, 168))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('isocitrate dehydrogenase', 'Gene', (139, 163))	('isocitrate dehydrogenase', 'Gene', '3417', (139, 163))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('gliomas', 'Disease', (102, 109))	('mutations', 'Var', (126, 135))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('intermediate-grade', 'Disease', (17, 35))
234226	27430748	IDH mutant gliomas tend to occur in younger adults and are associated with a favorable prognosis relative to their wild-type counterparts (Table 1).	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (4, 10))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
234227	27430748	IDH 1/2 mutant gliomas that progress to GBM are termed secondary GBM.	('IDH 1/2', 'Gene', (0, 7))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('mutant', 'Var', (8, 14))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('IDH 1/2', 'Gene', '3417;3418', (0, 7))
234228	27430748	These IDH 1/2 mutant GBM constitute ~5% of adult GBM and show a significantly favorable prognosis compared to IDH wild-type tumors (Table 1).	('IDH', 'Gene', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('IDH', 'Gene', (110, 113))	('mutant', 'Var', (14, 20))	('IDH 1/2', 'Gene', (6, 13))	('IDH', 'Gene', '3417', (6, 9))	('IDH', 'Gene', '3417', (110, 113))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('IDH 1/2', 'Gene', '3417;3418', (6, 13))
234231	27430748	Likewise, activating BRAF point mutations (V600E) are observed in other low-grade pediatric brain tumors like pleomorphic xanthoastrocytomas (70%), gangliogliomas (20%) and at lower frequencies in pilocytic astrocytomas and diffuse astrocytomas.	('astrocytomas', 'Disease', (128, 140))	('astrocytomas', 'Disease', (207, 219))	('astrocytomas', 'Disease', (232, 244))	('brain tumors', 'Disease', (92, 104))	('activating', 'PosReg', (10, 20))	('pilocytic astrocytomas', 'Disease', (197, 219))	('gangliogliomas', 'Disease', (148, 162))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('BRAF', 'Gene', '673', (21, 25))	('pleomorphic xanthoastrocytomas', 'Disease', (110, 140))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('astrocytomas', 'Disease', 'MESH:D001254', (128, 140))	('BRAF', 'Gene', (21, 25))	('astrocytomas', 'Disease', 'MESH:D001254', (207, 219))	('astrocytomas', 'Disease', 'MESH:D001254', (232, 244))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (197, 219))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (110, 140))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('V600E', 'Var', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (92, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (92, 104))	('brain tumor', 'Phenotype', 'HP:0030692', (92, 103))	('gangliogliomas', 'Disease', 'MESH:D018303', (148, 162))
234240	27430748	Of these, the proneural subtype is associated with IDH 1/2 mutations and have the best prognosis.	('IDH 1/2', 'Gene', '3417;3418', (51, 58))	('proneural subtype', 'Disease', (14, 31))	('associated', 'Reg', (35, 45))	('IDH 1/2', 'Gene', (51, 58))	('mutations', 'Var', (59, 68))
234244	27430748	Moreover, pharmacological inhibitors of mutant IDH1 show promise in IDH1 mutant but not in IDH wild-type glioma animal models.	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', '3417', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('glioma', 'Disease', (105, 111))	('mutant', 'Var', (73, 79))	('IDH', 'Gene', (91, 94))	('mutant', 'Var', (40, 46))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3417', (91, 94))	('IDH', 'Gene', (47, 50))	('glioma', 'Disease', 'MESH:D005910', (105, 111))
234255	27430748	For example, phosphorylated AKT enhances glycolysis by increasing expression of glucose transporters and by activating glycolytic enzymes such as hexokinase-2 (HK2) and phosphofructokinase-1 (PFK-1).	('phosphofructokinase-1', 'Gene', (169, 190))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('PFK-1', 'Gene', '5213', (192, 197))	('phosphorylated', 'Var', (13, 27))	('expression', 'MPA', (66, 76))	('increasing', 'PosReg', (55, 65))	('hexokinase-2', 'Gene', '3099', (146, 158))	('enhances', 'PosReg', (32, 40))	('HK2', 'Gene', (160, 163))	('HK2', 'Gene', '3099', (160, 163))	('AKT', 'Gene', (28, 31))	('activating', 'PosReg', (108, 118))	('glycolytic', 'MPA', (119, 129))	('glucose transporters', 'MPA', (80, 100))	('phosphofructokinase-1', 'Gene', '5213', (169, 190))	('PFK-1', 'Gene', (192, 197))	('glycolysis', 'MPA', (41, 51))	('hexokinase-2', 'Gene', (146, 158))	('AKT', 'Gene', '207', (28, 31))
234257	27430748	BRAFV600E and MYC can also stimulate the transcription networks related to glycolysis including glucose transporters and glycolytic enzymes.	('glycolytic enzymes', 'MPA', (121, 139))	('transcription networks', 'MPA', (41, 63))	('MYC', 'Gene', (14, 17))	('glycolysis', 'MPA', (75, 85))	('glucose transporters', 'MPA', (96, 116))	('MYC', 'Gene', '4609', (14, 17))	('stimulate', 'PosReg', (27, 36))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E', 'Var', (0, 9))
234291	27430748	Mutations in IDH1 and IDH2 are heterozygous and missense.	('IDH2', 'Gene', '3418', (22, 26))	('Mutations', 'Var', (0, 9))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))
234292	27430748	IDH1 mutations are the most common in gliomas (more than 90%) and involve the catalytic site arginine at position 132, which is mutated to histidine (R132H), while IDH2 mutations are rare in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('common', 'Reg', (28, 34))	('R132H', 'Mutation', 'rs121913500', (150, 155))	('gliomas', 'Phenotype', 'HP:0009733', (191, 198))	('gliomas', 'Disease', (191, 198))	('histidine', 'Chemical', 'MESH:D006639', (139, 148))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('gliomas', 'Disease', 'MESH:D005910', (191, 198))	('mutations', 'Var', (5, 14))	('IDH2', 'Gene', (164, 168))	('involve', 'Reg', (66, 73))	('arginine', 'Chemical', 'MESH:D001120', (93, 101))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Disease', (38, 45))	('IDH2', 'Gene', '3418', (164, 168))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
234293	27430748	IDH mutations result in the production of the metabolite (D)-2-hydroxyglutarate ((D)-2HG) (Figure 2).	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('production', 'MPA', (28, 38))	('(D)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (57, 79))	('result in', 'Reg', (14, 23))	('mutations', 'Var', (4, 13))
234297	27430748	As (D)-2HG is produced in IDH 1/2 mutant gliomas but not in wild-type gliomas, the non-invasive detection of (D)-2HG could serve as a biomarker for the diagnosis, treatment and surveillance of these tumors.	('IDH 1/2', 'Gene', (26, 33))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH 1/2', 'Gene', '3417;3418', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))	('mutant', 'Var', (34, 40))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
234298	27430748	Detection and quantification of (D)-2HG using in vivo MRS has been demonstrated in IDH1 mutant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('MRS', 'Gene', (54, 57))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('mutant', 'Var', (88, 94))	('IDH1', 'Gene', (83, 87))	('MRS', 'Gene', '148398', (54, 57))
234301	27430748	Using these techniques, (D)-2HG can be detected in milimolar ranges (1.7-8.9 mM) in IDH1/2 mutant but not in wild-type gliomas.	('IDH1/2', 'Gene', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('IDH1/2', 'Gene', '3417;3418', (84, 90))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('mutant', 'Var', (91, 97))
234302	27430748	Further, the detection of (D)-2HG in vivo correlates with better prognosis, mirroring previously reported next generation sequencing data However, while the detection of (D)-2HG may be sensitive in the assessment of IDH1/2 mutations, the specificity may depend on the size and cellularity of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('IDH1/2', 'Gene', '3417;3418', (216, 222))	('tumor', 'Disease', (296, 301))	('IDH1/2', 'Gene', (216, 222))	('mutations', 'Var', (223, 232))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
234304	27430748	The enzymatic function of mutant IDH 1/2 to catalyze the conversion of alpha-KG to (D)-2HG, detectable in vivo, may be harnessed using hyperpolarized 13C MRS For example, the conversion of alpha-KG labeled with 13C at the 1st carbon position (1-13C] alpha-KG) to [1-13C] (D)-2HG (Figure 2) can be detected in rats bearing IDH1 mutant but not IDH1 wild-type GBM xenografts.	('MRS', 'Gene', (154, 157))	('C] alpha', 'Species', '342041', (247, 255))	('carbon', 'Chemical', 'MESH:D002244', (226, 232))	('MRS', 'Gene', '148398', (154, 157))	('IDH1', 'Gene', (322, 326))	('rats', 'Species', '10116', (309, 313))	('alpha-KG', 'Chemical', 'MESH:D007656', (250, 258))	('mutant', 'Var', (327, 333))	('13C', 'Chemical', '-', (266, 269))	('13C', 'Chemical', '-', (211, 214))	('13C', 'Chemical', '-', (245, 248))	('IDH 1/2', 'Gene', '3417;3418', (33, 40))	('alpha-KG', 'Chemical', 'MESH:D007656', (71, 79))	('13C', 'Chemical', '-', (150, 153))	('IDH 1/2', 'Gene', (33, 40))	('alpha-KG', 'Chemical', 'MESH:D007656', (189, 197))
234305	27430748	While these observations are yet to be translated into the clinic, as the only imaging modality specific to IDH mutations, in vivo MRS (with or without hyperpolarization) represents an exciting foray into the use of a pharmacodynamic biomarker.	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (108, 111))	('mutations', 'Var', (112, 121))	('MRS', 'Gene', (131, 134))	('MRS', 'Gene', '148398', (131, 134))
234325	27430748	Along similar lines, activation of mTOR stimulates glutamine metabolism by increasing the activity of the enzyme glutamate dehydrogenase.	('glutamate', 'Chemical', 'MESH:D018698', (113, 122))	('stimulates', 'PosReg', (40, 50))	('increasing', 'PosReg', (75, 85))	('glutamine', 'Chemical', 'MESH:D005973', (51, 60))	('activity', 'MPA', (90, 98))	('mTOR', 'Gene', (35, 39))	('glutamate dehydrogenase', 'Enzyme', (113, 136))	('activation', 'Var', (21, 31))	('mTOR', 'Gene', '2475', (35, 39))	('glutamine metabolism', 'MPA', (51, 71))
234326	27430748	However, orthotopic GBM mouse models infused with 13C-labeled glutamine exhibit high tumor glutamine uptake but do not demonstrate glutamine metabolism in the TCA cycle.	('tumor', 'Disease', (85, 90))	('mouse', 'Species', '10090', (24, 29))	('glutamine', 'Chemical', 'MESH:D005973', (131, 140))	('TCA', 'Chemical', 'MESH:D014233', (159, 162))	('not', 'NegReg', (115, 118))	('glutamine', 'Chemical', 'MESH:D005973', (91, 100))	('13C-labeled', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('13C', 'Chemical', '-', (50, 53))	('high tumor glutamine', 'Phenotype', 'HP:0003217', (80, 100))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('glutamine', 'Chemical', 'MESH:D005973', (62, 71))
234371	27430748	We have thus far examined how different genetic alterations in primary brain tumors reprogram metabolism and how some of these pathways can be translated into non-invasive imaging in preclinical animal models and patients.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('brain tumors', 'Phenotype', 'HP:0030692', (71, 83))	('brain tumor', 'Phenotype', 'HP:0030692', (71, 82))	('brain tumors', 'Disease', 'MESH:D001932', (71, 83))	('brain tumors', 'Disease', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('reprogram', 'Reg', (84, 93))	('patients', 'Species', '9606', (213, 221))	('genetic', 'Var', (40, 47))
234375	27430748	Amino acid PET-based tumor volumes have been shown to extend beyond contrast-enhancing volume on conventional MRI by 2-3.5 cm for different tracers, and identifies tumor extent within non-specific regions of T2/FLAIR abnormality (Figure 5).	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (21, 26))	('Amino', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
234380	27430748	As IDH 1/2 mutant gliomas have better prognosis compared to IDH wild-type tumors, evaluating (D)-2HG levels could also serve as a prognostic indicator.	('gliomas', 'Disease', (18, 25))	('mutant', 'Var', (11, 17))	('IDH 1/2', 'Gene', (3, 10))	('IDH', 'Gene', '3417', (3, 6))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('IDH 1/2', 'Gene', '3417;3418', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('better', 'PosReg', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('IDH', 'Gene', (60, 63))	('IDH', 'Gene', '3417', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('IDH', 'Gene', (3, 6))	('tumors', 'Disease', (74, 80))
234384	27430748	Following treatment with cediranib, a direct metabolic effect and anti-tumoral response to anti-angiogenic treatment is seen with serial MRS, demonstrating a significant increase in NAA/choline.	('cediranib', 'Chemical', 'MESH:C500926', (25, 34))	('NAA', 'Chemical', 'MESH:C000179', (182, 185))	('NAA/choline', 'MPA', (182, 193))	('MRS', 'Gene', (137, 140))	('MRS', 'Gene', '148398', (137, 140))	('increase', 'PosReg', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cediranib', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('choline', 'Chemical', 'MESH:D002794', (186, 193))	('tumor', 'Disease', (71, 76))
234392	27430748	Recurrent GBMs are hypermutated and harbor many new driver mutations in the AKT/mTOR pathway.	('AKT', 'Gene', '207', (76, 79))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('AKT', 'Gene', (76, 79))	('mutations', 'Var', (59, 68))
234404	27430748	Imaging of (D)-2HG is a prime example, as IDH 1/2 mutations are characteristic of proneural secondary GBMs (Table 1).	('mutations', 'Var', (50, 59))	('IDH 1/2', 'Gene', (42, 49))	('IDH 1/2', 'Gene', '3417;3418', (42, 49))	('proneural secondary GBMs', 'Disease', (82, 106))
234417	27430748	Many of these genomic alterations reprogram cellular metabolism including glucose, amino acid and lipid metabolism.	('reprogram', 'Reg', (34, 43))	('glucose', 'MPA', (74, 81))	('lipid metabolism', 'MPA', (98, 114))	('alterations', 'Var', (22, 33))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('lipid', 'Chemical', 'MESH:D008055', (98, 103))
234425	27571068	Moreover, high ADAM9 expression also correlated with poor clinical outcome (p < 0.001 and p < 0.001, log-rank test, for PFS and OS, respectively) in LGG patients.	('patients', 'Species', '9606', (153, 161))	('OS', 'Chemical', '-', (128, 130))	('LGG', 'Disease', (149, 152))	('expression', 'MPA', (21, 31))	('ADAM9', 'Gene', '8754', (15, 20))	('high', 'Var', (10, 14))	('ADAM9', 'Gene', (15, 20))
234426	27571068	Further, multivariate analysis suggested ADAM9 expression to be an independent marker of poor survival (p = 0.002 and p = 0.003, for PFS and OS, respectively).	('OS', 'Chemical', '-', (141, 143))	('ADAM9', 'Gene', (41, 46))	('expression', 'Var', (47, 57))	('ADAM9', 'Gene', '8754', (41, 46))
234436	27571068	These types of scientific efforts have recently led to substantial progress and different tumor-specific molecular changes, such as isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q co-deletion, O6-methylguanine DNA methyltransferase promoter methylation, telomerase reverse transcriptase promoter mutation, epithelial growth factor receptor amplification and a few others, have been identified as predictive and prognostic indicators and/or therapeutic targets for glioma patients.	('isocitrate dehydrogenase 1', 'Gene', (132, 158))	('isocitrate dehydrogenase 1', 'Gene', '3417', (132, 158))	('IDH1', 'Gene', (160, 164))	('glioma', 'Disease', 'MESH:D005910', (467, 473))	('glioma', 'Phenotype', 'HP:0009733', (467, 473))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('O6-methylguanine DNA methyltransferase', 'Gene', (196, 234))	('IDH1', 'Gene', '3417', (160, 164))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (196, 234))	('glioma', 'Disease', (467, 473))	('patients', 'Species', '9606', (474, 482))	('mutation', 'Var', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
234439	27571068	The ADAM family proteins are usually considered to play a fundamental role in controlling homeostasis and development, and their aberrant expression is thought to be related with pathological states, including cancer, inflammation, diabetes and Alzheimer's disease.	('related', 'Reg', (166, 173))	('diabetes', 'Disease', 'MESH:D003920', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('inflammation', 'Disease', 'MESH:D007249', (218, 230))	('ADAM', 'Protein', (4, 8))	('diabetes', 'Disease', (232, 240))	('inflammation', 'Disease', (218, 230))	('expression', 'MPA', (138, 148))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (245, 264))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (245, 264))	("Alzheimer's disease", 'Disease', (245, 264))	('cancer', 'Disease', (210, 216))	('aberrant', 'Var', (129, 137))
234454	27571068	Additionally, we also found that the ADAM9 expression level was significantly associated with 1p/19q co-deletion in patients with lower-grade gliomas (p = 0.002, Chi-square test).	('associated', 'Reg', (78, 88))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('patients', 'Species', '9606', (116, 124))	('expression level', 'MPA', (43, 59))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('ADAM9', 'Gene', (37, 42))	('ADAM9', 'Gene', '8754', (37, 42))	('1p/19q co-deletion', 'Var', (94, 112))
234455	27571068	Student's t-test, used to determine this association, more specifically showed that ADAM9 expression was significantly lower in LGG patients with the 1p/19q co-deletion.	('lower', 'NegReg', (119, 124))	('LGG', 'Disease', (128, 131))	('1p/19q co-deletion', 'Var', (150, 168))	('ADAM9', 'Gene', '8754', (84, 89))	('expression', 'MPA', (90, 100))	('ADAM9', 'Gene', (84, 89))	('patients', 'Species', '9606', (132, 140))
234459	27571068	The Kaplan-Meier analysis showed that there was a significant difference in both progression-free survival (PFS, p < 0.001, log-rank test, Figure 3A) and overall survival (OS, p < 0.001, log-rank test, Figure 3B) between the LGG patients having high or low ADAM9 expression.	('overall survival', 'CPA', (154, 170))	('progression-free survival', 'CPA', (81, 106))	('OS', 'Chemical', '-', (172, 174))	('ADAM9', 'Gene', '8754', (257, 262))	('high', 'Var', (245, 249))	('patients', 'Species', '9606', (229, 237))	('ADAM9', 'Gene', (257, 262))	('low', 'NegReg', (253, 256))
234460	27571068	The LGG patients with low ADAM9 expression were observed to have a better survival than those with high ADAM9 expression.	('survival', 'CPA', (74, 82))	('LGG', 'Disease', (4, 7))	('low', 'Var', (22, 25))	('ADAM9', 'Gene', '8754', (104, 109))	('ADAM9', 'Gene', (104, 109))	('ADAM9', 'Gene', (26, 31))	('better', 'PosReg', (67, 73))	('ADAM9', 'Gene', '8754', (26, 31))	('patients', 'Species', '9606', (8, 16))
234464	27571068	It was observed that high ADAM9 expression appeared to be a predictor for poor clinical outcomes in the LGG patient population (p < 0.001 and p = 0.001 for PFS and OS, respectively, Table 3).	('ADAM9', 'Gene', (26, 31))	('high', 'Var', (21, 25))	('patient', 'Species', '9606', (108, 115))	('expression', 'MPA', (32, 42))	('OS', 'Chemical', '-', (164, 166))	('ADAM9', 'Gene', '8754', (26, 31))
234484	27571068	It has been widely accepted that 1p/19q co-deletion is the most established marker in predicting better prognosis in LGG and it also correlate closely with the oligodendroglial component of tumors.	('oligodendroglial component of tumors', 'Disease', 'MESH:D009369', (160, 196))	('LGG', 'Disease', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('oligodendroglial component of tumors', 'Disease', (160, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('1p/19q co-deletion', 'Var', (33, 51))
234485	27571068	In the current study, we also found that tumors with 1p/19q co-deletion have significantly lower ADAM9 expression.	('lower', 'NegReg', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('ADAM9', 'Gene', '8754', (97, 102))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('ADAM9', 'Gene', (97, 102))	('1p/19q co-deletion', 'Var', (53, 71))
234493	27571068	However, ADAM9, through other mechanisms, has been linked with the regulation of the tumor growth of various other human cancers; for example, the silencing of ADAM9 has been shown to reduce tumor cell proliferation and the migration of esophageal squamous cell carcinoma cells by inhibiting epidermal growth factor receptor (EGFR)/protein kinase B (AKT) signaling.	('tumor', 'Disease', (85, 90))	('protein kinase B', 'Gene', '2185', (332, 348))	('epidermal growth factor receptor', 'Gene', (292, 324))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (237, 271))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ADAM9', 'Gene', (9, 14))	('ADAM9', 'Gene', '8754', (9, 14))	('epidermal growth factor receptor', 'Gene', '1956', (292, 324))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('protein kinase B', 'Gene', (332, 348))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('cancers', 'Disease', (121, 128))	('inhibiting', 'NegReg', (281, 291))	('AKT', 'Gene', '207', (350, 353))	('ADAM9', 'Gene', '8754', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ADAM9', 'Gene', (160, 165))	('EGFR', 'Gene', (326, 330))	('esophageal squamous cell carcinoma', 'Disease', (237, 271))	('tumor', 'Disease', (191, 196))	('reduce', 'NegReg', (184, 190))	('migration', 'CPA', (224, 233))	('silencing', 'Var', (147, 156))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('human', 'Species', '9606', (115, 120))	('EGFR', 'Gene', '1956', (326, 330))	('AKT', 'Gene', (350, 353))
234496	27571068	The association of high ADAM9 expression with poor clinical outcomes has been broadly investigated and reported in various other human malignancies.	('high', 'Var', (19, 23))	('ADAM9', 'Gene', (24, 29))	('expression', 'MPA', (30, 40))	('ADAM9', 'Gene', '8754', (24, 29))	('human', 'Species', '9606', (129, 134))	('malignancies', 'Disease', 'MESH:D009369', (135, 147))	('malignancies', 'Disease', (135, 147))
234499	27571068	Importantly, a recent study showed that high ADAM9 expression was an independent factor linked with shortened survival and has been proposed to serve as a predictive biomarker for the selection of non-small cell lung cancer patients eligible for postoperative adjuvant chemotherapy treatment.	('high', 'Var', (40, 44))	('survival', 'MPA', (110, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (197, 223))	('ADAM9', 'Gene', '8754', (45, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('non-small cell lung cancer', 'Disease', (197, 223))	('ADAM9', 'Gene', (45, 50))	('shortened', 'NegReg', (100, 109))	('expression', 'MPA', (51, 61))	('patients', 'Species', '9606', (224, 232))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (197, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
234500	27571068	Concordant with these observations in other human cancers, we also observed that high ADAM9 mRNA expression was associated with poor clinical outcomes and thus we speculate that it could serve as an independent prognostic factor in LGGs.	('human', 'Species', '9606', (44, 49))	('ADAM9', 'Gene', '8754', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('mRNA expression', 'MPA', (92, 107))	('high', 'Var', (81, 85))	('cancers', 'Disease', (50, 57))	('ADAM9', 'Gene', (86, 91))	('LGGs', 'Disease', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
234513	27571068	Pyrosequencing of IDH1 mutation was supported by Gene-tech (Shanghai, China) and performed on the Pyro-Mark Q96 ID System (Qiagen, Dusseldorf, Germany).	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))
234522	27571068	Furthermore, a significant association between high ADAM9 expression and poor clinical outcome in LGG patients was observed.	('ADAM9', 'Gene', '8754', (52, 57))	('expression', 'MPA', (58, 68))	('high', 'Var', (47, 51))	('ADAM9', 'Gene', (52, 57))	('patients', 'Species', '9606', (102, 110))	('LGG', 'Disease', (98, 101))
234547	32537906	5 ,  6 ,  7  The authors of other studies have suggested differences in the molecular biology of LGGs as the reason for differences in tumor location, 8 ,  9 ,  10  with a higher rate of 1p deletion in the anterior part of the brain (in particular in the frontal lobe) 9  and a lower rate in the insula, 8  or the absence of IDH1 mutation within the insula 10  and its presence in tumors located within the frontal lobe.	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (381, 387))	('tumors', 'Phenotype', 'HP:0002664', (381, 387))	('tumor', 'Disease', (381, 386))	('tumor', 'Disease', (135, 140))	('mutation', 'Var', (330, 338))	('IDH1', 'Gene', (325, 329))	('tumors', 'Disease', 'MESH:D009369', (381, 387))	('tumor', 'Disease', 'MESH:D009369', (381, 386))	('IDH1', 'Gene', '3417', (325, 329))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
234556	32537906	1  Molecular verification including the IDH status (either IDH1/IDH2 mutant, IDHm; IDH wildtype, IDHwt) and LOH1p19q codeletion were recollected in all the available cases.	('IDH1', 'Gene', '3417', (59, 63))	('IDHm', 'Gene', '3418', (77, 81))	('IDHm', 'Gene', (77, 81))	('IDH', 'Gene', (97, 100))	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', '3417', (83, 86))	('IDH', 'Gene', (40, 43))	('IDH', 'Gene', (64, 67))	('IDH', 'Gene', '3417', (97, 100))	('IDH', 'Gene', (77, 80))	('IDH', 'Gene', '3417', (40, 43))	('IDH', 'Gene', '3417', (64, 67))	('IDH1', 'Gene', (59, 63))	('IDH', 'Gene', '3417', (77, 80))	('IDH', 'Gene', (59, 62))	('IDH2', 'Gene', (64, 68))	('IDH', 'Gene', (83, 86))	('mutant', 'Var', (69, 75))	('LOH1p19q', 'Var', (108, 116))	('IDH2', 'Gene', '3418', (64, 68))
234566	32537906	Mann-Whitney U test for independent samples was used for comparison between confirmed oligodendrogliomas (LOH1p19q+) and oligodendrogliomas NOS for numerical variables.	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (121, 139))	('oligodendrogliomas NOS', 'Disease', (121, 143))	('LOH1p19q+', 'Var', (106, 115))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (86, 104))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('oligodendrogliomas', 'Disease', (121, 139))	('oligodendrogliomas NOS', 'Disease', 'MESH:D009837', (121, 143))	('oligodendrogliomas', 'Disease', (86, 104))
234575	32537906	In 26/40 oligodendrogliomas, the diagnosis was confirmed by molecular analysis (IDH mutation and LOH1p19q+).	('oligodendrogliomas', 'Disease', (9, 27))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('LOH1p19q+', 'Var', (97, 106))	('IDH', 'Gene', (80, 83))	('IDH', 'Gene', '3417', (80, 83))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (9, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))
234578	32537906	In the oligodendrogliomas' group, no difference was displayed between LOH1p19q+ and NOS for age (P = .190), survival from diagnosis (P = .878), number of BG voxels (P = .474), volume (P = .492), EOR (P = .156), radiological borders (P = .399), and eloquent white matter infiltration (P = .866).	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('LOH1p19q+', 'Var', (70, 79))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (7, 25))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('oligodendrogliomas', 'Disease', (7, 25))
234582	32537906	The qualitative analysis demonstrated that the A3-4C1S2 voxels (frontal cortical-subcortical SMA on the left side) and the A3-4C2-3 S2 (cortical-subcortical insular region on the left side) had the highest rate of invasion in patients with diffuse astrocytomas.	('A3-4C2-3 S2', 'Var', (123, 134))	('A3-4C1S2', 'Var', (47, 55))	('SMA', 'Gene', '6606', (93, 96))	('SMA', 'Gene', (93, 96))	('astrocytomas', 'Disease', 'MESH:D001254', (248, 260))	('astrocytoma', 'Phenotype', 'HP:0009592', (248, 259))	('patients', 'Species', '9606', (226, 234))	('astrocytomas', 'Disease', (248, 260))
234583	32537906	In patients with oligodendrogliomas, the A2-3C2-S1-2 (fronto-mesial/fronto-striatal regions on both sides) were the most invaded BG voxels.	('A2-3C2-S1-2', 'Var', (41, 52))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (17, 35))	('C2-S1-2', 'CellLine', 'CVCL:Z232', (45, 52))	('oligodendrogliomas', 'Disease', (17, 35))	('patients', 'Species', '9606', (3, 11))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))
234610	32537906	2 ,  3 ,  5 ,  19 ,  29  Our results seem to radiologically confirm other studies suggesting a variability in terms of molecular biology among diffuse gliomas with regard to the tumor location, 8 ,  9 ,  10  with a higher rate of 1p deletion in the anterior part of the brain (in particular in the frontal lobe) 9  and a lower rate in the insula.	('tumor', 'Disease', (178, 183))	('1p deletion', 'Var', (230, 241))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('gliomas', 'Disease', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))
234620	32537906	If the eloquent white matter pathways were infiltrated, the patients had a slightly higher risk of shorter OS (HR 2.32), but this was, however, not statistically significant (P = .06; Table 2).	('patients', 'Species', '9606', (60, 68))	('eloquent', 'Pathway', (7, 15))	('infiltrated', 'Var', (43, 54))	('shorter OS', 'Disease', (99, 109))
234660	29862267	PPARalpha is aberrantly expressed in various cancers, and activated PPARalpha inhibits the proliferation of some tumor cells.	('tumor', 'Disease', (113, 118))	('activated', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('PPARalpha', 'Gene', (68, 77))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('inhibits', 'NegReg', (78, 86))	('cancers', 'Disease', (45, 52))
234663	29862267	PPARalpha activates transcription of dynamin-3 opposite strand (DNMO3os), which encodes a cluster of miR-214, miR-199a-3p, and miR-199a-5p microRNAs.	('transcription', 'MPA', (20, 33))	('miR-214', 'Var', (101, 108))	('miR-199a-3p', 'Gene', (110, 121))	('PPARalpha', 'Gene', (0, 9))	('DNMO3os', 'Chemical', '-', (64, 71))	('dynamin-3 opposite strand', 'Gene', '100628315', (37, 62))	('dynamin-3 opposite strand', 'Gene', (37, 62))	('activates', 'PosReg', (10, 19))	('miR-199a-3p', 'Gene', '406977', (110, 121))
234675	29862267	Overexpression of PPARalpha in glioma cells promoted transcription of DNMO3os, leading to increased expression of miR-214.	('DNMO3os', 'Chemical', '-', (70, 77))	('promoted', 'PosReg', (44, 52))	('increased', 'PosReg', (90, 99))	('miR-214', 'Var', (114, 121))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('DNMO3os', 'Gene', (70, 77))	('expression', 'MPA', (100, 110))	('glioma', 'Disease', (31, 37))	('transcription', 'MPA', (53, 66))
234677	29862267	Our results thus suggest that PPARalpha inhibits human glioma cell proliferation through a miR-214- and E2F2-dependent pathway and identify novel potential molecular targets for the treatment of human gliomas.	('glioma', 'Disease', (55, 61))	('human', 'Species', '9606', (195, 200))	('E2F2', 'Gene', '1870', (104, 108))	('gliomas', 'Disease', (201, 208))	('glioma', 'Disease', (201, 207))	('gliomas', 'Disease', 'MESH:D005910', (201, 208))	('PPARalpha', 'Var', (30, 39))	('human', 'Species', '9606', (49, 54))	('miR-214-', 'Gene', (91, 99))	('gliomas', 'Phenotype', 'HP:0009733', (201, 208))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('inhibits', 'NegReg', (40, 48))	('E2F2', 'Gene', (104, 108))	('glioma', 'Disease', 'MESH:D005910', (201, 207))
234678	29862267	Antibodies were purchased as follows: anti-PPARalpha was from Abcam (ab215270, Cambridge, UK), anti-E2F2 was from Santa Cruz Biotechnology (sc-633, Dallas, TX, USA), and antiglyceraldehyde 3-phosphate dehydrogenase (GAPDH) was from Cell Signaling Technology (#5174, Boston, MA, USA).	('GAPDH', 'Gene', (216, 221))	('E2F2', 'Gene', '1870', (100, 104))	('anti-PPARalpha', 'Var', (38, 52))	('GAPDH', 'Gene', '2597', (216, 221))	('E2F2', 'Gene', (100, 104))
234687	29862267	Lentiviruses expressing control protein (GFP), GFP-PPARalpha, control miRNA, or miR-214 were added to U87 and U251 cells.	('U251', 'CellLine', 'CVCL:0021', (110, 114))	('GFP-PPARalpha', 'Var', (47, 60))	('miR-214', 'Var', (80, 87))
234719	29862267	Indeed, basal transcription level was induced in U87 and U251 cells after overexpression of PPARalpha (Figure 3(a)), and consistent with this, miR-214, miR-199a-3p, and miR-199a-5p levels were higher in PPARalpha-expressing cells than in the control cells (Figure 3(b)).	('miR-214', 'MPA', (143, 150))	('miR-199a-3p', 'Gene', '406977', (152, 163))	('induced', 'PosReg', (38, 45))	('basal transcription level', 'MPA', (8, 33))	('PPARalpha', 'Gene', (92, 101))	('miR-199a-3p', 'Gene', (152, 163))	('miR-199a-5p levels', 'MPA', (169, 187))	('U251', 'CellLine', 'CVCL:0021', (57, 61))	('PPARalpha-expressing', 'Var', (203, 223))	('higher', 'PosReg', (193, 199))
234728	29862267	Consistent with this, cells overexpressing miR-214 showed reduced expression of E2F2 at the protein level compared with cells expressing a control miRNA (Figure 5(c)).	('expression', 'MPA', (66, 76))	('miR-214', 'Var', (43, 50))	('E2F2', 'Gene', '1870', (80, 84))	('reduced', 'NegReg', (58, 65))	('E2F2', 'Gene', (80, 84))
234729	29862267	Notably, overexpression of E2F2 partially restored the proliferation of miR-214-overexpressing cells, suggesting that the miR-214 effect was mediated by E2F2 (Figure 5(d)).	('E2F2', 'Gene', '1870', (27, 31))	('E2F2', 'Gene', (153, 157))	('proliferation', 'CPA', (55, 68))	('E2F2', 'Gene', (27, 31))	('E2F2', 'Gene', '1870', (153, 157))	('miR-214', 'Var', (122, 129))
234730	29862267	To determine whether miR-214 overexpression inhibited the growth of glioma cells in vivo as well as in vitro, we injected nude mice subcutaneously with U87 cells expressing either miR-214 or a control miRNA and analyzed tumor growth after 8 weeks.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('overexpression', 'PosReg', (29, 43))	('tumor', 'Disease', (220, 225))	('inhibited', 'NegReg', (44, 53))	('miR-214', 'Var', (180, 187))	('nude mice', 'Species', '10090', (122, 131))	('miR-214', 'Gene', (21, 28))	('glioma', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('growth', 'CPA', (58, 64))
234732	29862267	Western blot analysis of the excised tumors showed that E2F2 expression was lower in tumors derived from miR-214-expressing cells compared with control cells, as expected (Figure 5(g)).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('E2F2', 'Gene', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('miR-214-expressing cells', 'Var', (105, 129))	('E2F2', 'Gene', '1870', (56, 60))	('lower', 'NegReg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('expression', 'MPA', (61, 71))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('tumors', 'Disease', (85, 91))
234735	29862267	Importantly, glioma cell proliferation (Figure 6(a)) and E2F2 protein expression (Figure 6(b)) were both increased in PPARalpha-overexpressing cells infected with AS-miR-214 compared with PPARalpha sequence.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('protein', 'Protein', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('E2F2', 'Gene', '1870', (57, 61))	('E2F2', 'Gene', (57, 61))	('AS-miR-214', 'Var', (163, 173))	('increased', 'PosReg', (105, 114))	('glioma', 'Disease', (13, 19))	('PPARalpha-overexpressing', 'Gene', (118, 142))
234747	29862267	The DNMO3os transcription unit includes miR-199a and miR-214.	('miR-214', 'Var', (53, 60))	('miR-199a', 'Var', (40, 48))	('DNMO3os', 'Gene', (4, 11))	('DNMO3os', 'Chemical', '-', (4, 11))
234749	29862267	found that miR-214 inhibits the proliferation of hepatocellular carcinoma cells by reducing E2F2 mRNA levels.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (49, 73))	('hepatocellular carcinoma', 'Disease', (49, 73))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (49, 73))	('E2F2', 'Gene', (92, 96))	('reducing', 'NegReg', (83, 91))	('E2F2', 'Gene', '1870', (92, 96))	('proliferation', 'CPA', (32, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('inhibits', 'NegReg', (19, 27))	('miR-214', 'Var', (11, 18))
234751	29862267	Suzuki found that knockout of E2F2 could inhibit the proliferation and tumorigenicity of human embryonic stem cells.	('E2F2', 'Gene', '1870', (30, 34))	('human', 'Species', '9606', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('E2F2', 'Gene', (30, 34))	('inhibit', 'NegReg', (41, 48))	('knockout', 'Var', (18, 26))	('tumor', 'Disease', (71, 76))
234752	29862267	Our study extends these findings by showing that miR-214 targeting of E2F2 inhibits the proliferation of human brain glioma cells through a PPARalpha-regulated pathway.	('human', 'Species', '9606', (105, 110))	('E2F2', 'Gene', (70, 74))	('targeting', 'Var', (57, 66))	('brain glioma', 'Disease', 'MESH:C564230', (111, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('E2F2', 'Gene', '1870', (70, 74))	('brain glioma', 'Disease', (111, 123))	('PPARalpha-regulated pathway', 'Pathway', (140, 167))	('inhibits', 'NegReg', (75, 83))
234754	29862267	We also demonstrated that expression of miR-214, which is encoded by the DNMO3os transcription unit, correlated positively with PPARalpha levels and that miR-214 inhibits E2F2 expression.	('expression', 'MPA', (26, 36))	('miR-214', 'Gene', (40, 47))	('DNMO3os', 'Chemical', '-', (73, 80))	('PPARalpha levels', 'MPA', (128, 144))	('inhibits', 'NegReg', (162, 170))	('E2F2', 'Gene', (171, 175))	('miR-214', 'Var', (154, 161))	('expression', 'MPA', (176, 186))	('E2F2', 'Gene', '1870', (171, 175))
234817	25438812	Currently, the two most commonly referenced molecular genetic markers are 1p19q genotype in oligodendroglial tumors and EGF receptor (EGFR) amplification status in primary glioblastoma.	('EGFR', 'Gene', (134, 138))	('primary glioblastoma', 'Disease', (164, 184))	('EGF receptor', 'Gene', '1956', (120, 132))	('primary glioblastoma', 'Disease', 'MESH:D005909', (164, 184))	('EGF receptor', 'Gene', (120, 132))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (92, 115))	('oligodendroglial tumors', 'Disease', (92, 115))	('amplification status', 'Var', (140, 160))	('1p19q genotype', 'Var', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('EGFR', 'Gene', '1956', (134, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
234819	25438812	Currently, the diagnosis of 1p19q codeletion is made using tissues specimens obtained during primary surgical resection or selected tumor sampling.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('1p19q codeletion', 'Var', (28, 44))	('tumor', 'Disease', 'MESH:D009369', (132, 137))
234824	25438812	Taken together these observations suggest that, unlike astrocytic tumors, elevated CBV within oligodendroglial tumors with 1p19q codeletion may not be indicative of aggressive biological characteristics.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('astrocytic tumors', 'Disease', (55, 72))	('elevated CBV within oligodendroglial tumors', 'Disease', (74, 117))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('elevated CBV within oligodendroglial tumors', 'Disease', 'MESH:D001929', (74, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('astrocytic tumors', 'Disease', 'MESH:D001254', (55, 72))	('1p19q codeletion', 'Var', (123, 139))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))
234825	25438812	Recent advances in primary glial neoplasm molecular classification have identified EGFR mutation as a potential indicator of poor clinical outcomes in glioblastoma.	('EGFR', 'Gene', '1956', (83, 87))	('mutation', 'Var', (88, 96))	('EGFR', 'Gene', (83, 87))	('glioblastoma', 'Disease', (151, 163))	('glial neoplasm', 'Disease', 'MESH:D005910', (27, 41))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('neoplasm', 'Phenotype', 'HP:0002664', (33, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('glial neoplasm', 'Disease', (27, 41))
234826	25438812	Up to 50% of primary glioblastoma with this molecular classification have a mutated form of EGFR variant III (EGFRvIII).	('variant III', 'Var', (97, 108))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('mutated', 'Var', (76, 83))	('EGFR', 'Gene', '1956', (92, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('EGFR', 'Gene', (92, 96))	('primary glioblastoma', 'Disease', 'MESH:D005909', (13, 33))	('primary glioblastoma', 'Disease', (13, 33))
234827	25438812	EGFRvIII mutation encodes an in-frame deletion resulting in pro-oncogenic effects such as elevated proliferation, angiogenesis and tumor invasiveness.	('mutation', 'Var', (9, 17))	('elevated', 'PosReg', (90, 98))	('EGFR', 'Gene', (0, 4))	('tumor invasiveness', 'Disease', (131, 149))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor invasiveness', 'Disease', 'MESH:D009369', (131, 149))	('EGFR', 'Gene', '1956', (0, 4))	('angiogenesis', 'CPA', (114, 126))
234828	25438812	Multiple prior investigations have not definitively demonstrated a link between EGFRvIII mutation status and clinical outcomes in patients with primary glioblastoma.	('primary glioblastoma', 'Disease', 'MESH:D005909', (144, 164))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('primary glioblastoma', 'Disease', (144, 164))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('patients', 'Species', '9606', (130, 138))
234829	25438812	However, identification of EGFRvIII mutational status remains clinical relevant as it has been demonstrated to convey resistance to chemotherapies.	('mutational', 'Var', (36, 46))	('convey', 'Reg', (111, 117))	('EGFR', 'Gene', (27, 31))	('EGFR', 'Gene', '1956', (27, 31))
234832	25438812	To this end, prior investigators have identified morphologic and physiologic DSC perfusion MRI metrics that are differentially expressed between primary glioblastoma with and without EGFR mutations.	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('primary glioblastoma', 'Disease', 'MESH:D005909', (145, 165))	('primary glioblastoma', 'Disease', (145, 165))	('mutations', 'Var', (188, 197))
234833	25438812	has demonstrated that tumors with indistinct T2 hyperintensity borders and elevated T2 hyperintensity to enhancing volume ratio were more likely to demonstrate EGFRvIII mutation.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mutation', 'Var', (169, 177))	('T2 hyperintensity to enhancing volume ratio', 'MPA', (84, 127))	('T2 hyperintensity', 'MPA', (45, 62))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('EGFR', 'Gene', '1956', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('EGFR', 'Gene', (160, 164))	('tumors', 'Disease', (22, 28))
234834	25438812	have demonstrated an association between EGFRvIII mutational status and DSC perfusion metrics.	('EGFR', 'Gene', (41, 45))	('association', 'Interaction', (21, 32))	('mutational', 'Var', (50, 60))	('DSC', 'Disease', (72, 75))	('EGFR', 'Gene', '1956', (41, 45))
234835	25438812	EGFRvIII mutants demonstrated significantly elevated relative CBV when compared with those primary glioblastoma without the mutation (Figure 6).	('EGFR', 'Gene', (0, 4))	('elevated', 'PosReg', (44, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('relative CBV', 'MPA', (53, 65))	('mutants', 'Var', (9, 16))	('primary glioblastoma', 'Disease', 'MESH:D005909', (91, 111))	('primary glioblastoma', 'Disease', (91, 111))	('EGFR', 'Gene', '1956', (0, 4))
234836	25438812	have also demonstrated that glioblastoma EGFR mutational status was positively associated with PH and inversely associated with PSR metrics.	('EGFR', 'Gene', (41, 45))	('associated', 'Reg', (79, 89))	('PSR', 'Gene', '23210', (128, 131))	('PSR', 'Gene', (128, 131))	('mutational status', 'Var', (46, 63))	('glioblastoma', 'Disease', (28, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('EGFR', 'Gene', '1956', (41, 45))
234860	25438812	EGFR mutation is a potential indicator of poor clinical outcomes in glioblastoma.	('EGFR', 'Gene', (0, 4))	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
234958	20029975	VO2peak is a powerful independent predictor of mortality among non-cancer populations with underlying cardiac and pulmonary disease.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('pulmonary disease', 'Disease', (114, 131))	('O2', 'Chemical', 'MESH:D010100', (1, 3))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('VO2peak', 'Var', (0, 7))	('pulmonary disease', 'Disease', 'MESH:D008171', (114, 131))
234978	20029975	However, VO2peak and lean body mass (muscle strength approached significance) were inversely associated with fatigue.	('O2', 'Chemical', 'MESH:D010100', (10, 12))	('fatigue', 'Disease', 'MESH:D005221', (109, 116))	('lean body mass', 'CPA', (21, 35))	('VO2peak', 'Var', (9, 16))	('inversely', 'NegReg', (83, 92))	('fatigue', 'Disease', (109, 116))	('fatigue', 'Phenotype', 'HP:0012378', (109, 116))
234993	33614625	Furthermore, CFI was identified as an independent prognostic factor of glioma in the CGGA database.	('CFI', 'Var', (13, 16))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
234994	33614625	CFI knockdown in glioma cell lines inhibited growth in vitro and in vivo, whereas its ectopic expression increased glioma cell proliferation, migration, and invasion in vitro.	('glioma', 'Disease', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('migration', 'CPA', (142, 151))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('growth', 'CPA', (45, 51))	('invasion', 'CPA', (157, 165))	('CFI', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('glioma', 'Disease', (17, 23))	('inhibited', 'NegReg', (35, 44))	('increased', 'PosReg', (105, 114))	('knockdown', 'Var', (4, 13))
234999	33614625	For instance, expression of 1p/19q genes is a potential prognostic marker in 1p/19q non-codeletion gliomas, whereas isocitrate dehydrogenase (IDH) levels have prognostic value in wild-type IDH gliomas (Calvert et al.,; Chai et al.,).	('IDH', 'Gene', (189, 192))	('IDH gliomas', 'Disease', 'MESH:D005910', (189, 200))	('gliomas', 'Disease', (193, 200))	('IDH', 'Gene', (142, 145))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('1p/19q non-codeletion', 'Var', (77, 98))	('IDH', 'Gene', '3417', (189, 192))	('IDH gliomas', 'Disease', (189, 200))	('isocitrate dehydrogenase', 'Gene', (116, 140))	('gliomas', 'Disease', (99, 106))	('IDH', 'Gene', '3417', (142, 145))	('non-codeletion', 'Var', (84, 98))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('isocitrate dehydrogenase', 'Gene', '3417', (116, 140))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
235009	33614625	CFI was highly expressed in glioma cell lines and tissues, and its knockdown significantly inhibited glioma cell proliferation, migration, and invasion in vitro and in vivo.	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('inhibited', 'NegReg', (91, 100))	('knockdown', 'Var', (67, 76))	('glioma', 'Disease', (101, 107))	('migration', 'CPA', (128, 137))	('invasion', 'CPA', (143, 151))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('CFI', 'Gene', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Disease', (28, 34))
235010	33614625	In addition, glioma patients with high expression of CFI had worse prognosis compared to patients expressing low CFI.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('high expression', 'Var', (34, 49))	('CFI', 'Gene', (53, 56))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (20, 28))	('glioma', 'Disease', (13, 19))
235013	33614625	Gene Expression Profiling Interactive Analysis (GEPIA; http://gepia.cancer-pku.cn/index.html) was used to analyze survival differences between the CFIhigh and CFIlow glioblastoma multiform (GBM) and low-grade glioma (LGG) patients.	('gepia.cancer-pku', 'Disease', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('CFIlow glioblastoma', 'Disease', (159, 178))	('gepia.cancer-pku', 'Disease', 'MESH:D009369', (62, 78))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('CFIlow glioblastoma', 'Disease', 'MESH:D005909', (159, 178))	('patients', 'Species', '9606', (222, 230))	('CFIhigh', 'Var', (147, 154))	('glioma', 'Disease', (209, 215))
235025	33614625	Anti-FAK and anti-phospho-FAK (Tyr576/577) primary antibodies were purchased from Abcam.	('FAK', 'Gene', '5747', (26, 29))	('FAK', 'Gene', (26, 29))	('FAK', 'Gene', '5747', (5, 8))	('FAK', 'Gene', (5, 8))	('Tyr576/577', 'Var', (31, 41))	('Tyr576', 'Chemical', '-', (31, 37))
235049	33614625	Consistent with this, high CFI expression level also predicted worse prognosis for all glioma patients in the CGGA database (Figure 1F).	('glioma', 'Disease', (87, 93))	('patients', 'Species', '9606', (94, 102))	('worse', 'NegReg', (63, 68))	('high', 'Var', (22, 26))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('CFI expression level', 'MPA', (27, 47))
235055	33614625	We found that patients in high-risk groups had shorter OS than low-risk groups in IDH mutant grade II glioma and IDH mutant GBM subgroups (Supplementary Figures 1D,H).	('IDH', 'Gene', '3417', (82, 85))	('IDH', 'Gene', '3417', (113, 116))	('shorter', 'NegReg', (47, 54))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('II glioma', 'Disease', (99, 108))	('mutant', 'Var', (86, 92))	('II glioma', 'Disease', 'MESH:D005910', (99, 108))	('IDH', 'Gene', (82, 85))	('IDH', 'Gene', (113, 116))	('patients', 'Species', '9606', (14, 22))
235056	33614625	But, we observed no statistically significant difference in patients' OS between high-risk and low-risk groups in IDH wildtype grade II glioma, IDH mutant and 1p/19q codeleted or non-codeleted grade III glioma, and IDH wildtype GBM (Supplementary Figures 1E-G,I).	('II glioma', 'Disease', (133, 142))	('IDH', 'Gene', (144, 147))	('and 1p', 'Gene', '11169', (155, 161))	('and 1p', 'Gene', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('IDH', 'Gene', '3417', (144, 147))	('IDH', 'Gene', (114, 117))	('patients', 'Species', '9606', (60, 68))	('II glioma', 'Disease', 'MESH:D005910', (200, 209))	('mutant', 'Var', (148, 154))	('IDH', 'Gene', (215, 218))	('IDH', 'Gene', '3417', (114, 117))	('II glioma', 'Disease', (200, 209))	('II glioma', 'Disease', 'MESH:D005910', (133, 142))	('IDH', 'Gene', '3417', (215, 218))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
235061	33614625	Furthermore, glioma samples with IDH mutation or 1p/19q co-deletion expressed lower levels of CFI compared to the corresponding non-mutated samples (Figures 2E,F).	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('levels of CFI', 'MPA', (84, 97))	('IDH', 'Gene', '3417', (33, 36))	('1p/19q co-deletion', 'Var', (49, 67))	('IDH', 'Gene', (33, 36))	('glioma', 'Disease', (13, 19))	('lower', 'NegReg', (78, 83))
235063	33614625	In a previous study, we found that glioma patients expressing high levels of CFI had significantly worse OS and DFS compared to the CFIlow patients in TCGA and CGGA databases.	('CFI', 'Gene', (77, 80))	('glioma', 'Disease', (35, 41))	('high levels', 'Var', (62, 73))	('patients', 'Species', '9606', (139, 147))	('DFS', 'Disease', (112, 115))	('DFS', 'Disease', 'None', (112, 115))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('patients', 'Species', '9606', (42, 50))	('worse', 'NegReg', (99, 104))
235072	33614625	As shown in Figure 3D, WHO grade and CFI expression contributed the most to prognosis, followed by PRS type, 1p19q co-deletion status, chemotherapy status, IDH status, and age.	('IDH', 'Gene', (156, 159))	('prognosis', 'MPA', (76, 85))	('1p19q co-deletion', 'Var', (109, 126))	('IDH', 'Gene', '3417', (156, 159))
235082	33614625	In this study, we sought to gain insight into the role of CFI in VEGF pathway by immunoblot and the results showed that phosphorylation level of focal adhesion kinase (FAK) at tyrosine sites (Y576 and Y577) was markedly decreased after CFI depletion among various receptor molecules including VEGF receptor 2 (VEGFR2), FAK, protein kinase B (AKT), and p38 mitogen-activated protein kinase (p38 MAPK) (Supplementary Figure 4).	('focal adhesion kinase', 'Gene', '5747', (145, 166))	('depletion', 'NegReg', (240, 249))	('protein kinase B', 'Gene', '2185', (324, 340))	('FAK', 'Gene', (319, 322))	('protein kinase B', 'Gene', (324, 340))	('VEGF', 'Gene', '7422', (65, 69))	('AKT', 'Gene', '207', (342, 345))	('FAK', 'Gene', (168, 171))	('focal adhesion kinase', 'Gene', (145, 166))	('Y576', 'Var', (192, 196))	('VEGFR2', 'Gene', (310, 316))	('Y577', 'Var', (201, 205))	('VEGF', 'Gene', (65, 69))	('phosphorylation level', 'MPA', (120, 141))	('decreased', 'NegReg', (220, 229))	('FAK', 'Gene', '5747', (319, 322))	('FAK', 'Gene', '5747', (168, 171))	('VEGFR2', 'Gene', '3791', (310, 316))	('VEGF', 'Gene', '7422', (293, 297))	('VEGF receptor 2', 'Gene', (293, 308))	('VEGF', 'Gene', '7422', (310, 314))	('p38 mitogen-activated protein kinase', 'Gene', (352, 388))	('VEGF', 'Gene', (310, 314))	('VEGF', 'Gene', (293, 297))	('tyrosine', 'Chemical', 'MESH:D014443', (176, 184))	('p38 MAPK', 'Gene', '1432', (390, 398))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (352, 388))	('p38 MAPK', 'Gene', (390, 398))	('VEGF receptor 2', 'Gene', '3791', (293, 308))	('AKT', 'Gene', (342, 345))
235087	33614625	The expression level of CFI mRNA was also detected in normal human astrocytes (NHAs) and six GBM cell lines (A172, U118, LN229, U251, T98G, and U87), and all GBM cells except A172 expressed markedly higher levels of CFI mRNA compared to the NHAs (Figure 4C).	('U87', 'Gene', '641648', (144, 147))	('U251', 'Var', (128, 132))	('CFI mRNA', 'MPA', (216, 224))	('LN229', 'CellLine', 'CVCL:0393', (121, 126))	('higher', 'PosReg', (199, 205))	('human', 'Species', '9606', (61, 66))	('U87', 'Gene', (144, 147))
235090	33614625	Consistent with the bioinformatics results, Kaplan-Meier survival analysis suggested that patients with high CFI expression level had shorter overall and progression-free survival compared to those with low CFI expression (Figures 4G,H).	('high', 'Var', (104, 108))	('shorter', 'NegReg', (134, 141))	('patients', 'Species', '9606', (90, 98))
235095	33614625	Consistent with this, knocking down CFI also markedly reduced the number of colonies formed by the glioma cells (Figures 5C,D).	('CFI', 'Gene', (36, 39))	('reduced', 'NegReg', (54, 61))	('glioma', 'Disease', (99, 105))	('knocking down', 'Var', (22, 35))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
235105	33614625	Immunohistochemical staining showed decreased expression of CFI and Ki67 in CFI-knockdown tumors compared to control tumors in mice (Figure 7B).	('CFI-knockdown', 'Var', (76, 89))	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CFI', 'Gene', (60, 63))	('Ki67', 'Gene', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'MPA', (46, 56))	('Ki67', 'Gene', '17345', (68, 72))	('CFI-knockdown', 'Gene', (76, 89))	('decreased', 'NegReg', (36, 45))
235107	33614625	Consistent with these findings, Kaplan-Meier analysis demonstrated that the mice injected with shCFI-U251 cells survived considerably longer than those injected with the control U251 cells (Figure 7D).	('shCFI-U251 cells', 'Var', (95, 111))	('mice', 'Species', '10090', (76, 80))	('longer', 'PosReg', (134, 140))
235108	33614625	Together, inhibition of CFI impedes glioma growth in vivo, indicating its therapeutic potential.	('CFI', 'Gene', (24, 27))	('impedes', 'NegReg', (28, 35))	('glioma growth', 'Disease', (36, 49))	('inhibition', 'Var', (10, 20))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('glioma growth', 'Disease', 'MESH:D005910', (36, 49))
235111	33614625	Several clinically significant molecular alterations (including mutations in IDH, 1p/19q, MGMT, and EGFR) have been described in gliomas and combined with histology for tumor classification (Eckel-Passow et al.,; Hoshide and Jandial,; Louis et al.,; Jiang et al.,).	('EGFR', 'Gene', '1956', (100, 104))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('MGMT', 'Gene', (90, 94))	('EGFR', 'Gene', (100, 104))	('gliomas', 'Disease', (129, 136))	('MGMT', 'Gene', '4255', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (64, 73))	('IDH, 1p/19q', 'Gene', '3417', (77, 88))
235117	33614625	CFI was also significantly upregulated in glioma cell lines and tumor tissues, and its ectopic expression enhanced the invasion, migration, and proliferation of tumor cells in vitro.	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('enhanced', 'PosReg', (106, 114))	('invasion', 'CPA', (119, 127))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glioma', 'Disease', (42, 48))	('migration', 'CPA', (129, 138))	('CFI', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('upregulated', 'PosReg', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('ectopic expression', 'Var', (87, 105))
235122	33614625	In the current study, we found that higher WHO grade, wildtype IDH, 1p19q non-codeletion, higher histology grade, and older age correlated significantly with higher CFI expression, indicating that CFI is related to poor prognosis.	('IDH', 'Gene', (63, 66))	('1p19q', 'Var', (68, 73))	('CFI', 'Protein', (165, 168))	('IDH', 'Gene', '3417', (63, 66))	('higher', 'PosReg', (158, 164))	('expression', 'MPA', (169, 179))
235124	33614625	The respective AUC of the ROCs of different clinical variables indicated superior prognostic performance of CFI compared to IDH mutation status, 1p19q co-deletion status, or histology grade.	('superior', 'PosReg', (73, 81))	('IDH', 'Gene', (124, 127))	('IDH', 'Gene', '3417', (124, 127))	('CFI', 'Disease', (108, 111))	('1p19q', 'Var', (145, 150))
235127	33614625	Functional annotation of CFI further revealed that the JAK/STAT, NOD-like receptor, pathways in cancer, T cell receptor, and VEGF pathways were significantly enriched in the CFIhigh phenotype, indicating that CFI may drive glioma progression through the aforementioned signaling pathways.	('VEGF', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('cancer', 'Disease', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('CFIhigh', 'Var', (174, 181))	('drive', 'PosReg', (217, 222))	('VEGF', 'Gene', '7422', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('glioma', 'Disease', (223, 229))
235128	33614625	Furthermore, we provided experimental evidence that CFI may in part contribute to FAK activation in VEGF pathway.	('FAK', 'Gene', '5747', (82, 85))	('VEGF', 'Gene', '7422', (100, 104))	('FAK', 'Gene', (82, 85))	('CFI', 'Var', (52, 55))	('activation', 'PosReg', (86, 96))	('VEGF', 'Gene', (100, 104))
235130	33614625	Nevertheless, silencing CFI in the glioma cells significantly decreased their proliferation, invasion, and migration abilities, whereas its ectopic expression had the opposite effect.	('silencing', 'Var', (14, 23))	('decreased', 'NegReg', (62, 71))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('CFI', 'Gene', (24, 27))	('proliferation', 'CPA', (78, 91))	('invasion', 'CPA', (93, 101))	('migration abilities', 'CPA', (107, 126))	('glioma', 'Disease', (35, 41))
235137	33614625	Functional in vitro and in vivo assays further indicated that CFI knockdown suppressed glioma cell proliferation, invasion, and migration, whereas its overexpression had the opposite effects.	('glioma', 'Disease', (87, 93))	('migration', 'CPA', (128, 137))	('suppressed', 'NegReg', (76, 86))	('CFI', 'Gene', (62, 65))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('knockdown', 'Var', (66, 75))	('invasion', 'CPA', (114, 122))
235160	30867843	TMZ, as an alkylating agent, can induce approximately 13 DNA adducts, among which the minor adduct O6-methylguanine (O6-meG) possesses the strongest cytotoxicity.	('O6-methylguanine', 'Var', (99, 115))	('cytotoxicity', 'Disease', (149, 161))	('DNA', 'MPA', (57, 60))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (99, 115))	('cytotoxicity', 'Disease', 'MESH:D064420', (149, 161))	('O6-meG', 'Chemical', 'MESH:C008449', (117, 123))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
235161	30867843	O6-meG mispairs with thymine (T) to form O6-meG/T mismatches, which can activate the mismatch repair system (MMR) to perform futile repair cycles.	('mispairs', 'Var', (7, 15))	('O6-meG', 'Var', (0, 6))	('thymine', 'Chemical', 'MESH:D013941', (21, 28))	('activate', 'PosReg', (72, 80))	('mismatches', 'Var', (50, 60))	('O6-meG', 'Chemical', 'MESH:C008449', (41, 47))	('O6-meG', 'Chemical', 'MESH:C008449', (0, 6))	('O6-meG/T', 'Var', (41, 49))
235165	30867843	However, many studies have already verified that mutations in MSH6 frequently occur during TMZ treatment, which seriously impairs the effects of MSH6.	('TMZ', 'Chemical', 'MESH:D000077204', (91, 94))	('MSH6', 'Gene', (62, 66))	('occur', 'Reg', (78, 83))	('mutations', 'Var', (49, 58))
235166	30867843	Therefore, some investigators have intended to overexpress MSH6 to improve TMZ efficacy.	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))	('overexpress', 'Var', (47, 58))	('improve', 'PosReg', (67, 74))	('MSH6', 'Gene', (59, 63))
235185	30867843	Patient survival analysis revealed that high MSH6 expression predicted poor overall survival (OS) and disease-free survival (DFS) for all gliomas and LGG, rather than for GBM alone (Figure 1D).	('high', 'Var', (40, 44))	('gliomas', 'Disease', (138, 145))	('disease-free survival', 'CPA', (102, 123))	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('poor', 'NegReg', (71, 75))	('overall survival', 'CPA', (76, 92))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('MSH6', 'Gene', (45, 49))	('Patient', 'Species', '9606', (0, 7))	('LGG', 'Disease', (150, 153))	('expression', 'MPA', (50, 60))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))
235186	30867843	This phenomenon is likely due to the influence of TMZ, which can utilize the cell damage repair function of MSH6 to exert antitumor effects or induce mutations in MSH6 .	('MSH6', 'Gene', (108, 112))	('induce', 'Reg', (143, 149))	('MSH6', 'Gene', (163, 167))	('TMZ', 'Chemical', 'MESH:D000077204', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
235188	30867843	The results showed that the expression of p-EGFR (Tyr1173) and p-STAT3 (Tyr705) significantly decreased, while that of E-cadherin, Cyclin E1 and Bcl-2 increased after MSH6 alteration (Table S1).	('Cyclin E1', 'Gene', (131, 140))	('increased', 'PosReg', (151, 160))	('Bcl-2', 'Gene', (145, 150))	('Tyr1173', 'Chemical', '-', (50, 57))	('expression', 'MPA', (28, 38))	('E-cadherin', 'Gene', (119, 129))	('EGFR', 'Gene', '24329', (44, 48))	('Tyr705', 'Chemical', '-', (72, 78))	('Tyr1173', 'Var', (50, 57))	('decreased', 'NegReg', (94, 103))	('STAT3', 'Gene', '6774', (65, 70))	('E-cadherin', 'Gene', '999', (119, 129))	('Cyclin E1', 'Gene', '898', (131, 140))	('EGFR', 'Gene', (44, 48))	('STAT3', 'Gene', (65, 70))
235191	30867843	In many cases, genes related to antiapoptotic effects can impact the motility of tumor cells.	('genes', 'Var', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('impact', 'Reg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
235192	30867843	The expression of MSH6 in U87MG, U251 and T98G cells was detected using western blot analysis, and the results revealed that the MSH6 protein levels in U87MG cells were higher than those in U251 and T98G cells (Figure S4).	('higher', 'PosReg', (169, 175))	('U87MG', 'Var', (152, 157))	('U87MG', 'CellLine', 'CVCL:0022', (26, 31))	('MSH6', 'Gene', (129, 133))	('U87MG', 'CellLine', 'CVCL:0022', (152, 157))
235195	30867843	To investigate whether MSH6 could influence gliomagenesis in vivo, U251-Con, U251-MSH6, T98G- Con or T98G-MSH6 cells were injected subcutaneously in the flank of nude mice.	('nude mice', 'Species', '10090', (162, 171))	('U251-MSH6', 'Var', (77, 86))	('influence', 'Reg', (34, 43))	('glioma', 'Disease', (44, 50))	('T98G-', 'Var', (88, 93))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
235196	30867843	Earlier tumor formation was noticed in the U251-MSH6 group (5.32 +- 0.26 days) than in the U251-Con group (8.53 +- 0.78 days).	('Earlier', 'PosReg', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('U251-MSH6', 'Var', (43, 52))	('tumor', 'Disease', (8, 13))
235197	30867843	As shown in Figure 3D and Figure S7, the average tumor weight and volume of the U251-MSH6 group were approximately 2.5-fold higher than those of the U251-Con group at 4 weeks postinoculation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('U251-MSH6', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('higher', 'PosReg', (124, 130))
235198	30867843	Notably, T98G, which is not tumorigenic in nude mice (identified by the American Type Culture Collection), acquired a tumorigenic ability after overexpressing MSH6, while the cells of the T98G-Con group exhibited necrosis.	('necrosis', 'Disease', (213, 221))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('MSH6', 'Gene', (159, 163))	('T98G', 'Var', (9, 13))	('necrosis', 'Disease', 'MESH:D009336', (213, 221))	('nude mice', 'Species', '10090', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('overexpressing', 'PosReg', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
235200	30867843	Thus, H&E staining was used to determine tumor growth in all groups and incremental angiogenesis and microangiogenesis in the U251-MSH6 group (Figure 3E and Figure S8).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('incremental', 'CPA', (72, 83))	('tumor', 'Disease', (41, 46))	('and', 'CPA', (97, 100))	('H&E', 'Chemical', '-', (6, 9))	('the', 'Var', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
235202	30867843	B-mode ultrasonography showed that the tumors of the U251-MSH6 group grew faster than those of the U251-Con group, and the internal echogenicity of the U251-MSH6 group was slightly higher than that of the U251-Con group.	('internal echogenicity', 'CPA', (123, 144))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('U251-MSH6', 'Var', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('higher', 'PosReg', (181, 187))	('faster', 'PosReg', (74, 80))	('tumors', 'Disease', (39, 45))	('grew', 'CPA', (69, 73))
235203	30867843	Additionally, color Doppler flow imaging (CDFI) and color power angiography (CPA) revealed increased angiogenesis and microangiogenesis, respectively, in the U251-MSH6 group, which were consistent with the results of the H&E staining.	('angiogenesis', 'CPA', (101, 113))	('U251-MSH6', 'Var', (158, 167))	('H&E', 'Chemical', '-', (221, 224))	('CPA', 'Chemical', '-', (77, 80))	('CDFI', 'Chemical', '-', (42, 46))	('increased', 'PosReg', (91, 100))	('microangiogenesis', 'CPA', (118, 135))
235204	30867843	In the MRI observation, the average tumor size of the U251-MSH6 group was remarkably greater than that of the U251-Con group, which is consistent with the above USI results.	('U251-MSH6', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('greater', 'PosReg', (85, 92))	('tumor', 'Disease', (36, 41))
235205	30867843	In addition, tumors of the U251-Con group and the U251-MSH6 group all exhibited low signal intensity in T1WI, high signal intensity in T2WI/T2-SPIR, and low-intermediate signal intensity in T2-FLAIR.	('high signal intensity', 'MPA', (110, 131))	('low', 'NegReg', (80, 83))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('U251-Con', 'Var', (27, 35))	('T1WI', 'MPA', (104, 108))	('T2WI/T2-SPIR', 'MPA', (135, 147))	('T2-FLAIR', 'MPA', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
235207	30867843	No tumors formed in the T98G-Con group, while the tumors of the T98G-MSH6 group showed imaging features similar to those of the U251-MSH6 group.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('T98G-MSH6', 'Var', (64, 73))
235211	30867843	Notably, the tumors in the U251-MSH6 group and the T98G-MSH6 group infiltrated and destroyed the surrounding skin, which could partly reflect their enhanced invasiveness (Figure 3D).	('infiltrated', 'CPA', (67, 78))	('T98G-MSH6', 'Var', (51, 60))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('enhanced', 'PosReg', (148, 156))	('destroyed', 'NegReg', (83, 92))	('invasiveness', 'CPA', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('U251-MSH6', 'Var', (27, 36))
235212	30867843	To further elucidate the functions of MSH6 in GBM at the molecular level, we detected a series of typical regulatory factors and markers after silencing or elevating MSH6, including the following: the G1 phase regulatory factor Cyclin D1; the proapoptotic factor Bax; the antiapoptotic factor Bcl-2; the epithelial marker E-cadherin; the mesenchymal markers N- cadherin, Vimentin, MMP2, and MMP9; the stemness markers CD133 and SOX2; and the angiogenesis regulatory factors HIF1A and VEGFA.	('E-cadherin', 'Gene', (322, 332))	('stemness', 'Disease', 'MESH:D020295', (401, 409))	('stemness', 'Disease', (401, 409))	('elevating', 'PosReg', (156, 165))	('MSH6', 'Gene', (166, 170))	('E-cadherin', 'Gene', '999', (322, 332))	('silencing', 'Var', (143, 152))	('VEGFA', 'Gene', (484, 489))	('Vimentin', 'Gene', '7431', (371, 379))	('Bax', 'Gene', (263, 266))	('N- cadherin', 'Gene', '1000', (358, 369))	('Vimentin', 'Gene', (371, 379))	('Bax', 'Gene', '581', (263, 266))	('N- cadherin', 'Gene', (358, 369))	('MMP2', 'Gene', (381, 385))	('VEGFA', 'Gene', '7422', (484, 489))	('CD133', 'Gene', (418, 423))	('MMP9', 'Gene', (391, 395))	('CD133', 'Gene', '8842', (418, 423))	('MMP9', 'Gene', '4318', (391, 395))	('MMP2', 'Gene', '4313', (381, 385))
235216	30867843	The immunohistochemical assay of tumor tissues segmented from the U251-Con/MSH6 tumor-bearing nude mice showed that Cyclin D1, Bcl-2, N-cadherin, Nestin, SOX2, and HIF1A were increased in the U251-MSH6 group.	('nude mice', 'Species', '10090', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Bcl-2', 'MPA', (127, 132))	('N-cadherin', 'Protein', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('HIF1A', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (80, 85))	('increased', 'PosReg', (175, 184))	('Cyclin D1', 'MPA', (116, 125))	('tumor', 'Disease', (33, 38))	('U251-MSH6', 'Var', (192, 201))	('SOX2', 'Protein', (154, 158))	('Nestin', 'Protein', (146, 152))
235221	30867843	Then, the low pH value promotes HIF1A protein synthesis by triggering specific signaling pathways or transcription factors, such as the STAT3 signaling pathway, its most common collaborator.	('protein synthesis', 'MPA', (38, 55))	('promotes', 'PosReg', (23, 31))	('signaling pathways', 'Pathway', (79, 97))	('STAT3', 'Gene', '6774', (136, 141))	('triggering', 'Reg', (59, 69))	('low', 'Var', (10, 13))	('HIF1A', 'Gene', (32, 37))	('STAT3', 'Gene', (136, 141))
235222	30867843	Simultaneously, MSH6 overexpression might promote the synthesis of HIF1A protein by activating the STAT3 signaling pathway.	('overexpression', 'Var', (21, 35))	('STAT3', 'Gene', '6774', (99, 104))	('promote', 'PosReg', (42, 49))	('synthesis', 'MPA', (54, 63))	('MSH6', 'Gene', (16, 20))	('activating', 'Reg', (84, 94))	('STAT3', 'Gene', (99, 104))	('HIF1A', 'Gene', (67, 72))
235224	30867843	The results indicated that silencing MSH6 decreased the phosphorylation of STAT3 and Smad2/3 (Figure 5A, Figure S13 and Figure S14), whereas MSH6 overexpression increased the phosphorylation of these factors (Figure 5B and Figure S15).	('silencing', 'Var', (27, 36))	('decreased', 'NegReg', (42, 51))	('phosphorylation', 'MPA', (175, 190))	('S15', 'Gene', '6209', (230, 233))	('S14', 'Gene', (127, 130))	('STAT3', 'Gene', '6774', (75, 80))	('S14', 'Gene', '6208', (127, 130))	('MSH6', 'Gene', (37, 41))	('Smad2/3', 'Gene', (85, 92))	('STAT3', 'Gene', (75, 80))	('Smad2/3', 'Gene', '4087;4088', (85, 92))	('phosphorylation', 'MPA', (56, 71))	('increased', 'PosReg', (161, 170))	('S15', 'Gene', (230, 233))
235230	30867843	Therefore, we first detected the transcription and translation of the transcription factors Snail, Slug, Twist, ZEB1 and ZEB2 after silencing or overexpressing MSH6.	('Snail', 'Gene', (92, 97))	('detected', 'Reg', (20, 28))	('Twist', 'Gene', (105, 110))	('Slug', 'Gene', '6591', (99, 103))	('silencing', 'Var', (132, 141))	('Slug', 'Gene', (99, 103))	('MSH6', 'Gene', (160, 164))	('ZEB2', 'Gene', '9839', (121, 125))	('ZEB1', 'Gene', (112, 116))	('Snail', 'Gene', '6615', (92, 97))	('ZEB1', 'Gene', '6935', (112, 116))	('Twist', 'Gene', '7291', (105, 110))	('translation', 'MPA', (51, 62))	('ZEB2', 'Gene', (121, 125))
235232	30867843	In addition, immunofluorescence showed an increase in Slug and ZEB2 in the nuclei of U251-MSH6 and T98G-MSH6 cells (Figure 6C and Figure S18), suggesting that MSH6 could regulate the expression of Slug and ZEB2.	('S18', 'Gene', '6222', (137, 140))	('Slug', 'Gene', (54, 58))	('Slug', 'Gene', (197, 201))	('ZEB2', 'Gene', '9839', (63, 67))	('ZEB2', 'Gene', '9839', (206, 210))	('S18', 'Gene', (137, 140))	('Slug', 'Gene', '6591', (197, 201))	('expression', 'MPA', (183, 193))	('ZEB2', 'Gene', (206, 210))	('Slug', 'Gene', '6591', (54, 58))	('ZEB2', 'Gene', (63, 67))	('T98G-MSH6', 'Var', (99, 108))	('regulate', 'Reg', (170, 178))	('increase', 'PosReg', (42, 50))
235235	30867843	To confirm this possibility, we then knocked down Slug or ZEB2 using siRNA in MSH6-overexpressing GBM cells.	('knocked', 'Var', (37, 44))	('ZEB2', 'Gene', '9839', (58, 62))	('Slug', 'Gene', '6591', (50, 54))	('Slug', 'Gene', (50, 54))	('ZEB2', 'Gene', (58, 62))
235236	30867843	As expected, silencing Slug or ZEB2 abolished the proliferation, migration and invasion induced by MSH6 in U251-MSH6 and T98G-MSH6 cells (Figure 6D, E, F and Figure S19).	('migration', 'CPA', (65, 74))	('Slug', 'Gene', (23, 27))	('proliferation', 'CPA', (50, 63))	('ZEB2', 'Gene', '9839', (31, 35))	('abolished', 'NegReg', (36, 45))	('invasion', 'CPA', (79, 87))	('MSH6', 'Gene', (99, 103))	('Slug', 'Gene', '6591', (23, 27))	('ZEB2', 'Gene', (31, 35))	('silencing', 'Var', (13, 22))
235237	30867843	In addition, at the molecular level, western blot results showed that the expression of representative markers of the cell cycle, antiapoptotic effects, EMT, stemness and angiogenesis induced by increased MSH6 was also reversed by silencing Slug or ZEB2 (Figure 6G).	('expression', 'MPA', (74, 84))	('ZEB2', 'Gene', (249, 253))	('MSH6', 'Gene', (205, 209))	('silencing', 'Var', (231, 240))	('Slug', 'Gene', '6591', (241, 245))	('angiogenesis', 'CPA', (171, 183))	('EMT', 'CPA', (153, 156))	('stemness', 'Disease', (158, 166))	('stemness', 'Disease', 'MESH:D020295', (158, 166))	('Slug', 'Gene', (241, 245))	('increased', 'PosReg', (195, 204))	('ZEB2', 'Gene', '9839', (249, 253))	('antiapoptotic effects', 'MPA', (130, 151))
235239	30867843	Silencing MSH6 decreased the expression of TGFB1 (Figure 7A and Figure S20), whereas MSH6 overexpression increased the expression of this factor (Figure 7B).	('MSH6', 'Gene', (10, 14))	('expression', 'MPA', (119, 129))	('TGFB1', 'Gene', (43, 48))	('S20', 'Gene', (71, 74))	('S20', 'Gene', '6224', (71, 74))	('expression', 'MPA', (29, 39))	('decreased', 'NegReg', (15, 24))	('Silencing', 'Var', (0, 9))
235257	30867843	Moreover, we demonstrated that the probability of alterations in MSH6, CXCR4 and TGFB1 was very low in GBM (Figure 8C).	('CXCR4', 'Gene', '7852', (71, 76))	('alterations', 'Var', (50, 61))	('CXCR4', 'Gene', (71, 76))	('MSH6', 'MPA', (65, 69))	('low', 'NegReg', (96, 99))	('TGFB1', 'Gene', (81, 86))
235260	30867843	Unfortunately, TMZ can induce mutations in MSH6 after long-term treatment, resulting in TMZ insensitivity.	('TMZ insensitivity', 'MPA', (88, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (15, 18))	('TMZ', 'Chemical', 'MESH:D000077204', (88, 91))	('MSH6', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))
235261	30867843	Based on these data, we proposed that TMZ could utilize or inactivate the oncogenic MSH6 to damage GBM.	('MSH6', 'Gene', (84, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('inactivate', 'Var', (59, 69))
235269	30867843	Considering that the MSH6-CXCR4-TGFB1 feedback loop was the upstream regulator of p-STAT3, we hypothesized that PTT (a new technology for hyperthermia) could restrain GBM by inhibiting the MSH6-CXCR4-TGFB1 feedback loop.	('hyperthermia', 'Disease', 'MESH:D005334', (138, 150))	('hyperthermia', 'Phenotype', 'HP:0001945', (138, 150))	('restrain', 'NegReg', (158, 166))	('hyperthermia', 'Disease', (138, 150))	('inhibiting', 'NegReg', (174, 184))	('CXCR4', 'Gene', '7852', (26, 31))	('CXCR4', 'Gene', (194, 199))	('STAT3', 'Gene', '6774', (84, 89))	('PTT', 'Chemical', '-', (112, 115))	('STAT3', 'Gene', (84, 89))	('CXCR4', 'Gene', (26, 31))	('PTT', 'Var', (112, 115))	('CXCR4', 'Gene', '7852', (194, 199))	('GBM', 'CPA', (167, 170))
235279	30867843	The peaks at 2940, 1713, 1584, and 1411 cm-1 are ascribed to the C-H stretching vibration mode, -COOH stretching, COO- asymmetric stretching and COO- symmetric stretching, respectively, all of which originate from the PAA ligand.	('1713', 'Var', (19, 23))	('PAA', 'Chemical', 'MESH:C006903', (218, 221))	('C-H stretching vibration mode', 'MPA', (65, 94))	('COOH', 'Chemical', 'MESH:D002255', (97, 101))	('1411', 'Var', (35, 39))
235288	30867843	reported that CuO NPs could shorten the T1 relaxation time, leading to bright contrast in T1WI.	('T1 relaxation time', 'MPA', (40, 58))	('leading to', 'Reg', (60, 70))	('bright contrast in T1WI', 'MPA', (71, 94))	('shorten', 'NegReg', (28, 35))	('CuO NPs', 'Var', (14, 21))	('CuO', 'Chemical', '-', (14, 17))
235310	30867843	As shown in Figure 10E, F, under NIR irradiation, the existence of Cu2(OH)PO4@PAA clearly promoted the temperature increment of the tumor region, and the temperature slightly exceeded 50  C starting from 120 s after NIR irradiation, which was suitable to irreversibly eliminate the GBM tissue.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PAA', 'Chemical', 'MESH:C006903', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('temperature increment', 'MPA', (103, 124))	('tumor', 'Disease', (132, 137))	('PO4@PAA', 'Var', (74, 81))	('promoted', 'PosReg', (90, 98))	('Cu2', 'Gene', (67, 70))	('Cu2', 'Gene', '620105', (67, 70))
235318	30867843	Moreover, the variation tendencies of angiogenesis and microangiogenesis detected by CDFI and CPA, respectively, were in accordance with that of the tumor size (Figure 10I and Figure S28B).	('S28B', 'Var', (183, 187))	('S28B', 'SUBSTITUTION', 'None', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('CDFI', 'Chemical', '-', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CDFI', 'Gene', (85, 89))	('microangiogenesis', 'CPA', (55, 72))	('CPA', 'Chemical', '-', (94, 97))	('tumor', 'Disease', (149, 154))	('CPA', 'Gene', (94, 97))	('angiogenesis', 'CPA', (38, 50))
235348	30867843	Human GBM cell lines (U87MG, U251 and T98G), HUVECs, LO2 cells, and HK2 cells were originally supplied by ATCC (Manassas, VA, USA).	('Human', 'Species', '9606', (0, 5))	('U87MG', 'CellLine', 'CVCL:0022', (22, 27))	('U251', 'Var', (29, 33))	('U87MG', 'Var', (22, 27))	('HK2', 'CellLine', 'CVCL:0302', (68, 71))	('LO2', 'CellLine', 'CVCL:6926', (53, 56))	('T98G', 'Var', (38, 42))
235352	30867843	Silencing of MSH6, CXCR4, Slug and ZEB2 was achieved by transfecting specific siRNAs (GenePharma, Shanghai, China), which required the use of the Lipofectamine 2000 reagent (Invitrogen, Carlsbad, California, USA).	('ZEB2', 'Gene', (35, 39))	('Lipofectamine 2000 reagent', 'Chemical', '-', (146, 172))	('CXCR4', 'Gene', (19, 24))	('transfecting', 'Var', (56, 68))	('Slug', 'Gene', (26, 30))	('ZEB2', 'Gene', '9839', (35, 39))	('MSH6', 'Gene', (13, 17))	('CXCR4', 'Gene', '7852', (19, 24))	('Slug', 'Gene', '6591', (26, 30))
235400	26859681	To model this sequential genetic cooperativity, we coupled somatic lentivirus-mediated p53 knockdown in the adult right sciatic nerve with embryonic Schwann cell precursor Nf1 gene inactivation in two different Nf1 conditional knockout mouse strains.	('Nf1', 'Gene', (172, 175))	('inactivation', 'Var', (181, 193))	('p53', 'Gene', (87, 90))	('Nf1', 'Gene', '18015', (211, 214))	('p53', 'Gene', '22059', (87, 90))	('knockdown', 'Var', (91, 100))	('Nf1', 'Gene', '18015', (172, 175))	('Nf1', 'Gene', (211, 214))	('mouse', 'Species', '10090', (236, 241))
235413	26859681	As such, MPNST formation requires additional cooperating genetic events, the most frequent of which is mutational inactivation of the TP53 tumor suppressor gene, occurring in approximately 75% of cases.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mutational inactivation', 'Var', (103, 126))	('MPNST', 'Disease', (9, 14))
235414	26859681	In this regard, genetically-engineered mouse (GEM) lines with conditional Nf1 gene inactivation in Schwann cell precursors do not develop MPNSTs unless coupled with concomitant Trp53 loss, epidermal growth factor receptor (Egfr) amplification, Pten loss, or Ink4a deletion.	('Egfr', 'Gene', '13649', (223, 227))	('loss', 'NegReg', (183, 187))	('Ink4a', 'Gene', '12578', (258, 263))	('Nf1', 'Gene', '18015', (74, 77))	('Trp53', 'Gene', '22059', (177, 182))	('epidermal growth factor receptor', 'Gene', (189, 221))	('inactivation', 'Var', (83, 95))	('epidermal growth factor receptor', 'Gene', '13649', (189, 221))	('loss', 'NegReg', (249, 253))	('mouse', 'Species', '10090', (39, 44))	('Pten', 'Gene', (244, 248))	('Ink4a', 'Gene', (258, 263))	('Trp53', 'Gene', (177, 182))	('deletion', 'Var', (264, 272))	('Pten', 'Gene', '19211', (244, 248))	('Egfr', 'Gene', (223, 227))	('Nf1', 'Gene', (74, 77))
235415	26859681	In each of these GEM strains, the cooperating genetic mutation was introduced simultaneously with Schwann cell precursor Nf1 gene inactivation throughout the body.	('mutation', 'Var', (54, 62))	('Nf1', 'Gene', '18015', (121, 124))	('Nf1', 'Gene', (121, 124))
235418	26859681	The coupling of somatic retroviral knockdown and embryonic Nf1 gene inactivation establishes an experimentally-manipulable platform to evaluate other cooperating genetic changes in MPNST pathogenesis as well as preclinical mouse strains in which clinical symptomatology can be used to monitor tumor progression.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('mouse', 'Species', '10090', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('Nf1', 'Gene', (59, 62))	('tumor', 'Disease', (293, 298))	('Nf1', 'Gene', '18015', (59, 62))	('inactivation', 'Var', (68, 80))
235420	26859681	Analysis of these pathological specimens demonstrated an increasing proportion of cells with a somatic NF1 gene mutation (second hit) as the tumor progressed from a benign plexiform neurofibroma to a MPNST.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('neurofibroma', 'Disease', 'MESH:D009455', (182, 194))	('plexiform neurofibroma', 'Phenotype', 'HP:0009732', (172, 194))	('mutation', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('neurofibroma', 'Phenotype', 'HP:0001067', (182, 194))	('tumor', 'Disease', (141, 146))	('NF1', 'Gene', (103, 106))	('neurofibroma', 'Disease', (182, 194))
235421	26859681	These observations in a single patient support a model in which NF1 gene inactivation precedes TP53 mutation in the pathogenesis of NF1-associated MPNST.	('inactivation', 'NegReg', (73, 85))	('NF1-associated MPNST', 'Disease', (132, 152))	('mutation', 'Var', (100, 108))	('patient', 'Species', '9606', (31, 38))	('MPNST', 'Disease', (147, 152))	('NF1 gene', 'Gene', (64, 72))	('TP53', 'Gene', (95, 99))
235424	26859681	We first sought to generate mice with a germline null Nf1 gene mutation and a conditional Nf1 allele; however, the majority of Periostin-Cre; Nf1flox/null mice did not survive to weaning age (~3-4 weeks), as previously reported by others.	('Nf1', 'Gene', '18015', (54, 57))	('Nf1', 'Gene', '18015', (142, 145))	('Periostin', 'Gene', '50706', (127, 136))	('mice', 'Species', '10090', (28, 32))	('Nf1', 'Gene', (142, 145))	('mutation', 'Var', (63, 71))	('Nf1', 'Gene', (90, 93))	('mice', 'Species', '10090', (155, 159))	('Periostin', 'Gene', (127, 136))	('Nf1', 'Gene', (54, 57))	('Nf1', 'Gene', '18015', (90, 93))
235426	26859681	Importantly, neither strain develops MPNSTs without the introduction of additional genetic alterations (e.g., somatic p53 knockdown).	('p53', 'Gene', (118, 121))	('p53', 'Gene', '22059', (118, 121))	('knockdown', 'Var', (122, 131))
235435	26859681	Next, to introduce p53 knockdown specifically in cells within the sciatic nerve, we leveraged a lentiviral approach in which Nf1 and Trp53 knockdown occurs following p53 shRNA virus injection (Figure 2a).	('Nf1', 'Gene', '18015', (125, 128))	('Trp53', 'Gene', '22059', (133, 138))	('knockdown', 'Var', (139, 148))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '22059', (166, 169))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '22059', (135, 138))	('Nf1', 'Gene', (125, 128))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '22059', (19, 22))	('Trp53', 'Gene', (133, 138))
235454	26859681	While we cannot exclude the acquisition of additional genetic changes that effectively abrogate p53 signaling, previous reports in both mouse models and human pathological MPNST specimens have likewise support the concept that TP53 haploinsufficiency may be sufficient for MPNST formation.	('mouse', 'Species', '10090', (136, 141))	('haploinsufficiency', 'Disease', 'MESH:D058495', (232, 250))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '22059', (96, 99))	('MPNST', 'Disease', (273, 278))	('haploinsufficiency', 'Disease', (232, 250))	('TP53', 'Gene', (227, 231))	('changes', 'Var', (62, 69))	('human', 'Species', '9606', (153, 158))	('abrogate', 'NegReg', (87, 95))
235458	26859681	In this respect, similar differences have also been reported for murine Nf1 brain tumors: Nf1+/- stromal cells are required for low-grade murine optic glioma formation and continued growth in vivo, but high-grade glioblastoma development can occur following Nf1 and p53 inactivation in nestin+ neural stem cells alone in vivo.	('optic glioma', 'Disease', (145, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioblastoma', 'Disease', (213, 225))	('Nf1', 'Gene', (72, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (213, 225))	('optic glioma', 'Disease', 'MESH:D020339', (145, 157))	('brain tumors', 'Disease', (76, 88))	('p53', 'Gene', '22059', (266, 269))	('optic glioma', 'Phenotype', 'HP:0009734', (145, 157))	('Nf1', 'Gene', '18015', (72, 75))	('Nf1', 'Gene', (258, 261))	('Nf1', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inactivation', 'Var', (270, 282))	('murine', 'Species', '10090', (138, 144))	('brain tumors', 'Phenotype', 'HP:0030692', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('glioblastoma', 'Disease', 'MESH:D005909', (213, 225))	('p53', 'Gene', (266, 269))	('Nf1', 'Gene', '18015', (258, 261))	('brain tumors', 'Disease', 'MESH:D001932', (76, 88))	('murine', 'Species', '10090', (65, 71))	('Nf1', 'Gene', '18015', (90, 93))
235459	26859681	Since the early lethality (pre-weaning) observed in Nf1+/- mice with periostin-Cre-mediated Nf1 gene inactivation precluded an examination of the contribution of the Nf1+/- tumor microenvironment to MPNST biology, we sought to reduce the latency of MPNST development by coupling somatic retrovirus-mediated p53 knockdown and embryonic Schwann cell precursor Nf1 gene inactivation in the setting of an Nf1+/- microenvironment.	('Nf1', 'Gene', '18015', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('periostin', 'Gene', '50706', (69, 78))	('Nf1', 'Gene', (166, 169))	('Nf1', 'Gene', '18015', (358, 361))	('mice', 'Species', '10090', (59, 63))	('p53', 'Gene', '22059', (307, 310))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Nf1', 'Gene', '18015', (166, 169))	('Nf1', 'Gene', (92, 95))	('inactivation', 'Var', (367, 379))	('Nf1', 'Gene', (401, 404))	('Nf1', 'Gene', (52, 55))	('p53', 'Gene', (307, 310))	('Nf1', 'Gene', '18015', (401, 404))	('periostin', 'Gene', (69, 78))	('Nf1', 'Gene', (358, 361))	('tumor', 'Disease', (173, 178))	('Nf1', 'Gene', '18015', (92, 95))
235476	26859681	Moreover, the fact that bi-allelic inactivation of the NF1 gene is observed in most NF1-associated and sporadic MNPSTs supports a critical role for this tumor suppressor gene in MPNST pathogenesis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('bi-allelic inactivation', 'Var', (24, 47))	('NF1-associated', 'Disease', (84, 98))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('NF1', 'Gene', (55, 58))
235478	26859681	This lack of sufficiency is nicely illustrated in Nf1 GEM strains, where mice with conditional Nf1 gene inactivation in Schwann cell precursors alone also do not develop MPNSTs, including the GFAP-Cre; Nf1flox/null and Periostin-Cre; Nf1flox/flox mouse strains used in the current study.	('Periostin', 'Gene', (219, 228))	('mouse', 'Species', '10090', (247, 252))	('Nf1', 'Gene', (234, 237))	('Nf1', 'Gene', '18015', (50, 53))	('gene inactivation', 'Var', (99, 116))	('Nf1', 'Gene', (202, 205))	('Nf1', 'Gene', '18015', (95, 98))	('mice', 'Species', '10090', (73, 77))	('Periostin', 'Gene', '50706', (219, 228))	('sufficiency', 'Disease', 'None', (13, 24))	('Nf1', 'Gene', '18015', (202, 205))	('Nf1', 'Gene', '18015', (234, 237))	('Nf1', 'Gene', (50, 53))	('Nf1', 'Gene', (95, 98))	('sufficiency', 'Disease', (13, 24))
235481	26859681	Using a combination of conditional knockout mice and lentivirus-mediated somatic p53 inactivation, we describe an efficient platform for the generation of MPNSTs.	('mice', 'Species', '10090', (44, 48))	('p53', 'Gene', (81, 84))	('inactivation', 'Var', (85, 97))	('p53', 'Gene', '22059', (81, 84))
235484	26859681	Moreover, since somatic p53 knockdown is directed to the sciatic nerve, these mice develop a neurologic deficit (limp), similar to some patients with MPNSTs.	('p53', 'Gene', (24, 27))	('p53', 'Gene', '22059', (24, 27))	('neurologic deficit', 'Disease', 'MESH:D009461', (93, 111))	('neurologic deficit', 'Phenotype', 'HP:0000707', (93, 111))	('neurologic deficit', 'Disease', (93, 111))	('develop', 'Reg', (83, 90))	('patients', 'Species', '9606', (136, 144))	('limp', 'Phenotype', 'HP:0031955', (113, 117))	('knockdown', 'Var', (28, 37))	('mice', 'Species', '10090', (78, 82))
235485	26859681	First, we demonstrate that somatic reduction, but not absence, of Trp53 expression following Nf1 gene inactivation is sufficient for MPNST formation.	('inactivation', 'Var', (102, 114))	('Trp53', 'Gene', (66, 71))	('Nf1', 'Gene', (93, 96))	('expression', 'MPA', (72, 82))	('Nf1', 'Gene', '18015', (93, 96))	('Trp53', 'Gene', '22059', (66, 71))	('MPNST formation', 'Disease', (133, 148))	('reduction', 'NegReg', (35, 44))
235486	26859681	Second, we demonstrate that MPNST formation can occur in the absence of a microenvironment composed of cells heterozygous for a germline Nf1 gene mutation.	('Nf1', 'Gene', '18015', (137, 140))	('Nf1', 'Gene', (137, 140))	('mutation', 'Var', (146, 154))	('MPNST formation', 'CPA', (28, 43))
235587	26113841	In conclusion, the data presented here show that patients with DLGG in eloquent areas invading subcortical pathways may be at risk for neurological impairment already at the time of radiological diagnosis.	('DLGG', 'Var', (63, 67))	('neurological impairment', 'Disease', 'MESH:D009422', (135, 158))	('neurological impairment', 'Phenotype', 'HP:0000707', (135, 158))	('patients', 'Species', '9606', (49, 57))	('neurological impairment', 'Disease', (135, 158))
235597	23691191	In a later stage, up-regulation of PARP-TANKs and telomerase activation may occur together with an ADP-ribosylation of TRF1, causing a reduced ability to bind telomeric DNA, telomeres elongation and tumor malignant progression.	('up-regulation', 'PosReg', (18, 31))	('tumor', 'Disease', (199, 204))	('PARP', 'Gene', '142', (35, 39))	('TRF1', 'Gene', '7013', (119, 123))	('ability', 'MPA', (143, 150))	('telomerase', 'Enzyme', (50, 60))	('telomeric DNA', 'Protein', (159, 172))	('ADP-ribosylation', 'Var', (99, 115))	('telomeres elongation', 'CPA', (174, 194))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('reduced', 'NegReg', (135, 142))	('ADP', 'Chemical', 'MESH:D000244', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('bind', 'Interaction', (154, 158))	('TRF1', 'Gene', (119, 123))	('PARP', 'Gene', (35, 39))
235605	23691191	The ADP-ribosylation of TRF1 reduces its ability to bind telomeric DNA, allowing telomerase to elongate telomeres and extending the cellular life span.	('bind', 'Interaction', (52, 56))	('TRF1', 'Gene', (24, 28))	('cellular life span', 'CPA', (132, 150))	('extending', 'PosReg', (118, 127))	('ability', 'MPA', (41, 48))	('reduces', 'NegReg', (29, 36))	('TRF1', 'Gene', '7013', (24, 28))	('ADP-ribosylation', 'Var', (4, 20))	('elongate telomeres', 'CPA', (95, 113))	('ADP', 'Chemical', 'MESH:D000244', (4, 7))
235606	23691191	The alteration of telomere length homeostasis affects telomere structure and leads to genomic instability by generating chromosome end-to end fusion and chromosomal abnormalities.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (153, 178))	('genomic instability', 'CPA', (86, 105))	('affects', 'Reg', (46, 53))	('telomere structure', 'MPA', (54, 72))	('alteration', 'Var', (4, 14))	('generating', 'Reg', (109, 119))	('chromosome end-to end fusion', 'CPA', (120, 148))	('chromosomal abnormalities', 'Disease', (153, 178))	('leads to', 'Reg', (77, 85))
235659	23691191	In the absence of genome checkpoint functions, telomere dysfunction caused by telomere shortening accelerates genomic instability, facilitating cancer initiation and progression.	('telomere shortening', 'Var', (78, 97))	('facilitating', 'PosReg', (131, 143))	('accelerates', 'PosReg', (98, 109))	('telomere dysfunction', 'Disease', (47, 67))	('telomere dysfunction', 'Disease', 'MESH:C536801', (47, 67))	('telomere shortening', 'Phenotype', 'HP:0031413', (78, 97))	('cancer initiation', 'Disease', 'MESH:D009369', (144, 161))	('genomic instability', 'MPA', (110, 129))	('cancer initiation', 'Disease', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
235686	23691191	Later, telomere dysfunction caused by telomere shortening accelerates genomic instability, facilitating cancer initiation and progression.	('cancer initiation', 'Disease', 'MESH:D009369', (104, 121))	('telomere shortening', 'Var', (38, 57))	('cancer initiation', 'Disease', (104, 121))	('genomic instability', 'CPA', (70, 89))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('telomere shortening', 'Phenotype', 'HP:0031413', (38, 57))	('accelerates', 'PosReg', (58, 69))	('telomere dysfunction', 'Disease', (7, 27))	('telomere dysfunction', 'Disease', 'MESH:C536801', (7, 27))
235707	24234804	We hypothesize that high grade gliomas will result in greater deterioration of the DMN network, potentially related to their more invasive nature.	('high grade', 'Var', (20, 30))	('DMN network', 'Pathway', (83, 94))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('deterioration', 'NegReg', (62, 75))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
235749	24234804	Although speculative, these results suggest that large T2 lesions may not necessarily disrupt the DMN if they do not have histopathological features of malignancy, but rather may displace neural connections between functional regions.	('lesions', 'Var', (58, 65))	('displace', 'NegReg', (179, 187))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('DMN', 'CPA', (98, 101))	('malignancy', 'Disease', (152, 162))	('neural connections between functional regions', 'CPA', (188, 233))
235767	30987862	Immune checkpoint molecule herpes virus entry mediator is overexpressed and associated with poor prognosis in human glioblastoma Dysregulation of immune checkpoint molecules leads to immune evasion in human tumours but has become a viable target for tumour therapy.	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('human', 'Species', '9606', (201, 206))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('leads to', 'Reg', (174, 182))	('tumour', 'Disease', 'MESH:D009369', (250, 256))	('tumour', 'Disease', (250, 256))	('glioblastoma', 'Disease', (116, 128))	('tumours', 'Disease', (207, 214))	('Dysregulation of immune checkpoint', 'Phenotype', 'HP:0002958', (129, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('herpes virus entry mediator', 'Gene', (27, 54))	('immune evasion', 'MPA', (183, 197))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('human', 'Species', '9606', (110, 115))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('Dysregulation', 'Var', (129, 142))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('tumour', 'Disease', (207, 213))	('herpes virus entry mediator', 'Gene', '8764', (27, 54))
235772	30987862	HVEMhigh tumours tended to be associated with amplification of EGFR and loss of PTEN, while HVEMlow tumours harbored mutations in IDH1 (93%).	('EGFR', 'Gene', '1956', (63, 67))	('mutations', 'Var', (117, 126))	('HVEMhigh tumours', 'Disease', (0, 16))	('loss', 'NegReg', (72, 76))	('PTEN', 'Gene', (80, 84))	('HVEMlow tumours', 'Disease', 'MESH:D009369', (92, 107))	('amplification', 'Var', (46, 59))	('PTEN', 'Gene', '5728', (80, 84))	('EGFR', 'Gene', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('IDH1', 'Gene', (130, 134))	('HVEMhigh tumours', 'Disease', 'MESH:D009369', (0, 16))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('IDH1', 'Gene', '3417', (130, 134))	('HVEMlow tumours', 'Disease', (92, 107))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))
235778	30987862	The dysregulation of immune checkpoint molecules within tumors has been hotly investigated in recent years as a potential therapeutic target in human cancer.	('human', 'Species', '9606', (144, 149))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('dysregulation of immune checkpoint', 'Phenotype', 'HP:0002958', (4, 38))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
235806	30987862	High HVEM expression has also been correlated with poorer recurrence-free survival (RFS) and overall survival (OS) in hepatocellular carcinoma.	('HVEM', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('overall survival', 'CPA', (93, 109))	('HVEM', 'Gene', '8764', (5, 9))	('poorer', 'NegReg', (51, 57))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))
235860	30987862	Amplification of chr7 and deletion of chr10, which are both common genomic events in GBM, frequently occurred in the HVEMhigh cluster (Fig.	('chr10', 'Gene', (38, 43))	('chr7', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('HVEM', 'Gene', '8764', (117, 121))	('occurred', 'Reg', (101, 109))	('deletion', 'Var', (26, 34))	('HVEM', 'Gene', (117, 121))
235861	30987862	Deletion of 1p and 19q, a genomic hallmark of oligodendroglioma, however, more frequently appeared associated with the HVEMlow cluster (Fig.	('HVEM', 'Gene', (119, 123))	('oligodendroglioma', 'Disease', (46, 63))	('HVEM', 'Gene', '8764', (119, 123))	('oligodendroglioma', 'Disease', 'MESH:D009837', (46, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('associated', 'Reg', (99, 109))	('Deletion', 'Var', (0, 8))
235864	30987862	Analysis of somatic mutation profiles based on HVEM expression levels revealed a high frequency of mutations in EGFR (31%), PTEN (28%), TTN (25%) and NF1 (15%) in the HVEMhigh group (n = 163), while IDH1 (93%), ATRX (33%), CIC (28%) were more frequently mutated in the HVEMlow group (n = 162; Fig.	('PTEN', 'Gene', (124, 128))	('NF1', 'Gene', (150, 153))	('HVEM', 'Gene', '8764', (269, 273))	('HVEM', 'Gene', (47, 51))	('TTN', 'Gene', '7273', (136, 139))	('ATRX', 'Gene', (211, 215))	('IDH1', 'Gene', (199, 203))	('HVEM', 'Gene', (269, 273))	('ATRX', 'Gene', '546', (211, 215))	('PTEN', 'Gene', '5728', (124, 128))	('TTN', 'Gene', (136, 139))	('EGFR', 'Gene', (112, 116))	('IDH1', 'Gene', '3417', (199, 203))	('HVEM', 'Gene', '8764', (167, 171))	('HVEM', 'Gene', (167, 171))	('NF1', 'Gene', '4763', (150, 153))	('mutations', 'Var', (99, 108))	('HVEM', 'Gene', '8764', (47, 51))	('EGFR', 'Gene', '1956', (112, 116))
235866	30987862	HVEMlow expressing tumours, for example, harbored mutations associated with 2-oxocarboxylic acid metabolism, the TCA cycle, and glutathione metabolism.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('TCA', 'Chemical', 'MESH:D014238', (113, 116))	('glutathione metabolism', 'MPA', (128, 150))	('mutations', 'Var', (50, 59))	('harbored', 'Reg', (41, 49))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('HVEM', 'Gene', (0, 4))	('glutathione', 'Chemical', 'MESH:D005978', (128, 139))	('2-oxocarboxylic acid', 'Chemical', '-', (76, 96))	('HVEM', 'Gene', '8764', (0, 4))	('2-oxocarboxylic acid metabolism', 'MPA', (76, 107))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('associated', 'Reg', (60, 70))	('TCA', 'Enzyme', (113, 116))
235870	30987862	Moreover, in an independent dataset, glioma samples with 1p deletion expressed significantly lower levels of HVEM than 1p intact tumours (P < .01; Fig.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('HVEM', 'Gene', (109, 113))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('glioma', 'Disease', (37, 43))	('HVEM', 'Gene', '8764', (109, 113))	('tumours', 'Disease', (129, 136))	('lower', 'NegReg', (93, 98))	('1p deletion', 'Var', (57, 68))	('levels', 'MPA', (99, 105))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
235955	29797098	The most commonly used amino acid tracers in brain tumor imaging are 18F-fluoro-ethyl-l-tyrosine (FET) and 11C-methyl-l-methionine (MET).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('brain tumor', 'Phenotype', 'HP:0030692', (45, 56))	('11C-methyl-l-methionine', 'Var', (107, 130))	('brain tumor', 'Disease', 'MESH:D001932', (45, 56))	('brain tumor', 'Disease', (45, 56))	('11C-methyl-l-methionine', 'Chemical', '-', (107, 130))	('18F-fluoro-ethyl-l-tyrosine', 'Chemical', 'MESH:C545932', (69, 96))
235959	29797098	As shown in Table 1, PET studies with different amino acid tracers, mostly 18F-FET (n = 9) and 11C-MET (n = 6) and using static and dynamic uptake methods, were included.	('C-MET', 'Gene', '4233', (97, 102))	('18F-FET', 'Var', (75, 82))	('C-MET', 'Gene', (97, 102))
235976	29797098	Increased FET uptake was reported in 50 versus 100% of IDH mutated 1p19q codeleted LGG (i.e., oligodendrogliomas), 32 versus 89% in IDH mutated non-codeleted LGG (i.e., astrocytomas), and 66 versus 83% in IDH wild-type LGG.	('oligodendrogliomas', 'Disease', (94, 112))	('astrocytomas', 'Disease', (169, 181))	('IDH', 'Gene', (55, 58))	('IDH', 'Gene', (132, 135))	('FET uptake', 'MPA', (10, 20))	('IDH', 'Gene', (205, 208))	('1p19q codeleted', 'Var', (67, 82))	('IDH', 'Gene', '3417', (55, 58))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('Increased', 'PosReg', (0, 9))	('IDH', 'Gene', '3417', (132, 135))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (94, 112))	('IDH', 'Gene', '3417', (205, 208))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('astrocytomas', 'Disease', 'MESH:D001254', (169, 181))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
235996	29797098	When astrocytomas and oligodendrogliomas were examined separately, low MET uptake was prognostically favorable only in oligodendrogliomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (5, 16))	('low', 'Var', (67, 70))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (22, 40))	('astrocytomas', 'Disease', (5, 17))	('MET uptake', 'MPA', (71, 81))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (119, 137))	('oligodendrogliomas', 'Disease', (22, 40))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('oligodendrogliomas', 'Disease', (119, 137))	('astrocytomas', 'Disease', 'MESH:D001254', (5, 17))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
235997	29797098	evaluated dynamic 18F-FET uptake in gliomas and demonstrated that longer time-to-peak minimum (TTPmin) correlated with longer overall survival in the subgroup of tumors with IDH 1/2 mutation/1p19q-non-codel.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutation/1p19q-non-codel', 'Var', (182, 206))	('IDH 1/2', 'Gene', (174, 181))	('longer', 'PosReg', (119, 125))	('gliomas', 'Disease', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('overall survival', 'MPA', (126, 142))	('IDH 1/2', 'Gene', '3417;3418', (174, 181))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
236000	29797098	Of relevance, the IDH mutation and 1p19q codeletion do not only matter to classification but these markers also offer prognostic information.	('1p19q codeletion', 'Var', (35, 51))	('IDH', 'Gene', '3417', (18, 21))	('IDH', 'Gene', (18, 21))
236011	32859279	These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656).	('N546', 'Chemical', '-', (276, 280))	('TACC1', 'Gene', (177, 182))	('p.K656', 'Var', (284, 290))	('activating', 'PosReg', (6, 16))	('FGFR1', 'Gene', (17, 22))	('TACC1', 'Gene', '6867', (177, 182))	('missense mutations', 'Var', (210, 228))	('alterations', 'Var', (23, 34))	('FGFR1', 'Gene', '2260', (17, 22))	('tandem duplication', 'Var', (56, 74))
236013	32859279	Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations.	('FGFR1', 'Gene', (109, 114))	('FGFR1', 'Gene', '2260', (109, 114))	('alterations', 'Var', (115, 126))
236014	32859279	We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation.	('FGFR1', 'Gene', '2260', (145, 150))	('mutation', 'Var', (236, 244))	('epigenetic signature', 'MPA', (43, 63))	('PTPN11', 'Gene', (277, 283))	('PIK3CA', 'Gene', (219, 225))	('NF1', 'Gene', (270, 273))	('NF1', 'Gene', '4763', (270, 273))	('PIK3CA', 'Gene', '5290', (219, 225))	('RGNT', 'Phenotype', 'HP:0025171', (19, 23))	('FGFR1', 'Gene', (93, 98))	('PIK3R1', 'Gene', '5295', (229, 235))	('FGFR1', 'Gene', (145, 150))	('PIK3R1', 'Gene', (229, 235))	('PTPN11', 'Gene', '5781', (277, 283))	('FGFR1', 'Gene', '2260', (93, 98))	('missense mutations', 'Var', (173, 191))
236016	32859279	Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT.	('missense mutations', 'Var', (116, 134))	('kinase domain tandem duplication', 'Var', (72, 104))	('PIK3R1', 'Gene', '5295', (230, 236))	('pilocytic astrocytoma', 'Disease', (22, 43))	('DNT', 'Disease', (14, 17))	('PIK3R1', 'Gene', (230, 236))	('PTPN11', 'Gene', (174, 180))	('DNT', 'Chemical', '-', (14, 17))	('NF1', 'Gene', (167, 170))	('PIK3CA', 'Gene', (220, 226))	('mutation', 'Var', (181, 189))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (22, 43))	('NF1', 'Gene', '4763', (167, 170))	('PIK3CA', 'Gene', '5290', (220, 226))	('astrocytoma', 'Phenotype', 'HP:0009592', (32, 43))	('RGNT', 'Phenotype', 'HP:0025171', (265, 269))	('PTPN11', 'Gene', '5781', (174, 180))
236017	32859279	The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion.	('astrocytoma', 'Phenotype', 'HP:0009592', (267, 278))	('pilocytic astrocytomas', 'Disease', (127, 149))	('mutation', 'Var', (290, 298))	('BRAF', 'Gene', '673', (285, 289))	('BRAF', 'Gene', (285, 289))	('FGFR1', 'Gene', '2260', (155, 160))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (127, 149))	('Rosenthal fibers', 'Phenotype', 'HP:0100320', (222, 238))	('FGFR1', 'Gene', '2260', (34, 39))	('alterations', 'Var', (161, 172))	('biphasic pattern', 'MPA', (182, 198))	('Rosenthal fibers', 'CPA', (222, 238))	('pilocytic astrocytomas', 'Disease', (257, 279))	('alterations', 'Var', (40, 51))	('FGFR1', 'Gene', (155, 160))	('oligodendroglial morphology', 'Phenotype', 'HP:0100709', (82, 109))	('piloid processes', 'CPA', (200, 216))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (257, 279))	('FGFR1', 'Gene', (34, 39))	('lack', 'NegReg', (173, 177))
236018	32859279	Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.	('alterations', 'Var', (107, 118))	('LGNET', 'Disease', (90, 95))	('improves', 'PosReg', (24, 32))	('FGFR1', 'Gene', (101, 106))	('FGFR1', 'Gene', '2260', (101, 106))
236021	32859279	For example, IDH1/2 mutation is present in both diffuse astrocytic neoplasms and oligodendroglial neoplasms in the cerebral hemispheres of young adults.	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('neoplasms', 'Phenotype', 'HP:0002664', (67, 76))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('astrocytic neoplasms and oligodendroglial neoplasms', 'Disease', 'MESH:D009369', (56, 107))	('mutation', 'Var', (20, 28))	('IDH1/2', 'Gene', (13, 19))	('neoplasm', 'Phenotype', 'HP:0002664', (67, 75))	('astrocytic neoplasms', 'Phenotype', 'HP:0009592', (56, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (98, 106))
236022	32859279	As a second example, BRAF mutations or fusions are present in a diverse spectrum of neuroepithelial tumors, including ganglioglioma, pilocytic astrocytoma, and pleomorphic xanthoastrocytoma (PXA).	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (84, 105))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('pleomorphic xanthoastrocytoma', 'Disease', (160, 189))	('fusions', 'Var', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('mutations', 'Var', (26, 35))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (133, 154))	('neuroepithelial tumors', 'Disease', (84, 106))	('pilocytic astrocytoma', 'Disease', (133, 154))	('BRAF', 'Gene', '673', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('BRAF', 'Gene', (21, 25))	('ganglioglioma', 'Disease', 'MESH:D018303', (118, 131))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (84, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (143, 154))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (160, 189))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (84, 106))	('present', 'Reg', (51, 58))	('ganglioglioma', 'Disease', (118, 131))
236024	32859279	The most accurate diagnostic classification incorporates assessment of any accompanying alterations, such as those commonly co-occurring with IDH1/2 mutation (e.g.	('IDH1/2', 'Gene', (142, 148))	('IDH1/2', 'Gene', '3417;3418', (142, 148))	('mutation', 'Var', (149, 157))
236025	32859279	TP53 and ATRX mutation in astrocytomas vs. CIC, FUBP1, and TERT promoter mutations in oligodendrogliomas) or with BRAF mutation/fusion (e.g.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('mutation/fusion', 'Var', (119, 134))	('CIC', 'Gene', '23152', (43, 46))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('astrocytomas', 'Disease', (26, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (26, 37))	('TP53', 'Gene', '7157', (0, 4))	('TERT', 'Gene', (59, 63))	('FUBP1', 'Gene', (48, 53))	('TERT', 'Gene', '7015', (59, 63))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (86, 104))	('astrocytomas', 'Disease', 'MESH:D001254', (26, 38))	('CIC', 'Gene', (43, 46))	('ATRX', 'Gene', (9, 13))	('oligodendrogliomas', 'Disease', (86, 104))	('ATRX', 'Gene', '546', (9, 13))	('TP53', 'Gene', (0, 4))	('FUBP1', 'Gene', '8880', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
236026	32859279	CDKN2A homozygous deletion in PXA versus intact CDKN2A alleles in ganglioglioma and pilocytic astrocytoma).	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('ganglioglioma and pilocytic astrocytoma', 'Disease', 'MESH:D001254', (66, 105))	('CDKN2A', 'Gene', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (48, 54))	('deletion', 'Var', (18, 26))	('CDKN2A', 'Gene', '1029', (0, 6))
236027	32859279	The FGFR1 gene on chromosome 8p11.23 has emerged as a recurrently altered oncogene in a diverse spectrum of primary glial and glioneuronal tumor entities including DNT, RGNT, EVN, pilocytic astrocytoma, high-grade astrocytoma with piloid features, and H3 K27M-mutant diffuse midline glioma.	('K27M', 'Mutation', 'p.K27M', (255, 259))	('astrocytoma', 'Disease', 'MESH:D001254', (190, 201))	('FGFR1', 'Gene', '2260', (4, 9))	('astrocytoma', 'Disease', (190, 201))	('astrocytoma', 'Disease', 'MESH:D001254', (214, 225))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('astrocytoma', 'Disease', (214, 225))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (180, 201))	('pilocytic astrocytoma', 'Disease', (180, 201))	('EVN', 'Chemical', '-', (175, 178))	('midline glioma', 'Disease', (275, 289))	('FGFR1', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('astrocytoma', 'Phenotype', 'HP:0009592', (190, 201))	('DNT', 'Chemical', '-', (164, 167))	('glioneuronal tumor', 'Disease', 'MESH:D009369', (126, 144))	('astrocytoma', 'Phenotype', 'HP:0009592', (214, 225))	('RGNT', 'Disease', (169, 173))	('glioneuronal tumor', 'Disease', (126, 144))	('H3 K27M-mutant', 'Var', (252, 266))	('EVN', 'Disease', (175, 178))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (126, 144))	('midline glioma', 'Disease', 'MESH:D005910', (275, 289))	('DNT', 'Disease', (164, 167))	('RGNT', 'Phenotype', 'HP:0025171', (169, 173))	('neuronal tumor', 'Phenotype', 'HP:0025170', (130, 144))
236029	32859279	However, fusions involving other FGFR genes are recurrently found in PLNTY (mostly involving FGFR2) and IDH-wildtype glioblastoma in adults (mostly involving FGFR3, typically with TACC3 as the fusion partner).	('FGFR2', 'Gene', (93, 98))	('IDH-wildtype glioblastoma', 'Disease', (104, 129))	('fusions', 'Var', (9, 16))	('FGFR2', 'Gene', '2263', (93, 98))	('FGFR genes', 'Gene', (33, 43))	('TACC3', 'Gene', '10460', (180, 185))	('FGFR3', 'Gene', (158, 163))	('TACC3', 'Gene', (180, 185))	('found', 'Reg', (60, 65))	('IDH-wildtype glioblastoma', 'Disease', 'MESH:D005909', (104, 129))	('FGFR3', 'Gene', '2261', (158, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
236030	32859279	Therefore, while the identification of an FGFR1 alteration in a CNS tumor of uncertain subtype may help to narrow the differential diagnosis and exclude certain tumor entities, this single genetic finding in and of itself does not enable precise classification.	('tumor', 'Disease', (68, 73))	('CNS tumor', 'Phenotype', 'HP:0100006', (64, 73))	('FGFR1', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('alteration', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('narrow', 'NegReg', (107, 113))	('FGFR1', 'Gene', '2260', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('exclude', 'NegReg', (145, 152))	('tumor', 'Disease', (161, 166))
236031	32859279	Our study sought to refine classification of low-grade neuroepithelial tumors (LGNET) harboring FGFR1 alterations by investigating if the specific type of FGFR1 alteration, accompanying genetic alterations, tumor location, and epigenetic signature can help to more accurately stratify these tumors.	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('FGFR1', 'Gene', (96, 101))	('neuroepithelial tumors', 'Disease', (55, 77))	('tumors', 'Disease', (71, 77))	('FGFR1', 'Gene', '2260', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (291, 297))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (55, 77))	('alteration', 'Var', (161, 171))	('FGFR1', 'Gene', '2260', (96, 101))	('FGFR1', 'Gene', (155, 160))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (71, 76))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (55, 76))	('tumors', 'Disease', 'MESH:D009369', (291, 297))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (55, 77))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('alterations', 'Var', (102, 113))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (291, 296))
236032	32859279	Thirty patients with LGNET harboring pathogenic FGFR1 alterations were included in this study.	('pathogenic', 'Reg', (37, 47))	('FGFR1', 'Gene', (48, 53))	('FGFR1', 'Gene', '2260', (48, 53))	('alterations', 'Var', (54, 65))	('patients', 'Species', '9606', (7, 15))
236036	32859279	Genomic DNA was also extracted from a peripheral blood or buccal swab sample as a source of constitutional DNA for discrimination of somatic versus germline status of identified variants for seven of the patients (PA #1, PA #3, PA #4, PA #6, DNT #1, EVN #2, and uLGNET #5) using the QIAamp DNA Blood Midi Kit (Qiagen).	('patients', 'Species', '9606', (204, 212))	('variants', 'Var', (178, 186))	('DNT #1', 'Gene', '30833', (242, 248))	('Kit', 'Gene', (305, 308))	('DNT #1', 'Gene', (242, 248))	('Kit', 'Gene', '3815', (305, 308))	('EVN', 'Chemical', '-', (250, 253))
236037	32859279	Capture-based next-generation DNA sequencing was performed using an assay that targets all coding exons of 479 cancer-related genes, select introns and upstream regulatory regions of 47 genes to enable detection of structural variants including gene fusions, and DNA segments at regular intervals along each chromosome to enable genome-wide copy number and zygosity analysis, with a total sequencing footprint of 2.8 Mb (Additional file 1: Table S1).	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('variants', 'Var', (226, 234))
236050	32859279	The study cohort included 30 patients with LGNET that had next-generation sequencing performed demonstrating an activating FGFR1 alteration (Table 1 and Fig.	('patients', 'Species', '9606', (29, 37))	('alteration', 'Var', (129, 139))	('FGFR1', 'Gene', (123, 128))	('FGFR1', 'Gene', '2260', (123, 128))	('activating', 'PosReg', (112, 122))
236053	32859279	Among the 30 LGNET from this cohort, 21 tumors were identified with kinase domain hotspot missense mutations (12 with p.N546K, 8 with p.K656E, and 1 with dual p.N546S and p.K656E), 7 tumors with kinase domain tandem duplication, and 2 tumors with FGFR1-TACC1 in-frame gene fusion (Table 1, Fig.	('p.K656E', 'Mutation', 'rs869320694', (134, 141))	('p.N546S', 'Mutation', 'rs544967630', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('FGFR1', 'Gene', (247, 252))	('TACC1', 'Gene', '6867', (253, 258))	('p.N546K', 'Mutation', 'rs779707422', (118, 125))	('p.K656E', 'Var', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (183, 189))	('tumors', 'Disease', (40, 46))	('and 1', 'Gene', (143, 148))	('p.N546K', 'Var', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('missense', 'Var', (90, 98))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('p.K656E', 'Mutation', 'rs869320694', (171, 178))	('FGFR1', 'Gene', '2260', (247, 252))	('p.K656E', 'Var', (171, 178))	('tumors', 'Disease', (235, 241))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('TACC1', 'Gene', (253, 258))	('and 1', 'Gene', '11169', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
236054	32859279	Among the 21 LGNET with either FGFR1 p.N546 or p.K656 hotspot mutations, a second non-hotspot missense mutation in FGFR1 was also identified in 8 tumors, which were uniformly present in cis (on the same allele) as the hotspot mutation when phasing was possible (n = 4).	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('FGFR1', 'Gene', '2260', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('p.K656', 'Var', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('p.N546', 'Var', (37, 43))	('N546', 'Chemical', '-', (39, 43))	('FGFR1', 'Gene', (31, 36))	('tumors', 'Disease', (146, 152))	('FGFR1', 'Gene', (115, 120))	('FGFR1', 'Gene', '2260', (115, 120))
236055	32859279	In six tumors, the FGFR1 p.N546 or p.K656 mutation was present at an equal variant allele frequency as the second non-hotspot missense mutation, indicating that they were both acquired at a similar timepoint during tumorigenesis.	('tumor', 'Disease', (7, 12))	('FGFR1', 'Gene', '2260', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('p.N546', 'Var', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('N546', 'Chemical', '-', (27, 31))	('tumor', 'Disease', (215, 220))	('p.K656', 'Var', (35, 41))	('FGFR1', 'Gene', (19, 24))
236056	32859279	In one tumor (RGNT #4), the FGFR1 p.N546K mutation was present at 37% allele frequency whereas the second mutation (p.K523T) was subclonal and present at 8% allele frequency.	('p.N546K', 'Var', (34, 41))	('tumor', 'Disease', (7, 12))	('p.K523T', 'Var', (116, 123))	('p.N546K', 'Mutation', 'rs779707422', (34, 41))	('FGFR1', 'Gene', (28, 33))	('p.K523T', 'Mutation', 'p.K523T', (116, 123))	('RGNT', 'Phenotype', 'HP:0025171', (14, 18))	('FGFR1', 'Gene', '2260', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
236057	32859279	In another tumor (PA #2), the FGFR1 p.K656E hotspot mutation was present at 32% allele frequency whereas the second mutation (p.V561M) was present at an allele frequency of approximately 50%, suggestive of the latter non-hotspot mutation potentially being present in the germline and the former hotspot mutation likely being present as a somatic mutation acquired during tumor development.	('p.K656E', 'Mutation', 'rs869320694', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FGFR1', 'Gene', (30, 35))	('tumor', 'Disease', (371, 376))	('p.V561M', 'Mutation', 'rs1265135270', (126, 133))	('tumor', 'Disease', (11, 16))	('FGFR1', 'Gene', '2260', (30, 35))	('p.K656E', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))
236058	32859279	Notably, germline mutations in the FGFR1 gene have been found in kindreds with familial occurrence of DNT.	('FGFR1', 'Gene', (35, 40))	('DNT', 'Disease', (102, 105))	('DNT', 'Chemical', '-', (102, 105))	('found', 'Reg', (56, 61))	('germline mutations', 'Var', (9, 27))	('FGFR1', 'Gene', '2260', (35, 40))
236059	32859279	Additional accompanying mutations were identified in a subset of the LGNET involving PIK3CA (n = 8), PIK3R1 (n = 3), NF1 (n = 8), and PTPN11 (n = 3).	('NF1', 'Gene', '4763', (117, 120))	('PTPN11', 'Gene', '5781', (134, 140))	('PTPN11', 'Gene', (134, 140))	('PIK3CA', 'Gene', '5290', (85, 91))	('PIK3R1', 'Gene', '5295', (101, 107))	('mutations', 'Var', (24, 33))	('NF1', 'Gene', (117, 120))	('PIK3R1', 'Gene', (101, 107))	('PIK3CA', 'Gene', (85, 91))
236061	32859279	Additionally, five tumors had trisomy (n = 4) or tetrasomy (n = 1) of chromosome 8, which includes the FGFR1 locus and resulted in extra copies of the mutant or rearranged allele in tumor cells.	('tumors', 'Disease', (19, 25))	('tetrasomy', 'Disease', 'MESH:D058670', (49, 58))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutant', 'Var', (151, 157))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tetrasomy', 'Disease', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('FGFR1', 'Gene', (103, 108))	('tumor', 'Disease', (19, 24))	('trisomy', 'Var', (30, 37))	('rearranged', 'Var', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('FGFR1', 'Gene', '2260', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
236062	32859279	Another four tumors had copy-neutral loss of heterozygosity of chromosome 8p, which includes the FGFR1 locus and resulted in tumors with two copies of the mutant allele and zero copies of the wildtype allele.	('FGFR1', 'Gene', '2260', (97, 102))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutant', 'Var', (155, 161))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('loss', 'NegReg', (37, 41))	('FGFR1', 'Gene', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
236064	32859279	Associations between specific FGFR1 alteration, accompanying genetic alteration(s), tumor histology, and epigenetic signature are described in detail below.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('FGFR1', 'Gene', (30, 35))	('alteration', 'Var', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('FGFR1', 'Gene', '2260', (30, 35))	('tumor', 'Disease', (84, 89))
236065	32859279	DNA methylation profiling was performed on the 30 LGNET with FGFR1 alterations using the Infinium Human Methylation EPIC 850k BeadChip Arrays.	('Human', 'Species', '9606', (98, 103))	('alterations', 'Var', (67, 78))	('FGFR1', 'Gene', (61, 66))	('FGFR1', 'Gene', '2260', (61, 66))
236070	32859279	Notably, the predicted tumor content for two of these unclassifiable tumors was low, based on both microscopic assessment and also the FGFR1 p.K656E mutant allele frequencies being 10% for uLGNET #3 and 6% for uLGNET #4.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('p.K656E', 'Var', (141, 148))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('p.K656E', 'Mutation', 'rs869320694', (141, 148))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('FGFR1', 'Gene', (135, 140))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('FGFR1', 'Gene', '2260', (135, 140))
236071	32859279	However, the predicted tumor content for the other three unclassifiable tumors was high, based on both microscopic assessment and FGFR1 mutant allele frequencies greater than 25%.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FGFR1', 'Gene', (130, 135))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('FGFR1', 'Gene', '2260', (130, 135))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (23, 28))	('mutant', 'Var', (136, 142))
236077	32859279	Below we describe the clinical, histologic, and genetic features of the LGNET with FGFR1 alterations aligning with each of the different methylation classes based on the UMAP clustering analysis.	('alterations', 'Var', (89, 100))	('FGFR1', 'Gene', (83, 88))	('UMAP', 'Chemical', '-', (170, 174))	('FGFR1', 'Gene', '2260', (83, 88))
236082	32859279	Two of these tumors harbored an additional missense mutation in FGFR1 (p.K523T and p.D652G), both of which were present in cis (on the same allele) as the respective hotspot mutation.	('tumors', 'Disease', (13, 19))	('p.K523T', 'Mutation', 'p.K523T', (71, 78))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('FGFR1', 'Gene', (64, 69))	('p.D652G', 'Var', (83, 90))	('p.D652G', 'Mutation', 'rs371909721', (83, 90))	('FGFR1', 'Gene', '2260', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('p.K523T', 'Var', (71, 78))
236083	32859279	Four of the tumors (RGNT #2, #6, #7, and #9) harbored copy-neutral loss of heterozygosity of chromosome 8p containing the FGFR1 locus, resulting in two copies of the mutant FGFR1 allele being present.	('FGFR1', 'Gene', (173, 178))	('FGFR1', 'Gene', '2260', (173, 178))	('FGFR1', 'Gene', (122, 127))	('FGFR1', 'Gene', '2260', (122, 127))	('RGNT', 'Phenotype', 'HP:0025171', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('loss', 'NegReg', (67, 71))	('mutant', 'Var', (166, 172))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
236084	32859279	Additionally, one other tumor (RGNT #5) harbored trisomy of chromosome 8 containing the FGFR1 locus, resulting in two copies of the mutant FGFR1 allele being present.	('FGFR1', 'Gene', (139, 144))	('FGFR1', 'Gene', '2260', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('FGFR1', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (88, 93))	('tumor', 'Disease', (24, 29))	('trisomy', 'Var', (49, 56))	('mutant', 'Var', (132, 138))	('RGNT', 'Phenotype', 'HP:0025171', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
236085	32859279	In addition to FGFR1 mutation, nine of the ten tumors additionally harbored mutually exclusive mutations in either PIK3CA or PIK3R1, with seven containing activating mutations in the PIK3CA catalytic subunit and two containing inactivating small in-frame deletions in the PIK3R1 negative regulatory subunit.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('FGFR1', 'Gene', '2260', (15, 20))	('mutations', 'Var', (166, 175))	('PIK3R1', 'Gene', '5295', (272, 278))	('PIK3R1', 'Gene', '5295', (125, 131))	('PIK3R1', 'Gene', (272, 278))	('PIK3R1', 'Gene', (125, 131))	('activating', 'PosReg', (155, 165))	('mutation', 'Var', (21, 29))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutations', 'Var', (95, 104))	('PIK3CA', 'Gene', (115, 121))	('PIK3CA', 'Gene', (183, 189))	('PIK3CA', 'Gene', '5290', (115, 121))	('FGFR1', 'Gene', (15, 20))	('PIK3CA', 'Gene', '5290', (183, 189))
236087	32859279	However, in two tumors (RGNT #4 and #7), the FGFR1 mutant allele frequency was appreciably higher than the PIK3CA/PIK3R1 mutant allele frequency (beyond that explained by the loss of heterozygosity of chromosome 8p alone in RGNT #7), indicating that the FGFR1 mutation arose before the PIK3CA or PIK3R1 mutation during the clonal evolution of these two tumors.	('tumors', 'Disease', 'MESH:D009369', (353, 359))	('mutant', 'Var', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('FGFR1', 'Gene', (254, 259))	('RGNT', 'Phenotype', 'HP:0025171', (24, 28))	('PIK3CA', 'Gene', (107, 113))	('PIK3CA', 'Gene', '5290', (286, 292))	('tumors', 'Disease', (16, 22))	('FGFR1', 'Gene', '2260', (45, 50))	('PIK3R1', 'Gene', (296, 302))	('PIK3R1', 'Gene', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (353, 359))	('higher', 'PosReg', (91, 97))	('PIK3CA', 'Gene', (286, 292))	('FGFR1', 'Gene', (45, 50))	('FGFR1', 'Gene', '2260', (254, 259))	('PIK3CA', 'Gene', '5290', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('tumors', 'Disease', (353, 359))	('PIK3R1', 'Gene', '5295', (296, 302))	('PIK3R1', 'Gene', '5295', (114, 120))	('RGNT', 'Phenotype', 'HP:0025171', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
236088	32859279	Of the seven tumors with dual FGFR1 + PIK3CA mutations, four contained accompanying NF1 mutations (one frameshift, two missense, and one small in-frame deletion).	('contained', 'Reg', (61, 70))	('mutations', 'Var', (45, 54))	('FGFR1', 'Gene', (30, 35))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('NF1', 'Gene', (84, 87))	('PIK3CA', 'Gene', (38, 44))	('FGFR1', 'Gene', '2260', (30, 35))	('NF1', 'Gene', '4763', (84, 87))	('PIK3CA', 'Gene', '5290', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('missense', 'Var', (119, 127))	('frameshift', 'Var', (103, 113))
236089	32859279	Of the two tumors with dual FGFR1 + PIK3R1 mutations, one contained an accompanying PTPN11 mutation (p.A72T), which is a known mutational hotspot in myeloid neoplasms thus providing support for pathogenicity [Catalog of Somatic Mutations in Cancer database v91 release].	('neoplasm', 'Phenotype', 'HP:0002664', (157, 165))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('myeloid neoplasms', 'Disease', (149, 166))	('Cancer', 'Phenotype', 'HP:0002664', (241, 247))	('FGFR1', 'Gene', '2260', (28, 33))	('PIK3R1', 'Gene', (36, 42))	('PTPN11', 'Gene', (84, 90))	('Cancer', 'Disease', (241, 247))	('PTPN11', 'Gene', '5781', (84, 90))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (149, 166))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('FGFR1', 'Gene', (28, 33))	('Cancer', 'Disease', 'MESH:D009369', (241, 247))	('p.A72T', 'Mutation', 'rs121918453', (101, 107))	('PIK3R1', 'Gene', '5295', (36, 42))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (149, 166))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('tumors', 'Disease', (11, 17))	('mutations', 'Var', (43, 52))
236090	32859279	Only one of the 10 epigenetically confirmed RGNT harbored FGFR1 mutation without an accompanying PIK3CA or PIK3R1 mutation or any other accompanying likely pathogenic alterations.	('mutation', 'Var', (64, 72))	('RGNT', 'Phenotype', 'HP:0025171', (44, 48))	('PIK3R1', 'Gene', '5295', (107, 113))	('harbored', 'Reg', (49, 57))	('PIK3R1', 'Gene', (107, 113))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))	('PIK3CA', 'Gene', (97, 103))	('PIK3CA', 'Gene', '5290', (97, 103))
236096	32859279	Three of the eight tumors harbored tandem duplication of the 3' exons encoding the tyrosine kinase domain of FGFR1, and the remaining five tumors harbored hotspot missense mutations within the tyrosine kinase domain of FGFR1 (p.N546K, n = 3; p.K656E, n = 2).	('tandem duplication', 'Var', (35, 53))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('p.N546K', 'Mutation', 'rs779707422', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('FGFR1', 'Gene', (109, 114))	('p.K656E', 'Var', (242, 249))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('FGFR1', 'Gene', '2260', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('FGFR1', 'Gene', (219, 224))	('missense', 'Var', (163, 171))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('FGFR1', 'Gene', '2260', (219, 224))	('p.K656E', 'Mutation', 'rs869320694', (242, 249))	('p.N546K', 'Var', (226, 233))
236097	32859279	Two of these five tumors harbored an additional missense mutation in FGFR1 (p.R675G and p.V561M), both of which were too distant to phase from their respective hotspot mutations.	('p.V561M', 'Mutation', 'rs1265135270', (88, 95))	('FGFR1', 'Gene', (69, 74))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('p.R675G', 'Var', (76, 83))	('p.V561M', 'Var', (88, 95))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('FGFR1', 'Gene', '2260', (69, 74))	('p.R675G', 'Mutation', 'rs779546178', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
236098	32859279	Among the five tumors with FGFR1 kinase domain hotspot missense mutations, one harbored an accompanying NF1 frameshift mutation and one harbored an accompanying PTPN11 hotspot missense mutation (p.G60V), which is a known pathogenic variant.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PTPN11', 'Gene', '5781', (161, 167))	('hotspot', 'PosReg', (47, 54))	('p.G60V', 'Mutation', 'rs397507509', (195, 201))	('PTPN11', 'Gene', (161, 167))	('NF1', 'Gene', '4763', (104, 107))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('FGFR1', 'Gene', (27, 32))	('missense mutations', 'Var', (55, 73))	('FGFR1', 'Gene', '2260', (27, 32))	('p.G60V', 'Var', (195, 201))	('tumors', 'Disease', (15, 21))	('NF1', 'Gene', (104, 107))
236099	32859279	None of the three tumors with FGFR1 kinase domain tandem duplication were identified to have any additional likely pathogenic alterations, including the PIK3CA, PIK3R1, NF1, and PTPN11 genes.	('PIK3CA', 'Gene', '5290', (153, 159))	('NF1', 'Gene', (169, 172))	('FGFR1', 'Gene', (30, 35))	('PIK3R1', 'Gene', (161, 167))	('PTPN11', 'Gene', '5781', (178, 184))	('PIK3R1', 'Gene', '5295', (161, 167))	('NF1', 'Gene', '4763', (169, 172))	('PTPN11', 'Gene', (178, 184))	('FGFR1', 'Gene', '2260', (30, 35))	('kinase domain tandem duplication', 'Var', (36, 68))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('PIK3CA', 'Gene', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
236104	32859279	Three of the five tumors harbored tandem duplication of the 3' exons encoding the tyrosine kinase domain of FGFR1, and the remaining two tumors harbored hotspot missense mutations within the tyrosine kinase domain of FGFR1.	('FGFR1', 'Gene', '2260', (108, 113))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('missense mutations', 'Var', (161, 179))	('tumors', 'Disease', (18, 24))	('FGFR1', 'Gene', (217, 222))	('FGFR1', 'Gene', '2260', (217, 222))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tandem duplication', 'Var', (34, 52))	('FGFR1', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
236105	32859279	Interestingly, DNT #1 harbored two hotspot mutations in FGFR1 (both p.N546S and p.K656E, present at 33% and 38% allele frequencies, respectively) but which were too distant to phase.	('p.N546S', 'Var', (68, 75))	('p.K656E', 'Mutation', 'rs869320694', (80, 87))	('DNT #1', 'Gene', '30833', (15, 21))	('p.K656E', 'Var', (80, 87))	('FGFR1', 'Gene', (56, 61))	('DNT #1', 'Gene', (15, 21))	('p.N546S', 'Mutation', 'rs544967630', (68, 75))	('FGFR1', 'Gene', '2260', (56, 61))
236106	32859279	Notably, almost all mutations at codon 546 in the FGFR1 gene in glial and glioneuronal tumors have been either p.N546K or p.N546D, and the p.N546S substitution in this DNT is rare but also likely to be activating.	('DNT', 'Chemical', '-', (168, 171))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (74, 93))	('p.N546D', 'Var', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FGFR1', 'Gene', (50, 55))	('neuronal tumor', 'Phenotype', 'HP:0025170', (78, 92))	('p.N546K', 'Var', (111, 118))	('p.N546S', 'Var', (139, 146))	('FGFR1', 'Gene', '2260', (50, 55))	('p.N546D', 'Mutation', 'rs1057519898', (122, 129))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (74, 92))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (74, 93))	('p.N546K', 'Mutation', 'rs779707422', (111, 118))	('p.N546S', 'Mutation', 'rs544967630', (139, 146))	('glioneuronal tumors', 'Disease', (74, 93))
236107	32859279	DNT #2 harbored the p.N546K hotspot mutation in FGFR1 and also had an accompanying PTPN11 hotspot missense mutation (p.G503V), which is a known pathogenic variant.	('p.N546K', 'Var', (20, 27))	('PTPN11', 'Gene', '5781', (83, 89))	('p.N546K', 'Mutation', 'rs779707422', (20, 27))	('FGFR1', 'Gene', (48, 53))	('PTPN11', 'Gene', (83, 89))	('FGFR1', 'Gene', '2260', (48, 53))	('DNT #2', 'Gene', (0, 6))	('p.G503V', 'Var', (117, 124))	('DNT #2', 'Gene', '56953', (0, 6))	('p.G503V', 'Mutation', 'rs397507546', (117, 124))
236108	32859279	Two of the three tumors with FGFR1 kinase domain tandem duplications harbored accompanying NF1 mutations (one frameshift and one missense).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('FGFR1', 'Gene', '2260', (29, 34))	('frameshift', 'Var', (110, 120))	('NF1', 'Gene', (91, 94))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('kinase domain tandem duplications', 'Var', (35, 68))	('NF1', 'Gene', '4763', (91, 94))	('harbored', 'Reg', (69, 77))	('mutations', 'Reg', (95, 104))	('FGFR1', 'Gene', (29, 34))
236113	32859279	Besides the FGFR1-TACC1 fusion, no other additional likely pathogenic alterations were identified, including the PIK3CA, PIK3R1, NF1, and PTPN11 genes.	('FGFR1', 'Gene', (12, 17))	('TACC1', 'Gene', '6867', (18, 23))	('PIK3CA', 'Gene', (113, 119))	('fusion', 'Var', (24, 30))	('PIK3R1', 'Gene', (121, 127))	('PIK3CA', 'Gene', '5290', (113, 119))	('NF1', 'Gene', (129, 132))	('PIK3R1', 'Gene', '5295', (121, 127))	('FGFR1', 'Gene', '2260', (12, 17))	('PTPN11', 'Gene', '5781', (138, 144))	('NF1', 'Gene', '4763', (129, 132))	('TACC1', 'Gene', (18, 23))	('PTPN11', 'Gene', (138, 144))
236121	32859279	One unclassifiable LGNET harbored FGFR1 kinase domain tandem duplication as the solitary pathogenic alteration identified, whereas the other four all harbored hotspot missense mutations within the tyrosine kinase domain of FGFR1 (p.N546K, n = 1; p.K656E, n = 3).	('p.N546K', 'Mutation', 'rs779707422', (230, 237))	('FGFR1', 'Gene', (34, 39))	('p.K656E', 'Var', (246, 253))	('FGFR1', 'Gene', (223, 228))	('FGFR1', 'Gene', '2260', (223, 228))	('FGFR1', 'Gene', '2260', (34, 39))	('p.K656E', 'Mutation', 'rs869320694', (246, 253))	('p.N546K', 'Var', (230, 237))
236122	32859279	The one unclassifiable LGNET with FGFR1 p.N546K mutation harbored additional PIK3CA p.G118D missense mutation and an intragenic deletion involving exon 35 of the NF1 gene predicted to disrupt gene function.	('PIK3CA', 'Gene', (77, 83))	('p.G118D', 'Mutation', 'rs587777790', (84, 91))	('NF1', 'Gene', (162, 165))	('NF1', 'Gene', '4763', (162, 165))	('p.G118D missense', 'Var', (84, 100))	('PIK3CA', 'Gene', '5290', (77, 83))	('p.N546K', 'Mutation', 'rs779707422', (40, 47))	('p.N546K mutation', 'Var', (40, 56))	('FGFR1', 'Gene', (34, 39))	('FGFR1', 'Gene', '2260', (34, 39))	('deletion involving', 'Var', (128, 146))
236123	32859279	One of the three unclassifiable LGNET with FGFR1 p.K656E mutation harbored an accompanying PIK3R1 p.K567E missense mutation, which is a specific variant that has been recurrently found in gliomas and other tumor types [Catalog of Somatic Mutations in Cancer database v91 release].	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('FGFR1', 'Gene', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('p.K656E', 'Var', (49, 56))	('tumor', 'Disease', (206, 211))	('p.K656E', 'Mutation', 'rs869320694', (49, 56))	('FGFR1', 'Gene', '2260', (43, 48))	('p.K567E', 'Var', (98, 105))	('Cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Cancer', 'Disease', (251, 257))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('gliomas', 'Disease', (188, 195))	('Cancer', 'Disease', 'MESH:D009369', (251, 257))	('PIK3R1', 'Gene', '5295', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('p.K567E', 'Mutation', 'rs869320694', (98, 105))	('PIK3R1', 'Gene', (91, 97))
236124	32859279	The three unclassifiable LGNET with FGFR1 p.K656E each harbored additional missense mutations in FGFR1 (p.D652G, n = 2; p.I544V, n = 1).	('p.I544V', 'Var', (120, 127))	('missense', 'Var', (75, 83))	('p.K656E', 'Var', (42, 49))	('FGFR1', 'Gene', '2260', (97, 102))	('FGFR1', 'Gene', (36, 41))	('p.I544V', 'Mutation', 'rs1289702833', (120, 127))	('p.K656E', 'Mutation', 'rs869320694', (42, 49))	('FGFR1', 'Gene', '2260', (36, 41))	('p.D652G', 'Mutation', 'rs371909721', (104, 111))	('p.D652G', 'Var', (104, 111))	('FGFR1', 'Gene', (97, 102))
236125	32859279	These additional FGFR1 missense mutations were present in cis when phasing could be evaluated (two of the three tumors).	('missense mutations', 'Var', (23, 41))	('FGFR1', 'Gene', (17, 22))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('FGFR1', 'Gene', '2260', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
236126	32859279	Through combining histologic, genomic, and epigenetic profiling on a series of 30 LGNET with FGFR1 alterations, we have identified that some tumor entities (RGNT and EVN) have a distinct pattern of genetic alterations, while other tumor entities (pilocytic astrocytoma and DNT) have overlapping/indistinct patterns precluding accurate classification based solely on genetic aberrations (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('FGFR1', 'Gene', '2260', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('astrocytoma', 'Phenotype', 'HP:0009592', (257, 268))	('tumor', 'Disease', (141, 146))	('RGNT', 'Phenotype', 'HP:0025171', (157, 161))	('tumor', 'Disease', (231, 236))	('alterations', 'Var', (99, 110))	('pilocytic astrocytoma', 'Disease', (247, 268))	('EVN', 'Chemical', '-', (166, 169))	('FGFR1', 'Gene', (93, 98))	('DNT', 'Chemical', '-', (273, 276))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (247, 268))
236127	32859279	Epigenetically confirmed RGNT harbor either p.N546 or p.K656 hotspot missense mutations in the kinase domain of FGFR1, and do not have FGFR1 kinase domain tandem duplication or gene fusions.	('FGFR1', 'Gene', (112, 117))	('missense', 'Var', (69, 77))	('N546', 'Chemical', '-', (46, 50))	('FGFR1', 'Gene', '2260', (112, 117))	('p.K656', 'Var', (54, 60))	('RGNT', 'Phenotype', 'HP:0025171', (25, 29))	('p.N546', 'Var', (44, 50))	('FGFR1', 'Gene', (135, 140))	('FGFR1', 'Gene', '2260', (135, 140))
236128	32859279	Additionally, the vast majority of RGNT have accompanying, mutually exclusive mutations in either PIK3CA or PIK3R1, predicted to cause activation of the PI3-kinase-Akt-mTOR signaling pathway, along with additional NF1 or PTPN11 mutations in a subset.	('mTOR', 'Gene', (168, 172))	('mTOR', 'Gene', '2475', (168, 172))	('activation', 'PosReg', (135, 145))	('RGNT', 'Disease', (35, 39))	('PIK3CA', 'Gene', (98, 104))	('Akt', 'Gene', '207', (164, 167))	('NF1', 'Gene', '4763', (214, 217))	('PIK3R1', 'Gene', '5295', (108, 114))	('mutations', 'Var', (78, 87))	('NF1', 'Gene', (214, 217))	('PIK3CA', 'Gene', '5290', (98, 104))	('PIK3R1', 'Gene', (108, 114))	('PTPN11', 'Gene', '5781', (221, 227))	('Akt', 'Gene', (164, 167))	('PTPN11', 'Gene', (221, 227))	('RGNT', 'Phenotype', 'HP:0025171', (35, 39))
236129	32859279	While pilocytic astrocytoma and DNT can also harbor identical hotspot missense mutations in FGFR1, the combination of co-occurring FGFR1 p.N546 or p.K656 mutation together with either PIK3CA or PIK3R1 mutation in LGNET appears to be specific for RGNT and was not found in any epigenetically confirmed cases of pilocytic astrocytoma, DNT, and EVN in this cohort or the published literature to date.	('FGFR1', 'Gene', '2260', (92, 97))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (310, 331))	('astrocytoma', 'Phenotype', 'HP:0009592', (320, 331))	('PIK3R1', 'Gene', (194, 200))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (6, 27))	('pilocytic astrocytoma', 'Disease', (310, 331))	('FGFR1', 'Gene', '2260', (131, 136))	('RGNT', 'Phenotype', 'HP:0025171', (246, 250))	('pilocytic astrocytoma', 'Disease', (6, 27))	('missense mutations', 'Var', (70, 88))	('DNT', 'Chemical', '-', (32, 35))	('PIK3CA', 'Gene', (184, 190))	('astrocytoma', 'Phenotype', 'HP:0009592', (16, 27))	('DNT', 'Chemical', '-', (333, 336))	('EVN', 'Chemical', '-', (342, 345))	('FGFR1', 'Gene', (92, 97))	('N546', 'Chemical', '-', (139, 143))	('PIK3R1', 'Gene', '5295', (194, 200))	('p.N546', 'Var', (137, 143))	('FGFR1', 'Gene', (131, 136))	('p.K656 mutation', 'Var', (147, 162))	('PIK3CA', 'Gene', '5290', (184, 190))
236130	32859279	Moreover, our study confirms that epigenetically confirmed EVN is characterized by frequent FGFR1-TACC1 gene fusion, which is rare or absent in other LGNET subtypes including RGNT, DNT, pilocytic astrocytoma, and ganglioglioma both in this cohort and previous studies.	('FGFR1', 'Gene', (92, 97))	('DNT', 'Disease', (181, 184))	('TACC1', 'Gene', (98, 103))	('DNT', 'Chemical', '-', (181, 184))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (186, 207))	('ganglioglioma', 'Disease', (213, 226))	('EVN', 'Chemical', '-', (59, 62))	('FGFR1', 'Gene', '2260', (92, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (196, 207))	('RGNT', 'Phenotype', 'HP:0025171', (175, 179))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('ganglioglioma', 'Disease', 'MESH:D018303', (213, 226))	('TACC1', 'Gene', '6867', (98, 103))	('pilocytic astrocytoma', 'Disease', (186, 207))	('EVN', 'Disease', (59, 62))	('fusion', 'Var', (109, 115))
236135	32859279	While the RGNT, EVN, and DNT methylation clusters are composed of tumors with nearly universal FGFR1 alterations, the three pilocytic astrocytoma methylation clusters are composed of a mixture of tumors with alterations in various genes causing activation of the MAP kinase signaling pathway (e.g.	('MAP kinase signaling pathway', 'Pathway', (263, 291))	('alterations', 'Var', (101, 112))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (124, 145))	('DNT', 'Chemical', '-', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('FGFR1', 'Gene', (95, 100))	('pilocytic astrocytoma', 'Disease', (124, 145))	('EVN', 'Chemical', '-', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('activation', 'PosReg', (245, 255))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('tumors', 'Disease', (196, 202))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('alterations', 'Var', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumors', 'Disease', (66, 72))	('FGFR1', 'Gene', '2260', (95, 100))	('RGNT', 'Phenotype', 'HP:0025171', (10, 14))
236138	32859279	Accordingly, we document examples of pilocytic astrocytomas with FGFR1 alterations located throughout the neuroaxis and belonging to each of the three different methylation classes.	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('FGFR1', 'Gene', (65, 70))	('alterations', 'Var', (71, 82))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (37, 59))	('pilocytic astrocytomas', 'Disease', (37, 59))	('FGFR1', 'Gene', '2260', (65, 70))
236139	32859279	Here we demonstrate that the majority of LGNET with FGFR1 alterations, both pediatric and adult, epigenetically cluster with the previously defined reference DNA methylation classes.	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('alterations', 'Var', (58, 69))
236140	32859279	First is that the relative tumor content of these samples is low, which was the case for two of the five tumors (uLGNET #3 and #4) based on the low FGFR1 mutant allele frequencies of 10% and 6%, respectively.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('FGFR1', 'Gene', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (105, 110))	('FGFR1', 'Gene', '2260', (148, 153))	('mutant', 'Var', (154, 160))
236141	32859279	The remaining three tumors had high tumor content based on FGFR1 mutant allele frequencies of > 25%, indicating that the reason for failure to closely cluster was due to other causes.	('high tumor', 'Disease', (31, 41))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutant', 'Var', (65, 71))	('FGFR1', 'Gene', (59, 64))	('high tumor', 'Disease', 'MESH:D009369', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('FGFR1', 'Gene', '2260', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
236143	32859279	Notably, two of the unclassifiable LGNET with high tumor content (uLGNET #1 and #2) had genetic signatures of RGNT with FGFR1 kinase domain hotspot missense mutation in combination with PIK3CA or PIK3R1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PIK3R1', 'Gene', '5295', (196, 202))	('FGFR1', 'Gene', (120, 125))	('high tumor', 'Disease', (46, 56))	('PIK3R1', 'Gene', (196, 202))	('missense mutation', 'Var', (148, 165))	('FGFR1', 'Gene', '2260', (120, 125))	('PIK3CA', 'Gene', (186, 192))	('RGNT', 'Phenotype', 'HP:0025171', (110, 114))	('high tumor', 'Disease', 'MESH:D009369', (46, 56))	('RGNT', 'Disease', (110, 114))	('PIK3CA', 'Gene', '5290', (186, 192))
236155	32859279	Both of these tumors lacked the accompanying PIK3CA or PIK3R1 mutation that is characteristic of RGNT, and both had epigenetic profiles aligning with pilocytic astrocytoma rather than RGNT.	('pilocytic astrocytoma', 'Disease', (150, 171))	('lacked', 'NegReg', (21, 27))	('PIK3R1', 'Gene', '5295', (55, 61))	('tumors', 'Disease', (14, 20))	('PIK3CA', 'Gene', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('PIK3R1', 'Gene', (55, 61))	('mutation', 'Var', (62, 70))	('PIK3CA', 'Gene', '5290', (45, 51))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (150, 171))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('astrocytoma', 'Phenotype', 'HP:0009592', (160, 171))	('RGNT', 'Phenotype', 'HP:0025171', (97, 101))	('RGNT', 'Phenotype', 'HP:0025171', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
236157	32859279	Together with the prior study by Sievers et al., our findings further confirm that RGNT is a unique glioneuronal tumor type with both a distinct epigenetic signature and distinct combination of FGFR1 hotspot missense mutation together with mutually exclusive mutation of either PIK3CA or PIK3R1, the latter of which is a novel finding of this study.	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (100, 118))	('FGFR1', 'Gene', '2260', (194, 199))	('glioneuronal tumor', 'Disease', 'MESH:D009369', (100, 118))	('RGNT', 'Disease', (83, 87))	('PIK3CA', 'Gene', (278, 284))	('missense mutation', 'Var', (208, 225))	('RGNT', 'Phenotype', 'HP:0025171', (83, 87))	('PIK3CA', 'Gene', '5290', (278, 284))	('neuronal tumor', 'Phenotype', 'HP:0025170', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('hotspot', 'PosReg', (200, 207))	('PIK3R1', 'Gene', (288, 294))	('glioneuronal tumor', 'Disease', (100, 118))	('FGFR1', 'Gene', (194, 199))	('PIK3R1', 'Gene', '5295', (288, 294))
236158	32859279	Notably, a subset of RGNT (4/10, 40%) have copy-neutral loss of heterozygosity involving chromosome 8p that eliminates the wildtype allele and results in two copies of the mutant FGFR1 allele in tumor cells.	('mutant', 'Var', (172, 178))	('tumor', 'Disease', (195, 200))	('loss', 'NegReg', (56, 60))	('FGFR1', 'Gene', (179, 184))	('FGFR1', 'Gene', '2260', (179, 184))	('RGNT', 'Phenotype', 'HP:0025171', (21, 25))	('wildtype', 'MPA', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('results in', 'Reg', (143, 153))	('eliminates', 'NegReg', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
236161	32859279	Comparing the relative FGFR1 and PIK3CA/PIK3R1 mutant allele frequencies in RGNT when accounting for the impact caused by trisomy 8 or loss of heterozygosity involving chromosome 8p, we find that the FGFR1 mutation is uniformly clonal and present in all tumor cells as an early or initiating event, whereas the PIK3CA or PIK3R1 mutations either arise at a similar timepoint or occasionally as a later event during tumor evolution after FGFR1 mutation.	('mutation', 'Var', (442, 450))	('PIK3CA', 'Gene', '5290', (33, 39))	('FGFR1', 'Gene', (200, 205))	('PIK3CA', 'Gene', '5290', (311, 317))	('PIK3R1', 'Gene', (321, 327))	('PIK3R1', 'Gene', '5295', (40, 46))	('FGFR1', 'Gene', (23, 28))	('tumor', 'Disease', (414, 419))	('FGFR1', 'Gene', (436, 441))	('PIK3CA', 'Gene', (33, 39))	('PIK3CA', 'Gene', (311, 317))	('FGFR1', 'Gene', '2260', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (414, 419))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('PIK3R1', 'Gene', '5295', (321, 327))	('RGNT', 'Phenotype', 'HP:0025171', (76, 80))	('PIK3R1', 'Gene', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('FGFR1', 'Gene', '2260', (23, 28))	('FGFR1', 'Gene', '2260', (436, 441))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
236162	32859279	Interestingly, the majority of RGNT have at least two, and often three, different pathogenic mutations involving FGFR1, either PIK3CA or PIK3R1, and often also NF1 or PTPN11.	('PTPN11', 'Gene', (167, 173))	('PIK3R1', 'Gene', (137, 143))	('mutations', 'Var', (93, 102))	('NF1', 'Gene', (160, 163))	('FGFR1', 'Gene', (113, 118))	('NF1', 'Gene', '4763', (160, 163))	('PIK3CA', 'Gene', (127, 133))	('PIK3CA', 'Gene', '5290', (127, 133))	('FGFR1', 'Gene', '2260', (113, 118))	('PTPN11', 'Gene', '5781', (167, 173))	('RGNT', 'Phenotype', 'HP:0025171', (31, 35))	('RGNT', 'Disease', (31, 35))	('PIK3R1', 'Gene', '5295', (137, 143))
236163	32859279	As such, genetic activation of both the Ras-Raf-MEK-ERK and PI3-kinase-Akt-mTOR signaling pathways appears to be fundamental to the pathogenesis of RGNT.	('Akt', 'Gene', '207', (71, 74))	('ERK', 'Gene', '5594', (52, 55))	('Raf', 'Gene', '673;5894', (44, 47))	('ERK', 'Gene', (52, 55))	('Raf', 'Gene', (44, 47))	('Akt', 'Gene', (71, 74))	('MEK', 'Gene', (48, 51))	('MEK', 'Gene', '5609', (48, 51))	('activation', 'PosReg', (17, 27))	('RGNT', 'Disease', (148, 152))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('RGNT', 'Phenotype', 'HP:0025171', (148, 152))	('genetic', 'Var', (9, 16))
236165	32859279	BRAF mutation or fusion) causing activation of the MAP kinase signaling in isolation.	('activation', 'PosReg', (33, 43))	('MAP kinase signaling', 'MPA', (51, 71))	('fusion', 'Var', (17, 23))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
236167	32859279	TERT promoter mutation or ATRX inactivation) that protect against uncontrolled proliferation and malignant transformation.	('uncontrolled proliferation', 'CPA', (66, 92))	('ATRX', 'Gene', (26, 30))	('inactivation', 'Var', (31, 43))	('malignant transformation', 'CPA', (97, 121))	('TERT', 'Gene', (0, 4))	('ATRX', 'Gene', '546', (26, 30))	('TERT', 'Gene', '7015', (0, 4))
236168	32859279	In summary, we show that FGFR1 alterations occur in a wide spectrum of known tumor entities with overlapping histologic features.	('alterations', 'Var', (31, 42))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('FGFR1', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('FGFR1', 'Gene', '2260', (25, 30))	('occur', 'Reg', (43, 48))
236169	32859279	Integrating the pattern of genetic alterations and/or epigenetic signature for such low-grade glial and glioneuronal tumors can assist with accurate diagnostic classification and prognostication for affected patients.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patients', 'Species', '9606', (208, 216))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (104, 123))	('assist', 'Reg', (128, 134))	('glioneuronal tumors', 'Disease', (104, 123))	('low-grade', 'Disease', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('neuronal tumor', 'Phenotype', 'HP:0025170', (108, 122))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (104, 123))	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (104, 122))	('genetic alterations', 'Var', (27, 46))	('epigenetic signature', 'Var', (54, 74))
236178	30152087	Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63=1.50x10-9, OR54-63=1.28, 95%CI54-63=1.18-1.39; p64+=2.14x10-11, OR64+=1.32, 95%CI64+=1.21-1.43] and rs11979158 [p54-63=6.13x10-8, OR54-63=1.35, 95%CI54-63=1.21-1.50; p64+=2.18x10-10, OR64+=1.42, 95%CI64+=1.27-1.58]) but only in persons >54.	('persons', 'Species', '9606', (329, 336))	('rs723527', 'Var', (84, 92))	('rs11979158', 'Mutation', 'rs11979158', (201, 211))	('rs11979158', 'Var', (201, 211))	('rs723527', 'Mutation', 'rs723527', (84, 92))	('p64+=2.18x10-10', 'Var', (267, 282))
236179	30152087	There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53=9.30x10-11, OR18-53=1.76, 95%CI18-53=1.49-2.10).	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('rs55705857', 'Var', (118, 128))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('persons', 'Species', '9606', (133, 140))	('rs55705857', 'Mutation', 'rs55705857', (118, 128))	('glioma', 'Disease', (82, 88))
236182	30152087	The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioblastoma', 'Disease', (222, 234))	('IDH1/2', 'Gene', (50, 56))	('IDH1/2', 'Gene', '3417;3418', (96, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (222, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (222, 234))	('mutant', 'Var', (57, 63))	('glioma', 'Disease', (64, 70))	('IDH1/2', 'Gene', (96, 102))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
236189	30152087	Recent molecular characterization of gliomas (including both GBM and LGG) has determined that gliomas can be more precisely stratified using two common alterations: mutation in isocitrate dehydrogenase 1/2 (IDH1/2) and loss of the 1p/19q.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('IDH1/2', 'Gene', (207, 213))	('gliomas', 'Disease', (94, 101))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('GBM', 'Disease', 'MESH:D005909', (61, 64))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('mutation', 'Var', (165, 173))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('IDH1/2', 'Gene', '3417;3418', (207, 213))	('GBM', 'Disease', (61, 64))	('loss', 'NegReg', (219, 223))
236192	30152087	The contribution of common low-penetrance single nucleotide polymorphisms (SNPs) to the heritability of glioma in persons with no documented family history is estimated to be ~25%.	('single nucleotide polymorphisms', 'Var', (42, 73))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('persons', 'Species', '9606', (114, 121))	('glioma', 'Disease', (104, 110))
236208	30152087	Two other SNPs (rs723527 and rs11979158) were nominally significant in the age 18-53 strata, and reached genome-wide significance in the age 54-63, and age 64+ stratum.	('significant', 'Reg', (56, 67))	('rs11979158', 'Mutation', 'rs11979158', (29, 39))	('rs723527', 'Var', (16, 24))	('rs11979158', 'Var', (29, 39))	('rs723527', 'Mutation', 'rs723527', (16, 24))
236209	30152087	There was a nominal association in the case-only analysis between age-at-diagnosis and the previously identified SNP at 5p15.33 (rs10069690) and GBM (pfixed =0.0033, prandom =0.0053) with an increase in age of diagnosis of 0.76 years for each risk allele.	('GBM', 'Disease', (145, 148))	('rs10069690', 'Mutation', 'rs10069690', (129, 139))	('GBM', 'Disease', 'MESH:D005909', (145, 148))	('rs10069690', 'Var', (129, 139))	('GBM', 'Phenotype', 'HP:0012174', (145, 148))
236210	30152087	For both SNPs (rs12803321 and rs498872), each risk allele was associated with an increase of approximately 1.5 years in age-at-diagnosis.	('rs498872', 'Mutation', 'rs498872', (30, 38))	('rs12803321', 'Mutation', 'rs12803321', (15, 25))	('rs12803321', 'Var', (15, 25))	('increase', 'PosReg', (81, 89))	('rs498872', 'Var', (30, 38))
236212	30152087	In the subset of cases ages 54+, rs498872 remained nominally significantly associated with age-at-diagnosis (pfixed=0.0056, prandom=0.0225), with an estimated 0.52-year increase in age of diagnosis for each risk allele.	('rs498872', 'Var', (33, 41))	('associated', 'Reg', (75, 85))	('rs498872', 'Mutation', 'rs498872', (33, 41))	('increase', 'PosReg', (169, 177))
236216	30152087	Median age-at-diagnosis was lowest in IDH1/2 mutant GBM samples (38.5) and highest in IDH1/2 wild-type samples (62.0).	('mutant', 'Var', (45, 51))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('GBM', 'Disease', (52, 55))	('IDH1/2', 'Gene', '3417;3418', (86, 92))	('GBM', 'Disease', 'MESH:D005909', (52, 55))	('IDH1/2', 'Gene', (38, 44))	('lowest', 'NegReg', (28, 34))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('IDH1/2', 'Gene', (86, 92))
236217	30152087	Within the youngest age-group of individuals 18-53, 15/100 individuals had IDH1/2 mutant tumors (15%), as compared to 2/94 in those 54-63 (2.1%), and 1/121 in those 64+ (0.8%).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('IDH1/2', 'Gene', (75, 81))	('IDH1/2', 'Gene', '3417;3418', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutant', 'Var', (82, 88))
236220	30152087	This is the first genome-wide age-specific analysis focused specifically on the relationship between germline risk variants and age-at-diagnosis in GBM, and leverages multiple existing glioma GWAS datasets.	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('GBM', 'Disease', (148, 151))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('variants', 'Var', (115, 123))	('GBM', 'Disease', 'MESH:D005909', (148, 151))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('glioma', 'Disease', (185, 191))
236221	30152087	This study demonstrated that there are age-related differences in frequency of known heritable genetic risk variants in glioma, largely driven by differences in those less than 54 years of age.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('glioma', 'Disease', 'MESH:D005910', (120, 126))	('glioma', 'Disease', (120, 126))	('variants', 'Var', (108, 116))
236223	30152087	Now that molecular markers are routinely incorporated in glioma diagnosis, incorporation of these more precise phenotype classifications into GWAS is necessary in order to understand the pathways and mechanisms through which these risk variants confer increased susceptibility for GBM, and the extent to which these may vary by age.	('GBM', 'Disease', (281, 284))	('GBM', 'Disease', 'MESH:D005909', (281, 284))	('glioma', 'Disease', (57, 63))	('GBM', 'Phenotype', 'HP:0012174', (281, 284))	('susceptibility', 'Reg', (262, 276))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('variants', 'Var', (236, 244))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
236225	30152087	This analysis found that variants in TERT and RTEL1 reached genome-wide significance among all three age cohorts, with no substantial difference in estimated effect by age.	('RTEL1', 'Gene', (46, 51))	('variants', 'Var', (25, 33))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('RTEL1', 'Gene', '51750', (46, 51))
236226	30152087	In the case-only analysis, there was a nominally significant association between rs10069690 (TERT, pRandom=0.0053) and increased age-at-diagnosis, with an increase of 0.76 years of age per risk allele.	('rs10069690', 'Mutation', 'rs10069690', (81, 91))	('rs10069690', 'Var', (81, 91))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))	('increased', 'PosReg', (119, 128))
236227	30152087	There was no significant association between rs2297440 (RTEL1, pRandom=0.0512) and increased age-at-diagnosis.	('RTEL1', 'Gene', '51750', (56, 61))	('rs2297440', 'Var', (45, 54))	('rs2297440', 'Mutation', 'rs2297440', (45, 54))	('RTEL1', 'Gene', (56, 61))
236228	30152087	The analysis also reported association between risk alleles in PHLDB1 and decreased age-at-diagnosis.	('PHLDB1', 'Gene', '23187', (63, 69))	('PHLDB1', 'Gene', (63, 69))	('alleles', 'Var', (52, 59))	('decreased', 'NegReg', (74, 83))	('age-at-diagnosis', 'CPA', (84, 100))
236229	30152087	There was a nominally significant association between these SNPs in PHLDB1 and age-at-diagnosis in a case-only analysis, but when analysis was limited to those 54 years of age and older, the effect of these SNPs on age-at-diagnosis was null, suggesting that phenotypic differences between the younger and older cohort may be driving the observed allele frequency differences rather than a true effect on age-at-diagnosis.	('PHLDB1', 'Gene', '23187', (68, 74))	('PHLDB1', 'Gene', (68, 74))	('significant association', 'Reg', (22, 45))	('SNPs', 'Var', (60, 64))
236230	30152087	These variants were within one of two previously identified independent glioma risk loci located near EGFR, which is most strongly associated with risk for GBM.	('glioma', 'Disease', (72, 78))	('variants', 'Var', (6, 14))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('GBM', 'Disease', (156, 159))	('associated', 'Reg', (131, 141))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('GBM', 'Disease', 'MESH:D005909', (156, 159))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
236231	30152087	This SNP has been previously associated with non-GBMs:in particular low-grade tumors that have IDH1/2 mutation and 1p/19q co-deletion:and a significant association between this SNP and GBM has not been previously reported.	('tumors', 'Disease', (78, 84))	('GBM', 'Disease', (185, 188))	('GBM', 'Disease', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('IDH1/2', 'Gene', (95, 101))	('GBM', 'Disease', 'MESH:D005909', (185, 188))	('mutation', 'Var', (102, 110))	('GBM', 'Phenotype', 'HP:0012174', (185, 188))	('GBM', 'Disease', 'MESH:D005909', (49, 52))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IDH1/2', 'Gene', '3417;3418', (95, 101))
236232	30152087	While IDH1/2 mutation is most common in LGG (where ~80% of tumors have this alteration), only a minority of GBM (~5%) have this alteration.	('mutation', 'Var', (13, 21))	('GBM', 'Disease', (108, 111))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('tumors', 'Disease', (59, 65))	('GBM', 'Disease', 'MESH:D005909', (108, 111))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('common', 'Reg', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('LGG', 'Disease', (40, 43))	('IDH1/2', 'Gene', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
236233	30152087	Among individuals with tumors that appear histologically to be GBM, IDH1/2 mutation is known to occur more commonly in younger individuals.	('IDH1/2', 'Gene', '3417;3418', (68, 74))	('GBM', 'Disease', (63, 66))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('GBM', 'Disease', 'MESH:D005909', (63, 66))	('mutation', 'Var', (75, 83))	('IDH1/2', 'Gene', (68, 74))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
236234	30152087	Among the TCGA GBM set, IDH1/2 mutation occurred in 15% of cases in individuals 18-53, as compared to 2.1% and 0.8% in individuals 54-63 and 64+, respectively (p=0.0005).	('GBM', 'Phenotype', 'HP:0012174', (15, 18))	('IDH1/2', 'Gene', '3417;3418', (24, 30))	('mutation', 'Var', (31, 39))	('GBM', 'Disease', (15, 18))	('occurred', 'Reg', (40, 48))	('IDH1/2', 'Gene', (24, 30))	('GBM', 'Disease', 'MESH:D005909', (15, 18))
236235	30152087	These mutations occur very early in gliomagenesis, and as a result represent an entity that is distinct from IDH1/2 wild-type GBM.	('GBM', 'Disease', (126, 129))	('gliomagenesis', 'Disease', (36, 49))	('IDH1/2', 'Gene', (109, 115))	('GBM', 'Disease', 'MESH:D005909', (126, 129))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('gliomagenesis', 'Disease', 'None', (36, 49))	('IDH1/2', 'Gene', '3417;3418', (109, 115))	('mutations', 'Var', (6, 15))
236236	30152087	IDH1/2 mutation is generally considered to be a marker of 'secondary GBM', or GBM that has progressed from a previously undiagnosed LGG.	('GBM', 'Disease', (69, 72))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('GBM', 'Disease', 'MESH:D005909', (69, 72))	('IDH1/2', 'Gene', (0, 6))	("'secondary", 'Disease', (58, 68))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('mutation', 'Var', (7, 15))	('GBM', 'Disease', (78, 81))	('GBM', 'Disease', 'MESH:D005909', (78, 81))
236242	30152087	While classification using IDH1/2 mutation and 1p19q co-deletion was not codified until the release of the 2016 WHO classification scheme, these markers were gradually adopted for use in glioma diagnosis prior to the release of this scheme.	('1p19q co-deletion', 'Var', (47, 64))	('glioma', 'Disease', (187, 193))	('IDH1/2', 'Gene', '3417;3418', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('IDH1/2', 'Gene', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (187, 193))
236247	30152087	The association of a SNP known to confer risk for IDH1/2 mutant glioma with GBM within individuals 18-53 suggests that a substantial portion of younger individuals included in GBM research may present initially with 'secondary GBM.'	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('IDH1/2', 'Gene', (50, 56))	('GBM', 'Disease', (227, 230))	('GBM', 'Disease', (176, 179))	('GBM', 'Disease', (76, 79))	('GBM', 'Disease', 'MESH:D005909', (227, 230))	('mutant', 'Var', (57, 63))	('GBM', 'Disease', 'MESH:D005909', (176, 179))	('GBM', 'Disease', 'MESH:D005909', (76, 79))	('glioma', 'Disease', (64, 70))	('GBM', 'Phenotype', 'HP:0012174', (227, 230))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('GBM', 'Phenotype', 'HP:0012174', (176, 179))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
236248	30152087	The higher prevalence of IDH1/2 mutant GBM within this younger age-group is also evident within TCGA GBMs.	('IDH1/2', 'Gene', '3417;3418', (25, 31))	('GBM', 'Phenotype', 'HP:0012174', (39, 42))	('GBM', 'Disease', (101, 104))	('mutant', 'Var', (32, 38))	('IDH1/2', 'Gene', (25, 31))	('GBM', 'Disease', 'MESH:D005909', (101, 104))	('GBM', 'Disease', (39, 42))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('GBM', 'Disease', 'MESH:D005909', (39, 42))
236250	30152087	This is the first genome-wide association analysis examining age-at-diagnosis--which is strongly associated with incidence and prognosis--and germline risk variants in glioblastoma.	('variants', 'Var', (156, 164))	('glioblastoma', 'Disease', (168, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (168, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (168, 180))
236251	30152087	We detected a higher frequency of germline variants associated with lower grade gliomas (LGG) in the younger cohort, as well as high frequency of LGG-like somatic variants in The Cancer Genome Atlas GBM cohort.	('GBM', 'Disease', (199, 202))	('GBM', 'Disease', 'MESH:D005909', (199, 202))	('gliomas', 'Disease', (80, 87))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('variants', 'Var', (43, 51))
236252	29180699	Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies.	('malignancies', 'Disease', (204, 216))	('IDH1', 'Gene', (97, 101))	('IDH1', 'Gene', '15926', (7, 11))	('Mutations', 'Var', (84, 93))	('IDH1', 'Gene', '15926', (97, 101))	('gliomas', 'Disease', (180, 187))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('IDH2', 'Gene', (106, 110))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('drive', 'Reg', (155, 160))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('human', 'Species', '9606', (198, 203))	('IDH1', 'Gene', (7, 11))
236253	29180699	Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promote', 'PosReg', (44, 51))	('tumor', 'Disease', (52, 57))	('epigenetic changes', 'MPA', (20, 38))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Mutant', 'Var', (0, 6))	('induces', 'Reg', (12, 19))	('IDH1', 'Gene', (7, 11))
236254	29180699	Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming.	('glioma tumorsphere systems', 'Disease', 'MESH:D005910', (32, 58))	('mutant-IDH1-induced', 'Var', (95, 114))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('human', 'Species', '9606', (12, 17))	('glioma tumorsphere systems', 'Disease', (32, 58))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
236255	29180699	These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutant', 'Var', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('IDH', 'Gene', (141, 144))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '15926', (141, 144))	('tumors', 'Disease', (152, 158))	('IDH', 'Gene', '15926', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
236256	29180699	Mutations in IDH1 and IDH2 are found in over 80% of lowergrade gliomas (LGGs) and secondary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (92, 105))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('glioblastomas', 'Disease', 'MESH:D005909', (92, 105))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('glioblastomas', 'Disease', (92, 105))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('found', 'Reg', (31, 36))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
236257	29180699	IDH1 mutations commonly occur at codon 132 and lead to the production of 2-hydroxyglutarate (2HG).	('production of 2-hydroxyglutarate', 'MPA', (59, 91))	('occur', 'Reg', (24, 29))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (73, 91))	('lead to', 'Reg', (47, 54))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))
236258	29180699	In experimental models, introduction of mutant IDH1 and 2HG production lead to global DNA hypermethylation, histone methylation alterations, and differentiation block.	('global DNA hypermethylation', 'MPA', (79, 106))	('IDH1 and 2', 'Gene', '15926;269951', (47, 57))	('histone methylation alterations', 'MPA', (108, 139))	('differentiation block', 'CPA', (145, 166))	('mutant', 'Var', (40, 46))
236259	29180699	Pharmacological lowering of 2HG levels with inhibitors selective for mutant IDH does not completely reverse mutant-IDH-dependent epigenetic changes in vitro or in vivo, at least for the treatment durations tested.	('IDH', 'Gene', '15926', (76, 79))	('IDH', 'Gene', '15926', (115, 118))	('lowering', 'NegReg', (16, 24))	('mutant', 'Var', (69, 75))	('IDH', 'Gene', (76, 79))	('epigenetic changes', 'MPA', (129, 147))	('IDH', 'Gene', (115, 118))	('2HG levels', 'MPA', (28, 38))
236261	29180699	First, a comprehensive understanding of how mutant IDH alters chromatin states is lacking and needs to be established.	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', '15926', (51, 54))	('chromatin', 'MPA', (62, 71))	('alters', 'Reg', (55, 61))	('mutant', 'Var', (44, 50))
236262	29180699	Second, it is not known whether epigenomic reprogramming caused by mutant IDH is reversible and, if so, what the kinetics of reversibility are.	('IDH', 'Gene', '15926', (74, 77))	('IDH', 'Gene', (74, 77))	('mutant', 'Var', (67, 73))
236267	29180699	For IHAs with inducible expression of mutant IDH1 at baseline (Dox+), starting at ten passages following doxycycline withdrawal, cells in the doxycycline withdrawal state (Doxoff) were similar to cells that had never been exposed to doxycycline (Dox-) (Fig.	('mutant', 'Var', (38, 44))	('Dox', 'Chemical', 'MESH:D004318', (172, 175))	('doxycycline', 'Chemical', 'MESH:D004318', (142, 153))	('Dox', 'Chemical', 'MESH:D004318', (63, 66))	('Doxoff', 'Chemical', '-', (172, 178))	('doxycycline', 'Chemical', 'MESH:D004318', (105, 116))	('Dox', 'Chemical', 'MESH:D004318', (246, 249))	('doxycycline', 'Chemical', 'MESH:D004318', (233, 244))	('IDH1', 'Gene', (45, 49))
236274	29180699	To assess the relevance of our findings, we compared gene expression and methylation changes to those observed in IDH-mutant gliomas, finding similarly deregulated pathways in IHAs inducibly expressing mutant IDH1 and CpG island methylator phenotype positive (CIMP+) gliomas (Supplementary Fig.	('gliomas', 'Disease', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('IDH', 'Gene', (114, 117))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('deregulated', 'Reg', (152, 163))	('IDH', 'Gene', '15926', (209, 212))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('gliomas', 'Disease', (267, 274))	('gliomas', 'Disease', 'MESH:D005910', (267, 274))	('gliomas', 'Phenotype', 'HP:0009733', (267, 274))	('IDH', 'Gene', '15926', (114, 117))	('CIMP+', 'Chemical', '-', (260, 265))	('IDH', 'Gene', (209, 212))	('mutant', 'Var', (202, 208))
236275	29180699	Furthermore, hypermethylated loci in IHAs with inducible expression of mutant IDH1 displayed increased median methylation in CIMP+ LGGs as compared to CIMP- LGGs (Supplementary Fig.	('CIMP', 'Chemical', '-', (125, 129))	('increased', 'PosReg', (93, 102))	('IDH1', 'Gene', (78, 82))	('methylation', 'MPA', (110, 121))	('CIMP+', 'Chemical', '-', (125, 130))	('mutant', 'Var', (71, 77))	('CIMP', 'Chemical', '-', (151, 155))
236276	29180699	Interestingly, our study identified mutant-IDH1-dependent upregulation of CD24, which encodes a putative cell-surface marker for stem-like cell populations that is overexpressed in tumors and broadly expressed in many tissues, including the brain (Fig.	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutant-IDH1-dependent', 'Var', (36, 57))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('CD24', 'Gene', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('upregulation', 'PosReg', (58, 70))
236277	29180699	In IHAs inducibly expressing mutant IDH1, CD24 was upregulated as compared to non-induced cells, and its expression was decreased upon doxycycline withdrawal (Fig.	('decreased', 'NegReg', (120, 129))	('IDH1', 'Gene', (36, 40))	('doxycycline', 'Chemical', 'MESH:D004318', (135, 146))	('mutant', 'Var', (29, 35))	('upregulated', 'PosReg', (51, 62))	('CD24', 'Gene', (42, 46))	('expression', 'MPA', (105, 115))
236278	29180699	We confirmed higher CD24 expression in a cohort of CIMP+ LGGs (Supplementary Fig.	('CIMP+', 'Chemical', '-', (51, 56))	('expression', 'MPA', (25, 35))	('higher', 'PosReg', (13, 19))	('CD24', 'Protein', (20, 24))	('CIMP+', 'Var', (51, 56))
236279	29180699	We then sorted CD24- and CD24+ subpopulations from Dox+ IHAs expressing mutant IDH1 (~2-6% of these IHAs were CD24+).	('mutant', 'Var', (72, 78))	('IDH1', 'Gene', (79, 83))	('Dox', 'Chemical', 'MESH:D004318', (51, 54))
236280	29180699	CD24+ cells formed significantly more colonies in soft agar than CD24- cells (Supplementary Fig.	('agar', 'Chemical', 'MESH:D000362', (55, 59))	('more', 'PosReg', (33, 37))	('CD24+', 'Var', (0, 5))	('colonies in soft agar', 'CPA', (38, 59))
236282	29180699	We used RNA-seq data from the BrainSpan Developmental Transcriptome to determine the expression patterns of genes upregulated in CD24+ IHAs during human brain development.	('upregulated', 'PosReg', (114, 125))	('CD24+ IHAs', 'Var', (129, 139))	('human', 'Species', '9606', (147, 152))
236285	29180699	Taken together, these data suggest that CD24+ cells emerge in a progenitor-like state from astrocytes expressing IDH1 R132H and this process may contribute to epigenetic and transcriptional reprogramming.	('R132H', 'Mutation', 'rs121913500', (118, 123))	('contribute', 'Reg', (145, 155))	('IDH1 R132H', 'Var', (113, 123))
236286	29180699	ChIP-seq analysis of major histone modifications showed progressive enrichment of H3K4me3 (associated with actively transcribed genes), H3K36me3 (preventing intragenic cryptic transcript initiation during active transcription), and H3K9me3 and H4K20me3 (repressive marks enriched in heterochromatic regions) in successive passages of IHAs with stable expression of IDH1 R132H but not in parental astrocytes (Fig.	('H3K9me3', 'Var', (232, 239))	('R132H', 'Mutation', 'rs121913500', (370, 375))	('H3K36me3', 'Var', (136, 144))	('H3K4me3', 'Var', (82, 89))	('IDH1 R132H', 'Var', (365, 375))	('H4K20me3', 'Var', (244, 252))
236287	29180699	In contrast, the distribution of H3K4me3 peak locations extended to intronic and intergenic regions in IHAs expressing IDH1 R132H (Fig.	('R132H', 'Mutation', 'rs121913500', (124, 129))	('IDH1 R132H', 'Var', (119, 129))	('H3K4me3', 'Protein', (33, 40))
236288	29180699	Notably, we observed focal H3K4me3 gains at 4q12 in mutant-expressing astrocytes, including increased H3K4me3 within the DANCR locus and the transcriptional start site (TSS) of PDGFRA, an oncogene intimately linked to gliomagenesis (Fig.	('gains', 'PosReg', (35, 40))	('H3K4me3', 'Protein', (27, 34))	('DANCR', 'Gene', (121, 126))	('mutant-expressing', 'Var', (52, 69))	('glioma', 'Disease', (218, 224))	('PDGFRA', 'Gene', '18595', (177, 183))	('increased', 'PosReg', (92, 101))	('PDGFRA', 'Gene', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('H3K4me3', 'Protein', (102, 109))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('DANCR', 'Gene', '70036', (121, 126))
236289	29180699	We analyzed bulk histone methylation levels in IHAs with inducible expression of mutant IDH1 by liquid chromatography coupled with mass spectrometry of purified histones, confirming significant increases in H3K4me2, H3K4me3, H3K9me2, H3K9me3, and H3K36me3 in Dox+ IHAs (Supplementary Fig.	('H3K4me3', 'Protein', (216, 223))	('H3K36me3', 'Var', (247, 255))	('IDH1', 'Gene', (88, 92))	('H3K9me3', 'Var', (234, 241))	('H3K9me2', 'Protein', (225, 232))	('mutant', 'Var', (81, 87))	('increases', 'PosReg', (194, 203))	('H3K4me2', 'Protein', (207, 214))	('Dox', 'Chemical', 'MESH:D004318', (259, 262))
236290	29180699	To determine the reversibility of the changes in the histone methylation landscape, we performed ChIP-seq on H3K4me3, H3K27me3, H3K9me3, and H3K36me3 at baseline and at 40 passages following doxycycline withdrawal.	('H3K4me3', 'Var', (109, 116))	('doxycycline', 'Chemical', 'MESH:D004318', (191, 202))	('H3K36me3', 'Var', (141, 149))	('H3K27me3', 'Var', (118, 126))	('H3K9me3', 'Var', (128, 135))
236291	29180699	As for IHAs stably expressing mutant IDH1, we observed substantial H3K4me3 enrichment along with increases in H3K36me3 and H3K9me3 in Dox+ IHAs relative to Dox- IHAs at baseline (although the increases were more modest than those in IHAs with stable expression) (Fig.	('increases', 'PosReg', (97, 106))	('IDH1', 'Gene', (37, 41))	('Dox', 'Chemical', 'MESH:D004318', (156, 159))	('H3K4me3', 'Protein', (67, 74))	('H3K9me3', 'MPA', (123, 130))	('H3K36me3', 'Protein', (110, 118))	('mutant', 'Var', (30, 36))	('Dox', 'Chemical', 'MESH:D004318', (134, 137))
236293	29180699	Interestingly, as compared to Dox- and Doxoff cells, Dox+ IHAs had a greater percentage of their genomes in state 6 (largely devoid of histone marks), whose regions frequently transition to state 5 or state 8 (marked by high H3K36me3 signal), indicating that these regions are located near active elements (Fig.	('Doxoff', 'Chemical', '-', (39, 45))	('H3K36me3', 'MPA', (225, 233))	('Dox', 'Chemical', 'MESH:D004318', (30, 33))	('Dox', 'Chemical', 'MESH:D004318', (39, 42))	('Dox', 'Chemical', 'MESH:D004318', (53, 56))	('Dox+ IHAs', 'Var', (53, 62))
236294	29180699	These results show dramatic, specific, and dynamic histone mark reorganization in the presence of IDH1 R132H.	('R132H', 'Mutation', 'rs121913500', (103, 108))	('R132H', 'Var', (103, 108))	('IDH1', 'Gene', (98, 102))	('histone mark reorganization', 'MPA', (51, 78))
236296	29180699	Notably, 18,023 of the hypermethylated loci displayed at least 70% methylation in a patient-derived glioma tumorsphere harboring mutation of endogenous IDH1 encoding the R132H mutant (TS603) (P =1x10-6), suggesting methylation gain across similar loci (Supplementary Fig.	('IDH1', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('gain', 'PosReg', (227, 231))	('R132H', 'Var', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma tumorsphere', 'Disease', 'MESH:D005910', (100, 118))	('R132H', 'Mutation', 'rs121913500', (170, 175))	('glioma tumorsphere', 'Disease', (100, 118))	('methylation', 'MPA', (67, 78))	('methylation', 'MPA', (215, 226))	('patient', 'Species', '9606', (84, 91))
236301	29180699	The median beta-value difference (Deltabeta) for persistently methylated loci compared to baseline was a gain of 21% at the end of the doxycycline withdrawal time course (Supplementary Fig.	('beta-value', 'MPA', (11, 21))	('doxycycline', 'Chemical', 'MESH:D004318', (135, 146))	('persistently methylated', 'Var', (49, 72))	('gain', 'PosReg', (105, 109))
236304	29180699	In contrast, persistently hypomethylated loci had low H3K4me3 signal (similar to other clusters) but exhibited increased signal (with low enrichment) for H3K27me3, H3K36me3, and H3K9me3 in Dox- cells (Fig.	('Dox', 'Chemical', 'MESH:D004318', (189, 192))	('low', 'NegReg', (50, 53))	('increased', 'PosReg', (111, 120))	('H3K9me3', 'Var', (178, 185))	('H3K36me3', 'Var', (164, 172))	('H3K27me3', 'Var', (154, 162))	('signal', 'MPA', (121, 127))	('H3K4me3', 'Protein', (54, 61))
236306	29180699	These findings suggest that the small set of genes whose expression continues to be perturbed after withdrawal of IDH1 R132H are likely to be indirectly regulated by mutant IDH and that maintenance of an aberrant chromatin state is not necessary for persistent changes in gene expression.	('expression', 'MPA', (57, 67))	('R132H', 'Mutation', 'rs121913500', (119, 124))	('IDH', 'Gene', '15926', (173, 176))	('IDH', 'Gene', (114, 117))	('IDH', 'Gene', (173, 176))	('regulated by', 'Reg', (153, 165))	('mutant', 'Var', (166, 172))	('IDH', 'Gene', '15926', (114, 117))	('R132H', 'Var', (119, 124))
236310	29180699	9a) and, when TSSs were ranked by H3K4me3 occupancy across both inducible lines, the expression of several genes, including PDGFRA and CD9 with higher H3K4me3 ranking in Dox+ samples, was also upregulated by more than 1.5-fold (Supplementary Table 4).	('expression', 'MPA', (85, 95))	('CD9', 'Gene', (135, 138))	('CD9', 'Gene', '12527', (135, 138))	('PDGFRA', 'Gene', '18595', (124, 130))	('PDGFRA', 'Gene', (124, 130))	('H3K4me3', 'Var', (151, 158))	('Dox', 'Chemical', 'MESH:D004318', (170, 173))	('upregulated', 'PosReg', (193, 204))
236311	29180699	Although most H3K27me3, H3K9me3, and H3K36me3 peaks reverted to baseline levels following doxycycline withdrawal (Supplementary Fig.	('H3K9me3', 'Var', (24, 31))	('doxycycline', 'Chemical', 'MESH:D004318', (90, 101))	('H3K36me3', 'Var', (37, 45))	('H3K27me3', 'Protein', (14, 22))
236312	29180699	9b), a distinct proportion of the sites at which H3K4me3 peaks were gained in Dox+ IHAs maintained their aberrant histone methylation (Supplementary Fig.	('H3K4me3', 'Var', (49, 56))	('Dox', 'Chemical', 'MESH:D004318', (78, 81))	('aberrant histone methylation', 'MPA', (105, 133))
236315	29180699	We derived the 11,443 regions with the most significant H3K4me3 gain in Dox+ IHAs inducibly expressing mutant IDH1 relative to Dox- IHAs (Supplementary Table 6).	('Dox', 'Chemical', 'MESH:D004318', (127, 130))	('mutant', 'Var', (103, 109))	('H3K4me3', 'Protein', (56, 63))	('Dox', 'Chemical', 'MESH:D004318', (72, 75))	('gain', 'PosReg', (64, 68))	('IDH1', 'Gene', (110, 114))
236317	29180699	To further explore IDH1 R132H-specific chromatin alterations associated with H3K4me3, we performed ChIP-seq for H3K4me3 on TS603 and two IDH-wild-type tumorspheres (TS543 and TS667).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('IDH', 'Gene', '15926', (19, 22))	('R132H', 'Mutation', 'rs121913500', (24, 29))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('TS603', 'Var', (123, 128))	('IDH', 'Gene', '15926', (137, 140))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', (137, 140))
236319	29180699	Furthermore, differential enrichment analysis of models with mutant versus wild-type IDH1 identified 1,159 H3K4me3-binding sites that separated cell lines on the basis of IDH1 R132H status, and aberrant H3K4me3 remained at lower enrichment levels in the Doxoff state for these differentially enriched regions (Fig.	('H3K4me3', 'Protein', (203, 210))	('R132H', 'Mutation', 'rs121913500', (176, 181))	('Doxoff', 'Chemical', '-', (254, 260))	('mutant', 'Var', (61, 67))	('H3K4me3-binding', 'Protein', (107, 122))	('aberrant', 'Var', (194, 202))
236320	29180699	GSEA indicated a highly significant positive enrichment of genes within the interferon (IFN)-alpha response pathway gene set in astrocytes with inducible expression of mutant IDH (Fig.	('mutant', 'Var', (168, 174))	('interferon (IFN)-alpha', 'Gene', '111654', (76, 98))	('IDH', 'Gene', '15926', (175, 178))	('interferon (IFN)-alpha', 'Gene', (76, 98))	('IDH', 'Gene', (175, 178))	('GSEA', 'Chemical', '-', (0, 4))
236321	29180699	Given the upregulated interferon response, we considered whether endogenous retroviruses (ERVs) might be reactivated in response to IDH1 R132H expression.	('R132H', 'Mutation', 'rs121913500', (137, 142))	('interferon response', 'MPA', (22, 41))	('upregulated', 'PosReg', (10, 21))	('IDH1 R132H expression', 'Var', (132, 153))
236323	29180699	Therefore, it appears that IDH1 R132H may have a role in upregulating ERVs, which may contribute to genome instability or immune activation.	('upregulating', 'PosReg', (57, 69))	('genome instability', 'MPA', (100, 118))	('ERVs', 'Gene', (70, 74))	('R132H', 'Var', (32, 37))	('IDH1', 'Gene', (27, 31))	('contribute', 'Reg', (86, 96))	('R132H', 'Mutation', 'rs121913500', (32, 37))
236325	29180699	Analysis of copy number alterations using methylation data identified amplifications and deletions of several regions, including a higher frequency of broad deletions of chromosome 19q, in Dox+ IHAs inducibly expressing mutant IDH1 as compared to Dox- IHAs, but not in controls with empty vector (Fig.	('Dox', 'Chemical', 'MESH:D004318', (247, 250))	('Dox', 'Chemical', 'MESH:D004318', (189, 192))	('mutant', 'Var', (220, 226))	('deletions', 'Var', (89, 98))	('IDH1', 'Gene', (227, 231))
236327	29180699	We asked whether mutant-IDH1-associated phenotypes required continued presence of IDH1 R132H.	('R132H', 'Mutation', 'rs121913500', (87, 92))	('R132H', 'Var', (87, 92))	('IDH1', 'Gene', (82, 86))
236328	29180699	Consistent with previous studies, Dox+ IHAs exhibited defective contact inhibition and increased proliferation despite confluence (Fig.	('defective', 'NegReg', (54, 63))	('increased', 'PosReg', (87, 96))	('Dox', 'Chemical', 'MESH:D004318', (34, 37))	('Dox+ IHAs', 'Var', (34, 43))	('contact inhibition', 'CPA', (64, 82))	('proliferation', 'CPA', (97, 110))
236329	29180699	Strikingly, loss of contact inhibition was highly dependent on IDH1 R132H expression in vitro and returned to the normal state within six passages of doxycycline withdrawal, at a faster pace than for epigenetic and transcriptional reversion (Fig.	('R132H', 'Mutation', 'rs121913500', (68, 73))	('contact inhibition', 'MPA', (20, 38))	('loss', 'NegReg', (12, 16))	('doxycycline', 'Chemical', 'MESH:D004318', (150, 161))	('IDH1', 'Gene', (63, 67))	('R132H', 'Var', (68, 73))
236331	29180699	Animals were placed on a doxycycline-containing diet to induce IDH1 R132H expression.	('doxycycline', 'Chemical', 'MESH:D004318', (25, 36))	('IDH1', 'Gene', (63, 67))	('R132H', 'Mutation', 'rs121913500', (68, 73))	('R132H', 'Var', (68, 73))
236338	29180699	Overall, our results indicate that IHAs with IDH1 R132H have a greater potential to infiltrate and form tumors in an orthotopic model; however, tumors continue to grow when IDH1 R132H is removed.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('R132H', 'Mutation', 'rs121913500', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1 R132H', 'Var', (45, 55))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('infiltrate', 'CPA', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('R132H', 'Mutation', 'rs121913500', (50, 55))
236339	29180699	We have assembled an atlas of integrated longitudinal epigenomic and transcriptomic data from IDH1 R132H-expressing glial systems to map a detailed landscape of global remodeling and reversibility associated with IDH1 mutations.	('R132H', 'Mutation', 'rs121913500', (99, 104))	('mutations', 'Var', (218, 227))	('IDH1', 'Gene', (94, 98))	('IDH1', 'Gene', (213, 217))
236340	29180699	Our findings suggest alternate effector pathways associated with IDH mutations that may eventually be decoupled from the neomorphic enzymatic activity of mutant IDH protein.	('mutations', 'Var', (69, 78))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '15926', (161, 164))	('IDH', 'Gene', '15926', (65, 68))	('IDH', 'Gene', (161, 164))
236342	29180699	We identified L1CAM as being persistently upregulated despite long-term loss of mutant IDH1 expression, suggesting that continued L1CAM expression might contribute to the oncogenic phenotype conferred by mutant IDH1.	('L1CAM', 'Gene', '16728', (14, 19))	('loss', 'NegReg', (72, 76))	('L1CAM', 'Gene', '16728', (130, 135))	('mutant', 'Var', (80, 86))	('L1CAM', 'Gene', (130, 135))	('mutant', 'Var', (204, 210))	('upregulated', 'PosReg', (42, 53))	('L1CAM', 'Gene', (14, 19))	('IDH1', 'Gene', (87, 91))	('expression', 'MPA', (92, 102))
236345	29180699	Our results show that, in addition to repressive chromatin marks such as H3K9me3, there is enrichment of activating histone marks (such as H3K4me3) upon expression of mutant IDH1, highlighting the importance of understanding the chromatin landscape in IDH-mutant gliomas.	('IDH', 'Gene', '15926', (252, 255))	('histone marks', 'MPA', (116, 129))	('gliomas', 'Phenotype', 'HP:0009733', (263, 270))	('gliomas', 'Disease', (263, 270))	('IDH', 'Gene', '15926', (174, 177))	('gliomas', 'Disease', 'MESH:D005910', (263, 270))	('IDH', 'Gene', (252, 255))	('mutant', 'Var', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('IDH', 'Gene', (174, 177))	('activating', 'PosReg', (105, 115))
236347	29180699	Our observation that loss of 19q is accelerated in IDH1 R132H-expressing astrocytes suggests that, collectively, deregulation of histone marks and DNA methylation, and possibly activation of ERVs, may lead to genomic instability.	('genomic', 'MPA', (209, 216))	('loss', 'Var', (21, 25))	('accelerated', 'PosReg', (36, 47))	('R132H', 'Mutation', 'rs121913500', (56, 61))	('deregulation', 'MPA', (113, 125))	('DNA methylation', 'MPA', (147, 162))	('histone marks', 'Protein', (129, 142))	('IDH1', 'Gene', (51, 55))	('19q', 'Protein', (29, 32))	('lead to', 'Reg', (201, 208))
236348	29180699	We demonstrate gain in H3K4me3 at the PDGFRA promoter in IDH1 R132H-expressing astrocytes as early as passage 2.	('PDGFRA', 'Gene', (38, 44))	('R132H', 'Mutation', 'rs121913500', (62, 67))	('IDH1', 'Gene', (57, 61))	('R132H-expressing', 'Var', (62, 78))	('gain', 'PosReg', (15, 19))	('H3K4me3', 'Protein', (23, 30))	('PDGFRA', 'Gene', '18595', (38, 44))
236349	29180699	PDGFRA is overexpressed in gliomas, and previous work has shown that IDH mutations disrupt enhancer boundary function, leading to PDGFRA activation.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('PDGFRA', 'Gene', (0, 6))	('IDH', 'Gene', (69, 72))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('disrupt', 'NegReg', (83, 90))	('PDGFRA', 'Gene', '18595', (130, 136))	('PDGFRA', 'Gene', '18595', (0, 6))	('enhancer boundary function', 'MPA', (91, 117))	('PDGFRA', 'Gene', (130, 136))	('activation', 'PosReg', (137, 147))	('IDH', 'Gene', '15926', (69, 72))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('gliomas', 'Disease', (27, 34))	('mutations', 'Var', (73, 82))
236352	29180699	We also identified a CD24+ stem cell-like subpopulation with distinct molecular alterations within IDH-mutant cells.	('CD24+', 'Var', (21, 26))	('IDH', 'Gene', (99, 102))	('IDH', 'Gene', '15926', (99, 102))
236353	29180699	In soft agar assays, we observed the increased potential for colony formation of the CD24+ subpopulation, although further experimental confirmation is needed to establish a direct link between CD24 status and increased clonogenic ability.	('increased', 'PosReg', (210, 219))	('colony formation', 'CPA', (61, 77))	('clonogenic ability', 'CPA', (220, 238))	('increased', 'PosReg', (37, 46))	('agar', 'Chemical', 'MESH:D000362', (8, 12))	('CD24+', 'Var', (85, 90))
236355	29180699	Our findings show that mutant IDH1 inhibition by doxycycline withdrawal leads to a modest decrease in tumor growth in a brain orthotopic model of IDH1 R132H-expressing IHAs.	('doxycycline', 'Chemical', 'MESH:D004318', (49, 60))	('decrease', 'NegReg', (90, 98))	('R132H', 'Mutation', 'rs121913500', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('R132H-expressing', 'Var', (151, 167))	('IDH1', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('inhibition', 'NegReg', (35, 45))	('mutant', 'Var', (23, 29))
236356	29180699	While inhibition of mutant IDH1 is likely to offer benefit, there is a need to identify and target additional pathways to control growth of IDH-mutated tumors.	('IDH', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('IDH', 'Gene', '15926', (27, 30))	('IDH', 'Gene', '15926', (140, 143))	('tumors', 'Disease', (152, 158))	('mutant', 'Var', (20, 26))	('IDH', 'Gene', (140, 143))
236357	29180699	In summary, the integrated data presented here provide new insights into transcriptional and epigenetic dynamics associated with IDH1 mutations in unprecedented detail and may be useful for IDH-related studies and for the development of novel therapies for glioma.	('IDH', 'Gene', '15926', (190, 193))	('IDH', 'Gene', '15926', (129, 132))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('IDH', 'Gene', (190, 193))	('mutations', 'Var', (134, 143))	('IDH', 'Gene', (129, 132))	('glioma', 'Disease', (257, 263))
236361	29180699	Gliomaspheres (TS603, TS543, and TS667) were derived from patients undergoing tumor resection at Memorial Sloan Kettering Cancer Center (MSKCC).	('TS603', 'Var', (15, 20))	('Cancer', 'Disease', (122, 128))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TS667', 'Var', (33, 38))	('tumor', 'Disease', (78, 83))	('patients', 'Species', '9606', (58, 66))
236364	29180699	TS603 is a World Health Organization (WHO) grade III oligodendroglioma line with 1p/19q co-deletion and a mutation in endogenous IDH1 encoding R132H, and TS543 and TS667 are malignant glioma tumorsphere lines and harbor PDGFRA amplifications.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('malignant glioma tumorsphere lines', 'Disease', 'MESH:D005910', (174, 208))	('PDGFRA', 'Gene', '18595', (220, 226))	('PDGFRA', 'Gene', (220, 226))	('R132H', 'Mutation', 'rs121913500', (143, 148))	('IDH1', 'Gene', (129, 133))	('malignant glioma tumorsphere lines', 'Disease', (174, 208))	('TS543', 'Var', (154, 159))	('oligodendroglioma', 'Disease', (53, 70))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('R132H', 'Var', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('oligodendroglioma', 'Disease', 'MESH:D009837', (53, 70))	('TS667', 'Var', (164, 169))
236383	29180699	The probe mix consisted of BAC clones mapping to the following loci: 1p36.32 (RP4-785P20; labeled with Red dUTP), 1q23.3 (RP11-1038N13, RP11-1059C21; labeled with Aqua dUTP), 19p12 (RP11-359H18, CTD-2502P8; labeled with Orange dUTP), and 19q13.3 (CTD-2639E6, RP11-960B2; labeled with Green dUTP).	('RP11-1059C21', 'Var', (136, 148))	('RP11-960B2', 'Var', (259, 269))	('CTD-2639E6', 'Var', (247, 257))	('dUTP', 'Chemical', 'MESH:C027078', (107, 111))	('RP11-1038N13', 'Var', (122, 134))	('RP4-785P20;', 'Var', (78, 89))	('dUTP', 'Chemical', 'MESH:C027078', (290, 294))	('dUTP', 'Chemical', 'MESH:C027078', (168, 172))	('dUTP', 'Chemical', 'MESH:C027078', (227, 231))
236384	29180699	Deltabeta values were calculated by comparing Dox+ to Dox- samples for IHAs with inducible expression of mutant IDH1 at the baseline passage.	('Dox', 'Chemical', 'MESH:D004318', (54, 57))	('mutant', 'Var', (105, 111))	('Dox', 'Chemical', 'MESH:D004318', (46, 49))	('IDH1', 'Gene', (112, 116))
236385	29180699	To identify genes or loci specific to mutant IDH1, we excluded probes with equal or greater fold changes or Deltabeta in Dox+ versus Dox- inducible IHAs with empty vector.	('mutant', 'Var', (38, 44))	('Dox', 'Chemical', 'MESH:D004318', (121, 124))	('Deltabeta', 'MPA', (108, 117))	('IDH1', 'Gene', (45, 49))	('Dox', 'Chemical', 'MESH:D004318', (133, 136))
236386	29180699	First, pathway enrichment of differentially expressed genes in IHAs with inducible expression of mutant IDH1 (Dox+ versus Dox- across all passages) and CIMP+ versus CIMP- LGGs was compared using compareCluster (with the enrichPathway function) in the clusterProfiler R package.	('Dox', 'Chemical', 'MESH:D004318', (122, 125))	('Dox', 'Chemical', 'MESH:D004318', (110, 113))	('CIMP', 'Chemical', '-', (152, 156))	('CIMP+', 'Chemical', '-', (152, 157))	('mutant', 'Var', (97, 103))	('inducible', 'PosReg', (73, 82))	('CIMP', 'Chemical', '-', (165, 169))	('IDH1', 'Gene', (104, 108))
236402	29180699	First, MACS2 bed files were reformatted to HOMER peak file format, and the annotatePeaks script was then applied to determine whether a peak was in a TSS, TTS, exonic (coding), 5' UTR exon, 3' UTR exon, intronic, intergenic, or CpG island region.	('MACS2', 'Gene', (7, 12))	('MACS2', 'Gene', '17357', (7, 12))	('exonic', 'Var', (160, 166))
236436	12271162	For the postprocessing of perfusion MR data, changes in the relaxation rate (DeltaR2) can be calculated from signal intensity using the following equation: DeltaR2= ln (S/S0)/TE, where ln is the natural logarithm, S is signal intensity, and S0 is baseline signal intensity.	('DeltaR2', 'Var', (156, 163))	('DeltaR2', 'DELETION', 'None', (77, 84))	('DeltaR2', 'DELETION', 'None', (156, 163))	('DeltaR2', 'Var', (77, 84))
236437	12271162	Tracer recirculation was reduced by fitting a gamma-variate function to the measured DeltaR2 curve.	('DeltaR2', 'DELETION', 'None', (85, 92))	('DeltaR2', 'Var', (85, 92))	('Tracer recirculation', 'MPA', (0, 20))
236439	12271162	Time-to-peak (TTP) maps were also obtained as gray scale images from the measured DeltaR2 curve on a pixel-by-pixel basis.	('Time-to-peak', 'Gene', (0, 12))	('TTP', 'Gene', (14, 17))	('DeltaR2', 'DELETION', 'None', (82, 89))	('TTP', 'Gene', '7538', (14, 17))	('DeltaR2', 'Var', (82, 89))	('Time-to-peak', 'Gene', '7538', (0, 12))
236508	33348922	The histological characteristics of pediatric high-grade gliomas include hypercellularity, nuclear atypia, abnormally high mitotic activity, and increased angiogenesis and/or necrosis, the latter two associated primarily with GBM morphology.	('abnormally', 'Var', (107, 117))	('necrosis', 'Disease', 'MESH:D009336', (175, 183))	('hypercellularity', 'CPA', (73, 89))	('increased', 'PosReg', (145, 154))	('GBM', 'Phenotype', 'HP:0012174', (226, 229))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('is a', 'Gene', (165, 169))	('of', 'Gene', '6688', (33, 35))	('gliomas', 'Disease', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('nuclear atypia', 'CPA', (91, 105))	('is a', 'Gene', '312', (165, 169))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('necrosis', 'Disease', (175, 183))
236525	33348922	Most notably, the discovery of recurrent mutations in the genes encoding histone variants H3.3 (H3F3A) and H3.1 (HIST1H3B/C) demonstrated the unique biology of pediatric brain tumors (Figure 2).	('of', 'Gene', '6688', (157, 159))	('brain tumors', 'Disease', 'MESH:D001932', (170, 182))	('on', 'Gene', '20692', (47, 49))	('H3.3', 'Gene', (90, 94))	('brain tumors', 'Phenotype', 'HP:0030692', (170, 182))	('brain tumors', 'Disease', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('of', 'Gene', '6688', (28, 30))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('on', 'Gene', '20692', (128, 130))	('on', 'Gene', '20692', (77, 79))	('variants', 'Var', (81, 89))	('1 (HIST1', 'Gene', '3024', (110, 118))
236526	33348922	Three somatic mutations were identified, encoding amino acid substitutions resulting in replacement of lysine with methionine at residue 27 of histones H3.1 and H3.3 (K27M) in brainstem/midline pHGG or in glycine to arginine or valine substitution at residue 34 (G34R/V) of histone H3.3 in hemispheric pHGG.	('on', 'Gene', '20692', (278, 280))	('1 ', 'Gene', '3024', (155, 157))	('K27M', 'Var', (167, 171))	('on', 'Gene', '20692', (71, 73))	('K27M', 'Mutation', 'p.K27M', (167, 171))	('valine', 'Chemical', 'MESH:D014633', (228, 234))	('of', 'Gene', '6688', (271, 273))	('pHGG', 'Chemical', '-', (302, 306))	('on', 'Gene', '20692', (245, 247))	('on', 'Gene', '20692', (20, 22))	('replacement', 'Var', (88, 99))	('of', 'Gene', '6688', (140, 142))	('on', 'Gene', '20692', (147, 149))	('lysine with methionine at residue 27', 'Mutation', 'p.K27M', (103, 139))	('of', 'Gene', '6688', (100, 102))	('G34R', 'SUBSTITUTION', 'None', (263, 267))	('pHGG', 'Chemical', '-', (194, 198))	('G34R', 'Var', (263, 267))	('on', 'Gene', '20692', (120, 122))
236535	33348922	It is now clear that aberrant epigenetic changes play a critical role in almost every step of tumor development and progression, contributing to tumor heterogeneity and evolution, particularly in pediatric cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('on', 'Gene', '20692', (176, 178))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (145, 150))	('on', 'Gene', '20692', (125, 127))	('aberrant epigenetic changes', 'Var', (21, 48))	('of', 'Gene', '6688', (91, 93))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('on', 'Gene', '20692', (130, 132))
236545	33348922	On the other hand, the replacement variant H3.3 is constitutively expressed and is the substrate for replication-independent nucleosome assembly.	('on', 'Gene', '20692', (52, 54))	('on', 'Gene', '20692', (110, 112))	('H3.3', 'Protein', (43, 47))	('replacement', 'Var', (23, 34))
236549	33348922	These substitutions are mainly at the core of the histone protein and are responsive to the binding specificity of the chaperone proteins, which control the differential deposition of the nucleosomes and determine the differential localization patterns of the H3 variants within the genome.	('on', 'Gene', '20692', (54, 56))	('on', 'Gene', '20692', (178, 180))	('on', 'Gene', '20692', (78, 80))	('of', 'Gene', '6688', (181, 183))	(' to ', 'Gene', (84, 88))	('of', 'Gene', '6688', (253, 255))	('on', 'Gene', '20692', (241, 243))	('of', 'Gene', '6688', (43, 45))	('on', 'Gene', '20692', (125, 127))	('on', 'Gene', '20692', (146, 148))	('variants', 'Var', (263, 271))	('of', 'Gene', '6688', (112, 114))	('on', 'Gene', '20692', (16, 18))	(' to ', 'Gene', '6999', (84, 88))
236551	33348922	Other H3 histones are expressed in a tissue specific manner (H3.5, H3.X, and H3.Y), and CENP-A is a histone of the H3 family that is deposited only at centromeres.	('on', 'Gene', '20692', (143, 145))	('on', 'Gene', '20692', (13, 15))	('of', 'Gene', '6688', (108, 110))	('is a', 'Gene', (95, 99))	('on', 'Gene', '20692', (104, 106))	('is a', 'Gene', '312', (95, 99))	('H3.Y', 'Var', (77, 81))
236557	33348922	Tumors harboring the H3.3 G34R/V mutations are confined to the cerebral hemispheres, most commonly to the parietal and temporal lobes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('on', 'Gene', '20692', (39, 41))	(' to ', 'Gene', '6999', (98, 102))	('on', 'Gene', '20692', (48, 50))	(' to ', 'Gene', (98, 102))	(' to ', 'Gene', '6999', (55, 59))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('on', 'Gene', '20692', (94, 96))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('G34R', 'SUBSTITUTION', 'None', (26, 30))	(' to ', 'Gene', (55, 59))	('H3.3', 'Gene', (21, 25))	('G34R', 'Var', (26, 30))
236558	33348922	Patients with G34R/V mutant tumors represent an older cohort of pHGG, with a median age of 15 years and overall median overall survival of 18 months, with 2-year survival of 27.3%.	('G34R', 'SUBSTITUTION', 'None', (14, 18))	('of', 'Gene', '6688', (171, 173))	('on', 'Gene', '20692', (143, 145))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('G34R', 'Var', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('Patients', 'Species', '9606', (0, 8))	('of', 'Gene', '6688', (61, 63))	('pHGG', 'Chemical', '-', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('of', 'Gene', '6688', (88, 90))	('of', 'Gene', '6688', (136, 138))
236559	33348922	The G34R/V mutation defines a molecular subgroup of pHGG associated with loss of function mutations in tumor suppressor protein 53 (TP53) and mutations in ATRX or DAXX.	('of', 'Gene', '6688', (78, 80))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('G34R', 'SUBSTITUTION', 'None', (4, 8))	('on', 'Gene', '20692', (17, 19))	('G34R', 'Var', (4, 8))	('DAXX', 'Gene', '1616', (163, 167))	('pHGG', 'Disease', (52, 56))	('tumor', 'Disease', (103, 108))	('pHGG', 'Chemical', '-', (52, 56))	('on', 'Gene', '20692', (148, 150))	('on', 'Gene', '20692', (96, 98))	('ATRX', 'Gene', (155, 159))	('of', 'Gene', '6688', (49, 51))	('on', 'Gene', '20692', (87, 89))	('DAXX', 'Gene', (163, 167))	('53 (TP53', 'Gene', '7157', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
236561	33348922	The loss of function of ATRX and, less frequently, DAXX impairs telomeric stability and results in telomerase-independent maintenance through alternative lengthening of telomeres (ALT) in H3.3G34R/V mutant tumor cells.	('G34R/V', 'Mutation', 'rs763410206', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('of', 'Gene', '6688', (21, 23))	('telomerase-independent maintenance', 'MPA', (99, 133))	('results in', 'Reg', (88, 98))	('DAXX', 'Gene', '1616', (51, 55))	('DAXX', 'Gene', (51, 55))	('tumor', 'Disease', (206, 211))	('ATRX', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('H3.3G34R/V mutant', 'Var', (188, 205))	('on', 'Gene', '20692', (18, 20))	('of', 'Gene', '6688', (166, 168))	('impairs', 'NegReg', (56, 63))	('of', 'Gene', '6688', (9, 11))	('mutant', 'Var', (199, 205))	('telomeric', 'MPA', (64, 73))
236562	33348922	The ALT phenotype of G34R/V is strongly correlated to the loss of TP53/ATRX/DAXX; however, the role of TP53 in this process is not yet clear.	('loss', 'NegReg', (58, 62))	('on', 'Gene', '20692', (34, 36))	('G34R', 'Var', (21, 25))	('of', 'Gene', '6688', (100, 102))	('of', 'Gene', '6688', (18, 20))	('of', 'Gene', '6688', (63, 65))	(' to ', 'Gene', '6999', (50, 54))	('ALT', 'Disease', (4, 7))	('G34R', 'SUBSTITUTION', 'None', (21, 25))	(' to ', 'Gene', (50, 54))
236564	33348922	Although the G34R/V mutant residue is not posttranslationally modified itself, the mutant histone alters epigenetic regulation of the lysine residue at position 36 (H3F3A-K36).	('G34R', 'Var', (13, 17))	('on', 'Gene', '20692', (158, 160))	('of', 'Gene', '6688', (127, 129))	('mutant', 'Var', (83, 89))	('alters', 'Reg', (98, 104))	('on', 'Gene', '20692', (94, 96))	('on', 'Gene', '20692', (55, 57))	('lysine', 'Chemical', 'MESH:D008239', (134, 140))	('on', 'Gene', '20692', (124, 126))	('G34R', 'SUBSTITUTION', 'None', (13, 17))
236565	33348922	The K36 position can be methylated (K36me1/2/3) or acetylated (K36Ac), and trimethylation (me3) is a mark of transcriptional activation and is also implicated in alternative splicing and DNA repair mechanisms.	('K36me1/2/3', 'Var', (36, 46))	('is a', 'Gene', '312', (96, 100))	('on', 'Gene', '20692', (133, 135))	('is a', 'Gene', '312', (140, 144))	('of', 'Gene', '6688', (106, 108))	('K36Ac', 'Chemical', '-', (63, 68))	('on', 'Gene', '20692', (14, 16))	('on', 'Gene', '20692', (87, 89))	('is a', 'Gene', (140, 144))	('is a', 'Gene', (96, 100))	('on', 'Gene', '20692', (120, 122))
236566	33348922	H3.3 G34R/V mutant tumors display a global DNA hypomethylation phenotype but have differential distribution of H3K36me3 with distinct gene targets involved in cortical development and stemness.	('tumors', 'Disease', (19, 25))	('on', 'Gene', '20692', (60, 62))	('on', 'Gene', '20692', (105, 107))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('of', 'Gene', '6688', (108, 110))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutant', 'Var', (12, 18))	('K36me3', 'Chemical', '-', (113, 119))	('G34R', 'SUBSTITUTION', 'None', (5, 9))	('G34R', 'Var', (5, 9))	('H3.3', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('H3K36me3', 'Protein', (111, 119))
236567	33348922	Notably, oncogene MYCN was found to be significantly upregulated by increased distribution of H3K36me3 in H3.3 G34R/V tumors.	('on', 'Gene', '20692', (9, 11))	('H3K36me3', 'Protein', (94, 102))	(' to ', 'Gene', (32, 36))	('upregulated', 'PosReg', (53, 64))	('on', 'Gene', '20692', (88, 90))	('MYCN', 'Gene', (18, 22))	('G34R', 'SUBSTITUTION', 'None', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('G34R', 'Var', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('K36me3', 'Chemical', '-', (96, 102))	('of', 'Gene', '6688', (91, 93))	('tumors', 'Disease', (118, 124))	(' to ', 'Gene', '6999', (32, 36))	('increased', 'PosReg', (68, 77))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
236568	33348922	DNA methylation profiling has also revealed that H3.3 G34R/V is the only histone mutant subgroup of pHGG to display significantly elevated methylation levels at the promoter of O-6-Methylguanine-DNA Methyltransferase (MGMT), a DNA repair enzyme.	('on', 'Gene', '20692', (68, 70))	('of', 'Gene', '6688', (174, 176))	('on', 'Gene', '20692', (148, 150))	('on', 'Gene', '20692', (13, 15))	('-Methylguanine-DNA Methyltransferase (MGMT', 'Gene', (180, 222))	('of', 'Gene', '6688', (18, 20))	('elevated', 'PosReg', (130, 138))	('of', 'Gene', '6688', (97, 99))	('-Methylguanine-DNA Methyltransferase (MGMT)', 'Gene', '4255', (180, 223))	('G34R', 'SUBSTITUTION', 'None', (54, 58))	('G34R', 'Var', (54, 58))	('on', 'Gene', '20692', (77, 79))
236570	33348922	The first molecular studies revealed that K36 trimethylation is affected when a mutant G34 is expressed.	('mutant', 'Var', (80, 86))	('G34', 'Gene', (87, 90))	('on', 'Gene', '20692', (58, 60))	('is a', 'Gene', (61, 65))	('is a', 'Gene', '312', (61, 65))
236571	33348922	Nonetheless, K36 trimethylation is only decreased on the G34 mutant histone protein itself, with no consequences on K36me3 distribution at the wild type histone.	('on', 'Gene', '20692', (1, 3))	('on', 'Gene', '20692', (113, 115))	('on', 'Gene', '20692', (133, 135))	('G34', 'Var', (57, 60))	('on', 'Gene', '20692', (157, 159))	('K36me3', 'Chemical', '-', (116, 122))	('on', 'Gene', '20692', (35, 37))	('on', 'Gene', '20692', (72, 74))	('on', 'Gene', '20692', (29, 31))	('on', 'Gene', '20692', (101, 103))	('decreased', 'NegReg', (40, 49))	('on', 'Gene', '20692', (50, 52))
236580	33348922	This would explain why the G34 mutated histone itself has lower levels of K36me3.	('K36me3', 'MPA', (74, 80))	('lower', 'NegReg', (58, 63))	('K36me3', 'Chemical', '-', (74, 80))	('G34 mutated', 'Var', (27, 38))	('of', 'Gene', '6688', (71, 73))	('on', 'Gene', '20692', (43, 45))
236582	33348922	One of the consequences of the expression of H3.3G34R/V is the gain in H3K36me3 at specific loci.	('K36me3', 'Chemical', '-', (73, 79))	('G34R/V', 'Mutation', 'rs763410206', (49, 55))	('of', 'Gene', '6688', (42, 44))	('gain', 'PosReg', (63, 67))	('of', 'Gene', '6688', (4, 6))	('of', 'Gene', '6688', (24, 26))	('H3K36me3', 'Protein', (71, 79))	('on', 'Gene', '20692', (39, 41))	('H3.3G34R/V', 'Var', (45, 55))	('on', 'Gene', '20692', (12, 14))
236583	33348922	A recent study suggests that the increase in K36me3 is due to inhibition of KDM4 demethylases by the mutant histone.	('on', 'Gene', '20692', (112, 114))	('KDM4 demethylases', 'Enzyme', (76, 93))	('K36me3', 'MPA', (45, 51))	('increase', 'PosReg', (33, 41))	('mutant', 'Var', (101, 107))	(' to ', 'Gene', '6999', (58, 62))	('on', 'Gene', '20692', (70, 72))	('K36me3', 'Chemical', '-', (45, 51))	('of', 'Gene', '6688', (73, 75))	(' to ', 'Gene', (58, 62))
236584	33348922	H3.3G34R sequesters KDM4, inhibiting its activity, and consequently, the expression of G34R causes an abnormal accumulation of K36me3 and of H3K9me3, marks that are normally removed by KDM4.	('G34R', 'Mutation', 'rs1445093587', (4, 8))	('inhibiting', 'NegReg', (26, 36))	('G34R', 'Mutation', 'rs1445093587', (87, 91))	('G34R', 'Var', (87, 91))	('on', 'Gene', '20692', (56, 58))	('H3K9me3', 'Protein', (141, 148))	('on', 'Gene', '20692', (121, 123))	('of', 'Gene', '6688', (138, 140))	('of', 'Gene', '6688', (124, 126))	('K36me3', 'Chemical', '-', (127, 133))	('of', 'Gene', '6688', (84, 86))	('K36me3', 'Protein', (127, 133))	('activity', 'MPA', (41, 49))	('on', 'Gene', '20692', (81, 83))
236586	33348922	This model, firstly, predicts a reduction of the global KDM4 activity and, secondly, may imply that the local downregulation of K36me3 can be a consequence of the inability of SETD2 to interact with the mutant histone that is strongly bound to KDM4.	('of', 'Gene', '6688', (42, 44))	(' to ', 'Gene', '6999', (240, 244))	('KDM4', 'Enzyme', (56, 60))	(' to ', 'Gene', (240, 244))	('on', 'Gene', '20692', (214, 216))	('on', 'Gene', '20692', (39, 41))	('K36me3', 'MPA', (128, 134))	('on', 'Gene', '20692', (229, 231))	('K36me3', 'Chemical', '-', (128, 134))	('on', 'Gene', '20692', (78, 80))	(' to ', 'Gene', '6999', (181, 185))	(' to ', 'Gene', (181, 185))	('of', 'Gene', '6688', (125, 127))	('of', 'Gene', '6688', (173, 175))	('activity', 'MPA', (61, 69))	('mutant', 'Var', (203, 209))	('inability', 'NegReg', (163, 172))	('on', 'Gene', '20692', (122, 124))	('on', 'Gene', '20692', (145, 147))	('of', 'Gene', '6688', (156, 158))
236587	33348922	H3K36 methylation has been shown to antagonize with H3K27me3.	('on', 'Gene', '20692', (15, 17))	(' to ', 'Gene', (32, 36))	('H3K36', 'Protein', (0, 5))	('on', 'Gene', '20692', (41, 43))	(' to ', 'Gene', '6999', (32, 36))	('H3K27me3', 'Var', (52, 60))
236588	33348922	This phenomenon is associated with the inhibition of interaction of the K27 trimethylating complex PCR2 with H3 when the histone is marked with K36 trimethylation.	('K36', 'Var', (144, 147))	('on', 'Gene', '20692', (47, 49))	('of', 'Gene', '6688', (65, 67))	('on', 'Gene', '20692', (13, 15))	('on', 'Gene', '20692', (62, 64))	('is a', 'Gene', (16, 20))	('on', 'Gene', '20692', (125, 127))	('is a', 'Gene', '312', (16, 20))	('of', 'Gene', '6688', (50, 52))	('on', 'Gene', '20692', (160, 162))
236591	33348922	The results suggest that a global loss of K36me2/3 caused by the K36M mutation allows for spread of K27me3 by means of the activity of PCR2 in nucleosomes containing H3 K36me1 or non-methylated in K36.	('1 ', 'Gene', '3024', (174, 176))	('activity', 'MPA', (123, 131))	('K36me2/3', 'Protein', (42, 50))	('of', 'Gene', '6688', (97, 99))	('of', 'Gene', '6688', (39, 41))	('on', 'Gene', '20692', (76, 78))	('K36M', 'Mutation', 'p.K36M', (65, 69))	('K36M', 'Var', (65, 69))	('of', 'Gene', '6688', (132, 134))	('on', 'Gene', '20692', (180, 182))	('loss', 'NegReg', (34, 38))	('K27me3', 'Var', (100, 106))	('K36me2', 'Chemical', '-', (42, 48))	('of', 'Gene', '6688', (116, 118))	('on', 'Gene', '20692', (156, 158))
236593	33348922	H3.3G34R mutations not only affect the distribution of histone marks but also were demonstrated to interfere with the interaction of the histone tail with proteins that recognize K36 marks.	('affect', 'Reg', (28, 34))	('on', 'Gene', '20692', (15, 17))	('proteins', 'Protein', (155, 163))	('G34R', 'Mutation', 'rs1445093587', (4, 8))	(' to ', 'Gene', '6999', (95, 99))	('H3.3G34R', 'Gene', (0, 8))	('on', 'Gene', '20692', (23, 25))	('on', 'Gene', '20692', (127, 129))	('of', 'Gene', '6688', (52, 54))	('on', 'Gene', '20692', (59, 61))	(' to ', 'Gene', (95, 99))	('on', 'Gene', '20692', (141, 143))	('on', 'Gene', '20692', (49, 51))	('on', 'Gene', '20692', (86, 88))	('of', 'Gene', '6688', (130, 132))	('K36', 'Var', (179, 182))
236594	33348922	For example, the mismatch repair (MMR) protein MutSalpha, which in normal conditions recognizes specifically K36me3 in replicating chromatin to prime mismatch repair, is inhibited by G34 mutations.	(' to ', 'Gene', '6999', (140, 144))	('K36me3', 'Chemical', '-', (109, 115))	('mismatch repair', 'MPA', (150, 165))	(' to ', 'Gene', (140, 144))	('K36me3', 'Var', (109, 115))	('on', 'Gene', '20692', (193, 195))	('on', 'Gene', '20692', (81, 83))	('on', 'Gene', '20692', (75, 77))	('inhibited', 'NegReg', (170, 179))
236604	33348922	In this context, it was observed that H3F3A-G34R expression leads to an accumulation of K36me2 and a reduction of K36me3 and K36Ac levels.	('H3F3A-G34R', 'Var', (38, 48))	('on', 'Gene', '20692', (9, 11))	('on', 'Gene', '20692', (82, 84))	('K36me3', 'Chemical', '-', (114, 120))	('K36me2', 'Chemical', '-', (88, 94))	('K36me2', 'MPA', (88, 94))	('K36Ac levels', 'MPA', (125, 137))	(' to ', 'Gene', '6999', (65, 69))	('on', 'Gene', '20692', (108, 110))	('of', 'Gene', '6688', (111, 113))	('K36Ac', 'Chemical', '-', (125, 130))	(' to ', 'Gene', (65, 69))	('G34R', 'Mutation', 'rs1445093587', (44, 48))	('K36me3', 'MPA', (114, 120))	('on', 'Gene', '20692', (57, 59))	('of', 'Gene', '6688', (85, 87))
236607	33348922	G34R-mutated yeast were also more sensitive to compounds that affect DNA replication or induce DNA damage on DNA-replicating cells but not general DNA damage.	('affect', 'Reg', (62, 68))	('more', 'PosReg', (29, 33))	(' to ', 'Gene', '6999', (43, 47))	('on', 'Gene', '20692', (82, 84))	('DNA', 'MPA', (95, 98))	('G34R', 'Mutation', 'rs1445093587', (0, 4))	(' to ', 'Gene', (43, 47))	('G34R-mutated', 'Var', (0, 12))	('yeast', 'Species', '4932', (13, 18))	('on', 'Gene', '20692', (106, 108))	('DNA', 'MPA', (69, 72))
236608	33348922	The authors demonstrated that these results are linked to a defect of G34R mutant yeast to repair via the homologous recombination (HR) pathway.	(' to ', 'Gene', '6999', (54, 58))	(' to ', 'Gene', (54, 58))	('on', 'Gene', '20692', (15, 17))	('G34R mutant', 'Var', (70, 81))	('G34R', 'Mutation', 'rs1445093587', (70, 74))	(' to ', 'Gene', '6999', (87, 91))	(' to ', 'Gene', (87, 91))	('on', 'Gene', '20692', (128, 130))	('of', 'Gene', '6688', (67, 69))	('defect', 'NegReg', (60, 66))
236609	33348922	Remarkably, these defects were not observed in SET2 defective yeast, indicating that the decrease of K36me3 is not sufficient to account for the effects of G34R expression in yeast.	('of', 'Gene', '6688', (98, 100))	('K36me3', 'MPA', (101, 107))	('K36me3', 'Chemical', '-', (101, 107))	(' to ', 'Gene', '6999', (125, 129))	('decrease', 'NegReg', (89, 97))	('yeast', 'Species', '4932', (175, 180))	('G34R', 'Mutation', 'rs1445093587', (156, 160))	('of', 'Gene', '6688', (153, 155))	('yeast', 'Species', '4932', (62, 67))	('G34R', 'Var', (156, 160))	(' to ', 'Gene', (125, 129))	('on', 'Gene', '20692', (169, 171))
236611	33348922	Noteworthily, the differences on DNA repair responses between G34R mutant and SETD2-deffective non-brainstem (NBS) pHGGs indicate that each oncogenic lesion impacts other epigenetic mechanisms apart from the evident effect on H3K36me3.	('NBS', 'Disease', 'MESH:D049932', (110, 113))	('NBS', 'Disease', (110, 113))	('G34R', 'Mutation', 'rs1445093587', (62, 66))	('on', 'Gene', '20692', (154, 156))	('on', 'Gene', '20692', (140, 142))	('on', 'Gene', '20692', (223, 225))	('on', 'Gene', '20692', (48, 50))	('pHGG', 'Chemical', '-', (115, 119))	('on', 'Gene', '20692', (96, 98))	('oncogenic lesion impacts', 'Disease', 'MESH:D000074723', (140, 164))	('oncogenic lesion impacts', 'Disease', (140, 164))	('SETD2-deffective', 'Gene', (78, 94))	('epigenetic mechanisms', 'MPA', (171, 192))	('on', 'Gene', '20692', (30, 32))	('G34R mutant', 'Var', (62, 73))	('K36me3', 'Chemical', '-', (228, 234))
236617	33348922	This makes SETD2 knockout cells more resistant to DNA damage.	(' to ', 'Gene', (46, 50))	('knockout', 'Var', (17, 25))	('more', 'PosReg', (32, 36))	('SETD2', 'Gene', (11, 16))	(' to ', 'Gene', '6999', (46, 50))
236618	33348922	Another study confirms that G34R/V mutations themselves have a similar effect on MMR pHGG cells.	('on', 'Gene', '20692', (15, 17))	('on', 'Gene', '20692', (78, 80))	('G34R', 'SUBSTITUTION', 'None', (28, 32))	('G34R', 'Var', (28, 32))	('MMR pHGG cells', 'CPA', (81, 95))	('on', 'Gene', '20692', (41, 43))	('pHGG', 'Chemical', '-', (85, 89))
236619	33348922	This work demonstrates that G34R/V-mutated H3F3A interacts deficiently with the hMutSalpha complex, likely as a consequence of a decrease in K36me3 in the histone.	('on', 'Gene', '20692', (113, 115))	('interacts', 'Interaction', (49, 58))	('H3F3A', 'Gene', (43, 48))	('G34R', 'SUBSTITUTION', 'None', (28, 32))	('decrease', 'NegReg', (129, 137))	('on', 'Gene', '20692', (13, 15))	('G34R', 'Var', (28, 32))	('of', 'Gene', '6688', (124, 126))	('K36me3', 'MPA', (141, 147))	('on', 'Gene', '20692', (159, 161))	('deficiently', 'NegReg', (59, 70))	('K36me3', 'Chemical', '-', (141, 147))
236620	33348922	pHGG cells genetically engineered to express ectopically H3F3A-G34R exhibited increased mutation compared with isogenic H3F3A controls and the same trend on pHGG patient sample data.	('pHGG', 'Chemical', '-', (157, 161))	('ectopically H3F3A-G34R', 'Var', (45, 67))	(' to ', 'Gene', (33, 37))	('on', 'Gene', '20692', (154, 156))	('on', 'Gene', '20692', (127, 129))	('G34R', 'Mutation', 'rs1445093587', (63, 67))	('on', 'Gene', '20692', (94, 96))	('increased', 'PosReg', (78, 87))	('patient', 'Species', '9606', (162, 169))	(' to ', 'Gene', '6999', (33, 37))	('pHGG', 'Chemical', '-', (0, 4))
236624	33348922	Of note, the promoter of the MGMT (O-6-Methylguanine-DNA Methyltransferase) gene, which codes for an enzyme involved in DNA repair, is significantly increased in G34R tumors when compared with other hemispheric pHGGs, which may result in decreased MGMT expression and increased sensitivity to temozolomide, a DNA alkylating agent.	('MGMT', 'Gene', '4255', (248, 252))	('MGMT', 'Gene', (248, 252))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('increased', 'PosReg', (149, 158))	('sensitivity', 'MPA', (278, 289))	('MGMT', 'Gene', '4255', (29, 33))	('G34R', 'Mutation', 'rs1445093587', (162, 166))	('MGMT', 'Gene', (29, 33))	('on', 'Gene', '20692', (261, 263))	('G34R', 'Var', (162, 166))	('pHGG', 'Chemical', '-', (211, 215))	('Of', 'Gene', '6688', (0, 2))	('decreased', 'NegReg', (238, 247))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('of', 'Gene', '6688', (22, 24))	('promoter', 'MPA', (13, 21))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
236627	33348922	Inactivating mutations in the chromatin remodeler ATRX are found in hemispheric pHGG, showing close association with H3F3A-G34R/V mutations and being present within the IDH and the histone Wt epigenetic subtypes.	('on', 'Gene', '20692', (136, 138))	('on', 'Gene', '20692', (185, 187))	('pHGG', 'Chemical', '-', (80, 84))	('hemispheric pHGG', 'Disease', (68, 84))	('ATRX', 'Gene', (50, 54))	('G34R', 'SUBSTITUTION', 'None', (123, 127))	('on', 'Gene', '20692', (19, 21))	('G34R', 'Var', (123, 127))	('on', 'Gene', '20692', (109, 111))
236646	33348922	These functions are disrupted in loss-of-function mutants, which act as key drivers of gliomagenesis.	('glioma', 'Disease', (87, 93))	('on', 'Gene', '20692', (47, 49))	('of', 'Gene', '6688', (38, 40))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('of', 'Gene', '6688', (84, 86))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('mutants', 'Var', (50, 57))	('on', 'Gene', '20692', (12, 14))
236647	33348922	In vitro GBM cells with inactivated-mutant p53 were less susceptible to inhibitors targeting DNA repair, highlighting the mutant phenotype's ability to accumulate mutations at a faster rate and to promote tumor growth.	('inactivated-mutant', 'Var', (24, 42))	(' to ', 'Gene', '6999', (68, 72))	('GBM', 'Phenotype', 'HP:0012174', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	(' to ', 'Gene', (68, 72))	('mutant', 'Var', (122, 128))	(' to ', 'Gene', '6999', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('p53', 'Gene', (43, 46))	('on', 'Gene', '20692', (169, 171))	(' to ', 'Gene', (148, 152))	(' to ', 'Gene', (193, 197))	(' to ', 'Gene', '6999', (193, 197))
236652	33348922	Mutant P53 also often acts cooperatively with loss of PTEN (Phosphatase and tensin homolog), significantly increasing proliferation speed in double-mutant murine cell lines.	('on', 'Gene', '20692', (129, 131))	('of', 'Gene', '6688', (16, 18))	('loss of PTEN', 'Disease', 'MESH:D006223', (46, 58))	('of', 'Gene', '6688', (51, 53))	('P53', 'Gene', (7, 10))	('increasing', 'PosReg', (107, 117))	('loss of PTEN', 'Disease', (46, 58))	('Mutant', 'Var', (0, 6))	('murine', 'Species', '10090', (155, 161))
236666	33348922	In some contexts, P53 can also activate genes that are associated with apoptosis induction.	('on', 'Gene', '20692', (9, 11))	('on', 'Gene', '20692', (88, 90))	('activate', 'PosReg', (31, 39))	('genes', 'Gene', (40, 45))	('P53', 'Var', (18, 21))
236668	33348922	P53 entering into the mitochondria can also affect inner membrane potential, causing a halt in ATP production and resulting in necrosis.	('P53', 'Var', (0, 3))	('inner membrane potential', 'MPA', (51, 75))	('necrosis', 'Disease', 'MESH:D009336', (127, 135))	('halt', 'NegReg', (87, 91))	('on', 'Gene', '20692', (107, 109))	('on', 'Gene', '20692', (28, 30))	('affect', 'Reg', (44, 50))	('necrosis', 'Disease', (127, 135))	('ATP', 'Chemical', 'MESH:D000255', (95, 98))
236676	33348922	This effect was first evidenced by the fact that the expression of mutated-P53 increased tumorigenic potential.	('of', 'Gene', '6688', (64, 66))	('increased', 'PosReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutated-P53', 'Var', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('on', 'Gene', '20692', (61, 63))
236678	33348922	Recent research describes that some P53-dominant GOF induces the formation of oligomer aggregates between mutated and Wt TP53, exerting a prion-like dominant inactivating effect over the Wt p53 protein.	('on', 'Gene', '20692', (141, 143))	('oligomer aggregates', 'MPA', (78, 97))	('on', 'Gene', '20692', (72, 74))	('prion', 'Species', '36469', (138, 143))	('P53-dominant', 'Gene', (36, 48))	('of', 'Gene', '6688', (75, 77))	('mutated', 'Var', (106, 113))	('induces', 'Reg', (53, 60))
236681	33348922	The role of GOF P53 mutations in pHGG is currently understudied, and it is clear that new therapeutic opportunities will arise when we gain better insight into the consequences of mutant P53 expression in the pHGG context.	('on', 'Gene', '20692', (215, 217))	('on', 'Gene', '20692', (26, 28))	('on', 'Gene', '20692', (199, 201))	('mutant', 'Var', (180, 186))	('on', 'Gene', '20692', (165, 167))	('pHGG', 'Chemical', '-', (33, 37))	('of', 'Gene', '6688', (177, 179))	('P53', 'Gene', (187, 190))	('of', 'Gene', '6688', (9, 11))	('pHGG', 'Chemical', '-', (209, 213))
236687	33348922	PDGFRA mutation is significantly associated with TP53 (>70%), ATRX (>60%), and H3F3A G34R/V (>40%) mutations, exhibiting association with the G34 epigenetic subtype.	('G34R', 'Var', (85, 89))	('ATRX', 'Disease', (62, 66))	('on', 'Gene', '20692', (105, 107))	('on', 'Gene', '20692', (13, 15))	('H3F3A', 'Gene', (79, 84))	('PDGFR', 'Gene', (0, 5))	('associated', 'Reg', (33, 43))	('TP53', 'Disease', (49, 53))	('PDGFR', 'Gene', '5159', (0, 5))	('on', 'Gene', '20692', (130, 132))	('G34R', 'SUBSTITUTION', 'None', (85, 89))
236688	33348922	PDGFRA amplifications show the same trend, being more associated with P53 (approximately 61%) and H3F3A G34R/V (approximately 57%) mutations than to ATRX (approximately 38%).	(' to ', 'Gene', (145, 149))	('G34R', 'SUBSTITUTION', 'None', (104, 108))	('H3F3A', 'Gene', (98, 103))	('on', 'Gene', '20692', (137, 139))	('G34R', 'Var', (104, 108))	('PDGFR', 'Gene', (0, 5))	('on', 'Gene', '20692', (18, 20))	('PDGFR', 'Gene', '5159', (0, 5))	(' to ', 'Gene', '6999', (145, 149))	('P53', 'Gene', (70, 73))	('associated', 'Reg', (54, 64))
236703	33348922	Nevertheless, overactivation of the Akt pathway by other mechanisms (such as PTEN epigenetic silencing) is more frequent in pHGG and was associated with poorer prognosis.	('on', 'Gene', '20692', (26, 28))	('pHGG', 'Disease', (124, 128))	('pHGG', 'Chemical', '-', (124, 128))	('Akt pathway', 'Pathway', (36, 47))	('PTEN', 'Gene', (77, 81))	('of', 'Gene', '6688', (29, 31))	('epigenetic silencing', 'Var', (82, 102))
236714	33348922	BRAF (v-raf murine sarcoma viral oncogene homolog B1 gene/protein) Raf kinase-activating mutations occur in approximately 9% of NBS pHGGs, being the most commonly observed mutation BRAF V600E.	('BRAF', 'Var', (181, 185))	('raf', 'Gene', '22882', (8, 11))	('on', 'Gene', '20692', (158, 160))	('NBS pHGGs', 'Disease', 'MESH:D049932', (128, 137))	('on', 'Gene', '20692', (178, 180))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('murine', 'Species', '10090', (12, 18))	('raf', 'Gene', (8, 11))	('1 ', 'Gene', '3024', (51, 53))	('of', 'Gene', '6688', (125, 127))	('V600E', 'Var', (186, 191))	('V600E', 'Mutation', 'p.V600E', (186, 191))	('sarcoma', 'Disease', (19, 26))	('on', 'Gene', '20692', (33, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('NBS pHGGs', 'Disease', (128, 137))	('on', 'Gene', '20692', (95, 97))
236716	33348922	The kinase activity of BRAF V600E is significantly increased and activates ERK activity independently of RAS signaling.	('activity', 'MPA', (79, 87))	('V600E', 'Mutation', 'p.V600E', (28, 33))	('of', 'Gene', '6688', (20, 22))	('of', 'Gene', '6688', (102, 104))	('increased', 'PosReg', (51, 60))	('ERK', 'Pathway', (75, 78))	('kinase activity', 'MPA', (4, 19))	('activates', 'PosReg', (65, 74))	('BRAF V600E', 'Var', (23, 33))
236722	33348922	Individuals with NF1 have an increased risk for developing central nervous system neoplasm, and although the most common brain tumors associated with NF1 are low-grade glioma, pHGG can also emerge.	('developing', 'PosReg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('nervous system neoplasm', 'Phenotype', 'HP:0004375', (67, 90))	('brain tumors', 'Disease', (121, 133))	('brain tumors', 'Phenotype', 'HP:0030692', (121, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('central nervous system neoplasm', 'Disease', (59, 90))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('central nervous system neoplasm', 'Phenotype', 'HP:0100006', (59, 90))	('central nervous system neoplasm', 'Disease', 'MESH:D016543', (59, 90))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('pHGG', 'Chemical', '-', (176, 180))	('NF1', 'Var', (150, 153))	('on', 'Gene', '20692', (118, 120))	('glioma', 'Disease', (168, 174))	('NF1', 'Var', (17, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (82, 90))	('brain tumors', 'Disease', 'MESH:D001932', (121, 133))
236724	33348922	Loss of NF1 leads to activation of the MEK-ERK and PI3K-Alt-mTOR pathways, and for this reason, NF1 can be considered a tumor suppressor.	('NF1', 'Gene', (8, 11))	('on', 'Gene', '20692', (92, 94))	(' to ', 'Gene', '6999', (17, 21))	(' to ', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('on', 'Gene', '20692', (108, 110))	('on', 'Gene', '20692', (29, 31))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PI3K-Alt-mTOR pathways', 'Pathway', (51, 73))	('Loss', 'Var', (0, 4))	('of', 'Gene', '6688', (32, 34))	('tumor', 'Disease', (120, 125))	('of', 'Gene', '6688', (5, 7))
236726	33348922	Interestingly, NF1 loss shows little association with H3F3A-G34R/V mutations.	('NF1', 'Gene', (15, 18))	('loss', 'NegReg', (19, 23))	('on', 'Gene', '20692', (73, 75))	('G34R', 'SUBSTITUTION', 'None', (60, 64))	('G34R', 'Var', (60, 64))	('on', 'Gene', '20692', (46, 48))
236728	33348922	NTRK gene expression is normally silenced in neuronal lineages and in pHGG cells, and NTRK rearrangements result in fusions with genes actively transcribed in pHGG cells, such as neurofascin (NFASC) and brevican (BCAN) for NTRK1.	('NF', 'Gene', '23114', (192, 194))	('NTRK', 'Gene', (86, 90))	('brevican', 'Gene', '63827', (203, 211))	('NTRK1', 'Gene', (223, 228))	('pHGG', 'Chemical', '-', (70, 74))	('on', 'Gene', '20692', (49, 51))	('result in', 'Reg', (106, 115))	('of', 'Gene', '6688', (183, 185))	('pHGG', 'Chemical', '-', (159, 163))	('on', 'Gene', '20692', (18, 20))	('NTRK', 'Gene', (0, 4))	('rearrangements', 'Var', (91, 105))	('brevican', 'Gene', (203, 211))	('on', 'Gene', '20692', (120, 122))
236735	33348922	Tkr rearrangements play important roles in oncogenesis in various types of tumors, including pHGG.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('on', 'Gene', '20692', (43, 45))	('rearrangements', 'Var', (4, 18))	('of', 'Gene', '6688', (72, 74))	('pHGG', 'Disease', (93, 97))	('pHGG', 'Chemical', '-', (93, 97))	('roles', 'Reg', (34, 39))	('Tkr', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
236738	33348922	The isocitrate dehydrogenase genes, IDH1 and IDH2, are mutated with high frequency in adult secondary HGG.	('IDH1', 'Gene', (36, 40))	('mutated', 'Var', (55, 62))	('IDH2', 'Gene', '3418', (45, 49))	('IDH1', 'Gene', '3417', (36, 40))	('IDH2', 'Gene', (45, 49))	('1 ', 'Gene', '3024', (39, 41))	('on', 'Gene', '20692', (95, 97))
236741	33348922	Mutations on IDH enzymes result in acquisition of a new function: mutated IDH drive the conversion of alpha-ketoglutarate to r (-)-2-hydroxyglutarate (2-HG), an oncometabolite absent in normal conditions.	('mutated', 'Var', (66, 73))	('2-HG', 'Chemical', 'MESH:C019417', (151, 155))	('on', 'Gene', '20692', (194, 196))	('on', 'Gene', '20692', (44, 46))	('on', 'Gene', '20692', (89, 91))	('on', 'Gene', '20692', (161, 163))	('on', 'Gene', '20692', (6, 8))	('on', 'Gene', '20692', (62, 64))	('on', 'Gene', '20692', (96, 98))	('on', 'Gene', '20692', (10, 12))	('on', 'Gene', '20692', (200, 202))	('IDH', 'Gene', (74, 77))	('IDH', 'Gene', (13, 16))	('of', 'Gene', '6688', (99, 101))	('of', 'Gene', '6688', (47, 49))
236748	33348922	K27M mutations in H3.3 and H3.1 are predominant in brainstem pHGG.	('H3.3', 'Gene', (18, 22))	('K27M', 'Mutation', 'p.K27M', (0, 4))	('on', 'Gene', '20692', (11, 13))	('predominant', 'Reg', (36, 47))	('K27M', 'Var', (0, 4))	('1 ', 'Gene', '3024', (30, 32))	('brainstem pHGG', 'Disease', (51, 65))	('pHGG', 'Chemical', '-', (61, 65))
236749	33348922	H3F3A-K27M-mutant cortical pHGGs are rare (approximately 1.3% incidence).	('H3F3A-K27M-mutant', 'Var', (0, 17))	('K27M', 'Mutation', 'p.K27M', (6, 10))	('cortical pHGGs', 'CPA', (18, 32))	('pHGG', 'Chemical', '-', (27, 31))
236750	33348922	Lysine 27 is an amino acid that is commonly methylated and acetylated.	('is a', 'Gene', (10, 14))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('on', 'Gene', '20692', (39, 41))	('is a', 'Gene', '312', (10, 14))	('Lysine 27', 'Var', (0, 9))
236752	33348922	Predictably, these epigenetic signals are disrupted in K27M pHGG.	('pHGG', 'Gene', (60, 64))	('K27M', 'Mutation', 'p.K27M', (55, 59))	('disrupted', 'Reg', (42, 51))	('pHGG', 'Chemical', '-', (60, 64))	('K27M', 'Var', (55, 59))
236753	33348922	This has consequences on cell differentiation, proliferation, and neoplastic activation, i.e., K27M increased the frequency of transformation of NPC into a malignant phenotype.	('on', 'Gene', '20692', (85, 87))	('K27M', 'Mutation', 'p.K27M', (95, 99))	('increased', 'PosReg', (100, 109))	('on', 'Gene', '20692', (58, 60))	('NPC', 'Disease', (145, 148))	('on', 'Gene', '20692', (10, 12))	('of', 'Gene', '6688', (124, 126))	('K27M', 'Var', (95, 99))	('of', 'Gene', '6688', (142, 144))	('on', 'Gene', '20692', (139, 141))	('on', 'Gene', '20692', (43, 45))	('on', 'Gene', '20692', (22, 24))
236764	33348922	Notably, spatial-temporal gene analysis of H3F3A mutant pHGG revealed distinct developmental expression profiles for G34R and K27M tumors (Figure 3).	('G34R', 'Disease', (117, 121))	('H3F3A', 'Gene', (43, 48))	('mutant', 'Var', (49, 55))	('of', 'Gene', '6688', (106, 108))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('K27M', 'Mutation', 'p.K27M', (126, 130))	('G34R', 'Mutation', 'rs1445093587', (117, 121))	('pHGG', 'Chemical', '-', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('pHGG', 'Gene', (56, 60))	('K27M', 'Var', (126, 130))	('on', 'Gene', '20692', (101, 103))	('of', 'Gene', '6688', (40, 42))
236765	33348922	H3F3A G34R mutant tumors correlated to expression patterns of early embryonic and fetal development of the neocortex and striatum as well as early fetal development of the amygdala, inferior temporal cortex, and the ganglionic eminences.	('mutant', 'Var', (11, 17))	('on', 'Gene', '20692', (222, 224))	('G34R mutant', 'Var', (6, 17))	('on', 'Gene', '20692', (47, 49))	('G34R', 'Mutation', 'rs1445093587', (6, 10))	('of', 'Gene', '6688', (59, 61))	('of', 'Gene', '6688', (165, 167))	('H3F3A', 'Gene', (0, 5))	('of', 'Gene', '6688', (100, 102))	('development of the amygdala', 'Phenotype', 'HP:0025444', (153, 180))	('early fetal development', 'CPA', (141, 164))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('on', 'Gene', '20692', (73, 75))	(' to ', 'Gene', '6999', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	(' to ', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
236766	33348922	Meanwhile, expression signatures of H3F3A K27M mutant tumors were associated with embryonic development of the upper rhombic lip as well as fetal development of the thalamus, striatum, and cerebellum.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('of', 'Gene', '6688', (158, 160))	('H3F3A', 'Gene', (36, 41))	('associated', 'Reg', (66, 76))	('upper rhombic lip', 'Disease', (111, 128))	('of', 'Gene', '6688', (104, 106))	('K27M', 'Mutation', 'p.K27M', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('of', 'Gene', '6688', (33, 35))	('on', 'Gene', '20692', (87, 89))	('upper rhombic lip', 'Disease', 'MESH:C557819', (111, 128))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('K27M mutant', 'Var', (42, 53))	('on', 'Gene', '20692', (19, 21))	('tumors', 'Disease', (54, 60))
236769	33348922	Interestingly, G34R-mutant tumors have been found to express a number of genes for developmentally regulated transcription factors and surface markers, suggesting that these tumors exist in an NSC-like state.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('G34R-mutant', 'Var', (15, 26))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	(' to ', 'Gene', '6999', (49, 53))	('of', 'Gene', '6688', (70, 72))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('G34R', 'Mutation', 'rs1445093587', (15, 19))	(' to ', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('on', 'Gene', '20692', (120, 122))
236770	33348922	Combined methylation and gene expression profiling identified differential DNA hypermethylation at the loci for Oligodendrocyte Lineage Genes 1 and 2 (OLIG1 and OLIG2) and corresponding decreases in expression in G34R mutant tumors.	('G34R', 'Mutation', 'rs1445093587', (213, 217))	('OLIG1', 'Gene', '116448', (151, 156))	('1 ', 'Gene', '3024', (155, 157))	('on', 'Gene', '20692', (18, 20))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('on', 'Gene', '20692', (207, 209))	('on', 'Gene', '20692', (38, 40))	('decreases', 'NegReg', (186, 195))	('G34R mutant', 'Var', (213, 224))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('on', 'Gene', '20692', (93, 95))	('OLIG2', 'Gene', (161, 166))	('on', 'Gene', '20692', (179, 181))	('OLIG1', 'Gene', (151, 156))	('1 ', 'Gene', '3024', (142, 144))	('OLIG2', 'Gene', '10215', (161, 166))	('mutant', 'Var', (218, 224))	('tumors', 'Disease', (225, 231))	('of', 'Gene', '6688', (43, 45))
236771	33348922	This epigenetic repression of OLIG1/OLIG2 genes has been proposed as a mechanism by which G34R mutant cells avoid lineage commitment and retain pluripotency.	('OLIG1', 'Gene', (30, 35))	('OLIG2', 'Gene', (36, 41))	('of', 'Gene', '6688', (27, 29))	('G34R', 'Mutation', 'rs1445093587', (90, 94))	('on', 'Gene', '20692', (24, 26))	('epigenetic', 'Var', (5, 15))	('G34R', 'Gene', (90, 94))	('pluripotency', 'MPA', (144, 156))	('OLIG2', 'Gene', '10215', (36, 41))	('mutant', 'Var', (95, 101))	('lineage commitment', 'CPA', (114, 132))	('OLIG1', 'Gene', '116448', (30, 35))	('avoid', 'NegReg', (108, 113))
236772	33348922	Furthermore, differential binding of H3K36me3 has also been found to drive abnormal expression of stem-related genes in G34R mutant cells, including Musashi-1 (MSI1), eyes absent homolog 4 (EYA4), and, notably, SRY-Box Transcription Factor 2 (SOX2) required for stem cell maintenance and marker of NSCs.	('of', 'Gene', '6688', (295, 297))	('of', 'Gene', '6688', (95, 97))	('of', 'Gene', '6688', (34, 36))	('4 (EYA4', 'Gene', '2070', (187, 194))	('H3K36me3', 'Protein', (37, 45))	('on', 'Gene', '20692', (92, 94))	('K36me3', 'Chemical', '-', (39, 45))	('mutant', 'Var', (125, 131))	('on', 'Gene', '20692', (230, 232))	(' to ', 'Gene', '6999', (65, 69))	('binding', 'Interaction', (26, 33))	('stem-related genes', 'Gene', (98, 116))	(' to ', 'Gene', (65, 69))	('Transcription Factor 2 (SOX2', 'Gene', '6657', (219, 247))	('G34R', 'Gene', (120, 124))	('eyes absent', 'Phenotype', 'HP:0000528', (167, 178))	('G34R', 'Mutation', 'rs1445093587', (120, 124))
236773	33348922	Additionally, chromatin immunoprecipitation sequencing (ChIP-seq) analysis of differential H3K36me3 binding in G34R mutant patient samples demonstrated elevated expression of a number of transcription factors related to forebrain development, including FOXG1, DLX6, ARX, DLX5, FOXA1, NRSE1, POU3F2 and SP8, and MYCN.	('K36me3', 'Chemical', '-', (93, 99))	(' to ', 'Gene', '6999', (216, 220))	('FOXA1', 'Gene', '3169', (277, 282))	('binding', 'Interaction', (100, 107))	('of', 'Gene', '6688', (184, 186))	('G34R', 'Gene', (111, 115))	(' to ', 'Gene', (216, 220))	('on', 'Gene', '20692', (41, 43))	('DLX6', 'Gene', '1750', (260, 264))	('FOXA1', 'Gene', (277, 282))	('H3K36me3', 'Protein', (91, 99))	('DLX6', 'Gene', (260, 264))	('on', 'Gene', '20692', (142, 144))	('on', 'Gene', '20692', (198, 200))	('elevated', 'PosReg', (152, 160))	('on', 'Gene', '20692', (6, 8))	('mutant', 'Var', (116, 122))	('ARX,', 'Gene', '170302', (266, 270))	('of', 'Gene', '6688', (172, 174))	('patient', 'Species', '9606', (123, 130))	('2 and SP8', 'Gene', '221833', (296, 305))	('G34R', 'Mutation', 'rs1445093587', (111, 115))	('on', 'Gene', '20692', (169, 171))	('of', 'Gene', '6688', (75, 77))
236775	33348922	Collectively, such findings have led researchers to consider that the NSC-like features of H3 G34R-mutant pHGG are unlikely to be inherited from the cell of origin but may be the result of epigenetic reprogramming, mediating the dedifferentiation of OPC cells.	('pHGG', 'Chemical', '-', (106, 110))	('of', 'Gene', '6688', (154, 156))	('pHGG', 'Gene', (106, 110))	('of', 'Gene', '6688', (247, 249))	(' to ', 'Gene', '6999', (123, 127))	(' to ', 'Gene', (123, 127))	('H3 G34R-mutant', 'Var', (91, 105))	('on', 'Gene', '20692', (244, 246))	('G34R', 'Mutation', 'rs1445093587', (94, 98))	('of', 'Gene', '6688', (186, 188))	(' to ', 'Gene', '6999', (48, 52))	(' to ', 'Gene', (48, 52))	('NSC-like', 'Disease', (70, 78))	('of', 'Gene', '6688', (88, 90))	('on', 'Gene', '20692', (53, 55))
236793	33348922	As mentioned before, BRAF-activating mutations, such as BRAF V600E, are common in LGG and present in NBS pHGG.	('LGG', 'Disease', (82, 85))	('on', 'Gene', '20692', (43, 45))	('BRAF V600E', 'Var', (56, 66))	('on', 'Gene', '20692', (76, 78))	('NBS pHGG', 'Disease', (101, 109))	('on', 'Gene', '20692', (8, 10))	('NBS pHGG', 'Disease', 'MESH:D049932', (101, 109))	('V600E', 'Mutation', 'p.V600E', (61, 66))	('BRAF-activating', 'Gene', (21, 36))
236795	33348922	It must be observed that BRAF inhibitors not only have poor activity against BRAF-WT cells but also result in activation of the Raf-MEK-ERK pathway, enhancing tumor proliferation and aggressiveness.	('Raf-MEK-ERK pathway', 'Pathway', (128, 147))	('of', 'Gene', '6688', (121, 123))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('inhibitors', 'Var', (30, 40))	('on', 'Gene', '20692', (45, 47))	('on', 'Gene', '20692', (176, 178))	('tumor', 'Disease', (159, 164))	('aggressiveness', 'Disease', 'MESH:D001523', (183, 197))	('on', 'Gene', '20692', (118, 120))	('enhancing', 'PosReg', (149, 158))	('aggressiveness', 'Disease', (183, 197))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('aggressiveness', 'Phenotype', 'HP:0000718', (183, 197))
236797	33348922	Clinical trials are currently recruiting to assess the BRAF inhibitor monotherapy on BRAFV600E mutant pHGG.	('on', 'Gene', '20692', (71, 73))	('pHGG', 'Gene', (102, 106))	(' to ', 'Gene', (40, 44))	('on', 'Gene', '20692', (82, 84))	('V600E', 'Mutation', 'p.V600E', (89, 94))	(' to ', 'Gene', '6999', (40, 44))	('BRAFV600E', 'Var', (85, 94))	('pHGG', 'Chemical', '-', (102, 106))
236804	33348922	Histone deacetylases (HDAC) are responsible for removing acetyl marks from histone tails and HDAC inhibitors have been shown to restore these marks in K27M mutant cells in vitro.	('K27M', 'Mutation', 'p.K27M', (151, 155))	('removing acetyl marks', 'MPA', (48, 69))	('on', 'Gene', '20692', (4, 6))	('on', 'Gene', '20692', (79, 81))	(' to ', 'Gene', '6999', (124, 128))	(' to ', 'Gene', (124, 128))	('K27M mutant', 'Var', (151, 162))	('on', 'Gene', '20692', (36, 38))
236806	33348922	On the other hand, NBS pHGG harboring H3F3A G34R/V mutations do not demonstrate benefit from these drugs.	('on', 'Gene', '20692', (71, 73))	('on', 'Gene', '20692', (57, 59))	('H3F3A', 'Gene', (38, 43))	('G34R', 'SUBSTITUTION', 'None', (44, 48))	('NBS pHGG', 'Disease', (19, 27))	('NBS pHGG', 'Disease', 'MESH:D049932', (19, 27))	('G34R', 'Var', (44, 48))
236809	33348922	Other drugs may emerge to reverse epigenetic alterations caused by histone mutations or strategies to block the interaction of the mutant histone with target proteins.	('on', 'Gene', '20692', (71, 73))	(' to ', 'Gene', '6999', (22, 26))	(' to ', 'Gene', '6999', (98, 102))	('mutant', 'Var', (131, 137))	('epigenetic', 'MPA', (34, 44))	(' to ', 'Gene', (22, 26))	(' to ', 'Gene', (98, 102))	('on', 'Gene', '20692', (121, 123))	('of', 'Gene', '6688', (124, 126))	('on', 'Gene', '20692', (142, 144))	('on', 'Gene', '20692', (81, 83))	('on', 'Gene', '20692', (53, 55))
236834	33348922	Deficiencies in DNA repair and genomic instability not only can be targeted with DNA repair and cell cycle checkpoint inhibitors but also can be exploited to prime immune system responses.	('Deficiencies', 'Var', (0, 12))	(' to ', 'Gene', '6999', (154, 158))	('on', 'Gene', '20692', (182, 184))	('genomic instability', 'CPA', (31, 50))	(' to ', 'Gene', (154, 158))	('on', 'Gene', '20692', (55, 57))
236855	33348922	This work was supported by NIH/NINDS grants R37-NS094804, R01-NS105556, and 1R21NS107894 to M.G.C.	('R37-NS094804', 'Var', (44, 56))	(' to ', 'Gene', (88, 92))	(' to ', 'Gene', '6999', (88, 92))
236867	33035963	We found our approach to outperform competing methods that use only summary statistics to predict isocitrate dehydrogenase (IDH) mutation status.	('IDH', 'Gene', (124, 127))	('mutation', 'Var', (129, 137))	('isocitrate dehydrogenase', 'Gene', (98, 122))	('IDH', 'Gene', '3417', (124, 127))	('isocitrate dehydrogenase', 'Gene', '3417', (98, 122))
236893	33035963	Several molecular alterations have been shown to be associated with the overall survival of the LGG patients.	('alterations', 'Var', (18, 29))	('LGG', 'Disease', (96, 99))	('associated', 'Reg', (52, 62))	('as', 'Chemical', 'MESH:D001151', (52, 54))	('patients', 'Species', '9606', (100, 108))
236894	33035963	These include isocitrate dehydrogenase (IDH1/2) mutation status (collectively referred to as IDH mutations), 1p19q chromosomal arm codeletion, MGMT promoter methylation status, and TP53 mutation.	('1p19q', 'Var', (109, 114))	('TP53', 'Gene', (181, 185))	('IDH1', 'Gene', (40, 44))	('IDH', 'Gene', '3417', (40, 43))	('IDH', 'Gene', (93, 96))	('IDH1', 'Gene', '3417', (40, 44))	('IDH', 'Gene', (40, 43))	('IDH', 'Gene', '3417', (93, 96))	('MGMT', 'Gene', (143, 147))	('as', 'Chemical', 'MESH:D001151', (35, 37))	('isocitrate dehydrogenase', 'Gene', (14, 38))	('as', 'Chemical', 'MESH:D001151', (90, 92))	('MGMT', 'Gene', '4255', (143, 147))	('TP53', 'Gene', '7157', (181, 185))	('isocitrate dehydrogenase', 'Gene', '3417', (14, 38))
236895	33035963	Multiple molecular sub-types of LGG have been identified, which predominantly include IDH wild-type, IDH mutant with 1p19q codeleted, and IDH mutant with 1p19q noncodeleted groups.	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', (138, 141))	('IDH', 'Gene', '3417', (86, 89))	('1p19q', 'Var', (117, 122))	('IDH', 'Gene', '3417', (138, 141))	('IDH', 'Gene', (101, 104))	('IDH', 'Gene', '3417', (101, 104))
236897	33035963	Specifically in the case of glioblastoma, studies also indicate that patients with IDH1 mutation have better prognosis compared to the patients with wild-type.	('mutation', 'Var', (88, 96))	('patients', 'Species', '9606', (135, 143))	('IDH1', 'Gene', '3417', (83, 87))	('as', 'Chemical', 'MESH:D001151', (34, 36))	('as', 'Chemical', 'MESH:D001151', (21, 23))	('glioblastoma', 'Disease', (28, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('patients', 'Species', '9606', (69, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('IDH1', 'Gene', (83, 87))
236939	33035963	For both simulated and LGG data, we used the Z-score standardization for  for each entry  and imaging sequence r. In our LGG case study, we consider  gray-levels and  imaging sequences: T1W, T1CE, T2W and FLAIR as described in Section 1.2.	('as', 'Chemical', 'MESH:D001151', (211, 213))	('as', 'Chemical', 'MESH:D001151', (126, 128))	('T1W', 'Var', (186, 189))	('T2W', 'Var', (197, 200))	('T1CE', 'Var', (191, 195))
236956	33035963	That is, we adopt a data augmentation approach to define our predictive model as in (8) whereand  if subject i has a mutant IDH and  if subject i has a wild type IDH.	('IDH', 'Gene', (124, 127))	('as', 'Chemical', 'MESH:D001151', (112, 114))	('mutant', 'Var', (117, 123))	('IDH', 'Gene', (162, 165))	('as', 'Chemical', 'MESH:D001151', (78, 80))	('IDH', 'Gene', '3417', (124, 127))	('IDH', 'Gene', '3417', (162, 165))	('as', 'Chemical', 'MESH:D001151', (147, 149))
236964	33035963	For example, we observe stronger pairwise correlations between FLAIR and T2W, possibly as the tumor region is indicated by a mass-like hyperintense signal in both sequences.	('pairwise', 'Interaction', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('T2W', 'Disease', (73, 76))	('as', 'Chemical', 'MESH:D001151', (126, 128))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('FLAIR', 'Var', (63, 68))	('as', 'Chemical', 'MESH:D001151', (87, 89))	('correlations', 'Interaction', (42, 54))
237017	33035963	This is aligned with our simulated data where sequences FLAIR and T1CE are not associated with the binary response as they were generated with the same means and covariances between the two groups of responses (i.e  and ).	('as', 'Chemical', 'MESH:D001151', (115, 117))	('sequences', 'Var', (46, 55))	('as', 'Chemical', 'MESH:D001151', (79, 81))	('T1CE', 'Var', (66, 70))
237018	33035963	In this section, we summarize results from our methods applied to the TCGA LGG dataset described in Section 1.1, which consists of  TCGA LGG patients whose MRI scans were available for all  imaging sequences (T1W, T1CE, T2W and FLAIR).	('T1CE', 'Var', (214, 218))	('FLAIR', 'Var', (228, 233))	('T2W', 'Var', (220, 223))	('as', 'Chemical', 'MESH:D001151', (82, 84))	('T1W', 'Var', (209, 212))	('patients', 'Species', '9606', (141, 149))
237027	33035963	We can observe that only the imaging sequence T1CE does not have high probabilities which would confirm that sequences T1W, T2W and FLAIR are potential biomarkers for IDH status in LGG disease.	('FLAIR', 'Var', (132, 137))	('IDH status in LGG disease', 'Disease', 'MESH:D013226', (167, 192))	('sequences T1W', 'Var', (109, 122))	('IDH status in LGG disease', 'Disease', (167, 192))	('T2W', 'Var', (124, 127))
237029	33035963	However, with the T2W and FLAIR sequences, the tumor regions are usually observed with a mass-like hyperintense signal.	('T2W', 'Var', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('as', 'Chemical', 'MESH:D001151', (90, 92))	('tumor', 'Disease', (47, 52))
237030	33035963	This confirms with our findings as the marginal posterior probabilities corresponding to components from T1W, T2W and FLAIR are clearly higher as shown in Fig.	('as', 'Chemical', 'MESH:D001151', (32, 34))	('FLAIR', 'Var', (118, 123))	('higher', 'PosReg', (136, 142))	('as', 'Chemical', 'MESH:D001151', (143, 145))	('T2W', 'Var', (110, 113))	('T1W', 'Var', (105, 108))
237036	33035963	10(a)-(d) show estimated functional effects for the non-symmetric case, where we see that the effect sizes corresponding to the GLCM for T1CE are lower in magnitude in comparison to the other three imaging sequences.	('GLCM', 'Chemical', '-', (128, 132))	('lower', 'NegReg', (146, 151))	('T1CE', 'Var', (137, 141))	('as', 'Chemical', 'MESH:D001151', (67, 69))
237037	33035963	In case of T1W since the tumor region is usually observed to be hypointense compared to the white matter, we expect to see more voxels with intensities in the middle of the gray-scale.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('T1W', 'Var', (11, 14))	('tumor', 'Disease', (25, 30))	('as', 'Chemical', 'MESH:D001151', (4, 6))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
237043	33035963	For T2W and FLAIR sequences we see higher magnitudes on the higher-end of the gray-scale as the tumor region is observed to be hyperintense in the image which is also consistent with the non-symmetric case.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('T2W', 'Var', (4, 7))	('as', 'Chemical', 'MESH:D001151', (89, 91))	('tumor', 'Disease', (96, 101))	('as', 'Chemical', 'MESH:D001151', (202, 204))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
237062	31649675	C1q, the first recognition subcomponent of the complement classical pathway, has recently been shown to be involved in a range of pathophysiological functions that are not dependent on complement activation.	('men', 'Species', '9606', (53, 56))	('involved', 'Reg', (107, 115))	('C1q', 'Var', (0, 3))	('men', 'Species', '9606', (191, 194))
237073	31649675	In prostate cancer cells, C1q was recently shown to induce apoptosis by activating the tumor suppressor WOX1, thus acting as an anti-tumor humoral factor.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('WOX1', 'Gene', (104, 108))	('WOX1', 'Gene', '51741', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('induce', 'PosReg', (52, 58))	('activating', 'PosReg', (72, 82))	('prostate cancer', 'Disease', (3, 18))	('C1q', 'Var', (26, 29))	('apoptosis', 'CPA', (59, 68))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
237074	31649675	In ovarian cancer, C1q has been shown to induce apoptosis in a representative SKOV3 cell line via activation of TNF-alpha, upregulation of Fas, and downregulation of mammalian target of rapamycin, RICTOR, and RAPTOR survival pathways.	('RAPTOR', 'Gene', '57521', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('activation', 'PosReg', (98, 108))	('mammalian target of rapamycin', 'Gene', '2475', (166, 195))	('RICTOR', 'Gene', (197, 203))	('Fas', 'Protein', (139, 142))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('RICTOR', 'Gene', '253260', (197, 203))	('upregulation', 'PosReg', (123, 135))	('RAPTOR', 'Gene', (209, 215))	('ovarian cancer', 'Disease', (3, 17))	('C1q', 'Var', (19, 22))	('mammalian target of rapamycin', 'Gene', (166, 195))	('apoptosis', 'CPA', (48, 57))	('TNF-alpha', 'Gene', '7124', (112, 121))	('TNF-alpha', 'Gene', (112, 121))	('downregulation', 'NegReg', (148, 162))
237075	31649675	In a BALB-neuT mouse model of mammary carcinomas, C1q was shown to have a protective role against cancer progression.	('carcinomas', 'Disease', 'MESH:D002277', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinomas', 'Disease', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('mouse', 'Species', '10090', (15, 20))	('C1q', 'Var', (50, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))
237076	31649675	However, C1q can promote adhesion, migration, and proliferation of primary cells derived from malignant pleural mesothelioma patients, a relatively rare disease associated with exposure to asbestos.	('migration', 'CPA', (35, 44))	('proliferation', 'CPA', (50, 63))	('promote', 'PosReg', (17, 24))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (104, 124))	('C1q', 'Var', (9, 12))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (104, 124))	('adhesion', 'CPA', (25, 33))	('pleural mesothelioma', 'Disease', (104, 124))	('patients', 'Species', '9606', (125, 133))
237081	31649675	C1q can also interact with abnormal protein aggregates, such as betaA1-42, thus favoring neurodegenerative diseases progression.	('C1q', 'Var', (0, 3))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (89, 115))	('betaA1-42', 'Protein', (64, 73))	('favoring', 'PosReg', (80, 88))	('neurodegenerative diseases', 'Disease', (89, 115))	('interact', 'Interaction', (13, 21))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (89, 115))
237089	31649675	In the current study, we performed a bioinformatics analysis aimed at investigating whether C1q can serve as a potential prognostic marker for gliomas.	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('gliomas', 'Disease', (143, 150))	('C1q', 'Var', (92, 95))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))
237153	31649675	The genetic profile is characterized by epidermal growth factor receptor (EGFR) overexpression, phosphatase and tensin homolog (PTEN) mutation, p16 deletion, and chromosome 10 loss.	('overexpression', 'PosReg', (80, 94))	('deletion', 'Var', (148, 156))	('loss', 'NegReg', (176, 180))	('PTEN', 'Gene', (128, 132))	('epidermal growth factor receptor', 'Gene', '1956', (40, 72))	('PTEN', 'Gene', '5728', (128, 132))	('mutation', 'Var', (134, 142))	('p16', 'Gene', (144, 147))	('chromosome 10', 'CPA', (162, 175))	('EGFR', 'Gene', '1956', (74, 78))	('epidermal growth factor receptor', 'Gene', (40, 72))	('EGFR', 'Gene', (74, 78))	('p16', 'Gene', '1029', (144, 147))
237154	31649675	Secondary GBM derives from a malignant progression of diffuse or anaplastic astrocytomas (grade-II and -III, respectively), and occurs in younger patients, characterized by p53 mutation and a reduced state of heterozygosity in tumor cells (loss of heterozygosity) on chromosome 10q.	('mutation', 'Var', (177, 185))	('astrocytomas', 'Disease', (76, 88))	('GBM', 'Disease', (10, 13))	('p53', 'Gene', (173, 176))	('tumor', 'Disease', (227, 232))	('diffuse', 'Disease', (54, 61))	('GBM', 'Disease', 'MESH:D005909', (10, 13))	('p53', 'Gene', '7157', (173, 176))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))	('astrocytomas', 'Disease', 'MESH:D001254', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
237158	31649675	On one hand, C1q can be detrimental to cancer cell viability via its cell lytic, anaphylatoxin, and opsonin effector mechanisms.	('detrimental to cancer', 'Disease', 'MESH:D009369', (24, 45))	('cell lytic', 'CPA', (69, 79))	('detrimental to cancer', 'Disease', (24, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('C1q', 'Var', (13, 16))
237159	31649675	Alternatively, C1q can exert tumor-promoting functions which are independent of the classical pathway activation.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('C1q', 'Var', (15, 18))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))
237191	28207858	Lymphovascular invasion was associated with the ADC mean, 50th, 75th, 90th, and 95th percentiles, skewness, and kurtosis.	('kurtosis', 'Disease', (112, 120))	('kurtosis', 'Disease', 'None', (112, 120))	('Lymphovascular invasion', 'CPA', (0, 23))	('ADC', 'Var', (48, 51))
237223	28207858	The results of our ROC analysis of the histogram parameters between high- and low-grade tumors showed that the area under the curve (AUC) of the mean, 50th, 75th, 90th, and 95th percentiles of ADC were 0.706, 0.688, 0.713, 0.730, and 0.740, respectively.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('0.713', 'Var', (216, 221))	('ADC', 'Gene', (193, 196))	('0.688', 'Var', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
237224	28207858	The 95th percentile ADC achieved the highest AUC, with a cut-off value of 1634.1 x 10-6 mm2/sec, 84.6% sensitivity, and 66.7% specificity (Fig 2).	('mm2', 'Gene', '10687', (88, 91))	('mm2', 'Gene', (88, 91))	('AUC', 'MPA', (45, 48))	('1634.1', 'Var', (74, 80))
237241	28207858	In the studies of uterine cervical cancer, endometrial cancer, prostate cancer, bladder cancer, and brain glioma, low-percentile ADCs proved to be significant for differentiating high-grade from low-grade malignancies.	('low-percentile', 'Var', (114, 128))	('cancer', 'Disease', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (72, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('brain glioma', 'Disease', (100, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('malignancies', 'Disease', 'MESH:D009369', (205, 217))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('endometrial cancer', 'Phenotype', 'HP:0012114', (43, 61))	('malignancies', 'Disease', (205, 217))	('brain glioma', 'Disease', 'MESH:C564230', (100, 112))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('endometrial cancer', 'Disease', (43, 61))	('prostate cancer', 'Disease', (63, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('endometrial cancer', 'Disease', 'MESH:D016889', (43, 61))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (35, 41))
237260	25565956	In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lead to', 'Reg', (33, 40))	('tumor', 'Disease', (41, 46))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('GBM', 'Var', (25, 28))	('seizures', 'Disease', 'MESH:D012640', (55, 63))	('patients', 'Species', '9606', (96, 104))	('seizures', 'Disease', (55, 63))	('seizures', 'Phenotype', 'HP:0001250', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('seizure', 'Phenotype', 'HP:0001250', (55, 62))
237354	25565956	Vasogenic edema is caused by the disruption of the BBB, which allows leakage of fluids from the blood into the brain parenchyma (Ryan et al.,).	('disruption', 'Var', (33, 43))	('edema', 'Disease', (10, 15))	('caused by', 'Reg', (19, 28))	('edema', 'Disease', 'MESH:D004487', (10, 15))	('edema', 'Phenotype', 'HP:0000969', (10, 15))	('leakage of fluids from the blood', 'MPA', (69, 101))
237364	25565956	Other mechanisms implicated in steroid-reducing BTRE are reduced angiogenesis and diminished cytotoxicity, and the anti-inflammatory effect on reducing cytokine-induced BBB breakdown.	('steroid-reducing', 'Var', (31, 47))	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('reducing', 'NegReg', (143, 151))	('diminished', 'NegReg', (82, 92))	('steroid', 'Chemical', 'MESH:D013256', (31, 38))	('cytokine-induced BBB breakdown', 'MPA', (152, 182))	('cytotoxicity', 'Disease', (93, 105))	('BTRE', 'Disease', (48, 52))	('angiogenesis', 'CPA', (65, 77))	('reduced', 'NegReg', (57, 64))
237367	25565956	It is hypothesized that corticosteroid inhibition of NF-kappabeta causes reduction of edema via inhibition of cytokine-induced barrier breakdown and decreasing the expression of cell adhesion molecules, which mediate T-cell-BBB interactions and excessive leukocyte recruitment across the BBB (Pitzalis et al.,).	('inhibition', 'Var', (39, 49))	('edema', 'Disease', 'MESH:D004487', (86, 91))	('edema', 'Phenotype', 'HP:0000969', (86, 91))	('cell adhesion molecules', 'Protein', (178, 201))	('expression', 'MPA', (164, 174))	('cytokine-induced barrier breakdown', 'MPA', (110, 144))	('leukocyte', 'CPA', (255, 264))	('edema', 'Disease', (86, 91))	('NF-kappabeta', 'Gene', (53, 65))	('steroid', 'Chemical', 'MESH:D013256', (31, 38))	('excessive leukocyte', 'Phenotype', 'HP:0001974', (245, 264))	('NF-kappabeta', 'Gene', '4790', (53, 65))	('inhibition', 'NegReg', (96, 106))	('reduction', 'NegReg', (73, 82))	('decreasing', 'NegReg', (149, 159))
237375	25565956	Epileptic seizures often occur in brain-tumor patients, with reports of seizure risk of 60-100% among low-grade tumors and 40-60% in GBM (Vecht et al.,).	('patients', 'Species', '9606', (46, 54))	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('seizure', 'Disease', 'MESH:D012640', (72, 79))	('Epileptic', 'Disease', (0, 9))	('seizure', 'Disease', 'MESH:D012640', (10, 17))	('seizures', 'Disease', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('seizure', 'Phenotype', 'HP:0001250', (72, 79))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('seizure', 'Phenotype', 'HP:0001250', (10, 17))	('seizures', 'Disease', 'MESH:D012640', (10, 18))	('seizure', 'Disease', (72, 79))	('seizure', 'Disease', (10, 17))	('Epileptic', 'Disease', 'MESH:D004827', (0, 9))	('seizures', 'Phenotype', 'HP:0001250', (10, 18))	('brain-tumor', 'Phenotype', 'HP:0030692', (34, 45))	('low-grade', 'Var', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('brain-tumor', 'Disease', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('brain-tumor', 'Disease', 'MESH:D001932', (34, 45))	('tumors', 'Disease', (112, 118))
237384	25565956	Studies suggest that specific symptoms of the disease reflect not only the location of the tumor but also its biological behavior, because patients with low-grade glioma with early seizures in the beginning of the disease and concomitant early control have a higher survival rate than those who develop recurrent seizures (Danfors et al.,).	('seizures', 'Disease', (313, 321))	('glioma', 'Disease', (163, 169))	('patients', 'Species', '9606', (139, 147))	('seizures', 'Disease', 'MESH:D012640', (181, 189))	('seizures', 'Disease', 'MESH:D012640', (313, 321))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('low-grade', 'Var', (153, 162))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('seizures', 'Disease', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('seizures', 'Phenotype', 'HP:0001250', (181, 189))	('seizures', 'Phenotype', 'HP:0001250', (313, 321))	('seizure', 'Phenotype', 'HP:0001250', (313, 320))	('survival', 'CPA', (266, 274))	('tumor', 'Disease', (91, 96))	('seizure', 'Phenotype', 'HP:0001250', (181, 188))	('higher', 'PosReg', (259, 265))
237395	25565956	Some other possible mechanisms of epileptogenesis in high-grade gliomas are the perilesional focal ischemia, deafferentation of cortical areas by mass effect, and also increased iron in minor bleeding (Beaumont and Whittle,).	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('increased', 'PosReg', (168, 177))	('iron', 'Chemical', 'MESH:D007501', (178, 182))	('iron', 'MPA', (178, 182))	('bleeding', 'Disease', 'MESH:D006470', (192, 200))	('focal ischemia', 'Phenotype', 'HP:0002326', (93, 107))	('ischemia', 'Disease', (99, 107))	('gliomas', 'Disease', (64, 71))	('perilesional', 'Disease', (80, 92))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('bleeding', 'Disease', (192, 200))	('deafferentation', 'Var', (109, 124))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('ischemia', 'Disease', 'MESH:D007511', (99, 107))
237399	25565956	Disruption of the BBB may also lead to abnormal extravasation of plasma protein and other substances, including glutamate, contributing to hyperexcitability and development of seizure focus (Ivens et al.,).	('seizure', 'Phenotype', 'HP:0001250', (176, 183))	('glutamate', 'Chemical', 'MESH:D018698', (112, 121))	('abnormal extravasation of plasma protein', 'MPA', (39, 79))	('hyperexcitability', 'MPA', (139, 156))	('seizure', 'Disease', (176, 183))	('lead to', 'Reg', (31, 38))	('BBB', 'Gene', (18, 21))	('seizure', 'Disease', 'MESH:D012640', (176, 183))	('contributing', 'Reg', (123, 135))	('Disruption', 'Var', (0, 10))
237426	25565956	For instance, the imbalance of tenascin and fibronectin in the tumor contributes to vessel formation as we have previously demonstrated (Alves et al.,).	('tenascin', 'Gene', (31, 39))	('tumor', 'Disease', (63, 68))	('vessel formation', 'CPA', (84, 100))	('fibronectin', 'Gene', '2335', (44, 55))	('imbalance', 'Phenotype', 'HP:0002172', (18, 27))	('tenascin', 'Gene', '3371', (31, 39))	('contributes', 'Reg', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('fibronectin', 'Gene', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('imbalance', 'Var', (18, 27))
237435	21880180	A better understanding of PDGFRalpha signaling in glioma and their microenvironment, through the use of human or mouse models, is necessary to design a more effective therapeutic strategy against gliomas harboring the aberrant PDGFRalpha signaling.	('PDGFRalpha signaling', 'Gene', (227, 247))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (196, 202))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('glioma', 'Disease', (50, 56))	('human', 'Species', '9606', (104, 109))	('rat', 'Species', '10116', (181, 184))	('glioma', 'Disease', (196, 202))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))	('mouse', 'Species', '10090', (113, 118))	('aberrant', 'Var', (218, 226))
237446	21880180	For example, it is believed that low-grade astrocytomas and oligodendrogliomas may develop from common glial progenitor cells that acquire features of astrocytic tumors in the presence of TP53 mutations and oligodendrocytic tumors in the presence of 1p/19q chromosomal loss (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('TP53', 'Gene', '22059', (188, 192))	('TP53', 'Gene', (188, 192))	('astrocytic tumors', 'Disease', 'MESH:D001254', (151, 168))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('astrocytomas', 'Disease', (43, 55))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('oligodendrogliomas', 'Disease', (60, 78))	('mutations', 'Var', (193, 202))	('oligodendrocytic tumors', 'Disease', 'MESH:D009369', (207, 230))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('1p/19q chromosomal loss', 'Var', (250, 273))	('oligodendrocytic tumors', 'Disease', (207, 230))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('astrocytic tumors', 'Disease', (151, 168))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))
237447	21880180	Additionally, platelet-derived growth factor receptor alpha (PDGFRA)/PDGF-A overexpression and isocitrate dehydrogenase 1 (IDH1) mutations are some of the major genetic alterations found in low-grade gliomas as well as secondary GBMs.	('rat', 'Species', '10116', (173, 176))	('rat', 'Species', '10116', (101, 104))	('platelet-derived growth factor receptor alpha', 'Gene', (14, 59))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('gliomas', 'Disease', (200, 207))	('mutations', 'Var', (129, 138))	('isocitrate dehydrogenase 1', 'Gene', (95, 121))	('IDH1', 'Gene', (123, 127))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('PDGFRA', 'Gene', '18595', (61, 67))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('IDH1', 'Gene', '15926', (123, 127))	('/PDGF-A', 'Gene', (68, 75))	('PDGFRA', 'Gene', (61, 67))	('isocitrate dehydrogenase 1', 'Gene', '15926', (95, 121))	('platelet-derived growth factor receptor alpha', 'Gene', '18595', (14, 59))	('overexpression', 'PosReg', (76, 90))
237448	21880180	When the low-grade tumors progress toward the high-grade secondary GBMs, additional changes such as CDK-dependent kinase inhibitor (CDKN) 2A/CDKN2B deletion are acquired (Figure 1).	('deletion', 'Var', (148, 156))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('CDK-dependent kinase inhibitor (CDKN) 2A', 'Gene', '12578', (100, 140))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('CDKN2B', 'Gene', '12579', (141, 147))	('CDKN2B', 'Gene', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
237449	21880180	In the primary GBMs, however, a distinct set of genetic changes are observed, such as epidermal growth factor receptor (EGFR) amplification/mutation, phosphatase and tensin homolog (PTEN) mutations/deletion and Mdm2 p53 binding protein homolog (MDM2) overexpression (Figure 1), suggesting a different cell-of-origin of these tumors is responsible for generating primary GBMs.	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('Mdm2', 'Gene', (211, 215))	('epidermal growth factor receptor', 'Gene', (86, 118))	('MDM2', 'Gene', '17246', (245, 249))	('amplification/mutation', 'Var', (126, 148))	('overexpression', 'PosReg', (251, 265))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('p53', 'Gene', (216, 219))	('tumors', 'Disease', (325, 331))	('mutations/deletion', 'Var', (188, 206))	('Mdm2', 'Gene', '17246', (211, 215))	('PTEN', 'Gene', '19211', (182, 186))	('EGFR', 'Gene', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (325, 331))	('rat', 'Species', '10116', (355, 358))	('epidermal growth factor receptor', 'Gene', '13649', (86, 118))	('p53', 'Gene', '22059', (216, 219))	('MDM2', 'Gene', (245, 249))	('PTEN', 'Gene', (182, 186))
237455	21880180	Expression of long- or short-form PDGF-A results from alternative splicing of exon 6 of PDGFA and is cell-type specific.	('PDGFA', 'Gene', (88, 93))	('alternative splicing', 'Var', (54, 74))	('results from', 'Reg', (41, 53))	('PDGFA', 'Gene', '18590', (88, 93))	('PDGF-A', 'Gene', (34, 40))
237472	21880180	Upon association to Tyr-988 and -1018, it phosphorylates PIP2 to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which then mobilize intracellular Ca2+ and activates the PKC family, respectively (Figure 2).	('mobilize intracellular Ca2+', 'MPA', (146, 173))	('Tyr-988', 'Var', (20, 27))	('Tyr', 'Chemical', 'MESH:D014443', (20, 23))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (74, 102))	('IP3', 'Chemical', 'MESH:D015544', (104, 107))	('Ca2+', 'Chemical', 'MESH:D000069285', (169, 173))	('PIP2', 'Chemical', 'MESH:D019269', (57, 61))	('diacylglycerol', 'MPA', (113, 127))	('diacylglycerol', 'Chemical', 'MESH:D004075', (113, 127))	('PKC family', 'Enzyme', (192, 202))	('activates', 'PosReg', (178, 187))	('rat', 'Species', '10116', (69, 72))	('association', 'Interaction', (5, 16))	('DAG', 'Chemical', 'MESH:D004075', (129, 132))
237475	21880180	Their binding sites on PDGFRalpha autophosphorylated tyrosine sites are Tyr-572 and -574.	('PDGFRalpha', 'Gene', (23, 33))	('binding', 'Interaction', (6, 13))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('Tyr-572', 'Var', (72, 79))
237481	21880180	An allelic series of PDGFRA tyrosine-to-phenylalanine mutations disrupting association between the RTK with different downstream effectors and signaling pathways have been generated.	('PDGFRA', 'Gene', (21, 27))	('PDGFRA', 'Gene', '18595', (21, 27))	('rat', 'Species', '10116', (176, 179))	('tyrosine', 'Chemical', 'MESH:D014443', (28, 36))	('disrupting', 'NegReg', (64, 74))	('phenylalanine', 'Chemical', 'MESH:D010649', (40, 53))	('tyrosine-to-phenylalanine mutations', 'Var', (28, 63))	('association', 'Interaction', (75, 86))
237483	21880180	Using a similar strategy, PI3K and PLC-gamma were shown to play predominant roles in preventing apoptosis of mesoderm cells during early Xenopus embryo development.	('rat', 'Species', '10116', (18, 21))	('apoptosis of mesoderm cells', 'CPA', (96, 123))	('preventing', 'NegReg', (85, 95))	('Xenopus', 'Species', '8355', (137, 144))	('PI3K', 'Var', (26, 30))
237484	21880180	further generated knock-in mice that harbored one of the three mutants, PDGFRalpha-F7, PDGFRalpha-F731/42 or PDGFRalpha-F572/74.	('PDGFRalpha-F7', 'Var', (72, 85))	('rat', 'Species', '10116', (12, 15))	('mice', 'Species', '10090', (27, 31))	('PDGFRalpha-F572/74', 'Var', (109, 127))	('PDGFRalpha-F731/42', 'Var', (87, 105))
237485	21880180	Interestingly, mice that homozygously harbored PDGFRalpha-F731/42, as well as PDGFRalpha-F7, displayed phenotypes comparable to PDGF-A- or PDGFRalpha-null animals, including growth retardation, skeletal and lung development abnormalities.	('growth retardation', 'Disease', 'MESH:D006130', (174, 192))	('PDGFRalpha-F7', 'Var', (78, 91))	('growth retardation', 'Disease', (174, 192))	('lung development abnormalities', 'Disease', 'MESH:D002658', (207, 237))	('growth retardation', 'Phenotype', 'HP:0001510', (174, 192))	('mice', 'Species', '10090', (15, 19))	('lung development abnormalities', 'Disease', (207, 237))	('PDGFRalpha-F731/42', 'Var', (47, 65))
237492	21880180	Subsequent studies using PDGFRalpha-mutant-knock-in mice showed that downstream SFK and PI3K are important for normal myelination of the CNS.	('myelination', 'CPA', (118, 129))	('mice', 'Species', '10090', (52, 56))	('SFK', 'Gene', '20779', (80, 83))	('PDGFRalpha-mutant-knock-in', 'Var', (25, 51))	('PDGFRalpha-mutant-knock-in', 'Gene', (25, 51))	('SFK', 'Gene', (80, 83))
237512	21880180	However, unlike PDGF-A, neuron-specific PDGF-B knockout did not impact normal CNS development or astroglial and angiogenic responses to CNS injury.	('impact', 'Reg', (64, 70))	('knockout', 'Var', (47, 55))	('PDGF-B', 'Gene', (40, 46))	('CNS injury', 'Disease', (136, 146))	('CNS injury', 'Disease', 'MESH:D001927', (136, 146))
237519	21880180	Mice deficient in PDGF-C displayed a range of abnormalities and died perinatally due to difficulties in breathing and eating.	('PDGF-C', 'Gene', (18, 24))	('breathing', 'CPA', (104, 113))	('deficient', 'Var', (5, 14))	('Mice', 'Species', '10090', (0, 4))	('difficulties in breathing', 'Phenotype', 'HP:0002098', (88, 113))	('difficulties', 'Reg', (88, 100))
237528	21880180	Overexpression and gene amplification of PDGFRalpha occurred mostly in lower-grade gliomas as well as secondary GBMs, representing a distinct subtype of GBMs from those with EGFR overexpression (Figure 1).	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('secondary GBMs', 'Disease', (102, 116))	('occurred', 'Reg', (52, 60))	('PDGFRalpha', 'Gene', (41, 51))	('gene amplification', 'Var', (19, 37))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))
237535	21880180	Most of the previously appreciated genetic aberrations such as alterations in the RB, TP53 and RTK pathways were re-captured in the initial TCGA studies.	('rat', 'Species', '10116', (67, 70))	('alterations', 'Var', (63, 74))	('TP53', 'Gene', '22059', (86, 90))	('rat', 'Species', '10116', (47, 50))	('TP53', 'Gene', (86, 90))	('RTK pathways', 'Pathway', (95, 107))
237537	21880180	Further classification of these GBMs by gene expression signatures revealed that PDGFRA overexpression occurs together with TP53 and IDH1 mutations in the Proneural subtype of GBMs, which also express oligodendrocyte lineage genes such as OLIG2 and SOX .	('OLIG2', 'Gene', (239, 244))	('overexpression', 'PosReg', (88, 102))	('TP53', 'Gene', '22059', (124, 128))	('TP53', 'Gene', (124, 128))	('OLIG2', 'Gene', '50913', (239, 244))	('IDH1', 'Gene', (133, 137))	('PDGFRA', 'Gene', '18595', (81, 87))	('SOX', 'Gene', (249, 252))	('PDGFRA', 'Gene', (81, 87))	('IDH1', 'Gene', '15926', (133, 137))	('SOX', 'Gene', '104009', (249, 252))	('mutations', 'Var', (138, 147))
237538	21880180	Interestingly, within this subtype of GBMs, PDGFRA amplifications and PIK3CA/PIK3R1 mutations (leading to constitutively active PI3K subunits p110 and p85, respectively) mostly occur in a mutually exclusive manner, signifying an overlapping functionality between these two alterations in gliomagenesis.	('p110', 'Var', (142, 146))	('glioma', 'Disease', 'MESH:D005910', (288, 294))	('PIK3CA', 'Gene', '18706', (70, 76))	('p85', 'Gene', (151, 154))	('p85', 'Gene', '21981', (151, 154))	('mutations', 'Var', (84, 93))	('glioma', 'Disease', (288, 294))	('PIK3CA', 'Gene', (70, 76))	('rat', 'Species', '10116', (277, 280))	('PDGFRA', 'Gene', '18595', (44, 50))	('PIK3R1', 'Gene', '18708', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (288, 294))	('PDGFRA', 'Gene', (44, 50))	('PIK3R1', 'Gene', (77, 83))
237540	21880180	The Proneural subtype of GBMs harboring PDGFRA amplification from the TCGA dataset share similar gene expression profiles with the previously reported pro-neural (PN) subclass.	('amplification', 'Var', (47, 60))	('PDGFRA', 'Gene', (40, 46))	('PDGFRA', 'Gene', '18595', (40, 46))
237561	21880180	Spontaneous gliomas have been found to develop in transgenic mice overexpressing the long isoform of PDGF-A, PDGF-AL, under the control of a GFAP promoter (Table 1).	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('gliomas', 'Disease', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('transgenic mice', 'Species', '10090', (50, 65))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('PDGF-A', 'Gene', (101, 107))	('overexpressing', 'Var', (66, 80))	('develop', 'PosReg', (39, 46))
237562	21880180	Unlike hGFAPpPDGFB mice, hGFAPpPDGFAL mice did not require additional genetic aberrations such as p53 deletion in order to develop spontaneous tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mice', 'Species', '10090', (38, 42))	('p53', 'Gene', '22059', (98, 101))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('PDGFA', 'Gene', '18590', (31, 36))	('deletion', 'Var', (102, 110))	('hGFAPpPDGFB', 'Gene', (7, 18))	('rat', 'Species', '10116', (82, 85))	('p53', 'Gene', (98, 101))	('hGFAPpPDGFB', 'Gene', '2670;5155', (7, 18))	('PDGFA', 'Gene', (31, 36))	('mice', 'Species', '10090', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
237566	21880180	Although it is difficult to assess the tumor-promoting potential of PDGF-B, short-and long-form PDGF-A by comparing the transgenic mice generated by overexpression of these genes, due to the differences in promoter strength and transgenic copy numbers among these mice, these studies have suggested that glioma-specific long-form PDGF-A may exert tumorigenic effects through distinct signaling pathways than those stimulated by PDGF-B and short-form PDGF-A.	('glioma', 'Phenotype', 'HP:0009733', (304, 310))	('signaling pathways', 'Pathway', (384, 402))	('tumor', 'Disease', (347, 352))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('rat', 'Species', '10116', (140, 143))	('PDGF-A', 'Var', (330, 336))	('transgenic', 'Species', '10090', (228, 238))	('glioma', 'Disease', (304, 310))	('mice', 'Species', '10090', (264, 268))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('transgenic', 'Species', '10090', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tumor', 'Disease', (39, 44))	('transgenic mice', 'Species', '10090', (120, 135))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('glioma', 'Disease', 'MESH:D005910', (304, 310))
237568	21880180	In these studies, PDGF-B overexpression induces glioma growth from various cell types including glial progenitor cells, astrocytes and neural progenitor cells, and the resulting tumors frequently exhibited characteristics of oligodendrogliomas or mixed oligoastrocytomas (Table 1).	('oligodendrogliomas', 'Disease', 'MESH:D009837', (225, 243))	('PDGF-B', 'Gene', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('induces', 'PosReg', (40, 47))	('oligoastrocytomas', 'Disease', (253, 270))	('glioma', 'Phenotype', 'HP:0009733', (236, 242))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (253, 270))	('oligodendrogliomas', 'Disease', (225, 243))	('gliomas', 'Phenotype', 'HP:0009733', (236, 243))	('glioma', 'Disease', (48, 54))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('overexpression', 'Var', (25, 39))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('glioma', 'Disease', (236, 242))	('glioma', 'Disease', 'MESH:D005910', (236, 242))	('exhibited', 'Reg', (196, 205))
237578	21880180	When the tyrosine phosphorylation sites for PI3K binding were mutated to phenylalanine, PDGFRalpha lost the capacity to transform mouse astrocytes, both in vitro in soft agar and in vivo in the brain of mice.	('phenylalanine', 'Chemical', 'MESH:D010649', (73, 86))	('lost', 'NegReg', (99, 103))	('mice', 'Species', '10090', (203, 207))	('tyrosine', 'Chemical', 'MESH:D014443', (9, 17))	('transform mouse astrocytes', 'CPA', (120, 146))	('PDGFRalpha', 'Gene', (88, 98))	('agar', 'Chemical', 'MESH:D000362', (170, 174))	('mouse', 'Species', '10090', (130, 135))	('mutated', 'Var', (62, 69))
237619	20445000	The tumor's ability to repair radiation-induced                 injury accomplished by aberrant or amplified growth and survival signaling pathways                 are being appreciated.	('tumor', 'Disease', (4, 9))	('injury', 'Disease', (64, 70))	('injury', 'Disease', 'MESH:D058186', (64, 70))	('aberrant', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('growth', 'CPA', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('amplified', 'PosReg', (99, 108))
237620	20445000	Although of value in                 extending tumor control and survival in selected cases, Gliadel is associated with                 more frequent episodes of wound infection, cerebral edema, and wound breakdown in                 patients compared with individuals not receiving this intervention.	('cerebral edema', 'Disease', (179, 193))	('frequent episodes', 'Phenotype', 'HP:0002719', (141, 158))	('cerebral edema', 'Phenotype', 'HP:0002181', (179, 193))	('wound', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cerebral edema', 'Disease', 'MESH:D001929', (179, 193))	('frequent episodes of wound infection', 'Phenotype', 'HP:0001581', (141, 177))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Gliadel', 'Var', (93, 100))	('edema', 'Phenotype', 'HP:0000969', (188, 193))	('tumor', 'Disease', (47, 52))
237622	20445000	It is now commonly recognized that silencing of the                     MGMT gene promoter by methylation is associated with better                 tumor response to combination treatment with radiation and temozolomide.	('silencing', 'NegReg', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('MGMT', 'Gene', '4255', (72, 76))	('tumor', 'Disease', (148, 153))	('MGMT', 'Gene', (72, 76))	('better', 'PosReg', (125, 131))	('temozolomide', 'Chemical', 'MESH:D000077204', (207, 219))	('methylation', 'Var', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
237626	20445000	Excitement over the                 recent success of bevacizumab in brain tumors and other cancer sites is likely to be                 tempered by the increasing recognition that there are underlying genetic variations                 in VEGF that clearly influence sensitivity or resistance to this treatment                     agent.	('brain tumor', 'Phenotype', 'HP:0030692', (69, 80))	('resistance', 'MPA', (283, 293))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('VEGF', 'Gene', '7422', (240, 244))	('bevacizumab', 'Chemical', 'MESH:D000068258', (54, 65))	('sensitivity', 'MPA', (268, 279))	('influence', 'Reg', (258, 267))	('brain tumors', 'Phenotype', 'HP:0030692', (69, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('genetic variations', 'Var', (202, 220))	('brain tumors', 'Disease', 'MESH:D001932', (69, 81))	('VEGF', 'Gene', (240, 244))	('brain tumors', 'Disease', (69, 81))
237639	20445000	Cancers originate as the result of hereditary or somatic alterations in                     genes that control critical biological processes.	('genes', 'Gene', (92, 97))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('alterations', 'Var', (57, 68))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
237648	20445000	The                     latest breakthrough came in 2008, when the genes encoding isocitrate                     dehydrogenase 1 (IDH1) (and to a lesser extent IDH2) were found to be mutated in                     lower grade gliomas and a subset of glioblastomas (those of the proneural type                     or having evolved from lower grade tumors).	('isocitrate', 'Chemical', 'MESH:C034219', (82, 92))	('glioblastomas', 'Disease', 'MESH:D005909', (250, 263))	('mutated', 'Var', (183, 190))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (250, 262))	('IDH2', 'Gene', '3418', (160, 164))	('IDH1', 'Gene', (130, 134))	('glioblastomas', 'Disease', (250, 263))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('tumors', 'Disease', (348, 354))	('tumors', 'Disease', 'MESH:D009369', (348, 354))	('IDH1', 'Gene', '3417', (130, 134))	('gliomas', 'Disease', (226, 233))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('IDH2', 'Gene', (160, 164))	('glioblastomas', 'Phenotype', 'HP:0012174', (250, 263))
237671	20445000	Such tumors may also be responsive to inhibitors of Mdm2, the                     negative regulator of p53.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('p53', 'Gene', (104, 107))	('tumors', 'Disease', (5, 11))	('Mdm2', 'Gene', '4193', (52, 56))	('p53', 'Gene', '7157', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('inhibitors', 'Var', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('Mdm2', 'Gene', (52, 56))
237677	20445000	In this                     group, patients are younger, and overexpression or amplification/mutation of the                     gene encoding platelet-derived growth factor                         receptor-alpha (PDGFRA) and mutations in the                         IDH1 gene (30% of cases) are signature genetic                     alterations.	('overexpression', 'PosReg', (61, 75))	('platelet-derived growth factor                         receptor-alpha', 'Gene', '5156', (143, 212))	('IDH1', 'Gene', (267, 271))	('PDGFRA', 'Gene', (214, 220))	('IDH1', 'Gene', '3417', (267, 271))	('PDGFRA', 'Gene', '5156', (214, 220))	('mutations', 'Var', (226, 235))	('patients', 'Species', '9606', (35, 43))	('amplification/mutation', 'Var', (79, 101))
237678	20445000	Frequent mutations in TP53 (54%) and                         PIK3CA/PIK3R1 (19%) genes are also observed,                     whereas amplification of chromosome 7 and loss on chromosome 10 were significant                     (>50%) but less frequent findings than in the classical subtype.	('PIK3CA', 'Gene', (61, 67))	('PIK3R1', 'Gene', (68, 74))	('PIK3CA', 'Gene', '5290', (61, 67))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('PIK3R1', 'Gene', '5295', (68, 74))
237679	20445000	The                     finding of IDH1/2 gene mutations in lower grade gliomas also                     suggests that secondary glioblastoma might belong to this subtype.	('glioblastoma', 'Disease', (129, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('mutations', 'Var', (47, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))	('IDH1/2', 'Gene', (35, 41))
237680	20445000	This subtype may be most responsive to inhibitors of the                     hypoxia-inducible factor (HIF), PI3K, and PDGFRA pathways.	('inhibitors', 'Var', (39, 49))	('PDGFRA', 'Gene', '5156', (119, 125))	('hypoxia', 'Disease', (77, 84))	('PI3K', 'Pathway', (109, 113))	('PDGFRA', 'Gene', (119, 125))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
237693	20445000	This can be achieved through overexpression or genetic                         amplification of growth factor receptor genes (EGFR, ERBB2, PDGFRA, MET,                         etc), as well as through gene mutations that lead to ligand-independent                         signaling as occurs for the epidermal growth factor receptor vIII                         (EGFRvIII), a mutant that sends constitutive growth signals.	('mutations', 'Var', (206, 215))	('ERBB2', 'Gene', (132, 137))	('EGFR', 'Gene', (126, 130))	('MET', 'Gene', (147, 150))	('epidermal growth factor', 'Gene', (300, 323))	('epidermal growth factor', 'Gene', '1950', (300, 323))	('PDGFRA', 'Gene', '5156', (139, 145))	('PDGFRA', 'Gene', (139, 145))	('EGFR', 'Gene', '1956', (363, 367))	('EGFR', 'Gene', (363, 367))	('ERBB2', 'Gene', '2064', (132, 137))	('EGFR', 'Gene', '1956', (126, 130))	('lead to', 'Reg', (221, 228))
237694	20445000	Alternatively,                         intracellular signaling pathways can be constitutively activated when the                         positive signaling molecules are mutated and signal constitutively, as                         occurs for PI3K pathway subunits (PIK3A, PIK3R1) or when the negative                         regulators of the pathway are lost through gene loss or mutation (eg, the                         PTEN tumor suppressor).	('PI3K', 'Gene', (243, 247))	('intracellular signaling pathways', 'Pathway', (39, 71))	('mutated', 'Var', (170, 177))	('PTEN tumor', 'Disease', (424, 434))	('PIK3A', 'Gene', (266, 271))	('gene loss', 'Disease', 'MESH:D025063', (369, 378))	('gene loss', 'Disease', (369, 378))	('PIK3R1', 'Gene', '5295', (273, 279))	('PTEN tumor', 'Disease', 'MESH:D006223', (424, 434))	('mutation', 'Var', (382, 390))	('PIK3R1', 'Gene', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))	('activated', 'PosReg', (94, 103))
237699	20445000	Although p53 and Rb can be the direct targets of mutations,                         the inactivation of these cell cycle control pathways can also be achieved                         indirectly by mutation or overexpression of other signaling molecules in the                         pathway (Fig.	('mutations', 'Var', (49, 58))	('p53', 'Gene', (9, 12))	('overexpression', 'PosReg', (209, 223))	('p53', 'Gene', '7157', (9, 12))	('Rb', 'Phenotype', 'HP:0009919', (17, 19))	('inactivation', 'NegReg', (88, 100))	('cell cycle control pathways', 'Pathway', (110, 137))	('mutation', 'Var', (197, 205))
237702	20445000	To overcome this limitation in their growth,                         tumors will typically also genetically inactivate proapoptotic pathways or                         activate the over-expression of genes that can promote cell survival.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('promote', 'PosReg', (215, 222))	('cell survival', 'CPA', (223, 236))	('over-expression of', 'MPA', (181, 199))	('activate', 'PosReg', (168, 176))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('proapoptotic pathways', 'Pathway', (119, 140))	('tumors', 'Disease', (69, 75))	('genetically', 'Var', (96, 107))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('inactivate', 'NegReg', (108, 118))
237703	20445000	The                         inactivation of the p53 protein by mutation abrogates proapoptotic responses                         in the cell because this factor controls the transcription of both cell                         cycle arrest (p21CKI) and proapoptotic genes (Bax, Fas, etc).	('abrogates', 'NegReg', (72, 81))	('controls', 'Reg', (161, 169))	('p53', 'Gene', (48, 51))	('Bax', 'Gene', '581', (271, 274))	('p21', 'Gene', '644914', (239, 242))	('transcription', 'MPA', (174, 187))	('cell                         cycle arrest', 'CPA', (196, 237))	('p53', 'Gene', '7157', (48, 51))	('protein', 'Protein', (52, 59))	('mutation', 'Var', (63, 71))	('cell                         cycle arrest', 'Phenotype', 'HP:0011018', (196, 237))	('proapoptotic responses', 'MPA', (82, 104))	('Bax', 'Gene', (271, 274))	('p21', 'Gene', (239, 242))
237713	20445000	Nearly half of tumors with EGFR                         amplification also have a constitutively active EGFR mutant known as                         EGFRvIII, which has a large deletion in the extracellular domain and renders                         the receptor ligand independent for signaling.	('tumors', 'Disease', (15, 21))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('deletion', 'Var', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EGFR', 'Gene', '1956', (149, 153))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('EGFR', 'Gene', (149, 153))	('mutant', 'Var', (109, 115))	('amplification', 'Var', (56, 69))
237721	20445000	Recent phase 2 studies have combined EGFR inhibitors with                         temozolomide and radiotherapy for patients with newly diagnosed GBM.	('temozolomide', 'Chemical', 'MESH:D000077204', (82, 94))	('patients', 'Species', '9606', (116, 124))	('EGFR', 'Gene', '1956', (37, 41))	('inhibitors', 'Var', (42, 52))	('EGFR', 'Gene', (37, 41))
237722	20445000	Other current trials in patients                         with malignant glioma are evaluating irreversible EGFR inhibitors such as                         BIBW 2992 and PF-00299804, the dual EGFR and VEGF receptor (VEGFR) inhibitor                         vandetanib (ZD6474), and the humanized monoclonal antibody against EGFR,                         nimotuzumab.	('BIBW 2992', 'Chemical', 'MESH:D000077716', (155, 164))	('vandetanib', 'Chemical', 'MESH:C452423', (256, 266))	('VEGFR', 'Gene', (215, 220))	('EGFR', 'Gene', (107, 111))	('nimotuzumab', 'Chemical', 'MESH:C501466', (353, 364))	('VEGF receptor', 'Gene', (200, 213))	('EGFR', 'Gene', (216, 220))	('EGFR', 'Gene', '1956', (323, 327))	('VEGF receptor', 'Gene', '3791', (200, 213))	('EGFR', 'Gene', (191, 195))	('malignant glioma', 'Disease', 'MESH:D005910', (62, 78))	('ZD6474', 'Chemical', 'MESH:C452423', (268, 274))	('malignant glioma', 'Disease', (62, 78))	('EGFR', 'Gene', '1956', (107, 111))	('PF-00299804', 'Var', (169, 180))	('human', 'Species', '9606', (285, 290))	('EGFR', 'Gene', '1956', (216, 220))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (323, 327))	('patients', 'Species', '9606', (24, 32))	('VEGFR', 'Gene', '3791', (215, 220))
237728	20445000	Studies with more potent PDGFR inhibitors and agents with                         improved BBB penetration such as tandutinib (MLN518) currently are                         underway.	('PDGFR', 'Gene', (25, 30))	('PDGFR', 'Gene', '5159', (25, 30))	('MLN518', 'Var', (127, 133))	('MLN518', 'Chemical', 'MESH:C464670', (127, 133))	('tandutinib', 'Chemical', 'MESH:C464670', (115, 125))
237732	20445000	In                         malignant gliomas, PI3K/Akt/mTOR signaling is frequently increased because                         of receptor tyrosine kinase overactivity (EGFR, PDGFR, and                         mesenchymal-epithelial transition factor [MET]), mutated                         oncogenic PI3K subunits, and/or loss of PTEN tumor suppressor activity                             (Fig.	('EGFR', 'Gene', '1956', (168, 172))	('malignant gliomas', 'Disease', (27, 44))	('loss', 'NegReg', (322, 326))	('increased', 'PosReg', (84, 93))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('receptor tyrosine kinase', 'Gene', '5979', (129, 153))	('PTEN tumor', 'Disease', (330, 340))	('PDGFR', 'Gene', (174, 179))	('PDGFR', 'Gene', '5159', (174, 179))	('receptor tyrosine kinase', 'Gene', (129, 153))	('mutated', 'Var', (258, 265))	('mTOR', 'Gene', (55, 59))	('Akt', 'Gene', (51, 54))	('EGFR', 'Gene', (168, 172))	('PTEN tumor', 'Disease', 'MESH:D006223', (330, 340))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('Akt', 'Gene', '207', (51, 54))	('mTOR', 'Gene', '2475', (55, 59))	('malignant gliomas', 'Disease', 'MESH:D005910', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('overactivity', 'PosReg', (154, 166))
237737	20445000	Enzastaurin (LY317615) is a potent inhibitor of protein                         kinase C-beta2 that also suppresses PI3K/Akt pathway                         signaling.	('Akt', 'Gene', (121, 124))	('LY317615', 'Chemical', 'MESH:C504878', (13, 21))	('suppresses', 'NegReg', (105, 115))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('LY317615', 'Var', (13, 21))	('Akt', 'Gene', '207', (121, 124))
237741	20445000	Unfortunately, the FTI tipifarnib (R115777) did not                         demonstrate clear evidence of efficacy in a phase 2 trial in patients with                         recurrent malignant gliomas.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('malignant gliomas', 'Disease', (185, 202))	('R115777', 'Var', (35, 42))	('malignant gliomas', 'Disease', 'MESH:D005910', (185, 202))	('patients', 'Species', '9606', (137, 145))	('tipifarnib', 'Chemical', 'MESH:C402769', (23, 33))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))
237742	20445000	Histone deacetylase (HDAC) inhibitors interfere with transcriptional                         regulation and can induce growth arrest, terminal differentiation, and                         apoptosis of tumor cells.	('HDAC', 'Gene', '9734', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('growth arrest', 'Disease', (119, 132))	('transcriptional                         regulation', 'MPA', (53, 103))	('apoptosis', 'CPA', (188, 197))	('growth arrest', 'Disease', 'MESH:D006323', (119, 132))	('interfere', 'NegReg', (38, 47))	('inhibitors', 'Var', (27, 37))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('terminal differentiation', 'CPA', (134, 158))	('HDAC', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('induce', 'Reg', (112, 118))	('Histone deacetylase', 'Gene', (0, 19))	('growth arrest', 'Phenotype', 'HP:0001510', (119, 132))
237751	20445000	In                         preclinical models, multiple kinase inhibition is required to reduce                         signaling through the PI3K/Akt/mTOR pathway and decrease glioma cell                             survival.	('signaling', 'MPA', (120, 129))	('glioma', 'Disease', (177, 183))	('reduce', 'NegReg', (89, 95))	('Akt', 'Gene', '207', (147, 150))	('decrease', 'NegReg', (168, 176))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('inhibition', 'Var', (63, 73))	('mTOR', 'Gene', (151, 155))	('Akt', 'Gene', (147, 150))	('mTOR', 'Gene', '2475', (151, 155))
237753	20445000	Particular interest has focused on the                         combination of EGFR inhibitors and mTOR inhibitors.	('mTOR', 'Gene', '2475', (98, 102))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('mTOR', 'Gene', (98, 102))	('inhibitors', 'Var', (83, 93))
237756	20445000	For example, combinations of EGFR                         inhibitors with mTOR inhibitors have been associated with a high incidence                         of dermatologic toxicity and mucositis.	('combinations', 'Interaction', (13, 25))	('mucositis', 'Disease', (186, 195))	('associated', 'Reg', (100, 110))	('mTOR', 'Gene', (74, 78))	('mucositis', 'Disease', 'MESH:D052016', (186, 195))	('mTOR', 'Gene', '2475', (74, 78))	('inhibitors', 'Var', (58, 68))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('toxicity', 'Disease', 'MESH:D064420', (173, 181))	('toxicity', 'Disease', (173, 181))
237773	20445000	Ang-2                         inhibitors are therefore of interest as therapeutic agents.	('Ang-2', 'Gene', '285', (0, 5))	('inhibitors', 'Var', (30, 40))	('Ang-2', 'Gene', (0, 5))
237776	20445000	Inhibition of delta-like ligand 4 (Dll4) on endothelial cells in preclinical                         models promotes the growth of an abnormal neovasculature with reduced                         perfusion and tumor growth.	('growth', 'CPA', (121, 127))	('tumor', 'Disease', (209, 214))	('Dll4', 'Gene', '54567', (35, 39))	('delta-like ligand 4', 'Gene', (14, 33))	('reduced', 'NegReg', (163, 170))	('perfusion', 'MPA', (195, 204))	('delta-like ligand 4', 'Gene', '54567', (14, 33))	('Inhibition', 'Var', (0, 10))	('promotes', 'PosReg', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('Dll4', 'Gene', (35, 39))
237803	20445000	In addition to VEGF inhibitors, small molecule inhibitors of VEGFR                         have been tested in recurrent malignant gliomas.	('VEGF', 'Gene', '7422', (61, 65))	('tested', 'Reg', (101, 107))	('malignant gliomas', 'Disease', (121, 138))	('VEGFR', 'Gene', (61, 66))	('VEGF', 'Gene', (15, 19))	('small molecule inhibitors', 'Var', (32, 57))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('malignant gliomas', 'Disease', 'MESH:D005910', (121, 138))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('VEGF', 'Gene', (61, 65))	('VEGF', 'Gene', '7422', (15, 19))	('VEGFR', 'Gene', '3791', (61, 66))
237811	20445000	Other VEGFR inhibitors of interest for malignant gliomas are                         listed in Table 1.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('inhibitors', 'Var', (12, 22))	('VEGFR', 'Gene', '3791', (6, 11))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('VEGFR', 'Gene', (6, 11))	('malignant gliomas', 'Disease', (39, 56))	('malignant gliomas', 'Disease', 'MESH:D005910', (39, 56))
237813	20445000	Because of its role in pericyte                             recruitment, inhibition of                         PDGFR may prove useful.	('PDGFR', 'Gene', '5159', (111, 116))	('inhibition', 'Var', (73, 83))	('pericyte                             recruitment', 'CPA', (23, 71))	('PDGFR', 'Gene', (111, 116))
237814	20445000	Several trials of PDGFR and dually targeted                         VEGFR/PDGFR inhibitors are ongoing, as noted earlier.	('PDGFR', 'Gene', '5159', (18, 23))	('VEGFR', 'Gene', '3791', (68, 73))	('PDGFR', 'Gene', (74, 79))	('PDGFR', 'Gene', '5159', (74, 79))	('VEGFR', 'Gene', (68, 73))	('PDGFR', 'Gene', (18, 23))	('inhibitors', 'Var', (80, 90))
237816	20445000	Cilengitide                         (EMD121974) inhibits these integrins and appears promising in GBM patients                         with methylation of the MGMT gene promoter.	('inhibits', 'NegReg', (48, 56))	('methylation', 'Var', (140, 151))	('integrins', 'Protein', (63, 72))	('MGMT', 'Gene', '4255', (159, 163))	('patients', 'Species', '9606', (102, 110))	('MGMT', 'Gene', (159, 163))	('EMD121974', 'Var', (37, 46))	('GBM', 'Disease', (98, 101))
237823	20445000	Most human cancers, including high-grade gliomas, have abnormalities in                     cellular signal transduction pathways.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('abnormalities', 'Var', (55, 68))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('human', 'Species', '9606', (5, 10))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('gliomas', 'Disease', (41, 48))	('cellular signal transduction pathways', 'Pathway', (92, 129))
237866	20445000	Such approaches may                     lead to customized immunotherapy in the not-so-distant future, in which the                     patient's own immune system is boosted to produce antitumor                     responses.	('patient', 'Species', '9606', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('lead to', 'Reg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('approaches', 'Var', (5, 15))
237984	20445000	Two of the most common abnormalities noted                     in malignant gliomas are amplification/mutation of EGFR and                     loss of PTEN, resulting in PI3K activation.	('PI3K', 'Pathway', (170, 174))	('amplification/mutation', 'Var', (88, 110))	('malignant gliomas', 'Disease', (66, 83))	('activation', 'PosReg', (175, 185))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('EGFR', 'Gene', (114, 118))	('EGFR', 'Gene', '1956', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('malignant gliomas', 'Disease', 'MESH:D005910', (66, 83))	('loss', 'Var', (143, 147))	('PTEN', 'Gene', (151, 155))	('PTEN', 'Gene', '5728', (151, 155))
237985	20445000	Engineered glioma                     cells with decreased EGFR signaling result in greater radiosensitivity and expression of a mutant,                     constitutively active EGFR was found to produce radioresistance, primarily                     through activation of the PI3K pathway.	('EGFR', 'Gene', (179, 183))	('PI3K pathway', 'Pathway', (278, 290))	('radioresistance', 'CPA', (205, 220))	('EGFR', 'Gene', '1956', (179, 183))	('EGFR', 'Gene', (59, 63))	('produce', 'PosReg', (197, 204))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('activation', 'PosReg', (260, 270))	('Engineered glioma', 'Disease', (0, 17))	('greater', 'PosReg', (84, 91))	('Engineered glioma', 'Disease', 'MESH:D005910', (0, 17))	('radiosensitivity', 'MPA', (92, 108))	('EGFR', 'Gene', '1956', (59, 63))	('mutant', 'Var', (129, 135))
238074	31446127	LC2 decreases the mTREs to 1.57-1.75mm in RESECT and 2.52 mm in BITE (with a different set of parameters).	('LC2', 'Chemical', '-', (0, 3))	('BITE', 'Gene', '80321', (64, 68))	('mTREs', 'MPA', (18, 23))	('RESECT', 'CPA', (42, 48))	('BITE', 'Gene', (64, 68))	('LC2', 'Var', (0, 3))	('decreases', 'NegReg', (4, 13))
238084	31446127	Blue and white arrows point out tumor boundaries, yellow arrows the falx, and red arrows the sulci.	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('yellow', 'Var', (50, 56))
238119	24410805	High expression levels of epidermal growth factor receptor (EGFR), CD44, c-MER proto-oncogene tyrosine kinase (MERTK), platelet-derived growth factor receptor alpha, p53, oligodendrocyte transcription factor 2 (OLIG2) and isocitrate dehydrogenase 1 with the R132H mutation were assessed using immunohistochemistry (IHC).	('CD44', 'Gene', '960', (67, 71))	('CD44', 'Gene', (67, 71))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (119, 164))	('c-MER proto-oncogene tyrosine kinase', 'Gene', '10461', (73, 109))	('R132H', 'Var', (258, 263))	('R132H', 'Mutation', 'rs1034749666', (258, 263))	('c-MER proto-oncogene tyrosine kinase', 'Gene', (73, 109))	('p53', 'Gene', '7157', (166, 169))	('EGFR', 'Gene', '1956', (60, 64))	('platelet-derived growth factor receptor alpha', 'Gene', (119, 164))	('p53', 'Gene', (166, 169))	('oligodendrocyte transcription factor 2', 'Gene', '10215', (171, 209))	('epidermal growth factor receptor', 'Gene', (26, 58))	('OLIG2', 'Gene', (211, 216))	('MERTK', 'Gene', '10461', (111, 116))	('epidermal growth factor receptor', 'Gene', '1956', (26, 58))	('MERTK', 'Gene', (111, 116))	('OLIG2', 'Gene', '10215', (211, 216))	('EGFR', 'Gene', (60, 64))	('oligodendrocyte transcription factor 2', 'Gene', (171, 209))
238130	24410805	While growing, these tumours (with the exception of ependymoma) tend to diffusely infiltrate the surrounding brain tissue, as recently demonstrated for gliomas of WHO grade II/III and secondary GBM, with isocitrate dehydrogenase 1 (IDH1) bearing the R132H mutation (IDH1R132H).	('ependymoma', 'Disease', (52, 62))	('gliomas', 'Disease', 'MESH:D005910', (152, 159))	('ependymoma', 'Disease', 'MESH:D004806', (52, 62))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('gliomas', 'Disease', (152, 159))	('IDH1', 'Gene', (266, 270))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('IDH1', 'Gene', (232, 236))	('IDH1', 'Gene', '3417', (266, 270))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('R132H', 'Var', (250, 255))	('IDH1', 'Gene', '3417', (232, 236))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('ependymoma', 'Phenotype', 'HP:0002888', (52, 62))	('tumours', 'Disease', (21, 28))	('R132H', 'Mutation', 'rs1034749666', (250, 255))	('R132H', 'Mutation', 'rs1034749666', (270, 275))
238131	24410805	Accumulation of genetic alterations is involved in the initiation and progression of gliomas, leading to great genetic heterogeneity of these tumours.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('genetic alterations', 'Var', (16, 35))	('gliomas', 'Disease', (85, 92))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
238135	24410805	Furthermore, the tumour suppressor protein p53, oligodendrocyte transcription factor 2 (OLIG2) and IDH1 with the R132H mutation have also been reported to be of interest.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('oligodendrocyte transcription factor 2', 'Gene', '10215', (48, 86))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('OLIG2', 'Gene', '10215', (88, 93))	('oligodendrocyte transcription factor 2', 'Gene', (48, 86))	('tumour', 'Disease', (17, 23))	('p53', 'Gene', (43, 46))	('IDH1', 'Gene', (99, 103))	('p53', 'Gene', '7157', (43, 46))	('R132H', 'Var', (113, 118))	('R132H', 'Mutation', 'rs1034749666', (113, 118))	('IDH1', 'Gene', '3417', (99, 103))	('OLIG2', 'Gene', (88, 93))
238170	24410805	Sixty-seven per cent of grade II/III tumours and 11% of GBMs showed high IDH1R132H IR.	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('III tumours', 'Disease', 'MESH:D009369', (33, 44))	('III tumours', 'Disease', (33, 44))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('IDH1R132H IR', 'Var', (73, 85))
238321	32980599	A recent voxel-based morphometry study involving 84 patients with LGG in the insula detected a significant increase in the gray-matter volume of the contralesional insula.	('patients', 'Species', '9606', (52, 60))	('LGG in', 'Var', (66, 72))	('gray-matter volume', 'MPA', (123, 141))	('increase', 'PosReg', (107, 115))
238329	32980599	Accordingly, development of accurate surgical planning is deemed as crucial to prevent fatal injury by resection of this tract (e.g.,).	('fatal injury', 'Disease', 'MESH:C535933', (87, 99))	('fatal injury', 'Disease', (87, 99))	('resection', 'Var', (103, 112))
238334	32980599	For instance, reported the findings of a study on a cohort of 13 patients with LGG and observed that stimulation of the AF elicited phonological paraphasia in six patients, whereas all of them experienced semantic paraphasia under stimulation of the inferior frontal-occipital fasciculus (IFOF).	('AF', 'Disease', 'MESH:D001281', (120, 122))	('patients', 'Species', '9606', (163, 171))	('LGG', 'Disease', (79, 82))	('aphasia', 'Disease', (148, 155))	('aphasia', 'Phenotype', 'HP:0002381', (148, 155))	('aphasia', 'Disease', 'MESH:D001037', (217, 224))	('stimulation', 'Var', (101, 112))	('phonological', 'MPA', (132, 144))	('aphasia', 'Disease', 'MESH:D001037', (148, 155))	('phonological paraphasia', 'Phenotype', 'HP:0002427', (132, 155))	('patients', 'Species', '9606', (65, 73))	('aphasia', 'Disease', (217, 224))	('aphasia', 'Phenotype', 'HP:0002381', (217, 224))	('inferior frontal-occipital fasciculus', 'Disease', 'MESH:D006259', (250, 287))	('elicited', 'Reg', (123, 131))	('inferior frontal-occipital fasciculus', 'Disease', (250, 287))
238373	32980599	In relation to the sensorimotor system, many studies reported intrahemispheric reorganization following resection of gliomas in the motor (e.g.,) and in the somatosensory cortex (e.g.,).	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('resection', 'Var', (104, 113))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))
238374	32980599	Tumor resection in the central sulcus was observed to increase the frequency of activation in primary and secondary (i.e., premotor and SMA) motor cortices; applied TMS over the affected hemisphere and observed significant shifts (>10 mm) in the cortical motor representation as compared to the pre-surgery stage.	('SMA', 'Gene', '6606', (136, 139))	('SMA', 'Gene', (136, 139))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMS', 'Gene', (165, 168))	('TMS', 'Gene', '29108', (165, 168))	('increase', 'PosReg', (54, 62))	('activation', 'PosReg', (80, 90))	('Tumor resection', 'Var', (0, 15))	('shifts', 'Reg', (223, 229))
238385	32980599	For instance, observed that the resection of the posterior (but not anterior) portion of the left ILF caused the onset of global alexia, whereas the resection of the left posterior AF caused deficits in reading pseudowords and irregular words.	('alexia', 'Phenotype', 'HP:0010523', (129, 135))	('alexia', 'Disease', 'MESH:D004410', (129, 135))	('AF', 'Disease', 'MESH:D001281', (181, 183))	('resection', 'Var', (149, 158))	('irregular words', 'MPA', (227, 242))	('reading pseudowords', 'MPA', (203, 222))	('resection', 'Var', (32, 41))	('alexia', 'Disease', (129, 135))
238387	32980599	Some studies investigated the impact of tumor resection at the whole-brain level in a hodotopic perspective: Surgery may have effects even beyond the resected area and its surroundings and can also cause a complex pattern of changes at the functional connectivity level.	('cause', 'Reg', (198, 203))	('changes', 'Reg', (225, 232))	('functional connectivity', 'MPA', (240, 263))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Surgery', 'Var', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('effects', 'Reg', (126, 133))
238421	32980599	This network displayed a high compensation potential, with rare cases of permanent aphasia, mainly resulting from damage in the subcortical connections.	('subcortical', 'Protein', (128, 139))	('compensation potential', 'MPA', (30, 52))	('aphasia', 'Phenotype', 'HP:0002381', (83, 90))	('damage', 'Var', (114, 120))	('aphasia', 'Disease', 'MESH:D001037', (83, 90))	('aphasia', 'Disease', (83, 90))
238438	32788236	BRAFV600E mutation is immunogenic in children with LGG and may serve as a target for immune therapy.	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('LGG', 'Disease', (51, 54))	('BRAFV600E', 'Var', (0, 9))	('children', 'Species', '9606', (37, 45))
238472	32788236	These distinct subsets of T-cells could also be detected by multiplex immunofluorescence IHC, and tumors with PXA/GG subtypes had the highest proportion of T-cells with CD103+ TRM phenotype (figure 2E-F).	('tumors', 'Disease', (98, 104))	('CD103+ TRM', 'Var', (169, 179))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('PXA', 'Chemical', '-', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PXA/GG', 'Gene', (110, 116))
238478	32788236	In spite of a generally excellent prognosis, patients with low-grade tumors may experience recurrent disease, often at the site of initial tumor.	('experience', 'Reg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('low-grade', 'Var', (59, 68))	('recurrent', 'Disease', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
238480	32788236	As noted earlier, PA tumors had a lower proportion of CD103+ T-cells at baseline.	('CD103+', 'Var', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('PA tumors', 'Disease', 'MESH:D011471', (18, 27))	('PA tumors', 'Disease', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
238487	32788236	Although most pediatric LGG share activation of the BRAF-MAPK pathway as a common genomic alteration, the mechanism underlying BRAF activation in PXA/GG is commonly the V600E mutation, while BRAF-KIAA1549 fusion is observed in PAs.	('BRAF', 'Gene', (191, 195))	('activation', 'PosReg', (132, 142))	('KIAA1549', 'Gene', '57670', (196, 204))	('V600E', 'Mutation', 'rs113488022', (169, 174))	('BRAF', 'Gene', '673', (127, 131))	('KIAA1549', 'Gene', (196, 204))	('V600E', 'Var', (169, 174))	('BRAF', 'Gene', (127, 131))	('PXA', 'Chemical', '-', (146, 149))	('BRAF', 'Gene', '673', (52, 56))	('PXA/GG', 'Gene', (146, 152))	('BRAF', 'Gene', '673', (191, 195))	('BRAF', 'Gene', (52, 56))
238488	32788236	In order to test whether the BRAFV600E mutation could be immunogenic in pediatric tumors, we synthesized peptides encompassing this mutation and used these to detect and expand BRAFV600E-specific T-cells in culture.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BRAFV600E', 'Mutation', 'rs113488022', (177, 186))	('BRAFV600E', 'Gene', (29, 38))	('BRAFV600E-specific', 'Var', (177, 195))	('peptides', 'Chemical', 'MESH:D010455', (105, 113))
238489	32788236	In a patient with BRAFV600E-mutant LGG and available fresh T-cells, we could demonstrate the presence of V600E-specific T-cell immunity (online supplementary figure 2A).	('V600E-specific', 'Var', (105, 119))	('patient', 'Species', '9606', (5, 12))	('BRAFV600E', 'Mutation', 'rs113488022', (18, 27))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('BRAFV600E-mutant', 'Var', (18, 34))	('V600E', 'Mutation', 'rs113488022', (22, 27))
238490	32788236	In a different patient with a BRAFV600E-mutant anaplastic GG (classified as HGG, online supplementary table 1B), while we did not detect BRAFV600E mutation-specific T-cells in freshly isolated T-cells, we could demonstrate expansion of BRAFV600E-specific T-cells after stimulation with autologous dendritic cells pulsed with mutant peptide (online supplementary figure 2B).	('patient', 'Species', '9606', (15, 22))	('BRAFV600E-mutant', 'Var', (30, 46))	('BRAFV600E', 'Mutation', 'rs113488022', (137, 146))	('BRAFV600E', 'Mutation', 'rs113488022', (236, 245))	('expansion', 'PosReg', (223, 232))	('BRAFV600E-specific', 'Var', (236, 254))	('BRAFV600E', 'Mutation', 'rs113488022', (30, 39))
238498	32788236	Clinical response to such therapy has been reported in a melanoma patient, and our studies set the stage for consideration of neoantigen-directed T-cell therapy in BRAFV600E-mutant pediatric glioma.	('BRAFV600E-mutant', 'Var', (164, 180))	('glioma', 'Disease', (191, 197))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('patient', 'Species', '9606', (66, 73))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('BRAFV600E', 'Mutation', 'rs113488022', (164, 173))
238501	32788236	Whether the expression of these stemness markers contributes to exclusion of immune infiltration in glioma deserves further study, as targeting this gene may then enhance glioma immune therapies.	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('targeting', 'Var', (134, 143))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma', 'Disease', (171, 177))	('enhance', 'PosReg', (163, 170))	('stemness', 'Disease', 'MESH:D020295', (32, 40))	('stemness', 'Disease', (32, 40))
238502	32788236	Limitations of our study include small sample size and the lack of clinical follow-up data to understand the importance of the spatial location of the TCF1+ and CD103+ tumor-resident T-cells.	('TCF1', 'Gene', '6932', (151, 155))	('tumor', 'Disease', (168, 173))	('TCF1', 'Gene', (151, 155))	('CD103+', 'Var', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
238503	32788236	In addition, while we could detect BRAFV600E mutation-specific T-cells in pediatric glioma, we were not able to test lysis of autologous tumors by these T-cells.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BRAFV600E', 'Var', (35, 44))	('glioma', 'Disease', (84, 90))	('BRAFV600E', 'Mutation', 'rs113488022', (35, 44))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
238504	32788236	Our data also do not address the potential immunogenicity of other (non-V600E) alterations in the BRAF pathway in these patients.	('non-V600E', 'Var', (68, 77))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', (98, 102))	('patients', 'Species', '9606', (120, 128))	('V600E', 'Mutation', 'rs113488022', (72, 77))
238505	32788236	Our data provide novel insights into spatial aspects of heterogeneity of tumor-infiltrating lymphocytes in pediatric tumors, with identification of two major subtypes: TCF1+ T-cells mostly in the perivascular location and CD103+ T-cells within the tumor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CD103+', 'Var', (222, 228))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TCF1', 'Gene', '6932', (168, 172))	('TCF1', 'Gene', (168, 172))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', (73, 78))	('perivascular location', 'Phenotype', 'HP:0012520', (196, 217))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
238506	32788236	The subset of CD103+ T-cells within tumors is of particular interest, as this subset has been implicated in pathogen-specific tissue immunity and long-term protection in mouse models of viral central nervous system infection.	('CD103+', 'Var', (14, 20))	('viral central nervous system infection', 'Disease', (186, 224))	('viral central nervous system infection', 'Disease', 'MESH:D001102', (186, 224))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mouse', 'Species', '10090', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('central nervous system infection', 'Phenotype', 'HP:0011450', (192, 224))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('implicated', 'Reg', (94, 104))
238508	32788236	Recurrent tumors were also characterized by increased angiogenesis, which is consistent with prior studies correlating angiogenic factors such as VEGF (vascular endothelial growth factor) and loss of TRM , and support consideration of targeting these factors in combination with immune therapies to treat recurrent tumors.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (315, 321))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('angiogenesis', 'CPA', (54, 66))	('VEGF', 'Gene', (146, 150))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('angiogenic', 'MPA', (119, 129))	('VEGF', 'Gene', '7422', (146, 150))	('vascular endothelial growth factor', 'Gene', (152, 186))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('increased', 'PosReg', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('loss', 'Var', (192, 196))	('vascular endothelial growth factor', 'Gene', '7422', (152, 186))	('TRM', 'Gene', (200, 203))
238520	32788236	15-mer BRAF wild-type and mutated BRAFV600E peptides were synthesized by the Proteomics Resource Center at The Rockefeller University, as previously described.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('BRAF', 'Gene', '673', (34, 38))	('mutated', 'Var', (26, 33))	('BRAF', 'Gene', '673', (7, 11))	('peptides', 'Chemical', 'MESH:D010455', (44, 52))	('BRAF', 'Gene', (34, 38))	('BRAF', 'Gene', (7, 11))
238542	31104347	A recent genomic profiling study of tumors previously diagnosed as primitive neuroectodermal tumor of the central nervous system (CNS-PNET) identified a new subtype of high-grade neuroepithelial tumor unified by a recurrent internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene and a distinct genome-wide methylation profile compared to all other CNS tumor entities assessed to date.	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (179, 200))	('CNS tumor', 'Disease', 'MESH:D016543', (382, 391))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('internal tandem duplication', 'Var', (224, 251))	('neuroepithelial tumor', 'Disease', (179, 200))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (179, 200))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (77, 98))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('neuroectodermal tumor', 'Disease', (77, 98))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('high-grade', 'Disease', (168, 178))	('CNS tumor', 'Phenotype', 'HP:0100006', (382, 391))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('BCOR', 'Gene', '54880', (274, 278))	('tumors', 'Disease', (36, 42))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (77, 98))	('CNS tumor', 'Disease', (382, 391))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (67, 98))	('BCOR', 'Gene', (274, 278))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (93, 128))
238546	31104347	Inherited/constitutional mutations in the BCOR gene were identified in 2004 as the cause of an X-linked oculofaciocardiodental syndrome (Online Mendelian Inheritance in Man #300166) characterized by microphthalmia, congenital cataracts, long narrow face, dental radiculomegaly with persistent primary teeth, and cardiac septal defects.	('narrow face', 'Phenotype', 'HP:0000275', (242, 253))	('BCOR', 'Gene', '54880', (42, 46))	('X-linked oculofaciocardiodental syndrome', 'Disease', 'MESH:C537465', (95, 135))	('BCOR', 'Gene', (42, 46))	('mutations', 'Var', (25, 34))	('congenital cataracts', 'Phenotype', 'HP:0000519', (215, 235))	('persistent primary teeth', 'Phenotype', 'HP:0006335', (282, 306))	('cataracts', 'Disease', (226, 235))	('microphthalmia', 'Disease', 'MESH:D008850', (199, 213))	('radiculomegaly', 'Disease', (262, 276))	('X-linked oculofaciocardiodental syndrome', 'Disease', (95, 135))	('cause', 'Reg', (83, 88))	('radiculomegaly', 'Disease', 'MESH:C537465', (262, 276))	('septal defects', 'Phenotype', 'HP:0001671', (320, 334))	('microphthalmia', 'Disease', (199, 213))	('cataracts', 'Phenotype', 'HP:0000518', (226, 235))	('cardiac septal defects', 'Disease', 'MESH:D006331', (312, 334))	('long narrow face', 'Disease', (237, 253))	('cardiac septal defects', 'Disease', (312, 334))	('cataracts', 'Disease', 'MESH:D002386', (226, 235))	('microphthalmia', 'Phenotype', 'HP:0000568', (199, 213))
238547	31104347	Studies in osteodentinogenic mesenchymal stem cells from a patient with oculofaciocardiodental syndrome found that BCOR mutation disrupted homeostasis by resulting in increased methylation of lysine 4 and lysine 36 on the tail of histone H3, thereby reactivating transcription of silenced target genes.	('oculofaciocardiodental syndrome', 'Disease', 'MESH:C537465', (72, 103))	('homeostasis', 'MPA', (139, 150))	('disrupted', 'NegReg', (129, 138))	('BCOR', 'Gene', (115, 119))	('reactivating', 'PosReg', (250, 262))	('patient', 'Species', '9606', (59, 66))	('mutation', 'Var', (120, 128))	('oculofaciocardiodental syndrome', 'Disease', (72, 103))	('lysine', 'Chemical', 'MESH:D008239', (205, 211))	('BCOR', 'Gene', '54880', (115, 119))	('increased', 'PosReg', (167, 176))	('methylation', 'MPA', (177, 188))	('lysine', 'Protein', (192, 198))	('transcription', 'MPA', (263, 276))	('lysine', 'Chemical', 'MESH:D008239', (192, 198))
238549	31104347	Whereas constitutional mutations in the BCOR gene perturb organogenesis during development, somatic alterations in BCOR have now been identified as recurrent genetic drivers in a wide spectrum of human tumor types.	('BCOR', 'Gene', (115, 119))	('tumor', 'Disease', (202, 207))	('human', 'Species', '9606', (196, 201))	('BCOR', 'Gene', (40, 44))	('BCOR', 'Gene', '54880', (115, 119))	('BCOR', 'Gene', '54880', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('organogenesis during development', 'CPA', (58, 90))	('perturb', 'Reg', (50, 57))	('constitutional mutations', 'Var', (8, 32))	('alterations', 'Var', (100, 111))
238550	31104347	A recurrent internal tandem duplication within exon 15 of BCOR has been identified as the defining genetic alteration in clear cell sarcoma of the kidney, primitive myxoid mesenchymal tumor of infancy, and a subset of CNS high-grade neuroepithelial tumors.	('BCOR', 'Gene', '54880', (58, 62))	('tumor', 'Disease', (249, 254))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (233, 255))	('BCOR', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Disease', (184, 189))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (132, 153))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (233, 254))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (121, 153))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (132, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('neuroepithelial tumors', 'Disease', (233, 255))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (233, 255))	('internal tandem duplication', 'Var', (12, 39))	('sarcoma of the kidney', 'Disease', (132, 153))
238552	31104347	Lastly, somatic truncating mutations or homozygous deletions of BCOR have been recurrently found in acute myeloid leukemia, retinoblastoma, medulloblastoma, and diffuse gliomas .	('retinoblastoma', 'Disease', 'MESH:D012175', (124, 138))	('found', 'Reg', (91, 96))	('BCOR', 'Gene', '54880', (64, 68))	('medulloblastoma', 'Disease', 'MESH:D008527', (140, 155))	('gliomas', 'Disease', (169, 176))	('medulloblastoma', 'Phenotype', 'HP:0002885', (140, 155))	('BCOR', 'Gene', (64, 68))	('medulloblastoma', 'Disease', (140, 155))	('retinoblastoma', 'Phenotype', 'HP:0009919', (124, 138))	('acute myeloid leukemia', 'Disease', (100, 122))	('retinoblastoma', 'Disease', (124, 138))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('homozygous deletions', 'Var', (40, 60))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (100, 122))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (106, 122))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (100, 122))
238557	31104347	Ten children diagnosed with high-grade neuroepithelial tumors found to harbor BCOR exon 15 internal tandem duplication by targeted next-generation sequencing analysis at UCSF Medical Center were included in this study.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (39, 61))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (39, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (39, 61))	('BCOR', 'Gene', (78, 82))	('BCOR', 'Gene', '54880', (78, 82))	('internal tandem duplication', 'Var', (91, 118))	('children', 'Species', '9606', (4, 12))	('neuroepithelial tumors', 'Disease', (39, 61))
238560	31104347	Pathologic review of all tumors was conducted by a group of expert neuropathologists (S.P.F., M.P., A.W.B., T.T., A.P., and D.A.S.).	('T.T.', 'Var', (108, 112))	('M.P.', 'Var', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('A.P.', 'Var', (114, 118))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('A.W.B.', 'Var', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (25, 31))
238563	31104347	ER2 antigen retrieval was used for synaptophysin, BCOR, p53, and Ki67 antibodies.	('synaptophysin', 'Gene', '6855', (35, 48))	('p53', 'Gene', (56, 59))	('BCOR', 'Gene', (50, 54))	('Ki67', 'Var', (65, 69))	('p53', 'Gene', '7157', (56, 59))	('BCOR', 'Gene', '54880', (50, 54))	('synaptophysin', 'Gene', (35, 48))
238570	31104347	Capture-based next-generation DNA sequencing was performed using an assay that targets all coding exons of 479 cancer-related genes, select introns and upstream regulatory regions of 47 genes to enable detection of structural variants including gene fusions, and DNA segments at regular intervals along each chromosome to enable genome-wide copy number and zygosity analysis, with a total sequencing footprint of 2.8 Mb (UCSF500 Cancer Panel; Supplementary Table 1; reference).	('variants', 'Var', (226, 234))	('Cancer', 'Phenotype', 'HP:0002664', (429, 435))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
238571	31104347	In addition to the ten patients from this cohort, all previously reported cases of high-grade neuroepithelial tumors with confirmed BCOR exon 15 internal tandem duplication by targeted Sanger or next-generation sequencing were included in the clinical summary and survival analysis in Figure 10.	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (94, 116))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (94, 115))	('BCOR', 'Gene', (132, 136))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (94, 116))	('patients', 'Species', '9606', (23, 31))	('BCOR', 'Gene', '54880', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('internal tandem duplication', 'Var', (145, 172))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('neuroepithelial tumors', 'Disease', (94, 116))
238605	31104347	A tandem duplication within exon 15 of the BCOR gene was identified in all ten cases (Figures 7-8, Supplementary Table 5).	('BCOR', 'Gene', '54880', (43, 47))	('BCOR', 'Gene', (43, 47))	('tandem duplication', 'Var', (2, 20))
238606	31104347	The minimally duplicated codons across all ten tumors were p.L1713_G1738 (RefSeq transcript NM_001123385).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('p.L1713_G1738', 'Var', (59, 72))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
238607	31104347	In six cases, the BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified.	('BCOR', 'Gene', (18, 22))	('internal tandem duplication', 'Var', (31, 58))	('BCOR', 'Gene', '54880', (18, 22))
238608	31104347	Four cases contained additional genetic alterations considered likely to be contributing to tumor pathogenesis (Supplementary Tables 6 and 7).	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('genetic alterations', 'Var', (32, 51))	('tumor', 'Disease', (92, 97))
238609	31104347	These included SF-BCOR-9 with TERT promoter hotspot mutation and a splice site mutation in the SMARCA2 chromatin remodeling gene.	('BCOR', 'Gene', (18, 22))	('splice', 'Var', (67, 73))	('SMARCA2', 'Gene', (95, 102))	('SMARCA2', 'Gene', '6595', (95, 102))	('TERT', 'Gene', (30, 34))	('BCOR', 'Gene', '54880', (18, 22))	('TERT', 'Gene', '7015', (30, 34))
238610	31104347	SF-BCOR-6 contained an additional truncating frameshift mutation in the CREBBP histone acetyltransferase gene, while SF-BCOR-10 contained a damaging missense mutation in the TP53 tumor suppressor gene.	('BCOR', 'Gene', (120, 124))	('BCOR', 'Gene', '54880', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('TP53', 'Gene', (174, 178))	('missense mutation', 'Var', (149, 166))	('truncating', 'MPA', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('CREBBP', 'Gene', (72, 78))	('BCOR', 'Gene', '54880', (120, 124))	('BCOR', 'Gene', (3, 7))	('TP53', 'Gene', '7157', (174, 178))	('tumor', 'Disease', (179, 184))
238612	31104347	This recurrent tumor SF-BCOR-8 harbored BCOR exon 15 internal tandem duplication along with additional CDKN2A/B homozygous deletion, TERT promoter hotspot mutation (c.-124C>T), two truncating frameshift mutations in the BCORL1 gene, and a splice site mutation in the STAG2 gene.	('TERT', 'Gene', (133, 137))	('TERT', 'Gene', '7015', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('BCOR', 'Gene', '54880', (40, 44))	('BCORL1', 'Gene', '63035', (220, 226))	('BCOR', 'Gene', '54880', (24, 28))	('CDKN2A/B', 'Gene', (103, 111))	('BCOR', 'Gene', (40, 44))	('STAG2', 'Gene', '10735', (267, 272))	('BCORL1', 'Gene', (220, 226))	('BCOR', 'Gene', (24, 28))	('BCOR', 'Gene', '54880', (220, 224))	('STAG2', 'Gene', (267, 272))	('c.-124C>T', 'Var', (165, 174))	('tumor', 'Disease', (15, 20))	('CDKN2A/B', 'Gene', '1029;1030', (103, 111))	('BCOR', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('c.-124C>T', 'Mutation', 'rs1242535815', (165, 174))
238617	31104347	Three of the tumors demonstrated a paucity of chromosomal gains/losses (fewer than 4).	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('chromosomal gains/losses', 'Var', (46, 70))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
238619	31104347	No recurrent chromosomal gains or losses in more than two of the ten tumors were observed.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('losses', 'NegReg', (34, 40))	('chromosomal gains', 'Var', (13, 30))
238621	31104347	Both components contained the identical BCOR exon 15 internal tandem duplication and a damaging missense mutation in the TP53 tumor suppressor gene.	('missense mutation', 'Var', (96, 113))	('TP53', 'Gene', '7157', (121, 125))	('BCOR', 'Gene', (40, 44))	('TP53', 'Gene', (121, 125))	('BCOR', 'Gene', '54880', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('internal tandem duplication', 'Var', (53, 80))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
238644	31104347	HGNET BCOR ex15 ITD usually presents as a large, well-circumscribed, heterogeneous mass with reduced diffusion and variable enhancement in the cerebral or cerebellar hemispheres.	('BCOR', 'Gene', '54880', (6, 10))	('enhancement', 'PosReg', (124, 135))	('reduced', 'NegReg', (93, 100))	('ex15 ITD', 'Var', (11, 19))	('diffusion', 'MPA', (101, 110))	('BCOR', 'Gene', (6, 10))
238646	31104347	No sex predilection is apparent for this tumor entity, unlike other brain tumors entities such as astroblastoma-like neuroepithelial tumors with MN1 alteration that demonstrate a significant female predominance.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MN1', 'Gene', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('brain tumors', 'Disease', (68, 80))	('astroblastoma-like neuroepithelial tumors', 'Disease', 'MESH:D018302', (98, 139))	('tumor', 'Disease', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MN1', 'Gene', '4330', (145, 148))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (117, 139))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('brain tumors', 'Phenotype', 'HP:0030692', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('brain tumors', 'Disease', 'MESH:D001932', (68, 80))	('astroblastoma-like neuroepithelial tumors', 'Disease', (98, 139))	('brain tumor', 'Phenotype', 'HP:0030692', (68, 79))	('alteration', 'Var', (149, 159))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (117, 138))
238653	31104347	However, HGNET BCOR ex15 ITD have an unusual immunohistochemical profile with dual OLIG2 and NeuN positivity, along with sparse to absent GFAP expression and no synaptophysin expression, that can be helpful in distinguishing these tumors from potential histologic mimics.	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('GFAP', 'Gene', '2670', (138, 142))	('NeuN', 'Gene', (93, 97))	('BCOR', 'Gene', (15, 19))	('absent', 'NegReg', (131, 137))	('synaptophysin', 'Gene', (161, 174))	('BCOR', 'Gene', '54880', (15, 19))	('ex15 ITD', 'Var', (20, 28))	('OLIG2', 'Gene', (83, 88))	('NeuN', 'Gene', '146713', (93, 97))	('synaptophysin', 'Gene', '6855', (161, 174))	('GFAP', 'Gene', (138, 142))	('tumors', 'Disease', (231, 237))	('OLIG2', 'Gene', '10215', (83, 88))
238667	31104347	The high-grade neuroepithelial tumors in this cohort are all unified by the presence of an internal tandem duplication within exon 15 of the BCOR gene.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (15, 37))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (15, 37))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (15, 36))	('BCOR', 'Gene', (141, 145))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('BCOR', 'Gene', '54880', (141, 145))	('presence', 'Reg', (76, 84))	('internal tandem duplication', 'Var', (91, 118))	('neuroepithelial tumors', 'Disease', (15, 37))
238669	31104347	However, the specific mechanism by which this recurrent internal tandem duplication event in BCOR drives tumor development remains unknown, as are methods to therapeutically intervene using a precision medicine approach for these aggressive malignancies of childhood driven by BCOR exon 15 ITD.	('BCOR', 'Gene', (93, 97))	('internal tandem duplication event', 'Var', (56, 89))	('BCOR', 'Gene', '54880', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('child', 'Species', '9606', (257, 262))	('BCOR', 'Gene', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('aggressive malignancies', 'Disease', 'MESH:D009369', (230, 253))	('aggressive malignancies', 'Disease', (230, 253))	('BCOR', 'Gene', '54880', (277, 281))	('tumor', 'Disease', (105, 110))	('drives', 'Reg', (98, 104))
238670	31104347	Recent genomic investigation has revealed that distinct alterations in the BCOR gene are selected for in different brain tumor entities.	('brain tumor', 'Disease', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('alterations', 'Var', (56, 67))	('brain tumor', 'Phenotype', 'HP:0030692', (115, 126))	('BCOR', 'Gene', (75, 79))	('BCOR', 'Gene', '54880', (75, 79))	('brain tumor', 'Disease', 'MESH:D001932', (115, 126))
238672	31104347	These gliomas with EP300-BCOR fusions had histologic features somewhat resembling either pilocytic astrocytoma or dysembryoplastic neuroepithelial tumor and lacked the perivascular pseudorosettes and palisading necrosis that characterize HGNET BCOR ex15 ITD.	('BCOR', 'Gene', '54880', (25, 29))	('fusions', 'Var', (30, 37))	('BCOR', 'Gene', (25, 29))	('EP300', 'Gene', '2033', (19, 24))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (131, 152))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('EP300', 'Gene', (19, 24))	('necrosis', 'Disease', 'MESH:D009336', (211, 219))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))	('pilocytic astrocytoma or dysembryoplastic neuroepithelial tumor', 'Disease', 'MESH:D001254', (89, 152))	('BCOR', 'Gene', '54880', (244, 248))	('necrosis', 'Disease', (211, 219))	('BCOR', 'Gene', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('perivascular pseudorosettes', 'Phenotype', 'HP:0031929', (168, 195))	('rosettes', 'Phenotype', 'HP:0031925', (187, 195))	('lacked', 'NegReg', (157, 163))	('gliomas', 'Disease', (6, 13))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
238673	31104347	Additionally, truncating mutations or homozygous deletions of BCOR or its homolog BCORL1 have been recurrently found in retinoblastoma, medulloblastoma, and diffuse gliomas .	('BCOR', 'Gene', (82, 86))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('retinoblastoma', 'Disease', 'MESH:D012175', (120, 134))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('found', 'Reg', (111, 116))	('BCOR', 'Gene', '54880', (62, 66))	('BCORL1', 'Gene', '63035', (82, 88))	('medulloblastoma', 'Disease', 'MESH:D008527', (136, 151))	('BCOR', 'Gene', (62, 66))	('medulloblastoma', 'Phenotype', 'HP:0002885', (136, 151))	('retinoblastoma', 'Phenotype', 'HP:0009919', (120, 134))	('BCORL1', 'Gene', (82, 88))	('medulloblastoma', 'Disease', (136, 151))	('truncating mutations', 'Var', (14, 34))	('retinoblastoma', 'Disease', (120, 134))	('homozygous deletions', 'Var', (38, 58))	('gliomas', 'Disease', (165, 172))	('BCOR', 'Gene', '54880', (82, 86))
238674	31104347	Among diffuse gliomas, truncating mutations or homozygous deletions in the BCOR or BCORL1 genes are present in a significant fraction of H3 K27M-mutant diffuse midline gliomas, as well as high-grade gliomas in the cerebral hemispheres of children.	('BCOR', 'Gene', (75, 79))	('gliomas', 'Phenotype', 'HP:0009733', (199, 206))	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('children', 'Species', '9606', (238, 246))	('midline gliomas', 'Disease', 'MESH:D005910', (160, 175))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('H3 K27M-mutant', 'Var', (137, 151))	('gliomas', 'Disease', (168, 175))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('BCORL1', 'Gene', '63035', (83, 89))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('BCORL1', 'Gene', (83, 89))	('gliomas', 'Disease', (199, 206))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('midline gliomas', 'Disease', (160, 175))	('BCOR', 'Gene', '54880', (83, 87))	('truncating mutations', 'Var', (23, 43))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('K27M', 'Mutation', 'p.K27M', (140, 144))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('gliomas', 'Disease', (14, 21))	('BCOR', 'Gene', (83, 87))	('gliomas', 'Disease', 'MESH:D005910', (199, 206))	('BCOR', 'Gene', '54880', (75, 79))
238675	31104347	In contrast to the exon 15 internal tandem duplication and in-frame fusion with EP300 that are likely activating gain-of-function events, these recurrent nonsense or frameshift mutations as well as homozygous deletions in diffuse gliomas, medulloblastomas, and retinoblastomas are almost certainly functionally inactivating events.	('retinoblastomas', 'Disease', 'MESH:D012175', (261, 276))	('medulloblastoma', 'Phenotype', 'HP:0002885', (239, 254))	('retinoblastomas', 'Phenotype', 'HP:0009919', (261, 276))	('medulloblastomas', 'Disease', 'MESH:D008527', (239, 255))	('medulloblastomas', 'Disease', (239, 255))	('frameshift mutations', 'Var', (166, 186))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('retinoblastoma', 'Phenotype', 'HP:0009919', (261, 275))	('EP300', 'Gene', '2033', (80, 85))	('nonsense', 'Var', (154, 162))	('gliomas', 'Disease', 'MESH:D005910', (230, 237))	('EP300', 'Gene', (80, 85))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('gliomas', 'Disease', (230, 237))	('retinoblastomas', 'Disease', (261, 276))
238676	31104347	Thus, the oncogenic mechanisms by which BCOR alterations promote tumorigenesis are likely to be divergent dependent on the specific genetic alteration present.	('alterations', 'Var', (45, 56))	('tumor', 'Disease', (65, 70))	('promote', 'PosReg', (57, 64))	('BCOR', 'Gene', (40, 44))	('BCOR', 'Gene', '54880', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
238679	31104347	While the majority of cases in this patient cohort harbored BCOR exon 15 internal tandem duplication as the solitary pathogenic alteration, a subset harbored additional genetic alterations likely contributing to tumor pathogenesis.	('BCOR', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('internal tandem duplication', 'Var', (73, 100))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('BCOR', 'Gene', '54880', (60, 64))	('patient', 'Species', '9606', (36, 43))	('tumor', 'Disease', (212, 217))
238681	31104347	Why these tumors selected for additional genetic alterations predicted to disrupt gene expression profiles beyond the BCOR exon 15 ITD is uncertain.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('genetic alterations', 'Var', (41, 60))	('alterations', 'Var', (49, 60))	('tumors', 'Disease', (10, 16))	('BCOR', 'Gene', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('gene expression profiles', 'MPA', (82, 106))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('BCOR', 'Gene', '54880', (118, 122))
238684	31104347	Notably, none of the cases contained IDH1 p.R132 or IDH2 p.R172 mutations that define diffuse lower-grade gliomas in the cerebral hemispheres of adults.	('IDH2', 'Gene', (52, 56))	('IDH2', 'Gene', '3418', (52, 56))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('p.R172', 'Var', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('IDH1', 'Gene', (37, 41))	('IDH1', 'Gene', '3417', (37, 41))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('p.R132', 'Var', (42, 48))	('gliomas', 'Disease', (106, 113))
238685	31104347	None of the cases contained H3F3A or HIST1H3B p.K27M mutation that define the majority of diffuse gliomas within midline structures of the CNS.	('H3F3A', 'Gene', '3020', (28, 33))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('H3F3A', 'Gene', (28, 33))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('p.K27M', 'Var', (46, 52))	('gliomas', 'Disease', (98, 105))	('p.K27M', 'Mutation', 'p.K27M', (46, 52))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('diffuse', 'Disease', (90, 97))	('HIST1H3B', 'Gene', (37, 45))	('HIST1H3B', 'Gene', '8358', (37, 45))
238686	31104347	H3F3A p.G34 mutation or SETD2 truncating mutation that define a subset of high-grade gliomas in the cerebral hemispheres of teenagers and young adults were not present in any of the cases.	('H3F3A', 'Gene', '3020', (0, 5))	('H3F3A', 'Gene', (0, 5))	('gliomas', 'Disease', (85, 92))	('SETD2', 'Gene', '29072', (24, 29))	('gliomas', 'Disease', 'MESH:D005910', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('SETD2', 'Gene', (24, 29))	('p.G34 mutation', 'Var', (6, 20))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
238687	31104347	No cases contained amplification, mutation, or rearrangement of receptor tyrosine kinase genes such as EGFR, PDGFRA, MET, FGFR1-3, NTRK1-3, ALK, or ROS1 that are common in high-grade gliomas in children and adults.	('EGFR', 'Gene', '1956', (103, 107))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('children', 'Species', '9606', (194, 202))	('MET', 'Gene', '79811', (117, 120))	('FGFR1-3', 'Gene', (122, 129))	('PDGFRA', 'Gene', (109, 115))	('ALK', 'Gene', '238', (140, 143))	('PDGFRA', 'Gene', '5156', (109, 115))	('mutation', 'Var', (34, 42))	('ALK', 'Gene', (140, 143))	('ROS1', 'Gene', (148, 152))	('gliomas', 'Disease', (183, 190))	('EGFR', 'Gene', (103, 107))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('MET', 'Gene', (117, 120))	('NTRK1-3', 'Gene', (131, 138))	('rearrangement', 'Var', (47, 60))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('FGFR1-3', 'Gene', '2260;2263;2261', (122, 129))	('ROS1', 'Gene', '6098', (148, 152))	('NTRK1-3', 'Gene', '4914;4915;4916', (131, 138))
238688	31104347	None of the cases contained BRAF mutation or rearrangement, nor any other alteration in components of the Ras-Raf-MAP kinase signaling pathway that are common in pediatric low-grade gliomas.	('BRAF', 'Gene', '673', (28, 32))	('mutation', 'Var', (33, 41))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('rearrangement', 'Var', (45, 58))	('Raf', 'Gene', '673', (110, 113))	('gliomas', 'Disease', (182, 189))	('gliomas', 'Disease', 'MESH:D005910', (182, 189))	('BRAF', 'Gene', (28, 32))	('gliomas', 'Phenotype', 'HP:0009733', (182, 189))	('Raf', 'Gene', (110, 113))
238690	31104347	MYB or MYBL1 rearrangements that are common in pediatric low-grade gliomas were not found in any of the cases.	('MYB', 'Gene', (0, 3))	('rearrangements', 'Var', (13, 27))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('gliomas', 'Disease', (67, 74))	('MYB', 'Gene', '4602', (7, 10))	('MYB', 'Gene', '4602', (0, 3))	('MYBL1', 'Gene', (7, 12))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('MYB', 'Gene', (7, 10))	('MYBL1', 'Gene', '4603', (7, 12))
238692	31104347	Additionally, none of the cases contained RELA or YAP1 fusions or NF2 mutation that are common in ependymomas.	('ependymomas', 'Disease', 'MESH:D004806', (98, 109))	('NF2', 'Gene', (66, 69))	('ependymomas', 'Disease', (98, 109))	('ependymoma', 'Phenotype', 'HP:0002888', (98, 108))	('YAP1', 'Gene', (50, 54))	('YAP1', 'Gene', '10413', (50, 54))	('RELA', 'Gene', (42, 46))	('RELA', 'Gene', '5970', (42, 46))	('NF2', 'Gene', '4771', (66, 69))	('mutation', 'Var', (70, 78))	('fusions', 'Var', (55, 62))
238693	31104347	None of the cases contained SMARCB1 or SMARCA4 biallelic inactivation that defines atypical teratoid/rhabdoid tumor, although one tumor did harbor a heterozygous truncating mutation in the related SMARCA2 chromatin remodeling gene.	('SMARCB1', 'Gene', (28, 35))	('rhabdoid tumor', 'Disease', (101, 115))	('atypical', 'Disease', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (101, 115))	('SMARCB1', 'Gene', '6598', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SMARCA2', 'Gene', (197, 204))	('biallelic inactivation', 'Var', (47, 69))	('tumor', 'Disease', (130, 135))	('SMARCA4', 'Gene', (39, 46))	('SMARCA2', 'Gene', '6595', (197, 204))	('SMARCA4', 'Gene', '6597', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
238694	31104347	Thus, HGNET BCOR ex15 ITD appear to be genetically distinct from all other CNS tumor entities that have been molecularly defined to date.	('CNS tumor', 'Disease', 'MESH:D016543', (75, 84))	('CNS tumor', 'Phenotype', 'HP:0100006', (75, 84))	('BCOR', 'Gene', (12, 16))	('CNS tumor', 'Disease', (75, 84))	('ex15 ITD', 'Var', (17, 25))	('BCOR', 'Gene', '54880', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
238696	31104347	While the BCOR exon 15 ITD appears to be the solitary genetic driver in most cases, a subset also acquires additional genetic alterations that include TERT activation, CDKN2A homozygous deletion, and inactivating mutations in other transcriptional and epigenetic regulatory genes including EP300, SMARCA2, STAG2, and BCORL1.	('EP300', 'Gene', (290, 295))	('BCOR', 'Gene', (317, 321))	('EP300', 'Gene', '2033', (290, 295))	('SMARCA2', 'Gene', '6595', (297, 304))	('BCOR', 'Gene', '54880', (10, 14))	('STAG2', 'Gene', (306, 311))	('STAG2', 'Gene', '10735', (306, 311))	('TERT', 'Gene', (151, 155))	('BCOR', 'Gene', '54880', (317, 321))	('inactivating mutations', 'Var', (200, 222))	('BCORL1', 'Gene', '63035', (317, 323))	('CDKN2A', 'Gene', (168, 174))	('TERT', 'Gene', '7015', (151, 155))	('BCOR', 'Gene', (10, 14))	('SMARCA2', 'Gene', (297, 304))	('CDKN2A', 'Gene', '1029', (168, 174))	('BCORL1', 'Gene', (317, 323))
238697	31104347	Rare examples may also acquire TP53 mutational inactivation along with numerous chromosomal gains/losses that corresponds with histologic anaplasia.	('mutational inactivation', 'Var', (36, 59))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('gains/losses', 'PosReg', (92, 104))
238713	31384126	In addition to this, numerous studies have shown that DAXX mutations are present in various types of tumors, such as oral cancers, pancreatic neuroendocrine tumors, urothelial carcinomas, prostate cancers, glioblastomas, ovarian cancers, and so on.	('oral cancers', 'Disease', (117, 129))	('oral cancers', 'Disease', 'MESH:D009062', (117, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('pancreatic neuroendocrine tumors', 'Disease', (131, 163))	('present', 'Reg', (73, 80))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('glioblastomas', 'Disease', (206, 219))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('ovarian cancers', 'Disease', (221, 236))	('ovarian cancers', 'Disease', 'MESH:D010051', (221, 236))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancers', 'Disease', 'MESH:D011471', (188, 204))	('glioblastomas', 'Disease', 'MESH:D005909', (206, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('urothelial carcinomas', 'Disease', (165, 186))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('tumors', 'Disease', (157, 163))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (165, 186))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumors', 'Disease', (101, 107))	('ovarian cancers', 'Phenotype', 'HP:0100615', (221, 236))	('prostate cancers', 'Phenotype', 'HP:0012125', (188, 204))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('prostate cancers', 'Disease', (188, 204))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (142, 163))	('glioblastomas', 'Phenotype', 'HP:0012174', (206, 219))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (131, 163))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('DAXX', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
238744	31384126	It has been shown that endometrioid type carcinomas actually represent a heterogeneous group of carcinomas with different molecular signatures, such as copy-number low variant, POLE (DNA Polymerase Epsilon, Catalytic Subunit) gene hotspot mutated, and MSI-H (microsatellite instability-high), while the high-grade endometrial carcinomas tend to be high copy-number variant.	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('carcinomas', 'Disease', 'MESH:D002277', (326, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('endometrial carcinomas', 'Disease', (314, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('MSI-H', 'Disease', (252, 257))	('carcinomas', 'Disease', 'MESH:D002277', (96, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('carcinomas', 'Disease', 'MESH:D002277', (41, 51))	('endometrioid type carcinomas', 'Disease', 'MESH:D016889', (23, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (314, 335))	('endometrioid type carcinomas', 'Disease', (23, 51))	('carcinomas', 'Disease', (326, 336))	('MSI-H', 'Disease', 'MESH:D000848', (252, 257))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (314, 336))	('carcinomas', 'Disease', (41, 51))	('carcinomas', 'Disease', (96, 106))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (314, 336))	('mutated', 'Var', (239, 246))
238745	31384126	Studies have shown that loss of nuclear DAXX on IHC may be a surrogate marker for the presence of DAXX mutations, which may partly explain its pathogenesis in low-grade endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('mutations', 'Var', (103, 112))	('DAXX', 'Gene', (98, 102))	('endometrial carcinomas', 'Disease', (169, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (169, 191))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (169, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (169, 190))
238748	31384126	A common mechanism of carcinogenesis in telomerase-dependent pathway is mutations in the promoter of the telomerase reverse transcriptase (TERT) gene.	('mutations in', 'Var', (72, 84))	('TERT', 'Gene', '7015', (139, 143))	('carcinogenesis', 'Disease', (22, 36))	('telomerase reverse transcriptase', 'Gene', (105, 137))	('telomerase reverse transcriptase', 'Gene', '7015', (105, 137))	('TERT', 'Gene', (139, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))
238751	31384126	It has been reported that 80% of tumors with an ALT phenotype have mutations in either ATRX or DAXX.	('DAXX', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (67, 76))	('ATRX', 'Gene', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('ATRX', 'Gene', '546', (87, 91))
238752	31384126	Loss of ATRX and/or DAXX has been associated with an ALT phenotype in multiple tumor types, such as sarcomas, pancreatic neuroendocrine tumors, gliomas, and uterine leiomyosarcomas.	('ATRX', 'Gene', '546', (8, 12))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcomas', 'Disease', (100, 108))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (165, 180))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (110, 142))	('leiomyosarcomas', 'Disease', (165, 180))	('tumor', 'Disease', (136, 141))	('sarcomas', 'Disease', 'MESH:D012509', (172, 180))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (157, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (172, 180))	('tumor', 'Disease', (79, 84))	('pancreatic neuroendocrine tumors', 'Disease', (110, 142))	('sarcomas', 'Disease', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (165, 180))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (121, 142))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Loss', 'Var', (0, 4))	('gliomas', 'Disease', (144, 151))	('ALT', 'MPA', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('associated', 'Reg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('ATRX', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
238756	31384126	In vitro studies have already established its therapeutic value, as inhibiting DAXX was found to arrest the growth of glioblastoma in mice models.	('inhibiting', 'Var', (68, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('mice', 'Species', '10090', (134, 138))	('arrest', 'NegReg', (97, 103))	('growth', 'CPA', (108, 114))	('DAXX', 'Gene', (79, 83))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))
238759	31384126	In summary, we conclude that loss of DAXX protein expression is associated with low-grade endometrial carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('associated', 'Reg', (64, 74))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (90, 112))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (90, 112))	('DAXX protein', 'Protein', (37, 49))	('loss', 'Var', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (90, 111))	('expression', 'MPA', (50, 60))	('endometrial carcinomas', 'Disease', (90, 112))
238767	30737087	In vivo, V-ATPase subunits deregulation significantly impacts tumor growth and proliferation.	('proliferation', 'CPA', (79, 92))	('deregulation', 'Var', (27, 39))	('ATPase', 'Gene', '1769', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('impacts', 'Reg', (54, 61))	('tumor', 'Disease', (62, 67))	('ATPase', 'Gene', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
238785	30737087	Upon V-ATPase inhibition, changes in cytosolic pH stabilize proapoptotic proteins, alter trafficking of extracellular nutrients, or reverse V-ATPase-induced drug resistance.	('ATPase', 'Gene', '1769', (7, 13))	('cytosolic pH', 'MPA', (37, 49))	('drug resistance', 'Phenotype', 'HP:0020174', (157, 172))	('stabilize', 'Reg', (50, 59))	('changes', 'Var', (26, 33))	('reverse', 'NegReg', (132, 139))	('ATPase', 'Gene', '1769', (142, 148))	('ATPase', 'Gene', (7, 13))	('trafficking of extracellular nutrients', 'MPA', (89, 127))	('drug resistance', 'MPA', (157, 172))	('ATPase', 'Gene', (142, 148))	('alter', 'Reg', (83, 88))	('inhibition', 'NegReg', (14, 24))
238789	30737087	Delivery of V-ATPase specifically to the plasma membrane of breast cancer cells relies on overexpression of the V0A3 subunit, which is normally specific to osteoclasts; this suggests that changes in pump subunit composition support cancer-specific functions.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('breast cancer', 'Disease', (60, 73))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (232, 238))	('ATPase', 'Gene', '1769', (14, 20))	('changes', 'Var', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('ATPase', 'Gene', (14, 20))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('overexpression', 'PosReg', (90, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
238793	30737087	In this new context, mutated isocitrate dehydrogenase 1 or 2 enzymes (IDHmut) are a major classifier of disease, as well as being key genetic events during gliomagenesis.	('glioma', 'Disease', (156, 162))	('IDH', 'Gene', (70, 73))	('IDH', 'Gene', '3417', (70, 73))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('mutated', 'Var', (21, 28))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))
238797	30737087	These data suggest that changes in V-ATPase composition, and possibly activity, promote GBM aggressiveness and maintain the cancer stem cell niche.	('aggressiveness', 'Disease', (92, 106))	('cancer', 'Disease', (124, 130))	('promote', 'PosReg', (80, 87))	('aggressiveness', 'Phenotype', 'HP:0000718', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('aggressiveness', 'Disease', 'MESH:D001523', (92, 106))	('ATPase', 'Gene', '1769', (37, 43))	('changes', 'Var', (24, 31))	('ATPase', 'Gene', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
238803	30737087	Cases with mutated IDH1 or 2 were considered IDHmutant (IDHmut).	('IDH', 'Gene', (45, 48))	('IDH', 'Gene', (56, 59))	('IDH1', 'Gene', (19, 23))	('IDH', 'Gene', '3417', (45, 48))	('IDH', 'Gene', '3417', (56, 59))	('IDH1', 'Gene', '3417', (19, 23))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (19, 22))	('mutated', 'Var', (11, 18))
47465	30737087	In particular, experiments involving patients' derived NS were performed with five V1G1High- and five V1G1Low- NS in triplicate.	('NS', 'Chemical', '-', (111, 113))	('NS', 'Chemical', '-', (55, 57))	('patients', 'Species', '9606', (37, 45))	('V1G1High-', 'Var', (83, 92))	('V1G1Low- NS', 'Var', (102, 113))
238865	30737087	In addition, some core and regulatory subunit genes, such as ATP6V1A (V1A), ATP6V1H (V1H), and ATP6V1C (V1C), were downregulated in GBM, whereas ATP6V0B (V0B) was upregulated (Fig.	('ATP6V1A', 'Gene', (61, 68))	('ATP6V1H', 'Gene', (76, 83))	('ATP6V1C', 'Var', (95, 102))	('ATP6V0B', 'Gene', '533', (145, 152))	('ATP6V0B', 'Gene', (145, 152))	('ATP6V1A', 'Gene', '523', (61, 68))	('downregulated', 'NegReg', (115, 128))	('ATP6V1H', 'Gene', '51606', (76, 83))
238872	30737087	Gliomas generated from V1G1High NS completely invaded the normal brain parenchyma of mice (as shown by STEM121 staining; Fig.	('mice', 'Species', '10090', (85, 89))	('STEM121', 'Chemical', '-', (103, 110))	('NS', 'Chemical', '-', (32, 34))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))	('V1G1High NS', 'Var', (23, 34))
238903	30737087	Finally, homeobox genes deregulation was confirmed in a third series of gliomas (Gravendeel dataset; Fig.	('deregulation', 'Var', (24, 36))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('homeobox genes', 'Gene', (9, 23))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))
238915	30737087	Currently, glioma classification relies on determination of the mutational status of IDH1 and 2, followed by co-deletion of 1p/19q, loss of ATRX, and TP53 mutation.	('TP53', 'Gene', (150, 154))	('IDH1 and 2', 'Gene', '3417;3418', (85, 95))	('1p/19q', 'Protein', (124, 130))	('ATRX', 'Gene', (140, 144))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('loss', 'Var', (132, 136))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('mutation', 'Var', (155, 163))	('co-deletion', 'Var', (109, 120))	('ATRX', 'Gene', '546', (140, 144))	('TP53', 'Gene', '7157', (150, 154))	('glioma', 'Disease', (11, 17))
238916	30737087	The presence of IDH mutations and 1p/19q co-deletion defines the least aggressive subtype of glioma, the oligodendroglioma.	('glioma', 'Disease', (93, 99))	('glioma', 'Disease', (116, 122))	('IDH', 'Gene', (16, 19))	('oligodendroglioma', 'Disease', (105, 122))	('oligodendroglioma', 'Disease', 'MESH:D009837', (105, 122))	('IDH', 'Gene', '3417', (16, 19))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('mutations', 'Var', (20, 29))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
238925	30737087	In human, V0A1 is associated mainly with synaptic vesicles, V0A4 is associated mainly with the plasma membrane of non-neuronal cells, whereas V0A2 is overexpressed on the plasma membrane of ovarian cancer cells where it confers resistance to chemotherapy.	('ovarian cancer', 'Disease', (190, 204))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('V0A4', 'Var', (60, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))
238928	30737087	To this regard, the interaction between V1G and V1C is known to aid dissociation of the V1 sector from the V0 sector and V1H inhibits the ATPase activity of the catalytic V1 sector when not assembled on the membrane-embedded V0 pore.	('V1H', 'Var', (121, 124))	('ATPase', 'Gene', '1769', (138, 144))	('interaction', 'Interaction', (20, 31))	('activity', 'MPA', (145, 153))	('dissociation', 'MPA', (68, 80))	('ATPase', 'Gene', (138, 144))	('inhibits', 'NegReg', (125, 133))
238933	30737087	In gliomas harboring a GBM-like V-ATPase, such hypothesis is consistent with upregulation of homeobox-containing genes.	('ATPase', 'Gene', '1769', (34, 40))	('ATPase', 'Gene', (34, 40))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('GBM-like', 'Var', (23, 31))	('gliomas', 'Disease', (3, 10))
238945	32186930	Gray Areas in the Gray Matter: IDH1/2 Mutations in Glioma Since the first discovery of isocitrate dehydrogenase (IDH) mutations in cancer, considerable progress has been made in our understanding of their contribution to cancer development.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('Glioma', 'Disease', 'MESH:D005910', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('IDH1/2', 'Gene', (31, 37))	('isocitrate dehydrogenase', 'Gene', (87, 111))	('IDH', 'Gene', '3417', (113, 116))	('IDH', 'Gene', (31, 34))	('IDH1/2', 'Gene', '3418', (31, 37))	('Glioma', 'Phenotype', 'HP:0009733', (51, 57))	('cancer', 'Disease', (221, 227))	('mutations', 'Var', (118, 127))	('IDH', 'Gene', '3417', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Mutations', 'Var', (38, 47))	('Glioma', 'Disease', (51, 57))	('isocitrate dehydrogenase', 'Gene', '3417', (87, 111))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('IDH', 'Gene', (113, 116))
238946	32186930	For glioma, this has helped to identify two diagnostic groups of tumors (oligodendroglioma and astrocytoma IDHmt) with distinct clinical characteristics and that are now diagnosed by the presence of the IDH mutations.	('IDH', 'Gene', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('glioma', 'Disease', (84, 90))	('IDH', 'Gene', '3417', (203, 206))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('IDH', 'Gene', (107, 110))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('mutations', 'Var', (207, 216))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('IDH', 'Gene', '3417', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('oligodendroglioma and astrocytoma IDHmt', 'Disease', 'MESH:D009837', (73, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (95, 106))	('glioma', 'Disease', (4, 10))
238947	32186930	The metabolic changes occurring as the consequence of the altered substrate affinity of the mutant IDH protein results in a cascade of intracellular changes, also inducing a relative sensitivity to chemotherapy and radiotherapy compared with IDHwt tumors.	('IDH', 'Gene', '3417', (99, 102))	('results in', 'Reg', (111, 121))	('metabolic changes', 'MPA', (4, 21))	('cascade of intracellular changes', 'MPA', (124, 156))	('protein', 'Protein', (103, 110))	('IDH', 'Gene', (242, 245))	('IDHwt tumors', 'Disease', 'MESH:D009369', (242, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('inducing', 'Reg', (163, 171))	('mutant', 'Var', (92, 98))	('IDH', 'Gene', '3417', (242, 245))	('IDH', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('IDHwt tumors', 'Disease', (242, 254))	('altered', 'Reg', (58, 65))
238948	32186930	Pharmacologic blockade of the mutant enzyme with first-in-class inhibitors has been efficacious for the treatment of IDH-mutant acute myeloid leukemia (AML) and is currently being evaluated in phase III trials for IDH-mutant glioma (INDIGO) and cholangiocarcinoma (ClarIDHy).	('acute myeloid leukemia', 'Disease', (128, 150))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('AML', 'Disease', 'MESH:D015470', (152, 155))	('IDH', 'Gene', (269, 272))	('AML', 'Disease', (152, 155))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (128, 150))	('AML', 'Phenotype', 'HP:0004808', (152, 155))	('glioma', 'Disease', (225, 231))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (134, 150))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (128, 150))	('IDH', 'Gene', (214, 217))	('glioma', 'Disease', 'MESH:D005910', (225, 231))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (245, 263))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', '3417', (269, 272))	('cholangiocarcinoma', 'Disease', (245, 263))	('glioma', 'Phenotype', 'HP:0009733', (225, 231))	('mutant', 'Var', (30, 36))	('IDH', 'Gene', '3417', (214, 217))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (245, 263))	('IDH', 'Gene', '3417', (117, 120))
238949	32186930	It seems likely that acquired resistance to mutant IDH inhibitors will eventually emerge, and combination therapies to augment the antitumor activity of mutant IDH inhibitors have already been initiated.	('IDH', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IDH', 'Gene', '3417', (51, 54))	('tumor', 'Disease', (135, 140))	('mutant', 'Var', (153, 159))	('IDH', 'Gene', (160, 163))	('IDH', 'Gene', '3417', (160, 163))	('mutant', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
238952	32186930	In 2008, a genome-wide sequencing study observed unknown mutations in the gene encoding isocitrate dehydrogenase (IDH1) in 18 (12%) of 149 glioblastoma samples.	('IDH1', 'Gene', (114, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (139, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('IDH1', 'Gene', '15926', (114, 118))	('isocitrate dehydrogenase', 'Gene', (88, 112))	('isocitrate dehydrogenase', 'Gene', '3417', (88, 112))	('mutations', 'Var', (57, 66))	('glioblastoma', 'Disease', (139, 151))
238953	32186930	Remarkably, these mutations occurred in young patients with glioblastomas that had progressed from low-grade gliomas to what was known as secondary glioblastoma.	('glioblastoma', 'Disease', (60, 72))	('occurred', 'Reg', (28, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('patients', 'Species', '9606', (46, 54))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('glioblastomas', 'Disease', (60, 73))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('glioblastoma', 'Disease', (148, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (148, 160))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))	('mutations', 'Var', (18, 27))
238954	32186930	Moreover, patients with glioblastoma with IDH1 mutations had a much better survival compared with patients with glioblastomas without IDH1 mutations.	('IDH1', 'Gene', '15926', (42, 46))	('survival', 'CPA', (75, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (112, 125))	('glioblastoma', 'Disease', (112, 124))	('better', 'PosReg', (68, 74))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('glioblastomas', 'Disease', 'MESH:D005909', (112, 125))	('glioblastoma', 'Disease', (24, 36))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (98, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('IDH1', 'Gene', (134, 138))	('glioblastomas', 'Disease', (112, 125))	('glioblastoma', 'Disease', 'MESH:D005909', (24, 36))	('patients', 'Species', '9606', (10, 18))	('IDH1', 'Gene', (42, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (24, 36))	('IDH1', 'Gene', '15926', (134, 138))
238955	32186930	Shortly afterward, a series of studies showed that these mutations occurred in up to 80% of low-grade gliomas, and, in some IDH1wt glial tumors, mutations in the IDH2 gene were found that carried a similar prognostic significance.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('IDH1', 'Gene', '15926', (124, 128))	('IDH1', 'Gene', (124, 128))	('IDH2', 'Gene', '269951', (162, 166))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('mutations', 'Var', (145, 154))	('occurred', 'Reg', (67, 75))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mutations', 'Var', (57, 66))	('gliomas', 'Disease', (102, 109))	('glial tumors', 'Disease', 'MESH:D005910', (131, 143))	('gliomas', 'Disease', 'MESH:D005910', (102, 109))	('IDH2', 'Gene', (162, 166))	('glial tumors', 'Disease', (131, 143))
238956	32186930	Early clinical studies suggested the occurrence of IDH mutations was an early event in gliomagenesis, occurring before the development of a 1p/19q codeletion.	('glioma', 'Disease', (87, 93))	('IDH', 'Gene', (51, 54))	('mutations', 'Var', (55, 64))	('IDH', 'Gene', '3417', (51, 54))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))
238957	32186930	With more clinical data emerging, it became clear that virtually all 1p/19q codeleted tumors have an IDH1/2 mutation and that nearly all these tumors have MGMT promoter methylation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('MGMT', 'Gene', '4255', (155, 159))	('IDH1/2', 'Gene', (101, 107))	('MGMT', 'Gene', (155, 159))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('1p/19q', 'Gene', (69, 75))	('mutation', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
238958	32186930	Other mutations were found associated with IDH1/2 mutations, in particular, mutations in the TP53 and ATRX genes in tumors without 1p/19q codeletion and mutations in the TERT promoter region in IDH1/2-mutated tumors with 1p/19q codeletion.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (209, 215))	('IDH1/2', 'Gene', (43, 49))	('mutations', 'Var', (76, 85))	('ATRX', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('mutations', 'Var', (153, 162))	('mutations', 'Var', (50, 59))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('TP53', 'Gene', '7157', (93, 97))	('ATRX', 'Gene', '546', (102, 106))	('TP53', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('TERT', 'Gene', (170, 174))	('TERT', 'Gene', '7015', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
238959	32186930	Clinical studies showed that IDH1/2mt gliomas had a better outcome compared with histologically similar tumors without IDH1/2 mutations.	('gliomas', 'Phenotype', 'HP:0009733', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('tumors', 'Disease', (104, 110))	('IDH1/2mt', 'Var', (29, 37))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('gliomas', 'Disease', (38, 45))	('gliomas', 'Disease', 'MESH:D005910', (38, 45))
238961	32186930	This resulted in the revised 2016 World Health Organization (WHO) classification of brain tumors in which diffuse glioma are now classified according to their IDH1/2 mutational and 1p/19q status.	('brain tumors', 'Disease', 'MESH:D001932', (84, 96))	('brain tumors', 'Phenotype', 'HP:0030692', (84, 96))	('glioma', 'Disease', (114, 120))	('mutational', 'Var', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('brain tumors', 'Disease', (84, 96))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('IDH1/2', 'Gene', (159, 165))
238962	32186930	In the aftermath of that fundamental change, ongoing discussions (cIMPACT-NOW) have further moved the classification by renaming low-grade astrocytoma with mutations observed in classic glioblastoma (gain of 7 combined with loss of 10, and/or EGFR amplification, and/or TERT promoter mutations only) by "low-grade astrocytoma with molecular features of glioblastoma."	('glioblastoma', 'Disease', 'MESH:D005909', (353, 365))	('astrocytoma', 'Phenotype', 'HP:0009592', (314, 325))	('astrocytoma', 'Phenotype', 'HP:0009592', (139, 150))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('glioblastoma', 'Disease', (353, 365))	('gain', 'PosReg', (200, 204))	('glioblastoma', 'Phenotype', 'HP:0012174', (353, 365))	('EGFR', 'Gene', '1956', (243, 247))	('glioblastoma', 'Disease', (186, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('mutations', 'Var', (156, 165))	('astrocytoma', 'Disease', 'MESH:D001254', (314, 325))	('astrocytoma', 'Disease', 'MESH:D001254', (139, 150))	('astrocytoma', 'Disease', (314, 325))	('astrocytoma', 'Disease', (139, 150))	('TERT', 'Gene', (270, 274))	('loss', 'Var', (224, 228))	('TERT', 'Gene', '7015', (270, 274))	('EGFR', 'Gene', (243, 247))
238966	32186930	Other molecular indicators of poor prognosis have been proposed, but larger validation cohorts are needed to clarify the role of CDK4 amplification, increased copy number alterations, and absence of CpG island hypermethylation.	('increased', 'PosReg', (149, 158))	('CDK4', 'Gene', (129, 133))	('CDK4', 'Gene', '1019', (129, 133))	('CpG', 'Var', (199, 202))	('copy number alterations', 'Var', (159, 182))
238970	32186930	The first reports were inconsistent to the question of whether it was the 1p/19q status that was associated with improved outcome after adjuvant chemotherapy in grade 2 and 3 glioma, the IDH mutations that are invariably present in 1p/19q codeleted tumors, or MGMT promoter methylation that is usually present in IDHmt tumors.	('tumors', 'Disease', (319, 325))	('IDH', 'Gene', '3417', (313, 316))	('IDHmt tumors', 'Disease', 'MESH:D009369', (313, 325))	('MGMT', 'Gene', (260, 264))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (319, 325))	('mutations', 'Var', (191, 200))	('glioma', 'Disease', (175, 181))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('IDHmt tumors', 'Disease', (313, 325))	('IDH', 'Gene', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('MGMT', 'Gene', '4255', (260, 264))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))	('IDH', 'Gene', (313, 316))	('IDH', 'Gene', '3417', (187, 190))	('improved', 'PosReg', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumors', 'Disease', (249, 255))
238973	32186930	The early observation on the strong association between outcome and IDH mutations initiated further studies into the different clinical characteristics of these tumors.	('IDH', 'Gene', '3417', (68, 71))	('mutations', 'Var', (72, 81))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('IDH', 'Gene', (68, 71))
238978	32186930	The mutant IDH protein has an altered substrate affinity of the enzyme and catalyzes the conversion of alpha-ketoglutarate into 2-hydrogylutarate (2HG), during which process NADP+ is reduced to nicotinamide adenine dinucleotide phosphate hydrogen.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (103, 122))	('IDH', 'Gene', '3417', (11, 14))	('IDH', 'Gene', (11, 14))	('mutant', 'Var', (4, 10))	('NADP+', 'Chemical', 'MESH:D009249', (174, 179))	('substrate affinity', 'MPA', (38, 56))	('2HG', 'Chemical', '-', (147, 150))	('nicotinamide adenine dinucleotide phosphate hydrogen', 'Chemical', '-', (194, 246))	('altered', 'Reg', (30, 37))	('2-hydrogylutarate', 'Chemical', '-', (128, 145))
238980	32186930	Subsequent studies found that 2HG acts as an oncometabolite by altering many cellular functions resulting in genome-wide CpG island hypermethylation, increased double-stand DNA breaks, decrease in NADP, and loss of function because of depletion of alpha-ketoglutarate-dependent enzymes.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (248, 267))	('2HG', 'Chemical', '-', (30, 33))	('CpG island', 'Protein', (121, 131))	('double-stand DNA breaks', 'CPA', (160, 183))	('depletion', 'MPA', (235, 244))	('hypermethylation', 'Var', (132, 148))	('altering', 'Reg', (63, 71))	('decrease', 'NegReg', (185, 193))	('loss of function', 'NegReg', (207, 223))	('cellular', 'CPA', (77, 85))	('NADP', 'Chemical', 'MESH:D009249', (197, 201))	('increased', 'PosReg', (150, 159))	('alpha-ketoglutarate-dependent enzymes', 'Enzyme', (248, 285))	('double-stand', 'Phenotype', 'HP:0003698', (160, 172))	('NADP', 'MPA', (197, 201))
238981	32186930	From these data, two opposite treatment strategies have been developed: reduce the amount of intratumoral 2HG by directly inhibiting the function of mutant IDH enzyme, or do not reduce the amount of 2HG and instead exploit the the cellular consequences of 2HG accumulation, in particular, the impaired DNA repair mechanisms that may underly the increased sensitivity of IDH-mutant gliomas to radiotherapy and alkylating chemotherapy.	('inhibiting', 'NegReg', (122, 132))	('IDH', 'Gene', (370, 373))	('IDH', 'Gene', '3417', (370, 373))	('2HG', 'Chemical', '-', (256, 259))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('2HG', 'Chemical', '-', (106, 109))	('mutant', 'Var', (149, 155))	('2HG', 'Chemical', '-', (199, 202))	('glioma', 'Phenotype', 'HP:0009733', (381, 387))	('IDH', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IDH', 'Gene', '3417', (156, 159))	('tumor', 'Disease', (98, 103))	('reduce', 'NegReg', (72, 78))	('gliomas', 'Disease', 'MESH:D005910', (381, 388))	('gliomas', 'Phenotype', 'HP:0009733', (381, 388))	('gliomas', 'Disease', (381, 388))	('function', 'MPA', (137, 145))
238982	32186930	The discovery of somatic IDH mutations in glioblastoma and lower-grade gliomas jettisoned the mutant metabolic enzyme to the top of the list of new drug targets for diffuse glioma.	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioma', 'Disease', (173, 179))	('gliomas jettisoned', 'Disease', (71, 89))	('mutations', 'Var', (29, 38))	('glioma', 'Disease', (71, 77))	('gliomas', 'Phenotype', 'HP:0009733', (71, 78))	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('gliomas jettisoned', 'Disease', 'MESH:D005910', (71, 89))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
238983	32186930	First, cancer-associated IDH mutations cluster in key arginine residues within the enzyme's active site (R132 of IDH1 and R140 or R172 of IDH2), raising the possibility of developing mutantselective inhibitors with a wider therapeutic window.	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (138, 141))	('IDH', 'Gene', '3417', (113, 116))	('IDH', 'Gene', '3417', (25, 28))	('R132', 'Var', (105, 109))	('IDH1', 'Gene', '15926', (113, 117))	('cluster', 'Reg', (39, 46))	('cancer', 'Disease', (7, 13))	('IDH2', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('R172', 'Var', (130, 134))	('mutations', 'Var', (29, 38))	('arginine', 'Chemical', 'MESH:D001120', (54, 62))	('R140', 'Var', (122, 126))	('IDH2', 'Gene', '269951', (138, 142))	('IDH', 'Gene', (138, 141))	('IDH1', 'Gene', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('IDH', 'Gene', (113, 116))
238984	32186930	Second, mutant IDH1 (mIDH1) appeared to play a prominent role in the pathogenesis of lower-grade glioma given the extraordinarily high prevalence of IDH mutation in this disease (70%-80%), the distinct DNA hypermethylation pattern associated with IDH mutations, and the persistence of IDH-mutant tumor cell clones throughout the disease course.	('IDH', 'Gene', (247, 250))	('mIDH1', 'Gene', '15926', (21, 26))	('mIDH1', 'Gene', (21, 26))	('IDH1', 'Gene', '15926', (22, 26))	('IDH', 'Gene', '3417', (247, 250))	('IDH', 'Gene', (285, 288))	('IDH', 'Gene', (149, 152))	('IDH1', 'Gene', (15, 19))	('tumor', 'Disease', (296, 301))	('mutant', 'Var', (8, 14))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('glioma', 'Disease', (97, 103))	('IDH', 'Gene', '3417', (285, 288))	('IDH', 'Gene', '3417', (149, 152))	('IDH1', 'Gene', (22, 26))	('IDH', 'Gene', '3417', (22, 25))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('IDH', 'Gene', '3417', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('IDH1', 'Gene', '15926', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
238985	32186930	Third, 2HG, the direct product of the mutant enzyme, was sufficient to phenocopy the cancer-promoting effects of the mutant IDH enzyme in a reversible fashion, providing rationale for maximal 2HG inhibition as biologically relevant and readily quantifiable pharmacologic strategy.	('mutant', 'Var', (38, 44))	('IDH', 'Gene', (124, 127))	('mutant', 'Var', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('2HG', 'Chemical', '-', (192, 195))	('IDH', 'Gene', '3417', (124, 127))	('2HG', 'Chemical', '-', (7, 10))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
238986	32186930	Last, inhibition of the mutant IDH enzyme showed antitumor activity in experimental models of glioma and leukemia.	('mutant', 'Var', (24, 30))	('IDH', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('IDH', 'Gene', '3417', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('glioma and leukemia', 'Disease', 'MESH:D005910', (94, 113))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('tumor', 'Disease', (53, 58))	('inhibition', 'NegReg', (6, 16))
238988	32186930	In vitro studies using IDH1-mutant cancer cell lines, which often harbor genetically more complex genomes, suggest that several factors might relieve mutant IDH cancer cells from their dependency on the mutant enzyme for survival.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('IDH1', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('relieve', 'NegReg', (142, 149))	('IDH1', 'Gene', '15926', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (161, 167))	('mutant', 'Var', (150, 156))	('cancer', 'Disease', (35, 41))	('IDH', 'Gene', '3417', (23, 26))	('IDH', 'Gene', (157, 160))
238989	32186930	The clinical development of inhibitors of mIDH proceeded most expeditiously in patients with AML, another cancer type found to harbor mutations in IDH1 and, more commonly, IDH2.	('IDH1', 'Gene', '15926', (147, 151))	('IDH2', 'Gene', '269951', (172, 176))	('AML', 'Phenotype', 'HP:0004808', (93, 96))	('AML', 'Disease', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('mIDH', 'Chemical', '-', (42, 46))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (134, 143))	('IDH1', 'Gene', (147, 151))	('IDH2', 'Gene', (172, 176))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
238991	32186930	Ivosidenib, the first-in-class inhibitor of the mutant IDH1 enzyme, similarly induced clinical and molecular remissions in patients with advanced mIDH1 AML.	('IDH1', 'Gene', '15926', (147, 151))	('mutant', 'Var', (48, 54))	('IDH1', 'Gene', '15926', (55, 59))	('mIDH1', 'Gene', '15926', (146, 151))	('AML', 'Disease', (152, 155))	('AML', 'Phenotype', 'HP:0004808', (152, 155))	('patients', 'Species', '9606', (123, 131))	('mIDH1', 'Gene', (146, 151))	('IDH1', 'Gene', (147, 151))	('Ivosidenib', 'Chemical', 'MESH:C000627630', (0, 10))	('IDH1', 'Gene', (55, 59))	('AML', 'Disease', 'MESH:D015470', (152, 155))
238993	32186930	The role of mutant IDH in glioma and other solid tumors is currently under investigation.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('mutant', 'Var', (12, 18))	('glioma', 'Disease', (26, 32))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('IDH', 'Gene', (19, 22))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('IDH', 'Gene', '3417', (19, 22))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
238994	32186930	A phase I study with ivosidenib in subjects with advanced solid tumors, including glioma, with an IDH1 mutation (ClinicalTrials.gov identifier: NCT02073994) was initiated in March 2014 across 12 study sites in the United States and one in France and included 66 with glioma.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('glioma', 'Disease', (267, 273))	('ivosidenib', 'Chemical', 'MESH:C000627630', (21, 31))	('IDH1', 'Gene', (98, 102))	('IDH1', 'Gene', '15926', (98, 102))	('glioma', 'Disease', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (267, 273))	('mutation', 'Var', (103, 111))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
239002	32186930	A subsequent clinical trial (ClinicalTrials.gov identifier: NCT03343197) showed greater than 90% inhibition of the mutant IDH enzyme by ivosidenib in on-treatment biopsies from patients with nonenhancing gliomas.	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('gliomas', 'Disease', 'MESH:D005910', (204, 211))	('patients', 'Species', '9606', (177, 185))	('inhibition', 'NegReg', (97, 107))	('mutant', 'Var', (115, 121))	('gliomas', 'Disease', (204, 211))	('gliomas', 'Phenotype', 'HP:0009733', (204, 211))	('ivosidenib', 'Gene', (136, 146))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('ivosidenib', 'Chemical', 'MESH:C000627630', (136, 146))
239004	32186930	Vorasidenib (AG-881) is a first-in-class dual inhibitor of mutant IDH1 and 2, which was designed for enhanced brain penetrance.	('IDH1', 'Gene', '15926', (66, 70))	('mutant', 'Var', (59, 65))	('IDH1', 'Gene', (66, 70))	('AG-881', 'Chemical', '-', (13, 19))	('Vorasidenib', 'Chemical', '-', (0, 11))	('enhanced', 'PosReg', (101, 109))	('brain penetrance', 'CPA', (110, 126))
239012	32186930	This conclusion led to the design of a randomized, placebo-controlled phase III trial of AG-881 in participants with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation (INDIGO; ClinicalTrials.gov identifier: NCT04164901).	('IDH2', 'Gene', (170, 174))	('participants', 'Species', '9606', (99, 111))	('IDH1', 'Gene', '15926', (162, 166))	('mutation', 'Var', (175, 183))	('IDH2', 'Gene', '269951', (170, 174))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('AG-881', 'Chemical', '-', (89, 95))	('glioma', 'Disease', (147, 153))	('AG-881', 'Gene', (89, 95))	('IDH1', 'Gene', (162, 166))
239015	32186930	Mutant IDH1/2-induced 2HG typically exceeds a concentration of 1 to 2 mM in cells, and thus it is likely that nearly all of these dioxygenases are inhibited, albeit to varying degrees, by such high levels of oncometabolite production.	('IDH1/2-induced', 'Gene', (7, 21))	('inhibited', 'NegReg', (147, 156))	('dioxygenases', 'Enzyme', (130, 142))	('2HG', 'MPA', (22, 25))	('Mutant', 'Var', (0, 6))	('2HG', 'Chemical', '-', (22, 25))
239017	32186930	Synthetic lethality gained momentum after the publication of two seminal papers in the early 2000s, which reported that mutations in the homologous recombination (HR) genes, BRCA1 and BRCA2, confer exquisite sensitivity to PARP inhibitors.	('BRCA2', 'Gene', (184, 189))	('BRCA1', 'Gene', (174, 179))	('BRCA2', 'Gene', '675', (184, 189))	('PARP', 'Gene', (223, 227))	('HR', 'Gene', (163, 165))	('BRCA1', 'Gene', '672', (174, 179))	('mutations', 'Var', (120, 129))	('sensitivity', 'MPA', (208, 219))	('PARP', 'Gene', '142', (223, 227))
239020	32186930	In 2017, the Bindra and Glazer Laboratories were the first to report that mutant IDH1/2 induces an HR defect that confers PARP inhibitor sensitivity.	('induces', 'Reg', (88, 95))	('PARP', 'Gene', (122, 126))	('IDH1/2', 'Gene', (81, 87))	('HR defect', 'Disease', (99, 108))	('HR defect', 'Disease', 'MESH:D000014', (99, 108))	('PARP', 'Gene', '142', (122, 126))	('mutant', 'Var', (74, 80))
239021	32186930	Mechanistically, it was found that 2HG-induced suppression of two histone demethylases, KDM4A and KDM4B, induced an HR defect similar to that associated with BRCA1/2 mutations.	('KDM4A', 'Gene', (88, 93))	('BRCA1/2', 'Gene', '672;675', (158, 165))	('mutations', 'Var', (166, 175))	('KDM4B', 'Gene', (98, 103))	('KDM4B', 'Gene', '23030', (98, 103))	('2HG', 'Chemical', '-', (35, 38))	('HR defect', 'Disease', 'MESH:D000014', (116, 125))	('KDM4A', 'Gene', '9682', (88, 93))	('HR defect', 'Disease', (116, 125))	('BRCA1/2', 'Gene', (158, 165))	('suppression', 'NegReg', (47, 58))
239022	32186930	Soon after this initial discovery, several other groups reported a similar synthetic lethal interaction between PARP inhibition and mutant IDH1/2 across a wide range of tumor types.	('IDH1/2', 'Gene', (139, 145))	('PARP', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mutant', 'Var', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PARP', 'Gene', '142', (112, 116))	('tumor', 'Disease', (169, 174))	('inhibition', 'NegReg', (117, 127))
239023	32186930	Of note, the phenomenon of oncometabolite-induced HR suppression was further extended to tumor-associated mutations in other tricarboxylic acid cycle genes, such as fumarate and succinate.	('HR suppression', 'Disease', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('fumarate', 'Chemical', 'MESH:D005650', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutations', 'Var', (106, 115))	('succinate', 'Chemical', 'MESH:D019802', (178, 187))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (125, 143))	('HR suppression', 'Disease', 'MESH:D001919', (50, 64))	('tumor', 'Disease', (89, 94))
239024	32186930	This novel approach to target IDH1/2-mutant cancers with PARP inhibitors is now being tested in the clinic for glioma (ClinicalTrials.gov identifiers: NCT03749187 and NCT03914742), as well as many other tumor types, including chondrosarcoma and cholangiocarcinoma (ClinicalTrials.gov identifiers: NCT02576444 and NCT03212274).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (245, 263))	('glioma', 'Disease', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('PARP', 'Gene', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (226, 240))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('cancers', 'Disease', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('PARP', 'Gene', '142', (57, 61))	('NCT03212274', 'Var', (313, 324))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('chondrosarcoma and cholangiocarcinoma', 'Disease', 'MESH:D002813', (226, 263))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
239030	32186930	Another, albeit less potent, PARP inhibitor, veliparib, is also being tested in a cohort of pediatric patients with newly diagnosed glioma with IDH1/2 mutations (ClinicalTrials.gov identifier: NCT03581292).	('glioma', 'Disease', (132, 138))	('patients', 'Species', '9606', (102, 110))	('PARP', 'Gene', '142', (29, 33))	('IDH1/2', 'Gene', (144, 150))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('veliparib', 'Chemical', 'MESH:C521013', (45, 54))	('mutations', 'Var', (151, 160))	('PARP', 'Gene', (29, 33))
239031	32186930	It has also been shown that mutant IDH1/2-induced 2HG impairs alkylation damage repair via inhibition of the ALKBH family of alphaKG-dependent dioxygenases, ALKBH2 and ALKBH3, leading to enhanced sensitivity to multiple alkylating agents, including temozolomide.	('sensitivity to multiple alkylating agents', 'MPA', (196, 237))	('ALKBH3', 'Gene', (168, 174))	('2HG', 'Gene', (50, 53))	('ALKBH', 'Gene', (168, 173))	('ALKBH', 'Gene', '8846', (157, 162))	('ALKBH', 'Gene', (157, 162))	('IDH1/2-induced', 'Gene', (35, 49))	('ALKBH', 'Gene', '8846', (109, 114))	('impairs alkylation damage', 'Disease', (54, 79))	('ALKBH2', 'Gene', (157, 163))	('ALKBH2', 'Gene', '121642', (157, 163))	('impairs alkylation damage', 'Disease', 'MESH:D009422', (54, 79))	('ALKBH', 'Gene', (109, 114))	('inhibition', 'NegReg', (91, 101))	('enhanced', 'PosReg', (187, 195))	('mutant', 'Var', (28, 34))	('ALKBH3', 'Gene', '221120', (168, 174))	('ALKBH', 'Gene', '8846', (168, 173))	('temozolomide', 'Chemical', 'MESH:D000077204', (249, 261))	('2HG', 'Chemical', '-', (50, 53))	('alphaKG-dependent dioxygenases', 'Enzyme', (125, 155))
239032	32186930	It should be noted that IDH1/2 mutations frequently co-occur with MGMT promoter silencing, which is linked to the phenomenon of 2HG-induced CpG island methylator phenotype via TET inhibition discussed previously.	('mutations', 'Var', (31, 40))	('MGMT', 'Gene', (66, 70))	('MGMT', 'Gene', '4255', (66, 70))	('TET', 'Chemical', 'MESH:C010349', (176, 179))	('IDH1/2', 'Gene', (24, 30))	('co-occur', 'Reg', (52, 60))	('2HG', 'Chemical', '-', (128, 131))	('promoter', 'Disease', (71, 79))
239033	32186930	MGMT loss also confers alkylator sensitivity, but this pathway is distinct from ALKBH, and thus loss of both pathways in IDH1/2-mutant gliomas likely results in sensitivity to this class of drugs, which is at least additive.	('MGMT', 'Gene', (0, 4))	('ALKBH', 'Gene', '8846', (80, 85))	('sensitivity', 'MPA', (161, 172))	('IDH1/2-mutant', 'Gene', (121, 134))	('IDH1/2-mutant', 'Var', (121, 134))	('gliomas', 'Disease', 'MESH:D005910', (135, 142))	('gliomas', 'Phenotype', 'HP:0009733', (135, 142))	('gliomas', 'Disease', (135, 142))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('loss', 'NegReg', (5, 9))	('loss', 'NegReg', (96, 100))	('results', 'Reg', (150, 157))	('MGMT', 'Gene', '4255', (0, 4))	('ALKBH', 'Gene', (80, 85))	('alkylator sensitivity', 'MPA', (23, 44))
239035	32186930	This also suggests that mutant IDH1/2 inhibitors should not be given concurrently with alkylators, given the potential for antagonistic interactions, at least based on the effects of 2HG on ALKBH2/3 function.	('mutant', 'Var', (24, 30))	('ALKBH2/3', 'Gene', (190, 198))	('2HG', 'Chemical', '-', (183, 186))	('ALKBH2/3', 'Gene', '121642;221120', (190, 198))	('IDH1/2', 'Gene', (31, 37))
239036	32186930	A synthetic lethal interaction between mutant IDH1/2 and members of the BCL-2 family was first reported in AML tumor models but has since been shown in IDH1/2-mutant glioma.	('IDH1/2', 'Gene', (46, 52))	('AML', 'Phenotype', 'HP:0004808', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('AML tumor', 'Disease', (107, 116))	('BCL-2', 'Gene', '596', (72, 77))	('glioma', 'Disease', (166, 172))	('BCL-2', 'Gene', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('mutant', 'Var', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('AML tumor', 'Disease', 'MESH:D015470', (107, 116))	('synthetic lethal', 'CPA', (2, 18))
239038	32186930	As such, this strategy can be readily and feasibly tested in the clinic for IDH1/2-mutant gliomas in the future.	('gliomas', 'Disease', (90, 97))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('IDH1/2-mutant', 'Gene', (76, 89))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('IDH1/2-mutant', 'Var', (76, 89))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
239040	32186930	Mechanistically, they demonstrated that IDH1/2 mutations silence a key gene in NAD metabolism, nicotinate phosphoribosyltransferase (NAPRT), which leads to decreased levels of NAD+ and consequent NAMPT inhibitor sensitivity.	('silence', 'NegReg', (57, 64))	('NAMPT', 'Gene', (196, 201))	('NAPRT', 'Gene', (133, 138))	('nicotinate phosphoribosyltransferase', 'Gene', (95, 131))	('IDH1/2', 'Gene', (40, 46))	('mutations', 'Var', (47, 56))	('levels of NAD+', 'MPA', (166, 180))	('NAPRT', 'Gene', '93100', (133, 138))	('decreased', 'NegReg', (156, 165))	('nicotinate phosphoribosyltransferase', 'Gene', '93100', (95, 131))	('NAD+', 'Chemical', 'MESH:D009243', (176, 180))	('NAD metabolism', 'Disease', 'MESH:D008659', (79, 93))	('NAD metabolism', 'Disease', (79, 93))	('NAMPT', 'Gene', '10135', (196, 201))
239044	32186930	Since the first discovery of IDH mutations in cancer, considerable progress has been made in our understanding of their contribution to cancer development.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (136, 142))	('IDH', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IDH', 'Gene', '3417', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
239046	32186930	Pharmacologic blockade of the mutant enzyme with first-in-class inhibitors has been efficacious for the treatment of IDH-mutant AML and is currently being evaluated in phase III trials for IDH-mutant glioma (INDIGO) and cholangiocarcinoma (ClarIDHy).	('glioma', 'Disease', (200, 206))	('IDH', 'Gene', (189, 192))	('AML', 'Disease', (128, 131))	('IDH', 'Gene', (244, 247))	('AML', 'Phenotype', 'HP:0004808', (128, 131))	('IDH', 'Gene', (117, 120))	('cholangiocarcinoma', 'Disease', (220, 238))	('IDH', 'Gene', '3417', (189, 192))	('IDH', 'Gene', '3417', (244, 247))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (220, 238))	('IDH', 'Gene', '3417', (117, 120))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (220, 238))	('AML', 'Disease', 'MESH:D015470', (128, 131))	('mutant', 'Var', (30, 36))
239047	32186930	This will require a much deeper understanding of which of the many cellular and molecular effects associated with intratumoral 2HG accumulation in glioma are reversible following inhibition of the mutant enzyme.	('tumor', 'Disease', (119, 124))	('2HG', 'Chemical', '-', (127, 130))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutant', 'Var', (197, 203))	('glioma', 'Disease', (147, 153))
239049	32186930	Grade 4 tumors with IDH mutations will now be labeled astrocytoma, IDHmt grade 4.	('IDH', 'Gene', (20, 23))	('IDH', 'Gene', '3417', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('IDH', 'Gene', (67, 70))	('tumors', 'Disease', (8, 14))	('astrocytoma', 'Disease', 'MESH:D001254', (54, 65))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('IDH', 'Gene', '3417', (67, 70))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (24, 33))	('astrocytoma', 'Disease', (54, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))
239052	32186930	Drugs inhibiting the mutant IDH protein are effective in AML and cholangiocarcinoma and are currently being tested in glioma.	('IDH', 'Gene', (28, 31))	('glioma', 'Disease', (118, 124))	('mutant', 'Var', (21, 27))	('IDH', 'Gene', '3417', (28, 31))	('cholangiocarcinoma', 'Disease', (65, 83))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('inhibiting', 'NegReg', (6, 16))	('protein', 'Protein', (32, 39))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('effective', 'Reg', (44, 53))	('AML', 'Disease', (57, 60))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('AML', 'Phenotype', 'HP:0004808', (57, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))
239053	32186930	Other metabolic alterations in IDH mutations present other possible avenues for treatment, such as PARP inhibitors.	('IDH', 'Gene', (31, 34))	('PARP', 'Gene', (99, 103))	('metabolic', 'MPA', (6, 15))	('IDH', 'Gene', '3417', (31, 34))	('PARP', 'Gene', '142', (99, 103))	('mutations', 'Var', (35, 44))
239076	20461477	For example, glioblastomas are biologically heterogeneous tumors, and small studies have shown that the influence of specific genetic alterations, such as TP53 gene mutations, allelic loss of chromosome 1p, CDKN2A/P16 homozygous deletion, and epidermal growth factor receptor (EGFR) amplification, on patient outcome is age dependent.	('glioblastomas', 'Phenotype', 'HP:0012174', (13, 26))	('amplification', 'Var', (283, 296))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('EGFR', 'Gene', '1956', (277, 281))	('patient', 'Species', '9606', (301, 308))	('P16', 'Gene', '1029', (214, 217))	('TP53', 'Gene', (155, 159))	('mutations', 'Var', (165, 174))	('glioblastomas', 'Disease', (13, 26))	('epidermal growth factor receptor', 'Gene', (243, 275))	('P16', 'Gene', (214, 217))	('CDKN2A', 'Gene', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('epidermal growth factor receptor', 'Gene', '1956', (243, 275))	('loss', 'NegReg', (184, 188))	('glioblastomas', 'Disease', 'MESH:D005909', (13, 26))	('EGFR', 'Gene', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', '7157', (155, 159))	('CDKN2A', 'Gene', '1029', (207, 213))	('tumors', 'Disease', (58, 64))
239078	20461477	Patient characteristics also are important prognostic factors; poor performance status is a strong predictor of short survival, and comorbidities also may influence outcomes.	('influence', 'Reg', (155, 164))	('short', 'MPA', (112, 117))	('Patient', 'Species', '9606', (0, 7))	('poor performance', 'Var', (63, 79))
239086	20461477	We also retrospectively studied 394 glioblastoma patients aged 65 or older and demonstrated that gross total resection had a survival advantage over partial resection or biopsy.	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('survival advantage', 'CPA', (125, 143))	('gross total', 'Var', (97, 108))	('patients', 'Species', '9606', (49, 57))	('died', 'Disease', (27, 31))	('died', 'Disease', 'MESH:D003643', (27, 31))	('glioblastoma', 'Disease', (36, 48))
239087	20461477	Finally, a small prospective study of 23 patients aged 65 and over with malignant gliomas showed that resection improved survival compared with biopsy.	('survival', 'MPA', (121, 129))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('malignant gliomas', 'Disease', (72, 89))	('patients', 'Species', '9606', (41, 49))	('malignant gliomas', 'Disease', 'MESH:D005910', (72, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('resection', 'Var', (102, 111))	('improved', 'PosReg', (112, 120))
239089	20461477	The use of radiotherapy to treat glioblastoma has been standard practice since the 1970s, when randomized studies by the Brain Tumor Study Group showed a significant survival benefit from radiotherapy compared with supportive care alone (median survival of 36 weeks vs 14 weeks).	('glioblastoma', 'Disease', (33, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('Brain Tumor', 'Phenotype', 'HP:0030692', (121, 132))	('Tumor', 'Disease', 'MESH:D009369', (127, 132))	('Tumor', 'Phenotype', 'HP:0002664', (127, 132))	('survival benefit', 'CPA', (166, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('Tumor', 'Disease', (127, 132))	('radiotherapy', 'Var', (188, 200))
239112	20461477	Although there was no clear survival benefit of temozolomide over PCV (procarbazine, carmustine, and vincristine), patients who received temozolomide had a longer progression-free survival (PFS; 10.7 vs 6.9 months) and tolerated chemotherapy better.	('temozolomide', 'Chemical', 'MESH:D000077204', (137, 149))	('patients', 'Species', '9606', (115, 123))	('carmustine', 'Chemical', 'MESH:D002330', (85, 95))	('temozolomide', 'Var', (137, 149))	('procarbazine', 'Chemical', 'MESH:D011344', (71, 83))	('progression-free survival', 'CPA', (163, 188))	('temozolomide', 'Chemical', 'MESH:D000077204', (48, 60))	('vincristine', 'Chemical', 'MESH:D014750', (101, 112))	('longer', 'PosReg', (156, 162))
239196	29691296	Integrated cross-platform analyses coupling global metabolomic and gene-expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma.	('tryptophan metabolism', 'MPA', (113, 134))	('glioblastoma', 'Disease', (209, 221))	('aberrant', 'Var', (104, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (209, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (209, 221))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (104, 134))	('tryptophan', 'Chemical', 'MESH:D014364', (113, 123))
239198	29691296	Although GDC-0919 as a single agent did not demonstrate anti-tumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen.	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('GDC-0919', 'Var', (9, 17))	('RT response', 'MPA', (117, 128))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GDC-0919', 'Chemical', 'MESH:C000626065', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('enhancing', 'PosReg', (107, 116))	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('tumor', 'Disease', (61, 66))
239201	29691296	Tryptophan metabolism represents a metabolic node in glioblastoma and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immune suppression.	('RT-induced', 'MPA', (148, 158))	('glioblastoma', 'Disease', (53, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (53, 65))	('Tryptophan', 'Chemical', 'MESH:D014364', (0, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('mitigating', 'NegReg', (137, 147))	('enhances', 'PosReg', (104, 112))	('IDO1', 'Gene', (88, 92))	('inhibition', 'Var', (93, 103))	('therapeutic response', 'CPA', (113, 133))
239205	29691296	Dysfunction of these immune response "brakes" may lead to a variety of disorders, including autoimmune diseases, type 1 diabetes, inflammatory bowel disease, asthma and allergies.	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (130, 156))	('diabetes', 'Disease', (120, 128))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (113, 128))	('lead to', 'Reg', (50, 57))	('Dysfunction', 'Var', (0, 11))	('allergies', 'Disease', (169, 178))	('autoimmune diseases', 'Disease', (92, 111))	('inflammatory bowel disease', 'Disease', (130, 156))	('disorders', 'Disease', (71, 80))	('diabetes', 'Disease', 'MESH:D003920', (120, 128))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (92, 111))	('allergies', 'Phenotype', 'HP:0012393', (169, 178))	('asthma', 'Phenotype', 'HP:0002099', (158, 164))	('allergies', 'Disease', 'MESH:D004342', (169, 178))	('asthma', 'Disease', 'MESH:D001249', (158, 164))	('autoimmune diseases', 'Disease', 'MESH:D001327', (92, 111))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (130, 156))	('asthma', 'Disease', (158, 164))
239207	29691296	Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1), which negatively regulate T-cell activation, represent two specific immune checkpoints that have received recent attention, with inhibitors targeting these immune pathways demonstrating unprecedented clinical activity in a variety of solid tumors.	('solid tumors', 'Disease', (318, 330))	('PD-1', 'Gene', '18566', (77, 81))	('Cytotoxic T-lymphocyte-associated protein 4', 'Gene', '397286', (0, 43))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('CTLA-4', 'Gene', '397286', (45, 51))	('inhibitors', 'Var', (213, 223))	('solid tumors', 'Disease', 'MESH:D009369', (318, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('Cytotoxic T-lymphocyte-associated protein 4', 'Gene', (0, 43))	('PD-1', 'Gene', (77, 81))	('CTLA-4', 'Gene', (45, 51))
239211	29691296	Emerging studies have identified multifaceted strategies by which alterations in tumor metabolism may also contribute to a potent tolerogenic immune environment, thereby representing a line of next-generation immune checkpoints.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('potent tolerogenic immune environment', 'MPA', (123, 160))	('contribute', 'Reg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('alterations', 'Var', (66, 77))
239216	29691296	Kynurenine-activated AHRs are also responsible for providing a tolerogenic phenotype in dendritic cells (DCs), resulting in increased production of Tregs and reduced type 1 T helper (Th1) cells.	('Kynurenine-activated', 'Var', (0, 20))	('production', 'MPA', (134, 144))	('increased', 'PosReg', (124, 133))	('Tregs', 'CPA', (148, 153))	('Tregs', 'Chemical', '-', (148, 153))	('Kynurenine', 'Chemical', 'MESH:D007737', (0, 10))	('reduced', 'NegReg', (158, 165))
239220	29691296	The IDO1 pathway was later proposed to play a more direct role in tumor immune evasion, demonstrating a more robust T-cell response and delayed growth in vivo following pathway inhibition.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('delayed growth', 'Phenotype', 'HP:0001510', (136, 150))	('T-cell response', 'CPA', (116, 131))	('delayed growth', 'CPA', (136, 150))	('inhibition', 'Var', (177, 187))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
239222	29691296	TDO-mediated pathway activation in a panel of glioma cell lines resulted in inhibition of T-cell proliferation and modulating this pathway influenced tumor growth.	('inhibition', 'NegReg', (76, 86))	('influenced', 'Reg', (139, 149))	('modulating', 'Var', (115, 125))	('TDO', 'Gene', '56720', (0, 3))	('T-cell proliferation', 'CPA', (90, 110))	('glioma', 'Disease', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('TDO', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('activation', 'PosReg', (21, 31))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('tumor', 'Disease', (150, 155))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
239224	29691296	The majority of studies evaluating the immune consequences of aberrant tryptophan metabolism have largely focused on expression of its rate limiting enzymes rather than the individual metabolites involved in immune suppression.	('tryptophan metabolism', 'MPA', (71, 92))	('expression', 'MPA', (117, 127))	('aberrant', 'Var', (62, 70))	('tryptophan', 'Chemical', 'MESH:D014364', (71, 81))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (62, 92))
239240	29691296	Comparisons between tumor volumes in the subcutaneous tumor model was performed using 2 way ANOVA in combination with post-hoc operations to generate p values between RT and RT+GDC-0919.	('RT+GDC-0919', 'Var', (174, 185))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('GDC-0919', 'Chemical', 'MESH:C000626065', (177, 185))	('tumor', 'Disease', (54, 59))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (41, 59))	('tumor', 'Disease', (20, 25))
239247	29691296	Of the identified metabolites associated with tryptophan metabolism, kynurenine demonstrated the highest accumulation in glioblastoma when compared to LGG (6.07-fold, p<=0.0002; Fig.	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('kynurenine', 'Var', (69, 79))	('accumulation', 'PosReg', (105, 117))	('kynurenine', 'Chemical', 'MESH:D007737', (69, 79))	('tryptophan', 'Chemical', 'MESH:D014364', (46, 56))	('glioblastoma', 'Disease', (121, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))
239249	29691296	Using the TCGA database, we then sought to determine if aberrant expression of enzymes involved with tryptophan metabolism recapitulated these metabolic findings in glioma.	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('tryptophan', 'Chemical', 'MESH:D014364', (101, 111))	('aberrant expression', 'Var', (56, 75))	('glioma', 'Disease', (165, 171))
239251	29691296	We next sought to determine if aberrant tryptophan metabolism was unique to a specific glioblastoma molecular subtype.	('tryptophan metabolism', 'MPA', (40, 61))	('glioblastoma molecular subtype', 'Disease', (87, 117))	('aberrant', 'Var', (31, 39))	('glioblastoma molecular subtype', 'Disease', 'MESH:D005909', (87, 117))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (31, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('tryptophan', 'Chemical', 'MESH:D014364', (40, 50))
239255	29691296	The proneural subtype is characterized by mutations in isocitrate dehydrogenase 1 (IDH1), frequent alterations in expression of p53 and platelet derived growth factor receptor, alpha polypeptide (PDGFR-alpha), and a transcriptional signature typically present in LGG.	('p53', 'Gene', (128, 131))	('IDH1', 'Gene', '15926', (83, 87))	('isocitrate dehydrogenase 1', 'Gene', (55, 81))	('PDGFR-alpha', 'Gene', '18595', (196, 207))	('isocitrate dehydrogenase 1', 'Gene', '15926', (55, 81))	('PDGFR-alpha', 'Gene', (196, 207))	('platelet derived growth factor receptor, alpha polypeptide', 'Gene', '18595', (136, 194))	('alterations', 'Reg', (99, 110))	('proneural', 'Disease', (4, 13))	('p53', 'Gene', '22060', (128, 131))	('expression', 'MPA', (114, 124))	('mutations', 'Var', (42, 51))	('IDH1', 'Gene', (83, 87))
239264	29691296	Based on these findings, we sought to determine if aberrant tryptophan metabolism was unique in specific regions within an individual tumor.	('tryptophan metabolism', 'MPA', (60, 81))	('aberrant', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (51, 81))	('tryptophan', 'Chemical', 'MESH:D014364', (60, 70))	('tumor', 'Disease', (134, 139))
239266	29691296	As cross-platform analysis coupling metabolomics with transcriptional profiling identified aberrant tryptophan metabolism as a metabolic phenotype in glioblastoma, we extended investigations to preclinical models.	('tryptophan', 'Chemical', 'MESH:D014364', (100, 110))	('glioblastoma', 'Disease', (150, 162))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (91, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (150, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('tryptophan metabolism', 'MPA', (100, 121))	('aberrant', 'Var', (91, 99))
239273	29691296	To begin to explore the immune consequence of aberrant tryptophan metabolism in glioblastoma, we extended investigations to an adult astrocytic, genetically-engineered mouse (GEM) cell line to allow for in vivo studies using an immune competent model.	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (46, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('mouse', 'Species', '10090', (168, 173))	('tryptophan', 'Chemical', 'MESH:D014364', (55, 65))	('aberrant', 'Var', (46, 54))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))
239275	29691296	Briefly, after Cre-mediated recombination in vitro, lines express a truncation mutant of SV40 large T antigen (T) from the human Gfap promoter that inactivates all 3 Rb family proteins, a constitutively active KrasG12D mutant (R), and/or a homozygous Pten deletion (P).	('inactivates', 'NegReg', (148, 159))	('human', 'Species', '9606', (123, 128))	('3 Rb family proteins', 'Protein', (164, 184))	('Pten', 'Gene', '5728', (251, 255))	('Pten', 'Gene', (251, 255))	('deletion', 'Var', (256, 264))	('SV40', 'Gene', (89, 93))	('Gfap', 'Gene', '2670', (129, 133))	('Gfap', 'Gene', (129, 133))
239276	29691296	As an initial investigation, we performed metabolomic profiling of TRP cells grown orthotopically, which harbor all 3 of these mutations and displays the most aggressive phenotype, which confirmed pathway activation with high levels of kynurenine when compared to normal brain (Fig 2C).	('kynurenine', 'MPA', (236, 246))	('TRP', 'Chemical', 'MESH:D014364', (67, 70))	('activation', 'PosReg', (205, 215))	('mutations', 'Var', (127, 136))	('kynurenine', 'Chemical', 'MESH:D007737', (236, 246))
239287	29691296	Kynurenine production was completely inhibited in TRP ex vivo by GDC-0919 (5 muM).	('Kynurenine production', 'MPA', (0, 21))	('GDC-0919', 'Chemical', 'MESH:C000626065', (65, 73))	('inhibited', 'NegReg', (37, 46))	('TRP', 'Chemical', 'MESH:D014364', (50, 53))	('Kynurenine', 'Chemical', 'MESH:D007737', (0, 10))	('GDC-0919', 'Var', (65, 73))
239288	29691296	Interestingly, in a parallel study where mice were treated with GDC-0919 (200 mg/kg, BID for 3 days) in vivo prior to tumor excision, TRP cells demonstrated diminished production of both baseline and IFN-gamma-induced kynurenine (Fig.	('kynurenine', 'Chemical', 'MESH:D007737', (218, 228))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mice', 'Species', '10090', (41, 45))	('IFN-gamma-induced kynurenine', 'MPA', (200, 228))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('GDC-0919', 'Var', (64, 72))	('production', 'MPA', (168, 178))	('diminished', 'NegReg', (157, 167))	('tumor', 'Disease', (118, 123))	('baseline', 'MPA', (187, 195))	('TRP', 'Chemical', 'MESH:D014364', (134, 137))	('GDC-0919', 'Chemical', 'MESH:C000626065', (64, 72))	('BID', 'Gene', (85, 88))	('BID', 'Gene', '12122', (85, 88))
239290	29691296	Using LC-MS, we quantified GDC-0919 levels in normal brain (with no tumor implanted), intracranial tumors, subcutaneous tumors and plasma of mice following treatment with GDC-0919 (200 mg/kg BID) for 3 days, with tissue being extracted 2 hours after the last dose.	('tumors', 'Disease', (120, 126))	('mice', 'Species', '10090', (141, 145))	('BID', 'Gene', (191, 194))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('BID', 'Gene', '12122', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (107, 126))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('GDC-0919', 'Chemical', 'MESH:C000626065', (171, 179))	('intracranial tumors', 'Disease', (86, 105))	('GDC-0919', 'Chemical', 'MESH:C000626065', (27, 35))	('tumors', 'Disease', (99, 105))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (107, 125))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('intracranial tumors', 'Disease', 'MESH:D001932', (86, 105))	('GDC-0919', 'Var', (171, 179))	('GDC-0919', 'Gene', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
239291	29691296	Importantly, GDC-0919 achieved biologically relevant concentrations in intracranial tumors (~15 muM), which was comparable to levels achieved in subcutaneous tumors.	('tumors', 'Disease', (158, 164))	('intracranial tumors', 'Disease', 'MESH:D001932', (71, 90))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (145, 163))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('intracranial tumors', 'Disease', (71, 90))	('GDC-0919', 'Var', (13, 21))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('GDC-0919', 'Chemical', 'MESH:C000626065', (13, 21))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (145, 164))
239298	29691296	Continuing with the subcutaneous TRP model, GDC-0919 alone again demonstrated no anti-tumor activity, however when combined with RT (6 Gy x 1), demonstrated a significant growth delay when compared to RT alone (p<0.005; Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('TRP', 'Chemical', 'MESH:D014364', (33, 36))	('GDC-0919', 'Var', (44, 52))	('growth delay', 'Phenotype', 'HP:0001510', (171, 183))	('GDC-0919', 'Chemical', 'MESH:C000626065', (44, 52))	('growth delay', 'CPA', (171, 183))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
239312	29691296	However, kynurenine appeared to impart suppressiveness to Tregs, as the combination led to diminished proliferation of CD8+ T cells (Fig.	('suppressiveness', 'MPA', (39, 54))	('diminished', 'NegReg', (91, 101))	('kynurenine', 'Var', (9, 19))	('CD8+ T cells', 'CPA', (119, 131))	('Tregs', 'Chemical', '-', (58, 63))	('proliferation', 'CPA', (102, 115))	('kynurenine', 'Chemical', 'MESH:D007737', (9, 19))
239314	29691296	When combined with RT, GDC-0919 appeared to mitigate this immune suppressive response, normalizing Tregs, MDSCs, and TAMs back to baseline levels (Fig.	('Tregs', 'Chemical', '-', (99, 104))	('GDC-0919', 'Var', (23, 31))	('mitigate', 'NegReg', (44, 52))	('MDSCs', 'MPA', (106, 111))	('Tregs', 'MPA', (99, 104))	('GDC-0919', 'Chemical', 'MESH:C000626065', (23, 31))	('normalizing', 'PosReg', (87, 98))
239316	29691296	In addition to immune suppression, we sought to determine if GDC-0919, RT, or the combination influenced immune activation.	('influenced', 'Reg', (94, 104))	('immune activation', 'MPA', (105, 122))	('GDC-0919', 'Var', (61, 69))	('GDC-0919', 'Chemical', 'MESH:C000626065', (61, 69))
239320	29691296	When combined with RT, GDC-0919 led to further increases in both activated and cytotoxic T cells, which supports the observed enhanced anti-tumor response by this combination (Fig.	('enhanced', 'PosReg', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('GDC-0919', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('GDC-0919', 'Chemical', 'MESH:C000626065', (23, 31))	('increases', 'PosReg', (47, 56))	('tumor', 'Disease', (140, 145))
239322	29691296	As both the anti-tumor and immune response following IDO1 inhibition appeared RT-specific in our glioblastoma model, as an initial investigation, we sought to determine if RT could reactivate or further activate this immune checkpoint.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('inhibition', 'Var', (58, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('glioblastoma', 'Disease', (97, 109))	('IDO1', 'Gene', (53, 57))
239329	29691296	There have been several recent reports implicating aberrant tryptophan metabolism with glioblastoma immune tolerance.	('aberrant', 'Var', (51, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('glioblastoma', 'Disease', (87, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('tryptophan', 'Chemical', 'MESH:D014364', (60, 70))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (51, 81))
239344	29691296	In addition, these findings may imply that aberrant tryptophan metabolism is a late event in gliomagenesis and rational combinatorial strategies designed to also utilize agents specifically targeting the unique immune and/or signaling associated with tumor cell populations expanding in the infiltrative edge may lead to more durable control in these otherwise resistant tumors.	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', (371, 376))	('glioma', 'Disease', (93, 99))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (43, 73))	('tumors', 'Disease', (371, 377))	('tumors', 'Disease', 'MESH:D009369', (371, 377))	('tryptophan', 'Chemical', 'MESH:D014364', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('tryptophan metabolism', 'MPA', (52, 73))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('aberrant', 'Var', (43, 51))
239345	29691296	Aberrant tryptophan metabolism identified in patient-derived glioblastoma was recapitulated in our preclinical models, with robust pathway activation observed in all glioblastoma cell lines tested.	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('Aberrant', 'Var', (0, 8))	('activation', 'PosReg', (139, 149))	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('Aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (0, 30))	('tryptophan', 'Chemical', 'MESH:D014364', (9, 19))	('patient', 'Species', '9606', (45, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('glioblastoma', 'Disease', (166, 178))	('tryptophan metabolism', 'MPA', (9, 30))	('glioblastoma', 'Disease', 'MESH:D005909', (166, 178))
239348	29691296	Using this model, IDO1 inhibition with GDC-0919 did not demonstrate anti-tumor activity as a single agent in subcutaneous and orthotopic tumors or modulate the tumors' immune profile at baseline.	('tumors', 'Disease', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('modulate', 'Reg', (147, 155))	('tumors', 'Disease', (160, 166))	('orthotopic tumors', 'Disease', 'MESH:D009369', (126, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('GDC-0919', 'Chemical', 'MESH:C000626065', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Disease', (137, 142))	('orthotopic tumors', 'Disease', (126, 143))	('GDC-0919', 'Var', (39, 47))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
239349	29691296	Although molecular knockdown of IDO1 expression has been shown to influence glioblastoma growth, our results are consistent with other recent publications demonstrating minimal activity in glioblastoma when inhibiting IDO1 as a single targeted agent.	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma growth', 'Disease', (76, 95))	('knockdown', 'Var', (19, 28))	('glioblastoma', 'Disease', (189, 201))	('influence', 'Reg', (66, 75))	('IDO1', 'Gene', (32, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('glioblastoma', 'Disease', (76, 88))	('glioblastoma growth', 'Disease', 'MESH:D005909', (76, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))
239350	29691296	Although we did not observe any changes in the absolute number of Tregs following IDO1 inhibition, we did uncover an important role by which kynurenine modulates their activity, serving as a critical metabolite required for Treg-mediated suppression of CD8+ T cell proliferation.	('inhibition', 'NegReg', (87, 97))	('IDO1', 'Gene', (82, 86))	('activity', 'MPA', (168, 176))	('kynurenine', 'Var', (141, 151))	('modulates', 'Reg', (152, 161))	('Tregs', 'Chemical', '-', (66, 71))	('kynurenine', 'Chemical', 'MESH:D007737', (141, 151))
239351	29691296	Further work is needed to precisely define the role kynurenine and its downstream metabolic intermediates play in modulating Treg function and determine its mechanistic underpinnings.	('kynurenine', 'Chemical', 'MESH:D007737', (52, 62))	('modulating', 'Reg', (114, 124))	('kynurenine', 'Var', (52, 62))	('Treg function', 'CPA', (125, 138))
239359	29691296	Inhibiting tryptophan metabolism mitigates the observed accumulation of RT-induced Tregs and attenuates their suppressiveness.	('Inhibiting', 'Var', (0, 10))	('suppressiveness', 'CPA', (110, 125))	('tryptophan', 'Chemical', 'MESH:D014364', (11, 21))	('mitigates', 'NegReg', (33, 42))	('attenuates', 'NegReg', (93, 103))	('tryptophan metabolism', 'MPA', (11, 32))	('accumulation', 'PosReg', (56, 68))	('Tregs', 'Chemical', '-', (83, 88))
239362	29691296	In summary, aberrant tryptophan metabolism represents an important metabolic node in glioblastoma.	('tryptophan', 'Chemical', 'MESH:D014364', (21, 31))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (12, 42))	('glioblastoma', 'Disease', (85, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('tryptophan metabolism', 'MPA', (21, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('aberrant', 'Var', (12, 20))
239364	29691296	GDC-0919 is a potent IDO1 inhibitor with the capacity of crossing the BBB and enhancing RT response by mitigating RT-induced immune suppression, thereby shifting the immunologic balance towards a state of 'elimination', which was particularly striking when using a hypofractionated approach.	('enhancing', 'PosReg', (78, 87))	('immunologic balance', 'MPA', (166, 185))	('GDC-0919', 'Chemical', 'MESH:C000626065', (0, 8))	('RT response', 'MPA', (88, 99))	('RT-induced immune suppression', 'MPA', (114, 143))	('mitigating', 'NegReg', (103, 113))	('shifting', 'Reg', (153, 161))	('GDC-0919', 'Var', (0, 8))
239366	29691296	Through integrative, cross-platform analyses coupling global metabolomic profiling with gene expression arrays in over 100 patient-derived tumors, we identified aberrant tryptophan metabolism as an important metabolic node and immune checkpoint in glioblastoma.	('patient', 'Species', '9606', (123, 130))	('aberrant', 'Var', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('glioblastoma', 'Disease', (248, 260))	('aberrant tryptophan metabolism', 'Phenotype', 'HP:0004365', (161, 191))	('glioblastoma', 'Disease', 'MESH:D005909', (248, 260))	('tryptophan', 'Chemical', 'MESH:D014364', (170, 180))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (248, 260))	('tryptophan metabolism', 'MPA', (170, 191))
239369	29691296	Through these studies, we uncovered a potent synergy when combining an IDO1 inhibitor with hypofractionated radiation and a novel mechanism linking tryptophan metabolism with radiation-induced immune suppression involving immune checkpoint reactivation.	('inhibitor', 'Var', (76, 85))	('IDO1', 'Gene', (71, 75))	('tryptophan', 'Chemical', 'MESH:D014364', (148, 158))	('combining', 'Interaction', (58, 67))
239398	27770278	The mean sizes of the U87MG and LN229 EV were estimated as 92.6 +- 1.2 and 109.9 +- 2.9 nm, respectively (Fig.	('LN229', 'CellLine', 'CVCL:0393', (32, 37))	('U87MG', 'Var', (22, 27))	('LN229', 'Var', (32, 37))	('U87MG', 'CellLine', 'CVCL:0022', (22, 27))
239411	27770278	Transcript levels of ANXA1, IGF2R, ITGB1, PDCD6IP and ACTR3 were significantly higher in GBM specimens, compared with normal brain across all three datasets (Fig.	('ANXA1', 'Gene', (21, 26))	('IGF2R', 'Gene', (28, 33))	('ACTR3', 'Gene', '10096', (54, 59))	('GBM', 'Phenotype', 'HP:0012174', (89, 92))	('GBM', 'Var', (89, 92))	('ANXA1', 'Gene', '301', (21, 26))	('ITGB1', 'Gene', (35, 40))	('ACTR3', 'Gene', (54, 59))	('ITGB1', 'Gene', '3688', (35, 40))	('Transcript levels', 'MPA', (0, 17))	('IGF2R', 'Gene', '3482', (28, 33))	('PDCD6IP', 'Gene', '10015', (42, 49))	('higher', 'PosReg', (79, 85))	('PDCD6IP', 'Gene', (42, 49))
239421	27770278	Although 0.2 microm filtration would theoretically remove microvesicles larger than 200 nm, their presence cannot be discounted for NTA measurements are less precise for larger vesicles (Fig.	('rat', 'Species', '10116', (24, 27))	('microvesicles', 'Var', (58, 71))	('remove', 'NegReg', (51, 57))
239427	27770278	4) and high ANXA1 expression identified a group of astrocytoma and GBM patients with reduced survival.	('ANXA1', 'Gene', '301', (12, 17))	('patients', 'Species', '9606', (71, 79))	('astrocytoma', 'Disease', 'MESH:D001254', (51, 62))	('GBM', 'Disease', (67, 70))	('astrocytoma', 'Disease', (51, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (51, 62))	('ANXA1', 'Gene', (12, 17))	('expression', 'MPA', (18, 28))	('high', 'Var', (7, 11))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))	('reduced', 'NegReg', (85, 92))
239436	27770278	Following FN1-mediated ubiquitination of ITGA5, alpha5beta1 is sorted into MVEs via ESCRT machinery and destined for lysosomal degradation.	('ubiquitination', 'Var', (23, 37))	('ITGA5', 'Gene', (41, 46))	('FN1', 'Gene', '2335', (10, 13))	('ITGA5', 'Gene', '3678', (41, 46))	('FN1', 'Gene', (10, 13))
239440	27770278	There was a significant association between high levels of PDCD6IP (also known as ALIX) and ACTR3 and increased invadopodia formation.	('high', 'Var', (44, 48))	('ALIX', 'Gene', '10015', (82, 86))	('ACTR3', 'Gene', (92, 97))	('ALIX', 'Gene', (82, 86))	('ACTR3', 'Gene', '10096', (92, 97))	('increased', 'PosReg', (102, 111))	('PDCD6IP', 'Gene', '10015', (59, 66))	('PDCD6IP', 'Gene', (59, 66))	('invadopodia formation', 'CPA', (112, 133))
239485	26177924	GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice.	('VEGF', 'Gene', (63, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (138, 141))	('c-Met', 'Gene', '17295', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mice', 'Species', '10090', (21, 25))	('AG119', 'Var', (51, 56))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('VEGF', 'Gene', '22339', (63, 67))	('mice', 'Species', '10090', (183, 187))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('c-Met', 'Gene', (120, 125))	('glioma', 'Disease', (6, 12))	('GL261', 'Chemical', '-', (0, 5))	('AG119', 'Chemical', '-', (51, 56))
239487	26177924	Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mice', 'Species', '10090', (38, 42))	('AG119', 'Var', (56, 61))	('higher', 'PosReg', (80, 86))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('Percent survival', 'CPA', (0, 16))	('AG119', 'Chemical', '-', (56, 61))	('GL261', 'Chemical', '-', (20, 25))
239488	26177924	Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls.	('GL261', 'Chemical', '-', (66, 71))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('VEGF', 'Gene', '22339', (144, 148))	('TMZ', 'Chemical', 'MESH:D000077204', (212, 215))	('c-Met', 'Gene', (169, 174))	('AG119', 'Chemical', '-', (120, 125))	('lower', 'NegReg', (110, 115))	('mice', 'Species', '10090', (235, 239))	('VEGF', 'Gene', (144, 148))	('c-Met', 'Gene', '17295', (169, 174))	('Tumor volumes', 'CPA', (0, 13))	('AG119', 'Var', (120, 125))
239489	26177924	Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors.	('decreasing', 'NegReg', (83, 93))	('AG119', 'Chemical', '-', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('AG119', 'Var', (35, 40))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('reduce', 'NegReg', (62, 68))	('perfusion rates', 'MPA', (94, 109))	('TMZ', 'Var', (45, 48))	('TMZ', 'Chemical', 'MESH:D000077204', (45, 48))
239490	26177924	It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells.	('IC50 values', 'MPA', (23, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (76, 79))	('AG119', 'Chemical', '-', (39, 44))	('T98G', 'CellLine', 'CVCL:0556', (83, 87))	('lower', 'NegReg', (55, 60))	('AG119', 'Var', (39, 44))	('U251', 'CellLine', 'CVCL:0021', (92, 96))
239491	26177924	These data support further exploration of the anticancer activity AG119 in HGG, as this compound was able to increase animal survival and decrease tumor volumes in a mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.	('AG119', 'Chemical', '-', (66, 71))	('glioma', 'Phenotype', 'HP:0009733', (380, 386))	('cancer', 'Disease', (50, 56))	('increase', 'PosReg', (109, 117))	('AG119', 'Chemical', '-', (201, 206))	('mouse', 'Species', '10090', (166, 171))	('AG119', 'Chemical', '-', (326, 331))	('gliomas', 'Phenotype', 'HP:0009733', (380, 387))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('glioma', 'Disease', (178, 184))	('tumor', 'Disease', (147, 152))	('GL261', 'Chemical', '-', (172, 177))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('AG119', 'Var', (66, 71))	('animal survival', 'CPA', (118, 133))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('decrease', 'NegReg', (138, 146))	('AG119', 'Var', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('gliomas', 'Disease', (380, 387))	('TMZ', 'Chemical', 'MESH:D000077204', (305, 308))	('glioma', 'Disease', (380, 386))	('glioma', 'Disease', 'MESH:D005910', (380, 386))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('gliomas', 'Disease', 'MESH:D005910', (380, 387))
239524	26177924	U251 (TMZ-sensitive; low level of methyl guanine transferase (MGMT)) and T98G (TMZ-resistant; high level of MGMT) cells (American Type Culture Collection, Manassas, VA) were maintained at Dulbecco's minimal essential medium (DMEM) (Thermo Fisher Scientific) with 10 % Cosmic Calf Serum (CCS, Hyclone, Logan, UT) and added glutamine/pyruvate (HyClone) at 37  C with 5 % CO2.	('pyruvate', 'Chemical', 'MESH:D019289', (332, 340))	('T98G', 'Var', (73, 77))	('U251', 'CellLine', 'CVCL:0021', (0, 4))	('CO2', 'Chemical', '-', (369, 372))	('T98G', 'CellLine', 'CVCL:0556', (73, 77))	('glutamine', 'Chemical', 'MESH:D005973', (322, 331))	('DMEM', 'Chemical', '-', (225, 229))	('glutamine/pyruvate', 'MPA', (322, 340))	("Dulbecco's minimal essential medium", 'Chemical', '-', (188, 223))	('Calf', 'Species', '9913', (275, 279))	('TMZ', 'Chemical', 'MESH:D000077204', (6, 9))	('TMZ', 'Chemical', 'MESH:D000077204', (79, 82))
239530	26177924	Percent survival of tumor-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors, as depicted in Fig.	('AG119', 'Chemical', '-', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mice', 'Species', '10090', (34, 38))	('AG119', 'Var', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('higher', 'PosReg', (76, 82))	('Percent survival', 'CPA', (0, 16))	('tumor', 'Disease', (20, 25))
239532	26177924	It is important to note that TMZ, however, was found to have a significant increased percent survival when compared to AG119 (p < 0.01).	('TMZ', 'Var', (29, 32))	('TMZ', 'Chemical', 'MESH:D000077204', (29, 32))	('percent survival', 'CPA', (85, 101))	('AG119', 'Chemical', '-', (119, 124))	('increased', 'PosReg', (75, 84))
239534	26177924	Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119-treated mice (p < 0.001) compared to untreated controls (Fig.	('GL261', 'Chemical', '-', (66, 71))	('AG119-treated', 'Var', (120, 133))	('mice', 'Species', '10090', (134, 138))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('AG119', 'Chemical', '-', (120, 125))	('lower', 'NegReg', (110, 115))	('Tumor volumes', 'CPA', (0, 13))
239549	26177924	When comparing drug sensitivity of T98G cells to a relatively drug sensitive glioma line, U251, it was found that as expected the T98G cells were significantly less sensitive to TMZ (Fig.	('T98G', 'CellLine', 'CVCL:0556', (130, 134))	('less', 'NegReg', (160, 164))	('drug sensitivity', 'Phenotype', 'HP:0020174', (15, 31))	('U251', 'CellLine', 'CVCL:0021', (90, 94))	('glioma', 'Disease', (77, 83))	('T98G', 'Var', (130, 134))	('T98G', 'CellLine', 'CVCL:0556', (35, 39))	('sensitive to TMZ', 'MPA', (165, 181))	('TMZ', 'Chemical', 'MESH:D000077204', (178, 181))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
239553	26177924	In this work we demonstrate in the GL261 glioma model that AG119, a small molecule with combined anti-angiogenic and antimicrotubule activity, results in a significant increase in animal percent survival (p < 0.001), as well as a significant decrease in GL261 HGG tumor growth in vivo (p < 0.001), compared to untreated tumors.	('increase', 'PosReg', (168, 176))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('animal percent survival', 'CPA', (180, 203))	('decrease', 'NegReg', (242, 250))	('GL261', 'Var', (254, 259))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', (320, 325))	('glioma', 'Disease', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('GL261', 'Chemical', '-', (35, 40))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('AG119', 'Chemical', '-', (59, 64))	('GL261', 'Chemical', '-', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('tumors', 'Disease', (320, 326))	('AG119', 'Var', (59, 64))
239557	26177924	Regardless, this proof-of-concept study does indicate that AG119 has anti-cancer activity in a pre-clinical glioma model.	('glioma', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('AG119', 'Chemical', '-', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('AG119', 'Var', (59, 64))
239558	26177924	AG119 was also found to significantly decrease tumor perfusion rates as well as TMZ (both p < 0.05, when compared to untreated tumors).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (47, 52))	('TMZ', 'MPA', (80, 83))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('decrease', 'NegReg', (38, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AG119', 'Chemical', '-', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('AG119', 'Var', (0, 5))
239560	26177924	This is in keeping with previous findings that AG119 possessed inhibition of VEGFR2 kinase and anti-angiogenic activity in the chicken embryo chorioallantoic membrane (CAM) assay.	('VEGFR2', 'Gene', (77, 83))	('chicken', 'Species', '9031', (127, 134))	('anti-angiogenic activity', 'CPA', (95, 119))	('AG119', 'Chemical', '-', (47, 52))	('kinase', 'Enzyme', (84, 90))	('AG119', 'Var', (47, 52))	('inhibition', 'NegReg', (63, 73))
239566	26177924	Taken together, in this study we demonstrate that AG119, a small molecule with combined anti-angiogenic and antimicrotubule activity, can significantly increase animal percent survival, significantly decrease GL261 HGG tumor growth, significantly decrease tumor vascularity, compared to untreated tumors, and suggests that this compound is also not subject to MGMT mediated resistance.	('tumor', 'Disease', (219, 224))	('AG119', 'Chemical', '-', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (297, 302))	('animal percent survival', 'CPA', (161, 184))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('GL261 HGG', 'Protein', (209, 218))	('AG119', 'Var', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('tumor', 'Disease', (256, 261))	('GL261', 'Chemical', '-', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('decrease', 'NegReg', (247, 255))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumors', 'Disease', (297, 303))	('decrease', 'NegReg', (200, 208))	('increase', 'PosReg', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumors', 'Disease', 'MESH:D009369', (297, 303))
239567	26177924	These data support further exploration of the anticancer activity AG119 in HGG, perhaps together with SOC and/or newer agents like the c-Met inhibitors.	('AG119', 'Chemical', '-', (66, 71))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('AG119', 'Var', (66, 71))	('HGG', 'Disease', (75, 78))	('c-Met', 'Gene', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('c-Met', 'Gene', '17295', (135, 140))
239585	23801675	The correlation of tumor metabolism and perfusion metrics using the combination of 18F-FDG PET with MR permeability could provide a more complete understanding of tumor biology and aggressiveness, resulting in an improved ability to determine prognosis and therapy response, compared with 18F-FDG PET or MR permeability alone.	('aggressiveness', 'Disease', 'MESH:D001523', (181, 195))	('improved', 'PosReg', (213, 221))	('aggressiveness', 'Disease', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('aggressiveness', 'Phenotype', 'HP:0000718', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('18F-FDG', 'Chemical', 'MESH:D019788', (83, 90))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (19, 24))	('18F-FDG', 'Chemical', 'MESH:D019788', (289, 296))	('18F-FDG PET', 'Var', (83, 94))
239697	20635853	The specific aims of this study were as follows: 1) to determine PFS and OS for patients with LGGs that infiltrate eloquent brain areas; 2) to determine if intraoperative functional mapping modifies the risk of progression or modifies duration of survival in patients with LGGs presumed to involve eloquent cortex based on preoperative imaging; and 3) to determine if functional mapping increases the extent of resection of these lesions.	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (259, 267))	('modifies', 'Reg', (190, 198))	('OS', 'Chemical', 'MESH:D009992', (73, 75))	('mapping', 'Var', (182, 189))	('LGGs', 'Disease', (273, 277))	('modifies', 'Reg', (226, 234))
239733	20635853	After adjustment for other prognostic factors such as age, performance status, tumor histological type, and tumor size, we found that patients with eloquent-area LGGs demonstrated an increased hazard for shorter OS and PFS (OS, p < 0.001, HR 6.1, 95% CI 2.6-14.1; PFS, p = 0.003, HR 1.9, 95% CI 1.2-2.9; Cox proportional hazards).	('PFS', 'Disease', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('OS', 'Chemical', 'MESH:D009992', (224, 226))	('shorter OS', 'Disease', (204, 214))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('OS', 'Chemical', 'MESH:D009992', (212, 214))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', (108, 113))	('eloquent-area', 'Var', (148, 161))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('LGGs', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
239758	20635853	Subtotal resection is associated with recurrence of gliomas of a higher grade.	('gliomas', 'Disease', (52, 59))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('Subtotal resection', 'Var', (0, 18))
239798	22424569	Furthermore, we found that phosphorylated STAT-3 was correlated with poor survival of GBM patients.	('GBM', 'Disease', (86, 89))	('correlated', 'Reg', (53, 63))	('STAT-3', 'Gene', '6774', (42, 48))	('STAT-3', 'Gene', (42, 48))	('phosphorylated', 'Var', (27, 41))	('poor', 'NegReg', (69, 73))	('patients', 'Species', '9606', (90, 98))
239802	22424569	We hypothesized that if the virus affects tumor progression, a low grade HCMV infection in glioblastomas may be associated with longer patient survival.	('patient', 'Species', '9606', (135, 142))	('tumor', 'Disease', (42, 47))	('glioblastomas', 'Phenotype', 'HP:0012174', (91, 104))	('HCMV infection in glioblastomas', 'Disease', 'MESH:D005909', (73, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('low grade', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('longer', 'PosReg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HCMV infection in glioblastomas', 'Disease', (73, 104))
239811	22424569	Endogenous peroxidase activity was blocked with 3% H2O2, biotin and avidin were blocked with the Biotin/Avidin Blocking kit (DakoCytomation, Denmark) and Fc receptors were blocked with Fc receptor blocker (Innovex Sciences, US).	('Biotin', 'Chemical', 'MESH:D001710', (97, 103))	('Fc receptors', 'Protein', (154, 166))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('biotin', 'Chemical', 'MESH:D001710', (57, 63))	('activity', 'MPA', (22, 30))	('avidin', 'Protein', (68, 74))	('biotin', 'Protein', (57, 63))	('H2O2', 'Chemical', 'MESH:D006861', (51, 55))	('H2O2', 'Var', (51, 55))
239816	22424569	Proliferation of tumor cells (MIB index, Ki-67), p53 mutation, mitosis, glial fibrillary acidic protein (GFAP), were detected with automated immunohistochemical staining protocols at our hospital.	('mitosis', 'Disease', 'None', (63, 70))	('MIB', 'Gene', (30, 33))	('p53', 'Gene', (49, 52))	('tumor', 'Disease', (17, 22))	('mutation', 'Var', (53, 61))	('GFAP', 'Gene', (105, 109))	('p53', 'Gene', '7157', (49, 52))	('glial fibrillary acidic protein', 'Gene', (72, 103))	('GFAP', 'Gene', '2670', (105, 109))	('glial fibrillary acidic protein', 'Gene', '2670', (72, 103))	('MIB', 'Gene', '9780', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mitosis', 'Disease', (63, 70))
239844	22424569	In patients that survived > 18 months, p53 mutations were found in 8 of 12 (67%) samples with moderate to high-grade HCMV-IEA infection as compared with 4 of 13 (31%) in patients with no or low-grade infection.	('patients', 'Species', '9606', (170, 178))	('HCMV', 'Species', '10359', (117, 121))	('mutations', 'Var', (43, 52))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('patients', 'Species', '9606', (3, 11))	('found', 'Reg', (58, 63))
239845	22424569	p53 mutation was detected in 7 of 9 (78%) patients with moderate to high-grade HCMV-LA infection and in 5 of 16 (31%) with no or low-grade infection.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('HCMV', 'Species', '10359', (79, 83))	('mutation', 'Var', (4, 12))	('detected', 'Reg', (17, 25))	('patients', 'Species', '9606', (42, 50))
239846	22424569	In patients with overall survival <= 18 months, p53 mutation was detected in 5 of 19 (26%) patients with moderate to high-grade HCMV-IEA infection and in 1/3 (30%) with no or low-grade infection.	('detected', 'Reg', (65, 73))	('p53', 'Gene', (48, 51))	('patients', 'Species', '9606', (91, 99))	('p53', 'Gene', '7157', (48, 51))	('HCMV', 'Species', '10359', (128, 132))	('patients', 'Species', '9606', (3, 11))	('mutation', 'Var', (52, 60))
239847	22424569	In patients with moderate to high-grade HCMV-LA infection, p53 mutation was detected in 5/11 (45%) of patients as compared to 1 of 11 (9%) patients with no or low-grade HCMV-LA infection.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('patients', 'Species', '9606', (139, 147))	('detected', 'Reg', (76, 84))	('patients', 'Species', '9606', (102, 110))	('mutation', 'Var', (63, 71))	('HCMV', 'Species', '10359', (169, 173))	('patients', 'Species', '9606', (3, 11))	('HCMV', 'Species', '10359', (40, 44))
239848	22424569	While no association between p53 mutations was observed for HCMV IEA, we observed a significant association between HCMV late protein expression and p53 mutations (overall survival > 18 months; p .026) The extent of mitosis and MIB-index did not differ significantly between the two groups.	('p53', 'Gene', (149, 152))	('mutations', 'Var', (153, 162))	('p53', 'Gene', '7157', (149, 152))	('p53', 'Gene', (29, 32))	('MIB', 'Gene', '9780', (228, 231))	('HCMV', 'Species', '10359', (116, 120))	('mitosis', 'Disease', (216, 223))	('HCMV', 'Species', '10359', (60, 64))	('p53', 'Gene', '7157', (29, 32))	('mitosis', 'Disease', 'None', (216, 223))	('MIB', 'Gene', (228, 231))
239859	22424569	For instance HCMV-IE72 and IE86 proteins interact with p53 and Rb that result in enhanced cellular proliferation.	('interact', 'Interaction', (41, 49))	('p53', 'Gene', (55, 58))	('enhanced', 'PosReg', (81, 89))	('IE86', 'Var', (27, 31))	('p53', 'Gene', '7157', (55, 58))	('HCMV', 'Species', '10359', (13, 17))	('proteins', 'Protein', (32, 40))	('cellular proliferation', 'CPA', (90, 112))
239860	22424569	In this study, we found that p53 mutation was associated with HCMV-LA expression (p .026 in patients surviving > 18 months), which implies a potential viral effect on p53.	('mutation', 'Var', (33, 41))	('HCMV', 'Species', '10359', (62, 66))	('patients', 'Species', '9606', (92, 100))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (167, 170))	('HCMV-LA expression', 'Disease', (62, 80))	('p53', 'Gene', '7157', (29, 32))	('associated', 'Reg', (46, 56))	('p53', 'Gene', (167, 170))
239861	22424569	Interestingly, HCMV has been shown in vitro to cause mutations, in particular in p53 in cells that are transformed by IE72, IE86 and adenovirus E1A proteins.	('cause', 'Reg', (47, 52))	('mutations', 'Var', (53, 62))	('p53', 'Gene', '7157', (81, 84))	('HCMV', 'Species', '10359', (15, 19))	('p53', 'Gene', (81, 84))
239874	22424569	In this study, we demonstrate that low-grade HCMV infection is strongly associated with long-term survival in glioblastoma patients, and hence the level of HCMV infection may provide a useful prognostic marker for survival of glioblastoma patients.	('HCMV infection', 'Disease', 'MESH:D007239', (156, 170))	('glioblastoma', 'Disease', (226, 238))	('associated with', 'Reg', (72, 87))	('low-grade', 'Var', (35, 44))	('patients', 'Species', '9606', (239, 247))	('HCMV infection', 'Disease', (45, 59))	('patients', 'Species', '9606', (123, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (226, 238))	('glioblastoma', 'Disease', (110, 122))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (110, 122))	('HCMV infection', 'Disease', (156, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('HCMV infection', 'Disease', 'MESH:D007239', (45, 59))
239878	22424569	In summary, our results suggest that low grade HCMV infection in glioblastoma tumors is strongly associated with longer survival of GBM patients.	('HCMV infection', 'Disease', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (65, 84))	('longer', 'PosReg', (113, 119))	('glioblastoma tumors', 'Disease', (65, 84))	('HCMV infection', 'Disease', 'MESH:D007239', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (136, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('low grade', 'Var', (37, 46))
239896	33664816	A combination of histological and molecular characteristics of glioma, including the presence of isocitrate dehydrogenase-1 (IDH-1) mutations and 1p/19q codeletion, are associated with GBM according to the 2016 WHO classification.	('GBM', 'Disease', (185, 188))	('1p/19q codeletion', 'Var', (146, 163))	('mutations', 'Var', (132, 141))	('IDH-1', 'Gene', '3417', (125, 130))	('IDH-1', 'Gene', (125, 130))	('isocitrate dehydrogenase-1', 'Gene', (97, 123))	('isocitrate dehydrogenase-1', 'Gene', '3417', (97, 123))	('associated', 'Reg', (169, 179))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Disease', (63, 69))
239904	33664816	For example, V-ATPase is overexpressed at the plasma membrane of invasive MB231 human breast cancer cells, and inhibiting V-ATPase using proton pump inhibitors or small interfering RNAs can suppress cancer cell line proliferation and metastasis in animal models.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('V-ATPase', 'Gene', (13, 21))	('V-ATPase', 'Gene', (122, 130))	('V-ATPase', 'Gene', '1769', (13, 21))	('inhibiting', 'Var', (111, 121))	('suppress', 'NegReg', (190, 198))	('V-ATPase', 'Gene', '1769', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('human', 'Species', '9606', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('cancer', 'Disease', (199, 205))	('breast cancer', 'Disease', (86, 99))	('metastasis in animal models', 'CPA', (234, 261))	('MB231', 'CellLine', 'CVCL:0062', (74, 79))
239910	33664816	Overexpression of TCIRG1 has also been reported in hepatocellular carcinoma, melanoma and breast cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (51, 75))	('hepatocellular carcinoma', 'Disease', (51, 75))	('TCIRG1', 'Gene', (18, 24))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('reported', 'Reg', (39, 47))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (77, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (51, 75))
239938	33664816	In TCGA-GBM and GSE16011 datasets, high TCIRG1 expression predicted poor OS in GBM patients (Fig.	('GBM', 'Disease', (79, 82))	('poor OS', 'MPA', (68, 75))	('patients', 'Species', '9606', (83, 91))	('high', 'Var', (35, 39))	('expression', 'MPA', (47, 57))	('TCIRG1', 'Gene', (40, 46))
239947	33664816	The results indicated that there was a significant difference in immune and stromal scores of patients with GBM with high TCIRG1 compared with low TCIRG1 expression (Fig.	('TCIRG1', 'Gene', (122, 128))	('patients', 'Species', '9606', (94, 102))	('high', 'Var', (117, 121))
239957	33664816	V-ATPase is a macromolecular complex that is overexpressed in cancer cells, and subunit 'a' affects the subcellular localization of V-ATPase.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('V-ATPase', 'Gene', (0, 8))	('affects', 'Reg', (92, 99))	('subcellular localization', 'MPA', (104, 128))	('V-ATPase', 'Gene', '1769', (132, 140))	('V-ATPase', 'Gene', '1769', (0, 8))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	("subunit '", 'Var', (80, 89))	('V-ATPase', 'Gene', (132, 140))
239958	33664816	TCIRG1 is an a3 subunit of V-ATPase that is normally expressed in osteoclasts and insulin-containing secretory vesicles in pancreatic beta cells; however, aberrantly overexpressed TCIRG1 in cancer cells promotes tumor metastasis and migration potential, indicating that TCIRG1 might be a specific marker for tumor malignancy.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('tumor metastasis', 'Disease', 'MESH:D009362', (212, 228))	('tumor metastasis', 'Disease', (212, 228))	('insulin', 'Gene', (82, 89))	('aberrantly overexpressed', 'Var', (155, 179))	('V-ATPase', 'Gene', (27, 35))	('TCIRG1', 'Gene', (180, 186))	('promotes', 'PosReg', (203, 211))	('tumor malignancy', 'Disease', (308, 324))	('migration potential', 'CPA', (233, 252))	('V-ATPase', 'Gene', '1769', (27, 35))	('insulin', 'Gene', '3630', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor malignancy', 'Disease', 'MESH:D009369', (308, 324))
240006	31151091	Furthermore, suPAR has also been shown to be prognostic for development of cancer, CVD and type 2 diabetes as well as mortality in the general population.	('diabetes', 'Disease', 'MESH:D003920', (98, 106))	('CVD', 'Phenotype', 'HP:0001626', (83, 86))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('suPAR', 'Var', (13, 18))	('cancer', 'Disease', (75, 81))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (91, 106))	('suPAR', 'Chemical', '-', (13, 18))	('CVD', 'Disease', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('diabetes', 'Disease', (98, 106))
240044	31151091	Based on previously reported S-suPAR levels, we set S-suPAR <3 ng/mL in both genders as normal and >4.0 ng/mL as high risk for other diseases, including CVD and development of tumours.	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('>4.0 ng/mL', 'Var', (99, 109))	('tumours', 'Disease', (176, 183))	('CVD', 'Phenotype', 'HP:0001626', (153, 156))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('S-suPAR', 'Var', (52, 59))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('S-suPAR', 'Chemical', '-', (52, 59))	('S-suPAR', 'Chemical', '-', (29, 36))	('CVD', 'Disease', (153, 156))
240052	31151091	At baseline geometric mean suPAR in the total cohort was 2.9 ng/mL (2.7-3.3), >3 ng/mL in 28 patients, >4 ng/mL in 14 patients and >5 ng/mL in 4 patients.	('patients', 'Species', '9606', (145, 153))	('>4 ng/mL', 'Var', (103, 111))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (118, 126))	('>3 ng/mL', 'Var', (78, 86))	('suPAR', 'Chemical', '-', (27, 32))
240101	31151091	Furthermore, it has recently been shown that treatment with low-dose GH in patients with HIV non-significantly decreased suPAR levels.	('suPAR', 'Chemical', '-', (121, 126))	('suPAR levels', 'MPA', (121, 133))	('decreased', 'NegReg', (111, 120))	('patients', 'Species', '9606', (75, 83))	('low-dose', 'Var', (60, 68))	('GH', 'Gene', '2688', (69, 71))
240264	28407731	Segmentum: a tool for copy number analysis of cancer genomes Somatic alterations, including loss of heterozygosity, can affect the expression of oncogenes and tumor suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('oncogenes', 'Protein', (145, 154))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('expression', 'MPA', (131, 141))	('affect', 'Reg', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('loss of heterozygosity', 'Var', (92, 114))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
240267	28407731	We applied Segmentum to paired tumor/normal whole genome sequencing samples from 38 patients with low-grade glioma from the TCGA dataset and were able to confirm the recurrence of copy-neutral loss of heterozygosity in chromosome 17p in low-grade astrocytoma characterized by IDH1/2 mutation and lack of 1p/19q co-deletion, which was previously reported using SNP array data.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('mutation', 'Var', (283, 291))	('astrocytoma', 'Disease', (247, 258))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (247, 258))	('loss', 'NegReg', (193, 197))	('glioma', 'Disease', (108, 114))	('IDH1/2', 'Gene', (276, 282))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH1/2', 'Gene', '3417;3418', (276, 282))	('astrocytoma', 'Disease', 'MESH:D001254', (247, 258))
240270	28407731	Loss of heterozygosity (LOH) is an event in which one of the two alleles at a heterozygous locus is lost due to segmental aneuploidy, gene conversion, mitotic recombination, or mitotic nondisjunction.	('mitotic recombination', 'CPA', (151, 172))	('aneuploidy', 'Disease', 'MESH:D000782', (122, 132))	('Loss of heterozygosity', 'NegReg', (0, 22))	('mitotic nondisjunction', 'CPA', (177, 199))	('lost', 'NegReg', (100, 104))	('aneuploidy', 'Disease', (122, 132))	('gene conversion', 'Var', (134, 149))
240274	28407731	have shown recurring cnLOH at chromosome 17p (harboring TP53 gene) in low-grade astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (80, 91))	('cnLOH', 'Var', (21, 26))	('astrocytoma', 'Disease', (80, 91))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('astrocytoma', 'Phenotype', 'HP:0009592', (80, 91))
240299	28407731	In the presence of somatic copy number alterations, the BAF can diverge from 0.5 if the relative abundance of the two alleles changes.	('BAF', 'Gene', '8815', (56, 59))	('alterations', 'Var', (39, 50))	('BAF', 'Gene', (56, 59))
240310	28407731	To evaluate Segmentum in terms of segmentation accuracy, a simulator capable of simulating whole-genome RD for both normal and tumor samples and BAF based on events such as deletions, amplifications and cnLOH was developed.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BAF', 'Gene', '8815', (145, 148))	('tumor', 'Disease', (127, 132))	('cnLOH', 'Var', (203, 208))	('BAF', 'Gene', (145, 148))	('amplifications', 'Var', (184, 198))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('deletions', 'Var', (173, 182))
240313	28407731	The tumor sample RD is calculated using the copy number tracks, the simulated normal sample RD and the normal sample contamination (i.e., a parameter determined by user).	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('copy number', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (4, 9))
240327	28407731	These subtypes are distinguished with the following criteria: (1) mutation in IDH1/2 accompanied by co-deletion of chromosomes 1p and 19q (subtype I), (2) mutation in IDH1/2 without co-deletion of chromosomes 1p and 19q (subtype II), and (3) IDH1/2 wild type (subtype III).	('IDH1/2', 'Gene', '3417;3418', (78, 84))	('IDH1/2', 'Gene', (242, 248))	('IDH1/2', 'Gene', (167, 173))	('IDH1/2', 'Gene', (78, 84))	('IDH1/2', 'Gene', '3417;3418', (167, 173))	('mutation', 'Var', (66, 74))	('mutation', 'Var', (155, 163))	('IDH1/2', 'Gene', '3417;3418', (242, 248))
240329	28407731	We also identified a fourth subtype with a mutation in IDH1/2 without co-deletion of chromosomes 1p and 19q and no cnLOH at 17p (Fig.	('mutation', 'Var', (43, 51))	('IDH1/2', 'Gene', '3417;3418', (55, 61))	('IDH1/2', 'Gene', (55, 61))
240332	28407731	Segmentum is able to report recurrent cnLOH regions across multiple cancer genome samples; a characteristic of cancer genomes that has been neglected until recently.	('cnLOH regions', 'Var', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
240344	28407731	License: MIT license  Any restrictions to use by non-academics: None BAF B-Allele fraction BAM Binary alignment map CBS circular binary segmentation CGH Array comparative genomic hybridization cnLOH Copy-neutral loss of heterozygosity CNV Copy number variation dbSNP Single nucleotide polymorphism database DNA Deoxyribonucleic acid FISH Fluorescent in situ hybridization HMM Hidden Markov model HTS High throughput sequencing IGV Integrative genomics viewer JSI Jaccard similarity index LASSO Least absolute shrinkage eStimatOr LGG Low grade glioma LOH Loss of heterozygosity MAE Monoallelic expression PRAD PRostate ADenocarcinoma RD Read-depth SAM Sequence alignment/map SCNA Somatic copy number alteration SNP Single nucleotide polymorphism TCGA The cancer genome atlas WES Whole exome sequencing WGS Whole genome sequencing	('glioma', 'Disease', (543, 549))	('PRostate ADenocarcinoma', 'Disease', (609, 632))	('BAF', 'Gene', '8815', (69, 72))	('BAM', 'Gene', (91, 94))	('BAM', 'Gene', '9126', (91, 94))	('Single nucleotide polymorphism', 'Var', (714, 744))	('LGG Low', 'Phenotype', 'HP:0004315', (529, 536))	('cancer', 'Disease', 'MESH:D009369', (754, 760))	('glioma', 'Phenotype', 'HP:0009733', (543, 549))	('CBS', 'Disease', (116, 119))	('BAF', 'Gene', (69, 72))	('CBS', 'Disease', 'MESH:D006712', (116, 119))	('cancer', 'Disease', (754, 760))	('glioma', 'Disease', 'MESH:D005910', (543, 549))	('PRostate ADenocarcinoma', 'Disease', 'MESH:D011471', (609, 632))	('HTS', 'Disease', 'MESH:C537160', (396, 399))	('cancer', 'Phenotype', 'HP:0002664', (754, 760))	('HTS', 'Disease', (396, 399))
240349	25738367	miR-15/16), and thereby stalling progression through the S-phase of cell cycle.	('miR-15', 'Chemical', '-', (0, 6))	('miR-15/16', 'Var', (0, 9))	('stalling', 'NegReg', (24, 32))	('progression through the S-phase of cell cycle', 'CPA', (33, 78))
240355	25738367	Importantly, both modified antisense oligonucleotides (ASO) and viral "sponge" inhibitors of miR-10b cause cell death of glioma cells but not of normal brain cells, and this may present a basis for targeted therapies.	('ASO', 'Chemical', 'MESH:D016376', (55, 58))	('oligonucleotides', 'Chemical', 'MESH:D009841', (37, 53))	('death of glioma', 'Disease', 'MESH:D005910', (112, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('modified antisense oligonucleotides', 'Var', (18, 53))	('miR-10b', 'Gene', (93, 100))	('death of glioma', 'Disease', (112, 127))
240369	25738367	Inhibition of miR-10b resulted in two distinct cell cycle responses in glioma cells.	('cell cycle responses', 'CPA', (47, 67))	('glioma', 'Disease', (71, 77))	('Inhibition', 'Var', (0, 10))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('miR-10b', 'Gene', (14, 21))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
240370	25738367	A172 and U87 cell lines exhibited reduction of cells in S-phase of the cell cycle, and accumulation of cells in G2/M, while LN215 and U251 cells showed no down-regulation of S-phase, with arrest in the tetraploid state (Figure 2A, 2B).	('U251', 'CellLine', 'CVCL:0021', (134, 138))	('arrest', 'Disease', (188, 194))	('LN215', 'CellLine', 'CVCL:3954', (124, 129))	('G2/M', 'Var', (112, 116))	('reduction', 'NegReg', (34, 43))	('U87', 'CellLine', 'CVCL:0022', (9, 12))	('arrest', 'Disease', 'MESH:D006323', (188, 194))	('cells in S-phase of the cell cycle', 'CPA', (47, 81))
240382	25738367	P21 knock-down led to the rescue of E2F1 RNA and protein levels, as well as partial or near-complete rescue of many E2F1 target genes in A172 and U87 cells (Figure 4A-4D and Supplementary Figure 4A-4C).	('E2F1', 'Gene', (36, 40))	('P21', 'Gene', '492305', (0, 3))	('knock-down', 'Var', (4, 14))	('rescue', 'PosReg', (26, 32))	('U87', 'CellLine', 'CVCL:0022', (146, 149))	('P21', 'Gene', (0, 3))
240383	25738367	Consistently, p21 knock-down rescued the effect of miR-10b inhibition on S-phase progression, but not on the progression of cells through G2 phase and mitosis (Supplementary Figure 5), indicating that miR-10b regulation of G2/M is p21-independent.	('inhibition', 'NegReg', (59, 69))	('p21', 'Gene', (14, 17))	('miR-10b', 'Gene', (51, 58))	('S-phase progression', 'CPA', (73, 92))	('knock-down', 'Var', (18, 28))	('mitosis', 'Disease', (151, 158))	('mitosis', 'Disease', 'None', (151, 158))
240385	25738367	To test these possibilities, and validate direct interaction between p21 and E2F1, we immuno-precipitated E2F1 complexes from cells transfected with anti-miR-10b or control and determined the amount of Rb1 and p21 in the E2F1 co-immunoprecipitate.	('Rb1', 'Gene', '5925', (202, 205))	('interaction', 'Interaction', (49, 60))	('anti-miR-10b', 'Var', (149, 161))	('E2F1', 'Gene', (106, 110))	('Rb1', 'Gene', (202, 205))
240386	25738367	The levels of p21, but not Rb1, coimmunoprecipitated with E2F1 increased upon miR-10b inhibition, likely as the result of elevated p21 expression (Figure 4E).	('levels', 'MPA', (4, 10))	('p21', 'Var', (131, 134))	('increased', 'PosReg', (63, 72))	('Rb1', 'Gene', '5925', (27, 30))	('miR-10b', 'Gene', (78, 85))	('elevated', 'PosReg', (122, 130))	('expression', 'MPA', (135, 145))	('Rb1', 'Gene', (27, 30))	('inhibition', 'NegReg', (86, 96))	('E2F1', 'Gene', (58, 62))
240387	25738367	Interestingly, total levels of Rb1 dropped upon miR-10b inhibition, suggesting a feedback mechanism developed by cancer cells to maintain the levels of E2F activity.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Rb1', 'Gene', '5925', (31, 34))	('cancer', 'Disease', (113, 119))	('dropped', 'NegReg', (35, 42))	('inhibition', 'Var', (56, 66))	('miR-10b', 'Gene', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Rb1', 'Gene', (31, 34))
240399	25738367	The amount of miR-15a and miR-16 associated with Ago2 complex decreased upon anti-miR-10b treatment (Figure 5B), indicating that miR-10b modulates the activity of miR-15/16 family.	('miR-16', 'Gene', '51573', (26, 32))	('miR-15a', 'Gene', '406948', (14, 21))	('miR-16', 'Gene', (26, 32))	('decreased', 'NegReg', (62, 71))	('amount', 'MPA', (4, 10))	('miR-15a', 'Gene', (14, 21))	('Ago2', 'Gene', (49, 53))	('miR-15', 'Chemical', '-', (14, 20))	('miR-15', 'Chemical', '-', (163, 169))	('Ago2', 'Gene', '27161', (49, 53))	('anti-miR-10b', 'Var', (77, 89))	('activity', 'MPA', (151, 159))	('modulates', 'Reg', (137, 146))
240404	25738367	MiR-15a, -15b and -16 inhibitors moderately decreased the viability of glioma cells (Figure 5D, 5E), suggesting an unusual tumor-promoting role of miR-15/16 family in GBM.	('miR-15', 'Chemical', '-', (147, 153))	('tumor', 'Disease', (123, 128))	('inhibitors', 'Var', (22, 32))	('MiR-15a', 'Gene', '406948', (0, 7))	('glioma', 'Disease', (71, 77))	('MiR-15a', 'Gene', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('decreased', 'NegReg', (44, 53))
240405	25738367	There was no additive effect for miR-15/16 and miR-10b inhibitors on cell viability, implying a common pathway that includes both miR-10b and miR-15/16.	('miR-15', 'Chemical', '-', (142, 148))	('miR-10b', 'Gene', (47, 54))	('miR-10b', 'Var', (130, 137))	('miR-15', 'Chemical', '-', (33, 39))
240406	25738367	Conversely, miR-15a and miR-16 mimics protected glioma cells against the anti-miR-10b and improved cellular viability (Figure 5F).	('miR-16', 'Gene', (24, 30))	('cellular viability', 'CPA', (99, 117))	('anti-miR-10b', 'Var', (73, 85))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('miR-16', 'Gene', '51573', (24, 30))	('miR-15a', 'Gene', '406948', (12, 19))	('improved', 'PosReg', (90, 98))	('miR-15a', 'Gene', (12, 19))	('glioma', 'Disease', (48, 54))
240409	25738367	We found that FBXW7 knock down partially rescued the miR-10b mediated down-regulation of many critical S-phase proteins, such as E2F1, LSH, Ki67, Cyclin A2, and Cyclin E2 (Figure 5G).	('Cyclin E2', 'Gene', '9134', (161, 170))	('Cyclin A2', 'Gene', '890', (146, 155))	('miR-10b', 'Gene', (53, 60))	('FBXW7', 'Gene', '55294', (14, 19))	('Cyclin A2', 'Gene', (146, 155))	('Cyclin E2', 'Gene', (161, 170))	('LSH', 'Gene', (135, 138))	('LSH', 'Gene', '3070', (135, 138))	('FBXW7', 'Gene', (14, 19))	('down-regulation', 'NegReg', (70, 85))	('knock down', 'Var', (20, 30))
240411	25738367	In addition, knock-down of SMAD3 led to the partial rescue of anti-miR-10b-mediated down-regulation of proliferative marker Ki67, but not other tested cell cycle genes (Figure 5H).	('knock-down', 'Var', (13, 23))	('SMAD3', 'Gene', '4088', (27, 32))	('SMAD3', 'Gene', (27, 32))	('down-regulation', 'NegReg', (84, 99))	('anti-miR-10b-mediated', 'Gene', (62, 83))	('proliferative marker Ki67', 'MPA', (103, 128))
240412	25738367	We have not detected any significant effects of the CCPG1 knock-down on the expression of tested cell cycle genes (Supplementary Figure 8).	('knock-down', 'Var', (58, 68))	('CCPG1', 'Gene', (52, 57))	('CCPG1', 'Gene', '9236', (52, 57))
240418	25738367	Importantly, inhibition of miR-10b reduces the growth of cultured glioma cells and prolongs survival in mouse xenograft models of GBM.	('glioma', 'Disease', (66, 72))	('survival', 'CPA', (92, 100))	('reduces', 'NegReg', (35, 42))	('inhibition', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('mouse', 'Species', '10090', (104, 109))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('miR-10b', 'Gene', (27, 34))	('prolongs', 'PosReg', (83, 91))
240421	25738367	Alterations along the E2F-signaling axis, such as deactivation and mutations of Rb1 and p16/CDKN1A, and Cdk4/6 amplification, are frequently found in GBM.	('p16', 'Gene', (88, 91))	('CDKN1A', 'Gene', (92, 98))	('Cdk4/6', 'Gene', '1019;1021', (104, 110))	('Rb1', 'Gene', (80, 83))	('CDKN1A', 'Gene', '1026', (92, 98))	('mutations', 'Var', (67, 76))	('p16', 'Gene', '1029', (88, 91))	('Rb1', 'Gene', '5925', (80, 83))	('deactivation', 'MPA', (50, 62))	('Cdk4/6', 'Gene', (104, 110))
240424	25738367	Among them are KI67 and proliferating cell nuclear antigen (PCNA), commonly accepted proliferation markers associated with course of various cancers, including malignant gliomas.	('PCNA', 'Gene', (60, 64))	('proliferating cell nuclear antigen', 'Gene', (24, 58))	('KI67', 'Var', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('associated', 'Reg', (107, 117))	('PCNA', 'Gene', '5111', (60, 64))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('proliferating cell nuclear antigen', 'Gene', '5111', (24, 58))	('malignant gliomas', 'Disease', (160, 177))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('malignant gliomas', 'Disease', 'MESH:D005910', (160, 177))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('cancers', 'Disease', (141, 148))
240426	25738367	LSH promotes proliferation and prevents senescence in multiple malignancies, while its disruption causes a premature aging phenotype.	('LSH', 'Gene', (0, 3))	('LSH', 'Gene', '3070', (0, 3))	('proliferation', 'CPA', (13, 26))	('causes', 'Reg', (98, 104))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('promotes', 'PosReg', (4, 12))	('senescence', 'CPA', (40, 50))	('malignancies', 'Disease', (63, 75))	('premature aging', 'CPA', (107, 122))	('disruption', 'Var', (87, 97))
240431	25738367	We demonstrate that the miR-15/16, and to a lesser extent the miR-17/93 cluster is upregulated by miR-10b.	('miR-10b', 'Var', (98, 105))	('miR-17', 'Gene', (62, 68))	('miR-15', 'Chemical', '-', (24, 30))	('miR-17', 'Gene', '406952', (62, 68))	('miR-15/16', 'Gene', (24, 33))	('upregulated', 'PosReg', (83, 94))
240437	25738367	Given the abundance of miR-15 and -16 in GBM, this pathway may have profound effects on the glioma transcriptome.	('miR-15', 'Chemical', '-', (23, 29))	('miR-15', 'Var', (23, 29))	('glioma', 'Disease', (92, 98))	('effects', 'Reg', (77, 84))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
240438	25738367	A consequent question is whether the activation of miR-15/16 by miR-10b serves as a negative feedback on proliferation, or miR-15/16 paradoxically promote GBM growth, in a tissue-specific manner.	('miR-15/16', 'Var', (123, 132))	('promote', 'PosReg', (147, 154))	('miR-15', 'Chemical', '-', (51, 57))	('miR-10b', 'Gene', (64, 71))	('GBM growth', 'CPA', (155, 165))	('miR-15', 'Chemical', '-', (123, 129))
240442	25738367	Importantly, we found that knock-down of FBXW7 increases the levels of several cell cycle proteins, such as E2F1, LSH, KI67, Cyclin A2 and Cyclin E2, both in basic conditions, as well as in miR-10b - depleted glioma cells.	('Cyclin E2', 'Gene', (139, 148))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('LSH', 'Gene', (114, 117))	('LSH', 'Gene', '3070', (114, 117))	('Cyclin A2', 'Gene', '890', (125, 134))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('knock-down', 'Var', (27, 37))	('FBXW7', 'Gene', '55294', (41, 46))	('Cyclin A2', 'Gene', (125, 134))	('E2F1', 'MPA', (108, 112))	('Cyclin E2', 'Gene', '9134', (139, 148))	('glioma', 'Disease', (209, 215))	('increases', 'PosReg', (47, 56))	('FBXW7', 'Gene', (41, 46))	('levels of several cell cycle proteins', 'MPA', (61, 98))
240445	25738367	In addition, knock-down of SMAD3 increases the levels of proliferation marker KI67 in miR-10b depleted cells.	('knock-down', 'Var', (13, 23))	('SMAD3', 'Gene', '4088', (27, 32))	('SMAD3', 'Gene', (27, 32))	('increases', 'PosReg', (33, 42))	('levels of proliferation marker KI67', 'MPA', (47, 82))
240448	25738367	In conclusion, our data indicate that activation of miR-15/16 family through miR-10b/p21/E2F1 regulatory axis results in attenuation of FBXW7 and SMAD3, and therefore, increased levels of S-phase specific cell cycle proteins, providing support for cell cycle progression, in addition to the transcriptional up-regulation of these genes by E2F1 (Figure 6).	('miR-15', 'Chemical', '-', (52, 58))	('increased', 'PosReg', (168, 177))	('FBXW7', 'Gene', '55294', (136, 141))	('miR-10b/p21/E2F1', 'Gene', (77, 93))	('up-regulation', 'PosReg', (307, 320))	('levels of S-phase specific cell cycle proteins', 'MPA', (178, 224))	('FBXW7', 'Gene', (136, 141))	('SMAD3', 'Gene', '4088', (146, 151))	('SMAD3', 'Gene', (146, 151))	('E2F1', 'Var', (339, 343))	('miR-15/16', 'Gene', (52, 61))	('attenuation', 'NegReg', (121, 132))	('activation', 'PosReg', (38, 48))
240459	25738367	The following full-length antisense 2'-O-MOE-modified oligonucleotides with phosphate backbone were used for miRNA inhibition: mR-10b 5'-CACAAATTCGGTTCTACAGGGTA-3', miR-15b 5'-TGTAAACCATGATGTGCTGCTA-3', miR-16 5'-CGCCAATATTTACGTGCTGCTA-3', miR-15a 5'-CACAAACCATTATGTGCTGCTA-3', and the oligonucleotide 5'-ACATACTCCTTTCTCAGAGTCCA-3' was used as the chemistry-matched control.	('miR-15a', 'Gene', (240, 247))	('oligonucleotides', 'Chemical', 'MESH:D009841', (54, 70))	('miR-15a', 'Gene', '406948', (240, 247))	('miR-16', 'Gene', (203, 209))	('miR-16', 'Gene', '51573', (203, 209))	('miR-15b', 'Gene', '406949', (165, 172))	('mR-10b', 'Var', (127, 133))	('oligonucleotide', 'Chemical', 'MESH:D009841', (286, 301))	('oligonucleotide', 'Chemical', 'MESH:D009841', (54, 69))	('miR-15b', 'Gene', (165, 172))
240466	25738367	The following primary antibodies were used: anti-p21, 2947 (12D1), anti-E2F1 3742, anti-Rb1, 9313, anti-Cyclin A2, 4656, anti-Cyclin E2, 4132 (Cell Signaling), anti-E2F2 sc-633 (C-20), anti-E2F3 sc-878 (C-18), anti-LSH sc-28202 (H-240) (Santa Cruz Biotechnology), anti-KI67 ab16667, anti-beta-Actin ab3280 (Abcam), anti-alpha-Tubulin (Sigma, T9026, DM1A).	('Cyclin E2', 'Gene', '9134', (126, 135))	('C-18', 'Gene', (203, 207))	('Rb1', 'Gene', (88, 91))	('Cyclin A2', 'Gene', (104, 113))	('C-18', 'Gene', '27241', (203, 207))	('alpha-Tubulin', 'Gene', (320, 333))	('LSH', 'Gene', '3070', (215, 218))	('anti-KI67', 'Var', (264, 273))	('Cyclin E2', 'Gene', (126, 135))	('beta-Actin', 'Gene', (288, 298))	('beta-Actin', 'Gene', '728378', (288, 298))	('E2F3', 'Gene', (190, 194))	('E2F2', 'Gene', (165, 169))	('Rb1', 'Gene', '5925', (88, 91))	('Cyclin A2', 'Gene', '890', (104, 113))	('E2F2', 'Gene', '1870', (165, 169))	('LSH', 'Gene', (215, 218))	('alpha-Tubulin', 'Gene', '10376', (320, 333))	('E2F3', 'Gene', '1871', (190, 194))
240567	33669989	This link can be explained by a combination of white matter disruption, an increase in the extracellular space, and augmented tumor cell proliferation.	('augmented tumor', 'Disease', 'MESH:D009369', (116, 131))	('disruption', 'Var', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('augmented tumor', 'Disease', (116, 131))	('white matter disruption', 'Phenotype', 'HP:0002500', (47, 70))	('white matter', 'CPA', (47, 59))	('increase', 'PosReg', (75, 83))	('extracellular space', 'MPA', (91, 110))
240598	32933174	Recovery was observed following glioma resection in Broca's area, Wernicke's area, Rolandic area, or the insula.	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('resection', 'Var', (39, 48))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('glioma', 'Disease', (32, 38))
240614	32933174	For example, invasion of the right superior longitudinal fasciculus is correlated to a visuo-spatial deficit, invasion of the left inferior fronto-occipital fasciculus to a semantic deficit, or invasion of the right cingulate to a mentalization deficit.	('mentalization deficit', 'Phenotype', 'HP:0001249', (231, 252))	('fasciculus', 'Disease', (157, 167))	('fasciculus', 'Disease', 'None', (157, 167))	('mentalization', 'CPA', (231, 244))	('correlated', 'Reg', (71, 81))	('longitudinal fasciculus', 'Disease', 'MESH:D017887', (44, 67))	('longitudinal fasciculus', 'Disease', (44, 67))	('visuo-spatial deficit', 'CPA', (87, 108))	('invasion', 'Var', (13, 21))	('fasciculus', 'Disease', 'None', (57, 67))	('fasciculus', 'Disease', (57, 67))
240630	32933174	Furthermore, essential language regions were also evidenced by rTMS within the right hemisphere in tumor patients, particularly in the right inferior frontal gyrus.	('tumor', 'Disease', (99, 104))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('rTMS', 'Var', (63, 67))
240688	32933174	Functional compensation is nonetheless possible only if the WM tracts are preserved, since in the majority of patients who do not completely recover after surgery, the persistent impairment is related to a disconnection syndrome due to damage of the subcortical fascicles, whatever the function, e.g., language or executive control.	('damage', 'Var', (236, 242))	('disconnection syndrome', 'Disease', (206, 228))	('patients', 'Species', '9606', (110, 118))	('related', 'Reg', (193, 200))
240701	32933174	On the other hand, neuropsychological assessments performed after chemotherapy have evidenced that cognitive scores were similar or even improved, supporting that chemotherapy might facilitate neuroplastic mechanisms, especially when it induced a shrinkage of the glioma with a decrease of the tumoral infiltration along the WM tracts.	('glioma', 'Disease', (264, 270))	('tumoral', 'Disease', (294, 301))	('tumoral', 'Disease', 'MESH:D009369', (294, 301))	('shrinkage', 'NegReg', (247, 256))	('chemotherapy', 'Var', (163, 175))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('decrease', 'NegReg', (278, 286))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('neuroplastic mechanisms', 'CPA', (193, 216))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('facilitate', 'PosReg', (182, 192))
240728	33540759	5-aminolevulinic acid (5-ALA) is the most prominent and well-studied of these and has been shown to increase EOR and progression-free survival in malignant glioma based on the results of a 2006 phase III trial.	('5-ALA', 'Chemical', 'MESH:C000614854', (23, 28))	('malignant glioma', 'Disease', (146, 162))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (0, 21))	('progression-free survival', 'CPA', (117, 142))	('EOR', 'Chemical', '-', (109, 112))	('5-aminolevulinic acid', 'Var', (0, 21))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('increase', 'PosReg', (100, 108))	('malignant glioma', 'Disease', 'MESH:D005910', (146, 162))
240742	33540759	They concluded that intraoperative use of 5-ALA in HGG was safe and markedly increased complete resection rates (65% in 5-ALA vs. 36% control).	('5-ALA', 'Chemical', 'MESH:C000614854', (120, 125))	('increased', 'PosReg', (77, 86))	('5-ALA', 'Chemical', 'MESH:C000614854', (42, 47))	('5-ALA', 'Var', (120, 125))	('rat', 'Species', '10116', (106, 109))	('complete resection rates', 'CPA', (87, 111))	('rat', 'Species', '10116', (28, 31))
240755	33540759	PpIX accumulation in the cell can result from (1) increased 5-ALA levels, (2) 5-ALA synthase hyperactivity, or (3) dysfunction of the ferrochelatase (FECH) enzyme that produces heme from PpIX.	('hyperactivity', 'Phenotype', 'HP:0000752', (93, 106))	('ferrochelatase', 'Gene', '2235', (134, 148))	('5-ALA', 'Chemical', 'MESH:C000614854', (60, 65))	('5-ALA levels', 'MPA', (60, 72))	('PpIX', 'Chemical', 'MESH:C028025', (0, 4))	('ferrochelatase', 'Gene', (134, 148))	('dysfunction', 'Var', (115, 126))	('PpIX', 'Gene', (0, 4))	('increased', 'PosReg', (50, 59))	('heme', 'Chemical', 'MESH:D006418', (177, 181))	('PpIX', 'Chemical', 'MESH:C028025', (187, 191))	('5-ALA', 'MPA', (78, 83))	('hyperactivity', 'Disease', 'MESH:D006948', (93, 106))	('hyperactivity', 'Disease', (93, 106))	('accumulation', 'PosReg', (5, 17))	('5-ALA', 'Chemical', 'MESH:C000614854', (78, 83))
240783	33540759	reviewed the interconnectedness of the TCA cycle and the heme biosynthesis pathway and hypothesized that nicotinamide adenine dinucleotide phosphate (NADPH)-dependent heme degradation is impaired, based on knowledge that the IDH1R132H mutation perturbs NADPH homeostasis.	('mutation', 'Var', (235, 243))	('TCA', 'Chemical', 'MESH:D014233', (39, 42))	('NADPH', 'Chemical', 'MESH:D009249', (150, 155))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (105, 148))	('NADPH homeostasis', 'MPA', (253, 270))	('perturbs', 'NegReg', (244, 252))	('heme', 'Chemical', 'MESH:D006418', (167, 171))	('IDH', 'Gene', (225, 228))	('heme', 'Chemical', 'MESH:D006418', (57, 61))	('IDH', 'Gene', '3417', (225, 228))	('NADPH', 'Chemical', 'MESH:D009249', (253, 258))	('impaired', 'NegReg', (187, 195))
240784	33540759	Specifically, this mutation abrogates WT activity of the IDH1 enzyme, thereby blocking NADPH synthesis associated with the oxidative decarboxylation of isocitrate to alpha-KG.	('IDH', 'Gene', '3417', (57, 60))	('isocitrate', 'Chemical', 'MESH:C034219', (152, 162))	('mutation', 'Var', (19, 27))	('WT activity', 'MPA', (38, 49))	('NADPH synthesis', 'MPA', (87, 102))	('NADPH', 'Chemical', 'MESH:D009249', (87, 92))	('blocking', 'NegReg', (78, 86))	('IDH', 'Gene', (57, 60))	('abrogates', 'NegReg', (28, 37))	('alpha-KG', 'Chemical', 'MESH:D007656', (166, 174))
240787	33540759	Although this study highlighted metabolic alterations that lead to variance in 5-ALA-mediated fluorescence in IDH-mutated glioma cells, it is still not clear how IDH mutations influence glioma tissue fluorescence following 5-ALA treatment in the clinical setting.	('glioma', 'Disease', (186, 192))	('mutations', 'Var', (166, 175))	('IDH', 'Gene', (110, 113))	('rat', 'Species', '10116', (46, 49))	('IDH', 'Gene', (162, 165))	('5-ALA', 'Chemical', 'MESH:C000614854', (223, 228))	('glioma', 'Disease', (122, 128))	('IDH', 'Gene', '3417', (110, 113))	('5-ALA', 'Chemical', 'MESH:C000614854', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('IDH', 'Gene', '3417', (162, 165))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('5-ALA-mediated fluorescence', 'MPA', (79, 106))	('influence', 'Reg', (176, 185))	('variance', 'Reg', (67, 75))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
240788	33540759	In particular, the simultaneous high prevalence of IDH mutations and low 5-ALA-induced tissue fluorescence associated with LGGs appear to be in conflict with the thesis that mutant IDH action stimulates PpIX content in glioma.	('IDH', 'Gene', (181, 184))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('IDH', 'Gene', (51, 54))	('PpIX', 'Chemical', 'MESH:C028025', (203, 207))	('mutations', 'Var', (55, 64))	('glioma', 'Disease', 'MESH:D005910', (219, 225))	('IDH', 'Gene', '3417', (181, 184))	('IDH', 'Gene', '3417', (51, 54))	('stimulates', 'PosReg', (192, 202))	('low', 'NegReg', (69, 72))	('5-ALA-induced tissue fluorescence', 'MPA', (73, 106))	('glioma', 'Disease', (219, 225))	('5-ALA', 'Chemical', 'MESH:C000614854', (73, 78))	('PpIX content', 'MPA', (203, 215))	('mutant', 'Var', (174, 180))
240795	33540759	Silencing of PBGS and PBGD led to decreased 5-ALA-mediated fluorescence and decreased sensitivity to photodynamic therapy (PDT), whereas silencing of FECH led to the opposite effects on fluorescence and PDT sensitivity.	('PBGD', 'Gene', '3145', (22, 26))	('5-ALA', 'Chemical', 'MESH:C000614854', (44, 49))	('5-ALA-mediated fluorescence', 'MPA', (44, 71))	('decreased', 'NegReg', (34, 43))	('Silencing', 'Var', (0, 9))	('PBGS', 'Gene', (13, 17))	('decreased', 'NegReg', (76, 85))	('PBGS', 'Gene', '210', (13, 17))	('sensitivity to photodynamic therapy', 'MPA', (86, 121))	('PBGD', 'Gene', (22, 26))
240800	33540759	In one study, PpIX concentration diminished with the administration of a competitive peripheral benzodiazepine receptor blockade concurrently with 5-ALA. Another study showed that induction of PBR in glioma cell lines caused corresponding increases in intracellular PpIX concentration.	('glioma', 'Disease', (200, 206))	('peripheral benzodiazepine receptor', 'Gene', '706', (85, 119))	('PpIX', 'Chemical', 'MESH:C028025', (14, 18))	('PBR', 'Gene', '706', (193, 196))	('PBR', 'Gene', (193, 196))	('intracellular PpIX concentration', 'MPA', (252, 284))	('rat', 'Species', '10116', (26, 29))	('rat', 'Species', '10116', (61, 64))	('peripheral benzodiazepine receptor', 'Gene', (85, 119))	('increases', 'PosReg', (239, 248))	('induction', 'Var', (180, 189))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('5-ALA', 'Chemical', 'MESH:C000614854', (147, 152))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('PpIX', 'Chemical', 'MESH:C028025', (266, 270))	('rat', 'Species', '10116', (278, 281))
240826	33540759	Further, some studies have shown that in non-fluorescent LGG, there is still some level of resultant PpIX accumulation that is undetectable macroscopically, but detectable through spectroscopy.	('PpIX', 'Gene', (101, 105))	('non-fluorescent', 'Var', (41, 56))	('accumulation', 'PosReg', (106, 118))	('PpIX', 'Chemical', 'MESH:C028025', (101, 105))
240850	33540759	One study describing mechanisms of apoptosis associated with 5-ALA PDT reported an increased Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and apoptosis-inducing factor in U87MG GBM cells.	('GBM', 'Phenotype', 'HP:0012174', (190, 193))	('Bax', 'Gene', (93, 96))	('U87MG', 'CellLine', 'CVCL:0022', (184, 189))	('cytochrome c', 'Gene', (138, 150))	('Bcl-2', 'Gene', (97, 102))	('increased', 'PosReg', (83, 92))	('U87MG', 'Var', (184, 189))	('5-ALA', 'Chemical', 'MESH:C000614854', (61, 66))	('Bcl-2', 'Gene', '596', (97, 102))	('rat', 'Species', '10116', (103, 106))	('cytochrome c', 'Gene', '54205', (138, 150))	('Bax', 'Gene', '581', (93, 96))
240851	33540759	A similar study found that ALA-DT induces apoptosis via increased activity of caspase-3 and -9, increased cytochrome c, as well as decreased mitochondrial membrane potential.	('mitochondrial membrane potential', 'MPA', (141, 173))	('increased', 'PosReg', (96, 105))	('cytochrome c', 'Gene', '54205', (106, 118))	('caspase-3', 'Enzyme', (78, 87))	('increased', 'PosReg', (56, 65))	('activity', 'MPA', (66, 74))	('decreased', 'NegReg', (131, 140))	('ALA-DT', 'Var', (27, 33))	('ALA-DT', 'Chemical', '-', (27, 33))	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (131, 173))	('cytochrome c', 'Gene', (106, 118))
240853	33540759	There is also evidence to suggest that 5-ALA PDT destroys vascular endothelial cells, indirectly contributing to tumor necrosis by disrupting blood flow.	('tumor necrosis', 'Disease', (113, 127))	('blood', 'MPA', (142, 147))	('vascular endothelial cells', 'CPA', (58, 84))	('contributing', 'Reg', (97, 109))	('tumor necrosis', 'Disease', 'MESH:D009336', (113, 127))	('disrupting', 'NegReg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('5-ALA PDT', 'Var', (39, 48))	('5-ALA', 'Chemical', 'MESH:C000614854', (39, 44))
240927	33194678	Several reports have shown that isocitrate dehydrogenase (IDH) mutation plays a crucial role in the development and progression of glioma.	('isocitrate dehydrogenase', 'Gene', (32, 56))	('glioma', 'Disease', (131, 137))	('IDH', 'Gene', '3417', (58, 61))	('isocitrate dehydrogenase', 'Gene', '3417', (32, 56))	('mutation', 'Var', (63, 71))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('IDH', 'Gene', (58, 61))
240931	33194678	According to the phenotypes and genotypes, based on mutation of the IDH1 and IDH2 genes and codeletion of chromosomes 1p and 19q, lower-grade gliomas can be classified as three molecular subtypes: IDH wild type (IDHwt), IDH mutant with 1p/19q codeletion (IDHmut-Codel) or IDH mutant with no 1p/19q codeletion (IDHmut-Noncodel).	('IDH', 'Gene', (255, 258))	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', (272, 275))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('mutation', 'Var', (52, 60))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('IDH', 'Gene', '3417', (255, 258))	('IDH2', 'Gene', (77, 81))	('IDH', 'Gene', '3417', (272, 275))	('IDH', 'Gene', (310, 313))	('IDH', 'Gene', (77, 80))	('IDH', 'Gene', (197, 200))	('IDH2', 'Gene', '3418', (77, 81))	('IDH', 'Gene', (212, 215))	('IDH', 'Gene', (220, 223))	('IDH1', 'Gene', (68, 72))	('IDH', 'Gene', '3417', (197, 200))	('IDH', 'Gene', (68, 71))	('IDH', 'Gene', '3417', (310, 313))	('IDH', 'Gene', '3417', (77, 80))	('gliomas', 'Disease', (142, 149))	('IDH', 'Gene', '3417', (212, 215))	('IDH', 'Gene', '3417', (220, 223))	('IDH1', 'Gene', '3417', (68, 72))	('1p/19q codeletion', 'Var', (236, 253))
240979	33194678	The results of IHC also revealed that B7-H3 and TIM-3 were highly expressed in high FAM111A-expression LGG samples compared with the negative ones ( Supplementary Figure 4B ), evidently suggesting possible synergistic effects of FAM11A with these checkpoint genes.	('FAM111A', 'Gene', '63901', (84, 91))	('TIM-3', 'Gene', (48, 53))	('TIM-3', 'Gene', '84868', (48, 53))	('FAM111A', 'Gene', (84, 91))	('B7-H3', 'Gene', (38, 43))	('high', 'Var', (79, 83))	('FAM11A', 'Gene', (229, 235))	('FAM11A', 'Gene', '84548', (229, 235))	('B7-H3', 'Gene', '80381', (38, 43))
240987	33194678	When applied to the TCGA and CGGA RNA-seq datasets, FAM111A exhibited a significant association with glioma grades and IDH mutation status.	('FAM111A', 'Gene', (52, 59))	('IDH', 'Gene', '3417', (119, 122))	('glioma', 'Disease', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('mutation status', 'Var', (123, 138))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('IDH', 'Gene', (119, 122))	('FAM111A', 'Gene', '63901', (52, 59))
241001	33194678	C5 exhibits fewer tumor-associated immune cells and better outcome, with the enriched CpG island methylator phenotype-high (CIMP-H), the 1p/19q codeletion and pilocytic astrocytoma-like (PA-like) as well as the IDH mutations.	('tumor', 'Disease', (18, 23))	('astrocytoma', 'Disease', 'MESH:D001254', (169, 180))	('IDH', 'Gene', (211, 214))	('astrocytoma', 'Disease', (169, 180))	('astrocytoma', 'Phenotype', 'HP:0009592', (169, 180))	('IDH', 'Gene', '3417', (211, 214))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('1p/19q codeletion', 'Var', (137, 154))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
241043	32284966	There is evidence that many isocitrate dehydrogenase (IDH) mutation and non-1p19q-codeleted gliomas display a T2-FLAIR mismatch sign:complete or near-complete T2-hyperintense signal throughout but relatively hypointense signal on FLAIR sequences.	('T2-hyperintense signal', 'MPA', (159, 181))	('citrate', 'Chemical', 'MESH:D019343', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('IDH', 'Gene', (54, 57))	('mutation', 'Var', (59, 67))	('isocitrate dehydrogenase', 'Gene', (28, 52))	('IDH', 'Gene', '3417', (54, 57))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('isocitrate dehydrogenase', 'Gene', '3417', (28, 52))
241060	32284966	Many sporadic low-grade infiltrating gliomas have mutations in the IDH-1 or IDH-2 genes (see below); low-grade astrocytomas are also associated with somatic mosaic mutations in the IDH-1 or IDH-2 genes in patients with Ollier-type multiple enchondromatosis or with Maffucci syndrome.	('Maffucci syndrome', 'Disease', (265, 282))	('multiple enchondromatosis', 'Disease', (231, 256))	('low-grade infiltrating gliomas', 'Disease', (14, 44))	('IDH-2', 'Gene', '3418', (190, 195))	('IDH-2', 'Gene', (76, 81))	('IDH-1', 'Gene', '3417', (67, 72))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('mosaic mutations', 'Var', (157, 173))	('IDH-1', 'Gene', (181, 186))	('multiple enchondromatosis', 'Phenotype', 'HP:0005701', (231, 256))	('multiple enchondromatosis', 'Disease', 'MESH:D004687', (231, 256))	('low-grade astrocytomas', 'Disease', (101, 123))	('associated', 'Reg', (133, 143))	('IDH-2', 'Gene', '3418', (76, 81))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('IDH-2', 'Gene', (190, 195))	('IDH-1', 'Gene', (67, 72))	('IDH-1', 'Gene', '3417', (181, 186))	('mutations', 'Var', (50, 59))
241062	32284966	Isocitrate dehydrogenase-mutant oligodendrogliomas and astrocytomas are associated with a low-frequency single-nucleotide polymorphism (SNP) at 8p24.21.	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('single-nucleotide polymorphism', 'Var', (104, 134))	('oligodendrogliomas', 'Disease', (32, 50))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('astrocytomas', 'Disease', (55, 67))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
241063	32284966	Oligodendrogliomas are also associated with GSTT1 null genotype (glutathione S-transferase theta 1), SNPs in GLTSCR1 (gliomas tumor suppressor candidate region gene 2 protein) and ERCC2 genes, and germ line mutations in shelterin complex genes.	('gliomas tumor', 'Phenotype', 'HP:0009733', (118, 131))	('GSTT1', 'Gene', '2952', (44, 49))	('Oligodendrogliomas', 'Disease', (0, 18))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SNPs', 'Var', (101, 105))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas tumor', 'Disease', (118, 131))	('GSTT1', 'Gene', (44, 49))	('glutathione', 'Chemical', 'MESH:D005978', (65, 76))	('associated', 'Reg', (28, 38))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('ERCC2', 'Gene', (180, 185))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas tumor', 'Disease', 'MESH:D005910', (118, 131))	('ERCC2', 'Gene', '2068', (180, 185))	('GLTSCR1', 'Gene', (109, 116))	('glutathione S-transferase theta 1', 'Gene', (65, 98))	('GLTSCR1', 'Gene', '29998', (109, 116))	('glutathione S-transferase theta 1', 'Gene', '2952', (65, 98))
241066	32284966	An additional immunohistochemical workup demonstrated tumor expression of R132H-mutant IDH-1, loss of ATRX expression, and a relatively low Ki-67 proliferation index (Figure 2E-G).	('ATRX', 'Gene', (102, 106))	('Ki-67 proliferation index', 'CPA', (140, 165))	('loss', 'NegReg', (94, 98))	('IDH-1', 'Gene', (87, 92))	('ATRX', 'Gene', '546', (102, 106))	('expression', 'MPA', (107, 117))	('low', 'NegReg', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('R132H', 'Mutation', 'rs121913500', (74, 79))	('R132H-mutant', 'Var', (74, 86))
241077	32284966	The WHO regularly sponsors consensus meetings of expert brain tumor pathologists to update and revise the classification and grading of CNS neoplasms; an update in 2016 has now included the mutational status of IDH-1 or IDH-2 as an integral component of the diagnosis.	('brain tumor', 'Phenotype', 'HP:0030692', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CNS neoplasms', 'Phenotype', 'HP:0100006', (136, 149))	('IDH-2', 'Gene', (220, 225))	('CNS neoplasms', 'Disease', (136, 149))	('mutational', 'Var', (190, 200))	('CNS neoplasms', 'Disease', 'MESH:D016543', (136, 149))	('CNS neoplasm', 'Phenotype', 'HP:0100006', (136, 148))	('neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('IDH-1', 'Gene', (211, 216))	('neoplasm', 'Phenotype', 'HP:0002664', (140, 148))
241079	32284966	Methylation of the O-6-methylguanine DNA methyltransferase (MGMT) gene promoter is associated with improved response to chemotherapy and has become a standard assay that informs therapeutic decisions.	('response to chemotherapy', 'MPA', (108, 132))	('improved', 'PosReg', (99, 107))	('O-6-methylguanine DNA methyltransferase', 'Gene', (19, 58))	('Methylation', 'Var', (0, 11))	('MGMT', 'Gene', (60, 64))	('MGMT', 'Gene', '4255', (60, 64))	('O-6-methylguanine DNA methyltransferase', 'Gene', '4255', (19, 58))
241080	32284966	O-6-methylguanine DNA methyltransferase promoter methylation is thought to result in lower expression of the protein that confers cellular resistance against alkylating chemotherapy agents such as temozolomide, one of the mainstays of glioma chemotherapy.	('expression', 'MPA', (91, 101))	('lower', 'NegReg', (85, 90))	('methylation', 'Var', (49, 60))	('temozolomide', 'Chemical', 'MESH:D000077204', (197, 209))	('glioma', 'Phenotype', 'HP:0009733', (235, 241))	('cellular resistance against alkylating', 'MPA', (130, 168))
241081	32284966	Arginine (R) is substituted at specific active site positions in IDH-1 (R132) or IDH-2 (R172) in 90% of adult grade II and III gliomas and secondary glioblastomas.	('IDH-1', 'Gene', (65, 70))	('R132', 'Var', (72, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('secondary glioblastomas', 'Disease', (139, 162))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('glioblastomas', 'Phenotype', 'HP:0012174', (149, 162))	('IDH-2', 'Gene', (81, 86))	('R172', 'Var', (88, 92))
241082	32284966	These gain-of-function mutations result in the production of an oncometabolite, (D) 2-hydroxyglutarate, that competitively inhibits key enzymes involved in cell division and regulation of DNA methylation, resulting in hypermethylation of the tumor genome.	('cell division', 'CPA', (156, 169))	('hypermethylation', 'MPA', (218, 234))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (84, 102))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('mutations', 'Var', (23, 32))	('gain-of-function', 'PosReg', (6, 22))	('inhibits', 'NegReg', (123, 131))
241083	32284966	Ninety percent of IDH mutant gliomas harbor the IDH-1 R132H missense mutation and antibodies have been developed to identify the mutant protein in glioma specimens and are now in widespread use.	('IDH-1', 'Gene', (48, 53))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('gliomas', 'Disease', (29, 36))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('R132H', 'Var', (54, 59))	('R132H', 'SUBSTITUTION', 'None', (54, 59))	('IDH mutant', 'Gene', (18, 28))
241084	32284966	In addition to being used to identify the presence of the R132H IDH1 mutation in infiltrating gliomas, when the mutation is present, this immunostain enables the identification of tumor cells in even mildly infiltrated brain and, when positive, can aid in distinguishing gliomas from gliosis.	('aid', 'Gene', (249, 252))	('R132H', 'Var', (58, 63))	('gliosis', 'Disease', (284, 291))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('R132H', 'SUBSTITUTION', 'None', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('IDH1', 'Gene', (64, 68))	('gliosis', 'Phenotype', 'HP:0002171', (284, 291))	('aid', 'Gene', '57379', (249, 252))	('IDH1', 'Gene', '3417', (64, 68))	('gliosis', 'Disease', 'MESH:D005911', (284, 291))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('gliomas', 'Disease', (271, 278))	('gliomas', 'Phenotype', 'HP:0009733', (271, 278))
241085	32284966	The tumor is IDH-1 R132H-mutant with a loss of ATRX expression (Figure 2F and G).	('ATRX', 'Protein', (47, 51))	('R132H', 'Var', (19, 24))	('expression', 'MPA', (52, 62))	('loss', 'NegReg', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('R132H', 'SUBSTITUTION', 'None', (19, 24))
241094	32284966	The tumor was positive for an IDH-1 R132H mutation (not shown).	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('R132H', 'SUBSTITUTION', 'None', (36, 41))	('IDH-1', 'Gene', (30, 35))	('R132H', 'Var', (36, 41))
241099	32284966	More recent evidence has shown 1p/19q codeleted oligodendrogliomas treated with radiation and PCV may have a median survival closer to 20 and 15 years for grade II and III tumors, respectively.	('III tumors', 'Disease', 'MESH:D009369', (168, 178))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('1p/19q', 'Var', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('III tumors', 'Disease', (168, 178))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
241162	33889844	Our purpose was to visualize and compare the spatial distribution of different WHO 2016 gliomas, frequently aberrated single genes and DNA copy number alterations within subgroups, and groups of postoperative tumor volume.	('single genes', 'Var', (118, 130))	('postoperative tumor', 'Disease', 'MESH:D010149', (195, 214))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('postoperative tumor', 'Disease', (195, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
241164	33889844	Location heatmaps were created for each WHO 2016 glioma subgroup, frequently aberrated single genes and copy numbers (CNVs), as well as heatmaps according to groups of postoperative tumor volume.	('aberrated', 'Reg', (77, 86))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('postoperative tumor', 'Disease', 'MESH:D010149', (168, 187))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('single genes', 'Var', (87, 99))	('postoperative tumor', 'Disease', (168, 187))	('copy numbers', 'Var', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('glioma', 'Disease', (49, 55))
241167	33889844	We found no localizations of significant difference for single genes/CNVs in subgroups, except for loss of 9p in oligodendrogliomas with a predilection for the left parietal lobes.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (113, 131))	('oligodendrogliomas', 'Disease', (113, 131))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('loss', 'Var', (99, 103))
241177	33889844	Three major subtypes of diffuse low-grade (grade II) glioma (LGG) are recognized based on testing of 2 molecular markers: mutations of isocitrate dehydrogenase 1 or 2 gene [further abbreviated as IDH] and combined deletion of chromosomal arms 1p and 19q.	('deletion', 'Var', (214, 222))	('IDH', 'Gene', '3417', (196, 199))	('glioma', 'Disease', (53, 59))	('arms 1p', 'Gene', '3075', (238, 245))	('arms 1p', 'Gene', (238, 245))	('mutations', 'Var', (122, 131))	('diffuse', 'Disease', (24, 31))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('IDH', 'Gene', (196, 199))
241181	33889844	For example, it was shown that loss of 1p is associated with a more frequent location in the frontal lobes and that 1p19q co-deletion is absent in insular tumors.	('insular tumors', 'Disease', (147, 161))	('1p19q', 'Var', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('insular tumors', 'Disease', 'MESH:D009369', (147, 161))	('loss', 'Var', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))
241198	33889844	The panel assesses mutational status of IDH1/2, TP53, FUBP1, PTEN, CIC, CDKN2A, NOTCH1, ATRX (whole gene) and hotspots of EGFR (exon 3 + 15), H3F3A (exon 2), PIK3CA (exon 10 + 21), BRAF (exon 11 + 15), and also copy number variations (CNVs) of chromosome 1, 7, 9, 10, 12, and 19.	('IDH1/2', 'Gene', (40, 46))	('H3F3A', 'Gene', '3020', (142, 147))	('PTEN', 'Gene', (61, 65))	('FUBP1', 'Gene', '8880', (54, 59))	('NOTCH1', 'Gene', '4851', (80, 86))	('EGFR', 'Gene', (122, 126))	('TP53', 'Gene', '7157', (48, 52))	('CIC', 'Gene', (67, 70))	('PIK3CA', 'Gene', '5290', (158, 164))	('copy number variations', 'Var', (211, 233))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('H3F3A', 'Gene', (142, 147))	('PTEN', 'Gene', '5728', (61, 65))	('CDKN2A', 'Gene', (72, 78))	('EGFR', 'Gene', '1956', (122, 126))	('CDKN2A', 'Gene', '1029', (72, 78))	('CIC', 'Gene', '23152', (67, 70))	('ATRX', 'Gene', (88, 92))	('FUBP1', 'Gene', (54, 59))	('PIK3CA', 'Gene', (158, 164))	('ATRX', 'Gene', '546', (88, 92))	('TP53', 'Gene', (48, 52))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('NOTCH1', 'Gene', (80, 86))
241199	33889844	TERT promoter mutations (C228T and C250T) were assessed in a separate assay (SnaPshot).	('C250T', 'SUBSTITUTION', 'None', (35, 40))	('C228T', 'Var', (25, 30))	('TERT', 'Gene', (0, 4))	('C250T', 'Var', (35, 40))	('TERT', 'Gene', '7015', (0, 4))	('C228T', 'Mutation', 'c.228C>T', (25, 30))
241200	33889844	The following criteria for molecular classification were used: Oligodendroglioma: IDH1 or IDH2 mutated and loss of heterozygosity consistent with co-deletion of the entire 1p and 19q chromosomal arms.	('Oligodendroglioma', 'Disease', (63, 80))	('IDH2', 'Gene', '3418', (90, 94))	('IDH1', 'Gene', (82, 86))	('loss of', 'NegReg', (107, 114))	('Oligodendroglioma', 'Disease', 'MESH:D009837', (63, 80))	('mutated', 'Var', (95, 102))	('IDH1', 'Gene', '3417', (82, 86))	('IDH2', 'Gene', (90, 94))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
241201	33889844	IDH mutated astrocytoma: IDH1 or IDH2 mutated.	('mutated', 'Var', (38, 45))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (25, 28))	('IDH2', 'Gene', (33, 37))	('IDH', 'Gene', '3417', (0, 3))	('astrocytoma', 'Disease', 'MESH:D001254', (12, 23))	('IDH2', 'Gene', '3418', (33, 37))	('astrocytoma', 'Disease', (12, 23))	('IDH', 'Gene', (33, 36))	('astrocytoma', 'Phenotype', 'HP:0009592', (12, 23))	('IDH1', 'Gene', (25, 29))	('IDH', 'Gene', '3417', (33, 36))	('IDH1', 'Gene', '3417', (25, 29))
241219	33889844	For this, we analyzed CIC and FUBP1 mutations, and loss of chromosomal arm 9p for oligodendroglioma (Supplementary Figure 2).	('oligodendroglioma', 'Disease', 'MESH:D009837', (82, 99))	('CIC', 'Gene', '23152', (22, 25))	('FUBP1', 'Gene', (30, 35))	('mutations', 'Var', (36, 45))	('CIC', 'Gene', (22, 25))	('oligodendroglioma', 'Disease', (82, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('loss', 'NegReg', (51, 55))	('FUBP1', 'Gene', '8880', (30, 35))
241220	33889844	We found no preferential locations for any of those molecular aberrations, except for loss of 9p (compared with oligodendroglioma with intact 9p), which seemed to be more frequently located in the left parietal area (Supplementary Figure 3).	('loss', 'Var', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('oligodendroglioma', 'Disease', (112, 129))	('oligodendroglioma', 'Disease', 'MESH:D009837', (112, 129))
241221	33889844	In IDH-mutated astrocytoma, we created heatmaps of loss of chromosomal arm 9p and imbalance of chromosome 7, and found no preferential brain locations/voxels for either of those that showed P-values <0.05 (Supplementary Figure 4).	('astrocytoma', 'Disease', (15, 26))	('IDH', 'Gene', (3, 6))	('IDH', 'Gene', '3417', (3, 6))	('imbalance', 'Var', (82, 91))	('imbalance', 'Phenotype', 'HP:0002172', (82, 91))	('astrocytoma', 'Disease', 'MESH:D001254', (15, 26))	('loss', 'NegReg', (51, 55))	('astrocytoma', 'Phenotype', 'HP:0009592', (15, 26))	('chromosomal arm 9p', 'Protein', (59, 77))
241245	33889844	We performed an exploratory analysis to assess the spatial distribution of other frequently reported mutations and CNVs in glioma.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('mutations', 'Var', (101, 110))	('glioma', 'Disease', (123, 129))
241247	33889844	We found no specific spatial distributions for the tested aberrations however, except for loss of chromosome 9p in the context of oligodendroglioma.	('oligodendroglioma', 'Disease', 'MESH:D009837', (130, 147))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('loss', 'Var', (90, 94))	('oligodendroglioma', 'Disease', (130, 147))
241248	33889844	Oligodendrogliomas with loss of 9p were significantly more frequently located in the left parietal area.	('located', 'Reg', (70, 77))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('Oligodendrogliomas', 'Disease', (0, 18))	('Oligodendrogliomas', 'Disease', 'MESH:D009837', (0, 18))	('loss of 9p', 'Var', (24, 34))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
241259	33889844	However, a recent study showed that, in the context of glioblastoma, the frontal cortex is also significantly associated with the presence of IDH mutations.	('mutations', 'Var', (146, 155))	('IDH', 'Gene', (142, 145))	('glioblastoma', 'Disease', (55, 67))	('IDH', 'Gene', '3417', (142, 145))	('associated', 'Reg', (110, 120))	('frontal', 'Disease', (73, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))
241288	28944855	The raw count mRNAseq data of 83 glioma grade III patients and raw read miRNA data of five GBM normal patients (TCGA-06-AABW-11A-31R-A36H-07, TCGA-06-0678-11A-32R-A36H-07, TCGA-06-0675-11A-32R-A36H-07, TCGA-06-0681-11A-41R-A36H-07, TCGA-06-0680-11A-32R-A36H-07 and TCGA-HW-7493-01A-11R-2027-07), were selected.	('A36H', 'Mutation', 'p.A36H', (223, 227))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('patients', 'Species', '9606', (50, 58))	('glioma', 'Disease', (33, 39))	('TCGA-06-0675-11A-32R-A36H-07', 'Var', (172, 200))	('A36H', 'Mutation', 'p.A36H', (193, 197))	('A36H', 'Mutation', 'p.A36H', (163, 167))	('patients', 'Species', '9606', (102, 110))	('TCGA-HW-7493-01', 'CellLine', 'CVCL:F560', (265, 280))	('A36H', 'Mutation', 'p.A36H', (133, 137))	('A36H', 'Mutation', 'p.A36H', (253, 257))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))	('TCGA-06-0680-11A-32R-A36H-07', 'Var', (232, 260))
241293	28944855	The mRNAs with  log2foldchange >2 and miRNAs with  log2foldchange >2 are shown in Tables I and II.	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('log2foldchange >2', 'Var', (16, 33))
241310	28944855	Patients with a high expression of BUB1B had shorter survival rates.	('high expression', 'Var', (16, 31))	('BUB1B', 'Gene', '701', (35, 40))	('shorter', 'NegReg', (45, 52))	('BUB1B', 'Gene', (35, 40))	('survival rates', 'CPA', (53, 67))	('Patients', 'Species', '9606', (0, 8))
241324	28944855	In colorectal cancer, mutation of the BUB1 gene was found to be associated with lymph node metastasis and lower relapse-free survival rates following surgery.	('associated', 'Reg', (64, 74))	('lower', 'NegReg', (106, 111))	('BUB1', 'Gene', (38, 42))	('mutation', 'Var', (22, 30))	('lymph node metastasis', 'CPA', (80, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('relapse-free survival rates', 'CPA', (112, 139))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('BUB1', 'Gene', '699', (38, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
241325	28944855	Further investigations may be required to identify whether BUB1 mutations are important in the glioma process.	('BUB1', 'Gene', (59, 63))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma', 'Disease', (95, 101))	('mutations', 'Var', (64, 73))	('important', 'Reg', (78, 87))	('BUB1', 'Gene', '699', (59, 63))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
241327	28944855	SLC12A5 has been found have an important oncogenic role in colorectal carcinogenesis; its overexpression can be an independent prognostic factor for patients, and the mutation frequency of SLC12A5 may have potential oncogenic effects in colon cancer.	('patients', 'Species', '9606', (149, 157))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (59, 84))	('oncogenic effects', 'CPA', (216, 233))	('mutation frequency', 'Var', (167, 185))	('SLC12A5', 'Gene', (0, 7))	('colon cancer', 'Phenotype', 'HP:0003003', (237, 249))	('colon cancer', 'Disease', 'MESH:D015179', (237, 249))	('colorectal carcinogenesis', 'Disease', (59, 84))	('SLC12A5', 'Gene', '57468', (0, 7))	('SLC12A5', 'Gene', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('SLC12A5', 'Gene', '57468', (189, 196))	('overexpression', 'PosReg', (90, 104))	('colon cancer', 'Disease', (237, 249))
241329	28944855	The present study found that patients with a high expression of SLC12A5 showed improved prognosis (P=0.11).	('patients', 'Species', '9606', (29, 37))	('prognosis', 'CPA', (88, 97))	('improved', 'PosReg', (79, 87))	('SLC12A5', 'Gene', (64, 71))	('SLC12A5', 'Gene', '57468', (64, 71))	('high expression', 'Var', (45, 60))
241337	28944855	In addition, a high expression of SULT4A1 was associated with increased survival rates, compared with a low expression.	('increased', 'PosReg', (62, 71))	('survival rates', 'CPA', (72, 86))	('high expression', 'Var', (15, 30))	('SULT4A1', 'Gene', '25830', (34, 41))	('SULT4A1', 'Gene', (34, 41))
241344	28944855	A2BP1 serves to regulate the alternative splicing of TPM1 to promote cytoskeletal organization and terminal differentiation, and the loss of A2BP1 contributes to the tumorigenesis in GBM by causing compromised terminal differentiation.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('A2BP1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('contributes', 'Reg', (147, 158))	('tumor', 'Disease', (166, 171))	('A2BP1', 'Gene', '54715', (141, 146))	('A2BP1', 'Gene', (141, 146))	('causing', 'Reg', (190, 197))	('terminal differentiation', 'CPA', (99, 123))	('GBM', 'Phenotype', 'HP:0012174', (183, 186))	('cytoskeletal organization', 'CPA', (69, 94))	('loss', 'Var', (133, 137))	('terminal differentiation', 'CPA', (210, 234))	('A2BP1', 'Gene', '54715', (0, 5))
241380	26244119	hypothesized that stratification of gliomas based on alterations in the TERT promoter, IDH (including IDH1 and IDH2 mutations), and co-deletion of 1p19q would identify groups with similar clinical variables, acquired somatic alterations, and germline variants.	('gliomas', 'Disease', (36, 43))	('IDH2', 'Gene', '3418', (111, 115))	('IDH', 'Gene', (87, 90))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('IDH', 'Gene', (111, 114))	('IDH1', 'Gene', (102, 106))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('IDH', 'Gene', (102, 105))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('IDH', 'Gene', '3417', (87, 90))	('mutations', 'Var', (116, 125))	('IDH1', 'Gene', '3417', (102, 106))	('IDH', 'Gene', '3417', (111, 114))	('1p19q', 'Gene', (147, 152))	('IDH', 'Gene', '3417', (102, 105))	('co-deletion', 'Var', (132, 143))	('alterations', 'Var', (53, 64))	('IDH2', 'Gene', (111, 115))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
241382	26244119	Specifically, TERT encodes telomerase which is essential for telomere maintenance (shortened telomeres impede cellular division) and mutations in its promoter are often found in both oligodendroglioma and glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('shortened telomeres', 'Phenotype', 'HP:0031413', (83, 102))	('found', 'Reg', (169, 174))	('oligodendroglioma and glioblastoma', 'Disease', 'MESH:D005909', (183, 217))	('TERT', 'Gene', (14, 18))	('TERT', 'Gene', '7015', (14, 18))	('mutations', 'Var', (133, 142))	('cellular division', 'CPA', (110, 127))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))
241399	26244119	The study also demonstrated a relationship between TERT mutations and germline variants in telomere components (TERC/TERT/RTEL1), which is relevant given interest in telomeres and cancer more generally.	('TERC', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('germline variants', 'Var', (70, 87))	('TERT', 'Gene', (51, 55))	('RTEL1', 'Gene', '51750', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('RTEL1', 'Gene', (122, 127))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (117, 121))	('TERC', 'Gene', '7012', (112, 116))	('TERT', 'Gene', '7015', (117, 121))	('cancer', 'Disease', (180, 186))
241400	26244119	Similarly, it was confirmed that SNPs at chromosome locus 8q24 were highly associated with the IDH mutation, which suggests that this region contains a germline alteration that facilitates the development of IDH mutant gliomas.	('SNPs', 'Var', (33, 37))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('IDH', 'Gene', '3417', (95, 98))	('facilitates', 'PosReg', (177, 188))	('gliomas', 'Disease', (219, 226))	('IDH', 'Gene', (208, 211))	('IDH', 'Gene', (95, 98))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('associated', 'Reg', (75, 85))	('IDH', 'Gene', '3417', (208, 211))
241402	26244119	In short, their study demonstrated that clinical outcome was better predicted by molecular subclasses dictated by IDH, 1p19q, and TP53 status than by traditional histopathologic diagnosis.	('1p19q', 'Var', (119, 124))	('IDH', 'Gene', (114, 117))	('IDH', 'Gene', '3417', (114, 117))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))
241403	26244119	Similar to the previous study, the TCGA study found that patients with IDH mutations and 1p19q co-deletions had the most favorable prognosis and a strong histologic correlation with oligodendroglioma.	('oligodendroglioma', 'Disease', (182, 199))	('patients', 'Species', '9606', (57, 65))	('oligodendroglioma', 'Disease', 'MESH:D009837', (182, 199))	('1p19q co-deletions', 'Var', (89, 107))	('IDH', 'Gene', (71, 74))	('mutations', 'Var', (75, 84))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('IDH', 'Gene', '3417', (71, 74))
241404	26244119	Moreover, this class of patients frequently harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter.	('CIC', 'Gene', (66, 69))	('FUBP1', 'Gene', (71, 76))	('NOTCH1', 'Gene', '4851', (78, 84))	('NOTCH1', 'Gene', (78, 84))	('mutations', 'Var', (53, 62))	('FUBP1', 'Gene', '8880', (71, 76))	('patients', 'Species', '9606', (24, 32))	('TERT', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (94, 98))	('harbored', 'Reg', (44, 52))
241405	26244119	In contrast, those gliomas with IDH mutations but lacking 1p19q co-deletion had mutations in TP53 as well as ATRX inactivation and were generally associated with astrocytic histomorphology, including those tumors with mixed morphologies.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutations', 'Var', (80, 89))	('ATRX', 'Gene', '546', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (36, 45))	('tumors', 'Disease', (206, 212))	('gliomas', 'Disease', (19, 26))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('IDH', 'Gene', (32, 35))	('ATRX', 'Gene', (109, 113))	('IDH', 'Gene', '3417', (32, 35))	('associated with', 'Reg', (146, 161))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('astrocytic', 'Disease', (162, 172))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
241406	26244119	Finally, those lower grade tumors without IDH mutations had clinical behavior highly similar to glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('IDH', 'Gene', (42, 45))	('mutations', 'Var', (46, 55))	('IDH', 'Gene', '3417', (42, 45))	('glioblastoma', 'Disease', (96, 108))	('tumors', 'Disease', (27, 33))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))
241407	26244119	Interestingly, the authors queried the genomic data from these gliomas and were able to find clusters within groups related to DNA methylation, gene expression, DNA copy number, and microRNA expression.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('copy number', 'Var', (165, 176))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
241408	26244119	Consequently, they were able to show that classifying tumors based on IDH and 1p19q status mapped universally to a specific cluster, whereas histologic designation (i.e., oligodendroglioma, astrocytoma, and oligoastrocytoma) matched one-to-one with a cluster only 63% of the time.	('astrocytoma', 'Disease', 'MESH:D001254', (212, 223))	('astrocytoma', 'Disease', (212, 223))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('astrocytoma', 'Phenotype', 'HP:0009592', (212, 223))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('IDH', 'Gene', (70, 73))	('oligodendroglioma', 'Disease', 'MESH:D009837', (171, 188))	('astrocytoma', 'Disease', 'MESH:D001254', (190, 201))	('IDH', 'Gene', '3417', (70, 73))	('astrocytoma', 'Disease', (190, 201))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('oligoastrocytoma', 'Disease', 'MESH:D001254', (207, 223))	('oligoastrocytoma', 'Disease', (207, 223))	('oligodendroglioma', 'Disease', (171, 188))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('astrocytoma', 'Phenotype', 'HP:0009592', (190, 201))	('tumors', 'Disease', (54, 60))	('1p19q status', 'Var', (78, 90))
241411	26244119	In lower grade gliomas with IDH mutations and 1p19q co-deletion, the authors found frequent mutations in CIC, FUBP1, PI3 kinase pathway genes, NOTCH1, ZBTB20, and ARIDIA, in addition to activating TERT promoter mutations.	('IDH', 'Gene', '3417', (28, 31))	('FUBP1', 'Gene', '8880', (110, 115))	('PI3 kinase pathway', 'Pathway', (117, 135))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('NOTCH1', 'Gene', (143, 149))	('1p19q', 'Var', (46, 51))	('ZBTB20', 'Gene', '26137', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('TERT', 'Gene', (197, 201))	('TERT', 'Gene', '7015', (197, 201))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('NOTCH1', 'Gene', '4851', (143, 149))	('CIC', 'Gene', (105, 108))	('mutations', 'Var', (92, 101))	('activating', 'PosReg', (186, 196))	('FUBP1', 'Gene', (110, 115))	('IDH', 'Gene', (28, 31))	('ZBTB20', 'Gene', (151, 157))	('gliomas', 'Disease', (15, 22))
241412	26244119	Overall, the data suggested that lower grade gliomas with IDH mutations and 1p19q co-deletions are biologically distinct and arise from a sequence of IDH mutation and 1p19q deletion, TERT/PI3 kinase activation, and NOTCH1 inactivation.	('IDH', 'Gene', '3417', (58, 61))	('NOTCH1', 'Gene', (215, 221))	('arise from', 'Reg', (125, 135))	('IDH', 'Gene', (150, 153))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('NOTCH1', 'Gene', '4851', (215, 221))	('mutation', 'Var', (154, 162))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('activation', 'PosReg', (199, 209))	('IDH', 'Gene', '3417', (150, 153))	('mutations', 'Var', (62, 71))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('1p19q', 'Gene', (76, 81))	('TERT', 'Gene', (183, 187))	('1p19q deletion', 'Var', (167, 181))	('inactivation', 'NegReg', (222, 234))	('TERT', 'Gene', '7015', (183, 187))	('IDH', 'Gene', (58, 61))	('gliomas', 'Disease', (45, 52))
241413	26244119	In IDH mutant tumors without 1p19q deletion, TP53 mutations were most frequent along with inactivating mutations in ATRX.	('IDH', 'Gene', (3, 6))	('TP53', 'Gene', (45, 49))	('ATRX', 'Gene', (116, 120))	('IDH', 'Gene', '3417', (3, 6))	('mutations', 'Var', (50, 59))	('ATRX', 'Gene', '546', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', '7157', (45, 49))	('frequent', 'Reg', (70, 78))
241414	26244119	TERT mutations were rare, but mutations in ATRX are associated with the alternative mechanism of lengthening telomeres (ALT) process.	('ATRX', 'Gene', (43, 47))	('lengthening telomeres', 'Phenotype', 'HP:0031413', (97, 118))	('ATRX', 'Gene', '546', (43, 47))	('associated', 'Reg', (52, 62))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (30, 39))	('lengthening', 'NegReg', (97, 108))
241418	26244119	In general, however, these protein expression profiles highlighted the fundamental background biologic difference between IDH mutant and IDH wild-type tumors.	('IDH', 'Gene', '3417', (122, 125))	('IDH', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('IDH', 'Gene', '3417', (137, 140))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutant', 'Var', (126, 132))	('IDH', 'Gene', (137, 140))
241419	26244119	The two studies are notable in that they genomically validate the utility of previously reported molecular markers; for example, that IDH status and 1p19q co-deletion are more important prognostically than standard histopathologic diagnosis.	('IDH', 'Gene', '3417', (134, 137))	('1p19q co-deletion', 'Var', (149, 166))	('IDH', 'Gene', (134, 137))
241421	26244119	Additionally, these studies confirm that lower-grade gliomas with an IDH mutation have either 1p/19q co-deletion or a TP53 mutation, with few gaps or overlaps, reflecting two distinct molecular mechanisms of oncogenesis.	('IDH', 'Gene', (69, 72))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('IDH', 'Gene', '3417', (69, 72))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('1p/19q', 'Gene', (94, 100))	('mutation', 'Var', (73, 81))
241431	26244119	On the other hand, among Grade IV tumors, since there were only 11 TERT/IDH mutant tumors in the Grade IV group, compared to 347 in the TERT-only group, it is possible that this comparison lacked sufficient power to detect a survival advantage.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TERT', 'Gene', (67, 71))	('tumors', 'Disease', (34, 40))	('TERT', 'Gene', '7015', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('TERT', 'Gene', (136, 140))	('TERT', 'Gene', '7015', (136, 140))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('IDH', 'Gene', (72, 75))	('IDH', 'Gene', '3417', (72, 75))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
241445	22892428	Patients undergoing gross total resection/radical subtotal resection had the best OS and PFS.	('Patients', 'Species', '9606', (0, 8))	('gross', 'Var', (20, 25))	('PFS', 'CPA', (89, 92))	('OS', 'Chemical', '-', (82, 84))
241487	22892428	Patients undergoing STR had lower PFS than biopsy only (10-year PFS 8.2% with STR vs. 17% with biopsy; P = 0.02).	('lower', 'NegReg', (28, 33))	('PFS', 'MPA', (34, 37))	('STR', 'Var', (78, 81))	('Patients', 'Species', '9606', (0, 8))
241517	22892428	Codeletion of 1p/19q was reported in 80% of oligodendrogliomas and 43% of oligoastrocytomas tested.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (44, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('reported', 'Reg', (25, 33))	('Codeletion of 1p/19q', 'Var', (0, 20))	('astrocytoma', 'Phenotype', 'HP:0009592', (79, 90))	('oligodendrogliomas', 'Disease', (44, 62))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('oligoastrocytomas', 'Disease', (74, 91))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (74, 91))
241519	22892428	Higher PFS (5 y, 49% vs. 7%; P < 0.0001) and OS (10 y, 64% vs. 30%; P = 0.0001) were seen in patients with 1p/19q codeletions.	('OS', 'Chemical', '-', (45, 47))	('1p/19q codeletions', 'Var', (107, 125))	('patients', 'Species', '9606', (93, 101))	('PFS', 'CPA', (7, 10))
241520	22892428	Multivariate analysis of previously assessed prognostic factors with 1p/19q status replacing astrocytoma histology as a variable revealed a significant association between 1p/19q codeletions and improved PFS and OS (both P < 0.0001).	('improved', 'PosReg', (195, 203))	('astrocytoma', 'Disease', 'MESH:D001254', (93, 104))	('1p/19q codeletions', 'Var', (172, 190))	('PFS', 'Disease', (204, 207))	('astrocytoma', 'Disease', (93, 104))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('OS', 'Chemical', '-', (212, 214))
241545	22892428	When RT was removed from multivariate analysis, GTR/rSTR was strongly associated with higher OS, as expected.	('higher OS', 'Disease', (86, 95))	('associated with', 'Reg', (70, 85))	('OS', 'Chemical', '-', (93, 95))	('GTR/rSTR', 'Var', (48, 56))
241582	22892428	Other prognostic information unable to be recorded may have precluded statistically significant findings in size (51% unknown), radiographic enhancement (25%), 1p/19q (74%), p53 (not performed), and IDH1 status (not performed).	('enhancement', 'PosReg', (141, 152))	('IDH1', 'Gene', '3417', (199, 203))	('1p/19q', 'Var', (160, 166))	('p53', 'Gene', (174, 177))	('IDH1', 'Gene', (199, 203))	('p53', 'Gene', '7157', (174, 177))
241583	22892428	Our subgroup analysis of the 133 patients with available 1p/19q status was limited in scope, but found a significant association between 1p/19q codeletions and improved OS and PFS on univariate and multivariate analysis, consistent with existing literature.	('patients', 'Species', '9606', (33, 41))	('PFS', 'Disease', (176, 179))	('1p/19q codeletions', 'Var', (137, 155))	('OS', 'Chemical', '-', (169, 171))	('improved', 'PosReg', (160, 168))
241587	22892428	For example, EORTC 22844 and 22845 had 26% and 38% mixed oligoastrocytomas and oligodendrogliomas.	('oligoastrocytomas', 'Disease', 'MESH:D001254', (57, 74))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (79, 97))	('EORTC', 'Var', (13, 18))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('oligodendrogliomas', 'Disease', (79, 97))	('oligoastrocytomas', 'Disease', (57, 74))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
241591	22892428	In specimens with 1p/19q data, 80% of oligodendrogliomas and 43% of oligoastrocytomas had 1p/19q codeletions, further validating our histologic classification.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (68, 85))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (38, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('1p/19q codeletions', 'Var', (90, 108))	('oligodendrogliomas', 'Disease', (38, 56))	('oligoastrocytomas', 'Disease', (68, 85))
241605	25434593	The AUC, sensitivity, specificity and the cutoff value, respectively, for differentiating low- from high-grade gliomas for ADC, D and f, and differentiating high- from low-grade gliomas for D* were as follows: ADC, 0.926, 100%, 82.8%, and 0.7 x 10-3 mm2/sec; D, 0.942, 92.3%, 86.2%, and 0.623 x 10-3 mm2/sec; f, 0.902, 92.3%, 86.2%, and 35.3%; D*, 0.798, 79.3%, 84.6%, and 0.303 x 10-3 mm2/sec.	('gliomas', 'Disease', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('0.303 x 10-3', 'Var', (373, 385))	('0.798', 'Var', (348, 353))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('mm2', 'Gene', '10687', (386, 389))	('mm2', 'Gene', '10687', (300, 303))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('mm2', 'Gene', (386, 389))	('mm2', 'Gene', (300, 303))	('gliomas', 'Disease', (178, 185))	('mm2', 'Gene', '10687', (250, 253))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('mm2', 'Gene', (250, 253))
241632	25434593	Theoretically, high cellularity in advanced gliomas may impede free water diffusion and thus lead to a decreased ADC value.	('free water diffusion', 'MPA', (63, 83))	('ADC value', 'MPA', (113, 122))	('decreased', 'NegReg', (103, 112))	('water', 'Chemical', 'MESH:D014867', (68, 73))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('gliomas', 'Disease', (44, 51))	('high cellularity', 'Var', (15, 31))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('impede', 'NegReg', (56, 62))
241634	25434593	Another study also revealed a significantly higher frequency of low ADC values in high- compared with low-grade gliomas.	('ADC values', 'MPA', (68, 78))	('low', 'Var', (64, 67))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('high-', 'Disease', (82, 87))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
241653	25434593	Although the optimal b values remain unknown, we demonstrated that ADC, D, D*, and f could achieve relatively high AUC in grading gliomas preoperatively.	('ADC', 'Var', (67, 70))	('AUC', 'MPA', (115, 118))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
241654	25434593	It was indicated that a cutoff value of 0.7 x 10-3 mm2/sec for ADC, 0.623 x 10-3 mm2/sec for D, and 35.3% for f could produce relatively satisfactory sensitivity and specificity for identifying low- from high-grade gliomas.	('mm2', 'Gene', '10687', (51, 54))	('gliomas', 'Disease', (215, 222))	('mm2', 'Gene', (51, 54))	('gliomas', 'Disease', 'MESH:D005910', (215, 222))	('gliomas', 'Phenotype', 'HP:0009733', (215, 222))	('mm2', 'Gene', '10687', (81, 84))	('0.623 x 10-3', 'Var', (68, 80))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('mm2', 'Gene', (81, 84))
241673	25434593	Equation (1) can then be simplified, and the estimation of D can be obtained by using only b values greater than 200 sec/mm2, with a simple linear fit equation (2): Hence, for high b values (300, 500, 800, 1000, 1500, 2000, 3000 and 3500 sec/mm2) Sb was first fitted to equation (2) using a linear model, and the true diffusion coefficient D was calculated.	('300', 'Var', (191, 194))	('mm2', 'Gene', '10687', (121, 124))	('mm2', 'Gene', '10687', (242, 245))	('mm2', 'Gene', (121, 124))	('mm2', 'Gene', (242, 245))
241679	25434593	Receiver operating characteristic (ROC) analyses were performed to determine the optimal thresholds for differentiating the low-grade (WHO II) from the high-grade gliomas (WHO III and IV) by ADC, D, D*, and f value.	('ADC', 'Var', (191, 194))	('gliomas', 'Disease', (163, 170))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))
241712	32164789	In the most recent WHO iteration, both diffuse astrocytoma and oligodendroglioma have been split based on the presence or absence of IDH1 mutations, in addition to 1p/19q co-deletion for the latter.	('astrocytoma', 'Phenotype', 'HP:0009592', (47, 58))	('oligodendroglioma', 'Disease', (63, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('oligodendroglioma', 'Disease', 'MESH:D009837', (63, 80))	('absence', 'NegReg', (122, 129))	('IDH1', 'Gene', (133, 137))	('IDH1', 'Gene', '3417', (133, 137))	('astrocytoma', 'Disease', 'MESH:D001254', (47, 58))	('astrocytoma', 'Disease', (47, 58))	('mutations', 'Var', (138, 147))
241713	32164789	Tumors with the morphology of oligodendroglioma or diffuse astrocytoma in the pediatric age group often do not have IDH1 mutations and/or 1p/19q co-deletion and are therefore considered oligodendroglioma, NEC or, of even greater concern, diffuse astrocytoma, IDH-wildtype.	('IDH', 'Gene', '3417', (116, 119))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (121, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('oligodendroglioma', 'Disease', (186, 203))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('diffuse', 'Disease', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('Tumors', 'Disease', (0, 6))	('astrocytoma', 'Phenotype', 'HP:0009592', (246, 257))	('astrocytoma', 'Disease', 'MESH:D001254', (59, 70))	('astrocytoma', 'Disease', (59, 70))	('IDH1', 'Gene', (116, 120))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('IDH', 'Gene', (259, 262))	('IDH', 'Gene', (116, 119))	('oligodendroglioma', 'Disease', 'MESH:D009837', (30, 47))	('not', 'NegReg', (107, 110))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('astrocytoma', 'Disease', 'MESH:D001254', (246, 257))	('astrocytoma', 'Disease', (246, 257))	('oligodendroglioma', 'Disease', 'MESH:D009837', (186, 203))	('oligodendroglioma', 'Disease', (30, 47))	('IDH1', 'Gene', '3417', (116, 120))	('IDH', 'Gene', '3417', (259, 262))
241716	32164789	However, in IDH1 wild-type cases, pediatric oligodendrogliomas most frequently harbor alterations in FGFR1 including TKD-duplications or SNVs or BRAF p.V600E (Table 1).	('p.V600E', 'Mutation', 'rs113488022', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('BRAF', 'Gene', (145, 149))	('IDH1', 'Gene', (12, 16))	('pediatric oligodendrogliomas', 'Disease', (34, 62))	('pediatric oligodendrogliomas', 'Disease', 'MESH:D009837', (34, 62))	('p.V600E', 'Var', (150, 157))	('al', 'Chemical', 'MESH:D000535', (86, 88))	('TKD-duplications', 'Var', (117, 133))	('SNVs', 'Var', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('IDH1', 'Gene', '3417', (12, 16))	('FGFR1', 'Gene', (101, 106))	('FGFR1', 'Gene', '2260', (101, 106))	('BRAF', 'Gene', '673', (145, 149))
241719	32164789	These tumors do not harbor IDH1 mutations, but rather FGFR2/3 fusions (discussed further below) or BRAF p.V600E.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('p.V600E', 'Mutation', 'rs113488022', (104, 111))	('fusions', 'Var', (62, 69))	('IDH1', 'Gene', (27, 31))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('p.V600E', 'Var', (104, 111))	('IDH1', 'Gene', '3417', (27, 31))
241720	32164789	IDH1 wild-type diffuse astrocytoma most frequently harbor BRAF p.V600E mutations, accounting for ~40% of cases (Table 1).	('astrocytoma', 'Disease', (23, 34))	('astrocytoma', 'Phenotype', 'HP:0009592', (23, 34))	('astrocytoma', 'Disease', 'MESH:D001254', (23, 34))	('p.V600E', 'Mutation', 'rs113488022', (63, 70))	('BRAF', 'Gene', '673', (58, 62))	('IDH1', 'Gene', (0, 4))	('BRAF', 'Gene', (58, 62))	('p.V600E', 'Var', (63, 70))	('IDH1', 'Gene', '3417', (0, 4))
241725	32164789	In recognition of the increased understanding of the molecular underpinnings of diffuse gliomas in adults, IDH1 mutation and 1p/19q deletion status were incorporated into the most recent WHO revision in order to improve diagnostic reproducibility and provide important prognostic information for patients.	('IDH1', 'Gene', (107, 111))	('mutation', 'Var', (112, 120))	('IDH1', 'Gene', '3417', (107, 111))	('improve', 'PosReg', (212, 219))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('patients', 'Species', '9606', (296, 304))
241731	32164789	An overview of the most common RAS/MAPK pathway alterations in pLGG is shown in Fig.	('alterations', 'Var', (48, 59))	('RAS/MAPK pathway', 'Pathway', (31, 47))	('al', 'Chemical', 'MESH:D000535', (48, 50))	('pLGG', 'Chemical', '-', (63, 67))
241733	32164789	NF1 is caused by a germline mutation in the NF1 tumor suppressor gene, which encodes neurofibromin, a GTPase-activating protein that functions as a negative regulator RAS.	('tumor', 'Disease', (48, 53))	('neurofibromin', 'Gene', (85, 98))	('NF1', 'Gene', (44, 47))	('germline mutation', 'Var', (19, 36))	('NF1', 'Gene', '4763', (44, 47))	('NF1', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('neurofibromin', 'Gene', '4763', (85, 98))	('caused by', 'Reg', (7, 16))	('NF1', 'Gene', '4763', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
241748	32164789	Five separate KIAA1549-BRAF exon-exon junctions have been described including 16;9, 15;9, 16;11, 18;10, and 19;9 in order of prevalence, all resulting in the loss of BRAF's regulatory domain.	('al', 'Chemical', 'MESH:D000535', (137, 139))	('BRAF', 'Gene', (166, 170))	('BRAF', 'Gene', '673', (23, 27))	('16', 'Var', (90, 92))	('BRAF', 'Gene', (23, 27))	('KIAA1549-BRAF', 'Disease', (14, 27))	('KIAA1549-BRAF', 'Disease', '-', (14, 27))	('BRAF', 'Gene', '673', (166, 170))	('loss', 'NegReg', (158, 162))	('al', 'Chemical', 'MESH:D000535', (129, 131))
241749	32164789	Subtle clinical differences between fusion variants have been noted but whether their underlying biology differs, and if additional roles of KIAA1549 exist, remain unknown.	('al', 'Chemical', 'MESH:D000535', (13, 15))	('KIAA1549', 'Gene', '57670', (141, 149))	('KIAA1549', 'Gene', (141, 149))	('variants', 'Var', (43, 51))	('al', 'Chemical', 'MESH:D000535', (129, 131))
241757	32164789	In addition to KIAA1549-BRAF, BRAF rearrangements involving other fusion partners including RNF130, SRGAP, FAM131B, CLCN6, GNAI1, MKRN1, GIT2, and FXR1 among others have also been documented.	('KIAA1549-BRAF', 'Disease', '-', (15, 28))	('CLCN6', 'Gene', (116, 121))	('BRAF', 'Gene', (24, 28))	('FAM131B', 'Gene', (107, 114))	('BRAF', 'Gene', '673', (24, 28))	('KIAA1549-BRAF', 'Disease', (15, 28))	('FAM131B', 'Gene', '9715', (107, 114))	('RNF130', 'Gene', '55819', (92, 98))	('SRGAP', 'Gene', (100, 105))	('GIT2', 'Gene', (137, 141))	('GNAI1', 'Gene', (123, 128))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('GIT2', 'Gene', '9815', (137, 141))	('FXR1', 'Gene', '8087', (147, 151))	('GNAI1', 'Gene', '2770', (123, 128))	('CLCN6', 'Gene', '1185', (116, 121))	('FXR1', 'Gene', (147, 151))	('RNF130', 'Gene', (92, 98))	('rearrangements', 'Var', (35, 49))	('MKRN1', 'Gene', (130, 135))	('al', 'Chemical', 'MESH:D000535', (170, 172))	('MKRN1', 'Gene', '23608', (130, 135))
241758	32164789	As with KIAA1549-BRAF, these fusions result in the removal of BRAF's N-regulatory domain and result in constitutive up-regulation of the RAS/MAPK pathway.	('removal', 'NegReg', (51, 58))	('KIAA1549-BRAF', 'Disease', '-', (8, 21))	('al', 'Chemical', 'MESH:D000535', (56, 58))	('fusions', 'Var', (29, 36))	('BRAF', 'Gene', '673', (17, 21))	('N-regulatory domain', 'MPA', (69, 88))	('BRAF', 'Gene', (17, 21))	('up-regulation', 'PosReg', (116, 129))	('RAS/MAPK pathway', 'Pathway', (137, 153))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('KIAA1549-BRAF', 'Disease', (8, 21))
241763	32164789	Mutations in BRAF, primarily in which a valine is replaced with a glutamic acid at position 600 (p.V600E), act as a phosphomimetic within the RAS/MAPK pathway, rendering it constitutively active.	('p.V600E', 'Var', (97, 104))	('RAS/MAPK pathway', 'Pathway', (142, 158))	('BRAF', 'Gene', '673', (13, 17))	('valine is replaced with a glutamic acid at position 600', 'Mutation', 'rs113488022', (40, 95))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('p.V600E', 'Mutation', 'rs113488022', (97, 104))
241764	32164789	In pLGG, the prevalence of the BRAF p.V600E mutation varies notably depending on the histology and location of the tumor (Fig.	('al', 'Chemical', 'MESH:D000535', (17, 19))	('p.V600E', 'Mutation', 'rs113488022', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('p.V600E', 'Var', (36, 43))	('BRAF', 'Gene', '673', (31, 35))	('pLGG', 'Chemical', '-', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('BRAF', 'Gene', (31, 35))
241765	32164789	Pleomorphic xanthoastrocytoma (40-80%), diffuse astrocytoma (30-40%) and ganglioglioma (25-45%) frequently harbor BRAF p.V600E, while in pilocytic astrocytoma (5-10%) or glioneuronal tumors (5%), BRAF p.V600E is less common.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('astrocytoma', 'Phenotype', 'HP:0009592', (147, 158))	('astrocytoma', 'Disease', 'MESH:D001254', (48, 59))	('astrocytoma', 'Disease', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('neuronal tumors', 'Phenotype', 'HP:0025170', (174, 189))	('BRAF', 'Gene', '673', (196, 200))	('astrocytoma', 'Phenotype', 'HP:0009592', (18, 29))	('BRAF', 'Gene', (196, 200))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (170, 189))	('p.V600E', 'Mutation', 'rs113488022', (201, 208))	('astrocytoma', 'Disease', 'MESH:D001254', (147, 158))	('glioma', 'Disease', (80, 86))	('astrocytoma', 'Disease', (147, 158))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (170, 189))	('glioneuronal tumors', 'Disease', (170, 189))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (137, 158))	('p.V600E', 'Mutation', 'rs113488022', (119, 126))	('pilocytic astrocytoma', 'Disease', (137, 158))	('astrocytoma', 'Disease', 'MESH:D001254', (18, 29))	('astrocytoma', 'Disease', (18, 29))	('p.V600E', 'Var', (119, 126))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
241766	32164789	Supratentorial lesions are also more likely to harbor BRAF p.V600E as compared to cerebellar lesions, while the inverse is true for KIAA1549-BRAF (Fig.	('BRAF', 'Gene', (141, 145))	('al', 'Chemical', 'MESH:D000535', (27, 29))	('KIAA1549-BRAF', 'Disease', '-', (132, 145))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('Supratentorial lesions', 'Disease', (0, 22))	('p.V600E', 'Mutation', 'rs113488022', (59, 66))	('Supratentorial lesions', 'Disease', 'MESH:D015173', (0, 22))	('al', 'Chemical', 'MESH:D000535', (12, 14))	('KIAA1549-BRAF', 'Disease', (132, 145))	('p.V600E', 'Var', (59, 66))	('BRAF', 'Gene', '673', (141, 145))
241767	32164789	Importantly, despite these enrichments, BRAF p.V600E is neither histologically nor spatially restricted.	('BRAF', 'Gene', '673', (40, 44))	('BRAF', 'Gene', (40, 44))	('al', 'Chemical', 'MESH:D000535', (88, 90))	('p.V600E', 'Mutation', 'rs113488022', (45, 52))	('p.V600E', 'Var', (45, 52))	('al', 'Chemical', 'MESH:D000535', (74, 76))
241768	32164789	In addition to p.V600E, rare cases of BRAF p.V600D and BRAF p.V504_R506dup have been described in desmoplastic infantile astrocytomas/gliomas and pilocytic astrocytoma, respectively.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (146, 167))	('p.V600D', 'Mutation', 'rs121913377', (43, 50))	('p.V600D', 'Var', (43, 50))	('p.V600E', 'Mutation', 'rs113488022', (15, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (121, 132))	('desmoplastic infantile astrocytomas/gliomas', 'Disease', 'MESH:D005910', (98, 141))	('p.V504_R506dup', 'Mutation', 'p.504,506dup_R', (60, 74))	('desmoplastic infantile astrocytomas/gliomas', 'Disease', (98, 141))	('BRAF', 'Gene', '673', (38, 42))	('p.V504_R506dup', 'Var', (60, 74))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (55, 59))	('pilocytic astrocytoma', 'Disease', (146, 167))	('described', 'Reg', (85, 94))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('BRAF', 'Gene', (55, 59))
241769	32164789	As a group, pLGGs with BRAF p.V600E have worse OS and PFS compared to other pLGG.	('PFS', 'CPA', (54, 57))	('pLGG', 'Chemical', '-', (76, 80))	('BRAF', 'Gene', '673', (23, 27))	('pLGG', 'Chemical', '-', (12, 16))	('BRAF', 'Gene', (23, 27))	('p.V600E', 'Mutation', 'rs113488022', (28, 35))	('p.V600E', 'Var', (28, 35))	('OS', 'Chemical', '-', (47, 49))
241770	32164789	Further, BRAF p.V600E pLGG, especially in the context of co-occurring CDKN2A deletions (discussed further below), are significantly more likely to transform into HGG; an event which may occur 10-20 years after the initial diagnosis.	('al', 'Chemical', 'MESH:D000535', (34, 36))	('CDKN2A', 'Gene', '1029', (70, 76))	('HGG', 'Disease', (162, 165))	('al', 'Chemical', 'MESH:D000535', (219, 221))	('BRAF', 'Gene', (9, 13))	('pLGG', 'Chemical', '-', (22, 26))	('transform', 'Reg', (147, 156))	('p.V600E', 'Mutation', 'rs113488022', (14, 21))	('CDKN2A', 'Gene', (70, 76))	('p.V600E pLGG', 'Var', (14, 26))	('BRAF', 'Gene', '673', (9, 13))
241773	32164789	The increased likelihood of malignant behavior in pleomorphic xanthoastrocytoma and in BRAF p.V600E mutated tumors with CDKN2A deletion has led to a debate regarding the prognostic significance of BRAF p.V600E alone.	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('deletion', 'Var', (127, 135))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))	('increased', 'PosReg', (4, 13))	('mutated', 'Var', (100, 107))	('p.V600E', 'Mutation', 'rs113488022', (92, 99))	('CDKN2A', 'Gene', (120, 126))	('p.V600E', 'Mutation', 'rs113488022', (202, 209))	('al', 'Chemical', 'MESH:D000535', (29, 31))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (50, 79))	('p.V600E mutated', 'Var', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRAF', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (197, 201))	('CDKN2A', 'Gene', '1029', (120, 126))	('tumors', 'Disease', (108, 114))	('malignant behavior', 'CPA', (28, 46))	('al', 'Chemical', 'MESH:D000535', (210, 212))	('pleomorphic xanthoastrocytoma', 'Disease', (50, 79))	('tumors', 'Disease', 'MESH:D009369', (108, 114))
241775	32164789	While FGFR1 mutations and/or fusions are only present in 3% of adult GBM, it is the second most commonly altered gene in pLGG.	('GBM', 'Disease', (69, 72))	('mutations', 'Var', (12, 21))	('GBM', 'Disease', 'MESH:D005909', (69, 72))	('FGFR1', 'Gene', (6, 11))	('FGFR1', 'Gene', '2260', (6, 11))	('al', 'Chemical', 'MESH:D000535', (105, 107))	('pLGG', 'Chemical', '-', (121, 125))
241776	32164789	FGFR1 alterations in pLGG arise via three mechanisms: FGFR1 mutations, FGFR1-TACC1 fusions and FGFR1-TKD duplications.	('FGFR1', 'Gene', (71, 76))	('TACC1', 'Gene', (77, 82))	('FGFR1', 'Gene', (95, 100))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('pLGG', 'Chemical', '-', (21, 25))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', '2260', (71, 76))	('FGFR1', 'Gene', '2260', (95, 100))	('TACC1', 'Gene', '6867', (77, 82))	('mutations', 'Var', (60, 69))	('fusions', 'Var', (83, 90))
241777	32164789	FGFR1 mutations primarily consist of p.N546K and p.K656E and occur in 5-10% of patients.	('p.K656E', 'Var', (49, 56))	('p.K656E', 'Mutation', 'rs869320694', (49, 56))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('patients', 'Species', '9606', (79, 87))	('p.N546K', 'Var', (37, 44))	('p.N546K', 'Mutation', 'rs779707422', (37, 44))
241778	32164789	As with BRAF alterations, these are histologically and spatially enriched, most frequently arising in dysembryoplastic neuroepithelial tumors, other glioneuronal tumors, and in midline brain structures (Fig.	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (102, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (149, 168))	('al', 'Chemical', 'MESH:D000535', (159, 161))	('glioneuronal tumors', 'Disease', (149, 168))	('arising', 'Reg', (91, 98))	('midline brain', 'Disease', (177, 190))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (8, 12))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (119, 141))	('midline brain', 'Disease', 'MESH:D001927', (177, 190))	('al', 'Chemical', 'MESH:D000535', (46, 48))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('al', 'Chemical', 'MESH:D000535', (13, 15))	('dysembryoplastic neuroepithelial tumors', 'Disease', (102, 141))	('al', 'Chemical', 'MESH:D000535', (132, 134))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (119, 140))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('al', 'Chemical', 'MESH:D000535', (60, 62))	('neuronal tumors', 'Phenotype', 'HP:0025170', (153, 168))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (149, 168))	('alterations', 'Var', (13, 24))
241779	32164789	In these tumor subtypes, FGFR1 mutations occur in up to 20% of patients, and in rare cases may be germline events.	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('occur', 'Reg', (41, 46))	('tumor', 'Disease', (9, 14))	('FGFR1', 'Gene', (25, 30))	('patients', 'Species', '9606', (63, 71))	('FGFR1', 'Gene', '2260', (25, 30))
241780	32164789	However, FGFR1 mutations have also been reported in pilocytic astrocytoma, oligodendroglioma, and other histologies, and therefore are not histologically restricted.	('FGFR1', 'Gene', '2260', (9, 14))	('astrocytoma', 'Phenotype', 'HP:0009592', (62, 73))	('mutations', 'Var', (15, 24))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('al', 'Chemical', 'MESH:D000535', (149, 151))	('pilocytic astrocytoma', 'Disease', (52, 73))	('oligodendroglioma', 'Disease', (75, 92))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('reported', 'Reg', (40, 48))	('FGFR1', 'Gene', (9, 14))	('oligodendroglioma', 'Disease', 'MESH:D009837', (75, 92))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (52, 73))
241781	32164789	FGFR1 TKD-duplication and FGFR1-TACC1 fusions have each been described in 2-3% of tumors,.	('tumors', 'Disease', (82, 88))	('TACC1', 'Gene', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('FGFR1', 'Gene', (0, 5))	('TKD-duplication', 'Var', (6, 21))	('FGFR1', 'Gene', '2260', (0, 5))	('TACC1', 'Gene', '6867', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('described', 'Reg', (61, 70))	('fusions', 'Var', (38, 45))
241782	32164789	As with FGFR1 mutations, FGFR1 TKD-duplication is more common in dysembryoplastic neuroepithelial tumors and other glioneuronal tumors, while FGFR1-TACC1 is more common in pilocytic astrocytoma.	('common', 'Reg', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (82, 104))	('FGFR1', 'Gene', (25, 30))	('FGFR1', 'Gene', (142, 147))	('neuronal tumors', 'Phenotype', 'HP:0025170', (119, 134))	('FGFR1', 'Gene', (8, 13))	('TACC1', 'Gene', '6867', (148, 153))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (82, 103))	('TKD-duplication', 'Var', (31, 46))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (115, 134))	('dysembryoplastic neuroepithelial tumors', 'Disease', (65, 104))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (172, 193))	('astrocytoma', 'Phenotype', 'HP:0009592', (182, 193))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('pilocytic astrocytoma', 'Disease', (172, 193))	('glioneuronal tumors', 'Disease', (115, 134))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR1', 'Gene', '2260', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('FGFR1', 'Gene', '2260', (8, 13))	('dysembryoplastic neuroepithelial tumors', 'Disease', 'MESH:D018302', (65, 104))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('TACC1', 'Gene', (148, 153))
241784	32164789	All of these alterations result in FGFR1 autophosphorylation, leading to up-regulation of the RAS/MAPK pathway.	('al', 'Chemical', 'MESH:D000535', (13, 15))	('up-regulation', 'PosReg', (73, 86))	('alterations', 'Var', (13, 24))	('RAS/MAPK pathway', 'Pathway', (94, 110))	('result', 'Reg', (25, 31))	('autophosphorylation', 'MPA', (41, 60))	('FGFR1', 'Gene', (35, 40))	('FGFR1', 'Gene', '2260', (35, 40))
241786	32164789	Despite being the second most common alteration in pLGG, the clinical manifestations of FGFR1 alterations are still not well described.	('FGFR1', 'Gene', (88, 93))	('alterations', 'Var', (94, 105))	('FGFR1', 'Gene', '2260', (88, 93))	('al', 'Chemical', 'MESH:D000535', (94, 96))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('al', 'Chemical', 'MESH:D000535', (37, 39))	('pLGG', 'Chemical', '-', (51, 55))
241787	32164789	Becker et al., in their description of FGFR1 mutations in pilocytic astrocytoma, noted that mutated tumors had a worse prognosis than their wild-type counterparts.	('FGFR1', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (45, 54))	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('FGFR1', 'Gene', '2260', (39, 44))	('al', 'Chemical', 'MESH:D000535', (10, 12))	('pilocytic astrocytoma', 'Disease', (58, 79))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (58, 79))
241788	32164789	Whether this worsened outcome is due to the alteration itself or the propensity for FGFR1 mutated tumors to arise in the midline is unknown.	('FGFR1', 'Gene', (84, 89))	('FGFR1', 'Gene', '2260', (84, 89))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mutated', 'Var', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('al', 'Chemical', 'MESH:D000535', (44, 46))
241789	32164789	Importantly, FGFR1 mutations often contain additional alterations, most frequently a second event in FGFR1 resulting in an FGFR1 "dual hit".	('al', 'Chemical', 'MESH:D000535', (51, 53))	('FGFR1', 'Gene', (13, 18))	('mutations', 'Var', (19, 28))	('FGFR1', 'Gene', (123, 128))	('al', 'Chemical', 'MESH:D000535', (132, 134))	('FGFR1', 'Gene', '2260', (13, 18))	('al', 'Chemical', 'MESH:D000535', (54, 56))	('FGFR1', 'Gene', '2260', (123, 128))	('FGFR1', 'Gene', (101, 106))	('FGFR1', 'Gene', '2260', (101, 106))
241790	32164789	In addition, co-occurring alterations in BRAF, KRAS, NF1, PTPN11 and H3F3A have also been reported.	('PTPN11', 'Gene', '5781', (58, 64))	('NF1', 'Gene', (53, 56))	('H3F3A', 'Gene', '3020', (69, 74))	('al', 'Chemical', 'MESH:D000535', (80, 82))	('PTPN11', 'Gene', (58, 64))	('NF1', 'Gene', '4763', (53, 56))	('alterations', 'Var', (26, 37))	('BRAF', 'Gene', '673', (41, 45))	('KRAS', 'Gene', (47, 51))	('H3F3A', 'Gene', (69, 74))	('BRAF', 'Gene', (41, 45))	('KRAS', 'Gene', '3845', (47, 51))	('al', 'Chemical', 'MESH:D000535', (26, 28))
241792	32164789	However, the propensity for FGFR1 mutations (but not TKD duplication or FGFR1-TACC1) to co-occur with additional alterations is interesting and may provide insight into the underlying pathogenesis of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('TACC1', 'Gene', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('al', 'Chemical', 'MESH:D000535', (110, 112))	('FGFR1', 'Gene', (28, 33))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('TACC1', 'Gene', '6867', (78, 83))	('al', 'Chemical', 'MESH:D000535', (113, 115))	('FGFR1', 'Gene', '2260', (28, 33))	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', '2260', (72, 77))	('mutations', 'Var', (34, 43))
241793	32164789	Fusions involving CRAF (RAF1), a human homolog of the v-raf gene implicated in cell proliferation and survival, are infrequently identified in pLGG, most commonly in pilocytic astrocytoma.	('Fusions', 'Var', (0, 7))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (166, 187))	('CRAF', 'Gene', (18, 22))	('CRAF', 'Gene', '5894', (18, 22))	('al', 'Chemical', 'MESH:D000535', (108, 110))	('pLGG', 'Chemical', '-', (143, 147))	('RAF1', 'Gene', (24, 28))	('RAF1', 'Gene', '5894', (24, 28))	('human', 'Species', '9606', (33, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (176, 187))	('pilocytic astrocytoma', 'Disease', (166, 187))	('identified', 'Reg', (129, 139))
241795	32164789	As with non-canonical BRAF fusions, CRAF fusions have been shown to up-regulate the RAS/MAPK pathway.	('BRAF', 'Gene', '673', (22, 26))	('RAS/MAPK pathway', 'Pathway', (84, 100))	('BRAF', 'Gene', (22, 26))	('CRAF', 'Gene', (36, 40))	('CRAF', 'Gene', '5894', (36, 40))	('fusions', 'Var', (41, 48))	('up-regulate', 'PosReg', (68, 79))	('al', 'Chemical', 'MESH:D000535', (19, 21))
241798	32164789	NTRK fusions have been identified in various histological subtypes of pLGG, albeit at very low frequencies.	('pLGG', 'Chemical', '-', (70, 74))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (1, 4))	('al', 'Chemical', 'MESH:D000535', (55, 57))	('fusions', 'Var', (5, 12))	('al', 'Chemical', 'MESH:D000535', (76, 78))	('pLGG', 'Disease', (70, 74))	('identified', 'Reg', (23, 33))
241800	32164789	All these fusions are predicted to drive tumorigenesis via aberrant dimerization of the NTRK kinase domain, resulting in constitutive downstream activation that, at least in part, impacts both the RAS/MAPK and PI3K/AKT/mTOR pathways.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('activation', 'PosReg', (145, 155))	('mTOR', 'Gene', (219, 223))	('impacts', 'Reg', (180, 187))	('tumor', 'Disease', (41, 46))	('AKT', 'Gene', '207', (215, 218))	('TRK', 'Gene', (89, 92))	('TRK', 'Gene', '4914', (89, 92))	('dimerization', 'MPA', (68, 80))	('AKT', 'Gene', (215, 218))	('drive', 'PosReg', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mTOR', 'Gene', '2475', (219, 223))	('fusions', 'Var', (10, 17))
241802	32164789	A small subset of non-BRAF mutated pLGG harbor mutations in KRAS, an upstream molecule in the RAS/MAPK pathway (Fig.	('pLGG', 'Chemical', '-', (35, 39))	('al', 'Chemical', 'MESH:D000535', (4, 6))	('BRAF', 'Gene', '673', (22, 26))	('mutations', 'Var', (47, 56))	('pLGG', 'Gene', (35, 39))	('BRAF', 'Gene', (22, 26))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (60, 64))
241804	32164789	Most frequently, these are p.G12D or p.Q61H/K, although one report noted both novel and dual KRAS mutations within 2 patients.	('KRAS', 'Gene', (93, 97))	('al', 'Chemical', 'MESH:D000535', (90, 92))	('p.G12D', 'Mutation', 'rs121913529', (27, 33))	('p.Q61H', 'Var', (37, 43))	('p.Q61H', 'SUBSTITUTION', 'None', (37, 43))	('KRAS', 'Gene', '3845', (93, 97))	('patients', 'Species', '9606', (117, 125))	('p.G12D', 'Var', (27, 33))	('al', 'Chemical', 'MESH:D000535', (47, 49))
241805	32164789	Importantly, KRAS mutations are also seen in high grade gliomas and therefore cannot be used as a diagnostic marker for pLGG.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('pLGG', 'Chemical', '-', (120, 124))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('seen', 'Reg', (37, 41))	('al', 'Chemical', 'MESH:D000535', (32, 34))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
241806	32164789	Given the success of inhibiting downstream effectors of KRAS mutations in other cancer types, identifying these mutations in pLGG may offer access to targeted treatment approaches.	('pLGG', 'Chemical', '-', (125, 129))	('KRAS', 'Gene', (56, 60))	('pLGG', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('KRAS', 'Gene', '3845', (56, 60))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
241808	32164789	With regards to pLGG, specifically pilocytic astrocytoma, PTPN11 alterations have been reported in approximately 2% of cases.	('alterations', 'Var', (65, 76))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (35, 56))	('PTPN11', 'Gene', '5781', (58, 64))	('al', 'Chemical', 'MESH:D000535', (65, 67))	('astrocytoma', 'Phenotype', 'HP:0009592', (45, 56))	('PTPN11', 'Gene', (58, 64))	('pLGG', 'Chemical', '-', (16, 20))	('pilocytic astrocytoma', 'Disease', (35, 56))
241810	32164789	In the original report defining the mutation, the authors noted that PTPN11 over-expression alone did not significantly activate the RAS/MAPK pathway, but did when in the presence of FGFR1 mutations.	('al', 'Chemical', 'MESH:D000535', (13, 15))	('FGFR1', 'Gene', '2260', (183, 188))	('over-expression', 'PosReg', (76, 91))	('PTPN11', 'Gene', '5781', (69, 75))	('PTPN11', 'Gene', (69, 75))	('RAS/MAPK pathway', 'Pathway', (133, 149))	('al', 'Chemical', 'MESH:D000535', (92, 94))	('mutations', 'Var', (189, 198))	('FGFR1', 'Gene', (183, 188))
241813	32164789	This suggests that mTOR inhibitors may be more effective than RAS/MAPK inhibitors in pLGG harboring these alterations.	('al', 'Chemical', 'MESH:D000535', (106, 108))	('pLGG', 'Disease', (85, 89))	('mTOR', 'Gene', '2475', (19, 23))	('mTOR', 'Gene', (19, 23))	('pLGG', 'Chemical', '-', (85, 89))	('alterations', 'Var', (106, 117))
241814	32164789	The anaplastic lymphoma kinase (ALK) gene is thought to play a key role in the development and function of the nervous system and chromosomal alterations and gain of function mutations in it have been reported in a plethora of pediatric cancers.	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('ALK', 'Gene', (32, 35))	('anaplastic lymphoma kinase', 'Gene', '238', (4, 30))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('plethora', 'Phenotype', 'HP:0001050', (215, 223))	('al', 'Chemical', 'MESH:D000535', (142, 144))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('ALK', 'Gene', '238', (32, 35))	('gain of function', 'PosReg', (158, 174))	('anaplastic lymphoma kinase', 'Gene', (4, 30))	('mutations', 'Var', (175, 184))	('pediatric cancers', 'Disease', (227, 244))	('pediatric cancers', 'Disease', 'MESH:D009369', (227, 244))	('al', 'Chemical', 'MESH:D000535', (139, 141))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (4, 23))
241815	32164789	These alterations are most commonly fusion events that result in ectopic expression of the ALK fusion protein.	('alterations', 'Var', (6, 17))	('ALK', 'Gene', (91, 94))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('ALK', 'Gene', '238', (91, 94))	('ectopic expression', 'MPA', (65, 83))	('result', 'Reg', (55, 61))
241817	32164789	Despite the frequency of ALK alterations in pediatric cancer, reports of its presence in glioma are rare and often exist in isolated case reports.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', (54, 60))	('al', 'Chemical', 'MESH:D000535', (29, 31))	('ALK', 'Gene', (25, 28))	('glioma', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ALK', 'Gene', '238', (25, 28))
241819	32164789	Recently, ALK alterations were shown to form a unique clinical subgroup of infantile glioma that require would likely benefit from a refined treatment approach.	('alterations', 'Var', (14, 25))	('infantile glioma', 'Disease', 'MESH:D005910', (75, 91))	('ALK', 'Gene', '238', (10, 13))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('ALK', 'Gene', (10, 13))	('infantile glioma', 'Disease', (75, 91))	('al', 'Chemical', 'MESH:D000535', (60, 62))
241821	32164789	In pLGG, GOPC-ROS1 is the result of an intrachromosomal deletion that results in a constitutively active kinase fusion product sufficient to promote neoplastic transformation both in vitro and in vivo.	('deletion', 'Var', (56, 64))	('constitutively active kinase fusion product', 'MPA', (83, 126))	('neoplastic transformation', 'CPA', (149, 174))	('GOPC', 'Gene', '57120', (9, 13))	('ROS1', 'Gene', (14, 18))	('GOPC', 'Gene', (9, 13))	('ROS1', 'Gene', '6098', (14, 18))	('al', 'Chemical', 'MESH:D000535', (53, 55))	('promote', 'PosReg', (141, 148))	('pLGG', 'Chemical', '-', (3, 7))	('results in', 'Reg', (70, 80))
241824	32164789	Alterations including p.Q56P and small in-frame deletions in MAP2K1 were frequent in a small cohort of multinodular and vacuolating neuronal tumors (MVNT).	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('p.Q56P', 'Mutation', 'rs1057519729', (22, 28))	('al', 'Chemical', 'MESH:D000535', (35, 37))	('MAP2K1', 'Gene', '5604', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('neuronal tumors', 'Phenotype', 'HP:0025170', (132, 147))	('al', 'Chemical', 'MESH:D000535', (138, 140))	('MAP2K1', 'Gene', (61, 67))	('p.Q56P', 'Var', (22, 28))	('neuronal tumors', 'Disease', 'MESH:D009410', (132, 147))	('al', 'Chemical', 'MESH:D000535', (89, 91))	('neuronal tumors', 'Disease', (132, 147))	('frequent', 'Reg', (73, 81))
241827	32164789	These alterations in other malignancies have shown up-regulation of the RAS/MAPK pathway and may have a similar mechanism in MVNT.	('alterations', 'Var', (6, 17))	('up-regulation', 'PosReg', (51, 64))	('RAS/MAPK pathway', 'Pathway', (72, 88))	('al', 'Chemical', 'MESH:D000535', (28, 30))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('malignancies', 'Disease', 'MESH:D009369', (27, 39))	('malignancies', 'Disease', (27, 39))	('MVNT', 'Disease', (125, 129))
241828	32164789	Recurrent alterations involving FGFR2/3 (rather than the more frequent FGFR1) have been identified in a recently defined tumor type, PLNTY, which carries a good prognosis.	('FGFR1', 'Gene', (71, 76))	('alterations', 'Var', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('al', 'Chemical', 'MESH:D000535', (10, 12))	('FGFR1', 'Gene', '2260', (71, 76))	('tumor', 'Disease', (121, 126))	('FGFR2', 'Gene', (32, 37))	('identified', 'Reg', (88, 98))	('FGFR2', 'Gene', '2263', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
241832	32164789	PDGFRalpha mutations have been reported in low grade glioneuronal tumors of the septum pellucidum, despite more typically being associated with HGG in the context of other mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (11, 20))	('reported', 'Reg', (31, 39))	('al', 'Chemical', 'MESH:D000535', (117, 119))	('PDGFRalpha', 'Gene', (0, 10))	('al', 'Chemical', 'MESH:D000535', (63, 65))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (53, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('neuronal tumors', 'Phenotype', 'HP:0025170', (57, 72))	('associated', 'Reg', (128, 138))	('glioneuronal tumors', 'Disease', (53, 72))	('al', 'Chemical', 'MESH:D000535', (5, 7))	('HGG', 'Disease', (144, 147))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (53, 72))	('PDGFRalpha', 'Gene', '5156', (0, 10))
241838	32164789	It plays an important role in the control of proliferation and differentiation of hematopoietic and other progenitor cells and has well described proto-oncogenic functions in both human leukemia and solid tumors where it is thought that super-enhancers to c-MYB, as a consequence of chromosomal translocation, cause overexpression of c-MYB.	('chromosomal translocation', 'Var', (283, 308))	('al', 'Chemical', 'MESH:D000535', (292, 294))	('c-MYB', 'Gene', (256, 261))	('solid tumors', 'Disease', 'MESH:D009369', (199, 211))	('solid tumors', 'Disease', (199, 211))	('super-enhancers', 'PosReg', (237, 252))	('human', 'Species', '9606', (180, 185))	('c-MYB', 'Gene', '4602', (256, 261))	('leukemia', 'Phenotype', 'HP:0001909', (186, 194))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('leukemia', 'Disease', 'MESH:D007938', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('cause', 'Reg', (310, 315))	('leukemia', 'Disease', (186, 194))	('c-MYB', 'Gene', (334, 339))	('c-MYB', 'Gene', '4602', (334, 339))	('overexpression', 'PosReg', (316, 330))
241840	32164789	who identified MYB amplification in 2 of 14 diffuse astrocytomas and a focal deletion of the terminal region of MYB in 1 of 2 angiocentric gliomas.	('MYB', 'Gene', '4602', (15, 18))	('amplification', 'Var', (19, 32))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (126, 146))	('angiocentric gliomas', 'Disease', (126, 146))	('diffuse', 'Disease', (44, 51))	('MYB', 'Gene', (15, 18))	('deletion', 'Var', (77, 85))	('al', 'Chemical', 'MESH:D000535', (74, 76))	('astrocytomas', 'Disease', 'MESH:D001254', (52, 64))	('MYB', 'Gene', '4602', (112, 115))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('MYB', 'Gene', (112, 115))	('al', 'Chemical', 'MESH:D000535', (99, 101))	('astrocytomas', 'Disease', (52, 64))
241842	32164789	This finding was later confirmed, when 22% (8/36) of diffuse cerebral gliomas, including diffuse astrocytoma and angiocentric glioma, were shown to have a MYB 3' truncating fusion or, less commonly, amplification resulting in elevated expression at the protein level.	('angiocentric glioma', 'Disease', (113, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('MYB', 'Gene', (155, 158))	('expression at the', 'MPA', (235, 252))	('cerebral gliomas', 'Disease', 'MESH:C564230', (61, 77))	('angiocentric glioma', 'Disease', 'MESH:D005910', (113, 132))	('astrocytoma', 'Disease', 'MESH:D001254', (97, 108))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('astrocytoma', 'Disease', (97, 108))	('cerebral gliomas', 'Disease', (61, 77))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('elevated', 'PosReg', (226, 234))	('amplification', 'Var', (199, 212))	('MYB', 'Gene', '4602', (155, 158))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
241843	32164789	published that 10% (16/172) of their pLGG cohort contained MYB alterations, most commonly as MYB-QKI fusions, including 19/19 (discovery and validation cohorts) angiocentric gliomas.	('QKI', 'Gene', '9444', (97, 100))	('MYB', 'Gene', (59, 62))	('MYB', 'Gene', '4602', (93, 96))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('alterations', 'Var', (63, 74))	('angiocentric gliomas', 'Disease', 'MESH:D005910', (161, 181))	('MYB', 'Gene', (93, 96))	('angiocentric gliomas', 'Disease', (161, 181))	('pLGG', 'Chemical', '-', (37, 41))	('al', 'Chemical', 'MESH:D000535', (63, 65))	('al', 'Chemical', 'MESH:D000535', (142, 144))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('QKI', 'Gene', (97, 100))	('MYB', 'Gene', '4602', (59, 62))
241845	32164789	Work investigating the genetics of uncommon low-grade neuroepithelial tumors showed that 87% and 41% of angiocentric glioma and diffuse astrocytoma, respectively, harbored MYB alterations.	('astrocytoma', 'Phenotype', 'HP:0009592', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (54, 75))	('al', 'Chemical', 'MESH:D000535', (176, 178))	('neuroepithelial tumors', 'Disease', (54, 76))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (54, 76))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('alterations', 'Var', (176, 187))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (54, 76))	('astrocytoma', 'Disease', 'MESH:D001254', (136, 147))	('angiocentric glioma', 'Disease', (104, 123))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('astrocytoma', 'Disease', (136, 147))	('MYB', 'Gene', '4602', (172, 175))	('harbored', 'Reg', (163, 171))	('angiocentric glioma', 'Disease', 'MESH:D005910', (104, 123))	('MYB', 'Gene', (172, 175))
241851	32164789	in 28% (5/18) of diffuse astrocytomas, these MYBL1-driven tumors showed a partial duplication with truncation of its C-terminal regulatory.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MYBL1', 'Gene', '4603', (45, 50))	('tumors', 'Disease', (58, 64))	('truncation', 'MPA', (99, 109))	('astrocytomas', 'Disease', 'MESH:D001254', (25, 37))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('al', 'Chemical', 'MESH:D000535', (125, 127))	('C-terminal regulatory', 'MPA', (117, 138))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('al', 'Chemical', 'MESH:D000535', (79, 81))	('astrocytomas', 'Disease', (25, 37))	('partial duplication', 'Var', (74, 93))	('MYBL1', 'Gene', (45, 50))
241854	32164789	More recent reports of MYBL1 alterations in pLGG suggest MYBL1 alterations may be even rarer, being found in 2/17 (12%), 7/50 (14%), and 1/17 (6%) diffuse astrocytomas.	('alterations', 'Var', (63, 74))	('MYBL1', 'Gene', (23, 28))	('MYBL1', 'Gene', '4603', (23, 28))	('al', 'Chemical', 'MESH:D000535', (63, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (155, 167))	('MYBL1', 'Gene', (57, 62))	('pLGG', 'Chemical', '-', (44, 48))	('astrocytoma', 'Phenotype', 'HP:0009592', (155, 166))	('al', 'Chemical', 'MESH:D000535', (29, 31))	('MYBL1', 'Gene', '4603', (57, 62))	('diffuse', 'Disease', (147, 154))	('astrocytomas', 'Disease', (155, 167))	('found', 'Reg', (100, 105))
241855	32164789	No other histological diagnoses have been reported to harbor MYBL1 alterations.	('MYBL1', 'Gene', (61, 66))	('MYBL1', 'Gene', '4603', (61, 66))	('alterations', 'Var', (67, 78))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('al', 'Chemical', 'MESH:D000535', (19, 21))
241856	32164789	MYB and MYBL1 alterations were originally described in diffuse gliomas of childhood.	('alterations', 'Var', (14, 25))	('MYBL1', 'Gene', (8, 13))	('gliomas', 'Disease', (63, 70))	('MYB', 'Gene', (0, 3))	('described', 'Reg', (42, 51))	('MYB', 'Gene', '4602', (8, 11))	('child', 'Species', '9606', (74, 79))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('MYB', 'Gene', (8, 11))	('MYBL1', 'Gene', '4603', (8, 13))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('al', 'Chemical', 'MESH:D000535', (37, 39))	('MYB', 'Gene', '4602', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))
241862	32164789	However, this hypothesis merits further investigation as more of these rare cases, in particular those harboring MYBL1 alterations, are reported.	('alterations', 'Var', (119, 130))	('MYBL1', 'Gene', '4603', (113, 118))	('MYBL1', 'Gene', (113, 118))	('al', 'Chemical', 'MESH:D000535', (119, 121))
241864	32164789	Despite their frequency in adults, IDH1 mutations in pediatric glioma are rare, with reports ranging from 0-17% of cases.	('IDH1', 'Gene', (35, 39))	('pediatric glioma', 'Disease', (53, 69))	('IDH1', 'Gene', '3417', (35, 39))	('mutations', 'Var', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('pediatric glioma', 'Disease', 'MESH:D005910', (53, 69))
241865	32164789	As with adult tumors, the IDH1 mutation is usually in the context of either 1p/19q co-deletion or is associated with TP53 and ATRX mutations and as such, likely represent the lower end of the age spectrum of adult-type IDH-mutant glioma.	('IDH', 'Gene', '3417', (219, 222))	('ATRX', 'Gene', (126, 130))	('TP53', 'Gene', (117, 121))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('IDH1', 'Gene', (26, 30))	('adult tumors', 'Disease', 'MESH:C538052', (8, 20))	('ATRX', 'Gene', '546', (126, 130))	('IDH', 'Gene', '3417', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('al', 'Chemical', 'MESH:D000535', (46, 48))	('IDH1', 'Gene', '3417', (26, 30))	('TP53', 'Gene', '7157', (117, 121))	('mutation', 'Var', (31, 39))	('associated', 'Reg', (101, 111))	('glioma', 'Disease', (230, 236))	('IDH', 'Gene', (219, 222))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('IDH', 'Gene', (26, 29))	('adult tumors', 'Disease', (8, 20))
241866	32164789	There is a significant correlation between IDH1 alterations and patient age.	('patient', 'Species', '9606', (64, 71))	('alterations', 'Var', (48, 59))	('al', 'Chemical', 'MESH:D000535', (48, 50))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))
241867	32164789	In one report, IDH1 mutations were identified in 5% of pediatric gliomas which collectively had a median age of 16.	('pediatric gliomas', 'Disease', (55, 72))	('IDH1', 'Gene', (15, 19))	('identified', 'Reg', (35, 45))	('IDH1', 'Gene', '3417', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('pediatric gliomas', 'Disease', 'MESH:D005910', (55, 72))	('mutations', 'Var', (20, 29))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
241868	32164789	Likewise, a report from the Children's Oncology Group noted a 16% incidence of IDH1 mutations, all of which occurred in patients over the age of 14.	('IDH1', 'Gene', '3417', (79, 83))	('Children', 'Species', '9606', (28, 36))	('Oncology', 'Phenotype', 'HP:0002664', (39, 47))	('al', 'Chemical', 'MESH:D000535', (95, 97))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (120, 128))	('IDH1', 'Gene', (79, 83))
241869	32164789	In adults, IDH1 mutations are associated with a better prognosis and response to chemotherapy as compared to IDH1/2 wild-type glioma.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('IDH1', 'Gene', '3417', (11, 15))	('IDH1/2', 'Gene', (109, 115))	('IDH1', 'Gene', (109, 113))	('mutations', 'Var', (16, 25))	('IDH1', 'Gene', '3417', (109, 113))	('glioma', 'Disease', (126, 132))	('IDH1/2', 'Gene', '3417;3418', (109, 115))	('IDH1', 'Gene', (11, 15))
241870	32164789	While the clinical impact of IDH1 mutations in children is far less understood, it is likely that they will not behave in the same indolent way as most other pLGG over the long term.	('IDH1', 'Gene', (29, 33))	('IDH1', 'Gene', '3417', (29, 33))	('pLGG', 'Chemical', '-', (158, 162))	('children', 'Species', '9606', (47, 55))	('al', 'Chemical', 'MESH:D000535', (16, 18))	('mutations', 'Var', (34, 43))
241873	32164789	Mutations in histone variant H3F3A (H3.3) were first described in pediatric high grade glioma, specifically diffuse intrinsic pontine glioma (DIPG), where they are present in approximately 65% of tumors.	('DIPG', 'Chemical', '-', (142, 146))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('glioma', 'Disease', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('al', 'Chemical', 'MESH:D000535', (103, 105))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('H3.3', 'Gene', (36, 40))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('Mutations', 'Var', (0, 9))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Disease', (134, 140))	('H3.3', 'Gene', '3020', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('variant H3F3A', 'CellLine', 'CVCL:7204;0.05362164471108925', (21, 34))
241874	32164789	H3.3 p.K27M is exclusively observed in tumors arising in the midline, including the pons, diencephalon/thalamus and spinal cord.	('H3.3', 'Gene', '3020', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('diencephalon/thalamus', 'Disease', 'OMIM:614924', (90, 111))	('al', 'Chemical', 'MESH:D000535', (120, 122))	('observed', 'Reg', (27, 35))	('p.K27M', 'Var', (5, 11))	('H3.3', 'Gene', (0, 4))	('diencephalon/thalamus', 'Disease', (90, 111))	('p.K27M', 'Mutation', 'p.K27M', (5, 11))	('al', 'Chemical', 'MESH:D000535', (98, 100))	('al', 'Chemical', 'MESH:D000535', (105, 107))	('tumors', 'Disease', (39, 45))
241875	32164789	Although more frequent in HGG, H3.3 p.K27M has been reported in pLGG including pilocytic astrocytoma, ganglioglioma and diffuse astrocytoma.	('H3.3', 'Gene', (31, 35))	('HGG', 'Disease', (26, 29))	('reported', 'Reg', (52, 60))	('pilocytic astrocytoma', 'Disease', (79, 100))	('p.K27M', 'Mutation', 'p.K27M', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (89, 100))	('H3.3', 'Gene', '3020', (31, 35))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))	('pLGG', 'Disease', (64, 68))	('pLGG', 'Chemical', '-', (64, 68))	('p.K27M', 'Var', (36, 42))	('astrocytoma', 'Disease', 'MESH:D001254', (89, 100))	('astrocytoma', 'Disease', (89, 100))	('astrocytoma', 'Disease', 'MESH:D001254', (128, 139))	('glioma', 'Disease', (109, 115))	('astrocytoma', 'Disease', (128, 139))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (79, 100))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
241877	32164789	Interestingly, H3.3 p.K27M has been shown to co-occur with additional hotspot mutations, including BRAF p.V600E, FGFR1 p.N546K or p.K656E, and NF1 mutations.	('p.N546K', 'Mutation', 'rs779707422', (119, 126))	('FGFR1', 'Gene', (113, 118))	('H3.3', 'Gene', (15, 19))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('p.K656E', 'Var', (130, 137))	('NF1', 'Gene', (143, 146))	('FGFR1', 'Gene', '2260', (113, 118))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('p.V600E', 'Mutation', 'rs113488022', (104, 111))	('NF1', 'Gene', '4763', (143, 146))	('H3.3', 'Gene', '3020', (15, 19))	('p.N546K', 'Var', (119, 126))	('p.K27M', 'Mutation', 'p.K27M', (20, 26))	('p.V600E', 'Var', (104, 111))	('p.K27M', 'Var', (20, 26))	('p.K656E', 'Mutation', 'rs869320694', (130, 137))
241878	32164789	Patients with H3.3 p.K27M pLGG have the potential to live longer than patients with H3.3 p.K27M glioma with high grade histologic features.	('patients', 'Species', '9606', (70, 78))	('H3.3', 'Gene', '3020', (14, 18))	('al', 'Chemical', 'MESH:D000535', (47, 49))	('H3.3', 'Gene', (84, 88))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('p.K27M', 'Mutation', 'p.K27M', (89, 95))	('Patients', 'Species', '9606', (0, 8))	('pLGG', 'Chemical', '-', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('p.K27M', 'Var', (19, 25))	('p.K27M', 'Mutation', 'p.K27M', (19, 25))	('H3.3', 'Gene', '3020', (84, 88))	('H3.3', 'Gene', (14, 18))	('glioma', 'Disease', (96, 102))	('pLGG', 'Disease', (26, 30))
241880	32164789	In this regard, despite their comparatively longer survival, these tumors tend to mimic the clinical impact of H3.3 p.K27M in HGG in that they invariably progress and cause death, starkly contrasting the excellent survival of non-H3.3 p.K27M mutant pLGG as described above.	('H3.3', 'Gene', '3020', (230, 234))	('H3.3', 'Gene', (111, 115))	('al', 'Chemical', 'MESH:D000535', (220, 222))	('cause', 'Reg', (167, 172))	('progress', 'PosReg', (154, 162))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('pLGG', 'Chemical', '-', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('H3.3', 'Gene', '3020', (111, 115))	('p.K27M', 'Var', (116, 122))	('p.K27M', 'Mutation', 'p.K27M', (235, 241))	('p.K27M', 'Mutation', 'p.K27M', (116, 122))	('al', 'Chemical', 'MESH:D000535', (57, 59))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('HGG', 'Disease', (126, 129))	('H3.3', 'Gene', (230, 234))	('tumors', 'Disease', (67, 73))	('al', 'Chemical', 'MESH:D000535', (98, 100))
241881	32164789	Homozygous and hemizygous losses involving 9p21 are frequent in adult infiltrating glioma and GBM.	('glioma', 'Disease', (83, 89))	('GBM', 'Disease', (94, 97))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('9p21', 'Gene', (43, 47))	('GBM', 'Disease', 'MESH:D005909', (94, 97))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('losses', 'Var', (26, 32))	('frequent', 'Reg', (52, 60))
241882	32164789	One of the consequences of this deletion is the loss of the tumor suppressor CDKN2A, which endogenously functions as a G1 cell-cycle regulator.	('deletion', 'Var', (32, 40))	('CDKN2A', 'Gene', (77, 83))	('CDKN2A', 'Gene', '1029', (77, 83))	('loss of the tumor', 'Disease', 'MESH:D009369', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('loss of the tumor', 'Disease', (48, 65))
241885	32164789	Likewise, CDKN2A deletion frequently co-occurs with BRAF p.V600E, suggesting that it likely acts as a second molecular hit, promoting escape from cell cycle regulation.	('CDKN2A', 'Gene', '1029', (10, 16))	('escape', 'MPA', (134, 140))	('p.V600E', 'Mutation', 'rs113488022', (57, 64))	('promoting', 'PosReg', (124, 133))	('p.V600E', 'Var', (57, 64))	('deletion', 'Var', (17, 25))	('BRAF', 'Gene', '673', (52, 56))	('CDKN2A', 'Gene', (10, 16))	('BRAF', 'Gene', (52, 56))
241886	32164789	Tumors harboring both BRAF p.V600E and CDKN2A deletion comprise a distinct clinical subtype of pLGG prone to transformation into secondary HGG.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pLGG', 'Disease', (95, 99))	('CDKN2A', 'Gene', (39, 45))	('BRAF', 'Gene', '673', (22, 26))	('CDKN2A', 'Gene', '1029', (39, 45))	('pLGG', 'Chemical', '-', (95, 99))	('BRAF', 'Gene', (22, 26))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p.V600E', 'Mutation', 'rs113488022', (27, 34))	('p.V600E', 'Var', (27, 34))	('al', 'Chemical', 'MESH:D000535', (81, 83))	('secondary HGG', 'Disease', (129, 142))
241887	32164789	This is in line with reports showing that co-occurrence of CDKN2A deletion with BRAF p.V600E is associated with escape from oncogene-induced senescence and with having a worse OS and PFS.	('BRAF', 'Gene', (80, 84))	('OS', 'Chemical', '-', (176, 178))	('p.V600E', 'Mutation', 'rs113488022', (85, 92))	('associated', 'Reg', (96, 106))	('p.V600E', 'Var', (85, 92))	('CDKN2A', 'Gene', (59, 65))	('BRAF', 'Gene', '673', (80, 84))	('escape', 'CPA', (112, 118))	('CDKN2A', 'Gene', '1029', (59, 65))
241888	32164789	Interestingly, several reports have also shown that pediatric grade I gliomas harboring CDKN2A loss, despite their rarity, have a more aggressive clinical course consistent with that of a higher histological grade and co-occurrence of CDKN2A deletion with BRAF fusions has been described in anaplastic astrocytoma with piloid features.	('CDKN2A', 'Gene', (235, 241))	('BRAF', 'Gene', '673', (256, 260))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('al', 'Chemical', 'MESH:D000535', (152, 154))	('BRAF', 'Gene', (256, 260))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('CDKN2A', 'Gene', (88, 94))	('CDKN2A', 'Gene', '1029', (235, 241))	('al', 'Chemical', 'MESH:D000535', (205, 207))	('astrocytoma', 'Phenotype', 'HP:0009592', (302, 313))	('al', 'Chemical', 'MESH:D000535', (20, 22))	('deletion', 'Var', (242, 250))	('CDKN2A', 'Gene', '1029', (88, 94))	('gliomas', 'Disease', (70, 77))	('al', 'Chemical', 'MESH:D000535', (36, 38))	('astrocytoma', 'Disease', 'MESH:D001254', (302, 313))	('astrocytoma', 'Disease', (302, 313))	('loss', 'NegReg', (95, 99))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))
241889	32164789	As such, pLGG with CDKN2A deletions, especially in the context of BRAF p.V600E or with possible high grade histologic features, should be considered as high risk tumors that warrant close clinical follow-up.	('p.V600E', 'Mutation', 'rs113488022', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('deletions', 'Var', (26, 35))	('al', 'Chemical', 'MESH:D000535', (194, 196))	('CDKN2A', 'Gene', (19, 25))	('p.V600E', 'Var', (71, 78))	('pLGG', 'Chemical', '-', (9, 13))	('CDKN2A', 'Gene', '1029', (19, 25))	('BRAF', 'Gene', '673', (66, 70))	('tumors', 'Disease', (162, 168))	('al', 'Chemical', 'MESH:D000535', (43, 45))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('BRAF', 'Gene', (66, 70))
241892	32164789	Simple and robust tests which can be used to detect common alterations such as BRAF fusions and BRAF p.V600E allow molecular characterization of almost two thirds of pLGG.	('pLGG', 'Chemical', '-', (166, 170))	('al', 'Chemical', 'MESH:D000535', (59, 61))	('al', 'Chemical', 'MESH:D000535', (109, 111))	('p.V600E', 'Var', (101, 108))	('al', 'Chemical', 'MESH:D000535', (145, 147))	('BRAF', 'Gene', '673', (79, 83))	('pLGG', 'Disease', (166, 170))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', (79, 83))	('p.V600E', 'Mutation', 'rs113488022', (101, 108))
241896	32164789	With respect to pLGG, IHC has been faithfully utilized in the detection of BRAF p.V600E, H3.3 p.K27M and IDH1 p.R132H and can be used on formalin-fixed-paraffin-embedded (FFPE) tissue.	('p.V600E', 'Mutation', 'rs113488022', (80, 87))	('H3.3', 'Gene', '3020', (89, 93))	('p.V600E', 'Var', (80, 87))	('IDH1', 'Gene', (105, 109))	('p.K27M', 'Mutation', 'p.K27M', (94, 100))	('BRAF', 'Gene', '673', (75, 79))	('pLGG', 'Chemical', '-', (16, 20))	('paraffin', 'Chemical', 'MESH:D010232', (152, 160))	('p.K27M', 'Var', (94, 100))	('formalin', 'Chemical', 'MESH:D005557', (137, 145))	('p.R132H', 'Var', (110, 117))	('BRAF', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (105, 109))	('H3.3', 'Gene', (89, 93))	('p.R132H', 'Mutation', 'rs121913500', (110, 117))
241900	32164789	It can also be used for identifying co-occurring CDKN2A deletions.	('CDKN2A', 'Gene', '1029', (49, 55))	('deletions', 'Var', (56, 65))	('CDKN2A', 'Gene', (49, 55))	('al', 'Chemical', 'MESH:D000535', (7, 9))
241906	32164789	ddPCR can identify not only point mutations such as BRAF p.V600E, H3.3 p.K27M, IDH1 p.R132H, and FGFR1 p.N546K and p.K656E but also CDKN2A deletions, KIAA1549-BRAF, and FGFR1 TKD-duplication based on copy number comparisons.	('CDKN2A', 'Gene', (132, 138))	('KIAA1549-BRAF', 'Disease', '-', (150, 163))	('p.N546K', 'Mutation', 'rs779707422', (103, 110))	('p.K27M', 'Var', (71, 77))	('IDH1', 'Gene', (79, 83))	('BRAF', 'Gene', '673', (159, 163))	('deletions', 'Var', (139, 148))	('KIAA1549-BRAF', 'Disease', (150, 163))	('al', 'Chemical', 'MESH:D000535', (127, 129))	('BRAF', 'Gene', (159, 163))	('p.R132H', 'Mutation', 'rs121913500', (84, 91))	('CDKN2A', 'Gene', '1029', (132, 138))	('p.N546K', 'Var', (103, 110))	('TKD-duplication', 'Var', (175, 190))	('p.R132H', 'Var', (84, 91))	('H3.3', 'Gene', (66, 70))	('FGFR1', 'Gene', '2260', (97, 102))	('IDH1', 'Gene', '3417', (79, 83))	('FGFR1', 'Gene', '2260', (169, 174))	('p.K27M', 'Mutation', 'p.K27M', (71, 77))	('BRAF', 'Gene', '673', (52, 56))	('p.K656E', 'Mutation', 'rs869320694', (115, 122))	('BRAF', 'Gene', (52, 56))	('p.V600E', 'Mutation', 'rs113488022', (57, 64))	('H3.3', 'Gene', '3020', (66, 70))	('p.K656E', 'Var', (115, 122))	('p.V600E', 'Var', (57, 64))	('FGFR1', 'Gene', (97, 102))	('FGFR1', 'Gene', (169, 174))
241910	32164789	In cases where no specific alterations can be found using the gene specific tools, or when copy number alterations have a role in tumor management, genome-wide SNP arrays can be used.	('al', 'Chemical', 'MESH:D000535', (27, 29))	('al', 'Chemical', 'MESH:D000535', (103, 105))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('copy number alterations', 'Var', (91, 114))
241911	32164789	Their use in pLGG molecular profiling includes the identification of BRAF and FGFR fusions, MYB and MYBL1 alterations and CDKN2A deletions.	('deletions', 'Var', (129, 138))	('MYBL1', 'Gene', '4603', (100, 105))	('MYB', 'Gene', (100, 103))	('FGFR', 'Gene', (78, 82))	('al', 'Chemical', 'MESH:D000535', (106, 108))	('CDKN2A', 'Gene', (122, 128))	('MYB', 'Gene', (92, 95))	('CDKN2A', 'Gene', '1029', (122, 128))	('pLGG', 'Chemical', '-', (13, 17))	('MYB', 'Gene', '4602', (92, 95))	('BRAF', 'Gene', '673', (69, 73))	('alterations', 'Var', (106, 117))	('MYBL1', 'Gene', (100, 105))	('BRAF', 'Gene', (69, 73))	('MYB', 'Gene', '4602', (100, 103))	('fusions', 'Var', (83, 90))
241927	32164789	These events primarily occur as either gene fusions or mutations, but almost never both.	('occur', 'Reg', (23, 28))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('mutations', 'Var', (55, 64))
241929	32164789	These are almost exclusively observed with mutations and not gene fusions.	('mutations', 'Var', (43, 52))	('observed', 'Reg', (29, 37))	('al', 'Chemical', 'MESH:D000535', (10, 12))
241931	32164789	First generation BRAF inhibitors including dabrafenib and vemurafenib have shown excellent results in melanoma patients harboring BRAF p.V600E and are now being investigated for their utility in pLGG.	('p.V600E', 'Mutation', 'rs113488022', (135, 142))	('vemurafenib', 'Chemical', 'MESH:D000077484', (58, 69))	('dabrafenib', 'Chemical', 'MESH:C561627', (43, 53))	('BRAF', 'Gene', '673', (130, 134))	('p.V600E', 'Var', (135, 142))	('BRAF', 'Gene', '673', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('BRAF', 'Gene', (130, 134))	('melanoma', 'Disease', (102, 110))	('BRAF', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('pLGG', 'Chemical', '-', (195, 199))	('patients', 'Species', '9606', (111, 119))
241932	32164789	These findings were recently confirmed in a larger cohort of BRAF p.V600E tumors, in which either of these BRAF inhibitors induced significant cytoreduction and prolonged survival in patients.	('BRAF', 'Gene', (107, 111))	('prolonged', 'PosReg', (161, 170))	('survival', 'CPA', (171, 179))	('BRAF', 'Gene', '673', (61, 65))	('cytoreduction', 'CPA', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('p.V600E', 'Mutation', 'rs113488022', (66, 73))	('BRAF', 'Gene', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('al', 'Chemical', 'MESH:D000535', (177, 179))	('p.V600E', 'Var', (66, 73))	('BRAF', 'Gene', '673', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('patients', 'Species', '9606', (183, 191))	('tumors', 'Disease', (74, 80))
241934	32164789	Despite their efficacy in BRAF p.V600E tumors, first generation BRAF inhibitors result in paradoxical activation of RAS/MAPK signalling when used in KIAA1549-BRAF or BRAF wild-type tumors.	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BRAF', 'Gene', '673', (166, 170))	('tumors', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('KIAA1549-BRAF', 'Disease', '-', (149, 162))	('BRAF', 'Gene', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('BRAF', 'Gene', '673', (158, 162))	('KIAA1549-BRAF', 'Disease', (149, 162))	('BRAF', 'Gene', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Disease', (181, 187))	('RAS/MAPK signalling', 'MPA', (116, 135))	('al', 'Chemical', 'MESH:D000535', (99, 101))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('activation', 'PosReg', (102, 112))	('p.V600E', 'Mutation', 'rs113488022', (31, 38))	('p.V600E', 'Var', (31, 38))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('al', 'Chemical', 'MESH:D000535', (129, 131))
241942	32164789	Currently, four MEK inhibitors including selumetinib [9, 56)], trametinib (NCT03363217), cobimetinib (NCT02639546), and binimetinib (NCT02285439) are at various stages of clinical testing.	('NCT02639546', 'Var', (102, 113))	('selumetinib', 'Chemical', 'MESH:C517975', (41, 52))	('NCT03363217', 'Var', (75, 86))	('MEK', 'Gene', (16, 19))	('trametinib', 'Chemical', 'MESH:C560077', (63, 73))	('binimetinib', 'Chemical', 'MESH:C581313', (120, 131))	('al', 'Chemical', 'MESH:D000535', (177, 179))	('cobimetinib', 'Chemical', 'MESH:C574276', (89, 100))	('MEK', 'Gene', '5609', (16, 19))
241949	32164789	These include AZD4547 (NCT02824133) for treatment of malignant glioma harboring FGFR-TACC fusions and several others previously reviewed.	('al', 'Chemical', 'MESH:D000535', (107, 109))	('AZD4547', 'Chemical', 'MESH:C572463', (14, 21))	('malignant glioma', 'Disease', (53, 69))	('malignant glioma', 'Disease', 'MESH:D005910', (53, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('al', 'Chemical', 'MESH:D000535', (54, 56))	('FGFR-TACC', 'Gene', (80, 89))	('fusions', 'Var', (90, 97))
241951	32164789	Alterations in ALK, ROS1 and NTRK are relatively rare in pLGG.	('pLGG', 'Disease', (57, 61))	('ALK', 'Gene', (15, 18))	('ROS1', 'Gene', (20, 24))	('TRK', 'Gene', (30, 33))	('Alterations', 'Var', (0, 11))	('pLGG', 'Chemical', '-', (57, 61))	('TRK', 'Gene', '4914', (30, 33))	('ROS1', 'Gene', '6098', (20, 24))	('ALK', 'Gene', '238', (15, 18))
241952	32164789	Conveniently, alterations in these genes are common in adult malignancies including lung and colorectal cancer and as such, targeted agents with federal approval have already been developed and tested.	('alterations', 'Var', (14, 25))	('common', 'Reg', (45, 51))	('adult malignancies', 'Disease', 'MESH:D009369', (55, 73))	('al', 'Chemical', 'MESH:D000535', (62, 64))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('al', 'Chemical', 'MESH:D000535', (159, 161))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('al', 'Chemical', 'MESH:D000535', (150, 152))	('adult malignancies', 'Disease', (55, 73))	('colorectal cancer', 'Disease', (93, 110))	('lung', 'Disease', (84, 88))	('al', 'Chemical', 'MESH:D000535', (101, 103))	('al', 'Chemical', 'MESH:D000535', (167, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
241966	32164789	Molecular stratification of pLGG resulting in significant clinical implications is currently available and has been seen in trials for specific inhibitors such as BRAF p.V600E- and MEK-inhibitors.	('al', 'Chemical', 'MESH:D000535', (64, 66))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('al', 'Chemical', 'MESH:D000535', (127, 129))	('pLGG', 'Gene', (28, 32))	('MEK', 'Gene', (181, 184))	('MEK', 'Gene', '5609', (181, 184))	('p.V600E', 'Mutation', 'rs113488022', (168, 175))	('p.V600E-', 'Var', (168, 176))	('pLGG', 'Chemical', '-', (28, 32))
241968	32164789	Indeed, the current National Cancer Institute-Children's Oncology Group Pediatric MATCH trial (NCT03155620) aims to match actionable mutations to 9 investigational therapies, providing a glimpse into the future of pLGG treatment.	('al', 'Chemical', 'MESH:D000535', (161, 163))	('pLGG', 'Chemical', '-', (214, 218))	('Oncology', 'Phenotype', 'HP:0002664', (57, 65))	('to 9', 'Species', '1214577', (143, 147))	('Children', 'Species', '9606', (46, 54))	('mutations', 'Var', (133, 142))	('al', 'Chemical', 'MESH:D000535', (91, 93))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Cancer', 'Disease', (29, 35))	('al', 'Chemical', 'MESH:D000535', (26, 28))	('Cancer', 'Disease', 'MESH:D009369', (29, 35))
242045	26692824	Our data further highlight that although patients with low-grade glioma experienced significantly less functional and brain function-related burden than patients with high-grade tumors, the two groups reported similar emotional, social, and physical well-being.	('glioma', 'Disease', (65, 71))	('patients', 'Species', '9606', (153, 161))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('low-grade', 'Var', (55, 64))	('less', 'NegReg', (98, 102))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('patients', 'Species', '9606', (41, 49))	('functional and', 'MPA', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
242078	32727536	Activating EGFR mutations are common in IDH1 wild-type gliomas.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('Activating', 'PosReg', (0, 10))	('gliomas', 'Disease', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))
242081	32727536	We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord.	('glioma', 'Disease', (46, 52))	('mutant', 'Var', (8, 14))	('initiate', 'Reg', (37, 45))	('EGFR', 'Gene', (15, 19))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
242082	32727536	We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations.	('loss-of-function', 'NegReg', (137, 153))	('gliomas', 'Disease', (65, 72))	('amplifications', 'Var', (95, 109))	('mutant', 'Var', (83, 89))	('Tead2', 'Gene', (131, 136))	('Sub1', 'Gene', (114, 118))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('EGFR', 'Gene', (90, 94))	('mutations', 'Var', (154, 163))	('Trp53', 'Gene', (120, 125))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
242083	32727536	Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3.	('Cdkn2a', 'Gene', (184, 190))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('Nf1', 'Gene', (192, 195))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('Nav3', 'Gene', '260315', (209, 213))	('Nav3', 'Gene', (209, 213))	('Spred1', 'Gene', (197, 203))	('insertional', 'Var', (80, 91))	('gliomas', 'Disease', (48, 55))
242085	32727536	We discover shared and distinct driver mutations in brain and spinal gliomas and confirm in vivo differential tumor suppressive effects of Pten between these tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('Pten', 'Gene', (139, 143))	('tumor', 'Disease', (158, 163))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (39, 48))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('spinal gliomas', 'Disease', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('spinal gliomas', 'Disease', 'MESH:D005910', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
242086	32727536	Functional validation with CRISPR-Cas9-induced mutations in novel genes Tead2, Spred1, and Nav3 demonstrates heightened EGFRvIII-glioma cell proliferation.	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('Nav3', 'Gene', '260315', (91, 95))	('Spred1', 'Gene', (79, 85))	('Tead2', 'Gene', (72, 77))	('EGFRvIII-glioma', 'Disease', (120, 135))	('Nav3', 'Gene', (91, 95))	('mutations', 'Var', (47, 56))	('EGFRvIII-glioma', 'Disease', 'MESH:D005910', (120, 135))	('heightened', 'PosReg', (109, 119))
242087	32727536	Chemogenomic analysis of mutated glioma genes reveals potential drug targets, with several investigational drugs showing efficacy in vitro.	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('mutated', 'Var', (25, 32))	('glioma', 'Disease', (33, 39))
242088	32727536	Our work elucidates functional driver landscapes of EGFR-mutant gliomas, uncovering potential therapeutic strategies, and provides new tools for functional interrogation of gliomagenesis.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('EGFR-mutant', 'Var', (52, 63))	('glioma', 'Disease', (173, 179))	('EGFR-mutant', 'Gene', (52, 63))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', (64, 70))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
242094	32727536	A further complicating issue is that mutations in individual gliomas can affect different genes in various combinations.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('affect', 'Reg', (73, 79))	('gliomas', 'Disease', (61, 68))	('mutations', 'Var', (37, 46))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))
242097	32727536	Challenges to genetic analysis in normal mouse brains include efficiencies of genome manipulation, cell delivery, and tumor production as well as generating both activating and loss-of-function mutations in a single screen.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mouse', 'Species', '10090', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (194, 203))	('activating', 'PosReg', (162, 172))	('tumor', 'Disease', (118, 123))	('loss-of-function', 'NegReg', (177, 193))
242098	32727536	Conditional piggybac mutagenesis is a powerful cancer screening platform that has not previously been applied to central nervous system tumors.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('nervous system tumors', 'Phenotype', 'HP:0004375', (121, 142))	('nervous system tumors', 'Disease', (121, 142))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('nervous system tumors', 'Disease', 'MESH:D009423', (121, 142))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (113, 142))	('mutagenesis', 'Var', (21, 32))
242099	32727536	Activating mutations in the epidermal growth factor receptor (EGFR) occur in up to 60% of IDH1 wild-type GBMs of which EGFRvIII is the most common (an in-frame deletion of exon 2 to 7 in the extracellular domain leading to constitutive receptor activation).	('activation', 'PosReg', (245, 255))	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('vIII', 'Gene', (123, 127))	('EGFR', 'Gene', (62, 66))	('epidermal growth factor receptor', 'Gene', (28, 60))	('epidermal growth factor receptor', 'Gene', '13649', (28, 60))	('vIII', 'Gene', '1351', (123, 127))	('constitutive receptor', 'MPA', (223, 244))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))
242100	32727536	EGFR alterations, including amplification, point mutations, and vIII, confer similar drug sensitivities to EGFR inhibitors in patient-derived GBM cells, and EGFR amplification and EGFRvIII are retained in most recurrent GBMs (when present in primary tumors), suggesting these alterations have similar functional driving effects in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('GBM', 'Phenotype', 'HP:0012174', (142, 145))	('point mutations', 'Var', (43, 58))	('vIII', 'Gene', (64, 68))	('patient', 'Species', '9606', (126, 133))	('GBM', 'Phenotype', 'HP:0012174', (220, 223))	('vIII', 'Gene', '1351', (184, 188))	('tumors', 'Disease', (337, 343))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('alterations', 'Var', (5, 16))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('vIII', 'Gene', '1351', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('vIII', 'Gene', (184, 188))
242101	32727536	Frequent driver mutations and amplifications of EGFR, including extrachromosomal ones, have also been detected in IDH1 wild-type, histologically low-grade gliomas (LGGs).	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('amplifications', 'Var', (30, 44))	('EGFR', 'Gene', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('detected', 'Reg', (102, 110))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
242102	32727536	Some evidence suggests EGFRvIII is a late event human GBM: its expression is heterogeneous, and it is found on double minute chromosomes with EGFR inhibitors causing selective pressure to drive its disappearance yet unable to elicit a cure; however, the EGFRvIII mutation has also been detected throughout GBMs, including regions with and without its expression, suggesting EGFRvIII may be an early event in some cases.	('mutation', 'Var', (263, 271))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('human', 'Species', '9606', (48, 53))	('GBM', 'Phenotype', 'HP:0012174', (306, 309))	('EGFRvIII', 'Gene', (254, 262))
242106	32727536	However, the role of EGFR mutations in spinal gliomas and their cooperative genetic drivers in brain and spinal tumors remain largely unknown.	('EGFR', 'Gene', (21, 25))	('spinal tumor', 'Phenotype', 'HP:0010302', (105, 117))	('spinal tumors', 'Phenotype', 'HP:0010302', (105, 118))	('spinal gliomas', 'Disease', (39, 53))	('spinal gliomas', 'Disease', 'MESH:D005910', (39, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (26, 35))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('spinal tumors', 'Disease', (105, 118))	('spinal tumors', 'Disease', 'MESH:D013120', (105, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
242108	32727536	We hypothesized that conditional genome-wide piggyBac mutagenesis in the presence of a strong initiating EGFR mutation may be a fruitful approach for mapping cooperative glioma driver landscapes in vivo.	('glioma', 'Disease', (170, 176))	('mutation', 'Var', (110, 118))	('EGFR', 'Gene', (105, 109))	('mutagenesis', 'Var', (54, 65))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))
242111	32727536	To study the role of mutant EGFR in gliomagenesis, we generated double heterozygous mice carrying a conditional human EGFRvIII transgene and cre under the control of the Nestin promoter (nes-cre) which specifically activates EGFRvIII expression in the central nervous system, (Fig.	('mutant', 'Var', (21, 27))	('expression', 'MPA', (234, 244))	('EGFRvIII', 'Gene', (225, 233))	('glioma', 'Disease', (36, 42))	('activates', 'PosReg', (215, 224))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('human', 'Species', '9606', (112, 117))	('mice', 'Species', '10090', (84, 88))
242133	32727536	Across all tumors, we found 85 significant recurrently mutated genes with mutations in two or more tumors identified by MuSiC (adapted for mouse data); most had single-nucleotide variants (SNVs) but some genes exhibited INDELS (Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('exhibited', 'Reg', (210, 219))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mouse', 'Species', '10090', (139, 144))	('INDELS', 'Var', (220, 226))	('single-nucleotide variants', 'Var', (161, 187))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
242134	32727536	The median number of exonic mutations per tumor was 29 of which missense mutations were the most common.	('missense mutations', 'Var', (64, 82))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
242135	32727536	Sub1, a transcriptional coactivator, was the most frequently mutated gene (6 mutations in 5/17 tumors, p = 1.1 x 10-16, FDR 2.27 x 10-12, likelihood ratio test, LRT) displaying INDELs and SNVs, all in splice sites suggesting loss of function.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', (95, 101))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Sub1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
242136	32727536	Trp53, a known tumor suppressor in human LGG and GBM, was the second most frequently mutated gene (5/17 tumors had a Trp53 missense mutation, all within Trp53's DNA-binding domain; p = 1.13 x 10-12, FDR 7.75 x 10-9, LRT; Additional file 1: Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Trp53', 'Gene', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('missense mutation', 'Var', (123, 140))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('human', 'Species', '9606', (35, 40))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
242137	32727536	Similarly, Nf1, a known genetic driver of brain and spinal gliomas, was found to be mutated in two tumors (p = 0.0010, FDR 0.17, LRT).	('Nf1', 'Gene', (11, 14))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('mutated', 'Var', (84, 91))	('tumors', 'Disease', (99, 105))	('spinal gliomas', 'Disease', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('spinal gliomas', 'Disease', 'MESH:D005910', (52, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
242139	32727536	Tead2, a transcription factor in the Hippo pathway, had recurrent mutations across its TEA/ATTS (DNA-binding) domain (4 mutations in 3/17 tumors; p = 2.80 x 10-11, FDR 1.15 x 10-7, LRT), including splice site mutations and one frameshift mutation, suggesting loss of function.	('frameshift', 'Var', (227, 237))	('Tead2', 'Gene', (0, 5))	('mutations', 'Var', (66, 75))	('splice site mutations', 'Var', (197, 218))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
242140	32727536	Uimc1 and Itga6 had three mutations each (p = 1.39 x 10-7 and FDR 1.9 x 10-4, p = 2.7 x 10-7 and FDR 3.2 x 10-4, LRT, respectively), all of which were INDELS and one of which caused a frameshift in Itga6 (Fig.	('Itga6', 'Gene', (198, 203))	('frameshift', 'Var', (184, 194))	('Itga6', 'Gene', '16403', (10, 15))	('Uimc1', 'Gene', '20184', (0, 5))	('Itga6', 'Gene', (10, 15))	('Uimc1', 'Gene', (0, 5))	('Itga6', 'Gene', '16403', (198, 203))	('caused', 'Reg', (175, 181))
242141	32727536	These gliomas were all wild-type for Idh1, consistent with gliomas in humans in which IDH1 and EGFR mutations tend to be mutually exclusive.	('gliomas', 'Disease', (59, 66))	('mutations', 'Var', (100, 109))	('IDH1', 'Gene', (86, 90))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('Idh1', 'Gene', '3417', (37, 41))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('gliomas', 'Disease', (6, 13))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('humans', 'Species', '9606', (70, 76))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('Idh1', 'Gene', (37, 41))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))	('EGFR', 'Gene', (95, 99))
242143	32727536	Significant focal amplifications and deletions, identified by GISTIC2, were evident in regions with known cancer genes, for example, significant focal Cdkn2a deletions (GISTIC q value = 1.39 x 10-5) were evident and EGFRvIII (in Col1a1 locus, GISTIC q value = 0.017) was recurrently amplified.	('Col1a1', 'Gene', '12842', (229, 235))	('deletions', 'Var', (158, 167))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('Col1a1', 'Gene', (229, 235))	('Cdkn2a', 'Gene', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
242144	32727536	Significantly recurrent focal deletions were present in a novel putative glioma driver Adgrl2 (GISTIC q value = 2.19 x 10-6, Additional file 4: Table S3).	('glioma', 'Disease', (73, 79))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('Adgrl2', 'Gene', (87, 93))	('Adgrl2', 'Gene', '99633', (87, 93))	('focal deletions', 'Var', (24, 39))
242145	32727536	Several of the most significantly mutated genes were also in regions with frequent deletions, including Trp53, Tead2, and Uimc1, supporting putative tumor suppressive roles (Fig.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('Uimc1', 'Gene', '20184', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Trp53', 'Gene', (104, 109))	('deletions', 'Var', (83, 92))	('Uimc1', 'Gene', (122, 127))	('tumor', 'Disease', (149, 154))
242149	32727536	Recurrent deletions in previously unknown glioma genes NT5C2, ADGRL2, and UIMC1 were observed whilst SUB1, CES1, and ITGA6 were frequently methylated in human LGGs (Additional file 1: Fig.	('ADGRL2', 'Gene', '23266', (62, 68))	('NT5C2', 'Gene', (55, 60))	('CES1', 'Gene', '1066', (107, 111))	('SUB1', 'Gene', '10923', (101, 105))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('ADGRL2', 'Gene', (62, 68))	('NT5C2', 'Gene', '22978', (55, 60))	('UIMC1', 'Gene', '51720', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('SUB1', 'Gene', (101, 105))	('deletions', 'Var', (10, 19))	('ITGA6', 'Gene', (117, 122))	('ITGA6', 'Gene', '3655', (117, 122))	('human', 'Species', '9606', (153, 158))	('CES1', 'Gene', (107, 111))	('UIMC1', 'Gene', (74, 79))	('glioma', 'Disease', (42, 48))
242151	32727536	Subgroup analysis confirmed recurrent mutations/CNVs (> 2 tumors) in these genes specifically in EGFR-mutated/amplified human LGGs and GBMs.	('mutations/CNVs', 'Var', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('human', 'Species', '9606', (120, 125))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('GBM', 'Phenotype', 'HP:0012174', (135, 138))
242159	32727536	The endogenous Egfr gene was also upregulated (mean log2 fold change = 3.71) in both brain and spinal tumors, suggesting both mutant EGFR and wild-type Egfr expression are advantageous to tumor growth (Fig.	('tumor', 'Disease', (188, 193))	('advantageous', 'PosReg', (172, 184))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('spinal tumors', 'Disease', (95, 108))	('Egfr', 'Gene', (152, 156))	('spinal tumor', 'Phenotype', 'HP:0010302', (95, 107))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('mutant', 'Var', (126, 132))	('spinal tumors', 'Disease', 'MESH:D013120', (95, 108))	('Egfr', 'Gene', (15, 19))	('brain', 'Disease', (85, 90))	('Egfr', 'Gene', '1956', (152, 156))	('tumor', 'Disease', (102, 107))	('EGFR', 'Gene', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('spinal tumors', 'Phenotype', 'HP:0010302', (95, 108))	('Egfr', 'Gene', '1956', (15, 19))
242173	32727536	Given large chromosomal aberrations or transcriptional changes make pinpointing driver genes difficult to identify, we performed a conditional piggyBac transposon mutagenesis screen in vivo to further identify genes that cooperate with mutant EGFR in gliomagenesis.	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('mutant', 'Var', (236, 242))	('EGFR', 'Gene', (243, 247))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (12, 35))	('glioma', 'Disease', (251, 257))
242184	32727536	Nevertheless, whole chromosome 11 amplification was still common as well as focal amplifications of EGFRvIII (Col1a1 locus) and localized deletions in Cdkn2a and Adgrl2 in tumors arising from both cohorts.	('Adgrl2', 'Gene', '99633', (162, 168))	('Col1a1', 'Gene', '12842', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('deletions', 'Var', (138, 147))	('EGFRvIII', 'Gene', (100, 108))	('Col1a1', 'Gene', (110, 116))	('Adgrl2', 'Gene', (162, 168))	('Cdkn2a', 'Gene', (151, 157))
242187	32727536	Although the frequency of mutations in these genes was high (70-40%), Obscn and Hspg2 are particularly large genes (more likely to harbor mutations) and contained many synonymous changes, suggesting they were passengers.	('Obscn', 'Gene', (70, 75))	('Hspg2', 'Gene', '15530', (80, 85))	('Obscn', 'Gene', '380698', (70, 75))	('Hspg2', 'Gene', (80, 85))	('mutations', 'Var', (138, 147))
242188	32727536	Nevertheless, in EGFRvIII-PB mice, there were low-frequency mutations in a subset of putative drivers we previously identified in EGFRvIII-only tumors, including frequent splice site mutations in Sub1 and Nt5c2, and mutations in Trp53, Tead2, Uimc1, and Itga6 (Fig.	('tumors', 'Disease', (144, 150))	('Uimc1', 'Gene', '20184', (243, 248))	('Trp53', 'Gene', (229, 234))	('Sub1', 'Gene', (196, 200))	('mice', 'Species', '10090', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('Itga6', 'Gene', (254, 259))	('Uimc1', 'Gene', (243, 248))	('Nt5c2', 'Gene', (205, 210))	('vIII', 'Gene', (21, 25))	('vIII', 'Gene', (134, 138))	('Tead2', 'Gene', (236, 241))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('Itga6', 'Gene', '16403', (254, 259))	('Nt5c2', 'Gene', '76952', (205, 210))	('mutations', 'Var', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('vIII', 'Gene', '1351', (134, 138))	('vIII', 'Gene', '1351', (21, 25))
242194	32727536	Together, these results suggest that piggyBac mutagenesis substitutes for genomic instability and highlight the relevance of transposon-mediated mutations for gliomagenesis.	('glioma', 'Disease', (159, 165))	('mutagenesis', 'Var', (46, 57))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('genomic', 'MPA', (74, 81))
242199	32727536	Analysis of CIS genes with STRING showed PB mutagenesis significantly enriched for mutations that affect a functionally interacting network of proteins in gliomagenesis (Benjamini-Hochberg adjusted p = 4.9 x 10-13, hypergeometric test, Additional file 1: Fig.	('mutations', 'Var', (83, 92))	('functionally interacting', 'MPA', (107, 131))	('proteins', 'Protein', (143, 151))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('mutagenesis', 'Var', (44, 55))	('affect', 'Reg', (98, 104))	('glioma', 'Disease', (155, 161))
242200	32727536	Loss-of-function mutations of CDKN2A and NF1 have been observed as drivers in a range of human gliomas including LGG and GBM.	('Loss-of-function', 'NegReg', (0, 16))	('human', 'Species', '9606', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('GBM', 'Disease', (121, 124))	('CDKN2A', 'Gene', (30, 36))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('NF1', 'Gene', (41, 44))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('LGG', 'Disease', (113, 116))	('mutations', 'Var', (17, 26))
242201	32727536	Interestingly, Spred1 (whose product also acts as negative regulator of the Ras pathway and is a recently discovered melanoma tumor suppressor) ranked within the top 10 CIS and exhibited a disruptive piggyBac insertional pattern, suggesting Spred1 acts as a novel tumor suppressor in glioma (Fig.	('glioma', 'Phenotype', 'HP:0009733', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('Spred1', 'Gene', (15, 21))	('Spred1', 'Var', (241, 247))	('tumor', 'Disease', (264, 269))	('glioma', 'Disease', (284, 290))	('Ras pathway', 'Pathway', (76, 87))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('melanoma tumor', 'Disease', (117, 131))	('melanoma tumor', 'Disease', 'MESH:D008545', (117, 131))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('glioma', 'Disease', 'MESH:D005910', (284, 290))	('tumor', 'Disease', (126, 131))
242202	32727536	Other MAPK signaling-related genes with recurrent mutations include Prkca, Pebp4, and Map3k1.	('Map3k1', 'Gene', '26401', (86, 92))	('Map3k1', 'Gene', (86, 92))	('mutations', 'Var', (50, 59))	('Pebp4', 'Gene', (75, 80))	('Pebp4', 'Gene', '73523', (75, 80))	('Prkca', 'Gene', '18750', (68, 73))	('Prkca', 'Gene', (68, 73))	('MAPK signaling-related genes', 'Gene', (6, 34))
242206	32727536	Other genes involved in the PI3K pathway with recurrent insertional mutations include Cbl and Pik3c3.	('Cbl', 'Gene', '12402', (86, 89))	('Cbl', 'Gene', (86, 89))	('Pik3c3', 'Gene', '225326', (94, 100))	('insertional mutations', 'Var', (56, 77))	('Pik3c3', 'Gene', (94, 100))
242211	32727536	NAV3 silencing in breast cancer cells increased tumorigenicity in a xenograft model, supporting our data here for gliomas.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('gliomas', 'Disease', (114, 121))	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('NAV3', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('silencing', 'Var', (5, 14))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('increased', 'PosReg', (38, 47))
242212	32727536	Inactivating transposon insertion patterns suggest tumor suppressor roles for these genes (Fig.	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Inactivating transposon insertion', 'Var', (0, 33))	('tumor', 'Disease', (51, 56))
242213	32727536	Frequent insertional mutations were also observed in other genes with developmental roles: Qki, Zeb2, Dmd, Zfhx3, Zfhx4, and Exosc9.	('Qki', 'Gene', '19317', (91, 94))	('Zeb2', 'Gene', '24136', (96, 100))	('Zfhx4', 'Gene', '80892', (114, 119))	('Qki', 'Gene', (91, 94))	('Dmd', 'Gene', '13405', (102, 105))	('Exosc9', 'Gene', '50911', (125, 131))	('Dmd', 'Gene', (102, 105))	('Zfhx3', 'Gene', '11906', (107, 112))	('Zfhx4', 'Gene', (114, 119))	('Zeb2', 'Gene', (96, 100))	('insertional mutations', 'Var', (9, 30))	('Zfhx3', 'Gene', (107, 112))	('Exosc9', 'Gene', (125, 131))
242216	32727536	With the exception of clonal Pdgfra and Nav3 insertions in one tumor, transposon insertions in MAPK/PI3K pathway and neurodevelopmental genes (including Nf1, Pten, Pik3r1, Ptprj, Sox6, Sox5, and Tcf4) were subclonal in these tumors, implying these were late evolutionary events.	('insertions', 'Var', (45, 55))	('Tcf4', 'Gene', (195, 199))	('tumor', 'Disease', (225, 230))	('Sox5', 'Gene', '20678', (185, 189))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('Ptprj', 'Gene', '19271', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Sox5', 'Gene', (185, 189))	('insertions', 'Var', (81, 91))	('Nav3', 'Gene', '260315', (40, 44))	('tumor', 'Disease', (63, 68))	('Tcf4', 'Gene', '21413', (195, 199))	('transposon', 'Gene', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('Pdgfra', 'Gene', (29, 35))	('Nav3', 'Gene', (40, 44))	('Ptprj', 'Gene', (172, 177))	('Pdgfra', 'Gene', '18595', (29, 35))	('MAPK/PI3K pathway', 'Pathway', (95, 112))	('Pten', 'Gene', (158, 162))	('Nf1', 'Gene', (153, 156))	('tumors', 'Disease', (225, 231))
242220	32727536	Subgroup analysis confirmed these top CIS genes had recurrent mutations/CNVs (> 2 tumors) in EGFR-mutated/amplified human LGGs and GBMs.	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('mutations/CNVs', 'Var', (62, 76))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('human', 'Species', '9606', (116, 121))
242222	32727536	In mice, all four genes had recurrent piggyBac insertions across their sequence (implying gene disruption), supporting the hypothesis that there are multiple putative tumor suppressors in this region.	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('piggyBac insertions', 'Var', (38, 57))	('tumor', 'Disease', (167, 172))
242226	32727536	Moreover, deletions in these genes associate with correspondingly lower gene expression (Additional file 1: Figure, S25).	('S25', 'Gene', '56861', (116, 119))	('S25', 'Gene', (116, 119))	('lower', 'NegReg', (66, 71))	('deletions', 'Var', (10, 19))	('gene expression', 'MPA', (72, 87))
242238	32727536	Conversely, Sox6 has significantly more insertions in brain compared with spinal tumors (26 vs 3 insertions, respectively, p < 0.0001, Fisher's exact test; Fig.	('insertions', 'Var', (40, 50))	('spinal tumors', 'Phenotype', 'HP:0010302', (74, 87))	('spinal tumor', 'Phenotype', 'HP:0010302', (74, 86))	('brain', 'Disease', (54, 59))	('spinal tumors', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('spinal tumors', 'Disease', 'MESH:D013120', (74, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
242252	32727536	In addition to targeted EGFR therapies, the network highlights targets being investigated clinically for glioma treatment, including not only PI3K, but also ESR1 and PDGFRA, Additional file 9: Table S8 and Additional file 10: Table S9.	('ESR1', 'Gene', (157, 161))	('glioma', 'Disease', (105, 111))	('ESR1', 'Gene', '13982', (157, 161))	('PDGFRA', 'Gene', '18595', (166, 172))	('PI3K', 'Var', (142, 146))	('PDGFRA', 'Gene', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
242266	32727536	Lentiviral transduction enabled Cas9 expression from these tumor cells, and subsequent targeted sgRNA transduction led to the production of frequent on-target indels in coding exons of Tead2, Nav3, and Spred1.	('indels', 'Var', (159, 165))	('Tead2', 'Gene', (185, 190))	('tumor', 'Disease', (59, 64))	('Nav3', 'Gene', (192, 196))	('Nav3', 'Gene', '260315', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Spred1', 'Gene', (202, 208))
242267	32727536	Tumor cells with these alterations were assessed for gliomasphere growth at 4 weeks post-sgRNA transduction:loss of each of these genes led to significantly increased gliomasphere proliferation (Tead2-loss:6.44x, Nav3-loss:5.04x, Spred1-loss:3.58x, relative cell viability compared with non-targeting sgRNA control (1x); p < 0.0001, < 0.0001, and 0.036 respectively, adjusted one-way ANOVA test, 3D, CellTiter-Glo 3D cell viability assay, Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('loss', 'Var', (108, 112))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('gliomasphere growth', 'Disease', (53, 72))	('Nav3', 'Gene', '260315', (213, 217))	('Nav3', 'Gene', (213, 217))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('increased', 'PosReg', (157, 166))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('gliomasphere growth', 'Disease', 'MESH:D006130', (53, 72))
242268	32727536	S27b, c, Additional file 12: Table S11).	('S27b', 'Var', (0, 4))	('S11', 'Gene', '23997', (35, 38))	('S11', 'Gene', (35, 38))
242269	32727536	These results confirm that loss of these genes heightens tumor cell proliferation and gliomasphere growth and highlight the use of EGFRvIII-mouse gliomaspheres as a platform for functional genetic validation studies.	('mouse', 'Species', '10090', (140, 145))	('loss', 'Var', (27, 31))	('gliomaspheres', 'Disease', 'None', (146, 159))	('gliomasphere growth', 'Disease', (86, 105))	('gliomaspheres', 'Disease', (146, 159))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('heightens', 'PosReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('gliomasphere growth', 'Disease', 'MESH:D006130', (86, 105))	('genes', 'Gene', (41, 46))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('tumor', 'Disease', (57, 62))	('gliomas', 'Phenotype', 'HP:0009733', (86, 93))
242270	32727536	To demonstrate the utility of our model for pre-clinical drug testing, we conducted a proof-of-principle experiment comparing the sensitivity of EGFRvIII-gliomaspheres, with and without CRISPR-induced mutations in Nav3 and Spred1, to key small-molecule inhibitors.	('Nav3', 'Gene', (214, 218))	('Nav3', 'Gene', '260315', (214, 218))	('Spred1', 'Gene', (223, 229))	('EGFRvIII-gliomaspheres', 'Disease', (145, 167))	('mutations', 'Var', (201, 210))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('EGFRvIII-gliomaspheres', 'Disease', 'None', (145, 167))
242271	32727536	Although neither Spred1 nor Nav3 mutations affected tumor cell sensitivity to EGFR inhibition with afatinib (Additional file 1: Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('afatinib', 'Chemical', 'MESH:D000077716', (99, 107))	('tumor', 'Disease', (52, 57))	('mutations', 'Var', (33, 42))	('Nav3', 'Gene', '260315', (28, 32))	('Nav3', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Spred1', 'Gene', (17, 23))
242272	32727536	S27a), loss of Spred1 or Nav3 increased sensitivity of EGFRvIII-tumor cells to MEK inhibitor treatment with trametinib (Fig.	('tumor', 'Disease', (64, 69))	('loss', 'Var', (7, 11))	('MEK', 'Gene', (79, 82))	('Nav3', 'Gene', '260315', (25, 29))	('Nav3', 'Gene', (25, 29))	('increased', 'PosReg', (30, 39))	('trametinib', 'Chemical', 'MESH:C560077', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Spred1', 'Gene', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('sensitivity', 'MPA', (40, 51))	('MEK', 'Gene', '17242', (79, 82))
242273	32727536	Understanding how a cancer-initiating mutation influences downstream genomic evolution from human studies is challenging because of the absence of data from tumors before they become clinically overt, the large number of passenger mutations, co-occurring mutations caused by frank chromosomal anomalies and extensive tumor heterogeneity.	('tumor', 'Disease', (157, 162))	('frank chromosomal anomalies', 'Disease', (275, 302))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('caused', 'Reg', (265, 271))	('tumor', 'Disease', (317, 322))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('frank chromosomal anomalies', 'Disease', 'MESH:D002869', (275, 302))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('human', 'Species', '9606', (92, 97))	('mutations', 'Var', (255, 264))
242277	32727536	The most frequently mutated genes Sub1, Trp53, and Tead2 had loss-of-function mutations, and recurrent focal deletions in other novel genes were detected; many of the mutated and deleted genes are also altered in human patients, supporting tumor suppressor roles.	('human', 'Species', '9606', (213, 218))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('mutations', 'Var', (78, 87))	('Tead2', 'Gene', (51, 56))	('patients', 'Species', '9606', (219, 227))	('Trp53', 'Gene', (40, 45))	('Sub1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('loss-of-function', 'NegReg', (61, 77))
242282	32727536	Although EGFR mutations are present in multiple GBM subsets (based on transcriptional profiles), our tumors most strongly enriched for the human mesenchymal GBM signature (a subtype more responsive to aggressive treatment), likely because the specific cooperative drivers acquired in this model also occur in the human subset (including Nf1, Pten, and Trp53).	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('GBM', 'Phenotype', 'HP:0012174', (157, 160))	('human', 'Species', '9606', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('EGFR', 'Gene', (9, 13))	('human', 'Species', '9606', (139, 144))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', (101, 107))
242283	32727536	By using conditional piggyBac insertional mutagenesis, there was a trend for increased GBMs, although the expected reduction in mouse survival was not observed.	('insertional mutagenesis', 'Var', (30, 53))	('GBMs', 'CPA', (87, 91))	('mouse', 'Species', '10090', (128, 133))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('increased', 'PosReg', (77, 86))
242289	32727536	First, the observation of integration sites in the same (CIS) genes in a significant fraction of the 96 tumors provides strong statistical evidence for selection of these events as putative driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('integration sites', 'Var', (26, 43))
242290	32727536	Third, RNA-seq data support the integration pattern because the transposon is designed to affect gene expression:transcripts were observed emanating from transposons splicing into Rad51b, as were transcripts from the gene splicing into the acceptor sites encoded by the transposon thereby disrupting gene expression such as Cdkn2a, Nf1, Pten, Sox6, Sox5, Spred1, Qki, and Ust.	('Spred1', 'Disease', (355, 361))	('affect', 'Reg', (90, 96))	('Rad51b', 'Gene', (180, 186))	('transposons', 'Species', '2387', (154, 165))	('Cdkn2a', 'Gene', (324, 330))	('Sox5', 'Gene', (349, 353))	('Qki', 'Gene', '19317', (363, 366))	('Sox5', 'Gene', '20678', (349, 353))	('Ust', 'Gene', '338362', (372, 375))	('Qki', 'Gene', (363, 366))	('Rad51b', 'Gene', '19363', (180, 186))	('gene expression', 'MPA', (300, 315))	('Pten', 'Disease', (337, 341))	('Ust', 'Gene', (372, 375))	('transposons', 'Var', (154, 165))	('disrupting', 'NegReg', (289, 299))
242291	32727536	Fourth, the overlap of genes identified with mutations/focal deletions by exome sequencing and mutated by piggyBac cross-validates their biological selection:including Cdkn2a, Esr1, and Myo10 (focal deletions) and Nf1, Prex2, and Dgkb (recurrent mutations).	('Esr1', 'Gene', (176, 180))	('mutations/focal', 'Var', (45, 60))	('Dgkb', 'Gene', '217480', (230, 234))	('Esr1', 'Gene', '13982', (176, 180))	('Dgkb', 'Gene', (230, 234))	('Cdkn2a', 'Gene', (168, 174))	('Prex2', 'Gene', '109294', (219, 224))	('Myo10', 'Gene', (186, 191))	('Myo10', 'Gene', '17909', (186, 191))	('Prex2', 'Gene', (219, 224))	('Nf1', 'Gene', (214, 217))
242294	32727536	Relatively few activating insertions were detected with RNA-seq: this may reflect that glioma driver landscapes are dominated by tumor suppressors, but also be partly due to the biology of the transposon with gene disruption being a more likely event than activation.	('glioma', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('gene disruption', 'Var', (209, 224))	('tumor', 'Disease', (129, 134))
242295	32727536	Although these mutations occurred in the context of mutant EGFR (implying genetic cooperation), this does not preclude these being drivers in other contexts without EGFR, as exemplified by Pten and Nf1 also causing multiple glioma types with other drivers.	('Nf1', 'Gene', (198, 201))	('EGFR', 'Gene', (59, 63))	('mutant', 'Var', (52, 58))	('multiple glioma', 'Disease', (215, 230))	('multiple glioma', 'Disease', 'MESH:D005910', (215, 230))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('causing', 'Reg', (207, 214))	('Pten', 'Gene', (189, 193))
242300	32727536	A species differences between the mouse and human tumors is that most gliomas in this model were histologically low-grade, whereas in humans the majority with EGFRvIII mutations are histologically GBM.	('human', 'Species', '9606', (44, 49))	('human', 'Species', '9606', (134, 139))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mouse', 'Species', '10090', (34, 39))	('GBM', 'Phenotype', 'HP:0012174', (197, 200))	('humans', 'Species', '9606', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('gliomas', 'Disease', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('mutations', 'Var', (168, 177))	('EGFRvIII', 'Gene', (159, 167))
242301	32727536	However, recent work on human samples demonstrates histologically low-grade appearing, IDH1-wildtype astrocytomas with EGFR amplification likely represent early GBMs with corresponding molecular features and poor prognosis; also, extrachromosomal EGFR driver mutations and amplifications are frequently detected in both human LGGs and GBMs.	('astrocytomas', 'Disease', (101, 113))	('human', 'Species', '9606', (24, 29))	('mutations', 'Var', (259, 268))	('GBM', 'Phenotype', 'HP:0012174', (335, 338))	('GBM', 'Phenotype', 'HP:0012174', (161, 164))	('human', 'Species', '9606', (320, 325))	('astrocytomas', 'Disease', 'MESH:D001254', (101, 113))	('EGFR', 'Gene', (247, 251))
242304	32727536	The strength of the models here are molecular features recapitulating human EGFR-mutant gliomas, including the matched transcriptomic signatures and cooperative mutations.	('EGFR-mutant', 'Gene', (76, 87))	('gliomas', 'Disease', (88, 95))	('human', 'Species', '9606', (70, 75))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('EGFR-mutant', 'Var', (76, 87))
242305	32727536	It has been suggested EGFRvIII expression may induce senescence in the absence of tumor suppressor losses.	('senescence', 'CPA', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('vIII', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('induce', 'Reg', (46, 52))	('tumor', 'Disease', (82, 87))	('expression', 'Var', (31, 41))	('vIII', 'Gene', '1351', (26, 30))
242307	32727536	The genomic instability observed in the mouse tumors may be explained at least partially by oncogene-induced replicative stress, with the high frequency of Cdkn2a and Trp53 mutations indicating strong selection for mechanisms to bypass oncogene-induced senescence in early gliomagenesis.	('glioma', 'Phenotype', 'HP:0009733', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Cdkn2a', 'Gene', (156, 162))	('tumors', 'Disease', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('glioma', 'Disease', (273, 279))	('mutations', 'Var', (173, 182))	('Trp53', 'Gene', (167, 172))	('glioma', 'Disease', 'MESH:D005910', (273, 279))	('mouse', 'Species', '10090', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
242309	32727536	Although the frequency and nature of EGFR alterations (particularly extrachromosomal ones) in these tumors remains to be determined in larger studies, EGFR amplification and expression has been detected in a subset of human spinal tumors:leptomeningeal-disseminated pediatric spinal LGGs.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('alterations', 'Var', (42, 53))	('leptomeningeal-disseminated pediatric spinal LGGs', 'Disease', (238, 287))	('spinal tumors', 'Disease', (224, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('spinal tumors', 'Disease', 'MESH:D013120', (224, 237))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('detected', 'Reg', (194, 202))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('spinal tumor', 'Phenotype', 'HP:0010302', (224, 236))	('human', 'Species', '9606', (218, 223))	('spinal tumors', 'Phenotype', 'HP:0010302', (224, 237))	('EGFR', 'Gene', (37, 41))	('tumors', 'Disease', (231, 237))
242311	32727536	The mice have EGFRvIII as the driver, but these tumors could conceivably be generated by other mechanisms for increased EGFR signaling including alternative EGFR mutations, amplification, and/or overexpression.	('EGFR', 'Gene', (157, 161))	('mutations', 'Var', (162, 171))	('mice', 'Species', '10090', (4, 8))	('increased', 'PosReg', (110, 119))	('tumors', 'Disease', (48, 54))	('amplification', 'Var', (173, 186))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('overexpression', 'PosReg', (195, 209))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
242312	32727536	In patients, germline NF1-loss predisposes to spinal glioma and a study of spinal gliomas detected frequent CDKN2A deletion and loss of heterozygosity at 10q23 (containing PTEN).	('deletion', 'Var', (115, 123))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('loss', 'NegReg', (128, 132))	('spinal gliomas', 'Disease', (75, 89))	('spinal glioma', 'Disease', 'MESH:D005910', (46, 59))	('NF1-loss', 'Gene', (22, 30))	('spinal gliomas', 'Disease', 'MESH:D005910', (75, 89))	('spinal glioma', 'Disease', 'MESH:D005910', (75, 88))	('patients', 'Species', '9606', (3, 11))	('NF1-loss', 'NegReg', (22, 30))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('spinal glioma', 'Disease', (46, 59))	('CDKN2A', 'Gene', (108, 114))
242318	32727536	A key finding of this study is that many of the mutated glioma genes are druggable or predicted to be so.	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('mutated', 'Var', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))
242323	32727536	This is the first study to employ piggyBac mutagenesis in vivo in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('mutagenesis', 'Var', (43, 54))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))
242326	32727536	The finding of extensive cooperative mutations in mutant EGFR gliomas that can influence prognosis and drug treatment response highlights the importance of integrated genomic diagnosis for developing rational, personalized polytherapy strategies in patients to improve survival.	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('patients', 'Species', '9606', (249, 257))	('mutations', 'Var', (37, 46))	('influence', 'Reg', (79, 88))	('mutant', 'Var', (50, 56))	('gliomas', 'Disease', (62, 69))	('EGFR', 'Gene', (57, 61))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
242327	32727536	Understanding the driver landscapes in the context of mutant EGFR is essential for advancing targeted glioma therapies.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('mutant', 'Var', (54, 60))	('glioma', 'Disease', (102, 108))	('EGFR', 'Gene', (61, 65))
242328	32727536	We show mutant EGFR is sufficient to initiate gliomagenesis in the brain and spinal cord.	('glioma', 'Disease', (46, 52))	('mutant', 'Var', (8, 14))	('initiate', 'Reg', (37, 45))	('EGFR', 'Gene', (15, 19))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
242330	32727536	Functional genomic landscapes of EGFR-mutant gliomas were elucidated by genome-wide piggyBac transposon mutagenesis and transcriptomics, identifying 281 known and novel cancer genes (tumor suppressors and oncogenes), with clinical relevance demonstrated by confirming corresponding human genetic alterations in patients.	('cancer', 'Disease', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('human', 'Species', '9606', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('EGFR-mutant', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('patients', 'Species', '9606', (311, 319))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))	('EGFR-mutant', 'Gene', (33, 44))	('tumor', 'Disease', (183, 188))	('gliomas', 'Disease', 'MESH:D005910', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('gliomas', 'Disease', (45, 52))
242339	32727536	The strains of the original mice are as follows: EGFRvIII mice are FVB, nes-cre mice are C57BL/6J; the ATP1S2 and TSPB mice are C57BL/6J albino.	('mice', 'Species', '10090', (119, 123))	('C57BL/6J', 'Var', (89, 97))	('mice', 'Species', '10090', (28, 32))	('mice', 'Species', '10090', (58, 62))	('C57BL/6J', 'Var', (128, 136))	('mice', 'Species', '10090', (80, 84))
242347	32727536	For pre-treatment, either Ventana CC1 (950-124), equivalent to EDTA buffer, or Protease 1 (equivalent to pronase, 760-2018), was used.	('950-124', 'Var', (39, 46))	('CC1', 'Gene', (34, 37))	('EDTA', 'Chemical', 'MESH:D004492', (63, 67))	('CC1', 'Gene', '26365', (34, 37))
242349	32727536	The antibodies used were as follows: Olig2 (1:100, Millipore ab9610), Sox2 (1:500, Abcam ab97959), Nestin (1:500, Abcam ab22035), Ki67 (1:100, Cell Signaling 12202S), GFAP (1:1000, Dako Z0334), PDGFRalpha (pre-diluted, Abcam ab15501), EGFR (Invitrogen 280005), and EGFRvIII (1:100, Sigma MABS1915).	('vIII', 'Gene', (269, 273))	('GFAP', 'Gene', '14580', (167, 171))	('Ki67', 'Gene', '17345', (130, 134))	('GFAP', 'Gene', (167, 171))	('vIII', 'Gene', '1351', (269, 273))	('1:500', 'Var', (107, 112))	('Sox2', 'Gene', (70, 74))	('Ki67', 'Gene', (130, 134))	('PDGFRalpha', 'Gene', (194, 204))	('PDGFRalpha', 'Gene', '18595', (194, 204))	('1:500', 'Var', (76, 81))	('Sox2', 'Gene', '20674', (70, 74))	('Olig2', 'Gene', (37, 42))	('Olig2', 'Gene', '50913', (37, 42))
242359	32727536	Five chromosome pools were labeled with ATTO 425-, ATTO 488-, CY3-, CY5-, and Texas Red-dUTPs (Jena Bioscience), respectively, using WGA 3 re-amplification kit (Sigma-Aldrich) as described before (Gribble et al.	('CY5', 'Chemical', 'MESH:C085321', (68, 71))	('CY3-', 'Var', (62, 66))	('Texas Red', 'Chemical', 'MESH:C034657', (78, 87))	('CY3', 'Chemical', '-', (62, 65))	('dUTPs', 'Chemical', 'MESH:C027078', (88, 93))	('CY5-', 'Var', (68, 72))
242372	32727536	Significantly mutated genes (SMGs) were identified by MuSiC (Version 0.4) with default parameters; genes were called SMGs if mutated in two or more tumors, corrected likelihood ratio test p value < 0.01 and FDR < 0.2, and convolution test p value < 0.01.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutated', 'Var', (125, 132))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
242406	32727536	IC50Z-scores represent the relative sensitivity of a cell line to a given drug relative to all other cancer cell lines tested, with a value of - 2.0 taken to be statistically significant for sensitivity and values between - 0.5 and - 2.0 taken to represent partial or weak sensitivity.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('IC50Z-scores', 'Var', (0, 12))
242560	25795072	On the other hand, especially among younger children, the risks of surgery cannot be discounted as, in addition to the risk of perioperative mortality, surgery also can adversely affect neurological development and function.	('affect', 'Reg', (179, 185))	('surgery', 'Var', (152, 159))	('neurological development', 'CPA', (186, 210))	('children', 'Species', '9606', (44, 52))	('function', 'CPA', (215, 223))
242617	25795072	The only variable either correlated with seizure freedom rate at a study mean level or associated with seizure freedom at an individual level was degree of tumor resection, with subtotal resections virtually always associated with either the persistence or recurrence of seizures.	('seizures', 'Disease', 'MESH:D012640', (271, 279))	('subtotal resections', 'Var', (178, 197))	('seizure', 'Disease', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('seizure', 'Disease', (271, 278))	('seizure', 'Disease', 'MESH:D012640', (41, 48))	('seizure', 'Phenotype', 'HP:0001250', (271, 278))	('seizure', 'Disease', (103, 110))	('seizure', 'Disease', 'MESH:D012640', (271, 278))	('seizures', 'Phenotype', 'HP:0001250', (271, 279))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('seizure', 'Disease', 'MESH:D012640', (103, 110))	('seizures', 'Disease', (271, 279))	('tumor', 'Disease', (156, 161))	('seizure', 'Phenotype', 'HP:0001250', (41, 48))	('associated with', 'Reg', (215, 230))	('seizure', 'Phenotype', 'HP:0001250', (103, 110))
242641	25795072	From this review of 13 studies on DNET resections in children and adolescents, it is clear that surgical resection of the lesion is effective at improving seizures in almost all patients and at achieving long-term seizure freedom in the vast majority.	('improving', 'PosReg', (145, 154))	('seizure', 'Phenotype', 'HP:0001250', (214, 221))	('patients', 'Species', '9606', (178, 186))	('seizure', 'Disease', (155, 162))	('seizures', 'Disease', 'MESH:D012640', (155, 163))	('seizure', 'Disease', 'MESH:D012640', (155, 162))	('children', 'Species', '9606', (53, 61))	('seizures', 'Disease', (155, 163))	('surgical resection', 'Var', (96, 114))	('seizure', 'Disease', (214, 221))	('seizures', 'Phenotype', 'HP:0001250', (155, 163))	('seizure', 'Phenotype', 'HP:0001250', (155, 162))	('seizure', 'Disease', 'MESH:D012640', (214, 221))
242651	33937330	The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('HNSC', 'Phenotype', 'HP:0012288', (128, 132))	('BRCA', 'Gene', '672', (79, 83))	('BRCA', 'Gene', (79, 83))	('THCA', 'Phenotype', 'HP:0002890', (89, 93))	('KIRP', 'Disease', (68, 72))	('high', 'Var', (4, 8))	('THCA', 'Disease', (89, 93))	('PERK', 'Gene', (23, 27))	('LGG', 'Disease', (74, 77))	('PERK', 'Gene', '9451', (23, 27))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))
242654	33937330	Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('infiltration', 'CPA', (58, 70))	('deteriorate', 'NegReg', (136, 147))	('thyroid cancer', 'Phenotype', 'HP:0002890', (189, 203))	('PERK', 'Gene', '9451', (222, 226))	('patients', 'Species', '9606', (164, 172))	('outcomes', 'CPA', (152, 160))	('high expression', 'Var', (16, 31))	('promote', 'PosReg', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('tumor', 'Disease', (103, 108))	('PERK', 'Gene', (35, 39))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('breast and thyroid cancers', 'Disease', 'MESH:D001943', (178, 204))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('PERK', 'Gene', '9451', (35, 39))	('PERK', 'Gene', (222, 226))
242683	33937330	Inhibitors augment T-cell activity by blocking programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) and show remarkable clinical effects (Topalian et al.,; Gordon et al.,).	('PD-L1', 'Gene', '29126', (103, 108))	('blocking', 'NegReg', (38, 46))	('programmed cell death protein 1', 'Gene', (47, 78))	('augment', 'PosReg', (11, 18))	('programmed cell death protein 1', 'Gene', '5133', (47, 78))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (90, 94))	('PD-1', 'Gene', (90, 94))	('T-cell activity', 'CPA', (19, 34))	('PD-L1', 'Gene', (103, 108))	('PD-1', 'Gene', (80, 84))	('PD-1', 'Gene', '5133', (80, 84))
242714	33937330	A previous study has shown that PERK inhibition by siRNA or GSK2656157 (a small molecule inhibitor against the PERK/elF2alpha/ATF4 pathway) might improve clinical prognosis and enhance the treatment of esophageal squamous cell carcinoma (ESCC) patients (Wang et al.,), but little research is reported in other types of cancers.	('ATF4', 'Gene', '468', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('cancers', 'Disease', (319, 326))	('PERK', 'Gene', '9451', (111, 115))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('patients', 'Species', '9606', (244, 252))	('GSK2656157', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('inhibition', 'NegReg', (37, 47))	('clinical prognosis', 'CPA', (154, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('PERK', 'Gene', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (319, 326))	('treatment', 'CPA', (189, 198))	('GSK2656157', 'Chemical', 'MESH:C000597302', (60, 70))	('improve', 'PosReg', (146, 153))	('enhance', 'PosReg', (177, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('PERK', 'Gene', (111, 115))	('ATF4', 'Gene', (126, 130))	('PERK', 'Gene', '9451', (32, 36))
242716	33937330	According to the PrognoScan database, the high expression of PERK was associated with a poor prognosis in brain cancer (shorter OS, p = 0.003) and soft tissue cancer (shorter DRFS, p = 0.008) and related to a favorable prognosis in lung cancer (longer OS and RFS, p < 0.05, Figure 3).	('soft tissue cancer', 'Phenotype', 'HP:0031459', (147, 165))	('cancer', 'Disease', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('high expression', 'Var', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PERK', 'Gene', (61, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('brain cancer', 'Phenotype', 'HP:0030692', (106, 118))	('cancer', 'Disease', (237, 243))	('PERK', 'Gene', '9451', (61, 65))	('brain cancer', 'Disease', 'MESH:D001932', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('lung cancer', 'Disease', (232, 243))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('brain cancer', 'Disease', (106, 118))
242720	33937330	The high expression of PERK was associated with a favorable prognosis in bladder carcinoma (p = 0.006), esophageal squamous cell carcinoma (p = 0.0022), lung adenocarcinoma (p = 0.0054), rectum adenocarcinoma (p = 0.026), and thymoma (p = 0.039, Figure 4) and related to a poor prognosis in kidney renal papillary cell carcinoma (p = 0.014), liver hepatocellular carcinoma (p = 0.023), and thyroid carcinoma (p = 0.0036, Figure 4).	('bladder carcinoma', 'Phenotype', 'HP:0002862', (73, 90))	('thymoma', 'Disease', (226, 233))	('bladder carcinoma', 'Disease', 'MESH:D001749', (73, 90))	('high expression', 'Var', (4, 19))	('thymoma', 'Phenotype', 'HP:0100522', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('kidney renal papillary cell carcinoma', 'Disease', (291, 328))	('rectum adenocarcinoma', 'Disease', (187, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('PERK', 'Gene', '9451', (23, 27))	('lung adenocarcinoma', 'Disease', (153, 172))	('bladder carcinoma', 'Disease', (73, 90))	('esophageal squamous cell carcinoma', 'Disease', (104, 138))	('liver hepatocellular carcinoma', 'Disease', (342, 372))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (390, 407))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 172))	('thyroid carcinoma', 'Disease', (390, 407))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (291, 328))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (187, 208))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (390, 407))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (298, 328))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (348, 372))	('thymoma', 'Disease', 'MESH:D013945', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (104, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('PERK', 'Gene', (23, 27))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (342, 372))
242724	33937330	According to the UALCAN database, the high expression of PERK was associated with a poor prognosis in kidney renal papillary cell carcinoma (KIRP) (p = 0.01), brain lower grade glioma (LGG) (p = 0.00016), and THCA (p = 0.017, Figure 5).	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (109, 139))	('THCA', 'Phenotype', 'HP:0002890', (209, 213))	('high expression', 'Var', (38, 53))	('glioma', 'Disease', (177, 183))	('THCA', 'Disease', (209, 213))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', (102, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('PERK', 'Gene', (57, 61))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (102, 139))	('PERK', 'Gene', '9451', (57, 61))
242725	33937330	Consistent with the results of the Kaplan:Meier plotter database, PERK expression in BRCA had a poor prognosis (OS < 4,000 days, ~130 months, p = 0.025, Figure 5).	('BRCA', 'Gene', (85, 89))	('PERK', 'Gene', (66, 70))	('expression', 'Var', (71, 81))	('PERK', 'Gene', '9451', (66, 70))	('BRCA', 'Phenotype', 'HP:0003002', (85, 89))	('BRCA', 'Gene', '672', (85, 89))
242727	33937330	Together, the high expression of PERK is associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('THCA', 'Phenotype', 'HP:0002890', (98, 102))	('THCA', 'Disease', (98, 102))	('PERK', 'Gene', '9451', (33, 37))	('PERK', 'Gene', (33, 37))	('HNSC', 'Phenotype', 'HP:0012288', (137, 141))	('LGG', 'Disease', (83, 86))	('KIRP', 'Disease', (77, 81))	('high', 'Var', (14, 18))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('BRCA', 'Gene', '672', (88, 92))	('BRCA', 'Gene', (88, 92))	('HNSC', 'Disease', (137, 141))
242760	33937330	Lung cancer was an exception where high levels of PERK expression showed a better prognosis.	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('high levels', 'Var', (35, 46))	('PERK', 'Gene', (50, 54))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('PERK', 'Gene', '9451', (50, 54))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
242762	33937330	The UALCAN database analysis demonstrated that the high expression of PERK was associated with a poor prognosis in KIRP, LGG, THCA, and BRCA (Figure 5).	('KIRP', 'Disease', (115, 119))	('PERK', 'Gene', (70, 74))	('LGG', 'Disease', (121, 124))	('THCA', 'Phenotype', 'HP:0002890', (126, 130))	('THCA', 'Disease', (126, 130))	('PERK', 'Gene', '9451', (70, 74))	('BRCA', 'Gene', '672', (136, 140))	('high expression', 'Var', (51, 66))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('BRCA', 'Gene', (136, 140))
242765	33937330	Inhibition of CREB3L1 by genetic or pharmacological methods suppresses cancer cell invasion and metastasis (Feng et al.,).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CREB3L1', 'Gene', '90993', (14, 21))	('cancer', 'Disease', (71, 77))	('suppresses', 'NegReg', (60, 70))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CREB3L1', 'Gene', (14, 21))
242766	33937330	Another report showed that inhibition of the PERK-eIF2alpha-GRP94 signaling pathway silenced the epidermal growth factor receptor (EGFR) and then increased the radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells (Zhang et al.,).	('radiosensitivity', 'CPA', (160, 176))	('EGFR', 'Gene', (131, 135))	('inhibition', 'Var', (27, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('squamous cell carcinoma', 'Disease', (233, 256))	('PERK', 'Gene', '9451', (45, 49))	('increased', 'PosReg', (146, 155))	('silenced', 'NegReg', (84, 92))	('OSCC', 'Phenotype', 'HP:0012182', (258, 262))	('GRP94', 'Gene', '7184', (60, 65))	('EGFR', 'Gene', '1956', (131, 135))	('eIF2alpha', 'Gene', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('eIF2alpha', 'Gene', '83939', (50, 59))	('GRP94', 'Gene', (60, 65))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (219, 256))	('epidermal growth factor receptor', 'Gene', (97, 129))	('PERK', 'Gene', (45, 49))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))
242785	33937330	Expansion of myeloid-derived suppressor cells (MDSCs) has emerged as a key mechanism of antitumor immune evasion and correlates with a poor clinical outcome and resistance to cancer immunotherapy (Lu et al.,).	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('Expansion', 'Var', (0, 9))
242787	33937330	PERK deletion transformed MDSCs into myeloid cells that activated CD8+ T-cell-mediated immunity against cancer (Mohamed et al.,).	('PERK', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('PERK', 'Gene', '9451', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('activated', 'PosReg', (56, 65))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
242788	33937330	Another study showed that inhibition of PERK in CD8+ T cells abrogates mitochondrial ROS generation in PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs), which boosts CD8+ TIL viability and enhances antitumor immunity (Hurst et al.,).	('abrogates', 'NegReg', (61, 70))	('boosts', 'PosReg', (159, 165))	('CD8', 'Gene', '925', (48, 51))	('ROS', 'Chemical', '-', (85, 88))	('CD8', 'Gene', '925', (166, 169))	('CD8', 'Gene', '925', (109, 112))	('tumor', 'Disease', (202, 207))	('inhibition', 'Var', (26, 36))	('tumor', 'Disease', (114, 119))	('mitochondrial ROS generation', 'MPA', (71, 99))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PD-1', 'Gene', (103, 107))	('CD8', 'Gene', (48, 51))	('PERK', 'Gene', (40, 44))	('PD-1', 'Gene', '5133', (103, 107))	('enhances', 'PosReg', (189, 197))	('CD8', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CD8', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PERK', 'Gene', '9451', (40, 44))
242810	33681797	Importantly, the classification of diffuse gliomas (WHO grade II-IV) now involves the detection of mutations in isocitrate dehydrogenase (IDH) 1 and 2.	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('mutations', 'Var', (99, 108))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('isocitrate dehydrogenase (IDH) 1 and 2', 'Gene', '3417;3418', (112, 150))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
242811	33681797	IDH 1/2 mutations are largely associated with WHO grade II and III gliomas and secondary glioblastomas.	('associated', 'Reg', (30, 40))	('glioblastomas', 'Phenotype', 'HP:0012174', (89, 102))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('IDH 1/2', 'Gene', (0, 7))	('gliomas', 'Disease', (67, 74))	('III glioma', 'Disease', (63, 73))	('III glioma', 'Disease', 'MESH:D005910', (63, 73))	('mutations', 'Var', (8, 17))	('glioblastomas', 'Disease', 'MESH:D005909', (89, 102))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('glioblastomas', 'Disease', (89, 102))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('IDH 1/2', 'Gene', '3417;3418', (0, 7))
242815	33681797	Among the diffuse gliomas with IDH mutations, there further exist two molecular groups: (1) IDH-mutant diffuse gliomas with 1p/19q co-deletion and mutated TERT promoter and (2) IDH-mutant diffuse gliomas with mutations in ATRX and TP53.	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('ATRX', 'Gene', '546', (222, 226))	('TP53', 'Gene', '7157', (231, 235))	('IDH', 'Gene', '3417', (177, 180))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('IDH', 'Gene', (31, 34))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('TERT', 'Gene', (155, 159))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('TERT', 'Gene', '7015', (155, 159))	('mutated', 'Var', (147, 154))	('gliomas', 'Disease', (18, 25))	('IDH', 'Gene', '3417', (31, 34))	('IDH', 'Gene', (92, 95))	('TP53', 'Gene', (231, 235))	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('IDH', 'Gene', (177, 180))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('mutations', 'Var', (209, 218))	('gliomas', 'Disease', (196, 203))	('IDH', 'Gene', '3417', (92, 95))	('ATRX', 'Gene', (222, 226))
242817	33681797	Deletions in the 1p and 19q chromosomes have been observed in 40%-90% of biopsies and are the most common genetic alteration of oligodendrogliomas.	('oligodendrogliomas', 'Disease', (128, 146))	('observed', 'Reg', (50, 58))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (128, 146))	('common', 'Reg', (99, 105))	('Deletions', 'Var', (0, 9))
242822	33681797	For example, the molecular aberrations most commonly associated with glioma development include IDH mutations, epidermal growth factor receptor (EGFR) amplification, mutations in P53 and retinoblastoma protein, as well as abnormalities in the pathways involving receptor tyrosine kinase, protein kinase B (Akt), phosphoinositide 3-kinase and Ras.	('glioma', 'Disease', (69, 75))	('Ras', 'Pathway', (342, 345))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('epidermal growth factor receptor', 'Gene', (111, 143))	('abnormalities', 'Reg', (222, 235))	('amplification', 'Var', (151, 164))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))	('mutations', 'Var', (166, 175))	('IDH', 'Gene', '3417', (96, 99))	('phosphoinositide 3-kinase', 'Pathway', (312, 337))	('EGFR', 'Gene', (145, 149))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('associated', 'Reg', (53, 63))	('protein kinase B', 'Gene', '2185', (288, 304))	('retinoblastoma', 'Phenotype', 'HP:0009919', (187, 201))	('P53 and retinoblastoma protein', 'Gene', '7157', (179, 209))	('Akt', 'Gene', (306, 309))	('protein kinase B', 'Gene', (288, 304))	('receptor tyrosine kinase', 'Gene', '5979', (262, 286))	('Akt', 'Gene', '207', (306, 309))	('mutations', 'Var', (100, 109))	('receptor tyrosine kinase', 'Gene', (262, 286))	('IDH', 'Gene', (96, 99))
242823	33681797	In this regard, a large area of research has been focused on developing therapeutic agents that target EGFR and its mutant EGFR variant III (EGFRvIII) in glioblastoma.	('EGFR', 'Gene', (123, 127))	('variant', 'Var', (128, 135))	('glioblastoma', 'Disease', (154, 166))	('EGFR', 'Gene', (103, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))
242829	33681797	Mesenchymal glioblastomas commonly contained deletions and mutations in neurofibromatosis type 1 (NF1), a tumour suppressor gene associated with increased tumourigenesis and malignancy in glioblastoma.	('neurofibromatosis', 'Phenotype', 'HP:0001067', (72, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('deletions', 'Var', (45, 54))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('contained', 'Reg', (35, 44))	('glioblastomas', 'Phenotype', 'HP:0012174', (12, 25))	('tumour', 'Disease', (155, 161))	('malignancy in glioblastoma', 'Disease', (174, 200))	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('neurofibromatosis type 1', 'Gene', '4763', (72, 96))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('glioblastomas', 'Disease', (12, 25))	('increased', 'PosReg', (145, 154))	('tumour', 'Disease', (106, 112))	('mutations', 'Var', (59, 68))	('NF1', 'Gene', '4763', (98, 101))	('glioblastomas', 'Disease', 'MESH:D005909', (12, 25))	('malignancy in glioblastoma', 'Disease', 'MESH:D005909', (174, 200))	('NF1', 'Gene', (98, 101))	('neurofibromatosis type 1', 'Gene', (72, 96))
242831	33681797	Neuronal markers, including neurofilament light (NEFL), gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), chloride-potassium symporter 5 (SLC12A5) and synaptotagmin-1 (SYT1), were characteristic of neural glioblastoma, whereas IDH1 point mutations and platelet derived growth factor receptor alpha (PDGFRA) aberrations predominantly marked the proneural subtype.	('glioblastoma', 'Disease', (214, 226))	('neurofilament light', 'Gene', (28, 47))	('platelet derived growth factor receptor alpha', 'Gene', (261, 306))	('NEFL', 'Gene', '4747', (49, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (214, 226))	('synaptotagmin-1', 'Gene', (160, 175))	('PDGFRA', 'Gene', '5156', (308, 314))	('PDGFRA', 'Gene', (308, 314))	('chloride-potassium symporter 5', 'MPA', (115, 145))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (261, 306))	('neurofilament light', 'Gene', '4747', (28, 47))	('NEFL', 'Gene', (49, 53))	('point mutations', 'Var', (241, 256))	('SYT1', 'Gene', (177, 181))	('gamma-aminobutyric acid receptor subunit alpha-1', 'Gene', '2554', (56, 104))	('potassium', 'Chemical', 'MESH:D011188', (124, 133))	('GABRA1', 'Gene', '2554', (106, 112))	('SLC12A5', 'Gene', (147, 154))	('IDH1', 'Gene', (236, 240))	('gamma-aminobutyric acid receptor subunit alpha-1', 'Gene', (56, 104))	('GABRA1', 'Gene', (106, 112))	('SYT1', 'Gene', '6857', (177, 181))	('glioblastoma', 'Disease', 'MESH:D005909', (214, 226))	('chloride', 'Chemical', 'MESH:D002712', (115, 123))	('synaptotagmin-1', 'Gene', '6857', (160, 175))	('SLC12A5', 'Gene', '57468', (147, 154))	('IDH1', 'Gene', '3417', (236, 240))
242855	33681797	In fact, the expression patterns of copy number alteration (CNA) have been demonstrated to vary between different stages of tumour development.	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('copy number alteration', 'Var', (36, 58))	('tumour', 'Disease', (124, 130))
242916	33681797	ctDNA contains mutations present in the parental tumour and exists in higher abundance than CTCs.	('parental tumour', 'Disease', (40, 55))	('mutations', 'Var', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('CTCs', 'Chemical', '-', (92, 96))	('parental tumour', 'Disease', 'MESH:D063129', (40, 55))
242919	33681797	Indeed, ctDNA sequencing has been demonstrated to successfully facilitate the diagnosis of diffuse gliomas, allowing for the genomic analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A and HIST1H3B mutations.	('TP53', 'Gene', (157, 161))	('H3F3A', 'Gene', '3020', (175, 180))	('IDH1', 'Gene', (145, 149))	('gliomas', 'Disease', (99, 106))	('IDH1', 'Gene', '3417', (145, 149))	('H3F3A', 'Gene', (175, 180))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('TERT', 'Gene', (163, 167))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('TP53', 'Gene', '7157', (157, 161))	('TERT', 'Gene', '7015', (163, 167))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('ATRX', 'Gene', (169, 173))	('ATRX', 'Gene', '546', (169, 173))	('HIST1H3B', 'Gene', (185, 193))	('mutations', 'Var', (194, 203))	('HIST1H3B', 'Gene', '8358', (185, 193))	('IDH2', 'Gene', (151, 155))	('IDH2', 'Gene', '3418', (151, 155))
242921	33681797	Notably, the presence of ctDNA in the CSF of patients with glioma was associated with a fourfold higher risk of mortality.	('ctDNA', 'Gene', (25, 30))	('glioma', 'Disease', (59, 65))	('mortality', 'Disease', 'MESH:D003643', (112, 121))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('mortality', 'Disease', (112, 121))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('presence', 'Var', (13, 21))	('patients', 'Species', '9606', (45, 53))
242932	33681797	In fact, miRNAs have been reported to encompass a third of all non-coding RNAs in glioblastoma EVs.	('glioblastoma EVs', 'Disease', 'MESH:D005909', (82, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('glioblastoma EVs', 'Disease', (82, 98))	('non-coding RNAs', 'Var', (63, 78))
242942	33681797	In support of this, miR-21 knockdown inhibited glioblastoma cell proliferation in vitro and solid tumour formation in vivo.	('miR-21', 'Gene', (20, 26))	('knockdown', 'Var', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('inhibited', 'NegReg', (37, 46))	('glioblastoma', 'Disease', (47, 59))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('tumour', 'Disease', (98, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('miR-21', 'Gene', '406991', (20, 26))
242958	33681797	Furthermore, patients with glioblastoma who had undergone partial resection had increased YKL-40 levels relative to patients who had undergone total resection.	('patients', 'Species', '9606', (116, 124))	('partial', 'Var', (58, 65))	('increased', 'PosReg', (80, 89))	('patients', 'Species', '9606', (13, 21))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('YKL-40', 'Gene', '1116', (90, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('YKL-40', 'Gene', (90, 96))
243106	32628746	The present analysis revealed that patients who had MRI as part of surveillance were at a lower risk of visual deterioration (Table 1) in univariate analysis (crude OR: 0.36; 95% CI: 0.14-0.93) but not in the multivariable analysis (adjOR: 0.77, 95% CI: 0.25-2.34).	('visual deterioration', 'Disease', (104, 124))	('visual deterioration', 'Disease', 'MESH:C531604', (104, 124))	('MRI', 'Var', (52, 55))	('lower', 'NegReg', (90, 95))	('patients', 'Species', '9606', (35, 43))
243122	30745581	Additionally, in clonogenic survival analyses, DDIT4 induction conferred protection from radiotherapy and temozolomide, while DDIT4 gene suppression sensitised cells.	('DDIT4', 'Gene', '54541', (47, 52))	('protection', 'MPA', (73, 83))	('DDIT4', 'Gene', (47, 52))	('temozolomide', 'Chemical', 'MESH:C047246', (106, 118))	('DDIT4', 'Gene', (126, 131))	('induction', 'Var', (53, 62))	('DDIT4', 'Gene', '54541', (126, 131))
243130	30745581	Acquired resistance to temozolomide can involve defects in the DNA mismatch repair pathway reducing susceptibility to apoptosis.	('susceptibility to apoptosis', 'MPA', (100, 127))	('defects', 'Var', (48, 55))	('temozolomide', 'Chemical', 'MESH:C047246', (23, 35))	('reducing', 'NegReg', (91, 99))	('DNA mismatch repair pathway', 'Pathway', (63, 90))
243157	30745581	Membranes were incubated with antibodies to DDIT4 (Proteintech #10638-1-AP), hypoxia-inducible factor-1alpha (HIF-1alpha) (BD #610959), P-S6RP (Ser240/244; Cell Signalling #2215), P-S6K1 (Thr389; Cell Signalling #9205), S6K1 (Cell Signalling #9202), P-4E-BP1 (Thr37/46, Cell Signalling #9459), 4E-BP1 (Cell Signalling #9452) or actin (Santa Cruz Biotechnology #sc-1616).	('4E-BP1', 'Gene', '1978', (294, 300))	('HIF-1alpha', 'Gene', (110, 120))	('S6K1', 'Gene', '6198', (220, 224))	('S6K1', 'Gene', '6198', (182, 186))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (77, 108))	('4E-BP1', 'Gene', '1978', (252, 258))	('Ser', 'Chemical', 'MESH:C530429', (144, 147))	('4E-BP1', 'Gene', (294, 300))	('P-4E-BP1', 'Chemical', 'MESH:C110781', (250, 258))	('P-S6RP', 'Var', (136, 142))	('Ser240/244;', 'Var', (144, 155))	('4E-BP1', 'Gene', (252, 258))	('HIF-1alpha', 'Gene', '3091', (110, 120))	('hypoxia-inducible factor-1alpha', 'Gene', (77, 108))	('S6K1', 'Gene', (220, 224))	('DDIT4', 'Gene', (44, 49))	('S6K1', 'Gene', (182, 186))	('BD #610959', 'Chemical', 'MESH:C418322', (123, 133))	('DDIT4', 'Gene', '54541', (44, 49))
243207	30745581	Similar to our results with a physiological mTORC1 inhibitor, it appears possible that pharmacological mTORC1 inhibitors also render GB cells less sensitive to temozolomide (or radiation).	('GB', 'Phenotype', 'HP:0012174', (133, 135))	('mTORC1', 'Gene', '382056', (44, 50))	('temozolomide', 'Chemical', 'MESH:C047246', (160, 172))	('mTORC1', 'Gene', '382056', (103, 109))	('sensitive to temozolomide', 'MPA', (147, 172))	('mTORC1', 'Gene', (44, 50))	('GB', 'Disease', 'MESH:D005909', (133, 135))	('mTORC1', 'Gene', (103, 109))	('inhibitors', 'Var', (110, 120))	('less', 'NegReg', (142, 146))
243221	30745581	Therefore, DDIT4 is a potential target for therapeutic inhibition to disrupt tumour cell adaptation and sensitise GBs to the effects of the established treatment regimens.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('DDIT4', 'Gene', '54541', (11, 16))	('tumour', 'Disease', (77, 83))	('GB', 'Disease', 'MESH:D005909', (114, 116))	('DDIT4', 'Gene', (11, 16))	('GB', 'Phenotype', 'HP:0012174', (114, 116))	('inhibition', 'Var', (55, 65))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
243227	26757925	Aberrant methylation of CD133 was observed in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('observed', 'Reg', (34, 42))	('CD133', 'Protein', (24, 29))	('Aberrant', 'Var', (0, 8))	('methylation', 'MPA', (9, 20))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))
243228	26757925	To date, a direct link between CD133 methylation and patient outcome has not been established.To address this question, we studied CD133 expression and promoter methylation in a series of 170 gliomas of various grade and histology, and investigated the correlation of CD133 expression and promoter methylation with patient outcome.We detected five CD133 promoter methylation patterns in 170 glioma samples: methylation only (M+, U-), unmethylation only (M-, U+), both methylation and unmethylation equally (M+, U+), high methylation and low unmethylation (M+, Ul), and low methylation and high unmethylation (Ml, U+).	('methylation', 'Var', (407, 418))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('patient', 'Species', '9606', (315, 322))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('unmethylation', 'MPA', (541, 554))	('glioma', 'Disease', 'MESH:D005910', (391, 397))	('glioma', 'Phenotype', 'HP:0009733', (391, 397))	('CD133', 'Gene', (348, 353))	('gliomas', 'Disease', (192, 199))	('methylation', 'Var', (468, 479))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('glioma', 'Disease', (391, 397))	('glioma', 'Disease', (192, 198))	('low', 'NegReg', (537, 540))	('patient', 'Species', '9606', (53, 60))
243237	26757925	These markers included CD24, CD44, CD133, and CD166 that are also expressed in normal cells.	('CD44', 'Gene', (29, 33))	('CD24', 'Gene', '100133941', (23, 27))	('CD24', 'Gene', (23, 27))	('CD166', 'Gene', '214', (46, 51))	('CD166', 'Gene', (46, 51))	('CD133', 'Var', (35, 40))	('CD44', 'Gene', '960', (29, 33))
243245	26757925	Although the role of hypermethylation in the silencing of tumor suppressor genes is now well-documented, abnormal methylation contributes to neoplastic progression in numerous types of human cancer, including glioblastomas.	('hypermethylation', 'Var', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('human', 'Species', '9606', (185, 190))	('contributes to', 'Reg', (126, 140))	('glioblastomas', 'Phenotype', 'HP:0012174', (209, 222))	('silencing', 'MPA', (45, 54))	('abnormal methylation', 'Var', (105, 125))	('glioblastomas', 'Disease', 'MESH:D005909', (209, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (209, 221))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('glioblastomas', 'Disease', (209, 222))	('methylation', 'Var', (114, 125))	('neoplastic progression', 'CPA', (141, 163))
243261	26757925	Normal human lymphocyte DNA was used as negative control for methylated alleles of CD133, and placental DNA treated in vitro with SssI methyltransferase (New England Biolabs) was used as positive control.	('methylated', 'Var', (61, 71))	('human', 'Species', '9606', (7, 12))	('CD133', 'Gene', (83, 88))
243274	26757925	Methylation of the CD133 promoter was found in 106 of the 170 tumors (62.4 %).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Methylation', 'Var', (0, 11))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CD133', 'Gene', (19, 24))	('found', 'Reg', (38, 43))
243276	26757925	The presence of CD133 CpG island methylation in glioma patients was not associated with the sex (P = 0.26) or age of the patient (P = 0.19), but associated with the histological type of the tumor (P = 0.005) and grades (P = 0.005).	('methylation', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('associated', 'Reg', (145, 155))	('CD133', 'Gene', (16, 21))	('tumor', 'Disease', (190, 195))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))	('patient', 'Species', '9606', (121, 128))	('glioma', 'Disease', (48, 54))
243277	26757925	In low-grade tumors (WHO grade 2), the percentage of methylated and unmethylated CD133 were 74.2 % (46 of 62) and 25.8 % (16 of 62), respectively.	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('CD133', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('methylated', 'Var', (53, 63))
243280	26757925	While, patients with methylated CD133 promoter showed a tendency to an increased PFS (189.7 weeks, 95 % CI, 164.1-215.3) and OS (218.9 weeks, 95 % CI, 200.4-271.6).	('PFS', 'CPA', (81, 84))	('methylated', 'Var', (21, 31))	('CD133', 'Gene', (32, 37))	('increased', 'PosReg', (71, 80))	('patients', 'Species', '9606', (7, 15))
243281	26757925	2), suggesting that CD133 methylation of tumorigenic cells is associated with a more favorable prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'Var', (26, 37))	('CD133', 'Protein', (20, 25))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
243286	26757925	While, patients with methylated CD133 promoter showed a tendency to an increased PFS (271.0 weeks, 95 % CI, 235.7-306.3) and OS (286.2 weeks, 95 % CI, 260.5-311.9).	('PFS', 'CPA', (81, 84))	('methylated', 'Var', (21, 31))	('CD133', 'Gene', (32, 37))	('increased', 'PosReg', (71, 80))	('patients', 'Species', '9606', (7, 15))
243287	26757925	Such analysis indicated a strong correlation between CD133 promoter methylation status and both overall (P = 0.008) and progression-free (P = 0.035) survival, suggesting that CD133 methylation of tumorigenic cells is associated with a more favorable prognosis in LGG patients.	('patients', 'Species', '9606', (267, 275))	('tumor', 'Disease', (196, 201))	('methylation', 'Var', (181, 192))	('CD133', 'Gene', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('LGG', 'Disease', (263, 266))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
243289	26757925	While, patients with methylated CD133 promoter showed a tendency to an increased PFS (139.5 weeks, 95 % CI, 100.5-178.5) and OS (172.2 weeks, 95 % CI, 128.8-215.7).	('PFS', 'CPA', (81, 84))	('methylated', 'Var', (21, 31))	('CD133', 'Gene', (32, 37))	('increased', 'PosReg', (71, 80))	('patients', 'Species', '9606', (7, 15))
243290	26757925	Such analysis indicated a strong correlation between CD133 promoter methylation status and both overall (P < 0.01) and progression-free (P < 0.01) survival, suggesting that CD133 methylation of tumorigenic cells is also associated with a more favorable prognosis in HGG patients.	('patients', 'Species', '9606', (270, 278))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('CD133', 'Gene', (173, 178))	('HGG', 'Disease', (266, 269))	('methylation', 'Var', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))
243306	26757925	The presence of CD133 CpG island methylation in glioma patients was associated with grades of glioma.	('methylation', 'Var', (33, 44))	('associated', 'Reg', (68, 78))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Disease', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('CD133', 'Gene', (16, 21))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('patients', 'Species', '9606', (55, 63))	('presence', 'Var', (4, 12))	('glioma', 'Disease', (48, 54))
243310	26757925	We found CD133 hypermethylation to be significantly (almost two-fold) more common in long-term survivors (74 %) as compared to in short-term survivors (43 %) not only in high grade glioma, but in low grade glioma.	('CD133', 'Gene', (9, 14))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('hypermethylation', 'Var', (15, 31))	('glioma', 'Disease', (181, 187))	('common', 'Reg', (75, 81))	('more', 'PosReg', (70, 74))	('glioma', 'Disease', (206, 212))
243311	26757925	Multivariate analysis indicated CD133 methylation was a significant prognostic factor in gliomas, independent of tumor grade, extent of resection, and patient age.	('tumor', 'Disease', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('methylation', 'Var', (38, 49))	('patient', 'Species', '9606', (151, 158))	('CD133', 'Gene', (32, 37))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
243323	26757925	This result may be explained by the bona fide cancer stem cell being a subpopulation of the CD133+ tumor cells, but it is also likely that other non tumor stem cells apart from endothelial cells express CD133.	('tumor', 'Disease', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CD133', 'Var', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
243327	26757925	As discussed previously, another possible explanation for this finding is CD133 protein expression in entrapped pre-existing endothelial cells, which is confirmed by flow cytometry showing that CD133+ cells could have either blood vessel or glioma origin.	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('blood vessel', 'Disease', (225, 237))	('blood vessel', 'Disease', 'MESH:D009383', (225, 237))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('CD133', 'Gene', (74, 79))	('CD133+', 'Var', (194, 200))	('glioma', 'Disease', (241, 247))
243332	26757925	These data provide strong supportive evidence for the CSC model and the clinical relevance of the CD133 methylation status in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('CD133', 'Gene', (98, 103))	('methylation', 'Var', (104, 115))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))
243462	24146911	One recent report identified IDH mutation in Grades 2 and 3 astrocytomas as an indicator of better clinical outcome-addressing a pertinent challenge, as these lower-grade astrocytomas can have widely variable outcomes.	('astrocytomas', 'Disease', (60, 72))	('mutation', 'Var', (33, 41))	('astrocytomas', 'Disease', 'MESH:D001254', (171, 183))	('astrocytoma', 'Phenotype', 'HP:0009592', (171, 182))	('astrocytomas', 'Disease', (171, 183))	('IDH', 'Gene', (29, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (60, 72))	('IDH', 'Gene', '3417', (29, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))
243477	24146911	We selected differentially expressed genes (DEGs) for each adjacent pair of astrocytoma grades, (control vs. G2, G2 vs. G3, etc.)	('astrocytoma', 'Disease', 'MESH:D001254', (76, 87))	('G2 vs.', 'Var', (113, 119))	('astrocytoma', 'Disease', (76, 87))	('astrocytoma', 'Phenotype', 'HP:0009592', (76, 87))
243507	24146911	Up to 40% of GBMs display deletions in EGFR rendering it constitutively active, while others overexpress it through amplification or up-regulation of expression.	('expression', 'MPA', (150, 160))	('deletions', 'Var', (26, 35))	('up-regulation', 'PosReg', (133, 146))	('overexpress', 'PosReg', (93, 104))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
243509	24146911	Our observation that NOTCH shows greater variability in expression ordering at the higher grade-from 0.908 (in G2 tumors) to 0.856 (in G3 tumors)-supports the hypothesis that it plays different roles in tumorigenesis of low-grade astrocytomas and high-grade gliomas.	('tumor', 'Disease', (203, 208))	('0.856', 'Var', (125, 130))	('tumor', 'Disease', (138, 143))	('astrocytomas', 'Disease', (230, 242))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('gliomas', 'Disease', (258, 265))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('tumor', 'Disease', (114, 119))	('gliomas', 'Disease', 'MESH:D005910', (258, 265))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('astrocytomas', 'Disease', 'MESH:D001254', (230, 242))	('astrocytoma', 'Phenotype', 'HP:0009592', (230, 241))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('gliomas', 'Phenotype', 'HP:0009733', (258, 265))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', (114, 120))
243522	24146911	In addition, S1P connects to the earlier mentioned EGFR pathway through two sterol-regulatory element-binding proteins (SREBF1 and SREBF2) that are activated by PI3K.	('PI3K', 'Var', (161, 165))	('EGFR', 'Gene', (51, 55))	('SREBF1', 'Gene', '6720', (120, 126))	('SREBF2', 'Gene', (131, 137))	('S1P', 'Gene', '8720', (13, 16))	('SREBF1', 'Gene', (120, 126))	('S1P', 'Gene', (13, 16))	('activated', 'PosReg', (148, 157))	('SREBF2', 'Gene', '6721', (131, 137))	('EGFR', 'Gene', '1956', (51, 55))
243524	24146911	It has been reported that EGFR mutations (EGFRVIII) and PI3K promote tumor growth and survival through SREBP-1 dependent lipogenesis.	('EGFR', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (31, 40))	('EGFR', 'Gene', '1956', (42, 46))	('tumor', 'Disease', (69, 74))	('promote', 'PosReg', (61, 68))	('EGFR', 'Gene', (42, 46))	('lipogenesis', 'MPA', (121, 132))	('survival', 'CPA', (86, 94))	('EGFR', 'Gene', '1956', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('SREBP-1', 'Gene', (103, 110))	('SREBP-1', 'Gene', '6720', (103, 110))
243527	24146911	IDH mutations are commonly observed in lower-grade and secondary GBMs but rarely in primary GBMs.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('lower-grade', 'Disease', (39, 50))	('observed', 'Reg', (27, 35))	('mutations', 'Var', (4, 13))
243528	24146911	Thus, this network links IDH mutation to lipid homeostasis.	('mutation', 'Var', (29, 37))	('IDH', 'Gene', (25, 28))	('IDH', 'Gene', '3417', (25, 28))	('links', 'Reg', (19, 24))	('lipid', 'Chemical', 'MESH:D008055', (41, 46))	('lipid homeostasis', 'MPA', (41, 58))
243553	24146911	Loss of this region is known to occur in several cancers, and it is conceivable that loss of CPEB3 contributes to altered EGFR signaling along with PTEN loss.	('loss', 'Var', (85, 89))	('PTEN', 'Gene', (148, 152))	('PTEN', 'Gene', '5728', (148, 152))	('CPEB3', 'Gene', '22849', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('altered', 'Reg', (114, 121))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('EGFR', 'Gene', '1956', (122, 126))	('CPEB3', 'Gene', (93, 98))	('EGFR', 'Gene', (122, 126))
243570	24146911	Knockout of ACSL4 in embryonic stem cells was shown to significantly reduce neuronal differentiation.	('neuronal differentiation', 'CPA', (76, 100))	('ACSL4', 'Gene', '2182', (12, 17))	('ACSL4', 'Gene', (12, 17))	('Knockout', 'Var', (0, 8))	('reduce', 'NegReg', (69, 75))
243597	32851798	Function assays indicated that KLHDC8A knockdown inhibited proliferation, migration and invasion, blocked the cell cycle and promoted apoptosis in glioma cells.	('proliferation', 'CPA', (59, 72))	('invasion', 'CPA', (88, 96))	('knockdown', 'Var', (39, 48))	('blocked', 'NegReg', (98, 105))	('apoptosis', 'CPA', (134, 143))	('KLHDC8A', 'Gene', (31, 38))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('cell cycle', 'CPA', (110, 120))	('migration', 'CPA', (74, 83))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('glioma', 'Disease', (147, 153))	('inhibited', 'NegReg', (49, 58))	('promoted', 'PosReg', (125, 133))
243638	32851798	Small interfering RNA (siRNA) method was applied to knockdown KLHDC8A and LDHA.	('LDHA', 'Gene', (74, 78))	('knockdown', 'Var', (52, 61))	('KLHDC8A', 'Gene', (62, 69))	('LDHA', 'Gene', '3939', (74, 78))
243665	32851798	These results suggest that high expression of KLHDC8A may play a role in the development of glioma.	('glioma', 'Disease', (92, 98))	('high', 'Var', (27, 31))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('KLHDC8A', 'Gene', (46, 53))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('play', 'Reg', (58, 62))
243667	32851798	The RT-qPCR and Western blot assay shown that the mRNA level of KLHDC8A was significantly decreased in U87MG and U251 cells following KLHDC8A siRNAs transfection compared with negative control siRNA (Figure S2).	('transfection', 'Var', (149, 161))	('mRNA level of', 'MPA', (50, 63))	('decreased', 'NegReg', (90, 99))	('U251', 'CellLine', 'CVCL:0021', (113, 117))	('U87MG', 'CellLine', 'CVCL:0022', (103, 108))	('KLHDC8A', 'Var', (134, 141))
243669	32851798	As shown in Figure 3A,B, glioma cell growth was inhibited when the expression of KLHDC8A was knockdown.	('knockdown', 'Var', (93, 102))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('inhibited', 'NegReg', (48, 57))	('expression', 'MPA', (67, 77))	('glioma', 'Disease', (25, 31))	('KLHDC8A', 'Gene', (81, 88))
243670	32851798	Meanwhile, KLHDC8A knockdown also caused a decrease in glioma cell colony formation (Figure 3C).	('glioma', 'Disease', (55, 61))	('decrease', 'NegReg', (43, 51))	('KLHDC8A', 'Gene', (11, 18))	('knockdown', 'Var', (19, 28))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))
243673	32851798	In U87MG cells, the percentage of cells in the G0/G1 phase was increased from 57.0% (NC) to 64.7% (KLHDC8A siRNA), while the S phase was decreased from 27.25% (NC) to 21.72% (KLHDC8A siRNA).	('U87MG', 'Var', (3, 8))	('increased', 'PosReg', (63, 72))	('G0/G1 phase', 'CPA', (47, 58))	('U87MG', 'CellLine', 'CVCL:0022', (3, 8))
243675	32851798	Collectively, these results indicated that KLHDC8A knockdown could affect the progression of the cell cycle by inducing the G0/G1 phase arrest.	('inducing', 'PosReg', (111, 119))	('knockdown', 'Var', (51, 60))	('affect', 'Reg', (67, 73))	('progression of the cell cycle', 'CPA', (78, 107))	('arrest', 'Disease', (136, 142))	('arrest', 'Disease', 'MESH:D006323', (136, 142))	('KLHDC8A', 'Gene', (43, 50))
243684	32851798	As shown in Figure 5B, KLHDC8A knockdown inhibited the expression of the phosphorylated forms of ERK and p38 MAPK.	('p38 MAPK', 'Gene', '26416', (105, 113))	('ERK', 'Gene', (97, 100))	('p38 MAPK', 'Gene', (105, 113))	('expression', 'MPA', (55, 65))	('phosphorylated', 'MPA', (73, 87))	('inhibited', 'NegReg', (41, 50))	('knockdown', 'Var', (31, 40))
243688	32851798	The ratio of Bcl2/BAX and expression of MMP2 were increased in glioma cell with the KLHDC8A plasmid (Figure 6E).	('expression', 'MPA', (26, 36))	('ratio', 'MPA', (4, 9))	('increased', 'PosReg', (50, 59))	('Bcl2/BAX', 'MPA', (13, 21))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('KLHDC8A', 'Var', (84, 91))	('MMP2', 'Gene', (40, 44))	('glioma', 'Disease', (63, 69))
243690	32851798	When KLHDC8A overexpressed glioma cells were pretreated with ERK inhibitor U1026 and p38 MAPK inhibitor SB203580, 26 ,  27  phosphorylation of ERK and p38 MAPK was depressed.	('glioma', 'Disease', (27, 33))	('U1026', 'Var', (75, 80))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('U1026', 'Chemical', '-', (75, 80))	('p38 MAPK', 'Gene', '26416', (151, 159))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('p38 MAPK', 'Gene', '26416', (85, 93))	('SB203580', 'Chemical', 'MESH:C093642', (104, 112))	('phosphorylation', 'MPA', (124, 139))	('p38 MAPK', 'Gene', (151, 159))	('p38 MAPK', 'Gene', (85, 93))	('depressed', 'NegReg', (164, 173))
243698	32851798	Furthermore, knockdown of LDHA, which catalyses the conversion of pyruvate to lactate in glycolysis, 30  resulted in the decrease of glucose-induced expression of KLHDC8A (Figure 7D and Figure S4).	('lactate', 'Chemical', 'MESH:D019344', (78, 85))	('glucose-induced expression', 'MPA', (133, 159))	('KLHDC8A', 'Gene', (163, 170))	('pyruvate', 'Chemical', 'MESH:D019289', (66, 74))	('decrease', 'NegReg', (121, 129))	('glucose', 'Chemical', 'MESH:D005947', (133, 140))	('LDHA', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('LDHA', 'Gene', '3939', (26, 30))
243708	32851798	Meanwhile, DeltaEGFR knockdown significantly promoted the activation of ERK and p38 MAPK pathways.	('p38 MAPK', 'Gene', (80, 88))	('promoted', 'PosReg', (45, 53))	('activation', 'PosReg', (58, 68))	('knockdown', 'Var', (21, 30))	('DeltaEGFR', 'Gene', (11, 20))	('p38 MAPK', 'Gene', '26416', (80, 88))
243711	32851798	Interestingly, we found a significant decrease in the phosphorylation of both ERK and p38 MAPK after silencing of KLHDC8A.	('p38 MAPK', 'Gene', (86, 94))	('silencing', 'Var', (101, 110))	('KLHDC8A', 'Gene', (114, 121))	('decrease', 'NegReg', (38, 46))	('p38 MAPK', 'Gene', '26416', (86, 94))	('ERK', 'Protein', (78, 81))	('phosphorylation', 'MPA', (54, 69))
243713	32851798	Our further research data showed that both U0126 and SB203580 could abolish KLHDC8A overexpression-induced activation of ERK and p38 MAPK.	('SB203580', 'Chemical', 'MESH:C093642', (53, 61))	('SB203580', 'Var', (53, 61))	('p38 MAPK', 'Gene', '26416', (129, 137))	('U0126', 'Var', (43, 48))	('p38 MAPK', 'Gene', (129, 137))	('KLHDC8A', 'Gene', (76, 83))	('ERK', 'Pathway', (121, 124))	('U0126', 'Chemical', 'MESH:C113580', (43, 48))	('abolish', 'NegReg', (68, 75))	('activation', 'PosReg', (107, 117))
243714	32851798	Therefore, we hypothesized KLHDC8A-promoted glioma cells proliferation, migration and invasion via activating ERK/P38 MAPK pathway.	('activating', 'PosReg', (99, 109))	('KLHDC8A-promoted', 'Var', (27, 43))	('migration', 'CPA', (72, 81))	('P38 MAPK', 'Gene', (114, 122))	('KLHDC8A-promoted', 'PosReg', (27, 43))	('glioma', 'Disease', (44, 50))	('P38 MAPK', 'Gene', '26416', (114, 122))	('invasion', 'CPA', (86, 94))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
243724	32851798	KLHDC8A also modulates the ERK and p38 MAPK pathways.	('modulates', 'Reg', (13, 22))	('KLHDC8A', 'Var', (0, 7))	('p38 MAPK', 'Gene', '26416', (35, 43))	('p38 MAPK', 'Gene', (35, 43))
243768	30941158	We first identify 2,183 DEGs by performing leave-one-out meta-analysis (section 2.1) on four mRNA datasets (GSE7696, GSE4290, GSE90598, and GSE22866).	('GSE4290', 'Chemical', '-', (117, 124))	('GSE7696', 'Chemical', '-', (108, 115))	('GSE4290', 'Var', (117, 124))	('GSE22866', 'Var', (140, 148))	('GSE90598', 'Var', (126, 134))	('GSE7696', 'Var', (108, 115))
243769	30941158	Similarly, we analyze five methylation datasets (GSE60274, GSE22867, GSE50923, GSE79122, and GSE36278) and identify 1,205 DMGs.	('GSE50923', 'Var', (69, 77))	('GSE22867', 'Var', (59, 67))	('GSE36278', 'Var', (93, 101))	('DMGs', 'Chemical', '-', (122, 126))	('GSE60274', 'Var', (49, 57))	('GSE79122', 'Var', (79, 87))
243779	30941158	Similar to the previous study, here we perform leave-one-out meta-analysis on five mRNA datasets (GSE16011_cohort1, GSE16011_cohort2, GSE4290, GSE68848, and GSE4271) and three DNA methylation datasets (GSE90496, GSE109379, and GSE53227), and identify 1,564 DEGs and 2,721 DMGs respectively.	('GSE109379', 'Var', (212, 221))	('GSE16011_cohort2', 'Var', (116, 132))	('GSE4290', 'Chemical', '-', (134, 141))	('GSE16011_cohort1', 'Var', (98, 114))	('GSE68848', 'Var', (143, 151))	('GSE90496', 'Var', (202, 210))	('DMGs', 'Chemical', '-', (272, 276))	('GSE4290', 'Var', (134, 141))	('GSE53227', 'Var', (227, 235))	('GSE4271', 'Var', (157, 164))
243901	26545867	The median survival period was longer for patients who underwent total or subtotal resection compared with those who only underwent partial resection or biopsy (28 vs. 12 months, respectively).	('subtotal resection', 'Var', (74, 92))	('patients', 'Species', '9606', (42, 50))	('longer', 'PosReg', (31, 37))
244025	25838967	In the next step, because of color differences between MVP regions and non-MVP regions we desire to have different color shadings in the smoothed image such that MVP regions have darker pixel intensities and non-MVP regions are relatively brighter.	('MVP', 'Chemical', '-', (55, 58))	('darker', 'PosReg', (179, 185))	('pixel intensities', 'MPA', (186, 203))	('MVP', 'Chemical', '-', (162, 165))	('MVP', 'Chemical', '-', (75, 78))	('MVP', 'Var', (162, 165))	('MVP', 'Chemical', '-', (212, 215))
244082	30984614	Gangliogliomas harbor molecular deficiencies such as mutations in the B-rapidly accelerated fibrosarcoma (BRAF) gene, resulting in activation of a downstream signaling pathway and cancer development.	('activation', 'PosReg', (131, 141))	('B-rapidly accelerated fibrosarcoma', 'Gene', (70, 104))	('Gangliogliomas harbor molecular deficiencies', 'Disease', 'MESH:D018303', (0, 44))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('BRAF', 'Gene', '673', (106, 110))	('B-rapidly accelerated fibrosarcoma', 'Gene', '673', (70, 104))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (92, 104))	('mutations', 'Var', (53, 62))	('BRAF', 'Gene', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('gliomas', 'Phenotype', 'HP:0009733', (7, 14))	('downstream signaling pathway', 'Pathway', (147, 175))	('cancer', 'Disease', (180, 186))	('Gangliogliomas harbor molecular deficiencies', 'Disease', (0, 44))
244083	30984614	Vemurafenib is a BRAF inhibitor used to treat patients with BRAF V600E-mutated cancer.	('patients', 'Species', '9606', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('BRAF', 'Gene', '673', (17, 21))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (17, 21))	('V600E-mutated', 'Var', (65, 78))	('V600E', 'Mutation', 'rs113488022', (65, 70))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
244088	30984614	This is the first reported case of a response to vemurafenib in an adult with progressive spinal cord BRAF V600E-mutated ganglioglioma which was sustained after treatment discontinuation.	('glioma', 'Disease', (128, 134))	('BRAF', 'Gene', '673', (102, 106))	('vemurafenib', 'Chemical', 'MESH:D000077484', (49, 60))	('BRAF', 'Gene', (102, 106))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('V600E-mutated', 'Var', (107, 120))	('V600E', 'Mutation', 'rs113488022', (107, 112))
244098	30984614	One of the mutational hot spots of BRAF is at nucleotide 1799; mutations at this site lead to the exchange of valine with glutamate at amino acid position 600.	('mutations', 'Var', (63, 72))	('BRAF', 'Gene', (35, 39))	('exchange', 'Var', (98, 106))	('valine with glutamate at amino acid position 600', 'Mutation', 'rs113488022', (110, 158))	('valine with glutamate', 'MPA', (110, 131))	('lead to', 'Reg', (86, 93))	('BRAF', 'Gene', '673', (35, 39))
244099	30984614	The BRAF V600E mutant constitutively activates downstream signaling pathways.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('activates', 'PosReg', (37, 46))	('downstream signaling pathways', 'Pathway', (47, 76))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))
244101	30984614	Therefore, MAPK pathway inhibition is an attractive treatment option for recurrent or high-grade ganglioglioma.	('MAPK pathway', 'Pathway', (11, 23))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('inhibition', 'Var', (24, 34))	('glioma', 'Disease', (104, 110))
244102	30984614	Vemurafenib is a competitive small-molecule serine-threonine kinase inhibitor that functions by binding to the ATP-binding domain of mutant BRAF.	('binding', 'Interaction', (96, 103))	('BRAF', 'Gene', '673', (140, 144))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (140, 144))	('ATP', 'Chemical', 'MESH:D000255', (111, 114))	('mutant', 'Var', (133, 139))
244105	30984614	Some case reports have shown an objective tumor response to BRAF inhibitor treatment alone or in combination with chemotherapy or targeted therapy in pediatric and young adult BRAF V600E gangliogliomas.	('tumor', 'Disease', (42, 47))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('gliomas', 'Disease', (194, 201))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('V600E', 'Mutation', 'rs113488022', (181, 186))	('BRAF', 'Gene', '673', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('V600E', 'Var', (181, 186))	('BRAF', 'Gene', (176, 180))
244109	30984614	Herein, we describe a case of successful treatment with vemurafenib in a patient with a BRAF V600E-mutated progressive cervical spinal cord ganglioglioma, with a stable disease 21 months after treatment discontinuation.	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('spinal cord ganglioglioma', 'Disease', (128, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('patient', 'Species', '9606', (73, 80))	('vemurafenib', 'Chemical', 'MESH:D000077484', (56, 67))	('V600E', 'Mutation', 'rs113488022', (93, 98))	('V600E-mutated', 'Var', (93, 106))	('spinal cord ganglioglioma', 'Disease', 'MESH:D013118', (128, 153))
244121	30984614	Despite the presence of an IDH mutation, central pathological review led to the diagnosis of WHO grade I ganglioglioma.	('IDH', 'Gene', (27, 30))	('IDH', 'Gene', '3417', (27, 30))	('mutation', 'Var', (31, 39))	('glioma', 'Disease', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
244127	30984614	The results revealed a V600E BRAF mutation and no mutation in RAS.	('V600E', 'Mutation', 'rs113488022', (23, 28))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))
244147	30984614	In a recent study of 142 cases, all gangliogliomas in the cervicomedullary junction and all BRAF mutation-positive ganglioglioma were contrast-positive.	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('BRAF', 'Gene', '673', (92, 96))	('glioma', 'Disease', (43, 49))	('BRAF', 'Gene', (92, 96))	('glioma', 'Disease', (122, 128))	('gliomas', 'Disease', 'MESH:D005910', (43, 50))	('gliomas', 'Phenotype', 'HP:0009733', (43, 50))	('gliomas', 'Disease', (43, 50))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('mutation-positive', 'Var', (97, 114))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
244158	30984614	The presence of the BRAF V600E mutation suggests that use of BRAF inhibitors are efficient for treating recurrent gangliogliomas.	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('gliomas', 'Disease', (121, 128))	('BRAF', 'Gene', '673', (61, 65))	('V600E', 'Var', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('BRAF', 'Gene', (61, 65))	('BRAF', 'Gene', '673', (20, 24))	('V600E', 'Mutation', 'rs113488022', (25, 30))	('BRAF', 'Gene', (20, 24))
244159	30984614	BRAF mutation appears in 8% of human cancers.	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('human', 'Species', '9606', (31, 36))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('BRAF', 'Gene', '673', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
244160	30984614	The BRAF V600E mutation was found more often in pediatric low-grade than in high-grade gliomas, likely because low-grade gliomas are the most frequent brain tumors in children.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('brain tumors', 'Disease', 'MESH:D001932', (151, 163))	('brain tumors', 'Phenotype', 'HP:0030692', (151, 163))	('children', 'Species', '9606', (167, 175))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('gliomas', 'Disease', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('brain tumors', 'Disease', (151, 163))	('gliomas', 'Disease', (87, 94))	('gliomas', 'Disease', 'MESH:D005910', (121, 128))	('V600E', 'Var', (9, 14))	('low-grade', 'Disease', (58, 67))
244161	30984614	Patients with BRAF V600E mutation exhibit shorter progression-free survival.	('V600E', 'Mutation', 'rs113488022', (19, 24))	('shorter', 'NegReg', (42, 49))	('V600E', 'Var', (19, 24))	('BRAF', 'Gene', '673', (14, 18))	('progression-free survival', 'CPA', (50, 75))	('Patients', 'Species', '9606', (0, 8))	('BRAF', 'Gene', (14, 18))
244163	30984614	BRAF V600E mutations were detected in nearly 20% of gangliogliomas in a screen of 1,320 nervous system tumors.	('gliomas', 'Disease', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('nervous system tumors', 'Disease', (88, 109))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('nervous system tumors', 'Phenotype', 'HP:0004375', (88, 109))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('detected', 'Reg', (26, 34))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('nervous system tumors', 'Disease', 'MESH:D009423', (88, 109))
244167	30984614	Another group identified only two tumors among 19 (10%) intramedullary gangliogliomas harboring a BRAF V600E mutation.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumors', 'Disease', (34, 40))	('V600E', 'Var', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
244169	30984614	IDH mutations were reported in 8% of cases in a series of 100 gangliogliomas.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', (69, 76))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('mutations', 'Var', (4, 13))
244170	30984614	In the 2016 WHO classification, detection of IDH1 mutation in a tumor resembling a ganglioglioma strongly supported the diagnosis of an infiltrating glioma with ensnared neurons.	('IDH1', 'Gene', '3417', (45, 49))	('tumor', 'Disease', (64, 69))	('glioma', 'Disease', (149, 155))	('glioma', 'Disease', (90, 96))	('supported', 'Reg', (106, 115))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('IDH1', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutation', 'Var', (50, 58))
244171	30984614	However, as observed in our patient, it has been increasingly recognized that some circumscribed gliomas can harbor mutations typically encountered in diffuse gliomas (such as IDH and histone mutations).	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('IDH', 'Gene', (176, 179))	('IDH', 'Gene', '3417', (176, 179))	('patient', 'Species', '9606', (28, 35))	('mutations', 'Var', (116, 125))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
244172	30984614	Occasionally, H3K27M mutations have been reported in midline gangliogliomas.	('midline gangliogliomas', 'Disease', (53, 75))	('reported', 'Reg', (41, 49))	('midline gangliogliomas', 'Disease', 'MESH:D018303', (53, 75))	('mutations', 'Var', (21, 30))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('H3K27M', 'Protein', (14, 20))
244206	29499945	The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs.	('upregulated', 'PosReg', (36, 47))	('FOXP2', 'Gene', '93986', (80, 85))	('FOXP1', 'Gene', (74, 79))	('migration', 'CPA', (111, 120))	('FOXP1', 'Gene', (19, 24))	('expressions', 'MPA', (4, 15))	('FOXP2', 'Gene', (25, 30))	('viability', 'CPA', (100, 109))	('silencing', 'Var', (61, 70))	('tube formation of GECs', 'CPA', (126, 148))	('FOXP2', 'Gene', (80, 85))	('FOXP1', 'Gene', '27086', (19, 24))	('inhibited', 'NegReg', (86, 95))	('FOXP1', 'Gene', '27086', (74, 79))	('FOXP2', 'Gene', '93986', (25, 30))
244208	29499945	Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways.	('extracellular signal-regulated kinase (ERK)1/2', 'Gene', '5594;5595', (145, 191))	('viability', 'CPA', (47, 56))	('tube formation of', 'CPA', (73, 90))	('AKT', 'Gene', '207', (137, 140))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (100, 129))	('knockdown', 'Var', (13, 22))	('AGGF1', 'Gene', (26, 31))	('AKT', 'Gene', (137, 140))	('phosphatidylinositol 3-kinase', 'Gene', (100, 129))	('migration', 'CPA', (58, 67))	('suppressed', 'NegReg', (32, 42))
244209	29499945	Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.	('circ-SHKBP1', 'Var', (52, 63))	('FOXP1', 'Gene', '27086', (116, 121))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('FOXP2', 'Gene', (134, 139))	('FOXP2', 'Gene', '93986', (134, 139))	('FOXP1', 'Gene', (116, 121))	('gliomas', 'Disease', (249, 256))	('gliomas', 'Phenotype', 'HP:0009733', (249, 256))	('gliomas', 'Disease', 'MESH:D005910', (249, 256))	('regulated', 'Reg', (64, 73))	('miR-544a', 'Gene', '664613', (107, 115))	('angiogenesis of GECs', 'CPA', (78, 98))	('miR-544a', 'Gene', (107, 115))
244222	29499945	Both miR-379 and miR-544a are members of the miR-379-410 gene cluster, which is located on chromosome 14q32.31.	('miR-379', 'Var', (5, 12))	('miR-544a', 'Gene', (17, 25))	('miR-544a', 'Gene', '664613', (17, 25))
244234	29499945	FOXP2 is upregulated in the SH-SY5Y human neuroblastoma cell line, and a high level of FOXP2 leads to poor overall and relapse-free survival in patients.	('overall', 'CPA', (107, 114))	('FOXP2', 'Gene', (0, 5))	('upregulated', 'PosReg', (9, 20))	('high level', 'Var', (73, 83))	('relapse-free survival', 'CPA', (119, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (42, 55))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (28, 35))	('poor', 'NegReg', (102, 106))	('FOXP2', 'Gene', (87, 92))	('patients', 'Species', '9606', (144, 152))	('FOXP2', 'Gene', '93986', (0, 5))	('neuroblastoma', 'Disease', 'MESH:D009447', (42, 55))	('FOXP2', 'Gene', '93986', (87, 92))	('human', 'Species', '9606', (36, 41))	('neuroblastoma', 'Disease', (42, 55))
244239	29499945	Recent studies have revealed that AGGF1 can promote angiogenesis by stimulating proliferation, migration, and sprouting of endothelial cells, and overexpression of AGGF1 leads to increased angiogenesis by activating the AKT pathway in zebrafish embryos.	('AKT', 'Gene', (220, 223))	('angiogenesis', 'CPA', (52, 64))	('stimulating', 'PosReg', (68, 79))	('sprouting of endothelial cells', 'CPA', (110, 140))	('promote', 'PosReg', (44, 51))	('AGGF1', 'Gene', (164, 169))	('AGGF1', 'Gene', (34, 39))	('proliferation', 'CPA', (80, 93))	('overexpression', 'Var', (146, 160))	('AKT', 'Gene', '207', (220, 223))	('zebrafish', 'Species', '7955', (235, 244))	('activating', 'Reg', (205, 215))	('migration', 'CPA', (95, 104))	('increased', 'PosReg', (179, 188))	('angiogenesis', 'CPA', (189, 201))
244244	29499945	These data suggest that knockdown of circ-SHKBP1 impaired the angiogenesis of human glioma.	('human', 'Species', '9606', (78, 83))	('glioma', 'Disease', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('angiogenesis of human', 'CPA', (62, 83))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('knockdown', 'Var', (24, 33))	('impaired', 'NegReg', (49, 57))	('circ-SHKBP1', 'Gene', (37, 48))
244246	29499945	Overexpression or silencing of miR-544a/miR-379 was performed to further understand their role in the angiogenesis of GECs, and the transfection efficiency was evaluated by qRT-PCR (Figures S1G and S1H).	('miR-544a', 'Gene', (31, 39))	('silencing', 'Var', (18, 27))	('miR-544a', 'Gene', '664613', (31, 39))
244248	29499945	These data indicated that miR-544a and miR-379 significantly inhibited the angiogenesis of GECs.	('inhibited', 'NegReg', (61, 70))	('miR-544a', 'Gene', '664613', (26, 34))	('miR-544a', 'Gene', (26, 34))	('angiogenesis of GECs', 'CPA', (75, 95))	('miR-379', 'Var', (39, 46))
244249	29499945	Furthermore, overexpression of both miR-544a and miR-379 was simultaneously performed to detect the co-effects on the viability, migration, tube formation of GECs, and angiogenesis in vivo.	('miR-379', 'Var', (49, 56))	('miR-544a', 'Gene', (36, 44))	('migration', 'CPA', (129, 138))	('tube formation of GECs', 'CPA', (140, 162))	('angiogenesis', 'CPA', (168, 180))	('miR-544a', 'Gene', '664613', (36, 44))
244254	29499945	As expected, the relative luciferase activity was markedly suppressed (0.4934 +- 0.1050-fold) in the circ-SHKBP1 wild-type (WT) + miR-544a (+) group compared with that in the circ-SHKBP1 WT + miR-544a (+) NC group.	('miR-544a', 'Gene', '664613', (130, 138))	('miR-544a', 'Gene', '664613', (192, 200))	('circ-SHKBP1', 'Var', (101, 112))	('luciferase', 'Enzyme', (26, 36))	('miR-544a', 'Gene', (130, 138))	('suppressed', 'NegReg', (59, 69))	('miR-544a', 'Gene', (192, 200))	('activity', 'MPA', (37, 45))
244255	29499945	Nevertheless, there was no significant difference between the circ-SHKBP1 mutant (Mut) + miR-544a (+) group and the circ-SHKBP1 Mut + miR-544a (+) NC group (Figure 3C).	('miR-544a', 'Gene', '664613', (134, 142))	('miR-544a', 'Gene', '664613', (89, 97))	('miR-544a', 'Gene', (89, 97))	('miR-544a', 'Gene', (134, 142))	('mutant', 'Var', (74, 80))
244258	29499945	Subsequently, the expressions of miR-544a/miR-379 were significantly increased in the circ-SHKBP1 (-) group compared with the circ-SHKBP1 (-) NC group (Figures 3E and 3F).	('circ-SHKBP1', 'Var', (86, 97))	('increased', 'PosReg', (69, 78))	('miR-544a', 'Gene', (33, 41))	('expressions', 'MPA', (18, 29))	('miR-544a', 'Gene', '664613', (33, 41))
244259	29499945	Similarly, the expression of circ-SHKBP1 was significantly enhanced (1.5500 +- 0.1114 or 1.6900 +- 0.1153-fold) in the miR-544a (-) or miR-379 (-) group (Figures 3G and 3H).	('miR-544a', 'Gene', '664613', (119, 127))	('miR-544a', 'Gene', (119, 127))	('enhanced', 'PosReg', (59, 67))	('expression', 'MPA', (15, 25))	('miR-379', 'Var', (135, 142))	('circ-SHKBP1', 'Gene', (29, 40))
244272	29499945	In addition, the mRNA and protein expressions of FOXP1/FOXP2 were significantly reduced (0.5633 +- 0.1012/0.5567 +- 0.0982-fold and 0.5867 +- 0.0862/0.5933 +- 0.0851-fold) in the circ-SHKBP1 (-) group compared with the circ-SHKBP1 (-) NC group (Figures 4G-4J).	('reduced', 'NegReg', (80, 87))	('FOXP1', 'Gene', '27086', (49, 54))	('FOXP2', 'Gene', (55, 60))	('FOXP1', 'Gene', (49, 54))	('0.5867 +- 0.0862/0.5933 +- 0.0851-fold', 'Var', (132, 170))	('FOXP2', 'Gene', '93986', (55, 60))
244273	29499945	Meanwhile, the mRNA and protein expressions of FOXP1/FOXP2 were significantly decreased (0.3500 +- 0.0889/0.4267 +- 0.0643 folds and 0.3600 +- 0.0781/0.4533 +- 0.1222-fold) in the miR-544a/miR-379 (+) group compared with those in the miR-544a/miR-379 (+) NC group (Figures 4K-4N).	('0.3600 +- 0.0781/0.4533 +- 0.1222-fold', 'Var', (133, 171))	('miR-544a', 'Gene', (180, 188))	('FOXP2', 'Gene', '93986', (53, 58))	('FOXP1', 'Gene', '27086', (47, 52))	('FOXP1', 'Gene', (47, 52))	('miR-544a', 'Gene', '664613', (234, 242))	('miR-544a', 'Gene', (234, 242))	('miR-544a', 'Gene', '664613', (180, 188))	('decreased', 'NegReg', (78, 87))	('FOXP2', 'Gene', (53, 58))
244274	29499945	Furthermore, the mRNA and protein expressions of FOXP1/FOXP2 were significantly reduced (0.3333 +- 0.1285/0.2600 +- 0.0458 folds and 0.3100 +- 0.1277/0.2800 +- 0.0600-fold) in the circ-SHKBP1 (-) + miR-544a/miR-379 (+) group compared with those in the circ-SHKBP1 (-) NC + miR-544a/miR-379 (+) NC group (Figures 4O-4R).	('miR-544a', 'Gene', '664613', (273, 281))	('miR-544a', 'Gene', (198, 206))	('miR-544a', 'Gene', (273, 281))	('reduced', 'NegReg', (80, 87))	('FOXP1', 'Gene', '27086', (49, 54))	('0.3100 +- 0.1277/0.2800 +- 0.0600-fold', 'Var', (133, 171))	('FOXP2', 'Gene', (55, 60))	('FOXP1', 'Gene', (49, 54))	('miR-544a', 'Gene', '664613', (198, 206))	('FOXP2', 'Gene', '93986', (55, 60))
244275	29499945	However, there was no significant difference between the circ-SHKBP1 (-) + miR-544a/miR-379 (-) and circ-SHKBP1 (-) NC + miR-544a/miR-379 (-) NC groups, which indicated the reduction of FOXP1/FOXP2 mediated by circ-SHKBP1 knockdown was reversed by miR-544a/miR-379 silencing.	('FOXP1', 'Gene', (186, 191))	('miR-544a', 'Gene', '664613', (75, 83))	('reduction', 'NegReg', (173, 182))	('FOXP2', 'Gene', (192, 197))	('miR-544a', 'Gene', (75, 83))	('miR-544a', 'Gene', '664613', (248, 256))	('knockdown', 'Var', (222, 231))	('FOXP2', 'Gene', '93986', (192, 197))	('miR-544a', 'Gene', '664613', (121, 129))	('FOXP1', 'Gene', '27086', (186, 191))	('miR-544a', 'Gene', (248, 256))	('miR-544a', 'Gene', (121, 129))
244281	29499945	Subsequently, the mRNA and protein expressions of AGGF1 were detected in GECs after FOXP1/FOXP2 overexpression and silencing.	('FOXP1', 'Gene', (84, 89))	('silencing', 'Var', (115, 124))	('mRNA and', 'MPA', (18, 26))	('FOXP1', 'Gene', '27086', (84, 89))	('AGGF1', 'Gene', (50, 55))	('overexpression', 'PosReg', (96, 110))	('detected', 'Reg', (61, 69))	('FOXP2', 'Gene', (90, 95))	('FOXP2', 'Gene', '93986', (90, 95))
244282	29499945	The overexpression of FOXP1/FOXP2 upregulated the expression of AGGF1, whereas silencing of FOXP1/FOXP2 downregulated its expression (Figures 5I-5L).	('FOXP1', 'Gene', '27086', (92, 97))	('expression', 'MPA', (122, 132))	('FOXP1', 'Gene', (22, 27))	('FOXP1', 'Gene', (92, 97))	('FOXP1', 'Gene', '27086', (22, 27))	('FOXP2', 'Gene', (28, 33))	('upregulated', 'PosReg', (34, 45))	('FOXP2', 'Gene', '93986', (98, 103))	('downregulated', 'NegReg', (104, 117))	('FOXP2', 'Gene', '93986', (28, 33))	('AGGF1', 'Gene', (64, 69))	('silencing', 'Var', (79, 88))	('expression', 'MPA', (50, 60))	('FOXP2', 'Gene', (98, 103))
244285	29499945	As shown in Figures 6F-6H, the expressions of p-PI3K/t-PI3K, p-AKT/t-AKT, and p-ERK1/2/t-ERK1/2 were significantly decreased in the AGGF1 (-) group compared with the AGGF1 (-) NC group.	('ERK1/2', 'Gene', '5595;5594', (89, 95))	('AKT', 'Gene', (63, 66))	('AKT', 'Gene', (69, 72))	('p-PI3K/t-PI3K', 'Var', (46, 59))	('AGGF1', 'Gene', (132, 137))	('ERK1/2', 'Gene', (80, 86))	('expressions', 'MPA', (31, 42))	('ERK1/2', 'Gene', '5595;5594', (80, 86))	('decreased', 'NegReg', (115, 124))	('AKT', 'Gene', '207', (69, 72))	('p-ERK', 'Gene', '9451', (78, 83))	('p-ERK', 'Gene', (78, 83))	('AKT', 'Gene', '207', (63, 66))	('ERK1/2', 'Gene', (89, 95))
244290	29499945	Eventually, Matrigel plug assay in vivo was applied to further determine whether the angiogenesis in vivo was suppressed after circ-SHKBP1 knockdown and miR-544a/379 overexpression.	('miR-544a', 'Gene', '664613', (153, 161))	('miR-544a', 'Gene', (153, 161))	('knockdown', 'Var', (139, 148))	('circ-SHKBP1 knockdown', 'Var', (127, 148))	('angiogenesis', 'CPA', (85, 97))	('suppressed', 'NegReg', (110, 120))
244295	29499945	The expression of linear SHKBP1 was not upregulated in GECs, inferring that circ-SHKBP1 and linear SHKBP1 are two mutually independent RNA and might perform different functions, which is consistent with the role of circ-TTBK2 and circ-HIPK3.	('TTBK2', 'Gene', '146057', (220, 225))	('HIPK3', 'Gene', (235, 240))	('perform', 'Reg', (149, 156))	('TTBK2', 'Gene', (220, 225))	('HIPK3', 'Gene', '10114', (235, 240))	('circ-SHKBP1', 'Var', (76, 87))
244297	29499945	Our finding verified the binding sites between circ-SHKBP1 and miR-544a/miR-379, and indicated circ-SHKBP1 might act as an miR-544a/miR-379 sponge to modulate their functions in GECs.	('miR-544a', 'Gene', '664613', (123, 131))	('binding', 'Interaction', (25, 32))	('miR-544a', 'Gene', (123, 131))	('circ-SHKBP1', 'Var', (95, 106))	('miR-544a', 'Gene', '664613', (63, 71))	('modulate', 'Reg', (150, 158))	('GECs', 'Disease', (178, 182))	('miR-544a', 'Gene', (63, 71))
244300	29499945	Further studies manifested knockdown of circ-SHKBP1 significantly upregulated the expression of miR-544a/miR-379.	('knockdown', 'Var', (27, 36))	('expression', 'MPA', (82, 92))	('miR-544a', 'Gene', '664613', (96, 104))	('upregulated', 'PosReg', (66, 77))	('miR-544a', 'Gene', (96, 104))	('circ-SHKBP1', 'Gene', (40, 51))
244301	29499945	Moreover, silencing of miR-544a/miR-379 increased the expression of circ-SHKBP1, and vice versa.	('expression', 'MPA', (54, 64))	('circ-SHKBP1', 'Gene', (68, 79))	('miR-544a', 'Gene', '664613', (23, 31))	('miR-544a', 'Gene', (23, 31))	('increased', 'PosReg', (40, 49))	('silencing', 'Var', (10, 19))
244309	29499945	Consistent with our results, miR-379 can play a tumor suppressor role in glioblastoma tissues, cells, and GECs.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('tumor', 'Disease', (48, 53))	('glioblastoma', 'Disease', (73, 85))	('miR-379', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
244319	29499945	miR-379 targeted the 3' UTR region of EIF4G2 and decreased its mRNA and protein expressions to inhibit the proliferation, migration, and invasion of human osteosarcoma cells.	('miR-379', 'Var', (0, 7))	('proliferation', 'CPA', (107, 120))	('invasion', 'CPA', (137, 145))	('inhibit', 'NegReg', (95, 102))	('osteosarcoma', 'Disease', (155, 167))	('EIF4G2', 'Gene', (38, 44))	('osteosarcoma', 'Disease', 'MESH:D012516', (155, 167))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('decreased', 'NegReg', (49, 58))	('human', 'Species', '9606', (149, 154))	('EIF4G2', 'Gene', '1982', (38, 44))	('migration', 'CPA', (122, 131))
244330	29499945	Finally, our results demonstrated that the expressions of FOXP1/FOXP2 were decreased after stable knockdown of circ-SHKBP1 combined with miR-544a/miR-379 overexpression.	('expressions', 'MPA', (43, 54))	('miR-544a', 'Gene', '664613', (137, 145))	('FOXP1', 'Gene', '27086', (58, 63))	('FOXP2', 'Gene', (64, 69))	('knockdown', 'Var', (98, 107))	('miR-544a', 'Gene', (137, 145))	('circ-SHKBP1', 'Gene', (111, 122))	('FOXP2', 'Gene', '93986', (64, 69))	('FOXP1', 'Gene', (58, 63))	('decreased', 'NegReg', (75, 84))
244332	29499945	Altogether, circ-SHKBP1 regulates the angiogenesis of gliomas by targeting miR-544a/FOXP1/AGGF1 and miR-379/FOXP2/AGGF1 pathways.	('FOXP1', 'Gene', (84, 89))	('FOXP2', 'Gene', '93986', (108, 113))	('circ-SHKBP1', 'Var', (12, 23))	('miR-544a', 'Gene', '664613', (75, 83))	('miR-544a', 'Gene', (75, 83))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('regulates', 'Reg', (24, 33))	('targeting', 'Reg', (65, 74))	('FOXP2', 'Gene', (108, 113))	('FOXP1', 'Gene', '27086', (84, 89))	('angiogenesis', 'CPA', (38, 50))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
244333	29499945	Other reports on glioma present similar results with our findings: circ-TTBK2 promotes the malignant biological behavior of glioma cells via the miR-217/HNF1beta/Derlin-1 pathway and circ-cZNF292 suppresses the tube formation of glioma via the Wnt/beta-catenin signaling pathway.	('miR-217', 'Gene', '406999', (145, 152))	('promotes', 'PosReg', (78, 86))	('beta-catenin', 'Gene', (248, 260))	('glioma', 'Disease', (124, 130))	('Derlin-1', 'Gene', (162, 170))	('TTBK2', 'Gene', '146057', (72, 77))	('beta-catenin', 'Gene', '1499', (248, 260))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('miR-217', 'Gene', (145, 152))	('Derlin-1', 'Gene', '79139', (162, 170))	('HNF1beta', 'Gene', '6928', (153, 161))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', (17, 23))	('circ-cZNF292', 'Var', (183, 195))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('HNF1beta', 'Gene', (153, 161))	('TTBK2', 'Gene', (72, 77))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('glioma', 'Disease', (229, 235))	('suppresses', 'NegReg', (196, 206))	('glioma', 'Disease', 'MESH:D005910', (229, 235))
244337	29499945	Our study demonstrated that p-PI3K/PI3K, p-AKT/AKT, and p-ERK1/2/ERK1/2 expressions were significantly decreased in GECs after knockdown of AGGF1.	('p-PI3K/PI3K', 'Pathway', (28, 39))	('AKT', 'Gene', (47, 50))	('ERK1/2', 'Gene', '5595;5594', (58, 64))	('p-ERK', 'Gene', '9451', (56, 61))	('p-ERK', 'Gene', (56, 61))	('ERK1/2', 'Gene', (65, 71))	('AKT', 'Gene', '207', (43, 46))	('ERK1/2', 'Gene', '5595;5594', (65, 71))	('decreased', 'NegReg', (103, 112))	('AKT', 'Gene', '207', (47, 50))	('expressions', 'MPA', (72, 83))	('AGGF1', 'Gene', (140, 145))	('AKT', 'Gene', (43, 46))	('knockdown', 'Var', (127, 136))	('ERK1/2', 'Gene', (58, 64))
244398	28595907	Luciferase reporter assay verified that miR-141-3p specifically targeted the ATF5 3'-UTR in glioma cells.	('miR-141-3p', 'Var', (40, 50))	('glioma', 'Disease', (92, 98))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('targeted', 'Reg', (64, 72))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('ATF5', 'Gene', (77, 81))
244399	28595907	Functional studied suggested that miR-141-3p overexpression inhibited proliferation and promoted apoptosis of glioma cells (U87MG and U251).	('promoted', 'PosReg', (88, 96))	('glioma', 'Disease', (110, 116))	('proliferation', 'CPA', (70, 83))	('inhibited', 'NegReg', (60, 69))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('miR-141-3p', 'Var', (34, 44))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('overexpression', 'PosReg', (45, 59))	('apoptosis', 'CPA', (97, 106))	('U87MG', 'CellLine', 'CVCL:0022', (124, 129))
244400	28595907	Xenograft experiments proved the inhibition of miR-141-3p on glioma growth in vivo.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('inhibition', 'NegReg', (33, 43))	('glioma', 'Disease', (61, 67))	('miR-141-3p', 'Var', (47, 57))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
244418	28595907	Our data support the conclusion that miR-141-3p can serve as a crucial tumor suppressor modulating ATF5 in malignant glioma.	('malignant glioma', 'Disease', (107, 123))	('malignant glioma', 'Disease', 'MESH:D005910', (107, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('miR-141-3p', 'Var', (37, 47))	('crucial tumor', 'Disease', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('crucial tumor', 'Disease', 'MESH:D009369', (63, 76))
244458	28595907	Parallel results demonstrated the ATF5 siRNA successfully suppress the mRNA and protein expression of ATF5 in U87MG (Fig.	('U87MG', 'CellLine', 'CVCL:0022', (110, 115))	('U87MG', 'Var', (110, 115))	('ATF5', 'Gene', (102, 106))	('suppress', 'NegReg', (58, 66))
244459	28595907	As expected, dual luciferase assay proved that the relative luciferase activity was significantly lower (~50%) in the group which co-transfected with pMIR-3'-UTRWt and miR-141-3p than the group co-transfected with pMIR-3'-UTRWt and miR-cotrol.	("pMIR-3'-UTRWt", 'Var', (150, 163))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', '220972', (232, 235))	('miR', 'Gene', (168, 171))	('luciferase', 'Enzyme', (60, 70))	('activity', 'MPA', (71, 79))	('lower', 'NegReg', (98, 103))	('miR', 'Gene', (232, 235))
244460	28595907	These results indicated that ATF5 mRNA 3'-UTR is a specific functional target of miR-141-3p in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('miR-141-3p', 'Var', (81, 91))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))
244461	28595907	The expression of miR-141-3p in 33 glioma patient tissues and two glioma cell lines was detected by quantitative RT-PCR.	('glioma', 'Disease', (66, 72))	('miR-141-3p', 'Var', (18, 28))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('patient', 'Species', '9606', (42, 49))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('glioma', 'Disease', (35, 41))
244463	28595907	In a word, it indicated that the expression of miR-141-3p is related to the different malignant grade of glioma.	('glioma', 'Disease', (105, 111))	('related', 'Reg', (61, 68))	('miR-141-3p', 'Var', (47, 57))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
244467	28595907	Overexpression of miR-141-3p observably inhibited cell proliferation in both U87MG and U251 compared with control.	('miR-141-3p', 'Var', (18, 28))	('inhibited', 'NegReg', (40, 49))	('U87MG', 'CellLine', 'CVCL:0022', (77, 82))	('cell proliferation', 'CPA', (50, 68))
244469	28595907	It indicated that miR-141-3p may affect glioma cell proliferation and apoptosis through ATF5 (Fig.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('miR-141-3p', 'Var', (18, 28))	('affect', 'Reg', (33, 39))	('glioma', 'Disease', (40, 46))	('apoptosis', 'CPA', (70, 79))	('ATF5', 'Gene', (88, 92))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
244472	28595907	During the 24 days, tumors of miR-141-3p overexpression group grew much smaller and slower than control transfected group (Fig.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('miR-141-3p', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('slower', 'NegReg', (84, 90))
244473	28595907	At the endpoint of the experiments, the tumor volume and weight of miR-141-3p group was significantly lower than that of control group (Fig.	('lower', 'NegReg', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('miR-141-3p', 'Var', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
244476	28595907	The mRNA expression of ATF5 was decreased in cells transfected with miR-141-3p, while the ATF5 expression was obviously restored in cells co-transfected with miR-141-3p and pEF1alpha-ATF5 (Fig.	('expression', 'MPA', (95, 105))	('mRNA expression', 'MPA', (4, 19))	('miR-141-3p', 'Var', (68, 78))	('ATF5', 'Gene', (23, 27))	('decreased', 'NegReg', (32, 41))	('pEF1alpha-ATF5', 'Gene', (173, 187))	('pEF1alpha-ATF5', 'Gene', '22809', (173, 187))
244477	28595907	These data illustrated that miR-141-3p suppressed glioma cell proliferation through binding to ATF5 3'-UTR.	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('glioma', 'Disease', (50, 56))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('miR-141-3p', 'Var', (28, 38))	('binding', 'Interaction', (84, 91))	('suppressed', 'NegReg', (39, 49))
244482	28595907	Aberrant miRNAs expression, regulating transcription of targeted oncogenes or tumor suppressor genes, is closely related to various types of tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Aberrant', 'Var', (0, 8))	('related', 'Reg', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('miR', 'Gene', (9, 12))	('miR', 'Gene', '220972', (9, 12))	('transcription', 'MPA', (39, 52))
244484	28595907	For example, miR-141, acting as an oncogene, accelerates non-small cell lung cancer cell proliferation in vitro and tumor growth.	('miR-141', 'Var', (13, 20))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('accelerates', 'PosReg', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (116, 121))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))
244488	28595907	In this study, we have detected the low expression of miR-141-3p in 33 different malignant glioma tissues (low-grade glioma, anaplastic glioma and glioblastoma) for the first time.	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Disease', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('miR-141-3p', 'Var', (54, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('glioma', 'Disease', (136, 142))	('malignant glioma', 'Disease', (81, 97))	('malignant glioma', 'Disease', 'MESH:D005910', (81, 97))	('glioma', 'Disease', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
244495	28595907	We put forward that overexpression of miR-141-3p was related to the inhibition of cell proliferation as well as the promotion of apoptosis in U87MG and U251.	('U87MG', 'Var', (142, 147))	('apoptosis', 'CPA', (129, 138))	('cell proliferation', 'CPA', (82, 100))	('overexpression', 'PosReg', (20, 34))	('promotion', 'PosReg', (116, 125))	('inhibition', 'NegReg', (68, 78))	('miR-141-3p', 'Var', (38, 48))	('U87MG', 'CellLine', 'CVCL:0022', (142, 147))
244496	28595907	Xenograft experiments indicated miR-141-3p significantly inhibited glioma growth in vivo.	('glioma', 'Disease', (67, 73))	('inhibited', 'NegReg', (57, 66))	('miR-141-3p', 'Var', (32, 42))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
244497	28595907	In summary, miR-141-3p, which targets ATF5 mRNA 3'-UTR, was down-regulated ATF5 mRNA and protein expression leading to cell proliferation inhibition and cell apoptosis promotion in glioma.	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('down-regulated', 'NegReg', (60, 74))	('cell proliferation inhibition', 'CPA', (119, 148))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('miR-141-3p', 'Var', (12, 22))	('glioma', 'Disease', (181, 187))	('cell apoptosis', 'CPA', (153, 167))	('promotion', 'PosReg', (168, 177))
244504	27840009	SHOX2 expression and gene body methylation varied among LGG patients and highly significantly predicted poor overall survival.	('SHOX2', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('patients', 'Species', '9606', (60, 68))	('predicted', 'Reg', (94, 103))	('overall survival', 'MPA', (109, 125))	('methylation', 'Var', (31, 42))	('poor', 'NegReg', (104, 108))
244509	27840009	We have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival.	('LGG', 'Disease', (116, 119))	('expression', 'MPA', (30, 40))	('methylation', 'Var', (44, 55))	('IDH', 'Gene', '3417', (210, 213))	('patient', 'Species', '9606', (120, 127))	('patient', 'Species', '9606', (196, 203))	('SHOX2', 'Gene', (24, 29))	('patients', 'Species', '9606', (196, 204))	('overall', 'MPA', (249, 256))	('better', 'PosReg', (242, 248))	('LGG', 'Disease', (192, 195))	('IDH', 'Gene', (210, 213))
244514	27840009	Diffuse glioma brain tumors (gliomas encompassing astrocytomas and oligodedrogliomas, grades II and III), have highly variable, difficult to predict clinical courses and a number of specific alterations have been identified that have prognostic or therapeutic implications, whether as single markers or in various combinations.	('glioma brain tumors', 'Disease', 'MESH:C564230', (8, 27))	('brain tumors', 'Phenotype', 'HP:0030692', (15, 27))	('gliomas', 'Disease', (77, 84))	('alterations', 'Var', (191, 202))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Disease', (29, 36))	('glioma brain tumors', 'Disease', (8, 27))	('astrocytomas and oligodedrogliomas', 'Disease', 'MESH:D001254', (50, 84))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('gliomas', 'Disease', 'MESH:D005910', (29, 36))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('Diffuse', 'Disease', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
244515	27840009	The use of mutation status of the isocitrate dehydrogenase (IDH) enzyme genes has been demonstrated to be a potent prognostic marker greatly improving survival prognosis.	('IDH', 'Gene', (60, 63))	('survival prognosis', 'CPA', (151, 169))	('isocitrate dehydrogenase', 'Gene', (34, 58))	('IDH', 'Gene', '3417', (60, 63))	('improving', 'PosReg', (141, 150))	('mutation status', 'Var', (11, 26))	('isocitrate dehydrogenase', 'Gene', '3417', (34, 58))
244516	27840009	SHOX2 methylation was suggested to be associated with lung and breast cancers.	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (63, 77))	('SHOX2', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('methylation', 'Var', (6, 17))	('breast cancers', 'Disease', 'MESH:D001943', (63, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('breast cancers', 'Disease', (63, 77))	('lung', 'Disease', (54, 58))
244523	27840009	A relatively recent finding of major biological and clinical importance was the identification of mutations in the isocitrate dehydrogenase (IDH) enzyme genes IDH1 and IDH2.	('IDH2', 'Gene', '3418', (168, 172))	('IDH', 'Gene', (159, 162))	('IDH1', 'Gene', (159, 163))	('IDH', 'Gene', '3417', (168, 171))	('IDH', 'Gene', (141, 144))	('isocitrate dehydrogenase', 'Gene', '3417', (115, 139))	('IDH', 'Gene', '3417', (159, 162))	('IDH1', 'Gene', '3417', (159, 163))	('IDH', 'Gene', '3417', (141, 144))	('IDH', 'Gene', (168, 171))	('mutations', 'Var', (98, 107))	('IDH2', 'Gene', (168, 172))	('isocitrate dehydrogenase', 'Gene', (115, 139))
244525	27840009	They are rare in primary GBM and absent in pilocytic astrocytomas and are often associated with MGMT promoter hypermethylation, TP53 mutations as well as co-deletions of chromosome 1p or 19q (1p/19q codel).	('MGMT', 'Gene', '4255', (96, 100))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('associated', 'Reg', (80, 90))	('mutations', 'Var', (133, 142))	('pilocytic astrocytomas', 'Disease', (43, 65))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (43, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (53, 64))	('MGMT', 'Gene', (96, 100))
244526	27840009	IDH mutations are an early, possibly driver, event for LGG, and clinical trials of IDH inhibitors are underway.	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', (83, 86))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (83, 86))	('mutations', 'Var', (4, 13))
244527	27840009	Many studies have demonstrated that survival outcome of LGG patients is significantly different based on the status of IDH gene mutation, 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation, ATRX gene mutation, CpG island methylator phenotypes (CIMP), O-6-methylguanine-DNA methytransferase (MGMT) promoter methylation, the neural stem cell gene nestin (NES) expression and mRNA expression signatures by multiple genes.	('expression', 'MPA', (384, 394))	('telomerase reverse transcriptase', 'Gene', '7015', (157, 189))	('mutation', 'Var', (226, 234))	('nestin', 'Gene', '10763', (371, 377))	('NES', 'Gene', (379, 382))	('nestin', 'Gene', (371, 377))	('IDH', 'Gene', (119, 122))	('MGMT', 'Gene', '4255', (317, 321))	('patients', 'Species', '9606', (60, 68))	('mutation', 'Var', (128, 136))	('O-6-methylguanine-DNA methytransferase', 'Gene', (277, 315))	('O-6-methylguanine-DNA methytransferase', 'Gene', '4255', (277, 315))	('IDH', 'Gene', '3417', (119, 122))	('ATRX', 'Gene', (216, 220))	('NES', 'Gene', '10763', (379, 382))	('ATRX', 'Gene', '546', (216, 220))	('mutation', 'Var', (206, 214))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('telomerase reverse transcriptase', 'Gene', (157, 189))	('MGMT', 'Gene', (317, 321))	('CIMP', 'Chemical', '-', (270, 274))	('mRNA expression signatures', 'MPA', (399, 425))
244553	27840009	SHOX2 high methylation predicted a poor overall survival of LGG patients comparable to IDH mutation status, and was significantly correlated with CIMP-negative marker, a poor survival prognosis marker for LGG as demonstrated in three independent external 450 K methylation datasets (Fig.	('poor', 'NegReg', (35, 39))	('patients', 'Species', '9606', (64, 72))	('SHOX2', 'Gene', (0, 5))	('IDH', 'Gene', (87, 90))	('overall survival', 'MPA', (40, 56))	('IDH', 'Gene', '3417', (87, 90))	('high methylation', 'Var', (6, 22))	('LGG', 'Disease', (60, 63))	('CIMP', 'Chemical', '-', (146, 150))
244554	27840009	SHOX2 methylation (of the gene body associated with increased gene expression) was negatively correlated with CIMP status (methylation of promoter region of multiple genes associated with suppression of gene expression) (Fig.	('increased', 'PosReg', (52, 61))	('SHOX2', 'Gene', (0, 5))	('negatively', 'NegReg', (83, 93))	('gene expression', 'MPA', (62, 77))	('methylation', 'Var', (6, 17))	('CIMP', 'Chemical', '-', (110, 114))
244558	27840009	We observed that SHOX2 expression marker had a prognostic value comparable to IDH status marker, a widely-accepted potent prognostic marker for LGG [IDH wild type (IDHwt) vs mutant type (IDHmut) HR 6.52 (95% CI 4.49 to 9.47), p < 2.0E-16] (Figs.	('IDH', 'Gene', '3417', (164, 167))	('IDH', 'Gene', (149, 152))	('LGG', 'Disease', (144, 147))	('IDH', 'Gene', (187, 190))	('mutant type', 'Var', (174, 185))	('IDH', 'Gene', '3417', (149, 152))	('SHOX2', 'Gene', (17, 22))	('IDH', 'Gene', '3417', (187, 190))	('IDH', 'Gene', (78, 81))	('to 9', 'Species', '1214577', (216, 220))	('IDH', 'Gene', (164, 167))	('IDH', 'Gene', '3417', (78, 81))
244567	27840009	By contrast, combining SHOX2 expression or methylation had no or minimal effect on the favorable prognostic IDHmut subgroup.	('IDH', 'Gene', (108, 111))	('IDH', 'Gene', '3417', (108, 111))	('methylation', 'Var', (43, 54))	('SHOX2', 'Gene', (23, 28))
244568	27840009	The findings of the enhanced prognostic combination of SHOX2 and IDH markers led us to further study whether SHOX2 can aid the prognostic values of other LGG prognostic markers (NES expression, MGMT methylation, TERT promoter mutation or expression, 1p/19q codel and ATRX mutation).	('ATRX', 'Gene', (267, 271))	('1p/19q codel', 'Var', (250, 262))	('IDH', 'Gene', (65, 68))	('ATRX', 'Gene', '546', (267, 271))	('TERT', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (212, 216))	('IDH', 'Gene', '3417', (65, 68))	('MGMT', 'Gene', '4255', (194, 198))	('MGMT', 'Gene', (194, 198))	('NES', 'Gene', '10763', (178, 181))	('expression', 'MPA', (238, 248))	('NES', 'Gene', (178, 181))
244569	27840009	We found that 1p/19q codel or MGMT methylation as individual markers had a moderate prognostic effect, and NES, TERT and ATRX marker had no significant prognostic effect.	('TERT', 'Gene', (112, 116))	('NES', 'Gene', '10763', (107, 110))	('1p/19q', 'Var', (14, 20))	('TERT', 'Gene', '7015', (112, 116))	('NES', 'Gene', (107, 110))	('ATRX', 'Gene', (121, 125))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))	('ATRX', 'Gene', '546', (121, 125))
244570	27840009	In particular, we found that SHOX2 expression identified favorable prognostic subsets more significantly in the unfavorable prognosis subgroup determined by each individual marker, which was similar to our findings in the subset of IDHwt LGG (Fig.	('SHOX2', 'Gene', (29, 34))	('IDH', 'Gene', '3417', (232, 235))	('IDH', 'Gene', (232, 235))	('expression', 'Var', (35, 45))
244571	27840009	We observed that the prognostic value of other markers was improved in combination with IDH mutation status, as compared to utilization of each marker alone, especially TERT expression or mutation, MGMT methylation, ATRX mutation and NES expression (Appendix p21).	('TERT', 'Gene', '7015', (169, 173))	('ATRX', 'Gene', (216, 220))	('NES', 'Gene', (234, 237))	('improved', 'PosReg', (59, 67))	('mutation', 'Var', (188, 196))	('prognostic value', 'MPA', (21, 37))	('MGMT', 'Gene', (198, 202))	('MGMT', 'Gene', '4255', (198, 202))	('ATRX', 'Gene', '546', (216, 220))	('IDH', 'Gene', (88, 91))	('p21', 'Gene', (259, 262))	('TERT', 'Gene', (169, 173))	('IDH', 'Gene', '3417', (88, 91))	('p21', 'Gene', '644914', (259, 262))	('NES', 'Gene', '10763', (234, 237))
244578	27840009	By contrast, IDH, 1p/19q codel and MGMT but not TERT and NES showed moderate prognostic significance after adjusting by SHOX2 marker, based on their HR and p values (Fig.	('IDH', 'Gene', '3417', (13, 16))	('NES', 'Gene', (57, 60))	('MGMT', 'Gene', (35, 39))	('MGMT', 'Gene', '4255', (35, 39))	('TERT', 'Gene', (48, 52))	('1p/19q codel', 'Var', (18, 30))	('TERT', 'Gene', '7015', (48, 52))	('IDH', 'Gene', (13, 16))	('NES', 'Gene', '10763', (57, 60))
244579	27840009	The overall survival of LGG patients was previously reported to be related with age and histology We found that SHOX2 high methylation and expression were associated with astrocytoma histology type (Appendix p22).	('high', 'Var', (118, 122))	('astrocytoma', 'Disease', (171, 182))	('SHOX2', 'Gene', (112, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (171, 182))	('associated', 'Reg', (155, 165))	('p22', 'Gene', '11261', (208, 211))	('p22', 'Gene', (208, 211))	('expression', 'MPA', (139, 149))	('patients', 'Species', '9606', (28, 36))	('astrocytoma', 'Disease', 'MESH:D001254', (171, 182))
244584	27840009	In particular, a) most grades II and III diffuse gliomas have mutations in IDH1 or IDH2 genes; 2) most astrocytomas are 1p/19q intact and are often ATRX and TP53 mutant; 3) most or all oligodendrogliomas are 1p/19q co-deleted; and 4) combined oligoastrocytomas are no longer recognized as an entity, but should be reclassified based on their molecular features.	('TP53', 'Gene', (157, 161))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('oligodendrogliomas', 'Disease', (185, 203))	('ATRX', 'Gene', (148, 152))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('IDH1', 'Gene', '3417', (75, 79))	('astrocytomas', 'Disease', (103, 115))	('ATRX', 'Gene', '546', (148, 152))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('astrocytomas', 'Disease', 'MESH:D001254', (248, 260))	('astrocytoma', 'Phenotype', 'HP:0009592', (248, 259))	('IDH2', 'Gene', (83, 87))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('oligoastrocytomas', 'Disease', (243, 260))	('gliomas', 'Disease', (49, 56))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', '7157', (157, 161))	('are 1p', 'Gene', '6293', (204, 210))	('are 1p', 'Gene', '6293', (116, 122))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (243, 260))	('IDH2', 'Gene', '3418', (83, 87))	('astrocytomas', 'Disease', 'MESH:D001254', (103, 115))	('are 1p', 'Gene', (204, 210))	('astrocytoma', 'Phenotype', 'HP:0009592', (103, 114))	('are 1p', 'Gene', (116, 122))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (185, 203))	('IDH1', 'Gene', (75, 79))	('gliomas', 'Disease', (196, 203))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('astrocytomas', 'Disease', (248, 260))
244585	27840009	We present our analyses using traditional histology (omitting the category oligoastrocytoma) and grading, and the various molecular analyses including IDH, ATRX mutation status and 1p/19q co-deletions.	('oligoastrocytoma', 'Disease', 'MESH:D001254', (75, 91))	('ATRX', 'Gene', '546', (156, 160))	('oligoastrocytoma', 'Disease', (75, 91))	('IDH', 'Gene', '3417', (151, 154))	('1p/19q co-deletions', 'Var', (181, 200))	('astrocytoma', 'Phenotype', 'HP:0009592', (80, 91))	('ATRX', 'Gene', (156, 160))	('mutation status', 'Var', (161, 176))	('IDH', 'Gene', (151, 154))
244588	27840009	To date, IDH mutation status has been the most widely accepted and powerful prognostic factor, either alone or in combination with other factors.	('IDH', 'Gene', '3417', (9, 12))	('IDH', 'Gene', (9, 12))	('mutation status', 'Var', (13, 28))
244595	27840009	SHOX2 was suggested to be a novel epithelial-to-mesenchymal transition inducer in breast cancer cells, and overexpression of SHOX2 was able to induce canine mesenchymal stem cell differentiation into native pacemaker cells.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('overexpression', 'Var', (107, 121))	('induce', 'PosReg', (143, 149))	('canine', 'Species', '9615', (150, 156))	('SHOX2', 'Gene', (125, 130))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('canine mesenchymal stem cell differentiation', 'CPA', (150, 194))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
244596	27840009	We observed an upward trend of SHOX2 aberrant hypermethylation and expression from clinically benign pilocytic astrocytomas, intermediate malignant LGG to high malignant GBM.	('aberrant hypermethylation', 'Var', (37, 62))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (101, 123))	('pilocytic astrocytomas', 'Disease', (101, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('expression', 'MPA', (67, 77))	('SHOX2', 'Gene', (31, 36))
244600	27840009	In conclusion, we have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival.	('patient', 'Species', '9606', (135, 142))	('patients', 'Species', '9606', (211, 219))	('better', 'PosReg', (257, 263))	('overall', 'MPA', (264, 271))	('IDH', 'Gene', (225, 228))	('LGG', 'Disease', (131, 134))	('LGG', 'Disease', (207, 210))	('methylation', 'Var', (59, 70))	('IDH', 'Gene', '3417', (225, 228))	('patient', 'Species', '9606', (211, 218))	('SHOX2', 'Gene', (39, 44))
244603	25744348	Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion.	('astrocytomas/oligodendrogliomas', 'Disease', (123, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('gliomas', 'Disease', (147, 154))	('gliomas', 'Disease', (66, 73))	('circumscribe astrocytomas', 'Disease', (83, 108))	('mutations', 'Var', (286, 295))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('mutations', 'Var', (270, 279))	('BRAF', 'Gene', (340, 344))	('BRAF', 'Gene', '673', (340, 344))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('astrocytomas/oligodendrogliomas', 'Disease', 'MESH:D009837', (123, 154))	('circumscribe astrocytomas', 'Disease', 'MESH:D001254', (83, 108))	('TP53', 'Gene', (281, 285))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('glioblastoma', 'Disease', (160, 172))	('mutation/fusion', 'Var', (345, 360))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('co-deletion', 'Var', (297, 308))	('TP53', 'Gene', '7157', (281, 285))	('isocitrate dehydrogenases (IDHs) 1/2', 'Gene', '3417;3418', (233, 269))
244643	25744348	Characteristic genetic events in diffuse astrocytoma and anaplastic astrocytoma are isocitrate dehydrogenases (IDHs) 1/2 mutations that are followed by TP53 mutations and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (68, 79))	('mutations', 'Var', (121, 130))	('astrocytoma', 'Disease', (41, 52))	('alpha-thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (171, 225))	('TP53', 'Gene', '7157', (152, 156))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('ATRX', 'Gene', (227, 231))	('TP53', 'Gene', (152, 156))	('astrocytoma', 'Disease', 'MESH:D001254', (68, 79))	('isocitrate dehydrogenases (IDHs) 1/2', 'Gene', '3417;3418', (84, 120))	('astrocytoma', 'Disease', (68, 79))	('mental retardation', 'Phenotype', 'HP:0001249', (189, 207))	('astrocytoma', 'Disease', 'MESH:D001254', (41, 52))	('ATRX', 'Gene', '546', (227, 231))
244645	25744348	Recently, BRAF (the B-isoform of the rapidly growing fibrosarcoma oncogene) V600E mutation, which has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma, and non-small cell lung cancer was identified in epithelioid GBM at a relatively high frequency of 54%.	('fibrosarcoma', 'Disease', (53, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('melanoma', 'Disease', (174, 182))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (126, 153))	('V600E', 'Mutation', 'rs113488022', (76, 81))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (188, 214))	('papillary thyroid carcinoma', 'Disease', (126, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (126, 153))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (192, 214))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (53, 65))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (188, 214))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('fibrosarcoma', 'Disease', 'MESH:D005354', (53, 65))	('BRAF', 'Gene', (10, 14))	('colorectal cancer', 'Disease', (155, 172))	('non-small cell lung cancer', 'Disease', (188, 214))	('BRAF', 'Gene', '673', (10, 14))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (136, 153))	('V600E mutation', 'Var', (76, 90))
244649	25744348	Since IDH mutations are absent in the epithelioid as well as rhabdoid GBMs, they may represent distinct variants of pGBM.	('GBMs', 'Phenotype', 'HP:0012174', (70, 74))	('IDH', 'Gene', (6, 9))	('pGBM', 'Chemical', '-', (116, 120))	('IDH', 'Gene', '3417', (6, 9))	('rhabdoid GBM', 'Disease', (61, 73))	('rhabdoid GBM', 'Disease', 'MESH:D005910', (61, 73))	('mutations', 'Var', (10, 19))
244666	25744348	CFO corresponds to oligodendroglioma harboring IDH1 mutations and 1p/19q codeletion but lacking TP53 mutation (so called "double-positive" glioma) whereas NCFO to those lacking 1p/19q codeletion.	('mutations', 'Var', (52, 61))	('lacking', 'NegReg', (88, 95))	('TP53', 'Gene', (96, 100))	('glioma', 'Disease', (139, 145))	('IDH1', 'Gene', (47, 51))	('1p/19q codeletion', 'Var', (66, 83))	('oligodendroglioma', 'Disease', (19, 36))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('glioma', 'Disease', (30, 36))	('IDH1', 'Gene', '3417', (47, 51))	('oligodendroglioma', 'Disease', 'MESH:D009837', (19, 36))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('TP53', 'Gene', '7157', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
244667	25744348	Some of NCFO correspond to the tumors harboring an astrocytoma-like genotype, IDH1 and TP53 mutations without 1p/19q codeletion (Fig.	('TP53', 'Gene', '7157', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('astrocytoma', 'Disease', 'MESH:D001254', (51, 62))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('IDH1', 'Gene', (78, 82))	('TP53', 'Gene', (87, 91))	('astrocytoma', 'Disease', (51, 62))	('mutations', 'Var', (92, 101))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('astrocytoma', 'Phenotype', 'HP:0009592', (51, 62))	('IDH1', 'Gene', '3417', (78, 82))
244671	25744348	As mentioned partly above, major genetic alterations in gliomas include mutations in IDH-1/-2, the TP53 mutation, 1p/19q codeletion, telomerase reverse transcriptase (TERT) mutation, and those involving BRAF.	('IDH-1/-2', 'Gene', '3417;3418', (85, 93))	('TERT', 'Gene', (167, 171))	('mutations', 'Var', (72, 81))	('TP53', 'Gene', (99, 103))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Disease', (56, 63))	('telomerase reverse transcriptase', 'Gene', '7015', (133, 165))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('TERT', 'Gene', '7015', (167, 171))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('BRAF', 'Gene', '673', (203, 207))	('1p/19q', 'Var', (114, 120))	('mutation', 'Var', (104, 112))	('BRAF', 'Gene', (203, 207))	('TP53', 'Gene', '7157', (99, 103))	('telomerase reverse transcriptase', 'Gene', (133, 165))	('IDH-1/-2', 'Gene', (85, 93))
244673	25744348	Primary GBM, on the other hand, mostly develops without IDH1/2 mutations, although this tumor may occur via the acquisition of a TERT promoter mutation, CDKN2A mutation or homozygous deletion, EGFR amplification and/or PTEN mutation.	('PTEN', 'Gene', '5728', (219, 223))	('mutation', 'Var', (160, 168))	('CDKN2A', 'Gene', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IDH1/2', 'Gene', (56, 62))	('TERT', 'Gene', '7015', (129, 133))	('amplification', 'Var', (198, 211))	('EGFR', 'Gene', '1956', (193, 197))	('CDKN2A', 'Gene', '1029', (153, 159))	('mutation', 'Var', (224, 232))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('homozygous deletion', 'Var', (172, 191))	('Primary GBM', 'Disease', (0, 11))	('EGFR', 'Gene', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('TERT', 'Gene', (129, 133))	('PTEN', 'Gene', (219, 223))
244674	25744348	Secondary sGBM is characterized by TP53 mutations, IDH mutations, and lack of EGFR amplification.	('IDH', 'Gene', (51, 54))	('TP53', 'Gene', '7157', (35, 39))	('IDH', 'Gene', '3417', (51, 54))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('Secondary sGBM', 'Disease', (0, 14))
244676	25744348	The secondary GBM is characterized by IDH/TP53 mutations, a G-CIMP phenotype, and normal EGFR-PTEN-Notch signaling.	('TP53', 'Gene', '7157', (42, 46))	('PTEN', 'Gene', (94, 98))	('EGFR', 'Gene', (89, 93))	('IDH', 'Gene', (38, 41))	('PTEN', 'Gene', '5728', (94, 98))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('IDH', 'Gene', '3417', (38, 41))	('EGFR', 'Gene', '1956', (89, 93))
244677	25744348	The mesenchymal GBM, which is common in older adults, is associated with worse outcome and is characterized by EGFR amplification, PTEN loss, NF1 mutations, and Akt signaling.	('NF1', 'Gene', '4763', (142, 145))	('mesenchymal', 'CPA', (4, 15))	('PTEN loss', 'Disease', 'MESH:D006223', (131, 140))	('mutations', 'Var', (146, 155))	('EGFR', 'Gene', '1956', (111, 115))	('amplification', 'Var', (116, 129))	('Akt', 'Gene', '207', (161, 164))	('EGFR', 'Gene', (111, 115))	('PTEN loss', 'Disease', (131, 140))	('Akt', 'Gene', (161, 164))	('NF1', 'Gene', (142, 145))
244678	25744348	From a diagnostic point of view, using a threshold of 10% p53-positive tumor cells, p53 expression can be used as a surrogate marker for missense TP 53 mutation but not for non-missense mutations.	('TP 53', 'Gene', '7157', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TP 53', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('p53', 'Gene', (58, 61))	('tumor', 'Disease', (71, 76))	('mutation', 'Var', (152, 160))	('missense', 'Var', (137, 145))	('p53', 'Gene', '7157', (58, 61))
244680	25744348	Childhood gliomas rarely carry the genetic alterations seen in adults, including mutations and 1p/19q codeletion, which suggests that distinct sets of genetic aberrations underlie the clinicopathologic differences between adult and pediatric gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('genetic aberrations', 'Disease', 'MESH:D030342', (151, 170))	('gliomas', 'Disease', 'MESH:D005910', (242, 249))	('gliomas', 'Phenotype', 'HP:0009733', (242, 249))	('gliomas', 'Disease', (242, 249))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('pediatric gliomas', 'Disease', (232, 249))	('mutations', 'Var', (81, 90))	('genetic aberrations', 'Disease', (151, 170))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('pediatric gliomas', 'Disease', 'MESH:D005910', (232, 249))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
244682	25744348	IDH mutations in 1, and to a lesser extent 2, were first identified in 70-80% of low-grade gliomas and a subset of cases of GBM in 2008.	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', (91, 98))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('mutations', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
244684	25744348	Glioblastomas harboring IDH mutations are mostly secondary GBM lesions that have arisen via progression from lower-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('IDH', 'Gene', (24, 27))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('IDH', 'Gene', '3417', (24, 27))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('Glioblastomas', 'Disease', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('mutations', 'Var', (28, 37))
244687	25744348	IDH mutations are also found in approximately 5% of primary GBMs.	('IDH', 'Gene', (0, 3))	('found', 'Reg', (23, 28))	('IDH', 'Gene', '3417', (0, 3))	('GBMs', 'Phenotype', 'HP:0012174', (60, 64))	('mutations', 'Var', (4, 13))	('primary GBMs', 'Disease', (52, 64))
244688	25744348	Since primary GBM is a clinically defined entity and the presence of IDH1/2 mutations have been shown to be inversely related to or even mutually exclusive of EGFR and PTEN abnormalities, which are hallmarks of primary GBM, IDH-mutated GBM lesions may represent genetically "secondary" GBM tumors.	('mutations', 'Var', (76, 85))	('GBM tumors', 'Disease', (286, 296))	('IDH', 'Gene', (224, 227))	('GBM tumors', 'Disease', 'MESH:D005910', (286, 296))	('IDH', 'Gene', (69, 72))	('PTEN abnormalities', 'Disease', (168, 186))	('primary GBM', 'Disease', (6, 17))	('EGFR', 'Gene', '1956', (159, 163))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('IDH', 'Gene', '3417', (224, 227))	('IDH', 'Gene', '3417', (69, 72))	('EGFR', 'Gene', (159, 163))	('PTEN abnormalities', 'Disease', 'MESH:D006223', (168, 186))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('IDH1/2', 'Gene', (69, 75))
244689	25744348	IDH1/2 mutations are often associated with other genetic alterations that occur frequently in astrocytomas and oligodendrogliomas; for example, TP53 mutations as well as the mutation of ATRX occur together with IDH1/2 mutations in 60% to 70% of infiltrating astrocytomas, whereas 1p/19q codeletion is associated with IDH1/2 mutations in more than 90% of classic oligodendrogliomas.	('oligodendrogliomas', 'Disease', (362, 380))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (373, 379))	('astrocytomas', 'Disease', 'MESH:D001254', (258, 270))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (111, 129))	('IDH1/2', 'Gene', '3417;3418', (317, 323))	('astrocytoma', 'Phenotype', 'HP:0009592', (258, 269))	('gliomas', 'Phenotype', 'HP:0009733', (373, 380))	('IDH1/2', 'Gene', (0, 6))	('IDH1/2', 'Gene', (317, 323))	('TP53', 'Gene', '7157', (144, 148))	('IDH1/2', 'Gene', '3417;3418', (211, 217))	('ATRX', 'Gene', (186, 190))	('oligodendrogliomas', 'Disease', (111, 129))	('ATRX', 'Gene', '546', (186, 190))	('astrocytomas', 'Disease', (94, 106))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('IDH1/2', 'Gene', (211, 217))	('mutations', 'Var', (149, 158))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (362, 380))	('astrocytomas', 'Disease', (258, 270))	('TP53', 'Gene', (144, 148))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (94, 129))	('astrocytomas', 'Disease', 'MESH:D001254', (94, 106))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))
244690	25744348	Based on studies of initial and recurrent tumors, IDH mutations likely occur in the most upstream stage of development of astrocytomas and oligodendrogliomas.	('occur', 'Reg', (71, 76))	('astrocytoma', 'Phenotype', 'HP:0009592', (122, 133))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('IDH', 'Gene', (50, 53))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IDH', 'Gene', '3417', (50, 53))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (122, 157))
244692	25744348	Taken together, IDH mutations may occur in precursor cells that can give rise to both oligodendrocytes and astrocytes.	('IDH', 'Gene', '3417', (16, 19))	('mutations', 'Var', (20, 29))	('IDH', 'Gene', (16, 19))
244693	25744348	Following IDH mutation, additional mutations may specify tumor development along an astrocytic or oligodendrocytic lineage.	('IDH', 'Gene', (10, 13))	('oligodendrocytic', 'Disease', 'MESH:D056784', (98, 114))	('oligodendrocytic', 'Disease', (98, 114))	('IDH', 'Gene', '3417', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutation', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('specify', 'Reg', (49, 56))
244695	25744348	IDH1 mutations are associated with the methylation of O6-methylguanine-DNA methyl transferase (MGMT).	('associated', 'Reg', (19, 29))	('O6-methylguanine-DNA methyl transferase', 'Gene', (54, 93))	('mutations', 'Var', (5, 14))	('O6-methylguanine-DNA methyl transferase', 'Gene', '4255', (54, 93))	('MGMT', 'Gene', '4255', (95, 99))	('IDH1', 'Gene', (0, 4))	('MGMT', 'Gene', (95, 99))	('methylation', 'MPA', (39, 50))	('IDH1', 'Gene', '3417', (0, 4))
244696	25744348	Analyses of DNA promoter alterations in MGMT have revealed hypermethylation at the cytosine phosphate-guanine (CPG) island.	('alterations', 'Var', (25, 36))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('hypermethylation', 'MPA', (59, 75))	('cytosine phosphate-guanine', 'Chemical', '-', (83, 109))
244698	25744348	Among GBMs lacking IDH mutations, those with MGMT promoter methylation survive significantly longer than those without after receiving temozolomide.	('mutations', 'Var', (23, 32))	('IDH', 'Gene', (19, 22))	('temozolomide', 'Chemical', 'MESH:D000077204', (135, 147))	('GBMs', 'Phenotype', 'HP:0012174', (6, 10))	('MGMT', 'Gene', (45, 49))	('IDH', 'Gene', '3417', (19, 22))	('MGMT', 'Gene', '4255', (45, 49))
244699	25744348	The characteristic 1p/19q codeletion is identified in 50% to 90% of oligodendrogliomas, particularly those bearing a classic morphology, whereas approximately two-thirds of diffuse astrocytic lesions have a concurrent TP53 mutation.	('oligodendrogliomas', 'Disease', 'MESH:D009837', (68, 86))	('astrocytic lesions', 'Disease', 'MESH:D001254', (181, 199))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('TP53', 'Gene', '7157', (218, 222))	('astrocytic lesions', 'Disease', (181, 199))	('oligodendrogliomas', 'Disease', (68, 86))	('1p/19q', 'Var', (19, 25))	('TP53', 'Gene', (218, 222))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
244700	25744348	1p/19q codeletion and TP53 mutation are mutually exclusive.	('mutation', 'Var', (27, 35))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
244702	25744348	For example, whole-genome sequence studies have identified mutations of far upstream element binding protein 1 (FUBP1) on chromosome 19q13.2 as well as capicua homolog (CIC) on 1p31.1 in 83% and 20% of oligodendrogliomas, respectively.	('far upstream element binding protein 1', 'Gene', (72, 110))	('FUBP1', 'Gene', (112, 117))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('CIC', 'Gene', (169, 172))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (202, 220))	('far upstream element binding protein 1', 'Gene', '8880', (72, 110))	('oligodendrogliomas', 'Disease', (202, 220))	('mutations', 'Var', (59, 68))	('FUBP1', 'Gene', '8880', (112, 117))	('gliomas', 'Phenotype', 'HP:0009733', (213, 220))	('CIC', 'Gene', '23152', (169, 172))
244704	25744348	The 1p/19q codeletion is associated with a prolonged survival time and favorable response to procarbazine, CCNU, vincristine (PCV), and temozolomide chemotherapy or radiotherapy.	('vincristine', 'Chemical', 'MESH:D014750', (113, 124))	('temozolomide', 'Chemical', 'MESH:D000077204', (136, 148))	('1p/19q', 'Var', (4, 10))	('CCNU', 'Chemical', 'MESH:D008130', (107, 111))	('prolonged', 'PosReg', (43, 52))	('procarbazine', 'Chemical', 'MESH:D011344', (93, 105))
244705	25744348	analyzed IDH1 mutation, TP53 mutation, and 1p/19q codeletion in 88 low-grade gliomas and found that they are divided into four groups; group 1, IDH1R132H+/p53-/1p19q-; group 2, IDH1R132H+/p53-/1p19q+; group 3, IDH1R132H+/p53+/1p19q-; and group 4, triple negative glioma.	('IDH1', 'Gene', '3417', (210, 214))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', (177, 181))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('IDH1', 'Gene', (144, 148))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('TP53', 'Gene', '7157', (24, 28))	('glioma', 'Disease', (263, 269))	('IDH1', 'Gene', '3417', (9, 13))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('p53', 'Gene', '7157', (221, 224))	('IDH1', 'Gene', '3417', (177, 181))	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('p53', 'Gene', '7157', (188, 191))	('IDH1', 'Gene', '3417', (144, 148))	('p53', 'Gene', '7157', (155, 158))	('p53', 'Gene', (221, 224))	('p53', 'Gene', (188, 191))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('IDH1', 'Gene', (210, 214))	('p53', 'Gene', (155, 158))	('gliomas', 'Disease', (77, 84))	('TP53', 'Gene', (24, 28))	('mutation', 'Var', (14, 22))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))
244706	25744348	Since TP53 mutation and 1p/19q codeletion are always associated with IDH mutations, and since IDH mutations pose the lowest hazard ratio followed by that of 1p/19q codeletion, infiltrating gliomas can thus be classified as double positive (IDH+/1p19q+), single positive (IDH or 1p19q+), double negative (IDH-/1p19q-), and triple negative gliomas (IDH-/1p19q-/TP53-), in the sequence of prognosis (Fig.	('gliomas', 'Disease', (338, 345))	('IDH', 'Gene', (240, 243))	('TP53', 'Gene', (6, 10))	('TP53', 'Gene', '7157', (359, 363))	('lowest', 'NegReg', (117, 123))	('IDH', 'Gene', '3417', (304, 307))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('gliomas', 'Disease', 'MESH:D005910', (338, 345))	('IDH', 'Gene', '3417', (271, 274))	('IDH', 'Gene', (94, 97))	('IDH-/1p', 'Gene', '3417', (347, 354))	('IDH', 'Gene', '3417', (240, 243))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('associated', 'Reg', (53, 63))	('glioma', 'Phenotype', 'HP:0009733', (338, 344))	('gliomas', 'Phenotype', 'HP:0009733', (338, 345))	('TP53', 'Gene', '7157', (6, 10))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('IDH', 'Gene', (347, 350))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (94, 97))	('TP53', 'Gene', (359, 363))	('IDH-/1p', 'Gene', (347, 354))	('IDH-/1p', 'Gene', '3417', (304, 311))	('IDH', 'Gene', '3417', (347, 350))	('IDH', 'Gene', '3417', (69, 72))	('mutations', 'Var', (98, 107))	('IDH', 'Gene', (304, 307))	('gliomas', 'Disease', (189, 196))	('IDH', 'Gene', (271, 274))	('IDH-/1p', 'Gene', (304, 311))
244708	25744348	The two most common mutations are located at C228T and C250T, with identical hot spots also found in gliomas.	('C250T', 'Mutation', 'rs200901835', (55, 60))	('C228T', 'Var', (45, 50))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('C228T', 'Mutation', 'rs774905136', (45, 50))	('C250T', 'Var', (55, 60))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
244709	25744348	The highest incidence was identified among most tumors harboring 1p/19q loss and IDH1/2 mutations (98%), as well as IDH wild-type tumors with EGFR amplification (92%).	('tumors', 'Disease', (130, 136))	('IDH', 'Gene', (116, 119))	('IDH', 'Gene', '3417', (116, 119))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('1p/19q loss', 'Var', (65, 76))	('tumors', 'Disease', (48, 54))	('EGFR', 'Gene', (142, 146))	('mutations', 'Var', (88, 97))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('IDH1/2', 'Gene', (81, 87))	('EGFR', 'Gene', '1956', (142, 146))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('IDH', 'Gene', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('IDH1/2', 'Gene', '3417;3418', (81, 87))	('IDH', 'Gene', '3417', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
244714	25744348	In pilocytic astrocytomas, particularly those occurring in children, BRAF-KIAA1549 fusion caused by the duplication of 7q34 is a characteristic event that discriminates pilocytic astrocytomas from diffuse astrocytomas.	('duplication of', 'Var', (104, 118))	('astrocytomas', 'Disease', 'MESH:D001254', (179, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (179, 190))	('astrocytomas', 'Disease', (205, 217))	('caused by', 'Reg', (90, 99))	('BRAF-KIAA1549 fusion', 'Disease', (69, 89))	('astrocytomas', 'Disease', (13, 25))	('7q34', 'Gene', (119, 123))	('pilocytic astrocytomas', 'Disease', (3, 25))	('BRAF-KIAA1549 fusion', 'Disease', 'MESH:D000069337', (69, 89))	('pilocytic astrocytomas', 'Disease', (169, 191))	('astrocytomas', 'Disease', (179, 191))	('astrocytoma', 'Phenotype', 'HP:0009592', (205, 216))	('astrocytomas', 'Disease', 'MESH:D001254', (205, 217))	('astrocytomas', 'Disease', 'MESH:D001254', (13, 25))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (3, 25))	('astrocytoma', 'Phenotype', 'HP:0009592', (13, 24))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (169, 191))	('children', 'Species', '9606', (59, 67))
244715	25744348	The BRAF exon15 V600E mutation is found in approximately 60% of patients with pleomorphic xanthoastrocytoma (PXA).	('patients', 'Species', '9606', (64, 72))	('astrocytoma', 'Phenotype', 'HP:0009592', (96, 107))	('V600E', 'Mutation', 'rs113488022', (16, 21))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (78, 107))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('pleomorphic xanthoastrocytoma', 'Disease', (78, 107))	('V600E', 'Var', (16, 21))
244722	25744348	For example, oligodendrogliomas with a classic histology are highly correlated with the IDH mutation and 1p/19q codeletion, while those without a classic histology exhibit both heterogeneous histology and genotypes.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (13, 31))	('1p/19q codeletion', 'Var', (105, 122))	('IDH', 'Gene', (88, 91))	('oligodendrogliomas', 'Disease', (13, 31))	('correlated', 'Reg', (68, 78))	('IDH', 'Gene', '3417', (88, 91))
244752	21300619	During the period February 2006 - April 2008, subjects with a histologically confirmed diagnosis (ICDO-3 sites C70.0-C72.9 and C75.1-C75.3) of a primary glioma [glioblastoma (ICDO-3 histology codes 9440-9442), astrocytoma (9400-9411 and 9420-9421), mixed glioma (9382) or oligodendroglioma (9450-9460)], who were 18 or older, English speaking, and residents of the United States were eligible for participation in the study.	('9450-9460)]', 'Var', (291, 302))	('oligodendroglioma', 'Disease', 'MESH:D009837', (272, 289))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('ICDO-3', 'Var', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('oligodendroglioma', 'Disease', (272, 289))	('glioma', 'Disease', (153, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (161, 173))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('9400-9411', 'Var', (223, 232))	('glioma', 'Disease', (255, 261))	('astrocytoma', 'Disease', 'MESH:D001254', (210, 221))	('astrocytoma', 'Disease', (210, 221))	('glioblastoma', 'Disease', (161, 173))	('9382', 'Var', (263, 267))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('glioblastoma', 'Phenotype', 'HP:0012174', (161, 173))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('C75.1-C75.3', 'Var', (127, 138))	('glioma', 'Disease', (283, 289))	('glioma', 'Disease', 'MESH:D005910', (283, 289))
244832	20921210	In mice expressing both PDGF-B + Bcl-2 that were treated with WP1066, there was 55.5% increase in median survival time (P< 0.01), with an associated inhibition of intratumoral STAT3 and macrophages.	('Bcl', 'Phenotype', 'HP:0012191', (33, 36))	('inhibition', 'NegReg', (149, 159))	('increase', 'PosReg', (86, 94))	('WP1066', 'Var', (62, 68))	('tumor', 'Disease', (168, 173))	('PDGF-B + Bcl-2', 'Var', (24, 38))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('median survival time', 'CPA', (98, 118))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
244847	20921210	Moreover, STAT3 expression can reduce the cellular cytotoxicity of natural killer cells and neutrophils, as well as the expression of MHC II, CD80, CD86, and IL-12 in dendritic cells, rendering them unable to activate T cells and to generate antitumor immunity.	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('IL-12', 'Gene', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (246, 251))	('CD80', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('MHC II', 'Gene', (134, 140))	('cytotoxicity', 'Disease', (51, 63))	('reduce', 'NegReg', (31, 37))	('CD86', 'Gene', (148, 152))	('CD86', 'Gene', '12524', (148, 152))	('STAT3 expression', 'Var', (10, 26))	('MHC II', 'Gene', '111364', (134, 140))	('CD80', 'Gene', '12519', (142, 146))
244852	20921210	WP1066 can exert direct anti-tumor activity including the induction of caspase-dependent apoptotic cell death in and inhibition of angiogenesis.	('angiogenesis', 'CPA', (131, 143))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('WP1066', 'Var', (0, 6))	('caspase-dependent apoptotic cell death in', 'CPA', (71, 112))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('inhibition', 'NegReg', (117, 127))
244853	20921210	Moreover, WP1066 is a potent inducer of pro-inflammatory responses and can reverse the functional immunosuppression of macrophages and glioma cancer stem cells.	('glioma cancer', 'Disease', (135, 148))	('WP1066', 'Var', (10, 16))	('functional immunosuppression', 'MPA', (87, 115))	('glioma cancer', 'Disease', 'MESH:D005910', (135, 148))	('pro-inflammatory responses', 'MPA', (40, 66))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('inducer', 'PosReg', (29, 36))
244862	20921210	We hypothesized that the gliomas formed in Ntv-a mice are immunosuppressive, that the high-grade gliomas would be more immunosuppressive relative to the low-grade gliomas, and that this model of endogenously arising malignant gliomas could be used to test immunotherapeutics.	('gliomas', 'Disease', (163, 170))	('malignant gliomas', 'Disease', (216, 233))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (226, 233))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('Ntv-a', 'Var', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('gliomas', 'Disease', 'MESH:D005910', (226, 233))	('gliomas', 'Disease', (25, 32))	('glioma', 'Phenotype', 'HP:0009733', (226, 232))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('gliomas', 'Disease', (97, 104))	('mice', 'Species', '10090', (49, 53))	('gliomas', 'Phenotype', 'HP:0009733', (226, 233))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('Ntv', 'Chemical', '-', (43, 46))	('malignant gliomas', 'Disease', 'MESH:D005910', (216, 233))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))
244909	20921210	Because a subset of mice that were injected with RCAS-PDGF-B, (an inducer of p-STAT3) and the majority of mice injected with RCAS-PDGF-B + RCAS-Bcl-2 developed high-grade malignant gliomas, we determined if these tumors demonstrated induction of STAT3.	('RCAS-PDGF-B', 'Var', (49, 60))	('mice', 'Species', '10090', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', (213, 219))	('malignant gliomas', 'Disease', 'MESH:D005910', (171, 188))	('Bcl', 'Phenotype', 'HP:0012191', (144, 147))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('mice', 'Species', '10090', (20, 24))	('RCAS', 'Chemical', '-', (49, 53))	('RCAS', 'Chemical', '-', (139, 143))	('RCAS', 'Chemical', '-', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('malignant gliomas', 'Disease', (171, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))
244913	20921210	In the PDGF-B + Bcl-2 mice, the percentage of cells that expressed p-STAT3 was 24.1 +- 5.4% in high-grade tumors (range 0.1 - 49.7%, n = 12) and 2.6 +- 1.6% in low grade tumors (range 0.6 - 7.3%, n = 4).	('p-STAT3', 'Var', (67, 74))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('mice', 'Species', '10090', (22, 26))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('Bcl', 'Phenotype', 'HP:0012191', (16, 19))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', (170, 176))
244937	20921210	In addition, after 90 days, all 11/15 (73.3%) of the surviving mice treated with WP1066 had no evidence of any intracranial tumor on histopathological examination compared with 5/15 (33.3%, P=0.03) of the control mice.	('intracranial tumor', 'Disease', (111, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mice', 'Species', '10090', (213, 217))	('mice', 'Species', '10090', (63, 67))	('intracranial tumor', 'Disease', 'MESH:D001932', (111, 129))	('WP1066', 'Var', (81, 87))
244938	20921210	High-grade tumors developed in 1/15 (6.7%) of the WP1066 treated mice relative to 4/15 (26.7%) in the control mice (P=0.16).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('mice', 'Species', '10090', (65, 69))	('WP1066 treated', 'Var', (50, 64))	('mice', 'Species', '10090', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))
244939	20921210	The tumors in the mice treated with WP1066 showed a marked decrease in p-STAT3 expression (3.6 +- 1.6%, range 0.6 - 5.9%, n = 3) compared with the untreated mice (36.3 +- 10.6%, range 6.1 - 51.5, n = 4, P = 0.05) (Fig.	('mice', 'Species', '10090', (157, 161))	('p-STAT3 expression', 'MPA', (71, 89))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('mice', 'Species', '10090', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('decrease', 'NegReg', (59, 67))	('WP1066', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
244940	20921210	Similarly, WP1066 also decreased macrophage infiltration of tumors, with treated mice having 5.0 +- 3.3% F4/80-positive cells (range 1.6 - 11.5, n = 3) compared with 17.4 +- 4.9 (range 6.0 - 26.9%, n = 4, P = 0.05) in control mice (Fig.	('F4/80', 'Gene', '13733', (105, 110))	('mice', 'Species', '10090', (81, 85))	('mice', 'Species', '10090', (226, 230))	('WP1066', 'Var', (11, 17))	('decreased macrophage infiltration', 'Phenotype', 'HP:0012648', (23, 56))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('F4/80', 'Gene', (105, 110))	('decreased', 'NegReg', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
244942	20921210	The first is that WP1066 is demonstrating efficacy in a heterogeneous, orthotopic glioma model system.	('glioma', 'Disease', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('WP1066', 'Var', (18, 24))
244944	20921210	Previous preclinical studies of the effects of WP1066 on gliomas were confined to a clonotypic glioma in a non orthotopic position in an immunosuppressed murine model.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma', 'Disease', (57, 63))	('glioma', 'Disease', (95, 101))	('murine', 'Species', '10090', (154, 160))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('WP1066', 'Var', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
244945	20921210	Secondly, WP1066 is exerting a therapeutic effect on oligodendrogliomas, which has not been previously described.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('WP1066', 'Var', (10, 16))	('oligodendrogliomas', 'Disease', (53, 71))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (53, 71))
244947	20921210	Specifically, we demonstrated that the expression in vivo of STAT3 in the RCAS-PDGF-B and RCAS-PDGF-B + RCAS-Bcl-2 models of glioma correlated with glioma grade and prognosis, similar to the findings in human glioma patients.	('RCAS-PDGF-B', 'Var', (90, 101))	('correlated', 'Reg', (132, 142))	('glioma', 'Disease', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('RCAS-PDGF-B', 'Gene', (74, 85))	('glioma', 'Disease', (209, 215))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('STAT3', 'Gene', (61, 66))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('expression', 'MPA', (39, 49))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('patients', 'Species', '9606', (216, 224))	('RCAS', 'Chemical', '-', (74, 78))	('glioma', 'Disease', (125, 131))	('human', 'Species', '9606', (203, 208))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('RCAS', 'Chemical', '-', (104, 108))	('RCAS', 'Chemical', '-', (90, 94))	('prognosis', 'CPA', (165, 174))	('Bcl', 'Phenotype', 'HP:0012191', (109, 112))
244954	20921210	The STAT3 inhibitor WP1066 exerted a therapeutic benefit, inhibited intratumoral p-STAT3 expression, and suppressed intratumoral macrophage infiltration that correlated with treatment response.	('suppressed', 'NegReg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (73, 78))	('inhibited', 'NegReg', (58, 67))	('WP1066', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
244955	20921210	Although FoxP3 expression is under transcriptional control of STAT3 and WP1066 has been previously shown to inhibit Tregs in the systemic circulation, we did not find a decrease in the level of FoxP3 expression during treatment with WP1066.	('Tregs', 'CPA', (116, 121))	('FoxP3', 'Gene', '20371', (194, 199))	('WP1066', 'Var', (72, 78))	('Tregs', 'Chemical', '-', (116, 121))	('FoxP3', 'Gene', (9, 14))	('FoxP3', 'Gene', (194, 199))	('inhibit', 'NegReg', (108, 115))	('FoxP3', 'Gene', '20371', (9, 14))	('WP1066', 'Var', (233, 239))
244956	20921210	The failure of WP1066 to further decrease the numbers of FoxP3 expressing cells in the oligodendroglial-like tumors in this animal model system may simply reflect the low baseline levels.	('oligodendroglial-like tumors', 'Disease', (87, 115))	('FoxP3', 'Gene', '20371', (57, 62))	('decrease', 'NegReg', (33, 41))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('oligodendroglial-like tumors', 'Disease', 'MESH:D009369', (87, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('WP1066', 'Var', (15, 21))	('FoxP3', 'Gene', (57, 62))
244957	20921210	Although p-STAT3 is not ubiquitously expressed in all tumor cells in the murine model system, there is nonetheless marked in vivo efficacy.	('murine', 'Species', '10090', (73, 79))	('p-STAT3', 'Var', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
244958	20921210	This discrepancy can be resolved by the activity of WP1066 exerting both direct effects on tumor cells expressing p-STAT3 and the immune cells expressing p-STAT3, which restrains their anti-tumor activity including recognition of tumor-associated and tumor-specific antigens.	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('WP1066', 'Var', (52, 58))	('restrains', 'NegReg', (169, 178))	('tumor', 'Disease', (91, 96))	('p-STAT3', 'Var', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('p-STAT3', 'Var', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
244959	20921210	The inhibition of p-STAT3 restores anti-tumor immune clearance, and therefore we suspect that WP1066 exerts a bystander effect on p-STAT3 negative-expressing cells by eradicating those tumor cells that can by immunologically recognized.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('WP1066', 'Var', (94, 100))	('restores', 'PosReg', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('eradicating', 'NegReg', (167, 178))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('inhibition', 'NegReg', (4, 14))
244960	20921210	This contention is supported by the fact that therapeutic efficacy of WP1066 is lost in nude models systems and with in vivo depletions of the CD4 and CD8 subpopulations (unpublished data).	('CD4', 'Gene', (143, 146))	('CD4', 'Gene', '12504', (143, 146))	('WP1066', 'Var', (70, 76))	('CD8', 'Gene', (151, 154))	('lost', 'NegReg', (80, 84))	('depletions', 'MPA', (125, 135))
244972	32494639	Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lead to', 'Reg', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('drive', 'Reg', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('isocitrate dehydrogenase', 'Gene', (13, 37))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (133, 138))	('cancer', 'Disease', (68, 74))	('IDH', 'Gene', (39, 42))	('isocitrate dehydrogenase', 'Gene', '3417', (13, 37))	('epigenome', 'MPA', (112, 121))	('changes', 'Reg', (97, 104))
244973	32494639	Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive.	('mutations', 'Var', (63, 72))	('IDH', 'Gene', (59, 62))	('solid tumors', 'Disease', 'MESH:D009369', (36, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('solid tumors', 'Disease', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
244974	32494639	Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage.	('cholangiocarcinomas', 'Disease', (49, 68))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (49, 68))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('elevated', 'PosReg', (77, 85))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (49, 67))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('DNA damage', 'MPA', (86, 96))	('IDH-mutant', 'Var', (26, 36))
244975	32494639	Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis).	('PARP', 'Gene', '142', (293, 297))	('reduced', 'NegReg', (176, 183))	('glioma', 'Disease', (57, 63))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (68, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('mutant', 'Var', (215, 221))	('PARP', 'Gene', (293, 297))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('DNA damage repair', 'MPA', (184, 201))	('IDH', 'Gene', (222, 225))	('adenosine', 'Chemical', 'MESH:D000241', (237, 246))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('cholangiocarcinoma', 'Disease', (68, 86))
244977	32494639	Neomorphic mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) have been identified in multiple cancer types, including lower grade glioma (LGG), secondary glioblastoma, intrahepatic cholangiocarcinoma (ICC), acute myeloid leukemia (AML), chondrosarcoma (CS), and others.	('mutations', 'Var', (11, 20))	('C', 'Chemical', 'MESH:D002244', (227, 228))	('acute myeloid leukemia', 'Disease', (231, 253))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (237, 253))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('glioma', 'Disease', (154, 160))	('AML', 'Disease', 'MESH:D015470', (255, 258))	('leukemia', 'Phenotype', 'HP:0001909', (245, 253))	('AML', 'Disease', (255, 258))	('IDH1/2', 'Gene', '3417;3418', (77, 83))	('AML', 'Phenotype', 'HP:0004808', (255, 258))	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('chondrosarcoma', 'Disease', 'MESH:D002813', (261, 275))	('glioblastoma', 'Disease', (178, 190))	('chondrosarcoma', 'Disease', (261, 275))	('IDH1/2', 'Gene', (77, 83))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (231, 253))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('isocitrate dehydrogenase', 'Gene', '3417', (43, 67))	('identified', 'Reg', (95, 105))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (231, 253))	('cancer', 'Disease', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('intrahepatic cholangiocarcinoma', 'Disease', (192, 223))	('CS', 'Phenotype', 'HP:0006765', (277, 279))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (261, 275))	('C', 'Chemical', 'MESH:D002244', (277, 278))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('isocitrate dehydrogenase', 'Gene', (43, 67))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
244978	32494639	The mutant IDH enzyme (IDHmut) converts the Krebs cycle intermediate alpha-ketoglutarate (alphaKG) into 2-hydroxyglutarate (2-HG), which functions as an oncometabolite.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (69, 88))	('IDH', 'Gene', (11, 14))	('Krebs', 'Chemical', '-', (44, 49))	('mutant', 'Var', (4, 10))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (104, 122))	('2-HG', 'Chemical', 'MESH:C019417', (124, 128))
244979	32494639	2-HG can induce global DNA hypermethylation, inhibition of histone lysine demethylases, and block of cell differentiation.	('inhibition', 'NegReg', (45, 55))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('global DNA hypermethylation', 'MPA', (16, 43))	('lysine', 'Chemical', 'MESH:D008239', (67, 73))	('cell differentiation', 'CPA', (101, 121))	('histone', 'Protein', (59, 66))	('2-HG', 'Var', (0, 4))	('block', 'NegReg', (92, 97))
244980	32494639	One strategy to treat IDHmut tumors is to inhibit the mutant IDH protein and 2-HG production.	('2-HG production', 'MPA', (77, 92))	('tumors', 'Disease', (29, 35))	('IDH protein', 'Protein', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('inhibit', 'NegReg', (42, 49))	('mutant', 'Var', (54, 60))	('2-HG', 'Chemical', 'MESH:C019417', (77, 81))
244982	32494639	Recently, inhibitors of IDH2 (enasidenib) and IDH1 (ivosidenib) have been shown to induce differentiation of cancer cells in patients with recurrent or refractory AML.	('enasidenib', 'Chemical', 'MESH:C000605269', (30, 40))	('differentiation', 'CPA', (90, 105))	('AML', 'Phenotype', 'HP:0004808', (163, 166))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('AML', 'Disease', (163, 166))	('IDH1', 'Gene', (46, 50))	('ivosidenib', 'Chemical', 'MESH:C000627630', (52, 62))	('cancer', 'Disease', (109, 115))	('induce', 'PosReg', (83, 89))	('IDH2', 'Gene', (24, 28))	('inhibitors', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('IDH2', 'Gene', '3418', (24, 28))	('AML', 'Disease', 'MESH:D015470', (163, 166))	('patients', 'Species', '9606', (125, 133))
244984	32494639	Paradoxically, exogenous 2-HG can cause toxicity and slow down cell proliferation by inhibiting mammalian target of rapamycin signaling and mRNA m6A modification.	('toxicity', 'Disease', (40, 48))	('inhibiting', 'NegReg', (85, 95))	('2-HG', 'Chemical', 'MESH:C019417', (25, 29))	('2-HG', 'Protein', (25, 29))	('exogenous', 'Var', (15, 24))	('cell proliferation', 'CPA', (63, 81))	('mammalian target of rapamycin', 'Gene', (96, 125))	('mammalian target of rapamycin', 'Gene', '2475', (96, 125))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('slow down', 'NegReg', (53, 62))	('mRNA m6A modification', 'MPA', (140, 161))
244985	32494639	Furthermore, 2-HG directly inhibits homologous recombination (HR), thus weakening DNA damage repair (DDR) and potentially improving the outcome from DNA damaging agents in patients receiving standard-of-care cytotoxic therapies.	('DNA damage repair', 'MPA', (82, 99))	('inhibits', 'NegReg', (27, 35))	('weakening', 'NegReg', (72, 81))	('2-HG', 'Var', (13, 17))	('improving', 'PosReg', (122, 131))	('homologous recombination', 'MPA', (36, 60))	('patients', 'Species', '9606', (172, 180))	('2-HG', 'Chemical', 'MESH:C019417', (13, 17))
244986	32494639	IDH mutations are associated with better outcomes from radiation therapy (RT) and chemotherapy in patients with glioma.	('IDH', 'Gene', (0, 3))	('patients', 'Species', '9606', (98, 106))	('glioma', 'Disease', (112, 118))	('mutations', 'Var', (4, 13))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
244991	32494639	Cells with deficient HR, the main compensatory mechanism to manage the increased DSB stress imposed by PARPi, are unable to efficiently repair these DSB and enter mitotic catastrophe and apoptosis.	('PARP', 'Gene', '142', (103, 107))	('apoptosis', 'CPA', (187, 196))	('unable', 'NegReg', (114, 120))	('PARP', 'Gene', (103, 107))	('enter', 'PosReg', (157, 162))	('deficient', 'Var', (11, 20))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('mitotic catastrophe', 'CPA', (163, 182))
244998	32494639	We demonstrate in multiple in vitro contexts that expression of mutant IDH1 sensitizes the cell to radiation and PARPi.	('sensitizes', 'Reg', (76, 86))	('PARP', 'Gene', '142', (113, 117))	('IDH1', 'Gene', (71, 75))	('mutant', 'Var', (64, 70))	('PARP', 'Gene', (113, 117))
244999	32494639	Last, we used two orthotopic LGG and one heterotopic ICC xenograft animal model to show that PARPi sensitizes the tumors to IR and that this sensitization is specifically associated with IDH mutation status.	('PARP', 'Gene', '142', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IDH', 'Gene', (187, 190))	('sensitizes', 'Reg', (99, 109))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('PARP', 'Gene', (93, 97))	('mutation', 'Var', (191, 199))	('associated', 'Reg', (171, 181))
245001	32494639	Previous studies have suggested that repair of DNA damage by HR is impaired by mutant IDH1 expression in a human colon cancer cell line through the oncometabolite 2-HG.	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('IDH1', 'Gene', (86, 90))	('human', 'Species', '9606', (107, 112))	('repair', 'MPA', (37, 43))	('impaired', 'NegReg', (67, 75))	('mutant', 'Var', (79, 85))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('colon cancer', 'Disease', (113, 125))	('2-HG', 'Chemical', 'MESH:C019417', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
245002	32494639	To ascertain whether this effect is generalizable, we first used an immortalized human astrocyte (IHA) isogenic cell line system, which includes one line that expresses mutant IDH1 R132H (IHA-IDH1mut), and a matching isogenic control, which does not express mutant IDH1 (IHA-EV).	('IHA-EV', 'Chemical', '-', (271, 277))	('R132H', 'Mutation', 'rs121913500', (181, 186))	('IHA', 'Chemical', '-', (98, 101))	('IHA', 'Chemical', '-', (188, 191))	('mutant', 'Var', (169, 175))	('IHA', 'Chemical', '-', (271, 274))	('human', 'Species', '9606', (81, 86))	('R132H', 'Var', (181, 186))	('IDH1', 'Gene', (176, 180))
245003	32494639	Expression of mutant IDH1 induces changes in the DNA methylation and histone landscape, which recapitulates those in IDH1-mutant tumors and blocks differentiation.	('differentiation', 'CPA', (147, 162))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('blocks', 'NegReg', (140, 146))	('mutant', 'Var', (14, 20))	('changes', 'Reg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('DNA methylation', 'MPA', (49, 64))	('IDH1', 'Gene', (21, 25))	('histone landscape', 'MPA', (69, 86))
245006	32494639	The DSBs marked by gamma-H2AX positivity in IDH1mut cells indicates a higher level of unrepaired DNA damage.	('positivity', 'Var', (30, 40))	('gamma-H2AX', 'Gene', '15270', (19, 29))	('gamma-H2AX', 'Gene', (19, 29))	('DSBs', 'Disease', (4, 8))	('DSBs', 'Chemical', '-', (4, 8))
245008	32494639	IHA-IDH1mut displayed notably higher levels of KAP1 phosphorylation compared to IHA-EV, suggesting increased engagement of the replication stress pathway (Fig.	('IHA-EV', 'Chemical', '-', (80, 86))	('IHA', 'Chemical', '-', (80, 83))	('IHA-IDH1mut', 'Var', (0, 11))	('replication stress pathway', 'Pathway', (127, 153))	('higher', 'PosReg', (30, 36))	('levels', 'MPA', (37, 43))	('KAP1', 'Gene', (47, 51))	('IHA', 'Chemical', '-', (0, 3))	('KAP1', 'Gene', '10155', (47, 51))	('increased engagement', 'PosReg', (99, 119))
245010	32494639	However, consistent with previous reports, these unrepaired DNA damage sites did not induce significant change in cell death, likely due to concurrent inactivation of p53 as a part of immortalization.	('inactivation', 'NegReg', (151, 163))	('sites', 'Var', (71, 76))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', (167, 170))
245013	32494639	We reasoned that the IDH1mut-induced DDR deficiency can be targeted by PARP inhibition similar to the scenario in BRCA-mutant breast and ovarian cancer and that this synthetic lethality could be augmented by inflicting further DNA damage through radiotherapy.	('inhibition', 'NegReg', (76, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DDR deficiency', 'Disease', (37, 51))	('DDR deficiency', 'Disease', 'MESH:D007153', (37, 51))	('PARP', 'Gene', '142', (71, 75))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (126, 151))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('IDH1mut-induced', 'Var', (21, 36))	('PARP', 'Gene', (71, 75))
245015	32494639	Elevated gamma-H2AX positivity was observed in IHA-IDH1mut compared to IHA-EV at baseline (Fig.	('IHA', 'Chemical', '-', (71, 74))	('gamma-H2AX', 'Gene', (9, 19))	('IHA', 'Chemical', '-', (47, 50))	('IHA-EV', 'Chemical', '-', (71, 77))	('Elevated', 'PosReg', (0, 8))	('gamma-H2AX', 'Gene', '15270', (9, 19))	('positivity', 'MPA', (20, 30))	('IHA-IDH1mut', 'Var', (47, 58))
245017	32494639	IDH mutation was associated with a markedly reduced ability to repair DNA damage from IR and PARPi, as measured by the neutral Comet assay (Fig.	('IDH', 'Gene', (0, 3))	('PARP', 'Gene', '142', (93, 97))	('mutation', 'Var', (4, 12))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('reduced', 'NegReg', (44, 51))	('PARP', 'Gene', (93, 97))	('repair DNA damage', 'MPA', (63, 80))
245019	32494639	Moreover, the deficiency in DDR found in IHA-IDH1mut cells leads to a greater extent of cell death when treated with the combination as shown by annexin V flow cytometry (Fig.	('annexin V', 'Gene', '308', (145, 154))	('death', 'Disease', 'MESH:D003643', (93, 98))	('IHA', 'Chemical', '-', (41, 44))	('annexin V', 'Gene', (145, 154))	('DDR', 'Gene', (28, 31))	('deficiency', 'Var', (14, 24))	('death', 'Disease', (93, 98))
245022	32494639	However, treatment with strong PARP-trapping agents, such as olaparib and talazoparib, tends to confer resistance through genetic mutation.	('olaparib', 'Chemical', 'MESH:C531550', (61, 69))	('PARP', 'Gene', '142', (31, 35))	('PARP', 'Gene', (31, 35))	('genetic mutation', 'Var', (122, 138))	('talazoparib', 'Chemical', 'MESH:C586365', (74, 85))	('resistance', 'MPA', (103, 113))
245028	32494639	Under all IR conditions, IHA-EV yielded modest reduction of colonies when simultaneously treated with veliparib, while this reduction was markedly enhanced in IHA-IDH1mut (Fig.	('enhanced', 'PosReg', (147, 155))	('veliparib', 'MPA', (102, 111))	('veliparib', 'Chemical', 'MESH:C521013', (102, 111))	('IHA-IDH1mut', 'Var', (159, 170))	('reduction', 'NegReg', (47, 56))	('IHA', 'Chemical', '-', (25, 28))	('IHA', 'Chemical', '-', (159, 162))	('colonies', 'CPA', (60, 68))	('IHA-EV', 'Chemical', '-', (25, 31))
245031	32494639	TS603 GSC also showed notably amplified synthetic lethality when treated with IR and olaparib (fig.	('amplified', 'PosReg', (30, 39))	('olaparib', 'Chemical', 'MESH:C531550', (85, 93))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('TS603', 'Var', (0, 5))	('synthetic lethality', 'MPA', (40, 59))
245032	32494639	These results indicate that IR + PARPi preferentially inhibits the clonogenic growth of IDH-mutant cells.	('IDH-mutant', 'Gene', (88, 98))	('PARP', 'Gene', (33, 37))	('PARP', 'Gene', '142', (33, 37))	('inhibits', 'NegReg', (54, 62))	('IDH-mutant', 'Var', (88, 98))	('clonogenic growth', 'CPA', (67, 84))
245033	32494639	We tested whether the synthetic lethality conferred by PARPi in the setting of mutant IDH is observed in other tumor types that commonly harbor IDH mutations.	('PARP', 'Gene', '142', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutant', 'Var', (79, 85))	('tumor', 'Disease', (111, 116))	('PARP', 'Gene', (55, 59))
245036	32494639	We tested whether expression of mutant IDH1 sensitizes ICC cancer cells to PARPis.	('PARP', 'Gene', (75, 79))	('IDH1', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tested', 'Reg', (3, 9))	('mutant', 'Var', (32, 38))	('sensitizes', 'Reg', (44, 54))	('PARP', 'Gene', '142', (75, 79))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
245037	32494639	First, we expressed IDH1-R132H in a human cholangiocarcinoma cell line (HUCCT1) that is wild type for IDH.	('cholangiocarcinoma', 'Disease', (42, 60))	('R132H', 'Mutation', 'rs121913500', (25, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (42, 60))	('IDH1-R132H', 'Var', (20, 30))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('human', 'Species', '9606', (36, 41))
245042	32494639	Clonogenic capacity of HUCCT1 cells was severely decreased by IDH1mut expression, demonstrated by a 100-fold difference in clonogenicity when IDH1mut HUCCT1 cells were exposed to 6-Gy radiation and 4 muM olaparib (Fig.	('Clonogenic capacity', 'CPA', (0, 19))	('olaparib', 'Chemical', 'MESH:C531550', (204, 212))	('IDH1mut expression', 'Var', (62, 80))	('clonogenicity', 'CPA', (123, 136))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('decreased', 'NegReg', (49, 58))	('muM', 'Gene', '56925', (200, 203))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('Gy', 'Species', '214032', (181, 183))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('muM', 'Gene', (200, 203))	('C', 'Chemical', 'MESH:D002244', (25, 26))
245045	32494639	Together, we showed in two different cancers, using both engineered isogenic cells and native IDH-mutant tumor cell lines, that mutant IDH1 expression leads to hypersensitivity to PARPi, and this hypersensitivity is markedly amplified by radiation.	('leads to', 'Reg', (151, 159))	('hypersensitivity', 'Disease', 'MESH:D004342', (196, 212))	('PARP', 'Gene', '142', (180, 184))	('IDH1', 'Gene', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('hypersensitivity', 'Disease', (160, 176))	('cancers', 'Disease', (37, 44))	('mutant', 'Var', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('hypersensitivity', 'Disease', 'MESH:D004342', (160, 176))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('PARP', 'Gene', (180, 184))	('tumor', 'Disease', (105, 110))	('hypersensitivity', 'Disease', (196, 212))
245046	32494639	Having confirmed that expression of mutant IDH1 is associated with increased levels of DNA damage in vitro, we sought to ascertain whether this is true in patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('IDH1', 'Gene', (43, 47))	('patient', 'Species', '9606', (155, 162))	('levels of DNA damage', 'MPA', (77, 97))	('tumors', 'Disease', (163, 169))	('increased', 'PosReg', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('mutant', 'Var', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))
245048	32494639	With assistance from expert clinical pathologists at MSKCC, we determined the IDH mutation status of the tumors and ensured that the IDH-mutant and wild-type tumors were matched for similar disease stage, grade, and pathologic features.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('mutation', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IDH', 'Gene', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
245050	32494639	IDH1mut World Health Organization (WHO) grade III glioma sections showed elevated gamma-H2AX signals compared to their IDHwt controls, regardless of their histopathologic classification as oligodendroglioma or astrocytoma (Fig.	('gamma-H2AX', 'Gene', '15270', (82, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (210, 221))	('IDH1mut', 'Var', (0, 7))	('gamma-H2AX', 'Gene', (82, 92))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('oligodendroglioma or astrocytoma', 'Disease', (189, 221))	('III glioma', 'Disease', 'MESH:D005910', (46, 56))	('III glioma', 'Disease', (46, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('elevated', 'PosReg', (73, 81))	('oligodendroglioma or astrocytoma', 'Disease', 'MESH:D009837', (189, 221))
245051	32494639	Similarly, ICC tumor pairs collected at similar disease stage (T1, no lymph node or distant metastases, no neoadjuvant therapy, and no intrahepatic therapy before resection) demonstrated that IDH mutations lead to significantly augmented gamma-H2AX staining (Fig.	('gamma-H2AX', 'Gene', (238, 248))	('ICC tumor', 'Disease', 'MESH:C566123', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('metastases', 'Disease', (92, 102))	('ICC tumor', 'Disease', (11, 20))	('metastases', 'Disease', 'MESH:D009362', (92, 102))	('augmented', 'PosReg', (228, 237))	('gamma-H2AX', 'Gene', '15270', (238, 248))	('IDH', 'Gene', (192, 195))	('mutations', 'Var', (196, 205))
245057	32494639	Mice with TS543 (IDHwt) tumors showed similar OS in veliparib and control groups (median OS, 11 days versus 10 days) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('veliparib', 'Chemical', 'MESH:C521013', (52, 61))	('Mice', 'Species', '10090', (0, 4))	('TS543', 'Var', (10, 15))
245059	32494639	However, the IDH1mut tumors (TS603) showed significant improvement of OS in veliparib treated group (11 days) compared to control (8.5 days), as well as in RT + veliparib (21 days) versus RT alone (14 days) (Fig.	('improvement', 'PosReg', (55, 66))	('veliparib', 'Chemical', 'MESH:C521013', (161, 170))	('IDH1mut', 'Var', (13, 20))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('veliparib', 'Chemical', 'MESH:C521013', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
245067	32494639	To rule out the possibility that the observed sensitivity could be due to different genetic backgrounds (i.e., TS543 and TS603), we performed similar trials in a genetically engineered mouse model of glioma with RCAS-TVA (replication competent avian sarcoma-leukosis virus long terminal repeat with a splice acceptor)-mediated gene transfer of mutant IDH in an isogenic setting.	('glioma', 'Disease', (200, 206))	('sarcoma-leukosis virus long terminal repeat', 'Disease', 'MESH:D000647', (250, 293))	('mouse', 'Species', '10090', (185, 190))	('RCAS', 'Chemical', '-', (212, 216))	('IDH', 'Gene', (351, 354))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('mutant', 'Var', (344, 350))	('sarcoma-leukosis virus long terminal repeat', 'Disease', (250, 293))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('TVA', 'Chemical', '-', (217, 220))
245068	32494639	This is a previously established model where mutant IDH is expressed in endogenously generated gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('mutant', 'Var', (45, 51))	('IDH', 'Gene', (52, 55))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))
245069	32494639	In these animal models, tumors that express the wild-type or mutant IDH1 were generated through intracranial injection of DF1 cells that carry the corresponding expression cassette (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('IDH1', 'Gene', (68, 72))	('mutant', 'Var', (61, 67))
245073	32494639	On the contrary, IDH1mut gliomas are somewhat sensitive to both RT or veliparib as monotherapy (median OS, 22 days versus 22 days versus 14 days for vehicle control) and the combination of RT and veliparib substantially extended OS (median, 66 days, >4-fold longer OS than vehicle control and 3-fold longer than RT or veliparib alone) (Fig.	('veliparib', 'Chemical', 'MESH:C521013', (318, 327))	('IDH1mut', 'Var', (17, 24))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('extended', 'PosReg', (220, 228))	('veliparib', 'Chemical', 'MESH:C521013', (196, 205))	('veliparib', 'Chemical', 'MESH:C521013', (70, 79))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
245075	32494639	Representative MRI images of IDH1mut gliomas show similar initial sizes (Fig.	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('IDH1mut', 'Var', (29, 36))
245076	32494639	5D, circled areas) and demonstrate that veliparib limited the tumor growth compared to vehicle-treated tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('veliparib', 'Chemical', 'MESH:C521013', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('veliparib', 'Var', (40, 49))	('limited', 'NegReg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
245081	32494639	BGB-290 prolonged the OS of mice with IDH1mut glioma, both as monotherapy (median OS, 28 days) or in combination with RT (median OS, 44 days), with 4 of 13 mice living more than 90 days (Fig.	('mice', 'Species', '10090', (28, 32))	('glioma', 'Disease', (46, 52))	('IDH1mut', 'Var', (38, 45))	('BGB-290', 'Gene', (0, 7))	('prolonged', 'PosReg', (8, 17))	('mice', 'Species', '10090', (156, 160))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
245089	32494639	However, HUCCT1 cells competently form subcutaneous tumors in athymic nude mice regardless of the mutational status of IDH1.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (39, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('mutational', 'Var', (98, 108))	('IDH1', 'Gene', (119, 123))	('nude mice', 'Species', '10090', (70, 79))
245091	32494639	The IDH1mut tumors grew slightly slower than the wild-type tumors (median survival, 31 days versus 21 days; Fig.	('grew', 'CPA', (19, 23))	('tumors', 'Disease', (59, 65))	('IDH1mut', 'Var', (4, 11))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('slower', 'NegReg', (33, 39))
245101	32494639	Together, these in vivo findings support, in ICC cells, that IDH mutations confer vulnerability to PARPi, which can be further exploited by introducing DNA damaging agents, such as radiation.	('PARP', 'Gene', '142', (99, 103))	('IDH', 'Gene', (61, 64))	('PARP', 'Gene', (99, 103))	('mutations', 'Var', (65, 74))
245106	32494639	Although directly targeting the mutant IDH enzyme with small-molecule inhibitors has been shown to have benefits in patients with AML, concerns exist regarding their application to solid tumors, such as systemic availability of the drug, ability to penetrate into tumor, and lack of efficacy.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (264, 269))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('solid tumors', 'Disease', (181, 193))	('tumor', 'Disease', (187, 192))	('mutant', 'Var', (32, 38))	('AML', 'Disease', 'MESH:D015470', (130, 133))	('IDH', 'Gene', (39, 42))	('solid tumors', 'Disease', 'MESH:D009369', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('AML', 'Phenotype', 'HP:0004808', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('AML', 'Disease', (130, 133))	('benefits', 'PosReg', (104, 112))
245108	32494639	Moreover, in solid tumors, mutation of IDH typically portends a better prognosis compared to tumors with wild-type IDH.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('solid tumors', 'Disease', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('portends', 'Reg', (53, 61))	('mutation', 'Var', (27, 35))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('solid tumors', 'Disease', 'MESH:D009369', (13, 25))	('IDH', 'Gene', (39, 42))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
245110	32494639	We examine an approach to treating IDHmut tumors that takes advantage of their unique metabolic, genomic, and epigenetic state through exploitation of impaired HR associated with mutations in IDH1.	('impaired HR', 'Disease', (151, 162))	('impaired HR', 'Disease', 'MESH:D001919', (151, 162))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('IDH1', 'Gene', (192, 196))	('mutations', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
245114	32494639	Using these models, we were able to determine that IDH mutation confers sensitivity to DNA damaging agents and PARP inhibitors, and we established preclinical strategies to target these therapeutic vulnerabilities.	('PARP', 'Gene', '142', (111, 115))	('IDH', 'Gene', (51, 54))	('sensitivity', 'MPA', (72, 83))	('PARP', 'Gene', (111, 115))	('mutation', 'Var', (55, 63))
245120	32494639	Ongoing clinical trials have been set up to test this concept (e.g., NCT03212274, NCT03561870, NCT03749187, etc.	('C', 'Chemical', 'MESH:D002244', (96, 97))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('NCT03561870', 'Var', (82, 93))	('NCT03212274', 'Var', (69, 80))	('C', 'Chemical', 'MESH:D002244', (83, 84))	('NCT03749187', 'Var', (95, 106))
245126	32494639	Isogenic cell lines and genetically engineered tumors were produced by introducing mutant IDH1, along with appropriate controls.	('IDH1', 'Gene', (90, 94))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mutant', 'Var', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
245133	32494639	Parental IHAs (a gift from R. O. Peiper, University of California, San Francisco) were infected with a viral vector carrying expression cassette for IDH1-R132H or the empty vector control.	('Parental IHAs', 'Disease', 'MESH:D063129', (0, 13))	('IDH1-R132H', 'Var', (149, 159))	('infected', 'Disease', 'MESH:D007239', (87, 95))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('Parental IHAs', 'Disease', (0, 13))	('R132H', 'Mutation', 'rs121913500', (154, 159))	('infected', 'Disease', (87, 95))
245138	32494639	To generate HUCCT1 isogenic cells, the parental HUCCT1 cells were infected with pLNCX2 retroviruses expressing IDH1-R132H or the empty vector control.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('R132H', 'Mutation', 'rs121913500', (116, 121))	('IDH1-R132H', 'Var', (111, 121))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('infected', 'Disease', 'MESH:D007239', (66, 74))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('infected', 'Disease', (66, 74))	('C', 'Chemical', 'MESH:D002244', (83, 84))
245151	32494639	Ten glioma (five wild-type and six mutant) and six cholangiocarcinoma (three wild-type and three mutant) samples were included in this study.	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('cholangiocarcinoma', 'Disease', (51, 69))	('mutant', 'Var', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (51, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (51, 69))	('glioma', 'Disease', (4, 10))
245188	32494639	RCAS vectors carrying expression cassette for platelet-derived growth factor A (PDGFA), IDH1wt-shTP53, and IDH1R132H-shTP53 were gifts from E. Holland.	('IDH1R132H-shTP53', 'Var', (107, 123))	('RCAS', 'Chemical', '-', (0, 4))	('platelet-derived growth factor A', 'Gene', (46, 78))	('platelet-derived growth factor A', 'Gene', '18590', (46, 78))
245190	32494639	Cells expressing PDGFA were mixed with cells expressing IDH1wt-shTP53 or IDH1R132H-shTP53 at a ratio of 1:1 (3 x 105 total) and intracranially injected as described above.	('IDH1wt-shTP53', 'Var', (56, 69))	('PDGFA', 'Gene', (17, 22))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('R132H', 'Mutation', 'rs121913500', (77, 82))	('IDH1R132H-shTP53', 'Var', (73, 89))
245202	32012794	Human Serum/Plasma Glycoprotein Analysis by 1H-NMR, an Emerging Method of Inflammatory Assessment Several studies suggest that variations in the concentration of plasma glycoproteins can influence cellular changes in a large number of diseases.	('Human', 'Species', '9606', (0, 5))	('influence', 'Reg', (187, 196))	('variations', 'Var', (127, 137))	('cellular changes', 'CPA', (197, 213))	('1H', 'Chemical', '-', (44, 46))
245217	32012794	These modifications include phosphorylation, myristoylation, farnesylation, cysteine oxidation, ubiquitination, acetylation, phosphorylation, glycosylation, methylation, nitrosylation, etc., and influence almost all aspects of normal cell biology and pathogenesis.	('modifications', 'Var', (6, 19))	('methylation', 'MPA', (157, 168))	('myristoylation', 'MPA', (45, 59))	('ubiquitination', 'MPA', (96, 110))	('nitrosylation', 'MPA', (170, 183))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('acetylation', 'MPA', (112, 123))	('influence', 'Reg', (195, 204))	('phosphorylation', 'MPA', (28, 43))	('glycosylation', 'MPA', (142, 155))	('phosphorylation', 'MPA', (125, 140))	('farnesylation', 'MPA', (61, 74))	('cysteine oxidation', 'MPA', (76, 94))
245227	32012794	It is important to note that O-glycosylation is more abundant intracellularly and has been associated mostly with protein signaling and intracellular mechanisms, while N-glycosylation is predominant in circulating proteins.	('O-glycosylation', 'Var', (29, 44))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('protein signaling', 'MPA', (114, 131))	('associated', 'Reg', (91, 101))
245230	32012794	Because of the large number of biological processes in which glycans participate, it is not surprising that defects in the synthesis of glycans can be the direct cause of numerous diseases and, therefore, markers of the disease.	('defects', 'Var', (108, 115))	('synthesis', 'MPA', (123, 132))	('numerous diseases', 'Disease', 'MESH:D004194', (171, 188))	('glycans', 'Chemical', 'MESH:D011134', (136, 143))	('glycans', 'Chemical', 'MESH:D011134', (61, 68))	('cause', 'Reg', (162, 167))	('numerous diseases', 'Disease', (171, 188))
245239	32012794	It has been shown that the deregulation of selectins or their glycoprotein ligand are associated with atherosclerosis, thrombosis, and even the metastasis of tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('deregulation', 'Var', (27, 39))	('thrombosis', 'Disease', 'MESH:D013927', (119, 129))	('atherosclerosis', 'Disease', 'MESH:D050197', (102, 117))	('associated', 'Reg', (86, 96))	('metastasis of tumors', 'Disease', 'MESH:D009362', (144, 164))	('atherosclerosis', 'Phenotype', 'HP:0002621', (102, 117))	('metastasis of tumors', 'Disease', (144, 164))	('atherosclerosis', 'Disease', (102, 117))	('selectins', 'Protein', (43, 52))	('thrombosis', 'Disease', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
245271	32012794	This signal is produced by the -COCH3 acetyl groups of N-acetylglucosamine and N-acetylgalactosamine and N-acetylneuraminic acid.	('N-acetylglucosamine', 'Chemical', 'MESH:D000117', (55, 74))	('N-acetylgalactosamine', 'Chemical', 'MESH:D000116', (79, 100))	('COCH', 'Gene', (32, 36))	('N-acetylgalactosamine', 'Var', (79, 100))	('N-acetylneuraminic acid', 'Chemical', 'MESH:D019158', (105, 128))	('COCH', 'Gene', '1690', (32, 36))
245304	32012794	Alterations in glycosylation patterns regulate the development and progression of cancer, potentially serve as important biomarkers and provide a set of specific targets for therapeutic interventions.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('progression of', 'CPA', (67, 81))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('regulate', 'Reg', (38, 46))	('men', 'Species', '9606', (58, 61))	('development', 'CPA', (51, 62))	('glycosylation', 'MPA', (15, 28))
245305	32012794	Changes in glycosylation commonly associated with cancer include sialylation, fucosylation, increased GlcNAc-branching of N-glycans, over-expression of truncated mucin type O-glycans, and increased circulating N-acetyl glycoprotein levels.	('over-expression', 'PosReg', (133, 148))	('cancer', 'Disease', (50, 56))	('mucin', 'Gene', '100508689', (162, 167))	('truncated', 'Var', (152, 161))	('increased', 'PosReg', (92, 101))	('glycosylation', 'MPA', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('increased', 'PosReg', (188, 197))	('O-glycans', 'Chemical', '-', (173, 182))	('sialylation', 'MPA', (65, 76))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('fucosylation', 'MPA', (78, 90))	('N', 'Chemical', 'MESH:D009584', (210, 211))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('GlcNAc-branching of', 'MPA', (102, 121))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('circulating N-acetyl glycoprotein levels', 'MPA', (198, 238))	('GlcNAc', 'Chemical', '-', (102, 108))	('N-glycans', 'Chemical', '-', (122, 131))	('mucin', 'Gene', (162, 167))	('Changes', 'Reg', (0, 7))
245306	32012794	These changes increase structural glycan heterogeneity and alter the function of cells.	('glycan', 'Chemical', 'MESH:D011134', (34, 40))	('structural glycan heterogeneity', 'MPA', (23, 54))	('function', 'MPA', (69, 77))	('alter', 'Reg', (59, 64))	('changes', 'Var', (6, 13))	('increase', 'PosReg', (14, 22))
245328	32012794	However, other studies have shown a different trend: a relationship between low levels of NAG and the risk of developing hepatocellular carcinoma (HCC) and urothelial carcinoma (UTUC) in patients compared with healthy controls.	('patients', 'Species', '9606', (187, 195))	('NAG', 'Gene', (90, 93))	('urothelial carcinoma', 'Disease', (156, 176))	('NAG', 'Gene', '4669', (90, 93))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('hepatocellular carcinoma', 'Disease', (121, 145))	('low levels', 'Var', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (156, 176))
245336	32012794	Furthermore, GlycA has been shown to correlate with higher concentrations of triglycerides and other lipid levels, such as LDL cholesterol, in obese non-pregnant subjects and in obese and overweight pregnant women.	('concentrations', 'MPA', (59, 73))	('women', 'Species', '9606', (208, 213))	('GlycA', 'Var', (13, 18))	('cholesterol', 'Chemical', 'MESH:D002784', (127, 138))	('GlycA', 'Chemical', '-', (13, 18))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', 'MESH:D009765', (178, 183))	('overweight', 'Phenotype', 'HP:0025502', (188, 198))	('lipid levels', 'MPA', (101, 113))	('LDL', 'MPA', (123, 126))	('obese', 'Disease', (178, 183))	('higher', 'PosReg', (52, 58))	('triglycerides', 'Chemical', 'MESH:D014280', (77, 90))	('obese', 'Disease', (143, 148))	('lipid', 'Chemical', 'MESH:D008055', (101, 106))
245348	32012794	One of them, a cohort of 1664 US adolescents from the HEALTHY study (risk factors for type 2 diabetes in a sixth-grade multiracial cohort), showed that high GlycA values were associated with higher BMI and more related to girls than to boys, which can be explained by the progression of puberty.	('higher', 'PosReg', (191, 197))	('GlycA', 'Chemical', '-', (157, 162))	('progression of puberty', 'Phenotype', 'HP:0000826', (272, 294))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (86, 101))	('GlycA values', 'MPA', (157, 169))	('type 2 diabetes', 'Disease', (86, 101))	('boys', 'Species', '9606', (236, 240))	('BMI', 'MPA', (198, 201))	('high', 'Var', (152, 156))	('type 2 diabetes', 'Disease', 'MESH:D003924', (86, 101))	('girls', 'Species', '9606', (222, 227))
245358	32012794	by showing that in 4525 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, GlycA was an independent predictor of T2DM even after adjusting for traditional diabetes risk factors and hsCRP.	('GlycA', 'Var', (112, 117))	('diabetes', 'Disease', 'MESH:D003920', (192, 200))	('GlycA', 'Chemical', '-', (112, 117))	('CRP', 'Gene', (220, 223))	('participants', 'Species', '9606', (24, 36))	('T2DM', 'Disease', (150, 154))	('diabetes', 'Disease', (192, 200))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('CRP', 'Gene', '1401', (220, 223))
245363	32012794	They found that CRP levels and GlycA were higher in T2DM than in isolated impaired glucose tolerance, but GlycB was not increased.	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (74, 100))	('GlycA', 'Chemical', '-', (31, 36))	('GlycA', 'MPA', (31, 36))	('impaired glucose tolerance', 'Disease', (74, 100))	('CRP', 'Gene', (16, 19))	('CRP', 'Gene', '1401', (16, 19))	('GlycB', 'Chemical', '-', (106, 111))	('higher', 'PosReg', (42, 48))	('T2DM', 'Var', (52, 56))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (74, 100))
245399	32012794	All-cause mortality was significantly associated with both GlycA and low levels of small HDL particles.	('small HDL particles', 'Protein', (83, 102))	('associated', 'Reg', (38, 48))	('GlycA', 'Chemical', '-', (59, 64))	('GlycA', 'Disease', (59, 64))	('low', 'Var', (69, 72))	('All-cause', 'Disease', (0, 9))
245444	32012794	MetS and elevated circulating glycoproteins were also associated to risk of AD and mild cognitive impairment (MCI).	('cognitive impairment', 'Disease', (88, 108))	('elevated', 'PosReg', (9, 17))	('circulating glycoproteins', 'MPA', (18, 43))	('elevated circulating glycoproteins', 'Phenotype', 'HP:0040217', (9, 43))	('mild cognitive impairment', 'Phenotype', 'HP:0001256', (83, 108))	('MetS', 'Var', (0, 4))	('cognitive impairment', 'Disease', 'MESH:D003072', (88, 108))	('cognitive impairment', 'Phenotype', 'HP:0100543', (88, 108))	('AD', 'Disease', 'MESH:D000544', (76, 78))	('AD', 'Disease', (76, 78))
245556	31142339	The dysregulation of the protein complex NF-kappaB promotes tumor growth and angiogenesis in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('angiogenesis', 'CPA', (77, 89))	('promotes', 'PosReg', (51, 59))	('glioblastoma', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('NF-kappaB', 'Protein', (41, 50))
245557	31142339	The tumor suppressive miR-31 that targets TNF receptor associated death domain (TRADD) and inhibits NF-kappaB activation is deleted in the majority of HGGs and therefore tumor proliferation is increased.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('miR-31', 'Gene', '407035', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('NF-kappaB activation', 'MPA', (100, 120))	('deleted', 'Var', (124, 131))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('increased', 'PosReg', (193, 202))	('inhibits', 'NegReg', (91, 99))	('miR-31', 'Gene', (22, 28))	('HGGs', 'Disease', (151, 155))
245572	31142339	MiR-155 knockdown enhanced the effect of temozolomide through the induction of MAPK13 and MAPK14-mediated oxidative stress and apoptosis, representing a potential target for the treatment of glioma.	('MAPK13', 'Gene', (79, 85))	('knockdown', 'Var', (8, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (106, 122))	('temozolomide', 'Chemical', 'MESH:D000077204', (41, 53))	('glioma', 'Disease', (191, 197))	('MAPK14', 'Gene', (90, 96))	('apoptosis', 'CPA', (127, 136))	('enhanced', 'PosReg', (18, 26))	('MiR-155', 'Gene', '406947', (0, 7))	('induction', 'PosReg', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('MiR-155', 'Gene', (0, 7))	('MAPK14', 'Gene', '1432', (90, 96))	('MAPK13', 'Gene', '5603', (79, 85))	('effect of temozolomide', 'MPA', (31, 53))
245588	31142339	The BBB of AQP-11 deficient mice has no structural or functional changes.	('AQP-11', 'Gene', (11, 17))	('AQP-11', 'Gene', '66333', (11, 17))	('mice', 'Species', '10090', (28, 32))	('deficient', 'Var', (18, 27))
245604	31142339	injected single strand RNA molecules directly into the brain of mice and inhibited mutant Huntington proteins.	('mutant', 'Var', (83, 89))	('inhibited', 'NegReg', (73, 82))	('Huntington proteins', 'Disease', 'MESH:D006816', (90, 109))	('Huntington proteins', 'Disease', (90, 109))	('mice', 'Species', '10090', (64, 68))
245609	31142339	MiRNA inhibition can be achieved by antisense oligonucleotides (AMOs), miRNA masks, antagomirs, locked nucleic acid (LNA) anti-miRNAs, small molecular miRNA inhibitors (SMIRs) and miRNA sponges.	('mir', 'Gene', (90, 93))	('MiR', 'Gene', (0, 3))	('miR', 'Gene', (71, 74))	('oligonucleotides', 'Chemical', 'MESH:D009841', (46, 62))	('MiR', 'Gene', '220972', (0, 3))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (151, 154))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('antisense', 'Var', (36, 45))	('mir', 'Gene', '220972', (90, 93))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('miR', 'Gene', '220972', (71, 74))
245617	31142339	These chemical changes confer increased nuclease resistance and increased binding affinity of LNA anti-miRs to their target miRNAs.	('changes', 'Var', (15, 22))	('binding affinity', 'Interaction', (74, 90))	('nuclease resistance', 'MPA', (40, 59))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('increased', 'PosReg', (30, 39))	('increased', 'PosReg', (64, 73))	('miR', 'Gene', (124, 127))	('miR', 'Gene', '220972', (124, 127))
245621	31142339	AC1MMYR2 blocks the maturation of pre-miR21, leading to tumor suppression in orthotopic mouse models.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR21', 'Gene', (38, 43))	('tumor', 'Disease', (56, 61))	('mouse', 'Species', '10090', (88, 93))	('AC1MMYR2', 'Var', (0, 8))	('maturation', 'MPA', (20, 30))	('blocks', 'NegReg', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('miR21', 'Gene', '387140', (38, 43))
245734	30526857	Systematic identification of mutations and copy number alterations associated with cancer patient prognosis Successful treatment decisions in cancer depend on the accurate assessment of patient risk.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('copy number alterations', 'Var', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patient', 'Species', '9606', (90, 97))	('associated', 'Reg', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patient', 'Species', '9606', (186, 193))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', (142, 148))
245736	30526857	We find that mutations in almost all cancer driver genes contain remarkably little information on patient prognosis.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('patient', 'Species', '9606', (98, 105))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (13, 22))
245738	30526857	By performing a meta-analysis across independent patient cohorts, we identify robust prognostic biomarkers in specific cancer types, and we demonstrate that a subset of these alterations also confer specific therapeutic vulnerabilities.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('patient', 'Species', '9606', (49, 56))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('alterations', 'Var', (175, 186))
245743	30526857	Comparing the genomes of healthy and cancerous cells can help to understand which genetic modifications makes a cell go 'rogue' and start to multiply uncontrollably.	('genetic modifications', 'Var', (82, 103))	('modifications', 'Var', (90, 103))	('cancerous', 'Disease', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancerous', 'Disease', 'MESH:D009369', (37, 46))
245744	30526857	However, looking at genetic differences between cancerous cells from different patients, or different tumors, can shed light on how certain genetic changes make the disease deadlier or more likely to reoccur.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('deadlier', 'Disease', (173, 181))	('patients', 'Species', '9606', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('changes', 'Var', (148, 155))	('cancerous', 'Disease', (48, 57))
245746	30526857	The analysis revealed that specific genetic alterations were more common in either deadly or treatable cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('common', 'Reg', (66, 72))	('deadly', 'Disease', (83, 89))	('genetic alterations', 'Var', (36, 55))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
245747	30526857	These results suggest that while mutations certainly drive the development of the disease, other changes such as copy number alterations can tell us which cancers will be deadlier.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('drive', 'Reg', (53, 58))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('copy number alterations', 'Var', (113, 136))	('cancers', 'Disease', (155, 162))
245748	30526857	Through this approach, Smith and Sheltzer were also able to identify copy number alterations that were associated with patients responding well to certain drugs.	('copy number alterations', 'Var', (69, 92))	('Smith', 'Disease', (23, 28))	('patients', 'Species', '9606', (119, 127))	('Smith', 'Disease', 'MESH:D056735', (23, 28))
245749	30526857	Ultimately, being able to examine copy number alterations in tumors may help physicians to tailor treatment for a particular cancer, or even a specific tumor.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('particular cancer', 'Disease', (114, 131))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('particular cancer', 'Disease', 'MESH:D009369', (114, 131))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('copy', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
245753	30526857	Predictive biomarkers identify patients who are likely to respond to specific therapies, like the EGFR mutations that sensitize lung tumors to EGFR inhibition.	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', (143, 147))	('mutations', 'Var', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('lung tumors', 'Phenotype', 'HP:0100526', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('lung tumors', 'Disease', 'MESH:D008175', (128, 139))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', '1956', (143, 147))	('lung tumors', 'Disease', (128, 139))
245765	30526857	Outcome-associated analyses of genetic mutations have predominantly been conducted on a limited number of known oncogenes from single cancer types and have come to divergent conclusions.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutations', 'Var', (39, 48))
245766	30526857	Reports in the literature commonly suggest that mutations in driver oncogenes are associated with poor outcomes, including, for instance, KRAS mutations in lung cancer, PIK3CA mutations in breast cancer, and BRAF mutations in colorectal cancer.	('BRAF', 'Gene', '673', (208, 212))	('mutations', 'Var', (176, 185))	('associated', 'Reg', (82, 92))	('BRAF', 'Gene', (208, 212))	('KRAS', 'Gene', '3845', (138, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('KRAS', 'Gene', (138, 142))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Disease', (189, 202))	('mutations', 'Var', (213, 222))	('lung cancer', 'Disease', (156, 167))	('PIK3CA', 'Gene', (169, 175))	('mutations', 'Var', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('colorectal cancer', 'Disease', (226, 243))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('PIK3CA', 'Gene', '5290', (169, 175))
245770	30526857	However, these analyses have largely focused either on arm-length changes or on alterations that affect single oncogenes or tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('alterations', 'Var', (80, 91))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
245771	30526857	The functional importance of copy number changes in most genes at the single-gene level is unknown, and a pan-cancer, gene-by-gene analysis of prognostic copy number alterations has not been conducted.	('copy', 'Var', (29, 33))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
245776	30526857	If the presence of a mutation or copy number amplification is significantly associated with patient death, then a Z score >1.96 corresponds to a P value < 0.05 (Figure 1:figure supplement 2A-C).	('patient', 'Species', '9606', (92, 99))	('patient', 'Disease', (92, 99))	('mutation', 'Var', (21, 29))	('associated', 'Reg', (76, 86))	('death', 'Disease', 'MESH:D003643', (100, 105))	('death', 'Disease', (100, 105))	('copy number amplification', 'Var', (33, 58))
245777	30526857	In contrast, a Z score less than -1.96 indicates that the presence of a mutation is associated with survival or that a gene deletion is significantly associated with patient death.	('associated', 'Reg', (150, 160))	('gene deletion', 'Var', (119, 132))	('presence', 'Var', (58, 66))	('death', 'Disease', 'MESH:D003643', (174, 179))	('death', 'Disease', (174, 179))	('survival', 'CPA', (100, 108))	('associated', 'Reg', (84, 94))	('mutation', 'Var', (72, 80))	('patient', 'Species', '9606', (166, 173))
245784	30526857	We first set out to discover whether coding mutations in cancer genomes were associated with patient outcome.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('coding mutations', 'Var', (37, 53))	('cancer', 'Disease', (57, 63))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('associated', 'Reg', (77, 87))
245786	30526857	We next performed Cox proportional hazards analysis to compare the survival times for patients harboring mutant or wild-type copies of each gene.	('patients', 'Species', '9606', (86, 94))	('mutant', 'Var', (105, 111))	('Cox', 'Gene', (18, 21))	('Cox', 'Gene', '1351', (18, 21))
245787	30526857	This analysis uncovered very few mutations that were significantly associated with patient outcome (Figure 1 and Supplementary file 2A-B).	('patient', 'Species', '9606', (83, 90))	('associated', 'Reg', (67, 77))	('mutations', 'Var', (33, 42))
245789	30526857	TP53 mutations were linked to outcome in five of 16 cancer types, though the differences in patient survival were generally small (Figure 1:figure supplement 3A-B).	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TP53', 'Gene', (0, 4))	('patient', 'Species', '9606', (92, 99))	('mutations', 'Var', (5, 14))	('linked to', 'Reg', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (52, 58))
245791	30526857	While mutations in KRAS, PIK3CA, CDKN2A, BRAF, KMT2D, ATM, SMAD4, and many other genes were frequently observed, they were never significantly linked with patient outcome (Figure 1C).	('linked', 'Reg', (143, 149))	('CDKN2A', 'Gene', (33, 39))	('SMAD4', 'Gene', '4089', (59, 64))	('ATM', 'Gene', (54, 57))	('CDKN2A', 'Gene', '1029', (33, 39))	('KMT2D', 'Gene', (47, 52))	('KRAS', 'Gene', (19, 23))	('patient', 'Species', '9606', (155, 162))	('PIK3CA', 'Gene', (25, 31))	('KMT2D', 'Gene', '8085', (47, 52))	('KRAS', 'Gene', '3845', (19, 23))	('BRAF', 'Gene', '673', (41, 45))	('PIK3CA', 'Gene', '5290', (25, 31))	('ATM', 'Gene', '472', (54, 57))	('SMAD4', 'Gene', (59, 64))	('BRAF', 'Gene', (41, 45))	('observed', 'Reg', (103, 111))	('mutations', 'Var', (6, 15))
245792	30526857	To test this, we identified the 30 most-frequently mutated amino acid positions in the TCGA cohorts, and then asked whether patients harboring these alterations had different outcomes than those who did not.	('mutated amino acid', 'Var', (51, 69))	('patients', 'Species', '9606', (124, 132))	('TCGA', 'Gene', (87, 91))
245793	30526857	IDH1c132 mutations were significantly associated with a favorable prognosis in glioma, but other recurrently-mutated codons (KRASc12, PIK3CAc1047, TP53c273, etc.)	('PIK3CA', 'Gene', (134, 140))	('TP53', 'Gene', (147, 151))	('glioma', 'Disease', (79, 85))	('KRAS', 'Gene', (125, 129))	('mutations', 'Var', (9, 18))	('KRAS', 'Gene', '3845', (125, 129))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('PIK3CA', 'Gene', '5290', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('IDH1', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (147, 151))	('IDH1', 'Gene', '3417', (0, 4))
245798	30526857	Hyper-mutation within a subset of cancers could increase mutational 'noise' and decrease our ability to identify prognostic signatures, but excluding patients with hyper-mutated tumors had minimal effect on the prognostic significance of driver gene mutations (Figure 1:figure supplement 5B and Supplementary file 2C).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	("mutational 'noise'", 'MPA', (57, 75))	('Hyper-mutation', 'Var', (0, 14))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (150, 158))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('decrease', 'NegReg', (80, 88))	('increase', 'PosReg', (48, 56))
245799	30526857	We then asked whether the presence of mutations in multiple cancer driver genes might cooperate to confer a worse clinical outcome.	('multiple cancer', 'Disease', 'MESH:D009369', (51, 66))	('mutations', 'Var', (38, 47))	('multiple cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
245800	30526857	We found that, in general, patients harboring mutations in two cancer driver genes that were not prognostic alone had the same risk of death as patients with wild-type copies of one or both genes (Figure 1:figure supplement 5C).	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (144, 152))	('death', 'Disease', 'MESH:D003643', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('death', 'Disease', (135, 140))	('cancer', 'Disease', (63, 69))
245803	30526857	These analyses suggested that, in general, cancer driver gene mutations lacked significant patient stratification power.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('lacked', 'NegReg', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('patient', 'Species', '9606', (91, 98))	('mutations', 'Var', (62, 71))
245804	30526857	This led us to investigate whether mutations in genes other than recurrently-mutated oncogenes and tumor suppressors could affect prognosis.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('affect', 'Reg', (123, 129))	('mutations', 'Var', (35, 44))
245807	30526857	For instance, in breast cancer and lung adenocarcinoma, 128 and 3996 genes were mutated in >=2% of patients, respectively, but none of these mutations were significantly correlated with patient outcome at a 5% FDR.	('lung adenocarcinoma', 'Disease', (35, 54))	('patient', 'Species', '9606', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (35, 54))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('mutated', 'Var', (80, 87))	('patients', 'Species', '9606', (99, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('patient', 'Species', '9606', (186, 193))
245808	30526857	In total, these results indicate that most mutations in cancer genomes lack significant prognostic power.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (43, 52))	('lack', 'NegReg', (71, 75))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
245811	30526857	Among the top-scoring genes, we found that PTEN and EGFR mutations conferred dismal prognosis, while mutations in IDH1, TP53, and ATRX were associated with favorable prognosis (Figure 1:figure supplement 7A).	('IDH1', 'Gene', (114, 118))	('ATRX', 'Gene', (130, 134))	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (130, 134))	('PTEN', 'Gene', (43, 47))	('conferred', 'Reg', (67, 76))	('mutations', 'Var', (57, 66))	('IDH1', 'Gene', '3417', (114, 118))	('PTEN', 'Gene', '5728', (43, 47))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
245812	30526857	Mutations in these genes have previously been linked to distinct glioma subtypes, and we verified that mutations in IDH1, TP53, and ATRX were most frequently observed in low-grade gliomas, while mutations in PTEN and EGFR were most frequently observed in high-grade glioblastomas (Figure 1:figure supplement 7B).	('gliomas', 'Disease', (180, 187))	('ATRX', 'Gene', (132, 136))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('ATRX', 'Gene', '546', (132, 136))	('glioblastomas', 'Phenotype', 'HP:0012174', (266, 279))	('mutations', 'Var', (103, 112))	('EGFR', 'Gene', (217, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (266, 278))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('observed', 'Reg', (158, 166))	('TP53', 'Gene', (122, 126))	('glioma', 'Disease', (65, 71))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('observed', 'Reg', (243, 251))	('PTEN', 'Gene', (208, 212))	('glioblastomas', 'Disease', (266, 279))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('IDH1', 'Gene', (116, 120))	('glioma', 'Disease', (180, 186))	('EGFR', 'Gene', '1956', (217, 221))	('glioblastomas', 'Disease', 'MESH:D005909', (266, 279))	('PTEN', 'Gene', '5728', (208, 212))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH1', 'Gene', '3417', (116, 120))	('TP53', 'Gene', '7157', (122, 126))
245814	30526857	For instance, while IDH1 mutations were more common in low-grade gliomas, they were occasionally observed in high-grade tumors as well, and they were independently associated with prolonged survival in both cohorts (Figure 1:figure supplement 7C).	('gliomas', 'Disease', (65, 72))	('IDH1', 'Gene', '3417', (20, 24))	('common', 'Reg', (45, 51))	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('associated', 'Reg', (164, 174))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('prolonged', 'PosReg', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('IDH1', 'Gene', (20, 24))	('gliomas', 'Disease', 'MESH:D005910', (65, 72))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
245815	30526857	In contrast, when EGFR mutations were observed in low-grade gliomas, they were associated poor outcomes, but EGFR mutations were non-prognostic in high-grade glioblastomas (Figure 1:figure supplement 7D).	('glioblastomas', 'Phenotype', 'HP:0012174', (158, 171))	('EGFR', 'Gene', '1956', (18, 22))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('glioblastomas', 'Disease', 'MESH:D005909', (158, 171))	('gliomas', 'Disease', (60, 67))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', '1956', (109, 113))	('mutations', 'Var', (23, 32))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('glioblastomas', 'Disease', (158, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('EGFR', 'Gene', (109, 113))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
245816	30526857	Thus, in gliomas, mutations contain both subtype-dependent and subtype-independent prognostic information.	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('mutations', 'Var', (18, 27))
245817	30526857	However, outside of this cancer type and the tumor suppressor TP53, mutations in most cancer driver genes are non-prognostic.	('TP53', 'Gene', '7157', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', (45, 50))	('TP53', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancer', 'Disease', (86, 92))
245820	30526857	Surprisingly, we found that the copy number of these oncogenes and tumor suppressors was frequently linked with patient outcome (Figure 2 and Supplementary file 3A-B).	('copy number', 'Var', (32, 43))	('patient', 'Species', '9606', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('linked', 'Reg', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
245821	30526857	Amplification of EGFR, PIK3CA, and BRAF, and deletion of CDKN2A, RB1 and EP300 were strongly associated with shorter patient survival times in four or more cancer types each.	('BRAF', 'Gene', (35, 39))	('PIK3CA', 'Gene', (23, 29))	('RB1', 'Gene', '5925', (65, 68))	('EGFR', 'Gene', (17, 21))	('CDKN2A', 'Gene', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('deletion', 'Var', (45, 53))	('CDKN2A', 'Gene', '1029', (57, 63))	('PIK3CA', 'Gene', '5290', (23, 29))	('EGFR', 'Gene', '1956', (17, 21))	('patient', 'Species', '9606', (117, 124))	('EP300', 'Gene', '2033', (73, 78))	('Amplification', 'Var', (0, 13))	('RB1', 'Gene', (65, 68))	('patient survival times', 'CPA', (117, 139))	('cancer', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EP300', 'Gene', (73, 78))	('BRAF', 'Gene', '673', (35, 39))	('shorter', 'NegReg', (109, 116))
245822	30526857	Copy number was prognostic even for genes in which mutations were not linked with outcome: for instance, while mutations in PIK3CA were never informative, the copy number of PIK3CA was associated with outcome in breast, colorectal, glioma, lung-squamous, pancreas, and prostate cancers (Figure 2B and D).	('lung-squamous', 'Disease', (240, 253))	('PIK3CA', 'Gene', (124, 130))	('copy number', 'Var', (159, 170))	('breast', 'Disease', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('prostate cancers', 'Disease', 'MESH:D011471', (269, 285))	('glioma', 'Disease', (232, 238))	('associated with', 'Reg', (185, 200))	('PIK3CA', 'Gene', '5290', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('glioma', 'Disease', 'MESH:D005910', (232, 238))	('pancreas', 'Disease', (255, 263))	('prostate cancer', 'Phenotype', 'HP:0012125', (269, 284))	('prostate cancers', 'Phenotype', 'HP:0012125', (269, 285))	('prostate cancers', 'Disease', (269, 285))	('glioma', 'Phenotype', 'HP:0009733', (232, 238))	('PIK3CA', 'Gene', '5290', (124, 130))	('colorectal', 'Disease', (220, 230))	('PIK3CA', 'Gene', (174, 180))	('lung-squamous', 'Disease', 'MESH:D002294', (240, 253))
245823	30526857	Overall, among the 30 most frequently-mutated cancer driver genes, we detected 108 significant associations between gene copy number and outcome, compared to 23 associations between mutation and outcome.	('cancer', 'Disease', (46, 52))	('gene copy number', 'Var', (116, 132))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
245825	30526857	We conclude that determining the copy number of oncogenes and tumor suppressors in a primary tumor can better stratify patient risk than assessing single base-pair mutations.	('patient', 'Species', '9606', (119, 126))	('copy number', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (93, 98))	('stratify', 'Reg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
245830	30526857	The most significant survival-associated copy number changes genome-wide were found on chromosome 9p in a valley that precisely included the tumor suppressor CDKN2A.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('survival-associated', 'PosReg', (21, 40))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('CDKN2A', 'Gene', (158, 164))	('CDKN2A', 'Gene', '1029', (158, 164))	('copy number changes', 'Var', (41, 60))
245832	30526857	This overlap suggests that, in many instances, the copy number of these oncogenes and tumor suppressors directly influence the risk of cancer patient death.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (135, 141))	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('tumor', 'Disease', (86, 91))	('influence', 'Reg', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patient', 'Species', '9606', (142, 149))	('copy number', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
245840	30526857	For instance, we discovered that amplification of Cyclin E1 is associated with poor prognosis in ovarian cancer, and this remained true even when our analysis was restricted to high-purity tumor samples and samples that lacked significant leukocyte presence (Figure 2:figure supplement 2D).	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('tumor', 'Disease', (189, 194))	('Cyclin E1', 'Gene', (50, 59))	('ovarian cancer', 'Disease', (97, 111))	('amplification', 'Var', (33, 46))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('Cyclin E1', 'Gene', '898', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
245844	30526857	Thus, including gene-level copy-number assessment can significantly improve the stratification of patient risk beyond standard clinical parameters (Figure 2:figure supplement 3C-D).	('patient', 'Species', '9606', (98, 105))	('improve', 'PosReg', (68, 75))	('stratification', 'MPA', (80, 94))	('copy-number assessment', 'Var', (27, 49))
245846	30526857	Gene-level copy number values also remained prognostic when separating TCGA cohorts by cancer subtype (Figure 2:figure supplement 4 and Supplementary file 4F-G).	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('prognostic', 'Reg', (44, 54))	('copy number values', 'Var', (11, 29))
245847	30526857	While analyzing the GBM cohort separately abolished the prognostic significance of EGFR mutations (Figure 2:figure supplement 4D), EGFR amplifications remained associated with outcome in both the LGG and GBM cohorts (Figure 2:figure supplement 4B-C).	('EGFR', 'Gene', '1956', (83, 87))	('amplifications', 'Var', (136, 150))	('EGFR', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('associated with', 'Reg', (160, 175))
245848	30526857	Amplifications in MYC and PIK3CA were similarly prognostic in multiple tumor subtypes (Figure 2:figure supplement 4D-E and Supplementary file 4G).	('multiple tumor', 'Disease', 'MESH:D009369', (62, 76))	('PIK3CA', 'Gene', '5290', (26, 32))	('MYC', 'Gene', (18, 21))	('MYC', 'Gene', '4609', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Amplifications', 'Var', (0, 14))	('prognostic', 'Reg', (48, 58))	('multiple tumor', 'Disease', (62, 76))	('PIK3CA', 'Gene', (26, 32))
245851	30526857	CDKN2A deletion is a strong indicator of poor prognosis in the pan-kidney cohort, in clear cell carcinomas, and in papillary cell carcinomas, but did not reach statistical significance when kidney chromophobe carcinomas were analyzed independently (Figure 2:figure supplement 4F-G).	('kidney chromophobe carcinomas', 'Disease', 'MESH:C538614', (190, 219))	('papillary cell carcinomas', 'Disease', 'MESH:C538614', (115, 140))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (85, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('kidney chromophobe carcinomas', 'Disease', (190, 219))	('papillary cell carcinomas', 'Disease', (115, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('clear cell carcinomas', 'Disease', (85, 106))	('CDKN2A', 'Gene', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))
245852	30526857	In total, these results underscore the ability of driver gene CNAs to improve patient stratification when controlling for tumor identity, though larger cohort numbers may be needed to identify the strongest biomarkers in rare cancer subtypes.	('CNAs', 'Var', (62, 66))	('patient', 'Species', '9606', (78, 85))	('patient stratification', 'MPA', (78, 100))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
245853	30526857	Highly-aneuploid tumors tend to harbor mutations in TP53, and both TP53 mutations and arm-length aneuploidy have previously been associated with poor clinical outcomes.	('mutations', 'Var', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('aneuploid tumors', 'Disease', (7, 23))	('TP53', 'Gene', '7157', (52, 56))	('harbor', 'Reg', (32, 38))	('aneuploidy', 'Disease', (97, 107))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('aneuploidy', 'Disease', 'MESH:D000782', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('aneuploid tumors', 'Disease', 'MESH:D000782', (7, 23))
245855	30526857	To investigate the relationship between gene-level prognostic CNAs, TP53 status, and arm-length aneuploidy, we selected a set of 40 prognostic amplifications and deletions for additional analysis (Figure 3:figure supplement 2A).	('aneuploidy', 'Disease', (96, 106))	('deletions', 'Var', (162, 171))	('aneuploidy', 'Disease', 'MESH:D000782', (96, 106))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))
245860	30526857	These results indicate that assessing gene-level tumor CNAs can yield more prognostic information than simply screening for TP53 mutations or measuring bulk levels of tumor aneuploidy (Supplementary file 5).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TP53', 'Gene', '7157', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutations', 'Var', (129, 138))	('tumor aneuploidy', 'Disease', 'MESH:D000782', (167, 183))	('tumor', 'Disease', (49, 54))	('TP53', 'Gene', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor aneuploidy', 'Disease', (167, 183))	('tumor', 'Disease', (167, 172))
245861	30526857	We next set out to determine whether focal copy number alterations and broad copy number alterations could have distinct effects on patient outcome.	('patient', 'Species', '9606', (132, 139))	('effects', 'Reg', (121, 128))	('focal copy number alterations', 'Var', (37, 66))
245863	30526857	We interpret these results as a reflection of aneuploidy-induced fitness penalties: large copy number alterations change the dosage of multiple genes at once and can impair tumor growth, while targeted alterations that specifically affect driver gene copy number maximize malignant potential.	('aneuploidy-induced fitness penalties', 'Disease', (46, 82))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('dosage of multiple genes', 'MPA', (125, 149))	('malignant potential', 'CPA', (272, 291))	('copy number alterations', 'Var', (90, 113))	('aneuploidy-induced fitness penalties', 'Disease', 'MESH:D000782', (46, 82))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('change', 'Reg', (114, 120))	('maximize', 'PosReg', (263, 271))	('impair', 'NegReg', (166, 172))
245864	30526857	That is, we could observe that the amplification of a driver gene is prognostic only in tumors in which that driver gene is also mutated.	('amplification', 'Var', (35, 48))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutated', 'Var', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
245865	30526857	For instance, in colorectal cancer, amplification of EGFR was associated with death even in tumors that lacked EGFR mutations (Figure 3E).	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('associated with', 'Reg', (62, 77))	('EGFR', 'Gene', '1956', (111, 115))	('colorectal cancer', 'Disease', (17, 34))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('amplification', 'Var', (36, 49))	('EGFR', 'Gene', (111, 115))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('tumors', 'Disease', (92, 98))
245867	30526857	Together with our observation that focal changes tend to confer a worse prognosis than broad changes, these results support the recently-proposed 'cancer gene island' model of tumor genome evolution (discussed in more detail below).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	("'cancer", 'Disease', 'MESH:D009369', (146, 153))	('tumor', 'Disease', (176, 181))	('changes', 'Var', (41, 48))	("'cancer", 'Disease', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
245868	30526857	To determine the generality of our findings, we collected independent patient cohorts harboring mutation or copy number data linked to survival outcome (Supplementary file 1).	('patient', 'Species', '9606', (70, 77))	('copy number data', 'Var', (108, 124))	('mutation', 'Var', (96, 104))
245870	30526857	First, we identified prognostic mutations within a set of 16 patient cohorts from the International Cancer Genome Consortium (ICGC), comprising 3054 patients analyzed by whole-genome or whole-exome sequencing.	('patient', 'Species', '9606', (61, 68))	('patients', 'Species', '9606', (149, 157))	('mutations', 'Var', (32, 41))	('patient', 'Species', '9606', (149, 156))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Disease', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))
245871	30526857	Consistent with our TCGA analysis, mutations in TP53 were associated with outcome in more patient cohorts than any other gene (Figure 4C and Figure 1:figure supplement 3C-D).	('TP53', 'Gene', '7157', (48, 52))	('associated with', 'Reg', (58, 73))	('TP53', 'Gene', (48, 52))	('patient', 'Species', '9606', (90, 97))	('mutations', 'Var', (35, 44))
245872	30526857	Other mutations, including in known cancer driver genes, were rarely associated with outcome in individual cancer types and harbored minimal pan-cancer significance (Figure 4D-F and Supplementary file 6).	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (107, 113))	('mutations', 'Var', (6, 15))
245873	30526857	Mutations in KRAS, PIK3CA, BRAF, APC, PTEN, CDKN2A, and many others were frequently observed but were never correlated with outcome (Figure 4D).	('PIK3CA', 'Gene', (19, 25))	('PTEN', 'Gene', '5728', (38, 42))	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('PIK3CA', 'Gene', '5290', (19, 25))	('CDKN2A', 'Gene', (44, 50))	('BRAF', 'Gene', '673', (27, 31))	('CDKN2A', 'Gene', '1029', (44, 50))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (27, 31))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('PTEN', 'Gene', (38, 42))
245874	30526857	We next analyzed 2431 additional patients with CNA data curated by cBioportal, and found numerous amplifications and deletions associated with patient mortality (Supplementary file 6C).	('patient', 'Species', '9606', (33, 40))	('patients', 'Species', '9606', (33, 41))	('associated', 'Reg', (127, 137))	('patient', 'Species', '9606', (143, 150))	('deletions', 'Var', (117, 126))	('amplifications', 'Var', (98, 112))
245875	30526857	In breast cancer, we found prognostic amplifications that were centered around oncogenes, including ERBB2, MYC, and MDM2, while prognostic deletions encompassed tumor suppressors CDKN2A, PTEN, and TP53 (Figure 4G).	('PTEN', 'Gene', (187, 191))	('MYC', 'Gene', (107, 110))	('MDM2', 'Gene', (116, 120))	('CDKN2A', 'Gene', (179, 185))	('tumor', 'Disease', (161, 166))	('TP53', 'Gene', (197, 201))	('deletions', 'Var', (139, 148))	('MDM2', 'Gene', '4193', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PTEN', 'Gene', '5728', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('MYC', 'Gene', '4609', (107, 110))	('CDKN2A', 'Gene', '1029', (179, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('TP53', 'Gene', '7157', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ERBB2', 'Gene', (100, 105))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('ERBB2', 'Gene', '2064', (100, 105))
245877	30526857	For instance, in breast cancer, among 25 frequently-mutated genes, mutations in only two genes (TP53 and GATA3) displayed prognostic significance, while CNAs in 12 of those same genes were associated with patient outcome (Figure 4J).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('TP53', 'Gene', (96, 100))	('breast cancer', 'Disease', (17, 30))	('associated', 'Reg', (189, 199))	('CNAs', 'Var', (153, 157))	('mutations', 'Var', (67, 76))	('GATA3', 'Gene', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('GATA3', 'Gene', '2625', (105, 110))	('patient', 'Species', '9606', (205, 212))	('TP53', 'Gene', '7157', (96, 100))
245879	30526857	In particular, while mutations in most cancer driver genes are non-prognostic, copy number alterations in these same genes are tightly linked with patient outcome.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('patient', 'Species', '9606', (147, 154))	('copy number alterations', 'Var', (79, 102))	('linked', 'Reg', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (21, 30))
245880	30526857	In order to discover the biomarkers with the greatest potential clinical relevance, we next identified the individual mutations and CNAs that were consistently associated with outcome across independent patient cohorts.	('patient', 'Species', '9606', (203, 210))	('mutations', 'Var', (118, 127))	('CNAs', 'Gene', (132, 136))	('associated with', 'Reg', (160, 175))
245885	30526857	This approach revealed multiple high-confidence genetic biomarkers of patient outcome that, to our knowledge, were novel, including MDM4 amplifications in prostate cancer, NOTCH2 amplifications in melanoma, and 2q32 deletions in ovarian cancer (Supplementary file 8).	('amplifications', 'Var', (137, 151))	('ovarian cancer', 'Disease', (229, 243))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('NOTCH2', 'Gene', (172, 178))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', (197, 205))	('patient', 'Species', '9606', (70, 77))	('2q32 deletions', 'Var', (211, 225))	('amplifications', 'Var', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('MDM4', 'Gene', '4194', (132, 136))	('MDM4', 'Gene', (132, 136))	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('NOTCH2', 'Gene', '4853', (172, 178))	('prostate cancer', 'Disease', (155, 170))
245888	30526857	We hypothesized that some genetic alterations that were sufficient to affect overall patient survival could impact other facets of cancer behavior as well, including, potentially, drug sensitivity.	('affect', 'Reg', (70, 76))	('patient', 'Species', '9606', (85, 92))	('cancer behavior', 'Disease', (131, 146))	('drug sensitivity', 'Phenotype', 'HP:0020174', (180, 196))	('drug sensitivity', 'MPA', (180, 196))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer behavior', 'Disease', 'MESH:D009369', (131, 146))	('genetic alterations', 'Var', (26, 45))	('impact', 'Reg', (108, 114))
245889	30526857	We therefore sought to discover whether genetic alterations that drove aggressive disease could also sensitize patient tumors to specific therapeutic regimens.	('aggressive disease', 'Disease', 'MESH:D001523', (71, 89))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('sensitize', 'Reg', (101, 110))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('aggressive disease', 'Disease', (71, 89))	('genetic alterations', 'Var', (40, 59))	('patient', 'Species', '9606', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
245891	30526857	For instance, we identified Chr9 deletions that encompassed CDKN2A as a robust biomarker for poor prognosis in breast cancer (Supplementary file 8).	('Chr9', 'Gene', (28, 32))	('CDKN2A', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('CDKN2A', 'Gene', '1029', (60, 66))	('breast cancer', 'Disease', (111, 124))	('deletions', 'Var', (33, 42))
245892	30526857	We found that PDXs harboring CDKN2A deletions were profoundly sensitive to combination therapy with a CDK4/6 inhibitor and an mTOR inhibitor (Figure 5:figure supplement 2B), consistent with the fact that a protein encoded by CDKN2A, p16, functions as a natural inhibitor of CDK4/6, p. 4).	('CDKN2A', 'Gene', (29, 35))	('deletions', 'Var', (36, 45))	('CDK4/6', 'Gene', '1019;1021', (102, 108))	('CDKN2A', 'Gene', '1029', (29, 35))	('p16', 'Gene', (233, 236))	('CDKN2A', 'Gene', (225, 231))	('CDK4/6', 'Gene', (274, 280))	('CDK4/6', 'Gene', (102, 108))	('CDKN2A', 'Gene', '1029', (225, 231))	('p16', 'Gene', '1029', (233, 236))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('CDK4/6', 'Gene', '1019;1021', (274, 280))
245895	30526857	For instance, we identified mutations in STAG2 as a high-confidence biomarker of poor prognosis in glioma, and we found that STAG2-mutant gliomas were exquisitely sensitive to treatment with the PARP inhibitor olaparib (Figure 5A).	('gliomas', 'Phenotype', 'HP:0009733', (138, 145))	('gliomas', 'Disease', (138, 145))	('glioma', 'Disease', (138, 144))	('STAG2', 'Gene', (41, 46))	('STAG2', 'Gene', (125, 130))	('PARP', 'Gene', (195, 199))	('STAG2', 'Gene', '10735', (41, 46))	('olaparib', 'Chemical', 'MESH:C531550', (210, 218))	('STAG2', 'Gene', '10735', (125, 130))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', (99, 105))	('sensitive', 'Reg', (163, 172))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('gliomas', 'Disease', 'MESH:D005910', (138, 145))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('mutations', 'Var', (28, 37))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('PARP', 'Gene', '1302', (195, 199))
245900	30526857	Our analysis of prognostic biomarkers from 17,879 patients sheds light on these genetic differences, identifies a subset of patients who may benefit the most from aggressive intervention, and suggests therapeutic strategies for tumors harboring certain alterations associated with poor prognosis.	('patients', 'Species', '9606', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('alterations', 'Var', (253, 264))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('patients', 'Species', '9606', (124, 132))
245901	30526857	As cancers arise due to the accumulation of mutations in growth-promoting oncogenes and growth-inhibitory tumor suppressors, the presence and diversity of these mutations may be expected to dictate a tumor's clinical course.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('dictate', 'Reg', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancers', 'Disease', (3, 10))	('mutations', 'Var', (44, 53))	('mutations', 'Var', (161, 170))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
245906	30526857	First, our analysis revealed a subset of mutations with tissue-specific prognostic power, including TP53 mutations in breast cancer, RB1 mutations in bladder cancer, and FBXW7 mutations in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('mutations', 'Var', (176, 185))	('TP53', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('RB1', 'Gene', (133, 136))	('mutations', 'Var', (105, 114))	('FBXW7', 'Gene', '55294', (170, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('breast cancer', 'Disease', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('RB1', 'Gene', '5925', (133, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('TP53', 'Gene', '7157', (100, 104))	('colorectal cancer', 'Disease', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('FBXW7', 'Gene', (170, 175))	('mutations', 'Var', (137, 146))
245908	30526857	Thirdly, tumors themselves are composed of sub-clonal populations that harbor distinct sets of mutations, and recent evidence suggests that cancer heterogeneity can influence clinical course.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('influence', 'Reg', (165, 174))	('cancer', 'Disease', (140, 146))	('tumors', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
245910	30526857	Despite the limited stratification value of mutations in cancer driver genes, we found that copy number alterations of many of these same genes are broadly prognostic.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('prognostic', 'Reg', (156, 166))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('copy number alterations', 'Var', (92, 115))
245911	30526857	Focal CNAs tended to confer a worse prognosis than broad CNAs, consistent with a model in which large-scale gene dosage imbalances trigger proteotoxic stress and impose a fitness penalty on cancer cells.	('cancer', 'Disease', (190, 196))	('proteotoxic stress', 'MPA', (139, 157))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('imbalances', 'Phenotype', 'HP:0002172', (120, 130))	('fitness', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gene dosage imbalances', 'Var', (108, 130))	('fitness', 'Disease', 'MESH:D012640', (171, 178))	('trigger', 'Reg', (131, 138))
245914	30526857	Patients whose tumors harbor genetic alterations that drive mortality are in urgent need of improved treatment options.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('genetic alterations', 'Var', (29, 48))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (15, 21))
245943	30526857	A tumor was defined as having a focal amplification or deletion if its copy number was greater than 0.3 or less than -0.3, and the chromosomal interval with a copy number greater than 80% of the copy number at the gene of interest was less than or equal to 3 Mb.	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('deletion', 'Var', (55, 63))	('focal amplification', 'Var', (32, 51))	('A tumor', 'Disease', (0, 7))	('A tumor', 'Disease', 'MESH:D009369', (0, 7))
245948	30526857	For double mutation Z scores, we took the top 30 most common cancer driver genes and performed pairwise combinations.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('double mutation', 'Var', (4, 19))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
245956	30526857	Mutations were only included in downstream analyses if they were annotated as one of these types: disruptive inframe deletion, disruptive inframe insertion, frameshift variant, inframe deletion, missense variant, splice acceptor variant, splice donor variant, stop gained, or stop lost.	('disruptive inframe deletion', 'Disease', (98, 125))	('disruptive inframe insertion', 'Var', (127, 155))	('splice', 'MPA', (213, 219))	('inframe deletion', 'Var', (177, 193))	('missense variant', 'Var', (195, 211))	('donor variant', 'Species', '9606', (245, 258))	('frameshift variant', 'Var', (157, 175))	('splice', 'MPA', (238, 244))
245959	30526857	Mutations or CNAs significantly associated with patient prognosis (Z > 1.96 or Z < -1.96) in two or more independent cohorts from each cancer type were determined.	('cancer', 'Disease', (135, 141))	('CNAs', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (48, 55))	('associated with', 'Reg', (32, 47))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
245961	30526857	In some instances, amplifications that spanned continuous chromosomal regions were found to correlate with patient prognosis.	('correlate', 'Reg', (92, 101))	('patient', 'Species', '9606', (107, 114))	('amplifications', 'Var', (19, 33))
245962	30526857	For genes and therapies fitting these criteria, we next identified instances in which the therapy resulted in a clinical response in the mutant population, defined as an average 'Best Average Response'<15% tumor growth among PDXs with a mutation in the gene of interest.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('resulted', 'Reg', (98, 106))	('mutation', 'Var', (237, 245))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('mutant', 'Var', (137, 143))
245963	30526857	We reported therapies in which these criteria were met and tumors with mutation were more sensitive to the therapy than tumors with wild-type copies of the gene of interest (p < 0.01).	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutation', 'Var', (71, 79))	('more', 'PosReg', (85, 89))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('sensitive', 'MPA', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
245964	30526857	For genes and therapies fitting these criteria, we next identified instances in which the therapy resulted in a clinical response in the altered population, defined as an average 'Best Average Response'<15% tumor growth among PDXs with an amplification or deletion in the gene of interest.	('tumor', 'Disease', (207, 212))	('amplification', 'Var', (239, 252))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (207, 212))
245965	30526857	We reported therapies in which these criteria were met and tumors with a mutation were more sensitive to the therapy than tumors with wild-type copies of the gene of interest (p < 0.01).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('sensitive', 'MPA', (92, 101))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('more', 'PosReg', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutation', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
245982	30526857	Secondly, Cox models can accept both continuous and discrete input data, allowing this approach to be used to analyze both binary (e.g., mutant vs. non-mutant) and continuous (e.g., gene copy number) genomic features.	('Cox', 'Gene', (10, 13))	('Cox', 'Gene', '1351', (10, 13))	('mutant', 'Var', (137, 143))
245986	30526857	We similarly calculated Z scores for all genes harboring coding-sequence mutations; however, we discovered that this resulted in plateaus around the origin in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('multiple cancer', 'Disease', (159, 174))	('multiple cancer', 'Disease', 'MESH:D009369', (159, 174))	('mutations', 'Var', (73, 82))
245987	30526857	Considering only mutations that occurred in a certain percentage of cancer patients diminished the appearance of the plateaus, but high thresholds also eliminated from consideration mutations in a number of known cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('plateaus', 'MPA', (117, 125))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (213, 219))	('diminished', 'NegReg', (84, 94))	('mutations', 'Var', (17, 26))
245992	30526857	Secondly, we found that many well-established biomarkers hold prognostic significance in TCGA cohorts, including IDH1 mutations in glioma (Figure 1:figure supplement 7), TP53 mutations in breast cancer (Figure 1:figure supplement 3), tumor stage and grade in multiple cancer types (Figure 2:figure supplement 3), and more.	('glioma', 'Disease', (131, 137))	('tumor', 'Disease', (234, 239))	('multiple cancer', 'Disease', (259, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('IDH1', 'Gene', '3417', (113, 117))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('mutations', 'Var', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Disease', (188, 201))	('TP53', 'Gene', (170, 174))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('mutations', 'Var', (118, 127))	('multiple cancer', 'Disease', 'MESH:D009369', (259, 274))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('IDH1', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('TP53', 'Gene', '7157', (170, 174))
246000	30526857	Summary: The manuscript by Sheltzer and coworkers "Genetic determinants of cancer patient outcome" provides an extensive evaluation of the prognostic information associated with frequent mutations and copy number alterations across multiple tumors from the TCGA and other validation sets.	('multiple tumor', 'Disease', (232, 246))	('patient', 'Species', '9606', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (241, 247))	('cancer', 'Disease', (75, 81))	('multiple tumor', 'Disease', 'MESH:D009369', (232, 246))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('mutations', 'Var', (187, 196))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('copy number alterations', 'Var', (201, 224))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
246002	30526857	mutant EGFR in lung cancer) will ultimately have an important impact.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutant', 'Var', (0, 6))	('EGFR', 'Gene', (7, 11))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('EGFR', 'Gene', '1956', (7, 11))
246007	30526857	However, EGFR mutations are more common in lung cancer than they are in other solid tumor types.	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('solid tumor', 'Disease', (78, 89))	('common', 'Reg', (33, 39))	('solid tumor', 'Disease', 'MESH:D009369', (78, 89))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('mutations', 'Var', (14, 23))
246008	30526857	I also note that specific variants known to influence function are not accounted for - noting EGFR as an example, there is no acknowledgment of exon 19 del or L858R mutations (as opposed to variants of unknown clinical significance).	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (94, 98))	('L858R', 'Var', (159, 164))	('L858R', 'Mutation', 'rs121434568', (159, 164))	('del', 'Var', (152, 155))
246009	30526857	If these types of analyses are beyond the scope of what can be done in two months, the authors should clearly state that their paper is meant to highlight the role of CN in prognosis and acknowledge that disease- and mutation-specific analyses will be needed to assess the importance of mutations that activate specific oncoproteins in specific types of cancer.	('cancer', 'Disease', (354, 360))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('mutations', 'Var', (287, 296))	('oncoproteins', 'Protein', (320, 332))	('activate', 'PosReg', (302, 310))	('cancer', 'Disease', 'MESH:D009369', (354, 360))
246013	30526857	A more exhaustive exploration of gain/loss of function through the directionality of prognostic associations would be desirable: It is interesting that TP53 shows significant and inverse association with survival in the METABRIC set (Figure 4J); that might be an expected behavior for tumor suppressor genes with loss of function mutations; As opposed to gain of function oncogene hot spots (BRAF600, RAS12, etc.	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('mutations', 'Var', (330, 339))	('BRAF', 'Gene', '673', (392, 396))	('tumor', 'Disease', (285, 290))	('TP53', 'Gene', '7157', (152, 156))	('inverse', 'NegReg', (179, 186))	('TP53', 'Gene', (152, 156))	('BRAF', 'Gene', (392, 396))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
246015	30526857	5) The approach to quantify aneuploidy (Taylor et al., 2018) didn't report any association with outcome in their original manuscript, despite previous literature reports (Kallioniemi et al., 1987; Kokal et al., 1986; Friedlander et al., 1984; Merkel and McGuire, 1990; Zimmerman et al., 1987) and only weak associations were found in this manuscript (Figure S10B).	('S10B', 'Var', (358, 362))	('aneuploidy', 'Disease', (28, 38))	('aneuploidy', 'Disease', 'MESH:D000782', (28, 38))	('S10B', 'SUBSTITUTION', 'None', (358, 362))
246020	30526857	7) Copy number analysis is interesting but would benefit from a more in-depth look by disease type and perhaps by known oncogenic drivers within those cancer types.	('Copy', 'Var', (3, 7))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))
246026	30526857	In general, mutations in cancer driver genes in the TCGA cohorts are very likely to affect gene function.	('gene function', 'MPA', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (12, 21))	('affect', 'Reg', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
246027	30526857	For instance, across all 16 cancer types, 70% of mutations in KRAS are in a single codon (c12), while another 10% of mutations are in codon 13 - both clearly KRAS-activating.	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (158, 162))	('mutations', 'Var', (49, 58))	('KRAS', 'Gene', '3845', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('KRAS', 'Gene', (158, 162))	('cancer', 'Disease', (28, 34))
246028	30526857	Thus, by considering all KRAS mutations together, we do not believe that we are diluting a signal in the data by conflating KRAS-activating mutations with mutations that fail to affect protein function.	('KRAS', 'Gene', (124, 128))	('KRAS', 'Gene', '3845', (124, 128))	('mutations', 'Var', (140, 149))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
246032	30526857	Moreover, the most significant single-codon mutation (IDH1c132 in glioblastoma) recapitulated what was observed when all IDH1 mutations were considered together (Figure 1:figure supplement 7A).	('IDH1', 'Gene', (121, 125))	('IDH1', 'Gene', (54, 58))	('IDH1', 'Gene', '3417', (121, 125))	('single-codon mutation', 'Var', (31, 52))	('glioblastoma', 'Disease', (66, 78))	('IDH1', 'Gene', '3417', (54, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))
246035	30526857	Thus, for KRAS, we pooled patients with mutations in codon 12, 13, 61, etc., but eliminated the single patients with mutations in codon 8 and codon 22.	('KRAS', 'Gene', '3845', (10, 14))	('patients', 'Species', '9606', (26, 34))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (103, 111))	('KRAS', 'Gene', (10, 14))
246036	30526857	However, when we performed Cox modeling considering only patients who had mutations in a "hotspot" codon, we failed to detect any significant prognostic markers outside of GBMLGG (Figure 1:figure supplement 4E).	('Cox', 'Gene', '1351', (27, 30))	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (74, 83))	('Cox', 'Gene', (27, 30))
246038	30526857	This identified recurrent mutations that were observed across cancer types (like PIK3CAC545) and mutations that were unique to specific cancer types (like FGFR3c249 mutations in BLCA and GNASc844 mutations in PAAD).	('PIK3CA', 'Gene', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('PIK3CA', 'Gene', '5290', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('GNASc844', 'Gene', (187, 195))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FGFR3c249', 'Gene', (155, 164))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (165, 174))	('mutations', 'Var', (196, 205))
246040	30526857	The EGFRL858 alteration that the reviewers inquired about fell below our cut-off, but analyzing it separately we found that this alteration was also non-prognostic in this cohort.	('EGFR', 'Gene', (4, 8))	('alteration', 'Var', (13, 23))	('EGFR', 'Gene', '1956', (4, 8))
246041	30526857	Thus, while we agree that larger cohorts may yield additional prognostic mutations, using several different analytical approaches, we have been unable to identify robust codon-specific or disease-specific prognostic mutations, outside of glioma/glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (245, 257))	('glioma/glioblastoma', 'Disease', 'MESH:D005909', (238, 257))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('glioma/glioblastoma', 'Disease', (238, 257))	('mutations', 'Var', (73, 82))
246046	30526857	For cancer mutations, it does not appear that there is a strong link between the two.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (11, 20))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))
246047	30526857	For instance, IDH1 mutations are clearly oncogenic, but they are associated with a highly significant negative Z score (as it has been recognized that IDH1-mutant gliomas are less aggressive than gliomas driven by other alterations; Yan et al., 2010).	('negative', 'NegReg', (102, 110))	('gliomas', 'Disease', (163, 170))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('aggressive', 'CPA', (180, 190))	('Z score', 'MPA', (111, 118))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('mutations', 'Var', (19, 28))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('less', 'NegReg', (175, 179))	('IDH1', 'Gene', (151, 155))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('IDH1', 'Gene', (14, 18))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('gliomas', 'Disease', (196, 203))	('IDH1', 'Gene', '3417', (151, 155))	('IDH1', 'Gene', '3417', (14, 18))
246048	30526857	We've also found that tumor suppressor mutations can be associated with both positive Z scores (e.g., RB1 in BLCA) and negative Z scores (e.g., FBXW7 in COADREAD; Figure 2B).	('negative', 'NegReg', (119, 127))	('RB1', 'Gene', '5925', (102, 105))	('FBXW7', 'Gene', '55294', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('FBXW7', 'Gene', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (22, 27))	('RB1', 'Gene', (102, 105))
246050	30526857	For instance, in PRAD, 71% of tumors that have a PTEN mutation also have a PTEN deletion, likely reflecting a segmental LOH event.	('mutation', 'Var', (54, 62))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('deletion', 'Var', (80, 88))	('PTEN', 'Gene', '5728', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('PTEN', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PTEN', 'Gene', '5728', (75, 79))	('PTEN', 'Gene', (49, 53))
246051	30526857	In contrast, among COADREAD tumors with ARID1A mutations, only 8% have a deletion in ARID1A, suggesting that mutations and deletions are commonly mutually-exclusive methods of eliminating this gene.	('ARID1A', 'Gene', (40, 46))	('ARID1A', 'Gene', (85, 91))	('ARID1A', 'Gene', '8289', (40, 46))	('COADREAD tumors', 'Disease', (19, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (47, 56))	('deletion', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('COADREAD tumors', 'Disease', 'MESH:D009369', (19, 34))	('ARID1A', 'Gene', '8289', (85, 91))
246052	30526857	Nonetheless, these instances of overlap do not affect the overall conclusion that 95% of prognostic CNAs remain associated with outcome in multivariate models that include gene mutation status, indicating that even changes in wild-type loci can affect cancer aggressiveness (Figure 3D).	('cancer aggressiveness', 'Disease', (252, 273))	('aggressiveness', 'Phenotype', 'HP:0000718', (259, 273))	('changes', 'Var', (215, 222))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (252, 273))	('affect', 'Reg', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))
246053	30526857	5) The approach to quantify aneuploidy (Taylor et al., 2018) didn't report any association with outcome in their original manuscript, despite previous literature reports (Kallioniemi et al., 1987; Kokal et al., 1986; Friedlander et al., 1984; Merkel and McGuirer, 1990; Zimmerman et al., 1987) and only weak associations were found in this manuscript (Figure S10B).	('aneuploidy', 'Disease', (28, 38))	('aneuploidy', 'Disease', 'MESH:D000782', (28, 38))	('S10B', 'Var', (359, 363))	('S10B', 'SUBSTITUTION', 'None', (359, 363))
246056	30526857	Nonetheless, 75% of driver gene alterations remain significantly-associated with outcome in multivariate models that include tumor breakpoint burden, providing further evidence that the prognostic power of these alterations is not an indirect consequence of their correlation with chromosomal instability (Figure 3:figure supplement 2E-F).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('chromosomal instability', 'Phenotype', 'HP:0040012', (281, 304))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('alterations', 'Var', (32, 43))	('tumor', 'Disease', (125, 130))	('chromosomal instability', 'MPA', (281, 304))	('alterations', 'Var', (212, 223))
246057	30526857	As suggested by the reviewers, we built multivariate models combining the top-scoring copy number alterations with standard prognostic criteria (receptor status in breast cancer, Clark score in melanoma, Gleason score in prostate cancer, etc.).	('prostate cancer', 'Disease', (221, 236))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('melanoma', 'Disease', (194, 202))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('breast cancer', 'Disease', (164, 177))	('copy number alterations', 'Var', (86, 109))	('prostate cancer', 'Disease', 'MESH:D011471', (221, 236))	('prostate cancer', 'Phenotype', 'HP:0012125', (221, 236))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
246069	30526857	We have changed our Title to "Systematic identification of mutations and copy number alterations associated with cancer patient prognosis.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('patient', 'Species', '9606', (120, 127))	('cancer', 'Disease', (113, 119))	('copy number alterations', 'Var', (73, 96))	('mutations', 'Var', (59, 68))	('associated', 'Reg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
246070	22238333	Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas Recent studies have indicated that a significant survival advantage is conferred to patients with gliomas whose lesions harbor mutations in the genes isocitrate dehydrogenase 1 and 2 (IDH1/2).	('Gliomas', 'Disease', 'MESH:D005910', (67, 74))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('IDH1/2', 'Gene', '3417;3418', (259, 265))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('isocitrate', 'Chemical', 'MESH:C034219', (225, 235))	('IDH1/2', 'Gene', (259, 265))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('Gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('mutations', 'Var', (202, 211))	('survival', 'CPA', (124, 132))	('advantage', 'PosReg', (133, 142))	('IDH1', 'Gene', (259, 263))	('IDH1', 'Gene', (44, 48))	('Gliomas', 'Disease', (67, 74))	('patients', 'Species', '9606', (159, 167))	('gliomas', 'Disease', (173, 180))	('IDH1', 'Gene', '3417', (44, 48))	('IDH1', 'Gene', '3417', (259, 263))	('2-Hydroxyglutarate', 'Chemical', 'MESH:C019417', (22, 40))
246071	22238333	IDH1/2 mutations result in aberrant enzymatic production of the potential oncometabolite D-2-hydroxyglutarate (2HG).	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (89, 109))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('enzymatic production of', 'MPA', (36, 59))	('result in', 'Reg', (17, 26))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
246073	22238333	Relative 2HG levels from pathologically confirmed mutant IDH1 tissues correlated with levels of other ex vivo metabolites and histopathology parameters associated with increases in mitotic activity, relative tumor content, and cellularity.	('cellularity', 'CPA', (227, 238))	('increases', 'PosReg', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('IDH1', 'Gene', (57, 61))	('mitotic activity', 'CPA', (181, 197))	('levels of', 'MPA', (86, 95))	('mutant', 'Var', (50, 56))	('tumor', 'Disease', (208, 213))	('IDH1', 'Gene', '3417', (57, 61))
246075	22238333	These data provide extensive characterization of mutant IDH1 lesions while confirming the potential diagnostic value of 2HG as a surrogate marker of patient survival.	('mutant', 'Var', (49, 55))	('lesions', 'Var', (61, 68))	('IDH1', 'Gene', '3417', (56, 60))	('patient', 'Species', '9606', (149, 156))	('IDH1', 'Gene', (56, 60))
246081	22238333	In 2009, there was a shift in the prognostic paradigm for these lesions, when more than 70% of all patients with low-grade gliomas were discovered to have mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) genes, which have been associated with prolonged survival.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('isocitrate', 'Chemical', 'MESH:C034219', (172, 182))	('mutations', 'Var', (155, 164))	('associated', 'Reg', (237, 247))	('IDH1/2', 'Gene', '3417;3418', (206, 212))	('patients', 'Species', '9606', (99, 107))	('gliomas', 'Disease', (123, 130))	('gliomas', 'Disease', 'MESH:D005910', (123, 130))	('gliomas', 'Phenotype', 'HP:0009733', (123, 130))	('IDH1/2', 'Gene', (206, 212))
246085	22238333	Missense mutations of IDH1/2 genes were found to result in arginine being substituted by other amino acids at the substrate binding sites of IDH1/2 enzymes.	('result in', 'Reg', (49, 58))	('IDH1/2', 'Gene', (22, 28))	('IDH1/2', 'Gene', '3417;3418', (141, 147))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('IDH1/2', 'Gene', (141, 147))	('arginine', 'MPA', (59, 67))	('Missense mutations', 'Var', (0, 18))
246086	22238333	Recent in vitro studies have revealed that mutation of arginine 132 (R132) in IDH1 and of arginine 172 (R172) in IDH2 prevents enzymatic oxidative decarboxylation of isocitrate and confers a new ability to convert alpha-ketoglutarate to d-2-hydroxyglutarate (2HG).	('IDH2', 'Gene', (113, 117))	('mutation', 'Var', (43, 51))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (214, 233))	('IDH1', 'Gene', (78, 82))	('d-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (237, 257))	('ability', 'MPA', (195, 202))	('IDH2', 'Gene', '3418', (113, 117))	('convert alpha-ketoglutarate', 'MPA', (206, 233))	('arginine', 'Chemical', 'MESH:D001120', (55, 63))	('IDH1', 'Gene', '3417', (78, 82))	('isocitrate', 'Chemical', 'MESH:C034219', (166, 176))	('arginine', 'Chemical', 'MESH:D001120', (90, 98))	('prevents', 'NegReg', (118, 126))	('enzymatic oxidative decarboxylation of isocitrate', 'MPA', (127, 176))
246087	22238333	The arginine mutations result in accumulation of 2HG and a vast reduction in normal IDH1/2 enzymatic activity.	('IDH1/2', 'Gene', (84, 90))	('arginine', 'Chemical', 'MESH:D001120', (4, 12))	('reduction', 'NegReg', (64, 73))	('IDH1/2', 'Gene', '3417;3418', (84, 90))	('arginine mutations', 'Var', (4, 22))	('2HG', 'Protein', (49, 52))	('accumulation', 'PosReg', (33, 45))
246088	22238333	Although the function of both IDH-mutant enzymes and 2HG in gliomagenesis remains unclear, the improved prognosis associated with IDH1/2 mutations suggests that the presence of 2HG may be of prognostic value as a surrogate for favorable genotypes.	('IDH', 'Gene', '3417', (130, 133))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('IDH1/2', 'Gene', (130, 136))	('mutations', 'Var', (137, 146))	('glioma', 'Disease', (60, 66))	('improved', 'PosReg', (95, 103))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', (130, 133))	('IDH', 'Gene', '3417', (30, 33))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('IDH1/2', 'Gene', '3417;3418', (130, 136))
246092	22238333	We hypothesized that if 2HG was detected from 1H HR-MAS spectra, levels of the suspected oncometabolite would be significantly higher in tissue samples that had manifest IDH1 mutations.	('IDH1', 'Gene', (170, 174))	('IDH1', 'Gene', '3417', (170, 174))	('levels of', 'MPA', (65, 74))	('mutations', 'Var', (175, 184))	('higher', 'PosReg', (127, 133))	('1H', 'Chemical', '-', (46, 48))
246104	22238333	The IDH1 status of paired tissue samples from each patient (n = 52) was assessed to compare wild-type against mutant IDH1 spectral profiles.	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', '3417', (117, 121))	('mutant', 'Var', (110, 116))	('patient', 'Species', '9606', (51, 58))	('IDH1', 'Gene', (4, 8))	('IDH1', 'Gene', (117, 121))
246105	22238333	Antibody staining indicated that 38 patients had gliomas with histidine-mutated (R132H) IDH1 enzymes.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('patients', 'Species', '9606', (36, 44))	('IDH1', 'Gene', (88, 92))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('IDH1', 'Gene', '3417', (88, 92))	('R132H', 'Var', (81, 86))	('gliomas', 'Disease', (49, 56))	('histidine', 'Chemical', 'MESH:D006639', (62, 71))	('R132H', 'Mutation', 'rs121913500', (81, 86))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
246107	22238333	Because the IDH1R132H antibody is only selective for histidine mutations at residue R132 of IDH1, it was expected that samples with other IDH1 and IDH2 mutations would not be detected.	('histidine mutations at', 'Var', (53, 75))	('IDH1', 'Gene', (12, 16))	('histidine', 'Chemical', 'MESH:D006639', (53, 62))	('IDH1', 'Gene', '3417', (138, 142))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (92, 96))	('IDH2', 'Gene', (147, 151))	('IDH1', 'Gene', '3417', (12, 16))	('IDH1', 'Gene', (138, 142))	('IDH2', 'Gene', '3418', (147, 151))
246109	22238333	Overall, 40 patients were classified as being positive for IDH1 mutations (IDH1+) and 12 as IDH1-negative (IDH1-) (Table 2B).	('IDH1', 'Gene', '3417', (59, 63))	('IDH1', 'Gene', (107, 111))	('patients', 'Species', '9606', (12, 20))	('IDH1', 'Gene', '3417', (107, 111))	('IDH1', 'Gene', (92, 96))	('IDH1', 'Gene', (75, 79))	('IDH1', 'Gene', '3417', (92, 96))	('mutations', 'Var', (64, 73))	('positive', 'Reg', (46, 54))	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', (59, 63))
246120	22238333	CPMG spectra from patients with contrasting mutant and wild-type IDH1 genotypes show the characteristic presence and absence of 2HG, respectively (Fig.	('IDH1', 'Gene', '3417', (65, 69))	('CPMG', 'Chemical', '-', (0, 4))	('2HG', 'MPA', (128, 131))	('patients', 'Species', '9606', (18, 26))	('absence', 'NegReg', (117, 124))	('IDH1', 'Gene', (65, 69))	('mutant', 'Var', (44, 50))
246126	22238333	The remainder of discordant samples came from biopsies with insufficient tissue (<0.5 mg) for validation by genetic sequencing but may have harbored alternative IDH1 or IDH2 mutations (table S1).	('IDH1', 'Gene', '3417', (161, 165))	('harbored', 'Reg', (140, 148))	('IDH2', 'Gene', '3418', (169, 173))	('IDH1', 'Gene', (161, 165))	('mutations', 'Var', (174, 183))	('IDH2', 'Gene', (169, 173))
246136	22238333	Other brain metabolites related to malignancy, such as aspartate (Asp), GABA, threonine (Thr), hypotaurine (hypo-Tau), creatine and phosphocreatine (Cr, PCr), betaine (Bet), glycine (Gly), lactate (Lac), glutathione (GSH), phosphoethanolamine (PE), Glu, and Gln, were also seen to increase with 2HG levels.	('creatine', 'MPA', (119, 127))	('glycine', 'MPA', (174, 181))	('creatine', 'Chemical', 'MESH:D003401', (139, 147))	('threonine', 'Chemical', 'MESH:D013912', (78, 87))	('Lac', 'Chemical', 'MESH:D019344', (198, 201))	('PE', 'Chemical', 'MESH:C005448', (244, 246))	('hypo-Tau', 'Chemical', 'MESH:C003949', (108, 116))	('PC', 'Chemical', 'MESH:D010767', (153, 155))	('Glu', 'MPA', (249, 252))	('hypotaurine', 'MPA', (95, 106))	('betaine', 'Chemical', 'MESH:D001622', (159, 166))	('phosphoethanolamine', 'MPA', (223, 242))	('creatine', 'Chemical', 'MESH:D003401', (119, 127))	('lactate', 'Chemical', 'MESH:D019344', (189, 196))	('glycine', 'Chemical', 'MESH:D005998', (174, 181))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (223, 242))	('Cr', 'Chemical', 'MESH:D002857', (149, 151))	('Bet', 'Chemical', 'MESH:D001622', (168, 171))	('glutathione', 'MPA', (204, 215))	('Thr', 'Chemical', 'MESH:D013912', (89, 92))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('Asp', 'Chemical', 'MESH:D001224', (66, 69))	('2HG', 'Var', (295, 298))	('hypotaurine', 'Chemical', 'MESH:C003949', (95, 106))	('brain metabolites', 'MPA', (6, 23))	('phosphocreatine', 'Chemical', 'MESH:D010725', (132, 147))	('glutathione', 'Chemical', 'MESH:D005978', (204, 215))	('increase', 'PosReg', (281, 289))	('GABA', 'Chemical', 'MESH:D005680', (72, 76))	('aspartate', 'Chemical', 'MESH:D001224', (55, 64))	('Gln', 'Chemical', 'MESH:D005973', (258, 261))	('lactate', 'MPA', (189, 196))	('GSH', 'Chemical', 'MESH:D005978', (217, 220))	('betaine', 'MPA', (159, 166))	('malignancy', 'Disease', (35, 45))	('aspartate', 'MPA', (55, 64))	('Gln', 'MPA', (258, 261))	('Cr', 'Chemical', 'MESH:D002857', (154, 156))	('Gly', 'Chemical', 'MESH:D005998', (183, 186))	('Glu', 'Chemical', 'MESH:D018698', (249, 252))
246153	22238333	Despite these limitations, the higher-resolution ex vivo spectroscopy suggests that in vivo tCHO, Cr, and Lac are likely to be elevated in IDH-mutant lesions and to correlate with levels of 2HG, along with other metabolites found significant from ex vivo analyses (Table 3).	('lesions', 'Var', (150, 157))	('Lac', 'Chemical', 'MESH:D019344', (106, 109))	('tCHO', 'Gene', (92, 96))	('CHO', 'CellLine', 'CVCL:0213', (93, 96))	('elevated', 'PosReg', (127, 135))	('Cr', 'Chemical', 'MESH:D002857', (98, 100))	('IDH', 'Gene', (139, 142))	('Lac', 'MPA', (106, 109))	('IDH', 'Gene', '3417', (139, 142))
246156	22238333	These data corroborate the previously identified relationship between IDH1 mutation and the aberrant production of this metabolite that was validated using liquid chromatography-mass spectrometry analysis.	('IDH1', 'Gene', '3417', (70, 74))	('aberrant', 'MPA', (92, 100))	('mutation', 'Var', (75, 83))	('IDH1', 'Gene', (70, 74))
246161	22238333	The standing hypothesis that 2HG is a tumor-promoting oncometabolite currently lacks full mechanistic support; however, there are advantages to elucidating the biochemical pathways that are influenced by 2HG and may lead to improved survival for patients with IDH mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (264, 273))	('improved', 'PosReg', (224, 232))	('patients', 'Species', '9606', (246, 254))	('IDH', 'Gene', (260, 263))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('IDH', 'Gene', '3417', (260, 263))	('survival', 'MPA', (233, 241))
246165	22238333	The negative correlation between 2HG and normal delicate vascularity may assist in designing strategies for treating lesions with mutant IDH1 enzymes.	('mutant', 'Var', (130, 136))	('enzymes', 'Protein', (142, 149))	('IDH1', 'Gene', (137, 141))	('IDH1', 'Gene', '3417', (137, 141))
246168	22238333	It is therefore of clinical interest whether patients harboring IDH mutations may be ideal candidates for therapies that target 2HG production as well as antiangiogenic agents that promote vascular normalization.	('IDH', 'Gene', '3417', (64, 67))	('2HG production', 'MPA', (128, 142))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (68, 77))	('IDH', 'Gene', (64, 67))
246169	22238333	We also found a significant relationship between IDH1 mutants:as identified via 2HG levels in tissue:and in vivo MR diffusion parameters, which supports the potential role of diffusion imaging in evaluating whether the tissue architecture of mutant gliomas is distinct from that of other neoplasms.	('IDH1', 'Gene', '3417', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('gliomas', 'Phenotype', 'HP:0009733', (249, 256))	('gliomas', 'Disease', (249, 256))	('neoplasms', 'Phenotype', 'HP:0002664', (288, 297))	('gliomas', 'Disease', 'MESH:D005910', (249, 256))	('mutants', 'Var', (54, 61))	('mutant', 'Var', (242, 248))	('neoplasms', 'Disease', 'MESH:D009369', (288, 297))	('IDH1', 'Gene', (49, 53))	('neoplasms', 'Disease', (288, 297))
246171	22238333	The fact that the observed levels of 2HG from tissue samples expressing IDH1 mutations were similar to those of other routinely detected metabolites, such as Gln and Glu, supports the potential clinical use of 2HG as a noninvasive biomarker for IDH1.	('IDH1', 'Gene', (72, 76))	('IDH1', 'Gene', (245, 249))	('IDH1', 'Gene', '3417', (72, 76))	('Glu', 'Chemical', 'MESH:D018698', (166, 169))	('IDH1', 'Gene', '3417', (245, 249))	('mutations', 'Var', (77, 86))	('Gln', 'Chemical', 'MESH:D005973', (158, 161))
246172	22238333	Given that tissue samples taken from disparate regions of tumor were homogeneous in their mutation status, it is reasonable to assume that 2HG will be present throughout lesions expressing aberrant enzymes.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('aberrant enzymes', 'Var', (189, 205))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
246179	22238333	Considering the survival benefits associated with IDH1/2 mutations, the presence of 2HG may have significant prognostic value for patients with low-grade gliomas.	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH1/2', 'Gene', (50, 56))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (57, 66))	('gliomas', 'Disease', (154, 161))	('fits', 'Disease', 'MESH:D012640', (29, 33))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('fits', 'Disease', (29, 33))
246180	22238333	The characterization of IDH-mutated lesions using MR methods could also hold implications for the study of other human cancers that share these genetic abnormalities, including colorectal cancer, prostate cancer, and acute myeloid leukemia, which shows an adverse prognosis for IDH1/2 mutations, in contradistinction with gliomas.	('genetic abnormalities', 'Disease', 'MESH:D030342', (144, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (217, 239))	('gliomas', 'Disease', (322, 329))	('genetic abnormalities', 'Disease', (144, 165))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (223, 239))	('human', 'Species', '9606', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (322, 328))	('colorectal cancer', 'Disease', (177, 194))	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', (278, 281))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (322, 329))	('leukemia', 'Phenotype', 'HP:0001909', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (285, 294))	('IDH', 'Gene', '3417', (24, 27))	('IDH', 'Gene', '3417', (278, 281))	('acute myeloid leukemia', 'Disease', (217, 239))	('gliomas', 'Phenotype', 'HP:0009733', (322, 329))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('IDH1/2', 'Gene', '3417;3418', (278, 284))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('prostate cancer', 'Disease', (196, 211))	('IDH1/2', 'Gene', (278, 284))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (217, 239))
246205	22238333	This enabled a query of the relative prevalence of aberrant 2HG production among glioma grades and histological subtypes, even in cases where 2HG levels were insufficient for HR-QUEST fitting.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('aberrant', 'Var', (51, 59))	('2HG production', 'MPA', (60, 74))	('glioma', 'Disease', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
246210	22238333	There were two tissue samples from one patient in which the presence of 2HG had been assumed on the basis of histologic confirmation of IDH1 mutation, but was not corroborated by HR-MAS spectroscopy.	('IDH1', 'Gene', (136, 140))	('IDH1', 'Gene', '3417', (136, 140))	('mutation', 'Var', (141, 149))	('patient', 'Species', '9606', (39, 46))